PMID- 22809958 TI - Lower gastrointestinal bleeding in Crohn's disease: how (un-)common is it and how to tackle it? PMID- 22809959 TI - Errors and near misses in digestive endoscopy units. AB - BACKGROUND: Not much is known about errors and near misses in digestive endoscopy. AIMS: To verify whether an incident report, with certain facilitating features, gives useful information about unintended events, only excluding errors in medical diagnosis. METHOD: Nine endoscopy units took part in this cross sectional, prospective, multicentre study which lasted for two weeks. Members of the staff were required to report any unintended, potentially dangerous event observed during the daily work. A form was provided with a list of "reminders" and facilitators were appointed to help. The main outcome measurements were type of event, causes, corrective interventions, stage of occurrence in the workflow and qualification of the reporters. RESULTS: A total of 232 errors were reported (two were not related to endoscopy). The remaining 230 amount to 10.3% of 2239 procedures; 66 (29%) were considered errors with consequences, 164 (71%) "near misses". There were 150 pre-operative errors (65%), 22 operative (10%) and 58 post-operative (25%). Corrective interventions were provided for 60 cases of errors and 119 near misses. Most of the events were reported by the nurses (106 out of 232, 46%). CONCLUSIONS: Short-term incident reporting focusing on near misses, using forms with lists of "reminders", and the help of a facilitator, can give useful information on errors and near misses in digestive endoscopy. PMID- 22809960 TI - Increased insulinogenic index is an independent determinant of nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance. AB - BACKGROUND: Although insulin resistance is involved in nonalcoholic fatty liver disease, role of abnormalities in early phase of insulin secretion has not been examined. AIMS: We examined which anthropometric and metabolic parameters, including insulinogenic index during oral glucose tolerant test, were independently associated with the disease activity of nonalcoholic fatty liver disease. METHODS: A total of 114 consecutive biopsy-proven nonalcoholic fatty liver disease patients without type 2 diabetes were enrolled. RESULTS: Age, aspartate aminotransferase, free fatty acid, ferritin type IV collagen, hyaluronic acid, procollagen N-terminal peptide, fasting plasma glucose and 2-h insulin after glucose loading were significantly higher in patients with impaired glucose tolerance than those with normal glucose tolerance. Multiple stepwise regression analysis revealed that glycated haemoglobin, decreased density ratio of liver to spleen in computed tomography and increased insulinogenic index were independently associated with nonalcoholic fatty liver disease activity score in normal glucose tolerance patients, whereas aspartate aminotransferase and 2-h insulin in impaired glucose tolerance subjects. However, there were no significant independent correlations between insulinogenic index and steatosis grade/fibrosis stage in normal glucose tolerance patients. CONCLUSION: The present study suggests that increased early phase of insulin secretion may contribute to nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance. PMID- 22809961 TI - Metformin is synthetically lethal with glucose withdrawal in cancer cells. AB - Glucose deprivation is a distinctive feature of the tumor microecosystem caused by the imbalance between poor supply and an extraordinarily high consumption rate. The metabolic reprogramming from mitochondrial respiration to aerobic glycolysis in cancer cells (the "Warburg effect") is linked to oncogenic transformation in a manner that frequently implies the inactivation of metabolic checkpoints such as the energy rheostat AMP-activated protein kinase (AMPK). Because the concept of synthetic lethality in oncology can be applied not only to genetic and epigenetic intrinsic differences between normal and cancer cells but also to extrinsic ones such as altered microenvironment, we recently hypothesized that stress-energy mimickers such as the AMPK agonist metformin should produce metabolic synthetic lethality in a glucose-starved cell culture milieu imitating the adverse tumor growth conditions in vivo. Under standard high-glucose conditions, metformin supplementation mostly caused cell cycle arrest without signs of apoptotic cell death. Under glucose withdrawal stress, metformin supplementation circumvented the ability of oncogenes (e.g., HER2) to protect breast cancer cells from glucose-deprivation apoptosis. Significantly, representative cell models of breast cancer heterogeneity underwent massive apoptosis (by >90% in some cases) when glucose-starved cell cultures were supplemented with metformin. Our current findings may uncover crucial issues regarding the cell-autonomous metformin's anti-cancer actions: (1) The offently claimed clinically irrelevant, non-physiological concentrations needed to observe the metformin's anti-cancer effects in vitro merely underlie the artifactual interference of erroneous glucose-rich experimental conditions that poorly reflect glucose-starved in vivo conditions; (2) the preferential killing of cancer stem cells (CSC) by metformin may simply expose the best-case scenario for its synthetically lethal activity because an increased dependency on Warburg-like aerobic glycolysis (hyperglycolytic phenotype) is critical to sustain CSC stemness and immortality; (3) the microenvironment-mediated contextual synthetic lethality of metformin should be expected to enormously potentiate the anti cancer effect of anti-angiogenesis agents that promote severe oxygen and glucose deprivation in certain areas of the tumor tissues. PMID- 22809962 TI - The efficacy of Pelargonium sidoides in the treatment of upper respiratory tract infections in children with transient hypogammaglobulinemia of infancy. AB - Transient hypogammaglobulinemia of infancy (THI), defined as prolongation of physiological hypogammaglobulinemia normally seen between the initial 3rd and 6th months of life, is one of the most common immune deficiencies of childhood. Recurrent upper respiratory tract infections (URTI) are rather common in this group of patients, and generally, antibiotic treatment is the usual choice, although viruses involved in most cases. Pelargonium sidoides extract a herbal drug with known immunmodulator, antiviral and antibacterial effects. In this randomized, placebo controlled, prospective, monocentric pilot study, 14 of 28 patients with a diagnosed THI, were given Pelargonium sidoides, while 14 were given placebo during the period of URTI. Before and after the treatment period of one week, complete blood count, prothrombin time, activated prothromboplastin time, serum alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transpeptidase, total and direct bilirubin levels were measured. Mothers were asked to fill in a questionnaire for the recovery of the clinical symptoms during the treatment. The results were evaluated and compared in both group to assess the effect of Pelargonium sidoides. As a conclusion, the Pelargonium sidoides group showed increased appetite. The Pelargonium sidoides were found to beneficial for the nasal congestion, recovery of daily and nocturnal cough but not found be significant. Further studies with large number of participants are necessary to highlight the effect of Pelargonium sidoides in children with transient hypogammaglobulinemia of infancy. PMID- 22809965 TI - [Lupinus mutabilis (chocho) water intoxication]. PMID- 22809966 TI - [Symptomatic hypercalcemia presenting as a case of isolated splenic tuberculosis]. AB - BACKGROUND AND OBJECTIVE: To describe an unusual clinical presentation as isolated splenic tuberculosis. PATIENT AND METHODS: We report a case of isolated splenic tuberculosis, a rare form of extrapulmonary tuberculosis in an immunocompetent patient, and, as a peculiarity, debuts in the form of symptomatic hypercalcemia. RESULTS: We deeply report the clinical case and the procedures performed to exclude other diseases. We emphasize the usefulness of fine needle aspiration of the spleen to obtain microbiological samples, and the use of specific polymerase chain reaction for mycobacterias to establish the definitive diagnosis of this entity. In agreement with other authors, we chose initial medical treatment with antituberculous drugs, reserving surgery for refractory cases or in case of spontaneous splenic rupture. CONCLUSION: Hypercalcemia can be a presentation of granulomatous diseases. The isolated involvement of the spleen by mycobacterias is a rare form of extrapulmonary tuberculosis and more so in immunocompetent patients. PMID- 22809967 TI - [Association over time of Hodgkin lymphoma and non-Hodgkin lymphoma: study of 6 patients in one single center]. PMID- 22809968 TI - [Hyperplastic polyposis syndrome: phenotypic diversity and association to colorectal cancer]. AB - BACKGROUND AND OBJETIVE: Hyperplastic polyposis syndrome (HPS) is an uncommon disorder characterized by hyperplastic polyps (HP) occasionally associated with serrated adenomas (SA) or mixed polyps (MP) and defined by clinical criteria (OMS/Cleveland). HPS is heterogeneous regarding the number and size of polyps, and it is associated with colorectal cancer (CRC) and a family history. Its genetic basis is unknow. We describe individuals with HPS criteria from a series of families assessed in our Unit of Genetic Advice for colonic polyposis. Our objective is to identify the clinical characteristics of this syndrome. PATIENTS AND METHODS: Retrospective study of 197 families with colonic polyposis (1998 2011), identifying patients with HPS criteria. To know the number of polyps, we took into account polypectomies and/or the histologic study of surgical samples. Polyps were classified into adenomas, serrated lesiones (HP and SA) and MP. Genetic studies revealed: microsatellite instability (MSI), MUTYH gene variants (p.Tyr165Cys, p.Gly382Asp and p.Glu396GlyfsX43) and APC gene. RESULTS: Eighteen individuals, with a median age of 51.1 years, had criteria of HPS (11M/7F). Number of HP varied between 14 and 100 coexisting with classical adenomas, SA and MP in 14 individuals (77.8%). Localization of polyps: ascending and descending colon in 13 individuals (72.2%) and only descending colon in 5 (27.8%). A CRC was detected in 10/18 (55.6%) patients, and 3 of them had a double CRC, a family history in 3 patients (16.7%) and a history of HPS in one. IMS was not detected in 8 CRC nor in 3 adenomas studied; we detected 2/13 heterozygous mutations in the MUTYH gene (p.Gly382Asp) and one variant with an unknown biological significance in the APC gene (p.Ser926Pro). CONCLUSIONS: The phenotypic variability of HPS difficults its identification, hence it is important to adhere to the clinical criteria established for its classification as well as to establish screening guidelines for CRC on the basis of its high incidence. PMID- 22809969 TI - [Prescription of physical exercise: how to improve the adherence?]. PMID- 22809971 TI - Guidelines and interventions for obesity during pregnancy. AB - BACKGROUND: Obesity is a growing worldwide epidemic among women of reproductive age, including pregnant women. The increased prevalence of obesity has been accompanied by an increase in gestational weight gain. Maternal obesity has deleterious consequences for both mother and child. OBJECTIVE: To review the recent guidelines from the National Institute for Health and Clinical Excellence and the Institute of Medicine regarding gestational weight gain and interventions to treat obesity during pregnancy. METHODS: Guidelines on gestational weight gain from these organizations, as well as reports of gestational weight gain in the published literature, are summarized. RESULTS: Many normal and overweight parturients exceed the recommendations in the guidelines, which may contribute to postpartum obesity. CONCLUSION: Lifestyle changes, including dieting and increased activity, may help to limit excessive gestational weight gain but the optimal strategy remains unclear. PMID- 22809972 TI - Paliperidone ER versus risperidone for neurocognitive function in patients with schizophrenia: a randomized, open-label, controlled trial. AB - This study aims to determine the effectiveness of paliperidone extended release (ER) on cognitive function in patients with schizophrenia in comparison with risperidone. This was a 12-week, randomized, open-label study on schizophrenia patients who were receiving risperidone. The patients were randomized to a risperidone-continuation group or a paliperidone-switch group. The primary outcome measure was neurocognitive function, which was measured using a computerized battery. Secondary efficacy measures included the Positive and Negative Syndrome Scale, Social and Occupational Functioning Scale, and Calgary Depression Scale for Schizophrenia. In total, 58 patients participated in this trial. Improvements in recall after an interference phase in the verbal learning test were significantly greater in the paliperidone-switch than in the risperidone-continuation group. No significant differences in changes were observed in the other six neurocognitive domains measured. Improvements in the Social and Occupational Functioning Scale were significantly greater in the paliperidone ER-switch group than in the risperidone-continuation group. In other efficacy outcome measures, no significant differences were observed between the two drugs. Paliperidone ER had a side-effect profile similar to that of risperidone, including metabolic problems and prolactin-related adverse events. In conclusion, switching from risperidone to paliperidone ER may lead to additional cognitive and social functional improvements. PMID- 22809973 TI - Pyruvate dehydrogenase E1alpha phosphorylation is induced by glucose but does not control metabolism-secretion coupling in INS-1E clonal beta-cells. AB - Glucose-induced insulin secretion from pancreatic beta-cells depends on mitochondrial activation. In the organelle, glucose-derived pyruvate is metabolised along the oxidative and anaplerotic pathway to generate downstream signals leading to insulin granule exocytosis. Entry into the oxidative pathway is catalysed by pyruvate dehydrogenase (PDH) and controlled in part by phosphorylation of the PDH E1alpha subunit blocking enzyme activity. We find that glucose but not other nutrient secretagogues induce PDH E1alpha phosphorylation in INS-1E cells and rat islets. INS-1E cells and primary beta-cells express pyruvate dehydrogenase kinase (PDK) 1, 2 and 3, which mediate the observed phosphorylation. In INS-1E cells, suppression of the two main isoforms, PDK1 and PDK3, almost completely prevented PDH E1alpha phosphorylation. Under basal glucose conditions, phosphorylation was barely detectable and therefore the enzyme almost fully active (90% of maximal). During glucose stimulation, PDH is only partially inhibited (to 78% of maximal). Preventing PDH phosphorylation in situ after suppression of PDK1, 2 and 3 neither enhanced pyruvate oxidation nor insulin secretion. In conclusion, although glucose stimulates E1alpha phosphorylation and therefore inhibits PDH activity, this control mechanism by itself does not alter metabolism-secretion coupling in INS-1E clonal beta-cells. PMID- 22809975 TI - Journal information. PMID- 22809976 TI - Editor's Preface. PMID- 22809977 TI - Altered mental status. AB - PURPOSE OF REVIEW: : Altered mental status is a common reason for neurologic consultation. Although it is often due to a systemic infection or metabolic derangement, a host of other etiologies can lead to irreversible brain injury if they are not promptly identified and treated. A systematic approach to the patient is important, with an understanding of when to initiate a more advanced and potentially more resource-intense diagnostic workup. RECENT FINDINGS: : The last decade has seen advances in both the diagnosis and treatment of altered mental status. A significant step forward in the diagnosis of patients with otherwise unexplained encephalitis has been the identification of numerous antibodies associated with paraneoplastic and nonparaneoplastic autoimmune encephalitis. The use of continuous electroencephalography has shown that a significant proportion of otherwise unexplained altered mental status may be caused by nonconvulsive seizures. Several studies have demonstrated that proactive, multicomponent interventions may be effective in preventing hospital acquired delirium. The recent introduction of dexmedetomidine may lead to decreased rates of delirium in the intensive care unit if the results of clinical trials are borne out in practice. SUMMARY: : This article discusses causes of altered mental status, an initial approach to evaluating the patient, and elements of the advanced diagnostic workup. The article concludes with a general discussion of prevention and treatment. PMID- 22809978 TI - Evaluation of the patient with spells. AB - PURPOSE OF REVIEW: : The neurologic consultant is frequently called to evaluate the patient with transient neurologic deficits, or spells. Spells can present with a broad array of clinical features, making a systematic evaluation challenging. Familiarity with a variety of key features for different spell types will help the consultant create an appropriate differential diagnosis to guide the diagnostic evaluation. RECENT FINDINGS: : Recent practice parameters outline the appropriate evaluation for patients presenting with first unprovoked seizure, and an update in the International League Against Epilepsy classification scheme for seizures has shifted the terminology used to describe these spells. When a spell cannot be unambiguously identified as a seizure, recent studies propose features to help distinguish syncope, sleep disorders, and psychogenic nonepileptic seizures. For patients who are critically ill, extended EEG monitoring is increasingly available, and there is a growing appreciation for the high burden of seizures and status epilepticus in the intensive care unit population. SUMMARY: : This article reviews the most common paroxysmal spell types encountered on the acute care ward and in the intensive care unit, discusses clinical features that help distinguish various spell types, and proposes a systematic evaluation for use by the neurologic consultant. PMID- 22809979 TI - Meningitis and encephalitis. AB - PURPOSE OF REVIEW: : Neurologists have a vital role in the recognition of meningitis and encephalitis, the accurate evaluation and interpretation of CSF studies, and the management and prevention of the neurologic complications of CNS infectious diseases. RECENT FINDINGS: ;: Although the tetravalent meningococcal glycoconjugate vaccine has decreased the incidence of meningococcal meningitis, the vaccine does not contain serogroup B, which is responsible for one-third of cases of meningococcal disease. Thus, meningitis due to Neisseria meningitidis is still a concern in a vaccinated individual. Empiric therapy for meningitis associated with sinusitis, otitis, or mastoiditis should include antibiotic therapy for anaerobes. An organism that classically causes a subacute or chronic meningitis, such as Mycobacterium tuberculosis, may on occasion present with an acute onset of symptoms. SUMMARY: ;: Unlike most other diseases, the management of patients with suspected meningitis or encephalitis begins with empiric therapy. The etiologic organism cannot always be identified. The goal is to identify those that are treatable, provide supportive care for those that are not, and, when possible, prevent the neurologic complications of these infections. PMID- 22809980 TI - Stroke as a complication of acute cardiac disease. AB - PURPOSE OF REVIEW: : Stroke is one of the most feared complications of acute cardiac disease and cardiac procedures. Cardiologists, cardiothoracic surgeons, and internal medicine physicians often request neurologic consultations for inpatients with active cardiac disease and for patients with planned cardiac procedures. RECENT FINDINGS: : Neurologic consultations on cardiac inpatients are typically focused on two basic scenarios: (1) the risk of stroke and potential risk modifiers for patients in need of a particular cardiac procedure (eg, coronary artery bypass grafting [CABG]) or with a specific acute cardiac disease (eg, new atrial fibrillation or endocarditis); or (2) the evaluation of new neurologic deficits in periprocedural patients (eg, post-CABG) or those initially admitted with active cardiac disease (eg, worsening heart failure). Recent insights into these two scenarios are reviewed. SUMMARY: : This article reviews a general approach to neurologic questions commonly encountered in the cardiac inpatient setting. Unique features and important recent insights are discussed. Less attention is given to the acute management of stroke in these patients (eg, contraindications for IV thrombolysis, options for endovascular therapy) or chronic stroke prevention strategies. PMID- 22809981 TI - Hospital consultation for the patient with generalized weakness. AB - PURPOSE OF REVIEW: : This article provides a syndromic approach to generalized weakness for neurologists performing hospital consultations, with special consideration of the problems of neurogenic respiratory muscle weakness and failure to wean from mechanical ventilation. RECENT FINDINGS: : The differential diagnosis for generalized weakness is broad and requires careful review of the history and the key components of the patient's hospitalization as well as consideration of the inpatient context (intensive care unit, postoperative period, medical ward, or oncologic service). SUMMARY: : The likely diagnoses for generalized weakness are based largely on the hospital setting. Most cases are not due to primary neurologic diseases. PMID- 22809982 TI - In-hospital falls: evaluation and response. AB - PURPOSE OF REVIEW: : In-hospital falls are a significant source of morbidity in the inpatient setting and a common reason for neurologic consultation. Patients with neurologic disease are at increased risk for these falls. Neurologists should attempt to identify those who are at risk and mitigate risk using individualized and systemwide approaches. RECENT FINDINGS: : Organizations such as the Centers for Medicare & Medicaid Services and the Joint Commission have brought increased scrutiny on this serious issue. Care for in-hospital falls resulting in serious injury is no longer reimbursed by Medicare, and in-hospital falls represent sentinel events requiring investigation according to the Joint Commission. Even the best-performing fall risk stratification tools have limitations in both sensitivity and specificity. However, recent randomized trial data demonstrated the efficacy of targeted intervention to modifiable risk factors in reducing falls in the hospital. SUMMARY: : The combination of acute illness, patient vulnerability, and environmental factors in the hospital plays a critical role in determining fall likelihood. A systematic approach to identification of modifiable risk factors and application of measures designed to remove or compensate for them has the potential to reduce the burden of falls and their consequences. Careful evaluation of the patient who has fallen is important given the likelihood of harm in vulnerable patients as well as the potential for subtle presentations of serious injuries. It is incumbent on the practicing neurologist to be aware of the scope of the issue, the potential underlying risks in each patient, strategies to mitigate those risks, and how best to approach the patient who has fallen. PMID- 22809983 TI - Evaluation and management of increased intracranial pressure. AB - PURPOSE OF REVIEW: : Persistent elevation of intracranial pressure (ICP) can lead to cerebral ischemia, brain herniation, and possibly death. Understanding the fundamental mechanism that contributes to the rise in ICP and recognizing the specific intracranial compartment involved (brain, CSF, or blood) can lead to early diagnosis and effective treatment. This article reviews the conceptual approach to a patient with elevated ICP. RECENT FINDINGS: : The overall goal for patients with intracranial hypertension is to lower ICP below 20 mm Hg and to maintain cerebral perfusion pressure (CPP) between 60 mm Hg and 90 mm Hg to provide sufficient cerebral perfusion. Commonly used therapeutic interventions to lower ICP include decompressive surgery, osmotherapy, hyperventilation, barbiturate-induced metabolic suppression, and hypothermia; however, the selection of these interventions must be tailored to each patient by considering the particular diagnosis and intracranial pathophysiology. Emerging evidence suggests that cerebral autoregulation may fail at excessively high CPP (CPP greater than 100 mm Hg) as well as at low CPP (CPP less than 60 mm Hg) and that maximal cerebral autoregulation capacity may be achieved at an optimal CPP of 70 mm Hg to 90 mm Hg. SUMMARY: : Increased ICP is a neurologic emergency that requires immediate intervention. However, the treatment itself is not without risk; thus, the risks and benefits of medical and surgical intervention must be carefully evaluated and individualized for each patient. PMID- 22809984 TI - Hypoxic-ischemic brain injury and prognosis after cardiac arrest. AB - PURPOSE OF REVIEW: : Cardiac death is the leading cause of death in the United States, and patients who have out-of-hospital cardiac arrest have only a 1% to 10% survival rate, despite improvements in advanced life support. The neurologic sequelae of hypoxic-ischemic brain injury after cardiac arrest vary from subtle cognitive impairment to coma, persistent vegetative state, and brain death. Neurologists are commonly asked to prognosticate neurologic outcome after cardiac arrest. RECENT FINDINGS: : In 2002, two randomized controlled trials demonstrated that therapeutic hypothermia (32 degrees C to 34 degrees C [89.6 degrees F to 93.2 degrees F]) increases the odds of improved neurologic outcome and reduces the risk of death compared with normothermia when applied for the initial 12 to 24 hours after ventricular fibrillation or tachycardia cardiac arrest. Considerable research continues into neurologic prognostication after hypoxic ischemic brain injury, especially with the advent of therapeutic hypothermia and its effects on the clinical examination, neurophysiologic studies, and serum biomarkers of brain injury. Recent reports indicate that poor motor response 72 hours after cardiac arrest, absent cortical responses on median nerve somatosensory-evoked potentials, and elevated neuron-specific enolase may not necessarily indicate poor prognosis in patients treated with therapeutic hypothermia compared with historical populations not treated with hypothermia, perhaps because of sedation and neuromuscular blockade. SUMMARY: : Neurologic prognostication after cardiac arrest remains challenging because of the sedation and neuromuscular blocking agents given to patients who undergo therapeutic hypothermia. A multimodal algorithmic approach (clinical, electrophysiologic, and possibly serum biomarker testing) is suggested for cardiac arrest patients treated with hypothermia, but further research is needed to determine more accurate prognostic predictors. PMID- 22809985 TI - When physicians disagree: a case of nonconvulsive status epilepticus. AB - Differences of opinion among attending physicians, resident trainees, and nurses are not uncommon in hospital situations. When such cases arise, ethical dilemmas must be approached with mindfulness of basic ethics principles and communication. This article presents a case of nonconvulsive status epilepticus to highlight these considerations. PMID- 22809986 TI - Communication failures across facilities and at hospital discharge. AB - Inadequate communication has been identified as a significant factor in paid medical claims and is highlighted as one of the fundamental causes of patient adverse events. This article recounts an actual community hospital case illustrating both interfacility and physician-to-physician communication failures and their effect on patient care. Strategies for improving communication lie in optimizing facility transfer recordkeeping requirements and in improving discharge records by sharing accountability among all providers associated with a patient's hospitalization. PMID- 22809987 TI - Coding issues current procedural terminology evaluation and management coding for neurologic consultations. AB - Accurate coding is an important function of neurologic practice. This section of CONTINUUM, contributed by members of the AAN Medical Economics and Management Committee, includes helpful coding information and examples related to the issue topic. This section may include diagnosis coding, evaluation and management coding, procedure coding, or a combination, depending on which is most useful for the subject area of the issue. PMID- 22809989 TI - Multiple-choice questions. PMID- 22809990 TI - Multiple-choice questions-preferred responses. PMID- 22809991 TI - Patient management problem. PMID- 22809992 TI - Patient management problem-preferred responses. AB - Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study. PMID- 22809994 TI - Lysophosphatidic acid (LPA) and its receptors: role in airway inflammation and remodeling. AB - Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA(1-7) receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling. This article is part of a Special Issue entitled: Advances in Lysophospholipid Research. PMID- 22809995 TI - Sterols regulate 3beta-hydroxysterol Delta24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins. AB - 3beta-Hydroxysterol Delta24-reductase (DHCR24) catalyzes a final step in cholesterol synthesis, and has been ascribed diverse functions, such as being anti-apoptotic and anti-inflammatory. How this enzyme is regulated transcriptionally by sterols is currently unclear. Some studies have suggested that its expression is regulated by Sterol Regulatory Element Binding Proteins (SREBPs) while another suggests it is through the Liver X Receptor (LXR). However, these transcription factors have opposing effects on cellular sterol levels, so it is likely that one predominates. Here we establish that sterol regulation of DHCR24 occurs predominantly through SREBP-2, and identify the particular region of the DHCR24 promoter to which SREBP-2 binds. We demonstrate that sterol regulation is mediated by two sterol regulatory elements (SREs) in the promoter of the gene, assisted by two nearby NF-Y binding sites. Moreover, we present evidence that the dual SREs work cooperatively to regulate DHCR24 expression by comparison to two known SREBP target genes, the LDL receptor with one SRE, and farnesyl-diphosphate farnesyltransferase 1, with two SREs. PMID- 22809996 TI - A nanomedicine to treat ocular surface inflammation: performance on an experimental dry eye murine model. AB - MUC5AC is a glycoprotein with gel-forming properties, whose altered expression has been implicated in the pathogenesis of dry eye disease. The aim of our study was to achieve an efficient in vivo transfection of MUC5AC, restore its normal levels in an inflamed ocular surface and determine whether restored MUC5AC levels improve ocular surface inflammation. Cationized gelatin-based nanoparticles (NPs) loaded with a plasmid coding a modified MUC5AC protein (pMUC5AC) were instilled in healthy and experimental dry eye (EDE) mice. MUC5AC expression, clinical signs, corneal fluorescein staining and tear production were evaluated. Ocular specimens were processed for histopathologic evaluation, including goblet cell count and CD4 immunostaining. Neither ocular discomfort nor irritation was observed in vivo after NP treatment. Expression of modified MUC5AC was significantly higher in ocular surface tissue of pMUC5AC-NP-treated animals than that of controls. In healthy mice, pMUC5AC-NPs had no effect on fluorescein staining or tear production. In EDE mice, both parameters significantly improved after pMUC5AC-NP treatment. Anterior eye segment of treated mice showed normal architecture and morphology with lack of remarkable inflammatory changes, and a decrease in CD4+ T-cell infiltration. Thus, pMUC5AC-NPs were well tolerated and able to induce the expression of modified MUC5A in ocular surface tissue, leading to reduction of the inflammation and, consequently improving the associated clinical parameters, such as tear production and fluorescein staining. These results identify a potential application of pMUC5AC-NPs as a new therapeutic modality for the treatment of dry eye disease. PMID- 22809997 TI - Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53. AB - High-risk Human Papillomaviruses (HPV) has been found to be associated with carcinomas of the cervix, penis, vulva/vagina, anus, mouth and oro-pharynx. As the main tumorigenic effects of the HPV have been attributed to the expression of E6 and E7 genes, different gene therapy approaches have been directed to block their expression such as antisense oligonucleotides (ASO), ribozymes and small interfering RNAs. In order to develop a gene-specific therapy for HPV-related cancers, we investigated a potential therapeutic strategy of gene silencing activated under illumination. Our aim according to this antisense therapy consisted in regulating the HPV16 E6 oncogene by using an E6-ASO derivatized with a polyazaaromatic ruthenium (Ru(II)) complex (E6-Ru-ASO) able, under visible illumination, to crosslink irreversibly the targeted sequence. We examined the effects of E6-Ru-ASO on the expression of E6 and on the cell growth of cervical cancer cells. We demonstrated using HPV16(+) SiHa cervical cancer cells that E6 Ru-ASO induces after illumination, a reactivation of p53, the most important target of E6, as well as the inhibition of cell proliferation with a selective repression of E6 at the protein level. These results suggest that E6-Ru ASOs, activated under illumination and specifically targeting E6, are capable of inhibiting HPV16(+) cervical cancer cell proliferation. PMID- 22809998 TI - Mutation-independent rescue of a novel mouse model of Retinitis Pigmentosa. AB - Retinitis Pigmentosa (RP) is the leading cause of inherited blindness in the developed world, affecting approximately 1 in 3000 individuals. Although there is currently no cure for RP, the genetic pathology has been well established. In this study, we developed a novel mouse model of RP (huRhoP347S) expressing a pathogenic human rhodopsin gene with a Pro347Ser (P347S) mutation on a rhodopsin knockout background. These mice undergo severe retinal degeneration at 1 month of age. In contrast to prior studies, this model was administered a gene therapy treatment at 19 days postnata. We evaluated several self-complementary adeno associated virus (AAV) serotypes for photoreceptor tropism, including scAAV2/2, scAAV2/5, scAAV2/6.2 and scAAV2/9, and found that scAAV2/9 transduced photoreceptors with greater efficiency and expression than other vectors. We engineered an scAAV2/9 vector to contain a microRNA sequence specifically targeting the human rhodopsin gene and demonstrated its ability to silence rhodopsin by 60.2+/-8.2% in vitro. In addition, we constructed an scAAV2/9 vector to contain a replacement 'codon-modified' rhodopsin transgene (RhoR2) that was resistant to degradation by the microRNA. We found that delivery of the RhoR2 by scAAV2/9 is capable of restoring vision to rhodopsin knockout mice, and rescuing our novel transgenic huRhoP347S mouse model of dominant RP. Average a-wave responses of RhoR2-injected eyes were 1.8-fold higher than those of control injected eyes. We found that delivery of the microRNA and replacement rhodopsin in a 1:2 ratio produced an average electroretinography (ERG) a-wave response of 17.4+/-2.9 compared to 6.5+/-2.8 MUV for eyes injected with negative control virus. PMID- 22809999 TI - Effectiveness of low-intensity aquatic exercise on COPD: a randomized clinical trial. AB - BACKGROUND: Despite the growing number of studies reporting therapeutic success in water environments, research involving aquatic exercise among patients with Chronic Obstructive Pulmonary Disease (COPD) is scarce. This study evaluates the impact of low-intensity water and floor exercises on COPD. METHODS: Forty two individuals with moderate to very severe COPD, divided into 3 groups: Control Group (CG), Floor Group (FG) and the Aquatic Group (AG). All participants were assessed using spirometry, respiratory muscle strength (MIP and MEP), the 6 Minute Walk Test (6MWT), Medical Research Council (MRC), BODE index and the St George's Respiratory Questionnaire (SGRQ). RESULTS: A difference was recorded after intervention for the 6MWT in the AG (p = 0.02); for VEF(1) in the FG (p = 0.00) and AG (p = 0.01); for MIP in the FG (p = 0.01) and AG (p = 0.02); for MEP in the FG (p = 0.02) and AG (p = 0.01); the MRC fell in the AG (p = 0.00). The FG showed improved quality of life evidenced by the total score on the SGRQ (p = 0.00). The BODE index decreased in the FG (p = 0.00) and AG (p = 0.01). CONCLUSION: Results show that both forms of low-intensity physical exercise benefit patients with moderate and very severe COPD. The AG exhibited additional benefits in physical ability, indicating a new therapeutic modality targeting patients with COPD. PMID- 22810000 TI - Strategies for the removal of halides from drinking water sources, and their applicability in disinfection by-product minimisation: a critical review. AB - The presence of bromide (Br(-)) and iodide (I(-)) in source waters leads to the formation of brominated and iodinated disinfection by-products (DBPs), which are often more toxic than their chlorinated analogues. The increasing scarcity of water resources in Australia is leading to use of impaired and alternative water supplies with high bromide and iodide levels, which may result in the production of more brominated and iodinated DBPs. This review aims to provide a summary of research into bromide and iodide removal from drinking water sources. Bromide and iodide removal techniques have been broadly classified into three categories, namely; membrane, electrochemical and adsorptive techniques. Reverse osmosis, nanofiltration and electrodialysis membrane techniques are reviewed. The electrochemical techniques discussed are electrolysis, capacitive deionization and membrane capacitive deionization. Studies on bromide and iodide removal using adsorptive techniques including; layered double hydroxides, impregnated activated carbons, carbon aerogels, ion exchange resins, aluminium coagulation and soils are also assessed. Halide removal techniques have been compared, and areas for future research have been identified. PMID- 22810001 TI - [Orbital lymphangioma]. PMID- 22810002 TI - [Oxygen extraction as a predictor of mortality in patients on high frequency ventilation]. AB - INTRODUCTION: The high frequency oscillatory ventilation (HFOV) may reduce cardiac output. The haemodynamics were analysed and predictors of mortality identified. PATIENTS AND METHODS: A total of 48 children with respiratory failure undergoing HFOV between January 2003 and December 2010 were included. The study design was prospective, observational, and descriptive. Inclusion criteria were based on the existence of hypoxemia. The variables studied were: arterial and central venous pressure, arterial pH, venous saturation and oxygen extraction ratio, with determinations performed prior to HFOV, during, and before turning to conventional ventilation. Prognostic factors were identified by bivariate analysis and a predictive model of mortality was developed. RESULTS: The mean age was 21 [4 to 72] months. On admission, PRISM scales and Murray were 33 and 2.8, PaO(2)/FiO(2) of 61 and oxygenation index of 35. After HFOV an increase in pH (P<.001), mean arterial pressure (P<.001) and venous saturation, and decreased venous pressure and O(2) extraction (P<.001), was obtained. The prognostic factors of mortality at 24 hours after starting HFOV were: FiO(2), PaO(2)/FiO(2), oxygenation index, shunt, pH, central venous pressure and mean arterial pressure, venous saturation, and O(2) extraction. The model developed at 12 hours, consisting of EtO(2) and SvcO(2) was able to predict death with a probability of 92.3%. CONCLUSIONS: HFOV improves haemodynamics. The model at 12 hours is the best predictor of death. PMID- 22810003 TI - Regulation of sphingomyelin phosphodiesterase acid-like 3A gene (SMPDL3A) by liver X receptors. AB - Liver X receptor (LXR) alpha and LXRbeta function as physiological sensors of cholesterol metabolites (oxysterols), regulating key genes involved in cholesterol and lipid metabolism. LXRs have been extensively studied in both human and rodent cell systems, revealing their potential therapeutic value in the contexts of atherosclerosis and inflammatory diseases. The LXR genome landscape has been investigated in murine macrophages but not in human THP-1 cells, which represent one of the frequently used monocyte/macrophage cell systems to study immune responses. We used a whole-genome screen to detect direct LXR target genes in THP-1 cells treated with two widely used LXR ligands [N-(2,2,2-trifluoroethyl) N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl] benzenesulfonamide (T0901317) and 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2 diphenylethyl)amino]propyloxy] phenylacetic acid hydrochloride (GW3965)]. This screen identified the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene as a novel LXR-regulated gene, with an LXR response element within its promoter. We investigated the regulation of SMPDL3A gene expression by LXRs across several human and mouse cell types. These studies indicate that the induction of SMPDL3A is LXR-dependent and is restricted to human blood cells with no induction observed in mouse cellular systems. PMID- 22810004 TI - Estrogen receptor beta (ERbeta) produces autophagy and necroptosis in human seminoma cell line through the binding of the Sp1 on the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) promoter gene. AB - Testicular germ cell tumors are the most common tumor in male and the least studied. We focused on human seminoma using the TCAM2 cell line. Through ERbeta, 10 nM estradiol (E2) was able to induce PTEN gene expression and promoter transactivation. Transient transfections, ChIP and EMSA assays evidenced the 5' flanking region of PTEN gene promoter E2-responsive. The ERbeta binding to the Sp1 on PTEN promoter decreased cell survival. The presence of ERbeta or PTEN is necessary to induce the loss of cell survival upon E2, addressing their cooperation in this action. pAKT and AKT expression decreased under E2 and DPN, while known apoptotic markers appeared to be unchanged. The PI3K/AKT pathway inhibition also leads to autophagy: E2 and DPN enhanced the expression of autophagy-related markers such as PI3III, Beclin 1, AMBRA and UVRAG. MDC and TEM assays confirmed E2-induced autophagy. The absence of DNA fragmentation, caspase 9 and PARP1 cleavages suggested that necroptosis and/or parthanatos may occur. FACS analysis, LDH assay and RIP1 expression attested this hypothesis. Our study reveals a unique mechanism through which ERbeta/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis. These data, supporting estrogen-dependency of human seminoma, propose ERbeta ligands for therapeutic use in the treatment of this pathological condition. PMID- 22810005 TI - Coccidioidomycosis infection of a total knee arthroplasty in a nonendemic region. AB - Fungal prosthetic joint infections are rare and difficult to treat. There is an ongoing discussion about the type and duration of antifungal treatment and the necessity of prosthesis removal. We report the first European case of an infected total knee arthroplasty with Coccidioides immitis. Treatment consisted of lifelong treatment with oral fluconazole at a dose of 400 mg/d, without total knee arthroplasty removal. After 6 months, the initial complaints of pain and swelling were completely resolved. This case report clearly states that a travel history and culturing for fungi are helpful in patients with persisting complaints after joint arthroplasty. PMID- 22810006 TI - Factors independently associated with complications and length of stay after hip arthroplasty: analysis of the National Surgical Quality Improvement Program. AB - By analysis of the American College of Surgeons National Surgical Quality Improvement Program database, we identified factors associated with postoperative complications and increased hospital stay after total hip arthroplasty in 4281 patients. There was a minor complication rate of 2.7%, a major complication rate of 4.2%, and a mortality rate of 0.26% within 30 days of the procedure. After adjusted analysis, obesity, preoperative anemia, and longer operative time were all associated with wound complications. Preoperative anemia, higher American Society of Anesthesiologists class, and prolonged operative time were associated with development of a major complication. A predischarge major complication resulted in an increased length of stay of 6.248 days (+/-0.286, P < .0001). One in 25 hip arthroplasty patients developed a major postoperative complication, and 1 in 16, a medical complication after elective hip arthroplasty. PMID- 22810007 TI - Effect of femoral offset on pain and function after total hip arthroplasty. AB - The effects of altering patients' femoral offset (FO) during total hip arthroplasty on postoperative pain and function have not been well described. This study compared clinical outcomes as assessed by the Short Form 12 Health Survey and Western Ontario and McMaster University Osteoarthritis Index between patients who had their FOs restored to varying degrees (compared to the contralateral normal hip [CL]). We retrospectively measured postoperative FOs on standard anteroposterior pelvis radiographs and compared to the CL. Patients were categorized into one of 3 groups: decreased offset (< -5 mm compared to CL), normal offset (between -5 and +5 mm), and increased offset (> +5 mm). The decreased offset group exhibited Western Ontario and McMaster University Osteoarthritis Index Physical Function scores that were less than those of the normal offset and increased offset groups (72.03, 82.23, and 79.51, respectively [P = .019]). In conclusion, reducing a patients' native FO led to inferior functional outcome scores. PMID- 22810008 TI - Cruciate-retaining vs posterior-substituting inserts in total knee arthroplasty: functional outcome comparison. AB - Despite clinical success, it is unclear which one, posterior-substituting (PS) or cruciate-retaining (CR) insert, has superior functional outcomes or longevity. We compared the collected results from 2 institutional review board-approved, multicenter, prospective observational studies following CR (412) and PS inserts (328). Participants were evaluated preoperatively, at 6 weeks, at 3 months, and at 1 and 2 years regarding pain, motion, function (Knee Society Score, Krackow Activity Score, Short Form-36), and procedure variables such as anesthesia and preoperative/perioperative/postoperative complications. Implant longevity was recorded at the 2-year follow-up. Improvement was observed within each group; however, there was no difference between groups in terms of pain, motion, or function at any end point. Two-year survival rate was higher than 95%. A higher incidence of wound hematoma was observed in the PS group. Both inserts can be used expecting satisfactory outcomes and high survival rates at 2 years. PMID- 22810009 TI - Successful treatment of Candida albicans-infected total hip prosthesis with staged procedure using an antifungal-loaded cement spacer. AB - We present a rare case of an immunocompetent host who developed a Candida albicans-infected total hip prosthesis. The infection could not be eradicated with debridement and extensive antifungal therapy. Our patient first underwent a resection of the proximal femur and local treatment with gentamicin-loaded cement beads. In a second procedure, a handmade cement spacer impregnated with voriconazole, amphotericin B, and vancomycin was placed. After 3 months of additional systemic antibiotic therapy, the patient remained afebrile, and a tumor prosthesis was placed. Six years postoperatively, she is doing well, walking with a small limp and no signs of recurrent infection. This is the first report on elution of voriconazole and amphotericin B from bone cement delivered at clinically significant concentrations for at least 72 hours. PMID- 22810010 TI - Steinman pin technique for the removal of well-fixed femoral stems. AB - Femoral stems with the capacity for exuberant bony in-growth, such as hydroxyapatite- or porous-coated stems, pose a challenge in the revision setting if extraction is required. The goal of minimal bone loss is crucial. We present an adjunct technique for the removal of well-fixed femoral stems with the use of Steinman pins. PMID- 22810011 TI - Isocentric 3-dimensional C-arm imaging of component alignments in total knee arthroplasty with potential intraoperative and postoperative applications. AB - An intraoperative imaging tool for total knee arthroplasty could help avoid poor clinical outcomes related to malalignment. We investigated the feasibility of using isocentric (ISO-C) fluoroscopic imaging for this purpose. Three-dimensional ISO-C and computed tomographic (CT) images were acquired from 6 cadaveric specimens implanted with standard knee arthroplasty components and analyzed to determine rotational alignments. In comparison with standard CT measures, the ISO C-based measures had overall accuracies (determined as root mean square error) of 0.8 degrees and 1.3 degrees and corresponding SDs of 1.3 degrees and 1.4 degrees for the femoral and tibial components, respectively. With ISO-C imaging, it is possible to measure rotational alignment in knee arthroplasty with accuracy and repeatability comparable with CT. Isocentric imaging has strong potential as an intraoperative tool to accurately align arthroplasty components. PMID- 22810012 TI - Revision of minimal resection resurfacing unicondylar knee arthroplasty to total knee arthroplasty: results compared with primary total knee arthroplasty. AB - We compared a cohort of patients undergoing revision of a minimal resection resurfacing unicompartmental knee arthroplasty (UKA) to total knee arthroplasty (TKA) with a cohort of patients undergoing primary TKA. Both cohorts were matched in terms of age, sex, and body mass index. We collected data on preoperative and postoperative range of motion, International Knee Society scores, and radiologic data. We also collected data on the modes of failure of the primary UKA. There were 55 patients in each cohort. The average time the UKA was in place was 48.3 months. The average follow-up period from the time of revision was 39.2 months. The most common reason for revision was subsidence of the tibial base plate (58%). Forty percent of patients required particulate bone grafting for contained defects. Two patients required metal augments, and 1 required stems. There was no significant difference between the 2 groups in terms of range of motion, functional outcome, or radiologic outcomes. Revision of these types of implants to TKA is associated with similar results to primary TKA and is superior to revision of other forms of UKA. PMID- 22810013 TI - Postoperative pain assessment based on numeric ratings is not the same for patients and professionals: commentary on van Dijk et al. (2012). PMID- 22810014 TI - Cellular strain amplifies LPS-induced stress signaling in immature enterocytes: potential implications for preterm infant NCPAP. AB - BACKGROUND: Recent clinical observations of increased necrotizing enterocolitis (NEC) incidence in some nasal continuous positive airway pressure (NCPAP) patients raise concerns about whether the related abdominal distension is benign or contributes to NEC. We tested the hypothesis that mechanical strain causes an exaggerated enterocyte inflammatory response and decreased enterocyte growth and proliferation in the absence and presence of lipopolysaccharide (LPS). METHODS: First we used a confluent enterocyte (IEC-6) monolayer to investigate effects of strain on inflammatory cytokine production and Toll-like receptor 4 (TLR-4) gene expression. Then we used a low seeding density to measure cell growth and proliferation. Ten percent mechanical strain was applied. RESULTS: Significant increases in interleukin (IL)-8 and in IL-6 were observed after 8 and 24 h of cellular strain, respectively, and maintained throughout the study. TLR-4 expression was increased at 48 h. Mechanical strain led to slower proliferation and division whereas LPS alone had minimal effects. The responses of LPS and strain were supra-additive, suggesting synergistic cellular effects. CONCLUSION: We speculate intestinal distension associated with the use of NCPAP, especially in the presence of abnormal gut colonization, may result in increased inflammatory cytokine production and be a contributing factor to neonatal intestinal morbidities. PMID- 22810015 TI - Food as ego-protective remedy for people experiencing shame. Experimental evidence for a new perspective on weight-related shame. AB - The well-explored association between shame and bulimia is based on research with clinical samples, which limits its generalizability. Moreover, these correlational studies are unable to draw clear conclusions about causality. To fill this gap, we conducted two experimental studies to examine whether shame elicits a desire for food in nonclinical participants. Compared with controls, participants experiencing shame found a buffet meal more desirable and were more likely to binge eat (Experiment 1); they also ate more than controls in a comparative taste test (Experiment 2). Our findings suggest that shame elicits the desire to obtain food to protect the devalued self but may lead to overeating and the risk of losing control over one's weight. We provide the first experimental evidence showing the link between shame and desire for food and offer a new perspective on the causal relationship between shame and binge eating. PMID- 22810016 TI - Primary cavitating tuberculosis in a 2-month-old infant. AB - Cavitation in primary pulmonary tuberculosis is rare, particularly in infants. We report a case of a 2-month-old infant with primary cavitating tuberculosis. Computed tomography first showed consolidation of the left upper lobe, and results of a course of antimicrobial therapy demonstrated a cystic lesion. The cyst was demonstrated to be a tuberculous cavity by postoperative histopathologic examination. PMID- 22810017 TI - Cryptosporidiosis in children following solid organ transplantation. AB - BACKGROUND: Cryptosporidium parvum is a common cause of diarrhea. In immunocompetent individuals, spontaneous recovery is the rule. In immunocompromised patients, it may cause a serious disease. Data on cryptosporidiosis in children after solid organ transplantation are few. We report on 6 pediatric solid organ recipients with gastroenteritis caused by Cryptosporidium. PATIENTS AND METHODS: All episodes of gastroenteritis in solid organ transplant recipients hospitalized in Schneider Children's Medical Center from January 2008 to August 2011 were identified. Data on the episodes with positive staining for Cryptosporidium antigen in stool were reviewed. RESULTS: Fifty-seven episodes of gastroenteritis were recorded. In 6 (11%) patients (4 kidney recipient, 1 liver and kidney recipient and 1 heart transplant recipient) Cryptosporidium antigen was detected in stool. Mean age at transplantation was 3.7 +/- 2 years, mean time between transplantation and cryptosporidial disease was 39 +/- 53.9 months. Symptoms included prolonged diarrhea, fever, abdominal pain and weight loss. Mean duration of symptoms before diagnosis was 10.5 +/- 8.7 days. In 5 children, kidney function deteriorated, blood concentrations of tacrolimus increased in 5 patients and abnormal values of liver enzymes were detected in 4 patients. All patients were hospitalized and received intravenous fluid replacement and were treated with nitazoxanide for 5-21 days. Two patients had recurrence of symptoms after short course (5 days) therapy. All patients recovered eventually from the disease. CONCLUSION: Cryptosporidium should be routinely tested in solid organ transplant recipients with diarrhea. Delay in initiation of treatment can result in serious complications including acute renal failure. Long-term therapy with nitazoxanide (at least 14 days) may facilitate recovery. PMID- 22810018 TI - Mannose-binding lectin and the risk of HIV transmission and disease progression in children: a systematic review. AB - BACKGROUND: Mannose-binding lectin (MBL) can activate the complement system by binding to carbohydrates, such as those presented on the HIV virion surface. It is unclear whether genetically determined MBL deficiency is related to vertical HIV transmission and disease progression in HIV-infected children. METHODS: A literature search of Medline, Embase and Cochrane Central Register identified all relevant studies on MBL and HIV infection in children. We extracted information on the characteristics of the study group, method of MBL analysis, outcome definitions, follow-up and the risk estimates. The validity of each study was assessed. RESULTS: Nine studies were retrieved. Most were of good validity, but risk adjustment for confounders was missing in 6 studies. Age, treatment and outcome definitions differed between the study groups. In most of the studies, MBL deficiency was associated with an increased frequency of vertical HIV transmission and an increased speed of disease progression. In the 2 most valid studies, carriers of variant genes had an increased odds ratio for transmission and an increased relative hazard for disease progression and central nervous system impairment, especially in children <2 years of age. CONCLUSIONS: MBL deficiency is associated with an increased risk of vertical HIV transmission. How this risk relates to other factors that influence transmission is unclear. The association between HIV disease progression and MBL deficiency is most pronounced in children <2 years of age, probably due to immaturity of their adaptive immunity. PMID- 22810019 TI - Histopathological effects and bioaccumulation of mercury in the kidney of an Indian major carp, Labeo rohita (Hamilton). AB - The effect of mercuric chloride on the histo-morphology and bioaccumulation in the kidney of an Indian major carp, Labeo rohita (Hamilton) were examined after exposing the fish (15-20 cm) to three sublethal concentrations (0.033, 0.066 and 0.132 mg/L) of HgCl(2) for 30 days. Mercury deposition in kidney tissues had increased significantly with dose and exposure duration dependant manner. Several histological changes were noted in the kidney of all treated groups in compare to control group. PMID- 22810020 TI - Determination of metal (Cu, Zn, Se, Cr and Cd) levels in tissues of the cyprinid fish, Capoeta trutta (Heckel, 1843) from different regions of Keban Dam Lake (Euphrates-Turkey). AB - The aim of this study was to evaluate Copper (Cu), Zinc (Zn), Selenium (Se), Chromium (Cr) and Cadmium (Cd) concentrations in liver, muscle, gills and kidney tissues of Capoeta trutta collected from four sites of Keban Dam Lake, Turkey. The highest heavy metal level in all tissues was for Zn, while Cd was the lowest. The lowest heavy metal levels were generally found at Station 4 (Agin) for all tissues (p < 0.05). There were statistically significant differences among stations for Cu, Zn, Cr and Se in gills; for Cu, Zn, Se and Cr in liver and kidney; and Cu, Zn and Cr in muscle (p < 0.05). Cadmium concentrations did not differ between sites for any of the tissues. Turkish Food Codex sets the maximum limits of Zn, Cu and Cd as, 50, 20 and 0.05 mg kg(-1) dry weight, respectively, in the muscle of fish used for human consumption. In our study, the level of Zn was higher than Turkish permissible limits only at Station 3 (Guluskur). Cadmium levels were much higher than permissible limits at three stations [S1 (Pertek), S2 (Kockale) and S3], whereas Cu levels were within permissible limits in all stations. PMID- 22810021 TI - Post-modification of a MOF through a fluorescent-labeling technology for the selective sensing and adsorption of Ag+ in aqueous solution. AB - A new approach inspired by fluorescent labeling technology to fluorescently functionalize MOFs via post-modification is reported. A fluorescein-containing MOF FITC@BTPY-NH(2) was synthesized for selective sensing and adsorption of Ag(+) in aqueous solution. PMID- 22810024 TI - Journal information. PMID- 22810025 TI - Editor's Preface. PMID- 22810022 TI - The Jurdham procedure: endocardial left ventricular lead insertion via a femoral transseptal sheath for cardiac resynchronization therapy pectoral device implantation. AB - BACKGROUND: Endocardial stimulation of the left ventricle for cardiac resynchronization therapy is a growing field of investigation. Despite the excellent results and absence of significant complications demonstrated thus far in the literature, the lack of a simple, straightforward, and standard technique limits its widespread utilization. OBJECTIVE: To assess the feasibility, safety, simplicity, and complications of a technique for inserting the left ventricle lead through a femoral transseptal sheath to the pectoral implant site, termed "the Jurdham procedure." METHODS: We performed the Jurdham procedure in 10 patients (8 men; 60.5 +/- 1.8 years) in whom a coronary sinus lead implant had failed. A snared 85-cm standard active fixation endocardial pacing lead was implanted on the left ventricle endocardium through a femoral transseptal sheath with subsequent mobilization of the proximal end of the lead to the prepectoral area via the snare. RESULTS: Successful implant was achieved in all 10 patients without complications, with excellent acute and chronic pacing parameters. All patients remained on chronic oral anticoagulation therapy without thromboembolic or bleeding complications. No late complications have occurred. All patients have improved at least 1 New York Heart Association functional class and have remained clinically stable during the follow-up term. CONCLUSION: The Jurdham procedure is a reliable, technically easy technique to achieve cardiac resynchronization therapy via the endocardial approach. In our initial experience, there has been an excellent clinical response without significant complications during short term follow-up. Additional investigation is needed to define the precise indications and limitations of this procedure. PMID- 22810026 TI - Epidemiology and risk factors. AB - PURPOSE OF REVIEW: : This article presents current knowledge on stroke epidemiology. It covers recent data on the global burden of stroke, disparities, silent stroke, traditional and novel risk factors, and stroke triggers as well as the clinical implications of these findings. RECENT FINDINGS: : Stroke is the third leading cause of death and the leading cause of chronic disability in the United States, and the burden of stroke worldwide is even greater. Large international and US case-control and prospective cohort studies have demonstrated disparities in stroke mortality and incidence. They have also shed light on the relative importance of several well-established, modifiable risk factors for ischemic stroke, such as hypertension, atrial fibrillation, other cardiac diseases, hyperlipidemia, diabetes, cigarette smoking, physical inactivity, alcohol consumption, abdominal obesity, diet, and TIA. Research on other putative stroke risk factors (including inflammation, infection, renal disease, depression, stress, and others) is ongoing. Identifying stroke triggers may be another way to minimize stroke incidence if high-risk time windows can be determined. SUMMARY: : Stroke is a major global health burden. While many of the risk factors for stroke are well known and have been studied for decades, recent studies continue to shed light on the distribution and severity of these problems. PMID- 22810027 TI - Blood pressure reduction in secondary stroke prevention. AB - PURPOSE OF REVIEW: : Risk factor modification plays an important role in recurrent stroke prevention. These modifiable risk factors tend to cluster in stroke patients, but for a significant subgroup the only identifiable risk factor is high blood pressure or chronic hypertension. This article reviews the current evidence for management of blood pressure in secondary stroke prevention. RECENT FINDINGS: : Over the years, data from primary prevention trials have shown that antihypertensive drug treatment reduces the risk of first stroke by 32%. Similarly, various secondary prevention studies have shown a relative risk reduction in recurrent strokes of up to 30%. These trials have also shown that the impact of blood pressure reduction in stroke prevention is similar in patients with hypertension and patients without hypertension, and larger reductions in systolic blood pressure were associated with greater reduction in risk of recurrent stroke. SUMMARY: : Although it is clear from the current evidence that long-term blood pressure control is one of the most important interventions for secondary stroke prevention, the optimal management of blood pressure in the immediate poststroke period is not well defined. PMID- 22810028 TI - Dyslipidemia management. AB - PURPOSE OF REVIEW: : Numerous studies have been conducted in the past decade evaluating the use of statins and other lipid therapies for reducing vascular events. These studies have impacted the area of stroke prevention. RECENT FINDINGS: : For patients with established coronary artery disease, statins reduce the rate of stroke. High-dose statin treatment has also been found to reduce the rate of stroke in patients with recent cerebrovascular events and no evidence of heart disease. As a result, initiation of statin therapy for patients with stroke or TIA is now recommended in clinical guidelines. Whether agents that modulate high-density lipoprotein cholesterol are effective in reducing stroke is still the subject of clinical study. SUMMARY: : Most patients with stroke or TIA should be treated with statins. The era of multimodal medical therapy for stroke prevention is now well established. PMID- 22810029 TI - Antithrombotic therapy for secondary stroke prevention. AB - PURPOSE OF REVIEW: : Antithrombotic therapy is a key component of any strategy for the secondary prevention of ischemic stroke. A better understanding of the various therapeutic options will lead to improved stroke prevention, better medication adherence, and fewer complications. RECENT FINDINGS: : Antiplatelet agents and anticoagulants are the two major classes of antithrombotic therapy used for stroke prevention. The etiology and mechanism of the stroke must be considered in order to make the best decision regarding which agent(s) to use for secondary stroke prevention. The recent Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study showed that clopidogrel and aspirin plus extended-release dipyridamole had similar event rates in terms of recurrent stroke, but clopidogrel was better tolerated, with fewer bleeding events. Several new anticoagulants are poised to replace warfarin for stroke prevention in the setting of atrial fibrillation. These include dabigatran (a new oral direct thrombin inhibitor) and possibly apixaban (a new oral factor Xa inhibitor). These new medications are much easier to use than warfarin and may be more effective and safer, with fewer drug and food interactions and no need for routine blood monitoring. Thus, these new medications may improve adherence as well as clinicians' inclination to treat with anticoagulation. SUMMARY: : Because each antiplatelet agent or anticoagulant has certain advantages and disadvantages, clinicians must choose an agent that the patient can afford and tolerate in terms of side effects and adherence. The hope and expectation is that the proper use of these medications in accordance with current guidelines will reduce the risk of a recurrent stroke. PMID- 22810030 TI - Large artery revascularization. AB - PURPOSE OF REVIEW: : Large artery cerebrovascular disease accounts for approximately 20% of ischemic strokes. This review describes anatomic, epidemiologic, imaging, and therapeutic aspects of large vessel obstructive disease, with emphasis on revascularization methods. RECENT FINDINGS: : Considerable data have accumulated regarding the natural history, diagnosis, and optimal management of carotid disease, and the evidence regarding the optimal management of subclavian/brachiocephalic, vertebral, and intracranial obstructive disease continues to accrue. Advanced vascular imaging modalities have become integral to clinical decision making in the setting of complex cerebrovascular anatomy and physiology. The medical therapy and the surgical techniques have evolved remarkably over the past decades. Novel catheter-based endovascular therapies have rapidly emerged as an alternative or, in some cases, first-line treatment for large artery cerebrovascular disease. SUMMARY: : The evidence related to the diagnosis and treatment of large artery cerebrovascular disease has expanded remarkably. Sophisticated imaging protocols have minimized the need for invasive methods, and the efficacy of medical therapy (with newer antiplatelet agents and statins) has improved outcomes related to vascular disease. Endarterectomy and stenting have proven to be effective methods for carotid artery revascularization and stroke prevention. The best approach to patients with severe extracranial vertebral or intracranial stenosis warrants further investigation. PMID- 22810031 TI - Insulin resistance, obesity, metabolic syndrome, and lifestyle modification. AB - PURPOSE OF REVIEW: : This article provides an overview of the effects of obesity, metabolic syndrome, and insulin resistance on stroke risk; outlines the association between healthy lifestyle habits and stroke; and summarizes features of effective lifestyle interventions. RECENT FINDINGS: : General obesity, abdominal obesity, insulin resistance, and the metabolic syndrome are all independently linked with stroke risk and may worsen outcomes after stroke. Five key lifestyle factors-regular exercise, abstinence from smoking, a diet rich in fruits and vegetables, a body mass index of 18.5 to 24.9 kg/m, and moderate alcohol use-have been shown to lower the risk of stroke. Collaborative, multidisciplinary, intensive, patient-centered interventions tend to be the most effective for lifestyle change. SUMMARY: : Mounting obesity rates are threatening the gains that have been made in reducing stroke incidence through traditional risk factor control. In order to mitigate the burden of stroke, physicians need to regularly address lifestyle factors when caring for patients. PMID- 22810032 TI - Prevention of intracerebral hemorrhage recurrence. AB - PURPOSE OF REVIEW: : Limited data are available on the prevention of intracerebral hemorrhage (ICH) recurrence, which is substantial, especially in the case of lobar ICH related to cerebral amyloid angiopathy. In view of the relative paucity of prospectively generated data, current strategies for the secondary prevention of ICH involve the extrapolation of data on primary prevention of ICH to its secondary prevention and the avoidance of certain agents that have been shown in clinical series to be associated with increased risk of ICH recurrence. This review analyzes ways to approach the secondary prevention of ICH in the setting of a paucity of adequate prospectively generated data on the subject. RECENT FINDINGS: : Risk factors for ICH recurrence identified through data extrapolation include hypertension, diabetes, excessive alcohol consumption, cigarette smoking, and probably migraine with aura. Agents associated with increased risk of ICH recurrence include warfarin, antiplatelet agents, statins, and vitamin E. SUMMARY: : This article reviews the prevention of ICH recurrence based on extrapolating data from primary prevention of ICH along with the clinically appropriate strategy of avoiding the use of agents that have been shown to carry an increased risk of ICH recurrence. PMID- 22810033 TI - Systematic stroke prevention. AB - PURPOSE OF REVIEW: : This review summarizes the systematic approaches that can be used to optimize secondary stroke prevention. Systematic secondary stroke prevention involves not only prescribing stroke patients the appropriate medications to manage risk factors, but also optimizing the effectiveness of those drugs by focusing on medication adherence. Medication adherence is defined as the extent to which patients take their medications as prescribed by their providers. RECENT FINDINGS: : Many potential barriers to adherence exist, including relationships among patient, provider, and the health system. Medication reconciliation at discharge and early follow-up are steps that may increase medication adherence, decrease medication errors, and improve the transition to home. In addition, inclusion of the primary provider or stroke specialist in decisions regarding the management of antithrombotic therapy for procedures is important, as discontinuing these medications is often associated with recurrent ischemic events. SUMMARY: : Prevention of recurrent stroke should be a priority for patients, caregivers, providers, and health systems. Medication taking behavior should be considered from all of these perspectives in order to optimize adherence. PMID- 22810034 TI - Emergency management of acute ischemic stroke in incapacitated patients who have no surrogate decision makers. AB - When hospitalized patients with acute ischemic stroke are unable to make their own medical decisions, clinicians usually turn to advance directives and the patient's close family members and friends to define the patient's wishes and expectations regarding treatment and prognosis. In many jurisdictions, if there is no surrogate for an incapacitated patient, an emergency ethics or risk management consultation is advisable and is usually done with a representative of the hospital's law office. The ethics team can represent the patient's interests by hearing the recommendations of the treating physicians and then deciding whether their recommended treatment plan is ethically permissible and in the patient's interests. Depending on the jurisdiction, it is sometimes necessary for the courts to appoint a guardian for incapacitated patients who have no surrogate decision makers available. PMID- 22810035 TI - Cryptogenic stroke and patent foramen ovale. AB - In patients with cryptogenic stroke and patent foramen ovale, options for stroke prevention include medical therapy (antiplatelet therapy or anticoagulation) and percutaneous device closure. In the only completed randomized controlled trial comparing medical therapy and percutaneous device closure, there was no difference in outcome between the two forms of treatment, and both are viable options for stroke prevention. The choice of therapy is made after careful weighing of potential risks and benefits associated with each form of therapy based on the limited evidence to date and the anticipated patient adherence with the planned treatment. Participation in a clinical trial is a third option for these patients. PMID- 22810036 TI - Coding issues: coding for stroke prevention. AB - Accurate coding is an important function of neurologic practice. This section of CONTINUUM, contributed by members of the AAN Medical Economics and Management Committee, includes helpful coding information and examples related to the issue topic. This section may include diagnosis coding, evaluation and management coding, procedure coding, or a combination, depending on which is most useful for the subject area of the issue. PMID- 22810039 TI - Multiple-choice questions. PMID- 22810037 TI - Appendix a: stroke trial abbreviations. PMID- 22810040 TI - Multiple-choice questions-preferred responses. PMID- 22810041 TI - Patient management problem. PMID- 22810042 TI - Patient management problem-preferred responses. AB - Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study. PMID- 22810044 TI - Tricuspid regurgitation in acute phase of Kawasaki disease associated with intensive care unit admission. AB - Kawasaki disease (KD) is a systemic vasculitis and primarily affects children <5 years of age. Intensive care unit (ICU) admission is unusual, but there can be associated severe complications in KD patients. This study was conducted to identify risk factors for ICU admission. Retrospectively, we reviewed charts of all children who had a discharge diagnosis of KD from 2001 through 2009. Clinical presentation, laboratory data, and outcome were collected for analysis of the association with ICU admission in KD patients. Multifactor dimensionality reduction (MDR) was used to identify factor interactions. There were 334 KD patients, including 24 patients in ICU admission, included in the analysis. Coronary artery lesions (CALs) and failure of intravenous immunoglobulin (IVIG) treatment were more frequently found in the ICU group (P < 0.0001). Total counts of white blood cells, hemoglobin levels, C-reactive protein, and albumin levels showed significant association with ICU admission (P < 0.05). Moderate tricuspid regurgitation (TR) was found only in the ICU admission group. MDR analyses of factor interactions identified that TR interacted with CAL with a prediction accuracy of 77.78 %. (P = 0.001). Patients with KD who are IVIG resistant and/or who are found to have CALs are at increased risk for ICU admission. Most importantly, moderate TR was significantly found in KD patients only in the ICU group. This may highlight the great value of moderate TR in predicting ICU admission for patients with KD. PMID- 22810045 TI - Isolated right ventricular noncompaction in a newborn. AB - Noncompaction of the ventricular myocardium is a rare cardiomyopathy characterized by a pattern of prominent trabecular meshwork and deep intertrabecular recesses. The prevalence of left ventricular noncompaction is 0.01% in adults and 0.14% in pediatric patients. Although the usual site of involvement is the left ventricle, the right ventricle and septum can be affected as well. Previously, right ventricular noncompaction has been described only in a few cases of newborns with congenital heart defects and in adult patients. This report presents a newborn with isolated right ventricular noncompaction. To the authors' knowledge, this is the first newborn patient with isolated right ventricular noncompaction but no congenital heart defect involving only the right ventricle. PMID- 22810046 TI - Effects of functional interactivity on patients' knowledge, empowerment, and health outcomes: an experimental model-driven evaluation of a web-based intervention. AB - BACKGROUND: The effectiveness of eHealth interventions in terms of reach and outcomes is now well documented. However, there is a need to understand not only whether eHealth interventions work, but also what kind of functions and mechanisms enhance their effectiveness. The present investigation contributes to tackling these challenges by investigating the role played by functional interactivity on patients' knowledge, empowerment, and health outcomes. OBJECTIVES: To test whether health knowledge and empowerment mediate a possible relationship between the availability of interactive features on an eHealth application and individuals' health outcomes. We present an empirical, model driven evaluation of the effects of functional interactivity implemented in an eHealth application, based on a brief theoretical review of the constructs of interactivity, health knowledge, empowerment, and health outcomes. We merged these constructs into a theoretical model of interactivity effects that we tested on an eHealth application for patients with fibromyalgia syndrome (FMS). METHODS: This study used a pretest-posttest experimental design. We recruited 165 patients and randomly assigned them to three study groups, corresponding to different levels of functional interactivity. Eligibility to participate in the study required that patients (1) be fluent in Italian, (2) have access to the Internet, (3) report confidence in how to use a computer, and (4) have received a diagnosis of FMS from a doctor. We used structural equation modeling techniques to analyze changes between the pretest and the posttest results. RESULTS: The main finding was that functional interactivity had no impact on empowerment dimensions, nor direct observable effects on knowledge. However, knowledge positively affected health outcomes (b = -.12, P = .02), as did the empowerment dimensions of meaning (b = -.49, P < .001) and impact (b = -.25, P < .001). CONCLUSION: The theoretical model was partially confirmed, but only as far as the effects of knowledge and empowerment were concerned. The differential effect of interactive functions was by far weaker than expected. The strong impact of knowledge and empowerment on health outcomes suggests that these constructs should be targeted and enhanced by eHealth applications. PMID- 22810047 TI - IVF twins: buy one get one free? AB - There has been an overall increase in the incidence of multiple pregnancies and assisted reproduction technology is largely responsible for this rise. Although twins may appeal to couples undergoing in vitro fertilisation (IVF), they have been associated with serious health consequences to the babies, their mothers and the family unit, as well as having massive financial implications for the National Health Service. Transfer of more than one embryo during IVF is mainly responsible for IVF twins, and elective transfer of a single embryo at a time with cryopreservation of surplus embryos for later transfer has been shown to be an effective strategy to minimise the risk of twins without compromising IVF success rates. Factors that will impact on the success of the policy of elective single embryo transfer (eSET) include improvement in embryo selection for transfer, better cryopreservation techniques and adequate state funding for IVF. However, in implementing the policy of eSET it is important that each case is assessed on an individual basis since in some situations (e.g. in older women) the transfer of two embryos may be more cost effective. Adequate and continuous education of all stakeholders is essential if the policy of eSET is to be successful in the UK. PMID- 22810049 TI - A DFT study on the mechanisms for the cycloaddition reactions between 1-aza-2 azoniaallene cations and acetylenes. AB - The mechanisms of cycloaddition reactions between 1-aza-2-azoniaallene cations 1 and acetylenes 2 have been investigated using the global electrophilicity and nucleophilicity of the corresponding reactants as global reactivity indexes defined within the conceptual density functional theory. The reactivity and regioselectivity of these reactions were predicted by analysis of the energies, geometries, and electronic nature of the transition state structures. The theoretical results revealed that the reaction features a tandem process: an ionic 1,3-dipolar cycloaddition to produce the cycloadducts 3 H-pyrazolium salts 3 followed by a [1,2]-shift affording the thermodynamically more stable adducts 4 or 5. The mechanism of the cycloaddition reactions can be described as an asynchronous concerted pathway with reverse electron demand. The model reaction has also been investigated at the QCISD/6-31++G(d,p) and CCSD(T)/6 31++G(d,p)//B3LYP/6-31++G(d,p) levels as well as by the DFT. The polarizable continuum model, at the B3LYP/6-31++G(d,p) level of theory, was used to study solvent effects on all the studied reactions. In solvent dichloromethane, all the initial cycloadducts 3 were obtained via direct ionic process as the result of the solvent effect. The consecutive [1,2]-shift reaction, in which intermediates 3 are rearranged to the five-membered heterocycles 4/5, is proved to be a kinetically controlled reaction, and the regioselectivity can be modulated by varying the migrant. The LOL function and RDG function based on localized electron analysis were used to analysis the covalent bond and noncovalent interactions in order to unravel the mechanism of the title reactions. PMID- 22810050 TI - Real-time studies of hypertension using non-mydriatic fundus photography and computer-assisted intravital microscopy. AB - Hypertension is asymptomatic until late stages of pathogenesis, rendering an effective means of detection for early diagnosis essential. The current method of diagnosing hypertension requires two or more sphygmomanometric readings over two or more office visits, which potentially hinders early detection. Though retinopathy is an indicator of vascular damage, it generally presents in later stages of hypertension. Previous and related studies have suggested that the microvasculature in the bulbar conjunctiva may be a sensitive site to assess vasculopathy. Conjunctival microangiopathy was assessed using CAIM and reported on a severity index (SI). Images of the retinal fundus were taken via non mydriatic fundus photography and graded using the Scheie scale in the same subjects to compare with CAIM. Conjunctival microangiopathy was significantly elevated in hypertensive subjects (SI = 5.35 +/- 1.04, n = 20) compared to control subjects (SI = 1.75 +/- 1.39, n = 8; p <= 0.05), and correlated with time since disease diagnosis (R2 = 0.33). Hypertensive subjects with Grade 1 retinopathy displayed increased conjunctival microangiopathy (SI = 5.85 +/- 0.90, n = 13) compared to those without retinopathy (SI = 4.43 +/- 0.53, n = 7; p <= 0.05). These data indicate a possible pre-retinopathy time window during which conjunctival microangiopathy may indicate the risk of organ damage, supporting the hypothesis that the conjunctival microcirculation may serve as a platform for early detection and monitoring disease progression. PMID- 22810051 TI - Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke. AB - Statins reduce the risk of cardiovascular events by lowering the blood cholesterol. Many genes involved in the pharmacodynamic pathway of statins have been part of pharmacogenetic research in patients with hypercholesterolemia, with an emphasis on genes involved in the cholesterol pathway. The present study was carried out with an aim to evaluate the association between the genetic variants of lipoprotein lipase gene [HindIII (+/+)/HindIII (-/-)], multiple drug resistance gene (C3435T) and endothelial nitric oxide synthase gene (4a/4b) with clinical outcome including an increased risk of recurrent stroke or death in ischemic stroke patients on atorvastatin therapy. 525 stroke patients and 500 healthy controls were involved in the study. Follow-up telephone interviews were conducted with patients post-event to determine stroke outcome. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. A significant association of MDR1 and LPL gene variants with bad outcome in stroke patients on atorvastatin therapy was found. However, there was no significant association of 27 bp VNTR polymorphism of eNOS gene with outcome. MDR analysis was carried out to analyze gene-gene interaction involving these gene variants contributing to clinical outcome of patients on stratin therapy but no significant interaction between these variants was observed. In conclusion the individuals with HindIII (-/-) genotype of LPL and CC genotype of MDR1 gene would benefit more from atorvastatin therapy. PMID- 22810052 TI - Upper urinary tract and urethral recurrences following radical cystectomy: review of risk factors and outcomes between centres with different follow-up protocols. AB - PURPOSE: To examine which patient-related and tumour-related characteristics predict upper urinary tract recurrence (UUTR) and urethral recurrence (UR) of bladder cancer post-radical cystectomy (RC). Secondary objective is to evaluate whether or not recurrence patterns are similar between two centres with different post-RC follow-up (F/U) protocols. METHODS: A retrospective cohort study of 574 consecutive patients undergoing radical cystectomy for urothelial carcinoma of the bladder at two tertiary centres was performed. Clinicopathological factors associated with bladder cancer recurrence and patient-related outcomes, including time to recurrence and death, were collected. Risk factors for recurrences were examined using univariate and multivariable regression analyses. Likelihood of recurrence, time to recurrence, and survival were compared. RESULTS: There was a 3.7 % risk of UUTR (21/574) and a 3.6 % risk of UR (18/503) for the combined cohort at a median F/U of 45 months. When controlling for the effects of all variables modelled, female gender was a significant risk factor for UUT recurrence (OR 3.2, 95 % CI 1.0-9.5, p = 0.03) and prostatic urethral involvement was a significant risk factor for urethral recurrence (OR 7.8, 95 % CI 2.2-27.6, p = 0.001). UUTR were similar (p = 0.82) between Turku (8/205) and Toronto (12/369). Urethral recurrences trended (p = 0.06) towards being more common in Turku (9/151, 6.0 %) versus Toronto (9/352, 2.6 %), but no difference in overall survival was demonstrated between sites. CONCLUSION: The frequency of UUT and urethral recurrences post-cystectomy is relatively low and remained stable for the past 15 years. The ideal F/U protocol to maximize patient-survival remains unknown. PMID- 22810053 TI - Is there a difference in percutaneous nephrolithotomy outcomes among various types of pelvicaliceal system? AB - PURPOSE: During PNL procedures, stone clearance can be achieved by single access or multiple accesses for same stone size and configuration. At this point, we believed that pelvicaliceal system type may play a significant role on stone clearance. In our study, we aimed to investigate the effect of pelvicaliceal system type on PNL outcomes. METHODS: A total of 498 patients who had preoperative intravenous urography were enrolled in our study. PCSs of the patients were classified as A1, A2, B1, and B2 according to Sampaio system after evaluation of IVU images. The exclusion criteria were unclassified pelvicaliceal system due to the presence of exaggerated renal hydronephrosis, IVUs with poor quality, radiolucent renal stones, and absence of CT or IVU in postoperative period. RESULTS: There was no clinically significant difference for patient gender, history of open surgery, and history of previous SWL. Success rates of PNL were 79.5, 82.0, 74.3, and 80.3 % in Sampaio type A1, A2, B1, and B2 PCS, respectively (p 0.61). Multiple accesses were required for 35 (18.8 %), 14 (17.9 %), 55 (30.1 %), and 6 (11.8 %) patients according to Sampaio classification type A1, A2, B1, and B2, respectively (p 0.008). There was no clinically significant difference for stone size, stone configuration (simple or complex), and complications. CONCLUSION: Sampaio type B1 PCSs require increased number of access for achieving stone clearance. Therefore, surgeons should be aware and also inform patients that treatment of patients with Sampaio type B1 PCS may need high number of access during PNL procedure. PMID- 22810054 TI - Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy. AB - AIMS: The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins links the TNF receptor superfamily to cell signalling cascades. TRAF1 is involved in regulation of apoptosis, proliferation, differentiation and stress responses. It has a role in development of several malignancies, but no information for renal cell carcinoma (RCC) is available. METHODS: Expression profiles for TRAF1 were investigated in 121 samples of human RCC of various subtypes plus paired normal kidney prepared in tissue microarrays, in comparison with apoptosis (morphology, ApopTag) and mitosis (morphology, proliferating cell nuclear antigen/PCNA). TRAF1 function was tested in vitro in RCC ACHN cells. TRAF1 short interfering RNA (siRNA) was used to inhibit expression of TRAF1 in ACHN cells untreated or treated with cancer therapies known to induce apoptosis (20 Gy X-irradiation and/or 500 IU/mL interferon-alpha). RESULTS: In patient samples, TRAF1 localised to proximal tubular epithelium in normal kidney and was significantly decreased in clear cell RCC as one group (p < 0.01) and all other RCC subclassifications grouped together (p < 0.05). There was little apoptosis identified in any RCC samples. In vitro, TRAF1 siRNA caused significant reduction in TRAF1 expression and a concurrent decrease in apoptosis and increase in proliferative activity (both p < 0.05) in the ACHN RCC cells treated with radiation and interferon-alpha. CONCLUSION: TRAF1 may have a pro-apoptotic, anti mitotic role in RCC. The low TRAF1 expression in untreated RCC patient samples compared with normal kidney, and the localisation of TRAF1 to the proximal tubular epithelium from which many RCC originate, may indicate a potential for targeted therapy in RCC. PMID- 22810055 TI - Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis. AB - BACKGROUND: Methods to detect anti-nucleosome antibodies (ANuA) have been available for more than 10 years and the test has demonstrated its good sensitivity and high specificity in diagnosing systemic lupus erythematosus (SLE). Despite these data produced through clinical and laboratory research, the test is little used. OBJECTIVE: To verify the diagnostic performance of methods for measuring ANuA and to compare them with those for anti-dsDNA antibodies. DATA SOURCES: A systematic review of English and non-English articles using MEDLINE and EMBASE with the search terms "nucleosome", "chromatin", "anti-nucleosome antibodies" and "anti-chromatin antibodies". Additional studies were identified checking reference lists in the selected articles. STUDY SELECTION: We selected studies reporting on anti-nucleosome tests performed by quantitative immunoassays, on patients with SLE as the index disease (sensitivity) and a control group (specificity). A total of 610 titles were initially identified with the search strategy described. 548 publications were subsequently excluded based on abstract and title. Full-text review was undertaken as the next step on 62 publications providing data on anti-nucleosome testing; 25 articles were then excluded because they did not include either SLE patients or a control group, and 37 articles were selected for the metanalysis. Finally, a sub-metanalysis study was conducted on the 26 articles providing data on both ANuA and anti-dsDNA antibody assays in the same series of patients. DATA EXTRACTION: Extraction of data from selected articles was performed by two authors independently, using predefined criteria: the number of patients with SLE as the index case, and the number of healthy or diseased controls; specification of the analytical method used to detect anti-nucleosome and anti-dsDNA antibodies; the cut-off used in the study; and the sensitivity and specificity of the assay. Demographic and clinical data on the population investigated (adults or children; lupus patients with or without nephritis; patients with active or inactive disease) were also recorded and analyzed in a separate evaluation. RESULTS: The systematic review and metanalysis showed that the overall sensitivity of the ANuA assay is 61% (confidence interval-CI, 60-62) and the specificity 94% (CI, 94-95). The overall positive likelihood ratio is 13.81 (CI, 9.05-21.09) and the negative likelihood ratio 0.38 (CI, 0.33-0.44). The odds ratio for having SLE in ANuA-positive patients is 40.7. The comparative analysis on anti-dsDNA antibodies conducted on the 26 studies which provided data for both antibodies showed that ANuA have greater diagnostic sensitivity (59.9% vs 52.4%) and a specificity rating only slightly higher (94.9% vs 94.2%). The probability that a subject with positive ANuA have SLE is 41 times greater than a subject with negative ANuA, while for anti-dsDNA the probability is 28 times greater. These figures are even more impressive in children, in whom ANuA have an odds ratio for the diagnosis of SLE of 146, compared to 51 for anti-dsDNA antibodies. In selected studies, ANuA (p<0.0001) but not anti-dsDNA antibodies (p=0.256) were significantly associated with disease activity measured by the international score systems. However, neither antibody appears to correlate with kidney involvement. CONCLUSIONS: Data from the metanalysis have shown that ANuA have equal specificity but higher sensitivity and prognostic value than anti-dsDNA antibodies in the diagnosis of SLE. Despite a certain heterogeneity among the various studies, the use of ANuA appears more efficacious than anti-dsDNA. PMID- 22810056 TI - Evaluation of the national toxicology program report on carcinogens. AB - This study evaluates the National Toxicology Program's Report on Carcinogens program (RoCP) and compares it with the International Agency for Research on Cancer Monographs Program (IMP). We tracked agents classified in the RoCP since 1983 as known human carcinogens (A-List), or as reasonably anticipated to be human carcinogens (B-List). The first A-list included 24 agents, and twenty-four unique agents were added in the following 28years; twenty were listed by IMP as Group 1 (carcinogenic to humans) 7years before their A-list appearance. Group 1 also includes 30 or more agents eligible for, but not on, the A-list. The first B list included 98 agents, and this increased to 185. Of these, 39 are in Group 2A (probably carcinogenic), and 122 are in Group 2B (possibly carcinogenic). Only 5% of the 204 agents ever on the B-list have been upgraded to the A-list. The RoCP is severely limited because it evaluates few agents and because its B-list does not distinguish between probable and possible human carcinogens. Further, it mislabels likely non-carcinogens as reasonably anticipated to be carcinogens. If the RoCP were terminated there would be no loss or delay of information available to scientific, public health and regulatory communities. PMID- 22810057 TI - Financial factors and the implementation of medications for treating opioid use disorders. AB - OBJECTIVES: Despite the established effectiveness of pharmacotherapies for treating opioid use disorders, implementation of medications for addiction treatment (MAT) by specialty treatment programs is limited. This research examined relationships between organizational factors and the program-level implementation of MAT, with attention paid to specific sources of funding, organizational structure, and workforce resources. METHODS: Face-to-face structured interviews were conducted in 2008 to 2009 with administrators of 154 community-based treatment programs affiliated with the National Institute on Drug Abuse's Clinical Trials Network; none of these programs exclusively dispensed methadone without offering other levels of care. Implementation of MAT was measured by summing the percentages of opioid patients receiving buprenorphine maintenance, methadone maintenance, and tablet naltrexone. Financial factors included the percentages of revenues received from Medicaid, private insurance, criminal justice, the Federal block grant, state government, and county government. Organizational structure and workforce characteristics were also measured. RESULTS: Implementation of MAT for opioid use disorders was low. Greater reliance on Medicaid was positively associated with implementation after controlling for organizational structure and workforce measures, whereas the association for reliance on criminal justice revenues was negative. CONCLUSIONS: The implementation of MAT for opioid use disorders by specialty addiction treatment programs may be facilitated by Medicaid but may be impeded by reliance on funding from the criminal justice system. These findings point to the need for additional research that considers the impact of organizational dependence on different types of funding on patterns of addiction treatment practice. PMID- 22810058 TI - Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. AB - Early life experiences, including those in utero, have been linked to increased risk for adult-onset chronic disease. The underlying assumption is that there is a critical period of developmental plasticity in utero when selection of the fetal phenotype that is best adapted to the intrauterine environment occurs. The current study is the first to test the idea that extreme maternal psychosocial stressors, as observed in the Democratic Republic of Congo, may modify locus specific epigenetic marks in the newborn resulting in altered health outcomes. Here we show a significant correlation between culturally relevant measures of maternal prenatal stress, newborn birth weight and newborn methylation in the promoter of the glucocorticoid receptor NR3C1. Increased methylation may constrain plasticity in subsequent gene expression and restrict the range of stress adaptation responses possible in affected individuals, thus increasing their risk for adult-onset diseases. PMID- 22810059 TI - Metabolic potential of a single cell belonging to one of the most abundant lineages in freshwater bacterioplankton. AB - Actinobacteria within the acI lineage are often numerically dominating in freshwater ecosystems, where they can account for >50% of total bacteria in the surface water. However, they remain uncultured to date. We thus set out to use single-cell genomics to gain insights into their genetic make-up, with the aim of learning about their physiology and ecological niche. A representative from the highly abundant acI-B1 group was selected for shotgun genomic sequencing. We obtained a draft genomic sequence in 75 larger contigs (sum=1.16 Mb), with an unusually low genomic G+C mol% (~42%). Actinobacteria core gene analysis suggests an almost complete genome recovery. We found that the acI-B1 cell had a small genome, with a rather low percentage of genes having no predicted functions (~15%) as compared with other cultured and genome-sequenced microbial species. Our metabolic reconstruction hints at a facultative aerobe microorganism with many transporters and enzymes for pentoses utilization (for example, xylose). We also found an actinorhodopsin gene that may contribute to energy conservation under unfavorable conditions. This project reveals the metabolic potential of a member of the global abundant freshwater Actinobacteria. PMID- 22810060 TI - Taming the smallest predators of the oceans. AB - Protists (unicellular eukaryotes) arguably account for most eukaryotic diversity and are central players of the biosphere. Known protist diversity and biology is largely based on cultured strains. Yet, environmental molecular surveys have unveiled entirely novel lineages that, as their prokaryotic counterparts, are essentially uncultured. Culture bias is an important drawback for any microbe related science and is particularly severe for heterotrophic protists, which depend on organic food sources for growth. Here, we show how ecologically significant bacterivorous protists have been brought into culture by mimicking in situ conditions. Single cells sorted by serial dilution or flow cytometry were inoculated into seawater amended with natural bacterial assemblage at nearly in situ abundances. Strains belonging to lineages only known so far from environmental sequencing were isolated. Among them, Minorisa minuta gen. nov. sp. nov. forms a novel branch within Rhizaria, holding a key evolutionary position, and with an average size of 1.4 MUm represents one of the smallest bacterial grazers known to date. It has a worldwide planktonic distribution and can account for 5% of heterotrophic protists communities in coastal waters. Physiological features of this strain can partly explain its success in the environment. Culturing ecologically relevant but elusive protists provide invaluable material for ecophysiology, genomics, ecosystem modeling and evolutionary issues. PMID- 22810061 TI - Mechanisms determining the fate of dispersed bacterial communities in new environments. AB - Recent work has shown that dispersal has an important role in shaping microbial communities. However, little is known about how dispersed bacteria cope with new environmental conditions and how they compete with local resident communities. To test this, we implemented two full-factorial transplant experiments with bacterial communities originating from two sources (freshwater or saline water), which were incubated, separately or in mixes, under both environmental conditions. Thus, we were able to separately test for the effects of the new environment with and without interactions with local communities. We determined community composition using 454-pyrosequencing of bacterial 16S rRNA to specifically target the active fraction of the communities, and measured several functional parameters. In absence of a local resident community, the net functional response was mainly affected by the environmental conditions, suggesting successful functional adaptation to the new environmental conditions. Community composition was influenced both by the source and the incubation environment, suggesting simultaneous effects of species sorting and functional plasticity. In presence of a local resident community, functional parameters were higher compared with those expected from proportional mixes of the unmixed communities in three out of four cases. This was accompanied by an increase in the relative abundance of generalists, suggesting that competitive interactions among local and immigrant taxa could explain the observed 'functional overachievement'. In summary, our results suggest that environmental filtering, functional plasticity and competition are all important mechanisms influencing the fate of dispersed communities. PMID- 22810064 TI - Journal Information. PMID- 22810067 TI - Editor's Preface. PMID- 22810062 TI - Link between microbial composition and carbon substrate-uptake preferences in a PHA-storing community. AB - The microbial community of a fermented molasses-fed sequencing batch reactor (SBR) operated under feast and famine conditions for production of polyhydroxyalkanoates (PHAs) was identified and quantified through a 16 S rRNA gene clone library and fluorescence in situ hybridization (FISH). The microbial enrichment was found to be composed of PHA-storing populations (84% of the microbial community), comprising members of the genera Azoarcus, Thauera and Paracoccus. The dominant PHA-storing populations ensured the high functional stability of the system (characterized by high PHA-storage efficiency, up to 60% PHA content). The fermented molasses contained primarily acetate, propionate, butyrate and valerate. The substrate preferences were determined by microautoradiography-FISH and differences in the substrate-uptake capabilities for the various probe-defined populations were found. The results showed that in the presence of multiple substrates, microbial populations specialized in different substrates were selected, thereby co-existing in the SBR by adapting to different niches. Azoarcus and Thauera, primarily consumed acetate and butyrate, respectively. Paracoccus consumed a broader range of substrates and had a higher cell-specific substrate uptake. The relative species composition and their substrate specialization were reflected in the substrate removal rates of different volatile fatty acids in the SBR reactor. PMID- 22810068 TI - Clinical approach to peripheral neuropathy: anatomic localization and diagnostic testing. AB - PURPOSE OF REVIEW: This article provides a clinical approach to peripheral neuropathy based on anatomic localization and diagnostic testing. RECENT FINDINGS: Advances have been made in the evaluation of small fiber neuropathy and in the known genetic causes of neuropathy. SUMMARY: History and physical examination remain the most useful tools for evaluating peripheral neuropathy. Characterization of a neuropathy aids in limiting the differential diagnosis and includes consideration of temporal profile (tempo of onset and duration), heredity, and anatomic classification. Anatomic classification involves (1) fiber type (motor versus sensory, large versus small, somatic versus autonomic), (2) portion of fiber affected (axon versus myelin), and (3) gross distribution of nerves affected (eg, length-dependent, length-independent, multifocal). Diagnostic testing may include serologic and CSF evaluation, electrodiagnosis, skin biopsy, quantitative sensory testing, autonomic testing, nerve biopsy, confocal corneal microscopy, and laser Doppler imager flare. PMID- 22810069 TI - Charcot-Marie-Tooth disease and related genetic neuropathies. AB - PURPOSE OF REVIEW: The inherited peripheral neuropathies are a complex group of disorders caused by mutations in more than 50 genes. Scientifically, these disorders provide extensive information on molecular pathways that cause demyelination, axonal loss, and abnormal interactions between Schwann cells and the axons they ensheathe. Clinically, however, these neuropathies are confusing because it is difficult to determine what gene to test for in a given patient, inheritance patterns may differ among patients, and genetic testing is expensive. This review provides a biological context and guidelines to help neurologists better understand the basis and focus of genetic testing for these disorders. RECENT FINDINGS: In the past 5 years, many of the genetic causes of inherited neuropathies have been discovered and the phenotypes of inherited neuropathies have been characterized. Clinical trials of genetic neuropathies are now underway. SUMMARY: It is hoped that this review will lead to a better understanding of these fascinating neuropathies for health care professionals and that this improved understanding will facilitate treatment advances for these presently untreatable diseases. PMID- 22810070 TI - Diabetic neuropathy. AB - PURPOSE OF REVIEW: Diabetes is the most common cause of peripheral neuropathy in the world. More than half of patients with diabetes have neuropathy, and half of patients with neuropathy have diabetes. Diabetic neuropathy is a major cause of disability and health care expense. This article reviews the various forms of diabetic neuropathy with a focus on diagnosis and treatment. RECENT FINDINGS: Diabetes causes a wide variety of peripheral nerve problems. These can be divided into chronic neuropathies, of which distal symmetric polyneuropathy is the most common, and acute neuropathies, such as diabetic amyotrophy. There is growing evidence suggesting that prediabetic levels of hyperglycemia and other consequences of obesity and dyslipidemia contribute to neuropathy risk. Evolving literature suggests that many of the acute diabetic neuropathies are related to inflammatory mechanisms. An important exception is treatment-related neuropathy, previously known as "insulin neuritis". SUMMARY: While disease-altering therapy continues to prove elusive, our understanding of basic disease mechanisms is improving, and new diagnostic and research tools will hopefully lead to novel therapies for distal symmetric diabetic polyneuropathy. PMID- 22810071 TI - Immune-mediated neuropathies. AB - PURPOSE OF REVIEW: The immune-mediated neuropathies are an important group of treatable neuropathies that often lead to severe neurologic disability. This review guides clinicians in the recognition and treatment of these disorders. RECENT FINDINGS: Advances include new insights in classification and new treatment paradigms in many of these disorders. SUMMARY: Proper diagnosis and treatment require recognition of the characteristic clinical and laboratory findings and the use of appropriate electrophysiologic or pathologic examination. With proper treatment, partial or complete remission is possible, even in patients who are severely affected. PMID- 22810072 TI - Painful small fiber neuropathies. AB - PURPOSE OF REVIEW: This article reviews the clinical features, pathophysiology, and treatment of small fiber sensory neuropathy. RECENT FINDINGS: Neuropathic pain is prevalent among patients with peripheral neuropathies of diverse etiologies. For example, in one recent study using the sensitive Neuropathic Pain Symptom Inventory as a screening tool, neuropathic pain was reported in 94% of patients with different peripheral nervous system diseases. Neuropathic pain is frequently underrecognized or inadequately treated. Furthermore, the paucity of clinical signs with small fiber neuropathy may delay recognition of an organic process. Pain, or uncomfortable symptoms, typically results from damage to small unmyelinated nerve fibers (C fibers) or thinly myelinated nerve fibers (A delta fibers). Recent research has helped discover the location of the "pain generators" within the injured peripheral nerves. Small fiber neuropathies are relatively common in clinical practice, but until recently most of the available neurodiagnostic tests focused on large caliber nerve fibers. In the past two decades, the widespread use of quantitative sensory testing and punch skin biopsies to evaluate small caliber nerve fibers has substantially changed the neurologist's ability to diagnose and manage small fiber sensory neuropathy. SUMMARY: Neuropathic pain from small fiber neuropathy is prevalent and is caused by a wide variety of disorders, many of which are treatable, especially if recognized early in the process. PMID- 22810073 TI - Infectious neuropathies. AB - PURPOSE OF REVIEW: The purpose of this review is to address bacterial, viral, and other infectious causes of neuropathy or neuronopathy, with an emphasis on clinical manifestations and treatment. RECENT FINDINGS: Most infectious neuropathies have been well described for some time and treatments are well established. An exception is HIV-associated distal symmetric polyneuropathy, which is an area of active research. Current work in this area focuses on epidemiology, risk factors, and underlying mechanisms. SUMMARY: Infectious diseases are an important part of the differential diagnosis of peripheral nerve disorders because they are among the most amenable to treatment. However, diagnosis of infectious peripheral neuropathy may be challenging because of variability in a number of factors, including the pattern of deficits, geographic distribution of pathogens, length of time from the onset of infection to the development of neuropathy, and mechanism of nerve injury. PMID- 22810074 TI - Medication, toxic, and vitamin-related neuropathies. AB - PURPOSE OF REVIEW: Although medication, toxic, and vitamin-related neuropathies are rare causes of neuropathy, they are important to recognize because they are treatable and preventable. It is often difficult to conclusively demonstrate that a particular agent is the cause of neuropathy, but understanding the specific electrodiagnostic and clinical patterns produced by these agents is critical for making these assessments. RECENT FINDINGS: The clinical and electrodiagnostic features for many of these neuropathies have been well established. The exact mechanism by which some of these agents produce neuropathy is only now beginning to be revealed. These mechanisms are critical for both understanding the normal function of nerves as well as eventually devising specific treatments. SUMMARY: A large number of medications and toxins can produce neuropathy. This article reviews the clinical characteristics, electrodiagnostic features, and mechanism of action (when known) of those agents that produce the most severe, or perhaps the most unique features of, neuropathy. PMID- 22810075 TI - Neuropathic pain: mechanisms, therapeutic approach, and interpretation of clinical trials. AB - PURPOSE OF REVIEW: Neuropathic pain (NP) is caused by a lesion of the somatosensory system and is characterized by a combination of positive symptoms (ongoing pain, paroxysmal pain, evoked pain) and negative phenomena (sensory deficit in the painful area). Examples of NP include painful diabetic and nondiabetic neuropathies, postherpetic neuralgia, traumatic nerve lesions, radiculopathies, and central pain (eg, spinal cord injury pain, poststroke pain). This review presents the mechanisms and therapeutic options for NP. RECENT FINDINGS: Consensus recommendations for the treatment of NP or of some neuropathic conditions propose using antidepressants, antiepileptics, and topical lidocaine as first-line treatment and using tramadol and other opioids as second- or third-line treatment. Clinical advances in the management of NP include the implementation of comparative studies and combination therapy trials, the study of rarer and often neglected NP conditions, and the identification of responder profiles based on a detailed characterization of symptoms and signs using sensory examination and specific pain questionnaires. SUMMARY: The management of patients with chronic NP is challenging because of the multiplicity of mechanisms involved in NP conditions. Evidence-based recommendations for the pharmacologic treatment of NP have recently been proposed. PMID- 22810076 TI - Opioid administration for severe neuropathic pain in a patient with depression and prior heroin use. AB - The treatment of pain can raise ethical dilemmas. This article presents a case of a young woman with a pain crisis from severe neuropathic pain that is complicated by comorbidities of depression and prior (but not active) heroin use. Medical and ethical justifications for either withholding or providing opioids for her pain are examined. State and federal laws governing opioid prescriptions by physicians for pain management are reviewed. PMID- 22810077 TI - Difficult decisions: managing chronic neuropathic pain with opioids. AB - The decision to use opioids to treat chronic neuropathic pain is complex and somewhat controversial. Although opioid therapy may be appropriate for some patients with chronic neuropathic pain, physicians must implement strategies to reduce opioid abuse, addiction, and diversion. The decision to use chronic opioids should be made proactively with institution of best practices to ensure safe and effective use. As with all aspects of chronic pain management, better education of both health care providers and patients is necessary. Fortunately, specific recommendations for the safe and effective use of opioids are now available in several recently published guidelines. The best practices embodied in these guidelines should be considered for widespread adoption by both individual providers and health care systems. PMID- 22810078 TI - Coding issues. AB - Accurate coding is an important function of neurologic practice. This section of CONTINUUM, contributed by members of the AAN Medical Economics and Management Committee, includes helpful coding information and examples related to the issue topic. This section may include diagnosis coding, evaluation and management coding, procedure coding, or a combination, depending on which is most useful for the subject area of the issue. PMID- 22810079 TI - Guidelines in practice: treatment of painful diabetic neuropathy. AB - This article describes a patient with a painful diabetic peripheral neuropathy. Features of his history, examination, and diagnostic workup are presented. His treatment course is described as guided by the AAN's evidence-based guideline on the treatment of painful diabetic neuropathy. Lastly, features of coding for diabetic peripheral neuropathy are reviewed. PMID- 22810081 TI - Multiple-Choice Questions. PMID- 22810082 TI - Multiple-Choice Questions--Preferred Responses. PMID- 22810084 TI - Patient Management Problem--Preferred Responses. PMID- 22810083 TI - Patient Management Problem. PMID- 22810086 TI - IDN2 has a role downstream of siRNA formation in RNA-directed DNA methylation. AB - In plants, a particular class of short interfering (si)RNAs can serve as a signal to induce cytosine methylation at homologous genomic regions. If the targeted DNA has promoter function, this RNA-directed DNA methylation (RdDM) can result in transcriptional gene silencing (TGS). RNA-directed transcriptional gene silencing (RdTGS) of transgenes provides a versatile system for the study of epigenetic gene regulation. We used transcription of a nopaline synthase promoter (ProNOS) inverted repeat (IR) to provide a RNA signal that triggers de novo cytosine methylation and TGS of a homologous ProNOS copy in trans. Utilizing a ProNOS NPTII reporter gene showing high sensitivity to silencing in this two component system, a forward genetic screen for EMS-induced no rna-directed transcriptional silencing (nrd) mutations was performed in Arabidopsis thaliana. Three nrd mutant lines were found to contain one novel loss-of-function allele of idn2/rdm12 and two of nrpd2a/nrpe2a. IDN2/RDM12 encodes a XH/XS domain protein that is able to bind double-stranded RNA with 5' overhangs, while NRPD2a/NRPE2a encodes the common second-largest subunit of the plant specific DNA-dependent RNA polymerases IV and V involved in silencing processes. Both idn2/rdm12 and nrpd2a/nrpe2a release target transgene expression and reduce CHH context methylation at transgenic as well as endogenous RdDM target regions to similar extents. Nevertheless, accumulation of IR-derived siRNA is not affected, allowing us to present a refined model for the pathway of RdDM and RdTGS that positions function of IDN2 downstream of siRNA formation and points to an important role for its XH domain. PMID- 22810087 TI - Histological type is not an independent prognostic factor for the risk pattern of breast cancer recurrences. AB - Invasive lobular breast cancer (ILC) is less common than invasive ductal breast cancer (IDC) and appears to have a distinct biology. Inconsistent findings regarding disease-free survival (DFS) are probably due to the fact that histologic type is related to hormone receptor status. This study aims to determine whether the type of the primary breast cancer histology is an independent prognostic factor for DFS, the risk pattern of loco-regional recurrences and distant metastases (DM), and whether it is a prognostic factor for the site of DM. All Dutch women diagnosed between 2003 and 2005 with ILC (n = 2,949) or IDC (n = 22,378) were selected from the Netherlands Cancer Registry. DFS was assessed using proportional hazard regression analysis. Compared to patients with IDC, those with ILC were significantly older and more likely to have more than three positive lymph nodes and have larger, better differentiated, more multifocal, and hormone receptor positive tumors (all P < 0.001). ILC was more likely to metastasize to the gastrointestinal organs and bones and less likely to the lung, central nervous system, and lymph nodes. Within the ER+PR+ and ER+PR- subgroups ILC was still more likely to metastasize to gastrointestinal organs and less likely to the lung. The timing of recurrence was correlated to hormone receptor status, independent of histological type. Highest risks were observed among ER-PR- patients within 2 years of surgery. Multivariable analysis showed that histological type is not an independent significant prognostic factor of DFS for the first 3 years post-surgery and thereafter (<3 years HR 0.91, 95 % CI 0.78-1.06, >3 years HR 1.07, 95 % CI 0.88-1.30). Histological type should not be considered an important prognostic factor for the risk and risk pattern of recurrences. PMID- 22810089 TI - Co-ordination of physiological and morphological responses of stomata to elevated [CO2] in vascular plants. AB - Plant stomata display a wide range of short-term behavioural and long-term morphological responses to atmospheric carbon dioxide concentration ([CO(2)]). The diversity of responses suggests that plants may have different strategies for controlling gas exchange, yet it is not known whether these strategies are co ordinated in some way. Here, we test the hypothesis that there is co-ordination of physiological (via aperture change) and morphological (via stomatal density change) control of gas exchange by plants. We examined the response of stomatal conductance (G(s)) to instantaneous changes in external [CO(2)] (C(a)) in an evolutionary cross-section of vascular plants grown in atmospheres of elevated [CO(2)] (1,500 ppm) and sub-ambient [O(2)] (13.0 %) compared to control conditions (380 ppm CO(2), 20.9 % O(2)). We found that active control of stomatal aperture to [CO(2)] above current ambient levels was not restricted to angiosperms, occurring in the gymnosperms Lepidozamia peroffskyana and Nageia nagi. The angiosperm species analysed appeared to possess a greater respiratory demand for stomatal movement than gymnosperm species displaying active stomatal control. Those species with little or no control of stomatal aperture (termed passive) to C(a) were more likely to exhibit a reduction in stomatal density than species with active stomatal control when grown in atmospheres of elevated [CO(2)]. The relationship between the degree of stomatal aperture control to C(a) above ambient and the extent of any reduction in stomatal density may suggest the co-ordination of physiological and morphological responses of stomata to [CO(2)] in the optimisation of water use efficiency. This trade-off between stomatal control strategies may have developed due to selective pressures exerted by the costs associated with passive and active stomatal control. PMID- 22810088 TI - Epigenetics: the missing link to understanding beta-cell dysfunction in the pathogenesis of type 2 diabetes. AB - Type 2 diabetes (T2D) is a growing health problem worldwide. While peripheral insulin resistance is common during obesity and aging in both animals and people, progression to T2D is largely due to insulin secretory dysfunction and significant apoptosis of functional beta-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and nutrition play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular mechanisms by which these factors trigger beta-cell dysfunction and diabetes is still limited. Recent discoveries raise the possibility that epigenetic changes in response to environmental stimuli may play an important role in the development of diabetes. In this paper, we review emerging knowledge regarding epigenetic mechanisms that may be involved in beta cell dysfunction and pathogenesis of diabetes, including the role of nutrition, oxidative stress and inflammation. We will mainly focus on the role of DNA methylation and histone modifications but will also briefly review data on miRNA effects on the pancreatic islets. Further studies aimed at better understanding how epigenetic regulation of gene expression controls beta-cell function may reveal potential therapeutic targets for prevention and treatment of diabetes. PMID- 22810090 TI - Increase in platelet immunoglobulin in Alzheimer's disease is normalised following cholinesterase inhibitor treatment: preliminary results. AB - We report a 16.5% increase in platelet immunoglobulin (Ig) content in subjects with Alzheimer's disease (AD) in relation to cognitively intact individuals (p = 0.021), whereas the plasma Ig levels were unaltered (p = 0.428). The upregulation of platelet Ig was not explained by age, duration of dementia, or degree of cognitive impairment. However, AD subjects treated with cholinesterase inhibitors (n = 21) had lower levels of platelet Ig (p = 0.009) than AD subjects not treated with anti-dementia drugs (n = 4) and similar to those of control subjects (n = 24; p = 0.069). The anti-dementia treatment did not influence the plasma Ig levels (p = 0.177). These preliminary findings require further confirmation in studies on larger number of AD subjects with various stages of cognitive impairment, and who would be assessed prior to initiation of and during cholinesterase inhibitor treatment. PMID- 22810091 TI - The Alzheimer myth and biomarker research in dementia. AB - The focus of most of the research on Alzheimer's disease in the last decades has been on senile plaques and neurofibrillary tangles. The vast majority of patients with Alzheimer's disease are over 75 years of age, whereas most of the research focuses on younger subjects. To consider old-age dementia as a homogenous well defined condition ignores the complexity of this condition and limits the development of new diagnostic methods, preventive strategies, or treatment strategies that could be widely applicable in daily practice in the majority of the older patients. The current research on biomarkers focuses on correlates of plaques and tangles, which are poor markers in older dementia subjects. Acknowledging that dementia in old age is an essentially different condition from dementia at relatively younger age is needed and should lead to new approaches in dementia research. PMID- 22810092 TI - 5-HT4 receptor stimulation leads to soluble AbetaPPalpha production through MMP-9 upregulation. AB - Serotonin 4 (5-HT4) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer's disease (AD) through regulation of the production of soluble amyloid beta protein precursor alpha (sAbetaPPalpha). To analyze the relationship between 5-HT4 receptor signaling and sAbetaPPalpha production, we stably transfected H4 cells with AbetaPP and 5-HT4 receptor (H4/AbetaPP/5-HT4 cells). We found that 24 h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sAbetaPPalpha levels, whereas knockdown with MMP-9 siRNA decreased sAbetaPPalpha levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid beta peptide (Abeta) deposition, there was an increase in hippocampal levels of sAbetaPPalpha, C-terminal fragment alpha, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, Abeta40. Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves AbetaPP through alpha secretase-like activity, leading to an increase of sAbetaPPalpha levels and a reduction of Abeta load. PMID- 22810093 TI - Delayed audiovisual integration of patients with mild cognitive impairment and Alzheimer's disease compared with normal aged controls. AB - The human brain can anatomically combine task-relevant information from different sensory pathways to form a unified perception; this process is called multisensory integration. The aim of the present study was to test whether the multisensory integration abilities of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) differed from those of normal aged controls (NC). A total of 64 subjects were divided into three groups: NC individuals (n = 24), MCI patients (n = 19), and probable AD patients (n = 21). All of the subjects were asked to perform three separate audiovisual integration tasks and were instructed to press the response key associated with the auditory, visual, or audiovisual stimuli in the three tasks. The accuracy and response time (RT) of each task were measured, and the RTs were analyzed using cumulative distribution functions to observe the audiovisual integration. Our results suggest that the mean RT of patients with AD was significantly longer than those of patients with MCI and NC individuals. Interestingly, we found that patients with both MCI and AD exhibited adequate audiovisual integration, and a greater peak (time bin with the highest percentage of benefit) and broader temporal window (time duration of benefit) of multisensory enhancement were observed. However, the onset time and peak benefit of audiovisual integration in MCI and AD patients occurred significantly later than did those of the NC. This finding indicates that the cognitive functional deficits of patients with MCI and AD contribute to the differences in performance enhancements of audiovisual integration compared with NC. PMID- 22810094 TI - Cerebral blood flow regulation by nitric oxide in Alzheimer's disease. AB - Cerebral hypoperfusion due to impaired bioavailability of nitric oxide (NO) synthesized by endothelial nitric oxide synthase and neuronal nitric oxide synthase leads to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Risk factors for endothelial dysfunction, such as inadequate lifestyle, cardiovascular/metabolic diseases, and aging, evokes cerebral hypoperfusion, impaired autoregulation, and increased production of amyloid-beta peptides (Abeta) in association with vasculogenic memory loss and dementia. Decrease in parasympathetic nitrergic nerve activity also plays a role in cerebral hypoperfusion. Abeta is a functional obstacle to NO-mediated vasodilatation; therefore, it decreases cerebral blood flow. Generation of reactive oxygen species by Abeta is a major action in promoting NO degradation. Effective strategies for the prophylaxis or treatment of AD includes acetylcholinesterase inhibitors, drugs acting on the NO-cyclic GMP signaling pathway, antioxidants, peroxisome proliferator-activated receptor gamma-agonists, and hydroxymethylglutaryl-CoA reductase inhibitors. Here our hypothesis about the mechanisms underlying the actions of acetylcholinesterase inhibitors in relation to NO-mediated cerebral blood flow is presented. Future detailed analyses of the relationship between cerebral blood flow regulation by constitutive NO and cognitive decline/neurodegeneration will provide clues for developing novel prophylactic measures and therapeutic means to alleviate AD. PMID- 22810095 TI - Modifiable vascular markers for cognitive decline and dementia: the importance of arterial aging and hemodynamic factors. AB - Uncovering modifiable predictors of cognitive decline and dementia is crucial for early detection and prevention. Although high mid-life brachial blood pressure is considered a risk factor for later-life cognitive impairment, other non-invasive indices of arterial health, closely associated with aging, may improve risk stratification. This review discusses the contribution of vascular aging to cognitive decline, dementia, and brain pathology. Modifiable vascular markers are evaluated with respect to their prognostic value and ease of measurement. The notion of mitigating cognitive decline through improving cardiovascular health is also discussed. Anticipated mechanisms imply causal pathways between large artery stiffness, pulsatile pressures, and cognitive impairment through damage to small cerebral vessels. Accumulating evidence from human clinical studies now supports this mechanistic understanding. Aortic stiffness, measured as carotid-femoral pulse wave velocity, has been shown to predict cognitive decline in numerous studies. Aortic and carotid pulsatile pressures are also associated with cognitive impairment and brain pathology. Clinical evidence linking large arterial aging to dementia and associated pathology is scarce and requires further investigation. Future research is also required to investigate the extent to which the risk of cognitive decline can be perturbed by interventions that improve arterial health. PMID- 22810096 TI - Age-related cognitive decline in hypercholesterolemic LDL receptor knockout mice (LDLr-/-): evidence of antioxidant imbalance and increased acetylcholinesterase activity in the prefrontal cortex. AB - There is increasing evidence that hypercholesterolemia during midlife may represent a predictor of subsequent mild cognitive impairments and dementia decades later. However, the exact mechanism underlying this phenomenon remains unknown since plasmatic cholesterol is not able to cross the blood-brain barrier. In the present study, we evaluated the hypothesis that cognitive impairments triggered by hypercholesterolemia during aging may be related to brain oxidative stress and altered brain acetylcholinesterase (AChE) activity. We also performed a neuropathological investigation in order to analyze whether the cognitive impairments may be associated with stroke-related features. To address these questions we used three- and fourteen-month-old low-density lipoprotein receptor deficient mice (LDLr-/-). The current findings provide new evidence that aged LDLr-/- mice, exposed to over three-fold cholesterol levels from early life, show working, spatial reference, and procedural memory impairments, without alterations in motor function. Antioxidant imbalance and oxidative damage were evidenced by a marked increase in lipid peroxidation (thiobarbituric acid reactive substances levels) and glutathione metabolism (increase in glutathione levels, glutathione reductase, and glutathione peroxidase activities) together with a significant increase in the AChE activity in the prefrontal cortex of aged hypercholesterolemic LDLr-/- mice. Notably, hypercholesterolemia was not related to brain infarcts and neurodegeneration in mice, independent of their age. These observations provide new evidence that hypercholesterolemia during aging triggers cognitive impairments on different types of learning and memory, accompanied by antioxidant imbalance, oxidative damage, and alterations of cholinergic signaling in brain areas associated with learning and memory processes, particularly in the prefrontal cortex. PMID- 22810097 TI - Transforming growth factor beta1 modulates amyloid beta-induced glial activation through the Smad3-dependent induction of MAPK phosphatase-1. AB - Chronic neuroinflammation has been proposed as a driving force for Alzheimer's disease (AD), which is characterized by amyloid-beta (Abeta) deposition, neurofibrillary tangles, neuronal loss, and activation of glial cells. Persistent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) pathway has been reported, which induces an increased expression of inflammatory mediators. Transforming growth factor beta1 (TGFbeta1) is an inflammation modulator whose levels are increased in AD. However, its canonical signaling pathway, Smad, appears to be impaired. Our previous findings indicate that TGFbeta1 plays a key role in the pathogenesis of neuroinflammation, but the molecular mechanisms underlying its effects are not completely elucidated. Here, we studied the potential role of MKP-1, a phosphatase that exerts negative regulation on MAPK signaling, in the modulatory actions of TGFbeta1. Using rat primary glial cultures, we found that pretreatment with TGFbeta1 for 48 h reduced the production of inflammatory mediators induced by Abeta42, a result that was associated with prevention of MAPK p38 activation, attenuation of NF-kappaB p65 nuclear translocation, and an increase in MKP-1 levels. Moreover, suppression of MKP-1 expression by siRNA and inhibition of Smad3 reversed the modulation of inflammatory response exerted by TGFbeta1. These results indicate that TGFbeta1 induces the expression of MKP-1 in glial cells through the Smad pathway and inhibits MAPK and NF-kappaB signaling, thus revealing a novel mechanism for the neuroprotective actions of TGFbeta1. Further research would be important in order to characterize the role of this mechanism in the pathogenesis of AD. PMID- 22810098 TI - Walking the cognitive "minefield" between high and low blood pressure. AB - Vascular risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). There is an age-dependent relationship between blood pressure and the risk of AD. Given the potential temporal lag that can exist between the two conditions, longitudinal population studies offer the best opportunity to identify a causal relationship. Midlife hypertension increases the risk for AD, yet later-life hypertension does not appear to confer the same risk and may in fact be protective. Low diastolic blood pressure, especially in later-life, is associated with an increased risk of AD. Orthostatic hypotension and other neurocardiovascular syndromes may increase the risk for cognitive impairment and AD. Several physiopathological mechanisms may contribute to this increased risk. Dynamic blood pressure changes and impaired cerebrovascular autoregulation may result in cerebral hypoperfusion. Hypertensive patients also develop cerebral infarcts, resulting in diminished perfusion. Subsequent hypoxia driven pathways result in increased cerebral amyloid-beta and phosphorylated tau protein accumulation. Treatment of elevated blood pressure with antihypertensive medications attenuates the risk of AD attributable to elevated midlife hypertension. Certain antihypertensive compounds have neuroprotective properties that may reduce the risk of AD, independent of their effects on blood pressure. PMID- 22810099 TI - Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. AB - High caloric intake has been associated with an increased risk of cognitive impairment. Total caloric intake is determined by the calories derived from macronutrients. The objective of the study was to investigate the association between percent of daily energy (calories) from macronutrients and incident mild cognitive impairment (MCI) or dementia. Participants were a population-based prospective cohort of elderly persons who were followed over a median 3.7 years (interquartile range, 2.5-3.9) of follow-up. At baseline and every 15 months, participants (median age, 79.5 years) were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of MCI, normal cognition, or dementia. Participants also completed a 128-item food-frequency questionnaire at baseline; total daily caloric and macronutrient intakes were calculated using an established database. The percent of total daily energy from protein (% protein), carbohydrate (% carbohydrate), and total fat (% fat) was computed. Among 937 subjects who were cognitively normal at baseline, 200 developed incident MCI or dementia. The risk of MCI or dementia (hazard ratio, [95% confidence interval]) was elevated in subjects with high % carbohydrate (upper quartile: 1.89 [1.17-3.06]; p for trend = 0.004), but was reduced in subjects with high % fat (upper quartile: 0.56 [0.34-0.91]; p for trend = 0.03), and high % protein (upper quartile 0.79 [0.52-1.20]; p for trend = 0.03) in the fully adjusted models. A dietary pattern with relatively high caloric intake from carbohydrates and low caloric intake from fat and proteins may increase the risk of MCI or dementia in elderly persons. PMID- 22810100 TI - Alzheimer's disease: recent advances and future perspectives. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterized by the progressive loss of basal forebrain cholinergic neurons that innervate the hippocampus and cortex and the abnormal extracellular accumulation of amyloid-beta and intracellular tau protein. Current research on AD is focused on the mechanisms underlying the abnormal oligomerization, fibrillation, and accumulation of the amyloid-beta and tau proteins, mechanisms that may alter the dynamics of this accumulation and on experimental therapeutics approaches aimed at the clearance of the abnormally folded proteins and other potentially neuroprotective interventions. This review will summarize the main areas of investigation in AD and present ways forward for future work. PMID- 22810101 TI - Visuospatial perception: an emerging biomarker for Alzheimer's disease. AB - In recent years, the focus of research on Alzheimer's disease (AD) has shifted toward finding reliable diagnostic biomarkers that enable accurate detection of mild cognitive impairment (MCI) as well as AD. Functional magnetic resonance imaging (fMRI) has the potential to identify functional changes in the preclinical stages of AD. In addition to the cardinal deficits in memory, deficits in visuospatial cognition are pervasive in AD. Recent neurophysiological and imaging studies have revealed that changes in visuospatial perception (VSP) functions can be detected in the early stages of AD. This review highlights the scope of VSP functional alterations as a biomarker for AD. We describe the neuroanatomical regions involved in the processing of various VSP tasks, and discuss the effect of AD on these regions from a pathological as well as a functional point of view. A comprehensive synopsis of the existing fMRI literature that has assessed VSP in patients with MCI and AD has been provided. The diagnostic scope of monitoring the brain activation correlates of VSP processing in AD is discussed in terms of the key advantages of utilizing VSP related deficits in AD for early detection and longitudinal tracking of AD. PMID- 22810102 TI - Highly pathogenic Alzheimer's disease presenilin 1 P117R mutation causes a specific increase in p53 and p21 protein levels and cell cycle dysregulation in human lymphocytes. AB - Cell cycle (CC) reentry in neurons precedes the formation of amyloid-beta (Abeta) plaques in Alzheimer's disease (AD). CC alterations were also detected in lymphocytes from sporadic AD patients. In the present study, we investigated the influence of nine presenilin 1 (PS1) mutations (P117R, M139V, L153V, H163R, S170F, F177L, I213F, L226F, E318G) on CC and Abeta production in immortalized B lymphocytes from familial AD (FAD) patients and in stably transfected human embryonic kidney cells. In both cell types, only the P117R mutation increased levels of key G1/S phase regulatory proteins, p53, and its effector p21, causing G1 phase prolongation with simultaneous S phase shortening, and lowering basal apoptosis. The CC changes were rescued by inhibition of p53, but not of gamma secretase. Moreover, the investigated PS1 mutants showed differences in the increased levels of secreted Abeta40 and Abeta42 and in Abeta42/Abeta40 ratios, but these differences did not correlate with CC patterns. Altogether, we found that both CC regulation and Abeta production differentiate PS1 mutations, and that CC PS1 activity is mediated by p53/p21 signaling but not by gamma-secretase activity. The identified CC dysregulation linked with increased p53 and p21 protein levels distinguishes the highly pathogenic PS1 P117R mutation and may contribute to the specific severity of the clinical progression of FAD associated with the mutation in the PS1 117 site. These findings suggest that impairment in lymphocyte CC might play a pathogenic function in AD and are relevant to the development of new diagnostic approaches and personalized therapeutic strategies. PMID- 22810103 TI - Transcranial electromagnetic treatment against Alzheimer's disease: why it has the potential to trump Alzheimer's disease drug development. AB - The universal failure of pharmacologic interventions against Alzheimer's disease (AD) appears largely due to their inability to get into neurons and the fact that most have a single mechanism-of-action. A non-invasive, neuromodulatory approach against AD has consequently emerged: transcranial electromagnetic treatment (TEMT). In AD transgenic mice, long-term TEMT prevents and reverses both cognitive impairment and brain amyloid-beta (Abeta) deposition, while TEMT even improves cognitive performance in normal mice. Three disease-modifying and inter related mechanisms of TEMT action have been identified in the brain: 1) anti Abeta aggregation, both intraneuronally and extracellularly; 2) mitochondrial enhancement; and 3) increased neuronal activity. Long-term TEMT appears safe in that it does not impact brain temperature or oxidative stress levels, nor does it induce any abnormal histologic/anatomic changes in the brain or peripheral tissues. Future TEMT development in both AD mice and normal mice should involve head-only treatment to discover the most efficacious set of parameters for achieving faster and even greater cognitive benefit. Given the already extensive animal work completed, translational development of TEMT could occur relatively quickly to "proof of concept" AD clinical trials. TEMT's mechanisms of action provide extraordinary therapeutic potential against other neurologic disorders/injuries, such as Parkinson's disease, traumatic brain injury, and stroke. PMID- 22810104 TI - Aging affects the proportions of T and B cells in a group of elderly men in a developing country--a pilot study from Pakistan. AB - Immune status is different in the elderly and the young, but whether age associated differences are similar in developing and industrialized countries is unclear. To approach this question, peripheral blood immune cell phenotypes were analyzed by polychromatic flow cytometry in 50 young and 50 elderly men in a pilot study in a rural area of Pakistan. As a group, the elderly had a significantly lower CD4:CD8 ratio, a lower percentage of CD8+ naive T cells, and significantly higher percentage of late-differentiated memory cells than the young. No age-associated differences were seen in B cells or NK cells. CD8+ cells as a percentage of CD3+ T cells were positively associated with plasma CRP levels but not other factors. We conclude that there are differences between the peripheral immune cell phenotypes of young and elderly Pakistani men and that these seem broadly similar to those more extensively documented in industrialized countries, despite the marked societal, nutritional, and many other differences in these populations. PMID- 22810105 TI - Association of the MEFV gene variations with inflammatory bowel disease in Turkey. AB - BACKGROUND: Association of NOD2 (CARD15) gene mutations with inflammatory bowel diseases (IBD) is well known. We herein aimed to investigate the role of familial Mediterranean fever-associated MEFV variations in IBD patients as additional regional-specific risk factor. STUDY: One hundred thirty-seven (78 female, 56.9%) IBD patients [62 Crohn's disease (CD), 75 ulcerative colitis (UC)] were enrolled into the study. The diagnosis of all patients was confirmed by colonoscopy, histopathology, and the clinical findings. One hundred one healthy donors' samples were used as healthy controls. All patients were genotyped for the most common E148Q, M608I, M694V, and V726A variations of the MEFV and R702W, G908R, and 1007fs of the NOD2. RESULTS: The overall MEFV variation frequency was found to be higher in the IBD (25.5%) patients (28% in UC, 22.6% in CD) compared with controls (9.9%, P=0.006). This association was stronger with the penetrant exon 10 variations (M694V, M680I, V726A; odds ratio =4.5, P=0.001). Contribution of M694V was higher compared with the other variations (14.5% in CD, 17.3% in UC and 3% in controls, odds ratio =6.039, 95% confidence intervals, 1.7-20.7, P=0.002). The overall frequency of 3 NOD2 variants in the IBD group was not different from that of controls. CONCLUSIONS: The results of this study suggest that the MEFV variations may be an additional susceptibility factor for IBD in certain parts of the world where the carrier rate is high, and the genetic background of the IBD patients may show regional changes. PMID- 22810106 TI - The impact of ethnicity and obesity on the course of colonic diverticulitis. AB - BACKGROUND: Little research has been performed on the impact of race/ethnicity and obesity on the course of diverticulitis. PURPOSE: To determine whether patients of different racial/ethnic backgrounds and patients who are obese have disparate courses of disease with regard to complications, recurrence rates, and need for surgery. METHODS: We conducted a retrospective review of the charts of 347 patients with confirmed diverticulitis in 2 university teaching hospitals at Bronx, NY. RESULTS: African Americans were more likely [odds ratio (OR), 2.28, 95% confidence interval (CI), 1.04-5.00, P = 0.04] and Hispanics were less likely than other racial/ethnic groups (OR, 0.47; 95% CI, 0.22-0.97; P = 0.04) to require surgery for recurrent diverticulitis after at least 1 medically managed hospital admission for diverticulitis. Caucasians were less likely than other racial/ethnic groups to suffer a recurrence of diverticulitis (OR, 0.48; 95% CI, 0.27-0.86; P = 0.01). Obese patients [ body mass index (BMI) >30] were more likely than nonobese patients to experience a recurrent episode of diverticulitis (OR, 1.69; 95% CI, 1.08-2.64; P = 0.02). The odds of requiring surgery on the initial presentation of diverticulitis were not significantly different among the various races/ethnicities nor was the likelihood of surgery influenced by BMI. Complication rates did not differ significantly when patients were stratified by age, sex, race, BMI, or number of prior episodes of diverticulitis. CONCLUSIONS: Surgery for diverticulitis after at least 1 medically managed hospital admission for diverticulitis is more frequently needed in African Americans and less frequently needed in Hispanics. Caucasians are less likely than other races/ethnicities to suffer a recurrence of diverticulitis. Finally, obesity is a risk factor for recurrent diverticulitis, but not for surgical therapy of diverticulitis. PMID- 22810107 TI - The role of effective clinician-patient communication in the management of irritable bowel syndrome and chronic constipation. AB - Irritable bowel syndrome (IBS) and chronic constipation (CC) are common functional bowel disorders that are among the most frequent reasons for referral to a gastroenterologist. Diagnosis and management of these conditions can be challenging for both the clinician and the patient for a number of reasons. Diagnosis can be complicated by the lack of a specific diagnostic test and the fact that IBS and CC are multisymptomatic conditions, whereas management can be suboptimal, because the conditions are often undiagnosed and self-managed by the patient. Furthermore, these are chronic conditions that must be managed over the long term, which can often lead to frustration both on the part of the patient and the clinician. As such, the role of the therapeutic clinician-patient relationship in diagnosis and management of these conditions has been attracting increasing attention. A patient-centered approach with a strong focus on effective communication between the clinician and the patient has been recommended for management of functional bowel diseases such as IBS and CC and has been associated with improved outcomes, increased patient satisfaction, and decreased utilization of care. The potential benefit of such practices as asking open-ended questions, actively listening to the patient, and displaying empathy in strengthening the clinician-patient relationship are highlighted in this manuscript. These skills have broad application in clinical medicine and can be used to improve clinician-patient communication in the management of patients with chronic illnesses. PMID- 22810108 TI - Increased incidence of gastric cancer in renal transplant recipients. AB - OBJECTIVE: The risk of malignancy after transplantation is regarded to be higher than in the general population. The aim of this study was to evaluate the frequency of gastric cancer in renal transplant recipients. METHODS: A total of 820 renal transplantation recipients were invited for gastric cancer screening. Frequencies of gastric cancer in this cohort and in 10,080 asymptomatic subjects were compared. Cancer specimens were examined for Epstein-Barr virus by in situ hybridization. RESULTS: A total of 509 recipients (mean age, 48.1 +/- 10.7 y; men, 56.8%) participated. Fifteen (2.9%) and 10 (0.1%) cases of adenocarcinoma were identified among recipients and controls, respectively (P<0.001; odds ratio, 30.58). Early gastric cancer was detected in 9 of the 15 recipients, and 4 of the 9 were treated by endoscopic resection. Recipient age was found to be a significant factor of gastric cancer development. In cancer tissues, Epstein-Barr virus was detected in 5 (33.3%) renal recipients and in 1 (10%) of the controls, respectively. CONCLUSIONS: The frequency of gastric cancer was found to be higher in renal recipients than in controls. Gastric cancer screening should be considered after transplantation, because it would provide cure by minimally invasive treatment. PMID- 22810109 TI - How can we predict the presence of missed synchronous lesions after endoscopic submucosal dissection for early gastric cancers or gastric adenomas? AB - GOALS: To identify predictive factors associated with the presence of missed synchronous lesions after endoscopic submucosal dissection (ESD) for gastric adenoma or early gastric cancer (EGC). BACKGROUND: Secondary gastric neoplasms that develop during follow-up period after ESD for gastric adenoma or EGC are divided into metachronous lesions and missed synchronous lesions. METHODS: ESD was performed in 250 patients with EGC or gastric adenoma. The patients with endoscopic follow-ups of <1 year, patients without curative resection, and patients with additional surgery were excluded from the study. Missed synchronous lesions were defined as secondary gastric neoplasms detected within one year of ESD but initially missed. We compared clinicopathologic factors between patients with missed synchronous lesions and patients without missed synchronous lesions. RESULTS: Missed synchronous lesions were found in 11.6% of the patients (29/250). The occurrence of missed synchronous lesions had significant correlation with tumor number at the time of ESD and age in the univariate analysis. Tumor number at the time of ESD and age were significant independent predictive factors for presence of missed synchronous lesions by multivariate logistic regression analysis (odds ratio 5.302, P = 0.006; odds ratio 2.315, P = 0.040, respectively). Missed synchronous lesions tended to be smaller, often located in the same third of the stomach as the main lesions. CONCLUSIONS: Tumor number at the time of ESD and age could be predictive factors for the presence of missed synchronous lesions after ESD. Careful endoscopic surveillance should be performed after ESD for multiple lesions or for elderly patients. PMID- 22810110 TI - Comparison of hepatic venous pressure gradient and two models of end-stage liver disease for predicting the survival in patients with decompensated liver cirrhosis. AB - GOALS: We evaluated the efficacy of initial and follow-up hepatic venous pressure gradient (HVPG), models of end-stage liver disease (MELD), and MELD-Na for predicting the survival of patients with decompensated liver cirrhosis (LC). BACKGROUND: MELD with/without Na score and HVPG have been important predictors of mortality in patients with LC. STUDY: Between January 2006 and 2011, a total of 57 patients with decompensated LC, all of whom underwent >2 HVPG measurements for the confirmation of propranolol dosing, were enrolled. MELD and MELD-Na scores were calculated on the day of HVPG measurement. The prognostic accuracy of the initial and follow-up HVPG, MELD, and MELD-Na were analyzed, and independent factors for mortality were evaluated. RESULTS: Ten patients (17.5%) died from LC. Initial HVPG (0.883), initial MELD-Na (0.877), follow-up HVPG (0.829), and follow up MELD-Na (0.802) showed good area under the receiver operating characteristic curve scores in predicting 1-year mortality. In predicting 2-year mortality, only follow-up HVPG (0.821, cut-off value 18 mm Hg) showed good score. Overall area under the receiver operating characteristic curves (initial and follow-up) were 0.843 and 0.864 in HVPG, 0.721 and 0.674 in MELD, and 0.762 and 0.715 in MELD-Na, respectively. In the Cox regression analysis, only follow-up HVPG (P=0.02; odds ratio, 1.11) was associated with mortality. CONCLUSIONS: The efficacy of HVPG for predicting mortality is excellent compared with that of MELD or MELD-Na. Therefore, aside from the confirmation of adequate propranolol dosing, HVPG may be needed for predicting the survival of patients with decompensated LC. PMID- 22810111 TI - Biliary drainage in patients with unresectable, malignant obstruction where ERCP fails: endoscopic ultrasonography-guided choledochoduodenostomy versus percutaneous drainage. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography may fail because of malignant involvement of the second portion of the duodenum and the major papilla. Alternatives include percutaneous transhepatic biliary drainage (PTBD) or surgical bypass. Endoscopic ultrasonography-guided choledochoduodenostomy (EUS CD) has been reported as an alternative. OBJECTIVE: To prospectively compare EUS CD and PTBD in patients with unresectable malignant biliary obstruction. DESIGN: Prospective and randomized study. SETTING: Tertiary center. MAIN OUTCOME MEASUREMENTS: Success and efficacy comparison EUS-CD with PTBD. RESULTS: Twenty five subjects were randomized (13 EUS-CD and 12 PTBD). Mean age was 67 years (SD, 11.9). The 2 groups were similar before intervention in terms of quality of life [EUS-CD (58.3) vs. PTBD (57.8); P=0.78], total bilirubin (16.4 vs. 17.2; P=0.7), alkaline phosphatase (539 vs. 518; P=0.7), and gamma-glutamyl transferase (554.3 vs. 743.5; P=0.56). All procedures were technically and clinically successful in both groups. At 7-day follow-up there was a significant reduction in total bilirubin in both the groups (EUS-CD, 16.4 to 3.3; P=0.002 and PTBD, 17.2 to 3.8; P=0.01), although no difference was noted comparing the 2 groups (EUS-CD to PTBD; 3.3 vs. 3.8; P=0.2). There was no difference between the complication rates in the 2 groups (P=0.44), EUS-CD (2/13; 15.3%) and PTBD (3/12; 25%). Costs were similar in the 2 groups also ($5673-EUS-CD vs. $7570-PTBD; P=0.39). LIMITATIONS: Small sample size and single center study. CONCLUSIONS: EUS-CD can be an effective and safe alternative to PTBD with similar success, complication rate, cost, and quality of life. PMID- 22810112 TI - Association of common PAX9 variants with permanent tooth size variation in non syndromic East Asian populations. AB - Studies on the heredity of dental characteristics in humans have indicated that the variance in many dental traits results from genetic variation. However, the genetic factors that influence commonly occurring dental variants are poorly understood. Paired domain box 9 (PAX9) codes a transcription factor that is important in tooth development. We investigated whether PAX9 polymorphisms are associated with normal variations in tooth agenesis and morphology. The study subjects were 273 Japanese and 223 Korean adults. Single-nucleotide polymorphisms (SNPs) in PAX9 (rs2295222, rs4904155, rs2073244, rs12881240 and rs4904210) were genotyped, and third molar agenesis and mesiodistal and buccolingual diameters were measured. We found that four of the five SNPs were significantly associated with the crown size. However, no SNP was associated with third molar agenesis. In additional analyses on non-metric dental traits, we found significant associations of PAX9 SNPs with shoveling of upper first incisors. In summary, common variants in PAX9 contributed to morphological variation in permanent teeth in humans. PMID- 22810113 TI - On the Y-chromosome haplogroup C3c classification. AB - As there are ambiguities in classification of the Y-chromosome haplogroup C3c, relatively frequent in populations of Northern Asia, we analyzed all three haplogroup-defining markers M48, M77 and M86 in C3-M217-individuals from Siberia, Eastern Asia and Eastern Europe. We have found that haplogroup C3c is characterized by the derived state at M48, whereas mutations at both M77 and M86 define subhaplogroup C3c1. The branch defined by M48 alone would belong to subhaplogroup C3c*, characteristic for some populations of Central and Eastern Siberia, such as Koryaks, Evens, Evenks and Yukaghirs. Subhaplogroup C3c* individuals could be considered as remnants of the Neolithic population of Siberia, based on the age of C3c*-short tandem repeat variation amounting to 4.5 +/- 2.4 thousand years. PMID- 22810114 TI - Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. AB - The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia. This G deletion results in a frameshift mutation producing a premature stop codon in exon 25 of ALK tyrosine kinase domain. We also screened three human MB cell lines without finding any mutation of ALK gene. Quantitative expression analysis of 16 out of 52 samples showed overexpression of ALK mRNA in three MBs. In the present study, we report the first mutation of ALK found in MB. Moreover, a deletion of ALK gene producing a stop codon has not been detected in human tumors up to now. Further investigations are now required to elucidate whether the truncated form of ALK may have a role in signal transduction. PMID- 22810115 TI - Personalized treatment of alcohol dependence. AB - Pharmacogenetic and adaptive treatment approaches can be used to personalize care for alcohol-dependent patients. Preliminary evidence shows that variation in the gene encoding the MU-opioid receptor moderates the response to naltrexone when used to treat alcohol dependence. Studies have also shown moderating effects of variation in the gene encoding the serotonin transporter on response to serotonergic treatment of alcohol dependence. Adaptive algorithms that modify alcohol treatment based on patients' progress have also shown promise. Initial response to outpatient treatment appears to be a particularly important in the selection of optimal continuing care interventions. In addition, stepped-care algorithms can reduce the cost and burden of treatment while maintaining good outcomes. Finally, matching treatment to specific problems present at intake or that emerge during treatment can also improve outcomes. Although all of these effects require replication and further refinement, the future of personalized care for alcohol dependence appears bright. PMID- 22810116 TI - Pediatric psychopharmacology: context, model programs, and considerations for care. AB - Research indicates that one in five children and adolescents in the United States has a behavioral or emotional disorder and a substantial number use psychotropic medications. Pediatric primary care providers play an important role in prescribing and managing psychotropic medications. However, they face several challenges with respect to prescribing these medications, including training, confidence, and level of comfort. One way to meet these challenges is through comanagement of behavioral health care, including psychopharmacology, by pediatric primary care providers and child mental health care providers. The authors review literature on patterns of psychotropic medication prescribing for children and adolescents and the role of pediatric primary care providers. They describe two statewide models that were developed to improve pediatric primary care providers' ability to treat patients with behavioral health needs, including prescribing psychotropic medications, by linking them to support from child mental health providers. The authors conclude with recommendations to improve professional training and collaboration. PMID- 22810117 TI - Solvent-dependent modulation of metal-metal electronic interactions in a dinuclear cyanoruthenate complex: a detailed electrochemical, spectroscopic and computational study. AB - The dinuclear complex [{Ru(CN)(4)}(2)(MU-bppz)](4-) shows a strongly solvent dependent metal-metal electronic interaction which allows the mixed-valence state to be switched from class 2 to class 3 by changing solvent from water to CH(2)Cl(2). In CH(2)Cl(2) the separation between the successive Ru(II)/Ru(III) redox couples is 350 mV and the IVCT band (from the UV/Vis/NIR spectroelectrochemistry) is characteristic of a borderline class II/III or class III mixed valence state. In water, the redox separation is only 110 mV and the much broader IVCT transition is characteristic of a class II mixed-valence state. This is consistent with the observation that raising and lowering the energy of the d(pi) orbitals in CH(2)Cl(2) or water, respectively, will decrease or increase the energy gap to the LUMO of the bppz bridging ligand, which provides the delocalisation pathway via electron-transfer. IR spectroelectrochemistry could only be carried out successfully in CH(2)Cl(2) and revealed class III mixed valence behaviour on the fast IR timescale. In contrast to this, time-resolved IR spectroscopy showed that the MLCT excited state, which is formulated as Ru(III)(bppz(-))Ru(II) and can therefore be considered as a mixed-valence Ru(II)/Ru(III) complex with an intermediate bridging radical anion ligand, is localised on the IR timescale with spectroscopically distinct Ru(II) and Ru(III) termini. This is because the necessary electron-transfer via the bppz ligand is more difficult because of the additional electron on bppz(-) which raises the orbital through which electron exchange occurs in energy. DFT calculations reproduce the electronic spectra of the complex in all three Ru(II)/Ru(II), Ru(II)/Ru(III) and Ru(III)/Ru(III) calculations in both water and CH(2)Cl(2) well as long as an explicit allowance is made for the presence of water molecules hydrogen-bonded to the cyanides in the model used. They also reproduce the excited-state IR spectra of both [Ru(CN)(4)(MU-bppz)](2-) and [{Ru(CN)(4)}(2)(MU bppz)](4-) very well in both solvents. The reorganization of the water solvent shell indicates a possible dynamical reason for the longer life time of the triplet state in water compared to CH(2)Cl(2). PMID- 22810118 TI - Division of tongue tie: review of practice through a tertiary paediatric otorhinolaryngology service. AB - OBJECTIVES: Recent NICE guidance declared that evidence regarding surgical division of tongue tie was adequate to support the use of the procedure, provided that normal arrangements are in place for consent, audit and clinical governance. This work aimed to carry out a retrospective review of those patients who have previously undergone tongue tie division through a tertiary paediatric otorhinolaryngology service. We further aimed to identify the referral patterns, indications for, and outcomes following, division. METHODS: A retrospective chart review of all patients attending for division of tongue-tie between January 2010 and June 2011, inclusive. RESULTS: A total of 48 patients underwent division of tongue-tie over the study period. The median age of patients at the time of operation was 16 months (range 3-192). Delayed speech or articulation problems (27%), and parental concern (23%) were the most common reasons for referral. Overt difficulty with feeding was responsible for referral in just 4 cases. All cases were performed under general anaesthetic as day-case procedures; 7 patients had a second procedure performed at the same time. No complications, either early or late, were recorded across this cohort. CONCLUSIONS: Tongue-tie division is a safe procedure with minimal associated morbidity. Whilst the primary indication cited in the literature is that of feeding difficulty, it appears that the majority of division is performed for other reasons. PMID- 22810119 TI - Lesional infiltration of receptor activator of nuclear factor-kappaB ligand+ cells in experimental autoimmune neuritis rats. AB - Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system. Receptor activator of NF-kappaB ligand (RANKL), a member of the tumor necrosis factor family, regulates proliferation of mature T cells. Here, we have studied the expression of RANKL in sciatic nerves of EAN rats. EAN was induced in male Lewis rats. The spatiotemporal expression of RANKL in sciatic nerves of EAN rats was investigated using immunohistochemistry. In sciatic nerves of normal rats RANKL(+) cells were rarely seen. EAN induced a significant accumulation of RANKL(+) cells in sciatic nerves and there was a significant positive correlation of the time course of RANKL(+) cell accumulations with neurological scores of EAN rats. The major cellular resources of RANKL in sciatic nerves were T cells and macrophages. The positive association of RANKL(+) cell accumulations with neurological scores of EAN rats together with the known functions of RANKL indicated that RANKL might play a role in pathologic development of EAN and need further investigation. PMID- 22810120 TI - Vertical supranuclear gaze palsy in Niemann-Pick type C disease. AB - Vertical supranuclear gaze palsy (VSGP) is a key clinical feature in patients with Niemann-Pick type C disease (NP-C), a rare, autosomal recessive, neuro visceral disorder caused by mutations in either the NPC1 or NPC2 gene. VSGP is present in approximately 65 % of the cases and is, with gelastic cataplexy, an important risk indicator for NP-C. VSGP in NP-C is characterized by a paralysis of vertical saccades, especially downward, with the slow vertical eye movement systems (smooth pursuit and the vestibulo-ocular reflex) spared in the early phase of the disease. This dissociation is caused by a selective vulnerability of the neurons in the rostral interstitial nuclei of the medial longitudinal fasciculus (riMLF) in NP-C. Here we discuss VSGP in NP-C and how clinicians can best elicit this sign. PMID- 22810123 TI - Journal Information. PMID- 22810121 TI - Bilateral atherosclerotic internal carotid artery occlusion causing acute bihemispheric infarctions. PMID- 22810126 TI - Editor's Preface. PMID- 22810127 TI - Medical care of patients with brain tumors. AB - PURPOSE OF REVIEW: Patients with brain tumors require close attention to medical issues resulting from their disease or its therapy. Effective medical management results in decreased morbidity and mortality and improved quality of life. The most frequent neurology-related issues that arise in these patients include seizures, peritumoral edema, venous thromboembolism, fatigue, and cognitive dysfunction. This article focuses on the most recent findings for the management of the most relevant medical complications among patients with brain tumors. RECENT FINDINGS: Increasing evidence suggests that anticoagulation in patients with thromboembolic complications is safe even when they are receiving antiangiogenic therapy. There are also increasing data to support the use of newer, non-enzyme-inducing antiepileptic drugs, which have the advantage of lacking interactions with antineoplastic agents and are as effective as their older counterparts at preventing seizures. Relatively few studies have addressed the management of fatigue and depression, and definitive recommendations cannot be made. SUMMARY: Corticosteroids to treat vasogenic edema should be used at the minimum amount required to control symptoms and should be tapered as quickly as possible. Anticonvulsants should be used only if patients have had seizures. Non enzyme-inducing antiepileptic drugs are preferred to minimize interactions with concurrently administered chemotherapy. Thromboembolic complications are common and are preferably treated with low-molecular-weight heparins. Only patients with hemorrhagic complications require an inferior vena cava filter. Cognitive deficits are frequent in patients with brain tumors and include problems such as poor short-term memory, distractibility, personality change, emotional lability, loss of executive function, and decreased psychomotor speed. Stimulants can help to improve these symptoms. PMID- 22810128 TI - Brain metastases. AB - PURPOSE OF REVIEW: Brain metastases are the most common neurologic complication related to systemic cancer. With continued improvements in systemic treatment, the incidence is expected to increase. This article reviews the clinical presentation, pathophysiology, prognostic factors, and treatment of metastatic brain tumors. RECENT FINDINGS: Brain metastases from systemic cancer are up to 10 times more common than primary malignant brain tumors and are a significant burden in the management of patients with advanced cancer. Common presenting symptoms include headache, focal weakness or numbness, mental status change, and seizure. Management and treatment of metastatic brain tumors is complex and dependent on several factors, including age, performance status, number of metastases at presentation, and status of systemic disease. At the time of diagnosis, most patients have more than one brain metastasis, and treatment has traditionally consisted of whole-brain radiation therapy (WBRT). For those patients with single brain metastases, aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT has been shown to improve survival and neurologic outcomes compared with WBRT alone. In patients with a limited number of brain metastases, SRS alone is being increasingly explored as a treatment option that spares the upfront toxicity of WBRT. Currently, the role of chemotherapy is limited to experimental settings and salvage after radiation therapy. SUMMARY: Patients with brain metastases have complex needs and require a multidisciplinary approach in order to optimize intracranial disease control while maximizing neurologic function and quality of life. Patients with multiple metastases, uncontrolled systemic disease, and poor functional status are typically treated with WBRT alone, whereas surgery and SRS may be used for additional local control in a subset of patients with fewer tumors and good functional status. The incorporation of neuropsychological outcomes, neurologic function, and quality of life as end points in future studies will offer further guidance for providing comprehensive care to patients with metastatic brain tumors. PMID- 22810129 TI - Spinal cord disease in patients with cancer. AB - PURPOSE OF REVIEW: Spinal cord disease is not uncommon in patients with systemic cancer. Most cases are due to epidural tumor metastases with resulting cord compression, although intramedullary spinal cord metastases, radiation myelopathy, and myelopathic complications of chemotherapy must be considered. RECENT FINDINGS: Techniques for surgical decompression of the spinal cord in patients with epidural tumor have improved significantly over the past decade. Several studies have demonstrated improved neurologic outcome in a subset of patients with epidural spinal cord compression treated surgically. SUMMARY: This article outlines the clinical features, radiographic findings, and differential diagnosis of spinal cord disease in patients with cancer and describes the therapeutic approach to these patients. Early identification and treatment of patients with epidural spinal cord compression is critical to maintaining neurologic function and preserving quality of life. PMID- 22810130 TI - Leptomeningeal metastasis from systemic cancer. AB - PURPOSE OF REVIEW: Leptomeningeal metastasis (LM) is an uncommon, usually late, complication of cancer. This article discusses the clinical presentation, diagnosis, prognosis, and treatment of LM. RECENT FINDINGS: Neither gadolinium enhanced MRI nor CSF cytology is adequately sensitive to diagnose all cases of LM. SUMMARY: Patients with LM classically present with multifocal neurologic symptoms and signs, and the diagnosis is made via MRI, CSF cytologic analysis, or both. Treatment is palliative in nature and can involve focal radiation to symptomatic sites, systemic chemotherapy with agent(s) that cross the blood-brain barrier, or intrathecal delivery of chemotherapy. Patients may present with or later develop signs of hydrocephalus; ventriculoperitoneal shunting can provide symptomatic relief in certain patients. Overall prognosis is poor, with a median survival typically in the range of 2 to 3 months. PMID- 22810131 TI - Neurologic complications of radiation. AB - PURPOSE OF REVIEW: Radiation administered to treat CNS neoplasms or systemic cancers adjacent to the CNS can result in a variety of acute, subacute, and delayed clinical syndromes of the brain and spinal cord. Less commonly, the brachial or lumbosacral plexus or the cranial nerves are damaged by radiation therapy (RT). Cranial blood vessels can also be affected by brain RT, especially when it is administered during childhood and results in delayed vessel structural changes. These disorders are important because their presentation can mimic tumor recurrence. Knowledge of the classic clinical signs, imaging features, and time interval from RT will assist the practitioner in establishing the diagnosis and recommending treatment when appropriate. RECENT FINDINGS: The acute and subacute syndromes are temporary. An important subacute syndrome following focal external beam RT in combination with chemotherapy to treat newly diagnosed glioblastoma, termed pseudoprogression, has recently been characterized. In addition, recent clinical experience indicates that the delayed RT-induced CNS syndromes, once considered irreversible, can be treated effectively in some patients. SUMMARY: Recent and ongoing research is lending new insights into the mechanisms of RT related CNS injury and will hopefully lead to more effective methods for the prevention and treatment of this undesired, but typically unavoidable, complication of RT. PMID- 22810132 TI - Neurologic complications of cancer drug therapies. AB - PURPOSE OF REVIEW: The purpose of this article is to review neurologic complications associated with systemic anticancer therapies. RECENT FINDINGS: Although neurologic complications from traditional chemotherapies are well described, most neurologists are less familiar with complications from agents that target specific pathways or receptors. This article also reviews the most common neurologic adverse effects associated with newer targeted agents. SUMMARY: Patients with cancer are living longer because of earlier diagnoses and remarkable improvements in treatments. Unfortunately, both traditional chemotherapies and newer targeted agents are known to cause neurologic symptoms that can impact quality of life and play a role in limiting potential treatments. Acute, subacute, and chronic syndromes may affect the central or peripheral nervous system. Since treatments for therapy-induced neurotoxicity are limited, awareness of common neurologic complications is important to prevent permanent damage. PMID- 22810133 TI - Paraneoplastic disorders of the CNS and autoimmune synaptic encephalitis. AB - PURPOSE OF REVIEW: This article provides an update on classic paraneoplastic syndromes of the CNS and autoimmune encephalitis syndromes associated with antibodies against synaptic proteins, including the NMDA receptor, LGI1, and Caspr2, among others. RECENT FINDINGS: Most classic paraneoplastic syndromes are associated with antibodies against intracellular (onconeuronal) antigens, appear to be mediated by cytotoxic T-cell responses, and have limited response to treatment. The autoimmune synaptic disorders are associated with antibodies against extracellular epitopes, appear to be directly mediated by antibodies, and are responsive to immunotherapy. The syndromes associated with antibodies against intracellular antigens almost always occur in conjunction with cancer, and their clinical course is usually monophasic. In contrast, syndromes associated with antibodies against synaptic proteins may occur with or without cancer and often relapse. SUMMARY: The spectrum of autoimmune disorders of the CNS with distinct clinical and immunologic associations is expanding. Prompt diagnosis and treatment can result in recovery from some syndromes. PMID- 22810134 TI - CNS infections in patients with cancer. AB - PURPOSE OF REVIEW: This article provides a practical clinical approach to potential CNS infections in patients with cancer, discusses problematic presentations of posterior reversible encephalopathy syndrome and immune reconstitution inflammatory syndrome, and includes specific testing and treatment recommendations for bacterial meningitis, invasive fungal infections, and opportunistic viral infections. RECENT FINDINGS: The major deficits predisposing patients with cancer to CNS infection are neutropenia, barrier disruption, B lymphocyte or immunoglobulin deficiency, and impaired T lymphocyte-mediated immunity. Evolving patterns of drug resistance and prophylactic antimicrobial regimens have altered the timing and range of organisms causing infections. Increasingly intensive immunosuppression has made new groups of patients vulnerable to infections such as progressive multifocal leukoencephalopathy. New MRI sequences offer the potential to diagnose such infections earlier, at a stage when they are more treatable. SUMMARY: Despite improved prophylactic and therapeutic antibiotic regimens, CNS infections remain an important source of morbidity and mortality among several cancer patient groups, particularly those patients undergoing craniotomy and those with hematologic malignancies receiving either hematopoietic cell transplantation or other intensive chemotherapy regimens. PMID- 22810135 TI - Management of malignant gliomas and primary CNS lymphoma: standard of care and future directions. AB - PURPOSE OF REVIEW: This article review the current standard of care of astrocytic gliomas and primary CNS lymphoma and discusses promising new therapeutic targets. RECENT FINDINGS: Standard treatment modalities for primary malignant brain tumors include resection, radiation, local or systemic chemotherapy, and, most recently, antiangiogenic agents. However, these tumors often have a rapid course, and patients usually die within a few years of diagnosis. Improved surgical techniques and radiation and chemotherapy can prolong survival while maintaining quality of life, but these therapies remain inadequate. SUMMARY: The care of patients with malignant brain tumors is challenging. A better understanding of the pathogenesis of primary malignant brain tumors and the elucidation of aberrant molecular pathways are leading to novel treatment strategies and the ability to identify patients who may benefit from specific treatments. PMID- 22810136 TI - Should the cost of care for patients with glioblastoma influence treatment decisions? AB - This article presents the case of a patient with recurrent glioblastoma who questions whether he can or should pay for treatment with bevacizumab. There are differing views on the physician's role in dealing with cost and cost effectiveness issues for patients, but it is becoming increasingly unrealistic for physicians to disregard the cost of cancer care when making treatment recommendations. Physicians need to be able to address cost issues in order to allow individual patients to make the best informed decision about what treatment option is the most beneficial and the "best value" for them. PMID- 22810137 TI - Helping patients make the best decision regarding duration of temozolomide chemotherapy treatment. AB - Outcomes for patients with glioblastoma have improved with the addition of temozolomide (TMZ) chemotherapy to radiation therapy followed by adjuvant TMZ for up to 1 year. Patients often wish to continue chemotherapy after the standard 1 year course. Whether to continue or to stop TMZ is a complex and stressful decision for the patient and family, and the decision should be based on a discussion of the known risks and benefits of each choice. PMID- 22810138 TI - Coding issues: evaluation and management tips for neuro-oncology visits. AB - Accurate coding is an important function of neurologic practice. This section of CONTINUUM, contributed by members of the AAN Medical Economics and Management Committee, includes helpful coding information and examples related to the issue topic. This section may include diagnosis coding, evaluation and management coding, procedure coding, or a combination, depending on which is most useful for the subject area of the issue. PMID- 22810140 TI - Multiple-Choice Questions. PMID- 22810142 TI - Patient Management Problem. PMID- 22810141 TI - Multiple-Choice Questions--Preferred Responses. PMID- 22810143 TI - Patient Management Problem--Preferred Responses. PMID- 22810145 TI - The trochlear pre-ossification center: a normal developmental stage and potential pitfall on MR images. AB - BACKGROUND: The hypertrophic changes that occur in the cartilage of an epiphysis prior to the onset of ossification are known as the pre-ossification center. Awareness of the appearance of the pre-ossification center on MR images is important to avoid confusing normal developmental changes with pathology. OBJECTIVE: The purpose of this study was to determine the characteristics of the trochlear pre-ossification center on MR imaging and examine age and gender differences. MATERIALS AND METHODS: We retrospectively analyzed MR images from 61 children. The trochleas were categorized into three types on the basis of signal intensity (SI). Trochlear types were compared to age and gender. RESULTS: There was no significant difference between the ages of boys and girls. Type 1 trochleas showed homogeneous SI on all pulse sequences. Type 2 trochleas demonstrated a focus of high SI in the epiphyseal cartilage on fat-suppressed water-sensitive sequences, with high or intermediate SI on gradient-echo images (pre-ossification center). Type 3 trochleas showed low SI on fat-suppressed water sensitive sequences and gradient-echo images. Thirty-seven trochleas were described as type 1, sixteen as type 2 and eight as type 3. ANOVAs confirmed a statistically significant difference in the age of children with type 3 trochleas and those with types 1 and 2 (P < 0.001). Spearman rank correlations determined a positive relationship between trochlear type and age of the children (r = 0.53). CONCLUSION: Development-related changes in the trochlea follow a predictable pattern. The signal characteristics of the pre-ossification center likely reflect normal chondrocyte hypertrophy and an increase in free water in the matrix. PMID- 22810146 TI - Prospective study of cytomegalovirus serostatus and prostate cancer risk in the Prostate Cancer Prevention Trial. AB - PURPOSE: To investigate serologic evidence of infection by cytomegalovirus (CMV), a herpesvirus with known oncogenic potential that has been detected in malignant prostate tissue, in relation to prostate cancer (PCa) risk in a large case control study nested in the Prostate Cancer Prevention Trial (PCPT). METHODS: Cases were men with a confirmed diagnosis of PCa after visit 2 (n = 614), and controls were men not diagnosed with PCa during the trial who also had a negative end-of-study biopsy (n = 616). Controls were frequency-matched to cases by age, treatment arm, and family history of PCa. Sera from visit 2 were tested for CMV IgG antibodies. RESULTS: No association was observed between CMV serostatus and PCa risk (adjusted CMV seroprevalence = 67.9 % for cases and 65.2 % for controls, odds ratio = 1.13, 95 % CI 0.89-1.45). CONCLUSIONS: Considering our null findings in the context of the full CMV literature, CMV infection, as measured by serostatus, does not appear to increase PCa risk. PMID- 22810147 TI - DNA methyltransferase 3b (DNMT3b), tumor tissue DNA methylation, Gleason score, and prostate cancer mortality: investigating causal relationships. AB - PURPOSE: Aberrant DNA methylation plays a role in prostate cancer progression. We studied the relationships among DNA methyltransferase (DNMT) genotype, DNA methylation, Gleason score, and mortality in two cohorts of prostate cancer patients, previously reported with associations between DNA methylation in GSTP1, APC, and RUNX3 and prostate cancer mortality. Herein, we considered possible causal relationships between the studied variables, assuming that (1) DNMT activity affects tumor tissue methylation, (2) methylation status affects tumor morphology, and thus the Gleason score, and (3) DNA methylation affects mortality via Gleason score. METHODS: The cohorts comprised 438 patients diagnosed at one Italian pathology ward before 1997, with DNA obtained from paraffin-embedded tumor tissues. The polymorphism rs406193 in the DNMT3b gene was assessed by allele discrimination in real-time PCR. According to the assumed causal model, we analyzed the effects of rs406193 (T carriers vs others) on the Gleason score without adjusting for gene methylation, and the effects of rs406193 on gene methylation and prostate cancer mortality without adjusting for Gleason score. RESULTS: We found no evidence of association between T carriers and the number of methylated genes. However, T carriers had reduced risk of a Gleason score 8+ (odds ratio = 0.57, 95 % CI 0.39-0.85), and a hazard ratio of 0.81 (0.61-1.09) of dying from prostate cancer, which would have been erroneously estimated of 0.93 if adjusted for Gleason score. CONCLUSIONS: These findings provide clues on the role of a DNMT3b SNP in prostate cancer progression and illustrate the importance of considering possible causal relationships in the analyses. PMID- 22810148 TI - DFPE, partially fluorinated ether: a novel approach for experimental intravitreal tamponade. AB - PURPOSE: To evaluate decafluoro-di-n-pentyl ether (DFPE) as a vitreous tamponade by examining ocular tolerance in rabbits' eyes. METHODS: Thirteen rabbits were divided into 4 groups after mechanical vitrectomy and were followed up to 12 months. The tamponade remained in the eye for 6 months in group 1 (DFPE) and Group 3 (DFPE and silicone oil) and for 12 months in group 2 (DFPE). Group 4 served as control. RESULTS: In groups 1, 2, and 3, dispersion of the fluid appeared 2 weeks postoperatively. Posterior subcapsular cataracts appeared in rabbits' eyes with large fills of DFPE (>50%). Histologic findings in groups 1 and 2 showed no detectable change in outer nuclear layer thickness. Except for some vacuolations, the inner retina was well preserved in all injected rabbits' eyes. On the electroretinography of injected rabbits' eyes, there was no effect on the a wave amplitude and b wave implicit time, but the b wave amplitude was elevated with statistical significance (P < 0.001) at 1, 3, and 6 months postoperatively but with no statistical significance (P > 0.05) after that period when compared with group 4 and unoperated fellow rabbits' eyes of each group. CONCLUSION: Decafluoro-di-n-pentyl ether demonstrated minimum adverse effects in retinal rabbits; further studies are needed before clinical use as short-term tamponade. PMID- 22810149 TI - A force-sensing microsurgical instrument that detects forces below human tactile sensation. AB - PURPOSE: To test the sensitivity and reproducibility of a 25-gauge force-sensing micropick during microsurgical maneuvers that are below tactile sensation. METHODS: Forces were measured during membrane peeling in a "raw egg" and the chick chorioallantoic membrane models (N = 12) of epiretinal membranes. Forces were also measured during posterior hyaloid detachment and creation of retinal tears during vitrectomy in live rabbits (n = 6). RESULTS: With the raw egg model, 0.5 +/- 0.4 mN of force was detected during membrane peeling. In the chorioallantoic membrane model, delaminating the upper membrane produced 2.8 +/- 0.2 mN of force. While intentionally rupturing the lower membrane to simulate a retinal tear, 7.3 +/- 0.5 mN (range, 5.1-9.2 mN; P < 0.001) of force was generated while peeling the upper membrane. During vitrectomy, the minimum force that detached the posterior hyaloid was 6.7 +/- 1.1 mN, which was similar to the force of 6.4 +/- 1.4 mN that caused a retinal tear. The rate of force generation, as indicated by the first derivative of force generation, was 3.4 +/- 1.2 mN/second during posterior hyaloid detachment, compared with 7.7 +/- 2.4 mN/second during the creation of a retinal tear (P = 0.04). CONCLUSION: Force sensing microsurgical instruments can detect forces below tactile sensation, and importantly, they can distinguish the forces generated during normal maneuvers from those that cause a surgical complication. PMID- 22810150 TI - [Histological findings in bilateral asymmetrical vasoproliferative retinal tumor]. AB - We present a case of a bilateral vasoproliferative tumor of the retina in a young man. The first symptom was visual impairment due to vitreous hemorrhage. The right eye showed small tumors which were successfully treated by repeated cryocoagulation, photocoagulation and bevazicumab injection. The tumor in the left eye was larger and eventually led to a painful secondary glaucoma. After enucleation, this tumor was examined histologically and immunohistochemically. The clinical and histological differential diagnoses and therapeutic options are discussed. PMID- 22810151 TI - [A 7-year-old patient with sudden painful inflammation of the lower leg and eye]. PMID- 22810152 TI - Evaluation of the in vitro inhibitory impact of hypericin on placental glutathione S-transferase pi. AB - St John's Wort (SJW) extracts are herbal products which are available without prescription in most countries and widely used in the treatment of mild to moderate depression. Since it is a herbal product and available without prescription, use of SJW is common among pregnant and/or lactating woman. The principal of the study was to clarify the effects of hypericin, one of the components of SJW, on glutathione S-transferase-pi (GST-pi) purified from human placenta. The K (m) values of GST-pi were 0.21 +/- 0.03 mM for glutathione (GSH) and 2.29 +/- 0.54 mM for 1-chloro-2,4-dinitrobenzene (CDNB). At fixed [GSH], the V (m) value calculated was about 3 times higher than the conditions in which [CDNB] was fixed; 201 +/- 30 U/mg protein versus 74 +/- 3 U/mg protein. At constant substrate concentrations (1 mM), an average IC (50) value of 0.70 +/- 0.02 MUM was obtained. Hypericin inhibited GST-pi competitively with respect to both substrates. When GSH was the varied substrate a K (i) value of 0.31 +/- 0.05 MUM was found; when CDNB was the varied substrate, a K (i) value of 0.85 +/- 0.02 MUM was obtained. On the basis of these data considering transplacental transfer of hypericin and immature hepatic clearance of the baby, using this herbal product may cause abnormalites due to the inhibition of one of the most important placental detoxification enzymes, GST-pi. PMID- 22810153 TI - Impact of an enhanced recovery program on short-term outcomes after scheduled laparoscopic colon resection. AB - INTRODUCTION: Both enhanced recovery programs (ERP) and laparoscopy can reduce complications and length of stay (LOS) in colon surgery. We investigated whether ERP further improved the short-term outcomes of scheduled laparoscopic colectomies. METHODS: We performed an audit of all patients undergoing scheduled laparoscopic colon resection between January 2003 and August 2010 in our institution. An ERP including accelerated introduction of oral nutrition, mobilization, pain control, and catheter management was introduced in 2005. Demographic data, intra and postoperative details and 30-day ER visit and readmission rate were collected. We compared LOS and short-term outcomes for patients on the program with those receiving traditional postoperative care using Chi-square and regression models. Data are presented as median [25th, 75th percentile]. Statistical significance was defined as p < 0.05. RESULTS: 136 (46%) of 297 eligible patients were enrolled in the ERP. At baseline, the two groups had similar demographic characteristics, but patients in the ERP were more likely to have their operation by a colorectal surgeon (p = 0.01). Patients in the ERP ate solids earlier (p < 0.001) and had earlier removal of their urinary catheter (p < 0.001). LOS was 4 [3, 6] days for both groups (p < 0.01), with more patients in the ERP discharged by POD 3 (p < 0.001). After adjusting for other variables, ERP enrolment remained an independent predictor of LOS (p < 0.01), along with age (p < 0.01) and in-hospital complications (p < 0.001). Complication rates were similar between the two groups. Patients in the ERP had significantly fewer ER visits (p = 0.02), but there were no differences in readmission rates. CONCLUSION: In patients undergoing scheduled laparoscopic colectomy in a university-based clinical teaching unit, ERP can further reduce length of stay and postoperative ER visits without increasing readmission rates. PMID- 22810154 TI - Risk of postoperative urinary retention after laparoscopic (TAPP) or endoscopic (TEP) inguinal hernia repair. PMID- 22810155 TI - Facile synthesis of porous MnO/C nanotubes as a high capacity anode material for lithium ion batteries. AB - Porous MnO/C nanotubes are synthesized by a facile hydrothermal method followed by thermal annealing, and possess excellent cyclability and high rate capability as an anode for lithium ion batteries. PMID- 22810156 TI - Hip capsule dimensions in patients with femoroacetabular impingement: a pilot study. AB - BACKGROUND: Joint-preserving hip surgery, either arthroscopic or open, increasingly is used for the treatment of symptomatic femoroacetabular impingement (FAI). As a consequence of surgery, thickening of the joint capsule and intraarticular adhesions between the labrum and joint capsule and between the femoral neck and the joint capsule have been observed. These alterations are believed to cause persistent pain and reduced range of motion. Because the diagnosis is made with MR arthrography, knowledge of the normal capsular anatomy and thickness on MRI in patients is important. To date there is no such information available. QUESTIONS/PURPOSES: The purpose of this study was to establish thickness, length of the hip capsule, and the size of the perilabral recess in patients with FAI. METHODS: We reviewed the preoperative MR arthrography of 30 patients (15 men) with clinical symptoms of FAI. We measured capsular thickness and made observations on the perilabral recess. RESULTS: The joint capsule was thickest (6 mm) anterosuperiorly between 1 and 2 o'clock. The average length from the femoral head-neck junction to the femoral insertion of the capsule ranged from 19 to 33 mm. A perilabral recess was present circumferentially, even across the acetabular notch, where the labrum is supported by the transverse acetabular ligament. The shortest recess occurred superiorly. CONCLUSIONS: Knowledge of the capsular anatomy in patients with FAI before surgery is important to judge the postoperative changes and to plan potential further therapy including arthroscopic treatment of intraarticular adhesions. PMID- 22810157 TI - Complications of total knee arthroplasty: standardized list and definitions of the Knee Society. AB - BACKGROUND: Despite the importance of complications in evaluating patient outcomes after TKA, definitions of TKA complications are not standardized. Different investigators report different complications with different definitions when reporting outcomes of TKA. QUESTIONS/PURPOSES: We developed a standardized list and definitions of complications and adverse events associated with TKA. METHODS: In 2009, The Knee Society appointed a TKA Complications Workgroup that surveyed the orthopaedic literature and proposed a list of TKA complications and adverse events with definitions. An expert opinion survey of members of The Knee Society was used to test the applicability and reasonableness of the proposed TKA complications. For each complication, members of The Knee Society were asked "Do you agree with the inclusion of this complication as among the minimum necessary for reporting outcomes of knee arthroplasty?" and "Do you agree with this definition?" RESULTS: One hundred two clinical members (100%) of The Knee Society responded to the survey. All proposed complications and definitions were endorsed by the members, and 678 suggestions were incorporated into the final work product. The 22 TKA complications and adverse events include bleeding, wound complication, thromboembolic disease, neural deficit, vascular injury, medial collateral ligament injury, instability, malalignment, stiffness, deep joint infection, fracture, extensor mechanism disruption, patellofemoral dislocation, tibiofemoral dislocation, bearing surface wear, osteolysis, implant loosening, implant fracture/tibial insert dissociation, reoperation, revision, readmission, and death. CONCLUSIONS: We identified 22 complications and adverse events that we believe are important for reporting outcomes of TKA. Acceptance and utilization of these standardized TKA complications may improve evaluation and reporting of TKA outcomes. PMID- 22810158 TI - Arthroplasty knee surgery and alcohol use: risk factor or benefit? AB - BACKGROUND: Excessive alcohol consumption has been associated with adverse measures of health after elective surgery. However, associations of low/moderate consumption remain uncertain. QUESTION/PURPOSES: We determined differences among patients with three different self-reported consumption levels in (1) preoperative/postoperative patient-perceived outcomes and knee scores, (2) preoperative/postoperative changes in these scores, (3) preoperative demographics and comorbidities, and (4) length of stay (LOS) and inpatient charges. METHODS: We retrospectively studied 430 patients (545 TKAs). Based on a self-administered consumption questionnaire, patients were stratified into groups: (1) nondrinkers, (2) occasional drinkers, and (3) moderate drinkers. We compared the following variables between groups: demographics, BMI, American Society of Anesthesiologists score, Charlson Comorbidity Index, preoperative and postoperative Quality of Well-being Index (QWB-7), SF-36 score, WOMAC score, Knee Society (KS) Score, Hospital for Special Surgery (HSS) knee score, LOS, and hospital charges. QWB-7, SF-36, WOMAC, KS, and HSS scores were compared adjusting for patient characteristics. Minimum followup was 1 year (average, 3.4 years; range, 1-6 years). RESULTS: Preoperatively, compared to self-reported nondrinkers, moderate drinkers had better QWB-7, SF-36, and WOMAC scores. At followup, occasional and moderate drinkers had better KS function and HSS scores. However, nondrinkers had greater SF-36 general health improvement. Most nondrinkers were older, female, and Hispanic and had more comorbidities. Nondrinkers had a longer LOS. CONCLUSIONS: Self-reported alcohol consumption was more common among men and non-Hispanics. Moderate drinkers had better preoperative QWB-7, SF-36, and WOMAC scores and shorter LOS than nondrinkers. However, after surgery, self-reported abstainers achieved greater improvements in the SF-36 general health score. PMID- 22810159 TI - Does orthopaedic surgical training induce hypertension? A pilot study. AB - BACKGROUND: Elevated blood pressure (BP) is associated with increased cardiovascular risks manifested by ischemic heart disease and stroke. Studies of cardiothoracic surgeons and neurosurgeons suggest surgery induces a hemodynamic stress malresponse. However, it is unclear whether these occur in orthopaedic surgeons. QUESTIONS/PURPOSES: We measured the BP of surgeons during hallux valgus surgery, TKA, and THA with the: (1) trainee assisting the trainer, (2) the trainer assisting the trainee, (3) the trainee operating independently, and (4) compared the intraoperative changes in BP and heart rate of orthopaedic surgeons with those of a clinic day and during an exercise tolerance test. METHODS: We used an ambulatory BP monitor to measure the BP and heart rate of three consultants and their respective trainees during hallux valgus surgery, TKA, or THA. We noted if there were any differences in the stress response of the lead surgeon in comparison to when the same individual was assisting a trainee, and vice versa. Additionally, we recorded the trainee's BP and heart rate when they were operating independently. The intraoperative changes in BP and heart rate of orthopaedic surgeons were compared with those measured during a clinic day and during an exercise tolerance test. RESULTS: When the trainer was leading the operation, their mean arterial pressure gradually increased to 105 (range, 102 109) until implant placement. However, when the trainee was operating and the trainer assisting, the trainer's BP peaked (mean, 101; range, 95-111) at the beginning of the procedure and slowly declined as it progressed. The trainee's BP remained elevated throughout. The highest peaks for trainees were noted during independent operating. All of the surgeons had higher average BP readings (mean, 100; range, 95-108) and heart rate (mean, 86; range, 57-117) on days when they did surgery compared with baseline. CONCLUSIONS: The elective operations studied induced a hypertensive response. The response was more marked in trainees than in trainers, particularly if the trainee was operating independently. PMID- 22810160 TI - The classic: Case of bone transference. Use of a segment of fibula to supply a defect in the tibia. 1905. AB - This Classic Article is a reprint of the original work by T. W. Huntington, Case of bone transference. Use of a segment of fibula to supply a defect in the tibia. An accompanying biographical sketch of T. W. Huntington is available at DOI 10.1007/s11999-012-2495-0 . The classic article is 1905 and is reprinted courtesy of Wolters Kluwer Lippincott Williams & Wilkins from Huntington TW. Case of Bone Transference. Use of a Segment of Fibula to Supply a Defect in the Tibia. Ann Surg. 1905;41:249-251. PMID- 22810161 TI - Save the torn labrum in hips with borderline acetabular coverage. AB - BACKGROUND: Hip arthroscopy for labral tears improves short-term function, but reoperations occur in 5% to 47% of patients. The effect of borderline acetabular coverage on reoperation rate has been debated. Labral repair rather than debridement has been proposed to improve function, but the effect on reoperation rate is unclear. QUESTIONS/PURPOSES: We determined whether (1) borderline compared to adequate acetabular coverage increased reoperations and (2) labral repair compared to debridement reduced reoperations. METHODS: We retrospectively reviewed 106 patients (mean age, 39 years) who underwent hip arthroscopy for labral tears. Based on radiographs, we classified patients into those with borderline (n = 50) or adequate (n = 56) acetabular coverage. We further divided each group into those with labral debridement or repair: borderline acetabular coverage, n = 25 and 25, respectively; adequate acetabular coverage, n = 39 and 17, respectively. We assessed reoperations in borderline versus adequate acetabular coverage and labral debridement versus repair, modified Harris hip scores (mHHSs), and survival. Minimum followup was 12 months (mean, 33 months; range, 12-65 months). RESULTS: Twenty-three of 106 patients had reoperations. Reoperation rate was higher with borderline than with adequate acetabular coverage. Reoperation rate was lower with labral repair than with debridement. Survival to reoperation was similar in the four subgroups although there was a tendency for early reoperation in patients with borderline acetabular coverage with debridement. Improvement in mean mHHS was comparable in the four subgroups. CONCLUSIONS: We found borderline acetabular coverage increased reoperation rates. Labral repair reduced the likelihood of reoperation, especially in hips with borderline acetabular coverage. Hip arthroscopy for labral tears was associated with high reoperation rates in hips with borderline acetabular coverage. LEVEL OF EVIDENCE: Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810162 TI - An analytic solution for the magnetization of two-dimensional ferrofluids based on the mean spherical approximation. AB - An analytic formula is derived for the magnetization of a two-dimensional dipolar hard disk fluid using a variational functional series expansion of the free energy as a function of the orientational distribution function. The excess term expressing the effect of the intermolecular forces is calculated on the basis of the mean spherical approximation. Comparison with our own Monte Carlo simulation data shows excellent agreement for large external fields and for the zero-field susceptibility. At intermediate field strengths, the agreement is satisfactory for moderate dipole moments and densities. PMID- 22810163 TI - The impact of critical time intervention in reducing psychiatric rehospitalization after hospital discharge. AB - OBJECTIVES: This study examined the impact of critical time intervention (CTI) in reducing rehospitalization among formerly homeless individuals with severe and persistent mental illness after discharge from inpatient psychiatric treatment. METHODS: CTI is a nine-month care coordination intervention designed to support persons with severe mental illness in the transition from institutions to community living. After discharge from inpatient psychiatric treatment, 150 previously homeless men and women were randomly assigned to receive either usual services only or CTI in addition to usual services. Study participants were assessed every six weeks for 18 months after entering the community. RESULTS: At the end of the follow-up period, psychiatric rehospitalization was significantly lower for the group assigned to CTI compared with the usual services group (odds ratio=.11, 95% confidence interval=.01-.96). CONCLUSIONS: This study demonstrated that CTI, primarily designed to prevent recurrent homelessness, also reduced the occurrence of rehospitalization after discharge. PMID- 22810164 TI - A bilingual advantage in visual language discrimination in infancy. AB - The origins of the bilingual advantage in various cognitive tasks are largely unknown. We tested the hypothesis that bilinguals' early capacities to track their native languages separately and learn about the properties of each may be at the origin of such differences. Spanish-Catalan bilingual and Spanish or Catalan monolingual infants watched silent video recordings of French-English bilingual speakers and were tested on their ability to discern when the language changed from French to English or vice versa. The infants' performance was compared with that of previously tested French-English bilingual and English monolingual infants. Although all groups of monolingual infants failed to detect the change between English and French, both groups of bilingual infants succeeded. These findings reveal that bilingual experience can modulate the attentional system even without explicit training or feedback. They provide a basis for explaining the ontogeny of the general cognitive advantages of bilinguals. PMID- 22810165 TI - Greater exposure to sexual content in popular movies predicts earlier sexual debut and increased sexual risk taking. AB - Early sexual debut is associated with risky sexual behavior and an increased risk of unplanned pregnancy and sexually transmitted infections later in life. The relations among early movie sexual exposure (MSE), sexual debut, and risky sexual behavior in adulthood (i.e., multiple sexual partners and inconsistent condom use) were examined in a longitudinal study of U.S. adolescents. MSE was measured using the Beach method, a comprehensive procedure for media content coding. Controlling for characteristics of adolescents and their families, analyses showed that MSE predicted age of sexual debut, both directly and indirectly through changes in sensation seeking. MSE also predicted engagement in risky sexual behaviors both directly and indirectly via early sexual debut. These results suggest that MSE may promote sexual risk taking both by modifying sexual behavior and by accelerating the normal rise in sensation seeking during adolescence. PMID- 22810166 TI - Using game theory to examine incentives in influenza vaccination behavior. AB - The social good often depends on the altruistic behavior of specific individuals. For example, epidemiological studies of influenza indicate that elderly individuals, who face the highest mortality risk, are best protected by vaccination of young individuals, who contribute most to disease transmission. To examine the conditions under which young people would get vaccinated to protect elderly people, we conducted a game-theory experiment that mirrored real-world influenza transmission, with "young" players contributing more than "elderly" players to herd immunity. Participants could spend points to get vaccinated and reduce the risk of influenza. When players were paid according to individual point totals, more elderly than young players got vaccinated, a finding consistent with the Nash equilibrium predicting self-interested behavior. When players were paid according to group point totals, however, more young than elderly players got vaccinated-a finding consistent with the utilitarian equilibrium predicting group-optimal behavior-which resulted in higher point totals than when players were paid for their individual totals. Thus, payout structure affected whether individuals got vaccinated for self-interest or group benefit. PMID- 22810167 TI - Interactions between apparent motion rivalry in vision and touch. AB - In multistable perception, the brain alternates between several perceptual explanations of ambiguous sensory signals. It is unknown whether multistable processes can interact across the senses. In the study reported here, we presented subjects with unisensory (visual or tactile), spatially congruent visuotactile, and spatially incongruent visuotactile apparent motion quartets. Congruent stimulation induced pronounced visuotactile interactions, as indicated by increased dominance times for both vision and touch, and an increased percentage bias for the percept already dominant under unisensory stimulation. Thus, the joint evidence from vision and touch stabilizes the more likely perceptual interpretation and thereby decelerates the rivalry dynamics. Yet the temporal dynamics depended also on subjects' attentional focus and was generally slower for tactile than for visual reports. Our results support Bayesian approaches to perceptual inference, in which the probability of a perceptual interpretation is determined by combining visual, tactile, or visuotactile evidence with modality-specific priors that depend on subjects' attentional focus. Critically, the specificity of visuotactile interactions for spatially congruent stimulation indicates multisensory rather than cognitive-bias mechanisms. PMID- 22810168 TI - The tiger on your tail: choosing between temporally extended behaviors. AB - The time spent choosing between temporally extended behaviors cannot, in general, last as long as the behaviors themselves; otherwise, the tiger on your tail would have you for lunch. Previous reaction time studies provide little information on this topic, which was explored in the study reported here by showing participants images of scenes for which they could choose a left or right walking-and-reaching path. The paths they chose were nearly identical to ones chosen by participants who actually performed the task in a previous study. Moreover, the times participants took to choose the actions were about 5 times shorter than the times it took to perform them. The choice-time data were inconsistent with the idea that participants picked the path with a lower cost after mentally simulating the paths one after the other. Showing real-world scenes and having participants choose actions for them holds promise for future research in cognitive psychology, ecological psychology, and behavioral ecology. PMID- 22810169 TI - Coming to terms: quantifying the benefits of linguistic coordination. AB - Sharing a public language facilitates particularly efficient forms of joint perception and action by giving interlocutors refined tools for directing attention and aligning conceptual models and action. We hypothesized that interlocutors who flexibly align their linguistic practices and converge on a shared language will improve their cooperative performance on joint tasks. To test this prediction, we employed a novel experimental design, in which pairs of participants cooperated linguistically to solve a perceptual task. We found that dyad members generally showed a high propensity to adapt to each other's linguistic practices. However, although general linguistic alignment did not have a positive effect on performance, the alignment of particular task-relevant vocabularies strongly correlated with collective performance. In other words, the more dyad members selectively aligned linguistic tools fit for the task, the better they performed. Our work thus uncovers the interplay between social dynamics and sensitivity to task affordances in successful cooperation. PMID- 22810171 TI - A differential equation model of collagen accumulation in a healing wound. AB - Wound healing is a complex biological process which involves many cell types and biochemical signals and which progresses through multiple, overlapping phases. In this manuscript, we develop a model of collagen accumulation as a marker of wound healing. The mathematical model is a system of ordinary differential equations which tracks fibroblasts, collagen, inflammation and pathogens. The model was validated by comparison to the normal time course of wound healing where appropriate activity for the inflammatory, proliferative and remodeling phases was recorded. Further validation was made by comparison to collagen accumulation experiments by Madden and Peacock (Ann. Surg. 174(3):511-520, 1971). The model was then used to investigate the impact of local oxygen levels on wound healing. Finally, we present a comparison of two wound healing therapies, antibiotics and increased fibroblast proliferation. This model is a step in developing a comprehensive model of wound healing which can be used to develop and test new therapeutic treatments. PMID- 22810170 TI - Development and validation of a falls-grading scale. AB - BACKGROUND AND PURPOSE: The recording of fall events is usually subjective and imprecise, which limits clinical practice and falls-related research. We sought to develop and validate a scale to grade near-fall and fall events on the basis of their severity represented by the use of health care resources, with the goal of standardizing fall reporting in the clinical and research settings. METHODS: Qualitative instrument development was based on a literature review and semistructured interviews to assess face and content validity. We queried older individuals and health care professionals with expertise in the care of patients at risk of falling about clinically important differences to detect and how to optimize the scale's ease of use. To assess the scale's interrater reliability, we created 30 video-vignettes of falls and compared how health care professionals and volunteers rated each of the falls according to our grading scale. RESULTS: We developed the illustrated 4-point Hopkins Falls Grading Scale (HFGS). The grades distinguish a near-fall (grade 1) from a fall for which an individual did not receive medical attention (grade 2), a fall associated with medical attention but not hospital admission (grade 3), and a fall associated with hospital admission (grade 4). Overall, the HFGS exhibited good face and content validity and had an intraclass correlation coefficient of 0.998. CONCLUSION: The 4-point HFGS demonstrates good face and content validity and high interrater reliability. We predict that this tool will facilitate the standardization of falls reporting in both the clinical and research settings. PMID- 22810172 TI - High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension. AB - Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility and sympathetic nerve activation, the relationship between leptin and blood pressure (BP) in resistant hypertension (RHTN) is unknown. We aimed to assess the correlation of plasma leptin and aldosterone levels with BP in uncontrolled controlled RHTN (UCRHTN) and CRHTN patients. Plasma leptin and aldosterone levels, office BP, ambulatory BP monitoring and heart rate were measured in 41 UCRHTN, 39 CRHTN and 31 well controlled HTN patients. No differences were observed between the three groups regarding gender, body mass index and age. The UCRHTN group had increased leptin when compared with CRHTN and well-controlled HTN patients (38.2+/-21.4, 19.6+/ 8.7 and 20.94+/-13.9 ng ml(-1), respectively; P<0.05). Aldosterone levels values were also statistically different when comparing RHTN, CRHTN and well-controlled HTN patients (9.6+/-3.8, 8.1+/-5.0 and 8.0+/-4.7 ng dl(-1), respectively; P<0.05). As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients (86.2+/-7.2, 83.5+/-6.7 and 83.4+/-8.5, respectively; P<0.05). Plasma leptin positively correlated with systolic (SBP) and diastolic BP (DBP), and aldosterone (r=0.43, 0.35 and 0.47, respectively; all P<0.05) in UCRHTN, but neither in the CRHTN nor in the HTN group. Simple linear regression showed that SBP, DBP and aldosterone may be predicted by leptin (r(2)=0.16, 0.15 and 0.19, respectively; all P<0.05) only in the UCRHTN subgroup. In conclusion, UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with CRHTN and HTN subjects. PMID- 22810173 TI - Antibiotic therapy in necrotising external otitis: case series of 32 patients and review of the literature. AB - Necrotising external otitis (NEO) is a rare but severe bone infection, usually due to Pseudomonas aeruginosa, the management of which is not standardised. Systemic antibiotic therapy is usually prescribed for at least 6 weeks, but no review has been published on this topic. We report our experience and have reviewed the literature regarding antibiotic therapy in NEO. Here we describe a case-series of consecutive NEO cases seen over an 8-year period (2004-2011) in a French tertiary-care teaching hospital. Since 2009 we have shortened the duration of antibiotic therapy to 6 weeks. We also present a review of the literature regarding antibiotic therapy in NEO. We include 32 NEO cases, with positive microbiological cultures in 30 cases. Among the 30 patients with suspected or proven P. aeruginosa infections, 27 received an initial combination therapy of ceftazidime and ciprofloxacin. The duration of antibiotic therapy and length of hospital stay were significantly reduced after 2009 (9.4 +/- 3.2 weeks versus 5.8 +/- 0.7, P < .0.001; and 18.2 +/- 8.7 days versus 11.6 +/- 6.9, P = .0.03, respectively). Patient outcomes were favorable in all cases, with a 14-month median duration of follow-up. Our literature review (30 case series) shows that initial combination therapy is associated with better outcomes as compared with single therapy (97 % versus 83 %, P < .0.001). We suggest 3 weeks of initial combination therapy (ceftazidime + ciprofloxacin, high doses) followed by 3 weeks single therapy with ciprofloxacin in susceptible P. aeruginosa NEO. A close collaboration between ear, nose and throat and infectious diseases specialists is needed. PMID- 22810174 TI - From antipsychotic to anti-schizophrenia drugs: role of animal models. AB - Current drugs for treating schizophrenia are mostly variations on a theme that was started over 50 years ago. Sadly, clinical efficacy has not improved substantially over the years. We argue that both clinical and preclinical researchers have focused too much on psychosis, which is only one of the hallmarks of schizophrenia. This narrow focus has hampered the development of relevant animal models and human experimental medicine paradigms. Other fields in psychiatry, most notably in the realms of addiction and anxiety, have prospered from results obtained in parallel studies using animal models and experimental human studies. Lessons to be learned from those models and recent genetic and cognitive insights in schizophrenia can be utilized to develop better animal and human models and, potentially, novel treatment strategies. PMID- 22810176 TI - Water-soluble, luminescent iridium(III)-ytterbium(III) complexes using dipyrido[3,2-a:2',3'-c]phenazine derivatives as bridging units. AB - Amino-substituted dipyrido[3,2-a:2',3'-c]phenazine (L(1)) and dimethyl dipyrido[3,2-a:2',3'-c]phenazine (L(2)) have been investigated as: (i) chromophores in cyclen-based ligands for lanthanide(III) ions; (II) ancillary co ligands in cyclometalated iridium(III) complexes; (III) bridging, linker units in covalently linked, water-soluble bimetallic lanthanide(III) iridium(III) hybrid complexes. The dipyrido[3,2-a:2',3'-c]phenazine (dppz) derivatives can act as sensitising chromophores (lambda(ex) 400 nm) for Yb(III), resulting in characteristic near-IR emission at 950-1050 nm. The incorporation of dppz-type ligands into cyclometalated Ir(III) complexes of the general type [Ir(epqc)(2)(L(n))](PF(6)) (where epqc = ethylphenylquinoline carboxylate) gave luminescent species with solvent-sensitive emission properties. Steady state and time-resolved luminescence measurements on the water-soluble d-f hybrid species showed that Yb(III) can be sensitised using visible light. PMID- 22810175 TI - Development of optimal medium for production of commercially important monoclonal antibody 520C9 by hybridoma cell. AB - Hybridoma HB-8696 produces monoclonal antibody (mAb) 520C9 (mouse IgG(1)), which recognizes breast cancer oncoprotein c-erbB2. The objective of this study was to optimize the medium recipe of HB 8696 cell for production of mAb 520C9. The optimization consisted of two steps: (1) screening of significant nutrients to make subsequent experiments more efficient with less runs and (2) locating their optimal concentrations. 29 variables including essential and non-essential amino acids, glucose, serum and 6 salts, namely NaCl, KCl, CaCl(2), NaH(2)PO(4), MgSO(4) and Na-pyruvate were chosen in screening phase. The Plackett-Burman method was used to screen the variables influencing mAb production. Seven factors namely glucose, serum, asparagine, threonine, serine, NaCl and NaH(2)PO(4) were identified to have a positive influencing role on mAb production with a confidence level >90 % (p < 0.1). Finally, Response surface methodology revealed the optimal level of the variables. The mAb production and average specific mAb production rate were enhanced by 111.05 and 105 %, respectively, compared to control medium. PMID- 22810177 TI - Faculty. PMID- 22810178 TI - Editor'S preface. PMID- 22810179 TI - Overview of common movement disorders. AB - Movement disorders are a diverse group of hypokinetic and hyperkinetic neurologic diseases characterized by abnormal function of the basal ganglia. In this chapter, we will discuss the four most common diagnoses encountered in subspecialty movement disorders clinics: Parkinson disease, essential tremor, dystonia, and spasticity. The presentation and natural history of each of these disorders varies widely in terms of age of onset, anatomic distribution, and severity. We will review the demographics, clinical characteristics, diagnostic criteria, natural history, and management of these diseases. The medical and surgical management of Parkinson disease will be covered in the chapters "Update on the Medical Management of Parkinson Disease" and "Deep Brain Stimulation in Movement Disorders," respectively. PMID- 22810180 TI - Overview of rare movement disorders. AB - Movement disorders that are infrequently seen in clinical practice can be difficult to recognize and accurately diagnose. Familiarity with these disorders can help the clinician distinguish them from more common movement disorders, such as Parkinson disease, which is associated with a significantly different prognosis and treatment approach. Rare disorders with predominate parkinsonism include multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, whereas Huntington disease is the primary movement disorder characterized by chorea. This chapter will provide an overview of the diagnostic, pathologic, and imaging advances from recent literature as well as discuss current treatments for these rare movement disorders. PMID- 22810181 TI - Update on the genetics of movement disorders. AB - The significant contribution of genetic research has resulted in substantial progress in our understanding of the pathophysiology of movement disorders. This will allow for earlier diagnosis of patients with the potential to influence future therapeutics. However, given the complicated patterns of inheritance and consequences for successive generations, a review of the current state of knowledge as well as basic genetic principles is important. In this review we will discuss current classification systems, and clinical and neuropathologic features of the major genetic etiologies for Parkinson disease, dystonia, chorea, and ataxia. PMID- 22810182 TI - Update on the medical management of Parkinson disease. AB - Dopaminergic agents remain the principal treatments for patients with Parkinson disease (PD). In many patients, however, a combination of relatively resistant motor symptoms, motor complications such as dyskinesias, or nonmotor symptoms such as dysautonomia may lead to substantial disability in spite of dopaminergic therapy. This chapter will review both dopaminergic and nondopaminergic therapies for motor and nonmotor symptoms in PD.Although the basic principles of pharmacotherapy for the motor symptoms of PD have largely remained unchanged over the past decade, several new therapies have become available to refine treatment. In addition, there has been an increasing interest in agents targeting nonmotor symptoms, such as dementia and sleepiness. As patients with PD live longer and acquire additional comorbidities, addressing these nonmotor symptoms has become increasingly important. In this chapter, the major antiparkinsonian dopaminergic compounds will be reviewed, followed by a patient-focused guide to implementation of these treatments as part of an overall management plan. PMID- 22810183 TI - Deep brain stimulation in movement disorders. AB - After more than 2 decades since it was introduced, deep brain stimulation (DBS) has gained widespread popularity as a surgical treatment for medically refractory symptoms of Parkinson disease, essential tremor, and dystonia. In this chapter, authors review the benefits, risks, indications, limitations, and targets for DBS in patients with Parkinson disease, essential tremor, and dystonia. A brief outline of the DBS procedure and programming is also given. PMID- 22810184 TI - Neurotoxin injection for movement disorders. AB - The therapeutic use of botulinum neurotoxin has exploded since the first US Food and Drug Administration indication was obtained in 1989, and today it represents the first-line therapy for several hyperkinetic movement disorders. Of the seven serotypes (A to G), types A and B have been approved for use in the United States. Two type A toxins, onabotulinumtoxinA (Botox) and abobotulinumtoxinA (Dysport), are available, and one type B toxin, rimabotulinumtoxinB (Myobloc) is available. The commercially available toxins differ by protein target, duration of action, and adverse event profile; no formula exists for interconversion. The clinical development of the toxin is outlined and methods for muscle targeting are compared. Treatment regimens should be designed to achieve a specific care or functional goal by interdisciplinary teams consisting of physicians, patients, caregivers, and therapists, when appropriate. We discuss dosing considerations and safety profiles in the context of hyperkinetic movement disorders commonly encountered by neurologists, including cervical dystonia, spasticity, pediatric spasticity, blepharospasm, focal limb dystonias, and essential tremor. Finally, the multiple illustrative cases sprinkled throughout the chapter demonstrate the highly individualized, goal-focused nature of treatment with neurotoxins. PMID- 22810185 TI - Patient management problem. PMID- 22810186 TI - Ethical perspectives in neurology. PMID- 22810187 TI - Practice issues in neurology. PMID- 22810189 TI - APPENDIX B: AAN Summary of Evidence-Based Guidelines for Clinicians: Use of Botulinum Neurotoxin for the Treatment of Movement Disorders. PMID- 22810188 TI - APPENDIX A: Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). PMID- 22810191 TI - Preferred responses. PMID- 22810190 TI - Multiple-choice questions. PMID- 22810193 TI - Effect of beta-carotene on immunity function and tumour growth in hepatocellular carcinoma rats. AB - The aim of the present study was to investigate the anticancer and immunity activity of beta-carotene in hepatocellular carcinoma (HCC) rats. Three days after transplantation, forty Wistar rats were randomly divided into four groups, each group consisting of 10 animals. These groups were control group (untreated), low-dose beta-carotene-treated group (20 mg/kg), middle-dose group (40 mg/kg) and high-dose (60 mg/kg) group. beta-Carotene-treated groups were fed with beta carotene (20, 40, 60 mg/kg b.w.) orally for 30 days. Control group was treated with the same volume of physiological saline. Another ten rats were served as the normal group. Results showed that 30 days of beta-carotene treatment could significantly inhibit tumour growth, enhance blood NK, IL-2, TNF-alpha, WBC, TP, ALB and A/G levels, and decrease blood ALT, AST and ALP activities in HCC rats. Pathological analysis of liver tissue showed that beta-carotene treatment may decrease damage of liver tissue in HCC rats. It can be concluded that beta carotene may improve the immunity function and inhibit tumour growth in HCC rats. PMID- 22810194 TI - IBS-catalyzed regioselective oxidation of phenols to 1,2-quinones with Oxone(r). AB - We have developed the first example of hypervalent iodine(V)-catalyzed regioselective oxidation of phenols to o-quinones. Various phenols could be oxidized to the corresponding o-quinones in good to excellent yields using catalytic amounts of sodium salts of 2-iodobenzenesulfonic acids (pre-IBSes) and stoichiometric amounts of Oxone(r) as a co-oxidant under mild conditions. The reaction rate of IBS-catalyzed oxidation under nonaqueous conditions was further accelerated in the presence of an inorganic base such as potassium carbonate (K2CO3), a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu4NHSO4), and a dehydrating agent such as anhydrous sodium sulfate (Na2SO4). PMID- 22810195 TI - Metabolism of tanshinone IIA, cryptotanshinone and tanshinone I from Radix Salvia miltiorrhiza in zebrafish. AB - The study aimed to investigate the potential of zebrafish in imitating mammal phase I metabolism of natural compounds. Three diterpenoid quinones from Radix Salvia miltiorrhiza, namely tanshinone IIA (TIIA), cryptotanshinone (Cry) and tanshinone I (TI) were selected as model compounds, and their metabolites mediated by zebrafish were characterized using a high-performance liquid chromatography coupled ion-trap mass spectrometry (HPLC/IT-MSn) method with electrospray ionization in positive mode. The separation was performed with a Zorbax C-18 column using a binary gradient elution of 0.05% formic acid acetonitrile/0.05% formic acid water. According to the MS spectra and after comparison with reference standards and literature reports, hydroxylation, dehydrogenation or D-ring hydrolysis metabolites of TIIA and Cry but not of TI were characterized, which coincided with those reported using regular in vivo or in vitro metabolic analysis methods, thus verifying that zebrafish can successfully imitate mammalian phase I metabolism which instills further confidence in using zebrafish as a novel and prospective metabolism model. PMID- 22810196 TI - Anti-hepatitis B virus activity of chickweed [Stellaria media (L.) Vill.] extracts in HepG2.2.15 cells. AB - Stellaria media (Linn.) Villars is a traditional Chinese medicine that has been used for over 200 years, mainly for the treatment of dermatitis and other skin diseases. It has also been used as an anti-viral agent. All the fresh chickweed juice samples used in this study were prepared using macroporous resin and ultrafiltration technology. The anti-hepatitis B virus (HBV) activity of S. media was evaluated in vitro using the human HBV-transfected liver cell line HepG2.2.15. The concentrations of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in HepG2.2.15 cell culture medium were determined by enzyme-linked immunosorbent assay (ELISA) after S. media-n (SM-n) treatment for 6 or 9 days. HBV DNA was quantified using transcription-mediated amplification and real-time polymerase chain reaction. In HepG2.2.15 cells, 30 MUg/mL SM-3 effectively suppressed the secretion of HBsAg and HBeAg with inhibition rates of 27.92% and 25.35% after 6 days of treatment, respectively. Consistent with the reduction in HBV antigens, SM-3 also reduced the level of HBV DNA in a dose-dependent manner. The characterization and quantitation of the chemical composition of SM-3 showed the presence of flavonoid C-glycosides, polysaccharides, and protein, which exhibited diverse antiviral activities. In conclusion, our results demonstrate that SM-3 possesses potential anti-HBV activity in vitro. This is the first report demonstrating the anti-HBV effects of S. media, which is currently under early development as a potential anti-HBV drug candidate. PMID- 22810197 TI - Assessment of religious and spiritual capital in African American communities. AB - African American faith communities are an important source of social capital. The present study adapted a theory-based social capital instrument to result in religious (e.g., from organized worship) and spiritual (e.g., from relationship with higher power) capital measures. Data from a national sample of 803 African Americans suggest the instruments have high internal reliability and are distinct from general religiosity. Measurement models confirmed factor structures. Religious capital was positively associated with self-rated health status. Religious and spiritual capital were negatively associated with depressive symptoms, but these associations largely became nonsignificant in multivariate models that controlled for demographic characteristics. An exception is for spiritual capital in the form of community participation, which retained a negative association with depressive symptoms. These instruments may have applied value for health promotion research and practice in African American communities. PMID- 22810200 TI - Cloning, sequence, and association analysis of porcine OSAP gene. AB - Ovary-specific acidic protein (OSAP) is an important reproduction-related gene. In this study, we cloned the full-length cDNA sequence of porcine OSAP gene through the rapid amplification of cDNA ends method. The porcine OSAP gene encodes a protein of 238 amino acids which shares high homology with the OSAP of five species: rhesus monkey (72 %), human (70 %), cattle (68 %), horse (68 %), and dog (61 %). This gene is structured in four exons and three introns as revealed by computer-assisted analysis. PCR-RFLP was established to detect the GU373669:c.854A>T substitution of porcine OSAP gene mRNA and association of this mutation with litter size traits was assessed in Large White (n=100) and Landrace (n=100) pig populations. Results demonstrated that this polymorphic locus was significantly associated with the litter size of all parities in Large White sows and Landrace sows (P<0.05). Therefore, OSAP gene could be a useful candidate gene in selection for increasing litter size in pigs. These data serve as a foundation for further insight into this novel porcine gene. PMID- 22810201 TI - In vivo detection of copper ions by magnetic resonance imaging using a prion based contrast agent. AB - Abnormal distributions of transition metals inside the body are potential diagnostic markers for several diseases, including Alzheimer's disease, Parkinson's disease, Wilson's disease, and cancer. In this article, we demonstrate that P57/Gd, a novel prion-based contrast agent, can selectively image tissues with excessive copper accumulation using magnetic resonance imaging (MRI). P57/Gd selectivity binds copper(II) over other physiologically relevant cations such as zinc, iron, manganese, and calcium. To simulate a metabolic copper disorder, we treated mice with an intraperitoneal injection of a CuSO(4) solution to induce a renal copper overload. The MRI signal intensities from the renal cortex and medulla of copper spiked animals that were administered P57/Gd were found to correlate with the ex vivo copper concentrations determined by inductively coupled plasma mass spectrometry. PMID- 22810202 TI - Improvement of thermostability and activity of firefly luciferase through [TMG][Ac] ionic liquid mediator. AB - Firefly luciferase catalyzes production of light from luciferin in the presence of Mg(2+)-ATP and oxygen. This enzyme has wide range of applications in biotechnology and development of biosensors. The low thermal stability of wild type firefly luciferase is a limiting factor in most applications. Improvements in activity and stability of few enzymes in the presence of ionic liquids were shown in many reports. In this study, kinetic and thermal stability of firefly luciferase from Photinus pyralis in the presence of three tetramethylguanidine based ionic liquids was investigated. The enzyme has shown improved activity in the presence of [1, 1, 3, 3-tetramethylguanidine][acetate], but in the presence of [TMG][trichloroacetate] and [TMG][triflouroacetate] activity, it decreased or unchanged significantly. Among these ionic liquids, only [TMG][Ac] has increased the thermal stability of luciferase. Incubation of [TMG][Ac] with firefly luciferase brought about with decrease of K(m) for ATP. PMID- 22810203 TI - Magnetoelastic effects in multiferroic YMnO3. AB - We have investigated magnetoelastic effects in multiferroic YMnO(3) below the antiferromagnetic phase transition, T(N) ~ 70 K, using neutron powder diffraction. The a lattice parameter of the hexagonal unit cell of YMnO(3) decreases normally above T(N), but decreases anomalously below T(N), whereas the c lattice parameter increases with decreasing temperature and then increases anomalously below T(N). The unit cell volume also undergoes an anomalous contraction below T(N). By fitting the background thermal expansion for a non magnetic lattice with the Einstein-Gruneisen equation, we determined the lattice strains Deltaa, Deltac and DeltaV due to the magnetoelastic effects as a function of temperature. We have also determined the temperature variation of the ordered magnetic moment of the Mn ion by fitting the measured Bragg intensities of the nuclear and magnetic reflections with the known crystal and magnetic structure models and have established that the lattice strain due to the magnetoelastic effect in YMnO(3) couples with the square of the ordered magnetic moment or the square of the order parameter of the antiferromagnetic phase transition. PMID- 22810204 TI - A high-throughput, quantitative cell-based screen for efficient tailoring of RNA device activity. AB - Recent advances have demonstrated the use of RNA-based control devices to program sophisticated cellular functions; however, the efficiency with which these devices can be quantitatively tailored has limited their broader implementation in cellular networks. Here, we developed a high-efficiency, high-throughput and quantitative two-color fluorescence-activated cell sorting-based screening strategy to support the rapid generation of ribozyme-based control devices with user-specified regulatory activities. The high-efficiency of this screening strategy enabled the isolation of a single functional sequence from a library of over 10(6) variants within two sorting cycles. We demonstrated the versatility of our approach by screening large libraries generated from randomizing individual components within the ribozyme device platform to efficiently isolate new device sequences that exhibit increased in vitro cleavage rates up to 10.5-fold and increased in vivo activation ratios up to 2-fold. We also identified a titratable window within which in vitro cleavage rates and in vivo gene-regulatory activities are correlated, supporting the importance of optimizing RNA device activity directly in the cellular environment. Our two-color fluorescence activated cell sorting-based screen provides a generalizable strategy for quantitatively tailoring genetic control elements for broader integration within biological networks. PMID- 22810205 TI - Right- and left-loop short shRNAs have distinct and unusual mechanisms of gene silencing. AB - Small hairpin RNAs (shRNAs) having duplex lengths of 25-29 bp are normally processed by Dicer into short interfering RNAs (siRNAs) before incorporation into the RNA-induced silencing complex (RISC). However, shRNAs of <= 19 bp [short shRNAs (sshRNAs)] are too short for Dicer to excise their loops, raising questions about their mechanism of action. sshRNAs are designated as L-type or R type according to whether the loop is positioned 3' or 5' to the guide sequence, respectively. Using nucleotide modifications that inhibit RNA cleavage, we show that R- but not L-sshRNAs require loop cleavage for optimum activity. Passenger arm slicing was found to be important for optimal functioning of L-sshRNAs but much less important for R-sshRNAs that have a cleavable loop. R-sshRNAs could be immunoprecipitated by antibodies to Argonaute-1 (Ago1); complexes with Ago1 contained both intact and loop-cleaved sshRNAs. In contrast, L-sshRNAs were immunoprecipitated with either Ago1 or Ago2 and were predominantly sliced in the passenger arm of the hairpin. However, 'pre-sliced' L-sshRNAs were inactive. We conclude that active L-sshRNAs depend on slicing of the passenger arm to facilitate opening of the duplex, whereas R-sshRNAs primarily act via loop cleavage to generate a 5'-phosphate at the 5'-end of the guide strand. PMID- 22810206 TI - Repair of cisplatin-induced DNA interstrand crosslinks by a replication independent pathway involving transcription-coupled repair and translesion synthesis. AB - DNA interstrand crosslinks (ICLs) formed by antitumor agents, such as cisplatin or mitomycin C, are highly cytotoxic DNA lesions. Their repair is believed to be triggered primarily by the stalling of replication forks at ICLs in S-phase. There is, however, increasing evidence that ICL repair can also occur independently of replication. Using a reporter assay, we describe a pathway for the repair of cisplatin ICLs that depends on transcription-coupled nucleotide excision repair protein CSB, the general nucleotide excision repair factors XPA, XPF and XPG, but not the global genome nucleotide excision repair factor XPC. In this pathway, Rev1 and Polzeta are involved in the error-free bypass of cisplatin ICLs. The requirement for CSB, Rev1 or Polzeta is specific for the repair of ICLs, as the repair of cisplatin intrastrand crosslinks does not require these genes under identical conditions. We directly show that this pathway contributes to the removal of ICLs outside of S-phase. Finally, our studies reveal that defects in replication- and transcription-dependent pathways are additive in terms of cellular sensitivity to treatment with cisplatin or mitomycin C. We conclude that transcription- and replication-dependent pathways contribute to cellular survival following treatment with crosslinking agents. PMID- 22810207 TI - Three-dimensionally designed protein-responsive RNA devices for cell signaling regulation. AB - The three-dimensional (3D) structures of many biomacromolecules have been solved to reveal the functions of these molecules. However, these 3D structures have rarely been applied to constructing efficient molecular devices that function in living cells. Here, we demonstrate a 3D structure-based molecular design principle for constructing short hairpin RNA (shRNA)-mediated genetic information converters; these converters respond to specific proteins and trigger the desired gene expression by modulating the function of the RNA-processing enzyme Dicer. The inhibitory effect on Dicer cleavage against the shRNA designed to specifically bind to U1A spliceosomal protein was correlated with the degree of steric hindrance between Dicer and the shRNA-protein complex in vitro: The level of the hindrance was predicted based on the models. Moreover, the regulation of gene expression was achieved by using the shRNA converters designed to bind to the target U1A or nuclear factor-kappaB (NF-kappaB) p50 proteins expressed in human cells. The 3D molecular design approach is widely applicable for developing new devices in synthetic biology. PMID- 22810208 TI - Kinetics of endogenous mouse FEN1 in base excision repair. AB - The structure specific flap endonuclease 1 (FEN1) plays an essential role in long patch base excision repair (BER) and in DNA replication. We have generated a fluorescently tagged FEN1 expressing mouse which allows monitoring the localization and kinetics of FEN1 in response to DNA damage in living cells and tissues. The expression of FEN1, which is tagged at its C-terminal end with enhanced yellow fluorescent protein (FEN1-YFP), is under control of the endogenous Fen1 transcriptional regulatory elements. In line with its role in processing of Okazaki fragments during DNA replication, we found that FEN1-YFP expression is mainly observed in highly proliferating tissue. Moreover, the FEN1 YFP fusion protein allowed us to investigate repair kinetics in cells challenged with local and global DNA damage. In vivo multi-photon fluorescence microscopy demonstrates rapid localization of FEN1 to local laser-induced DNA damage sites in nuclei, providing evidence of a highly mobile protein that accumulates fast at DNA lesion sites with high turnover rate. Inhibition of poly (ADP-ribose) polymerase 1 (PARP1) disrupts FEN1 accumulation at sites of DNA damage, indicating that PARP1 is required for FEN1 recruitment to DNA repair intermediates in BER. PMID- 22810209 TI - Lesion-specific DNA-binding and repair activities of human O6-alkylguanine DNA alkyltransferase. AB - Binding experiments with alkyl-transfer-active and -inactive mutants of human O(6)-alkylguanine DNA alkyltransferase (AGT) show that it forms an O(6) methylguanine (6mG)-specific complex on duplex DNA that is distinct from non specific assemblies previously studied. Specific complexes with duplex DNA have a 2:1 stoichiometry that is formed without accumulation of a 1:1 intermediate. This establishes a role for cooperative interactions in lesion binding. Similar specific complexes could not be detected with single-stranded DNA. The small difference between specific and non-specific binding affinities strongly limits the roles that specific binding can play in the lesion search process. Alkyl transfer kinetics with a single-stranded substrate indicate that two or more AGT monomers participate in the rate-limiting step, showing for the first time a functional link between cooperative binding and the repair reaction. Alkyl transfer kinetics with a duplex substrate suggest that two pathways contribute to the formation of the specific 6mG-complex; one at least first order in AGT, we interpret as direct lesion binding. The second, independent of [AGT], is likely to include AGT transfer from distal sites to the lesion in a relatively slow unimolecular step. We propose that transfer between distal and lesion sites is a critical step in the repair process. PMID- 22810210 TI - Aortic artery distensibility shows inverse correlation with heart rate variability in elderly non-hypertensive, cardiovascular disease-free individuals: the Ikaria Study. AB - The aim of this study was to evaluate the relation between aortic artery distensibility, expressed by pulse pressure (PP) and autonomic nervous system function expressed by heart rate variability (HRV), among elders. During 2009, 469 individuals (50 % males, mean age 75 +/- 6 years old), permanent inhabitants of Ikaria Island, were enrolled. Among several sociodemographic, bioclinical, lifestyle, and dietary characteristics, and biochemical parameters related to cardiovascular risk, a digital, standard, 12-lead electrocardiogram (ECG) and 5 min ECG monitoring were recorded. Smart ECG measurement and interpretation programs were used for the automated measurement and interpretation of ECG intervals. Autonomic nervous system tone was estimated with the HRV-standard deviation of normal to normal intervals (SDNN)-in surface ECG. Pulse pressure was calculated as the difference between systolic and diastolic blood pressures. Pulse pressure showed a positive association with age, systolic blood pressure levels, and presence of diabetes mellitus (all P < 0.001) and an inverse correlation with logSDNN. Multiadjusted logistic regression analysis revealed that 10-unit increase in SDNN values decreases by 26 % the likelihood of having PP above 70 mmHg; when the analysis was stratified according to hypertension status, the relationship remained significant only among non-hypertensive individuals. These data support the hypothesis that cardiac sympathovagal disturbance correlates with impaired elasticity properties of aorta, indicating parallel impairment in cardiac autonomic modulation and mechanical vessel wall properties in elderly non-hypertensive individuals. PMID- 22810211 TI - Distress symptoms and high-risk behaviors prospectively associated with treatment use among returning veterans. AB - OBJECTIVE: Distress symptoms and high-risk behaviors among Iraq and Afghanistan veterans were examined as predictors of treatment utilization. METHODS: Veterans (N=618) completed self-report measures upon treatment enrollment (2005-2008). Two year utilization data were obtained for five settings: primary care, mental health within primary care, outpatient mental health, emergency room, and inpatient psychiatric. RESULTS: Pain was associated with primary care use; depression, panic, posttraumatic stress disorder (PTSD), alcohol misuse, and aggression were associated with use of other settings. After adjustment for comorbidity, veterans with high levels of PTSD and depression symptoms had more treatment visits across several settings than veterans with lower levels. Specialty mental health utilization was low among those reporting elevated psychiatric symptoms (for example, a mean of 8.8 outpatient visits over two years). CONCLUSIONS: Symptoms and high-risk behaviors were differentially associated with treatment settings; PTSD and depression predicted greater treatment use. Veterans may have overutilized emergency care while underutilizing specialty mental health services. PMID- 22810212 TI - Erythropoietin treatment for methanol optic neuropathy. AB - BACKGROUND: To present the effect of erythropoietin for the treatment of methanol optic neuropathy. METHODS: Two patients with methanol optic neuropathy were treated with 10,000 IU of intravenous erythropoietin twice a day for 3 days, 500 mg of methylprednisolone twice a day for 5 days (followed by 2 weeks of oral prednisolone [1 mg/kg per day]), and daily doses of vitamin B12, vitamin B6, and folic acid for 1 month. RESULTS: At presentation, the patients had no perception of light in both eyes, associated with mildly swollen optic discs. Both responded dramatically to the treatment regimen. In the first patient, visual acuity improved to 20/20 in both eyes within 3 days, whereas in the second patient, visual acuity returned to counting fingers at 6 feet, right eye, and 20/30, left eye, within 3 weeks. CONCLUSION: Intravenous erythropoietin may be an effective adjuvant when combined with current treatment for patients with methanol optic neuropathy. PMID- 22810213 TI - [ECG changes in patients with chronic non-cancer pain: a prospective observational study]. AB - BACKGROUND: Patients with chronic non-cancer pain not only show reduced quality of life, but also chronic morbidity and increased mortality. However, little is known about prevalence and type of abnormal electrocardiogram (ECG) recordings in these individuals. MATERIAL AND METHODS: A total of 100 consecutive patients (>= 18 years) with chronic (>= 3 months) non-cancer pain were examined prospectively using ECG recordings and a questionnaire [German Pain Society (DGSS); further questions]. Data were collected at the first and next two follow-up outpatients' clinic appointments. RESULTS: Participation rate was 98%. Of all patients, 26% had an abnormal ECG, while 5% of these patients had an abnormal ECG first at the follow-up when consuming a different analgesic regimen. Findings were QTc prolongation (16%), ventricular block (7%), artrioventricular block (6%), and atrial fibrillation (4%). CONCLUSION: The prevalence of abnormal ECG recordings should be considered in the pain management of these patients. General ECG screening in this population should be discussed. Future studies should examine a larger population to identify potential risk factors (e.g., medication). PMID- 22810214 TI - [Pain assessment in elderly nursing home residents: methods paper for the S3 guideline development]. AB - In Germany, there is currently no guideline for pain assessment in elderly people. Pain management in nursing home residents is, however, legally required. For this particular group, especially for people with dementia, suitable interdisciplinary orientations for health care are lacking in Germany. The working group "Pain and Age" of the German Pain Society ("Deutschen Schmerzgesellschaft") in conjunction with the German Centre for Neurodegenerative Diseases ("Deutschen Zentrum fur Neurodegenerative Erkrankungen"), Witten, has embarked on the development of interdisciplinary S3-Guideline for "Pain Assessment in Elderly People in Nursing Homes", based on the methodology suggested by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V."), the German Agency for Quality in Medicine ("Arztliche Zentrum fur Qualitat in der Medizin"), and that described in the DELBI ("Deutschen Leitlinien Bewertungsinstrument"). Delegates of the 38 scientific societies and interest groups currently participating can contribute to the contents on three different levels. The present article outlines the methods for developing the guideline. PMID- 22810215 TI - [Clinical pain consultation. Profiles of clinical pain consultation and requirements for management of complex pain patients in inpatient care]. AB - BACKGROUND: The aim of this investigation was to describe the performance profile and the requirements for the management of complex pain patients for the structures of a consultation service. MATERIAL AND METHODS: The content and number of all inpatient consultations of the pain department (as an independent service in addition to acute pain and palliative care services) were evaluated for the period from 2008-2010. RESULTS: During the study, 1,391 contacts were made in 882 patients; in approx. 50% of the consultations diagnostic or specific (interventional) procedures were requested. Beside additional diagnostic tests, physiotherapy (19.2%), psychological and psychiatric care (11.1%), and other therapeutic approaches (e.g., mirror therapy, transcutaneous electrical nerve stimulation, progressive muscle relaxation) or the long-term follow-up in specialized pain service (20.5%) were recommended. CONCLUSION: Within the scope of the pain consultation, a wide spectrum of pain diagnoses and difficult patients are examined. Mixed forms of acute, chronic, and tumor-related pain are often present. Therapeutically, optimization of only the pharmacological regimen is often not sufficient. Similar requirements for a multimodal diagnosis and therapeutic concept as established in ambulatory and/or specialist care are ultimately needed. PMID- 22810216 TI - Evidence of parallels between mercury intoxication and the brain pathology in autism. AB - The purpose of this review is to examine the parallels between the effects mercury intoxication on the brain and the brain pathology found in autism spectrum disorder (ASD). This review finds evidence of many parallels between the two, including: (1) microtubule degeneration, specifically large, long-range axon degeneration with subsequent abortive axonal sprouting (short, thin axons); (2) dentritic overgrowth; (3) neuroinflammation; (4) microglial/astrocytic activation; (5) brain immune response activation; (6) elevated glial fibrillary acidic protein; (7) oxidative stress and lipid peroxidation; (8) decreased reduced glutathione levels and elevated oxidized glutathione; (9) mitochondrial dysfunction; (10) disruption in calcium homeostasis and signaling; (11) inhibition of glutamic acid decarboxylase (GAD) activity; (12) disruption of GABAergic and glutamatergic homeostasis; (13) inhibition of IGF-1 and methionine synthase activity; (14) impairment in methylation; (15) vascular endothelial cell dysfunction and pathological changes of the blood vessels; (16) decreased cerebral/cerebellar blood flow; (17) increased amyloid precursor protein; (18) loss of granule and Purkinje neurons in the cerebellum; (19) increased pro inflammatory cytokine levels in the brain (TNF-alpha, IFN-gamma, IL-1beta, IL-8); and (20) aberrant nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). This review also discusses the ability of mercury to potentiate and work synergistically with other toxins and pathogens in a way that may contribute to the brain pathology in ASD. The evidence suggests that mercury may be either causal or contributory in the brain pathology in ASD, possibly working synergistically with other toxic compounds or pathogens to produce the brain pathology observed in those diagnosed with an ASD. PMID- 22810217 TI - Protective effect of treatment with black cumin oil on spatial cognitive functions of rats that suffered global cerebrovascular hypoperfusion. AB - The fixed oil of black cumin seeds, Nigella sativa L. (NSO), has shown considerable antioxidant and anti-inflammatory activities. Chronic cerebral hypoperfusion has been linked to neurodegenerative disorders including Alzheimer's disease (AD) and its subsequent cognitive impairment in which oxidative stress and neuroinflammation are the principal culprits. Cerebrovascular hypoperfusion was experimentally achieved by bilateral common carotid arteries occlusion (2VO) in rats. Morris water maze (MWM) test was employed to assess the effects of NSO on spatial cognitive function before and after 2VO intervention. Rats were divided into long-term memory (LTM) and short term memory (STM) groups, each was further subdivided into 3 subgroups: sham control, untreated 2VO and NSO treated 2VO group. All subgroups were tested with MWM at the tenth postoperative week. Working memory test results for both sham control and NSO treated groups showed significantly lower escape latency time and total distance travelled than untreated 2VO group. Similarly, LTM and STM MWM tests for sham control and NSO treated groups revealed significantly better maze test performance as compared to untreated 2VO group. Sham control and NSO treated 2VO groups demonstrated superior probe memory test performance as compared to untreated 2VO group. The fixed oil of Nigella sativa seeds has demonstrated noticeable spatial cognitive preservation in rats challenged with chronic cerebral hypoperfusion which indicates a promising prospective neuroprotective effect. PMID- 22810218 TI - Behavioral improvement in MPTP-treated nonhuman primates in the HALLWAY task after transfer of TH cDNA to host astrocytes. AB - Parkinson's disease is a neurodegenerative disease, resulting from deterioration of the substantia nigra which in turn leads to a decrease of dopamine levels in the striatum. Clinically the syndrome is characterized by motor alterations that are treated by the oral administration of levodopa. However, this treatment typically loses efficacy over time and therefore new treatments that procure a steady long term supplement of dopamine are needed. Here we tested the expression of a tyrosine hydroxilase (TH) transgene in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) treated primates own astrocytes. The transgene, whose expression of TH cDNA was controlled by a glial fibrillary acidic protein (GFAP) promoter, was injected into MPTP treated primate's brains using liposomes as a delivery system. Monkeys were tested before and after MPTP administration, and after gene therapy treatment on the HALLWAY behavioral task. Results showed both transgene expression and significant behavioral improvements in the hallway task after the TH cDNA transfer. The behavioral recovery observed in the primates whose astrocytes expressed rat TH, is a first step that warrant further studies using primate's astrocytes as a good cell lineage to express therapeutic molecules. PMID- 22810219 TI - Influence of carbenoxolone on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats. AB - Abnormal synchronized neuronal discharges mediated by gap junctions have an important role in epileptic seizures. The analysis of anticonvulsant drugs acting on gap junctions is still a priority in epilepsy research. Therefore, the present study was designed to investigate the effect of carbenoxolone, a gap junction blocker, on the anticonvulsant efficacy of phenytoin in pentylenetetrazole kindled rats. Male Wistar albino rats, 14 weeks of age, were used. In the first step of the study, animals were given PTZ 35 mg/kg intraperitoneally (i.p.) three times a week until kindling was produced. Then, indwelling screw electrodes - allowing EEG monitoring of conscious rats - were implanted into the crania of the kindled rats. In this way, we were able to record EEG activity and evaluate seizure stage at the same time. In the second step of the study, the interaction between carbenoxolone (40 mg/kg i.p.) and phenytoin (60 mg/kg, i.p.) was investigated. The data analysis was performed using a one-way ANOVA with LSD post hoc test. Total spike number and the generalized seizure duration were reduced in the carbenoxolone treated group compared to the PTZ group. Phenytoin decreased generalized seizure duration, total spike number and seizure severity score. Carbenoxolone and phenytoin have anti-seizure effects in PTZ kindled rats. There was no significant difference between the carbenoxolone + phenytoin combination and phenytoin in terms of generalized seizure duration, total spike number and seizure stage. The results indicate that carbenoxolone combined with phenytoin is not more effective than the use of these drugs alone. PMID- 22810220 TI - Region-related modular nerve-dependent motor activity in anorectum--cholinergic and nitrergic contribution to rat model. AB - Disturbances of enteric nerve-mediated anorectal evacuation mechanisms have medical and social impact. The study aimed at further eliciting the contribution of cholinergic and nitrergic neurotransmission systems to modular nerve networks in different regions of Wistar rat anorectum. Electrical field stimulation (EFS, 0.8 ms, 40 V, 2, 5 or 10 Hz, 20 s), computerized mechanographic on-line setup and drugs were used to evaluate the motor responses of isolated rings from circular muscle of rectum (proximal, middle, and distal part), internal anal sphincter, and anal canal. Twitch-like frequency-dependent contractions, more pronounced in rectal preparations, characterized the modular motor responses of rectal circular muscle rings and anal canal. Depending on the frequency of stimulation, the motor activity of internal anal sphincter varied from deep long-lasting relaxation to initial short-lasting relaxation, followed by a contraction. Electrically-evoked responses of anorectal preparations were tetrodotoxin (0.1 microM)-sensitive. In the presence of atropine (0.3 microM) the contractions of rectal rings decreased, relaxation of internal anal sphincter increased and inhibition of the contractions of the anal canal occurred, followed by relaxation. During atropine treatment, NG-nitro-L-arginine (0.5 microM) increased the contractile responses and suppressed internal anal sphincter relaxations. L-arginine (0.5 microM) decreased the contractions and extended the relaxations of internal anal sphincter and anal canal. Our results suggest that cholinergic and nitrergic systems are not equally involved in modular nerve networks of various regions of anorectum. Cholinergic transmission is more expressed in distal rectum, underlying its contractile potency, while nitric oxide-dependent transmission(s) control the relaxation ability of the internal anal sphincter and anal canal. PMID- 22810221 TI - The vascular disrupting agent ombrabulin (AVE8062) enhances the efficacy of standard therapies in head and neck squamous cell carcinoma xenograft models. AB - Targeting tumor vasculature is an emerging strategy in cancer treatment. Promising results have been shown in preclinical studies when vascular disrupting agents (VDAs) are used in combination with other anticancer therapies. Because radiation therapy with concurrent cisplatin or cetuximab has become standard treatment for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), we investigated whether the VDA ombrabulin (AVE8062) could improve the antitumor activity of radiation plus cisplatin and radiation plus cetuximab combinations. HNSCC HEP2 or FaDu tumor bearing mice were treated with ombrabulin, cisplatin, cetuximab, local radiation therapy or combinations of these treatments. Ombrabulin attenuated tumor growth of HEP2 and FaDu xenografts compared to control tumors. A more pronounced tumor growth delay and tumor regression were induced when ombrabulin was added to local irradiation, cisplatin or cetuximab in FaDu tumors compared to single agent treatments. Finally, triple agent therapies combining ombrabulin, irradiation, and either cisplatin or cetuximab were more effective than double combination treatment regimens and increased tumor growth delay in both HEP2 and FaDu tumor models. Of note, complete tumor regression was achieved in FaDu tumor model for the triple combination including platinum. Immunohistochemistry on FaDu tumors demonstrated a specificity of ombrabulin towards intratumoral vessels, in contrast to peritumoral vasculature. Our results provide a rationale for the use of ombrabulin in combination with two standard treatment regimens that are concurrent cisplatin-based chemoradiation and cetuximab plus ionizing radiation therapies, for the treatment of HNSCC. PMID- 22810222 TI - Structures of the PelD cyclic diguanylate effector involved in pellicle formation in Pseudomonas aeruginosa PAO1. AB - The second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di GMP) plays a vital role in the global regulation in bacteria. Here, we describe structural and biochemical characterization of a novel c-di-GMP effector PelD that is critical to the formation of pellicles by Pseudomonas aeruginosa. We present high-resolution structures of a cytosolic fragment of PelD in apo form and its complex with c-di-GMP. The structure contains a bi-domain architecture composed of a GAF domain (commonly found in cyclic nucleotide receptors) and a GGDEF domain (found in c-di-GMP synthesizing enzymes), with the latter binding to one molecule of c-di-GMP. The GGDEF domain has a degenerate active site but a conserved allosteric site (I-site), which we show binds c-di-GMP with a K(d) of 0.5 MUm. We identified a series of residues that are crucial for c-di-GMP binding, and confirmed the roles of these residues through biochemical characterization of site-specific variants. The structures of PelD represent a novel class of c-di-GMP effector and expand the knowledge of scaffolds that mediate c-di-GMP recognition. PMID- 22810223 TI - Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis. AB - Insulin controls fatty acid (FA) release from white adipose tissue (WAT) through direct effects on adipocytes and indirectly through hypothalamic signaling by reducing sympathetic nervous system outflow to WAT. Uncontrolled FA release from WAT promotes lipotoxicity, which is characterized by inflammation and insulin resistance that leads to and worsens type 2 diabetes. Here we tested whether early diet-induced insulin resistance impairs the ability of hypothalamic insulin to regulate WAT lipolysis and thus contributes to adipose tissue dysfunction. To this end we fed male Sprague-Dawley rats a 10% lard diet (high fat diet (HFD)) for 3 consecutive days, which is known to induce systemic insulin resistance. Rats were studied by euglycemic pancreatic clamps and concomitant infusion of either insulin or vehicle into the mediobasal hypothalamus. Short term HFD feeding led to a 37% increase in caloric intake and elevated base-line free FAs and insulin levels compared with rats fed regular chow. Overfeeding did not impair insulin signaling in WAT, but it abolished the ability of mediobasal hypothalamus insulin to suppress WAT lipolysis and hepatic glucose production as assessed by glycerol and glucose flux. HFD feeding also increased hypothalamic levels of the endocannabinoid 2-arachidonoylglycerol after only 3 days. In summary, overfeeding impairs hypothalamic insulin action, which may contribute to unrestrained lipolysis seen in human obesity and type 2 diabetes. PMID- 22810224 TI - Enhanced energy metabolism contributes to the extended life span of calorie restricted Caenorhabditis elegans. AB - Caloric restriction (CR) markedly extends life span and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification, and life span analysis was used to determine how CR, which occurs in the Caenorhabditis elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses. A switch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes were detected. Life span analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the overexpression of the gene for the nematode analog of the cytosolic form of phosphoenolpyruvate carboxykinase caused a marked extension of the life span in C. elegans, presumably by enhancing energy metabolism via an altered rate of cataplerosis of tricarboxylic acid cycle anions. We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny. PMID- 22810225 TI - Arabidopsis molybdopterin biosynthesis protein Cnx5 collaborates with the ubiquitin-like protein Urm11 in the thio-modification of tRNA. AB - The thio-modification of tRNA that occurs in virtually all organisms affects the accuracy and efficiency of protein translation and is therefore biologically important. However, the molecular mechanism responsible for this tRNA modification in plants is largely unclear. We demonstrate here that Arabidopsis sulfurtransferase Cnx5, a ubiquitin-activating enzyme-like (UBA) protein involved in molybdopterin (MPT) biosynthesis, is strictly required for the thio modification of cytosolic tRNAs in vivo. A previously uncharacterized ubiquitin like (Ubl) protein Urm11 is also essential for tRNA thio-modification in Arabidopsis. When expressed in Saccharomyces cerevisiae, Cnx5 and Urm11 can substitute for the corresponding yeast orthologs ScUba4 and ScUrm1, respectively, in the thio-modification of yeast cytosolic tRNAs. However, another Ubl protein, Cnx7 of Arabidopsis, which is involved in MPT biosynthesis in conjunction with Cnx5, cannot replace yeast ScUrm1. Interestingly, the expression of a mutant form of Cnx7 in which the carboxyl-terminal six amino acids are substituted by those of Urm11 can significantly restore the thio-modification of tRNAs in the yeast urm1Delta mutant. These findings suggest that in Arabidopsis the common UBA protein Cnx5 collaborates with two functionally differentiated Ubl proteins, Urm11 and Cnx7, in the thio-modification of tRNA and MPT biosynthesis, respectively. Phylogenetic analysis revealed that although most eukaryotes contained a Cnx5-Urm11 ortholog pair and the tRNA thio-modification some fungi, including S. cerevisiae, had lost the Cnx7 ortholog and the ability to synthesize the molybdenum cofactor. PMID- 22810226 TI - Mycobacterium tuberculosis directs T helper 2 cell differentiation by inducing interleukin-1beta production in dendritic cells. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), resides and replicates within phagocytes and persists in susceptible hosts by modulating protective innate immune responses. Furthermore, M. tuberculosis promotes T helper 2 (Th2) immune responses by altering the balance of T cell polarizing cytokines in infected cells. However, cytokines that regulate Th2 cell differentiation during TB infection remain unknown. Here we show that IL-1beta, produced by phagocytes infected by virulent M. tuberculosis strain H37Rv, directs Th2 cell differentiation. In sharp contrast, the vaccine strain bacille Calmette Guerin as well as RD-1 and ESAT-6 mutants of H37Rv failed to induce IL-1beta and promote Th2 cell differentiation. Furthermore, ESAT-6 induced IL-1beta production in dendritic cells (DCs), and CD4(+) T cells co-cultured with infected DCs differentiated into Th2 cells. Taken together, our findings indicate that IL 1beta induced by RD-1/ESAT-6 plays an important role in the differentiation of Th2 cells, which in turn facilitates progression of TB by inhibiting host protective Th1 responses. PMID- 22810228 TI - Structural and functional basis for substrate specificity and catalysis of levan fructotransferase. AB - Levan is beta-2,6-linked polymeric fructose and serves as reserve carbohydrate in some plants and microorganisms. Mobilization of fructose is usually mediated by enzymes such as glycoside hydrolase (GH), typically releasing a monosaccharide as a product. The enzyme levan fructotransferase (LFTase) of the GH32 family catalyzes an intramolecular fructosyl transfer reaction and results in production of cyclic difructose dianhydride, thus exhibiting a novel substrate specificity. The mechanism by which LFTase carries out these functions via the structural fold conserved in the GH32 family is unknown. Here, we report the crystal structure of LFTase from Arthrobacter ureafaciens in apo form, as well as in complexes with sucrose and levanbiose, a difructosacchride with a beta-2,6-glycosidic linkage. Despite the similarity of its two-domain structure to members of the GH32 family, LFTase contains an active site that accommodates a difructosaccharide using the 1 and -2 subsites. This feature is unique among GH32 proteins and is facilitated by small side chain residues in the loop region of a catalytic beta-propeller N domain, which is conserved in the LFTase family. An additional oligosaccharide binding site was also characterized in the beta-sandwich C-domain, supporting its role in carbohydrate recognition. Together with functional analysis, our data provide a molecular basis for the catalytic mechanism of LFTase and suggest functional variations from other GH32 family proteins, notwithstanding the conserved structural elements. PMID- 22810227 TI - Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons. AB - Dendrites are the main site of information input into neurons. Their development is a multistep process controlled by mammalian target of rapamycin (mTOR) among other proteins. mTOR is a serine/threonine protein kinase that forms two functionally distinct complexes in mammalian cells: mTORC1 and mTORC2. However, the one that contributes to mammalian neuron development remains unknown. This work used short hairpin RNA against Raptor and Rictor, unique components of mTORC1 and mTORC2, respectively, to dissect mTORC involvement in this process. We provide evidence that both mTOR complexes are crucial for the proper dendritic arbor morphology of hippocampal neurons. These two complexes are required for dendritic development both under basal conditions and upon the induction of mTOR dependent dendritic growth. We also identified Akt as a downstream effector of mTORC2 needed for proper dendritic arbor morphology, the action of which required mTORC1 and p70S6K1. PMID- 22810229 TI - Nucleotide binding site communication in Arabidopsis thaliana adenosine 5' phosphosulfate kinase. AB - Adenosine 5'-phosphosulfate kinase (APSK) catalyzes the ATP-dependent synthesis of adenosine 3'-phosphate 5'-phosphosulfate (PAPS), which is an essential metabolite for sulfur assimilation in prokaryotes and eukaryotes. Using APSK from Arabidopsis thaliana, we examine the energetics of nucleotide binary and ternary complex formation and probe active site features that coordinate the order of ligand addition. Calorimetric analysis shows that binding can occur first at either nucleotide site, but that initial interaction at the ATP/ADP site was favored and enhanced affinity for APS in the second site by 50-fold. The thermodynamics of the two possible binding models (i.e. ATP first versus APS first) differs and implies that active site structural changes guide the order of nucleotide addition. The ligand binding analysis also supports an earlier suggestion of intermolecular interactions in the dimeric APSK structure. Crystallographic, site-directed mutagenesis, and energetic analyses of oxyanion recognition by the P-loop in the ATP/ADP binding site and the role of Asp(136), which bridges the ATP/ADP and APS/PAPS binding sites, suggest how the ordered nucleotide binding sequence and structural changes are dynamically coordinated for catalysis. PMID- 22810230 TI - A bacterial electron-bifurcating hydrogenase. AB - The Wood-Ljungdahl pathway of anaerobic CO(2) fixation with hydrogen as reductant is considered a candidate for the first life-sustaining pathway on earth because it combines carbon dioxide fixation with the synthesis of ATP via a chemiosmotic mechanism. The acetogenic bacterium Acetobacterium woodii uses an ancient version of the pathway that has only one site to generate the electrochemical ion potential used to drive ATP synthesis, the ferredoxin-fueled, sodium-motive Rnf complex. However, hydrogen-based ferredoxin reduction is endergonic, and how the steep energy barrier is overcome has been an enigma for a long time. We have purified a multimeric [FeFe]-hydrogenase from A. woodii containing four subunits (HydABCD) which is predicted to have one [H]-cluster, three [2Fe2S]-, and six [4Fe4S]-clusters consistent with the experimental determination of 32 mol of Fe and 30 mol of acid-labile sulfur. The enzyme indeed catalyzed hydrogen-based ferredoxin reduction, but required NAD(+) for this reaction. NAD(+) was also reduced but only in the presence of ferredoxin. NAD(+) and ferredoxin reduction both required flavin. Spectroscopic analyses revealed that NAD(+) and ferredoxin reduction are strictly coupled and that they are reduced in a 1:1 stoichiometry. Apparently, the multimeric hydrogenase of A. woodii is a soluble energy converting hydrogenase that uses electron bifurcation to drive the endergonic ferredoxin reduction by coupling it to the exergonic NAD(+) reduction. PMID- 22810231 TI - A substrate binding hinge domain is critical for transport-related structural changes of organic cation transporter 1. AB - Organic cation transporters are membrane potential-dependent facilitative diffusion systems. Functional studies, extensive mutagenesis, and homology modeling indicate the following mechanism. A transporter conformation with a large outward-open cleft binds extracellular substrate, passes a state in which the substrate is occluded, turns to a conformation with an inward-open cleft, releases substrate, and subsequently turns back to the outward-open state. In the rat organic cation transporter (rOct1), voltage- and ligand-dependent movements of fluorescence-labeled cysteines were measured by voltage clamp fluorometry. For fluorescence detection, cysteine residues were introduced in extracellular parts of cleft-forming transmembrane alpha-helices (TMHs) 5, 8, and 11. Following expression of the mutants in Xenopus laevis oocytes, cysteines were labeled with tetramethylrhodamine-6-maleimide, and voltage-dependent conformational changes were monitored by voltage clamp fluorometry. One cysteine was introduced in the central domain of TMH 11 replacing glycine 478. This domain contains two amino acids that are involved in substrate binding and two glycine residues (Gly-477 and Gly-478) allowing for helix bending. Cys-478 could be modified with the transported substrate analog [2-(trimethylammonium)-ethyl]methanethiosulfonate but was inaccessible to tetramethylrhodamine-6-maleimide. Voltage-dependent movements at the indicator positions of TMHs 5, 8, and 11 were altered by substrate applications indicating large conformational changes during transport. The G478C exchange decreased transporter turnover and blocked voltage-dependent movements of TMHs 5 and 11. [2-(Trimethylammonium)-ethyl]methanethiosulfonate modification of Cys-478 blocked substrate binding, transport activity, and movement of TMH 8. The data suggest that Gly-478 is located within a mechanistically important hinge domain of TMH 11 in which substrate binding induces transport-related structural changes. PMID- 22810232 TI - Involvement of c-Src tyrosine kinase upstream of class I phosphatidylinositol (PI) 3-kinases in Salmonella Enteritidis Rck protein-mediated invasion. AB - The Salmonella outer membrane protein Rck mediates a Zipper entry mechanism controlled by tyrosine phosphorylation and class I phosphatidylinositol 3-kinase (PI 3-kinase). However, the underlying mechanism leading to this signaling cascade remains unclear. The present study showed that using Rck-coated beads or Rck-overexpressing Escherichia coli, Rck-mediated actin polymerization and invasion were blocked by PP2, a Src family tyrosine kinase inhibitor. In addition, phosphorylation of Src family kinases significantly increased after stimulation with Rck. The specific contribution of c-Src, one member of the Src family kinases, was demonstrated using c-Src-deficient fibroblasts or c-Src siRNA transfected epithelial cells. We also observed that Rck-mediated internalization led to the formation of a complex between c-Src and at least one tyrosine phosphorylated protein. Furthermore, our results revealed that the c-Src signal molecule was upstream of PI 3-kinase during the Rck-mediated signaling pathway as Rck-mediated PI 3-kinase activation was blocked by PP2, and PI 3-kinase inhibitor had no effect on the Src phosphorylation. These results demonstrate the involvement of c-Src upstream of the PI 3-kinase in the Zipper entry process mediated by Rck. PMID- 22810233 TI - SNAREpin assembly by Munc18-1 requires previous vesicle docking by synaptotagmin 1. AB - Regulated exocytosis requires the general membrane fusion machinery-soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) and Sec1/Munc18 (SM) proteins. Using reconstituted giant unilamellar vesicles containing preassembled t-SNARE proteins (syntaxin 1.SNAP-25), we determined how Munc18-1 controls the docking, priming, and fusion of small unilamellar vesicles containing the v-SNARE VAMP2 and the Ca(2+) sensor synaptotagmin 1. In vitro assays allowed us to position Munc18-1 in the center of a sequential reaction cascade; vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion. Complexin II stalls SNAREpin zippering at a late stage and, hence, contributes to synchronize membrane fusion in a Ca(2+)- and synaptotagmin 1-dependent manner. Thus, at the neuronal synapse, the priming factor Munc18-1 may accelerate the conversion of docked synaptic vesicles into a readily releasable pool by activating SNAREs for efficient membrane fusion. PMID- 22810234 TI - The zinc regulated antivirulence pathway of Salmonella is a multiprotein immunoglobulin adhesion system. AB - The co-evolutionary relationship between pathogen and host has led to a regulatory cycle between virulence factors needed for survival and antivirulence factors required for host transmission. This is exemplified in Salmonella spp. by the zirTS antivirulence genes: a secretion pathway comprised of the outer membrane transporter ZirT, and its secreted partner, ZirS. ZirTS act within the gastrointestinal tract to function as a virulence modulator and during Salmonella shedding in anticipation of a new host. Together, ZirT and ZirS decrease virulence by lowering bacterial colonization at systemic sites through an unknown mechanism. To understand this mechanism, we have probed the zirTS pathway both structurally and biochemically. The NMR derived structural ensemble of the C terminal domain of ZirS reveals an immunoglobin superfamily fold (IgSF). Stable isotope labeling by amino acids in cell culture experiments show that the ZirS IgSF domain interacts with its transporter ZirT, and reveal a new protein interaction partner of the pathway, a protein encoded adjacent to zirTS that we have designated as ZirU. ZirU is secreted by ZirT and is also a predicted IgSF. Biochemical analysis delineates ZirT into an N-terminal porin-like beta domain and C-terminal extracellular soluble IgSF domain, whereas biophysical characterization suggests that the transporter undergoes self-association in a concentration-dependent manner. We observe that ZirS and ZirU directly interact with each other and with the extracellular domains of ZirT. Here we show that the zir antivirulence pathway is a multiprotein immunoglobulin adhesion system consisting of a complex interplay between ZirS, ZirT, and ZirU. PMID- 22810235 TI - The structure- and metal-dependent activity of Escherichia coli PgaB provides insight into the partial de-N-acetylation of poly-beta-1,6-N-acetyl-D glucosamine. AB - Exopolysaccharides are required for the development and integrity of biofilms produced by a wide variety of bacteria. In Escherichia coli, partial de-N acetylation of the exopolysaccharide poly-beta-1,6-N-acetyl-D-glucosamine (PNAG) by the periplasmic protein PgaB is required for polysaccharide intercellular adhesin-dependent biofilm formation. To understand the molecular basis for PNAG de-N-acetylation, the structure of PgaB in complex with Ni(2+) and Fe(3+) have been determined to 1.9 and 2.1 A resolution, respectively, and its activity on beta-1,6-GlcNAc oligomers has been characterized. The structure of PgaB reveals two (beta/alpha)(x) barrel domains: a metal-binding de-N-acetylase that is a member of the family 4 carbohydrate esterases (CE4s) and a domain structurally similar to glycoside hydrolases. PgaB displays de-N-acetylase activity on beta 1,6-GlcNAc oligomers but not on the beta-1,4-(GlcNAc)(4) oligomer chitotetraose and is the first CE4 member to exhibit this substrate specificity. De-N acetylation occurs in a length-dependent manor, and specificity is observed for the position of de-N-acetylation. A key aspartic acid involved in de-N acetylation, normally seen in other CE4s, is missing in PgaB, suggesting that the activity of PgaB is attenuated to maintain the low levels of de-N-acetylation of PNAG observed in vivo. The metal dependence of PgaB is different from most CE4s, because PgaB shows increased rates of de-N-acetylation with Co(2+) and Ni(2+) under aerobic conditions, and Co(2+), Ni(2+) and Fe(2+) under anaerobic conditions, but decreased activity with Zn(2+). The work presented herein will guide inhibitor design to combat biofilm formation by E. coli and potentially a wide range of medically relevant bacteria producing polysaccharide intercellular adhesin-dependent biofilms. PMID- 22810236 TI - Recovery of RNA polymerase III transcription from the glycerol-repressed state: revisiting the role of protein kinase CK2 in Maf1 phosphoregulation. AB - Maf1 is a conserved regulator of RNA polymerase (pol) III transcription and is required for transcriptional repression under diverse stress conditions. In yeast, Maf1 function is negatively regulated at seven phosphosites by the overlapping action of protein kinase A (PKA) and the TORC1-regulated kinase Sch9. Under stress conditions, Maf1 is dephosphorylated at these sites leading to its nuclear accumulation, increased association with pol III genes and direct physical interactions with the polymerase which ultimately inhibit transcription. These changes are reversed upon return to optimal growth conditions. Transcription in this system is also regulated by protein kinase CK2. CK2 stimulates pol III transcription in yeast and human cells via phosphorylation of the initiation factor TFIIIB. Recently it was proposed that CK2 phosphorylation of Maf1 is required for reactivation of pol III transcription following growth on glycerol. We have examined this hypothesis using two Maf1 mutants (Maf1-id S388A and Maf1-ck2(0)) which lack all of the CK2 phosphosites implicated in the response. Both mutant proteins are phosphoregulated, function normally during repression and transcription is fully restored to the wild-type level upon transfer from glycerol to glucose. Additionally, phos-tag gel analysis of Maf1 7SA, a functional mutant that cannot be phosphorylated by PKA/Sch9, did not reveal any evidence for differential phosphorylation of Maf1 during carbon source switching. Together, these data do not support the proposed requirement for CK2 phosphorylation of Maf1 during derepression of pol III transcription. PMID- 22810237 TI - Structure and mechanism of human UDP-xylose synthase: evidence for a promoting role of sugar ring distortion in a three-step catalytic conversion of UDP glucuronic acid. AB - UDP-xylose synthase (UXS) catalyzes decarboxylation of UDP-D-glucuronic acid to UDP-xylose. In mammals, UDP-xylose serves to initiate glycosaminoglycan synthesis on the protein core of extracellular matrix proteoglycans. Lack of UXS activity leads to a defective extracellular matrix, resulting in strong interference with cell signaling pathways. We present comprehensive structural and mechanistic characterization of the human form of UXS. The 1.26-A crystal structure of the enzyme bound with NAD(+) and UDP reveals a homodimeric short-chain dehydrogenase/reductase (SDR), belonging to the NDP-sugar epimerases/dehydratases subclass. We show that enzymatic reaction proceeds in three chemical steps via UDP-4-keto-D-glucuronic acid and UDP-4-keto-pentose intermediates. Molecular dynamics simulations reveal that the D-glucuronyl ring accommodated by UXS features a marked (4)C(1) chair to B(O,3) boat distortion that facilitates catalysis in two different ways. It promotes oxidation at C(4) (step 1) by aligning the enzymatic base Tyr(147) with the reactive substrate hydroxyl and it brings the carboxylate group at C(5) into an almost fully axial position, ideal for decarboxylation of UDP-4-keto-D-glucuronic acid in the second chemical step. The protonated side chain of Tyr(147) stabilizes the enolate of decarboxylated C(4) keto species ((2)H(1) half-chair) that is then protonated from the Si face at C(5), involving water coordinated by Glu(120). Arg(277), which is positioned by a salt-link interaction with Glu(120), closes up the catalytic site and prevents release of the UDP-4-keto-pentose and NADH intermediates. Hydrogenation of the C(4) keto group by NADH, assisted by Tyr(147) as catalytic proton donor, yields UDP-xylose adopting the relaxed (4)C(1) chair conformation (step 3). PMID- 22810238 TI - Structural and functional characterization of NikO, an enolpyruvyl transferase essential in nikkomycin biosynthesis. AB - Nikkomycins are peptide-nucleoside compounds with fungicidal, acaricidal, and insecticidal properties because of their strong inhibition of chitin synthase. Thus, they are potential antibiotics especially for the treatment of immunosuppressed patients, for those undergoing chemotherapy, or after organ transplants. Although their chemical structure has been known for more than 30 years, only little is known about their complex biosynthesis. The genes encoding for proteins involved in the biosynthesis of the nucleoside moiety of nikkomycins are co-transcribed in the same operon, comprising the genes nikIJKLMNO. The gene product NikO was shown to belong to the family of enolpyruvyl transferases and to catalyze the transfer of an enolpyruvyl moiety from phosphoenolpyruvate to the 3' hydroxyl group of UMP. Here, we report activity and inhibition studies of the wild-type enzyme and the variants C130A and D342A. The x-ray crystal structure revealed differences between NikO and its homologs. Furthermore, our studies led to conclusions concerning substrate binding and preference as well as to conclusions about inhibition/alkylation by the antibiotic fosfomycin. PMID- 22810242 TI - Journal Information. PMID- 22810239 TI - Allosteric regulation of the carbohydrate-binding ability of a novel conger eel galectin by D-mannoside. AB - Conger eel has two galectins, termed congerins I and II (Con I and II), that function in mucus as biodefense molecules. Con I and II have acquired a novel protein fold via domain swapping and a new ligand-binding site by accelerated evolution, which enables recognition of some marine bacteria. In this study, we identified a new congerin isotype, congerin P (Con-P), from the peritoneal cells of conger eel. Although Con-P displayed obvious homology with galectins, we observed substitution of 7 out of 8 amino acid residues in the carbohydrate recognition domain that are conserved in all other known galectins. To understand the structure-function relationships of this unique galectin, recombinant Con-P was successfully expressed in Escherichia coli by using a Con II-tagged fusion protein system and subsequently characterized. In the presence of D-mannose, Con P displayed 30-fold greater hemagglutinating activity than Con I; however, no activity was observed without mannose, indicating that D-mannoside can act as a modulator of Con-P. Frontal affinity chromatography analysis showed that activated Con-P, allosterically induced by mannose, displayed affinity for oligomannose-type sugars as well as N-acetyllactosamine-type beta-galactosides. Thus, Con-P represents a new member of the galectin family with unique properties. PMID- 22810245 TI - Preface. Lifelong learning in neurology. PMID- 22810246 TI - Prognosis of coma after cardiac arrest in the era of hypothermia. AB - PURPOSE OF REVIEW: Outcome prediction is more difficult in comatose survivors of cardiac arrest who are treated with hypothermia than in those who are kept normothermic. This article compares prognostication measures in these two groups of patients. RECENT FINDINGS: The introduction of therapeutic hypothermia for cardiac arrest has resulted in reduced mortality and better neurologic outcomes among survivors. However, it has also introduced greater uncertainty into the process of prognostication. For guidance on predicting outcome, most neurologists have relied on the 2006 AAN practice parameter. The studies on which the practice parameter was based, however, were performed before the advent of hypothermia. Data from posthypothermia era studies suggest a change in the predictive power of some markers that are regularly used to assess prognosis in post-cardiac arrest patients. It is unclear whether the same rules apply when predicting outcomes after cardiac arrest in cooled patients. In this new era of hypothermia, caution must be exercised when using the current AAN practice parameter to predict prognosis in post-cardiac arrest comatose survivors. SUMMARY: This article compares and contrasts prognostication before and after the introduction of hypothermia in an attempt to provide new guidance on predicting outcomes. PMID- 22810247 TI - Severe traumatic brain injury. AB - PURPOSE OF REVIEW: Although adherence to traumatic brain injury (TBI) guidelines has been associated with improved patient outcomes, guideline adherence remains suboptimal in practice. With neurologists becoming increasingly involved in specialized neurointensive care units and in the care of patients with severe TBI, familiarization with these guidelines is essential. RECENT FINDINGS: Intracranial monitoring of different physiologic variables has increased in the past few years. Intracranial pressure (ICP)-driven therapy has been replaced by ICP-cerebral perfusion pressure (CPP)-driven therapy. More recently, the importance of brain oxygen optimization in addition to ICP-CPP has been recognized, and clinical trials are underway to study the effect of this approach. Surgical management of patients with TBI is also evolving rapidly with further studies on decompressive craniectomy. These are significant advances to improve TBI outcomes. SUMMARY: This article summarizes the routine monitoring of patients with severe TBI and offers insight into some novel physiologic monitoring devices available. The guidelines for management of patients with severe TBI are summarized along with outcome measures. PMID- 22810248 TI - Critical care management of acute ischemic stroke. AB - PURPOSE OF REVIEW: Acute ischemic stroke (AIS) can have profound and devastating effects on the CNS and several other organs. Approximately 15% to 20% of patients with AIS are admitted to an intensive care unit and cared for by a multidisciplinary team. This article discusses the critical care management of patients with AIS. RECENT FINDINGS: Patients with AIS require attention to airway, pulmonary status, blood pressure, glucose, temperature, cardiac function, and, sometimes, life-threatening cerebral edema. SUMMARY: The lack of disease specific data has led to numerous management approaches and limited guidance on choosing among them. Existing guidelines emphasize risk factors, prevention, natural history, and prevention of bleeding but provide little discussion of the complex critical care issues involved in caring for patients with AIS. PMID- 22810249 TI - Status epilepticus and the use of continuous EEG monitoring in the intensive care unit. AB - PURPOSE OF REVIEW: Status epilepticus (SE) is one of the major neurologic emergencies. Newer data about the genesis and treatment of this condition are available to help improve our understanding and management. RECENT FINDINGS: Approximately 150,000 cases of generalized convulsive SE occur in the United States each year. Clinically apparent seizures complicate about 8% of intensive care unit admissions, and another 10% of ICU patients suffer electrographic seizures in the course of another critical illness. Some of these cases result from previously under-recognized epileptogenic effects of commonly used drugs, such as cefepime. Continuous EEG (cEEG) recording is necessary for both diagnosis and management in these patients, especially since anticonvulsant drugs may abolish motor activity without stopping seizures. Recent studies have underscored the utility of benzodiazepines as the first-line agents for SE termination. The recently published Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) demonstrates that the more rapidly treatment is administered, the more effective it will be. When SE fails to respond to usual doses of benzodiazepines, it should be considered refractory to conventional anticonvulsants, and a general anesthetic approach is likely to be necessary. SUMMARY: While definitions have varied, patients should be managed for SE after 5 minutes of seizure activity. Management of a patient with SE involves three phases: termination of SE, prevention of recurrence, and treatment of complications. The typical anticonvulsants have limited ability to terminate SE; lorazepam is the most useful, controlling SE in 65% of patients experiencing generalized convulsive SE. If the first conventional anticonvulsant fails, others are unlikely to be useful, and one of the newer anticonvulsants or a general anesthetic agent should be considered. EEG is crucial in the diagnosis and classification of potential seizures. cEEG monitoring helps to guide anticonvulsant therapy in patients with SE and those with frequent seizures. In addition, cEEG has the potential for presymptomatic diagnosis of delayed neurologic deterioration in patients with subarachnoid hemorrhage and for the differential diagnosis of stroke subtypes, especially when cEEG is subjected to signal processing. PMID- 22810250 TI - Management of delayed cerebral ischemia after subarachnoid hemorrhage. AB - PURPOSE OF REVIEW: The purpose of this article is to describe the modern management of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH). SAH causes an inflammatory reaction to blood products in the basal cisterns of the brain, which may produce cerebral ischemia and strokes through progressive narrowing of the cerebral artery lumen. This process, known as cerebral vasospasm, is the most common cause of DCI after SAH. Untreated DCI may result in strokes, which account for a significant portion of the death and long-term disability after SAH. RECENT FINDINGS: A number of publications, including two recent consensus statements, have clarified many best practices for defining, diagnosing, monitoring, preventing, and treating DCI. DCI is best defined as new onset of focal or global neurologic deficits or strokes not attributable to another cause. In addition to the clinical examination, radiographic studies such as transcranial Doppler ultrasonography, CT angiography, and CT perfusion may have a role in determining which patients are at high risk for developing DCI. The mainstay of prevention and treatment of DCI is maintenance of euvolemia, which can be a difficult therapeutic target to measure. Hemodynamic augmentation with induced hypertension with or without inotropic support has become the first-line treatment of DCI. The ideal method of measuring hemodynamic values and volume status in patients with DCI remains elusive. In patients who do not adequately respond to or cannot tolerate hemodynamic augmentation, endovascular therapy (intraarterial vasodilators and balloon angioplasty) is a complementary strategy. Optimal triggers for escalation and de-escalation of therapies for DCI have not been well defined. SUMMARY: Recent guidelines and consensus statements have clarified many aspects of prevention, monitoring, and treatment of DCI after SAH. Controversies continue regarding the optimal methods for measurement of volume status, the role of invasive neuromonitoring, and the targets for hemodynamic augmentation therapy. PMID- 22810251 TI - Update on intracerebral hemorrhage. AB - PURPOSE OF REVIEW: This article provides an update on the latest diagnostic and therapeutic trials relating to the management of intracerebral hemorrhage (ICH). RECENT FINDINGS: Early hematoma expansion and worsening cerebral edema may account for delayed neurologic deterioration after ICH. SUMMARY: Despite advances in other areas of stroke, there has been no significant improvement in the morbidity and mortality after ICH. The cause of ICH has been shifting from chronic hypertension to other etiologies. Current understanding of the pathophysiologic processes involved with hematoma expansion and the development of secondary injury after ICH has focused the treatment strategies on prevention of these potential complications. Care for the patient after ICH includes basic medical care, prevention of hematoma expansion, and treatment of potential secondary complications. Trials are underway to evaluate the effect of acute blood pressure control on hematoma expansion and the development of cerebral edema. Similarly, new surgical techniques are being explored for clot removal, and medical therapies are being developed to prevent secondary neurotoxic damage. PMID- 22810252 TI - Metabolic encephalopathies in the critical care unit. AB - PURPOSE OF REVIEW: This article summarizes the most common etiologies and approaches to management of metabolic encephalopathy. RECENT FINDINGS: Metabolic encephalopathy is a frequent occurrence in the intensive care unit setting. Common etiologies include hepatic failure, renal failure, sepsis, electrolyte disarray, and Wernicke encephalopathy. Current treatment paradigms typically focus on supportive care and management of the underlying etiology. Directed therapies that target neurochemical and neurotransmitter pathways that mediate encephalopathy are not currently available and represent an important area for future research. Although commonly thought of as reversible neurologic insults, delirium and encephalopathy have been associated with increased mortality, prolonged length of stay and hospital complications, and worse long-term cognitive and functional outcomes. SUMMARY: Recognition and treatment of encephalopathy is critical to improving outcomes in critically ill patients. PMID- 22810253 TI - Osmotherapy for intracranial hypertension: mannitol versus hypertonic saline. AB - PURPOSE OF REVIEW: Hyperosmolar therapy is one of the core medical treatments for brain edema and intracranial hypertension, but controversy exists regarding the use of the most common agents, mannitol, and hypertonic saline. This article describes the relative merits and adverse effects of these agents using the best available clinical evidence. RECENT FINDINGS: Mannitol is effective and has been used for decades in the treatment of traumatic brain injury, but it may precipitate acute renal failure if serum osmolarity exceeds 320 mOsm/L. Hypertonic saline appears to be safe, and serum sodium has been elevated to as high as 180 mEq/L in clinical settings without significant neurologic, cardiac, or renal injury. In small comparative trials both agents are effective and no clinically significant difference has been noted, but a properly powered trial has not yet been performed. SUMMARY: Both mannitol and hypertonic saline are effective and have an acceptable risk profile for use in the treatment of elevated intracranial pressure secondary to brain edema. PMID- 22810254 TI - Surrogate decision making in neurocritical care. AB - Patients with critical neurologic illness typically have impaired capacity to make their own medical decisions. In these cases, neurologists need to make medical decisions based on advance directives (such as a living will) or the decisions of a surrogate. A hypothetical case of a 60-year-old man with an intracerebral hemorrhage is used to highlight some of the difficulties that can occur when attempting to apply general statements made in a living will to a specific medical treatment decision. The ethical and legal issues surrounding surrogate decision making as they apply to acute critical neurologic disease are discussed, along with suggestions for how to resolve potential disagreements. PMID- 22810255 TI - Brain death dilemmas and the use of ancillary testing. AB - The Uniform Determination of Death Act indicates that "an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead," with brain death being determined based on "accepted medical standards." The AAN has published practice guidelines providing medical standards for the determination of brain death. The most recent AAN guideline update notes that "because of the deficiencies in the evidence base, clinicians must exercise considerable judgment when applying the criteria in specific circumstances" and that "ancillary tests can be used when uncertainty exists about the reliability of parts of the neurologic examination or when the apnea test cannot be performed. This article presents two cases commonly encountered in clinical practice in which the findings of the guideline-specified clinical neurologic assessment may be difficult to interpret, hampering the clinical determination of brain death. In these circumstances, ancillary testing specifically assessing for cerebral circulatory arrest may be helpful. PMID- 22810256 TI - Coding issues in critical care patients with an emphasis on encephalopathy. AB - Accurate coding is an important function of neurologic practice. This section of CONTINUUM, contributed by members of the AAN Medical Economics and Management Committee, includes helpful coding information and examples related to the issue topic. This section may include diagnosis coding, evaluation and management coding, procedure coding, or a combination, depending on which is most useful for the subject area of the issue. PMID- 22810259 TI - Multiple-Choice Questions-Preferred Responses. PMID- 22810258 TI - Multiple-Choice Questions. PMID- 22810260 TI - Patient Management Problem. PMID- 22810261 TI - Patient Management Problem-Preferred Responses. PMID- 22810262 TI - Mechanical properties of thin confined polymer films close to the glass transition in the linear regime of deformation: theory and simulations. AB - Over the past twenty years experiments performed on thin polymer films deposited on substrates have shown that the glass transition temperature T(g) can either decrease or increase depending on the strength of the interactions. Over the same period, experiments have also demonstrated that the dynamics in liquids close to the glass transition temperature is strongly heterogeneous, on the scale of a few nanometers. A model for the dynamics of non-polar polymers, based on percolation of slow subunits, has been proposed and developed over the past ten years. It proposes a unified mechanism regarding these two features. By extending this model, we have developed a 3D model, solved by numerical simulations, in order to describe and calculate the mechanical properties of polymers close to the glass transition in the linear regime of deformation, with a spatial resolution corresponding to the subunit size. We focus on the case of polymers confined between two substrates with non-negligible interactions between the polymer and the substrates, a situation which may be compared to filled elastomers. We calculate the evolution of the elastic modulus as a function of temperature, for different film thicknesses and polymer-substrate interactions. In particular, this allows to calculate the corresponding increase of glass transition temperature, up to 20 K in the considered situations. Moreover, between the bulk T(g) and T(g) + 50 K the modulus of the confined layers is found to decrease very slowly in some cases, with moduli more than ten times larger than that of the pure matrix at temperatures up to T(g) + 50 K. This is consistent with what is observed in reinforced elastomers. This slow decrease of the modulus is accompanied by huge fluctuations of the stress at the scale of a few tens of nanometers that may even be negative as compared to the solicitation, in a way that may be analogous to mechanical heterogeneities observed recently in molecular dynamics simulations. As a consequence, confinement may result not only in an increase of the glass transition temperature, but in a huge broadening of the glass transition. PMID- 22810263 TI - Shear-affected depletion interaction. AB - We investigate the influence of flow fields on the strength of the depletion interaction caused by disc-shaped depletants. At low mass concentration of discs, it is possible to continuously decrease the depth of the depletion potential by increasing the applied shear rate until the depletion force is not perceivable experimentally. Above a threshold in the platelet mass concentration, the depletion potential can no longer be affected by flow in the accessible range of shear rates. While the observed decrease of depletion strength at low depletant concentration may be ascribed to flow alignment of the discs, it is not clear why the influence of flow is vanishing at high concentrations. In order to observe these effects, a modification of the established total internal reflexion microscopy (TIRM) technique is be implemented. We show the suitability of these modifications to measure particle-wall interaction potentials under non equilibrium conditions for systems where particles are exposed to a shear. PMID- 22810264 TI - Pertussis epidemic--Washington, 2012. AB - Since mid-2011, a substantial rise in pertussis cases has been reported in the state of Washington. In response to this increase, the Washington State Secretary of Health declared a pertussis epidemic on April 3, 2012. By June 16, the reported number of cases in Washington in 2012 had reached 2,520 (37.5 cases per 100,000 residents), a 1,300% increase compared with the same period in 2011 and the highest number of cases reported in any year since 1942. To assess clinical, epidemiologic, and laboratory factors associated with this increase, all pertussis cases reported during January 1-June 16, 2012, were reviewed. Consistent with national trends, high rates of pertussis were observed among infants aged <1 year and children aged 10 years. However, the incidence in adolescents aged 13-14 years also was increased, despite high rates of vaccination with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, suggesting early waning of immunity. The focus of prevention and control efforts is the protection of infants and others at greatest risk for severe disease and improving vaccination coverage in adolescents and adults, especially those who are pregnant. Pertussis vaccination remains the single most effective strategy for prevention of infection. PMID- 22810265 TI - Motor vehicle crash deaths in metropolitan areas--United States, 2009. AB - Although rates have declined in recent years, motor vehicle crashes (MVCs) remain a leading cause of injury death in the United States. In 2009, a total of 34,485 MVC deaths were reported among U.S. residents, and 22% of those who died were aged 15-24 years. MVCs were the leading cause of death for that age group, which represents approximately 14% of the total U.S. population. To assess patterns in MVC death rates for persons of all ages and for those aged 15-24 years, in recognition of the elevated risk for this age group, CDC used data from the National Vital Statistics System (NVSS) and the U.S. Census Bureau for 2009 representing the 50 most populous U.S. metropolitan statistical areas (MSAs). The overall MVC death rate (age-adjusted) for all 50 MSAs combined was 8.2 per 100,000 residents, compared with a national rate of 11.1; among MSAs, rates ranged from 4.4 to 17.8. For persons aged 15-24 years, the MVC death rate was 13.0 per 100,000 residents for all MSAs combined (range: 7.3-25.8), compared with a national rate of 17.3. Although rates for the MSAs generally were lower than the rate for the nation as a whole, higher rates for persons aged 15-24 years were observed both in the MSAs and nationally. The wide variation in rates among MSAs suggests a need to better understand how urban development patterns might relate to MVC deaths and to identify and implement effective strategies to reduce the number of such deaths. PMID- 22810266 TI - Tornado-related fatalities--five states, Southeastern United States, April 25-28, 2011. AB - During April 25-28, 2011, a massive storm system generated 351 tornadoes (including 15 registering 4 or 5 on the Enhanced Fujita [EF] scale*), killing 338 persons in Alabama, Arkansas, Georgia, Mississippi, and Tennessee. This was the third-deadliest tornado event in the United States, surpassing an April 1974 event that resulted in 315 fatalities. This event also was historic because of the record number of fatalities that occurred despite modern advances in tornado forecasting, advanced warning times, and media coverage. Risk factors for death and injury from tornadoes are sheltering in mobile homes, proximity to an EF-4 or EF-5 tornado, being an older adult (aged >=65 years), lack of accessibility to safe rooms (e.g., basements or reinforced shelters), and a night-time tornado impact. To describe the fatalities by demographic characteristics, type of shelter used, cause of death, and tornado severity and location, CDC reviewed data from the American Red Cross (Red Cross), death certificates, and the National Weather Service (NWS). This report summarizes the results of that review. Among the 338 decedents, median age was 55.0 years (range: 4 days-97 years); approximately one third were older adults. On tornado impact, 46.7% of decedents were in single-family homes, and 26.6% were in mobile homes. The leading cause of death was traumatic injury, including 21.9% with head injuries. Half of the deadly tornadoes were rated EF-4 or EF-5 and were responsible for 89.5% of the deaths. To prevent tornado-related deaths, health messaging should encourage the public (especially older adults and residents of mobile/manufactured homes) to pre-identify an accessible safe room, prepare the room with personal protection items (e.g., blankets and helmets), and monitor local weather. PMID- 22810267 TI - Alcohol use and binge drinking among women of childbearing age--United States, 2006-2010. AB - Alcohol use during pregnancy is a leading preventable cause of birth defects and developmental disabilities. Alcohol-exposed pregnancies (AEPs) can lead to fetal alcohol syndrome and other fetal alcohol spectrum disorders (FASDs), which result in neurodevelopmental deficits and lifelong disability. In 2005, the Surgeon General issued an advisory urging women who are pregnant or who might become pregnant to abstain from alcohol use. Healthy People 2020 set specific targets for abstinence from alcohol use (MICH-11.1) and binge drinking (MICH-11.2) for pregnant women. To estimate the prevalence of any alcohol use and binge drinking in the past 30 days among women aged 18-44 years, CDC analyzed 2006-2010 Behavioral Risk Factor Surveillance System (BRFSS) data. Based on their self reports, an estimated 51.5% of nonpregnant women used alcohol, as did 7.6% of pregnant women. The prevalence of binge drinking was 15.0% among nonpregnant women and 1.4% among pregnant women. Among pregnant women, the highest prevalence estimates of reported alcohol use were among those who were aged 35-44 years (14.3%), white (8.3%), college graduates (10.0%), or employed (9.6%). Among binge drinkers, the average frequency and intensity of binge episodes were similar, approximately three times per month and six drinks on an occasion, among those who were pregnant and those who were not. Clinical practices that advise women about the dangers associated with drinking while pregnant, coupled with community level interventions that reduce alcohol-related harms, are necessary to mitigate AEP risk among women of childbearing age and to achieve the Healthy People 2020 objectives. PMID- 22810268 TI - Notes from the field: tuberculosis cluster associated with homelessness--Duval County, Florida, 2004-2012. AB - Despite a decrease in incidence of tuberculosis (TB) in Duval County, Florida, from 102 cases (11.2 per 100,000 population) in 2008 to 71 cases (8.2 per 100,000) in 2011,* analysis of Mycobacterium tuberculosis genotyping data revealed a substantial increase in the percentage of TB cases with the same genotype.? That percentage increased from 27% (10 of 37) of genotyped cases in 2008 to 51% (30 of 59) of genotyped cases in 2011 (Florida Department of Health, unpublished data, 2012). During this period, the percentage of patients with this genotype who were homeless or who abused substances also increased. Because of concern over potential ongoing TB transmission involving these hard-to-reach populations, the Duval County Health Department, Florida Department of Health, and CDC conducted an investigation during February 15-March 13, 2012. As of March 13, review of medical records and interviews with TB patients had identified 99 cases related to the cluster based on matching genotype results and epidemiologic links (48 cases), matching genotype only (22), epidemiologic links only (22), or common social risk factors for TB (e.g., homelessness, incarceration, or substance abuse within 1 year of TB diagnosis) and suspected epidemiologic links (seven). The first known case with a matching genotype occurred in 2004. PMID- 22810269 TI - Notes from the field: severe varicella in an immunocompromised child exposed to an unvaccinated sibling with varicella--Minnesota, 2011. AB - Varicella usually is a self-limited disease but can result in serious complications (e.g., encephalitis, pneumonia, sepsis, hemorrhagic varicella, and death), especially among immunocompromised persons. Implementation of the varicella vaccination program in the United States, beginning in 1995, has led to declines of >95% in varicella-related hospitalizations and deaths among populations routinely vaccinated (1). PMID- 22810270 TI - Merging tribenzotriquinacene with hexa-peri-hexabenzocoronene: a cycloheptatriene unit generated by Scholl reaction. AB - The single-wing extension of the bowl-shaped tribenzotriquinacene (TBTQ) framework with polycondensed aromatic hydrocarbon units has been reported. In the course of a Scholl reaction, one of the three-dimensional bays of the TBTQ core has been bridged by a PAH unit to generate a seven-membered ring within the merged TBTQ-(hexa-peri-hexabenzocoronene) scaffold. PMID- 22810271 TI - Resistance-associated epitopes of HIV-1C-highly probable candidates for a multi epitope vaccine. AB - Earlier studies have identified a large number of immunogenic epitopes in HIV-1. Efforts are required to prioritize these epitopes in order to identify the best candidates for formulating an effective multi-epitope vaccine for HIV. We modeled 155 known cytotoxic T lymphocyte epitopes of HIV-1 subtype C on the 3D structure of HLA-A*0201, HLA-B*2705, and HLA-B*5101 using MODPROPEP, as these alleles are known to be associated with resistance to HIV/slow progression to AIDS. Thirty six epitopes were identified to bind to all the three HLA alleles with better binding affinity than the control peptides complexed with each HLA allele but not to any of the HLA alleles reported to be associated with susceptibility to HIV infection/rapid progression to disease. As increase in stability of the epitope HLA complex results in increased immunogenicity, the short-listed epitopes could be suitable candidates for vaccine development. Twenty of the 36 epitopes were polyfunctional in nature adding to their immunological relevance for vaccine design. Further, 9 of the 20 polyfunctional epitopes were found to bind to all three resistance-associated HLA alleles using an additional method, adding worth to their potential as candidates for a vaccine formulation for HIV-1C. PMID- 22810272 TI - Computational study of ADD1 gene polymorphism associated with hypertension. AB - We have determined the non-synonymous single-nucleotide polymorphisms (nsSNPs) of alpha adducin 1 (ADD1) gene and its variations in different populations to understand its role in hypertension. Out of 1,113 SNPs, 9 are found to be non synonymous, of which 7 showed significant damaging effect and one of them showed SNP variability with large differences among the minor allele frequency observed in various populations. The amino acid change found for rs4961 is from glycine to tryptophan, i.e., from an alkyl amino acid to an aromatic amino acid. This residual change is observed in the coiled region of the protein and is also predicted to be disordered by computational algorithm. Protein disorder plays an important role in structural and functional genomics. Hence, because of the complete change in side chains of the amino acid residues occurring in the coiled and disordered region of the protein, the structure of the protein might be altered and the function might be affected, leading to the risk for hypertension. PMID- 22810273 TI - Robust inference in discrete hazard models for randomized clinical trials. AB - Time-to-event data in which failures are only assessed at discrete time points are common in many clinical trials. Examples include oncology studies where events are observed through periodic screenings such as radiographic scans. When the survival endpoint is acknowledged to be discrete, common methods for the analysis of observed failure times include the discrete hazard models (e.g., the discrete-time proportional hazards and the continuation ratio model) and the proportional odds model. In this manuscript, we consider estimation of a marginal treatment effect in discrete hazard models where the constant treatment effect assumption is violated. We demonstrate that the estimator resulting from these discrete hazard models is consistent for a parameter that depends on the underlying censoring distribution. An estimator that removes the dependence on the censoring mechanism is proposed and its asymptotic distribution is derived. Basing inference on the proposed estimator allows for statistical inference that is scientifically meaningful and reproducible. Simulation is used to assess the performance of the presented methodology in finite samples. PMID- 22810275 TI - Pediatric neurosurgery at the Hospital for Sick Children, The University of Toronto. PMID- 22810276 TI - Magnetic properties of the seven-coordinated nanoporous framework material Co(bpy)1.5(NO3)2 (bpy = 4,4'-bipyridine). AB - The magnetic properties of the porous metal-organic complex Co(bpy)(1.5)(NO(3))(2) (bpy = 4,4'-bipyridine), investigated by SQUID magnetometry, EPR and heat capacity measurements, are reported. The tongue-and groove structure of this complex is formed by the assembly of T-shaped building blocks, where each Co is bound to three bpy ligands. Co(II) is hepta-coordinated by three N atoms from the bpy units, and four O atoms from two nitrate groups. Experimental results showed a large crystal field effect induced anisotropy with a zero field splitting of Delta = 198 K between the ground and excited Kramers doublets, a factor of two larger than previously reported values in Co(II) hepta coordinated complexes. EPR revealed orthorhombic crystal field anisotropy, with gyromagnetic principal values of g(1)* = 6.1, g(2)* = 4.2 and g(3)* = 2.2, in an S* = 1/2 effective spin on the ground state Kramers doublet. Ab initio simulations allowed us to assign the anisotropy easy axis of magnetization to the binary symmetry axis of the molecule, aligned with the Co-N apical direction of the T-block. PMID- 22810277 TI - Faculty. PMID- 22810278 TI - Editor'S preface. PMID- 22810279 TI - Alzheimer disease update. AB - Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting more than 37 million people worldwide and increasing in incidence based on its primary risk factor, advancing age. A growing body of knowledge regarding amyloid and tau neuropathology, genetic and environmental risk modifiers, early and atypical clinical presentations, and the use of symptom-modifying medical and psychosocial therapies is available to aid in the diagnosis and management of patients with AD. Exciting recent advances in neurobiology render the areas of genetic susceptibility, biomarkers for early disease detection and assessment of disease progression, and novel therapeutic strategies to modify the natural history of the disease compelling, but in need of further study before implementation into routine clinical practice is feasible. PMID- 22810280 TI - Rapidly progressive dementia: prion diseases and other rapid dementias. AB - Dementias that occur over weeks to months require a different differential than the slowly progressive dementias that occur over years. Because of the rapidity of decline in cognition, the evaluation of the patient is usually urgent and requires an extensive workup with multiple tests running in parallel. Creutzfeldt Jakob disease, perhaps the prototypic rapidly progressive dementia (RPD), is often the first diagnosis many neurologists consider when faced with a patient with rapid cognitive decline. Many conditions other than prion disease, however, can present with RPD. Other etiologies include autoimmune conditions, cancers, uncommon presentations of other more common neurodegenerative dementias, and others. This chapter discusses some of the major etiologies for RPDs and offers an algorithm for diagnosis. Some topics, such as other neurodegenerative dementias and autoimmune dementias, are covered in other chapters in this issue, and will be mentioned here only briefly. PMID- 22810282 TI - Immunotherapy-responsive dementias and encephalopathies. AB - The diagnosis of an autoimmune dementia requires the detection of objective improvements in cognitive decline (usually subacute in onset with a fluctuating course) after a course of immunotherapy. Serum and CSF antibody markers of autoimmunity (particularly those with neural antigen specificity) as well as other CSF markers of inflammation increase the suspicion for an autoimmune cause. The detection of neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, NMDA receptor antibodies are associated with teratoma). MRI, EEG, functional imaging, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention allows reversal of deficits in many patients. Chronic treatment is often required to maintain remission. PMID- 22810281 TI - Parkinsonian dementias. AB - Parkinsonian dementia syndromes entail a combination of motor and cognitive symptoms and a variety of underlying etiologies. Lewy body dementias are most common, encompassing Parkinson disease (PD) with dementia and dementia with Lewy bodies, which share the common pathologic substrate of intracellular neuronal inclusion bodies that contain alpha-synuclein. Multiple system atrophies (MSAs), which are now divided into parkinsonian and cerebellar subtypes, are related disorders with core features that include autonomic and parkinsonian motor signs and alpha-synuclein-containing glial intracytoplasmic inclusion bodies. Progressive supranuclear palsy and corticobasal degeneration are parkinsonian dementias that superficially resemble PD and MSA in terms of motor features, but are distinguished pathologically by neurofibrillary tau protein abnormalities. Some other causes of dementia associated with parkinsonism include drug-induced parkinsonism, vascular parkinsonism, normal pressure hydrocephalus, prion diseases including Gerstmann-Straussler-Scheinker syndrome (see the chapter "Rapidly Progressing Dementias"), Alzheimer disease with extrapyramidal signs (see the chapter "Alzheimer Disease Update"), and metabolic derangements that have a predilection for basal ganglia structures. This review will discuss clinical presentations, differential diagnoses, laboratory and neuroimaging characteristics, and therapeutic strategies for the synucleinopathies and several parkinsonian dementia syndromes. PMID- 22810283 TI - Leukoencephalopathies and leukodystrophies. AB - The leukoencephalopathies encompass a heterogeneous group of disorders that involve the brain white matter. The cause may be acquired or inherited; in the latter case, mutations have been found in genes that encode protein components of the myelin membrane or enzymes implicated in the turnover of myelin. In patients with cognitive dysfunction and white matter lesions evident on MRI, analysis of the type, pattern, and distribution of lesions can enable a presumptive diagnosis, which can be confirmed by biochemical and/or molecular testing. The presence or absence of peripheral neuropathy and/or autonomic dysfunction can be a helpful clue in differentiating individual diagnoses. Often, patients may be suspected of having and being initially treated inappropriately for a case of primary or secondary progressive multiple sclerosis. In a significant number of patients, the diagnosis may not be made, even after an extensive search. Establishing the cause enables counseling regarding prognosis, family planning, monitoring for disease-related complications, and introducing therapy, when available. PMID- 22810284 TI - Delirium. AB - Delirium is a commonly encountered clinical problem and, contrary to popular belief, should be treated as an acute neurologic emergency. It can be caused by a multitude of conditions and is frequently observed in hospitalized patients. In some cases, delirium results from the direct effect of a toxin, as observed with anticholinergic medications, or from neuronal injury, as seen in herpes simplex virus encephalitis. Because the treatment of delirium rests on the identification and treatment of the underlying illness, the astute clinician must tease apart these various possibilities with a careful history and physical examination and judicious use of laboratory tests and imaging studies. This chapter will review an approach to the patient with delirium and discuss management strategies based on current evidence. PMID- 22810285 TI - Cognitive impairment among older adults with late-life schizophrenia or bipolar disorder. AB - Neurologists are increasingly faced with the daunting task of disentangling dementia from primary psychiatric conditions or recognizing their coexistence in older patients. Both schizophrenia and bipolar disorder are characterized by substantial intergroup cognitive heterogeneity among older and younger patients. In schizophrenia, deficits in many cognitive domains are common; however, "rapid forgetting," loss of crystallized knowledge, and greater than age-normal declines in cognitive function are rare and warrant careful evaluation for secondary causes. The cognitive deficits associated with bipolar disorder tend be most severe during acute affective episodes, but some deficits tend to persist even during periods of relative euthymia. Lifetime number of affective episodes in bipolar disorder may adversely affect cognitive functions in bipolar disorder, but severe deficits and/or substantive declines over a period of a few years are unusual and warrant careful evaluation for secondary causes. PMID- 22810286 TI - Neuroimaging in dementia. AB - As treatment of neurodegenerative disease moves toward therapies aimed at specific molecular abnormalities, the importance of early and accurate diagnosis will increase, as will the need for sensitive measures for tracking disease progression. Brain imaging, using MRI and PET scanning, offers a variety of highly reliable techniques that examine the structure, chemical content, metabolic state, and functional capacity of the brain. For all the major neurodegenerative disorders, relatively specific findings can be identified with some or all of these techniques. New approaches for imaging specific molecular pathology likely will revolutionize brain imaging and be combined with established imaging approaches to obtain a complete molecular, structural, and metabolic characterization, which could be used to improve diagnosis, and to stage each patient and follow disease progression and response to treatment. PMID- 22810287 TI - Neurocognitive assessment. AB - Neurocognitive symptoms are a prominent feature of nearly all neurodegenerative dementias. Specialized assessment of memory, executive functions, language, and visuospatial skills may aid in the differential diagnosis. This chapter describes the neuropsychological assessment of these domains and provides typical neurocognitive profiles of various dementia types. PMID- 22810288 TI - Frontotemporal degeneration. AB - Frontotemporal degeneration (FTD), one of the most prevalent causes of presenile dementia, includes three subtypes: (1) behavioral variant FTD (bvFTD), (2) semantic variant (SV), and (3) progressive nonfluent aphasia (PNFA). Corticobasal degeneration, progressive supranuclear palsy, and FTD-ALS are linked clinically and pathologically to FTD. The clinical presentation of these FTD-related disorders comprises a wide spectrum, including behavioral and psychiatric symptoms, aphasia, motor neuron findings, and parkinsonism. Two types of proteinopathies, tau and TAR DNA-binding protein 43 (TDP-43), are seen in most cases at autopsy. Mutations on the genes for tau and progranulin on chromosome 17 each account for 5% to 10% of familial FTD cases. Imaging reveals focal bifrontal atrophy and hypometabolism in bvFTD, asymmetric bilateral anterior temporal lobe changes in SV, and left perisylvian abnormalities in PNFA. Treatments for FTD are under active investigation and may soon reach clinical trials.Continuum Lifelong Learning Neurol 2010;16(2):191-211. PMID- 22810289 TI - Patient management problem. PMID- 22810290 TI - Ethical perspectives in neurology. PMID- 22810291 TI - Practice issues in neurology. PMID- 22810292 TI - Coding table. PMID- 22810293 TI - Multiple-choice questions. PMID- 22810294 TI - Preferred responses. PMID- 22810296 TI - On WD40 proteins: propelling our knowledge of transcriptional control? AB - A direct effect of post-translational modifications (PTMs) on nucleosomes is the formation of a dynamic platform able to assemble the transcriptional machinery and to recruit chromatin modifiers. The histone code hypothesis suggests that histone PTMs can act as binding sites for chromatin readers and effector proteins, such as the bromodomains, that selectively interact with acetylated lysines, or the "Royal family" and the PHD finger domains, which are able to recognize methylated arginines and lysines. In this review we will discuss recent data describing the function of WD40 proteins as a new class of histone readers, with particular emphasis on the ones able to recognize methylated arginine and lysine residues. We will discuss how WDR5, a classical seven-bladed WD40 propeller, is able to bind with similar affinities both the catalytic subunit of the Trithorax-like complexes, and the histone H3 tail either unmodified or symmetrically dimethylated on arginine 2 (H3R2me2s). Furthermore, we will speculate on how these mutually exclusive interactions of WDR5 may play a role in mediating different degrees of H3K4 methylations at both promoters and distal regulatory sites. Finally, we will summarize recent literature elucidating how other WD40 proteins such as NURF55, EED and LRWD1 recognize methylated histone tails, highlighting similarities and differences among them. PMID- 22810297 TI - Laparoscopic versus open appendectomy for complicated and uncomplicated appendicitis in children. AB - BACKGROUND: Appendectomy is one of the most common emergency operations performed in the pediatric population. The aim of this pooled analysis is to compare the outcome from complicated appendicitis (CA) and uncomplicated appendicitis (UA) following laparoscopic appendectomy (LA) and open appendectomy (OA) in children. METHODS: A systematic literature search was performed. Primary outcome measures were incidence of complications, intra-abdominal abscess, and wound infection. Secondary outcomes were length of operation, length of hospital stay, incidence of bowel obstruction, and readmission. RESULTS: Seventy-three thousand one hundred fifty appendectomies for UA and 34,474 appendectomies for CA were included. For UA, the only significant difference between the groups was a reduced length of hospital stay following LA. LA in CA was associated with reduced complications (pooled odds ratio [POR] = 0.53; P < 0.05), wound infections (POR = 0.42; P < 0.05), length of hospital stay (WMD = -0.67; P < 0.05), and bowel obstruction episodes (POR = 0.8; P < 0.05), but an increased incidence of intra-abdominal abscess and length of operation. CONCLUSION: Pooled analysis demonstrates that, in children with uncomplicated acute appendicitis, LA is associated with a reduced hospital stay but broad equivalence in postoperative morbidity when compared with the conventional approach. Although overall morbidity is reduced when the laparoscopic approach is utilized, in cases of CA, the risk of intra-abdominal abscess is increased. PMID- 22810298 TI - A comparative analysis of hepatocellular carcinoma after hepatic resection in young versus elderly patients. AB - PURPOSE: The aim of this study was to investigate the clinical outcomes after surgical treatment of hepatocellular carcinoma (HCC) in the elderly patients compared with younger patients. METHODS: Clinicopathological data and treatment outcomes in 61 elderly (>=70 years old) and 90 younger (<=40 years old) patients with HCC who underwent curative liver resection between 2000 and 2010 were retrospectively collected and compared using various parameters. RESULTS: The older HCC group was more likely to have hepatitis C virus and non-B non-C hepatitis virus infection, higher values of indocyanine green retention at 15 min (ICGR)(15), more preoperative comorbidities, and more postoperative complications. There were no significant differences in intraoperative parameters and pathologic features. The recurrence rate, overall survival and disease-free survival rates were similar amongst the two groups. The only independent prognostic factor of overall survival was postoperative complications. CONCLUSION: Our findings suggest that age by itself does not have an adverse effect on operative outcomes, including long-term prognosis. For young and elderly HCC patients, hepatic resection is a safe and effective treatment. PMID- 22810299 TI - Dietary patterns at 6, 15 and 24 months of age are associated with IQ at 8 years of age. AB - Diet supplies the nutrients needed for the development of neural tissues that occurs over the first 2 years of life. Our aim was to examine associations between dietary patterns at 6, 15 and 24 months and intelligence quotient (IQ) scores at 8 years. Participants were enrolled in an observational birth cohort (ALSPAC study, n = 7,097). Dietary data was collected by questionnaire and patterns were extracted at each time using principal component analysis. IQ was measured using the Wechsler Intelligence Scale for Children at 8 years. Associations between dietary patterns and IQ were examined in regression analyses adjusted for potential confounding and by propensity score matching, with data imputation for missing values. At all ages, higher scores on a Discretionary pattern (characterized by biscuits, chocolate, sweets, soda, crisps) were associated with 1-2 point lower IQ. A Breastfeeding pattern at 6 months and Home made contemporary patterns at 15 and 24 months (herbs, legumes, cheese, raw fruit and vegetables) were associated with 1-to-2 point higher IQ. A Home-made traditional pattern (meat, cooked vegetables, desserts) at 6 months was positively associated with higher IQ scores, but there was no association with similar patterns at 15 or 24 months. Negative associations were found with patterns characterized by Ready-prepared baby foods at 6 and 15 months and positive associations with a Ready-to-eat foods pattern at 24 months. Propensity score analyses were consistent with regression analyses. This study suggests that dietary patterns from 6 to 24 months may have a small but persistent effect on IQ at 8 years. PMID- 22810300 TI - Engineering Escherichia coli with acrylate pathway genes for propionic acid synthesis and its impact on mixed-acid fermentation. AB - Fermentation-derived products are in greater demand to meet the increasing global market as well as to overcome environmental problems. In this work, Escherichia coli has been metabolically engineered with acrylate pathway genes from Clostridium propionicum for the conversion of D-lactic acid to propionic acid. The introduced synthetic pathway consisted of seven genes encoding the enzymes propionate CoA-transferase (Pct), lactoyl-CoA dehydratase (Lcd) and acryloyl-CoA reductase (Acr). The engineered strain synthesised propionic acid at a concentration of 3.7 +/- 0.2 mM upon fermentation on glucose. This low production level could be attributed to the low activity of the recombinant enzymes in particular the rate-limiting enzyme, Acr. Interestingly, the recombinant pathway caused an increased lactate production in E. coli with a yield of 1.9 mol/mol of glucose consumed along with a decrease in other by-products. Down-regulation of the pfl (pyruvate formate lyase) genes and a possible inhibition of Pfl activity by the acrylate pathway intermediate, acryloyl-CoA, could have reduced carbon flow to the Pfl pathway with a concomitant increase in lactate production. This study reports a novel way of synthesising propionic acid by employing a non native, user-friendly organism through metabolic engineering. PMID- 22810301 TI - Significance of the Cgl1427 gene encoding cytidylate kinase in microaerobic growth of Corynebacterium glutamicum. AB - The Cgl1427 gene was previously found to be relevant to the microaerobic growth of Corynebacterium glutamicum (Ikeda et al. Biosci Biotechnol Biochem 73:2806 2808, 2009). In the present work, Cgl1427 was identified as a cytidylate kinase gene (cmk) by homology analysis of its deduced amino acid sequence with that of other bacterial cytidylate kinases (CMP kinases) and on the basis of findings that deletion of Cgl1427 results in loss of CMP kinase activity. Deletion of the cmk gene significantly impaired the growth of C. glutamicum in oxygen-limiting static culture, and the impaired growth was restored by introducing a plasmid containing the cmk gene, suggesting that this gene plays an important role in the microaerobic growth of C. glutamicum. On the other hand, in the main culture with aerobic shaking, a prolonged lag phase was observed in the cmk disruptant, despite an unchanged growth rate, compared to the behavior of the wild-type strain. The prolongation was observed when using seed culture grown to later growth stages in which oxygen limitation occurred, but it was not observed when using seed culture grown to an earlier growth stage in which oxygen remained relatively plentiful. Since nucleotide biosynthesis in C. glutamicum requires oxygen, we hypothesized that the ability of the cmk disruptant to synthesize nucleotides was influenced by oxygen limitation in the later growth stages of the seed culture, which caused the prolongation of the lag phase in the following shaken culture. To verify this hypothesis, a plasmid containing genes encoding all components of a homologous ribonucleotide reductase, a key enzyme for nucleotide synthesis that requires oxygen for its reaction, was introduced into the cmk disruptant, which significantly ameliorated the lag phase prolongation. Furthermore, this experimental setup almost completely restored the growth of the cmk disruptant in the oxygen-limiting static culture. These results indicate that CMP kinase plays an important role in normal nucleotide biosynthesis under an oxygen-limiting environment. PMID- 22810302 TI - IL-6 blockade attenuates the development of murine sclerodermatous chronic graft versus-host disease. AB - Systemic sclerosis (scleroderma) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. Serum IL-6 levels are reported to be elevated in human scleroderma and chronic graft versus-host disease (cGVHD) patients. IL-6 blockade using anti-IL-6 receptor mAb (anti-IL-6R mAb) results in amelioration of the pathologic symptoms of some autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis. In this study, we examined the effects of anti-IL-6R mAb on either prevention or treatment of murine sclerodermatous cGVHD (Scl-cGVHD). We found that serum IL-6 levels in Scl-cGVHD mice gradually increased after bone marrow transplantation. Administration of anti-IL-6R mAb attenuated the development of severe Scl-cGVHD and fibrosis and resulted in an increase in CD4(+)CD25(+)FoxP3(+) regulatory T cells. However, treatment of established Scl cGVHD with anti-IL-6R mAb showed no effects on disease severity. The effects of anti-IL-6R mAb were mostly inhibited by anti-CD25 mAb. Together, our results indicate that IL-6 has an important role in the pathogenesis of Scl-cGVHD. IL-6 blockade may be an effective approach for preventing Scl-cGVHD and treating cGVHD and scleroderma in humans. PMID- 22810304 TI - Differential effects of neurofibromin gene dosage on melanocyte development. AB - Mutations in neurofibromin (NF1) cause the dominant genetic disorder neurofibromatosis type 1. Neurofibromatosis is characterized by Schwann cell based tumors and skin hyperpigmentation, resulting from both haploinsufficiency and loss of heterozygosity. The fact that some pigment cells (melanocytes) arise from Schwann cell precursors suggests that neurofibromin could be required during the common precursor stage. In this study, we found a missense mutation in neurofibromin in Dark skin 9 (Dsk9) mutant mice, revealing that Nf1 mutations cause skin hyperpigmentation in mice, as they do in humans. Using tissue-specific knockouts, we found that haploinsufficiency of neurofibromin in melanocytes via Mitf-cre is insufficient to cause darker skin, whereas haploinsufficiency in bipotential Schwann cell-melanoblast precursors via Plp1-creER is sufficient. These findings suggest that there is a narrow developmental window during which Nf1 haploinsufficiency acts on pigment cells. Using fate mapping, we discovered differences in the colonization of the dermis and epidermis by melanocytes that arise from Schwann cell precursors, an unexpected complexity of melanocyte development. As homozygous knockout of Nf1 via Mitf-cre is sufficient to cause darker skin, we conclude that reduced gene dosage can act by a mechanism different from complete gene loss, even when the end result of both is very similar. PMID- 22810303 TI - Predictors of basal cell carcinoma in high-risk patients in the VATTC (VA Topical Tretinoin Chemoprevention) trial. AB - Basal cell carcinoma (BCC) is the most common cancer in the United States today, and patients who have had one are likely to have multiple carcinomas over time. Predictors of new BCCs on the face and ears among those at very high risk have not been studied in detail. We sought to do so prospectively in the context of a 6-year trial. We found that the number of BCCs in the prior 5 years was the most important predictor. Age, sun sensitivity, occupational sun exposure before the age of 30 years (but not afterward), lower educational level, history of eczema, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and more sunscreen use in the week, but not the 6 months, before enrollment were also independent predictors, but sunburns, baseline sun exposure, and other sun-protective measures, other skin cancers, and actinic keratoses were not. None of the eczema patients had a history of topical calcineurin use. The cumulative risk of BCC was 55% at 5 years. These findings document the key risk factors in this very high-risk population, suggesting that the history of eczema may increase the risk in those at high risk and that early sun exposure is important even in this group, and underscoring the need for chemopreventive strategies. PMID- 22810305 TI - Insulin-like growth factor-1 promotes wound healing in estrogen-deprived mice: new insights into cutaneous IGF-1R/ERalpha cross talk. AB - Although it is understood that endogenous IGF-1 is involved in the wound repair process, the effects of exogenous IGF-1 administration on wound repair remain largely unclear. In addition, the signaling links between IGF-1 receptor (IGF-1R) and estrogen receptors (ERs), which have been elucidated in other systems, have yet to be explored in the context of skin repair. In this study, we show that locally administered IGF-1 promotes wound repair in an estrogen-deprived animal model, the ovariectomized (Ovx) mouse, principally by dampening the local inflammatory response and promoting re-epithelialization. Using specific IGF-1R and ER antagonists in vivo, we reveal that IGF-1-mediated effects on re epithelialization are directly mediated by IGF-1R. By contrast, the anti inflammatory effects of IGF-1 are predominantly via the ERs, in particular ERalpha. Crucially, in ERalpha-null mice, IGF-1 fails to promote healing, and local inflammation is increased. Our findings illustrate the complex interactions between IGF-1 and estrogen in skin. The fact that IGF-1 may compensate for estrogen deficiency in wound repair, and potentially other contexts, is an important consideration for the treatment of postmenopausal pathology. PMID- 22810306 TI - Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. AB - beta-Catenin, a key transducer molecule of Wnt signaling, is required for adult hair follicle growth and regeneration. However, the cellular source of Wnt ligands required for Wnt/beta-catenin activation during anagen induction is unknown. In this study, we genetically deleted Wntless (Wls), a gene required for Wnt ligand secretion by Wnt-producing cells, specifically in the hair follicle epithelium during telogen phase. We show that epithelial Wnt ligands are required for anagen, as loss of Wls in the follicular epithelium resulted in a profound hair cycle arrest. Both the follicular epithelium and dermal papilla showed markedly decreased Wnt/beta-catenin signaling during anagen induction compared with control hair follicles. Surprisingly, hair follicle stem cells that are responsible for hair regeneration maintained expression of stem cell markers but exhibited significantly reduced proliferation. Finally, we demonstrate that epidermal Wnt ligands are critical for adult wound-induced de novo hair formation. Collectively, these data show that Wnt ligands secreted by the hair follicle epithelium are required for adult hair follicle regeneration and provide new insight into potential cellular targets for the treatment of hair disorders such as alopecia. PMID- 22810307 TI - GSK3beta inhibition blocks melanoma cell/host interactions by downregulating N cadherin expression and decreasing FAK phosphorylation. AB - This study addresses the role of glycogen synthase kinase (GSK)-3beta signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3beta to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3beta were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3beta signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3beta signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3beta signaling in invasion was suggested by the ability of GSK3beta inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3beta in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3beta in defined subsets of melanoma. PMID- 22810308 TI - IgG autoantibody response against keratinocyte cadherins in endemic pemphigus foliaceus (fogo selvagem). AB - It is well established that autoantibodies against desmoglein 3 and desmoglein 1 (Dsg1) are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form fogo selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine whether FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E cadherin. By testing a large number of FS and endemic control sera by ELISA, we found a consistent and specific autoantibody response against Dsg1 and other keratinocyte cadherins in these individuals, which is quite different from healthy individuals from the United States (US controls). Overall, the highest correlations among the autoantibody responses tested were in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross-reactive, keratinocyte cadherins are recognized by FS patients and endemic controls. PMID- 22810309 TI - Smoking topography and biomarkers of exposure among Japanese smokers: associations with cigarette emissions obtained using machine smoking protocols. AB - OBJECTIVES: Although the relative risk of lung cancer due to smoking is reported to be lower in Japan than in other countries, few studies have examined the characteristics of Japanese cigarettes or potential differences in smoking patterns among Japanese smokers. METHODS: To examine tar, nicotine and carbon monoxide (TNCO) emissions from ten leading cigarettes in Japan, machine smoking tests were conducted using the International Organization for Standardization (ISO) protocol and the Health Canada Intense (HCI) protocol. Smoking topography and tobacco-related biomarkers were collected from 101 Japanese smokers to examine measures of exposure. RESULTS: The findings indicate considerable variability in the smoking behavior of Japanese smokers. On average, puffing behaviors observed among smokers were more similar to the parameters of the HCI protocol, and brands with greater ventilation that yielded lower machine values using the ISO protocol were smoked more intensely than brands with lower levels of ventilation. The smokers of "ultra-low/low" nicotine-yield cigarettes smoked 2.7-fold more intensively than those of "medium/high" nicotine-yield cigarette smokers to achieve the same level of salivary cotinine (p = 0.024). CO levels in expiratory breath samples were associated with puff volume and self-reported smoking intensity, but not with nominal values of nicotine-yield reported on cigarette packages. CONCLUSIONS: Japanese smokers engaged in "compensatory smoking" to achieve their desired nicotine intake, and levels of exposure were greater than those suggested by the nominal value of nicotine and tar yields reported on cigarette packages. PMID- 22810310 TI - Faculty. PMID- 22810312 TI - Editor'S letter. PMID- 22810313 TI - The classification of seizures and epilepsy syndromes. AB - This chapter focuses on the classification of seizures and epilepsy syndromes based on the International League Against Epilepsy's classification systems from 1981 and 1989, respectively, which are still used today in clinical practice and have formed the basis for a worldwide standardized approach to diagnosing, treating, and studying seizure disorders. This classification system is based on clinical seizure semiology and EEG correlation and makes a distinction between focal and generalized seizures. The clinical semiology and localization of simple partial, complex partial, and generalized seizures are discussed. Some common partial and generalized epilepsy syndromes are also highlighted. PMID- 22810314 TI - Differential diagnosis of epilepsy. AB - Epilepsy is a relatively common neurologic disorder that has important implications for patients, health care providers, and society. Making the correct diagnosis for transient neurologic events as with many neurologic conditions starts with an accurate and complete history and consequently leads to a directed diagnostic workup. In this chapter, we present transient neurologic events that are commonly included in the differential diagnosis for epilepsy and how to evaluate and distinguish among the possibilities. Making the correct diagnosis of epilepsy or one of its mimickers allows the practitioner to prescribe appropriate therapy for what are often divergent conditions. PMID- 22810315 TI - Pediatric epilepsy syndromes. AB - Epilepsy syndromes denote specific constellations of clinical seizure type(s), EEG findings, and other characteristic clinical features. Most syndromes recognized in epilepsy are genetic and developmental disorders that begin in the pediatric years. Epilepsy syndromes are divided into idiopathic (primary) types, in which the presumed etiology is genetic, versus symptomatic (secondary) types, in which there is either an underlying etiology that is known or presumed based on other evidence of brain dysfunction. Epilepsies are also classified by those with generalized seizures and those with localization-related seizures. Identification of a specific syndrome is important to define the best treatment and accurately prognosticate long-term outcome for children with epilepsy. In this chapter, clinical and electrographic features as well as inheritance patterns of common pediatric epilepsy syndromes are discussed. PMID- 22810316 TI - Epilepsy comorbidities. AB - Psychiatric and cognitive disorders in persons with epilepsy (PWE) are often overlooked or undertreated. Studies have shown that they occur in all types of epilepsy, but they are especially prominent when epilepsy is severe and multiple antiepileptic drugs are used. In particular, the clinician should be vigilant about the coexistence of depression with epilepsy. The depression must be properly treated to improve quality of life and also to prevent the mood disorder from interfering with epilepsy treatment.Mortality in PWE is overall twice that in the general population, but most of the increased mortality is due to major conditions with which the epilepsy is associated. The clinician should be aware that some PWE have increased risk for suicide. The phenomenon of sudden unexplained death in epilepsy occurs at the highest rate in persons with uncontrolled seizures, especially generalized convulsive seizures. For now, optimizing seizure control appears to be the best way to reduce the risk for this still mysterious and catastrophic event. PMID- 22810317 TI - Antiepileptic drug therapy: when to start, when to stop. AB - We are fortunate to practice in an era in which multiple antiepileptic drug (AED) options are available for use in the treatment of epilepsy and seizures. However, clinical decisions regarding when AED therapy should be initiated and when discontinuation can be considered remain complex. It is known that not every patient presenting with a seizure will suffer a recurrence, and some will do well without treatment. It is also known that a certain proportion of patients with a past history of seizures will enter remission, in which case AEDs can be discontinued. In this chapter, the subjects of AED initiation and discontinuation will be reviewed. PMID- 22810318 TI - Choosing among antiepileptic drugs. AB - Selecting an antiepileptic drug (AED) for treatment of seizures is daunting because there are now 20 from which to choose. Following simple principles allows a systematic approach to drug selection. Efficacy studies provide limited information. For initial monotherapy of partial seizures, high-level evidence exists for the efficacy of lamotrigine, carbamazepine, oxcarbazepine, and topiramate. For initial monotherapy of generalized seizures, high-level evidence is available for valproate, lamotrigine, topiramate, and oxcarbazepine. For initial monotherapy of absence seizures, high-level evidence exists for valproate, lamotrigine, and ethosaximide. All second-generation AEDs have efficacy as adjunctive therapy for partial seizures. AEDs are often useful for comorbid conditions or have properties that should be avoided in some groups. Thus, AEDs should usually be selected on the basis of comorbid conditions, including depression, migraine, chronic pain, obesity, and nephrolithiasis, or patient characteristics, especially for women of childbearing potential and older adults. PMID- 22810319 TI - Antiepileptic drugs: adverse effects and drug interactions. AB - The goal of epilepsy treatment is no seizures and no side effects. Antiepileptic drugs (AEDs) are the mainstay of treatment. Chronic use, however, often leads to serial drug changes over time, exposing patients with epilepsy (PWE) to recurrent risks due to adverse effects (AEs) and drug interactions. Both unwanted acute and chronic AEs may occur that are usually dose-related, suggested by AED pharmacology, and addressed with appropriate use of serum drug concentrations. Idiosyncratic AEs can pose significant health issues for PWE and be lifesaving with early identification. AED pharmacokinetics and pharmacodynamic properties serve as the foundation for anumber of drug interactions. Hepatic enzyme systems may facilitate AED interaction with other coadministered medication through induction or inhibition of drug metabolism and result in AEs or seizures from drug interactions. A working knowledge of AED pharmacology is an essential component of good clinical practice to help clinicians predict potential AEs and DIs in the treatments of PWE. PMID- 22810320 TI - Women'S issues and epilepsy. AB - Women with epilepsy (WWE) may experience changes in seizure control related to alterations in neuronal excitability mediated by estrogen and progesterone. A third or more of women will reliably note seizures that are linked to menstruation or ovulation. Reproductive hormone-related exacerbation of seizure control is also observed during perimenopause. Seizures and antiepileptic drugs (AEDs) also can adversely affect reproductive health. WWE have higher than expected rates of menstrual disorders and infertility. Enzyme-inducing AEDs interact with hormonal contraceptives, potentially limiting options for birth control. Exposure to AEDs during pregnancy increases the risk of congenital malformations and cognitive impairments in children born to WWE. Chronic AED use increases the risk of vitamin D deficiency, decreased bone quality and density, and fractures. These concerns heighten the need to taper AEDs when appropriate and to manage WWE on the simplest AED regimen that will maintain seizure freedom. PMID- 22810321 TI - Epilepsy surgery and electronic devices. AB - Epilepsy is a chronic disorder characterized by recurrent and unprovoked seizures. The lifetime risk of developing epilepsy is 4%. Approximately 90% of the incident cases in adults have partial epilepsy. The initial response to medication is of prognostic importance. Patients with symptomatic neurologic disease, foreign-tissue lesion, or developmental delay are less likely to be rendered seizure free. The goal of treatment is to render the individual seizure free. Many patients with partial epilepsy will not attain a seizure remission with antiepileptic drug therapy. Epilepsy surgery is an effective and safe alternative form of therapy for selected patients with intractable partial epilepsy. Electronic stimulation is being considered for patients with partial seizures who are not candidates for a focal cortical resection. PMID- 22810322 TI - Status epilepticus. AB - Status epilepticus (SE) is one of the most commonly occurring neurologic emergencies. About 40% of SE cases occur in people with epilepsy. Convulsive SE is easily recognized, but nonconvulsive SE is not and requires both a high index of suspicion and EEG confirmation. SE has a high mortality risk and requires rapid effective treatment for optimal response to therapy and outcome. The goal of treatment is to stop all clinical and electrographic seizures while maintaining vital functions. If seizures continue after initial treatment with a benzodiazepine, additional antiepileptic therapy should be administered. When SE is refractory to these treatments, continuous IV infusion with midazolam, propofol, or a barbiturate suppresses seizure activity. Standard treatment protocols are useful in promoting rapid intervention with appropriate medications. PMID- 22810323 TI - Patient management problem. PMID- 22810324 TI - Ethical perspectives in neurology: ethical considerations in sudden unexplained death in epilepsy. PMID- 22810325 TI - Practice issues in neurology: patient care, practice income, and quality. PMID- 22810326 TI - Coding table. PMID- 22810327 TI - APPENDIX A: AAN Summary of Evidence-Based Guideline for Clinicians: Evaluating an Apparent Unprovoked First Seizure in Adults. PMID- 22810329 TI - APPENDIX C: AAN Summary of Evidence-Based Guidelines for Clinicians: Management Issues for Women With Epilepsy-Teratogenesis and Perinatal Outcomes. PMID- 22810328 TI - APPENDIX B: AAN Summary of Evidence-Based Guidelines for Clinicians: Management Issues for Women With Epilepsy-Focus on Pregnancy: Obstetrical Complications and Change in Seizure Frequency. PMID- 22810330 TI - APPENDIX D: AAN Summary of Evidence-Based Guidelines for Clinicians: Management Issues for Women With Epilepsy-Vitamin K, Folic Acid, Blood Levels, and Breast feeding. PMID- 22810331 TI - Multiple-choice questions. PMID- 22810332 TI - Preferred responses. PMID- 22810333 TI - Quintessentials. PMID- 22810334 TI - EPILEPSY: Part 1-Baseline Questionnaire. PMID- 22810335 TI - Preferred responses: part 1-baseline. PMID- 22810337 TI - [The intraoperative auto- and allohemotransfusion by massive bleeding in emergency abdominal surgery]. AB - The results of intraoperative hemotransfusion of 112 patients with abdominal injuries, complicated with bleeding and the loss of more then 70% of the circulating blood. The aim of the study was to compare the efficacy of auto- and allohemotransfusion. The first method allowed to decrease both the overall lethality (p=0.039) and postoperative lethality (p=0.018). The odds ratio by the predominate autohemotransfusion was 1.385 (95% 1.101-1.741), where as the odds ratio by the predominate allohemotransfusion was 0.403 (95% 0.183-0.885; p=0.011). PMID- 22810338 TI - [The videolaparoscopic splenectomy by spleen injuries]. AB - The results of 9 videolaparoscopic splenectomies were analyzed. Indications and contraindications to the procedure were formulated, as well as the operative technique. The videolaparoscopic splenectomy proved to be more safe and effective in comparison with the traditional method. PMID- 22810339 TI - [The postoperative pancreatitis after the pancreatic surgery]. AB - The results of 302 operations on the pancreas were analyzed: of them 107 were pancreatoduodenal resections; 67 were distal resections of the pancreas; 74 were various resections of the head of the pancreas and middle resections and 54 other operations. The postoperative pancreatitis was registered in 178 patients. The preventive use of the octreotide intraoperatively and in early postoperative period showed no influence on the frequency and severity of the postoperative pancreatitis. The ultrasound was the optimal screening diagnostig method, whereas the computed tomography was the best in pancreonecrosis diagnostics and the volume of the pancreatic tissue damaged. Of 178 patients with the postoperative pancreatitis 17 died, the lethality rate was 9.5%. PMID- 22810340 TI - [The morphologic changes of gastric mucosa before and after the surgical operations]. AB - The article outlines the morphologic evaluation of the gastric mucosa in 159 patients with different types of pyloroduodenal ulcers. The comparative characteristics of the gastric mucosa of 80 patients before and after the gastric resection. The complete restoration of the mucosa within the year after the selective proximal vagotomy was registered. The gastric resection leads to the chronic gastritis with dystrophic changes and intestinal or pseudopyloric metaplasia. PMID- 22810341 TI - [The novel method of intestinal anastomosis after the colon resection]. AB - The novel method of the invagination colic anastomosis was suggested and experimentally approved. The results of surgical treatment with the use of the anastomosis in 23 patients were analyzed. The thorough and all-sided analysis permitted to state that the novel way of ileo-colic and colo-colic anastomosis was effective and safe for the surgical treatment of patients with diseases of the colon. PMID- 22810342 TI - [The sutureless lung resection with Ligasure device: the possibilities and perspectives]. AB - The experimental study of the durability of the "collagen" suture of the lung, performed with the use of the Ligasure device, was conducted. 17 patients, whom 21 lung resection was performet took part in the study. In the experimental part of the study the average rupture pressure of the collagen plomb was 413+/-99.4 mm Hg for the intact lung parenchyma and 212+/-66.7 mm Hg for the emphisematously changed tissue. The prolonged aerostatic insufficiency was registered only in two cases. The Ligasure suturing device proved to be the highly effective and safe for the use in thoracic surgery. PMID- 22810343 TI - [The acute appendicitis' diagnostic Alvorado's system]. AB - The recent studies prove that the treatment of the acute appendicitis should aim the preservation of the organ, considering the important functions of the least. The combined antimicrobial therapy allows the successful conservative treatment of all cases of the acute appendicitis but the gangrenous, which should be treated operatively. The use of glucocorticosteroids together with antibiotics is pathogenetically substantiated. To improve the diagnostics of the acute appendicitis, the modernized Alvorado's system was suggested by the authors. The least is adopted for the diagnostics of intraabdominal abscesses and gangrenous appendicitis. PMID- 22810344 TI - [The detox and antioxidant activity of the reamberine in the complex treatment of the acute destructive lung disease]. PMID- 22810345 TI - [The use antibiotics' enreached glue substance for the abdominal surgery]. PMID- 22810346 TI - [The surgical treatment of the thoracic trachea stenosis in combination with rupture of the trachea and the left main bronchus]. PMID- 22810347 TI - [The combination of the ischemic heart disease and lung cancer]. PMID- 22810348 TI - [The unrevealed arteria injury]. PMID- 22810350 TI - [To the problem of the simultaneous operations]. PMID- 22810349 TI - [The treatment of the giant scrotal hernia]. PMID- 22810351 TI - Non-equilibrium cation distribution and enhanced spin disorder in hollow CoFe2O4 nanoparticles. AB - We present magnetic properties of hollow and solid CoFe(2)O(4) nanoparticles that were obtained by annealing of Co(33)Fe(67)/CoFe(2)O(4) (core/shell) nanoparticles. Hollow nanoparticles were polycrystalline whereas the solid nanoparticles were mostly single crystal. Electronic structure studies were performed by photoemission which revealed that particles with hollow morphology have a higher degree of inversion compared to solid nanoparticles and the bulk counterpart. Electronic structure and the magnetic measurements show that particles have uncompensated spins. Quantitative comparison of saturation magnetization (M(S )), assuming bulk Neel type spin structure with cationic distribution, calculated from quantitative XPS analysis, is presented. The thickness of uncompensated spins is calculated to be significantly large for particles with hollow morphology compared to solid nanoparticles. Both morphologies show a lack of saturation up to 7 T. Moreover magnetic irreversibility exists up to 7 T of cooling fields for the entire temperature range (10-300 K). These effects are due to the large bulk anisotropy constant of CoFe(2)O(4) which is the highest among the cubic spinel ferrites. The effect of the uncompensated spins for hollow nanoparticles was investigated by cooling the sample in large fields of up to 9 T. The magnitude of horizontal shift resulting from the unidirectional anisotropy was more than three times larger than that of solid nanoparticles. As an indication signature of uncompensated spin structure, 11% vertical shift for hollow nanoparticles is observed, whereas solid nanoparticles do not show a similar shift. Deconvolution of the hysteresis response recorded at 300 K reveals the presence of a significant paramagnetic component for particles with hollow morphology which further confirms enhanced spin disorder. PMID- 22810352 TI - Labor management and mode of delivery among migrant and Spanish women: does the variability reflect differences in obstetric decisions according to ethnic origin? AB - Based on previous findings showing both better birth outcomes in migrant than in Spanish women and different rates of medical intervention according to mother's origin, we hypothesize that mode of delivery decisions to solve similar problems differ according to ethnic origin. Ethnic differences for maternal characteristics, medical intervention, and mode of delivery were evaluated in 16,589 births from a Maternity Hospital in Madrid (Spain). Multinomial logistic regression analysis was used to evaluate the effect of mother's ethnic origin on the mode of delivery, adjusting for mother's age, parity, gestational age, birth weight, and epidural anesthesia. Compared with the Spanish mothers, the risk of having a Caesarean section is significantly higher in Latin Americans and significantly lower for the Chinese. Both low birth weight and macrosomic deliveries are at higher risk for Caesarean section. The interventionist system characterizing Spain is being extended to all ethnic groups and, at the same time, different medical interventions are applied to similar problems depending on women's ethnic origin. Obstetric interventions might be contributing to the increasing trend of low birth weight and late preterm/early full term deliveries (37-38 weeks) observed in Spain. Behavioral and cultural values of the women and of the health care providers may contribute to systematic differences in labor management and mode of delivery. PMID- 22810353 TI - Microfluidic platform for on-demand generation of spatially indexed combinatorial droplets. AB - We propose a highly versatile and programmable nanolitre droplet-based platform that accepts an unlimited number of sample plugs from a multi-well plate, performs digitization of these sample plugs into smaller daughter droplets and subsequent synchronization-free, robust injection of multiple reagents into the sample daughter droplets on-demand. This platform combines excellent control of valve-based microfluidics with the high-throughput capability of droplet microfluidics. We demonstrate the functioning of a proof-of-concept device which generates combinatorial mixture droplets from a linear array of sample plugs and four different reagents, using food dyes to mimic samples and reagents. Generation of a one dimensional array of the combinatorial mixture droplets on the device leads to automatic spatial indexing of these droplets, precluding the need to include a barcode in each droplet to identify its contents. We expect this platform to further expand the range of applications of droplet microfluidics to include applications requiring a high degree of multiplexing as well as high throughput analysis of multiple samples. PMID- 22810354 TI - Maturation timing of stamens and pistils in the dioecious plant Silene latifolia. AB - The dioecious plant Silene latifolia depends on nocturnal insects for pollination. To increase the chance of cross-pollination, pollen grains seem to be released and stigmas seem to be receptive simultaneously at night. We divided the floral development of S. latifolia into 1-20 stages, and determined the timetables of male and female function. The corolla of both male and female flowers opens at sunset (1900 hours) and closes at sunrise (0900 hours). To investigate the period of the reproductive phase of male and female function, we measured the germination rate on a pollen medium and the pollen germination rate on stigma during the period when stamens and stigmas were viable in the timetable. Male flowers had early- and late-maturing stamens that had the highest pollen viability, germination rate and pollen tube growth at midnight (0000 hours) at 1 day after flowering (DAF) and 0000 hours at 2 DAF. In contrast, female flowers maintained a germination rate of nearly 100 % from 1800 hours at 1 DAF to 1200 hours at 3 DAF. These results suggested that S. latifolia transferred the matured pollen grains from male flowers to female flowers only at night. PMID- 22810355 TI - The problem with actually tattooing DNR across your chest. PMID- 22810356 TI - Interval examination: establishment of a hospitalist-staffed discharge clinic. PMID- 22810357 TI - Morbid obesity: obscuring the diagnosis of aortic stenosis in a patient with cardiogenic wheezing. AB - We report the case of a morbidly obese 65-year-old female who presented with repeated hypotensive episodes following dialysis. She was misdiagnosed as suffering from asthma, and eventually was found to have severe aortic stenosis. Obesity has become a common and formidable obstacle to gathering important diagnostic information in patients. Modern diagnostic lab tests and imaging modalities such as transthoracic echocardiography (TTE) can provide spurious data in the morbidly obese population, which can ultimately lead to misdiagnosis. In this clinical vignette, we discuss the relationship between the basic pathophysiologic mechanisms underlying aortic stenosis and patient clinical presentation. We also review the relevant literature and discuss the impact of obesity on the diagnosis of this condition. PMID- 22810358 TI - Levels and variation in overuse of fecal occult blood testing in the Veterans Health Administration. AB - BACKGROUND: Policy-makers have called for efforts to reduce overuse of cancer screening tests, including colorectal cancer screening (CRCS). Overuse of CRCS tests other than colonoscopy has not been well documented. OBJECTIVE: To estimate levels and correlates of fecal occult blood test (FOBT) overuse in a national Veterans Health Administration (VHA) sample. DESIGN: Observational PARTICIPANTS: Participants included 1,844 CRCS-eligible patients who responded to a 2007 CRCS survey conducted in 24 VHA facilities and had one or more FOBTs between 2003 and 2009. MAIN MEASURES: We combined survey data on race, education, and income with administrative data on region, age, gender, CRCS procedures, and outpatient visits to estimate overuse levels and variation. We coded FOBTs as overused if they were conducted <10 months after prior FOBT, <9.5 years after prior colonoscopy, or <4.5 years after prior barium enema. We used multinomial logistic regression models to examine variation in overuse by reason (sooner than recommended after prior FOBT; sooner than recommended after colonoscopy, barium enema, or a combination of procedures), adjusting for clustering of procedures within patients, and patients within facilities. KEY RESULTS: Of 4,236 FOBTs received by participants, 885 (21 %) met overuse criteria, with 323 (8 %) sooner than recommended after FOBT, and 562 (13 %) sooner than recommended after other procedures. FOBT overuse varied across facilities (9-32 %, p<0.0001) and region (12-23 %, p< .0012). FOBT overuse after prior FOBT declined between 2003 and 2009 (8 %-5 %, p= .0492), but overuse after other procedures increased (11-19 %, p= .0002). FOBT overuse of both types increased with number of outpatient visits (OR 1.15, p<0.001), but did not vary by patient demographics. More than 11 % of overused FOBTs were followed by colonoscopy within 12 months. CONCLUSIONS: Many FOBTs are performed sooner than recommended in the VHA. Variation in overuse by facility, region, and outpatient visits suggests addressing FOBT overuse will require system-level solutions. PMID- 22810359 TI - Mesenchymal stem cell: does it work in an experimental model with acute respiratory distress syndrome? AB - We hypothesized that bone marrow-derived mesenchymal stem cells (BM-MSCs) would have a possible role in the treatment of acute respiratory distress syndrome (ARDS). ARDS disease model was developed in Wistar albino male rats by intratracheal instillation of physiological saline solution. Anesthezied and tracheotomized rats (n = 8) with ARDS were pressure-controlled ventilated. Isolated and characterized rat (r-) BM-MSCs were labeled with GFP gene, and introduced in the lungs of the ARDS rat-model. After applying of MSCs, the life span of each rat was recorded. When rats died, their lung tissues were removed for histopathological examination. Also the tissue sections were analyzed for GFP labeled rBM-MSCs and stained for vimentin, CK19, proinflammatory (MPO, IL-1beta, IL-6 and MIP-2) and anti-inflammatory [IL-1ra and prostaglandin E2 receptor (EP3)] cytokines. The histopathological signs of rat-model ARDS were similar to the acute phase of ARDS in humans. rBM-MSCs were observed to home in lung paranchyma. Although the infiltration of neutrophils slightly decreased in the interalveolar, peribronchial and perivascular area, a notable improvement was determined in the degree of hemorrhage, edema and hyaline membrane formation in rats treated with rBM-MSCs. Also decreased proinflammatory cytokines levels and increased the intensity of anti-inflammatory cytokines were established. Therefore MSCs could promote alveolar epithelial repair by mediating of cytokines from a proinflammatory to an anti-inflammatory response. As a novel therapeutic approach, mesenchymal stem cell treatment with intratracheal injection could be helpful in the management of critically ill patients with ARDS. PMID- 22810361 TI - Electrochemical detection for dynamic analyses of a redox component in droplets using a local redox cycling-based electrochemical (LRC-EC) chip device. AB - This report describes the electrochemical detection of a redox component in droplets using a local redox cycling-based electrochemical (LRC-EC) chip device consisting of 256 sensors. The time-course analyses showed that the redox compound in the droplet was dynamically changed during droplet evaporation or mass transfer through a water/oil interface. PMID- 22810360 TI - VEGF induces neuroglial differentiation in bone marrow-derived stem cells and promotes microglia conversion following mobilization with GM-CSF. AB - PURPOSE: Evaluation of potential tropic effects of vascular endothelial growth factor (VEGF) on the incorporation and differentiation of bone-marrow-derived stem cells (BMSCs) in a murine model of anterior ischemic optic neuropathy (AION). METHODS: In the first approach, small-sized subset of BMCs were isolated from GFP donors mice by counterflow centrifugal elutriation and depleted of hematopoietic lineages (Fr25lin(-)). These cells were injected into a peripheral vein (1 * 10(6) in 0.2 ml) or inoculated intravitreally (2 * 10(5)) to syngeneic mice, with or without intravitreal injection of 5 MUg/2MUL VEGF, simultaneously with AION induction. In a second approach, hematopoietic cells were substituted by myelablative transplant of syngeseic GFP + bone marrow cells. After 3 months, progenitors were mobilized with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by VEGF inoculation into the vitreous body and AION induction . Engraftment and phenotype were examined by immunohistochemistry and FISH at 4 and 24 weeks post-transplantation, and VEGF receptors were determined by real time PCR. RESULTS: VEGF had no quantitative effect on incorporation of elutriated cells in the injured retina, yet it induced early expression of neuroal markers in cells incorporated in the RGC layer and promoted durable gliosis, most prominent perivascular astrocytes. These effects were mediated by VEGF-R1/Flt-1, which is constitutively expresses in the elutriated fraction of stem cells. Mobilization with GM-CSF limited the differentiation of bone marrow progenitors to microglia, which was also fostered by VEGF. CONCLUSIONS: VEGF signaling mediated by Flt-1 induces early neural and sustained astrocytic differentiation of stem cells elutriated from adult bone-marrow, with significant contribution to stabilization retinal architecture following ischemic injury. PMID- 22810362 TI - Lupus nephritis. How latest insights into its pathogenesis promote novel therapies. AB - PURPOSE OF REVIEW: Lupus nephritis is a complex autoimmune disease that develops its own dynamic upon damaging the renal ultrastructure. Here, we summarize the latest pathophysiological concepts of lupus nephritis and how these translate into novel therapeutic options. RECENT FINDINGS: Multidisciplinary research activities form a better understanding about how lupus develops from an unfortunate combination of gene variants that promote the loss of tolerance, that impair the clearance of dying cells, that regulate the immune interpretation of autoantigens as well as the peripheral control of autoreactive lymphocytes. As a new entry, nuclear particles also act as autoadjuvants mimicking viral particles and triggering interferon-alpha-dependent antiviral immune responses that cause symptoms similar to viral infection. SUMMARY: A set of novel drugs have the potential to more specifically interfere with these pathomechanisms and raise hope to more efficiently treat lupus nephritis with fewer side-effects in the near future. PMID- 22810363 TI - The complement system in pediatric systemic lupus erythematosus, atypical hemolytic uremic syndrome, and complocentric membranoglomerulopathies. AB - PURPOSE OF REVIEW: This review summarizes the recent advances in complement biology and the evolving understanding of these contributions to the pathophysiology and treatment of predominantly pediatric disease syndromes. RECENT FINDINGS: Identification of lupus patients with complete deficiencies of one of the plasma complement proteins enabled the field to move beyond the notion of complement as a laboratory curiosity. Clinical investigation of the manifestations observed in deficient patients has further defined the biology of the system in normal individuals. Definition of the assembly of the C3 convertases, particularly that of the alternative pathway and its regulation, has led to the appreciation that the complement system includes membrane inhibitors that are every bit as important as those in plasma. The exploration of disease states in which significant complement deposition occurs has moved the field away from consideration of this finding as a bystander effect. Dissection of these syndromes has led to the unanticipated finding of a central role for function altering mutations in the complement proteins that form or regulate the alternative pathway C3 convertase and has opened the door to new therapeutic approaches. The disease states discussed in the review - pediatric systemic lupus erythematosus, atypical hemolytic uremic syndrome, and the complocentric membranoglomerulopathies - illustrate this evolutionary history of complement biology. SUMMARY: This review emphasizes that both the lack of classical pathway complement activation and excessive activation of the alternative pathway contribute to distinct disease pathogenesis, and emphasizes the critical importance of homeostatic regulation, in both plasma and in tissues, of the system as a whole. PMID- 22810365 TI - Lipids and eicosanoids in fibrosis: emerging targets for therapy. AB - PURPOSE OF REVIEW: Lipid mediators including the lysophospholipids, sphingolipids and eicosanoids have long been implicated in inflammation, cancer and numerous other diseases. Over the last decade, new research suggests a role for these mediators in fibrosis. RECENT FINDINGS: Recent developments in the study of fibrotic mediators have centered on lysophospholipids and eicosanoids. New research is evaluating metabolic-profiling strategies to quantitatively measure lipid mediators in human plasma. Lysophosphatidic acid receptor antagonists are currently under development with early phase trials scheduled for idiopathic pulmonary fibrosis and scleroderma dermal fibrosis. Eicosanoids have long been implicated in maintaining tissue homeostasis, and the balance of profibrotic and antifibrotic effects has drawn attention in recent years. Targeting the prostanoids, specifically PGE2 and PGI2, as well as the leukotrienes is now being considered for antifibrotic therapies. SUMMARY: Lipid mediators have significant roles in many disease processes. Significant research now suggests a critical role for these mediators in the pathogenesis of fibrosis. Targeting these mediators is a promising area of drug discovery. PMID- 22810364 TI - Effects of anti-tumor necrosis factor alpha agents on bone. AB - PURPOSE OF REVIEW: Tumor necrosis factor (TNF) inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. RECENT FINDINGS: There are many studies of the effects of TNF inhibitors on markers of bone turnover; however, few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the antiresorptive effects of anti-TNF therapy are related to control of disease activity. SUMMARY: The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional nonbiologic therapies in the prevention of bone loss and fractures. PMID- 22810366 TI - Serum lactate level predict mortality in elderly patients with cirrhosis. AB - BACKGROUND: Cirrhotic patients admitted to the intensive care unit (ICU) usually have multi-organ failure. Multiple organ failure entails a very poor outcome in all intensive care patients. Cirrhotic patients show high morbidity and mortality rates compared with other critically ill patients. Severity scores have been developed for cirrhotic patients admitted to ICU. The main aim of this study was to determine whether lactate level gives any predictive value for mortality in cirrhotic elderly patients admitted to the ICU. METHODS: In all the patients enrolled, a diagnosis of cirrhosis was confirmed either histologically or by resorting to clinical, laboratory, and ultrasonographic findings. During this period, patients with cirrhosis were admitted to the ICU with varying indications. Child-Turcotte-Pugh (CTP), Model for End-stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores and lactate were compared between deceased and discharged patients. RESULTS: A total of 90 consenting patients were enrolled in this study. The mean age of all the patients was 69 +/- 5.919. We detected etiological factors for cirrhosis as HBV, HCV, alcohol, and cryptogenic cirrhosis. Hepatorenal syndrome and spontaneous bacterial peritonitis were significantly higher in patients who died than in those who were discharged from the ICU (p values were 0.01 and 0.028, respectively). Lactate level, CTP, APACHE II, MELD and SOFA scores were significantly higher in patients who died than in those who were discharged from the ICU (p values were 0.002, < 0.001, < 0.001, and < 0.001, respectively). CONCLUSIONS: Many factors may be useful as a predictor of mortality in ICU in elderly patients with cirrhosis. In terms of prognostic value, the lactate level and APACHE II score are the two best predictive factors in cirrhotic elderly patients admitted to the ICU. PMID- 22810367 TI - Serum vitronectin levels in patients with Behcet's disease. AB - BACKGROUND/AIMS: To determine serum vitronectin levels in Behcet patients with and without ocular involvement, and to evaluate the relationship between vitronectin concentrations and clinical manifestations of Behcet's disease (BD). METHODS: Sixty-five patients with BD and 21 control subjects were included. All patients were queried for the clinical manifestations of BD. Serum vitronectin concentrations were determined by using in vitro enzyme immunoassay kits. RESULTS: Serum vitronectin levels between the patients and the control subjects were not different. There was no statistically significant difference between vitronectin levels in Behcet patients with and without ocular involvement. No correlation was found between vitronectin concentrations and clinical manifestations. CONCLUSION: This is the first study evaluating vitronectin levels in Behcet patients. Further studies involving larger numbers of subjects would be useful to improve our understanding of the functions of vitronectin in BD. PMID- 22810368 TI - Lactoferrin restrains allergen-induced pleurisy in mice. AB - OBJECTIVES: The aim of this study was to assess the utility of lactoferrin (LF), a natural immunomodulator, to restrain allergen-induced pleurisy in mice. MATERIAL AND SUBJECTS: BALB/c female mice, 8- to 10-week old, weighing 24 g on average, were used. TREATMENT: Mice were immunized intraperitoneally with 50 MUg of ovalbumin (OVA) and the pleurisy was elicited 14 days later by intrapleural injection of 12.5 MUg of OVA. LF was given 24 and 3 h before elicitation of the allergic reaction. METHODS: The cytokine levels in the pleural exudates were measured by immunoassays. The blood and pleural exudates smears were stained with Giemsa and May-Grunwald reagents and reviewed histologically. Lung sections were stained with eosin and hematoxylin for histological evaluation. RESULTS: Lactoferrin significantly decreased manifestation of pleurisy induced by OVA in a sensitized mouse model. In particular, the percentages of eosinophils in blood and pleural exudates were strongly diminished. The histological analysis of lungs revealed that LF diminished the development of pathological lesions, such as pulmonary edema, diffuse alveolar hemorrhage and hemosiderosis, which were found in the lungs after injection of the eliciting dose of OVA. LF also decreased the level of IL-5 secreted into the pleural fluid. CONCLUSIONS: This is a first demonstration that LF significantly decreases antigen-specific pleurisy in a sensitized mouse model. PMID- 22810369 TI - Combined 3D rotational fluoroscopic-MRI cloacagram procedure defines luminal and extraluminal pelvic anatomy prior to surgical reconstruction of cloacal and other complex pelvic malformations. AB - PURPOSE: Cloacal anomalies represent one of the greatest surgical challenges in pediatric surgery. A recent advancement in the imaging of these anomalies is 3D rotational fluoroscopic cloacagram. However, a disadvantage is that obstructed lumens and extraluminal soft tissue structures are poorly delineated. We describe the development of a novel imaging technique whereby 3D rotational fluoroscopy is combined with high-resolution 3D pelvic MR imaging. METHODS: 3D rotational fluoroscopic cloacagram was initially performed. Catheters were directed into the urinary bladder, colon, and vagina. Low-osmolality iodinated contrast material mixed with a small amount of gadolinium contrast material was used to distend the catheterized cavities. After securing the catheters in place, patients underwent high-resolution 3D MRI of the pelvis. 3D MRI reconstructions were created. RESULTS: 3D rotational fluoroscopic cloacagram provided excellent luminal definition and accurate measurements of channel/fistula lengths, using intraoperative findings as the reference standard. 3D pelvic MRI measurements were easily and accurately made (using intraoperative and 3D rotational fluoroscopic cloacagram as reference standards), and soft tissue structures outside the lumens of the bladder, vagina, and rectum were well-defined. 3D pelvic MRI was able to identify a small vesicovaginal fistula that was not seen at 3D rotational fluoroscopy. CONCLUSION: This novel form of preoperative imaging results in excellent delineation channel/fistula lengths, luminal anatomy, and extra-luminal soft tissue structures to aid in operative planning. PMID- 22810370 TI - MDSC: a new player in HIV immunopathogenesis. PMID- 22810371 TI - Mapping community viral load and social boundaries: geographies of stigma and exclusion. PMID- 22810373 TI - Comparison of Roche Amplicor Ultrasensitive and Abbott RealTime assays for samples with low or undetectable HIV RNA levels. PMID- 22810374 TI - HIV incidence among men who have sex with men prescribed postexposure prophylaxis. PMID- 22810376 TI - Radiological versus surgical implantation of first catheter for peritoneal dialysis: a randomized non-inferiority trial. AB - BACKGROUND: The success of peritoneal dialysis (PD) is dependent on timely and adequate PD catheter access. In many centres, including our own, PD catheter insertion technique has evolved by laparoscopic surgery. An alternative method of catheter insertion is performed by radiologists using a percutaneous modified Seldinger technique under fluoroscopic guidance. However, there are no clinical trials comparing these two methods of catheter insertion. METHODS: From 1 April 1999 to 30 August 2004, we randomly assigned 113 pre-dialysis patients to receive PD catheter insertion using fluoroscopic guidance under local anaesthesia by radiologists or insertion using laparoscopy under general anaesthesia by a surgeon. The primary endpoint was the occurrence of dialysis catheter complications (complication-free catheter survival) by Day 365, a composite endpoint that included complications secondary to mechanical and infectious causes. Secondary endpoints were the occurrence of catheter removal (overall catheter survival) and death from any cause (patient survival) by Day 365, procedure pain, procedure time, procedure room utilization time, length of inpatient admission and direct hospital costs. Results were analysed by univariate and multivariate methods and by Kaplan-Meier survival curves. RESULTS: Complication-free catheter survival was significantly higher at 42.5% [95% confidence interval (CI) 29.3-55] in the radiological group compared with 18.1% (95% CI 8.9-29.8) in the laparoscopic group (P-value = 0.03). Excess complications in the laparoscopic group included peritonitis, peritoneal dialysate leaks and umbilical herniae. One-year overall catheter survival and 1 year subject survival were not different between the groups. Hospital costs were significantly higher in the laparoscopic group by almost a factor of two. CONCLUSIONS: Radiological insertion of first PD catheters using fluoroscopy is a clinically non-inferior and cost-effective alternative to surgical laparoscopic insertion. PMID- 22810377 TI - Facile self-assembly of porphyrin-embedded polymeric vesicles for theranostic applications. AB - A robust and uniform porphysome, which reveals an efficient photodynamic therapy and contrast-enhanced ultrasonic imaging for theranostic applications, can be fabricated from a 4-armed porphyrin-polylactide conjugate. PMID- 22810378 TI - Preconcentration of metal ions through chelation on a synthesized resin containing O, O donor atoms for quantitative analysis of environmental and biological samples. AB - Nascent Amberlite XAD-4 has been used as the polymeric support for the synthesis of a stable extractor of metal ions, by incorporating phthalic acid through azo bridging. Elemental analyses and infra-red spectral and thermal studies were carried out for its characterization. The water regain value and hydrogen ion capacity were found to be 12.50 and 5.75 mmol g(-1), respectively. The optimum pH range for the maximum sorption of Ni(II), Mn(II), Cu(II), Zn(II), Cd(II), Cr(III), and Co(II) was observed at pH 5.5-8.0 with the corresponding half loading time (t (1/2)) of 9, 5, 9, 9, 3, 9, and 5 min, respectively. The preconcentration factor for Ni(II), Mn(II), Cu(II), Zn(II), Cd(II), Cr(III), and Co(II) are 190, 190, 190, 180, 180, 160, and 160, with the corresponding limit of preconcentration in the range of 5.25-6.25 MUg L(-1). The detection limits, for flame atomic absorption spectrophotometry, were found to be 0.62, 0.60, 0.65, 0.75, 0.72, 0.84, and 0.85 MUg L(-1), respectively. Method has been successfully applied to the analysis of water samples, multivitamin formulations, infant food substitutes, hydrogenated oil, and fishes. PMID- 22810379 TI - Airborne load of Cassia pollen in West Bengal, eastern India: its atmospheric variation and health impact. AB - A Burkard personal volumetric sampler was used at Sriniketan, a town about 150 km northwest of Calcutta, in the state of West Bengal, in eastern India to record the frequency of three common airborne Cassia pollen types, Cassia tora, Cassia occidentalis, and Cassia fistula for two consecutive years (2004-2006). Correlation was made between the meteorological factors and the pollen concentration in the atmosphere. The study reports Cassia pollinosis by in vivo skin prick test in respiratory allergic patients. The highest positive reactions were exhibited by C. tora (34.7 %), C. fistula (33.3 %), and C. occidentalis (28.5 %). The allergic potential of these was investigated by in vitro enzyme linked immunosorbent assay test. Their protein components were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, in the range of 15.8-81.5 kDa. In C. occidentalis and C. fistula, 11 bands were found, while it was 10 in C. tora. The results show that the Cassia pollen occur significantly in the atmosphere with the potential to elicit an allergic response in susceptible patients. PMID- 22810380 TI - Concentrations of Cu, Fe, Mn, and Zn in tropical soils amended with sewage sludge and composted sewage sludge. AB - Sewage sludge may be used as an agricultural fertilizer, but the practice has been criticized because sludge may contain trace elements and pathogens. The aim of this study was to compare the effectiveness of total and pseudototal extractants of Cu, Fe, Mn, and Zn, and to compare the results with the bioavailable concentrations of these elements to maize and sugarcane in a soil that was amended with sewage sludge for 13 consecutive years and in a separate soil that was amended a single time with sewage sludge and composted sewage sludge. The 13-year amendment experiment involved 3 rates of sludge (5, 10, and 20 t ha(-1)). The one-time amendment experiment involved treatments reflecting 50, 100, and 200 % of values stipulated by current legislation. The metal concentrations extracted by aqua regia (AR) were more similar to those obtained by Environmental Protection Agency (EPA) 3052 than to those obtained by EPA3051, and the strongest correlation was observed between pseudo(total) concentrations extracted by AR and EPA3052 and bioavailable concentrations obtained by Mehlich III. An effect of sewage sludge amendment on the concentrations of heavy metals was only observed in samples from the 13-year experiment. PMID- 22810381 TI - Effects of aqueous suspensions of titanium dioxide nanoparticles on Artemia salina: assessment of nanoparticle aggregation, accumulation, and toxicity. AB - Aquatic stability and impact of titanium dioxide nanoparticles (TiO2 NPs, 10-30 nm) were investigated using Artemia salina. Acute exposure was conducted on nauplii (larvae) and adults in seawater in a concentration range from 10 to 100 mg/L TiO2 NPs for 24 and 96 h. Rapid aggregation occurred in all suspensions of TiO2 NPs to form micrometer size particles. Yet, both nauplii and adults accumulated the aggregates significantly. Average TiO2 content in nauplii ranged from 0.47 to 3.19 and from 1.29 to 4.43 mg/g in 24 and 96 h, respectively. Accumulation in adults was higher ranging from 2.30 to 4.19 and from 4.38 to 6.20 mg/g in 24 and 96 h, respectively. Phase contrast microscopy images revealed that Artemia were unable to excrete the particles. Thus, the TiO2 aggregates filled inside the guts. No significant mortality or toxicity occurred within 24 h at any dose. Lipid peroxidation levels characterized with malondialdehyde concentrations were not statistically different from those of the controls (p > 0.05). These results suggested that suspensions of the TiO2 NPs were nontoxic to Artemia, most likely due to the formation of benign TiO2 aggregates in water. In contrast, both mortality and lipid peroxidation increased in extended exposure to 96 h. Highest mortality occurred in 100 mg/L TiO2 NP suspensions; 18 % for nauplii and 14 % for adults (LC50 > 100 mg/L). These effects were attributed to the particle loading inside the guts leading to oxidative stress as a result of impaired food uptake for a long period of time. PMID- 22810382 TI - Optimization of a lipitoid-based plasmid DNA transfection protocol for bovine trophectoderm CT-1 cells. AB - Embryo-derived cell lines are important in vitro models for investigating the molecular mechanisms directing embryonic tissue lineage segregation and maintenance. The bovine trophectoderm-derived CT-1 cell line has been widely used to identify regulatory mechanisms of interferon tau gene expression, and it possesses potential as a model for characterizing the gene regulatory network controlling trophoblast lineage differentiation and development. This functional potential, however, is severely limited as CT-1 cells are very recalcitrant to standard transfection methods. The focus of this study was to test the cationic lipitoid reagent as an effective transfection reagent for DNA plasmid delivery. Optimization of liptoid-based transfection of plasmid DNA resulted in 9% transfection efficiency averaged across entire CT-1 colonies, with many subregions of CT-1 colonies achieving transfection rates of 15%. These rates are a substantial improvement over near-zero efficiencies achieved using other standard transfection techniques. CT-1 cells were also successfully adapted to substrate-free culture for over 20 passages, eliminating the need to culture CT-1 colonies on feeder cells or matrix-coated cultureware. Together, these results increase the utility of the CT-1 cell line as an in vitro bovine trophoblast model and provide insight into overcoming DNA delivery difficulties in other cell lines not amenable to genetic manipulation. PMID- 22810383 TI - Optofluidic devices and applications in photonics, sensing and imaging. AB - Optofluidics integrates the fields of photonics and microfluidics, providing new freedom to both fields and permitting the realization of optical and fluidic property manipulations at the chip scale. Optofluidics was formed only after many breakthroughs in microfluidics, as understanding of fluid behaviour at the micron level enabled researchers to combine the advantages of optics and fluids. This review describes the progress of optofluidics from a photonics perspective, highlighting various optofluidic aspects ranging from the device's property manipulation to an interactive integration between optics and fluids. First, we describe photonic elements based on the functionalities that enable fluid manipulation. We then discuss the applications of optofluidic biodetection with an emphasis on nanosensing. Next, we discuss the progress of optofluidic lenses with an emphasis on its various architectures, and finally we conceptualize on where the field may lead. PMID- 22810384 TI - Commentary: role of hydration in health and exercise. PMID- 22810385 TI - Miracle pills and fireproof trainers: user endorsement in social media. PMID- 22810386 TI - The truth about sports drinks. PMID- 22810387 TI - How valid is the European Food Safety Authority's assessment of sports drinks? PMID- 22810388 TI - Forty years of sports performance research and little insight gained. PMID- 22810389 TI - Mythbusting sports and exercise products. PMID- 22810390 TI - To drink or not to drink to drink recommendations: the evidence. PMID- 22810391 TI - Health damage from alcohol misuse has been underplayed in government strategy, say MPs. PMID- 22810394 TI - [Considering housing arrangements in elderly life: factors influencing plans concerning future housing arrangements and preferences in a representative sample of 45+ year olds]. AB - BACKGROUND: Providing care and support for the elderly is a future challenge. MATERIALS AND METHODS: Using regression analysis, a representative population based sample (n = 1,445) was examined with respect to whether they had considered future housing and which variables influenced their thoughts and preferences. RESULTS: The majority of the sample reported thinking about housing in old age and preferred to stay at home in old age. Thoughts about future housing and housing preferences were predicted by different factors in the age groups analyzed. Thinking about future housing was positively associated with increasing age and depression. Other relevant predictors were gender, living with a partner, images of old age (especially negative ones), and anticipated subjective health. These variables also predicted housing preferences. CONCLUSIONS: Thoughts about future living arrangements are widespread, and their importance increases with age. The wishes reported do contrast to a certain extent with reality. Planning future care as well as developing consultation guidelines should address these issues while considering the reported influences. PMID- 22810393 TI - MicroRNAs: a light into the "black box" of neuropediatric diseases? AB - Although there have been tremendous advances in the diagnosis and treatment of pediatric brain diseases in the last few decades, the causes and pathogenesis of these diseases remain to be elucidated. Pediatric central nervous system (CNS) diseases create both short- and long-term impairments and disabilities and are therefore one of the leading causes for emotional, financial, and social burden to patients, their families, and their social network. The significant pediatric morbidity and mortality rates caused by CNS diseases call for equally significant efforts toward a better understanding of the etiology and nature of these disorders. Recent studies show the involvement of microRNAs (miRNAs) in various aspects of central nervous system development and neuropsychiatric diseases. This review focuses on the role of miRNAs in different pediatric neurological conditions. We emphasize the importance of microRNA-based research in combating pediatric neurological disorders. We believe this approach will result in novel therapies to secure normal development and prevent disabilities in the pediatric population. PMID- 22810395 TI - A multicenter randomized controlled trial comparing single-row with double-row fixation in arthroscopic rotator cuff repair. AB - BACKGROUND: Controversy exists regarding the optimal technique for arthroscopic rotator cuff repair. The purpose of this multicenter, randomized, double-blind controlled study was to compare the functional outcomes and healing rates after use of single-row and double-row suture techniques for repair of the rotator cuff. METHODS: Ninety patients undergoing arthroscopic rotator cuff repair were randomized to receive either a single-row or a double-row repair. The primary objective was to compare the Western Ontario rotator cuff index (WORC) score at twenty-four months. Secondary objectives included comparison of the constant and american shoulder and elbow surgeons (ASES) scores and strength between groups. Anatomical outcomes were assessed with magnetic resonance imaging (MRI) or ultrasonography to determine the postoperative healing rates. RESULTS: Baseline demographic data including age (p = 0.29), sex (p = 0.68), affected side (p = 0.39), and rotator cuff tear size (p = 0.28) did not differ between groups. The WORC score did not differ significantly between groups at any time point (p = 0.48 at baseline, p = 0.089 at three months, p = 0.52 at six months, p = 0.83 at twelve months, and p = 0.60 at twenty-four months). The WORC score at each postoperative time point was significantly better than the baseline value. The Constant score, ASES score, and strength did not differ significantly between groups at any time point. Logistic regression analysis demonstrated that a smaller initial tear size and double-row fixation were associated with higher healing rates. CONCLUSIONS: No significant differences in functional or quality of-life outcomes were identified between single-row and double-row fixation techniques. A smaller initial tear size and a double-row fixation technique were associated with higher healing rates as assessed with ultrasonography or MRI. LEVEL OF EVIDENCE: Therapeutic level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810396 TI - Reliability of predictors for screw cutout in intertrochanteric hip fractures. AB - BACKGROUND: Following internal fixation of intertrochanteric hip fractures, tip apex distance, fracture classification, position of the screw in the femoral head, and fracture reduction are known predictors for screw cutout, but the reliability of these measurements is unknown. We investigated the reliability of the tip apex distance measurement, the Cleveland femoral head dividing system, the three-grade classification system of Baumgaertner for fracture reduction, and the AO classification system as predictors for screw cutout. METHODS: All patients with an intertrochanteric hip fracture who were managed with either a dynamic hip screw or a gamma nail between January 2007 and June 2010 were evaluated from our hip trauma database. RESULTS: The tip apex distance measurement was reliable and patients with device cutout had a significantly higher tip apex distance. The agreement between observers with regard to screw position and fracture reduction was moderately reliable. After adjustment for tip apex distance and screw position, A3 fractures were at more risk of cutout compared with A1 fractures. Poor fracture reduction was significantly related with a higher incidence of cutout in univariate analysis, but not in multivariate analysis. Central-inferior and anterior-inferior positions, after adjustment for tip apex distance and screw position, were significantly protective against cutout. CONCLUSION: To decrease probable risks of cutout, the tip apex distance needs to stay small or the screw needs to be placed central-inferiorly or anterior-inferiorly. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810397 TI - Evaluation of muscle size and fatty infiltration with MRI nine to eleven years following hamstring harvest for ACL reconstruction. AB - BACKGROUND: The long-term effect of hamstring tendon harvest for anterior cruciate ligament (ACL) reconstruction on muscle morphology is not well documented. Our hypothesis was that harvest of the hamstring tendons for ACL reconstruction would result in persistent loss of volume and cross-sectional area of the gracilis and semitendinosus muscles. METHODS: Magnetic resonance images were made of both limbs of ten patients nine to eleven years after they had ACL reconstruction with ipsilateral hamstring autograft. The volume of the individual thigh muscles bilaterally was calculated. The peak cross-sectional area and the cross-sectional area 7 cm proximal to the joint line was measured for the gracilis and semitendinosus muscles. Data were evaluated with use of the paired t test and Wilcoxon signed-rank test. The gracilis and semitendinosus muscles on the operatively treated side were evaluated for fatty infiltration and tendon regeneration. RESULTS: The mean volume on the operatively treated side was 54.2% of that on the noninvolved side for the gracilis muscle and 58.5% for the semitendinosus muscle. A 7% decrease in quadriceps volume and an 8% increase in the volume of the long head of the biceps on the operatively treated extremity were noted. The semimembranosus muscle and short head of the biceps muscle showed no difference in volume. The gracilis and semitendinosus muscles also showed a decrease in peak cross-sectional area, a decrease in the cross-sectional area 7 cm proximal to the joint line, and evidence of fatty infiltration. There was variable evidence of tendon or scar formation within the tendon bed, with most patients having some tissue that blended into either the sartorius muscle or medial gastrocnemius fascia at a level proximal to the joint line. CONCLUSIONS: At nine to eleven years after ACL reconstruction with ipsilateral hamstring autograft, the gracilis and semitendinosus muscles showed persistent atrophy on the operatively treated side with evidence of fatty infiltration and variability in tendon regeneration. There was also persistent atrophy of the quadriceps muscles and compensatory hypertrophy of the long head of the biceps. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810398 TI - The safety of controlled hypotension for shoulder arthroscopy in the beach-chair position. AB - BACKGROUND: The safety of controlled hypotension during arthroscopic shoulder procedures with the patient in the beach-chair position is controversial. Current practice for the management of intraoperative blood pressure is derived from expert opinion among anesthesiologists, but there is a paucity of clinical data validating their practice. The purpose of this study was to evaluate the effect of controlled hypotension on cerebral perfusion with use of continuous electroencephalographic monitoring in patients undergoing shoulder arthroscopy in the beach-chair position. METHODS: Fifty-two consecutive patients who had undergone shoulder arthroscopy in the beach-chair position were enrolled prospectively in this study. All patients underwent preoperative blood pressure measurements, assignment of an American Society of Anesthesiologists (ASA) grade, and a preoperative and postoperative neurological and Mini-Mental State Examination (MMSE). The target systolic blood pressure for all patients was 90 to 100 mm Hg during surgery. Continuous intraoperative monitoring was performed with standard ASA monitors and a ten-lead portable electroencephalography monitor. Real-time electroencephalographic monitoring was performed by an attending-level neurophysiologist. RESULTS: All patients violated at least one recommended limit for blood pressure reduction. The average decrease in systolic blood pressure and mean arterial pressure from baseline was 36% and 42%, respectively. Three patients demonstrated ischemic changes on electroencephalography that resolved with an increase in blood pressure. No adverse neurological sequelae were observed in any patient on the basis of the MMSE. CONCLUSIONS: This study provides the first prospective data on global cerebral perfusion during shoulder arthroscopy in the beach-chair position with use of controlled hypotension. Our study suggests that patients may be able to safely tolerate a reduction in blood pressure greater than current recommendations. In the future, intraoperative cerebral monitoring may play a role in preventing neurological injury in patients undergoing shoulder arthroscopy in the beach-chair position. PMID- 22810399 TI - Simple guidelines for efficient referral of soft-tissue sarcomas: a population based evaluation of adherence to guidelines and referral patterns. AB - BACKGROUND: Optimal treatment of soft-tissue sarcoma requires multidisciplinary management at a sarcoma center. However, these rare tumors are often misinterpreted as benign and many are inadequately treated outside a sarcoma center, with an increased risk of local recurrence that often requires further extensive surgical treatment. To improve referral and centralization of soft tissue sarcoma management in the southern Sweden health care region, an open access outpatient clinic at our sarcoma center and simple referral guidelines have been established for the past thirty years. The guidelines call for referral of all deep-seated soft-tissue tumors and of all >=5-cm superficial tumors before open biopsy or surgery. We evaluated adherence to these guidelines and characterized referral patterns. We also studied the consequences of our strategy with regard to the relative numbers of benign and malignant diagnoses among referred patients. METHODS: Adherence to guidelines, referral pathways, and time to referral to the sarcoma center were analyzed in a population-based series of 100 consecutive patients with soft-tissue sarcoma in the extremities or trunk wall. We also analyzed diagnosis and management of benign and malignant tumors in a second cohort consisting of 464 consecutive patients referred to the sarcoma center because of a soft-tissue tumor. RESULTS: Ninety-seven of the 100 patients with soft-tissue sarcoma were referred to the sarcoma center. All fifty-eight of the deep-seated soft-tissue sarcomas and twenty-eight of the forty-two superficial tumors were referred before open biopsy or surgery. Three-quarters of the patients with soft-tissue sarcoma first presented to a general practitioner. One-quarter of these patients were directly referred to the sarcoma center, which cut the referral time in half compared with patients initially referred to a local hospital. One-quarter of all patients referred to the outpatient clinic were diagnosed with a malignancy, with the majority of the malignancies being soft-tissue sarcoma. CONCLUSIONS: Our simple referral guidelines and open-access outpatient clinic resulted in nearly complete referral of patients with soft tissue sarcoma to the sarcoma center. The "excess work" associated with referral of benign tumors according to our strategy was limited to the diagnosis of three benign tumors for each malignant tumor. We consider this surplus evaluation of benign tumors acceptable and probably necessary to achieve a high referral rate of soft-tissue sarcoma before initial surgery. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810400 TI - Selective plantar fascia release for nonhealing diabetic plantar ulcerations. AB - BACKGROUND: Achilles tendon lengthening can decrease plantar pressures, leading to resolution of forefoot ulceration in patients with diabetes mellitus. However, this procedure has been reported to have a complication rate of 10% to 30% and can require a long period of postoperative immobilization. We have developed a new technique, selective plantar fascia release, as an alternative to Achilles tendon lengthening for managing these forefoot ulcers. METHODS: We evaluated sixty patients with diabetes for a mean of 23.5 months after selective plantar fascia release for the treatment of nonhealing diabetic neuropathic ulcers in the forefoot. Preoperative and postoperative dorsiflexion range of motion of the affected metatarsophalangeal joint and wound-healing data were used to evaluate the effectiveness of the procedure and to determine the relationship between plantar fascia release and ulcer healing. Complications were recorded. RESULTS: Thirty-six (56%) of the ulcers healed within six weeks, including twenty-nine (60%) of the plantar toe ulcers and seven (44%) of the metatarsophalangeal joint ulcers. The mean range of motion of the affected metatarsophalangeal joint increased from 15.3 degrees +/- 7.8 degrees to 30.6 degrees +/- 14.1 degrees postoperatively (p < 0.05). All patients in whom the preoperative dorsiflexion of the affected metatarsophalangeal joint was between 5 degrees and 30 degrees and in whom the range of motion of that joint increased by >=13 degrees after the procedure experienced healing of the ulcer. No ulcer recurrence in the original location was identified during follow-up. No patients experienced any complications associated with the selective plantar fascia release. CONCLUSIONS: Our results suggest that selective plantar fascia release can lead to healing of neuropathic plantar forefoot ulcers in diabetic patients. Ulcers in patients in whom the preoperative dorsiflexion angle of the affected metatarsophalangeal joint is between 5 degrees and 30 degrees and in whom the increase in range of motion is >=13 degrees postoperatively have the greatest chance of being cured. LEVEL OF EVIDENCE: Therapeutic level IV. See Instructions for Authors for a complete description of the levels of evidence. PMID- 22810401 TI - A clove-hitch suture method for small-caliber tendon ends. AB - BACKGROUND: The choices of suture methods used to secure the end of a small caliber tendon with a combination of suture materials passing through and looping around the tendon are not well documented. A secure stitch-tendon unit may be an important factor in preserving muscle function, by facilitating healing without gapping or failure. METHODS: Five types of suture methods utilizing four or fewer passes through the tendon end were mechanically tested on 178 canine flexor digitorum profundus tendons. An Instron apparatus was used to test the load to failure. RESULTS: The single and double clove-hitch suture methods demonstrated improved repair strength when compared with the three other methods studied in this small-caliber canine tendon model. CONCLUSIONS: The single and double clove hitch suture method better secured the end of a small-caliber tendon compared with other methods. CLINICAL RELEVANCE: The single (pull-out) and double (non pull-out) clove-hitch suture methods are reliable alternatives for the repair of small-caliber tendons. PMID- 22810402 TI - Arthroscopic Bankart repair and capsular shift for recurrent anterior shoulder instability: functional outcomes and identification of risk factors for recurrence. AB - BACKGROUND: Arthroscopic Bankart repair and capsular shift is a well-established technique for the treatment of anterior shoulder instability. The purpose of this study was to evaluate the outcomes following arthroscopic Bankart repair and capsular shift and to identify risk factors that are predictive of recurrence of glenohumeral instability. METHODS: We performed a retrospective review of a prospectively collected database consisting of 302 patients who had undergone arthroscopic Bankart repair and capsular shift for the treatment of recurrent anterior glenohumeral instability. The prevalence of patient and injury-related risk factors for recurrence was assessed. Cox proportional hazards models were used to estimate the predicted probability of recurrence within two years. The chief outcome measures were the risk of recurrence and the two-year functional outcomes assessed with the Western Ontario shoulder instability index (WOSI) and disabilities of the arm, shoulder and hand (DASH) scores. RESULTS: The rate of recurrent glenohumeral instability after arthroscopic Bankart repair and capsular shift was 13.2%. The median time to recurrence was twelve months, and this complication developed within one year in 55% of these patients. The risk of recurrence was independently predicted by the patient's age at surgery, the severity of glenoid bone loss, and the presence of an engaging Hill-Sachs lesion (all p < 0.001). These variables were incorporated into a model to provide an estimate of the risk of recurrence after surgery. Varying the cutoff level for the predicted probability of recurrence in the model from 50% to lower values increased the sensitivity of the model to detect recurrences but decreased the positive predictive value of the model to correctly predict failed repairs. There was a significant improvement in the mean WOSI and DASH scores at two years postoperatively (both p < 0.001), but the mean scores in the group with recurrence were significantly lower than those in the group without recurrence (both p < 0.001). CONCLUSIONS: Our study identified factors that are independently associated with a higher risk of recurrence following arthroscopic Bankart repair and capsular shift. These data can be useful for counseling patients undergoing this procedure for the treatment of recurrent glenohumeral instability and individualizing treatment options for particular groups of patients. LEVEL OF EVIDENCE: Prognostic level I. See Instructions for authors for a complete description of levels of evidence. PMID- 22810403 TI - The benefits of implant removal from the foot and ankle. AB - BACKGROUND: Following successful orthopaedic surgical procedures, implant removal is generally not necessary or recommended. However, patients with pain related to implants may benefit from this elective procedure. The foot and ankle may be more symptomatic from retained implants because of weight-bearing activities, shoe wear, and limited soft-tissue cushioning. In such cases, implant removal may provide good and reliable relief of symptoms. METHODS: A prospective study of sixty-nine patients who underwent elective removal of symptomatic implants from the foot and ankle was undertaken to evaluate the patients' pain experience. The short-form McGill pain questionnaire was administered preoperatively and six weeks postoperatively. Postoperatively, patients were also asked whether they would repeat the procedure and whether they were satisfied with the results. RESULTS: Patients reported significantly less pain following the procedure, with the average rating of pain on the visual analog scale (VAS) decreasing from 3.06 to 0.88 and the average rating of present pain intensity decreasing from 2.03 to 0.58 (p < 0.05 for both). Sixty-five percent of the patients reported no pain on either measure at six weeks postoperatively. Preoperative pain was correlated with postoperative pain (r = 0.24 and p < 0.05 for VAS, and r = 0.16 and p > 0.05 for present pain intensity).With the small sample size, preoperative and postoperative pain did not show a significant difference on the basis of implant location or patient age or sex. Ninety-four percent of patients said they would repeat the procedure under the same circumstances, and 91% of patients were satisfied with the results. CONCLUSIONS: Following successful orthopaedic surgical procedures, removal of implants causing symptoms can result in pain relief and a high rate of patient satisfaction. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810404 TI - American Academy of Orthopaedic Surgeons clinical practice guideline on: the diagnosis and treatment of osteochondritis dissecans. PMID- 22810405 TI - Fractures and dislocations of the midfoot: Lisfranc and Chopart injuries. PMID- 22810406 TI - What's new in shoulder and elbow surgery. PMID- 22810407 TI - Suture number determines strength of rotator cuff repair. AB - BACKGROUND: Failure of surgical repair of a rotator cuff tear continues to be a clinical problem. For other tendon repairs, increasing the number of sutures improves both biomechanical performance and clinical outcomes. Several investigators have shown biomechanical advantages of double-row techniques but have used many more sutures than were used with the single-row techniques with which the double-row techniques were compared. The purposes of our study were to establish whether using a greater number of sutures would improve the biomechanical properties of a rotator cuff repair model, and whether using equal numbers of sutures would lead to equivalent results between single and double-row configurations. METHODS: Fresh-frozen sheep infraspinatus tendons underwent single-row repair with two, four, or six mattress sutures and double-row repair with use of four mattress sutures. Specimens were pretensioned at 10 N for one minute, then cycled from 10 to 180 N for 200 cycles at 0.2 Hz; this was followed by load to failure. Cyclic gap formation, failure load, and failure type were recorded. RESULTS: The four-suture single-row and four-suture double-row repairs had similar gap formation during cyclic testing, with no significant differences between them. Cyclic gap formation in the two-suture single-row group was 6.7 and 7.1 mm (97% and 109%) greater than that in the four and six-suture single-row groups after 200 cycles (p < 0.001). The average loads to failure of the two, four, and six-suture single-row groups were 274, 362, and 572 N (p < 0.0001). The average load to failure of the four-suture double-row group was 386 N, which was similar to the value in the four-suture single-row group (p = 0.58). CONCLUSIONS: In an ovine rotator cuff tendon repair model, increasing the number of sutures decreased cyclic gap formation and increased load to failure. Single and double row repairs are biomechanically equivalent when the number of sutures is kept constant. CLINICAL RELEVANCE: The results of this study support the use of greater numbers of sutures in rotator cuff repair and disagree with the assertion that double-row repairs are biomechanically superior to single-row repairs. PMID- 22810408 TI - Obesity, diabetes, and preoperative hyperglycemia as predictors of periprosthetic joint infection: a single-center analysis of 7181 primary hip and knee replacements for osteoarthritis. AB - BACKGROUND: Diabetes and obesity are common in patients undergoing joint replacement. Studies analyzing the effects of diabetes and obesity on the occurrence of periprosthetic joint infection have yielded contradictory results, and the combined effects of these conditions are not known. METHODS: The one-year incidence of periprosthetic joint infections was analyzed in a single-center series of 7181 primary hip and knee replacements (unilateral and simultaneous bilateral) performed between 2002 and 2008 to treat osteoarthritis. The data regarding periprosthetic joint infection (defined according to Centers for Disease Control and Prevention criteria) were collected from the hospital infection register and were based on prospective, active surveillance. Patients diagnosed with diabetes were identified from the registers of the Social Insurance Institution of Finland. The odds ratios (ORs) for infection and the accompanying 95% confidence intervals (CIs) were calculated with use of binary logistic regression with adjustment for age, sex, American Society of Anesthesiologists risk score, arthroplasty site, body mass index, and diabetic status. RESULTS: Fifty-two periprosthetic joint infections occurred during the first postoperative year (0.72%; 95% CI, 0.55% to 0.95%). The infection rate increased from 0.37% (95% CI, 0.15% to 0.96%) in patients with a normal body mass index to 4.66% (95% CI, 2.47% to 8.62%) in the morbidly obese group (adjusted OR, 6.4; 95% CI, 1.7 to 24.6). Diabetes more than doubled the periprosthetic joint infection risk independent of obesity (adjusted OR, 2.3; 95% CI, 1.1 to 4.7). The infection rate was highest in morbidly obese patients with diabetes; this group contained fifty-one patients and periprosthetic infection developed in five (9.8%; 95% CI, 4.26% to 20.98%). In patients without a diagnosis of diabetes at the time of the surgery, there was a trend toward a higher infection rate in association with a preoperative glucose level of >=6.9 mmol/L (124 mg/dL) compared with <6.9 mmol/L. The infection rate was 1.15% (95% CI, 0.56% to 2.35%) in the former group compared with 0.28% (95% CI, 0.15% to 0.53%) in the latter, and the adjusted OR was 3.3 (95% CI, 0.96 to 11.0). The type of diabetes medication was not associated with the infection rate. CONCLUSIONS: Diabetes and morbid obesity increased the risk of periprosthetic joint infection following primary hip and knee replacement. The benefits of joint replacement should be carefully weighed against the incidence of postoperative infection, especially in morbidly obese patients. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810409 TI - The prognosis for improvement in comfort and function after the ream-and-run arthroplasty for glenohumeral arthritis: an analysis of 176 consecutive cases. AB - BACKGROUND: Knowledge of the factors affecting the prognosis for improvement in function and comfort with time after shoulder arthroplasty is important to clinical decision-making. This study sought to identify some of these factors in 176 consecutive patients undergoing the ream-and-run procedure. METHODS: The time course for improvement in patient function and comfort was determined for the entire group as well as for subsets by sex, age, diagnosis, preoperative function, and surgery date. Patients having repeat surgery were analyzed in detail. RESULTS: Shoulder comfort and function increased progressively after the ream-and-run procedure, reaching a steady state by approximately twenty months. The shoulders in 124 patients with at least two years of follow-up were improved by a minimal clinically important difference. The shoulders in sixteen patients with at least two years of follow-up were not improved by the minimal clinically important difference. Twenty-two patients had repeat procedures, but only seven had revision to a total shoulder arthroplasty. Fourteen patients did not have either a known revision arthroplasty or two years of follow-up. The best prognosis was for male patients over the age of sixty years, with primary osteoarthritis, no prior surgical procedures, a preoperative score on the simple shoulder test of >=5 points, and surgery after 2004. Repeat surgical procedures were more common in patients who had a greater number of surgical procedures before the ream-and-run surgery. CONCLUSIONS: This study is unique in that it characterizes the factors affecting the time course for improvement in shoulder comfort and function after a ream-and-run procedure. Improvement occurs after this procedure for at least 1.5 years. This procedure appears to be best suited for an older male patient with reasonable preoperative shoulder function without prior shoulder surgery. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for authors for a complete description of levels of evidence. PMID- 22810410 TI - Adverse outcomes in hip arthroplasty: long-term trends. AB - BACKGROUND: Total hip arthroplasty is a common surgical procedure, but little is known about longitudinal trends in associated adverse outcomes. Our objective was to describe long-term trends in demographics, comorbidities, and adverse outcomes for older patients who underwent primary and revision total hip arthroplasty. METHODS: We identified a retrospective, observational cohort of 1,405,379 Medicare beneficiaries who underwent primary total hip arthroplasty and 337,874 who underwent revision total hip arthroplasty between 1991 and 2008. The primary outcome was a composite representing the occurrence of one or more of the following adverse outcomes during the index admission or during readmission within ninety days after discharge: death, hemorrhage, infection, pulmonary embolism, sepsis, deep venous thrombosis, and myocardial infarction. Secondary outcomes included each of these outcomes assessed individually. RESULTS: Between 1991 and 2008, the mean age and the mean comorbidity burden increased for all total hip arthroplasty patients. The length of hospital stay after primary and revision total hip arthroplasty declined by approximately 50% over the study period. However, the rate of readmission for any cause has recently increased and has surpassed 10% for primary total hip arthroplasty and 20% for revision total hip arthroplasty. The composite rate of adverse outcomes after primary total hip arthroplasty declined from 4% to 3.4% over the study period, whereas the composite adverse outcome rate after revision total hip arthroplasty slowly increased from 7% to 10.9%. We observed a steady decline in the rates of most individual adverse outcomes after primary total hip arthroplasty over the majority of the study period. Many of these rates stabilized or began to increase slightly near the end of the study period. In contrast, an increase in the rates of many adverse outcomes was observed in the revision total hip arthroplasty population even after accounting for changes in patient complexity. Postoperative hemorrhage has gradually increased after both primary and revision total hip arthroplasty. CONCLUSIONS: Patients undergoing primary and revision total hip arthroplasty are becoming more complex. Despite this increasing complexity, patient outcomes for primary total hip arthroplasty improved markedly before stabilizing in recent years. In contrast, patient outcomes after revision total hip arthroplasty have gradually worsened, likely reflecting the increase in the medical comorbidities and surgical complexity of these patients. Length of hospital stay has demonstrated a substantial decline, which has recently been coupled with an increased readmission rate. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810411 TI - Management of periprosthetic joint infection: the current knowledge: AAOS exhibit selection. AB - Periprosthetic joint infection continues to frustrate the medical community. Although the demand for total joint arthroplasty is increasing, the burden of such infections is increasing even more rapidly, and they pose a unique challenge because their accurate diagnosis and eradication can prove elusive. This review describes the current knowledge regarding diagnosis and treatment of periprosthetic joint infection. A number of tools are available to aid in establishing a diagnosis of periprosthetic joint infection. These include the erythrocyte sedimentation rate, serum C-reactive protein concentration, synovial white blood-cell count and differential, imaging studies, tissue specimen culturing, and histological analysis. Multiple definitions of periprosthetic joint infection have been proposed but there is no consensus. Tools under investigation to diagnose such infections include the C-reactive protein concentration in the joint fluid, point-of-care strip tests for the leukocyte esterase concentration in the joint fluid, and other molecular markers of periprosthetic joint infection. Treatment options include irrigation and debridement with prosthesis retention, one-stage prosthesis exchange, two-stage prosthesis exchange with intervening placement of an antibiotic-loaded spacer, and salvage treatments such as joint arthrodesis and amputation. Treatment selection is dependent on multiple factors including the timing of the symptom onset, patient health, the infecting organism, and a history of infection in the joint. Although prosthesis retention has the theoretical advantages of decreased morbidity and improved return to function, two-stage exchange provides a lower rate of recurrent infection. As the burden of periprosthetic joint infection increases, the orthopaedic and medical community should become more familiar with the disease. It is hoped that the tools currently under investigation will aid clinicians in diagnosing periprosthetic joint infection in an accurate and timely fashion to allow appropriate treatment. Given the current knowledge and planned future research, the medical community should be prepared to effectively manage this increasingly prevalent disease. PMID- 22810412 TI - The projected shortage of orthopaedists may be our fault. PMID- 22810413 TI - Controversy remains regarding the optimal technique for arthroscopic rotator cuff repair: Commentary on an article by Peter L.C. Lapner, MD, FRCSC, et al.: "A multicenter randomized controlled trial comparing single-row with double-row fixation in arthroscopic rotator cuff repair". PMID- 22810414 TI - Anatomic muscular deficits persist in the medial hamstrings nine to eleven years following harvest, but the clinical consequences remain unclear: Commentary on an article by Brian J. Snow, MD, et al.: "Evaluation of muscle size and fatty infiltration with MRI nine to eleven years following hamstring harvest for ACL reconstruction". PMID- 22810415 TI - Breaking bad news. PMID- 22810416 TI - ACR Appropriateness Criteria(r) definitive therapy for early-stage cervical cancer. AB - OBJECTIVES: The definitive treatment of early-stage cervical cancer involves multidisciplinary decision making. This expert panel was convened to reach consensus on the selection of appropriate therapies based on patient and disease characteristics at presentation. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or the treatment. RESULTS: Three clinical variants were developed to represent common scenarios in the treatment of early-stage cervical cancer. Group members reached consensus on the appropriateness of therapeutic options. This process yielded numerical ratings and descriptive commentary. CONCLUSIONS: This manuscript represents the consensus opinion of an expert panel based on a survey of all available medical literature. This manuscript may be used to inform the clinical decision making of physicians involved in the treatment of early-stage cervical cancer. PMID- 22810417 TI - Incorporating integrative medicine into standard oncologic management. PMID- 22810418 TI - Ischemic preconditioning may reduce hyperglycemia associated with intermittent Pringle maneuver in hepatic resection. PMID- 22810419 TI - Diversity of tuco-tucos (Ctenomys, Rodentia) in the Northeastern wetlands from Argentina: mitochondrial phylogeny and chromosomal evolution. AB - Tuco-tucos (small subterranean rodents of the genus Ctenomys) that inhabit sandy soils of the area under the influence of the second largest wetland of South America, in Northeastern Argentina (Corrientes province), are a complex of species and forms whose taxonomic status were not defined, nor are the evolutionary relationships among them. The tuco-tuco populations of this area exhibit one of the most ample grades of chromosomal variability within the genus. In order to analyze evolutionary relationships within the Corrientes group and its chromosomal variability, we completed the missing karyotypic information and performed a phylogenetic analysis. We obtained partial sequences of three mitochondrial markers: D-loop, cytochrome b and cytochrome oxidase I. The Corrientes group was monophyletic and split into three main clades that grouped related karyomorphs. The phylogeny suggested an ancestral condition of the karyomorph with diploid number (2n) 70 and fundamental number (FN) 84 that has evolved mainly via reductions of the FN although amplifications occurred in certain lineages. We discuss the relationship between patterns of chromosomal variability and species and groups boundaries. From the three main clades the one named ibera exhibited a remarkable karyotypic homogeneity, and could be considered as an independent and cohesive evolutionary lineage. On the contrary, the former recognized species C. dorbignyi is a polyphyletic lineage and hence its systematic classification should be reviewed. PMID- 22810420 TI - Reasons and operative outcomes after reversal of gastric bypass and jejunoileal bypass. AB - Limited information is available regarding reversal of gastric bypass. While reversal will lead to weight regain and return of comorbid conditions, procedure reversal is sometimes necessary due to complications. The decision to reverse versus revise is difficult; currently, there are no established guidelines. The objective was to review one center's experience with reversals of gastric bypass and jejunoileal bypass procedures and identify potential indications as well as technical feasibility and short-term outcomes. A retrospective review of a prospectively collected database from 1999 to 2010 was conducted; 12 patients who underwent reversal of non-banding bariatric procedures were included. There was no major perioperative morbidity in elective patients; one patient whose reversal was part of a second-look operation had massive intestinal necrosis. There was one (8.3 %) non-procedure-related postoperative death. No leaks were identified in any of the reversals. Leak rates were compared with other revisional procedures such as reversals, revisions, and conversions, with no statistical significance regarding leak rates between all three groups; however, revisions and conversions were performed via open or laparoscopic approach, while reversals were performed exclusively via open approach. Reversals of bariatric (non banding) procedures, either combined or purely malabsorptive, are technically challenging. Indications remain poorly defined. In our experience, short gut syndrome, renal failure, marginal ulceration, and malnutrition were the most common indications for reversal, differing from previously published data. Indications can depend on patient and surgeon preferences, but primarily on surgeon experience and type of complications. Based on this initial experience, these operations can be performed using the open approach with good outcomes. PMID- 22810421 TI - p68 RNA helicase promotes glioma cell proliferation in vitro and in vivo via direct regulation of NF-kappaB transcription factor p50. AB - The DEAD-box RNA helicase p68 plays a very important role in early organ development and maturation. However, the role of p68 in glioma is unclear. In this study, we showed that p68 protein levels were significantly elevated in high grade gliomas compared to low-grade gliomas and normal adjacent brain tissues. Importantly, the expression of p68 was significantly associated with poorer overall survival and enhanced resistance to treatment with radiotherapy plus temozolomide for glioma patients. Ectopic expression of p68 enhanced glioma cell proliferation both in vitro and in vivo. In contrast, knockdown of endogenous p68 prevented glioma cell proliferation. Using a tandem affinity purification assay, we found a new p68-binding protein, nuclear factor (NF)-kappaB p50. We found that p68 bound with the N-terminal of NF-kappaB p50, and the mutant of p68 lacking the p50-interaction domain failed to stimulate glioma cell proliferation and tumor growth. Moreover, p68 induced NF-kappaB p50 accumulation in the nucleus through release of NF-kappaB p50 from IkappaBalpha and increased NF-kappaB p50 target luciferase transcription activity. Knockdown of NF-kappaB p50 rescued the phenotypes induced by p68 both in vitro and in vivo. We concluded that p68 induces glioma tumor growth through binding with NF-kappaB p50, regulating NF kappaB p50 nucleus accumulation and transcription activity. PMID- 22810422 TI - Effects of non-symbolic numerical information suggest the existence of magnitude space synesthesia. AB - In number-space synesthesia, numbers are visualized in spatially defined arrays. In a recent study (Gertner et al. in Cortex, doi: 10.1016/j.cortex.2012.03.019 , 2012), we found that the size congruency effect (SiCE) for physical judgments (i.e., comparing numbers' physical sizes while ignoring their numerical values, for example, 8) was modulated by the spatial position of the presented numbers. Surprisingly, we found that the neutral condition, which is comprise solely of physical sizes (e.g., 3), was affected as well. This pattern gave rise to the idea that number-space synesthesia might entail not only discrete, ordered, meaningful symbols (i.e., Arabic numbers) but also continuous non-symbolic magnitudes (i.e., sizes, length, luminance, etc.). We tested this idea by assessing the performance of two number-space synesthetes and 12 matched controls in 3 comparative judgment tasks involving symbolic and non-symbolic stimuli: (1) Arabic numbers, (2) dot clusters, and (3) sizes of squares. The spatial position of the presented stimuli was manipulated to be compatible or incompatible with respect to the synesthetic number-space perceptions. Results revealed that for synesthetes, but not for controls, non-symbolic magnitudes (dot clusters) as well as symbolic magnitudes (i.e., Arabic numbers) interacted with space. Our study suggests that number-space synesthetes might have a general magnitude-space association that is not restricted to concrete symbolic stimuli. These findings support recent theories on the perception and evaluation of sizes in numerical cognition. PMID- 22810423 TI - Gaze and eye-tracking solutions for psychological research. AB - Eye-tracking technology is a growing field used to detect eye movements and analyze human processing of visual information for interactive and diagnostic applications. Different domains in scientific research such as neuroscience, experimental psychology, computer science and human factors can benefit from eye tracking methods and techniques to unobtrusively investigate the quantitative evidence underlying visual processes. In order to meet the experimental requirements concerning the variety of application fields, different gaze- and eye-tracking solutions using high-speed cameras are being developed (e.g., eye tracking glasses, head-mounted or desk-mounted systems), which are also compatible with other analysis devices such as magnetic resonance imaging. This work presents an overview of the main application fields of eye-tracking methodology in psychological research. In particular, two innovative solutions will be shown: (1) the SMI RED-M eye-tracker, a high performance portable remote eye-tracker suitable for different settings, that requires maximum mobility and flexibility; (2) a wearable mobile gaze-tracking device--the SMI eye-tracking glasses--which is suitable for real-world and virtual environment research. For each kind of technology, the functions and different possibilities of application in experimental psychology will be described by focusing on some examples of experimental tasks (i.e., visual search, reading, natural tasks, scene viewing and other information processing) and theoretical approaches (e.g., embodied cognition). PMID- 22810424 TI - Single-cell electroporation using a multifunctional pipette. AB - We present here a novel platform combination, using a multifunctional pipette to individually electroporate single-cells and to locally deliver an analyte, while in their culture environment. We demonstrate a method to fabricate low-resistance metallic electrodes into a PDMS pipette, followed by characterization of its effectiveness, benefits and limits in comparison with an external carbon microelectrode. PMID- 22810425 TI - C-reactive protein concentration as a significant correlate for metabolic syndrome: a Chinese population-based study. AB - Increasing evidence suggests that chronic, low-grade inflammation may be a common soil involving the pathogenesis of metabolic syndrome (MetS) and cardiovascular disease. We examined the association between C-reactive protein (CRP) concentration, an extensively studied biomarker of low-grade inflammation, and the MetS in a representative sample of Chinese adults in Taiwan. We performed a cross-sectional analysis of data from 4234 subjects [mean (+/-SD) age, 47.1 (+/ 18.2) years; 46.4 % males] who participated in a population-based survey on prevalences of hypertension, hyperglycemia, and hyperlipidemia in Taiwan. CRP levels were measured by the immunoturbidimetric CRP-latex high-sensitivity assay. The MetS was defined by an unified criteria set by several major organizations. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated with logistic regression model. Overall, there were 938 subjects with MetS among 4,234 participants, resulting in a prevalence rate of 22.1 %. A significantly progressive increase in the prevalence of MetS across quartiles of CRP was observed (p for trend <0.001). Participants in the second, third, and upper quartiles of CRP had significantly higher risk of having MetS when compared with those in the lowest quartile [adjusted ORs (95 % CIs) were 2.18 (1.62-2.94), 4.39 (3.31-5.81), and 7.11 (5.39-9.38), respectively; p for trend <0.001]. Furthermore, there was a strong stepwise increase in CRP levels as the number of components of the MetS increased. The prevalence of MetS showed a graded increase according to CRP concentrations. The possible utility of CRP concentration as a marker for MetS risk awaits further evaluation in prospective studies. PMID- 22810426 TI - Evolution of leaf form correlates with tropical-temperate transitions in Viburnum (Adoxaceae). AB - Strong latitudinal patterns in leaf form are well documented in floristic comparisons and palaeobotanical studies. However, there is little agreement about their functional significance; in fact, it is still unknown to what degree these patterns were generated by repeated evolutionary adaptation. We analysed leaf form in the woody angiosperm clade Viburnum (Adoxaceae) and document evolutionarily correlated shifts in leafing habit, leaf margin morphology, leaf shape and climate. Multiple independent shifts between tropical and temperate forest habitats have repeatedly been accompanied by a change between evergreen, elliptical leaves with entire margins and deciduous, more rounded leaves with toothed or lobed margins. These consistent shifts in Viburnum support repeated evolutionary adaptation as a major determinant of the global correlation between leaf form and mean annual temperature. Our results provide a new theoretical grounding for the inference of past climates using fossil leaf assemblages. PMID- 22810428 TI - Explaining differences in the lifespan and replicative capacity of cells: a general model and comparative analysis of vertebrates. AB - A better understanding of the factors that govern individual cell lifespan and the replicative capacity of cells (i.e. Hayflick's limit) is important for addressing disease progression and ageing. Estimates of cell lifespan in vivo and the replicative capacity of cell lines in culture vary substantially both within and across species, but the underlying reasons for this variability remain unclear. Here, we address this issue by presenting a quantitative model of cell lifespan and cell replicative capacity. The model is based on the relationship between cell mortality and metabolic rate, which is supported with data for different cell types from ectotherms and endotherms. These data indicate that much of the observed variation in cell lifespan and cell replicative capacity is explained by differences in cellular metabolic rate, and thus by the three primary factors that control metabolic rate: organism size, organism temperature and cell size. Individual cell lifespan increases as a power law with both body mass and cell mass, and decreases exponentially with increasing temperature. The replicative capacity of cells also increases with body mass, but is independent of temperature. These results provide a point of departure for future comparative studies of cell lifespan and replicative capacity in the laboratory and in the field. PMID- 22810429 TI - Individual contributions to territory defence in a cooperative breeder: weighing up the benefits and costs. AB - While investment in territory defence is expected to be influenced by its benefits, the additional role that costs may play is rarely considered. Here, we quantify both benefits and costs of repelling prospecting males in cooperative meerkats, and demonstrate that both are required to explain the substantial variation in individual contributions to the defence observed. Males benefit more from repelling prospectors than females, as males may lose dominance and be expelled during intrusions. Accordingly, males invest the most in repelling prospectors. We also show that males experience an associated cost in the form of reduced weight gain and, as such, heavier males contribute more to chasing prospectors. Finally, we show evidence of a cost not restricted to individuals engaged in chasing: both males and females reduce their contributions to feeding dependent pups when prospectors are present, resulting in a reduction in pup weight gain in this context. Males appear to adjust their contributions to chasing in light of this cost, chasing at lower rates when their group contains dependent young. Our findings support the view that investment in cooperative behaviours can be attributed to benefits and costs, and highlight the additional importance of considering trade-offs in investment between cooperative behaviours. PMID- 22810430 TI - Enzyme activity demonstrates multiple pathways of innate immunity in Indo-Pacific anthozoans. AB - Coral reefs are threatened by increasing levels of coral disease and the functional loss of obligate algal symbionts (bleaching). Levels of immunity relate directly to susceptibility to these threats; however, our understanding of fundamental aspects of coral immunology is lacking. We show that three melanin synthesis pathway components (mono-phenoloxidase, ortho-diphenoloxidase (tyrosinase-type pathway) and para-diphenoloxidase (laccase-type pathway)) are present in both their active (phenoloxidase, PO) and inactive (prophenoloxidase, PPO) forms across a diverse range of 22 species of healthy Indo-Pacific anthozoans. We also demonstrate transglutaminase activity of the coagulation cascade for, to our knowledge, the first time in a coral. Melanin-synthesis enzyme activities varied among taxa, although they were generally lowest in the coral family Acroporidae and highest in the Poritidae and Oculinidae. Inactive tyrosinase-type activity (PPO) and active laccase-type activity (PO) correlate with taxonomic patterns in disease resistance, whereas the converse pattern in activity levels correlates with bleaching resistance. Overall, we demonstrate the presence of several melanin-synthesis pathways in Indo-Pacific corals, co regulation among some pathway components, and highlight their potential roles in coral health. PMID- 22810431 TI - Flying in the rain: hovering performance of Anna's hummingbirds under varied precipitation. AB - Flight in rain represents a greater challenge for smaller animals because the relative effects of water loading and drop impact are greater at reduced scales given the increased ratios of surface area to mass. Nevertheless, it is well known that small volant taxa such as hummingbirds can continue foraging even in extreme precipitation. Here, we evaluated the effect of four rain intensities (i.e. zero, light, moderate and heavy) on the hovering performance of Anna's hummingbirds (Calypte anna) under laboratory conditions. Light-to-moderate rain had only a marginal effect on flight kinematics; wingbeat frequency of individuals in moderate rain was reduced by 7 per cent relative to control conditions. By contrast, birds hovering in heavy rain adopted more horizontal body and tail positions, and also increased wingbeat frequency substantially, while reducing stroke amplitude when compared with control conditions. The ratio between peak forces produced by single drops on a wing and on a solid surface suggests that feathers can absorb associated impact forces by up to approximately 50 per cent. Remarkably, hummingbirds hovered well even under heavy precipitation (i.e. 270 mm h(-1)) with no apparent loss of control, although mechanical power output assuming perfect and zero storage of elastic energy was estimated to be about 9 and 57 per cent higher, respectively, compared with normal hovering. PMID- 22810432 TI - Lethal effects of habitat degradation on fishes through changing competitive advantage. AB - Coral bleaching has caused catastrophic changes to coral reef ecosystems around the world with profound ecological, social and economic repercussions. While its occurrence is predicted to increase in the future, we have little understanding of mechanisms that underlie changes in the fish community associated with coral degradation. The present study uses a field-based experiment to examine how the intensity of interference competition between juveniles of two species of damselfish changes as healthy corals degrade through thermal bleaching. The mortality of a damselfish that is a live coral specialist (Pomacentrus moluccensis) increased on bleached and dead coral in the presence of the habitat generalist (Pomacentrus amboinensis). Increased mortality of the specialist was indirectly owing to enhanced aggression by the generalist forcing the specialist higher up and further away from shelter on bleached and dead coral. Evidence from this study stresses the importance of changing interspecific interactions to community dynamics as habitats change. PMID- 22810427 TI - Extraordinarily rapid life-history divergence between Cryptasterina sea star species. AB - Life history plays a critical role in governing microevolutionary processes such as gene flow and adaptation, as well as macroevolutionary processes such speciation. Here, we use multilocus phylogeographic analyses to examine a speciation event involving spectacular life-history differences between sister species of sea stars. Cryptasterina hystera has evolved a suite of derived life history traits (including internal self-fertilization and brood protection) that differ from its sister species Cryptasterina pentagona, a gonochoric broadcast spawner. We show that these species have only been reproductively isolated for approximately 6000 years (95% highest posterior density of 905-22 628), and that this life-history change may be responsible for dramatic genetic consequences, including low nucleotide diversity, zero heterozygosity and no gene flow. The rapid divergence of these species rules out some mechanisms of isolation such as adaptation to microhabitats in sympatry, or slow divergence by genetic drift during prolonged isolation. We hypothesize that the large phenotypic differences between species relative to the short divergence time suggests that the life history differences observed may be direct responses to disruptive selection between populations. We speculate that local environmental or demographic differences at the southern range margin are possible mechanisms of selection driving one of the fastest known marine speciation events. PMID- 22810433 TI - Parental antagonism and parent-offspring co-adaptation interact to shape family life. AB - The family is an arena for conflicts between offspring, mothers and fathers that need resolving to promote the evolution of parental care and the maintenance of family life. Co-adaptation is known to contribute to the resolution of parent offspring conflict over parental care by selecting for combinations of offspring demand and parental supply that match to maximize the fitness of family members. However, multiple paternity and differences in the level of care provided by mothers and fathers can generate antagonistic selection on offspring demand (mediated, for example, by genomic imprinting) and possibly hamper co-adaptation. While parent-offspring co-adaptation and parental antagonism are commonly considered two major processes in the evolution of family life, their co occurrence and the evolutionary consequences of their joint action are poorly understood. Here, we demonstrate the simultaneous and entangled effects of these two processes on outcomes of family interactions, using a series of breeding experiments in the European earwig, Forficula auricularia, an insect species with uniparental female care. As predicted from parental antagonism, we show that paternally inherited effects expressed in offspring influence both maternal care and maternal investment in future reproduction. However, and as expected from the entangled effects of parental antagonism and co-adaptation, these effects critically depended on postnatal interactions with caring females and maternally inherited effects expressed in offspring. Our results demonstrate that parent offspring co-adaptation and parental antagonism are entangled key drivers in the evolution of family life that cannot be fully understood in isolation. PMID- 22810435 TI - Acute myocardial infarction and cardiogenic shock: prognostic impact of cytokines: INF-gamma, TNF-alpha, MIP-1beta, G-CSF, and MCP-1beta. AB - BACKGROUND: The IABP SHOCK trial was designed as a morbidity-based randomized controlled trial to determine the effect of intraaortic balloon pulsation (IABP) in patients with infarct-related cardiogenic shock (CS). The primary endpoint was the change in the APACHE II score over a 4-day period. The prospective hypothesis was that adding IABP therapy to "standard care" would reduce CS-triggered multiorgan dysfunction syndrome (MODS). The primary endpoint showed no difference between conventionally managed cardiogenic shock patients and those with additional IABP support. In an inflammatory marker substudy, we analyzed the prognostic value of the cytokines interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1beta (MIP-1beta), granulocyte-colony stimulating factor (G-CSF), and monocyte chemoattractant protein-1beta (MCP-1beta). We also investigated the influence of IABP support, age, and gender on cytokine levels. DESIGN: The inflammatory marker substudy of the prospective, randomized, controlled, open label IABP SHOCK Trial (ClinicalTrials.gov ID NCT00469248). MATERIALS AND METHODS: A prospective, randomized, single-center study in a 12-bed intensive care unit at a university hospital was performed. A total of 40 consecutive patients were enrolled. The observational period was 96 h. RESULTS: The investigated cytokines showed a significant contribution in the prediction of mortality. Initial (on admission) and maximal cytokine levels during the observational period showed a similar predictive power. Patients with elevated levels of pro- and antiinflammatory cytokines had a higher risk of dying. The maximal level measured over the observation period in the hospital was also suited to identify the survivors. Close correlations between maximal cytokine levels resulted in the choice of only one independent marker (MIP-1beta) into the multivariate model (OR 1.024, 95% CI 1.005-1.043). Initial cytokine levels were also suitable to predict the survivors; the risk of death significantly increases with increasing IFN-gamma level (OR 1.119, 95% CI 1.005-1.246). Cytokine levels were not affected by the presence of IABP support. Age (< 75 or > 75 years) and gender did not have a clinically relevant effect on INF-gamma, TNF-alpha, MIP-1beta, G-CSF, and MCP-1 in CS patients. CONCLUSION: The inflammatory response in patients with myocardial infarction complicated by CS, as reflected by the inflammatory markers INF-gamma, TNF-alpha, MIP-1beta, G-CSF, and MCP-1beta, have been shown to be of prognostic value in estimating clinical outcome. PMID- 22810437 TI - Randomized trials in orthopaedic surgery: one step closer. PMID- 22810436 TI - Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies. AB - Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid beta load on positron emission tomography are associated with the Alzheimer's disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer's disease-related pathology such as hippocampal volume, brain amyloid-beta load on (11)C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer's Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent (11)C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical (11)C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive (11)C Pittsburgh compound B positron emission tomography scan declined and those who had a negative (11)C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer's disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment. PMID- 22810438 TI - Randomized trials in surgery: how far have we come? AB - Randomized controlled trials continue to be at the pinnacle of the evidence hierarchy. With this unique vantage point, they inform medical practice, clinical guidelines, health policy, and reimbursement. Prior to an emphasis on randomized controlled trials, traditional clinical research consisted primarily of uncontrolled case series and expert opinions. Randomized controlled trials are a true experiment in clinical practice and provide the most valid answers to clinical questions by reducing bias originating from patients, providers, and investigators. Riding on the coattails of other medical subspecialties, orthopaedic surgeons have recognized the importance of evidence-based medicine. From 1975 to 2005, the number of Level-I studies increased over fivefold and comprised >20% of studies published in The Journal of Bone and Joint Surgery (American Volume) (JBJS). With the emergence of comparative effectiveness research, the definition and methods of best evidence may continue to evolve. In conclusion, substantial improvements in both the quantity and the quality of randomized controlled trials in orthopaedic surgery have occurred, although unique considerations still limit their widespread use. PMID- 22810439 TI - Ethical issues in the design of randomized trials: to sham or not to sham. AB - The placebo effect is based on the expectations of the patient regarding the effectiveness of the treatment. The high levels of stress and rituals involved with surgery can lead to a strong placebo effect. However, the ethical principles of performing sham surgery to measure any placebo effect have been questioned, and sham-controlled surgical trials are rarely conducted. While there are a number of ethical principles that must be considered to justify the implementation of a sham-controlled surgical clinical trial, four areas deserve particular attention: equipoise, risk minimization, informed consent, and deception. Particularly in orthopaedics, where equipoise is common, sham controlled trials may be important to ensure that inferior or ineffective treatments do not become standard practice. PMID- 22810440 TI - Lessons learned from benchmark orthopaedic trials. AB - Benchmark trials in orthopaedics are designed to address a question of substantial interest to clinicians and patients. They are also designed to have prospective data collection, an adequate sample size, an appropriate duration of follow-up based on the injury or treatment under study, blinded adjudication of the outcome variables, appropriate statistical analyses, and widespread and effective dissemination of the information learned in the trial. There are multiple lessons to be gleaned from these trials: (1) Identifying an engaging and relevant clinical question will make it easier to identify centers that are willing to participate. (2) Individual site leadership, both of the overall project and at the individual site, is critical to the success of any trial. (3) Not every trial needs to have a randomized design; observational trials can provide data that will impact clinical care. (4) Patients should understand the long-term goals of the project when they are enrolled so that they have a sense of the importance of their role in the study. (5) Follow-up rates that are >90% are possible for orthopaedic trials, but effort and money are required to achieve this. (6) Patients who do not agree to be randomized should be enrolled as subjects in a parallel observational design if it is available. (7) Blinded adjudication of the outcome variables is recommended whenever feasible. (8) Partnership with the academic community is mandatory for the success of industry funded, phase-3 United States Food and Drug Administration trials. (9) Intention to-treat analysis and as-treated analysis should be reported. Benchmark orthopaedic trials can and will change clinical practice, but detailed planning must occur to ensure that the results are believable and relevant to the orthopaedic community. These trials are time-consuming and expensive, but with the use of careful initial planning and continued oversight during the trial, Level-I evidence will be obtained and will be useful in clinical care. PMID- 22810441 TI - Pilot randomized trials: is there a need? AB - A pilot randomized study is often essential to ensure the feasibility of conducting a large, randomized study. Pilot studies help to define the sample size, establish measurable outcomes, promote methodological rigor, establish the ability to recruit participants, assess the risk-benefit ratio of the treatments, and evaluate the economic viability of a definitive study. PMID- 22810442 TI - The tactics of large randomized trials. AB - Single-center studies and small randomized controlled trials often provide contradictory or inconclusive results. In contrast, large randomized controlled trials are designed to definitively answer a relevant and practice-changing research question. These studies rely on large sample sizes to gain adequate precision of the results and substantial funding to support the research infrastructure necessary to minimize bias. Tactics for successfully completing a large randomized controlled trial are outlined with examples from recent orthopaedic trials. PMID- 22810443 TI - Emerging designs in orthopaedics: expertise-based randomized controlled trials. AB - In this article, we discuss the limitations of conventional randomized controlled trials (RCTs) in the surgical field. Surgeons are often believers in certain surgical techniques and therefore can be reluctant to learn new interventions. In expertise-based trials, the patients are randomized to surgeons with expertise in the intervention under investigation. In conventional RCTs, patients are randomized to an intervention, and surgeons will perform this intervention regardless of whether this is the surgery they typically undertake. Conventional randomization may lead to surgery performed by a less experienced or less motivated surgeon, resulting in differential expertise bias. Expertise-based trials can overcome these limitations if potential pitfalls are taken into account. PMID- 22810444 TI - Adaptive Bayesian randomized trials: realizing their potential. AB - Bayesian adaptive designs offer the flexibility to adapt the conduct of a trial in response to accumulating evidence. This ability of the trial to adapt is especially appealing when studying an intervention that evolves rapidly. Examples of design adaptations include dropping arms from a study, sample size re estimation, or stopping a trial early. The choice of adaptive design must match the objectives of the trial, and this paper gives examples of designs suitable for exploratory trials, explanatory trials, and trials assessing cost effectiveness. PMID- 22810445 TI - Efficient designs: factorial randomized trials. AB - As an alternative to conducting multiple parallel group randomized controlled trials, the factorial design is an efficient means of evaluating multiple interventions. This review highlights when it is appropriate to conduct a factorial trial, considers the structure and nomenclature of factorial designs, and discusses various methodological considerations, including sample size calculation, the role of statistical interactions between different interventions, and statistical power. Several pertinent examples in orthopaedics and medicine are used to highlight the key concepts. PMID- 22810446 TI - The tactics of modern-day regulatory trials. AB - Fractures are an important public health problem affecting patients of all ages. Although most fractures heal quickly, some heal poorly and some do not heal at all. To achieve an optimal healing outcome, the standard of care for most fractures consists of reduction followed by immobilization, with a myriad of options regarding the approach to fracture-healing. Currently, biopharmaceutical companies are sponsoring research with regard to products that aim to enhance or accelerate fracture-healing; however, as there are no approved and marketed systemic therapies for fracture-healing, the development and commercialization process for such products will require close collaboration between industry, academia, and regulators to determine how to bring these products to market in the most efficient manner. The following manuscript provides a brief overview of the regulatory process in the United States for systemic therapies in fracture healing and discusses key issues that may arise in connection with the regulatory approval of these novel investigational treatments. PMID- 22810447 TI - Managing data in surgical trials: a guide to modern-day data management systems. AB - Data management is the strategy that is used for collecting, organizing, and managing data within an organization. Clinical data management plays a key part in the success of any clinical trial. The use of technology and computerized systems in the conduct of clinical trials has increased over the years and is now mainstream. The United States Food and Drug Administration has established requirements to ensure that electronic records and electronic signatures are trustworthy and reliable. Critical to the success of a data management protocol are the experienced members of the data management team. We review common aspects of data management and management systems. PMID- 22810448 TI - The darker side of randomized trials: recruitment challenges. AB - Randomized trials are thought to provide optimal evidence if carried out correctly. Their application to important questions is the best guide to clinical decision-making. However, these trials are expensive to complete and have a variety of challenges in design and application. This article will review some of the factors that affect our ability to recruit patients into randomized controlled trials for conditions that may be treated surgically by different methods or for conditions for which both nonsurgical and surgical treatments exist. PMID- 22810449 TI - The dangers of stopping a trial too early. AB - To ensure that participants in randomized controlled trials are protected from harm, interim analyses and review of results by an independent data monitoring committee have become standard practice. If an analysis of accumulating data partway through a trial reveals an unanticipated degree of benefit or toxicity, or differences in outcomes between the intervention and control groups are so unimpressive that any prospect of a positive result with the planned sample size is extremely unlikely, investigators may stop the trial earlier than originally scheduled. The practice of stopping randomized controlled trials early is, however, problematic, especially if the trial is stopped for apparent benefit. Concerns in trials stopped early for apparent benefit include appropriate interpretation of results and ethical problems concerning trial participants, clinicians, and society as a whole. In this article, we review the epidemiology of trials stopped early and illustrate some of the problems and controversies associated with stopping randomized controlled trials early for apparent benefit. Finally, we offer guidance for clinicians, those running clinical trials, and authors of systematic reviews. PMID- 22810450 TI - Subgroup analyses: when should we believe them? PMID- 22810451 TI - Use and interpretation of composite end points in orthopaedic trials. AB - Randomized controlled trials in orthopaedics are often underpowered to detect important differences in outcomes. Composite end points (CEPs) hold promise as a strategy to address this issue by combining multiple end points into one summary measure, thus increasing the observed event rate. The use of CEPs by trialists, however, can be problematic when they include components that vary greatly in importance to patients and when differences in apparent effect between components are large. We present an overview of CEPs with a focus on appropriate design and interpretation of results. PMID- 22810452 TI - Adjudicating outcomes: fundamentals. AB - The adjudication of outcomes has rarely been reported in the orthopaedic literature, although this process is commonly used and reported in clinical trials of other medical disciplines. Adjudication of outcomes provides more reliable and valid outcome assessment, especially when the outcome is subjective as in the case of fracture-healing. The successful implementation of adjudication in a clinical trial is an important and complex process. The process requires a substantial infrastructure of research personnel to oversee data collection at the clinical sites. The development of an adjudication charter specific to the study is a critical aspect of adjudication as it outlines the adjudication committee membership as well as their roles and responsibilities and defines the adjudication process and the decision rules. Web-based adjudication has facilitated the process as it allows rapid, efficient, and timely adjudication. This article provides an overview of the adjudication process, along with details on the common pearls and pitfalls associated with this method of outcomes assessment. PMID- 22810453 TI - Revisiting sample size: are big trials the answer? AB - The superiority of the evidence generated in randomized controlled trials over observational data is not only conditional to randomization. Randomized controlled trials require proper design and implementation to provide a reliable effect estimate. Adequate random sequence generation, allocation implementation, analyses based on the intention-to-treat principle, and sufficient power are crucial to the quality of a randomized controlled trial. Power, or the probability of the trial to detect a difference when a real difference between treatments exists, strongly depends on sample size. The quality of orthopaedic randomized controlled trials is frequently threatened by a limited sample size. This paper reviews basic concepts and pitfalls in sample-size estimation and focuses on the importance of large trials in the generation of valid evidence. PMID- 22810454 TI - On the prevention and analysis of missing data in randomized clinical trials: the state of the art. AB - We summarize and elaborate on the recently published National Research Council report entitled "The Prevention and Treatment of Missing Data in Clinical Trials." We tailor our discussion to orthopaedic trials. In particular, we discuss the intent-to-treat principle, review study design and prevention ideas to minimize missing data, and present state-of-the-art sensitivity analysis methods for analyzing and reporting the results of studies with missing data. PMID- 22810455 TI - The changing landscape of product development and randomized trials. AB - Controversy exists about whether or not similar standards apply to the clinical evaluation of orthopaedic implants and pharmaceuticals. The long-lasting dispute is likely to be abandoned shortly, given that certain regulatory bodies in Europe now mandate proof of effectiveness by randomized controlled trials (RCTs) prior to market approval of innovative devices. This is a timely signal--it will help to strengthen both the credibility of orthopaedic researchers among all health care disciplines and the role of manufacturers as creative minds and scientific partners. Yet, it must be accompanied by substantial changes in the current trial landscape. Given the level of perfection of available orthopaedic technology, superiority of a new product over an established standard will become a rare finding. Noninferiority or equivalence must be accepted as important trial results by investigators, sponsors, clinicians, and health authorities to enhance the spectrum of therapeutic options and help to individualize patient care. Specific problems are slow recruitment rates and long intervals from the protocol stage to publication of results. This may counteract the innovative potential of a novel product. Pragmatic trial designs, lean but complete documentation, limited but precise end points, the avoidance of competing trials, and the fostering of international collaboration are possible ways to streamline clinical trials of orthopaedic devices. Finally, RCTs should be conducted, conditional to the presumed level of innovation of a new implant, and supplemented by data from registries to fully determine the utility, value, and safety of the intervention. PMID- 22810456 TI - Global randomized trials: the promise of India and China. AB - Although modern clinical trials are traditionally conducted in Western countries, currently there is a shift to involve developing countries, particularly China and India. For these trials, the large population size of India and China means that substantial numbers of individuals affected by rare diseases may be found, increasing the likelihood of successfully completing enrollment in a clinical trial. Furthermore, the increasing involvement of Asian countries in global clinical trials is likely to lead to greater appreciation of the value of evidence-based treatment decisions in the region. These sites are more cost effective, although this advantage is being eroded over time. Asian participants in clinical trials are also typically more likely to complete study follow-up and procedures, and to adhere to their randomized treatment allocation than individuals from Western countries. Challenges include relevance of the proposed trial to the region, capacity limitations because of undeveloped training, and ensuring research implementation quality and different intellectual property practices. There are specific challenges to conducting clinical trials in India, such as the status of ethics committees, health insurance and coverage for participants, and variability in languages and record-keeping. Challenges in both countries are substantial but are able to be managed with appropriate planning. PMID- 22810457 TI - Orthopaedic trial networks. AB - Randomized controlled trials (RCTs) are considered the most robust design for evaluating health care interventions. However, it is difficult to acquire funding for RCTs, and they are complex to set up. Threats to their successful conduct and impact on clinical practice, particularly in surgical trials, include problems with recruitment, notably in terms of clinical equipoise and patient acceptability. Historically, RCTs are less common in surgical specialties, and their contribution to the orthopaedic literature remains small. Orthopaedic networks, such as orthopaedic associations, specialist societies, travel fellowships, and clinical research networks, provide an opportunity to meet the challenges of promoting RCTs in orthopaedic clinical practice. This can include identifying important research questions to help prioritize funding; educating and training surgeons in the design and practice of RCTs; helping to promote and coordinate RCTs; and disseminating the findings of RCTs. Orthopaedic trial networks should be encouraged to promote a research culture in which RCTs are feasible and to ensure that scarce resources utilized to support their funding are used most efficiently and to best effect. In particular, the use of networks is encouraged to support the conduct of RCTs in achieving patient recruitment, which is crucial in providing the evidence base to inform orthopaedic practice. Furthermore, to improve generalizability, acceptance of study findings and communication between orthopaedic surgeons, as well as international collaboration in trials, should be part of the strategy for the future. PMID- 22810458 TI - Overcoming the funding challenge: the cost of randomized controlled trials in the next decade. AB - Randomized controlled trials (RCTs) represent the gold standard of evidence-based medicine. However, over the last several decades, the cost associated with conducting RCTs has increased dramatically. Several factors contribute to higher costs associated with clinical trials. This paper describes important barriers to conducting surgical RCTs, identifies funding sources available to finance RCTs, and suggests strategies to maintain cost-efficient study practices as we move into the next decade. PMID- 22810459 TI - Participating in multicenter randomized controlled trials: what's the relative value? AB - The value of high-quality, large-scale, multicenter randomized controlled trials (RCTs) in orthopaedic surgery is becoming well recognized; however, the efforts of investigators participating in RCTs are often underappreciated in areas such as academic merit. Within this manuscript, we discuss how involvement in a large scale RCT can lead to benefits, such as improvements to clinical practice and decision-making as well as personal incentives. We also examined how investigators' contributions to large multicenter RCTs are perceived and recognized by academic promotion committees. We found that academic promotion committees undervalue contributions to multicenter RCTs as compared with participation in studies that offer lower levels of evidence. The culture of academic promotion needs to evolve to ensure that participation in large multicenter RCTs is appropriately valued by these committees. PMID- 22810460 TI - Observational studies in the era of randomized trials: finding the balance. AB - Randomized controlled trials (RCTs) constitute the gold standard for the generation of evidence-based medicine, but may not always be feasible. Furthermore, randomization alone does not guarantee the utility of the research, as evidenced by thousands of uninformative RCTs documented in the literature. Observational studies, including longitudinal, retrospective, and case-control designs, can contribute to the body of evidence in meaningful ways, provide useful information when an RCT is unethical or not feasible, generate hypotheses for RCTs, or provide preliminary work to better inform design of future RCTs. They can also be used to study rare outcomes, risk factors, and side effects, and to examine whether results from RCTs translate into effective treatment in routine practice. Use of modern statistical techniques, both in the study design and in the analysis stage, can improve the usefulness of the evidence obtained from observational studies. PMID- 22810461 TI - Early central airways lung cancer. AB - Early central airways lung cancer accounts for very small percentage of all lung cancers. Given this fact, it is much difficult to carry out a prospective randomized comparative clinical trial. Even retrospective studies can offer important information. Early central airways lung cancer is usually detected by sputum cytology. If sputum cytology shows atypical epithelial cells implying malignancy, the next thing we have to do is bronchoscopy. Both autofluorescence bronchoscopy and white light bronchoscopy were superior to white light bronchoscopy alone in detecting this type of lung cancer. Natural history of this cancer showed about the two-thirds of the patients die from original disease within 10 years. If the tumor length is 10 mm or less, photodynamic therapy is a first-line modality. After photodynamic therapy, a 5-year overall survival of about 80 % and a 10-year overall survival of 70 % can be expected. If a cancer does not meet the criteria for photodynamic therapy, surgical resection is recommended, and 5-year overall survival of about 80 % can be expected. Segmentectomy should be considered because of pulmonary function preservation if a tumor is located at segmental bronchi or beyond it. The frequency of multicentricity is high. Treatment strategy for subsequent primary lung cancer is an important key for the prognosis of patients with treated early central airways lung cancer. Surgical resection is still the most reliable treatment of subsequent primary lung cancer, except for in situ or microinvasive carcinoma located centrally, which could be cured by photodynamic therapy. PMID- 22810462 TI - Role of the surgeon in quality and safety in the operating room environment. AB - Medical errors in the OR can result in substantial morbidity, poor functional outcomes and mortality. They are associated with significant increases in direct and indirect healthcare costs. In addition, errors in the OR associated with harm often have a profound negative impact on the patient, their family, and the medical providers' psychological and social well being. The majority of medical errors are believed to be preventable. Rarely, an error is the result of an isolated single failure in the delivery of care. More commonly, multiple linked processes contribute to the error. Poorly designed systems of care delivery, poor information and knowledge transfer, ambiguous communication between providers and poor coordination of care are frequently identified as the underlying drivers of errors. Solving the problem is as complex as the causes. Raising awareness that an error is more than an individual's problem or behavior is the first step toward a solution. Thoughtful planning in developing systems of care delivery through optimizing and leveraging the knowledge of the team members that provide care is the single most important defense against medical errors. Surgeons play an important role in facilitating the development of and empowering the teams they work through their active participation and effective leadership within the operating room team. PMID- 22810463 TI - The polyphenol-rich extracts from black chokeberry and grape seeds impair changes in the platelet adhesion and aggregation induced by a model of hyperhomocysteinemia. AB - OBJECTIVE: The mechanism action of the polyphenol-rich extracts from berries of Aronia melanocarpa (black chokeberry) and from grape seeds in the defence against homocysteine (Hcy) and its derivatives action in blood platelets is still unknown. In this study, the influence of the aronia extract and grape seeds extract (GSE) on the platelet adhesion to collagen and fibrinogen and the platelet aggregation during a model of hyperhomocysteinemia was investigated. The aim of our study in vitro was also to investigate superoxide anion radicals (O2 *) production after incubation of platelets with Hcy, HTL and the aronia extract and GSE during a model of hyperhomocysteinemia (induced by reduced form of homocysteine at final dose of 100 MUM) and the most reactive form of Hcy--its cyclic thioester, homocysteine thiolactone (HTL, 1 MUM). Moreover, the additional aim of our study was also to establish and compare the influence of the aronia extract, GSE and resveratrol (3,4',5-trihydroxystilben), a phenolic compound, which has been supposed to be beneficial for the prevention of cardiovascular events, on selected steps of platelet activation. METHODS: The effects of tested extracts on adhesion of blood platelets to collagen and fibrinogen were determined according to Tuszynski and Murphy. The platelet aggregation was determined by turbidimetry method using a Chrono-log Lumi-aggregometer. RESULTS: We have observed that HTL, like its precursor-Hcy stimulated the generation of O2 * (measured by the superoxide dismutase-inhibitable reduction of cytochrome c) in platelets and caused an augmentation of the platelet adhesion and aggregation induced by the strong physiological agonist-thrombin. Our present results in vitro also demonstrated that the aronia extract and grape seeds extract reduced the toxicity action of Hcy and HTL on blood platelet adhesion to collagen and fibrinogen, the platelet aggregation and superoxide anion radicals production in platelets, suggesting its potential protective effects on hemostasis during hyperhomocysteinemia. CONCLUSION: In the comparative studies, the aronia extract was found to be more effective antiplatelet factors, than GSE or resveratrol during a model of hyperhomocysteinemia. It gives hopes for development of diet supplements, which may be important during hyperhomocysteinemia. PMID- 22810464 TI - The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease. AB - PURPOSE: To comprehensively review the data on the relationship between the consumption of dairy fat and high-fat dairy foods, obesity, and cardiometabolic disease. METHODS: We have conducted a systematic literature review of observational studies on the relationship between dairy fat and high-fat dairy foods, obesity, and cardiometabolic disease. We have integrated these findings with data from controlled studies showing effects of several minor dairy fatty acids on adiposity and cardiometabolic risk factors, and data on how bovine feeding practices influence the composition of dairy fat. RESULTS: In 11 of 16 studies, high-fat dairy intake was inversely associated with measures of adiposity. Studies examining the relationship between high-fat dairy consumption and metabolic health reported either an inverse or no association. Studies investigating the connection between high-fat dairy intake and diabetes or cardiovascular disease incidence were inconsistent. We discuss factors that may have contributed to the variability between studies, including differences in (1) the potential for residual confounding; (2) the types of high-fat dairy foods consumed; and (3) bovine feeding practices (pasture- vs. grain-based) known to influence the composition of dairy fat. CONCLUSIONS: The observational evidence does not support the hypothesis that dairy fat or high-fat dairy foods contribute to obesity or cardiometabolic risk, and suggests that high-fat dairy consumption within typical dietary patterns is inversely associated with obesity risk. Although not conclusive, these findings may provide a rationale for future research into the bioactive properties of dairy fat and the impact of bovine feeding practices on the health effects of dairy fat. PMID- 22810465 TI - Antioxidant and inflammatory response following high-fat meal consumption in overweight subjects. AB - PURPOSE: Postprandial metabolic stress as a consequence of ingestion of high energy meals is recognized as an important risk factor for cardiovascular disease. The objective of this study was to evaluate the inflammatory and antioxidant response of the body to the acute ingestion of a high-fat meal (HFM). METHODS: Fifteen healthy overweight subjects were recruited for the study. After HFM consumption, plasma glucose, insulin, uric acid (UA), triglycerides (TG), total cholesterol (TC), thiols (SH), inflammatory cytokines (IL-6 and TNF-alpha) and dietary antioxidants were measured at 0, 0, 5, 1, 2, 4, 6 and 8 h points from ingestion. RESULTS: The ingestion of HFM induced significant increases in both TG and TC, with peaks at 4 h (p < 0.001) and 8 h (p < 0.01), respectively. IL-6 and TNF-alpha significantly increased postprandially, reaching maximum concentrations 8 h after meal consumption (p < 0.001). Whereas plasma concentrations of vitamins and carotenoids were not changed by HFM, SH and UA increased, peaking 2-4 h postingestion (p < 0.001 and 0.01, respectively). Increments of SH and UA were positively correlated with AUC for TG (Pearson coefficient 0.888, p < 0.001 and 0.923, p < 0.001, respectively). CONCLUSIONS: Present results indicate that as a consequence of an excess of dietary fat, the body responds through an inflammatory reaction, which is accompanied by an increment of endogenous antioxidant defenses, mediated by UA and SH, but not by vitamins C and E and carotenoids. Although further studies are needed, results of the current investigation represent novel findings on endogenous strategies of redox defense from fat overloads. PMID- 22810466 TI - Scientific research and the case report. PMID- 22810467 TI - The uses of surgical history. PMID- 22810468 TI - Practice parameters for the management of colon cancer. PMID- 22810469 TI - Abdominoperineal excision: evolution of a centenary operation. AB - During the last century, great improvements have been made in rectal cancer management regarding preoperative staging, pathologic assessment, surgical technique, and multimodal therapies. Surgically, there was a move from a strategy characterized by simple perineal excision to complex procedures performed by means of a laparoscopic approach, and more recently with the aid of robotic systems. Perhaps the most important advance is that rectal cancer is no longer a fatal disease as it was at the beginning of the 20th century. This achievement is definitely due in part to Ernest Mile's contribution regarding lymphatic spread of tumor cells, which helped clarify the natural history of the disease and the proper treatment alternatives. He advocated a combined approach with the rationale to clear "the zone of upward spread." The aim of the present paper is to present a brief review concerning the evolution of rectal cancer surgery, focusing attention on Miles' abdominoperineal excision of the rectum (APR) and its controversies and refinements over time. Although APR has currently been restricted to a small proportion of patients with low rectal cancer, recent propositions to excise the rectum performing a wider perineal and a proper pelvic floor resection have renewed interest on this procedure, confirming that Ernest Miles' original ideas still influence rectal cancer management after more than 100 years. PMID- 22810470 TI - Short- and long-term outcome following laparoscopic versus open resection for carcinoma of the rectum in the multimodal setting. AB - BACKGROUND: Laparoscopic resection for rectal cancer has remained controversial because of the lack of level 1 evidence regarding oncologic safety and long-term survival. OBJECTIVES: The aim of this study was to assess the impact of laparoscopic versus open resection for rectal cancer on clinical and oncologic outcome in the multimodal setting. DESIGN: This is a review of prospectively gathered data from a single-institution rectal cancer database. SETTINGS: This study was conducted in the Central Hospital of Central Finland. PATIENTS: From January 1999 to December 2006, 191 selected patients were included. INTERVENTIONS: One hundred patients underwent laparoscopic resection, and 91 patients, also suitable for laparoscopic surgery, underwent open major rectal resection in the multimodal setting. MAIN OUTCOME MEASURES: The main measures of outcome were early recovery and short- and long-term morbidity; local recurrence and survival were secondary outcomes. LIMITATIONS: This is not a randomized study. RESULTS: The study groups were balanced for baseline characteristics. Conversion rate to open surgery was 22%. Laparoscopic surgery resulted in significantly less bleeding (175 mL vs 500 mL, p < 0.001), 1 day earlier recovery of normal diet (3 days vs 4 days, p = 0.001), and shorter postoperative hospital stay (7 days vs 9 days, p < 0.001). Postoperative 30-day mortality (1% vs 3%), morbidity (31% vs 43%), readmission (11% vs 15%), and reoperation (6% vs 9%) rates were similar in the 2 groups, but significantly fewer patients in the laparoscopic group had long-term complications (19% vs 36%, p = 0.033). The 5 year disease-free survival (78% vs 80%, p = 0.74) and local recurrence (5% vs 6%, p = 0.66) rates were similar in the laparoscopic and open group for those 175 patients treated for cure. CONCLUSION: Laparoscopic surgery resulted in faster postoperative recovery and fewer long-term complications than open surgery without apparently compromising the long-term oncologic outcome. Our results indicate that laparoscopic rectal resection is an acceptable alternative to open surgery in selected patients with rectal cancer. PMID- 22810471 TI - Strictureplasty in selected Crohn's disease patients results in acceptable long term outcome. AB - BACKGROUND: Strictureplasty is an alternative to resection in patients with Crohn's disease. OBJECTIVE: The objective of this study was to evaluate the long term results of patients who have undergone strictureplasty. DESIGN: This is a retrospective cohort study. SETTING: This study was conducted at a tertiary referral center, Mount Sinai Hospital, Toronto, Ontario, Canada. PATIENTS: All patients who had a strictureplasty of the small bowel between 1985 and 2010 were identified from a prospective database. MAIN OUTCOME MEASURES: The main outcomes were short-term complications, need for further surgery, and surgery-free survival. Multivariate analysis was performed to determine factors affecting the need for further surgery. Quality of life was measured by use of the short version of the Inflammatory Bowel Disease Questionnaire. RESULTS: Ninety-four patients (42 women; age at first strictureplasty, 33.4 +/- 9.7 years) underwent 119 operations (range per patient, 1-4). The number of strictureplasties was 278 (range, 1-11), including 9 in the duodenum and 269 in the jejunum-ileum. The most common type of procedure was the Heineke-Mickulicz (258, 92.8%). Median follow-up of the patients was 94 months (interquartile range, 27-165 months). The surgery free survival at 5 and 10 years was 70.7% (95% CI 59.8, 81.7) and 26.6% (95% CI 13.6, 39.6). In multivariate analysis, only age at the time of first strictureplasty was associated with the need for further surgery. Fifty-seven (64.8%) patients returned the questionnaire. The average score was 5.2 +/- 1.2 (range, 2.2-7.0) with no significant differences between patients with or without previous surgery (p = 0.22), with or without simultaneous resection (p = 0.71) or with or without further surgery (p = 0.11). LIMITATIONS: This study was limited by its sample size and retrospective design. CONCLUSIONS: Strictureplasty is a safe procedure with acceptable long-term outcomes. The risk of needing further surgery is high, which reflects the complexity of this disease. Younger age is associated with a higher risk of need for further surgery. However, most patients have a satisfactory quality of life. PMID- 22810472 TI - Effectiveness and safety of local adalimumab injection in patients with fistulizing perianal Crohn's disease: a pilot study. AB - BACKGROUND: Various blockers of tumor necrosis factor-alpha are available for treatment of Crohn's disease. Randomized controlled trials have demonstrated the effects of systemic therapy with adalimumab, a fully humanized monoclonal antibody against tumor necrosis factor-alpha. OBJECTIVE: The aim of this study was to investigate the effectiveness and safety of local injection of adalimumab along the fistula in the treatment of perianal Crohn's disease. DESIGN AND SETTING: This was a prospective, uncontrolled, open-label observational study performed at a university tertiary care center. PATIENTS: A total of 12 outpatients (9 women, 3 men) treated for fistulizing perianal Crohn's disease between 2009 and 2010 were enrolled. The mean age was 43.5 (range, 27-59) years. The fistula was classified as anovaginal in 3 patients, transsphincteric in 7 patients (low in 2, high in 5), and complex (multiple tracts) in 2 patients. Pikarsky's Perianal Crohn's Disease Activity Index was used to evaluate severity of the perianal disease. INTERVENTION: Adalimumab was injected locally along the fistula tract and around the internal orifice every 2 weeks. MAIN OUTCOME MEASURES: The primary end point of the study was the proportion of patients in whom complete or improved healing of fistulas was observed at follow-up, with improvement based on the number of daily changes of sanitary pads. RESULTS: The median number of injections per patient was 7 (range, 4-16). The mean length of follow-up was 17.5 (range, 5-30) months; 75% of patients (9 of 12) reached complete cessation of fistula drainage, and 3 patients (25%), all with transsphincteric fistula, showed improvement. Comparison of overall follow-up scores on the Perianal Crohn's Disease Activity Index with baseline showed significant improvement (p = 0.002). No adverse side effects were noted. LIMITATIONS: The study was limited by its small sample size and by the absence of a control group. CONCLUSIONS: This pilot study suggests that a high local concentration of adalimumab favors prompt and definitive healing of the fistulous tract in patients with perianal Crohn's disease. Future randomized trials with well-defined selection criteria are needed to determine the relative risks and benefits of available anti-TNF-alpha blockers (chimeric vs fully humanized) and the optimal mode of administration (systemic use vs local injection) in the treatment of fistulizing perianal Crohn's disease. PMID- 22810473 TI - Functional outcome of sacral nerve stimulation in patients with severe constipation. AB - BACKGROUND: Sacral nerve stimulation has been reported as an effective treatment for constipation. OBJECTIVE: This study aimed to evaluate the therapeutic efficacy of permanent sacral nerve stimulation on the treatment of idiopathic constipation resistant to medical and behavioral management over a median follow up period of 25.6 (range, 6-96) months. DESIGN: A retrospective review of a prospectively maintained institutional review board-approved database was performed. SETTING: The study was performed at 2 tertiary-care European institutions with expertise in sacral nerve stimulation. PATIENTS: Patients were considered eligible if they had had symptoms for at least 1 year and if conservative treatment had failed. INTERVENTION: Patients were tested by percutaneous nerve evaluation before the procedure. If this evaluation was successful, patients underwent sacral nerve therapy with an implanted device. MAIN OUTCOME MEASURE: Patients were evaluated by means of a bowel function diary and the Wexner constipation score. RESULTS: A total of 48 consecutive patients (39 females, median age 50.0 years (range, 17-79 years) entered the study. Twenty three patients were implanted with a permanent stimulator. On an intention-to treat basis, only 14 of 48 patients (29.2%) met the definition of a successful outcome at the latest follow-up period (median, 25.6 (range, 6-96) months). The mean Wexner score decreased from 20.2 (SD 3.6) at baseline to 5.8 (SD 4.1) at the latest follow-up examination (p < 0.001). However, 6 of 14 patients (42.8%) were still using laxatives and/or enemas at the last follow-up. LIMITATIONS: The study was limited by the pragmatic approach necessary to evaluate the results in routine clinical practice. CONCLUSIONS: This study shows that sacral nerve stimulation has limited efficacy on an intention-to-treat basis as a routinely recommended therapy for intractable idiopathic constipation. PMID- 22810474 TI - Clinical features and oncologic outcomes in patients with rectal cancer and ulcerative colitis: a single-institution experience. AB - BACKGROUND: Patients with chronic ulcerative colitis are at increased risk of developing colorectal cancer. Limited data exists in ulcerative colitis patients with rectal cancer regarding clinical and oncologic outcomes, and the ideal operative approach. OBJECTIVE: To describe our experience in the management of patients with rectal cancer in the setting of chronic ulcerative colitis and their outcomes. DESIGN: This study is a retrospective review of all patients with ulcerative colitis who underwent a colorectal operation between 1990 and 2009. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: Adult patients with rectal adenocarcinoma undergoing a colorectal operation for chronic ulcerative colitis were included in this study. Patients with colonic malignancy, indeterminate colitis, and Crohn's disease were excluded. MAIN OUTCOME MEASURES: Clinical features and long-term oncologic outcomes are described. RESULTS: Forty one patients were identified; their mean age was 53.9 years. Mean duration of ulcerative colitis was 22.5 years. Thirty-four patients (83%) were known to have cancer preoperatively; in 7 patients it was discovered on postoperative pathology. Eight of the tumors were in the proximal rectum, 19 in the mid rectum, and 13 in the distal rectum. The most common operation performed was total proctocolectomy with end ileostomy (n = 21), followed by IPAA. The majority of patients (n = 28, 68%) had stage I or II disease. Estimates of overall survival at 1 and 5 years were 83% and 62%, and, for disease-free survival, the estimates were 93% and 62%. Local and distant recurrence was seen in 5 and 9 patients. Eighty-nine percent of the observed recurrences were in patients with stage III and IV disease. Pouch failure occurred in 2 patients. LIMITATIONS: This retrospective study was possibly underpowered, given the small sample sizes. CONCLUSION: In our cohort, rectal cancer in the setting of chronic ulcerative colitis was rare, often presented at an early stage, and was not always diagnosed preoperatively. The presence of early-stage rectal cancer should not be considered a contraindication for IPAA. PMID- 22810475 TI - The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. AB - BACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome defined by >= 5 GI juvenile polyps or >= 1 juvenile polyps with a family history of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when >= 3 criteria including clinical manifestations or a family history, are present. A juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation. OBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our juvenile polyposis SMAD4 patients. DESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (>= 3 criteria diagnostic; 2 criteria suspect of). MAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients. RESULTS: Forty-one juvenile polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally. LIMITATIONS: There was a single, tertiary referral center. CONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in juvenile polyposis. Health care providers must be cognizant of the juvenile polyposis hereditary hemorrhagic telangiectasia overlap syndrome and the implications for management of these patients. PMID- 22810476 TI - Perianal versus endoanal application of glyceryl trinitrate 0.4% ointment in the treatment of chronic anal fissure: results of a randomized controlled trial. Is this the solution to the headaches? AB - BACKGROUND: Application of nitroglycerin (glyceryl trinitrate) ointment with perianal administration is a widely used treatment for chronic anal fissure. However, headache occurs after application in 20% to 70% patients and leads to withdrawal in 10% of patients. OBJECTIVE: The aim of the study was to investigate whether endoanal application of the ointment may lower the frequency of headaches without sacrificing effectiveness. compare the effects of perianal versus endoanal administration of nitroglycerin ointment on frequency of headache and rate of healing in the treatment of chronic anal fissure. DESIGN: This was a prospective randomized clinical trial (ClinicalTrial.gov, NCT01132391). SETTINGS AND PATIENTS: Study participants were consecutive patients with a diagnosis of chronic anal fissure treated at a university teaching hospital in Elche, Alicante, Spain. INTERVENTION: Patients were randomly assigned to receive perianal (n = 26) or endoanal (n = 26) administration of 0.4% nitroglycerin ointment (375 mg of ointment containing 1.5 mg of glyceryl trinitrate), applied every 12 hours over an 8-week period. MAIN OUTCOME MEASURES: The primary endpoint of the study was the number of patients with headache within 3 hours after application of the ointment, analyzed with the intention-to-treat principle. Intensity of headache pain was rated on a 10-point visual analog scale. Secondary endpoints included frequencies of fissure healing, anorectal pain, rectal bleeding, pruritus, and incontinence. RESULTS: Headaches were reported in 14 (54%) patients with perianal treatment and in 6 patients (23%) with anorectal treatment (p = 0.003). The median headache pain score was 6 (range, 0-10) in the perianal group and 4.5 (range, 0-10) in the endoanal group (p = 0.03). Disabling headaches led to crossover from perianal to endoanal treatment in 4 patients (15%), and from endoanal to perianal treatment in 1 patient (4%) (p = 0.004). Of the 4 patients who switched from perianal to endoanal treatment, 2 reported improvement in headaches and 2 stopped treatment. The patient who switched from endoanal to perianal treatment also showed no improvement and stopped treatment. The healing rate at 24-week follow-up was 62% (16 patients) with perianal treatment and 77% (20 patients) with endoanal treatment (p < 0.05). LIMITATIONS: Effects on sphincter pressure were not evaluated because manometric measurements were not available. CONCLUSIONS: Endoanal application significantly reduces the frequency of headaches due to treatment with 0.4% nitroglycerin ointment and results in a higher healing rate compared with perianal administration. However, roughly 1 in 4 patients still experiences headaches. Our data suggest that endoanal application may be a better option for treatment of anal fissure with nitroglycerin ointment. PMID- 22810477 TI - The incidence and survival rates of colorectal cancer in India remain low compared with rising rates in East Asia. AB - BACKGROUND: During the past 3 decades, the incidence of colorectal cancer was at a low level in urban and rural populations in India, in comparison with figures observed in developed countries of North America and Europe. OBJECTIVE: The aim of this study was to describe the time trends of incidence and mortality, and the survival rates of colorectal cancer, as well, in India. DESIGN: This is an ecological study. MAIN OUTCOME MEASURES: The primary outcome measured is the incidence data extracted from selected Indian cancer registries in the volumes on cancer incidence in 5 continents. RESULTS: Low and stable incidence and mortality rates from colon and rectum cancers were observed in India in both men and women. However, this low incidence rate was associated with a low 5-year relative survival rate. CONCLUSIONS: It is likely that the prevailing environmental factors and lifestyle, including a reduced consumption of sugars, calories and fat-rich food, an increased consumption of vegetables and fruits, and an adequate physical activity with avoidance of overweight and obesity, are responsible for the low risk of colorectal cancers. In contrast, the low survival, even for localized cases, suggests severe deficiencies in early diagnosis and effective treatment in India. A strategy to control the disease in India, based on improving awareness of the risk factors for colorectal cancer while keeping the traditional lifestyle, and on investments in early diagnosis and adequate treatment should be implemented. However, an organized, population-based screening of colorectal cancer may not prove cost-effective, given the low burden of colorectal cancer. PMID- 22810478 TI - Important points for protection of the autonomic nerves during total mesorectal excision. AB - BACKGROUND: One of the most important aspects for patients undergoing rectal cancer surgery is quality of life, which is closely related to postoperative sexual, urinary, and bowel functions. To preserve these functions, surgeons need to pay special attention to the fascial planes and autonomic nerve plexuses. OBJECTIVE: The aim of this study is to describe the locations of autonomic nerves in critical areas and to demonstrate the correct surgical planes for protecting these nerves during total mesorectal excision. DESIGN AND SETTINGS: Macroscopic and microscopic surgical dissections were performed in the anatomy laboratory. The dissections were recorded as video clips. METHODS: Dissections were performed in accordance with the total mesorectal excision technique down to the pelvic floor on 2 female and 7 male cadavers. Autonomic nerves and related fascias were shown. RESULTS: Autonomic nerves can be damaged during total mesorectal excision in 4 crucial areas: around the origin of the inferior mesenteric artery, in front of the promontory, the side walls of the pelvis, and the posterolateral corners of the prostate close to the anterior rectal wall. Fibers extending in front of the aorta and fibers coming from the sympathetic trunks combine to form the inferior mesenteric plexus around the origin of the inferior mesenteric artery. Most of the fibers that form the superior hypogastric plexus were fibers going downward from the inferior mesenteric plexus. The erigent nerves merge with the pelvic plexuses through the fascia of piriformis, which is part of the pelvic parietal fascia. LIMITATIONS: The number of cadavers should be increased, especially the number of female cadavers. CONCLUSIONS: The autonomic nerves must be protected during rectal cancer surgery to maintain the patient's quality of life. Therefore, knowledge of autonomic nerve positions and their relationship with surgical planes are very important for rectal surgeons. PMID- 22810479 TI - Is K-ras gene mutation a prognostic factor for colorectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: : The K-ras gene is one of the commonly mutated oncogenes associated with colorectal cancer. However, its prognostic significance for patients with colorectal cancer remains inconclusive. OBJECTIVE: : To derive a more precise estimation of the prognostic significance of K-ras gene mutations, a systematic review and meta-analysis were performed. DATA SOURCES: : We searched PubMed, Embase, and the Cochrane databases from January 1992 to November 2011. STUDY SELECTION: : The prognostic value of K-ras gene mutations was examined in patients with colorectal cancer who did not receive preoperative chemotherapy or radiation. MAIN OUTCOME MEASURES: : The effect of K-ras gene mutations on the overall survival was measured by the HR and 95% CIs. RESULTS: : The pooled HR for the association between K-ras gene mutations and overall survival in patients with colorectal cancer was 1.04 (95% CI: 0.99-1.10, p = 0.11). Subgroup analysis showed significant reductions in the overall survival associated with mutations at K-ras codon 12, the articles that reported HR directly, and the studies published before and after 2005, although publication bias was present. All the associations disappeared after adjustment with the trim-and-fill method. The pooled HR of 3 studies examining mutations at K-ras codon 13 was 1.47 (95% CI: 1.09-1.97, p = 0.02), and no publication bias was observed. No significant association was observed in different study regions. LIMITATIONS: : The heterogeneity in the study populations is a potential problem, the use of different staging systems or small groups of different stages may contribute to heterogeneity, and residual confounding may have influenced the results in those studies that did not completely adjust for other factors. CONCLUSIONS: : Overall K-ras gene mutations seem not to correlate with the prognosis of patients with colorectal cancer. The association remains to be confirmed with a more precise analysis of a large sample. PMID- 22810480 TI - Endoscopic submucosal dissection: a more effective treatment for rectal carcinoma? PMID- 22810485 TI - Continuous measurement of the cumulative amplitude and duration of hyperglycemia best predicts outcome after traumatic brain injury. AB - BACKGROUND: This study aimed to assess the accuracy and utility of high resolution continuous glucose recording in patients with traumatic brain injury (TBI) and to establish whether a relationship exists between the cumulative amplitude and duration of hyperglycemia and outcome after TBI. METHODS: Glucose data for 56 TBI patients were collected continuously at 5-min intervals. The degree and duration of hyperglycemia above treatment thresholds were calculated as "glucose times time dose" (GTD; mg/dL d) using continuous recordings (GTD) for early stage (first 3 days). Long-term neurological functional outcome was assessed using the extended Glasgow Outcome Scale (GOSE). Receiver operating characteristic (ROC) curves were constructed to determine the predictive values of GTD, percentage readings, mean, and range of glucose for in-hospital mortality and GOSE. RESULTS: All measurements of GTD were statistically significantly higher in the group that died. GTD of glucose >150 and glucose >180 had a high predictive power for in-hospital mortality (areas under the ROC curve [AUC] = 0.917; 95 % CI, 0.837-0.998 and 0.876; 95 % CI, 0.784-0.967, respectively) and demonstrated significantly higher predictive power for mortality when compared with %reading >150 and %reading >180, respectively (p < 0.05). GTD of glucose >150 also had a significantly higher predictive power for mortality than mean glucose and range of glucose. GTD of glucose >150 and glucose >180 also had a high-predictive power for poor outcome (areas under the ROC curve [AUC] = 0.913; 95 % CI, 0.843-0.983 and 0.858; 95 % CI, 0.760-0.956, respectively). CONCLUSIONS: Continuous collection of glucose recordings is more reliable and accurate than routine discontinuous recordings. Assessing both the duration and the amplitude of the episodes using continuous collection of glucose data helps in better predicting outcomes than the total duration of episodes. PMID- 22810486 TI - Neurocritical Care Research Networks--pediatric considerations. PMID- 22810487 TI - Nuclear medicine in NET. AB - Neuroendocrine tumors (NET) are, despite increasing incidence, still rare, usually slow growing neoplasms with resemblance to nerve cells and the endocrine capability of hormone production. In contrast to commonly used conventional imaging procedures, nuclear imaging is feasible to visualize the presence of molecular biomarkers, particularly the overexpression of somatostatin receptors (sstr) with high diagnostic accuracy which has led to the establishment of somatostatin receptor scintigraphy (SRS) as essential component and gold standard of functional imaging in the workup of NET. Another major feature is the selection of patients with inoperable or metastasized tumors showing sufficient uptake for peptide receptor radionuclide therapy (PRRT). While somatostatin receptor PET and PET/CT using Ga-68-labeled SSR analogs represents the consistent further development of SRS, FDG-PET can only be used in tumors with high proliferative activity but not on a routine basis for imaging of neuroendocrine tumors. (18)F-DOPA represents an alternative PET tracer worth mentioning currently under assessment for NET imaging. PMID- 22810488 TI - Changing iron content of the mouse brain during development. AB - Iron is crucial to many processes in the brain yet the percentages of the major iron-containing species contained therein, and how these percentages change during development, have not been reliably determined. To do this, C57BL/6 mice were enriched in (57)Fe and their brains were examined by Mossbauer, EPR, and electronic absorption spectroscopy; Fe concentrations were evaluated using ICP MS. Excluding the contribution of residual blood hemoglobin, the three major categories of brain Fe included ferritin (an iron storage protein), mitochondrial iron (consisting primarily of Fe/S clusters and hemes), and mononuclear nonheme high-spin (NHHS) Fe(II) and Fe(III) species. Brains from prenatal and one-week old mice were dominated by ferritin and were deficient in mitochondrial Fe. During the next few weeks of life, the brain grew and experienced a burst of mitochondriogenesis. Overall brain Fe concentration and the concentration of ferritin declined during this burst phase, suggesting that the rate of Fe incorporation was insufficient to accommodate these changes. The slow rate of Fe import and export to/from the brain, relative to other organs, was verified by an isotopic labeling study. Iron levels and ferritin stores replenished in young adult mice. NHHS Fe(II) species were observed in substantial levels in brains of several ages. A stable free-radical species that increased with age was observed by EPR spectroscopy. Brains from mice raised on an Fe-deficient diet showed depleted ferritin iron but normal mitochondrial iron levels. PMID- 22810490 TI - Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. AB - Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya((r))) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-alpha treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-alpha treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration. PMID- 22810491 TI - MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. AB - The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types. PMID- 22810494 TI - Comparison between innominate osteotomy and arthrodistraction as a primary treatment for Legg-Calve-Perthes disease: a prospective controlled trial. AB - PURPOSE: Legg-Calve-Perthes (LCP) disease is currently managed by mechanical containment of the femoral head in the hip socket. As evidence suggests that hip distraction may offer a new treatment strategy, we used arthrodistraction as a primary treatment for active forms of LCP disease and prospectively compared the results with the Salter innominate osteotomy. METHODS: A total of 54 children, six years or older of both genders with severe forms of LCP disease in the stages of necrosis or revascularisation, were enrolled. Patients were submitted to either Salter innominate osteotomy (n = 28) or hip arthrodistraction (n = 26). Final radiographs were used to evaluate the Mose index, Wiberg angle, extrusion index and the Stulberg et al. classification. RESULTS: There were no significant differences in gender, age, lateral pillar classification and average follow-up time between the two groups. The osteotomy group progressed without major complications, but children in the joint distraction group experienced episodes of pin tract pain and infection, leading to the early removal of the external device in one case. Two patients developed joint stiffness, treated by physiotherapy or manipulation, and one child developed subluxation of the femoral head. The average time in distraction was 4.44 months (2.53-7.23 months). In the final evaluation the osteotomy group showed better containment of the femoral head. The Mose index and the Stulberg et al. classification were statistically similar between the two groups. CONCLUSIONS: Despite similar final radiological results, arthrodistraction was associated with a higher morbidity. Consequently, we do not recommend hip distraction as a primary treatment for the early stages of LCP disease. PMID- 22810495 TI - Abstracts of the Winter Scientific Meeting of the Faculty of Public Health Medicine, Royal College of Physicians of Ireland. December 14, 2011. Dublin, Ireland. PMID- 22810497 TI - Ph2PI as a reduction/phosphination reagent: providing easy access to phosphine oxides. AB - The reaction of aldehydes with Ph(2)PI provides a facile way to the synthesis of pentavalent phosphine compounds with moderate to good yields. PMID- 22810499 TI - Genetic variants of EGFR (142285G>A) and ESR1 (2014G>A) gene polymorphisms and risk of breast cancer. AB - Breast cancer is one of the most common cancers in women worldwide. The estrogen receptor alpha (ESR1) and epidermal growth factor receptor (EGFR) have been known to play a vital role in development and progression of breast cancer. The aim of the present study was to determine the relationship, if any, between genetic polymorphism in (ESR1) 2014G>A (T594T) and (EGFR) 142285G>A (R521K) with risk of breast cancer and the prognosis in a heterogeneous North Indian population that is known for its diverse ethnicity. A case-control study in a total of 300 individuals comprising of 150 breast cancer patients and 150 normal controls was performed. PCR-RFLP was employed for genotyping. The G/A heterozygous genotype EGFR R521K, was slightly higher in cases (56.7 %) than in controls (48.3 %) (P = 0.20). The results indicated that EGFR polymorphism does not show any significant association with breast cancer in this population. On the other hand, the mutant A/A genotype ESR1 codon 594, showed a 6.4-folds risk for breast cancer and this association was highly significant (P = 0.00) as compared to wild GG genotype, the heterozygous G/A genotype also showed a significant association with disease (P = 0.00, OR = 2.03). In addition, the frequency of A allele was also higher in cases (36 %) than in controls (19 %) and a highly significant difference was observed with wild G allele (63.3 % in cases and 6.6 % in controls). This clearly indicates that there appears to be an influence of ESR1 codon 594 genotypes on genetic susceptibility to breast cancer. Further a significantly higher risk was observed in individuals who had diabetes {OR = 3.04 (1.68-5.50), P = 0.00} and females with ESR polymorphism in pre-menopause patients that had undergone menopause above the age of 50 years {OR = 3.58 (1.86-6.90), P < 0.05}. The different ethnic backgrounds and geographical locations have complimented the present genotypic analysis and have highlighted the influence of ethnicity, race and geographic location in genetic predisposition to breast cancer. PMID- 22810498 TI - Macroparasite infections of amphibians: what can they tell us? AB - Understanding linkages between environmental changes and disease emergence in human and wildlife populations represents one of the greatest challenges to ecologists and parasitologists. While there is considerable interest in drivers of amphibian microparasite infections and the resulting consequences, comparatively little research has addressed such questions for amphibian macroparasites. What work has been done in this area has largely focused on nematodes of the genus Rhabdias and on two genera of trematodes (Ribeiroia and Echinostoma). Here, we provide a synopsis of amphibian macroparasites, explore how macroparasites may affect amphibian hosts and populations, and evaluate the significance of these parasites in larger community and ecosystem contexts. In addition, we consider environmental influences on amphibian-macroparasite interactions by exploring contemporary ecological factors known or hypothesized to affect patterns of infection. While some macroparasites of amphibians have direct negative effects on individual hosts, no studies have explicitly examined whether such infections can affect amphibian populations. Moreover, due to their complex life cycles and varying degrees of host specificity, amphibian macroparasites have rich potential as bioindicators of environmental modifications, especially providing insights into changes in food webs. Because of their documented pathologies and value as bioindicators, we emphasize the need for broader investigation of this understudied group, noting that ecological drivers affecting these parasites may also influence disease patterns in other aquatic fauna. PMID- 22810500 TI - Pharmacological inhibition of GSK-3beta produces late phase of cardioprotection in hyperlipidemic rat: possible involvement of HSP 72. AB - The acute, as well as late, phase of cardioprotection induced by ischemic preconditioning is abolished in hyperlipidemic (HL) rat heart. The pharmacological inhibition of glycogen synthase kinase-3beta (GSK-3beta), has earlier been reported to restore this attenuated acute cardioprotective effect. However, it not known whether GSK-3beta inhibitors administered 24 h before the ischemic injury would restore the late cardioprotective in HL rat and, if yes, the role of heat shock protein 72 (HSP 72) in its modulation. Hyperlipidemia was produced in rat by feeding high-fat diet for 6 weeks. Isolated perfused rat heart was subjected to 30 min of ischemia followed by 120 min of reperfusion (I/R). Myocardial infarct size was estimated by triphenyltetrazolium chloride staining, while lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) levels were analyzed from coronary effluent. GSK-3beta inhibitors, SB 216763 (SB, 0.6 mg/kg, i.p.), and indirubin-3 monoxime (IND, 0.4 mg/kg, i.p.), administered 24 h before the isolation of heart, significantly decreased the I/R-induced myocardial infarct size and the release of LDH and CK-MB. The cardioprotective effect of GSK 3beta inhibitors was significantly attenuated by quercetin (4 mg/kg, i.p.), a HSP 72 inhibitor, administered 1 h before the administration of SB or IND. That the late phase of cardioprotection induced by pretreatment with GSK-3beta inhibitors is not attenuated/lost in HL rat heart is a new finding in our study. Our results indicate that HSP 72 acts on pathway of GSK-3beta and plays a significant role in cardioprotection. PMID- 22810501 TI - Implication of BBM lipid composition and fluidity in mitigated alkaline phosphatase activity in renal cell carcinoma. AB - Previous study has documented reduced alkaline phosphatase (ALP) activity in brush border membrane (BBM) isolated from renal cell carcinoma (RCC). Diminished activity of ALP is associated with alteration in both increased K(m) as well as decreased V(max) of enzyme suggests that there may be a change in the conformation of enzyme as well as decreased number of ALP active molecules. The present study was conducted to find out any role of BBM lipid composition and its fluidity in diminished activity of alkaline phosphatase in renal cell carcinoma. Total phospholipids and glycolipids were significantly augmented in BBM from RCC as compared to control. Fractional analysis of total phospholipids revealed significantly increased phosphatidylethanolamine. Decreased fractions of sphingomyelin and phosphatidylinositol were observed. Cholesterol-to-total phospholipid molar ratios in tumor BBM was a significantly lower in tumor BBM. A significant reduction in polarization and microviscosity was found in BBM from RCC. Therefore, we conclude that alteration in membrane lipid composition and fluidity may play a substantial role in reduced activity of ALP in RCC. PMID- 22810502 TI - Early involvement of spinal cord in diabetic peripheral neuropathy may influence patient outcome after neuraxial anesthesia. PMID- 22810504 TI - Dramatic change of water-cluster accessibility of highly pure double-walled carbon nanotubes with high temperature annealing. AB - Highly pure double-walled carbon nanotubes (DWCNTs) synthesized by a catalytic chemical vapour deposition method have a well-ordered bundle structure giving explicit diffraction peaks by synchrotron X-ray diffraction measurement. The changes of nanopore structural properties and water adsorptivity of DWCNTs with high-temperature heat treatment were investigated using molecular probe adsorption methods. It was founded that their nanoporosities and apparent hydrophilicities decreased with thermal annealing. However, a specific surface area of 275 m(2) g(-1) and the residual microporosity of more than 60% even after heat treatment at 2673 K suggest their unique applications. PMID- 22810503 TI - RadRAT: a radiation risk assessment tool for lifetime cancer risk projection. AB - Risk projection methods allow for timely assessment of the potential magnitude of radiation-related cancer risks following low-dose radiation exposures. The estimation of such risks directly through observational studies would generally require infeasibly large studies and long-term follow-up to achieve reasonable statistical power. We developed an online radiation risk assessment tool (RadRAT) which can be used to estimate the lifetime risk of radiation-related cancer with uncertainty intervals following a user-specified exposure history (https://irep.nci.nih.gov/radrat). The uncertainty intervals constitute a key component of the program because of the various assumptions that are involved in such calculations. The risk models used in RadRAT are broadly based on those developed by the BEIR VII committee for estimating lifetime risk following low dose radiation exposure of the US population for eleven site-specific cancers. We developed new risk models for seven additional cancer sites, oral, oesophagus, gallbladder, pancreas, rectum, kidney and brain/central nervous system (CNS) cancers, using data from Japanese atomic bomb survivors. The lifetime risk estimates are slightly higher for RadRAT than for BEIR VII across all exposure ages mostly because the weighting of the excess relative risk and excess absolute risk models was conducted on an arithmetic rather than a logarithmic scale. The calculator can be used to estimate lifetime cancer risk from both uniform and non uniform doses that are acute or chronic. It is most appropriate for low-LET radiation doses < 1 Gy, and for individuals with life-expectancy and cancer rates similar to the general population in the US. PMID- 22810505 TI - An Unusual Presentation of GIST. PMID- 22810506 TI - The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. PMID- 22810508 TI - Faculty. PMID- 22810507 TI - Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance. AB - Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in a large cohort of CK-AML with known TP53 status (TP53(altered), n=57; TP53(unaltered), n=31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and miR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53(unaltered) CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53(biallelic altered) CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53(biallelic altered) cell lines treated with 15-deoxy-Delta(12,14) prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in TP53(altered) CK-AML. PMID- 22810510 TI - Memory systems. AB - Converging evidence from patient and neuroimaging studies suggests that memory is a collection of abilities that use different neuroanatomic systems. Neurologic injury may impair one or more of these memory systems. Episodic memory allows us to mentally travel back in time and relive an episode of our life. Episodic memory depends on the hippocampus, other medial temporal lobe structures, the limbic system, and the frontal lobes, as well as several other brain regions. Semantic memory provides our general knowledge about the world and is unconnected to any specific episode of our life. Although semantic memory likely involves much of the neocortex, the inferolateral temporal lobes (particularly the left) are most important. Procedural memory enables us to learn cognitive and behavioral skills and algorithms that operate at an automatic, unconscious level. Damage to the basal ganglia, cerebellum, and supplementary motor area often impair procedural memory. PMID- 22810511 TI - Naming and language production. AB - Naming and sentence production are complex tasks, each requiring a number of cognitive processes and representations, which can be selectively impaired by focal brain damage, such as stroke, or by neurodegenerative disease. The types of errors made by the patient and the pattern of performance across tasks can provide clues regarding the location of the lesion and sometimes the most likely pathology. Understanding the nature of the deficit can help the physician provide guidance on how to facilitate communication. PMID- 22810512 TI - Comprehension. AB - Comprehension is the aspect of cognition in which information is retrieved and consciously integrated. It occurs between the input of perception and memory, and the output of language and executive functioning. This article focuses on disorders of comprehension of linguistic information and semantic knowledge. Comprehension of speech begins with the interpretation of acoustic-phonetic input as word forms. These concepts to which the word forms are semantically associated must then be retrieved, in parallel with interpretation of word order and grammatical marking, to achieve comprehension of discourse. Neural systems for semantic memory are closely related to those for lexical processing. Disorders of language comprehension and semantic knowledge for concrete entities give insight into the relationship of these processes to neural systems. PMID- 22810513 TI - Reading, writing, and their disorders. AB - Reading and writing are complex forms of communication. Disorders of these abilities reflect this complexity. Although distinct syndromes do exist, it is more common to see these disorders in the context of related dysfunction. For example, alexia and agraphia commonly occur together. Not only do they occur together, but frequently, although not exclusively, a patient with both has similar patterns of performance in each modality. Reading, the transformation of written symbols into spoken output, is intimately related to visual input and speech. Disorders of these abilities are commonly reflected in alexia. Writing, the transformation of oral input (writing to dictation) or conceptual thought into written symbols, is interconnected with speech and motor function. Again, disorders of these abilities are commonly reflected in agraphia. Understanding alexia and agraphia allows insight into multiple realms of left hemispheric dysfunction and provides significant clinical insight into patients with left hemispheric lesions. PMID- 22810514 TI - Social cognition. AB - Social cognitive neuroscience is a novel field of interdisciplinary research that examines socio-emotional cognition and behavior by emphasizing the neural substrates of these processes. Insights from this biological perspective have established that socio-emotional processing does not happen in a sequential order but in a recursive and interlinked fashion; that individual brain regions are not associated with one, but multiple, distinct social functions; and that brain regions are organized into dynamically interacting networks. These factors explain why it is difficult to pinpoint the neural substrates of particular social deficits in patients with brain diseases. With that said, there are specific brain regions that are highly specialized for the perception, regulation, and modulation of emotion and behavior. This article will review key aspects of social processing beginning with their underlying neural substrates, including (1) perception of social signals, (2) social and emotional evaluation, and (3) behavioral response generation and selection. Case studies will be used to illustrate the real-life social deficits resulting from distinct patterns of neuroanatomic damage, highlighting the brain regions most critical for adequate social behavior. Continuum Lifelong Learning Neurol 2010;16(4):69-85. PMID- 22810515 TI - Apraxia. AB - Humans need to perform skilled movements to successfully interact with their environment as well as take care of themselves and others. These important skilled purposeful actions are primarily performed by the forelimb, and the loss of these skills is called apraxia. This review describes the means of testing, the pathophysiology, and the clinical characteristics that define five different general forms of forelimb apraxia including: (1) ideational apraxia, an inability to correctly sequence a series of acts leading to a goal; (2) conceptual apraxia, a loss of mechanical tool knowledge; (3) ideomotor apraxia, a loss of the knowledge of how when making transitive and intransitive movements to correctly posture and move the forelimb in space; (4) dissociation apraxia, a modality specific deficit in eliciting learned skilled acts; and (5) limb-kinetic apraxia, a loss of hand-finger deftness. PMID- 22810516 TI - Disorders of visuospatial processing. AB - Disorders of visuospatial function are common but poorly understood. In this article we review the clinical symptoms, assessment, and processing impairments underlying a number of clinical disorders in which visuospatial processing is the primary manifestation. We start with a consideration of the neglect syndrome, a disorder in which subjects exhibit deficits in attending to or representing information from the contralesional side of space. We also discuss the syndrome of simultanagnosia, a disorder characterized by an inability to see more than one object at a time. Although often unrecognized, misreaching to visualized targets, or optic ataxia, is not uncommon; we review the manner in which this potentially disabling disorder can be identified. Finally, we review the disorders of visuospatial processing that are associated with degenerative diseases of the brain. These disorders may be the initial and, for a number of years, the only manifestation of Alzheimer disease and other disorders. PMID- 22810517 TI - Disorders of color and object recognition: syndromes of the ventral occipitotemporal pathway. AB - Although lesions of the striate cortex are associated with hemifield defects, lesions of the inferior and medial occipitotemporal cortex often are associated with disorders of more high-level and complex visual processing. These disorders of the ventral processing stream can be considered as impairing the perception of color and recognition of objects, in contrast to the problems with motion and spatial localization seen with lesions of the dorsal occipitoparietal stream. Dysfunction in the ventral stream leads to the prototypic syndromes of achromatopsia, general visual agnosia, prosopagnosia, alexia without agraphia, and some forms of topographagnosia. Most of these are not single entities but families of disorders in which dysfunction in different cognitive and perceptual processes can lead to the same symptom. Continuum Lifelong Learning Neurol 2010;16(4):111-127. PMID- 22810518 TI - Attentional and confusional States. AB - The term attention refers to the preferential allocation of cognitive and neural resources to events that have become behaviorally relevant. Attention is modulated by the bottom-up influence of the ascending reticular activating system and the top-down influence of association and limbic cortices. Focal lesions that interfere with the bottom-up or top-down regulation of attention, or multifocal partial lesions that interrupt multiple domain-specific processing pathways, can disrupt the attentional matrix and give rise to the acute confusional state syndrome. PMID- 22810520 TI - Patient management problem. PMID- 22810519 TI - Executive resources. AB - Executive resources allow for flexible, adaptive, goal-directed responses to environmental circumstances in essentially all facets of daily living. Executive function is composed of related, but separable, components. This article will highlight three essential aspects of executive function: (1) working memory, (2) planning and organizing, and (3) inhibitory control. Working memory is the system by which information is maintained in an active mental state so that it can be used for other purposes. Planning and organizing of behavior involves the way in which individuals optimize the execution of multistep tasks to achieve a goal. Inhibitory control allows an individual to inhibit inappropriate responses and to shift responses when necessary. These aspects of executive function appear to depend in part on large-scale neural networks that are centered in distinct areas of prefrontal cortex, working in concert with other brain regions, such as parietal cortex and the basal ganglia. Executive function is a fundamental aspect of human cognition that is compromised in patients with a wide range of medical conditions. PMID- 22810521 TI - Ethical perspectives in neurology: prescriptions to help healthy patients focus. PMID- 22810522 TI - Practice issues in neurology: optimizing cognitive function in the cognitively fragile patient. PMID- 22810523 TI - Coding table. PMID- 22810525 TI - Preferred responses. PMID- 22810524 TI - Multiple-choice questions. PMID- 22810527 TI - Editor'S letter. PMID- 22810528 TI - [Rethoracotomy in thoracic surgery]. AB - Technical progress of recent years allowed thoracic surgery to become a safer procedure. Experience of thoracic operations in our institution counts up to 14 962 cases (1963-2009 yy). Of them 223 (1.5%) patients had rethoracotomies on the reason of various operative complications. 112 patients had the intrapleural bleeding, 56 patients were reoperated on the reason of coagulated hemothorax, 57 patients demonstrated the bronchial stump insufficiency, and 11 were reoperated on other reasons. The frequency of rethoracotomy had decreased from 2.5 to 0.2%. The on-time rethoracotomy allows to save the patients' life and do not aggravate the overall result of the treatment. PMID- 22810529 TI - [The surgical treatment of thoracic tumors, invading the upper vena cava and the pulmonary trunk]. AB - The actual problems of technique and tactics by surgical treatment of thoracic tumors, invading the upper vena cava and the pulmonary trunk are highlighted in the article. The thorough analysis of clinical cases is adduced. PMID- 22810530 TI - [The videoendoscopic sanations of the abdominal cavity by the spread peritonitis]. AB - The treatment results of 109 patients with the disseminated septic peritonitis were analyzed. All patients were divided in two statistically similar groups. The first group of patients was treated using the standart approach (open surgery, eliminating the cause of peritonitis followed by further endoscopic planned sanations of the abdominal cavity). Difference of the treatment approach among the patients of the second group (n=41) was in using the pulsing stream of anticeptic for fibrine onlays elimination and the use of 200 ml of immobilized form of sodium hypochlorite gel for the final sanation. The treatment results among these patients were significantly better (the endotoxicosis parameters were 1.5 times lower and the recovery of motor intestinal function was 2 times faster). The morbidity level was 9% lower and the lethality level was 4% lower in comparison with patients of the 1st group. PMID- 22810531 TI - [The results of the practical use of the destructive peritonitis' standartized treatment]. AB - The results of inspection and treatment 117 patients with an acute destructive pancreatitis from 1998 to 2010 are presented. Distinguishing features of management approach of the patients, which was hospitalized in clinic from 2005 to 2010, were high frequency of octreotide use, de-escalated orientation of antibacterial therapy, without early laparotomy interventions and expansion of indications to program sanitation by development of widespread forms of infected pancreatic necrosis. Achievements of intensive therapy of last years and change of surgical tactics have allowed to reduce postoperative mortality by sterile necrosis from 21.1 to 11.8%, to reduce frequency of infected pancreatic necrosis from 68.3 to 40.4%. Development of the infected pancreatic necrosis accompanied by statistically significant growth of frequency of local purulent complications and the tendency to increase--extended. PMID- 22810532 TI - [The immune reactions by the esophagus injuries, complicated by mediastinitis]. AB - The comparative analysis of 56 immunograms of patients with mediastinitis, caused by the esophagus trauma is represented. The mean values of 9 immunologic parameteres (the so called "norm of the pathology") were set for patients with noncomplicated mediastinitis. A novel method of the immune status evaluation for the patients with the acute surgical conditions and SIRS has been suggested. If early applied, the method allows substantive immunotherapy for such patients. PMID- 22810533 TI - [The treatment of pulmonary bleedings and its' complicsations by the blunt thoracic trauma]. AB - The experience of treatment of 224 patients with pulmonary bleeding after the blunt thoracic trauma were analyzed. All patients were diagnosed with lung contusion, of them 134 had traumatic cavities (hematomas) in the lung. The complete regression of contusion foci was observed within 13.7+/-4.2 days, whereas only 65.4% of patients demonstrated the regression of lung hematomas after 3 months of follow-up. 5.36% of pulmonary bleeding required the urgent thoracotomy on the reason of the continuous bleeding. The thorough analysis of etiology of posttraumatic infectious pulmonary complications after the blunt thoracic trauma is submitted. The drainage of septic foci allowed the fast recovery of the majority of patients. 7,4% of lung abscesses and pleural empyem required thoracotomy. PMID- 22810534 TI - [The use of thrombocytic growth factors and collagen-containing substances in treatment of the chronic wounds of various etiology]. AB - The technical aspects of wound biocoverage production from the platelets' enriched plasma is represented. The substance shows high regenerative potential by causing the activation of thrombocytic growth factors. The authors' experience of the treatment of 38 patients with chronic trophic ulcers of various etiology is analyzed. PMID- 22810535 TI - [The experience of 500 vascular reconstructions of the aorticfemoral segment using a miniaccess]. AB - The immediate and long-term results of 500 reconstructive operations on the aorticfemoral segment using a miniaccess were analyzed. 443 patients suffered from the obliterative atherosclerosis and 57 were operated on the infrarenal aortic aneurism. The size of the surgical access was 5-12 sm (418 through laparotomy, 82 through the retroperitoneal access). The access enlargement was necessary in 5.0% of cases. The mean time of the operation was 166.6+/-7.8 min (90-255 min). Time of the aortic clamping was 26.2+/-1.5 min by the aortic by pass and 32.3+/-4.5 min by the aortic resection. The postoperative leathality rate was 1.6%, the morbidity rate was 20.0% (local vascular complications 7.2%; local non-vascular complications 7.2%, systemic complication 7.6%). 5-year by pass patency was 91.9+/-2.8%, the limb was preserved in 93.6+/-2.4%. PMID- 22810536 TI - [The minimally invasive surgical access to the thyroid and parathyroid glands through the oral cavitiy]. AB - The use of minimally invasive surgical access and technologies allows the substantial improvement in rates of the postoperative rehabilitation, shorten the hospital stay and improve the cosmtic result of the operation. The thorough topographic description of the transoral access to the thyroid and parathyroid glands is highlighted in the article. The construction of the original wound expander is depicted. The operative technique of the hemythyroidectomy is expamled. PMID- 22810537 TI - [The immediate and long results of treatment of posttraumatic fistulas of the rectum with application of modern laser technologies]. AB - The immediate and long-term results of the posttraumatic rectal fistulae treatment in 134 patients were analyzed. The differentiated choice of surgical tactics, the use of modern laser methods and the original complex of diagnostic and treatment measures allowed to decrease the frequency of such posttraumatic complications from 19.0 to 7.9%. Good medical and social adaptadion and rehabilitation rates were achieved in 98.5% of patients. PMID- 22810538 TI - [The role of computed tomography in benign tumors and tumor-like lesions of the bones]. AB - The results of these studies coincided with domestic and foreign literature. X ray, CT and MRI findings were compared with postoperative assessment histological data. Usefulness of x-ray, CT and MRI studies amounted to respectively 57,1+/ 6,5%, 85,0+/-3,7% and 75,1+/-5,1%. This, in turn, shows the great role of CT in diagnosis of benign bone tumours and tumour-like formations. PMID- 22810539 TI - [The pentaglobin transfusion for the early postpneumonectomy complications' prophylaxis in patients with polyresistant lung tuberculosis]. PMID- 22810540 TI - [Vacuum-therapy in pediatrics]. PMID- 22810541 TI - [The immune activity of cytoflavine in the treatment of the diffuse septic peritonitis]. AB - Influence of citoflavin on dynamics of functional condition of mitogen-induced immunocompetent blood cells at patients with widespread purulent peritonitis is studied. It is established that investigated immunocompetent cells have regulating effect on migration of neutrophil leukocytes at widespread purulent peritonitis during all postoperative period. PHA-activated mononuclear cells don't cause inhibition of migration of neutrophil granulocytes, observed in norm. At the same time the LPS-activated monocytes lead to migration strengthening of neutrophil granulocytes, in comparison with the data received in norm. Usage of citoflavin at patients with widespread purulent peritonitis renders corrective action on immunocompetent cells, changing their properties of regulation of migratory activity of neutrophil granulocytes. It is revealed that such action of citoflavin is connected with function restoration of mononuclear cells to inhibit migration of neutrophil leukocytes and with restoration of stimulation of migration of neutrophil leukocytes under the influence of the LPS-activated monocytes to the values received in norm. The revealed effects at use of citoflavin are most expressed by the 5th day of the postoperative period. PMID- 22810542 TI - [The treatment of the sponateneous biloma and choledocholithiasis after the liver resection on the reason of the giant hemangioma]. AB - Patient with giant rapidly growing liver hemangioma who carried out right hemihepatectomy is reported. The feature if this case is choledocholithiasis after liver resection followed by its rare complication (spontaneous biloma) in 6 years after surgery. Minimally invasive procedures (percutaneous drainage, endoscopic papillotomy and stenting) eliminated each of bile collection and cause of biliary obstruction without surgical intervention. PMID- 22810543 TI - [The intravenous leiomyomatosis]. PMID- 22810545 TI - [Extended donor criteria defined by the German Medical Association : study on their usefulness as prognostic model for early outcome after liver transplantation]. AB - INTRODUCTION: Expansion of the donor pool by the use of grafts with extended donor criteria reduces waiting list mortality with an increased risk for graft and patient survival after liver transplantation. The ability of the number of fulfilled extended donor criteria as currently defined by the German Medical Association (BAK-Score) to predict early outcome is unclear. PATIENTS: A total of 291 consecutive adult liver transplantations (01.01.2007-31.12.2010) in 257 adult recipients were analyzed. METHODS: Primary study endpoints were 30 day mortality, 3 month mortality, 3 month patient and graft survival and the necessity of acute retransplantation within 30 days. For primary study endpoints a ROC curve analysis was performed to calculate sensitivity, specificity and overall model correctness of the BAK score as a predictive model. Further methods included Kaplan-Meier estimates, log-rank tests, Cox regression analysis, logistic regression analysis and chi(2)-tests. RESULTS: The number of extended donor criteria fulfilled had no statistically significant influence on the primary study endpoints (p > 0.05) or on patient survival (p > 0.05). ROC curve analysis revealed areas under the curve <= 0.561 for the prediction of primary study endpoints (overall model correctness < 58%, sensitivity < 52%). CONCLUSIONS: The number of fulfilled extended donor criteria as currently defined by the German Medical Association is unable to predict early outcome after liver transplantation. PMID- 22810546 TI - The two-incision, minimally invasive approach in the treatment of acetabular fractures. AB - OBJECTIVES: To present a novel two-incision minimally invasive (TIMI) method for the treatment of anterior acetabular fractures. DESIGN: Prospective consecutive case series. SETTING: Level I University Trauma Centre. PATIENTS: Twenty-six patients (mean age, 67 +/- 19 years). INTERVENTION: The first TIMI-incision is performed by a pararectal approach at the level of the proximal third of the arcuate line of the ilium. After transection of the abdominal wall, the iliac vessels are mobilized medially and the neuromuscular bundle laterally. The second approach lies above the medial pubic bone. The soft tissue is held using a retraction system. After fracture reduction and fixation by isolated screws, a conventional reconstruction plate is inserted for fracture neutralization. MAIN OUTCOME MEASUREMENTS: Perioperative course, postoperative radiological evaluation, functional outcome Harris hip score, and quality of life (EQ 5D). RESULTS: Mean operative time was 109 +/- 30 mins. All incisions healed primarily. Postoperative radiological exam revealed an anatomic reduction in 20 fractures and a satisfactory reduction in 6. There were no local soft-tissue complications, and no revisions were needed. Follow-up examinations were performed after a minimum of 12 months in 19 patients (73%). The Harris hip score was 86,6 +/- 8. Quality of life was comparable to persons in the same age group. CONCLUSION: The TIMI approach represents a viable alternative to the ilioinguinal approach. Despite the limited incisions, a comparable quality of fracture reduction is achieved. The authors believe this technique would be most useful in those patients with a higher risk for postoperative soft-tissue complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810547 TI - Treatment of protrusio fractures of the acetabulum in patients 70 years and older. AB - OBJECTIVE: To present clinical, radiographic, and functional outcomes in patients 70 years and older with a protrusio-type acetabulum fracture. DESIGN: Retrospective case series. SETTING: Two level 1 trauma centers. PATIENTS: Between November 2000 and December 2009, 39 consecutive patients older than 70 years with protrusio acetabulum fractures were enrolled. INTERVENTION: Open reduction internal fixation using a combination of pelvic brim and infrapectineal plates. MAIN OUTCOME MEASUREMENTS: Clinical, radiographic, and functional outcomes as assessed with the modified Merle d'Aubigne score. RESULTS: Twelve patients were lost to follow-up (<12 months), and one patient was excluded from analysis because he was treated with a percutaneous technique. The remaining 26 (67%) had a mean follow-up of 34 months (12-127 months). At the final follow-up, radiographic grades were excellent in 15, good in 3, poor in 3, and 5 patients had a total hip arthroplasty (19%) at an average of 18 months after the index procedure .The average modified Merle d'Aubigne score was 16 (9-18); categorized as excellent in 10, very good in 4, good in 7, fair in 2, and poor in 3. CONCLUSION: In the senior patient with a protrusio acetabulum fracture, a treatment strategy that optimizes preoperative conditions, minimizes operative time and blood loss, achieves a stable concentric hip joint, and encourages immediate postoperative ambulation can result in reasonable clinical, radiographic, and functional outcomes with acceptable morbidity. This appears to remain true even in the face of a less than anatomic reduction. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810548 TI - Does application position of the T-POD affect stability of pelvic fractures? AB - OBJECTIVE: Most trauma centers place pelvic binders on unstable pelvic fractures for acute management and control of hemorrhage. It has been proposed that the binders be placed at the level of the greater trochanters of the femur. Our hypothesis was that application of the T-POD at this site would provide better immobilization of an unstable pelvic injury than a more cephalad location. METHODS: Unstable pelvic injuries (OTA type 61-C1) were surgically created in 9 fresh whole human cadavers. Electromagnetic sensors were affixed to the intact and injured sides of the pelvis. A Fastrak, three-dimensional electromagnetic motion analysis device was used to determine the angular motion occurring at the fractured sites. Maximum displacements for sagittal, coronal, and axial rotation were recorded during application of the binder, while performing bed transfers, while logrolling, and elevating the head of the bed. The T-POD device was placed either over the greater trochanters or at the level of the anterior superior iliac spine as per manufacturer's recommendations. RESULTS: There were no significant differences in the amount of motion produced during application of the T-POD at either location. There was less motion observed in all planes of motion during all maneuvers when the T-POD was placed at the level of the greater trochanters versus anterior superior iliac spine. During bed transfers, this was statistically significant in all planes. This was statistically significant while logrolling in the axial plane and the coronal plane during head of bed elevation. CONCLUSIONS: We advocate the placement of pelvic binder devices at the level of the greater trochanters for improved control of the fracture in an unstable pelvic injury. This may result in improved control of hemorrhage, better access to the abdomen, and greater patient comfort. PMID- 22810549 TI - Quality of life after osteosynthesis of fractures of the proximal humerus. AB - OBJECTIVE: Most clinical evaluations after fracture treatment focus on pure functional and radiological outcome. However, this may not appreciate the impact on quality of life (QoL). The aim of this study was to assess QoL and its improvement during the first year of postoperative recovery after fracture treatment. DESIGN: Prospective single-centre observational study. SETTING: Trauma unit. City hospital. PATIENTS: From March 2003 to June 2008 inclusion of 269 consecutive patients (72 years, 77% female) was possible. All were treated by open reduction and internal fixation (ORIF) with PHILOS because of isolated traumatic fractures of the proximal humerus. INTERVENTION: Clinical follow-up examinations were performed at 6 weeks and 3, 6, and 12 months, postoperatively. MAIN OUTCOME MEASUREMENTS: Constant-Murley score (CMS) and the QoL (SF-36 questionnaire) were used to assess outcome. All results were stratified according to length of follow-up, age, and fracture type. RESULTS: CMS and SF-36, including the corresponding subgroups Physical Component Summary and Mental Component Summary, demonstrated continuing improvement during the period of observation. US norm values for the SF-36 were achieved after 6 months. However, speed of progress varied greatly between the scores and age groups. The fracture type significantly impacted CMS. Increasing age and complexity of fracture influenced the results negatively and cumulatively. CONCLUSION: This study highlights and defines subjective improvements and changes of QoL up to 1 year after ORIF of these fractures. Increasing age and a more complex fracture type is correlated with a deceleration of functional improvement. The CMS shows a definite positive correlation with the unassisted self-evaluation of SF-36, but exchangeability could not be demonstrated. PMID- 22810550 TI - Anteroinferior 2.7-mm versus 3.5-mm plating for AO/OTA type B clavicle fractures: a comparative cohort clinical outcomes study. AB - OBJECTIVES: To compare the Disability of the Arm, Shoulder, and Hand (DASH) and Constant scores, time to union, rate of union, patient cosmetic satisfaction rate, and the need for secondary procedures between 2.7- and 3.5-mm anteroinferior plating for Arbeitsgemeinschaft fur Osteosynthesefragen (AO)/Orthopaedic Trauma Association (OTA) type B clavicle fractures. DESIGN: Retrospective, comparative cohort clinical outcomes study. SETTING: Level I university trauma center. PATIENTS/PARTICIPATION: Thirty-seven patients with an AO/OTA type B clavicle fracture who underwent open reduction internal fixation with either a 2.7- or 3.5-mm reconstruction plate placed in the anterior-inferior position. The main outcome comparisons included DASH score, Constant score, time to union, rate of union, rate of hardware failure, cosmetic satisfaction, and secondary procedure. MAIN OUTCOME MEASUREMENT: DASH score, constant score, time to union, rate of union, cosmetic satisfaction, secondary procedure. RESULTS: At 1-year follow-up, analysis yielded no significant differences in DASH scores (P = 0.26) and Constant Shoulder scores (P = 0.79) between the 2 cohorts. There were no statistically significant differences in the time to union (P = 0.86) and the rate of union (P = 0.49). Although the 2.7-mm cohort had a lower reoperation rate, it was not statistically significant (P = 0.11). However, the 2.7-mm cohort did demonstrate a significantly higher rate of cosmetically acceptable reconstruction (P = 0.003). CONCLUSIONS: Compared with 3.5-mm anterior-inferior plating, 2.7-mm anteroinferior plating for AO/OTA type B clavicle fractures leads to significantly higher rates of cosmetic acceptability while reducing the need for a secondary procedure and achieving excellent clinical outcomes as measured by the DASH and Constant scores. There were no differences between the 2.7 and 3.5 cohorts in time to union or in union rate. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22810551 TI - Management of first-time dislocations of the shoulder in patients older than 40 years: the prevalence of iatrogenic fracture. AB - OBJECTIVE: To evaluate the prevalence of iatrogenic humeral neck fracture after attempted closed reduction in patients older than 40 years who present with a first-time anterior dislocation. DESIGN: Retrospective cohort study, evidence based medicine level IV. PATIENTS: Ninety-two patients older than 40 years (mean 66.6 years of age) with a first-time anterior dislocation of the shoulder. INTERVENTION: Closed reductions by the emergency medicine physicians under conscious sedation, in the emergency department. MAIN OUTCOME MEASUREMENTS: Prevalence of iatrogenic fracture on postreduction radiographs. RESULTS: Nineteen (20.7%) patients were diagnosed with a concomitant greater tuberosity fracture on initial radiograph. In the postreduction radiographs, 5 patients (5.4%) were identified with a postreduction humeral neck fracture, and all of them had a greater tuberosity fracture on initial radiographs. A highly significant association (P < 0.0001) was observed between the finding of a greater tuberosity fracture on the initial radiographs and the occurrence of iatrogenic humeral neck fracture after close reduction. DISCUSSION: Previous case reports have described an iatrogenic humeral neck fracture with reduction attempt of shoulder dislocation. In our retrospective study, 21% of the cohort of patients older than 40 years had a concomitant greater tuberosity fracture; 26% of them had an iatrogenic humeral neck fracture after reduction attempt under sedation in the emergency room. These patients ended up with poor outcome. CONCLUSIONS: Patients older than 40 years, presenting with a first-time anterior shoulder dislocation with an associated fracture of the greater tuberosity have a significant rate of iatrogenic humeral neck fracture during closed reduction under sedation. PMID- 22810552 TI - Management of unstable ankle lateral malleolar fractures: what is the safest approach. PMID- 22810553 TI - Functional outcomes in elderly patients with acetabular fractures treated with minimally invasive reduction and percutaneous fixation. PMID- 22810554 TI - The reliability of measurement of tissue pressure in compartment syndrome. PMID- 22810555 TI - Biometric study of eyelid shape and dimensions of different races with references to beauty. AB - BACKGROUND: There are few studies that evaluate the differences in the perception of beauty and attractiveness of different races or ethnicities. The purpose of this study was to determine whether there are any actual differences in the configuration of beautiful eyes among different races. METHODS: Using seven composite faces of different races or ethnicities, photogrammetric measurements were performed to determine the relative differences in the average and attractive configuration of the eyes. Fourteen distance measurements and five angular measurements were performed for analyzing the morphological differences in the configuration of attractive and average faces. RESULTS: The results of our study found that attractive Korean faces have relatively wide-set eyes and that the medial and lateral eye fissure height is greater than that in average Korean faces. Attractive Korean faces have larger but not ptotic eyes than those in average Korean faces and they have a narrow double fold line; however, attractive Asian faces have a slightly higher double fold line. Attractive Korean or Asian faces do not have an epicanthus and there is a lot of exposure of white in the medial and lateral area of the eyes. Attractive Caucasian and African faces have an acute or keen shape to the eyes like the jaguar's eye. Attractive Asian faces have a less steep slant of the palpebral fissure compared to that of the average Asian face, but attractive Caucasian and African faces have a steeper palpebral slant than that of average Caucasian and African faces. Attractive Caucasian and African faces have a relatively narrower palpebral fissure height and width than average Caucasian and African faces. Regardless of race, attractive faces have wide-set eyes and a lower brow position than average faces. CONCLUSIONS: "Beautiful eyes" can be defined as youthful, brilliant, vivid, and attractive. We found that there are some common and some different characteristics in the configuration of beautiful eyes according to racial background. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. PMID- 22810556 TI - Inferior pole length and long-term aesthetic outcome after superior and inferior pedicled reduction mammaplasty. AB - BACKGROUND: Long-term aesthetic results after reduction mammaplasty remain an important issue for evaluating the success of different techniques. Superior pedicled techniques are reported to maintain a better breast projection with less bottoming-out of the inferior mammary pole than inferior pedicled techniques. METHODS: The outcomes of 18 patients who had undergone the superior pedicled technique described by Pitanguy and 16 patients operated on using the inferior pedicled technique by Robbins were compared. RESULTS: The mean follow-up period was 49 months in the Pitanguy group and 35 months in the Robbins group. The distance between the inframammary crease and the inferior margin of the nipple areola complex (NAC) showed a mean elongation of 3.3 cm (80.5 %) after the superior pedicled Pitanguy technique and 3.9 cm (92.9 %) after the inferior pedicled Robbins technique (p = 0.077). Using postoperative photographs, the overall aesthetic result after Pitanguy's technique was judged significantly better than the result after Robbins' technique (p = 0.002). CONCLUSIONS: Distinct postoperative elongation of the inferior mammary pole length must be considered in the preoperative marking for inferior and superior pedicled reduction mammaplasty. Guide values for the elongation can be used for planning unilateral adjustment reduction mammaplasty. To avoid bottoming-out of the inferior mammary pole, the NAC should be located at the level of the inframammary crease and the distance between the inframammary crease and the inferior border of the NAC should not exceed 4-4.5 cm. The definite position of the NAC should be decided after final shaping of the reduced breast toward the end of the operation. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. PMID- 22810557 TI - Feminization of the forehead in a transgender: frontal sinus reshaping combined with brow lift and hairline lowering. AB - The case of a 39-year-old male-to-female transgender patient who underwent feminization of his masculine forehead is presented. Surgical techniques to feminize his forehead were as follows. The outer table of the frontal sinus was removed and divided into four pieces with an oscillation saw. These pieces were reshaped, regrafted, and fixed back along with two microplates. The bilateral supraorbital ridges were shaved with a surgical bur. Brow lifting and lowering of the frontolateral hairline were performed simultaneously. There were no complications during the 1-year follow-up. The patient is satisfied with the more feminine forehead. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. PMID- 22810558 TI - Predictions from a model of global psychophysics about differences between perceptual and physical matches. AB - A well-known phenomenon is that "matched" successive signals do not result in physical identity. This phenomenon has mostly been studied in terms of how much the second of two signals varies from the first, which is called the time-order error (TOE). Here, theoretical predictions led us to study the more general question of how much the matching signal differs from the standard signal, independent of the position of the matching signal as the first or second in a presentation. This we call non-equal matches (NEM). Using Luce's (Psychological Review, 109, 520-532, 2002, Psychological Review, 111, 446-454, 2004, Psychological Review, 115, 601, 2008, Psychological Review, 119, 373-387, 2012) global psychophysical theory, we predicted NEM when an intensity z is perceived to be "1 times a standard signal x." The theory predicts two different types of individual behaviors for the NEM, and these predictions were evaluated and confirmed in an experiment. We showed that the traditional definition of TOE precludes the observation, and thus the study, of the NEM phenomenon, and that the NEM effect is substantial enough to alter conclusions based on data that it affects. Furthermore, we demonstrated that the custom of averaging data over individuals clearly leads to quite misleading results. An important parameter in this modeling is a reference point that plays a central role in creating variability in the data, so that the key to obtaining regular data from respondents is to stabilize the reference point. PMID- 22810559 TI - Stroboscopic visual training improves information encoding in short-term memory. AB - The visual system has developed to transform an undifferentiated and continuous flow of information into discrete and manageable representations, and this ability rests primarily on the uninterrupted nature of the input. Here we explore the impact of altering how visual information is accumulated over time by assessing how intermittent vision influences memory retention. Previous work has shown that intermittent, or stroboscopic, visual training (i.e., practicing while only experiencing snapshots of vision) can enhance visual-motor control and visual cognition, yet many questions remain unanswered about the mechanisms that are altered. In the present study, we used a partial-report memory paradigm to assess the possible changes in visual memory following training under stroboscopic conditions. In Experiment 1, the memory task was completed before and immediately after a training phase, wherein participants engaged in physical activities (e.g., playing catch) while wearing either specialized stroboscopic eyewear or transparent control eyewear. In Experiment 2, an additional group of participants underwent the same stroboscopic protocol but were delayed 24 h between training and assessment, so as to measure retention. In comparison to the control group, both stroboscopic groups (immediate and delayed retest) revealed enhanced retention of information in short-term memory, leading to better recall at longer stimulus-to-cue delays (640-2,560 ms). These results demonstrate that training under stroboscopic conditions has the capacity to enhance some aspects of visual memory, that these faculties generalize beyond the specific tasks that were trained, and that trained improvements can be maintained for at least a day. PMID- 22810560 TI - Short-term memory for event duration: modality specificity and goal dependency. AB - Time perception is involved in various cognitive functions. This study investigated the characteristics of short-term memory for event duration by examining how the length of the retention period affects inter- and intramodal duration judgment. On each trial, a sample stimulus was followed by a comparison stimulus, after a variable delay period (0.5-5 s). The sample and comparison stimuli were presented in the visual or auditory modality. The participants determined whether the comparison stimulus was longer or shorter than the sample stimulus. The distortion pattern of subjective duration during the delay period depended on the sensory modality of the comparison stimulus but was not affected by that of the sample stimulus. When the comparison stimulus was visually presented, the retained duration of the sample stimulus was shortened as the delay period increased. Contrarily, when the comparison stimulus was presented in the auditory modality, the delay period had little to no effect on the retained duration. Furthermore, whenever the participants did not know the sensory modality of the comparison stimulus beforehand, the effect of the delay period disappeared. These results suggest that the memory process for event duration is specific to sensory modality and that its performance is determined depending on the sensory modality in which the retained duration will be used subsequently. PMID- 22810562 TI - Visual nesting impacts approximate number system estimation. AB - The approximate number system (ANS) allows people to quickly but inaccurately enumerate large sets without counting. One popular account of the ANS is known as the accumulator model. This model posits that the ANS acts analogously to a graduated cylinder to which one "cup" is added for each item in the set, with set numerosity read from the "height" of the cylinder. Under this model, one would predict that if all the to-be-enumerated items were not collected into the accumulator, either the sets would be underestimated, or the misses would need to be corrected by a subsequent process, leading to longer reaction times. In this experiment, we tested whether such miss effects occur. Fifty participants judged numerosities of briefly presented sets of circles. In some conditions, circles were arranged such that some were inside others. This circle nesting was expected to increase the miss rate, since previous research had indicated that items in nested configurations cannot be preattentively individuated in parallel. Logically, items in a set that cannot be simultaneously individuated cannot be simultaneously added to an accumulator. Participants' response times were longer and their estimations were lower for sets whose configurations yielded greater levels of nesting. The level of nesting in a display influenced estimation independently of the total number of items present. This indicates that miss effects, predicted by the accumulator model, are indeed seen in ANS estimation. We speculate that ANS biases might, in turn, influence cognition and behavior, perhaps by influencing which kinds of sets are spontaneously counted. PMID- 22810561 TI - Value-driven attentional and oculomotor capture during goal-directed, unconstrained viewing. AB - Covert shifts of attention precede and direct overt eye movements to stimuli that are task relevant or physically salient. A growing body of evidence suggests that the learned value of perceptual stimuli strongly influences their attentional priority. For example, previously rewarded but otherwise irrelevant and inconspicuous stimuli capture covert attention involuntarily. It is unknown, however, whether stimuli also draw eye movements involuntarily as a consequence of their reward history. Here, we show that previously rewarded but currently task-irrelevant stimuli capture both attention and the eyes. Value-driven oculomotor capture was observed during unconstrained viewing, when neither eye movements nor fixations were required, and was strongly related to individual differences in visual working memory capacity. The appearance of a reward associated stimulus came to evoke pupil dilation over the course of training, which provides physiological evidence that the stimuli that elicit value-driven capture come to serve as reward-predictive cues. These findings reveal a close coupling of value-driven attentional capture and eye movements that has broad implications for theories of attention and reward learning. PMID- 22810563 TI - Cardiopulmonary exercise testing predicts postoperative outcome in patients undergoing gastric bypass surgery. AB - BACKGROUND: For several types of non-cardiac surgery, the cardiopulmonary exercise testing (CPET)-derived variables anaerobic threshold (AT), peak oxygen consumption (VO2 peak), and ventilatory equivalent for CO(2) (VE/VCO2 ) are predictive of increased postoperative risk: less physically fit patients having a greater risk of adverse outcome. We investigated this relationship in patients undergoing gastric bypass surgery. METHODS: All patients (<190 kg) who were referred for CPET and underwent elective gastric bypass surgery at the Whittington Hospital NHS Trust between September 1, 2009, and February 25, 2011, were included in the study (n=121). Fifteen patients did not complete CPET. CPET variables (VO2 peak, AT, and VE/VCO2 ) were derived for 106 patients. The primary outcome variables were day 5 morbidity and hospital length of stay (LOS). The independent t-test and Fisher's exact test were used to test for differences between surgical outcome groups. The predictive capacity of CPET markers was determined using receiver operating characteristic (ROC) curves. RESULTS: The AT was lower in patients with postoperative complications than in those without [9.9 (1.5) vs 11.1 (1.7) ml kg(-1) min(-1), P=0.049] and in patients with a LOS>3 days compared with LOS <= 3 days [10.4 (1.4) vs 11.3 (1.8) ml kg(-1) min(-1), P=0.023]. ROC curve analysis identified AT as a significant predictor of LOS>3 days (AUC 0.640, P=0.030). The VO2 peak and VE/VCO2 were not associated with postoperative outcome. CONCLUSIONS: AT, determined using CPET, predicts LOS after gastric bypass surgery. PMID- 22810564 TI - Monitoring of real changes of plasma membrane potential by diS-C(3)(3) fluorescence in yeast cell suspensions. AB - The fluorescent dye 3,3'-dipropylthiadicarbocyanine, diS-C(3)(3), is a suitable probe to monitor real changes of plasma membrane potential in yeast cells which are too small for direct membrane potential measurements with microelectrodes. A method presented in this paper makes it possible to convert changes of equilibrium diS-C(3)(3) fluorescence spectra, measured in yeast cell suspensions under certain defined conditions, into underlying membrane potential differences, scaled in the units of millivolts. Spectral analysis of synchronously scanned diS C(3)(3) fluorescence allows to assess the amount of dye accumulated in cells without otherwise necessary sample taking and following separation of cells from the medium. Moreover, membrane potential changes can be quantified without demanding calibration protocols. The applicability of this approach was demonstrated on the depolarization of Rhodotorula glutinis yeast cells upon acidification of cell suspensions and/or by increasing extracellular K(+) concentration. PMID- 22810565 TI - [Guidelines for dental care in hemophilia patients]. AB - Dentist usually lacking knowledge about congenital blood-clotting disorders. That leads to unreasonable limitations in use of modern dental care techniques. The following study result obtained in specialized center for blood-clotting disorders treatment should serve as guidelines for dental care in hemophilia patients. PMID- 22810566 TI - [The results of medicolegal proceedings involving dental care services]. AB - The paper deals with the results of medicolegal proceedings involving inappropriate dental care service in both criminal and civil cases. The authors also propose measures for prevention of pitfalls described in the study. PMID- 22810567 TI - [Smoking effect on oral fluid oxidative balance]. AB - Smoking effect on oral fluid protein metabolism and oxidative balance were studied in medical school students (15 smokers and 15 none-smokers as a control group, mean age 19,8+/-1,4 years). Smoking caused intensification of lipoperoxidation and decrease in antioxidation activity thus proving it to be the reason of harmful metabolic shift in oral fluid. PMID- 22810568 TI - [Modern hygiene products impact on oral microbial, pH and mineral balance]. AB - Several toothpastes are compared in the study: "Zhemchuzhnaya-complex protection" containing as abrasive substance finely dispersed dicalcium phosphate phosphathydrate, "Noviy zhemchug ftor" and "Zhemchug svezhaya myata" with calcium carbonate. "Zhemchuzhnaya-complex protection" and "Noviy zhemchug ftor" both contain sodium monophosphate as active substance. Impact of these toothpastes on oral microbial, pH and mineral balance was assessed in the study. PMID- 22810569 TI - [Dental decay treatment in hemophilia patients]. AB - Intensive dental decay is a constant symptom in hemophilia patients while its treatment may be challenging because of need for effective but sparing techniques. Rational and safe techniques for dental decay treatment in hemophilia patients are discussed in the study. PMID- 22810570 TI - [Sugar substitute products impact on oral fluid biochemical properties]. AB - Sugar substitute products impact on oral fluid protein and carbohydrate content, as well as oxidative balance were studied in 60 medical school students in compare with conventional sugar. Sugar intake proved to cause cariesogenic carbohydrate metabolism disorders in oral fluid, intensification of lipoperoxidation and decrease in antioxidation activity. Sugar substitute products help to prevent dental decay. PMID- 22810571 TI - [Life quality improvement in hemophilia patients after esthetical teeth restoration]. AB - OBJECTIVE: to study the effect of esthetical teeth restoration on life quality in hemophilia patients. Life quality was assessed by means of adapted OHIP-14 questionary translated into Russian. The study showed life quality to be sensible to dental status: cavities, dental arch defects, poor restorations and dentures. Dental treatment tends to improve life quality in hemophilia patients. PMID- 22810572 TI - [Facial furuncles and carbuncles incidence and morbidity]. AB - The retrospective study included analysis of 5764 hospital records in maxillo facial surgery unit of Samara State Medical University Clinic to reveal facial furuncles and carbuncles incidence and morbidity. Patients attended in 2007-2010 were included in the study. Treatment options in 380 patients with facial furuncles and carbuncles were also analyzed. The authors recommend early treatment in the in-patient maxillofacial unit and adequate active surgical tactic. PMID- 22810573 TI - [Self-tapping cylindrical screw implants with polished neck and internal hexagon: outcomes and perspectives]. AB - The article summarizes clinical experience on 1173 self-tapping cylindrical screw implants with polished neck and internal hexagon placed in 432 patients. The patients were followed-up for 38+/-3.7 months (1 to 7 years) after restorative phase of treatment. Final clinical effectiveness was 93.7%. Best results were obtained when placing implants 3 to 12 months after teeth extraction. Rational perspective in implant construction improvement is switched and universal platform approach. PMID- 22810574 TI - [Bone augmentation by dental implant procedures in the esthetic zone]. AB - Several options for bone tissue augmentation by dental implant procedures in upper incisors, canines and bicuspids area are described were are discussed in the study. Seventy-three patients were included in the study. Bone auto- and allogenic grafts, Beta-3-calcium phosphate as well as their combination were used as osteoplastic materials. Guided tissue regeneration was performed if indicated, in some cases augmentation without membrane before implantation or simultaneously was carried-out. Bone augmentation results and pos-op esthetic features were analyzed in the study. PMID- 22810575 TI - [Restorative treatment by means of short porous-surfaced implants]. AB - OBJECTIVE: to assess clinical efficiency of restorative treatment on short porous surfaced implants. One hundred and fifty-five porous-surfaced 5, 7 and 9 mm implants were placed in 71 patients with partial teeth loss and significant alveolar bone loss. Only one implant failure was observed one month after placement. Other 154 implants were used as restoration abutments. One year after restorative treatment mean periotest rate was -5,3, mean radiologicaly confirmed marginal bone loss 0,31 mm. No treatment failure were revealed during 3 years of follow-up. PMID- 22810576 TI - [TMJ pathology in hemophilia patients]. AB - Hemarthrosis is one of the leading symptoms in congenital blood-clotting disorders. This condition leads to significant pain syndrome, joint deformation impaired function and diminished life quality. TMJ pathology showing all signs of hemophilic arthropathy is common in hemophilia patients. PMID- 22810577 TI - [Dental preparation features by subgingival location of circular ledge]. AB - To prevent periodontal complications after esthetic rehabilitation it is essential to minimize soft tissues injury in case of subgingival ledge position. It was established that the border of ledge should not interfere with biological width of the tooth. Clinical researches showed that location of circular edge at 0.5 mm distance and more from epithelial attachment decreases the danger of periodontal tissues inflammatory response. From the clinical point of view the main factor determining subgingival level of preparation is an adequate assessment of gingival groove depth. This assessment is however complicated by the variations of morphometric features of biological width causing inaccuracy of subgingival border preparation and leading to undesirable effects in periodontal tissues (gingivitis, periodontitis, recession). PMID- 22810578 TI - [Incidence of cleft lip and palate in Kirov region. Organization of multidisciplinary center for CLP infants rehabilitation]. AB - The incidence of cleft lip and/or palate (CLP) in Kirov region is 1:1078 newborns. More than half of the patients (52%) have both cleft lip and palate thus requiring more complex and time consuming treatment. Multidisciplinary approach to CLP patients rehabilitation used in tertiary care center is described in the study. PMID- 22810579 TI - Metal overlayer on metal carbide substrate: unique bimetallic properties for catalysis and electrocatalysis. AB - Transition metal carbides often display electronic and catalytic properties that are similar to Pt-group metals. In this tutorial review, we describe the feasibility of replacing the Pt-group metal component in bimetallic systems with metal carbides. By supporting a metal monolayer on a carbide substrate, these bimetallic surfaces exhibit similar catalytic and electrocatalytic activity to the corresponding Pt-based bimetallic systems while demonstrating the advantages of lower cost and higher thermal stability. Another promising aspect is that the carbide substrates often promote the formation of small, flat metal particles with novel catalytic properties. We review the synthesis, characterization, and utilization of carbide-supported metal surfaces in heterogeneous catalysis and electrocatalysis. An overview is given for both theoretical and experimental investigations, and trends are drawn from the literature. We also discuss opportunities for future research on carbide-supported metal surfaces. PMID- 22810580 TI - Improving the quality of medical care: the normativity of evidence-based performance standards. AB - Poor quality medical care is sometimes attributed to physicians' unwillingness to act on evidence about what works best. Evidence-based performance standards (EBPSs) are one response to this problem, and they are increasingly employed by health care regulators and payers. Evidence in this instance is judged according to the precepts of evidence-based medicine (EBM); it is probabilistic, and the randomized controlled trial (RCT) is the gold standard. This means that EBPSs suffer all the infirmities of EBM generally-well rehearsed problems with the external validity of research findings as well as the inferential leap from study results in the aggregate to individual patient care. These theoretical weaknesses promise to have a practical impact on the care of patients. To avoid this, EBPSs should be understood as guidelines indicative of average effectiveness rather than standards to be applied in every case. PMID- 22810581 TI - Where should we draw the line between quality of care and other ethical concerns related to medical registries and biobanks? AB - Together with large biobanks of human samples, medical registries with aggregated data from many clinical centers are vital parts of an infrastructure for maintaining high standards of quality with regard to medical diagnosis and treatment. The rapid development in personalized medicine and pharmaco-genomics only underscores the future need for these infrastructures. However, registries and biobanks have been criticized as constituting great risks to individual privacy. In this article, I suggest that quality with regard to diagnosis and treatment is an inherent, morally normative requirement of health care, and argue that quality concerns in this sense may be balanced with privacy concerns. PMID- 22810582 TI - Defining "quality of care" persuasively. AB - As the quality movement in health care now enters its fourth decade, the language of quality is ubiquitous. Practitioners, organizations, and government agencies alike vociferously testify their commitments to quality and accept numerous forms of governance aimed at improving quality of care. Remarkably, the powerful phrase "quality of care" is rarely defined in the health care literature. Instead it operates as an accepted and assumed goal worth pursuing. The status of evidence based medicine, for instance, hinges on its ability to improve quality of care, and efforts are made by both proponents and detractors to unpack the contents and outcomes of evidence-based practice while the contents of "quality of care" are presumed to be understood. Because the goals of medicine are far from obvious, this paper investigates the neglected term, "quality of care," in an effort to understand what it is that health care practices are so uncritically assumed to be striving for. Finding lack of consensus on the terminology in the quality literature, I propose that the term operates rhetorically by way of persuasive appeal (and lack of descriptive meaning). Unsatisfied that "quality of care" operates as a mere buzzword in morally contentious debates over resource allocation and duties of care, I implore health care communities to go beyond mere commitments to quality and, instead, to focus attention on the difficult task of specifying what counts as quality care within an economically constrained health care system. PMID- 22810583 TI - Influence of different mineral nitrogen sources (NO3(-)-N vs. NH4(+)-N) on arbuscular mycorrhiza development and N transfer in a Glomus intraradices-cowpea symbiosis. AB - Labeled nitrogen ((15)N) was applied to a soil-based substrate in order to study the uptake of N by Glomus intraradices extraradical mycelium (ERM) from different mineral N (NO(3)(-) vs. NH(4)(+)) sources and the subsequent transfer to cowpea plants. Fungal compartments (FCs) were placed within the plant growth substrate to simulate soil patches containing root-inaccessible, but mycorrhiza-accessible, N. The fungus was able to take up both N-forms, NO(3)(-) and NH(4)(+). However, the amount of N transferred from the FC to the plant was higher when NO(3)(-) was applied to the FC. In contrast, analysis of ERM harvested from the FC showed a higher (15)N enrichment when the FC was supplied with (15)NH(4)(+) compared with (15)NO(3)(-). The (15)N shoot/root ratio of plants supplied with (15)NO(3)(-) was much higher than that of plants supplied with (15)NH(4)(+), indicative of a faster transfer of (15)NO(3)(-) from the root to the shoot and a higher accumulation of (15)NH (4)(+) in the root and/or intraradical mycelium. It is concluded that hyphae of the arbuscular mycorrhizal fungus may absorb NH(4)(+) preferentially over NO(3)(-) but that export of N from the hyphae to the root and shoot may be greater following NO(3)(-) uptake. The need for NH(4)(+) to be assimilated into organically bound N prior to transport into the plant is discussed. PMID- 22810584 TI - Sex-specific volatile compounds influence microarthropod-mediated fertilization of moss. AB - Sexual reproduction in non-vascular plants requires unicellular free-motile sperm to travel from male to female reproductive structures across the terrestrial landscape. Recent data suggest that microarthropods can disperse sperm in mosses. However, little is known about the chemical communication, if any, that is involved in this interaction or the relative importance of microarthropod dispersal compared to abiotic dispersal agents in mosses. Here we show that tissues of the cosmopolitan moss Ceratodon purpureus emit complex volatile scents, similar in chemical diversity to those described in pollination mutualisms between flowering plants and insects, that the chemical composition of C. purpureus volatiles are sex-specific, and that moss-dwelling microarthropods are differentially attracted to these sex-specific moss volatile cues. Furthermore, using experimental microcosms, we show that microarthropods significantly increase moss fertilization rates, even in the presence of water spray, highlighting the important role of microarthropod dispersal in contributing to moss mating success. Taken together, our results indicate the presence of a scent-based 'plant-pollinator-like' relationship that has evolved between two of Earth's most ancient terrestrial lineages, mosses and microarthropods. PMID- 22810585 TI - Viral immune modulators perturb the human molecular network by common and unique strategies. AB - Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies. PMID- 22810586 TI - Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. AB - Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer. PMID- 22810587 TI - APJ acts as a dual receptor in cardiac hypertrophy. AB - Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Galphai and elicits a protective response, stretch signals in an APJ dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of beta-arrestins or by pharmacological doses of apelin acting through Galphai. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy. PMID- 22810588 TI - A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. AB - Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes. PMID- 22810589 TI - A subset of dopamine neurons signals reward for odour memory in Drosophila. AB - Animals approach stimuli that predict a pleasant outcome. After the paired presentation of an odour and a reward, Drosophila melanogaster can develop a conditioned approach towards that odour. Despite recent advances in understanding the neural circuits for associative memory and appetitive motivation, the cellular mechanisms for reward processing in the fly brain are unknown. Here we show that a group of dopamine neurons in the protocerebral anterior medial (PAM) cluster signals sugar reward by transient activation and inactivation of target neurons in intact behaving flies. These dopamine neurons are selectively required for the reinforcing property of, but not a reflexive response to, the sugar stimulus. In vivo calcium imaging revealed that these neurons are activated by sugar ingestion and the activation is increased on starvation. The output sites of the PAM neurons are mainly localized to the medial lobes of the mushroom bodies (MBs), where appetitive olfactory associative memory is formed. We therefore propose that the PAM cluster neurons endow a positive predictive value to the odour in the MBs. Dopamine in insects is known to mediate aversive reinforcement signals. Our results highlight the cellular specificity underlying the various roles of dopamine and the importance of spatially segregated local circuits within the MBs. PMID- 22810590 TI - Structured spheres generated by an in-fibre fluid instability. AB - From drug delivery to chemical and biological catalysis and cosmetics, the need for efficient fabrication pathways for particles over a wide range of sizes, from a variety of materials, and in many different structures has been well established. Here we harness the inherent scalability of fibre production and an in-fibre Plateau-Rayleigh capillary instability for the fabrication of uniformly sized, structured spherical particles spanning an exceptionally wide range of sizes: from 2 mm down to 20 nm. Thermal processing of a multimaterial fibre controllably induces the instability, resulting in a well-ordered, oriented emulsion in three dimensions. The fibre core and cladding correspond to the dispersed and continuous phases, respectively, and are both frozen in situ on cooling, after which the particles are released when needed. By arranging a variety of structures and materials in a macroscopic scaled-up model of the fibre, we produce composite, structured, spherical particles, such as core-shell particles, two-compartment 'Janus' particles, and multi-sectioned 'beach ball' particles. Moreover, producing fibres with a high density of cores allows for an unprecedented level of parallelization. In principle, 10(8) 50-nm cores may be embedded in metres-long, 1-mm-diameter fibre, which can be induced to break up simultaneously throughout its length, into uniformly sized, structured spheres. PMID- 22810593 TI - Faculty. PMID- 22810592 TI - Assessing the reliability of dose coefficients for inhaled and ingested radionuclides. AB - Consideration of uncertainties on doses can provide numerical estimates of the reliability of the protection quantities (dose coefficients) used in radiation protection to assess exposures to radionuclides that enter the body by ingestion or inhalation ('internal emitters'). Uncertainty analysis methods have been widely applied to quantify uncertainties on doses, including effective dose. However, it is not always clear how the distributions of effective dose per unit intake that result from such analyses should be interpreted with respect to the intended use of effective dose in radiation protection and the use of dose coefficients as reference values. The ICRP system of radiological protection is reviewed briefly and it is argued that the reliability of an effective dose coefficient as a protection device can best be determined by comparing the nominal detriment adjusted cancer risk associated with the dose coefficient, with a best estimate of risk for the exposure pathway and exposed population group, considering uncertainties in biokinetic, dosimetric and risk parameters. Because it is the uncertainty on the population mean of this quantity that is required, the effect of parameter variability should be distinguished from the effect of parameter uncertainty when performing uncertainty analyses. A methodology for performing the uncertainty analysis is discussed and studies that quantify uncertainty on doses and risk from intakes of radionuclides are reviewed. PMID- 22810591 TI - Addition of an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy improves survival in advanced malignancies. AB - Studies have shown that cancer requires two conditions for tumor progression: cancer cell proliferation and an environment permissive to and conditioned by malignancy. Chemotherapy aims to control the number and proliferation of cancer cells, but it does not effectively control the two best-known conditions of the tumor-permissive environment: neoangiogenesis and tolerogenic immunity. Many malignant diseases exhibit poor outcomes after treatment with chemotherapy. Therefore, we investigated the potential benefits of adding an induction regimen of antiangiogenesis and antitumor immunity to chemotherapy in poor outcome disease. In a prospective, randomized trial, we included patients with advanced, unresectable pancreatic adenocarcinomas, non-small cell lung cancer, or prostate cancer. Two groups of each primary condition were compared: group 1 (G1), n = 30, was treated with the standard chemotherapy and used as a control, and group 2 (G2), n = 30, was treated with chemotherapy plus an induction regimen of antiangiogenesis and antitumor immunity. This induction regimen included a low dose of metronomic cyclophosphamide, a high dose of Cox-2 inhibitor, granulocyte colony-stimulating factor, a sulfhydryl (SH) donor, and a hemoderivative that contained autologous tumor antigens released from patient tumors into the blood. After treatment, the G2 group demonstrated significantly longer survival, lower blood level of neoangiogenesis and immune-tolerance mediators, and higher blood levels of antiangiogenesis and antitumor immunity mediators compared with the G1 group. Toxicity and quality of life were not significantly different between the groups. In conclusion, in several advanced malignancies of different primary localizations, an increase in survival was observed by adding an induction regimen of antiangiogenesis and antitumor immunity to standard chemotherapy. PMID- 22810595 TI - Editor'S letter. PMID- 22810596 TI - Diagnosis and differential diagnosis of multiple sclerosis. AB - No single test to diagnose multiple sclerosis is available, and its cause is unknown. The diagnosis relies on recognition of the clinical patterns of the disease as well as exclusion of other possible mimics. Waxing and waning neurologic deficits that localize to the CNS are the hallmark of the disease in most patients. The diagnosis can be supported by laboratory studies, including MRI of the brain and spinal cord, analysis of CSF, and evoked-potential studies of the visual and somatosensory pathways. PMID- 22810597 TI - MRI in multiple sclerosis. AB - Over the past 2 decades, MRI has been integrated into the diagnosis of multiple sclerosis (MS), the study of MS pathobiology, and the development and monitoring of MS treatments. This integration has irrevocably changed the way we think about the disease. New treatments, advanced through early stages of development using MRI outcome measures, have revolutionized the treatment of MS. Although MS remains a clinical diagnosis, conventional MRI is now a requisite adjunct to that diagnosis. Early in the disease, MRI monitoring of a patient on immunomodulatory therapy is helpful in identifying breakthrough disease activity that may predict long-term outcome. Advanced MRI technologies, although currently relegated to the research realm, are improving the detection of previously underappreciated aspects of MS pathology and may help lead to the evaluation of new therapeutic strategies. PMID- 22810598 TI - Current and emerging multiple sclerosis therapeutics. AB - For a disease whose cause remains elusive, there has been a paradoxical growth in multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs for MS were brought to market. All of these disease-modifying therapies (DMTs) have shown a beneficial effect in reducing the number of exacerbations in double-blind placebo-controlled trials, and three drugs (subcutaneous [SC]/IM interferon beta-1a, natalizumab) have been shown to reduce relapses, decrease MRI activity, and reduce the risk of sustained disability after 2 years of treatment. No controlled studies exist to show long-term benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies continue to play a role in the management of patients who fail to respond to immunomodulatory agents. These agents, however, have shown mixed data in terms of efficacy and put patients at higher risk for the development of secondary cancers. Plasma exchange for severe relapses not responsive to corticosteroid therapy has regained interest in the past few years. Furthermore, six new agents that will dramatically impact our ability to prevent disability in patients with MS are in late-stage or have completed phase 3 clinical development. Determining the risk-benefit calculations that we will need to employ toward these new drugs and the algorithms for switching therapies will be critical issues in the next 5 years. This article highlights the clinical efficacy of the current DMTs/ISDs and discusses the current treatment options for clinically isolated syndrome, relapsing-remitting MS (RRMS), and exacerbations of RRMS. It also addresses the management of a suboptimal response to the DMTs; discusses the challenge of primary progressive MS; and presents an overview of emerging therapeutic options. PMID- 22810599 TI - Complementary and alternative medicine in multiple sclerosis. AB - Complementary and alternative medicine (CAM) is used by one-half to three-fourths of patients with multiple sclerosis (MS). Despite this widespread use, CAM may not be discussed in the course of a conventional medical visit. When considered in the context of MS, CAM therapies have a wide range of risk-benefit profiles. Some CAM therapies, such as acupuncture, cranberry, vitamin D, tai chi, and yoga, are low risk and possibly beneficial. Other CAM therapies, such as immune stimulating supplements, bee venom, and hyperbaric oxygen, are ineffective, dangerous, or unstudied. Providing access to information about the risks and benefits of CAM therapies may increase the quality of care that is provided to patients with MS. PMID- 22810600 TI - Symptomatic therapy of multiple sclerosis. AB - Despite the important advances being made in disease-modifying multiple sclerosis (MS) therapies, patients are often affected by a wide variety of symptoms caused by neurologic injury in MS. Common symptoms that patients with MS experience during the course of their illness include weakness, ambulatory impairment, sensory disturbances that may be unpleasant or even painful, ataxia and tremor, bladder and bowel dysfunction, sexual dysfunction, fatigue, spasticity, vertigo, depression and other psychiatric symptoms, cognitive impairment, and paroxysmal symptoms such as cramps, spasms, Lhermitte symptom, and Uhthoff phenomenon. These MS symptoms can cause loss of vocation and social isolation. Neurologic care of patients with MS often involves a greater degree of management of the symptoms caused by MS than appropriate prescription of disease-modifying treatments. In addition, many of the disease-modifying therapies have unpleasant side effects that may also require treatment. This article will focus on medical treatments, use of rehabilitation medicine, and, in select cases, surgical interventions for management of MS symptoms. PMID- 22810601 TI - Neuromyelitis optica spectrum disorders. AB - Neuromyelitis optica is an uncommon inflammatory demyelinating CNS disorder that is distinct from multiple sclerosis with respect to clinical, laboratory, neuroimaging, and prognostic characteristics. Autoantibodies that target aquaporin-4 are highly specific for neuromyelitis optica and have helped define a spectrum of disease beyond the classic definition of acute transverse myelitis and optic neuritis. Accumulating evidence supports the pathogenic potential that these autoantibodies possess in relation to the unique vasculocentric immunopathology of the disease. Current treatment strategies therefore include the use of corticosteroids and plasmapheresis for acute attacks and general or humoral immunosuppression for attack prevention. Ongoing research will focus on establishing the pathogenic mechanisms of the disease, in part derived from newly reported animal models, and testing-focused treatment strategies that evolve from this knowledge. PMID- 22810602 TI - The neuro-ophthalmology of multiple sclerosis. AB - Multiple sclerosis (MS) is the quintessential neurologic disorder from which to understand the principles of afferent and efferent neuro-ophthalmology. Perhaps with the exception of stroke, no other disorder is associated with nearly every sign and symptom of abnormalities targeting the visual system and the ocular motor apparatus. This focused review will underscore the most common syndromes and their derivative signs and symptoms that affect vision as a consequence of MS. PMID- 22810603 TI - Uncovering the genetic architecture of multiple sclerosis. AB - Multiple sclerosis (MS) is a disease in which genetic, environmental, and stochastic factors interact to trigger an inflammatory disease of the CNS that also has a neurodegenerative component. Over the past 3 years, progress in high throughput technologies and analysis methods has synergized with the collaborative efforts of investigators studying MS genetics to enable the discovery of more than a dozen genes involved in making individuals susceptible to MS. These genes are beginning to suggest molecular pathways that may be particularly vulnerable to genetic variation in MS. Soon, a comprehensive map of common genetic variants affecting MS susceptibility will be assembled, and communal efforts will need to focus on the more challenging issue of understanding the genetic architecture of disease course and treatment response in MS. Early efforts integrating different dimensions of information, including genomics, imaging, transcriptomics, and proteomics, with precise phenotypic data from clinicians illustrate the way forward for prognostic algorithms in MS and suggest that these approaches will yield a new series of insights in the next decade. PMID- 22810604 TI - Immunopathogenesis of multiple sclerosis: new insights and therapeutic implications. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disorder of the CNS. The etiology of MS remains unknown. However, it is well established that immune dysregulation plays a critical role in the neuropathogenesis of this disorder. In this review, we discuss the current hypotheses concerning the complex cellular and molecular interactions involved in the immunopathogenesis of MS. Although CD4 T lymphocytes have long been considered the critical cellular factor in the immunopathology of MS, the role of other cell types has also recently been investigated. It appears that the spatial distribution of CD4 and CD8 cells in MS lesions is distinct. Yet another T lymphocyte subset, gamma/delta T cells, can be detected in very early MS lesions. The prevalent dogma suggests that CD4 helper T (TH) type 1 cells release cytokines and inflammatory mediators that cause tissue damage, while CD4 TH2 cells might be involved in modulation of these effects. However, a mounting body of evidence suggests that additional T-cell subsets, including TH17 cells, CD8 effector T cells, and CD4 CD25 regulatory T cells, also affect disease activity. In addition, clinical and paraclinical data are accumulating on the prominent role of B lymphocytes and other antigen-presenting cells in MS neuropathogenesis. Given these observations, new therapeutic interventions for MS will need to focus on resetting multiple components of the immune system. PMID- 22810605 TI - Pediatric multiple sclerosis. AB - Multiple sclerosis (MS) onset in childhood occurs in a small proportion of individuals with the disease, although the precise incidence of pediatric MS is unknown. It may be difficult to distinguish the initial attack of pediatric MS from acute disseminated encephalomyelitis, particularly in very young children. Environmental and genetic factors that appear to increase the risk of pediatric MS include prior infection with Epstein-Barr virus, exposure to cigarette smoke, and HLA-DRB1*15 haplotype. Children may have more posterior fossa involvement at onset and a higher relapse rate than adults with MS. Although time to disability may be longer than in adults, pediatric MS is associated with an earlier age of disability. Off-label use of standard disease-modifying therapies for adult MS is common, although data regarding the efficacy and safety for these medications are limited. PMID- 22810606 TI - Sex differences in multiple sclerosis. AB - Sex and sex hormones affect the CNS and the immune system differentially, and thus a sexual dimorphism may be anticipated across arenas in multiple sclerosis (MS). Information from the past few decades has elucidated the impact of sex on broad aspects of MS, such as susceptibility, disease course, and radiologic phenotypes. Specific concerns regarding family planning and managing reproductive issues influenced by MS are likely to arise, given the typical age of onset during reproductive years. Thus, information regarding reproductive health in male and female patients with MS can potentiate the role of the neurologist in the management of these important aspects of clinical care. PMID- 22810607 TI - Primary progressive multiple sclerosis. AB - Primary progressive multiple sclerosis (MS), comprising 10% to 15% of all cases of MS, is characterized by an insidious progression from the onset of disease, making it clinically distinct from the commonest form, relapsing remitting MS. Making the diagnosis can be challenging, and misdiagnosis and delay in diagnosis are common. Although no effective treatments are currently known, insights into the pathogenesis of this phenotype aid in understanding the processes that drive progression in all forms of MS. PMID- 22810608 TI - Patient management problem. PMID- 22810609 TI - Ethical perspectives in neurology: ethical considerations when doctor and patient perspectives on treatment risks differ. PMID- 22810610 TI - Practice issues in neurology: point of care online resources. PMID- 22810611 TI - Coding table. PMID- 22810612 TI - APPENDIX: American Academy of Neurology Practice Guidelines for Multiple Sclerosis. PMID- 22810613 TI - Multiple-choice questions. PMID- 22810614 TI - Preferred responses. PMID- 22810615 TI - Quintessentials. PMID- 22810616 TI - MULTIPLE SCLEROSIS: Part 1-Baseline Questionnaire. PMID- 22810617 TI - Preferred responses: part 1-baseline. PMID- 22810619 TI - Neuraxial analgesia versus intravenous remifentanil for pain relief in early labor in nulliparous women. AB - OBJECTIVE: To assess if there is a difference in duration of labor, the mode of delivery, average Visual Analog Scale (VAS) pain scores, maternal overall satisfaction with analgesia, side effects and neonatal outcomes in nulliparous women who received early labor analgesia with either epidural, patient-controlled IV analgesia (PCIA) with remifentanil or combined spinal-epidural (CSE) techniques. STUDY DESIGN: This is a prospective randomized interventional study. SUBJECTS AND METHODS: The study included 1,140 healthy nulliparous women (with term, singleton pregnancies) early in labor, requesting labor analgesia, during the period from September 2009 to August 2011 at TAIBA Hospital in Kuwait. The participants were randomized to receive either epidural analgesia (Group I), or PCIA with remifentanil (Group II) or CSE analgesia (Group III). The primary outcome was the rate of cesarean delivery. RESULTS: CSE analgesia was associated with a statistically highly significant decrease in labor duration (from analgesia to vaginal delivery), duration of latent and active phases of the first stage, and duration of the second stage of labor, average VAS pain scores, and a highest maternal overall satisfaction score with analgesia (P<0.01) as compared to epidural analgesia or PCIA with remifentanil. CONCLUSION: In terms of labor duration, average VAS pain scores, and maternal overall satisfaction score with analgesia, CSE analgesia is superior to that provided by epidural analgesia or PCIA with remifentanil for pain relief in early labor in nulliparous women. However, there were no differences in the mode of delivery, side effects or neonatal outcomes between the three techniques. PMID- 22810620 TI - Episiotomy: the final cut? AB - OBJECTIVE: To investigate whether episiotomy prevents 3rd or 4th degree perineal tears in critical conditions such as shoulder dystocia, instrumental deliveries (vacuum or forceps), persistent occiput-posterior position, fetal macrosomia (>4,000 g), and non-reassuring fetal heart rate (NRFHR) patterns. METHODS: A retrospective study comparing 3rd and 4th degree perineal tears during vaginal deliveries with or without episiotomy, in selected critical conditions was performed. Multiple gestations, preterm deliveries (<37 weeks' gestation) and cesarean deliveries were excluded from the analysis. Stratified analysis (using the Mantel-Haenszel technique) was used to obtain the weighted odds ratio (OR), while controlling for these variables. RESULTS: During the study period, there were 168,077 singleton vaginal deliveries. Of those, 188 (0.1%) had 3rd or 4th degree perineal tears. Vaginal deliveries with episiotomy had statistically significant higher rates of 3rd or 4th degree perineal tears than those without episiotomy (0.2 vs. 0.1%; P<0.001). The association between episiotomy and severe perineal tears remained significant even in the critical conditions. Stratified analysis revealed that the adjusted ORs for 3rd or 4th degree perineal tears in these critical conditions (Macrosomia OR=2.3; instrumental deliveries OR=1.8; NRFHR patterns OR=2.1; occipito-posterior position OR=2.3; and shoulder dystocia OR=2.3) were similar to the crude OR (OR=2.3). CONCLUSIONS: Mediolateral episiotomy is an independent risk factor for 3rd or 4th degree perineal tears, even in critical conditions such as shoulder dystocia, instrumental deliveries, occiput-posterior position, fetal macrosomia, and NRFHR. Prophylactic use of episiotomy in these conditions does not seem beneficial if performed to prevent 3rd or 4th degree perineal tears. PMID- 22810621 TI - Risk factors for postpartum hemorrhage requiring transfusion in cesarean deliveries for Japanese twins: comparison with those for singletons. AB - OBJECTIVE: The aim of this study was to identify the factors associated with the increased risk of postpartum hemorrhage requiring transfusion in Japanese twin pregnancies in comparison with those in Japanese singleton pregnancies. METHODS: We reviewed the obstetric records of all singleton and twin deliveries after 22 weeks' gestation at the Japanese Red Cross Katsushika Maternity Hospital from 2003 through 2011. Potential risk factors for transfusion due to hemorrhage after cesarean delivery were selected according to previous studies of postpartum hemorrhage or transfusion or both after delivery: maternal age, parity, previous cesarean deliveries, history of infertility therapies such as in vitro fertilization, gestational age at delivery, neonatal birth weight, placenta previa, uterine myoma>=6 cm, hypertensive disorders, placental abruption, emergency cesarean deliveries and general anesthesia. RESULTS: Using multiple logistic regression, the independent risk factors for postpartum hemorrhage requiring transfusion in singleton pregnancies were preterm delivery [odds ratio (OR) 2.40, 95% confidence interval (CI) 1.2-4.6, p<0.01], placenta previa (OR 8.08, 95% CI 3.9-16, p<0.01) and placental abruption (OR 12.8, 95% CI 2.3-76, p<0.01). In twin pregnancies, however, the independent risk factors for postpartum hemorrhage requiring transfusion were gestational age at >=41 weeks (OR 8.20, 95% CI 1.3-40, p<0.01) and hypertensive disorders (OR 5.45, 95% CI 2.2 14, p<0.01). CONCLUSIONS: The factors associated with postpartum hemorrhage requiring transfusion in cesarean deliveries of twins seemed to be different from those in singleton cesarean deliveries. PMID- 22810622 TI - Neocortical dendritic complexity is controlled during development by NOMA-GAP dependent inhibition of Cdc42 and activation of cofilin. AB - Neocortical neurons have highly branched dendritic trees that are essential for their function. Indeed, defects in dendritic arborization are associated with human neurodevelopmental disorders. The molecular mechanisms regulating dendritic arbor complexity, however, are still poorly understood. Here, we uncover the molecular basis for the regulation of dendritic branching during cortical development. We show that during development, dendritic branching requires post mitotic suppression of the RhoGTPase Cdc42. By generating genetically modified mice, we demonstrate that this is catalyzed in vivo by the novel Cdc42-GAP NOMA GAP. Loss of NOMA-GAP leads to decreased neocortical volume, associated specifically with profound oversimplification of cortical dendritic arborization and hyperactivation of Cdc42. Remarkably, dendritic complexity and cortical thickness can be partially restored by genetic reduction of post-mitotic Cdc42 levels. Furthermore, we identify the actin regulator cofilin as a key regulator of dendritic complexity in vivo. Cofilin activation during late cortical development depends on NOMA-GAP expression and subsequent inhibition of Cdc42. Strikingly, in utero expression of active cofilin is sufficient to restore postnatal dendritic complexity in NOMA-GAP-deficient animals. Our findings define a novel cell-intrinsic mechanism to regulate dendritic branching and thus neuronal complexity in the cerebral cortex. PMID- 22810625 TI - The Y factor in the cardiac syndrome X. PMID- 22810623 TI - Chromosome end protection by blunt-ended telomeres. AB - Single-stranded telomeric DNA protrusions are considered to be evolutionarily conserved structural elements essential for chromosome end protection. Their formation at telomeres replicated by the leading strand mechanism is thought to involve poorly understood post-replicative processing of blunt ends. Unexpectedly, we found that angiosperm plants contain blunt-ended and short (1- to 3-nucleotide) G-overhang-containing telomeres that are stably retained in post mitotic tissues, revealing a novel mechanism of chromosome end protection. The integrity of blunt-ended telomeres depends on the Ku70/80 heterodimer but not on another telomere capping protein, STN1. Curiously, Ku-depleted telomeres are fully functional. They are resected by exonuclease 1, promoting intrachromatid recombination, which may facilitate formation of an alternative capping structure. These data challenge the view that telomeres require ssDNA protrusions for forming a functional capping structure and demonstrate flexibility in solutions to the chromosome end protection problem. PMID- 22810624 TI - Transcription initiation by human RNA polymerase II visualized at single-molecule resolution. AB - Forty years of classical biochemical analysis have identified the molecular players involved in initiation of transcription by eukaryotic RNA polymerase II (Pol II) and largely assigned their functions. However, a dynamic picture of Pol II transcription initiation and an understanding of the mechanisms of its regulation have remained elusive due in part to inherent limitations of conventional ensemble biochemistry. Here we have begun to dissect promoter specific transcription initiation directed by a reconstituted human Pol II system at single-molecule resolution using fluorescence video-microscopy. We detected several stochastic rounds of human Pol II transcription from individual DNA templates, observed attenuation of transcription by promoter mutations, observed enhancement of transcription by activator Sp1, and correlated the transcription signals with real-time interactions of holo-TFIID molecules at individual DNA templates. This integrated single-molecule methodology should be applicable to studying other complex biological processes. PMID- 22810626 TI - Determination of soil erosion risk in the Mustafakemalpasa River Basin, Turkey, using the revised universal soil loss equation, geographic information system, and remote sensing. AB - Sediment transport from steep slopes and agricultural lands into the Uluabat Lake (a RAMSAR site) by the Mustafakemalpasa (MKP) River is a serious problem within the river basin. Predictive erosion models are useful tools for evaluating soil erosion and establishing soil erosion management plans. The Revised Universal Soil Loss Equation (RUSLE) function is a commonly used erosion model for this purpose in Turkey and the rest of the world. This research integrates the RUSLE within a geographic information system environment to investigate the spatial distribution of annual soil loss potential in the MKP River Basin. The rainfall erosivity factor was developed from local annual precipitation data using a modified Fournier index: The topographic factor was developed from a digital elevation model; the K factor was determined from a combination of the soil map and the geological map; and the land cover factor was generated from Landsat-7 Enhanced Thematic Mapper (ETM) images. According to the model, the total soil loss potential of the MKP River Basin from erosion by water was 11,296,063 Mg year(-1) with an average soil loss of 11.2 Mg year(-1). The RUSLE produces only local erosion values and cannot be used to estimate the sediment yield for a watershed. To estimate the sediment yield, sediment-delivery ratio equations were used and compared with the sediment-monitoring reports of the Dolluk stream gauging station on the MKP River, which collected data for >41 years (1964-2005). This station observes the overall efficiency of the sediment yield coming from the Orhaneli and Emet Rivers. The measured sediment in the Emet and Orhaneli sub basins is 1,082,010 Mg year(-1) and was estimated to be 1,640,947 Mg year(-1) for the same two sub-basins. The measured sediment yield of the gauge station is 127.6 Mg km(-2) year(-1) but was estimated to be 170.2 Mg km(-2) year(-1). The close match between the sediment amounts estimated using the RUSLE-geographic information system (GIS) combination and the measured values from the Dolluk sediment gauge station shows that the potential soil erosion risk of the MKP River Basin can be estimated correctly and reliably using the RUSLE function generated in a GIS environment. PMID- 22810627 TI - Local and national advocacy support. AB - Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient's experience and circumstance and greater awareness of product choice. Advocacy by physicians on these issues at the local level is needed, as are national efforts by organizations such as the American Academy of Allergy, Asthma & Immunology and their regional societies. PMID- 22810629 TI - [The modern view of toxico-allergic manifestations of chronic tonsillar pathology, its etiological and pathological role in the evolvement and development of general diseases]. AB - The objective of the present study was to analyse etiological and pathogenetic mechanisms underlying the development of toxico-allergic manifestations in the patients presenting with chronic tonsillitis. The overview of the publications in the Russian and foreign literature provided materials for substantiating the expediency of the treatment of various forms of chronic tonsillitis on an individual basis. The necessity of further studies of toxico-allergic manifestations of chronic tonsillitis and the use of the active surgical strategies for the management of toxico-allergic forms of the disease is emphasized. PMID- 22810628 TI - A lateral flow biosensor for detection of single nucleotide polymorphism by circular strand displacement reaction. AB - A lateral flow biosensor for detection of single nucleotide polymorphism based on circular strand displacement reaction (CSDPR) has been developed. Taking advantage of high fidelity of T4 DNA ligase, signal amplification by CSDPR, and the optical properties of gold nanoparticles, this assay has reached a detection limit of 0.01 fM. PMID- 22810630 TI - [Peculiarities of the surgical treatment of nasal septum perforations]. AB - The objective of the present study was the retrospective analysis of the results of nasal septum perforation (NSP) surgery. We report our experience with the operations on the perforated nasal septum based on the treatment of a total of 84 patients. Plastic repair of the perforated nasal septum was undertaken in 54 of them. The endonasal approach with the use of local tissue flaps was employed in 47 cases. Additional bucco-gingival flaps were used in another 4 patients and the open rhinoplastic approach in 3 cases. The complete closure of nasal septum perforations was achieved in 34 (63%) patients. The reduction of the size of perforations was documented in 17 (31%) patients whereas in the remaining three the perforation size slightly increased. The surgical technique and peculiarities of the postoperative management of the patients are described; the possible causes of NSP relapses following surgery are discussed. PMID- 22810631 TI - [The potential of multislice computed tomography for the detection of specific anatomic and topographic features of the facial nerve canal prior to stapedoplasty]. AB - The objective of the present study was to estimate the potential of multislice computed tomography (MSCT) for the detection of specific anatomic and topographic features in the structure of the middle ear and the oval window region prior to stapedoplasty. We analysed the results of MSCT of the temporal bones in 20 patients presenting with otosclerosis (40 observations). All these patients underwent stapedoplasty, and the intraoperative findings were compared with the MSCT data. Specificity and sensitivity of MSCT for the detection of structural abnormalities in the middle ear were estimated at 91.3% and 84.6% respectively. It is concluded that the preoperative MSCT examination of the temporal bones yields the data that allow for the more accurate planning of the succeeding surgical intervention as well as for choosing its optimal strategy and extent, proper instruments, the type and length of the implant (prosthesis), and thereby for avoiding the possible complications and improving the prognosis of the treatment. PMID- 22810632 TI - [The state of the stirrup prosthesis estimated from the results of functional multispiral computed tomography]. AB - The objective of the present study was to estimate the state of the stirrup prosthesis based on the results of functional multispiral computed tomography (fMSCT). A total of 30 patients suffering otosclerosis and treated by stapedoplasty were examined using the modified fMSCT technique developed by the authors. The data obtained were compared with the results of the audiologic study. It was shown that modified fMSCT makes it possible to objectively and visually estimate the state of the stirrup prosthesis, elucidate the causes of poor outcome of the surgical treatment and identify the indications for the second operation. The study has demonstrated that a more pronounced decrease of the air-bone gap (ABG) is associated with a rise in the amplitude of prosthesis movements whereas the degree of reduction of bone conduction does not significantly correlate with the depth to which the prosthesis reaches into the vestibulim. PMID- 22810633 TI - [The assessment of the state of the immune system in the patients presenting with bronchial asthma and concomitant diseases of the nasal cavity and paranasal sinuses]. AB - The objective of the present investigation was to study the influence of diseases of the nasal cavity (NC) and paranasal sinuses (PNS) concomitant with bronchial asthma (BA) on the development of peculiar features of the patients' immune status. Phenotypic characteristics of the main lymphocyte subpopulations from peripheral blood of 101 patients were obtained by means of flow cytometry with the use of fluorescein isocyanate- or phycoerythrin-labeled monoclonal antibodies. Special emphasis was laid on the elucidation of characteristics of humoral and cell-mediated immunity in the patients presenting with BA and concomitant NC and PNS diseases and their comparison with the respective parameters in the patients with isolated lesions in the upper respiratory tract (allergic rhinitis and polypous rhinosinusitis) and lower respiratory tract (bronchial asthma). It was shown that the patients with concurrent lesions of the upper and lower respiratory tracts experience marked intensification of the immune reactions in the form of the elevated number of activated B-lymphocytes (CD23+), serum IgE level, and peripheral eosinophil count. PMID- 22810634 TI - [The influence of the surgical and medicamental treatment on the olfactory function in the patients presenting with polypous rhinosinusitis]. AB - The objective of the present investigation was to study dynamics of the olfactory function in the patients presenting with polypous rhinosinusitis receiving medicamental therapy and in different periods after the surgical intervention. A total of 40 patients were available for the examination in the "Sniffin Sticks" test. The patients of group 1 (n=20) were treated with intramuscular injections of dexamethasone (8 mg twice daily) with gradual tapering the dose during 10 days. The patients comprising group 2 underwent bilateral endoscopic polysinusotomy. Both treatment modalities were followed by momethasone fuorate therapy 6 months in duration. Examination of the patients on the first control visit (i.e. within 1 month after the onset of the treatment) revealed the significant improvement of all measured olfactory parameters that were not significantly different between the two groups. On the second control visit (within 4 months after the onset of the treatment), the patients of group 1 showed a significantly impaired ability to identify smells although other olfactory parameters remained virtually unaltered as compared with those on the first visit. At the same time, no significant impairment of the olfactory function was apparent in the patients of group 2. It is concluded that the patients having non-obstructive polyps in the nasal cavity should be advised in the first place to undergo a course of glucocorticosteroid therapy rather than surgical treatment because the results of conservative therapy and endoscopic polysinusotomy do not differ significantly, at least within the first 4 months after the beginning of the treatment. PMID- 22810635 TI - [On the classification of vascular structures in children]. AB - Vascular structures are a common childhood pathology that may cause not only the development of extensive cosmetic defects but also functional disorders of respiration, swallowing, vision, and hearing. These conditions not infrequently lead to severe disability and sometimes have a fatal outcome. The choice of the treatment modality depends on the type of the so-called "hemangiomas", the classification of these tumours remaining poorly developed. Our experience with the treatment of the children with these vascular structures (including those of "critical" localization) enabled us to propose a classification of vascular lesions according to which all vascular structures are subdivided into vascular hyperplasias, vascular malformations, and vascular tumour-like structures (both benign and malignant). It is believed that the rational use of this classification may be helpful for the choice of the adequate treatment strategies. PMID- 22810636 TI - [Our experience with the application of collagen-based preparations in reconstructive surgery of the middle ear]. AB - This paper summarizes our experience with the application of collagen-based preparations for reconstructive surgery of the middle ear. The best morphological results (88.46%) were obtained by the closure of extensive defects with the Oblecolum membrane as a temporary supporting structure and the outer atraumatic dressing for the tympanic transplant (in 30 patients) or by the use of the compact-porous explants from the "Sanguicol" preparation as an overlay on the transplant (in 22 patients). Twenty seven patients presenting with the so-called "operated ear disease" underwent mastoidoplasty with the use of the compact porous preparation "Stimul-oss" as a supporting structure to induce the ingrowth of the bone tissue and the subsequent substitution of the defect. This treatment ensured the reduction of the volume of the bony trepanation cavity. In addition, we have obtained preliminary encouraging results of the application of collagene preparations for the surgical intervention on the stirrup in the patients suffering otosclerosis. PMID- 22810637 TI - [The estimation of the efficacy of manual therapy included in the combined treatment of cochlear-vestibular disorders based on the results of computed stabilography]. AB - The objective of the present study was to estimate the efficacy of the combined treatment of spondylogenic cochlear-vestibular disorders with the use of both medicamental and non-medicamental modalities. Computed static stabilometry was applied for diagnostics of postural disbalance and evaluation of the treatment outcomes. It was shown that the application of manual therapy for the management of 56 patients presenting with spondylogenic cochlear-vestibular disorders resulted in the decrease of tinnitus and the improvement of vestibular and cochlear functions. PMID- 22810638 TI - [A new technique for local immunotherapy of allergic rhinosinusitis--intranasal aerosol therapy with the use of a cycloferon solution]. AB - The objective of this study was to estimate the clinical and immunological efficacy of local immunotherapy with the use of a cycloferon solution. The authors describe a new highly efficacious method for the treatment of allergic rhinosinusitis by means of the intranasal introduction of the cycloferon aerosol (125 mg/ml). A total of 79 patients presenting with this pathology were included in the study. Comparative evaluation of clinical and immunological efficiency of intranasal aerosol therapy using the cycloferon solution and its standard parenteral administration has demonstrated the high efficiency and safety of intranasal aerosol therapy in a group of immunocompromised patients with allergic rhinosinusitis. The study revealed correlation between clinical symptoms and characteristics of the patients' cytokine status which suggests the high informative value of measuring principle cytokine levels and especially their local fractions. PMID- 22810639 TI - [The experience with the supervision and treatment of the patients presenting with external otitis]. AB - This clinical study was designed to estimate the efficacy and tolerability of the locally applied Pimafucort preparation for the treatment of diffuse otitis of bacterial and mycotic origin. The results of dynamic bacteriological investigation in conjunction with clinical observations give reason to recommend the local therapy as the sole treatment of uncomplicated forms of diffuse external otitis. PMID- 22810640 TI - [The importance of the pharmaceutical form and the routes of administration of B group vitamins for the efficacious treatment of neurosensorial hearing loss]. AB - The objective of the present comparative study was to estimate the efficacy of the treatment of neurosensorial hearing loss (NSHL) with the use of milgamma, milgamma compositum, and vitamins B1 and B2 monotherapy. The best results were obtained after the treatment with milgamma and milgamma compositum. It is concluded that the use of these preparations for the combined treatment of neurosensorial hearing loss is pathogenetically justified since it permits to achieve the improvement of the functional state of the cochleovestibular nerve and the enhancement of patient compliance; moreover, it reduces the work load on the medical personnel. PMID- 22810641 TI - [Experience with the use of IRS-19 for the rehabilitation of children after acute respiratory infections]. AB - The purpose of this work was to evaluate the efficacy of the prevention of recurrent respiratory infections with the use of the immunomodulatory respiratory spray (IRS-19). The study involved 60 children at the age from 4 to 7 years allocated to three groups. Group 1 was comprised of 20 children treated by two daily irrigation of nasal sinuses with a seawater solution. Group 2 included 20 children treated by irrigation of nasal sinuses with IRS-19 twice daily during 2 weeks.. Group 3 consisted of 20 children treated by irrigation of nasal sinuses with a saline solution and topical immunostimulator IRS-19 twice daily. It was shown that therapy with IRS-19 resulted in a more than two-fold reduction in the frequency of relapses of the acute respiratory infections as compared with control. PMID- 22810642 TI - [The role of mucolytic therapy in the treatment of sinobronchial syndrome]. AB - The objective of the present study was to estimate the therapeutic efficacy and safety of myrtol standardized (gelomyrtol forte) and acetylcysteine given to 11 and 13 patients respectively presenting with sinobronchial syndrome. Dynamics of clinical and roentgenological signs and symptoms in these patients was investigated throughout the period of therapy. The best clinical results were obtained using myrtol standardized. Specifically, the summary score characterizing the change of clinical symptoms decreased from the initial value of 32 to 0.73 on the 7th day after the initiation of therapy and to 0.18 after its termination. The decrease of the same parameter in the group of the patients treated with acetylcysteine to 1.3 and 0.38 (mean score for the group) was documented on days 7 and 10 after the beginning of therapy respectively. PMID- 22810644 TI - [A case of congenital (juvenile) otosclerosis]. AB - The present paper reports a case of congenital (juvenile) otosclerosis. This pathology is known to occur in 10% of the patients and cause severe hearing impairment. Precise diagnostics of the activity and extent of the otosclerotic process based on the results of functional multispiral computed tomography (MSCT) enables the practicing surgeons to identify indications for the surgical intervention, choose the adequate method and time for its performance, and make prognosis of its outcome. This inference is confirmed by the clinical observation described in this communication. PMID- 22810643 TI - [The experience with the topical application of non-steroidal anti-inflammatory agents for the treatment of otitis media]. AB - The objective of the present study was to estimate the therapeutic efficacy and safety of the topically applied otinum ear drops. The authors present the results of the combined treatment of acute catarrhal otitis in the children with the use of choline salicilate (otinum). The study included 50 patients randomized into two identical groups. The children of group 1 received systemic therapy supplemented by the topical application of otinum, those in group 2 were prescribed a 3% alcoholic solution of boric acid. The study has demonstrated a significantly more pronounced positive dynamics of clinical conditions in the patients of group 1 compared with those of the control group. The total duration of therapy in the first group was 37.5% shorter than in the second. The results of the study confirmed the strong anti-inflammatory and analgesic action of choline salicilate. The pain was relieved within 7 minutes on the average after the application of this agent. It is concluded that otinum can be recommended for the introduction into combined therapy of acute catarrhal otitis media as an efficacious anti-inflammatory and analgetic drug. PMID- 22810645 TI - [A case of successful surgical treatment of labyrinth fistula in the sole hearing ear]. AB - The objective of this communication is to demonstrate success of the surgical intervention on the sole hearing ear in the presence of absolute indications for such treatment, viz. the presence of cholesteatoma and labyrinth fistula (LF). The sensorineural loss of hearing is a rather common serious complication of LF surgery in the patients with cholesteatoma. The present observation concerns a 41 year-old woman with the history of an episode of suppurative otitis media experienced in the childhood. After a period of prolonged remission, she suffered systemic dizziness despite the intact tympanic membranes. The patient was examined with the use of multispiral computed tomography (MSCT) that revealed serious lesions in the middle ear (labyrinth fistula). It made possible careful planning and performing sanation surgery on the middle ear including tympano- and mastoidoplasty. This treatment produced good morphological and functional result. PMID- 22810646 TI - [A rare case of nasal hemorrhage from the internal carotid artery aneurism]. AB - The objective of this paper is to report a rare clinical case of persistently recurring nasal hemorrhage. Reccurent nasal hemorrhage in the examined patient was associated with the presence of the false internal carotid artery aneurism. This condition was diagnosed and managed with the use of the angiographic technique in conjunction with subsequent selective endovascular embolization of the affected vessels that made it possible to purposefully block the source of hemorrhage. Angiography and selective endovascular embolization provide the sole reliable method for diagnostics and arrest of nasal hemorrhage as is confirmed by the present clinical observation. PMID- 22810647 TI - [The use of functional multispiral computed tomography for differential diagnostics of otosclerosis and congenital malformation of the internal and middle ear (a case report)]. AB - This paper reports a rare clinical observation of congenital malformation of the internal and middle ear diagnosed with the help of functional multispiral computed tomography (fMSCT). The patient presenting with conductive hearing loss was suspected to have otosclerosis. However, the use of fMSCT made it possible to arrive at a more precise diagnosis, that is congenital malformation of the internal and middle ear that clinically manifested itself as the conductive loss of hearing. It was decided to refrain from the surgical intervention: first, because its efficacy in this case was considered to be doubtful and second, it was fraught with the high risk of development of postoperative complications. PMID- 22810648 TI - Neuroprotective properties of aucubin in diabetic rats and diabetic encephalopathy rats. AB - In this study, we determined the neuroprotective effect of aucubin on diabetes and diabetic encephalopathy. With the exception of the control group, all rats received intraperitoneal injections of streptozotocin (STZ; 60 mg/kg) to induce type 1 diabetes mellitus (DM). Aucubin (1, 5, 10 mg/kg ip) was used after induction of DM (immediately) and diabetic encephalopathy (65 days after the induction of diabetes). The diabetic encephalopathy treatment groups were divided into short-term and long-term treatment groups. Treatment responses to all parameters were examined (body weight, plasma glucose, Y-maze error rates and proportion of apoptotic cells). In diabetic rats, aucubin controlled blood glucose levels effectively, prevented complications, and improved the quality of life of diabetic rats. In diabetic encephalopathy, aucubin significantly rescued neurons in the hippocampal CA1 subfield and reduced working errors during behavioral testing. The significant neuroprotective effect of aucubin could be seen not only in the short term (15 days) but also in the long term (45 days), which was a highly encouraging finding. These data suggest that aucubin may be a potential neuroprotective agent. PMID- 22810649 TI - MTHFR polymorphisms and ovarian cancer risk: a meta-analysis. AB - The C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been reported to alter the risk of ovarian cancer. However, the results are still inconclusive. For better understanding of the effect of these two polymorphisms on ovarian cancer risk, a meta-analysis was performed. An extensive search was performed to identify all case-control studies investigating such association. The strength of association between these two polymorphisms and ovarian cancer risk was assessed by odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI). 3,496 cases and 3,631 controls for C677T polymorphism and 3,280 cases and 3,346 controls for A1298C polymorphism were included in this meta-analysis. The results suggested that there were no significant associations between C677T and A1298C polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (For C677T: TT vs. CC: OR = 0.94, 95 % CI = 0.71-1.24, P = 0.65; CT vs. CC: OR = 1.03, 95 % CI = 0.93 1.14, P = 0.57; TT/CT vs. CC: OR = 1.01, 95 % CI = 0.88-1.16, P = 0.87; TT vs. CC/CT: OR = 0.93, 95 % CI = 0.72-1.20, P = 0.58. For A1298C: CC vs. AA: OR = 1.05, 95 % CI = 0.88-1.25, P = 0.65; CA vs. AA: OR = 0.98, 95 % CI = 0.88-1.08, P = 0.66; CC/CA vs. AA: OR = 0.99, 95 % CI = 0.90-1.09, P = 0.85; CC vs. AA/CA: OR = 1.06, 95 % CI = 0.90-1.26, P = 0.46). Subgroup analysis based on ethnicities and influence analysis did not perturb the results. In conclusion, the results of this meta-analysis indicate that the MTHFR C677T and A1298C polymorphisms are not associated with ovarian cancer risk, especially in Caucasians. PMID- 22810650 TI - The binding characteristics of the interaction between 3-(2-cyanoethyl) cytosine and human serum albumin. AB - The binding characteristics of the interaction between 3-(2-cyanoethyl) cytosine (CECT) and human serum albumin (HSA) were investigated using fluorescence, UV absorption spectroscopic and molecular modeling techniques under simulative physiological conditions. The intrinsic fluorescence intensity of HSA was decreased with the addition of CECT. The fluorescence data handled by Stern Volmer equation proved that the quenching mechanism of the interaction between CECT and HSA was a static quenching procedure. The binding constants evaluated utilizing the Lineweaver-Burk equation at 17, 27 and 37 degrees C, were 2.340 * 10(4), 2.093 * 10(4) and 1.899 * 10(4) L mol(-1), respectively. The thermodynamic parameters were calculated according to van't Hoff equations. Negative enthalpy (DeltaH) and positive entropy (DeltaS) values indicated that both hydrogen bond and hydrophobic force played a major role in the binding process of CECT to HSA, which was consistent with the results of the molecular modeling study. In addition, the effect of other ions on the binding constant of CECT-HSA was examined. PMID- 22810651 TI - TNFAIP1 interacts with KCTD10 to promote the degradation of KCTD10 proteins and inhibit the transcriptional activities of NF-kappaB and AP-1. AB - The broad-complex, tramtrack, and bric-a-brac/poxvirus and zinc finger domain containing protein tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) was first identified as a gene whose expression can be induced by the tumor necrosis factor alpha. Some studies showed that TNFAIP1 may function in DNA replication, apoptosis and human diseases. However, the definite functions and the mechanisms of TNFAIP1 are poorly known. In this study, we performed a yeast two-hybrid assay and used TNFAIP1 as the bait to screen human brain cDNA library. Potassium channel tetramerisation domain containing 10 (KCTD10) was identified as TNFAIP1 interacting partner. The KCTD10-TNFAIP1 interaction was then confirmed by the in vitro GST pull-down assays and the in vivo co-immunoprecipitation and colocalization assays. In addition, protein degradation and ubiquitin assays revealed TNFAIP1 overexpression resulted in ubiquitin-mediated degradation of KCTD10 proteins, which was significantly alleviated with the proteasome inhibitor MG132 treatment. Furthermore, transient transfection assays with two reporters showed that TNFAIP1 and KCTD10 inhibited the transcriptional activities of nuclear factor kappa B (NF-kappaB) and activating protein-1 reporters. Taken together, our results indicated the novel interaction and function between KCTD10 and TNFAIP1 in human PDIP1 family. PMID- 22810652 TI - Crystal structure and chemical bonding of the intermetallic Zintl phase Yb11AlSb9. AB - High resolution single crystal synchrotron X-ray diffraction data measured at 15(2) K were used to solve the structure of the complex intermetallic Zintl phase, Yb(11)AlSb(9) (space group Iba2), made up of Yb cations and polyanions along with isolated Sb anions. The 15(2) K cell parameters are a = 11.7383(4) A, b = 12.3600(4) A, c = 16.6796(6) A. The temperature dependence of the structure was investigated through high resolution synchrotron powder X-ray diffraction (PXRD) data measured from 90 K to 1000 K. Rietveld refinements of the crystal structure revealed near linear thermal expansion of Yb(11)AlSb(9) with expansion coefficients of 1.49(2) * 10(-5) K(-1), 1.71(3) * 10(-5) K(-1), 1.13(1) * 10(-5) K(-1) for a, b and c, respectively. The chemical bonding in Yb(11)AlSb(9) was analyzed using atomic Hirshfeld surfaces, and the analysis supports the presence of the structural elements of Yb cations, [AlSb(4)](9-) tetrahedra, [Sb(2)](4-) dimers and isolated Sb(3-) anions. However, indications of interatomic interactions between the Zintl anions and the Yb cations were also observed. PMID- 22810653 TI - Death of evidence. PMID- 22810654 TI - A different agenda. PMID- 22810655 TI - London calling. PMID- 22810656 TI - Wildfires ignite debate on global warming. PMID- 22810667 TI - The legacy of Lonesome George. PMID- 22810668 TI - Theorists feast on Higgs data. PMID- 22810669 TI - Gene data to hit milestone. PMID- 22810670 TI - Wary approval for drug to prevent HIV. PMID- 22810671 TI - Cosmic survey finds global appeal. PMID- 22810672 TI - Europe joins UK open-access bid. PMID- 22810674 TI - Florida abuzz over mosquito plan. PMID- 22810675 TI - Performance enhancement: Superhuman athletes. PMID- 22810676 TI - Science at the Olympics: Team science. PMID- 22810677 TI - Public health: Towards a cure for HIV. PMID- 22810678 TI - Olympics: Run for your life. PMID- 22810679 TI - Olympics: Genetically enhanced Olympics are coming. PMID- 22810684 TI - Sanitation: Sewage recycles antibiotic resistance. PMID- 22810685 TI - Open science: Data sharing is harder to reward. PMID- 22810686 TI - Open access: A green light for archiving. PMID- 22810687 TI - Environment: Costa Rica pioneers ecosystem services. PMID- 22810689 TI - Open access: Let's go for gold. PMID- 22810690 TI - Prenatal diagnostics: Fetal genes in mother's blood. PMID- 22810691 TI - Biogeochemistry: The great iron dump. PMID- 22810692 TI - Cardiology: Bad matters made worse. PMID- 22810693 TI - Chemical biology: Greasy tags for protein removal. PMID- 22810694 TI - Nuclear physics: Nucleons come together. PMID- 22810695 TI - Deep carbon export from a Southern Ocean iron-fertilized diatom bloom. AB - Fertilization of the ocean by adding iron compounds has induced diatom-dominated phytoplankton blooms accompanied by considerable carbon dioxide drawdown in the ocean surface layer. However, because the fate of bloom biomass could not be adequately resolved in these experiments, the timescales of carbon sequestration from the atmosphere are uncertain. Here we report the results of a five-week experiment carried out in the closed core of a vertically coherent, mesoscale eddy of the Antarctic Circumpolar Current, during which we tracked sinking particles from the surface to the deep-sea floor. A large diatom bloom peaked in the fourth week after fertilization. This was followed by mass mortality of several diatom species that formed rapidly sinking, mucilaginous aggregates of entangled cells and chains. Taken together, multiple lines of evidence-although each with important uncertainties-lead us to conclude that at least half the bloom biomass sank far below a depth of 1,000 metres and that a substantial portion is likely to have reached the sea floor. Thus, iron-fertilized diatom blooms may sequester carbon for timescales of centuries in ocean bottom water and for longer in the sediments. PMID- 22810697 TI - High velocity dispersion in a rare grand-design spiral galaxy at redshift z = 2.18. AB - Although grand-design spiral galaxies are relatively common in the local Universe, only one has been spectroscopically confirmed to lie at redshift z > 2 (HDFX 28; z = 2.011); and it may prove to be a major merger that simply resembles a spiral in projection. The rarity of spirals has been explained as a result of disks being dynamically 'hot' at z > 2 (refs 2-5), which may instead favour the formation of commonly observed clumpy structures. Alternatively, current instrumentation may simply not be sensitive enough to detect spiral structures comparable to those in the modern Universe. At z < 2, the velocity dispersion of disks decreases, and spiral galaxies are more numerous by z ~ 1 (refs 7, 13-15). Here we report observations of the grand-design spiral galaxy Q2343-BX442 at z = 2.18. Spectroscopy of ionized gas shows that the disk is dynamically hot, implying an uncertain origin for the spiral structure. The kinematics of the galaxy are consistent with a thick disk undergoing a minor merger, which can drive the formation of short-lived spiral structure. A duty cycle of <100 Myr for such tidally induced spiral structure in a hot massive disk is consistent with its rarity. PMID- 22810698 TI - How atomic nuclei cluster. AB - Nucleonic matter displays a quantum-liquid structure, but in some cases finite nuclei behave like molecules composed of clusters of protons and neutrons. Clustering is a recurrent feature in light nuclei, from beryllium to nickel. Cluster structures are typically observed as excited states close to the corresponding decay threshold; the origin of this phenomenon lies in the effective nuclear interaction, but the detailed mechanism of clustering in nuclei has not yet been fully understood. Here we use the theoretical framework of energy-density functionals, encompassing both cluster and quantum liquid-drop aspects of nuclei, to show that conditions for cluster formation can in part be traced back to the depth of the confining nuclear potential. For the illustrative example of neon-20, we show that the depth of the potential determines the energy spacings between single-nucleon orbitals in deformed nuclei, the localization of the corresponding wavefunctions and, therefore, the degree of nucleonic density clustering. Relativistic functionals, in particular, are characterized by deep single-nucleon potentials. When compared to non-relativistic functionals that yield similar ground-state properties (binding energy, deformation, radii), they predict the occurrence of much more pronounced cluster structures. More generally, clustering is considered as a transitional phenomenon between crystalline and quantum-liquid phases of fermionic systems. PMID- 22810699 TI - Dodecagonal tiling in mesoporous silica. AB - Recent advances in the fabrication of quasicrystals in soft matter systems have increased the length scales for quasicrystals into the mesoscale range (20 to 500 angstroms). Thus far, dendritic liquid crystals, ABC-star polymers, colloids and inorganic nanoparticles have been reported to yield quasicrystals. These quasicrystals offer larger length scales than intermetallic quasicrystals (a few angstroms), thus potentially leading to optical applications through the realization of a complete photonic bandgap induced via multiple scattering of light waves in virtually all directions. However, the materials remain far from structurally ideal, in contrast to their intermetallic counterparts, and fine control over the structure through a self-organization process has yet to be attained. Here we use the well-established self-assembly of surfactant micelles to produce a new class of mesoporous silicas, which exhibit 12-fold (dodecagonal) symmetry in both electron diffraction and morphology. Each particle reveals, in the 12-fold cross-section, an analogue of dodecagonal quasicrystals in the centre surrounded by 12 fans of crystalline domains in the peripheral part. The quasicrystallinity has been verified by selected-area electron diffraction and quantitative phason strain analyses on transmission electron microscope images obtained from the central region. We argue that the structure forms through a non equilibrium growth process, wherein the competition between different micellar configurations has a central role in tuning the structure. A simple theoretical model successfully reproduces the observed features and thus establishes a link between the formation process and the resulting structure. PMID- 22810700 TI - Solid-liquid iron partitioning in Earth's deep mantle. AB - Melting processes in the deep mantle have important implications for the origin of the deep-derived plumes believed to feed hotspot volcanoes such as those in Hawaii. They also provide insight into how the mantle has evolved, geochemically and dynamically, since the formation of Earth. Melt production in the shallow mantle is quite well understood, but deeper melting near the core-mantle boundary remains controversial. Modelling the dynamic behaviour of deep, partially molten mantle requires knowledge of the density contrast between solid and melt fractions. Although both positive and negative melt buoyancies can produce major chemical segregation between different geochemical reservoirs, each type of buoyancy yields drastically different geodynamical models. Ascent or descent of liquids in a partially molten deep mantle should contribute to surface volcanism or production of a deep magma ocean, respectively. We investigated phase relations in a partially molten chondritic-type material under deep-mantle conditions. Here we show that the iron partition coefficient between aluminium bearing (Mg,Fe)SiO(3) perovskite and liquid is between 0.45 and 0.6, so iron is not as incompatible with deep-mantle minerals as has been reported previously. Calculated solid and melt density contrasts suggest that melt generated at the core-mantle boundary should be buoyant, and hence should segregate upwards. In the framework of the magma oceans induced by large meteoritic impacts on early Earth, our results imply that the magma crystallization should push the liquids towards the surface and form a deep solid residue depleted in incompatible elements. PMID- 22810702 TI - Spinal subdural hematoma as a complication of spinal surgery: can it happen without dural tear? AB - Post spinal surgery subdural hematoma is a rare entity. This is a report of a case of acute post-operative spinal subdural hematoma, without any dural injury. The case was managed expectantly and went on to complete resolution of the hematoma and full clinical recovery. PMID- 22810703 TI - Reviewer's comment concerning "the management of vertebral artery injury in anterior cervical spine operation: a systematic review of published cases" (DOI:10.1007/s00586-012-2423-8 by Hyung-Ki Park and Hae-Dong Jho). PMID- 22810704 TI - Discrepancies between patients and physicians in their perceptions of rheumatoid arthritis disease activity. AB - OBJECTIVE: Patients and physicians often differ in their perceptions of rheumatoid arthritis (RA) disease activity, as quantified by the patient's global assessment (PGA) and by the evaluator's global assessment (EGA). The purpose of this study was to explore the extent and reasons for this discordance. METHODS: We identified variance components for the PGA and EGA in RA patients who were starting therapy with methotrexate in an academic outpatient setting. We analyzed predictors of the observed discrepancy in these measures (calculated as the PGA minus the EGA) and in their changes (calculated as the PGA(change) minus the EGA(change) ). RESULTS: We identified 646 RA patients, and among them, 77.4% of the variability in the PGA and 66.7% of the variability in the EGA were explainable. The main determinants for the PGA were pain (75.6%), function (1.3%, by Health Assessment Questionnaire), and number of swollen joints (0.5%); those for the EGA were the number of swollen joints (60.9%), pain (4.5%), function (0.6%), C-reactive protein (0.4%), and the number of tender joints (0.3%). Increased pain led to a discrepancy toward worse patient perception, while increased numbers of swollen joints led to a discrepancy toward worse evaluator perception, both explaining 65% of the discordance between the PGA and the EGA. Likewise, changes in pain scores and numbers of swollen joints proved to be the main determinants for discrepant perceptions of changes in RA disease activity, explaining 34.6% and 12.5% of the discordance, respectively. CONCLUSION: The most significant determinants for the cross-sectional and longitudinal discrepancy between the PGA and the EGA are pain and joint swelling, respectively. Understanding the reasons for a discordant view of disease activity will help to facilitate the sharing of decision-making in the management of RA. PMID- 22810706 TI - [Differentiation of cystic pancreas lesions by magnetic resonance diffusion imaging]. PMID- 22810707 TI - Faculty. PMID- 22810709 TI - Mission and scope. PMID- 22810705 TI - [Ultrasound diagnostics of diffuse liver diseases]. AB - The current improvements in modern high resolution ultrasound technology, like Tissue Harmonic Imaging (THI), Speckle Reduction Imaging (SRI), partial color coding of B-mode (Color Coded Imaging), and also the advent of ultrasound based elastography as well as contrast-enhanced ultrasound (CEUS) offer fundamentally new ways to characterize diffuse alterations of the liver parenchyma. Besides metabolic disease, disorders of liver fat distribution, infectious and malignant diseases can cause diffuse alterations of the liver parenchyma. In case of liver fibrosis, only a combination of different ultrasound techniques including CEUS, allows the differentiation between benign dysplastic and malignant lesions. Ultrasound elastography allows assessing the extent of the fibrosis. This article focuses on the different ultrasound based diagnostic possibilities in case of diffuse liver disease. PMID- 22810696 TI - Comprehensive molecular characterization of human colon and rectal cancer. AB - To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase epsilon (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. PMID- 22810710 TI - Editor'S preface. PMID- 22810711 TI - Mild traumatic brain injury update. AB - Traumatic brain injury (TBI) is a prevalent condition throughout the civilian and military populations. Although TBI can be classified as mild, moderate, or severe, most TBIs are considered mild. Understanding the pathophysiologic mechanism(s) of mild TBI through basic science and clinical cohort studies is an area of active research. While it is well understood that most people recover from a mild TBI with minimal treatment, some patients experience long-term consequences that require rehabilitation and specialized care. Common characteristics of brain injury include loss of consciousness (LOC), posttraumatic amnesia (PTA), and postconcussion syndrome (PCS). The development of LOC, PTA, and PCS greatly depends on the nature of the injury, and the degrees to which they develop are not necessarily consistent with symptom presentation. In recent years, sports concussions have become an area of increased research and public interest in the civilian population; similarly, blast TBI has gained attention in the military. Depending on the nature of the injury, different outcomes may result in the two populations. Consequently, treatments for mild TBI are rather diverse, and early intervention is the key to maximizing outcomes following a TBI. These topics and more will be discussed throughout this article. PMID- 22810712 TI - Diagnosis and management of traumatic brain injury. AB - This article will provide an overview of the initial evaluation and management of traumatic brain injury (TBI). In cases of mild injury, conventional imaging in the absence of focal neurologic deficits is generally unrevealing. In the case of moderate or severe TBI, a review of neurocritical care is provided. PMID- 22810713 TI - Sports concussion. AB - Concussion is an injury to the brain occurring as the result of biomechanical forces, generally characterized by the rapid onset of a constellation of symptoms or cognitive impairment, which is typically self-limited and resolves spontaneously. Concussion as the result of playing sports is particularly common, estimated to occur up to 3.8 million times each year in the United States. Although most concussions can be considered benign, the symptoms are often severe enough to interfere with daily function. A small percentage of concussions can be more serious, resulting in a prolonged symptom course, significant morbidity, or even death. The management of concussion in the athlete presents a unique set of challenges for the clinician, requiring not only a detailed neurologic history and examination, but also careful consideration of an athlete's risk of further injury and possible long-term sequelae. PMID- 22810714 TI - Posttraumatic headache. AB - Headache is a common symptom after traumatic head injury and is a frequent feature of the postconcussive syndrome. A variety of headache subtypes can be precipitated by head trauma, although posttraumatic headaches most often resemble migraine or tension-type headache. A lack of clinical trials limits evidence based treatment recommendations for both acute and chronic posttraumatic headaches. However, numerous pharmacologic and nonpharmacologic interventions can be used to successfully manage posttraumatic headaches. This article reviews the classification, epidemiology, prognosis, and pathophysiology of headaches after head trauma and provides a practical clinical approach for evaluating and treating patients with posttraumatic headaches. PMID- 22810715 TI - Memory impairment after mild traumatic brain injury. AB - Concerns of memory impairment are common after mild traumatic brain injury (mTBI). Acute effects after mTBI may include posttraumatic amnesia, which may last up to 24 hours. In the postacute phase, memory concerns are usually linked with increased distractibility; impaired attention, working memory, retrieval; and executive dysfunction. These acute and postacute impairments have distinct neuroanatomic and pathophysiologic correlates. Cognitive assessment should be undertaken during the acute phase after an mTBI using a standardized tool that can be administered quickly and is sensitive to cognitive impairment. Early validation of the patient's symptoms and concerns (especially the expectation of recovery), coupled with educational and emotional support after the mTBI, remains the core approach to treatment. The effects of comorbidities, recurrent mTBIs, and blast exposures in military personnel on protracted symptoms and long-term cognitive deficits will be discussed. PMID- 22810716 TI - Epilepsy, sleep disturbances, and psychiatric consequences. AB - Neurologic impairment after TBI causes serious morbidity for patients and their families. Prior articles have discussed headache and memory impairment. In this article, epilepsy, sleep disturbances, and psychiatric consequences will be covered. People who have suffered traumatic brain injury are at risk for any of these disturbances, and each person will have a constellation of neurologic symptoms spanning the spectrum from no difficulty in any area to symptoms in each of these areas. PMID- 22810717 TI - Rehabilitation in the patient with mild traumatic brain injury. AB - Traumatic brain injury (TBI) has garnered increased public attention in the past several years because of high-profile athletes with possible long-term effects of their injuries as well as large numbers of returning combat veterans injured by blast explosions. Most of these injuries are mild in nature and require no specific surgical treatment but may benefit from brief rehabilitation interventions. To appropriately rehabilitate patients with mild traumatic brain injury (mTBI), one must fully understand its clinical course and the factors that accelerate or delay recovery. Education is the centerpiece of mTBI treatment and should be included in the rehabilitation plan. When devising the rehabilitation plan, the neurologist should take into account the goals of the patient and establish a reasonable time frame for treatment paralleling the expected recovery course. Cognitive and vestibular functions are commonly affected after mTBI and are particularly responsive to rehabilitation interventions. Vocational rehabilitation and community reentry planning are aspects of the global rehabilitation plan that should not be neglected. Combat-injured veterans with mTBI present unique challenges to the rehabilitation team, and assessment of these patients often needs to include assessment of psychological function. PMID- 22810718 TI - Patient management problem. PMID- 22810719 TI - Ethical perspectives in neurology: sports-acquired traumatic brain injury. PMID- 22810720 TI - Practice issues in neurology: traumatic brain injury: enhancing our ability to improve communication with families. PMID- 22810722 TI - APPENDIX A: Practice Guidelines for Traumatic Brain Injury. PMID- 22810721 TI - Coding table. PMID- 22810723 TI - APPENDIX B a. PMID- 22810725 TI - Multiple-choice questions. PMID- 22810724 TI - APPENDIX C: Rancho Los Amigos Scale-Revised. PMID- 22810726 TI - Preferred responses. PMID- 22810728 TI - Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans. AB - Genetic differences in the dopamine and serotonin systems have been suggested as potential factors underlying interindividual variability in risk taking and in brain activation during the processing of feedback. Here, we studied the effects of dopaminergic (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT]) and serotonergic (serotonin transporter [5HTTLPR]) polymorphisms on risk taking and brain responses following feedback in 60 healthy female subjects. The subjects completed a well-established experimental gambling paradigm while an electroencephalogram was recorded. During the task, risk-taking behavior and prefrontal brain responses (feedback-related negativity [FRN]) following monetary gains and losses were assessed. FRN amplitudes were enhanced for nine-repeat-allele carriers of the DAT1 and short-allele carriers of 5HTTLPR, which are both presumably linked to less transporter activity and higher neurotransmitter levels. Moreover, nine-repeat DAT1 carriers displayed a trend toward increased risk taking in general, whereas 5HTTLPR short-allele carriers showed decreased risk taking following gains. COMT val158met genotype was unrelated to FRN amplitude and average risk taking. However, COMT met/met carriers showed a pronounced feedback P3 amplitude independent of valence, and a gradual increase in risk taking during the gambling task. In sum, the present findings underline the importance of genetic variability in the dopamine and serotonin systems regarding the neurophysiology of feedback processing. PMID- 22810729 TI - Late pseudocoarctation syndrome after stent-graft implantation for traumatic aortic rupture. AB - The present observation illustrates an unusual complication occurring after stent grafting (S-graft) for aortic isthmus rupture. A 22-year-old patient, treated by S-graft in the emergency department for traumatic aortic rupture, was readmitted 10 months later with pseudocoarctation syndrome. A membrane was found inside the stent-graft that had induced a pseudo-dissection, which caused the pseudocoarctation syndrome. Surgical treatment consisted of removing the stent graft and membrane and replacing it with a vascular implant. The patient's clinical course was fair. The suggested mechanism was circumferential neoendothelialization of the stent-graft. Dehiscence caused the superior part of the membrane to drop into the lumen of the stent-graft creating a "false channel" that compressed the "true lumen" and induced "pseudocoarctation" syndrome. The cause of the extensive neointimalization remains unexplained. Thoracic aortic stent-grafts require regular follow-up monitoring by angioscan or angio-magnetic resonance imaging. PMID- 22810733 TI - [Effect of social-economic factors on mental health indices in the population of the Russian Federation in 1992-2008: epidemiological models]. AB - Based on system, correlation and regression analyses of official medical and social/economic information over 1992-2008, we developed epidemiological models linking parameters of morbidity and incidence of mental disorders in the Russia Federation with main medical-demographic and social-economic factors. These models may be used for optimal planning of medical/social programs in the field of mental health protection, its operative monitoring and optimal planning of the structure and activity of the Russian system for psychiatric aid. PMID- 22810731 TI - Taurine and inflammatory diseases. AB - Taurine (2-aminoethanesulfonic acid) is the most abundant free amino acid in humans and plays an important role in several essential biological processes such as bile acid conjugation, maintenance of calcium homeostasis, osmoregulation and membrane stabilization. Moreover, attenuation of apoptosis and its antioxidant activity seem to be crucial for the cytoprotective effects of taurine. Although these properties are not tissue specific, taurine reaches particularly high concentrations in tissues exposed to elevated levels of oxidants (e.g., inflammatory cells). It suggests that taurine may play an important role in inflammation associated with oxidative stress. Indeed, at the site of inflammation, taurine is known to react with and detoxify hypochlorous acid generated by the neutrophil myeloperoxidase (MPO)-halide system. This reaction results in the formation of less toxic taurine chloramine (TauCl). Both haloamines, TauCl and taurine bromamine (TauBr), the product of taurine reaction with hypobromous acid (HOBr), exert antimicrobial and anti-inflammatory properties. In contrast to a well-documented regulatory role of taurine and taurine haloamines (TauCl, TauBr) in acute inflammation, their role in the pathogenesis of inflammatory diseases is not clear. This review summarizes our current knowledge concerning the role of taurine, TauCl and TauBr in the pathogenesis of inflammatory diseases initiated or propagated by MPO-derived oxidants. The aim of this paper is to show links between inflammation, neutrophils, MPO, oxidative stress and taurine. We will discuss the possible contribution of taurine and taurine haloamines to the pathogenesis of inflammatory diseases, especially in the best studied example of rheumatoid arthritis. PMID- 22810732 TI - The traits of five types of tongue movement in Han of Shaanxi, China. AB - The study sample consisting of 429 people (207 males, 222 females) of Han nationality in Shaanxi, China. Five types of tongue movements were investigated, including tongue rolling, tongue folding, tongue twisting, pointed tongue and clover-leaf tongue. The results revealed that the frequencies of tongue rolling, tongue folding, tongue twisting, pointed tongue and clover-leaf tongue were 63.6, 14.0, 12.6, 54.8 and 0 %, respectively. There were no significant gender differences except with pointed tongue. Compared with other nationalities, tongue rolling, tongue folding, and pointed tongue of Han in Shaanxi had an average frequency. Tongue twisting and clover-leaf tongue had low frequencies. There were significant differences in frequency of clover-leaf tongue between Han and another seven nationalities of China (P < 0.01). Furthermore, only three pairs of trait correlations were exhibited among ten pairs of types of tongue movement combination traits when analyzed using Pearson's correlation coefficient. The data indicated that the correlations of tongue movement were between tongue rolling and tongue folding, between pointed tongue and tongue rolling, and also between tongue folding and pointed tongue, respectively. Additionally, there were significant differences in frequency of tongue movements with age. The possible mechanism of variations of tongue movements with aging may involve the degradation of tongue function, and differential gene activation and modulation, or protein translation. PMID- 22810734 TI - [Syphilitic cerebral vasculitis: diagnostic possibilities]. AB - We studied 1387 patients with different forms of syphilis for neurological deficiency. Thirty patients had vascular neurosyphilis. Two cases are described in detail. A 40-year-old man had recurring episodes of acute disturbance of the cerebral blood flow and progressive cognitive disorders. A 32-year-old patient presented with progressive dementia, hallucinatory symptoms and minor multifocal neurological changes. The diagnosis of neurosyphilis was verified by CSF-test results. The diagnosis of cerebral vasculitis was proved by the data of magnetic resonance imaging (MRI), magnetic resonance (MR) angiography, ophthalmological methods, and duplex scanning of brachiocephalic arteries, transcranial duplex scanning. Diagnostic criteria of syphilitic cerebral vasculitis were defined and presented. PMID- 22810735 TI - [Cognitive disorders in patients with myotonic dystrophy type I: a clinical and magnetic resonance study]. AB - We studied 20 patients with myotonic dystrophy (MD) type I, mean age 34.4+/-12.3 years. A control group consisted of 10 healthy people, mean age 35.2+/-13.7 years. Cognitive status was assessed using the Brief Cognitive Rating Scale (BCRS), the Frontal Assessment battery (FAB), the Clock drawing test, the Luria memory ten-word retrieval test. The characteristic signs for cognitive deficit in MD were disturbances of visual-spatial functions revealed even in patients with high score on BCRS and FAD, the decrease in verbal fluency, generalization ability and the volume of auditory-speech memory. MRI data indicate the involvement of the gray matter (cortex athrophy) and the white matter (dilatation of the ventricular system, strengthening of the perivascular spaces, areas of T2 and FLAIR hyperintensity) in the pathological process. The lesion of the white matter in MD is similar to the imaging of demyelinization that should be taken into account in making the diagnosis by experts in neuroimaging, neurologists and geneticists. PMID- 22810736 TI - [Clinical characteristics of initial stages of schizotypal disorder]. AB - The study of clinical-psychopathological characteristics of initial stages of schizotypal disorder was carried out on a sample of 54 male inpatients. Based on the results of clinical-psychopathological and follow-up studies, authors found that symptoms of initial stages of schizotypal disorder presented by non psychotic depressive disorders. Dissociation of depressive symptoms, heterogeneity and unsteadiness of leading affect, marked polymorphism of depressive presentations, presence of concomitant neurotic-like and psychopathic like disorders are characteristic of these depressive disorders. Five clinical variants of states described in the initial stages of disease are singled out: depression with symptom- complex of asthenic incompetence (25.9%), apathic adynamic depression (27.7%), anxiety-depressive (16.6%), depersonalization depressive (20.4%) states, hypochondriac depressions (9.3%). PMID- 22810737 TI - [Valproate (depakine chrono) in adult patients with partial epilepsy: results of a multicentral prospective non-comparative study]. AB - We present results of an open multicentral prospective non-comparative clinical study on the efficacy and tolerability of depakine-chrono in patients with newly or recently diagnosed partial epilepsy (VIPe-1) that has been carried out in the Russian Federation. The study included 299 patients. It's duration was 6 months. Efficacy and tolerability of the drug used in mean dose 1479.0+/-448.7 mg/day were evaluated. After 6 month of treatment, 65.9% (95% CI 60.2 -71.2%) of patients were seizure-free. There was no significant difference in seizure-free rate in patients with different types of focal seizures. The improvement assessed with the Clinical Global Impression Scale (CGI) was seen in 73.3% of patients. Adverse events (mild or moderate) were recorded in 8% of patients. The most common adverse events were weight gain in (1.7%), hair loss (1.7%) and gastrointestinal disorders (1.3%). A serious adverse event (thrombocytopenia) occurred only in one case (0.3%). The results confirmed the high efficacy and good tolerability of depakine-chrono as first line monotherapy in adult patients with partial epilepsy. PMID- 22810738 TI - [Concentrations of urine 6-sulfatoxymelatonin during the treatment of patients with epilepsy: a pilot clinical trial]. AB - The effect of the epiphysis hormone melatonin on the brain bioelectrical activity is understudied: the data of experimental and clinical studies of melatonin effects are inconclusive and related mostly to exogenous administration. We studied 43 patients with focal epilepsy, 25 patients with cryptogenic epilepsy and 18 with symptomatic epilepsy. Carbamazepine and valproate were used as anticonvulsive drugs. Morning and evening urine concentrations of 6 sulfatoxymelatonin (6-COM), the main melatonin metabolite, were determined twice using immunoassay method: in autumn at the inclusion in the study and beginning of the anticonvulsant treatment and after 6 months, in spring, when anticonvulsant doses had been adjusted. The presence of epileptic seizures was associated with the reduction of melatonin concentration in the body that was supported by the decrease of urine 6-COM, in particular in the morning, in non treated patients. Prescription of anticonvulsant treatment resulted in the increase of 6-COM. The concentration of the morning urine 6-COM was higher in patients with focal epilepsy receiving anticonvulsant treatment with valproate compared to those receiving carbamazepine: 49.28+/-6.71 and 37.09+/-5.43 ng/ml versus 20.00+/-3.6 and 13.11+/-2.08 ng/ml in patients treated with valproate and carbamazepine, respectively, before and after the adjustment. PMID- 22810739 TI - [The prognostic significance of brain-derived neurotrophic factor (BDNF) for phobic anxiety disorders, vegetative and cognitive impairments during conservative treatment including adaptol of some functional and organic diseases of nervous system]. AB - We have studied the efficacy of adaptol in the treatment of 45 patients with somatoform dysfunction of the autonomic nervous system and 30 patients with closed head injury. The condition of patients during the treatment was evaluated with clinical and neuropsychological scales. The serum level of BDNF before and after the treatment has been studied as well. Adaptol has been shown to enhance the production of BDNF, reduce significantly the intensity of anxiety, autonomic disorders and improve intellectual processes. The dose-dependent effect of the drug has been demonstrated. In conclusion, adaptol can be recommended for treatment of diseases that demand stimulation of neuroplasticity in the CNS. PMID- 22810740 TI - [Preventive and cessation therapy of mental disorders in patients with the acute coronary syndrome]. AB - An open prospective trial of 93 inpatients divided into two main groups (61 patients) - with mental disorders (31) and without mental disorders (30) and a comparison group (32 patients) was carried out. All patients survived the acute coronary syndrome (myocardial infarction, unstable angina). The efficacy and safety of both preventive and cessation therapy with pantogam active in mean doses 1.8 and 1.2 g /daily, respectively, was demonstrated in respect of heterogeneous depressive, anxiety and somatoform disorders of the neurotic level. PMID- 22810741 TI - [Efficacy of mexidol in the combination with thrombolytic therapy in patients with ischemic stroke]. AB - Comparative efficiency of ethylmethylhydroxypyridine succinate (Mexidol) in combination with thrombolytic therapy in patients with ischemic stroke was studied in 116 patients. All patients divided into 2 groups: group (46 patients) received thrombolysis with mexidol and group (70 patients) received thrombolysis with standard therapy. These results showed that the synergy this one therapy leads to significantly faster normalize acute indicators, which correlated with the degree of reduction the neurological deficiency. Thus, the results showed that the synergistic therapy creates the conditions not only for the restoration of neurological status, but also to prevent secondary brain damage. PMID- 22810742 TI - [Efficacy of vestibo in the treatment of vertebrobasilar insufficiency]. PMID- 22810743 TI - [Morphochemical characteristics of hippocampal neuron's response to the hypofunction of the dopaminergic system]. AB - Differences in the response of August rats' hippocampal field SA1 and SA3 neurons to the chronic haloperidol administration (a model of parkinsonism) were revealed by interferometric methods. Based on the morphochemical parameters (nuclear and cytoplasmic area, protein content and concentration), the changes of field SA1 neurons can be regarded as functionally active (all parameters are significantly higher than in controls), and those of field SA3 neurons - as initial stages of degeneration (the significant decrease of neuron sizes). The differences in the response found in this study can be associated with the functional characteristics of SA1 and SA3 fields. PMID- 22810745 TI - [A comparative evaluation of morbidity dynamics and disability due to mental disorders in children]. PMID- 22810744 TI - [Pathomorphology of myocardium in the neuroleptic malignant syndrome]. AB - It was performed morphometric analysis of 55 cases which formed 4 groups: 1 - control group - 10 patients without neuroleptic treatment and heart diseases; 2 - 12 patients without heart disease treated with antipsychotic drugs; 3 - 17 - without cardias pathology who died from neuroleptic malignant syndrome (NMS); 4 - 16 patients with neuroleptic cardiomyopathy (NCMP) who died from NMS. The damage of myocardium in NMS is a relatively acute process involving disturbances of microcirculation, interstitial edema and dystrophic-degenerative changes of cardiomyocytes (CMC). These changes worsen the previous abnormal state of the heart muscle (microfibrosis, CMC atrophy) caused by cardiotoxic side-effects of neuroleptics. The severity of the total myocardium damage in NMS is directly depended on the absence or presence of NCMP. PMID- 22810746 TI - [A role of a myogenic factor in a clinical picture of migraine]. PMID- 22810747 TI - [Emotional disorders in the pathogenesis of cervical headache]. PMID- 22810748 TI - [The use of neuromidin in the treatment of chronic cerebral isshemia]. PMID- 22810749 TI - [Impact of stress on sleep]. PMID- 22810750 TI - Mortality pattern in childhood acute lymphoblastic leukemia with sepsis as a major barrier. PMID- 22810751 TI - Cancer incidence and survival among children and adolescents in Israel during the years 1998 to 2007. AB - Our goal was to describe childhood cancer incidence and survival in Israel and to identify demographic and epidemiologic variations among children and adolescents with cancer. We used data from the Israel National Cancer Registry to examine the incidence and survival of pediatric cancer in Israeli children aged 0 to 19 years, diagnosed during the years 1998 to 2007. Cases were analyzed according to sex, age, ethnicity, and geographic region. Among the 4255 cases of childhood cancer, there was a total age-adjusted incidence rate of 172.4 per million for children aged 0 to 19 years and 153.4 per million for children aged 0 to 14 years. The incidence rate for boys was higher than for girls (192.5 and 153.3, respectively) and higher for Jewish children than for Arab children (177.6 and 156.8, respectively). The largest groups were leukemias (22%), lymphomas (20.2%), and central nervous system tumors (17.4%). The number of new cases increased each year, but the incidence rate remained steady. The survival probability updated to December 2008 was estimated and the 5-year survival was calculated for the new cases until the end of 2003. The overall survival at 5 years was 80.8%, with 72.8% for the Arabic population and 83.2% for the Jewish population, and depended on the diagnosis. Incidence and survival in childhood cancer in Israel is at the same medium level compared with other parts of the world. This study may set the basis for investigating the genetic and environmental factors that cause pediatric cancer in Israel, delineating the genetic basis for ethnic origin disparities in survival. PMID- 22810752 TI - Pediatric feeding and swallowing disorders after bone marrow transplant. AB - Reduced oral intake is a known complication of bone marrow transplant (BMT) and may result in short-term tube feedings. Although most children return to typical eating habits, a subgroup of children requires intervention. The focus of the current investigation was to retrospectively identify the incidence and characteristics of feeding and swallowing disorders in pediatric patients during the first 100 days after BMT and to determine what factors contribute to feeding/swallowing disorders past the BMT acute phase (100+ d). The charts of 292 sequential patients undergoing BMT were reviewed. Seventy-two children (25%) were referred for feeding and/or swallowing intervention with a mean age of 78.6 months (SD=+/-63.4). Sixteen patients underwent instrumental evaluation with swallowing dysfunction identified in 50% (n=8) of the patients. Oral-motor dysfunction was reported in 33% (n=24) and feeding disorders occurred in 61% (n=44) of the patients referred for treatment. This single-institution review describes the impact of this interruption in the first 100 days after transplant on feeding and swallowing and determined what factors place a child at an increased risk for requiring tube feeding for 100+ days after transplant. The type of BMT, the use of a tube during the first 100 days, and the age were all significant predictors of requiring a tube when considered together for the individual patient. Children who do not require a tube in the first 100 days are significantly less likely to require one in future, approximately 85% less likely to require one whereas children receiving an autologous transplant are approximately 70% less likely to require a tube than children receiving an allogenic transplant. Providers should consider an intervention for younger children undergoing BMT to help maintain or facilitate the development of their feeding and swallowing skills. This may lead to improved feeding outcome in the pediatric BMT population. PMID- 22810753 TI - Thalidomide therapy for aggressive histiocytic lesions in the pediatric population. AB - Aggressive histiocytic lesions are uncommon in the pediatric population. These neoplasms occur in isolation or after therapy for other types of hematopoietic malignancy such as T-cell acute lymphoblastic leukemia. The etiology of these lesions is poorly understood, and no definitive standard of care has been established for patients with these diagnoses. Here, we report the success of thalidomide treatment for 2 subtypes of histiocytic proliferation--metastatic histiocytic sarcoma and extracutaneous juvenile xanthogranuloma--in pediatric patients. Our findings highlight the importance of considering thalidomide therapy in this unique and difficult to treat patient population. PMID- 22810754 TI - Cardiorespiratory fitness in survivors of pediatric posterior fossa tumor. AB - Advances in medical therapies have greatly improved survivorship rates in children diagnosed with brain tumor; as a result, morbidities associated with survivorship have become increasingly important to identify and address. In general, pediatric posterior fossa tumor survivors tend to be less physically active than peers. This may be related to late effects of diagnosis and treatment, including cardiovascular, endocrine, psychological, and neurocognitive difficulties. Exercise has been shown to be effective in improving physical functioning, mood, and even cognitive functioning. Consequently, the benefits of physical exercise need to be explored and incorporated into the daily lives of pediatric posterior fossa tumor survivors. The primary aim of the present study was to establish the feasibility and safety of cardiorespiratory fitness testing in pediatric posterior fossa tumor survivors who had received cranial radiation therapy. In addition, comparing our cohort with previously published data, we found that pediatric posterior fossa tumor survivors tended to be less fit than children with pulmonary disease and healthy controls and approximately as fit as children with chronic heart disease and survivors of other types of childhood cancer. The importance of cardiorespiratory fitness in pediatric posterior fossa tumor survivors is discussed along with implications for future directions. PMID- 22810755 TI - Successful H1N1 influenza vaccination of children receiving chemotherapy for solid tumors. AB - BACKGROUND: The hemato-oncology community has been seriously concerned about the H1N1 pandemic of 2009. Here, we report on the evaluation of the immunogenicity and tolerability of H1N1v monovalent vaccines in young patients with cancer during this pandemic. PROCEDURE: Between December 7, 2009 and February 26, 2010, 20 children receiving chemotherapy for solid tumors at the Institute of Hematology and Pediatric Oncology of Lyon, were immunized by 2 doses of either AS03-adjuvanted or nonadjuvanted vaccine. The level of specific antibodies was assessed at D21 and D42. RESULTS: Seroconversion was observed in 13 of the 20 cases (65%), and 18 of 20 cases (90%) had protective titers after the 2 doses. Exploratory univariate analysis failed to show a significant influence of prevaccination lymphocyte counts on seroresponse rates. CONCLUSIONS: These data suggest that H1N1v monovalent vaccines were well tolerated by young cancer patients while on chemotherapy and achieved protective immune response in most cases. PMID- 22810756 TI - Reticulocyte parameters: markers of early response to oral treatment in children with severe iron-deficiency anemia. AB - The aim of the present study was to determine the effects of exclusive oral iron supplementation (iron sulphate 2 mg/kg/die) in asymptomatic children with severe iron-deficiency anemia [median hemoglobin (Hb) level before treatment 6.3 g/dL; range 4.5 to 7 g/dL] and to investigate the accuracy of Hb, reticulocyte hemoglobin content (CHr), and absolute reticulocyte count (ARC) as markers for monitoring early response to treatment. The increase in ARC and CHr was statistically significant at day +3. There was a significant association between suitable logarithmic functions of the percentage increase in CHr and ARC at day +3 and the fraction of required Hb increase compared with baseline to reach the mean reference value for age and sex at day +14. If these results are confirmed in a larger population, ARC and CHr could be considered affordable and widely available markers to detect early responders to oral iron therapy, and to switch unresponsive children to parenteral iron supplementation or transfusion. PMID- 22810757 TI - Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus. AB - BACKGROUND: In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. OBJECTIVE: To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naive to antiviral therapy. METHODS: Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon alpha plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response-namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. RESULTS: Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. CONCLUSION: Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naive to antiviral therapy. PMID- 22810758 TI - Treatment of idiopathic pulmonary fibrosis with losartan: a pilot project. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease with no current effective therapies. Treatment has focused on antifibrotic agents to stop proliferation of fibroblasts and collagen deposition in the lung. We present the first clinical trial data on the use of losartan, an antifibrotic agent, to treat idiopathic pulmonary fibrosis. The primary objective was to evaluate the effect of losartan on progression of idiopathic pulmonary fibrosis measured by the change in percentage of predicted forced vital capacity (%FVC) after 12 months. Secondary outcomes included the change in forced expiratory volume at 1 second, diffusing capacity of carbon monoxide, 6-minute walk test distance, and baseline/transition dyspnea index. METHODS: Patients with idiopathic pulmonary fibrosis and a baseline %FVC of >=50 % were treated with losartan 50 mg by mouth daily for 12 months. Pulmonary function testing, 6-minute walk, and breathlessness indices were measured every 3 months. RESULTS: Twenty participants with idiopathic pulmonary fibrosis were enrolled and 17 patients were evaluable for response. Twelve patients had a stable or improved %FVC at study month 12. Similar findings were observed in secondary end-point measures, including 58, 71, and 65 % of patients with stable or improved forced expiratory volume at 1 second, diffusing capacity for carbon monoxide, and 6-minute walk test distance, respectively. No treatment-related adverse events that resulted in early study discontinuation were reported. CONCLUSION: Losartan stabilized lung function in patients with idiopathic pulmonary fibrosis over 12 months. Losartan is a promising agent for the treatment of idiopathic pulmonary fibrosis and has a low toxicity profile. PMID- 22810759 TI - Readability analysis of internet-based patient information regarding skull base tumors. AB - Readability is an important consideration in assessing healthcare-related literature. In order for a source of information to be the most beneficial to patients, it should be written at a level appropriate for the audience. The National Institute of Health recommends that health literature be written at a maximum level of sixth grade. This is not uniformly found in current health literature, putting patients with lower reading levels at a disadvantage. In February 2012, healthcare-oriented education resources were retrieved from websites obtained using the Google search phrase skull base tumors. Of the first 25 consecutive, unique website hits, 18 websites were found to contain information for patients. Ten different assessment scales were utilized to assess the readability of the patient-specific web pages. Patient-oriented material found online for skull base tumors was written at a significantly higher level than the reading level of the average US patient. The average reading level of this material was found to be at a minimum of eleventh grade across all ten scales. Health related material related to skull base tumors available through the internet can be improved to reach a larger audience without sacrificing the necessary information. Revisions of this material can provide significant benefit for average patients and improve their health care. PMID- 22810760 TI - Raising the bar. PMID- 22810761 TI - A new era of GPCR structural and chemical biology. AB - G protein-coupled receptors (GPCRs) are versatile molecular machines that regulate the majority of physiological responses to chemically diverse hormones and neurotransmitters. Recent breakthroughs in structural studies have advanced our understanding of GPCR signaling, particularly the selectivity of ligand recognition and receptor activation of G proteins. PMID- 22810762 TI - Where have all the active receptor states gone? AB - Defining G protein-coupled receptor ligand efficacy and biased agonism in precise chemical terms is one challenge posed by the current structural data that exists for this receptor family. Concepts classically used for understanding enzymes and other nonreceptor proteins may lead us in the right direction. PMID- 22810771 TI - Metals: ironing out copper toxicity. PMID- 22810772 TI - Microbiology: sensing stability. PMID- 22810780 TI - [The future of urological care: the current situation in healthcare political environment]. AB - The healthcare system is the largest economic market in Germany. The specific requirements demand an intelligent mixture of market, self-administration and federal regulation, which must be permanently adapted to continuously altering environmental conditions. Urological care exemplifies the adaptation of healthcare to altered economic, social and medical environmental conditions. PMID- 22810779 TI - Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients. AB - PURPOSE: The purpose of this study was to describe inhaled colistin pharmacokinetics in patients with ventilator-associated tracheobronchitis (VAT) due to polymyxin-only susceptible Gram-negative bacteria (GNB). METHODS: Inhaled colistimethate sodium (CMS) was administered at a dose of 80 mg every 8 h for 7 days. Mini bronchoalveolar lavage (BAL) was performed before and at 1, 4 and 8 h, while blood samples were collected before and at 0.16, 0.5, 1, 2, 4 and 8 h after the first dose. Colistin concentrations in BAL and serum were determined by high performance liquid chromatography. RESULTS: Our study population included 20 patients. At the end of treatment, cure was achieved in 16 patients and favorable microbiological response in 12 patients. Median (25-75 % interquartile range) colistin concentrations in epithelial lining fluid (ELF) were 6.7 (4.8-10.1), 3.9 (2.5-6.0) and 2.0 (1.0-3.8) MUg/ml at 1, 4 and 8 h, respectively, and fivefold higher than those achieved in serum. Median ELF concentrations at 1 and 4 h were above the minimum inhibitory concentrations of all isolated pathogens; however, the 4-h median was below the European Committee on Antimicrobial Susceptibility Guidelines (EUCAST) breakpoints for Pseudomonas aeruginosa and the 8-h median was low relative to EUCAST breakpoints for all GNB. Colistin pharmacokinetic/pharmacodynamic parameters in ELF were associated with favorable microbiological response at the end of treatment. CONCLUSION: Inhaled colistin may achieve high drug concentrations in the lung. However, a dose of 80 mg of inhaled CMS every 8 h may not be adequate for the treatment of lower respiratory tract infections due to multi-drug resistant GNB. PMID- 22810773 TI - Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology. AB - Glycoconjugates are ubiquitous biomolecules found in all kingdoms of life. These diverse structures are metabolically responsive and occur in a cell line- and protein-specific manner, conferring tissue type-specific properties. Glycans have essential roles in diverse processes, including, for example, intercellular signaling, inflammation, protein quality control, glucohomeostasis and cellular adhesion as well as cell differentiation and proliferation. Many mysteries remain in the field, however, and uncovering the physiological roles of various glycans remains a key pursuit. Realizing this aim necessitates the ability to subtly and selectively manipulate the series of different glycoconjugates both in cells and in vivo. Selective small-molecule inhibitors of glycan processing enzymes hold great potential for such manipulation as well as for determining the function of 'orphan' carbohydrate-processing enzymes. In this review, we discuss recent advances and existing inhibitors, the prospects for small-molecule inhibitors and the challenges associated with generating high-quality chemical probes for these families of enzymes. The coordinated efforts of chemists, biochemists and biologists will be crucial for creating and characterizing inhibitors that are useful tools both for advancing a basic understanding of glycobiology in mammals as well as for validating new potential therapeutic targets within this burgeoning field. PMID- 22810781 TI - [Ferdinand Eisenberger research stipendiums of the German Society for Urology: scholarships in 2012 and planned projects in the third round of calls for applications]. PMID- 22810782 TI - Neurologic manifestations of acute and chronic renal disease. AB - Acute and chronic renal disease is prevalent in hospitalized and ambulatory patient populations. Most patients with acute or chronic renal disease exhibit some degree of neurologic dysfunction affecting the CNS, peripheral nervous system, or both. Neurologic manifestations may be a direct consequence of the uremic state or a consequence of renal replacement therapy. Early recognition of common central and peripheral nervous system dysfunction as it relates to renal disease may provide opportunities for therapeutic intervention and improved outcomes. This review will summarize the most frequently encountered manifestations of acute and chronic renal disease, organized with respect to their occurrence as a direct consequence of advanced renal dysfunction or renal replacement therapy. PMID- 22810784 TI - Journal information. PMID- 22810785 TI - Editor's Preface. PMID- 22810786 TI - Cardiac manifestations of neurologic disorders. AB - The cardiac complications of certain neurologic diseases have been well recognized for over 50 years and are mostly evident for cerebrovascular accidents. Although these complications are frequent and in most circumstances benign, detrimental cardiac side effects, such as serious arrhythmias and myocardial infarctions, may occur. The link to most of these cardiac derangements is a transient or chronic autonomic dysfunction, depending on the specific neurologic disease. Myocardial infarcts, left ventricular dysfunction, and arrhythmias are well-recognized complications of subarachnoid hemorrhage, intracranial bleed, and ischemic strokes. Seizures may present with atonia or sudden death from asystole. Degenerative brain disorders, namely the synucleinopathies, may affect the central control areas or peripheral ganglia of the autonomic nervous system, causing autonomic dysfunction. In addition, cardiac conduction defects and cardiomyopathy are common in certain neuromuscular disorders, namely the dystrophies and mitochondrial myopathies. PMID- 22810787 TI - Deep venous thrombosis and pulmonary embolism in neurologic and neurosurgical disease. AB - Patients with neurologic disease are at high risk of venous thromboembolism (VTE) (deep venous thrombosis [DVT] or pulmonary embolism [PE]) because of relative immobility or an increased risk of hypercoagulable states. Patients with spinal cord injuries, brain tumors, and strokes are at particularly high risk for VTE. Well-established risk assessment tools and a number of well-defined diagnostic tests to establish a VTE diagnosis are available. Unfortunately, physicians, in both the inpatient and outpatient settings, often do not have a sufficiently high level of clinical suspicion for DVT or PE, and the diagnosis is sometimes missed. The treatment of VTE is anticoagulation unless the patient is at unacceptably high risk for serious bleeding complications. The duration of anticoagulation depends on the presence of underlying hypercoagulable states and a prior history of VTE. PMID- 22810788 TI - Neurologic complications of hemoglobinopathies. AB - The hemoglobinopathies, including sickle cell disease and its variants, are genetic abnormalities of hemoglobin. Hemoglobin SS (sickle cell disease) is the most common form of hemoglobin mutation in North America. Complications of hemoglobinopathies are numerous and involve many organ systems, including the nervous system. This article is intended to introduce the reader to the epidemiology, diagnosis, treatment, and prevention of neurologic complications of hemoglobinopathies, focusing specifically on sickle cell disease because of its prevalence. PMID- 22810789 TI - Neurologic aspects of lymphoma and leukemias. AB - The leukemias and lymphomas represent a heterogenous group of hematologic malignancies with protean manifestations. Neurologic sequelae of the diseases have been recognized almost since the time the conditions were first described in the mid-1800s. Although our understanding of the various presentations of these blood disorders has evolved along with our knowledge of the malignancies, accurate diagnosis can still be difficult. It is critical for neurologists to have a high index of clinical suspicion to appropriately recognize the heralding features. This review focuses on the relevant clinical neurologic features and diagnostic studies to identify leukemias and lymphomas affecting the nervous system. PMID- 22810790 TI - The neurologic side effects of chemotherapeutic agents. AB - Neurologic dysfunction is a common side effect of many chemotherapy drugs. For several agents neurotoxicity is common, severe, and can be dose limiting. As the list of newer chemotherapy agents and systemic targeted therapies grows, so does the number and variety of potential neurotoxicities. This article reviews the clinical features of chemotherapy-induced syndromes involving the central and peripheral nervous systems. PMID- 22810791 TI - The neurology of parasitic diseases and malaria. AB - Neurologists should be aware of parasitic diseases occurring in travelers and recent migrants because the world has become a global village as a result of tourism and immigration. Global warming is changing the distribution of diseases formerly confined to the tropics. The two most common parasitic diseases of the nervous system are Plasmodium falciparum malaria presenting as a febrile encephalopathy with normal CSF and neurocysticercosis causing seizures with focal MRI lesions or with intracranial hypertension. Numerous parasites may cause larva migrans with eosinophilic meningitis. Spinal cord involvement is the signature presentation of schistosomiasis. Trypanosoma cruzi, the agent of Chagas disease in the Americas, may cause myocardiopathy and embolic stroke. Sleeping sickness remains the most common manifestation of African trypanosomiasis. These conditions are challenging to diagnose unless a history of travel is elicited. Prospective travelers should be advised of preventive measures to avoid potentially severe infections of the nervous system. PMID- 22810792 TI - Neurologic complications of anesthesia. AB - Neurologic complications after anesthesia are relatively uncommon but occasionally severe. Intraoperative intracranial hypertension in patients with brain masses, delayed arousal, and postoperative delirium and cognitive dysfunction are among the main complications of general anesthesia. Neuropathy and transient gluteal and leg pain are the most frequent complications of regional blockade. Seizures are infrequent with both anesthesia modalities. Patients with primary neurologic disorders, such as neurodegenerative or neuromuscular conditions, can be at risk for specific complications, and the anesthesia plan must be cautiously adjusted in these patients. In the neurointensive care unit, the complications from large doses of anesthetic agents used for suppression of seizures or control of intracranial pressure are different from those seen perioperatively. Propofol infusion syndrome can be life threatening when administered for those indications. PMID- 22810793 TI - A young man with spinal muscular atrophy and impending respiratory arrest. AB - From a statutory standpoint, the decision-making capacity of adolescents differs significantly from that of adults because adolescents are considered to lack the experience and judgment necessary to make legally binding decisions. Furthermore, in the case of minors, the principle of protection of life tends to outweigh the principle of autonomy. Here we present the hypothetical case of a 16-year-old boy with spinalmuscular atrophy type II who was admitted to the intensive care unit for severe respiratory distress. We focus on the tension that developed among the patient, his parents, and his physicians when the need for emergency mechanical ventilation became apparent. We review the legal and ethical premises under which adolescents are permitted to make legally binding decisions, ie, the emancipated minor and the mature minor doctrines. Finally, we discuss the concepts of protectionism and liberationism as they apply to adolescents' decision-making capacity. PMID- 22810794 TI - An Approach to Preoperative Neurologic Consultation for Non-neurologic Surgery. AB - Neurologists are commonly asked to provide outpatient or inpatient consultation prior to non-neurologic surgery in patients with an underlying neurologic disorder; however, a paucity of neurologic literature and no evidence-based guidelines exist regarding how to approach this common clinical problem. Extrapolating on the literature regarding the process of preoperative consultation by internists and internal medicine subspecialists, this article attempts to provide a general framework for the neurologist who is asked to evaluate a patient preoperatively. The importance of timely and effective communication, including discussion and clarification with the referring surgeon regarding the neurologist's role in each preoperative assessment, is stressed. PMID- 22810797 TI - Multiple-choice questions. PMID- 22810795 TI - Coding table. PMID- 22810798 TI - Multiple-choice questions-preferred responses. PMID- 22810799 TI - Patient management problem. PMID- 22810800 TI - Patient management problem-preferred responses. PMID- 22810802 TI - The decrease on Na(+), K(+)-ATPase activity in the cortex, but not in hippocampus, is reverted by antioxidants in an animal model of sepsis. AB - In the present study, we investigated whether sepsis induced by cecal ligation and puncture (CLP) modifies Na(+), K(+)-ATPase activity, mRNA expression, and cerebral edema in hippocampus and cerebral cortex of rats and if antioxidant (ATX) treatment prevented the alterations induced by sepsis. Rats were subjected to CLP and were divided into three groups: sham; CLP-rats were subjected to CLP without any further treatment; and ATX-CLP plus administration of N acetylcysteine plus deferoxamine. Several times (6, 12, and 24) after CLP or sham operation, the rats were killed and hippocampus and cerebral cortex were isolated. Na(+), K(+)-ATPase activity was inhibited in the hippocampus 24 h after sepsis, and ATX treatment was not able to prevent this inhibition. The Na(+), K(+)-ATPase activity also was inhibited in cerebral cortex 6, 12, and 24 h after sepsis. No differences on Na(+), K(+)-ATPase catalytic subunit mRNA levels were found in the hippocampus and cerebral cortex after sepsis. ATX treatment prevents Na(+), K(+)-ATPase inhibition only in the cerebral cortex. Na(+), K(+)-ATPase inhibition was not associated to increase brain water content. In conclusion, the present study demonstrated that sepsis induced by CLP inhibits Na(+), K(+)-ATPase activity in a mechanism dependent on oxidative stress, but this is not associated to increase brain water content. PMID- 22810803 TI - Visualizing multiple word similarity measures. AB - Although many recent advances have taken place in corpus-based tools, the techniques used to guide exploration and evaluation of these systems have advanced little. Typically, the plausibility of a semantic space is explored by sampling the nearest neighbors to a target word and evaluating the neighborhood on the basis of the modeler's intuition. Tools for visualization of these large scale similarity spaces are nearly nonexistent. We present a new open-source tool to plot and visualize semantic spaces, thereby allowing researchers to rapidly explore patterns in visual data that describe the statistical relations between words. Words are visualized as nodes, and word similarities are shown as directed edges of varying strengths. The "Word-2-Word" visualization environment allows for easy manipulation of graph data to test word similarity measures on their own or in comparisons between multiple similarity metrics. The system contains a large library of statistical relationship models, along with an interface to teach them from various language sources. The modularity of the visualization environment allows for quick insertion of new similarity measures so as to compare new corpus-based metrics against the current state of the art. The software is available at www.indiana.edu/~semantic/word2word/. PMID- 22810804 TI - Diazaborolyl-boryl push-pull systems with ethynylene-arylene bridges as 'turn-on' fluoride sensors. AB - Two linear pi-conjugated systems with 1,3-diethyl-1,3,2-benzodiazaborolyl [C(6)H(4)(NEt)(2)B-] as a donor group and dimesitylboryl (-BMes(2)) as acceptor were synthesised with -ethynylene-phenylene- (-C=C-1,4-C(6)H(4)-, 3) and ethynylene-thiophene- (-C=C-2,5-C(4)H(2)S-12) bridges between the boron atoms. An assembly (20) consisting of two diazaborolyl-ethynylene-phenylene-boryl units, [C(6)H(4)(NCy)(N')B-C=C-1,4-C(6)H(4)-BMes(2)] joined via a 1,4-phenylene unit at the nitrogen atoms (N') of the diazaborolyl units was also synthesised. The three push-pull systems, 3, 12 and 20, form salts on fluoride addition with the BMes(2) groups converted into (BMes(2)F)(-) anions. The molecular structures of 3, 12 and (NBu(4))(12.F) were elucidated by X-ray diffraction analyses. The borylated systems 3, 12 and 20 show intense blue luminescence in cyclohexane with quantum yields (Phi(fl)) of 0.99, 0.44 and 0.94, respectively, but weak blue-green luminescence in tetrahydrofuran (Phi(fl) = 0.02-0.05). The charge transfer nature of these transitions is supported by TD-DFT computations with the CAM-B3LYP functional. Addition of tetrabutylammonium fluoride to tetrahydrofuran solutions of 3 and 20 resulted in strong violet-blue luminescence with emission intensities up to 46 times more than the emission intensities observed prior to fluoride addition. Compounds 3 and 20 are demonstrated here as remarkable 'turn-on' fluoride sensors in tetrahydrofuran solutions. PMID- 22810805 TI - Phase 1 study of ganitumab (AMG 479), a fully human monoclonal antibody against the insulin-like growth factor receptor type I (IGF1R), in Japanese patients with advanced solid tumors. AB - PURPOSE: This study was to investigate the safety and tolerability of ganitumab in Japanese patients with advanced solid tumors. METHODS: Patients were enrolled into 1 of 3 dose cohorts (6, 12, or 20 mg/kg) of single-agent ganitumab administered intravenously every 2 weeks. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of ganitumab in Japanese patients with advanced solid tumors. An exploratory pharmacodynamic analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF1R pathway (IGFBP-3 and total IGF-1). RESULTS: Nineteen patients with ECOG performance status 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of ganitumab. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCLC (2), thymic (2), and other cancers (6). No DLTs were observed. The most common grade >=3 adverse events were neutropenia (21 %), leukopenia (16 %) and lymphopenia (11 %). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-ganitumab antibodies were detected during this study. Dose-linearity on PK of ganitumab was indicated in the dose range. Tumor response was assessed for 19 patients. Stable disease as best response was reported in 7 patients. CONCLUSIONS: Ganitumab up to 20 mg/kg was tolerable in Japanese patients with advanced solid tumors. The safety and PK profiles were similar to those previously observed in non-Japanese patients. PMID- 22810806 TI - Dose escalation and pharmacokinetic study of nanoparticle curcumin... by Kanai et al., CCP 69:65-70, 2012. PMID- 22810807 TI - Treatment of unstable posterior pelvic ring fracture with percutaneous reconstruction plate and percutaneous sacroiliac screws: a comparative study. AB - OBJECTIVE: The aim of this study is to compare the clinical effects of percutaneous reconstruction plate and percutaneous sacroiliac screws in treatment of unstable posterior pelvic ring fracture. METHODS: Fifty-eight patients with unstable posterior pelvic ring fracture treated with two methods from March 2002 to October 2007 were enrolled in the study and divided into two groups according to two kinds of internal fixation: percutaneous reconstruction plate (20 males and 9 females, at mean age 37.3 +/- 11.3 years) and percutaneous sacroiliac screws (21 males and 8 females, at mean age 39.3 +/- 10.4 years). Causes of injury included traffic accident in 38 patients, fall from height in 17, and crush in 3. The correlative data of operation duration, number of X-ray exposures, intraoperative bleeding volume, length of incision, Majeed postoperative functional evaluation, and postoperative complications were analyzed statistically. RESULTS: All 58 patients were followed up for 12-36 months (mean duration 21.3 months). There was statistical difference for operation duration, number of X-ray exposures, size of incision, and intraoperative bleeding volume between the two groups. Majeed postoperative functional evaluation indicated excellent and good rates of 86.1% for percutaneous reconstruction plate and 88.2% for percutaneous sacroiliac screws. CONCLUSIONS: The clinical effect of the two methods is similar in treatment of Tile C pattern posterior pelvic ring fracture. However, the percutaneous reconstruction plate has lower risk of damaging nerves and blood vessels than the percutaneous sacroiliac screws. Moreover, intraoperative fluoroscopy is rarely performed. PMID- 22810808 TI - Responsiveness of the Japanese version of the patient-rated wrist evaluation (PRWE-J) and physical impairment measurements in evaluating recovery after treatment of ulnocarpal abutment syndrome. AB - BACKGROUND: We evaluated the responsiveness of patient-derived questionnaires and physical findings in evaluating recovery after treatment of ulnocarpal abutment syndrome. METHODS: Patients were assessed at their initial visit to our clinic and again 3 months after the treatment. At each visit, patients completed a Short Form-36, the Japanese Society for Surgery of the Hand version of Disability of the Arm, Shoulder, and Hand questionnaire (DASH-JSSH), and the Japanese version of patient-rated wrist evaluation (PRWE-J). Grip strength, range of motion, and visual analogue scale for wrist pain were also examined at each visit. Satisfaction with treatment was questioned after 3 months using a Likert scale. Standardized response means (SRM) and effect sizes were calculated to evaluate the responsiveness. RESULTS: The PRWE-J (SRM, 1.35) was the most responsive questionnaire, followed by the DASH-JSSH (SRM, 0.81) and the Short Form-36 (SRM, 0.38 to -1.19). Of the physical tests, grip strength (SRM, 0.81) was more responsive than range of motion (SRM, 0.01 to -0.29). The visual analogue pain scale (SRM, 1.56) was highly responsive. Changes in the PRWE score were correlated with the satisfaction rating for the treatment. CONCLUSIONS: Responsive patient-derived scales can assist in the outcome evaluation of patients with ulnocarpal abutment syndrome. PMID- 22810809 TI - Catching the X-waves. PMID- 22810812 TI - Suppressing the rejection of pancreatic tumours. PMID- 22810815 TI - Journal information. PMID- 22810810 TI - The rationale for targeting the LOX family in cancer. AB - The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics. PMID- 22810811 TI - NRF2 and cancer: the good, the bad and the importance of context. AB - Many studies of chemopreventive drugs have suggested that their beneficial effects on suppression of carcinogenesis and many other chronic diseases are mediated through activation of the transcription factor NFE2-related factor 2 (NRF2). More recently, genetic analyses of human tumours have indicated that NRF2 may conversely be oncogenic and cause resistance to chemotherapy. It is therefore controversial whether the activation, or alternatively the inhibition, of NRF2 is a useful strategy for the prevention or treatment of cancer. This Opinion article aims to rationalize these conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data. PMID- 22810816 TI - Editor's Preface. PMID- 22810813 TI - Identification of direct forkhead box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation. AB - AIMS/HYPOTHESIS: The transcription factor, forkhead box (FOX)O1, is involved in fatty acid-induced apoptosis in pancreatic beta cells, but the precise mechanism is poorly understood. We aimed to identify which direct downstream targets of FOXO1 are involved in palmitate-induced apoptosis in the pancreatic beta cell line MIN6. METHODS: Chromatin immunoprecipitation (ChIP) coupled to a DNA selection and ligation technique (ChIP-DSL) was used to identify the direct targets of FOXO1. The mRNA level was examined by real-time PCR assay. The ChIP DSL results were verified using ChIP-PCR and luciferase assay, respectively. The cell apoptosis rate was determined by TUNEL assay and by scoring cells with pycnotic nuclei. RESULTS: We identified 189 target genes and selected 106 targets for expression analysis in MIN6 cells treated with palmitate. The results showed that six genes were significantly upregulated and four were downregulated. Binding of FOXO1 to the promoters was determined by ChIP-PCR and confirmed by luciferase assay. Among the ten up- and downregulated genes, mRNA expression of A930038C07Rik was significantly decreased and that of Ppa1 was increased in 8 week-old db/db mice. The apoptosis assay showed that overproduction of the protein 'RIKEN cDNA A930038C07' (A930038C07Rik) drastically enhanced palmitate induced apoptosis, while pyrophosphatase (inorganic) 1 (PPA1) partially protected the cells from apoptosis. Knockdown of PPA1, moreover, significantly increased apoptosis. CONCLUSIONS/INTERPRETATION: We identified for the first time FOXO1 targets in MIN6 cells treated with palmitate, thus revealing the important roles of A930038C07Rik and PPA1 in palmitate-induced cell apoptosis. These results shed light on the mechanisms of palmitate-induced apoptosis in pancreatic beta cells. PMID- 22810817 TI - Just in time: an update on continuum neurogenetics. AB - The field of neurogenetics has been revolutionized by the advances in genome wide association testing. Recent gene discoveries for disorders of neurodegeneration, CNS demyelination, and neurodevelopmental and cerebrovascular syndromes begin to shape our understanding of the complexity of their underlying genetic architecture. In the future, this knowledge should advance risk prediction, prevention, diagnosis, and treatment strategies for patients with neurologic disorders and their families. PMID- 22810819 TI - Primer on genetic counseling. AB - Once limited to rare mendelian disorders, genetic counseling is playing an ever increasing role in the multidisciplinary approach to predicting, diagnosing, and managing neurologic disease. However, genetic counseling services may not be optimized because of lack of availability and lack of knowledge regarding when it is appropriate to refer, what occurs in genetic counseling, and how genetic counseling can affect care. These issues are addressed in this article, along with corresponding clinical scenarios. Websites to find genetic counseling services and resources are also provided. PMID- 22810818 TI - Genomic medicine and neurology. AB - The application of genetics to the understanding of neurology has been highly successful over the past several decades. During the past 10 years, tools were developed to begin genetic investigations into more common disorders such as Alzheimer disease, multiple sclerosis, autism, and Parkinson disease. The era of genomic medicine now has begun and will have an increasing effect on the daily care of common neurologic diseases. Thus it is important for neurologists to have a basic understanding of genomic medicine and how it differs from the traditional clinical genetics of the past. This article provides some basic information about genomic medicine and pharmacogenetics in neurology to help neurologists to begin to adopt these principles into their practice. PMID- 22810820 TI - Genetic evaluation of inherited muscle diseases. AB - Inherited muscle diseases are common and can present to the neurologist as anything from an incidentally found high creatine kinase level with muscle soreness in an adult to severe weakness at birth. Although a vast number of gene mutations can cause muscle degeneration, a solid understanding of the clinical presentation and gene diagnostic methods of the three most common forms of inherited muscle disease (Duchenne, myotonic, and facioscapulohumeral muscular dystrophy) will allow for the accurate diagnosis in most cases. Additionally, a general understanding of the cellular pathways involved in maintaining proper muscle fiber integrity helps provide a road map for evaluating less common disorders that are more of a diagnostic challenge, including limb-girdle muscular dystrophy, distal myopathy, congenital myopathy, and congenital muscular dystrophy. PMID- 22810821 TI - Inherited peripheral neuropathies. AB - Mutations in genes expressed in Schwann cells and the axons they ensheathe cause the hereditary motor and sensory neuropathies, also known as Charcot-Marie-Tooth disease (CMT). More than 40 different genes have been shown to cause inherited neuropathies; chromosomal localizations of many other distinct inherited neuropathies have been mapped, and new genetic causes for inherited neuropathies continue to be discovered. How to keep track of all of these disorders, when to pursue genetic testing, and what tests to order for specific patients are difficult challenges for any neurologist. This review addresses these issues and provides illustrative cases to help in dealing with them. CMT serves as a living system to identify molecules necessary for normal peripheral nervous system (PNS) function. Understanding how these various molecules interact will provide a better understanding of the pathogenesis of peripheral neuropathies in general as well as other neurodegenerative disorders involving the PNS. PMID- 22810822 TI - Genetic testing in clinical practice. AB - The availability of genetic testing for neurologic conditions is increasing rapidly. Although several cases are discussed that present the different challenges confronting today's neurologist in using genetic testing, the focus of this article is on concepts and questions that neurologists can use to help make genetic testing decisions. Genetic testing is one of the most rapidly changing aspects of clinical medicine and will continue to evolve with the availability of whole-genome sequencing in the near future. PMID- 22810823 TI - Genetics of dementia. AB - Neurodegenerative adult-onset dementias are complex and multifactorial diseases that are most commonly caused by environmental, genetic, or mixed environmental and genetic factors. Regarding the genetic causes, a variety of phenotypes may present. This article reviews several of the genetic risk factors for the most common dementias encountered in neurology. Practical implications of genetic testing and pharmacogenomic considerations for clinical practice are also discussed. PMID- 22810824 TI - Presymptomatic and early symptomatic genetic testing. AB - This article presents a hypothetical case of a boy with early symptoms of Becker muscular dystrophy whose family wishes to defer genetic testing because of concerns about genetic discrimination. The possibility of genetic discrimination in this case is discussed, especially in the context of the Genetic Information Nondiscrimination Act (GINA) that took effect in 2009. GINA protects individuals who are asymptomatic, not those who have "manifested disease." The patient under discussion has symptoms, albeit subtle, of Becker muscular dystrophy, and thus would be regarded by most observers as having "manifested disease." Thus, there appears to be no disadvantage for a patient under these circumstances to have genetic testing, and the neurologist should advise such patients to have confirmatory genetic testing performed. PMID- 22810825 TI - Interpretation of genetic testing: variants of unknown significance. AB - As the number of genes available for commercial sequencing increases and the promise of clinical whole-genome sequencing becomes a reality, the interpretation of the results of these tests becomes more challenging for the practicing neurologist as these studies have the potential to detect novel genetic variants. Such reports are becoming more frequent in general practice, and neurologists are often left to puzzle over the relevance of these "variants of unknown significance," as such genetic changes are often described, and how to communicate this information to the patients and their families. This article will briefly illustrate how clinicians can use such results in the care of their patients. Only genetic variants involving coding sequence will be considered, although similar methods may also be applied to changes such as noncoding alterations or copy number variations. It is also important to note that in some cases, particularly those involving tests that only sequence select exons, negative test results may also require special interpretation. PMID- 22810827 TI - APPENDIX A: Glossary of Useful Genetic Terms. PMID- 22810826 TI - Coding table. PMID- 22810830 TI - Multiple-choice questions-preferred responses. PMID- 22810829 TI - Multiple-choice questions. PMID- 22810831 TI - Patient management problem. PMID- 22810832 TI - Patient management problem-preferred responses. AB - Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study. PMID- 22810834 TI - The changing impact of family size on adolescents' schooling: assessing the exogenous variation in fertility using twins in Brazil. AB - Researchers have long been interested in the influence of family size on children's educational outcomes. Simply put, theories have suggested that resources are diluted within families that have more children. Although the empirical literature on developed countries has generally confirmed the theoretical prediction that family size is negatively related to children's education, studies focusing on developing societies have reported heterogeneity in this association. Recent studies addressing the endogeneity between family size and children's education have also cast doubt on the homogeneity of the negative role of family size on children's education. The goal of this study is to examine the causal effect of family size on children's education in Brazil over a 30-year period marked by important social and demographic change, and across extremely different regions within the country. We implement a twin birth instrumental variable approach to the nationally representative 1977-2009 PNAD data. Our results suggest an effect of family size on education that is not uniform throughout a period of significant social, economic, and demographic change. Rather, the causal effect of family size on adolescents' schooling resembles a gradient that ranges from positive to no effect, trending to negative. PMID- 22810835 TI - The Rho-kinase (ROCK) inhibitor Y-27632 protects against excitotoxicity-induced neuronal death in vivo and in vitro. AB - Rho-associated coil kinase (ROCK) inhibitors reportedly prevent neurodegeneration, and abnormal ROCK activation in the central nervous system induces neurite collapse and retraction. However, it is unclear whether the ROCK inhibitor Y-27632 directly protects hippocampal neurons from excitotoxicity. Here, we determined the effects of Y-27632 on neuroprotection following kainic acid (KA)-induced seizures in mice and during glutamate-induced excitotoxicity in HT22 cells. One day after Y-27632 injection, mice were treated with KA and killed 1-2 days later. Fluoro-Jade B and rapid Golgi staining showed that Y-27632 protected against KA-induced neurodegeneration and neurite dystrophy. Y-27632 inhibited increases in hippocampal RhoA and ROCK2 in KA-treated mice as determined by western blot analysis. Immunohistochemical analysis revealed ROCK2 positive neurons and astrocytes in the KA-treated hippocampus. In HT22 cells, Y 27632 also protected neurons and neurite formation during glutamate-induced excitotoxicity in vitro. These results indicate that ROCK inhibition modulates neurite growth and protects neurons from excitotoxicity-induced cell death. PMID- 22810836 TI - Novel imaging method to quantify stratum corneum in dermatopharmacokinetic studies: proof-of-concept with acyclovir formulations. AB - PURPOSE: Tape-stripping the stratum corneum (SC) is used in the assessment of dermatopharmacokinetics (DPK). The amount of SC per tape can be determined gravimetrically, but a novel imaging method offers advantages in terms of sensitivity, reproducibility, precision, stability and speed. High-resolution images, acquired under controlled conditions, are analysed in terms of pixel greyscale values and distributions, and their usefulness in DPK studies is demonstrated in this study using acyclovir. METHODS: At all tape-stripped sites, the SC amount per tape was measured gravimetrically and by imaging. In a first series of experiments, untreated sites were stripped to determine total SC thickness. Subsequently, post-application of two acyclovir creams, drug permeation profiles were constructed. RESULTS: The greyscale values from the imaging data can be used directly to estimate total SC thickness and DPK parameters. The results compared favourably with the traditional weighing method. The concentration of drug on each tape, as a function of the relative position within the SC, permitted diffusivity and partitioning parameters characterising the penetration of acyclovir to be derived. CONCLUSION: The new imaging approach offers a sensitive, reproducible, precise, and rapid technique to quantify the relative SC amount removed on tape-strips, and facilitates the acquisition of DPK data. PMID- 22810837 TI - Surgical treatment of melanoma patients with early sentinel node involvement. AB - Sentinel lymph node biopsy (SLNB) is a standard staging procedure for many patients with clinically node negative, invasive melanoma, providing excellent prognostic information in appropriately selected patients. The broad acceptance of SLNB into clinical practice has resulted in substantial numbers of patients found to have microscopic nodal metastases. For patients with a positive sentinel node, a completion lymph node dissection (CLND) is the current standard of care. The majority of patients who undergo CLND are found to have histologically negative non-sentinel nodes, and yet are exposed to the potential morbidity of CLND, including infection, wound complications, and lymphedema. We do not yet know if there is a survival benefit from CLND that justifies its morbidity and we are currently unable to identify clinical and pathologic factors that may be associated with the likelihood of benefit from CLND. Controversy regarding the management of melanoma patients with a positive sentinel node highlights the need for continued investigation in melanoma biology, treatment, and outcomes. Patients with minimal tumor burden in their regional nodes would especially benefit from a better understanding of the appropriate management strategies. Ongoing clinical trials are aimed at determining whether CLND is superior to nodal observation and surveillance in patients with positive sentinel nodes, and at determining the outcome of patients with minimal disease in their sentinel node who forego CLND. These studies may help to resolve the uncertainties of the management in these patients. Until we have further information, CLND for melanoma patients with positive sentinel nodes remains the preferred, standard management strategy. PMID- 22810838 TI - Video-based gait analysis for functional evaluation of healing achilles tendon in rats. AB - Video-based walking track systems have been developed for gait analysis in rat models. However, there is no previous study using video-based tracking systems to address the gait parameters to evaluate the recovery of Achilles tendon rupture models. This study conducted a comprehensive gait analysis using a video-based image processing system. Eighteen Sprague-Dawley rats were randomly assigned to one of three interventional conditions: sham surgery, Achilles tendon repair, and Achilles tendon defect. After surgery, all animals were evaluated using a video based walking track system. The gait parameters and the Achilles functional index (AFI) were further analyzed. The ankle joint angles of the injury side at mid stance and pre-swing were highly correlated with the AFI. However, lack of sensitivity was found for the AFI. Increased measurement sensitivity of the Achilles tendon healing condition was found in the ankle joint angle of the involved side at the pre-swing and the level of asymmetry of the hindlimb joint position and stance/swing time. The overall sensitivity of the ankle motion analysis was significantly higher than that of AFI. We conclude that the ankle motion analysis is a reliable, reproducible, and sensitive tool for Achilles tendon analysis in rats. PMID- 22810839 TI - In vivo tracking of superparamagnetic iron oxide nanoparticle labeled chondrocytes in large animal model. AB - Chondrocytes have been widely used as tissue engineered seed cells for repair of focal cartilage lesions in clinic. However, in vivo behaviors of delivered chondrocytes are still poorly understood. In this study, the feasibility of in vivo tracking of superparamagnetic iron oxide nanoparticle (SPIO)-labeled chondrocytes by magnetic resonance imaging (MRI) for articular cartilage repair in minipig model was investigated. Results showed that chondrocytes were efficiently labeled by SPIO at optimal low dosages while maintaining essential cell properties. MRI SET2WI sequence revealed that marked hypointense signal void areas representing the transplanted labeled chondrocytes could be observed for at least 12 weeks. Histochemical staining confirmed the presence of Prussian blue positive cells and GFP-positive cells at the hypointense signal void areas. These findings provide knowledge on the in vivo tracking of SPIO labeled chondrocytes on cartilage repair following transplantation in minipigs. PMID- 22810840 TI - Time-frequency approaches for the detection of interactions and temporal properties in renal autoregulation. AB - We compare the influence of time-frequency methods on analysis of time-varying renal autoregulation properties. Particularly, we examine if detection probabilities are similar for amplitude and frequency modulation for a modulated simulation signal among five time-frequency approaches, and if time-varying changes in system gain are detected using four approaches for estimating time varying transfer functions. Detection of amplitude and frequency modulation varied among methods and was dependent upon background noise added to the simulated data. Three non-parametric time-frequency methods accurately detected modulation at low frequencies across noise levels but not high frequencies; while the converse was true for a fourth, and a fifth non-parametric approach was not capable of modulation detection. When applied to estimation of time-varying transfer functions, the parametric approach provided the most accurate estimations of system gain changes, detecting a 1 dB step increase. Application of the appropriate methods to laser Doppler recordings of cortical blood flow and arterial pressure data in anesthetized rats reaffirm the presence of time-varying dynamics in renal autoregulation. An increase in the peak system gain and detection of amplitude modulation of the Myogenic mechanism both occurred after inhibition of nitric oxide synthase, suggesting a connection between the operation of underlying regulators and system performance. PMID- 22810841 TI - High sodium intake is associated with masked hypertension in Japanese patients with type 2 diabetes and treated hypertension. AB - BACKGROUND: Knowledge regarding the association between dietary sodium intake and the incidence of masked hypertension is limited. METHODS: A total of 193 Japanese type 2 diabetic outpatients who had been treated with antihypertensive agents and with office blood pressures <140/90 mm Hg were recruited. Masked hypertension was defined as having office blood pressure <140/90 mm Hg and 24-h mean ambulatory blood pressure >=130/80 mm Hg. The dietary sodium intake was estimated by measuring the 24-h urinary sodium excretion. RESULTS: Masked hypertension was found in 128 (66.3%) patients. An age- and sex-adjusted univariate logistic regression analysis showed that urinary albumin excretion, renin-angiotensin system inhibitor use, office systolic blood pressure, and amount of dietary sodium intake were significantly associated with masked hypertension. A multivariate logistic regression analysis also identified an older age, renin angiotensin system inhibitor use, an office elevated systolic blood pressure, and high dietary sodium intake to be independently associated with masked hypertension. When compared with those who consumed a low salt diet (sodium <120 mEq/day), the odds ratio for the risk of exhibiting masked hypertension in patients who consumed a medium salt diet (sodium 120 to <200 mEq/day) or a high salt diet (sodium >=200 mEq/day) were 5.3 (P < 0.001) and 12.6 (P < 0.001), respectively. CONCLUSIONS: Masked hypertension is a common feature in type 2 diabetic patients being treated for hypertension. The observed association with sodium intake raised the hypothesis that excessive sodium intake may play a part in the genesis of masked hypertension in these patients. PMID- 22810842 TI - Long-term effectiveness of non-drug recommendations to treat hypertension in a clinical setting. AB - BACKGROUND: Nonpharmacological interventions have been efficacious to control blood pressure (BP) in clinical trials, but their long-term effectiveness in clinical practice was still not documented. METHODS: This is a prospective cohort study of 825 patients who received repeated nonpharmacological recommendations to treat hypertension. The outcomes were BP change and rate of BP control by pattern of adherence (informed by the patients) to the recommendations to follow low-salt and low-calorie diets and to do physical activities. RESULTS: Patients were followed for 23.1 +/- 8.4 months. Between group deltas of BP change in patients with and without adherence to the low-salt diet, adjusted for baseline BP, body mass index (BMI), age, and number of drugs in use, were 5.1 (95% confidence interval: 1.7-8.6) mm Hg for systolic (P = 0.003) and 2.1 (0.2-3.9) mmHg for diastolic BP (P = 0.02). For adherence to low-calorie diet, the deltas were 6.6 (2.9-10.2) mm Hg (P < 0.001) and 2.0 (0.1-3.9) mm Hg (P = 0.045). Adherence to physical activities was not associated with a BP-lowering effect. Relative risks for a fall of 10 mm Hg in systolic or 5 mm Hg in diastolic BP, with adjustment for confounding, were 0.69 (95% confidence interval: 0.55-0.87) for adherence to the low-salt diet, 0.83 (0.66-1.05) for low-calorie diet, and 0.99 (0.79-1.24) for exercise. CONCLUSIONS: Adherence to low-salt and low-calorie diets is associated with clinically relevant long-term BP reduction and better hypertension control in a clinical setting. PMID- 22810843 TI - Leg blood pressure measured in orthostatic posture is associated with left ventricular mass in normotensive subjects. AB - BACKGROUND: Changing from a supine to an orthostatic posture is associated with substantial increments in leg blood pressure (BP) levels, which could ultimately influence the hemodynamic burden imposed on the heart. This study investigated the relationship between brachial and leg BP measurements and the left cardiac chamber's structure and assessed the role of body posture changes in this regard. METHODS: One hundred and thirty normotensive, nondiabetic, nonsmoking, normolipemic subjects were evaluated by a clinical history, anthropometry, the analysis of metabolic parameters, echocardiography, and the measurement of BP in the arm and the calf in both supine and orthostatic positions. RESULTS: Significant correlation coefficients between the leg BP measurements and the cardiac structure were detected, especially between the orthostatic pulse pressure (PP) and the left ventricular (LV) wall thickness (r = 0.38; P < 0.001), the orthostatic PP and the LV mass (r = 0.37; P < 0.001), and the orthostatic systolic BP (SBP) and the left atrial size (r = 0.35; P < 0.001). Stepwise and standard regression analysis adjusted for brachial BP and anthropometric and metabolic variables confirmed that the leg orthostatic PP was independently related to the LV wall thickness and mass. Moreover, the leg orthostatic SBP was associated with the left atrial dimension even after adding the LV mass to the statistical models. Finally, triglyceride levels and body surface area showed significant relationship with leg orthostatic PP and SBP, whereas brachial orthostatic PP and SBP were only associated with age and anthropometric variables. CONCLUSIONS: Orthostatic leg BP is independently associated with the cardiac structure in normotensive subjects. PMID- 22810844 TI - Association of frailty syndrome in the elderly with higher blood pressure and other cardiovascular risk factors. AB - BACKGROUND: Few studies have evaluated blood pressure (BP) and cardiovascular risk in older persons with frailty syndrome. The objective of the present study was to assess the cardiovascular risk factors of subjects with frailty syndrome with emphasis on BP, as compared with individuals without frailty or with prefrailty. METHODS: This was a cross-sectional study in which 77 frail, prefrail, and nonfrail older subjects were selected according to the criteria of Fried et al.: self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. Anthropometric and BP measurements were obtained in the office, and home blood pressure monitoring (HBPM) and ambulatory blood pressure monitoring (ABPM) were also performed. Fasting glucose and plasma lipids were collected. Data were analyzed by linear fixed effects model and ANOVA. RESULTS: Mean age was 74.5 +/- 7.5 years. There was no difference in office BP or HBPM between groups, but ABPM of frail group demonstrated higher systolic and diastolic BP values over the 24 h (135/74 mm Hg, P = 0.02 and P = 0.04) and during sleep (135/74 mm Hg, P = 0.01 and P = 0.02) than nonfrail group (122/68 mm Hg and 120/67 mm Hg, respectively). Body mass index and fasting glucose were similar among groups, although abdominal circumference was greater (P = 0.04) and high-density lipoproteins (HDL) were lower (P = 0.03) in the frail group than nonfrail one (P = 0.04). CONCLUSIONS: Subjects with frailty syndrome had higher BP evaluated by ABPM and other cardiovascular risk factors such as lower HDL and more abdominal fat than nonfrailty group. PMID- 22810845 TI - Association of blood pressure with the start of renal replacement therapy in elderly compared with young patients receiving predialysis care. AB - BACKGROUND: In the growing elderly predialysis population, little is known about the effect of identified risk factors on the progression to end-stage renal disease. Therefore, we investigated the association of systolic (SBP) and diastolic blood pressure (DBP) with the start of renal replacement therapy (RRT), in elderly (>=65 years) compared with young (<65 years) predialysis patients. METHODS: In the PREPARE-1 cohort, 547 incident predialysis patients, referred as part of the usual care to eight Dutch predialysis care outpatient clinics, were included (1999-2001) and followed until the start of dialysis, transplantation, death, or until 1 January 2008. The outcome was the start of RRT. All analyses were stratified for age; <65 years (young) and >=65 years (elderly). RESULTS: In young predialysis patients (n = 268) higher SBP (every 20 mm Hg increase) and high DBP (DBP >=100 mm Hg compared with 80-89 mm Hg) were associated with a higher rate of starting RRT (adjusted hazard ratio (HR) (95% confidence interval) 1.21 (1.09;1.34) and 1.74 (1.16;2.62), respectively). However, in elderly predialysis patients (n = 240) only patients with SBP >=180 mm Hg had an increased rate compared with patients with 140-159 mm Hg (adjusted HR 2.33 (1.41;3.87)). Furthermore, patients with DBP <70 or >=100 mm Hg had an increased rate of starting RRT, independent of SBP, compared with patients with 80-89 mm Hg (fully adjusted HR 1.72 (1.01;2.94) and 2.05 (1.13;3.73), respectively). CONCLUSIONS: The association of SBP and DBP with the start of RRT is different between elderly and young predialysis patients. PMID- 22810846 TI - Osteolipoma presenting as a submandibular mass: a rare presentation. AB - Osteolipomas are rare tumors, particularly in the head and neck region, in contrast to lipomas which are the most common benign neoplasms in this location. Osseous changes are benign and mainly occur in long-standing lipomas. Despite its rarity, this neoplasm has a characteristic histopathologic appearance with lamellar bony spicules within the mature adipose tissue. Of the 19 cases previously reported in the oropharyngeal area, only two were located in the submandibular region. We report the third case of submandibular osteolipoma, presenting as an asymptomatic mass in a middle-aged man. Our review of head and neck osteolipomas would be of particular interest to pathologists and head and neck surgeons, in order to avoid inappropriate treatment of an otherwise benign lesion. PMID- 22810847 TI - Laminin induced local axonal translation of beta-actin mRNA is impaired in SMN deficient motoneurons. AB - Reduced levels of the SMN (survival of motoneuron) protein cause spinal muscular atrophy, the main form of motoneuron disease in children and young adults. In cultured motoneurons, reduced SMN levels lead to disturbed axon growth that correlates with reduced actin mRNA and protein in growth cones, indicating that anterograde transport and local translation of beta-actin mRNA are altered in this disease. However, it is not fully understood how local translation of the beta-actin mRNA is regulated in SMN-deficient motoneurons. Here, we established a lentiviral GFP-based reporter construct to monitor local translation of beta actin mRNA. Time-lapse imaging of fluorescence recovery after photobleaching (FRAP) in living motoneurons revealed that beta-actin is locally translated in the growth cones of embryonic motoneurons. Interestingly, local translation of the beta-actin reporter construct was differentially regulated by various Laminin isoforms, indicating that Laminins provide extracellular cues for the regulation of local translation in growth cones. Notably, local translation of beta-actin mRNA was deregulated in motoneurons from a mouse model for the most severe form of SMA (Smn(-/-);SMN2). Taken together our findings suggest that local translation of beta-actin in growth cones of motoneurons is regulated by Laminin signalling and that this signalling is disturbed in SMA. PMID- 22810849 TI - epsilon-Keggin-based coordination networks: Synthesis, structure and application toward green synthesis of polyoxometalate@graphene hybrids. AB - Four coordination networks based on the {epsilon PMo(V)(8)Mo(VI)(4)O(40)(OH)(4)Zn(4)} Keggin unit (epsilonZn) have been synthesized under hydrothermal conditions. (TBA)(3){PMo(V)(8)Mo(VI)(4)O(36)(OH)(4)Zn(4)}[C(6)H(4)(COO)(2)](2) (epsilon(isop)(2)) is a 2D material with monomeric epsilonZn units connected via 1,3 benzenedicarboxylate (isop) linkers and tetrabutylammonium (TBA) counter cations lying between the planes. In (TPA)(3){PMo(V)(8)Mo(VI)(4)O(37)(OH)(3)Zn(4)}[C(6)H(3)(COO)(3)] (TPA[epsilon(trim)](infinity)), 1D inorganic chains formed by the connection of epsilonZn POMs, via Zn-O bonds, are linked via 1,3,5 benzenetricarboxylate (trim) ligands into a 2D compound with tetrapropylammonium (TPA) cations as counter cations. (TBA){PMo(V)(8)Mo(VI)(4)O(40)Zn(4)}(C(7)H(4)N(2))(2)(C(7)H(5)N(2))(2).12H(2)O (epsilon(bim)(4)) is a molecular material with monomeric epsilonZn POMs bound to terminal benzimidazole (bim) ligands. Finally, (TBA)(C(10)H(10)N(4))(2)(HPO(3)){PMo(V)(8)Mo(VI)(4)O(40)Zn(4)}(2)(C(10)H(9)N(4))( )(C(10)H(8)N(4)) (epsilon(2)(pazo)(4)) is a 1D compound with dimeric (epsilonZn)(2) POMs connected by HPO(3)(2-) ions and terminal para-azobipyridine (pazo) ligands. In this compound an unusual bond cleavage of the central N[double bond, length as m-dash]N bond of the pazo ligand is observed. We report also a green chemistry-type one-step synthesis method carried out in water at room temperature using epsilon(2)(pazo)(4) and epsilon(isop)(2) as reducing agent of graphite oxide (GO) to obtain graphene (G). The POM@G hybrids were characterized by X-ray photoelectron spectroscopy, Raman spectroscopy, powder X-ray diffraction, energy dispersive X-ray analysis, infrared spectroscopy, scanning electron microscopy, transmission electron microscopy and cyclic voltammetry. PMID- 22810848 TI - Cancer cachexia alters intracellular surfactant metabolism but not total alveolar surface area. AB - Dyspnoea is frequently observed in cancer cachectic patients. Little is known whether this is accompanied by structural or functional alterations of the lung. We hypothesized that in analogy to calorie restriction cancer cachexia leads to loss of alveolar surface area and surfactant. Mice were subjected to subcutaneous injection of Lewis lung carcinoma cells (tumour group, TG) or saline (control group, CG). Twenty-one days later blood samples and the lungs were taken. Using design-based stereology, the alveolar surface area and the lamellar body (Lb) content were quantified. Messenger RNA expression of surfactant proteins, ABCA3 and various growth factors was investigated by quantitative RT-PCR. Intraalveolar surfactant subtype composition was analyzed by differential centrifugation. TG mice showed reduced body weight and anaemia but no reduction of lung volume or alveolar surface area. The volume of Lb was significantly reduced and mRNA levels of ABCA3 transporter tended to be lower in TG versus CG. Surfactant protein expression and the ratio between active and inactive intraalveolar surfactant subtypes were not altered in TG. Growth factor mRNA levels were not different between CG and TG lungs but the tumour expressed growth factor mRNA. Vascular endothelial growth factor was significantly enhanced in blood plasma. The present study demonstrates structural alterations of the lung associated with cancer cachexia. These include reduction of Lb content despite normal intraalveolar surfactant and alveolar surface area. The pulmonary phenotype of the cancer cachectic mouse differs from the calorie restricted mouse possibly due to growth factors released from the tumour tissue. PMID- 22810851 TI - Emergency department of a university hospital: who is admitted and who is transferred? AB - OBJECTIVES: Our main aim was to describe the path of patients seen in our emergency department (ED) and either admitted or transferred and to compare the characteristics of patients hospitalized in our hospital with those of transferred patients. Our secondary aim was to compare the receipts linked to patient hospital stays. POPULATION AND METHODS: All patients seen in the ED of our hospital and ill enough to be either admitted or transferred were prospectively enrolled during 2 consecutive weeks. Information was obtained from the hospital discharge report and from local medical databases. The characteristics of the patients and receipts were compared according to their path. RESULTS: Among the 251 patients included in the study, 9% were transferred directly from the ED to another hospital. Among admitted patients, two-thirds were admitted to the short-stay unit (SSU). Schematically, patients transferred from the ED are more likely to be men around 50 years of age with few comorbidities, requiring surgery with relatively short hospital stays. Patients transferred from the SSU were more likely to be women around 67 years of age with severe comorbidities requiring medical care and longer stays. The mean receipt per day was two to three times greater for patients transferred from the ED as compared with patients hospitalized in our hospital. The mean receipt per day for patients transferred from the SSU also tended to be higher. CONCLUSION: Our results show that patients requiring shorter care are transferred, whereas more severe patients are hospitalized on site. Hospitals will need solutions to optimize their receipts while fulfilling their public missions such as continuity of care. PMID- 22810850 TI - Patients who present to the emergency department and leave without being seen: prevalence, predictors and outcomes. AB - OBJECTIVE: To identify the prevalence, predictors and outcomes of patients who leave without being seen (LWBS) in one hospital emergency department (ED). MATERIALS AND METHODS: A descriptive, retrospective cohort study design was used. Data were extracted from the ED Information System. Multivariate logistic regression identified independent predictors of patients who LWBS. Two main outcomes were studied: the proportion of patients who waited longer than recommended and the proportion of patients who represented to the ED within 72 h. SETTING: A large regional teaching hospital ED in South East Queensland, Australia. SAMPLE: A total of 64 292 patient presentations made to the ED from 9 August 2008 to 8 August 2009. RESULTS: The prevalence of patients who LWBS was 10.7%. Independent predictors of LWBS included younger age, lower urgency triage category allocation, arrival by means other than ambulance, evening and night shift presentations, winter season, weekend presentations and presenting complaint category of 'gastrointestinal' or 'paediatric'. When compared with patients who waited, those who LWBS comprised higher proportions of waiting longer than recommended (LWBS: 77.2% vs. waited: 52.0%, P<0.001) and higher proportions of representations to ED within 72 h (LWBS: 10.3% vs. waited: 5.4%, P<0.001). CONCLUSION: Outcomes investigated in this study indicate that room for improvement exists not only for patients who LWBS but all patients presenting to the ED. The most powerful predictors of LWBS were lower urgency triage allocation and evening and night shift presentations. This suggests that service improvements could be targeted during 'out of business hours' for those with less emergent conditions. PMID- 22810852 TI - Vascular scaffolding to seal giant aneurysms: a new technique. PMID- 22810853 TI - Challenges for nanomechanical sensors in biological detection. AB - Nanomechanical biosensing relies on changes in the movement and deformation of micro- and nanoscale objects when they interact with biomolecules and other biological targets. This field of research has provided ever-increasing records in the sensitivity of label-free detection but it has not yet been established as a practical alternative for biological detection. We analyze here the latest advancements in the field, along with the challenges remaining for nanomechanical biosensors to become a commonly used tool in biology and biochemistry laboratories. PMID- 22810857 TI - Journal information. PMID- 22810854 TI - Illiteracy and schizophrenia in China: a population-based survey. AB - PURPOSE: Illiterate people may frequently experience social discrimination and exclusion in our modern society. It has been suggested that social adversity increases risk of schizophrenia. The current study examines the relation between illiteracy and schizophrenia. METHODS: We utilized data on 1,909,205 representative Chinese people of age 18 years or older collected by the Second China National Sample Survey on Disability in 2006 (participation rate 99.8%). Experienced clinical psychiatrists diagnosed schizophrenia among those who were psychiatrically disabled with the ICD-10 symptom checklist. RESULTS: Strikingly high prevalence of schizophrenia was observed among the young illiterates aged 18 29 years (prevalence 1.64%, 95% confidence interval (CI) 1.35, 1.93) and 30-39 years (prevalence 1.51%, 95% CI 1.34, 1.68), much higher than the prevalence estimates for general Chinese population of similar age reported by any of the previous studies in mainland China. Among people aged less than 40 years, we found that the illiterates were 2.08 times more likely to develop schizophrenia than the literates with no school or primary school education (odds ratio (OR) = 2.08, 95% CI 1.84, 2.36). The association remained statistically significant after adjustment for age, gender, marital status, household income, and location of residence. Consistently, a strong association between illiteracy and schizophrenia (OR = 2.8, 95% CI 1.28, 6.11) was found in conditional logistic regression analysis among matched sibling sets aged less than 40 years that further adjusted for genetic confounding. CONCLUSION: The risk of schizophrenia may have increased among the socially disadvantaged illiterate people. PMID- 22810859 TI - Editor's Preface. PMID- 22810860 TI - Introduction: the evolving field of neurorehabilitation. AB - Over the past 15 years, our understanding of how the nervous system responds to brain injury, spinal cord injury, and stroke has expanded exponentially. Research demonstrates that the CNS, once thought to be unable to regenerate, maintains a degree of plasticity that responds to activity and pharmacologic therapy, producing both neurophysiologic changes and clinical recovery. Removing barriers to optimize axonal regrowth appears to further enhance this plasticity. Functional imaging, magnetic stimulation, and quantitative electroencephalography allow investigators to localize and monitor changes in brain activity during both spontaneous recovery and treatment paradigms. Neurorehabilitation research is difficult and funding is insufficient. Newer research approaches and better collaboration between researchers and clinicians are warranted. Clinical adoption is slow because of cost and time pressures. Demonstration that treatments promoting CNS plasticity result in better functional outcomes and reduced overall costs is needed. PMID- 22810861 TI - Neurologic examination in rehabilitation. AB - The focus of the neurologic examination of the patient with rehabilitation needs is on determining deficits that impair functional recovery and identifying a patient's ability to carry out certain tasks. This article discusses the "team concept" of rehabilitation and the roles of each of the team members, including the rehabilitation physician. The article also reviews the aspects of the neurologic examination as they specifically relate to the patient undergoing rehabilitation. PMID- 22810862 TI - Cognitive and behavioral disorders in neurorehabilitation. AB - Assessment and management of cognitive and behavioral issues in the neurorehabilitation of patients with brain injuries are extremely important. Because cognitive impairments can impede post-brain injury adaptive functioning, it is necessary to carefully assess the major neurocognitive functions to help determine potential obstacles to rehabilitation and to plan for effective interventions. Likewise, behavioral and emotional problems following brain injury, whether directly or secondarily caused by the injury, can hamper or undermine what may otherwise be an efficacious rehabilitative treatment plan. This article describes some of the most common cognitive, emotional, and behavioral deficits and provides practical suggestions about how to address them. PMID- 22810863 TI - Treatment of language, motor speech impairments, and Dysphagia. AB - Language, speech, cognitive-associated communication deficits, and dysphagia are common following acquired brain injury (stroke, traumatic brain injury, and others). Treatment of these disorders can be divided into restorative, compensatory, and supportive approaches. Although therapy must be individualized for each person, components of all three approaches are necessary to maximize an individual's recovery. This article provides a general overview of traditional as well as state-of-the-art treatment for aphasia, cognitive-linguistic impairments, dysarthria, apraxia, and dysphagia. PMID- 22810864 TI - Orthoses and adaptive equipment. AB - In the past decade, advancements in orthoses have focused on using concepts of functional electrical stimulation, constraint-induced movement therapy, and robotic mechanisms. This article reviews newer technologies in orthotic use as well as common orthoses used in stroke, traumatic brain injury, and other neuromuscular disorders. A review of the gait cycle focuses on impairments caused by the neurologic disorder and the use of orthoses to help obtain a more functional gait. Adaptive equipment enables one to increase independence, decrease energy expenditure, and reduce pain. Common adaptive equipment used in the home setting, an integral part of neurorehabilitation, is also reviewed. Finally, the role of medications in treating spasticity to aid use of adaptive equipment, optimize orthotic use, and improve one's gait cycle is examined. PMID- 22810865 TI - Management of medical complications. AB - Medical comorbidities and complications are expected following stroke, traumatic brain injury, and spinal cord injury. The neurorehabilitation physician's role is to manage these comorbidities, prevent complications, and serve as a medical and neurologic resource for the patient, family, and neurorehabilitation team. The most common comorbidities are similar to those found in the general population, namely hypertension, dyslipidemia, diabetes mellitus, and ischemic heart disease. Frequent complications encountered in the neurorehabilitation unit relate to medication side effects, medical comorbidities, and the direct effect of the neurologic injury. They include orthostatic hypotension; syncope or presyncope; cardiac arrhythmia; bowel and bladder dysfunction; seizures; pressure sores; dysphagia-related pneumonia, dehydration, and malnutrition; venous thromboembolism; falls; and sexual dysfunction. This article discusses strategies for managing comorbidities and avoiding complications. PMID- 22810866 TI - Emerging therapies in neurorehabilitation. AB - Just as advancing technology has furthered our understanding of how the nervous system recovers, technology also enables the development of novel approaches to treatment. Because nervous system disease and injury often lead to severely impaired function, patients and families are willing to try anything, so therapies are often adopted with little evidence that they actually work. Evidence shows that comprehensive rehabilitation programs produce better outcomes, but it is still not understood what components of these multifaceted programs are critical to their success. Functional neuroimaging and other modalities now allow monitoring of neurophysiologic changes that can be paired with assessments detailing clinical changes, furthering our understanding of the factors that influence the recovery process. This article discusses several novel and emerging therapies in neurorehabilitation as well as recent multistudy reviews of selected treatments. PMID- 22810867 TI - Stroke rehabilitation. AB - Despite improvements in prevention and acute management, stroke remains a common condition and a major cause of permanent disability. For patients who have had a stroke, an effective rehabilitation program is critical to maximize functional recovery and quality of life. Rehabilitation can occur in a number of different physical settings and is often coordinated by a comprehensive interdisciplinary team of professionals. Rehabilitation includes retraining to regain loss of function and teaching compensatory strategies when that is not possible. A number of interesting training approaches have been developed in recent years to supplement more traditional rehabilitation programs. A variety of adaptive devices is available to improve mobility and performance of self-cares, and these devices should be prescribed for appropriate patients. Physicians caring for patients during stroke rehabilitation must be aware of potential medical complications, as well as a number of special problems that may complicate recovery, including dysphagia, urinary incontinence, shoulder pain, spasticity, falls, and poststroke depression. Involvement of the patient and caregivers in the rehabilitation process is essential. It is important to train and educate these individuals in the physical aspects of poststroke care, the expectations for recovery, and secondary stroke prevention. Issues related to community reintegration, including driving and vocational aspects, should be addressed in appropriate patients. Stroke rehabilitation is an important part of the "stroke continuum of care," which includes prevention, acute management, rehabilitation, and secondary prevention. PMID- 22810868 TI - Spinal cord injury. AB - A spinal cord injury is a devastating, life-changing neurologic event that challenges patients, families, and caregivers. A myriad of neurologic and medical sequelae occur subsequent to the original insult. This article discusses epidemiology, primary and secondary injuries, acute therapy, and neuroprotective agents as well as the exciting areas of spinal cord recovery and regeneration, with an emphasis on cellular transplantation. Neurologic neurorehabilitation techniques and equipment are also reviewed, with a focus on their relation to increasing the independence and functional capacity of the patient. The article concludes with the clinical presentation and management of common spinal cord injury complications. PMID- 22810869 TI - Traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability in both children and adults. TBI is complex, as it involves injury to multiple brain areas caused by both the initial injury and secondary events. The most persistent sequelae of TBI are cognitive and behavioral, reflecting the fact that the preponderance of damage is to the frontal lobes. Although the sequence of recovery follows a pattern, TBI is a heterogeneous disorder and rehabilitation programs must be tailored to the needs of the individual and his or her social situation. Specific therapy approaches, environmental structure, and medications all play a role. Many of the emerging approaches to facilitating CNS plasticity can be applied. PMID- 22810870 TI - Neurorehabilitation for other neurologic disorders. AB - Rehabilitation treatment and the interdisciplinary approach to care may improve the function of those with progressive neurologic disorders such as multiple sclerosis, Parkinson disease, ALS, muscular dystrophy, and neuropathy. Appropriate goals and therapies are specific to the stage of the disease as well as the needs and values of the individual patient. Preliminary evidence exists to support moderate aerobic and strengthening regimens in these patients. Close monitoring and avoidance of fatigue are paramount. Assistive technologies play an ever-increasing role in maintaining independence during all stages of the disease. PMID- 22810871 TI - Management of acute neurorehabilitation programs. AB - Outcome management, performance improvement, evidence-based practice, and policy payment mechanisms are critical operational drivers at every level of health care delivery. It is essential that all health care providers involved in patient care have a working knowledge of health care operations, including the policies and reimbursement mechanisms that drive their particular clinical practice. Providing excellent patient care includes understanding health care policies, regulations, and outcomes that have a historical and current impact on health care delivery. Some of these factors include patient access, patient safety, and information measurement and management. Inpatient acute neurorehabilitation programs have standard outcome measures and a unique set of fiscal rules and regulations. This article discusses the most common variables and terms found in program evaluation systems for acute neurorehabilitation programs as well as some of the clinical and regulatory requirements and reimbursement and level-of-care considerations that are critical for neurorehabilitation health care practitioners. The current health care environment requires providers to understand and continually evaluate quality outcomes, patient access, and patient safety, all within the confines of an efficacy-based care delivery system. PMID- 22810872 TI - The review of systems in spinal cord injury and dysfunction. AB - Individuals with spinal cord injury or dysfunction represent unique diagnostic challenges when they present with symptoms of generalized malaise or "feeling lousy." Those individuals with injury or dysfunction at or above the T6 level are specifically at risk for the phenomenon known as autonomic dysreflexia, which is a medical emergency. The underlying cause of autonomic dysreflexia as well as other secondary complications in the patient with a spinal cord injury can best be uncovered through a comprehensive review of systems, which encompasses constitutional, head, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, respiratory, skin, neurologic, psychiatric, endocrinologic, hematologic, and immunologic issues. PMID- 22810873 TI - Coding table. PMID- 22810874 TI - The limits of parental authority to accept or refuse medical treatment. AB - The legal and ethical right of parents to refuse medical treatment for their children differs from the authority possessed by competent adults with decisional capacity. Parents have a duty to act in the best interests of their children from the children's perspective and not to inflict harm. Best interests are determined by weighing benefits and burdens, which includes using evidence-based outcomes and value judgments. The result is placed along a risk/benefit spectrum. If the result is close to low risk/high benefit, the parents have a strong obligation to accept a health care team recommendation. Otherwise, parents may choose between reasonable medical options without threat or coercion. PMID- 22810876 TI - APPENDIX B: Rancho Los Amigos Scale-Revised. PMID- 22810875 TI - APPENDIX A: American Spinal Injury Association Standard Neurological Classification of Spinal Cord Injury. PMID- 22810877 TI - APPENDIX C: Rehabilitation Impairment Categories and Associated Impairment Group Codes. PMID- 22810879 TI - APPENDIX E: Definitions of Cognitive Functional Independence Measure Items. PMID- 22810878 TI - APPENDIX D: Definitions of Motor Functional Independence Measure Items. PMID- 22810881 TI - Multiple-choice questions. PMID- 22810882 TI - Multiple-choice questions-preferred responses. PMID- 22810883 TI - Patient management problem. PMID- 22810884 TI - Patient management problem-preferred responses. AB - Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study. PMID- 22810885 TI - Return to work and clinical outcome after open wedge HTO. AB - PURPOSE: The purpose of this study was to examine the incapacity of work related to work load according to the classification that has been introduced by the REFA Association and the clinical outcome after open wedge HTO with autologous bone graft from the iliac crest. METHODS: A total of 32 patients who were employed and able to work at the time of the surgery as well as treated with an open wedge HTO with the LC-DCP and autologous bone wedges from the iliac crest could be included in the radiological and clinical examination (77 months, SD +/- 19). Postoperative duration of the incapacity of work and subjective ratings were based on the information provided by the patients themselves. The German classification that has been established by the REFA Association was used to classify the work load. Several clinical scores were used for clinical assessment. RESULTS: The duration of incapacity of work (median, 87 days; range, 14-450) demonstrated a relation to work load according to REFA. The Lysholm score, the HSS score and the score according to Lequesne augmented by 19.2 +/- 16.8 (p < 0.0001), 15.6 +/- 13.2 (p < 0.0001) and -6.0 +/- 5.1 (p < 0.0001), respectively. The Tegner score gained from median 3 (range, 1-5) to 4 (range, 1 8). CONCLUSION: In this study, a relation was found between work load divided into different categories according to the classification established by the REFA Association and the duration of incapacity of work after open wedge HTO. An improvement of all clinical scores was observed. Typical neurological complications after autologous bone transplantation from the iliac crest were observed in 19% of our patient population. LEVEL OF EVIDENCE: IV. PMID- 22810886 TI - PRP: more words than facts... PMID- 22810887 TI - The family medical history as a tool in preconception consultation. AB - A multigenerational medical family history graphically recorded as a pedigree or family tree is a cost-effective tool in preconception counseling to identify couples at risk to have offspring with inherited disorders and to identify if either partner has a personal risk for a disorder with a genetic etiology. Interpretation of a medical family history can provide risk assessment for reproductive planning and choices, inform a diagnosis to help identify a patient's medical screening needs and clinical management, and build rapport with the patient or couple. The use of standardized pedigree nomenclature is paramount to healthcare delivery as electronic medical records become universal. The trend towards having patients prepare a medical family history in advance of the first clinic visit is a way to empower patients to take charge of their health, and also allow health professionals to spend more focused time in confirming and interpreting family history at the visit instead of constructing family history. This article reviews standardized pedigree symbols, clues to identifying "red flags" in family history (with a focus on preconception genetic counseling), the pedigree as a psychosocial tool, and resources for obtaining a medical family history. PMID- 22810888 TI - Lack of benefit of preoperative antimicrobial prophylaxis in children with acute appendicitis: a prospective cohort study. AB - BACKGROUND: Preoperative antimicrobial prophylaxis is widely used in pediatric patients undergoing appendectomy, but evidence showing a reduction of postoperative infectious complications is lacking. METHODS: A prospective consecutive cohort study on changing from preoperative antimicrobial prophylaxis to no prophylaxis in children undergoing urgent appendectomy was undertaken. The impact of this change in management on postoperative infectious complications was evaluated by comparing the outcome in 100 patients receiving (group A) and a subsequent 100 patients not receiving prophylaxis (group B), which consisted of a preoperative single dose of intravenous metronidazole (10 mg/kg body weight). RESULTS: Histology confirmed acute appendicitis in 92 patients of group A and 95 patients of group B. In patients with histological simple appendicitis, postoperative infectious complications were noted in 2 (3.0 %) of 69 patients from group A and in none of 70 patients from group B, and in patients with histological perforated appendicitis in 5 (22 %) of 23 and 4 (16 %) of 25 patients from groups A and B, respectively. Postoperative infectious complications were more frequent (p < 0.05) in perforated than in simple appendicitis. These infectious complications included in simple appendicitis two wound infections in group A, and in perforated appendicitis four intraabdominal abscesses and one wound infection in group A and two intraabdominal abscesses and two wound infections in group B. CONCLUSION: Postoperative infectious complications were seen more often in patients with perforated appendicitis than in those with simple appendicitis. Preoperative antimicrobial prophylaxis with metronidazole did not reduce the rates of postoperative infectious complications. PMID- 22810889 TI - Bioresorbable scaffolds: current evidence and ongoing clinical trials. AB - Bioresorbable scaffolds (BRS) represent a novel approach in coronary stent technology. In contrast to the metallic stents, they provide transient scaffolding, thereby safeguarding early vessel patency and acute gain. Subsequently a process of "decomposition" occurs, that results in the complete absorption of the scaffold. This reduces the risk of late complications, allowing the vessel to maintain its integrity and physiological function. This unique ability has attracted interest and nowadays several BRS are available. The aim of this review article is to describe the advances in the field, present the evidence from the preclinical and clinical evaluation of these devices, and provide an overview of the ongoing clinical trials that were designed to examine the effectiveness of BRS in the clinical setting. PMID- 22810890 TI - Impact of community pharmaceutical care on patient health and quality of drug treatment in Parkinson's disease. AB - BACKGROUND: The well-being of patients with Parkinson's disease may be improved by pharmaceutical care in community pharmacies. OBJECTIVE: To investigate the effects of standardised pharmaceutical care on health outcomes and quality of drug treatment in patients with Parkinson's disease. SETTING: Community pharmacies in Germany. METHOD: An open-label, multicentre, longitudinal, parallel group study was conducted in outpatients with idiopathic Parkinson's disease who were receiving anti-parkinsonian medication. Patients were recruited by 32 community pharmacists (pharmacy group) and local offices of the German Parkinson's disease patients' association (comparison group). All patients were assessed at baseline and at 8 months' follow-up. In the intervening period, the pharmacists provided patients in the pharmacy group with standardised pharmaceutical care. MAIN OUTCOME MEASURE: Mean change in symptom-related impairment of health status, assessed using the 23-item Parkinson's Scale Total Score. RESULTS: In total 235 patients were enrolled into the study (113 pharmacy group; 122 comparison group). Between-group analysis showed that the mean changes in the primary and secondary endpoints, all 23-item Parkinson's Scale sub-scores and the EuroQol 5-Dimension Questionnaire Index Score were significantly in favour of the pharmacy group after 8 months (p < 0.05 to p < 0.001), using a mixed model analysis. No significant changes were observed in prescribers' guideline adherence, but there was a significant decrease in the proportion of patients receiving inappropriate drugs according to the Beers List in the pharmacy group (p < 0.01). CONCLUSION: This study shows that significant benefits in patient health outcomes and age-related quality of drug treatment were gained when patients with Parkinson's disease were provided with standardised pharmaceutical care in community pharmacies. PMID- 22810891 TI - Epidemiology and cost analysis of pharmacist interventions at Ghent University Hospital. AB - BACKGROUND: Performing bedside clinical recommendations is important for the prevention of adverse drug events. From an economic perspective, the economic value of adverse drug event avoidance needs to be weighed against the labour costs of pharmacists. OBJECTIVE: To perform a cost analysis of pharmacist interventions with valproic acid, digoxin, methotrexate and penicillin. SETTING: Ghent University Hospital in Belgium (1,062-beds). METHOD: Interventions for valproic acid, digoxin, methotrexate and penicillin were selected from a clinical pharmacy database, CLINOR. The average number of registered interventions per year was 1,209 (period 2005-mid 2011). MAIN OUTCOME MEASURE: Cost difference (cost value) between that of the avoided toxicity and that of the intervention (a positive cost value is cost saving). RESULTS: Per annum, pharmacists performed interventions for valproic acid (n = 18) and digoxin (n = 21); the annual cost value of interventions for valproic acid was ?18,853.7 with a standard deviation of ?15,020.6; for digoxin it was ?41,832.0 +/- ?15,348.5. With oral methotrexate, accidental toxicity occurs rarely but it can be life threatening. Two important pharmacist interventions were reported per year. The routine switching of penicillin therapy to alternative antibiotics, in patients with previous allergy, may invoke costs rather than benefits (two interventions per year). In half of cases, therapy was reinitiated without any further adverse drug event. CONCLUSION: Clinically important pharmacy interventions are not automatically cost beneficial. Interventions that prevent digoxin and valproic acid toxicity were cost effective in this setting. The routine advice to switch the antibiotic class for every reported penicillin allergy is unlikely to avoid adverse drug events and challenges the cost value of this intervention. Interventions with methotrexate are relevant because they can be lifesaving. However, due to their low incidence, effective detection of these errors is crucial for reducing harm. PMID- 22810893 TI - Sensitivity and specificity of a visual depression screening instrument among HIV positive individuals in Uganda, an area with low literacy. AB - Given the high prevalence of depression in PHC, the use of depression screening instruments has often been recommended. The aim of this study was to construct and validate a visual depression screening instrument in a setting of low literacy and a high burden of HIV/AIDS. We engaged the help of a fine artist to draw pictures depicting DSM-IV-TR criteria for a depressive episode. We then validated this instrument named the Akena's visual depression inventory (AVIDI), in 92 persons living with HIV/AIDS in Uganda. The performance of the AVIDI in those with high and low education levels was determined. The area under curve (AUC) score of the AVIDI was 0.82. There was no difference between the AUC scores in persons with lower versus higher education levels. The AVIDI demonstrated a good psychometric property and can therefore be used to screen for depression in settings with higher rates of illiteracy. PMID- 22810892 TI - Prevalence and correlates of non-disclosure of HIV serostatus to sex partners among HIV-infected female sex workers and HIV-infected male clients of female sex workers in India. AB - This study examines non-disclosure of HIV serostatus to sex partners among HIV infected adults involved with transactional sex in Mumbai, India. Surveys were conducted with HIV-infected female sex workers (n = 211) and infected male clients (n = 205) regarding HIV knowledge, awareness of sex partners' HIV serostatus, alcohol use, transactional sex involvement post-HIV diagnosis and non disclosure of HIV serostatus. Gender-stratified multiple logistic regression models were used for analysis. Non-disclosure of one's serostatus to all sex partners was reported by almost three-fifths of females and two-fifths of males. Predictors of non-disclosure included lack of correct knowledge about HIV and no knowledge of sex partners' HIV serostatus. Among females, recent alcohol consumption also predicted non-disclosure. Among males, 10 + paid sexual partners in the year following HIV diagnosis predicted non-disclosure. Secondary HIV prevention efforts in India require greater focus on HIV disclosure communication and integrated alcohol and sexual risk reduction. PMID- 22810894 TI - Voxel-based comparison of preoperative FDG-PET between mesial temporal lobe epilepsy patients with and without postoperative seizure-free outcomes. AB - OBJECTIVE: This study aims to elucidate differences in preoperative cerebral glucose metabolism between patients who did and did not become seizure free after unilateral mesial temporal lobe epilepsy (mTLE) surgery. We hypothesized that regional glucose metabolism on preoperative fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with seizure-free outcomes differed from that in patients who were not seizure free after appropriate epilepsy surgery for unilateral mTLE. In this study, we compared preoperative FDG-PET findings between these two patient groups by applying a statistical analysis approach, with a voxel-based Asymmetry index (AI), to improve sensitivity for the detection of hypometabolism. METHODS: FDG-PET scans of 28 patients with medically refractory mTLE, of whom 17 achieved a seizure-free outcome (Engel class 1 a-b) during a postoperative follow-up period of at least 2 years, were analyzed retrospectively. Voxel values were adjusted by the AI method as well as the global normalization (GN) method. Two types of statistical analysis were performed. One was a voxel severity analysis with comparison of voxel values at the same coordinate, and the other was extent analysis with comparison of the number of significant voxels in the anatomical areas predefined with Talairach's atlas. RESULTS: In the voxel severity analysis, significant hypometabolism restricted to the ipsilateral temporal tip and hippocampal area was detected in the postoperative seizure-free outcome group as compared to controls. No significant area was detected in the non-seizure-free group as compared to controls (family-wise error corrected, p < 0.05). With extent analysis using a low threshold, the extents of hypometabolism in the ipsilateral hippocampal, frontal and thalamic areas were larger in the seizure-free than in the non seizure-free group (p = 0.01, 0.03 and 0.01, respectively.) On the other hand, in the contralateral frontal and thalamic areas, extents of hypometabolism were smaller in the seizure-free than in the non-seizure-free group (p = 0.01 and 0.01). CONCLUSIONS: We found the preoperative distribution of hypometabolism to differ between the two patient groups. Severe hypometabolism restricted to the unilateral temporal lobe, with ipsilateral dominant hypometabolism including mild decreases, may support the existence of an epileptogenic focus in the unilateral temporal lobe and a favorable seizure outcome after mTLE surgery. PMID- 22810895 TI - GSK3-like kinases integrate brassinosteroid signaling and stomatal development. AB - Developmental pathways are often regulated by multiple signals, and a major challenge is to understand how the different signaling pathways triggered by these signals interact to modulate a specific process. Brassinosteroids (BRs) are plant hormones that regulate cell expansion, cell division, and photomorphogenesis. A key regulator in BR signaling, the GSK3- and SHAGGY-like kinase BRASSINOSTEROID INSENSITIVE2, regulates two distinct steps in the stomatal development signaling pathway to either enhance or inhibit this process. PMID- 22810896 TI - Epidermal growth factor receptor is essential for Toll-like receptor 3 signaling. AB - Toll-like receptors (TLRs) recognize specific microbial products and elicit innate immune signals to activate specific transcription factors that induce protective proteins, such as interferon. TLR3 is localized to endosomes and recognizes double-stranded RNA (dsRNA), which is generated by virally infected or apoptotic cells. TLR3 has been genetically linked to several human diseases, including some without viral etiology. Unlike other TLRs, TLR3 requires phosphorylation of two specific tyrosine residues in its cytoplasmic domain to recruit the adaptor protein TRIF (Toll-interleukin-1 receptor domain-containing adaptor protein inducing interferon-beta) and initiate the antiviral response. We showed that two protein tyrosine kinases, the epidermal growth factor receptor (EGFR) ErbB1 and Src, bound sequentially to dsRNA-activated TLR3 and phosphorylated the two tyrosine residues. In cells lacking EGFR or treated with an inhibitor of EGFR, viral replication was enhanced and induction of antiviral genes was impaired. Thus, these results reveal a connection between antiviral innate immunity and cell growth regulators. PMID- 22810898 TI - Synchronisation effects on the behavioural performance and information dynamics of a simulated minimally cognitive robotic agent. AB - Oscillatory activity is ubiquitous in nervous systems, with solid evidence that synchronisation mechanisms underpin cognitive processes. Nevertheless, its informational content and relationship with behaviour are still to be fully understood. In addition, cognitive systems cannot be properly appreciated without taking into account brain-body- environment interactions. In this paper, we developed a model based on the Kuramoto Model of coupled phase oscillators to explore the role of neural synchronisation in the performance of a simulated robotic agent in two different minimally cognitive tasks. We show that there is a statistically significant difference in performance and evolvability depending on the synchronisation regime of the network. In both tasks, a combination of information flow and dynamical analyses show that networks with a definite, but not too strong, propensity for synchronisation are more able to reconfigure, to organise themselves functionally and to adapt to different behavioural conditions. The results highlight the asymmetry of information flow and its behavioural correspondence. Importantly, it also shows that neural synchronisation dynamics, when suitably flexible and reconfigurable, can generate minimally cognitive embodied behaviour. PMID- 22810897 TI - Abl family kinases modulate T cell-mediated inflammation and chemokine-induced migration through the adaptor HEF1 and the GTPase Rap1. AB - Chemokine signaling is critical for T cell function during homeostasis and inflammation and directs T cell polarity and migration through the activation of specific intracellular pathways. Here, we uncovered a previously uncharacterized role for the Abl family tyrosine kinases Abl and Arg in the regulation of T cell dependent inflammatory responses and showed that the Abl family kinases were required for chemokine-induced T cell polarization and migration. Our data demonstrated that Abl and Arg were activated downstream of chemokine receptors and mediated the chemokine-induced tyrosine phosphorylation of human enhancer of filamentation 1 (HEF1), an adaptor protein that is required for the activity of the guanosine triphosphatase Rap1, which mediates cell adhesion and migration. Phosphorylation of HEF1 by Abl family kinases and activation of Rap1 were required for chemokine-induced T cell migration. Mouse T cells that lacked Abl and Arg exhibited defective homing to lymph nodes and impaired migration to sites of inflammation. These findings suggest that Abl family kinases are potential therapeutic targets for the treatment of T cell-dependent immune disorders that are characterized by chemokine-mediated inflammation. PMID- 22810899 TI - Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas. AB - BACKGROUND: Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes, including epidermal growth factor receptor (EGFR) and KRAS. Mutations in EGFR are associated with both improved survival as well as response to treatment with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and remains controversial. For the current report, the authors examined the association of EGFR and KRAS mutations with survival among patients with advanced lung adenocarcinomas. METHODS: Data were analyzed from patients with advanced lung adenocarcinomas who had known EGFR and KRAS mutation status evaluated between 2002 and 2009. The collected clinical variables included age, sex, Karnofsky performance status, smoking history, and treatment history. Overall survival from the diagnosis of advanced disease was analyzed using Kaplan-Meier and Cox proportional hazard methods. RESULTS: In total, 1036 patients were evaluated, including 610 women (59%) and 344 never-smokers (33%). The median patient age was 65 years (range, 25-92 years), and the majority of patients (81%) had a Karnofsky performance status >=80%. In multivariate analysis, EGFR mutations were associated with longer overall survival (hazard ratio, 0.6; P < .001), and KRAS mutations were associated with shorter survival (hazard ratio, 1.21; P = .048). CONCLUSIONS: KRAS mutations predicted shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are diagnosed with advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic factors. PMID- 22810900 TI - Synthesis of unsymmetrical biaryl ethers through nickel-promoted coupling of polyfluoroarenes with arylboronic acids and oxygen. AB - Polyfluoro-substituted unsymmetrical biaryl ethers were synthesized via a novel Ni-catalyzed cross-coupling reaction of polyfluoroarenes with arylboronic acids and oxygen. The polyfluorinated arenes presumably captured the phenoxide intermediate efficiently, which made the oxygen-insertion proceed smoothly via the S(N)Ar protocol. The (18)O labeling experiment demonstrated that the oxygen introduced into unsymmetrical diaryl ether originated from very trace amounts of oxygen in the reaction system. A plausible mechanism was also suggested. PMID- 22810902 TI - 1,2-Nucleophilic addition of 2-(picolyl)organoboranes to nitrile, aldehyde, ketone, and amide. AB - A series of 2-(picolyl)borane molecules were synthesized as products of the reaction between 2-(picolyl)lithium and R(2)BOMe (R = ethyl, 9-BBN, phenyl, 9 borafluorenyl). The 2-(picolyl)boranes were dimeric; whereas, monomers coordinated to LiOMe could be isolated when the synthesis was carried out in the presence of TMEDA and THF. The 2-(picolyl)boranes undergo reaction with nitriles, ketones, aldehydes, and amides with apparent 1,2-addition of the B-C(picolyl) bond to the unsaturated bond. Theoretical models reveal the presence of a donor orbital on the 2-(picolyl)borane with significant electron density at the benzylic carbon that we conclude was involved in nucleophilic attack on the electrophilic center of unsaturated organic functional groups. PMID- 22810903 TI - Structure refinement and superspace description of the system Bi(2(n + 2))Mo(n)O(6(n + 1)) (n = 3, 4, 5 and 6). AB - The system Bi(2(n + 2))Mo(n)O(6(n + 1)) is described within the superspace formalism. Two superspace models are proposed for the different members of this family, depending on the parity of the parameter n. The superspace model for the odd members is constructed through the embedding of the cationic distribution of the member with n = 3, and the modification of a superspace model previously proposed for the compound Bi(2)MoO(6). However, this model cannot be applied to the even members of the family. Performing the appropriate transformations, a suitable superspace model for the even members is obtained. The atomic structure of the different compounds of the family have been refined through the Rietveld method combining synchrotron X-ray and neutron powder diffraction data. PMID- 22810901 TI - Refractory celiac disease: from bench to bedside. AB - Refractory celiac disease is defined by the persistence of symptoms of malnutrition and intestinal villous atrophy for more than 6-12 months despite strict gluten-free diet in celiac patients. Diagnosis of this rare condition is made after excluding other causes of chronic small intestinal inflammation and villous atrophy and inadvertent intake of gluten. Over the past 15 years, multidisciplinary approaches have been developed to assess the mechanism of resistance to the diet, and two distinct entities have been delineated. Type II refractory celiac disease (RCD) can be defined as a low-grade intraepithelial lymphoma. RCD II is characterised by a massive accumulation of abnormal IEL that display an aberrant hybrid NK/T cell phenotype, contain clonal T cell rearrangement(s) and can mediate a cytolytic attack of the gut epithelium. This condition has a severe prognosis, largely due to the frequent transformation of RCDII IEL into overt aggressive enteropathy-type-associated T cell lymphoma. In contrast, in type I RCD, intestinal lymphocytes have a normal phenotype, and this generally milder condition remains often difficult to differentiate from uncomplicated CD except for the resistance to gluten-free diet (GFD). Several mechanisms may underlie resistance to gluten. Herein, we review the distinctive characteristics of RCD I and RCD II, the mechanisms underlying the onset of resistance to GFD, the risk of developing high grade lymphoma and possible clues to improve their treatment. PMID- 22810904 TI - Unified (3 + 1)-dimensional superspace description of the 2212-type stair-like [Bi2Sr3Fe2O9]m[Bi4Sr6Fe2O16] family of compounds. AB - The (3 + 1)-dimensional superspace approach is applied to describe and refine a series of sheared compounds related to layered high T(c) superconducting oxides. Two commensurate members (m = 4, 5) of the 2212 stair-like [Bi(2)Sr(3)Fe(2)O(9)](m)[Bi(4)Sr(6)Fe(2)O(16)] family of compounds, previously studied using single-crystal diffraction data, are analyzed. A common average unit cell has been identified and a composition-dependent modulation wavevector is proposed. The model is built using only three independent atomic domains, one for the metal atoms and two for the O atoms. The three Sr, Bi and Fe species are described using close-connected crenel-like functions forming a continuous atomic domain along the internal space. The two oxygen domains are represented by crenel functions and the displacive modulation functions are built up by Legendre polynomials recently implemented in the program JANA2006. Surprisingly, the results of the refinements show a striking similarity of the displacive modulations for the two compounds analyzed, indicating that a unique model can be used to describe the correlations between the atomic displacements of the 2212 stair-like series. This final model is then applied to predict the structure of new members of the family. PMID- 22810905 TI - The natural tiling approach to cation conductivity in KAlO2 polymorphs. AB - A detailed analysis of correlations between structural features and cation conductivity is performed for KAlO(2) polymorphs in a wide temperature range of 300-1023 K. To explore the migration maps of K(+) cations we have used neutron diffraction data for low- and high-temperature KAlO(2) polymorphs and applied for the first time a novel algorithm based on the natural tiling concept and implemented it into the program package TOPOS. Five independent elementary channels for the K(+) cation migration have been revealed whose cross-sections were found to be essentially different in the low-temperature form, indicating a high anisotropy of the cation conductivity. During the transition to the cubic high-temperature phase all five channels become equivalent with sharply increased cross-sections that account for the jump-like increase of the cation conductivity and gives rise to its three-dimensional character. PMID- 22810906 TI - On the charge transfer between conventional cations: the structures of ternary oxides and chalcogenides of alkali metals. AB - The structures of ternary oxides and chalcogenides of alkali metals are dissected in light of the extended Zintl-Klemm concept. This model, which has been successfully extended to other compounds different to the Zintl phases, assumes that crystal structures can be better understood if the cation substructures are contemplated as Zintl polyanions. This implies the occurrence of charge transfer between cations, even if they are of the same kind. In this article, the charge transfer between cations is even more illustrative because the two alkali atoms have different electronegativity, so that the less electropositive alkali metal and the O/S atom always form skeletons characteristic of the group 14 elements. Thus, partial structures of the zincblende-, wurtzite-, PbO- and SrAl(2)-type are found in the oxides/sulfides. In this work, such an interpretation of the structures remains at a topological level. The analysis also shows that this interpretation is complementary to the model developed by Andersson and Hyde which contemplates the structures as the intergrowth of structural slabs of more simple compounds. PMID- 22810907 TI - Crystallographic input data for (001)-, (110)- and (111)-oriented superlattices. AB - General aspects concerned with (001)-, (110)- and (111)-oriented superlattices (SLs) have been investigated. In particular, the symmetry of these systems have been derived and given in detail. As a test, the obtained data have been utilized to calculate electronic structures and gaps of a standard GaAs/AlAs system using an accurate version of the first principle full potential linear muffin-tin orbital (FPLMTO) method based on a local-density functional approximation (LDA). PMID- 22810908 TI - [Ni(MeCN)(H2O)2(NO3)2].(15-crown-5).MeCN: detailed study of a four-phase sequence that includes an intermediate modulated phase. AB - A sequence of four phases has been found for an acetonitrile-solvated co-crystal with 15-crown-5 of the nickel complex [acetonitrilediaqua-kappa(1)O-nitrato kappa(2)O-nitratonickel(II)]. The structure could be determined at intervals of ca 10 K in the range 90-273 K because crystals remain single through the three transitions. In phase (I) (T >= ca 240 K; P2(1)/m, Z' = 1/2), there is extensive disorder, which is mostly resolved in phase (III) (ca 230-145 K; P2(1)/c, Z' = 1). Phase (IV) (ca 145-90 K, and probably below; P 1, Z' = 2) is ordered. Phase (II) (ca 238-232 K) is modulated, but the satellite reflections are too weak to allow the structure to be determined within its stability range by standard methods. Most crystals that were flash-cooled from room temperature to 90 K have a metastable P2(1), Z' = 5 superstructure that (at least in a commensurate approximation) was identified as similar to the structure of phase (II) by comparison of reconstructed reciprocal-lattice slices and by analogy with the phase behavior of the very similar compound [Ni(H(2)O)(6)](NO(3))(2).(15-crown 5).2H(2)O [Siegler et al. (2011). Acta Cryst. B67, 486-498]. In the phase (II) structure slab-like regions that are like the disordered phase (I) structure alternate with regions of similar shape and size that are like the more ordered phase (III) structure. PMID- 22810909 TI - Synthesis, structure and spectroscopic properties of a novel compound bis(benzylamino)silver(I) benzylcarbamate. AB - A novel silver-containing compound, bis(benzylamino)silver(I) benzylcarbamate, with an unusual molecular structure is easily synthesized by the reaction of benzylammonium benzylcarbamate and silver oxide. It crystallizes in the triclinic crystal system with the space group P 1 with a = 5.2006 (5), b = 14.6298 (15), c = 14.7246 (15) A, alpha = 68.729 (2), beta = 83.507 (2), gamma = 85.412 (2) degrees and Z = 2. In the crystal, one Ag atom coordinates with the two amino groups in two benzylamine molecules, and there are no silver-silver and silver oxygen interactions. The carboxylate groups take part in balancing the electric charge and forming hydrogen bonds. Both the compound and the starting material benzylammonium benzylcarbamate exhibit room-temperature solid-state emissions with the peaks at 300 and 406 nm, respectively. PMID- 22810910 TI - Structure determination of L-arabinitol by powder X-ray diffraction. AB - Powder X-ray diffraction patterns of the commercial phase of L-arabinitol were recorded with a laboratory diffractometer. The starting structural model was found by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinements with soft restraints on the interatomic bond lengths and bond angles. H atoms of hydroxyl groups were localized by minimization of the crystalline energy. The cell is triclinic with the space group P1 and contains two molecules. The crystalline cohesion is achieved by an important network of O-H...O hydrogen bonds. PMID- 22810911 TI - X-ray diffraction and Raman study of DL-alanine at high pressure: revision of phase transitions. AB - The effect of pressure on DL-alanine has been studied by X-ray powder diffraction (up to 8.3 GPa), single-crystal X-ray diffraction and Raman spectroscopy (up to ~6 GPa). No structural phase transitions have been observed. At ~1.5-2 GPa, cell parameters b and c become accidentally equal to each other, but the space-group symmetry does not change. There is no phase transition between 1.7 and 2.3 GPa, contrary to what has been reported earlier [Belo et al. (2010). Vibr. Spectrosc. 54, 107-111]. The presence of the second phase transition, which was claimed to appear within the pressure range from 6.0 to 7.3 GPa (Belo et al., 2010), is also argued. The changes in the Raman spectra have been shown to be continuous in all the pressure ranges studied. PMID- 22810912 TI - A time-resolved powder diffraction study of in-situ photodimerization kinetics of 9-methylanthracene using a CCD area detector and parametric Rietveld refinement. AB - The [4pi + 4pi] photodimerization process of the 9-substituted anthracene derivative crystalline 9-methylanthracene (9-MA) was investigated using time resolved X-ray powder diffraction. The study was carried out in-situ using a CCD area detector. Sequential and parametric Rietveld refinement was applied for quantitative phase analysis. The results of traditional sequential Rietveld refinement showed that the evolution of the dimerization process can be described using the Johnson-Mehl-Avrami-Kolmogorov (JMAK) model. The parameters of the JMAK equation were obtained successfully by parametric Rietveld refinement and suggest that the reaction follows heterogeneous nucleation and one-dimensional growth with a decreasing nucleation rate. PMID- 22810913 TI - Cocrystals of 5-fluorocytosine. I. Coformers with fixed hydrogen-bonding sites. AB - The antifungal drug 5-fluorocytosine (4-amino-5-fluoro-1,2-dihydropyrimidin-2 one) was cocrystallized with five complementary compounds in order to better understand its drug-receptor interaction. The first two compounds, 2 aminopyrimidine (2-amino-1,3-diazine) and N-acetylcreatinine (N-acetyl-2-amino-1 methyl-5H-imidazol-4-one), exhibit donor-acceptor sites for R(2)(2)(8) heterodimer formation with 5-fluorocytosine. Such a heterodimer is observed in the cocrystal with 2-aminopyrimidine (I); in contrast, 5-fluorocytosine and N acetylcreatinine [which forms homodimers in its crystal structure (II)] are connected only by a single hydrogen bond in (III). The other three compounds 6 aminouracil (6-amino-2,4-pyrimidinediol), 6-aminoisocytosine (2,6-diamino-3H pyrimidin-4-one) and acyclovir [acycloguanosine or 2-amino-9-[(2 hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one] possess donor-donor-acceptor sites; therefore, they can interact with 5-fluorocytosine to form a heterodimer linked by three hydrogen bonds. In the cocrystals with 6-aminoisocytosine (Va) (Vd), as well as in the cocrystal with the antiviral drug acyclovir (VII), the desired heterodimers are observed. However, they are not formed in the cocrystal with 6-aminouracil (IV), where the components are connected by two hydrogen bonds. In addition, a solvent-free structure of acyclovir (VI) was obtained. A comparison of the calculated energies released during dimer formation helped to rationalize the preference for hydrogen-bonding interactions in the various cocrystal structures. PMID- 22810914 TI - Cocrystals of 5-fluorocytosine. II. Coformers with variable hydrogen-bonding sites. AB - Two flexible molecules, biuret and 6-acetamidouracil, were cocrystallized with 5 fluorocytosine to study their conformational preferences. In the cocrystal with 5 fluorocytosine (I), biuret exhibits the same conformation as in its hydrate. In contrast, 6-acetamidouracil can adopt two main conformations depending on its crystal environment: in crystal (II) the trans form characterized by an intramolecular hydrogen bond is observed, while in the cocrystal with 5 fluorocytosine (III), the complementary binding induces the cis form. Three cocrystals of 6-methylisocytosine demonstrate that complementary binding enables the crystallization of a specific tautomer. In the cocrystals with 5 fluorocytosine, (IVa) and (IVb), only the 3H tautomer of 6-methylisocytosine is present, whereas in the cocrystal with 6-aminoisocytosine, (V), the 1H tautomeric form is adopted. The complexes observed in the cocrystals are stabilized by three hydrogen bonds similar to those constituting the Watson-Crick C.G base pair. PMID- 22810915 TI - 42 salt forms of tyramine: structural comparison and the occurrence of hydrate formation. AB - The single-crystal diffraction structures of 38 salt forms of the base tyramine (4-hydroxyphenethylamine) are reported for the first time. Together with literature examples, these structures are discussed with respect to cation conformation, cation packing, hydrogen bonding and hydrate formation. It is found that isostructural cation packing can occur even with structurally different anions, with different hydration states and with different hydrogen bonding. Hydrate formation is found to be more likely both (i) when there is an increase in the total number of potential hydrogen bond acceptor and donor atoms; and (ii) when the ratio of potential hydrogen bond donor to acceptor atoms is low. PMID- 22810917 TI - Attention-deficit/hyperactivity disorder (ADHD) and adaptation night as determinants of sleep patterns in children. AB - Sleep problems are a prominent feature in children with attention deficit/hyperactivity disorder (ADHD) but their relationships to sleep structure are not consistent across studies. We aimed at further examining the sleep architecture in children with ADHD, while considering the role of the first-night effect (FNE) as a possible confounder. Twenty unmedicated children with ADHD combined type (8-15 years old; mean 11.24, SD 2.31) and 19 healthy controls, matched for age and gender, underwent polysomnography during an adaptation and a consecutive second night. ADHD and controls displayed a typical FNE without group differences. Independently of testing night, children with ADHD spent more time in sleep and had shortened rapid eye movement (REM) sleep latency and a greater amount of REM sleep relative to controls. However, the increased REM sleep amount in ADHD children was more expressed in the second night when it was also significantly related to scores of inattention and hyperactivity. Our results (1) document similar sleep adaptation processes in children with ADHD and typically developing children, (2) reveal that REM sleep changes in association with ADHD specific psychopathology may characterize sleep in ADHD children, which is evident only when the FNE is accounted for, (3) indicate that ADHD psychopathology and adaptation night may exert opposite effects on REM sleep in children. These results may prompt the awareness of clinicians about the importance of actual sleep alterations and their precise evaluation in children with ADHD, which could significantly contribute to better diagnostic, treatment and early prevention strategies. PMID- 22810918 TI - A comparison of DXA and CT based methods for estimating the strength of the femoral neck in post-menopausal women. AB - The study goal was to compare simple two-dimensional (2D) analyses of bone strength using dual energy x-ray absorptiometry (DXA) data to more sophisticated three-dimensional (3D) finite element analyses using quantitative computed tomography (QCT) data. DXA- and QCT-derived femoral neck geometry, simple strength indices, and strength estimates were well correlated. INTRODUCTION: Simple 2D analyses of bone strength can be done with DXA data and applied to large data sets. We compared 2D analyses to 3D finite element analyses (FEA) based on QCT data. METHODS: Two hundred thirteen women participating in the Study of Women's Health Across the Nation (SWAN) received hip DXA and QCT scans. DXA BMD and femoral neck diameter and axis length were used to estimate geometry for composite bending (BSI) and compressive strength (CSI) indices. These and comparable indices computed by Hip Structure Analysis (HSA) on the same DXA data were compared to indices using QCT geometry. Simple 2D engineering simulations of a fall impacting on the greater trochanter were generated using HSA and QCT femoral neck geometry; these estimates were benchmarked to a 3D FEA of fall impact. RESULTS: DXA-derived CSI and BSI computed from BMD and by HSA correlated well with each other (R=0.92 and 0.70) and with QCT-derived indices (R=0.83-0.85 and 0.65-0.72). The 2D strength estimate using HSA geometry correlated well with that from QCT (R=0.76) and with the 3D FEA estimate (R=0.56). CONCLUSIONS: Femoral neck geometry computed by HSA from DXA data corresponds well enough to that from QCT for an analysis of load stress in the larger SWAN data set. Geometry derived from BMD data performed nearly as well. Proximal femur breaking strength estimated from 2D DXA data is not as well correlated with that derived by a 3D FEA using QCT data. PMID- 22810919 TI - Bisphosphonates and colon cancer. PMID- 22810920 TI - Percutaneous closure of atrial septal defect via transjugular approach with Blockaid device in a patient with interrupted inferior vena cava. AB - Percutaneous ASD closure was successfully performed through the internal jugular approach in a 40-year old female with IVC interruption and azygos continuation. This case demonstrates the feasibility of transcatheter ASD closure in a difficult anatomy which precludes the standard transfemoral approach. PMID- 22810921 TI - A successful treatment for a lesion of chronic total occlusion using a virtual 3 Fr guiding catheter. AB - A 43 year-old man was admitted due to effort related chest squeezing for 3 months. Coronary angiogram showed a total occlusion of the proximal right coronary artery (RCA) with collateral vessels from left anterior descending artery. The 5F sheathless guiding catheter was engaged into the RCA and the 3F JL3.5 catheter was inserted into left coronary artery via left radial artery for simultaneous contra lateral angiography. We advanced the wire through the lesion with 2 wire technique. Three XIENCE stents (2.5 mm * 28 mm) was inserted from distal to mid RCA, and a 3.0 mm * 15 mm XIENCE stent was inserted to proximal RCA. The final angiographic result showed well expanded stent. The treatment of chronic total occlusion could be possible even slender device by getting hold of the characteristics of the device and evaluating an objective assessment of lesion characteristics. PMID- 22810922 TI - A case of percutaneous coronary intervention procedure successfully bailed out from multiple complications in hemodialysis patient. AB - A 73 year-old male who underwent coronary artery bypass surgery (CABG) 8 years ago had PCI performed on him for a diffuse calcified stenotic lesion in the right coronary artery (RCA). Following 2.5 mm non-compliant balloon dilatation supported with a child catheter (Dio from Goodman), we implanted a stent to the distal RCA through this catheter. However, because the tip of Dio was trapped by the implanted stent, it was stretched and almost ruptured by pulling it. Next, we tried to implant a stent for mid RCA with buddy wire technique, but we could not deploy it because of calcification. When we tried to withdraw this stent system, the stent was accidentally dislodged from the balloon. We could withdraw the stent with twisting two wires. However, because one of these wires had crossed a small artery in the distal RCA at twisting, a tip of this wire was fractured when the stent was removed. We could remove this wire with gooseneck snare. Finally, we successfully implanted stents in the mid RCA with balloon anchor technique and to the proximal RCA. PMID- 22810923 TI - Percutaneous coronary intervention by retrograde approach for chronic total occlusion of the proximal left anterior descending artery via a gastroepiploic artery graft. AB - Coronary arteries connecting to septal branch are often occluded in post-coronary artery bypass graft cases. A 70-year-old male had undergone CABG; radial artery graft to the LCX, and gastroepiploic artery (GEA) graft to the RCA. Coronary angiography revealed total occlusion in proximal LAD, while both graft vessels had good flow. Retrograde percutaneous coronary intervention (PCI) procedure from the septal channel via GEA graft to the RCA was performed for total occlusion of LAD. Despite the tortuous GEA, deep engagement with a 4-french guiding catheter ensured powerful back-up force. After retrograde wire crossing, two drug-eluting stents were implanted, successfully. PMID- 22810924 TI - Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse. AB - Loss of dystrophin protein due to mutations in the DMD gene causes Duchenne muscular dystrophy. Dystrophin loss also leads to the loss of the dystrophin glycoprotein complex (DGC) from the sarcolemma which contributes to the dystrophic phenotype. Tyrosine phosphorylation of dystroglycan has been identified as a possible signal to promote the proteasomal degradation of the DGC. In order to test the role of tyrosine phosphorylation of dystroglycan in the aetiology of DMD, we generated a knock-in mouse with a phenylalanine substitution at a key tyrosine phosphorylation site in dystroglycan, Y890. Dystroglycan knock in mice (Dag1(Y890F/Y890F)) had no overt phenotype. In order to examine the consequence of blocking dystroglycan phosphorylation on the aetiology of dystrophin-deficient muscular dystrophy, the Y890F mice were crossed with mdx mice an established model of muscular dystrophy. Dag1(Y890F/Y890F)/mdx mice showed a significant improvement in several parameters of muscle pathophysiology associated with muscular dystrophy, including a reduction in centrally nucleated fibres, less Evans blue dye infiltration and lower serum creatine kinase levels. With the exception of dystrophin, other DGC components were restored to the sarcolemma including alpha-sarcoglycan, alpha-/beta-dystroglycan and sarcospan. Furthermore, Dag1(Y890F/Y890F)/mdx showed a significant resistance to muscle damage and force loss following repeated eccentric contractions when compared with mdx mice. While the Y890F substitution may prevent dystroglycan from proteasomal degradation, an increase in sarcolemmal plectin appeared to confer protection on Dag1(Y890F/Y890F)/mdx mouse muscle. This new model confirms dystroglycan phosphorylation as an important pathway in the aetiology of DMD and provides novel targets for therapeutic intervention. PMID- 22810926 TI - Journal information. PMID- 22810927 TI - Editor's Preface. PMID- 22810928 TI - Treatment of acute transverse myelitis and its early complications. AB - Acute transverse myelitis (ATM) has many potential etiologies, but a significant proportion of cases are categorized as idiopathic despite thorough evaluation. Clinical presentation of ATM typically includes some combination of motor weakness, sensory symptoms, and bowel and bladder dysfunction. Prompt recognition, even before a final etiologic diagnosis is reached, is critical to initiating early therapeutic intervention to reduce the harmful effects of inflammation. Acute therapeutic options for ATM include corticosteroids, plasma exchange, IV immunoglobulin, and chemotherapeutic agents such as cyclophosphamide. In some instances, combinations of these therapies are used. This article examines the therapeutic approach to ATM and its various acute clinical manifestations. PMID- 22810929 TI - Diagnostic approach to myeloneuropathy. AB - Disorders that concomitantly affect the spinal cord and peripheral nerves can be characterized as myeloneuropathies. Such conditions can be broadly categorized as metabolic, inflammatory, infectious, or hereditary disorders. Because these disorders may present with predominantly myelopathic or peripheral neuropathic signs and symptoms, a careful neurologic examination and a thoughtful diagnostic evaluation are necessary to establish a diagnosis of myeloneuropathy. This article outlines an approach to the identification, evaluation, and treatment of myeloneuropathy. PMID- 22810930 TI - Infectious myelopathies. AB - Every genus of microorganism, as well as prions, has been associated with disease of the spinal cord. The spectrum of pathogens resulting in myelopathy varies with the population. Myelopathy is uniquely associated with certain retroviruses, particularly HIV type 1 and human T-cell lymphotropic virus type I, but the myelopathies that occur with these viruses are chiefly limited to "at risk" populations. In the immunocompromised population, a diverse array of pathogens may cause spinal cord disease, especially viruses from the Herpesviridae family, most notably cytomegalovirus and varicella-zoster virus. The prototypical myelopathy resulting from bacterial infection is tabes dorsalis, but this disorder is vanishingly rare in the modern era. In developing countries, Mycobacterium tuberculosis and schistosomiasis remain significant causes of myelopathy. PMID- 22810931 TI - Autoimmune myelopathies. AB - The differential diagnosis of inflammatory myelopathies is broad. Autoimmune myelopathies represent a heterogeneous but significant portion of inflammatory myelopathies. The discovery of serologic biomarkers of autoimmune myelopathies (including aquaporin-4 and collapsin response-mediator protein-5 [CRMP-5] immunoglobulin [Ig]Gs) supports the concept of an autoimmune attack targeting the spinal cord. Neuroimaging, in particular MRI, may reveal distinctive patterns of signal abnormality suggesting an autoimmune etiology, such as longitudinally extensive transverse myelitis in neuromyelitis optica spectrum disorders or tract specific changes in paraneoplastic disorders. IgG biomarkers of autoimmune myelopathies enable more precise disease classification and have the potential to direct a cancer search, predict outcome, guide therapeutic decision making, and lead to future development of antigen-specific targeted therapies. The goal of initial immunotherapy is to reverse or halt progression. Long-term immunotherapy aims to maintain remission and prevent relapse. PMID- 22810932 TI - Hereditary myelopathies. AB - Hereditary myelopathies comprise a diverse group of disorders whose signs and symptoms include progressive spasticity, limb ataxia without additional cerebellar signs, impaired vibration and positional sensation, and a variable degree of neurogenic weakness, all suggesting spinal cord impairment. Recent progress in the understanding of hereditary myelopathies has revealed that many are systemic processes with widespread axonal degeneration. However, the concept of hereditary myelopathies remains clinically helpful in differentiating hereditary myelopathies from other potentially treatable myelopathies. In this article, hereditary myelopathies are divided into four categories: hereditary spastic paraplegias, motor neuron disorders, spinocerebellar and spastic ataxias, and metabolic disorders, including leukodystrophies. PMID- 22810933 TI - Rehabilitation in transverse myelitis. AB - The consequences of neurologic injuries related to transverse myelitis (TM) are long-lasting and require rehabilitative interventions in about two-thirds of cases. Because numerous neural repair mechanisms are dependent on maintenance of an optimal amount of activity both above and below the injury level, rehabilitation and exercise are useful not only for compensatory functional purposes but also as tools in neural system restoration. The application of established neurophysiologic principles to post-TM rehabilitation has substantial impact on optimizing residual functional capabilities while facilitating the processes of central plasticity and reorganization of sensory and motor programming. The process of neurorehabilitation thereby serves both to treat the patient with TM and to help physicians interrogate and dissect the mechanisms involved in spinal cord injury, neuroprotection, and, ultimately, recovery. Post TM rehabilitation is lifelong and should be integrated into daily living in a home setting as part of the global management of paralysis, a chronic condition with significant comorbidities. PMID- 22810934 TI - Acute and chronic polyradiculopathies. AB - Polyradiculopathies are uncommon peripheral nervous system syndromes that result from a variety of conditions. The clinical manifestations are variable but often include symmetric or asymmetric distal and proximal weakness with a variable degree of sensory loss and reduction or loss of reflexes. The most common cause of an acute polyradiculopathy is acute inflammatory demyelinating polyradiculopathy (also known as Guillain-Barre syndrome); however, other inflammatory, infectious, or neoplastic causes can present with similar features. Chronic polyradiculopathies include chronic inflammatory demyelinating polyradiculopathy as well as paraprotein-related syndromes and other inflammatory and infectious causes. Evaluation using a combination of serologic studies, electrodiagnostic testing, and CSF evaluation can help to identify the underlying etiology and implement the appropriate treatment. This article reviews the approach to patients with suspected polyradiculopathy and the features of the more common causes of acute and chronic polyradiculopathies. PMID- 22810935 TI - Metastases involving spinal cord, roots, and plexus. AB - Neurogenic pain is common in patients with widespread metastatic cancer. Pain of this type is often severe and typically results from neoplastic invasion of the peripheral nerves, spinal roots, or spinal cord. Tumors may invade the cervical, brachial, or lumbosacral plexuses either by direct extension from contiguous structures or in association with metastases to regional soft tissues and lymph nodes. Most of these patients experience progressive pain, motor loss, and sensory dysfunction. Metastases directly to the peripheral nerves are rare in patients with solid tumors but are more frequently encountered in patients with hematologic malignancies. Metastases to the spinal roots and the spinal cord usually occur in patients who also have demonstrable evidence of leptomeningeal or intraparenchymal brain metastases. These conditions may overlap and must be distinguished from other causes of plexus, nerve, or spinal cord disorders in the patient with cancer. Early identification and appropriate treatment allow these patients to remain functional and interactive with family and friends. PMID- 22810936 TI - Spinal cord injury and a request to stop treatment. AB - When a person who is not terminally ill requests that life-prolonging treatment be stopped, the treating physician must systematically consider all relevant diagnostic, prognostic, and psychosocial elements of that request. First, the patient's decision-making capacity must be confirmed. Next, medical facts, patient preferences, quality of life, and contextual matters surrounding the request must be evaluated and interpreted. Finally, to respect the patient fully, the treating physician must engage all clinical and paraclinical resources needed to ensure that the request is truly informed and autonomous. PMID- 22810937 TI - Motor vehicle operation in the setting of multiple sclerosis with myelopathy: assessment, adaptive equipment, counseling, and cessation of driving. AB - Many individuals with multiple sclerosis are safe drivers; others self-regulate their driving or cease driving altogether because of their own safety concerns. When patients are unsafe to drive and have poor insight into their condition, they may ignore a provider's repeated communication to stop driving. Addressing this issue when a person is initially diagnosed with multiple sclerosis and continuing the discussion over time when assessing other activities of daily living may ease the process of driving cessation. Referral for a driving evaluation may be appropriate, in conjunction with referrals to a social worker for mobility counseling and to a psychologist for grief and loss issues associated with driving cessation. When repeated recommendations to stop driving are ignored, notifying the appropriate government agencies should be considered. PMID- 22810938 TI - Coding table. PMID- 22810940 TI - Multiple-choice questions. PMID- 22810941 TI - Multiple-choice questions-preferred responses. PMID- 22810942 TI - Patient management problem. PMID- 22810943 TI - Patient management problem-preferred responses. AB - Following are the preferred responses for the Patient Management Problem in this CONTINUUM issue. The case, questions, and answer options are repeated, and the preferred response appears in bold print, followed by an explanation and a reference with which you may seek more specific information. You are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references included with each question are intended to encourage independent study. PMID- 22810946 TI - Tonopen XL assessment of intraocular pressure through silicone hydrogel contact lenses. AB - OBJECTIVES: To assess the accuracy of Tonopen XL measurement of intraocular pressure (IOP) through low-power (-0.25 to -3.00) and high power (-3.25 to -6.00) silicone hydrogel lenses of 3 different materials (galyfilcon A, senofilcon A, and lotrafilcon B). METHODS: Seventy-eight patients were recruited for participation in this study. All were habitual wearers of silicone hydrogel contact lenses, and none had been diagnosed with glaucoma, ocular hypertension, or anterior surface disease. IOP was measured with and without lenses in place in the right eye only. Patients were randomized to initial measurement either with or without the lens in place. A single examiner collected all data. RESULTS: No statistically significant differences were noted between IOP measured without lenses and IOP measured through low-power lotrafilcon B lenses or high-power or low-power galyfilcon A and senofilcon A lenses. However, we did find a statistically significant difference between IOP measured without lenses and IOP measured through high-power lotrafilcon B lenses. CONCLUSION: In general, Tonopen XL measurement of IOP through silicone hydrogel lenses may be sufficiently accurate for clinical purposes. However, Tonopen XL may overestimate IOP if performed through a silicone hydrogel lens of relatively high modulus. PMID- 22810947 TI - Transitioning DNA-engineered nanoparticle superlattices from solution to the solid state. PMID- 22810948 TI - Establishment of pomegranate (Punica granatum) hairy root cultures for genetic interrogation of the hydrolyzable tannin biosynthetic pathway. AB - In contrast to the numerous reports on the human therapeutic applications of hydrolyzable tannins (HTs), genes involved in their biosynthesis have not been identified at the molecular level from any plant species. Although we have previously identified candidate HT biosynthetic genes in pomegranate using transcriptomic and bioinformatic analyses, characterization of in planta enzyme function remains a critical step in biochemical pathway elucidation. We here report the establishment of a pomegranate (Punica granatum) hairy root culture system that produces HTs. Agrobacterium rhizogenes strains transformed with a binary vector harboring a yellow fluorescent protein (YFP) gene were used for hairy root induction, allowing visual, non-destructive, detection of transgene incorporation. It also demonstrated that the pomegranate hairy root culture system is suitable for expressing heterologous genes (YFP in this case). Expression of 26 putative UDP-glycosyltransferase (UGT) genes, obtained from a pomegranate fruit peel (a tissue highly abundant in HTs) RNA-Seq library, were verified in wild type and hairy roots. In addition, two candidate UGTs for HT biosynthesis were identified based on HPLC and differential gene expression analyses of various pomegranate tissues. Together with in vitro enzyme activity assays, the hairy root culture system holds great promise for revealing the undivulged HT biosynthetic pathway using pomegranate as a model system. PMID- 22810950 TI - Renal denervation: time to open Pandora's box. AB - Depending on the populations studied and the definitions applied, the prevalence of treatment-resistant hypertension varies from 10% to 15%, but is higher in conditions associated with increased sympathetic drive, such as obesity, obstructive sleep apnoea, diabetes or renal dysfunction. The Symplicity studies recently demonstrated that reducing sympathetic tone by intravascular renal denervation is feasible in treatment-resistant hypertension, but failed to provide conclusive evidence on the size and durability of the antihypertensive, renal and sympatholytic effects, long-term safety, quality of life, the possibility to relax antihypertensive drug treatment, cost-effectiveness, and long-term hard cardiovascular-renal outcomes. Renal denervation should therefore only be offered within a clinical research context at highly skilled tertiary referral centres that participate in international registries constructed independent of the manufacturers. PMID- 22810945 TI - Chlorophyll a fluorescence induction: a personal perspective of the thermal phase, the J-I-P rise. AB - The fast (up to 1 s) chlorophyll (Chl) a fluorescence induction (FI) curve, measured under saturating continuous light, has a photochemical phase, the O-J rise, related mainly to the reduction of Q(A), the primary electron acceptor plastoquinone of Photosystem II (PSII); here, the fluorescence rise depends strongly on the number of photons absorbed. This is followed by a thermal phase, the J-I-P rise, which disappears at subfreezing temperatures. According to the mainstream interpretation of the fast FI, the variable fluorescence originates from PSII antenna, and the oxidized Q(A) is the most important quencher influencing the O-J-I-P curve. As the reaction centers of PSII are gradually closed by the photochemical reduction of Q(A), Chl fluorescence, F, rises from the O level (the minimal level) to the P level (the peak); yet, the relationship between F and [Q(A) (-)] is not linear, due to the presence of other quenchers and modifiers. Several alternative theories have been proposed, which give different interpretations of the O-J-I-P transient. The main idea in these alternative theories is that in saturating light, Q(A) is almost completely reduced already at the end of the photochemical phase O-J, but the fluorescence yield is lower than its maximum value due to the presence of either a second quencher besides Q(A), or there is an another process quenching the fluorescence; in the second quencher hypothesis, this quencher is consumed (or the process of quenching the fluorescence is reversed) during the thermal phase J-I-P. In this review, we discuss these theories. Based on our critical examination, that includes pros and cons of each theory, as well mathematical modeling, we conclude that the mainstream interpretation of the O-J-I-P transient is the most credible one, as none of the alternative ideas provide adequate explanation or experimental proof for the almost complete reduction of Q(A) at the end of the O J phase, and for the origin of the fluorescence rise during the thermal phase. However, we suggest that some of the factors influencing the fluorescence yield that have been proposed in these newer theories, as e.g., the membrane potential DeltaPsi, as suggested by Vredenberg and his associates, can potentially contribute to modulate the O-J-I-P transient in parallel with the reduction of Q(A), through changes at the PSII antenna and/or at the reaction center, or, possibly, through the control of the oxidation-reduction of the PQ-pool, including proton transfer into the lumen, as suggested by Rubin and his associates. We present in this review our personal perspective mainly on our understanding of the thermal phase, the J-I-P rise during Chl a FI in plants and algae. PMID- 22810952 TI - Effects of dihydronaphthyl-based [60]fullerene bisadduct regioisomers on polymer solar cell performance. AB - The effects of fullerene bisadduct regioisomers on solar cell performance have been examined for the first time and the two substituent positions on C(60) have been found to have a large impact on the solar cell performance. PMID- 22810951 TI - The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. AB - Type 1 diabetes (T1D) is a disease that in most individuals results from autoimmune attack of a single tissue type, the pancreatic islet. A fundamental, unanswered question in T1D pathogenesis is how the islet tissue environment influences immune regulation. This crosstalk is likely to be communicated through the extracellular matrix (ECM). Here, we review what is known about the ECM in insulitis and examine how the tissue environment is synchronized with immune regulation. In particular, we focus on the role of hyaluronan (HA) and its interactions with Foxp3+ regulatory T-cells (Treg). We propose that HA is a "keystone molecule" in the inflammatory milieu and that HA, together with its associated binding proteins and receptors, is an appropriate point of entry for investigations into how ECM influences immune regulation in the islet. PMID- 22810953 TI - Simulation modeling of policies directed at youth sugar-sweetened beverage consumption. AB - Childhood obesity is a significant public health problem requiring innovative solutions. While recent reviews indicate that some policies show promise, there is a lack of information regarding which policies, and policy combinations, work best. Low-nutrition, energy-dense foods and beverages such as sugar-sweetened beverages (SSBs) have been identified as a major contributor to the problem. The purpose of this paper is to use simulation modeling to show how changes in three categories of SSB policies-school nutrition, school-based education, and taxes impact SSB and other food consumption. The model shows that policies directed at SSBs, particularly tax hikes, could lead to substantial reductions in the number of calories consumed by youth. The estimates, however, are subject to a high degree of uncertainty. Estimates from school-based nutrition and school-based education policies, while also helping to reduce caloric intake, generally show smaller effects than tax policies and considerable variation around parameter estimates for individual and combined policies. We conclude with a discussion of the limits of the model, and suggest where additional information is needed. Limitations notwithstanding, simulation modeling is a promising methodology that can help advance our understanding of policy effects, thereby helping policymakers to better formulate effective policies to reduce obesity prevalence and the associated social harms. PMID- 22810954 TI - Recruiting young adult cancer survivors for behavioral research. AB - Young adults have been dramatically underrepresented in cancer survivorship research. One contributing factor is the difficulty recruiting this population. To identify effective recruitment strategies, the current study assessed the yield of strategies used to recruit young survivors for an exercise intervention including: clinic-based recruitment, recruitment at cancer-related events, mailings, telephone-based recruitment, advertising on the internet, radio, television and social networking media, distributing brochures and word-of-mouth referrals. When taking into account the strategies for which we could track the number of survivors approached, recruitment at an oncology clinic was the most productive: 38 % of those approached were screened and 8 % enrolled. When evaluating which strategy yielded the greatest percentage of the sample, however, mailings were the most productive. Given widespread use of the internet and social networking by young adults, investigators should also consider these low cost recruitment strategies. PMID- 22810955 TI - -Omics and cancer biomarkers: link to the biological truth or bear the consequences. PMID- 22810956 TI - Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified. METHODS: The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat shock protein 90 (HSP90) inhibitors with therapeutic potentials. RESULTS: Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit alpha/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen activated protein kinase (KRAS/MAPK) pathway. CONCLUSIONS: Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA. PMID- 22810957 TI - Plasma levels of interleukin-6 and interleukin-18 after an acute physical exercise: relation with post-exercise energy intake in twins. AB - Increased interleukin-6 (IL-6) plasma levels have been described to occur during physical exercise. A relative reduction in energy intake after physical activity has also been reported after exercise, indicating a possible involvement of IL-6 as an anorexigenic factor. Given the possible effect of interleukins on appetite, we assessed whether a controlled physical activity bout is related with changes in IL-6, IL-6 soluble receptor (IL-6sR), gp130 and interleukin-18 (IL-18) plasma levels, as well as their relation with post-exercise energy intake. A co-twin intervention study was carried out with five young male monozygotic twin pairs. One co-twin performed 45 min of submaximal exercise on a treadmill near the anaerobic threshold ending with 7 min at 90 % VO(2) max, while his co-twin remained non-active. Ad libitum energy intake was tested through a carbohydrate rich meal test. Venous blood samples were drawn at baseline, immediately after exercise and after the meal ingestion. Plasma concentrations of IL-6, IL-6sR, gp130 and IL-18 were measured via ELISA. IL-6 plasma levels increased after physical activity bout (2.6-fold change; p = 0.04). A less marked trend, although still significant, was observed for plasma levels of IL-6sR and gp130. Plasma levels of IL-18 did not significantly change during exercise. The twins who exercised exhibited significantly lower energy intake (181 versus 1,195 kcal; p = 0.04), compared to the co-twins who remained resting. The present study in monozygotic twins shows increased IL-6 plasma levels after acute physical exercise with a significant reduction in energy intake, supporting a linkage between IL-6 and acute post-exercise eating behaviour. PMID- 22810958 TI - Differential display of abundantly expressed genes of Trichoderma harzianum during colonization of tomato-germinating seeds and roots. AB - The identification of Trichoderma genes whose expression is altered during early stages of interaction with developing roots of germinated seeds is an important step toward understanding the rhizosphere competency of Trichoderma spp. The potential of 13 Trichoderma strains to colonize tomato root and promote plant growth has been evaluated. All used strains successfully propagated in spermosphere and continued their growth in rhizoplane simultaneously root enlargement while the strains T6 and T7 were the most abundant in the apical segment of roots. Root colonization in most strains associated with promoting the roots and shoots growth while they significantly increased up to 43 and 40 % roots and shoots dry weights, respectively. Differential display reverse transcriptase-PCR (DDRT-PCR) has been developed to detect differentially expressed genes in the previously selected strain, Trichoderma harzianum T7, during colonization stages of tomato-germinating seeds and roots. Amplified DDRT PCR products were analyzed on gel agarose and 62 differential bands excised, purified, cloned, and sequenced. Obtained ESTs were submit-queried to NCBI database by BLASTx search and gene ontology hierarchy. Most of transcripts (29 EST) corresponds to known and hypothetical proteins such as secretion-related small GTPase, 40S ribosomal protein S3a, 3-hydroxybutyryl-CoA dehydrogenase, DNA repair protein rad50, lipid phosphate phosphatase-related protein type 3, nuclear essential protein, phospholipase A2, fatty acid desaturase, nuclear pore complex subunit Nup133, ubiquitin-activating enzyme, and 60S ribosomal protein L40. Also, 13 of these sequences showed no homology (E > 0.05) with public databases and considered as novel genes. Some of these ESTs corresponded to genes encodes enzymes potentially involved in nutritional support of microorganisms which have obvious importance in the establishment of Trichoderma in spermosphere and rhizosphere, via potentially functioning in acquisition of nutrients from energy rich carbon compounds leaked from the germinating seeds and roots. PMID- 22810959 TI - The importance of rhamnolipid-biosurfactant-induced changes in bacterial membrane lipids of Bacillus subtilis for the antimicrobial activity of thiosulfonates. AB - The antimicrobial properties of methyl (MTS) and ethyl (ETS) esters of thiosulfonic acid alone and in combination with rhamnolipid-biosurfactant (RL) have been characterized for their ability to disrupt the normal physiological functions of living pathogens. Bactericidal and fungicidal activities of MTS and ETS and their combination with rhamnolipid were demonstrated on strains of Pseudomonas aeruginosa, Bacillus subtilis, Alcaligenes faecalis, and Rhizopus ngtricans. It was found that the combination of rhamnolipid and thiosulfonic esters has a synergistic effect leading to decreasing of bactericidal and fungicidal concentrations of MTS and ETS. More extensively was studied the effect of rhamnolipid on the lipid composition of B. subtilis bacterial membrane. To our knowledge, in this article is reported for the first time a remarkable increase of negatively charged phospholipid cardiolipin in the presence of rhamnolipid. The capacity of RL as a surface-active substance was confirmed by scanning electron microscopy (SEM). The occurrence of surface infolds and blebs on B. subtilis shown by SEM, was not accompanied by changes in membrane permeability tested by a live/dead viability staining for fluorescence microscopy. When RL was applied in combination with MTS, a dramatic permeability shift for propidium iodide was observed in vegetative cells. PMID- 22810960 TI - Iodine activation of coordinated white phosphorus: formation and transformation of 1,3-dihydride-2-iodidecyclotetraphosphane. AB - Double stabilization: Previously unknown polyphosphorus compounds are obtained by activation of white phosphorus (P(4)) coordinated between two CpRu(PPh(3))(2) moieties with iodine, and subsequent hydrolysis. The polyphosphorus compounds (P(4) H(2) I, P(4) H(2), P(3) H(5); see scheme, Cp=cyclopentadienyl) are all stabilized by coordination to two ruthenium centers. PMID- 22810961 TI - A practical entry to beta-aryl-beta-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor. AB - The 1,2-addition of alkyl Grignard reagents to readily available N-tert butanesulfinyl ketimines, bearing an alpha-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed beta-secretase (BACE1) inhibitor. PMID- 22810964 TI - Using fibrin degradation products level to facilitate diagnostic evaluation of potential acute aortic dissection. AB - This study evaluated whether degradation products of plasma fibrin and fibrinogen (FDP) level can be used to differentiate acute aortic dissection (AAD) from acute myocardial infarction (AMI), angina pectoris, acute cerebral infarction, or transient cerebral ischemic attack (TIA). Ninety-six consecutive patients with definitive diagnosis of AAD by contrast-enhanced computed tomography scan underwent measurement of FDP on admission. Of these patients, 45 had a patent false lumen (patent-type), and 51 had complete thrombosis of the false lumen (thrombosed-type). Control groups were patients admitted during the same period for whom a diagnosis of either AMI (n = 187), angina pectoris (n = 142), cerebral infarction (n = 353), or TIA (n = 94) was confirmed. FDP was significantly higher in patients with patent-type AAD (median, 210 MUg/mL; interquartile range, 70-358 MUg/mL) than in those with thrombosed-type AAD (16.5, 7.2-50.1). Patients with patent-type AAD or thrombosed-type AAD had a significantly higher FDP than patients in any of the control groups. Receiver operating characteristic curve analysis indicated that FDP >= 12.6 MUg/mL was the cutoff value that best differentiated patients with patent-type AAD from patients in any of the control groups (sensitivity, 100%; negative predictive value [NPV], 100%). And, this FDP cutoff level was associated with a high positive predictive value (PPV) (80-92%). The cutoff value to differentiate patients with thrombosed-type AAD from patients in any of the control groups was FDP >= 5.6 MUg/mL (sensitivity, 100%; NPV, 100%). However, this FDP cutoff level was associated with a low PPV (36-81%). FDP and D-dimer were measured at the same time on admission in 30 patients with AAD and 41 patients in control groups. A simple liner regression, calculated using FDP and D-dimer values from a total of 71 patients, yielded a correlation coefficient (R2) of 0.95, indicating a strong correlation. In symptomatic patients with suspected AAD, a diagnosis of patent-type AAD should be considered if FDP >= 12.6 MUg/mL. Patients with FDP >= 5.6 MUg/mL have the possibility of thrombosed-type AAD. PMID- 22810965 TI - Comparison of retinal nerve fiber layer thickness measurements by spectral-domain optical coherence tomography systems using a phantom eye model. AB - To quantify differences in nerve fiber layer thickness measurements by various spectral-domain optical coherence tomography (SD-OCT) systems, we developed a phantom eye model. We tested twelve SD-OCT systems of four manufacturers. All systems combined overestimated the 49 um thick phantom RNFL thickness on average by 18 um. Within brands, thickness measurements differed statistically significant for one Topcon, one RTVue and one Cirrus. Between brands, thickness determined with RTVue and Topcon differed statistically significant from Cirrus and Spectralis. The maximum difference between mean thicknesses is 3.6 um within brands and 7.7 um between brands. PMID- 22810966 TI - Test-retest and intrarater reliability of 2-dimensional ultrasound measurements of distance between rectus abdominis in women. AB - STUDY DESIGN: Single-group test-retest reliability study. OBJECTIVES: To evaluate the test-retest intraobserver reliability of 2-dimensional ultrasound measurement of the distance between the rectus abdominis muscles, the interrectus distance (IRD). BACKGROUND: Diastasis recti is defined as the separation of the 2 rectus abdominis muscles, with a reported prevalence of between 30% and 70% in women during pregnancy and in the postpartum period. The condition is difficult to measure, and ultrasound imaging has been suggested as a useful method to quantify the diastasis. However, to date, no studies have investigated intratester or intertester reliability of ultrasound to measure the distance between the rectus abdominis muscles during rest and contraction. METHODS: Ultrasound images from the rectus abdominis were recorded in 24 healthy female volunteers at rest and under 2 conditions of abdominal contraction: abdominal crunch and drawing-in exercises. The probe was positioned at 2 locations: below and above the umbilicus. A blinded investigator measured the IRD offline from 2 different ultrasound images collected on 2 different days (test-retest). Additionally, reanalyses of the same ultrasound images were done on 2 separate occasions (intra image). RESULTS: Test-retest measurements of IRD demonstrated good to very good reliability, with intraclass correlation coefficient values between 0.74 and 0.90. The only exception was for IRD measured 2 cm below the umbilicus during the abdominal crunch exercise, which had an intraclass correlation coefficient of 0.50. For intratester reliability of the same images, the intraclass correlation coefficient values were all above 0.90. CONCLUSION: Ultrasound imaging is a reliable method for measuring the IRD at rest and during abdominal crunch and drawing-in exercises. PMID- 22810967 TI - Anatomic location of PET-positive aortocaval nodes in patients with locally advanced cervical cancer: implications for surgical staging. AB - OBJECTIVE: Pathologic evaluation of aortocaval nodes in patients with locally advanced cervical cancer in an effort to better tailor radiotherapy has gained popularity. We sought to determine which aortocaval nodes should be sampled during surgical staging procedures. METHODS: From 2004 to 2011, 246 patients with locally advanced cervical cancer underwent positron emission tomography (PET) before definitive chemoradiation. We reviewed the imaging studies to determine the location of PET-positive aortocaval nodes in relationship to the inferior mesenteric artery (IMA). RESULTS: Forty-two patients (17%) had PET images suggesting aortocaval metastasis. Ten patients had stage IB, 1 had stage IIA, 13 had stage IIB, 13 had stage IIIB, and 5 had stage IV disease. Of these 42 patients, 39 (93%) had FDG-avid pelvic nodes, 1 (2%) had PET-negative pelvic nodes but FDG-avid common iliac nodes, and 2 (5%) had direct spread to the aortocaval nodes. Three patients (7%) had FDG-avid aortocaval nodes above the IMA without FDG-avid nodes between the aortic bifurcation and IMA. All 3 of these patients also had FDG-avid nodes in the pelvis. Nineteen patients (45%) had FDG avid nodes above and below the IMA, and 20 (48%) had FDG-avid nodes below the IMA only. CONCLUSIONS: This hypothesis-generating study revealed that a small number of patients have PET-positive aortocaval nodes above the IMA only. For patients undergoing surgical staging for locally advanced cervical cancer, dissection to the renal vessels may be necessary. A future international, randomized study will prospectively evaluate the locations of pathologically positive aortocaval lymph nodes. PMID- 22810968 TI - Detection of gynecologic cancers in indigent women in an urban inner-city hospital. AB - OBJECTIVE: Access to care is a major concern for impoverished urban communities in the United States, whereas early detection of gynecologic malignancies significantly influences ultimate survival. Our goal was to compare the stage at detection of common gynecologic cancers at an urban county hospital with national estimates, and to describe the demographic and socioeconomic characteristics of this population. METHODS: All new patients presenting to the John H. Stroger, Jr. Hospital of Cook County gynecologic oncology clinic from January 1, 2008, to December 31, 2009, were reviewed under an institutional review board-approved protocol. Patients receiving primary treatment at the institution during these dates were included for analysis. We used chi tests to compare the institution's stage distributions to national estimates. RESULTS: Two hundred nineteen patients met inclusion criteria over the 2-year study period. Racial and ethnic minorities represented 72.5% of the population. Of the 219 patients, 56.1% (123/219) were uninsured and 37.9% (83/219) were covered by Medicaid or Medicare. We identified 97 (43.9%) cervical, 95 (43%) uterine, and 29 (13.1%) ovarian cancers, including 2 synchronous primaries. Compared to the National Cancer Data Base, women with uterine cancer at our institution were significantly more likely to present with later-stage disease (P < 0.05), whereas cervical cancer and ovarian cancer stage distributions did not differ significantly. CONCLUSIONS: Compared to national trends, women with uterine cancer presenting to an urban tertiary care public hospital have significantly more advanced disease, whereas those with cervical cancer do not. Nationally funded cervical cancer screening is successful but does not address all barriers to accessing gynecologic cancer care. Promotion of public education of endometrial cancer symptoms may be a vital need to impoverished communities with limited access to care. PMID- 22810969 TI - Positron emission tomography/computed tomography predictors of overall survival in stage IIIC/IV ovarian cancer. AB - OBJECTIVE: To evaluate the role of 2-deoxy-2-(F)fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) for selecting patients with extensive ovarian cancer (OC) for neoadjuvant chemotherapy by evaluating predictors of overall survival in patients with stage IIIC/IV OC. MATERIALS AND METHODS: From September 1, 2004, to November 20, 2011, 514 consecutive patients with a pelvic tumor underwent preoperative PET/CT; 179 patients had stage IIIC/IV OC. Patients' characteristics were collected from 153 patients with stage IIIC/IV OC who underwent primary surgery. In 152 patients with stage IIIC/IV OC, clinical predictors and PET/CT predictors of survival were evaluated. RESULTS: Median age was 64 years (range, 38-88 years); 87% (113) of the 153 patients had a performance status of less than 2; 55% (84) of the 153 patients had PET/CT stage III, and 45% (69) of the 153 patients had PET/CT stage IV. Using univariate analysis, incomplete debulking (P = 0.0001), pleural exudates (P = 0.001), postmenopausal state (P = 0.01), WHO performance status greater than 2 (P = 0.01), PET/CT stage IV (P = 0.01), and large bowel mesentery implants (P = 0.02) were statistically significant prognostic variables. Using multivariate Cox regression analysis, incomplete debulking was the only statistically significant independent prognostic variable (P = 0.0001). Median overall survival was significantly longer in the 53 patients with no residual tumor than in the 99 patients with residual tumor (33.3 vs 25.5 months; P = 0.0001) CONCLUSION: Suggested PET/CT criteria for referral of patients with advanced OC to neoadjuvant chemotherapy are PET/CT stage IV, pleural exudates, and PET-positive large bowel mesentery implants. Evaluation of selection criteria for neoadjuvant chemotherapy should be promoted in prospective clinical trials, with survival as the primary end point. PMID- 22810970 TI - Prognostic significance of volume-based metabolic parameters in uterine cervical cancer determined using 18F-fluorodeoxyglucose positron emission tomography. AB - OBJECTIVE: We compared the prognostic value of volume-based metabolic parameters determined using fluorine 18 (F) fluorodeoxyglucose (FDG) positron emission tomography (PET) (F-FDG PET) (with other prognostic parameters in uterine cervical cancer. METHODS: The subjects were 73 female patients who had an initial diagnosis of uterine cervical cancer and who underwent F-FDG PET. Various metabolic or volume-based PET parameters including maximum and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in primary cervical tumors. Survival analysis for disease free survival or progression-free survival was performed with a Kaplan-Meier method using PET parameters and other clinical variables. For determining independent prognostic factors, Cox regression analysis was performed. RESULTS: Recurrence or disease progression occurred in 23 patients (31.5%). In univariate analysis, patient age (cutoff, 57 years, P < 0.05), International Federation of Gynecology and Obstetrics stage (P = 0.07), primary tumor size (cutoff, 6.7 cm; P < 0.05), lymph node status on PET (P < 0.005), treatment method (P < 0.01), metabolic tumor volume (cutoff, 82 cm; P = 0.001), and TLG (cutoff, 7600; P = 0.005) were significant predictors of recurrence or progression. In multivariate analysis, both lymph node status on PET (hazard ratio, 1.042 [negative vs intrapelvic metastasis only], 7.008 [negative vs extrapelvic metastasis]; P < 0.001) and TLG (cutoff, 7600; hazard ratio, 2.981; P < 0.05) were independent prognostic factors for predicting recurrence. CONCLUSIONS: In uterine cervical cancer, TLG, a volume-based metabolic parameter, and lymph node status on PET may be significant independent prognostic factors for event-free survival. PMID- 22810971 TI - Up-regulation of cadherin 17 and down-regulation of homeodomain protein CDX2 correlate with tumor progression and unfavorable prognosis in epithelial ovarian cancer. AB - OBJECTIVE: Cadherin 17 (CDH17), belonging to the 7D-cadherin superfamily, represents a novel oncogene, which is involved in tumor invasion and metastasis. Its expression has been demonstrated to be regulated by caudal-related homeobox transcription factor CDX2. The roles of 2 biomarkers have been conflictingly explained. Therefore, the aims of this study were to investigate the expression patterns of CDH17 and CDX2 in human epithelial ovarian cancer (EOC) and to evaluate the clinical significance of these 2 markers in the progression and prognosis of EOC. METHODS: CDH17 and CDX2 expressions in 182 paraffin-embedded EOC specimens were detected by immunohistochemical staining. Associations of their expression with clinical pathological factors and overall survival were statistically evaluated. RESULTS: Compared with normal surface ovarian epithelium tissues, CDH17 expression was upregulated and CDX2 expression was downregulated in EOC tissues. There was a negative correlation between CDH17 and CDX2 expression in EOC tissues (r = -0.76, P = 0.001). Tumors with high CDH17 expression were more likely to have advanced stage (P = 0.01) and higher grade (P = 0.03). Patients with low CDX2 expression were more frequently to be at the advanced stage of disease (P = 0.01). In addition, univariate analysis indicated that the patients with high CDH17 expression correlated with poor prognosis in patients with EOC (P = 0.001), as opposed to CDX2 (P = 0.003). Especially, the survival rate of patients with EOC with CDH17-high/CDX2-low expression was the lowest (P < 0.001). Multivariate statistical analysis showed that the conjoined expression of CDH17/CDX2 was an independent prognostic indicator of EOC (P = 0.01). CONCLUSIONS: Our data suggest that both the up-regulation of CDH17 and the down-regulation of CDX2 may be associated with the advanced stage of EOC. A conjoined detection of CDH17/CDX2 expression may be associated with unfavorable prognosis in patients with this disease. PMID- 22810975 TI - Variants in the LEPR gene are nominally associated with higher BMI and lower 24-h energy expenditure in Pima Indians. AB - Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with a high prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1,082 subjects (P = 0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n = 80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n = 2,842) and several common variants including rs2025804 were nominally associated with BMI (P = 0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n = 2,969) and three of the variants showed nominal replication (P = 0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P = 0.0003 0.0001). A subset of these individuals (n = 403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24-h energy expenditure (24hEE) as assessed in a human respiratory chamber (P = 0.0007 adjusted for age, sex, fat mass, fat-free mass, activity, and family membership). We conclude that common noncoding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans. PMID- 22810979 TI - Autoimmune enteropathy: a review and update of clinical management. AB - Autoimmune enteropathy (AIE) is a rare condition characterized by intractable diarrhea, histologic changes on small intestinal biopsy, and failed response to dietary manipulation that also may present with extraintestinal manifestations. In many patients, immunosuppressive therapies are necessary. Although AIE is more common in infants, adult involvement has also been documented. Much of what is known about AIE has been gathered from case reports and small case series; therefore, more research in this evolving field is needed. IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) and APECED (autoimmune phenomena, polyendocrinopathy, candidiasis, and ectodermal dystrophy) are systemic forms of AIE. PMID- 22810980 TI - Precocious adrenarche in children born appropriate for gestational age: is there a difference between genders? AB - We aimed to determine whether precocious adrenarche (PA) has a different impact on screening tests for metabolic issues and pubertal timing in boys and girls born appropriate for gestational age (AGA). Puberty and initial metabolic screening results of 47 girls and 23 boys with PA born AGA followed up from our outpatient endocrinology clinic between May 2000 and October 2009 were reviewed. Initial anthropometric measurements except for body mass index standard deviation score (SDS) being higher in boys than girls (p = 0.01), bone age (BA) SDS, homeostasis model assessment of insulin resistance, and plasma lipids were similar between sexes. Hormone levels except for significantly higher dehydroepiandrosterone sulfate levels in boys than girls (p = 0.0006) were also similar between the sexes. BA SDS and BA/chronological age were significantly advanced (p < 0.05) with respect to initial evaluation in 28 girls at onset of gonadarche unlike the case in 13 boys with PA (p > 0.05). In conclusions, PA in children born AGA does not herald any significant differences with respect to adverse metabolic screening results between sexes, and it appears to be a discrete process from onset of puberty in girls unlike boys, in whom it is likely a variant of normal puberty. PMID- 22810981 TI - Differences in erythrocyte folate concentrations in older adults reached steady state within one year in a two-year, controlled, 1 mg/d folate supplementation trial. AB - Daily supplementation with folate increases erythrocyte folate concentrations; however, the time to reach steady-state concentrations has not been empirically demonstrated. Previous predictions of time to steady state or time to 90% steady state concentration, based on modeling changes in erythrocyte folate during short term trials, range widely from 40 to 86 wk. We sought to determine the time to steady-state erythrocyte folate concentrations following the initiation of daily folate supplementation using data collected from a 2-y, double-blind, placebo controlled, randomized trial involving 276 participants aged 65 y or older. The daily supplement contained 1 mg of folate. Erythrocyte folate concentrations were measured, using a microbiological assay, at baseline and at 6, 12, 18, and 24 mo. The mean plasma and erythrocyte folate concentrations in the folate-supplemented group were higher than in the placebo group at 6, 12, 18, and 24 mo (P < 0.001). Adjusted for baseline differences, the difference in erythrocyte folate concentrations between the folate and placebo group at 6 mo was 1.78 MUmol/L (95% CI: 1.62-1.95 MUmol/L). The difference increased significantly to 2.02 MUmol/L (95% CI: 1.85-2.18 MUmol/L) at 12 mo. This difference (between the folate and placebo groups) did not significantly change after a further year of folate supplementation; at 18 mo, it was 2.09 MUmol/L (95% CI: 1.92-2.27 MUmol/L) and at 24 mo it was 1.98 MUmol/L (95% CI: 1.18-2.15 MUmol/L). Twelve months of daily folate supplementation with 1 mg is sufficient time to cause erythrocyte folate concentrations to reach a new steady state. PMID- 22810982 TI - Maize porridge enriched with a micronutrient powder containing low-dose iron as NaFeEDTA but not amaranth grain flour reduces anemia and iron deficiency in Kenyan preschool children. AB - Few studies have evaluated the impact of fortification with iron-rich foods such as amaranth grain and multi-micronutrient powder (MNP) containing low doses of highly bioavailable iron to control iron deficiency anemia (IDA) in children. We assessed the efficacy of maize porridge enriched with amaranth grain or MNP to reduce IDA in Kenyan preschool children. In a 16-wk intervention trial, children (n = 279; 12-59 mo) were randomly assigned to: unrefined maize porridge (control; 4.1 mg of iron/meal; phytate:iron molar ratio 5:1); unrefined maize (30%) and amaranth grain (70%) porridge (amaranth group; 23 mg of iron/meal; phytate:iron molar ratio 3:1); or unrefined maize porridge with MNP (MNP group; 6.6 mg iron/meal; phytate:iron molar ratio 2.6:1; 2.5 mg iron as NaFeEDTA). Primary outcomes were anemia and iron status with treatment effects estimated relative to control. At baseline, 38% were anemic and 30% iron deficient. Consumption of MNP reduced the prevalence of anemia [-46% (95% CI: -67, -12)], iron deficiency [-70% (95% CI: -89, -16)], and IDA [-75% (95% CI: -92, -20)]. The soluble transferrin receptor [-10% (95% CI: -16, -4)] concentration was lower, whereas the hemoglobin (Hb) [2.7 g/L (95% CI: 0.4, 5.1)] and plasma ferritin [40% (95% CI: 10, 95)] concentrations increased in the MNP group. There was no significant change in Hb or iron status in the amaranth group. Consumption of maize porridge fortified with low-dose, highly bioavailable iron MNP can reduce the prevalence of IDA in preschool children. In contrast, fortification with amaranth grain did not improve iron status despite a large increase in iron intake, likely due to high ratio of phytic acid:iron in the meal. PMID- 22810983 TI - Variable iodine intake persists in the context of universal salt iodization in China. AB - Iodine deficiency disorders were prevalent in China until the introduction of universal salt iodization in 1995. Concerns have recently arisen about possible excess iodine intake in this context. To document iodine intake and the contribution from iodized salt in China, we surveyed dietary iodine intake during China's nationally representative 2007 total diet study (TDS) and during an additional TDS in 4 coastal provinces and Beijing in 2009. Iodine intake was broken down by age and sex in 2009. Mean daily iodine and salt intake and the contribution from different food and beverage groups (and in 2009, individual items) was measured. The iodine in food cooked with iodized and noniodized salt was also assessed. The mean calculated iodine intake of a standard male in China was 425 MUg/d in 2007 and 325 MUg/d in coastal areas in 2009, well below the upper limit (UL) in all provinces. In 2009, iodine intake was above the UL in only 1-7% of age-sex groups, except among children (18-19%). A concerning number of individuals consumed less than the WHO-recommended daily allowance, including 31.5% of adult women. Salt contributed 63.5% of food iodine, and 24.6% of salt iodine was lost in cooking. Overall salt consumption declined between the surveys. Salt iodization assures iodine nutrition in China where environmental iodine is widely lacking. The risk of iodine excess is low, but planned decreases in salt iodization levels may increase the existing risk of inadequate intake. Regular monitoring of urinary iodine and more research on the impact of excess iodine intake is recommended. PMID- 22810984 TI - Household food security is inversely associated with undernutrition among adolescents from Kilosa, Tanzania. AB - Household food insecurity contributes to poor nutritional health, with negative consequences on growth and development during childhood. Although early childhood nutrition needs have received much attention, another important nutritional phase is adolescence. In a sample of 670 adolescents from Kilosa District, Tanzania, this study used 3 approaches to better understand the relationship between food insecurity and undernutrition. First, this study examined the associations between 3 commonly used measures of household food security and undernutrition among 670 adolescents from Kilosa District, Tanzania. The measures of household food security, energy adequacy per adult equivalent, dietary diversity score, and coping strategies index, were strongly correlated with each other and household assets (P < 0.05). Second, this study measured the nutritional status of adolescents in this district, finding a high prevalence of undernutrition (21% with BMI-for-age <5th percentile of the National Center for Health Statistics/WHO reference). Third, this study measured the association between the log odds of undernutrition (as the dependent variable) and each of the 3 measures of household food security. In separate models, household energy adequacy per adult equivalent and household dietary diversity score were inversely associated with undernutrition after adjusting for gender, age, puberty, and the interaction between age and puberty. By contrast, a greater use of coping strategies was not associated with undernutrition. Strategies focused on increasing household energy intake and improving dietary diversity among the most vulnerable households could improve the nutritional health of adolescents. PMID- 22810985 TI - A six-month intervention with two different types of micronutrient-fortified complementary foods had distinct short- and long-term effects on linear and ponderal growth of Vietnamese infants. AB - Traditional complementary foods (CF) with a low nutrient density have been implicated in growth faltering, stunting, and other adverse outcomes in children. The efficacy of 2 types of locally produced, micronutrient-fortified CF to prevent stunting of infants living in rural Vietnam was evaluated. In a village randomized controlled study, 426 infants, 5 mo of age, received for 6 mo a fortified CF, either as an instant flour (FF) or a food complement (FC) in village canteens, or traditional CF at home (C). After 6 mo of intervention, weight, length, length-for-age Z-score (LAZ) and weight-for-age Z-score were greater in the 2 intervention groups compared with the C group, with an estimated effect of +0.22 LAZ for the FF group and +0.21 LAZ for the FC group. At the last follow-up, 18 mo after the intervention, there was no significant difference in height-for-age Z-score (HAZ) between the groups, even though the HAZ in the FF group was 0.17 greater than that in the C group (P = 0.18). In contrast, the weight-for-height Z-score and BMI Z-score, indices of ponderal growth, were greater in the FF group (-0.49 and -0.26, respectively) than in the FC group ( 0.73 and -0.49, respectively), with Z-scores in the C group intermediate and not significantly different from the others. This study shows that regular provision of locally produced CF fortified with micronutrients partly stopped growth faltering in Vietnamese infants, with differential effects on long-term length and ponderal growth. Providing only micronutrients instead of a complete array of nutrients might result in only short-term length growth benefits. PMID- 22810986 TI - Total fat intake is associated with decreased mortality in Japanese men but not in women. AB - Dietary guidelines generally recommend avoiding a high-fat diet. However, the relationship between fat subtypes and mortality remains unclear especially in a population with a relatively low intake of fat. We aimed to prospectively examine the relationship between dietary fat intake and all-cause and cause-specific mortality in a Japanese community. In 1992, a total of 28,356 residents of Takayama, Japan, without cancer, stroke, or coronary heart disease, responded to a validated 169-item FFQ. We identified 4616 deaths during a 16-y follow-up. The HR of mortality according to the percentage of energy from the total and subtypes of fat when substituted for an isoenergic quantity of carbohydrate was calculated after controlling for potential confounders. A high intake of total fat and PUFA was associated with a decrease in all-cause mortality in men; the HR for the highest compared with the lowest quintile were 0.83 (95% CI: 0.70, 0.99; P-trend = 0.048) for total fat and 0.77 (95% CI: 0.62, 0.95; P-trend = 0.05) for PUFA. Both fats were associated with a decrease in mortality from cancer and diseases other than cardiovascular disease. In women, a higher SFA intake was associated with higher all-cause mortality [HR = 1.22 (95% CI: 0.99, 1.49; P-trend = 0.03)]. A favorable effect was suggested for total fat and PUFA intakes on mortality in men except for that from cardiovascular disease, whereas increased SFA intake may be associated with adverse health consequences in women. PMID- 22810987 TI - The Mediterranean diet is associated with a reduction in premature mortality among middle-aged adults. AB - The available large prospective studies supporting an inverse association between better adherence to the Mediterranean diet and lower mortality have mainly included older adults. It is not clear whether this inverse association is also present among younger individuals at lower mortality risk. Our aim was to assess the association between adherence to the Mediterranean diet and total mortality in middle-aged adults from the Seguimiento Universidad de Navarra (SUN) Project. We followed 15,535 Spanish university graduates for a mean of 6.8 y. Their mean age was 38 +/- 12 y, 59.6% were females, and all were initially free of cardiovascular disease, cancer, and diabetes. A validated FFQ was used to assess dietary habits. Adherence to the Mediterranean diet was categorized into 3 groups according to the Mediterranean Diet Score (low, 0-2 points; moderate, 3-5 points; and high, 6-9 points). The outcome variable was total mortality. Cox proportional hazards models were used to estimate HR and 95% CI. We adjusted the estimates for sex, age, years of university education, BMI, smoking, physical activity, television watching, history of depression and baseline hypertension, and hypercholesterolemia. We observed 125 deaths during 105,980 person-years of follow-up. The fully adjusted HR for moderate and high adherence were 0.58 (95% CI: 0.34, 0.99; P = 0.05) and 0.38 (95% CI: 0.21, 0.70; P = 0.002), respectively. For each 2-point increment in the Mediterranean Diet Score, the HR of death was 0.72 (95% CI: 0.58, 0.91; P = 0.006). Among highly educated, middle-aged adults, adherence to the traditional Mediterranean diet was associated with reduced risk of death. PMID- 22810989 TI - Margarines fortified with alpha-linolenic acid, eicosapentaenoic acid, or docosahexaenoic acid alter the fatty acid composition of erythrocytes but do not affect the antioxidant status of healthy adults. AB - We aimed to investigate the effects of increased intake of alpha-linolenic acid (ALA), EPA, or DHA incorporated into a food matrix on the fatty acid composition of erythrocytes and on biomarkers of oxidant/antioxidant status. To this end, a controlled dietary study was conducted in 74 healthy men and women. The participants were randomly assigned to 1 of 3 interventions in which margarines fortified with either 10 weight percent ALA, EPA, or DHA ethyl esters replaced their normal spread for 6 wk. The total intakes of ALA, EPA, and DHA were 4.4, 2.2, and 2.3 g/d, respectively. Consuming EPA increased the erythrocyte proportion of EPA (394%) and the omega-3 index (sum of EPA and DHA, 38%). Consumption of DHA increased erythrocyte DHA (91%), the omega-3 index (98%), and EPA (137%). The omega-3 index increased to a significantly greater extent in the DHA group than in the EPA group. ALA did not increase erythrocyte EPA or the omega-3 index. We found no change in plasma uric acid or antioxidant capacity in any of the groups. Plasma malondialdehyde (MDA) increased with the EPA and DHA interventions. All 3 interventions decreased erythrocyte linoleic acid hydroperoxides but did not affect their MDA concentrations. In conclusion, the intake of both isolated EPA and DHA incorporated into margarine resulted in an enhanced incorporation of EPA and DHA into erythrocytes. Our findings indicate that DHA is quantitatively superior to EPA in view of the EPA+DHA tissue incorporation and also that 4 g/d ALA is not sufficient to increase the omega-3 index over a 6-wk period. PMID- 22810988 TI - Serum antioxidant concentrations and metabolic syndrome are associated among U.S. adolescents in recent national surveys. AB - Specific micronutrients, including retinol, retinyl esters, carotenoids [alpha carotene, beta-carotene (cis+trans), beta-cryptoxanthin, lutein+zeaxanthin, and total lycopene], vitamin E, and vitamin C have antiinflammatory and antioxidant effects, properties shown to reduce oxidative stress, a process that accompanies the pathogenesis of many chronic diseases. It is still largely unknown whether they are associated with the occurrence of metabolic syndrome (MetS) in the adolescent U.S. population. MetS was defined by the International Diabetes Federation (IDF) criteria. Other non-MetS outcomes relying on blood measurements were elevated HOMA-IR, C-reactive protein (CRP), and hyperuricemia. We tested associations between serum antioxidants and MetS outcomes among adolescents aged 12-19 y using cross-sectional data from NHANES 2001-2006 (n = 782-4285). IDF MetS prevalence was estimated at 7% among boys and 3% among girls. In adjusted models, adolescents with MetS had consistently lower carotenoid concentrations compared with their counterparts without MetS. Total carotenoids were also inversely related to HOMA-IR and CRP. Vitamin C was inversely related to uric acid level and MetS binary outcome. Retinol+retinyl esters exhibited an inverse relationship with CRP and a positive relationship with uric acid and HOMA-IR as well as MetS binary outcome. Vitamin E had no association with MetS, particularly after controlling for serum cholesterol and TG. In conclusion, among U.S. adolescents, serum carotenoid concentrations were inversely associated with MetS status, HOMA IR, and CRP, whereas serum vitamin C was inversely related to MetS status and serum uric acid. Vitamin E had no consistent association with MetS, whereas retinol+retinyl esters had a positive relationship with HOMA-IR, uric acid, and MetS, while being inversely related to CRP. These associations need further study. PMID- 22810990 TI - Ruminant-produced trans-fatty acids raise plasma HDL particle concentrations in intact and ovariectomized female Hartley guinea pigs. AB - Cardiovascular disease (CVD) is the leading cause of death among women worldwide, and risk for developing CVD increases postmenopause. Consumption of trans-fatty acids (tFA) has been positively associated with CVD incidence and mortality. The current study was designed to assess the effects of diets high in industrially produced (IP)-tFA, from partially hydrogenated vegetable oils (PHVO), and ruminant-produced (RP)-tFA, from butter oil (BO), on risk factors for CVD. Thirty two female Hartley guinea pigs, one-half of which were ovariectomized (OVX) to mimic the postmenopausal condition, were fed hypercholesterolemic diets containing 9% by weight PHVO or BO (n = 8/diet and ovariectomy) for 8 wk. The plasma and hepatic lipids did not differ between IP- and RP-tFA groups or between intact and OVX guinea pigs. The BO diet resulted in higher concentrations of plasma total and small HDL particle subclass concentrations than the PHVO diet regardless of ovariectomy status. The intact BO group had higher concentrations of large HDL particles than the intact PHVO group. HDL mean particle size tended to be larger (P = 0.07) in the PHVO groups compared with the BO groups regardless of ovariectomy status. There was a trend toward an interaction between diet and ovariectomy status for LDL mean particle size, which tended to be larger in OVX guinea pigs fed PHVO (P = 0.07). In summary, consumption of IP- and RP-tFA resulted in differential effects on HDL particle subclass profiles in female guinea pigs. The effect of tFA consumption and hormonal status on HDL particle subclass metabolism and the subsequent impact on CVD in females warrants further investigation. PMID- 22810991 TI - Grape polyphenols reduce blood pressure and increase flow-mediated vasodilation in men with metabolic syndrome. AB - We evaluated the effects of grape polyphenols in individuals classified with metabolic syndrome (MetS). Men (n = 24) aged 30-70 y were randomly assigned to consume either a freeze-dried grape polyphenol powder (GRAPE) or a placebo for 30 d in a double-blind, crossover design, separated by a 3-wk washout period. Participants were asked to maintain their usual diet and physical activity during the study and abstain from consuming polyphenol-rich foods. MetS criteria including blood pressure (BP) and markers of vascular endothelial function including brachial artery flow-mediated vasodilation (FMD), plasma total nitrite + nitrate (NOx) to estimate NO production, plasma soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured at the end of each dietary period. Systolic BP (P < 0.0025) and plasma sICAM-1 concentrations (P < 0.025) were lower, whereas the FMD response was higher (P < 0.0001), during the GRAPE compared with the placebo period. In addition, changes in sVCAM-1 concentrations between periods were positively correlated with changes in systolic BP (r = 0.45; P < 0.05). Although NOx concentrations did not differ between periods, changes in systolic BP were negatively correlated with changes in NOx concentrations (r = -0.44; P < 0.05), indicating the vasodilating properties of NO. Other MetS variables did not differ between the GRAPE and placebo periods. These results suggest that GRAPE polyphenols may potentiate vasorelaxation and reduce BP and circulating cell adhesion molecules, resulting in improvements in vascular function. PMID- 22810992 TI - Biometric characteristics of the pelvis in female-to-male transsexuals. AB - The objective of the study was to evaluate the metric features of pelvises of 24 female-to-male (FtM) transsexuals as compared to control groups of 24 healthy males and 24 healthy females. The participants had their pelvises X-rayed with the same X-ray apparatus and in the same position. Seventeen measurements were taken on the basis of X-ray pictures of FtM transsexuals' pelvises and both comparison groups. Additionally, their body height was compared. The results showed that FtM transsexuals having female body height represent an intermediate size of three pelvic features and male values of five variables. In order to develop a model based on metric variables of the pelvis that would best discriminate the FtM transsexuals, the control females, and the control males, a discriminant analysis was applied. The model included four variables out of 17 metric features: the height of the pubic symphysis, the greatest pelvic breadth, the interischial distance, and the acetabular diameter. The model was found to be the best in discriminating males from females and FtM transsexuals, but considerably less effective in discriminating transsexuals from the two control groups. The results demonstrate that a number of FtM transsexuals' pelvic measurements reveal "masculinization," which confirms current results demonstrating a shift in the somatometric traits of transsexual females towards male traits. A discriminant analysis based only on pelvic metric features shows some differences between the size of the pelvis and chromosomal sex in FtM transsexuals, which might indicate a biological basis for gender identity disorder. PMID- 22810993 TI - A reassessment of the possible effects of the serotonin transporter gene linked polymorphism 5-HTTLPR on premature ejaculation. AB - A population-based sample of 1673 (valid phenotypic and genotypic data were available from 1412 individuals) Finnish male twins and siblings of twins aged 18 45 years provided questionnaire data regarding ejaculatory function as well as saliva samples for genotype analyses. Genotypic analyses were conducted controlling for between-subjects dependence. No significant association was found between the 5-HTTLPR polymorphism and a composite variable measuring premature ejaculation or between this polymorphism and a self-report measure of ejaculation latency time. Previously conducted studies have found contradicting results regarding the possible role of 5-HTTLPR in premature ejaculation. Methodological inconsistencies have been pointed out in these studies, which have all been conducted on rather small samples. While differences in terms of measurement of ejaculatory function could partly explain why positive findings from some earlier studies could not be replicated, the present study, given the large sample size and multifactorial measures used, indicated that the 5-HTTLPR polymorphism has a limited, if any, impact on ejaculatory function. PMID- 22810995 TI - Comment on Cantor (2011). PMID- 22810994 TI - Shared psychotic disorder with sexual delusions. AB - Shared psychotic disorder (SPD) is perceived as a relatively rare and poorly understood psychiatric phenomenon. Patients sharing sexual delusions may refer to sex therapists looking for treatment of an alleged sexual pathology. This might cause significant diagnostic and therapeutic challenges. The aim of this article was to discuss diagnostic and management difficulties of SPD with special interest in patients sharing sexual delusions. PubMed selective search was provided for publications with keywords including SPD, induced delusional disorder, folie a deux, and induced psychosis. One case is presented and discussed according to recent diagnostic criteria and the medical and legal issues of the therapy. PMID- 22810996 TI - The attitudes toward transgendered individuals scale: psychometric properties. AB - Gay, lesbian, bisexual, and transgendered individuals are sexual and gender minorities subject to stigma in a heteronormative culture with binary gender role norms. Although much research has examined sexual stigma in the form of homophobia, or negative attitudes and reactions to homosexuals and homosexuality, little is known about the stigma experienced by transgendered individuals. Transgendered people are those whose gender identity (sense of oneself as a man or a woman) or gender expression (expression of oneself as a man or a woman in behavior, manner, and/or dress) differ from conventional expectations for their physical sex. Although a scale exists to measure transphobia or negative attitudes and reactions to transgendered individuals, it includes items tapping into overt behavioral expression of this stigma, or gender-bashing, and fails to identify or define transgendered persons as the attitudinal target of the items. A new scale was developed and evaluated in an effort to assess transgender related stigma, separately from discrimination and violence, among members of the general population. Using two separate samples of college students ranging in age from 18-64 years, exploratory (N = 134) and confirmatory factor analyses (N = 237) were performed. The resulting 20-item, self-report measure demonstrated a single-factor structure, high internal consistency reliability, and evidence of convergent and discriminant construct validity. PMID- 22810997 TI - Seasonal variation in internet keyword searches: a proxy assessment of sex mating behaviors. AB - The current study investigated seasonal variation in internet searches regarding sex and mating behaviors. Harmonic analyses were used to examine the seasonal trends of Google keyword searches during the past 5 years for topics related to pornography, prostitution, and mate-seeking. Results indicated a consistent 6 month harmonic cycle with the peaks of keyword searches related to sex and mating behaviors occurring most frequently during winter and early summer. Such results compliment past research that has found similar seasonal trends of births, sexually transmitted infections, condom sales, and abortions. PMID- 22810998 TI - Are there parental socialization effects on the sex-typed behavior of individuals with congenital adrenal hyperplasia? AB - Influences of prenatal androgen exposure on human sex-typical behavior have been established largely through studies of individuals with congenital adrenal hyperplasia (CAH). However, evidence that addresses the potential confounding influence of parental socialization is limited. Parental socialization and its relationship to sex-typical toy play and spatial ability were investigated in two samples involving 137 individuals with CAH and 107 healthy controls. Females with CAH showed more boy-typical toy play and better targeting performance than control females, but did not differ in mental rotations performance. Males with CAH showed worse mental rotations performance than control males, but did not differ in sex-typical toy play or targeting. Reported parental encouragement of girl-typical toy play correlated with girl-typical toy play in all four groups. Moreover, parents reported encouraging less girl-typical, and more boy-typical, toy play in females with CAH than in control females and this reported encouragement partially mediated the relationship between CAH status and sex typical toy play. Other evidence suggests that the reported parental encouragement of sex-atypical toy play in girls with CAH may be a response to the girls' preferences for boys' toys. Nevertheless, this encouragement could further increase boy-typical behavior in girls with CAH. In contrast to the results for toy play, we found no differential parental socialization for spatial activities and little evidence linking parental socialization to spatial ability. Overall, evidence suggests that prenatal androgen exposure and parental socialization both contribute to sex-typical toy play. PMID- 22810999 TI - Vaginal intercourse orgasm consistency accounts for concordance of vaginal and subjective sexual arousal. PMID- 22811000 TI - Asymmetric organocatalytic diboration of alkenes. AB - The use of chiral alcohols to form the Lewis acid-base *RO(-)-> bis(pinacolato)diboron adduct, in situ, provides an opportunity to induce asymmetry in the organocatalytic diboration of alkenes and complements the well established transition metal-mediated enantioselective diboration. PMID- 22811001 TI - Circulating miRNA is a novel marker for head and neck squamous cell carcinoma. AB - The aim of the study is to investigate the alteration of plasma miRNA in head and neck squamous cell carcinoma (HNSCC). Altered microRNAs (miRNAs) expression has been found in many cancers, including lung cancer, breast cancer, prostate cancer, bladder cancer and colorectal cancer. Many recent studies have demonstrated that aberrant plasma miRNAs were also found in various types of cancers. However the alteration of plasma expression in HNSCC remains unclear. In this present study, the expression profiles of ten miRNAs, let-7a, miR-21, miR26b, miR-34c, miR-99a, miR-133a, miR-137, miR-184, miR-194a, and miR-375, in plasma from 50 patients and 36 healthy subjects were evaluated using real-time quantitative polymerase chain reaction (PCR). Our results demonstrated that the expression level of miR-21 was significantly up-regulated in plasma samples obtained from HNSCC patients (p < 0.01) than those from healthy subjects, which were in consistent with our finding in HNSCC tissues. A 7.7-fold increase of miR 21 in cancerous parts when compared to their non-cancerous counterparts (p < 0.0001) was observed in HNSCC tissues. In addition, the expression levels of miR 21 and miR-26b were both reduced in post-operative HNSCC patients with good prognosis. In contrast, the concentration of plasma miR-21 and miR-26b stayed high after tumor removal in the expired cases. Our study suggests that detecting circulating miR-21 and miR-26b pre- and post-operatively might provide a novel tumor marker for HNSCC. PMID- 22811002 TI - Functionalized graphene sheets as molecular templates for controlled nucleation and self-assembly of metal oxide-graphene nanocomposites. PMID- 22811003 TI - MicroRNA profiling of primary high-grade soft tissue sarcomas. AB - High-grade soft tissue sarcomas are a heterogeneous and complex group of tumors. MicroRNAs (miRNAs) are considered as attractive candidates that may improve diagnostic, prognostic, and predictive characterization of this group of malignancies. We performed a comprehensive miRNA expression analysis in a series of 76 untreated, primary high-grade soft tissue sarcomas representing eight subtypes, and in a panel of 15 representative sarcoma cell lines using microarray technology. This screening revealed unique miRNA expression patterns for synovial sarcomas, myxoid liposarcomas, and leiomyosarcomas, and defined unique sets of miRNAs discriminating the different liposarcoma subtypes from non-neoplastic adipose tissue. The over-represented miRNAs included members of the miR-200 family in synovial sarcomas, and the tumor-associated miR-9 and miR-9* in myxoid liposarcomas compared to adipose tissue. Moreover, we found coexpression of 63 miRNAs clustering in a genetically imprinted chromosomal region 14q32.2 separating primary sarcoma samples and sarcoma cell lines into two molecular subgroups. Taken together, our comprehensive miRNA profiling identified a novel set of miRNAs that might contribute to sarcomagenesis and provide a starting point for experimental modulation of relevant targets for new therapeutic strategies in high-grade sarcomas. PMID- 22811004 TI - Volatiles emission patterns in poplar clones varying in response to ozone. AB - The volatiles emitted from young and old leaves of two poplar clones (Populus deltoides x maximowiczii, Eridano, and P. x euramericana, I-214) were sampled after exposure to ozone (80 ppb, 5 h d(-1), for 10 consecutive days) by solid phase microextraction and characterized by GC-MS. Only mature leaves of the ozone sensitive Eridano clone developed necrosis in response to ozone exposure, and their membrane integrity was significantly affected by ozone (+86 and +18 % of levels of thiobarbituric acid reactive substances in mature and young leaves). The headspace of the poplar clones studied here contained mono- and sesquiterpenes, both hydrocarbons and oxygenated ones in Eridano, and only hydrocarbons in the clone I-214. Furthermore, some non-terpenes, such as C(9) C(15) straight-chain aldehydes and C(12)-C(16) saturated and unsaturated aliphatic hydrocarbons, were detected. Other common non-terpene volatiles were oxygenated aliphatic compounds, mainly C(6)-alcohols and their acetates. Ozone exposure induced a strong change in volatile profiles, depending on clones and leaf age. Regardless of leaf age, in clone I-214, quantities of oxygenated monoterpenes tended to increase after ozone exposure, however, "O(3) x leaf age" was not significant. In clone Eridano, increases were observed in emissions of hydrocarbons and oxygenated sesquiterpenes in response to ozone treatment. (Z)-3 Hexen-1-ol and (Z)-3-hexenol acetate were present in traces in the headspace of untreated Eridano mature leaves, but quantities slightly increased after ozone treatment. Quantities of non-terpene oxygenated compounds dropped in the headspace of young leaves of both clones (-24 and -44 % in Eridano and I-214) and also in mature ones of I-214 (-50 %) after ozone exposure. Similarly, quantities of non-terpene hydrocarbons in the emissions from mature leaves of both clones ( 58 and -49 %, respectively) decreased, while these compounds increased in young leaves of Eridano (+83 %). We suggest that the resistance of the poplar clone I 214 to O(3) is achieved by: i) monoterpenes constitutively present in young leaves and ii) increase of monoterpene content induced by O(3) in mature leaves. PMID- 22811007 TI - Second-order nonlinear optical activity induced by ordered dipolar chromophores confined in the pores of an anionic metal-organic framework. AB - Frequency doubling: A strategy for incorporating dipolar organic chromophores into the one-dimensional channels of an anionic metal-organic framework (MOF) has been developed to generate highly active nonlinear optical materials (see picture). The resulting MOF material shows a second-harmonic generation intensity of 18.3 versus alpha quartz. PMID- 22811008 TI - Concurrent repetition enhancement and suppression responses in extrastriate visual cortex. AB - Visual cortical responses are usually attenuated by repetition, a phenomenon known as repetition suppression (RS). Here, we use multivoxel pattern analyses of functional magnetic resonance imaging (fMRI) data to show that RS co-occurs with the converse phenomenon (repetition enhancement, RE) in a single cortical region. We presented human volunteers with short sequences of repeated faces and measured brain activity using fMRI. In an independently defined face-responsive extrastriate region, the response of each voxel to repetition (RS vs. RE) was consistent across scanner runs, and multivoxel patterns for both RS and RE voxels were stable. Moreover, RS and RE voxels responded to repetition with dissociable latencies and exhibited different patterns of connectivity with lower and higher visual regions. Computational simulations demonstrated that these effects must be due to differences in repetition sensitivity, and not feature selectivity. These findings establish that 2 classes of repetition responses coexist within 1 visual region and support models acknowledging this distinction, such as predictive coding models where perception requires the computation of both predictions (which are enhanced by repetition) and prediction errors (which are suppressed by repetition). PMID- 22811009 TI - Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. AB - BACKGROUND: Newer systemic therapies have significantly advanced the treatment of multiple myeloma, but additional agents are needed. Bortezomib is a proteasome inhibitor with efficacy in relapsed/refractory multiple myeloma that inhibits tumor angiogenesis, a process that has been implicated in multiple myeloma pathogenesis. METHODS: In AMBER("A Randomized, Blinded, Placebo-Controlled, Multicenter, Phase II Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma"), patients with relapsed or refractory multiple myeloma were randomized to receive bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of each 21-day cycle) and either placebo or bevacizumab (15 mg/kg on day 1 of each cycle) for up to 8 cycles. At completion, patients in the bortezomib-plus-bevacizumab arm could continue bevacizumab until they developed progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: The stratified hazard ratio of PFS for the bevacizumab-containing arm (n = 49) relative to the bortezomib monotherapy arm (n = 53) was 0.743 (95% confidence interval [CI], 0.43-1.28; P = .2804); the median PFS was 6.2 months (95% CI, 4.4-8.5 months) and 5.1 months (95% CI, 4.2 7.2 months), respectively; the overall response rates were 51% and 43.4% (P = .4029), respectively; and the median response duration was 6.9 months (95% CI, 4.73-11.83 months) and 6.0 months (95% CI, 4.86-8.31 months), respectively. Frequent adverse events occurred at similar rates across treatment arms, but hypertension, fatigue, and neuralgia occurred more frequently in the bevacizumab containing arm. CONCLUSIONS: The addition of bevacizumab to bortezomib in unselected patients with pretreated multiple myeloma did not result in significant improvements in efficacy outcomes. The combination was well tolerated, and no new safety concerns for either agent were identified. PMID- 22811010 TI - Infection and autoimmune disease. AB - Most infectious agents, such as viruses, bacteria and parasites, can trigger autoimmunity via different mechanisms. The development of an autoimmune disorder after infection tends to occur in genetically susceptible individuals. Some parameters, such as genetic predisposition, feature of the infectious agent and sometimes protective effect of the infections, have a significant role in this process. These parameters and various pathogens that could lead to enhancement or exacerbation of autoimmune disease were examined in this review. Recent studies were reviewed from a microbiological perspective. PMID- 22811012 TI - When the parrot's beak becomes the crocodile's mouth: a story on shoulder ultrasound. PMID- 22811011 TI - Relationship of ultrasonographic findings with synovial angiogenesis modulators in different forms of knee arthritides. AB - Angiogenesis is controlled by a variety of angiogenesis stimulators and inhibitors. The increased power Doppler (PD) signals determined by ultrasonography is an indirect marker of synovial vascularity in arthritis. We aimed to investigate relationship between ultrasonographic findings and synovial angiogenesis modulators. Thirteen Behcet's disease (BD), 15 spondyloarthropathy, 21 rheumatoid arthritis (RA), and 15 osteoarthritis (OA) patients with knee arthritis were included. Cumulative effusion, synovial hypertrophy, and PD signal scores were calculated in arthritic joints. In synovial fluid samples, angiogenesis inhibitors (angiostatin, thrombospondin-1, and endostatin) and stimulators [bFGF (basic fibroblast growth factor), angiopoietin-1] were studied. The comparisons between groups were made by Kruskal-Wallis test, and correlation analysis was calculated with Pearson and Spearman tests. Effusion scores were significantly higher in inflammatory arthritis than in OA. Synovial hypertrophy scores were higher in RA and spondylarthritis than in OA and BD. PD scores were not different between the groups. Synovial angiostatin and bFGF levels were significantly higher in patients with inflammatory arthritis than in OA. Cumulative effusion scores were positively correlated with angiopoietin-1, angiostatin, and bFGF and negatively correlated with thrombospondin-1 levels. Synovial hypertrophy scores were positively correlated with angiostatin and bFGF levels and negatively correlated with thrombospondin-1. No correlation was found between PD scores and modulators of angiogenesis. In large joints like knee, detecting PD signals alone was not sufficient to assess the angiogenesis. However, cumulative activity scores were positively correlated with angiogenesis stimulators. Therefore, when investigating the angiogenesis, PD technique should be added to gray-scale examinations. PMID- 22811013 TI - Towards automated segmentation of cells and cell nuclei in nonlinear optical microscopy. AB - Nonlinear optical (NLO) imaging techniques based e.g. on coherent anti-Stokes Raman scattering (CARS) or two photon excited fluorescence (TPEF) show great potential for biomedical imaging. In order to facilitate the diagnostic process based on NLO imaging, there is need for an automated calculation of quantitative values such as cell density, nucleus-to-cytoplasm ratio, average nuclear size. Extraction of these parameters is helpful for the histological assessment in general and specifically e.g. for the determination of tumor grades. This requires an accurate image segmentation and detection of locations and boundaries of cells and nuclei. Here we present an image processing approach for the detection of nuclei and cells in co-registered TPEF and CARS images. The algorithm developed utilizes the gray-scale information for the detection of the nuclei locations and the gradient information for the delineation of the nuclear and cellular boundaries. The approach reported is capable for an automated segmentation of cells and nuclei in multimodal TPEF-CARS images of human brain tumor samples. The results are important for the development of NLO microscopy into a clinically relevant diagnostic tool. PMID- 22811014 TI - ERK activation and expression of neuronal cell cycle markers in the hippocampus after entorhinal cortex lesion. AB - Current findings suggest that neuronal cell death is frequently associated with the aberrant expression of cell cycle-regulatory proteins in postmitotic neurons. Aberrant cell cycle reentry has been implicated in diverse neurodegenerative conditions, including Alzheimer's disease (AD). Previously we reported that the appearance of cell cycle markers in postmitotic neurons of the entorhinal cortex (EC) after excitotoxic hippocampal damage is associated with the expression of phospho-tau and amyloid precursor protein (APP). However, the question of the signaling pathway involved in this cell cycle reentry remains unresolved. Differentiated neurons use the molecular mechanisms initially acquired to direct cell proliferation, such as the Ras-extracellular signal-regulated kinase (ERK1/2) pathway, to regulate synaptic plasticity. In this work we explored whether ERK1/2-related signaling might contribute to the cell cycle reentry in hippocampal neurons after a unilateral EC lesion. We showed that, within the first 24 hr after hippocampal deafferentation, numerous neurons expressed phospho ERK1/2, concomitantly with the gradual increases in cyclin D1 and cyclin B immunoreactivity in the dentate gyrus and hilus. Several of these immunopositive cells to phospho-ERK1/2 and cyclin B in hippocampus are postmitotic neurons, insofar as they are positive to NeuN. The intracisternal administration of U0126 (an MEK inhibitor), previous to the excitotoxic lesion, decreased the activation of ERK1/2 and the expression of cyclin D1 and cyclin B in the hippocampus. The present findings support the notion that ERK1/2 plays a role in cell cycle reactivation in mature neurons efferently connected to the lesion site. PMID- 22811015 TI - Pregnancy mediated improvement of rheumatoid arthritis. AB - QUESTION UNDER STUDY: To investigate pregnancy related changes of rheumatoid factor (RF) isotypes and anti-citrullinated protein antibodies (ACPA) and their association with disease activity and therapy in patients with rheumatoid arthritis. METHODS: In 22 rheumatoid arthritis patients disease activity (DAS28 CRP), therapy as well as the levels of rheumatoid factor isotypes (IgG, IgA, IgM) and ACPA were analysed longitudinally within 4 months before conception, once at each trimester and at 6,12 and 24 weeks postpartum. In addition, immunoglobulin isotypes (IgG, IgA, IgM) were measured in the pregnant rheumatoid arthritis patients as well as in 29 healthy pregnant women at the time points mentioned above. RESULTS: Our results showed that pregnancy significantly reduced systemic levels of the immunoglobulin isotypes IgG and IgA, but did not change the levels of IgG-RF, IgA-RF nor those of IgG-ACPA using assays with different antigen preparations. However, patients with active disease before and during pregnancy showed significantly higher levels of ACPA as compared to patients with low disease activity during pregnancy. Significantly more patients with low disease activity during pregnancy received pregnancy compatible disease modifying antirheumatic drugs or TNF-inhibitor therapy within four months before conception (P = 0.025). CONCLUSIONS: Our results suggest that treatment should be adjusted to pregnancy compatible drugs preconceptionally and continued until conception and beyond to allow for stable inactive disease during gestation and control the levels of autoantibodies. PMID- 22811018 TI - A perspective on the hepatoblastoma symposium. PMID- 22811017 TI - The effect of titanium with electrochemical anodization on the response of the adherent osteoblast-like cell. AB - PURPOSE: The osseointegration of titanium dental implants is essential for successful therapy, and this is strongly affected by the surface chemistry and roughness. In this study, using electrochemical anodization after sand blasting, and acid etching of Ti surface (SLA), SLA specimens with the high wettability of the thick TiO2 layer (SLAffinity) surface was developed to superimpose the nanoscale topographies on the microscale roughness of SLA surface without greatly altering the surface features. MATERIALS: The surface characteristics of SLAffinity specimens were investigated using scanning electron microscopy, atomic force microscopy, and x-ray photoelectron spectroscopy. The viability and proliferation of osteoblast-like cells (MG63 cells), which were seeded on SLAffinity specimens, were analyzed. RESULTS: Such electrochemically anodized specimens were predominantly composed of bioactive TiO2. The cell culturing tests revealed that the microscale roughness in combination with the nanoscale structures and bioactive properties improved osteoblast viability and differentiation on the SLAffinity surface. CONCLUSION: The favorable biological response of SLAffinity surfaces to MG63 osteoblast-like cells suggested that electrochemical anodization after SLA treatments is a potential procedure for better osseointegration in vivo. PMID- 22811019 TI - Feasibility of sequential PET/MRI using a state-of-the-art small animal PET and a 1 T benchtop MRI. AB - PURPOSE: Combined PET/MRI studies receive increasing attention, as their combination allows deeper insight into disease progression. We evaluated a novel 1 T benchtop MRI scanner (1T-MRI) for its use in sequential PET/MRI studies. PROCEDURES: Phantom studies were performed, addressing the attenuation caused by the MRI coils. For in vivo studies, PET/MRI data acquired with the 1T-MRI were compared with data using a conventional small animal high-field MRI (7T-MRI) in combination with the same PET scanner. RESULTS: Phantom and in vivo measurements show that the animal beds have no negative impact on the PET scanner performance compared to the 7T-MRI animal bed. Representative images of various animal studies are shown, indicating a wide field for sequential PET-benchtop MRI applications. CONCLUSION: Phantom and in vivo data indicate that sequential PET/MRI studies with this novel setup are comparable to sequential PET/MRI studies using a 7T-MRI in combination with a dedicated PET scanner. PMID- 22811020 TI - Transferrin-coated gadolinium nanoparticles as MRI contrast agent. AB - PURPOSE: In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated. PROCEDURES: HSA-NPs were conjugated with Gd-DTPA (Gd-HSA-NPs) and coupled with transferrin (Gd-HSA-NP-Tf). Mice underwent MRI before or after injection of Gd DTPA, Gd-HSA-NP, or Gd-HSA-NP-Tf. RESULTS: All the studied contrast agents provided a contrast enhancement (CE) in the blood, heart muscle, and liver. Compared to Gd-DTPA, CE with HSA-NP was achieved at lower Gd doses. Gd-HSA-NP-Tf yielded significantly higher CE than Gd-HSA-NP in the skeletal muscle, blood, cardiac muscle, and liver (p < 0.05). Gd-HSA-NP-Tf achieved a significantly higher CE than Gd-HSA-NP and Gd-DTPA in the blood, cardiac muscle, and liver (p < 0.05). In the brain, only Gd-HSA-NP-Tf was found to cause a significant CE (p < 0.05). CONCLUSIONS: The Gd-HSA nanoparticles have potential as MRI contrast agents. In particular, Gd-HSA-NP-Tf has a potential as a specific contrast agent for the brain, while the blood-brain barrier is still intact, as well as in the heart, liver, and skeletal muscle. PMID- 22811021 TI - Non-animal approaches in skin toxicology. PMID- 22811022 TI - Metabolism of arsenic and its toxicological relevance. AB - Arsenic is a worldwide environmental pollutant and a human carcinogen. It is well recognized that the toxicity of arsenicals largely depends on the oxidoreduction states (trivalent or pentavalent) and methylation levels (monomethyl, dimethyl, and trimethyl) that are present during the process of metabolism in mammals. However, presently, the specifics of the metabolic pathway of inorganic arsenicals have yet to be confirmed. In mammals, there are two possible mechanisms that have been proposed for the metabolic pathway of inorganic arsenicals, oxidative methylation, and glutathione conjugation. Oxidative methylation, which was originally proposed in fungi, is based on findings that arsenite (iAs(III)) is sequentially converted to monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) in both humans and in laboratory animals such as mice and rats. However, recent in vitro observations have demonstrated that arsenic is only methylated in the presence of glutathione (GSH) or other thiol compounds, which strongly suggests that arsenic is methylated in trivalent forms. The glutathione conjugation mechanism is supported by findings that have shown that most intracellular arsenicals are trivalent and excreted from cells as GSH conjugates. Since non-conjugated trivalent arsenicals are highly reactive with thiol compounds and are easily converted to less toxic corresponding pentavalent arsenicals, the arsenic-glutathione conjugate stability may be the most important factor for determining the toxicity of arsenicals. In addition, "being a non anionic form" also appears to be a determinant of the toxicity of oxo-arsenicals or thioarsenicals. The present review discusses both the metabolism of arsenic and the toxicity of arsenic metabolites. PMID- 22811023 TI - Characterization of identity, metabolism and androgenic activity of 17 hydroxyandrosta-3,5-diene by GC-MS and a yeast transactivation system. AB - Anabolic-androgenic steroids are frequently misused compounds in sports, and they belong to the controlled substances according to the requirements of the World Anti-Doping Agency. The classical techniques of steroid detection are mass spectrometry coupled to gas or liquid chromatography. Biological methods that base on the ability of substances to bind the steroid receptor are not applied in routine doping control procedures so far, but they appear to be useful for characterization of steroid androgenic potential. In this study we used the yeast androgen receptor reporter system (YAS), which in the past has already successfully been applied to both various androgenic substances and also urine samples. Giving attention to the androgenic potential of steroidal dietary supplements, we exemplified the analysis using both mass spectrometry techniques and the YAS-based assay on the product "Syntrax Tetrabol" which was a confiscated dietary supplement and marketed as a steroid precursor. Identification, structure and the kinetic behavior of its excreted metabolites were analyzed by NMR, GC-MS and LC-MS/MS. The androgenic potential of the parent compound as well as its metabolites in urine was evaluated with the help of the YAS. The application of urine samples with a previous deconjugation and the inclusion of urine density values were carried out and led to increased responses on the YAS. Further, the possibility of a complementary application of structure-based instrumental analysis and biological detection of androgenicity with the help of the YAS seems to be desirable and is discussed. PMID- 22811024 TI - Oxidative stress in apoptosis and cancer: an update. AB - The oxygen paradox tells us that oxygen is both necessary for aerobic life and toxic to all life forms. Reactive oxygen species (ROS) touch every biological and medical discipline, especially those involving proliferative status, supporting the idea that active oxygen may be increased in tumor cells. In fact, metabolism of oxygen and the resulting toxic byproducts can cause cancer and death. Efforts to counteract the damage caused by ROS are gaining acceptance as a basis for novel therapeutic approaches, and the field of prevention of cancer is experiencing an upsurge of interest in medically useful antioxidants. Apoptosis is an important means of regulating cell numbers in the developing cell system, but it is so important that it must be controlled. Normal cell death in homeostasis of multicellular organisms is mediated through tightly regulated apoptotic pathways that involve oxidative stress regulation. Defective signaling through these pathways can contribute to both unbalance in apoptosis and development of cancer. Finally, in this review, we discuss new knowledge about recent tools that provide powerful antioxidant strategies, and designing methods to deliver to target cells, in the prevention and treatment of cancer. PMID- 22811025 TI - The rat prepubertal uterine myometrium and not the luminal epithelium is predominantly affected by a chronic dietary genistein exposure. AB - Current knowledge about dietary soy isoflavone-induced hormonal effects and potential priming effects for the responsiveness of the organism to other estrogens is insufficient. The present study examined the effects of pre- and postnatal soy isoflavone exposure on estrogen responsiveness by estrogen receptor agonists in the uteri of prepubertal Wistar rats. To this end, offspring were generated from dams already maintained on three dietary groups, (1) a phytoestrogen-free diet, (2) a soy isoflavone-rich diet with 232 ppm daidzein and 240 ppm genistein or (3) a custom-made diet supplemented with 700 ppm genistein (GEN). Then, F1 females continuously exposed to isoflavones from GD1 to PND21 and non-exposed controls were subjected to an immature uterotrophic assay to compare physiological parameters and the response to subcutaneous treatment with 17beta estradiol, GEN or an estrogen receptor subtype (ERalpha and ERbeta)-specific agonist. Uterine wet weight (UWW), luminal epithelial height (LEH) and myometrial thickness (MMT) were determined. In addition, isoflavone plasma levels and mRNA expression profiles of relevant steroid receptors and of molecular markers for proliferation and estrogenicity were assessed for all groups. The influence of dietary isoflavones on the sensitivity to various estrogenic stimuli in these prepubertal animals was minor. Yet, the uterus of immature rats with high chronic GEN exposure alone showed already an increase in UWW, LEH and MMT. The myometrial response to GEN was more pronounced than that of the luminal epithelium, which may be due to a non-uniform distribution of steroid receptors, in particular the progesterone receptor. In conclusion, although the impact of a continuous, prenatally initiated exposure to dietary isoflavones on the uterine physiology of juvenile rats is modest, the possible priming effects of this exposure for beneficial or adverse late-onset consequences in adults should not be neglected. PMID- 22811026 TI - A hydrogen peroxide-responsive O2 nanogenerator for ultrasound and magnetic resonance dual modality imaging. PMID- 22811028 TI - Insulin and fiber type in the offspring of T2DM subjects with resistance training and detraining. AB - PURPOSE: Effects of resistance training and detraining on glucose and insulin responses to an oral glucose load, muscle fiber type, and muscular performance in the offspring of those with type 2 diabetes (familial insulin resistant (FIR)) were investigated. METHODS: Six FIR participants and 10 controls (C) completed 9 wk of resistance training and 9 wk of detraining. Measures of strength and power, an oral glucose tolerance test, and a muscle biopsy to determine myosin heavy chain (MHC) fiber composition were taken at baseline (T1), after training (T2), and after detraining (T3). RESULTS: Three-repetition maximum increased (P <= 0.001) similarly in both groups in all strength measures, e.g., leg press (FIR T1, T2: 121 +/- 34 kg, 186 +/- 50 kg; C T1, T2: 137 +/- 42 kg, 206 +/- 64 kg, respectively (means +/- SD)). Wingate peak power increased (FIR T1, T2: 505 +/- 137 W, 523 +/- 143 W; C T1, T2: 636 +/- 211 W, 672 +/- 223 W, respectively; P <= 0.005 (means +/- SD)). Training reduced insulin area under the curve more (P = 0.050) in FIR (T1, T2: 1219 +/- 734 pmol.L, 837 +/- 284 pmol.L, respectively (means +/- SD)) than that in C (T1, T2: 647 +/- 268 pmol.L, 635 +/- 258 pmol.L, respectively (means +/- SD)). MHC distribution did not change with training. Strength (three-repetition maximum measures) decreased with detraining (P <= 0.001) although Wingate power did not. Detraining increased insulin area under the curve (P = 0.018) in FIR (T2, T3: 837 +/- 285 pmol.L, 1040 +/- 194 pmol.L, respectively (means +/- SD)) but not in C (T2, T3: 635 +/- 258 pmol.L, 625 +/- 213 pmol.L, respectively (means +/- SD)). MHC IIX fibers increased with detraining (P = 0.026). CONCLUSION: FIR appears to have exaggerated responses to resistance training and detraining, with a greater reduction in insulin release with glucose ingestion after training and increase when training ceases. Resistance training has a significant effect on insulin responses and may reduce future risk of type 2 diabetes mellitus among FIR. PMID- 22811027 TI - Subcutaneous fungal infections. AB - Subcutaneous mycoses are common in tropical and subtropical regions of the world. These infections have multiple features in common, including similar epidemiology, mode of transmission, indolent chronic presentation with low potential for dissemination in immunocompetent hosts, and pyogranulomatous lesions on histopathology. Herein, we provide up-to-date epidemiologic, clinical, diagnostic, and therapeutic data for three important subcutaneous mycoses: chromoblastomycosis, mycetoma, and sporotrichosis. PMID- 22811029 TI - ACSM and CHAMP summit on sickle cell trait: mitigating risks for warfighters and athletes. AB - INTRODUCTION: An estimated 300 million people worldwide have sickle cell trait (SCT). Although largely benign, SCT has been associated with exertional rhabdomyolysis and exercise-related sudden death in warfighters/athletes (WA). The National Collegiate Athletic Association's policy to confirm a student athlete's SCT status during their preparticipation medical examination prompted reaction from some organizations regarding the rationale and ethical justification of the policy. METHODS: On September 26 and 27, 2011, a summit, composed of military and civilian experts in sports medicine and SCT, was convened at the Uniformed Services University in Bethesda, MD. The expert panel was charged with two objectives: 1) to provide specific recommendations to further mitigate the apparent risk with strenuous exercise in WA with SCT and 2) to develop clinical guidelines to identify, treat, and return to duty/play WA suspected to have incurred nonfatal sickle cell collapse. RESULTS: New terminology is introduced, areas of current controversy are explored, consensus recommendations for mitigating risk and managing the WA with SCT are reviewed, and important areas for future research are identified. CONCLUSION: Further research is needed before conclusions can be drawn regarding the etiology of the increased death rate observed in WA with SCT, and the possibility exists that SCT is a surrogate for as yet another contributing factor for the unexplained deaths. PMID- 22811030 TI - Sodium nitrate supplementation does not enhance performance of endurance athletes. AB - PURPOSE: Supplementation with inorganic nitrate has been suggested to be an ergogenic aid for athletes as nitric oxide donor. The purpose of this study was to determine whether ingestion of inorganic sodium nitrate benefits well-trained athletes performing a 40-min exercise test in laboratory conditions. In addition, we investigated the effect of this supplement on plasma levels of endothelin-1 (ET-1) and in nitrated proteins. METHODS: Thirteen trained athletes participated in this randomized, double-blind, crossover study. They performed a 40-min cycle ergometer distance-trial test after two 3-d periods of dietary supplementation with sodium nitrate (10 mg.kg of body mass) or placebo. RESULTS: Concentration of plasma nitrate (256 +/- 35 MUM) and nitrite (334 +/- 86 nM) increased significantly (P < 0.05) after nitrate supplementation compared with placebo (nitrate: 44 +/- 11 MUM; nitrite: 187 +/- 43 nM). In terms of exercise performance, there were no differences in either the mean distance (nitrate: 26.4 +/- 1.1 km; placebo: 26.3 +/- 1.2 km; P = 0.61) or mean power output (nitrate: 258 +/- 28 W; placebo: 257 +/- 28 W; P = 0.89) between treatments. Plasma ET-1 increased significantly (P < 0.05) just after exercise in nitrate (4.0 +/- 0.8 pg.mL) and placebo (2.4 +/- 0.4 pg.mL) conditions. This increase was significantly greater (P < 0.05) in the nitrate group. Levels of nitrated proteins did not differ between treatments (nitrate: preexercise, 91% +/- 23%; postexercise, 81% +/- 23%; placebo: preexercise, 95% +/- 20%; postexercise, 99% +/- 19%). CONCLUSION: Sodium nitrate supplementation did not improve a 40-min distance-trial performance in endurance athletes. In addition, concentration of plasma ET-1 increased significantly after exercise after supplementation with sodium nitrate. PMID- 22811031 TI - Body mapping of sweating patterns in athletes: a sex comparison. AB - PURPOSE: Limited regional sweat rate (RSR) data are available for females, with only a small number of sites measured across the body. Similarly, sex differences in sweating concentrate on whole body values, with limited RSR data available. METHODS: A modified absorbent technique was used to collect sweat at two exercise intensities (60% (I1) and 75% (I2) VO2max) in 13 aerobically trained females (21 +/- 1 yr, 59.5 +/- 10 mL.min.kg VO2max) in moderately warm conditions (25 degrees C, 45% relative humidity, 2 m.s air velocity). Females were compared with nine aerobically trained males (23 +/- 3 yr, 70.2 +/- 13 mL.min.kg VO2max) tested under the same conditions. RESULTS: Female I1 RSR was highest at the central upper back, heels, and dorsal foot and between the breasts (223, 161, 139, and 139 g.m.h, respectively). Lowest values were over the breasts and the middle and lower outer back (<16 g.m.h). At I2, the central upper back, bra triangle, and lower back showed the highest RSR (723, 470, and 333 g.m.h, respectively). Regions of the breasts and palms had the lowest RSR at I2 (<82 g.m.h). Significantly greater gross sweat loss and thus RSR were observed in males versus females at both exercise intensities. For the same metabolic heat production (male I1 vs female I2), absolute and normalized RSR showed a significant region sex interaction (P < 0.001), with a greater distribution toward the arms and hands in females versus males. CONCLUSIONS: Despite some differences in distribution, both sexes showed highest RSR on the central upper back and the lowest toward the extremities. No correlation was observed between local skin temperature and RSR, failing to explain RSR variation observed. These data have important applications for sex-specific clothing design, thermophysiological modeling, and thermal manikin design. PMID- 22811032 TI - Exercise training improves HR responses and VO2peak in predialysis kidney patients. AB - PURPOSE: The current pilot and feasibility study was designed to examine the effect of 48 wk of moderate-intensity exercise training and dietary modification on kidney function and vascular parameters in chronic kidney disease (CKD) patients. METHODS: Twenty-one stage 2-4 CKD patients (age, 18-70 yr) were randomly assigned to either the training group (TG, n = 10) or the usual care group (n = 11) for 48 wk. The TG received 48 wk of personal training (3 d.wk for up to 55 min per session at 50%-60% VO2peak) and dietary counseling, whereas individuals in the usual care group received standard of care and were instructed not to start a structured exercise program while in the study. VO2peak, estimated glomerular filtration rate (eGFR), resting and ambulatory HR, plasma lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), and inflammatory markers (high-sensitivity C-reactive protein and interleukin 6) were assessed at baseline and weeks 24 and 48. An independent group's t-test was used to compare glomerular filtration rate slopes between groups, whereas all other data were analyzed with ANCOVA using the baseline value as the covariate. RESULTS: There were no statistically significant differences in any of the parameters at baseline. The 48-wk intervention led to a significant increase in VO2peak, reductions in both resting and ambulatory HR, and increases in LDL cholesterol and in TG, but it had no effect on the rate of change of eGFR over time. CONCLUSIONS: A 48-wk exercise training program, primarily focused on aerobic exercise, increases VO2peak and favorably alters autonomic function as evidenced by reductions in HR in stages 2-4 CKD patients. The exercise intervention had no effect on kidney function as assessed by eGFR. PMID- 22811033 TI - Task-specific training reduces trip-related fall risk in women. AB - PURPOSE: The potential of task-specific training as a fall-prevention intervention was studied. The primary purpose of the study was to determine the extent to which a task-specific training protocol decreased the number of falls by middle-age and older women after a laboratory-induced trip. Secondary purposes were to explore the ability of trunk kinematics during the initial recovery step and the length of the initial recovery step to correctly classify the trip outcome and to quantify the extent to which the training protocol affected these variables. METHODS: Healthy community-dwelling women (n = 52) were assigned to either a training group or a control group that received no training. Training group women participated in an individually tailored, task-specific training protocol during which forward-directed stepping responses were necessary to avoid a fall after treadmill-delivered postural disturbances. Following the protocol, the ability to avoid a fall after a laboratory-induced trip was assessed. The primary outcome variable was the success (recover) or failure (fall) of the posttrip stepping response. RESULTS: Compared with the control group, there were fewer falls by the trained women after the laboratory-induced trip (P < 0.001; odds ratio = 0.13). Using logistic regression, falls and recoveries after the trip were sensitively classified by trunk flexion angle at the completion of the initial recovery step and the length of the initial recovery step (sensitivity = 0.67, specificity = 0.98), the former of which improved as a result of the task specific training protocol. CONCLUSIONS: The task-specific training protocol significantly reduced the number of falls after a laboratory-induced trip. Prospective study is required to determine whether this task-specific training reduces falls in the community and, consequently, may complement currently used exercise-based fall prevention intervention methods. PMID- 22811034 TI - Influence of lean body mass and strength on landing energetics. AB - PURPOSE: Less lean body mass may limit one's ability to produce adequate muscle forces to safely control landing from a jump, thus increasing the risk for injury. The primary objective of this study was to determine the effect of lower extremity lean mass (LELM) and eccentric muscle strength on lower extremity energy absorption (EA) during a drop jump landing. METHODS: Seventy athletic subjects (35 men and 35 women) were measured for LELM with dual-energy x-ray absorptiometry, maximal eccentric strength of the quadriceps (QuadECC) and hamstrings (HamECC), and lower extremity joint energetics during the initial landing of a drop jump. A mediation analysis examined the extent to which LELM predicted EA at each lower extremity joint (EAHIP, EAKNEE, and EAANK) and subsequently whether these relationships were mediated by each subject's maximal eccentric strength capabilities. RESULTS: LELM was a significant predictor of EAKNEE (R = 0.22, P < 0.01) in females but not in males (R = 0.03, P = 0.16). In females, QuadECC was a significant mediator of the effect of LELM on EA at the knee (ab = 179.72, 95% confidence interval [CI] = 10.43-423.42) and ankle (ab = 1.71, 95% CI = [0.16, 3.94]), whereas HamECC was a significant mediator of the relationship between LELM and EAHIP (ab = 4.89, 95% CI = 2.05-8.40). No significant relationships were observed in males. CONCLUSIONS: LELM was a significant factor in energetic capabilities for females but not males. For females, this relationship was evident secondary to the stronger underlying relationship between maximal strength and EA. Thus, the maximal eccentric strength capabilities may be a more important determinant of energetic behaviors compared with the available quantity of lean mass alone. More work is needed to investigate these relationships and to reveal the underlying sex-specific mechanisms that determine EA capabilities. PMID- 22811035 TI - Metabolic dysfunction in diabetic offspring: deviations in metabolic flexibility. AB - In type 2 diabetes (T2D), insulin resistance is related to comorbidities, including high lipotoxicity, poor glucoregulation, and loss of metabolic flexibility. Controversy exists regarding whether reduced metabolic flexibility precedes insulin resistance or vice versa. PURPOSE: The purpose of this study was to determine whether a family history of T2D leads to metabolic inflexibility. METHODS: To examine potential loss of metabolic flexibility at early stages, we used a hooded metabolic cart to compare metabolic characteristics in people with T2D, family history of T2D (FH+), and controls (FH-) 1) at rest, 2) with passive stretching (PS) and recovery, and 3) with oral glucose load. Testing of 9 T2D, 11 FH+, and 9 FH- occurred after a 12-h fast under resting conditions. Expired gas and blood glucose (BG) were measured before and after each condition. RESULTS: PS lowered BG (P < 0.05) in FH- and FH+ (mean +/- SD, -2.7 +/- 5.9 and -5.8 +/- 7.5 mg.mL(-1)) compared with T2D (-0.9 +/- 7.7). CHO use (kcal.min(-1)) increased with PS in all groups (0.04 +/- 0.18, 0.03 +/- 0.26, and 0.22 +/- 1.6 mg.mL(-1) in FH-, FH+, and T2D, respectively). For oral glucose load, different metabolic flexibility existed between FH- as well as FH+ (0.16 +/- 0.07) as well as T2D (0.16 +/- 0.07), with no difference between FH- and T2D. CONCLUSION: PS increases glycolytic activity without affecting BG in T2D, and reductions in metabolic flexibility exist in T2D and FH+ without glucoregulatory impairment in FH+, indicating early stage of mitochondrial dysfunction in FH+. Findings indicate PS is an important tool for assessing metabolic flexibility. PMID- 22811036 TI - Respiratory muscle pressure development during breath holding in apnea divers. AB - INTRODUCTION: We sought to characterize the patterns of active pressure development of the inspiratory and expiratory rib cage muscles (P(rcm,i) and P(rcm,e)), the diaphragm (P(di,i)), and the expiratory abdominal muscles (P(abm,e)) during maximal "dry" breath holding in trained apnea divers (n = 8). METHODS: Respiratory contractions were assessed via esophageal and gastric manometry. It was expected that inspiratory/expiratory pressures would progressively increase in both magnitude and frequency during the struggle phase, and that inspiratory rib cage muscle pressures would rise at a rate exceeding that of the diaphragm by the break point. RESULTS: P(rcm,i), P(di,i), P(rcm,e), and P(abm,e) significantly increased from the beginning until the end of the struggle phase (P < 0.05). Moreover, P(di,i)/P(rcm,i) and P(abm,e)/P(rcm,e) ratios had declined by the break point (P < 0.05), indicating that rib cage muscles increased their contribution to net inspiratory/expiratory pressure development by the end of the breath hold, relative to that contributed by the diaphragm and abdominal muscles. The pressure-time indices of the diaphragm and inspiratory rib cage muscles continuously increased over the struggle phase (P < 0.05). CONCLUSIONS: The "extradiaphragmatic" shift in inspiratory muscle recruitment, commensurate with increasing P(rcm,e) and P(abm,e), may reflect an extreme loading response to breathing against a heavy elastance (i.e., closed glottis). In addition, the relative intensity of diaphragmatic and inspiratory rib cage muscle contractions approaches potentially "fatiguing" levels by the break point of maximal breath holding. PMID- 22811037 TI - Dietary supplements: physician knowledge and adverse event reporting. AB - PURPOSE: Dietary supplement (DS) use among US military personnel is widespread. Many consume several different DS with multiple ingredients one or more times each week, representing a potential public health concern. The overall purpose of the study was to assess the knowledge and behaviors of health professionals and physicians regarding patterns of DS use and possible adverse events (AE) associated with DS use. We also determined how providers address the issue of DS with patients and evaluated provider knowledge regarding reporting systems. METHODS: Two prospective, cross-sectional, web-based questionnaires were administered. First, health care providers who accessed the Natural Medicines Comprehensive Database to gather evidenced-based information on DS and herbal products were queried. Second, physicians who had graduated from the Uniformed Services University were sent a web-based questionnaire regarding DS knowledge, AE knowledge and reporting, and communication with patients about DS. The frequencies of responses were evaluated. RESULTS: Although 60% of the military physicians who responded to the questionnaires believed they had observed AE in association with a DS, only 18% actually reported them. Three of four physician respondents (approximately 73%) did not know how or where to report AE associated with DS. The majority of physicians (66%) routinely asked most of their patients about DS use, and 65% did not have a reliable source of information for herbal and DS products. CONCLUSIONS: Information gaps in DS information and AE reporting were identified. A centralized AE reporting system could serve to identify potentially harmful DS for further evaluation. Health professionals need to remain vigilant for AE associated with DS use and better informed on how to report these events. PMID- 22811039 TI - Spectroscopic observation of a Group 12 oxyfluoride: a matrix-isolation and quantum-chemical investigation of mercury oxyfluorides. PMID- 22811038 TI - Metabolic syndrome and daily ambulation in children, adolescents, and young adults. AB - PURPOSES: To compare daily ambulatory measures in children, adolescents, and young adults with and without metabolic syndrome and to assess which metabolic syndrome components, demographic measures, and body composition measures are associated with daily ambulatory measures. METHODS: Two-hundred fifty subjects between the ages of 10 and 30 yr were assessed on metabolic syndrome components, demographic and clinical measures, body fat percentage, and daily ambulatory strides, durations, and cadences during seven consecutive days. Of the 250 subjects, 45 had metabolic syndrome, as defined by the International Diabetes Federation. RESULTS: Subjects with metabolic syndrome ambulated at a slower daily average cadence than those without metabolic syndrome (13.6 +/- 2.2 vs 14.9 +/- 3.2 strides per minute; P = 0.012), and they had slower cadences for continuous durations of 60 min (P = 0.006), 30 min (P = 0.005), 20 min (P = 0.003), 5 min (P = 0.002), and 1 min (P = 0.001). However, the total amount of time spent ambulating each day was not different (P = 0.077). After adjustment for metabolic syndrome status, average cadence is linearly associated with body fat percentage (P < 0.001) and fat mass (P < 0.01). Group difference in average cadence was no longer significant after adjusting for body fat percentage (P = 0.683) and fat mass (P = 0.973). CONCLUSIONS: Children, adolescents, and young adults with metabolic syndrome ambulate more slowly and take fewer strides throughout the day than those without metabolic syndrome, although the total amount of time spent ambulating is not different. Furthermore, the detrimental influence of metabolic syndrome on ambulatory cadence is primarily a function of body fatness. PMID- 22811040 TI - A novel reconfigurable optical biosensor based on DNA aptamers and a DNA molecular beacon. AB - In order to alter a typical molecular aptamer beacon (MAB) to detect a different analyte there is currently a need to change the whole sensor unit including the expensive labeling fluorophores. In this work a DNA-based reconfigurable molecular aptamer beacon was developed. It is composed of two parts: a variable part and a constant part. The variable part comprises an aptamer strand and its complementary strand while the constant part is an oligonucleotide doubly labeled with a Forster Resonance Energy Transfer (FRET) pair and the two parts become joined via DNA hybridization. The sensor exists in two conformations: a folded (high FRET) and an unfolded (low FRET) in the absence and presence of the aptamer target binding respectively. This sensor can be reconfigured by washing away the aptamer and the complementary strand using proper complementary strands, called washers. As a proof of the principle, a sensor that bound the enzyme thrombin, an analyte with a strong binding, was first constructed and then reconfigured to bind adenosine, selected as an analyte with a weak binding. We believe that the design is of universal use applicable to many types of aptamers. PMID- 22811041 TI - Shattered and stitched chromosomes-chromothripsis and chromoanasynthesis manifestations of a new chromosome crisis? AB - Chromothripsis (chromosome shattering) has been described as complex rearrangements affecting single chromosome(s) in one catastrophic event. The chromosomes would be "shattered" and "stitched together" during this event. This phenomenon is proposed to constitute the basis for complex chromosomal rearrangements seen in 2-3% of all cancers and in ~ 25% of bone cancers. Here we discuss chromothripsis, the use of this term and the evidence presented to support a single catastrophic event that remodels the genome in one step. We discuss why care should be taken in using the term chromothripsis and what evidence is lacking to support its use while describing complex rearrangements. PMID- 22811043 TI - Differential gene regulation by V(IV) and V (V) ions in the branchial sac, intestine, and blood cells of a vanadium-rich ascidian, Ciona intestinalis. AB - Ascidians are hyperaccumulators that have been studied in detail. Proteins and genes involved in the accumulation process have been identified, but regulation of gene expression related to vanadium accumulation remains unknown. To gain insights into the regulation of gene expression by vanadium in a genome-wide manner, we performed a comprehensive study on the effect of excess vanadium ions on a vanadium-rich ascidian, Ciona intestinalis, using a microarray. RT-PCR and enzyme activity assay were performed from the perspective of redox and accumulation of metal ions in each tissue. Glutathione metabolism-related proteins were significantly up-regulated by V(IV) treatment. Several genes involved in the transport of vanadium and protons, such as Nramp and V-ATPase, were significantly up-regulated by V(IV) treatment. We observed significant up regulation of glutathione synthesis and degradation pathways in the intestine and branchial sac. In blood cells, expression of Ci-Vanabin4, glutathione reductase activity, glutathione levels, and vanadium concentration increased after V(IV) treatment. V(IV) treatment induced significant changes related to vanadium exclusion, seclusion, and redox pathways in the intestine and branchial sac. It also induced an enhancement of the vanadium reduction and accumulation cascade in blood cells. These differential responses in each tissue in the presence of excess vanadium ions suggest that vanadium accumulation and reduction may have regulatory functions. This is the first report on the gene regulation by the treatment of vanadium-rich ascidians with excess vanadium ions. It provided much information for the mechanism of regulation of gene expression related to vanadium accumulation. PMID- 22811044 TI - The isolated prolonged PTT. AB - It is increasingly difficult to choose the proper tests to investigate an abnormal laboratory result, delaying the time to reach the correct diagnosis and increasing the cost of care. A wrong choice may also lead to clinically significant errors, which can be life threatening. To show how errors in test selection occur in routine medical practice, the authors describe an algorithm to evaluate patients with a prolonged activated partial thromboplastin time (PTT) and a normal prothrombin time. This exercise challenges the commonly held belief that errors in laboratory utilization occur primarily with esoteric and/or genetic testing, rather than in patients with common abnormalities such as a prolonged PTT. PMID- 22811045 TI - Increased circulating apoptotic lymphocytes in children with Down syndrome. AB - Down syndrome (DS) resembles immunodeficiency with increased infections, auto immune diseases, and hematological malignancies. Until now, immunological studies in DS mainly focused on T-lymphocytes. We recently described a profound B lymphocytopenia in children with DS. This could be caused by increased apoptosis. Therefore, we determined expression of flowcytometric markers for apoptosis [Annexin-V (AV) and propidium iodide (PI)] on peripheral lymphocytes in 72 children with DS and 32 age-matched controls (AMC). Within the total lymphocyte compartment, apoptosis was more pronounced in DS; it increased with age. Moreover, apoptosis was highest within the B-lymphocyte compartment which may be a contributing factor to the B-lymphocytopenia found in DS. Pediatr Blood Cancer 2012; 59: 1310-1312. (c) 2012 Wiley Periodicals, Inc. PMID- 22811046 TI - Anterior temporal lobe white matter abnormal signal (ATLAS) as an indicator of seizure focus laterality in temporal lobe epilepsy: comparison of double inversion recovery, FLAIR and T2W MR imaging. AB - OBJECTIVES: To investigate the diagnostic capability of anterior temporal lobe white matter abnormal signal (ATLAS) for determining seizure focus laterality in temporal lobe epilepsy (TLE) by comparing different MR sequences. METHODS: This prospective study was approved by the institutional review board and written informed consent was obtained. Three 3D sequences (double inversion recovery (DIR), fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging (T2WI)) and two 2D sequences (FLAIR and T2WI) were acquired at 3 T. Signal changes in the anterior temporal white matter of 21 normal volunteers were evaluated. ATLAS laterality was evaluated in 21 TLE patients. Agreement of independent evaluations by two neuroradiologists was assessed using kappa statistics. Differences in concordance between ATLAS laterality and clinically defined seizure focus laterality were analysed using McNemar's test with multiple comparisons. RESULTS: Pre-amygdala high signals (PAHS) were detected in all volunteers only on 3D-DIR. Inter-evaluator agreement was moderate to almost perfect for each sequence. Correct diagnosis of seizure laterality was significantly more frequent on 3D-DIR than on any other sequences (P <= 0.031 for each evaluator). CONCLUSIONS: The most sensitive sequence for detecting ATLAS laterality was 3D-DIR. ATLAS laterality on 3D-DIR can be a good indicator for determining seizure focus localization in TLE. PMID- 22811047 TI - Alterations of microbial populations and composition in the rhizosphere and bulk soil as affected by residual acetochlor. AB - Acetochlor is a widely used herbicide in maize fields; however, the ecological risk of its residue in the soil-plant system remains unknown. We investigated the dissipation dynamics of field dose acetochlor and clarified its impact on microbial biomass and community structure both in the rhizosphere and bulk soil over 1 month after its application. Soil microbial parameters such as quantities of culturable bacteria and fungi represented by colony-forming units, soil microbial biomass carbon (SMB(C)), and phospholipid fatty acids (PLFAs) were determined across different sampling times. The results showed that the dissipation half-lives of acetochlor were, respectively, 2.8 and 3.4 days in the rhizosphere and bulk soil, and 0.02-0.07 MUg/g residual acetochlor could be detected in the soil 40 days after its application. Compared to the bulk soil, microbial communities in the rhizosphere soil were inclined to be affected by the application of acetochlor: SMB(C) content and bacterial growth were most likely to be increased; however, fungal growth was prone to be inhibited. The principal component analysis of PLFAs, as well as the comparisons of fungi/bacteria and cy17:0/C16:1omega9c ratios between different treatments over sampling time, revealed that the soil microbial community composition was significantly affected by acetochlor at its early application stage (at day 15); thereafter, the effects of acetochlor were attenuated or even could not be detected. Our results suggested that residual acetochlor did not confer a long-term impairment on viable bacterial groups in the rhizosphere and bulk soil. PMID- 22811048 TI - Interrater agreement of anal cytology. AB - BACKGROUND: The majority of anal cancers are caused by persistent infections with carcinogenic human papillomaviruses (HPV). Similar to cervical carcinogenesis, the progression from HPV infection to anal cancer occurs through precancerous lesions that can be treated to prevent invasion. In analogy to cervical cytology, anal cytology has been proposed as a screening tool for anal cancer precursors in high-risk populations. METHODS: The authors analyzed the interobserver reproducibility of anal cytology in a population of 363 human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Liquid-based cytology (LBC) specimens were collected in the anal dysplasia clinic before the performance of high-resolution anoscopy on all patients. Papanicolaou-stained LBC slides were evaluated by 2 cytopathologists, each of whom was blinded to the clinical outcome and the other pathologist's results, using the revised Bethesda terminology. RESULTS: Overall agreement between the 2 observers was 66% (kappa, 0.54; linear weighted kappa, 0.69). Using dichotomizing cytology results (atypical squamous cells of undetermined significance [ASC-US] or worse vs less than ASC-US), the agreement increased to 86% (kappa, 0.69). An increasing likelihood of testing positive for markers associated with HPV-related transformation, p16/Ki-67, and HPV oncogene messenger RNA was observed, with increasing severity of cytology results noted both for individual cytologists and for consensus cytology interpretation (P value for trend [p(trend)] < .0001 for all). CONCLUSIONS: Moderate to good agreement was observed between 2 cytopathologists evaluating anal cytology samples collected from HIV-positive MSM. A higher severity of anal cytology was associated with biomarkers of anal precancerous lesions. Anal cytology may be used for anal cancer screening in high-risk populations, and biomarkers of HPV-related transformation can serve as quality control for anal cytology. PMID- 22811049 TI - Pericyte coverage of differentiated vessels inside tumor vasculature is an independent unfavorable prognostic factor for patients with clear cell renal cell carcinoma. AB - BACKGROUND: The objective of this study was to evaluate the effect of pericyte coverage (PC) of differentiated tumor microvessels on the prognosis of patients with clear cell renal cell carcinoma (CCRCC). METHODS: Samples from 2 cohorts of patients with CCRCC (101 Asian patients and 524 US patients) were prepared using 2 different histologic approaches: routine sectioning versus tissue microarray. Then, the samples were immunohistochemically doubled-stained for a pericyte marker (alpha smooth muscle actin [alpha-SMA]) and a differentiated vessel marker (cluster of differentiation 34 [CD34]), followed by multispectral image capturing and computerized image analyses to quantify the microvessel density (MVD) and the PC of differentiated vessels. The correlations of PC and the MVD:PC ratio with clinicopathologic characteristics were analyzed. RESULTS: There was an inverse correlation between differentiated MVD and PC. Higher PC correlated with more aggressive clinicopathologic characteristics of CCRCC in both cohorts, including more advanced T-classification, higher pathologic grades, and the occurrence of tumor necrosis. The MVD:PC ratio was an independent favorable prognostic factor for overall and recurrence-free survival in the Asian cohort and for recurrence free survival in the US cohort. PC also was an independent prognostic factor, with higher PC predicting a poorer outcome. The combination of PC and MVD was better at distinguishing the outcome of patients with CCRCC. PC combined with differentiated MVD or with the MVD:PC ratio provided additional, independent prognostic information to the Leibovich risk model, and that information was used to generate improved risk models. CONCLUSIONS: The authors consistently observed that higher PC was correlated with more aggressive clinicopathologic characteristics. PC was an independent unfavorable prognostic factor. The authors concluded that pericytes should be considered for therapeutic targeting. PMID- 22811050 TI - [Sustainable publishing]. PMID- 22811051 TI - [Autonomy: to what extent is the concept relevant in psychiatry?]. AB - BACKGROUND: Autonomy is an important concept in psychiatry, but because it is a somewhat abstract and ambiguous notion, it is not applicable in its entirety in a psychiatric context. This becomes obvious in situations where patients are receiving long term care and treatment. AIM: To modify the concept of autonomy in such a way that it acquires an extra dimension that renders it applicable to daily psychiatric practice. METHOD: The literature was reviewed in order to find articles that reveal the tensions that arise between autonomy and dependence in psychiatry and that reflect the human characteristics that are concealed behind the modern concepts of autonomy, freedom and respect for autonomy. RESULTS: Concepts such as person, identity, acknowledgement, dialogical ethics and life histories are used as an addition to the concepts of autonomy of Kant and Mill. A phenomenological and a context sensitive conception of autonomy is needed within the perspective of dialogical ethics. A dialogical perspective requires from psychiatric professionals a susceptibility for what the patient as a human being really has to say. On the basis of a dialogue where there is space and attention for life histories, backgrounds and the potentials of patients, a new perspective can be developed that is shared by the persons involved. CONCLUSION: In psychiatry, statements about real autonomy and genuine respect for autonomy are only truly meaningful within the context of doctors, nurses and patients. A hermeneutic approach to patients which involves dialogue creates new opportunities in the field of staff-patient relations. PMID- 22811052 TI - [Cenesthetic schizophrenia revisited]. AB - BACKGROUND: In 1957 Huber introduced the concept 'cenesthetic schizophrenia', a subtype of schizophrenia that is characterised primarily by aberrant bodily sensations. Clinical practice shows that patients with schizophrenia frequently suffer from disturbed bodily sensations. Nevertheless, the current 1CD-10 en DSM IV classifications pay hardly any attention to symptoms of this kind. AIM: To describe the characteristics of cenesthetic schizophrenia. METHOD: We obtained background information from historical literature and the PubMed database. We also report a case-study in which a patient experienced atypical physical symptoms which closely resembled those that characterised Huber's cenesthetic schizophrenia. RESULTS: Huber's description led to new insights into the development and course of schizophrenia where the main focus was on the patient's subjectively experienced symptomatology. Both the background literature and the case-study show that the time has come for a revaluation of cenesthetic schizophrenia. CONCLUSION: We recommend that cenesthetic schizophrenia be included as a subtype within the spectrum of schizophrenia. Further longitudinal research is needed into other characteristics of this type of schizophrenia, its etiopathogenesis and the currently available therapeutical options. PMID- 22811053 TI - [Creativity and psychiatric disorders: exploring a marginal area]. AB - BACKGROUND: Creativity is an important human quality on which many of man's achievements are based. AIM: To give a historical and cultural context, to facilitate meaningful scientific research into the link between creativity and psychiatric disorders. METHOD: Review of relevant literature. RESULTS: The possibility of a link between creativity and psychiatric vulnerability was first discussed in antiquity. Modern interest in the subject stems from the romantic era and acquired a scientific aura in the 19th century. In the 20th century creativity and psychopathology became still further entangled as a result of the influence that mentally disturbed artists exerted on art. The history of the Prinzhorn collection illustrates many aspects of this interaction. Psychometric, psychodiagnostic and genetic research supports a link between creativity and psychiatric illness within the bipolar-psychotic continuum, with schizotypy/thymotypy as prototypes of creativity-related disorders. Evolutionary hypotheses connect the schizophrenia paradox to a survival advantage obtained as a result of enhanced creative ability. Neuro-aesthetics explains the neurologic correlates of the aesthetic experience on the basis of the features of the visual system. CONCLUSION: A specific challenge for scientific research in this complex and heterogeneous area is appropriate operationalisation of creativity and psychiatric illness within an truly artistic context. There is a continuing need for meaningful definitions and measurement instruments and for a multidisciplinary collaboration. PMID- 22811054 TI - [Gilles de la Tourette: The history of the man and his illness; a medical historical study]. AB - BACKGROUND: Description of the life, illness and work of Georges Gilles de la Tourette (1857-1904) and the history of his eponym. AIM: To provide an historical overview of the different views about the disease of Gilles de la Tourette and the Tourette Syndrome. METHOD: Literature review. RESULTS: In 1885 Gilles de la Tourette published a paper on a rare disorder whose symptoms were sudden movements (tics) and the shouting out of obscene language (coprolalia). According to Charcot it was a specific neurological disease which he named after his pupil: la maladie des tics de Gilles de la Tourette. Gilles de la Tourette was potentially successor to Charcot as Professor of Neurology. His bad temper, the first symptoms of neurolues with megalomania, and the fact that the ideas of hysteria had undergone a drastic change, deterred him from taking up the position. After his premature death in 1904 his name was soon forgotten. In the early part of the 20th century the disease of tics was regarded as a psychiatric disorder and from 1920 those suffering from tics were referred for psychoanalysis. After 1970 the disease of Gilles de la Tourette experienced a revival. The American couple Shapiro rediscovered the disorder as a neurological disease and named it the Tourette Syndrome. Thanks to the efforts of an influential American patient organisation Gilles de la Tourette has become famous worldwide with the exception of France. In that country their compatriot is not only less well known, but the belief is still held that it is a neuropsychiatric phenomenon that requires psychotherapeutic treatment. CONCLUSION: The disease of Gilles de la Tourette or the Tourette syndrome has been regarded in different periods either as a neurological or a psychiatric disorder. PMID- 22811055 TI - [Reaction on 'The God image in relation to autistic traits and religious denomination']. PMID- 22811056 TI - [Reaction on 'Emergency compulsory admission in crisis situations; the Amsterdam Study of Acute Psychiatry']. PMID- 22811057 TI - Dynamics of oscillatory changes associated with the perception of human motion. AB - Neurophysiological evidence suggests that a specialized cortical network is involved in the visual perception of biological motion; however, the temporal dynamics underlying this network is largely unexplored. We used magnetoencephalography to determine the spatial distribution and task-related temporal dynamics of the oscillatory activity of random and human motion. We recorded cortical responses in healthy adults while they passively viewed point light displays of static dots, random, and human motion. By analyzing differences in the time-frequency distributions between pairs of conditions, we found that: (a) the perception of both motion conditions resulted in a significant decrease in the alpha/beta band in the right superior occipital gyrus and a significant decrease in the beta band in the right insula and (b) the human motion condition was associated with specific alterations in alpha, beta, and gamma bands with significant reductions in the alpha band in the right superior temporal gyrus, right precuneus, and left inferior parietal lobule, significant reductions in the beta band in the bilateral superior temporal gyrus, together with a significant increase in the gamma band in the left inferior parietal lobule and superior temporal regions. These data suggest that although the perception of both random and human motion involves desynchronization of oscillatory activity in alpha and beta bands in similar cortical regions, only human motion is associated with a larger network and significant alterations in the alpha/beta band particularly in the right hemisphere. PMID- 22811058 TI - False memory and level of processing effect: an event-related potential study. AB - Event-related potentials (ERPs) were used to determine the effects of level of processing on true and false memory, using the Deese-Roediger-McDermott (DRM) paradigm. In the DRM paradigm, lists of words highly associated to a single nonpresented word (the 'critical lure') are studied and, in a subsequent memory test, critical lures are often falsely remembered. Lists with three critical lures per list were auditorily presented here to participants who studied them with either a shallow (saying whether the word contained the letter 'o') or a deep (creating a mental image of the word) processing task. Visual presentation modality was used on a final recognition test. True recognition of studied words was significantly higher after deep encoding, whereas false recognition of nonpresented critical lures was similar in both experimental groups. At the ERP level, true and false recognition showed similar patterns: no FN400 effect was found, whereas comparable left parietal and late right frontal old/new effects were found for true and false recognition in both experimental conditions. Items studied under shallow encoding conditions elicited more positive ERP than items studied under deep encoding conditions at a 1000-1500 ms interval. These ERP results suggest that true and false recognition share some common underlying processes. Differential effects of level of processing on true and false memory were found only at the behavioral level but not at the ERP level. PMID- 22811059 TI - The expression changes of EphA3 receptor during synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptor. AB - We have reported that systemic application of nicotinic agonists results in expression of a long-term potentiation-like facilitation, a model of synaptic plasticity, in the mouse hippocampus in vivo. Eph receptors and their ephrin ligands, are thought to participate in synaptic plasticity. The present study was conducted to clarify the involvement of EphA3 receptor in synaptic plasticity by investigating the time-dependent change of the expression levels of EphA3 receptor during long-term potentiation-like facilitation in the mouse hippocampus. EphA3 receptor mRNA and protein expression was found in adult mouse hippocampus. EphA3 receptor was localized in neuronal cells but not astrocytes or microglia of hippocampus. After intraperitoneal application of nicotine (3 mg/kg), the protein expression of EphA3 receptor in hippocampus increased during 2-24-h period, significantly increasing during 2-12-h period, and finally returned to the basal level in 72 h, although the mRNA expression of EphA3 receptor was not changed for 24 h. This enhanced expression of EphA3 receptor protein at 4 h was inhibited by pretreatment of mecamylamine (0.5 mg/kg, intraperitoneally), a nonselective nicotinic acetylcholine receptor antagonist. Our findings demonstrated that EphA3 receptor localized only in neuronal cells of the hippocampus was enhanced without transcriptional regulation during synaptic plasticity through activation of the nicotinic acetylcholine receptor. These results suggest that the enhancement of EphA3 receptor after synaptic plasticity may contribute to long-lasting synaptic plasticity through positive, feedforward mechanisms. PMID- 22811061 TI - Using ion purity scores for enhancing quantitative accuracy and precision in complex proteomics samples. AB - To accurately determine the quantitative change of peptides and proteins in complex proteomics samples requires knowledge of how well each ion has been measured. The precision of each ions' calculated area is predicated on how uniquely it occupies its own space in m/z and elution time. Given an initial assumption that prior to the addition of the "heavy" label, all other ion detections are unique, which is arguably untrue, an initial attempt at quantifying the pervasiveness of ion interference events in a representative binary SILAC experiment was made by comparing the centered m/z and retention time of the ion detections from the "light" variant to its "heavy" companion. Ion interference rates were determined for LC-MS data acquired at mass resolving powers of 20 and 40 K with and without ion mobility separation activated. An ion interference event was recorded, if present in the companion dataset was an ion within +/- its Delta mass at half-height, +/-15 s of its apex retention time and if utilized by +/-1 drift bin. Data are presented illustrating a definitive decrease in the frequency of ion interference events with each additional increase in selectivity of the analytical workflow. Regardless of whether the quantitative experiment is a composite of labeled samples or label free, how well each ion is measured can be determined given knowledge of the instruments mass resolving power across the entire m/z scale and the ion detection algorithm reporting both the centered m/z and Delta mass at half-height for each detected ion. Given these measurements, an effective resolution can be calculated and compared with the expected instrument performance value providing a purity score for the calculated ions' area based on mass resolution. Similarly, chromatographic and drift purity scores can be calculated. In these instances, the error associated to an ions' calculated peak area is estimated by examining the variation in each measured width to that of their respective experimental median. Detail will be disclosed as to how a final ion purity score was established, providing a first measure of how accurately each ions' area was determined as well as how precise the calculated quantitative change between labeled or unlabelled pairs were determined. Presented is how common ion interference events are in quantitative proteomics LC-MS experiments and how ion purity filters can be utilized to overcome and address them, providing ultimately more accurate and precise quantification results across a wider dynamic range. PMID- 22811060 TI - Association between maternal occupational exposure to organic solvents and congenital heart defects, National Birth Defects Prevention Study, 1997-2002. AB - OBJECTIVE: To examine the relation between congenital heart defects (CHDs) in offspring and estimated maternal occupational exposure to chlorinated solvents, aromatic solvents and Stoddard solvent during the period from 1 month before conception through the first trimester. METHODS: The study population included mothers of infants with simple isolated CHDs and mothers of control infants who delivered from 1997 through 2002 and participated in the National Birth Defects Prevention Study. Two methods to assess occupational solvent exposure were employed: an expert consensus-based approach and a literature-based approach. Multiple logistic regression was used to calculate adjusted ORs and 95% CIs for the association between solvent classes and CHDs. RESULTS: 2951 control mothers and 2047 CHD case mothers were included. Using the consensus-based approach, associations were observed for exposure to any solvent and any chlorinated solvent with perimembranous ventricular septal defects (OR 1.6, 95% CI 1.0 to 2.6 and OR 1.7, 95% CI 1.0 to 2.8, respectively). Using the literature-based approach, associations were observed for: any solvent exposure with aortic stenosis (OR 2.1, 95% CI 1.1 to 4.1) and Stoddard solvent exposure with d transposition of the great arteries (OR 2.0, 95% CI 1.0 to 4.2), right ventricular outflow tract obstruction defects (OR 1.9, 95% CI 1.1 to 3.3) and pulmonary valve stenosis (OR 2.1, 95% CI 1.1 to 3.8). CONCLUSIONS: The authors found evidence of associations between occupational exposure to solvents and several types of CHDs. These results should be interpreted in light of the potential for misclassification of exposure. PMID- 22811062 TI - Vanadium bromoperoxidase-coupled fluorescent assay for flow cytometry sorting of glucose oxidase gene libraries in double emulsions. AB - A Vanadium bromoPeroxidase-coupled fluorescent assay (ViPer) for ultrahigh throughput screening of glucose oxidase (GOx) gene libraries employing double emulsions and flow cytometry was developed. The assay is based on detection of the product of a GOx reaction, hydrogen peroxide, that is first converted to a hypobromide by vanadium bromoperoxidase in the presence of sodium bromide. The hypobromide is afterwards detected in a reaction with a fluorogenic probe, 3 carboxy-7-(4'-aminophenoxy)-coumarine, where fluorescent 3-carboxy-coumarine is released. The ViPer screening system is three times more sensitive than a horseradish peroxidase coupled detection system and more resistant to bleaching of fluorescence in excess of peroxide. Using the ViPer screening system a high epPCR gene library containing 100,000 different GOx variants was screened for active clones in less than 1 h by flow cytometry. A library containing 0.15% of yeast cells expressing active enzyme variants and with an average GOx activity in the liquid culture of 0.47 U/mL, after one round of sorting, had 28.12% of the yeast cells expressing the active GOx (an enrichment factor of 200) and 26.8 U/mL of the GOx activity in the liquid culture (an enrichment factor of 57). The developed screening system could be adapted and used in a directed evolution of GOx and other hydrogen peroxide-producing enzymes (oxidases) and glycosidases if coupled with a carbohydrate oxidase. PMID- 22811064 TI - Resolving the problem of chromatographic overlap by 3D cross correlation (3DCC) processing of LC, MS and NMR data for characterization of complex glycan mixtures. AB - Chromatographic overlap is a common problem in the analysis of complex mixtures. As a result, it is not possible to identify the components because each resulting NMR or MS spectrum contains multiple components. We introduce three-dimensional cross correlation (3DCC) that dissects NMR spectra of a mixture into spectra of the individual components without actually separating them. Correlation of peaks from MS and NMR profiles along a common LC time domain yields 3DCC NMR spectra of pure components correlated with a mass and a retention time. The method requires an LC run followed by fractionation and recording of MS and NMR spectra. The method is applicable to mixtures of any classes of molecules. Here, we demonstrate its application to a mixture of complex glycans obtained from a glycoprotein. Fourteen glycans eluting within only 3 min showed heavy overlap in the chromatographic run. 3DCC allowed their direct characterization without separation. Some of these structures from the glycoprotein bovine fibrinogen had not previously been described. The 3DCC procedure has been implemented in standard software. Actually, 3DCC can be used for any combination of separation techniques, like LC or GC, combined with two characterization methods like UV, IR, Raman, NMR or MS. PMID- 22811063 TI - Comparing the efficiencies of hydrazide labels in the study of protein carbonylation in human serum albumin. AB - In this work, we establish a methodology for comparing the efficiencies of different hydrazide labels for detecting protein carbonyls. We have chosen acrolein-modified human serum albumin as a model. This system provides a convenient means of reproducibly generating carbonylated protein. Five hydrazide based labels were tested. Three carry a biotin affinity tag, and the others are simple fatty acid hydrazides. For the biotin-based labels, the yield of the labeling reaction varies considerably, and the most commonly used label, biotin hydrazide, gives the lowest yield. The total tandem mass spectrometry (MS/MS) spectrum counts of modified peptides are similar for all of the biotin-based tags, indicating that factors beyond the labeling efficiency are important in determining the effectiveness of the label. In addition, there is a large variation in the number of spectra obtained for specific, modified peptides depending on the nature of the labeling group. This variation implies that the relative detectability of a particular modification site is highly dependent on the tagging reagent, and more importantly, titration schemes aimed at identifying the most reactive site based on its threshold concentration will be biased by the choice of tagging reagent. The fatty acid hydrazides are somewhat more effective than the biotin-based hydrazides in generating identifiable MS/MS spectra but offer no opportunity for enrichment. For the biotin-based tags, avidin affinity chromatography was used with the tryptic digests, and each tag led to similar enrichment levels. PMID- 22811065 TI - New luminescent oxygen-sensing and temperature-sensing materials based on gadolinium(III) and europium(III) complexes embedded in an acridone-polystyrene conjugate. AB - New sensing materials have been developed which rely on the use of luminescent europium(III) and gadolinium(III) complexes with thenoylacetylacetonate embedded in an acridone-polystyrene conjugate. Acridone acts as an antenna which efficiently absorbs violet light. Covalent coupling to the polystyrene backbone prevents aggregation and enables very high antenna loading (16% w/w). Energy transfer from the antenna to the lanthanide complexes results in efficient red luminescence from the Eu(III) complex or green phosphorescence originating from the Gd(III) chelate. The luminescence of the material based on the Eu(III) complex is only slightly affected by oxygen but is highly sensitive to temperature under physiological conditions (20-40 degrees C). The Gd(III) complex has long phosphorescence decay times of approximately 1 ms and high sensitivity to oxygen. Ultra-thin (250 nm) sensing layers with sufficient absorption at the excitation wavelength enable monitoring of rapid oxygen changes virtually in real time. Immobilization of both complexes in a single matrix results in a dual-luminescence material with emissions almost ideally matching the red and green channels of a digital camera. Thus, oxygen imaging using a very simple and inexpensive set-up can be realized. Additionally, the material can be used for simultaneous sensing of oxygen and temperature. PMID- 22811067 TI - Dimerization in the Grb7 protein. AB - In previous studies, we showed that the tyrosine phosphorylation state of growth factor receptor-bound protein 7 (Grb7) affects its ability to bind to the transcription regulator FHL2 and the cortactin-interacting protein, human HS-1 associated protein-1. Here, we present results describing the importance of dimerization in the Grb7-Src homology 2 (SH2) domain in terms of its structural integrity and the ability to bind phosphorylated tyrosine peptide ligands. A tyrosine phosphorylation-mimic mutant (Y80E-Grb7-SH2) is largely dimerization deficient and binds a tyrosine-phosphorylated peptide representative of the receptor tyrosine kinase (RTK) erbB2 with differing thermodynamic characteristics than the wild-type SH2 domain. Another dimerization-deficient mutant (F99R-Grb7 SH2) binds the phosphorylated erbB2 peptide with similarly changed thermodynamic characteristics. Both Y80E-Grb7-SH2 and F99R-Grb7-SH2 are structured by circular dichroism measurements but show reduced thermal stability relative to the wild type-Grb7-SH2 domain as measured by circular dichroism and nuclear magnetic resonance. It is well known that the dimerization state of RTKs (as binding partners to adaptor proteins such as Grb7) plays an important role in their regulation. Here, we propose the phosphorylation state of Grb7-SH2 domain tyrosine residues could control Grb7 dimerization, and dimerization may be an important regulatory step in Grb7 binding to RTKs such as erbB2. In this manner, additional dimerization-dependent regulation could occur downstream of the membrane-bound kinase in RTK-mediated signaling pathways. PMID- 22811068 TI - Fluorescence correlation spectroscopy study of protein transport and dynamic interactions with clustered-charge peptide adsorbents. AB - Ion-exchange chromatography relies on electrostatic interactions between the adsorbent and the adsorbate and is used extensively in protein purification. Conventional ion-exchange chromatography uses ligands that are singly charged and randomly dispersed over the adsorbent, creating a heterogeneous distribution of potential adsorption sites. Clustered-charge ion exchangers exhibit higher affinity, capacity, and selectivity than their dispersed-charge counterparts of the same total charge density. In the present work, we monitored the transport behavior of an anionic protein near clustered-charge adsorbent surfaces using fluorescence correlation spectroscopy. We can resolve protein-free diffusion, hindered diffusion, and association with bare glass, agarose-coated, and agarose clustered peptide surfaces, demonstrating that this method can be used to understand and ultimately optimize clustered-charge adsorbent and other surface interactions at the molecular scale. PMID- 22811069 TI - Purification and characterization of a mannose/N-acetyl-D-glucosamine-specific lectin from the seeds of Platymiscium floribundum Vogel. AB - Platymiscium floribundum lectin (PFL), a mannose/N-acetyl-D-glucosamine-specific lectin, was isolated from P. floribundum seeds using Sepharose-mannose affinity media chromatography. PFL is a glycoprotein that is a potent agglutinin for rabbit erythrocytes. In addition, PFL is highly stable because it is able to maintain its hemagglutinating activity after exposure to temperatures of up to 60 degrees C for 1 h and exposure to a wide pH range. The PFL purification process was monitored using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the results showed that the purified lectin consists of a single band with a molecular mass of approximately 29 kDa in either the presence or the absence of a reducing agent. The analysis of purified PFL by electrospray ionization-mass spectrometry showed that most ions had a molecular weight of 27,053 +/- 2 Da, and other less abundant ions had similar molecular weights. Gel filtration shows that the lectin exists as a dimer in solution with mass at approximately 65 kDa. Sixteen peptides were sequenced, and as a result, a total of 130 amino acids were identified and resulted in a coverage of approximately 65% of the PFL sequence. The partial sequence of PFL was aligned with sequences of other lectins from evolutionarily related species, and PFL showed considerable similarity to the other lectins. PMID- 22811066 TI - Circadian rhythm disruption in cancer biology. AB - Circadian rhythms show universally a 24-h oscillation pattern in metabolic, physiological and behavioral functions of almost all species. This pattern is due to a fundamental adaptation to the rotation of Earth around its own axis. Molecular mechanisms of generation of circadian rhythms organize a biochemical network in suprachiasmatic nucleus and peripheral tissues, building cell autonomous clock pacemakers. Rhythmicity is observed in transcriptional expression of a wide range of clock-controlled genes that regulate a variety of normal cell functions, such as cell division and proliferation. Desynchrony of this rhythmicity seems to be implicated in several pathologic conditions, including tumorigenesis and progression of cancer. In 2007, the International Agency for Research on Cancer (IARC) categorized "shiftwork that involves circadian disruption [as] probably carcinogenic to humans" (Group 2A in the IARC classification system of carcinogenic potency of an agentagent) (Painting, Firefighting, and Shiftwork; IARC; 2007). This review discusses the potential relation between disruptions of normal circadian rhythms with genetic driving machinery of cancer. Elucidation of the role of clockwork disruption, such as exposure to light at night and sleep disruption, in cancer biology could be important in developing new targeted anticancer therapies, optimizing individualized chronotherapy and modifying lighting environment in workplaces or homes. PMID- 22811071 TI - Biomarkers in traumatic brain injury. AB - Traumatic brain injury (TBI) is a common cause of neurological morbidity globally, and neurologic sequelae may occur even in the setting of mild injury. At present, the tools that guide diagnostic and prognostic evaluation of patients who suffer from TBI remain limited, especially for prehospital evaluation. Biomarkers of brain injury hold promise in facilitating early management and triage decisions in the civilian and military settings. The identification of biomarkers of brain injury may also be helpful in guiding end-of-life decision making and may facilitate the design of neuroprotective trials. PMID- 22811072 TI - Neighborhood walking among overweight and obese adults: age variations in barriers and motivators. AB - Walking is a popular form of physical activity that can bring many public health benefits. It can be even more beneficial to those who are currently obese or overweight. However, many barriers discourage people from walking, ranging from lack of motivation to unsafe neighborhood environments, and such barriers vary with age. This study addresses barriers and motivators to walking among overweight and obese adults, and examines their age variations. Particular emphasis was given to modifiable environmental factors as the priority intervention targets. A survey of 161 overweight and obese adults recruited from a large integrated healthcare system in central Texas provided data on walking, demographics, motivators and barriers. Descriptive statistics and correlation analysis were conducted. The respondents had a mean age of 48.4 (20-86), and were predominantly female (80.8%), non-Hispanic White (86.0%), and obese (mean BMI = 32.5). Popular environmental barriers to walking were: bad weather, inadequate lighting, no shade, unattended dogs, disconnected sidewalks, poor walking surfaces, no interesting places to walk nearby, and no benches (74.5-38.5%). Even and smooth walking surfaces and benches were more frequently reported by older adults as motivators. Proximity to recreational facilities was a stronger motivator for younger adults. Two safety related barriers, fear of injury (older adults) and traffic safety concerns (younger adults), also showed significant age differences. Overweight and obese adults experience substantial environmental barriers to walking, but many of them are modifiable. Observed age variations suggest that future interventions may be more effective if tailored to address age-specific barriers. PMID- 22811073 TI - Prevalence and risk factors associated with sexually transmitted diseases (STDs) in Sikkim. AB - The population of Sikkim is a unique blend of multi-tribal and metropolitan culture. However, till date, no data regarding prevalence of sexually transmitted diseases (henceforth abbreviated as STDs) among this population is available and hence requires attention. Hence the objective is to determine the prevalence of STDs in Sikkim and to describe associated risk factors. A cross-sectional study involving 'Questionnaire-based anonymous feedback system' was followed to collect data from 2,000 individuals across the society. The four most common STDs, gonorrhea, syphilis, chlamydia and HIV, were considered for the study. Total 69 (3.6%) cases of STDs were found in 1,918 individuals was affected by at least one of the STDs, out of which 43 were males and 26 were females. Cases of gonorrhea, syphilis, chlamydiasis and HIV were 25, 22, 4 and 18 respectively. Out of total 69 cases of STDs, 20 individuals were also suffering from some kind of hepatitis. Addictions like alcoholism, smoking and drugs were also found in significant number, with 1,019 (>50%) individuals with at least one of these addictions. Relative risk analysis indicates that gender-wise females are more vulnerable to STDs than males. The number of partners, addictions, especially alcohol and drug abuse, also contribute to STD cases. STDs act as a significant risk factor in transmitting some of the types of hepatitis. In such cases, females are more vulnerable than males. The results suggest that new community health programs are essential for both, HIV and non-HIV STDs in Sikkim. PMID- 22811074 TI - Gram-scale synthesis of nickel(II) norcorrole: the smallest antiaromatic porphyrinoid. AB - Small is beautiful: A ring-contracted sister of porphyrin, norcorrole, has been synthesized efficiently as a stable molecule by a nickel-templated strategy. The norcorrole complex is stable but exhibits a distinct antiaromatic character according to the Huckel rule. Oxidation of the norcorrole complex provides an aromatic oxacorrole complex. PMID- 22811076 TI - Microanatomy of the paired-fin pads of ostariophysan fishes (Teleostei: Ostariophysi). AB - Members of the teleost superorder Ostariophysi dominate freshwater habitats on all continents except Antarctica and Australia. Obligate benthic and rheophilic taxa from four different orders of the Ostariophysi (Gonorynchiformes, Cypriniformes, Characiformes, and Siluriformes) frequently exhibit thickened pads of skin along the ventral surface of the anteriormost ray or rays of horizontally orientated paired (pectoral and pelvic) fins. Such paired-fin pads, though convergent, are externally homogenous across ostariophysan groups (particularly nonsiluriform taxa) and have been considered previously to be the result of epidermal modification. Histological examination of the pectoral and/or pelvic fins of 44 species of ostariophysans (including members of the Gonorynchiforms, Cypriniformes, Characiformes, and Siluriformes) revealed a tremendous and previously unrecognized diversity in the cellular arrangement of the skin layers (epidermis and subdermis) contributing to the paired-fin pads. Three types of paired-fin pads (Types 1-3) are identified in nonsiluriform ostariophysan fishes, based on differences in the cellular arrangement of the epidermis and subdermis. The paired-fin pads of siluriforms may or may not exhibit a deep series of ridges and grooves across the surface. Two distinct patterns of unculus producing cells are identified in the epidermis of the paired-fin pads of siluriforms, one of which is characterized by distinct bands of keratinization throughout the epidermis and is described in Amphilius platychir (Amphiliidae) for the first time. General histological comparisons between the paired fins of benthic and rheophilic ostariophysan and nonostariophysan percomorph fishes are provided, and the possible function(s) of the paired-fin pads of ostariophysan fish are discussed. PMID- 22811075 TI - Conformational isomers of calcineurin follow distinct dissociation pathways. AB - In the gas-phase, ions of protein complexes typically follow an asymmetric dissociation pathway upon collisional activation, whereby an expelled small monomer takes a disproportionately large amount of the charges from the precursor ion. This phenomenon has been rationalized by assuming that upon activation, a single monomer becomes unfolded, thereby attracting charges to its newly exposed basic residues. Here, we report on the atypical gas-phase dissociation of the therapeutically important, heterodimeric calcium/calmodulin-dependent serine/threonine phosphatase calcineurin, using a combination of tandem mass spectrometry, ion mobility mass spectrometry, and computational modeling. Therefore, a hetero-dimeric calcineurin construct (62 kDa), composed of CNa (44 kDa, a truncation mutant missing the calmodulin binding and auto-inhibitory domains), and CNb (18 kDa), was used. Upon collisional activation, this hetero dimer follows the commonly observed dissociation behavior, whereby the smaller CNb becomes highly charged and is expelled. Surprisingly, in addition, a second atypical dissociation pathway, whereby the charge partitioning over the two entities is more symmetric is observed. The presence of two gas-phase conformational isomers of calcineurin as revealed by ion mobility mass spectrometry (IM-MS) may explain the co-occurrence of these two dissociation pathways. We reveal the direct relationship between the conformation of the calcineurin precursor ion and its concomitant dissociation pathway and provide insights into the mechanisms underlying this co-occurrence of the typical and atypical fragmentation mechanisms. PMID- 22811077 TI - A scalable, micropore, platelet rich plasma separation device. AB - We have designed a novel, low energy platelet-rich-plasma (PRP) separator capable of producing 50 mL of PRP in 30 min, intended for military and emergency applications. Blood flows over a 3 mm length of sieve at high rates of shear. A plasma-platelet filtrate passes through the sieve's pores while erythrocytes remain. The filtrate is flowed over a second 3 mm length of smaller-pored sieve that withdraws plasma. Bulk blood volume is maintained by returning platelet-free plasma to the erythrocyte pool, enabling a nearly complete multi-pass platelet extraction. The total percentage of platelets extracted is:theta(T)=1-exp ( V(f)(T)Phi(P)/V) where V is the original plasma volume, V ( f )(T) is the total filtered volume, and phi ( P ) is platelet passage ratio (filtrate concentration/bulk average concentration) taken to be constant. Maximum theta(T) occurs at maximum V ( f )(T)* phi ( P ) Test microsieves, 3 mm long * 3 mm wide, were used. phi ( P ) values measured at various filtrate flow rates (20-100 uL/min) and utilizing various filter pore sizes (1.2-3.5 MUm), was as high as 150 %. Maximum V ( f )(T)* phi ( P ) was achieved utilizing the 3.5 um filters at the highest flow rate, 100 uL/min. Erythrocyte leakages were always below 2,000/uL, far below the allowable limit stipulated by the American Association of Blood Banking. These data imply that a 13.7 cm(2) filter area is sufficient to achieve the target separation of 50 mL of platelet concentrate in 30 min. The filtration cartridge would consist of multiple microporous strips of 3 mm width arranged in parallel so that each element would see the conditions used in the prototype experiments presented here. Other microfiltration schemes suggest no method of scaling to practical levels. PMID- 22811078 TI - First-line combination of gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE extranodal natural killer/T-cell lymphoma. AB - BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma in which the upper aerodigestive tract is the most commonly involved site. To date, optimal treatment strategies and prognosis for patients with ENKTL have not been fully defined. METHODS: This prospective study was conducted to evaluate the efficacy and safety profiles of first-line combined gemcitabine, oxaliplatin, and L-asparaginase (GELOX) followed by involved-field radiation therapy for patients with stage IE/IIE ENKTL. The primary endpoints were the complete response rate, the objective response rate, and toxicities. Secondary endpoints were overall survival and progression-free survival. RESULTS: Twenty-seven patients with newly diagnosed ENKTL were enrolled and completed the entire course of treatment. At the end of treatment, the overall response rate was 96.3%, including 20 patients (74.1%) who attained a complete response and 6 patients (22.2%) who attained a partial response. No patients developed disease progression during therapy. Grade 1 and 2 toxicities were frequent during GELOX, but grade 3 and 4 toxicities were few, and no treatment-related deaths occurred. At a median follow-up of 27.37 months, 7 patients (25.9%) experienced disease progression, and 4 of those patients died of disease. The rates of 2-year overall and progression-free survival were both 86%, and patients who attained a complete response at the end of treatment had significantly longer progression-free survival (P = .012) and overall survival (P = .021) than patients who did not attain a complete response. CONCLUSIONS: The current results indicated that GELOX followed by involved-field radiation therapy can be an effective and feasible treatment strategy for patients with stage IE/IIE ENKTL of the upper aerodigestive tract. These results will require further investigation in larger prospective trials. PMID- 22811079 TI - Immune markers of disease severity and treatment response in pediatric acquired aplastic anemia. AB - BACKGROUND: To investigate the immune status among pediatric patients with aplastic anemia (AA) and explore PNH-status, T-regulatory and NK-cell frequency as potential markers of clinical response. METHODS: Data were retrospectively analyzed from twenty-six patients diagnosed with AA. PNH populations, T- and NK subsets were determined via flow cytometry. RESULTS: At diagnosis, 9/23 patients with severe AA (SAA) versus 1/3 with moderate AA (MAA) were PNH(pos) . Among PNH(pos) patients treated with ATG based immunosuppression, 2/6 had a complete response (CR), while 4/6 had a partial response (PR), similarly 2/6 PNH(neg) patients had a CR and 4/6 had a PR. Lymphocyte subset immunophenotyping revealed that T-regulatory cells represented 7.2% of total lymphocytes at diagnosis. Their frequency varied with disease severity (5.5% for SAA and 14.1% for MAA) and response (8.9% for CR and 1.5% for PR), generally increasing following therapy with IST (14.6%). The NK cell frequency was not substantially different based on disease severity or response. CONCLUSIONS: Neither PNH cell populations, nor NK cell frequency corresponded with disease severity or response. T-regulatory cell frequency, although not statistically significant given the small sample size, corresponded with both severity and response, indicating potential utility as a prognostic tool. PMID- 22811081 TI - Biometric technology in law enforcement. PMID- 22811080 TI - Human pancreatic cancer fusion 2 (HPC2) 1-B3: a novel monoclonal antibody to screen for pancreatic ductal dysplasia. AB - BACKGROUND.: Pancreatic ductal adenocarcinoma is rarely detected early enough for patients to be cured. The objective of the authors was to develop a monoclonal antibody to distinguish adenocarcinoma and precancerous intraductal papillary mucinous neoplasia (IPMN) from benign epithelium. METHODS.: Mice were immunized with human pancreatic adenocarcinoma cells and monoclonal antibodies were screened against a panel of archived pancreatic tissue sections, including pancreatitis (23 cases), grade 1 IPMN (16 cases), grade 2 IPMN (9 cases), grade 3 IPMN (13 cases), and various grades of adenocarcinoma (17 cases). One monoclonal antibody, human pancreatic cancer fusion 2 (HPC2) 1-B3, which specifically immunostained adenocarcinoma and all grades of IPMN, was isolated. Subsequently, HPC2 1-B3 was evaluated in a retrospective series of 31 fine-needle aspiration (FNA) biopsies from clinically suspicious pancreatic lesions that had long-term clinical follow-up. RESULTS.: HPC2 1-B3 was negative in all 31 cases of chronic pancreatitis that were tested. In contrast, HPC2 1-B3 immunostained the cytoplasm and luminal surface of all 16 well- to moderately differentiated pancreatic ductal adenocarcinomas. It demonstrated only weak focal staining of poorly differentiated carcinomas. All high-grade IPMNs were found to be positive for HPC2 1-B3. The majority of low-grade to intermediate-grade IPMNs were positive (66% of cases). Immunostaining a separate series of pancreatic FNA cell blocks for HPC2 1-B3 demonstrated that the relative risk for detecting at least low grade dysplasia (2.0 [95% confidence interval, 1.23-3.26]) was statistically significant (P = .002 by the Fisher exact test). CONCLUSIONS.: To reduce the mortality of pancreatic cancer, more effective early screening methods are necessary. The data from the current study indicate that a novel monoclonal antibody, HPC2 1-B3, may facilitate the diagnosis of early pancreatic dysplasia. PMID- 22811082 TI - Rate of return to military active duty after single level lumbar interbody fusion: a 5-year retrospective review. AB - BACKGROUND: Lumbar interbody fusion has been extensively studied in the civilian population; however, data regarding its efficacy in the military are lacking. OBJECTIVE: To identify the rate of return to unrestricted active military duty after single-level lumbar interbody fusion surgery. METHODS: The surgical database at a single tertiary care military treatment facility was queried for active-duty patients who underwent a single-level lumbar interbody fusion over a 5-year period. A retrospective chart review was performed with backward stepwise logistic regression analysis, and Fisher exact and Wilcoxon rank sum tests were used for statistical analysis. RESULTS: A total of 102 patients met the inclusion criteria. Mean age at surgery was 34.0 years (range, 19-51 years). Most surgeries (59%) were performed for discogenic pain secondary to degenerative disc disease; the remaining patients underwent surgery for spondylolisthesis (39%) or spinal stenosis (2%). Thirty-nine patients (38%) were treated via an anterior approach (anterior lumbar interbody fusion), whereas 63 patients (62%) underwent fusion via a posterior approach (transforaminal or posterior lumbar interbody fusion). Fifty-six patients (55%) were able to return to unrestricted full active duty, and the remaining 46 patients (45%) were separated from the military. The return to active duty rate was significantly higher in older patients and those ranking E7 (Chief Petty Officer) and above (84.8%). CONCLUSION: Fifty-five percent of the service members who underwent a single-level lumbar interbody fusion returned to unrestricted full duty. Older age and higher rank were statistically significant positive predictors of a successful return to active duty. PMID- 22811083 TI - Shorter disease duration correlates with improved long-term deep brain stimulation outcomes in young-onset DYT1 dystonia. AB - BACKGROUND: Treatment with deep brain stimulation (DBS) of the globus pallidus internus in children with DYT1 primary torsion dystonia is highly effective; however, individual response to stimulation is variable, and a greater understanding of predictors of long-term outcome is needed. OBJECTIVE: To report the long-term outcomes of subjects with young-onset DYT1 primary torsion dystonia treated with bilateral globus pallidus DBS. METHODS: Fourteen subjects (7 male, 7 female) treated consecutively from 2000 to 2010 at our center were included in this retrospective study. The Burke-Fahn-Marsden Dystonia Rating Scale was performed at baseline and at 1, 2, and up to 6 years postoperatively. RESULTS: Pallidal DBS was well tolerated and highly effective, with mean Burke-Fahn Marsden Dystonia Rating Scale movement scores improving from baseline by 61.5% (P < .001) at 1 year, 64.4% (P < .001) at 2 years, and 70.3% (P < .001) at the final follow-up visit (mean, 32 months; range, 7-77 months). Disability scores also improved significantly. Multiple linear regression analysis revealed a significant influence of duration of disease as a predictor of percent improvement in Burke-Fahn-Marsden Dystonia Rating Scale movement score at long term follow-up (duration of disease, P < .05). Subjects with fixed orthopedic deformities (4) had less improvement in these regions. Location of the active DBS electrode used at final follow-up visit was not predictive of clinical outcome. CONCLUSION: Our findings highlight the sustained benefit from DBS and the importance of early referral for DBS in children with medically refractory DYT1 primary torsion dystonia, which can lead to improved long-term benefits. PMID- 22811084 TI - The SILVER (Silver Impregnated Line Versus EVD Randomized trial): a double-blind, prospective, randomized, controlled trial of an intervention to reduce the rate of external ventricular drain infection. AB - BACKGROUND: Cerebrospinal fluid (CSF) infections associated with external ventricular drain (EVD) placement attract major consequences. Silver impregnation of catheters attempts to reduce infection. OBJECTIVE: To assess the efficacy of silver catheters against CSF infection. METHODS: We performed a randomized, controlled trial involving 2 neurosurgical centers (June 2005 to September 2009). A total of 356 patients requiring an EVD were assessed for eligibility; 325 patients were enrolled and randomized (167 plain, 158 silver); 278 patients were analyzed (140 plain, 138 silver). The primary outcome measure was CSF infection as defined by organisms seen on Gram stain or isolated by culture. Secondary outcome measures included ventriculoperitoneal (VP) shunting. RESULTS: There was a significant difference in infection risk between the 2 study arms: 21.4% (30/140) for plain catheters vs 12.3% (17/138) for silver catheters (P = .0427; 95% confidence interval [CI]: 1.015-3.713). Patients who had an EVD infection had more than double the risk of requiring a VP shunt compared with patients without an EVD infection (45.7% [21/46] vs 19.7% [45/229], respectively, P = .0002; 95% CI: 1.766-6.682). There was also a significant difference in VP shunt risk with infection: plain (55.2%; 16/29) vs the silver arm (29.4%; 5/17); P = .0244 (95% CI: 1.144-11.695). A multivariate analysis demonstrated that infection risk was increased by duration of EVD placement (odds ratio: 1.160), spontaneous intracranial hemorrhage (odds ratio 4.958) and decreased by silver catheters (odds ratio: 0.423). CONCLUSION: The study provides Class I evidence that silver impregnated catheters reduce CSF infection. PMID- 22811085 TI - A systematic review of nerve transfer and nerve repair for the treatment of adult upper brachial plexus injury. AB - Nerve reconstruction for upper brachial plexus injury consists of nerve repair and/or transfer. Current literature lacks evidence supporting a preferred surgical treatment for adults with such injury involving shoulder and elbow function. We systematically reviewed the literature published from January 1990 to February 2011 using multiple databases to search the following: brachial plexus and graft, repair, reconstruction, nerve transfer, neurotization. Of 1360 articles initially identified, 33 were included in analysis, with 23 nerve transfer (399 patients), 6 nerve repair (99 patients), and 4 nerve transfer + proximal repair (117 patients) citations (mean preoperative interval, 6 +/- 1.9 months). For shoulder abduction, no significant difference was found in the rates ratio (comparative probabilities of event occurrence) among the 3 methods to achieve a Medical Research Council (MRC) scale score of 3 or higher or a score of 4 or higher. For elbow flexion, the rates ratio for nerve transfer vs nerve repair to achieve an MRC scale score of 3 was 1.46 (P = .03); for nerve transfer vs nerve transfer + proximal repair to achieve an MRC scale score of 3 was 1.45 (P = .02) and an MRC scale score of 4 was 1.47 (P = .05). Therefore, for elbow flexion recovery, nerve transfer is somewhat more effective than nerve repair; however, no particular reconstruction strategy was found to be superior to recover shoulder abduction. When considering nerve reconstruction strategies, our findings do not support the sole use of nerve transfer in upper brachial plexus injury without operative exploration to provide a clear understanding of the pathoanatomy. Supraclavicular brachial plexus exploration plays an important role in developing individual surgical strategies, and nerve repair (when donor stumps are available) should remain the standard for treatment of upper brachial plexus injury except in isolated cases solely lacking elbow flexion. PMID- 22811087 TI - Intracranial pressure vs intracranial pressure-wave amplitude. PMID- 22811198 TI - Novel triple-modality molecular imaging approach holds promise for improving brain tumor resection. PMID- 22811199 TI - Magnetic resonance imaging-based oxygen challenge technique replaced PET in ischemic penumbra. PMID- 22811200 TI - The role of Notch in development and regression of vascular fistulas. PMID- 22811201 TI - Closing the loop in neuromodulation: concurrent sensing and stimulation. PMID- 22811203 TI - HCAHPS replaces Press Ganey survey as quality measure for patient hospital experience. PMID- 22811202 TI - Evaluating the accuracy of robotic assistance in spine surgery. PMID- 22811204 TI - Deep brain stimulation of entorhinal cortex shows early promise for enhancement of memory function. PMID- 22811205 TI - Case volumes in vascular neurosurgery: potential implications for comprehensive stroke center designation. PMID- 22811206 TI - Getting a neural stem cell from a fibroblast. PMID- 22811207 TI - Predicting intracerebral hemorrhage growth with a spot. PMID- 22811208 TI - High strength silk protein scaffolds: the future of spinal fusions. PMID- 22811209 TI - Purification of Phenylalkanoids and monoterpene glycosides from Rhodiola rosea L. roots by high-speed counter-current chromatography. AB - INTRODUCTION: Rhodiola rosea L. is a medicinal herb used for its adaptogenic properties. The main active components are the phenylpropanoids collectively referred to as rosavins. OBJECTIVES: To develop an isolation method for phytochemicals present in Rhodiola rosea roots using high-speed counter-current chromatography (HSCCC). METHODOLOGY: The roots of Rhodiola rosea were extracted with methanol and fractionated using liquid-liquid partition and polyamide column clean-up. The purified fraction (100 mg) was subjected to semi-preparative HSCCC using the two-phase solvent system ethyl acetate:butanol:water (3:2:5). The head to-tail elution mode was employed with a flow rate of 1.5 mL/min and a rotary speed of 1000 rpm. RESULTS: The separation yielded six main fractions with four components more than 90% pure. The sixth fraction was further purified using semi preparative HPLC with a Synergi-hydro RP C18 -column to obtain rosin and geranyl 1-O-alpha-l-arabinopyranosyl(1 -> 6)-beta-d-glucopyranoside. The main components isolated were rosavin (3.4 mg, 97% purity), salidroside (0.5 mg, 90% purity), benzyl-O-beta-d-glucopyranoside (1.2 mg, 85% purity), rosarin (1.3 mg, 99% purity), rosiridin (1.8 mg, 92% purity), rosin (1.2 mg, 95% purity) and geranyl 1 O-alpha-l-arabinopyranosyl(1 -> 6)-beta-d-glucopyranoside (6.5 mg, 97% purity). The identity and purity of these components were confirmed using ultrafast liquid chromatography-diode-array detector-MS/MS analysis, 1H- and 13C-NMR spectroscopy. CONCLUSION: High-speed counter-current chromatography was successful in the isolation of several phytochemicals present in Rhodiola rosea roots, including two components that are not commercially available. PMID- 22811210 TI - Referral patterns of nonmalignant patients to an Irish specialist palliative medicine service: a retrospective review. AB - BACKGROUND: Our perception is that the proportion of referrals made to the specialist palliative medicine service (SPMS) in our institution for patients with a primary diagnosis of nonmalignant disease is high and that these patients are often referred late in their illness. We aimed to review the symptom burden and referral patterns of patients with a noncancer diagnosis to the SPMS in our centre. METHODS: All new non-malignant referrals to the SPMS in 2009 were included. Data were collected from patients' medical records and analyzed using Excel. RESULTS: Ninety-two referrals were identified: 60 (65%) female, 32 (35%) male. Mean age 76.5 years (21-92). Reasons for referral included: end-of-life care (n=55, 60%), symptom control (n=23, 25%), home care support (n=13, 14%) and psychological support (n=1, 1%). Mean time from admission to referral was 24.9 days (<1-165). Fifty-six (61%) patients were commenced on a syringe driver (CSCI), with a mean time spent on a CSCI of 2.8 days (< 1-17). Primary outcomes included: death (n=72, 78.5%), home discharge (n=9, 10%), discharge to another care institution (n=6, 6.5%), discharge from service (n=3, 3%) and hospice transfer (n=2, 2%). Mean time from referral to outcome was 4.6 days (<1-35). CONCLUSION: The proportion of noncancer patients referred to the SPMS is our institution is high. This study confirms that nonmalignant referrals are commonly sent to the SPMS when patients are actively dying or very imminently dying. Further education of colleagues is warranted in the role of the SPMS, particularly with regard to earlier referral. PMID- 22811211 TI - Palliative health care: ancient wisdom. AB - An ancient story from Bhagavata Purana may be relevant to the psychology and spirituality of palliative care in modern medicine. This article brings an ancient Indian story that people still use during the grieving process. Symbolism of the old story is explained in a modern perspective. PMID- 22811212 TI - Waking. AB - An indubitable aspect of laboring in the realm of hospice care is the "everydayness" of human loss or the stark encounter of death in the human experience. This can pose as opportunity to adopt each day in a particular manner. As such, the focus of my reflection is on transposing certain dynamics of a (funeral) wake to broader professional and personal socioexistential processes. PMID- 22811213 TI - Holding on to what you have got: keeping hospice palliative care volunteers volunteering. AB - In all, 119 hospice palliative care volunteers from 3 community-based hospice programs completed the Volunteer Retention Questionnaire (VRQ), a 33-item survey designed for this study. The VRQ asks volunteers to rate the importance of each item to their decision to continue volunteering. The items that received the highest mean importance ratings included enjoying the work they do, feeling adequately prepared/trained to perform their role, and learning from their patients' experiences/listening to their patients' life stories. Being recognized (eg, pins for years of service or being profiled in the hospice newsletter), receiving phone calls/cards from their volunteer coordinator on special occasions, and being reimbursed for out-of-pocket expenses were among the items that received the lowest mean importance ratings. Suggestions for improving volunteer retention are provided. PMID- 22811214 TI - Providing quality palliative care in end-stage Alzheimer disease. AB - Providing quality palliative care is a daunting task profoundly impacted by diminished patient capacity at the end of life. Alzheimer disease (AD) is a disorder that erases our memories and is projected to increase dramatically for decades to come. By the time the patients with AD reach the end stage of the disease, the ability of patients to provide pertinent subjective complaints of pain and discomfort would have vanished. Historical perspectives of palliative care, exploration of the AD process, ethical issues, and crucial clinical considerations are provided to improve the understanding of disease progression and quality of care for patients with end-stage AD. PMID- 22811215 TI - Interaction of cortical networks mediating object motion detection by moving observers. AB - The task of parceling perceived visual motion into self- and object motion components is critical to safe and accurate visually guided navigation. In this paper, we used functional magnetic resonance imaging to determine the cortical areas functionally active in this task and the pattern connectivity among them to investigate the cortical regions of interest and networks that allow subjects to detect object motion separately from induced self-motion. Subjects were presented with nine textured objects during simulated forward self-motion and were asked to identify the target object, which had an additional, independent motion component toward or away from the observer. Cortical activation was distributed among occipital, intra-parietal and fronto-parietal areas. We performed a network analysis of connectivity data derived from partial correlation and multivariate Granger causality analyses among functionally active areas. This revealed four coarsely separated network clusters: bilateral V1 and V2; visually responsive occipito-temporal areas, including bilateral LO, V3A, KO (V3B) and hMT; bilateral VIP, DIPSM and right precuneus; and a cluster of higher, primarily left hemispheric regions, including the central sulcus, post-, pre- and sub-central sulci, pre-central gyrus, and FEF. We suggest that the visually responsive networks are involved in forming the representation of the visual stimulus, while the higher, left hemisphere cluster is involved in mediating the interpretation of the stimulus for action. Our main focus was on the relationships of activations during our task among the visually responsive areas. To determine the properties of the mechanism corresponding to the visual processing networks, we compared subjects' psychophysical performance to a model of object motion detection based solely on relative motion among objects and found that it was inconsistent with observer performance. Our results support the use of scene context (e.g., eccentricity, depth) in the detection of object motion. We suggest that the cortical activation and visually responsive networks provide a potential substrate for this computation. PMID- 22811216 TI - Transcriptional signatures mediated by acetylation overlap with early-stage Alzheimer's disease. AB - The mechanisms by which environmental influences lead to the development of complex neurodegenerative diseases are largely unknown. It is known, however, that epigenetic mechanisms can mediate alterations in transcription due to environmental influences. In order to identify genes susceptible to regulation in the adult cortex by one type of epigenetic mechanism, histone, and protein acetylation, we treated mice with the histone deacetylase inhibitor Trichostatin A (TSA). After 1 week of treatment with TSA, RNA was extracted from the brain cortices of mice and gene expression differences were analyzed by microarray profiling. The altered genes were then compared with genes differentially expressed in microarray studies of disease by database and literature searches. Genes regulated by TSA were found to significantly overlap with differentially expressed genes in the Alzheimer's disease (AD) brain. Several TSA-regulated genes involved in chromatin remodeling and epigenetic reprogramming including histone cluster 1, H4 h (Hist1H4 h), methionine adenosyltransferase II, alpha (Mat2a), and 5-methyltetrahydrofolate homocysteine reductase (Mtrr) overlapped with genes altered in early-stage AD in gray matter. We also show that the expression of hemoglobin, which has been shown to be altered in neurons in the AD brain, is regulated by TSA treatment. This analysis suggests involvement of epigenetic mechanisms in neurons in early stages of AD. PMID- 22811217 TI - Evidence from bilateral recordings of sympathetic nerve activity for lateralisation of vestibular contributions to cardiovascular control. AB - Using low-frequency (0.08-0.18 Hz) sinusoidal galvanic vestibular stimulation (sGVS), we recently showed that two peaks of modulation of muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) occurred for each cycle of stimulation: a large peak associated with the positive peak of the sinusoid (defined as the primary peak) and a smaller peak (defined as the secondary peak) related to the negative peak of the sinusoid. However, these recordings were only made from the left common peroneal nerve, so to investigate lateralisation of vestibulosympathetic reflexes, concurrent recordings were made from both sides of the body. Tungsten microelectrodes were inserted into muscle or cutaneous fascicles of the left and right common peroneal nerves in 17 healthy individuals. Bipolar binaural sinusoidal GVS (+/-2 mA, 100 cycles) was applied to the mastoid processes at 0.08 Hz. Cross-correlation analysis revealed that vestibular modulation of MSNA (10 bilateral recordings) and SSNA (6 bilateral recordings) on the left side was expressed as a primary peak related to the positive phase of the sinusoid and a secondary peak related to the negative phase of the sinusoid. Conversely, on the right side, the primary and secondary peaks were reversed: the secondary peak on the right coincided with the primary peak on the left and vice versa. Moreover, differences in pattern of outflow were apparent across sides. We believe the results support the conclusion that the left and right vestibular nuclei send both an ipsilateral and contralateral projection to the left and right medullary output nuclei from which MSNA and SSNA originate. This causes a "flip-flop" patterning between the two sympathetic outflows: when vestibular modulation of a burst is high on the left, it is low on the right, and when modulation is low on the left, it is high on the right. PMID- 22811218 TI - Factors associated with uptake of pandemic influenza vaccine among general practitioners and practice nurses in Shropshire, UK. AB - BACKGROUND: At the time of the 2009-10 influenza pandemic there was considerable unease about vaccination. Early surveys suggested that the intention to be vaccinated amongst healthcare workers was low. AIMS: To determine what influenced vaccination uptake among general practice healthcare workers in Shropshire County Primary Care Trust in the UK. METHODS: A cross-sectional survey was distributed to all frontline healthcare workers in Shropshire County's general practices in June 2010. All 45 practices participated. Questionnaires were distributed by practice managers to frontline staff and returned by post. Practices with the lowest return rates were reminded by telephone after 3 months. RESULTS: 205 valid replies were received, giving a response rate of 48.0%. 10.0% reported being infected with the pandemic H1N1 strain by the time they received the questionnaire. 172 (83.9%) respondents reported that they had been vaccinated against H1N1. Influenza infection prior to vaccination had a negative impact on uptake (adjusted OR 0.17, 95% CI 0.05 to 0.56) and previous vaccination against seasonal influenza was associated with increased uptake (adjusted OR 4.07, 95% CI 1.62 to 10.24). Those who received the pandemic vaccine were seven times more likely to accept future vaccines (adjusted OR 7.04, 95% CI 2.70 to 18.37). CONCLUSIONS: Vaccination uptake was significantly higher than the national (40.3%), regional (40.9%), and county averages (49.3%). Motivation for and against vaccination was very similar to that for seasonal vaccination, with previous vaccination having the greatest influence. Ensuring healthcare workers receive vaccination early in their career is likely to set a precedent for future vaccination. This is the first detailed study purely in general practice in England. PMID- 22811219 TI - [Primary epiploic appendagitis]. PMID- 22811220 TI - Spontaneous and simultaneous bilateral tubal pregnancy. PMID- 22811221 TI - [Mental disorders in adrenocortical insufficiency]. PMID- 22811222 TI - [The role of bisphosphonate in the treatment of bone metastases from prostate cancer]. AB - BACKGROUND: Bone metastasis is very frequent in prostate cancer. It is a turning point that marks the severity of the disease. Before metastasis become symptomatic, treatment preventing bone events should be indicated. AIM: To evaluate the role of bisphosphonate in the treatment of bone metastases from prostate cancer. METHODS: A review of literature. RESULTS: Bisphosphonates play a very important role to prevent bone mass loss and to reduce bone complication events. CONCLUSION: Bisphosphonates are recommended as preventive treatment at the time of diagnosis of bone metastatic prostate cancer. PMID- 22811223 TI - [Immunogenetics of psoriasis: update]. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease often benign, affecting 2-3% of the total world population. Psoriasis is a multifactorial disease. AIM: To present recent advances in the immunologic mechanisms and susceptibility genes involved in the pathogenesis of psoriasis. METHODS: We presented a literature review of recent genetic and immunological basis of psoriasis to better understand the pathomecanisms of this disease and discuss the contribution of the Tunisian work in this area. RESULTS: Recent works focalized mainly in immunology and genetics. Current progresses in molecular biology have allowed to better characterize the immunogenetic abnormalities in psoriasis. CONCLUSION: Psoriasis is a multifactorial disease model in which environmental factors (psychological, climate, traumatic, infectious, and viral) seem to be triggering factors when associated with a particular immunogenetics predisposition. PMID- 22811224 TI - [Epidemiological changes of paediatric urolithiasis in Tunisia]. AB - BACKGROUND: The clinical and biological characteristics of urolithiasis in children are still evolving in our country. Since the eighties no study has been conducted to determine incidence of urolithiasis in Tunisia. AIM: To define the current status of urolithiasis in Tunisian children. METHODS: The records of 414 children with urolithiasis treated between 1983 and 2007 were found in a multi centric study which took into consideration to age, sex, and history diagnosis and physical, laboratory, and radiologic findings. Clinical and biological date were performed in 344 cases. Stone analysis was performed by spectrophotometry. RESULTS: The incidence of paediatric urolithiasis has steadily decreased from 0.7/ 10 000 of the child population / year in 1991-1994 to 0.1 cases/10 000 children/ year in 2007. There was a continuous decrease in bladder stone over the past 25 years (47.1% in 1982-1986 Vs 10.2% in 2002-2007). Stones were homogeneous in 31.4% of cases. The main component was calcium oxalate stones in 36.4% of the cases. Since the eighties the increase of oxalates stones (15.6% in eighties Vs 51.5% actually) were with depends to purines and struvite stones. CONCLUSION: Epidemiologic characteristics of the urinary lithiasis (sex, age, localization and composition) have changed in Tunisia, due to the the improvements of standard of living. The occidentalization of the nutritional practices and the receding of the culinary traditions gave birth to new risks of urolithiasis characterized by the emergence of calcium oxalate stones. PMID- 22811225 TI - [Basal fsh level is only predictive of the quantitative aspect of the ovarian response]. AB - BACKGROUND: Determination FSH and LH at day 3 of the menstrual cycle predicts the response to stimulation. AIM: To evaluate the value of FSH and LH measurements compared with women's age in predicting qualitative and quantitative ovarian response to gonadotrophin stimulation. METHODS: 305 patients underwent at least one intra cytoplasmic sperm injection (ICSI) cycle. The levels of FSH and LH at day 3 were determined in an earlier cycle. A good quantitative ovarian response was defined as 33 oocytes retrieved and 3 embryos obtained. A good qualitative ovarian response was defined as a percentage of mature oocytes 375% and immature ones215% of the total number of oocytes retrieved with at least one top quality embryo obtained. RESULTS: Receiver operating characteristic (ROC) curves were generated for FSH, LH and female age. FSH is better than female age in predicting the number of oocytes retrieved (respectively ROCAUC=0.77, p=10-3 versus ROCAUC=0.73, p=10-3) and the number of embryos obtained (ROCAUC=0.69, p=10-3 versus ROCAUC=0.66, p=10-3). LH is non predictive. None of the three tested parameters was predictive of the fertilization and pregnancy rates. An FSH cutoff was calculated and a value of 7.8mUI/ml is associated with a sensitivity of 73% and a specificity of 70% for the prediction of ovarian response to controlled stimulation. CONCLUSION: Basal FSH level predicts good quantitative rather than qualitative response. LH is non predictive. FSH and LH do not predict pregnancy rate. Patients having high FSH levels should not be excluded from IVF/ICSI treatment. PMID- 22811226 TI - Is there any change in the prevalence of intestinal and urinary parasitosis among "non-permanent resident" students in Tunisia ? AB - BACKGROUND: Intestinal parasitosis are cosmopolitan affections, often related to the fecal peril. However urinary bilharziosis is a disease eliminated in Tunisia. As part of monitoring the emergence and re-emergence of intestinal parasitosis and urinary bilharziasis, foreign students benefit from parasitological systematic monitoring stool and urine during their enrollment to the University. AIM: To study the prevalence of various intestinal parasitosis and urinary bilharziasis among non permanent resident students in Tunisia. METHODS: A retrospective survey was carried at the Laboratory of Parasitology- Mycology of Charles Nicolle Hospital of Tunis during the inscription period of 6 university years 2005-2010. 328 students profited from a parasitological examination of stool and urine. RESULTS: 144 students (43.9%) harbored intestinal parasites. More than one parasite was detected in 69 students (47.9%). Intestinal protozoa were the majority of identified parasites (96.9%). 9.7% of identified parasites were pathogenic. Three cases (0.91%) of urinary bilharziasis were diagnosed. CONCLUSION: The prevalence of intestinal and urinary parasitism among the "non permanent residents" students in Tunisia has not changed. This justifies a systematic parasitologic monitoring for students coming from areas of high endemicity of parasitosis in order to avoid the introduction of these. PMID- 22811227 TI - [Acute mesenteric ischemia: study of predictive factors of mortality]. AB - BACKGROUND: Acute mesenteric ischemia is a surgical emergency that requires a quick diagnosis and therapeutic care. Without treatment, the outcome is towards intestinal infarction whose prognosis remains grim. AIM: To look for predictive factors of mortality of this disease. METHODS: We retrospectively reviewed the clinical data of patients hospitalized between January 2000 and December 2008 for acute mesenteric ischemia. Univariate and multivariate analysis of factors that could influence mortality was conducted. RESULTS: 26 patients, predominantly male, were included. The mean age was 60 years. These patients were cared for on average 4 days after the onset of symptoms. The diagnosis was made pre operatively in 9 patients, by CT scan in 8 patients and by Doppler ultrasound in 1 patient. The cause of AMI was arterial thrombosis in 19 cases, venous thrombosis in 4 cases and non occlusive mesenteric ischemia in 3 cases. 25 patients were operated on emergency 24 times by a laparotomy and one time by a laparoscopy. The surgery consisted in bowel resection in 15 patients; an abstention was decided in one case of venous mesenteric ischemia and in 9 cases where necrosis affected all small bowels. Revascularization of the superior mesenteric artery was associated in 4 cases. Outcome was simple in 8 patients. The mortality rate was 69%, death occurred in a period of J0 to J90 after surgery. This rate wasn't influenced by age or sex. It was higher in patients with preoperative collapse (p = 0.02) and having an expansive bowel necrosis (p=.0001). The prognosis is better in cases of venous infarction with a mortality rate of zero. CONCLUSION: Prognosis of acute mesenteric ischemia depends on the aetiology and the quickness of treatment. It is directly linked to the extension of intestinal infarction. An urgent and multidisciplinary care is necessary. PMID- 22811228 TI - [Alterations in lipidic metabolism in hemodialysis patients]. AB - BACKGROUND: Chronic kidney failure is associated with dyslipidemia and accelerated atherosclerosis. AIM: To study lipidic metabolism alterations in patients with chronic kidney failure on hemodialysis. METHODS: The study interested 45 hemodialysis patients with a mean age of 49.04 +/-15.92 years old and 45 healthy controls. A blood sample was collected from each patient and control to measure total cholesterol, triglycerides, HDL- cholesterol, LDL cholesterol, apolipoproteins AI and B100, lipoprotein (a) and C Reactive Protein. RESULTS: A significant increase of serum triglycerides (p= 0.002), lipoprotein (a) (p = 0.001) and C Reactive Protein (p = 0.008) was observed in patients when compared with healthy controls. A significant decrease of serum total cholesterol (p=0.01), HDLcholesterol (p<0.001), LDL-cholesterol (p=0.005) and apolipoprotein AI (p<0.001) was also observed in patients. CONCLUSION: Disorders of lipidic metabolism are frequent in hemodialysis patients. These alterations can lead to cardiovascular disease in uremic patients. PMID- 22811229 TI - [Acute myocardial infarction in elderly patients]. AB - BACKGROUND: Age is the most important determinant of outcome for patients with acute coronary syndromes (ACS) and ischemic heart disease is the leading cause of death among elderly patients. AIM: To determine the epidemiologic particularities, the clinical presentation, and the treatment of Acute Myocardial Infarction (AMI) in patients over 65 years. METHODS: One hundred patients >65 years of age with myocardial infarction were hospitalized in intensive care of cardiologic unit of Military Hospital of Tunis between 2000 and 2008. Clinical characteristics, reperfusion therapy and outcomes of in-hospital period and for one year follow-up were seen for every patient. RESULTS: The mean age of our population was 77 years. Sex-ratio was 3/1.Our population was divided into tow groups; patients aged between 65 and 75 years (48 patients) and those aged more than 75 years (52 patients). Only 44 % of our patients had arrived at the hospital within the first 12 hours. STEMI was found in 65 % of our patients. At admission, 40 % had congestive heart failure (3 Killip II), 10 % were in cardiogenic shock. Urgent reperfusion therapy was given to 58 % of our patients; 33% received a thrombolytic therapy and 25 % were allocated to primary PCI. During in-hospital period, 40 % have developed congestive heart failure, 20 % have had a cardiogenic shock and 12 % were died. All these events were more frequent in patients aged over 75 years and reperfusion therapy was associated with best outcome. CONCLUSION: In our study invasive treatment such as fibrinolysis and PCI was associated to better outcome in acute period and at 12 months of follow up in elderly patients treated for AMI. PMID- 22811230 TI - [Thrombosis and cancer: retrospective study of 17 cases]. AB - BACKGROUND: The association cancer and venous thrombosis is almost always an independent criterion of poor prognosis of cancer. Thus, venous thromboembolic disease is with infection and organ failure, one of the leading causes of death in patients with malignant disease. AIM: To identify the characteristics of the association between cancer and venous thrombosis in any patient with deep vein thrombosis of lower limbs seemingly unexplained. METHODS: This is a retrospective study from January 1994 to December 2008, concerning 17 cases of patients with deep vein thrombosis of lower limbs associated with neoplasia, hospitalized in internal medicine department at Habib Thameur hospital between a total of 290 patients with deep vein thrombosis of lower limbs. Only patients hospitalized for deep vein thrombosis of lower limbs complicated or not by a pulmonary embolism were included. RESULTS: Our study concerned 17 patients. There were 10 women and 7 men with a sex ratio (Female / Male) at 1, 42. The average age was 68.7 years, with extreme ages ranging from 40 to 90 years. Cancer has formed 6% of the causes of deep venous thrombosis of lower limbs. Eight of our patients were known to suffer from a cancerous disease. Six cases of cancers were discovered at an advanced stage of evolution with multiple metastases. In seven cases the etiological could not be achieved. Deep venous thrombosis was complicated by pulmonary embolism in four inaugural events, five patients had recurrent thrombosis, and two cases of bleeding complications were noted. CONCLUSION: Venous thromboembolism is common in cancer patients. It can be the first manifestation of cancer completely silent. The course and prognosis depend on the stage of cancer combined. PMID- 22811231 TI - [Safety of Magnesium sulfate in severe preeclampsia]. AB - BACKGROUND: Several observational studies and randomized trials have described the use of various regimens of magnesium sulfate to prevent or reduce the rate of seizures and complications in women with severe preeclampsia. AIM: To assess the validity of a service protocol in the management of severe pre-eclampsia all specifying the benefits, complications and side effects of magnesium sulfate . METHODS: We have performed a retrospective descriptive study over two years (2009 2010) concerning 150 patients affected with severe preeclampsia in the department "B" of gynecology and obstetrics of the "Rabta" at the Centre of Maternity and Neonatology of Tunis (third level maternity). The protocol consisted in the administration of 3 grammes of magnesium sulfate followed by intravenous dose of 1 g/hour associated with an anti-hypertensive treatment. RESULTS: One hundred and forty patients (93%) had 2 or more criteria of severity associated. Seventy-eight (52 %) patients with severe preeclampsia have profited an anti-hypertensive treatment based on nicardipine associated with magnesium sulfate without notable secondary effects. In two cases (1.3 %) an eclampsia was noted with magnesium sulfate, 27.4 % of severe preeclampsia was noted at a term within 34 week of amenorrhea. Only one case of surdosage was noted in post partum. CONCLUSION: The use of magnesium sulfate in practice does not appear to increase the risk of complications or major side effects in the mother and fetus. PMID- 22811232 TI - [Emotional disorders and inflammatory bowel disease]. AB - BACKGROUND: The co-occurrence of emotional disorders (alexithymia, depression and anxiety) and inflammatory bowel disease (IBD) is reported in the literature. There are several possible explanations for this co morbidity. AIM: To evaluate the prevalence of alexithymia, anxiety and depression among patients with IBD and to compare them with a control group of healthy individuals and to discuss the relation between emotional disorders and IBD. METHODS: We built a case - control study of 50 patients with IBD (ulcerative colitis (UC) and Crohn's disease (CD)). The control group compounded 50 subjects without IBD and paired according sex, age, and school level. Alexithymia was assessed with the 20-item version of the Toronto Alexithymia Scale (TAS -20). Participants completed the Hospital Anxiety and Depression Scale (HADS), which is a 14-item self-report scale providing separate subscale scores for anxiety (HADS-A) and depression (HADS-D). RESULTS: Among the group of patients, the rates of anxiety, depression and alexithymia were, respectively, 52%, 44% and 54%. In this group, there were significantly more anxious, depressed, and alexithymic subjects than in the control group (p respectively, 0,007, 0,015 and 0,002). The anxiety and the depression were more frequent among patients who had active disease or symptoms than those in remission (p respectively, 0,011 and 0,035). CONCLUSION: The comorbidity of emotional disorders and IBD seems to be frequent. Therefore, clinicians should look for those disorders in patients with IBD, by using specific scales. The adjunction of emotional disorder treatment, if needed, would allow optimizing the management of MICI. PMID- 22811233 TI - [Validation of the Ankylosing Spondylitis Quality of Life questionnaire in Tunisian language]. AB - BACKGROUND: The Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire is a Wide-world used, unidimensional, disease-specific measure of quality of life. Arabic or Tunisian versions of ASQoL or any other quality of life index are not provided. AIM: To adapt the Ankylosing Spondylitis Quality of life Questionnaire (ASQoL) for use in Tunisian and to test its reliability and validity. METHODS: 99 patients who fulfilled the modified New York criteria for ankylosing spondylitis (AS) were included in this study (84 male and 15 female). The translation process included the recent guidelines for cross-cultural adaptation. Reliability of the Tunisian version of the ASQoL was assessed by test-retest method (day 1 and day 10) and internal consistency using Cronbach's alpha coefficient. For construct validity, ASQoL scores were correlated with specific instruments of AS. RESULTS: The mean age of patients was 38.35 years +/- 12.26 (18- 73) and the mean disease duration was 11.3 years +/- 9.4 (0.6 - 40). The mean time to complete the questionnaire was 5 minutes. Reproducibility was good with no significant difference between ASQoL0 (mean score = 9.8 +/- 5.04) and ASQoL10 (mean score = 9.46 +/- 5.89) as well as the statically significant positive correlation intra class coefficient: 0.87 (IC 95%: 0.79-0.92). Internal consistency was good (Cronbach: 0.933; IC95%=0.86-0.95). ASQoL was significantly correlated with BASDAI (p<0.001), BASFI (p<0.001), BASG-s (p<0.001), BASMI (p=0.026), MASES (p=0.024) and all items of SF-36. CONCLUSION: Validation of the ASQoL for use in Tunisia was successful. The results of the present study indicate that the Tunisian version for ASQoL is reliable and valid. PMID- 22811234 TI - [Chondroblastoma of bone ]. AB - BACKGROUND: Chondroblastoma is a rare and benign cartilaginous tumor of bone often localized in the epiphysis of long bones and affecting young persons between 10 and 20 years. AIM: To study the epidemiological, clinical and radiological aspects of bone chondroblastoma, to assess the outcome of chirurgical treatment and factors associated with recurrence. METHODS: It's a retrospective study, concerning 13 patients with chondroblastoma of bone, attending the orthopedic department of Sahloul hospital between 1991 and 2007. The patients' age, sex, clinical features, radiological aspects, treatment and evolution were recorded. After initial clinical examination, all patients have had plane radiographs. Twelve patients were explored by Computed tomography. The treatment was surgical in every case: curettage of the lesion in 11 cases associated with bone grafting in 5 cases and cementation in one case, one in-bloc resection and one simple biopsy. Histology confirmed the diagnostic in all cases. RESULTS: The average age of patients was 18, 2 years and sex ratio was 2, 3. the long bones are the most commonly involved. The main presenting symptoms were pain in all cases and local swelling in 8 cases. Radiographs showed a lytic geographic well-defined lesion in 7 cases. Computed tomography showed better calcifications and soft tissue extension. The mean follow-up of our patients was 8 years (6 mois 18 ans). Two recurrences were noted. Functional results were good in 11 cases. CONCLUSION: Chondroblastoma is a rare and benign cartilaginous tumor of bone which usually involves the epiphysis of long bones. Plane radiographs are sufficient for diagnostic in typical cases. MRI is interesting in unusual presentations and localizations. Curettage and grafting constitute the treatment of choice. Prognosis depends basically on a relatively high rate of recurrence. Aggressive feature of the lesion and incomplete curettage are the most important predictive factors of recurrence. PMID- 22811235 TI - Cystic thymoma. PMID- 22811236 TI - [Acute rupture of a hydatid cyst of the liver in the right pleura]. PMID- 22811237 TI - [Non operative management of pancreatic injury with a pancreatic duct rupture]. PMID- 22811238 TI - [Cytomegalovirus super infection in patients with inflammatory bowel disease]. PMID- 22811239 TI - [Spontaneous calyceal rupture due to prostate cancer]. PMID- 22811240 TI - [Thyrlipoma]. PMID- 22811242 TI - Clock accuracy and precision evolve as a consequence of selection for adult emergence in a narrow window of time in fruit flies Drosophila melanogaster. AB - Although circadian clocks are believed to have evolved under the action of periodic selection pressures (selection on phasing) present in the geophysical environment, there is very little rigorous and systematic empirical evidence to support this. In the present study, we examined the effect of selection for adult emergence in a narrow window of time on the circadian rhythms of fruit flies Drosophila melanogaster. Selection was imposed in every generation by choosing flies that emerged during a 1 h window of time close to the emergence peak of baseline/control flies under 12 h:12 h light:dark cycles. To study the effect of selection on circadian clocks we estimated several quantifiable features that reflect inter- and intra-individual variance in adult emergence and locomotor activity rhythms. The results showed that with increasing generations, incidence of adult emergence and activity of adult flies during the 1 h selection window increased gradually in the selected populations. Flies from the selected populations were more homogenous in their clock period, were more coherent in their phase of entrainment, and displayed enhanced accuracy and precision in their emergence and activity rhythms compared with controls. These results thus suggest that circadian clocks in D. melanogaster evolve enhanced accuracy and precision when subjected to selection for emergence in a narrow window of time. PMID- 22811243 TI - Persistence of circannual rhythms under constant periodic and aperiodic light conditions: sex differences and relationship with the external environment. AB - The timing and duration of gonadal phases in the year indicates that breeding cycles are regulated by endogenous mechanisms. The present study on tropical spotted munia (Lonchura punctulata) investigates whether such mechanisms are based on circannual rhythms, and whether circannual rhythms between sexes differ in their relationship with the light environment. Birds were subjected to 12 h light per day (12L:12D), alternate days of light and darkness (24L:24D, LL/DD) and continuous light (LL), with L=22 lx and D<=1 lx, for 28 months at constant temperature (18+/-1 degrees C). Groups kept on natural day lengths (NDL) served as controls. Measurement of body mass, gonads and molts of the primary wing feathers and body plumage at regular intervals showed that birds underwent repeated cycles in gonads and molt, but not in body mass. Under NDL, gonadal phases in both sexes cycled with 12 month periods. Under other conditions, males cycled with similar periods of ~11 months, but females cycled with relatively large period variations, ~10-13 months. Gonadal recrudescence-regression phase was longer in males than in females and, in both sexes, longer in the second year compared with the first year. The molt of wing primaries was more closely coupled to gonadal maturation in groups on NDL and 12L:12D than in groups on LL and LL/DD, but this relationship drifted apart in the second year. Body plumage molts were relatively more highly variable in both frequency and pattern in females than in males. It is suggested that annual breeding cycle in spotted munia is regulated by the self-sustained circannual rhythms, which probably interact with the annual photoperiodic cycle to synchronize breeding cycles to calendar year. Both sexes seem to have independent timing strategies, but females appear to share a greater role in defining the reproductive season in relation with the environment. PMID- 22811244 TI - Exposure to critical thermal maxima increases oxidative stress in hearts of white but not red-blooded Antarctic notothenioid fishes. AB - Antarctic icefishes have a significantly lower critical thermal maximum (CT(max)) compared with most red-blooded notothenioid fishes. We hypothesized that the lower thermal tolerance of icefishes compared with red-blooded notothenioids may stem from a greater vulnerability to oxidative stress as temperature increases. Oxidative muscles of icefishes have high volume densities of mitochondria, rich in polyunsaturated fatty acids, which can promote the production of reactive oxygen species (ROS). Moreover, icefishes have lower levels of antioxidants compared with red-blooded species. To test our hypothesis, we measured levels of oxidized proteins and lipids, and transcript levels and maximal activities of antioxidants in heart ventricle and oxidative pectoral adductor muscle of icefishes and red-blooded notothenioids held at 0 degrees C and exposed to their CT(max). Levels of oxidized proteins and lipids increased in heart ventricle of some icefishes but not in red-blooded species in response to warming, and not in pectoral adductor muscle of any species. Thus, increases in oxidative damage in heart ventricles may contribute to the reduced thermal tolerance of icefishes. Despite an increase in oxidative damage in hearts of icefishes, neither transcript levels nor activities of antioxidants increased, nor did they increase in any tissue of any species in response to exposure to CT(max). Rather, transcript levels of the enzyme superoxide dismutase (SOD) decreased in hearts of icefishes and the activity of SOD decreased in hearts of the red-blooded species Gobionotothen gibberifrons. These data suggest that notothenioids may have lost the ability to elevate levels of antioxidants in response to heat stress. PMID- 22811245 TI - Intense flight and endotoxin injection elicit similar effects on leukocyte distributions but dissimilar effects on plasma-based immunological indices in pigeons. AB - Most birds rely on flight for survival. Yet as an energetically taxing and physiologically integrative process, flight has many repercussions. Studying pigeons (Columba livia) and employing physiological and immunological indices that are relevant to ecologists working with wild birds, we determined what, if any, acute immune-like responses result from bouts of intense, non-migratory flight. We compared the effects of flight with the effects of a simulated bacterial infection. We also investigated indices in terms of their post-flight changes within individuals and their relationship with flight speed among individuals. Compared to un-flown controls, flown birds exhibited significant elevations in numbers of heterophils relative to numbers of lymphocytes and significant reductions in numbers of eosinophils and monocytes. Furthermore, within-individual changes in concentrations of an acute phase protein were greater in flown birds than in controls. However, none of the flight-affected indices showed any evidence of being related to flight speed. While some of the effects of flight were comparable to the effects of the simulated bacterial infection, other effects were observed only after one of these two physiological challenges. Our study suggests that flight by pigeons yields immune-like responses, and these responses have the potential to complicate the conclusions drawn by ecologists regarding immune function in free-living birds. Still, a better understanding of the repercussions of flight can help clarify the ties between the physiology of exercise and the disease ecology of migration and will ultimately assist in the broader goal of accounting for immunological variation within and among species. PMID- 22811246 TI - Light-induced degeneration and microglial response in the retina of an epibenthonic pigmented teleost: age-dependent photoreceptor susceptibility to cell death. AB - Constant intense light causes apoptosis of photoreceptors in the retina of albino fish. However, very few studies have been performed on pigmented species. Tench (Tinca tinca) is a teleost inhabiting dimly lit environments that has a predominance of rods within the photoreceptor layer. To test the hypothesis that constant high intensity light can result in retinal damage in such pigmented epibenthonic teleost species, photodegeneration of the retina was investigated in the larvae and in juveniles of tench to assess whether any damage may also be dependent on fish age. We exposed both groups of animals to 5 days of constant darkness, followed by 4 days of constant 20,000 lx light, and then by 6 days of recovery in a 14 h light:10 h dark cycle. The results showed that the retina of the larvae group exhibited abundant photoreceptor cell apoptosis during the time of exposition to intense light, whereas that of juveniles was indifferent to it. Damaged retinas showed a strong TUNEL signal in photoreceptor nuclei, and occasionally a weak cytoplasmic TUNEL signal in Muller glia. Specific labelling of microglial cells with Griffonia simplicifolia lectin (GSL) histochemistry revealed that photoreceptor cell death alerts microglia in the degenerating retina, leading to local proliferation, migration towards the injured outer nuclear layer (ONL), and enhanced phagocytosis of photoreceptor debris. During the first days of intense light treatment, Muller cells phagocytosed dead photoreceptor cells but, once microglial cells became activated, there was a progressive increase in the phagocytic capacity of the microglia. PMID- 22811247 TI - Solubility of nitrogen in marine mammal blubber depends on its lipid composition. AB - Understanding the solubility of nitrogen gas in tissues is a crucial aspect of diving physiology, especially for air-breathing tetrapods. Adipose tissue is of particular interest because of the high solubility of nitrogen in lipids. Surprisingly, nothing is known about nitrogen solubility in the blubber of any marine mammal. We tested the hypothesis that N(2) solubility is dependent on the lipid composition of blubber; most blubber is composed of triacylglycerols, but some toothed whales deposit large amounts of waxes in blubber instead. The solubility of N(2) in the blubber of 13 toothed whale species ranged from 0.062 to 0.107 ml N(2) ml(-1) oil. Blubber with high wax ester content had higher N(2) solubility, observed in the beaked (Ziphiidae) and small sperm (Kogiidae) whales, animals that routinely make long, deep dives. We also measured nitrogen solubility in the specialized cranial acoustic fat bodies associated with echolocation in a Risso's dolphin; values (0.087 ml N(2) ml(-1) oil) were 16% higher here than in its blubber (0.074 ml N(2) ml(-1) oil). As the acoustic fats of all Odontocetes contain waxes, even if the blubber does not, these tissues may experience greater interaction with N(2). These data have implications for our understanding and future modeling of diving physiology in Odontocetes, as our empirically derived values for nitrogen solubility in toothed whale adipose were up to 40% higher than the numbers traditionally assumed in marine mammal diving models. PMID- 22811248 TI - Inorganic nutrient availability affects organic matter fluxes and metabolic activity in the soft coral genus Xenia. AB - The release of organic matter (OM) by scleractinian corals represents a key physiological process that importantly contributes to coral reef ecosystem functioning, and is affected by inorganic nutrient availability. Although OM fluxes have been studied for several dominant reef taxa, no information is available for soft corals, one of the major benthic groups in tropical reef environments. Thus, this study investigates OM fluxes along with other key physiological parameters (i.e. photosynthesis, respiration and chlorophyll a tissue content) in the common soft coral genus Xenia after a 4-week exposure period to elevated ammonium (N; 20.0 MUmol l(-1)), phosphate (P; 2.0 MUmol l(-1)) and combined inorganic nutrient enrichment treatment (N+P). Corals maintained without nutrient enrichment served as non-treated controls and revealed constant uptake rates for particulate organic carbon (POC) (-0.315+/-0.161 mg POC m(-2) coral surface area h(-1)), particulate nitrogen (PN) (-0.053+/-0.018 mg PN m(-2) h(-1)) and dissolved organic carbon (DOC) (-4.8+/-2.1 mg DOC m(-2) h(-1)). Although DOC uptake significantly increased in the N treatment, POC flux was not affected. The P treatment significantly enhanced PN release as well as photosynthesis and respiration rates, suggesting that autotrophic carbon acquisition of zooxanthellae endosymbionts influences OM fluxes by the coral host. Our physiological findings confirm the significant effect of inorganic nutrient availability on OM fluxes and key metabolic processes for the soft coral Xenia, and provide the first clues on OM cycles initiated by soft corals in reef environments exposed to ambient and elevated inorganic nutrient concentrations. PMID- 22811249 TI - Ovary ecdysteroidogenic hormone activates egg maturation in the mosquito Georgecraigius atropalpus after adult eclosion or a blood meal. AB - The rockpool mosquito, Georgecraigius atropalpus, is a facultatively autogenous species that produces its first egg clutch without a blood meal shortly after emergence. Several days after depositing this clutch, females must take a blood meal to produce a second egg clutch. Decapitation of females shortly after emergence or blood ingestion prevents egg maturation. Here, we report that a single injected dose of the neuropeptide ovary ecdysteroidogenic hormone (OEH) fully restored egg maturation in decapitated females in both circumstances. This neuropeptide and two insulin-like peptides (ILPs) are potent gonadotropins in the related yellow fever mosquito, Aedes aegypti. ILP3 was marginally restorative in decapitated G. atropalpus, and ILP4 had no effect. Egg maturation in non- and blood-fed G. atropalpus was dependent on the enzymatic mobilization of amino acids from stored protein or the blood meal for yolk protein (vitellogenin, VG) synthesis and uptake by oocytes. We further show that OEH stimulates serine protease activity in the fat body of newly eclosed females or in the midgut of blood-fed ones, and ecdysteroid hormone production by the ovaries of both females. In contrast, only 20-hydroxyecdysone stimulated VG synthesis in the fat body of non- and blood-fed females. Using RNA interference to knock down expression of the insulin receptor, we found that OEH still fully restored autogenous egg maturation. In summary, our results identify OEH as a primary regulator of egg maturation in both autogenous and blood-fed G. atropalpus females and suggest the shift from blood meal-dependent to blood meal-independent release of OEH is a key factor in the evolution of autogeny in this species. PMID- 22811251 TI - Vibrational playback by means of airborne stimuli. AB - Substrate-borne vibrational communication is a common form of communication in animals. Current contact-based playback methods limit the number of substrates that can be stimulated simultaneously and potentially change the transmission properties of the substrate. Here, we explore a solution to these limitations by broadcasting airborne stimuli onto plant substrates to impart vibrational playbacks. We demonstrate that one can effectively compensate for the filtering properties of any individual plant across a range of frequencies. We then address how well both compensated broad-band and pure-tone stimuli for one plant individual apply to other individuals across days. Variation within and between plants was similar across the range tested but was quite variable at certain frequencies. Focusing on a subset of this range, at low frequencies, responses were flat across days and pure-tone frequency stimuli in this range were consistently transmitted despite repositioning of plants relative to the loudspeaker. Our results present a potential solution to researchers interested in exposing large samples of individuals to vibrational signals but also highlight the importance of validating the use of airborne stimuli as vibrational playbacks to the particular substrate type and frequency range of interest. PMID- 22811250 TI - Task-dependent activity of motor unit populations in feline ankle extensor muscles. AB - Understanding the functional significance of the morphological diversity of mammalian skeletal muscles is limited by technical difficulties of estimating the contribution of motor units with different properties to unconstrained motor behaviours. Recently developed wavelet and principal components analysis of intramuscular myoelectric signals has linked signals with lower and higher frequency contents to the use of slower and faster motor unit populations. In this study we estimated the relative contributions of lower and higher frequency signals of cat ankle extensors (soleus, medial and lateral gastrocnemii, plantaris) during level, downslope and upslope walking and the paw-shake response. This was done using the first two myoelectric signal principal components (PCI, PCII), explaining over 90% of the signal, and an angle theta, a function of PCI/PCII, indicating the relative contribution of slower and faster motor unit populations. Mean myoelectric frequencies in all walking conditions were lowest for slow soleus (234 Hz) and highest for fast gastrocnemii (307 and 330 Hz) muscles. Motor unit populations within and across the studied muscles that demonstrated lower myoelectric frequency (suggesting slower populations) were recruited during tasks and movement phases with lower mechanical demands on the ankle extensors--during downslope and level walking and in early walking stance and paw-shake phases. With increasing mechanical demands (upslope walking, mid-phase of paw-shake cycles), motor unit populations generating higher frequency signals (suggesting faster populations) contributed progressively more. We conclude that the myoelectric frequency contents within and between feline ankle extensors vary across studied motor behaviours, with patterns that are generally consistent with muscle fibre-type composition. PMID- 22811252 TI - Locomotion analysis identifies roles of mechanosensory neurons in governing locomotion dynamics of C. elegans. AB - The simple and well-characterized nervous system of C. elegans facilitates the analysis of mechanisms controlling behavior. Locomotion is a major behavioral output governed by multiple external and internal signals. Here, we examined the roles of low- and high-threshold mechanosensors in locomotion, using high resolution and detailed analysis of locomotion and its dynamics. This analysis revealed a new role for touch receptor neurons in suppressing an intrinsic direction bias of locomotion. We also examined the response to noxious mechanical stimuli, which was found to involve several locomotion properties and to last several minutes. Effects on different locomotion properties have different half lives and depend on different, partly overlapping sets of sensory neurons. PVD and FLP, high-threshold mechanosensors, play a major role in some of these responses. Overall, our results demonstrate the power of detailed, prolonged and high-resolution analysis of locomotion and locomotion dynamics in enabling better understanding of gene and neuron function. PMID- 22811253 TI - Plasma exchange in a 13-year-old male with acute intravascular hemolysis and acute kidney injury after placement of a ventricular assist device. AB - Intravascular hemolysis and resulting plasma-free hemoglobin elevation has been associated with acute kidney injury via several mechanisms. Proximal tubular injury due to iron compound deposition and nitric oxide sequestration with subsequent impairment of the microcirculation and hypoperfusion are specific adverse effects of intravascular hemolysis that may contribute to acute kidney injury. Therefore, removal of plasma-free hemoglobin and restoration of normal nitric oxide vasodilatory mechanisms may play a beneficial role in treating acute kidney injury secondary to acute intravascular hemolysis. We report herein the case of a 13-year-old patient with severe intravascular hemolysis and acute kidney injury and describe the role of plasma exchange with plasma replacement in his successful recovery. PMID- 22811255 TI - Host cell protein quantification by Fourier transform mid infrared spectroscopy (FT-MIR). AB - Process development in up- and downstream processing requires enhanced, non-time consuming, and non-expensive monitoring techniques to track product purity, for example, the level of endotoxins, viral particles, and host cell proteins (HCPs). Currently, HCP amounts are measured by laborious and expensive HCP-enzyme-linked immunosorbent assay (ELISA) assays best suited for measuring HCP amounts in the low concentration regime. The measurement of higher HCP amounts using this method requires dilution steps, adding dilution errors to the measurement. In this work we evaluated the suitability of attenuated total reflection spectroscopy for HCP quantification in process development, using clarified cell culture fluid from monoclonal antibody producing Chinese hamster ovary-cells after treatment with different polyelectrolytes for semi-selective clarification. Forty undiluted samples were chosen for multivariate data analysis in the middle infrared range and predicted HCP-values were in good agreement with results obtained by an ELISA assay, suggesting the suitability of this new method for HCP-quantification. As this method is able to quantify HCP titers ranging from approximately at least 20,000-200,000 ng mL(-1), it is suitable especially for monitoring of process development steps with higher HCP concentrations, omitting dilution errors associated with ELISA assays. PMID- 22811256 TI - Transient myeloproliferative disorder progression and acquired chromosomal abnormalities in children with Down syndrome. PMID- 22811254 TI - Systems biology of skeletal muscle: fiber type as an organizing principle. AB - Skeletal muscle force generation and contraction are fundamental to countless aspects of human life. The complexity of skeletal muscle physiology is simplified by fiber type classification where differences are observed from neuromuscular transmission to release of intracellular Ca(2+) from the sarcoplasmic reticulum and the resulting recruitment and cycling of cross-bridges. This review uses fiber type classification as an organizing and simplifying principle to explore the complex interactions between the major proteins involved in muscle force generation and contraction. PMID- 22811257 TI - Laparoscopic posterior retroperitoneal adrenalectomy. AB - Almost more than a decade ago laparoscopic retroperitoneal adrenalectomy was introduced as an alternative to lateral approach. Today both of the techniques have become standard in removal of adrenal tumors and many surgeons showed favorable results in malignant tumors. This review outlines the technical details of the procedure and provides a summary of the literature. PMID- 22811258 TI - Prognostic value of quantitative parameters derived on initial staging 18F fluorodeoxyglucose positron emission tomography/computed tomography in patients with high-grade non-Hodgkin's lymphoma. AB - OBJECTIVES: This study was carried out to evaluate the role of quantitative parameters in staging PET in predicting prognosis in patients with high-grade non Hodgkin's lymphoma (NHL). METHODS: A total of 51 histopathologically proven high grade NHL patients treated with conventional chemotherapy regimens were included in the study. Total lesion glycolysis (TLG) and functional volumes (FVs) were defined as per the PET Response Criteria in Solid Tumors (PERCIST) criteria. All patients were followed up for a minimum period of 1 year or until an event, whichever occurred earlier. RESULTS: Of the four semiquantitative parameters studied, SUV max and SUV mean did not show a statistically significant correlation with progression-free survival or overall survival, whereas TLG and FV showed a weak but statistically significant negative correlation. Using the receiver operating characteristic curve analysis, optimal cut-offs were derived for FV and TLG to predict progression and death. Using the cut-off values of 416 cm3 and 3340 g for FV and TLG, respectively, a statistically significant difference in progression-free survival and overall survival was obtained in the groups with FV and TLG above and below the threshold. On multivariate analysis of all the conventional prognostic factors and TLG more than 3340 and FV more than 416 cm3, only age greater than 60 years (P=0.013) and FV more than 416 cm3 (P=0.012) were found to be independently associated with disease progression. CONCLUSION: Our results indicate that FV and TLG in staging PET/CT could be useful indices in predicting outcomes in patients with high-grade NHL treated with standard first-line chemotherapy regimens. PMID- 22811259 TI - Fetal intracerebral hemorrhage and COL4A1 mutation: promise and uncertainty. PMID- 22811260 TI - The use of medication against attention deficit/hyperactivity disorder in Denmark: a drug use study from a patient perspective. AB - AIM: Our aim was to characterize utilization patterns for drugs used to treat attention deficit/hyperactivity disorder (ADHD) on the level of the individual patient among Danish users, focusing on treatment duration, doses used, and concurrent use of ADHD and non-ADHD drugs. METHODS: Using the Danish Registry of Medicinal Product Statistics, we extracted data on 1,085,099 prescriptions for ADHD drugs issued to a total of 54,024 persons in the study period 1 January 1995 to 30 September 2011. For users in the final year of the study period, we further extracted 315,365 prescriptions for non-ADHD drugs. Drug utilization was characterized using descriptive statistics. RESULTS: The mean duration of ADHD treatment was highest (3.6-4.2 years) for patients initiating therapy at a young age (age<13). Dropout rate after receiving only one prescription was highest among off-label users (age<6 and age >17). All age categories showed an increase in the average daily dosage of methylphenidate used from 2003 to 2010. Concomitant treatment with methylphenidate and atomoxetine was rare, as only 2 % of methylphenidate treatment overlapped with atomoxetine treatment. Nineteen percent of methylphenidate instant-release treatment overlapped with methylphenidate controlled-release treatment. Users of ADHD drugs across all age categories had an increased use of drugs related to the nervous system, especially antipsychotics [standardized morbidity rate (SMR), 6.4-19.5] and antiepileptics (SMR, 4.0-5.5). CONCLUSION: We found certain traits that warrant further investigation: the apparent increase in average daily doses, the low adherence to treatment among off-label users, and the increased use of other psychotropic medication. PMID- 22811262 TI - Pediatric therapeutic plasma exchange indications and patterns of use in US children's hospitals. AB - PURPOSE: Therapeutic plasma exchange (TPE) has been increasingly used over the past decade as a first-line and lifesaving treatment for various conditions classified by the American society for apheresis (ASFA). To date, the degree to which utilization of TPE in pediatrics mirrors recommendations is unknown. METHODS: Using inpatient administrative data from 42 children's hospitals we conducted an 8-year retrospective cohort study of children (<=18 years) with an international classification of diseases-9-clinical modification (ICD-9-CM) discharge diagnosis indicating an ASFA Category I or II condition, or a procedure code indicating receipt of TPE during hospitalization. RESULTS: TPE was performed during 4,190 hospitalizations of 3,449 patients, of whom 310 (9.0%) and 77 (2.2%) had a primary discharge diagnosis of an ASFA Category I or II condition, respectively. Rates of TPE use for Category I conditions were highest for children with thrombotic thrombocytopenic purpura (TTP), Goodpasture's syndrome, and myasthenia gravis. TPE use in children's hospitals significantly increased from 2003 to 2010, but TPE was performed during only 13.4 and 9.3% of hospitalizations for ASFA Category I and II conditions, respectively. There was significant between-hospital variation in the use of TPE for Category I conditions as a group and individual Category I conditions including TTP. CONCLUSION: We found low levels of TPE use across hospitals for key indications, including TTP, a condition for which TPE is considered a first-line and life saving procedure. The variation identified may contribute to varying clinical outcomes between hospitals, warrants further investigation, and represents an important opportunity to improve quality of care. PMID- 22811263 TI - The use of Enhancing Quality Use of Medication Self-Reported Questionniare (EQUIM SRQ) among mental health consumers: a pilot study. AB - OBJECTIVE: To assess the applicability, interpretability and potential limitations of an adverse event screening questionnaire (the Enhancing Quality Use of Medication Self-Reported Questionnaire [EQUIM-SRQ]) in an Australian mental health outpatient population. METHOD: Questionnaires were distributed amongst two Australian adult mental health clinics for completion either at the clinic (onsite), or externally (postal option), during March-May 2011. Assistance was offered to participants completing the questionnaire onsite. Clients who were visited in their homes by clinic staff were invited to participate as external participants. RESULTS: Of 160 questionnaires distributed, 29 (18%) were completed. Of those, 22 were completed onsite, and seven were completed externally. Of the questionnaires completed onsite, 11 were fully completed, with 4 participants requiring assistance. A further 11 questionnaires were partially completed, with 2 participants requiring assistance. Of the questionnaires completed externally, 5 were fully completed. CONCLUSION: Although the response rate was low, the EQUIM-SRQ was applicable, interpretable and acceptable when completed or partially completed questionnaires were assessed. The potential exists to apply the EQUIM-SRQ in further research, and thereafter, clinical practice. PMID- 22811264 TI - Antiretroviral neurotoxicity. AB - Combination antiretroviral therapy (CART) has proven to effectively suppress systemic HIV burden, however, poor penetration into the central nervous system (CNS) provides incomplete protection. Although the severity of HIV-associated neurocognitive disorders (HAND) has been reduced, neurological disease is expected to exert an increasing burden as HIV-infected patients live longer. Strategies to enhance penetration of antiretroviral compounds into the CNS could help to control HIV replication in this reservoir but also carries an increased risk of neurotoxicity. Efforts to target antiretroviral compounds to the CNS will have to balance these risks against the potential gain. Unfortunately, little information is available on the actions of antiretroviral compounds in the CNS, particularly at concentrations that provide effective virus suppression. The current studies evaluated the direct effects of 15 antiretroviral compounds on neurons to begin to provide basic neurotoxicity data that will serve as a foundation for the development of dosing and drug selection guidelines. Using sensitive indices of neural damage, we found a wide range of toxicities, with median toxic concentrations ranging from 2 to 10,000 ng/ml. Some toxic concentrations overlapped concentrations currently seen in the CSF but the level of toxicity was generally modest at clinically relevant concentrations. Highest neurotoxicities were associated with abacavir, efavarenz, etravirine, nevaripine, and atazanavir, while the lowest were with darunavir, emtracitabine, tenofovir, and maraviroc. No additive effects were seen with combinations used clinically. These data provide initial evidence useful for the development of treatment strategies that might reduce the risk of antiretroviral neurotoxicity. PMID- 22811266 TI - An orthologue of the Myelin-gene Regulatory Transcription Factor regulates Dictyostelium prestalk differentiation. AB - The prestalk region of the Dictyostelium slug is comprised of an anterior population of pstA cells and a posterior population of pstO cells. They are distinguished by their ability to utilize different parts of the promoter of the ecmA gene. We identify, by mutational analysis and DNA transformation, CA-rich sequence elements within the ecmA promoter that are essential for pstA-specific expression and sufficient to direct pstA-specific expression when multimerised. The CA-rich region was used in affinity chromatography with nuclear extracts and bound proteins were identified by mass spectrometry. The CA-rich elements purify MrfA, a protein with extensive sequence similarity to animal Myelin-gene Regulatory Factor (MRF)-like proteins. The MRF-like proteins and MrfA also display more spatially limited but significant sequence similarity with the DNA binding domain of the yeast Ndt80 sporulation-specific transcription factor. Furthermore, the ecmA CA-rich elements show sequence similarity to the core consensus Ndt80 binding site (the MSE) and point mutation of highly conserved arginine residues in MrfA, that in Ndt80 make critical contacts with the MSE, ablate binding of MrfA to its sites within the ecmA promoter. MrfA null strains are delayed in multicellular development and highly defective in pstA-specific gene expression. These results provide a first insight into the intracellular signaling pathway that directs pstA differentiation and identify a non-metazoan orthologue of a family of molecularly uncharacterised transcription factors. PMID- 22811267 TI - Identification and characterization of ADAM41, a novel ADAM metalloproteinase in Xenopus. AB - The ADAM family of transmembrane metalloproteinases has important functions in fertilization, development and disease, and is widely distributed throughout the Metazoa. In this study, we identified a novel ADAM protein in Xenopus tropicalis (X. tropicalis) with closest overall sequence similarity to the Xenopus ADAM10 protein. Based on comparisons of available sequence information, putative orthologs of this ADAM (which we designate ADAM41) are identified in several other vertebrate species including non-placental mammals, but absent from placental mammals and aves. ADAM41 mRNA is maternally deposited in X. tropicalis with subsequent zygotic expression detected in the neural plate at neurula stages. Antisense morpholino knockdown of ADAM41 results in a delay in early neuronal marker expression, which can be rescued by a non-targeted ADAM41 transcript. Thus, ADAM41 is likely required for maintaining proper timing of neurogenesis in X. tropicalis. PMID- 22811268 TI - Regulation of Merkel cell development by Pax6. AB - Merkel cells are mechanoreceptors widely distributed in the vertebrate skin. In rodents, Merkel cells within the whisker pads are innervated by free sensory nerve endings derived from the maxillary branch of the trigeminal nerve. This study identified expression of the transcription factor Pax6 in Merkel cells and investigated its role. Immunohistochemistry and Western blot for Pax6 and Merkel cell markers, cytokeratin-8 (K8) and cytokeratin-20 (K20) were performed in wild type and Pax6 (-/-) fetuses. The subcellular localisation of Pax6 in Merkel cells in vitro was manipulated using hydrogen peroxide. Pax6 was primarily localised within the cytoplasm of the Merkel cells at birth, but postnatally was also detected within the nuclei. In vitro, after 4 days in culture Pax6 protein was completely relocated to the nuclei of fetal-derived Merkel cells, mimicking the in vivo situation, suggesting that Pax6 acts as an active nucleo-cytoplasmic shuttling protein in common with many other homeodomain transcription factors. The subcellular localisation of Pax6 could be modulated in vitro by changing the redox potential of the culture medium for Merkel cells. Differentiation of cultured Pax6 (-/-) Merkel cells was shown to be inhibited. At perinatal stages, it was found that Pax6 is required for maintaining cytokeratin-8 expression, an early Merkel cell marker, whereas cytokeratin-20 was retained by the Pax6 (-/-) mutant cells. Pax6 is expressed in developing Merkel cells as a nucleo cytoplasmic shuttling protein and its activity is required for normal differentiation, possibly through regulating cell maturation. PMID- 22811265 TI - 14-3-3s are potential biomarkers for HIV-related neurodegeneration. AB - Over the last decade, it has become evident that 14-3-3 proteins are essential for primary cell functions. These proteins are abundant throughout the body, including the central nervous system and interact with other proteins in both cell cycle and apoptotic pathways. Examination of cerebral spinal fluid in humans suggests that 14-3-3s including 14-3-3epsilon (YWHAE) are up-regulated in several neurological diseases, and loss or duplication of the YWHAE gene leads to Miller Dieker syndrome. The goal of this review is to examine the utility of 14-3-3s as a marker of human immune deficiency virus (HIV)-dependent neurodegeneration and also as a tool to track disease progression. To that end, we describe mechanisms implicating 14-3-3s in neurological diseases and summarize evidence of its interactions with HIV accessory and co-receptor proteins. PMID- 22811269 TI - KDEL tagging: a method for generating dominant-negative inhibitors of the secretion of TGF-beta superfamily proteins. AB - Most endoplasmic reticulum (ER)-retained proteins contain a carboxy-terminal signal sequence called the ER retention signal motif such as the Lys-Asp-Glu-Leu (KDEL) motif. Using this molecular mechanism, we developed a new dominant negative assay, designated the KDEL-tag trap assay, to negatively regulate secretion of disulfide bond-dependent protein dimers, as typified by TGF-beta superfamily proteins. First, we tested this method on the Nodal protein Xnr5, which is a well-studied mesoderm inducer in vertebrates. Tagging of Xnr5 protein with KDEL at the carboxy-terminus effectively blocked the secretion of Xnr5, resulting in complete inhibition of mesoderm induction in Xenopus embryogenesis. Second, we examined the usefulness of the KDEL-tag trap assay on BMPs, which are well-known negative regulators of neural induction and ventralizing factors during early development, and demonstrated that the functions of the BMP family proteins BMP4 and ADMP were blocked by the KDEL-tag trap assay. Moreover, the technical feasibility of the KDEL-tag trap assay was confirmed in a cell culture system using mouse osteoblasts. Taken together, these results suggest that the KDEL-tag trap assay can be adapted to inhibit a variety of plasma membrane or secreted proteins of a multimeric nature. PMID- 22811270 TI - An immunohistochemical analysis of Rab27B distribution in fetal and adult tissue. AB - Regulated secretory pathways coordinated by small Rab GTPases are critically involved in intercellular communications. Here, we report the expression and localization of Rab27B in developing and differentiated epithelial human tissues by immunohistochemistry. Rab27B is poorly expressed in fetal tissues suggesting that several developmental mechanisms involved in epithelial differentiation and functions are mediated by other secretory Rab GTPases, such as Rab27A or Rab3 family members. In adult tissues, Rab27B is expressed in a wide variety of differentiated secretory epithelial cells, including those lining the salivary gland, gastrointestinal, mammary and prostate tracts. The complex pattern of Rab27B expression indicates that dysregulation of Rab27B-mediated secretion may have profound implications for disease pathology. PMID- 22811271 TI - Expression of Sox family genes in early lamprey development. AB - Members of the Sox (Sry-related high mobility group box) family of transcription factors play a variety of roles during development of both vertebrates and invertebrates. A marked expansion in gene number occurred during the emergence of vertebrates, apparently via gene duplication events that are thought to have facilitated new functions. By screening a macroarrayed library as well as the lamprey genome, we have isolated genes of the Sox B, D, E and F subfamilies in the basal jawless vertebrate, lamprey. The expression patterns of all identified Sox genes were examined from gastrulation through early organogenesis (embryonic day 4-14), with particular emphasis on the neural crest, a vertebrate innovation. Coupled with phylogenetic analysis of these Sox genes, the results provide insight into gene duplication and di-vergence in paralog deployment occurring during early vertebrate evolution. PMID- 22811272 TI - Expression of serotonergic system components during early Xenopus embryogenesis. AB - Despite abundant research studies on the physiological and biochemical nature of embryonic neurotransmitter function, little is known about the molecular genetic mechanisms involved. The expression of the main components of the serotonergic system during early Xenopus embryogenesis was investigated using RT-PCR, real time PCR and in situ hybridization. Transcripts encoding the serotonin receptors HTR2C and HTR7, as well as the vesicular monoamine transporter VMAT2, the serotonin transporter (SERT) and the serotonin synthesis enzymes tryptophan hydroxylase (TPH2) and aromatic amino acid decarboxylase (AAAD) were found to be expressed during the cleavage division stages, whereas the degradation enzyme monoamine oxidase A (MAOA) was absent. The main components of the serotonergic system were found to be expressed during the earliest stages of embryonic development. The embryonic transmitter mechanism, its complexity, and its variability among various species are discussed. PMID- 22811273 TI - Identification and characterization of Xenopus kctd15, an ectodermal gene repressed by the FGF pathway. AB - The FGF pathway regulates a variety of developmental processes in animals through activation and/or repression of numerous target genes. Here we have identified a Xenopus homolog of potassium channel tetramerization domain containing 15 (KCTD15) as an FGF-repressed gene. Kctd15 expression is first detected at the gastrula stage and gradually increases until the tadpole stage. Whole-mount in situ hybridization reveals that the spatial expression of kctd15 is tightly regulated during early embryogenesis. While kctd15 is uniformly expressed throughout the presumptive ectoderm at the early gastrula stage, its expression becomes restricted to the non-neural ectoderm and is excluded from the neural plate at the early neurula stage. At the mid-neurula stage, kctd15 shows a more restricted distribution pattern in regions that are located at the anterior, lateral or medial edge of the neural fold, including the preplacodal ectoderm, the craniofacial neural crest and the prospective roof plate. At the tailbud stage, kctd15 expression is mainly detected in neural crest- or placode-derived tissues that are located around the eye, including the mandibular arch, trigeminal ganglia and the olfactory placode. FGF represses kctd15 expression in ectodermal explants, and the inhibition of FGF receptor with a chemical compound dramatically expands the region expressing kctd15 in whole embryos. Dorsal depletion of kctd15 in Xenopus embryos leads to bent axes with reduced head structures, defective eyes and abnormal somites, while ventral depletion causes defects in ventral and caudal morphologies. These results suggest that kctd15 is an FGF-repressed ectodermal gene required for both dorsal and ventral development. PMID- 22811274 TI - Noggin4 expression during chick embryonic development. AB - We describe here the expression pattern of Noggin4 during the early development of the chick embryo (Gallus gallus). The expression of this gene starts with the onset of gastrulation (stage HH4), in two bilateral bands along the primitive streak, with a local maximum around Hensen's node. By the end of gastrulation, Noggin4 transcripts are distributed diffusely throughout the epiblast, with the highest concentration in the head ectoderm. Interestingly, the expression of Noggin4 during the first half of gastrulation demonstrates a clear left-right asymmetry in Hensen's node, being much more intensive in its right anterior portion. During neurulation, Noggin4 is expressed mainly in the neuroectoderm, with the most intensive expression in the head and lateral neural folds. In mesoderm derivatives, expression is seen in somites but not in the notochord. In general, primarily ectodermal and diffusive expression of Noggin4 in chick embryo, with a maximum in the anterior neurectoderm, resembles that of its ortholog in Xenopus, which indicates a conservative function of this gene in evolution. PMID- 22811275 TI - Modest advances in survival for patients with colorectal-associated peritoneal carcinomatosis in the era of modern chemotherapy. AB - BACKGROUND: The treatment of metastatic colorectal cancer (CRC) has evolved rapidly over the last decade, with combination chemotherapy and targeted biologic agents leading to significant improvements in survival. Despite these advances, little is known about their effectiveness in CRC-associated peritoneal carcinomatosis. The purpose of this study was to evaluate outcomes in patients with CRC-associated PC treated in the era of modern chemotherapy. METHODS: We retrospectively reviewed an institutional tumor database from 1996 to 2008. Survival data were evaluated for patients treated with PC before and after 2003. No patients before 2003 were treated with combination chemotherapy or biologic therapy. The modern chemotherapy group consisted of patients treated after 2003. Survival curves were estimated. RESULTS: Overall, 173 patients were identified. Median follow-up was 8.6 months. Median survival in the historic group (n = 91) was 8.9 months and 16.3 months in the modern chemotherapy group (n = 82) (P < 0.004). Age was the only significant covariate. The survival difference between the modern chemotherapy cohort and control cohort persisted after adjustment for age. In a subset of patients in the modern chemotherapy era group, for which treatment regimen could be definitively identified, survival was even greater 23.8 months. CONCLUSIONS: Patients with CRC-associated PC treated with modern combination chemotherapy and biologic therapy have a significantly longer median survival compared to our historical cohort. Despite these improvements, outcomes still remain poor. Therapeutic adjuncts such as surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in appropriately selected patients remain promising options to improve outcomes for patients with peritoneal-based disease. PMID- 22811276 TI - Pseudoaminopterin syndrome. AB - Pseudoaminopterin syndrome or aminopterin syndrome-like sine aminopterin (ASSA syndrome--OMIM 600325] is a rare autosomal recessive syndrome defined by characteristic dysmorphic features, skeletal defects, limb anomalies, cryptorchidism, and growth retardation. The syndrome owes its name to the fact that patients resemble the children exposed to aminopterin or to methotrexate, two dihydrofolate reductase inhibitors used for chemotherapy, or as an abortificient in early pregnancy. Ten patients have been described with pseudoaminopterin syndrome. Their phenotype is variable, and differs from the phenotype resulting from folic acid deprivation, leading to the notion that the pathogenesis may be more complex than simple vitamin deficiency. We report on an Algerian patient with pseudoaminopterin syndrome, review the previously reported cases and confirm that pseudoaminopterin syndrome does not result from a detectable contiguous gene imbalance as high resolution CGH array was normal in this child. PMID- 22811278 TI - Three-dimensional nanocharacterization of porous hydrogel with ion and electron beams. AB - Porous hydrogels provide an excellent environment for cell growth and tissue regeneration, with high permeability for oxygen, nutrients, and other water soluble metabolites through their high water-content matrix. The ability to image three-dimensional (3D) cell growth is crucial for understanding and studying various cellular activities in 3D context, particularly for designing new tissue engineering scaffold, but it is still challenging to study cell-biomaterial interfaces with high resolution imaging. We demonstrate using focused ion beam (FIB) milling, electron imaging, and associated microanalysis techniques that novel 3D characterizations can be performed effectively on cells growing inside 3D hydrogel scaffold. With FIB-tomography, the porous microstructures were revealed at nanometer resolution, and the cells grown inside. The results provide a unique 3D measurement of hydrogel porosity, as compared with those from porosimetry, and offer crucial insights into material factors affecting cell proliferation at specific regions within the scaffold. We also proved that high throughput correlative imaging of cell growth is viable through a silicon membrane based environment. The proposed approaches, together with the protocols developed, provide a unique platform for analysis of the microstructures of novel biomaterials, and for exploration of their interactions with the cells as well. PMID- 22811277 TI - Reply: To PMID 21901859. PMID- 22811279 TI - Synthesis and evaluation of a new series of tri-, di-, and mono-N alkylcarbamylphloroglucinols as conformationally constrained inhibitors of cholesterol esterase. AB - 1,3,5-Tri-N-alkylcarbamylphloroglucinols (1-4) are synthesized as conformationally constrained analogs of triacylglycerols (TGs) to probe Jenck's proximity effect in the cholesterol esterase inhibition. For the cholesterol esterase inhibition, inhibitors 1-4 are 220-760-fold more potent than 1,2,3-tri-N alkylcarbamylglycerols (13-15) that are substrate analogs of TG. Comparison of tridentate inhibitors 1-4, bidentate inhibitors 3,5-di-N-n alkylcarbamyloxyphenols (5-8) and monodentate inhibitors 5-N-n alkylcarbamyloxyresorcinols (9-12) indicates that inhibitory potencies are as followed: tridentate inhibitor > bidentate inhibitor > monodentate inhibitor. The log k(i) and pK(i) values of tridentate inhibitors, bidentate inhibitors, and monodentate inhibitors are linearly correlated with the alkyl chain length indicating a common mechanism in each inhibition. Also, positive slopes of these correlations indicate that the longer chain inhibitors bind more tightly to the enzyme than the shorter ones. Molecular dockings of tridentate 1, bidentate 5, and monodentate 9 into the X-ray crystal structure of cholesterol esterase suggest that one carbamyl group in the cis form of the inhibitor binds to the acyl chain-binding site of the enzyme. The second carbamyl groups in the trans forms of inhibitors 1 and 5 bind to the second acyl chain-binding site of the enzyme. The third carbamyl group in the trans form of inhibitor 1 binds to the third acyl chain-binding site of the enzyme. Moreover, the configuration of the inhibitor in the enzyme-inhibitor complex is the (1,3,5)-(cis, trans, trans) tricarbamate form that mimics the (+gauche, -gauche)-conformation of TG. PMID- 22811280 TI - Cx43 associates with Na(v)1.5 in the cardiomyocyte perinexus. AB - Gap junctions (GJs) are aggregates of channels that provide for direct cytoplasmic connection between cells. Importantly, this connection is thought responsible for cell-to-cell transfer of the cardiac action potential. The GJ channels of ventricular myocytes are composed of connexin43 (Cx43). Interaction of Cx43 with zonula occludens-1 (ZO-1) is localized not only at the GJ plaque, but also to the region surrounding the GJ, the perinexus. Cx43 in the perinexus is not detectable by immunofluorescence, yet localization of Cx43/ZO-1 interaction to this region indicated the presence of Cx43. Therefore, we hypothesized that Cx43 occurs in the perinexus at a lower concentration per unit membrane than in the GJ itself, making it difficult to visualize. To overcome this, the Duolink protein-protein interaction assay was used to detect Cx43. Duolink labeling of cardiomyocytes localized Cx43 to the perinexus. Quantification demonstrated that signal in the perinexus was lower than in the GJ but significantly higher than in nonjunctional regions. Additionally, Duolink of Triton X-100-extracted cultures suggested that perinexal Cx43 is nonjunctional. Importantly, the voltage gated sodium channel Na(v)1.5, which is responsible for initiation of the action potential, was found to interact with perinexal Cx43 but not with ZO-1. This work provides a detailed characterization of the structure of the perinexus at the GJ edge and indicates that one of its potential functions in the heart may be in facilitating conduction of action potential. PMID- 22811282 TI - System for measuring planar lipid bilayer properties. AB - We present a system for measuring planar lipid bilayer properties. The system is composed of a control unit, an output stage, an LCR meter, pumps for filling reservoirs, a bath with temperature regulation and a measurement chamber with four electrodes. The planar lipid bilayer is automatically formed using a folding method on apertures of different sizes. The automatization is assured by two syringes, which are clamped in actuators. Actuators are driven and controlled by a control unit via RS-232 communication. The temperature of the planar lipid bilayer can be regulated between 15 and 55 degrees C. The regulation is assured by insertion of the measurement chamber into the temperature-regulated bath. Different shapes of voltage- or current-clamp signals can be applied to the planar lipid bilayer. By measuring the response of the planar lipid bilayer to the applied signal, the capacitance and breakdown voltage of the planar lipid bilayer can be determined. The cutoff frequencies of the system output stage for voltage- and current-clamp methods are 11 and 17 kHz, respectively. PMID- 22811284 TI - A pilot study to monitor Graves' ophthalmopathy with a combination of pattern reversal and motion-onset visual evoked potentials. AB - OBJECTIVE: The aim of this pilot study was to evaluate the efficacy of visual evoked potentials (VEPs) in the monitoring of visual function during a high-dose intravenous steroid pulse therapy and apheresis treatment of severe Graves' ophthalmopathy (GO). PATIENTS AND RESEARCH DESIGN: Nine patients with severe and active GO were treated with high-dose methylprednisolone (1 g day(-1) three times within 1 week, then 0.5 g day(-1) seven times for 2 weeks) combined with plasma filtration (twice a week in weeks 1, 2, 4, 7, and 10). Pattern-reversal and motion-onset VEPs were examined three times, pretreatment, after steroid pulses, and after the last apheresis. RESULTS: After 10 steroid pulses, the visual acuity was significantly better and the pattern-reversal VEP amplitudes (element size of only 20') had a similar trend for improvement. However, this effect disappeared after 7 weeks when only apheresis treatment was performed. No significant changes in the latencies of any of the tested VEP variants were found in relationship to the treatment. CONCLUSION: Only the observed large intraindividual variability of the VEP parameters between repeated examinations of patients with the shortest duration of GO might be recognized as a marker for functional changes of the visual pathway due to GO. Although this pilot study cannot provide a definite view on the usefulness of the extended set of VEPs in objective monitoring of GO, it seems that the steroid pulse therapy effect is detectable in contrast to the lack of influence by apheresis on the electrophysiological parameters tested. PMID- 22811281 TI - Adhesion signals of phospholipid vesicles at an electrified interface. AB - General adhesion behavior of phospholipid vesicles was examined in a wide range of potentials at the mercury electrode by recording time-resolved adhesion signals. It was demonstrated that adhesion-based detection is sensitive to polar headgroups in phospholipid vesicles. We identified a narrow potential window around the point of zero charge of the electrode where the interaction of polar headgroups of phosphatidylcholine vesicles with the substrate is manifested in the form of bidirectional signals. The bidirectional signal is composed of the charge flow due to the nonspecific interaction of vesicle adhesion and spreading and of the charge flow due to a specific interaction of the negatively charged electrode and the most exposed positively charged choline headgroups. These signals are expected to appear only when the electrode surface charge density is less than the surface charge density of the choline groups at the contact interface. In comparison, for the negatively charged phosphatidylserine vesicles, we identified the potential window at the mercury electrode where charge compensation takes place, and bidirectional signals were not detected. PMID- 22811285 TI - Anterior mediastinal lymphangioma: pre- and postnatal sonographic findings. AB - Anterior mediastinal lymphangiomas are very rare in utero with only a few cases reported in literature. We present a case of anterior mediastinal lymphangioma that was diagnosed on prenatal sonography (US) at 22 weeks' gestation. It appeared as a well-defined, multi-septated anechoic mass, in the anterior mediastinum between the heart base and right chest wall. There was no solid component and no internal flow on color Doppler US. The pre- and postnatal US findings are correlated with prenatal MRI and postnatal CT findings. PMID- 22811286 TI - Growth charts of Down syndrome in Egypt: a study of 434 children 0-36 months of age. AB - The aim of the study was to construct new reference growth charts for weight, length and head circumference of Egyptian children with Down syndrome (DS) from birth to 36 months of age. These specific charts may be used by health professionals involved in medical, physical and developmental care of Egyptian children with Down syndrome. The study included 434 children with non-disjunction trisomy 21, 0-36 months of age. They were 54.4% males and 45.6% females and had no concomitant chronic disease (congenital heart disease, gastrointestinal malformations, hypothyroidism, and blood disorders). Overall, 1,955 observations were performed of weight, length and head circumference. The data for each sex were divided into 37 different age groups with 1-month intervals. All measurements were taken using standardized equipments and following the international recommendations. Values were statistically analyzed and growth curves were plotted as means and standard deviations (SD). Growth measurements evaluated in all age groups of both sexes were significantly lower than those of the controls. There was a gender difference in weight, length and head circumference, males with Down syndrome had higher values. In conclusion, we suggest that these new growth charts specific for Down syndrome children may be used in optimizing direct Egyptian DS children care and in providing anticipatory guidance in term of optimal physical growth and early detection of hidden factors affecting growth. PMID- 22811287 TI - Quantitative analysis of enzymatic fractionation of multiple substrate mixtures. AB - The enzymatic conversion of mixtures of multiple substrates was studied quantitatively, based on established methodology used for the enzymatic kinetic resolution of racemic mixtures, involving the use of competitive factors: ratios of specificity constants (k(cat)/K(M)) of substrate pairs. The competitive factors of the substrates were defined in relation to a reference substrate. These competitive factors were used to predict the composition of the reaction mixture as a function of the degree of conversion of the reaction. The methodology was evaluated using three different lipases to hydrolyze a model mixture of four fatty acid methyl esters and for the esterification of a mixture of the same fatty acids in free form with ethanol. In most cases, the competitive factors determined from the initial phase of the reactions predicted the product composition during the rest of the reaction very well. The slowest reacting fatty acid was erucic acid (both in free form and as methyl ester), which was thus enriched in the remaining substrate fraction, while the other fatty acids: lauric acid, palmitic acid and oleic acid were converted faster. Simulations of the compositions of reaction mixtures with different values of the competitive factors were carried out to provide an overview of what could be achieved using enzymatic enrichment. Possible applications include reactions involving homologous substrates and mixtures of multiple isomers. The analysis presented provides guidelines that can be useful in the screening and development of enzymes for enzymatic enrichment applications. PMID- 22811289 TI - Evening cortisol is associated with intra-individual instability in daytime napping in nursing home residents with dementia: an allostatic load perspective. AB - BACKGROUND: Circadian rhythm disruption, reflected in alterations in sleep-wake activity and daytime napping behavior, is consistently reported in nursing home (NH) residents with dementia. This disruption may be reflected in day-to-day instability. The concept of allostatic load (AL), a measure of cumulative biological burden over a lifetime, may be a helpful model for understanding cortisol diurnal rhythm and daytime napping activity in this population. The purpose of this study was to examine the association between intra-individual daytime napping episodes and basal cortisol diurnal rhythm in NH residents with dementia in the context of AL. METHOD: U sing a within-individual longitudinal design (N = 51), the authors observed and recorded daytime napping activity every 20 min for 10 hr per day across 4 consecutive days. The authors obtained saliva samples 4 times each day (upon participants' waking and within 1 hr, 6 hr, and 12 hr of participants' wake time) for cortisol analysis. RESULTS: The authors categorized participants as high changers (HCs; day-to-day instability in napping activity) or low changers (LCs; day-to-day stability). There were no significant differences in resident characteristics between groups. There was a significant difference between HCs and LCs in napping episodes (F = 4.86, p = .03), with an interaction effect of evening cortisol on napping episodes in the HC group (F = 10.161, p = .001). CONCLUSIONS: NH residents with unstable day-to-day napping episodes are more responsive to alterations in evening cortisol, an index of a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. They may also be more amenable to environmental intervention, an avenue for further research. PMID- 22811290 TI - Current trends in alpha-helical membrane protein crystallization: an update. AB - alpha-Helical membrane proteins (MPs) are the targets for many pharmaceutical drugs and play important roles in human physiology. In recent years, significant progress has been made in determining their atomic structure using X-ray crystallography. However, a major bottleneck in MP crystallography still remains, namely, the identification of conditions that give crystals that are suitable for structural determination. In 2008, we undertook an analysis of the crystallization conditions for 121 alpha-helical MPs to design a rationalized sparse matrix crystallization screen, MemGold. We now report an updated analysis that includes a further 133 conditions. The results reveal the current trends in alpha-helical MP crystallization with notable differences since 2008. The updated information has been used to design new crystallization and additive screens that should prove useful for both initial crystallization scouting and subsequent crystal optimization. PMID- 22811288 TI - The human fetal lung xenograft: validation as model of microvascular remodeling in the postglandular lung. AB - BACKGROUND: Coordinated remodeling of epithelium and vasculature is essential for normal postglandular lung development. The value of the human-to-rodent lung xenograft as model of fetal microvascular development remains poorly defined. AIM: The aim of this study was to determine the fate of the endogenous (human derived) microvasculature in fetal lung xenografts. METHODS: Lung tissues were obtained from spontaneous pregnancy losses (14-22 weeks' gestation) and implanted in the renal subcapsular or dorsal subcutaneous space of SCID-beige mice (T, B, and NK-cell-deficient) and/or nude rats (T-cell-deficient). Informed parental consent was obtained. Lung morphogenesis, microvascular angiogenesis, and epithelial differentiation were assessed at 2 and 4 weeks post-transplantation by light microscopy, immunohistochemical, and gene expression studies. Archival age matched postmortem lungs served as control. RESULTS: The vascular morphology, density, and proliferation of renal subcapsular grafts in SCID-beige mice were similar to age-matched control lungs, with preservation of the physiologic association between epithelium and vasculature. The microvasculature of subcutaneous grafts in SCID-beige mice was underdeveloped and dysmorphic, associated with significantly lower VEGF, endoglin, and angiopoietin-2 mRNA expression than renal grafts. Grafts at both sites displayed mild airspace dysplasia. Renal subcapsular grafts in nude rats showed frequent infiltration by host lymphocytes and obliterating bronchiolitis-like changes, associated with markedly decreased endogenous angiogenesis. CONCLUSION: This study demonstrates the critical importance of host and site selection to ensure optimal xenograft development. When transplanted to severely immune suppressed, NK-cell-deficient hosts and engrafted in the renal subcapsular site, the human-to-rodent fetal lung xenograft provides a valid model of postglandular microvascular lung remodeling. PMID- 22811291 TI - Development of the subcortical brain structures in the second trimester: assessment with 7.0-T MRI. AB - INTRODUCTION: This study aims to obtain the signal intensity changes and quantitative measurements of the subcortical brain structures of 12-22 weeks gestational age (GA). METHODS: Sixty-nine fetal specimens were selected and scanned by 7.0-T MR. The signal intensity changes of the subcortical brain structures were analyzed. The three-dimensional visualization models of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus were rebuilt with Amira 4.1, and the developmental trends between the measurements and GA were analyzed. RESULTS: The germinal matrix was delineated on 7.0-T MR images at 12 weeks GA, with high signals on T1-weighted images (WI). While at 16 weeks GA, the caudate nucleus, lentiform nucleus, and internal and external capsules could be distinguished. The caudate nucleus was high signal intensity on T1WI. The signal intensity of the putamen was high on T1WI during 15-17 weeks GA and was delineated as an area with uneven signal intensities. The signal intensity of the peripheral area of the putamen became higher after 18 weeks GA. The signal intensity of the globus pallidus was high on T1WI and low on T2WI after 20 weeks GA. At 18 weeks GA, the claustrum was delineated with low signals on T2WI. Measurements of the germinal matrix, caudate nucleus, lentiform nucleus, and dorsal thalamus linearly increased with the GA. CONCLUSION: Development of the subcortical brain structures during 12-22 weeks GA could be displayed with 7.0-T MRI. The measurement provides significant reference beneficial to the clinical evaluation of fetal brain development. PMID- 22811292 TI - [Nursing errors and the consequences. Results of a survey of nurses from inpatient care institutions]. AB - Internationally, research on the consequences of errors caused by nurses is quite comprehensive. In contrast, the body of knowledge on the effects that errors have on the nurses themselves is rather small. It is well known that errors can have profoundly negative outcomes on nurses. In some cases, however, errors can have useful ramifications. This paper shows the research results of a representative cross-sectional survey that covers 1,100 nurses working in German hospitals and nursing homes and illustrates the effects of errors on them. Most participants in the sample mentioned feelings of regret/remorse and irritation/annoyance/stress as an effect when they made a mistake. More than half of the nurses state that they also learnt from their errors. Hospital nurses frequently suffer from psychological effects while nursing home nurses experience more often professional or legal consequences. With increasing age and professional experience the nurses indicate a lower error impact. The answers given by nurse assistants differ from those of nurses with a three-year training course. The results suggest an amount of stress that may reduce efficiency and increase susceptibility to mistakes and which, therefore, needs to be remedied. PMID- 22811293 TI - [Medication safety in the home care setting: error-prone process steps]. AB - So far, little is known about drug-related problems in the homecare setting. It is estimated that up to 30% of homecare patients experience a potential medication error, most frequently happening during preparation and administration of drugs. In order to identify error-prone process steps in a Swiss homecare organisation caring for 1854 patients per year, direct observation of the medication use process, including the analysis of 10% of all prescriptions, was executed. Three complimentary methods were combined for the assessment of qualitative aspects of the medication use process: the analysis of a critical incident reporting system, a survey among homecare nurses, and a failure, mode and effects analysis. The medication use process is complex, consisting of 20 individual steps. Patients are prescribed an average of 7.5 +/- 3.5 drugs per day, including 1 to 9 doses not suitable for deblistering into weekly dispensing systems. Of 84 reported errors, 74% happened during drug preparation. Communication with physicians, patients interrupting drug preparation and not transmitted changes of the drug regimen were considered the most critical process steps. PMID- 22811295 TI - [Magnet hospitals. 1988]. PMID- 22811294 TI - [Temporal and structural differences in the care of obese and non-obese people in nursing homes]. AB - Obesity is a common disease in Germany. Although care facilities are confronted with an increasing number of obese people, the care of them in nursing homes is barely investigated. The present study examines the amount of work using the example of the activity of dressing obese and non-obese nursing home residents and discloses with its temporal and structural differences. In five nursing homes in Berlin a fully structured observational study based on a convenience sample was conducted. 48 nurses were observed while performing the activity of dressing 70 residents aged 65 years and older. The residents' demographic data and medical diagnoses were taken from the nursing records. Information about the functional/cognitive status and pain events were collected by using the interRAI Contact Assessment. Further data regarding the nurses were obtained through face to-face interviews. The results show a significant correlation between Body Mass Index and the required time of dressing. No correlations exist between age, qualifications and nurses' level of education and the time of dressing. Structural differences in the care of obese and non-obese residents appear by changes of, single activity sequences. The care of the obese residents is associated with increased time requirements and structurally differs from the care of the non-obese residents. This should lead to further research because it has implications for staffing in nursing homes. PMID- 22811296 TI - Magnet hospital: institutions of excellence. PMID- 22811297 TI - [Testing an intervention to support pain self management in oncologic patients: a mixed method pilot study]. PMID- 22811299 TI - Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human peripheral blood lymphocyte-reconstituted mice. AB - Lack of adherence, inaccessibility to viral reservoirs, long-term drug toxicities, and treatment failures are limitations of current antiretroviral therapy (ART). These limitations lead to increased viral loads, medicine resistance, immunocompromise, and comorbid conditions. To this end, we developed long-acting nanoformulated ART (nanoART) through modifications of existing atazanavir, ritonavir, and efavirenz suspensions in order to establish cell and tissue drug depots to achieve sustained antiretroviral responses. NanoART's abilities to affect immune and antiviral responses, before or following human immunodeficiency virus type 1 infection were tested in nonobese severe combined immune-deficient mice reconstituted with human peripheral blood lymphocytes. Weekly subcutaneous injections of drug nanoformulations at doses from 80 mg/kg to 250 mg/kg, 1 day before and/or 1 and 7 days after viral exposure, elicited drug levels that paralleled the human median effective concentration, and with limited toxicities. NanoART treatment attenuated viral replication and preserved CD4(+) Tcell numbers beyond that seen with orally administered native drugs. These investigations bring us one step closer toward using long-acting antiretrovirals in humans. PMID- 22811300 TI - The impact of chronic hepatitis C virus infection on mortality. PMID- 22811301 TI - Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. AB - BACKGROUND: The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths. METHODS: A cohort of 23 820 adults aged 30-65 years old were enrolled during 1991-1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008. RESULTS: There were 19,636 HBsAg-seronegatives, including 18,541 anti-HCV seronegatives and 1095 anti HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA. CONCLUSIONS: Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C. PMID- 22811302 TI - Apheresis in the treatment of idiopathic dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) causes significant morbidity and mortality and is the number one indication for cardiac transplantation in the United States. A large percentage of cases of DCM have no identifiable cause with evidence suggesting that these may represent an autoimmune disorder triggered by viral myocarditis. There is a growing body of literature suggesting that a number of immunoadsorption techniques, as well as plasma exchange, may have a role in the treatment of idiopathic DCM. The hypothesized autoimmune mechanism behind idiopathic DCM as well as the published evidence for the use of apheresis in this disorder are reviewed. The available evidence suggests that apheresis may be an effective treatment, but additional research is needed to identify markers that will predict response and the most effective apheresis technique. PMID- 22811303 TI - Integrating CAM and biomedicine in primary care settings: physicians' perspectives on boundaries and boundary work. AB - In this article, we present the results of a study that was conducted among 15 family physicians who had incorporated complementary and alternative medicine (CAM) into their clinical work in Israel. We aimed to explore the types of boundaries those physicians encountered, how these boundaries were contoured, and under what circumstances they were crossed. We conducted in-depth interviews with the physicians in 2008, and found that epistemological and cognitive boundaries did not pose a problem for them. However, with regard to the organizational boundary, the participants indicated that it was necessary to use a variety of strategies before they could utilize their CAM skills. Many of the participants indicated that the epistemological differences between the biomedical and CAM paradigms, such as the absence of evidence-based medicine in CAM practices, are not important. The ease with which boundaries were crossed in the complex social context described here is characteristic of postmodern societies. On the whole, the integrative physicians interviewed can be viewed as "postmodern" professionals who reject the impermeability of many long-established boundaries and hierarchies. PMID- 22811304 TI - Teamwork for clinical emergencies: interprofessional focus group analysis and triangulation with simulation. AB - Our purpose was to investigate health care professionals' beliefs about effective teamwork in medical emergencies based on their experiences. We used framework analysis of interprofessional focus groups in four secondary and tertiary maternity units. The participants were randomly selected senior and junior doctors, senior and junior midwives, and health care assistants, in five groups of 5 to 7 participants each. We found that optimal teamwork was perceived to be dependent on good leadership and availability of experienced staff. The participants described a good leader as one who verbally declares being the leader, communicates clear objectives, and allocates critical tasks, including communication with patients or their family, to suitable individual members. We triangulated the results with evidence from simulation to identify convergent findings and issues requiring further research. The findings will inform the development of teaching programs for medical teams who manage emergencies to improve patient safety and experience. PMID- 22811305 TI - Sperm vacuoles are linked to capacitation and acrosomal status. AB - STUDY QUESTION: Is the presence of nuclear vacuoles really a negative parameter? SUMMARY ANSWER: As sperm vacuoles are associated with acrosomal and capacitation status, they appear to be a reflection of normal sperm physiology. WHAT IS KNOWN ALREADY: The selection of sperm under a high magnification has been proposed as a strategy to increase the success rates of ICSI, through a better selection of sperm for injection. The presence of vacuoles on the sperm head is said to be a negative parameter. STUDY DESIGN, SIZE, DURATION: We incubated processed sperm for 90 min with two strong inducers of acrosome reaction (AR), i.e. hyaluronic acid (HA) and follicular fluid (FF) and studied the evolution of nuclear vacuoles, sperm morphology and chromatin compaction. PARTICIPANTS/MATERIALS, SETTING, METHODS: We tested the effect of incubating sperm samples with HA and FF for 90 min at 37 degrees C on nuclear vacuoles. MAIN RESULTS AND THE ROLE OF CHANCE: Both HA and FF strongly induce AR after 90 min, without significantly modifying sperm nuclear condensation and morphology (Bartoov's criteria). We simultaneously observed a highly significant decrease in the presence of vacuoles. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study based on in vitro manipulations. WIDER IMPLICATIONS OF THE FINDINGS: Although intracytoplasmic morphologically selected sperm injection may be of benefit for couples with specific treatment indications, the results of this study make it difficult to justify its large-scale application. STUDY FUNDING/COMPETING INTEREST(S): Funding was granted by Laboratoire d'Eylau, Unilabs. PMID- 22811306 TI - Oral, transdermal and vaginal combined contraceptives induce an increase in markers of chronic inflammation and impair insulin sensitivity in young healthy normal-weight women: a randomized study. AB - STUDY QUESTION: What is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion, chronic inflammation, glucose tolerance and lipid profile? SUMMARY ANSWER: The use of oral, transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Oral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers, whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables. STUDY DESIGN, SIZE AND DURATION: This randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital, Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment, and serum levels of 17 hydroxyprogesterone, androstenedione, testosterone, C-reactive protein (CRP), sex hormone-binding globulin (SHBG), glucose, insulin, C-peptide, total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list, with an allocation ratio of 1:1:1 and block size of six, was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit. PARTICIPANTS AND SETTING: Forty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13), transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles, at least a 2-month washout as regards hormonal contraceptives and no medication. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI, oral: 1.3 (95% confidence interval, CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58), P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0), P= 0.004 0.024]. Levels of HDL cholesterol, triglycerides and CRP rose in all three groups [CRP, oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7, a negative value due to skewed distribution to right) mg/l, P<= 0.002 in all groups] and PTX-3 levels increased in the oral and transdermal study groups (P = 0.007 and P = 0.002). WIDER IMPLICATIONS OF THE FINDINGS: Although the long-term consequences of the present results remain undetermined, these findings emphasize the importance of monitoring glucose metabolism during the use of CCs, especially in women with known risks of type 2 diabetes or cardiovascular diseases. BIAS, LIMITATIONS, GENERALIZABILITY: The number of subjects was relatively low. Moreover, the 9-week exposure to CCs is too short to draw conclusions about the long-term health consequences. However, as the subjects were healthy, normal weight young women, the possible alterations in the glucose and inflammatory profiles among women with known metabolic risks might be even greater. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Medical Foundation, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional Fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu and the Finnish Norwegian Medical Foundation. No competing interests. TRIAL REGISTRATION NUMBER: NCT01087879. PMID- 22811307 TI - Physiological sex steroid replacement in premature ovarian failure. PMID- 22811309 TI - Anti-tubercular treatment, genital TB and infertility. PMID- 22811308 TI - Uterine leiomyomata and fecundability in the Right from the Start study. AB - BACKGROUND: Previous research suggests the removal of uterine leiomyomata may improve ability to conceive. Most of this previous research was conducted in infertility clinics. We investigated the association between leiomyoma characteristics on time to pregnancy among women enrolled from the general population. METHODS: We enrolled a cohort study of women in early pregnancy. Participants retrospectively reported their time to conception. Leiomyomata characteristics were determined by first-trimester ultrasound. We used discrete time hazard models to estimate the effects of uterine leiomyomata on time to pregnancy. RESULTS: In this population of 3000 women, 11% (324) with one or more leiomyomata, we found no association between leiomyomata presence, type, location, segment or size on time to pregnancy. CONCLUSIONS: These results suggest that leiomyomata have little effect on time to pregnancy in this cohort of women. The study excluded women who had been treated for infertility, and this may have resulted in underestimation of the association. However, differences between our study and previous studies in specialty clinics may be, in part, attributable to differences between our community-recruited population of women and women receiving fertility care, as well as difference in leiomyomata size or type in women having myomectomies to treat infertility. PMID- 22811310 TI - The zygote. PMID- 22811311 TI - Overlooking intention-to-treat results. PMID- 22811312 TI - The oocyte. PMID- 22811313 TI - The impact of androgen metabolism and FMR1 genotypes on pregnancy potential in women with dehydroepiandrosterone (DHEA) supplementation. AB - BACKGROUND: For decades androgens have been considered detrimental to follicle maturation. Animal studies now suggest that they are essential for normal folliculogenesis. Especially in women with premature ovarian aging (POA), recent IVF data in humans are supportive. The literature also suggests an association between recently reported ovarian genotypes of the FMR1 gene and ovarian aging patterns. We, therefore, attempted to determine a potential difference in androgen concentrations and androgen interactions in women with POA who do or do not become pregnant while undergoing androgen supplementation, and whether androgen concentrations and pregnancy chances are affected by FMR1 genotypes. METHODS: We longitudinally assessed androgen metabolism in 91 women with POA, following pre-supplementation with micronized dehydroepiandrosterone (DHEA) prior to IVF. IVF outcomes were assessed based on androgen levels and ovarian FMR1 genotypes. RESULTS: The mean age of the women was 39.8 +/- 4.4 years; the clinical pregnancy rate was 25.3%. Total androgen concentrations were not associated with pregnancy; however, in women with abnormal FMR1 genotypes, but not those with the normal genotype, free testosterone significantly affected clinical pregnancy potential (beta = 1.101, SE +/- 0.508, P = 0.03). At the start of the IVF cycle, interactions of DHEA with total and free testosterone also significantly affected subsequent pregnancy rates (beta = -0.058, SE +/- 0.023, P = 0.01 and beta = -0.496, SE +/- 0.197, P = 0.012). CONCLUSIONS: Androgen interactions significantly influence IVF pregnancy rates in women with POA, with the impact of total androgens on cycle outcomes varying according to FMR1 genotypes. These observations suggest that the effectiveness of androgen supplementation in women with POA varies based on FMR1 genotypes, and defines androgen deficiency as a subset of diminished ovarian reserve. PMID- 22811314 TI - Metformin exposure affects human and mouse fetal testicular cells. AB - BACKGROUND: Metformin is a drug used in the treatment of diabetes and of some disorders related to insulin resistance, such as polycystic ovary syndrome. Gestational diabetes can cause complications for both mother and child, and some studies have shown a beneficial effect of metformin during pregnancy without an increase in perinatal complications. However, the effects on the gonads have not been properly studied. Here we investigated the effect of metformin administered during pregnancy on the development and function of the fetal testis. METHODS: A dual approach in vitro and in vivo using human and mouse models was chosen. Cultures of human and murine organotypic testes were made and in vivo embryonic testes were analysed after oral administration of metformin to pregnant mice. RESULTS: In human and mouse organotypic cultures in vitro, metformin decreased testosterone secretion and mRNA expression of the main factors involved in steroid production. In vitro, the lowest observed effect concentration (LOEC) on testosterone secretion was 50 uM in human, whereas it was 500 uM in mouse testis. Lactate secretion was increased in both human and mouse organotypic cultures with the same LOEC at 500 uM as observed in other cell culture models after metformin stimulation. In vivo administration of metformin to pregnant mice reduced the testicular size of the fetal and neonatal testes exposed to metformin during intrauterine life. Although the number of germ cells was not affected by the metformin treatment, the number of Sertoli cells, the nurse cells of germ cells, was slightly yet significantly reduced in both periods (fetal period: P = 0.007; neonatal period: P = 0.03). The Leydig cell population, which produces androgens, and the testosterone content were diminished only in the fetal period at 16 days post-coitum. CONCLUSIONS: This study showed a potentially harmful effect of metformin treatment on the development of the fetal testis and should encourage future human epidemiological studies. PMID- 22811315 TI - Assessment of abnormal bowel perfusion using contrast-enhanced ultrasonography after small bowel transplantation: a case report. AB - A 59-year-old man with short-bowel syndrome received a small bowel transplantation. Because the recipient complained of severe abdominal pain 40 hours after the surgery and was highly suspected of having mesenteric vascular thrombosis, contrast-enhanced sonography (CEUS) was performed at his bedside. CEUS demonstrated that the superior mesenteric artery was patent, but the bowel graft showed hypoenhancement, indicating severely inadequate perfusion of the graft. Due to this complication, the patient underwent an exploratory laporatomy, and the bowel graft was removed. The pathologic findings support the diagnosis of acute vascular rejection after intestinal transplantation. This case suggests that CEUS can be used to assess perfusion and vascular complications after intestinal transplantation, as it is noninvasive and easily performed at bedside. PMID- 22811316 TI - Effectiveness of copper chloride in protecting against alterations induced by mercury chloride in newborn rats. AB - This work investigated the effects of copper as preventive treatment against mercury-induced alterations in young rats. Wistar rats were treated (subcutaneous) with saline or CuCl(2) . 2H(2) O (6.9 mg/kg/day) from 3 to 7 days old and with saline or HgCl(2) (5.0 mg/kg/day) from 8 to 12 days old. Rats were sacrificed 24 h after the last dose. Mercury-exposed rats presented inhibition of liver (43%) and kidney (52%) porphobilinogen (PBG)-synthase activity and serum lactic dehydrogenase activity (50%). Also, an increase of the serum creatinine and urea levels around threefold and fivefold was observed, respectively. Pre exposure to copper partially prevented the mercury effect on liver but not on kidney PBG synthase, and prevented the increase of the creatinine levels. Blood and brain PBG synthase and serum alanineaminotransferase activities, as well as glycemia, and liver glycogen content were not altered by treatments. These results show that copper, although being an essential metal, is inefficient as a preventive agent against mercury poisoning in parameters investigated after the end of mercury exposure. PMID- 22811317 TI - Neural mechanisms of rhythm perception: current findings and future perspectives. AB - Perception of temporal patterns is fundamental to normal hearing, speech, motor control, and music. Certain types of pattern understanding are unique to humans, such as musical rhythm. Although human responses to musical rhythm are universal, there is much we do not understand about how rhythm is processed in the brain. Here, I consider findings from research into basic timing mechanisms and models through to the neuroscience of rhythm and meter. A network of neural areas, including motor regions, is regularly implicated in basic timing as well as processing of musical rhythm. However, fractionating the specific roles of individual areas in this network has remained a challenge. Distinctions in activity patterns appear between "automatic" and "cognitively controlled" timing processes, but the perception of musical rhythm requires features of both automatic and controlled processes. In addition, many experimental manipulations rely on participants directing their attention toward or away from certain stimulus features, and measuring corresponding differences in neural activity. Many temporal features, however, are implicitly processed whether attended to or not, making it difficult to create controlled baseline conditions for experimental comparisons. The variety of stimuli, paradigms, and definitions can further complicate comparisons across domains or methodologies. Despite these challenges, the high level of interest and multitude of methodological approaches from different cognitive domains (including music, language, and motor learning) have yielded new insights and hold promise for future progress. PMID- 22811318 TI - Physical activity and exercise-induced bronchoconstriction in Greek schoolchildren. AB - OBJECTIVE: To investigate the association between physical activity and exercise induced bronchoconstriction (EIB) in an urban population sample of schoolchildren, taking into account potential confounders such as asthma symptoms and overweight. METHODS: Children aged 10-12 years answered validated questionnaires on physical activity (Physical Activity and Lifestyle Questionnaire) and asthma symptoms (ISAAC questionnaire), and were categorized according to their body mass index (BMI). EIB (FEV(1) decrease from baseline >=13%) was assessed by a standardized free running Exercise Challenge Test (ECT). RESULTS: Six hundred seven children completed the ECT. There were no differences among asthma groups (diagnosed asthma, asthma-related symptoms not diagnosed as asthma, no asthma-related symptoms) regarding total daily energy expenditure and time spent in mild (1.1-2.9 metabolic equivalents-METs), moderate (3-6 METs), and vigorous (>6 METs) activities. Only overweight/obese EIB-positive children had shorter duration of vigorous activity as compared to their EIB-negative or non overweight/obese EIB-positive peers. Total daily energy expenditure and duration of mild- and moderate-intensity activity were negatively associated with EIB independently of BMI status or asthma-related symptoms. CONCLUSIONS: Decreased levels of physical activity are associated with EIB irrespectively of BMI status and asthma-related symptoms. Longitudinal studies are needed to confirm the negative impact of sedentary lifestyle on the development of EIB suggested by these findings. PMID- 22811319 TI - A pore-hindered diffusion and reaction model can help explain the importance of pore size distribution in enzymatic hydrolysis of biomass. AB - Until now, most efforts to improve monosaccharide production from biomass through pretreatment and enzymatic hydrolysis have used empirical optimization rather than employing a rational design process guided by a theory-based modeling framework. For such an approach to be successful a modeling framework that captures the key mechanisms governing the relationship between pretreatment and enzymatic hydrolysis must be developed. In this study, we propose a pore-hindered diffusion and kinetic model for enzymatic hydrolysis of biomass. When compared to data available in the literature, this model accurately predicts the well-known dependence of initial cellulose hydrolysis rates on surface area available to a cellulase-size molecule. Modeling results suggest that, for particles smaller than 5 * 10(-3) cm, a key rate-limiting step is the exposure of previously unexposed cellulose occurring after cellulose on the surface has hydrolyzed, rather than binding or diffusion. However, for larger particles, according to the model, diffusion plays a more significant role. Therefore, the proposed model can be used to design experiments that produce results that are either affected or unaffected by diffusion. Finally, by using pore size distribution data to predict the biomass fraction that is accessible to degradation, this model can be used to predict cellulose hydrolysis with time using only pore size distribution and initial composition data. PMID- 22811320 TI - Characterization of the highly conserved VFMGD motif in a bacterial polyisoprenyl phosphate N-acetylaminosugar-1-phosphate transferase. AB - Polyisoprenyl-phosphate N-acetylaminosugar-1-phosphate transferases (PNPTs) constitute a family of eukaryotic and prokaryotic membrane proteins that catalyze the transfer of a sugar-1-phosphate to a phosphoisoprenyl lipid carrier. All PNPT members share a highly conserved 213-Valine-Phenylalanine-Methionine-Glycine Aspartic acid-217 (VFMGD) motif. Previous studies using the MraY protein suggested that the aspartic acid residue in this motif, D267, is a nucleophile for a proposed double-displacement mechanism involving the cleavage of the phosphoanhydride bond of the nucleoside. Here, we demonstrate that the corresponding residue in the E. coli WecA, D217, is not directly involved in catalysis, as its replacement by asparagine results in a more active enzyme. Kinetic data indicate that the D217N replacement leads to more than twofold increase in V(max) without significant change in the K(m) for the nucleoside sugar substrate. Furthermore, no differences in the binding of the reaction intermediate analog tunicamycin were found in D217N as well as in other replacement mutants at the same position. We also found that alanine substitutions in various residues of the VFMGD motif affect to various degrees the enzymatic activity of WecA in vivo and in vitro. Together, our data suggest that the highly conserved VFMGD motif defines a common region in PNPT proteins that contributes to the active site and is likely involved in the release of the reaction product. PMID- 22811321 TI - Evolutionary toxicogenomics: diversification of the Cyp12d1 and Cyp12d3 genes in Drosophila species. AB - Gene duplication and divergence are overwhelmingly considered to be the primary mechanisms by which cytochrome P450 monooxygenases (P450s) have radiated into a large and diverse gene superfamily. To address how environmental stress drives the fixation and diversification of gene duplications, we have analyzed Cyp12d1 and Cyp12d3, a pair of duplicated genes found in the sequenced Drosophila genomes of the melanogaster group. The paralog Cyp12d3, which is not found in Drosophila melanogaster, is basal to the melanogaster group, after it split from the obscura group (ca. 50 mya), and has a significant signature of positive selection in two species (D. sechellia and D. ananassae). Examination of the Cyp12d1 region in D. melanogaster wildtype and isoline populations revealed variation both in copy number and sequence, including splice-site variations, which certainly alter gene function. Further investigations of several strains have identified three cases in which differences in the Cyp12d1 gene region are associated with the differences in transcript abundance and transcriptional responses to the environmental stresses that have not been seen for other detoxificative loci. Together, these data highlight the value of using both macro- and microevolutionary approaches in studying the duplication and divergence events associated with detoxification genes and lay important groundwork for future studies in the field of evolutionary toxicogenomics, which uses the principles of phylogenetic analysis to predict possible enzymatic functions. PMID- 22811322 TI - A digestive lipase of Pieris brassicae L. (Lepidoptera: Pieridae): purification, characterization, and host plants effects. AB - The properties of a digestive lipase from the larval midgut of Pieris brassicae were studied by performing biochemical purification, characterization, effect of host plants, and extracted inhibitors. The purification process revealed a lipase with a purification fold of 42, recovery of 18.12%, molecular weight mass of 72.3 kDa, optimal pH at 11, and optimal temperature at 30 degrees C, as well as stability at the optimal temperature for 12 h. The purified enzyme was inhibited by the ions Na(+), Mn(+), Fe(2+), and Cu(2+) and the inhibitors SDS, EDTA, TTHA, and mercaptoethanol. Ca(2+) and Mg(2+) increased activity of the purified lipase, but urea, PMSF, EGTA, and DTC had no effect on enzymatic activity. Feeding of larvae on three host plants, Trepaeolus majus, Brassica olearcea var. alba, and B. olearcea var. rubra revealed the highest lipase activity on T. majus, but the two varieties of B. olearcea significantly decreased lipase activity. Extraction of a crude inhibitor from two varieties of B. olearcea demonstrated that the crude inhibitor inhibited the purified lipase up to 75%. The inhibitor changed the kinetic parameters of the enzyme by elevating the K(m), as in competitive inhibition. The data suggest a possible role for plant lipase inhibitors in host plant resistance. PMID- 22811324 TI - Are pediatricians doing more family "therapy" than they realize? Changing families through single encounters. PMID- 22811325 TI - [Myocarditis: from symptom to diagnosis]. PMID- 22811327 TI - [Therapeutic approaches in Melanoma - a paradigm for personalized medicine]. AB - Progress in molecular biology has facilitated a new classification for melanoma. Melanomas today are considered as a heterogeneous group of tumors. The different subtypes are characterized by specific genetic alterations, including mutations in kinase, such as B-RAF or c-kit. New medications like vemurafenib have been developed and are available for the systemic therapy of advanced melanomas in subpopulations identified by mutation tests. In addition, interferon therapy holds the highest promises to dates in subpopulations of patients characterized by microscopic lymph node involvement and ulceration of the primary tumor. These developments are the first steps resulting in a personalized treatment approach for individuals affected by melanoma. PMID- 22811328 TI - [Personal genomics: are we debating the right Issues?]. AB - The debate about personal genomics and their role in personalized medicine has been, to some extent, hijacked by the controversy about commercially available genomic tests sold directly to consumers. The clinical validity and utility of such tests are currently limited and most medical associations recommend that consumers refrain from testing. Conversely, DTC genomics proponents and particularly the DTC industry argue that there is personal utility in acquiring genomic information. While it is necessary to debate risks and benefits of DTC genomics, we should not lose sight of the increasingly important role that genomics will play in medical practice and public health. Therefore, and in anticipation of this shift we also need to focus on important implications from the use of genomics information such as genetic discrimination, privacy protection and equitable access to health care. Undoubtedly, personal genomics will challenge our social norms maybe more than our medicine. Sticking to the polarization of "to have or not to have DTC genomics" risks to takes us away from the critical issues we need to be debating. PMID- 22811329 TI - [Personalized medicine - legal aspects]. PMID- 22811330 TI - [Genome analysis - what does the future hold, what is science fiction? Interview by Prof. Dr. med. Johann Steurer]. PMID- 22811331 TI - [Epistaxis]. PMID- 22811332 TI - [There's not only Alzheimer's disease]. AB - We report the case of a 59 year old man with a rapidly progressive cognitive decline, neurologic symptoms and recurrent falls. One of the most important differential diagnoses was the lithiumintoxication with normal lithium blood levels. After reducing the lithiumdosis the neurological symptoms regressed completely, and only few cognitive impairments persisted. PMID- 22811333 TI - [PSA screening for 55 to 69 year old med reduced prostate cancer-specific mortality]. PMID- 22811334 TI - [Stretching before going to bed reduces the frequency and severity of nocturnal leg cramps]. PMID- 22811339 TI - Sonographic assessment of acute changes in plaque size and echogenicity and in intima-media thickness of carotid arteries after neck radiation therapy. AB - BACKGROUND: Ultrasonic assessment of acute changes in carotid artery walls before and after neck radiation therapy (RT). METHODS: Fifty cancer patients scheduled for curative neck irradiation were included and underwent sonographic examination of carotid arteries, with assessment of intima-media thickness (IMT) and plaque size and echogenicity before and immediately after completion of RT. RESULTS: IMT was linearly correlated with age and before RT (r = 0.267, p = 0.007) and increased after RT (0.68 +/- 0.11 versus 0.87 +/- 0.16, p < 0.001), without correlation with total RT dose and protocol. New plaques (six hypoechoic, one hyperechoic, and one calcified) were found in eight patients after RT, while 17 of the 44 plaques that were present before RT increased in size, and 8 soft and 1 dense plaques in nine patients became calcified. CONCLUSIONS: Radiation in the acute phase not only increases the IMT but also causes new plaque formation and changes in plaque size and echogenicity. PMID- 22811340 TI - Missing studies: obstetric and perinatal outcomes. PMID- 22811341 TI - Role of spontaneous breathing trial in predicting successful extubation in premature infants. AB - BACKGROUND: The ability of clinicians to predict successful extubation in mechanically ventilated premature neonates is limited. Identifying objective criteria for predicting successful extubation may reduce the incidence of failed extubation and the duration of mechanical ventilation. OBJECTIVE: To evaluate the validity of objective measures of lung function and spontaneous breathing trial (SBT) in predicting successful extubation among premature neonates with attempted extubations within the first 3 weeks of life. METHODS: Respiratory compliance (Crs) along with SBT was performed prior to elective extubations within 3 weeks of age in premature infants <= 32 weeks. Extubation was considered successful if patients remained extubated for > 72 hr. Ventilator settings including mean airway pressure (MAP), set rate, and fraction of inspired oxygen (FiO2) 24 hr after re-intubation were compared with pre-extubation settings, in patients requiring re-intubation. RESULTS: Thirty-nine of 49 infants (80%) were successfully extubated. Of 41 babies who passed SBT, only 5 infants failed extubation. SBT had 92% sensitivity, 50% specificity, 88% positive predictive, and 63% negative predictive value for successful extubation. Crs was comparable between infants who were successfully extubated and those who were not. CONCLUSIONS: A SBT prior to extubation may be a practical objective adjunct in predicting successful extubation in ventilated premature infants. PMID- 22811342 TI - Electronic patient-reported outcome systems in oncology clinical practice. AB - Patient-reported outcome (PRO) questionnaires assess topics a patient can report about his or her own health. This includes symptoms (eg, nausea, fatigue, diarrhea, pain, or frequent urination), physical functioning (eg, difficulty climbing stairs or difficulty fastening buttons), and mental health (eg, anxiety, fear, or worry). Electronic PRO (ePRO) systems are used in oncology clinical care because of 1) their ability to enhance clinical care by flagging important symptoms and saving clinicians time; 2) the availability of standardized methods for creating and implementing PROs in clinics; and 3) the existence of user friendly platforms for patient self-reporting like tablet computers and automated telephone surveys. Many ePRO systems can provide actionable links to clinical care such as summary reports in a patient's electronic medical record and real time e-mail alerts to providers when patients report acute needs. This review presents 5 examples of ePRO systems currently in use in oncology practice. These systems support multiple clinical activities, including assessment of symptoms and toxicities related to chemotherapy and radiation, postoperative surveillance, and symptom management during palliative care and hospice. Patient self-reporting is possible both at clinical visits and between visits over the Internet or by telephone. The implementation of an ePRO system requires significant resources and expertise, as well as user training. ePRO systems enable regular monitoring of patient symptoms, function, and needs, and can enhance the efficiency and quality of care as well as communication with patients. PMID- 22811343 TI - Alcaftadine for the prevention of itching associated with allergic conjunctivitis. AB - OBJECTIVE: To evaluate the safety and efficacy of alcaftadine for the prevention of itching associated with allergic conjunctivitis. DATA SOURCES: A medical literature search was conducted in MEDLINE/PubMed (2006-February 2012) and EMBASE (2006-February 2012) using the search terms alcaftadine and Lastacaft. References from these publications were reviewed for additional resources. Additional information was collected from Web sites of the US government (http://www.clinicaltrials.gov, http://www.fda.gov) and of Allergan Inc., the manufacturer of Lastacaft (http://www.lastacaft.com). STUDY SELECTION AND DATA EXTRACTION: All identified articles and publications in English were reviewed for pharmacology, pharmacokinetics, efficacy, and safety data. Priority was placed on clinical trials. DATA SYNTHESIS: Two published clinical trials evaluated the efficacy of alcaftadine in the prevention of ocular itching and conjunctival redness associated with allergic conjunctivitis. One trial compared alcaftadine to placebo, and another trial compared alcaftadine to placebo and olopatadine HCl to placebo. Both studies showed superior efficacy, both clinically and statistically, in the prevention of ocular itching associated with allergic conjunctivitis compared to placebo. Although conjunctival redness was evaluated in the 2 trials, neither trial demonstrated both clinical and statistical significance. Both trials demonstrated a rapid onset of action of less than 15 minutes, as well as a duration of action greater than 16 hours, which supports the use of once-daily administration. Overall, alcaftadine was well tolerated, and common adverse effects, reported in less than 4% of patients, included ocular irritation, pruritus, erythema, and stinging or burning upon instillation. Ocular adverse effects were typically mild in severity and self-limiting. CONCLUSIONS: Alcaftadine is a safe and effective option for the prevention of ocular itching associated with allergic conjunctivitis, is dosed once daily, and is competitively priced among prescription medications for allergic conjunctivitis. Additional studies are needed to further evaluate the comparative efficacy among ocular antihistamine/mast cell stabilizing medications. PMID- 22811344 TI - Prasugrel-induced rash. PMID- 22811345 TI - Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors. AB - OBJECTIVE: To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). DATA SOURCES: An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. DATA SYNTHESIS: GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. CONCLUSIONS: A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity does not impact EC MPA and bioavailability is maintained with this formulation during PPI coadministration. The clinical impact of this interaction is unknown, yet one can theorize that reduced exposure to MPA in SOT recipients can increase the risk of allograft rejection and/or failure. PMID- 22811346 TI - Strategies for transitioning therapy to aripiprazole from other antipsychotics in schizophrenia. AB - OBJECTIVE: To determine the optimal approach for transitioning therapy to aripiprazole from other antipsychotics in schizophrenia and to describe these strategies. DATA SOURCES: MEDLINE (January 2000-March 2012) and PubMed (January 2000-March 2012) searches were conducted using the search terms aripiprazole, switch, and switching. Citations from references were reviewed to identify additional primary literature. STUDY SELECTION AND DATA EXTRACTION: Articles identified as primary literature were considered for inclusion. Case series, opinion papers, and review articles were also examined. Literature was required to be in English. For evaluation purposes, included articles were randomized trials specifically comparing different switching strategies from an alternative antipsychotic to aripiprazole. Randomized trials and single-arm studies that evaluated the effect of a change to aripiprazole and reported switching methods were also reviewed but not evaluated. DATA SYNTHESIS: Aripiprazole, an atypical antipsychotic agent with a unique mechanism of action, causes fewer adverse effects when compared with other atypical antipsychotics. Patients unable to tolerate or unresponsive to their current regimens might benefit from a change to aripiprazole, but the best method for switching is unknown. Four randomized trials were identified that compared the efficacy, safety, and tolerability of at least 2 different switching strategies. The 5 strategies used a combination of immediate or titrated initiation of aripiprazole with immediate or tapered discontinuation of the current antipsychotic. A significant worsening of symptoms in the abrupt discontinuation group when compared with the combined tapered discontinuation groups was seen in 1 trial at week 2; however, all other comparisons yielded no significant differences among switching strategies. CONCLUSIONS: Strategies for transitioning therapy to aripiprazole from alternative antipsychotics in schizophrenia have been investigated in randomized trials, but studies have failed to establish a preferred method. Despite the lack of evidence, experts recommend an overlap strategy that includes maintaining the current antipsychotic dosage while titrating to a therapeutic dose of aripiprazole. PMID- 22811347 TI - Psychotropic-related hip fractures: meta-analysis of first-generation and second generation antidepressant and antipsychotic drugs. AB - BACKGROUND: In 2007, more than 18,000 adults aged 65 or older died from injuries related to falls, with up to 30% experiencing severe injuries such as hip fracture or head trauma. The economic impact of falls and fractures among older people is substantial, with direct economic consequences totaling $19 billion in 2000. OBJECTIVE: To evaluate the association between antipsychotic and antidepressant agents and the risk of hip fracture in older adults, across multiple studies. METHODS: An English-language PubMed/MEDLINE search for studies from January 1966 to January 2011 was conducted, using key words including aged, hip fracture, fractures, antidepressive agents, and antipsychotic agents, as well as individual drug names. Criteria for study inclusion were mean subject age greater than or equal to 65 years, adjusted for age and sex, hip fracture specific results provided, data specific to a drug class, subclass, or single agents, and cohort or case-controlled study design. Two authors reviewed all studies for inclusion/exclusion. A random effects model was used to calculate summary odds ratios. RESULTS: A total of 166 studies were identified in the initial search. Ten antipsychotic-related and 14 antidepressant-related studies, representing more than 70,000 hip fracture cases and approximately 270,000 subjects from 4 continents, met the inclusion criteria. Summary odds ratios (95% CI) were first-generation (conventional) antipsychotics 1.68 (1.43 to 1.99), second-generation (atypical) antipsychotics 1.30 (1.14 to 1.49), first-generation (tricyclic) antidepressants 1.71 (1.43 to 2.04), and second-generation (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and unique agents such as bupropion, mirtazapine, and trazodone) antidepressants 1.94 (1.37 to 2.76). Clear evidence of heterogeneity was noted among all antidepressant study analyses (I(2) > 87%; Q statistic p < 0.05). CONCLUSIONS: All drug classes studied-first- and second-generation antipsychotics and antidepressants-were associated with an increased risk of hip fracture in predominantly older adult populations. PMID- 22811348 TI - Oral modified-release tranexamic acid for heavy menstrual bleeding. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety profile of an oral modified-release (MR) formulation of tranexamic acid. DATA SOURCES: Literature was accessed through MEDLINE (1966-July 2012), Iowa Drug Information Service (1997-July 2012), and bibliographies of pertinent articles. Search terms included tranexamic acid, Lysteda, menorrhagia, menstrual blood loss, and heavy menstrual bleeding. STUDY SELECTION AND DATA EXTRACTION: All available English-language abstracts and human studies were identified for review. Data provided by the manufacturer and the Food and Drug Administration were also evaluated. Efficacy was evaluated in 2 clinical trials, change in quality of life was evaluated in 3 clinical trials, and safety was evaluated in 4 clinical trials. DATA SYNTHESIS: Tranexamic acid is a synthetic lysine analogue with antifibrinolytic activity. It interferes with the binding of plasminogen to fibrin, resulting in enhanced fibrin clot integrity. A novel MR formulation of oral tranexamic acid is approved for treatment of cyclic heavy menstrual bleeding. MR tranexamic acid is initiated at the beginning of heavy menstrual bleeding and can be taken for up to 5 days per cycle. Clinical trials show it to be safe and effective. Dosage adjustments are needed for women with renal insufficiency. Adverse effects are considered mild to moderate, with the most common being menstrual discomfort, headache, and back pain. The most significant safety concerns relate to the risk of thromboembolism. CONCLUSIONS: MR tranexamic acid offers a new first-line therapy for patients with cyclic heavy menstrual bleeding. It is reported to be safe and effective. There are no labeled equivalents to MR tranexamic acid for cyclic heavy menstrual bleeding. PMID- 22811349 TI - Successful treatment of extensively drug-resistant Acinetobacter baumannii peritoneal dialysis peritonitis with intraperitoneal polymyxin B and ampicillin sulbactam. AB - OBJECTIVE: To describe a case of extensively drug-resistant (XDR) Acinetobacter baumannii peritoneal dialysis (PD)-associated peritonitis successfully treated with combination antibiotics, including intraperitoneal polymyxin B, with retention of the catheter. CASE SUMMARY: A 54-year-old woman with end-stage renal disease receiving chronic PD and recent antibiotic and hospital exposure presented with abdominal pain, nausea, and vomiting. She was found to have XDR A. baumannii PD peritonitis. Treatment was initiated with intravenous and intraperitoneal ampicillin-sulbactam, followed by the addition of intraperitoneal polymyxin B based on susceptibilities. The patient recovered without the need for catheter removal or switch to hemodialysis. DISCUSSION: The frequency of XDR A. baumannii as a nosocomial pathogen is increasing, and polymyxins are being used more often as part of combination therapy for infections caused by this organism. Neither XDR A. baumannii PD peritonitis nor the use of intraperitoneal polymyxin B has been well described. In our patient, intraperitoneal dosing of polymyxin B was determined based on limited published pharmacokinetic and pharmacodynamic data. CONCLUSIONS: A case of XDR A. baumannii PD peritonitis was successfully treated with combination antibiotic therapy, including intraperitoneal polymyxin B, without major complications. PMID- 22811350 TI - Echinocandin resistance in Candida species: mechanisms of reduced susceptibility and therapeutic approaches. AB - OBJECTIVE: To summarize published data regarding mechanisms of reduced echinocandin susceptibility in Candida spp., the impact of echinocandin resistance on the fitness and virulence of Candida isolates, and current and future treatment approaches. DATA SOURCES: A search of MEDLINE databases (1966 September 2011) was conducted. STUDY SELECTION AND DATA EXTRACTION: Databases were searched using the terms echinocandin, resistance, and Candida. Citations from publications were reviewed for additional references. DATA SYNTHESIS: Echinocandins have in vitro activity against most Candida spp. and are first-line agents in the treatment of candidemia. However, case reports describing echinocandin treatment failure due to resistant isolates have been published. Reduced echinocandin susceptibility has been shown to occur via 3 main mechanisms: (1) adaptive stress responses, which result in elevated cell wall chitin content and paradoxical growth in vitro at supra minimum inhibitory concentrations (MICs); (2) acquired FKS mutations, which confer reduced glucan synthase sensitivity, elevated MICs, and are associated with clinical failure; and (3) intrinsic FKS mutations, which are naturally occurring mutations in C. parapsilosis and C. guilliermondii, which confer elevated MIC levels but a lower level of reduced glucan synthase sensitivity compared with acquired FKS mutations. Some FKS mutants have been shown to have significantly reduced fitness and virulence versus wild type isolates and may contribute to the low incidence of echinocandin resistance reported in large surveillance studies. Treatment strategies evaluated for FKS mutants include echinocandin dose escalation and combination with agents such as calcineurin inhibitors, HSP90 inhibitors, and chitin synthase inhibitors. CONCLUSIONS: While the incidence of echinocandin resistance in Candida spp. is low, it can present a significant therapeutic challenge, especially in multidrug-resistant Candida isolates. Dose escalation is unlikely to be effective in treating FKS mutant isolates, and significant adverse effects limit the clinical use of agents evaluated as combination therapy. Patients with infections failing to respond to echinocandin therapy should undergo susceptibility testing and be treated with an alternative antifungal agent if possible. PMID- 22811351 TI - Interdomain orientation of cardiac troponin C characterized by paramagnetic relaxation enhancement NMR reveals a compact state. AB - Cardiac troponin C (cTnC) is the calcium binding subunit of the troponin complex that triggers the thin filament response to calcium influx into the sarcomere. cTnC consists of two globular EF-hand domains (termed the N- and C-domains) connected by a flexible linker. While the conformation of each domain of cTnC has been thoroughly characterized through NMR studies involving either the isolated N domain (N-cTnC) or C-domain (C-cTnC), little attention has been paid to the range of interdomain orientations possible in full-length cTnC that arises as a consequence of the flexibility of the domain linker. Flexibility in the domain linker of cTnC is essential for effective regulatory function of troponin. We have therefore utilized paramagnetic relaxation enhancement (PRE) NMR to assess the interdomain orientation of cTnC. Ensemble fitting of our interdomain PRE measurements reveals that isolated cTnC has considerable interdomain flexibility and preferentially adopts a bent conformation in solution, with a defined range of relative domain orientations. PMID- 22811352 TI - The characteristics of ABO antibodies in group O Thai blood donors. AB - This study aimed to characterize anti-A and anti-B hemolysins, IgM, and IgG titers in Thai blood donors. Altogether, 300 serum samples from group O donors at the National Blood Centre, Thai Red Cross Society, were screened for anti-A and anti-B hemolysins and treated with 0.01 M dithiothreitol to characterize IgM and IgG titers by standard tube technique. Antibody titers were compared with hemolysis grade. Male and female ratio = 1:1.3 and ages ranged from 17 to 60 years. The overall prevalence of anti-A and anti-B hemolysins was 69%. Anti-A and anti-B hemolysins comprised 18.3% and 16.7%, respectively and 34% had both antibodies. High titers of anti-A hemolysins were associated with females (P< 0.05), and only anti-B IgM titers were associated with age (P< 0.05). Interestingly, the association of anti-A IgM titers, anti-A IgG titers, and hemolysin grade was demonstrated (P< 0.05). A significant association between hemolysin grade and anti-B IgM titers was found (P< 0.05). The prevalence of anti A and anti-B hemolysins and high titers of IgM and IgG in Thais are high. Hemolysin grade showed significant associations with IgM titers; therefore, when providing ABO-incompatible platelet transfusion, especially for female plateletpheresis donors, IgM high titers of anti-A and anti-B screening is suggested. PMID- 22811353 TI - The new LOCI digoxin assay on the Vista 1500 analyzer is virtually free from interferences of herbal supplements hawthorn and ashwagandha (Indian ginseng). AB - Herbal supplements hawthorn and ashwagandha (Indian ginseng) are indicated for cardiac illnesses and may be taken by patients receiving digoxin therapy. Because both hawthorn and ashwagandha are known to interfere with serum digoxin measurements using certain digoxin immunoassays, we investigated potential interference of these two herbal supplements with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of hawthorn (three different commercial preparations) or ashwagandha (two different commercial preparations) and apparent digoxin values were measured using LOCI digoxin assay on Dimension Vista 1500 analyzer we observed none-detected values except when aliquots were supplemented with very high amounts of the herbal extracts. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin) where further supplemented with various amounts of these supplements and digoxin concentrations were remeasured, statistically significant falsely higher digoxin values were observed only in specimens containing very high amounts of these supplements. Such interference may not be clinically significant. We conclude that new LOCI digoxin assay is virtually free from interferences of herbal supplements, hawthorn, and ashwagandha. PMID- 22811355 TI - Plasma amyloid-beta peptides in acute cerebral ischemia: a pilot study. AB - BACKGROUND: Blood-based tests for a rapid and valid diagnosis as well as outcome prognosis of acute stroke are desirable. Recently, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. METHODS: We investigated eight plasma samples of patients with clinical signs of acute cerebral ischemia for derangements of plasma amyloid-beta (Abeta) peptide patterns as compared to 13 patients with other neuropsychiatric diseases. For the analysis of plasma, we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. RESULTS: The major outcome was a striking decrease of Abeta1-40 in plasma paralleled by an increase in the ratio of Abeta1-38/Abeta1-40 in two patients with acute stroke. Interestingly, these patients had an onset of symptoms within only 2-4 hr before venous puncture and there was a strong correlation of Abeta1 38/Abeta1-40 levels with the time span between onset of symptoms and venous puncture. CONCLUSION: From these results, we suggest the ratio of plasma Abeta1 38/Abeta1-40 as a possible biomarker for the early diagnosis of acute stroke. PMID- 22811354 TI - Prolidase and oxidative stress in chronic hepatitis C. AB - BACKGROUND: Hepatitis C infection represents a common healthcare issue worldwide. The present trial was designed to investigate the role of prolidase, an enzyme that is significantly involved in the biosynthesis of collagen, and of the oxidative stress that is considered to be involved in the pathogenesis of various diseases, in the chronic hepatitis C infection. The trial was performed to assess the serum prolidase enzyme level and the oxidative-antioxidative status and to determine the relation between the serum prolidase activity and the oxidative stress parameters. METHODS: A total of 95 individuals, including 55 patients with chronic hepatitis C infection (CHC) and 40 healthy adults, were enrolled in the trial. The values for prolidase, the total antioxidant status (TAS), the total oxidative stress (TOS), the oxidative stress index (OSI), sulfhydryl (SH), lipid peroxidation LOOH, catalase (CAT), and ceruloplasmin were measured and compared between the patient groups. RESULTS: The prolidase, TOS, LOOH, CAT, and the OSI values were higher in the chronic hepatitis C group compared to the control group (P < 0.001). The TAS, SH, and ceruloplasmin levels were lower in the CHC group relative to the control group (P < 0.001). CONCLUSION: We suppose that the values of prolidase and the oxidative stress are increased while the antioxidant levels are decreased in CHC. As a result, prolidase and the oxidative stress seem to be related with the progression of the disease. PMID- 22811356 TI - An unusual case of a primary blood collection tube with floating separator gel. AB - We describe an unusual case of a primary evacuated blood collection tube with floating separator gel, which has been collected from a 50-year-old man submitted to a percutaneous coronary intervention (PCI). The sample was collected from the femoral artery in a primary evacuated blood collection tube containing lithium heparin. After centrifugation of the specimen, an unusual positioning of the separator gel was observed, which migrated at the topmost layer, whereas the packed blood cells remained in the middle and the plasma at the bottom. The potential interfering substance was found to be a contrast dye, 140 ml of which were administered to the patient during a revascularization procedure for acute myocardial infarction. The potential aspiration of the gel inappropriately positioned at the top of the tube by laboratory instrumentation can produce several technical and clinical problems, when not reliably detected. First, the needle of the instrument might be partially or completely obstructed by the gel, thus jeopardizing the integrity and correct functioning of the instrument. The aspiration of gel along with the sample matrix might also spuriously modify the test results, since an inappropriate amount of serum or plasma would be analyzed. PMID- 22811357 TI - Risk of overestimation of kidney function using GFR-estimating equations in patients with low inulin clearance. AB - BACKGROUND: Accurate estimation of the glomerular filtration rate (GFR) is very important in clinical practice. Although renal inulin clearance (Cin) is the gold standard for measuring GFR, the procedure for Cin measurement is complicated. Use of GFR-estimating equations has been increasing recently due to their simplicity. The objectives of the present study are to analyze the correlation between Cin and other GFR-estimating parameters and to investigate their clinical usefulness and limitation. METHODS: Seventy-two Japanese patients were enrolled in this study. Cin was measured by the continuous infusion method. Serum creatinine (s Cr), cystatin C, uric acid (UA), and hemoglobin (Hb) were measured. The Japanese formula of estimated GFR (eGFR) was as follows: eGFR (ml/min/1.73m(2) ) = 194 * s Cr(-1.094) * Age(-0.287) * 0.739 (if female). The endogenous creatinine clearance test was also performed. RESULTS: Levels of Cin were highly correlated with those of endogenous creatinine clearance (Ccr) (R(2) = 0.7585) and eGFR (R(2) = 0.5659). However, patients with lower Cin showed unexpectedly elevated levels of endogenous Ccr and eGFR. Moreover, the levels of eGFR tended to be unexpectedly increased in patients with low body surface area. CONCLUSION: Although GFR estimating equations are useful for estimating GFR accurately, they pose a risk of overestimation of kidney function in patients with decreased GFRor a poor physique. PMID- 22811358 TI - Effect of temperature and distance on the viral outcome of clinical specimens from acute flaccid paralysis cases in Nigeria. AB - AIM: The effect of cold box temperature and distance on virus titers, poliovirus isolation rate, and appearance of orphan polioviruses was investigated. METHODS: Cold boxes with stools were randomly selected and examined for internal temperature over a 7-month period. After virus isolation in Rhabdomyosarcoma (RD) cell line RDand L20B, titer calculations and intratypic differentiation were done on isolates. Sequencing and molecular studies were done on the isolates periodically in the order of arrival in the laboratory for a period of 30 months. RESULTS: Seventy-one (51.1%) boxes had the temperature range of 1 -4 degrees C, 53 (38.1%) had 4.5 -8 degrees C,. while 15 (10.8%) had temperature between 8.5 degrees C and 17.0 degrees C. Poliovirus was isolated from 24 (8.6%) specimens made up of 13 wild 1 and 2 and 11 Sabins 1, 2, 3 with titers between 10(1.8) and 10(5.4) TCID(50) /100 MUl. Temperature and titer were inversely proportional and statistically significant. (r = -0.83, P < 0.05). Distance to laboratory was not significantly related (r = -0.025) to temperature when appropriate cold box temperature was maintained. Of the 18,188 acute flaccid paralysis (AFP) specimens received in the laboratory between June 2008 and December 2010, 1,752 poliovirus isolates (9.6%) consisting of 480 wild and 82 orphans were found. A positive correlation between the distance and orphan viruses (r = 0.425; P = 0.027) was observed. CONCLUSION: While poliovirus titer depends on the inside temperature of the cold box, distance to the laboratory was found to be a predisposing factor to the appearance of orphan viruses. PMID- 22811359 TI - A comparison of INNOVANCE(r) PFA P2Y and VerifyNow P2Y12 assay for the assessment of clopidogrel resistance in patients undergoing percutaneous coronary intervention. AB - INTRODUCTION: VerifyNow P2Y12 is commonly used to measure responsiveness to clopidogrel. We sought to compare the results obtained from novel INNOVANCE(r) PFA P2Y and VerifyNow P2Y12 assay to assess the clopidogrel resistance in patients undergoing percutaneous coronary intervention. METHODS: A total of 255 patients undergoing percutaneous coronary intervention, preliminarily treated with 100 mg/day of aspirin followed by coadministration of clopidogrel (loading dose, 600 mg; maintenance dose, 75 mg/day), were enrolled in this study. Platelet aggregation was measured by INNOVANCE(r) PFA P2Y and VerifyNow P2Y12. RESULTS: INNOVANCE(r) PFA P2Y and VerifyNow P2Y12 assay showed moderate correlations with INNOVANCE(r) PFA P2Y vs. VerifyNow%inhibition: r = 0.412, P < 0.0001; INNOVANCE(r) PFA P2Yvs.VerifyNow P2Y12 reaction units (PRU): r = -0.402, P < 0.0001. The agreement between INNOVANCE(r) PFA P2Y and VerifyNow%inhibition was 85% and that of INNOVANCE(r) PFA P2Y and VerifyNow PRU was 79%. The k statistics between INNOVANCE(r) PFA P2Y and VerifyNow%inhibition and PRU were 0.52 and 0.44, respectively. CONCLUSIONS: The sensitivity of INNOVANCE(r) PFA P2Y in detecting clopidogrel resistance is comparable to that of VerifyNow P2Y12 assay. As the PFA 100(r) system is already widely used, the new test cartilage may be a useful tool for the assessment of clopidogrel effects. Additional clinical correlation studies are required to validate the effectiveness of INNOVANCE(r) PFA P2Y in predicting long-term clinical outcomes. PMID- 22811360 TI - The clinical significance of serum cystatin C in critically ill newborns with normal serum creatinine. AB - BACKGROUND: The aim of this study is to evaluate the clinical significance of cystatin C(CysC) in the newborns who show normal serum creatinine (Cr) and who are in an intensive care unit. METHODS: From July 2009 to May 2010, a total of 106 patients (53 male and 53 female newborns) in a neonatal intensive care unit at Kyung Hee Medical Center were enrolled in this study. When clinicians ordered CysC, it was tested using HiSens Cystatin-C LTIA(HBi, An-yang, Korea) on a Toshiba chemical analyzer (Toshiba, Nasushiobara, Japan). RESULTS: The range of serum Cr and CysCwas from 0.1 to 0.8 mg/dL and from 1.0 to 2.3 mg/L, respectively. CysCpresented the wider amplitude of the changes in acute renal failure. CONCLUSION: In this study, CysCwithout an increased Cr showed only a mild increase. However, CysCreflected more delicate changes in newborns than the serum Cr. This characteristic of CysCcould make it very appropriate for a pediatric population, especially for critically ill newborns. PMID- 22811361 TI - Relationship of -55C/T polymorphism of uncoupling protein 3 (UCP3) gene with metabolic syndrome by ATP III classification. AB - BACKGROUND AND AIMS: The relation of -55C/T polymorphism of uncoupling protein 3 (UCP3) with metabolic syndrome (MS) has been evaluated only in one previous study with contradictory results. The aim of our study was to investigate the association of -55C/T polymorphism of UCP3 gene with MS. DESIGN: A population of 817 obese Caucasian patients was analyzed in a cross-sectional survey. Genotype of UCP3 gene -55C/T was studied. To estimate the prevalence of MS , the definitions of the ATPIII were considered. RESULTS: Five hundred and ninety-four patients (72.7%) had the genotype -55CC (wild group), whereas 223 patients (27.3%) had the genotype -55C/T. Genotype -5TT was not detected. Prevalence of mutant UCP genotypes was similar in patients with MS (75.7% wild genotype and 24.3% mutant genotype) and without MS (69.7% wild genotype and 30.3% mutant genotype). Odds ratio of MS wild vs. mutant genotype was 1.17 CI 95%: 0.99-1.38). Total cholesterol and low density lipoprotein (LDL) cholesterol concentrations were lower in mutant-type group than wild-type group in patients with MS. No differences in other parameters were detected between genotypes in the same group of MS. CONCLUSION: -55C/T UCP polymorphism is not major risk factor for the MS. However, in mutant group of -55CC UCP3 gene in patients with MS, total cholesterol and LDL cholesterol were lower than wild-type patients. PMID- 22811362 TI - Ribonucleic acid extraction from archival formalin fixed paraffin embedded myocardial tissues for gene expression and pathogen detection. AB - INTRODUCTION: Archival tissue samples preserved in formalin are a great source of treasure for biomedical research and diagnostics. Formalin, though is a good preservative, causes the modification of nucleic acid limiting the application of fixed tissues. The present study evaluated three methods of RNA extraction for constitutive gene expression and pathogen detection. MATERIAL AND METHODS: Sixteen archival formalin-fixed paraffin-embedded (FFPE) myocardial tissues were subjected to RNA extraction by Trizol, SDS, and RNeasy FFPE kit followed by RT PCR and Taqman Real-Time PCR to study the expression of housekeeping genes. RESULTS: RNA was extracted from all 16 myocardial tissues (100%) by RNeasy FFPE kit, as compared to 14/16 by Trizol and 8/10 by SDS methods. The expression of Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)was observed in RNA extracted by RNeasy FFPE kit and Trizol. High yield of RNA was obtained by RNeasy FFPE kit than Trizol (P = 0.002) and SDS(P = 0.012). Of the three methods, RNeasy FFPE kit was evaluated for Enterovirus RNA detection in 16 other histopathologically confirmed FFPE tissues of dilated cardiomyopathy (DCM) cases and Enterovirus genome was detected in 4/16 (25%) FFPE tissues of DCM cases. The enteroviral sequences of the viral isolates revealed 99% homology with Human coxsackievirus B5. CONCLUSION: The Qiagen RNeasy FFPE kit resulted in significantly high reproducibility of RNA from FFPE myocardial tissues, which are suitable for amplification by Taq-Man Real-Time and RT-PCR. Thus, the results show that these FFPE tissues can be used for gene expression, pathogen detection, and epidemiological studies. PMID- 22811363 TI - Detection and quantification of tricyclic antidepressants and other psychoactive drugs in urine by HPLC/MS/MS for pain management compliance testing. AB - A sensitive, specific, and rapid high-pressure liquid chromatography/mass spectrometry/mass spectrometry method was developed for the quantitation of 11 tricyclic antidepressants and/or their metabolites; fluoxetine and norfluoxetine; cyclobenzaprine; and trazodone in urine. Samples were alkalinized with 0.2 N NaOH and extracted into 2 ml of hexane: ethyl acetate (1:1), evaporated to dryness, and reconstituted with 100 MUl of 20 mM ammonium formate: methanol (20:80). The chromatographic separation was performed using an Allure Biphenyl 100 * 3.2 mm, 5 MU column with a mobile phase consisting of 20 mM ammonium formate: methanol (20:80 v/v) at a flow rate of 0.5 ml/min. The detection was accomplished by multiple-reaction monitoring via electrospray ionization source operating in the positive ionization mode. The calibration curve was linear over the investigated concentration range, 25-2,000 ng/ml, for each analyte using 1.0 ml of urine. The lower limit of quantitation for each analyte was 25 ng/ml. The intra- and inter day precisions had coefficient of variation less than 15% and the accuracy was within the range from 88% to 109%. The method proved adequate for the tricyclic antidepressants analysis of urine for emergency clinical toxicology and pain management compliance testing. PMID- 22811364 TI - Serum neutrophil gelatinase-associated lipocalin and interleukin-18 as predictive biomarkers for delayed graft function after kidney transplantation. AB - BACKGROUND: Early biomarkers for acute kidney injury after kidney transplantation have been studied because delayed graft function (DGF) is associated with increased risk of acute rejection and graft loss. We investigated the usefulness of serum neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL 18) for the prediction of DGF after kidney transplantation. MATERIALS AND METHODS: Fifty-nine kidney transplant recipients were included and they were separated into DGF and immediate graft function (IGF) groups. Serum samples were collected on the preoperative day as well as days 1, 5, and 14 after the transplantation, and assayed for NGAL and IL-18. RESULTS: After transplantation, serum levels of NGAL were significantly higher at any time in patients with DGF compared to those with IGF. Serum concentrations of IL-18 were not different between both groups. The receiver operating characteristics(ROC)-area under the curve (AUC) values of NGAL, IL-18, and creatinine on day 1 for the discrimination of DGF from IGF were 0.86, 0.63, and 0.65. On POD1, the sensitivities of NGAL and creatinine were respectively 78.6%, and 50.0% at 77.8% specificity, and the AUC values for any combinations including NGAL and that for NGAL alone were higher than that of creatinine. CONCLUSION: Serum NGAL is an early and sensitive marker of graft dysfunction in kidney transplantation, while serum IL-18 showed limited values. PMID- 22811365 TI - The effect of age on the paraoxonase and arylesterase activity of pregnant mothers and their infants. AB - AIM: The study aimed to research the effect of maternal age at pregnancy on the paraoxonase (PON) and arylesterase activity levels of mothers and infants. METHOD: The study comprised 30 mothers aged more than 35 years and their infants, and 30 mothers aged under 25 years and their infants. All pregnancies had been of 38-42 weeks with normal spontaneous vaginal birth. PON and arylesterase activities were measured using paraoxon and phenylacetate substrates. RESULTS: When the PON and arylesterase enzyme activities were compared, the PON and arylesterase activity of the mothers aged more than 35 years was found to be statistically significantly lower compared to that of the mothers aged under 25 years (P = 0.006 and P = 0.03, respectively), while there was no statistically significant difference in PON and arylesterase enzyme activity between the two groups of infants (P > 0.05). CONCLUSION: While the PON and arylesterase enzyme activity of the mothers aged more than 35 years was found to be significantly lower compared to that of the mothers aged under 25 years, there was no statistical significance between the infants. This can be explained by the reduced PON and arylesterase enzyme activity during pregnancies at an older age, although this did not affect the PON and arylesterase enzyme activity of the infants. PMID- 22811366 TI - Comparative study of immunofluorescent antinuclear antibody test and line immunoassay detecting 15 specific autoantibodies in patients with systemic rheumatic disease. AB - Based on the currently proposed algorithms, antibodies specificities (sp-ANAs) are identified mainly in samples positive for fluorescent antinuclear antibodies (FANA) screening tests. The purpose of the present study was to compare diagnostic performances of FANA and line immune assay (LIA) detecting 15 sp-ANAs in patients with systemic rheumatic diseases (SRD). In 948 sera from the patients with SRD (n = 590) and non-SRD (n = 358), we evaluated the fluorescent patterns and intensities in the FANA test, and compared the FANA results with sp-ANAs against nRNP, Sm, SS-A, Ro52, SS-B, Scl-70, PM/Scl, Jo-1, CENP B, PCNA, dsDNA, nucleosome, histone, ribosomal-P, and M2. The sensitivity and specificity was 75.9% and 52.5% of FANA test and 62.0% and 84.4% of sp-ANAs test for SRD detection. The overall agreement between FANA and sp-ANAs results was 69.2% (Kappa coefficient; 0.404). According to the clinical diagnosis, the levels of agreement varied from 33.3% to 83.1%. The positive predictive values of each FANA pattern for the detection of sp-ANAs were less than 50% except for the discrete speckled pattern (91.7%). The 1:100 intensity of FANA as well as the monoreactivity of LIA, anti-SSA(-)/anti-Ro52(+), or FANA(-)/sp-ANAs(+) was associated with non-SRD. Antibodies against ribosomal-P or PCNA were specific for systemic lupus eryhthematosus. This study highlights the need for careful interpretation of FANA test results to assess sp-ANAs and the application of sp ANAs tests including less-common autoantibodies. In patients with clinical suspicion of SRD, screening with both FANA and sp-ANAs tests could improve diagnostic efficiency. PMID- 22811368 TI - Cross-section imaging with M-mode as an alternative method for the measurement of brachial artery flow-mediated vasodilation. AB - PURPOSE: Endothelial dysfunction is well known as a risk marker for initiation and progression of atherosclerosis. Flow-mediated vasodilation (FMD) of the brachial artery induced by postischemic forearm hyperemia is a widely used noninvasive method for evaluating endothelial function. M-mode ultrasonography offers high spatial and temporal resolution and is therefore suitable for diameter measurement of pulsatile vessels. We intended to compare FMD values obtained by M-mode on cross-section images and by the conventional method, ie, measurement with B-mode ultrasonography on longitudinal images. METHODS: We recruited 37 subjects (19 women, mean age: 48.3 +/- 15.2 years; range: 23-71 years) in whom we measured the brachial artery diameters at baseline and at maximum dilation after forearm ischemia. FMD was calculated as the percentage of postischemic dilation. RESULTS: Baseline (3.92 +/- 0.72 versus 3.91 +/- 0.58 mm; p = 0.97) and maximal dilated diastolic diameter (4.26 +/- 0.76 versus 4.23 +/- 0.61 mm; p = 0.84), FMD (8.98 +/- 3.84 versus 8.14 +/- 1.99%; p = 0.84), and time to maximum dilation (48.7 +/- 9.0 versus 49.3 +/- 6.4 seconds, p = 0.64) were not different between the two methods. CONCLUSIONS: M-mode brachial artery diastolic and systolic diameter measurement is feasible, suitable, and accurate for the assessment of FMD without the need for electrocardiography. PMID- 22811369 TI - Music perception and cognition: a review of recent cross-cultural research. AB - Experimental investigations of cross-cultural music perception and cognition reported during the past decade are described. As globalization and Western music homogenize the world musical environment, it is imperative that diverse music and musical contexts are documented. Processes of music perception include grouping and segmentation, statistical learning and sensitivity to tonal and temporal hierarchies, and the development of tonal and temporal expectations. The interplay of auditory, visual, and motor modalities is discussed in light of synchronization and the way music moves via emotional response. Further research is needed to test deep-rooted psychological assumptions about music cognition with diverse materials and groups in dynamic contexts. Although empirical musicology provides keystones to unlock musical structures and organization, the psychological reality of those theorized structures for listeners and performers, and the broader implications for theories of music perception and cognition, awaits investigation. PMID- 22811371 TI - Distribution of pesticides and PCBs in sediments of agricultural drains in the Culiacan Valley, Sinaloa, Mexico. AB - Agriculture is one of the most important economic activities in Sinaloa, Mexico. The Culiacan Valley is an extensive agricultural region characterized by a variety of crops with high-yield productions. In this study, concentrations of organochlorine (OCPs) and organophosphorus (OPs) pesticides and polychlorobiphenyls (PCBs) were determined in sediments of the agricultural drainage system of Culiacan Valley. Overall, 32 compounds were detected, with concentrations widely ranging from 0.03 to 1 294 ng g(-1) dry weight. OCP concentrations (15) ranged from 0.1 to 20.19 ng g(-1) dw. OP concentrations (8) ranged from 0.03 to 1294 ng g(-1) dw, and diazinon was the compound with the highest concentration. PCB concentrations were also determined and varied from 0.05 to 3.29 ng g(-1) dw. Other compounds detected included permethrin, triadimefon, and fipronil. The central zone registered the higher concentrations and the greatest number of compounds, which could be related to the occurrence of horticultural fields in this zone. According to sediment quality guidelines, the compounds exceeding the probable effect level were gamma-HCH, p,p'-DDT and p,p' DDE, while the pesticides above the maximum permissible concentration were endosulfan, azinphos methyl, diazinon, dichlorvos, and permethrin. Although Sinaloa is an important agricultural crop producer in northwest Mexico, there are not many studies dealing with pesticide distribution in agricultural areas. PMID- 22811372 TI - Groundwater iron assessment and consumption by women in rural northwestern Bangladesh. AB - In Bangladesh, approximately 97 % of the rural population uses groundwater as a drinking source. In many areas of the country this water is known to have elevated levels of iron. The contribution to iron intake that this exposure provides, and the impact on health, are unknown. In the pre- and post-monsoon seasons of 2008, we measured iron content of household tube well water, explored local water collection methods, and estimated iron intake through consumption of groundwater for 276 women of reproductive age in a rural setting in northwestern Bangladesh. Groundwater samples were analyzed for total iron (mg/L), arsenic (category of ug/L), pH, temperature ( degrees C), and oxidation-reduction potential (Eh). Participants drank [mean (SD); 2.7 (0.8) L] of water per day, all of which was collected from domestic tube wells. Total iron concentration in groundwater was high, [median (IQR) 16.3 (6.9, 28.2) mg/L], and variable throughout the area. Using this value, estimated daily iron intake [median (IQR)] was 41.1 (16.0, 71.0) mg from drinking water alone. The amount of water consumed was unrelated to its iron concentration (r = - 0.06; p = 0.33) despite potentially unpleasant organoleptic qualities of high iron content in water. Groundwater contributes substantially to daily iron intake of rural Bangladeshi women and currently represents an under-assessed potential source of dietary iron. PMID- 22811373 TI - Carotenoids and vitamins C and E in the prevention of cardiovascular disease. AB - Atherosclerotic cardiovascular diseases (CVD) are a major source of mortality and morbidity in the general population. Oxidative modification of low-density lipoprotein cholesterol (LDL-C) represents the most important determinant factor in the development and progression of atherosclerotic lesions. Oxidative damage and the production of free radicals (FRs) in the endothelium are some of the main factors involved in the pathogenesis of the atherosclerotic process that causes CVD. Appropriate nutritional practices are of central importance in managing risk and treatment of CVD; in fact, many current guidelines for a healthy general population contain nutritional recommendations to reduce the risk of these diseases. Observational studies of vitamins C and E, the most prevalent natural antioxidant vitamins, suggest that supplemental use of these vitamins may lower the risk for coronary events. Despite these data, several large, randomized controlled trials have failed to confirm the benefits of vitamin C and E in cardiovascular prevention. The aim of this review is to examine the published studies regarding the effect of vitamins (C and E) and beta-carotene supplementation in the prevention of CVD due to atherosclerosis. PMID- 22811374 TI - Bone turnover markers and vitamin D status in postmenopausal Turkish women. AB - The aim of this study was to examine some biochemical markers of bone metabolism such as C-telopeptide of type 1 collagen (CTx), procollagen I N-peptide (PINP), 25 hydroxy vitamin D [25(OH)D], parathormone (PTH), and alkaline phosphatase (total- and bone-ALP) in postmenopausal Turkish women, and to evaluate the influence of dietary factors on these parameters. This cross-sectional study comprised 70 postmenopausal and 25 premenopausal subjects from a similar socio economical status. The postmenopausal group was further stratified with regard to vitamin plus calcium supplementation. A fasting blood sample was obtained for the biochemical analysis of bone markers. Ca, P, tALP, and CTx levels were significantly higher in postmenopausal women free of supplementation than those in premenopausal period; whereas 25(OH)D concentrations were below the reference value in both groups. Supplementations of vitamin and calcium resulted in significantly lower levels of PINP in the postmenopausal group (p = 0.017). A significant association was found between plasma 25(OH)D level and frequency of fish consumption. Dietary strategies to fortify calcium and vitamin D intake should be considered to decrease the complications due to D hypovitaminosis after the onset of menopause. PMID- 22811375 TI - Abnormality in expression levels of gluconeogenesis-related genes by high-dose supplementation with pyridoxamine in mice. AB - Pyridoxamine supplementation caused the alteration of the expression of genes encoding six gluconeogenesis-related proteins. The expression levels of phosphoenolpyruvate carboxykinase, pyruvate kinase, and pyruvate dehydrogenase kinase 4 in the pyridoxamine-supplemented mice were higher than those in the control mice. In contrast, the pyridoxamine supplementation caused lower expression levels of peroxisome proliferator-activated receptor-gamma coactivator 1alpha, carbohydrate response element-binding protein, glucocorticoid receptor, and glucose-6-phosphatase. The pyridoxamine-supplemented mice showed significantly low glucose clearance in a glucose tolerance test, but they showed no symptoms of diabetes, which was estimated according to the levels of hemoglobin A1c and blood glucose. Pyruvate challenge testing suggested that pyridoxamine supplementation enhanced gluconeogenic activity from pyruvate. The results showed that a high-dose of pyridoxamine may require a careful inquiry concerning its validity. PMID- 22811376 TI - Complementary effects of multivitamin and omega-3 fatty acid supplementation on indices of cardiovascular health in individuals with elevated homocysteine. AB - Homocysteine (HCY), C-reactive protein (hsCRP), and triglycerides (TG) are risk factors for cardiovascular disease (CVD). While multivitamins (MVit) may reduce HCY and hsCRP, omega-3 fatty acids (N3) reduce TG; yet, they are seldom studied simultaneously. We randomly assigned 100 participants with baseline HCY (> 8.0 umol/L) to the daily ingestion of: (1) placebo, (2) MVit (VitC: 200 mg; VitE: 400 IU; VitB6: 25 mg; Folic Acid: 400 ug; VitB12: 400 ug) + placebo, (3) N3 (2 g N3, 760 mg EPA, 440 mg DHA)+placebo, or (4) MVit + N3 for 12 weeks. At follow-up, we observed significant reductions in HCY (umol/L) for the MVit (- 1.43, 95 %CI, - 2.39, - 0.47) and MVit + N3 groups (- 1.01, 95 %CI, - 1.98, - 0.04) groups, both being significant (p < 0.05) vs. placebo (- 0.57, 95 %CI, - 1.49, 0.35) and N3 (1.11, 95 % CI, 0.07, 2.17). hsCRP (nmol/L) was significantly reduced in the MVit (- 6.00, 95 %CI, - 1.04, - 0.15) and MVit + N3 (- 0.98, 95 %CI, - 1.51, - 0.46) groups, but not vs. placebo (- 0.15, 95 %CI, - 0.74, 0.43) or N3 (- 0.53, 95 %CI, - 1.18, 0.12). Lastly, we observed significant reductions in TG for the N3 (- 0.41, 95 %CI, - 0.69, - 0.13) and MVit + N3 (- 0.71, 95 %CI, - 0.93, - 0.46) groups, both significant vs. placebo (- 0.10, 95 %CI, - 0.36, 0.17) and MVit groups (0.15, 95 %CI, - 12, 0.42). The co-ingestion of MVit + N3 provides synergistic affects on HCY, hsCRP, and plasma TG. PMID- 22811377 TI - The relationship between vitamin D and severe early childhood caries: a pilot study. AB - INTRODUCTION: Children with Severe Early Childhood Caries (S-ECC) routinely require dental surgery. S-ECC is known to affect childhood health and well-being. The objective of this pilot study was to assess vitamin D [25(OH)D] levels and determine whether differences exist between children with and without S-ECC. METHODS: During July-September 2008, children undergoing surgery for S-ECC < 72 months of age from southern Manitoba were recruited. Age-matched controls were caries-free. Parents completed an interviewed questionnaire. A serum sample was obtained for 25(OH)D and parathyroid hormone (PTH) levels. This study was approved by the University of Manitoba's Ethics Board. Statistics included chi square analysis, t-tests, and multiple and logistic regression. A p value of <= 0.05 was significant. RESULTS: Thirty-eight children participated (50 % with S ECC). There was no significant age difference between groups (p = 0.82). The majority of the entire sample (84.2 %) had inadequate vitamin D levels. Children with S-ECC had lower concentrations of 25(OH)D (52.9 +/- 15.1 nmol/L vs. 64.4 +/- 21.3, p = 0.032) and were at twice the odds of having inadequate levels (<75 nmol/L). Children with S-ECC also had significantly higher PTH levels than caries free children (53.5 +/- 17.6 cm/L vs. 33.9 +/- 12.9, p < 0.001). A greater number with S-ECC had elevated PTH levels (68.4 % vs. 21.1 %, p < 0.01). CONCLUSIONS: This pilot study is the first to report differences in 25(OH)D between those with S-ECC and cavity-free controls. Children with S-ECC have lower vitamin D levels and increased PTH levels compared to age-matched controls. PMID- 22811378 TI - Effects of antioxidants on CD4 and viral load in HIV-infected women in sub Saharan Africa - dietary supplements vs. local diet. AB - In sub-Sahara Africa, micronutrient deficiency, especially of antioxidant micronutrients including vitamins A, C, and E, beta-carotene, selenium, zinc, and polyphenols is very common in HIV-positive patients. Amongst adults, women are the most vulnerable. Antioxidants are known to play a vital role in the immune system, reducing oxidative stress. Oxidative stress is induced by excess production of reactive oxygen species (ROS), due to the HIV infection. Such damage may be prevented or moderated through adequate oral intake of antioxidants, scavenging ROS, as well as protecting cells and tissues against oxidative stress. Antioxidants can be provided to the body through locally available antioxidant rich-diets such as fruit-and-vegetable-based diets and/or dietary supplements. Provision of antioxidants through local diets or dietary supplements exercise beneficial effects on biological markers of the immune system (CD4 and viral load). However, while dietary supplements represent a costly and short-term strategy to limiting antioxidant deficiency, local diets, combined with adequate nutritional education, can provide a low-cost and long term strategy to reduce oxidative stress, prevent micronutrient deficiency, and slow down HIV disease progression. The former can be applicable in countries around the West, Central, and South coast of Africa, which are rich in natural food resources. In contrast with significant evidence that dietary supplements confer benefits in HIV patients, fewer data are available relating to the benefits of local diets. Thus the need to do more research in this area arises. This review compares available data on effects of antioxidants on CD4 and viral load in HIV-positive women noneligible for antiretroviral therapy. Intake of antioxidants though dietary supplements and local diet, associated with nutritional education, is compared. Studies conducted in sub-Sahara Africa are considered. PMID- 22811379 TI - Unconventional chain-growth mode in the assembly of colloidal gold nanoparticles. PMID- 22811380 TI - Comparison of designed and randomly generated catalysts for simple chemical reactions. AB - There has been recent success in designing enzymes for simple chemical reactions using a two-step protocol. In the first step, a geometric matching algorithm is used to identify naturally occurring protein scaffolds at which predefined idealized active sites can be realized. In the second step, the residues surrounding the transition state model are optimized to increase transition state binding affinity and to bolster the primary catalytic side chains. To improve the design methodology, we investigated how the set of solutions identified by the design calculations relate to the overall set of solutions for two different chemical reactions. Using a TIM barrel scaffold in which catalytically active Kemp eliminase and retroaldolase designs were obtained previously, we carried out activity screens of random libraries made to be compositionally similar to active designs. A small number of active catalysts were found in screens of 103 variants for each of the two reactions, which differ from the computational designs in that they reuse charged residues already present in the native scaffold. The results suggest that computational design considerably increases the frequency of catalyst generation for active sites involving newly introduced catalytic residues, highlighting the importance of interaction cooperativity in enzyme active sites. PMID- 22811381 TI - Infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis. PMID- 22811382 TI - Authorship ethics with the dissertation manuscript option. PMID- 22811383 TI - Patient decision aids for cancer treatment: are there any alternatives? AB - BACKGROUND: Although patient decision aids (pDAs) are effective, widespread use of pDAs for cancer treatment has not been achieved. The objectives of this study were to perform a systematic review to identify alternate types of decision support interventions (DSIs) for cancer treatment and a meta-analysis to compare the effectiveness of these DSIs to pDAs. METHODS: The inclusion criteria for the study were: 1) all published studies using a randomized, controlled trial design, and 2) DSIs involving treatment decision-making for breast, prostate, colorectal, and/or lung cancer. For this analysis, DSIs were classified as pDAs if: 1) one reported outcome measure mapped onto the International Patient Decision Aids Standards Collaboration effectiveness criterion, and 2) the DSI was evaluated relative to standard consultation. Random effects models were used to compare the effectiveness of pDAs relative to other identified DSIs for reported outcomes. RESULTS: A total of 71 studies were reviewed, and 24 met the inclusion criteria. Overall, there were no significant differences in knowledge, satisfaction, anxiety, or decisional conflict scores between pDAs and other DSIs. CONCLUSIONS: This study showed that the effectiveness of other DSIs, including question prompt lists and audiorecording of the consultation, is similar to pDAs. This is important because it may be that these less complex DSIs may be all that is necessary to achieve similar outcomes as pDAs for cancer treatment. PMID- 22811384 TI - Cognitive science and the cultural nature of music. AB - The vast majority of experimental studies of music to date have explored music in terms of the processes involved in the perception and cognition of complex sonic patterns that can elicit emotion. This paper argues that this conception of music is at odds both with recent Western musical scholarship and with ethnomusicological models, and that it presents a partial and culture-specific representation of what may be a generic human capacity. It argues that the cognitive sciences must actively engage with the problems of exploring music as manifested and conceived in the broad spectrum of world cultures, not only to elucidate the diversity of music in mind but also to identify potential commonalities that could illuminate the relationships between music and other domains of thought and behavior. PMID- 22811386 TI - An acyclic imino-substituted silylene: synthesis, isolation, and its facile conversion into a zwitterionic silaimine. AB - A new type of Si(II): A novel silylene stabilized by a Cp* and an imidazolin-2 iminato ligand has been prepared using two different methods. The X-ray crystallographic structure shows that the silicon(II) center is coordinated to an eta(2)-Cp* ligand and the nitrogen atom of an imidazolin-2-iminato ligand. This silylene easily reacts with B(C(6)F(5))(3) to give a stable borane adduct having a zwitterionic resonance structure. PMID- 22811388 TI - Cheap and long-life reusable polymer for asymmetric organozinc catalysis based on camphor-derived hydroxyamides. AB - Polystyrene grafted with a chiral zinc-complexing camphor-derived N,N disubstituted hydroxyamide is proposed as a new type of functional polymer of high reusability for the development of sustainable organozinc-catalyzed asymmetric reactions. The main goal of this new functional polymer is the ease of the hydroxyamide-moiety preparation (cheap chiral ligand obtained straightforwardly from an enantiopure starting material coming from the chiral pool), as well as its chemical robustness when compared with other related zinc complexing functional groups. The latter allows the polymer to be active after multiple applications, without significant loss of its catalytic activity. This fact is exemplified by the design and preparation of a polymer functionalized with a bis(hydroxyamide) proved previously as active in the homogeneous enantioselective addition of diethylzinc to aldehydes. The result is a cheap functional polymer with a very high reusability (the enantioselectivity and chemical yield are maintained practically constant after 20 applications). Additionally, a methodology for the multicycle use of these functional polymers is presented. PMID- 22811389 TI - An Editor's last editorial. PMID- 22811387 TI - Domain organization of XAF1 and the identification and characterization of XIAP(RING) -binding domain of XAF1. AB - X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) has been implicated as a novel tumor suppressor, which was proposed to exert pro apoptotic effect by antagonizing the anticaspase activity of XIAP. Here, we delineated the domain architecture of XAF1 by applying limited proteolysis and peptide mass fingerprinting analysis. Our results indicated that XAF1 has a distinct domain organization, with a highly compact N-terminal domain (XAF1(NTD) ) followed by a middle domain (XAF1(MD) ), a 42-residue unstructured linker and a C-terminal domain (XAF1(CTD) ). The search of XIAP binding region within XAF1 revealed that a modest affinity XIAP(RING) binding site (dissociation constant, K(d) , ~18 MUM) is located at the C-terminal portion of XAF1. This C-terminal region, embracing XAF1(CTD) and a flexible tail at C-terminus (residue Thr251 Ser301), is functionally identified as XIAP(RING) -binding domain of XAF1 (XAF1(RBD) ) in the present study. We have also mapped the interaction sites for XAF1(RBD) on XIAP(RING) by using NMR spectroscopy. By applying in vitro ubiquitination assay, we observed that XAF1(RBD) /XIAP interaction is essential for the ubiquitination of GST-XAF1(RBD) fusion protein. In addition, the C terminal XAF1 fragment harboring XAF1(RBD) was found to be substantially ubiquitinated by XIAP(RING) . Base on these observations, we speculate a possible role of XAF1(RBD) in targeting XAF1 for XIAP-mediated ubiquitination. PMID- 22811391 TI - Music cognition: a developmental perspective. AB - Although music is universal, there is a great deal of cultural variability in music structures. Nevertheless, some aspects of music processing generalize across cultures, whereas others rely heavily on the listening environment. Here, we discuss the development of musical knowledge, focusing on four themes: (a) capabilities that are present early in development; (b) culture-general and culture-specific aspects of pitch and rhythm processing; (c) age-related changes in pitch perception; and (d) developmental changes in how listeners perceive emotion in music. PMID- 22811390 TI - BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. AB - BACKGROUND: Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. METHODS: Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia-BRCA pathway. Ten cases with < 10% serous histology were also assessed. RESULTS: Seven subjects (4.6%) carried germline loss-of-function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. CONCLUSIONS: Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations. PMID- 22811392 TI - White fluorescence from core-shell silica nanoparticles. AB - Into the white: Encapsulation of a naphthalimide moiety in the core of silica nanoparticles afforded nanospheres with a strong green excimeric emission. Together with the blue emission of the monomeric naphthalimide and the yellow fluorescence of the tetrazine acceptor on the outer shell, the added contributions provide intense white fluorescence upon 330 nm UV excitation. PMID- 22811393 TI - Adsorption features of flavonoids on macroporous adsorption resins functionalized with ionic liquids. AB - A series of macroporous adsorption resins (MARs) with novel structures is synthesized via Friedel-Crafts catalyzed reaction. The adsorption kinetics of the synthetic resins with respect to the purification effect is systematically investigated by means of the response surface methodology (RSM). The kinetic data cannot be fitted to the classical model because it does not take multicompartments and desorption rates into consideration. A new multicompartment louver-tide theory is thus developed considering that adsorption is an indefinite dynamic equilibrium process, which can be divided into innumerable ingredients with different desorption rates. This theory produces much better fits to the experimental data and provides a quantitative explanation with multicompartments and adsorption/desorption rates. PMID- 22811395 TI - Can this manuscript be saved? PMID- 22811394 TI - Multistate approaches in computational protein design. AB - Computational protein design (CPD) is a useful tool for protein engineers. It has been successfully applied towards the creation of proteins with increased thermostability, improved binding affinity, novel enzymatic activity, and altered ligand specificity. Traditionally, CPD calculations search and rank sequences using a single fixed protein backbone template in an approach referred to as single-state design (SSD). While SSD has enjoyed considerable success, certain design objectives require the explicit consideration of multiple conformational and/or chemical states. Cases where a "multistate" approach may be advantageous over the SSD approach include designing conformational changes into proteins, using native ensembles to mimic backbone flexibility, and designing ligand or oligomeric association specificities. These design objectives can be efficiently tackled using multistate design (MSD), an emerging methodology in CPD that considers any number of protein conformational or chemical states as inputs instead of a single protein backbone template, as in SSD. In this review article, recent examples of the successful design of a desired property into proteins using MSD are described. These studies employing MSD are divided into two categories--those that utilized multiple conformational states, and those that utilized multiple chemical states. In addition, the scoring of competing states during negative design is discussed as a current challenge for MSD. PMID- 22811396 TI - Pre-melting structure transformation of water clusters in nanoporous molecular crystals. PMID- 22811397 TI - Synthesis and antimicrobial activities of oximes derived from O benzylhydroxylamine as FabH inhibitors. AB - Forty-three oxime derivatives were synthesized by allowing O-benzylhydroxylamines to react with primary benzaldehydes or salicylaldehydes; these products were gauged as potential inhibitors of beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH). Among the 43 compounds, 38 are reported herein for the first time. These compounds were assayed for antimicrobial activities against Escherichia coli, Pseudomonas aeruginosa, Pseudomonas fluorescens, Bacillus subtilis, Staphylococcus aureus, and Enterococcus faecalis. Compounds with prominent antibacterial activities were tested for their E. coli FabH inhibitory activities. 3-((2,4-Dichlorobenzyloxyimino)methyl)benzaldehyde O-2,4 dichlorobenzyl oxime (44) showed the best antibacterial activity, with minimum inhibitory concentrations of 3.13-6.25 MUg mL(-1) against the tested bacterial strains, exhibiting the best E. coli FabH inhibitory activity, with an IC(50) value of 1.7 mM. Docking simulations were performed to position compound 44 into the E. coli FabH active site in order to determine the most probable binding conformation. PMID- 22811398 TI - Dinuclear gold catalysis: are two gold centers better than one? PMID- 22811399 TI - One-step electrodeposition to layer-by-layer graphene-conducting-polymer hybrid films. AB - One-step fabrication of graphene-polyaniline (graphene-PANI) hybrid film was facilely achieved by cyclic voltammetric electrolysis of a bath containing both graphene oxide (GO) and aniline, where graphene is obtained by electrochemical reduction of GO and PANI is simultaneously obtained by aniline electropolymerization. As there is no strong attraction between aniline and GO under the electrodeposition conditions, the independent depositions of PANI and reduced GO nanosheets at their greatly differed potentials led to alternate layered graphene-PANI films, with the topmost layer being PANI particles or graphene sheets just by changing the initial scan directions. The two kinds of graphene-PANI hybrid films present excellent but different electrical and electrochemical behaviors. PMID- 22811400 TI - High thermal responsiveness of a reduced graphene oxide field-effect transistor. PMID- 22811401 TI - Dialkyl-14H-benzo[4,5]isoquino[2,3-a]perimidin-14-one-3,4,10,11-tetracarboxylic diimides: a new family of n-type organic semiconductors. PMID- 22811402 TI - Ceria in hydrogenation catalysis: high selectivity in the conversion of alkynes to olefins. AB - Active and selective: Ceria shows a high activity and selectivity in the gas phase hydrogenation of alkynes to olefins. This unprecedented behavior has direct impact on the purification of olefin streams and, more importantly, it opens new perspectives for exploring this fascinating oxide as a catalyst for the selective hydrogenation of other functional groups. PMID- 22811403 TI - Quantifying large effects of framework flexibility on diffusion in MOFs: CH4 and CO2 in ZIF-8. AB - Breathe in, breathe out: efficient methods are introduced for assessing the role of framework flexibility on molecular diffusion in metal-organic frameworks (MOFs) that does not require defining a classical forcefield for the MOF. These methods combine ab initio MD of the MOF with classical MD simulation of the diffusing molecules. The effects of flexibility are shown to be large for CH(4), but not for CO(2), in ZIF-8. PMID- 22811404 TI - Emergency management of bleeding associated with old and new oral anticoagulants. AB - As major prescribers of oral anticoagulants, cardiologists must be familiar with strategies to manage bleeding, the principal complication associated with all anticoagulants, and to reverse anticoagulant effects in acute-care settings. The purpose of this manuscript is to review currently available information regarding dabigatran and rivaroxaban, the 2 novel oral anticoagulants approved to date in the United States. Further, we suggest reasonable interventions for the clinician faced with a patient who suffers a major bleeding event while receiving one of these agents. Data sources were peer-reviewed publications, US Food and Drug Administration documents in the public domain, and approved US prescribing information for dabigatran (Pradaxa) and rivaroxaban (Xarelto). Strategies for management of bleeding and reversal of anticoagulant effects from warfarin include vitamin K, fresh frozen plasma, and prothrombin complex concentrates. For rivaroxaban and dabigatran, appropriate therapies include support and observation, which are likely to be effective for the majority of patients because of the short half-lives of these agents. In severe life-threatening hemorrhage, clotting-factor substitutes may be appropriate in certain situations. Validated protocols specific to each agent remain to be developed. PMID- 22811406 TI - At the frontiers of knowledge in chemistry: the 47th Burgenstock Conference. PMID- 22811405 TI - Strategies for the synthesis of poly(2-oxazoline)-based hydrogels. AB - Poly(2-oxazoline)-based networks currently receive great interest due to their versatile properties that can be tailor made by desktop-planned modifications. This feature summarizes strategies for the preparation of these networks, comprising the in situ cross-linking as well as polymer-analogous cross-linking routines such as (reversible) complex formation, physical processes, and covalent bond formation (involving reactions with olefinic species as well as with epoxides, isocyanates, aldehydes, acids, and their derivatives). Reflecting prominent application examples in the biomedic(in)al sector, poly(2-oxazoline)-co polyester networks are described in a dedicated section. PMID- 22811407 TI - High-performance lithium-ion anodes with hierarchically assembled single-crystal SnO2 nanoflake spheres. AB - A large-scale hierarchical assembly route is reported for the formation of SnO(2) on the nanoscale that contains rigid and robust spheres with irregular channels for rapid access of Li ions into the hierarchically structured interiors. Large volume changes during the process of Li insertion and extraction are accommodated by the SnO(2) nanoflake spheres' internal porosity. The hierarchical SnO(2) nanoflake spheres exhibit good lithium storage properties with high capacity and long-lasting performance when used as lithium-ion anodes. A reversible capacity of 517 mA h g(-1), still greater than the theoretical capacity of graphite (372 mA h g(-1)), after 50 charge-discharge cycles is attained. Meanwhile, the synthesis process is simple, inexpensive, safe, and broadly applicable, providing new avenues for the rational engineering of electrode materials with enhanced conductivity and power. PMID- 22811408 TI - Prognostic significance of high nuclear grade in patients with pathologic T1a renal cell carcinoma. AB - OBJECTIVE: A reliable prognostic indicator in patients with pathologic T1a renal cell carcinoma has not yet been fully elucidated. The aim of this study was to investigate the prognosis of pathologic T1a renal cell carcinoma cases with a special focus on pathological factors. METHODS: The study population consisted of 338 patients diagnosed with solitary renal cell carcinoma at our hospital between 1996 and 2009. The relationship between disease progression and clinicopathologic features was analyzed retrospectively to determine if it affected recurrence and distant metastasis. RESULTS: The Fuhrman nuclear grade distribution between the tumors was 1, 2, 3 and 4 in 68 (20.1%), 242 (71.6%), 21 (6.2%) and 7 cases (2.1%), respectively. A total of 11 subjects were identified as having recurrent tumors (3.3%), 9 of whom had metastatic lesions. Multivariate analysis showed that the appearance of tumor Grade 3 and 4 (hazard ratio: 13.0, 95% confidence interval: 3.90-43.0, P < 0.001) was an independent risk factor for tumor recurrence, while no significant correlation was found between tumor recurrence and age, gender, tumor side, tumor size, surgical methods, histology, microvascular invasion or surgical margin status. The 5-year recurrence-free survival rate was 67.8% in patients with a high nuclear grade tumor, and 96.8% in their counterparts. CONCLUSIONS: High nuclear grade is possibly one of the most important prognostic factors for predicting tumor recurrence and metastasis after surgery in pathologic T1a renal cell carcinoma. Thus, careful follow-up may be required in patients with pathologic T1a renal cell carcinoma of a high nuclear grade. PMID- 22811409 TI - Comparison of treatment outcomes between involved-field and elective nodal irradiation in limited-stage small cell lung cancer. AB - OBJECTIVE: The present study was performed to assess the usefulness of involved field irradiation and the impact of (18)F-fluorodeoxyglucose-positron emission tomography-based staging on treatment outcomes in limited-stage small cell lung cancer. METHODS: Eighty patients who received definitive chemoradiotherapy for limited-stage small cell lung cancer were retrospectively analyzed. Fifty patients were treated with involved-field irradiation, which means that the radiotherapy portal includes only clinically identifiable tumors. The other 30 patients were irradiated with a comprehensive portal, including uninvolved mediastinal and/or supraclavicular lymph nodes, so-called elective nodal irradiation. No significant difference was seen in clinical factors between the two groups. RESULTS: At a median follow-up of 27 months (range, 5-75 months), no significant differences were observed in 3 year overall survival (44.6 vs. 54.1%, P= 0.220) and 3 year progression-free survival (24.4 vs. 42.8%, P= 0.133) between the involved-field irradiation group and the elective nodal irradiation group, respectively. For patients who did not undergo positron emission tomography scans, 3 year overall survival (29.3 vs. 56.3%, P= 0.022) and 3 year progression free survival (11.0 vs. 50.0%, P= 0.040) were significantly longer in the elective nodal irradiation group. Crude incidences of isolated nodal failure were 6.0% in the involved-field irradiation group and 0% in the elective nodal irradiation group, respectively. All isolated nodal failures were developed in patients who had not undergone positron emission tomography scans in their initial work-ups. CONCLUSION: If patients did not undergo positron emission tomography-based staging, the omission of elective nodal irradiation resulted in impaired survival outcomes and raised the risk of isolated nodal failure. Therefore, involved-field irradiation for limited-stage small cell lung cancer might be reasonable only with positron emission tomography scan implementation. PMID- 22811410 TI - Long-term follow-up of a randomized Phase II study of cisplatin/5-FU concurrent chemoradiotherapy for esophageal cancer (KROSG0101/JROSG021). AB - OBJECTIVE: Long-term survival and late toxicities of a randomized Phase II study of chemoradiotherapy for esophageal cancer were analyzed. METHODS: Eligible patients were <75 years old and performance status 0-2, and had Stages II-IVA esophageal cancer. For arm A (short-term infusion), cisplatin 70 mg/m(2) Days 1 and 29 and 5-fluorouracil 700 mg/m(2) Days 1-5 and 29-33 were given concurrently with radiotherapy of 60 Gy/30 fr/7 weeks (1 week split). For arm B (protracted infusion), cisplatin 7 mg/m(2) Days 1-5, 8-12, 29-33 and 36-40, and 5 fluorouracil 250 mg/m(2) Days 1-14 and 29-42 were given with the same radiotherapy. Two cycles of consolidation cisplatin/5-fluorouracil chemotherapy were given to both arms. RESULTS: Between 2001 and 2006, 91 patients were enrolled; 46 were randomized to arm A, and 45 to arm B. The 2- and 5-year overall survival rates for arm A were 46 and 35% (95% confidence interval: 22-48%), while those for arm B were 44 and 22% (11-35%), respectively. Excluding four patients with early death, seven (17%) patients in arm A and eight (18%) in arm B showed late toxicities of Grade 3 or more. Most of the toxicities were cardiac or pleural toxicities. Patients with severe late toxicities often had coexistent hypothyroidism. There were three patients with a secondary malignancy possibly related to treatment. CONCLUSIONS: Low-dose protracted infusion chemotherapy with radiotherapy is not superior to full-dose short-term infusion chemotherapy with radiotherapy for esophageal cancer. Late toxicities, including cardiac and pleural toxicities, hypothyroidism and secondary malignancy, should be carefully monitored. PMID- 22811411 TI - Diminished responsiveness to human beta-defensin-3 and decreased TLR1 expression on monocytes and mDCs from HIV-1-infected patients. AB - hBD-3 is an antimicrobial peptide that may contribute to adaptive immune responses by activating professional APCs via a TLR1/2-dependent mechanism. Patients with HIV disease experience increased susceptibility to mucosal infections, which may, in part, stem from diminished APC function. Our current studies demonstrate a reduced capacity of hBD-3 to induce the expression of a costimulatory molecule, CD80, on monocytes and mDCs from HIV-infected persons compared with cells from healthy controls. Although the expression of TLR1 and TLR2 on monocytes was not a strong predictor of hBD-3 responsiveness in bivariate analyses, monocytes and mDCs from HIV-infected persons expressed significantly lower levels of TLR1. Monocyte expression of the activation marker CD69, in cells from HIV-infected persons with therapeutically controlled viremia, was correlated directly with TLR2 and TLR4 expression but not with TLR1 expression. Overall, these studies suggest that immune activation may affect TLR2 and TLR4 expression but may not fully account for reduced TLR1 expression in monocytes from HIV infected persons. Impairments in hBD-3 responsiveness and TLR1 expression are likely to contribute to increased risk of mucosal infection in HIV disease. PMID- 22811412 TI - Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine. AB - The multiple transmembrane protein Niemann-Pick C1 like1 (NPC1L1) is essential for intestinal cholesterol absorption. Ezetimibe binds to NPC1L1 and is a clinically used cholesterol absorption inhibitor. Recent studies in cultured cells have shown that NPC1L1 mediates cholesterol uptake through vesicular endocytosis that can be blocked by ezetimibe. However, how NPC1L1 and ezetimibe work in the small intestine is unknown. In this study, we found that NPC1L1 distributed in enterocytes of villi and transit-amplifying cells of crypts. Acyl CoA cholesterol acyltransferase 2 (ACAT2), another important protein for cholesterol absorption by providing cholesteryl esters to chylomicrons, was mainly presented in the apical cytoplasm of enterocytes. NPC1L1 and ACAT2 were highly expressed in jejunum and ileum. ACAT1 presented in the Paneth cells of crypts and mesenchymal cells of villi. In the absence of cholesterol, NPC1L1 was localized on the brush border of enterocytes. Dietary cholesterol induced the internalization of NPC1L1 to the subapical layer beneath the brush border and became partially colocalized with the endosome marker Rab11. Ezetimibe blocked the internalization of NPC1L1 and cholesterol and caused their retention in the plasma membrane. This study demonstrates that NPC1L1 mediates cholesterol entering enterocytes through vesicular endocytosis and that ezetimibe blocks this step in vivo. PMID- 22811414 TI - In search of vulnerable plaque. PMID- 22811415 TI - Myocardial crypts: a prephenotypic marker of hypertrophic cardiomyopathy? PMID- 22811413 TI - The PCSK9 decade. AB - PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. In recent years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 concerning the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. As PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases. PMID- 22811416 TI - Emerging role of multimodality imaging to evaluate patients at risk for sudden cardiac death. PMID- 22811418 TI - Acute myocardial infarction secondary to thrombosis in the right coronary sinus of Valsalva. PMID- 22811417 TI - Non-ST-segment elevation acute coronary syndromes: targeted imaging to refine upstream risk stratification. PMID- 22811419 TI - Congenital absence of the left atrial appendage. PMID- 22811420 TI - Circulation: Cardiovascular Imaging editors' picks: Most important articles in clinical translation of novel imaging technologies (part 2). AB - The following articles are being highlighted as part of Circulation: Cardiovascular Imaging's Topic Review. This series summarize the most important articles, as selected by the editors, that have been published in the Circulation portfolio. The studies included in this article represent the most significant research in clinical translation of novel imaging technologies. PMID- 22811421 TI - Letter by Obeyesekere regarding article, "Combined cardiac magnetic resonance imaging and C-reactive protein levels identify a cohort at low risk for defibrillator firings and death". PMID- 22811424 TI - Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. AB - The interstitium describes the fluid, proteins, solutes, and the extracellular matrix (ECM) that comprise the cellular microenvironment in tissues. Its alterations are fundamental to changes in cell function in inflammation, pathogenesis, and cancer. Interstitial fluid (IF) is created by transcapillary filtration and cleared by lymphatic vessels. Herein we discuss the biophysical, biomechanical, and functional implications of IF in normal and pathological tissue states from both fluid balance and cell function perspectives. We also discuss analysis methods to access IF, which enables quantification of the cellular microenvironment; such methods have demonstrated, for example, that there can be dramatic gradients from tissue to plasma during inflammation and that tumor IF is hypoxic and acidic compared with subcutaneous IF and plasma. Accumulated recent data show that IF and its convection through the interstitium and delivery to the lymph nodes have many and diverse biological effects, including in ECM reorganization, cell migration, and capillary morphogenesis as well as in immunity and peripheral tolerance. This review integrates the biophysical, biomechanical, and biological aspects of interstitial and lymph fluid and its transport in tissue physiology, pathophysiology, and immune regulation. PMID- 22811423 TI - Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. AB - Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O(2)-regulated HIF-1alpha or HIF-2alpha subunit and a constitutively expressed HIF-1beta subunit. Induction of HIF activity under conditions of reduced O(2) availability requires stabilization of HIF-1alpha and HIF-2alpha due to reduced prolyl hydroxylation, dimerization with HIF-1beta, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O(2) sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1alpha and HIF-2alpha that causes oxidative stress, leading to cardiorespiratory pathology. PMID- 22811425 TI - Role of the gut in lipid homeostasis. AB - Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors. PMID- 22811428 TI - Kisspeptins and reproduction: physiological roles and regulatory mechanisms. AB - Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function. PMID- 22811429 TI - Dynamic of ion channel expression at the plasma membrane of cardiomyocytes. AB - Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine tune ion channel expression and control cardiac excitability. PMID- 22811427 TI - End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. AB - The synapse is a localized neurohumoral contact between a neuron and an effector cell and may be considered the quantum of fast intercellular communication. Analogously, the postsynaptic neurotransmitter receptor may be considered the quantum of fast chemical to electrical transduction. Our understanding of postsynaptic receptors began to develop about a hundred years ago with the demonstration that electrical stimulation of the vagus nerve released acetylcholine and slowed the heart beat. During the past 50 years, advances in understanding postsynaptic receptors increased at a rapid pace, owing largely to studies of the acetylcholine receptor (AChR) at the motor endplate. The endplate AChR belongs to a large superfamily of neurotransmitter receptors, called Cys loop receptors, and has served as an exemplar receptor for probing fundamental structures and mechanisms that underlie fast synaptic transmission in the central and peripheral nervous systems. Recent studies provide an increasingly detailed picture of the structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction. PMID- 22811432 TI - Atomic imaging and spectroscopy of low-dimensional materials with interrupted periodicities. AB - Identification of individual atoms and examination of their electronic properties in materials are the ultimate goal of all microscopy-based analytical techniques. Here, we demonstrate successful single-atom imaging and spectroscopy in low dimensional materials using (scanning) transmission electron microscopy together with electron energy-loss spectroscopy (EELS). Edges and point defects in single layered materials such as graphene, hexagonal boron nitride and WS(2) nanoribbons are investigated by annular dark-field imaging and EELS fine-structure analysis. Individual dopant atoms are unambiguously identified in nano-peapods. It is noteworthy that irradiation damage and specimen contamination even at the single atom level are crucial issues in these experiments. PMID- 22811433 TI - Availability of Rubisco small subunit up-regulates the transcript levels of large subunit for stoichiometric assembly of its holoenzyme in rice. AB - Rubisco is composed of eight small subunits coded for by the nuclear RBCS multigene family and eight large subunits coded for by the rbcL gene in the plastome. For synthesis of the Rubisco holoenzyme, both genes need to be expressed coordinately. To investigate this molecular mechanism, the protein synthesis of two subunits of Rubisco was characterized in transgenic rice (Oryza sativa) plants with overexpression or antisense suppression of the RBCS gene. Total RBCS and rbcL messenger RNA (mRNA) levels and RBCS and RbcL synthesis simultaneously increased in RBCS-sense plants, although the increase in total RBCS mRNA level was greater. In RBCS-antisense plants, the levels of these mRNAs and the synthesis of the corresponding proteins declined to a similar extent. The amount of RBCS synthesized was tightly correlated with rbcL mRNA level among genotypes but not associated with changes in mRNA levels of other major chloroplast-encoded photosynthetic genes. The level of rbcL mRNA, in turn, was tightly correlated with the amount of RbcL synthesized, the molar ratio of RBCS synthesis to RbcL synthesis being identical irrespective of genotype. Polysome loading of rbcL mRNA was not changed. These results demonstrate that the availability of RBCS protein up-regulates the gene expression of rbcL primarily at the transcript level in a quantitative manner for stoichiometric assembly of Rubisco holoenzyme. PMID- 22811434 TI - Cytokinin activity of cis-zeatin and phenotypic alterations induced by overexpression of putative cis-Zeatin-O-glucosyltransferase in rice. AB - cis-Zeatin (cZ) is generally regarded as a cytokinin with little or no activity, compared with the highly active trans-zeatin (tZ). Although recent studies suggested possible roles for cZ, its physiological significance remains unclear. In our studies with rice (Oryza sativa), cZ inhibited seminal root elongation and up-regulated cytokinin-inducible genes, and its activities were comparable to those of tZ. Tracer experiments showed that exogenously supplied cZ-riboside was mainly converted into cZ derivatives but scarcely into tZ derivatives, indicating that isomerizations of cZ derivatives into tZ derivatives are a minor pathway in rice cytokinin metabolism. We identified three putative cZ-O-glucosyltransferases (cZOGT1, cZOGT2, and cZOGT3) in rice. The cZOGTs preferentially catalyzed O glucosylation of cZ and cZ-riboside rather than tZ and tZ-riboside in vitro. Transgenic rice lines ectopically overexpressing the cZOGT1 and cZOGT2 genes exhibited short-shoot phenotypes, delay of leaf senescence, and decrease in crown root number, while cZOGT3 overexpressor lines did not show shortened shoots. These results propose that cZ activity has a physiological impact on the growth and development of rice. PMID- 22811438 TI - Vitamin intake and liver cancer risk: a report from two cohort studies in China. AB - BACKGROUND: Epidemiologic studies on the relationship between vitamin intake and liver cancer risk are sparse and inconsistent. METHODS: We evaluated vitamin intake from diet and supplements and risk of liver cancer in 132,837 women and men from China who were recruited into the Shanghai Women's Health Study from 1997 to 2000 or the Shanghai Men's Health Study from 2002 to 2006. In-person interviews, using a validated food-frequency questionnaire, were conducted to collect data on dietary habits. Follow-up consisted of in-person surveys and record linkage. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazard models with adjustment for potential confounders to compare liver cancer risk among participants with high vs low vitamin intake. All statistical tests were two-sided. RESULTS: After excluding the first 2 years of follow-up, 267 participants (including 118 women and 149 men) developed liver cancer during an average of 10.9 (Shanghai Women's Health Study) or 5.5 (Shanghai Men's Health Study) years of follow-up. Dietary vitamin E intake was inversely associated with liver cancer risk (P(trend) = .01), as was vitamin E supplement use (hazard ratio = 0.52, 95% confidence interval = 0.30 to 0.90). This association was consistent among participants with and without self-reported liver disease or a family history of liver cancer. Vitamin C and multivitamin use was associated with increased risk among participants with self-reported liver disease or family history of liver cancer, whereas intake of vitamin C and other vitamins from dietary sources was unrelated to liver cancer risk. CONCLUSIONS: Vitamin E intake, either from diet or supplements, may reduce the risk of liver cancer. PMID- 22811430 TI - Intercellular Ca(2+) waves: mechanisms and function. AB - Intercellular calcium (Ca(2+)) waves (ICWs) represent the propagation of increases in intracellular Ca(2+) through a syncytium of cells and appear to be a fundamental mechanism for coordinating multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca(2+) from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra- and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiological functions of ICWs. PMID- 22811435 TI - Functional characterization of the GATA transcription factors GNC and CGA1 reveals their key role in chloroplast development, growth, and division in Arabidopsis. AB - Chloroplasts develop from proplastids in a process that requires the interplay of nuclear and chloroplast genomes, but key steps in this developmental process have yet to be elucidated. Here, we show that the nucleus-localized transcription factors GATA NITRATE-INDUCIBLE CARBON-METABOLISM-INVOLVED (GNC) and CYTOKININ RESPONSIVE GATA1 (CGA1) regulate chloroplast development, growth, and division in Arabidopsis (Arabidopsis thaliana). GNC and CGA1 are highly expressed in green tissues, and the phytohormone cytokinin regulates their expression. A gnc cga1 mutant exhibits a reduction in overall chlorophyll levels as well as in chloroplast size in the hypocotyl. Ectopic overexpression of either GNC or CGA1 promotes chloroplast biogenesis in hypocotyl cortex and root pericycle cells, based on increases in the number and size of the chloroplasts, and also results in expanded zones of chloroplast production into the epidermis of hypocotyls and cotyledons and into the cortex of roots. Ectopic overexpression also promotes the development of etioplasts from proplastids in dark-grown seedlings, subsequently enhancing the deetiolation process. Inducible expression of GNC demonstrates that GNC-mediated chloroplast biogenesis can be regulated postembryonically, notably so for chloroplast production in cotyledon epidermal cells. Analysis of the gnc cga1 loss-of-function and overexpression lines supports a role for these transcription factors in regulating the effects of cytokinin on chloroplast division. These data support a model in which GNC and CGA1 serve as two of the master transcriptional regulators of chloroplast biogenesis, acting downstream of cytokinin and mediating the development of chloroplasts from proplastids and enhancing chloroplast growth and division in specific tissues. PMID- 22811431 TI - Sirtuin 1 and sirtuin 3: physiological modulators of metabolism. AB - The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease. PMID- 22811439 TI - Mammography screening and breast cancer mortality in Sweden. AB - BACKGROUND: Swedish women aged 40-69 years were gradually offered regular mammography screening since 1974, and nationwide coverage was achieved in 1997. We hypothesized that this gradual implementation of breast cancer screening would be reflected in county-specific mortality patterns during the last 20 years. METHODS: Using data from the Swedish Board of Health and Welfare from 1960 to 2009, we used joinpoint regression to analyze breast cancer mortality trends in women aged 40 years and older (1,286,000 women in 1995-1996). Poisson regression models were used to compare observed mortality trends with expected trends if screening had resulted in breast cancer mortality reductions of 10%, 20%, or 30% among women screened during 18 years of follow-up after the introduction of screening. All statistical tests were two-sided. RESULTS: From 1972 to 2009, breast cancer mortality rates in Swedish women aged 40 years and older declined by 0.98% annually, from 68.4 to 42.8 per 100,000, and it continuously declined in 14 of the 21 Swedish counties. In three counties, breast cancer mortality declined sharply during or soon after the implementation of screening; in two counties, a steep decline started at least 5 years after screening was introduced; and in two counties, breast cancer mortality increased after screening started. In counties in which screening started in 1974-1978, mortality trends during the next 18 years were similar to those before screening started, and in counties in which screening started in 1986-1987, mortality increased by approximately 12% (P = .007) after the introduction of screening compared with previous trends. In counties in which screening started in 1987-1988 and in 1989 1990, mortality declined by approximately 5% (P = .001) and 8% (P < .001), respectively, after the introduction of screening. Conclusion County-specific mortality statistics in Sweden are consistent with studies that have reported limited or no impact of screening on mortality from breast cancer. PMID- 22811440 TI - Screening mammography: what good is it and how can we know if it works? PMID- 22811441 TI - Is the breast cancer mortality decrease in Sweden due to screening or treatment? Not the right question. PMID- 22811443 TI - Appropriate protein provision in critical illness: a systematic and narrative review. AB - BACKGROUND: Widely varying recommendations have been published with regard to the appropriate amount of protein or amino acids to provide in critical illness. OBJECTIVE: We carried out a systematic review of clinical trials that compared the metabolic or clinical effects of different protein intakes in adult critical illness and comprehensively reviewed all of the available evidence pertinent to the safe upper limit of protein provision in this setting. DESIGN: MEDLINE was searched for clinical trials published in English between 1948 and 2012 that provided original data comparing the effects of different levels of protein intake on clinically relevant outcomes and evidence pertinent to the safe upper limit of protein provision to critically ill adults. RESULTS: The limited amount and poor quality of the evidence preclude conclusions or clinical recommendations but strongly suggest that 2.0-2.5 g protein substrate . kg normal body weight-1 . d-1 is safe and could be optimum for most critically ill patients. At the present time, most critically ill adults receive less than half of the most common current recommendation, 1.5 g protein . kg-1 . d-1, for the first week or longer of their stay in an intensive care unit. CONCLUSION: There is an urgent need for well-designed clinical trials to identify the appropriate level of protein provision in critical illness. PMID- 22811442 TI - The influence of abdominal visceral fat on inflammatory pathways and mortality risk in obstructive lung disease. AB - BACKGROUND: Low-grade systemic inflammation, particularly elevated IL-6, predicts mortality in chronic obstructive pulmonary disease (COPD). Although altered body composition, especially increased visceral fat (VF) mass, could be a significant contributor to low-grade systemic inflammation, this remains unexplored in COPD. OBJECTIVE: The objective was to investigate COPD-specific effects on VF and plasma adipocytokines and their predictive value for mortality. DESIGN: Within the Health, Aging, and Body Composition (Health ABC) Study, an observational study in community-dwelling older persons, we used propensity scores to match n = 729 persons with normal lung function to n = 243 persons with obstructive lung disease (OLD; defined as the ratio of forced expiratory volume in 1 s to forced vital capacity < lower limit of normal). Matching was based on age, sex, race, clinic site, BMI, and smoking status. Within this well-balanced match, we compared computed tomography-acquired visceral fat area (VFA) and plasma adipocytokines, analyzed independent associations of VFA and OLD status on plasma adipocytokines, and studied their predictive value for 9.4-y mortality. RESULTS: Whereas whole-body fat mass was comparable between groups, persons with OLD had increased VFA and higher plasma IL-6, adiponectin, and plasminogen activator inhibitor 1 (PAI-1). Both OLD status and VFA were independently positively associated with IL-6. Adiponectin was positively associated with OLD status but negatively associated with VFA. PAI-1 was no longer associated with OLD status after VFA was accounted for. Participants with OLD had increased risk of all cause, respiratory, and cardiovascular mortality, of which IL-6 was identified as an independent predictor. CONCLUSION: Our data suggest that excessive abdominal visceral fat contributes to increased plasma IL-6, which, in turn, is strongly associated with all-cause and cause-specific mortality in older persons with OLD. PMID- 22811444 TI - Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. AB - BACKGROUND: In cirrhosis, hepatic endothelial dysfunction as a result of oxidative stress contributes to the postprandial increase in hepatic venous pressure gradient (HVPG). OBJECTIVE: We aimed at testing the hypothesis that dark chocolate, which holds potent antioxidant properties, might attenuate the postprandial increase in HVPG in patients with cirrhosis. DESIGN: In this phase 2, double-blind, controlled study, 22 cirrhotic patients referred for HVPG measurement were included and randomly assigned to receive a liquid meal containing either dark chocolate (active treatment; 85% cocoa, 0.55 g/kg body wt; n = 11) or isocaloric amounts of white chocolate (devoid of cocoa flavonoids; control subjects; n = 11). HVPG, arterial pressure, portal blood flow, serum flavonoids (catechin and epicatechin), and nitric oxide were measured at baseline and 30 min after meal administration. The main outcome measure was the change in HVPG 30 min after the test meal. RESULTS: Postprandial hyperemia was accompanied by a marked increase in HVPG in the white-chocolate group (16.0 +/- 4.7-19.7 +/- 4.1 mm Hg or +26.4 +/- 12.7%; P < 0.0001), whereas the postprandial increase in HVPG was markedly attenuated in the dark-chocolate group (16.9 +/- 2.9-18.7 +/- 3.5 mm Hg or +11.5 +/- 15.9%; P = 0.02 compared with white chocolate). Portal blood flow increased similarly after meals containing dark or white chocolate (median increase: 32% compared with 39%). Plasma flavonoids increased 15-50-fold after dark chocolate consumption. Dark but not white chocolate induced a mild increase in arterial pressure (+8.8 +/- 8.8% compared with -0.3 +/- 4.9%; P = 0.002). CONCLUSION: In patients with cirrhosis, dark chocolate blunted the postprandial increase in HVPG by improving flow-mediated hepatic vasorelaxation and ameliorated systemic hypotension. This trial was registered at clinicaltrials.gov as NCT01408966. PMID- 22811445 TI - Parental and offspring associations of the metabolic syndrome in the Fels Longitudinal Study. AB - BACKGROUND: Evidence shows that some causes of the metabolic syndrome (MS) begin in childhood, which could indicate a familial association, through either genetic inheritance or cohabitation. OBJECTIVE: This study examined associations between parents and adult offspring diagnoses of the MS and its risk factors. DESIGN: Measurements were obtained from adult participants and their adult offspring enrolled in the Fels Longitudinal Study, with simultaneous waist circumference, systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, HDL, and glucose observations used for diagnosis. On the basis of repeated measurements (in some cases), adult participants were classified as having the MS at least once or as never having the MS. Chi-square tests, ORs, and mixed-effects models were used to study familial associations. RESULTS: Maternal (OR: 2.5; 95% CI: 1.1, 5.5) and paternal (OR: 4.1; 95% CI: 1.4, 12.1) MS classifications were significantly associated with MS classification in sons. MS classification in mothers and daughters (OR: 2.7; 95% CI: 0.9, 8.7; P = 0.08) was similar to that in sons but was not significant, whereas fathers and daughters were not associated (OR: 1.1; 95% CI: 0.4, 3.5). Maternal MS diagnoses were significantly and positively associated with triglycerides in male offspring and were significantly associated with SBP, DBP, and triglycerides in females. Paternal diagnoses were significantly associated only with DBP and HDL in male offspring. CONCLUSIONS: Parental MS diagnosis is significantly associated with MS diagnosis in adult male offspring, and adverse levels of certain risk factors are associated between offspring and parents, although these associations vary across risk factors and child sex. PMID- 22811447 TI - The impact of occupational therapy in Parkinson's disease: a randomized controlled feasibility study. AB - AIM: To evaluate the feasibility of a randomized controlled trial including process and potential impact of occupational therapy in Parkinson's disease. DESIGN: Process and outcome were quantitatively and qualitatively evaluated in an exploratory multicentre, two-armed randomized controlled trial at three months. PARTICIPANTS: Forty-three community-dwelling patients with Parkinson's disease and difficulties in daily activities, their primary caregivers and seven occupational therapists. INTERVENTION: Ten weeks of home-based occupational therapy according to the Dutch guidelines of occupational therapy in Parkinson's disease versus no occupational therapy in the control group. MAIN MEASURES: Process evaluation measured accrual, drop-out, intervention delivery and protocol adherence. Primary outcome measures of patients assessed daily functioning: Canadian Occupational Performance Measure (COPM) and Assessment of Motor and Process Skills. Primary outcome for caregivers was caregiver burden: Zarit Burden Inventory. Participants' perspectives of the intervention were explored using questionnaires and in-depth interviews. RESULTS: Inclusion was 23% (43/189), drop out 7% (3/43) and unblinding of assessors 33% (13/40). Full intervention protocol adherence was 74% (20/27), but only 60% (71/119) of baseline Canadian Occupational Performance Measure priorities were addressed in the intervention. The outcome measures revealed negligible to small effects in favour of the intervention group. Almost all patients and caregivers of the intervention group were satisfied with the results. They perceived: 'more grip on the situation' and used 'practical advices that make life easier'. Therapists were satisfied, but wished for a longer intervention period. CONCLUSIONS: The positive perceived impact of occupational therapy warrants a large-scale trial. Adaptations in instructions and training are needed to use the Canadian Occupational Performance Measure as primary outcome measure. PMID- 22811446 TI - Churches as targets for cardiovascular disease prevention: comparison of genes, nutrition, exercise, wellness and spiritual growth (GoodNEWS) and Dallas County populations. AB - BACKGROUND: We compared cardiovascular (CV) risk factors (CVRFs) of community based participatory research (CBPR) participants with the community population to better understand how CBPR participants relate to the population as a whole. METHODS: GoodNEWS participants in 20 African-American churches in Dallas, Texas were compared with age/sex-matched African-Americans in the Dallas Heart Study (DHS), a probability-based sample of Dallas County residents. DHS characteristics were sample-weight adjusted to represent the Dallas County population. RESULTS: Despite having more education (college education: 75 versus 51%, P< 0.0001), GoodNEWS participants were more obese (mean body mass index: 34 versus 31 kg/m(2), P< 0.001) and had more diabetes (23 versus 12%, P< 0.001) and hyperlipidemia (53 versus 14%, P< 0.001) compared with African-Americans in Dallas County. GoodNEWS participants had higher rates of treatment and control of most CVRFs (treated hyperlipidemia: 95 versus 64%, P< 0.001; controlled diabetes: 95 versus 21%, P< 0.001; controlled hypertension: 70 versus 52%, P= 0.003), were more physically active (233 versus 177 metabolic equivalent units-min/week, P< 0.0001) and less likely to smoke (10 versus 30%, P< 0.001). CONCLUSIONS: Compared with African-Americans in Dallas County, CBPR participants in church congregations were more educated, physically active and had more treatment and control of most CVRFs. Surprisingly, this motivated population had a greater obesity burden, identifying them as a prime target for CBPR-focused obesity treatment. PMID- 22811449 TI - Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage. AB - BACKGROUND AND PURPOSE: The effectiveness of prothrombin complex concentrate (PCC) products available in the United States that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin associated intracranial hemorrhage (wICH). METHODS: In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine. Additional treatment with fresh-frozen plasma was at the discretion of the treating physician. Medical records of all patients receiving PCC for wICH between November 1, 2007, and December 7, 2011 were reviewed. Correction of the international normalized rate (INR) was defined as an INR <1.4. RESULTS: Seventy wICH patients were treated with Profilnine, including 46 (66%) with intraparenchymal hemorrhage, 22 (31%) with subdural hemorrhage, and 2 (3%) with subarachnoid hemorrhage. Mean INR was reduced from 3.36 to 1.96, and in 44 (62.9%) patients the INR corrected to <1.4. Baseline INR >=3.0 decreased the likelihood of INR correction. Concomitant administration of fresh-frozen plasma (mean, 2.6 U) did not increase the likelihood of INR correction. Seven (10%) patients had serious adverse events during their hospital course, including 2 sudden deaths from suspected pulmonary embolism. CONCLUSIONS: Reversal of coagulopathy in wICH with Profilnine was incomplete and associated with serious adverse events. In the absence of available 4-factor PCC, options for urgent reversal of anticoagulation in wICH remain limited. PMID- 22811448 TI - A method for utilizing co-primary efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical trials. AB - BACKGROUND: Most Phase II clinical trials utilize a single primary end point to determine the promise of a regimen for future study. However, many disorders manifest themselves in complex ways. For example, migraine headaches can cause pain, auras, photophobia, and emesis. Investigators may believe that a drug is effective at reducing migraine pain and the severity of emesis during an attack. Nevertheless, they could still be interested in proceeding with the development of the drug if it is effective against only one of these symptoms. Such a study would be a candidate for a clinical trial with co-primary end points. PURPOSE: The purpose of the article is to provide a method for designing a single arm, two stage clinical trial with dichotomous co-primary end points of efficacy that has the ability to detect activity on either response measure with high probability when the drug is active on one or both measures, while at the same time rejecting the drug with high probability when there is little activity on both dimensions. The design enables early closure for futility and is flexible with regard to attained accrual. METHODS: The design is proposed in the context of cancer clinical trials with tumor response and progression-free survival (PFS) status after a certain period. Both end points are assumed to be distributed as binomial random variables, and uninteresting probabilities of success are determined from historical controls. Given the necessity of accrual flexibility, exhaustive searching algorithms to find optimum designs do not seem feasible at this time. Instead, critical values are determined for realized sample sizes using specific procedures. Then accrual windows are found to achieve a design's desired level of significance, probability of early termination (PET), and power. RESULTS: The design is illustrated with a clinical trial that examined bevacizumab in patients with recurrent endometrial cancer. This study was negative by tumor response but positive by 6-month PFS. The procedure was compared to modified procedures in the literature, indicating that the method is competitive. LIMITATIONS: Although the procedure allows investigators to construct designs with desired levels of significance and power, the PET under the null hypothesis is smaller than for single end point studies. CONCLUSIONS: The impact of adding an additional end point on the sample size is often minimal, but the study gains sensitivity to activity on another dimension of treatment response. The operating characteristics are fairly robust to the level of association between the two end points. Software is available online. PMID- 22811450 TI - Role of protease-activated receptor-1 in brain injury after experimental global cerebral ischemia. AB - BACKGROUND AND PURPOSE: Evidence suggests that the protease-activated receptor-1 (PAR-1), a thrombin receptor, mediates neuronal injury in experimental cerebral ischemia. The present study investigated whether PAR-1 plays a role in brain injury after global cerebral ischemia. METHODS: Adult male wild-type or PAR-1 knockout mice underwent a 20-minute bilateral common carotid artery occlusion or a sham operation. Behavior tests were performed before ischemia and 1, 2, and 3 days after bilateral common carotid artery occlusion. Mice were euthanized at different time points for thrombin activity, brain edema, Western blot analysis, and brain histology. RESULTS: Thrombin activity and PAR-1 expression were increased in the brain after bilateral common carotid artery occlusion. Compared with wild-type mice, PAR-1 knockout mice had less brain edema formation, neuronal death, and behavior impairment after bilateral common carotid artery occlusion. In addition, bilateral common carotid artery occlusion-induced activation of mitogen-activated protein kinases was absent in PAR-1 knockout mice. CONCLUSIONS: PAR-1 contributes to the brain injury induced by global cerebral ischemia, which may be related to activation of mitogen-activated protein kinases. PMID- 22811451 TI - Systematic review of outcome after ischemic stroke due to anterior circulation occlusion treated with intravenous, intra-arterial, or combined intravenous+intra arterial thrombolysis. AB - BACKGROUND AND PURPOSE: The optimal approach to recanalization in acute ischemic stroke is unknown. We performed a literature review and meta-analysis comparing the relative efficacy of 6 reperfusion strategies: (1) 0.9 mg/kg intravenous tissue-type plasminogen activator; (2) intra-arterial chemical thrombolysis; (3) intra-arterial mechanical thrombolysis; (4) intra-arterial combined chemical/mechanical thrombolysis; (5) 0.6 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis; and (6) 0.9 mg/kg intravenous tissue-type plasminogen activator and intra-arterial thrombolysis. METHODS: A literature search in Medline, Embase, and the Cochrane database identified case series, observational studies, and treatment arms of randomized trials of anterior circulation arterial occlusion treated with thrombolytic therapy. Included studies had >=10 subjects, mean time to treatment <6 hours, and treatment specific reporting of disability, death, and intracerebral hemorrhage. Multivariable metaregression evaluated the effects of treatment group on outcome at the same time as accounting for differences in baseline covariates. RESULTS: A total of 2986 abstracts were identified from which 54 studies (5019 subjects) were included. There were significant differences across groups in age (P=0.0008), baseline National Institutes of Health Stroke Scale (P=0.0002), and time to treatment initiation (P<0.0001). There were also differences in mean modified Rankin Scale (P<0.0001), mortality (P=0.0024), and symptomatic intracerebral hemorrhage (P=0.0305). Differences in modified Rankin Scale were not significant in the metaregression and likely attributable to differences in baseline covariates between studies. CONCLUSIONS: This study found no evidence that one reperfusion strategy is superior with respect to efficacy or safety, supporting clinical equipoise between reperfusion strategies. Intravenous tissue type plasminogen activator remains the standard of care for acute ischemic stroke. Randomized clinical trials are necessary to determine the efficacy of alternative reperfusion strategies. Participation in such trials is strongly recommended. PMID- 22811452 TI - Freeze the stroke: public awareness program for immediate detection of first symptoms. AB - BACKGROUND AND PURPOSE: The capacity of the general population to identify stroke signs is a major determinant for success of prehospital emergency pathways. Previous educational strategies using the media were usually short-lived and expensive. Tailoring information programs for special subgroups like acute stroke relatives may improve this situation. METHODS: A poster was assembled that included a list of stroke signs and instructions to call 911. Consecutive admissions to the stroke unit were randomized. Intervention consisted of an educational session with relatives, in which a nurse delivered 5 posters and asked for their placement on the freezer door at the kitchen of the patient's house and each of 4 neighboring houses. One month later, a questionnaire was administered to both groups. RESULTS: Sixty admissions were randomized (30 interventions), and 150 posters were distributed. One month after discharge, response rates were 81% for intervention group and 48% for control group. In the intervention arm, 64.5% had all the 4 answers correct, and 74.2% identified all first signs of stroke. For the control group, these values were 8% and 20%, respectively (P<0.001). CONCLUSIONS: This stroke unit-based information strategy improved awareness of relatives and neighbors when compared with the usual discharge plan. The program avoids the media and explores regional health care structure and family and social organizations, and it targets a subgroup keen to receive and spread information. The low cost, ease of use, and duration of the stimulus facilitate further testing and evaluation of impact on hospital presentation and thrombolytic treatment rates. PMID- 22811453 TI - Primary stroke centers should be located using maximal coverage models for optimal access. AB - BACKGROUND AND PURPOSE: The current self-initiated approach by which hospitals acquire Primary Stroke Center (PSC) certification provides insufficient coverage for large areas of the United States. An alternative, directed, algorithmic approach to determine near optimal locations of PSCs would be justified if it significantly improves coverage. METHODS: Using geographic location-allocation modeling techniques, we developed a universal web-based calculator for selecting near optimal PSC locations designed to maximize the population coverage in any state. We analyzed the current PSC network population coverage in Iowa and compared it with the coverage that would exist if a maximal coverage model had instead been used to place those centers. We then estimated the expected gains in population coverage if additional PSCs follow the current self-initiated model and compared it against the more efficient coverage expected by use of a maximal coverage model to select additional locations. RESULTS: The existing 12 self initiated PSCs in Iowa cover 37% of the population, assuming a time-distance radius of 30 minutes. The current population coverage would have been 47.5% if those 12 PSCs had been located using a maximal coverage model. With the current self-initiated approach, 54 additional PSCs on average will be needed to improve coverage to 75% of the population. Conversely, only 31 additional PSCs would be needed to achieve the same degree of population coverage if a maximal coverage model is used. CONCLUSIONS: Given the substantial gain in population access to adequate acute stroke care, it appears justified to direct the location of additional PSCs or recombinant tissue-type plasminogen activator-capable hospitals through a maximal coverage model algorithmic approach. PMID- 22811454 TI - Letter by santos-pontelli et Al regarding article, "prevalence and length of recovery of pusher syndrome based on cerebral hemispheric lesion side in patients with acute stroke". PMID- 22811455 TI - Hemostatic therapy should be used for acute treatment of anticoagulation-related intracerebral hemorrhage. PMID- 22811456 TI - Intravenous thrombolysis and endovascular therapy for acute ischemic stroke with internal carotid artery occlusion: a systematic review of clinical outcomes. AB - BACKGROUND AND PURPOSE: Strokes secondary to acute internal carotid artery (ICA) occlusion are associated with extremely poor prognosis. The best treatment approach to acute stroke in this setting is unknown. We sought to determine clinical outcomes in patients with acute ischemic stroke attributable to ICA occlusion treated with intravenous (IV) systemic thrombolysis or intra-arterial endovascular therapy. METHODS: Using the PubMed database, we searched for studies that included patients with acute ischemic stroke attributable to ICA occlusion who received treatment with IV thrombolysis or intra-arterial endovascular interventions. Studies providing data on functional outcomes beyond 30 days and mortality and symptomatic intracerebral hemorrhage (sICH) rates were included in our analysis. We compared the proportions of patients with favorable functional outcomes, sICH, and mortality rates in the 2 treatment groups by calculating chi(2) and confidence intervals for odds ratios. RESULTS: We identified 28 studies with 385 patients in the IV thrombolysis group and 584 in the endovascular group. Rates of favorable outcomes and sICH were significantly higher in the endovascular group than the IV thrombolysis-only group (33.6% vs 24.9%, P=0.004 and 11.1% vs 4.9%, P=0.001, respectively). No significant difference in mortality rate was found between the groups (27.3% in the IV thrombolysis group vs 32.0% in the endovascular group; P=0.12). CONCLUSIONS: According to our systematic review, endovascular treatment of acute ICA occlusion results in improved clinical outcomes. A higher rate of sICH after endovascular treatment does not result in increased overall mortality rate. PMID- 22811457 TI - Jugular veins in transient global amnesia: innocent bystanders. AB - BACKGROUND AND PURPOSE: Transient global amnesia (TGA) has been associated with an increased prevalence of internal jugular valve insufficiency and many patients report Valsalva-associated maneuvers before TGA onset. These findings have led to the assumption of hemodynamic alterations in intracranial veins inducing focal hippocampal ischemia. We investigated this hypothesis in patients with TGA and control subjects. METHODS: Seventy-five patients with TGA and 75 age- and sex matched healthy subjects were enrolled into a cross-sectional study. Extracranial and transcranial high-resolution venous echo-color-Doppler sonography was performed blindly in all patients and control subjects. Blood flow direction and velocities were recorded at the internal jugular veins, basal veins of Rosenthal, and vein of Galen, both at rest and during Valsalva-associated maneuvers. RESULTS: Mean age of patients with TGA was 60.3+/-8.0 years (median, 60 years; range, 44-78 years); 44 (59%) were female (female/male ratio: 1.42). Internal jugular valve insufficiency (left, right, or bilateral) was found to be more frequent in patients with TGA than in control subjects: 53 (70.7%) versus 22 (29.3%; P<0.05). Blood flow velocities in the deep cerebral veins of patients with TGA did not differ from control subjects both at rest and during Valsalva associated maneuvers. Intracranial venous reflux was neither observed in patients with TGA nor in control subjects despite unilateral or bilateral internal jugular valve insufficiency during prolonged and maximal Valsalva-associated maneuvers. CONCLUSIONS: This study, although confirming the association between TGA and internal jugular valve insufficiency, challenges the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of TGA. PMID- 22811458 TI - Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator. AB - BACKGROUND AND PURPOSE: There are few validated models for prediction of risk of symptomatic intracranial hemorrhage (sICH) after intravenous tissue-type plasminogen activator treatment for ischemic stroke. We used data from Get With The Guidelines-Stroke (GWTG-Stroke) to derive and validate a prediction tool for determining sICH risk. METHODS: The population consisted of 10 242 patients from 988 hospitals who received intravenous tissue-type plasminogen activator within 3 hours of symptom onset from January 2009 to June 2010. This sample was randomly divided into derivation (70%) and validation (30%) cohorts. Multivariable logistic regression identified predictors of intravenous tissue-type plasminogen activator-related sICH in the derivation sample; model beta coefficients were used to assign point scores for prediction. RESULTS: sICH within 36 hours was noted in 496 patients (4.8%). Multivariable adjusted independent predictors of sICH were increasing age (17 points), higher baseline National Institutes of Health Stroke Scale (42 points), higher systolic blood pressure (21 points), higher blood glucose (8 points), Asian race (9 points), and male sex (4 points). The C-statistic was 0.71 in the derivation sample and 0.70 in the independent internal validation sample. Plots of observed versus predicted sICH showed good model calibration in the derivation and validation cohorts. The model was externally validated in National Institute of Neurological Disorders and Stroke trial patients with a C-statistic of 0.68. CONCLUSIONS: The GWTG-Stroke sICH risk "GRASPS" score provides clinicians with a validated method to determine the risk of sICH in patients treated with intravenous tissue-type plasminogen activator within 3 hours of stroke symptom onset. PMID- 22811459 TI - Intravenous thrombolysis in ischemic stroke patients with isolated homonymous hemianopia: analysis of Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register (SITS-ISTR). AB - BACKGROUND AND PURPOSE: Hemianopia can cause considerable disability. Only scarce data are available for ischemic stroke patients presenting with isolated homonymous hemianopia and being treated with intravenous thrombolysis. We analyzed outcome of such patients registered in the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). METHODS: The SITS-ISTR (n=45 079) was searched for patients who presented with isolated homonymous hemianopia. We identified 72 such patients. We report their baseline and demographic characteristics, radiological data, change in their National Institutes of Health Stroke Scale score within 7 days after thrombolysis, and their 3-month modified Rankin Scale (mRS) score. Univariate analysis of parameters associated with any improvement was performed. Hemianopia was assessed with perimetric examination. RESULTS: Of 72 patients, 40 (56%) improved within 7 days after thrombolysis; 19 (26%) had full recovery. Those who improved had significantly lower systolic blood pressure before thrombolysis and were less often administered antiplatelet agents before index stroke. Infarction was visible on 24-hour computed tomography scan in 65% of patients who improved compared with 81.2% of those without improvement (P=0.32). No symptomatic intracranial hemorrhage occurred in patients who improved compared with 1 (3.1%) patient in the nonimproved group (P=0.08). Seventy-one percent of all patients had 3-month mRS score 0 to 2, and 51% had mRS score 0 to 1. Those who improved within 7 days had a significantly better 3-month outcome (median mRS [interquartile range], 0 [0-1] vs 2 [1-2]). CONCLUSIONS: Relatively few ischemic stroke patients received thrombolysis because of isolated homonymous hemianopia. Thrombolysis seems to be safe in these patients. Of those treated, more than half improved and more than two-thirds had good outcome. PMID- 22811461 TI - Hemostatic therapy should not be used for acute treatment of anticoagulation related intracerebral hemorrhage. PMID- 22811460 TI - Chronic valproate treatment enhances postischemic angiogenesis and promotes functional recovery in a rat model of ischemic stroke. AB - BACKGROUND AND PURPOSE: Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke. METHODS: Male rats underwent middle cerebral artery occlusion for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function through the Rotarod test; infarct volume through T2-weighted MRI; microvessel density through immunohistochemistry; relative cerebral blood flow through perfusion-weighted imaging; protein levels of proangiogenic factors through Western blotting; and matrix metalloproteinase-2/9 activities through gelatin zymography. RESULTS: Postischemic VPA treatment robustly improved the Rotarod performance of middle cerebral artery occlusion rats on Days 7 and 14 after ischemia and significantly reduced brain infarction on Day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased relative cerebral blood flow in the ipsilateral cortex. The transcription factor hypoxia-inducible factor-1alpha and its downstream proangiogenic factors, vascular endothelial growth factor and matrix metalloproteinase-2/9, were upregulated after middle cerebral artery occlusion and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on Rotarod performance and microvessel density were abolished by hypoxia-inducible factor 1alpha inhibition. CONCLUSIONS: Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve histone deacetylase inhibition and upregulation of hypoxia-inducible factor 1alpha and its downstream proangiogenic factors vascular endothelial growth factor and matrix metalloproteinase-2/9. PMID- 22811463 TI - The role of hemostatic therapy in anticoagulation-associated intracerebral hemorrhage: intuition versus evidence. PMID- 22811426 TI - Control of sleep and wakefulness. AB - This review summarizes the brain mechanisms controlling sleep and wakefulness. Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and basal forebrain converge onto common effector systems in the thalamus and cortex. Sleep results from the inhibition of wake promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurons in the preoptic area of the hypothalamus, resulting in large-amplitude, slow EEG oscillations. Local, activity-dependent factors modulate the amplitude and frequency of cortical slow oscillations. Non-rapid-eye movement (NREM) sleep results in conservation of brain energy and facilitates memory consolidation through the modulation of synaptic weights. Rapid-eye movement (REM) sleep results from the interaction of brain stem cholinergic, aminergic, and GABAergic neurons which control the activity of glutamatergic reticular formation neurons leading to REM sleep phenomena such as muscle atonia, REMs, dreaming, and cortical activation. Strong activation of limbic regions during REM sleep suggests a role in regulation of emotion. Genetic studies suggest that brain mechanisms controlling waking and NREM sleep are strongly conserved throughout evolution, underscoring their enormous importance for brain function. Sleep disruption interferes with the normal restorative functions of NREM and REM sleep, resulting in disruptions of breathing and cardiovascular function, changes in emotional reactivity, and cognitive impairments in attention, memory, and decision making. PMID- 22811462 TI - An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. AB - BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents. METHODS: Human recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was administered intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion in mice and embolic stroke in rats. The 3K3A-APC was additionally administered for 3 to 4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke. RESULTS: In all models, tPA alone had no effects on the infarct volume or behavior (ie, neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared with vehicle. The tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient middle cerebral artery occlusion in mice and 7 days after embolic stroke in rats by 65%, 63%, and 52%, respectively, significantly (P<0.05) improved behavior and eliminated tPA-induced intracerebral microhemorrhages. CONCLUSIONS: The 3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy also should be considered for treating stroke in humans. PMID- 22811464 TI - Patients with the malignant profile within 3 hours of symptom onset have very poor outcomes after intravenous tissue-type plasminogen activator therapy. AB - BACKGROUND AND PURPOSE: The malignant profile has been associated with poor outcomes after reperfusion in the 3- to 6-hour time window. The aim of this study was to estimate the incidence and prognostic implications of the malignant profile, as identified by CT perfusion, in intravenous tissue-type plasminogen activator-treated patients who were imaged <3 hours from stroke onset. METHODS: The incidence of the malignant profile, based on the previously published optimal perfusion-weighted imaging definition, was assessed in consecutive patients using a fully automated software program (RApid processing of Perfusion and Diffusion [RAPID]). A receiver operating characteristic curve analysis was done to identify time to maximum and core volume thresholds that optimally identify patients with poor outcome (modified Rankin Scale 5-6). RESULTS: Forty-two patients had an interpretable CT perfusion performed within 3 hours of symptom onset. Mean age was 74+/-14 years and median (interquartile range) National Institutes of Stroke Scale score was 13 (6-19). Four patients (9.5%) met the prespecified criteria for the malignant profile and all 4 had poor outcome. Receiver operating characteristic analysis determined that the best CT perfusion measure to identify patients with poor outcome was a cerebral blood flow based infarct core >53 mL (100% specificity and 67% sensitivity). This criterion identified 5 patients as malignant (12%). The poor outcome rate in these patients was 100% versus 7.1% in the 37 nonmalignant patients (P<0.001). CONCLUSIONS: The incidence of the malignant profile on CT perfusion is approximately 10% in tissue-type plasminogen activator-eligible patients imaged within 3 hours of symptom onset. The clinical outcome of these patients is very poor despite intravenous tissue-type plasminogen activator therapy. PMID- 22811465 TI - Racial-ethnic biases, time pressure, and medical decisions. AB - This study examined two types of potential sources of racial-ethnic disparities in medical care: implicit biases and time pressure. Eighty-one family physicians and general internists responded to a case vignette describing a patient with chest pain. Time pressure was manipulated experimentally. Under high time pressure, but not under low time pressure, implicit biases regarding blacks and Hispanics led to a less serious diagnosis. In addition, implicit biases regarding blacks led to a lower likelihood of a referral to specialist when physicians were under high time pressure. The results suggest that when physicians face stress, their implicit biases may shape medical decisions in ways that disadvantage minority patients. PMID- 22811466 TI - MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro. AB - Abnormal microRNA (miRNA) expression profiles have recently been associated with sporadic pituitary adenomas, suggesting that miRNAs can contribute to tumor formation; miRNAs are small noncoding RNAs that inhibit posttranscriptional expression of target mRNAs by binding to target sequences usually located in the 3'-UTR. In this study, we investigated the role played by miR-107, a miRNA associated with different human cancers, in sporadic pituitary adenomas and its interaction with the pituitary tumor suppressor gene aryl hydrocarbon receptor interacting protein (AIP). miR-107 expression was evaluated in pituitary adenoma and normal pituitary samples using microRNA screen TLDA (TaqMan Low-Density Array) and RT-qPCR assays. We show that miR-107 expression was significantly upregulated in GH-secreting and nonfunctioning pituitary adenomas. We found that human AIP-3'-UTR is a target of miR-107 since miR-107 inhibited in vitro AIP expression to 53.9 +/- 2% of the miRNA control in a luciferase assay and reduced endogenous AIP mRNA expression to 53 +/- 22% of the miRNA control in human cells. However, we did not observe a negative correlation between AIP and miR-107 expression in the human tumor samples. Furthermore, we show that miR-107 overexpression inhibited cell proliferation in human neuroblastoma and rat pituitary adenoma cells. In conclusion, miR-107 is overexpressed in pituitary adenomas and may act as a tumor suppressor. We have identified and confirmed AIP as a miR-107 target gene. Expression data in human samples suggest that the expression of AIP and miR-107 could be influenced by a combination of tumorigenic factors as well as compensatory mechanisms stimulated by the tumorigenic process. PMID- 22811468 TI - Comparative expression of hCG beta-genes in human trophoblast from early and late first-trimester placentas. AB - Human chorionic gonadotropin (hCG) displays a major role in pregnancy initiation and progression and is involved in trophoblast differentiation and fusion. However, the site and the type of dimeric hCG production during the first trimester of pregnancy is poorly known. At that time, trophoblastic plugs present in the uterine arteries disappear, allowing unrestricted flow of maternal blood to the intervillous space. The consequence is an important modification of the trophoblast environment, including a rise of oxygen levels from about 2.5% before 10 wk of amenorrhea (WA) to ~8% after 12 WA. Two specific beta-hCG proteins that differ from three amino acids have been described: type 1 (CGB7) and type 2 (CGB3, -5, and -8). Here, we demonstrated in situ and ex vivo on placental villi and in vitro in primary cultures of human cytotrophoblasts that type 1 and 2 beta hCG RNAs and proteins were expressed by trophoblasts and that these expressions were higher before blood enters in the intervillous space (8-9 vs. 12-14 WA). hCG was immunodetected in villous mononucleated cytotrophoblasts (VCT) and syncytiotrophoblast (ST) at 8-9 WA but only in ST at 12-14 WA. Furthermore, hCG secretion was fourfold higher in VCT cultures from 8-9 WA compared with 12-14 WA. Interestingly, VCT from 8-9 WA placentas were found to exhibit more fusion features. Taken together, we showed that type 1 and type 2 beta-hCG are highly expressed by VCT in the early first trimester, contributing to the high levels of hCG found in maternal serum at this term. PMID- 22811467 TI - Molecular inflammation and adipose tissue matrix remodeling precede physiological adaptations to pregnancy. AB - Changes in adipose tissue metabolism are central to adaptation of whole body energy homeostasis to pregnancy. To gain insight into the molecular mechanisms supporting tissue remodeling, we have characterized the longitudinal changes of the adipose transcriptome in human pregnancy. Healthy nonobese women recruited pregravid were followed in early (8-12 wk) and in late (36-38 wk) pregnancy. Adipose tissue biopsies were obtained in the fasting state from the gluteal depot. The adipose transcriptome was examined via whole genome DNA microarray. Expression of immune-related genes and extracellular matrix components was measured using real-time RT-PCR. Adipose mass, adipocyte size, and cell number increased in late pregnancy compared with pregravid measurements (P < 0.001) but remained unchanged in early pregnancy. The adipose transcriptome evolved during pregnancy with 10-15% of genes being differently expressed compared with pregravid. Functional gene cluster analysis revealed that the early molecular changes affected immune responses, angiogenesis, matrix remodeling, and lipid biosynthesis. Increased expression of macrophage markers (CD68, CD14, and the mannose-6 phosphate receptor) emphasized the recruitment of the immune network in both early and late pregnancy. The TLR4/NF-kappaB signaling pathway was enhanced specifically in relation to inflammatory adipokines and chemokines genes. We conclude that early recruitment of metabolic and immune molecular networks precedes the appearance of pregnancy-related physiological changes in adipose tissue. This biphasic pattern suggests that physiological inflammation is an early step preceding the development of insulin resistance, which peaks in late pregnancy. PMID- 22811469 TI - Sertoli-secreted FGF-2 induces PFKFB4 isozyme expression in mouse spermatogenic cells by activation of the MEK/ERK/CREB pathway. AB - Sertoli cells play a central role in the control and maintenance of spermatogenesis by secreting growth factors, in response to hormonal stimulation, that participate in the paracrine regulation of this process. In this study, we investigated how the hormonal regulation of spermatogenesis modulates 6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) isozyme expression in two mouse spermatogenic cell lines, GC-1 spg and GC-2 spd (ts). For this purpose, TM4 Sertoli cells were used to obtain conditioned medium that was treated or not with dihydrotestosterone for 2 days [dihydrotestosterone conditioned medium (TCM) and basal conditioned medium (BCM), respectively]. We observed an increase in the expression of PFKFB4 along with a decrease in PFKFB3 in spermatogenic cell lines treated with TCM. These effects were inhibited by the antiandrogen drug flutamide and by heat-inactivated TCM, indicating the protein nature of the TCM mediator and its dependence on Sertoli cell stimulation by dihydrotestosterone. In addition, adult rat testes treated with the GnRH antagonist Degarelix exhibited a reduction in the expression of PFKFB4 in germ cells. Addition of exogenous FGF-2 mimicked the changes in the Pfkfb gene expression, whereas neutralizing antibodies against FGF-2 abolished them. Interestingly, similar effects on Pfkfb gene expression were observed using different MAPK inhibitors (U-0126, PD-98059, and H-89). Luciferase analysis of Pfkfb4 promoter constructs demonstrated that a putative CRE-binding sequence located at -1,463 relative to the transcription start site is required to control Pfkfb4 gene expression after TCM treatment. Pulldown assays showed the binding of the CREB transcription factor to this site. Altogether, these results show how the paracrine regulation orchestrated by Sertoli cells in response to testosterone controls glycolysis in germ cells. PMID- 22811472 TI - Photoperiod regulates dietary preferences and energy metabolism in young developing Fischer 344 rats but not in same-age Wistar rats. AB - The effects of photoperiod on dietary preference were examined using young growing Fischer 344 and Wistar rats, which are seasonal and nonseasonal breeders, respectively. Rats were provided a low-fat, high-carbohydrate diet (LFD: 66/10/24% energy as carbohydrate/fat/protein) and high-fat, low-carbohydrate diet (HFD: 21/55/24% energy as carbohydrate/fat/protein) simultaneously under long- (LD: 16 h light/day) and short-day (SD: 8 h light/day) conditions for 3 wk. Fischer 344 rats preferred the LFD to the HFD under the LD condition, whereas preference for both diets was equivalent under the SD condition. Consequently, their body weight and total energy intake exhibited 11-15 and 10-13% increases, respectively, under the LD condition. Calculation of energy intake from macronutrients revealed that rats under the LD condition consumed 20-24 and 9-13% higher energy of carbohydrates and proteins, respectively, than those under the SD condition. In contrast, Wistar rats preferred the LFD to the HFD irrespective of photoperiod and exhibited no photoperiodic changes in any parameters examined. Next, Fischer 344 rats were provided either the LFD or HFD for 3 wk under LD or SD conditions. Calorie intake was 10% higher in the rats fed the LFD than those fed the HFD under SD condition. However, rats under LD condition exhibited 5-10, 14, and 64% increases in body weight, epididymal fat mass, and plasma leptin levels, respectively, compared with those under the SD condition irrespective of dietary composition. In conclusion, photoperiod regulates feeding and energy metabolism in young growing Fischer 344 rats via the interactions with dietary macronutrient composition. PMID- 22811471 TI - Dynamic testosterone responses to near-physiological LH pulses are determined by the time pattern of prior intravenous LH infusion. AB - The long-lived glycoprotein hormone, human chorionic gonadotropin (hCG), downregulates testosterone (T) biosynthesis in vitro and in vivo in animals and humans. The degree to which short-lived pulses of pituitary luteinizing hormone (LH) do so, particularly at physiological concentrations, is not known. We test the hypothesis that continuous LH infusion compared with bolus injections of LH every 1 h or every 2 h overnight downregulates T secretory responses to a subsequent fixed template of three consecutive intravenous pulses of a physiological amount of recombinant human (rh) LH (triple stimulus). Nineteen healthy men ages 18-49 yr each underwent four separate randomly ordered overnight gonadotropin-releasing hormone-receptor antagonist treatments with superimposed intravenous infusions of saline or rhLH (1-h pulses, 2-h pulses, or continuously). Each 12-h infusion protocol was followed by the triple rhLH-pulse stimulus the next morning. During the triple stimulus, basal (nonpulsatile) as well as total (basal plus pulsatile) T secretion was higher after overnight 2- and 1-h rhLH pulses than after continuous rhLH or saline delivery. Approximate entropy, a probabilistic measure of feedforward-induced irregularity of T concentration time series, was higher after 1-h rhLH pulses than after continuous rhLH. Analytical estimation of pulsatile rhLH-T dose-response measures revealed higher T secretory sensitivity and greater rhLH potency (lower EC50) after exposure to 1-h than 2-h rhLH pulses. Collectively, these data indicate that in vivo dynamics of LH-stimulated T secretion under standardized conditions in men depend on the prior time mode of LH delivery in the bloodstream. PMID- 22811470 TI - Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating beta-catenin and CREB activities. AB - Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db/db mice and conducted a 14 day intervention with daily injection of a therapeutic dose of d-INS or human insulin (h-INS) in these mice. The body weight of the mice after 14-day daily injection of d-INS (5 IU/kg) was decreased significantly compared with those injected with the same dose of h-INS or saline. The weight-sparing effect of d INS was associated with significantly elevated circulating levels of total GLP-1 and reduced food intake. Histochemistry analysis demonstrated that d-INS induced rapid phosphorylation of protein kinase B (Akt) in the gut L cells of normal mice. Western blotting showed that d-INS stimulated Akt activation in a more rapid and enhanced fashion in the mouse distal ileum compared with those by h INS. In vitro investigation in primary fetal rat intestinal cell (FRIC) cultures showed that d-INS increased Gcg mRNA expression as determined by Northern blotting and real-time RT-PCR. Consistent with these in vivo investigations, d INS significantly increased GLP-1 secretion in FRIC cultures. Consistently, d-INS was also shown to induce rapid phosphorylation of Akt in the clonal gut cell line GLUTag. Furthermore, d-INS increased beta-catenin phosphorylation, its nuclear translocation, and enhanced cAMP response element-binding protein (CREB) phosphorylation in a phosphatidylinositol 3-kinase and/or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-sensitive manner. We suggest that the weight-sparing benefit of d-INS in mice is related to its intestinal tissues preference that leads to profound stimulation of Gcg expression and enhanced GLP-1 secretion in intestinal L cells, potentially involving the activation of insulin/beta-catenin/CREB signaling pathways. PMID- 22811474 TI - Examining the effectiveness of a restorative justice program for various types of juvenile offenders. AB - Restorative justice (RJ) programs have become widespread in the United States and in other countries. These programs are often seen as a viable alternative to traditional retributive processing, especially for minor, and sometimes more serious, forms of delinquency and adult criminality. The programs hold promise for achieving several goals, including increased community and victim involvement, greater satisfaction with the case outcomes, improved offender compliance, increased perceptions of fairness, and even recidivism reduction. Meta-analyses have demonstrated varying degrees of program success in recidivism reduction, which may in part reflect differential effectiveness of the RJ approach for various kinds of offenders. This study examined whether an RJ program for juvenile offenders had differential impacts on recidivism across various offender characteristics (including age, gender, racial group, offending history, and current offense). Results generally support the effectiveness of the program for many types of offenders. Implications for future research and potential improvements to the RJ model are discussed. PMID- 22811473 TI - Upregulation of ACE2-ANG-(1-7)-Mas axis in jejunal enterocytes of type 1 diabetic rats: implications for glucose transport. AB - The inhibitory effects of the angiotensin-converting enzyme (ACE)-ANG II angiotensin type 1 (AT1) receptor axis on jejunal glucose uptake and the reduced expression of this system in type 1 diabetes mellitus (T1DM) have been documented previously. The ACE2-ANG-(1-7)-Mas receptor axis is thought to oppose the actions of the ACE-ANG II-AT1 receptor axis in heart, liver, and kidney. However, the possible involvement of the ACE2-ANG-(1-7)-Mas receptor system on enhanced jejunal glucose transport in T1DM has yet to be determined. Rat everted jejunum and Caco-2 cells were used to determine the effects of ANG-(1-7) on glucose uptake and to study the ACE2-ANG-(1-7)-Mas receptor signaling pathway. Expression of target gene and protein in jejunal enterocytes and human Caco-2 cells were quantified using real-time PCR and Western blotting. T1DM increased jejunal protein and mRNA expression of ACE2 (by 59 and 173%, respectively) and Mas receptor (by 55 and 100%, respectively) in jejunum. One millimolar ANG-(1-7) reduced glucose uptake in jejunum and Caco-2 cells by 30.6 and 30.3%, respectively, effects that were abolished following addition of 1 MUM A-779 (a Mas receptor blocker) or 1 MUM GF-109203X (protein kinase C inhibitor) to incubation buffer for jejunum or Caco-2 cells, respectively. Finally, intravenous treatment of animals with ANG-(1-7) significantly improved oral glucose tolerance in T1DM but not control animals. In conclusion, enhanced activity of the ACE2-ANG (1-7)-Mas receptor axis in jejunal enterocytes is likely to moderate the T1DM induced increase in jejunal glucose uptake resulting from downregulation of the ACE-ANG II-AT1 receptor axis. Therefore, altered activity of both ACE and ACE2 systems during diabetes will determine the overall rate of glucose transport across the jejunal epithelium. PMID- 22811475 TI - Recidivism after treatment in a forensic youth-psychiatric setting: the effect of treatment characteristics. AB - The aim of this study was to examine the effect of treatment characteristics on recidivism in a forensic youth-psychiatric outpatient clinic. The treatment offered comprised functional family therapy (FFT), individual cognitive behavioural therapy (CBT), or CBT in combination with parent training. Some of the youth additionally participated in aggression replacement training (ART). FFT and ART were implemented as a trial version, meaning that most therapists had not received formal training yet. Treatment characteristics related to recidivism were length of treatment, type of treatment, number of sessions, and the therapist. The longer the period of treatment and the greater the number of sessions, the higher the recidivism, even after controlling for risk of recidivism based on static risk factors. Juveniles who participated in ART reoffended more often than juveniles who had not participated in such training. Given the fact that FFT and ART were not well-implemented trial versions, it can be concluded that poorly implemented treatment leads to poor outcomes. PMID- 22811476 TI - Evaluation of phosphatidylserine-binding peptides targeting apoptotic cells. AB - The inhibition or dysregulation of apoptosis plays an intimate role in the initiation and progression of cancer by confounding normal tissue homeostasis. We currently do not have a clinical method to assess apoptosis induced by cancer therapies. Phosphatidylserine (PS) is an attractive target for imaging apoptosis because it is on the exterior of the apoptotic cells and PS externalization is an early marker of apoptosis. PS-binding peptides are an attractive option for developing an imaging probe to detect apoptosis using positron emission tomography. In this study, four peptides were evaluated for PS-binding characteristics using a plate-based assay system, a liposome mimic of cell membrane PS presentation, and a cell assay of apoptosis. This work also describes two screening techniques to enable researchers to identify and optimize compounds that bind to PS. The results of our study indicate that all four peptides bind to PS and are specific to apoptotic cells. Two of the peptides in particular that have an additional cysteine residue are good potential candidates for development into imaging probes because they bind to PS with high affinity and specificity and they can be easily radiolabelled with (18)F. PMID- 22811477 TI - High-content imaging-based screening of microenvironment-induced changes to stem cells. AB - Effective screening methodologies for cells are challenged by the divergent and heterogeneous nature of phenotypes inherent to stem cell cultures, particularly on engineered biomaterial surfaces. In this study, we showcase a high-content, confocal imaging-based methodology to parse single-cell phenotypes by quantifying organizational signatures of specific subcellular reporter proteins and applied this profiling approach to three human stem cell types (embryonic-human embryonic stem cell [hESC], induced pluripotent-induced pluripotent stem cell [iPSC], and mesenchymal-human mesenchymal stem cell [hMSC]). We demonstrate that this method could distinguish self-renewing subpopulations of hESCs and iPSCs from heterogeneous populations. This technique can also provide insights into how incremental changes in biomaterial properties, both physiochemical and mechanical, influence stem cell fates by parsing the organization of stem cell proteins. For example, hMSCs cultured on polymeric films with varying degrees of poly(ethylene glycol) to modulate osteogenic differentiation were parsed using high-content organization of the cytoskeletal protein F-actin. In addition, hMSCs cultured on a self-assembled monolayer platform featuring compositional gradients were screened and descriptors obtained to correlate substrate variations with adipogenic lineage commitment. Taken together, high-content imaging of structurally sensitive proteins can be used as a tool to identify stem cell phenotypes at the single-cell level across a diverse range of culture conditions and microenvironments. PMID- 22811478 TI - Lipid-sensing high-throughput ApoA-I assays. AB - Apolipoprotein A-I (ApoA-I), a primary protein component of high-density lipoprotein (HDL), plays an important role in cholesterol metabolism mediating the formation of HDL and the efflux of cellular cholesterol from macrophage foam cells in arterial walls. Lipidation of ApoA-I is mediated by adenosine triphosphate (ATP) binding cassette A1 (ABCA1). Insufficient ABCA1 activity may lead to increased risk of atherosclerosis due to reduced HDL formation and cholesterol efflux. The standard radioactive assay for measuring cholesterol transport to ApoA-I has low throughput and poor dynamic range, and it fails to measure phospholipid transfer. We describe the development of two sensitive, nonradioactive high-throughput assays that report on the lipidation of ApoA-I: a homogeneous assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) and a discontinuous assay that uses the label-free Epic platform. The TR-FRET assay employs HiLyte Fluor 647-labeled ApoA-I with N-terminal biotin bound to streptavidin-terbium. When fluorescent ApoA-I was incorporated into HDL, TR-FRET decreased proportionally to the increase in the ratio of lipids to ApoA I, demonstrating that the assay was sensitive to the amount of lipid bound to ApoA-I. In the Epic assay, biotinylated ApoA-I was captured on a streptavidin coated biosensor. Measured resonant wavelength shift was proportional to the amount of lipids associated with ApoA-I, indicating that the assay senses ApoA-I lipidation. PMID- 22811479 TI - Positive predictive value of albumin: globulin ratio for feline infectious peritonitis in a mid-western referral hospital population. AB - Low albumin to globulin ratio has been found previously to have a high positive predictive value for feline infectious peritonitis (FIP) in cats with clinical signs highly suggestive of the disease. However, FIP can have a more vague clinical presentation. This retrospective study found that the positive predictive value of an albumin:globulin (A:G) ratio of <0.8 and <0.6 was only 12.5% and 25%, respectively, in a group of 100 cats with one or more clinical signs consistent with FIP. The negative predictive value was 100% and 99% for an A:G ratio of <0.8 and A:G<0.6%, respectively. Therefore, when the prevalence of FIP is low, the A:G ratio is useful to rule out FIP but is not helpful in making a positive diagnosis of FIP. PMID- 22811480 TI - Osteomyelitis of the coxofemoral joint due to Mycobacterium species in a feline renal transplant recipient. AB - A 4-year-old castrated male Russian Blue cat was evaluated for acute right hind limb lameness 18 months after receiving a renal transplant. Radiographs showed a subluxated right femoral head and lysis of the acetabulum and femoral neck. A femoral head and neck ostectomy was performed on the right coxofemoral joint. Histologic evaluation of the right femoral head revealed lesions indicative of a chronic, granulomatous osteomyelitis and periostitis associated with an intralesional Mycobacterium species. However, the cat's clinical condition declined despite treatment and the owner elected humane euthanasia. All renal transplant recipients receive immunosuppressive therapy to prevent allograft rejection. The non-tuberculous mycobacterial infection of the coxofemoral joint was thought to develop secondary to long-term immunosuppressive treatment. This report illustrates the need to consider these rare opportunistic infections even many months to years following renal transplantation. Early awareness, stringent immunosuppressive drug monitoring and targeted treatment once a diagnosis has been made may be important in the successful management and prevention of mycobacterial infections in this population of patients. PMID- 22811481 TI - Feline low-grade alimentary lymphoma: how common is it? AB - Low-grade alimentary lymphoma (LGAL) requires histological assessment of biopsies for diagnosis whereas intermediate- (IGAL) and high-grade (HGAL) alimentary lymphoma (AL) can be diagnosed by cytology of intestinal or mesenteric lymph node aspirates. Assessment of the relative frequency of subtypes of AL using histology alone may be skewed towards an increased frequency of LGAL as cases of IGAL or HGAL diagnosed cytologically may not progress to biopsy. We investigated the relative prevalence of AL subtypes diagnosed by both histopathology and cytology among primary accession cases across Australia during a 5-year period. Clinicopathological features of LGAL were compared with those of IGAL/HGAL. Fifty three cases of AL were identified, including 30 diagnosed by histology (15 LGAL, 13 HGAL, two IGAL) and 23 IGAL/HGAL diagnosed by cytology. LGAL cases comprised 50% of histological diagnoses, but only 28% of all AL. A palpable abdominal mass was more common in IGAL/HGAL (43%) than in LGAL (7%) [odds ratio (OR) 7.6, P = 0.01]. Anaemia was more common in IGAL/HGAL (41%) compared with LGAL (7%) (OR 9.6, P = 0.02). On abdominal ultrasound, a gastrointestinal mural mass was visualised in 41% of IGAL/HGAL and 0% of LGAL (P = 0.01). Where a detailed abdominal ultrasound report was provided, gastric/intestinal wall thickening was the most commonly reported abnormality (82%). In cats with intestinal thickening, a loss of normal layering was more common (P = 0.02) in cats with IGAL/HGAL (71%) compared with those with LGAL (20%). The relative prevalence of LGAL was lower when cases diagnosed by cytology were included in addition to those diagnosed by histology in the study population. The relative frequency with which LGAL is diagnosed has increased since initial reports from this region. A number of significant clinicopathological findings are useful to distinguish LGAL from IGAL/HGAL. PMID- 22811482 TI - Renoprotective effects of C-peptide in the Dahl salt-sensitive rat. AB - Previous studies have demonstrated that renoprotective effects of C-peptide in experimental models of diabetes-induced renal disease may be mediated via lowering blood glucose. The present study examined the renoprotective effects of C-peptide in a model of nondiabetic renal disease, the Dahl salt-sensitive (SS/jr) rat. SS/jr rats were placed on a 2% NaCl diet for 2 wk (HS2, resulting in mild to moderate renal injury) or 4 wk (HS4, resulting in advanced renal injury) and then received either vehicle (veh) or C-peptide (Cpep) for additional 4 wk. Urine albumin (UAE) and protein (UPE) excretion rates were measured at baseline (i.e., before initiation of veh or Cpep treatment) and 4 wk later (i.e., at the time of death). Glomerular permeability, indexes of glomerulosclerosis and tubulointerstitial fibrosis, the presence of inflammatory cells, and protein expression of transforming growth factor-beta (TGF-beta) and podocin were measured at the time of death. In HS2 + veh rats, UAE and UPE increased by 74 and 92%, respectively, from baseline and the time of death. While HS2 + Cpep attenuated this increase in UAE and UPE, HS4 + Cpep had no effect on these parameters. Similarly, HS2 + Cpep reduced glomerular permeability, tubulointerstitial fibrosis, renal inflammation, TGF-beta, and podocin protein expression, while HS4 + Cpep had no effect. These studies indicate that C-peptide is renoprotective in nondiabetic experimental models with mild to moderate renal injury. PMID- 22811484 TI - Role of connexin40 in the autoregulatory response of the afferent arteriole. AB - Connexins in renal arterioles affect autoregulation of arteriolar tonus and renal blood flow and are believed to be involved in the transmission of the tubuloglomerular feedback (TGF) response across the cells of the juxtaglomerular apparatus. Connexin40 (Cx40) also plays a significant role in the regulation of renin secretion. We investigated the effect of deleting the Cx40 gene on autoregulation of afferent arteriolar diameter in response to acute changes in renal perfusion pressure. The experiments were performed using the isolated blood perfused juxtamedullary nephron preparation in kidneys obtained from wild-type or Cx40 knockout mice. Renal perfusion pressure was increased in steps from 75 to 155 mmHg, and the response in afferent arteriolar diameter was measured. Hereafter, a papillectomy was performed to inhibit TGF, and the pressure steps were repeated. Conduction of intercellular Ca(2+) changes in response to local electrical stimulation was examined in isolated interlobular arteries and afferent arterioles from wild-type or Cx40 knockout mice. Cx40 knockout mice had an impaired autoregulatory response to acute changes in renal perfusion pressure compared with wild-type mice. Inhibition of TGF by papillectomy significantly reduced autoregulation of afferent arteriolar diameter in wild-type mice. In Cx40 knockout mice, papillectomy did not affect the autoregulatory response, indicating that these mice have no functional TGF. Also, Cx40 knockout mice showed no conduction of intercellular Ca(2+) changes in response to local electrical stimulation of interlobular arteries, whereas the Ca(2+) response to norepinephrine was unaffected. These results suggest that Cx40 plays a significant role in the renal autoregulatory response of preglomerular resistance vessels. PMID- 22811483 TI - Pendrin protein abundance in the kidney is regulated by nitric oxide and cAMP. AB - Pendrin is a Cl(-)/HCO(3)(-) exchanger, expressed in the apical regions of some intercalated cell subtypes, and is critical in the pressor response to angiotensin II. Since angiotensin type 1 receptor inhibitors reduce renal pendrin protein abundance in mice in vivo through a mechanism that is dependent on nitric oxide (NO), we asked if NO modulates renal pendrin expression in vitro and explored the mechanism by which it occurs. Thus we quantified pendrin protein abundance by confocal fluorescent microscopy in cultured mouse cortical collecting ducts (CCDs) and connecting tubules (CNTs). After overnight culture, CCDs maintain their tubular structure and maintain a solute gradient when perfused in vitro. Pendrin protein abundance increased 67% in CNT and 53% in CCD when NO synthase was inhibited (N(G)-nitro-L-arginine methyl ester, 100 MUM), while NO donor (DETA NONOate, 200 MUM) application reduced pendrin protein by ~33% in the CCD and CNT. When CNTs were cultured in the presence of the guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (10 MUM), NO donors did not alter pendrin abundance. Conversely, pendrin protein abundance rose when cAMP content was increased by the application of an adenylyl cyclase agonist (forskolin, 10 MUM), a cAMP analog (8-bromo-cAMP, 1 mM), or a phosphodiesterase inhibitor (BAY60-7550, 50 MUM). Since NO reduces cellular cAMP in the CNT, we asked if NO reduces pendrin abundance by reducing cAMP. With blockade of cGMP-stimulated phosphodiesterase II, NO did not alter pendrin protein abundance. We conclude that NO acts through cAMP to reduce pendrin total protein abundance by enhancing cAMP degradation. PMID- 22811486 TI - Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis. AB - Podocyte foot process retraction is a hallmark of proteinuric glomerulonephritis. Cytoskeletal rearrangement causes a redistribution of slit membrane proteins from the glomerular filtration barrier towards the cell body. However, the underlying signaling mechanisms are presently unknown. Recently, we have developed a new experimental model of immune-mediated podocyte injury in mice, the antipodocyte nephritis (APN). Podocytes were targeted with a polyclonal antipodocyte antibody causing massive proteinuria around day 10. Rho-kinases play a central role in the organization of the actin cytoskeleton of podocytes. We therefore investigated whether inhibition of Rho-kinases would prevent podocyte disruption. C57/BL6 mice received antipodocyte serum with or without daily treatment with the specific Rho kinase inhibitor HA-1077 (5 mg/kg). Immunoblot analysis demonstrated activation of Rho-kinase in glomeruli of antipodocyte serum-treated mice, which was prevented by HA-1077. Increased Rho-kinase activity was localized to podocytes in APN mice by immunostainings against the phosphorylated forms of Rho-kinase substrates. Rho-kinase inhibition significantly reduced podocyte loss from the glomerular tuft. Periodic acid staining demonstrated less podocyte hypertrophy in Rho-kinase-inhibited APN mice, despite similar amounts of immune complex deposition. Electron microscopy revealed reduced foot process effacement compared with untreated APN mice. Internalization of the podocyte slit membrane proteins nephrin and synaptopodin was prevented by Rho-kinase inhibition. Functionally, Rho-kinase inhibition significantly reduced proteinuria without influencing blood pressure. In rats with passive Heymann nephritis and human kidney biopsies from patients with membranous nephropathy, Rho-kinase was activated in podocytes. Together, these data suggest that increased Rho-kinase activity in the podocyte may be a mechanism for in vivo podocyte foot process retraction. PMID- 22811485 TI - Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. AB - Kallistatin (KS) levels are reduced in the kidney and blood vessels under oxidative stress conditions. To determine the function of endogenous KS in the renal and cardiovascular systems, KS levels were depleted by daily injection of anti-rat KS antibody into DOCA-salt hypertensive rats for 10 days. Administration of anti-KS antibody resulted in reduced KS levels in the circulation but increased levels of serum thiobarbituric acid reactive substances (an indicator of lipid peroxidation) as well as superoxide formation in the aorta. Moreover, anti-KS antibody injection resulted in increased NADH oxidase activity and superoxide production but decreased nitric oxide levels in the kidney and heart. Endogenous KS blockade aggravated renal dysfunction, damage, hypertrophy, inflammation, and fibrosis as evidenced by decreased creatinine clearance and increased serum creatinine, blood urea nitrogen and urinary protein levels, tubular dilation, protein cast formation, glomerulosclerosis, glomerular enlargement, inflammatory cell accumulation, and collagen deposition. In addition, rats receiving anti-KS antibody had enhanced cardiac injury as indicated by cardiomyocyte hypertrophy, inflammation, myofibroblast accumulation, and fibrosis. Renal and cardiac injury caused by endogenous KS depletion was accompanied by increases in the expression of the proinflammatory genes tumor necrosis factor-alpha and intercellular adhesion molecule-1 and the profibrotic genes collagen I and III, transforming growth factor-beta, and tissue inhibitor of metalloproteinase-1. Taken together, these results implicate an important role for endogenous KS in protection against salt-induced renal and cardiovascular injury in rats by suppressing oxidative stress, inflammation, hypertrophy, and fibrosis. PMID- 22811487 TI - Vasopressin V1a receptor is required for nucleocytoplasmic transport of mineralocorticoid receptor. AB - We previously reported that a deficiency in the vasopressin V1a receptor (V1aR) results in type 4 renal tubular acidosis, which suggests that vasopressin exerts direct effects on the physiological actions of aldosterone. We investigated the role of vasopressin for nucleocytoplasmic transport of mineralocorticoid receptor (MR) in the intercalated cells. Vasopressin V1aR-deficient (V1aR(-/-)) mice showed largely decreased expression of MR and 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) in the medulla of the kidney, which was partially ameliorated by fludrocortisone treatment. The incubation of IN-IC cells, an intercalated cell line established from temperature-sensitive SV40 large T antigen-expressing rats, with aldosterone or vasopressin increased the nuclear-to-cytoplasmic ratio of the MR from 11.2 to 47.2% and from 18.7 to 61.2%, respectively, in 30 min without any changes in MR expression from the whole cell extract. The immunohistochemistry analysis of the IN-IC cells revealed the nuclear accumulation of MRs after a 30 min incubation with aldosterone or vasopressin. These effects were accompanied by an increase in regulator of chromosome condensation-1 (RCC-1) due to aldosterone and a decrease in Ran GTPase-activating protein 1 (Ran Gap1) due to vasopressin. RNA interference against V1aR abolished the nuclear accumulation of MR induced by aldosterone or vasopressin. Vasopressin increased PKCalpha and -beta(1) expression, and aldosterone increased PKCdelta and -zeta expression, but these effects were abolished with a V1aR knockdown. These results suggest that vasopressin directly regulates the nucleocytoplasmic transport of MRs via the V1aR in the intercalated cells of the collecting ducts. PMID- 22811488 TI - Insignificant effect of secretin in rodent models of polycystic kidney and liver disease. AB - Polycystic kidney (PKD) and liver (PLD) diseases cause significant morbidity and mortality. A large body of evidence indicates that cyclic AMP plays an important role in their pathogenesis. Clinical trials of drugs that reduce cyclic AMP levels in target tissues are now in progress. Secretin may contribute to adenylyl cyclase-dependent urinary concentration and is a major agonist of adenylyl cyclase in cholangiocytes. To investigate the role of secretin in PKD and PLD, we have studied the expression of secretin and the secretin receptor in rodent models orthologous to autosomal recessive (PCK rat) and dominant (Pkd2(-/WS25) mouse) PKD; the effects of exogenous secretin administration to PCK rats, PCK rats lacking circulating vasopressin (PCK(di/di)), and Pkd2(-/WS25) mice; and the impact of a nonfunctional secretin receptor on disease development in Pkd2( /WS25):SCTR(-/-) double mutants. Renal and hepatic secretin and secretin receptor mRNA and plasma secretin were increased in both models, and secretin receptor protein was increased in the kidneys and liver of Pkd2(-/WS25) mice. However, exogenous secretin administered subcutaneously via osmotic pumps had minimal or negligible effects and the absence of a functional secretin receptor had no influence on the severity of PKD or PLD. Therefore, it is unlikely that by itself secretin plays a significant role in the pathogenesis of PKD and/or PLD. PMID- 22811489 TI - Pyk2 regulates H+-ATPase-mediated proton secretion in the outer medullary collecting duct via an ERK1/2 signaling pathway. AB - Acid-secreting intercalated cells respond to changes in systemic pH through regulation of apical H(+) transporters. Little is known about the mechanism by which these cells sense changes in extracellular pH (pH(o)). Pyk2 is a nonreceptor tyrosine kinase activated by autophosphorylation at Tyr402 by cell specific stimuli, including decreased pH, and is involved in the regulation of MAPK signaling pathways and transporter activity. We examined whether the Pyk2 and MAPK signaling pathway mediates the response of transport proteins to decreased pH in outer medullary collecting duct cells. Immunoblot analysis of phosphorylated Pyk2 (Tyr402), ERK1/2 (Thr202/Tyr204), and p38 (Thr180/Tyr182) was used to assay protein activation. To examine specificity of kinase activation and its effects, we used Pyk2 small interfering RNA to knockdown Pyk2 expression levels, the Src kinase inhibitor 4-amino-5-(4-methylphenyl)-7-(t butyl)pyrazolo[3,4-d]-pyrimidine (PP 1) to inhibit Pyk2 phosphorylation, and the MEK inhibitor U0126 to inhibit ERK1/2 phosphorylation. The pH-sensitive fluorescent probe 2'-7'-bis(carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) was used to assay H(+) transporter activity. The activity of H(+) transporters was measured as the rate of intracellular pH (pH(i)) recovery after an NH(4)Cl prepulse. We show that Pyk2 is endogenously expressed and activated by acid pH in mouse-derived outer medullary collecting duct (mOMCD1) cells. Incubation of mOMCD1 cells in acid media [extracellular pH (pH(o)) 6.7] increased the phosphorylation of Pyk2, ERK1/2, and p38. Reduction in pH(i) induced by an NH(4)Cl prepulse also increased the phosphorylation of Pyk2, ERK1/2, and p38. Consistent with our previous studies, we found that mOMCD1 cells exhibit H(+)-ATPase and H(+),K(+)-ATPase activity. Pyk2 inhibition by Pyk2 siRNA and PP 1 prevented Pyk2 phosphorylation as well as H(+)-ATPase-mediated recovery in mOMCD1 cells. In addition, ERK1/2 inhibition by U0126 prevented acid-induced ERK1/2 phosphorylation and H(+)-ATPase-mediated pH(i) recovery but not phosphorylation of p38. We conclude that Pyk2 and ERK1/2 are required for increasing H(+)-ATPase, but not H(+),K(+)-ATPase, activity at decreased pH(i) in mOMCD1 cells. PMID- 22811491 TI - Podocyte-specific knockout of myosin 1e disrupts glomerular filtration. AB - Myosin 1e (myo1e) is an actin-dependent molecular motor that plays an important role in kidney functions. Complete knockout of myo1e in mice and Myo1E mutations in humans are associated with nephrotic syndrome and focal segmental glomerulosclerosis. In this paper, we tested the hypothesis that myo1e is necessary for normal functions of glomerular visceral epithelial cells (podocytes) using podocyte-targeted knockout of myo1e. Myo1e was selectively knocked out in podocytes using Cre-mediated recombination controlled by the podocin promoter. Myo1e loss from podocytes resulted in proteinuria, podocyte foot process effacement, and glomerular basement membrane disorganization. Our findings indicate that myo1e expression in podocytes is necessary for normal glomerular filtration and that podocyte defects are likely to represent the primary pathway leading to glomerular disease associated with Myo1E mutations. PMID- 22811490 TI - VEGF165b overexpression restores normal glomerular water permeability in VEGF164 overexpressing adult mice. AB - Vascular endothelial growth factor (VEGF)-A, a family of differentially spliced proteins produced by glomerular podocytes, maintains glomerular filtration barrier function. The expression of VEGF molecules is altered in human nephropathy. We aimed to determine the roles of the angiogenic VEGF(164) isoform, and the antiangiogenic VEGF(165)b isoform in mature, adult glomeruli in vivo using conditional, inducible transgenic overexpression systems in mice. Podocyte specific VEGF(164) overexpression (up to 100 days) was induced by oral administration of doxycycline to adult podocin-rtTA/TetO-VEGF(164) double transgenic mice. The consequences of simultaneous overexpression of VEGF(164) and VEGF(165)b were assessed in triple-transgenic podocin-rtTA/TetO-VEGF(164)/nephrin VEGF(165)b mice. Persistent VEGF(164) overexpression did not cause proteinuria but did increase glomerular ultrafiltration coefficient between days 3 and 7. Despite persistently increased VEGF(164) levels, glomerular ultrafiltration coefficient normalized by day 14 and remained normal up to 100 days. Decreased subpodocyte space (SPS) coverage of the glomerular capillary wall accompanied increased glomerular hydraulic conductivity in VEGF(164)-overexpressing mice. The changes in glomerular ultrafiltration coefficient and SPS coverage induced by 7 days of overexpression of VEGF(164) were not present in triple transgenic VEGF(164) and VEGF(165)b overexpressing mice. These results indicate that 1) the adult mouse glomerulus is relatively resistant to induced VEGF(164) overexpression. VEGF(164) overexpression altered glomerular permeability but did not cause proteinuria in these mature, adult animals; 2) the SPS is a dynamic VEGF-responsive modulator of glomerular function; and 3) the balance of VEGF isoforms plays a critical role in the regulation of glomerular permeability. VEGF(165)b is capable of preventing VEGF(164)-induced changes in glomerular permeability and ultrastructure in vivo. PMID- 22811492 TI - Using administrative medical claims data to supplement state disease registry systems for reporting zoonotic infections. AB - OBJECTIVE: To determine what, if any, opportunity exists in using administrative medical claims data for supplemental reporting to the state infectious disease registry system. MATERIALS AND METHODS: Cases of five tick-borne (Lyme disease (LD), babesiosis, ehrlichiosis, Rocky Mountain spotted fever (RMSF), tularemia) and two mosquito-borne diseases (West Nile virus, La Crosse viral encephalitis) reported to the Tennessee Department of Health during 2000-2009 were selected for study. Similarly, medically diagnosed cases from a Tennessee-based managed care organization (MCO) claims data warehouse were extracted for the same time period. MCO and Tennessee Department of Health incidence rates were compared using a complete randomized block design within a general linear mixed model to measure potential supplemental reporting opportunity. RESULTS: MCO LD incidence was 7.7 times higher (p<0.001) than that reported to the state, possibly indicating significant under-reporting (~196 unreported cases per year). MCO data also suggest about 33 cases of RMSF go unreported each year in Tennessee (p<0.001). Three cases of babesiosis were discovered using claims data, a significant finding as this disease was only recently confirmed in Tennessee. DISCUSSION: Data sharing between MCOs and health departments for vaccine information already exists (eg, the Vaccine Safety Datalink Rapid Cycle Analysis project). There may be a significant opportunity in Tennessee to supplement the current passive infectious disease reporting system with administrative claims data, particularly for LD and RMSF. CONCLUSIONS: There are limitations with administrative claims data, but health plans may help bridge data gaps and support the federal administration's vision of combining public and private data into one source. PMID- 22811493 TI - Ambient air pollution and the risk of stillbirth. AB - The purpose of the present study was to examine the risk of stillbirth associated with ambient air pollution during pregnancy. Using live birth and fetal death data from New Jersey from 1998 to 2004, the authors assigned daily concentrations of air pollution to each birth or fetal death. Generalized estimating equation models were used to estimate the relative odds of stillbirth associated with interquartile range increases in mean air pollutant concentrations in the first, second, and third trimesters and throughout the entire pregnancy. The relative odds of stillbirth were significantly increased with each 10-ppb increase in mean nitrogen dioxide concentration in the first trimester (odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.03, 1.31), each 3-ppb increase in mean sulfur dioxide concentration in the first (OR = 1.13, 95% CI: 1.01, 1.28) and third (OR = 1.26, 95% CI: 1.03, 1.37) trimesters, and each 0.4-ppm increase in mean carbon monoxide concentration in the second (OR = 1.14, 95% CI: 1.01, 1.28) and third (OR = 1.14, 95% CI: 1.06, 1.24) trimesters. Although ambient air pollution during pregnancy appeared to increase the relative odds of stillbirth, further studies are needed to confirm these findings and examine mechanistic explanations. PMID- 22811494 TI - Modification of the association between ambient air pollution and lung function by frailty status among older adults in the Cardiovascular Health Study. AB - The susceptibility of older adults to the health effects of air pollution is well recognized. Advanced age may act as a partial surrogate for conditions associated with aging. The authors investigated whether gerontologic frailty (a clinical health status metric) modified the association between ambient level of ozone or particulate matter with an aerodynamic diameter less than 10 um and lung function in 3,382 older adults using 7 years of follow-up data (1990-1997) from the Cardiovascular Health Study and its Environmental Factors Ancillary Study. Monthly average pollution and annual frailty assessments were related to up to 3 repeated measurements of lung function using cumulative summaries of pollution and frailty histories that accounted for duration as well as concentration. Frailty history was found to modify long-term associations of pollutants with forced vital capacity. For example, the decrease in forced vital capacity associated with a 70-ppb/month greater cumulative sum of monthly average ozone exposure was 12.3 mL (95% confidence interval: 10.4, 14.2) for a woman who had spent the prior 7 years prefrail or frail as compared with 4.7 mL (95% confidence interval: 3.8, 5.6) for a similar woman who was robust during all 7 years (interaction P < 0.001). PMID- 22811495 TI - dupA1 is associated with duodenal ulcer and high interleukin-8 secretion from the gastric mucosa. PMID- 22811497 TI - Documenting the methods history: would it improve the interpretability of studies? PMID- 22811498 TI - Improving ST-elevation-myocardial infarction care. PMID- 22811499 TI - Patient-centered adherence intervention after acute coronary syndrome hospitalization. AB - BACKGROUND: Adherence to cardioprotective medications in the year after acute coronary syndrome hospitalization is generally poor and is associated with increased risk of rehospitalization and mortality. Few interventions have specifically targeted this high-risk patient population to improve medication adherence. We hypothesize that a multifaceted patient-centered intervention could improve adherence to cardioprotective medications. METHODS AND RESULTS: To evaluate this intervention, we propose enrolling 280 patients with a recent acute coronary syndrome event into a multicenter randomized, controlled trial. The intervention comprises 4 main components: (1) pharmacist-led medication reconciliation and tailoring; (2) patient education; (3) collaborative care between pharmacist and primary care provider/cardiologist; and (4) 2 types of voice messaging (educational and medication refill reminder calls). Patients in the intervention arm will visit with the study pharmacist ~1 week post-hospital discharge. The pharmacist will work with the patient and collaborate with providers to reconcile medication issues. Voice messages will augment the educational process and remind patients to refill their cardioprotective medications. The study will compare the intervention versus usual care for 12 months. The primary outcome of interest is adherence using the ReComp method. Secondary and tertiary outcomes include achievement of targets for blood pressure and low-density lipoprotein, and reduction in the combined cardiovascular end points of myocardial infarction hospitalization, coronary revascularization, and all-cause mortality. Finally, we will also evaluate the cost-effectiveness of the intervention compared with usual care. CONCLUSIONS: If the intervention is effective in improving medication adherence and demonstrating a lower cost, the intervention has the potential to improve cardiovascular outcomes in this high risk patient population. PMID- 22811500 TI - Putting the Pediatric Cardiac Care Consortium in context: evaluation of scope and case mix compared with other reported surgical datasets. PMID- 22811501 TI - Reducing the cardiovascular disease burden: justified means for getting to the end. PMID- 22811502 TI - Performance measures in million hearts: 2 partners' perspective. PMID- 22811503 TI - Million hearts--where population health and clinical practice intersect. PMID- 22811504 TI - What works and in whom? A simple, easily applied, evidence-based approach to guidelines for statin therapy. PMID- 22811505 TI - Defining heart failure end points in ST-segment elevation myocardial infarction trials: integrating past experiences to chart a path forward. PMID- 22811507 TI - Circulation: cardiovascular quality and outcomes annual report, 2012. PMID- 22811506 TI - Coronary artery calcium and primary prevention risk assessment: what is the evidence? An updated meta-analysis on patient and physician behavior. PMID- 22811508 TI - Most important articles on cardiovascular disease among racial and ethnic minorities. AB - The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have published in the Circulation portfolio. The objective of this new series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research in the area of cardiovascular disease among racial and ethnic minorities. PMID- 22811509 TI - Experimental test for adaptive differentiation of ginseng populations reveals complex response to temperature. AB - BACKGROUND AND AIMS: Local climatic adaptation can influence species' response to climate change. If populations within a species are adapted to local climate, directional change away from mean climatic conditions may negatively affect fitness of populations throughout the species' range. METHODS: Adaptive differentiation to temperature was tested for in American ginseng (Panax quinquefolius) by reciprocally transplanting individuals from two populations, originating at different elevations, among temperature treatments in a controlled growth chamber environment. Fitness-related traits were measured in order to test for a population * temperature treatment interaction, and key physiological and phenological traits were measured to explain population differences in response to temperature. KEY RESULTS: Response to temperature treatments differed between populations, suggesting genetic differentiation of populations. However, the pattern of response of fitness-related variables generally did not suggest 'home temperature' advantage, as would be expected if populations were locally adapted to temperature alone. CONCLUSIONS: Failure consistently to detect a 'home temperature' advantage response suggests that adaptation to temperature is complex, and environmental and biotic factors that naturally covary with temperature in the field may be critical to understanding the nature of adaptation to temperature. PMID- 22811510 TI - Congratulations, you have been carefully chosen to represent an important developmental regulator! AB - BACKGROUND: Studying a process in a new species often relies on focusing our attention to a candidate gene, encoding a protein similar to one with a known function. Not all the choices seem to be prudent. SCOPE: This Viewpoint includes an overview of issues that are encountered during research of candidate genes. Defining a match for a gene of interest, deciding whether variation in ESTs or RNAseq data for a certain transcript, represent more than one gene. The problem of incorrect annotation of genes due to incorrect in-silico splicing, is also mentioned. The author's humble opinion on how to deal with these issues is provided. CONCLUSIONS: The vast amount of new sequence data provides us with great possibilities for giant leaps in our understanding. Still, we cannot afford to skip over the tedious steps required to confirm that we are indeed studying the correct gene, and try to be sure that the complex expression pattern we observe is not a composite of several genes. PMID- 22811511 TI - Spray cryotherapy is effective for bronchoscopic, endoscopic and open ablation of thoracic tissues. AB - OBJECTIVES: Spray cryotherapy (SCT) delivers a liquid nitrogen spray via a catheter to produce cellular death. This study seeks to determine the histological changes after bronchoscopic, endoscopic and open SCT on tissues in the thoracic cavity. METHODS: Yorkshire pigs underwent flexible bronchoscopy, endoscopy and thoracotomy for SCT of the airway, oesophagus and other intrathoracic structures, respectively. Variations in the duration and number of spray cycles for the same dosimetry were compared. RESULTS: Bronchoscopic SCT of the airway resulted in cellular death up to the cartilage layer. Endoscopic SCT of the oesophagus led to cell death up to the adventitial layer. Tissue necrosis was severe in the lung, of full thickness in the pleura, but very superficial in the great vessels. The extracellular matrix (ECM) of treated tissues remained well-preserved. Having shorter but more cycles of SCT decreased the depth of the cellular necrosis. One pig developed ventricular fibrillation during the surgery and expired. CONCLUSIONS: SCT causes reproducible tissue injury with the preserved ECM of most tissues within the thoracic cavity, making it enticing for ablation around vital structures like the great vessels with a decreased long term risk. Further study is warranted to investigate the adverse events during SCT. PMID- 22811512 TI - Is recombinant activated factor VII effective in the treatment of excessive bleeding after paediatric cardiac surgery? AB - A best evidence topic in paediatric cardiac surgery was written according to a structured protocol. The question addressed was whether recombinant activated factor VII was effective for the treatment of excessive bleeding after paediatric cardiac surgery. Altogether 150 papers were found using the reported search; 13 papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. A total of 311 children experienced excessive bleeding following cardiac surgery that was refractory to the conventional methods of achieving haemostasis. One hundred and ninety-two patients received the rFVIIa while 116 were in control arm from five studies. The primary end-point was on chest tube drainage, the plasma prothrombin time, the activated partial thromboplastin time after the administration of rFVIIa and the secondary end-point was reduction of blood products transfusion. Thrombosis was a complication in 8 patients (4.2%); three deaths (1.6%) but not attributable to thromboembolic events following the use of rFVIIa. Most of the studies failed to clearly state the doses but the extracted doses ranged between 30 and 180 ug/kg/dose, the interval between doses ranged between 15 and 120 min with a maximum of four doses. However, most of the patients had 180 ug/kg/dose with interval between dose of 2 h and maximum of two doses with dosage moderated with respect to weight, prior coagulopathy and responsiveness. There were two randomized studies with good sample size. One showed no significant differences in the secondary end points between the two arms and noted no adverse complications. However, the rFVIIa was used prophylactically. The other observed that there were no increase in thromboembolic events rather rFVIIa was effective in decreasing excessive bleeding that may complicate cardiac surgery in children. In conclusion, the studies were in support of the notion that the use of rFVIIa was effective in decreasing excessive bleeding which may complicate paediatric cardiac surgery, and care should be exercised when using it in the children on ECMO circuit. PMID- 22811516 TI - Understanding cancer mechanisms through network dynamics. AB - Cancer is a complex, multifaceted disease. Cellular systems are perturbed both during the onset and development of cancer, and the behavioural change of tumour cells usually involves a broad range of dynamic variations. To an extent, the difficulty of monitoring the systemic change has been alleviated by recent developments in the high-throughput technologies. At both the genomic as well as proteomic levels, the technological advances in microarray and mass spectrometry, in conjunction with computational simulations and the construction of human interactome maps have facilitated the progress of identifying disease-associated genes. On a systems level, computational approaches developed for network analysis are becoming especially useful for providing insights into the mechanism behind tumour development and metastasis. This review emphasizes network approaches that have been developed to study cancer and provides an overview of our current knowledge of protein-protein interaction networks, and how their systemic perturbation can be analysed by two popular network simulation methods: Boolean network and ordinary differential equations. PMID- 22811513 TI - Population survival from childhood cancer in Britain during 1978-2005 by eras of entry to clinical trials. AB - BACKGROUND: Inclusion in clinical trials is generally viewed as best practice for most newly diagnosed childhood cancers, but the impact on population-based survival has rarely been examined. PATIENTS AND METHODS: The population-based data were analysed for 25 853 children (66% of all registered childhood cancers) diagnosed in Britain during 1978-2005 with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma, non-Hodgkin lymphoma, medulloblastoma, neuroblastoma, Wilms tumour, hepatoblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and germ-cell tumours. The Kaplan-Meier survival curves were compared by log-rank tests. Time trends were analysed by Cox regression. Separate analyses were done for children with ALL, medulloblastoma and neuroblastoma according to clinically relevant age thresholds. RESULTS: Survival increased significantly during 1978-2005 for every diagnostic category; the annual reduction in risk of death ranged from 2.7% (rhabdomyosarcoma) to 12.0% (gonadal germ-cell tumours). Survival increased steadily between trial eras for ALL (age 1-14 years) and neuroblastoma (age 1-14 years), but changed little since the mid-1980s for medulloblastoma (age 0-2 years), osteosarcoma or Ewing sarcoma. CONCLUSIONS: Changes in survival between trial eras parallel those reported by the relevant clinical trials. The increasing level of participation in trials, facilitated by the organisation of specialist care, has underpinned the substantial improvements in survival seen at the population level. PMID- 22811517 TI - Local motifs in proteins combine to generate global functional moves. AB - Literature on the topological properties of folded proteins that has emerged as a field in its own right in the past decade is reviewed. Physics-based construction of coarse-grained models of proteins from knowledge of all-atom coordinates of the average structure is discussed. Once network is thus obtained with the node and link information, local motifs provide plethora of information on protein function. The hierarchical structure of the proteins manifested in the interrelations of local motifs is emphasized. Motifs are also related to modularity of the structure, and they quantify shifts in the landscapes upon conformational changes induced by, e.g. ligand binding. Redundancy emerges as a balance between local and global network descriptors and is related to the collectivity of the protein motions. Introducing weight on links followed by sequential removal of least cohesive contacts allows interactions in proteins to be represented as the superposition of essential and redundant sets. Lack of the former makes the network non-functional, while the latter ensures robust functioning under a wide range of perturbation scenarios. PMID- 22811518 TI - Risk of immunodeficiency virus infection may increase with vaccine-induced immune response. AB - To explore the efficacy of novel complementary prime-boost immunization regimens in a nonhuman primate model for HIV infection, rhesus monkeys primed by different DNA vaccines were boosted with virus-like particles (VLP) and then challenged by repeated low-dose rectal exposure to simian immunodeficiency virus (SIV). Characteristic of the cellular immune response after the VLP booster immunization were high numbers of SIV-specific, gamma interferon-secreting cells after stimulation with inactivated SIV particles, but not SIV peptides, and the absence of detectable levels of CD8(+) T cell responses. Antibodies specific to SIV Gag and SIV Env could be induced in all animals, but, consistent with a poor neutralizing activity at the time of challenge, vaccinated monkeys were not protected from acquisition of infection and did not control viremia. Surprisingly, vaccinees with high numbers of SIV-specific, gamma interferon secreting cells were infected fastest during the repeated low-dose exposures and the numbers of these immune cells in vaccinated macaques correlated with susceptibility to infection. Thus, in the absence of protective antibodies or cytotoxic T cell responses, vaccine-induced immune responses may increase the susceptibility to acquisition of immunodeficiency virus infection. The results are consistent with the hypothesis that virus-specific T helper cells mediate this detrimental effect and contribute to the inefficacy of past HIV vaccination attempts (e.g., STEP study). PMID- 22811519 TI - The adenovirus L4-22K protein is multifunctional and is an integral component of crucial aspects of infection. AB - A variety of cellular and viral processes are coordinately regulated during adenovirus (Ad) infection to achieve optimal virus production. The Ad late gene product L4-22K has been associated with disparate activities during infection, including the regulation of late gene expression, viral DNA packaging, and infectious virus production. We generated and characterized two L4-22K mutant viruses to further explore L4-22K functions during viral infection. Our results show that L4-22K is indeed important for temporal control of viral gene expression not only because it activates late gene expression but also because it suppresses early gene expression. We also show that the L4-22K protein binds to viral packaging sequences in vivo and is essential to recruit two other packaging proteins, IVa2 and L1-52/55K, to this region. The elimination of L4-22K gave rise to the production of only empty virus capsids and not mature virions, which confirms that the L4-22K protein is required for Ad genome packaging. Finally, L4 22K contributes to adenovirus-induced cell death by regulating the expression of the adenovirus death protein. Thus, the adenovirus L4-22K protein is multifunctional and an integral component of crucial aspects of infection. PMID- 22811520 TI - Strain-specific role of RNAs in prion replication. AB - Several lines of evidence suggest that various cofactors may be required for prion replication. PrP binds to polyanions, and RNAs were shown to promote the conversion of PrP(C) into PrP(Sc) in vitro. In the present study, we investigated strain-specific differences in RNA requirement during in vitro conversion and the potential role of RNA as a strain-specifying component of infectious prions. We found that RNase treatment impairs PrP(Sc)-converting activity of 9 murine prion strains by protein misfolding cyclic amplification (PMCA) in a strain-specific fashion. While the addition of RNA restored PMCA conversion efficiency, the effect of synthetic polynucleotides or DNA was strain dependent, showing a different promiscuity of prion strains in cofactor utilization. The biological properties of RML propagated by PMCA under RNA-depleted conditions were compared to those of brain-derived and PMCA material generated in the presence of RNA. Inoculation of RNA-depleted RML in Tga20 mice resulted in an increased incidence of a distinctive disease phenotype characterized by forelimb paresis. However, this abnormal phenotype was not conserved in wild-type mice or upon secondary transmission. Immunohistochemical and cell panel assay analyses of mouse brains did not reveal significant differences between mice injected with the different RML inocula. We conclude that replication under RNA-depleted conditions did not modify RML prion strain properties. Our study cannot, however, exclude small variations of RML properties that would explain the abnormal clinical phenotype observed. We hypothesize that RNA molecules may act as catalysts of prion replication and that variable capacities of distinct prion strains to utilize different cofactors may explain strain-specific dependency upon RNA. PMID- 22811521 TI - Early HLA-B*57-restricted CD8+ T lymphocyte responses predict HIV-1 disease progression. AB - Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57(+)) slow progressors and B57(+) rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57(+) individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57. PMID- 22811522 TI - The breadth and titer of maternal HIV-1-specific heterologous neutralizing antibodies are not associated with a lower rate of mother-to-child transmission of HIV-1. AB - It has been hypothesized that neutralizing antibodies (NAbs) should have broad specificity to be effective in protection against diverse HIV-1 variants. The mother-to-child transmission model of HIV-1 provides the opportunity to examine whether the breadth of maternal NAbs is associated with protection of infants from infection. Samples were obtained at delivery from 57 transmitting mothers (T) matched with 57 nontransmitting mothers (NT) enrolled in the multicenter French perinatal cohort (ANRS EPF CO1) between 1990 and 1996. Sixty-eight (59.6%) and 46 (40.4%) women were infected by B and non-B viruses, respectively. Neutralization assays were carried out with TZM-bl cells, using a panel of 10 primary isolates of 6 clades (A, B, C, F, CRF01_AE, and CRF02_AG), selected for their moderate or low sensitivity to neutralization. Neutralization breadths were not statistically different between T and NT mothers. However, a few statistically significant differences were observed, with higher frequencies or titers of NAbs toward several individual strains for NT mothers when the clade B infected or non-clade B-infected mothers were analyzed separately. Our study confirms that the breadth of maternal NAbs is not associated with protection of infants from infection. PMID- 22811523 TI - Cytoplasmic trafficking, endosomal escape, and perinuclear accumulation of adeno associated virus type 2 particles are facilitated by microtubule network. AB - Understanding adeno-associated virus (AAV) trafficking is critical to advance our knowledge of AAV biology and exploit novel aspects of vector development. Similar to the case for most DNA viruses, after receptor binding and entry, AAV traverses the cytoplasm and deposits the viral genome in the cell nucleus. In this study, we examined the role of the microtubule (MT) network in productive AAV infection. Using pharmacological reagents (e.g., nocodazole), live-cell imaging, and flow cytometry analysis, we demonstrated that AAV type 2 (AAV2) transduction was reduced by at least 2-fold in the absence of the MT network. Cell surface attachment and viral internalization were not dependent on an intact MT network. In treated cells at 2 h postinfection, quantitative three-dimensional (3D) microscopy determined a reproducible difference in number of intracellular particles associated with the nuclear membrane or the nucleus compared to that for controls (6 to 7% versus 26 to 30%, respectively). Confocal microscopy analysis demonstrated a direct association of virions with MTs, further supporting a critical role in AAV infection. To investigate the underling mechanisms, we employed single-particle tracking (SPT) to monitor the viral movement in real time. Surprisingly, unlike other DNA viruses (e.g., adenovirus [Ad] and herpes simplex virus [HSV]) that display bidirectional motion on MTs, AAV2 displays only unidirectional movement on MTs toward the nuclei, with peak instantaneous velocities at 1.5 to 3.5 MUm/s. This rapid and unidirectional motion on MTs lasts for about 5 to 10 s and results in AAV particles migrating more than 10 MUm in the cytoplasm reaching the nucleus very efficiently. Furthermore, electron microscopy analysis determined that, unlike Ad and HSV, AAV2 particles were transported on MTs within membranous compartments, and surprisingly, the acidification of AAV2-containing endosomes was delayed by the disruption of MTs. These findings together suggest an as-yet-undescribed model in which after internalization, AAV2 exploits MTs for rapid cytoplasmic trafficking in endosomal compartments unidirectionally toward the perinuclear region, where most acidification events for viral escape take place. PMID- 22811524 TI - Transmembrane protein aptamers that inhibit CCR5 expression and HIV coreceptor function. AB - We have exploited the ability of transmembrane domains to engage in highly specific protein-protein interactions to construct a new class of small proteins that inhibit HIV infection. By screening a library encoding hundreds of thousands of artificial transmembrane proteins with randomized transmembrane domains (termed "traptamers," for transmembrane aptamers), we isolated six 44- or 45 amino-acid proteins with completely different transmembrane sequences that inhibited cell surface and total expression of the HIV coreceptor CCR5. The traptamers inhibited transduction of human T cells by HIV reporter viruses pseudotyped with R5-tropic gp120 envelope proteins but had minimal effects on reporter viruses with X4-tropic gp120. Optimization of two traptamers significantly increased their activity and resulted in greater than 95% inhibition of R5-tropic reporter virus transduction without inhibiting expression of CD4, the primary HIV receptor, or CXCR4, another HIV coreceptor. In addition, traptamers inhibited transduction mediated by a mutant R5-tropic gp120 protein resistant to maraviroc, a small-molecule CCR5 inhibitor, and they dramatically inhibited replication of an R5-tropic laboratory strain of HIV in a multicycle infection assay. Genetic experiments suggested that the active traptamers specifically interacted with the transmembrane domains of CCR5 and that some of the traptamers interacted with different portions of CCR5. Thus, we have constructed multiple proteins not found in nature that interfere with CCR5 expression and inhibit HIV infection. These proteins may be valuable tools to probe the organization of the transmembrane domains of CCR5 and their relationship to its biological activities, and they may serve as starting points to develop new strategies to inhibit HIV infection. PMID- 22811525 TI - Preexposure to CpG protects against the delayed effects of neonatal respiratory syncytial virus infection. AB - Severe respiratory viral infection in early life is associated with recurrent wheeze and asthma in later childhood. Neonatal immune responses tend to be skewed toward T helper 2 (Th2) responses, which may contribute to the development of a pathogenic recall response to respiratory infection. Since neonatal Th2 skewing can be modified by stimulation with Toll-like receptor (TLR) ligands, we investigated the effect of exposure to CpG oligodeoxynucleotides (TLR9 ligands) prior to neonatal respiratory syncytial virus (RSV) infection in mice. CpG preexposure was protective against enhanced disease during secondary adult RSV challenge, with a reduction in viral load and an increase in Th1 responses. A similar Th1 switch and reduction in disease were observed if CpG was administered in the interval between neonatal infection and challenge. In neonates, CpG pretreatment led to a transient increase in expression of major histocompatibility complex class II (MHCII) and CD80 on CD11c-positive cells and gamma interferon (IFN-gamma) production by NK cells after RSV infection, suggesting that the protective effects may be mediated by antigen-presenting cells (APC) and NK cells. We conclude that the adverse effects of early-life respiratory viral infection on later lung health might be mitigated by conditions that promote TLR activation in the infant lung. PMID- 22811526 TI - Evolution of the hepatitis E virus polyproline region: order from disorder. AB - The hepatitis E virus (HEV) polyproline region (PPR) is an intrinsically unstructured region (IDR). This relaxed structure allows IDRs, which are implicated in the regulation of transcription and translation, to bind multiple ligands. Originally the nucleotide variability seen in the HEV PPR was assumed to be due to high rates of insertion and deletion. This study shows that the mutation rate is about the same in the PPR as in the rest of the nonstructural polyprotein. The difference between the PPR and the rest of the polyprotein is due to the higher tolerance of the PPR for substitutions at the first and second codon positions. With this higher promiscuity there is a shift in nucleotide occupation of these codons leading to translation of more cytosine residues: a shift that leads to more proline, alanine, serine, and threonine being encoded rather than histidine, phenylalanine, tryptophan, and tyrosine. This pattern of amino acid usage is typical of proline-rich IDRs. Increased usage of cytosine also leads to >22% of all amino acids in the PPR being prolines. Alignments of PPR sequences from HEV strains representing all genotypes indicate that all zoonotic isolates share an ancestor, and the carboxyl half of the PPR is more tolerant of mutations than the amino half. The evolution of HEV PPR, in contrast with that of the rest of the nonstructural polyprotein, is molded by pressures that lead toward increased proline usage with a corresponding decrease in the usage of aromatic amino acids, favoring formation of IDR structures. PMID- 22811527 TI - Three murine leukemia virus integration regions within 100 kilobases upstream of c-myb are proximal to the 5' regulatory region of the gene through DNA looping. AB - Retroviruses integrated into genomic DNA participate in long-range gene activation from as far away as several hundred kilobases. Hypotheses have been put forth to account for these phenomena, but data have not been provided to support a physical mechanism that explains long-range activation. In murine leukemia virus-induced myeloid leukemia in mice, integrated proviruses have been found upstream of c-myb in three regions, named Mml1, Mml2, and Mml3 (25, 50, and 70 kb upstream, respectively). The transcription factor c-Myb is an oncogene whose dysregulation and/or mutation can lead to human leukemia. We hypothesized that the murine c-myb upstream region contains regulatory elements accessed by the retrovirus. To identify regulatory sites in the murine c-myb upstream region, we looked by chromatin immunoprecipitation with microarray technology (ChIP-on chip) for histone modifications implicating gene activation in normal cells. H3K4me3, H3K4me1, and H3K9/14ac were enriched at Mml1 and/or Mml2 in the myeloblastic cell line M1, which expresses c-myb. The enrichment of all of these histone marks decreased with differentiation-induced downregulation of the gene in M1 cells but increased and spread in tumor cells containing integrated provirus. Importantly, using chromosome conformation capture (3C)-quantitative PCR assays, interactions between the 5' region, including the promoter and all Mml sites (Mml1, Mml2, and Mml3), were detected due to DNA looping in M1 cells and tumor cells with provirus in Mml1, Mml2, or Mml3. Therefore, our study provides a new mechanism of retrovirus insertional mutagenesis whereby spatial chromatin organization allows distally located provirus, with its own enhancer elements, to access the 5' regulatory region of the gene. PMID- 22811528 TI - Moloney leukemia virus type 10 inhibits reverse transcription and retrotransposition of intracisternal a particles. AB - Moloney leukemia virus type 10 protein (MOV10) is an RNA helicase that is induced by type I interferon. It inhibits HIV replication at several steps of its replicative cycle. Of interest, MOV10 is a component of mRNA processing (P) bodies, which inhibit retrotransposition (RTP) of intracisternal A particles (IAP). In this report, we studied the effects of MOV10 on IAP RTP and its dependence on P bodies. Indeed, MOV10 inhibited IAP RTP. It decreased significantly not only the products of reverse transcriptase but also its endogenous activity. MOV10 also associated with IAP RNA. Furthermore, although it was found in IAP virus-like particles, it did not affect their incorporation of IAP RNA, primer tRNAPhe (phenylalanine tRNA), or IAP Gag. Concerning P bodies, the exogenously expressed MOV10 had no effect on their size and number, and the inhibition of IAP RTP persisted despite the depletion of their RCK subunit. Thus, by interfering with reverse transcription, MOV10 inhibits IAP RTP, and this inhibition is independent of P bodies. PMID- 22811529 TI - Crystallographic Analysis of Rotavirus NSP2-RNA Complex Reveals Specific Recognition of 5' GG Sequence for RTPase Activity. AB - Rotavirus nonstructural protein NSP2, a functional octamer, is critical for the formation of viroplasms, which are exclusive sites for replication and packaging of the segmented double-stranded RNA (dsRNA) rotavirus genome. As a component of replication intermediates, NSP2 is also implicated in various replication-related activities. In addition to sequence-independent single-stranded RNA-binding and helix-destabilizing activities, NSP2 exhibits monomer-associated nucleoside and 5' RNA triphosphatase (NTPase/RTPase) activities that are mediated by a conserved H225 residue within a narrow enzymatic cleft. Lack of a 5' gamma-phosphate is a common feature of the negative-strand RNA [(-)RNA] of the packaged dsRNA segments in rotavirus. Strikingly, all (-)RNAs (of group A rotaviruses) have a 5' GG dinucleotide sequence. As the only rotavirus protein with 5' RTPase activity, NSP2 is implicated in the removal of the gamma-phosphate from the rotavirus ( )RNA. To understand how NSP2, despite its sequence-independent RNA-binding property, recognizes (-)RNA to hydrolyze the gamma-phosphate within the catalytic cleft, we determined a crystal structure of NSP2 in complex with the 5' consensus sequence of minus-strand rotavirus RNA. Our studies show that the 5' GG of the bound oligoribonucleotide interacts extensively with highly conserved residues in the NSP2 enzymatic cleft. Although these residues provide GG-specific interactions, surface plasmon resonance studies suggest that the C-terminal helix and other basic residues outside the enzymatic cleft account for sequence independent RNA binding of NSP2. A novel observation from our studies, which may have implications in viroplasm formation, is that the C-terminal helix of NSP2 exhibits two distinct conformations and engages in domain-swapping interactions, which result in the formation of NSP2 octamer chains. PMID- 22811530 TI - HLA class I-mediated control of HIV-1 in the Japanese population, in which the protective HLA-B*57 and HLA-B*27 alleles are absent. AB - We investigated the effect of HLA class I alleles on clinical parameters for HIV 1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B*57 and HLA-B*27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power. PMID- 22811531 TI - Adenovirus serotype 26 utilizes CD46 as a primary cellular receptor and only transiently activates T lymphocytes following vaccination of rhesus monkeys. AB - The cellular receptor utilized by adenovirus serotype 26 (Ad26) has remained unclear. Here we show that Ad26 transduction is CD46-dependent and is efficiently blocked by anti-CD46 but not anti-CAR antibodies, demonstrating that Ad26 utilizes CD46 as a primary cellular receptor. Moreover, following Ad26 vaccination of rhesus monkeys, we did not observe sustained activation of peripheral or mucosal vector-specific CD4(+) T lymphocytes. These data contribute to our understanding of Ad26 as a candidate vaccine vector. PMID- 22811532 TI - Selective modification of adenovirus replication can be achieved through rational mutagenesis of the adenovirus type 5 DNA polymerase. AB - Mutations that reduce the efficiency of deoxynucleoside (dN) triphosphate (dNTP) substrate utilization by the HIV-1 DNA polymerase prevent viral replication in resting cells, which contain low dNTP concentrations, but not in rapidly dividing cells such as cancer cells, which contain high levels of dNTPs. We therefore tested whether mutations in regions of the adenovirus type 5 (Ad5) DNA polymerase that interact with the dNTP substrate or DNA template could alter virus replication. The majority of the mutations created, including conservative substitutions, were incompatible with virus replication. Five replication competent mutants were recovered from 293 cells, but four of these mutants failed to replicate in A549 lung carcinoma cells and Wi38 normal lung cells. Purified polymerase proteins from these viruses exhibited only a 2- to 4-fold reduction in their dNTP utilization efficiency but nonetheless could not be rescued, even when intracellular dNTP concentrations were artificially raised by the addition of exogenous dNs to virus-infected A549 cells. The fifth mutation (I664V) reduced biochemical dNTP utilization by the viral polymerase by 2.5-fold. The corresponding virus replicated to wild-type levels in three different cancer cell lines but was significantly impaired in all normal cell lines in which it was tested. Efficient replication and virus-mediated cell killing were rescued by the addition of exogenous dNs to normal lung fibroblasts (MRC5 cells), confirming the dNTP-dependent nature of the polymerase defect. Collectively, these data provide proof-of-concept support for the notion that conditionally replicating, tumor selective adenovirus vectors can be created by modifying the efficiency with which the viral DNA polymerase utilizes dNTP substrates. PMID- 22811533 TI - Spread of a distinct Stx2-encoding phage prototype among Escherichia coli O104:H4 strains from outbreaks in Germany, Norway, and Georgia. AB - Shiga toxin 2 (Stx2)-producing Escherichia coli (STEC) O104:H4 caused one of the world's largest outbreaks of hemorrhagic colitis and hemolytic uremic syndrome in Germany in 2011. These strains have evolved from enteroaggregative E. coli (EAEC) by the acquisition of the Stx2 genes and have been designated enteroaggregative hemorrhagic E. coli. Nucleotide sequencing has shown that the Stx2 gene is carried by prophages integrated into the chromosome of STEC O104:H4. We studied the properties of Stx2-encoding bacteriophages which are responsible for the emergence of this new type of E. coli pathogen. For this, we analyzed Stx bacteriophages from STEC O104:H4 strains from Germany (in 2001 and 2011), Norway (2006), and the Republic of Georgia (2009). Viable Stx2-encoding bacteriophages could be isolated from all STEC strains except for the Norwegian strain. The Stx2 phages formed lysogens on E. coli K-12 by integration into the wrbA locus, resulting in Stx2 production. The nucleotide sequence of the Stx2 phage P13374 of a German STEC O104:H4 outbreak was determined. From the bioinformatic analyses of the prophage sequence of 60,894 bp, 79 open reading frames were inferred. Interestingly, the Stx2 phages from the German 2001 and 2011 outbreak strains were found to be identical and closely related to the Stx2 phages from the Georgian 2009 isolates. Major proteins of the virion particles were analyzed by mass spectrometry. Stx2 production in STEC O104:H4 strains was inducible by mitomycin C and was compared to Stx2 production of E. coli K-12 lysogens. PMID- 22811534 TI - Optimum length and flexibility of reovirus attachment protein sigma1 are required for efficient viral infection. AB - Reovirus attachment protein sigma1 is an elongated trimer with head-and-tail morphology that engages cell-surface carbohydrate and junctional adhesion molecule A (JAM-A). The sigma1 protein is comprised of three domains partitioned by two flexible linkers termed interdomain regions (IDRs). To determine the importance of sigma1 length and flexibility at different stages of reovirus infection, we generated viruses with mutant sigma1 molecules of altered length and flexibility and tested these viruses for the capacity to bind the cell surface, internalize, uncoat, induce protein synthesis, assemble, and replicate. We reduced the length of the alpha-helical sigma1 tail to engineer mutants L1 and L2 and deleted midpoint and head-proximal sigma1 IDRs to generate DeltaIDR1 and DeltaIDR2 mutant viruses, respectively. Decreasing length or flexibility of sigma1 resulted in delayed reovirus infection and reduced viral titers. L1, L2, and DeltaIDR1 viruses but not DeltaIDR2 virus displayed reduced cell attachment, but altering sigma1 length or flexibility did not diminish the efficiency of virion internalization. Replication of DeltaIDR2 virus was hindered at a postdisassembly step. Differences between wild-type and sigma1 mutant viruses were not attributable to alterations in sigma1 folding, as determined by experiments assessing engagement of cell-surface carbohydrate and JAM-A by the length and IDR mutant viruses. However, DeltaIDR1 virus harbored substantially less sigma1 on the outer capsid. Taken together, these data suggest that sigma1 length is required for reovirus binding to cells. In contrast, IDR1 is required for stable sigma1 encapsidation, and IDR2 is required for a postuncoating replication step. Thus, the structural architecture of sigma1 is required for efficient reovirus infection of host cells. PMID- 22811535 TI - Comparable fitness and transmissibility between oseltamivir-resistant pandemic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation. AB - Limited antiviral compounds are available for the control of influenza, and the emergence of resistant variants would further narrow the options for defense. The H275Y neuraminidase (NA) mutation, which confers resistance to oseltamivir carboxylate, has been identified among the seasonal H1N1 and 2009 pandemic influenza viruses; however, those H275Y resistant variants demonstrated distinct epidemiological outcomes in humans. Specifically, dominance of the H275Y variant over the oseltamivir-sensitive viruses was only reported for a seasonal H1N1 variant during 2008-2009. Here, we systematically analyze the effect of the H275Y NA mutation on viral fitness and transmissibility of A(H1N1)pdm09 and seasonal H1N1 influenza viruses. The NA genes from A(H1N1)pdm09 A/California/04/09 (CA04), seasonal H1N1 A/New Caledonia/20/1999 (NewCal), and A/Brisbane/59/2007 (Brisbane) were individually introduced into the genetic background of CA04. The H275Y mutation led to reduced NA enzyme activity, an increased K(m) for 3'-sialylactose or 6'-sialylactose, and decreased infectivity in mucin-secreting human airway epithelial cells compared to the oseltamivir-sensitive wild-type counterparts. Attenuated pathogenicity in both RG-CA04(NA-H275Y) and RG-CA04 * Brisbane(NA H275Y) viruses was observed in ferrets compared to RG-CA04 virus, although the transmissibility was minimally affected. In parallel experiments using recombinant Brisbane viruses differing by hemagglutinin and NA, comparable direct contact and respiratory droplet transmissibilities were observed among RG NewCal(HA,NA), RG-NewCal(HA,NA-H275Y), RG-Brisbane(HA,NA-H275Y), and RG NewCal(HA) * Brisbane(NA-H275Y) viruses. Our results demonstrate that, despite the H275Y mutation leading to a minor reduction in viral fitness, the transmission potentials of three different antigenic strains carrying this mutation were comparable in the naive ferret model. PMID- 22811536 TI - Expression of the infectious salmon anemia virus receptor on atlantic salmon endothelial cells correlates with the cell tropism of the virus. AB - Infectious salmon anemia (ISA) is a World Organization for Animal Health (OIE) listed disease of farmed Atlantic salmon, characterized by slowly developing anemia and circulatory disturbances. The disease is caused by ISA virus (ISAV) in the Orthomyxoviridae family; hence, it is related to influenza. Here we explore the pathogenesis of ISA by focusing on virus tropism, receptor tissue distribution, and pathological changes in experimentally and naturally infected Atlantic salmon. Using immunohistochemistry on ISAV-infected Atlantic salmon tissues with antibody to viral nucleoprotein, endotheliotropism was demonstrated. Endothelial cells lining the circulatory system were found to be infected, seemingly noncytolytic, and without vasculitis. No virus could be found in necrotic parenchymal cells. From endothelium, the virus budded apically and adsorbed to red blood cells (RBCs). No infection or replication within RBCs was detected, but hemophagocytosis was observed, possibly contributing to the severe anemia in fish with this disease. Similarly to what has been done in studies of influenza, we examined the pattern of virus attachment by using ISAV as a probe. Here we detected the preferred receptor of ISAV, 4-O-acetylated sialic acid (Neu4,5Ac(2)). To our knowledge, this is the first report demonstrating the in situ distribution of this sialic acid derivate. The pattern of virus attachment mirrored closely the distribution of infection, showing that the virus receptor is important for cell tropism, as well as for adsorption to RBCs. PMID- 22811537 TI - Homeostasis and function of regulatory T cells in HIV/SIV infection. AB - Regulatory T cells (Tregs) play a pivotal role in the maintenance of tolerance as well as in the control of immune activation, particularly during chronic infections. In the setting of HIV infection, the majority of studies have reported an increase in Treg frequency but a decrease in absolute number in all immune compartments of HIV-infected individuals. Several nonexclusive mechanisms have been postulated to explain this preferential Treg accumulation, including peripheral survival, increased proliferation, increased peripheral conversion, and tissue redistribution. The role played by Tregs during HIV infection is still poorly understood, as two opposing hypotheses have been proposed. A detrimental role of Tregs during HIV infection was suggested based on the evidence that Tregs suppress virus-specific immune responses. Conversely, Tregs could be beneficial by limiting immune activation, thus controlling the availability of HIV targets as well as preventing immune-based pathologies. Despite the technical difficulties, getting a better understanding of the mechanisms regulating Treg dynamics remains important, as it will help determine whether we can successfully manipulate Treg function or number to the advantage of the infected host. The aim of this review is thus to discuss the recent findings on Treg homeostasis and function in the setting of HIV infection. PMID- 22811538 TI - Cleavage activation of the human-adapted influenza virus subtypes by matriptase reveals both subtype and strain specificities. AB - Cleavage activation of the hemagglutinin (HA) precursor is an essential step in the influenza virus replication cycle that is driven by host cell proteases. HA cleavage activation is required for virus-endosome membrane fusion and the subsequent release of the influenza virus genome into the cytoplasm. Previous studies have determined that HA cleavage is most likely driven by either membrane bound or extracellular trypsin-like proteases that reside in the respiratory tract. However, there is still uncertainty regarding which proteases are critical for HA cleavage in vivo. Therefore, further investigation of HA cleavage activation is needed in order to gain insight into the critical proteases involved. Matriptase is a member of the type II transmembrane serine protease family that is highly expressed in a membrane-bound form throughout the respiratory tract. One feature of matriptase is that, once activated, the catalytic domain is secreted into the extracellular space and so serves as a functional extracellular protease. In this study, we have determined that the secreted, catalytic domain of matriptase has the ability to cleave and activate HA from the influenza virus H1 subtype but not the H2 and H3 subtypes. Furthermore, matriptase selectively cleaved the HA of particular strains within the H1 subtype, revealing both subtype and H1 strain specificity. Matriptase was also found to activate thrombolytic zymogens that have been shown to cleave and activate the influenza virus HA. Our data demonstrate that matriptase has the ability to cleave HA directly or indirectly by activating HA-cleaving zymogens. PMID- 22811539 TI - TNFRSF25 agonistic antibody and galectin-9 combination therapy controls herpes simplex virus-induced immunoinflammatory lesions. AB - Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4(+) T cells. Hence, targeting proinflammatory CD4(+) T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naive animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4(+) gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness. PMID- 22811540 TI - Serological profile of torque teno sus virus species 1 (TTSuV1) in pigs and antigenic relationships between two TTSuV1 genotypes (1a and 1b), between two species (TTSuV1 and -2), and between porcine and human anelloviruses. AB - The family Anelloviridae includes human and animal torque teno viruses (TTVs) with extensive genetic diversity. The antigenic diversity among anelloviruses has never been assessed. Using torque teno sus virus (TTSuV) as a model, we describe here the first investigation of the antigenic relationships among different anelloviruses. Using a TTSuV genotype 1a (TTSuV1a) or TTSuV1b enzyme-linked immunosorbent assay (ELISA) based on the respective putative ORF1 capsid antigen and TTSuV1-specific real-time PCR, the combined serological and virological profile of TTSuV1 infection in pigs was determined and compared with that of TTSuV2. TTSuV1 is likely not associated with porcine circovirus-associated disease (PCVAD), because both the viral loads and antibody levels were not different between affected and unaffected pigs and because there was no synergistic effect of concurrent PCV2/TTSuV1 infections. We did observe a higher correlation of IgG antibody levels between anti-TTSuV1a and -TTSuV1b than between anti-TTSuV1a or -1b and anti-TTSuV2 antibodies in these sera, implying potential antigenic cross-reactivity. To confirm this, rabbit antisera against the putative capsid proteins of TTSuV1a, TTSuV1b, or TTSuV2 were generated, and the antigenic relationships among these TTSuVs were analyzed by an ELISA and by an immunofluorescence assay (IFA) using PK-15 cells transfected with one of the three TTSuV ORF1 constructs. The results demonstrate antigenic cross-reactivity between the two genotypes TTSuV1a and TTSuV1b but not between the two species TTSuV1a or -1b and TTSuV2. Furthermore, an anti-genogroup 1 human TTV antiserum did not react with any of the three TTSuV antigens. These results have important implications for an understanding of the diversity of anelloviruses as well as for the classification and vaccine development of TTSuVs. PMID- 22811541 TI - Live attenuated influenza vaccine provides superior protection from heterologous infection in pigs with maternal antibodies without inducing vaccine-associated enhanced respiratory disease. AB - Control of swine influenza A virus (IAV) in the United States is hindered because inactivated vaccines do not provide robust cross-protection against the multiple antigenic variants cocirculating in the field. Vaccine efficacy can be limited further for vaccines administered to young pigs that possess maternally derived immunity. We previously demonstrated that a recombinant A/sw/Texas/4199-2/1998 (TX98) (H3N2) virus expressing a truncated NS1 protein is attenuated in swine and has potential for use as an intranasal live attenuated influenza virus (LAIV) vaccine. In the present study, we compared 1 dose of intranasal LAIV with 2 intramuscular doses of TX98 whole inactivated virus (WIV) with adjuvant in weanling pigs with and without TX98-specific maternally derived antibodies (MDA). Pigs were subsequently challenged with wild-type homologous TX98 H3N2 virus or with an antigenic variant, A/sw/Colorado/23619/1999 (CO99) (H3N2). In the absence of MDA, both vaccines protected against homologous TX98 and heterologous CO99 shedding, although the LAIV elicited lower hemagglutination inhibition (HI) antibody titers in serum. The efficacy of both vaccines was reduced by the presence of MDA; however, WIV vaccination of MDA-positive pigs led to dramatically enhanced pneumonia following heterologous challenge, a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). A single dose of LAIV administered to MDA-positive pigs still provided partial protection from CO99 and may be a safer vaccine for young pigs under field conditions, where dams are routinely vaccinated and diverse IAV strains are in circulation. These results have implications not only for pigs but also for other influenza virus host species. PMID- 22811542 TI - Construction of a gammaretrovirus with a novel tropism and wild-type replication kinetics capable of using human APJ as entry receptor. AB - We have constructed a replication-competent gammaretrovirus (SL3-AP) capable of using the human G-protein-coupled receptor hAPJ as its entry receptor. The envelope protein of the virus was made by insertion of the 13-amino-acid peptide ligand for hAPJ, flanked by linker sequences, into one of the variable loops of the receptor binding domain of SL3-2, a murine leukemia virus (MLV) that uses the xenotropic-polytropic virus receptor Xpr1 and which has a host range limited to murine cells. This envelope protein can utilize hAPJ as well as murine Xpr1 for entry into host cells with equal efficiencies. In addition, the SL3-AP virus replicates in cells expressing either of its receptors, hAPJ and murine Xpr1, and causes resistance to superinfection and downregulation of hAPJ in infected cells. Thus, SL3-AP is the first example of a retargeted replication-competent retrovirus, with replication characteristics and receptor interference properties similar to those of natural isolates. PMID- 22811543 TI - An effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of herpes simplex virus 2 infection. AB - Herpes simplex virus 2 infection is characterized by cycles of viral quiescence and reactivation. CD8(+) T cells persist at the site of viral reactivation, at the genital dermal-epidermal junction contiguous to neuronal endings of sensory neurons, for several months after herpes lesion resolution. To evaluate whether these resident CD8(+) T cells frequently encounter HSV antigen even during times of asymptomatic viral infection, we analyzed the transcriptional output of CD8(+) T cells captured by laser microdissection from human genital skin biopsy specimens during the clinically quiescent period of 8 weeks after lesion resolution. These CD8(+) T cells expressed a characteristic set of genes distinct from those of three separate control cell populations, and network and pathway analyses revealed that these T cells significantly upregulated antiviral genes such as GZMB, PRF1, INFG, IL-32, and LTA, carbohydrate and lipid metabolism related genes such as GLUT-1, and chemotaxis and recruitment genes such as CCL5 and CCR1, suggesting a possible feedback mechanism for the recruitment of CD8(+) T cells to the site of infection. Many of these transcripts are known to have half-lives of <48 h, suggesting that cognate antigen is released frequently into the mucosa and that resident CD8(+) T cells act as functional effectors in controlling viral spread. PMID- 22811544 TI - CD8 marks a subpopulation of lung-derived dendritic cells with differential responsiveness to viral infection and toll-like receptor stimulation. AB - An increasing number of studies suggest that individual subsets of dendritic cells (DC) exhibit distinct capabilities with regard to the generation of the adaptive immune response. In this study, we evaluated the properties of a relatively unexplored DC subset present in the lung-draining mediastinal lymph node. This subset expresses the airway dendritic cell marker CD103 together with CD8. These DC were of interest given that our previous studies using a model of respiratory infection with vaccinia virus revealed a distinct difference in the ability of CD103(+) DC to prime T cells that correlated inversely with the expression of CD8, suggesting a differential role of these DC in the context of respiratory virus infection. To expand our understanding of the role of this DC population, we performed analyses to elucidate the phenotype, migratory capacity, responsiveness to innate stimuli, and priming capacity of CD8(+) CD103(+) DC. We found that expression of surface markers on these DC was similar to that of CD8( ) CD103(+) DC, supporting their close relationship. Further, the two DC types were similar with regard to antigen uptake. However, although both CD103(+) subsets originated from the lung, CD8-bearing CD103(+) DC appeared in the lymph node with delayed kinetics following virus infection. While this subset exhibited increased responsiveness to a number of Toll-like receptor (TLR) agonists, their response to infection was virus specific, demonstrating poor responsiveness to vaccinia virus infection but robust maturation following infection with parainfluenza virus 5 or influenza virus. These findings show that CD8 marks a population of lung airway-derived DC with distinct migratory and maturation responses that likely contribute differentially to the immune response depending on the infecting pathogen. PMID- 22811545 TI - A reversed framework for the identification of microRNA-target pairs in plants. AB - Most plant microRNAs (miRNAs) perform their repressive regulation through target cleavages. The resulting slicing sites on the target transcripts could be mapped by sequencing of the 3'-cleavage remnants, called degradome sequencing. The high sequence complementarity between miRNAs and their targets has greatly facilitated the development of the target prediction tools for plant miRNAs. The prediction results were then subjected to degradome sequencing data-based validation, through which numerous miRNA-target interactions have been extracted. However, some drawbacks are unavoidable when using this forward approach. Essentially, a known list of plant miRNAs should be obtained in advance of target prediction and validation. This becomes an obstacle to discover novel miRNAs and their targets. Here, after reviewing the current available algorithms for reverse identification of miRNA-target pairs in plants, a case study was performed by using a newly established framework with adjustable parameters. In this workflow, integration of degradome and ARGONAUTE 1-enriched small RNA sequencing data was recommended to do a relatively comprehensive and reliable search. Besides, several computational algorithms such as BLAST, target plots and RNA secondary structure prediction were used. The results demonstrated the prevalent utility of the reversed approach for uncovering miRNA-target interactions in plants. PMID- 22811546 TI - Fast and accurate read alignment for resequencing. AB - MOTIVATION: Next-generation sequence analysis has become an important task both in laboratory and clinical settings. A key stage in the majority sequence analysis workflows, such as resequencing, is the alignment of genomic reads to a reference genome. The accurate alignment of reads with large indels is a computationally challenging task for researchers. RESULTS: We introduce SeqAlto as a new algorithm for read alignment. For reads longer than or equal to 100 bp, SeqAlto is up to 10 * faster than existing algorithms, while retaining high accuracy and the ability to align reads with large (up to 50 bp) indels. This improvement in efficiency is particularly important in the analysis of future sequencing data where the number of reads approaches many billions. Furthermore, SeqAlto uses less than 8 GB of memory to align against the human genome. SeqAlto is benchmarked against several existing tools with both real and simulated data. AVAILABILITY: Linux and Mac OS X binaries free for academic use are available at http://www.stanford.edu/group/wonglab/seqalto CONTACT: whwong@stanford.edu. PMID- 22811547 TI - Troponin T and plasma collagen peptides in heart failure. PMID- 22811548 TI - The three-phase terrain of heart failure readmissions. PMID- 22811549 TI - Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical staging. PMID- 22811550 TI - Management of left ventricular rupture after myocardial infarction solely with ECMO. PMID- 22811551 TI - Eptifibatide for the treatment of HeartMate II left ventricular assist device thrombosis. PMID- 22811552 TI - A diagnostic long shot: dyspnea and cardiomegaly in a 32-year-old male with unilateral leg swelling. PMID- 22811554 TI - Letter by Palazzuoli et al regarding article, "Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function". PMID- 22811556 TI - Palliative sedation: not just normal medical practice. Ethical reflections on the Royal Dutch Medical Association's guideline on palliative sedation. AB - The main premise of the Royal Dutch Medical Association's (RDMA) guideline on palliative sedation is that palliative sedation, contrary to euthanasia, is normal medical practice. Although we do not deny the ethical distinctions between euthanasia and palliative sedation, we will critically analyse the guideline's argumentation strategy with which euthanasia is demarcated from palliative sedation. First, we will analyse the guideline's main premise, which entails that palliative sedation is normal medical treatment. After this, we will critically discuss three crucial propositions of the guideline that are used to support this premise: (1) the patient's life expectancy should not exceed 2 weeks; (2) the aim of the physician should be to relieve suffering and (3) expert consultation is optional. We will conclude that, if inherent problematic aspects of palliative sedation are taken seriously, palliative sedation is less normal than it is now depicted in the guideline. PMID- 22811557 TI - ABCC6 localizes to the mitochondria-associated membrane. AB - RATIONALE: Mutations of the orphan transporter ABCC6 (ATP-binding cassette, subfamily C, member 6) cause the connective tissue disorder pseudoxanthoma elasticum. ABCC6 was thought to be located on the plasma membrane of liver and kidney cells. OBJECTIVE: Mouse systems genetics and bioinformatics suggested that ABCC6 deficiency affects mitochondrial gene expression. We therefore tested whether ABCC6 associates with mitochondria. METHODS AND RESULTS: We found ABCC6 in crude mitochondrial fractions and subsequently pinpointed its localization to the purified mitochondria-associated membrane fraction. Cell-surface biotinylation in hepatocytes confirmed that ABCC6 is intracellular. Abcc6 knockout mice demonstrated mitochondrial abnormalities and decreased respiration reserve capacity. CONCLUSIONS: Our finding that ABCC6 localizes to the mitochondria-associated membrane has implications for its mechanism of action in normal and diseased states. PMID- 22811558 TI - Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22alpha promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. AB - RATIONALE: We previously identified conserved G/C Repressor elements in the promoters of most smooth muscle cell (SMC) marker genes and demonstrated that mutation of this element within the SM22alpha promoter nearly abrogated repression of this transgene after vascular wire injury or within lesions of ApoE /- mice. However, the mechanisms regulating the activity of the G/C Repressor are unknown, although we have previously shown that phenotypic switching of cultured SMC is dependent on Krupple-like factor (KLF)4. OBJECTIVE: The goals of the present studies were to ascertain if (1) injury-induced repression of SM22alpha gene after vascular injury is mediated through KLF4 binding to the G/C Repressor element and (2) the transcriptional repressor activity of KLF4 on SMC marker genes is dependent on cooperative binding with pELK-1 (downstream activator of the mitogen-activated protein kinase pathway) and subsequent recruitment of histone de-acetylase 2 (HDAC2), which mediates epigenetic gene silencing. METHODS AND RESULTS: Chromatin immunoprecipitation (ChIP) assays were performed on chromatin derived from carotid arteries of mice having either a wild-type or G/C Repressor mutant SM22alpha promoter-LacZ transgene. KLF4 and pELK-1 binding to the SM22alpha promoter was markedly increased after vascular injury and was G/C Repressor dependent. Sequential ChIP assays and proximity ligation analyses in cultured SMC treated with platelet-derived growth factor BB or oxidized phospholipids showed formation of a KLF4, pELK-1, and HDAC2 multiprotein complex dependent on the SM22alpha G/C Repressor element. CONCLUSIONS: Silencing of SMC marker genes during phenotypic switching is partially mediated by sequential binding of pELK-1 and KLF4 to G/C Repressor elements. The pELK-1-KLF4 complex in turn recruits HDAC2, leading to reduced histone acetylation and epigenetic silencing. PMID- 22811559 TI - Detection of anti-beta1-AR autoantibodies in heart failure by a cell-based competition ELISA. AB - RATIONALE: Autoantibodies directed against the second extracellular loop of the cardiac beta1-adrenergic receptor (beta1-AR) are thought to contribute to the pathogenesis of dilated cardiomyopathy (DCM) and Chagas heart disease. Various approaches have been used to detect such autoantibodies; however, the reported prevalence varies largely, depending on the detection method used. OBJECTIVE: We analyzed sera from 167 DCM patients (ejection fraction<45%) and from 110 age matched volunteers who did not report any heart disease themselves, with an often used simple peptide-ELISA approach, and compared it with a novel whole cell-based ELISA, using cells expressing the full transgene for the human beta1-AR. Additionally, 35 patients with hypertensive heart disease with preserved ejection fraction were investigated. METHODS AND RESULTS: The novel assay was designed according to the currently most reliable anti-TSH receptor antibody-ELISA used to diagnose Graves disease ("third-generation assay") and also detects the target antibodies by competition with a specific monoclonal anti-beta1-AR antibody (beta1-AR MAb) directed against the functionally relevant beta1-AR epitope. Anti beta1-AR antibodies were detected in ~60% of DCM patients and in ~8% of healthy volunteers using the same cutoff values. The prevalence of these antibodies was 17% in patients with hypertensive heart disease. Anti-beta1-AR antibody titers (defined as inhibition of beta1-AR MAb-binding) were no longer detected after depleting sera from IgG antibodies by protein G adsorption. In contrast, a previously used ELISA conducted with a linear 26-meric peptide derived from the second extracellular beta1-AR loop yielded a high number of false-positive results precluding any specific identification of DCM patients. CONCLUSIONS: We established a simple and efficient screening assay detecting disease-relevant beta1-AR autoantibodies in patient sera yielding a high reproducibility also in high throughput screening. The assay was validated according to "good laboratory practice" and can serve as a companion biodiagnostic assay for the development and evaluation of antibody-directed therapies in antibody-positive heart failure. PMID- 22811561 TI - Evaluation of homocysteine levels in dogs with chronic mitral valve insufficiency. PMID- 22811562 TI - Spironucleosis in cultured red tilapia. PMID- 22811563 TI - Daughters of mothers with multiple sclerosis: their experiences of play. AB - The play experiences of daughters who were caregivers to their mothers with multiple sclerosis were described. The experiences of four Caucasian women aged 19-26 years were captured using the interpretive phenomenological methods of interviews, field notes, and artifacts. Family systems theory provided the conceptual framework for the study and facilitated the interpretation of the findings. The thematic analysis revealed three themes: (a) being a good daughter, (b) blurred relationship boundaries, and (c) encumbered play. Being a good daughter encompassed personal caregiving for their mothers. The associated guilt and worry was perceived to mature the participants beyond their years. Excessive caregiving exacerbated by limited social networks contributed to the blurring of mother-daughter relationships. Play, although restricted, provided a welcomed escape from caregiving responsibilities. Impoverished play experiences as caregivers were reported to negatively impact adult physical activity and recreation pursuits. PMID- 22811560 TI - Mitochondrial ROMK channel is a molecular component of mitoK(ATP). AB - RATIONALE: Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown. OBJECTIVE: To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP). METHODS AND RESULTS: Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase beta. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death. CONCLUSIONS: The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel. PMID- 22811564 TI - Exercise and quality of life in women with multiple sclerosis. AB - The purpose of this study was to evaluate perceptions of quality of life after a 4-month progressive resistance training program for individuals with multiple sclerosis (MS). A second purpose was to examine participants' views about factors that facilitated or impeded exercise behavior. Qualitative interviews were conducted with eight females (Mage = 49.86, SD = 6.94) with relapsing remitting MS. Audio-tape recorded interviews were transcribed verbatim and coded. Walking performance improved (M = 13.08%, SD = 7.11). All participants perceived improvements in muscular strength and endurance while six indicated improvements in walking endurance and performance in tasks of daily living. Social benefits of participation were discussed by seven participants including interactions in the exercise environment. We concluded that supervised resistance training may promote improvements in QOL for women with relapsing remitting MS. PMID- 22811565 TI - Barriers to physical activity for people with long-term neurological conditions: a review study. AB - People with disability are insufficiently physically active for health. This study identified the volume, quality, and findings of research that exposes environmental and personal barriers of physical activity participation for people with neurological conditions. CINAHL, Sport Discus, EMBASE, Medline, and AMED were systematically searched between 1999 and week one 2010 for peer reviewed studies that fit the aim of the review. Identified barriers to physical activity participation were categorized into the World Health Organization's ICF framework of domains. Of the 2,061 studies uncovered in the search, 29 met inclusion criteria and 28 met quality appraisal. Findings showed that barriers to physical activity participation arise from personal factors that, coupled with lack of motivational support from the environment, challenge perceptions of safety and confidence to exercise. PMID- 22811566 TI - Locomotor tests predict community mobility in children and youth with cerebral palsy. AB - Ambulatory children and youth with cerebral palsy have limitations in locomotor capacities and in community mobility. The ability of three locomotor tests to predict community mobility in this population (N = 49, 27 boys, 6-16 years old) was examined. The tests were a level ground walking test, the 6-min-Walk-Test (6MWT), and two tests of advanced locomotor capacities, the 10-meter-Shuttle-Run Test (10mSRT) and the Timed-Up-and-Down-Stairs-Test (TUDS). Community mobility was measured with the Assessment of Life Habits mobility category. After age and height were controlled, regression analysis identified 10mSRT and TUDS values as significant predictors of community mobility. They explained about 40% of the variance in the Life Habits mobility category scores. The 10mSRT was the strongest predictor (standardized Beta coefficient = 0.48, p = 0.002). The 6MWT was not a significant predictor. Thus, advanced locomotor capacity tests may be better predictors of community mobility in this population than level ground walking tests. PMID- 22811567 TI - Candidate genes associated with testicular development, sperm quality, and hormone levels of inhibin, luteinizing hormone, and insulin-like growth factor 1 in Brahman bulls. AB - Bull fertility is an important target for genetic improvement, and early prediction using genetic markers is therefore a goal for livestock breeding. We performed genome-wide association studies to identify genes associated with fertility traits measured in young bulls. Data from 1118 Brahman bulls were collected for six traits: blood hormone levels of inhibin (IN) at 4 mo, luteinizing hormone (LH) following a gonadotropin-releasing hormone challenge at 4 mo, and insulin-like growth factor 1 (IGF1) at 6 mo, scrotal circumference (SC) at 12 mo, ability to produce sperm (Sperm) at 18 mo, and percentage of normal sperm (PNS) at 24 mo. All the bulls were genotyped with the BovineSNP50 chip. Sires and dams of the bull population (n = 304) were genotyped with the high density chip (~800 000 polymorphisms) to allow for imputation, thereby contributing detail on genome regions of interest. Polymorphism associations were discovered for all traits, except for Sperm. Chromosome 2 harbored polymorphisms associated with IN. For LH, associated polymorphisms were located in five different chromosomes. A region of chromosome 14 contained polymorphisms associated with IGF1 and SC. Regions of the X chromosome showed associations with SC and PNS. Associated polymorphisms yielded candidate genes in chromosomes 2, 14, and X. These findings will contribute to the development of genetic markers to help select cattle with improved fertility and will lead to better annotation of gene function in the context of reproductive biology. PMID- 22811568 TI - Towards an understanding of the evolution of the chorioallantoic placenta: steroid biosynthesis and steroid hormone signaling in the chorioallantoic membrane of an oviparous reptile. AB - Amniotes, mammals, reptiles, and birds form common extraembryonic membranes during development to perform essential functions, such as protection, nutrient transfer, gas exchange, and waste removal. Together with the maternal uterus, extraembryonic membranes of viviparous (live-bearing) amniotes develop as an endocrine placenta that synthesizes and responds to steroid hormones critical for development. The ability of these membranes to synthesize and respond to steroid hormone signaling has traditionally been considered an innovation of placental amniotes. However, our laboratory recently demonstrated that this ability extends to the chorioallantoic membrane (CAM) of an oviparous (egg-laying) amniote, the domestic chicken, and we hypothesized that steroidogenic extraembryonic membranes could be an evolutionarily conserved characteristic of all amniotes because of similarities in basic structure, function, and shared evolutionary ancestry. In this study, we examined steroid hormone synthesis and signaling in the CAM of another oviparous amniote, the American alligator (Alligator mississippiensis). We quantified mRNA expression of a steroidogenic factor involved in the regulation of steroidogenesis (NR5A1), the key steroidogenic enzymes involved in the synthesis of progestins (HSD3B1), androgens (CYP17A1), and estrogens (CYP19A1), and the receptors involved in the signaling of progestins (PR), androgens (AR), estrogens (ESR1 and ESR2), and glucocorticoids (GR). Furthermore, we performed protein immunolocalization for PR and ESR1. Collectively, our findings indicate that the alligator CAM has the capability to regulate, synthesize, and respond to steroid hormone signaling, thus, supporting our hypothesis that the extraembryonic membranes of Amniota share a unifying characteristic, that is, the ability to synthesize and respond to steroid hormones. PMID- 22811569 TI - The effects of insulin and follicle-simulating hormone (FSH) during in vitro development of ovarian goat preantral follicles and the relative mRNA expression for insulin and FSH receptors and cytochrome P450 aromatase in cultured follicles. AB - The actions of different concentrations of insulin alone or in combination with follicle-stimulating hormone (FSH) were evaluated by in vitro follicular development and mRNA expression of cytochrome P450 aromatase (CYP19A1) and as receptors for insulin (INSR) and FSH (FSHR) from isolated, cultured goat preantral follicles. Goat preantral follicles were microdissected and cultured for 18 days in the absence or presence of insulin (5 and 10 ng/ml or 10 MUg/ml) alone or in combination with FSH. After 18 days, the addition of the maximum concentration of insulin to the culture medium reduced follicular survival and antrum formation rates significantly compared to the other treatments. However, when FSH was added to the culture medium, no differences between these two parameters were observed. Preantral and antral follicles from the fresh control as well as from all cultured follicles still presented a normal ultrastructural pattern. In medium supplemented with FSH, only insulin at 10 ng/ml presented oocytes with higher rates of meiosis resumption compared to control, as well as oocytes in metaphase II. Treatment with insulin (10 ng/ml) plus FSH resulted in significantly increased levels of INSR and CYP19A1 mRNA compared to that with other treatments. In conclusion, 10 ng/ml insulin associated with FSH was more efficient in promoting resumption of oocyte meiosis, maintaining survival, stimulating follicular development, and increasing expression of the INSR and CYP19A1 genes in goat preantral follicles. PMID- 22811570 TI - Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial stromal cell responsiveness to interleukin 1: a new possible mechanism underlying embryo implantation. AB - Deep functional changes occurring within the endometrium during implantation are orchestrated by embryonic and maternal signals. Human chorionic gonadotropin (hCG), a major embryonic signal, plays a critical role in the initiation and maintenance of pregnancy. Interleukin (IL) 1, one of the earliest embryonic signals, appears to exert a direct impact on the receptive endometrium and to induce major molecular changes that are essential for embryo implantation. Herein we investigate whether hCG can modulate endometrial stromal cell (ESC) receptivity to IL1 during the implantation window and assess the impact on angiogenesis in vitro. Primary cultures of ESCs from normal fertile women during the implantation window were treated for 24 h with different concentrations of hCG (0-100 ng/ml) and stimulated for 24 h with IL1B (0-0.1 ng/ml). IL1 receptors (IL1Rs), IL1R antagonist (IL1RA), and monocyte chemotactic protein (MCP) 1 were analyzed by real-time PCR, ELISA, and Western blotting. The angiogenic activity in vitro was studied using human microvascular endothelial cell line, scratch wound assay, and cell proliferation via BrdU incorporation into DNA. Human CG induced a dose-dependent imbalance in ESC receptivity to IL1 by significantly upregulating the functional signaling IL1R1 and concomitantly downregulating the decoy inhibitory IL1R2 and IL1RA upon subsequent exposure to IL1B. Prior exposure to hCG amplified MCP1 secretion by ESCs in response to IL1B and triggered the release of angiogenic activity in vitro in which MCP1 appeared to play a significant role. Overexpression of IL1R2 using cell transfection inhibited IL1 and hCG/IL1B-mediated MCP1 secretion. These findings suggest that hCG coordinates embryonic signal interaction with the maternal endometrium, and point to a new possible pathway by which it may promote embryonic growth. PMID- 22811572 TI - Disrupted redox homeostasis and aberrant redox gene expression in porcine oocytes contribute to decreased developmental competence. AB - The objective of this study was to identify specific redox-related genes whose function contributes to oocyte quality and to characterize the role of redox homeostasis in oocyte development. We determined the redox genes glutaredoxin 2 (GLRX2), protein disulfide isomerase family A, members 4 and 6 (PDIA4, PDIA6), and thioredoxin reductase 1 (TXNRD1) were differentially expressed between adult (more competent) and prepubertal (less competent) porcine in vitro-matured (IVM) oocytes. The association between these genes and oocyte quality was further validated by comparing transcript abundance in IVM with that in in vivo-matured (VVM) prepubertal and adult oocytes. By maturing oocytes in variable redox environments, we demonstrated that a balanced redox environment is important for oocyte quality, and over-reduction of the environment is as detrimental as excess oxidation. Critical levels of reactive oxygen species (ROS) and glutathione (GSH) are required for oocyte competence. Elevated GSH and lower ROS in prepubertal oocytes suggest disrupted redox homeostasis exists in these cells. By further comparing GLRX2, PDIA4, PDIA6, and TXNRD1 expression levels in oocytes matured under these different redox environments, we found aberrant expression patterns in prepubertal oocytes but not in adult oocytes when the maturation medium contained high concentrations of antioxidants. These results suggest that prepubertal oocytes are less competent in regulating redox balance than adult oocytes, contributing to lower oocyte quality. In conclusion, aberrant redox gene expression patterns and disrupted redox homeostasis contribute to decreased developmental competence in prepubertal and IVM porcine oocytes. The balance between ROS and GSH plays an important role in oocyte quality. PMID- 22811571 TI - Validation of the aging hen (Gallus gallus domesticus) as an animal model for uterine leiomyomas. AB - Uterine leiomyomas, or fibroids, are the most frequent gynecological tumors in premenopausal women with as many as 65% of women becoming clinically symptomatic. Uterine fibroids are benign myometrial tumors that produce large quantities of extracellular matrix proteins. Despite its high morbidity, the molecular basis underlying the development of uterine leiomyomas is not well understood. Domestic hens of Gallus gallus domesticus develop oviductal leiomyomas similar to those found in humans. We investigated the natural history of chicken leiomyomas, in vivo expression of protein biomarkers, and in vitro expression of ovarian steroid receptors. Based on the analysis of 263 hens, tumor prevalence, tumor number per hen, and tumor size increased as the hens aged. Immunohistochemistry for alpha smooth muscle actin (SMA) and desmin confirmed the smooth muscle phenotype of the chicken leiomyomas. Intense collagen expression was detected in these oviductal leiomyomas by Mason's trichrome, and the tumors also showed increased expression of TGFB3 and collagen type I mRNAs. Consistent with human leiomyomas, chicken fibroids displayed increased BCL2 and estrogen (E) and progesterone (P) receptor expression. Chicken leiomyomas were dissociated for in vitro culture. Cells from explants were positive for SMA, desmin, and E and P receptors until the fourth passage. These cells also displayed a response similar to human cells when challenged with halofuginone, an antifibrotic agent. Our findings indicate that the chicken is an excellent complementary model for studies involving the pathophysiology of human uterine leiomyomas. PMID- 22811574 TI - Variants of stretch-activated two-pore potassium channel TREK-1 associated with preterm labor in humans. AB - Spontaneous preterm labor (PTL) is a uniquely human problem that results in preterm delivery of an underdeveloped fetus. The underlying cause remains elusive. The cost to societies in human suffering and treasure is enormous. The stretch-activated two pore potassium channel TREK-1 is up-regulated during gestation to term such that it may maintain uterine quiescence by hyperpolarizing the smooth muscle cell membrane. We have hypothesized that the human TREK-1 channel is involved in myometrial relaxation during pregnancy and that splice variants of the TREK-1 channel expressed in preterm myometrium are associated with preterm delivery by interaction with full-length TREK-1. We detected three wild-type human TREK-1 transcript isoforms in nonpregnant and pregnant human myometrium. Using RT-PCR, we identified five unique TREK-1 splice variants in myometrium from women in PTL. These myometrial TREK-1 variants lack either the pore or the transmembrane domains or both. In transiently transfected HEK293T cells, wild-type TREK-1 was predominantly expressed at the plasma membrane. However, individual splice variants were expressed uniformly throughout the cell. Wild-type TREK-1 was localized at the plasma membrane and cytoplasm close to the plasma membrane when coexpressed with each splice variant. Co-immunoprecipitation of FLAG epitope-tagged TREK-1 and six-His epitope-tagged splice variants using Ni bead columns successfully pulled down wild-type TREK-1. These results suggest that each of four TREK-1 splice variants interacts with full-length wild-type TREK-1 and that in vivo, such interactions may contribute to a PTL phenotype. PMID- 22811575 TI - The hedgehog system in ovarian follicles of cattle selected for twin ovulations and births: evidence of a link between the IGF and hedgehog systems. AB - Hedgehog signaling is involved in regulation of ovarian function in Drosophila, but its role in regulating mammalian ovarian folliculogenesis is less clear. Therefore, gene expression of Indian hedgehog (IHH) and its type 1 receptor, patched 1 (PTCH1), were quantified in bovine granulosa (GC) or theca (TC) cells of small (1-5 mm) antral follicles by in situ hybridization and of larger (5-17 mm) antral follicles by real-time RT-PCR from ovaries of cyclic cows genetically selected (Twinner) or not selected (control) for twin ovulations. Expression of IHH mRNA was localized to GC and cumulus cells, whereas PTCH1 mRNA was greater in TC than in GC. Estrogen-active (E-A; follicular fluid concentration of estradiol > progesterone) versus estrogen-inactive follicles had a greater abundance of mRNA for IHH in GC and PTCH1 in TC. Abundance of IHH mRNA in GC was not affected by cow genotype, whereas TC PTCH1 mRNA was less in large E-A follicles of Twinners than in controls. In vitro, estradiol and wingless-type (WNT) 3A increased IHH mRNA in IGF1-treated GC. IGF1 and BMP4 treatments decreased PTCH1 mRNA in small TC. Estradiol and LH increased PTCH1 mRNA in IGF1-treated TC from large and small follicles, respectively. In summary, functional status of ovarian follicles was associated with differences in hedgehog signaling in GC and TC. We hypothesize that as follicles grow and develop, increased free IGF1 may suppress expression of IHH mRNA by GC and PTCH1 mRNA by TC, and these effects are regulated in a paracrine way by estradiol and other intra- and extragonadal factors. PMID- 22811573 TI - Transforming growth factor Beta 1 stimulates profibrotic activities of luteal fibroblasts in cows. AB - Luteolysis is characterized by angioregression, luteal cell apoptosis, and remodeling of the extracellular matrix characterized by deposition of collagen 1. Transforming growth factor beta 1 (TGFB1) is a potent mediator of wound healing and fibrotic processes through stimulation of the synthesis of extracellular matrix components. We hypothesized that TGFB1 stimulates profibrotic activities of luteal fibroblasts. We examined the actions of TGFB1 on luteal fibroblast proliferation, extracellular matrix production, floating gel contraction, and chemotaxis. Fibroblasts were isolated from the bovine corpus luteum. Western blot analysis showed that luteal fibroblasts expressed collagen 1 and prolyl 4 hydroxylase but did not express markers of endothelial or steroidogenic cells. Treatment of fibroblasts with TGFB1 stimulated the phosphorylation of SMAD2 and SMAD3. [(3)H]thymidine incorporation studies showed that TGFB1 caused concentration-dependent reductions in DNA synthesis in luteal fibroblasts and significantly (P < 0.05) reduced the proliferative effect of FGF2 and fetal calf serum. However, TGFB1 did not reduce the viability of luteal fibroblasts. Treatment of luteal fibroblasts with TGFB1 induced the expression of laminin, collagen 1, and matrix metalloproteinase 1 as determined by Western blot analysis and gelatin zymography of conditioned medium. TGFB1 increased the chemotaxis of luteal fibroblasts toward fibronectin in a transwell system. Furthermore, TGFB1 increased the fibroblast-mediated contraction of floating bovine collagen 1 gels. These results suggest that TGFB1 contributes to the structural regression of the corpus luteum by stimulating luteal fibroblasts to remodel and contract the extracellular matrix. PMID- 22811576 TI - Molecular mechanisms and pathways involved in bovine embryonic genome activation and their regulation by alternative in vivo and in vitro culture conditions. AB - Understanding gene expression patterns in response to altered environmental conditions at different time points of the preimplantation period would improve our knowledge on regulation of embryonic development. Here we aimed to examine the effect of alternative in vivo and in vitro culture conditions at the time of major embryonic genome activation (EGA) on the development and transcriptome profile of bovine blastocysts. Four different blastocyst groups were produced under alternative in vivo and in vitro culture conditions before or after major EGA. Completely in vitro- and in vivo-produced blastocysts were used as controls. We compared gene expression patterns between each blastocyst group and in vivo blastocyst control group using EmbryoGENE's bovine microarray. The data showed that changing culture conditions from in vivo to in vitro or vice versa, either before or after the time of major EGA, had no effect on the developmental rates; however, in vitro conditions during that time critically influenced the transcriptome of the blastocysts produced. The source of oocyte had a critical effect on developmental rates and the ability of the embryo to react to changing culture conditions. Ontological classification highlighted a marked contrast in expression patterns for lipid metabolism and oxidative stress response between blastocysts generated in vivo versus in vitro, with opposite trends. Molecular mechanisms and pathways that are influenced by altered culture conditions during EGA were defined. These results will help in the development of new strategies to modify culture conditions at this critical stage to enhance the development of competent blastocysts. PMID- 22811577 TI - Multiple arterial grafts improve late survival of patients undergoing coronary artery bypass graft surgery: analysis of 8622 patients with multivessel disease. AB - BACKGROUND: Use of the left internal mammary artery (LIMA) in multivessel coronary artery disease improves survival after coronary artery bypass graft surgery; however, the survival benefit of multiple arterial (MultArt) grafts is debated. METHODS AND RESULTS: We reviewed 8622 Mayo Clinic patients who had isolated primary coronary artery bypass graft surgery for multivessel coronary artery disease from 1993 to 2009. Patients were stratified by number of arterial grafts into the LIMA plus saphenous veins (LIMA/SV) group (n=7435) or the MultArt group (n=1187). Propensity score analysis matched 1153 patients. Operative mortality was 0.8% (n=10) in the MultArt and 2.1% (n=154) in the LIMA/SV (P=0.005) group, which was not statistically different (P=0.996) in multivariate analysis or the propensity-matched analysis (P=0.818). Late survival was greater for MultArt versus LIMA/SV (10- and 15-year survival rates were 84% and 71% versus 61% and 36%, respectively [P<0.001], in unmatched groups and 83% and 70% versus 80% and 60%, respectively [P=0.0025], in matched groups). MultArt subgroups with bilateral internal mammary artery/SV (n=589) and bilateral internal mammary artery only (n=271) had improved 15-year survival (86% and 76%; 82% and 75% at 10 and 15 years [P<0.001]), and patients with bilateral internal mammary artery/radial artery (n=147) and LIMA/radial artery (n=169) had greater 10-year survival (84% and 78%; P<0.001) versus LIMA/SV. In multivariate analysis, MultArt grafts remained a strong independent predictor of survival (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P=0.007). CONCLUSIONS: In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery, arterial grafting of the non-left anterior descending vessels conferred a survival advantage at 15 years compared with SV grafting. It is still unproven whether these results apply to higher-risk subgroups of patients. PMID- 22811578 TI - MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-beta1 pathway. AB - BACKGROUND: Cardiac interstitial fibrosis is a major cause of the deteriorated performance of the heart in patients with chronic myocardial infarction. MicroRNAs (miRs) have recently been proven to be a novel class of regulators of cardiovascular diseases, including those associated with cardiac fibrosis. This study aimed to explore the role of miR-101 in cardiac fibrosis and the underlying mechanisms. METHODS AND RESULTS: Four weeks after coronary artery ligation of rats, the expression of miR-101a and miR-101b (miR-101a/b) in the peri-infarct area was decreased. Treatment of cultured rat neonatal cardiac fibroblasts with angiotensin II also suppressed the expression of miR-101a/b. Forced expression of miR-101a/b suppressed the proliferation and collagen production in rat neonatal cardiac fibroblasts, as revealed by cell counting, MTT assay, and quantitative reverse transcription-polymerase chain reaction. The effect was abrogated by cotransfection with AMO-101a/b, the antisense inhibitors of miR-101a/b. c-Fos was found to be a target of miR-101a because overexpression of miR-101a decreased the protein and mRNA levels of c-Fos and its downstream protein transforming growth factor-beta1. Silencing c-Fos by siRNA mimicked the antifibrotic action of miR 101a, whereas forced expression of c-Fos protein canceled the effect of miR-101a in cultured cardiac fibroblasts. Strikingly, echocardiography and hemodynamic measurements indicated remarkable improvement of the cardiac performance 4 weeks after adenovirus-mediated overexpression of miR-101a in rats with chronic myocardial infarction. Furthermore, the interstitial fibrosis was alleviated and the expression of c-Fos and transforming growth factor-beta1 was inhibited. CONCLUSION: Overexpression of miR-101a can mitigate interstitial fibrosis and the deterioration of cardiac performance in postinfarct rats, indicating the therapeutic potential of miR-101a for cardiac disease associated with fibrosis. PMID- 22811579 TI - Cardiac fibrosis revisited by microRNA therapeutics. PMID- 22811580 TI - Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target. AB - PURPOSE: Patients with neurofibromatosis type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNST), which are often inoperable and do not respond well to current chemotherapies or radiation. The goal of this study was to use comprehensive gene expression analysis to identify novel therapeutic targets. EXPERIMENTAL DESIGN: Nerve Schwann cells and/or their precursors are the tumorigenic cell types in MPNST because of the loss of the NF1 gene, which encodes the RasGAP protein neurofibromin. Therefore, we created a transgenic mouse model, CNP-HRas12V, expressing constitutively active HRas in Schwann cells and defined a Ras-induced gene expression signature to drive a Bayesian factor regression model analysis of differentially expressed genes in mouse and human neurofibromas and MPNSTs. We tested functional significance of Aurora kinase overexpression in MPNST in vitro and in vivo using Aurora kinase short hairpin RNAs (shRNA) and compounds that inhibit Aurora kinase. RESULTS: We identified 2,000 genes with probability of linkage to nerve Ras signaling of which 339 were significantly differentially expressed in mouse and human NF1-related tumor samples relative to normal nerves, including Aurora kinase A (AURKA). AURKA was dramatically overexpressed and genomically amplified in MPNSTs but not neurofibromas. Aurora kinase shRNAs and Aurora kinase inhibitors blocked MPNST cell growth in vitro. Furthermore, an AURKA selective inhibitor, MLN8237, stabilized tumor volume and significantly increased survival of mice with MPNST xenografts. CONCLUSION: Integrative cross-species transcriptome analyses combined with preclinical testing has provided an effective method for identifying candidates for molecular-targeted therapeutics. Blocking Aurora kinases may be a viable treatment platform for MPNST. PMID- 22811581 TI - Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. AB - PURPOSE: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer. EXPERIMENTAL DESIGN: The Wnt pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1 mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model. RESULTS: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFbeta class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear beta-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFbeta class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear beta-catenin. Sorafenib decreased Wnt signaling and beta-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFbeta class), SNU398 (CTNNB1 mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals. CONCLUSIONS: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt related molecular classes (CTNNB1 and Wnt-TGFbeta), accounting for half of all HCC patients. Sorafenib modulates beta-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature. PMID- 22811582 TI - RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer. AB - PURPOSE: We sought to determine whether dysregulation of the retinoblastoma (RB) tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer. EXPERIMENTAL DESIGN: An RB-loss signature was used to analyze the association between pathway status and pathologic complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB pathway was conducted on pretreatment biopsies to determine the association with pathologic response to neoadjuvant chemotherapy. RESULTS: An RB-loss gene expression signature was associated with increased pathologic complete response in datasets from breast cancer patients treated with 5-fluorouracil/adriamycin/cytoxan (FAC; P < 0.001), T/FAC (P < 0.001), and Taxane/Adriaymcin (P < 0.001) neoadjuvant therapy encompassing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both estrogen receptor (ER)-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss signature (R = 0.493-0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathologic complete response in the same datasets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (P = 0.0018) or elevated p16ink4a (P = 0.0253) with pathologic complete response. In addition, by Miller-Payne and clinicopathologic scoring analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy. CONCLUSION: Disruption of the RB pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathologic response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be used to inform treatment. PMID- 22811583 TI - HDAC inhibitors augmented cell migration and metastasis through induction of PKCs leading to identification of low toxicity modalities for combination cancer therapy. AB - PURPOSE: Histone deacetylase inhibitors (HDACi) are actively explored as new generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy. EXPERIMENTAL DESIGN: Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice. RESULTS: We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo. CONCLUSION: Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease. PMID- 22811585 TI - Prognostic value of CD133 caused by mutant K-Ras and B-Raf--letter. PMID- 22811588 TI - Hepatocellular adenoma: evaluation with contrast-enhanced ultrasound and MRI and correlation with pathologic and phenotypic classification in 26 lesions. AB - Purpose. To review the contrast-enhanced ultrasonographic (CEUS) and magnetic resonance (MR) imaging findings in 25 patients with 26 hepatocellular adenomas (HCAs) and to compare imaging features with histopathologic results from resected specimen considering the new immunophenotypical classification. Material and Methods. Two abdominal radiologists reviewed retrospectively CEUS cineloops and MR images in 26 HCA. All pathological specimens were reviewed and classified into four subgroups (steatotic or HNF 1alpha mutated, inflammatory, atypical or beta catenin mutated, and unspecified). Inflammatory infiltrates were scored, steatosis, and telangiectasia semiquantitatively evaluated. Results. CEUS and MRI features are well correlated: among the 16 inflammatory HCA, 7/16 presented typical imaging features: hypersignal T2, strong arterial enhancement with a centripetal filling, persistent on delayed phase. 6 HCA were classified as steatotic with typical imaging features: a drop out signal, slight arterial enhancement, vanishing on late phase. Four HCA were classified as atypical with an HCC developed in one. Five lesions displayed important steatosis (>50%) without belonging to the HNF1alpha group. Conclusion. In half cases, inflammatory HCA have specific imaging features well correlated with the amount of telangiectasia and inflammatory infiltrates. An HCA with important amount of steatosis noticed on chemical shift images does not always belong to the HNF1alpha group. PMID- 22811587 TI - Klatskin-like lesions. AB - Hilar cholangiocarcinoma, also known as Klatskin tumour, is the commonest type of cholangiocarcinoma. It poses unique problems in the diagnosis and management because of its anatomical location. Curative surgery in the form of major hepatic resection entails significant morbidity. About 5-15% of specimens resected for presumed Klatskin tumour prove not to be cholangiocarcinomas. There are a number of inflammatory, infective, vascular, and other pathologies, which have overlapping clinical and radiological features with a Klatskin tumour, leading to misinterpretation. This paper aims to summarise the features of such Klatskin like lesions that have been reported in surgical literature. PMID- 22811590 TI - Prevalence of human papillomavirus in women from Mexico City. AB - INTRODUCTION: Cervical cancer is the most common cancer among Mexican women. The goal of the present study was to determine the prevalence and distribution of HPV types in women from Mexico City. METHODS: Our study was conducted in the Clinica de Especialidades de la Mujer de la Secretaria de la Defensa Nacional, Mexico. Random samples were taken from 929 healthy women requesting a cervical Papanicolaou examination. Detection and genotyping of HPV were performed by multiplex PCR, with the HPV4A ACE Screening kit (Seegene). RESULTS: 85 of nine hundred twenty-nine women (9.1%) were infected with HPV. Of HPV-positive women, 99% and 1% had high- and low-risk HPV genotypes, respectively. The prevalence of the 16 high-risk (HR) HPV types that were screened was 43% : 42% (18) were HPV positive and 14% (16) were HPV positive, which includes coinfection. Multiple infections with different viral genotypes were detected in 10% of the positive cases. Abnormal cervical cytological results were found in only 15.3% of HPV positive women, while 84.7% had normal cytological results. CONCLUSIONS: We found a similar prevalence of HPV to previous studies in Mexico. The heterogeneity of the HPV genotype distribution in Mexico is evident in this study, which found a high frequency of HPV HR genotypes, the majority of which were HPV 18. PMID- 22811589 TI - Inflammatory pathways as promising targets to increase chemotherapy response in bladder cancer. AB - While more and more physicians are choosing chemotherapy for patients with bladder cancer, the current treatment is still far from satisfactory due to low response rate and severe side effects. Emerging evidence indicates that inflammatory microenvironment is involved in the pathogenesis of bladder cancer. Recent studies have also provided ample evidence that chemotherapy response is influenced by activation of major inflammatory mediators, including transcription factors, cytokines, chemokines, and COX-2. We reviewed all published literature addressing the roles of inflammatory microenvironment in bladder cancer and evaluating emerging evidence that inflammatory pathways represent potential therapeutic targets to enhance chemotherapy of bladder cancer. PMID- 22811591 TI - Probiotic interference of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 with the opportunistic fungal pathogen Candida albicans. AB - Candida albicans is the most important Candida species causing vulvovaginal candidiasis (VVC). VVC has significant medical and economical impact on women's health and wellbeing. While current antifungal treatment is reasonably effective, supportive and preventive measures such as application of probiotics are required to reduce the incidence of VVC. We investigated the potential of the probiotics Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 towards control of C. albicans. In vitro experiments demonstrated that lactic acid at low pH plays a major role in suppressing fungal growth. Viability staining following cocultures with lactobacilli revealed that C. albicans cells lost metabolic activity and eventually were killed. Transcriptome analyses showed increased expression of stress-related genes and lower expression of genes involved in fluconazole resistance, which might explain the increased eradication of Candida in a previous clinical study on conjoint probiotic therapy. Our results provide insights on the impact of probiotics on C. albicans survival. PMID- 22811592 TI - Genital tract infections, bacterial vaginosis, HIV, and reproductive health issues among Lima-based clandestine female sex workers. AB - Sociodemographic and behavioral characteristics of 212 Peruvian female sex workers (FSWs) were analyzed. The association between genital tract infections (GTIs) and risk factors by multivariate analysis was evaluated. Eighty-eight percent of FSWs were diagnosed with at least one GTI (HSV-2 80.1%, BV 44.8%, candidiasis 9.9%, syphilis seropositivity 9.4%, Trichomonas vaginalis 2.4%, HIV seropositivity 2.4%). Reported condom use with clients was nearly universal (98.3%), but infrequent with husband/regular partners (7.3%). In multivariate analysis BV was negatively associated with more consistent condom use (PRR = 0.63, 95% CI, 0.42-0.96). Many had not visited a Sexually Transmitted Infection (STI) clinic or been tested for HIV in the past year (40.6%, 47.1%, resp.). Nonclient contraceptive use was low (57%) and induced abortion was common (68%). High GTI burden and abortions suggest that a services-access gap persists among marginalized FSWs. Continued health outreach programs and integrating family planning and reproductive health services into existing STI clinic services are recommended. PMID- 22811594 TI - Construction of a llama bacterial artificial chromosome library with approximately 9-fold genome equivalent coverage. AB - The Ilama is an important agricultural livestock in much of South America. The llama is increasing in popularity in the United States as a companion animal. Little work has been done to improve llama production using modern technology. A paucity of information is available regarding the llama genome. We report the construction of a llama bacterial artificial chromosome (BAC) library of about 196,224 clones in the vector pECBAC1. Using flow cytometry and bovine, human, mouse, and chicken as controls, we determined the llama genome size to be 2.4 * 109 bp. The average insert size of the library is 137.8 kb corresponding to approximately 9-fold genome coverage. Further studies are needed to further characterize the library and llama genome. We anticipate that this new library will help facilitate future genomic studies in the llama. PMID- 22811595 TI - Control and augmentation of long-term plasmid transgene expression in vivo in murine muscle tissue and ex vivo in patient mesenchymal tissue. AB - PURPOSE: In vivo gene therapy directed at tissues of mesenchymal origin could potentially augment healing. We aimed to assess the duration and magnitude of transene expression in vivo in mice and ex vivo in human tissues. METHODS: Using bioluminescence imaging, plasmid and adenoviral vector-based transgene expression in murine quadriceps in vivo was examined. Temporal control was assessed using a doxycycline-inducible system. An ex vivo model was developed and optimised using murine tissue, and applied in ex vivo human tissue. RESULTS: In vivo plasmid based transgene expression did not silence in murine muscle, unlike in liver. Although maximum luciferase expression was higher in muscle with adenoviral delivery compared with plasmid, expression reduced over time. The inducible promoter cassette successfully regulated gene expression with maximum levels a factor of 11 greater than baseline. Expression was re-induced to a similar level on a temporal basis. Luciferase expression was readily detected ex vivo in human muscle and tendon. CONCLUSIONS: Plasmid constructs resulted in long-term in vivo gene expression in skeletal muscle, in a controllable fashion utilising an inducible promoter in combination with oral agents. Successful plasmid gene transfection in human ex vivo mesenchymal tissue was demonstrated for the first time. PMID- 22811596 TI - The difference in pharmacokinetics and pharmacodynamics between extended-release fluvastatin and immediate-release fluvastatin in healthy Chinese subjects. AB - The aim of this study was to evaluate the difference in pharmacokinetics and pharmacodynamics between extended-release (ER) fluvastatin tablet and its immediate-release (IR) capsule in Chinese healthy subjects. This was an open label, single/multiple-dose, two-period, two-treatment, crossover, randomized trial with a minimum washout period of 7 days. Twenty healthy male adult subjects were given fluvastatin ER tablet 80 mg QD by oral administration or fluvastatin IR capsule 40 mg BID for seven days. Blood samples were collected up to 24 hours after dosing on day 1 and day 7. Serum concentrations of fluvastatin were determined by LC-MS/MS. For fluvastatin ER tablet 80 mg QD, C(max) was 61.0 +/- 39.0 and 63.9 +/- 29.7 ng/mL, and AUC(0-24 h) was 242 +/- 156 and 253 +/- 91.1 ng.h/mL on day 1 and 7, respectively. For fluvastatin IR capsule 40 mg BID, C(max) was 283 +/- 271 and 382 +/- 255 ng/mL, and AUC(0-24 h) was 720 +/- 776 and 917 +/- 994 ng.h/mL on day 1 and day 7, respectively. The relative bioavailability of fluvastatin ER tablet 80 mg QD to fluvastatin IR capsule 40 mg BID is (45.3 +/- 23.9)% and (43.3 +/- 24.1)% on day 1 and day 7, respectively. T(max) for fluvastatin ER tablet was 2.50 and 2.60 h and for capsule was 0.78 and 0.88 h on day 1 and day 7, respectively. In the first period, compared to baseline, cholesterol decreased 15.3% in fluvastatin ER tablet 80 mg QD and 16.9% in fluvastatin IR capsule 40 mg BID. Triglyceride decreased 3.7% in fluvastatin ER tablet 80 mg QD and 19.1% in fluvastatin IR capsule 40 mg BID. The difference has no statistical significance at P > 0.05 in reduction percent of cholesterol and triglyceride between the two groups. No adverse events were recorded. The results indicated that C(max) of fluvastatin ER tablet is reduced and T(max) is prolonged compared with IR capsule. There is no accumulation for ER formulation after multiple doses. PMID- 22811597 TI - Involvement of the intrarenal renin-angiotensin system in experimental models of glomerulonephritis. AB - The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN. PMID- 22811598 TI - Detection of canonical hedgehog signaling in breast cancer by 131-iodine-labeled derivatives of the sonic hedgehog protein. AB - Activation of hedgehog (HH) pathway signaling is observed in many tumors. Due to a feedback loop, the HH receptor Patched (PTCH-1) is overexpressed in tumors with activated HH signaling. Therefore, we sought to radiolabel the PTCH-1 ligand sonic (SHH) for detection of cancer cells with canonical HH activity. Receptor binding of 131I-SHH was increased in cell lines with high HH pathway activation. Our findings also show that PTCH-1 receptor expression is decreased upon treatment with HH signaling inhibitors, and receptor binding of 131I-SHH is significantly decreased following treatment with cyclopamine. In vivo imaging and biodistribution studies revealed significant accumulation of 131I-SHH within tumor tissue as compared to normal organs. Tumor-to-muscle ratios were approximately 8 : 1 at 5 hours, while tumor to blood and tumor to bone were 2 : 1 and 5 : 1, respectively. Significant uptake was also observed in liver and gastrointestinal tissue. These studies show that 131I-SHH is capable of in vivo detection of breast tumors with high HH signaling. We further demonstrate that the hedgehog receptor PTCH-1 is downregulated upon treatment with hedgehog inhibitors. Our data suggests that radiolabeled SHH derivatives may provide a method to determine response to SHH-targeted therapies. PMID- 22811599 TI - Treatment with aqueous extract from Croton cajucara Benth reduces hepatic oxidative stress in streptozotocin-diabetic rats. AB - Croton cajucara Benth is a plant found in Amazonia, Brazil and the bark and leaf infusion of this plant have been popularly used to treat diabetes and hepatic disorders. The present study was designed to evaluate the oxidative stress as well as the therapeutic effect of Croton cajucara Benth (1.5 mL of the C. cajucara extract i.g.) in rats with streptozotocin-induced diabetes. Croton cajucara Benth was tested as an aqueous extract for its phytochemical composition, and its antioxidant activity in vitro was also evaluated. Lipid peroxidation and superoxide dismutase, catalase, and glutathione reductase activities were measured in the hepatic tissue, as well as the presence activation of p65 (NF-kappaB), through western blot. Phytochemical screening of Croton cajucara Benth detected the presence of flavonoids, coumarins and alkaloids. The extract exhibited a significant antioxidant activity in the DPPH scavenging and the hypoxanthine/xanthine oxidase assays. Liver lipid peroxidation increased in diabetic animals followed by a reduction in the Croton-cajucara Benth-treated group. There was activation of p65 nuclear expression in the diabetic animals, which was attenuated in the animals receiving the Croton cajucara Benth aqueous extract. The liver tissue in diabetic rats showed oxidative alterations related to the streptozotocin treatment. In conclusion the Croton cajucara Benth aqueus extract treatment effectively reduced the oxidative stress and contributed to tissue recovery. PMID- 22811601 TI - Synergetic effects of doxycycline-loaded chitosan nanoparticles for improving drug delivery and efficacy. AB - INTRODUCTION: Doxycycline, a broad-spectrum antibiotic, is the most commonly prescribed antibiotic worldwide for treating infectious diseases. It may be delivered orally or intravenously but can lead to gastrointestinal irritation and local inflammation. For treatment of uterine infections, transcervical administration of doxycycline encapsulated in nanoparticles made of biodegradable chitosan may improve sustained delivery of the drug, thereby minimizing adverse effects and improving drug efficacy. METHODS AND MATERIALS: As a first step toward assessing this potential, we used an ionic gelation method to synthesize blank and doxycycline-loaded chitosan nanoparticles (DCNPs), which we then characterized in terms of several properties relevant to clinical efficacy: particle size, shape, encapsulation efficiency, antibacterial activity, and in vitro cytotoxicity. Two particle formulations were examined, with one (named DCNP6) containing approximately 1.5 times the crosslinker concentration of the other (DCNP4). RESULTS: The two formulations produced spherically shaped drug loaded nanoparticles. The spheres ranged in size from 30 to 220 nm diameter for DCNP4 and 200 to 320 nm diameter for DCNP6. Average encapsulation yield was 53% for DCNP4 and 56% for DCNP6. In terms of drug release, both formulations showed a burst effect within the first 4 to 5 hours, followed by a slow, sustained release for the remainder of the 24-hour monitoring period. The in vitro antibacterial activity against Escherichia coli was high, with both formulations achieving more than 90% inhibition of 4-hour bacterial growth. Cytotoxic effects of the DCNPs on normal human ovarian surface epithelial cells were significantly lower than those of unencapsulated doxycycline. After 5 days, cultures exposed to the unencapsulated antibiotic showed a 61% decrease in cell viability, while cultures exposed to the DCNPs exhibited less than a 10% decrease. CONCLUSION: These laboratory results suggest that DCNPs show preliminary promise for possible eventual use in transcervical drug delivery and improved efficacy in the treatment of bacterial uterine infections. PMID- 22811600 TI - Toxic effects of mercury on the cardiovascular and central nervous systems. AB - Environmental contamination has exposed humans to various metal agents, including mercury. This exposure is more common than expected, and the health consequences of such exposure remain unclear. For many years, mercury was used in a wide variety of human activities, and now, exposure to this metal from both natural and artificial sources is significantly increasing. Many studies show that high exposure to mercury induces changes in the central nervous system, potentially resulting in irritability, fatigue, behavioral changes, tremors, headaches, hearing and cognitive loss, dysarthria, incoordination, hallucinations, and death. In the cardiovascular system, mercury induces hypertension in humans and animals that has wide-ranging consequences, including alterations in endothelial function. The results described in this paper indicate that mercury exposure, even at low doses, affects endothelial and cardiovascular function. As a result, the reference values defining the limits for the absence of danger should be reduced. PMID- 22811602 TI - Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles. AB - BACKGROUND: This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats. METHODS: Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed. RESULTS: The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues. CONCLUSION: ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs. PMID- 22811603 TI - Poly-l-lysine-coated magnetic nanoparticles as intracellular actuators for neural guidance. AB - PURPOSE: It has been proposed in the literature that Fe(3)O(4) magnetic nanoparticles (MNPs) could be exploited to enhance or accelerate nerve regeneration and to provide guidance for regenerating axons. MNPs could create mechanical tension that stimulates the growth and elongation of axons. Particles suitable for this purpose should possess (1) high saturation magnetization, (2) a negligible cytotoxic profile, and (3) a high capacity to magnetize mammalian cells. Unfortunately, the materials currently available on the market do not satisfy these criteria; therefore, this work attempts to overcome these deficiencies. METHODS: Magnetite particles were synthesized by an oxidative hydrolysis method and characterized based on their external morphology and size distribution (high-resolution transmission electron microscopy [HR-TEM]) as well as their colloidal (Z potential) and magnetic properties (Superconducting QUantum Interference Devices [SQUID]). Cell viability was assessed via Trypan blue dye exclusion assay, cell doubling time, and MTT cell proliferation assay and reactive oxygen species production. Particle uptake was monitored via Prussian blue staining, intracellular iron content quantification via a ferrozine-based assay, and direct visualization by dual-beam (focused ion beam/scanning electron microscopy [FIB/SEM]) analysis. Experiments were performed on human neuroblastoma SH-SY5Y cell line and primary Schwann cell cultures of the peripheral nervous system. RESULTS: This paper reports on the synthesis and characterization of polymer-coated magnetic Fe(3)O(4) nanoparticles with an average diameter of 73 +/ 6 nm that are designed as magnetic actuators for neural guidance. The cells were able to incorporate quantities of iron up to 2 pg/cell. The intracellular distribution of MNPs obtained by optical and electronic microscopy showed large structures of MNPs crossing the cell membrane into the cytoplasm, thus rendering them suitable for magnetic manipulation by external magnetic fields. Specifically, migration experiments under external magnetic fields confirmed that these MNPs can effectively actuate the cells, thus inducing measurable migration towards predefined directions more effectively than commercial nanoparticles (fluidMAG-ARA supplied by Chemicell). There were no observable toxic effects from MNPs on cell viability for working concentrations of 10 MUg/mL (EC(25) of 20.8 MUg/mL, compared to 12 MUg/mL in fluidMAG-ARA). Cell proliferation assays performed with primary cell cultures of the peripheral nervous system confirmed moderate cytotoxicity (EC(25) of 10.35 MUg/mL). CONCLUSION: These results indicate that loading neural cells with the proposed MNPs is likely to be an effective strategy for promoting non-invasive neural regeneration through cell magnetic actuation. PMID- 22811604 TI - Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity. AB - BACKGROUND: The success of gene transfection is largely dependent on the development of a vehicle or vector that can efficiently deliver a gene to cells with minimal toxicity. METHODS: A liver cancer-targeted specific peptide (FQHPSF sequence) was successfully synthesized and linked with chitosan-linked polyethylenimine (CP) to form a new targeted gene delivery vector called CPT (CP/peptide). The structure of CPT was confirmed by (1)H nuclear magnetic resonance spectroscopy and ultraviolet spectrophotometry. The particle size of CPT/ DNA complexes was measured using laser diffraction spectrometry and the cytotoxicity of the copolymer was evaluated by methylthiazol tetrazolium method. The transfection efficiency evaluation of the CP copolymer was performed using luciferase activity assay. Cellular internalization of the CP/DNA complex was observed under confocal laser scanning microscopy. The targeting specificity of the polymer coupled to peptide was measured by competitive inhibition transfection study. The liver targeting specificity of the CPT copolymer in vivo was demonstrated by combining the copolymer with a therapeutic gene, interleukin 12, and assessed by its abilities in suppressing the growth of ascites tumor in mouse model. RESULTS: The results showed that the liver cancer-targeted specific peptide was successfully synthesized and linked with CP to form a new targeted gene delivery vector called CPT. The composition of CPT was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa), CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer. CONCLUSION: The synthesized CPT copolymer was proven to be an effective liver cancer-targeted vector for therapeutic gene delivery, which could be a potential candidate for targeted cancer gene therapy. PMID- 22811605 TI - Optical imaging to trace near infrared fluorescent zinc oxide nanoparticles following oral exposure. AB - BACKGROUND: Understanding how nanomaterials are distributed in the body after exposure is important for assessing whether they are safe. In this study, we investigated the behavior and accumulation of nanoscaled and submicron-scaled zinc oxide (ZnO) particles in the body using optical imaging following oral exposure. METHODS: To trace these nanoparticles in the body, ZnO nanoparticles were conjugated with a monoreactive hydroxysuccinimide ester of Cy5.5 (Cy5.5 NHS), and the conjugation-stabilizing effect of Cy5.5 on the nanoparticles was evaluated in simulated gastric fluid (pH 1.2) for 7 hours. To compare the distribution of Cy5.5-NHS and Cy5.5-conjugated ZnO nanoparticles, Cy5.5-NHS 0.5 mg/kg and Cy5.5-conjugated ZnO nanoparticles 250 mg/kg were administered orally to healthy rats. We collected blood from the rats at predesignated time points for 7 hours after administration, and optical imaging studies were performed at 1, 2, 3, 5, and 7 hours after dosing. To investigate the extent of nanoparticle accumulation in the organs and tissues, the mice were sacrificed at 23 hours after administration, and the organs were removed and imaged. RESULTS: Cy5.5 conjugated ZnO nanoparticles were stable in simulated gastric fluid for 7 hours. The signal intensity of Cy5.5-NHS in blood was highest 3 hours after oral administration, and Cy5.5-conjugated ZnO nanoparticles showed the highest signal intensity in blood 5-7 hours after administration. In vivo optical images indicated that Cy5.5-NHS showed optical signals in the lung, liver, and gastrointestinal tract after oral administration, whereas Cy5.5-conjugated ZnO nanoparticles were seen only in the gastrointestinal tract. Seven hours following administration, biodistribution studies demonstrated that Cy5.5-NHS accumulated in the lung and liver, and Cy5.5-conjugated ZnO nanoparticles resulted in a strong signal in the kidney and liver. Different-sized ZnO nanoparticles showed dissimilar patterns of biodistribution in ex vivo optical images. CONCLUSION: ZnO nanoparticles are absorbed into the tissues following oral exposure and their behavior can be monitored and evaluated using optical imaging. PMID- 22811606 TI - alpha-Cyclodextrin dimer complexes of dopamine and levodopa derivatives to assess drug delivery to the central nervous system: ADME and molecular docking studies. AB - This paper attempts to predict and emphasize molecular interactions of dopamine, levodopa, and their derivatives (Dopimid compounds) containing 2-phenyl imidazopyridine moiety with the alpha-cyclodextrin dimer in order to assess and improve drug delivery to the central nervous system. The molecular docking method is used to determine the energetic profiles, hydrogen bond formation, and hydrophobic effect of 14 host-guest complexes. The results show that the "chemical branching" represented by additional ethyl-acetate residue is energetically unfavorable and promotes a conformational shift due to the high root mean square deviation levels. This phenomenon is characterized by a low number of H-bonds and a significant decrease of the host-guest hydrophobic potential surface. Finally, the overall docking procedure presents a powerful rationale for screening and analyzing various sets of promising drug-like chemical compounds in the fields of supramolecular chemistry, molecular sensing, synthetic receptors, and nanobiotechnology. PMID- 22811607 TI - Review of the Berosus Leach of Venezuela (Coleoptera, Hydrophilidae, Berosini) with description of fourteen new species. AB - The species of the water scavenger beetle genus Berosus Leach occurring in Venezuela are reviewed. Thirty-six species are recorded, including fifteen new species, fourteen of which are described here as new: Berosus araguasp. n., Berosus asymmetricussp. n., Berosus capanaparosp. n., Berosus castaneussp. n., Berosus corozosp. n., Berosus ebeninussp. n., Berosus garciaisp. n., Berosus humeralissp. n., Berosus jolyisp. n., Berosus llanensissp. n., Berosus megaphallussp. n., Berosus ornaticollissp. n., Berosus repertussp. n., and Berosus tramidrumsp. n. The fifteenth new species, known from a single female, is left undescribed pending the collection of males. Twelve species are recorded from Venezuela for the first time: Berosus ambogynus Mouchamps, Berosus consobrinus Knisch, Berosus elegans Knisch, Berosus geayi d'Orchymont, Berosus ghanicus d'Orchymont, Berosus guyanensis Queney, Berosus holdhausi Knisch, Berosus marquardti Knisch, Berosus olivae Queney, Berosus reticulatus Knisch, Berosus wintersteineri Knisch, and Berosus zimmermanni Knisch. PMID- 22811609 TI - Analysis of the mineral composition of the human calcified cartilage zone. AB - As the connecting tissue between the hyaline articular cartilage and the subchondral bone, calcified cartilage zone (CCZ) plays a great role in the force transmission and materials diffusion. However, the questions that remain to be resolved are its mineral composition and organization. In this study, 40 healthy human knee specimens were harvested; first the CCZ was dissected and observed by Safranin O/fast green staining, then CCZ chemical characteristics were measured by using amino acid assay and X-ray diffraction. The percentage of dry weight of type II collagen as an organic compound of CCZ was 20.16% +/- 0.96%, lower than that of the hyaline cartilage layer (61.39% +/- 0.38%); the percentage of dry weight of hydroxyapatite as an inorganic compound was 65.09% +/- 2.31%, less than that of subchondral bone (85.78% +/- 3.42%). Our study provides the accurate data for the reconstruction of the CCZ in vitro and the elucidation of CCZ structure and function. PMID- 22811608 TI - BioShuttle mobility in living cells studied with high-resolution FCS & CLSM methodologies. AB - With the increase in molecular diagnostics and patient-specific therapeutic approaches, the delivery and targeting of imaging molecules and pharmacologically active agents gain increasing importance. The ideal delivery system does not exist yet. The realization of two features is indispensable: first, a locally high concentration of target-specific diagnostic and therapeutic molecules; second, the broad development of effective and safe carrier systems. Here we characterize the transport properties of the peptide-based BioShuttle transporter using FFM and CLSM methods. The modular design of BioShuttle-based formulations results in a multi-faceted field of applications, also as a theranostic tool. PMID- 22811610 TI - Knowledge of and attitude to nuclear power among residents around Tianwan Nuclear Power Plant in Jiangsu of China. AB - AIMS: The aims of this paper were to determine the level of knowledge of and attitude to nuclear power among residents around Tianwan Nuclear power plant in Jiangsu of China. DESIGN: A descriptive, cross-sectional design was adopted. PARTICIPANTS: 1,616 eligible participants who lived around the Tianwan nuclear power plant within a radius of 30km and at least 18 years old were recruited into our study and accepted epidemiological survey. METHODS: Data were collected through self-administered questionnaires consisting of a socio-demographic sheet. Inferential statistics, t-test, ANOVA test and multivariate regression analysis were used to compare the differences between each subgroup and correlation analysis was conducted to understand the relationship between different factors and dependent variables. RESULTS: Our investigation found that the level of awareness and acceptance of nuclear power was generally not high. Respondents' gender, age, marital status, residence, educational level, family income and the distance away from the nuclear power plant are important effect factors to the knowledge of and attitude to nuclear power. CONCLUSIONS: The public concerns about nuclear energy's impact are widespread. The level of awareness and acceptance of nuclear power needs to be improved urgently. PMID- 22811611 TI - 18alpha-glycyrrhetinic acid down-regulates expression of type I and III collagen via TGF-Beta1/Smad signaling pathway in human and rat hepatic stellate cells. AB - OBJECTIVE: To investigate the effects of 18alpha-glycyrrhetinic acid (18alpha-GA) on the expression of type I and III collagen in human and rat hepatic stellate cells (HSC) and to explore the role of TGF-beta1/Smad signaling pathway involved. METHODS: Following 18alpha-GA treatment, the cell viability and cell growth were detected to determine the optimal concentration of 18alpha-GA. The expressions of TGF-beta1/Smad signaling-related genes including type I and III collagen in human and rat HSCs before and after 18alpha-GA treatment were measured by real time PCR. The expression of related proteins was verified by western blot assay. The phosphorylation level of Smad2 and Smad3 was detected by immunocytochemistry. The DNA binding activities of SP-1, AP-1 and NF-kappaB were measured by both EMSA and ArrayStar transcription factor activity assay. RESULTS: 18alpha-GA could decrease the mRNA and protein expression of Smad3, type I and III collagen, increase the Smad7 expression in human and rat HSCs (P<0.05), and reduce phosphorylation level of Smad3 at 24 h and 48 h after treatment. The DNA binding activities of transcription factors were suppressed by 18alpha-GA in human and rat HSCs at 24 h, and the activities reduced in a time dependent manner with the lowest activities at 48 h, especially for SP-1. CONCLUSION: 18alpha-GA could inhibit the mRNA and protein expression of type I and III collagen in human and rat HSCs, which may be attributed to down-regulation of Smad3, up-regulation of Smad7, and inhibition of DNA binding activities of SP-1, AP-1 and NF-kappaB. PMID- 22811612 TI - Analysis on the pathogenesis of symptomatic pulmonary embolism with human genomics. AB - BACKGROUND: In the present study, the whole human genome oligo microarray was employed to investigate the gene expression profile in symptomatic pulmonary embolism (PE). METHODS: Twenty patients with PE and 20 age and gender matched patients without PE as controls were enrolled into the present study in the same period. The diagnosis of PE was based on the clinical manifestations and findings on imaging examinations. Acute arterial and/or venous thrombosis was excluded in controls. The whole human genome oligo microarray was employed for detection. Statistical analysis was performed with t test following analysis of very small samples of repeated measurements and Gene Ontology (GO) analysis. RESULTS: Genomic data showed no damage to vascular endothelial cells in PE patients. Genomic data only found increased mRNA expression of a small amount of coagulation factors in PE patients. In the PE group, anticoagulant proteins, Fibrinolytic system and proteins related to platelet functions only played partial roles in the pathogenesis of PE. In addition, the mRNA expressions of a fraction of adhesion molecules were markedly up-regulated. Gene Ontology analysis showed the genes with down-regulated expressions mainly explain the compromised T cell immunity. Symptomatic VTE patients have compromised T cell immunity. CONCLUSION: The damage to vascular endothelial cells is not necessary in the pathogenesis of VTE, and only a fraction of factors involved in the shared coagulation cascade are activated. Genomic results may provide a new clue for clinical diagnosis, treatment and prevention of VTE. PMID- 22811613 TI - A large amniocele with protruded umbilical cord diagnosed by 3D ultrasound. AB - An amniocele is a herniation of the amniotic sac through a uterine defect. Uterine rupture during pregnancy may develop as a result of a pre-existing injury, uterine anomaly, or unscarred uterus. A 30-year-old patient, with a history of 2 vaginal deliveries, presented an amniocele complicated by left fundal perforation and was evaluated with 3-dimensional ultrasound at 23 weeks. Because of worsening lower abdominal pain and vaginal bleeding, she underwent exploratory laparotomy. Herein, we report a uterine rupture with amniocele. PMID- 22811615 TI - The role of alpha-synuclein and tau hyperphosphorylation-mediated autophagy and apoptosis in lead-induced learning and memory injury. AB - Lead (Pb) is a well-known heavy metal in nature. Pb can cause pathophysiological changes in several organ systems including central nervous system. Especially, Pb can affect intelligence development and the ability of learning and memory of children. However, the toxic effects and mechanisms of Pb on learning and memory are still unclear. To clarify the mechanisms of Pb-induced neurotoxicity in hippocampus, and its effect on learning and memory, we chose Sprague-Dawley rats (SD-rats) as experimental subjects. We used Morris water maze to verify the ability of learning and memory after Pb treatment. We used immunohistofluorescence and Western blotting to detect the level of tau phosphorylation, accumulation of alpha-synuclein, autophagy and related signaling molecules in hippocampus. We demonstrated that Pb can cause abnormally hyperphosphorylation of tau and accumulation of alpha-synuclein, and these can induce hippocampal injury and the ability of learning and memory damage. To provide the new insight into the underlying mechanisms, we showed that Grp78, ATF4, caspase-3, autophagy-related proteins were induced and highly expressed following Pb-exposure. But mTOR signaling pathway was suppressed in Pb-exposed groups. Our results showed that Pb could cause hyperphosphorylation of tau and accumulation of alpha-synuclein, which could induce ER stress and suppress mTOR signal pathway. These can enhance type II program death (autophgy) and type I program death (apoptosis) in hippocampus, and impair the ability of learning and memory of rats. This is the first evidence showing the novel role of autophagy in the neurotoxicity of Pb. PMID- 22811616 TI - Association of CTLA4 gene polymorphisms with susceptibility and pathology correlation to pulmonary tuberculosis in Southern Han Chinese. AB - The cytotoxic T lymphocyte antigen-4 (CTLA4) gene is a key negative regulator of the T lymphocyte immune response. It has been found that CTLA4 +49A>G (rs231775), +6230G>A (rs3087243), and 11430G>A (rs11571319) polymorphisms are associated with susceptibility to many autoimmune diseases, and can down-regulate the inhibition of cellular immune response of CTLA4. Three SNPs in CTLA4 were genotyped by using the PCR and DNA sequencing methods in order to reveal the susceptibility and pathology correlation to pulmonary tuberculosis in Southern Han Chinese. We found that the frequency of CTLA4 +49AG genotype in the pulmonary tuberculosis patients (38.42%) was significantly lower than that of the healthy controls (49.77%), (P(cor)=0.038, OR 0.653, 95% CI 0.436-0.978). But, no associations were found between the other 2 SNPs (+6230G>A, 11430G>A) and tuberculosis (P>0.05). Haplotype analysis showed that the frequency of haplotype AGG in the healthy controls group (6.9%) was significantly higher than the pulmonary tuberculosis patients group (1.4%), (global P=0.005, P(cor)=0.0002, OR 0.183, 95% CI 0.072 0.468). In addition, haplotype GGA was found to be significantly related to tuberculosis with double lung lesion rather than single lung lesion (P(cor)=0.042). This study is the first to report that genetic variants in the CTLA4 gene can be associated with pulmonary tuberculosis in Southern Han Chinese, and CTLA4 +49AG genotype as well as haplotype AGG may reduce the risk of being infected with pulmonary tuberculosis. The GGA haplotype was related to tuberculosis with double lung lesion, which provides a new experimental basis to clarify the pathogenesis of pulmonary tuberculosis. PMID- 22811614 TI - Honey--a novel antidiabetic agent. AB - Diabetes mellitus remains a burden worldwide in spite of the availability of numerous antidiabetic drugs. Honey is a natural substance produced by bees from nectar. Several evidence-based health benefits have been ascribed to honey in the recent years. In this review article, we highlight findings which demonstrate the beneficial or potential effects of honey in the gastrointestinal tract (GIT), on the gut microbiota, in the liver, in the pancreas and how these effects could improve glycemic control and metabolic derangements. In healthy subjects or patients with impaired glucose tolerance or diabetes mellitus, various studies revealed that honey reduced blood glucose or was more tolerable than most common sugars or sweeteners. Pre-clinical studies provided more convincing evidence in support of honey as a potential antidiabetic agent than clinical studies did. The not-too-impressive clinical data could mainly be attributed to poor study designs or due to the fact that the clinical studies were preliminary. Based on the key constituents of honey, the possible mechanisms of action of antidiabetic effect of honey are proposed. The paper also highlights the potential impacts and future perspectives on the use of honey as an antidiabetic agent. It makes recommendations for further clinical studies on the potential antidiabetic effect of honey. This review provides insight on the potential use of honey, especially as a complementary agent, in the management of diabetes mellitus. Hence, it is very important to have well-designed, randomized controlled clinical trials that investigate the reproducibility (or otherwise) of these experimental data in diabetic human subjects. PMID- 22811617 TI - Differentially expressed genes distributed over chromosomes and implicated in certain biological processes for site insertion genetically modified rice Kemingdao. AB - Release of genetically modified (GM) plants has sparked off intensive debates worldwide partly because of concerns about potential adverse unintended effects of GM plants to the agro system and the safety of foods. In this study, with the aim of revealing the molecular basis for unintended effects of a single site insertion GM Kemingdao (KMD) rice transformed with a synthetic cry1Ab gene, and bridging unintended effects of KMD rice through clues of differentially expressed genes, comparative transcriptome analyses were performed for GM KMD rice and its parent rice of Xiushui11 (XS11). The results showed that 680 differentially expressed transcripts were identified from 30-day old seedlings of GM KMD rice. The absolute majority of these changed expression transcripts dispersed and located over all rice chromosomes, and existed physical distance on chromosome from the insertion site, while only two transcripts were found to be differentially expressed within the 21 genes located within 100 kb up and down stream of the insertion site. Pathway and biology function analyses further revealed that differentially expressed transcripts of KMD rice were involved in certain biological processes, and mainly implicated in two types of pathways. One type was pathways implicated in plant stress/defense responses, which were considerably in coordination with the reported unintended effects of KMD rice, which were more susceptible to rice diseases compared to its parent rice XS11; the other type was pathways associated with amino acids metabolism. With this clue, new unintended effects for changes in amino acids synthesis of KMD rice leaves were successfully revealed. Such that an actual case was firstly provided for identification of unintended effects in GM plants by comparative transciptome analysis. PMID- 22811620 TI - Health & healing overview. PMID- 22811621 TI - A call to action. PMID- 22811619 TI - Turning on myogenin in muscle: a paradigm for understanding mechanisms of tissue specific gene expression. AB - Expression of the myogenin (Myog) gene is restricted to skeletal muscle cells where the transcriptional activator turns on a gene expression program that permits the transition from proliferating myoblasts to differentiating myotubes. The strict temporal and spatial regulation on Myog expression in the embryo makes it an ideal gene to study the developmental regulation of tissue-specific expression. Over the last 20 years, our knowledge of the regulation of Myog expression has evolved from the identification of the minimal promoter elements necessary for the gene to be transcribed in muscle, to a mechanistic understanding of how the proteins that bind these DNA elements work together to establish transcriptional competence. Here we present our current understanding of the developmental regulation of gene expression gained from studies of the Myog gene. PMID- 22811622 TI - Healing metabolism: a naturopathic medicine perspective on achieving weight loss and long-term balance. PMID- 22811618 TI - Complexities of TGF-beta targeted cancer therapy. AB - Many advanced tumors produce excessive amounts of Transforming Growth Factor-beta (TGF-beta) which, in normal epithelial cells, is a potent growth inhibitor. However, in oncogenically activated cells, the homeostatic action of TGF-beta is often diverted along alternative pathways. Hence, TGF-beta signaling elicits protective or tumor suppressive effects during the early growth-sensitive stages of tumorigenesis. However, later in tumor development when carcinoma cells become refractory to TGF-beta-mediated growth inhibition, the tumor cell responds by stimulating pathways with tumor progressing effects. At late stages of malignancy, tumor progression is driven by TGF-beta overload. The tumor microenvironment is a target of TGF-beta action that stimulates tumor progression via pro-tumorigenic effects on vascular, immune, and fibroblastic cells. Bone is one of the richest sources of TGF-beta in the body and a common site for dissemination of breast cancer metastases. Osteoclastic degradation of bone matrix, which accompanies establishment and growth of metastases, triggers further release of bone-derived TGF-beta. This leads to a vicious positive feedback of tumor progression, driven by ever increasing levels of TGF-beta released from both the tumor and bone matrix. It is for this reason, that pharmaceutical companies have developed therapeutic agents that block TGF-beta signaling. Nonetheless, the choice of drug design and dosing strategy can affect the efficacy of TGF-beta therapeutics. This review will describe pre-clinical and clinical data of four major classes of TGF-beta inhibitor, namely i) ligand traps, ii) antisense oligonucleotides, iii) receptor kinase inhibitors and iv) peptide aptamers. Long term dosing strategies with TGF-beta inhibitors may be ill advised, since this class of drug has potentially highly pleiotropic activity, and development of drug resistance might potentiate tumor progression. Current paradigms for the use of TGF-beta inhibitors in oncology have therefore moved towards the use of combinatorial therapies and short term dosing, with considerable promise for the clinic. PMID- 22811623 TI - Encountering particulars: a life in medicine. PMID- 22811624 TI - Preparing for successful surgery: an implementation study. AB - OBJECTIVES: To evaluate the implementation of a mind-body program for surgical patients in a community hospital, assessing patient participation, patient perception, and program impact on anxiety, pain, and quality of sleep during the perioperative period. METHODS: Two hundred thirty patients having total hip replacement, total knee replacement, hysterectomy, or colectomy participated in this investigation. One hundred fifteen patients were assigned to the control group before the start of the mind-body program and received routine care. The subsequent 115 patients were assigned to the intervention group and were given an audio CD (containing guided imagery, affirmations, and relaxation music) and a brochure three to seven days before surgery. The brochure recommended that patients listen to the CD twice a day before and after surgery. Anxiety, pain at rest, pain with movement, quality of sleep, and program participation were assessed for the first two postoperative days, and patient perception of the program was assessed at the end of the two days. RESULTS: Anxiety scores were lower in the intervention group on the evening of surgery. Despite a trend toward lower pain scores in the intervention group, no difference between the intervention and control groups reached statistical significance, including quality of sleep. Of patients in the intervention group, 74% listened to the CD at least once after surgery, and 37% listened to the program three or more times. Most patients who used the CD at least once rated it as helpful, and 87% said they would use it for future operations. CONCLUSIONS: Patient response to a perioperative mind-body program was favorable. Most patients listened to the program CD at least once, and a third used the CD repeatedly, as recommended. The majority of patients who used the CD felt it had been helpful and would use it again. Program participants experienced less anxiety on the night of surgery. PMID- 22811625 TI - A quarter century of hospice care: the southern california kaiser permanente experience. AB - Kaiser Permanente (KP) has been a pioneer in the development of hospice services in the United States. Since 1978, when hospice services were introduced in the KP Southern California Region, they have been gradually expanded to benefit thousands of patients and their families. However, important barriers to timely, appropriate utilization of hospice care remain. A pilot project conducted in our TriCentral Service Area has shown that palliative care-a newer development in end of-life care-can be cost-effective in addition to being beneficial for patients and their families. Efforts are underway to emulate this model of care at other KP facilities. Availability of both home-based and inpatient palliative care services can expand the number and type of patients who, as they near the end of life, can benefit from effective symptom control and other support. PMID- 22811626 TI - High-Quality Asthma Care: It's Not Just About Drugs. AB - ASTHMA CARE IS BASED ON THREE SIMPLE, BASIC CONCEPTS: reduce triggers, use controller medicine, and take early action in flare-ups. Implementing these concepts is difficult, however, and nonadherence is common. The patient, family, and health care system tend to focus their attention on crisis care instead of on control, and long-standing behaviors are hard to change. Adherence to asthma control regimens can be improved if clinicians and their patients focus more attention on communication skills, mutual problem solving, and follow-up. Use of a stages-of-change model also can be valuable for facilitating important behavioral change. PMID- 22811627 TI - Malnutrition in the elderly: a multifactorial failure to thrive. PMID- 22811628 TI - Chronic Pain is a Chronic Condition, Not Just a Symptom. PMID- 22811629 TI - Bariatric Surgery in the KP Northwest Region: Optimizing Outcomes by Using a Multidisciplinary Program. AB - Although bariatric surgery can be an appropriate treatment option for extremely obese patients, uncertainty exists as to how to optimize treatment outcomes. This article describes a coordinated multidisciplinary program designed to educate and behaviorally prepare patients for bariatric surgery and to support long-term behavioral change.Key aspects of our program include adequate preoperative obesity-related assessment, including nutritional, psychosocial, and physical assessment; emphasis on preoperative behavior change; changing the inpatient surgical treatment care path to decrease the length of hospital stay; and providing long-term management by using enhanced clinical decision support that includes Intranet-based practice resources embedded in the electronic medical record. Self-care is facilitated through group classes and support groups.A multidisciplinary bariatric program optimizes short- and long-term postoperative success and maximizes the safety and cost-effectiveness of bariatric surgery. PMID- 22811630 TI - How can we reduce the incidence of contrast-induced acute renal failure? PMID- 22811631 TI - A symposium on meditation, prayer and spiritual healing. PMID- 22811632 TI - Meditation, prayer and spiritual healing: the evidence. PMID- 22811634 TI - Spiritual moments. PMID- 22811633 TI - Meditation. PMID- 22811635 TI - Pastoral spiritual care. PMID- 22811637 TI - Spirituality symposium: panel discussion. PMID- 22811636 TI - Spirituality in the medical encounter: the grace of presence. PMID- 22811638 TI - From standardized patient to care actor: evolution of a teaching methodology. AB - Standardized patients have been utilized for nearly 40 years in teaching medical curricula. Since the introduction of this teaching methodology in the early 1960s, the use of standardized patients has steadily gained acceptance and is now incorporated into medical education across the country. This "standardization" was useful for teaching and evaluating medical students and residents. However, as this modality expanded beyond medical schools to include seasoned physicians, the limitations of "one-size-fits-all" clinical scenarios became apparent. In teaching clinician-patient communication (CPC) courses to practicing physicians, we have discovered that flexibility and improvisation on the part of the actor enhances the educational experience. The term "care actor" more accurately describes this role than standardized patient. The care actors in our CPC courses have become integral contributors to the education process, serving not only as simulated patients but also as coaches and collaborators. This article outlines the history of standardized patients in medical education and presents a three part framework for effectively using care actors to teach clinician-patient communication: setting the stage, skill practice, and providing feedback. PMID- 22811639 TI - Treating chronic pain: new knowledge, more choices. PMID- 22811640 TI - What to do with hypertension and a murmur found during a preparticipation physical evaluation? PMID- 22811641 TI - Stereotactic radiosurgery: instrumentation and theoretical aspects-part 1. AB - In the five decades since its introduction as a concept, radiosurgery has been technically refined to the point where it has revolutionized many aspects of treating central nervous system disease.This article reviews the technical basis of stereotactic radiosurgery as well as the radiobiologic principles underlying its use. PMID- 22811642 TI - Facilitating physician access to medical reference information. AB - CONTEXT: Computer-based medical reference information is augmenting-and in some cases, replacing-many traditional sources. For Kaiser Permanente (KP) physicians, this change presents both advantages and obstacles to finding medical reference information. OBJECTIVE: To improve understanding of physician information-seeking behavior and the barriers that limit use of both print-based and computer-based medical reference resources. DESIGN: During 2002 and 2003, two quality improvement surveys were distributed to full-time KP physicians. Survey instruments sent by conventional mail and by e-mail were based on results of telephone interviews and focus groups, and were designed to be concise and easy to use. Participant response rates exceeded 83%. OUTCOMES MEASURES: The surveys examined physician use of online medical reference information, medical libraries and services, self-directed learning resources, and continuing medical education (CME). RESULTS: Of the physicians who responded to the survey, 89% used online resources frequently to enhance care, to inform clinical decisions, to update knowledge, to educate patients, or for a combination of these purposes. Compared with responses from older physicians, responses from younger physicians showed a greater proclivity for using nearly all types of online information. Most physicians obtained CME credits primarily through in-person education programs; few physicians used self-directed electronic learning tools. Obstacles to effective access to information included lack of time, overly complex access methods, and lack of awareness about available resources. CONCLUSIONS: A considerable gap exists between physicians' need for information and the resources currently available for delivering this information. Although we observed a clear shift from using printed medical references to using computer based resources, many barriers prevent their effective use. Clinicians need easy to-use, seamless systems of medical reference information that are accessible remotely anytime. PMID- 22811644 TI - The ideal: innovation and transfer. PMID- 22811643 TI - The coordinated clinical studies network: a multidisciplinary alliance to facilitate research and improve care. AB - The NIH Roadmap is a major effort to reshape the US health research enterprise to accelerate medical discovery and to do so in such a way that actually hastens population health improvement through research. The Roadmap's ultimate goal resonates with the HMO Research Network, a consortium of integrated health care systems that uses its collective scientific capabilities to integrate research, practice, and policy for the improvement of health and health care among diverse populations. (See page 6 for abstracts from the HMO Research Network annual conference.) As such, the HMO Research Network was ideally suited to propose a new consortium project as a part of the NIH Roadmap, the Coordinated Clinical Studies Network (CCSN). The CCSN was funded in 2004 to create a path-breaking research facility that leverages several distinctive features of the HMO Research Network: the multidisciplinary scientific capabilities of its researchers; the ability to rapidly move clinical research findings into care delivery; its large, diverse patient populations; and a commitment to placing its findings in the public domain. Among the goals of the CCSN are to augment the capacity and infrastructure for conducting research, and to use considerable investments in health informatics to improve the scope and efficiency of research data collection. The NIH Roadmap is a revolutionary step toward a new paradigm for research and responds to both a compelling social need and rapid technological advances in biomedicine. The CCSN's participation in the Roadmap Initiative is a unique opportunity for researchers, clinicians, and our patients. PMID- 22811645 TI - The care management institute: harvesting innovation, maximizing transfer. PMID- 22811647 TI - Fail often to succeed sooner: adventures in innovation. PMID- 22811646 TI - Innovation in the Kaiser Permanente Colorado Region: Where We've Been, Where We Are Going. PMID- 22811648 TI - Practical Steps for Practice Transfer: The Four A's of Adoption. PMID- 22811649 TI - Stealing shamelessly: practice transfer success factors. PMID- 22811650 TI - How to find a sponsor for your practice innovation. PMID- 22811652 TI - Shifting from traditional to biopsychosocial pediatrics modifying the pediatrician-parent relationship to promote normal childhood development. PMID- 22811651 TI - Roundtable discussion: transfer of successful practices. PMID- 22811653 TI - Owning our own health-modeling healthy living. PMID- 22811654 TI - Post-tsunami malaria in indonesia-the pivotal contributions of permanente physicians. PMID- 22811655 TI - Permanente and the tsunami relief efforts-one year later-the volunteers' stories: a journal. PMID- 22811656 TI - Alkene cleavage catalysed by heme and nonheme enzymes: reaction mechanisms and biocatalytic applications. AB - The oxidative cleavage of alkenes is classically performed by chemical methods, although they display several drawbacks. Ozonolysis requires harsh conditions ( 78 degrees C, for a safe process) and reducing reagents in a molar amount, whereas the use of poisonous heavy metals such as Cr, Os, or Ru as catalysts is additionally plagued by low yield and selectivity. Conversely, heme and nonheme enzymes can catalyse the oxidative alkene cleavage at ambient temperature and atmospheric pressure in an aqueous buffer, showing excellent chemo- and regioselectivities in certain cases. This paper focuses on the alkene cleavage catalysed by iron cofactor-dependent enzymes encompassing the reaction mechanisms (in case where it is known) and the application of these enzymes in biocatalysis. PMID- 22811657 TI - Review of the BCI Competition IV. AB - The BCI competition IV stands in the tradition of prior BCI competitions that aim to provide high quality neuroscientific data for open access to the scientific community. As experienced already in prior competitions not only scientists from the narrow field of BCI compete, but scholars with a broad variety of backgrounds and nationalities. They include high specialists as well as students. The goals of all BCI competitions have always been to challenge with respect to novel paradigms and complex data. We report on the following challenges: (1) asynchronous data, (2) synthetic, (3) multi-class continuous data, (4) session-to session transfer, (5) directionally modulated MEG, (6) finger movements recorded by ECoG. As after past competitions, our hope is that winning entries may enhance the analysis methods of future BCIs. PMID- 22811659 TI - Selectivity of odorant receptors in insects. AB - Insect olfactory receptors (ORs) detect chemicals, shape neuronal physiology, and regulate behavior. Although ORs have been categorized as "generalists" and "specialists" based on their ligand spectrum, both electrophysiological studies and recent pharmacological investigations show that ORs specifically recognize non-pheromonal compounds, and that our understanding of odorant-selectivity mirrors our knowledge of insect chemical ecology. As we are progressively becoming aware that ORs are activated through a variety of mechanisms, the molecular basis of odorant-selectivity and the corollary notion of broad-tuning need to be re-examined from a pharmacological and evolutionary perspective. PMID- 22811660 TI - Effects of methimepip and JNJ-5207852 in Wistar rats exposed to an open-field with and without object and in Balb/c mice exposed to a radial-arm maze. AB - The role of the histamine H(3) receptor (H(3)R) in anxiety is controversial, due to limitations in drug selectivity and limited validity of behavioral tests used in previous studies. In the present report, we describe two experiments. In the first one, Wistar rats were treated with an H(3)R agonist (methimepip), and exposed to an open-field. In the second one, Balb/c mice were treated with H(3)R agonist (methimepip) or antagonist (JNJ-5207852), and exposed to an open space 3D maze which is a modified version of the radial-arm maze. C57BL/6J saline treated mice were included for comparisons. When exposed to an empty open field, Wistar rats spent more time in the outer area and made very low number of brief crossings in the central area. However, when an object occupied the central area, rats crossed frequently into and spent a long time in the central area. Administration of a range of different doses of methimepip (selective H(3)R agonist) reduced the entries into the central area with a novel object, indicating enhanced avoidance response. In the 3D maze, both Balb/c and C57BL/6J saline-treated mice crossed frequently onto the bridges that radiate from the central platform but only C57BL/6J mice crossed onto the arms which extend the bridges. This suggests that Balb/c mice are more anxious than C57BL/6J mice. Neither methimepip nor JNJ-5207852 (selective H(3)R antagonist/inverse agonist) induced entry into the arms of the maze, indicative of lack of anxiolytic effects. PMID- 22811661 TI - Stimulus generalization and return of fear in C57BL/6J mice. AB - Return of fear following successful exposure therapy is a common problem. More insight into the characteristics of extinction learning is crucial in enhancing the efficiency of therapeutic interventions. In particular, understanding the mechanisms that underlie the generalization of extinction learning to other discrete stimuli is indispensable. Presently, little is known about the molecular and genetic mechanisms underlying this phenomenon. In this study, we attempt to develop a new conditioning protocol to study return of fear, caused by a stimulus change after extinction, in the most commonly used mouse strain of behavioral genetics, C57BL/6J. Perceptual changes to an auditory fear conditioned stimulus led to return of fear after initially successful fear-reduction, relative to appropriate control treatment. We argue that this protocol will be a useful tool to unravel the neurobiological underpinnings that regulate generalization of extinction and return of fear. Key questions for future research include the identification of crucial brain structures, neurotransmitters and signaling pathways that underly this behavioral phenomenon. Arguably, such research will open up new perspectives for neurobiological therapy augmentation. PMID- 22811658 TI - Control of neuronal ion channel function by glycogen synthase kinase-3: new prospective for an old kinase. AB - Glycogen synthase kinase 3 (GSK-3) is an evolutionarily conserved multifaceted ubiquitous enzyme. In the central nervous system (CNS), GSK-3 acts through an intricate network of intracellular signaling pathways culminating in a highly divergent cascade of phosphorylations that control neuronal function during development and adulthood. Accumulated evidence indicates that altered levels of GSK-3 correlate with maladaptive plasticity of neuronal circuitries in psychiatric disorders, addictive behaviors, and neurodegenerative diseases, and pharmacological interventions known to limit GSK-3 can counteract some of these deficits. Thus, targeting the GSK-3 cascade for therapeutic interventions against this broad spectrum of brain diseases has raised a tremendous interest. Yet, the multitude of GSK-3 downstream effectors poses a substantial challenge in the development of selective and potent medications that could efficiently block or modulate the activity of this enzyme. Although the full range of GSK-3 molecular targets are far from resolved, exciting new evidence indicates that ion channels regulating excitability, neurotransmitter release, and synaptic transmission, which ultimately contribute to the mechanisms underling brain plasticity and higher level cognitive and emotional processing, are new promising targets of this enzyme. Here, we will revise this new emerging role of GSK-3 in controling the activity of voltage-gated Na(+), K(+), Ca(2+) channels and ligand-gated glutamate receptors with the goal of highlighting new relevant endpoints of the neuronal GSK-3 cascade that could provide a platform for a better understanding of the mechanisms underlying the dysfunction of this kinase in the CNS and serve as a guidance for medication development against the broad range of GSK-3-linked human diseases. PMID- 22811662 TI - Better ways to improve standards in brain-behavior correlation analysis. PMID- 22811663 TI - Population spikes in cortical networks during different functional states. AB - Brain computational challenges vary between behavioral states. Engaged animals react according to incoming sensory information, while in relaxed and sleeping states consolidation of the learned information is believed to take place. Different states are characterized by different forms of cortical activity. We study a possible neuronal mechanism for generating these diverse dynamics and suggest their possible functional significance. Previous studies demonstrated that brief synchronized increase in a neural firing [Population Spikes (PS)] can be generated in homogenous recurrent neural networks with short-term synaptic depression (STD). Here we consider more realistic networks with clustered architecture. We show that the level of synchronization in neural activity can be controlled smoothly by network parameters. The network shifts from asynchronous activity to a regime in which clusters synchronized separately, then, the synchronization between the clusters increases gradually to fully synchronized state. We examine the effects of different synchrony levels on the transmission of information by the network. We find that the regime of intermediate synchronization is preferential for the flow of information between sparsely connected areas. Based on these results, we suggest that the regime of intermediate synchronization corresponds to engaged behavioral state of the animal, while global synchronization is exhibited during relaxed and sleeping states. PMID- 22811664 TI - Renewing the respect for similarity. AB - In psychology, the concept of similarity has traditionally evoked a mixture of respect, stemming from its ubiquity and intuitive appeal, and concern, due to its dependence on the framing of the problem at hand and on its context. We argue for a renewed focus on similarity as an explanatory concept, by surveying established results and new developments in the theory and methods of similarity-preserving associative lookup and dimensionality reduction-critical components of many cognitive functions, as well as of intelligent data management in computer vision. We focus in particular on the growing family of algorithms that support associative memory by performing hashing that respects local similarity, and on the uses of similarity in representing structured objects and scenes. Insofar as these similarity-based ideas and methods are useful in cognitive modeling and in AI applications, they should be included in the core conceptual toolkit of computational neuroscience. In support of this stance, the present paper (1) offers a discussion of conceptual, mathematical, computational, and empirical aspects of similarity, as applied to the problems of visual object and scene representation, recognition, and interpretation, (2) mentions some key computational problems arising in attempts to put similarity to use, along with their possible solutions, (3) briefly states a previously developed similarity based framework for visual object representation, the Chorus of Prototypes, along with the empirical support it enjoys, (4) presents new mathematical insights into the effectiveness of this framework, derived from its relationship to locality sensitive hashing (LSH) and to concomitant statistics, (5) introduces a new model, the Chorus of Relational Descriptors (ChoRD), that extends this framework to scene representation and interpretation, (6) describes its implementation and testing, and finally (7) suggests possible directions in which the present research program can be extended in the future. PMID- 22811665 TI - Spatially invariant computations in stereoscopic vision. AB - PERCEPTION OF STEREOSCOPIC DEPTH REQUIRES THAT VISUAL SYSTEMS SOLVE A CORRESPONDENCE PROBLEM: find parts of the left-eye view of the visual scene that correspond to parts of the right-eye view. The standard model of binocular matching implies that similarity of left and right images is computed by inter ocular correlation. But the left and right images of the same object are normally distorted relative to one another by the binocular projection, in particular when slanted surfaces are viewed from close distance. Correlation often fails to detect correct correspondences between such image parts. We investigate a measure of inter-ocular similarity that takes advantage of spatially invariant computations similar to the computations performed by complex cells in biological visual systems. This measure tolerates distortions of corresponding image parts and yields excellent performance over a much larger range of surface slants than the standard model. The results suggest that, rather than serving as disparity detectors, multiple binocular complex cells take part in the computation of inter ocular similarity, and that visual systems are likely to postpone commitment to particular binocular disparities until later stages in the visual process. PMID- 22811666 TI - Endothelial Cells Derived from the Blood-Brain Barrier and Islets of Langerhans Differ in their Response to the Effects of Bilirubin on Oxidative Stress Under Hyperglycemic Conditions. AB - Unconjugated bilirubin (UCB) is a neurotoxic degradation product of heme. Its toxic effects include induction of apoptosis, and ultimately neuronal cell death. However, at low concentrations, UCB is a potent antioxidant that may protect cells and tissues against oxidative stress by neutralizing toxic metabolites such as reactive oxygen species (ROS). High glucose levels (hyperglycemia) generate reactive metabolites. Endothelial cell dysfunction, an early vascular complication in diabetes, has been associated with hyperglycemia-induced oxidative stress. Both glucose and UCB are substrates for transport proteins in microvascular endothelial cells of the blood-brain barrier (BBB). In the current study we show that UCB (1-40 MUM) induces apoptosis and reduces survival of bEnd3 cells, a mouse brain endothelial cell line which serves as an in vitro model of the BBB. These deleterious effects of UCB were enhanced in the presence of high glucose (25 mM) levels. Interestingly, the bEnd3 cells exhibited an increased sensitivity to the apoptotic effects of UCB when compared to the MS1 microcapillary endothelial cell line. MS1 cells originate from murine pancreatic islets of Langerhans, and are devoid of the barrier characteristics of BBB derived endothelial cells. ROS production was increased in both bEnd3 and MS1 cells exposed to high glucose, as compared with cells exposed to normal (5.5 mM) glucose levels. While UCB (0.1-40 MUM) did not alter ROS production in cells exposed to normal glucose, relatively low ("physiological") UCB concentrations (0.1-5 MUM) attenuated ROS generation in both cell lines exposed to high glucose levels. Most strikingly, higher UCB concentrations (20-40 MUM) increased ROS generation in bEnd3 cells exposed to high glucose, but not in similarly treated MS1 cells. These results may be of critical importance for understanding the vulnerability of the BBB endothelium upon exposure to increasing UCB levels under hyperglycemic conditions. PMID- 22811667 TI - Antitumor and Immunomodulatory Effects of Polysaccharides from Broken-Spore of Ganoderma lucidum. AB - The antitumor and immunomodulatory activity of broken-spore of Ganodermalucidum polysaccharides (Gl-BSP) were investigated in vivo and in vitro. It was showed that Gl-BSP (50, 100, and 200 mg kg(-1)) exhibited antitumor effect against Sarcoma 180 (S180) in BALB/c mice. The Gl-BSP was not cytotoxicity in S180 cells and PG cells (human lung carcinoma cell) in vitro. However, serum from Gl-BSP treated S180-bearing mice significantly inhibited S180 and PG cells proliferation in vitro. Moreover, Gl-BSP promoted the splenic lymphocyte proliferation induced by Con A or LPS, enhanced nature killer cell (NK cell) cytotoxic activity, augmented the percentage of neutral red phagocytosis by macrophages, and increased the percentage of the CD4(+) or CD8(+) subset in S180-bearing mice. The serum level of IFN-gamma, TNF-alpha, and nitric oxide was increased by Gl-BSP. Gl BSP also showed immunomodulatory activities in tumor-bearing mice. Furthermore, neutralization with anti-TNF-alpha and/or anti-IFN-gamma significantly diminished growth inhibition induced by Gl-BSP-treated serum of S180-bearing mice in S180 or PG cells. These observations suggest that the antitumor activity of Gl-BSP may be mainly related to the activation of the immune response of the host organism by the stimulation of NK cells, T cells, and macrophages. PMID- 22811668 TI - The role of bile pigments in health and disease: effects on cell signaling, cytotoxicity, and cytoprotection. PMID- 22811670 TI - New challenges and frontiers in the research for neuropsychiatric disorders. PMID- 22811672 TI - On the role of theta-driven syllabic parsing in decoding speech: intelligibility of speech with a manipulated modulation spectrum. AB - Recent hypotheses on the potential role of neuronal oscillations in speech perception propose that speech is processed on multi-scale temporal analysis windows formed by a cascade of neuronal oscillators locked to the input pseudo rhythm. In particular, Ghitza (2011) proposed that the oscillators are in the theta, beta, and gamma frequency bands with the theta oscillator the master, tracking the input syllabic rhythm and setting a time-varying, hierarchical window structure synchronized with the input. In the study described here the hypothesized role of theta was examined by measuring the intelligibility of speech with a manipulated modulation spectrum. Each critical-band signal was manipulated by controlling the degree of temporal envelope flatness. Intelligibility of speech with critical-band envelopes that are flat is poor; inserting extra information, restricted to the input syllabic rhythm, markedly improves intelligibility. It is concluded that flattening the critical-band envelopes prevents the theta oscillator from tracking the input rhythm, hence the disruption of the hierarchical window structure that controls the decoding process. Reinstating the input-rhythm information revives the tracking capability, hence restoring the synchronization between the window structure and the input, resulting in the extraction of additional information from the flat modulation spectrum. PMID- 22811671 TI - Can post-error dynamics explain sequential reaction time patterns? AB - We investigate human error dynamics in sequential two-alternative choice tasks. When subjects repeatedly discriminate between two stimuli, their error rates and reaction times (RTs) systematically depend on prior sequences of stimuli. We analyze these sequential effects on RTs, separating error and correct responses, and identify a sequential RT tradeoff: a sequence of stimuli which yields a relatively fast RT on error trials will produce a relatively slow RT on correct trials and vice versa. We reanalyze previous data and acquire and analyze new data in a choice task with stimulus sequences generated by a first-order Markov process having unequal probabilities of repetitions and alternations. We then show that relationships among these stimulus sequences and the corresponding RTs for correct trials, error trials, and averaged over all trials are significantly influenced by the probability of alternations; these relationships have not been captured by previous models. Finally, we show that simple, sequential updates to the initial condition and thresholds of a pure drift diffusion model can account for the trends in RT for correct and error trials. Our results suggest that error based parameter adjustments are critical to modeling sequential effects. PMID- 22811673 TI - Conditioned Flavor Preference and the US Postexposure Effect in the House Musk Shrew (Suncus Murinus). AB - The house musk shrew (Suncus murinus) is the only species of mammalian insectivore that can be domesticated and used as a laboratory animal, and is an interesting subject in terms of evolutionary and comparative aspects. The present study on the learning faculties of shrews examines the possibility of acquiring a conditioned flavor preference and the effects of US postexposure. Subjects were allowed to a drink sucrose solution with flavor A and tap water with flavor B during training. Two extinction tests were administered after every four conditioning trials, and a significant preference for flavor A was observed. After each test, the animals were divided into two groups. Subjects in Group US were presented with a sucrose solution without flavor, while those in Group Water were given tap water. After these trials, all subjects received choice tests where they were presented with water containing the two flavors. The preference ratio was lower in Group US than in Group Water, suggesting a postexposure effect. The findings were discussed in terms of habituation to the US. PMID- 22811669 TI - Calcium Signaling and Gliotransmission in Normal vs. Reactive Astrocytes. AB - A prominent area of neuroscience research over the past 20 years has been the acute modulation of neuronal synaptic activity by Ca(2+)-dependent release of the transmitters ATP, D-serine, and glutamate (called gliotransmitters) by astrocytes. Although the physiological relevance of this mechanism is under debate, emerging evidence suggests that there are critical factors in addition to Ca(2+) that are required for gliotransmitters to be released from astrocytes. Interestingly, these factors include activated microglia and the proinflammatory cytokine Tumor Necrosis Factor alpha (TNFalpha), chemotactic cytokine Stromal cell-Derived Factor-1alpha (SDF-1alpha), and inflammatory mediator prostaglandin E2 (PGE(2)). Of note, microglial activation and release of inflammatory molecules from activated microglia and reactive astrocytes can occur within minutes of a triggering stimulus. Therefore, activation of astrocytes by inflammatory molecules combined with Ca(2+) elevations may lead to gliotransmitter release, and be an important step in the early sequence of events contributing to hyperexcitability, excitotoxicity, and neurodegeneration in the damaged or diseased brain. In this review, we will first examine evidence questioning Ca(2+) dependent gliotransmitter release from astrocytes in healthy brain tissue, followed by a close examination of recent work suggesting that Ca(2+)-dependent gliotransmitter release occurs as an early event in the development of neurological disorders and neuroinflammatory and neurodegenerative diseases. PMID- 22811674 TI - The body knows what it should do: automatic motor compensation for illusory heaviness contagion. AB - We can share various feelings with others just through observation, as if it were an automatic resonance. This connective function between the self and others could promote the facilitation of our social communication; however, it is still unclear as to how it works in terms of self-other representation. In this study, we showed participants a picture of a model holding a ball, which was weighted with sand. We instructed participants to move one of their arms to a horizontal position and hold it immobile. Those participants who knew the actual weight of the ball (1 kg) tended to raise this arm above the horizontal, in response to their expectation of the need to resist the weight of the ball. This compensatory reaction to the illusion of heaviness suggests that our bodily resonance could be mandatory and predictive. We discuss this new behavioral phenomenon in terms of motor simulation or the mirror-neuron system. PMID- 22811675 TI - The role of native-language knowledge in the perception of casual speech in a second language. AB - Casual speech processes, such as /t/-reduction, make word recognition harder. Additionally, word recognition is also harder in a second language (L2). Combining these challenges, we investigated whether L2 learners have recourse to knowledge from their native language (L1) when dealing with casual speech processes in their L2. In three experiments, production and perception of /t/ reduction was investigated. An initial production experiment showed that /t/ reduction occurred in both languages and patterned similarly in proper nouns but differed when /t/ was a verbal inflection. Two perception experiments compared the performance of German learners of Dutch with that of native speakers for nouns and verbs. Mirroring the production patterns, German learners' performance strongly resembled that of native Dutch listeners when the reduced /t/ was part of a word stem, but deviated where /t/ was a verbal inflection. These results suggest that a casual speech process in a second language is problematic for learners when the process is not known from the leaner's native language, similar to what has been observed for phoneme contrasts. PMID- 22811677 TI - Comparative genomic and transcriptional analyses of CRISPR systems across the genus Pyrobaculum. AB - Within the domain Archaea, the CRISPR immune system appears to be nearly ubiquitous based on computational genome analyses. Initial studies in bacteria demonstrated that the CRISPR system targets invading plasmid and viral DNA. Recent experiments in the model archaeon Pyrococcus furiosus have uncovered a novel RNA-targeting variant of the CRISPR system. Because our understanding of CRISPR system evolution in other archaea is limited, we have taken a comparative genomic and transcriptomic view of the CRISPR arrays across six diverse species within the crenarchaeal genus Pyrobaculum. We present transcriptional data from each of four species in the genus (P. aerophilum, P. islandicum, P. calidifontis, P. arsenaticum), analyzing mature CRISPR-associated small RNA abundance from over 20 arrays. Within the genus, there is remarkable conservation of CRISPR array structure, as well as unique features that are have not been studied in other archaeal systems. These unique features include: a nearly invariant CRISPR promoter, conservation of direct repeat families, the 5' polarity of CRISPR associated small RNA abundance, and a novel CRISPR-specific association with homologues of nurA and herA. These analyses provide a genus-level evolutionary perspective on archaeal CRISPR systems, broadening our understanding beyond existing non-comparative model systems. PMID- 22811676 TI - Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. AB - Mild traumatic brain injury (mTBI) represents a significant challenge for the civilian and military health care systems due to its high prevalence and overall complexity. Our earlier works showed evidence of neuroinflammation, a late onset of neurobehavioral changes, and lasting memory impairment in a rat model of mild blast-induced TBI (mbTBI). The aim of our present study was to determine whether acute treatment with the non-steroidal anti-inflammatory drug minocycline (Minocin((r))) can mitigate the neurobehavioral abnormalities associated with mbTBI, Furthermore, we aimed to assess the effects of the treatment on select inflammatory, vascular, neuronal, and glial markers in sera and in brain regions associated with anxiety and memory (amygdala, prefrontal cortex, ventral, and dorsal hippocampus) following the termination (51 days post-injury) of the experiment. Four hours after a single exposure to mild blast overpressure or sham conditions, we treated animals with a daily dose of minocycline (50 mg/kg) or physiological saline (vehicle) for four consecutive days. At 8 and 45 days post injury, we tested animals for locomotion, anxiety, and spatial memory. Injured animals exhibited significantly impaired memory and increased anxiety especially at the later testing time point. Conversely, injured and minocycline treated rats' performance was practically identical to control (sham) animals in the open field, elevated plus maze, and Barnes maze. Protein analyses of sera and brain regions showed significantly elevated levels of all of the measured biomarkers (except VEGF) in injured and untreated rats. Importantly, minocycline treatment normalized serum and tissue levels of the majority of the selected inflammatory, vascular, neuronal, and glial markers. In summary, acute minocycline treatment appears to prevent the development of neurobehavioral abnormalities likely through mitigating the molecular pathologies of the injury in an experimental model of mbTBI. PMID- 22811681 TI - Modeling the hydrodynamics of Phloem sieve plates. AB - Sieve plates have an enormous impact on the efficiency of the phloem vascular system of plants, responsible for the distribution of photosynthetic products. These thin plates, which separate neighboring phloem cells, are perforated by a large number of tiny sieve pores and are believed to play a crucial role in protecting the phloem sap from intruding animals by blocking flow when the phloem cell is damaged. The resistance to the flow of viscous sap in the phloem vascular system is strongly affected by the presence of the sieve plates, but the hydrodynamics of the flow through them remains poorly understood. We propose a theoretical model for quantifying the effect of sieve plates on the phloem in the plant, thus unifying and improving previous work in the field. Numerical simulations of the flow in real and idealized phloem channels verify our model, and anatomical data from 19 plant species are investigated. We find that the sieve plate resistance is correlated to the cell lumen resistance, and that the sieve plate and the lumen contribute almost equally to the total hydraulic resistance of the phloem translocation pathway. PMID- 22811678 TI - Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation. AB - Current clinical strategies to control the alloimmune response after transplantation do not fully prevent induction of the immunological processes which lead to acute and chronic immune-mediated graft rejection, and as such the survival of a solid organ allograft is limited. Experimental research on naturally occurring CD4(+)CD25(high)FoxP3(+) Regulatory T cells (Tregs) has indicated their potential to establish stable long-term graft acceptance, with the promise of providing a more effective therapy for transplant recipients. Current approaches for clinical use are based on the infusion of freshly isolated or ex vivo polyclonally expanded Tregs into graft recipients with an aim to redress the in vivo balance of T effector cells to Tregs. However mounting evidence suggests that regulation of donor-specific immunity may be central to achieving immunological tolerance. Therefore, the next stages in optimizing translation of Tregs to organ transplantation will be through the refinement and development of donor alloantigen-specific Treg therapy. The altering kinetics and intensity of alloantigen presentation pathways and alloimmune priming following transplantation may indeed influence the specificity of the Treg required and the timing or frequency at which it needs to be administered. Here we review and discuss the relevance of antigen-specific regulation of alloreactivity by Tregs in experimental and clinical studies of tolerance and explore the concept of delivering an optimal Treg for the induction and maintenance phases of achieving transplantation tolerance. PMID- 22811680 TI - The salivary scavenger and agglutinin binds MBL and regulates the lectin pathway of complement in solution and on surfaces. AB - The salivary scavenger and agglutinin (SALSA), also known as gp340, salivary agglutinin and deleted in malignant brain tumor 1, is a 340-kDa glycoprotein expressed on mucosal surfaces and secreted into several body fluids. SALSA binds to a broad variety of microbes and endogenous ligands, such as complement factor C1q, surfactant proteins D and A, and IgA. Our search for novel ligands of SALSA by direct protein-interaction studies led to the identification of mannan-binding lectin (MBL) as a new binding partner. We observed that surface-associated SALSA activates complement via binding of MBL. On the other hand, soluble SALSA was found to inhibit Candida albicans-induced complement activation. Thus, SALSA has a dual complement activation modifying function. It activates the lectin pathway when bound to a surface and inhibits it when free in the fluid phase. These activities are mediated via a direct interaction with MBL. This suggests that SALSA could target the innate immune responses to certain microorganisms and simultaneously limit complement activation in the fluid phase. PMID- 22811679 TI - Galectins as self/non-self recognition receptors in innate and adaptive immunity: an unresolved paradox. AB - Galectins are characterized by their binding affinity for beta-galactosides, a unique binding site sequence motif, and wide taxonomic distribution and structural conservation in vertebrates, invertebrates, protista, and fungi. Since their initial description, galectins were considered to bind endogenous ("self") glycans and mediate developmental processes and cancer. In the past few years, however, numerous studies have described the diverse effects of galectins on cells involved in both innate and adaptive immune responses, and the mechanistic aspects of their regulatory roles in immune homeostasis. More recently, however, evidence has accumulated to suggest that galectins also bind exogenous ("non self") glycans on the surface of potentially pathogenic microbes, parasites, and fungi, suggesting that galectins can function as pattern recognition receptors (PRRs) in innate immunity. Thus, a perplexing paradox arises by the fact that galectins also recognize lactosamine-containing glycans on the host cell surface during developmental processes and regulation of immune responses. According to the currently accepted model for non-self recognition, PRRs recognize pathogens via highly conserved microbial surface molecules of wide distribution such as LPS or peptidoglycan (pathogen-associated molecular patterns; PAMPs), which are absent in the host. Hence, this would not apply to galectins, which apparently bind similar self/non-self molecular patterns on host and microbial cells. This paradox underscores first, an oversimplification in the use of the PRR/PAMP terminology. Second, and most importantly, it reveals significant gaps in our knowledge about the diversity of the host galectin repertoire, and the subcellular targeting, localization, and secretion. Furthermore, our knowledge about the structural and biophysical aspects of their interactions with the host and microbial carbohydrate moieties is fragmentary, and warrants further investigation. PMID- 22811682 TI - "Scanning mutagenesis" of the amino acid sequences flanking phosphorylation site 1 of the mitochondrial pyruvate dehydrogenase complex. AB - The mitochondrial pyruvate dehydrogenase complex (mtPDC) is regulated by reversible seryl-phosphorylation of the E1alpha subunit by a dedicated, intrinsic kinase. The phospho-complex is reactivated when dephosphorylated by an intrinsic PP2C-type protein phosphatase. Both the position of the phosphorylated Ser residue and the sequences of the flanking amino acids are highly conserved. We have used the synthetic peptide-based kinase client (KiC) assay plus recombinant pyruvate dehydrogenase E1alpha and E1alpha-kinase to perform "scanning mutagenesis" of the residues flanking the site of phosphorylation. Consistent with the results from "phylogenetic analysis" of the flanking sequences, the direct peptide-based kinase assays tolerated very few changes. Even conservative changes such as Leu, Ile, or Val for Met, or Glu for Asp, gave very marked reductions in phosphorylation. Overall the results indicate that regulation of the mtPDC by reversible phosphorylation is an extreme example of multiple, interdependent instances of co-evolution. PMID- 22811683 TI - A vision for 21st century agricultural research. PMID- 22811684 TI - Potential roles for Kinesins at the cortical division site. AB - Spatial control of cytokinesis is critical for cell and plant morphology. The plane of cell division is established at G2/M transition and is initially demarcated at the cortex of the cell by the cytoskeletal preprophase band (PPB) and subsequently throughout mitosis by the cortical division zone (CDZ). Few kinesins, belonging to different classes of the superfamily, either display a distinct spatio-temporal localization at the PPB and CDZ, or genetic evidence proposes a specific function there. Protein phosphorylation and degradation are likely directing the cell cycle-dependent localization and activity of some of these kinesins, as indicated by mutation of respective conserved motifs. Furthermore, kinesins are required for continuous recruitment of CDZ identity markers to the CDZ. This review summarizes the limited current knowledge of kinesins potentially involved in the steps required for correctly oriented division planes, considering localization patterns and genetic evidence, and discussing kinesin function in context with interaction partners and cell cycle regulation. PMID- 22811685 TI - Effector-triggered post-translational modifications and their role in suppression of plant immunity. AB - Plant-pathogen interactions feature complex signaling exchanges between host and microbes that ultimately determine association outcomes. Plants deploy pattern recognition receptors to perceive pathogen-associated molecular patterns, mount pattern-triggered immunity (PTI), and fend off potential pathogens. In recent years an increasing number of defense-signaling components have been identified along with a mechanistic understanding of their regulation during immune responses. Post-translational modifications (PTMs) are now thought to play a crucial role in regulating defense signaling. In a bid to suppress PTI and infect their host, pathogens have evolved large repertoires of effectors that trigger susceptibility and allow colonization of host tissues. While great progress has been made in elucidating defense-signaling networks in plants and the activities of effectors in immune suppression, a critical gap exists in our understanding of effector mechanism-of-action. Given the importance of PTMs in the regulation of defense signaling, we will explore the question: how do effectors modify the post translational status of host proteins and thus interfere with host processes required for immunity? We will consider how emerging proteomics-based experimental strategies may help us answer this important question and ultimately open the pathogens' effector black box. PMID- 22811686 TI - Get with the guidelines stroke performance indicators in a brazilian tertiary hospital. AB - BACKGROUND: Stroke is the fourth leading killer in the US, the first in Brazil and a leading cause of adult long-term disability in both countries. In spite of widespread recommendation, clinical practice guidelines have had limited effect on changing physician behavior. Recognizing that both knowledge and acceptance of guidelines do not necessarily imply guideline adherence, the American Heart Association/American Stroke Association (AHA/ASA) developed a national stroke quality improvement program, the 'Get With The Guidelines (GWTG) stroke'. Even though GWTG has produced remarkable results in the US, other countries have not adopted the program. METHODS: We compared the stroke treatment quality indicators from a private Brazilian tertiary hospital to those published by the GWTG stroke program. Seven predefined performance measures selected by the GWTG stroke program as targets for stroke quality improvement were evaluated: (1) tissue plasminogen activator use in patients who arrived <2 h from symptom onset; (2) antithrombotic medication use within 48 h of admission; (3) deep vein thrombosis prophylaxis within 48 h of admission for nonambulatory patients; (4) discharge use of antithrombotics; (5) discharge use of anticoagulation for atrial fibrillation; (6) dosing of LDL and treatment for LDL >100 mg/dl in patients meeting the National Cholesterol Education Program Adult Treatment Panel (NCEP) III guidelines, and (7) counseling for smoking cessation. RESULTS: A total of 343 consecutive patients with acute ischemic stroke (70.8%) or transient ischemic attack (29.2%) were evaluated from August 2008 to December 2010. Antithrombotic medication within 48 h was used in 98.5% of the eligible patients and deep vein thrombosis prophylaxis in 100%. A total of 123 patients arrived within 2 h from symptoms onset, 23 were eligible for intravenous thrombolysis and 16 were treated (69.5%). All eligible patients were discharged using antithrombotic medication, and 86.9% of the eligible patients who had atrial fibrillation received anticoagulation. Only 56.1% of the eligible patients were treated according to the NCEP III guidelines. Counseling for smoking cessation was done in 63.6% of the eligible patients. CONCLUSIONS: Our study is the first in Brazil and the second outside the US to analyze compliance with the GWTG recommendations. Close attention to a better implementation of these measures may produce an improvement in such results similar to what happened after the full implementation of the program in the US. Whether or not a US disease-based registry such as GWTG can be adopted with success beyond the US is still a matter of debate. PMID- 22811687 TI - Urinary Urgency Medications May Compromise Discrete rather than Global Cognitive Skills. AB - BACKGROUND/AIMS: Prior research about cognitive problems associated with the use of urinary urgency medication (UUM) has reported mixed results that suggest procedures and/or assessments may need to be refined. METHODS: Ten elderly subjects who were actively taking a UUM were assessed with neuropsychological testing before and after a 4-week UUM washout period. Results were evaluated by examining discrete subtest results, full-scale scores, and the reliable change index methodology. RESULTS: Four controls and 5 subjects with mild cognitive impairment showed significant improvement in at least one subtest score on well characterized instruments. CONCLUSION: In this case study of 10 subjects, withdrawal of oxybutynin and tolterodine resulted in significant changes in subtest scores with different patterns for each subject that were not necessarily reflected in their total scores. Thus, future clinical studies should always include analysis of subtest results as these changes may be the only indication that cognition has been improved or has declined significantly. PMID- 22811688 TI - Yamaguchi Facial Expression-Making Task in Alzheimer's Disease: A Novel and Enjoyable Make-a-Face Game. AB - BACKGROUND: To assess the ability to make emotional facial expressions, we newly developed the Yamaguchi facial expression-making task (Y-FEMT). METHOD: We recruited 20 normal controls and 61 outpatients: 10 with amnestic mild cognitive impairment (aMCI), 34 with mild Alzheimer's disease (AD), and 17 with moderate AD. In the Y-FEMT, smile and anger expressions were made by arranging face parts. We examined the relationship between each Y-FEMT score and the Mini-Mental State Examination (MMSE) score or overlapping figure identification test (Fig-test). RESULTS: The Total score (0-20) was nearly achieved in controls (18.9 +/- 1.4) and declined with AD progression (aMCI 17.2 +/- 2.4, mild AD 15.7 +/- 2.6, moderate AD 12.3 +/- 2.7). The Anger score (0-10) was significantly lower than the Smile score (0-10) in mild and moderate AD (p = 0.007 and p = 0.006, respectively). The Structure score (0-6 each) correlated well with both the MMSE score (r = 0.44, p < 0.001) and Fig-test (r = 0.45, p < 0.001), whereas the Expression score (0-4 each) correlated only with the MMSE score (r = 0.33, p = 0.01). The Subjective scores (0-4), evaluated by 10 therapists, highly correlated with the Total score. Additionally, the Y-FEMT promoted laughter and a convivial atmosphere. CONCLUSION: The Y-FEMT pleasantly assessed the ability to make emotional facial expressions without special equipment. Furthermore, the Y-FEMT may provide helpful clues for caregivers to achieve good communication with AD patients for better care. PMID- 22811689 TI - DNA hypermethylation and inflammatory markers in incident Japanese dialysis patients. AB - BACKGROUND/AIMS: Inflammation is an established mortality risk factor in chronic kidney disease (CKD) patients. Although a previous report showed that uremic Caucasian patients with inflammation had signs of global DNA hypermethylation, it is still unknown whether DNA hypermethylation is linked to inflammatory markers including a marker of bacterial infections in Japanese CKD patients. METHODS: In 44 consecutive incident dialysis patients (26 males, mean age 59 +/- 12 years) without clinical signs of infection, global DNA methylation was evaluated in peripheral blood DNA using the HpaII/MspI ratio by the luminometric methylation assay method. A lower ratio of HpaII/MspI indicates global DNA hypermethylation. Procalcitonin (PCT), a marker of inflammation due to bacterial infections, was measured using an immunochromatographic assay. RESULTS: The patients were divided into hyper- and hypomethylation groups based on the median value of the HpaII/MspI ratio 0.31 (range 0.29-0.37). Whereas patients in the hypermethylation group had higher ferritin levels [133.0 (51.5-247.3) vs. 59.5 (40.0-119.0) ng/ml; p = 0.046], there were no significant differences in age, gender, diabetes, smoking, anemia or serum albumin levels. However, the HpaII/MspI ratio showed significant negative correlations with PCT (rho = -0.32, p = 0.035) and ferritin (rho = -0.33, p = 0.027) in Spearman's rank test. In a multiple linear regression analysis, PCT and ferritin were associated with a lower HpaII/MspI ratio (R(2) = 0.24, p = 0.013). CONCLUSION: In this study, global DNA hypermethylation was associated with ferritin and, most likely, PCT, suggesting that inflammation induced by subclinical bacterial infection promoted DNA methylation. PMID- 22811690 TI - Serum Beta 2-microglobulin/cystatin C index: a useful biomarker in lupus nephritis? AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with frequent flares. Our aim was to evaluate the beta 2 microglobulin/cystatin C (beta2M/CysC) index versus other markers as a predictor factor for assessment of SLE reactivation. METHODS: We prospectively analyzed 42 patients with lupus nephritis. Disease activity was classified using SLEDAI-2K and BILAG. Routine renal function and laboratory markers of SLE activity were performed, as well as serum beta2M (Sbeta2M)/serum CysC (SCysC) and Sbeta2M/serum creatinine (SCreat) indexes determinations. RESULTS: The 42 enrolled patients had a mean age of 37.7 +/- 13.1 years, 88% were female and 67% Caucasians; mean estimated glomerular filtration rate was 61.9 +/- 20.0 ml/min/1.73 m(2). There was a strong correlation between SCreat versus SCysC (r = 0.887), SCreat versus Sbeta2M (r = 0.865), and SCysC versus Sbeta2M (r = 0.880). Multivariate analysis showed that the Sbeta2M/SCreat index is a prognostic factor predicting active lupus nephritis. CONCLUSION: As SCysC is a good marker of renal function, it would be expected that the Sbeta2M/SCysC index could be a better indicator of renal activity than Sbeta2M/SCreat, but in the present study it did not add relevant clinical information in the assessment of renal activity in SLE. PMID- 22811691 TI - Nephroprotective Effect of Echinodorus macrophyllus Micheli on Gentamicin-Induced Nephrotoxicity in Rats. AB - BACKGROUND/AIMS: Leaves of Echinodorus macrophyllus (EM), from the Alismataceae family, have been used in Brazilian folk medicine for their anti-inflammatory and diuretic properties. In this work, the diuretic and nephroprotective activities of crude extracts of EM were evaluated. METHODS: Normal Wistar rats were given 0.9% NaCl containing either EM (10-300 mg/kg), furosemide (13 mg/kg) or arginine vasopressin (0.2 mg/kg). Thereafter, the rats were individually housed in metabolic cages, and urine volume was measured every 30 min for a total of 3 h. Acute kidney injury was induced by gentamicin (GM, 80 mg.kg(-1).day(-1), b.i.d., 5 days). Along with GM, 0.9% NaCl (control) or EM (30 mg/kg) was given to the rats by gavage. RESULTS: EM produced a dose-dependent reduction in urine elimination. EM was effective in reversing all GM-induced alterations such as polyuria and glomerular filtration rate reduction. The GM-induced morphological alterations were not observed when EM was given concomitantly with GM. CONCLUSION: This study provides evidence that EM possesses nephroprotective effect which indicates that EM may have therapeutic applications in GM-induced acute kidney injury. PMID- 22811692 TI - Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients. AB - BACKGROUND: Accelerated formation and tissue accumulation of advanced glycation endproducts (AGEs), reflecting cumulative glycemic and oxidative stress, occur in age-related and chronic diseases like diabetes mellitus (DM) and renal failure, and contribute to vascular damage. Skin autofluorescence (AF), a noninvasive measurement method, reflects tissue accumulation of AGEs. The aim of our study was to determine the predictive value of skin AF on overall and cardiovascular mortality in hemodialysis patients. METHODS: Baseline skin AF was measured in 105 patients on hemodialysis, 23 had DM. Survival status was assessed after a mean follow-up period of 4.9 years (interquartile range 2.3-6.9 years). RESULTS: Multivariate Cox regression analysis showed skin AF (hazard ratio (HR) 1.83; 95% confidence interval (CI) 1.32-2.54), preexisting cardiovascular disease (CVD) (HR 2.77; 95% CI 1.48-5.18), renal replacement therapy duration (HR 1.10; 95% CI 1.01 1.19), age (HR 1.03; 95% CI 1.01-1.06), serum albumin (HR 0.90; 95% CI 0.85 0.95), hematocrit (HR 0.92; 95% CI 0.86-0.98), phosphorus (HR 2.01; 95% CI 1.15 3.49), and parathyroid hormone (HR 0.99; 95% CI 0.98-0.996) to be predictors of mortality, whereas DM was not. Preexisting CVD and serum phosphorus were the only predictors of cardiovascular mortality. CONCLUSION: Skin AF showed to be an independent predictor of overall mortality in hemodialysis patients, but it had no predictive value for cardiovascular mortality. PMID- 22811693 TI - Increased Prevalence and Severity of Coronary Artery Calcification in Patients with Chronic Kidney Disease Stage III and IV. AB - BACKGROUND: Cardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). The pathophysiology of coronary artery disease in CKD is multifactorial including, in addition to traditional risk factors (hypertension, hyperlipidemia, diabetes mellitus), parameters related to uremia. METHODS: The study consisted of measuring coronary artery calcification (CAC) score in patients with CKD stage III and IV without history of CVD and in a group of controls with normal renal function matched for age, gender and risk factors using multi-detector computed tomography. RESULTS: The study included 49 patients and 49 controls. CAC was present in 79.6% in the CKD group versus 59.2% in the control group (p = 0.028). The median CAC score value in CKD patients was 139 (interquartile range (IQR): 23-321) versus 61 (IQR: 6 205) in controls (p = 0.007). CAC was associated with traditional risk factors such as older age, hypertension and baseline cardiovascular risk score, while CKD patients with severe calcification had marginally lower estimated glomerular filtration rate and increased levels of parathormone. CONCLUSIONS: CAC is more frequent and severe in patients with CKD stage III and IV compared to matched controls with normal renal function, even though kidney disease-related parameters are not directly correlated with intensity of calcification. PMID- 22811694 TI - Amlodipine Reduces Inflammation despite Promoting Albuminuria in the Streptozotocin-Induced Diabetic Rat. AB - Amlodipine reduces blood pressure; however, its effect in the diabetic kidney irrespective of its blood pressure-lowering effects is unclear. This study examined the effects of amlodipine (0, 5, 10 and 20 mg/kg; D(A0), D(A5), D(A10) and D(A20), respectively) for 12 weeks on renal functional and structural changes in the streptozotocin-induced diabetic rat, a nonhypertensive model of diabetes associated hyperfiltration. Compared with nondiabetic rats, diabetes (D) was associated with increased urine albumin excretion (UAE, 12.6 +/- 3.40 vs. 3.73 +/ 1.14 mg/day), glomerular filtration rate (2.17 +/- 0.09 vs. 1.64 +/- 0.12 ml/min/g kidney weight), glomerulosclerosis (0.21 +/- 0.03 vs. 0.05 +/- 0.01 AU) and infiltration of inflammatory cells (18.5 +/- 2.78 vs. 6.92 +/- 0.70 cells/cm(2)), but did not affect mean arterial pressure (MAP, 110 +/- 4.70 vs. 109 +/- 5.33 mm Hg). While D(A20) abolished glomerular hyperfiltration (1.49 +/- 0.05 ml/min/g kidney weight) and inflammatory cell abundance (6.0 +/- 0.79 cells/cm(2)), it exacerbated UAE (43.5 +/- 8.49 mg/day) and increased MAP (132 +/ 3.76 mm Hg), but had no effect on renal pathology. These data suggest that amlodipine reduces renal inflammation and abolished glomerular hyperfiltration, but increases blood pressure and exacerbates albuminuria in the rat model of normotensive diabetic kidney disease. We conclude that amlodipine may have limited renoprotective effects in the face of hyperfiltration and absence of elevated blood pressure. PMID- 22811695 TI - Statistics for next generation sequencing - meeting report. PMID- 22811696 TI - Recent progress in paleontological methods for dating the Tree of Life. AB - Dating the Tree of Life (TOL) has become a major goal of biological research. Beyond the intrinsic interest of reconstructing the history of taxonomic diversification, time-calibrated trees (timetrees for short, as used throughout below) are required in many types of comparative analyses, where branch lengths are used to assess the conservation importance of lineages, correlation between characters, or to assess phylogenetic niche conservatism, among other uses. Improvements in dating the TOL would thus benefit large segments of the biological community, ranging from conservation biology and ecology through functional biology and paleontology. Recently, progress has been made on several fronts: in compiling databases and supertrees incorporating paleontological data, in computing confidence intervals on the true stratigraphic range of taxa, and in using birth-and-death processes to assess the probability distribution of the time of origin of specified taxa. Combined paleontological and molecular dating has also progressed through the insertion of extinct taxa into data matrices, which allows incorporation of their phylogenetic uncertainty into the dating analysis. PMID- 22811698 TI - A protocol for measurement of noncoding RNA in human serum. AB - MicroRNAs (miRNAs) are small noncoding RNAs that act as regulators of gene expression by targeting mature messenger RNAs. Following the initial report of the presence of miRNAs in serum and plasma a number of studies have successfully demonstrated the use of these miRNAs as biomarkers of disease. Currently, there are many methods of isolating total RNA from liquid samples. Here, we describe a simple, cost effective method for extraction of RNA from human serum as well as subsequent real time PCR analysis of miRNA levels. PMID- 22811699 TI - CUDAICA: GPU optimization of Infomax-ICA EEG analysis. AB - In recent years, Independent Component Analysis (ICA) has become a standard to identify relevant dimensions of the data in neuroscience. ICA is a very reliable method to analyze data but it is, computationally, very costly. The use of ICA for online analysis of the data, used in brain computing interfaces, results are almost completely prohibitive. We show an increase with almost no cost (a rapid video card) of speed of ICA by about 25 fold. The EEG data, which is a repetition of many independent signals in multiple channels, is very suitable for processing using the vector processors included in the graphical units. We profiled the implementation of this algorithm and detected two main types of operations responsible of the processing bottleneck and taking almost 80% of computing time: vector-matrix and matrix-matrix multiplications. By replacing function calls to basic linear algebra functions to the standard CUBLAS routines provided by GPU manufacturers, it does not increase performance due to CUDA kernel launch overhead. Instead, we developed a GPU-based solution that, comparing with the original BLAS and CUBLAS versions, obtains a 25x increase of performance for the ICA calculation. PMID- 22811700 TI - Development of probiotic candidate in combination with essential oils from medicinal plant and their effect on enteric pathogens: a review. AB - Medicinal plants and probiotics both have very high potential in terms of their antimicrobial activity against antibiotic-resistant enteric pathogens. The probiotics being enteric microorganism do not have any parasitic effect on human beings. They have been an integral part of daily food for centuries. They have been shown to have health beneficiary properties. The probiotics retard the growth of the microorganisms, while essential oil kills them. Combining the effect of medicinal plant extract and probiotics may be a new approach due to their complementary antimicrobial effects and practically no side effects. The synergistic effect of the essential oil and probiotics will be necessarily higher than using them alone as health product. PMID- 22811697 TI - Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders. AB - Non-coding RNAs (ncRNAs) have emerged as critical regulators of transcription, epigenetic processes, and gene silencing, which make them ideal candidates for insight into molecular evolution and a better understanding of the molecular pathways of neuropsychiatric disease. Here, we provide an overview of the current state of knowledge regarding various classes of ncRNAs and their role in neural plasticity and cognitive function, and highlight the potential contribution they may make to the development of a variety of neuropsychiatric disorders, including schizophrenia, addiction, and fear-related anxiety disorders. PMID- 22811702 TI - Hyperthermic intraperitoneal chemotherapy with melphalan: a summary of clinical and pharmacological data in 34 patients. AB - Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases. The optimal agents for HIPEC have not been established. Melphalan is a drug with broad activity and a favorable profile for intraperitoneal application. The purpose of this study is to review our experience using melphalan for HIPEC. Pharmacologic data was obtained. Thirty four patients who underwent CRS for peritoneal metastases received melphalan for HIPEC between 2003 and 2011. The first 10 patients received 70 mg/m(2); subsequent 24 received 60 or 70 mg/m(2). The mean PCI was 21 +/- 7. Twenty-eight patients (83%) had a CC score of 1 or 2. The mean length of stay was 18 +/- 2 days. Nine patients (26%) had a grade 3 and 6 (17%) had grade 4 morbidity. There were no postoperative deaths. The pharmacologic analysis of plasma to peritoneal fluid levels of melphalan showed an AUC ratio of 33 while the tumor nodules to peritoneal ratio was 8. Melphalan is an acceptable agent for use in HIPEC. The morbidity of intraperitoneal melphalan at the dose of 60-70 mg/m(2) appears acceptable. Further studies comparing the effectiveness of melphalan and other HIPEC agents are needed. PMID- 22811703 TI - Penile enhancement procedures with simultaneous penile prosthesis placement. AB - Here we present an overview of various techniques performed concomitantly during penile prosthesis surgery to enhance penile length and girth. We report on the technique of ventral phalloplasty and its outcomes along with augmentation corporoplasty, suprapubic lipectomy, suspensory ligament release, and girth enhancement procedures. For the serious implanter, outcomes can be improved by combining the use of techniques for each scar incision. These adjuvant procedures are a key addition in the armamentarium for the serious implant surgeon. PMID- 22811701 TI - Atypical celiac disease: from recognizing to managing. AB - The nonclassic clinical presentation of celiac disease (CD) becomes increasingly common in physician's daily practice, which requires an awareness of its many clinical faces with atypical, silent, and latent forms. Besides the common genetic background (HLA DQ2/DQ8) of the disease, other non-HLA genes are now notably reported with a probable association to atypical forms. The availability of high-sensitive and specific serologic tests such as antitissue transglutuminase, antiendomysium, and more recent antideamidated, gliadin peptide antibodies permits to efficiently uncover a large portion of the submerged CD iceberg, including individuals having conditions associated with a high risk of developing CD (type 1 diabetes, autoimmune diseases, Down syndrome, family history of CD, etc.), biologic abnormalities (iron deficiency anemia, abnormal transaminase levels, etc.), and extraintestinal symptoms (short stature, neuropsychiatric disorders, alopecia, dental enamel hypoplasia, recurrent aphtous stomatitis, etc.). Despite the therapeutic alternatives currently in developing, the strict adherence to a GFD remains the only effective and safe therapy for CD. PMID- 22811704 TI - Pathogenic and Diagnostic Potential of BLCA-1 and BLCA-4 Nuclear Proteins in Urothelial Cell Carcinoma of Human Bladder. AB - Transitional cell carcinoma (TCC) of the bladder is one of the most common malignancies of genitourinary tract. Patients with bladder cancer need a life long surveillance, directly due to the relatively high recurrence rate of this tumor. The use of cystoscopy represents the gold standard for the followup of previously treated patients. Nevertheless, several factors, including cost and invasiveness, render cystoscopy not ideal for routine controls. Advances in the identification of specific alterations in the nuclear structure of bladder cancer cells have opened novel diagnostic landscapes. The members of nuclear matrix protein family BLCA-1 and BLCA-4, are currently under evaluation as bladder cancer urinary markers. They are involved in tumour cell proliferation, survival, and angiogenesis. In this paper, we illustrate the role of BLCA-1 and BLCA-4 in bladder carcinogenesis and their potential exploitation as biomarkers in this cancer. PMID- 22811705 TI - Priapism: comorbid factors and treatment outcomes in a contemporary series. AB - Objective. The goal of this study is to describe comorbid characteristics in patients who have priapism, and their treatment outcomes. Methods. Chart review was undertaken on men who had a diagnosis of priapism from a tertiary medical center, from 2000-2010. Men with priapism due exclusively to the use of prescription erectile aids and medications were not included in the review. Results. We identified 79 patients with the priapism. The most common type of priapism was the low flow variant. High flow priapism was identified in 2 patients. The most common general comorbid condition associated with priapism was mental illness (including substance abuse), which was present in 56% of the patients. Neurogenic priapism accounted for 19% of the total priapism events. Psychopharmaceutical agents and recreational drugs were commonly associated with ischemic priapism. Acute complications of priapism treatment were not common, but long-term complications, especially erectile dysfunction, were frequent. Conclusions. We describe the characteristics and outcomes of a large group of patients with priapism. Our experience at a tertiary care center indicates that mental illness, including substance abuse disorders, is a highly prevalent comorbid condition in men who experience priapism. Consistent with previous reports, erectile dysfunction is the most common complication from priapism and its treatment, occurring in the majority of men. PMID- 22811706 TI - Detecting cancer outlier genes with potential rearrangement using gene expression data and biological networks. AB - Gene alterations are a major component of the landscape of tumor genomes. To assess the significance of these alterations in the development of prostate cancer, it is necessary to identify these alterations and analyze them from systems biology perspective. Here, we present a new method (EigFusion) for predicting outlier genes with potential gene rearrangement. EigFusion demonstrated excellent performance in identifying outlier genes with potential rearrangement by testing it to synthetic and real data to evaluate performance. EigFusion was able to identify previously unrecognized genes such as FABP5 and KCNH8 and confirmed their association with primary and metastatic prostate samples while confirmed the metastatic specificity for other genes such as PAH, TOP2A, and SPINK1. We performed protein network based approaches to analyze the network context of potential rearranged genes. Functional gene rearrangement Modules are constructed by integrating functional protein networks. Rearranged genes showed to be highly connected to well-known altered genes in cancer such as AR, RB1, MYC, and BRCA1. Finally, using clinical outcome data of prostate cancer patients, potential rearranged genes demonstrated significant association with prostate cancer specific death. PMID- 22811707 TI - Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA. AB - Thimerosal generates ethylmercury in aqueous solution and is widely used as preservative. We have investigated the toxicology of Thimerosal in normal human astrocytes, paying particular attention to mitochondrial function and the generation of specific oxidants. We find that ethylmercury not only inhibits mitochondrial respiration leading to a drop in the steady state membrane potential, but also concurrent with these phenomena increases the formation of superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated hydroxyl radical. These oxidants increase the levels of cellular aldehyde/ketones. Additionally, we find a five-fold increase in the levels of oxidant damaged mitochondrial DNA bases and increases in the levels of mtDNA nicks and blunt-ended breaks. Highly damaged mitochondria are characterized by having very low membrane potentials, increased superoxide/hydrogen peroxide production, and extensively damaged mtDNA and proteins. These mitochondria appear to have undergone a permeability transition, an observation supported by the five-fold increase in Caspase-3 activity observed after Thimerosal treatment. PMID- 22811708 TI - Procoagulant and anticoagulant factors in childhood hypothyroidism. AB - The aim of this study was to investigate the effects of thyroid hormone deficiencies in childhood on the elements of coagulation proteins. Consecutive 54 children with hypothyroidism and 55 healthy controls aged 1 month-16 years were enrolled. One year after Na-L-thyroxine treatment, the study parameters were reevaluated. Thyroid function tests, procoagulant and anticoagulant proteins were performed for children with hypothyroidism and healthy controls. Significant decreased results were found in children with hypothyroidism in terms of fibrinogen, TT, and anticoagulant proteins including AT, PC, PS, and fPS. Significant increases were found with respect to APTT, fibrinogen, and TT. In the evaluation of posttreatment changes a statistically significant increase was found in vWF, FVIII, AT, PC, PS, and fPS. A positive correlation was found between fT4 and vWF, FVIII, PC, and PS. We would like to emphasize that the coagulation system especially vWF and FVIII, and particularly the anticoagulant system, should be monitored closely in patients followed up for hypothyroidism. Thyroid hormones should be examined and, if necessary, hormone replacement therapy should be administered in patients followed up for a predisposition to coagulation. Additionally, further studies with larger series are needed to investigate the effects of hypothyroidism on the coagulation system. PMID- 22811709 TI - Chemical methods to induce Beta-cell proliferation. AB - Pancreatic beta-cell regeneration, for example, by inducing proliferation, remains an important goal in developing effective treatments for diabetes. However, beta cells have mainly been considered quiescent. This "static" view has recently been challenged by observations of relevant physiological conditions in which metabolic stress is compensated by an increase in beta-cell mass. Understanding the molecular mechanisms underlining these process could open the possibility of developing novel small molecules to increase beta-cell mass. Several cellular cell-cycle and signaling proteins provide attractive targets for high throughput screening, and recent advances in cell culture have enabled phenotypic screening for small molecule-induced beta-cell proliferation. We present here an overview of the current trends involving small-molecule approaches to induce beta-cell regeneration by proliferation. PMID- 22811710 TI - Malignant melanoma and its stromal nonimmune microecosystem. AB - In recent years, rapid advances were reached in the understanding of a series of biologic signals influencing cutaneous malignant melanoma (CMM) cells. CMM is in close contact with a peculiar dermal extracellular matrix (ECM). Stromal cells store and release various structural ECM components. The impact on CMM growth and progression is mediated through strong and long-lasting effects of ECM products. This paper summarizes some peculiar aspects of the peri-CMM stroma showing intracytoplasmic loads in Factor XIIIa, CD34, versican, and alpha (IV) collagen chains. The restricted peri-CMM skin territory exhibiting such changes corresponds to the area showing neoangiogenesis and extravascular unicellular metastatic spread. The latter inconspicuous migratory CMM cells possibly correspond to CMM stem cells or to CMM cells with aberrant HOX gene expression. Their presence is associated with an increased risk for metastases in the regional sentinel lymph nodes. In conclusion, the CMM-stroma connection appears crucial to the growth regulation, invasiveness and initial metastatic spread of CMM cells. Although much remains to be learned in this field, the active intervention of the peri-CMM stroma is likely involved in the inconspicuous early metastatic migration of CMM cells. PMID- 22811712 TI - Soft and Hard Tissue Management in Implant Therapy-Part II: Prosthetic Concepts. AB - The ongoing pursuit of aesthetic excellence in the field of implant therapy has incorporated prosthetic concepts in the early treatment-planning phase, as well as the previously discussed surgical concepts. The literature has addressed these prosthetic and laboratory approaches required to enhance and perfect the soft and hard tissue management (SHTM). After surgically providing an acceptable hard tissue architecture and adequate timing of loading of the implant, the prosthetic phase is responsible for the soft tissue modeling, through correctly planned and executed procedures, which induce a satisfactory soft tissue profile by considering the microvasculature, the abutment connection and positioning, and the implementation of an adequate provisional phase. The objectives are the modeling of the soft tissues through the use of a conforming periorestorative interface which will produce desired and stable results. PMID- 22811711 TI - The Role of the Endothelium in HPS Pathogenesis and Potential Therapeutic Approaches. AB - American hantaviruses cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect endothelial cells and cause dramatic changes in barrier functions of the endothelium without disrupting the endothelium. Instead hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions of capillaries. The endothelium of arteries, veins, and lymphatic vessels is unique and central to the function of vast pulmonary capillary beds, which regulate pulmonary fluid accumulation. The endothelium maintains vascular barrier functions through a complex series of redundant receptors and signaling pathways that serve to both permit fluid and immune cell efflux into tissues and restrict tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to alter capillary permeability but also defines potential therapeutic targets for regulating acute pulmonary edema and HPS disease. Here we discuss interactions of HPS causing hantaviruses with the endothelium, potential endothelial cell-directed permeability mechanisms, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease. PMID- 22811713 TI - The Chemical Interplay between Nitric Oxide and Mitochondrial Cytochrome c Oxidase: Reactions, Effectors and Pathophysiology. AB - Nitric oxide (NO) reacts with Complex I and cytochrome c oxidase (CcOX, Complex IV), inducing detrimental or cytoprotective effects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX-NO(2) (-), PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying different persistency and O(2) competitiveness. In the mitochondrion, during turnover with O(2), one pathway prevails over the other one depending on NO, cytochrome c(2+) and O(2) concentration. High cytochrome c(2+), and low O(2) proved to be crucial in favoring CcOX nitrosylation, whereas under standard cell-culture conditions formation of the nitrite derivative prevails. All together, these findings suggest that NO can modulate physiologically the mitochondrial respiratory/OXPHOS efficiency, eventually being converted to nitrite by CcOX, without cell detrimental effects. It is worthy to point out that nitrite, far from being a simple oxidation byproduct, represents a source of NO particularly important in view of the NO cell homeostasis, the NO production depends on the NO synthases whose activity is controlled by different stimuli/effectors; relevant to its bioavailability, NO is also produced by recycling cell/body nitrite. Bioenergetic parameters, such as mitochondrial DeltaPsi, lactate, and ATP production, have been assayed in several cell lines, in the presence of endogenous or exogenous NO and the evidence collected suggests a crucial interplay between CcOX and NO with important energetic implications. PMID- 22811715 TI - Plant Growth Promoting of Endophytic Sporosarcina aquimarina SjAM16103 Isolated from the Pneumatophores of Avicennia marina L. AB - Endophytic Sporosarcina aquimarina SjAM16103 was isolated from the inner tissues of pneumatophores of mangrove plant Avicennia marina along with Bacillus sp. and Enterobacter sp. Endophytic S. aquimarina SjAM16103 was Gram variable, and motile bacterium measured 0.6-0.9 MUm wide by 1.7-2.0 MUm long and light orange-brown coloured in 3-day cultures on tryptone broth at 26 degrees C. Nucleotide sequence of this strain has been deposited in the GenBank under accession number GU930359. This endophytic bacterium produced 2.37 MUMol/mL of indole acetic acid and siderophore as it metabolites. This strain could solubilize phosphate molecules and fixes atmospheric nitrogen. Endophytic S. aquimarina SjAM16103 was inoculated into four different plants under in vitro method to analyse its growth-promoting activity and role inside the host plants. The growth of endophytic S. aquimarina SjAM16103 inoculated explants were highly significant than the uninoculated control explants. Root hairs and early root development were observed in the endophytic S. aquimarina SjAM16103 inoculated explants. PMID- 22811716 TI - Linear epidermal nevus of the oral cavity: a rare diagnosis. AB - Linear epidermal nevus is an uncommon diagnosis of benign lesions of the oral cavity. It is characterized by a congenital malformation arising from the ectoderm cells, which are arranged according to a typical linear configuration known as Blaschko's lines. We report a case of linear epidermal nevus of oral cavity in a 51-year-old lady or woman. The linear epidermal nevus of the oral cavity, although rare, can be considered a differential diagnosis of oral papillomatosis (OP). The histopathological studies and detailed description are the center of the diagnostic and clinical evolution. PMID- 22811717 TI - Sternal Osteomyelitis and Abscess Caused by Elbowing during a Basketball Game. AB - A 15-year-old boy was referred to our hospital for further investigation and treatment of sternal osteomyelitis due to blunt chest trauma, more specifically elbowing during a basketball game 19 days earlier. On an initial presentation, his chest was markedly swollen and chest computed tomography demonstrated a sternal fracture and massive fluid collection in the chest wall. Since his general condition remained fairly good, we initially selected minimal drainage concomitant with antibiotics; if it was unsuccessful, we planned to switch to a more radical debridement procedure. The patient recovered without further invasive intervention and was discharged on postoperative day 26. There is no sign of recurrence six months after operation. This case report indicates that minimal drainage would be a good option for treatment in a phased strategy. PMID- 22811714 TI - Pathogen recognition and activation of the innate immune response in zebrafish. AB - The zebrafish has proven itself as an excellent model to study vertebrate innate immunity. It presents us with possibilities for in vivo imaging of host-pathogen interactions which are unparalleled in mammalian model systems. In addition, its suitability for genetic approaches is providing new insights on the mechanisms underlying the innate immune response. Here, we review the pattern recognition receptors that identify invading microbes, as well as the innate immune effector mechanisms that they activate in zebrafish embryos. We compare the current knowledge about these processes in mammalian models and zebrafish and discuss recent studies using zebrafish infection models that have advanced our general understanding of the innate immune system. Furthermore, we use transcriptome analysis of zebrafish infected with E. tarda, S. typhimurium, and M. marinum to visualize the gene expression profiles resulting from these infections. Our data illustrate that the two acute disease-causing pathogens, E. tarda and S. typhimurium, elicit a highly similar proinflammatory gene induction profile, while the chronic disease-causing pathogen, M. marinum, induces a weaker and delayed innate immune response. PMID- 22811718 TI - Glomus tumor of the cheek: a case report. AB - Glomus tumors are benign, subcutaneous neoplasms of the perivasculature. Though facial location is rare, the diagnosis of a glomus tumor should be considered in cases of undiagnosed painful facial nodules or chronic facial pain. Imaging aids in defining the tumor and planning a complete excision in order to avoid recurrence. Histological examination is mandatory after every attempted excision. A case of glomus tumor of the cheek along with the possible pitfalls of diagnosis and treatment and a brief review of the limited associated literature are presented. PMID- 22811719 TI - Myeloma as a Second Malignancy following AML: Is a Second Allo Equivalent to Auto? AB - We report a young male patient who developed plasma cell myeloma/plasmacytoma 11 years after having received an allogeneic hematopoietic cell transplantation for AML. The patient received a second transplantation from the same donor without immunosuppression and developed graft-versus-host disease (GVHD). Our observation has two aspects that warrant attention: first, insufficiency of long-term tolerance to prevent GVHD in the absence of immunosuppression and second, a stromal or genetic susceptibility to develop hematologic malignancies despite of a complete donor-type chimerism. PMID- 22811720 TI - Diphencyprone induced vitiligo: a case report. AB - Diphencyprone (DCP) is a contact sensitizer which is used to treat dermatological disorders with an immunological origin, such as extensive alopecia areata (AA). Vitiligo is a rare but known side effect of DPCP therapy which is formed in the treatment site or remote areas. In this paper a 37-year-old man developed alopecia totalis with loss of eyebrows and eyelashes who presented some vitiligo patches on his scalp and arm distant from the location of DPCP application and a 42-year-old woman with 25 years history of hair loss and 3 months DPCP application who revealed some vitiligo patches on the scalp with distant to the site of application at the 6th week are reported. Considering the absence of personal and family history of Vitiligo in our two cases, the hypothesis of latent Vitiligo is not proved. The positive patch test in left arm of one of the patients also suggests the direct role of DPCP as the cause of Vitiligo occurrence. As the development of vitiligo by DCP is unpredictable and the depigmentation may persist indefinitely, it is important to inform all patients about this potential adverse effect before starting the treatment. PMID- 22811721 TI - Features of the atrophic corpus mucosa in three cases of autoimmune gastritis revealed by magnifying endoscopy. AB - Atrophic gastritis, whether caused by Helicobacter pylori infection or as a result of an autoimmune process, is associated with corpus atrophy. However, whereas atrophic gastritis caused by H. pylori involves the antrum, the antrum is spared in autoimmune gastritis. Here, we report the use of magnifying endoscopy to identify and distinguish atrophic gastritis caused by H. pylori from autoimmune gastritis. The mucosal pattern in autoimmune gastritis is that of closely arranged small round and oval pits, thus differing from the pattern seen in atrophic mucosa due to H. pylori infection. We speculate that this reflects differences in inflammation between the two types of gastritis. In autoimmune gastritis the inflammation is directed primarily against gastric glands, whereas in H. pylori infection the inflammation is directed against the bacteria on or near the surface and the damage initially affects the surface epithelium. During repair, the normal regular round pits are destroyed, whereas they remain largely intact in mucosa with autoimmune-associated atrophy. Confirmation of the features of autoimmune gastritis revealed by magnifying endoscopy would not only make the endoscopic diagnosis of autoimmune gastritis more accurate, but also help to elucidate changes in the surface epithelial structure of gastritis due to various causes. PMID- 22811722 TI - Glomus Tumor Presenting as Raynaud's Phenomenon. AB - Glomus tumors are rare tumors that often include hands and feet; they present characteristically with paroxysmal pain, exquisite point tenderness, and cold sensitivity. Such diagnosis needs to be confirmed by imaging like ultrasound and magnetic resonance imaging (MRI). Surgical excision is the treatment of choice for glomus tumors. There are only few case reports of glomus tumors in association with Raynaud's phenomenon; this is considered to be the 4th case. PMID- 22811723 TI - Hodgkin lymphoma untreated for six years presenting with tracheoesophageal fistula. AB - Hodgkin lymphoma is a highly curable cancer with modern therapy, with five-year survival rates in excess of 80%. However, the natural history of the untreated disease is largely unknown. We present the case of a patient with Hodgkin lymphoma who went untreated for over 5 years due to patient choice. Eventually, the patient developed hypoxemia, significant weight loss, and a tracheoesophageal fistula. After a placement of a gastrostomy tube and tracheal stent, treatment with standard chemotherapy was initiated. The patient achieved an excellent response, the fistula closed without further intervention, and there is no evidence of relapse six years later. Even in a patient with significant Hodgkin lymphoma-related sequelae, standard therapy can result in excellent long-term outcomes. PMID- 22811724 TI - Catheter displacement into inferior epigastric vein causing local phlebitis and cellulitis. AB - Catheter insertion for intravenous hyperalimentation is a commonly and widely used clinical technique. When compared with the incidence of complications associated with insertions into the internal jugular vein or the subclavian vein, complications associated with insertions into the femoral vein are less frequent. In this paper, we describe a very rare complication of femoral vein catheter insertion-namely, catheter displacement into the inferior epigastric vein. PMID- 22811725 TI - An unusual presentation of giant cell arteritis. AB - Giant cell arteritis (GCA) is a chronic vasculitis that typically presents with headache, fever and polymyalgia although atypical presentations are known. We present a case of GCA with nonproductive cough and pyrexia of unknown origin emphasizing this atypical nature of presentation. We report a rare association of GCA with granulomatous hepatitis. We also support the use of PET scanning in diagnosing and monitoring this condition. PMID- 22811726 TI - An unusual case of tracheoesophageal fistulae. AB - Acquired tracheoesophageal fistulae (TEF) are commonly due to malignancy (M. F. Reed and D. J. Mathisen, 2003). We present the case of a patient with a deceptive history for TEF and report an approach that provides adequate oxygenation, ventilation, surgical exposure, and postoperative analgesia with excellent outcome. PMID- 22811727 TI - Atypical presentation of skull metastasis from rectal adenocarcinoma as an initial symptom of recurrence. AB - Most malignant rectal tumors are histopathologically characterized as adenocarcinoma and generally metastasize to distant organs such as the lungs or the liver. Metastasis of rectal carcinomas to the skull is extremely rare. This study reports the initial diagnosis of rectal adenocarcinoma recurrence in a 65 year-old female with scalp metastasis. The patient's history indicated a colorectal adenocarcinoma that was resected five years earlier. A skull metastasis from a rectal adenocarcinoma has not yet been reported in the literature as an initial symptom for recurrence. This paper suggests that skull metastasis from any part of the body must be considered in the differential diagnosis of soft tissue tumors in the skull even in the absence of intestinal symptoms. PMID- 22811728 TI - A Case of Microangiopathic Antiphospholipid-Associated Syndromes during Pregnancy: Review of the Literature. AB - Microangiopathic antiphospholipid-associated syndromes (MAPSs) are reported as encompassing several conditions mainly affecting the microvasculature of selected organs: the liver in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet); kidney, brain, and skin in TTP (thrombotic thrombocytopenic purpura). It is predominant in patients with catastrophic antiphospholipid syndrome (APS). A recent report suggests that APS is not only a thrombotic disease but also associated with microangiopathic features, and it can explain the greater prevalence of HELLP syndrome in these patients. We here report a case of MAPS during pregnancy associated with systemic lupus erythematosus (SLE) in early second trimester. PMID- 22811729 TI - A rare variation of the heterotaxy syndrome. AB - Heterotaxy syndrome is a rare, complex, and confusing type of the situs anomalies. It is not possible to estimate the degree of lateralization, isomerism, and rotational variation in these types of cases. Heart and abdominal organ anatomy is specific to the individual, and it should be defined specifically on the basis of each case due to possible cardiac and extracardiac surgical interventions in patients with heterotaxy syndrome. Here, we present our findings obtained from a 58-year-old female patient with heterotaxy syndrome. The main components of this rare variation consist of right-hand-sided aorta, aortic arc, cardiac apex, gall bladder and left-hand-sided inferior vena cava, stomach, and spleen (polysplenia, 3 foci) according to the midline. Besides, the components include left-dominant liver, right-hand-sided large intestines, and left-hand-sided small intestines. PMID- 22811730 TI - Appendiceal mucocele diagnosed in patients with inflammatory bowel disease using endoscopic ultrasound. AB - When a bulging appendiceal orifice is observed during surveillance colonoscopy, the possibility of appendiceal mucocele must be considered. Appendiceal mucocele is a rare group of lesions characterized by mucinous distension of the appendiceal lumen with the dangerous potential to rupture, resulting in the development of pseudomyxoma peritonei. Early recognition and diagnosis of appendiceal mucocele can prevent the dreaded complication of pseudomyxoma peritonei but it requires a high index of suspicion. Patients with inflammatory bowel disease are at increased risk for colorectal neoplasm but neoplasm of the appendix is infrequently reported. We report two of the first cases of appendiceal mucoceles diagnosed in patients with inflammatory bowel disease using endoscopic ultrasound. PMID- 22811731 TI - It takes a mouth to eat and a nose to breathe: abnormal oral respiration affects neonates' oral competence and systemic adaptation. AB - Mammalian, including human, neonates are considered to be obligate nose breathers. When constrained to breathe through their mouth in response to obstructed or closed nasal passages, the effects are pervasive and profound, and sometimes last into adulthood. The present paper briefly surveys neonates' and infants' responses to this atypical mobilisation of the mouth for breathing and focuses on comparisons between human newborns and infants and the neonatal rat model. We present the effects of forced oral breathing on neonatal rats induced by experimental nasal obstruction. We assessed the multilevel consequences on physiological, structural, and behavioural variables, both during and after the obstruction episode. The effects of the compensatory mobilisation of oral resources for breathing are discussed in the light of the adaptive development of oromotor functions. PMID- 22811732 TI - Surgical management of patients with Chiari I malformation. AB - Chiari malformations (CMs) constitute a variety of four mainly syndromes (I, II, III, and IV), which describe the protrusion of brain tissue into the spinal canal through the foramen magnum. These malformations frequently occur in combination with other pathological entities such as myelomeningocele, hydrocephalus, and/or hydrosyringomyelia. The recent improvement of imaging techniques has increased not only the rate of CM diagnosis but also the necessity for its early treatment. Several different surgical techniques have been employed in the treatment of patients with symptomatic CM-I. In our current study, a systematic and critical review of the pertinent literature was made for identifying the most commonly employed surgical procedures in the management of these patients. Emphasis was given in outlining the advantages and disadvantages of each surgical approach. Moreover, an attempt was made for defining those parameters that may be prognostic factors for their surgical outcome. There is a consensus that surgical treatment is reserved only for symptomatic patients with CM-I. It has also been postulated that early surgically intervention is usually associated with better outcome. Despite the large number of previously published clinical series, further clinical research with large-scale studies is necessary for defining surgical treatment guidelines in these patients. PMID- 22811733 TI - Infant Feeding Practices and Nut Allergy over Time in Australian School Entrant Children. AB - Aim. To measure the association between infant feeding practices and parent reported nut allergy in school entrant children. Method. The Kindergarten Health Check Questionnaire was delivered to all 110 Australian Capital Territory (ACT) primary schools between 2006 and 2009. Retrospective analyses were undertaken of the data collected from the kindergarten population. Results. Of 15142 children a strong allergic reaction to peanuts and other nuts was reported in 487 (3.2%) and 307 (3.9%), children, respectively. There was a positive association between parent reported nut allergy and breast feeding (OR = 1.53; 1.11-2.11) and having a regular general practitioner (GP) (OR = 1.42; 1.05-1.92). A protective effect was found in children who were fed foods other than breast milk in the first six months (OR = 0.71; 0.60-0.84). Conclusion. Children were at an increased risk of developing a parent-reported nut allergy if they were breast fed in the first six months of life. PMID- 22811734 TI - Prenatal Mouth Movements: Can We Identify Co-Ordinated Fetal Mouth and LIP Actions Necessary for Feeding? AB - Observations of prenatal movement patterns of mouth and lips essential for feeding could have the potential for an assessment of the readiness to feed after birth. Although there is some research on sucking per se, we know very little about prenatal preparatory movements for sucking, namely, the ability to co ordinate opening the mouth widely and then pursing the lips as if around a teat or nipple in utero. The purpose of the present study was to test two hypotheses using an adapted version of the Facial Action Coding Scheme: first that mouth stretch (AU 27) will be followed by lip pucker (AU 18), and second that these coordinated movement patterns will increase as a function of gestational age. Fifteen healthy fetuses were scanned four times between 24 and 36 weeks gestation using 4D ultrasound visualization. Results showed a decreased number of mouth stretches with increasing fetal age. Contrary to our expectations, we did not find an increase in movement patterns of mouth stretch followed by lip pucker in preparation for feeding ex utero. The results are discussed in terms of sensory triggers in utero required to elicit preparatory movements for feeding ex utero. PMID- 22811735 TI - A meta-analysis of the therapeutic effects of glucagon-like Peptide-1 agonist in heart failure. AB - We conducted a meta-analysis of the existing literature of the therapeutic effects of using GLP-1 agonists to improve the metabolism of the failing heart. Animal studies showed significant improvement in markers of cardiac function, such as left ventricular ejection fraction (LVEF), with regular GLP-1 agonist infusions. In clinical trials, the potential effects of GLP-1 agonists in improving cardiac function were modest: LVEF improved by 4.4% compared to placebo (95% C.I 1.36-7.44, P = 0.005). However, BNP levels were not significantly altered by GLP-1 agonists in heart failure. In two trials, a modest increase in heart rate by up to 7 beats per minute was noted, but meta-analysis demonstrated this was not significant statistically. The small number of studies plus variation in the concentration and length of the regime between the trials would limit our conclusions, even though statistically, heterogeneity chi-squared tests did not reveal any significant heterogeneity in the endpoints tested. Moreover, studies in non-diabetics with heart failure yielded conflicting results. In conclusion, the use of GLP-1 agonists has at best a modest effect on ejection fraction improvement in heart failure, but there was no significant improvement in BNP levels in the meta-analysis. PMID- 22811736 TI - Play equipment, physical activity opportunities, and children's activity levels at childcare. AB - This study investigated the association between physical activity facilities at childcare (e.g., play equipment) and physical activity of 2- and 3-year olds. Observations of physical activity intensity were performed among 175 children at 9 childcare centers in The Netherlands, using the OSRAC-P. The physical activity facilities were assessed for indoors and outdoors separately, using the EPAO instrument. Regular (single-level) multivariate and multilevel linear regression analyses examined the association of the facilities and child characteristics (age and sex) with children's activity levels. Various physical activity facilities were available in all childcare centers (e.g., balls). Riding toys and a small playing area were associated with lower indoor physical activity levels. Outdoor physical activity levels were positively associated with the availability of portable jumping equipment and the presence of a structured track on the playground. Portable slides, fixed swinging equipment, and sandboxes were negatively associated with outdoor activity levels. In addition, the 3-year old children were more active outdoors than the 2-year olds. In conclusion, not all physical activity facilities at childcare were indeed positively associated with children's activity levels. The current findings provide concrete leads for childcare providers regarding which factors they can improve in the physical environment to facilitate children's physical activity. PMID- 22811738 TI - In situ expression of regulatory cytokines by heart inflammatory cells in Chagas' disease patients with heart failure. AB - Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi. The immune system plays an important role in the reduction of parasite load, but may also contribute to the development of lesions observed during the chronic phase of the disease. We analyzed cytokines produced by inflammatory heart cells in 21 autopsy samples obtained from patients with Chagas' disease divided according to the presence or absence of heart failure (HF). Left ventricular sections were analyzed by immunohistochemistry using antibodies against human IL-4, IFN-gamma, TGF-beta, TNF-alpha, and NOS2. In situ mRNA expression was quantified by a Low Density Array. The number of IFN-gamma-positive cells was significantly higher than IL-4 positive cells. TNF-alpha, TGF-beta and NOS2 were detected in 65%, 62% and 94% of samples respectively. There was an association between TNF-alpha producing cells and the presence of HF. Subjects with HF presented higher levels of STAT4 mRNA, whereas FoxP3 and STAT6 levels were similar in the two groups. A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas' disease patients associated with HF. High degree of fibrosis was associated with low NOS2 expression. These results support the idea that Th1 immune responses are involved in heart lesions of Chagas' disease patients. PMID- 22811737 TI - The tuberculous granuloma: an unsuccessful host defence mechanism providing a safety shelter for the bacteria? AB - One of the main features of the immune response to M. Tuberculosis is the formation of an organized structure called granuloma. It consists mainly in the recruitment at the infectious stage of macrophages, highly differentiated cells such as multinucleated giant cells, epithelioid cells and Foamy cells, all these cells being surrounded by a rim of lymphocytes. Although in the first instance the granuloma acts to constrain the infection, some bacilli can actually survive inside these structures for a long time in a dormant state. For some reasons, which are still unclear, the bacilli will reactivate in 10% of the latently infected individuals, escape the granuloma and spread throughout the body, thus giving rise to clinical disease, and are finally disseminated throughout the environment. In this review we examine the process leading to the formation of the granulomatous structures and the different cell types that have been shown to be part of this inflammatory reaction. We also discuss the different in vivo and in vitro models available to study this fascinating immune structure. PMID- 22811740 TI - Involvement of Stat1 in the phagocytosis of M. avium. AB - Mycobacterium avium is an intracellular pathogen preferentially infecting human macrophages where they activate the JAK/STAT1 pathway. This activation enhances the survival of infected cells, but, at the same time, makes macrophages optimal targets for drugs development against p-tyr(701)stat1. In this study, we demonstrate that the fast and transient activity of the JAK/STAT1 pathway occurs immediately after macrophages internalization of heat-killed M. avium or inert particles. Furthermore, we show that a persistent Stat1 pathway activation occurs only when an intracellular M. avium infection is established in macrophages. These results strongly indicate different mechanisms of p-tyr(701)Stat1 activation. In particular, here we report findings aiming at explaining the short time enhancement of p-tyr(701)Stat1 and shows its predominant relationship with FcgammaRs engagement during the internalization process. Furthermore, we demonstrate that opsonized live M. avium is phagocytosed by macrophages involving membrane receptors not related with JAK/STAT1 signalling pathway. On the contrary, heat-inactivated bacilli or latex particles seem to be internalized only after involvement of FcgammaRs and subsequent Stat1 phosphorylation. PMID- 22811739 TI - Epstein-Barr virus and systemic lupus erythematosus. AB - The etiology of SLE is not fully established. SLE is a disease with periods of waning disease activity and intermittent flares. This fits well in theory to a latent virus infection, which occasionally switches to lytic cycle, and EBV infection has for long been suspected to be involved. This paper reviews EBV immunobiology and how this is related to SLE pathogenesis by illustrating uncontrolled reactivation of EBV as a disease mechanism for SLE. Studies on EBV in SLE patients show enlarged viral load, abnormal expression of viral lytic genes, impaired EBV-specific T-cell response, and increased levels of EBV directed antibodies. These results suggest a role for reactivation of EBV infection in SLE. The increased level of EBV antibodies especially comprises an elevated titre of IgA antibodies, and the total number of EBV-reacting antibody isotypes is also enlarged. As EBV is known to be controlled by cell-mediated immunity, the reduced EBV-specific T-cell response in SLE patients may result in defective control of EBV causing frequent reactivation and expression of lytic cycle antigens. This gives rise to enhanced apoptosis and amplified cellular waste load resulting in activation of an immune response and development of EBV directed antibodies and autoantibodies to cellular antigens. PMID- 22811741 TI - Recent advances in dermatitis herpetiformis. AB - Dermatitis herpetiformis is an autoimmune bullous disease that is associated with gluten sensitivity which typically presents as celiac disease. As both conditions are multifactorial disorders, it is not clear how specific pathogenetic mechanisms may lead to the dysregulation of immune responses in the skin and small bowel, respectively. Recent studies have demonstrated that IgA and antibodies against epidermal transglutaminase 3 play an important role in the pathogenesis of dermatitis herpetiformis. Here, we review recent immunopathological progress in understanding the pathogenesis of dermatitis herpetiformis. PMID- 22811742 TI - Breast milk jaundice and maternal diet with chinese herbal medicines. AB - Our objective was to identify the association between maternal diet with Chinese herbal medicines and prolonged jaundice of breast-fed infants. Healthy infants at 25 to 45 days of age were eligible for enrollment into this prospective study. Jaundice was defined as a transcutaneous bilirubin (TcB) value >= 5 mg/dL. A questionnaire survey asking feeding type, stool pattern, and maternal diet was conducted at the time of TcB measurement. A total of 1148 infants were enrolled, including 151 formula-fed, 436 combination-fed, and 561 breast-fed infants. The incidences of jaundice were 4.0% in formula-fed infants, 15.1% in combination-fed infants, and 39.8% in breast-fed infants (P < 0.001). In addition, jaundice was noted in 37.1% of preterm infants and 25.0% of term infants (P < 0.001). Furthermore, jaundice was more common in breast-fed infants whose mothers did not consume the traditional Chinese herbal medicines than in breast-fed infants whose mothers did consume such medicines (P < 0.001). In conclusion, this cohort study has identified late-preterm birth and breast feeding as the contributory factors for prolonged jaundice of apparently well infants. The data indicate that postpartum diet with Chinese herbal medicines is associated with breast milk jaundice. PMID- 22811743 TI - "We're All in the Same Boat": A Review of the Benefits of Dragon Boat Racing for Women Living with Breast Cancer. AB - This narrative review summarizes findings from quantitative and qualitative research literature that has been published over the past 15 years since an initial, community-based pilot study first challenged the long-held medical belief that vigorous, upper-body exercise would lead to lymphedema in women who were at risk due to treatments for breast cancer. Dragon boat racing originated in China more than 2000 years ago and has become a popular recreational and competitive support around the world. From the advent of the world's first breast cancer survivor dragon boat team, Abreast in a Boat launched in Vancouver, British Columbia, in 1996, there are now more than 140 breast cancer survivor dragon boat teams paddling and competing in 12 different countries. The wealth of quantitative and qualitative research that has ensued since that pilot study further supports the initial hypothesis that resistance exercise, for example, dragon boat paddling, is not only safe for women recovering from conventional breast cancer therapies but also shows that dragon boating has been embraced as a complementary exercise therapy by the cancer survivors participating in this magical sport. PMID- 22811744 TI - Evaluation of the Chinese Medicinal Herb, Graptopetalum paraguayense, as a Therapeutic Treatment for Liver Damage in Rat Models. AB - The incidence of cirrhosis is rising due to the widespread occurrence of chronic hepatitis, as well as the evident lack of an established therapy for hepatic fibrosis. In the search for hepatoprotective therapeutic agents, Graptopetalum paraguayense (GP) showed greater cytotoxicity toward hepatic stellate cells than other tested herbal medicines. Histopathological and biochemical analyses suggest that GP treatment significantly prevented DMN-induced hepatic inflammation and fibrosis in rats. Microarray profiling indicated that expression of most of metabolism- and cell growth and/or maintenance-related genes recovered to near normal levels following GP treatment as classified by gene ontology and LSM analysis, was observed. ANOVA showed that expression of 64% of 256 liver damage related genes recovered significantly after GP treatment. By examining rat liver samples with Q-RT-PCR, five liver damage-related genes were identified. Among them, Egr1 and Nrg1 may serve as necroinflammatory markers, and Btg2 may serve as a fibrosis marker. Oldr1 and Hmgcs1 were up- and down-regulated markers, respectively. A publicly accessible website has been established to provide access to these data Identification of 44 necroinflammation-related and 62 fibrosis-related genes provides useful insight into the molecular mechanisms underlying liver damage and provides potential targets for the rational development of therapeutic drugs such as GP. PMID- 22811745 TI - Auricular point acupressure for chronic low back pain: a feasibility study for 1 week treatment. AB - Objectives. The objective of this one-group, repeated-measures design was to explore the acceptance of auricular point acupressure (APA) to reduce chronic low back pain (CLBP) and estimate minimum clinically important differences (MCIDs) for pain intensity change. Methods. Subjects received 7-day APA treatment. After appropriate acupoints were identified, vaccaria seeds were carefully taped onto each selected auricular point for 7-day. The Brief Pain Inventory Short Form (BPI) was used to collect outcome data. Results. A total of 74 subjects participated in the study. Ten subjects dropped out and the retention rate was 87%. Subjects reported a 46% reduction in BPI worst pain, and over 50% reduction in BPI average pain, overall pain severity and pain interference by the end of study, and 62.5% subjects also reported less pain medication use. The MCIDs for the subscale of BPI ranged from .70 to 1.86 points. The percentage improvement of MCIDs from baseline was between 14.5-24.9%. Discussion. APA appears to be highly acceptable to patients with CLBP. A sham group is needed in order to differentiate the true effects of APA from the possible psychological effects of more frequent visits by the auricular therapist and patients' expectation of the APA treatment. PMID- 22811747 TI - The role of acupuncture in assisted reproductive technology. AB - The aim of this paper was to provide reliable evidence by performing a systematic review and meta-analysis for evaluating the role of acupuncture in assisted reproductive technology. All randomized controlled trials that evaluated the effects of acupuncture, including manual, electrical, and laser acupuncture (LA) techniques, on the clinical pregnancy rate (CPR) and live birth rate (LBR) of in vitro fertilization (IVF) or artificial insemination were included. The controlled groups consisted of no acupuncture and sham acupuncture groups. The sham acupuncture included sham acupuncture at acupoints, sham acupuncture at non- or inappropriate points, sham LA, and adhesive tapes. Twenty-three trials (a total of 5598 participants) were included in this paper. The pooled CPR from all acupuncture groups was significantly higher than that from all controlled groups, whereas the LBR was not significantly different between the two groups. However, the results were quite distinct when the type of control and/or different acupuncture times were examined in a sensitivity analysis. The results mainly indicate that acupuncture, especially around the time of the controlled ovarian hyperstimulation, improves pregnancy outcomes in women undergoing IVF. More positive effects from acupuncture in IVF can be expected if a more individualized acupuncture programs are used. PMID- 22811746 TI - Herbal Extracts Combination (WNK) Prevents Decline in Spatial Learning and Memory in APP/PS1 Mice through Improvement of Hippocampal Abeta Plaque Formation, Histopathology, and Ultrastructure. AB - To investigate the cognitive enhancement effect of WNK, an extracts combination of P. ginseng, G. biloba, and C. sativus L. and possible mechanisms, 5-month-old APP/PS1 transgenic mice were used in this study. After 3 months of administration, all mice received Morris water maze (MWM) training and a probe test. Mouse brain sections were detected by immunohistochemistry, HE staining, and transmission electron microscopy. MWM results showed significant difference between transgenic mice and nontransgenic littermates (P < 0.05, P < 0.01). WNK treated mice exhibited enhanced maze performance over the training progression, especially better spatial memory retention in probe test compared to transgenic mice (P < 0.05, P < 0.01) and better spatial learning and memory at the fourth day of MWM test compared to EGB761- (G. biloba extract-) treated ones (P < 0.05). Hippocampal Abeta plaque burden significantly differed between APP/PS1 and littermate mice (P < 0.001), while decreased Abeta plaque appeared in WNK- or EGB761-treated transgenic brains (P < 0.05). Neurodegenerative changes were evident from light microscopic and ultrastructural observations in transgenic brains, which were improved by WNK or EGB761 treatment. These data indicate WNK can reduce the decline in spatial cognition, which might be due to its effects on reducing Abeta plaque formation and ameliorating histopathology and ultrastructure in hippocampus of APP/PS1 mouse brain. PMID- 22811748 TI - Uncaria tomentosa-Adjuvant Treatment for Breast Cancer: Clinical Trial. AB - Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma-Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer. PMID- 22811749 TI - Gallic Acid Attenuates Platelet Activation and Platelet-Leukocyte Aggregation: Involving Pathways of Akt and GSK3beta. AB - Platelet activation and its interaction with leukocytes play an important role in atherothrombosis. Cardiovascular diseases resulted from atherothrombosis remain the major causes of death worldwide. Gallic acid, a major constituent of red wine and tea, has been believed to have properties of cardiovascular protection, which is likely to be related to its antioxidant effects. Nonetheless, there were few and inconsistent data regarding the effects of gallic acid on platelet function. Therefore, we designed this in vitro study to determine whether gallic acid could inhibit platelet activation and the possible mechanisms. From our results, gallic acid could concentration-dependently inhibit platelet aggregation, P-selectin expression, and platelet-leukocyte aggregation. Gallic acid prevented the elevation of intracellular calcium and attenuated phosphorylation of PKCalpha/p38 MAPK and Akt/GSK3beta on platelets stimulated by the stimulants ADP or U46619. This is the first mechanistic explanation for the inhibitory effects on platelets from gallic acid. PMID- 22811750 TI - Inchingorei-san (TJ-117) and Artemisiae Capillaris Herba Induced Prolonged Survival of Fully Mismatched Cardiac Allografts and Generated Regulatory Cells in Mice. AB - We investigated Inchingorei-san (TJ-117), a 6-component Japanese herbal medicine, on alloimmune responses in murine cardiac allograft transplantation. CBA mice underwent transplantation of a C57BL/6 (B6) heart and received oral administration of TJ-117 or each component of TJ-117 from the day of transplantation until 7 days afterward. Naive CBA mice rejected B6 cardiac grafts acutely (median survival time (MST), 7 days). CBA recipients given 1 g/kg/day of TJ-117 had prolonged B6 allograft survival (MST, 37 days). Moreover, given 1 g/kg/day of Artemisiae Capillaris Herba (ACH), one component of TJ-117, indefinitely prolonged B6 allograft survival (MST, >100 days). However, other five components of TJ-117 were less effective than TJ-117 and ACH. Secondary CBA recipients given whole splenocytes, CD4(+), and CD4(+)CD25(+) cells from primary ACH-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MSTs, 57, >100, and >100 days, resp.). Flow cytometry studies showed that the CD4(+)CD25(+)Foxp3(+) regulatory cell population was increased in transplant recipients given ACH. Cell proliferation, interleukin-2, and interferon-gamma were suppressed in ACH-treated mice, whereas interleukin-4 and interleukin-10 were upregulated. In conclusion, ACH, one component of TJ-117, as well as TJ-117 induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4(+)CD25(+)Foxp3(+) regulatory cells. PMID- 22811751 TI - Antiatherosclerotic Effect of Canarium odontophyllum Miq. Fruit Parts in Rabbits Fed High Cholesterol Diet. AB - The effect of C. odontophyllum (CO) fruit parts was investigated in hypercholesterolemic rabbits. Forty-nine rabbits, which were randomly divided into seven groups of seven animals (n = 7), received a diet containing different parts of CO fruit parts for 8 weeks. The groups were as follows: (1) normal diet: NC group and (2) hypercholesterolemic diet: PC, HS (10 mg/kg/day simvastatin), HPO (20 g kg(-1) oil extracted from the pulp of CO), HKO (20 g kg(-1) oil extracted from the kernel of CO), HF (50 g kg(-1) fullfat pulp of CO), and HD (50 g kg(-1) defatted pulp of CO). Among these groups, rabbits receiving defatted pulp of CO showed the greatest cholesterol lowering effect as it had reduced plasma LDL-C, TC, and thiobarbiturate reactive substance (TBARS) levels as well as atherosclerotic plaques. The presence of high dietary fiber and antioxidants activity are potential factors contributing to the cholesterol lowering effect. Consequently, these results indicate the potential use of CO defatted pulp as a cholesterol lowering and antioxidant agent. PMID- 22811752 TI - Shengjie Tongyu Granule Inhibits Vascular Remodeling in ApoE-Gene-Knockout Mice. AB - The aim of the present paper was to investigate the effect of Shengjie Tongyu granule on vascular remodeling in atherosclerotic mice and the relevant underlying mechanism. Sixty male ApoE-gene-knockout mice, fed a high-fat diet from 6 weeks of age, were randomized into a Shengjie Tongyu granule group (4.00 g/kg/d), a simvastatin group (9.01 mg/kg/d), and a control group (normal saline: 0.2 mL/d). At the ages of 30 and 40 weeks, we sacrificed the mice for various measurements. The results show that treatment with Shengjie Tongyu granule and simvastatin significantly decreased lumen and plaque areas in the aortic root at 30 and 40 weeks of age, decreased grade II elastic fiber lesions in the ascending aorta at 30 weeks of age, and decreased both grade II and III lesions at 40 weeks of age, compared to controls. The content of superoxide anions, and expression of MOMA-2, plasma ICAM-1, and NFkappaB p50 in 30- and 40-week-old mice in the Shengjie Tongyu granule and simvastatin groups were also significantly reduced compared to the control group. In conclusion, Shengjie Tongyu granule has a clear inhibitory effect on vascular remodeling and on inflammatory pathways in ApoE gene-knockout mice. PMID- 22811753 TI - Fundamental dynamical modes underlying human brain synchronization. AB - Little is known about the long-term dynamics of widely interacting cortical and subcortical networks during the wake-sleep cycle. Using large-scale intracranial recordings of epileptic patients during seizure-free periods, we investigated local- and long-range synchronization between multiple brain regions over several days. For such high-dimensional data, summary information is required for understanding and modelling the underlying dynamics. Here, we suggest that a compact yet useful representation is given by a state space based on the first principal components. Using this representation, we report, with a remarkable similarity across the patients with different locations of electrode placement, that the seemingly complex patterns of brain synchrony during the wake-sleep cycle can be represented by a small number of characteristic dynamic modes. In this space, transitions between behavioral states occur through specific trajectories from one mode to another. These findings suggest that, at a coarse level of temporal resolution, the different brain states are correlated with several dominant synchrony patterns which are successively activated across wake sleep states. PMID- 22811754 TI - Valuing the IJTMB Manuscript Review Board. PMID- 22811755 TI - Integrating massage, chiropractic, and acupuncture in university clinics: a guided student observation. AB - BACKGROUND: Several studies have reported on the health benefits of applying an integrated complementary health care model. PURPOSE: This paper presents the results of pilot research focusing on the observations massage therapy students made about complementary health care education and integration during massage, chiropractic, and acupuncture treatments at two university clinics. SETTING: Observations took place at Northwestern Health Sciences University's associated clinics that offered massage, chiropractic, and acupuncture. RESEARCH DESIGN: Students directly observed how clinicians and interns educated their patients and integrated other forms of complementary health care into their practice. PARTICIPANTS: chiropractors, massage therapists, and acupuncturists, and their patients. All participants were English-speaking and 18-65 years old. MAIN OUTCOME MEASURES: Observations recorded by students in journals about education and integration during massage therapy, chiropractic, and acupuncture treatments were coded and counted. RESULTS: Qualitative observations showed that clinicians and interns educated patients to some degree, but the clinicians were less apt to integrate other modalities than the interns. CONCLUSIONS: Observations support that professional integrity may limit clinicians in their ability to integrate multiple modalities of health care while treating patients. Since it is well established that integration of multiple health care modalities is beneficial to patient health, it is recommended that clinics assist their clinical staff in applying an integrative approach to their practice. PMID- 22811756 TI - What is the Academic Consortium for Complementary and Alternative Health Care (ACCAHC)? PMID- 22811757 TI - Therapeutic Massage Provides Pain Relief to a Client with Morton's Neuroma: A Case Report. AB - BACKGROUND: Morton's neuroma is a common cause of pain that radiates from between the third and fourth metatarsals and which, when symptomatic, creates sensations of burning or sharp pain and numbness on the forefoot. Many conservative and surgical interventions are employed to reduce associated pain, but not enough research has been conducted to recommend patients to any one approach as the most reliable source of pain management. PURPOSE: The objective of this case report is to describe the effect of massage therapy on one woman with symptomatic Morton's neuroma. PARTICIPANT: A physically active 25-year-old female with diagnosed symptomatic Morton's neuroma who has not found relief with previous conservative intervention. INTERVENTION: Six session of massage therapy once weekly for 60-75 minutes focused on postural alignment and localized foot and leg treatment. The client also completed an at-home exercise each day. Change was monitored each week by the massage therapist reassessing posture and by the client filling out a pain survey based on a Visual Analog Scale. RESULTS: The client reported progressive change in the character of the pain from burning and stabbing before the first session to a dull, pulsing sensation after the third session. She also recorded a reduction in pain during exercise from a 5/10 to 0/10 (on a scale where 10 is extreme pain). CONCLUSION: This study describes how massage therapy reduced pain from Morton's neuroma for one client; however, larger randomized control studies need to be done in order to determine the short- and long-term effects of massage therapy on this painful condition. PMID- 22811758 TI - Calcium binding promotes prion protein fragment 90-231 conformational change toward a membrane destabilizing and cytotoxic structure. AB - The pathological form of prion protein (PrP(Sc)), as other amyloidogenic proteins, causes a marked increase of membrane permeability. PrP(Sc) extracted from infected Syrian hamster brains induces a considerable change in membrane ionic conductance, although the contribution of this interaction to the molecular mechanism of neurodegeneration process is still controversial. We previously showed that the human PrP fragment 90-231 (hPrP90-231) increases ionic conductance across artificial lipid bilayer, in a calcium-dependent manner, producing an alteration similar to that observed for PrP(Sc). In the present study we demonstrate that hPrP90-231, pre-incubated with 10 mM Ca++ and then re suspended in physiological external solution increases not only membrane conductance but neurotoxicity as well. Furthermore we show the existence of a direct link between these two effects as demonstrated by a highly statistically significant correlation in several experimental conditions. A similar correlation between increased membrane conductance and cell degeneration has been observed assaying hPrP90-231 bearing pathogenic mutations (D202N and E200K). We also report that Ca++ binding to hPrP90-231 induces a conformational change based on an alteration of secondary structure characterized by loss of alpha-helix content causing hydrophobic amino acid exposure and proteinase K resistance. These features, either acquired after controlled thermal denaturation or induced by D202N and E200K mutations were previously identified as responsible for hPrP90 231 cytotoxicity. Finally, by in silico structural analysis, we propose that Ca++ binding to hPrP90-231 modifies amino acid orientation, in the same way induced by E200K mutation, thus suggesting a pathway for the structural alterations responsible of PrP neurotoxicity. PMID- 22811759 TI - Limitations of the human reference genome for personalized genomics. AB - Data from the 1000 genomes project (1KGP) and Complete Genomics (CG) have dramatically increased the numbers of known genetic variants and challenge several assumptions about the reference genome and its uses in both clinical and research settings. Specifically, 34% of published array-based GWAS studies for a variety of diseases utilize probes that overlap unanticipated single nucleotide polymorphisms (SNPs), indels, or structural variants. Linkage disequilibrium (LD) block length depends on the numbers of markers used, and the mean LD block size decreases from 16 kb to 7 kb,when HapMap-based calculations are compared to blocks computed from1KGP data. Additionally, when 1KGP and CG variants are compared, 19% of the single nucleotide variants (SNVs) reported from common genomes are unique to one dataset; likely a result of differences in data collection methodology, alignment of reads to the reference genome, and variant calling algorithms. Together these observations indicate that current research resources and informatics methods do not adequately account for the high level of variation that already exists in the human population and significant efforts are needed to create resources that can accurately assess personal genomics for health, disease, and predict treatment outcomes. PMID- 22811760 TI - An automated flow for directed evolution based on detection of promiscuous scaffolds using spatial and electrostatic properties of catalytic residues. AB - The aspiration to mimic and accelerate natural evolution has fueled interest in directed evolution experiments, which endow or enhance functionality in enzymes. Barring a few de novo approaches, most methods take a template protein having the desired activity, known active site residues and structure, and proceed to select a target protein which has a pre-existing scaffold congruent to the template motif. Previously, we have established a computational method (CLASP) based on spatial and electrostatic properties to detect active sites, and a method to quantify promiscuity in proteins. We exploit the prospect of promiscuous active sites to serve as the starting point for directed evolution and present a method to select a target protein which possesses a significant partial match with the template scaffold (DECAAF). A library of partial motifs, constructed from the active site residues of the template protein, is used to rank a set of target proteins based on maximal significant matches with the partial motifs, and cull out the best candidate from the reduced set as the target protein. Considering the scenario where this 'incubator' protein lacks activity, we identify mutations in the target protein that will mirror the template motif by superimposing the target and template protein based on the partial match. Using this superimposition technique, we analyzed the less than expected gain of activity achieved by an attempt to induce beta-lactamase activity in a penicillin binding protein (PBP) (PBP-A from T. elongatus), and attributed this to steric hindrance from neighboring residues. We also propose mutations in PBP-5 from E. coli, which does not have similar steric constraints. The flow details have been worked out in an example which aims to select a substitute protein for human neutrophil elastase, preferably related to grapevines, in a chimeric anti-microbial enzyme which bolsters the innate immune defense system of grapevines. PMID- 22811761 TI - Molecular characterization of circulating tumor cells in human metastatic colorectal cancer. AB - Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream and, concordantly, the presence of these Circulating Tumor Cells (CTC) is associated with a poor prognosis. In this work, the molecular characterization of CTC from mCRC patients was approached, with the aim of understanding their biology and improving their clinical utility in the management of colorectal cancer patients. For this, EpCAM based immunoisolation of CTC was combined with whole transcriptome amplification and hybridization onto cDNA microarrays. Gene expression data from mCRC patients, once the background of unspecific immunoisolation from a group of controls had been subtracted, resulted in 410 genes that characterized the CTC population. Bioinformatics were used for the biological interpretation of the data, revealing that CTC are characterized by genes related to cell movement and adhesion, cell death and proliferation, and cell signalling and interaction. RTqPCR on an independent series of mCRC patients and controls was used for the validation of a number of genes related to the main cellular functions characterizing the CTC population. Comparison between primary carcinomas and lung and liver metastases further involved the CTC-genes in the promotion of metastasis. Moreover, the correlation of CTC-gene expression with clinical parameters demonstrated detection and prognosis significance. In conclusion, the molecular characterization of CTC from mCRC patients and the identification of diagnostic and prognostic biomarkers represent an innovative and promising approach in the clinical management of this type of patients. PMID- 22811762 TI - Morphological alterations in newly born dentate gyrus granule cells that emerge after status epilepticus contribute to make them less excitable. AB - Computer simulations of external current stimulations of dentate gyrus granule cells of rats with Status Epilepticus induced by pilocarpine and control rats were used to evaluate whether morphological differences alone between these cells have an impact on their electrophysiological behavior. The cell models were constructed using morphological information from tridimensional reconstructions with Neurolucida software. To evaluate the effect of morphology differences alone, ion channel conductances, densities and distributions over the dendritic trees of dentate gyrus granule cells were the same for all models. External simulated currents were injected in randomly chosen dendrites belonging to one of three different areas of dentate gyrus granule cell molecular layer: inner molecular layer, medial molecular layer and outer molecular layer. Somatic membrane potentials were recorded to determine firing frequencies and inter-spike intervals. The results show that morphologically altered granule cells from pilocarpine-induced epileptic rats are less excitable than control cells, especially when they are stimulated in the inner molecular layer, which is the target area for mossy fibers that sprout after pilocarpine-induced cell degeneration. This suggests that morphological alterations may act as a protective mechanism to allow dentate gyrus granule cells to cope with the increase of stimulation caused by mossy fiber sprouting. PMID- 22811763 TI - What can crossmodal aftereffects reveal about neural representation and dynamics? AB - The brain continuously adapts to incoming sensory stimuli, which can lead to perceptual illusions in the form of aftereffects. Recently we demonstrated that motion aftereffects transfer between vision and touch.(1) Here, the adapted brain state induced by one modality has consequences for processes in another modality, implying that somewhere in the processing stream, visual and tactile motion have shared underlying neural representations. We propose the adaptive processing hypothesis-any area that processes a stimulus adapts to the features of the stimulus it represents, and this adaptation has consequences for perception. This view argues that there is no single locus of an aftereffect. Rather, aftereffects emerge when the test stimulus used to probe the effect of adaptation requires processing of a given type. The illusion will reflect the properties of the brain area(s) that support that specific level of representation. We further suggest that many cortical areas are more process-dependent than modality-dependent, with crossmodal interactions reflecting shared processing demands in even 'early' sensory cortices. PMID- 22811765 TI - Health Vision 2050 Oman: A Committed Step towards Reforms. PMID- 22811764 TI - Therapeutic approach to neurodegenerative diseases by medical gases: focusing on redox signaling and related antioxidant enzymes. AB - Oxidative stress in the central nervous system is strongly associated with neuronal cell death in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In order to overcome the oxidative damage, there are some protective signaling pathways related to transcriptional upregulation of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD)-1/-2. Their expression is regulated by several transcription factors and/or cofactors like nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha). These antioxidant enzymes are associated with, and in some cases, prevent neuronal death in animal models of neurodegenerative diseases. They are activated by endogenous mediators and phytochemicals, and also by several gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and hydrogen (H(2)). These might thereby protect the brain from severe oxidative damage and resultant neurodegenerative diseases. In this paper, we discuss how the expression levels of these antioxidant enzymes are regulated. We also introduce recent advances in the therapeutic uses of medical gases against neurodegenerative diseases. PMID- 22811766 TI - Fibromyalgia syndrome: an overview of pathophysiology, diagnosis and management. AB - Fibromyalgia Syndrome (FMS) is a chronic condition causing pain, stiffness, and tenderness of the muscles, tendons, and joints. It is also characterized by restless sleep, tiredness, fatigue, anxiety, depression, and disturbances in bowel functions. The etiology of fibromyalgia remains unknown, but recent advances and discoveries have helped to unravel some of the mysteries of this disease. Research highlights some of the biochemical, metabolic, and immunoregulatory abnormalities associated with fibromyalgia. Management of FMS at the present time is very difficult as it has multiple etiological factors and psychological predispositions; however, a patient centered approach is essential to handle this problem. PMID- 22811767 TI - Immunophenotyping of HPV Types 16 and 18 among Sudanese Patients with Oral Lesions. AB - OBJECTIVE: The aim of this study was to screen patients with oral lesions for the presence of Human Papilloma Virus (HPV) types 16 and 18. METHODS: Sixty patients aged between 11-80 years with a mean age of 46 years were examined using immunohistological techniques. All samples were retrieved from RICK during the period from August 2009 to August 2010. Out of 60 patients, 50 had Oral Squamous Cell Carcinomas (OSCCs) and the remaining ten had benign oral lesions, included as internal control. RESULTS: Of the 50 patients with OSCCs, 10 (20%) showed positive immunohistochemical results for HPV types 16 and 18 of which 50% were detected among males and 50% were demonstrated among females. The ten positive findings were Immunophenotyped as follows: five were positive with HPV type 16, four with type 18 and one was positive for HPV types 16 and18. All patients with benign oral lesions were negative for HPV immunohistochemistry. CONCLUSION: The study suggests the role of HPV 16 and 18 in the etiology of oral cancers in different parts of Sudan. However, the use of molecular techniques such as PCR are needed to confirm the results of immunohistochemistry in the role of the HPV in developing of OSCC in Sudan. PMID- 22811768 TI - Clinical Features and Outcome of 65 Laboratory Confirmed Cases of H1N1 in Muscat, Sultanate of Oman. AB - OBJECTIVES: Responding to Pandemic Influenza A (H1N1) virus alert in 2009, Ministry of Health (MoH), Sultanate Of Oman arranged task force to deal with the emergency. MOH published articles in newspapers, prepared guidelines and hospitals were assigned to admit patients of H1N1. All the patients suspected of H1N1 were admitted and isolated as per the guidelines. This report describes clinical features and outcomes of 65 laboratory confirmed cases of H1N1 in Muscat, Sultanate of Oman. METHODS: From July to October 2009, 101 cases suspected of suffering from Pandemic Influenza A (H1N1) virus were admitted and isolated in Al Nahdha Hospital in Muscat. All the patients on admission were tested for H1N1, by real time reverse transcriptase polymerase chain reaction (RT PCR). Immediately on admission, all of them were treated with Oseltamivir and antibiotics. RESULTS: Of the 65 confirmed cases of H1N1, 53.84% were males. Age of patients varied from 14 to 60 years, while 53.7% were aged between 31 to 55 years. Results showed that 70.8% had underlying co-morbidity; among which diabetes mellitus and respiratory illness were common. The most common presenting symptoms were fever (95%) and cough (94%). Also, 20% of the patients had leucopenia and 10.8% leucocytosis. Deranged LFT was observed in 26 (42.6%) of cases while 14 (21.5%) had hypokalemia. One patient (0.01%) with underlying severe co-morbidity died. Two patients (3.1%) had ARDS (Acute Respiratory Distress Syndrome); both recovered. Radiological infiltration was documented in 84.6% of cases, with lower zone involvement as the common finding. Hospital stay was between 1 to 12 days, 49.2% of patients were discharged within 3 days. CONCLUSION: Mainly adult population was affected during this epidemic. H1N1 infection can lead to severe illness. Incidence of H1N1 was higher in patients with underlying co-morbidity. Timely intervention and administration of Oseltamivir may need to be modified. PMID- 22811769 TI - Predictive value of a 4-hour accelerated diagnostic protocol in patients with suspected ischemic chest pain presenting to an emergency department. AB - OBJECTIVES: Currently recommended risk stratification protocols for suspected ischemic chest pain in the emergency department (ED) includes point-of-care availability of exercise treadmill/nuclear tests or CT coronary angiograms. These tests are not widely available for most of the ED's. This study aims to prospectively validate the safety of a predefined 4-hour accelerated diagnostic protocol (ADP) using chest pain, ECG, and troponin T among suspected ischemic chest pain patients presenting to an ED of a tertiary care hospital in Oman. METHODS: One hundred and thirty-two patients aged over 18 years with suspected ischemic chest pain presenting within 12 hours of onset along with normal or non diagnostic first ECG and negative first troponin T (<0.010 MUg/l) were recruited from September 2008 to February 2009. Low-probability acute coronary syndrome (ACS) patients at 4-hours defined as absent chest pain and negative ECG or troponin tests were discharged home and observed for 30-days for major adverse cardiac events (MACE) (Group I: negative ADP). High-probability ACS patients at 4 hours were defined by recurrent or persistent chest pain, positive ECG or troponin tests and were admitted and observed for in-hospital MACE (Group II: positive ADP). RESULTS: One hundred and thirty-two patients were recruited and 110 patients completed the study. The overall 30-day MACE in this cohort was 15% with a mortality of less than 1%. 30-days MACE occurred in 8/95 of group I patients (8.4%) and 9/15 of the in-hospital MACE patients in group II. The ADP had a sensitivity of 52% (95% CI: 0.28-0.76), specificity of 93% (0.85-0.97), a negative predictive value of 91% (0.83-0.96), a positive predictive value of 60% (0.32-0.82), negative likelihood ratio of 0.5 (0.30-0.83) and a positive likelihood ratio of 8.2 (3.3-20) in predicting MACE. CONCLUSION: A 4-hour ADP using chest pain, ECG, and troponin T had high specificity and negative predictive value in predicting 30-day MACE among low probability ACS patients discharged from ED. However, 30-day MACE in ADP negative patients was relatively high in contrast to guideline recommendations. Hence, there is a need to establish ED chest pain unit and adopt new protocols especially adding a point-of care exercise treadmill test in the ED. PMID- 22811770 TI - Prevalence and risk factors of diabetic nephropathy in omani type 2 diabetics in Al-dakhiliyah region. AB - OBJECTIVE: To assess the prevalence and risk factors of diabetic nephropathy among Omani type 2 diabetics in Al-Dakhiliyah region of the Sultanate of Oman. METHODS: A cross-sectional and a case control study designs were used to assess the prevalence and risk factors respectively. For the prevalence study a sample of 699 diabetic subjects were selected randomly from two polyclinics in Al Dakhiliyah region; Sumail and Nizwa polyclinics. For the case control study, a sample consisting of 215 cases and 358 controls were randomly selected from those who were included in the cross-sectional study. A well designed questionnaire has been used to collect data regarding the disease and risk factors. Data was analyzed using SPSS19 statistical program. RESULTS: Total prevalence of diabetic nephropathy was calculated as 42.5% (95% C.I: 38.83% - 46.15%). The difference in the prevalence in the two polyclinic catchment area was not significant. The prevalence was significantly higher among males (51.6%) compared to females (36.5%). Crude analysis of the risk factors showed significant association between diabetic nephropathy and the following factors; male gender, decreased literacy, long duration of diabetes mellitus, hypertension, retinopathy, neuropathy, family history of diabetic nephropathy, poor glycemic control (high HbA1c), and hypertriglyceridemia. Multivariate analysis showed the following factors to be independent risk factors; male gender, decreased literacy, long duration of diabetes, family history of diabetic nephropathy and poor glycaemic control (high HbA1c). CONCLUSION: The prevalence of diabetic nephropathy in this study was 42.5% and the significant risk factors associated with it included male gender, decreased literacy, long duration of diabetes, family history of diabetic nephropathy and poor glycemic control (high HbA1c). PMID- 22811771 TI - Assessment of educational environment of surgical theatre at a teaching hospital of a saudi university: using surgical theatre educational environment measures. AB - OBJECTIVES: This study was aimed to determine how medical interns perceive the important factors of the learning environment the surgical theatre at the teaching hospital of the medical school, University of Dammam (UoD). The study also investigated the relationships between the learning environment and academic achievements. Finally, it determined the role and significance of gender on the above perceptions and relationships. METHODS: The Surgical Theatre Educational Environment Measure (STEEM) was used to identify the perceptions of interns on the most important factors prevalent in the surgical theatre as an educational environment. STEEM was administered to all interns during the period of June September 2009. Ninety-one out of 145 students completed the questionnaire representing a response rate of 63%. Non-parametric statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) Version 17. RESULTS: The STEEM was shown to be internally consistent for the assessment of the overall educational environment in the surgical theatre of UoD. The overall STEEM mean score was 110. For male and female students, the mean scores were 114 and 107 respectively. There were statistically significant gender differences in the perceptions of "learning opportunities" and "teaching and training". Females rated these subscales lower than males. There were no significant associations between academic achievements and perceptions of the educational environment. CONCLUSION: The interns perceived the learning environment of the surgical theatre as less than satisfactory. In comparison with the males; the perception of the females was less positive, particularly in the areas of learning opportunities, and teaching and training. The study also revealed some other problematic areas in the learning environment of surgical theatre of the teaching hospital of UoD. The results imply that there is much room for improvement. They also indicate that equal opportunities for learning and training should be given to both sexes. PMID- 22811772 TI - Hyperhomocysteinemia in HIV-Infected Individuals: Correlation of a Frequent Prothrombotic Factor with CD4+ Cell Count. AB - OBJECTIVE: This study was aimed at providing an analysis of the correlation between CD4/CD8 counts and some coagulation factors in HIV-Positive Iranian patients. METHODS: A case-control study on 58 HIV-infected patients and control group (58 healthy individuals). Patients and controls were matched for sex and age. In this study, several blood parameters were measured in 58 HIV-infected patients and the controls. Laboratory data were then measured including hemoglobin, platelets, homocysteine, serum levels of IgM and IgG antiphospholipid antibodies (aPL), IgM and IgG anticardiolipin antibotdies (aCL), and CD4(+) and CD8(+) cell count. RESULTS: The HIV-infected patients, compared to healthy controls, showed a significant decline in platelets, CD4 count and CD8 count (p<0.0001), and an increase of homocysteine (p<0.0001) and IgG aPL levels (p<0.0001). No statistical difference was found between patients with CD4 count <=200 and CD4 count >200 in the evaluated variables. CONCLUSION: The results showed that thrombophilic abnormality in the form of hyperhomocysteinemia is more frequent in HIV-infected patients and should be considered by clinicians in view of an early diagnosis of the hypercoagulability state to prevent thrombotic complications. PMID- 22811773 TI - Screening for cryptococcal antigenemia in anti-retroviral naive AIDS patients in benin city, Nigeria. AB - OBJECTIVES: Cryptococcus neoformans is the most incriminated fungal pathogen causing meningitis in acquired immune deficiency syndrome (AIDS) patients, and is known to constitute a major cause of deaths in AIDS patients. This study thus aimed to determine the baseline sero-prevalence of Cryptococcus neoformans infection in anti-retroviral naive (ART-naive) AIDS patients using the serum Cryptococcal antigen (crag) detection method. Baseline effect of variation in CD4 counts, as well as sex and age with sero-positivity for crag were also determined. METHODS: This descriptive cross-sectional study included 150 (61 males and 89 females) ART-naive AIDS patients attending the Human Immunodeficiency Virus clinic (HIV) at the University of Benin Teaching hospital, Benin City, Nigeria, within the period from February 2011- July 2011. Forty (18 males and 22 females) HIV positive outpatients with CD4 counts >200 cells/ul who were ART-naive were recruited and used as controls. The sero-prevalence of crag in the patients and the control group was measured using the cryptococcal antigen latex agglutination system (CALAS) (Meridian Bioscience, Europe) and CD4 counts were measured using flow cytometry (Partec flow cytometer, Germany). RESULTS: Of the 150 ART-naive AIDS patients with CD4 counts <=200 cells/uL; 19 (12.7%) were positive for serum Cryptococcal antigen. ART-naive AIDS patients with CD4 count <=50 cells/ul had the highest prevalence of serum crag. Lower CD4 counts were significantly associated with positivity for serum crag (p<0.001). Age and sex had no significant effect on the sero-positivity for serum crag. One (2.5%) of the controls was sero-positive for crag. Thus, serum crag was significantly associated with AIDS but not with HIV (p<0.001). CONCLUSION: This study uncovers a high prevalence of crag in ART- naive AIDS patients in Benin City. The prevalence of crag was higher in ART-naive AIDS patients with lower CD4 counts. There is an urgent need to introduce routine screening for crag in ART- naive AIDS patients in our locality to reduce the rapid mortality from Cryptococcal meningitis which accounts for a majority of the morbidity factor if undiagnosed during ART therapy. PMID- 22811774 TI - Prevalence of Malaria and Anemia among Pregnant Women Attending a Traditional Birth Home in Benin City, Nigeria. AB - OBJECTIVES: To determine the prevalence of malaria and anemia among pregnant women attending a traditional birth center as well as the effect of herbal remedies, gravidity, age, educational background and malaria prevention methods on their prevalence. METHODS: Blood specimens were collected from 119 pregnant women attending a Traditional Birth Home in Benin City, Nigeria. Malaria parasitemia was diagnosed by microscopy while anemia was defined as hemoglobin concentration <11 g/dL. RESULTS: The prevalence of malaria infection was (OR=4.35 95% CI=1.213, 15.600; p=0.016) higher among primigravidae (92.1%). Pregnant women (38.5%) with tertiary level of education had significantly lower prevalence of malaria infection (p=0.002). Malaria significantly affected the prevalence of anemia (p<0.05). Anemia was associated with consumption of herbal remedies (OR=2.973; 95% CI=1.206, 7.330; p=0.017). The prevalence of malaria parasitemia and anemia were not affected by malaria prevention methods used by the participants. CONCLUSION: The overall prevalence of malaria infection and anemia observed in this study were 78.9% and 46.2%, respectively. Higher prevalence of malaria infection was associated with primigravidae and lower prevalence with tertiary education of subjects. Anemia was associated with consumption of herbal remedies. There is urgent need to control the prevalence of malaria and anemia among pregnant women attending traditional birth homes. PMID- 22811775 TI - Kirner's Deformity Misdiagnosed as Fracture: A Case Report. AB - Kirner's deformity or dystelephalangy is a rare entity which presents with painless, progressive, bilateral radiovolar curving of the terminal phalanges of the little fingers. It is a clinicoradiological diagnosis. Herein, we present a case where the patient was being treated as having a fracture of the distal phalanx because of misdiagnosis of Kirner's deformity. Given the rarity of the deformity, we believe it useful to present our case report as a contribution to the literature. PMID- 22811776 TI - Hats Off to HIT: A Case Report. AB - Thrombocytopenia is a well- recognized complication of heparin therapy. The diagnosis is mostly clinical and the main value of laboratory testing is in excluding the diagnosis. We describe here a patient with stroke who had aspiration pneumonia leading to sepsis. She developed atrial fibrillation and received heparin which had to be stopped prematurely due to melena. Within 5 days of heparin, she had thrombocytopenia which was heparin-induced thrombocytopenia (HIT), but the diagnosis was missed initially as heparin was no longer on the drug chart. PMID- 22811777 TI - Oral Lesion as the first Clinical Presentation in Sarcoidosis: A Case Report. AB - Sarcoidosis is a common multi-system disease characterized histolopathologically by the formation of non-caseating granulomas in the affected tissues. The oral involvement of sarcoidosis is relatively rare with less than 70 reported cases in literature while an oral lesion as the initial presenting sign is even less common. Oral lesions of sarcoidosis may mimic the lesions of other serious systemic diseases including Crohn's disease and tuberculosis as well as lesions localized to the orofacial region such as orofacial granulomatosis. This report presents a case of non-progressive sarcoidosis where the initial presenting symptom was a lesion in the buccal vestibule attached to the gingivae. A brief review of the pathology and clinical features is also presented. PMID- 22811778 TI - Preparing and conducting objective structured clinical examination for oman medical specialty board r1-r4 residents. AB - The Objective Structured Clinical Examination (OSCE) has been a common tool of assessment in both undergraduate and postgraduate medicine, and has been reported to have both higher reliability and validity over the oral exam. In addition, another advantage is that it reduces luck by standardizing both examiners and patients. This article describes our experience in organizing and conducting an OSCE for Oman Medical Specialty Board residents in Psychiatry. PMID- 22811779 TI - The effect of gag reflex on cardiac sympatovagal tone. AB - OBJECTIVES: Heart velocity may be influenced by gagging. The medulla oblongata receives the afferents of gag reflex. Neuronal pools of vomiting, salivation and cardiac parasympathetic fibers are very close in this area. So, their activities may be changed by spillover from each other. Using the heart rate variability (HRV) analysis, the effect of gagging on cardiac sympatovagal balance was studied. METHODS: ECG was recorded from 12 healthy nonsmoker volunteer students for 10 minutes in the sitting position between 10 and 11 AM. Gagging was elicited by tactile stimulation of the posterior pharyngeal wall. At 1 kHz sampling rate, HRV was calculated. The mean of heart rate at low and high frequencies (LF: 0.04 0.15; HF: 0.15-0.4 Hz) were compared before and after the stimulus. RESULTS: The mean of average heart rate, LF and HF in normalized units (nu) and the ratio of them (LF/HF) before and after the gagging were 89.9 +/- 3 and 95.2 +/- 3 bpm; 44.2 +/- 5.8 and 21.2 +/- 4; 31.1 +/- 5.3 and 39.4 +/- 3.8; and 1.7 +/- 0.3 and 0.6 +/- 0.2 respectively. CONCLUSION: Gagging increased heart velocity and had differential effect on two branches of cardiac autonomic nerves. The paradoxical relation between average heart rate and HRV indexes of sympatovagal tone may be due to unequal rate of change in autonomic fiber activities which is masked by 5 minutes interval averaging. PMID- 22811780 TI - Blue toes. PMID- 22811781 TI - Prevention of Intra-operative Cerebral Ischemia during Carotid Endarterectomy, Loco-regional versus General Anesthesia. AB - Carotid endarterectomy (CEA), as a prophylactic operation is becoming more popular. It is performed in patients who are at risk of stroke from dislodged atheromatous plaque at the carotid bifurcation. The major concern during CEA is the detection of cerebral hypoperfusion or ischemia during carotid cross clamping. Some studies have shown that the introduction of loco-regional anesthesia has lowered the incidence of major complications compared with general anesthesia since ischemia detection is easier in conscious patient. PMID- 22811782 TI - Do we need a new medical paradigm? PMID- 22811783 TI - The expanding sphere of primary prevention for coronary artery disease in persons with erectile dysfunction. PMID- 22811784 TI - Estimated Glomerular Filtration rate (eGFR): A Serum Creatinine-Based Test for the Detection of Chronic Kidney Disease and its Impact on Clinical Practice. PMID- 22811785 TI - View on the problem of managing of medical care quality. PMID- 22811786 TI - Exercise Stress Echocardiography with Tissue Doppler Imaging (TDI) Detects Early Systolic Dysfunction in Beta-Thalassemia Major Patients without Cardiac Iron Overload. AB - OBJECTIVES: To evaluate left and right myocardial performance at rest and after maximal exercise by conventional and Tissue Doppler Imaging (TDI) echocardiography. BACKGROUND: Iron Overload Cardiomyopathy (IOC) is the main cause of death in thalassemia major (TM) patients but conventional Echocardiography fails to predict early cardiac dysfunction. As TDI is able to demonstrate regional myocardial dysfunction and stress test may reveal abnormalities which are not evident at rest, we wondered if echocardiographic parameters may reveal abnormalities when applied first at rest and then after a physical effort. METHODS: We enrolled 46 consecutive beta-TM patients and 39 control subjects without evidence of cardiac disease; two echocardiograms, at baseline and at the end of maximal exercise on supine bicycle ergometer, were done. All TM patients had a liver iron assessment by SQUID (Superconducting Quantum Interference Device) and a cardiac iron one by MRI (T2*) evaluation. RESULTS: 38 TM patients had no evidence of cardiac iron overload. Whereas TM patients did not shown diastolic dysfunction and all of them presented a good global response to exercise, TDI detected a reduced increase of the S' waves of left ventricle basal segment during exercise. This finding seems to have some weak but interesting relations with iron overload markers. Pulmonary artery systolic pressure (PAPs) values were greater than in control subjects both at rest and after exercise CONCLUSIONS: in our study, exercise stress TDI echocardiography was able to demonstrate subtle systolic abnormalities that were missed by Conventional Echocardiography. Further studies are required to determine the meaning and the clinical impact of these results. PMID- 22811787 TI - Madurella mycetomatis infection following allogenic stem cell transplantation for aplastic anemia. PMID- 22811788 TI - Fatal cryptococcal meningitis in a patient with chronic lymphocytic leukemia. AB - Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections, especially opportunistic infections. We have described a patient with CLL who had cryptococcal meningitis. Despite lack of previous immunosuppressive treatment history, the patient experienced serious and fatal fungal infection. Physicians should be alert for a diagnosis of cryptococcal meningitis in patient with CLL who developed fever and headache. PMID- 22811789 TI - Systemic granulomatous reaction secondary to treatment of bladder cancer with bacillus calmette-guerin. AB - Intravesical instillation of Bacillus Calmette-Guerin is the elective treatment for transitional cell and in situ bladder carcinoma. Severe complications occur very seldom, but must be known and promptly recognized. We describe the case of a 48-year-old man, treated with chemo-immunotherapy ten years before for a follicular lymphoma, who developed a systemic granulomatous reaction after his twelfth intravescical BCG instillation for bladder cancer. PMID- 22811790 TI - Single Agent Lenalidomide Activity in Multiple Myeloma Relapse Evidenced Uniquely by CT/PET. AB - A 71 year old female with multiple myeloma presented with back pain seven year after autologous stem cell transplant. Skeletal bone survey and magnetic resonance imaging did not show a relapse that was evidenced by CT/PET. Lenalidomide as single agent induced a complete disappearance of the lesions 6 months later and confirmed after one year at CT/PET. PMID- 22811791 TI - Incidence of Common Fusion Transcripts in Adult and Pediatric Acute Myeloid Leukemia (AML) Cases: Experience of a Tertiary Care Research institute. AB - INTRODUCTION: The incidence of common fusion transcripts in AML is 40-45%, but data from Indian sub-continent is limited. AIMS #ENTITYSTARTX00026; OBJECTIVES: The aim of the present study is to note the incidence of common fusion transcripts of AML1-ETO, PML-RARA and CBFbeta-MYH11 in adult and pediatric AML cases. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 116 AML cases diagnosed on bone marrow, cytochemistry and Flow-cytometry over a period of 2 year were enrolled and bone marrow samples in EDTA were processed by multiplex RT-PCR assay. RESULTS: Of 116 cases, 96 (83%) were adult and 20 (17%) pediatric cases. A total of 39/116 (33.6%) cases showed positivity for fusion transcripts of which 28/96 (29.16%) were adult and 11/20 (55%) pediatric cases. Of the 28 positive adult cases, 14/96 (14.58%) were positive for AML1-ETO, 12/96 (12.5%) for PML RARA and 2/96 (2.08%) for CBFbeta-MYH11. In the 11 positive pediatric cases, 6/20 (30%) were positive for AML1-ETO, 3/20 (15%) for PML-RARA and 2/20 (10%) for CBFbeta-MYH11. DISCUSSION #ENTITYSTARTX00026; CONCLUSION: The incidence of the common fusion transcripts in our pilot study is in accordance with that described in western studies. It is important to identify these transcripts as they provide useful prognostic information to the treating clinician. PMID- 22811792 TI - JC Virus Leuko-Encephalopathy in Reduced Intensity Conditioning Cord Blood Transplant Recipient with a Review of the Literature. AB - We report here the case of progressive multifocal leukoencephalopathy (PML) related to human polyomavirus JC (JCV) infection after an allogeneic transplantation with umbilical cord blood cells in 59-year-old woman with follicular Non Hodgkin lymphoma. She presented with dysphagia and weakness; magnetic resonance imaging demonstrated marked signal abnormality in the sub cortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was positive for John Cunningham (JC) virus. JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Brain biopsy was not done. Extensive investigations for other viral infections seen in immuno compromised patients were negative. The patient's neurologic deficits rapidly increased throughout her hospital stay, and she died one month after the diagnosis. These findings could have practical implications and demonstrate that in patients presenting neurological symptoms and radiological signs after UCBT, the JCV encephalitis must be early suspected. PMID- 22811793 TI - Patients with >= 20 * 10(9)/l platelets at baseline may have a prompt response to romiplostim during the early phase of treatment: an italian single-institution experience. AB - Patients with chronic immune thrombocytopenia treated with romiplostim may benefit from a higher starting dose when a rapid increase in count is needed, but it could be avoided in those with a prompt response to the standard dosage. We hypothesized that a platelet count >= 20 * 10(9)/l at baseline could distinguish subjects with such response from those with a delayed one during the early phase of treatment. Our work is a retrospective and single-institution analysis comparing the median platelet count, the median weekly dosage of romiplostim and the median number of weekly platelet counts < 50 * 10(9)/l between patients with a baseline >= 20 * 10(9)/l platelets (n=10, 2 splenectomized) and those with a lower one (n=8, 3 splenectomized) during the first month of treatment with romiplostim. The results show a higher median platelet count (79,5 vs 40,5 * 10(9)/l, p=0,002) and a lower median dose of romiplostim (1 vs 2 mcg/kg/week, p=0,01) in subjects with a baseline >= 20 * 10(9)/l platelets, who also had a trend of less weekly counts < 50 * 10(9)/l platelets (1 vs 2, p=0,054). These data suggest that patients with >= 20 * 10(9)/l platelets at baseline may achieve a prompt response with the standard dose of romiplostim, but further and larger data are needed in order to assess whether it can be considered in clinical practice. PMID- 22811794 TI - Prophylaxis of malaria. AB - Malaria prevention in travelers to endemic areas remains dependent principally on chemoprophylaxis. Although malaria chemoprophylaxis refers to all malaria species, a distinction should be drawn between falciparum malaria prophylaxis and the prophylaxis of the relapsing malaria species (vivax & ovale). While the emergence of drug resistant strains, as well as the costs and adverse reactions to medications, complicate falciparum prophylaxis use, there are virtually no drugs available for vivax prophylaxis, beside of primaquine.Based on traveler's malaria data, a revised recommendation for using chemoprophylaxis in low risk areas should be considered. PMID- 22811795 TI - Sickle cell disease and bartonella spp. Infection. PMID- 22811797 TI - Message from the Editor-in-Chief. PMID- 22811796 TI - Ph-negative chronic myeloproliferative neoplasm (primary myelofibrosis) - as one of the reasons of the budd-Chiari syndrome. PMID- 22811798 TI - Predicting, preventing, treating and understanding radiation nephropathy. PMID- 22811799 TI - Giving oligometastases the best shot using stereotactic body radiosurgery with image guidance. How far is the cat out of the bag? PMID- 22811800 TI - Association of Technetium(99m) MAG-3 renal scintigraphy with change in creatinine clearance following chemoradiation to the abdomen in patients with gastrointestinal malignancies. AB - BACKGROUND: Information on differential renal function following abdominal chemoradiation is limited. This study evaluated the association between renal function as measured by biochemical endpoints and scintigraphy and dose volume parameters in patients with gastrointestinal malignancies. MATERIALS AND METHODS: Patients who received abdominal chemoradiation between 2002 and 2009 were identified for this study. Technetium(99m) MAG-3 scintigraphy and laboratory data were obtained prior to and after chemoradiation in 6 month intervals. Factors assessed included age, gender, hypertension, diabetes, and dose volume parameters. Renal function was assessed by biochemical endpoints and renal scintigraphy. RESULTS: Significant reductions in relative renal function of the primarily irradiated kidney and creatinine clearance were seen. Split renal function decreased from 49.75% pre-radiation to 47.74% and 41.28% at 6-12 months and >12 months post-radiation (P=0.0184). Creatinine clearance declined from 90.67ml/min pre-radiation to 82.23ml/min and 74.54ml/min at 6-12 months and >12 months post-radiation (P<0.0001). Univariate analysis of patients who had at least one post-radiation renogram showed the percent volumes of the primarily irradiated kidney receiving >= 25 Gy (V(25)) and 40 Gy (V(40)) were significantly associated with >=5% decrease in relative renal function (P=0.0387 and P=0.0438 respectively). CONCLUSION: Decline in split renal function using Technetium(99m) MAG-3 scintigraphy correlates with decrease in creatinine clearance and radiation dose-volume parameters following abdominal chemoradiation. Change in split perfusion can be detected as early as 6 months post-radiation. Scintigraphy may provide early determination and quantification of subclinical renal injury prior to clinical evidence of nephropathy. PMID- 22811801 TI - Single-fraction image-guided extracranial radiosurgery for recurrent and metastatic abdominal and pelvic cancers: short-term local control, metabolic response, and toxicity. AB - PURPOSE: Extracranial radiosurgery (ECRS) is a novel treatment for inoperable recurrent or metastatic abdominopelvic cancers. However, local control, metabolic response, and acute toxicity remain undefined. We therefore analyzed these endpoints in patients treated with single-fraction image-guided ECRS at Emory University. METHODS: 20 patients with recurrent or metastatic inoperable abdominal or pelvic cancers (23 sites) were treated with single-fraction ECRS using a Varian linear accelerator between 08/2006 and 02/2008. Patients with pancreas, biliary and liver cancer were part of an IRB-approved ongoing dose escalation trial. 14 patients had received prior abdominal or pelvic external beam radiation. In 13 patients pre-treatment PET/CT was used to delineate the target volume. Image-guidance was provided by implanted fiducial markers and on board imaging in 13 patients, and with cone-beam CT in 1 patient. 8 Patients were treated with respiratory gating. The median single-fraction dose delivered was 18 Gy. Each patient was assessed at 1 week, 1 month, and 3 months after radiosurgery for toxicity, and at approximately 1 month and 3 months with PET/CT for metabolic tumor response. Partial response was defined as a reduction in size of > 10% on CT and a decrease in maximum SUV of > 15% on PET. Complete response was defined as complete resolution on CT, and a reduction of SUV to background levels on PET. RESULTS: The median follow-up was 6.3 months (range 1.5-12.2 months). The overall response rate (the sum of complete responses and partial responses) by treated site was noted in 36% (1 month), 47% (3 months) and 48% (final). A complete response was achieved in 13% (3 sites). At last follow-up, local control (sum of response rate and stable disease) was 74%. The metabolic response rate by pet only(sum of partial and complete responders) was 85% on final analysis. 23% of pet avid sites achieved a complete response. Two pet avid treated sites (13%) did show evidence of progression at 3 months, but subsequent CT/FDG-PET scans showed a decrease in maximum SUV; no patients suffered progressive disease based on metabolic imaging at last follow-up. Grade 1-2 upper GI acute toxicity (nausea, vomiting, gastritis, and pain) was noted in 47% and 55% of patients at 1 week and 1 month, respectively. Correspondingly, acute lower GI toxicity (diarrhea, pain) was lower at 12% and 6%. Overall grade 1-2 GI toxicity was seen in 59% of patients at 1 week (pain and nausea being the most common) and 61% of patients at 1 month post stereotactic body radiotherapy (SBRT) (nausea being the most common). CONCLUSIONS: Single-fraction image-guided ECRS for recurrent or metastatic abdominopelvic cancers is safe and effective in the short term. 3 month local control was very good , and was predicted by an early metabolic response as seen on PET/CT. Acute side effects were mild, with no patient experiencing grade 3 or greater toxicity. Dose escalation and long-term studies are warranted for this treatment approach. PMID- 22811802 TI - Personalized therapy for pancreatic cancer: Myth or reality in 2010? PMID- 22811803 TI - HIV- positive anal cancer: an update for the clinician. AB - Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demographics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+) population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal cancer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per 100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailoring treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer patients including recent clinical trials. PMID- 22811804 TI - Do all locally advanced rectal cancers require radiation? A review of literature in the modern era. AB - Potentially curable rectal cancer is primarily treated with surgical resection. Adjuvant or neoadjuvant radiotherapy is often utilized for patients deemed to be at unacceptable risk for local recurrence. The purpose of this article is to review the pertinent literature and elucidate the role of radiotherapy in patients with an intermediate risk of local recurrence. The addition of chemoradiotherapy is recommended in the majority of patients with transmural or node positive rectal cancer. However, some patients with favorable characteristics may have only a small incremental benefit from the addition of radiotherapy. The decision to treat or not to treat should take into consideration the patient and physician tolerance of risk of recurrence and risk of treatment related toxicity. The primary factors identified for determining low risk patients are circumferential radial margin (CRM), location within the rectum, and nodal status. Patients at lowest risk have widely negative CRM (>2mm), proximal lesions (>10cm from the anal verge), and no nodal disease. Patients with all three low risk factors have an absolute reduction in local recurrence that is <5% and may be eligible to forego radiotherapy. Additional factors identified which may impact local recurrence risk are elevated serum CEA level, lymphovascular space invasion, pathologic grade, and extramural space invasion. PMID- 22811806 TI - Aorto-esophageal fistula: a rare fatal case caused by esophageal malignancy. PMID- 22811807 TI - Esophageal cancer: Is preoperative chemoradiation the new standard? PMID- 22811805 TI - MicroRNAs and esophageal cancer. AB - Cancer of the esophagus is a highly aggressive disease associated with an overall poor prognosis. There is an insistent need for improving our understanding of the molecular basis of this disease. The recent emergence of observations on the role of microRNAs in cancer and their potential as biomarkers has prompted many investigations to examine their relevance to esophageal cancer. This article provides an introduction to microRNA biology and the techniques involved in studying them, and summates what is now known about their role and utility in regard to neoplastic esophageal diseases. PMID- 22811808 TI - Does postoperative radiation therapy benefit patients with esophageal cancer? PMID- 22811809 TI - Predictive or non-predictive, prognostic or non-prognostic: Dilemmas generated through small retrospective studies. PMID- 22811810 TI - Challenges toward personalized treatment of localized colorectal cancer. PMID- 22811811 TI - Bax expression is a candidate prognostic and predictive marker of colorectal cancer. AB - OBJECTIVE: Since the anti-tumor activity of 5-fluorouracil (5-FU) is due to induction of apoptosis, we assessed the value of expression of key apoptotic molecules (Bax, Bcl-2 and p53) in predicting the efficacy of 5-FU therapy for colorectal adenocarcinomas (CRCs). METHODS: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 patients matched for age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation who had undergone only surgery (without any pre- or post-surgery therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2, and p53. Also, these CRCs were evaluated for Bax mutations. The predictive capacity or prognostic value of these markers was assessed by estimating overall survival. RESULTS: The majority of low Bax expressing CRCs have exhibited mutations at the G (8) tract. There was no significant difference in overall survival rates between the categories of surgery alone and 5-FU treated patients. However, a better survival was observed for patients who received chemotherapy when their CRCs had low Bax/Bcl2 ratio (HR, 1.55; 95% CI: 1.46-31.00). Patients who received surgery alone and whose CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (95% CI: 1.78-15.94), when controlled for tumor stage and other confounders. Bcl 2 and nuclear p53 accumulation had no predictive value in either patient group. CONCLUSION: These findings are the first to demonstrate that high Bax expression is a good prognosticator for patients who underwent surgery alone, and that patient with low Bax/Bcl-2 expression ratio benefit from 5-FU-based adjuvant therapies. PMID- 22811812 TI - KRAS status and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFOX chemotherapy. AB - BACKGROUND: Two previous first-line studies showed an improved trend in response rate (RR) and progression free survival (PFS) in metastatic colorectal cancer (CRC) patients with KRAS mutation. Others have reported a worsened outlook for metastatic CRC patients with KRAS mutation and a higher likelihood of metastatic disease to the lungs. In this study, we aimed to address the impact of KRAS on the pattern of metastatic disease at presentation and on RR and PFS with first line 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. METHODS: Patients with CRC who underwent KRAS testing using DxS assay at Roswell Park Cancer Institute (RPCI) were identified. Patients with metastatic CRC treated with first-line FOLFOX +/- bevacizumab were assessed for response and survival using RECIST 1.1 guidelines. A two-sided Fisher's exact test was used to determine the statistical significance. RESULTS: 181 patients with metastatic CRC and KRAS testing were identified. 83/181 patients were treated with FOLFOX (+/- bevacizumab) in the first-line setting at RPCI and were evaluable as per study guidelines. KRAS mutation (MT) occurred in 40.31% cases. There was no difference in organ-metastases distribution, RR (56.60% in KRAS wild-type (WT) and 50% in KRAS mutant) or PFS (9.3 months KRAS WT and 8.7 months in KRAS MT) based on KRAS status. CONCLUSION: In this single institute study, our findings do not support any predictive role for KRAS-MT in terms of response to FOLFOX first-line chemotherapy, or in terms of sites of metastatic disease at mCRC presentation. PMID- 22811813 TI - Cetuximab-induced hypomagnesaemia aggravates peripheral sensory neurotoxicity caused by oxaliplatin. AB - Calcium and magnesium replacement is effective in reducing oxaliplatin-induced neurotoxicity. However, cetuximab treatment has been associated with severe hypomagnesaemia. Therefore, we retrospectively investigated whether cetuximab induced hypomagnesaemia exacerbated oxaliplatin-induced neurotoxicity. Six patients with metastatic colorectal cancer who were previously treated with oxaliplatin-fluorouracil combination therapy were administered cetuximab in combination with irinotecan alone or irinotecan and fluorouracil as a second-line treatment. All patients had normal magnesium levels before receiving cetuximab. The Common Terminology Criteria for Adverse Events version 3.0 was used to evaluate the grade of neurotoxicity, hypomagnesaemia, hypocalcaemia, and hypokalemia every week. All six patients had grade 1 or higher hypomagnesaemia after starting cetuximab therapy. The serum calcium and potassium levels were within the normal range at the onset of hypomagnesaemia. Oxaliplatin-induced neurotoxicity occurred in all patients at the beginning of cetuximab therapy, with grade 1 neurotoxicity in five patients and grade 2 in one patient. After cetuximab administration, the neurotoxicity worsened in all six patients, and three progressed to grade 3. Among the three patients with grade 3 neurotoxicity, two required a dose reduction and one had to discontinue cetuximab therapy. A discontinuation or dose reduction in cetuximab therapy was associated with exacerbated oxaliplatin-induced neurotoxicity due to cetuximab-induced hypomagnesaemia in half of patients who had previously received oxaliplatin. Therefore, when administering cetuximab after oxaliplatin therapy, we suggest serially evaluating serum magnesium levels and neurotoxicity. PMID- 22811814 TI - Radiation therapy in the postoperative management of esophageal cancer. AB - The optimal management of esophageal cancer is complicated since institutional preferences vary, patient characteristics often guide management, and there are data to support multiple approaches for locally advanced esophageal cancer. Although surgery is an important component of therapy, alone it results in unacceptably high rates of local relapse and poor long-term survival rates. Well studied adjuvant approaches include upfront chemoradiation therapy with or without surgery, periopera-tive chemotherapy, adjuvant radiation or adjuvant chemoradiation. This review article seeks to examine thoroughly the role of postoperative therapeutic options for the management of esophageal cancer, and in so doing, also overviews prospective trials in the neoadjuvant, definitive and perioperative settings. Studies evaluating radiation field design are also discussed. PMID- 22811815 TI - Management of stage II/III rectal cancer. AB - Pelvic and distant recurrences in rectal cancer can be associated with substantial morbidity, and patients with stage II and III disease are at increased risk for both local and distant failure when compared to patients with earlier stage disease. Refinement of surgical techniques have helped to reduce the risk of recurrence, and adjuvant therapies such as radiation to the tumor and regional lymph nodes and 5-fluorouracil-based systemic therapies have helped to further provide local control and may have an impact on overall survival. Numerous studies have been completed internationally in an effort to determine the optimal treatment regimen for this patient population. The importance of pre therapy staging is of key importance as sequencing of therapy appears to significantly impact outcome. In the United States, patients with stage II/III rectal cancer are recommended to undergo preoperative concurrent pelvic radiation and chemotherapy followed by surgery several weeks later in order to maximize treatment response, which is then followed by approximately 4 months of adjuvant 5-fluorouracil-based systemic therapy. In Europe, there is substantial evidence supporting the use of neoadjuvant radiation therapy, however the role of concurrent chemotherapy remains a question of debate. Regardless of definitive management strategy, close follow-up in the post-treatment setting is important for early tumor detection and for managing treatment-related side-effects. PMID- 22811816 TI - Rapid onset of myelodysplastic syndrome after treatment for anal cancer: A case report. PMID- 22811817 TI - Endoscopic sealing of a rectovesical fistula with a combination of an over the scope clip and cyano-acrylate injection. PMID- 22811818 TI - Low risk of prevalent submucosal invasive cancer among patients undergoing esophagectomy for treatment of Barrett's esophagus with high grade dysplasia. PMID- 22811819 TI - Low prevalence of invasive adenocarcinoma and occult cancer on esophageal resection for Barrett's esophagus with high-grade dysplasia: Evidence for conservative management. PMID- 22811820 TI - Obesity, insulin and chemoresistance in colon cancer. PMID- 22811821 TI - Insulin-resistant conditions: A favorable milieu for aggressive drug-resistant malignancies. PMID- 22811822 TI - Emergency surgery for perforated gastric malignancy: An institution's experience and review of the literature. AB - OBJECTIVES: The aim was to evaluate the outcome of patients who underwent surgery for perforated gastric malignancies. METHODS: A review of all patients who underwent surgery for perforated gastric malignancy was performed. RESULTS: Twelve patients (nine gastric adenocarcinoma and three B-cell lymphoma) formed the study group. Ten (83.3%) had subtotal gastrectomy performed, while two (16.7%) underwent total gastrectomy. All eight patients with adenocarcinoma who survived the initial operation fared poorly. The two patients with lymphoma who survived the surgery underwent subsequent chemotherapy has no disease recurrence currently. CONCLUSION: Surgery in perforated gastric malignancy is fraught with numerous challenges. PMID- 22811823 TI - A pilot study evaluating the safety and toxicity of epirubicin, cisplatin, and UFT (ECU regimen) in advanced gastric carcinoma. AB - BACKGROUND: Best response rates have been achieved with three-drug regimens containing 5-FU in the treatment of advanced gastric cancer (AGC) and oral fluoropyrimidines are the best alternatives as substitutes for infusional 5-FU. This study aimed to evaluate the safety and toxicity of epirubicin, cisplatin, and UFT (ECU regimen) regimens in AGC outpatients. MATERIALS AND METHODS: Forty one patients with AGC received epirubicin, cisplatin, and oral UFT plus leucovorin. Epirubicin 50 mg/m(2) and cisplatin 60mg/m(2) were administered on Day 1. Three hundreds (300) mg/m(2)/day UFT was administered with leucovorin at a fixed oral dose of 90 mg/day for 21 days, followed by a 7-day rest period. Cycles were repeated every 4 weeks. Performance status was either as 0 and 1. RESULTS: Among the 41 patients enrolled, complete and partial response was achieved in 7.3% and 36.6% of patients, respectively, with an overall response rate of 43.9%. Stable disease was observed in 34.1% of patients and 22% showed disease progression. Median time to progression was 5.2 months and median survival was 12.3 months. A median of 4 cycles (range: 1-6) of chemotherapy were administered. The main grade III-IV toxicities were nausea/vomiting (19.4%) and neutropenia (12.1%). Grade IV toxicities were gastric perforation and renal failure. CONCLUSION: ECU appears to be an effective regimen in the treatment of AGC, with acceptable tolerability and manageable toxicity. In three-drug regimens, substitution of infusional 5-FU by UFT offers the possibility of increased AGC outpatient compliance. PMID- 22811824 TI - Insulin caused drug resistance to oxaliplatin in colon cancer cell line HT29. AB - INTRODUCTION: Obesity is associated with poor prognosis of colon cancer and the mechanism for this is unknown. This study tested insulin-caused resistance to oxaliplatin via activation of PI3K/Akt pathway in HT29 cells. METHODS: The effect of insulin on oxaliplatin cytotoxicity was tested by pre-incubation with 1uM insulin followed by addition of oxaliplatin. Phosphorylated Akt was determined by Western blotting. RESULTS: Addition of 1uM insulin decreased the cytotoxicity of oxaliplatin. PI3K specific inhibitor Ly294002 abolished such an effect of insulin. pAkt were highly activated by insulin plus oxaliplatin and inhibited by addition of Ly294002. CONCLUSION: Insulin decreased drug efficacy of oxaliplatin in HT29 cells, which could be mediated by the activation of the PI3K/Akt pathway. PMID- 22811825 TI - Prevalence of adenocarcinoma at esophagectomy for Barrett's esophagus with high grade dysplasia. AB - BACKGROUND: Barrett's esophagus with high grade dysplasia (HGD) may require surgical resection because of the risk of concomitant adenocarcinoma. The prevalence of invasive, occult carcinoma (>=stage 1B) in this setting has varied. We investigated the association of adenocarcinoma at operative resection for high grade dysplasia. METHODS: Using an electronic medical record, we identified patients who underwent esophagectomy for high grade dysplasia at the University of Pittsburgh Medical Center between 1993 and 2007. Preoperative diagnosis was confirmed by reviewing endoscopic, radiologic and pathology reports. Postoperative pathology reports were compared to the preoperative diagnosis. RESULTS: 68 patients (12 females and 56 males) with a preoperative diagnosis of high grade dysplasia underwent operative resection. The mean age was 64 years (range 36 to 86 years). Of 68 patients, 12 (17.6%) had adenocarcinoma, 2 (2.9%) were downgraded to low grade dysplasia, and 54 (79.4%) were confirmed as HGD. Of the 12 patients with adenocarcinoma, 4 (5.9% of total cohort) had intramucosal cancer (Stage 1A) and 8 (11.7% of total cohort) had invasive cancer with submucosal invasion or more advanced disease. Of the 8 patients with invasive adenocarcinoma, 4 did not have preoperative endoscopic or radiologic testing suggestive of advanced disease. CONCLUSION: The overall prevalence of adenocarcinoma in association with a preoperative diagnosis of HGD was 17.6%. Invasive adenocarcinoma was present in 11.7% of subjects and was clinically occult in 5.9%. PMID- 22811826 TI - FDG PET imaging in the staging and management of gastric cancer. AB - Gastric cancer is a leading cause of cancer death worldwide. Complete resection offers the only chance for permanent control, and accurate staging and evaluation of treatment response are crucial for appropriate management. Positron Emission Tomography (PET) is increasingly used to complement anatomic imaging in cancer management. PET use in gastric cancer has been limited by 1) some gastric histologies are not PET avid, 2) spatial resolution limits the ability to distinguish between primary tumor and compartment I or II lymph nodes, and 3) the lack of a unified criteria in how to interpret PET for management decisions. New criteria have been proposed establishing response metrics in the utilization of PET. More study is needed to support these criteria in routine practice and establish the place of PET in the staging and management of gastric cancer. PMID- 22811827 TI - Unusual metastases of gastrointestinal stromal tumor and genotypic correlates: Case report and review of the literature. PMID- 22811828 TI - Coexistence of gastrointestinal stromal tumour and colorectal adenocarcinoma: Two case reports. AB - TThis paper reports two rare cases of patients with synchronous gastrointestinal stromal tumour (GIST) and colorectal adenocarcinoma (CRC) where adjuvant FOLFOX chemotherapy was administered concurrently with imatinib mesylate. The first case is a 67-year-old woman with a large gastrointestinal stromal tumour with metastasis masking a co-existing primary colon cancer, which was diagnosed after tumour response to imatinib mesylate. The second case presents a 61-year-old male with a primary colon cancer and a suspected metastatic lymph node, later confirmed to be a co-existing primary gastric GIST during colon surgery. While colorectal cancer is the third most common cause of cancer-related death in North America, the prevalence of GISTs remains rare. To date, very few cases of synchronous GIST and CRC adenocarcinoma have been reported in the literature. Although the coexistence of these two tumour types is rare, it is important to be aware of their disease patterns. PMID- 22811829 TI - Benign multicystic peritoneal mesothelioma: A rare case presenting as pneumoperitoneum and pneumotosis intestinalis. PMID- 22811830 TI - Endoscopic innovation through animal experiments: a new in-vitro platform. PMID- 22811831 TI - Splenectomy revisited in 2011: Impact on hematologic toxicities while performing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PMID- 22811832 TI - A new experimental model to allow use of clinical-scale endoscopes in small animal tumor models. AB - BACKGROUND: The evaluation of novel endoscopes may require testing in experimental tumor models, particularly when employing new biomarkers. Tumor models, however, exist almost exclusively in small animals. Therefore, we aimed to develop an experimental setting that allows the use of clinical-scale endoscopes in small animals. METHODS: In our approach, the proximal large bowel with intact blood supply is exposed on a movable and height-adjustable table. The endoscope's tip may be inserted into the bowel; the dark environment of the bowel lumen in vivo is simulated by mounting a light-tight curtain around the endoscope. Proof-of-principle experiments were done in Wag/Rij rats following cecal injection of the cell line R1H. RESULTS: Using high-definition television white-light endoscopy, narrow-band and autofluorescence imaging, and miniprobe based confocal laser microscopy (CLM) marked differences were observed between normal mucosa and tumors. Depending on the techniques, mean examination times ranged from 3 to 10 minutes. Even after 90 minutes the colon displayed an intact blood supply, imaged by Evans blue injection and by CLM. CONCLUSION: These experiments demonstrate that our model allows in vivo examination of small animals by clinical-scale endoscopes. Therefore, it may be useful for evaluation, at various stages of GI carcinogenesis, of both new biomarkers and endoscopic technologies. PMID- 22811833 TI - Splenectomy ameliorates hematologic toxicity of hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is a promising modality for peritoneal carcinomatosis. Splenectomy is frequently required, however effect upon hematotoxicity is unknown. METHODS: 195 patients undergoing the procedure were evaluated and granulocyte colony stimulating factor administered for white blood cell counts <4.0. RESULTS: 52% of 195 underwent splenectomy; average white blood cell and platelet nadirs were 6.1,172. Non splenectomy patients averaged white blood cell nadir 4.6, platelet nadir 164.1. Granulocyte colony stimulating factor administered in 29% of splenectomy, 43% of non-splenectomy (P=0.043). CONCLUSION: Splenectomy ameliorates hematotoxicity of hyperthermic intraperitoneal chemotherapy and significantly reduces post operative granulocyte colony stimulating factor requirements. PMID- 22811834 TI - Survival of metastatic gastric cancer: Significance of age, sex and race/ethnicity. AB - BACKGROUND: Despite the success of modern chemotherapy in the treatment of large bowel cancers, patients with metastatic gastric cancer continue to have a dismal outcome. Identifying predictive and prognostic markers is an important step to improving current treatment approaches and extending survival. METHODS: Extracting data from the US NCI's Surveillance, Epidemiology, and End Results (SEER) registries, we compared overall survival for patients with metastatic gastric cancer by gender, age, and ethnicity using Cox proportional hazards models. 13,840 patients (>= 18 years) were identified from 1988-2004. Males and females were categorized by age grouping and ethnicity. RESULTS: 19% of Hispanic patients were diagnosed < 45 years of age as compared to 5.5% of Caucasians. Caucasian patients and men were more likely to be diagnosed with tumors in the gastric cardia (P<0.001). In our survival analysis, we found that women had a lower risk of dying as compared to men (P<0.001). Overall survival diminished with age (P<0.001). The median overall survival was 6 months in patients of <= 44 years old as compared to 3 months in patients 75 years and older. Gender differences in overall survival significantly varied by race and tumor grade/differentiation (P for interaction = 0.003 and 0.005, respectively). CONCLUSION: This is the largest study of metastatic gastric cancer patients from the SEER registry to show that age, gender, and tumor location are significant independent prognostic factors for overall survival in patients with metastatic gastric cancer. PMID- 22811836 TI - Skin metastases from esophageal and esophagogastric junction cancer. PMID- 22811835 TI - Emerging therapies in pancreas cancer. AB - Pancreas cancer has a grave prognosis and treatment options remain limited despite advancement in anti-cancer chemotherapeutics. This review provides an overview of the emerging therapies for pancreas cancer, focusing on novel signal transduction inhibitors (insulin-like growth factor receptor, hedgehog/Smo, PI3k/Akt/mTOR) and cytotoxics (nab-paclitaxel) that are currently in clinical development. Despite the impact molecularly targeted agents have on other tumor types, their application without cytotoxics in pancreas cancer remains limited. In addition, recent report of the superiority of an intensive cytotoxic regimen using fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) over gemcitabine reminded us of the importance of cytotoxics in this disease. As such, the future of pancreas cancer therapy may be combination regimens consisting of cytotoxics and molecularly targeted agents. PMID- 22811837 TI - Massive upper gastrointestinal hemorrhage due to adenosquamous carcinoma of the pancreas: Case report and literature review. PMID- 22811838 TI - Patient with synchronous low grade leiomyosarcoma of the thigh, primary pancreatic neuroendocrine tumor, and lung metastases: Why biopsy of metastases should be the standard. PMID- 22811839 TI - Hepatic necrosis and hemorrhage following hyperthermic intraperitoneal chemotherapy with oxaliplatin: A review of two cases. PMID- 22811840 TI - Sustained response to FOLFOX and Bevacizumab in metastatic bronchial carcinoid - A case report and review of the literature. PMID- 22811841 TI - Pancreatic cancer: current standards, research updates and future directions. PMID- 22811842 TI - Current surgical management of pancreatic cancer. AB - En bloc resection is the treatment of choice for localized pancreatic cancer. While the perioperative mortality associated with resection is low, it still carries a significant morbidity rate of up to 50% in certain high-risk subsets of patients. With advances in perioperative care, radical resection with inclusion of adjacent vascular structure to achieve negative margin status can be performed with comparable mortality and morbidity in high-volume centers. Early results with the use of minimally invasive technique in pancreatic surgery are promising. Recent data on perioperative care to decrease morbidity with pancreatic surgery will also be discussed. PMID- 22811843 TI - Preoperative therapies for resectable and borderline resectable pancreatic cancer. AB - In the era of multidetector high quality CT imaging, it is feasible and critical to use objective criteria to define resectable pancreatic cancer. This allows accurate pretreatment staging and the development of stage-specific therapy. Tumors of borderline resectability have emerged as a distinct subset and the definition has been expanded in the last few years. Borderline resectable tumors are defined as those with tumor abutment of <180degrees (< 50%) of the SMA or celiac axis, short segment abutment or encasement of the common hepatic artery typically at the gastroduodenal artery origin, SMV-PV abutment with impingement and narrowing or segmental venous occlusion with sufficient venous flow above and below the occlusion to allow an option for venous reconstruction. Most of the patients whose cancer meet these CT criteria are candidates for preoperative systemic chemotherapy followed by chemoradiation since they are at a high risk for margin positive resection with upfront surgery. Patients whose imaging studies show radiographic stability or regression proceed to pancreaticoduodenectomy (or pancreatectomy) and this may require vascular resection and reconstruction. Prospective biomarker and functional imaging enriched studies are warranted to determine the best overall treatment strategy for these patients. PMID- 22811844 TI - Can pancreaticoduodenectomy performed at a comprehensive community cancer center have comparable results as major tertiary center? AB - BACKGROUND: Pancreatic resection is a definitive treatment modality for pancreatic neoplasm. Pancreaticoduodenectomy (PD) is the primary procedure for tumor arising from head of pancreas. Prognosis is overwhelmingly poor despite adequate resection. We maintained a prospective database covering years 2001 to 2010. Outcome data is analyzed and compared with those from tertiary centers. METHODS: Sixty-two patients with various histology were included. Pylorus preserving pancreatico-duodenectomy (PPPD), classic pancreaticoduodenectomy, and subtotal pancreatectomy were procedures performed. Three patients had portal venorrhaphy performed to obtain clinically negative margin. Forty six patients had malignancy on final pathologic analysis. RESULTS: The average age of patients was 63. Mean preoperative CA19-9 for exocrine pancreatic malignancies was higher than for more benign lesions. There was a decrease in operative time during this period. Blood transfusion was uncommon. There was very few pancreatic leak among the patients. Two bile leaks were identified, one controlled with the drainage tube and the other one required repeat surgery. The primary reason for the prolonged hospitalization was gastric ileus. For patients without a gastrostomy tube, nasogastric tube was kept in until gastric ileus resolved. 30 days mortality rate was calculated at 4.8. Mean survival time during our follow up was 30.6 months. Comparing to published literature, present series' mortality, morbidity, and survival are similar. Five year survival was 39%. CONCLUSION: Despite overall poor outcome for patients with pancreatic and biliary malignancies, we conclude that surgery can be performed in community hospitals with special interest in treating pancreatic disorder, offering patients equivalent survival and quality of life as those operated in tertiary centers. PMID- 22811845 TI - The role of epithelial-mesenchymal transition in pancreatic cancer. AB - Pancreatic cancer is the fourth leading cause of cancer related death in the US. Despite the advances in medical and surgical treatment, the 5-year survival rate for such cancer is only approximately 5% when considering all stages of disease. The lethal nature of pancreatic cancer stems from its high metastatic potential to the lymphatic system and distant organs. Lack of effective chemotherapies, which is believed to be due to drug-resistance, also contributes to the high mortality of pancreatic cancer. Recent evidence suggests that epithelial mesenchymal transition of pancreatic cancer cells contributes to the development of drug resistance and an increase in invasiveness. Future strategies that specifically target against epithelial-mesenchymal transition phenotype could potentially reduce tumoral drug resistance and invasiveness and hence prolong the survival of patients with pancreatic cancer. PMID- 22811846 TI - The role of radiotherapy in management of pancreatic cancer. AB - Pancreatic cancer is one of the leading causes of cancer death. The treatment options in pancreatic cancer remain limited. This review provides an overview of the role of radiotherapy (RT) alone or in combination with systemic treatment at different settings of treatment strategy. Neoadjuvant chemoradiotherapy (CRT) may downstage the borderline resectable disease and make resection possible, which could translate to a survival benefit. Although the benefit of adjuvant CRT remains controversial due to inconsistent outcome of randomized trials, in North America it is still a common recommendation of the treatment. For locally advanced pancreatic cancer, the treatment option could either be chemotherapy or chemoradiotherapy. By using advanced radiotherapy modalities, the toxicity of RT could be reduced and RT dose escalation becomes possible to improve locoregional control. PMID- 22811847 TI - Imaging of pancreatic cancer: An overview. AB - Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death in the United States. The median size of pancreatic adenocarcinoma at the time of diagnosis is about 31 mm and has not changed significantly in last three decades despite major advances in imaging technology that can help diagnose increasingly smaller tumors. This is largely because patients are asymptomatic till late in course of pancreatic cancer or have nonspecific symptoms. Increased awareness of pancreatic cancer amongst the clinicians and knowledge of the available imaging modalities and their optimal use in evaluation of patients suspected to have pancreatic cancer can potentially help in diagnosing more early stage tumors. Another major challenge in the management of patients with pancreatic cancer involves reliable determination of resectability. Only about 10% of pancreatic adenocarcinomas are resectable at the time of diagnosis and would potentially benefit from a R0 surgical resection. The final determination of resectability cannot be made until late during surgical resection. Failure to identify unresectable tumor pre-operatively can result in considerable morbidity and mortality due to an unnecessary surgery. In this review, we review the relative advantages and shortcomings of imaging modalities available for evaluation of patients with suspected pancreatic cancer and for preoperative determination of resectability. PMID- 22811848 TI - HIFU for palliative treatment of pancreatic cancer. AB - High intensity focused ultrasound (HIFU) is a novel non-invasive modality for ablation of various solid tumors including uterine fibroids, prostate cancer, hepatic, renal, breast and pancreatic tumors. HIFU therapy utilizes mechanical energy in the form of a powerful ultrasound wave that is focused inside the body to induce thermal and/or mechanical effects in tissue. Multiple preclinical and non-randomized clinical trials have been performed to evaluate the safety and efficacy of HIFU for palliative treatment of pancreatic tumors. Substantial tumor related pain reduction was achieved in most cases after HIFU treatment, and no significant side-effects were observed. This review provides a description of different physical mechanisms underlying HIFU therapy, summarizes the clinical experience obtained to date in HIFU treatment of pancreatic tumors, and discusses the challenges, limitations and new approaches in this modality. PMID- 22811849 TI - Nanovector-based therapies in advanced pancreatic cancer. AB - Systemic therapy for advanced pancreatic cancer has been largely disappointing owing to the unfavorable pharmacokinetic profile and poor penetration of current chemotherapeutic agents ,as well as the fragile patient population with compromised tolerance to toxic chemotherapies. Nanovectors can provide passive drug delivery through abnormal tumor neo-vasculature microanatomy or active targeting via binding to receptors or macromolecules associated with the tumor. In such a manner, nanovector-based therapy may not only modulate the pharmacokinetics and therapeutic index of chemotherapeutic agents but also provide new treatment options in patients with advanced pancreatic cancer. In this article, we present the rationale and currently available clinical results of nanovector-based therapies to highlight the potential use of this class of agent in patients with advanced pancreatic cancer. PMID- 22811850 TI - The value of cyst fluid analysis in the pre-operative evaluation of pancreatic cysts. PMID- 22811851 TI - EUS and pancreatic cyst fluid analysis: Is the juice worth the aqueeze? PMID- 22811852 TI - Tumor exosomes: a novel biomarker? PMID- 22811853 TI - Colorectal cancer screening using protected microRNAs. PMID- 22811854 TI - Fluid analysis prior to surgical resection of suspected mucinous pancreatic cysts. A single centre experience. AB - OBJECTIVE: EUS-FNA cytology and fluid analysis are frequently utilized to evaluate pancreatic cysts. Elevated cyst fluid CEA is usually indicative of a mucinous pancreatic cyst but whether CEA or amylase values can subclassify various mucinous cysts is unknown. The purpose of this study is to determine whether cyst fluid CEA and amylase obtained by EUS-FNA can differentiate between mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs). METHODS: Using our prospective hospital EUS and surgical databases, we identified all patients who underwent EUS of a pancreatic cyst prior to surgical resection, in the last 10 years. Cysts were pathologically sub-classified as MCNs or IPMNs; all other cysts were considered non-mucinous. Values of cyst fluid CEA and amylase were correlated to corresponding surgical histopathology and compared between the two groups. RESULTS: 134 patients underwent surgery for pancreatic cysts including 82 (63%) that also had preoperative EUS. EUS-FNA was performed in 61/82 (74%) and cyst fluid analysis in 35/61 (57%) including CEA and amylase in 35 and 33 patients, respectively. Histopathology in these 35 cysts demonstrated nonmucinous cysts in 10 and mucinous cysts in 25 including: MCNs (n=9) and IPMNs (n=16). Cyst fluid CEA (p=0.19) and amylase (p=0.64) between all IPMNs and MCNs were similar. Between branched duct IPMNs and MCNs alone, cyst fluid CEA (p=0.34) and amylase (p=0.92) were also similar. CONCLUSION: In this single center study, pancreatic cyst fluid amylase and CEA levels appeared to be of limited value to influence the differential of mucinous pancreatic cysts. Larger studies are recommended to evaluate this role further. PMID- 22811855 TI - Exosome can prevent RNase from degrading microRNA in feces. AB - BACKGROUND: Because the stability of miRNA in feces has not been clarified, we examined the stability of miRNA in feces. METHODS: RNase was added into culture media of HT-29 cells and fecal homogenates. The relative quantifications of miRNA were analyzed by real-time RT-PCR. RESULTS: Cellular miRNA or exosomal miRNA were protected from RNase by the cellular membrane or the exosome; meanwhile, free miRNA was degraded immediately and completely by RNase. CONCLUSION: The present study revealed that exosome or cellular membrane could prevent RNase from degrading miRNA inside the exosome or cells even in a dreadful condition, as in feces. PMID- 22811856 TI - Increasing incidence in liver cancer in Canada, 1972-2006: Age-period-cohort analysis. AB - BACKGROUND/AIMS: Our study aimed to assess 1) the temporal trends in incidence and mortality of liver cancer and 2) age-period-cohort effects on the incidence in Canada. METHODS: We analyzed data obtained from the Canadian Cancer Registry Database and Canadian Vital Statistics Death Database. We first examined temporal trends by sex, age group, and birth cohort between 1972 and 2006. Three-year period rates and annual percentage change (APC) were calculated to compare the changes over the study period. We used age-period-cohort modelling to estimate underlying effects on the observed trends in incidence. RESULTS: The overall age adjusted incidence rates increased from 2.6 and 1.5 per 100 000 in 1972-74 to 6.5 (APC: 2.9) and 2.2 (APC: 1.2) per 100 000 in 2004-06 among males and females, respectively. The age-adjusted mortality rates increased from 3.3 and 2.0 per 100 000 in 1972-74 to 6.0 (APC: 2.3) and 2.6 (APC: 1.2) per 100 000 in 2004-06 among males and females, respectively. The incidence increased most rapidly in men aged 45-54 years (APC: 4.1) and women aged 65-74 years (APC: 1.7) over the period of study. CONCLUSIONS: The age-period-cohort analysis suggests that birth-cohort effect is underlying the increase in incidence. While the exact reason for the increased incidence of liver cancer remains unknown, reported increase in HBV and HCV infections, and immigration from high-risk regions of the world may be important factors. PMID- 22811857 TI - Comparison of adiponectin concentration between pancreatic cancer and colorectal cancer. AB - INTRODUCTION: Adiponectin (ADP) is an adipocytokine secreted by the adipose tissue which can be a useful marker in oncogenesis. Preliminary studies suggest that adiponectin rates differ according to the type of cancer. AIM OF STUDY: Compare ADP plasma levels in pancreatic cancer (PC) and colorectal cancer (CRC) in a prospective monocentric study. PATIENTS AND METHODS: The study included all the incident cases of PC gathered from a university hospital in France from January 2006 till September 2007. A control population of incident cases of colorectal cancer (CRC), matching on age, gender, and tumor staging was set in the same period. In addition to demographic data, the other parameters analyzed were: ADP rate, insulinoresistance (Homa-test), presence of a dysmetabolic syndrome, evolution of weight and data concerning the tumor (staging, tumor markers: ACE, CA19.9). RESULTS: 33 CRC and 53 PC were analyzed. Type 2 diabetes was found in 18.2% of the CRC cases and 39.6% of the PC (p = 0.037). The mean ADP level was significantly higher in PC versus CRC (20.9 microgram/l versus 15.9 microgram/l; p = 0.03). In multivariate analysis , after adjusting for gender, age, bilirubinemia and weigth loss, the variables independently associated with a high level of ADP (> 10 microG/L) were type 2 diabetes (OR = 0.05, p = 0.01), insulinoresistance (OR = 0.42, p = 0.05) and PC (OR = 12.03, p = 0.047). CONCLUSION: ADP concentration is higher in PC patients than in CRC patients. ADP concentration > 10 microgram/l was independently associated with pancreatic cancer. Our data confirm that adiponectin rates differ strongly according to the type of cancer. PMID- 22811859 TI - Large cell neuroendocrine carcinoma of the colon: A rare and aggressive tumor. PMID- 22811858 TI - The role of taxanes in the management of gastroesphageal cancer. AB - Upper gastrointestinal cancers commonly referred to as gastroesophageal carcinomas encompass cancers of the esophagus, stomach and gastroesophageal junction. Although the number of newly diagnosed cases of gastric cancer has decreased in the United States, the whole burden of upper gastrointestinal carcinomas on society remains significantly high, with only a small improvement in overall survival achieved over the past two decades. Traditionally, therapeutic agents used to treat gastroesophageal cancers have been platinums and fluoropyrimidines. Taxanes are di-terpenes produced by the plants of the genus Taxus (yews). As their name suggests, taxanes were first derived from natural sources, but now they are all synthesized artificially. Interfering with cellular microtubular function during cell division is the main mechanism of action for currently available taxanes. Since their introduction into therapeutic oncology, many different other taxane-derivatives have been manufactured and are being developed. Changing the formulation of the drug to improve delivery such as liposomal encapsulation, and target deliver with antibody-drug conjugation, as well as introducing new class of cytotoxic agents that can overcome taxane resistance. The two most commonly used taxanes are paclitaxel and docetaxel. Taxane is a class of cytotoxic agents more commonly administered in patients with breast and lung cancers. However, the regulatory approval of docetaxel to treat patients with metastatic or advanced gastroesophageal cancers in 2006 established the role of taxanes in the management of upper gastroesophageal cancers. This paper will review the current data of taxanes in the management of patients with upper gastrointestinal cancers. PMID- 22811860 TI - Hirschsprung disease of the colon, a vaginal mass and medullary thyroid cancer - a RET oncogene driven problem. AB - This case report emphasizes the fact that all patients with Hirschsprung disease should be screened for RET Oncogene mutation as there is a well known association between Hirschsprung Disease and Multiple Endocrine Neoplasia (MEN) Type 2A. It also reminds us that Medullary Thyroid Carcinoma is known to cause elevated levels of CEA which does not originate from gastrointestinal tract. PMID- 22811861 TI - A 37 year-old pregnant woman with pancreatic adeno-carcinoma treated with surgery and adjuvant chemotherapy: A case report and literature review. PMID- 22811862 TI - Squamous cell carcinoma of the rectum, primary or metastatic? PMID- 22811863 TI - Surgical treatment of colorectal cancer hepatic metastasis. PMID- 22811864 TI - Patient selection for hepatic resection for metastatic colorectal cancer. PMID- 22811865 TI - Preoperative imaging for hepatic resection of colorectal cancer metastasis. AB - Despite recent advances in chemotherapeutic agents, the prognosis for metastatic colon cancer remains poor. Over the past two decades, hepatic metastasectomy has emerged as a promising technique for improving survival in patients with metastatic colon cancer and in some cases providing long-term cure. To maximize safety and efficacy of metastasectomy, appropriate pre-operative imaging is needed. Advancements in computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have led to improved detection of occult lesions and better definition of surgical anatomy. While CT, PET and MRI have a comparable sensitivity for detection of large liver metastases, MRI excels at detection of subcentimeter liver metastases compared to CT and FDG-PET, especially with the combination of diffusion weighted imaging (DWI) and hepatocyte-specific contrast agents. CT may be useful as a screening modality or in preoperative planning such as volumetric estimation of the remnant liver size or in defining preoperative arterial anatomy for hepatic artery infusion pump placement. While technologic advancements have led to unprecedented image quality and clarity, this does not replace the need for a dedicated, competent radiologist with experience in hepatic imaging. PMID- 22811867 TI - Techniques of hepatic resection. AB - Liver resections are high risk procedures performed by experienced surgeons. The role of liver resection in malignant disease has changed over the last 100 years with great improvement in morbidity, mortality and long term survival. New understanding in liver anatomy, improved perioperative care, anesthesia techniques, and technological advances has improved this aspect of patient care. With improved techniques, patients previously considered unresectable have an opportunity to undergo curative surgery. This review article describes the various approaches and techniques for liver resection. The relevant anatomy and terminology of hepatic resections is discussed, as well as the role of anatomic vs. nonanatomic resection. Methods of vascular control are examined and the multiple strategies of parenchymal transection are compared, as well as minimally invasive techniques. Finally, a brief review of the authors' practice in terms of surgical technique is offered. PMID- 22811866 TI - Perioperative management of hepatic resection. PMID- 22811868 TI - Postoperative management after hepatic resection. AB - Hepatic resection has become the mainstay of treatment for both primary and certain secondary malignancies. Outcomes after hepatic resection have significantly improved with advances in surgical and anesthetic techniques and perioperative care. Metabolic and functional changes after hepatic resection are unique and cause significant challenges in management. In-depth understanding of hepatic physiology is essential to properly address the postoperative issues. Strategies implemented in the postoperative period to improve outcomes include adequate nutritional support, proper glycemic control, and interventions to reduce postoperative infectious complications among several others. This review article focuses on the major postoperative issues after hepatic resection and presents the current management. PMID- 22811869 TI - Synchronous resection of colorectal primary and hepatic metastasis. AB - Up to 50% of the over 140,000 new colorectal cancer patients will present with synchronous colorectal cancer and liver metastasis. Surgical management of patients with resectable synchronous colorectal hepatic metastasis is complex and must consider multiple factors, including the presence of symptoms, location of primary tumor and liver metastases, extent of tumor (both primary and metastatic), patient performance status, and underlying comorbidities. Possible approaches to this select group of patients have included a synchronous resection of the colorectal primary and the hepatic metastases or a staged resection approach. The available literature regarding the safety of synchronous versus staged approaches confirms that a simultaneous resection may be performed in selected patients with acceptable morbidity and mortality. Perioperative mortality when minor hepatectomies are combined with colorectal resection is consistently <=5%. Perioperative morbidity varies considerably following both synchronous and staged resections. However, the bulk of the existing literature confirms that simultaneous resections are both feasible and safe when hepatic resections are limited to <3 segments. Data regarding the oncologic outcomes following synchronous versus staged resections for Stage IV colorectal cancer are more limited than those available regarding postoperative morbidity and mortality. The available data suggest equivalent overall and disease-free survival regardless of timing of resection. Experience with minimally invasive combined colorectal and hepatic resections is extremely limited to date and consists exclusively of small single center series. The potential benefits of a minimally invasive approach will await the results of larger studies. PMID- 22811870 TI - Resection of non-hepatic colorectal cancer metastasis. PMID- 22811872 TI - Circulating tumor cells in biliary cancer: First step or false step? PMID- 22811871 TI - Thermal tumor ablation therapy for colorectal cancer hepatic metastasis. AB - Surgical resection for colorectal hepatic metastases (CRHM) is the preferred treatment for suitable candidates, and the only potentially curative modality. However, due to various limitations, the majority of patients with CRHM are not candidates for liver resection. In recent years, there has been an increasing interest in the role of thermal tumor ablation (TTA) as a component of combined resection-ablation strategies, staged hepatic resections, or as standalone adjunct treatment for patients with CRHM. Thus, ablative approaches have expanded the group of patients with CRHM that may benefit from liver-directed treatment strategies. PMID- 22811873 TI - Detection of circulating tumor cells in gastrointestinal cancer: Has its time come? PMID- 22811874 TI - How to overcome resistance to therapy? PMID- 22811875 TI - Ca19-9 and pancreatic cancer: Is it really that good? PMID- 22811876 TI - A phase II study of capecitabine and lapatinib in advanced refractory colorectal adenocarcinoma: A Wisconsin Oncology Network study. AB - BACKGROUND: Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects. METHODS: This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m(2) by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol. RESULTS: Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients. CONCLUSIONS: Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma. PMID- 22811877 TI - Detection of circulating tumor cells in cancers of biliary origin. AB - BACKGROUND: Circulating Tumor Cells (CTCs) have been described in malignancies of epithelial origin. In this study we examined the detection of CTCs using CellSearch assay in cholangiocarcinoma and gallbladder cancer. METHODS: The clinical outcomes and detection of CTCs were examined in sixteen patients with biliary cancer using the CellSearch assay. Stages of cancer, baseline demographic data and overall survival were evaluated. RESULTS: Thirteen patients had cholangiocarcinoma and three had gallbladder cancer. Using a cut off of two or more CTCs per 7.5 mL of blood, 3/13 cholangiocarcinoma and 1/3 gallbladder cancer patients had detectable CTCs. At 12 months of follow up from time CTC is drawn; 1/4(25%) of patients with positive CTC were alive while 6/12 (50%) of patients with negative CTC remained alive without a significant difference in survival between the two groups. CONCLUSIONS: Our finding that 25% of patients with cholangiocarcinoma and gallbladder cancer have two or more detectable CTCs/7.5 mL is the first report to our knowledge in this disease. Larger patient numbers are needed to determine the prognostic significance of finding CTCs in biliary cancer. Prospective validation of the role of CTC in advanced biliary cancer patients is on going. PMID- 22811878 TI - The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. AB - BACKGROUND: Serum carbohydrate antigen (CA 19-9) is the most common tumor marker assessed in pancreatic cancer patients; nevertheless few articles have comprehensively evaluated the evidence for its utility in pancreatic cancer management. METHODS: Literature search was performed using Medline with keywords "pancreatic cancer", "tumor markers", "CA 19-9", "diagnosis", "screening", "prognosis", "resectability" and "recurrence". All English language articles pertaining to the role of CA 19-9 in pancreatic cancer were critically analyzed to determine its utility as a biomarker for pancreatic cancer. RESULTS: Serum CA 19-9 is the most extensively validated pancreatic cancer biomarker with multiple clinical applications. CA 19-9 serum levels have a sensitivity and specificity of 79-81% and 82-90% respectively for the diagnosis of pancreatic cancer in symptomatic patients; but are not useful as a screening marker because of low positive predictive value (0.5-0.9%). Pre-operative CA 19-9 serum levels provide useful prognostic information as patients with normal levels (<37 U/mL) have a prolonged median survival (32-36 months) compared to patients with elevated levels (>37 U/mL) (12-15 months). A CA 19-9 serum level of <100 U/mL implies likely resectable disease whereas levels >100 U/mL suggest unresectablity or metastatic disease. Normalization or a decrease in post-operative CA 19-9 serum levels by >=20-50% from baseline following surgical resection or chemotherapy is associated with prolonged survival compared to failure of CA 19-9 serum levels to normalize or an increase. Important limitations to CA 19-9 serum level evaluation in pancreatic cancer include poor sensitivity, false negative results in Lewis negative phenotype (5-10%) and increased false positivity in the presence of obstructive jaundice (10-60%). CONCLUSIONS: CA 19-9 is the most extensively studied and validated serum biomarker for the diagnosis of pancreatic cancer in symptomatic patients. CA 19-9 serum levels can provide important information with regards to prognosis, overall survival, and response to chemotherapy as well as predict post-operative recurrence. However, non-specific expression in several benign and malignant diseases, false negative results in Lewis negative genotype and an increased false positive results in the presence of obstructive jaundice severely limit the universal applicability of serum CA 19-9 levels in pancreatic cancer management. PMID- 22811879 TI - Management of gastrointestinal carcinoid tumours - 10 years experience at a district general hospital. AB - BACKGROUND: There is paucity of guidelines regarding management of gastrointestinal carcinoid tumours in district hospitals. METHODS: This study was undertaken at a district hospital to analyse the management pathway of gastrointestinal carcinoid tumours. RESULTS: Over a period of 10 years there were 35 patients, with an estimated annual incidence of 2.5 per 100,000 population. After a median follow up of 24 months, 22 (63%) patients were alive and disease free. Only 56% patients were referred to the regional neuro-endocrine multidisciplinary team. CONCLUSIONS: Management of patients with carcinoid tumours in district hospitals needs streamling with increased utilisation of regional neuroendocrine multidisciplinary teams. PMID- 22811880 TI - What is the potential role of hepatic arterial infusion chemo-therapy in the current armamentorium against colorectal cancer. AB - The management of colorectal cancer patients with liver metastases is a common clinical problem. If patients can undergo resection of liver metastases, long term survival can be achieved. Converting a patient from unresectable to resectable, however, remains a major challenge. The majority of patients who undergo liver resection for colorectal metastases recur; therefore, adjuvant treatment following resection should be considered. Emerging literature suggests that hepatic arterial infusion (HAI) can be combined with systemic chemotherapy. Both therapies can be given at nearly full doses, thus improving resectability and outcomes for patients with colorectal liver metastases. HAI plus systemic can also be a useful option for adjuvant treatment after hepatic resection. PMID- 22811881 TI - Hepatoid adenocarcinoma of the peritoneal cavity: Prolonged survival after debulking surgery and 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) therapy. AB - Hepatoid adenocarcinoma is an alpha-fetoprotein producing adenocarcinoma arising in numerous extra-hepatic organs. The diagnosis may be difficult because of the varied presentation but immunohistochemistries help make the diagnosis. The prognosis is often poor but in this report, we present a young female with hepatoid carcinoma who is doing well more than three years after her diagnosis. PMID- 22811882 TI - Effectiveness of radiation therapy in GIST: A case report. PMID- 22811883 TI - Primary mesenteric liposarcoma: An unusual presentation of a rare condition. AB - Primary mesenteric liposarcoma is a rare neoplasm. Here, we report the case of a 50 year old Indian man with a pleomorphic liposarcoma of the mesentery. The clinical findings pointed towards a retroperitoneal growth but imaging resolved the issue. A laparotomy was performed and a 20 cm * 20 cm multilobulated tumour arising from the mesentery and weighing 1.8 kilograms was excised with a segment of jejunum. The cut surface had a variegated appearance with regions of necrosis. The histological features were suggestive of pleomorphic liposarcoma. Tumour cells were positive for S-100 and negative for SMA/Desmin. Complete resection is curative although the role of chemotherapy remains to be established. PMID- 22811884 TI - Enterocytozoon bieneusi Identification Using Real-Time Polymerase Chain Reaction and Restriction Fragment Length Polymorphism in HIV-Infected Humans from Kinshasa Province of the Democratic Republic of Congo. AB - Objective. To determine the prevalence and the genotypes of Enterocytozoon bieneusi in stool specimens from HIV patients. Methods. This cross-sectional study was carried out in Kinshasa hospitals between 2009 and 2012. Detection of microsporidia including E. bieneusi and E. intestinalis was performed in 242 HIV infected patients. Typing was based on DNA polymorphism of the ribosomal DNA ITS region of E. bieneusi. PCRRFLP generated with two restriction enzymes (Nla III and Fnu 4HI) in PCR-amplified ITS products for classifying strains into different lineages. The diagnosis performance of the indirect immune-fluorescence monoclonal antibody (IFI-AcM) was defined in comparison with real-time PCR as the gold standard. Results. Out of 242 HIV-infected patients, using the real-time PCR, the prevalence of E. bieneusi was 7.9% (n = 19) among the 19 E. bieneusi, one was coinfected with E. intestinalis. In 19 E. bieneusi persons using PCR-RFLP method, 5 type I strains of E. bieneusi (26.3%) and 5 type IV strains of E. bieneusi (26.3%) were identified. The sensitivity of IFI-AcM was poor as estimated 42.1%. Conclusion. Despite different PCR methods, there is possible association between HIVinfection, geographic location (France, Cameroun, Democratic Republic of Congo), and the concurrence of type I and type IV strains. PMID- 22811885 TI - Interaction of Schistosoma mansoni Sporocysts and Hemocytes of Biomphalaria. AB - Human infection by Schistosoma mansoni affects more than 100 million people worldwide, most often in populations of developing countries of Africa, Asia, and Latin America. The transmission of S. mansoni in human populations depends on the presence of some species of Biomphalaria that act as an intermediate host. The compatibility between S. mansoni and its intermediate host is influenced by behavioral, physiological, and genetical factors of the mollusc and the parasite. The susceptibility level of the mollusc has been attributed to the capacity of internal defense system (IDS)-hemocytes and soluble components of the hemolymph to recognize and destroy the parasite, and this will be the center of interest of this paper. The schistosome-resistant Biomphalaria can be an alternative strategy for the control of schistosomiasis. PMID- 22811886 TI - Anterior chamber angle evaluation with fourier-domain optical coherence tomography. AB - New advances in anterior segment optical coherence tomography (OCT) technology development allow visualizing the anterior chamber angle of the eye with high speed and high resolution. Fourier-domain (FD) OCT instruments working at 840 nm can reliably identify fine angle structures such as the Schwalbe's line. This paper demonstrates quantitative angle assessment with 840 nm FD-OCT and provides diagnostic cutoff values for occludable angle detection. This is useful for angle closure glaucoma diagnosis and management. Moreover, 840 nm FD-OCT is a useful tool for postsurgical evaluation in glaucoma patients. PMID- 22811887 TI - Ocular manifestations of systemic lupus erythematosus: a review of the literature. AB - About one-third of patients suffering from systemic lupus erythematosus have ocular manifestations. The most common manifestation is keratoconjunctivitis sicca. The most vision threatening are retinal vasculitis and optic neuritis/neuropathy. Prompt diagnosis and treatment of eye disease is paramount as they are often associated with high levels of systemic inflammation and end organ damage. Initial management with high-dose oral or IV corticosteroids is often necessary. Multiple "steroid-sparing" treatment options exist with the most recently studied being biologic agents. PMID- 22811888 TI - Weight loss is still an essential intervention in obesity and its complications: a review. AB - The prevalence of obesity is more than 20% in many developed countries and it increases in developing countries. Obesity is associated with metabolic disorders, cardiovascular diseases, pulmonary diseases, digestive diseases, and cancers. Although other specific treatments for these complications exist, weight loss is still an essential intervention in obesity and its complications. Therapeutic life change, behavior modification, pharmacotherapy, and surgery are major approaches to weight loss. In addition, medicine used in diabetes such as Glucagon-like peptide-1 analogues may be a new type of medicine for obesity, at least for those obese patients with diabetes. PMID- 22811889 TI - Applying a common-sense approach to fighting obesity. AB - The obesity epidemic is a threat to the health of millions and to the economic viability of healthcare systems, governments, businesses, and nations. A range of answers come to mind if and when we ask, "What can we, health professionals (physicians, nurses, nutritionists, behavioral psychologists), do about this epidemic?" In this paper, we describe the Common-Sense Model of Self-Regulation as a framework for organizing existent tools and creating new tools to improve control of the obesity epidemic. Further, we explain how the Common-Sense Model can augment existing behavior-change models, with particular attention to the strength of the Common-Sense Model in addressing assessment and weight maintenance beyond initial weight loss. PMID- 22811890 TI - Psychosocial factors of different health behaviour patterns in adolescents: association with overweight and weight control behaviours. AB - Physical activity, nutrition, and sedentary behaviour combine to influence the risk of overweight among adolescents. This paper aims to identify psychosocial factors of different health behaviour patterns in adolescents and its association with overweight and weight control behaviours. The 3069 adolescents of both genders (average of 14.8 years old) from the 2010 Portuguese survey of Health Behaviour School-Aged Children (HBSC) answered the 2010 HBSC self-reported questionnaire. It used the cluster k-means (nonhierarchy method), qui-square, one way ANOVA, and logistic regression. Three clusters with different behavioural patterns (physical activity, sedentary, and eating) composed the results obtained. The sedentary group (34%) had lower self-regulation, body satisfaction, health and wellness, family and classmates relationships, communication with the father than the other two groups. The active gamers (25%) had a smaller BMI but used more unhealthy weight control strategies than the other two groups. The healthy group (41%) was more motivated and more satisfied with school but was not different than the active gamers in most psychosocial variables. Differences were found between clusters for weight control behaviours and psychosocial variables. Different strategies for different patterns were necessary in order to promote obesity prevention and, simultaneously, target healthy lifestyle and wellbeing in adolescents. PMID- 22811891 TI - The Genetics of PTPN1 and Obesity: Insights from Mouse Models of Tissue-Specific PTP1B Deficiency. AB - The protein tyrosine phosphatase PTP1B is a negative regulator of both insulin and leptin signaling and is involved in the control of glucose homeostasis and energy expenditure. Due to its prominent role in regulating metabolism, PTP1B is a promising therapeutic target for the treatment of human obesity and type 2 diabetes. The PTP1B protein is encoded by the PTPN1 gene on human chromosome 20q13, a region that shows linkage with insulin resistance, type 2 diabetes, and obesity in human populations. In this paper, we summarize the genetics of the PTPN1 locus and associations with metabolic disease. In addition, we discuss the tissue-specific functions of PTP1B as gleaned from genetic mouse models. PMID- 22811892 TI - Examination of the Relationship between Psychosocial Mediators and Intervention Effects in It's Your Game: An Effective HIV/STI/Pregnancy Prevention Intervention for Middle School Students. AB - A set of mediation analyses were carried out in this study using data from It's Your Game. . .Keep It Real (IYG), a successful HIV/STI/pregnancy prevention program. The IYG study evaluated a skill and normbased. HIV/STI/pregnancy prevention program that was implemented from 2004 to 2007 among 907 urban low income middle school youth in Houston, TX, USA. Analyses were carried out to investigate the degree to which a set of proposed psychosocial measures of behavioral knowledge, perceived self-efficacy, behavioral, and normative beliefs, and perceived risky situations, all targeted by the intervention, mediated the intervention's effectiveness in reducing initiation of sex. The mediation process was assessed by examining the significance and size of the estimated effects from the mediating pathways. The findings from this study provide evidence that the majority of the psychosocial mediators targeted by the IYG intervention are indeed related to the desired behavior and provide evidence that the conceptual theory underlying the targeted psychosocial mediators in the intervention is appropriate. Two of the psychosocial mediators significantly mediated the intervention effect, knowledge of STI signs and symptoms and refusal self efficacy. This study suggests that the underlying causal mechanisms of action of these interventions are complex and warrant further analyses. PMID- 22811893 TI - Comparison of Serum Apolipoprotein Levels of Diabetic Children and Healthy Children with or without Diabetic Parents. AB - Introduction. The association of diabetes and atherosclerosis with disorders of lipids and lipoproteins, notably high apolipoprotein B (apoB) and low apolipoprotein A1(apoA1) is well established. Because of the beginning of the atherosclerosis' process from early life, in this study, the plasma levels of apoA1 and apoB were compared in diabetic children with type I diabetes mellitus(DM), healthy children with diabetic parents (HDPs),and healthy children with nondiabetic parents (HNDPs). Methods. This case-control study was conducted among 90 children aged 9-18 years. Serum levels of apoA and apoB were compared among 30 diabetic children (DM), 30 healthy children with diabetic parents (HDPs), and 30 healthy children with nondiabetic parents (HNDP). Results. The mean serum apoA1 was higher in DM (153 +/- 69 mg/dL) followed by HNDPs (138 +/- 58 mg/dL) and HDPs (128 +/- 56 mg/dl), but the difference was not statistically significant. The mean apoB value in HNDPs was significantly lower than DM and HDPs (90 +/- 21 mg/dL versus 127 +/- 47 and 128 +/- 38 mg/dL, P < 0.05, respectively). The mean apoB levels in DM (127 +/- 47 mg/dl) and HDP (128 +/- 38 mg/dL) were not statistically significantly different (P > 0.05). Conclusions. Diabetic children and healthy children with diabetic parent(s) are at higher risk of dyslipidemia and atherosclerosis. Thus for primordial and primary prevention of atherosclerosis, we suggest screening these children for low plasma apoA1 and high plasma apoB levels. PMID- 22811894 TI - Are dietary cholesterol intake and serum cholesterol levels related to nonalcoholic Fatty liver disease in obese children? AB - Background. Nonalcoholic fatty liver disease (NAFLD) in children has been recognized as a major health burden. Serum lipids as well as dietary cholesterol (DC) intake may positively relate to development of NAFLD. The purpose of this study was to investigate anthropometric, biochemical, and dietary intake parameters of obese Greek children with and without NAFLD. Materials and Methods. Eighty-five obese children aged 8-15 (45 boys/40 girls) participated in the study. NAFLD was diagnosed by ultrasonography (US) in all subjects. Liver indexes were measured in all children. A 3-day dietary was recorded for all subjects. Results. 38 out of 85 children (44.7%) were found to have fatty liver. Obese children with increased levels of TC (95% CI: 1.721-3.191), low density lipoprotein (LDL) (95% CI: 1.829-3.058), and increased dietary cholesterol intakes (95% CI: 1.511-2.719) were 2.541, 2.612, and 2.041 times more likely to develop NAFLD compared with the children without NAFLD. Conclusion. The present study showed that TC, LDL, and DC were the strongest risk factors of development of NAFLD. Reducing body weight and dietary cholesterol intakes as well as decreasing serum TC and LDL levels are urgently necessary in order to prevent NAFLD and possible other health implications later in life. PMID- 22811895 TI - The Triglyceride to HDL Ratio and Its Relationship to Insulin Resistance in Pre- and Postpubertal Children: Observation from the Wausau SCHOOL Project. AB - Insulin resistance (IR) is a risk factor for ischemic heart disease and diabetes and raises the triglyceride/high-density lipoprotein (TG/HDL) ratio in adults, but is not well defined in children. Purpose. To investigate the TG/HDL ratios in children as an IR marker. Methods. Wausau SCHOOL Project assessed 99 prepubertal and 118 postpubertal children. The TG/HDL ratio was correlated with numerous risk factors. Results. TG/HDL ratio was significantly correlated with QUICKI, HOMA-IR, zBMI, waist-to hip ratio, systolic and diastolic BP, LDL size and LDL number. A group of 32 IR children (HOMA-IR > 1 SD from the mean, i.e., >2.45) had significantly higher TG/HDL (3.11 +/- 1.77) compared to non-IR children (1.86 +/- 0.75). A TG/HDL ratio of >=2.0 identified 32 of the 40 children deemed IR by HOMA IR (>2.45) with a sensitivity of 0.80 and a specificity of 0.66. Children with TG/HDL ratio >=3 were heavier and had higher BP, glucose, HOMA-IR, LDL number, and lower HDL level, QUICKI, and LDL size, regardless of pubertal status. Conclusion. The TG/HDL ratio is strongly associated with IR in children, and with higher BMI, waist hip ratio, BP, and more athrogenic lipid profile. PMID- 22811896 TI - Comment on "effectiveness of physiotherapy for ventilator-associated pneumonia". PMID- 22811897 TI - Mental health services required after disasters: learning from the lasting effects of disasters. AB - Disasters test civil administrations' and health services' capacity to act in a flexible but well-coordinated manner because each disaster is unique and poses unusual challenges. The health services required differ markedly according to the nature of the disaster and the geographical spread of those affected. Epidemiology has shown that services need to be equipped to deal with major depressive disorder and grief, not just posttraumatic stress disorder, and not only for victims of the disaster itself but also the emergency service workers. The challenge is for specialist advisers to respect and understand the existing health care and support networks of those affected while also recognizing their limitations. In the initial aftermath of these events, a great deal of effort goes into the development of early support systems but the longer term needs of these populations are often underestimated. These services need to be structured, taking into account the pre-existing psychiatric morbidity within the community. Disasters are an opportunity for improving services for patients with posttraumatic psychopathology in general but can later be utilized for improving services for victims of more common traumas in modern society, such as accidents and interpersonal violence. PMID- 22811898 TI - Neopterin as a marker of response to antiviral therapy in hepatitis C virus patients. AB - Predicting the efficacy of antiviral treatment of hepatitis C virus (HCV) is of importance for both patient well-being and health care expense. The expression of interferon-stimulated genes (IFN-SGs) in the liver was suggested as a marker of response to anti-viral therapy. IFN-SGs encode the guanosine triphosphate cyclohydrolase 1 (GTPCH), a rate-limiting enzyme of pteridines biosynthesis. Neopterin, a stable byproduct of GTPCH-catalyzed reaction, is used as a marker of interferon-induced GTPCH activation. We hypothesized that assessment of neopterin concentrations might predict the response to antiviral therapy. Neopterin concentrations were evaluated in 260 HCV patients treated by pegylated interferon combined with ribavirin. Mean and median pretreatment neopterin concentrations were lower in patients with sustained virological response than in nonresponders. The rate of response was twofold higher among patients with pretreatment neopterin levels <16 nmol/L than in patients with neopterin levels >=16 nmol/L, even after controlling for HCV genotype status. Our study suggests that the pretreatment level of neopterin might be used in routine clinical practice as rapid and cost-effective marker to predict the response to antiviral therapy in HCV patients. PMID- 22811899 TI - A Novel Technique for Transvaginal Retrieval of Enlarged Pelvic Viscera during Minimally Invasive Surgery. AB - Introduction. With the widespread adoption of laparoscopic and robotic surgery, more and more women are undergoing minimally invasive surgery for complex gynecological procedures. The rate-limiting step is often the delivery of an intact uterus or an unruptured adnexal mass. To avoid conversion to a minilaparotomy for specimen retrieval, we describe a novel technique using an Anchor Tissue Retrieval System bag in conjunction with a pneumo-occluder to easily retrieve large specimens through a colpotomy incision. Surgical Technique. After completion of the robotic-assisted hysterectomy, the uterus, fallopian tubes, and ovaries were too large to be retrieved intact despite multiple attempts of delivery through the colpotomy incision. Prior to resorting to a minilaparotomy or morcellation of the specimen, a 15 mm anchor retrieval bag with a pneumo-occluder was placed through the vagina and the intact specimen was easily placed inside the bag under direct visualization and removed through the colpotomy incision intact. Conclusion. We routinely utilize this technique to retrieve hysterectomy specimens that are not readily delivered through the colpotomy incision and find this technique to be safe, highly efficient, and cost effective when there is a need to remove large intact specimens during minimally invasive surgery. PMID- 22811900 TI - Laparoscopic gastric plication for the treatment of morbid obesity: a review. AB - Introduction. Laparoscopic greater curvature plication is an operation that is gaining ground in the treatment of morbid obesity, as it appears to replicate the results of laparoscopic sleeve gastrectomy with fewer complications. Aim. Review of current literature, especially results on weight loss and complications. Method. 11 (eleven) published articles on laparoscopic gastric plication, of which 1 preclinical study, 8 prospective studies for a total of 521 patients and 2 case reports of unusual complications. Results. Reported Paracentage of EWL in all studies is comparable to Laparoscopic Sleeve Gastrectomy (around 50% in 6 months, 60-65% in 12 months, 60-65% in 24 months) and total complication rate is at 15,1% with minor complications in 10,7%, major complications in 4,4%. Reoperation rate was 3%, conversion rate was 0,2%, and mortality was zero. Conclusion. Current literature on gastric plication and its modifications is limited and sketchy at times. Low cost, short hospital stay, absence of prosthetic material, and reversibility make it an attractive option. Initial data show that LGCP is effective for short- and medium-term weight loss, complication and reoperation rates are low, and GERD symptoms are unaffected. More data is required, and randomized control trials must be completed in order to reach safe conclusions. PMID- 22811901 TI - Pivotal Role of AKAP12 in the Regulation of Cellular Adhesion Dynamics: Control of Cytoskeletal Architecture, Cell Migration, and Mitogenic Signaling. AB - Cellular dynamics are controlled by key signaling molecules such as cAMP dependent protein kinase (PKA) and protein kinase C (PKC). AKAP12/SSeCKS/Gravin (AKAP12) is a scaffold protein for PKA and PKC which controls actin-cytoskeleton reorganization in a spatiotemporal manner. AKAP12 also acts as a tumor suppressor which regulates cell-cycle progression and inhibits Src-mediated oncogenic signaling and cytoskeletal pathways. Reexpression of AKAP12 causes cell flattening, reorganization of the actin cytoskeleton, and the production of normalized focal adhesion structures. Downregulation of AKAP12 induces the formation of thickened, longitudinal stress fibers and the proliferation of adhesion complexes. AKAP12-null mouse embryonic fibroblasts exhibit hyperactivation of PKC, premature cellular senescence, and defects in cytokinesis, relating to the loss of PKC scaffolding activity by AKAP12. AKAP12 null mice exhibit increased cell senescence and increased susceptibility to carcinogen-induced oncogenesis. The paper describes the regulatory and scaffolding functions of AKAP12 and how it regulates cell adhesion, signaling, and oncogenic suppression. PMID- 22811902 TI - A Survey of Primary Care Offices: Triage of Poisoning Calls without a Poison Control Center. AB - Poison control centers hold great potential for saving health care resources particularly by preventing unnecessary medical utilization. We developed a four question survey with three poisoning-related scenarios, based on common calls to our poison center, and one question regarding after-hours calls. We identified primary care provider offices in our poison center's region from an internet search. We contacted these offices via telephone and asked to speak to an office manager or someone responsible for triaging patient phone queries. Using a scripted form, trained investigators questioned 100 consecutive primary care provider offices on how they would handle these poisoning-related calls if there was no poison center to refer their patients to. Results of our survey suggest that 82.5% of poisoning-related calls to primary care offices would be referred to 911 or an emergency department if there was no poison center. These results further support the role that poison centers play in patient care and health care utilization. PMID- 22811903 TI - Secrecy and the pathogenesis of hypertension. AB - Literature supporting a relationship between emotions and regulation of blood pressure dates back to the early 1900s. Theoretical explanations of the pathophysiology of the correlation have centered on several possible trajectories, the most likely being cardiovascular reactivity to stress. Prospective studies have demonstrated that chronic stress and enduring traits such as defensiveness and anxiety, impacts the development of hypertension. An analysis of 195 genetic males seeking contrary hormones for treatment of gender dysphoria revealed a significantly increased prevalence of hypertension in this cohort. The authors attribute this increased prevalence to the known effects of emotional disclosure on health and conclude that the inhibition of emotional expressiveness is significant in the etiology and maintenance of essential hypertension in this population. As hypertension is associated with morbidity and mortality, the implications for the family medicine physician treating gender nonconforming individuals and other patients in the context of a general medical practice will be discussed. PMID- 22811904 TI - Extracellular matrix proteins modulate antimigratory and apoptotic effects of Doxorubicin. AB - Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin induced apoptosis (SFM-DR). PMID- 22811905 TI - Fibroblast Growth Factor and Mineral Metabolism Parameters among Prevalent Kidney Transplant Patients. AB - Background. Chronic kidney disease (CKD) related mineral bone disorders persist after kidney transplantation, but little is known about the relationship between fibroblast growth factor-23 (FGF-23) and mineral metabolism in prevalent post transplant patients. Objectives. To examine mineral metabolism parameters and their relationship to FGF-23 and parathyroid hormone (PTH) in prevalent kidney transplant patients. Methods. Cross-sectional study of 106 kidney transplant patients enrolled November 2005-October 2009 at Tufts Medical Center (TMC), Boston. Results. The prevalence of hypophosphatemia was 34%, hypercalcemia 3%, and elevated PTH levels 66%, at a median (25th-75th percentile) duration of 12.8 (7.5-30.9) months post-transplant. Males had significantly higher levels of PTH (P = 0.04) and lower levels of serum phosphate (P = 0.002). Serum PTH levels did not relate to eGFR, corrected calcium levels or serum phosphate. FGF-23 levels were above the reference limits in 7% of patients; higher levels were associated with higher serum phosphate and PTH levels after adjustment for transplant kidney function. Conclusion. FGF-23 is an important driver of mineral metabolism in prevalent transplant patients. Its modulatory role in mineral metabolism homeostasis may be heightened as feedback suppression of PTH is disturbed. Its role in long term cardiovascular and graft outcomes needs further study. PMID- 22811906 TI - A single-center 7-year experience with end-stage renal disease care in Nigeria-a surrogate for the poor state of ESRD care in Nigeria and other sub-saharan african countries: advocacy for a global fund for ESRD care program in sub saharan african countries. AB - Background. A single-center ESRD care experience in a Nigerian teaching hospital is presented as a surrogate case to demonstrate the prevailing ESRD care situation in Nigeria and most SSA countries. Methods. The data of 320 consecutive ESRD patients undergoing maintenance haemodialysis treatment during a seven-year period were retrospectively analyzed. Results. Over 80% of the subjects funded dialysis treatments from direct out of pocket payment. The mean duration on dialysis before dropout was 5.2 +/- 7.6 weeks, with majority 314 (98.1%) of the patients unable to sustain dialysis above 12 weeks. Total dialysis sessions during the 7-year period was 1476 giving an average weekly dialysis session of 0.013 (0.05 hour/week) per patient per week. One hundred and twenty-eight (40%) patients died within 90 days of entry into dialysis care. Conclusions. ESRD care in this single centre was characterized by gross dialysis inadequacy and case fatality due to the inability to access and afford care. The opportunities for kidney transplantation are also very low. Poverty and the absence of government support for ESRD care are responsible for the poor outcomes. A global focus on ESRD care in SSA countries has thus become imperative. PMID- 22811907 TI - Doppler parameters of hepatic and renal hemodynamics in patients with liver cirrhosis. AB - Introduction. There are limited studies on simultaneous evaluation of liver and renal blood flow using Doppler methods. We evaluated and compared the changes of liver and renal Doppler US parameters in patients with liver cirrhosis according to the degree of liver disease. Material and Methods. We assessed a large spectrum of liver and renal Doppler US parameters in 67 patients with liver cirrhosis. Results. Significant differences between Child's classes or score, as well as MELD score, were observed in all investigated intrarenal blood flow Doppler US parameters, except renal artery peak systolic velocity, but only in some of the hepatic ones. The deviations of renal Doppler US parameters were also related with the complications of liver cirrhosis, as well as serum urea and creatinine levels. There was relationship between Doppler US parameters of hepatic artery and the corresponding renal artery Doppler US parameters. The changes of Doppler US parameters were age independent. Conclusion. Our results show, renal Doppler US parameters correlate with the severity and complications of liver cirrhosis. Because of dynamic deviations of renal Doppler US parameters with advance of liver cirrhosis, we recommend Doppler US of renal artery as a part of follow up of these patients. PMID- 22811908 TI - Restriction of Retroviral Replication by Tetherin/BST-2. AB - Tetherin/BST-2 is an important host restriction factor that limits the replication of HIV and other enveloped viruses. Tetherin is a type II membrane glycoprotein with a very unusual domain structure that allows it to engage budding virions and retain them on the plasma membrane of infected cells. Following the initial report identifying tetherin as the host cell factor targeted by the HIV-1 Vpu gene, knowledge of the molecular, structural, and cellular biology of tetherin has rapidly advanced. This paper summarizes the discovery and impact of tetherin biology on the HIV field, with a focus on recent advances in understanding its structure and function. The relevance of tetherin to replication and spread of other retroviruses is also reviewed. Tetherin is a unique host restriction factor that is likely to continue to provide new insights into host-virus interactions and illustrates well the varied ways by which host organisms defend against viral pathogens. PMID- 22811909 TI - The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents. AB - Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2'-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells. PMID- 22811911 TI - Does physical activity increase life expectancy? A review of the literature. AB - Physical activity reduces many major mortality risk factors including arterial hypertension, diabetes mellitus type 2, dyslipidemia, coronary heart disease, stroke, and cancer. All-cause mortality is decreased by about 30% to 35% in physically active as compared to inactive subjects. The purpose of this paper was to synthesize the literature on life expectancy in relation to physical activity. A systematic PubMed search on life expectancy in physically active and inactive individuals was performed. In addition, articles comparing life expectancy of athletes compared to that of nonathletes were reviewed. Results of 13 studies describing eight different cohorts suggest that regular physical activity is associated with an increase of life expectancy by 0.4 to 6.9 years. Eleven studies included confounding risk factors for mortality and revealed an increase in life expectancy by 0.4 to 4.2 years with regular physical activity. Eleven case control studies on life expectancy in former athletes revealed consistently greater life expectancy in aerobic endurance athletes but inconsistent results for other athletes. None of these studies considered confounding risk factors for mortality. In conclusion, while regular physical activity increases life expectancy, it remains unclear if high-intensity sports activities further increase life expectancy. PMID- 22811912 TI - Transmetatarsal amputation: a case series and review of the literature. AB - Foot ulceration is a major cause of morbidity amongst patients with diabetes. In severe cases of ulceration, osteomyelitis and amputation can ensue. A distinct lack of agreement exists on the most appropriate level of amputation in cases of severe foot ulceration/infection to provide predictable healing rates. This paper provides an overview of the transmetatarsal amputation (TMA) as a limb salvage procedure and is written with the perspective and experiences of the Department of Podiatric Surgery at West Middlesex University Hospital (WMUH). We have reflected on the cases of 11 patients (12 feet) and have found the TMA to be an effective procedure in the management of cases of severe forefoot ulceration and infection. PMID- 22811910 TI - Retroviral env glycoprotein trafficking and incorporation into virions. AB - Together with the Gag protein, the Env glycoprotein is a major retroviral structural protein and is essential for forming infectious virus particles. Env is synthesized, processed, and transported to certain microdomains at the plasma membrane and takes advantage of the same host machinery for its trafficking as that used by cellular glycoproteins. Incorporation of Env into progeny virions is probably mediated by the interaction between Env and Gag, in some cases with the additional involvement of certain host factors. Although several general models have been proposed to explain the incorporation of retroviral Env glycoproteins into virions, the actual mechanism for this process is still unclear, partly because structural data on the Env protein cytoplasmic tail is lacking. This paper presents the current understanding of the synthesis, trafficking, and virion incorporation of retroviral Env proteins. PMID- 22811913 TI - Ubiquitin C-terminal hydrolase l1 in tumorigenesis. AB - Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1, aka PGP9.5) is an abundant, neuronal deubiquitinating enzyme that has also been suggested to possess E3 ubiquitin-protein ligase activity and/or stabilize ubiquitin monomers in vivo. Recent evidence implicates dysregulation of UCH-L1 in the pathogenesis and progression of human cancers. Although typically only expressed in neurons, high levels of UCH-L1 have been found in many nonneuronal tumors, including breast, colorectal, and pancreatic carcinomas. UCH-L1 has also been implicated in the regulation of metastasis and cell growth during the progression of nonsmall cell lung carcinoma, colorectal cancer, and lymphoma. Together these studies suggest UCH-L1 has a potent oncogenic role and drives tumor development. Conversely, others have observed promoter methylation-mediated silencing of UCH-L1 in certain tumor subtypes, suggesting a potential tumor suppressor role for UCH-L1. In this paper, we provide an overview of the evidence supporting the involvement of UCH L1 in tumor development and discuss the potential mechanisms of action of UCH-L1 in oncogenesis. PMID- 22811914 TI - Combination effects of docetaxel and Doxorubicin in hormone-refractory prostate cancer cells. AB - Combination effects of docetaxel (DOC) and doxorubicin (DOX) were investigated in prostate cancer cells (PC3 and DU145). Combination indices (CIs) were determined using the unified theory in various concentrations and mixing ratios (synergy: CI < 0.9, additivity: 0.9 < CI < 1.1, and antagonism: CI > 1.1). DOC showed a biphasic cytotoxicity pattern with the half maximal inhibitory concentration (IC50) at the picomolar range for PC3 (0.598 nM) and DU145 (0.469 nM), following 72 h drug exposure. The IC50s of DOX were 908 nM and 343 nM for PC3 and DU145, respectively. Strong synergy was seen when PC3 was treated with DOC at concentrations lower than its IC50 values (0.125~0.5 nM) plus DOX (2~8 times IC50). Equipotent drug combination treatments (7 * 7) revealed that the DOC/DOX combination leads to high synergy and effective cell death only in a narrow concentration range in DU145. This study provides a convenient method to predict multiple drug combination effects by the estimated CI values as well as cell viability data. The proposed DOC/DOX mixing ratios can be used to design combination drug cocktails or delivery systems to improve chemotherapy for cancer patients. PMID- 22811916 TI - Meniscofibular ligament: morphology and functional significance of a relatively unknown anatomical structure. AB - Purpose. A relatively unknown ligamentous structure of the posterolateral corner of the knee joint, the so-called meniscofibular ligament (MFL), was investigated as regards its macroscopic morphology, its histological features, and its reaction to knee movements. Material and Methods. MFL was exposed on 21 fresh frozen unpaired knee joints. Its microscopic morphology was examined utilizing for comparison the fibular collateral and the popliteofibular ligament. Results. MFL was encountered in 100% of the specimens as a thin striplike fibrous band extending between the lower border of the lateral meniscus and the head of the fibula. MFL was tense during knee extension and external rotation of the tibia, whereas its histological features were similar to those of fibular collateral and popliteofibular ligament. Discussion. Its precise histological nature is studied as well as its tension alterations during knee movements. The potential functional significance of the MFL with respect to its role in avoidance of lateral meniscus and lateral coronary ligament tears is discussed. Conclusions. MFL presumably provides an additional protection to the lateral meniscus during the last stages of knee extension, as well as to the lateral coronary ligament reducing the possibility of a potential rupture. PMID- 22811915 TI - Strategies to Identify Recognition Signals and Targets of SUMOylation. AB - SUMOylation contributes to the regulation of many essential cellular factors. Diverse techniques have been used to explore the functional consequences of protein SUMOylation. Most approaches consider the identification of sequences on substrates, adaptors, or receptors regulating the SUMO conjugation, recognition, or deconjugation. The large majority of the studied SUMOylated proteins contain the sequence [IVL]KxE. SUMOylated proteins are recognized by at least 3 types of hydrophobic SUMO-interacting motifs (SIMs) that contribute to coordinate SUMO dependent functions. Typically, SIMs are constituted by a hydrophobic core flanked by one or two clusters of negatively charged amino acid residues. Multiple SIMs can integrate SUMO binding domains (SBDs), optimizing binding, and control over SUMO-dependent processes. Here, we present a survey of the methodologies used to study SUMO-regulated functions and provide guidelines for the identification of cis and trans sequences controlling SUMOylation. Furthermore, an integrative analysis of known and putative SUMO substrates illustrates an updated landscape of several SUMO-regulated events. The strategies and analysis presented here should contribute to the understanding of SUMO controlled functions and provide rational approach to identify biomarkers or choose possible targets for intervention in processes where SUMOylation plays a critical role. PMID- 22811917 TI - Radiotherapy for metastatic merkel cell carcinoma: a review of the literature. AB - Introduction. Merkel cell carcinoma is a rare form of non-melanoma skin cancer of neuroendocrine origin. Optimal management of patients is controversial and the role of radiotherapy is unclear. Purpose. The purpose of this study was to review the efficacy of RT in the treatment of both local and distant metastatic disease from MCC. Methods. A literature search was conducted in MEDLINE (1946-January Week 1 2012) and Embase (1980-2012 Week 2). Articles of interest analyze the efficacy of radiotherapy for treatment of metastatic MCC and did not exclude case reports. Results. All articles except one focusing on the role of radiotherapy were of retrospective origin or case series. Significant limitations applied in all studies due to limited sample sizes and the retrospective nature of these studies. Radiotherapy improves locoregional control in the adjuvant setting, and many series suggest an improvement in overall survival. In cases where surgery is not possible, definitive radiotherapy may be an as-efficacious alternative. The radiosensitive nature of MCC coupled with existing reports suggests that treatment via current protocols for other primary tumors is adequate. Conclusion. Further studies should be conducted prospectively to clarify the true role of radiotherapy in metastatic MCC. PMID- 22811918 TI - The janus face of lipids in human breast cancer: how polyunsaturated Fatty acids affect tumor cell hallmarks. AB - For several years, lipids and especially n - 3 and n - 6 polyunsaturated fatty acids (PUFAs) receive much attention in human health. Epidemiological studies tend to correlate a PUFA-rich diet with a reduced incidence of cancer, including breast cancer. However, the molecular and cellular mechanisms supporting the effect of PUFAs in breast cancer cells remain relatively unknown. Here, we review some recent progress in understanding the impact that PUFA may have on breast cancer cell proliferation, apoptosis, migration, and invasion. While most of the results obtained with docosahexaenoic acid and/or eicosapentaenoic acid show a decrease of tumor cell proliferation and/or aggressivity, there is some evidence that other lipids, which accumulate in breast cancer tissues, such as arachidonic acid may have opposite effects. Finally, lipids and especially PUFAs appear as potential adjuvants to conventional cancer therapy. PMID- 22811920 TI - Acute Liver Failure Caused by Amanita phalloides Poisoning. AB - Mushroom poisoning is a relatively rare cause of acute liver failure (ALF). The present paper analyzes the pathogenesis, clinical features, prognostic indicators, and therapeutic strategies of ALF secondary to ingestion of Amanita phalloides, which represents the most common and deadly cause of mushroom poisoning. Liver damage from Amanita phalloides is related to the amanitins, powerful toxins that inhibit RNA polymerase II resulting in a deficient protein synthesis and cell necrosis. After an asymptomatic lag phase, the clinical picture is characterized by gastrointestinal symptoms, followed by the liver and kidney involvement. Amatoxin poisoning may progress into ALF and eventually death if liver transplantation is not performed. The mortality rate after Amanita phalloides poisoning ranges from 10 to 20%. The management of amatoxin poisoning consists of preliminary medical care, supportive measures, detoxification therapies, and orthotopic liver transplantation. The clinical efficacy of any modality of treatment is difficult to demonstrate since randomized, controlled clinical trials have not been reported. The use of extracorporeal liver assist devices as well as auxiliary liver transplantation may represent additional therapeutic options. PMID- 22811919 TI - Improving survival in decompensated cirrhosis. AB - Mortality in cirrhosis is consequent of decompensation, only treatment being timely liver transplantation. Organ allocation is prioritized for the sickest patients based on Model for End Stage Liver Disease (MELD) score. In order to improve survival in patients with high MELD score it is imperative to preserve them in suitable condition till transplantation. Here we examine means to prolong life in high MELD score patients till a suitable liver is available. We specially emphasize protection of airways by avoidance of sedatives, avoidance of Bilevel Positive Airway Pressure, elective intubation in grade III or higher encephalopathy, maintaining a low threshold for intubation with lesser grades of encephalopathy when undergoing upper endoscopy or colonoscopy as pre transplant evaluation or transferring patient to a transplant center. Consider post-pyloric tube feeding in encephalopathy to maintain muscle mass and minimize risk of aspiration. In non intubated and well controlled encephalopathy, frequent physical mobility by active and passive exercises are recommended. When renal replacement therapy is needed, night-time Continuous Veno-Venous Hemodialysis may be useful in keeping the daytime free for mobility. Sparing and judicious use of steroids needs to be borne in mind in treatment of ARDS and acute hepatitis from alcohol or autoimmune process. PMID- 22811922 TI - The Use of Epoetin-alpha in Revision Knee Arthroplasty. AB - Introduction. To evaluate the efficacy of epoetin-alpha prior to revision total knee arthroplasty, we hypothesized that epoetin-alpha will reduce blood transfusion. Methods. Eighty-one patients were compared in this retrospective review; twenty-eight patients received our dosing regimen. All patients were mildly anemic. Epoetin-alpha to control (1 : 2) patient matching occurred so that one of two attending surgeons, gender, BMI, complexity of surgery, ASA score, and age were similar between groups. The clinical triggers for blood transfusion during or after the procedure were determined based on peri- and postoperative hemoglobin levels, ASA score, and/or clinical symptoms consistent with anemia. Blood salvage was not used. Results. Blood transfusion and length of stay were lower in the study group. None of the patients who received epoetin-alpha underwent transfusion. Hemoglobin increased from 11.97 to 13.8, preoperatively. Hemoglobin at day of surgery and time of discharge were higher. Gender, BMI, ASA score, total and hidden blood losses, calculated blood loss, preop PLT, PT, PTT, and INR were similar between groups. One Epogen patient had an uncomplicated DVT (3.6%). Conclusions. Epoetin-alpha may have a role in the mildly anemic revision knee patient. It may also decrease patient length of stay allowing for earlier readiness to resume normal activities and/or meet short-term milestones. A randomized study to evaluate the direct and indirect costs of such a treatment methodology in the mildly anemic revision patient may be warranted. PMID- 22811921 TI - Regulation of signal transduction and role of platelets in liver regeneration. AB - Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor kappaB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described. PMID- 22811923 TI - Comparison of the tendon damage caused by four different anchor systems used in transtendon rotator cuff repair. AB - Objectives. The objective of this study was to compare the damage to the rotator cuff tendons caused by four different anchor systems. Methods. 20 cadaveric human shoulder joints were used for transtendon insertion of four anchor systems. The Healix Peek, Fastin RC, Bio-Corkscrew Suture, and Healix Transtend anchors were inserted through the tendons using standard transtendon procedures. The areas of tendon damage were measured. Results. The areas of tendon damage (mean +/- standard deviation, n = 7) were 29.1 +/- 4.3 mm(2) for the Healix Peek anchor, 20.4 +/- 2.3 mm(2) for the Fastin RC anchor, 23.4 +/- 1.2 mm(2) for the Bio Corkscrew Suture anchor, 13.7 +/- 3.2 mm(2) for the Healix Transtend anchor inserted directly, and 9.1 +/- 2.1 mm(2) for the Healix Transtend anchor inserted through the Percannula system (P < 0.001 or P < 0.001, compared to other anchors). Conclusions. In a cadaver transtendon rotator cuff repair model, smaller anchors caused less damage to the tendon tissues. The Healix Transtend implant system caused the least damage to the tendon tissues. Our findings suggest that smaller anchors should be considered when performing transtendon procedures to repair partial rotator cuff tears. PMID- 22811924 TI - Comparison of the anterior limit of the dentition in patients treated with self ligating straight-wire, conventional straight-wire and standard edgewise appliances. AB - THE AIM OF THIS STUDY WAS TO IDENTIFY AND COMPARE ANY DIFFERENCES IN THE POSITION OF THE ANTERIOR LIMIT OF THE DENTITION PROVOKED BY THREE DIFFERENT TYPES OF ORTHODONTIC MECHANICS: traditional edgewise, straightwire and self-ligating. A sample of 54 patients (selected from a group of 289 patients) possessed a range of Little's Irregularity Index values for the upper and lower dental arches between a minimum of 6.5 and a maximum of 13.5 at T0, and corresponding final values no greater than 2 and hence of minimal irregularity. The 54 patients were subdivided into three groups according to the type of brackets used in their treatment: Group 1 was composed of 24 patients treated using the self-ligating technique, Group 2 of 15 patients treated using a conventional straight-wire technique (Roth) and Group 3 of 15 patients treated using the standard edgewise technique. Cephalometric tracings were performed on laterolateral teleradiography. Group 1 value was found to be nonsignificant, whereas significant labial inclination was noted in Groups 2 and 3 (P < 0.05). A significant labial inclination of the upper incisors was also evidenced in all three sample groups. PMID- 22811925 TI - HPV Type Distribution and Cervical Cytology among HIV-Positive Tanzanian and South African Women. AB - Background. There are limited data on high-risk human papillomavirus (hr-HPV) genotypes among HIV-positive women in Africa, and little is known about their relationship with cervical cytology in these populations. Methods. We conducted a cross-sectional study among 194 HIV-positive women (143 from Tanzania, and 51 from South Africa) to evaluate HPV genotypes among HIV-positive women with normal and abnormal cytology. Cervical samples were genotyped for HPV types, and slides were evaluated for atypical squamous cell changes according to the Bethesda classification system. Results. Prevalence of high grade squamous intraepithelial dysplasia (HSIL) was 9%. Overall, more than half (56%) of women were infected with an hr-HPV type; 94% of women with HSIL (n = 16), 90% of women with LSIL (n = 35), and 42% of women within normal limits (WNL) (n = 58) tested positive for hr HPV. Overall, the most prevalent hr-HPV subtypes were HPV16 (26%) and HPV52 (30%). Regional differences in the prevalence of HPV18 and HPV35 were found. Conclusion. Regional differences in HPV genotypes among African women warrant the need to consider different monitoring programmes for cervical preneoplasia. HPV based screening tests for cervical preneoplasia would be highly inefficient unless coupled with cytology screening of the HPV-positive sample, especially in HIV-positive women. PMID- 22811926 TI - Urinary tract infection prophylaxis in children with neurogenic bladder with cranberry capsules: randomized controlled trial. AB - Objectives. The aim of this randomized controlled prospective study is to evaluate the efficacy of cranberry capsules for prevention of UTI in children with neurogenic bladder caused by myelomeningocele. Patients and Methods. To be eligible for this study, patients had to be diagnosed as neurogenic bladder caused by myelomeningocele, evaluated urodynamically, followed up with clean intermittent catheterization and anticholinergic drugs. Intervention. Six months of treatment with placebo; after a week of wash-out period treatment of cranberry extract tablets (1 capsule/day) for an additional 6 months. Randomization was performed sequentially. Patients and care givers were blinded to drug assignment. Main outcome measure was infection rate. Group comparisons were performed with Wilcoxon test. Results. The study population included 20 (F/M: 13/7) patients with neurogenic bladder with the mean age of 7.25 +/- 3.49 (4, 18) years. The median UTI rate was 0.5/year during placebo usage whereas 0/year during cranberry capsule usage. Decrease in infection rate was significant with cranberry capsule usage (P = 0.012). Decrease in the percentage of the pyuria was also recorded as significant (P = 0.000). Any adverse events or side effects were not recorded. Conclusion. We concluded that cranberry capsules could be an encouraging option for the prevention of recurrent UTI in children with neurogenic bladder caused by myelomeningocele. PMID- 22811927 TI - Cochlear Dysfunction in Children following Cardiac Bypass Surgery. AB - Background. Sensorineural hearing loss after procedures including extracorporeal circulation and hypothermia is greater than general population. Mild hypothermia has a protective role on cochlea; however, deep hypothermia may result in cochlear injury. This research aimed at assessing auditory function in children after open heart surgery in relation to different hypothermic techniques. Subjects and Methods. Forty children with acyanotic heart diseases who underwent open heart surgery were included: group I: twenty patients subjected to mild hypothermia (33 degrees to 37 degrees C), group II: twenty patients subjected to moderate hypothermia (28 degrees to 32 degrees C). Audiological assessment included basic evaluation and otoacoustic emissions. Results. Both groups had distortion-product otoacoustic emissions (DPOAEs) amplitude >3 dB SPL at all frequencies. However, group II showed lower amplitude at overall and at high frequencies (4.416-8.837 KHz) than group I. Transient evoked otoacoustic emissions (TEOAEs) showed partial pass in three patients of group I (15%) and in 15 patients of group II (75%). Moreover, group II showed statistical significant reduction in overall TEOAEs amplitude as well as at high frequencies (2-4 KHz). Conclusions. Patients exposed to moderate hypothermic technique had subtle cochlear dysfunction. Otoacoustic emissions should be used for early detection of subtle cochlear dysfunction in operated cardiac children. PMID- 22811928 TI - Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients. AB - Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are "time to progression to next disease level" and "incidence of adverse drug events before disease progression." Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies. PMID- 22811929 TI - Effects of prickly pear dried leaves, artichoke leaves, turmeric and garlic extracts, and their combinations on preventing dyslipidemia in rats. AB - The successful use of herbal combinations in managing diseases or conditions over a single herb has lead us to evaluate the anti-dyslipidemic properties of the combination of the artichoke leaves extract, turmeric extract, prickly pear dried leaves (PPL) and garlic extract versus each one alone in two different hyperlipidemic animal models. A two-week treatment of each of the natural extracts, combination 1 (artichoke, turmeric and PPL) or combination 2 (artichoke, turmeric, PPL and garlic) prior to a single intraperitoneal injection of Pluronic F-127 resulted in decreasing significantly serum LDL levels by garlic and PPL extracts and serum LDL/HDL ratios by turmeric, PPL, combination 1 and 2. In a 10-day high fat diet model, only the combination 1 and 2 lowered serum cholesterol, LDL by 8-12%, decreased significantly triglycerides, LDL/HDL ratio; and increased significantly HDL (P < 0.0001). However, a long term treatment of each natural product for 7 weeks resulted in decreasing significantly serum LDL levels and LDL/HDL ratio (P < 0.05-0.0001). Furthermore, only artichoke and PPL inhibited significantly HMG-CoA reductase activity (P < 0.05). In conclusion, short term, as well as long term, treatment using the combination of artichoke, turmeric, PPL and garlic extract prevents dyslipidemia; partially through inhibiting HMG-CoA reductase. PMID- 22811930 TI - Nephroprotective effect of ursolic Acid in a murine model of gentamicin-induced renal damage. AB - The present study evaluates the nephroprotective effects of ursolic acid in a murine model of gentamicin induced renal damage. Wistar albino rats of either sex, weighing 150-200 g were divided into 5 groups; normal saline, gentamicin 80 mg/kg, intraperitoneally for 8 days, ursolic acid at 2, 5, and 10 mg/kg, per oral for 8 days, ursolic acid administered 3 days prior and concurrently with gentamicin for 5 days. Blood urea, serum creatinine, uric acid and blood urea nitrogen analyses and microscopic examination of kidney were performed. Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum urea, serum uric acid, serum creatinine and blood urea nitrogen (162.33 +/- 9.92 mg/dL, 3.13 +/- 0.12 mg/dL, 6.85 +/- 0.35 mg/dL and 75.86 +/- 4.64 mg/dL; resp.) when compared to the saline treated groups. Co-administration of ursolic acid with gentamicin decreased the rise in these parameters in a dose dependent manner. Histopathological analysis revealed epithelial loss with intense granular degeneration in gentamicin treated rats, whereas ursolic acid mitigated the severity of gentamicin-induced renal damage. To conclude, our data suggest that ursolic acid exhibits renoprotective effect in gentamicin induced renal damage and further studies on its mechanis of action are warranted. PMID- 22811931 TI - Biomarkers in Alzheimer's disease: a review. AB - Alzheimer's disease is the most common form of dementia affecting millions of individuals worldwide. It is currently diagnosed only via clinical assessments and confirmed by postmortem brain pathology. The development of validated biomarkers for Alzheimer's disease is essential to improve diagnosis and accelerate the development of new therapies. Biochemical and neuroimaging markers could facilitate diagnosis, predict AD progression from a pre-AD state of mild cognitive impairment (MCI), and be used to monitor efficacies of disease modifying therapies. Cerebrospinal fluid (CSF) levels of Abeta40, Abeta42, total tau, and phosphorylated tau have diagnostic values in AD. Measurements of the above CSF markers in combination are useful in predicting the risk of progression from MCI to AD. New potential biomarkers are emerging, and CSF or plasma marker profiles may eventually become part of the clinician's toolkit for accurate AD diagnosis and management. These biomarkers along with clinical assessment, neuropsychological testing, and neuroimaging could achieve a much higher diagnostic accuracy for AD and related disorders in the future. PMID- 22811932 TI - Biofeedback Intervention for Stress and Anxiety among Nursing Students: A Randomized Controlled Trial. AB - Purpose. It has been well documented that nursing students across the world experience stress and anxiety throughout their education and training. The purpose of this randomized controlled study is to investigate the impact of biofeedback intervention program on nursing students' levels of stress and anxiety during their first clinical training. Methods. Participants consisted of 60 second-year baccalaureate nursing students. The 30 participants in the biofeedback group received training on how to use the biofeedback device to assist in stress and anxiety management for 5 weeks while the 30 in the control group did not receive any training. Findings. Results indicated that the biofeedback group was able to maintain the stress level while the control group had a significant increase in the stress level over the 5-week period of clinical training. Additionally, the biofeedback group had a significant reduction in anxiety, while the control group had a moderate increase in anxiety. Conclusions. The better the nursing students can manage their stress and anxiety, the more successful they can be in their clinical training. Ultimately, the more psychologically healthy the nursing students are, the more likely they will flourish and graduate to become productive and contributing members of the nursing profession. PMID- 22811933 TI - The Patient's View of Nursing Care after Hip Fracture. AB - Background. The pathway for patients with a hip fracture described in this study is a fast track. Many studies have focused on prevention of various complications but, so far, the patient's view of nursing care has not been highlighted. Aim. The aim of the study is to illuminate the patient's view on nursing care when treated for a hip fracture. Method. Ten patients were interviewed. A content analysis design was conducted. Findings. From the analysis, four main categories emerged: waiting times; pain/pain relief and mobilisation; attitude/information and sense of security; complications. Conclusion. Patients generally felt satisfied with the nursing provided. The staff created a feeling of security and showed interest and empathy for the patient. However, patients experienced a stressful waiting for surgery, and patients who developed confusion waited more than 24 hours for surgery. Therefore, waiting time must be decreased. Furthermore, patients' descriptions of a variety of pain problem show, for example, that good collaboration between the nurse and physiotherapist is critical for achieving good pain relief before mobilisation. Nursing staff need to be attentive and should elicit the patient's feelings through patient-focused communication in order to relieve anxiety about going home. PMID- 22811935 TI - Novel m.15434C>A (p.230L>I) Mitochondrial Cytb Gene Missense Mutation Associated with Dilated Cardiomyopathy. AB - Background. Previously it has been shown that various types of hypertrophic and dilative cardiomyopathy (hCMP, dCMP) can be attributed to disturbed mitochondrial oxidative energy metabolism. Several studies described mutations in mitochondrial DNA-located genes encoding for subunits of respiratory chain complexes, including the cytochrome b gene (MT-CYB), causing CMPs. Methods and Results. In the present study the MT-CYB gene was analysed in 30 patients with hCMP, 40 patients with dCMP, and 50 controls for alterations. Altogether, 27 MT-CYB variants were detected. Twenty-four of them were single nucleotide polymorphisms defining common haplogroups. The variant m.15434C>A was found in a single patient with severe dCMP and assessed as novel mutation, since it was not found in healthy controls or available data sets, and was nonhaplogroup associated with Phylotree. This variant altered an amino acid (L230I) with a high interspecific amino acid conservation index (CI = 97.7%) indicative of the functional importance of the residue. Conclusions. Though the L230I mutation seems to play a causative role for dCMP, prospective studies on yeast or transgenic mice models with defined mutation are warranted to study the pathogenetic impact of this mutation. PMID- 22811934 TI - M-CHAT Mexican Version Validity and Reliability and Some Cultural Considerations. AB - The Modified Checklist for Autism in Toddlers (M-CHAT) questionnaire is a brief measure available in Spanish which needs to be validated for the Mexican population. Parents of children from (1) community with typical development (TD) and (2) psychiatric outpatient unit completed the CBCL/1.5-5 and the Mexican/MM CHAT-version. The study sample consisted of 456 children (age M = 4.46, SD = 1.12), 74.34% TD children and 26.65% with Autism Spectrum Disorders (ASD). The MM CHAT mean score for failed key items was higher for the ASD group compared with the TD group. Internal consistency for the Mexican/M-CHAT version was .76 for total score and .70 for the 6 critical items. Correlations between the MM-CHAT and the CBCL/1.5: PDD and Withdrawn subscales and with ADI-R dimensions: B non verbal) and A were high, and were moderate with ADI-R dimensions B1 (verbal) and C The failure rate of the MM-CHAT between the groups did not reproduce all the critical items found in other studies. Although the instrument has good psychometric properties and can be used for screening purposes in primary settings or busy specialized psychiatric clinics, these results support evidence for cultural differences in item responses, making it difficult to compare M-CHAT results internationally. PMID- 22811936 TI - Is leukocytosis a predictor for recurrence of ischemic events after coronary artery bypass graft surgery? A cohort study. AB - Objective. Studies have shown that inflammation plays an important role in pathogenesis of coronary artery disease. The present study was designed to evaluate the role of high WBC count before CABG in predicting the risk of ischemic events after CABG. Methods and Results. This prospective study was carried out on 380 patients who underwent CABG surgery. Ninety seven patients (25.5%) had recurrent ischemic event. Mean WBC count before CABG surgery in patients with recurrent ischemic event was 7267 mic/lit +/- 1863, which was significantly higher than the others, with a mean WBC count of 6721 mic/lit +/- 1734 (P = 0.011). Patients with a WBC count more than 6000 mic/lit were at the highest risk for recurrent ischemic event (OR = 2.11, 95% CI = 1.18-3.44, P = 0.009). After adjustment for age, sex, family history, smoking, hyperlipidemia, Logestic Euro score, post opretive enzyme release (CK.mb), arterial graft and BMI, the relationship between the group with WBC count higher than 6000 mic/lit and recurrent of ischemic event remained significant (OR = 2.25, 95% CI = 1.2 to 4, P = 0.005). Conclusions. High WBC count before CABG surgery is an independent risk factor for ischemic events one year after the surgery. PMID- 22811937 TI - Factors related to long-term survival in patients affected by well-differentiated endocrine tumors of the pancreas. AB - Aim. To identify factors related to survival in patients affected by well differentiated PETs (benign, uncertain behavior, and carcinoma) who underwent R0 pancreatic resection. Methods. Retrospective study of 74 consecutive patients followed up from January 1980 to December 2011. Prognostic factors were sex, age, type of tumor, presence of symptoms, type of surgical procedure, size of tumor, lymph nodes status, WHO classification, and TNM stage. Overall survival was evaluated using the Kaplan-Meier method. Cox regression analyses were used to identify the factors associated with prognosis in univariate and multivariate analysis. Results. The mean follow-up of all the patients was 106 +/- 89 months. The 5-10-year long-term survival was 90.9% and 79.1%, respectively. At univariate analysis, patient age <55 years was significantly related to a better long-term survival compared to patients age >=55 years (307 +/- 15 months versus 192 +/- 25 months; P = 0.010). Multivariate analysis showed that female gender (P = 0.006), patients without comorbidities (P = 0.033), and patients affected by well differentiated benign pancreatic endocrine tumors (P = 0.008 and P = 0.002 in relation to tumors with uncertain behavior and carcinomas, resp.) were factors significantly related to a better long-term survival. Conclusions. Patients factors were strongly related to a better long-term survival in patients observed. WHO classification is a very useful prognostic tool for well differentiated PETs. PMID- 22811938 TI - Intracellular Ca2+ stores and Ca2+ influx are both required for BDNF to rapidly increase quantal vesicular transmitter release. AB - Brain-derived neurotrophic factor (BDNF) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity. One potential mechanism to initiate BDNF actions is through its modulation of quantal presynaptic transmitter release. In response to local BDNF application to CA1 pyramidal neurons, the frequency of miniature excitatory postsynaptic currents (mEPSC) increased significantly within 30 seconds; mEPSC amplitude and kinetics were unchanged. This effect was mediated via TrkB receptor activation and required both full intracellular Ca(2+) stores as well as extracellular Ca(2+). Consistent with a role of Ca(2+)-permeable plasma membrane channels of the TRPC family, the inhibitor SKF96365 prevented the BDNF-induced increase in mEPSC frequency. Furthermore, labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post-BDNF destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mEPSCs reflects vesicular fusion events. Indeed, BDNF application to CA3-CA1 synapses in TTX rapidly enhanced FM1-43 or FM2-10 destaining with a time course that paralleled the phase of increased mEPSC frequency. We conclude that BDNF increases mEPSC frequency by boosting vesicular fusion through a presynaptic, Ca(2+)-dependent mechanism involving TrkB receptors, Ca(2+) stores, and TRPC channels. PMID- 22811940 TI - In Vitro and In Vivo Evaluation of pH-Sensitive Hydrogels of Carboxymethyl Chitosan for Intestinal Delivery of Theophylline. AB - Chitosan is a natural polymer which has limited solubility. Chitosan gets solubilized at acidic pH but is insoluble at basic pH. In the present study, carboxymethyl chitosan (CMC) was prepared which shows high swelling in basic pH and thus can delay the drug release and can act as matrix for extended release formulation. CMC was characterized by FTIR and NMR. pH-sensitive hydrogels of theophylline were formulated using CMC and carbopol 934. Hydrogels were evaluated for swelling, drug content in vitro drug release studies, and in vivo studies on rabbit. The swelling studies have shown little swelling in acidic pH 432% at the end of two hours and 1631% in basic pH at the end of 12 hours. The release profile of the formulation I containing CMC and carbopol in 1 : 1 ratio showed sustained release. In vivo studies showed that the release of theophylline from the prepared hydrogel formulation (Test) exhibit better prolonged action when compared to (standard) marketed sustained release formulation. The studies showed that the pH-sensitive hydrogel of CMC can be used for extended release of theophylline in intestine and can be highly useful in treating symptoms of nocturnal asthma. PMID- 22811941 TI - Mis- or missed diagnosis: a series of four cases. AB - Diagnosis forms the backbone of treatment planning. Accurate diagnosis is essential to initiate the appropriate treatment at the apt time. Diagnosis involves eliciting the signs and symptoms of the patient and their accurate interpretations. The subtle signs that can go unnoticed lead to misdiagnosis and subsequent agony to the patient. Alertness on part of the clinician is important to avoid this error. Reported in this paper are four cases that were wrongly diagnosed either due to lack of clinical experience or due to omission of careful clinical, radiographic, and histopathological examinations. PMID- 22811942 TI - Multiple gastric metastases from ovarian carcinoma diagnosed by endoscopic ultrasound with fine needle aspiration. AB - Metastasis to the stomach from nongastric tumors is a rare event. We present a case of ovarian cancer metastasis to the gastric wall that presented as multiple subepithelial gastric lesions. A 55-year-old female with known stage III b serous ovarian cancer was admitted to the hospital with melena and anemia. A 1.5 to 2 cm subepithelial mass with superficial overlying erosion in the antrum was seen in Esophagogastroduodenoscopy (EGD). Initial endoscopic mucosal biopsies were normal. An Endoscopic Ultrasound (EUS) was performed, which revealed two subepithelial lesions with the typical appearance of a gastrointestinal stromal tumor. Fine needle aspiration (FNA) of both masses revealed papillary adenocarcinoma from an ovarian papillary serous adenocarcinoma. This is the first reported case of multiple gastric metastatic lesions from ovarian cancer diagnosed by EUS FNA. PMID- 22811939 TI - Pathological plasticity in fragile X syndrome. AB - Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease. PMID- 22811943 TI - Gravid uterus in an umbilical hernia. AB - Umbilical hernias large enough to contain a gravid uterus are rare. We report a case of a woman with prolapse of a gravid uterus through a previously repaired umbilical hernia. Our plans for elective surgery with caesarean section and hernia repair were foiled by poor compliance. The hernia was repaired during an emergency caesarean section. We provide details of her management and briefly review the literature on umbilical hernias and pregnancy. Surgical management offers an opportunity for hernia repair and can ensure a safe delivery for the mother and child. PMID- 22811944 TI - Tetralogy of fallot associated with dysplastic kidneys, cloacal anomalies, and female pseudohermaphroditism: a systemic anomaly of septation? AB - A 20-week fetus was diagnosed with tetralogy of Fallot and multicystic kidneys. The postmortem study showed missing mullerian structures with small streak ovaries, external male genitalia, and an abnormal cloacal septation (imperforate anus with a sigmoid colon opening in the bladder). As the observed anomalies were related with septation, a mechanism related with the activation of specific growth factors, we discuss the possibility of a disorder in the function of the bone morphogenetic proteins as a common cause for the widespread anomalies found in this fetus. PMID- 22811945 TI - Histopathological Findings after Descemet's Stripping Automated Endothelial Keratoplasty for the Management of Descemet's Membrane Breaks Secondary to Obstetrical Forceps Injury. AB - Case of a 39 y/o male patient that presented due to decreased vision and pain in the left eye secondary to corneal edema related to vertical Descemet's membrane breaks. The patient's past medical history was remarkable for a complicated vaginal delivery with the use of obstetrical forceps and presumed obstetrical forceps corneal injury. Herein, we demonstrate for the first time the use of descemet's stripping automated endothelial keratoplasty (DSAEK) in the management of this complication and for the first time show histologically the area of prior descemet's membrane break in the submitted stripped descemet's membrane. PMID- 22811946 TI - Unusual cause of orocutaneous fistula in the neck. AB - A case of orocutaneous fistula secondary to submandibular sialolithiasis, which was masquerading clinically as branchial fistula is presented. This case highlights the importance of conducting fistulogram in the evaluation of discharging lesions in the neck. PMID- 22811947 TI - Relative Preservation of Advanced Activities in Daily Living among Patients with Mild-to-Moderate Dementia in the Community and Overview of Support Provided by Family Caregivers. AB - Little is known about the extent to which advanced activities of daily living among patients with dementia are preserved and how family caregivers of these patients support them in the community. In this cross-sectional assessment of pairs of patients with dementia and their family caregivers, we evaluated basic, instrumental, and advanced activities of daily living by comparing past and present status observed by caregivers with subjective estimations by patients with dementia. We also asked about ways in which support was provided by family caregivers. Thirty-nine pairs of patients with dementia and caregivers who presented to our memory clinic were interviewed. The mean age of patients with dementia was 75.3 +/- 7.0 years, and Mini-Mental State Examination scores were 22.3 +/- 3.4. We found relative preservation of advanced activities of daily living compared with instrumental activities of daily living. Caregivers provided instrumental, informational, and reminding support to patients with dementia. These findings may reinforce the concept of person-centered support of patients with dementia in the community. PMID- 22811948 TI - Alternative splicing: a potential source of functional innovation in the eukaryotic genome. AB - Alternative splicing (AS) is a common posttranscriptional process in eukaryotic organisms, by which multiple distinct functional transcripts are produced from a single gene. The release of the human genome draft revealed a much smaller number of genes than anticipated. Because of its potential role in expanding protein diversity, interest in alternative splicing has been increasing over the last decade. Although recent studies have shown that 94% human multiexon genes undergo AS, evolution of AS and thus its potential role in functional innovation in eukaryotic genomes remain largely unexplored. Here we review available evidence regarding the evolution of AS prevalence and functional role. In addition we stress the need to correct for the strong effect of transcript coverage in AS detection and set out a strategy to ultimately elucidate the extent of the role of AS in functional innovation on a genomic scale. PMID- 22811949 TI - Novel genes from formation to function. AB - The study of the evolution of novel genes generally focuses on the formation of new coding sequences. However, equally important in the evolution of novel functional genes are the formation of regulatory regions that allow the expression of the genes and the effects of the new genes in the organism as well. Herein, we discuss the current knowledge on the evolution of novel functional genes, and we examine in more detail the youngest genes discovered. We examine the existing data on a very recent and rapidly evolving cluster of duplicated genes, the Sdic gene cluster. This cluster of genes is an excellent model for the evolution of novel genes, as it is very recent and may still be in the process of evolving. PMID- 22811950 TI - The role of S100A12 as a systemic marker of inflammation. AB - S100A12 is a member of the S100 family of calcium-binding proteins with important extracellular activities. In recent years, investigators across a number of fields have delineated the patterns of S100A12 expression in a variety of conditions. These data suggest that S100A12 can be used as a valuable serum inflammatory marker. PMID- 22811951 TI - Bone mineral density of adolescent female tennis players and nontennis players. AB - The purpose of this study was to determine differences in bone mineral density (BMD) among adolescent female tennis players (TPs) and nontennis players (NTPs) and to assess body composition as a predictor variable of BMD. Nineteen female TPs and 19 female NTPs, ages 14 to 18 years, participated in this study. Lumbar spine, total hip, femoral neck, forearms BMD, and body composition were assessed using dual-energy X-ray absorptiometry (DXA). Lumbar spine and total hip BMD measurements for TP were greater than NTP. However, these differences were not statistically significant (P = 0.37 and 0.12, resp.). TP had significantly greater femoral neck BMD than NTPs (P = 0.02). This difference might play an important role in preventing osteoporosis and decreasing the risk of fractures at the hip later in life. PMID- 22811952 TI - Thrombocytopenia as an indicator of malaria in adult population. AB - Objectives. To evaluate the predictive value of thrombocytopenia in malaria. Patients and Methods. It was a prospective observational study on all febrile patients with thrombocytopenia presenting to the Medical Unit of Hayat Abad Medical Complex during November 2008 to November 2010. Results. Of the total of 228 patients with fever and thrombocytopenia, 121 patients (53%) proved to be suffering from malaria. Of them 82 patients (68%) had falciparum malaria while 39 patients (32%) had vivax infection. Of these 121 patients, platelet counts ranged between 25,000 and 150,000/dL with a mean value of 101,000/dL (SD +/- 47, 500) and a median of 75,000/dL. Of the 107 patients who were not suffering from malaria, the counts ranged between 10,000 and 150,000/dL with a mean value of 58,000/dL (SD +/- 54, 000) and median of 50,000/dL. Conclusions. The presence of thrombocytopenia may be a predictor of malaria in adult population. PMID- 22811953 TI - Multi-field-of-view strategy for image-based outcome prediction of multi parametric estrogen receptor-positive breast cancer histopathology: Comparison to Oncotype DX. AB - In this paper, we attempt to quantify the prognostic information embedded in multi-parametric histologic biopsy images to predict disease aggressiveness in estrogen receptor-positive (ER+) breast cancers (BCa). The novel methodological contribution is in the use of a multi-field-of-view (multi-FOV) framework for integrating image-based information from differently stained histopathology slides. The multi-FOV approach involves a fixed image resolution while simultaneously integrating image descriptors from many FOVs corresponding to different sizes. For each study, the corresponding risk score (high scores reflecting aggressive disease and vice versa), predicted by a molecular assay (Oncotype DX), is available and serves as the surrogate ground truth for long term patient outcome. Using the risk scores, a trained classifier is used to identify disease aggressiveness for each FOV size. The predictions for each FOV are then combined to yield the final prediction of disease aggressiveness (good, intermediate, or poor outcome). Independent multi-FOV classifiers are constructed for (1) 50 image features describing the spatial arrangement of cancer nuclei (via Voronoi diagram, Delaunay triangulation, and minimum spanning tree graphs) in H and E stained histopathology and (2) one image feature describing the vascular density in CD34 IHC stained histopathology. In a cohort of 29 patients, the multi-FOV classifiers obtained by combining information from the H and E and CD34 IHC stained channels were able to distinguish low- and high-risk patients with an accuracy of 0.91 +/- 0.02 and a positive predictive value of 0.94 +/- 0.10, suggesting that a purely image-based assay could potentially replace more expensive molecular assays for making disease prognostic predictions. PMID- 22811954 TI - Biomechanical model-based deformable registration of MRI and histopathology for clinical prostatectomy. AB - A biomechanical model-based deformable image registration incorporating specimen specific changes in material properties is optimized and evaluated for correlating histology of clinical prostatectomy specimens with in vivo MRI. In this methodology, a three-step registration based on biomechanics calculates the transformations between histology and fixed, fixed and fresh, and fresh and in vivo states. A heterogeneous linear elastic material model is constructed based on magnetic resonance elastography (MRE) results. The ex vivo tissue MRE data provide specimen-specific information for the fresh and fixed tissue to account for the changes due to fixation. The accuracy of the algorithm was quantified by calculating the target registration error (TRE) by identifying naturally occurring anatomical points within the prostate in each image. TRE were improved with the deformable registration algorithm compared to rigid registration alone. The qualitative assessment also showed a good alignment between histology and MRI after the proposed deformable registration. PMID- 22811955 TI - A comparison of sampling strategies for histological image analysis. AB - Histological image analysis methods often employ machine-learning classifiers in order to adapt to the huge variability of histological images. To train these classifiers, the user must select samples of the relevant image objects. In the field of active learning, there has been much research on sampling strategies that exploit the uncertainty of the current classification in order to guide the user to maximally informative samples. Although these approaches have the potential to reduce the training effort and increase the classification accuracy, they are very rarely employed in practice. In this paper, we investigate the practical value of uncertainty sampling in the context of histological image analysis. To obtain practically meaningful results, we have devised an evaluation algorithm that simulates the way a human interacts with a user interface. The results show that uncertainty sampling outperforms common random or error sampling strategies by achieving more accurate classification results with a lower number of training images. PMID- 22811956 TI - Learning histopathological patterns. AB - AIMS: The aim was to demonstrate a method for automated image analysis of immunohistochemically stained tissue samples for extracting features that correlate with patient disease. We address the problem of quantifying tumor tissue and segmenting and counting cell nuclei. MATERIALS AND METHODS: Our method utilizes a flexible segmentation method based on sparse coding trained from representative image samples. Nuclei counting is based on a nucleus model that takes size, shape, and nucleus probability into account. Nuclei clustering and overlays are resolved using a gray-weighted distance transform. We obtain a probability measure for pixels belonging to a nucleus from our segmentation procedure. Experiments are carried out on two sets of immunohistochemically stained images - one set based on the estrogen receptor (ER) and the other on antigen KI-67. For the nuclei separation we have selected 207 ER image samples from 58 tissue micro array-cores corresponding to 58 patients and 136 KI-67 image samples also from 58 cores. The images are hand-annotated by marking the center position of each nucleus. For the ER data we have a total of 1006 nuclei and for the KI-67 we have 796 nuclei. Segmentation performance was evaluated in terms of missing nuclei, falsely detected nuclei, and multiple detections. The proposed method is compared to state-of-the-art Bayesian classification. STATISTICAL ANALYSIS USED: The performance of the proposed method and a state-of-the-art algorithm including variations thereof is compared using the Wilcoxon rank sum test. RESULTS: For both the ER experiment and the KI-67 experiment the proposed method exhibits lower error rates than the state-of-the-art method. Total error rates were 4.8 % and 7.7 % in the two experiments, corresponding to an average of 0.23 and 0.45 errors per image, respectively. The Wilcoxon rank sum tests show statistically significant improvements over the state-of-the-art method. CONCLUSIONS: We have demonstrated a method and obtained good performance compared to state-of-the-art nuclei separation. The segmentation procedure is simple, highly flexible, and we demonstrate how it, in addition to the nuclei separation, can perform precise segmentation of cancerous tissue. The complexity of the segmentation procedure is linear in the image size and the nuclei separation is linear in the number of nuclei. Additionally the method can be parallelized to obtain high-speed computations. PMID- 22811957 TI - Graphical processing unit implementation of an integrated shape-based active contour: Application to digital pathology. AB - Commodity graphics hardware has become a cost-effective parallel platform to solve m any general computational problems. In medical imaging and more so in digital pathology, segmentation of multiple structures on high-resolution images, is often a complex and computationally expensive task. Shape-based level set segmentation has recently emerged as a natural solution to segmenting overlapping and occluded objects. However the flexibility of the level set method has traditionally resulted in long computation times and therefore might have limited clinical utility. The processing times even for moderately sized images could run into several hours of computation time. Hence there is a clear need to accelerate these segmentations schemes. In this paper, we present a parallel implementation of a computationally heavy segmentation scheme on a graphical processing unit (GPU). The segmentation scheme incorporates level sets with shape priors to segment multiple overlapping nuclei from very large digital pathology images. We report a speedup of 19* compared to multithreaded C and MATLAB-based implementations of the same scheme, albeit with slight reduction in accuracy. Our GPU-based segmentation scheme was rigorously and quantitatively evaluated for the problem of nuclei segmentation and overlap resolution on digitized histopathology images corresponding to breast and prostate biopsy tissue specimens. PMID- 22811958 TI - Local isotropic phase symmetry measure for detection of beta cells and lymphocytes. AB - Diabetes can be associated with a reduction in functional beta cell mass, which must be restored if the disease is to be cured or progress is to be arrested. To study the cell count, it is also necessary to determine the number of nuclei within the insulin stained area. It can take a single experimentalist several months to complete a single study of this kind, results of which may still be quite subjective. In this paper, we propose a framework based on a novel measure of local symmetry for detection of cells. The local isotropic phase symmetry measure (LIPSyM) is designed to give high values at or near the cell centers. We demonstrate the effectiveness of our algorithm for detection of two types of specific cells in histology images, cells in mouse pancreatic sections and lymphocytes in human breast tissue. Experimental results for these two problems show that our algorithm performs better than human experts for the former problem, and outperforms the best reported results for the latter. PMID- 22811959 TI - Prostate cancer detection: Fusion of cytological and textural features. AB - A computer-assisted system for histological prostate cancer diagnosis can assist pathologists in two stages: (i) to locate cancer regions in a large digitized tissue biopsy, and (ii) to assign Gleason grades to the regions detected in stage 1. Most previous studies on this topic have primarily addressed the second stage by classifying the preselected tissue regions. In this paper, we address the first stage by presenting a cancer detection approach for the whole slide tissue image. We propose a novel method to extract a cytological feature, namely the presence of cancer nuclei (nuclei with prominent nucleoli) in the tissue, and apply this feature to detect the cancer regions. Additionally, conventional image texture features which have been widely used in the literature are also considered. The performance comparison among the proposed cytological textural feature combination method, the texture-based method and the cytological feature based method demonstrates the robustness of the extracted cytological feature. At a false positive rate of 6%, the proposed method is able to achieve a sensitivity of 78% on a dataset including six training images (each of which has approximately 4,000*7,000 pixels) and 1 1 whole-slide test images (each of which has approximately 5,000*23,000 pixels). All images are at 20X magnification. PMID- 22811960 TI - Automatic annotation of histopathological images using a latent topic model based on non-negative matrix factorization. AB - Histopathological images are an important resource for clinical diagnosis and biomedical research. From an image understanding point of view, the automatic annotation of these images is a challenging problem. This paper presents a new method for automatic histopathological image annotation based on three complementary strategies, first, a part-based image representation, called the bag of features, which takes advantage of the natural redundancy of histopathological images for capturing the fundamental patterns of biological structures, second, a latent topic model, based on non-negative matrix factorization, which captures the high-level visual patterns hidden in the image, and, third, a probabilistic annotation model that links visual appearance of morphological and architectural features associated to 10 histopathological image annotations. The method was evaluated using 1,604 annotated images of skin tissues, which included normal and pathological architectural and morphological features, obtaining a recall of 74% and a precision of 50%, which improved a baseline annotation method based on support vector machines in a 64% and 24%, respectively. PMID- 22811961 TI - A fully automated approach to prostate biopsy segmentation based on level-set and mean filtering. AB - With modern automated microscopes and digital cameras, pathologists no longer have to examine samples looking through microscope binoculars. Instead, the slide is digitized to an image, which can then be examined on a screen. This creates the possibility for computers to analyze the image. In this work, a fully automated approach to region of interest (ROI) segmentation in prostate biopsy images is proposed. This will allow the pathologists to focus on the most important areas of the image. The method proposed is based on level-set and mean filtering techniques for lumen centered expansion and cell density localization respectively. The novelty of the technique lies in the ability to detect complete ROIs, where a ROI is composed by the conjunction of three different structures, that is, lumen, cytoplasm, and cells, as well as regions with a high density of cells. The method is capable of dealing with full biopsies digitized at different magnifications. In this paper, results are shown with a set of 100 H and E slides, digitized at 5*, and ranging from 12 MB to 500 MB. The tests carried out show an average specificity above 99% across the board and average sensitivities of 95% and 80%, respectively, for the lumen centered expansion and cell density localization. The algorithms were also tested with images at 10* magnification (up to 1228 MB) obtaining similar results. PMID- 22811962 TI - Feasibility analysis of high resolution tissue image registration using 3-D synthetic data. AB - BACKGROUND: Registration of high-resolution tissue images is a critical step in the 3D analysis of protein expression. Because the distance between images (~4 5MUm thickness of a tissue section) is nearly the size of the objects of interest (~10-20MUm cancer cell nucleus), a given object is often not present in both of two adjacent images. Without consistent correspondence of objects between images, registration becomes a difficult task. This work assesses the feasibility of current registration techniques for such images. METHODS: We generated high resolution synthetic 3-D image data sets emulating the constraints in real data. We applied multiple registration methods to the synthetic image data sets and assessed the registration performance of three techniques (i.e., mutual information (MI), kernel density estimate (KDE) method [1], and principal component analysis (PCA)) at various slice thicknesses (with increments of 1MUm) in order to quantify the limitations of each method. RESULTS: Our analysis shows that PCA, when combined with the KDE method based on nuclei centers, aligns images corresponding to 5MUm thick sections with acceptable accuracy. We also note that registration error increases rapidly with increasing distance between images, and that the choice of feature points which are conserved between slices improves performance. CONCLUSIONS: We used simulation to help select appropriate features and methods for image registration by estimating best-case-scenario errors for given data constraints in histological images. The results of this study suggest that much of the difficulty of stained tissue registration can be reduced to the problem of accurately identifying feature points, such as the center of nuclei. PMID- 22811963 TI - Atlas-guided correction of brain histology distortion. AB - Histological tissue preparation stages (e.g., cutting, sectioning, etc.) often introduce tissue distortions that prevent a smooth 3D reconstruction from being built. In this paper, we propose a method to correct histology distortions by running a piecewise registration scheme. It takes the information of several consecutive slices in a neighborhood into account. In order to achieve an accurate anatomic presentation, we run the method iteratively with the assistance from a pre-segmented brain atlas. The registration parameters are optimized to accommodate different brain sub-regions, e.g., cerebellum, hippocampus, etc. The results are evaluated by both visual and quantitative approaches. The proposed method has been proved to be robust enough for reconstructing an accurate and smooth mouse brain volume. PMID- 22811964 TI - Global error minimization in image mosaicing using graph connectivity and its applications in microscopy. AB - Several applications such as multiprojector displays and microscopy require the mosaicing of images (tiles) acquired by a camera as it traverses an unknown trajectory in 3D space. A homography relates the image coordinates of a point in each tile to those of a reference tile provided the 3D scene is planar. Our approach in such applications is to first perform pairwise alignment of the tiles that have imaged common regions in order to recover a homography relating the tile pair. We then find the global set of homographies relating each individual tile to a reference tile such that the homographies relating all tile pairs are kept as consistent as possible. Using these global homographies, one can generate a mosaic of the entire scene. We derive a general analytical solution for the global homographies by representing the pair-wise homographies on a connectivity graph. Our solution can accommodate imprecise prior information regarding the global homographies whenever such information is available. We also derive equations for the special case of translation estimation of an X-Y microscopy stage used in histology imaging and present examples of stitched microscopy slices of specimens obtained after radical prostatectomy or prostate biopsy. In addition, we demonstrate the superiority of our approach over tree-structured approaches for global error minimization. PMID- 22811965 TI - Interactive registration of 2D histology and 3D CT data for assessment of radiofrequency ablation treatment. AB - Histological investigation of a lesion induced by radiofrequency ablation (RFA) treatment provides ground-truth about the true lesion size, thus verifying the success or failure of the RFA treatment. This work presents a framework for registration of two-dimensional large-scale histological sections and three dimensional CT data typically used to guide the RFA intervention. The focus is on the developed interactive methods for reconstruction of the histological volume data by fusion of histological and high-resolution CT (MicroCT) data and registration into CT data based on natural feature points. The framework is evaluated using RFA interventions in a porcine liver and applying medically relevant metrics. The results of registration are within clinically required precision targets; thus the developed methods are suitable for validation of the RFA treatment. PMID- 22811967 TI - Welsh Government consults on compulsory microchipping of dogs. PMID- 22811966 TI - Line shape distortion effects in infrared spectroscopy. AB - This paper explores different phenomena that cause distortions of infrared absorption spectra by mixing of reflective and absorptive band shape components of infrared spectra, and the resulting distortion of observed band shapes. In the context of this paper, we refer to the line shape of the variations of the refractive index in spectral regions of an absorption maximum (i.e., in regions of "anomalous dispersion") as "dispersive" or "reflective" line shape contributions, in analogy to previous spectroscopic literature. These distortions usually result in asymmetric bands with a negative intensity contribution at the high wavenumber of the band, accompanied by a shift toward lower wavenumber, and confounded band intensities. In extreme cases of band distortions caused by the "resonance Mie" (RMie) mechanism, spectral peaks may be split into doublets of peaks, change from positive to negative peaks, or appear as derivative-shaped features. PMID- 22811968 TI - Government sets out its plans for protecting animals used in research. PMID- 22811969 TI - Vet appointed to the House of Lords. PMID- 22811971 TI - RCVS Council elections deemed fair. PMID- 22811970 TI - Liver fluke infection could be hindering detection of bovine TB. PMID- 22811972 TI - Grass is best for beef and the environment, says National Trust. PMID- 22811973 TI - EFSA opinion on the welfare of beef cattle. PMID- 22811974 TI - EFRACom to investigate dog control and welfare policies. PMID- 22811975 TI - Where should the line be drawn on surgery and treatment? PMID- 22811976 TI - When the giving is easy. PMID- 22811977 TI - Integrative Cancer Therapies. In this issue. PMID- 22811978 TI - The placebo effect revisited. PMID- 22811980 TI - Brain nanomedicine up the nose. PMID- 22811979 TI - Oral insulin: active targeting to the intestinal mucosa. PMID- 22811981 TI - A dusty business. PMID- 22811982 TI - Anthrax--where does the real threat lie? PMID- 22811983 TI - [Professor Jean Bariety (November 9, 1933 - April 21, 2011)]. PMID- 22811984 TI - (99m)Tc-DTPA uptake in clear-cell renal carcinoma metastases. PMID- 22811985 TI - A flanker effect for moving visual stimuli. AB - Visual motion perception is essential for appropriate behavior in a dynamic visual world. It is influenced by voluntary attention towards or away from moving objects as well as by the capture of automatic attention by salient stimuli. Both kinds of attention play a major role in the Eriksen Flanker Task (EFT),where a central stimulus has to be identified in the presence of flanking distractors. For static visual stimuli incongruent peripheral flankers are known to reduce accuracy rates and prolong reaction times. However,it is not known if a similar flanker effect also affects speeded responses to moving stimuli. We therefore examined whether a flanker effect exists for moving random dot patterns (RDPs) and compared it to the effect elicited by static visual triangles in human subjects. We observed a motion flanker effect,both for response times and accuracy rates. Incongruently moving peripheral flankers caused a slowing of response time and a reduction of accuracy rates compared to congruently moving RDPs. These motion flanker effects were not significantly different from those in the static flanker task. The presence of a motion flanker effect and its similarity to the flanker effect for static stimuli suggests that visual motion engages competitive attention and control mechanisms for perception and decision making similar to those engaged by non-moving features. PMID- 22811986 TI - Multiplexing in the primate motion pathway. AB - This article begins by reviewing recent work on 3D motion processing in the primate visual system. Some of these results suggest that 3D motion signals may be processed in the same circuitry already known to compute 2D motion signals. Such "multiplexing" has implications for the study of visual cortical circuits and neural signals. A more explicit appreciation of multiplexing--and the computations required for demultiplexing--may enrich the study of the visual system by emphasizing the importance of a structured and balanced "encoding/decoding" framework. In addition to providing a fresh perspective on how successive stages of visual processing might be approached, multiplexing also raises caveats about the value of "neural correlates" for understanding neural computation. PMID- 22811988 TI - Surgical technology international. Forward. PMID- 22811989 TI - Surgical technology international. Introduction. PMID- 22811990 TI - Direct-to-consumer cardiac screening tests: user beware. PMID- 22811987 TI - Responses to second-order texture modulations undergo surround suppression. AB - First-order (contrast) surround suppression has been well characterized both psychophysically and physiologically,but relatively little is known as to whether the perception of second-order visual stimuli exhibits analogous center-surround interactions. Second-order surround suppression was characterized by requiring subjects to detect second-order modulation in stimuli presented alone or embedded in a surround.Both contrast- (CM) and orientation-modulated (OM) stimuli were used. For most subjects and both OM and CM stimuli, second-order surrounds caused thresholds to be higher, indicative of second-order suppression. For CM stimuli, suppression was orientation-specific, i.e., higher thresholds for parallel than for orthogonal surrounds. However, the evidence for orientation specificity of suppression for OM stimuli was weaker. These results suggest that normalization, leading to surround suppression, operates at multiple stages in cortical processing. PMID- 22811991 TI - A new era of genetic testing and its impact on research and clinical care. PMID- 22811992 TI - Tackling neglected areas of oncology with provocative questions. PMID- 22811994 TI - The vocabulary of medical school administration. PMID- 22811993 TI - When may ignorance become a blessing? PMID- 22811995 TI - [An overview of biomarkers in Alzheimer's disease]. AB - Alzheimer's disease (AD), also called presenile dementia, is one of the most common neurodegenerative diseases in elderly people. The main pathological features of AD include senile plaques (SPs), neurofibrillary tangles (NFTs) and neuron loss. A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Class biomarkers of AD such as Abeta and phosphorylated tau have been widely used in clinical diagnosis of AD patients. Recently, novel technologies like proteomics, genomics, and imaging techniques have expanded the role of a biomarker from early diagnosis to monitoring the progression of diseases and evaluating the response to various treatments. In this article, we will review the progress of various biomarkers of AD. PMID- 22811996 TI - [Thoughts and exploration on pharmacokinetic study of herbal medicines based on metabonomics and complex network]. AB - The change of drug development pattern pushes the innovation of drug valuation methods. The pharmacokinetic research of traditional Chinese medicines (TCM) is an important part of TCM modernization and plays a key role in novel drug development of TCM. However, the research methods and techniques are in consistent with the specific characteristics of TCM, i.e., multiple-components is still in the infant. This review makes a brief summary of current pharmacokinetic exploration of TCM, metabonomics and complex network, and puts forward a new strategy based on complex network and metabonomics to study TCM pharmacokinetic in order to disclose the active components and mechanism of TCM. PMID- 22811997 TI - [Role of transporters in hepatic drug disposition]. AB - Liver is regarded as one of the most important organs for drug clearance in the body, which mediates both the metabolism and biliary excretion of drugs. Transporters are a class of functional membrane proteins and control the movement of substances into or out of cells. Transporters, which are extensively expressed in the liver, play important roles in the drug hepatic disposition by regulating the uptake of drugs from blood into hepatocytes or the efflux of drugs and their metabolites into bile. In this review, the localization, functions and substrate selectivity of the major transporters in the liver will be summarized, and the impacts of these transporters on drug hepatic disposition, the potential drug drug interactions as well as their genetic polymorphisms will also be reviewed. PMID- 22811998 TI - [Combinatorial RNAi and its application in cancer gene therapy]. AB - RNA interference (RNAi) has been proved as a novel approach for gene therapy. However, RNAi mono-therapy only aims at single gene, it therefore may ultimately fail to cure cancers caused by polygene variation. To overcome the deficiency of RNAi mono-therapy, "combinatorial RNA interference" (coRNAi) was put forward as a new strategy. By co-expressing the inducers of RNAi triggering single or multiple targets directly and other RNA- or protein-based silencers, coRNAi keeps target genes silent, prevents carcinogenic progression and induces apoptosis of tumor cells. This paper mainly reviews the major strategies of coRNAi and their applications in cancer gene therapy. PMID- 22811999 TI - [Research advances in antitumor activities of pyrimidine derivatives]. AB - Pyrimidine derivatives have been the subject of much attention in pesticide and medicine fields owing to their unique biological properties. Particularly, a large number of these compounds have recently been reported to show substantial antitumor activities, and some of them have been investigated in clinical trials. Although these structurally novel compounds have a common chemical moiety of a pyrimidine ring, there are a variety of mechanisms of their antitumor action, such as, inhibition of cyclin-dependent-kinases, inhibition of protein tyrosine kinase, inhibition of carbonic anhydrases, inhibition of dihydrofolate reductase and disruption of microtubule assembly. In this paper, we described the latest advances in the research of such pyrimidine derivatives as antitumor drug according to their action on targets. PMID- 22812000 TI - [Antitumor effect research progress of shikonin and its derivatives]. AB - Shikonin, the main active ingredient of Lithospermum, and its derivatives have been proved to have antitumor effects, and the anti-tumor mechanisms involve multiple targets. Based on recent literatures, this review focuses on the antitumor effects and its mechanisms. More emphases are given on the aspects of induction of apoptosis, induction of necrosis, acting on matrix metalloproteinase, acting on the protein tyrosine kinase and antiangiogenesis. The current status and problems of shikonin derivatives in antitumor effects are simply summarized and lookout for the development of antitumor drugs with shikonin as leading compounds. PMID- 22812001 TI - [Correlation between reversing effect of cepharanthine hydrochloride on multidrug resistance and P-glycoprotein expression and function of K562/ADR cells]. AB - In this study, cepharanthine hydrochloride (CH) was tested for its potential ability to modulate the expression and function of P-glycoprotein (P-gp) in the multidrug-resistant human chronic myelogenous leukemia cell line K562/ADR. Cytotoxicity of adriamycin (ADR) alone or in combination with CH or verapamil (VER) in K562 and K562/ADR cells was determined by MTT assay. Based on flow cytometric technology, the effect of CH or VER on the uptake and efflux of rhodamine123 (Rho123) and the accumulation of ADR in these cells was detected by measuring Rho123 or ADR-associated mean fluorescence intensity (MFI). The effects of CH and VER on P-glycoprotein (P-gp) expression in K562 and K562/ADR cells were also measured using a flow cytometry with PE-conjugated P-glycoprotein antibody. The results show that CH significantly enhanced the sensitivity of K562/ADR cells to ADR, 4 micromol x L(-1) of CH enhanced the sensitivity of K562/ADR cells to ADR by 7.43 folds, the reversal activity was 3.19 times higher than that of verapamil. However, CH had no effect on drug-sensitive K562 cells (P < 0.05). CH increased Rho123 and ADR accumulation in a concentration-dependent manner (2-8 micromol x L(-1)) and inhibited the efflux of Rho123 from these cells, but did not affect the accumulation and efflux of Rho123 from the wild-type drug sensitive K562 cells. The inhibition effect of CH on P-gp expression in K562/ADR cells is in a time- and concentration-dependent manner. The reversal activity of CH is possibility related to inhibition of P-gp function and expression, which lead to an increased intracellular accumulation of anticancer drugs. PMID- 22812002 TI - [Neuroprotective effect of longistyline A against corticosterone-induced neurotoxicity in PC12 cells]. AB - This study is to investigate the protective effect of longistyline A against corticosterone-induced neurotoxicity in PC12 cells. While PC12 cells were exposed to 100 micromol x L(-1) corticosterone for 48 h, cell survival rate was reduced and lactate dehydrogenase (LDH) release increased. In parallel, corticosterone caused significant elevations of DNA fragmentation, [Ca2+]i and caspase-3 activity. However, when the PC12 cells were incubated with longistyline A (4.0, 8.0 and 16.0 micromol x L(-1)) in the presence of 100 micromol x L(-1) corticosterone for 48 h, the effects were evidently alleviated, but dose dependent manner was not obvious. In summary, longistyline A could generate a neuroprotective effect against corticosterone-induced neurotoxicity in PC12 cells possibly by decreasing [Ca2+]i and caspase-3 activity. PMID- 22812003 TI - [Effects of the effective components group of xiaoshuantongluo formula on rat acute blood stasis model]. AB - Effects of the effective components group of Xiaoshuantongluo formula (XECG) on rat acute blood stasis model were studied under the guidance of the concept of effective components group. Rat acute blood stasis model was induced by subcutaneous injection of epinephrine combined with ice water bath. Hemorheology indices such as whole blood viscosity, plasma viscosity, erythrocyte aggregation index and platelet aggregation rate; coagulation parameters including PT, APTT, TT and FIB; 6-keto-PGF1alpha, TXB2 and D-dimer levels were determined to evaluate the effects of XECG. The results showed that XECG significantly reduced ADP induced platelet aggregation, but showed little influence on the whole blood viscosity, plasma viscosity and erythrocyte aggregation rate. XECG extended PT and TT slightly, but had no effects on APTT and FIB content. D-dimer levels significantly decreased after administration of XECG with a little decrease of TXB2, but the content of 6-keto-PGF1alpha did not change significantly. The results suggest that the role of XECG of anti-aggregation is more prominent. PMID- 22812004 TI - [Puerarin inhibits DNA damage of HaCaT cells induced by UVB via ceramide pathway]. AB - This study is to investigate the effect and mechanism of puerarin on DNA damage of HaCaT cells induced by UVB. Puerarin pre-treated cells were irradiated with UVB at 30 mJ x cm(-2). Twenty four hours after irradiation, DNA damage was detected by comet assay, ceramide was measured by thin layer chromatography and gas chromatography, intracellular free calcium ion was analyzed by flow cytometry, the phosphorylation level of p38 protein was examined by Western blotting method. Levels of DNA damage, ceramide, free calcium ion and p-p38 protein were elevated in UVB model cells. Contrary to the model group, all indicators above were reduced in all groups pre-treated by puerarin. Puerarin restrains the ceramide accumulation to block downstream p38 MAPK pathway and calcium ion rising, therefore reduces DNA damage in HaCaT cells induced by UVB. PMID- 22812005 TI - [Design, synthesis and in vitro antifungal activity of 3-substituted methylenechroman-4-ones]. AB - Substituted phenols as the starting materials were transformed into substituted chromanones by substitution reaction and cyclization reaction, and then 3 (hydroxymethylene)chroman-4-ones were synthesized from substituted chromanones by condensation reaction; at last, the target compounds were synthesized from 3 (hydroxymethylene)chroman-4-ones by chlorination reaction. Their structures were confirmed by 1H NMR and MS. The antifungal activity of the target compounds in vitro was measured by consecutive double dilution, and the result of antifungal experiment indicated that the target compounds had good antifungal action on most fungi tested in vitro. The MIC value of compounds 4c, 4e, 4g and 4h on M. gypseum is 1 microg x mL(-1), better than fluconazole and amphotericin B. PMID- 22812006 TI - [A novel C27-steroidal glycoside sulfate from Liriope graminifolia]. AB - An unusual novel C27-steroidal glycoside sulfate was isolated from the underground organs of Liriope graminifolia (Linn.) Baker with three known compounds. Their chemical structures were determined by spectral analysis, including HR-MS, 1D and 2D NMR as (25S)-ruscogenin 1-sulfate-3-O-alpha-L rhamnopyranoside (1), (25S)-ruscogenin 1-O-beta-D-xylopyranosyl-3-O-alpha-L rhamnopyranoside (2), hesperidin (3), and 4', 7-dihydroxy-5-methoxyflavanone (4). Compound 1 has cytotoxic activities against K562 and HL60 cells with IC50 values of 18.6 microg x mL(-1) and 16.5 microg x mL(-1), respectively. PMID- 22812007 TI - Pharmacokinetic variation of ofloxacin based on gender-related difference in the expression of multidrug resistance-associated protein (Abcc2/Mrp2) in rat kidney. AB - The present study aimed to investigate the pharmacokinetic variation of ofloxacin based on gender-related difference in the expression of multidrug resistance associated protein (Abcc2/Mrp2) in rat kidney. The concentrations of ofloxacin in rat plasma and urine were determined after tail vein administration (30 mg x kg( 1)) by high-performance liquid chromatography (HPLC) method. Expression of Mrp2 in kidney of male and female rats was qualitatively and quantitatively detected by immunohistochemistry and flow cytometry, separately. The results showed that AUC value of ofloxacin was lower in male rats than that in female rats and the total amount of ofloxacin excreted in the urine was higher in male rats than that in female rats. And the expression of Mrp2 in male rat kidney was higher than that in female rats. All results suggested that gender-related differences in pharmacokinetics of ofloxacin may be attributed to the differences in the expression of Mrp2 in kidney of male and female rats. PMID- 22812008 TI - [Qualitative and quantitative analysis of fluoxetine hydrochloride by 19F NMR]. AB - The chemical shift of fluoxetine hydrochloride appears at delta 14.15 in 19F NMR analysis. The delta moved upfield slightly from 14.158 to 14.145 when the concentration of solution became diluted from 2.00 to 0.05 mmol x L(-1). Spiking test was suggested to confirm the existence of the compound for qualitative analysis. 19F NMR detection sensitivity test illustrated that a concentration of 17 mg in 1 L water could be detected while the sample was scanned 500 times with optimum parameters. In quantitative analysis, standard curve of concentration versus fluorine signal intensity was proposed to determine the amount of fluoxetine. Long capillary tube containing trifluoroacetic acid was used as internal standard for the integration measurements and straight line was obtained with good fitting. Direct additions of trifluoroethanol to fluoxetine solutions gave a poorer standard curve. PMID- 22812009 TI - [In vivo distribution of FITC-labeled boanmycin hydrochloride in situ gel]. AB - This study is to evaluate the sustained-release effect of the thermosensitive in situ gel for injection of boanmycin hydrochloride (BAM) by bioluminescence imaging in nude mice. BAM was labeled with fluorescein isothiocyanate (FITC). The FITC-labeled BAM (FITC-BAM) was purified by dialysis and Sephadex G25 gel column, and then was identified by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF). The model of experimental hepatoma HepG-2 nude mice was established, and the optical imaging system was applied to evaluate the distribution of FITC-BAM in vivo. Results of MALDI-TOF proved that the major molecular ratio of BAM : FITC was 1 : 1 or 1 : 2. Bioluminescence imaging showed that the diffusion of FITC-BAM in situ gel group was significantly delayed compared with the negative control group. This study demonstrated that the thermosensitive in situ gel can effectively delay the release of boanmycin hydrochloride, and extend the retention time in vivo. PMID- 22812010 TI - [Micromeritic evaluation of the direct compression excipient LubriTose AN]. AB - This study is to report the evaluation of the micromeritic properties of LubriTose AN, which is expected to provide preliminary theoretical basis for the direct compression technology. From the aspects of flowability, compressibility and dilution potential, the angle of repose, flow velocity, the Carr' index, tensile strength, elastic recovery, yield pressure and the lubricating ability of LubriTose AN were determined. Also, model drugs were selected to investigate the dilute potential under the desirable compressing performance. Compared to the physical mixtures, the flowability of LubriTose AN was better, and the deformation mechanism was the same with anhydrous lactose, both brittle deformation. The compressibility and compaction of LubriTose AN was slightly better than that of physical mixtures under low and moderate pressure. The dilution potential of LubriTose AN were high for most of hydrophobic drugs. The lubricate ability was desirable under different rotational speeds. LubriTose AN is an excellent co-processed excipient, which is helpful for the promotion and improvement of the tablet manufacturing level. PMID- 22812011 TI - [In vivo imaging in tumor-bearing animals and pharmacokinetics of PEGylated liposomes modified with RGD cyclopeptide]. AB - The hydroxycamptothecin (HCPT) PEGylated liposomes (HCPT-LP) were modified with RGD cyclopeptide formed the tumor-targeting liposomes (HCPT-RGD-LP). HCPT-LP and HCPT-RGD-LP were injected intravenously with single dose of 5 mg x kg(-1) to rats. The drug concentration in plasma was determined and the pharmacokinetic behaviour was compared. The HCPT distribution in heart, liver, spleen, lung, kidney and plasma of mice was investigated following intravenous administration of HCPT-LP and HCPT injection. The nude mice implanted human hepatoma HepG2 cells were studied by in vivo imaging. The fluorescent probe was DiR and the nude mice were injected with DiR PEGylated liposomes (DiR-LP) and DiR-LP modified with RGD cyclopeptide (DiR-RGD-LP). The results showed that there was no significant difference (P > 0.05) of main pharmacokinetic parameters t1/2beta, CL, V(c), AUC(0-48 h), AUC(0-inifinity), MRT(0-48 h), MRT(0-infinity) between HCPT-RGD-LP and HCPT-LP. HCPT-LP had a remarkably better long-circulating effect than HCPT injection in mice and the concentration of HCPT was highest in liver. The DiR accumulation in tumors of DiR-RGD-LP was higher than that of DiR-LP by the visualized fluorescence of in vivo imaging. It indicated that such PEGylated liposomes modified with RGD cyclopeptide could improve the tumor targeting efficacy. PMID- 22812012 TI - [Brucine chitosan thermosensitive hydrogel for intra-articular injection]. AB - The aim of this study was to develop a sustained release converse thermosensitive hydrogel for intra-articular injection using chitosan-glycerol-borax as matrix, its physical properties and biocompatibility were investigated. Taking gelation time and gelation condition as index, the influence of concentration of chitosan, ratio of chitosan to glycerol, pH on physical properties of hydrogel were investigated. And then the in vitro drug release, rheological properties and biocompatibility were studied. The thermosensitive hydrogel flows easily at room temperature and turns to gelation at body temperature, which can certainly prolong the release of drug and has good biocompatibility. PMID- 22812013 TI - [Multiple analysis of the difference in intestinal absorption between the main components and the extract of Glycyrrhiza uralensis]. AB - The aim of this study is to investigate the rat intestinal absorption behavior of two main active components, liquiritin, glycyrrhizin and the extract of Glycyrrhiza uralensis. The rat intestinal perfusion model was employed. Concentrations of the compounds of the interest in the intestinal perfusate, bile and plasma samples were determined by HPLC and UPLC. At the same time, the intestinal enzymes incubation test and the partition coefficient determination, the absorption of liquiritin and glycyrrhizin alone and the extract were multiple analyzed. The results showed that the P(eff) (effective permeability) of liquiritin or glycyrrhizin alone or the extract was less than 0.3, which suggested their poor absorption in the intestine. The P(eff) of the two main active components or the extract was not significantly different in duodenum, jejunum, colon and ileum segment. The P(eff) of the glycyrrhizin in the extract had no significant difference in the four intestinal segments compared with the glycyrrhizin alone. The absorption of the liquiritin displayed significant difference (P < 0.05) at ileum segment compared with the liquiritin alone, while it had no markedly change in the other three segments. This phenomenon indicated that some ingredients in the extract might improve the absorption of liquiritin. Moreover, no parent compounds and their metabolites were found in the intestinal perfusate, bile and the plasma samples. The results demonstrated that the influence of the other ingredients in the extract on the two components might not increase the amount of liquiritin and glycyrrhizin in the bile and plasma within the duration of the test. PMID- 22812014 TI - [C-ring cleavage of liquiritigenin extracted from licorice roots by an oxygen tolerant bovine rumen bacterium strain Aeroto-Niu-O16]. AB - Aeroto-Niu-O16, an oxygen-tolerant bovine rumen bacterium, is capable of aerobically reducing isoflavones daidzein and genistein to dihydrodaidzein and dihydrogenistein through catalytic hydrogenation. In this study, it was found that bacterium strain Aeroto-Niu-O16 was able to cleavage the C-ring of liquiritigenin (LG), which is one of the main biologically active components of licorice roots, in the presence of atmospheric oxygen. LG was prepared by acid hydrolysis of the crude extract of licorice roots. The metabolite of LG obtained in strain Aeroto-Niu-O16 was identified as davidigenin (DG) based on the data of UV, MS, 1H and 13C NMR. The maximal concentration of LG that the strain Aeroto Niu-O16 was able to transform effectively was 0.8 mmol x L(-1) and the average productivity of the metabolite DG was 71.7%. Furthermore, when 0.1% (m/v) of L cysteine or sodium thiosulfate was added in the cultural medium, the average bioconversion rate of LG was increased from 71.7% to 78.3% and 77.2%, respectively. The in vitro antioxidant investigation showed that 1, 1-diphenyl-2 picrylhydrazyl (DPPH) radical-scavenging activity of DG was significantly or extremely significantly higher than that of LG at the concentrations from 0.2 mmol x L(-1) to 1.6 mmol x L(-1). We discoverd for the first time that LG can be converted to DG, which has stronger and wider biological activities, through microbial biotransformation method. PMID- 22812015 TI - [Rapid cloning and functional characterization of hypericin synthase gene]. AB - Hypericin, a red-colored naphtodianthrone, is a natural product synthesized in the medicinal plant Hypericum perforatum, commonly known as St. John's wort. Hypericin has attracted a growing attention of the pharmaceutical industry because of its potential application to various therapies, including the treatment of depression and remarkable antiviral and photodynamic activities, hyp 1 gene encodes for phenolic coupling protein which catalyzes in vitro direct and specific conversion of emodin to hypericin which, however, has not formed common opinion so far. Six pairs of primers specific to hyp-1 gene were synthesized. The rapid cloning of hyp-1 gene was performed based on step-by-step extension of a short region of the gene through a series of PCR reactions. All cloned sequences were confirmed by DNA sequencing. A vector named pET32ahyp containing hyp-1 gene was constructed and was transformed into E. coli to induce heterologous expression. SDS-PAGE and Western blot results showed the recombinant Hyp-1 protein was expressed successfully in E. coli. The soluble fraction was used to test the function of the recombinant Hyp-1. Hypericin was detected by LC-MS/MS with emodin as a substrate under in vitro conditions. The above results corroborated the Hyp-1 function, a confusing question, which lay a material foundation for the synthesis of hypericin by synthetic biotechnology. PMID- 22812016 TI - [Comparison of the brain pharmacokinetics of nasal tetramethylpyrazine phosphate pH-sensitive in situ gel in normal rats and model rats]. AB - The study is to investigate the brain pharmacokinetics change of nasal tetramethylpyrazine phosphate (TMPP) pH-sensitive in situ gel in normal and model rats. Acute cerebral ischemia rat model was successfully established by middle cerebral artery occlusion (MCAO) method. Both normal and model rats were given nasal TMPP pH-sensitive in situ gel (10 mg x kg(-1)). Perfusates of brain striatum area were collected at each time point by microdialysis. The content of TMPP was determined by HPLC. The pharmacokinetics parameters were calculated by Kinetica 4.4 software at each time point of the brain drug concentration. The main pharmacokinetics parameters of TMPP were fitted with compartments 2. After nasal TMPP pH-sensitive in situ gel the values of C(max) and AUC of both components in brain showed as follows: the value of model group > that of normal group. Significant difference can be observed in the process of brain pharmacokinetics in normal and model rats after giving nasal TMPP pH-sensitive in situ gel. PMID- 22812017 TI - [Triterpenoids from Inonotus obliquus protect mice against oxidative damage induced by CCl4]. AB - To investigate the effects of lanosterol (1), inotodiol (2) and trametenolic acid (3) from Inonotus obliquus against oxidative damage induced by CCl4 in mice, 1, 2 and 3 (20, 10 and 5 mg x kg(-1)) were respectively administered to mice, once a day for 3 days. Then the mice were induced to oxidative damage by CCl4 on the third day 30 min after the administration. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX) and the content of malondialdehyde (MDA) and reductive glutathione (GSH) in serum and liver homogenate were determined. And the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and interleukin-6 (IL-6) concentration in serum were detected. The results showed that treatment with compound 1, 2 and 3 could significantly increase the activities of SOD, CAT and GSH-PX in serum and liver homogenate. Furthermore, the content of GSH in serum and liver homogenate increased and MDA content decreased markedly. In addition, compound 1, 2 and 3 could significantly inhibit the activities of ALT and AST in serum, and decrease the IL-6 concentration in serum remarkably. So, compound 1, 2 and 3 can protect mice against oxidative stress injury induced by CCl4. Furthermore, compound 1, 2 and 3 can protect cells from damage through inhibition on ALT, AST and the expression of IL-6. PMID- 22812018 TI - [Synthesis of benzothiazole derivatives and their binding characteristics with beta-amyloid]. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease endangering human health seriously. Recent reports have revealed that beta-amyloid aggregates play a key role in the pathogenesis of AD. Thus, targeting the Abeta plaques benzothiazole derivatives were synthesized with the scaffold of the most promising imaging agent PIB ([11C]-6-OH-BTA-1, [11C]-2-(4-(methylamino)phenyl)-6 hydroxybenzothiazole) and C = N as linker to study the binding characteristics with the target protein through surface plasmon resonance (SPR) technique. These derivatives were synthesized through simple yet effective method with high yields and characterized by 1H NMR and FTIR. The binding properties (K(D)) were determined with Biacore X-100 instrument according to the fitting-plot curve. Compounds 3a and 3f showed high binding affinity for Abeta1-40. The results suggest that benzothiazole derivatives could be served as a scaffold to develop novel beta-amyloid imaging agents for the diagnosis of AD. PMID- 22812027 TI - New American Association of Colleges of Nursing data show enrollment surge in baccalaureate and graduate programs amid calls for more highly educated nurses. PMID- 22812029 TI - Small employers and self-insured health benefits: too small to succeed? AB - Over the past decade, large employers increasingly have bypassed traditional health insurance for their workers, opting instead to assume the financial risk of enrollees' medical care through self-insurance. Because self-insurance arrangements may offer advantages--such as lower costs, exemption from most state insurance regulation and greater flexibility in benefit design--they are especially attractive to large firms with enough employees to spread risk adequately to avoid the financial fallout from potentially catastrophic medical costs of some employees. Recently, with rising health care costs and changing market dynamics, more small firms--100 or fewer workers--are interested in self insuring health benefits, according to a new qualitative study from the Center for Studying Health System Change (HSC). Self-insured firms typically use a third party administrator (TPA) to process medical claims and provide access to provider networks. Firms also often purchase stop-loss insurance to cover medical costs exceeding a predefined amount. Increasingly competitive markets for TPA services and stop-loss insurance are making self-insurance attractive to more employers. The 2010 national health reform law imposes new requirements and taxes on health insurance that may spur more small firms to consider self-insurance. In turn, if more small firms opt to self-insure, certain health reform goals, such as strengthening consumer protections and making the small-group health insurance market more viable, may be undermined. Specifically, adverse selection- attracting sicker-than-average people--is a potential issue for the insurance exchanges created by reform. PMID- 22812030 TI - Where is the accountability NMBA? PMID- 22812031 TI - Bullied leave the profession. PMID- 22812034 TI - Australia leading on minimum wages. PMID- 22812032 TI - Not disinterested in students: just time-deficient. PMID- 22812035 TI - Leading the way in telehealth. PMID- 22812036 TI - A sobering reflection! PMID- 22812037 TI - Has your super been stuck on 'set and forget'? PMID- 22812038 TI - Nurses in general practice: entering a new era. PMID- 22812039 TI - Friends of Huong Phuong orphanage. PMID- 22812040 TI - Unethical professional conduct. PMID- 22812041 TI - Nursing in rehab. PMID- 22812042 TI - New fertility resource for young women with breast cancer. PMID- 22812043 TI - A health career puts Indigenous women first. PMID- 22812044 TI - Reflecting on 34 years nursing in Papua New Guinea. PMID- 22812045 TI - Women's heart health. PMID- 22812046 TI - To have or not have a child in contemporary Taiwan? Motherhood decision making. PMID- 22812047 TI - McGrath breast care nurse supports women and families. PMID- 22812048 TI - Queensland mobile women's health service turns 21. PMID- 22812049 TI - Women's health: the journey of childbirth. PMID- 22812050 TI - Nurses play direct role in the care of prostate cancer patients. PMID- 22812051 TI - Workplace agent or victim. PMID- 22812052 TI - [Artificial nutrition and preoperative fasting]. AB - Preoperative fasting is a currently adopted measure since Mendelson's report pertaining to aspiration pneumonia as a cause of death following general anesthesia. From a metabolic point of view fasting is detrimental because surgery in itself causes a state of hypercatabolism and hyperglycemia as a result of insulinresistance. Preoperative fasting has become almost obsolete in certain elective surgical procedures. In these cases the use of clear liquids is now well established and this paper focuses on the safe use of clear fluids, postoperative insulinresistance, patient comfort and postoperative outcome as well as its effect on the length of stay. PMID- 22812053 TI - [Attention-deficit/hyperactivity disorder (ADHD) and child maltreatment: a review]. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder of childhood with a prevalence rate of 5 % among school-age children. This disorder have a strong impact on parent-child relationships. This review synthesizes recent research evidence regarding the rate of child abuse among ADHD children. At least one per 30 chidren have been maltreated in a general population. All authors are asking for better prevention of abuse by a better knowledge of which children are at greater risk of abuse. ADHD children, like children with disabilities, are most frequently maltreated. In this group of children, abuse are often associated with co-occurrence of oppositionnal defiant disorder (ODD) or behavioral difficulties. Maltreated ADHD children have an increased risk of substance use disorders (SUDs) at adolescence. Through this review, we hypothesize about the reasons of an increased risk of abuse by ADHD children. With our clinical experience, we will try to plan prevention and detection strategies about abuse in ADHD children, which have a strong impact on children's pronostic. PMID- 22812054 TI - [Religion and brain functioning (part 2): does religion have a positive impact on mental health?]. AB - Religion's impact on mental health has been largely studied, but results are often difficult to interpret due to methodological concerns: definition of religion and of spirituality ; measuring issues ; identification of specific components such as social dimension, cognitive schemas influencing world perception and meditating behaviors such as prayers. Furthermore, correlations between religious dimensions and mental health variables are too often considered as evidence of causality. Despite all those methodological problems, it appears that religiosity, defined as a global concept encompassing all aspects of religious life, might be a protective factor against several mental health problems, namely substance abuse, depression, suicide and anxiety disorders. This protective property isn't likely due to religions per se, but to associated components: risky behaviors' prevention due to shared moral standards, social support, sense of meaning, purposefulness and control, and meditation habits, exercising an inhibiting influence on chronic stress. PMID- 22812055 TI - [Screening strategy and diagnostic criteria for gestational diabetes. Proposals of the GGOLFB]. AB - For nearly 50 years, the strategy of screening and the diagnostic criteria for gestational diabetes have been the subject of endless controversies. They differ between countries and from one center to another, mainly because of the lack of hard data allowing to define glycemic thresholds at which a therapeutic management is needed. Recently, a large observational study has demonstrated the existence of a robust relationship between maternal blood sugar and several fetomaternal perinatal complications. This relationship is linear, with no clear threshold that would define gestational diabetes unambiguously. Meanwhile, two randomized intervention trials have shown that the therapeutic management of mild gestational diabetes was associated with improved perinatal outcomes. Based on these data, the " International Association of Diabetes and Pregnancy Study Group "(IADPSG) released new recommendations on screening methods and diagnostic criteria for gestational diabetes. Although already endorsed by several international associations and implemented in some countries, these recommendations still raise questions and criticisms. This is why the "Groupement des Gynecologues Obstetriciens de Langue Francaise de Belgique " (GGOLFB) organized a meeting between diabetologists and gynecologists which allowed to reach a consensus on the strategy that we intend to implement in our respective centers. The purpose of this paper is to briefly overview the recent advances in gestational diabetes and more particularly to make our key conclusions known to the medical community. This will enable the standardization of the management of gestational diabetes in the French-speaking part of Belgium. PMID- 22812056 TI - [Treatment by Bach flowers: magical potion or factual medicine? A review of the literature]. AB - In 1930, Dr Edward Bach developed flower essences known as Bach flowers. Today, over 70 years later, they are becoming more and more popular and are used by many practitioners, despite a total lack of scientific support for their use. A review of the literature on the controversial use of this alternative treatment is discussed. PMID- 22812057 TI - [A case of breast necrosis]. AB - We describe a case of a tumor-like lesion of the breast of a 45-year-old woman. The initial presentation is a persistent breast abscess after three courses of antibiotics. The association with multiple lung nodules suggests a presumed diagnosis of metastatic carcinoma. Fine needle biopsies of breast and pulmonary nodule reveal necrotic tissue without any evidence of malignancy. Systemic symptoms appear after three weeks of evolution : fever, spread cutaneous ulcers, livedo reticularis, arthralgias. The final diagnosis is made on both mastectomy sample analysis demonstrating necrotizing granulomatous vasculitis and presence of antineutrophil antibodies, thus defining Wegener granulomatosis, which initial involvement on the breast is very atypical. PMID- 22812058 TI - [Supervision of anatomical demonstrations between 1834 and 1940]. AB - Between 1834, year of the founding of the Universite libre de Bruxelles, since 1940, many distinguished physicians and surgeons were in charge to participate to the anatomical demonstrations. We review successively the life and contributions of Hippolyte Guillery, Sebastien Tirifahy, Leon Warnots, Edmond Rouffart, Remy Lavise, Edouard Willems, Auguste Brunin, Alexandre Wilmart and Lucien Wilmart to the teaching of human anatomy. PMID- 22812059 TI - [Claire Page: mental health nursing. Interview by Suzanne Decarie]. PMID- 22812060 TI - [Atrial fibrillation: a quality improvement pilot project]. PMID- 22812061 TI - [Growth curves]. PMID- 22812062 TI - [Inaccurate measurements]. PMID- 22812063 TI - [Outdated methods]. PMID- 22812064 TI - [New organization of elder care in Monteregie]. PMID- 22812065 TI - [Management of hepatitis C. Strength in numbers]. PMID- 22812066 TI - [The role of the nurse in the changing healthcare system]. PMID- 22812067 TI - [Diane Demers. Let's not be like the Titanic]. PMID- 22812068 TI - [Danielle D'Amour and Carl-Ardy Dubois. Maintaining a better professional practice through innovation]. PMID- 22812069 TI - [Carole Deshaies. Professional inspections are an ally in quality improvement]. PMID- 22812070 TI - [Agnes Gaudreault. An integrated network in which the nurse is the first person to greet the patient]. PMID- 22812071 TI - [Damien Contandrio-Poulos. Paying more and having less]. PMID- 22812072 TI - [Gertrude Bourdon. An absolute clinical governance]. PMID- 22812073 TI - [The benefits of physical activity]. PMID- 22812074 TI - [Asbestos. Occupational exposure surveillance to asbestos and the illnesses it creates]. PMID- 22812075 TI - [Understanding the impact of seclusion and restraint: perceptions and recommendations discussed at the conference held at the Hospital Louis H Lafontaine]. PMID- 22812076 TI - [Help with choosing contraceptives. Part 2: hormone contraception and headaches]. PMID- 22812077 TI - [Diet quiz]. PMID- 22812078 TI - [Living with a stoma. Part 5. Caring for a stoma: collection appliances and treatment of complications]. PMID- 22812079 TI - [Avoiding emergencies: a study confirms the risks associated with elderly nursing home residents]. PMID- 22812080 TI - [Lawnmowers and children: a dangerous combination]. PMID- 22812081 TI - [Antibiotics: better education, better usage]. PMID- 22812083 TI - [Market volatility: 5 strategies for controlling your emotions]. PMID- 22812082 TI - [Celexa: an antidepressant with potential cardiac toxicity ]. PMID- 22812084 TI - [Treatment of clavicular fractures]. PMID- 22812085 TI - [Treatment of adolescent clavicular fracture with titanium elastic nails]. AB - OBJECTIVE: To investigate the feasibility and clinical effects of titanium elastic nails (TEN) for adolescent clavicular fracture. METHODS: From October 2008 to November 2009, 17 adolescent patients with clavicular fracture were treated with internal fixation, including 11 males and 5 females who ranged in age from 12 to 18 years (mean 15.3 years). The mean time from injury to surgery was 3.5 days (2-7 days). Constant function score before surgery and that 3 months after surgery and shoulder ROM before surgery and that 2 months after surgery were compared. Fracture reduction and healing were followed up by X-rays to analyze internal fixation with the TEN technique. RESULTS: All patients were followed up for a mean of 6.5 months (range 3-8 months), during which no infection, TEN fracture or skin bursting was observed. The Constant score rose from preoperative (45.3 +/- 6.1) to (85.6 +/- 4.3) at 3-month follow up (t = 22.164, P < 0.01),and the shoulder activity degree at 2-week follow up was improved obviosly from preoperative (P < 0.01). X-ray at 12-16 weeks after surgery showed good bone healing and recovery of shoulder function. CONCLUSION: Internal fixation with TEN in the treatment of adolescent clavicular fracture is safe, minimally invasive,reliable and cosmetic. This technique provides a liable ption for the treatment of adolescent clavicular fractire PMID- 22812086 TI - [Use of titanium elastic intramedullary nails in the treatment of adult midshaft clavicular fractures: technical skills, precautions and complications]. AB - OBJECTIVE: To discuss surgical skills,precautions and complications of using titanium elastic intramedullary nails in the treatment of adult midshaft clavicular fractures and evaluate the therapeutic efficacy. METHODS: From June 2006 to January 2009, 28 patients with completely displaced midshaft clavicular fractures (15 simple fractures, 8 wedge fractures and 5 comminuted fractures) were enrolled in the study,included 19 males and 9 females with a mean age of 39.0 years (range 19-67 years). The injury was on the left side in 14 cases and on the right side in 14 cases. The mean course of disease was 2.9 days. The shoulders of the patients were swollen, deformed and disabled before operation. X rays revealed complete displacement of the clavicle. The mean clavicular shortening after injury was 6.76% vs. that measured after bone healing. The Constant-Murley Shoulder Scoring System was used to assess shoulder function, and the DASH Score was used to assess the disability degree of the upper arm. RESULTS: Closed operation with titanium elastic intramedullary nails was undertaken in 26 cases, and open reduction was performed in the remaining two cases. Satisfactory reduction was achieved in all patients, who were followed up for a mean of 10 months (range 6-15 months). The mean union time was 11.5 weeks. No severe complication occurred in any patient. The mean clavicular shortening after bone healing was 3.38%, which was significantly different as compared with the mean clavicular shortening after injury. Constant-Murley Shoulder Score was (97.0 +/- 4.2), and DASH score was (3.4 +/- 4.8). Anatomical reduction, functional recovery and appearance were satisfactory in all patients. CONCLUSION: Treatment of adult midshaft clavicular fractures with titanium elastic intramedullary nails is advantageous and may prove to be an alternative option for nonsurgical treatment and plate osteosynthesis of midshaft clavicular fractures in adults. PMID- 22812087 TI - [Surgical and nonsurgical treatment of clavicular midpiece fracture in adults: a case-control study]. AB - OBJECTIVE: To compared surgical and nonsurgical treatment of clavicular midpiece fracture. METHODS: From September 2002 to September 2011, 254 adult cases of displaced midshaft clavicle fractures were retrospective analyzed, including 188 males and 66 females who ranged in age from 19 to 62 years (mean 39.3 years). There were 38 cases of transverse fracture, 71 cases of oblique fracture,and 145 cases of comminuted fracture. All cases were fresh single fractures. According to the treatment methods, these patients were divided into conservative group and surgical group. In conservative group, 127 patients (96 male and 31 female; mean age 40.1 +/- 6.02) were treated by manipulative reduction and fixation with "infinity" shaped bandage. In surgical group, .96 patients (92 male and 35 female; mean age 39.0 +/- 5.11) were treated by open reduction and internal fixation with reconstruction plates. Appearance satisfaction, the cost of treatment and the incidence of complications were compared between the two groups. Therapeutic efficacy was evaluated according to Han's standard. RESULTS: All patients of both groups were followed up for 8-10 months (mean 9.8 months). In surgical group,the curative effect was excellent in 110 cases, good in 12 cases and fair in 3 cases; in conservative group, the curative effect was excellent in 62 cases,good in 28 cases and fair in 37 cases. The therapeutic efficacy in surgical group was better than that in conservative group. The appearance satisfaction of conservative group was higher than that of surgical group. The cost of treatment and complications were lower in conservative group than those in surgical group. CONCLUSION: Treatment modalities for adult clavicle fractures should be selected on the basis of comprehensive analysis. Non-surgical treatment should be the treatment of choice, and indication for surgical treatment should be controlled strictly. PMID- 22812088 TI - [Kirschner wire for clavicle fracture fixation is broken and displaces to the neck: a case report]. PMID- 22812089 TI - [Combined use of compound nanxing pain paste with blood-promoting and diuretic chinese herbal medicines in treatment of chronic knee synovitis]. AB - OBJECTIVE: To observe the clinical efficacy of combined use of Compound Nanxing Pain Paste with blood-promoting and diuretic Chinese herbal medicines in treatment of chronic knee synovitis. METHODS: From October 2008 to March 2011, 120 patients with chronic knee synovitis were equally divided into three groups: oral treatment group, external treatment group and combined treatment group. Patients in oral treatment group had a mean age of (56.58 +/- 5.47) years and a course of disease about (7.35 +/- 2.59) months,involving the left knee in 18 cases,the right knee in 17 cases and both knees in 5 cases, who were administered orally with blood-promoting and diuretic Chinese herbal medicines composed of Wu Ling San and Tao Hong Si Wu Decoction. Patients in external treatment group had a mean age of (56.25 +/- 6.35) years and a course of disease about (7.68 +/- 2.76) months,involving the left knee in 16 cases, the right knee in 20 and both knees in 4 cases, who were treated externally with Compound Nanxing Pain Paste. Patients in combined treatment group had a mean age of (55.65 +/- 4.49) years and a course of disease about (7.50 +/- 3.36) months, involving the left knee in 16 cases, the right knee in 18 and both knees in 6 cases, who were given both oral and external treatments. The clinical effects and knee function of the three groups were assessed and compared. RESULTS: Finally, a total of 118 patients were included in the result analysis, including 40 patients in oral treatment group, 39 patients in external treatment group and 39 patients in combined treatment group. In combined treatment group, 27 patients were clinically cured, 9 were improved, and 3 patients were ineffective vs. 15, 16 and 8 patients in external treatment group, and 13, 16 and 11 in oral treatment group. The overall effective rate of combined treatment group was better than that of oral group and external treatment groups (P < 0.05). The function comprehensive score of knee joints in combined treatment group was better than that of oral treatment group,while the function comprehensive score of knee joints in oral treatment group was better than that in external treatment group in terms of demand for assistance, stair climbing ability, lameness, and swelling pain. CONCLUSION: Combined use of oral blood-promoting and diuretic Chinese herbal medicines with Nanxing offers a good therapeutic effect on chronic knee synovitis in relieving pain, reducing swelling and improving joint function,while Nanxing could also reduce pain and improve joint function to a certain extent. PMID- 22812090 TI - [Simple Pemberton's ilium osteotomy and combined unter-trochanter derotation varisation osteotomy for developmental dysplasia of the hip]. AB - OBJECTIVE: To retrospectively compare the therapeutic effects of simple Pemberton's ilium osteotomy and combined unter-trochanter derotation-varisation osteotomy for developmental dysplasia of the hip (DDH). METHODS: Clinical data of 141 DDH patients who received either simple Pemberton's ilium osteotomy (n=57; 12 male and 45 female; age range 3-8 years) or combined unter-trochanter derotation varisation osteotomy (n=84; 15 male and 69 female; age range 4-9 years) from January 2004 to January 2009 were collected. Postoperative complications, Severin's radiological outcomes and therapeutic outcomes as evaluated by Mcay criteria were compared between the two groups 2 years after operation. RESULTS: The patients in simple Pemberton group were followed-up for 30-52 months (mean 38 months) and the patients in the combination group were followed-up for 32-51 months (mean 37 months). There were 7 cases of dislocation, 4 cases of avescular necrosis of femoral head and 5 cases of joint stiffness in simple Pemberton group vs 0 case of dislocation, contraction of the limb and ANFH,2 cases of joint stiffness in the combination group. Two years after surgery, the result as evaluated by McKay criteria was excellent in 27 cases, good in 18 cases and fair in 12 cases in simple Pemberton group vs. 52, 25 and 7 cases in the combination group. The overall clinical outcome in the combination group was better than that in simple Pemberton group. Severin X-ray evaluation showed excellent in 27 cases, good in 15 cases and fair in 15 cases in simple Pemberton group vs. 53, 22 and 9 cases in the combination group,indicating that the overall result in the combination group was better than that in simple Pemberton group. CONCLUSION: The overall clinical outcome of the combination group is better than that of simple Pemberton group in the treatment of pediatric DDH, especially in reducing postoperative complications and functional recovery. The patients in the combination group reported a higher postoperative satisfaction as compared with those in simple Pemberton group. PMID- 22812091 TI - [Debridement and bone grafting with internal fixation via the anterior approach for treatment of cervicothoracic tuberculosis]. AB - OBJECTIVE: To investigate the outcome of radical debridement, reconstruction with bone autograft or allograft and plate internal fixation via the anterior approach for the treatment of cervicothoracic tuberculosis. METHODS: From Jun. 2000 to Dec. 2010, 20 patients with cervicothoracic tuberculosis were treated by debridement and bone grafting with internal fixation via the anterior approach. They included 17 males and 3 females who ranged in age from 25 to 46 years (mean 38 years). The course of disease ranged from 3 months to 2 years (mean 12 months). The onset of the disease was chronic in all patients, with main complaints of persistent pain, and cervical stiffness and deformity accompanied with low fever,night sweating and pathologic leanness. Preoperative X-ray, CT or MRI showed that the pathologic change occurred in C7-T1 segment in 10 cases, T1 segment in 6 cases, T1-T3 segment in 3 cases,and T2-T3 segment in 1 case. The Cobb angle ranged from 25 degrees to 60 degrees (mean 35 degrees) before surgery. The Frankel classification was as follows: 2 cases at grade A, 4 cases at grade B, 7 cases at grade C, 2 cases at grade D, and 5 cases at grade E. All the patients underwent a standard cervical approach by combined partial median steotomy and transverse steotomy through the synostosis between the manubrium and body of the sternum to expose the lesion adequately. Radical debridement was performed, and then a tricortical iliac crest bone autograft or allograft was placed and secured by internal fixation to reconstruct the spinal column. The change in Cobb angle and fusion of bone grafting were reexamined by X-ray regularly. The clinical symptoms and neurological function were evaluated according to NDI (neck disability index) score and Frankel classification. RESULTS: There was no injury to blood vessels, spinal cord or recurrent nerve during surgery. All patients were followed-up from 16 to 39 (mean 25) months. The tuberculosis symptoms disappeared after surgery and there was no tuberculosis recurrence,incision infection, sinus formation and internal fixation failure in any of these patients. ESR re-examination recovered normally. Bony fusion was obtained in all patients and internal fixation position was normal at 3 to 6 month postoperatively. The Cobb angle ranged from 10 degrees to 16 degrees (mean 12 degrees) and NDI was reduced from (48.2 +/- 2.9) to (22.5 +/- 3.1) at the final followed-up. Except for 2 patients at grade A showing no recovery preoperatively, the Frankel classification of the other patients raised 1.5 grade on average at the final followed-up, and the nerve function of the spinal cord recovered at different degrees: 2 at grade A, 1 at grade B, 1 at grade C, 3 at grade D, and 13 at grade E. CONCLUSION: The anterior approach can provide direct and safe access to the lesion. The decompression effect of the vertebral canal is significant. The structural iliac crest autograft or allograft and anterior instrumentation could work effectively to stabilize the cervicothoracic junction. PMID- 22812092 TI - [Clinical observation on influence of vertebral fixation through or across the affected vertebra on vertebral morphology]. AB - OBJECTIVE: To compare the long-term influence of vertebral fixation through or across the affected vertebra on vertebral morphology. METHODS: Clinical data of 48 patients with simple thoracic and lumbar spinal fractures who were admitted between Jan. 2008 and Dec. 2010 were analyzed retrospectively. Among them 36 cases (28 males and 8 females) were fixed through the injured vertebra (group A) and 12 cases (8 males and 4 females) were fixed across the injured vertebra (group B). All patients were followed up for 6-36 months (mean 11.5 months). The vertebral body height, endplate angle and neurofunction were compared between the two groups before surgery, a week after surgery and at the end of the follow-up period. RESULTS: There was no statistically significant difference in vertebral body height,endplate angle and neurofunction before operation between group A and B (P > 0.05). Vertebral body height and endplate angle improved in both groups a week after operation and at the end of the follow-up period as compared with those before operation (P < 0.05), and the efficacy in group B was significantly better than that in group A (P < 0.05). There was no significant difference in neurofunction between the two groups (P > 0.05). CONCLUSION: The fixation method through the injured vertebra had a better reduction effect, more stable fixation, and a better long-term effect on vertebral morphology than that across the injured vertebra in the treatment of thoracolumbar vertebral fractures. PMID- 22812094 TI - [Case-control study on two different approaches for the treatment of thoracolumbar fracture without neurological symptoms]. AB - OBJECTIVE: To investigate the clinical effects of two surgical approaches for the treatment of thoracolumbar fracture without neurological symptoms. METHODS: From January 2008 to December 2009, 40 cases with thoracolumbar fractures without neurological symptoms treated by surgery were respectively analyzed. Among the patients, there were 13 males and 27 females, with an average age of 46 years (ranged, 26 to 61 years). Twenty patients in group A treated through posterior median approach; twenty patients in group B were treated through paraspinal muscle approach. All the patients were received the same posterior spinal internal fixation (Sofamor Inc (Basis)). Operating time, blood loss, postoperative drainage, postoperative bed time, VAS score 24 and 72 hours after operation, postoperative Cobb angle correction rate, correction rate of vertebral collapse were analyzed. RESULTS: There were no significant difference in postoperative Cobb angle correction rate and vertebral collapse rate (P < 0.05); while the index such as operating time, blood loss, postoperative drainage, postoperative bed time and VAS score 24 h and 72 h after operation in group B is better than group A. CONCLUSION: Treatment of thoracolumbar fracture through posterior median approach has an advantage of minimal invasive, less bleeding and rapidly recovery, but the patients with neural symptoms and intraspinal occupying more than 1/3 is not suggested. PMID- 22812093 TI - [Posterior osteotomy and long-segment internal fixation for the treatment of senile thoracolumbar kyphotic deformity]. AB - OBJECTIVE: To explore the therapeutic effects of posterior osteotomy and long segment internal fixation in the treatment of senile thoracolumbar kyphotic deformity and provide the reference for operative treatment. METHODS: From April 2007 to April 2010, 19 older patients with thoracolumbar kyphotic deformity were respectively analyzed. There were 12 males and 7 females with an average age of 62 years (ranged, 58 to 74 years). Among patients, 11 cases were old fracture, 3 cases were ankylosing spondylitis, and 5 cases were old spinal tuberculosis. According to preoperative Frankel classification, 12 cases were grade E, 4 cases were grade D, 2 cases were C and 1 case was grade B. All patients were treated by posterior osteotomy and long-segment internal fixation and followed up above 1 year. VAS score preoperative, 2 weeks and 1 year after operation, Cobb's angle,n erve function and complication were observed. RESULTS: VAS score preoperative, 2 weeks and 1 year after operation separately was (7.0 +/- 1.2),(1.1 +/= .7) and (1.3 +/- .8); while Cobb's angle separately was (44.1 +/- .9), (10.9 +/- .1) and (11.5 +/- .8); there was significant difference in VAS score and Cobb's angle between preoperative and 2 weeks after operation (P < 0.05) w hile no significant difference between 2 weeks and 1 year after operation (P > 0.05). Eighteen cases met the standard of osseous fusion, 1 case occurred nonunion, but not looseness 1 year after operation. Nerve function: 3 cases changed grade E from 4 cases with grade D, 2 cases with grade C changed to grade D, 1 case with grade B changed to grade CONCLUSION: Posterior osteotomy and long-segment internal fixation for the treatment of senile thoracolumbar kyphotic deformity can receive a good short time effects. PMID- 22812095 TI - [Analysis of mechanisms and treatment of hyponatremia in acute spinal cord injuries]. AB - OBJECTIVE: To investigate etiologic factors,mechanisms and treatment of hyponatremia in patients with acute spinal cord injury. METHODS: From January 2005 to July 2010, 57 patients with hyponatremia after acute spinal cord injuries from severe trauma were treated. They included 46 males and 11 females who ranged in age from 26 to 69 years (mean 39.5 years). Of the 57 cases, 55 cases were complicated by cervical dislocation or fracture, and the remaining two cases were without dislocation or fracture. Among them, 28 patients had complete spinal cord injury, 29 had incomplete spinal cord injury. Nerve function was assessed according to the ASIA criteria, revealing type A in 28 cases, type B in 25 cases, and type C in 4 cases. Heart rate, blood pressure, 24-hour urine volume and serum sodium were measured daily, and fluid and sodium replacement was administered when the diagnosis of hyponatremia was confirmed. Urine sodium, serum osmotic pressure and urine osmotic pressure were measured every 3 days. The potential cause of the hyponatremia was supposed to be cerebral salt wasting syndrome (CSWS) or inappropriate antidiuretic hormone secretion (SIADH) according to the results and therapeutic reaction. Intravenous fluid infusion and salt replacement were required in patients with CSWS, while fluid restriction and intravenous salt replacement were administered for patients with SIADH. Parameters before and after treatment were analyzed with t-test. RESULTS: There were 42 patients with SCWS,and 15 patients with SIADH. Heart rate, serum sodium and serum osmotic pressure were higher 3 weeks after admission in all patients (all P < 0.01), while blood pressure and urine osmotic pressure were higher and urine sodium was lower (all P < 0.05). There was no significant difference in 24-h urine volume (P > 0.05). Heart rate, serum osmotic pressure, urine osmotic pressure showed further improvement by the time of discharge, while 24-h urine volume decreased, urine sodium further decreased (all P < 0.05). There was no significant change in blood pressure (P > 0.05). CONCLUSION: CSWS and SIADH are two potential causes of hyponatremia in patients with acute spinal cord injury. Distinguishing between these two disorders is of crucial importance because treatment of each condition is quite different, one needing vigorous salt replacement while the other needing fluid restriction. PMID- 22812096 TI - [Comparison between open reduction internal fixation with kirschner nails and mini-plates in treatment of Mason type II and III fractures of radial head: a case-control study]. AB - OBJECTIVE: To compare the effect between open reduction internal fixation with Kirschner nails and miniplates in the treatment of Mason type II and III fractures of radial head. METHODS: From May 2004 to March 2010, 50 cases of Mason type II and III fractures of radial head were treated with Kirschner nails or mini-plates. In Kirschner nail group, there were 13 males and 10 females (mean age 42.5 +/- 0.7 years), and 14 cases of Mason type II and 9 cases of Mason type III fracture. In mini-plate group, there were 17 males and 10 females (mean age 41.7 +/- 0.5 years), and 16 cases of Mason type II and 11 cases of Mason type of III fracture. The excellent and good rates according to the Broberg and Morrey Elbow Score, and the rate of ectopic ossification were compared. RESULTS: All the patients were followed up for 12-24 (mean 16.5 +/- 1.3) months. The Broberg and Morrey Elbow Score of mini-plate group was (90.5 +/- 11.6), and that of Kirschner nail group was (70.6 +/- 11.3). The result of mini-plate group was excellent in 15 cases, good in 9 cases, fair in 2 cases, and poor in 1 case; The result of Kirschner nail group was excellent in 8 cases, good in 9 cases, fair in 3 cases and poor in 3 cases. The effect of mini-plate group was better than that of Kirschner nail group. There was no statistic difference in the rate of ectopic ossification between the two groups (P > 0.05). CONCLUSION: Fractures of radial head can be well treated with open reduction and internal fixation by mini plates, which offer better results than Kirschner nails. PMID- 22812097 TI - [Case-control studies between two methods of minimally invasive surgery and traditional open operation for thoracolumbar fractures]. AB - OBJECTIVE: To investigate the surgical therapeutic result of thoracolumbar fracture treated by two minimally invasive surgery or by traditional open operation. METHODS: From June 2004 to April 2010, 76 patients (45 males and 31 females, with an average age of 36.4 years, ranging from 21 to 58 years) with thoracolumbar fracture were divided into three groups. In group A, 24 patients were treated with minimally invasive internal fixation by endoscope. In group B, 20 patients were treated by Sextant percutaneous pedicle screws fiaxation. In group C, 32 patients were performed with traditional open fixation surgery. The perioperative index and radiographic factor were compared among the three groups. RESULTS: All patients were followed-up for 1 year in average. The internal fixation devices were taken out averaged 1 year after operation,there were no complications related to the internal fixaton systems. The perioperative index of groups A and B including the incision size, surgical blood loss, surgical draining loss, hospital stay time and post-operation VAS score were significant smaller than group C (P < 0.05). The Cobb's angle, sagittal index, and anterior height of the fracture vertebral body were all significantly different between pre-operation and post-operation in each group (P < 0.05). CONCLUSION: These two methods of minimally invasive surgical treatments are effective and safe for patients with thoracolumbar fracture,because of less damage to muscles, less blood loss and quicker recovery, compared to the traditional open operation. PMID- 22812098 TI - [Imaging observation of live cells originating from osteoclasts of the blood system]. AB - OBJECTIVE: To study the application of the live cell imaging method to observe the whole process of osteoclast formation induced by monocyte macrophages in the blood system in order to clarify the origin of osteoclasts and their cytodynamics. METHODS: Blood samples (8 ml) were collected from the abdominal aorta of male SD rats weighing 280 g. Mononuclear cells were obtained by density gradient centrifugation and induced by RANKL and M-CSF. The cells were cultured and divided into four groups: inverted phase contrast microscope (IPCM) group, TRAP group, SEM group and live cell imaging (LCI) group. Images of the IPCM group were captured by a digital microscopic imaging system and recorded daily. The TRAP group was identified by enzyme activity staining after a 21-day cultivation period. The SEM group was SEM-observed after a 21-day cultivation period. The LCI group was consecutively and dynamically observed for 35 days. RESULTS: After 2 week cultivation, IPCM observations showed the formation of numerous apocytes. These cells displayed round, fusiform, fan-shaped, elliptic or irregular gibbous profiles. TRAP staining showed that most apocytes and monocytes had positive(+)reaction. SEM observations showed many bone absorption lacunae, hollows and channels, in which many osteoclasts with absorption activity were observed. Live cell imaging observations found that multinuclear osteoclasts originating from peripheral blood were generated by fusion of monocytes and apocytes and intercross fusion of monocytes and apocytes,which occurred at the adherent stage of the cells. Cytodynamic observations showed that the cell form of osteoclasts was complex and changeable. CONCLUSION: RANKL and M-CSF can induce differentiation and formation from monocytes in rat peripheral blood into multinuclear osteoclasts with bone absorption activity. The osteoclasts were formed by various cell fusion processes at the adherent stage. The adherent property of osteoclasts is important for their survival and function. Osteoclasts have phagocytosis and their morphological structure is dynamically changeable, involving not only apocytes but monocytes. The osteoclast property of multinuclear giant cells formed by cell fusion may be a special biological behavior for their adaptation of functional needs and bone absorption efficiency. This experiment has further evidenced the theory of osteoclast origination in the blood system and provided new experimental clues for clarifying the cytodynamic and cytobiological properties of osteoclasts. PMID- 22812099 TI - [Effects of mesangial cell on proliferation and function of osteoblast in vitro]. AB - OBJECTIVE: To explore the effects and mechanism of mesangial cell (MC) on proliferation and function of osteoblast in vitro from growth factors. METHODS: Osteoblast cultured in vitro were divided into normal blood serum group and MC group and cultured supernatant fluid by 10% serum culture medium and 20% MC culture medium. MTF was used to checked the proliferation of osteoblast at the end of 24, 48, 72, 120 h; Expression of BGP and OPN were tested 72 h and 144 h after culture; Expression of IGF-alpha and TGF-beta were tested 144 h after culture. RESULTS: The proliferation of osteoblast in MC group was obviously higher than normal blood serum group in different times (P < 0.05); The level of BGP and OPN of osteoblast was obviously higher than normal blood serum group (11.3%, 16.4%, 55.0% and 39.6%); and the level of IGF-alpha and TGF-beta of osteoblast was obviously higher than normal blood serum group (10.1% and 47.7%). CONCLUSION: MC can directly act on osteoblast, promote the proliferation and function of osteoblast by promoting secretion of TGF-beta. PMID- 22812100 TI - [Study on the mechanism of Feng's spinal manipulation for treatment of lumbar disk hernation with a calcified herniated mass using 3D CT]. AB - OBJECTIVE: To measure position changes of lumber disk herniation before and after treatment of Feng's spinal manipulation to study the mechanism of the manipulation for lumber disk herniation. METHODS: In 2010, 8 patients with lumber disk herniation were treated by Feng's spinal manipulation, including 3 males and 5 females who ranged in age from 14 to 53 years with a mean of 35.4 years. The patients received CT scan before and after treatment. All images were reconstructed to measure the distance between the apex of the calcified lumber disk herniation and the top of the next adjacent spinal process. RESULTS: The position of calcified lumber disk herniation underwent change after Feng's spinal manipulation, with a slight subluxation between the two adjacent vertebrae. CONCLUSION: If subluxation is restored,the relation between the nerve root and the hernation will undergo change, followed by subsequent change of the hernation mass, thus restoring the inner-outer balance of the spinal column system. PMID- 22812101 TI - [Pressure interlocking intramedullary nailing fixation and bone grafting for treatment of tibial fracture nonunion]. AB - OBJECTIVE: To explore the curative effect of intramedullary nailing pressure within a fixed period with a bone graft taken from the opening of intramedullary nailing on tibial fracture nonunion. METHODS: From February 2008 to October 2010, 18 patients with nonunion of tibial shaft were treated by pressurized intramedullary nail fixation and bone grafting taken from the opening of intramedullary nailing. They included 12 males and 6 females ranging in age from 31 to 67 (mean 42) years. The time from injury to surgery was 6-18 months (mean 8 months). There were 11 cases of nonunion and 7 cases of delayed union. After operation, the knee function was evaluated according to HSS scoring. The therapeutic effect was assessed by Tenny-Wiss scoring system. RESULTS: All patients were followed up for 12-36 (mean 18) months. The wound healed well without infection or skin necrosis. All patients had no nonunion, infection, deformity, and re-fracture. The bone healing time was from 4 to 8 months (mean 6 months). The HHS score of knee function 1 year after surgery averaged (89.97 +/- 3.21). The effect result of Tenny and Wiss scoring system was excellent in 16 cases and good in 2 cases. CONCLUSION: Open reduction by intramedullary nail fixed within a period with bone graft (from the opening of intramedullary nailing) for treatment of nonunion and delayed union of tibial fracture can improve the fracture healing rate, avoid complications from iliac bone grafting, and reduce medical expenses. PMID- 22812102 TI - [Double-loop cerclage wire No. 10 with the two-part patellar concertration for treatment of patellar comminuted fractures]. AB - OBJECTIVE: To investigate the clinical effects of double-loop cerclage wire No. 10 and the two-part patellar concertration for treatment of comminuted patellar fracture. METHODS: From June 2004 to June 2011, 86 patients with comminuted patellar fracture were treated with double-loop cerclage wire No. 10 and the two part patellar concertration. They included 48 males and 38 females ranging in age from 19 to 75 (mean 42.5) years. Fifty-two cases were affected in the left and 34 cases in the right, with 3 fracture pieces in 32 cases, 4 fracture pieces in 25 cases and more than 4 fracture pieces in 29 cases. The operation time was 40-70 minutes. The therapeutic effects were evaluated by Bostman patella fractures criteria in all patients. RESULTS: All patients were followed-up for 3 months to 6 years (mean 3.5 years). The overall Bdstman score was (27.65 +/- 2.05). The outcome was excellent in 78 cases and good in 8 cases. CONCLUSION: The double loop cerclage wire No. 10 and the two-part patellar concertration for comminuted patellar fracture is advantageous due to simplicity, good reduction, stable fixation,early functional exercise, and satisfactory functional recovery. PMID- 22812103 TI - [Combined anterior and posterior surgeries for double column acetabular fracture]. AB - OBJECTIVE: To explore the clinical effects and related factors of combined anterior and posterior surgeries in treatment of double column acetabular fracture. METHODS: From August 2007 to July 2009, 19 patients with double column acetabular fracture were treated. There were 13 males and 6 females, with a mean age of 39.6 years (ranged, 27 to 52 years). Among the patients, upper double column fracture was in 11 cases, lower double column fracture was in 8 cases and double column fracture involved sacroiliac joint in 1 case. The mean time from injury to operation was 5.8 days (ranged, 4 to 10 days). All patients were received combined anterior and posterior surgeries, reconstructed plate and fixed by screw. RESULTS: One patient was death, other patients were followed up from 12 to 18 months (with a mean time of 13.6 months). According to Harris standard, 9 cases got excellent results, 7 good cases and 2 fair. CONCLUSION: Combined anterior and posterior surgeries for double column acetabular fracture can get satisfactory effects. PMID- 22812104 TI - [Shock manipulation for the treatment of endoduction Monteggia fracture in children]. PMID- 22812105 TI - [Posterior dislocation of the shoulder joint: report of two cases]. PMID- 22812106 TI - [Operative treatment for adult patients with simultaneous fracture and dislocation of ipsilateral elbow and radiocarpal joint: 3 cases report]. PMID- 22812107 TI - [Update of research on minimally invasive treatment of lumbar disc herniation]. AB - There has been rapid progress in endoscopy-and imaging technology-based minimally invasive surgery for the treatment of lumbar disc herniation (LDH). It is advategeous over conventional surgery in that it not only reduces surgical trauma but relieves sufferings of patients. However, endoscopy-and imaging technology based minimally invasive surgery cannot completely replace traditional surgery at present because of its limited indications. How to expand the indications and solve the practical problem of lumbar reconstruction remains to be the direction of future breakthrough. This article is a summary of the progress and current situation of minimally invasive percutaneous and endoscopic techniques for the treatment of LDH. PMID- 22812108 TI - [Recent progress in the treatment of posterior tibial plateau fractures]. AB - There is a lack of ideal clinical classification systems for posterior tibial plateau fractures, and they need to be perfected in clinical practices. There are controversies over surgical approaches due to special characters of posterior tibial plateau fractures. It is difficult for the conventional techniques and approaches to achieve satisfactory reduction and fixation. A modified posterior approach is an ideal approach for the treatment of posterior tibial plateau fractures. This paper summarizes the classification, approach and internal fixation of posterior tibial plateau fractures. PMID- 22812109 TI - Population dynamics and "outbreaks" of diamondback moth (Lepidoptera: Plutellidae) in Guangdong province, China: climate or failure of management? AB - Diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), became the major pest of Brassica vegetable production in Guangdong, a province in southeastern China, in the late 1980s and has continued to challenge growers, particularly during the spring and autumn. Control has relied on insecticides and, as has happened in other parts of the world, resistance to these has evolved and subsequent field control failures have occurred. We review and summarize the history of diamondback moth management in Guangdong. We show that the geographic distribution of the pest in China is well described by a simple climate niche model. Our model predicts the seasonal phenology and some of the variation in abundance among years in Guangdong. Discrepancies may reflect migration and insecticide use at a landscape level. The scale of the pest problem experienced varies with management practices. Local production breaks, and strict post harvest hygiene are associated with lower pest pressure on large-scale production units. As more and more insecticides become ineffective the need to implement an insecticide resistance management strategy, as well as basic integrated pest management practices, will become more pressing. The potential use and development of a better forecasting system for diamondback moth that will assist these developments is outlined. PMID- 22812111 TI - Delaying corn rootworm resistance to Bt corn. AB - Transgenic crops producing Bacillus thuringiensis (Bt) toxins for insect control have been successful, but their efficacy is reduced when pests evolve resistance. To delay pest resistance to Bt crops, the U.S. Environmental Protection Agency (EPA) has required refuges of host plants that do not produce Bt toxins to promote survival of susceptible pests. Such refuges are expected to be most effective if the Bt plants deliver a dose of toxin high enough to kill nearly all hybrid progeny produced by matings between resistant and susceptible pests. In 2003, the EPA first registered corn, Zea mays L., producing a Bt toxin (Cry3Bb1) that kills western corn rootworm, Diabrotica virgifera virgifera LeConte, one of the most economically important crop pests in the United States. The EPA requires minimum refuges of 20% for Cry3Bb1 corn and 5% for corn producing two Bt toxins active against corn rootworms. We conclude that the current refuge requirements are not adequate, because Bt corn hybrids active against corn rootworms do not meet the high-dose standard, and western corn rootworm has rapidly evolved resistance to Cry3Bb1 corn in the laboratory, greenhouse, and field. Accordingly, we recommend increasing the minimum refuge for Bt corn targeting corn rootworms to 50% for plants producing one toxin active against these pests and to 20% for plants producing two toxins active against these pests. Increasing the minimum refuge percentage can help to delay pest resistance, encourage integrated pest management, and promote more sustainable crop protection. PMID- 22812110 TI - Distribution of Bemisia tabaci (Hemiptera: Aleyrodidae) biotypes in North America after the Q invasion. AB - After the 2004 discovery of the Bemisia tabaci (Gennadius) (Hemiptera Aleyrodidae) Q biotype in the United States, there was a vital need to determine the geographical and host distribution as well as its interaction with the resident B biotype because of its innate ability to rapidly develop high-level insecticide resistance that persists in the absence of exposure. As part of a coordinated country-wide effort, an extensive survey of B. tabaci biotypes was conducted in North America, with the cooperation of growers, industry, local, state, and federal agencies, to monitor the introduction and distribution of the Q biotype. The biotype status of submitted B. tabaci samples was determined either by polymerase chain reaction amplification and sequencing of a mitochondrial cytochrome oxidase I small subunit gene fragment and characterization of two biotype discriminating nuclear microsatellite markers or esterase zymogram analysis. Two hundred and eighty collections were sampled from the United States, Bermuda, Canada, and Mexico during January 2005 through December 2011. Host plants were split between ornamental plant and culinary herb (67%) and vegetable and field crop (33%) commodities. The New World biotype was detected on field-grown tomatoes (Solanum lycopersicum L.) in Mexico (two) and in commercial greenhouses in Texas (three) and represented 100% of these five collections. To our knowledge, the latter identification represents the first report of the New World biotype in the United States since its rapid displacement in the late 1980s after the introduction of biotype B. Seventy-one percent of all collections contained at least one biotype B individual, and 53% of all collections contained only biotype B whiteflies. Biotype Q was detected in 23 states in the United States, Canada (British Columbia and Ontario territories), Bermuda, and Mexico. Forty-five percent of all collections were found to contain biotype Q in samples from ornamentals, herbs and a single collection from tomato transplants located in protected commercial horticultural greenhouses, but there were no Q detections in outdoor agriculture (vegetable or field crops). Ten of the 15 collections (67%) from Canada and a single collection from Bermuda contained biotype Q, representing the first reports of biotype Q for both countries. Three distinct mitochondrial haplotypes of B. tabaci biotype Q whiteflies were detected in North America Our data are consistent with the inference of independent invasions from at least three different locations. Of the 4,641 individuals analyzed from 517 collections that include data from our previous work, only 16 individuals contained genetic or zymogram evidence of possible hybridization of the Q and B biotypes, and there was no evidence that rare hybrid B-Q marker co-occurrences persisted in any populations. PMID- 22812112 TI - An experiment on comb orientation by honey bees (Hymenoptera: Apidae) in traditional hives. AB - The orientation of combs in traditional beehives is extremely important for obtaining a marketable honey product. However, the factors that could determine comb orientation in traditional hives and the possibilities of inducing honey bees, Apis mellifera (L.), to construct more desirable combs have not been investigated. The goal of this experiment was to determine whether guide marks in traditional hives can induce bees to build combs of a desired orientation. Thirty two traditional hives of uniform dimensions were used in the experiment. In 24 hives, ridges were formed on the inner surfaces of the hives with fermented mud to obtain different orientations, circular, horizontal, and spiral, with eight replicates of each treatment. In the remaining eight control hives, the inner surface was left smooth. Thirty-two well-established honey bee colonies from other traditional hives were transferred to the prepared hives. The colonies were randomly assigned to the four treatment groups. The manner of comb construction in the donor and experimental hives was recorded. The results showed that 22 (91.66%) of the 24 colonies in the treated groups built combs along the ridges provided, whereas only 2 (8.33%) did not. Comb orientation was strongly associated with the type of guide marks provided. Moreover, of the 18 colonies that randomly fell to patterns different from those of their previous nests, 17 (94.4%) followed the guide marks provided, irrespective of the comb orientation type in their previous nest. Thus, comb orientation appears to be governed by the inner surface pattern of the nest cavity. The results suggest that even in fixed comb hives, honey bees can be guided to build combs with orientations suitable to honey harvesting, without affecting the colonies. PMID- 22812113 TI - Strain specificity and simultaneous transmission of closely related strains of a Potyvirus by Myzus persicae. AB - Potato virus Y (PVY), a Potyvirus, is transmitted by aphids in a nonpersistent manner. PVY severely affects potato production worldwide. Single and mixed infections of PVY strains, namely PVY(O), PVY(NTN), and PVY(N:O) are a common occurrence in potato systems. However, information available on the ability of aphids to simultaneously transmit multiple PVY strains, specificity associated with simultaneous transmission, and factors affecting specificity are limited. Aphid-mediated transmission experiments were conducted to test the ability of individual aphids to transmit multiple strains using a PVY indicator host. Preliminary results revealed that aphids can transmit at least two viral strains simultaneously. Subsequently, aphid-mediated transmission of three dual-strain combinations was tested using potato plants. Individual aphids transmitted two viral strains simultaneously for all three dual-strain combinations. In all aphid mediated dual-strain infections involving PVY(NTN), the rate of PVY(NTN) infection was greater than the infection rates of the second strain and dual strain combinations, indicating specificity associated with transmission of PVY strains. Results of aphid-mediated transmission experiments were compared with results obtained through mechanical transmission. In general, PVY infection rates from aphid-mediated transmission were lower than the rates obtained through mechanical transmission. Unlike aphid-mediated transmission, component strains in dual-strain inoculations were not eliminated during mechanical transmission. These results suggest that there may also be interference associated with aphid mediated transmission of closely related PVY strains. Perhaps, the observed specificity and/or interference may explain the increase in the incidence of PVY(NTN) and other necrotic strains in recent years. PMID- 22812114 TI - Critical rearing parameters of Tetrastichus planipennisi (Hymenoptera: Eulophidae) as affected by host plant substrate and host-parasitoid group structure. AB - In laboratory assays, we evaluated the potential impact of host plant substrate types, host-parasitoid group sizes (densities), and parasitoid-to-host ratios on select fitness parameters of the larval endoparasitoid Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae), newly introduced for biological control of emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), in the United States. Results from our study showed that offspring production and critical fitness parameters (body size and sex ratio) of T. planipennisi from parasitized emerald ash borer larvae are significantly influenced by host plant substrate type, host-parasitoid group size, parasitoid-to-host ratio, or a combination in the primary exposure assay. The number of both female and male T. planipennisi progeny was significantly greater when emerald ash borer larvae were inserted into tropical ash [Fraxinus uhdei (Wenz.) Lingelsh.] logs rather than green ash (Fraxinus pensylvanica Marshall). When maintained at a constant 1:1 parasitoid-to-host ratio, assays with larger host-parasitoid group sizes (3:3 12:12) produced significantly greater numbers of both male and female offspring per parental wasp compared with those with the single host-parasitoid (1:1) group treatment. As the parasitoid-to-host ratio increased from 1:1 to 8:1 in the assay, the average brood size (number of offspring per parasitized emerald ash borer larva) increased significantly, whereas the average brood sex ratio (female to male) changed from being female-biased (6:1) to male-biased (1:2); body size of female offspring as measured by the length of ovipositor and left hind tibia also was reduced significantly. Based on these findings, we suggest that the current method of rearing T. planipennisi with artificially infested-emerald ash borer larvae use the tropical ash logs for emerald ash borer insertion, a larger (> or = 3:3) host-parasitoid group size and 1:1 parasitoid-to-host ratio in the primary parasitoid exposure assays. PMID- 22812115 TI - A comparison of artificial diets for mass rearing Brontispa longissima (Coleoptera: Chrysomelidae) as hosts for the larval and the pupal parasitoids. AB - The coconut hispine beetle, Brontispa longissima (Gestro) (Coleoptera: Chrysomelidae) is a serious pest of coconut palm. In this study, we developed an artificial diet for B. longissima so that the beetle could be used as a host for rearing two of its parasitoids, Asecodes hispinarum Boucek (Hymenoptera: Eulophidae) and Tetrastichus brontispae Ferriere (Hymenoptera: Eulophidae). The new artificial diet represents an improvement of our previous diet, which we used as a control. When beetle larvae were reared on the new diet, which contains cysteine but not cellulose powder and has twice as much coconut leaf powder as in the control, the adult emergence was 71% (approximately 2 times that in the control). We also examined the suitability of beetles fed on the new diet as hosts for the larval parasitoid A. hispinarum and the pupal parasitoid T. brontispae. The percentage of wasps that emerged from hosts that were fed the new diet was higher than that from the control-fed hosts. The new diet allowed both A. hispinarum and T. brontispae to produce adult wasps of the next generation, whereas the control only allowed T. brontispae to produce the next generation. These results suggest that the new diet is suitable for B. longissima and will facilitate mass-rearing of A. hispinarum and T. brontispae. PMID- 22812116 TI - Oxygenated phosphine fumigation for control of Nasonovia ribisnigri (Homoptera: Aphididae) on harvested lettuce. AB - Low temperature regular phosphine fumigations under the normal oxygen level and oxygenated phosphine fumigations under superatmospheric oxygen levels were compared for efficacy against the aphid, Nasonovia ribisnigri (Mosley), and effects on postharvest quality of romaine and head lettuce. Low temperature regular phosphine fumigation was effective against the aphid. However, a 3 d treatment with high phosphine concentrations of > or = 2,000 ppm was needed for complete control of the aphid. Oxygen greatly increased phosphine toxicity and significantly reduced both treatment time and phosphine concentration for control of N. ribisnigri. At 1,000 ppm phosphine, 72 h regular fumigations at 6 degrees C did not achieve 100% mortality of the aphid. The 1,000 ppm phosphine fumigation under 60% O2 killed all aphids in 30 h. Both a 72 h regular fumigation with 2,200 ppm phosphine and a 48 h oxygenated fumigation with 1,000 ppm phosphine under 60% O2 were tested on romaine and head lettuce at 3 degrees C. Both treatments achieved complete control of N. ribisnigri. However, the 72 h regular fumigation resulted in significantly higher percentages of lettuce with injuries and significantly lower lettuce internal quality scores than the 48 h oxygenated phosphine fumigation. Although the oxygenated phosphine fumigation also caused injuries to some treated lettuce, lettuce quality remained very good and the treatment is not expected to have a significant impact on marketability of the lettuce. This study demonstrated that oxygenated phosphine fumigation was more effective and less phytotoxic for controlling N. ribisnigri on harvested lettuce than regular phosphine fumigation and is promising for practical use. PMID- 22812117 TI - Acute exposure to low-dose radiation disrupts reproduction and shortens survival of Wasmannia auropunctata (Hymenoptera: Formicidae) queens. AB - Irradiation is a postharvest quarantine treatment option to control ants and other hitchhiker pests on fresh horticultural products exported from Hawaii. The radiotolerance of the invasive little fire ant, Wasmannia auropunctata (Roger) (Hymenoptera: Formicidae: Myrmicinae), was studied to determine a dose sufficient for its control. Queens from each of five laboratory microcolonies started from five geographic locations in Argentina were irradiated at 20, 50, 70, or 100 Gy or left untreated as controls and then followed for 13 wk to observe colony growth. In general, queen survivorship, and the number of eggs, larvae, and pupae observed in the microcolonies decreased with increasing irradiation dose. In the 50-, 70-, and 100-Gy treatments, the number of eggs observed was reduced by 68, 66, and 76%, respectively, compared with untreated control microcolonies. The number of larvae in the 50-, 70-, and, 100-Gy treatments was reduced by 99.6%, and only one pupa was observed in the 50-Gy treatment and none in the 70- and 100 Gy treatments during the 13-wk experiment. Queens in the 100-Gy treatment had significantly reduced longevity compared with queens in the other treatments. Radiation doses > or = 70 Gy stopped reproduction in W. auropunctata queens and should be sufficient as a phytosanitary treatment. Information from additional invasive ants in Myrmicinae and other subfamilies is needed before recommending a generic irradiation treatment for ants. PMID- 22812118 TI - Understanding long-term fruit fly (Diptera: Tephritidae) population dynamics: implications for areawide management. AB - Fruit flies (Diptera: Tephritidae) are devastating agricultural pests worldwide but studies on their long-term population dynamics are sparse. Our aim was to determine the mechanisms driving long-term population dynamics as a prerequisite for ecologically based areawide pest management. The population density of three pestiferous Anastrepha species [Anastrepha ludens (Loew), Anastrepha obliqua (Macquart), and Anastrepha serpentina (Wiedemann)] was determined in grapefruit (Citrus x paradisi Macfad.), mango (Mangifera indica L.), and sapodilla [Manilkara zapota (L.) P. Royen] orchards in central Veracruz, Mexico, on a weekly basis over an 11-yr period. Fly populations exhibited relatively stable dynamics over time. Population dynamics were mainly driven by a direct density dependent effect and a seasonal feedback process. We discovered direct and delayed influences that were correlated with both local (rainfall and air temperature) and global climatic variation (El Nino Southern Oscillation [ENSO] and North Atlantic Oscillation [NAO]), and detected differences among species and location of orchards with respect to the magnitude and nature (linear or nonlinear) of the observed effects, suggesting that highly mobile pest outbreaks become uncertain in response to significant climatic events at both global and local levels. That both NAO and ENSO affected Anastrepha population dynamics, coupled with the high mobility of Anastrepha adults and the discovery that when measured as rate of population change, local population fluctuations exhibited stable dynamics over time, suggests potential management scenarios for the species studied lie beyond the local scale and should be approached from an areawide perspective. Localized efforts, from individual growers will probably prove ineffective, and nonsustainable. PMID- 22812119 TI - A comparison of trap type and height for capturing cerambycid beetles (Coleoptera). AB - Wood-boring beetles in the family Cerambycidae (Coleoptera) play important roles in many forest ecosystems. However, increasing numbers of invasive cerambycid species are transported to new countries by global commerce and threaten forest health in the United States and worldwide. Our goal was to identify effective detection tools for a broad array of cerambycid species by testing some known cerambycid attractants and a pheromone in different trap designs placed across a range of habitats. We compared numbers and species richness of cerambycid beetles captured with cross-vane panel traps and 12-unit Lindgren multiple-funnel traps, placed either at ground level (1.5 m high) or canopy level (approximately 3-10 m high), at eight sites classified as either residential, industrial, deciduous forest, or conifer forest. We captured 3,723 beetles representing 72 cerambycid species from 10 June to 15 July 2010. Species richness was highest for the subfamilies Cerambycinae and Lamiinae, which accounted for 33 and 46% of all species captured, respectively. Overall, the cross-vane panel traps captured approximately 1.5 times more beetles than funnel traps. Twenty-one species were captured exclusively in traps at one height, either in the canopy or at ground level. More species were captured in hardwood sites (59 species) where a greater diversity of host material was available than in conifer (34 species), residential (41 species), or industrial (49) sites. Low numbers of beetles (n < 5) were recorded for 28 of the beetle species. The number of species captured per week ranged from 49 species on 21 June to 37 species on 12 July. Cross-vane panel traps installed across a vertical gradient should maximize the number of cerambycid species captured. PMID- 22812120 TI - Feeding preference and movement of Nezara viridula and Euschistus serous (Hemiptera: Pentatomidae) on individual cotton plants. AB - Experiments were conducted in an environmental growth chamber to determine the movement and feeding preferences of Nezara viridula (L.) and Euschistus serous (Say) on individual cotton plants. Fifth instars were caged by species on a single cotton plant (FM 9063 B2F) containing four discrete boll sizes ranging from 1.1 to 3.0 cm in diameter over a period of 5 d per replication. Two digital video cameras were simultaneously focused on each of the four bolls per plant to visually confirm stink bug resting and movement. During the study, a total of 4,080 h of video footage was recorded and analyzed. Results showed that N. viridula and E. serous did not prefer the exact same boll sizes. In a trial with eight stink bugs per plant, N. viridula spent more time on the three larger boll classes, 1.6-2.0, 2.1-2.5, and 2.6-3.0 cm. In a separate trial with one stink bug per plant, N. viridula spent more time on the larger boll classes while E. serous exhibited the strongest preference for 1.1-1.5 and 2.1-2.5 cm bolls. N. viridula moved more often than E. serous and both species moved more often during photophase compared with scotophase. Regardless of species or number of bugs released, bolls in the smallest boll size class fell off the plant about 3 d after the bugs were released. These results confirm that scouts who are estimating stink bug damage should select bolls in the 2.1-2.5 cm diameter boll size class. PMID- 22812121 TI - Impact of wheat-mung bean intercropping on English grain aphid (Hemiptera: Aphididae) populations and its natural enemy. AB - The effects of intercropping wheat, Triticum aestivum L., with mung bean, Vigna radiate L., on the populations of English grain aphid, Sitobion avenae (F.) (Hemiptera: Aphididae), and its natural enemies were evaluated by field and laboratory experiments. The population densities of aphids and their natural enemies were evaluated in the intercropped field against different row ratio combinations of wheat-mung bean. Results showed that wheat-mung bean intercropping caused a drop in aphid densities, and the ratio 12 wheat: 4 mung bean brought about the largest drop (> 8%). In addition, the population densities of coccinellids (ladybirds) and parasitoids and the species diversity of all the natural enemies of aphid were higher in the intercropped field than in the field planted only with wheat. However, intercropping did not influence the community indices (evenness and index of dominance concentration) of the natural enemies. Y tube olfactometer bioassays were carried out in the laboratory to test whether odor blends of host and nonhost plants affect the host selection of S. avenae. Bioassays indicated that both apterous and alate aphids significantly preferred host plant odor over odor blends of host and intercropped species. Hence, the olfactory-based host location of aphids in the field might be affected by intercropping. The intercropping experiment clearly showed that increased crop species diversity suppresses aphid population growth and preserves the population of natural enemies of aphids. Our results also provide support for the "resource concentration hypothesis" and the "enemies hypothesis". PMID- 22812122 TI - Temperature dependent development of Lygus hesperus (Hemiptera: Miridae) nymphs. AB - Lygus hesperus Knight (Hemiptera: Miridae) is a key pest of fruit and vegetable crops, forages, and cotton (Gossypium spp.) in the western United States. Accurate models describing relationships between temperature and L. hesperus development are critical to the study of seasonal L. hesperus population dynamics. Development of L. hesperus nymphs was assessed at nine constant temperatures from 10 to 37.8 degrees C. The relationships between temperature and development for each L. hesperus instar, and for the entire nymphal stage, were best described by six-parameter biophysical models indicating both low- and high temperature inhibition of development. Development rates asymptotically approached zero with decreasing temperature in the lower thermal range, and decreased with increasing temperatures above 32.2 degrees C. Nymphs did not survive from egg hatch to adulthood at either 10 or 37.8 degrees C, and nymph mortality was > 90% at both 12.8 and 35.0 degrees C. The fifth instar exhibited the longest stadium, whereas the shortest stadia were associated with the second and third instars. Development rates of males and females did not differ, and the ratio of males to females was not different from 1:1 at any temperature. Our temperature-dependent development rate models for L. hesperus nymphs will facilitate control of insect physiological age in controlled laboratory experiments, and should be useful in planning and interpreting field studies on L. hesperus population dynamics. PMID- 22812123 TI - Laboratory-based toxicological assessments of new insecticides on mortality and fecundity of Neoseiulus fallacis (Acari: Phytoseiidae). AB - Neoseiulus fallacis (Garman) is one of the most abundant predatory phytoseid in deciduous fruit orchards under an integrated pest management (IPM) regimen in eastern North America. Laboratory studies using N. fallacis, and the 'modified excised leaf disc method' identified four insecticides out of six, that would require second-tier field studies before inclusion in an IPM program for deciduous orchards. The overall egg mortality caused by flubendiamide, chlorantraniliprole, chlothianidin, novaluron, Spinetoram, and spirotetramat ranked from 0 to 37.6%. Larval mortality caused by spirotetramat, spinetoram, novaluron, and chlothianidin ranged from 100 to 78.3%, respectively. Chlorantraniliprole and flubendiamide were virtually nontoxic to larvae. Spinetoram, chlothianidin, and spirotetramat caused 100, 61.4, and 40.2% mortality of adult N. fallacis, respectively. Spirotetramat and chlothianidin significantly reduced fecundity, whereas novaluron, flubendiamide, and chlorantraniliprole had no such adverse effect for the duration of the study (168 h). Chlorantraniliprole and flubendiamide do not require further second tier field studies and may be included in deciduous orchard IPM programs. Spirotetramat is toxic to several growth stages but it has a very short residual activity, and along with novaluron, which is toxic only to larvae, should be evaluated in second-tier field studies. Clothianidin and spinetoram should be evaluated in second-tier field studies only if alternatives are unavailable. PMID- 22812124 TI - Costs of insecticide resistance in Cydia pomonella (Lepidoptera: Tortricidae). AB - The obvious benefits associated with insecticide resistance for pest species may come at a cost to other life-history traits. In this study, we compared the larval and pupal developmental times, pupal mass wing surface area and wing fluctuating asymmetry (FA) in insecticide resistant and control strains of codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), collected from apple (Malus spp.) orchards in central Canada. Resistant strains had significantly longer larval developmental times and lower pupal masses compared with the susceptible strain. Although the forewings of resistant moths were smaller in resistant than control strain, no difference in wing FA was detected. Longer developmental times could increase exposure time to natural enemies, and reduced adult size could affect longevity and total reproductive output. PMID- 22812125 TI - Silica and nitrogen modulate physical defense against chewing insect herbivores in bioenergy crops Miscanthus x Giganteus and Panicum virgatum (Poaceae). AB - Feedstock crops selected for bioenergy production to date are almost exclusively perennial grasses because of favorable physiological traits that enhance growth, water use, and nutrient assimilation efficiency. Grasses, however, tend to rely primarily on physical defenses, such as silica, to deter herbivores. Silica impedes processing of feedstocks and introduces a trade-off between managing for cost efficiency (i.e., yield) and plant defenses. To test how silica modulates herbivory in two of the most preferred feedstock crops for production across the central United States, miscanthus (Miscanthus x giganteus Greef and Deuter ex Hodkinson and Renvoize) and switchgrass (Panicum virgatum L.), we examined the performance of two immature generalist insect herbivores, fall armyworm (Spodoptera frugiperda (J.E. Smith) and the American grasshopper [Schistocerca americana (Drury)], on grasses grown under silica and nitrogen amendment. Both miscanthus and switchgrass assimilated nitrogen and silica when grown in amended soil that altered the consumption and conversion efficiency of herbivores consuming leaf tissue. The magnitude of nutrient assimilation, however, depended on intrinsic plant traits. Nitrogen increased conversion efficiency for both fall armyworm and American grasshopper but increased consumption rate only for fall armyworm. Silica reduced conversion efficiency and increased consumption rate only for the American grasshopper. Because of this variability, management strategies that reduce silica or increase nitrogen content in feedstock crops to enhance yields may directly influence the ability of bioenergy grasses to deter certain generalist herbivores. PMID- 22812126 TI - Impact of neonicotinoid seed treatments on thrips (Thysanoptera: Thripidae) and soybean yield in Virginia and North Carolina. AB - Currently there are several neonicotinoid insecticide seed treatments registered for use on soybean (Glycine max L.), with disparity in adoption rates in the eastern United States. A complex of seedling insect pests is found in mid-south soybean, but thrips are the primary early season pest of soybean in Virginia and North Carolina. Published knowledge regarding their impact on soybean yield is minimal, as is the impact of thrips on soybean yield; thrips species composition is also understudied. In 2008 through 2010, nine field experiments in Virginia and North Carolina were conducted to evaluate the impact on thrips population dynamics; the influence on yield of neonicotinoid seed treatments, imidacloprid and thiamethoxam, was reported from nine of these experiments. Moreover, thrips species abundance was recorded in three of these experiments. Both imidacloprid and thiamethoxam reduced thrips densities compared with untreated soybean. Thiamethoxam was more effective than imidacloprid in reducing adult thrips densities at 5 wk after planting. Adult densities peaked at 3 wk after planting, followed by larval densities, which peaked at 4 wk after planting. The most abundant thrips species was Frankliniella fusca (Hinds), followed by Neohydatothrips variabilis (Beach). Other common species included F. occidentalis (Pergande) and F. tritici (Fitch). In general, F. fusca was more common earlier in the season, while N. variabilis was more common later in the season. There were no significant differences in yield among any of the treatments or in the untreated controls. Although neonicotinoid insecticides reduced thrips abundance, data collected in these studies demonstrated that there was no positive yield response. PMID- 22812127 TI - Pan trapping soybean aphids (Hemiptera: Aphididae) using attractants. AB - Since its introduction into the United States in the past 10 yr, soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), has been a damaging pest to soybean, Glycine max (L.) Merrill. During 2008 and 2009, fields in central and north central Iowa experienced pockets of high soybean aphid populations. Electroantennograms have shown that soybean aphid alatae are capable of detecting host plant volatiles and sex pheromones. Here, we evaluated baited pan traps as a potential soybean aphid attractant. Yellow pan traps were placed in soybean fields after planting along with lures that contained plant volatiles and sex pheromones in 2008 or sex pheromones only in 2009. Pan trap contents were collected weekly, and plant counts also were conducted. Aphids were identified, and soybean aphids were counted to determine whether one chemical lure was more attractive to spring migrants than other lures. In both years, soybean aphids collected in pan traps with lures were not significantly different from the other products tested. PMID- 22812128 TI - Sampling strategies for square and boll-feeding plant bugs (Hemiptera: Miridae) occurring on cotton. AB - Sampling methods for square and boll-feeding plant bugs (Hemiptera: Miridae) occurring on cotton, Gossypium hirsutum L., were compared with the intent to assess if one approach was viable for two species occurring from early-season squaring to late bloom in 25 fields located along the coastal cotton growing region of south Texas. Cotton fleaphopper, Pseudatomoscelis seriatus (Reuter), damages squares early-season and dominated collections using five sampling methods (approximately 99% of insects collected). A major species composition shift occurred beginning at peak bloom in coastal fields, when verde plant bug, Creontiades signatus Distant, represented 55-65% of collections. Significantly more cotton fleahoppers were captured by experienced samplers with the beat bucket and sweep net than with the other methods (30-100% more). There were more than twice as many verde plant bugs captured by experienced and inexperienced samplers with the beat bucket and sweep net than captured with the KISS and visual methods. Using a beat bucket or sweep net reduced sampling time compared with the visual method for the experienced samplers. For both species, comparing regressions of beat bucket-based counts to counts from the traditional visual method across nine cultivar and water regime combinations resulted in only one combination differing from the rest, suggesting broad applicability and ability to translate established visual-based economic thresholds to beat bucket-based thresholds. In a first look at sample size considerations, 40 plants (four 10 plant samples) per field site was no more variable than variation associated with larger sample sizes. Overall, the beat bucket is much more effective in sampling for cotton fleahopper and verde plant bug than the traditional visual method, it is more suited to cotton fleahopper sampling early-season when plants are small, it transitions well to sample for verde plant bug during bloom, and it performs well under a variety of soil moisture conditions and cultivar selections. PMID- 22812129 TI - Blending synthetic pheromones of cerambycid beetles to develop trap lures that simultaneously attract multiple species. AB - We evaluated attraction of cerambycid beetle species to blends of known cerambycid pheromones to determine whether such blends could be used as effective trap lures for detecting and monitoring multiple species simultaneously. Pheromone-baited traps captured 1,358 cerambycid beetles of which 1,101 (81.1%) belonged to three species in the subfamily Cerambycinae: Neoclytus acuminatus (F.), Neoclytus mucronatus (F.), and Xylotrechus colonus (F.). Beetles of these species were significantly attracted to synthetic blends that contained their pheromone components (isomers of 3-hydroxy-2-hexanone, 2,3-hexanediol, or both), despite the presence of pheromone components of different species, including other isomers of 2,3-hexanediol, (E/Z)-6,10-dimethyl-5,9-undecadien-2-yl acetate, and citral. In some cases, attraction was partially inhibited by the pheromone components of heterospecific species, whereas for N. acuminatus, attraction was completely inhibited when blends contained (2R*,3S*)-hexanediol, the racemic mixture of diastereomers of its pheromone, (2S,3S)-hexanediol. Among the remaining beetles captured were three species in the subfamily Lamiinae: Astyleiopus variegatus (Haldeman), Graphisurus fasciatus (Degeer), and Lepturges angulatus (LeConte). All three lamiine species were previously known to be attracted to (E/Z)-6,10-dimethyl-5,9-undecadien-2-yl acetate and were captured in significant numbers by blends containing that compound. Our results suggest that different types of cerambycid pheromones can be combined to create effective multispecies lures for use in surveillance programs that target exotic cerambycid species. PMID- 22812130 TI - Systemic insecticide and gibberellin reduced cone damage and increased flowering in a spruce seed orchard. AB - Insects feeding in conifer cones are difficult to control with nonsystemic insecticides. Newly developed systemic insecticides that can be injected into tree trunks may be a possible way of reducing both insect damage and negative side-effects to the surrounding environment, compared with conventional spraying. Several insecticides that could be injected into tree stems were tested on Picea abies (L.) Karst. In one experiment, insecticides (bifenthrin, deltamethrin, abamectin, and imidacloprid) were injected during flowering; in a second experiment two of these insecticides (abamectin and imidacloprid) were injected 1 yr before the expected flowering. In the second experiment insecticide treatment was also combined with treatments with the flower stimulating hormone, gibberellin (GA(4/7)). The only insecticide that reduced damage was abamectin, both after injection during flowering and after injection 1 yr before the expected flowering. Injections with GA(4/7) increased flowering and were as efficient as the conventional application method of drilling but abamectin was not effective in combination with the drilling method. There was no negative effect of the insecticide injections on seed quality. The injections were ineffective against the seed chalcid Megastigmus strobilobius (Ratzeburg), which was found to have an unexpected, negative effect on seed quality. Our results suggest that it may be possible to reduce damage from certain insect species, and to increase flowering by injecting abamectin and GA(4/7) in the year before a cone crop. PMID- 22812131 TI - Role of ipsdienol, ipsenol, and cis-verbenol in chemical ecology of Ips avulsus, Ips calligraphus, and Ips grandicollis (Coleoptera: Curculionidae: Scolytinae). AB - Stressed or damaged pine (Pinus sp.) trees in the southeastern United States are often colonized simultaneously by three southern Ips species (Coleoptera: Curculionidae: Scolytinae): small southern pine engraver, Ips avulsus (Eichhoff); sixspined ips, Ips calligraphus (Germar); and eastern fivespined ips, Ips grandicollis (Eichhoff). All three species mediate colonization of host material with volatile pheromones. All of the southern Ips produce cis-verbenol, and either ipsdienol or ipsenol, and electrophysiological studies have demonstrated that all three southern Ips are able to detect all three compounds. This study examined the role of ipsdienol, ipsenol, and cis-verbenol in the chemical ecology of the southern Ips in Georgia and Louisiana. The most attractive blends of pheromones, with the fewest number of components, were ipsdienol plus ipsenol for I. avulsus, cis-verbenol plus ipsdienol for I. calligraphus, and either cis verbenol plus ipsenol or ipsdienol plus ipsenol for I. grandicollis. Cross attraction of I. grandicollis to the pheromone blend most attractive to I. avulsus was observed. Although the presence of heterospecific pheromone reduced the catches of all three species (i.e., the tertiary blend captured fewer beetles than the most attractive binary blends) in both states (significantly in two cases), high numbers of all three species were still captured in traps baited with all three compounds. These results suggest that the pheromones cis-verbenol, ipsdienol, and ipsenol can be combined for monitoring all three species of the southern Ips simultaneously. PMID- 22812132 TI - Influence of plant combinations on population characteristics of Bemisia tabaci biotypes B and Q. AB - In recent years, the dominant biotype of Bemisia tabaci (Gennadius) has shifted from biotype B to Q in many locations of China. Our field monitoring showed that B. tabaci biotype Q could be found on pepper Capsicum frutescens L. while biotype B could not be found on the plant. To study the role of the host plant in the displacement of biotype B by Q, the adult mortality, female fecundity, and adult emergence of both biotypes B and Q on different host combinations were studied using a model system involving pepper and eggplant. The results showed that pepper is not a preferred host for either biotype B or Q adults in comparison with eggplant. The negative impact of pepper to biotype B is, however, much greater than that to biotype Q. Because both the survival rates of the adult whitefly and the average number of emerged adults per female of biotype Q on pepper are higher than that of biotype B, biotype Q showed higher fitness in comparison with biotype B. Our results suggest that the existence and differential impact of a nonpreferred host might affect the population fitness and therefore could play a role in the displacement of biotype B in some regions. PMID- 22812133 TI - Comparison of three dispenser distribution patterns for pheromone mating disruption of Paralobesia viteana (Lepidoptera: Tortricidae) in vineyards. AB - Over two growing seasons, Isomate GBM-Plus tube-type dispensers releasing the major pheromone component of grape berry moth, Paralobesia viteana (Clemens) (Lepidoptera: Tortricidae), were evaluated in vineyards (Vitis spp.) in Michigan, New York, and Pennsylvania. Dispensers were deployed in three different density arrangement treatments: 124 dispensers per ha, 494 dispensers per ha, and a combined treatment with 124 dispensers per ha in the vineyard interior and 988 dispensers per ha at the vineyard border, equivalent to an overall density of 494 dispensers per ha. Moth captures and cluster infestation levels were compared at the perimeter and interior of vineyards receiving these different pheromone treatments and in vineyards receiving no pheromone. Orientation of male moths to pheromone-baited traps positioned at the perimeter and interior of vineyards was reduced as a result of mating disruption treatments compared with the nontreated control. These findings were consistent over both years of the study. Disruption of male moth captures in traps varied from 93 to 100% in treated vineyards, with the 494 dispensers per ha application rates providing significantly higher level of disruption than the 124 dispensers per ha rate, but only in 2007. Measurements of percentage of cluster infestation indicated much higher infestation at perimeters than in the interior of the vineyards in all three regions, but in both sample positions there was no significant effect of dispenser density on cluster infestation levels in either year. The contrasting results of high disruption of moth orientation to traps in vineyards that also had low levels of crop protection from this pheromone treatment are discussed in the context of strategies to improve mating disruption of this tortricid pest. PMID- 22812134 TI - Effectiveness of tomato-spotted wilt virus management tactics. AB - Tomato-spotted wilt (TSW) is caused by the tomato-spotted wilt virus (TSWV) and is a major disease affecting the production of tomato and pepper in the Southeastern United States. Before initiating a multistate, regional project addressing this issue, a survey was conducted in North Carolina, South Carolina, Georgia, and Florida to assess the need for improved management of TSWV in these crops. We investigated farmer's stated effectiveness of four common TSWV management tactics (reflective mulch, resistant cultivar, imidacloprid, and Actiguard) in pepper and tomato production using logistic regression. We found that the odds that farmers were satisfied with the use of reflective mulch alone in controlling TSWV is 9-1, about one and a half times the amount obtained from using Actiguard alone. Moreover, the odds that farmers were satisfied with a practice that combines reflective mulch and Actiguard was far greater than that obtained from using each of the technique separately. We found some similarities between farmer's stated effectiveness and revealed effectiveness from experiments. PMID- 22812135 TI - Reproductive biology of Pseudococcus maritimus (Hemiptera: Pseudococcidae). AB - This study characterized several parameters associated with reproductive behaviors of a Californian population of the grape mealybug, Pseudococcus maritimus (Ehrhorn). Experiments with caged adults confirmed that females from this population could not reproduce parthenogenetically. Both sexes were capable of mating multiple times on the same day and on sequential days. Median times between copulations were short (< 10 min) on the first day that males were presented with females, but tended to increase with sequential copulation events. Unmated females lived for up to 19 wk, whereas mating and oviposition resulted in reduced longevity. We hypothesized that constant exposure to pheromone might stimulate males to leave their cocoons sooner and increase their activity levels compared with males that were not exposed to pheromone, resulting in shortened life-spans. However, whereas exposure to pheromone did stimulate males to emerge slightly sooner than control males, pheromone exposure had no effect on the longevity of males. The implications of the results of these experiments for pheromone-based methods of detection and control of mealybugs are discussed. PMID- 22812136 TI - Ineffectiveness of over-the-counter total-release foggers against the bed bug (Heteroptera: Cimicidae). AB - Field-collected bed bugs (Cimex lectularius L.) showed little, if any, adverse effects after 2-h direct exposure to the aerosolized pyrethroid(s) from three over-the-counter total-release foggers ('bug bombs' or 'foggers'); Hotshot Bedbug and Flea Fogger, Spectracide Bug Stop Indoor Fogger, and Eliminator Indoor Fogger. One field-collected population, EPM, was an exception in that there was significant mortality at 5-7 d when bugs out in the open had been exposed to the Spectracide Fogger; mortality was low when these bugs had access to an optional harborage, a situation observed for all field-collected populations when exposed to the three foggers. Even the Harlan strain, the long-term laboratory population that is susceptible to pyrethroids and that served as an internal control in these experiments, was unaffected if the bugs were covered by a thin cloth layer that provided harborage. In residences and other settings, the majority of bed bugs hide in protected sites where they will not be directly contracted by the insecticide mist from foggers. This study provides the first scientific data supporting the position that total-release foggers should not be recommended for control of bed bugs, because 1) many field-collected bed bugs are resistant to pyrethroids, and they are not affected by brief exposure to low concentrations of pyrethrins and/or pyrethroids provided by foggers; and 2) there is minimal, if any, insecticide penetration into typical bed bug harborage sites. This study provides strong evidence that Hotshot Bedbug and Flea Fogger, Spectracide Bug Stop Indoor Fogger, and Eliminator Indoor Fogger were ineffective as bed bug control agents. PMID- 22812137 TI - Effect of temperature on the fitness of a Vip3A resistant population of Heliothis virescens (Lepidoptera: Noctuidae). AB - Microbial insecticides derived from the soil bacterium Bacillus thuringiensis (Bt) have become increasingly important for pest management. In addition to crystal (Cry) insecticidal protein toxins formed during sporulation, vegetative insecticidal protein (Vip) toxins can be produced during the vegetative phase. Resistance to Cry toxins has been reported in laboratory- and field-selected populations of various Lepidoptera species and several studies have identified fitness costs associated with Cry toxin resistance. Here, fitness costs are examined in the first insect population to be reported with resistance to a Vip toxin, a laboratory-selected Vip3A-resistant subpopulation of the tobacco budworm, Heliothis virescens (L.) (Vip-Sel). The Vip-Sel population showed reduced survival to adult eclosion compared with an unselected subpopulation at all test temperatures, including the culture temperature (25 degrees C). Vip3A resistance was also associated with reduced egg viability and mating success and a lower intrinsic rate of population increase (r(m)) at temperatures below (20 degrees C) and above (30 degrees C) the optimal laboratory culture temperature. The latter findings agree with previous studies, that fitness costs associated with resistance are usually greater under stressful conditions. Such data can help predict the impact of fitness costs on the rate of development of resistance in the field and in the development of resistance management strategies that more fully exploit fitness costs. PMID- 22812138 TI - Association of esterases with insecticide resistance in Culex quinquefasciatus (Diptera: Culicidae). AB - The southern house mosquito, Culex quinquefasciatus Say, is a competent vector of human disease and an important target of mosquito abatement programs. However, these management programs have been compromised by development of insecticide resistance. In the current study, susceptibilities to naled and resmethrin, two adulticides used in mosquito abatement, were monitored using a topical and contact bioassay, respectively, in five field- collected populations of C. quinquefasciatus (MARC, HOOD1, HOOD2, MINLOVE, and THIB). Frequencies of resistance, measured as survival after treatment with discriminating concentrations (i.e., sufficient to kill > 90% of a reference susceptible strain) were high (88.0-96.8%) in all field collections treated with naled, but were variable (3.3-94.2%) with resmethrin. In addition, esterase activities in mosquitoes from these collections were quantified using alpha-naphthyl acetate and ranged from 1.08 to 3.39 micromol alpha-naphthol produced min(-1) mg prot( 1). Heightened activities were associated with decreased insecticide susceptibility in HOOD1, THIB, and MINLOVE but not HOOD2. Esterases were visualized using native polyacrylamide gel electrophoresis, and intra- and interstrain differences in banding patterns were detected. In addition, esterases from MINLOVE mosquitoes were more numerous and intensely staining when compared with those from a laboratory-susceptible strain. Finally, naled synergized the toxicity of resmethrin in populations with decreased insecticide susceptibility and increased esterase activity by 2.5-(MINLOVE) to three-fold (THIB). Results from this study will allow management strategies for populations of C. quinquefasciatus to be optimized, and provide a foundation for further studies exploring use of esterase inhibitors as synergists of pyrethroid toxicity. PMID- 22812139 TI - Field assessments of control agents for lesser mealworm (Coleoptera: Tenebrionidae) using litter sampling. AB - Spinosad, diatomaceous earth, and cyfluthrin were assessed on two broiler farms at Gleneagle and Gatton in southeastern Queensland, Australia in 2004-2005 and 2007-2009, respectively to determine their effectiveness in controlling lesser mealworm, Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae). Insecticide treatments were applied mostly to earth or 'hard' cement floors of broiler houses before the placement of new bedding. Efficacy of each agent was assessed by regular sampling of litter and counting of immature stages and adult beetles, and comparing insect counts in treatments to counts in untreated houses. Generally, the lowest numbers of lesser mealworm were recorded in the house with hard floors, these numbers equalling the most effective spinosad applications. The most effective treatment was a strategic application of spinosad under feed supply lines on a hard floor. In compacted earth floor houses, mean numbers of lesser mealworms for two under-feed-line spinosad treatments (i.e., 2-m-wide application at 0.18 g of active insecticide (g [AI]) in 100-ml water/m2, and 1-m wide application at 0.11 g ([AI] in 33-ml water/m2), and an entire floor spinosad treatment (0.07 g [AI] in 86-ml water/m2) were significantly lower (i.e., better control) than those numbers for cyfluthrin, and no treatment (controls). The 1-m wide under-feed-line treatment was the most cost-effective dose, providing similar control to the other two most effective spinosad treatments, but using less than half the active component per broiler house. No efficacy was demonstrated when spinosad was applied to the surface of bedding in relatively large volumes of water. All applications of diatomaceous earth, applied with and without spinosad, and cyfluthrin at the label rate of 0.02 g (AI)/100-ml water/m2 showed no effect, with insect counts not significantly different to untreated controls. Overall, the results of this field assessment indicate that cyfluthrin (the Australian industry standard) and diatomaceous earth were ineffective on these two farms and that spinosad can be a viable alternative for broiler house use. PMID- 22812140 TI - Differential susceptibilities of Brontispa longissima (Coleoptera: Hispidae) to insecticides in Southeast Asia. AB - To present the susceptibility of Brontispa longissima (Gestro) (Coleoptera: Hispidae) to insecticides, 22 populations were collected in Southeast Asia from 2007 to 2010. Moreover, the laboratory susceptible strain was maintained. The results demonstrated that the lethal concentration50 value of the susceptible strain to avermectin, beta-cypermethrin, and acetamiprid was 0.034, 0.024, and 1.843 mg liter(-1), respectively. Compared with the susceptible strain, 10 populations developed a medium level of resistance to avermectin (10.8-fold < resistance ratio [RR] < 34.7-fold) and 11 populations had low or minor resistance (3.6-fold < RR < 9.6-fold), only one population from Qionghai still remained susceptible (RR = 2.04-fold). The Zhangjiang population expressed high resistance (RR = 46.1-fold), five populations expressed medium resistance (10.6-fold < RR < 18.1-fold), and 12 populations had low resistance (5.36-fold < RR < 9.66-fold) for beta-cypermethrin, only four populations maintained low resistance or susceptibility (2.08-fold < RR< 3.49-fold). All populations were susceptible to acetamiprid (1.65-fold < RR < 2.89-fold), except for the Jakarta population that developed minor resistance (4.33-fold). This study shows that the resistance to beta-cypermethrin and avermectin in B. longissima is widespread. However, most populations remain susceptible to acetamiprid. Acetamiprid may be considered an available option for the control of B. longissima and should be considered when designing pest management programs. PMID- 22812141 TI - Effects of entomopathogenic nematodes on evolution of pink bollworm resistance to Bacillus thuringiensis toxin Cry1Ac. AB - The evolution of resistance by pests can reduce the efficacy of transgenic crops that produce insecticidal toxins from Bacillus thuringiensis (Bt). However, fitness costs may act to delay pest resistance to Bt toxins. Meta-analysis of results from four previous studies revealed that the entomopathogenic nematode Steinernema riobrave (Rhabditida: Steinernematidae) imposed a 20% fitness cost for larvae of pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), that were homozygous for resistance to Bt toxin Cry1Ac, but no significant fitness cost was detected for heterozygotes. We conducted greenhouse and laboratory selection experiments to determine whether S. riobrave would delay the evolution of pink bollworm resistance to Cry1Ac. We mimicked the high dose/refuge scenario in the greenhouse with Bt cotton (Gossypium hirsutum L.) plants and refuges of non-Bt cotton plants, and in the laboratory with diet containing Cry1Ac and refuges of untreated diet. In both experiments, half of the replicates were exposed to S. riobrave and half were not. In the greenhouse, S. riobrave did not delay resistance. In the laboratory, S. riobrave delayed resistance after two generations but not after four generations. Simulation modeling showed that an initial resistance allele frequency > 0.015 and population bottlenecks can diminish or eliminate the resistance-delaying effects of fitness costs. We hypothesize that these factors may have reduced the resistance-delaying effects of S. riobrave in the selection experiments. The experimental and modeling results suggest that entomopathogenic nematodes could slow the evolution of pest resistance to Bt crops, but only under some conditions. PMID- 22812142 TI - Novel cytochrome P450 genes, CYP6EB1 and CYP6EC1, are over-expressed in acrinathrin-resistant Frankliniella occidentalis (Thysanoptera: Thripidae). AB - Control of Frankliniella occidentalis (Pergande) is a serious problem for agriculture all over the world because of the limited range of insecticides that are available. Insecticide resistance in F. occidentalis has been reported for all major insecticide groups. Our previous studies showed that cytochrome P450 mediated detoxification is a major mechanism responsible for insecticide resistance in this pest. Degenerate polymerase chain reaction was used to identify P450 genes that might be involved in acrinathrin resistance, in a laboratory population of F. occidentalis. Associated sequences were classified as belonging to the CYP4 and CYP6 families. Real-time quantitative polymerase chain reaction analyses revealed that two genes, CYP6EB1 and CYP6EC1, were over expressed in adults and L2 larvae of the resistant population, when compared with the susceptible population, suggesting their possible involvement in resistance to acrinathrin. PMID- 22812143 TI - High levels of resistance to chlorantraniliprole evolved in field populations of Plutella xylostella. AB - Chlorantraniliprole is the first commercial insecticide from a new class of chemistry, the anthranilic diamides. Chlorantraniliprole provides an effective alternative insecticide for control of Plutella xylostella (L.) populations resistant to other insecticides. Baseline susceptibility to chlorantraniliprole for P. xylostella was surveyed previously from 16 geographical populations sampled from China during 2008-2009, and the median lethal concentrations (LC50s) varied among populations from 1.8- to 8.9-fold higher than the LC50 of a susceptible strain (Roth). In the present work, 20 field populations of P. xylostella sampled in 2010-2011 from China were tested with laboratory bioassays to determine if resistance to chlorantraniliprole had evolved in the field. The LC50s of the 14 populations from northern China ranged from 1.7- to 5.4-fold compared with the LC50 of Roth, which indicates these populations remain reasonably susceptible to chlorantraniliprole. However, the LC50s of the six populations from southern China (Guangdong Province) were 2.6-, 12-, 18-, 81-, 140-, and 2,000-fold higher than the LC50 of Roth. The results showed that high levels of resistance to chlorantraniliprole had evolved in field populations from Guangdong Province of southern China. Intensive use and misuse of chlorantraniliprole may be responsible for the rapid evolution of high-level resistance in P. xylostella in this region. The implementation of resistance monitoring plans and resistance management strategies is urgently needed in China to preserve susceptibility to chlorantraniliprole in P. xylostella. PMID- 22812144 TI - Insecticide susceptibility of Nezara viridula (Heteroptera: Pentatomidae) and three other stink bug species composing a soybean pest complex in Japan. AB - The susceptibility of the stink bug species Nezara viridula (L.), Nezara antennata Scott, Piezodorus hybneri (Gmelin), and Riptortus pedestris (F.) to insecticides was tested, establishing their 50% lethal dose (LD50) values as baseline data. Third instars and adults of the four species were treated by topical application with seven insecticides: fenitrothion, fenthion, etofenprox, silafluofen, dinotefuran, clothianidin, and ethiprole. The weight of the stink bug and weight of the insecticide applied to each bug were used as explanatory variables in the probit regression analysis. The effect of the body weight on the dose-response relationship, the proportional model, was not uniform among the tested insecticide-stink bug combinations. However, the basic model fit all combinations and could estimate LD50 values successfully. Therefore, LD50 values at the medium (average) weight estimated by the basic model were selected to describe the susceptibility of the stink bugs. The LD50 value of silafluofen for N. viridula adults, and that of silafluofen and etofenprox for N. antennata adults, was at least 2,338 ng greater than the other species exposed to each insecticide. Almost all of the LD50 values for adults were over 10 times greater than those of the same species' nymphs treated with the same insecticide. Thus monitoring of occurring species and their developmental stages is important for controlling effectively the stink bug pest complex by insecticides, especially by silafluofen or etofenprox. The estimated LD50 values can be used as baseline data to compare the susceptibility of the species collected in another year or location. PMID- 22812145 TI - Induction of detoxification enzymes by quercetin in the silkworm. AB - Quercetin is one of the most abundant flavonoids and the defense secondary metabolites in plants. In this study, the effect of quercetin on the growth of the silkworm larvae was investigated. Cytochrome P450 monooxygenases (P450s), glutathione S-transferases (GSTs), and carboxylesterases (COE) were assayed after exposure to different concentrations of quercetin for 3 d (short-term) and 7 d (long-term), respectively. The results showed that the weight gain of the silkworm larvae significantly decreased after the larvae were treated by different concentrations of quercetin except for the treatment with 0.5% quercetin. Activities of P450, GST, and COE were induced by 0.5 or 1% concentration of quercetin. In the midgut, the induction activity of P450s was reached to the highest level (2.3-fold) by 1% quercetin for 7 d, the highest induction activities of GSTs toward CHP and CDNB were 4.1-fold and 2.6-fold of controls by 1% quercetin after 7 d exposure, respectively. For COEs, the highest activity (2.3-fold) was induced by 0.5% quercetin for 7 d. However, P450s in whole body were higher inducible activities in short-term treatment than those in long-term treatment. The responses of eight cytochrome P450 (CYP) genes belonged to CYP6 and CYP9 families and seven GST genes were detected with real-time polymerase chain reaction. In addition, the genes induced by quercetin significantly were confirmed by qRT-PCR. CYP6AB5, CYP6B29, and GSTe8 were identified as inducible genes, of which the highest induction levels were 10.9 fold (0.5% quercetin for 7 d), 6.2-fold (1% quercetin for 7 d), and 7.1-fold (1% quercetin for 7 d), respectively. PMID- 22812146 TI - Molecular-based identification and phylogeny of Oligonychus species (Acari: Tetranychidae). AB - The genus Oligonychus has been morphologically divided into two groups based on the direction of curvature of the aedeagus and includes some morphologically similar species that are difficult to distinguish. To develop DNA-based methods for identifying Oligonychus species and to determine the phylogenetic relationships among them, we examined the cytochrome c oxidase subunit I gene of mitochondrial DNA and the internal transcribed spacer and 28S regions of nuclear ribosomal RNA gene for 17 species. Based on the genetic distances (p-distances) of the three DNA regions, the range of intraspecific divergence was found to be below (and not overlap) the range of interspecific divergence, which allowed the 17 species to be discriminated correctly, consistent with their classification based on morphology. Phylogenetic trees constructed by neighbor-joining and Bayesian methods clearly showed two clades, consisting of species whose aedeagi curve ventrally and dorsally, respectively. Three Oligonychus species inhabiting gramineous plants formed clearly defined subclades. PMID- 22812147 TI - Genetic consequences of domestication and mass rearing of pest fruit fly Bactrocera tryoni (Diptera: Tephritidae). AB - Tephritid fruit flies, an important pest of horticulture worldwide, are increasingly targeted for control or eradication by large-scale releases of sterile flies of the same species. For each species treated, strains must be domesticated for mass rearing to provide sufficiently large numbers of individuals for releases. Increases in productivity of domesticated tephritid strains are well documented, but there have been few systematic studies of the genetic consequences of domestication in tephritids. Here, we used nine DNA microsatellite markers to monitor changes in genetic diversity during the early generations of domestication in replicated lines of the fruit fly Bactrocera tryoni (Froggatt) (Diptera: Tephritidae). The observed changes in heterozygosity and allelic richness were compared with the expected changes in heterozygosity generated by a stochastic simulation including genetic drift but not selection. The results showed that repeatable genetic bottlenecks occur in the early generations and that selection occurs in the later generations. Furthermore, using the same simulation, we show that there is inadvertent selection for increased productivity for the entire life on a mass-rearing colony, in addition to intentional selection for increased productivity. That additional selection results from the common practice of establishing the next generation of the breeding colony from a small proportion of one day's pupae collection (the pupal raffle). That selection occurs during all generations and acts only on fecundity variation. Practical methods to counter that unavoidable loss of genetic diversity during the domestication process in B. tryoni are discussed. PMID- 22812148 TI - Cyclical parthenogenetic reproduction in the Russian wheat aphid (Hemiptera: Aphididae) in the United States: sexual reproduction and its outcome on biotypic diversity. AB - In 1986, the Russian wheat aphid, Diuraphis noxia (Kurdjumov) (Hemiptera: Aphididae), became an invasive species of United States. Nearly 20 yr later, new biotypes appeared that were capable of overcoming most sources of resistance and became a renewed threat to wheat, Triticum aestivum L., production. Cyclical (CP) and obligate (OP) parthenogenesis enables aphids to both adapt to changing environments and exploit host resources. We documented these forms of reproduction for Russian wheat aphid in wheat and wild grasses in the Central Great Plains and Rocky Mountain regions during falls 2004-2009. Colonies from sample sites also were held under unheated greenhouse conditions and observed for the presence of sexual morphs and eggs through the winter. Russian wheat aphid populations were mainly OP and attempted to overwinter as adults, regardless of region sampled. A few populations contained oviparae but no males (gynocyclic) and were not specific to any particular region. Observation of the Russian wheat aphid colonies under greenhouse conditions failed to produce males or eggs. In spring 2007, CP was confirmed in a small population of Russian wheat aphid that eclosed from eggs (fundatricies) on wild grasses and wheat near Dove Creek, CO, in the Colorado Plateau region where other aphid species undergo CP. Lineages from ninety-three fundatricies were screened against 16 resistant and susceptible cereal entries to determine their biotypic classification. A high degree of biotypic diversity (41.4%) was detected in this population. Although CP was a rare in Russian wheat aphid populations, genetic recombination during the sexual cycle creates new biotypes and can have significant effects on population genetics. PMID- 22812149 TI - Constitutive and inducible resistance to Atherigona soccata (Diptera: Muscidae) in Sorghum bicolor. AB - Host plant resistance is one of the important components for minimizing the losses because of sorghum shoot fly, Atherigona soccata (Diptera: Muscidae) attack. Therefore, we studied the constitutive and inducible biochemical mechanisms of resistance to A. soccata in a diverse array of sorghum genotypes to identify lines with diverse mechanisms of resistance to this insect. Fifteen sorghum genotypes with different levels of resistance to A. soccata were evaluated. Methanol extracts of 10-d old damaged and undamaged sorghum seedlings were subjected to high-performance liquid chromatography analysis. Association between peak areas of the identified and unidentified compounds with parameters measuring A. soccata resistance was determined through correlation analysis. Amounts of p-hydroxy benzaldehyde and the unidentified compounds at RTs 24.38 and 3.70 min were associated with susceptibility to A. soccata. Genotypes exhibiting resistance to A. soccata were placed in four groups, and the lines showing constitutive and/or induced resistance to A. soccata with different combinations of biochemical factors potentially could be used for increasing the levels of resistance to A. soccata in sorghum. PMID- 22812150 TI - Sequential hypothesis testing with spatially correlated presence-absence data. AB - A pest management decision to initiate a control treatment depends upon an accurate estimate of mean pest density. Presence-absence sampling plans significantly reduce sampling efforts to make treatment decisions by using the proportion of infested leaves to estimate mean pest density in lieu of counting individual pests. The use of sequential hypothesis testing procedures can significantly reduce the number of samples required to make a treatment decision. Here we construct a mean-proportion relationship for Oligonychus perseae Tuttle, Baker, and Abatiello, a mite pest of avocados, from empirical data, and develop a sequential presence-absence sampling plan using Bartlett's sequential test procedure. Bartlett's test can accommodate pest population models that contain nuisance parameters that are not of primary interest. However, it requires that population measurements be independent, which may not be realistic because of spatial correlation of pest densities across trees within an orchard. We propose to mitigate the effect of spatial correlation in a sequential sampling procedure by using a tree-selection rule (i.e., maximin) that sequentially selects each newly sampled tree to be maximally spaced from all other previously sampled trees. Our proposed presence-absence sampling methodology applies Bartlett's test to a hypothesis test developed using an empirical mean-proportion relationship coupled with a spatial, statistical model of pest populations, with spatial correlation mitigated via the aforementioned tree-selection rule. We demonstrate the effectiveness of our proposed methodology over a range of parameter estimates appropriate for densities of O. perseae that would be observed in avocado orchards in California. PMID- 22812151 TI - Effect of short exposures to spinetoram against three stored-product beetle species. AB - Laboratory bioassays were carried out to evaluate the effectiveness of two formulations of spinetoram, water dispersible granules (WG), and suspension concentrate (SC-NC), against three major stored-grain beetle species, the lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae); the rice weevil, Sitophilus oryzae (L.) (Coleoptera: Curculionidae); and the confused flour beetle, Tribolium confusum Jacquelin du Val (Coleoptera: Tenebrionidae). Adults of the above species were exposed on wheat treated with spinetoram at 1 ppm (1 mg/kg of wheat) for 0, 2, 4, 6, 8, 16, 40, and 72 h. After this interval, mortality was recorded (immediate mortality) and the surviving individuals were transferred in untreated wheat, where mortality was recorded again 7 d later (delayed mortality). Then, all adults were removed, and the number of progeny production in the untreated substrate was measured 65 d later. From the species tested, R. dominica was by far the most susceptible, given that immediate and delayed mortality for the 72-h exposure interval reached 44 and 97%, respectively. At the same time, progeny production was low, in most of the exposure intervals tested. In contrast, for S. oryzae, delayed mortality was negligible, with the exception of 72 h at the SC-NC formulation. However, in most of the cases examined, progeny production for S. oryzae was high. Finally, adult mortality for T. confusum was extremely low, regardless of the exposure interval and the type of the formulation. Nevertheless, offspring emergence of this species was low. By combining the results of the current study and the data that are available from the literature for short exposures to spinosad, we can conclude that the two ingredients were equally effective against these three stored-grain beetle species. PMID- 22812152 TI - Efficacy of natural products against Callosobruchus chinensis (Coleoptera: Bruchidae) in Nepal. AB - This study was conducted to determine the efficacy of local natural products against the beetle, Callosobruchus chinensis L. (Coleoptera: Bruchidae), in stored chickpea Cicer arietinum L. (Fabaceae) in Chitwan, Nepal. Five natural products and one synthetic pesticide (Malathion) and two storage regimes (aluminum sheet bin vs. jute bags with plastic lining) were tested for their effect on stored pulse with respect to damage by C. chinensis. The five natural products included Xanthoylum armatum DC (Rutaceae) fruit powder, Acorus calamus L. (Araceae) rhizome powder, Cinnamom camphora L. (Lauraceae) balls, oil of Sesamum indicum L. (Pedaliaceae), and leaf powder of Azadirachta indica A. Juss. (Meliaceae). Treatments of stored pulses with natural products or with Malathion all caused significantly higher mortality of C. chinensis at 15 d after treatment (DAT) than stored pulses receiving no treatments. The balls of C. camphora, rhizome powder of A. calamus and sesame oil outperformed all other treatments, including the Malathion at 45 and 75 DAT and resulted in significantly reduced damage or deterioration of stored pulses compared with other treatments. Storage regimes performed similarly, although the jute bags did protect seed integrity for some treatments. Our results indicate that incorporating these natural products into stored pulses can protect the seeds from C. chinensis for up to two generations, something that Malathion cannot do. These products are readily available to most farmers in the region and their use will lead to 1) reduction of losses to significant stored product pests, and 2) a reduction of contamination of foodstuffs and the environment by synthetic pesticides like Malathion. PMID- 22812153 TI - A SCAR-based method for rapid identification of four major lepidopterous stored product pests. AB - Since Taiwan became a World Trade Organization member in 2002, large quantities of grain have been imported from different countries, and insect pests are frequently intercepted from these imported commodities in quarantine inspection. Because most insects are intercepted as immature forms, morphological identification is problematic; therefore, we developed a DNA identification method based on a sequence-characterized amplified region- polymerase chain reaction (SCAR-PCR). Three sets of multiplex SCAR-PCR mixtures, namely SCAR-I, II, and -III, were developed with each set composed of four species-specific primer pairs derived from the genomic DNA of four major lepidopterous stored product pests: Corcyra cephalonica (Stainton), Cadra cautella (Walker), Sitotroga cerealella Oliver, and Plodia interpunctella (Hubner). The SCAR-I amplicons of C. cephalonica, C. cautella, S. cerealella, and P. interpunctella were 205, 550, 324, 382 bp, respectively, while those of SCAR-II were 341, 565, 261, and 170 bp, and those of SCAR-III were 514, 555, 445, and 299 bp. These multiplex PCR mixtures could sensitively and unambiguously detect and identify in approximately 5 h individuals among the four lepidopterous pests intercepted in imported stored products. In summary, the SCAR-PCR method we developed represents a rapid, sensitive and accurate technique for identifying insect species of stored products in plant quarantine operation. PMID- 22812154 TI - [The placebo mystery or neurobiology of the soul]. AB - The "placebo" concept started with Saint Jerome's mistranslation of the first word of the ninth line of Psalm 116: instead of "I will walk before the Lord", he wrote "I will please the Lord" (Placebo Domino instead of ambulabo coram Domino). The placebo story is filled with quiproquos, mistakes and abuses. After many avatars, the placebo notion became firmly linked to medicine, and especially pharmacology. Nowadays, all new treatments are required to have proved their efficacy in randomized, placebo-controlled, double-blind trials. After a plethora of hypotheses based on psychology, behavorism, ethology, anthropology and sociology, proposing mechanisms of action based on patients' suggestibility and expectations induced by doctors' enthusiasm and beliefs, the past two decades have seen several new findings focusing on pharmacobiological phenomena. Animal studies provide fascinating information on immunological mechanisms and cancer outcomes in conditions of stress and pain. Placebo and nocebo mechanisms are now explained in terms of pain, endorphins, cholecystokinin and dopamine system activation, and possibly inflammation control. PET scans have been used to investigate these effects in depression and Parkinson's disease. A role of genetic mechanisms is also emerging in the field of placebo neurobiology. In fact, the placebo effect might simply result from the medical art. Further studies are needed to maximize the placebo effect and to make it more consistent. PMID- 22812155 TI - [The doctor-patient relationship: new psychological models]. AB - The physician-patient relationship involves both ethical and psychological aspects. The notion of empathy has been extensively described, and this "asymmetric dialogue" has been shown capable of affecting patient behavior. The Internet, and particularly medical websites, are modifying the physician-patient relationship by providing patients with knowledge of their disease, and are changing the social perception of medicine. More recent theories on medical relationships underline the importance of patience, tolerance and the ability to accept opposition and disappointment. PMID- 22812156 TI - [Patient education in France]. AB - Patient education is an increasingly important component of therapeutic strategies, especially for chronic illnesses, which currently affect about 12% of the French population and will undoubtedly increase in coming years. Patient education aims to enhance patients' personal responsibility and participation in their therapeutic management and quality of life. Article 84 of French health legislation passed in 2009 inscribes patient education in the Public Health Code for the first time. It distinguishes personalized therapeutic education, patient accompaniment, and learning programs. Direct links between patients and drug companies are prohibited. However, the notion of patient accompaniment remains to be defined, along with the evaluation of patient education, funding sources and practical modalities. PMID- 22812157 TI - [From nociception to subjective pain: pain in the medical relationship]. PMID- 22812158 TI - [Progress in our understanding of the architecture of paradoxical sleep since William Dement and Michel Jouvet]. AB - Paradoxical or REM sleep, characterized by cortical activation combined with muscle atonia and rapid eye movements, was discovered at the end of the 1950s by Michel Jouvet and William C. Dement. Studies over the next twenty years suggested that the onset and maintenance of paradoxical sleep was due to a reciprocal inhibitory interaction between monoaminergic neurons inhibiting PS and cholinergic neurons generating PS located in a small part of the pontine reticular formation called the sublaterodorsal tegmental nucleus. Our recent studies rather indicate that these neurons are respectively GABAergic and glutamatergic. Further, they suggest that three populations of GABAergic neurons and population of hypothalamic neurons expressing melanin concentrating hormone, a peptide, play a important role in PS control. PMID- 22812159 TI - [Internal clock desynchronization, light and melatonin]. AB - The internal clock is synchronized by environmental factors. In humans the main factors are the light-dark alternation, the sleep-wake cycle, and social life. Rhythm desynchronization occurs when the clock is no longer in phase (harmony) with the environment, resulting in a phase shift (phase advance or phase delay) which can produce fatigue, sleep disorders and mood disorders. Clock desynchronization is related to a a loss of adaptation between the clock and synchronizers, to an inability of the clock to be entrained, or to a dysfunction of the clock itself Shiftwork and nightwork, transmeridian flights, depressive states and other psychiatric disorders, as well as blindness, aging and intake in some medications and psychoactive agents like alcohol are among the numerous causes of rhythm desynchronization. Melatonin and light exposure are able to control and resynchronize the clock. The phase response curve (PRC) clearly demonstrates that light exposure and/or melatonin administration are able to shift (advance or delay, depending on their timing) and thereby reset the clock. PMID- 22812160 TI - [Sleep and wakefulness regulation: molecular players]. AB - By combining brain section/lesion studies and sleep analysis, neurophysiologists have identified the brain areas responsible for regulating sleep and wakefulness during the first half of the 20th century. Identification of the phenotypic nature of the neurons underlying the regulation of vigilance, as well as their anatomical and functional connections led to a theoretical model based on mutual inhibitory interactions between sleep-on neurons (namely GABAergic neurons of the hypothalamic preoptic region) and wake-on neurons (mainly monoaminergic and cholinergic neurons). In addition to the corresponding neurotransmitters (serotonin, acetylcholine and GABA), other neuroactive molecules that play key roles in sleep and wakefulness regulation have recently been discovered, leading to an updated model. Hypocretin, also known as orexin, is a key neuropeptide involved in the sleep disorder narcolepsy. Extensive characterization of the respective roles of these neurotransmitters has led to the identification of novel therapeutic targets for the treatment of sleep disorders. For example, blockade of hypocretin receptors has hypnotic effects. PMID- 22812161 TI - [Hypocretin disturbance and sleep disorders]. AB - The hypothalamic hypocretin (orexin) system plays a crucial role in the regulation of sleep and wakefulness. The strongest evidence is the fact that the primary sleep disorder narcolepsy is caused by disrupted hypocretin signaling in humans as well as in various animal models. Today there is growing interest in the role of hypocretin defects in sleep disorders associated with neurodegenerative diseases. One of the most controversial issues is the functional relevance of partial hypocretin defects in these disorders. PMID- 22812162 TI - [Treatment of insomnia. Pharmacological approaches and their limitations]. AB - Far more people complain of inadequate sleep than of true insomnia warranting prescription of a hypnotic drug. The number of available hypnotics has fallen markedly in recent years. Numerous brain areas, transmitters and receptors are involved in sleep. Currently, the main hypnotics (benzodiazepine derivatives and the so-called 4Z group. Zolpidem, Zopiclone, EsZopiclone and Zaleplon) increase GABAergic transmission by acting on components of chloride channels, thereby inducing Cl entry to neurons and resulting in their hyperpolarisation. This pre eminence of GABAergic transmission should not make us ignore other important transmitters and their receptors as potential targets for new hypnotic drugs; these include histamine (and H1 receptors), dopamine (D1 and D2), norepinephrine (alpha1), serotonin (5HT2), glutamate (NMDA), acetylcholine (nicotinic), hypocretin (OX1 and OX2), melatonin (MLT1 and MLT2), prostaglandin E2 (EP), prostaglandin D2 (DP1), and endocannabinoids (CB1). Knowledge of the pharmacodynamic, pharmacokinetic and clinical characteristics of current hypnotic drugs has allowed us to establish the profile of an ideal hypnotic for the future. PMID- 22812163 TI - [Phenomenology of dreams]. AB - A phenomenology of dreams searches for meaning, with the aim not only of explaining but also of understanding the experience. What and who is it for? And what about the nearly forgotten dream among the moderns, the banal returning to the nightmare, sleepiness, or dreamlike reverie. Nostalgia for the dream, where we saw a very early state of light, not a ordinaire qu duel. Regret for the dreamlike splendor exceeded by the modeling power of modern aesthetics--film and the explosion of virtual imaging technologies. Disappointment at the discovery of a cognitive permanence throughout sleep and a unique fit with the real upon awaking? An excess of methodological rigor where we validate the logic of the dream, correlating the clinical improvement in psychotherapy and the ability to interpret one's own dreams. The dangerous psychological access when the dream primarily is mine, viewed as a veiled expression of an unspoken desire, or when the dream reveals to me, in an existential conception of man, through time and space, my daily life, my freedom beyond my needs. Might its ultimate sense also mean its abolition? From the story of a famous forgotten dream, based on unexpected scientific data emerges the question: do we dream to forget? The main thing would not be consciousness but confidence, when " the sleeping man, his regard extinguished, dead to himself seizes the light in the night " (Heraclitus). PMID- 22812164 TI - [Surviving sleep: when the heart and brain are damaged by apnea]. AB - Sleep apnea generally results from pharyngeal collapse and leads to the so-called obstructive sleep apnea syndrome (OSAS). OSAS is associated with excessive daytime sleepiness and chronic fatigue and has cardiovascular consequences. Acute hemodynamic changes during obstructive apnea are mainly due to sympathetic activation. These result from changes in blood oxygen and carbon dioxide content, as well as sleep fragmentation and intrathoracic pressure changes. Chronic consequences are linked to the sustained increase in sympathetic activity as well as endothelial dysfunction and vascular remodeling. These vascular changes seem to be a consequence of the oxidative stress and systemic inflammation associated with OSA. Metabolic impairment also plays a role. OSA increases the risk of hypertension, coronary heart disease, arrhythmias, sudden death and cardiovascular mortality. Continuous positive airway pressure (CPAP) has been the first-line treatment for the last 30 years, and partly prevents the excess cardiovascular morbidity and mortality. PMID- 22812165 TI - [Sleep and accidents]. AB - The evolution of society and labor organization (24/7 working) has significantly changed our lifestyles and increased the number of workers with sleep debt and staggered hours. Populations are particularly at risk of excessive sleepiness due to sleep deprivation (professional obligations), circadian factors (e.g. night driving) and sleep disorders (e.g. obstructive sleep apnea syndrome and hypersomnia). Excessive daytime sleepiness (i.e. difficulty staying awake) is estimated to affect about 5 % of the population. Public health studies have shown that sleepiness at the wheel and other risks associated with sleep are responsible for 5% to 30% of road accidents, depending on the type of driver and/or road. Strategies to reduce accidents related to sleepiness include- reliable diagnosis and treatment of sleep disorders,--management of chronobiological conflicts,--adequate catch-up sleep, and--countermeasures against sleepiness at the wheel. PMID- 22812166 TI - [Conclusion of the National Academy of Medicine session topic of sleep]. PMID- 22812167 TI - [The liver]. AB - Hepatocyte transplantation has not yet reached therapeutic status, as it has proven difficult to transplant a sufficient number of functional hepatocytes able to integrate and proliferate inside liver plates. It has recently been shown that whole livers can be decellularized by portal infusion of detergents, yielding a decellularized scaffold with a well preserved vascular network and specific liver matrix. Perfusion of different combinations of cells through the portal vein of these scaffolds results in reconstitution of a complete functional organ that can be transplanted in small animals. An auto-constructed human liver could be engineered from exogenous liver scaffolds seeded with various cell populations, including autologous cells derived from induced pluripotent stem cells. Auto constructed livers might replace conventional liver grafts in future. PMID- 22812168 TI - [The kidney]. AB - Whole-organ engineering of the kidney is particularly difficult because of its structural complexity and of the morphological and functional heterogeneity of renal cell types. As for other organs, research is currently focused on:--the matrix to support recellularization: synthetic, biodegradable or biological. Use of the extracellular matrix as a biological scaffold is the most promising approach. Rodent, porcine and rhesus monkey kidneys have been decellularized to obtain scaffolds with a preserved extracellular matrix and vasculature.--The source of cells for recellularization: embryonic stem cells, fetal cells, adult derived stem cells, progenitor cells and adult-derived inducible, pluripotent stem cells have all been used. Nephron development results from mutual inducive interactions between the urethral bud and the metanephric mesenchyme, a process that can be reproduced in vitro. Ex-vivo "fabrication" of a kidney that could be implanted with no risk of rejection in patients with chronic renal failure appears ultimately feasible. Another area of research is the use of renal assistance devices--the bioartificial kidney--based on a bioreactor containing renal epithelial cells derived from tubules that maintain their reabsorptive, metabolic and endocrine functions. Phase II clinical trials have given encouraging results. PMID- 22812169 TI - [The heart]. AB - The growing incidence of heart failure and the limitations of cardiac transplantation and totally implantable artificial hearts justify the search for alternative therapies. Self-reconstruction of the heart might be one of them. It is based on the use of an animal-derived decellularized scaffold reseeded with cells able to reconstitute a contractile, vascular and valvular pattern affording normal cardiac function. Whereas decellularization techniques are currently well controlled, the choice of cell type to generate the different constituents of cardiac tissue (cardiomyocytes, endothelial cells, smooth vascular cells, myofibroblasts), and the optimal mode of cell transfer, are still far from clear. Furthermore, scaffold recolonization is not only dependent on the phenotype of the grafted cells: it is also influenced by the nature of the biochemical signals emitted by the scaffold and by the physical state of the substrate. Modulation of these two factors can influence the contractile performance of the self-rebuilt organ. The complexity of these challenges is such that total replacement of the heart by a self-built organ is at best a far-off perspective. However, continued pursuit of this objective stimulates the development of bioengineering techniques, and partial replacement of heart tissue by cell-seeded scaffolds appears more feasible. Applications could include the strengthening of infarcted myocardium and, possibly, cardiac valve replacement. PMID- 22812170 TI - [The lung]. AB - Lung transplantation is still the only curative treatment for end-stage pulmonary diseases. The results remain poor, however, because of the limited availability of lung donors, chronic rejection, and complications related to immunosuppressive therapy. The use of a bioartificial lung generated from autologous cells could offer a solution. We have demonstrated that in vivo epithelial and cartilage regeneration of the airways is feasible with the use of an aortic tissue matrix. Other studies show that in vitro and in vivo airway regeneration, respectively, can be obtained by using bio-engineering and heterotopic allograft implantation. A more complex challenge is the creation of an artificial lung Indeed, this would require the use of an elastic matrix that can promote regeneration of the different lung components (airways, alveoli, vessels) over a large surface area, thus allowing ventilation, blood perfusion and gas exchanges. Recent studies have demonstrated the possibility of in vitro and in vivo regeneration of lung tissue from autologous cells, and especially stem cells. This emerging research field is currently dominated by the use of decellularized lung matrices and autologous epithelial and endothelial cells. Implantation of such a recellularized matrix in animals has proved the feasibility of a functional bio-artificial lung. The first human transplantation of a bio-artificial lung should be possible within 10-20 years. PMID- 22812171 TI - [DNA repair mechanisms: from basic biology to genetic pathology]. PMID- 22812172 TI - [Neurologic disabilities after road traffic accidents]. AB - Car crashes lead to central nervous system damages inducing mainly either locomotor and bladder in case of spinal injury or cognitive impairment after brain injury. Recently the way of management of locomotor disability changes a lot due to economical, philosophical reasons and scientific progress. A better understanding of mechanisms of ladder dysfunctions after spinal lesions lead to introduce new therapeutics solution in these patients which significantly reduce mortality and morbidity. Cognitive impairments following traumatic brain injury are now better characterised and their management becomes more efficient. PMID- 22812173 TI - [Conclusion: humanism and handicap]. PMID- 22812174 TI - [Early pioneers in antenatal diagnostics]. PMID- 22812175 TI - [Comparison between two diagnostic tests for preterm rupture of membrane]. AB - BACKGROUND: Rupture premature of membranes occurs in 8% of all births constituting one of main causes of prematurity. OBJECTIVE: Determine qualitatively the presence of human chorionic gonadotropin hormone in vagina and used as diagnostic test to rupture of membranes. PATIENTS AND METHOD: We performed a study of diagnostic test observational, transverse, comparative, prospective, not blind type; in 175 healthy pregnant woman with 20 to 42 weeks of gestation, with suspicion of vaginal liquid outlet, at the Obstetrics Department Academic Hospital "Dr Jose Eleuterio Gonzalez" during the period of April 2009 to June 2011, crystallography and vaginal human chorionic gonadotropin hormone test were performed. RESULTS: We analyzed 175 patients, average age was 22.35 years old, was obtained sensibility and specificity of 98.90% y 77.38% to crystallography and 93.41% y 73.81% to vaginal human chorionic gonadotropin hormone test, with value positive predictive of 79.44% and value negative predictive of 91.18% for this last. CONCLUSIONS: Determine qualitatively the presence of human chorionic gonadotropin hormone in vagina is a diagnostic test useful for detecting premature rupture of membranes has been shown to be as effective as crystallography. PMID- 22812176 TI - [Posplacenta intrauterine device. Guide wires not visible]. AB - BACKGROUND: Little information exists about the follow- up of the strings of intrauterine device (IUD) applied posplacenta. When the strings are of 10 cm in length are within the uterine cavity should be visible after postpartum involution. OBJECTIVE: To know the incidence of visible strings of intrauterine device (IUD) after posplacental insertion and to establish guidelines of follow up when strings are not seen. METHODS: A prospective cohort study of 530 women with posplacental insertion of T Cu 380-A IUD with strings 10 cm long. Follow-up was at 6 weeks, 3, 6, 9 and 12 months after IUD insertion, at each visit women were questioned about IUD expulsion or removal and the cervix was inspected to visualize the strings of IUD. We analyzed the cumulative incidence of visible strings and procedures that were performed to locate the IUD when strings were not seen. RESULTS: At one year of follow-up the IUD was in situ in 398 women (75.1%), there were 44 expulsions (8.3%), 24 removals (4.5%) and 64 lost to follow up (12.1%). In women with IUDs in situ the strings were seen in 90.2% (n = 359) and were not seen in 9.8% (n = 39). In 65 women uterine cavity was probed identifying the IUD in situ in 64 cases, we performed 33 pelvic ultrasounds with IUDs in situ in 31 cases and in 2 cases with IUD in the cervical canal.. CONCLUSIONS: Strings of IUD after postplacental insertion was seen in most women at one year of follow up. When we are reasonably sure the woman is not pregnant, interventions for the location of the IUD should be avoided. A pelvic ultrasound should be the initial procedure and usually sufficient to locate IUDs whose strings are not visible. PMID- 22812177 TI - [New genovariantes of Chlamydia trachomatis serovar L2 proctitis causing]. AB - Lymphogranuloma venereum (LGV) is a chronic disease of the lymphatic system that is transmitted sexually and whose etiologic agents are L1, L2 and L3 serotypes of Chlamydia trachomatis. Since 2003 in Europe, USA, Canada and Australia have had outbreaks of L2 serotype infection that develops proctitis in place of LGV in men who have sex with men. It appears that these strains are a new genovariant of L2 serotype (L2b) that is developing a different pathology to LGV. However, the analysis of L2b genome not differs significantly to L2 genome (L2/434 UB) for which L2b is considered as a classic L2 strain. Despite this, new genovariantes of L2 and L2b are appearing, which develop or not LGV or proctitis so we need to do an analysis of its genome to identify genetic changes that these strains shown. PMID- 22812178 TI - [Anti-D isoimmunization severe in a twin pregnancy. Case report]. AB - Perinatal hemolytic disease occurs secondary to a hemolytic phenomenon of immune origin resulting in fetal or neonatal anemia. A 38-year-old pregnant woman was referred to the Department of high risk Obstetrics, Hospital Universitario La Paz Madrid because of presenting a dichorionic diamniotic twin pregnancy spontaneously, pre-pregnancy diabetes poorly controlled and severe alloinmunization anti-D. Her first pregnancy ended in a normal delivery at term; in the period of 4 years, she has three newborn with 36, 34 and 40 weeks respectively, who die with a week of life. After that, two intrauterine fetal death occur at 26 weeks of gestation. The patient who is RhD negative, suffers anti-D inmunization with a antibody titration of 1/1024 with 14 weeks of gestation. Twelve plasmapheresis, eight doses of anti-D inmunoglobulins and intrauterine transfusions has been the treatment received. A severe anemia is found during the ultrasound control of the middLe cerebral artery peak systolic velocity in both twins since the 16th week. It remains stable thanks to the treatment. Finally at the 28th week of gestation, pregnancy is terminated with a cesarean section. The twins are born alive and premature, but with good general state. The measurement of the middle cerebral artery peak systolic velocity predicts moderate-severe fetal anemia cases, which are the most important in the clinical management because of the need of active treatment or finish the pregnancy. PMID- 22812179 TI - [Uterine sarcoma. Case report]. AB - 55 years female patient who is sent to the New Hospital Durango management fibroids and anemia, why not start the study protocol for hysterectomy, preoperative presenting within normal parameters, transvaginal ultrasound uterine fibroids and endometrial hyperplasia, biopsy endometrium with endometrial hyperplasia without atypia simple, and is scheduled for total abdominal hysterectomy with bilateral salpingo-oophorectomy. Surgical procedure is performed with the incident of tearing the uterine body on the right side with extension to the neck and externalization of endometrial tissue, the event is completed without complications. Histopathologic endometrial stromal sarcoma of high grade. Management in a row by the oncology department by 25 sessions of radio and brachytherapy. PMID- 22812180 TI - [Bilateral tuberculous mastitis nulliparous patient, initially treated as idiopathic granulomatous mastitis]. AB - The breast infection by M tuberculosis is rare, when it occurs, clinical and histologically confused with other forms of granulomatous inflammation, making it essential to use other diagnostic methods also may be negative. We report a patient with fimica mastitis that originally was treated as idiopathic granulomatous mastitis with apparent satisfactory clinical response. However, frequent relapses forced to look for other etiologies. Fortunately, the PCR showed the cause and was managed with specific treatment with disappearance of the disease. Clinical suspicion should be in mind when faced with a case like ours. PMID- 22812181 TI - [Volvulus in pregnancy: a case report]. AB - There are several etiologies of abdominal pain during pregnancy, including an extremely rare: the intestinal volvulus. Have been reported about 78 cases in the literature of intestinal volvulus complicating pregnancy, we reported this case occurred in our hospital and to assess the difficult diagnosis of intestinal volvulus in pregnancy. PMID- 22812182 TI - [History of obstetrics and gynecology in Sinaloa]. PMID- 22812183 TI - [Some ethical problems in obstetrics and gynecology. 1957]. PMID- 22812184 TI - Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis involving 23,998 subjects. AB - Cyclin D1 (CCND1) plays an essential role in tumor development and progression through regulating the cell transition from G1 to the proliferative S phase. The CCND1 G870A polymorphism has been associated with an increased susceptibility to squamous cell carcinoma of the head and neck, bladder, prostate, and gastric cardiac cancers. There are a number of studies that explored the relationship between CCND1 G870A polymorphism and breast cancer risk, with inconsistent conclusions. In order to better define the predictive value of CCND1 G870A polymorphism in breast cancer, we searched PubMed and EBSCO for relevant publications. A total of 13 studies were indentified, which included 11,235 cases and 12,763 controls. We calculated the summary odds ratios and the corresponding 95% confidence interval. Our meta-analysis showed that carriers of AA genotype have a significantly higher risk in developing breast cancer compared with that of GG genotype (OR = 1.08, 95% CI = 1.01-1.17, p > = 0.03) in overall population. Furthermore, in subgroup analysis, CCND1 G870A polymorphism was associated with a marginally increased risk of breast cancer for Chinese compared to Caucasian populations with an OR = 1.14, 95% CI = 1.00-1.20, p-trend = 0.06 for AA + GA versus GG, if the controls were hospital-based population with an OR = 1.21, 95% CI = 0.99-1.47, p = 0.06 for AA versus GG and if the distributions of genotypes in control groups were consistent with the Hardy-Weinberg equilibrium (HWE) with an OR = 1.08, 95% CI = 1.00-1.15, p = 0.04 for AA versus GA + GG. Our meta analysis represents the largest study to date indicating that the G870A polymorphism in CCND1 confers an increased risk for breast cancer. Further studies are warranted to explore the preventive measures to detect and manage the breast cancers attributable to the G870A polymorphism. PMID- 22812185 TI - RIN1-Ras-ERK pathway plays an important role in carcinogenesis in colon cancer cell line LoVo. AB - The RIN1 protein has SH2, three domains, and H-Ras binding domains; thus, it is presumed to be an important molecule in an intracellular signaling pathway. We examined the effect of the introduction of a membrane protein-encoding, mutated (S351A)RIN1 gene into a colon cancer. In the LoVo colon cancer cell line, endogenous RIN1 protein was strongly expressed in the cytoplasmic fraction, and the RIN1 protein in the cytoplasmic fraction was strongly bound to the 14-3-3 protein. In the mutated (S351A)RIN1-transfected LoVo cells, the mutated (S351A)RIN1 protein was identified in the cell membrane, and was bound to HRas protein. Also, in vitro the proliferative capacity of the mutated (S351A)RIN1 transfected LoVo cells was significantly inhibited, compared with that of their empty vector-transfected counterparts. In the mutated (S351A)RIN1-transfected LoVo cells, the phosphorylation of ERK1/2 proteins downstream of the H-Ras molecule was inhibited, compared with the counterparts. This study is the first to show that the localization of RIN1 protein plays an important role in the carcinogenesis in colon cancer cells LoVo (i.e., signal transduction in the Ras ERK pathway). PMID- 22812186 TI - Gene silence-induced downregulation of survivin inhibits bladder cancer cells. AB - Urinary bladder cancer accounts for approximately 3% of all cancers in humans. Treatment for urinary bladder is not satisfactory. The present study aims to elucidate the effect of gene silencing of survivin on the inhibition of bladder cancer cells. In this study, we constructed survivin shRNA-carrying lentiviral vectors. Bladder cancer cell lines, T24 cells and BJ cells, were transduced with the constructed shRNA of survivin. The frequency of apoptotic bladder cancer cells was assessed by flow cytometry. The results showed that transfection with survivin shRNA significantly inhibited cell proliferation of both T24 and BJ cells. Most T24 and BJ cells accumulated at the G2/M stage; a portion of them was at sub-G1 stage. An increase in the fraction of bladder cancer cells undergoing apoptosis was noted. Among eight apoptosis-associated proteins, the amounts of BAX and BAD were significantly increased in the survivin-deficient bladder cancer cells. The findings suggest that survivin may be a therapeutic target of bladder cancer to selectively inhibit cell proliferation of bladder cancer cells. PMID- 22812187 TI - Decrease of the regulatory T-cell population by adoptive T-cell transfer in a mouse colorectal cancer transplant model. AB - We examined the effects of adoptive T-cell transfer (ACT) on the population of regulatory T cells (Tregs) in a mouse colorectal cancer transplant model. In an in vivo study, Treg populations in Balb/c mice colon26 transplant model after ACT were analyzed in peripheral blood, local lymph node, and tumor. In an in vitro study CD4+ cells were cultured in medium containing TGF-beta to induce Tregs. LAK cells were added or not in this Treg induction system. Treg induction after coculture with LAK was investigated. We also studied the role of IFN-gamma in the mechanism of Treg induction. Tregs in the draining lymph nodes and tumor were significantly suppressed by ACT. The induction of Tregs in vitro was inhibited by coculture with LAK cells. Furthermore, Tregs in the cultured cells were significantly inhibited by addition of exogenous IFN-gamma. Moreover, Tregs were increased by addition of IFN-gamma mAb. ACT may decrease Tregs in tumor-bearing hosts. One of the mechanisms is considered to be IFN-gamma inhibiting the induction of Tregs. PMID- 22812188 TI - CXCR4-positive subset of glioma is enriched for cancer stem cells. AB - CXC chemokine receptor 4 (CXCR4) is a cell surface molecule expressed in a distinct subset of glioma cells with enhanced tumorigenicity, and it is related to many important biological activities of the tumor. We supposed that this receptor might be a cell surface "marker" for glioma stem cells. This hypothesis was tested both in vitro and in vivo. The CXCR4+ and CXCR4- subsets were sorted from three human malignant glioma specimens. They were tested for the capability of colony formation in soft agar, generation of tumorosphere, self-renewal, and multipotent differentiation in vitro, and the capability of xenograft tumor in vivo. Drug and radiation resistance and coexpression with CD133 were studied for each subset. CXCR4+ glioma cells, but not CXCR4- cells, were capable of generating tumorospheres in serum-free medium. In addition, these spheres were able to self-renew after passage, and had multipotent differentiation after being induced in serum-containing medium. In soft agar assay, CXCR4+ cells generate much more colonies. The animal experiment revealed that CXCR4+ subpopulation had stronger tumorigenicity than the unsorted parental glioma cells, while the CXCR4- cells did not generate xenograft tumor. CXCR4-possitive cells were more resistant to temozolomide and radiation treatment. Both CXCR4+ and CXCR4- subsets contained very few CD133+ cells. The CXCR4+ subsets of glioma cells fulfill the standard of "cancer stem cell". PMID- 22812189 TI - PIK3CA is critical for the proliferation, invasiveness, and drug resistance of human tongue carcinoma cells. AB - PIK3CA is an oncogene component of phosphatidylinositol 3-kinase (PI3K) signaling pathway and is associated with cell proliferation and carcinogenesis in a variety of human cancers. PIK3CA mutation is correlated with the aggressiveness of many epithelial cancers. And so PIK3CA is considered as a major oncogene in many human epithelial malignancies. However, its role in tongue carcinoma is unknown. We used lentiviral-mediated interfering short hairpin RNAs (shRNAs) to knock down PIK3CA expression in tongue carcinoma Tca8113 cells, and then we tested the cell proliferation by MTT assay and cell invasiveness by cell invasion assay. To examine whether PIK3CA is involved in the response of Tca8113 cells to an anticancer drug, cisplatin, we further performed cell death analysis by fluorescence-activated cell sorting (FACS). We found that knocking down PIK3CA led to slower cell growth and lessened cell invasiveness. In addition, PIK3CA downregulation increased Tca8113 cell death after cisplatin treatment, suggesting that PIK3CA downregulation might be helpful to increase the effects of some anticancer drugs. Moreover, in a mouse model of established large sized OSCC, we showed that suppression of PIK3CA markedly diminished tumorigenicity in vivo. To understand its molecular mechanism of action, we measured expression of phospho PTEN (Ser380) and phospho-AKT (Ser473) by Western blot and found that suppression of PIK3CA inhibited OSCC growth through downregulation of p-PTEN and p-AKT. Our study highlights critical roles for PIK3CA in the tongue cancer, and suggests that PIK3CA gene might be considered as a therapeutic target for clinical tongue cancer. PMID- 22812190 TI - Inhibition of SPHK1 suppresses phorbol 12-myristate 13-acetate-induced metastatic phenotype in colorectal cancer HT-29 cells. AB - Expression of sphingosine kinase 1 (SPHK1) plays a role in colorectal cancer progression. This study aimed to demonstrate the mechanism of human colorectal cancer cell metastatic phenotype through SPHK1 knockdown. Human colorectal cancer HT-29 cells were stimulated by phorbol 12-myristate 13-acetate (PMA) with or without SPHK1 siRNA transfection. Tumor cell phenotypic changes were analyzed by using invasion, motility, cell viability, and apoptosis assays. Gene expressions were assessed using Western blot. PMA induced a metastatic phenotype in colorectal cancer cells, as indicated by cell viability, migration and invasion capacity, and ERK1/2 phosphorylation, whereas SPHK1 siRNA transfection suppressed the metastatic phenotype of tumor cells and antagonized PMA's effects. SPHK1 knockdown also inhibited secretion of MMP-2 and MMP-9 into the tumor cell conditioned medium. Suppression of SPHK1 expression suppresses the PMA-induced metastatic phenotype via ERK1/2 phosphorylation in human colorectal cancer cells. PMID- 22812191 TI - Episodic hemorrhage during honeybee venom anaphylaxis: potential mechanisms. AB - Episodic hemorrhage is not a typical symptom of anaphylactic reaction to insect stings. Cases of reactions to honeybee (HB) sting or venom immunotherapy in which the uterus is the main target organ are very rare. Hemorrhage can be induced by HB venom components, especially melittin, which interfere with complement cleavage and bradykinin release. Both mechanisms are directly or indirectly associated with coagulation, thrombolysis, hemolysis, and smooth muscle tone. Induction of episodic hemorrhage through pathway destabilization in a defective bradykinin system or vulnerable organ may not be compensated by appropriate regulatory mechanisms. The pathological role of effectors is generally offset by the interaction of various regulatory systems, and the probability of hemorrhage is minimized thanks to this compensatory capability. In endometrial bleeding, the uterus becomes more vulnerable as a result of postmenstrual vascular fragility and additional induction of anaphylaxis-related uterine contractions. Episodic hemorrhage, especially metrorrhagia, as a consequence of HB venom activity may be suspected by an allergologist, but not by a physician. Melittin-free or recombinant allergens of HB venom, as well as modulators of the biochemical systems involved, could help to reduce the likelihood of hemorrhage. However, further investigation is required before these strategies can be introduced in clinical practice. PMID- 22812192 TI - Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region. AB - BACKGROUND: Hazelnut (Corylus avellana) allergy exhibits age and geographically distinct sensitization patterns that have not yet been fully resolved. OBJECTIVE: To study sensitization to Cor a 11 in different age groups of hazelnut-allergic patients and infants with atopic dermatitis (AD) sensitized to hazelnut in a birch-endemic region. METHODS: Sera from 80 hazelnut-allergic patients, 33 infants under 1 year of age with AD (24 sensitized and 9 not sensitized to hazelnut), 32 healthy control individuals, and 29 birch pollen-allergic but hazelnut-tolerant individuals were tested for immunoglobulin (Ig) E reactivity to Cor a 11 by ImmunoCAP. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 was studied by ISAC microarray. RESULTS: Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitized to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitized to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitization to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. CONCLUSION: Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy, a finding that is consistent with observations concerning sensitization to Cor a 9. PMID- 22812193 TI - Lack of association between GSTM1, GSTP1, and GSTT1 gene polymorphisms and asthma in adult patients from Rome, central Italy. AB - BACKGROUND: Asthma is a complex multifactorial disease that is not yet fully understood. Oxidative stress due to an imbalance between the oxidative forces and the antioxidant defense systems has been implicated in asthma pathogenesis. However, much debate still surrounds the key genetic factors involved in the development of this disease. Candidate genes include the glutathione S transferases (GSTs). In particular, mu, pi, and theta classes of GSTs play an important role in regulating inflammatory responses. However, few and contradictory data are available on the association between asthma development and GST gene polymorphisms (GSTM1, GSTP1, and GST1). OBJECTIVE: To investigate whether GSTM1, GSTT1, and GSTP1 polymorphisms are associated with asthma development. METHODS: We recruited 200 unrelated healthy individuals and 199 asthmatic patients from Rome in Central Italy. Genotyping of GSTMI and GSTT1 genes was performed by a multiplex polymerase chain reaction (PCR) while the GSTP1 polymorphism (rs1695) was determined using PCR-restriction fragment length polymorphism analysis. RESULTS: Our results suggest that the GST polymorphisms analyzed are not associated with asthma, confirming the uncertain role of GST genes in the development of asthma. CONCLUSIONS: Oxidative stress is certainly involved in the development of asthma, and GSTs may therefore influence asthma risk, although, as our results show, their role in pathogenesis remains to be elucidated. Future studies should focus on the interactions of GST genes with the environment and other antioxidant genes to shed light on the role of GSTs in asthma. PMID- 22812194 TI - Association between polymorphisms in IL17F and male asthma in a Chinese population. AB - BACKGROUND AND OBJECTIVES: Interleukin (IL) 17F is a marker of type 17 helper T cells and has a proinflammatory role in asthma.The aim of the present study was to assess the possible association between asthma and polymorphisms in the IL17F gene in a Chinese population. METHODS: A total of 318 asthmatic patients and 352 nonasthmatic controls were recruited. Two single-nucleotide polymorphisms in IL17F (rs763780 and rs13209590) were detected using GenomeLab SNPstream. Logistic regression methods were used to analyze data. RESULTS: A significantly lower frequency of the C allele in rs763780 was observed in the control group (P = .0148). The rs763780 TC heterozygote was associated with an increased risk of asthma, and a similar trend was observed assuming a codominant genotype effect (adjusted OR, 1.58; 95% CI, 1.06-2.36; P = .0148; adjusted OR, 1.64; 95% CI, 1.10 2.45; P = .0217). Furthermore, a novel finding of the present study was that this association was exclusive to males (adjusted OR, 1.79; 95% CI, 1.06-3.05; P = .0308) and patients with higher immunoglobulin E levels (> or = 1.85 IU/mL) (adjusted OR, 1.88; 95% CI, 1.10-3.22; P = .0213). We also found that the haplotype with minor alleles for rs763780 was associated with an increased risk of asthma (adjusted OR, 1.62; 95% CI, 1.11-2.35; P = .0115). CONCLUSION: Our findings indicated that polymorphisms might play a role in susceptibility to asthma. PMID- 22812195 TI - Effect of asthma, aeroallergen category, and gender on the psychological status of patients with allergic rhinitis. AB - BACKGROUND: Despite increasing evidence for an association between allergy and psychological disorders in patients with allergic rhinitis (AR), the relationship between comorbid AR and asthma is not clear. The objective of this study was to investigate the effect of concomitant asthma, gender, and sensitization to a particular aeroallergen category on the psychological status of AR patients. METHODS: We analyzed 524 AR patients (311 males/213 females) aged 16 to 60 years using the Symptom Checklist-90 (SCL-90) and found that 34.2% had persistent AR and 65.8% intermittent AR. Overall, 61 patients (11.6%) had concomitant asthma. RESULTS: The SCL-90 scores of AR patients were significantly higher for the somatization, obsessive-compulsive, hostility, and psychoticism dimensions than those of the healthy controls. In contrast, the SCL-90 scores for persistent AR and intermittent AR patients were significantly different. Concomitant asthma significantly impacted theAR individuals' SCL-90 dimension scores for the obsessive-compulsive, interpersonal sensitivity, depression, and paranoid ideation subscales. Gender and sensitization to a particular aeroallergen category did not affect the SCL-90 scores of AR patients individually, but led to significant differences in SCL-90 scores for the phobic anxiety and psychoticism subscales when considered in combination. CONCLUSION: Our results suggest that comorbid asthma exerts an independent main effect on the psychological status of AR patients. PMID- 22812196 TI - Variable content of Fel d 1 variants in house dust and cat extracts may have an impact on allergen measurement. AB - BACKGROUND: The major cat allergen, Fel d 1, is a tetrameric glycoprotein composed of 2 heterodimers. Polymorphisms in this allergen are well documented. Recent work shows that Fel d 1 samples can contain core fragments of variable immunoreactivity. OBJECTIVES: Our objective was to compare Fel d 1 polymorphism in cat extracts and house dust, which is used as an indicator of allergen exposure and to understand how the combination of individual Fel d 1 variants can affect cat allergen measurement. METHODS: Natural Fel d 1 allergens were water extracted from house dust and from the chest area and anal sacs of a cat. Recombinant Fel d 1 was provided commercially. The samples were analyzed by immunoblotting; variants were isolated using gel electrophoresis and tested using enzyme-linked immunosorbent assay. RESULTS: Four Fel d 1 variants of 40, 30, 19 21, and 14-16 kDa were consistently identified in Fel d 1 samples. Fel d 1 patterns found in house dust and the chest area wash were similar. Dimers were shown to be the major variant, while intact or truncated tetramers and core fragments were found in variable amounts. Intact and truncated dimers of Fel d 1 displayed similar antibody binding. Conversely, the intact tetramer-but not the core tetramer-was found to bind twice the antibody amount as the dimers and core fragments. CONCLUSIONS: Despite a common pattern of Fel d 1 variants in cat extracts and house dust, variations in the tetramer-to-dimer ratio among samples may introduce major discordances in cat allergen measurements using immunoassays. Our findings indicate the need for further harmonization of allergen immunoassays. PMID- 22812197 TI - Epidemiology of cypress pollen allergy in Montpellier. AB - BACKGROUND: Cupressaceae pollen allergy is a worldwide winter pollinosis. Exposure to cypress pollen has increased enormously during recent decades, and cypress pollen allergy has become a major health problem, especially in Mediterranean countries. OBJECTIVES: We aimed to evaluate the prevalence of cypress pollen sensitization and allergy in the Montpellier area and the symptoms presented by sensitized patients. METHODS: We included all 6185 consecutive patients who were referred to our center for any allergic disorder during a 36 month period. For each patient, we evaluated skin prick test results, allergy symptoms, pulmonary function test results, and the need for allergen immunotherapy. RESULTS: We found that 20.7% of patients were sensitized to cypress pollen and 46.4% presented symptoms during the pollen season. The main symptoms were rhinoconjunctivitis and asthma. Oral allergy syndrome to peach was detected in 4% of sensitized and symptomatic patients. Allergen immunotherapy was necessary to control symptoms in 57.9% of cases. CONCLUSIONS: Cypress pollen allergy is one of the leading causes of respiratory allergy in the Montpellier area. Symptoms are often severe and include pollen-induced asthma. Moreover,many patients need allergen immunotherapy in order to achieve better control of their symptoms. PMID- 22812198 TI - Strongyloidiasis: an emerging infectious disease that simulates allergic diseases. PMID- 22812200 TI - Salmonella vertebral osteitis and sepsis in a girl with interferon gamma pathway deficiency. PMID- 22812199 TI - Urticaria-angioedema due to carboxymethylcellulose eye drops. PMID- 22812201 TI - Skin reactions to gadolinium-based contrast media. PMID- 22812202 TI - Occupational asthma due to western red cedar in a guitar maker. PMID- 22812203 TI - Frey syndrome in children: a nonallergic cause of facial erythema triggered by food. PMID- 22812204 TI - Anaphylaxis due to orange soft drinks. PMID- 22812205 TI - Nasal challenge test in the diagnosis of latex-related systemic reactions. PMID- 22812206 TI - Persistence of allergy to goat's milk after specific induction of tolerance to cow's milk. PMID- 22812207 TI - Successful desensitization to rabbit antithymocyte globulin in a patient with aplastic anemia. PMID- 22812208 TI - Delayed-type hypersensitivity to fenofibrate. PMID- 22812209 TI - A sea urchin roe tropomyosin-like protein is recognized in vitro by shrimp allergic individuals. PMID- 22812210 TI - Jessner lymphocytic infiltrate as a side effect of bee venom immunotherapy. PMID- 22812211 TI - Allergy to mint (Mentha spicata). PMID- 22812212 TI - Variations in TGF-beta, IL-10, and IL-17 after specific immunotherapy and correlations with symptoms in patients with allergic rhinitis. PMID- 22812213 TI - [Relationship between PMI and fourier transform infrared spectral changes in muscle of rats after death caused by mechanical asphyxial]. AB - OBJECTIVE: To observe the postmortem degradation process in rat myocardium and skeletal muscle using Fourier transform infrared (FTIR) spectroscopy and to provide a new method for estimating postmortem interval (PMI). METHODS: Left ventricle and skeletal muscles of rats dying of mechanical asphyxiated were sampled at different PMIs. The changes of different chemical functional group in the myocardium and skeletal muscle samples were measured by FTIR spectroscopy. The different absorbance (A) ratios of peaks were calculated and the curve estimation analysis between absorbance ratios (x) and PMI (y) were performed to establish six mathematical models. RESULTS: FTIR spectral absorption peak of rat myocardium and skeletal muscle showed three changes: increase, decrease and stable. The cubic model function showed the strongest correlation coefficient. The A1080/A1396 ratio of skeletal muscle showed the strongest correlation coefficient (r = 0.832) with more accurate determination of PMI. CONCLUSION: FYIR spectroscopy can be potentially used as an effective method for estimating PMI in forensic practice using myocardium and skeletal muscle. PMID- 22812214 TI - [Application of serum total IgE, tryptase and chymase in the identification of death caused by drug anaphylactic shock]. AB - OBJECTIVE: To explore the application value of serum total IgE, tryptase and chymase in the identification of death caused by drug anaphylactic shock. METHODS: The general information from 235 cases of non-drug anaphylactic shock and 32 cases of drug anaphylactic shock were analyzed. The serum IgE level had been detected in the cases. Ten cases caused by coronary disease and 10 cases caused by sudden manhood death syndrome were selected from non-drug anaphylactic shock cases for the control group. Expressions of tryptase and chymase in the lung and heart were detected using immunohistochemistry method. The number and IOD of positive mast cells were counted. RESULTS: In the drug anaphylactic shock group, the IgE value of 18 samples (56.25%) was significantly higher than the normal upper limit of 120 IU/mL. In the non-drug anaphylactic shock group, the IgE value of 67 samples (28.51%) was higher than 120 IU/mL. The expressions of tryptase and chymase were significantly increased in lung and myocardial tissue in drug anaphylactic shock group (P < 0.05). CONCLUSION: Tryptase and chymase are more superior than that of the serum total IgE in the diagnosis of death caused by drug anaphylactic shock, and are more suitable in forensic practice. PMID- 22812215 TI - [Basophil CD63 expression in the blood of the anaphylactic shock rat]. AB - OBJECTIVE: To explore the value of flow cytometry in anaphylactic shock diagnosis by CD63 expression being detected using flow cytometry to conform the activation of basophils. METHODS: Sixteen rats were randomly divided into two groups: control group and anaphylactic shock group. The model of anaphylactic shock rat with ovalbumin injection was established. CD63, CD45 and CD203c antibody combination, flow cytometry was employed to detected blood basophil CD63 expression. Immunofluorescence method was employed to observe the CD63 immunofluorescence staining in the rat lung tissue. RESULTS: (1) Pure basophils were obtained by CD45 and CD203c gating. (2) The percentages of basophils CD63 were (17.34 +/- 2.04)% and (1.52 +/- 0.35)% in the experimental and control group, respectively. The differences between two groups were statistically significant (P < 0.01). (3) Compared with the control group, the expression of CD63 in basophils increased in anaphylactic shock lung tissue. CONCLUSION: The detection of CD63 by flow cytometry could be the supplement of vivo allergic reactions and have good clinical value. PMID- 22812216 TI - [Changes of prostaglandin D2,carboxypeptidase A3 and platelet activating factor in guinea pig in anaphylactic shock]. AB - OBJECTIVE: To detect the changes of leukotriene E4(LTE4), prostaglandin D2(PGD2), carboxypeptidase A3(CPA3) and platelet activating factor (PAF) in guinea pigs died from anaphylactic shock. METHODS: Guinea pigs were used for establishing anaphylactic shock models. The levels of LTE4, PGD2 and CPA3, and PAF were detected in urine, plasma, and brain tissues with ELISA kit, respectively. The significant biomarkers were selected comparing with control group. The changes of PGD2, CPA3 and PAF in the guinea pigs at time zero, 12 and 24 hours after death were observed and compared respectively. The effect of platelet activating factor acetylhydrolase (PAF-AH) to PAF in guinea pig brain was examined and compared. RESULTS: There were no statistically differences of LTE4 levels in urine observed between experimental group and control group. The levels of CPA3, PGD2 and PAF in the experimental group were significantly higher than that in the control group at 0 h. The levels of PAF at 12 and 24 hours after anaphylactic shock were significantly higher than that in the control group. The levels of PAF decreased significantly after pretreatment with PAF-AH. CONCLUSION: LTE4 in urine cannot be selected as a biomarker to determine the anaphylactic shock. PGD2 and CPA3 in plasma, and PAF in brain tissue may be used as biomarkers to determine the anaphylactic shock. PAF-AH may be potentially useful for clinical treatment of anaphylactic shock. PMID- 22812217 TI - [Time-dependent expression of vascular endothelial growth factor after acute myocardial ischemia in rats]. AB - OBJECTIVE: To investigate the immunohistochemical distributions and expressions of vascular endothelial growth factor (VEGF) in the model of rat myocardial ischemia. METHODS: The model of myocardial ischemia was established by ligating the left anterior descending (LAD) coronary artery of rats. The changes of VEGF expression were detected by immunohistochemistry and Western blot at time points after myocardial ischemia. The electrocardiographic changes were evaluated uninterruptedly. RESULTS: The expression of VEGF was not be found in control group. Fifteen minutes after LAD ligation, weak positive expression of VEGF were found in the ischemic myocardium. The expression of VEGF reached the peak at 3 hours after ligation. The VEGF distribution was mainly localized in the ischemic and peri-ischemic regions. Six hours after LAD ligation, the expression of VEGF decreased comparing with 3 hours and showed a relatively higher level. Fatal arrhythmia was found in nine rats by the electrocardiograph. CONCLUSION: The immunohistochemical staining of VEGF could be helpful for investigating the location and severity of acute myocardial ischemia. Fatal arrhythmia may be secondary to myocardial ischemia. PMID- 22812218 TI - [Inspection of left metal particles on skin impacted by the steel hammers]. AB - OBJECTIVE: To establish a new method to estimate injury-tool by analyzing the components of left metal particles from hammers impact on pig skin and filter paper using scanning electron microscope and energy dispersive X-ray spectrometer (SEM-EDX). METHODS: The pig skin and filter paper were stricken by two steel hammers. The left metal particles were examined by SEM-EDX and the results were statistically analyzed by SPSS 13.0. RESULTS: The characteristics of left particles showed stable by several impacts using one steel hammer. The left particles showed no statistical difference for impact on pig skin and filter paper. The left particles displayed a statistical difference using two hammer with different components. CONCLUSION: SEM-EDX can be used to detect the left metal particles from the steel hammer and can provide a method for estimating injury-tool. PMID- 22812219 TI - [MSCT optimal examination time for unconspicuous rib fracture]. AB - OBJECTIVE: To explore MSCT optimal examination time for patients with unconspicuous rib fracture. METHODS: Sixty-three patients with thoracic trauma from January 2009 to June 2011 were collected. They were examined by MSCT in the first week after trauma and re-examined during eighth weeks after trauma. The number of rib which had been found fractured in the first examination was compared to that in re-examinations. RESULTS: Patients with fine rib fracture often have different diagnostic results at different examination time after trauma. There was statistical difference between the number in the first week and the third week to the fifth week. CONCLUSION: MSCT could show the pathophysiological changes of rib fracture objectively in the stage between the third week and the fifth week after trauma, which is optimal examination time for the fine rib fracture. PMID- 22812220 TI - [Identification of sibling brothers using STR and Y-biallelic markers]. AB - OBJECTIVE: To explore the methods for identification of sibling brothers with Y STR locus mutation by detection of genetic markers on autosome and Y-biallelic. METHODS: Goldeneye 20A and 18NC kit were used to genotyped the 35 STRs on autosome from two men. PowerPlex Y kit and Yfiler kit were used to genotyped the 16 STRs on Y chromosome full sibling index was calculated by ITO method. Twenty Y biallelic markers were genotyped by fragment length discrepant allele specific PCR or general PCR. RESULTS: Relationship of sibling brothers was found to have mutation of 2 loci on 16 Y-STR and the identical genetype of 20 Y-biallelic markers as well as a cumulative full sibling index of 4.3149 x 10(6) from 35 STRs on autosome. CONCLUSION: In identification of paternal linage of Y-STR mutation, more genetic information can be acquired by detection of Y-biallelic markers including SNP and InDel. PMID- 22812221 TI - [Polymorphisms of rs4906902 and rs8179184 loci in the promoter of the GABRB3 gene and their relevance with schizophrenia]. AB - OBJECTIVE: To investigate the polymorphisms of rs4906902 and rs8179184 loci in the promoter of the gamma-aminobutyric acid(GABA) receptor A, beta3 subunit gene (GABRB3), and their relevance with schizophrenia. METHODS: PCR and DNA sequencing were used to detect the polymorphisms of rs4906902 and rs8179184 loci in 210 healthy individuals (control group) and 206 schizophrenic patients (case group) of the Han population in northern China. The chi2 test was used to identify Hardy Weinberg equilibrium of the genotype distribution in the control group followed by comparing differences in genotype and haplotype frequency distributions between two groups. RESULTS: Distributions of the genotype frequencies fit the law of Hardy-Weinberg equilibrium in the control group. rs4906902 and rs8179184 loci were in linkage disequilibrium and showed two haplotypes which were T-G and C-A. The differences of genotypic frequencies and haplotype frequencies were statistically significant between the two groups (P < 0.05). The frequency of haplotype C-A in the case group was significantly higher than in the control group. Genotypic and haplotype frequencies in the maternal line and paternal line were statistically significant in the case group (P < 0.05). CONCLUSION: The haplotype of C-A in rs4906902 and rs8179184 loci in the promoter of GABRB3 gene may be maternally inherited and positively associated with schizophrenia and may be a useful tool in the forensic identification of schizophrenia. PMID- 22812222 TI - [Postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pigs]. AB - OBJECTIVE: To investigate the postmortem distribution of tetrodotoxin in tissues and body fluids of guinea pig, and to provide method and evidence for forensic identification and clinical diagnosis and treatment. METHODS: Guinea pigs were intragastric administrated with 100, 50, 15 microg/kg tetrodotoxin, respectively. The poisoning symptoms were observed. The samples of heart, liver, spleen, lung, kidney, brain, stomach, intestines, bile, heart blood and urine were collected. The concentrations of tetrodotoxin in tissues and body fluids were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: After administrated with tetrodotoxin, all guinea pigs came out poisoning signs including tachypnea, weary and dead finally. Tetrodotoxin concentrations in lung, stomach, intestines and urine were higher, followed by blood, heart and brain. The concentration in bile was the lowest. CONCLUSION: Postmortem distribution of tetrodotoxin in guinea pig is uneven. The concentration in the lung, stomach, intestines, urine and heart blood are higher, those tissues could be used for diagnosis of tetrodotoxin poisoning. PMID- 22812223 TI - [Analysis of 12 death cases of medical tangles after trauma]. AB - OBJECTIVE: To explore the main problems and ideas in the death cases of medical tangles after trauma. METHODS: Twelve death cases of medical tangles after trauma were selected from a forensic science institute during recent six years. Traumatic conditions, medical malpractices and contribute degree of malpractice were estimated and analyzed. RESULTS: The reasons of trauma included accidents and intentional injury. Among these cases, there were 10 involved in malpractice, of which 7 cases played secondary role. CONCLUSION: Diagnosis, symptom observation and emergency therapy are the important keys for determining the responsibility in death cases of medical tangles after trauma. PMID- 22812224 TI - [Progress in diagnosis of neurogenic erectile dysfunction]. AB - Recently, with application of evoked potentials technology in the test of somatic and autonomic nerves, quantitative sensory testing in the detection of small nerve fiber function, and functional magnetic resonance imaging in the detection of senior central function, the detection of neural function has become more accurate. This article reviews the progress and application of diagnostic methods about neurogenic erectile dysfunction in order to provide a reference for forensic diagnosis and research in the future. PMID- 22812225 TI - [Application of diffusion tensor imaging and 1H-magnetic resonance spectroscopy in diagnosis of traumatic brain injury]. AB - Mild traumatic brain injury (mTBI) is a common type of brain disorders among young adults. The dysfunction of the brain is often exacerbated due to diffuse axonal injury (DAI) which based on the injury of white matter fibers and axons. Since mild and moderate brain injury or DAI are diffuse and subtle, conventional CT and MRI are difficult to make a positive diagnosis. Recent clinical study indicated that functional magnetic resonance imaging has a high detection rate in the diagnosis of acute mild and moderate brain injury, especially the diffusion tensor imaging (DTI) and 1H-magnetic resonance spectroscopy (1H-MRS). This paper has reviewed the principles and characteristics of DTI and 1H-MRS, and recent research in the clinical and animal experiments on brain injury. PMID- 22812226 TI - [Effect of FK506 and CsA on vascular endothelium of hyperlipidemic rats]. AB - OBJECTIVE: To observe the influence of ciclosporin A (CsA) or/and FK506 on vascular endothelium of hyperlipidemic rats. METHODS: Hyperlipidemic rat model was established as previously described. The injury of vascular endothelium of these rats was observed after stimulation with FK506 or/and CsA. The mRNA transcription and protein expression of the vascular endothelium growth factor (VEGF), decay-accelerating factor (DAF) and C reactive protein (CRP) in vascular endothelium of rats were measured. The serum reactive oxygen species (ROS) was detected. RESULTS: Compared with FK506, CsA was more likely to cause injury of vascular endothelium, damaging the integrity of endothelium of hyperlipidemic rats. CsA inhibited the expression of VEGF and the complement inhibitor DAF and increased the expression of CRP of vascular endothelial cells. CsA also up regulated the serum level of ROS. FK506 showed no such impacts. CONCLUSION: CsA can damage vascular endothelium of hyperlipidemic rats by activating the complement system induced by VEGF/DAF and ROS/CRP pathway. FK506 has no influence on the VEGF/DAF pathway and the expression of ROS/CRP. PMID- 22812227 TI - [Construction and expression of the recombinant plasmid pGEX-Sj14-3-3 of Schistosoma japonicum in BL21(DE3)]. AB - OBJECTIVE: To construct and research the expression of the recombinant plasmid pGEX-Sj14-3-3 in Escherichia coli BL21 (DE3). METHODS: Sj14-3-3 gene was amplified by RT-PCR from template of the total RNA extracted from adult worms of S. japonicum, and then cloned into the vector pGEX-1gammaT to construct pGEX-Sj14 3-3. The recombinant plasmid pGEX-Sj14-3-3 was transformed into E. coli BL21 (DE3). BL21 (pGEX-Sj14-3-3) was induced with isopropyl-beta-D thiogalactopyranosid (IPTG), and the expressed products were identified by SDS PAGE and Western blot. RESULTS: A 399 bp fragment of Sj14-3-3 coding gene was successfully amplified by RT-PCR and cloned into the vector pGEX-1gammaT, and the recombinant plasmid pGEX-Sj14-3-3 was constructded successfully. The molecular mass of the expressed recombinant protein was proximately 40 000 Dolton as detected by SDS-PAGE. The amount of the expressed protein was about 21% of the total bacterial protein. Western blot confirmed that the expressed protein could be recognized by the immune sera from rabbit infected with Schistosoma japonicum. CONCLUSION: The recombinant plasmid pGEX-Sj14-3-3 was successfully constructed. The Sj14-3-3 protein was highly expressed in E. coli and the expressed recombinant protein possessed specific antigenicity. PMID- 22812228 TI - [The effect of leptin on Cx43 expression in protecting mice cerebral ischemia/reperfusion injury]. AB - OBJECTIVE: To explore the effect of leptin on expression of Cx43 after rat cerebral ischemia/ reperfusion injury and its related mechanism. METHODS: Forty five male kunming mice were randomly divided into 3 groups: sham group, model group and leptin group. Mouse models of transient focal cerebral ischemia were established by occlusion of the right middle cerebral artery for 2 h followed by 24 h reperfusion in model and leptin group. Mice of leptin group were intraperitoneally injected with 1 mg/kg leptin at 0 minute after ischemia. The infarct volume and neurological deficit scores following leptin treatment were determined using TTC staining and the Longa's score, respectively, to evaluate the protective effect of leptin against ischemic cerebral injury. The histopathological changes in the brain were observed with HE staining. The astrocytes of SD rat cerebral cotex were cultured primaryly and purified, and then divided them into four groups: control, model, leptin 100 microg/L, and leptin 500 microg/L. The cerebral astrocytes with hypoxia/reoxygenation injury were induced. The cellular viability of injury was detected by MTT assay. The effect of leptin on Cx43 expression was detected by Western blot in brain tissues and astrocytes. RESULTS: Compared with the model group, the neurological deficits and cerebral infarct volume of leptin group were reduced (P< 0.05), the histopathological injury in the brain tissues was alleviated and the expression of Cx43 was decreased markedly (P < 0.01). The survival rate of astrocytes was increased significantly in leptin 500 microg/L group (P < 0.01), whereas the Cx43 expression of astrocytes decreased (P < 0.01). But the difference of leptin 100 mcirog/L was not significant (P > 0.05). CONCLUSION: Leptin can ameliorate cerebral pathological changes in the event of IR injury by suppressing the expression of Cx43 both in vivo and vitro experiments. PMID- 22812229 TI - [The protection effects of resveratrol on irradiated human pneumonic cell lines and its mechanism]. AB - OBJECTIVE: This study was to explore whether resveratrol could protect human bronchial epithelial cells (HBE) and human fetal lung fibroblasts (MRC5) from radiation injury and to investigate its potential HBE and MRC5 were divided into four groups: Group 1 (Vehicle), control group, only mechanism. METHODS: treated with vehicle; Group 2 (resveratrol, Res), the resveratrol group, treated with 5 micromol/L resveratrol; Group 3 (RT+Vehicle), the X-ray irradiation group, only subjected to irradiation of 20 Gy X-ray; Group 4 (RT+Res), the combination therapy group, 2 hours before X-ray treatment (20 Gy, 8. 33 Gy/min for 144 s), 5 micromol/L resveratrol was added to the cells. Several experimental methods were used to observe cellular morphology, ultrastructure, viability, DNA damage, apoptosis, and to determine the change of oxidative stress indexes such as reactive oxygen species (ROS), malondialdehyde (MDA), total glutathione (GSH) and superoxide dismutase (SOD). RESULTS: X-ray could induce HBE and MRC5 cell injury. Resveratrol could significantly ease the morphological and ultrastructure injury, relieve the decrease of cellular viability and the damage of DNA, and reduce cellular apoptosis. Besides, oxidative stress indexes including ROS, MDA, GSH, SOD were improved by resveratrol after irradiation. CONCLUSION: Resveratrol protect HBE and MRC5 from radiation injury, which is related to the alleviation of oxidative stress injury. PMID- 22812230 TI - [Influence of Erigeron breviscapus on the expression of collagen type I , MMP1 and TIMP1 of MRC-5 cells under hypoxia]. AB - OBJECTIVE: Study the influence of Erigeron breviscapus on collagen type I, matrix metalloproteinase1 (MMP1) and tissue inhibitor of metalloproteinase1(TIMP1) in human embryo lung fibroblast MRC-5 under hypoxia. METHODS: MRC-5 cultured in vitro were individed into 4 groups, including normoxia control, hypoxia, hypoxia and staurosporine (SP), hypoxia and erigeron breviscapus. The expression of hypoxia-inducible factor-1 alpha (HIF-1alpha), pro-collal and phospho-smad2 (p smad2) were evaluated by Western blot. The level of collagen type I, MMP1 and TIMP1 in supernatant fluid were detected by ELISA. RESULTS: Expressed pro collalpha1, p-smad2 in MRC-5 cells under nomoxia were detected, but not HIF lalpha. A low level of collagen type I, MMP1 and TIMP1 was also detected in the cell supernatant. In nomoxia secreted pro-collalpha1, p-smad2, collagen type I , MMP1 and TIMP1, hardly secreted HIF-lalpha. Under hypoxia, the expression of all of them was increased when compared with those of under nomoxia condition (P < 0.05). MMP1 expression was significantly further upregluted by pre-cubation with SP in hypoxia, however collagen type I, TIMP1 in supernatant fluid and pro collalpha1, p-smad2 in cells were inhibited (P < 0.05, vs. hypoxia group). Treated with Erigeron breviscapus (12. 5 microg/mL, 50 microg/mL) under hypoxia condition, significantly reduced expression of pro-collalpha1, p-smad2, HIF 1alpha in MRC-5 cells and collagen type I, MMP1, TIMP1 in supernatant fluid were observed (P < 0.05, vs. hypoxia). CONCLUSION: Erigeron breviscapus can decrase the expression of HIF-1alpha of MRC-5 cells under hypoxia condition by inhibit the expression of collagen type I and TIMP1 partly through the Smad2 signaling pathways. PMID- 22812231 TI - [DNA damage response in ovarian clear cell adenocarcinoma]. AB - OBJECTIVE: To study the relationship between ovarian clear cell adenocarcinoma and DNA damage. METHODS: 14 samples were selected from clinical ovarian cases including 3 cases with normal ovarian tissue, 6 cases with poorly differentiated ovarian tumor, 5 cases with ovarian clear cell adenocarcinoma, treated by X-ray irradiation and frozen sections respectively. DNA damage response was analyzed by immunofluorescence and Western blot. RESULTS: Before X-ray irradiation, compared to normal ovarian tissue, a large number of endogenous damage existed in ovarian clear cell adenocarcinoma, and phosphorylation of histone family 2A variant (H2AX) was abnormally enhanced 1 hour after irradiation treatment, however, DNA repair was normal in ovarian clear cell adenocarcinoma. Phosphorylation of H2AX was dispensable for p53 binding protein 1 (53BP1) activation and couldn't be colocalized in clear-type ovarian cancer tissues. CONCLUSION: The abnormal DNA damage activation implies that the network of DNA damage signaling pathway may be defective. PMID- 22812232 TI - [Study on curcumin-induced apoptosis in ovarian cancer resistant cell lines COC1/DDP]. AB - OBJECTIVE: To investigate the effect and possible mechanism of curcumin to induce apoptosis in ovarian cancer resistant cell lines COC1/DDP. METHODS: COC1/DDP cells were treated with different concentration of curcumin, with or without the combination of chemotherapy drugs cisplatin (DDP) and paclitaxel (PIX) for 48 hours. The growth inhibition rates of COC1/DDP cells were studied by MTT method, and the apoptotic ratios were measured with flow cytometry. The expression of phosphoinositide 3-kinase catalytic subunit (PI3KCA) mRNA was studied by RT-PCR in curcumin treated cells, DDP treated cells and their combination treated cells. RESULTS: After the treatment of different concentration of curcumin for 48 hours, the growth inhibition rates and the apoptotic rate of COC1/DDP cells were gradually increased accordingly with increasing curcumin concentration. Furthurmore, curcumin in combination with chemotherapy drug obtained higher inhibition rate and apoptosis rate than single chemotherapy drug did (P < 0.05). The expression of PI3KCA mRNA of COC1/DDP cells treated with curcumin combined DDP was much lower than that treated only with DDP (P < 0.05). CONCLUSION: Curcumin can increase the apoptotic rate of COC1/DDP cells, so has synergistic effect on with chemotherapy drugs on the induction of cell apoptosis. Its possible mechanism may be related to the down-regulation of PI3KCA. PMID- 22812233 TI - [Antitumor effect of adriamycin conjugated with downsized anti-endoglin monclonal antibody]. AB - OBJECTIVE: To study the antitumor efficacy of an immunoconjugate composed of adriamycin (ADM) and downsized Fab fragment of mouse anti-Endoglin monoclonal antibody. METHODS: The Fab fragment of mouse anti-Endoglin monoclonal antibody was downsized and conjugated with ADM by m-Maleimidobenzoyl-N-hydroxysuccinimide ester (MBS). The antitumor effect of the conjugate was tested in mice bearing subcutaneous injection of H22 tumor in vivo. RESULTS: The molecular ratio of Fab:ADM in conjugate was approximately 1:2. The Fab-ADM conjugate inhibited the growth of H22 by 91.94% on day 14 after injection at the dose of 0.4 mg/ kg, much higher the inhibition rate of 25.00% by the equivalent dose of free ADM. The median survival time of the mice treated with the conjugate was longer than those treated with free ADM. The Fab-ADM conjugate was significantly more effective than free ADM in tumor suppression and life span prolongation. CONCLUSION: Fab ADM displayed more significant antitumor efficacy than free ADM in vivo and might be a novel candidate for cancer treatment. PMID- 22812234 TI - [Primary culture of human trophoblastic cells and their susceptibility to human cytomegalovirus]. AB - OBJECTIVE: To determine the susceptibility of primary human trophoblastic cells (HTCs) to human cytomegalovirus (HCMV) infection. METHODS: 30 villus of healthy pregnant women were digested with a mixture of 0.25% trypsin and 0.2% DNase. The digestion was then filtered by a 200 mesh stainless steel sieve. HTCs were purified by Percoll gradient centrifugation and repeat purification with trypsin during cell passage. HTCs were identified by cell morphology and immunofluorescence. PCR, Western blot and immunofluorescent staining were performed to detect HCMV gene and protein 72 hours post infection of HCMV. RESULTS: The combination of 0.25% trypsin and 0.2% DNase with Percoll gradient centrifugation isolated and purified primary HTCs. More than 90 percent cells expressed CK-7 related antigen. The results of PCR, western blot and immunofluorescence showed positive expressions of CMV gB and virus proteins. CONCLUSION: HTCs is susceptible to HCMV infection, which suggests a possible route of HCMV infection at the fetal-maternal interface. PMID- 22812235 TI - [The effects of activin A and inhibin A on the IVM of mice immature oocytes]. AB - OBJECTIVE: To study the effects of activin A (ACTA) and inhibin A (INHA) on the in vitro maturation (IVM) of mice immature eggs and early embryonic development. METHODS: 1. The mice oocytes were cultured in the culture medium contained different concentration of ACTA and INHA (50 ng/mL, 100 ng/mL, 200 ng/mL) to find the optimum concentration; 2. The effects of different concentration of ACTA, INHA, ACTA+ INHA on the mature rates of mice oocytes were compared; 3. The effects of different concentration of ACTA, INHA, ACTA+INHA on the fertility rates and blastocysts formation rates of IVM mice eggs were also compared. RESULTS: The mature rates of mice oocytes in culture medium contained (100 ng/mL and 200 ng/mL) ACTA and INHA were significantly higher than that contained 50 ng/mL ACTA and INHA (P < 0.05); There was no difference between 100 ng/mL and 200 ng/mL groups. The mature rates, fertility rates and blastocyst rates of mice oocytes were significantly higher than those of control (P < 0.05). CONCLUSION: The mature rates, fertility rates and embryonic development potential after fertilization of mice oocytes were significantly promoted by ACTA, INHA. The optimum concentration of ACTA and INHA in culture medium was 100 ng/mL. PMID- 22812236 TI - [Effect of hyaluronic acid on promoting bone marrow-derived mesenchymal stem cells to differentiate into neural cells in vitro]. AB - OBJECTIVE: To determine the effect of hyaluronic acid (HA) on promoting bone marrow-derived mesenchymal stem cells (BMSCs) to differentiate into neural cells. METHODS: BMSCs were purified and monitored. NSE+/NF+ cells and nestin+ cells were detected by immunocytochemistry. The mRNA levels of NSE, NF and nestin were determined by RT-PCR. RESULTS: The BMSCs adhered to HA hydrogel, with many surface projections, branches or crossing (Group A). Those cultured in brain tissue culture medium grew projections with fewer branches (Group B). Group A had more NSE+ cells (92.58 +/- 15.84) than Group B (80.26 +/- 16.47), and more NF+ cells (71.25 +/- 17.44) than Group B (52.37 +/- 14.75) (P < 0.05). At day 2 post stimulation, more nestin+ cells were found in Group A (48.3 +/- 7.7) compared with Group B (34.6 +/- 5.2) (P < 0.05). At day 7, the mRNA levels of NSE and NF increased in both groups, but more in Group A. Nestin mRNA increased at day 2 post-stimulation and dropped at day 7 in both groups, where more significant in Group A. CONCLUSION: HA hydrogel provides structural support and proper microenvironment for the growth, proliferation and differentiation of BMSCs, and promotes BMSCs to differentiate into neuron cells. PMID- 22812237 TI - [Re-mineralization ability of Galla chinensis extracts on root carious lesions with or without non-collagen proteins]. AB - OBJECTIVE: To evaluate the re-mineralization ability of Galla Chinensis extracts (GCE) on two artificial carious lesions in bovine root de-mineralized in vitro. METHODS: Fourteen bovine root blocks were divided into two parts from buccal to lingual direction. The mesial blocks were treated with a demineralization solution and the distant blocks were treated with another demineralization solution. Two specimens from each group were selected randomly and examined with polarization microscope (PLM). After all blocks were demineralized, half surface of the demineralized zone was covered and the another half was treated with 0.5% NaCl to extract soluble dentin phosphate protein (S-DPP). Then all specimens were submitted to pH-cycling for one week. In the first four days, all specimens were treated with GCE for 21 h and with demineralization solution for 3 h. In the remaining three days, all specimens were treated with GCE. The re-mineralization ability of GCE on the specimens was evaluated by laser scanning confocal microscope (LSCM). RESULTS: There existed intact surface layers on subsurface lesions but no surface layers were produced on erosive lesions. The re mineralization ability of GCE on erosive lesions improved significantly with the treatment of 0.5% NaCl solution (P < 0.05). But it had no significant effect on subsurface lessions. CONCLUSION: Extraction of S-DPP with 0.5% NaCl can improve the re-mineralization ability of GCE on root caries with erosive lesions. This finding supports the proposition that Galla Chinesis may be a promising anti caries natural medicine in the future. PMID- 22812238 TI - [Anti-tumor effect of tanshinone II A, tetrandrine, honokiol, curcumin, oridonin and paeonol on leukemia cell lines]. AB - OBJECTIVE: To study the anti-tumor effect of tanshinon II A, tetrandrine, honokiol, curcumin, oridonin and paeonol on leukemia cell lines SUP-B15, K562, CEM, HL-60 and NB4. METHODS: To study the anti-tumor effect of tanshinone II A, tetrandrine, honokiol, curcumin, The leukemia cell lines were exposed to the six Chinese herbal components for 96 hours. The proliferative inhibitory effects were detected with MTT and described by IC50 value. RESULTS: Tanshinone II A inhibited the proliferations of SUP-B15, K562, CEM, HL-60 and NB4 cell lines, with HL-60 showing the least impact. Tetrandrine, honokiol, curcumin and oridonin inhibited the proliferations of SUP-B15, K562, CEM, HL-60 and NB4 cell lines and there was no significant difference between the cell lines. Paeonol did not have significant inhibitory effect on leukemia cell lines. CONCLUSION: Tetrandrine, honokiol, curcumin and oridonin inhibit the proliferation of five cell lines SUP B15, K562, CEM, HL-60, NB4, and the effects are similar, which means that their anticancer effects are quite broad. Tanshinone II A has better anti-leukemia effects on SUP-B15, K562, CEM, NB4 than on HL-60. The effect of paeonol against leukemia cell lines is poor. PMID- 22812239 TI - [Effect of sinusoidal electricity magnetic fields on the proliferation and differentiation of osteoblasts in vitro]. AB - OBJECTIVE: To investigate the effect of sinusoidal electricity magnetic fields (SEMFs) on the proliferation and differentiation of osteoblasts in vitro. METHODS: Calvarial osteoblasts of newborn rats were isolated by enzyme digestion and randomly divided into 3 groups after subculture. Two groups of cells were exposed to 50 Hz 1.8 mT SEMFs for 30 min/d in parallel and vertical, respectively. Those without SEMFs exposure served as control. The cells were observed under the contrast phase microscope each day. After 48 h, cell proliferation was assayed by MTT method. The alkaline phasphatase (ALP) activities and calcium contents were measured after 3, 6, 9, and 12 days. The ALP positive colonies were histochemically stained after 10 days and the calcified nodules were stained by Alizarin Bordeaux after 12 days. Expressions of ALP, bone morphogenetic protein-2 (BMP-2) and Osterix (OSX) mRNA were measured at 0 h, 24 h, 48 h and 96 h. RESULTS: The cells exposed to the SEMFs were arranged in spiral appearance after 3 days. Compared with control, SEMFs inhibited cell proliferation (P < 0.01 or P < 0.05), but enhanced the maturation and mineralization of the osteoblasts. The results showed that SEMFs improved ALP activities, promoted calcium contents, increased calcified nodulues numbers, boosted expressions of ALP, BMP-2 and OSX mRNA. SEMFs with magnetic lines of force in parallel has stronger activities than those in vertical. CONCLUSION: The SEMFs at 1.8 mT and 50 Hz inhibit the proliferation of osteoblasts, but enhance the maturation and mineralization of osteoblasts. PMID- 22812240 TI - [Repairing bone defect with nano-hydroxyapatite and polyamide 66 composite after giant cell tumor operations]. AB - OBJECTIVE: To evaluate the clinical effectiveness and safety of using granular type nano-hydroxyapatite and polyamide 66 (n-HA/PA66) composite in repairing bone defects caused by giant cell tumors. METHODS: 48 patients with giant cell tumors, who underwent lesion curettage, inactivation and cavities fill-in with granular type n-HA/PA66 from December 2007 to May 2011, were followed up. Routine blood tests, liver and kidney functions, serum calcium and phosphorus, and immunologic parameters were examined before and after the surgeries. Radiological examinations were carried out 1 week and 1, 3, 6 and 12 months post operations to monitor the bone repairing process. The n-HA/ PA66 in bone issues was detected with hematoxylin-eosin staining. RESULTS: 45 patients completed the follow-up. No significant abnormalities in routine blood tests, serum calcium and phosphorus, and immunologic parameters were found pre- and post-operations. Nor abnormal liver and kidney functional lesions were identified. The radiological examination showed gradual increase in the density of the focal zone after bone implanting operations. The bone density of the implanted areas got close to normal 1 year after operations. The histological examination found that osteoblasts grew into the hole of n-HA/PA66; calcium was deposited on the materials; and large amount of osteocytes inlaid into the composite. The composite was integrated into new bone and surrounding tissues. CONCLUSION: n-HA/PA66 has good biocompatibility and biological safety. It also has good osteoconduction and osteogenesis activity. The n-HA/PA66 composite is one perfect bone repair material. PMID- 22812241 TI - [Interleukin-10-1082 promoter polymorphism and the risk of gastric cancer]. AB - OBJECTIVE: To investigate the association between Interleukin-10 (IL-10) promoter polymorphism and the gastric cancer risk in Chinese Han patients. METHODS: DNA was extracted from blood samples of gastric cancer patients (n = 75) and controls (n = 75). IL-10 -1082 promoter polymorphism in both patient and control group (three genotypes distribution: AA, AG and GG) was identified by PCR-RFLP and its relationship with gastric cancer risk, clinic and pathologic features was also analyzed. RESULTS: Patients with gastric cancer had a significantly lower frequency of AA (OR = 0.43, 95% CI = 0.20, 0.92; P = 0.03) than controls. Patients with proximal gastric cancer had a significantly higher frequency of GG (OR = 3.06, 95% CI = 1.12, 8.36; P = 0.03) than those with distant gastric cancer. Patients with advanced (stage II/IV) gastric cancer had a significantly higher frequency of AA (OR = 5.09, 95% CI = 1.05, 24.70; P = 0.04) than those with early (stage I /IV) gastric cancer. When stratified by the Lauren's classification, histological differentiation of gastric cancer, no statistically significant results was observed. CONCLUSION: This study suggests that the IL-1 1082 promoter polymorphism may be associated with gastric cancer in Chinese Han patients, and the difference in genotype distribution may be associated with the location and stage of gastric cancer. PMID- 22812242 TI - [Effects of TNF-alpha, IFN-gamma on the ability of keratinocytes to kill intracellular Staphylococcus aureus]. AB - OBJECTIVE: To study the bactericidal activity of keratinocytes to Staphylococcus aureus in the presence of TNF-alpha, IFN-gamma and their combination. METHODS: The keratinocytes were co-cultured with Staphylococcus aureus to establish the Staphylococcus invasion model of skill cell, then the differenct concentrations of TNF-alpha, IFN-gamma and their combinationt were added into the culture. 24 h later the number of intracellular viable bacteria was counted, while the same amount of sterilized PBS was used as control. RESULTS: Compared with the control group, each the number of intracellular viable bacteria did not change significantly under the condition of 20 ng/mL of either TNF-alpha or IFN-gamma (P > 0.05), as well as 40 ng/mL of TNF-alpha (P < 0.05). However, it was reduced significantly after the addtion of 40 ng/mL of IFN-gamma (P < 0.05), while was also decreased by the combination of TNF-alpha and IFN-gamma, of which effect was less than that achieved by IFN-gamma alone (P > 0.05). CONCLUSION: IFN-gamma, not TNF-alpha, can enhance the bactericidal function of keratinocytes, and the bactericidal effect, is weaker when treatment is combing IFN-gamma with TNF alpha. PMID- 22812243 TI - [Antibacterial mechanism of sulforaphane on Escherichia coli]. AB - OBJECTIVE: To investigate the antibacterial mechanism of sulforaphaneon (SFN) on Escherichia coli. METHODS: To determine membrane penetrability, changes of SDS PAGE protein spectra, soluble protein and alkaline phosphatase and reducing sugar were determined. Cellular nucleic acid synthesis was detected by 4, 6- diamidino 2-phenylindole (DAPI) staining assay. RESULTS: SFN affected the membrane permeability of Escherichia coli. Ions and small molecules could leak out of the cells. But it did not destroy the membrane integrity directly. After 16 hours of treatment with SFN, the total contents of intracellular and extracellular proteins decreased by 42.5% and 17.6%, respectively, while the quantity of DNA and RNA reduced by 34.8% and 48.5% respectively. CONCLUSION: SFN can affect cell membrane permeability, material and energy metabolism and inhibit the synthesis of nucleic acid and protein. PMID- 22812244 TI - [Nasal carriage of community-acquired Staphylococcus aureus and drug sensitivity tests in healthy children in Chengdu]. AB - OBJECTIVE: To investigate nasal carriage of community-acquired Staphylococcus aureus and its drug sensitivities in healthy children in Chengdu. METHODS: Nasal swabs were collected from healthy children from primary schools and kindergartens in Chengdu in two stages (2005-2007 and 2008-2010). All specimens were cultivated. Once S. aureus was identified, drug susceptibility tests (disk diffusion method) were performed with penicillin, erythromycin, clindamycin, ceftazidime and vancomycin. RESULTS: 430 S. aureus were identified from 2373 specimens, with a positive rate of 18.12%. Resistant to penicillin was found in 90% of tests. The isolated S. aureus was also resistant (6.28%) to methicillin resistant Staphylococcus aureus (MRSA). The first stage identified higher rate of MRSA than the second stage (4.28% versus 9.25%, P = 0.037). Isolates from children living in cities were more likely to be resistant to cefoxitin than isolates from children living in countryside (14.74% versus 2.56%, P = 0.006) in the second stage. We did not find vancomycin-resistant S. aureus. CONCLUSION: Nasal carriage of S. aureus among healthy children in Chengdu is common and the nasal carried S. aureus is highly resistant to commonly used antibiotics. PMID- 22812245 TI - [The role of CD14 promoter - 159 C-> T polymorphism on changes of serum lipid ratios induced by high-carbohydrate/low-fat diets in healthy Chinese Han youth]. AB - OBJECTIVE: To investigate the role of CD14 promoter - 159 C-> T polymorphism on ratios of serum lipids and its interaction on the ratios with a high carbohydrate/low-fat (HC/LF) diet in a young and healthy Chinese Han population. METHODS: After a washout diet for seven days, fifty six healthy young subjects (22.89 +/- 1.80 years) were given the HC/LF diet for six days. Twelve-hour fasting venous blood samples were collected in the mornings of the first, the eighth and the fourteenth days. The serum lipid profiles and the CD14 -159 C->T polymorphism were analyzed. The ratios of triglyceride/high density lipoprotein cholesterol (TG/HDL-c), log (TG/HDL-c), total cholesterol/high density lipoprotein-cholesterol (TC/HDL-c) and low density lipoprotein-cholesterol/high density lipoprotein-cholesterol (LDL-c/HDL-c) were calculated. RESULTS: The male carriers of the C allele had significantly higher TG/HDL-c and log (TG/HDL-c) than the female carriers at baseline, after the washout diet and after the HC/LF diet, higher TC/HDL-c at baseline and after the washout diet, and higher LDL c/HDL-c only after the washout diet. The female subjects with the TT genotype had higher TG/HDL-c and log (TG/HDL-c) than the female carriers of the C allele at baseline, after the washout diet and after the HC/LF diet, higher LDL-c/HDL-c at baseline and after the HC/LF diet, and higher TC/HDL-c only after the washout diet. Compared with that before the HC/LF diet, TC/HDL-c was significantly decreased after the HC/LF diet regardless of gender and the genotype of the CD14 159 polymorphism. LDL-c/HDL-c was significantly decreased in both the male and female carriers of the C allele. TG/HDL-c and log (TG/HDL-c) were significantly increased only in the female carriers of the C allele. CONCLUSION: In the subjects with C allele, the HC/LF diet is a minor factor and its effects on the lipid ratios can be masked by the effects of the C allele at CD14 -159. The interaction between the HC/LF diet and the C allele at CD14 -159 can decrease LDL c/HDL-c in both males and females and increase TG/ HDL-c and log (TG/HDL-c) in the females. PMID- 22812246 TI - [Relationship between depression and family function in old patients with coronary heart disease]. AB - OBJECTIVE: To investigate the relationship between depression and family function in elderly patients with coronary heart disease. METHODS: 122 patients of 80 years old or above with coronary artery disease were invited to complete a questionnaire through face to face interview. The Hamilton Rating Scale for Depression (17th edition) was used to assess depression status and the APGDR Questionnaire was used to assess family functions. One-way analysis of variance and logistic regression analysis were performed to test the association of family functions with depression. RESULTS: 60.7% of the respondents had depression and 56.6% had severe abnormal family functions. The respondents with good family functions, moderate abnormal family functions and severe abnormal family functions had a depression score of 9.08, 20.72 and 26.88 respectively. The prevalence of depression in the patients with severe abnormal family functions was 3.274 times of that of those with good family functions. The prevalence of depression was also influenced by residency and care models. CONCLUSION: Depression is prevalent in elderly patients with coronary heart disease. It is associated with family functions. PMID- 22812247 TI - [Development of a predicting model to estimate the probability of malignancy of solitary pulmonary nodules]. AB - OBJECTIVE: To evaluate the role of (18)F-FDG PET/CT in characterizating solitary pulmonary nodule (SPN) and bone lesions. METHODS: 105 patients with a SPN smaller than 30 mm in axial diameter were recruited for this study. PET/CT images were obtained 60 min after intravenous injection of (18)F-FDG. Logistic regression analysis was performed to identify clinical predictors of SPN malignancy including age, sex, smoking history, malignant history, family history, symptoms, size, location, CT appearances, (18)F-FDG uptake, and to develop a clinical prediction model to estimate the probability of malignancy in the patients with SPN. The model fit was evaluated and the area under curve (AUC) of receiver operating characteristic (ROC) was used to evaluate the power of the model. RESULTS: The logistic regression analysis indicated that male, a positive smoking history, older age, larger nodule diameter, nodule with specula and nodule with high (18)F-FDG uptake were more likely to have malignant SPN. The clinical prediction model is described by the following equation: Logit(P) = -8.722 + 2.448 (gender) + 2.023(smoking) + 0. 851(age) + 1.057 (diameter) + 2.432 (spiculation) + 1.502 (FDG uptake). The AUC of the model was 0.892 (95% confidence interval 0.817 - 0.941). The prediction model had high accuracy in predicting malignant SPN, with 90.2%, 84.1 % and 87.6% sensitivity, specificity and accuracy respectively when the cut off value was set at 0.67. CONCLUSION: The prediction model is valid in predicting the probability of malignant SPN. PMID- 22812248 TI - [Integrated management of diabetic kidney disease: from prevention to treatment, from biomedicine to translation medicine]. AB - Diabetes Mellitus (DM) is a worldwide epidemic health and life threatening disease with rapidly increasing prevalence and incidence. Diabetic kidney disease (DKD) is one of the most critical microvascular complications of DM, acts as the leading cause of end stage renal disease (ESRD) in developed countries with less great break in the fields of prevention, treatment and research. The comprehensive therapy of DKD includes the management of blood glucose, blood pressure and lipid, the usage of rennin-angiotension-aldosterone system inhibitors, the improvement of endothelial dysfunction, hemorheology and so on. However, once macroproteinura is detected, the progression into ESRD is irreversible and renal replacement therapy is needed. Cardiovascular morbidity and other complications of DKD patients contribute greatly to the poor outcome. In west China, DKD patients are characterized with low disease awareness, late treatment, low treatment rates, severe status of the illness, long period of hospitalization, more complicated situation and higher mortality rate. Therefore, comprehensive management and care should play more important role in the prevention, treatment and research of DKD, which is composed of health education, guidelines implementation, early screening and diagnosis; standardizing the treatment of DKD according to clinical and pathologic characteristics; individualized renal replacement treatment modalities; practicing translational medicine, carrying out more clinical trials, applying new ideas, techniques and new equipment to the clinical practice and basic researches. PMID- 22812249 TI - [Relation between bone matrix proteins and monocyte chemoattractant protein-1 in renal small artery in diabetic nephropathy rats]. AB - OBJECTIVE: To observe the expressions of bone matrix proteins and monocyte chemoattractant protein-1 ((MCP-1) in the renal arteriole of diabetic nephropathy (DN) rats and analyze their correlations and roles in diabetic nephropathy. METHODS: Adult Sprague-Dawley male rats were used to establish the animal model of diabetic nephropathy induced by peritoneal injection of 55 mg/kg of streptozocin. Calcium deposit around the renal arteriole was observed by alizarin red staining. The protein and mRNA levels of core-bind factor alpha 1 (cbfalpha1), bone morphogenetic protein 2 (BMP-2) and matrix Gla protein (MGP) in renal arteriole of DN rats were detected by immunohistochemistry, in-situ hybridization and real-time PCR. The biochemical indices were detected by routine test. RESULTS: 1. Blood glucose and Urine protein of 24 h were significantly increased in the renal arteriole of DN rats versus the control rats (P < 0.05), serum creatinine (SCr) and phosphorus were significantly increased from 12 weeks. 2. Little deposit of calcium salt was observed in the renal arteriole of DN rats at the 4th week and a large amount of deposit was observed at 24th week, but no calcium deposit was observed in control rats. 3. Cbfalpha1 and BMP-2 expressions were significantly increased in the renal arteriole of DN rats from 4 to 24 weeks vs. the control rats. MGP mRNA expression in the renal arteriole of DN rats was significantly decreased from 4 to 24 weeks. MCP-1 expression was obviously upregulated in the renal arteriole of DN rats at 24th week versus that at 4th and 12th week. No MCP-1 expression was observed in the renal arterioles of control rats. MCP-1 were positively correlated with the expression of cbfalpha1 and BMP 2. CONCLUSION: Bone matrix proteins has already expressed in renal arteriole before the formation of vascular calcification. MCP-1 can affect the expression of cbfalpha1, BMP-2; cbfalpha1, BMP-2, MGP and MCP-1 may be involved in the formation of vascular lesions of DN. PMID- 22812250 TI - [Vitamin D deficiency and carotid artery intima-media thickness and coronary calcification in patients with diabetic nephropathy]. AB - OBJECTIVE: To investigate the deficiencey and insufficiency of 25-hydroxyvitamin D3 [25 (OH) D3], 1,25- dihydroxyvitamin D3 [1,25 (OH)2 D3] in patients with diabetic nephropathy (DN), an their association with carotid artery intima-media thickness (IMT) and coronary artery calicfication. METHODS: The concentrations of 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and intact parathyroid hormone (iPTH) were determined by radioimmunoassay in 151 DN patients. Based on the level of 25-hydroxyvitamin D3, the patients were divided into Vitamin D deficiency group (Vit-D-D group, <15 ng/mL), insufficiency group (Vit-D-I group, 15-30 ng/mL), and normal group (Vit-D-N group, >30 ng/mL). The association of Vitamin D with IMT and coronary artery calcification was examined through group comparisons, logistic regression analysis and multiple linear regression analysis. RESULTS: The mean level of 25-hydroxyvitamin D3 was (28 +/- 18.1) ng/mL, with an interquartile range of 16.92 - 35.45 ng/mL. The incidence of 25 hydroxyvitamin D3 insufficiency and deficiency was 47.01% (71/151) and 18.574% (28/151) respectively. The mean level of 1,25-dihydroxyvitamin D3 was (28.93 +/- 33.13) pg/mL, with an interquartile rang of 10.36 - 31.08 pg/mL. The incidence of 1,25-dihydroxyvitamin D3 insufficiency was 77.5% (117/151). Compared with the normal controls, the BMI, 24 h urine protein, CHO and LDL of those with Vitamin D deficiency increased significantly (P < 0.05). IMT ws associated with age, sex, and serum phosphorous. Coronary clcification was negative correlated with 1,25 dihydroxyvitamin D3. CONCLUSION: The incidence of vitamin D deficiency and insufficiency in DN patients is high. The patients with vitamin D deficiency have higher urinary protein, CHO and LDL. Corornary artery calcification is reversely correlated with 1,25(OH)2D3. PMID- 22812251 TI - [Comparison of the effects of alpha-keto/ amino acid supplemented low protein diet and diabetes diet in patients with diabetic nephropathy]. AB - OBJECTIVE: To investigate if a-keto/amino acid supplemented low protein diet can slow down the progression of diabetic nephrophathy in comparison with non supplemented diabetes diet. METHODS: A prospective, randomized, controlled clinical study was conducted. Twenty three cases of type 2 diabetic nephropathy in IV stage were randomly divided into alpha-keto/amino acid supplemented diet group (trial group) and conventional diabetes diet group (control group), The treatment duration was 52 weeks. 24 h urine protein was measured at 0, 12, 20, 36 and 52 weeks. Before and after the 52 weeks treatment, all the patients received the measurement of glomerular filtration rate (GFR), blood glucose, blood lipids, inflammatory markers, as well as nutritional status. RESULTS: After the treatment for 20, 36, 52 weeks, mean 24 h urine protein decreased significantly in trial groups (P < 0.05), and 24 h urine protein in trial group were significantly decreased (P < 0.05) compared with control group in 20 weeks after treatment. Either in trial group or in control group, GFR remained relatively stable during the observation period. Nutrition status, inflammatory markers, and serum calcium, phosphorus levels between the two groups were no significantly difference. The adverse events experienced by the patients in trial group were similar and consistent with the patients underlying renal diseases. CONCLUSION: Alpha-keto/amino acid can reduce proteinuria more effectively, while improve renal function and nutritional status in diabetic nephropathy patients with well toleration. PMID- 22812253 TI - [Continuous blood purification therapy on 16 patients with diabetic ketoacidosis and acute kidney injury]. AB - OBJECTIVE: To determine the effectiveness of Continuous blood purification (CBP) therapy on diabetic ketoacidosis (DKA) and acute kidney injury (AKI) in diabetic nephropathy (DN) patients. METHODS: Sixteen DN patients who developed severe DKA and AKI between 2008 and 2011 in the West China Hospital were recruited. All of the recruited patients presented with severe metabolic acidosis, electrolyte disturbance and dehydration. In addition to routine treatments, continuous venovenous hemofiltration (CVVH) was performed for at least 48 h with Baxter Accura or B. Braun Diapact CRRT machine and B. Braun Diacap Acute M hemofilter. Hemofiltration was accomplished using predilution bicarbonate replacement fluid at the rate of 3000 mL/h and citrate or low-molecular weight heparin (LMWH) for anticoagulation, with blood flow rates of 180 to 250 mL/min. RESULTS: One patient died unexpectedly 10 h after admission to hospital. The other fifteen patients had significant improvements in metabolic acidosis index after 12 hours of CVVH therapy, such as an average increase of 7.21 +/- 0.07 carbon dioxide combining power (CO2CP)and improvement of arterial PH. The blood urea nitrogen (BUN), serum creatinine (SCr), serum glucose (Glu), serum potassium (K(+)) and bloodosmotic pressure of the 15 patients decreased significantly after 48 hours of CVVH therapy. Eleven cases entered into diuretic phase and had renal functions recovered (12 +/- 5) d and (18 +/- 12) d after admission to the hospital, respectively. CONCLUSION: CVVH therapy as an early intervention can bring significant benefits to DN patients with DKA and AKI. Early institution of CVVH therapy may be considered not only for treating uremia and fluid retention but also for correcting metabolic abnormalities like metabolic acidosis. PMID- 22812252 TI - [Blood pressure variation of hypertensive diabetic nephropathy patients undergoing peritoneal dialysis]. AB - OBJECTIVE: To investigate the variance of blood pressure of hypertensive diabetic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: Twenty hypertensive CAPD patients older than 40 years with diabetic nephropathy (DN-PD group) and twenty patients with chronic glomerular nephritis (CGN-PD group) were recruited. Peritoneal status and dialysis adequacy of the patients in the two groups were calculated using PD Adequest. All patients were given 24-hour ambulatory blood pressure monitoring (ABPM). Parameters of blood pressure variation were calculated and compared between the two groups, which included 24 h systolic and diastolic blood pressure variability (24 h SBPV/DBPV) and coefficient of variation (24 h SBPCV/24 h DBPCV), daytime systolic anid diastolic blood pressure variability (dSBPV/ DBPV) and coefficient of variation (dSBPCV/dDBPCV), and night time systolic and diastolic blood pressure variability (nSBPV/ DBPV) and coefficient of variation (nSBPCV/nDBPCV). RESULTS: No significant differences in clinical characteristics were found between the two groups of patients except for fast glucose. No significant differences in average systolic and diastolic blood pressures, average piulse pressure and mean 24 h, daytime, and nighttime arterial pressures were found between the two groups. However, the DN-PD group had significantly higher 24 h SBPV, 24 h SBPCV, dSBPV and dSBPCV than the CGN-PD group (P < 0.05). CONCLUSION: Hypertensive diabetic nephropathy patients undergoing peritoneal dialysis have greater blood pressure variance than those with hypertensive chronic glomerular nephritis, despite a similar result of blood pressure control. PMID- 22812254 TI - [Association of diabetes and early failure of arteriovenous fistula in the end stage of renal diseases]. AB - OBJECTIVE: To determine the association of diabetes and glycemic control with early failure of native arteriovenous fistula(AVF). METHODS: 266 patients with end stage renal diseases(ESRD) were recruited and divided into non-diabetic group (165), HbA1C < 7% group (51) and HbA1C > or = 7% group (50). Clinical indicators and early failure of AVF were examined. RESULTS: In total, 63 (23.7%) patients had AVF early failure. The AVF early failure occurred in 18. 1% of patients in the non-diabetic group and 21.6% of patients in the HbA1C < 7% group, significantly less than that in the HbA1C > or = 7% group (44%). The COX regression model showed that increased HbA1C, total cholesterol (TC) and decreased high-density lipoprotein (HDL)increased the risk of AVF failure. CONCLUSION: The levels of glycemic and serum lipid subfractions are associated with AVF early failure in ESRD patients. Good control of glycemic and lipid can lower the rates of AVF early failure. PMID- 22812255 TI - [A comparison of clinical characteristics and survival between diabetic nephropathy patients and non-diabetic nephropathy patients undergoing peritoneal dialysis]. AB - OBJECTIVE: To investigate clinical characteristics and survival of diabetic patients with end-stage renal disease on peritoneal dialysis (PD). METHODS: The clinical data were collected from the patients who initiated PD in our PD Center from Jan, 2009 through Aug, 2011. The patients were divided into diabetic group and non-diabetic group, the survival of patients and risk factors of death were analyzed and compared between the two groups by using Kaplan-Meier and Cox regression analysis. RESULTS: There were 460 PD patients included in this study, 64 (13.9%) of them were diabetic and 396 (86.1%) were non-diabetic. Compared with non-diabetic PD patients, the PD patients with diabetes were older [(63 +/- 13) yr. versus (45 +/- 16) yr. , P < 0.001], while had higher level of high sensitive C reaction protein (hsCRP), lower levels of serum albumin and prealbumin, as well as lower levels of triglyceride and nPCR. There was no statistical difference in serum concentrations of hemoglobin, parathyroid hormone, cholesterol, and Kt/V and residual renal function between the two groups. The survival rates of PD patients with diabetics versus non-diabetics were 73.3% versus 90.7% at 1 year, and 61.8% versus 82.5% (P < 0.05) at 2 years. Mean survival time of diabetic PD patients (24.6 months) was significantly inferior to non-diabetic PD patients (30.1 months) (P < 0.05). The relative risk of mortality in diabetic PD patients was 2. 449 times of that in non-diabetic patients. Multivariate Cox regression analysis, indicated that serum albumin level and patient age were significant risk factors for mortality. CONCLUSION: Diabetic patients tended to be elderly, malnutrition and microinflammation at the beginning of PD. The survival of diabetic PD patients is inferior to non-diabetic PD patients on CAPD. Age and albumin level were risk factors for mortality in PD patients. PMID- 22812256 TI - [Sustained low efficiency dialysis on patients with multiple organ failure resulted from diabetic kidney disease]. AB - OBJECTIVE: To investigate the effect of sustained low efficiency dialysis (SLED) on patients with multiple organ failure resulted from diabetic kidney disease (DKD). METHODS: Five DKD patients who developed MOF between Nov. 2011 and Jan. 2012 were recruited for SLED treatment (dose: 200 ml/min, for 8 to 12 hours every other day) in the West China Hospital. Meanwhile, other therapeutic measures, such as underlying disease management, infection control and nutritional support were applied. Biochemical changes and progress of disease were observed. RESULTS: One patient died unexpectedly 12h after admission to hospital. The main cause of death was multiple organ failure. The other four patients had sharp improvements in high potassium concentration and (or) metabolic acidosis after SLED therapy, with obvious amelioration of main organs functions and oxygenation index [PO2 (103.3 +/- 25.7) mm Hg]. Two ventilator dependent patients successfully weaned from mechanical ventilation 3 to 5 days after the treatment. BNP of the patients decreased from > 35,000 ng/mL before the treatment to (13,312 +/- 3,537) pg/mL after the treatment (P < 0.05). APACHE II decreased by 10.3%, 41.9% and 67.8% within 24 hours, three days and five days respectively. CONCLUSION: SLED as early intervention can bring significant benefits to DKD patients with multiple organ failure (MOF). SLED has the same efficacy as continuous renal replacement therapy (CRRT) in the treatment of MOF for patients with DKD. PMID- 22812257 TI - [Effect of diagnostic ultrasound-mediated microbubble contrast and urokinase on augmentation thrombolysis and optimization of the major parameters: an in vitro study]. AB - OBJECTIVE: To investigate the efficacy of diagnostic ultrasound and microbubble contrast (MB) on enhancing thrombolysis in combination with urokinase (UK) and to determine the optimal combination for thrombolysis in vitro. METHODS: Four types of standardized red thrombus were prepared in vitro, including 3-hour-old (3 h), 6-hour-old (6 h), 12-hour-old (12 h), and 24-hour-old (24 h). The major parameters for the designed experiments included transmit powers of ultrasound (factor A, 5%, 25%, 50%, 100%), MB volumes (factor B, 50 microL, 100 microL, 200 microL, 400 microL), UK concentrations (factor C, 100 U/mL, 200 U/mL, 400 U/mL, 800 U/mL), and lysis time (factor D, 10 min, 20 min, 30 min, 40 min). An orthogonal array experimental design (OAD) based on four levels L16 (4(5)) of the above four parameters was employed to optimize the thrombolysis conditions. During the procedure of thrombolysis, the diagnostic ultrasound frequency was fixed at 1.82 MHz. The histopathological changes measured by HE staining and scanning electron microscope (SEM) were carried out to observe the clots before and after thrombolysis. The loss of clot weight before and after treatment was measured to determine the lysis efficiency (LE). Analysis of variance (ANOVA) was performed to assess the LE according to the L16 (4(5)) matrix. RESULTS: The HE staining and SEM observation of thrombolysis under the following experimental conditions of 5% ultrasound transmit power, 400 microL MB volume, 800 U/mL UK concentration, and 40 min lysis time showed remarkable disaggregation of fibrin nets. The above four factors had significant impact on thrombus (all P < 0.05), among which UK concentrations (factor C) was the most significant one. The optimal scheme was determined as a C4-D4-A1-B4 mode, with UK concentration 800 U/mL, lysis time 40 min, transmit power 5%, and MB volume 400 microL, respectively. The LE curves for 3h clots were superior to the others. The lysis efficiencies for the clots showed significant differences among different type of thrombus (all P < 0.05). CONCLUSION: 1.82 MHz diagnostic ultrasound and microbubble contrast can be applied to augment thrombolysis in vitro even with a transmit power as low as 5%. Under the condition of fixed ultrasound frequency, the LE of thrombus increase with increased UK concentrations, lysis time and MB volumes, and decrease with increased thrombus ages. PMID- 22812258 TI - [Preparation and quality control of pyridostigmine bromide orally disintegrating tablet]. AB - OBJECTIVE: To prepare orally disintegrating tablets containing pyridostigmine bromide and optimize formulations. METHODS: Solid dispersion was prepared using solvent evaporation-deposition method. The formulation was optimized by central composite design-response surface methodology (RSM plus CCD) with disintegration time as a reference parameter. RESULTS: The orally disintegrating tablets showed integrity and were smooth with desirable taste and feel in mouth. The disintegration time was less than 30 s. The cumulative drug dissolution was around 8.5% (around 2.5 mg which was less than bitterness threshold of pyridostigmine bromide of 3 mg) within 5 min in water while the cumulative drug dissolution was higher than 95% within 2 min in 0.1 N HCl. CONCLUSION: The orally disintegrating tablets are reasonable in formulation, feasible in technology and patient-friendly. PMID- 22812259 TI - [Left ventricular diastolic function of patients with newly diagnosed hyperthyroidism]. AB - OBJECTIVE: To evaluate the left ventricular diastolic function of patients with newly diagnosed hyperthyroidism. METHODS: 43 patients with newly diagnosed hyperthyroidism and 45 healthy participants were recruited to have their left ventricular diastolic function assessed with conventional echocardiography (Mitral inflow) and by indicators such as valsalva maneuver, pulmonary venous flow, Tissue Doppler imaging and Left atrial volume index (LAVI). RESULTS: 1. Hyperthyroidism patients had higher heart rate and left ventricular ejection fraction than the controls (P < 0.05). 2. There was no significant difference in LAVI (P > 0.05) between the two groups. Both groups had E/A>1. E'/A'<1 during Valsalva maneuver were found in both groups, but with significant difference (P < 0.05). The hyperthyroidism patients had significantly longer A duration than the controls (P < 0.05). 3. The hyperthyroidism patients had greater peak anterograde diastolic velocity (D), peak velociey in late diastole (Ar), duration of the Ar (Ar duration) in pulmonary venous waveforms and time difference between Ar and mitral A-wave duration (Ar -A duration) than the controls(P < 0.05). Significant difference in S/D was found between the two groups (P < 0.05). 4. Em/Am<1 and E/Em>8 was found in the patients while Em/Am>l and E/Em<8 was found in the controls (P < 0.05). CONCLUSION: 1. Hyperthyroidism patients have impaired Left ventricular diastolic function. 2. Combined use of pulmonary venous flow, Tissue doppler imaging and mitral inflow during Valsalva maneuver is more sensitive than conventional Doppler echocardiography for assessing diastolic dysfunction. PMID- 22812260 TI - [Characteristics of the patients with primary Sjogren's syndrome complicated with lymphoma]. AB - OBJECTIVE: To improve the understanding of diagnosis and treatment of patients with primary The data of clinical features, laboratory Sjogren's syndrome (pSS) complicated with lymphoma. METHODS: findings, therapeutic response and follow-up of patients with primary Sjogren's syndrome complicated with lymphoma from January 2006 to January 2011 in our single center were retrospectively analyzed. RESULTS: Totally twelve inpatients with pSS complicated with lymphoma were diagnosed, which accounted for 1.29% of newly-diagnosed lymphoma inpatients during the same period. The characteristic immunologic changes were hyperimmunoglobulinemia, hypocomplementemia and decrease of CD4 T cell number. In our study, non-Hodgkin's lymphoma (NHL) was the most common type, and the main pathological subtype was diffuse large B cell lymphoma (DLBCL). Most of the patients were in advanced stages, Ann Arbor stage IIl-IV, at diagnosis. Extranodal involvement was common, most frequently in the livers and the lungs. All of the patients received combination chemotherapy. Most of the NHL patients received CHOP/R-CHOP-like regimens, and the Hodgkin's lymphoma (HL) patient received AVD regimen. The median follow-up time was 27 months (range 1-56 months). In terms of median survival time and overall survival there were no statistical significant differences between both low C3 and low C4 group and control group (P > 0.05). In terms of median survival time and overall survival there were no statistical significant differences between rituximab treatment group and control group (P > 0.05). CONCLUSION: The patients with pSS complicated with lymphoma were not uncommon clinically. Hypocomplementemia could not be identified as a risk factor for the prognosis of pSS complicated with lymphoma in our study. Although expected prognosis of these patients was unfavorable, we found that treatment with rituximab combination chemotherapy could not improve the therapeutic effects and survival of patients with pSS complicated with lymphoma. PMID- 22812261 TI - [Education renewing of the dental curriculum]. PMID- 22812262 TI - [Restoration treatment in fearful children should be kept to a minimum. Yes]. PMID- 22812263 TI - [Restoration treatment in fearful children should be kept to a minimum. No]. PMID- 22812264 TI - [Ehlers-Danlos Syndrome]. PMID- 22812265 TI - [A non-pigmented naevus as an uncommon gingival swelling]. AB - A 67-year-old woman had an epulis-like swelling of the gingiva in the region of teeth 32 and 33. On histopathologic examination, it became clear that it was a non-pigmented intramucosal naevus which rarely occurs in the oral cavity. PMID- 22812266 TI - [Innovations in education for the digital student]. AB - A significant percentage of today's teaching staff received their professional training before the revolution in information and communication technology took place. Students, by contrast, are so-called 'digital natives': they grew up surrounded by digital technology. Present day students are used to multi-tasking and expect to be facilitated in using educationalfacilities regardless of time and place. Adapting higher education to present day students' study behaviour and expectations requires reconsideration of educationalform and methods. Several types of staff can be distinguished in their attitude towards technological innovation in education. Among them are staff who are reluctant in accepting innovations. Dental schools face the challenge of finding supportfor innovations with all their teaching staff and to better adapt to the twenty-first century student. In order to introduce technological innovations successfully, students need to become involved and sufficient attention must be paid to qualifying instructors. PMID- 22812267 TI - [The Simodont in dental education]. AB - The Simodont is a virtual learning environment for students of dentistry which is intended to expand and optimize the preparation ofstudents for the treatment ofpatients so that the transition in education from pre-clinic to clinic is reduced. The Simodont makes it possible to offer students more realistic clinical problems. In that way, students can practice much more extensively than they can in the pre-clinic on phantom heads. The Simodont also provides a safe learning environment in which unlimited mistakes can be made without unfortunate consequencesfor the student and patient. The simulator is coordinated with reading material on a computer, which makes it possible to integrate techniques and theory in dental education. Virtual teeth, with and without pathology, have been created for application in the Simodont, to allow unlimited possibilities for practice. The future possibilities for the Simodont offer many opportunities for students in dental education, for supplementary and post-graduate education andfor the re-integration of dentists in their profession. PMID- 22812268 TI - [Educational science, 'the hardest science of all']. AB - Educational research not only showed that student characteristics are of major importance for study success, but also that education does make a difference. Essentially, teaching is about stimulating students to invest time in learning and to use that time as effectively as possible. Assessment, goal-orientated work, and feedback have a major effect. The teacher is the key figure. With the aim to better understand teaching and learning, educational researchers usefindingsfrom other disciplines more and more often. A pitfall is to apply the findings of educational research without taking into consideration the context and the specific characteristics of students and teachers. Because of the large number offactors that influence the results ofeducation, educational science is referred as 'the hardest science of all'. PMID- 22812269 TI - [The integration of science in the clinical dental programme at the University of Nijmegen]. AB - To be able to make a well founded clinical decision on the basis of evidence, the concept of 'evidence based practice' offers a solution by making it possible to select the appropriate knowledge from the increasing amount of scientific clinical information. Competence is required to put the concept (combining the best available scientific clinical evidence, experience and skills of the dentist and preferences of the patient) into practice. To prepare the undergraduate student for future clinical practice, the Nijmegen dental school has adopted evidence based practice to be implemented from the first year of dental training. The experiences of both students and lecturers are modest. The probable reason is that many clinical decisions are (can be) taken on the basis of experience and routine. The challenge is to base life-long learning on the practice of evidence based dentistry. PMID- 22812270 TI - [Education and dental practice offer possibilities to exchange competences]. AB - The 3 dental schools in the Netherlands have the same goals for their graduates, in terms of knowledge and skills, but the contents of the curricula are different. The curricula are all based on the pillars of scientific education, medical education, dental education, and professionalism. Within this construction a student is trained as the manager of an oral health team. At graduation, the new generation of dentists have many (new) competences and relatively limited clinical experience and need support in acquiring clinical experience. Moreover, dentists who have recently graduated may be faced with methods and materials to which they were not introduced in their educational programme. A dentist with considerable clinical experience can test the newly acquired competences of the new generation ofdentists, with the benefit of a critical eye, against (routine) daily practices. PMID- 22812271 TI - [The collaboration between dentists and dental hygienists: from paradox to resolution]. AB - The occupation of dental hygienist has changed since the introduction of vertical task redistribution. However, this change has not yet resulted in an optimal collaboration between dentists and dental hygienists. Four typical characteristics of vertical task redistribution are considered to be influentialfactors with respect to collaboration and the acceptance of vertical task redistribution: the transition from a hierarchical work relation to a more functional work relation, educational level as related to competence and social status, the relation between vertical task redistribution and professional identity and the perceived usefulness of interprofessional collaboration and task redistribution. Implications for educational development are based on scientific literature and are illustrated by an example from the dental curriculum in the Dutch city of Groningen. Even though interprofessional collaboration does not seem to be optimal at the present time, there are insights that suggest ways of improving interprofessional collaboration between dentists and dental hygienists. However, more clues are needed. In particular, the paradox between professional identity and interprofessional collaboration has not yet received much scientific attention. PMID- 22812272 TI - [Professional behaviour in dental education]. AB - The professional behaviour of future dentists is an important topic in dental curricula. Aspects of professional behaviour are, among other things: being respectful to patients, putting the interest of the patients first, reliability, integrity, and knowing one's professional limitations and acting according to them when treating patients. Throughout the curriculum students receive feedback on their functioning with regard to professional behaviour and are also examined on those points. At the programme at the Academic Centre for Dentistry Amsterdam, experience has been gained in recent years in addressing and evaluating (un)professional behaviour among students. PMID- 22812273 TI - [Assessing the clinical competence of dental students]. AB - Nowadays, the competences of dental students are tested more on the basis of quality of their achievements than the quantity. 'Objective Structured Clinical Examinations' (OSCEs) can be used in a pre-clinical phase to test these clinical competences. For the clinical phase, the general examination and the digital portfolio have been developed. Tests are used to stimulate the learning process and to determine whether students are ready for the next step; in addition, the quality of the programme is protected by the set of examinations. The results of the last 5 general examinations reveal the pattern that the number of correct answers increases as the study progresses. The Amsterdam Academic Centre for Dentistry (ACTA) introduced a digital portfolio which was evaluated 1 year later with the help ofan anonymous questionnaire. Students judged the use of the digital portfolio in the clinic to be useful but also costly in time. PMID- 22812274 TI - Ultraviolet ZnSe1-xSx gradient-alloyed nanocrystals via a noninjection approach. AB - Highly emissive ultraviolet ZnSeS nanocrystals (NCs), with a core-shell-like structure, were designed and synthesized via a one-step noninjection approach in 1-octadecene (ODE). These ultraviolet ZnSeS NCs exhibit bright bandgap emission with high color purity and little trap emission. With full width at half-maximum (fwhm) of ~21 nm only, photoluminescent (PL) quantum yield (QY) of ~60% was estimated for one ensemble dispersed in toluene exhibiting bandgap absorption peaking at ~380 nm and bandgap emission at ~389 nm. These alloyed ZnSeS NCs present a cubic crystal structure consisting of a Se-rich core and a S-rich shell. Such a gradiently alloyed structure was suggested by our investigation on the temporal evolution of optical properties of the growing ZnSeS NCs monitored from 80 to 300 degrees C, together with structural and compositional characterization performed with XRD, XPS, EDX, and TEM. This newly developed one step noninjection approach was achieved with zinc oleate (Zn(OA)(2)), diphenylphosphine selenide (SeDPP), and diphenylphosphine sulfide (SDPP) as Zn, Se, and S precursors, respectively. ZnSe monomers mainly participated in nucleation at ~120 degrees C, while both ZnSe and ZnS monomers contributed to NC formation in later growth stages (~160 degrees C and higher). (31)P NMR study demonstrates that SeDPP is more reactive than SDPP toward Zn(OA)(2), and also supports such a model proposed on the combination of ZnSe and ZnS monomers leading to nucleation/growth of ZnSeS alloyed NCs. The present study offers conceptual methodology to various highly photoluminescent alloyed NCs with high quality, high particle yield, and high synthetic reproducibility. PMID- 22812372 TI - Arylgold(I) complexes from base-assisted transmetalation: structures, NMR properties, and density-functional theory calculations. AB - The synthesis of gold(I) complexes of the type LAuR (L = PCy(3), IPr; R = aryl; IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) starting from LAuX (X = Br, OAc) and boronic acids in the presence of Cs(2)CO(3) has been investigated. The reactions proceed smoothly in good to excellent yields over the course of 24 48 h in isopropyl alcohol at 50-55 degrees C. The aryl groups include a variety of functionalities and steric bulk, and in two cases, are heterocyclic. All of the products have been characterized by multinuclear NMR spectroscopy and elemental analysis and most by X-ray crystallography. This work affirms that, almost without exception, base-assisted auration is a useful and reliable way to form gold-carbon bonds. PMID- 22812373 TI - Sequential allenylidene/vinylidene cyclization for stereoselective construction of bicyclic carbocycles from propargyl alcohol. AB - Consecutive cyclization reactions of phenyl propargyl alcohols 1 and 2 are catalyzed by [Ru]NCCH(3)(+) ([Ru] = Cp(PPh(3))(2)Ru) in cosolvent CHCl(3)/MeOH at 60 degrees C, to afford the fused cyclic compounds 11a (R = Me) and 10a (R = Me), respectively. PMID- 22812374 TI - Structural transitions from triangular to square molecular arrangements in the quasi-one-dimensional molecular conductors (DMEDO-TTF)2XF6 (X = P, As, and Sb). AB - A series of quasi-one-dimensional molecular conductors (DMEDO-TTF)(2)XF(6) (X = P, As, and Sb), where DMEDO-TTF is dimethyl(ethylenedioxy)tetrathiafulvalene, undergo characteristic structural transitions in the range of 130-195 K for the PF(6) salt and 222-242 K for the AsF(6) salt. The dramatic structural transition is induced by the order of the ethylenedioxy moiety, and the resulting anion rotation leads to the reconstruction of the H...F interaction between the methyl groups and the anions. The unique hydrogen bonds play a crucial role in the transition. As a result, the molecular packing is rearranged entirely; the high temperature molecular stacks with an ordinary quasi-triangular molecular network transforms to a quasi-square-like network, which has never been observed among organic conductors. Nonetheless, the low-temperature phase exhibits a good metallic conductivity as well, so the transition is a metal-metal (MM) transition. The resistivity measured along the perpendicular direction to the conducting ac-plane (rho(?)) and the calculation of the Fermi surface demonstrate that the high-temperature metal phase is a one-dimensional metal, whereas the low temperature metal phase has considerable interchain interaction. In the SbF(6) salt, a similar structural transition takes place around 370 K, so that the quasi square-like lattice is realized even at room temperature. Despite the largely different MM transition temperatures, all these salts undergo metal-insulator (MI) transitions approximately at the same temperature of 50 K. The low temperature insulator phase is nonmagnetic, and the reflectance spectra suggest the presence of charge disproportionation with small charge difference (0.14). PMID- 22812375 TI - The effectiveness of neuromuscular warm-up strategies, that require no additional equipment, for preventing lower limb injuries during sports participation: a systematic review. AB - BACKGROUND: Lower limb injuries in sport are increasingly prevalent and responsible for large economic as well as personal burdens. In this review we seek to determine which easily implemented functional neuromuscular warm-up strategies are effective in preventing lower limb injuries during sports participation and in which sporting groups they are effective. METHODS: Seven electronic databases were searched from inception to January 2012 for studies investigating neuromuscular warm-up strategies and injury prevention. The quality of each included study was evaluated using a modified version of the van Tulder scale. Data were extracted from each study and used to calculate the risk of injury following application of each evaluated strategy. RESULTS: Nine studies were identified including six randomized controlled trials (RCT) and three controlled clinical trials (CCT). Heterogeneity in study design and warm-up strategies prevented pooling of results. Two studies investigated male and female participants, while the remaining seven investigated women only. Risk Ratio (RR) statistics indicated 'The 11+' prevention strategy significantly reduces overall (RR 0.67, confidence interval (CI) 0.54 to 0.84) and overuse (RR 0.45, CI 0.28 to 0.71) lower limb injuries as well as knee (RR 0.48, CI 0.32 to 0.72) injuries among young amateur female footballers. The 'Knee Injury Prevention Program' (KIPP) significantly reduced the risk of noncontact lower limb (RR 0.5, CI 0.33 to 0.76) and overuse (RR 0.44, CI 0.22 to 0.86) injuries in young amateur female football and basketball players. The 'Prevent Injury and Enhance Performance' (PEP) strategy reduces the incidence of anterior cruciate ligament (ACL) injuries (RR 0.18, CI 0.08 to 0.42). The 'HarmoKnee' programme reduces the risk of knee injuries (RR 0.22, CI 0.06 to 0.76) in teenage female footballers. The 'Anterior Knee Pain Prevention Training Programme' (AKP PTP) significantly reduces the incidence of anterior knee pain (RR 0.27, CI 0.14 to 0.54) in military recruits. CONCLUSIONS: Effective implementation of practical neuromuscular warm-up strategies can reduce lower extremity injury incidence in young, amateur, female athletes and male and female military recruits. This is typically a warm-up strategy that includes stretching, strengthening, balance exercises, sports specific agility drills and landing techniques applied consistently for longer than three consecutive months. In order to optimize these strategies, the mechanisms for their effectiveness require further evaluation. PMID- 22812376 TI - Seasonality of self-destructive behaviour: seasonal variations in demographic and suicidal characteristics in Van, Turkey. AB - OBJECTIVE: Seasonality is one of the most interesting but still elusive issue in suicide research. Linkages of seasonality in suicides to possible contributors such as gender, type of method used, and climatic factors have received attention in different cultures. We aimed at evaluating seasonal trends in suicidal behaviour according to demographic characteristics, reasons for self-destructive behaviour and means preferred in suicide. METHODS: Our aim was to assess the seasonal variation in self-destructive behaviour in terms of completed and attempted suicides in a 3-year time period from 2008 to 2010 in Van, Turkey. A total of 1448 cases were registered over a 3-year time period in the city. Seasonal deviations in demographic characteristics, reasons for suicide, and methods of suicide were evaluated. RESULTS: Seasonal distribution of both completed and attempted suicides by gender did not significantly deviate. On the other hand, we found a significant decline in self-destructive behaviours among those who were single and student in the spring. We found a peak in self destructive behaviours in the autumn among Individuals who suffer from psychological problems. CONCLUSIONS: Subjects with psychological difficulties were more prone to commit suicide in autumn. Seasonal differences in methods of suicide used by suicidal subjects were not significant. PMID- 22812377 TI - Antibiotic optimization and chemical structure stabilization of thiomuracin A. AB - Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity. PMID- 22812378 TI - Apical root resorption due to orthodontic treatment detected by cone beam computed tomography. AB - OBJECTIVE: To determine the frequency of apical root resorption (ARR) due to orthodontic treatment using cone beam computed tomography (CBCT) in a sample of 1256 roots from 30 patients. MATERIALS AND METHODS: All patients had Class I malocclusion with crowding. Of the 30 patients evaluated, 11 were boys and 19 were girls; their mean age was 13 years (11 to 16 years). Orthodontic treatment followed the nonextraction treatment. CBCT images were obtained before and after orthodontic treatment, and ARR was determined using Axial Guided Navigation of CBCT images. RESULTS: All patients had ARR. No statistically significant association was found between resorption frequency, gender, and age. ARR was detected using CBCT in 46% of all roots that underwent orthodontic treatment. CONCLUSIONS: CBCT was effective for detecting in vivo even minimal degrees of ARR due to orthodontic treatment and allowed three-dimensional evaluation of dental roots and visualization of palatine roots of maxillary molars. The highest frequencies and the most significant ARR occurred in incisors and distal roots of first maxillary and mandibular molars. PMID- 22812380 TI - The effect of a designated tool on person-centred goal identification and service planning among older people receiving homecare in New Zealand. AB - This study sought to determine the ability of a designated tool developed to identify client-directed goals in a sample of older people referred for homecare. A retrospective pre/post-intervention design was used and a total of 360 older people in an urban centre in New Zealand were included in the analysis. All clients receiving services at the time of data collection (July 2007) who were referred for service provision between July 2003 and the implementation in January 2007 of a restorative model of homecare were included in the analysis. The restorative model of homecare included a designated goal-facilitation tool [Towards Achieving Realistic Goal in Elders Tool (TARGET)]. Prior to the use of TARGET, participants had a goal recorded for their home-care episode in 31 cases (8.6%), whereas following the implementation of TARGET, goals were recorded in 339 cases (94.2%). At a quarterly review, eight clients (2.2%) achieved their goal prior to TARGET, whereas 172 clients (47.8%) fully achieved their goal when TARGET was utilised. Within the sample, multinomial logistic regression showed that the use of TARGET significantly improved goal attainment. Furthermore, moderate-to-severe cognitive impairment significantly reduced the successful attainment of goals. The study highlighted the importance of a designated tool for facilitating older people to set goals that are then used in developing support plans to structure services to assist them in the home. The need for alternative strategies for goal setting for people with significant cognitive impairment was highlighted. This study, in attempting to determine the effect of a goal-facilitation tool as a driver for quality improvement in homecare, had an observational comparative design, this being the most pragmatic option to assess the feasibility of TARGET prior to further work being undertaken. The results do show that in this sample of older people receiving homecare, the use of TARGET led to a greater proportion of goal identification, higher rates of goal attainment and a more diverse range of categories of goals than traditional non structured methods of goal setting. PMID- 22812379 TI - Interleukin-27 suppresses osteoclastogenesis via induction of interferon-gamma. AB - Interleukin (IL)-27 is a heterodimeric cytokine that is known to have both stimulatory and inhibitory functions during immune responses. We investigated the effects of IL-27 on arthritis and bone erosion in the murine collagen-induced arthritis (CIA) model. We demonstrate that the inhibitory effect of IL-27 on osteoclastogenesis is associated with interferon-gamma (IFN-gamma) production by using an IFN-gamma knockout mouse model. The IL-27-Fc was injected into both CIA and IFN-gamma-deficient mice. The effects of IL-27-Fc on osteoclast differentiation were evaluated both in vitro and in vivo. The IL-27-Fc-injected mice showed significantly lower arthritis indices and fewer tartrate-resistant acid-phosphatase-positive osteoclasts in their joint tissues than untreated mice. Interleukin-27 inhibited osteoclastogenesis from bone marrow-derived mononuclear cells in vitro, which was counteracted by the addition of anti-IFN-gamma antibody. The IL-27-Fc did not affect arthritis in IFN-gamma knockout mice. Interleukin-27 also suppressed osteoclast differentiation in human and intriguingly, it could promote the expression of IFN-gamma on priming osteoclasts. These results imply that IL-27 suppressed the generation of CIA and osteoclastogenesis, which were mediated by the induction of IFN-gamma. PMID- 22812381 TI - Aerosol-based efficient delivery of azithromycin to alveolar macrophages for treatment of respiratory infections. AB - The efficacy of aerosol-based delivery of azithromycin (AZM) for the treatment of respiratory infections caused by pathogenic microorganisms infected in alveolar macrophages (AMs) was evaluated by comparison with oral administration. The aerosol formulation of AZM (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer((r)). The oral formulation of AZM (50 mg/kg) was used for comparison. Time-courses of concentrations of AZM in AMs following administration were obtained, and then the therapeutic availability (TA) was calculated. In addition, the area under the concentrations of AZM in AMs - time curve/minimum inhibitory concentration at which 90% of isolates ratio (AUC/MIC90) were calculated to estimate the antibacterial effects in AMs. The TA of AZM in AMs following administration of aerosol formulation was markedly greater than that following administration of oral formulation. In addition, the AUC/MIC90 of AZM in AMs was markedly higher than the effective values. This indicates that the aerosol formulation could be useful for the treatment of respiratory infections caused by pathogenic microorganisms infected in AMs. This study suggests that aerosolized AZM is an effective pulmonary drug delivery system for the treatment of respiratory infections. PMID- 22812383 TI - Overweight and impaired insulin sensitivity present in growing cats. AB - Obesity is a growing problem in pets as well as in humans. Overweight and obesity are linked to insulin sensitivity and subsequently in older cats, to an increased risk of developing diabetes mellitus. In the experimental cat population of the Institute of Animal Nutrition of the Vetsuisse Faculty, University of Zurich, an overweight phenotype in intact cats younger than 1 year became evident. The aims of the present study were to determine whether an association between insulin sensitivity and body condition score (BCS) or feline body mass index (FBMI) is already present during young adulthood in these cats and to test the hypothesis that the phenotype lean/overweight is significantly associated with monthly body weight during the growing period. Therefore, 41 kittens from the mentioned cat breeding colony were studied. They were weighed weekly and checked monthly (third to eighth month after birth) for BCS and FBMI. At the age of 8 months, they were classified into an overweight and lean phenotype based on BCS on a scale of 9 (median; maximum and minimum: overweight male (6.4; 6.8; 6.0); overweight female (6.1; 6.2; 6.0); lean male (5.4; 5.7; 5.0); lean female (5.2; 5.6; 5.0). A significant association between the phenotype and body weight was obvious during the growing period from the third to the 8 months (p = 0.0001). At month 8, body fat content was measured by dual energy X-ray absorptiometry and a glucose tolerance test to determine the insulin sensitivity index was performed. Insulin sensitivity was significantly associated with BCS (p = 0.0007) and body fat content (p < 0.0001) but not with sex (p = 0.61). Our data provide evidence that already in young intact cats; insulin insensitivity is significantly associated with BCS or a presumed phenotype lean/overweight. PMID- 22812382 TI - 5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress. AB - BACKGROUND: Cardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil(5-FU) and it can have detrimental effects both in patients and workers involved in the preparation of chemotherapy. METHODS: Specifically, we have assessed the effects of increasing concentrations of 5-FU and doxorubicin (DOXO) on proliferation of H9c2 rat cardiocytes and HT-29 human colon adenocarcinoma cells by MTT assay. Cells were treated for 24, 48 and 72 h with different concentrations of the two drugs alone or with 5-FU in combination with 10(-4) M of levofolene (LF). RESULTS: 5-FU induced a time- and dose dependent growth inhibition in both cell lines. The 50% growth inhibition (IC:50) was reached at 72 h with concentrations of 4 MUM and 400 MUM on HT-29 and H9c2, respectively. The addition of LF to 5-FU enhanced this effect. On the other hand, the IC:50 of DOXO was reached at 72 h with concentrations of 0.118 MUM on H9c2 and of 0.31 MUM for HT-29. We have evaluated the cell death mechanism induced by 50% growth inhibitory concentrations of 5-FU or DOXO in cardiocytes and colon cancer cells. We have found that the treatment with 400 MUM 5-FU induced apoptosis in 32% of H9c2 cells. This effect was increased by the addition of LF to 5-FU (38% of apoptotic cells). Apoptosis occurred in only about 10% of HT-29 cells treated with either 5-FU or 5-FU and LF in combination. DOXO induced poor effects on apoptosis of both H9c2 and HT-29 cells (5-7% apoptotic cells, respectively). The apoptosis induced by 5-FU and LF in cardiocytes was paralleled by the activation of caspases 3, 9 and 7 and by the intracellular increase of O(2 ) levels. CONCLUSIONS: These results suggest that cardiotoxic mechanism of chemotherapy agents are different and this disclose a new scenario for prevention of this complication. PMID- 22812384 TI - The efficiency of C4 photosynthesis under low light conditions in Zea mays, Miscanthus x giganteus and Flaveria bidentis. AB - The efficiency of C(4) photosynthesis in Zea mays, Miscanthus x giganteus and Flaveria bidentis in response to light was determined using measurements of gas exchange, (13) CO(2) photosynthetic discrimination, metabolite pools and spectroscopic assays, with models of C(4) photosynthesis and leaf (13) CO(2) discrimination. Spectroscopic and metabolite assays suggested constant energy partitioning between the C(4) and C(3) cycles across photosynthetically active radiation (PAR). Leakiness (phi), modelled using C(4) light-limited photosynthesis equations (phi(mod)), matched values from the isotope method without simplifications (phi(is)) and increased slightly from high to low PAR in all species. However, simplifications of bundle-sheath [CO(2)] and respiratory fractionation lead to large overestimations of phi at low PAR with the isotope method. These species used different strategies to maintain similar phi. For example, Z. mays had large rates of the C(4) cycle and low bundle-sheath cells CO(2 ) conductance (g(bs)). While F. bidentis had larger g(bs) but lower respiration rates and M. giganteus had less C(4) cycle capacity but low g(bs), which resulted in similar phi. This demonstrates that low g(bs) is important for efficient C(4) photosynthesis but it is not the only factor determining phi. Additionally, these C(4) species are able to optimize photosynthesis and minimize phi over a range of PARs, including low light. PMID- 22812385 TI - Cross-cultural adaptation and translation of a quality of life tool for new mothers: a methodological and experiential account from six countries. AB - AIM: To examine the challenges and solutions encountered in the translation and cross-cultural adaptation of an English language quality of life tool in India, China, Iran, Portugal, Brazil, and Poland. BACKGROUND: Those embarking on research involving translation and cross-cultural adaptation must address certain practical and conceptual issues. These include instrument choice, linguistic factors, and cultural or philosophical differences, which may render an instrument inappropriate, even when expertly translated. Publication bias arises when studies encountering difficulties do not admit to these, or are not published at all. As an educative guide to the potential pitfalls involved in the cross-cultural adaptation process, this article reports the conceptual, linguistic, and methodological experiences of researchers in six countries, who translated and adapted the Mother-Generated Index, a quality of life tool originally developed in English. DATA SOURCES: Principal investigator experience from six stand-alone studies (two published) ranging from postgraduate research to citywide surveys. DISCUSSION/IMPLICATIONS FOR NURSING: This analysis of a series of stand-alone cross-cultural studies provides lessons about how conceptual issues, such as the uniqueness of perceived quality of life and the experience of new motherhood, can be addressed. This original international approach highlights practical lessons relating to instrument choice, and the resources available to researchers with different levels of experience. Although researchers may be confident of effective translation, conceptual and practical difficulties may be more problematic. CONCLUSION: Instrument choice is crucial. Researchers must negotiate adequate resources for cross-cultural research, including time, translation facilities, and expert advice about conceptual issues. PMID- 22812386 TI - Ruthenium metallopolymer: Dawson polyoxomolybdate alpha-[Mo18O54(SO4)2]4- adduct films: sensitization for visible photoelectrocatalysis. AB - Thin films of the adduct formed from the electrostatic association of the metallopolymer, [Ru(bpy)(2)(PVP)(10)](2+), and the Dawson polyoxomolybdate alpha [Mo(18)O(54)(SO(4))(2)](4-), POMo, have been formed on ITO electrodes using an alternate immersion approach. The Ru/POMo ratio is 4.5:1, which exceeds the 2:1 ratio expected on the basis of the charges of the Ru(2+) and POMo(4-) building blocks. This behavior arises because of the polymeric character of the cation. In the presence of a substrate that has an abstractable proton such as benzyl alcohol, these ruthenium-sensitized polyoxomolybdate films generate significant photocurrents under visible irradiation. Significantly, increasing the surface coverage of the adduct from 1.4 * 10(-10) to 8.1 * 10(-10) mol cm(-2) does not measurably increase the photocurrent observed. Scan-rate-dependent cyclic voltammetry reveals that the rate of homogeneous charge transport through the film is slow, which most likely results in only a fraction of the film thickness being active for photoelectrocatalysis. The photocurrent increases markedly when the driving force for the oxidation of POMo(5-), created by the photoelectrocatalytic oxidation of benzyl alcohol, is increased. This result is consistent with the dynamics of heterogeneous electron transfer being centrally important to the regeneration of the photoelectrocatalyst. A system in which the surface coverage and applied overpotential are optimized produces a photocurrent density of 190 +/- 18 nA cm(-2) under 480 +/- 5 nm irradiation. PMID- 22812387 TI - Early treatment response evaluated by a clinical scoring system correlates with the prognosis of pulmonary tuberculosis patients in Ethiopia: a prospective follow-up study. AB - BACKGROUND: In resource-limited settings the monitoring of tuberculosis (TB) patients is challenging, and early identification of TB patients with a high mortality risk is important. The aim of this study was to investigate prospectively whether early changes in a clinical scoring system (TB score) can predict treatment outcome in Ethiopian patients with pulmonary tuberculosis. METHOD: TB patients (n = 250) and blood donors (n = 82) were recruited prospectively at Gondar University Hospital, Ethiopia. Clinical scoring was performed using an interview-based questionnaire and clinical examination. RESULTS: Among TB patients (53.6% of whom were HIV co-infected) the median TB score declined from week 0 to week 2 (8 (interquartile range (IQR) 6-9) vs 4 (IQR 2-6)) and dropped to a low level at week 8, which was still significantly higher than that found in blood donors (2 (IQR 1-4) vs 0 (IQR 0-1), p < 0.0001). Patients who died had a significantly higher TB score at week 0, week 2, and week 8 than survivors. Mortality was associated with a failure to achieve a decrease greater than 25% in the TB score at 2 weeks. Baseline CD4 + cell counts (< 200 cells/mm3) were associated with mortality but not with initial TB score results. CONCLUSIONS: The TB score was increased during the first 2 months of treatment among patients who died. Failure to achieve a greater than 25% decrease in TB score after 2 weeks of treatment was associated with increased mortality. Repeated clinical scoring during the intensive phase of TB treatment could be useful to identify high-risk patients. PMID- 22812388 TI - Predictors of competing mortality to invasive breast cancer incidence in the Canadian National Breast Screening study. AB - BACKGROUND: Evaluating the cost-effectiveness of breast cancer screening requires estimates of the absolute risk of breast cancer, which is modified by various risk factors. Breast cancer incidence, and thus mortality, is altered by the occurrence of competing events. More accurate estimates of competing risks should improve the estimation of absolute risk of breast cancer and benefit from breast cancer screening, leading to more effective preventive, diagnostic, and treatment policies. We have previously described the effect of breast cancer risk factors on breast cancer incidence in the presence of competing risks. In this study, we investigate the association of the same risk factors with mortality as a competing event with breast cancer incidence. METHODS: We use data from the Canadian National Breast Screening Study, consisting of two randomized controlled trials, which included data on 39 risk factors for breast cancer. The participants were followed up for the incidence of breast cancer and mortality due to breast cancer and other causes. We stratified all-cause mortality into death from other types of cancer and death from non-cancer causes. We conducted separate analyses for cause-specific mortalities. RESULTS: We found that "age at entry" is a significant factor for all-cause mortality, and cancer-specific and non-cancer mortality. "Menstruation length" and "number of live births" are significant factors for all-cause mortality, and cancer-specific mortality. "Ever noted lumps in right/left breasts" is a factor associated with all-cause mortality, and non-cancer mortality. CONCLUSIONS: For proper estimation of absolute risk of the main event of interest common risk factors associated with competing events should be identified and considered. PMID- 22812389 TI - Canine ocular tumors following ciliary body ablation with intravitreal gentamicin. AB - Iridociliary tumors are the second most common primary ocular tumor in dogs and are usually benign. A review of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) database in 2009 suggested a potential correlation between malignant iridociliary epithelial tumors and ciliary body ablation by intravitreal gentamicin injection for the treatment of glaucoma. The purpose of this case series was to determine whether there is evidence of such a correlation in the COPLOW collection. Mining of the COPLOW database revealed that a significant number (39.5%) of canine globes with a history of ciliary body ablation were subsequently diagnosed with primary ocular tumors at enucleation, most commonly iridociliary epithelial tumors and melanocytic tumors. It is possible that neoplasia was present but unrecognized at the time of ciliary body ablation. These tumors had a higher than expected incidence of malignancy. These cases underscore the importance of reserving ciliary body ablation with gentamicin for disease-free eyes. PMID- 22812391 TI - Throwing the kitchen sink at melanoma drug development. PMID- 22812390 TI - Fibronectin-alpha4beta1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway. AB - Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical settings. The expression of fibronectin (FN) by endothelial cells is a prominent feature of the hepatic response to injury. Here we investigate the effects of the connecting segment-1 (CS-1) peptide therapy, which blocks FN-alpha4beta1 integrin leukocyte interactions, in a well-established model of 24-h cold liver IRI. CS-1 peptides significantly inhibited leukocyte recruitment and local release of proinflammatory mediators (COX-2, iNOS and TNF-alpha), ameliorating liver IRI and improving recipient survival rate. CS1 therapy inhibited the phosphorylation of p38 MAPK, a kinase linked to inflammatory processes. Moreover, in addition to downregulating the expression of matrix metalloproteinase-9 (MMP-9) in hepatic IRI, CS-1 peptide therapy depressed the expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) by macrophages, a membrane-tethered MMP important for focal matrix proteolysis. Inhibition of p38 MAPK activity, with its pharmacological antagonist SB203580, downregulated MMP-9 and MT1-MMP/MMP-14 expressions by FN-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls FN-mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of FN in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI. PMID- 22812392 TI - National context and patterns of alcohol use: the devil is in the data. AB - This commentary addresses several data-related challenges confronting the research described by Allamani et al. (2011) The topics briefly reviewed here include considerations of the optimal unit of analysis, sources of measurement error in social indicators, the heterogeneity and homogeneity of measurements within and across nations, and the data structures being employed. PMID- 22812393 TI - Encapsulation and controlled release of recombinant human erythropoietin from chitosan-carrageenan nanoparticles. AB - Novel chitosan-carrageenan nanoparticles were produced through the process of ionotropic gelation for the encapsulation and controlled release of recombinant human erythropoietin (rHu-EPO). The effects of chitosan concentration, chitosan to carrageenan mass ratio and solution pH on the nanoparticle diameter, polydispersity and surface charge were explored through both screening and response surface modeling (RSM) methods. The chitosan-carrageenan nanoparticles created had particle diameters between 200 and 1000 nm, surfaces charges between 40 and 55 mV, and polydispersity between 0.2 and 0.35. RSM optimized chitosan carrageenan nanoparticles demonstrated an increased rHu-EPO encapsulation efficiency of 47.97 +/- 4.10% and a more sustained in vitro release of ~50% over a 2 week period when compared to previous nano/microparticle delivery systems. Studies on the effect of surface charge and chitosan molecular weight on the encapsulation and controlled release of rHu-EPO revealed that increasing either led to improved encapsulation efficiency and reduced release rate. PMID- 22812394 TI - Cobalt(II)-polybenzimidazole complexes as a nonviral gene carrier: effects of charges and benzimidazolyl groups. AB - The successful delivery of nucleic acids into cells and their availability at the intracellular sites of action remain a major challenge in gene therapy, because cells are resistant to the uptake of genetic materials and contain a variety of mechanisms that degrade nucleic acids. To develop a nonviral carrier, we have recently designed a series of metal complexes with polybenzimidazole (pbzim) that serve as DNA-condensing agents. In this study, we prepared a group of Co(II) pbzim complexes that bear variable numbers of both positive charges and benzimidazole (bzim) groups. First, the formation of condensates at varied molar ratios of complex to DNA was examined by multiple biophysical measurements at pH 7.4. The results showed that the size, morphology, and surface charge of the condensates formed via a Co(II) complex dose-dependent process can be controlled by utilization of different complexes. Then, the imaging examination performed with both confocal and fluorescence microscope indicated that the DNA condensates can be internalized into cells. Luciferase activity assay showed that the DNA condensates formed at 1:1 of molar ratio are in favor of cell transfection because of their appropriate size, profile, and positive surface charges. The addition of the helper lipid DOPE can enhance both cellular uptake of the condensates and expression of the transferred genes. The MTT data indicated that cytotoxicity of both Co(II) complexes and condensates is enhanced with increasing positive charges and bzim groups. All the results revealed that the physical properties, cell transfection, and cytotoxicity of the condensates are regulated by the positive charges and bzim groups on the metal complexes. PMID- 22812395 TI - Permeation of PLGA nanoparticles across different in vitro models. AB - Many drug delivery systems have indicated improvement in delivery of various drug molecules and among these biodegradable and biocompatible polymers such as poly(D,L-lactide-co-glycolide) (PLGA) have been shown to enhance intracellular uptake of drug candidates when formulated as nanoparticles. PLGA nanoparticles were prepared by means of a double emulsion solvent evaporation technique and evaluated in terms of size, encapsulation efficiency, surface charge, isoniazid release and in vitro transport. The nanoparticles have an average size of 237 nm and were previously shown to be distributed in several tissues after oral administration without triggering an immune response. This study focussed on the in vitro permeation of the PLGA nanoparticles across different membranes and showed that although Rhodamine 6G-labelled nanoparticles are efficiently delivered across the intestinal epithelium, its epithelial permeability changes when a drug such as isoniazid is encapsulated. Future studies should focus on ways to optimise PLGA nanoparticle delivery when a drug such as isoniazid is encapsulated for instance by coating with polymers such as polyethylene glycol. PMID- 22812396 TI - Incomplete joint side tear of the subscapularis tendon with a small fragment in an adolescent tennis player: a case report. AB - CASE: In this case report, we presented the case of an adolescent tennis player with avulsion injury of the subscapularis tendon of the right shoulder. PATIENTS: A 17-year-old right-hand-dominant male tennis player visited our hospital complaining of pain in the anterior aspect of the right shoulder. We performed X ray and three-dimensional computed tomography (3D-CT) and magnetic resonance imaging (MRI) scans for the diagnosis. RESULTS: Plain radiographs did not reveal the presence of lesion; however, 3D-CT and MRI scans showed a small bony fragment located between the humeral head and the glenoid of the scapula and a high intensity area of the subscapularis tendon. He was subsequently diagnosed with incomplete joint side tear of the subscapularis tendon with a small bony fragment. Subsequently, we performed arthroscopic excision of the bony fragment and repair of the subscapularis tendon. CONCLUSIONS: This case highlighted the presence of an injury with minor trauma associated with repeated tennis strokes in a skeletally immature patient. PMID- 22812398 TI - Effect of metal ions on photoluminescence, charge transport, magnetic and catalytic properties of all-inorganic colloidal nanocrystals and nanocrystal solids. AB - Colloidal semiconductor nanocrystals (NCs) provide convenient "building blocks" for solution-processed solar cells, light-emitting devices, photocatalytic systems, etc. The use of inorganic ligands for colloidal NCs dramatically improved inter-NC charge transport, enabling fast progress in NC-based devices. Typical inorganic ligands (e.g., Sn(2)S(6)(4-), S(2-)) are represented by negatively charged ions that bind covalently to electrophilic metal surface sites. The binding of inorganic charged species to the NC surface provides electrostatic stabilization of NC colloids in polar solvents without introducing insulating barriers between NCs. In this work we show that cationic species needed for electrostatic balance of NC surface charges can also be employed for engineering almost every property of all-inorganic NCs and NC solids, including photoluminescence efficiency, electron mobility, doping, magnetic susceptibility, and electrocatalytic performance. We used a suite of experimental techniques to elucidate the impact of various metal ions on the characteristics of all inorganic NCs and developed strategies for engineering and optimizing NC-based materials. PMID- 22812400 TI - Paracetamol use (and/or misuse) in children in Enugu, South-East, Nigeria. AB - BACKGROUND: Paracetamol (also known as acetaminophen) is the commonest available analgesic and anti-pyretic. It is readily accessed from pharmacy, patent medicine and provision shops as over the counter drug making it a potential drug of abuse, especially in children. We sought to find its use and/or misuse in children seen at the paediatric outpatient clinic of the University of Nigeria Teaching Hospital (UNTH) Ituku-Ozalla, Enugu. OBJECTIVE: To determine the dosage, formulation, and frequency of paracetamol administration to children by caregivers and factors associated with its use and/or misuse. METHOD: An observational prospective study involving 231 children and their caregivers seen at the paediatric outpatient clinic of the University of Nigeria Teaching Hospital, Ituku - Ozalla, Enugu between June and November 2011 was undertaken. Data on paracetamol use before presentation to the clinic, in addition to demographic and other data were obtained from the caregivers using a structured questionnaire. Ethical consent for the study was obtained from the Hospital Ethics and Research Committee and informed consent was further obtained from the caregivers of the children. RESULTS: A total of 231 children aged six weeks to 16 years and their caregivers participated in this study. The mean ages of the children and their caregivers were 3.8 and 33.9 years, respectively. One hundred and thirty three of the children studied were males while 98 were females. Most of the children (75.6%) received paracetamol at home before presenting. Paracetamol tablet alone or in combination with the syrup was mostly used (60%) and this observation was made across all age groups. The commonest reason for using paracetamol tablet instead of the syrup was that it was more effective. Most caregivers relied on past experience (71.2%) rather than on enclosed information leaflet to decide the appropriate dosage. Half of the children also received other medications, mainly anti-malarials and antibiotics. CONCLUSIONS: Paracetamol was commonly given to children on "self prescription" basis and the tablet formulation was most frequently used, with the possibility of misuse and overdose. Caregivers need to be educated on age-appropriate formulations which are less likely to lead to overdose. PMID- 22812401 TI - A "catch-react-release" method for the flow synthesis of 2-aminopyrimidines and preparation of the Imatinib base. AB - The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2 aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R(1) = 2-methyl-5-nitrobenzyl, R(2) = H). PMID- 22812402 TI - Differential protein analysis of lymphocytes between children with acute lymphoblastic leukemia and healthy children. AB - We identified differential proteins in lymphocytes between patients with childhood acute lymphoblastic leukemia (c-ALL) and healthy children. Samples of bone marrow lymphocytes from children with c-ALL and peripheral blood lymphocytes from healthy children were collected, and total proteins were extracted and separated from these samples followed by two-dimensional gel electrophoresis for comparative analysis. The differential protein spots in c-ALL cells were digested in situ, and then analyzed with matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF-MS) followed by identification using the relevant database. Fifteen differential expression proteins were obtained by comparative proteomics analysis. Of the 15 differential proteins, eight were identified. Of the eight proteins, two had high expression and six low expression in c-ALL cells. The eight differential proteins are expected to become new diagnostic markers and drug targets for c-ALL. PMID- 22812403 TI - Novel class of heterometallic cubane and boride clusters containing heavier group 16 elements. AB - Thermolysis of an in situ generated intermediate, produced from the reaction of [Cp*MoCl(4)] (Cp* = eta(5)-C(5)Me(5)) and [LiBH(4).THF], with excess Te powder yielded isomeric [(Cp*Mo)(2)B(4)TeH(5)Cl] (2 and 3), [(Cp*Mo)(2)B(4)(MU(3) OEt)TeH(3)Cl] (4), and [(Cp*Mo)(4)B(4)H(4)(MU(4)-BH)(3)] (5). Cluster 4 is a notable example of a dimolybdaoxatelluraborane cluster where both oxygen and tellurium are contiguously bound to molybdenum and boron. Cluster 5 represents an unprecedented metal-rich metallaborane cluster with a cubane core. The dimolybdaheteroborane 2 was found to be very reactive toward metal carbonyl compounds, and as a result, mild pyrolysis of 2 with [Fe(2)(CO)(9)] yielded distorted cubane cluster [(Cp*Mo)(2)(BH)(4)(MU(3)-Te){Fe(CO)(3)}] (6) and with [Co(2)(CO)(8)] produced the bicapped pentagonal bipyramid [(Cp*MoCo)(2)B(3)H(2)(MU(3)-Te)(MU-CO){Co(3)(CO)(6)}] (7) and pentacapped trigonal prism [(Cp*MoCo)(2)B(3)H(2)(MU(3)-Te)(MU-CO)(4){Co(6)(CO)(8)}] (8). The geometry of 8 is an example of a heterometallic boride cluster in which five Co and one Mo atom define a trigonal prismatic framework. The resultant trigonal prism core is in turn capped by two boron, one Te, and one Co atom. In the pentacapped trigonal prism unit of 8, one of the boron atoms is completely encapsulated and bonded to one molybdenum, one boron, and five cobalt atoms. All the new compounds have been characterized in solution by IR, (1)H, (11)B, and (13)C NMR spectroscopy, and the structural types were unambiguously established by crystallographic analysis of 2 and 4-8. PMID- 22812404 TI - Effect of surface functionalization of metal wire on electrophysical properties of inductive elements. AB - The development of the microelectronics industry requires a new element basis with reduced size and increased functionality. The most important components in modern microelectronic integrated circuits are passive elements. One of the key challenges in order to improve the functionality of integrated circuits is to increase the quality of passive elements composing them. In this paper we suggest a novel approach to increase the quality factor Q of inductors by the surface modification and functionalization of the metal components. Ultrasound induced surface modification of metal wires led to the formation of a porous surface structure, which further can be functionalized with magnetite nanoparticles using layer-by-layer assembly technique. The surface modification and deposition of magnetite nanoparticles was investigated with SEM, XRD, and contact angle measurements. Additionally, inductance and resistance measurements, as the main parameters determining the Q-factor of inductors, were carried out. Samples with high number of magnetic nanoparticle-polyelectrolyte bilayers demonstrate a significant increase in inductance and a slight decrease in resistance in comparison to uncoated ones. The combination of these factors led to enhancement the Q-factor of the investigated inductive elements. PMID- 22812405 TI - Nurses' intervention goal categories for persons with spinal cord injury based on the International Classification of Functioning, Disability and Health: an international Delphi survey. AB - AIM: To examine whether the International Classification of Functioning, Disability and Health can be used as standard language to express intervention goals on the part of nurses caring for persons with spinal cord injury. BACKGROUND: This classification is multipurpose and is designed to organize a wide range of health-related information that can be used in any healthcare context and especially by interdisciplinary teams. DESIGN: A three-round, consensus-building, electronic-mail survey using the Delphi technique. METHODS: In the Delphi process spinal cord injury nurses were asked to name the problems, resources, and aspects of the environment that they address when treating patients with spinal cord injury. The answers were linked to the categories of the International Classification of Functioning, Disability and Health. The study was carried out in 2007. RESULTS: Nurses (N = 35) from 17 countries provided 823 answers that were linked to a set of 143 categories, 24 personal factors, and 51 concepts categorized as 'Not-covered', of which 32 were areas of fundamental importance to nurses. These were mainly risks that persons with spinal cord injury may face, such as the risk for future impairments. CONCLUSION: The use of the data set resulting from this study should help determine and document the needs that pertain to spinal cord injury nursing on an international level. Future research should confirm the usefulness of such a data set in clinical practice and can contribute to the update process of the International Classification of Functioning, Disability and Health. PMID- 22812406 TI - Four chromosome replication origins in the archaeon Pyrobaculum calidifontis. AB - Replication origins were mapped in hyperthermophilic crenarchaea, using high throughput sequencing-based marker frequency analysis. We confirm previous origin mapping in Sulfolobus acidocaldarius, and demonstrate that the single chromosome of Pyrobaculum calidifontis contains four replication origins, the highest number detected in a prokaryotic organism. The relative positions of the origins in both organisms coincided with regions enriched in highly conserved (core) archaeal genes. We show that core gene distribution provides a useful tool for origin identification in archaea, and predict multiple replication origins in a range of species. One of the P. calidifontis origins was mapped in detail, and electrophoretic mobility shift assays demonstrated binding of the Cdc6/Orc1 replication initiator protein to a repeated sequence element, denoted Orb-1, within the origin. The high-throughput sequencing approach also allowed for an annotation update of both genomes, resulting in the restoration of open reading frames encoding proteins involved in, e.g., sugar, nitrate and energy metabolism, as well as in glycosylation and DNA repair. PMID- 22812407 TI - Seroprevalence of hepatitis E virus in humans and geographically matched food animals in Egypt. AB - The aim of current study was to investigate the epidemiology of Hepatitis E virus (HEV) in humans and geographically matched food animals as a novel zoonotic assessment in Egypt. Blood samples were collected from patients who had a history of jaundice and attended to fever and general hospitals. Animal blood samples were collected from cows, buffaloes, sheep and goats convenient to HEV seropositive humans. Enzyme Immuno Assay (EIA) protocol was used to determine IgG anti-HEV. Sex and pregnancy were investigated as potential risk factors for HEV infection. Of 134 examined humans, 51 (38.1%) were positive for IgG anti-HEV. The males showed 26.8% seropositivity while the recorded female seropositivity was 50.8%, with a significant difference at P = 0.005, Odds Ratio (OR) = 0.35 at 95% confidence interval (CI): 0.17-0.73. There was a significant difference at P = 0.02 between seropositivity in pregnant (25%) and non-pregnant women (59.6%); OR was 0.23 (95% CI: 0.06-0.81). Anorexia was the most common symptom whereas paraesthesia and back pain were the least within icteric seropositive HEV humans. Hepatitis E virus seropositivity was recorded in 21.6%, 14%, 4.4% and 9.4% from examined cows, buffaloes, sheep and goats, respectively. The infected food animals were convenient to positive HEV humans who may declare the epidemiological picture of potential zoonotic HEV. PMID- 22812408 TI - Born to run. Studying the limits of human performance. AB - It is recognised that regular physical activity and a high level of fitness are powerful predictors of positive health outcomes. There is a long and rich history of significant feats of human endurance with some, for example, the death of the first marathon runner, Pheidippides, associated with negative health outcomes. Early studies on endurance running used X-ray and interview techniques to evaluate competitors and comment on performance. Since then, comparatively few studies have looked at runners competing in distances longer than a marathon. Those that have, tend to show significant musculoskeletal injuries and a remarkable level of adaptation to this endurance load. The TransEurope Footrace Project followed ultra-endurance runners aiming to complete 4,500 Km of running in 64 days across Europe. This pioneering study will assess the impact of extreme endurance on human physiology; analysing musculoskeletal and other tissue/organ injuries, and the body's potential ability to adapt to extreme physiological stress. The results will be of interest not only to endurance runners, but to anyone interested in the limits of human performance. Please see related article: http://www.biomedcentral.com/1741-7015/10/78. PMID- 22812409 TI - Comparison of CCL28, interleukin-8, interleukin-1beta and tumor necrosis factor alpha in subjects with gingivitis, chronic periodontitis and generalized aggressive periodontitis. AB - BACKGROUND AND OBJECTIVE: Cytokines produced by various cells are strong local mediators of inflammation. Mucosa-associated epithelial chemokine (CCL28), interleukin-8 (IL-8), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) are major cytokines that play important roles in the periodontal inflammatory process. In this study we aimed to compare the levels of CCL28, IL-8, IL-1beta and TNF-alpha in the gingival crevicular fluid of both periodontally healthy subjects and in subjects diagnosed with gingivitis, chronic periodontitis and generalized aggressive periodontitis. MATERIAL AND METHODS: A total of 84 subjects participated in the study: 21 subjects had gingivitis, 21 subjects had chronic periodontitis, 21 subjects had generalized aggressive periodontitis and 21 were periodontally healthy. The levels of CCL28, IL-8, IL 1beta and TNF-alpha were analyzed using enzyme-linked immune sorbent assay (ELISA). RESULTS: The total levels of CCL28 and IL-8 in the gingival crevicular fluid of the generalized aggressive periodontitis group (324.74 +/- 42.62 pg/30 s, 487.62 +/- 49.21 pg/30 s) were significantly higher than those of the chronic periodontitis group (268.81 +/- 28.64 pg/30 s, 423.65 +/- 35.24 pg/30 s), the gingivitis group (146.35 +/- 17.46 pg/30 s, 310.24 +/- 48.20 pg/30 s) and the periodontally healthy group (92.46 +/- 22.04 pg/30 s, 148.41 +/- 24.64 pg/30 s). Similarly, the total levels of IL-1beta and TNF-alpha in the generalized aggressive periodontitis group (110.23 +/- 9.20 pg/30 s, 1284.46 +/- 86.32 pg/30 s) were significantly higher than those in the chronic periodontitis group (423.65 +/- 35.24 pg/30 s, 82.64 +/- 9.12 pg/30 s), the gingivitis group (52.10 +/- 7.15 pg/30 s, 824.24 +/- 44.68 pg/30 s) and the periodontally healthy group (36.44 +/- 8.86 pg/30 s, 628.26 +/- 34.61 pg/30 s). CONCLUSION: CCL28, IL-8, IL 1beta and TNF-alpha may play key roles in the host response to inflammation in periodontal diseases. As the severity of periodontal diseases increases, destruction of periodontal tissues also increases. Inflammation is one among many factors that trigger periodontal tissue destruction. Identification of the mediators that influence the development and progression of inflammation in periodontal diseases may be very important in understanding the prognoses of periodontal diseases. PMID- 22812410 TI - Infantile fibrosarcoma - an important differential diagnosis of congenital vascular tumors. AB - We present the case of a female newborn with life-threatening bleeding of a ruptured infantile fibrosarcoma (IFS) and consecutive multiorgan dysfunction syndrome shortly after birth. After stabilization, the tumor could be treated without amputation due to surgery, laser therapy, and chemotherapy. The patient is free of tumor and doing functionally well after 4 years of follow-up. PMID- 22812411 TI - Clinical implications of recent insights into the structural biology of beta2 adrenoceptors. AB - Analysis of the crystal structure of beta-2 adrenoceptors (beta2ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the beta2AR is the best understood in terms of function, expression and activation. Regarding the interaction of beta2ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for beta2ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of beta2ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of beta2AR agonists. The deepening the understanding of the factors involved in ligand affinity for beta2ARs will assist in the development of beta2AR agonists that are more selective and potent, and that have longer term action. Not only are beta2AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human beta2ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of beta2ARs. PMID- 22812412 TI - Human metapneumovirus infections on the ICU: a report of three cases. AB - Although human metapneumovirus (hMPV) is primarily known as a causative agent of respiratory tract infections in children, the virus also can cause respiratory infections in adults. hMPV infections tend to be mild and are self-limiting, but the infections can be severe in the elderly and immunocompromised patients. Because hMPV infection is quite common, it should be considered in every patient with respiratory failure in the intensive care unit (ICU). We describe three adult patients, including a young pregnant woman, with hMPV infection who required admission to our ICU. Two of them developed respiratory failure with indication for mechanical ventilation. PMID- 22812413 TI - Histochemical distribution of digestive enzymes in the intestine of the common two-banded seabream, Diplodus vulgaris, Geoffroy St-Hilaire 1817. AB - The histochemical localization of non-specific esterase, alkaline and acid phosphatase as well as aminopeptidase in the intestine of the free-living common two-banded sea bream (Diplodus vulgaris) was investigated. Fish were caught near the town of Zadar (Adriatic Sea, Croatia). Samples of pyloric caeca and three parts of the intestine proper (anterior, middle and posterior) were used for the description of non-specific esterase, alkaline and acid phosphatase as well as aminopeptidase. Non-specific esterase activity was found in the cytoplasm of enterocytes in pyloric caeca and in all investigated intestinal segments. The activity was stronger in the anterior and posterior part of the intestine than in the pyloric caeca and middle segment of the intestine. Intestinal alkaline phosphatase was detected in brush border of enterocytes of all investigated intestinal segments. Enzymatic activity gradually decreased in a posterior direction. Acid phosphatase activity was observed as a fine granular reaction product in the supranuclear region of enterocytes. This activity was almost equal in pyloric caeca as well as in the anterior intestinal segment, while it was stronger in the middle and posterior intestinal segment. Aminopeptidase was present along the intestinal epithelium brush border in all investigated parts of the digestive tube. The intensity of aminopeptidase increased posteriorly. The possible role of investigated enzymes in intracellular digestion and transport is discussed. PMID- 22812414 TI - Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. AB - In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent. PMID- 22812415 TI - BetaSuperposer: superposition of protein surfaces using beta-shapes. AB - The comparison between two protein structures is important for understanding a molecular function. In particular, the comparison of protein surfaces to measure their similarity provides another challenge useful for studying molecular evolution, docking, and drug design. This paper presents an algorithm, called the BetaSuperposer, which evaluates the similarity between the surfaces of two structures using the beta-shape which is a geometric structure derived from the Voronoi diagram of molecule. The algorithm performs iterations of mix-and-match between the beta-shapes of two structures for the optimal superposition from which a similarity measure is computed, where each mix-and-match step attempts to solve an NP-hard problem. The devised heuristic algorithm based on the assignment problem formulation quickly produces a good superposition and an assessment of similarity. The BetaSuperposer was fully implemented and benchmarked against popular programs, the Dali and the Click, using the SCOP models. The BetaSuperposer is freely available to the public from the Voronoi Diagram Research Center ( http://voronoi.hanyang.ac.kr ). PMID- 22812416 TI - High relative air humidity and continuous light reduce stomata functionality by affecting the ABA regulation in rose leaves. AB - Plants developed under high (90%) relative air humidity (RH) have previously been shown to have large, malfunctioning stomata, which results in high water loss during desiccation and reduced dark induced closure. Stomatal movement is to a large extent regulated by abscisic acid (ABA). It has therefore been proposed that low ABA levels contribute to the development of malfunctioning stomata. In this study, we investigated the regulation of ABA content in rose leaves, through hormone analysis and beta-glucosidase quantification. Compared with high RH, rose plants developed in moderate RH (60%) and 20 h photoperiod contained higher levels of ABA and beta-glucosidase activity. Also, the amount of ABA increased during darkness simultaneously as the ABA-glucose ester (GE) levels decreased. In contrast, plants developed under high RH with 20 h photoperiod showed no increase in ABA levels during darkness, and had low beta-glucosidase activity converting ABA-GE to ABA. Continuous lighting (24 h) resulted in low levels of beta glucosidase activity irrespective of RH, indicating that a dark period is essential to activate beta-glucosidase. Our results provide new insight into the regulation of ABA under different humidities and photoperiods, and clearly show that beta-glucosidase is a key enzyme regulating the ABA pool in rose plants. PMID- 22812417 TI - Determination of the coalescence temperature of latexes by environmental scanning electron microscopy. AB - A new methodology for quantitative characterization of the coalescence process of waterborne polymer dispersion (latex) particles by environmental scanning electron microscopy (ESEM) is proposed. The experimental setup has been developed to provide reproducible latex monolayer depositions, optimized contrast of the latex particles, and a reliable readout of the sample temperature. Quantification of the coalescence process under dry conditions has been performed by image processing based on evaluation of the image autocorrelation function. As a proof of concept the coalescence of two latexes with known and differing glass transition temperatures has been measured. It has been shown that a reproducibility of better than 1.5 degrees C can be obtained for the measurement of the coalescence temperature. PMID- 22812419 TI - Structure, function and control of complement C5 and its proteolytic fragments. AB - As part of the innate immune system, the complement system recognises a wide range of non-self structures present on pathogens or altered self cells. Its activation elicits proteolytic cascades which eventually results in the cleavage of the C5 protein into two fragments, C5a and C5b. The small anaphylatoxin C5a induces a variety of biological responses upon binding to the 7TM receptors C5aR and the C5L2, while the large C5b fragment nucleates formation of the membrane attack complex capable of killing susceptible pathogens by the formation of a pore structure in association with complement components C6, C7, C8, and C9. A number of regulatory molecules help to control C5 mediated immune responses towards host cells, but in several major inflammatory conditions including sepsis and arthritis, C5a is believed to contribute significantly to disease etiology. Inhibition of membrane attack complex assembly is already approved for treatment of paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome. A number of recent crystal structures have provided a comprehensive insight into the architecture and properties of intact C5 and its fragments, and how pathogens interfere with their function. Here we review the functional and structural aspects of C5 and its fragments, the pathological conditions associated with them, and strategies employed by pathogens to interfere with the biological function of C5. Structural insight and elucidation of evasion strategies employed by pathogens present a unique opportunity for promoting the development of novel selective C5 inhibitors with therapeutic applications. PMID- 22812418 TI - Design and synthesis of multifunctional gold nanoparticles bearing tumor associated glycopeptide antigens as potential cancer vaccines. AB - The development of vaccines against specific types of cancers will offer new modalities for therapeutic intervention. Here, we describe the synthesis of a novel vaccine construction prepared from spherical gold nanoparticles of 3-5 nm core diameters. The particles were coated with both the tumor-associated glycopeptides antigens containing the cell-surface mucin MUC4 with Thomsen Friedenreich (TF) antigen attached at different sites and a 28-residue peptide from the complement derived protein C3d to act as a B-cell activating "molecular adjuvant". The synthesis entailed solid-phase glycopeptide synthesis, design of appropriate linkers, and attachment chemistry of the various molecules to the particles. Attachment to the gold surface was mediated by a novel thiol containing 33 atom linker which was further modified to be included as a third "spacer" component in the synthesis of several three-component vaccine platforms. Groups of mice were vaccinated either with one of the nanoplatform constructs or with control particles without antigen coating. Evaluation of sera from the immunized animals in enzyme immunoassays (EIA) against each glycopeptide antigen showed a small but statistically significant immune response with production of both IgM and IgG isotypes. Vaccines with one carbohydrate antigen (B, C, and E) gave more robust responses than the one with two contiguous disaccharides (D), and vaccine E with a TF antigen attached to threonine at the 10th position of the peptide was selected for IgG over IgM suggesting isotype switching. The data suggested that this platform may be a viable delivery system for tumor-associated glycopeptide antigens. PMID- 22812420 TI - Suspected brainstem anesthesia following retrobulbar block in a cat. AB - A 10-year-old, male, neutered, domestic shorthair cat was anesthetised for enucleation of a perforated left globe. A retrobulbar injection of local anesthetic (lidocaine/bupivacaine) was performed prior to surgery to provide intra- and postoperative analgesia. Following administration of the injection, the cat developed apnea and heart rate increased. Mechanical ventilation was initiated and surgery went ahead as planned. At the conclusion of surgery, the cat remained apnoeic requiring positive pressure ventilation until spontaneous ventilatory effort resumed. Upon recovery, the cat demonstrated neurological signs including tremors, nystagmus and absent dazzle reflex. These signs were attributed to brainstem anesthesia from the retrobulbar block and fully resolved within 3 h. This is the first report of suspected intrathecal spread of local anesthetic following retrobulbar block in a cat to the authors' knowledge. PMID- 22812421 TI - Risk factors for suicide behaviors in the observational schizophrenia outpatient health outcomes (SOHO) study. AB - BACKGROUND: To identify risk factors for suicide using data from a large, 3-year, multinational follow-up study of schizophrenia (SOHO study). METHODS: Baseline characteristics of 8,871 adult patients with schizophrenia were included in a logistic regression post-hoc analysis comparing patients who attempted and/or committed suicide during the study with those who did not. RESULTS: 384 (4.3%) patients attempted or committed suicide. Completed suicides were 27 (0.3%). The significant risk factors for suicide behaviors were previous suicidality, depressive symptoms, prolactin-related adverse events, male gender and history of hospitalization for schizophrenia. CONCLUSIONS: In view of the observational design of the study and the post-hoc nature of the analysis, the identified risk factors should be confirmed by ad-hoc specifically designed studies. PMID- 22812422 TI - Pleural effusions in patients with acute leukemia and myelodysplastic syndrome. AB - Pleural effusions are rarely observed in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL) and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN). Therefore the underlying etiology of pleural effusions and the efficacy and safety of pleural procedures in this population has not been well studied. In a retrospective review of cases from 1997 to 2007, we identified 111 patients with acute leukemia or MDS/MPN who underwent pleural procedures. Clinical characteristics were reviewed, and survival outcomes were estimated by Kaplan-Meier methods. A total of 270 pleural procedures were performed in 111 patients (69 AML, 27 ALL, 15 MDS/MPN). The main indications for pleural procedures were possible infection (49%) and respiratory symptoms (48%), and concomitant clinical symptoms included fever (34%), dyspnea (74%), chest pain (24%) and cough (37%). Most patients had active disease (61%). The most frequent etiology of pleural effusions was infection (47%), followed by malignancy (36%). Severe thrombocytopenia (platelet count < 20 * 10(3)/uL) was present in 43% of the procedures, yet the procedural complication rate was only 1.9%. Multivariate analysis revealed that older age, AML, MDS/MPN and active disease status were associated with a shorter median overall survival. Infection and malignant involvement are the most common causes of pleural effusion in patients with acute leukemia or MDS. After optimizing platelet count and coagulopathy, thoracentesis may be performed safely and with high diagnostic yield in this population. Survival in these patients is determined by the response to treatment of the hematologic malignancy. PMID- 22812423 TI - Evaluation of inflammatory biomarkers associated with oxidative stress and histological assessment of magnetic therapy on experimental myopathy in rats. AB - The effect of pulsed electromagnetic field (PEMF) therapy, also called magnetic therapy, upon inflammatory biomarkers associated with oxidative stress plasma fibrinogen, nitric oxide (NO), L-citrulline, carbonyl groups, and superoxide dismutase (SOD) was evaluated through histological assessment, in rats with experimental myopathy. The groups studied were: (A) control (intact rats that received PEMF sham exposures); (B) rats with myopathy and sacrificed 24 h later; (C) rats with myopathy; (D) rats with myopathy and treated with PEMF; and (E) intact rats treated with PEMF. Groups A, C, D, and E were sacrificed 8 days later. Myopathy was induced by injecting 50 MUl of 1% carrageenan lambda (type IV) once sub-plantar. Treatment was carried out with PEMF emitting equipment with two flat solenoid disks for 8 consecutive days in groups D and E, at 20 mT and 50 Hz for 30 min/day/rat. The biomarkers were determined by spectrophotometry. The muscles (5/8) were stained with Hematoxylin-Eosin and examined by optic microscopy. Quantitative variables were statistically analyzed by the Fisher test, and categorical applying Pearson's Chi Squared test at p < 0.05 for all cases. In Groups B and C, the biomarkers were significantly increased compared to A, D, and E groups: fibrinogen (p < 0.001); NO, L-citrulline and carbonyl groups (p < 0.05); SOD (p < 0.01) as well as the percentage of area with inflammatory infiltration (p < 0.001). PEMF caused decreased levels of fibrinogen, L-citrulline, NO, SOD, and carbonyl groups and significant muscle recovery in rats with experimental myopathies. PMID- 22812424 TI - Ultramarathon is an outstanding model for the study of adaptive responses to extreme load and stress. AB - Ultramarathons comprise any sporting event involving running longer than the traditional marathon length of 42.195 km (26.2 miles). Studies on ultramarathon participants can investigate the acute consequences of ultra-endurance exercise on inflammation and cardiovascular or renal consequences, as well as endocrine/energetic aspects, and examine the tissue recovery process over several days of extreme physical load. In a study published in BMC Medicine, Schutz et al. followed 44 ultramarathon runners over 4,487 km from South Italy to North Cape, Norway (the Trans Europe Foot Race 2009) and recorded daily sets of data from magnetic resonance imaging, psychometric, body composition and biological measurements. The findings will allow us to better understand the timecourse of degeneration/regeneration of some lower leg tissues such as knee joint cartilage, to differentiate running-induced from age-induced pathologies (for example, retropatelar arthritis) and finally to assess the interindividual susceptibility to injuries. Moreover, it will also provide new information about the complex interplay between cerebral adaptations/alterations and hormonal influences resulting from endurance exercise and provide data on the dose-response relationship between exercise and brain structure/function. Overall, this study represents a unique attempt to investigate the limits of the adaptive response of human bodies.Please see related article: http://www.biomedcentral.com/1741 7015/10/78. PMID- 22812425 TI - Enhancing the photocurrent in diketopyrrolopyrrole-based polymer solar cells via energy level control. AB - A series of diketopyrrolopyrrole (DPP)-based small band gap polymers has been designed and synthesized by Suzuki or Stille polymerization for use in polymer solar cells. The new polymers contain extended aromatic pi-conjugated segments alternating with the DPP units and are designed to increase the free energy for charge generation to overcome current limitations in photocurrent generation of DPP-based polymers. In optimized solar cells with [6,6]phenyl-C(71)-butyric acid methyl ester ([70]PCBM) as acceptor, the new DPP-polymers provide significantly enhanced external and internal quantum efficiencies for conversion of photons into collected electrons. This provides short-circuit current densities in excess of 16 mA cm(-2), higher than obtained so far, with power conversion efficiencies of 5.8% in simulated solar light. We analyze external and internal photon to collected electron quantum efficiencies for the new polymers as a function of the photon energy loss, defined as the offset between optical band gap and open circuit voltage, and compare the results to those of some of the best DPP-based polymers solar cells reported in the literature. We find that for the best solar cells there is an empirical relation between quantum efficiency and photon energy loss that presently limits the power conversion efficiency in these devices. PMID- 22812426 TI - An image classification approach to analyze the suppression of plant immunity by the human pathogen Salmonella Typhimurium. AB - BACKGROUND: The enteric pathogen Salmonella is the causative agent of the majority of food-borne bacterial poisonings. Resent research revealed that colonization of plants by Salmonella is an active infection process. Salmonella changes the metabolism and adjust the plant host by suppressing the defense mechanisms. In this report we developed an automatic algorithm to quantify the symptoms caused by Salmonella infection on Arabidopsis. RESULTS: The algorithm is designed to attribute image pixels into one of the two classes: healthy and unhealthy. The task is solved in three steps. First, we perform segmentation to divide the image into foreground and background. In the second step, a support vector machine (SVM) is applied to predict the class of each pixel belonging to the foreground. And finally, we do refinement by a neighborhood-check in order to omit all falsely classified pixels from the second step. The developed algorithm was tested on infection with the non-pathogenic E. coli and the plant pathogen Pseudomonas syringae and used to study the interaction between plants and Salmonella wild type and T3SS mutants. We proved that T3SS mutants of Salmonella are unable to suppress the plant defenses. Results obtained through the automatic analyses were further verified on biochemical and transcriptome levels. CONCLUSION: This report presents an automatic pixel-based classification method for detecting "unhealthy" regions in leaf images. The proposed method was compared to existing method and showed a higher accuracy. We used this algorithm to study the impact of the human pathogenic bacterium Salmonella Typhimurium on plants immune system. The comparison between wild type bacteria and T3SS mutants showed similarity in the infection process in animals and in plants. Plant epidemiology is only one possible application of the proposed algorithm, it can be easily extended to other detection tasks, which also rely on color information, or even extended to other features. PMID- 22812427 TI - What are the priorities for developing culturally appropriate palliative and end of-life care for older people? The views of healthcare staff working in New Zealand. AB - This paper explores the views of healthcare staff regarding the provision of culturally appropriate palliative care for Maori, Pacific Island and Chinese elders living in Auckland, New Zealand. The ageing population is culturally and ethnically diverse and, along with other developed countries experiencing high levels of migration, the challenge is balancing the rise in numbers of older people from different ethnic and cultural groups with end-of-life care, which reflects personal values and beliefs. Two joint interviews and ten focus groups were conducted with eighty staff across a range of primary, secondary and speciality care settings in 2010. The findings demonstrated that participants viewed the involvement of family as fundamental to the provision of palliative care for Maori, Pacific Island and Chinese elders. For Maori and Pacific Islanders, healthcare staff indicated the importance of enabling family members to provide 'hands-on' care. The role of family in decision-making was fundamental to the delivery of and satisfaction with care for older Chinese family members. Care staff highlighted the need to be cognisant of individual preferences both within and across cultures as a fundamental aspect of palliative care provision. The role of family in 'hands-on' palliative care and decision-making requires care staff to relinquish their role as 'expert provider'. Counter to the prioritisation of autonomy in Western health-care, collective decision-making was favoured by Chinese elders. Providing families with the requisite knowledge and skills to give care to older family members was important. Whilst assumptions are sometimes made about preferences for end-of-life care based on cultural values alone, these data suggest that care preferences need to be ascertained by working with family members on an individual basis and in a manner that respects their involvement in palliative care provision. PMID- 22812428 TI - Structural insight in histo-blood group binding by the F18 fimbrial adhesin FedF. AB - F18-positive enterotoxigenic and Shiga toxin-producing Escherichia coli are responsible for post-weaning diarrhoea and oedema disease in pigs and lead to severe production losses in the farming industry. F18 fimbriae attach to the small intestine of young piglets by latching onto glycosphingolipids with A/H blood group determinants on type 1 core. We demonstrate the N-terminal domain of the F18 fimbrial subunit FedF to be responsible for ABH-mediated attachment and present its X-ray structure in ligand-free form and bound to A and B type 1 hexaoses. The FedF lectin domain comprises a 10-stranded immunoglobulin-like beta sandwich. Three linear motives, Q(47) -N(50), H(88) -S(90) and R(117) -T(119), form a shallow glycan binding pocket near the tip of the domain that is selective for type 1 core glycans in extended conformation. In addition to the glycan binding pocket, a polybasic loop on the membrane proximal surface of FedF lectin domain is shown to be required for binding to piglet enterocytes. Although dispensable for ABH glycan recognition, the polybasic surface adds binding affinity in the context of the host cell membrane, a mechanism that is proposed to direct ABH-glycan binding to cell-bound glycosphingolipids and could allow bacteria to avoid clearance by secreted glycoproteins. PMID- 22812429 TI - Discriminating D-amino acid-containing peptide epimers by radical-directed dissociation mass spectrometry. AB - The presence of a single D-amino acid in a peptide is very difficult to detect. Mass spectrometry-based approaches rely on differences in fragmentation between all L-amino acid-containing peptides and single D-amino acid-containing peptides (which are epimers) for identification. The success of this approach is dependent on the structural sensitivity of the fragmentation method. Recently, experiments have demonstrated that fragmentation initiated by radical chemistry, or radical directed dissociation (RDD), is particularly sensitive to the structure of the ion being fragmented. Herein, RDD is used to identify the presence of D-serine, D alanine, or D-aspartic acid in eight biologically relevant peptides. It is demonstrated that chiral disambiguation by RDD is dependent on both the initial radical site and subsequent radical migration. Fortuitously, RDD can be initiated by a variety of different radical precursors which can be associated with the peptide via covalent or noncovalent means, and RDD can be examined in all observable charge states (both positive and negative). This diversity enables numerous initial radical sites and migration pathways to be explored. For all but one of the peptides that were examined, RDD provides significantly better chiral discrimination than CID. Quantitation of peptide epimers by RDD is also described. PMID- 22812430 TI - Predominant immunoreactivity of Porphyromonas gingivalis heat shock protein in autoimmune diseases. AB - BACKGROUND AND OBJECTIVE: Autoimmune diseases, including atherosclerosis, diabetes mellitus and rheumatoid arthritis, can be triggered and aggravated by the pathogen-driven antigenic peptide from Porphyromonas gingivalis HSP60. P. gingivalis is the major pathogen of chronic periodontitis, which is a global epidemic prevalent in two-thirds of the adult population. The monoclonal antibody raised against peptide 19 (Pep19: TLVVNRLRGSLKICAVKAPG) from P. gingivalis HSP60 was polyreactive to the human homolog. The aim of this study was to determine if Pep19 from P. gingivalis HSP60 manifests itself as a predominant antigen in infection-triggered autoimmune diseases. MATERIAL AND METHODS: Pep19 from P. gingivalis HSP60, Mycobacterium tuberculosis HSP60 and Chlamydia pneumoniae HSP60 was synthesized for comparative recognition by the sera from patients with atherosclerosis, type 2 diabetes and rheumatoid arthritis, all with ongoing periodontal disease, and by the sera of a control group of patients with periodontal disease but with no history of atherosclerosis, type 2 diabetes or rheumatoid arthritis. RESULTS: Of the Pep19 peptides from P. gingivalis HSP60, M. tuberculosis HSP60 and C. pneumoniae HSP60, Pep19 from P. gingivalis HSP60 was the peptide epitope predominantly and most consistently recognized by the serum samples of the four disease groups (chronic periodontitis, atherosclerosis, type 2 diabetes mellitus and rheumatoid arthritis). CONCLUSION: Seroreactivity to Pep19 of P. gingivalis HSP60, an oral pathogen, was predominant in patients with autoimmune disease with ongoing periodontal disease. PMID- 22812431 TI - Adiponectin and osteocalcin: relation to insulin sensitivity. AB - Obesity and osteoporosis have grave consequences for human health, quality of life, and even the efficiency of the labor force. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. Recent findings show that high adipocyte count in bone marrow is directly related to bone loss, as fat cells replace osteoblasts resulting in reduced bone mineral density and increased propensity towards osteoporosis. This close relationship has a positive aspect, whereby higher osteocalcin levels results in increased adiponectin production while the presence of adiponectin influences osteoblast proliferation and differentiation in a positive way. We focus on how osteoblasts and adipocytes affect each other and ultimately insulin resistance through the hormones they produce. This approach to whole animal physiology is the main stay of Alternative Medicine. It is assumed that the body is linked together intricately, and treating one is equal to treating the whole body. As we go further into bone and adipocytes physiology, it is evident that these organs affect each other. Therefore, elucidation on the actions of fat on bone and vice versa will unravel the complex mechanism of insulin resistance. PMID- 22812432 TI - Lewis acid catalyzed alpha-functionalization of ketals for the regioselective synthesis of alpha-carbamoyl ketals. AB - Treatment of 1 with DEAD in the presence of BF(3).OEt(2) gave 2 (R = H), which was N-alkylated to give 2 (R = CH(2)CO(2)Et), and insitu eliminated (E1cb) to give alpha-carbamoyl ketals. PMID- 22812433 TI - 1H NMR probe for in situ monitoring of dopamine metabolism and its application to inhibitor screening. AB - Dopamine (DA) is a monoamine neurotransmitter that plays important roles in the brain, and whose levels in the brain are associated with several neurological and psychiatric disorders. Therefore, DA metabolism inhibitors have been used as therapeutic agents. Here, we report a (1)H NMR probe for the in situ analysis of DA metabolism, and its application to DA inhibitor screening. We designed doubly (13)C-labeled DA ((13)C(2)-DA) as the probe. The combination of the (13)C(2)-DA and (1)H-{(13)C-(13)C'} NMR technique allowed the selective and thus in situ monitoring of DA metabolism. Using (13)C(2)-DA, we successfully measured the efficacies of different inhibitors in a tissue sample, allowing us to improve the in situ inhibitory efficacy of the known DA metabolism inhibitor, clorgyline. PMID- 22812434 TI - Winter season temperature drops and sulfur dioxide levels affect on exacerbation of refractory asthma in South Korea: a time-trend controlled case-crossover study using soonchunhyang asthma cohort data. AB - OBJECTIVE: According to the American Thoracic Society, approximately 5% of all asthmatics have refractory asthma (RA); these patients fail to recover lost lung function even after long-term treatment with high doses of medications. METHODS: Using a time-trend controlled case-crossover study design, we calculated odds ratios to evaluate whether exposure to ambient air pollutants and certain meteorological conditions on the day of admission (Lag 0) and up to 3 days before admission (Lag1 through Lag 3) were associated with acute RA exacerbation. Results were obtained after controlling for the effects of seasonality, smoking, and allergen sensitivity; we stratified our data into four seasons with respect to the median temperature of each month and further stratified them according to self-reported smoking status and skin-prick test results. RESULTS: In our study, RA patients (n = 82), living in metropolitan city of Seoul and Kyunggi Province, accounted for 3.7% of all asthmatics (n = 2298) registered in our asthma cohort between 2005 and 2009. In winter, a 1 degrees C decrease in ambient temperature and a 1 ppb increase in sulfur dioxide concentration on the day of Lag 1 were associated with 14.8% (95% confidence interval [CI]: 0.9-26.7) and 19.7% (95% CI: 3.3-38.7) increases in the risk of RA exacerbation among nonsmokers, respectively. Similar associations were obtained on the day of Lag 2. The association remained unchanged after excluding patients sensitive to Dermatophagoides farinae and Dermatophagoides pteronyssinus. CONCLUSIONS: Exposure to temperature drops and increased sulfur dioxide concentrations are positively associated with the occurrence of acute RA exacerbation during winter with 1 or 2 day lags. PMID- 22812435 TI - Dioxygen oxidation Cu(II) -> Cu(III) in the copper complex of cyclo(Lys-dHis betaAla-His): a case study by EXAFS and XANES approach. AB - A former spectroscopic study of Cu(II) coordination by the 13-membered ring cyclic tetrapeptide c(Lys-dHis-betaAla-His) (DK13), revealed the presence, at alkaline pH, of a stable peptide/Cu(III) complex formed in solution by atmospheric dioxygen oxidation. To understand the nature of this coordination compound and to investigate the role of the His residues in the Cu(III) species formation, Cu K-edge XANES, and EXAFS spectra have been collected for DK13 and two other 13-membered cyclo-peptides: the diastereoisomer c(Lys-His-betaAla-His) (LK13), and c(Gly-betaAla-Gly-Lys) (GK13), devoid of His residues. Comparison of pre-edge peak features with those of Cu model compounds, allowed us to get information on copper oxidation state in two of the three peptides, DK13 and GK13: DK13 contains only Cu(III) ions in the experimental conditions, while GK13 binds only with Cu(II). For LK13/Cu complex, EXAFS spectrum suggested and UV-vis analysis confirmed the presence of a mixture of Cu(II) and Cu(III) coordinated species. Theoretical XANES spectra have been calculated by means of the MXAN code. The good agreement between theoretical and experimental XANES data collected for DK13, suggests that the refined structure, at least in the first coordination shell around Cu, is a good approximation of the DK13/Cu(III) coordination species present at strongly alkaline pH. All the data are consistent with a slightly distorted pyramidal CuN(4) unit, coming from the peptide bonds. Surprisingly, the His side-chains seemed not involved in the final, stable, Cu(III) scaffold. PMID- 22812436 TI - A systematic review of methods for tissue analysis in animal studies on orthodontic mini-implants. AB - Anchorage devices are increasingly used in orthodontics, and their clinical performance is directly dependent on the tissue response to these devices. This study aims to identify assessment parameters for evaluating tissue reactions around orthodontically loaded implants and to propose parameters to be included in a standardized method. Several electronic databases (PubMed, ScienceDirect, the Cochrane database) were explored for papers from January 1999 to December 2009. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was used as a guideline for the methodology of systematic reviews. Twenty-five publications were selected from 123 potentially relevant abstracts. The selected studies mainly aimed to answer a clinical question and particularly the ability of immediate loading in orthodontics. Very few studies aimed to understand the healing mechanism around the devices leading to a lack of information on this topic. The most frequent combination of assessment methods was clinical evaluation, histology/histomorphometry and intravital bone labeling. Although the dog model is mainly used, pigs represent an interesting animal model, especially when studying devices in growing bone. Despite the extensive use of miniscrews in growing individuals, only few studies have included young subjects in their protocol. Moreover, in such studies, an oral hygiene program is absolutely necessary to avoid complications. Finite element analysis could improve the knowledge of the relationship between design and bone reaction; unfortunately, this elaborated method is complex and impossible to perform routinely. For standardization, the authors recommend to include specific criteria in study protocols when assessing tissue response to orthodontically loaded devices. PMID- 22812437 TI - The mouse palate and its cellular responses to midpalatal suture expansion forces. AB - OBJECTIVES: To investigate the anatomy of the mouse palate, the midpalatal suture, and the cellular characteristics in the sutures before and immediately after midpalatal suture expansion. MATERIALS AND METHODS: Wild-type C57BL/6 male mice, aged between 6 weeks and 12 months, were chosen for all the experiments. The complete palate of the non-operated group and the midpalatal suture-expanded group at different ages was used for histological, micro-CT, immunohistochemistry, and sutural cell analyses. RESULTS: This study documents precise morphological and histological characteristics of the mouse palatal sutures. In addition to the opening of the midpalatal suture caused by expansion, both transverse and interpalatine sutures were also seen to be affected. Cellular density was decreased in different types of sutures following the application of mechanical force. CONCLUSIONS: The detailed morphology and histology of the mouse palate and the cellular changes that occur following midpalatal suture expansion, as described here, will be helpful as a basis for further investigations of palatal suture tissue responses to mechanical force. PMID- 22812438 TI - Transverse changes determined by rapid and slow maxillary expansion--a low-dose CT-based randomized controlled trial. AB - OBJECTIVES: To compare transverse skeletal changes produced by rapid (RME) and slow (SME) maxillary expansion using low-dose computed tomography. The null hypothesis was that SME and RME are equally effective in producing skeletal maxillary expansion in patients with posterior crossbite. SETTING AND SAMPLE POPULATION: This study was carried out at the Department of Oral Sciences, University of Naples Federico II, Italy. Twelve patients (seven males, five females, mean age +/- SD: 10.3 +/- 2.5 years) were allocated to the SME group and 14 patients (six males, eight females, mean age +/- SD: 9.7 +/- 1.5 years) to the RME group. MATERIALS AND METHODS: All patients received a two-band palatal expander and were randomly allocated to either RME or SME. Low-dose computed tomography was used to identify skeletal and dental landmarks and to measure transverse maxillary changes with treatment. RESULTS: A significant increase in skeletal transverse diameters was found in both SME and RME groups (anterior expansion = 2.2 +/- 1.4 mm, posterior expansion = 2.2 +/- 0.9 mm, pterygoid expansion = 0.9 +/- 0.8 mm). No significant differences were found between groups at anterior (SME = 1.9 +/- 1.3 mm; RME = 2.5 +/- 1.5 mm) or posterior (SME = 1.9 +/- 1.0 mm; RME = 2.4 +/- 0.9 mm) locations, while a statistically significant difference was measured at the pterygoid processes (SME = 0.6 +/- 0.6 mm; RME = 1.2 +/- 0.9 mm, p = 0.04), which was not clinically relevant. CONCLUSION: Rapid maxillary expansion is not more effective than SME in expanding the maxilla in patients with posterior crossbite. PMID- 22812439 TI - The influence of malocclusion on the diagnostic value of the orthopantomogram in the maxillary labial segment. AB - OBJECTIVE: To investigate the effect of malocclusion and incisor inclination on the diagnostic value of the orthopantomogram in the maxillary labial segment. SETTING: The Department of Orthodontics at The Royal London Hospital. MATERIAL AND METHOD: A literature review identified seven key features of an ideal radiograph of the upper labial segment. This provided the 'Gold Standard'. Four previously extracted maxillary incisors were set-up with a complementary acrylic dentition in a dry human skull. The maxillary base was modified to facilitate the movement of the upper jaw to simulate a total of nine malocclusions, based on skeletal I, II with III patterns with varying upper incisor inclination. A lateral cephalogram was taken to quantify the upper incisor inclination. An orthopantomogram (OPG), upper standard occlusal (USO) and four long-cone periapical radiographs (PA) were also taken. Each radiograph was scored against the Gold Standard. In addition, a clinical audit involving 100 new orthodontic patients was carried out to determine whether in vivo findings mirrored the in vitro results. RESULTS: The orthopantomogram provides low levels of diagnostic value in the maxillary incisor region. The diagnostic value for the skeletal I skull set-up ranged from 57 per cent for the OPG, 71 per cent for the USO and 86 per cent for the PA view. CONCLUSION: The orthopantomogram showed poor diagnostic value in relation to the upper incisor teeth. Long-cone periapicals are recommended as the supplementary view of choice in the maxillary incisor region. PMID- 22812440 TI - The effect of chewing gum on the impact, pain and breakages associated with fixed orthodontic appliances: a randomized clinical trial. AB - OBJECTIVES: To determine whether the use of chewing gum reduced the impact and pain of fixed orthodontic appliances. SETTING AND SAMPLE POPULATION: The Orthodontic Department of the Charles Clifford Dental Hospital, Sheffield, UK. Fifty-seven patients aged 18 years or younger and who were about to start fixed orthodontic appliance treatment. SUBJECTS AND METHODS: A randomized clinical trial with two parallel groups either allocated to receive chewing gum after placement of their appliance or who were asked not to chew gum. The patients completed a previously validated Impact of Fixed Appliances questionnaire at 24 h and 1 week following each visit up until the placement of the working archwire. A visual analogue scale (VAS) was used to assess the intensity of pain. Appliance breakages were recorded to the end of treatment. RESULTS: The difference between the median Total Impact Score of the two groups at 24 h was 16, which was significant (p = 0.031; Mann-Whitney U-test). The difference between the median VAS between the two groups at 24 h was 25 mm, which was significant (p = 0.038; Mann-Whitney U-test). There were no differences at 1 week. None of the risk ratios for appliance breakages were significant. CONCLUSION: Chewing gum significantly decreased both the impact and pain from the fixed appliances. There was no evidence that chewing gum increased the incidence of appliance breakages. PMID- 22812441 TI - New insights on age-related association between nasopharyngeal airway clearance and facial morphology. AB - OBJECTIVES: To evaluate the relation between adenoid hypertrophy and facial morphology across age in a pediatric population. SETTING AND SAMPLE POPULATION: The American University of Beirut Department of Otolaryngology. Two-hundred consecutive children (age 6.00 +/- 2.62 years) referred from the Pediatric Otolaryngology unit to the Orthodontic division and requiring a lateral cephalogram for adenoid hypertrophy assessment. METHODS: Cephalometric measurements included relations among cranial base, maxilla and mandible, and airway clearance measured from adenoid to soft palate (AD). The children were classified into two age groups, Group 1: <= 6 years (n = 124) and Group 2: >= 6.01 years (n = 76), and also stratified in four subgroups (A, B, C, D) based on maxillo-mandibular divergence (palatal to mandibular plane angle, PP-MP): A- PP MP <= 27.5 degrees , n = 34; B- 27.5 degrees < PP-MP <= 32 degrees , n = 68; C- 32 degrees = 36.5 degrees , n = 31. Statistics included t-tests and anova for group differences. RESULTS: Differences between groups 1 and 2 were statistically significant (p < 0.05) for AD (Group 1: 3.19 +/- 2.32 mm, Group 2: 4.78 +/- 2.80 mm), ANB (5.38 +/- 2.24 degrees , 4.38 +/- 2.54 degrees ), LFH (56.61 +/- 1.95%, 55.38 +/- 1.84%), PP-H ( 8.41 +/- 3.28 degrees , -6.49 +/- 3.46 degrees ), and overbite (0.55 +/- 2.00 mm, 1.16 +/- 2.36 mm). Among subgroups, statistically significant differences (p < 0.05) occurred mainly between the most hyperdivergent group (D) and the hypodivergent (A) and normodivergent (B) groups. CONCLUSIONS: Airway measurements were smallest in children <= 6 years and those presenting severe hyperdivergent pattern, which denoted the most severe airway obstruction. The findings suggest airway clearance before age 6 in the most severely affected children, but follow up research on actual adenoidectomies in younger children is needed to determine guidelines. PMID- 22812442 TI - Pre-treatment radiographic features predict root resorption of treated impacted maxillary central incisors. AB - OBJECTIVES: To determine independent predictors of root resorption for surgical orthodontic treatment of impacted maxillary central incisors. SETTING AND SAMPLE POPULATION: The Department of Dentistry at Show Chwan Hospital, Changhua, Taiwan. Eighty patients with unilateral osseous-impacted maxillary central incisors receiving a surgical-orthodontic treatment. MATERIAL AND METHODS: This is a retrospective observational study. Root resorption and its predictors were abstracted from patients' charts, pre-treatment cephalometric radiographs, and post-treatment periapical radiographs. Predictors included demographics, treatment duration, crown angle, crown height, crown depth, and root dilacerations. RESULTS: The patients' mean age was 9.2 +/- 2.3 years (6.4-20.6 years), and 60% were females. Impacted maxillary central incisors had greater root resorption than naturally erupted contralateral incisors (Delta = -2.8 mm, p < 0.001). Independent predictors of root resorption for impacted maxillary central incisors were shown by linear regression analysis to be crown height (beta = -0.2, p < 0.01), crown depth (beta = -0.3, p = 0.001), treatment duration (beta = 0.2, p < 0.01), and root dilacerations (beta = 3.1, p = 0.001). CONCLUSIONS: Impacted maxillary central incisors had greater root resorption during surgical-orthodontic treatment than their naturally erupted contralateral incisors. Predictors of a greater root resorption were highly and deeply impacted incisors, longer treatment, and root dilacerations. These predictors may help to inform patient and family counseling before treatment. PMID- 22812443 TI - Non-pathogenic rhizobacteria interfere with the attraction of parasitoids to aphid-induced plant volatiles via jasmonic acid signalling. AB - Beneficial soil-borne microbes, such as mycorrhizal fungi or rhizobacteria, can affect the interactions of plants with aboveground insects at several trophic levels. While the mechanisms of interactions with herbivorous insects, that is, the second trophic level, are starting to be understood, it remains unknown how plants mediate the interactions between soil microbes and carnivorous insects, that is, the third trophic level. Using Arabidopsis thaliana Col-0 and the aphid Myzus persicae, we evaluate here the underlying mechanisms involved in the plant mediated interaction between the non-pathogenic rhizobacterium Pseudomonas fluorescens and the parasitoid Diaeretiella rapae, by combining ecological, chemical and molecular approaches. Rhizobacterial colonization modifies the composition of the blend of herbivore-induced plant volatiles. The volatile blend from rhizobacteria-treated aphid-infested plants is less attractive to an aphid parasitoid, in terms of both olfactory preference behaviour and oviposition, than the volatile blend from aphid-infested plants without rhizobacteria. Importantly, the effect of rhizobacteria on both the emission of herbivore-induced volatiles and parasitoid response to aphid-infested plants is lost in an Arabidopsis mutant (aos/dde2-2) that is impaired in jasmonic acid production. By modifying the blend of herbivore-induced plant volatiles that depend on the jasmonic acid-signalling pathway, root-colonizing microbes interfere with the attraction of parasitoids of leaf herbivores. PMID- 22812444 TI - Synthesis and evaluation of a peptide targeted small molecular Gd-DOTA monoamide conjugate for MR molecular imaging of prostate cancer. AB - Tumor extracellular matrix has an abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. Innovative design and development of safe and effective targeted contrast agents to these biomarkers would allow effective MR cancer molecular imaging with high spatial resolution. In this study, we synthesized a low molecular weight CLT1 peptide targeted Gd(III) chelate CLT1-dL-(Gd-DOTA)(4) specific to clotted plasma proteins in tumor stroma for cancer MR molecular imaging. CLT1-dL-(Gd-DOTA)(4) was synthesized by conjugating four Gd-DOTA monoamide chelates to a CLT1 peptide via generation 1 lysine dendrimer. The T(1) relaxivity of CLT1-dL-(Gd-DOTA)(4) was 40.4 mM(-1) s( 1) per molecule (10.1 mM(-1) s(-1) per Gd) at 37 degrees C and 1.5 T. Fluorescence imaging showed high binding specificity of CLT1 to orthotopic PC3 prostate tumor in mice. The contrast agent resulted in improved tumor contrast enhancement in male athymic nude mice bearing orthotopic PC3 prostate tumor xenograft at a dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for high-resolution MR molecular imaging of prostate tumor. PMID- 22812445 TI - Fludarabine, cytarabine, granulocyte-colony stimulating factor and amsacrine: an effective salvage therapy option for acute myeloid leukemia at first relapse. AB - Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18-70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (>= 60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (<6 months). We conclude that FLAG-amsacrine is a useful salvage option for AML at first relapse. PMID- 22812446 TI - Superb adsorption capacity and mechanism of flowerlike magnesium oxide nanostructures for lead and cadmium ions. AB - A facile method based on microwave-assisted solvothermal process has been developed to synthesize flowerlike MgO precursors, which were then transformed to MgO by simple calcinations. All the chemicals used (magnesium nitrate, urea, and ethanol) were low cost and environmentally benign. The products were characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, high-resolution TEM, and N(2) adsorption desorption methods. These flowerlike MgO nanostructures had high surface area and showed superb adsorption properties for Pb(II) and Cd(II), with maximum capacities of 1980 mg/g and 1500 mg/g, respectively. All these values are significantly higher than those reported on other nanomaterials. A new adsorption mechanism involving solid-liquid interfacial cation exchange between magnesium and lead or cadmium cations was proposed and confirmed. PMID- 22812447 TI - Vasculitic emergencies in the intensive care unit: a special focus on cryoglobulinemic vasculitis. AB - Vasculitis is characterized by the infiltration of vessel walls by inflammatory leukocytes with reactive damage and subsequent loss of vessel integrity. The clinical course of systemic vasculitis may be punctuated by acute life threatening manifestations that require intensive care unit (ICU) admission. Furthermore, the diagnosis may be established in the ICU after admission for a severe inaugural symptom, mostly acute respiratory failure. Among the systemic vasculitides, cryoglobulinemic vasculitis (CV) has been rarely studied in an ICU setting. Severe CV-related complications may involve the kidneys, lungs, heart, gut, and/or central nervous system. The diagnosis of CV in the ICU may be delayed or completely unrecognized. A high level of suspicion is critical to obtain a timely and accurate diagnosis and to initiate appropriate treatment. We describe severe acute manifestations of CV based on six selected patients admitted to our ICU. That all six patients survived suggests the benefit of prompt ICU admission of patients with severe CV. PMID- 22812448 TI - Introducing Cichorium Pumilum as a potential therapeutical agent against drug induced benign breast tumor in rats. AB - Cichorium Pumilum (chicory) is could be a promising cancer treatment in which a photosensitizing drug concentrates in benign tumor cells and activated by quanta at certain wavelength. Such activated extracts could lead to cell death and tumor ablation. Previous studies have shown that Cichorium Pumilum (chicory) contains photosensitive compounds such as cichoriin, anthocyanins, lactucin, and Lactucopicrin. In the present study, the protective effect of sun light-activated Cichorium against the dimethylbenz[a]anthracene (DMBA) induced benign breast tumors to female Sprague-Dawley rats was investigated. Chicory's extract has significantly increase P.carbonyl (PC) and malondialdehyde (MDA) and decreases the hepatic levels of total antioxidant capacity (TAC) and superoxide dismutase (SOD) in benign breast tumors-induced group compared to control. It also significantly decrease the number of estrogen receptors ER-positive cells in tumor masses. These results suggest that chicory extracts could be used as herbal photosensitizing agent in treating benign breast tumor in rats. PMID- 22812449 TI - Age matters: differential impact of service quality on contraceptive uptake among post-abortion clients in Kenya. AB - This paper analyses the impact of high quality, user-friendly, comprehensive sliding-scale post-abortion services on clients' uptake of contraception in a Kenyan town. Data were drawn from detailed physician records in a private clinic that served 1080 post-abortion clients in 2006. All clients received confidential family planning counselling and were offered a complete range of contraceptives at no additional cost. One quarter of clients were below age 19. Prior to the abortion, no client aged 10-18 years reported having used contraception, as compared to 60% of clients aged 27-46 years. After the abortion and family planning counselling session, only 6% of clients aged 10-18 chose a method, as compared to 96% of clients aged 27-46, even though contraception was free, the provider strongly promoted family planning to everyone and all clients had just experienced an unwanted pregnancy. Significant predictors of contraceptive uptake post-abortion were: having a child, a previous termination, prior contraceptive use and being older than 21. These findings suggest that availability, affordability and youth-friendliness are not sufficient to overcome psycho-social barriers to contraceptive use for sexually-active young people in Kenya. To reduce unwanted pregnancies, more attention may be needed to developing youth friendly communities that support responsible sexuality among adolescents. PMID- 22812451 TI - Principles and applications of selective biophysical methods for characterization and comparability assessment of a monoclonal antibody. AB - The strategy for a comparability assessment is developed on a hierarchical risk based approach. Critical analysis of physicochemical and biological characterization assays is essential for the development of a good comparability protocol. Therefore, selection and sensitivity of these assays is very important. This article discusses a case study to evaluate the sensitivity of various methods in a comparability assessment of three lots of an IgG1 monoclonal antibody (mAb). Analysis with eighteen methods demonstrated that only six of the methods were sensitive enough to show a measurable difference of comparability under accelerated conditions (40 degrees C). Samples stored at 4 degrees C were found to be comparable by all methods. A brief comparison of the results of biochemical and functional assays with biophysical analysis is discussed. Basic principles, applications, strength, and limitations of different biophysical methods are also discussed here. PMID- 22812450 TI - The TransEurope FootRace Project: longitudinal data acquisition in a cluster randomized mobile MRI observational cohort study on 44 endurance runners at a 64 stage 4,486 km transcontinental ultramarathon. AB - BACKGROUND: The TransEurope FootRace 2009 (TEFR09) was one of the longest transcontinental ultramarathons with an extreme endurance physical load of running nearly 4,500 km in 64 days. The aim of this study was to assess the wide spectrum of adaptive responses in humans regarding the different tissues, organs and functional systems being exposed to such chronic physical endurance load with limited time for regeneration and resulting negative energy balance. A detailed description of the TEFR project and its implemented measuring methods in relation to the hypotheses are presented. METHODS: The most important research tool was a 1.5 Tesla magnetic resonance imaging (MRI) scanner mounted on a mobile unit following the ultra runners from stage to stage each day. Forty-four study volunteers (67% of the participants) were cluster randomized into two groups for MRI measurements (22 subjects each) according to the project protocol with its different research modules: musculoskeletal system, brain and pain perception, cardiovascular system, body composition, and oxidative stress and inflammation. Complementary to the diverse daily mobile MR-measurements on different topics (muscle and joint MRI, T2*-mapping of cartilage, MR-spectroscopy of muscles, functional MRI of the brain, cardiac and vascular cine MRI, whole body MRI) other methods were also used: ice-water pain test, psychometric questionnaires, bioelectrical impedance analysis (BIA), skinfold thickness and limb circumference measurements, daily urine samples, periodic blood samples and electrocardiograms (ECG). RESULTS: Thirty volunteers (68%) reached the finish line at North Cape. The mean total race speed was 8.35 km/hour. Finishers invested 552 hours in total. The completion rate for planned MRI investigations was more than 95%: 741 MR-examinations with 2,637 MRI sequences (more than 200,000 picture data), 5,720 urine samples, 244 blood samples, 205 ECG, 1,018 BIA, 539 anthropological measurements and 150 psychological questionnaires. CONCLUSIONS: This study demonstrates the feasibility of conducting a trial based centrally on mobile MR measurements which were performed during ten weeks while crossing an entire continent. This article is the reference for contemporary result reports on the different scientific topics of the TEFR project, which may reveal additional new knowledge on the physiological and pathological processes of the functional systems on the organ, cellular and sub-cellular level at the limits of stress and strain of the human body. Please see related articles: http://www.biomedcentral.com/1741-7015/10/76 and http://www.biomedcentral.com/1741-7015/10/77. PMID- 22812452 TI - The Nla6S protein of Myxococcus xanthus is the prototype for a new family of bacterial histidine kinases. AB - Myxococcus xanthus has a large number of histidine kinase (HK) signal transduction proteins and many of these HKs are important for fruiting body development. Nla6S is an uncharacterized HK that lacks many of the conserved sequence motifs of typical HK proteins. In this study, we report that expression of the nla6S gene increases about sixfold during fruiting body development, that the Nla6S protein has the in vitro properties of HKs and that Nla6S is the prototype for a new family of HKs. To date, these Nla6-like HKs are found only in fruiting members of the Cystobacterineae suborder of the myxobacteria. PMID- 22812454 TI - Superomniphobic magnetic microtextures with remote wetting control. AB - Universal remote control of wetting behavior enabling the transition from a superomniphobic to an omniphilic wetting state in an external magnetic field via the alternation of reentrant curvature of a microstructured surface is demonstrated. This reconfigurable microtexture made of Ni micronails repels water, water-surfactant solutions, and practically all organic liquids, whereas it gets wetted by all of these liquids after a magnetic field pulse is applied. PMID- 22812453 TI - Glucocorticoid receptor mRNA and protein isoform alterations in the orbitofrontal cortex in schizophrenia and bipolar disorder. AB - BACKGROUND: The orbitofrontal cortex (OFC) may play a role in the pathogenesis of psychiatric illnesses such as bipolar disorder and schizophrenia, in which hypothalamic-pituitary-adrenal (HPA) axis abnormalities are observed and stress has been implicated. A critical component of the HPA axis which mediates cellular stress responses in the OFC, and has been implicated in psychiatric illness, is the glucocorticoid receptor (GR). METHODS: In the lateral OFC, we employed quantitative real-time PCR and western blotting to investigate GR mRNA and protein expression in 34 bipolar disorder cases, 35 schizophrenia cases and 35 controls. Genotype data for eleven GR gene (NR3C1) polymorphisms was also used to explore possible effects of NR3C1 sequence variation on GR mRNA and protein expression in the lateral OFC. RESULTS: We found no diagnostic differences in pan GR, GR-1C or GR-1F mRNA expression. However, the GR-1B mRNA transcript variant was decreased (14.3%) in bipolar disorder cases relative to controls (p < 0.05), while GR-1H mRNA was decreased (22.0%) in schizophrenia cases relative to controls (p < 0.005). By western blotting, there were significant increases in abundance of a truncated GRalpha isoform, putative GRalpha-D1, in bipolar disorder (56.1%, p < 0.005) and schizophrenia (31.5% p < 0.05). Using genotype data for eleven NR3C1 polymorphisms, we found no evidence of effects of NR3C1 genotype on GR mRNA or GRalpha protein expression in the OFC. CONCLUSIONS: These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously. Our results suggest that the GRalpha-D1 protein isoform may be up regulated widely across the frontal cortex in psychiatric illness. PMID- 22812455 TI - The coming of age of the LeuO regulator. AB - LeuO is a quiescent genetic regulator present in many bacteria, which forms part of the H-NS regulon. LeuO in turn has been proposed to activate a subset of genes of the regulon by antagonizing H-NS. In the paper by Dillon et al., binding of LeuO to the S. Typhimurium genome was observed by ChIP-chip to some of the previously described LeuO-regulated genes, upon growth under stress conditions. However, studies at a higher LeuO concentration from a cloned inducible promoter rendered many more binding sites, pointing towards the importance of the abundance of the regulator in the cell, in a given moment. Binding of LeuO was observed not only to intergenic sequences, but in the majority of cases to intragenic sequences, and co-binding was observed with H-NS in many sites and with RNA polymerase to the majority of sites. The authors define a binding motif that allowed the detection of several other LeuO-regulated genes that were not detected by ChIP-chip, which were possibly missed because LeuO binds and bridges distal sites, in those instances. The observations reported open new questions regarding the mode of action for LeuO. PMID- 22812457 TI - Use of plerixafor in patients with Hodgkin lymphoma with poor mobilization of peripheral blood stem cells. PMID- 22812456 TI - Antibacterial effects of blackberry extract target periodontopathogens. AB - BACKGROUND AND OBJECTIVE: Antimicrobial agents provide valuable adjunctive therapy for the prevention and the control of oral diseases. Limitations in their prolonged use have stimulated the search for new, naturally occurring agents with more specific activity and fewer adverse effects. Here we sought to determine the antibacterial properties of blackberry extract (BBE) in vitro against oral bacterial commensals and periodontopathogens. MATERIAL AND METHODS: The effects of whole and fractionated BBE on the metabolism of 10 different oral bacteria were evaluated using the colorimetric water-soluble tetrazolium-1 assay. The bactericidal effects of whole BBE against Fusobacterium nucleatum were determined by quantitating the numbers of colony-forming units (CFUs). Cytotoxicity was determined in oral epithelial (OKF6) cells. RESULTS: BBE at 350-1400 MUg/mL reduced the metabolic activity of Porphyromonas gingivalis, F. nucleatum and Streptococcus mutans. The reduced metabolic activity observed for F. nucleatum corresponded to a reduction in the numbers of CFUs following exposure to BBE for as little as 1 h, indicative of its bactericidal properties. An anthocyanin enriched fraction of BBE reduced the metabolic activity of F. nucleatum, but not of P. gingivalis or S. mutans, suggesting the contribution of species-specific agents in the whole BBE. Oral epithelial cell viability was not reduced following exposure to whole BBE (2.24-1400 MUg/mL) for <= 6 h. CONCLUSION: BBE alters the metabolic activity of oral periodontopathogens while demonstrating a minimal effect on commensals. The specific antibacterial properties of BBE shown in this study, along with its previously demonstrated anti-inflammatory and antiviral properties, make this natural extract a promising target as an adjunct for prevention and/or complementary therapy of periodontal infections. PMID- 22812458 TI - Drought resistance in early and late secondary successional species from a tropical dry forest: the interplay between xylem resistance to embolism, sapwood water storage and leaf shedding. AB - The mechanisms of drought resistance that allow plants to successfully establish at different stages of secondary succession in tropical dry forests are not well understood. We characterized mechanisms of drought resistance in early and late successional species and tested whether risk of drought differs across sites at different successional stages, and whether early and late-successional species differ in resistance to experimentally imposed soil drought. The microenvironment in early successional sites was warmer and drier than in mature forest. Nevertheless, successional groups did not differ in resistance to soil drought. Late-successional species resisted drought through two independent mechanisms: high resistance of xylem to embolism, or reliance on high stem water storage capacity. High sapwood water reserves delayed the effects of soil drying by transiently decoupling plant and soil water status. Resistance to soil drought resulted from the interplay between variations in xylem vulnerability to embolism, reliance on sapwood water reserves and leaf area reduction, leading to a tradeoff of avoidance against tolerance of soil drought, along which successional groups were not differentiated. Overall, our data suggest that ranking species' performance under soil drought based solely on xylem resistance to embolism may be misleading, especially for species with high sapwood water storage capacity. PMID- 22812460 TI - Synthesis of Enantiopure tertiary skipped diynes via one-pot desymmetrizing TMS cleavage. AB - Enantiopure tetrasubstituted skipped diynes were readily synthesized from N protected amino esters upon addition of lithium TMS-acetylide which was found to be desymmetrizing through one-pot selective TMS-cleavage. The deprotection of the TMS group was realized through a one-pot silicon atom attack by the liberated methoxide, which was diastereoselective due to a conformational favorable chelate. PMID- 22812459 TI - Degradation of different pectins by fungi: correlations and contrasts between the pectinolytic enzyme sets identified in genomes and the growth on pectins of different origin. AB - BACKGROUND: Pectins are diverse and very complex biomolecules and their structure depends on the plant species and tissue. It was previously shown that derivatives of pectic polymers and oligosaccharides from pectins have positive effects on human health. To obtain specific pectic oligosaccharides, highly defined enzymatic mixes are required. Filamentous fungi are specialized in plant cell wall degradation and some produce a broad range of pectinases. They may therefore shed light on the enzyme mixes needed for partial hydrolysis. RESULTS: The growth profiles of 12 fungi on four pectins and four structural elements of pectins show that the presence/absence of pectinolytic genes in the fungal genome clearly correlates with their ability to degrade pectins. However, this correlation is less clear when we zoom in to the pectic structural elements. CONCLUSIONS: This study highlights the complexity of the mechanisms involved in fungal degradation of complex carbon sources such as pectins. Mining genomes and comparative genomics are promising first steps towards the production of specific pectinolytic fractions. PMID- 22812462 TI - The bovine athlete: sport showcases bucking-bull prowess, veterinary ingenuity. PMID- 22812463 TI - Limitations in veterinary workforce outlook predictions. PMID- 22812464 TI - Everyday leadership: make your mark. PMID- 22812465 TI - What is your diagnosis? Actinobacillus pleuropneumonia. PMID- 22812466 TI - What is your diagnosis? Abdominal adhesion. PMID- 22812467 TI - Diagnostic imaging in veterinary dental practice. PMID- 22812468 TI - Pathology in practice. Leiomyosarcoma. PMID- 22812469 TI - Enteropathogens identified in cats entering a Florida animal shelter with normal feces or diarrhea. AB - OBJECTIVE: To determine the frequency of enteropathogens in cats entering an animal shelter with normal feces or diarrhea. DESIGN: Cross-sectional study. ANIMALS: 100 cats evaluated at an open-admission municipal animal shelter in Florida. PROCEDURES: Fecal samples collected within 24 hours after admission from 50 cats with normal feces and 50 cats with diarrhea were tested by fecal flotation, antigen testing, PCR assay, and electron microscopy for selected enteropathogens. RESULTS: 12 enteropathogens were identified. Cats with diarrhea were no more likely to be infected with >= 1 (84%) enteropathogens than were cats with normal feces (84%). Only feline coronavirus was significantly more prevalent in cats with diarrhea (58%) than in cats with normal feces (36%). Other enteropathogens identified in cats with and without diarrhea included Clostridium perfringens enterotoxin A (42% and 50%, respectively), Cryptosporidium spp (10% and 20%, respectively), Giardia spp (20% and 8%, respectively), Cystoisospora spp (14% and 10%, respectively), hookworms (10% and 18%, respectively), ascarids (6% and 16%, respectively), Salmonella spp (6% and 4%, respectively), astrovirus (8% and 2%, respectively), feline panleukopenia virus (4% and 4%, respectively), calicivirus (0% and 2%, respectively), and Spirometra spp (0% and 2%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: In the present study, cats entered the shelter with a variety of enteropathogens, many of which are pathogenic or zoonotic. Most infections were not associated with diarrhea or any specific risk factors such as signalment, source, or body condition, making it difficult to predict which cats were most likely to be infected. It is not possible to test all shelter cats for all possible infections, so practical guidelines should be developed to treat routinely for the most common and important enteropathogens. PMID- 22812471 TI - Frequency of vomiting during the postoperative period in hydromorphone-treated dogs undergoing orthopedic surgery. AB - OBJECTIVE: To determine the frequency of postoperative vomiting in dogs undergoing routine orthopedic surgery that were treated with hydromorphone and whether that frequency would vary on the basis of administration route. DESIGN: Noncontrolled clinical trial. Animals-58 client-owned dogs with cranial cruciate ligament deficiency. PROCEDURES: Before surgery, all dogs received hydromorphone (0.1 mg/kg [0.045 mg/lb], IM or IV) and 41 dogs also received acepromazine. Anesthesia was induced with diazepam and propofol and maintained with isoflurane in oxygen. Dogs subsequently underwent surgical stabilization of the stifle joint. After surgery, dogs were randomly assigned to receive hydromorphone (0.1 mg/kg) via one of the following routes: IM, IV quickly (for 1 to 2 seconds), or IV slowly (for approx 1 minute). Dogs were monitored for vomiting. RESULTS: A median of 4 doses of hydromorphone/dog was administered after surgery. One dog was observed to regurgitate once prior to postoperative IM administration of hydromorphone; no dogs vomited at any point during the study period, regardless of the method of hydromorphone administration. CONCLUSIONS AND CLINICAL RELEVANCE: The method of hydromorphone administration had no apparent effect on the likelihood of dogs vomiting. Because no dogs vomited, a particular administration method cannot be recommended. However, findings suggested that hydromorphone can be administered to dogs following orthopedic surgery without a clinically important risk of vomiting or regurgitation. PMID- 22812470 TI - Enteropathogens identified in dogs entering a Florida animal shelter with normal feces or diarrhea. AB - OBJECTIVE: To determine the frequency of enteropathogens in dogs entering an animal shelter with normal feces or diarrhea. DESIGN: Cross-sectional study. ANIMALS: 100 dogs evaluated at an open-admission municipal animal shelter in Florida. PROCEDURES: Fecal samples were collected within 24 hours after admission from 50 dogs with normal feces and 50 dogs with diarrhea. Feces were tested by fecal flotation, antigen testing, PCR assay, and electron microscopy for selected enteropathogens. RESULTS: 13 enteropathogens were identified. Dogs with diarrhea were significantly more likely to be infected with >= 1 enteropathogens (96%) than were dogs with normal feces (78%). Only Clostridium perfringens enterotoxin A gene was significantly more common in dogs with diarrhea (64%) than in dogs with normal feces (40%). Other enteropathogens identified in dogs with and without diarrhea included hookworms (58% and 48%, respectively), Giardia spp (22% and 16%, respectively), canine enteric coronavirus (2% and 18%, respectively), whipworms (12% and 8%, respectively), Cryptosporidium spp (12% and 2%, respectively), ascarids (8% and 8%, respectively), Salmonella spp (2% and 6%, respectively), Cystoisospora spp (2% and 4%, respectively), canine distemper virus (8% and 0%, respectively), Dipylidium caninum (2% and 2%, respectively), canine parvovirus (2% and 2%, respectively), and rotavirus (2% and 0%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Dogs entered the shelter with a variety of enteropathogens, many of which are pathogenic or zoonotic. Most infections were not associated with diarrhea or any specific dog characteristics, making it difficult to predict the risk of infection for individual animals. Guidelines for preventive measures and empirical treatments that are logistically and financially feasible for use in shelters should be developed for control of the most common and important enteropathogens. PMID- 22812472 TI - Use of locking-loop pigtail nephrostomy catheters in dogs and cats: 20 cases (2004-2009). AB - OBJECTIVE: To describe the procedure and clinical usefulness of locking-loop pigtail nephrostomy catheter (PNC) placement in dogs and cats. DESIGN: Retrospective case series. ANIMALS: 16 cats (18 kidneys) and 4 dogs (4 kidneys) that underwent PNC placement. PROCEDURES: Medical records of patients that underwent PNC placement were reviewed. The PNCs were placed percutaneously with ultrasonographic and fluoroscopic guidance or via a ventral midline laparotomy with fluoroscopic guidance. Either a modified Seldinger technique or a 1-stab trocar introduction technique was used for PNC placement. Preoperative renal pelvic size, postoperative renal pelvic decompression, catheter patency, serum biochemical changes, and results of microbial culture of urine samples were reviewed. Length of time the catheter was in place, reason and method for catheter removal, complications, and clinical outcomes were noted. RESULTS: Reasons for PNC placement were ureterolithiasis (15 kidneys), ureteral stricture (3), malignant obstruction (2), and percutaneous nephrolithotomy (2). Seven of 22 catheters were placed percutaneously, and 15 were placed via a ventral midline laparotomy. Catheters were either size 5F (n = 17) or 6F (5). The PNCs remained indwelling for a median of 7 days (range, 1 to 28 days). Catheter-associated complications included urine leakage (n = 1) and accidental dislodgement by the patient at home (1). All catheters performed successfully by providing temporary urine diversion and drainage for successful renal pelvis decompression. CONCLUSIONS AND CLINICAL RELEVANCE: Placement of locking-loop PNCs was safe, effective, and well tolerated in dogs and cats for temporary urine diversion to achieve renal pelvis decompression. PMID- 22812473 TI - Treatment of intestinal pythiosis in a dog with a combination of marginal excision, chemotherapy, and immunotherapy. AB - CASE DESCRIPTION: A 1.5-year-old mixed-breed dog was examined because of a 1 month history of anorexia, vomiting, diarrhea, and weight loss. CLINICAL FINDINGS: The dog was very thin on physical examination (body condition score, 3/9). Results of all diagnostic tests were within reference limits except intestinal thickening and lymphadenopathy were identified on abdominal ultrasound examination. During exploratory laparotomy, thickening at the ileocecal-colic junction and within the transverse colon and mesenteric lymphadenopathy were identified, and the ileocecal-colic junction was resected. Histopathologic evaluation of the ileocecal-colic junction and full-thickness biopsy specimens from other sites as well as results of a serum ELISA were diagnostic for gastrointestinal Pythium insidiosum infection. TREATMENT AND OUTCOME: Pythiosis was initially treated medically with administration of itraconazole and terbinafine by mouth, but the colonic lesion was progressive with this regimen. Two months after diagnosis, a subtotal colectomy was performed; marginal excision (0.6 cm) was obtained at the aboral margin. The dog was treated with 3 doses of a pythiosis vaccine beginning approximately 2 weeks after surgery and was continued on itraconazole and terbinafine for 5 months. Parenteral and enteral nutrition as well as considerable general supportive care were required postoperatively. Six months after treatment, the dog had a normal serum ELISA titer. Two years after treatment, the dog had returned to preoperative weight and was clinically normal. CLINICAL RELEVANCE: This patient had an unusually positive therapeutic response to chronic, extensive, marginally excised gastrointestinal pythiosis. PMID- 22812474 TI - Total scapulectomy for the treatment of chondrosarcoma in a cat. AB - CASE DESCRIPTION: A 10-year-old neutered male domestic shorthair cat was admitted for treatment of a mass affecting the right scapula. CLINICAL FINDINGS: A firm soft tissue mass located over the craniolateral aspect of the right scapula was evident during palpation. The mass extended close to the shoulder joint but did not cause lameness of the affected limb. TREATMENT AND OUTCOME: Examination of a biopsy specimen obtained from the mass indicated chondrosarcoma. Total scapulectomy was performed to allow wide excision of the tumor. Weight bearing on the operated limb was tolerated 12 hours after surgery. Six months after surgery, limb function was assessed and considered excellent. The owner reported that the cat had its typical amount of activity and was able to jump and play normally. No recurrence of the tumor was evident 6 months after surgery. CLINICAL RELEVANCE: On the basis of the functional outcome after surgery, total scapulectomy may be a viable limb-sparing technique for the treatment of local neoplasms in cats. Subtotal scapulectomy has been reported previously, with a good to excellent clinical outcome expected. Total scapulectomy associated with only a fair clinical outcome has been reported previously, which has led to the general recommendation that scapulectomy be performed with preservation of the shoulder joint. The information provided in this report revealed that total scapulectomy can be associated with an excellent outcome in a cat. PMID- 22812475 TI - Laparoscopic adrenalectomy for management of a functional adrenal tumor in a cat. AB - CASE DESCRIPTION: A 9-year-old castrated male domestic shorthair cat was examined because of hypertension that persisted after resolution of the patient's hyperthyroidism. Bilateral hypertensive retinopathy, a systolic heart murmur, left ventricular hypertrophy, and tachycardia were present. CLINICAL FINDINGS: Biochemical analysis revealed mild hypokalemia, normonatremia, high serum creatine kinase activity, high serum aldosterone concentration, and low plasma renin activity consistent with hyperaldosteronism. Hypercalcemia with an associated high serum parathyroid hormone concentration and an exaggerated low dose dexamethasone suppression test result were consistent with concurrent hyperparathyroidism and hyperadrenocorticism, respectively. Ultrasonographic examination revealed a markedly enlarged left adrenal gland, an abnormally small right adrenal gland, and 2 nodules in the right thyroid and parathyroid glands. TREATMENT AND OUTCOME: Laparoscopic left adrenalectomy was performed concurrently with right thyroidectomy and parathyroidectomy. Histologic evaluation revealed an adrenal cortical adenoma, thyroid adenoma, and parathyroid adenoma. The cat recovered from surgery without complications. The hypercalcemia and hypertension resolved after surgery. Follow-up echocardiography revealed improvement in the left ventricular hypertrophy. Ultrasonographic examinations performed up to 26 months after adrenalectomy showed no evidence of regrowth of the adrenal mass. The patient survived for 44 months after adrenalectomy with no signs of recurrent hyperaldosteronism or hyperadrenocorticism. CLINICAL RELEVANCE: Laparoscopic adrenalectomy may be a plausible method for the treatment of unilateral functional adrenal neoplasia in feline patients when diagnostic imaging has ruled out intravascular invasion and metastatic disease. In addition, in a feline patient with hyperthyroidism and hypertension, other endocrine glands should be investigated. PMID- 22812476 TI - An assessment of the relationship between informal caring and quality of life in older community-dwelling adults - more positives than negatives? AB - The main objective of the study was to apply the recently developed Index of Capability (ICECAP-O) instrument to measure and value the quality of life of a representative sample of the older South Australian population (aged >= 65 years) according to carer status. A Health Omnibus survey including the ICECAP-O instrument, carer status (informal carer vs. non-carer) and several socio demographic questions was administered in 2009 as a face-to-face interview to 789 individuals aged 65 years or older in their own homes. A total of 671 individuals (85%) characterised themselves as a non-carer and 115 individuals (15%) characterised themselves as an informal carer. In general, carers exhibited relatively high quality of life as measured by the ICECAP-O, with carers having comparable mean ICECAP-O scores to non-carers in the general population [carers: mean (SD) 0.848 (0.123), non-carers: mean (SD) 0.838 (0.147)]. The results of the multivariate regression model for the total sample indicated statistically significant variations in overall ICECAP-O scores according to age (with younger participants tending to have slightly higher scores on average), country of birth (with those participants who were born in Australia having higher scores on average than those who were born elsewhere) and household income (with participants with higher income levels having higher scores on average). The results of the multivariate regression model differentiated by carer status also indicated some important differences. Specifically, average ICECAP-O scores were noticeably lower for carers who are separated or divorced and for carers who lived alone and these differences were statistically significant. The study findings provide support for the existence of process utility in informal care giving. The provision of informal care may be associated with a positive impact upon quality of life for many caregivers, which may mediate the negative aspects arising from the burden associated with informal care-giving. PMID- 22812477 TI - Separation of variant methylated histone tails by differential ion mobility. AB - Differential ion mobility spectrometry (field asymmetric waveform ion mobility spectrometry (FAIMS)) is emerging as a broadly useful tool for separation of isomeric modified peptides with post-translational modifications (PTMs) attached to alternative residues. Such separations were anticipated to become more challenging for smaller PTMs and longer peptides. Here, we show that FAIMS can fully resolve localization variants involving a PTM as minuscule as methylation, even for larger peptides in the middle-down range. PMID- 22812478 TI - Lnk deficiency partially mitigates hematopoietic stem cell aging. AB - Upon aging, the number of hematopoietic stem cells (HSCs) in the bone marrow increases while their repopulation potential declines. Moreover, aged HSCs exhibit lineage bias in reconstitution experiments with an inclination toward myeloid at the expense of lymphoid potential. The adaptor protein Lnk is an important negative regulator of HSC homeostasis, as Lnk deficiency is associated with a 10-fold increase in HSC numbers in young mice. However, the age-related increase in functional HSC numbers found in wild-type HSCs was not observed in Lnk-deficient animals. Importantly, HSCs from aged Lnk null mice possess greatly enhanced self-renewal capacity and diminished exhaustion, as evidenced by serial transplant experiments. In addition, Lnk deficiency ameliorates the aging associated lineage bias. Transcriptome analysis revealed that WT and Lnk deficient HSCs share many aging-related changes in gene expression patterns. Nonetheless, Lnk null HSCs displayed altered expression of components in select signaling pathways with potential involvement in HSC self-renewal and aging. Taken together, these results suggest that loss of Lnk partially mitigates age related HSC alterations. PMID- 22812479 TI - Continuous and sensitive acid phosphatase assay based on a conjugated polyelectrolyte. AB - We report a novel continuous and sensitive fluorescence turn-on assay for ACPs, which consists of a cationic conjugated polyelectrolyte (PPE4+) and a commonly used phosphatase substrate p-nitrophenyl phosphate (pNPP). The kinetics of the ACP catalyzed hydrolysis of the substrate pNPP was monitored by the fluorescence change of PPE4+ and corresponding kinetic parameters were derived to be consistent with the literature reports. The applications of PPE4+/pNPP-based ACP assay in high-throughput screening of ACP inhibitors and detection of prostatic acid phosphotase (PAP) in vitro were demonstrated. PMID- 22812481 TI - Advances in sports nutrition, exercise and medicine: Olympic issues, the legacy and beyond. AB - In the run up to the London 2012 Olympics, this editorial introduces the cross journal article collection Advances in Sports Nutrition, Exercise and Medicine http://www.biomedcentral.com/series/asnem. PMID- 22812480 TI - Tobacco mosaic virus as a new carrier for tumor associated carbohydrate antigens. AB - Tumor-associated carbohydrate antigens (TACAs) are being actively studied as targets for antitumor vaccine development. One serious challenge was the low immunogenecity of these antigens. Herein, we report the results of using the tobacco mosaic virus (TMV) capsid as a promising carrier of a weakly immunogenic TACA, the monomeric Tn antigen. The copper(I) catalyzed azide-alkyne cycloaddition reaction was highly efficient in covalently linking Tn onto the TMV capsid without resorting to a large excess of the Tn antigen. The location of Tn attachment turned out to be important. Tn introduced at the N terminus of TMV was immunosilent, while that attached to tyrosine 139 elicited strong immune responses. Both Tn specific IgG and IgM antibodies were generated as determined by enzyme-linked immunosorbent assay and a glycan microarray screening study. The production of high titers of IgG antibodies suggested that the TMV platform contained the requisite epitopes for helper T cells and was able to induce antibody isotype switching. The antibodies exhibited strong reactivities toward Tn antigen displayed in its native environment, i.e., cancer cell surface, thus highlighting the potential of TMV as a promising TACA carrier. PMID- 22812483 TI - Evaluation of single cell oil (SCO) from a tropical marine yeast Yarrowia lipolytica NCIM 3589 as a potential feedstock for biodiesel. AB - Single cell oils (SCOs) accumulated by oleaginous yeasts have emerged as potential alternative feedstocks for biodiesel production. As lipid accumulation is species and substrate specific, selection of an appropriate strain is critical. Five strains of Y. lipolytica, a known model oleaginous yeast, were investigated to explore their potential for biodiesel production when grown on glucose and inexpensive wastes. All the strains were found to accumulate > 20% (w/w) of their dry cell mass as lipids with neutral lipid as the major fraction when grown on glucose and on wastes such as waste cooking oil (WCO), waste motor oil (WMO). However, amongst them, Y. lipolytica NCIM 3589, a tropical marine yeast, exhibited a maximal lipid/biomass coefficient, YL/X on 30 g L-1 glucose (0.29 g g-1) and on 100 g L-1 WCO (0.43 g g-1) with a high content of saturated and monounsaturated fatty acids similar to conventional vegetable oils used for biodiesel production. The experimentally determined and predicted biodiesel properties of strain 3589 when grown on glucose and WCO, such as density (0.81 and 1.04 g cm-3), viscosity (4.44 and 3.6 mm2 s-1), SN (190.81 and 256), IV (65.7 and 37.8) and CN (56.6 and 50.8) are reported for the first time for Y. lipolytica and correlate well with specified standards. Thus, the SCO of oleaginous tropical marine yeast Y. lipolytica NCIM 3589 could be used as a potential feedstock for biodiesel production. PMID- 22812484 TI - The perceptions on male circumcision as a preventive measure against HIV infection and considerations in scaling up of the services: a qualitative study among police officers in Dar es Salaam, Tanzania. AB - BACKGROUND: In recent randomized controlled trials, male circumcision has been proven to complement the available biomedical interventions in decreasing HIV transmission from infected women to uninfected men. Consequently, Tanzania is striving to scale-up safe medical male circumcision to reduce HIV transmission. However, there is a need to investigate the perceptions of male circumcision in Tanzania using specific populations. The purpose of the present study was to assess the perceptions of male circumcision in a cohort of police officers that also served as a source of volunteers for a phase I/II HIV vaccine (HIVIS-03) trial in Dar es Salaam, Tanzania. METHODS: In-depth interviews with 24 men and 10 women were conducted. Content analysis informed by the socio-ecological model was used to analyze the data. RESULTS: Informants perceived male circumcision as a health-promoting practice that may prevent HIV transmission and other sexually transmitted infections. They reported male circumcision promotes sexual pleasure, confidence and hygiene or sexual cleanliness. They added that it is a religious ritual and a cultural practice that enhances the recognition of manhood in the community. However, informants were concerned about the cost involved in male circumcision and cleanliness of instruments used in medical and traditional male circumcision. They also expressed confusion about the shame of undergoing circumcision at an advanced age and pain that could emanate after circumcision. The participants advocated for health policies that promote medical male circumcision at childhood, specifically along with the vaccination program. CONCLUSIONS: The perceived benefit of male circumcision as a preventive strategy to HIV and other sexually transmitted infections is important. However, there is a need to ensure that male circumcision is conducted under hygienic conditions. Integrating male circumcision service in the routine childhood vaccination program may increase its coverage at early childhood. The findings from this investigation provide contextual understanding that may assist in scaling-up male circumcision in Tanzania. PMID- 22812486 TI - Worldview implications of believing in free will and/or determinism: politics, morality, and punitiveness. AB - OBJECTIVE: We used the FAD-Plus to investigate the association of free will belief (FWB) with political orientation, moral attitudes, and punitiveness. Other goals included (a) confirming the independence of believing in free will and determinism and (b) contrasting scientific determinism with fatalistic determinism. METHOD: Three studies were conducted via online questionnaires. Studies 1 and 3 recruited undergraduate students: Study 1, N = 220, M(age) = 20.96; Study 3, N = 161, M(age) = 20.2. Study 2 participants were recruited from a broader community sample: N = 253, M(age) = 34.29. RESULTS: Studies 1 and 2 found that FWB is associated with traditional conservative attitudes, including authoritarianism, religiosity, and belief in a just world. Study 2 replicated this pattern but narrowed the religiosity link to the intrinsic style. In Study 3, FWB was associated with binding moral foundations and retributive punishment of hypothetical criminals. CONCLUSIONS: Belief in free will is associated with a conservative worldview, including such facets as authoritarianism, religiosity, punitiveness, and moralistic standards for judging self and others. The common element appears to be a strong sense of personal responsibility. Evidence for distinct correlates of scientific and fatalistic determinism reinforces the need for treating them separately. PMID- 22812485 TI - PCR/RFLP-based allelic variants of streptokinase and their plasminogen activation potencies. AB - PCR-restriction fragment length polymorphism (PCR/RFLP)-based analysis of beta domain variable region of streptokinase genes (sk) has previously identified 14 sk alleles (sk1-sk14) in group A (GAS), C (GCS) and G (GGS) streptococci isolates from a few geographically distinct regions. However, the relation of sk allelic variants to their plasminogen activation potencies remained as a matter of debate. Herein, employing the same PCR/RFLP assay, we analysed sk allelic variants of GAS and GCS/GGS isolates from Iranian patients. In total, 21 sk allelic variants including 14 new alleles (sk14-sk28) were identified. Results implied the horizontal gene transfer of sk fragments between GAS and GCS/GGS strains and did not prove the specificity of particular sk alleles to GCS/GGS or GAS groups. Measurement of streptokinase (SK) activity in streptococcal culture supernatants by colorimetric assay (S2251 substrate) ranged from 9 to 182 IU mL( 1). Although some strains with the highest SK activity were detected in definite variants, no significant correlation between sk alleles and plasminogen activation was detected (P value > 0.05). Analysis of DNA sequences and restriction site mapping of selective sk variants with similar SK activity pointed to the inadequacy of the currently available PCR/RFLP method for differentiation of critical/silent nucleotides to precisely categorize sk alleles for their functional properties. PMID- 22812487 TI - Off-flavor related volatiles in soymilk as affected by soybean variety, grinding, and heat-processing methods. AB - Off-flavor of soymilk is a barrier to the acceptance of consumers. The objectionable soy odor can be reduced through inhibition of their formation or through removal after being formed. In this study, soymilk was prepared by three grinding methods (ambient, cold, and hot grinding) from two varieties (yellow Prosoy and a black soybean) before undergoing three heating processes: stove cooking, one-phase UHT (ultrahigh temperature), and two-phase UHT process using a Microthermics direct injection processor, which was equipped with a vacuuming step to remove injected water and volatiles. Eight typical soy odor compounds, generated from lipid oxidation, were extracted by a solid-phase microextraction method and analyzed by gas chromatography. The results showed that hot grinding and cold grinding significantly reduced off-flavor as compared with ambient grinding, and hot grinding achieved the best result. The UHT methods, especially the two-phase UHT method, were effective to reduce soy odor. Different odor compounds showed distinct concentration patterns because of different formation mechanisms. The two varieties behaved differently in odor formation during the soymilk-making process. Most odor compounds could be reduced to below the detection limit through a combination of hot grinding and two-phase UHT processing. However, hot grinding gave lower solid and protein recoveries in soymilk. PMID- 22812488 TI - A new transcutaneous bidirectional communication for monitoring implanted artificial heart using the human body as a conductive medium. AB - A transcutaneous communication system (TCS) is a key technology for monitoring and controlling artificial hearts and other artificial organs in the body. In this study, we developed a new TCS that uses the human body as a conductive medium. Direct data exchange provides a higher level of communication security compared to that of wireless methods without physical constraints such as an external wire. The external and internal units of the new TCS each consist mainly of a data transmitter and a data receiver. The data transmitter has an amplitude shift keying (ASK) modulator (carrier frequencies: 4 and 10 MHz) and an electrode. The ASK-modulated data current is led into the body through the electrode, and it flows back to the energy source through the body, the data receiver, and the earth ground that includes all conductors and dielectrics in the environment that are in close proximity to the patient. Performance of the TCS was evaluated by a communication test on the surface of the human body and in an animal experiment using a goat. The TCS was able to transmit data concurrently for 4 weeks between everywhere on the surface of the body and everywhere inside the body under full-duplex communication at a transmission rate of 115 kbps. The power consumption of each TCS unit was 125 mW with an ASK-modulated current of 7 mA (root-mean-square). While further study is required to secure its safety, the newly developed TCS has promise to be a next-generation transcutaneous communication device. PMID- 22812489 TI - Catalytic radical cation salt induced C(sp3)-H functionalization of glycine derivatives: synthesis of substituted quinolines. AB - A domino C(sp(3))-H functionalization of glycine derivatives was achieved under catalytic radical cation salt induced conditions, producing a series of quinolines. The proposed mechanism shows that a peroxyl radical cation, which is generated by the coupling between O(2) and TBPA(+*), might be involved to initiate the catalytic oxidation. PMID- 22812490 TI - Comparison of calculations to estimate gastric emptying half-time of solids in humans. AB - BACKGROUND: Measuring solid gastric emptying (GE) at 4 h is used to identify gastroparesis. GE half-time (GE T(1/2) ) is useful to assess overall and early GE. AIM: To examine the validity of hourly imaging as a measurement of GE T(1/2) compared with estimates from more detailed imaging. METHODS: 155 human subjects (99 female, 56 male) underwent scintigraphic GE of a solid-liquid meal. We calculated the GE T(1/2) using linear interpolation based on a full set of abdominal images obtained over 4 h, and the GE T(1/2) based on images at 1, 2, 3, and 4 after the meal with interpolation of data. KEY RESULTS: Differences in GE T(1/2) values (entire set of scan times compared with just the hourly scans) were small [overall median (5th, 95th percentiles) = -0.2[-7.5, 4.6] min] with slightly greater differences in males compared with females. The agreement between the two methods was very high [concordance correlation coefficient (CCC) (95% CI) = .993 (0.990, 0.995)] and a Bland-Altman plot indicated the variation in the results between the two methods did not change appreciably across the range of GE studied (within +/-10 in for all but four subjects). Calculated GE T(1/2) values, omitting the 3-h data from the hourly measurements, were associated with similar high accuracy overall and for fast GE, but were less accurate with slow GE. CONCLUSIONS & INFERENCES: sults of GE T(1/2) solids, using hourly imaging over 4 , are accurate in the range 75-235 n which reflects the typical range of GE of solids in health and disease. PMID- 22812492 TI - Fundamental mechanisms of DNA radiosensitization: damage induced by low-energy electrons in brominated oligonucleotide trimers. AB - The replacement of nucleobases with brominated analogs enhances DNA radiosensitivity. We examine the chemistry of low-energy electrons (LEEs) in this sensitization process by experiments with thin films of the oligonucleotide trimers TBrXT, where BrX = 5-BrU (5-bromouracil), 5-BrC (5-bromocytosine), 8-BrA (8-bromoadenine), or 8-BrG (8-bromoguanine). The products induced from irradiation of thin (~ 2.5 nm) oligonucleotide films, with 10 eV electrons, under ultrahigh vacuum (UHV) are analyzed by HPLC-UV. The number of damaged brominated trimers ranges from about 12 to 15 * 10(-3) molecules per incident electron, whereas under the identical conditions, these numbers drop to 4-7 * 10(-3) for the same, but nonbrominated oligonucleotides. The results of HPLC analysis show that the main degradation pathway of trinucleotides containing brominated bases involve debromination (i.e., loss of the bromine atom and its replacement with a hydrogen atom). The electron-induced sum of products upon bromination increases by factors of 2.1 for the pyrimidines and 3.2 for the purines. Thus, substitution of any native nucleobase with a brominated one in simple models of DNA increases LEE-induced damage to DNA and hence its radiosensitivity. Furthermore, besides the brominated pyrimidines that have already been tested in clinical trials, brominated purines not only appear to be promising sensitizers for radiotherapy, but could provide a higher degree of radiosensitization. PMID- 22812491 TI - Development and characterization of a novel human Waldenstrom macroglobulinemia cell line: RPCI-WM1, Roswell Park Cancer Institute - Waldenstrom Macroglobulinemia 1. AB - Understanding the biology of Waldenstrom macroglobulinemia is hindered by a lack of preclinical models. We report a novel cell line, RPCI-WM1, from a patient treated for WM. The cell line secretes human immunoglobulin M (h-IgM) with kappa light chain restriction identical to the primary tumor. The cell line has a modal chromosomal number of 46 and harbors chromosomal changes such as deletion of 6q21, monoallelic deletion of 9p21 (CDKN2A), 13q14 (RB1) and 18q21 (BCL-2), with a consistent amplification of 14q32 (immunoglobulin heavy chain; IgH) identical to its founding tumor sample. The clonal relationship is confirmed by identical CDR3 length and single nucleotide polymorphisms as well as a matching IgH sequence of the cell line and founding tumor. Both also harbor a heterozygous, non-synonymous mutation at amino acid 265 in the MYD88 gene (L265P). The cell line expresses most of the cell surface markers present on the parent cells. Overall, RPCI-WM1 represents a valuable model to study Waldenstrom macroglobulinemia. PMID- 22812493 TI - Tunnelized preauricular transposition flap for reconstruction of auricular defect. AB - BACKGROUND: Reconstruction of surgical defects of the auricular region is a complex challenge, especially when they are localized in the anterior surface, due to the convexities and concavities of this region. PATIENTS AND RESULTS: The authors present the case of an 89-year-old woman who underwent radical excision of basal cell carcinoma localized in the left scapha. The reconstruction of the resulting defect was performed using a preauricular transposition flap tunnelized through a cartilaginous fistula created at the crus helicis. The flap was deepithelialized at its base to allow the closure in a single step. The donor site was primarily closed. The procedure was performed under local anesthesia without complications and with acceptable aesthetic results. DISCUSSION: There are various surgical procedures described for the reconstruction of the anterior auricle, including local flaps, skin grafts and even healing by secondary intention. The authors consider the tunnelized preauricular transposition flap a good option especially when compared to interpolated flaps, since it allows a reconstruction in a single surgical step with decreased morbidity and favorable cosmetic results. PMID- 22812494 TI - The phosphotransferase protein EIIA(Ntr) modulates the phosphate starvation response through interaction with histidine kinase PhoR in Escherichia coli. AB - Many Proteobacteria possess the paralogous PTS(Ntr), in addition to the sugar transport phosphotransferase system (PTS). In the PTS(Ntr) phosphoryl-groups are transferred from phosphoenolpyruvate to protein EIIA(Ntr) via the phosphotransferases EI(Ntr) and NPr. The PTS(Ntr) has been implicated in regulation of diverse physiological processes. In Escherichia coli, the PTS(Ntr) plays a role in potassium homeostasis. In particular, EIIA(Ntr) binds to and stimulates activity of a two-component histidine kinase (KdpD) resulting in increased expression of the genes encoding the high-affinity K(+) transporter KdpFABC. Here, we show that the phosphate (pho) regulon is likewise modulated by PTS(Ntr). The pho regulon, which comprises more than 30 genes, is activated by the two-component system PhoR/PhoB under conditions of phosphate starvation. Mutants lacking EIIA(Ntr) are unable to fully activate the pho genes and exhibit a growth delay upon adaptation to phosphate limitation. In contrast, pho expression is increased above the wild-type level in mutants deficient for EIIA(Ntr) phosphorylation suggesting that non-phosphorylated EIIA(Ntr) modulates pho. Protein interaction analyses reveal binding of EIIA(Ntr) to histidine kinase PhoR. This interaction increases the amount of phosphorylated response regulator PhoB. Thus, EIIA(Ntr) is an accessory protein that modulates the activities of two distinct sensor kinases, KdpD and PhoR, in E. coli. PMID- 22812495 TI - Platelets from WAS patients show an increased susceptibility to ex vivo phagocytosis. AB - The thrombocytopenia of Wiskott-Aldrich syndrome (WAS) is thought to be due to both reduced platelet production and accelerated platelet consumption. We have previously demonstrated that platelets from WASP-deficient mice are consumed more rapidly in vivo than are WT platelets, and that opsonization accelerates their uptake by bone marrow- derived macrophages more than it does that of WT platelets. Here we asked whether platelets from WAS patients show similar features. We show that ex vivo phagocytosis by activated THP-1 cells of DIO labeled platelets from a series of WAS or XLT patients is increased in comparison to that of normal control platelets. Using a numerical analysis method, we distinguish this effect from a concurrent effect on the amount of detectable fluorescent signal transferred to the macrophage per phagocytosed platelet. We show that the latter quantity is reduced by platelet WASP deficiency, as might be expected if the fluorescence transferred from these smaller platelets is more rapidly quenched. We are unable to detect a differential effect of opsonization with anti-CD61 antibody on the uptake of WASP(-) vs. WT platelets. However, the high probability of phagocytosis per adsorbed WASP(-) platelet could limit the sensitivity of the assay in this case. We also see no effect of sera from WAS patients on the uptake of normal control platelets, suggesting that in vivo opsonization is not the cause of increased uptake of WASP(-) platelets. Finally, we show little, if any, increase in the reticulated platelet fraction in WAS patients, suggesting that impaired production of reticulated platelets contributes to the thrombocytopenia. Our findings suggest that rapid in vivo platelet consumption contributes significantly to the thrombocytopenia of WAS. They also demonstrate the feasibility of routinely performing functional assays of phagocytosis of small numbers of platelets obtained at remote locations, a method which should be applicable to the study of other types of thrombocytopenia such as ITP. PMID- 22812496 TI - Physical activity and self-reported symptoms of insomnia, restless legs syndrome, and depression: the comprehensive dialysis study. AB - Symptoms of sleep and mood disturbances are common among patients on dialysis and are associated with significant decrements in survival and health-related quality of life. We used data from the Comprehensive Dialysis Study (CDS) to examine the association of self-reported physical activity with self-reported symptoms of insomnia, restless legs syndrome (RLS), and depression in patients new to dialysis. The CDS collected data on physical activity, functional status, and health-related quality of life from 1678 patients on either peritoneal (n = 169) or hemodialysis (n = 1509). The Human Activity Profile was used to measure self reported physical activity. Symptoms were elicited in the following manner: insomnia using three questions designed to capture difficulty in initiating or maintaining sleep, RLS using three questions based on the National Institutes of Health workshop, and depression using the two-item Patient Health Questionnaire. We obtained data on symptoms of insomnia and depression for 1636, and on symptoms of RLS for 1622 (>98%) patients. Of these, 863 (53%) reported one of three insomnia symptoms as occurring at a persistent frequency. Symptoms of RLS and depression occurred in 477 (29%) and 451 (28%) of patients, respectively. The Adjusted Activity Score of the Human Activity Profile was inversely correlated with all three conditions in models adjusting for demographics, comorbid conditions, and laboratory variables. Sleep and mood disturbances were commonly reported in our large, diverse cohort of patients new to dialysis. Patients who reported lower levels of physical activity were more likely to report symptoms of insomnia, RLS, and depression. PMID- 22812498 TI - Chemical macrocyclization of peptides fused to antibody Fc fragments. AB - To extend the plasma half-life of a bicyclic peptide antagonist, we chose to link it to the Fc fragment of the long-lived serum protein IgG1. Instead of chemically conjugating the entire bicyclic peptide, we recombinantly expressed its peptide moiety as a fusion protein to an Fc fragment and subsequently cyclized the peptide by chemically reacting its three cysteine residues with tris (bromomethyl)benzene. This reaction was efficient and selective, yielding completely modified peptide fusion protein and no side products. After optimization of the linker and the Fc fragment format, the bicyclic peptide was fully functional as an inhibitor (K(i) = 76 nM) and showed an extended terminal half-life of 1.5 days in mice. The unexpectedly clean reaction makes chemical macrocyclization of peptide-Fc fusion proteins an attractive synthetic approach. Its good compatibility with the Fc fragment may lend the bromomethylbenzene-based chemistry also for the generation of antibody-drug conjugates. PMID- 22812497 TI - Pleurotus giganteus (Berk.) Karunarathna & K.D. Hyde: Nutritional value and in vitro neurite outgrowth activity in rat pheochromocytoma cells. AB - BACKGROUND: Drugs dedicated to alleviate neurodegenerative diseases like Parkinson's and Alzheimer's have always been associated with debilitating side effects. Medicinal mushrooms which harness neuropharmacological compounds offer a potential possibility for protection against such diseases. Pleurotus giganteus (formerly known as Panus giganteus) has been consumed by the indigenous people in Peninsular Malaysia for many years. Domestication of this wild mushroom is gaining popularity but to our knowledge, medicinal properties reported for this culinary mushroom are minimal. METHODS: The fruiting bodies P. giganteus were analysed for its nutritional values. Cytotoxicity of the mushroom's aqueous and ethanolic extracts towards PC12, a rat pheochromocytoma cell line was assessed by using 3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Neurite outgrowth stimulation assay was carried out with nerve growth factor (NGF) as control. To elucidate signaling mechanisms involved by mushroom extract induced neurite outgrowth, treatment of specific inhibitor for MEK/ERK and PI3K signalling pathway was carried out. RESULTS: The fruiting bodies of P. giganteus were found to have high carbohydrate, dietary fibre, potassium, phenolic compounds and triterpenoids. Both aqueous and ethanolic extracts induced neurite outgrowth of PC12 cells in a dose- and time-dependant manner with no detectable cytotoxic effect. At day 3, 25 MUg/ml of aqueous extract and 15 MUg/ml of ethanolic extract showed the highest percentage of neurite-bearing cells, i.e. 31.7 +/- 1.1% and 33.3 +/- 0.9%; respectively. Inhibition treatment results suggested that MEK/ERK and PI3K/Akt are responsible for neurite outgrowth of PC12 cells stimulated by P. giganteus extract. The high potassium content (1345.7 mg/100 g) may be responsible for promoting neurite extension, too. CONCLUSIONS: P. giganteus contains bioactive compounds that mimic NGF and are responsible for neurite stimulation. Hence, this mushroom may be developed as a nutraceutical for the mitigation of neurodegenerative diseases. PMID- 22812499 TI - Randomized trial of intracardiac echocardiography during cavotricuspid isthmus ablation. AB - Randomized Trial of ICE During CTI Ablation. INTRODUCTION: Despite a high success rate, radio-frequency ablation (RFA) of the cavotricuspid isthmus (CTI) can be unusually challenging in some cases. We postulated that visualization of the CTI with intracardiac echocardiography (ICE) could maximize the success rate, decrease the procedure and ablation time, and minimize the radiation exposure. METHODS AND RESULTS: In our prospective, randomized study, we included 102 patients scheduled for CTI ablation. We randomized patients in 2 groups: guided only by fluoroscopy (n = 52) or ICE-guided (n =50) group. Procedure time, fluoroscopy time, and the time spent for RFA were significantly shorter, radiation exposure (dose-area product-DAP) and the sum of delivered radio frequency energy were significantly lower in the ICE-group (68.06 +/- 15.09 minutes vs 105.94 +/- 36.51 minutes, P < 0.001, 5.54 +/- 3.77 minutes vs 18.63 +/ 10.60 minutes, P <0.001, 482.80 +/- 534.12 seconds vs 779.76 +/- 620.82 seconds, P = 0.001 and 397.62 +/- 380.81 cGycm(2) vs 1,312.92 +/- 1,129.28 cGycm(2) , P < 0.001, 10,866.84 +/- 6,930.84 Ws vs 16,393.56 +/- 13,995.78 Ws, P = 0.048, respectively). Seven patients (13%) from the fluoroscopy-only group crossed over to ICE-guidance because of prolonged unsuccessful RFA and were all treated successfully. Four vascular complications and 2 recurrences were equally distributed between the 2 groups. CONCLUSIONS: ICE-guided ablation of the CTI significantly shortens the procedure and fluoroscopy time, markedly decreases radiation exposure, and time spent for ablation in comparison with fluoroscopy only procedures. At the same time, visualization with ICE allowed successful ablation in challenging cases. (J Cardiovasc Electrophysiol, Vol. 23, pp. 996 1000, September 2012). PMID- 22812500 TI - Chips and tags suggest plant-environment interactions differ for two alpine Pachycladon species. AB - BACKGROUND: Expression profiling has been proposed as a means for screening non model organisms in their natural environments to identify genes potentially important in adaptive diversification. Tag profiling using high throughput sequencing is a relatively low cost means of expression profiling with deep coverage. However the extent to which very short cDNA sequences can be effectively used in screening for candidate genes is unclear. Here we investigate this question using an evolutionarily distant as well as a closely related transcriptome for referencing tags. We do this by comparing differentially expressed genes and processes between two closely related allopolyploid species of Pachycladon which have distinct altitudinal preferences in the New Zealand Southern Alps. We validate biological inferences against earlier microarray analyses. RESULTS: Statistical and gene annotation enrichment analyses of tag profiles identified more differentially expressed genes of potential adaptive significance than previous analyses of array-based expression profiles. These include genes involved in glucosinolate metabolism, flowering time, and response to cold, desiccation, fungi and oxidation. In addition, despite the short length of 20mer tags, we were able to infer patterns of homeologous gene expression for 700 genes in our reference library of 7,128 full-length Pachycladon ESTs. We also demonstrate that there is significant information loss when mapping tags to the non-conspecific reference transcriptome of A. thaliana as opposed to P. fastigiatum ESTs but also describe mapping strategies by which the larger collection of A. thaliana ESTs can be used as a reference. CONCLUSION: When coupled with a reference transcriptome generated using RNA-seq, tag sequencing offers a promising approach for screening natural populations and identifying candidate genes of potential adaptive significance. We identify computational issues important for the successful application of tag profiling in a non-model allopolyploid plant species. PMID- 22812501 TI - Continuous-flow synthesis of monoarylated acetaldehydes using aryldiazonium salts. AB - Anilines and ethyl vinyl ether can be used as precursors for a process that is the synthetic equivalent of the alpha-arylation of acetaldehyde enolate. The reaction manifests a high level of functional group compatibility, allowing the ready preparation of a number of synthetically valuable compounds. PMID- 22812502 TI - Genetic mismatch affects the immunosuppressive properties of mesenchymal stem cells in vitro and their ability to influence the course of collagen-induced arthritis. AB - INTRODUCTION: The immunological and homing properties of mesenchymal stem cells (MSCs) provide a potentially attractive treatment for arthritis. The objective of this study was to determine effects of genetic disparity on the immunosuppressive potential of MSCs in vitro and in vivo within collagen induced arthritis (CIA). METHODS: The ability of DBA/1, FVB and BALB/c MSC preparations to impact the cytokine release profile of CD3/CD28 stimulated DBA/1 T cells was assessed in vitro. The effect of systemically delivered MSCs on the progression of CIA and cytokine production was assessed in vivo. RESULTS: All MSC preparations suppressed the release of TNFalpha and augmented the secretion of IL-4 and IL-10 by stimulated DBA/1 T-cells. However, assessment of the ratio of IFNgamma to IL-4 production indicated that the more genetically distant BALB/c MSCs had significantly less immunosuppressive capacity. Systemic delivery of BALB/c MSC resulted in an exacerbation of CIA disease score in vivo and a higher erosive disease burden. This was not seen after treatment with syngeneic or partially mismatched MSCs. An increase in serum levels of IL-1beta was observed up to 20 days post treatment with allogeneic MSCs. An initial elevation of IL-17 in these treatment groups persisted in those treated with fully mismatched BALB/c MSCs. Over the course of the study, there was a significant suppression of serum IL-17 levels in groups treated with syngeneic MSCs. CONCLUSIONS: These data demonstrate a significant difference in the immunosuppressive properties of syngeneic and allogeneic MSCs in vitro and in vivo, which needs to be appreciated when developing MSC based therapies for inflammatory arthritis. PMID- 22812503 TI - Weighting positive versus negative: the fundamental nature of valence asymmetry. AB - OBJECTIVE: The relation between weighting of valence information in attitude generalization and evaluation of novel/hypothetical situations was explored. METHOD: Undergraduate participants played a computer game requiring them to learn which stimuli (beans) would increase/decrease their points. Later, participants classified the valence of game beans and novel ones varying in resemblance to game beans. The weighting bias in attitude generalization was estimated as the average response to novel beans, controlling for game bean learning. We examined whether this bias related to judgments of hypothetical situations concerning interpersonal relationships (Study 1), threat assessment (Study 2), risk propensities (Study 3), and risk behavior (Study 6). We also assessed whether valence weighting is specifically predictive of novel situations (Studies 4 and 5). Finally, we explored participants' ability to self-report their weighting bias (Study 7). RESULTS: Valence weighting in attitude generalization was related to judgments of novel situations and risk behavior. The performance-based measure did not correlate with responses to various questionnaires related to valence weighting. CONCLUSIONS: There is a fundamental individual difference associated with valence weighting, resulting in the relation between two processes unrelated in content, but sharing the essential characteristic of valence weighting attitude generalization and evaluation of novel situations. PMID- 22812504 TI - Iron acquisition in the marine actinomycete genus Salinispora is controlled by the desferrioxamine family of siderophores. AB - Many bacteria produce siderophores for sequestration of growth-essential iron. Analysis of the Salinispora genomes suggests that these marine actinomycetes support multiple hydroxamate- and phenolate-type siderophore pathways. We isolated and characterized desferrioxamines (DFOs) B and E from all three recognized Salinispora species and linked their biosyntheses in S. tropica CNB 440 and S. arenicola CNS-205 to the des locus through PCR-directed mutagenesis. Gene inactivation of the predicted iron-chelator biosynthetic loci sid2-4 did not abolish siderophore chemistry. Additionally, these pathways could not restore the native growth characteristics of the des mutants in iron-limited media, although differential iron-dependent regulation was observed for the yersiniabactin-like sid2 pathway. Consequently, this study indicates that DFOs are the primary siderophores in laboratory cultures of Salinispora. PMID- 22812505 TI - A qualitative inquiry into consumer beliefs about the causes of mental illness. AB - This paper examines consumer or service user beliefs about the causes of mental illness. It presents a qualitative, participatory action research study involving semi-structured in-depth interviews with 16 people who had been diagnosed with a mental illness and attended a community mental health centre in metropolitan South Australia. Inductive thematic analysis was undertaken, with a range of beliefs about the possible cause of mental illness identified. Findings are organized within two key areas: social or environmental factors and physical or biological factors. The social or environmental category included varied situations, clustered under the subcategories of: stress during childhood, events in adulthood and religious beliefs. Physical or biological factors included beliefs that mental illness was inherited, caused by brain malfunction or chemical imbalance. Of note, one-third of consumer participants who discussed possible causes of mental illness identified multiple potential causes. Implications for service delivery, specifically related to therapeutic trust and engagement, are also considered. PMID- 22812506 TI - An in vitro liver model--assessing oxidative stress and genotoxicity following exposure of hepatocytes to a panel of engineered nanomaterials. AB - BACKGROUND: Following exposure via inhalation, intratracheal instillation or ingestion some nanomaterials (NM) have been shown to translocate to the liver. Since oxidative stress has been implicated as a possible mechanism for NM toxicity this study aimed to investigate the effects of various materials (five titanium dioxide (TiO2), two zinc oxide (ZnO), two multi-walled carbon nanotubes (MWCNT) and one silver (Ag) NM) on oxidative responses of C3A cell line as a model for potential detrimental properties of nanomaterials on the liver. RESULTS: We noted a dose dependant decrease in the cellular glutathione content following exposure of the C3A cells to Ag, the ZnO and the MWCNTs. Intracellular ROS levels were also measured and shown to increase significantly following exposure of the C3A to the low toxicity NMs (MWCNT and TiO(2)). The antioxidant Trolox in part prevented the detrimental effect of NMs on cell viability, and decreased the NM induced IL8 production after exposure to all but the Ag particulate. Following 4 hr exposure of the C3A cells to sub-lethal levels of the NMs, the largest amount of DNA damage was induced by two of the TiO(2) samples (7 nm and the positively charged 10 nm particles). CONCLUSIONS: All ten NMs exhibited effects on the hepatocyte cell line that were at least in part ROS/oxidative stress mediated. These effects included mild genotoxicity and IL8 production for all NM except the Ag possibly due to its highly cytotoxic nature. PMID- 22812508 TI - The management of gastrointestinal follicular lymphoma: some observations on a rare disease. PMID- 22812507 TI - The beneficial effects of Momordica charantia (bitter gourd) on wound healing of rabbit skin. AB - Momordica charantia (MC; bitter gourd) is a traditional herbal commonly used for its antidiabetic, antioxidant, contraceptive and antibacterial properties. In the current study, the authors aim to observe the topical effect of MC cream on the wound-healing process in rabbits. Moreover, they compare the healing potential with conventional creams used therapeutically. Towards this aim, 28 New Zealand rabbits were divided into four groups and excision wounds (7 cm2) were made on their backs. Open wound dressing was carried out daily for 28 days among the experimental groups with the application of dekspanthenol (Bepanthen(r); BP group, n = 7), nitrofurazon (Furacin(r); FR group, n = 7) and olive oil extract of MC (MC group, n = 7). No application was made to the control group. At the end of day 28, areas of the skin with initial wound area were en bloc dissected and prepared for histopathological and stereological analysis. Inflammatory cells were abundant in the control group and cream application led to a decrease in the number of these cells, especially in the MC group. The highest number of fibroblasts was detected in the MC group. Furthermore, the MC group displayed the highest fractions of epidermis to papillary dermis, fibroblasts to reticular dermis and collagen fibres to reticular dermis. The MC group also presented a high density of blood vessels, moderate density of collagen fibres and mature fibroblasts. The BP group showed better epithelialisation compared with the FR group, but the latter provided more effective reorganisation of the dermis. Different cream supplements caused healthy and fast wound healing according to untreated controls and the results show that administration of the MC extract improves and accelerates the process of wound healing in rabbits in comparison with the BP and FR extracts. PMID- 22812509 TI - Conformational analysis of a model synthetic prodiginine. AB - A conformational analysis of a synthetic model prodiginine was carried out. In solution this compound showed a strong preference for the beta conformation, in which all the heterocycles are mutually cis. This conformation provided an ideal alignment of the three N-H groups for interacting with anions when the molecule is protonated. A different conformation was also detected in d(6)-DMSO for the mesylate salt, assigned to the alpha conformation, in which the C ring is engaged in an intramolecular hydrogen bond with the OMe group. The formation of a homodimer was observed in concentrated CDCl(3) solutions of the neutral free base form of this prodiginine derivative. DFT calculations and the solid state structures of the hydrochloric and methanesulfonic acid salts were in good agreement with the results observed in solution. A complete study of the relative energies of different tautomers, isomers, and supramolecular complexes supported the preference for the beta conformation both in water and in the gas phase. PMID- 22812514 TI - Relationship between telmisartan dose and glycaemic control in Japanese patients with type 2 diabetes mellitus and hypertension: a retrospective study. AB - BACKGROUND AND OBJECTIVES: Telmisartan has been reported to have beneficial effects on insulin resistance and lipid profiles by acting as a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. In this study we investigated the relationship between telmisartan dose and glycaemic control in Japanese subjects with type 2 diabetes mellitus and hypertension. METHODS: Patients (n = 263) who were prescribed telmisartan 20, 40 or 80 mg/day at our clinic were retrospectively identified from our clinical database. Only patients without changes in their treatments for diabetes and hypertension for 6 months after starting telmisartan were included in this study. Glycosylated haemoglobin A(1c) (HbA(1c)) levels were measured at 0, 3 and 6 months after starting telmisartan. RESULTS: At 3 and 6 months after starting telmisartan, HbA(1c) levels were significantly decreased in patients treated with telmisartan 40 or 80 mg/day but not in patients treated with telmisartan 20 mg/day (mean +/- standard error change at 6 months: -0.29 +/- 0.10%, p < 0.001; -0.48 +/- 0.15%, p < 0.001; and -0.03 +/- 0.10%, p = 0.33; respectively). When patients were classified into two groups by telmisartan dose (20 vs >=40 mg/day), there was no significant correlation between baseline HbA(1c) and change in HbA(1c) levels over time in the 20 mg/day group. However, in patients treated with >=40 mg/day of telmisartan, baseline HbA(1c) was negatively correlated with the change in HbA(1c) at 6 months. Multiple regression analysis confirmed that baseline HbA(1c) and telmisartan dose were the predictive factors. CONCLUSION: Our results suggest that telmisartan influences glycaemic control in a dose-dependent manner; doses >=40 mg/day may be needed to improve glycaemic control. Our data also suggest that patients with higher baseline HbA(1c) may experience greater improvements in glycaemic control with telmisartan. PMID- 22812510 TI - Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. AB - Dual-specificity MAP kinase phosphatases (MKPs) provide a complex negative regulatory network that acts to shape the duration, magnitude and spatiotemporal profile of MAP kinase activities in response to both physiological and pathological stimuli. Individual MKPs may exhibit either exquisite specificity towards a single mitogen-activated protein kinase (MAPK) isoform or be able to regulate multiple MAPK pathways in a single cell or tissue. They can act as negative feedback regulators of MAPK activity, but can also provide mechanisms of crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules. In this review, we explore the current state of knowledge with respect to the regulation of MKP expression levels and activities, the mechanisms by which individual MKPs recognize and interact with different MAPK isoforms and their role in the spatiotemporal regulation of MAPK signalling. PMID- 22812515 TI - Direct binding targets of the stringent response alarmone (p)ppGpp. AB - The Escherichia coli stringent response, mediated by the alarmone ppGpp, is responsible for the reorganization of cellular transcription upon nutritional starvation and other stresses. These transcriptional changes occur mainly as a result of the direct effects of ppGpp and its partner transcription factor DksA on RNA polymerase. An often overlooked feature of the stringent response is the direct targeting of other proteins by ppGpp. Here we review the literature on proteins that are known to bind ppGpp and, based on sequence homology, X-ray crystal structures and in silico docking, we propose new potential protein binding targets for ppGpp. These proteins were found to fall into five main categories: (i) cellular GTPases, (ii) proteins involved in nucleotide metabolism, (iii) proteins involved in lipid metabolism, (iv) general metabolic proteins and (v) PLP-dependent basic aliphatic amino acid decarboxylases. Bioinformatic rationale is provided for expanding the role of ppGpp in regulating the activities of the cellular GTPases. Proteins involved in nucleotide and lipid metabolism and general metabolic proteins provide an interesting set of structurally varied stringent response targets. While the inhibition of some PLP dependent decarboxylases by ppGpp suggests the existence of cross-talk between the acid stress and stringent response systems. PMID- 22812516 TI - Magneto-LC effects in hydrogen-bonded all-organic radical liquid crystal. AB - To identify the origin of the magneto-LC effects, which refer to the enhancement of intermolecular magnetic interactions in the LC phases of all-organic radical compounds, we have designed and synthesized H-bonded all-organic radical compounds showing nematic and cholesteric phases for the first time. They show stronger magneto-LC effects than in the same LC phases of analogous covalent bonded all-organic radical LC compounds. Variable-temperature electron paramagnetic resonance spectroscopy of the hydrogen-bonded compounds reveals that the inhomogeneous intermolecular contacts give rise to the magneto-LC effects. PMID- 22812517 TI - Organic anion-transporting polypeptides 1a/1b control the hepatic uptake of pravastatin in mice. AB - Organic anion-transporting polypeptides (OATPs) mediate the hepatic uptake of many drugs. Hepatic uptake is crucial for the therapeutic effect of pravastatin, a cholesterol-lowering drug and OATP1A/1B substrate. We aimed to gain empirical insight into the relationship between OATPs and pravastatin pharmacokinetics and toxicity. We therefore compared the distribution and toxicity of pravastatin in wild-type and Oatp1a/1b-null mice. Intestinal absorption of pravastatin was not affected by Oatp1a/1b absence, but systemic plasma exposure (AUC) increased up to 30-fold after oral bolus administration. This increased plasma exposure resulted from reduced hepatic uptake, as evident from 10 to 100-fold lower liver-to-plasma concentration ratios. However, the reductions in liver exposure were far smaller (<2-fold) than the increases in plasma exposure. Reduced pravastatin liver uptake in Oatp1a/1b-null mice was more obvious shortly after intravenous administration, with 8-fold lower biliary pravastatin excretion. Although mice chronically exposed to pravastatin for 60 days evinced little muscular toxicity, Oatp1a/1b null mice displayed 10-fold higher plasma concentrations and 8-fold lower liver concentrations than wild-type mice. Thus, Oatp1a/1b transporters importantly control the hepatic uptake of pravastatin. Activity-reducing human OATP1B polymorphisms may therefore both reduce pravastatin therapeutic efficacy in the liver and increase systemic toxicity risks, thus compromising its therapeutic index in a two-edged way. PMID- 22812518 TI - Nurse-physician relationships in ambulatory oncology settings. AB - PURPOSE: The purpose of this study was to explore nurses' perceptions of nurse physician relationships in ambulatory oncology settings, which are linked to patient safety. DESIGN: This cross-sectional, descriptive study analyzed survey data collected in 2010 from oncology nurses employed in ambulatory settings. The sampling frame was the nurse licensure database in one state in the Southeastern United States. Nurses completed the Practice Environment Scale of the Nursing Work Index (PES-NWI), reported on the quality of care in their setting, and commented on factors that promoted or inhibited high-quality care delivery. METHODS: Data analysis used three study variables: empirically derived values from the PES-NWI, a scale of nurse-reported quality of care in their setting, and open-text comments about features in their workplace that promoted or hindered high-quality care. After categorizing open-text comments, analysis of variance was used to evaluate differences in PES-NWI subscales by comment category. Chi square test statistics were calculated to examine differences in overall practice environment and quality of care by comment category. RESULTS: Nurses reported their relationships with physicians as generally favorable. Qualitative findings suggest two themes that influence how nurses characterize their working relationships with physicians: (a) physician behaviors and (b) structural factors. Both PES-NWI scores and quality of care were rated significantly higher by nurses who wrote favorably about physicians. CONCLUSIONS: Favorable nurse physician relationships in ambulatory settings may reflect positive workplaces and promote high-quality care. CLINICAL RELEVANCE: Consistent with findings from inpatient units, nurse-physician relationships are important to the quality of ambulatory oncology care. Systematic measurement and attention to reported deficits in these relationships may promote higher quality care. PMID- 22812519 TI - What is the role of the neurosurgeon in neuroethical discourse? PMID- 22812520 TI - Platelet-adenovirus vs. inert particles interaction: effect on aggregation and the role of platelet membrane receptors. AB - Platelets are involved in host defense via clearance of bacteria from the circulation, interaction with virus particles, and uptake of various size particulates. There is a growing interest in micro- and nanoparticles for drug delivery and there is evidence that the properties of these particles critically influence their interaction and uptake by various tissues and cells including platelets. Virus mediated gene therapy applications are still challenged by the resultant thrombocytopenia and the mechanism(s) of platelet-foreign particles interaction remains unclear. We studied the specifics of platelet interaction with an active biological agent (adenovirus) and inert latex microspheres (MS) and investigated the role of platelet proteins in this interaction. We show that activated and not resting platelets internalize MS, without influencing platelet aggregation. In contrast, adenovirus induces and potentiates ADP-induced platelet aggregation and results in rapid expression of P-selectin. Platelets then internalize adenovirus and viral particles appear inside the open canalicular system. Inhibition of platelet alphaIIbbeta3, GPIbalpha, and P-selectin decreases both platelet aggregation and internalization of MS. Inhibition of alphaIIbbeta3 and alphaVbeta3 does not abolish adenovirus platelet internalization and adenovirus-induced platelet activation is maintained. Our study demonstrates that platelets react differentially with foreign particles and that alphaIIbbeta3 is a key player in platelet engulfing of foreign particles but not in mediating adenovirus internalization. Other platelet candidate molecules remain to be investigated as potential targets for management of adenovirus-induced thrombocytopenia. PMID- 22812522 TI - Teaching the Rational Use of Medicines to medical students: a qualitative research. AB - BACKGROUND: Prescribing is a complex and challenging task that must be part of a logical deductive process based on accurate and objective information and not an automated action, without critical thinking or a response to commercial pressure. The objectives of this study were 1) develop and implement a discipline based on the WHO's Guide to Good Prescribing; 2) evaluate the course acceptance by students; 3) assess the impact that the Rational Use of Medicines (RUM) knowledge had on the students habits of prescribing medication in the University Hospital. METHODS: In 2003, the RUM principal, based in the WHO's Guide to Good Prescribing, was included in the official curriculum of the Botucatu School of Medicine, Brazil, to be taught over a total of 24 hours to students in the 4th year. We analyzed the students' feedback forms about content and teaching methodology filled out immediately after the end of the discipline from 2003 to 2010. In 2010, the use of RUM by past students in their medical practice was assessed through a qualitative approach by a questionnaire with closed-ended rank scaling questions distributed at random and a single semistructured interview for content analysis. RESULTS: The discipline teaches future prescribers to use a logical deductive process, based on accurate and objective information, to adopt strict criteria (efficacy, safety, convenience and cost) on selecting drugs and to write a complete prescription. At the end of it, most students considered the discipline very good due to the opportunity to reflect on different actions involved in the prescribing process and liked the teaching methodology. However, former students report that although they are aware of the RUM concepts they cannot regularly use this knowledge in their daily practice because they are not stimulated or even allowed to do so by neither older residents nor senior medical staff. CONCLUSIONS: This discipline is useful to teach RUM to medical students who become aware of the importance of this subject, but the assimilation of the RUM principles in the institution seems to be a long-term process which requires the involvement of a greater number of the academic members. PMID- 22812521 TI - Targeting iron assimilation to develop new antibacterials. AB - INTRODUCTION: Since the first application of antibiotics to treat bacterial infections, the development and spread of resistance has been a persistent threat. An ever evolving pipeline of next-generation therapeutics is required for modern medicine to remain one step ahead of pathogens. AREAS COVERED: This review describes recent efforts to develop drugs that interrupt the assimilation of iron by bacteria: a process that is vital to cellular homeostasis and is not currently targeted by antibiotics used in the clinic. This review also covers the mechanisms by which bacteria acquire iron for their environment, and details efforts to intervene in these processes, using small molecule inhibitors that target key steps in these pathways, with a special emphasis on recent advances published during the 2010 - 2012 period. EXPERT OPINION: For decades, the routes used by bacteria to assimilate iron from host and environmental settings have been the subject of intense study. While numerous investigations have identified inhibitors of these pathways, many have stopped short of translating the in vitro results to in vivo proof of concept experiments. The extension of preliminary findings in this manner will significantly increase the impact of the field. PMID- 22812523 TI - Transcription, DNA damage and beyond: the roles of histone ubiquitination and deubiquitination. AB - Myriad covalent post-translational modifications of histones have been demonstrated to play crucial roles in regulating gene transcription, gene repression, DNA damage and repair, and beyond. It has been long known that these modifications are often dynamic, such as histone ubiquitination and deubiquitination, and the processes through adding and/or removing these modified marks catalyzed by various classes of enzymes commonly influence many important physiological functions. In recent few years, studies on histone ubiquitination re-garners much attention arising from lots of new exciting findings emerged. Several important histone ubiquitination sites have been mapped in different organisms. In addition, the identification and characterization of numerous ubiquitin modifying enzymes, especially ligases and deubiquitinases, have facilitated the progress in understanding the roles of histone ubiquitination/deubiquitination events. Of particular interest, histone ubiquitination interplays with many other chromatin modifications, namely "crosstalk", which contributes to a variety of cellular events. In this review, I summarize the enzymes and factors involved in regulating the attachment and removal of ubiquitin from histones, and focus on what essential roles this modification plays. I also present new evidence that links histone ubiquitination with other histone modifications, which comprises an intricate crosstalk network. PMID- 22812524 TI - gp78: a multifaceted ubiquitin ligase that integrates a unique protein degradation pathway from the endoplasmic reticulum. AB - The endoplasmic reticulum (ER) is the site for maturation of proteins destined for the secretory pathway. Failure in maturation leads to production of misfolded proteins that are eliminated through the ER-associated degradation (ERAD) pathway. ERAD is a complex process that includes misfolded protein recognition, retrotranslocation to the cytosol, ubiquitination and proteasomal degradation. gp78 is an E3 ubiquitin ligase that integrates these ERAD steps by nucleating a unique degradation machine, which uses the p97/VCP-Npl4 complex for retrotranslocation instead of the wellknown p97/VCP-Ufd1-Npl4 complex. A growing list of substrates have been identified for gp78, which highlights the importance of gp78-mediated ERAD in essential physiological pathways and pathological processes. PMID- 22812525 TI - Structural aspects of ubiquitin binding specificities. AB - Ubiquitin (Ub) is widely distributed in eukaryotic cells as its name means. There are many kinds of Ub-like proteins (for example, SUMO, NEDD8 and ISG15) and Ub like domains (UbLs) included in multi-domain proteins. To date, a large number of Ub-binding domains (UBDs), such as UBA, CUE, UIM, ZnF, and Pru, are coming up to us with different affinities to Ub and its homologues. The binding specificities provide the basis for controlling various cellular events as well as for delivering ubiquitinated proteins to proteasome for degradation. Structural details of these UBDs and their complexes with Ub might as well show us the delicate mechanism of Ub recognition and regulation. This review summarizes recent progresses on deciphering the structure-based Ub-binding specificities, which are the importantly fundamental elements in orchestrating the ubiquitination and deubiquitination processes in eukaryotic cells. PMID- 22812526 TI - Roles of ubiquitin in endoplasmic reticulum-associated protein degradation (ERAD). AB - In the secretory pathway, quality control for the correct folding of proteins is largely occurring in the endoplasmic reticulum (ER), at the earliest possible stage and in an environment where early folding intermediates mix with terminally misfolded species. An elaborate cellular mechanism aims at dividing the former from the latter and promotes the selective transport of misfolded species back into the cytosol, a step called retrotranslocation. During retrotranslocation proteins will become ubiquitinated on the cytosolic side of the ER membrane by dedicated machineries and will be targeted to the proteasome for degradation. The entire process, from protein recognition to final degradation, has been named ER associated protein degradation, or simply ERAD. Ubiquitin has well known functions in aiding late steps of substrate retrotranslocation and in targeting substrates to the proteasome. Recent results show that several cytosolic machineries allow ubiquitinated substrates to undergo extensive remodeling, or processing, on their poly-ubiquitin chains (PUCs). Although still ill-defined, PUC processing might have a unique function for ERAD in that it might provide a mechanism to generate optimal PUCs for recognition by proteasomal ubiquitin receptors. Ubiquitination might also have a previously unanticipated role in quality control of ER membrane proteins. This review recapitulates the current knowledge and recent findings about ERAD-specific roles of ubiquitin. PMID- 22812529 TI - Editorial: protein ubiquitination and deubiquitination. PMID- 22812527 TI - Roles of p97-associated deubiquitinases in protein quality control at the endoplasmic reticulum. AB - To maintain protein homeostasis in the ER, an ER protein quality control system retains unfolded polypeptides and misassembled membrane proteins, allowing only properly folded proteins to exit the ER. Misfolded proteins held in the ER are retrotranslocated into the cytosol, ubiquitinated, and degraded by the proteasome through the ER-associated degradation pathway (ERAD). By timely eliminating misfolded proteins, the ERAD system alleviates cytotoxic stress imposed by protein misfolding. It is well established that ER-associated ubiquitin ligases play pivotal roles in ERAD by assembling ubiquitin conjugates on retrotranslocation substrates, which serve as degradation signals for the proteasome. Surprisingly, recent studies have revealed an equally important function for deubiquitinases (DUBs), enzymes that disassemble ubiquitin chains, in ERAD. Intriguingly, many ERAD specific DUBs are physically associated with the retrotranslocation- driving ATPase p97. Here we discuss the potential functions of p97-associated DUBs including ataxin-3 and YOD1. Our goal is to integrate the emerging evidence into models that may explain how protein quality control could benefit from deubiquitination, a process previously deemed destructive for proteasomal degradation. PMID- 22812528 TI - SUMOylation in control of accurate chromosome segregation during mitosis. AB - Posttranslational protein modification by small ubiquitin-related modifier (SUMO) has emerged as an important regulatory mechanism for chromosome segregation during mitosis. This review focuses on how SUMOylation regulates the centromere and kinetochore activities to achieve accurate chromosome segregation during mitosis. Kinetochores are assembled on the specialized chromatin domains called centromeres and serve as the sites for attaching spindle microtubule to segregate sister chromatids to daughter cells. Many proteins associated with mitotic centromeres and kinetochores have been recently found to be modified by SUMO. Although we are still at the early stage of elucidating how SUMOylation controls chromosome segregation during mitosis, a substantial progress has been achieved over the past decade. Furthermore, a major theme that has emerged from the recent studies of SUMOylation in mitosis is that both SUMO conjugation and deconjugation are critical for kinetochore assembly and disassembly. Lastly, we propose a model that SUMOylation coordinates multiple centromere and kinetochore activities to ensure accurate chromosome segregation. PMID- 22812530 TI - Activatable near-infrared fluorescent probe for in vivo imaging of fibroblast activation protein-alpha. AB - Fibroblast activation protein-alpha (FAPalpha) is a cell surface glycoprotein which is selectively expressed by tumor-associated fibroblasts in malignant tumors but rarely on normal tissues. FAPalpha has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPalpha inhibitors has led to the discovery of many FAPalpha targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPalpha in vivo has largely lagged behind. Herein, we report an activatable near-infrared (NIR) fluorescent probe (ANP(FAP)) for in vivo optical imaging of FAPalpha. The ANP(FAP) consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPalpha cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANP(FAP), high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPalpha both in vitro and in vivo. In vitro assay on ANP(FAP) indicated the specificity of the probe to FAPalpha. The in vivo optical imaging using ANP(FAP) showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPalpha expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPalpha expression, demonstrating the in vivo targeting specificity of the ANP(FAP). Ex vivo imaging also demonstrated ANP(FAP) had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANP(FAP) could serve as a useful NIR optical probe for early detection of FAPalpha expressing tumors. PMID- 22812531 TI - Rumen microbial and fermentation characteristics are affected differently by bacterial probiotic supplementation during induced lactic and subacute acidosis in sheep. AB - BACKGROUND: Ruminal disbiosis induced by feeding is the cause of ruminal acidosis, a digestive disorder prevalent in high-producing ruminants. Because probiotic microorganisms can modulate the gastrointestinal microbiota, propionibacteria- and lactobacilli-based probiotics were tested for their effectiveness in preventing different forms of acidosis. RESULTS: Lactic acidosis, butyric and propionic subacute ruminal acidosis (SARA) were induced by feed chalenges in three groups of four wethers intraruminally dosed with wheat, corn or beet pulp. In each group, wethers were either not supplemented (C) or supplemented with Propionibacterium P63 alone (P) or combined with L. plantarum (Lp + P) or L. rhamnosus (Lr + P). Compared with C, all the probiotics stimulated lactobacilli proliferation, which reached up to 25% of total bacteria during wheat-induced lactic acidosis. This induced a large increase in lactate concentration, which decreased ruminal pH. During the corn-induced butyric SARA, Lp + P decreased Prevotella spp. proportion with a concomitant decrease in microbial amylase activity and total volatile fatty acids concentration, and an increase in xylanase activity and pH. Relative to the beet pulp-induced propionic SARA, P and Lr + P improved ruminal pH without affecting the microbial or fermentation characteristics. Regardless of acidosis type, denaturing gradient gel electrophoresis revealed that probiotic supplementations modified the bacterial community structure. CONCLUSION: This work showed that the effectiveness of the bacterial probiotics tested depended on the acidosis type. Although these probiotics were ineffective in lactic acidosis because of a deeply disturbed rumen microbiota, some of the probiotics tested may be useful to minimize the occurrence of butyric and propionic SARA in sheep. However, their modes of action need to be further investigated. PMID- 22812532 TI - Ten-year rank-order stability of personality traits and disorders in a clinical sample. AB - OBJECTIVE: This study compares the 10-year retest stability of normal traits, pathological traits, and personality disorder dimensions in a clinical sample. METHOD: Ten-year rank-order stability estimates for the Revised NEO Personality Inventory, Schedule for Nonadaptive and Adaptive Personality, and Diagnostic Interview for DSM-IV Personality Disorders were evaluated before and after correcting for test-retest dependability and internal consistency in a clinical sample (N = 266). RESULTS: Dependability-corrected stability estimates were generally in the range of.60-.90 for traits and.25-.65 for personality disorders. CONCLUSIONS: The relatively lower stability of personality disorder symptoms may indicate important differences between pathological behaviors and relatively more stable self-attributed traits and imply that a full understanding of personality and personality pathology needs to take both traits and symptoms into account. The five-factor theory distinction between basic tendencies and characteristic adaptations provides a theoretical framework for the separation of traits and disorders in terms of stability in which traits reflect basic tendencies that are stable and pervasive across situations, whereas personality disorder symptoms reflect characteristic maladaptations that are a function of both basic tendencies and environmental dynamics. PMID- 22812533 TI - Unmasking of axial spondyloarthritis and oligoarthritis following discontinuation of tumour necrosis factor inhibitor therapy for psoriasis. AB - Psoriatic arthritis remains a common cause of morbidity in patients with psoriasis. Little is known about the natural history of the disease and dermatologists do not consistently screen for its presence. We describe a patient with severe psoriasis where long-term biologic therapy with a tumour necrosis factor inhibitor was interrupted for clinical reasons, leading to a rapidly evolving axial spondyloarthritis and oligoarthritis. This unusual presentation of psoriatic arthritis may reflect masking of the disease by long-term treatment with a tumour necrosis factor inhibitor. We advocate the use of screening for psoriatic arthritis, including before and during treatment with biologic therapies. PMID- 22812535 TI - Value of dynamic substrate mapping to identify the critical diastolic pathway in postoperative ventricular reentrant tachycardias after surgical repair of tetralogy of fallot. AB - Characterization of the Critical Isthmus in VT in TOF. INTRODUCTION: The complexity of postoperative ventricular reentrant tachycardias may limit success of catheter ablation. The objective of this analysis was to compare the usefulness of dynamic substrate mapping (DSM) versus color-coded isopotential mapping of the noncontact mapping system for the identification of the critical diastolic pathway of postoperative ventricular reentrant tachycardias (VT) after surgical repair of tetralogy of Fallot (TOF). METHODS: Postoperative VT had been studied applying isopotential maps with the noncontact mapping system EnSite in 7 patients, and radiofrequency current lesion lines had been applied across the shortest isthmus to target during sinus rhythm. Data of the noncontact mapping system were reanalyzed applying the DSM algorithm. For DSM, a 2-Hz filter and color settings between 0 mV and 50% of peak negative voltage (PNV) with autofocus turned off were used. DSM was initially applied over the QRS complex duration during sinus rhythm. Abnormal myocardium was defined as <35-40% of PNV. DSM was subsequently applied to ventricular diastole during the final 33% of VT cycle length. Areas with >70% of PNV within this time frame were to identify the critical diastolic pathway. RESULTS: Applying DSM, the critical diastolic pathway of the VT was identified in all 7 patients that corresponded to the regions targeted for ablation. CONCLUSION: By focusing the time reference to electrical diastole, when the VT wavefront is moving through the low-voltage area, the region of greatest relative voltage could be highlighted, which corresponded to the diastolic pathway. (J Cardiovasc Electrophysiol, Vol. 23, pp. 930-937, September 2012). PMID- 22812534 TI - Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. AB - INTRODUCTION: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3 phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1 (benzylcarbamoyl)propyl)benzamide using preclinical models. METHODS: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells. RESULTS: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment. CONCLUSION: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance. PMID- 22812536 TI - The conundrum of pH in water nanodroplets: sensing pH in reverse micelle water pools. AB - In aqueous environments, acidity is arguably the most important property dictating the chemical, physical, and biological processes that can occur. However, in a variety of environments where the minuscule size limits the number of water molecules, the conventional macroscopic description of pH is no longer valid. This situation arises for any and all nanoscopically confined water including cavities in minerals, porous solids, zeolites, atmospheric aerosols, enzyme active sites, membrane channels, and biological cells and organelles. To understand pH in these confined spaces, we have explored reverse micelles as a model system that confines water to nanoscale droplets. At the appropriate concentrations, reverse micelles form in ternary or higher order solutions of nonpolar solvent, polar solvent (usually water), and amphipathic molecules, usually surfactants or lipids. Measuring the acidity, or local density of protons, commonly known as pH, of these nanoscopic water pools in reverse micelles is challenging. First, because the volume of the water in these reverse micelles is so minute, we cannot probe its proton concentration using traditional pH meters. Second, the traditional concept of pH breaks down in a nanosystem that includes fewer than 10(7) water molecules. Third, the interpretation of results from studies attempting to measure acidity or pH in these environments is nontrivial because the conditions fall outside the accepted IUPAC definition for pH. Researchers have developed experimental methods to measure acidity indirectly using various spectroscopic probe molecules. Most measurements of intramicellar pH have employed optical spectroscopy of organic probe molecules containing at least one labile proton coupled to electronic transitions to track pH changes in the environment. These indirect measurements of the pH reflect the local environment sensed by the probe and are complicated by the probe location within the sample and how that location affects properties such as pK(a). Thus, interpretation of the measurement in the highly heterogeneous reverse micellar environment can be challenging. Organic pH probes can often produce ambiguous acidity measurements, because the probes can readily associate with or penetrate the micellar interface. Protonation can also dramatically change the polarity of the probe and shift the probe's location within the system. As a result, researchers have developed highly charged pH-sensitive probes such as hydroxypyrene trisulfonate, vanadate or phosphate that reside in the water pool both before and after protonation. For inorganic probes researchers have used multinuclear NMR spectroscopy to directly measure conditions in the water droplet. Regardless of the probe and method employed, reverse micellar studies include many implicit assumptions. All reported pH measurements comprise averages of molecular ensembles rather than the response of a single molecule. Experiments also represent averages of the dynamic reverse micelles over the time of the experiments. Thus the experiments report results from an average molecular position, pK(a), ionic strength, viscosity, etc. Although the exact meaning of pH in nanosized waterpools challenges scientific intuition and experimental data are non-trivial to interpret, continued experimental studies are critical to improve understanding of these nanoscopic water pools. Experimental data will allow theorists the tools to develop the models that further explore the meaning of pH in nanosized environments. PMID- 22812537 TI - Serotype-dependent expression patterns of stabilized lipopolysaccharide aggregates in Aggregatibacter actinomycetemcomitans strains. AB - Above a critical concentration, amphiphilic lipopolysaccharide (LPS) molecules in an aqueous environment form aggregate structures, probably because of interactions involving hydrophobic bonds. Ionic bonds involving divalent cations stabilize these aggregate structures, making them resistant to breakdown by detergents. The aim of this study was to examine expression patterns of stabilized LPS aggregates in Aggregatibacter actinomycetemcomitans, a microorganism that causes periodontitis. A. actinomycetemcomitans strains of various serotypes and truncated LPS mutants were prepared for this study. Following treatment with a two-phase separation system using the detergent Triton X-114, crude LPS extracts of the study strains were separated into detergent phase LPS (DP-LPS) and aqueous-phase LPS (AP-LPS). Repeated treatment of the aqueous phase with the two-phase separation system produced only a slight decrease in AP-LPS, suggesting that AP-LPS was resistant to the detergent and thus distinguishable from DP-LPS. The presence of divalent cations increased the yield of AP-LPS. AP-LPS expression patterns were serotype-dependent; serotypes b and f showing early expression, and serotypes a and c late expression. In addition, highly truncated LPS from a waaD (rfaD) mutant were unable to generate AP-LPS, suggesting involvement of the LPS structure in the generation of AP-LPS. The two-phase separation was able to distinguish two types of LPS with different physical states at the supramolecular structure level. Hence, AP-LPS likely represents stabilized LPS aggregates, whereas DP-LPS might be derived from non stabilized aggregates. Furthermore, time-dependent expression of stabilized LPS aggregates was found to be serotype-dependent in A. actinomycetemcomitans. PMID- 22812539 TI - Association between acute geriatric syndromes and medication-related hospital admissions. AB - BACKGROUND: Elderly patients are at a 4-fold higher risk of adverse drug events (ADEs) and drug-related hospitalization. Hospitalization of an elderly patient is often preceded by geriatric syndromes, like falls or delirium. OBJECTIVES: The primary aim of this study was to investigate whether geriatric syndromes were associated with ADEs in acutely admitted elderly patients. METHODS: Consecutive medical patients, aged 65 years or more, who were acutely admitted, were enrolled. An initial multidisciplinary evaluation was completed and baseline characteristics were collected. A fall before admission was retrieved from medical charts. Delirium was determined by the Confusion Assessment Method. RESULTS: A total of 641 patients were included. Over 25% had an ADE present at admission, 26% presented with delirium and 12% with a fall. Delirium was associated with the use of antidepressants, antipsychotics and antiepileptics. In all ADEs (n = 167), ADEs were associated with a fall, with non-steroidal anti inflammatory drugs or diuretics, but not with pre-existing functioning, delirium or older age. For ADEs involving psychoactive medication (n = 35), an association was found between delirium, falls, opioids and antipsychotics in bivariate analyses. A fall just before hospitalization (odds ratio [OR] 3.69 [95% CI 1.41, 9.67]), antipsychotics (OR 3.70 [95% CI 1.19, 11.60]) and opioids (OR 14.57 [95% CI 2.02, 105.30]) remained independently associated with an ADE involving psychoactive medication. CONCLUSION: This prospective study demonstrated that, in a cohort of elderly hospital patients, a fall before admission and prevalent delirium are associated with several pharmacological groups and/or with ADE related hospital admission. PMID- 22812538 TI - A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. AB - BACKGROUND: Mild cognitive deficits are experienced by 18% of community-dwelling older adults, many of whom do not progress to dementia. The effect of commonly used medication on subtle impairments in cognitive function may be under recognized. OBJECTIVE: The aim of the review was to examine the evidence attributing amnestic or non-amnestic cognitive impairment to the use of medication with anticholinergic, antihistamine, GABAergic or opioid effects. METHODS: MEDLINE and EMBASE were searched for randomized, double-blind, placebo controlled trials of adults without underlying central nervous system disorders who underwent detailed neuropsychological testing prior to and after oral administration of drugs affecting cholinergic, histaminergic, GABAergic or opioid receptor pathways. Seventy-eight studies were identified, reporting 162 trials testing medication from the four targeted drug classes. Two investigators independently appraised study quality and extracted relevant data on the occurrence of amnestic, non-amnestic or combined cognitive deficits induced by each drug class. Only trials using validated neuropsychological tests were included. Quality of the evidence for each drug class was assessed based on consistency of results across trials and the presence of a dose-response gradient. RESULTS: In studies of short-, intermediate- and long-acting benzodiazepine drugs (n = 68 trials), these drugs consistently induced both amnestic and non-amnestic cognitive impairments, with evidence of a dose-response relationship. H(1)-antihistamine agents (n = 12) and tricyclic antidepressants (n = 15) induced non-amnestic deficits in attention and information processing. Non benzodiazepine derivatives (n = 29) also produced combined deficits, but less consistently than benzodiazepine drugs. The evidence was inconclusive for the type of cognitive impairment induced by different bladder relaxant antimuscarinics (n = 9) as well as for narcotic agents (n = 5) and antipsychotics (n = 5). Among healthy volunteers >60 years of age, low doses of commonly used medications such as lorazepam 0.5 mg, oxybutynin immediate release 5 mg and oxycodone 10 mg produced combined deficits. CONCLUSION: Non-amnestic mild cognitive deficits are consistently induced by first-generation antihistamines and tricyclic antidepressants, while benzodiazepines provoke combined amnestic and non-amnestic impairments. Risk-benefit considerations should be discussed with patients in order to enable an informed choice about drug discontinuation or substitution to potentially reverse cognitive adverse effects. PMID- 22812540 TI - Perspective and agency during video gaming influences spatial presence experience and brain activation patterns. AB - BACKGROUND: The experience of spatial presence (SP), i.e., the sense of being present in a virtual environment, emerges if an individual perceives himself as 1) if he were actually located (self-location) and 2) able to act in the virtual environment (possible actions). In this study, two main media factors (perspective and agency) were investigated while participants played a commercially available video game. METHODS: The differences in SP experience and associated brain activation were compared between the conditions of game play in first person perspective (1PP) and third person perspective (3PP) as well as between agency, i.e., active navigation of the video game character (active), and non-agency, i.e., mere passive observation (passive). SP was assessed using standard questionnaires, and brain activation was measured using electroencephalography (EEG) and sLORETA source localisation (standard low resolution brain electromagnetic tomography). RESULTS: Higher SP ratings were obtained in the 1PP compared with the 3PP condition and in the active compared with the passive condition. On a neural level, we observed in the 1PP compared with the 3PP condition significantly less alpha band power in the parietal, the occipital and the limbic cortex. In the active compared with the passive condition, we uncovered significantly more theta band power in frontal brain regions. CONCLUSION: We propose that manipulating the factors perspective and agency influences SP formation by either directly or indirectly modulating the ego-centric visual processing in a fronto-parietal network. The neuroscientific results are discussed in terms of the theoretical concepts of SP. PMID- 22812542 TI - Does head CT scan pathology predict outcome after mild traumatic brain injury? AB - BACKGROUND AND PURPOSE: More evidence is needed to forward our understanding of the key determinants of poor outcome after mild traumatic brain injury (MTBI). A large, prospective, national cohort of patients was studied to analyse the effect of head CT scan pathology on the outcome. METHODS: One-thousand two-hundred and sixty-two patients with MTBI (Glasgow Coma Scale score 15) at 39 emergency departments completed a study protocol including acute head CT scan examination and follow-up by the Rivermead Post Concussion Symptoms Questionnaire and the Glasgow Outcome Scale Extended (GOSE) at 3 months after MTBI. Binary logistic regression was used for the assessment of prediction ability. RESULTS: In 751 men (60%) and 511 women (40%), with a mean age of 30 years (median 21, range 6-94), we observed relevant or suspect relevant pathologic findings on acute CT scan in 52 patients (4%). Patients aged below 30 years reported better outcome both with respect to symptoms and GOSE as compared to patients in older age groups. Men reported better outcome than women as regards symptoms (OR 0.64, CI 0.49-0.85 for >=3 symptoms) and global function (OR 0.60, CI 0.39-0.92 for GOSE 1-6). CONCLUSIONS: Pathology on acute CT scan examination had no effect on self reported symptoms or global function at 3 months after MTBI. Female gender and older age predicted a less favourable outcome. The findings support the view that other factors than brain injury deserve attention to minimize long-term complaints after MTBI. PMID- 22812541 TI - Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/ ) mice. AB - Ribavirin is frontline treatment for hepatitis C virus infection. To determine the role of nucleoside transporters in the intestinal absorption of orally administered ribavirin, we perfused the intestines of Ent1(-/-) and wild-type mice, in situ, with [(3)H] ribavirin (20, 200, and 5000 MUM) in the presence and absence of sodium. The decrease in luminal ribavirin concentration over 30 min was measured at 5 min intervals. Blood samples were collected approximately every 10 min. Ribavirin plus phosphorylated metabolite concentrations (hereafter referred to as ribavirin) were determined in tissue, blood, and plasma by HPLC fractionation and scintillation counting. There was no significant difference between wild-type and Ent1(-/-) mice in intestinal loss of ribavirin at any ribavirin concentration studied. Perfusions without sodium drastically reduced the intestinal loss of ribavirin in both wild-type and Ent1(-/-) mice. After 20 MUM ribavirin perfusions, Ent1(-/-) intestinal tissue contained 8-fold greater ribavirin than wild-type mice (p < 0.01). Ribavirin concentrations in the wild type intestinal tissue were 70-fold higher after 200 vs 20 MUM perfusions (p < 0.001), indicating saturation of intestinal ribavirin efflux and possibly other processes as well. Ribavirin plasma concentrations were significantly higher in wild-type mice (2.7-fold) vs Ent1(-/-) mice at 30 min after the 20 MUM perfusion (p < 0.01). These results suggest that, at lower intestinal concentrations of ribavirin, concentrative and equilibrative nucleoside transporters are important in the intestinal absorption of ribavirin. At higher intestinal concentrations, these transporters are saturated and other processes in the intestine (transport and/or metabolism) play an important role in the absorption of ribavirin. PMID- 22812543 TI - Identification of Hic-5 as a novel regulatory factor for integrin alphaIIbbeta3 activation and platelet aggregation in mice. AB - BACKGROUND: Integrin alphaIIbbeta3 plays key roles in platelet aggregation and subsequent thrombus formation. Hydrogen peroxide-inducible clone-5 (Hic-5), a member of the paxillin family, serves as a focal adhesion adaptor protein associated with alphaIIbbeta3 at its cytoplasmic strand. OBJECTIVES: Hic-5 function in alphaIIbbeta3 activation and subsequent platelet aggregation remains unknown. To address this question, platelets from Hic-5(-/-) mice were analyzed. METHODS AND RESULTS: Hic-5(-/-) mice displayed a significant hemostatic defect and resistance to thromboembolism, which were explained in part by weaker thrombin-induced aggregation in Hic-5(-/-) platelets. Mechanistically, Hic-5(-/-) platelets showed limited activation of alphaIIbbeta3 upon thrombin treatment. Morphological alteration in Hic-5(-/-) platelets after thrombin stimulation on fibrinogen plates was also limited. As a direct consequence, the quantity of actin co-immunoprecipitating with the activated alphaIIbbeta3 was smaller in Hic 5(-/-) platelets than in wild-type platelets. CONCLUSION: We identified Hic-5 as a novel and specific regulatory factor for thrombin-induced alphaIIbbeta3 activation and subsequent platelet aggregation in mice. PMID- 22812544 TI - The anion dependence of the interaction strength between ions in imidazolium based ionic liquids probed by far-infrared spectroscopy. AB - We have shown that far-infrared (FIR) spectroscopy is a sensitive probe for detecting the anion-cation interaction strength in imidazolium-based ionic liquids (ILs). Supported by density functional theory (DFT) calculations of frequencies and energies for large IL aggregates, it is observed that frequency shifts stem mainly from varying interaction strength rather than from different reduced masses of the anions. The strongest interaction is observed for the IL containing the acetate anion which is well-known for its effective dissolution power for cellulose. PMID- 22812545 TI - Value for money of drug regulation. PMID- 22812546 TI - Using exercise to fight fatigue in breast cancer survivors: challenges and future directions. PMID- 22812548 TI - The cost-effectiveness of risperidone long-acting injection in the treatment of schizophrenia. AB - Schizophrenia is an extremely costly disease for families and society owing to the age of onset, chronicity and severity of impact in social, academic and vocational domains. Relapse and often consequent hospitalizations are the most significant healthcare cost drivers, and are closely related to partial- and non adherence to treatment. Long-acting injections of first-generation antipsychotics or depots were initially developed to attempt to address the adherence problems that are inherent in the treatment of a disorder characterized by difficulties in therapeutic engagement and alliance, as well as impaired insight. Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available in a long-acting formulation. Determining the pharmacoeconomic benefit of a long-acting injection compared with other treatments is challenging, as there are many different factors and costs involved. Data from pharmacoeconomic modeling, hospitalization, mirror image and other studies suggest that, in general, the greater initial acquisition cost of RLAI is offset by reductions in other domains including hospitalization. However, most of the published studies are open label and are subject to significant selection and sponsor bias. While overall cost-effectiveness in a wide array of different healthcare systems and diverse patient populations has been demonstrated with RLAI, not all studies show a clear benefit. Furthermore, there are unique challenges with RLAI in terms of storage and administration that add to the costs of this treatment. PMID- 22812549 TI - Evaluating the impact of Medicare Part D on quality metrics. AB - Subsidized access to medical and pharmacy benefits is not a goal in and of itself; it is a means toward an end (improved health outcomes). Accordingly, the addition of an outpatient prescription drug benefit (Part D) to Medicare in 2006 will be deemed a success if it provides better, more affordable access to outpatient prescription drugs for Medicare beneficiaries and, more importantly, improves drug adherence and health outcomes, together with reducing or at least bending the cost curve by offsetting certain healthcare costs such as hospitalizations and emergency room visits. Priest and colleagues examine these claims and find suboptimal outcomes despite improved access. PMID- 22812550 TI - Modeling cost-effectiveness of pharmaceuticals in Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disorder characterized by cognitive and behavioral deficits. Donepezil and memantine are two medications used to treat the symptoms of cognitive decline in Alzheimer's disease. A modeled cost effectiveness analysis found that treatment with donepezil to be less costly and more effective than no treatment or treatment with memantine in Germany. However, the model drew on non-German population data and could have been more transparent with regard to 'back-end' processes. In addition, the authors would question the extent to which the differences in effectiveness between treatments would be considered clinically significant. Identifying sources of cost savings for donepezil remains an important issue for future consideration. PMID- 22812551 TI - Quality-of-life results used to endorse changes in standard of care for recurrent platinum-sensitive ovarian cancer. AB - Most women with ovarian cancer will suffer a recurrence. Unfortunately, although initial treatment can lead to undetectable disease, recurrent disease is often more challenging to control. As curative intent is less common after relapse, patients and doctors argue for improving quality-of-life (QoL) outcomes when therapies are selected. The article reviewed here discusses the QoL results of a trial in platinum-sensitive recurrent ovarian cancer where over 900 patients were randomized to the standard treatment (carboplatin and paclitaxel) versus carboplatin and pegylated liposomal doxorubicin. In the paper under evaluation, the standard of care is challenged based on a favorable clinical outcome in addition to QoL results in the experimental arm. PMID- 22812552 TI - Role of health technology assessment in the process of implementation of the EU Transparency Directive: relevant experience from Central Eastern European countries. AB - A total of 7 years after the addition of Poland, the Czech Republic and Hungary to the EU, the pricing and reimbursement regulations introduced in these countries are still considered to be not fully compliant with Directive 89/105/EEC, commonly referred to as the 'Transparency Directive' (TD). The TD aims to ensure the transparency of the pricing and reimbursement processes for medicinal products established by the member states. Among the most difficult barriers on the way to successful implementation of the TD discussed are meeting the timelines indicated by the TD, the implementation of objective and verifiable criteria for decisions, and the availability of remedies for negative decisions. Health technology assessment (HTA) has been introduced in to the reimbursement systems in Poland, the Czech Republic and Hungary almost simultaneously to their accession to the EU. Even though Central Eastern European (CEE) countries faced similar challenges during the transformation to a democratic system, certain differences in the extent to which HTA principles have been implemented in these countries could be distinguished. Hence, it is thought-provoking to consider the different views of HTA experts on the role of HTA in the adaptation of the TD in the CEE region. The key objective of this article will be to discuss whether the adaptation of HTA principles has supported or only triggered additional challenges in the process of successful implementation of the TD in the CEE region. In particular, the article will discuss whether the introduction of mandatory HTA recommendations or explicit willingness-to-pay threshold would encourage or discourage implementation of the TD. The importance of the independent HTA agency as a condition for successful introduction of the TD will also be debated. PMID- 22812553 TI - Personalized medicine policy challenges: measuring clinical utility at point of care. AB - Pharmacogenomics, driven by advances in genomics, helps to explain patients' individual variability in response to therapies. Personalized medicine, the application of the increasing understanding of pharmacogenomics, and information technology are intertwined from discovery to delivery at point of care, through to tracking clinical outcomes. Although exemplary cases of personalized medicine adoption demonstrate patient benefit and cost-effectiveness, a remaining barrier to large-scale real-world uptake of this novel approach in medicine is policy change. At point-of-care implementation, case studies will need to measure personalized medicine application outcomes of relevance to policy-makers and as evidence of clinical utility. Assessments need to be consistent across case studies. Standardizing specifications for case studies will better inform policy makers performing economic evaluations on the use of personalized medicine. PMID- 22812554 TI - Cost-effectiveness of preventing weight gain and obesity: what we know and what we need to know. AB - The objective of this study was to show gaps and inconsistencies in selected literature on the cost-effectiveness of preventing weight gain and obesity and to set an agenda for future research. A review and qualitative analysis of the literature was carried out on the cost-effectiveness of preventing weight gain and obesity, with a primary focus on programs that influence health outcomes and directly change individual behavior through physical activity promotion (i.e., energy expenditure increase). A literature search reveals that computer simulation models on the lifetime cost of obese versus normal-weight persons show conflicting results. Studies on programs to promote physical activity as a means to prevent obesity also show varying cost-effectiveness ratios, with a key variable from a societal perspective being the cost of time required to exercise. In particular, this review found a need for more parsimonious simulation models and more information on the comparative cost-effectiveness of programs to prevent weight gain/obesity. PMID- 22812555 TI - Cost-effectiveness of TNF-alpha inhibition in active ankylosing spondylitis: a systematic appraisal of the literature. AB - Ankylosing spondylitis (AS) is the most frequent prototype of spondyloarthritides. Substantial direct costs and productivity losses often arise in young patients. Currently, tumor necrosis factor (TNF) inhibitors are the only approved therapy escalation when usual care (physiotherapy and NSAIDs) proves to be insufficient. Owing to their high medication costs, TNF inhibitors are a target of cost-effectiveness analyses. There is consistent evidence regarding the use of TNF inhibitors according to recommendations in patients with active AS finding TNF inhibitors to be cost effective from a societal perspective. However, there are relevant uncertainties (discontinuation rate and progression rate) in the long-term estimates of the cost-effectiveness analyses analyzed. Whether TNF inhibitors are cost effective from an insurance perspective in the long run will have to be addressed by models based on observational data. PMID- 22812556 TI - When is switching warranted among biologic therapies in rheumatoid arthritis? AB - Switching among biologic therapies is common practice in patients with rheumatoid arthritis who have an inadequate response or intolerable adverse events. Evidence from observational studies and association guidelines supports the use of sequential biologic therapy for these reasons. Owing to recent economic pressures on healthcare budgets, patients with rheumatoid arthritis who are well controlled on and tolerant of their current biologic therapy may be switched to alternative biologics, despite limited evidence supporting this practice. Clinical research and experience suggest that TNF antagonists are not interchangeable, as meaningful differences have been observed in their efficacy and safety profiles. Additional research is needed to assess the risk:benefit ratio of specific sequences of biologic therapies and the validity of switching biologic therapies for nonclinical purposes. PMID- 22812557 TI - Impact of adverse events on costs and quality of life in protease inhibitor-based combination therapy for hepatitis C. AB - Protease inhibitor with pegylated interferon and ribavirin therapy (PI-PR) increases hepatitis C virus treatment efficacy versus standard of care pegylated interferon and ribavarin therapy [PR]. The adverse event (AE) impact of PI-PR remains under-reported. The authors estimated the AE impact on costs, treatment discontinuation and health-related quality of life (HRQoL) in PI-PR- and PR treated patients through literature review and cost analysis. HRQoL and safety data were synthesized by instrument, AE and discontinuation rate. AE-related treatment costs were estimated with trial-based AE rates and literature-based protocols, resource utilization and standard costs. No PI-PR study reported HRQoL outcomes. Five PR studies reported that anemia, depression, fatigue and/or influenza-like symptoms negatively affected HRQoL. Decreased HRQoL predicted treatment discontinuation in two PR studies. PI-PR and PR had comparable AE related treatment discontinuation rates (~12%). Weighted AE-related treatment costs were US$2042, $1835 and $1076 in boceprevir-based PI-PR, PR and telaprevir based PI-PR, respectively. AE-related burden may increase with PI-PR. Future studies should incorporate AE-related economic and HRQoL outcomes to comprehensively assess costs/benefits. PMID- 22812558 TI - Comparing prognostic factors in patients with spinal metastases: a literature review. AB - For cancer patients with spinal metastases, palliative treatments are directed toward improving the patient's symptoms and quality of life. The expected prognosis of patients plays a large role in guiding treatment decisions, particularly when deciding between surgical management and conservative treatments, such as radiotherapy. This study aims to review the factors that can accurately predict the survival of patients with spinal metastases. The authors conducted a literature search on studies identifying prognostic factors using PubMed (1966-2011), Ovid MEDLINE (1948 to July 2011) and EMBASE (1947-2011) databases. Articles in English were included if they conducted retrospective or prospective analyses on predictors of survival for patients with spinal metastases; articles validating or examining the accuracy of existing scoring systems using prognostic factors were also included. A total of 29 studies were identified. A general consensus of the literature was found with respect to three prognostic factors: the patient's primary cancer site, the extent of the metastases and the general condition or performance score. Further research is recommended to assess the prognostic value of other factors identified by several studies, including age, neurological deficit and previous treatments. For future studies, the authors encourage the development of models capable of inclusion of all patients with spinal metastases. PMID- 22812559 TI - Categorization of methods used in cost-effectiveness analyses of vaccination programs based on outcomes from dynamic transmission models. AB - The aim of this study is to categorize methods used to estimate the cost effectiveness of vaccination programs using dynamic transmission models, and assess value to decision-makers. A targeted literature search of PubMed has been carried out for this purpose. A review of 43 articles presenting cost effectiveness analyses of vaccination programs based on dynamic transmission models identified four methods for the estimation of a cost-effectiveness ratio: cumulative population values over a fixed time horizon; population values for a steady-state year; cohort values from time of program initiation; and cohort values at steady state. Cost-effectiveness estimates are sensitive to the choice of time horizon or number of cohorts included. Estimates at steady state are the most comparable to estimates for other healthcare interventions but do not account for pre-steady-state periods. Population values provide estimates of budget impact. In conclusion, four different methods were identified for converting clinical outcomes from a dynamic transmission model to cost effectiveness estimates. Sensitivity analyses for time horizon or number of cohorts considered should be routinely performed. PMID- 22812560 TI - Initiatives to improve prescribing efficiency for drugs to treat Parkinson's disease in Croatia: influence and future directions. AB - Parkinson's disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency. PMID- 22812562 TI - Double locking of an Escherichia coli promoter by two repressors prevents premature colicin expression and cell lysis. AB - The synthesis of Eschericha coli colicins is lethal to the producing cell and is repressed during normal growth by the LexA transcription factor, which is the master repressor of the SOS system for repair of DNA damage. Following DNA damage, LexA is inactivated and SOS repair genes are induced immediately, but colicin production is delayed and induced only in terminally damaged cells. The cause of this delay is unknown. Here we identify the global transcription repressor, IscR, as being directly responsible for the delay in colicin K expression during the SOS response, and identify the DNA target for IscR at the colicin K operon promoter. Our results suggest that, IscR stabilizes LexA at the cka promoter after DNA damage thus, preventing its cleavage and inactivation, and this cooperation ensures that suicidal colicin K production is switched on only as a last resort. A similar mechanism operates at the regulatory region of other colicins and, hence, we suggest that many promoters that control the expression of 'lethal' genes are double locked. PMID- 22812563 TI - Personality change predicts self-reported mental and physical health. AB - OBJECTIVE: Personality dimensions are known to predict mortality and other health outcomes, but almost no research has assessed the effects of changes in personality traits on physical and mental health outcomes. In this article, we examined the effects of changes in the Big Five personality dimensions on health as assessed by the Short Form Health Survey (SF-36). METHOD: Respondents were 11,105 Australian adults aged 20-79 years (52.7% female). Latent difference score modeling was used to examine whether personality change over a 4-year period was associated with mental and physical health, and whether these effects were moderated by birth cohort. RESULTS: Increases in Conscientiousness and Extraversion were found to be associated with improved mental and physical health, whereas increased Neuroticism was linked with poorer health. The nature of these associations varied significantly by birth cohort. CONCLUSION: The findings have implications for understanding how changes in personality traits over time are related to health, and could be used to aid the development of effective health promotion strategies targeted to specific personality traits and birth cohorts. PMID- 22812565 TI - Integrating the results of user research into medical device development: insights from a case study. AB - BACKGROUND: It is well established that considering users is an important aspect of medical device development. However it is also well established that there are numerous barriers to successfully conducting user research and integrating the results into product development. It is not sufficient to simply conduct user research, it must also be effectively integrated into product development. METHODS: A case study of the development of a new medical imaging device was conducted to examine in detail how users were involved in a medical device development project. Two user research studies were conducted: a requirements elicitation interview study and an early prototype evaluation using contextual inquiry. A descriptive in situ approach was taken to investigate how these studies contributed to the product development process and how the results of this work influenced the development of the technology. Data was collected qualitatively through interviews with the development team, participant observation at development meetings and document analysis. The focus was on investigating the barriers that exist to prevent user data from being integrated into product development. RESULTS: A number of individual, organisational and system barriers were identified that functioned to prevent the results of the user research being fully integrated into development. The user and technological aspects of development were seen as separate work streams during development. The expectations of the developers were that user research would collect requirements for the appearance of the device, rather than challenge its fundamental concept. The manner that the user data was communicated to the development team was not effective in conveying the significance or breadth of the findings. CONCLUSION: There are a range of informal and formal organisational processes that can affect the uptake of user data during medical device development. Adopting formal decision making processes may assist manufacturers to take a more integrated and reflective approach to development, which should result in improved business decisions and a higher quality end product. PMID- 22812566 TI - Advances in platelet function testing assessing bleeding complications in patients with coronary artery disease. AB - Antiplatelet therapy is the cornerstone of treatment in preventing ischemic events in patients with coronary artery disease (CAD), particularly in the setting of acute coronary syndromes and percutaneous coronary interventions. However, antiplatelet therapy is also associated with an increased risk of bleeding complications, which are more frequent with the use of more potent antiplatelet treatment regimens. Therefore, defining the balance between the risk of thrombotic events and the risk of bleeding is essential to improve overall clinical outcomes. The pharmcodynamic effects of antiplatelet agents vary broadly and may be associated with differences in outcomes. In particular, patients are at an increased risk of ischemic or bleeding complications if the pharmacodynamic effects are reduced or enhanced, respectively. Multiple platelet function assays are currently available to assess the pharmacodynamic effects of commonly used antiplatelet agents. The present manuscript will review the prognostic value of platelet function testing to identify patients with CAD at risk of bleeding complications and the potential applications of these tests in the modern era of antiplatelet pharmacotherapy. PMID- 22812564 TI - Chronic lead exposure reduces doublecortin-expressing immature neurons in young adult guinea pig cerebral cortex. AB - BACKGROUND: Chronic lead (Pb) poisoning remains an environmental risk especially for the pediatric population, and it may affect brain development. Immature neurons expressing doublecortin (DCX+) exist around cortical layer II in various mammals, including adult guinea pigs and humans. Using young adult guinea pigs as an experimental model, the present study explored if chronic Pb exposure affects cortical DCX + immature neurons and those around the subventricular and subgranular zones (SVZ, SGZ). RESULTS: Two month-old guinea pigs were treated with 0.2% lead acetate in drinking water for 2, 4 and 6 months. Blood Pb levels in these animals reached 10.27 +/- 0.62, 16.25 +/- 0.78 and 19.03 +/- 0.86 MUg/dL at the above time points, respectively, relative to ~3 MUg/dL in vehicle controls. The density of DCX + neurons was significantly reduced around cortical layer II, SVZ and SGZ in Pb-treated animals surviving 4 and 6 months relative to controls. Bromodeoxyuridine (BrdU) pulse-chasing studies failed to find cellular colocalization of this DNA synthesis indicator in DCX + cells around layer II in Pb-treated and control animals. These cortical immature neurons were not found to coexist with active caspase-3 or Fluoro-Jade C labeling. CONCLUSION: Chronic Pb exposure can lead to significant reduction in the number of the immature neurons around cortical layer II and in the conventional neurogenic sites in young adult guinea pigs. No direct evidence could be identified to link the reduced cortical DCX expression with alteration in local neurogenesis or neuronal death. PMID- 22812568 TI - Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence. AB - The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs. PMID- 22812567 TI - Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple negative breast cancer. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is diagnosed in approximately 15% of all human breast cancer (BrCa) patients. Currently, no targeted therapies exist for this subtype of BrCa and prognosis remains poor. Our laboratory has previously identified a proliferation/DNA repair/cell cycle gene signature (Tag signature) that is characteristic of human TNBC. We hypothesize that targeting the dysregulated biological networks in the Tag gene signature will lead to the identification of improved combination therapies for TNBC. METHODS: Cross-species genomic analysis was used to identify human breast cancer cell lines that express the Tag signature. Knock-down of the up-regulated genes in the Tag signature by siRNA identified several genes that are critical for TNBC cell growth. Small molecule inhibitors to two of these genes were analyzed, alone and in combination, for their effects on cell proliferation, cell cycle, and apoptosis in vitro and tumor growth in vivo. Synergy between the two drugs was analyzed by the Chou-Talalay method. RESULTS: A custom siRNA screen was used to identify targets within the Tag signature that are critical for growth of TNBC cells. Ribonucleotide reductase 1 and 2 (RRM1 and 2) and checkpoint kinase 1 (CHK1) were found to be critical targets for TNBC cell survival. Combination therapy, to simultaneously attenuate cell cycle checkpoint control through inhibition of CHK1 while inducing DNA damage with gemcitabine, improved therapeutic efficacy in vitro and in xenograft models of TNBC. CONCLUSIONS: This combination therapy may have translational value for patients with TNBC and improve therapeutic response for this aggressive form of breast cancer. PMID- 22812569 TI - Paroxysmal tachycardia with pauses to ponder. PMID- 22812570 TI - Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes. AB - To identify proteins that regulate CCN2 activity, we carried out GAL4-based yeast two-hybrid screening with a cDNA library derived from a chondrocytic cell line, HCS-2/8. CCN2/CTGF and CCN3/NOV polypeptides were picked up as CCN2-binding proteins, and CCN2-CCN2 and CCN2-CCN3 binding domains were identified. Direct binding between CCN2 and CCN3 was confirmed by coimmunoprecipitation in vitro and in vivo and surface plasmon resonance, and the calculated dissociation constants (K(d)) were 1.17 * 10(-9) m for CCN2 and CCN2, and 1.95 * 10(-9) m for CCN2 and CCN3. Ectopically overexpressed green fluorescent protein-CCN2 and Halo-CCN3 in COS7 cells colocalized, as determined by direct fluorescence analysis. We present evidence that CCN2-CCN3 interactions modulated CCN2 activity such as enhancement of ACAN and col2a1 expression. Curiously, CCN2 enhanced, whereas CCN3 inhibited, the expression of aggrecan and col2a1 mRNA in HCS-2/8 cells, and combined treatment with CCN2 and CCN3 abolished the inhibitory effect of CCN3. These effects were neutralized with an antibody against the von Willebrand factor type C domain of CCN2 (11H3). This antibody diminished the binding between CCN2 and CCN2, but enhanced that between CCN3 and CCN2. Our results suggest that CCN2 could form homotypic and heterotypic dimers with CCN2 and CCN3, respectively. Strengthening the binding between CCN2 and CCN3 with the 11H3 antibody had an enhancing effect on aggrecan expression in chondrocytes, suggesting that CCN2 had an antagonizing effect by binding to CCN3. PMID- 22812571 TI - Chemical analysis of complex organic mixtures using reactive nanospray desorption electrospray ionization mass spectrometry. AB - Reactive nanospray desorption electrospray ionization (nano-DESI) combined with high-resolution mass spectrometry was utilized for the analysis of secondary organic aerosol produced through ozonolysis of limonene (LSOA). Previous studies have shown that LSOA constituents are multifunctional compounds containing at least one aldehyde or ketone groups. In this study, we used the selectivity of the Girard's reagent T (GT) toward carbonyl compounds to examine the utility of reactive nano-DESI for the analysis of complex organic mixtures. In these experiments, 1-100 MUM GT solutions were used as the working solvents for reactive nano-DESI analysis. Abundant products from the single addition of GT to LSOA constituents were observed at GT concentrations in excess of 10 MUM. We found that LSOA dimeric and trimeric compounds react with GT through a simple addition reaction resulting in formation of the carbinolamine derivative. In contrast, reactions of GT with monomeric species result in the formation of both the carbinolamine and the hydrazone derivatives. In addition, several monomers did not react with GT on the time scale of our experiment. These molecules were characterized by relatively high values of the double bond equivalent and low oxygen content. Furthermore, because addition of a charged GT tag to a neutral molecule eliminates the discrimination against the low proton affinity compounds in the ionization process, reactive nano-DESI analysis enables quantification of individual compounds in the complex mixture. For example, we were able to estimate for the first time the amounts of dimers and trimers in the LSOA mixture. Specifically, we found that the most abundant LSOA dimer was detected at the ~0.5 pg level and the total amount of dimers and trimers in the analyzed sample was ~11 pg. Our results indicate that reactive nano-DESI is a valuable approach for examining the presence of specific functional groups and for the quantification of compounds possessing these groups in complex mixtures. PMID- 22812572 TI - Cohort study examining long-term respiratory health, career duration and racing performance in racehorses that undergo left-sided prosthetic laryngoplasty and ventriculocordectomy surgery for treatment of left-sided laryngeal hemiplegia. AB - REASONS FOR PERFORMING STUDY: The risk of respiratory conditions, such as inflammatory airway disease (IAD) and exercise-induced pulmonary haemorrhage (EIPH), are thought to be higher in racehorses that undergo prosthetic laryngoplasty with ventriculocordectomy (PLVC) surgery to treat left-sided laryngeal hemiplegia (LLH) than in racehorses with normal laryngeal function. However, this has not been investigated formally owing to the difficulty of obtaining reliable follow-up data. OBJECTIVES: To determine the incidence of respiratory conditions (IAD and EIPH), duration of racing career, number of starts and number of starts for which stakes money was earned in racehorses that had undergone PLVC surgery to treat LLH, compared with racehorses that did not have LLH or undergo any laryngeal surgery. METHODS: A retrospective cohort study design was used, with surgical, clinical and race data of Thoroughbred racehorses obtained from the time of importation until retirement. The surgical cohort consisted of racehorses that had undergone PLVC for LLH and met specific inclusion criteria. Every surgical case was matched, according to trainer, year of import into Hong Kong and pre-import international handicap rating, to 2 unexposed racehorses. RESULTS: Respiratory conditions, such as excessive tracheal mucus and epistaxis due to severe EIPH, were significantly increased in the surgical cohort, compared with the matched unexposed cohort (P values <0.001 and <0.004, respectively). Racing career duration in the surgical cohort was significantly shorter than in the unexposed cohort, which was primarily due to retirement because of epistaxis. The number of race starts was fewer in the surgical than in the unexposed cohort after surgery/matching, but the number of starts for which stakes money was earned was not significantly different. CONCLUSIONS AND POTENTIAL RELEVANCE: Owners and trainers should be advised that racehorses with LLH that undergo PLVC surgery are at an increased risk of respiratory conditions (IAD and severe EIPH), which is likely to shorten their racing career compared to racehorses with normal laryngeal function. Racing performance in terms of race starts was significantly less in racehorses that had undergone PLVC surgery; however, the number of starts for which stakes money was earned was similar to those racehorses that were unexposed. PMID- 22812574 TI - Commentary on "Cystic duct leaks after laparoendoscopic single-site cholecystectomy": a word of caution. PMID- 22812573 TI - High-risk estrogen-receptor-positive breast cancer: identification and implications for therapy. AB - The estrogen receptor (ER) has long been recognized as a key discriminative feature of breast cancer, which carries profound implications for management. However, recent advances in the understanding of breast cancer heterogeneity have demonstrated the importance of biologic context to the interpretation of ER as a prognostic and predictive factor. The use of tumor subtyping methods and prognostic indicators based on molecular profiling of tumor tissue is now helping to delineate high-risk ER-positive cancer types that have distinct risk and treatment response profiles. These new approaches to breast cancer classification will have a major impact on the conduct of clinical trials and individual patient assessment in the future. PMID- 22812575 TI - Complex post-cholecystectomy biliary injuries: management with 10 years' experience in a major referral center. AB - PURPOSE: A prospective and retrospective work to evaluate management of post cholecystectomy biliary injuries. PATIENTS AND METHODS: From March 2000 to February 2010, 419 patients (224 females and 195 males) complaining of post cholecystectomy biliary injuries were managed using surgery in 135 patients and endoscopy in 317 patients, in addition to percutaneous techniques in 32 patients. RESULTS: Endoscopy was very successful initial treatment of 317 patients (76%), as being less invasive, with low morbidity and mortality, and being competitive with surgery in treatment of mild/moderate biliary leakage (82%) and biliary stricture (74%). Its success increased by 2.8% and 8.3% for leakage and stricture, respectively, by addition of percutaneous techniques. However, surgery was needed for major leakage and massive stricture in 19% and 14% of cases, respectively. Surgery remains the choice in common bile duct transection, ligation, and combined injuries of stones, stricture, and leakage in 60% of cases. Bilio-enteric anastomosis was the procedure of choice, done in 76 cases, with trans-anastomotic stent in 30 cases with unhealthy or small ducts. Stricture was encountered in 5 cases (6.5%), treated by the percutaneous route in 3 cases and repeat surgery in 2 cases. The learning curve seems influential in both endoscopy and surgery. The cumulative experience increased the success of endoscopy from 60% to 95%. Also, surgery improved with decreased morbidity and mortality. CONCLUSIONS: Endoscopy was competitive with surgery in initial treatment of simple problems, but in major leak, ligation, transection, and complex problems, surgery plays the main treatment with its invasiveness and high morbidity and morbidity. Cumulative experience influences endoscopic and surgical treatment of such challenging problems. PMID- 22812576 TI - Commentary on "Spinal versus general anesthesia for day-case laparoscopic cholecystectomy: a prospective randomized study". PMID- 22812577 TI - Long-term dietary intervention trials: critical issues and challenges. AB - BACKGROUND: There are many challenges involved in running randomised controlled dietary intervention trials that investigate health outcomes. The aim of this paper was to evaluate the recruitment process, retention of participants and challenges faced in our dairy intervention trial, and to provide strategies to combat the difficulties of running long-term dietary intervention trials. METHODS: A 12-month, randomised, two-way crossover study was conducted in overweight adults with habitually low dairy food consumption to assess the effects of a high dairy intake (4 servings of reduced-fat dairy per day) compared with a low dairy intake (1 serving of reduced-fat dairy per day) on measures of cardiometabolic and cognitive health. On completion of the high dairy intake phase, each participant was interviewed about their experience in the trial and responses were used to evaluate the key issues for study participants. RESULTS: Although the recruitment target was achieved, high rates of attrition (49.3%) and difficulties maintaining participant compliance (reported by 37.8% of participants) were major threats to the viability of the study. Factors that contributed to the high attrition included inability to comply with the dietary requirements of the study protocol (27.0%), health problems or medication changes (24.3%) and time commitment (10.8%). CONCLUSION: Attrition and adherence to study requirements present challenges to trials requiring longer-term dietary change. Including a run-in period to further assess the motivation, commitment and availability of participants, maintaining regular contact with participants during control phases, minimising time commitment, providing flexibility with dietary requirements, facilitating positive experiences, and stringent monitoring of diet are some key recommendations for future dietary intervention trials. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ACTRN 12608000538347). PMID- 22812579 TI - Polymorphism identification in goat GNRH1 and GDF9 genes and their association analysis with litter size. AB - This study investigated the polymorphisms of GNRH1 and GDF9 genes in 641 goats of three breeds: Xinong Saanen, Guanzhong and Boer. Two allelic variants were identified in the GNRH1 gene (JN645280:g.3548A>G and JN645281:g.3699G>A) and one allelic variant was found in the GDF9 gene (JN655693:g.4093G>A). Furthermore, g.4093G>A was a missense mutation (p.Val397Ile of GDF9). Results of an association analysis indicated that SNPs g.3548A>G and g.4093G>A had significant effects on litter size (P < 0.05). The combination genotypes of SNPs g.3548A>G, g.3699G>A and g.4093G>A also affected litter size with the C5 genotype having the highest litter size in the first, third, fourth and average parity. Hence, the biochemical and physiological functions, together with the results obtained in our investigation, suggest that the GNRH1 and GDF9 genes could serve as genetic markers for litter size in goat breeding. PMID- 22812578 TI - Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum. AB - The recent reports of artemisinin (ART) resistance in the Thai-Cambodian border area raise a serious concern on the long-term efficacy of ARTs. To elucidate the resistance mechanisms, we performed in vitro selection with dihydroartemisinin (DHA) and obtained two parasite clones from Dd2 with more than 25-fold decrease in susceptibility to DHA. The DHA-resistant clones were more tolerant of stressful growth conditions and more resistant to several commonly used antimalarial drugs than Dd2. The result is worrisome as many of the drugs are currently used as ART partners in malaria control. This study showed that the DHA resistance is not limited to ring stage, but also occurred in trophozoites and schizonts. Microarray and biochemical analyses revealed pfmdr1 amplification, elevation of the antioxidant defence network, and increased expression of many chaperones in the DHA-resistant parasites. Without drug pressure, the DHA resistant parasites reverted to sensitivity in approximately 8 weeks, accompanied by de-amplification of pfmdr1 and reduced antioxidant activities. The parallel decrease and increase in pfmdr1 copy number and antioxidant activity and the up and down of DHA sensitivity strongly suggest that pfmdr1 and antioxidant defence play a role in in vitro resistance to DHA, providing potential molecular markers for ART resistance. PMID- 22812580 TI - Evaluation of WO2012037132 - a novel scaffold for selective JAK1 inhibition. AB - Novel 1-anilino-4-phenylphthalazine derivatives, compositions containing them, and their use as JAK1 inhibitors and for the treatment of cancer, inflammatory and autoimmune diseases are claimed. This represents a novel scaffold for JAK inhibitors and is highly distinct from the JAK1 inhibitors previously described, although the same scaffold has been employed in other kinase inhibitors. PMID- 22812581 TI - Prometheus: the Supreme Court redefines the patentability of diagnostic inventions. AB - The United States Supreme Court recently issued an opinion regarding the patentability of claims directed to diagnostic methods in Mayo Collab. Service v. Prometheus Lab., Inc. In this opinion, the Supreme Court held that correlations between metabolite levels in the human body and either therapeutic efficacy or adverse effects are unpatentable laws of nature. It further found that a patent claim to a method including such a correlation is unpatentable if the remainder of the claim contains only conventional and well-known steps. The Prometheus decision creates uncertainty regarding the scope of patentable subject matter, particularly in the fields of diagnostic and personalized medicine, that will remain until future cases apply this new doctrine. PMID- 22812582 TI - Glucocerebrosidase mutations in a Serbian Parkinson's disease population. AB - BACKGROUND AND PURPOSE: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. METHODS: Glucocerebrosidase exons 8 11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. RESULTS: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. CONCLUSION: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population. PMID- 22812583 TI - Body mass index contributes to sympathovagal imbalance in prehypertensives. AB - BACKGROUND: The present study was conducted to assess the nature of sympathovagal imbalance (SVI) in prehypertensives by short-term analysis of heart rate variability (HRV) to understand the alteration in autonomic modulation and the contribution of BMI to SVI in the genesis of prehypertension. METHODS: Body mass index (BMI), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP) and HRV indices such as total power (TP), low-frequency power (LF), normalized LF (LFnu), high-frequency power (HF), normalized HF (HFnu), LF-HF ratio, mean heart rate (mean RR), square root of the mean squared differences of successive normal to normal intervals (RMSSD), standard deviation of normal to normal RR interval (SDNN), the number of interval differences of successive NN intervals greater than 50 ms (NN50) and the proportion derived by dividing NN50 by the total number of NN intervals (pNN50) were assessed in three groups of subjects: normotensives having normal BMI (Group 1), prehypertensives having normal BMI (Group 2) and prehypertensives having higher BMI (Group 3). SVI was assessed from LF-HF ratio and correlated with BMI, BHR, BP and RPP in all the groups by Pearson correlation. The contribution of BMI to SVI was assessed by multiple regression analysis. RESULTS: LF and LFnu were significantly increased and HF and HFnu were significantly decreased in prehypertensive subjects in comparison to normotensive subjects and the magnitude of these changes was more prominent in subjects with higher BMI compared to that of normal BMI. LF-HF ratio, the sensitive indicator of sympathovagal balance had significant correlation with BMI (P=0.000) and diastolic blood pressure (DBP) (P=0.002) in prehypertensives. BMI was found to be an independent contributing factor to SVI (P=0.001) in prehypertensives. CONCLUSIONS: It was concluded that autonomic imbalance in prehypertensives manifested in the form of increased sympathetic activity and vagal inhibition. In prehypertensives with higher BMI, vagal withdrawal was predominant than sympathetic overactivity. Magnitude of SVI (alteration in LF-HF ratio) was linked to changes in BMI and DBP. BMI had an independent influence on LF-HF ratio. It was advised that life-style modifications such as yoga and exercise would enable achieve the sympathovagal balance and blood pressure homeostasis in prehypertensives. PMID- 22812584 TI - Protein kinase Cepsilon and protein kinase Ctheta double-deficient mice have a bleeding diathesis. AB - BACKGROUND: In comparison to the classical isoforms of protein kinase C (PKC), the novel isoforms are thought to play minor or inhibitory roles in the regulation of platelet activation and thrombosis. OBJECTIVES: To measure the levels of PKCtheta and PKCepsilon and to investigate the phenotype of mice deficient in both novel PKC isoforms. METHODS: Tail bleeding and platelet activation assays were monitored in mice and platelets from mice deficient in both PKCtheta and PKCepsilon. RESULTS: PKCepsilon plays a minor role in supporting aggregation and secretion following stimulation of the collagen receptor GPVI in mouse platelets but has no apparent role in spreading on fibrinogen. PKCtheta, in contrast, plays a minor role in supporting adhesion and filopodial generation on fibrinogen but has no apparent role in aggregation and secretion induced by GPVI despite being expressed at over 10 times the level of PKCepsilon. Platelets deficient in both novel isoforms have a similar pattern of aggregation downstream of GPVI and spreading on fibrinogen as the single null mutants. Strikingly, a marked reduction in aggregation on collagen under arteriolar shear conditions is observed in blood from the double but not single deficient mice along with a significant increase in tail bleeding. CONCLUSIONS: These results reveal a greater than additive role for PKCtheta and PKCepsilon in supporting platelet activation under shear conditions and demonstrate that, in combination, the two novel PKCs support platelet activation. PMID- 22812585 TI - Primary bone lymphoma of the shoulder. PMID- 22812586 TI - Folding dynamics of cytochrome c using pulse radiolysis. AB - Pulse radiolysis is a powerful method to realize real-time observation of various redox processes, which induces various structural and functional changes occurring in biological systems. However, its application has been mainly limited to studies of the redox reactions of rather smaller biological systems such as DNA because of an undesired reaction due to various free radicals generated by pulse radiolysis. For application of pulse radiolysis to generate plenty of redox reactions of biological systems, selective redox reactions induced by electron pulses have to be developed. In this study, we report that in the presence of the high concentration of the denaturant, guanidine HCl (GdHCl), the selective reduction of the oxidized cytochrome c (Cyt c) takes place in time scales of a few microseconds by the electron transfer from the guanidine radical that is formed by the fast reaction of e(aq)(-) with GdHCl, consequently leading to folding kinetics of Cyt c. By providing insight into the folding dynamics of Cyt c, we show that the pulse radiolysis technique can be used to track the folding dynamics of various biomolecules in the presence of a denaturant including GdHCl. PMID- 22812587 TI - Clients' and therapists' stories about psychotherapy. AB - This article provides an overview of the emerging field of research on clients' stories about their experiences in psychotherapy. The theory of narrative identity suggests that individuals construct stories about their lives in order to provide the self with a sense of purpose and unity. Psychotherapy stories serve both psychological functions. Focusing on the theme of agency as a vehicle for operationalizing purpose and coherence as a way of operationalizing unity, this article will describe the existing scholarship connecting psychotherapy stories to clients' psychological well-being. Results from cross-sectional qualitative and quantitative studies as well as longitudinal research indicate a connection between the stories clients tell about therapy and their psychological well-being, both over the course of treatment and after it is over. In addition, a preliminary analysis of therapists' stories about their clients' treatment is presented. These analyses reveal that the way therapists recount a particular client's therapy does not impact the relationships between clients' narratives and their improvement. The article concludes with a discussion of how this body of scholarship might be fruitfully applied in the realm of clinical practice. PMID- 22812588 TI - Factors associated with the utilization and costs of health and social services in frail elderly patients. AB - BACKGROUND: Universal access is one of the major aims in public health and social care. Services should be provided on the basis of individual needs. However, municipal autonomy and the fragmentation of services may jeopardize universal access and lead to variation between municipalities in the delivery of services. This paper aims to identify patient-level characteristics and municipality-level service patterns that may have an influence on the use and costs of health and social services of frail elderly patients. METHODS: Hierarchical analysis was applied to estimate the effects of patient and municipality-level variables on services utilization. RESULTS: The variation in the use of health care services was entirely due to patient-related variables, whereas in the social services, 9% of the variation was explained by the municipality-level and 91% by the patient level characteristics. Health-related quality of life explained a major part of variation in the costs of health care services. Those who had reported improvement in their health status during the preceding year were more frequent users of social care services. Low informal support, poor functional status and poor instrumental activities of daily living, living at a residential home, and living alone were associated with higher social services expenditure. CONCLUSIONS: The results of this study showed municipality-level variation in the utilization of social services, whereas health care services provided for frail elderly people seem to be highly equitable across municipalities. Another important finding was that the utilization of social and health services were connected. Those who reported improvement in their health status during the preceding year were more frequently also using social services. This result suggests that if municipalities continue to limit the provision of support services only for those who are in the highest need, this saving in the social sector may, in the long run, result in increased costs of health care. PMID- 22812589 TI - Implantable cardioverter defibrillator therapy in patients with cardiac sarcoidosis. AB - ICD Shocks in Cardiac Sarcoidosis. BACKGROUND: An implantable cardioverter defibrillator (ICD) is indicated for some patients with cardiac sarcoidosis (CS) for prevention of sudden death. However, there are little data regarding the event rates of ICD therapies in these patients. We sought to identify the incidence and characteristics of ICD therapies in this patient population. METHODS: We performed a cohort study of patients with ICDs at 3 institutions. Cases were those patients with CS and an ICD implanted for primary or secondary prevention of sudden death. Additionally, we included a comparison with historical controls of ICD therapy rates reported in clinical trials evaluating the ICD for primary and secondary prevention of sudden death. RESULTS: Of the 112 CS subjects identified, 36 (32.1%) received appropriate therapies for ventricular tachyarrhythmias (VT) over a mean follow-up period of 29.2 months. VT storm (>3 episodes in 24 hours) occurred in 16 (14.2%) CS subjects. Inappropriate therapies occurred in 13 CS subjects (11.6%). Covariates associated with appropriate ICD therapies included left ventricular ejection fraction (LVEF) <55% (OR 6.52 [95% CI 2.43-17.5]), right ventricular dysfunction (OR 6.73 [95% CI 2.69-16.8]), and symptomatic heart failure (OR 4.33 [95% CI 1.86-10.1]). CONCLUSIONS: In our cohort of patients with CS and ICDs, almost one-third receive appropriate therapies. This may be due to a myocardial inflammatory process leading to increased triggered activity and subsequent scarring leading to reentrant tachyarrhythmias. Adjusted predictors of ICD therapies in this population include left or right ventricular dysfunction. (J Cardiovasc Electrophysiol, Vol. 23, pp. 925-929, September 2012). PMID- 22812590 TI - Development of the diffusive gradients in thin films technique for the measurement of labile gold in natural waters. AB - Gold is a precious metal that exists in most soils, sediments, and natural waters at extremely low concentrations (<1 MUg/kg). The diffusive gradients in thin films (DGT) technique, used extensively for measuring trace metal concentrations in soils, sediments, and waters, has potential for geochemical exploration for gold, but has not been developed for this metal. This work investigates the possibility of measuring labile gold using DGT by introducing a new binding layer based on activated carbon. The performance of this new technique was assessed using gold(III) chloride in solution by: (1) determining the diffusion coefficient of gold(III) in hydrogels; (2) determining the uptake of gold(III) chloride by the new activated carbon binding layer; (3) determining an elution methodology for the binding layer and evaluating its efficiency; (4) assessing the capacity of the activated carbon binding layer to adsorb gold; (5) determining the effect of pH and ionic strength (as NaCl) on performance, and (6) assessing the selectivity of the new binding layer for gold. It was found that the diffusion coefficient of gold(III) increased as solution pH decreased. The diffusion coefficient also increased at high ionic strength (>=0.1 M NaCl). Accounting for these phenomena, the DGT technique behaved predictably under all tested conditions. The technique can potentially be used as a geochemical exploration tool for gold in soils and in aqueous environments, with method detection limits as low as 0.9 ng/L for a 7-day deployment. PMID- 22812591 TI - Weight loss strategies used by African American women: possible implications for tailored messages. AB - BACKGROUND: African American women have the highest rates of obesity in the USA. They are less likely to participate in weight loss programmes and are less successful in their weight loss attempts. The present study aimed to identify weight loss strategies used by African American women and to determine whether those strategies varied by weight status. The study also examined the emotional issues that lead to compulsive overeating and identified the types of information that African American women need to help manage their weight. METHODS: A self administered survey was completed by 413 adult African American women in 2009. Participants were weighed and measured by a member of the research team. RESULTS: Based on body mass index classification, 43% of women were obese, 25% were overweight, 30% were normal weight and 2% were underweight. Sixty percent had tried to lose weight in the past 12 months. Weight loss practices included: cutting back on fried foods (53%), cutting back on sweets (51%) and increasing physical activity, skipping meals (22%), fasting (17%), and using diet pills (7%). Obese women were significantly more likely to fast and use diet pills than overweight women (P < 0.001). Obese women also were significantly more likely to say they wanted information on how to choose a weight loss programme (P < 0.001), manage stress (P < 0.001) and increase self-esteem (P < 0.001). CONCLUSIONS: Our findings suggest that weight loss messages and programmes may need to be specifically developed for obese women compared to overweight and normal weight women who just need to 'lose a few pounds'. PMID- 22812592 TI - Mice housed in groups of 4-6 exhibit a diurnal surge in their platelet count. AB - The number of circulating platelets in humans exhibits diurnal rhythmicity, with lowest numbers often recorded in the morning. It has been demonstrated that a similar diurnal rhythmicity in the platelet count exists in mice. In this brief communication, it is reported that husbandry conditions affect the diurnal rhythm of platelet abundance in mice. The platelet count in mice, housed one per cage and entrained to a 12 hour : 12 hour light : dark cycle, fluctuated over 24 hours, with peak counts occurring during the animals' rest period. In contrast, this pattern was dramatically altered in mice housed as groups of 4-6 mice per cage. In group-housed mice, there was a transient surge in both platelet and reticulated platelet numbers at the transition from light to dark, corresponding to the time that animals initiate daily locomotor activity. It is speculated that this difference may reflect the circadian regulation of a stress response experienced by group-housed mice, possibly upon sampling. This finding highlights a new component to the mammalian platelet count that has not been reported before. This is an important observation because the surge in platelet and reticulated platelet numbers and the mechanism controlling it, may contribute to the diurnal incidence of cardiovascular events seen in humans. PMID- 22812593 TI - Improvement of skin barrier function in atopic dermatitis patients with a new moisturizer containing a ceramide precursor. AB - BACKGROUND: Atopic dermatitis (AD) is characterized by barrier abnormalities, including insufficient ceramides in the stratum corneum (SC). OBJECTIVE: To measure the effects of a new moisturizer (CRM) containing a ceramide precursor in improving skin barrier function in patients with controlled atopic dermatitis. METHODS: In this randomized, intra-individual comparison, investigator-blinded study, CRM was applied to the test area of one lower leg for 27 days (the other leg remained as untreated control). Evaluations at baseline and day 28 included transepidermal water loss (TEWL), skin hydration by corneometry, dryness severity, Raman spectroscopy, and collection of adverse events. RESULTS: After 4 weeks of treatment, results showed a significantly greater reduction of TEWL and clinical dryness scores, and increased skin hydration (all p < 01) in the CRM treated than untreated area. A significantly higher level of ceramide (p < 05) and a trend toward increased water content was observed with Raman in the SC for CRM than for the control. There were no related AEs. CONCLUSION: Skin barrier function and hydration were significantly improved after CRM treatment. PMID- 22812595 TI - Diagnosing celiac disease by video capsule endoscopy (VCE) when esophagogastroduodenoscopy (EGD) and biopsy is unable to provide a diagnosis: a case series. AB - BACKGROUND: Video capsule endoscopy (VCE) is mainly used to evaluate patients with celiac disease in whom their course after diagnosis has been unfavorable and the diagnosis of adenocarcinoma, lymphoma or refractory celiac disease is entertained, but it has been suggested that VCE could replace esophagogastroduodenoscopy (EGD) and biopsy under certain circumstances. METHODS: We report a single center case series of 8 patients with suspected celiac disease who were diagnosed by VCE. RESULTS: EGD and biopsy had been performed in 4 patients resulting in a negative biopsy, declined by 2, and contraindicated in 2 due to hemophilia and von Willebrand disease. In all patients, mucosal changes of scalloping, mucosal mosaicism and reduced folds were seen in either the duodenum or jejunum on VCE. Follow-up in 7 patients demonstrated improvement in either their serological abnormalities or their presenting clinical features on a gluten free diet. CONCLUSIONS: Our case series demonstrates that VCE and the visualization of the characteristic mucosal changes of villous atrophy may replace biopsy as the mode of diagnosis when EGD is either declined or contraindicated, or when duodenal biopsies are negative and there remains a high index of suspicion. Further study is needed to clarify the role and cost of diagnosing celiac disease with VCE. PMID- 22812596 TI - Harmful or helpful: perceived solicitous and facilitative partner responses are differentially associated with pain and sexual satisfaction in women with provoked vestibulodynia. AB - INTRODUCTION: Provoked vestibulodynia (PVD) is a highly prevalent vulvovaginal pain condition that negatively affects women's emotional, sexual, and relationship well-being. Recent studies have investigated the role of interpersonal variables, including partner responses. AIM: We examined whether solicitous and facilitative partner responses were differentially associated with vulvovaginal pain and sexual satisfaction in women with PVD by examining each predictor while controlling for the other. METHODS: One hundred twenty-one women (M age = 30.60, SD = 10.53) with PVD or self-reported symptoms of PVD completed the solicitous subscale of the spouse response scale of the Multidimensional Pain Inventory, and the facilitative subscale of the Spouse Response Inventory. Participants also completed measures of pain, sexual function, sexual satisfaction, trait anxiety, and avoidance of pain and sexual behaviors (referred to as "avoidance"). MAIN OUTCOME MEASURES: Dependent measures were the (i) Pain Rating Index of the McGill Pain Questionnaire with reference to pain during vaginal intercourse and (ii) Global Measure of Sexual Satisfaction Scale. RESULTS: Controlling for trait anxiety and avoidance, higher solicitous partner responses were associated with higher vulvovaginal pain intensity (beta = 0.20, P = 0.03), and higher facilitative partner responses were associated with lower pain intensity (beta = -0.20, P = 0.04). Controlling for sexual function, trait anxiety, and avoidance, higher facilitative partner responses were associated with higher sexual satisfaction (beta = 0.15, P = 0.05). CONCLUSIONS: Findings suggest that facilitative partner responses may aid in alleviating vulvovaginal pain and improving sexual satisfaction, whereas solicitous partner responses may contribute to greater pain. PMID- 22812597 TI - New trends in micro- and nano-systems development for pharmaceutical actives release. PMID- 22812598 TI - Calcium metabolism and treatment of hypercalcemia. PMID- 22812599 TI - Utilization of SABRE-derived hyperpolarization to detect low-concentration analytes via 1D and 2D NMR methods. AB - The characterization of materials by the inherently insensitive method of NMR spectroscopy plays a vital role in chemistry. Increasingly, hyperpolarization is being used to address the sensitivity limitation. Here, by reference to quinoline, we illustrate that the SABRE hyperpolarization technique, which uses para-hydrogen as the source of polarization, enables the rapid completion of a range of NMR measurements. These include the collection of (13)C, (13)C{(1)H}, and NOE data in addition to more complex 2D COSY, ultrafast 2D COSY and 2D HMBC spectra. The observations are made possible by the use of a flow probe and external sample preparation cell to re-hyperpolarize the substrate between transients, allowing repeat measurements to be made within seconds. The potential benefit of the combination of SABRE and 2D NMR methods for rapid characterization of low-concentration analytes is therefore established. PMID- 22812600 TI - Aspirin versus anticoagulation in intra- and extracranial vertebral artery dissection. AB - BACKGROUND AND PURPOSE: To evaluate the incidence and predictors of ischaemic recurrent stroke and the adverse events of antithrombotic therapy in patients with first intra- or extracranial vertebral artery dissection (VAD) who were treated with aspirin or oral anticoagulation (OA). METHODS: A 21-year database of consecutive patients with confirmed diagnoses of VAD (n = 110, 63% men; mean age 37.9 +/- 8.5 years) without intracerebral hemorrhage and who were treated with aspirin or OA were analyzed retrospectively. In all cases, the admission diagnosis was ischaemic stroke. Three groups were defined according to the site of the dissection: (i) extracranial, (ii) intracranial, and (iii) intra /extracranial. Clinical follow-up was obtained by neurologic examination. Outcome measures were (i) recurrent ischaemic events (ischaemic stroke or transient ischaemic attack) and (ii) intra- and extracranial major bleeding. RESULTS: No difference in age, smoking, or hypertension was found between patients treated with OA (n = 49) and those treated with aspirin (n = 50). Extracranial artery dissection (49%) had preponderance over intracranial (27%) or intra-/extracranial (23%) location. During the follow-up, recurrent ischaemic events were rare (one case). There were no bleeding complications. The treatment that was used did not influence the functional outcome or recanalization. A good functional outcome (modified Rankin score <= 2) was observed in 82 patients. CONCLUSIONS: Although this was a non-randomized study, our data suggest that the frequency of recurrent ischaemic stroke in patients with intra- or extracranial VAD is low and most likely independent of the type of antithrombotic treatment. PMID- 22812594 TI - Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. AB - AIMS: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group. METHODS: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually. RESULTS: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study. CONCLUSION: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups. PMID- 22812602 TI - Face to (face)book: the two faces of social behavior? AB - Social networking sites such as Facebook represent a unique and dynamic social environment. OBJECTIVE: This study addresses three theoretical issues in personality psychology in the context of online social networking sites: (a) the temporal consistency of Facebook activity, (b) people's awareness of their online behavior, and (c) comparison of social behavior on Facebook with self- and informant-reported behavior in real life. METHOD: Facebook Wall pages of 99 college students (mean age = 19.72) were downloaded six times during 3 weeks and coded for quantity and quality of activity. Everyday social interactions were assessed by self- and friend report. RESULTS: Facebook activity showed significant consistency across time, and people demonstrated awareness of their online behavior. There was significant similarity between everyday traits and interactions and Facebook behavior (e.g., more posts by friends are related to Agreeableness). Some differences between online and everyday interactions warrant further research (e.g., individuals with more positive offline relationships are less likely to engage in back-and-forth conversations on Facebook). CONCLUSIONS: The results indicate substantial similarity between online and offline social behavior and identify avenues for future research on the possible use of Facebook to compensate for difficulty in everyday interactions. PMID- 22812601 TI - Fundoplication in chronic intractable cough. AB - BACKGROUND: Airway reflux is a common cause of chronic cough and this is often refractory to medical therapy. Surgery in the form of Nissen fundoplication has been highly successful in the treatment of the classic reflux symptoms of heartburn and dyspepsia. There is a paucity of data regarding response to fundoplication in patients presenting with chronic cough. METHODS: We retrospectively reviewed the case notes of patients from the Hull Cough Clinic who had undergone Nissen fundoplication over the past 6 years. Demographic details, duration of symptoms, presence of other symptoms, results of oesophageal studies, outcome and complications were recorded. Patients were contacted by post and asked to complete a questionnaire detailing current symptoms. In a subgroup with continued troublesome cough 24 hour pharyngeal pH measurements were undertaken. RESULTS: Forty seven patients underwent fundoplication. The average duration of pre-operative cough was 8 years. Gastro intestinal symptoms were present in the majority. In 30 (64%) patients a positive response to treatment was recorded. Mild dysphagia or bloating was seen in 18 patients following surgery. Four patients needed repeat surgical intervention for modification of fundoplication. One patient developed aspiration pneumonia eight weeks following surgery and died of a myocardial infarction. Two thirds of patients with persisting cough had evidence of airway reflux on pharyngeal pH monitoring. CONCLUSION: In these patients with intractable cough a long term response rate of 63% represents a useful therapeutic option. Treatment failure is more frequent than for classic peptic symptoms and may be related to persistent gaseous reflux. PMID- 22812603 TI - Associations between infections and clinical outcome parameters in status epilepticus: a retrospective 5-year cohort study. AB - PURPOSE: Status epilepticus (SE) represents a life-threatening condition, requiring pharmacologic therapy and neurointensive care. Infectious complications in SE are suspected to be frequent and worsen outcome. However, little is known about their incidence during SE and their impact on course and outcome. The aim of this study was to determine the incidence and time of onset of infections during SE, as well as their association with particular SE courses, length of hospitalization, intensive care unit (ICU) stay, and outcome. METHODS: All consecutive ICU patients hospitalized due to SE from 2005 to 2009 at the University Hospital Basel were included. Electroencephalography (EEG) recordings and microbiologic data were extracted from two prospectively established databases. Length of SE, ICU, and hospital stay; development of refractory status epilepticus (RSE); and destinations at discharge or death were assessed by comprehensive medical chart review. KEY FINDINGS: Of 160 patients, 23% had infections during SE. Of those, 94% were respiratory tract infections, 29% were ventilator-associated pneumonias. Patients with infections during SE had longer SE duration (p < 0.0001), longer ICU stay (p = 0.0041), higher risk of RSE (odds ratio [OR] 4.8, p = 0.0002), and higher mortality (OR 5.2, p = 0.0003) than those without infectious complications. Infections during the first 3 days after SE onset were significantly associated with longer SE duration, higher rate of RSE, and higher mortality compared to infections detected before SE. SIGNIFICANCE: Infections during SE are frequent and associated with higher mortality, prolonged ICU stay, and higher rates of RSE. Further trials are needed to provide evidence of a causative relation between infections and outcomes of SE, followed by investigations on underlying mechanisms and preventive strategies. PMID- 22812604 TI - Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. AB - BACKGROUND: Inherited deficiencies of antithrombin (AT), protein C (PC) and protein S (PS) are risk factors for venous thromboembolism (VTE). They are usually defined by laboratory cut-offs (in our setting 81, 70 and 63 IU dL(-1), respectively), which give only a rough idea of the VTE risk associated with plasma levels of these proteins. OBJECTIVES: We investigated whether the risk of VTE associated with the plasma deficiencies of AT, PC or PS has a dose-response effect, and whether low borderline levels of these proteins are associated with an increased risk of VTE, both in the whole study population and separately in carriers of either factor V Leiden or G20210A prothrombin gene mutation. PATIENTS/METHODS: A case-control study of 1401 patients with a first objectively documented VTE and 1847 healthy controls has been carried out. RESULTS: A dose response effect on the VTE risk was observed for all the three anticoagulant proteins. Compared with individuals with AT, PC or PS levels > 100 IU/dL, the adjusted odds ratio (95% CI) of VTE was 2.00 (1.44-2.78) for AT levels between 76 and 85 IUdL(-1) , 2.21 (1.54-3.18) and 1.84 (1.31-2.59) for PC and PS levels between 61 and 75 IUdL(-1) . The risk of unprovoked VTE in factor V Leiden or prothrombin G20210A carriers appears 2 to 3-fold increased when levels of AT or PS are low borderline. CONCLUSIONS: Low borderline plasma levels of AT, PC and PS are associated with a 2-fold increased risk of VTE and should be considered in the assessment of the individual VTE risk. PMID- 22812605 TI - A genome-wide SNP scan reveals two loci associated with the chicken resistance to Marek's disease. AB - Marek's disease (MD) is a neoplastic disease in chickens, caused by the Marek's disease virus (MDV). To investigate host genetic resistance to MD, we conducted a genome-wide association study (GWAS) on 67 MDV-infected chickens based on a case and control design, including 57 susceptible chickens in the case group and 10 resistant chickens as controls. After searching 38 655 valid genomic markers, two SNPs were found to be associated with host resistance to MD. One SNP, rs14527240, reaching chromosome-wide significance level (P < 0.01) was located in the SPARC related modular calcium-binding 1 (SMOC1) gene on GGA5. The other one, GGaluGA156129, reaching genome-wide significance (P < 0.05), was located in the protein tyrosine phosphatase, non-receptor type 3 (PTPN3) gene on GGA2. In addition, expression patterns of these two genes in spleens were detected by qPCR. The expression of SMOC1 was significantly up-regulated (P < 0.05), whereas the expression of PTNP3 did not show significance when the case group was compared with the control group. Up-regulation of SMOC1 in susceptible spleens suggests its important roles in MD tumorigenesis. This is the first study to investigate MD-resistant loci, and it demonstrates the power of GWASs for mapping genes associated with MD resistance. PMID- 22812606 TI - Role-shifting PKCzeta fosters its own proapoptotic destruction by complexing with Bcl10 at the nuclear envelope of human cervical carcinoma cells: a proteomic and biochemical study. AB - Many features of deadly human cervical cancers (HCCs) still require elucidation. Among HCC-derived cell lines, here we used the C4-I one since its quantitative gene expression pattern most closely mimics invasive HCCs, including protein kinase-Czeta (PKCzeta) overexpression. Via proteomic, bioinformatic, and biochemical approaches we identified 31 and 33 proteins co-immunoprecipitating with PKCzeta from nuclear membranes (NMs) of, respectively, untreated or VP-16 exposed C4-I cells. Such proteins belonged to eight functional groups, whose compositions and relative sizes changed with either context. Of the 56 proteins identified, only eight were shared between the two subproteomes, including Bcl10. Surprisingly, proteins known to associate with Bcl10, like Carma1/3 and Malt1, in so-called CBM signalosomes were absent. Notably, in VP-16-treated C4-I cells, PKCzeta*Bcl10 complexes increasingly accrued at NMs, where PKCzeta phosphorylated Bcl10, as PKCzeta also did in vitro and in cell-free systems, both processes being thwarted by interfering RNA (iRNA) PKCzeta depletion. Caspase-3 was associated with PKCzeta*Bcl10 complexes and proteolyzed PKCzeta leading to its inactivation/destruction; both events were prevented by Bcl10 iRNA suppression. Thus, PKCzeta's molecular interactions and functional roles changed strikingly according to the untreated or apoptogen-treated cells context, and by complexing with Bcl10, PKCzeta surprisingly favored its own demise, which suggests both proteins as HCCs therapeutic targets. PMID- 22812607 TI - Evaluation of WO2012078210--development process for the preparation of a DP2 receptor antagonist; Ironwood's first development DP2 antagonist. AB - This application claims processes for the preparation of a series of pyrrole based DP2 receptor antagonists, in particular 2-[3-cyano-2,5-dimethyl-4-[(2 pyrrolidin-1-ylsulfonylphenyl)methyl]pyrrol-1-yl]acetic acid. The nature of the filing points to this compound being a development compound and it may be IW-1221 which has previously been identified as a DP2 antagonist. PMID- 22812608 TI - What do peer support workers do? A job description. AB - BACKGROUND: The extant literature suggests that poorly defined job roles make it difficult for peer support workers to be successful, and hinder their integration into multi-disciplinary workplace teams. This article uses data gathered as part of a participatory evaluation of a peer support program at a psychiatric tertiary care facility to specify the work that peers do. METHODS: Data were gathered through interviews, focus groups, and activity logs and were analyzed using a modified grounded theory approach. RESULTS: Peers engage in direct work with clients and in indirect work that supports their work with clients. The main types of direct work are advocacy, connecting to resources, experiential sharing, building community, relationship building, group facilitation, skill building/mentoring/goal setting, and socialization/self-esteem building. The main types of indirect work are group planning and development, administration, team communication, supervision/training, receiving support, education/awareness building, and information gathering and verification. In addition, peers also do work aimed at building relationships with staff and work aimed at legitimizing the peer role. Experience, approach, presence, role modeling, collaboration, challenge, and compromise can be seen as the tangible enactments of peers' philosophy of work. CONCLUSIONS: Candidates for positions as peer support workers require more than experience with mental health and/or addiction problems. The job description provided in this article may not be appropriate for all settings, but it will contribute to a better understanding of the peer support worker position, the skills required, and the types of expectations that could define successful fulfillment of the role. PMID- 22812609 TI - Use of recombinant factor VII in cardiac surgery. AB - The off-label use of recombinant human coagulation factor VIIa has been increasing to a number of different treatment areas since its original approval in 1999. Several US patents describe claims for FVIIa utilization in nonhemophilia patients, treatment of bleeding due to trauma, as a means to reverse major bleeding, including intracranial bleeding, induced from fibrinolytic therapy as well as a patent for using FVIIa in the treatment of bleeding for patients with bleeding disorders not caused by hemophilia, but rather bleeding disorders due to thrombocytopenia, platelet disorders, and von Willebrand's disease. Bleeding after cardiac surgery remains a serious complication that can increase both morbidity and mortality. We review the off label usage of recombinant factor VIIa as a hemostatic agent that may help control bleeding following cardiac surgery. PMID- 22812610 TI - Targeted absolute quantification of intact proteins by reversed phase liquid chromatography-mass spectrometry, charge reduced electrospray, and condensation particle counting. AB - A novel approach involving the use of reversed phase liquid chromatography-mass spectrometry (RPLC-MS), charge reduced electrospray (CRES), and condensation particle counting (CPC) for the absolute quantification of intact proteins in liquid solutions is introduced. Under analysis conditions optimized for the quantification of select proteins within their predetermined linear ranges, a set of at least five protein standards with molecular weights (MW) spanning the dynamic ranges of both a quadrupole time-of-flight (QTOF) MS and a suitably selected RPLC column is used to generate a calibration curve of CPC detection efficiency (DE) as a function of the square root of MW. Next, the sample of interest is analyzed, and from the MS-generated MW data, the DE of each target protein is determined from the calibration curve. On the basis of MW, DE, and number concentration (molecules/unit volume), absolute quantification is achieved for each protein of interest. Application of this approach to the absolute quantification of cytochrome C (as target compound) in a commercial protein mixture is demonstrated with a deviation of 8%, a coefficient of variation (CV) of 5%, and a quantification limit of 432 fmol. For nontarget components of the mixture (ribonuclease A, holotransferrin, and apomyoglobin), the percent deviation from the stated concentrations and the CV varied from 0.20 to 23 and from 4.1 to 18, respectively. Performance of the method was further assessed by analyzing a laboratory quality control mixture comprising 0.33 MUM of cytochrome C. The calculated value was 0.34 (CV: 5.1%). Universal in essence, the new technique holds strong promise for the absolute quantification of select proteins in liquid samples under conditions of good peak resolution and stable baseline. PMID- 22812611 TI - Do ICD lead recalls affect physician--or patient--behavior? If not, why not? PMID- 22812612 TI - The application of Goal Management Training to aspects of financial management in individuals with traumatic brain injury. AB - Executive functions encompass planning, problem-solving and self-monitoring abilities, abilities that are implicit in goal attainment and often compromised in individuals with traumatic brain injury (TBI). Goal Management Training (GMT) is a theoretically based rehabilitation protocol that was developed to improve goal-directed behaviour. To date, there is evidence to support the efficacy of GMT in healthy older adults and in one previously high functioning individual with acquired brain injury. However, there is no evidence that, in individuals with TBI and severe cognitive impairments, GMT leads to sustained improvement on everyday tasks requiring planning and organisation. The current study was conducted to explore the efficacy of GMT in helping individuals with TBI to improve aspects of their day-to-day financial management. Four participants with severe TBI completed a modified GMT module. Outcomes were assessed using Goal Attainment Scaling. Five control participants were also recruited as a comparison group for the Multiple Errands Task which was used to measure generalisation. The outcomes in each case were variable. Overall the results showed that the structured GMT intervention assisted some TBI individuals to improve their performance on financial management tasks, with evidence of generalisation in some cases. PMID- 22812613 TI - The hybrid approach for the surgical treatment of lone atrial fibrillation: one year results employing a monopolar radiofrequency source. AB - BACKGROUND: The hybrid technique combines a mono or bilateral epicardial approach with a percutaneous endocardial ablation in a single-step procedure. We present our early results with this technique employing a monopolar radiofrequency source through a right thoracoscopy in patients with lone atrial fibrillation (LAF). METHODS: Between June 2009 and December 2010 nineteen consecutive patients (mean 60.8 +/- 8.6 years, 84.2% male) underwent right unilateral minimally invasive hybrid procedure for LAF at our Institution. Ten patients (52.6.6%) had long standing persistent AF while four (21.1%) had persistent and five (26.3%) paroxysmal AF. All patients were followed-up according the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society (HRS/EHRA/ECA) and Society of Thoracic Surgeon (STS) guidelines. RESULTS: There were neither early nor late deaths. It was possible to complete all the procedures as planned without any conversion to cardiopulmonary bypass. No patient died during the follow up. At one year, 7/19 (36.8%) patients were in sinus rhythm with no episode of AF and off antiarrhythmic drugs (AAD). Time related prevalence of postoperative AF peaked at 44.4% (41.3-47.4) at two weeks, was 30.4% (27.3-34.9) at three months, fell to 14.2% (11.6-18.1) by 6 months and was 13.3% (11.0-17.4) at 12 months Among patients with long-standing persistent (LSP) AF, 20% (2/10) were in Sinus rythm and off AAD. One-year success rates were 50% (2/4) in persistent and 60% (3/5) in paroxysmal AF. At 12 months estimated prevalence of antyarrhythmic drugs and Warfarin use were 26% (22.4-33.1) and 48% (37.2-53.2), respectively. CONCLUSIONS: One year results combining the percutaneous endocardial with the right thoracoscopic epicardial technique were, in our experience, not satisfactory, particularly in patients with LSP and persistent AF. Our findings need to be confirmed by larger studies. PMID- 22812614 TI - Immunopathology of Brucella infection. AB - In spite of the protean nature of the disease, inflammation is a hallmark of brucellosis and affected tissues usually exhibit inflammatory infiltrates. As Brucella lacks exotoxins, exoproteases or cytolysins, pathological findings in brucellosis probably arise from inflammation-driven processes. The cellular and molecular bases of immunopathological phenomena probably involved in Brucella pathogenesis have been unraveled in the last few years. Brucella-infected osteoblasts, either alone or in synergy with infected macrophages, produce cytokines, chemokines and matrixmetalloproteinases (MMPs), and similar phenomena are mounted by fibroblast-like synoviocytes. The released cytokines promote the secretion of MMPs and induce osteoclastogenesis. Altogether, these phenomena may contribute to the bone loss and cartilage degradation usually observed in brucellar arthritis and osteomyelitis. Proinflammatory cytokines may be also involved in the pathogenesis of neurobrucellosis. B. abortus and its lipoproteins elicit an inflammatory response in the CNS of mice, leading to astrogliosis, a characteristic feature of neurobrucellosis. Heat-killed bacteria (HKBA) and the L Omp19 lipoprotein elicit astrocyte apoptosis and proliferation (two features of astrogliosis), and apoptosis depends on TNF-alpha signaling. Brucella also infects and replicates in human endothelial cells, inducing the production of chemokines and IL-6, and an increased expression of adhesion molecules. The sustained inflammatory process derived from the longlasting infection of the endothelium may be important for the development of endocarditis. Therefore, while Brucella induces a low grade inflammation as compared to other pathogens, its prolonged intracellular persistence in infected tissues supports a long lasting inflammatory response that mediates different pathways of tissue damage. In this context, approaches to avoid the invasion of host cells or limit the intracellular survival of the bacterium may be suitable to prevent the pathological consequences of Brucella infections. The article presents some of the recent patents related to such approaches. PMID- 22812615 TI - Antibiotic susceptibility and treatment of brucellosis. AB - Brucellosis, a zoonotic infection caused by the genus Brucellae, is an ancient condition linked to the consumption of milk and milk products. The disease has global importance due to its impact. Therapeutic options for brucellosis rely mostly on uncontrolled, nonrandomized, non-blinded studies. The choice and duration of therapy are related to patient characteristics and the presence of a focal disease. The usual therapy of acute brucellosis is a combination of doxycycline plus rifampicin for 6 weeks. An aminoglycoside could be substituted for rifampin for the initial week of combination therapy. Other alternatives include a combination of doxycycline plus trimethoprim-sulfamethoxazole, or a fluoroquinolone plus rifampicin. The presence of spondylitis or endocarditis usually indicates that the required treatment will be of a longer duration or a combination of therapy. The article has the discussion of some recent patents related to antibiotic susceptibility and Brucellosis. PMID- 22812616 TI - Update on childhood brucellosis. AB - In endemic regions of brucellosis, childhood brucellosis includes up to one-third of all cases of human brucellosis. The main source of infection in children is consumption of unpasteurized dairy products and traditional local foods containing dairy products. The older boys are more involved in animal care. Boys are more commonly infected than girls. Common symptoms and signs include fever, arthralgia, sweating, peripheral arthritis and splenomegaly. Peripheral arthritis especially monoarthritis is more common and the most commonly affected joints are hip and knee. All organs may involve during the course of the disease. Isolation of Brucella spp. from the blood, bone marrow or other tissue fluids is the hallmark of diagnosis. Serologic tests are the main tools of diagnosis of brucellosis in endemic regions. Standard agglutination test (SAT) with titers > 1:160 and the 2-mercaptoethanol (2ME) test >= 1:80 are suggestive of active infection. Children older than 8 years should be treated with doxycycline for 45 days or 8 weeks plus gentamicin for 7 or 5 days respectively or doxycycline for 45 days and streptomycin for 14 days. Also doxycycline plus rifampin or cotrimoxazole plus rifampin for 45 days may be alternative regimens. Cotrimoxazole plus rifampin for six weeks is the regimen of choice for the treatment of patients younger than 8 years old. Gentamicin for 5 days plus cotrimoxazole for six weeks may be a suitable alternative regimen. The article presented few of the patents associated with Brucellosis. PMID- 22812617 TI - Microbiology of Brucella. AB - The genus Brucella is a member of family Brucellaceae and includes ten species which are small, non-motile, non-sporing, aerobic, gram-negative intracellular coccobacilli. They are catalase, oxidase and urea positive bacteria. Members of the genus can grow on enriched media like blood agar or chocolate agar. Identification in species level can be done by agglutination with monospecific serum, cultivating the strains in the presence of dyes and/or with PCR methods. Antigenic structure of the Brucella is composed of surface, intracellular, and in vivo antigens. Thanks to various virulence factors that act as metabolic regulators, Brucella strains can protect themselves from immune system of the host, adapt easily to different environmental conditions, and multiply intracellular. Classification, epidemiological features, isolation and identification, antigenic structure and virulence factors of Brucella species along with the discussion of very few patents associated with Brucellosis have been reviewed in this paper. PMID- 22812618 TI - Pregnancy associated brucellosis. AB - Brucellosis zoonotic infection caused by Brucella spp. In endemic countries, the disease does not spare the pregnant. There is evidence that brucellosis can induce abortion in humans. Positive cultures of brucella from human placenta, aborted fetuses, and other products of conception were reported previously. It is speculated that brucellosis causes fewer spontaneous abortions in humans than animals due to the absence of Erythritol in the human placenta and fetus. In addition, the presence of anti-brucella activity in human amniotic fluid may also play a role. Rifampin is considered the mainstay of treatment of brucellosis during pregnancy, in various combinations. In a retrospective study of brucellosis in pregnancy, antepartum treatment with antimicrobial agents was more protective against the occurrence of abortion than no or inadequate treatment. It seems that the incidence of abortion is not different among patients treated with either trimethoprim-sulfamethoxazole with or without rifampicin. With therapy during pregnancy, the overall success rate resulting in normal delivery is 90%. The article discussed few of the patents associated with brucellosis. PMID- 22812619 TI - Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. AB - BACKGROUND: One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. OBJECTIVES: This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran associated bleeding diathesis. METHODS: Anesthetized rabbits were treated with 0.4 mg kg(-1) dabigatran followed by PCC doses of 20, 35 or 50 IU kg(-1) or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. RESULTS: From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21 8.67 mL per 10 IU kg(-1) increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg(-1) blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg(-1) increment in PCC dose (rate ratio, 2.89; CI, 1.64-5.09). CONCLUSIONS: In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted. PMID- 22812621 TI - Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. AB - The objective of the present study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the new recombinant FVIII compound turoctocog alfa and a Glyco-PEGylated FVIII derivative thereof (N8-GP) in Haemophilia A dogs. Six haemophilic dogs divided into two groups were included in the study. Each dog was administered a dose of 125 U kg(-1) , blood samples were collected at predetermined time points for both pharmacokinetic (FVIII measured by one stage aPTT assay) and pharmacodynamic [whole blood clotting time (WBCT)] evaluations. After intravenous administration to haemophilic dogs, the plasma concentration at the first sampling point was comparable for turoctocog alfa and N8-GP, and the clearance was estimated to be 6.5 and 3.9 mL h(-1) kg(-1) for turoctocog alfa and N8-GP respectively. Both turoctocog alfa and N8-GP were able to reduce the WBCT time to normal levels (<20 min), however, the reduced clearance was reflected in the WBCT, which returned to baseline at a later time point for N8-GP as compared with dogs dosed with turoctocog alfa. The clearance was 40% reduced for N8-GP as compared with turoctocog alfa. Simulations of a multiple dosing regimen in dogs, suggest that to maintain WBCT <20 min N8-GP can be dosed at reduced intervals, e.g. with 4 days between doses, whereas turoctocog alfa will have to be dosed with 21/2 day between doses. Data thereby supports N8 GP as an alternative to standard rFVIII replacement therapy, with a more convenient dosing regimen. PMID- 22812622 TI - Plantago lanceolata L. leaves prevent obesity in C57BL/6 J mice fed a high-fat diet. AB - The highly abundant and widely dispersed plant Plantago lanceolata L. (narrow leaf or English plantain) has been used for culinary and medicinal purposes since ancient times. Here, we investigated the anti-obesity effects of P. lanceolata leaf powder (shortly PL) when fed to male C57BL/6 J mice. Addition of PL to a high-fat diet did not affect food intake but significantly reduced food efficiency, suppressed body weight gain and visceral fat accumulation, and reduced serum free-fatty acid and glucose levels. PL-fed mice exhibited marked increases in HSL, Adrd3 and Cpt2 mRNA levels, and significant decreases in Fas transcripts in epididymal white adipose tissue (WAT). These findings suggest that dietary PL exerts anti-obesity effects by stimulating metabolism throughout visceral fat tissue by activating lipolysis, accelerating fatty acid beta oxidation and suppressing fatty acid synthase in WAT. To our knowledge, this is the first demonstration of anti-obesity substances derived from a Plantago species. PMID- 22812620 TI - N-terminal region of CusB is sufficient for metal binding and metal transfer with the metallochaperone CusF. AB - Gram-negative bacteria, such as Escherichia coli, utilize efflux resistance systems in order to expel toxins from their cells. Heavy-metal resistance is mediated by resistance nodulation cell division (RND)-based efflux pumps composed of a tripartite complex that includes an RND-transporter, an outer-membrane factor (OMF), and a membrane fusion protein (MFP) that spans the periplasmic space. MFPs are necessary for complex assembly and have been hypothesized to play an active role in substrate efflux. Crystal structures of MFPs are available, however incomplete, as large portions of the apparently disordered N- and C termini are unresolved. Such is the case for CusB, the MFP of the E. coli Cu(I)/Ag(I) efflux pump CusCFBA. In this work, we have investigated the structure and function of the N-terminal region of CusB, which includes the metal-binding site and is missing from previously determined crystal structures. Results from mass spectrometry and X-ray absorption spectroscopy show that the isolated N terminal 61 residues (CusB-NT) bind metal in a 1:1 stoichiometry with a coordination site composed of M21, M36, and M38, consistent with full-length CusB. NMR spectra show that CusB-NT is mostly disordered in the apo state; however, some slight structure is adopted upon metal binding. Much of the intact protein's function is maintained in this fragment as CusB-NT binds metal in vivo and in vitro, and metal is transferred between the metallochaperone CusF and CusB NT in vitro. Functional analysis in vivo shows that full-length CusB is necessary in an intact polypeptide for full metal resistance, though CusB-NT alone can contribute partial metal resistance. These findings reinforce the theory that the role of CusB is not only to bind metal but also to play an active role in efflux. PMID- 22812623 TI - Antifungal effects of a 1444-nm neodymium:Yttrium-aluminum-garnet laser on onychomycosis: a pilot study. AB - Investigations of laser- or light-assisted antibacterial and antifungal treatments have been introduced. In the present study, we investigated the antifungal activities of 1444-nm Nd:YAG lasers against onychomycosis by microbiologic analysis and scanning electron microscopy. Scraped toenails from 20 participants with mycologically confirmed onychomycosis were prepared on polystyrene weighing dishes and treated with a 1444-nm Nd:YAG laser. The samples were analyzed for the presence of colony-forming units (CFUs) and scanning electron microscopy was performed using an toenail treated with the 1444-nm Nd:YAG laser. The mean reduction rate achieved by treatment with a total energy of 300 J was 75.9% (range: 33.3-100), and by treatment with 450 J was 85.5% (range: 66.7-100). However, the difference in CFU reduction rates between the laser settings of 300 J and 450 J was not significant. Analysis by scanning electron microscope revealed numerous disintegrated spores on the lower portions of the nail plate treated with the 1444-nm laser, while the upper portion of the nail plate presented only a few small and greatly disintegrated fungal spores. Our results suggest that a Nd:YAG laser with a wavelength of 1444 nm has antifungal effects on onychomycosis. However, further investigations should be performed to determine the long-term clinical and microbiologic effects of this treatment. PMID- 22812624 TI - Endothelial cell adhesiveness is a function of environmental lighting and melatonin level. AB - The endothelial layer regulates the traffic of cells and substances between the blood and tissues and plays a central role in the mounting of an inflammatory response. We have recently shown that inhibition of the nocturnal melatonin surge during the mounting of an inflammatory response primes endothelial cells to a highly reactive state, increasing the expression of adhesion molecules and inducible nitric oxide synthase (iNOS) as well as the in vitro adherence of leukocytes. Here, we investigated whether physiological variations in the plasma melatonin levels owing to the light/dark environmental cycle could also prime the reactive state of endothelial cells. Cultured endothelial cells (16-20 days) obtained from rats killed during the daytime adhere more neutrophils, expressed more adhesion molecules and iNOS, and had a higher content of the transcription factor nuclear factor kappa B (NF-kB) translocated to the nuclei. We also evaluated the expression of 84 genes (using real-time PCR array) related to the innate inflammatory response and observed a higher expression of 19 genes in cultures obtained during the daytime. In addition, the only gene that was highly expressed in cells obtained from rats killed during nighttime was one that encodes a protein that negatively modulates inflammatory response. In conclusion, the daily rhythm of melatonin also primes the ability of endothelial cells to adhere to neutrophils. This new approach for evaluating the influence of the donor on cells maintained in culture should have applications for the standardization of cell banks. PMID- 22812625 TI - How does "being real" feel? The experience of state authenticity. AB - OBJECTIVE: We propose that the experience of state authenticity-the subjective sense of being one's true self-ought to be considered separately from trait authenticity as well as from prescriptions regarding what should make people feel authentic. METHODS: In Study 1 (N = 104), online participants rated the frequency of and motivation for experiences of authenticity and inauthenticity. Studies 2 (N = 268) and 3 (N = 93) asked (local or online, respectively) participants to describe their experiences of authenticity or inauthenticity. Participants in Studies 1 and 2 also completed measures of trait authenticity, and participants in Study 3 rated their experience with respect to several phenomenological dimensions. RESULTS: Study 1 demonstrated that people are motivated to experience state authenticity and avoid inauthenticity and that such experiences are common, regardless of one's degree of trait authenticity. Coding of Study 2's narratives identified the emotions accompanying and needs fulfilled in each state. Trait authenticity generally did not qualify the nature of (in)authentic experiences. Study 3 corroborated the results of Study 2 and further revealed positive mood and nostalgia as consequences of reflecting on experiences of authenticity. CONCLUSIONS: We discuss implications of these findings for conceptualizations of authenticity and the self. PMID- 22812626 TI - Investigation of hypoxia-inducible factor-1alpha in hippocampal sclerosis: a postmortem study. AB - PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) is involved in critical aspects of cell survival in response to hypoxia and regulates vascular endothelial growth factor (VEGF) expression. Previous experimental and human studies in epilepsy show up-regulation of VEGF following seizures, although expression of HIF-1alpha as its potential regulator has not been explored. We used a postmortem (PM) series from patients with epilepsy and hippocampal sclerosis (HS) to investigate patterns of expression of HIF-1alpha and VEGF and their potential contribution to neuroprotection. METHOD: In 33 PMs (17 cases with unilateral HS, 3 with bilateral HS, 3 with No-HS, and 10 controls), we quantified neuronal immunolabeling for HIF-1alpha and VEGF in hippocampal subfields. KEY FINDINGS: HIF-1alpha- and VEGF-immunopositive hippocampal neurones were observed in HS, No-HS, and also in control cases; there was no significant difference in overall labeling between epilepsy cases and controls. In positive cases, HIF 1alpha and VEGF neuronal labeling localized primarily in CA1, CA4, and CA3 subfields in all groups; significantly more positive neurons were seen in the entorhinal cortex in epilepsy cases (p < 0.05). Labeling lateralized to the side of sclerosis in unilateral HS cases, with significant differences between hemispheres (p < 0.05). There was a trend for high HIF-1alpha labeling scores in patients with Dravet syndrome without HS and sudden unexpected death in epilepsy (SUDEP) cases, and lower scores with long seizure-free periods prior to death. Hippocampal HIF-1alpha and VEGF labeling showed a significant correlation. There was neuronal colocalization of HIF-1alpha and VEGF. SIGNIFICANCE: Regional expression patterns are in keeping with seizure-related activation of HIF-1alpha and VEGF. The prominent expression in non-HS cases could support an overall neuroprotective effect. Correlation between HIF-1alpha and VEGF neuronal immunolabeling supports HIF-1alpha-mediated induction of VEGF in epilepsy. PMID- 22812627 TI - Networking between community health programs: a case study outlining the effectiveness, barriers and enablers. AB - BACKGROUND: In India, since the 1990s, there has been a burgeoning of NGOs involved in providing primary health care. This has resulted in a complex NGO Government interface which is difficult for lone NGOs to navigate. The Uttarakhand Cluster, India, links such small community health programs together to build NGO capacity, increase visibility and better link to the government schemes and the formal healthcare system. This research, undertaken between 1998 and 2011, aims to examine barriers and facilitators to such linking, or clustering, and the effectiveness of this clustering approach. METHODS: Interviews, indicator surveys and participant observation were used to document the process and explore the enablers, the barriers and the effectiveness of networks improving community health. RESULTS: The analysis revealed that when activating, framing, mobilising and synthesizing the Uttarakhand Cluster, key brokers and network players were important in bridging between organisations. The ties (or relationships) that held the cluster together included homophily around common faith, common friendships and geographical location and common mission. Self interest whereby members sought funds, visibility, credibility, increased capacity and access to trainings was also a commonly identified motivating factor for networking. Barriers to network synthesizing included lack of funding, poor communication, limited time and lack of human resources. Risk aversion and mistrust remained significant barriers to overcome for such a network. CONCLUSIONS: In conclusion, specific enabling factors allowed the clustering approach to be effective at increasing access to resources, creating collaborative opportunities and increasing visibility, credibility and confidence of the cluster members. These findings add to knowledge regarding social network formation and collaboration, and such knowledge will assist in the conceptualisation, formation and success of potential health networks in India and other developing world countries. PMID- 22812628 TI - Psychosexual functioning and body image following a diagnosis of ductal carcinoma in situ. AB - INTRODUCTION: There has been exponential growth in diagnoses of ductal carcinoma in situ (DCIS) in the past decade, yet little is known about sexual functioning and body image in women after diagnosis of DCIS. This is of particular importance because many of the parallel treatment modalities also used to treat invasive breast cancer, e.g., surgery and hormonal therapy, have been shown to have a detrimental effect on psychosexual function. AIM: The aim was to explore changes in sexual function and body image after diagnosis and treatment of in situ cancer. MAIN OUTCOME MEASURES: Evidence-based self-report measures assessing psychosexual functioning and body image. METHODS: Women diagnosed with DCIS within the past 3 months and who reported being sexually active completed measures assessing various aspects of psychosocial and sexual functioning and body image. Outcomes were evaluated at baseline, 9-, and 18-month time points. All statistical tests were two sided. RESULTS: Three hundred four women completed this prospective survey. Overall, sexual function in women with DCIS appears to be very similar to women in the general population and does not seem to be significantly disrupted by a diagnosis of DCIS. Sexual function and body image were notably stable across the 18-month length of follow-up. Of those patients who underwent mastectomy, there were no differences in sexual satisfaction for patients who had reconstruction compared with patients who did not. CONCLUSION: Although it has been shown that women with DCIS have a number of psychosocial challenges, results from this large-scale prospective study of women suggest that sexual function and body image may not be significantly negatively affected by this diagnosis. Of note, these results were also the case for women who underwent mastectomy and hormonal therapy. These findings are reassuring for both patients and physicians in the context of decision making about treatment options. PMID- 22812630 TI - Generation and trapping of a cage annulated vinylidenecarbene and approaches to its cycloalkyne isomer. AB - A novel cage-annulated (bis-homocubyl) vinylidenecarbene has been generated and successfully trapped without any intermediacy of its cycloalkyne isomer. The greater kinetic and thermodynamic stability of the vinylidenecarbene vis-a-vis its cycloalkyne isomer has been predicted by DFT B3LYP/6-31G* calculations. The calculated results suggest the prospects of the cycloalkyne becoming amenable for trapping, if generated under suitable experimental conditions, owing to the substantial kinetic energy barrier associated with its possible ring contraction via 1,2-shift to the vinylidenecarbene isomer and marginal ground state energy difference. However, all of our attempts to directly generate and trap the cycloalkyne yielded unsatisfactory results. Attempted generation and trapping of a C2-symmetric bis-vinylidenecarbene from a bis-vinylidenedibromide met with unexpected failure. PMID- 22812629 TI - Proton transfer from C-6 of uridine 5'-monophosphate catalyzed by orotidine 5' monophosphate decarboxylase: formation and stability of a vinyl carbanion intermediate and the effect of a 5-fluoro substituent. AB - The exchange for deuterium of the C-6 protons of uridine 5'-monophosphate (UMP) and 5-fluorouridine 5'-monophosphate (F-UMP) catalyzed by yeast orotidine 5' monophosphate decarboxylase (ScOMPDC) at pD 6.5-9.3 and 25 degrees C was monitored by (1)H NMR spectroscopy. Deuterium exchange proceeds by proton transfer from C-6 of the bound nucleotide to the deprotonated side chain of Lys 93 to give the enzyme-bound vinyl carbanion. The pD-rate profiles for k(cat) give turnover numbers for deuterium exchange into enzyme-bound UMP and F-UMP of 1.2 * 10(-5) and 0.041 s(-1), respectively, so that the 5-fluoro substituent results in a 3400-fold increase in the first-order rate constant for deuterium exchange. The binding of UMP and F-UMP to ScOMPDC results in 0.5 and 1.4 unit decreases, respectively, in the pK(a) of the side chain of the catalytic base Lys-93, showing that these nucleotides bind preferentially to the deprotonated enzyme. We also report the first carbon acid pK(a) values for proton transfer from C-6 of uridine (pK(CH) = 28.8) and 5-fluorouridine (pK(CH) = 25.1) in aqueous solution. The stabilizing effects of the 5-fluoro substituent on C-6 carbanion formation in solution (5 kcal/mol) and at ScOMPDC (6 kcal/mol) are similar. The binding of UMP and F-UMP to ScOMPDC results in a greater than 5 * 10(9)-fold increase in the equilibrium constant for proton transfer from C-6, so that ScOMPDC stabilizes the bound vinyl carbanions, relative to the bound nucleotides, by at least 13 kcal/mol. The pD-rate profile for k(cat)/K(m) for deuterium exchange into F-UMP gives the intrinsic second-order rate constant for exchange catalyzed by the deprotonated enzyme as 2300 M(-1) s(-1). This was used to calculate a total rate acceleration for ScOMPDC-catalyzed deuterium exchange of 3 * 10(10) M(-1), which corresponds to a transition-state stabilization for deuterium exchange of 14 kcal/mol. We conclude that a large portion of the total transition-state stabilization for the decarboxylation of orotidine 5'-monophosphate can be accounted for by stabilization of the enzyme-bound vinyl carbanion intermediate of the stepwise reaction. PMID- 22812631 TI - Syncytial giant cell hepatitis associated with chronic lymphocytic leukemia: a case report. AB - BACKGROUND: Syncytial giant cell hepatitis (GCH) is an uncommon and an underreported disease entity. In two previously reported cases of GCH in patients with Chronic Lymphocytic Leukemia (CLL) liver failure ensued. Autoimmune and infective causes have been implicated but its etiology remains unclear. CASE PRESENTATION: A 60-year-old female with CLL presented with acute hepatitis with negative viral and auto-immune serologies and without any prior toxic exposure. Liver biopsy showed typical histological features of GCH. The patient was successfully treated with corticosteroids and intravenous immunoglobulin (IVIG). Her liver enzymes returned to baseline and have remained normal as of the last follow up almost 4 years later. CONCLUSIONS: Association of GCH with CLL may be under recognized. Clinical suspicion of GCH in CLL patients with serology negative hepatitis, early liver biopsy and therapeutic intervention may influence outcome. This is the first case report of successful treatment of GCH in CLL patients. Moreover, our case also demonstrates the ability to resume effective CLL therapy post-GCH diagnosis without detriment to the liver. PMID- 22812632 TI - Length-dependent pleural inflammation and parietal pleural responses after deposition of carbon nanotubes in the pulmonary airspaces of mice. AB - BACKGROUND: Carbon nanotubes (CNT) are fibre-like nanomaterials whose structural similarity to asbestos has raised concerns that they may also pose a mesothelioma hazard. The objective of this study was to examine the inflammatory potential of three CNT samples of differing length on the lungs and pleural cavity following introduction into the airspaces of mice. RESULTS: Aspiration of the two short/tangled and one long CNT sample into the lungs of mice resulted in a length dependent inflammatory response at 1 week, i.e., only the long CNT sample caused acute neutrophilic inflammation in bronchoalveolar lavage at 1 week and progressive thickening of the alveolar septa. The authors also report length dependent inflammatory responses in the pleural lavage after exposure only to the long CNT. The inflammatory response in the pleural cavity to long fibres and the appearance of lesions along the chest wall and diaphragm was not present at 1 week and only evident by 6 weeks post-exposure. CONCLUSION: Length-dependent pathogenicity is a feature of asbestos and the results presented in this study demonstrate similar length-dependent pathogenicity of CNT in the lungs and pleural space following airspace deposition. The data support the contention that long CNT reach the pleura from the airspaces, and that they are retained at the parietal pleura and cause inflammation and lesion development. The parietal pleura is the site of origin of mesothelioma and inflammation is considered to be a process involved in asbestos carcinogenesis and so the data support the contention that CNT may pose an asbestos-like mesothelioma hazard. PMID- 22812633 TI - Assessment of vitamin and carotenoid concentrations of emerging food products: edible microgreens. AB - Microgreens (seedlings of edible vegetables and herbs) have gained popularity as a new culinary trend over the past few years. Although small in size, microgreens can provide surprisingly intense flavors, vivid colors, and crisp textures and can be served as an edible garnish or a new salad ingredient. However, no scientific data are currently available on the nutritional content of microgreens. The present study was conducted to determine the concentrations of ascorbic acid, carotenoids, phylloquinone, and tocopherols in 25 commercially available microgreens. Results showed that different microgreens provided extremely varying amounts of vitamins and carotenoids. Total ascorbic acid contents ranged from 20.4 to 147.0 mg per 100 g fresh weight (FW), while beta carotene, lutein/zeaxanthin, and violaxanthin concentrations ranged from 0.6 to 12.1, 1.3 to 10.1, and 0.9 to 7.7 mg/100 g FW, respectively. Phylloquinone level varied from 0.6 to 4.1 MUg/g FW; meanwhile, alpha-tocopherol and gamma-tocopherol ranged from 4.9 to 87.4 and 3.0 to 39.4 mg/100 g FW, respectively. Among the 25 microgreens assayed, red cabbage, cilantro, garnet amaranth, and green daikon radish had the highest concentrations of ascorbic acids, carotenoids, phylloquinone, and tocopherols, respectively. In comparison with nutritional concentrations in mature leaves (USDA National Nutrient Database), the microgreen cotyledon leaves possessed higher nutritional densities. The phytonutrient data may provide a scientific basis for evaluating nutritional values of microgreens and contribute to food composition database. These data also may be used as a reference for health agencies' recommendations and consumers' choices of fresh vegetables. PMID- 22812634 TI - Structural and biochemical characterization of human adenylosuccinate lyase (ADSL) and the R303C ADSL deficiency-associated mutation. AB - Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive disorder, which causes a defect in purine metabolism resulting in neurological and physiological symptoms. ADSL executes two nonsequential steps in the de novo synthesis of AMP: the conversion of phosphoribosylsuccinyl-aminoimidazole carboxamide (SAICAR) to phosphoribosylaminoimidazole carboxamide, which occurs in the de novo synthesis of IMP, and the conversion of adenylosuccinate to AMP, which occurs in the de novo synthesis of AMP and also in the purine nucleotide cycle, using the same active site. Mutation of ADSL's arginine 303 to a cysteine is known to lead to ADSL deficiency. Interestingly, unlike other mutations leading to ADSL deficiency, the R303C mutation has been suggested to more significantly affect the enzyme's ability to catalyze the conversion of succinyladenosine monophosphate than that of SAICAR to their respective products. To better understand the causation of disease due to the R303C mutation, as well as to gain insights into why the R303C mutation potentially has a disproportional decrease in activity toward its substrates, the wild type (WT) and the R303C mutant of ADSL were investigated enzymatically and thermodynamically. Additionally, the X-ray structures of ADSL in its apo form as well as with the R303C mutation were elucidated, providing insight into ADSL's cooperativity. By utilizing this information, a model for the interaction between ADSL and SAICAR is proposed. PMID- 22812635 TI - Complement C1q production by osteoclasts and its regulation of osteoclast development. AB - C1q deficiency is the strongest known risk factor for SLE (systemic lupus erythematosus) but its endogenous cellular origin remains limitedly understood. In the present study we investigate the production of C1q by both cultured and endogenous bone osteoclasts. Blood monocytes were cultured with RANKL (receptor activator of nuclear factor kappaB ligand) and M-CSF (macrophage colony stimulating factor) to generate osteoclasts and these cells expressed C1Q mRNA and also secreted C1q protein. Intracellular C1q was detectable in developing osteoclasts at day 3 by Western blotting and was also detectable by flow cytometry. By immunofluorescence microscopy, C1q was preferentially detected in immature osteoclasts. By multiple detection methods, C1q expression was markedly increased after IFNgamma (interferon gamma) treatment. By immunohistochemistry, C1q was also detected in endogenous bone osteoclasts. When osteoclasts were cultured on immobilized C1q, these cells exhibited 2-7-fold increases in the expression of signature osteoclast genes [TRAP (tartrate-resistant acid phosphatase), cathepsin K, calcitonin receptor, carbonic anhydrase II and NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1)], suggesting an osteoclastogenic capability. This is the first report of C1q production by osteoclasts. Its ability to enhance osteoclast development implies reduced osteoclastogenesis in patients with SLE as they often experience decreased C1q levels. This is consistent with the non-erosive nature of lupus arthritis. PMID- 22812636 TI - Possible proarrhythmia with dronedarone. PMID- 22812637 TI - Two new diterpenes from Caesalpinia minax Hance. AB - Two new cassane-type diterpenes, Caesalpinolide F (1) and Caesalpinolide G (2) were isolated from Caesalpinia minax Hance. Their structures were elucidated on the basis of 1D and 2D NMR, MS and CD analysis. Compounds 1 and 2 were tested against colon carcinoma (HCT-8) and breast cancer (MCF-7) human cancer cell lines, and showed mild cytotoxicity activities. PMID- 22812639 TI - Polymorphisms in the promoter region of the adiponectin (ADIPOQ) gene are presumably associated with transcription level and carcass traits in pigs. AB - The main goal of this study was to screen for polymorphisms in the porcine adiponectin (ADIPOQ) gene promoter, analyse their influence on transcription and identify any association with production traits in pigs. A 1018-bp region of the ADIPOQ gene promoter was analysed in 113 pigs, and seven novel polymorphisms found. Luciferase assays were performed in HEK293 (human embryonic kidney) cells and primary porcine adipose mesenchymal stem cells (pADMSCs) to investigate their affect on promoter activity. A 16-bp indel (c.-106_-91delGCCAGGGGTGTGAGCC) was found to influence promoter strength in vitro. In the HEK293 cell line, the Del/Del genotype showed greater luciferase activity than did the Ins/Ins genotype (P < 0.01). In pADMSCs, the insertion genotype of the ADIPOQ promoter showed greater luciferase activity than did the deletion genotype (P < 0.01). An association study performed for two novel polymorphisms, c.-67G>A and the 16-bp indel, showed significant correlation with loin measurements in Polish Landrace (P < 0.05) and synthetic line 990 (P < 0.01) pigs. PMID- 22812638 TI - Online sample conditioning for portable breath analyzers. AB - Various innovative chemical sensors have been developed in recent years to sense dangerous substances in air and trace biomarkers in breath. However, in order to solve real world problems, the sensors must be equipped with efficient sample conditioning that can, e.g., control the humidity, which is discussed much less in the literature. To meet the demand, a miniaturized mouthpiece was developed for personal breath analyzers. A key function of the mouthpiece is to condition the humidity in real breath samples without changing the analyte concentrations and introducing substantial backpressure, which is achieved with optimized packing of desiccant particles. Numerical simulations were carried out to determine the performance of the mouthpiece in terms of various controllable parameters, such as the size, density, and geometry of the packing. Mouthpieces with different configurations were built and tested, and the experimental data validated the simulation findings. A mouthpiece with optimized performance reducing relative humidity from 95% (27,000 ppmV) to 29% (8000 ppmV) whereas retaining 92% nitric oxide (50 ppbV to 46 ppbV) was built and integrated into a hand-held exhaled nitric oxide sensor, and the performance of exhaled nitric oxide measurement was in good agreement with the gold standard chemiluminescence technique. Acetone, carbon dioxide, oxygen, and ammonia samples were also measured after passing through the desiccant mouthpiece using commercial sensors to examine wide applicability of this breath conditioning approach. PMID- 22812640 TI - Health status of seabirds and coastal birds found at the German North Sea coast. AB - BACKGROUND: Systematic pathological investigations to assess the health status of seabirds and coastal birds in Germany were performed. The investigation was conducted to obtain data on possible causes of decline in seabird and coastal bird populations. METHODS: 48 individuals of 11 different species of seabirds and coastal birds were collected by the stranding network along the entire German North Sea coast from 1997 to 2008, including mainly waders such as Eurasian oystercatchers (Haematopus ostralegus) and red knots (Calidris canutus) as well as seabirds such as northern fulmars (Fulmaris glacialis) and common scoters (Melanitta nigra).For most birds (n = 31) found dead along the shore no obvious cause of death was evident, while 17 individuals were killed by collisions with lighthouses. RESULTS: Overall, the nutritional status of the investigated birds was very poor, and the body mass in most cases was significantly lower compared to masses of living birds caught during the same periods of the year. This is partly linked to chronic parasitic or bacterial infections in different organs or to septicaemia. In some cases infections with zoonotic tuberculosis caused by Mycobacterium spp. were found. Avian influenza was not found in any of the collected birds. CONCLUSION: The presented data contribute to the evaluation of the health status of birds in the German North Sea. Moreover, they present an important tool for the assessment of potential pathogens with an impact on the health status of seabirds and coastal birds. PMID- 22812641 TI - Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. AB - PURPOSE: Glut 1 deficiency syndrome (DS) is defined by hypoglycorrhachia with normoglycemia, acquired microcephaly, episodic movements, and epilepsy refractory to standard antiepileptic drugs (AEDs). Gold standard treatment is the ketogenic diet (KD), which provides ketones to treat neuroglycopenia. Our purpose is (1) to describe epilepsy phenotypes in a large Glut 1 DS cohort, to facilitate diagnosis; and (2) to describe cases in which non-KD agents achieved seizure freedom (SF), highlighting potential adjunctive treatments. METHODS: Retrospective review of 87 patients with Glut 1 DS (45% female, age range 3 months-35 years, average diagnosis 6.5 years) at Columbia University, from 1989 to 2010. KEY FINDINGS: Seventy-eight (90%) of 87 patients had epilepsy, with average onset at 8 months. Seizures were mixed in 68% (53/78): generalized tonic clonic (53%), absence (49%), complex partial (37%), myoclonic (27%), drop (26%), tonic (12%), simple partial (3%), and spasms (3%). We describe the first two cases of spasms in Glut 1 DS. Electrophysiologic abnormalities were highly variable over time; only 13 (17%) of 75 had exclusively normal findings. KD was used in 82% (64/78); 67% (41/61) were seizure-free and 68% of seizure-free patients (28/41) resolved in <1 week and 76% (31/41) in <1 month. Seven patients achieved SF with broad agents only. SIGNIFICANCE: Glut 1 DS is a genetic metabolic encephalopathy with variable focal and multifocal seizure types and electroencephalographic findings. Infants with seizures, spasms, or paroxysmal events should be tested for Glut 1 DS. Evidence is insufficient to recommend specific AEDs as alternatives to KD. Early diagnosis and initiation of KD and prevention of unnecessary AED trials in Glut 1 DS are important goals for the treatment of children with epilepsy. PMID- 22812642 TI - An attachment perspective on therapeutic processes and outcomes. AB - Over the past decade, there has been an explosion of interest in clinical applications of attachment theory. In the present article, we briefly describe John Bowlby's model of therapeutic change, the therapeutic relationship, and the therapist's role in emotional healing. We then review empirical evidence for three key propositions in Bowlby's model. First, a client's sense of security during therapy is crucial for facilitating therapeutic work. Second, a therapist's own sense of security contributes to positive therapeutic outcomes. Third, attachment insecurities can be effectively reduced in therapy, and movement toward greater attachment security is central to achieving favorable therapeutic outcomes. In sum, research evidence confirms the importance of establishing what Bowlby called a safe haven and a secure base within a therapeutic relationship. PMID- 22812643 TI - Identification of a dicer homologue gene (DCL2) in Nicotiana tabacum. AB - Eukaryotes possess a mechanism that generates small interfering RNA (siRNA) and microRNA (miRNA) and use these to regulate gene expression at the transcriptional or post-transcriptional level. These small RNAs (21-24nt) are processed from long double-stranded RNA precursors by type III RNase enzymes, referred to as DICER or DICER-LIKE proteins (DCLs). In Arabidopsis, there are four DCL genes and their role in small RNA biogenesis and silencing has been the subject of intense study. DCL2 is less well studied than the other DCL proteins although it is known to play a role in formation of natural antisense siRNA and may be involved in transitive silencing of transgene transcripts. This study provides basic genomic information on DCL2 in the Nicotiana tabacum (NtDCL2) gene family and its probable roles in plant growth and development. PMID- 22812644 TI - Ratiometric imaging of calcium during ischemia-reperfusion injury in isolated mouse hearts using Fura-2. AB - BACKGROUND: We present an easily implementable method for measuring Fura-2 fluorescence from isolated mouse hearts using a commercially available switching light source and CCD camera. After calibration, it provides a good estimate of intracellular [Ca2+] with both high spatial and temporal resolutions, permitting study of changes in dispersion of diastolic [Ca2+], Ca2+ transient dynamics, and conduction velocities in mouse hearts. In a proof-of-principle study, we imaged isolated Langendorff-perfused mouse hearts with reversible regional myocardial infarctions. METHODS: Isolated mouse hearts were perfused in the Landendorff-mode and loaded with Fura-2. Hearts were then paced rapidly and subjected to 15 minutes of regional ischemia by ligation of the left anterior descending coronary artery, following which the ligation was removed to allow reperfusion for 15 minutes. Fura-2 fluorescence was recorded at regular intervals using a high-speed CCD camera. The two wavelengths of excitation light were interleaved at a rate of 1 KHz with a computer controlled switching light source to illuminate the heart. RESULTS: Fura-2 produced consistent Ca2+ transients from different hearts. Ligating the coronary artery rapidly generated a well defined region with a dramatic rise in diastolic Ca2+ without a significant change in transient amplitude; Ca2+ handling normalized during reperfusion. Conduction velocity was reduced by around 50% during ischemia, and did not recover significantly when monitored for 15 minutes following reperfusion. CONCLUSIONS: Our method of imaging Fura-2 from isolated whole hearts is capable of detecting pathological changes in intracellular Ca2+ levels in cardiac tissue. The persistent change in the conduction velocities indicates that changes to tissue connectivity rather than altered intracellular Ca2+ handling may be underlying the electrical instabilities commonly seen in patients following a myocardial infarction. PMID- 22812645 TI - IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. AB - INTRODUCTION: Morbidity/mortality is higher in men with below-normal serum testosterone. Restoring testosterone to normal is beneficial. AIM: Assessment of safety and effectiveness of injectable long-acting testosterone undecanoate (TU) in hypogonadal men in daily clinical practice. METHODS: An international, multicenter, one-arm, prospective observational study in 23 countries. MAIN OUTCOME MEASURES: Parameters of erectile function, libido, vigor/vitality, mood, and ability to concentrate assessed by physician interview using items and five point Likert scales. Physical and circulatory parameters as well as hematocrit, prostate-specific antigen (PSA) levels, glucose control, and lipid profiles. IPASS: An International, multicenter, Post-Authorisation (after authorized use in respective country) Surveillance Study on long-acting-intramuscular TU conducted at 155 centers in 23 countries in Europe, Asia, Latin America, and Australia. Patients received up to five TU injections during 9-12 months. RESULTS: Of the 1,493 hypogonadal men enrolled, 1,438 (aged 49.2 +/- 13.9 years) having received 6,333 injections were analyzed. Scores of mental and psychosexual functions (libido, vigor, overall mood, and ability to concentrate) improved markedly, while mean waist circumference decreased from 100 to 96 cm. Blood pressure and lipid parameters were altered in a favorable and significant manner. After four TU injection intervals, the percentage of patients with "low" or "very low" levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%. At the last observation, 89% of patients were "satisfied" or "very satisfied" with TU therapy. Adverse events and adverse drug reactions (ADRs) occurred in 12% and 6% of patients, respectively, mostly mild to moderate. The most common ADRs were increase in hematocrit, increase in PSA, and injection site pain (all <1%). No case of prostate cancer was observed. CONCLUSION: In this largest worldwide sample of hypogonadal men, injectable long-acting TU was effective and well tolerated. PMID- 22812646 TI - Shear stress is required for the endocytic uptake of the factor VIII-von Willebrand factor complex by macrophages. AB - BACKGROUND: Low-density lipoprotein (LDL) receptor family members contribute to the cellular uptake of factor VIII. How von Willebrand factor fits into this endocytic pathway has remained poorly understood. OBJECTIVES: It has been suggested that macrophages contribute to the clearance of the factor VIII (FVIII) von Willebrand factor (VWF) complex. We now assessed the mechanisms of uptake employing human monocyte-derived macrophages. METHODS: A confocal microscopy study was employed to study the uptake by monocyte-derived macrophages of a functional green fluorescent FVIII-GFP derivative in the presence and absence of VWF. RESULTS: The results revealed that FVIII-GFP is internalized by macrophages. We found that FVIII-GFP co-localizes with LDL receptor-related protein (LRP), and that the LRP antagonist Receptor Associated Protein (RAP) blocks the uptake of FVIII-GFP. However, FVIII-GFP was not detected in the macrophages in the presence of VWF, suggesting that the FVIII-VWF complex is not internalized by these cells at all. Apart from static conditions, we also investigated the effect of shear stress on the uptake of FVIII-GFP in presence of VWF. Immunofluorescence studies demonstrated that VWF does not block endocytosis of FVIII-GFP under flow conditions. Moreover, VWF itself was also internalized by the macrophages. Strikingly, in the presence of RAP, endocytosis of FVIII-GFP and VWF was inhibited. CONCLUSION: The results show that shear stress is required for macrophages to internalize both constituents of the FVIII-VWF complex. PMID- 22812647 TI - Maternal rib fracture after manual uterine fundal pressure. PMID- 22812648 TI - A thematic analysis of causes attributed to weight gain: a female slimmer's perspective. AB - BACKGROUND: Obesity prevalence has shown a marked increase in recent years. Strategies designed to manage the trend are not always effective in the long term. This qualitative study investigated perceived causes of weight gain in a group of female slimmer's. Understanding beliefs about the causes of a problem can help explain behaviour and find solutions. It is therefore justified and timely to explore beliefs about causes of weight gain. METHODS: A group of 11 (adult) slimmer's were interviewed using a semi-structured approach, and the data obtained were analysed thematically. RESULTS: Four main themes were identified; importance of habits, influence of learning early models about the world through food, eating beyond feeling full and use of food as therapy. CONCLUSIONS: Behavioural causes were given to explain weight gain, perceived to be mediated by modern lifestyles or changes in circumstances. In addition, beliefs about food and its function related to personal history or childhood experience, which subsequently were used negatively in adulthood. The potential contributions of these findings for practice are explored. PMID- 22812649 TI - Effects of multi-polar radiofrequency and pulsed electromagnetic field treatment in Koreans: case series and survey study. AB - BACKGROUND: Recently, a novel combined multi-polar radiofrequency and pulsed electromagnetic field device was developed for non-ablative skin tightening. However, little is known about the clinical effects of this device. OBJECTIVES: The present study evaluated the clinical efficacy and safety of the multi-polar radiofrequency and pulsed electromagnetic field device. MATERIALS AND METHODS: Ten Korean patients underwent eight treatment sessions over 6 weeks. Clinical photographs of the skin were taken before and after the treatment at each week of treatment. Satisfaction score (0; dissatisfied, 5; neutral, 10; very satisfied) and pain score (0; no pain, 10; too painful) was determined using weekly questionnaires. A dermatologist evaluated the improvement of facial skin aging, including laxity, nasolabial fold, facial contour, skin texture, and skin color tone. RESULTS: The mean satisfaction score was high (>8) and the mean pain score was low (1.5). Improved skin laxity, nasolabial fold, and facial contour were observed in four, one, and three patients, respectively. Skin texture and skin color tone improved in 90% and 70% of the patients, respectively. CONCLUSION: The novel combined multi-polar radiofrequency and pulsed electromagnetic field device is safe and effective for rejuvenating aged skin in Korean subjects. PMID- 22812650 TI - Comparison of hexamethyldisiloxane dissociation processes in plasma. AB - Different hexamethyldisiloxane (HMDSO) dissociation processes are investigated by means of absorption spectroscopy and mass spectrometry. All of these processes are expected to occur in plasma containing Ar-HMDSO gas mixture. We successively study interactions of the HMDSO molecule with electrons (energy ranges from 15 to 70 eV), with Ar((3)P(2)) metastable species (internal energy 11.55 eV) and with VUV photon (7.3 to 10.79 eV). The studies of HMDSO interactions with Ar((3)P(2)) and VUV photon provide new results concerning the dissociation pathways and the collision cross-sections. In the case of Ar((3)P(2)), the dissociation mechanisms result mainly in Si-C or Si-O bond breaking, producing SiMe(2,1) radicals. Less efficient mechanisms involve also Si-C and Si-O bond breaking producing Me, Si(2)Me(5)O, or SiMe(3), on one hand, and, on the other hand, Si-C and C-H bond breaking producing Si(2)Me(4)OH. In the case of photon interaction, the dissociation process is more selective and mainly produces Si(2)OMe(5) pentadisiloxane and methyl radicals due to Si-C bond breaking. Si-O bond breaking produces also SiMe(3) in a lower concentration. Dissociation cross-section values of HMDSO ranging from sigma = 45 * 10(-20) m(2) to 180 * 10(-20) m(2) and from sigma = 0.7 * 10(-22) m(2) to 18.3 * 10(-22) m(2), correspond to a global dissociation mechanism by Ar((3)P(2)) collision and to a selective dissociation mechanism (producing Si(2)OMe(5) and Me) by VUV photon interaction, respectively. All results are compared and discussed. PMID- 22812652 TI - Secular trends in impact factor of neonatology publications over a 10-year period. AB - AIM: To test the hypotheses that published randomized clinical trials (RCTs) in neonatology with negative results (NR) are more likely to be published in journals with lower impact factor (IF) than those with positive results (PR); that there is an increase in the number of yearly published RCTs; that studies with large sample sizes are likely to be published in journals with higher IF. METHODS: We used all English-written RCTs registered in MEDLINE between 1/1/2001-31/12/2010 in the field of neonatology. Each RCT was classified as having a PR or NR. IF of each journal was determined for the year of publication. RESULTS: We identified 329 RCTs. Yearly number of RCTs varied between 19 and 46, with no significant consistent linear increase over the years. There was no significant change over the years in average IF or in average patient size. IF and sample size of the studies were not significantly higher in studies with PR than in studies with NR. CONCLUSION: The number of RCTs per year in the field of neonatology has stabilized in the past 10 years, and RCTs with positive or negative results are published in journals of similar IF. PMID- 22812651 TI - The diagnosis of urinary tract infections in young children (DUTY): protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness. AB - BACKGROUND: Urinary tract infection (UTI) is common in children, and may cause serious illness and recurrent symptoms. However, obtaining a urine sample from young children in primary care is challenging and not feasible for large numbers. Evidence regarding the predictive value of symptoms, signs and urinalysis for UTI in young children is urgently needed to help primary care clinicians better identify children who should be investigated for UTI. This paper describes the protocol for the Diagnosis of Urinary Tract infection in Young children (DUTY) study. The overall study aim is to derive and validate a cost-effective clinical algorithm for the diagnosis of UTI in children presenting to primary care acutely unwell. METHODS/DESIGN: DUTY is a multicentre, diagnostic and prospective observational study aiming to recruit at least 7,000 children aged before their fifth birthday, being assessed in primary care for any acute, non-traumatic, illness of <= 28 days duration. Urine samples will be obtained from eligible consented children, and data collected on medical history and presenting symptoms and signs. Urine samples will be dipstick tested in general practice and sent for microbiological analysis. All children with culture positive urines and a random sample of children with urine culture results in other, non-positive categories will be followed up to record symptom duration and healthcare resource use. A diagnostic algorithm will be constructed and validated and an economic evaluation conducted.The primary outcome will be a validated diagnostic algorithm using a reference standard of a pure/predominant growth of at least >103, but usually >105 CFU/mL of one, but no more than two uropathogens.We will use logistic regression to identify the clinical predictors (i.e. demographic, medical history, presenting signs and symptoms and urine dipstick analysis results) most strongly associated with a positive urine culture result. We will then use economic evaluation to compare the cost effectiveness of the candidate prediction rules. DISCUSSION: This study will provide novel, clinically important information on the diagnostic features of childhood UTI and the cost effectiveness of a validated prediction rule, to help primary care clinicians improve the efficiency of their diagnostic strategy for UTI in young children. PMID- 22812653 TI - Regio- and diastereoselective synthesis of beta-lactam-triazole hybrids via Passerini/CuAAC sequence. AB - Passerini (P-3CR) and Passerini-Smiles reactions were investigated in azetidine 2,3-diones, affording the corresponding 3,3-disubstituted-beta-lactams with complete diastereoselectivity in high yields. The study has been carried out using different isocyanides, carboxylic acids, and phenols showing the scope of both reactions. In addition, the regioselective synthesis of highly functionalized beta-lactam-triazole hybrids has been developed via a Passerini/CuAAC sequence. Interestingly, the use of dialkynes/diazides or trialkynes/triazides as linkers in the CuAAC step has allowed the synthesis of C(2) and C(3) symmetric beta-lactam-triazole hybrids, respectively. PMID- 22812655 TI - A transmission electron microscopy study of the electrochemical process of lithium-oxygen cells. AB - The electrochemical reaction of a lithium-oxygen cell using a tetraethylene glycol dimethyl ether-lithium triflate, TEGDME-LiCF(3)SO(3) electrolyte, is investigated by a detailed transmission electron microscopy analysis. The results confirm the reversibility of the process by showing the formation-dissolution of lithium peroxide, Li(2)O(2), upon repeating cell charge and discharge cycles. PMID- 22812654 TI - The structure of the BfrB-Bfd complex reveals protein-protein interactions enabling iron release from bacterioferritin. AB - Ferritin-like molecules are unique to cellular iron homeostasis because they can store iron at concentrations much higher than those dictated by the solubility of Fe(3+). Very little is known about the protein interactions that deliver iron for storage or promote the mobilization of stored iron from ferritin-like molecules. Here, we report the X-ray crystal structure of Pseudomonas aeruginosa bacterioferritin (Pa-BfrB) in complex with bacterioferritin-associated ferredoxin (Pa-Bfd) at 2.0 A resolution. As the first example of a ferritin-like molecule in complex with a cognate partner, the structure provides unprecedented insight into the complementary interface that enables the [2Fe-2S] cluster of Pa-Bfd to promote heme-mediated electron transfer through the BfrB protein dielectric (~18 A), a process that is necessary to reduce the core ferric mineral and facilitate mobilization of Fe(2+). The Pa-BfrB-Bfd complex also revealed the first structure of a Bfd, thus providing a first view to what appears to be a versatile metal binding domain ubiquitous to the large Fer2_BFD family of proteins and enzymes with diverse functions. Residues at the Pa-BfrB-Bfd interface are highly conserved in Bfr and Bfd sequences from a number of pathogenic bacteria, suggesting that the specific recognition between Pa-BfrB and Pa-Bfd is of widespread significance to the understanding of bacterial iron homeostasis. PMID- 22812656 TI - Mark A. Wood. M.D. PMID- 22812657 TI - Serum levels of cytokines, glucose, and hemoglobin as possible predictors of poststroke depression, and association with poststroke fatigue. AB - Depression is a frequent and potentially disabling sequela of stroke. In the present study, we investigated the ability of stroke type, infarct volume, and laterality, and the levels of various cytokines and other blood components in the acute phase of acute ischemic stroke (AIS) in 45 patients, to predict the level of depression (Beck Depression Inventory [BDI] score) at 6, 12, and 18 months after its onset. The BDI score at 12 months poststroke was positively correlated with the acute serum level of glucose (r = 0.32, p = .038). When excluding the patients using antidepressants, the correlation between glucose level and later depression became significant at all three time points. A general association was found between depression and fatigue. Novel findings are that high acute serum levels of glucose may predict depression after AIS, a glucose level of approximately 126 mg/dL at admission might be a critical limit. Furthermore, depression and fatigue are two generally related-although independent-sequelae of stroke. Our findings did not support a causal immunological etiology for poststroke depression (PSD), as has been suggested previously for poststroke fatigue (PSF) in the same study sample. PMID- 22812658 TI - Nutrition and the healthy heart with an exercise boost. AB - In this era of potent medications and major cardiovascular (CV) procedures, the value of nutrition can be forgotten. A healthy diet is essential, regardless of CV risk. Caloric balance is inherent to a good diet. Despite patients who say they eat little, ideal weight can be maintained if calories are burned. Composition is another component of a healthy diet. The Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets provide proof of CV benefit from their specific content. Metabolic syndrome (MS) is associated with poor diet and obesity. A healthy diet with good nutrition benefits the MS patient and associated conditions such as obesity and diabetes. Exercise, in conjunction with a healthy diet and good nutrition, helps maintain optimal weight and provides CV benefit such as decreased inflammation and increased vasodilatation. Whether vitamins or other nutritional supplements are important in a healthy diet is unproven. Nevertheless, the most promising data of added benefit to a healthy diet is with vitamin D. Some dietary supplements also have promise. Alcohol, in moderation, especially red wine, has nutritional and heart protective benefits. Antioxidants, endogenous or exogenous, have received increased interest and appear to play a favorable nutritional role. CV health starts with good nutrition. PMID- 22812659 TI - Androgen insensitivity syndrome. AB - Androgen insensitivity syndrome (AIS) is a disorder caused by a mutation of the gene encoding the androgen receptor (AR; Xq11-q12). The prevalence of AIS has been estimated to be one case in every 20,000 to 64,000 newborn males for the complete syndrome (CAIS), and the prevalence is unknown for the partial syndrome (PAIS). The symptoms range from phenotypically normal males with impaired spermatogenesis to phenotypically normal women with primary amenorrhea. Various forms of ambiguous genitalia have been observed at birth. The diagnosis is confirmed by determining the exact mutation in the AR gene. PAIS individuals require precise diagnosis as early as possible so that the sex can be assigned, treatment can be recommended, and they can receive proper genetic counseling. After birth, differential diagnosis should be performed using other forms of abnormal sexual differentiation of primary amenorrhea. The treatment of AIS is based on reinforcement sexual identity, gonadectomy planning, and hormone replacement therapy. The prognosis for CAIS is good if the testicular tissue is removed at the appropriate time. For PAIS, the prognosis depends on the ambiguity of the genitalia and physical and psychosocial adjustment to the assigned sex. PMID- 22812660 TI - The socioeconomic consequences of optic neuritis with and without multiple sclerosis: a controlled national study. AB - OBJECTIVES: Optic neuritis (ON) often precedes multiple sclerosis (MS). MS is associated with a significant socioeconomic burden. However, the burden of ON with and without MS before and after its diagnosis has never been calculated. METHODS: Using complete national records from the Danish National Patient Registry (1998-2006), we identified 1677 patients with ON and compared them with 6708 randomly selected citizens matched for age, sex and geography. A societal perspective is taken towards the cost analyses. Costs included in the analysis are those of the health sector, including all contacts with primary and secondary sectors, and the use and costs of drugs. Productivity losses included labour supply and income. All social transfer payments were also calculated. RESULTS: Patients with ON had higher rates of contact with healthcare services, medication use and income from employment, all of which incurred a higher socioeconomic cost. Employed patients had lower income than control subjects. The total annual excess costs relative to matched controls were ?3501 for ON patients and ?9215 for patients with a dual diagnosis of ON and MS. The ON and ON+MS patients received an annual mean excess social transfer income of ?1175 and ?4619. ON/ON+MS patients presented social and economic consequences up to 8 years before diagnosis, and these increased after the diagnosis was established. CONCLUSIONS: ON, especially if combined with a diagnosis of MS, has a significant socioeconomic consequence for the individual patient and for society. Productivity losses are a far more important economic factor than health sector costs. PMID- 22812661 TI - Drought-induced shifts in the floristic and functional composition of tropical forests in Ghana. AB - The future of tropical forests under global environmental change is uncertain, with biodiversity and carbon stocks at risk if precipitation regimes alter. Here, we assess changes in plant functional composition and biomass in 19 plots from a variety of forest types during two decades of long-term drought in Ghana. We find a consistent increase in dry forest, deciduous, canopy species with intermediate light demand and a concomitant decrease in wet forest, evergreen, sub-canopy and shade-tolerant species. These changes in composition are accompanied by an increase in above-ground biomass. Our results indicate that by altering composition in favour of drought-tolerant species, the biomass stocks of these forests may be more resilient to longer term drought than short-term studies of severe individual droughts suggest. PMID- 22812662 TI - In vitro formation and characterization of the skeletal muscle alpha.beta tropomyosin heterodimers. AB - Tropomyosin (Tm) is a dimer made of two alpha helical chains associated into a parallel coiled-coil. In mammalian skeletal and cardiac muscle, the Tm is expressed from two separate genes to give the alpha- and beta-Tm isoforms. These associate in vivo to form homo- (alpha(2)) and heterodimers (alpha.beta) with little beta(2) normally observed. The proportion of alpha(2) vs alpha.beta varies across species and across muscle types from almost 100% alpha(2)- to 50% alpha.beta-Tm. The ratio can also vary during development and in disease. The functional significance of the presence of these two isoforms has not been defined because it is difficult to isolate or purify the alpha.beta dimer for functional studies. Here we report an effective method for purifying bacterially expressed Tm as alpha.beta dimers using a cleavable N-terminal tag on one of the two chains. The same method can be used to isolate Tm dimers in which one chain carries a mutation. We go on to show that the alpha.beta dimers differ in key properties (actin affinity, thermal stability) from either the alpha(2)- or beta(2)-Tm. However, the ability to regulate myosin binding when combined with cardiac troponin appears unaffected. PMID- 22812663 TI - A pharmacokinetic study of a topical anesthetic (EMLA(r) ) in mouse soft tissue laceration. AB - The use of topical anesthesia instead of injection of local anesthetics for managing soft tissue lacerations in the emergency situations may be a relief for both patients and surgeons. Topical anesthesia in the form of a cream eutectic mixture of local anesthetics (EMLA(r)) containing 2.5% lidocaine and 2.5% prilocaine has been reported as an efficient anesthetic on skin before venipuncture anesthesia and as an alternative to injection anesthesia in some minor surgery situations. The aim of this study was to compare the pharmacokinetics of EMLA(r) when applied in a laceration with topical skin application in the mouse. A total of 120 Albino Laboratory-bred strain mouse (BALB-c) male mice were divided into three groups with regard to application mode of EMLA(r). Group A: with laceration, 48 mice; Group B: on intact shaved skin, 48 mice; Group C: control group (24 mice) with same procedures but without application of EMLA(r). Blood levels were collected at 0, 10, 20, 30, 45, 60, 75, and 90 min post-EMLA(r) application. Plasma sample analysis was carried out by employing liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method, and the pharmacokinetic analysis of the mouse plasma samples was estimated by standard non-compartmental methods. The pharmacokinetic parameters of lidocaine and prilocaine were significantly altered following EMLA(r) application to lacerated mouse skin in contrast to intact skin. The absorption of lidocaine and prilocaine was rapid following application of EMLA(r) to lacerated and intact mouse skin. Maximum drug plasma concentration (C(max) ) and area under the drug plasma concentration-time curve (AUC) values of lidocaine were significantly increased by 448.6% and 161.5%, respectively, following application of EMLA to lacerated mouse skin in comparison with intact mouse skin. Similarly, prilocaine's C(max) and AUC values were also increased by 384% and 265.7%, respectively, following EMLA application to lacerated mouse skin, in contrast to intact skin. Further pharmacokinetic studies on different carriers of lidocaine/prilocaine are warranted before any firm conclusions for the clinic can be drawn. PMID- 22812664 TI - Synthesis and insecticidal activities of novel anthranilic diamides containing acylthiourea and acylurea. AB - Two series of anthranilic diamides containing acylthiourea and acylurea linkers were designed and synthesized, with changed length and flexibility of the linkers to compare to known anthranilic diamide insecticides. In total, 26 novel compounds were synthesized, and all compounds were characterized by (1)H nuclear magnetic resonance and high-resolution mass spectrometry. Their insecticidal activities against oriental armyworm (Mythimna separata), mosquito larvae (Culex pipiens pallens), and diamondback moth (Plutella xylostella) were evaluated. The larvicidal activities against oriental armyworm indicated that the introduction of acylthiourea into some structures could retain their insecticidal activity; 8 of the 15 compounds (13a-13e, 14a-14e, and 15a-15e) exhibited 100% larvicidal activity at 10 mg/L. However, the introduction of acylurea decreased the insecticidal activity; only 3 of the 11 compounds (17a-17k) exhibited 100% larvicidal activity at 200 mg/L. The whole-cell patch-clamp technique indicated that compound 13b and chlorantraniliprole exhibited similar effects on the voltage-gated calcium channel. The calcium-imaging technique was also applied to investigate the effects of compounds 13b and 15a on the intracellular calcium ion concentration ([Ca(2+)](i)), which indicated that they released stored calcium ions from endoplasmic reticulum. Experimental results denoted that several new compounds are potential activators of the insect ryanodine receptor (RyR). PMID- 22812665 TI - Increased phosphodiesterase type 5 levels in a mouse model of type 2 diabetes mellitus. AB - INTRODUCTION: Diabetes mellitus (DM) is a major risk factor for developing erectile dysfunction (ED) and men with DM are often less responsive to phosphodiesterase type 5 (PDE5) inhibitors than ED due to other causes. AIMS: The aim of this study was to explore potential mechanisms whereby PDE5 inhibitors may have reduced efficacy in type 2 DM. METHODS: At 4 weeks of age, mice were either fed a high-fat diet (HFD) for 22-36 weeks or fed regular chow (control). An additional group of mice in the same genetic background had a genetic form of type 1 DM. MAIN OUTCOME MEASURES: Glucose tolerance testing, intracorporal pressures (ICPs), oxidative stress (OS), apoptotic cell death (active caspase-3 and apostain), PDE5, p53, and cyclic guanosine monophosphate (cGMP) levels, and histological examination of inflow arteries were performed in mice fed a HFD and control mice. A group of mice with type 1 DM were studied for PDE5 expression levels. RESULTS: All mice fed a HFD had impaired glucose tolerance compared with the age-matched mice fed on standard chow diet (control). HFD fed mice had reduced maximum ICPs following in vivo cavernous nerve electrical stimulation and increased apoptotic cell death, OS, and p53 levels in the corporal tissue. Interestingly, PDE5 levels were increased and cGMP levels were decreased. In contrast, mice with type 1 DM did not have increases in PDE5. CONCLUSIONS: Taken together, our results suggest that type 2 DM-induced ED is associated with findings that could lead to reduced cGMP and may account for reduced efficacy of PDE5 inhibitors. PMID- 22812666 TI - No influence of serotonin levels in foetal bovine sera on radiation-induced bystander effects and genomic instability. AB - PURPOSE: The aim of this study was to contribute to an inter-laboratory investigation within the Non-Targeted Effects of Ionising Radiation Integrated project (NOTE) (2006-2010) to investigate the role of serum serotonin concentration on radiation-induced bystander effects using our successful experimental design. Two sera of high and low serotonin levels were tested alongside standard serum used in our laboratory. MATERIALS AND METHODS: Primary Human Fibroblast 19 (HF19) cells were sham/irradiated with 0.5 Gy alpha particles, in medium supplemented with serum of different levels of serotonin. Filtered medium was transferred to unirradiated HF19 bystander cells. Cells from irradiated and bystander populations were harvested for chromosomal analysis at early and delayed times post-irradiation/media transfer to assess initial damaging effects and induction of delayed chromosomal instability respectively. RESULTS: Chromosomal damage was elevated to significant levels (p = <= 0.005) above respective controls in both cell populations in all groups. Induction of delayed chromosomal instability was significantly observed in all groups at delayed time post irradiation/medium transfer. Furthermore, induction of bystander effects at early and delayed times was not significantly different between groups. CONCLUSIONS: No effect of serotonin on the induction of either bystander effects of genomic instability was observed using this experimental system. PMID- 22812668 TI - Relating chloroethene respiration rates in Dehalococcoides to protein and mRNA biomarkers. AB - Molecular biomarkers could provide critical insight into myriad in situ microbial activities. In this study we explore correlations of both mRNA and protein biomarkers with chloroethene respiration rate in Dehalococcoides. In a series of continuously fed dechlorinating mixed-culture microcosm experiments (n = 26), we varied respiratory substrates, substrate ratios and feeding rates. Transcript levels for most biomarkers were responsive down to 0.01* the culture's maximum respiration rate. The dehalogenase TceA and the Ni-Fe hydrogenase HupL transcripts were positively correlated (Pearson's r of 0.89 and 0.88, respectively) with respiration rates on log-log plots between 1.5 and 280 MUeeq/L hr for mRNA abundances of 10(7) to 10(10) transcripts/mL (0.07-230 transcripts/genome). These trends were independent of the types of chloroethene or electron donors fed. Other mRNA target levels plateaued or declined at respiration rates above 5 MUeeq/L-hr. Using both relative and absolute protein quantification methods, we found that per-genome protein abundances of most targeted biomarkers did not statistically change over the experimental time frames. However, quantified enzyme levels allowed us to calculate in vivo enzyme specific rate constants (k(cat)) for the dehalogenases PceA and TceA: 400 and 22 substrate molecules/enzyme-sec, respectively. Overall, these data support the promise of both mRNA and protein biomarkers for estimating process rates through either empirical (mRNA-based) or kinetic (protein-based) models, but they require follow-up studies in other cultures and at active remediation sites. PMID- 22812667 TI - Pupillometric analysis for assessment of gene therapy in Leber Congenital Amaurosis patients. AB - BACKGROUND: Objective techniques to assess the amelioration of vision in patients with impaired visual function are needed to standardize efficacy assessment in gene therapy trials for ocular diseases. Pupillometry has been investigated in several diseases in order to provide objective information about the visual reflex pathway and has been adopted to quantify visual impairment in patients with Leber Congenital Amaurosis (LCA). In this paper, we describe detailed methods of pupillometric analysis and a case study on three Italian patients affected by Leber Congenital Amaurosis (LCA) involved in a gene therapy clinical trial at two follow-up time-points: 1 year and 3 years after therapy administration. METHODS: Pupillary light reflexes (PLR) were measured in patients who had received a unilateral subretinal injection in a clinical gene therapy trial. Pupil images were recorded simultaneously in both eyes with a commercial pupillometer and related software. A program was generated with MATLAB software in order to enable enhanced pupil detection with revision of the acquired images (correcting aberrations due to the inability of these severely visually impaired patients to fixate), and computation of the pupillometric parameters for each stimulus. Pupil detection was performed through Hough Transform and a non parametric paired statistical test was adopted for comparison. RESULTS: The developed program provided correct pupil detection also for frames in which the pupil is not totally visible. Moreover, it provided an automatic computation of the pupillometric parameters for each stimulus and enabled semi-automatic revision of computerized detection, eliminating the need for the user to manually check frame by frame. With reference to the case study, the amplitude of pupillary constriction and the constriction velocity were increased in the right (treated eye) compared to the left (untreated) eye at both follow-up time-points, showing stability of the improved PLR in the treated eye. CONCLUSIONS: Our method streamlined the pupillometric analyses and allowed rapid statistical analysis of a range of parameters associated with PLR. The results confirm that pupillometry is a useful objective measure for the assessment of therapeutic effect of gene therapy in patients with LCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00516477. PMID- 22812669 TI - Agency-communion and self-esteem relations are moderated by culture, religiosity, age, and sex: evidence for the "self-centrality breeds self-enhancement" principle. AB - OBJECTIVE: Who has high self-esteem? Is it ambitious, competitive, outgoing people-agentic personalities? Or is it caring, honest, understanding people communal personalities? The literature on agency-communion and self-esteem is sparse, indirect, and inconsistent. Based on William James's theorizing, we propose the "self-centrality breeds self-enhancement" principle. Accordingly, agency will be linked to self-esteem, if agency is self-central. Conversely, communion will be linked to self-esteem, if communion is self-central. But what determines the self-centrality of agency and communion? The literature suggests that agency is self-central in agentic cultures, as well as among nonreligious individuals, men, and younger adults. Communion is self-central in communal cultures, as well as among religious individuals, women, and older adults. METHOD: This study examined 187,957 people (47% female; mean age = 37.49 years, SD = 12.22) from 11 cultures. The large sample size afforded us the opportunity to test simultaneously the effect of all four moderators in a single two-level model (participants nested in cultures). RESULTS: Results supported the unique moderating effect of culture, religiosity, age, and sex on the relation between agency-communion and self-esteem. CONCLUSIONS: Agentic and communal people can both have high self-esteem, depending on self-centrality of agency and communion. PMID- 22812670 TI - Cadmium exposure is accompanied by increased prevalence and future growth of atherosclerotic plaques in 64-year-old women. AB - OBJECTIVES: There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries. DESIGN AND SUBJECTS: The analyses were performed in a screening-based cohort of 64-year-old Caucasian women with stratified, random selection to groups with normal glucose tolerance, impaired glucose tolerance and diabetes (n = 599). We measured cadmium concentrations in blood and urine at baseline. In addition, we performed ultrasound examination to determine the prevalence and area of atherosclerotic plaques in the carotid arteries and assessed smoking history and other cardiovascular risk factors at baseline and at a follow-up examination after a mean of 5.4 years. RESULTS: At baseline, blood cadmium levels were associated with increased risk of plaque and a large plaque area after adjustment for confounders. In women who had never smoked, blood cadmium levels correlated positively with plaque area at baseline. The occurrence of large plaques and the change in plaque area at follow-up were associated with blood and creatinine corrected urinary cadmium concentrations at baseline after adjustment for confounders. Blood and urine cadmium levels added information to established cardiovascular risk factors in predicting progress of atherosclerosis. CONCLUSIONS: We have shown that cadmium levels in blood and urine are independent factors associated with the development of atherosclerotic plaques at baseline as well as prospectively. This novel observation emphasizes the need to consider cadmium as a pro-atherogenic pollutant. PMID- 22812671 TI - Leukemoid reaction in a patient with adenocarcinoma of the lung: a case report. AB - INTRODUCTION: Lung cancers are characterized by high incidence, prevalence and mortality. They may be associated with numerous paraneoplastic syndromes. Mild leukocytosis is not rare. The case described here, however, is of a female patient with adenocarcinoma of the lung who developed extreme leukocytosis at over 140,000 cells/MUL. Descriptions of such leukemic forms of lung cancer are few and far between in the literature. In our case, the complete hematological diagnostic investigation, which included cytological, immunocytological, cytogenetic, histological and molecular genetic tests of the bone marrow (mutation analyses of BCR-ABL and JAK2), was accompanied for the first time by a molecular genetic workup of the primary tumor for epidermal growth factor receptor and K-RAS gene mutations. CASE PRESENTATION: We present the medical case of a 51-year-old female Caucasian patient, who was diagnosed with a poorly differentiated stage IV (International Union Against Cancer staging) adenocarcinoma of the lung. While undergoing treatment, our patient developed extreme leukocytosis, for which, despite extensive diagnostic tests, no infection related or hematological cause could be identified. The tumor proved to be highly resistant to treatment. Our patient died only five months after the initial diagnosis. CONCLUSION: A leukemoid course can most likely be interpreted as the paraneoplastic production of hematopoietic growth factors. Despite the absence of a verified primary hematological origin, this possibility should always be investigated in all patients in a comparable situation. PMID- 22812673 TI - Threshold collision-induced dissociation and theoretical studies of hydrated Fe(II): binding energies and Coulombic barrier heights. AB - The first experimentally determined bond dissociation energies for losing water from Fe(2+)(H(2)O)(n) complexes, n = 4-11, are measured using threshold collision induced dissociation (TCID) in a guided ion beam tandem mass spectrometer coupled to an electrospray ionization source that forms thermalized complexes. In this technique, absolute cross-sections for dissociation induced by collisions with Xe at systematically varied kinetic energies are obtained. After accounting for multiple collisions, kinetic shifts, and energy distributions, these cross sections are analyzed to yield the energy thresholds for losing one, two, or three water ligands at 0 K. The 0 K threshold measurements are converted to 298 K values to give the hydration enthalpies and free energies for sequentially losing water ligands from each complex. Comparisons to previous results for hydration of Zn(2+) indicate that the bond energies are dominated by electrostatic interactions, with no obvious variations associated with the open shell of Fe(2+). Theoretical geometry optimizations and single-point energy calculations are performed using several levels of theory for comparison to experiment, with generally good agreement. In addition to water loss channels, the charge separation process generating hydrated FeOH(+) and protons is observed for multiple reactant complexes. Energies of the rate-limiting transition states are calculated at several levels of theory with density functional approaches (B3LYP and B3P86) disagreeing with MP2(full) results. Comparisons to our kinetic energy dependent cross-sections suggest that the energetics of the MP2(full) level are most accurate. PMID- 22812672 TI - Switch therapy in hospitalized patients with community-acquired pneumonia: tigecycline vs. levofloxacin. AB - BACKGROUND: Switch therapy is a management approach combining early discontinuation of intravenous (IV) antibiotics, switch to oral antibiotics, and early hospital discharge. This analysis compares switch therapy using tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia (CAP). METHODS: A prospective, randomized, double-blind, Phase 3 clinical trial; patients were randomized to IV tigecycline (100 mg, then 50 mg q12h) or IV levofloxacin (500 mg q24h). Objective criteria were used to define time to switch therapy; patients were switched to oral levofloxacin after >=6 IV doses if criteria met. Switch therapy outcomes were assessed within the clinically evaluable (CE) population. RESULTS: In the CE population, 138 patients were treated with IV tigecycline and 156 were treated with IV levofloxacin. The proportion of the population that met switch therapy criteria was 67.4% (93/138) for tigecycline and 66.7% (104/156) for levofloxacin. The proportion that actually switched to oral therapy was 89.9% (124/138) for tigecycline and 87.8% (137/156) for levofloxacin. Median time to actual switch therapy was 5.0 days each for tigecycline and levofloxacin. Clinical cure rates for patients who switched were 96.8% for tigecycline and 95.6% for levofloxacin. Corresponding cure rates for those that met switch criteria were 95.7% for tigecycline and 92.3% for levofloxacin. CONCLUSIONS: Switch therapy outcomes in hospitalized patients with CAP receiving initial IV therapy with tigecycline are comparable to those of patients receiving initial IV therapy with levofloxacin. These data support the use of IV tigecycline in hospitalized patients with CAP when the switch therapy approach is considered. CLINICALTRIALS.GOV IDENTIFIER: NCT00081575. PMID- 22812675 TI - Quality of life in young adults who underwent resective surgery for epilepsy in childhood. AB - PURPOSE: This study investigated quality of life (QOL) in young adults who had undergone epilepsy surgery before the age of 16 years. The contribution to QOL of seizure status in the prior year, sex, number of antiepileptic drugs, and mood were evaluated. METHODS: Sixty-nine young adults who had undergone surgery were subdivided into those who were seizure-free in the past year (n = 38) and those who had seizures (n = 31) in that time. A nonsurgical comparison group of young adults (n = 29) with childhood-onset medically intractable epilepsy was also studied. All groups completed measures of QOL and mood. KEY FINDINGS: After accounting for mood, sex, and number of antiepileptic drugs, the seizure-free group reported better cognitive and physical function and overall QOL, experienced less seizure worry, and had better self-perception. Mood was the most consistently predictive covariate, and was independently predictive of many aspects of QOL. SIGNIFICANCE: Seizure freedom associated with surgery in childhood is associated with improved QOL in certain domains. Findings highlight the importance of mood in determining self-perception of QOL. PMID- 22812674 TI - Closeness and separation in neonatal intensive care. AB - In this paper, we highlight the need for acknowledging the importance and impact of both physical and emotional closeness between the preterm infant and parent in the neonatal intensive care unit. Physical closeness refers to being spatially close and emotional closeness to parental feelings of being emotionally connected to the infant (experiencing feelings of love, warmth and affection). Through consideration of the literature in this area, we outline some of the reasons why physical closeness and emotional closeness are crucial to the physical, emotional and social well-being of both the infant and the parent. These include positive effects on infant brain development, parent psychological well-being and on the parent-infant relationship. The influence of the neonatal unit environment and culture on physical and emotional closeness is also discussed. CONCLUSIONS: Culturally sensitive care practices, procedures and the physical environment need to be considered to facilitate parent-infant closeness, such as through early and prolonged skin-to-skin contact, family-centred care, increased visiting hours, family rooms and optimization of the space on the units. Further research is required to explore factors that facilitate both physical and emotional closeness to ensure that parent-infant closeness is a priority within neonatal care. PMID- 22812676 TI - Associations between body mass index and clinico-pathological characteristics of papillary thyroid cancer. AB - OBJECTIVE: Epidemiological studies have demonstrated that excess weight increases the risk of thyroid cancer. However, the associations between excess weight and prognostic factors for thyroid cancer are uncertain. We evaluated the relationships between body mass index (BMI) and clinico-pathological features and outcomes of papillary thyroid cancer (PTC). PATIENTS AND METHODS: Retrospective analysis of 2057 patients with PTC was performed. Patients were grouped according to BMI (underweight, normal weight, overweight and obesity)-based World Health Organization standardized categories. Logistic regression models were used to assess the relationships between BMI and clinico-pathological features of PTC. A Cox proportional hazards model was used to examine the association between BMI and disease recurrence. RESULTS: A 5-kg/m(2) increase in BMI was associated with PTC tumours larger than 1 cm [odds ratio (OR) 1.31, P < 0.001], with microscopic extrathyroidal invasion (OR 1.23, P = 0.006), and with advanced tumour-node metastasis (TNM) stage (OR, 1.30, P = 0.003), which is independent of confounding variables such as gender, age, serum TSH, total cholesterol and fasting glucose level. The multivariate-adjusted OR [95% confidence intervals (CI)] in the overweight (25.0-29.9 kg/m(2)) and obese (BMI >= 30) groups for tumours larger than 1 cm were 1.41 (1.10-1.81) and 2.17 (1.23-3.82), respectively, compared to the normal weight group (BMI 18.5-24.9). The multivariate-adjusted OR (95% CI) for microscopic extrathyroidal extension in the obesity group was 1.88 (1.06 3.32), and the OR for advanced TNM stage in the overweight group was 1.35 (1.02 1.79) compared to the normal weight group. During follow-up (median, 84 month; range, 1-185), 43 patients (2.1%) experienced recurrence. There were no significant differences in recurrence of PTCs among BMI groups. CONCLUSIONS: Higher BMI was strongly associated with larger tumour size, extrathyroidal invasion and advanced TNM stage of PTCs. However, there was no difference in recurrence rate among BMI groups. This study suggests that excess weight is associated with aggressive features of PTCs. Further studies with long-term follow-up are needed to confirm this finding. PMID- 22812677 TI - Synthesis and evaluation of molecular rotors with large and bulky tert butyldiphenylsilyloxy-substituted trityl stators. AB - The search for voluminous stators that may accommodate large rotator units and speed rotational dynamics in the solid state led us to investigate a simple and efficient method for the synthesis of molecular rotors with tert butyldiphenylsilyl-protected (TBDPS) triphenylmethyl stators. Additionally, solid state characterization of these systems with two-, four-, and six-TBDPS groups provided us with a description of their crystallinity and thermal stability. Among them, molecular rotor 7c with the largest and most symmetric stator resulting from six peripheral silyl groups showed the best tendency to crystallize, and the study of its isotopologue 7c-d(4) by solid state (2)H NMR revealed a 2-fold motion of the 1,4-diethynylphenylene-d(4) rotator in the kHz regime. PMID- 22812679 TI - Ovarian cysts during tamoxifen use may affect the prognostic markers of premenopausal breast cancer. AB - OBJECTIVES: Only a few studies have suggested the association between ovarian cysts and serum estrogen levels during tamoxifen use. However, increased estrogen levels with ovarian cysts would affect the prognosis of breast cancer; this association has not yet been studied. We aimed to investigate the association between ovarian cysts and prognostic markers in premenopausal breast cancer patients undergoing tamoxifen treatment. METHODS: A retrospective review of 65 premenopausal breast cancer patients who underwent tamoxifen treatment was performed. Serum hormone levels were measured either specifically between cycle days 2 and 5 in menstruating patients or at any time in amenorrheic participants. RESULTS: The study population consisted of premenopausal patients with (n = 23) and without ovarian cysts (n = 42). Serum estradiol (E(2)) levels and tumor markers were not statistically different based on ovarian cyst status. In the subgroup analysis, serum E(2) levels were significantly higher in menstruating women with ovarian cysts, and E(2) levels were positively correlated with serum cancer antigen 15-3 and insulin-like growth factor-1 in these women. CONCLUSIONS: Ovarian cysts during tamoxifen use may affect the markers associated with the clinical course of premenopausal breast cancer. PMID- 22812678 TI - Ethanol exposure suppresses bone marrow-derived dendritic cell inflammatory responses independent of TLR4 expression. AB - Acute alcohol (ethanol) exposure is linked with increased susceptibility to infection and increased mortality in trauma and burn patients. Dendritic cells (DCs) are central mediators in innate and adaptive immune responses, and they play a role in the presentation of pathogens to adaptive immune cells. We investigated the effects of acute ethanol exposure on bone marrow-derived DC (BM DC) responses. Total bone marrow cells, obtained from 8 to 10 week old C57BL/6 male mice, were cultured in the presence of granulocyte/monocyte-colony stimulating factor and interleukin (IL)-4 for 7 days. BM-DCs were harvested and treated with increasing doses of ethanol (50, 100, and 250 mM) at the time of, or 3 h before, lipopolysaccharide (LPS). After LPS, supernatants were collected for cytokine measurement, and cells were harvested for flow cytometry. Concurrent acute ethanol exposure and LPS treatment resulted in a dose-dependent suppression of IL-6, IL-12p40, IL-23, and IL-10. In addition, ethanol exposure before LPS dysregulated the IL-12p40/IL-23 balance and more profoundly suppressed IL-6 and IL-10 secretion by BM-DCs, as compared with cells concurrently treated with ethanol and LPS. Ethanol treatment did not affect either toll-like receptor (TLR)4 or TLR2 expression. In summary, our study demonstrates that acute ethanol exposure suppresses BM-DC LPS-induced responses, irrespective of affecting TLR4 or TLR2 expression. PMID- 22812680 TI - Qualitative needs assessment: healthcare experiences of underserved populations in Montgomery County, Virginia, USA. AB - INTRODUCTION: Portions of Montgomery County, Virginia, are designated a Medically Underserved Area with a large portion of this population experiencing limited access to healthcare services. In September 2008, the Federal Bureau of Primary Care awarded the authors a planning grant to assess community need in Montgomery County and to develop a strategic plan to establish a Federally Qualified Health Center (FQHC) to best meet these needs. An FQHC is a federally funded clinic mandated to provide medical, dental and mental health services to underserved communities. As part of the planning process, the decision was made to include qualitative data to better understand the needs of underserved residents in the community. Descriptive studies of target populations can provide further insight into community priorities for effective health improvement and planning. The objective of the study was to investigate and describe the perceptions, beliefs and practices that impact healthcare utilization among underserved populations in Montgomery County, Virginia. This study was conducted as part of a comprehensive community assessment to determine the feasibility of developing a FQHC. METHODS: Community focus groups were conducted with target populations which were representative of the community. A thematic analysis of the transcribed field notes and group interviews was conducted. Qualitative data analysis was performed using the Analysis Software for Word-Based Records (AnSWR) developed by the Centers for Disease Control. RESULTS: Three important categories of beliefs which may impact healthcare utilization emerged from the discussions: (1) cultural health perceptions; (2) perceived barriers to care; and (3) coping strategies. Participants expressed a right to access quality care, preferred to spend money on basic living expenses rather than healthcare services; frequently neglected seeking care for adults while rarely neglecting to seek care for their children; valued but infrequently utilized preventative care; and had a lack of confidence in the care that was provided. Perceived barriers to healthcare services reported by participants included a lack of access to affordable care; complexities of health insurance and payer status; limited hours of clinic operation; lack of transportation and geographic distance; and the complexity of navigating the healthcare system. Finally, participants reported using various coping strategies to overcome barriers to accessing healthcare services. These strategies included delaying treatment and self-care; seeking financial and transportation assistance; and using community resources to navigate the system. CONCLUSION: Establishing care that is culturally relevant, targets perceived barriers and incorporates and enhances coping strategies is needed to increase accessibility and utilization of preventative and comprehensive healthcare services. The findings from this study will assist in creating a strategic plan for a FQHC that capitalizes on community strengths while addressing the challenges and complex needs of the community. PMID- 22812681 TI - Highly monodisperse M(III)-based soc-MOFs (M = In and Ga) with cubic and truncated cubic morphologies. AB - In this work, we carry out an investigation on shape-controlled growth of In(III) and Ga(III)-based square-octahedral metal-organic frameworks (soc-MOFs). In particular, controllable crystal morphological evolution from simple cubes to complex octadecahedra has been achieved, and resultant highly uniform crystal building blocks promise new research opportunities for preparation of self assembled MOF materials and related applications. PMID- 22812682 TI - The modulator of the general stress response, MgsR, of Bacillus subtilis is subject to multiple and complex control mechanisms. AB - The alternative sigma factor sigma(B) is the master regulator of the general stress regulon that comprises approximately 200 genes whose products confer a comprehensive stress resistance to Bacillus subtilis. The characterization of MgsR (modulator of the general stress response) revealed that the activation and induction of sigma(B) are a prerequisite but not sufficient for a full expression of all general stress genes. MgsR is a paralogue of the global regulator of the diamide stress response, Spx, and controls a subregulon of the general stress response. Here we demonstrate that MgsR activity is controlled at multiple levels. These mechanisms include a positive autoregulatory loop on mgsR transcription, a post-translational redox-sensitive activation step by an intramolecular disulfide bond formation in response to ethanol stress in vivo, as well as rapid proteolytic degradation of MgsR by the ClpXP and ClpCP proteases. Our results indicate an elaborate regulatory network integrating secondary oxidative stress signals into a sigma(B) -mediated regulatory cascade that is aimed at rapid and finely tuned target gene expression to coordinately fulfil the physiological needs of the cell in the face of multiple environmental changes. PMID- 22812683 TI - Espresso coffee residues: a valuable source of unextracted compounds. AB - Espresso spent coffee grounds were chemically characterized to predict their potential, as a source of bioactive compounds, by comparison with the ones from the soluble coffee industry. Sampling included a total of 50 samples from 14 trademarks, collected in several coffee shops and prepared with distinct coffee machines. A high compositional variability was verified, particularly with regard to such water-soluble components as caffeine, total chlorogenic acids (CGA), and minerals, supported by strong positive correlations with total soluble solids retained. This is a direct consequence of the reduced extraction efficiency during espresso coffee preparation, leaving a significant pool of bioactivity retained in the extracted grounds. Besides the lipid (12.5%) and nitrogen (2.3%) contents, similar to those of industrial coffee residues, the CGA content (478.9 mg/100 g), for its antioxidant capacity, and its caffeine content (452.6 mg/100 g), due to its extensive use in the food and pharmaceutical industries, justify the selective assembly of this residue for subsequent use. PMID- 22812684 TI - Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature. AB - BACKGROUND: Nitric oxide (NO) is a multifunctional signaling molecule that regulates important cellular events in inflammation including leukocyte recruitment. Previous studies have shown that pharmacological inhibition of NO synthesis induces leukocyte recruitment in various in vitro and animal models. However, it is not known whether NO modulation has similar effects on leukocyte endothelial cell interactions within the human microvasculature. The present study explored the effect of systemic L-NAME treatment on leukocyte recruitment in the SCID-hu mouse model. METHODS: Human skin xenografts were transplanted in SCID mice to study human leukocyte dynamics in human vasculature. Early events of human leukocyte recruitment in human vasculature were studied using intravital microscopy. NO synthesis was pharmacologically inhibited using NG-nitro-L arginine methyl ester (L-NAME). Immunohistochemical analysis was performed to elucidate E-selectin expression in human xenograft skin. Human neutrophil endothelial cell interactions were also studied in an in vitro flow chamber assay system. P- and E-selectin expression on cultured human umbilical vein endothelial cells (HUVECs) was measured using ELISA. Platelet-activating factor (PAF) synthesis was detected using a TLC-based assay. RESULTS: L-NAME treatment significantly enhanced the rolling and adhesion of human leukocytes to the human vasculature. Functional blocking of P- and E-selectins significantly inhibited rolling but not adhesion induced by inhibition of NO synthesis. Systemic L-NAME treatment enhanced E-selectin expression in human xenograft skin. L-NAME treatment significantly enhanced P- and E-selectin expression on HUVECs. L-NAME treatment did not significantly modify neutrophil rolling or adhesion to HUVECs indicating that L-NAME-induced subtle P- and E-selectin expression was insufficient to elicit dynamic neutrophil-HUVEC interactions in vitro. Moreover, synthesis of endothelial-derived PAF was not significantly modified by L-NAME treatment. These results point to the accelerated leukocyte recruitment in human vasculature following suppression of NO synthesis, effects that are mediated by P and E-selectins. The findings are, however, not supported by the in vitro data. CONCLUSION: Inhibition of endogenous NO triggers early events of human leukocyte recruitment in human vasculature, involving complex cellular or molecular mechanisms in addition to P- and E-selectin-mediated leukocyte rolling. PMID- 22812685 TI - Intrinsic factors affecting adequacy of thyroid nodule fine-needle aspiration cytology. AB - OBJECTIVE: To evaluate intrinsic nodule features predictive of an inadequate report in fine-needle aspiration cytology (FNAC). DESIGN: Single-centre cross sectional study. METHODS: Between May 2005 and April 2011, 3279 ultrasonography assisted FNACs were carried out and features of nodules recorded prospectively. Univariate logistic regression analyses were performed to estimate the association between nondiagnostic cytology and variables such as age, gender, single nodule, maximum nodule diameter and estimated volume. RESULTS: Inadequate or nondiagnostic samples were reported in 1195 FNACs. All diameters were found to be predictors of nondiagnostic cytology; estimated nodule volume, on the other hand, was not. Nodules with a diameter <10 mm were more frequently nondiagnostic (OR 1.65, 95% CI 1.40-1.94, P < 0.001). Neither micro- nor macrocalcification increased the risk of inadequacy. On the contrary, mixed lesions were more frequently diagnostic (OR 0.68, 95% CI 0.85-0.80, P < 0.001). Solid nodule aspiration was performed more easily on isoechogenic nodules (OR 0.64, 95% CI 0.54-0.77, P < 0.001); the same procedure was more cumbersome on hypoechogenic lesions (OR 1.87, 95% CI 1.62-2.16, P < 0.001). Increased vascularization did not cause a significant increase in the nondiagnostic results. Blurred margins increased the inadequacy rate (OR 1.45, 95% CI 1.24-1.69, P < 0.001), while presence of a hypoechogenic halo decreased it (OR 0.67, 95% CI 0.54-0.82, P < 0.001). CONCLUSIONS: Some ultrasonographic features suggestive of malignancy may be predictive of inadequate cytology. Patients must be notified that the FNA report may be nondiagnostic and that this represents a limitation of the technique related to the structure of lesions. PMID- 22812686 TI - The impact of inpatient point-of-care blood glucose quality control testing. AB - Analyze the effectiveness of mandated point-of-care (POC) blood glucose (BG) meter quality control (QC) testing. All POC BG QC tests were analyzed to evaluate operator and strip/meter error rates and institutional cost. POC BG QC test failure (17/103,580 over 24 months) was low and no meters failed subsequent linearity testing. Examining individual QC measures shows that operator error occurs frequently and total error rate is related to QC familiarity (>50 QC tests/month, 2.4%; <50 QC tests/month, 3.8%, p < .001). Even among the most competent operators, strip/meter error (1.2 +/- 0.3%) accounted for 50% of total error. Compared with manufacturer-recommended QC testing, Joint Commission mandated POC BG QC testing during 2008/2009 incurred excess costs of approximately US$127,000. POC BG meter failure within current guidelines is rare and does not justify the cost of daily QC testing. Frequent QC testing can identify operators needing retraining in POC testing. Strip/meter QC errors are common, are not prevented by current QC testing standards, and may contribute to clinical errors. PMID- 22812687 TI - Innovation in hospital quality improvement activities--acute postoperative pain management (APOP) self-help toolkit audits as an example. AB - It is often difficult to maintain quality improvement change. Many behavioral strategies have been used to improve uptake of new practices and knowledge. One effective way of changing medication prescribing is audit and feedback with specific educational feedback. The challenge however is to maintain ongoing quality improvement activities. In Australia, unique downloadable "toolkits" are now available to assist hospitals to maintain prescribing quality improvement activities. The first designed to improve the management of acute postoperative pain (APOP toolkit) has been piloted. The toolkit includes data collection and educational tools, an automated feedback report on key indicators, with complete instructions for use. The APOP toolkit has been used in 73 hospitals, in two facilitated "snapshot" audits. There was continued improvement in performance, assessed by increases in the percentage of patients with measured pain and sedation scores and in those with documented pain management plans at discharge, compared with earlier APOP project audits. Using this example of the APOP toolkit and "snapshot" audits, we have now demonstrated that hospitals nationwide are able to undertake quality improvement activities voluntarily to maintain optimal performance. Encouragement, guidance, and availability of ready-made tools developed by a national team facilitate opportunities for ongoing quality improvements. PMID- 22812688 TI - Luminescent metallogels of bis-cyclometalated alkynylgold(III) complexes. AB - A series of luminescent bis-cyclometalated alkynylgold(III) complexes have been synthesized and characterized. Some of the complexes have been demonstrated to exhibit gelation properties driven by pi-pi stacking and hydrophobic-hydrophobic interactions. The gelation properties have been investigated in detail through variable-temperature UV-vis absorption and emission studies, and the morphology of the gels has also been characterized by scanning electron microscopy and transmission electron microscopy. PMID- 22812689 TI - Changes in COPD demographics and costs over 20 years. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the US and responsible for significant healthcare resource use. The purpose of this study was to examine the changes in COPD costs over 20 years and assess total direct cost trends over the last 10. METHODS: A cross-sectional study of a population-based survey (2007 Medical Expenditure Panel Survey compared to the 1987 National Medical Expenditures Panel Survey) of respondents aged 40 and older with COPD (ICD-9-CM codes 491.xx, 492.xx, or 496.xx) was assessed for demographic and healthcare services use characteristics and compared to reported statistics from 1987. Ten-year trends in total direct medical costs from 1997-2007 are presented. RESULTS: In 2007, there were 416 survey respondents with COPD compared to 228 in 1987. In 1987, women were only 39% of the COPD sample, while in 2007 they made up 58% of the sample. Mean cost per COPD patient was $16,135 (2007 dollars) in 2007, which was up from $11,807 (2007 dollars) in 1987 or a 37% increase. The proportional cost of emergency department visits (183%) and prescription drugs (170%) from 1987-2007 was high compared to other healthcare services. However, the mean cost of a hospitalization was the highest actual increase ($2289). Ten-year trends show a similar gradual increase. CONCLUSIONS: The prevalence of COPD among females as well as the mean cost per COPD patient has risen sharply over the last 20 years. Cost-shifting from acute services to preventive services may allow US payers and healthcare providers to improve care and better manage costs for patients with COPD. More attention on prevention, diagnosis, and management needs to be directed to women at risk of COPD. PMID- 22812690 TI - Health economic evaluation of insulin glargine vs NPH insulin in intensified conventional therapy for type 1 diabetes in Germany. AB - OBJECTIVE: Basal insulin analogs are well established in the treatment of type 1 diabetes in Germany. However, little is known about their economic impact. The aim of this study for an adult population was to compare, from the perspective of the Statutory Health Insurance (SHI), the cost effectiveness of the long-acting insulin analog glargine (GLA) with intermediate-acting neutral protamine Hagedorn (NPH) insulin in basal bolus therapy, considering the interaction between glycemic control and the rate of hypoglycemia. METHODS: A validated discrete event simulation model was adapted to the German setting to project clinical and cost outcomes over 40 years. Resources were valued with German official prices in 2009/2010 Euros. Health-related disutilities were taken from UK sources. Patient characteristics and risk factors were partially extracted from German sources in a sensitivity analysis. RESULTS: In the base-case analysis, GLA was dominant as it increased life expectancy by 0.196 years and improved quality-adjusted life years (QALYs) by 0.396 units while at the same time leading to savings of ?5246 each per patient after 40 years compared to NPH. These results were robust in the sensitivity analyses. Monte Carlo simulation confirmed dominance of GLA in 70% (life-years gained) and 80% (QALYs gained) of the iterations. The price of GLA had the highest impact on savings. In extreme scenarios, incremental cost effectiveness ratios increased up to ?9576 per QALY gained. Limitations of the evaluation included no myocardial re-infarction(s) and no recurrent stroke(s), patient characteristics, risk factors, and disutilities from the UK due to scarce data in Germany, and that not all diabetes-related direct costs were included, namely insulin pens and blood glucose meters. CONCLUSION: GLA appears to be cost effective or even cost saving among type 1 diabetics with basal bolus therapy from the perspective of SHI compared to NPH depending on the scenario chosen. PMID- 22812691 TI - Steady-state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers. AB - PURPOSE: To evaluate the pharmacokinetics and tolerability of once-daily eslicarbazepine acetate (ESL) and twice-daily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration. METHODS: Single-center, open-label, randomized, parallel-group study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1-3 and 1,200 mg on days 4-9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1-3 and 600 mg on days 4-9, twice daily. Plasma and CSF sampling was performed following the last dose. KEY FINDINGS: Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R-licarbazepine and oxcarbazepine was approximately four-fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak-to-trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R-licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment-emergent adverse events (TEAEs) were reported with OXC and ESL, respectively. SIGNIFICANCE: In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak-to-trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once-daily dosing of ESL. PMID- 22812692 TI - Parametric effects of the potential energy function on the geometrical features of ternary Lennard-Jones clusters. AB - The impact of parameters in potential function for describing atomic or molecular clusters is complex due to the complicated potential energy surface. Ternary Lennard-Jones (TLJ) A(l)B(m)C(n) clusters with two-body potential are investigated to study the effect of parameters. In the potential, the size parameter (sigma(AA)) of A atoms is fixed, and corresponding parameters of B and C atoms (relative to A atoms), i.e., sigma(BB)/sigma(AA) and sigma(CC)/sigma(AA) > 1.00, are used to control the atomic interaction among A, B, and C atoms in TLJ clusters. The minimum energy configurations of A(l)B(m)C(n) clusters with different species are optimized by adaptive immune optimization algorithm. Ternary cluster structures, bonds, and energies of the putative minima are studied. The results show that two different structures based on double icosahedra are found in 30-atom TLJ clusters. Furthermore, with increasing potential size parameters of B and C atoms, A atoms tend to be more compact for the increasing numbers of A-A bonds, but the short-range attractive part in TLJ clusters becomes weaker. To lower the potential energy, B and C atoms grow around the A atoms in pursuit of a compact configuration. The results are also approved in A(l)B(m)C(n) (l + m + n = 9-55) clusters and A(l)B(m)C(n) (l = 13, m + n = 42) clusters. PMID- 22812693 TI - Subcutaneous metastases from colon cancer: a case report. AB - INTRODUCTION: Dukes A stages of colorectal cancer are rarely reported to metastasize. Subcutaneous or skin metastases from colon cancer are rare events and usually indicate widespread disease. CASE PRESENTATION: We present the case of a 72-year-old Caucasian woman with Dukes A colorectal cancer at diagnosis and, three years later, a single secondary subcutaneous involvement with no other metastatic sites. The description of this case is supported by critical analysis of its clinical, radiological and pathological features. Our report illustrates that diagnosis can be difficult and controversial when relapse occurs in early stage patients and at uncommon sites. CONCLUSION: The unusual and aggressive course of the reported disease stresses the importance of intensive follow-up in colorectal cancer patients with good prognostic factors. PMID- 22812694 TI - Copper sulfide nanoparticles as a new class of photoacoustic contrast agent for deep tissue imaging at 1064 nm. AB - Photoacoustic tomography (PAT) is an emerging molecular imaging modality. Here, we demonstrate use of semiconductor copper sulfide nanoparticles (CuS NPs) for PAT with an Nd:YAG laser at a wavelength of 1064 nm. CuS NPs allowed visualization of mouse brain after intracranial injection, rat lymph nodes 12 mm below the skin after interstitial injection, and CuS NP-containing agarose gel embedded in chicken breast muscle at a depth of ~5 cm. This imaging approach has great potential for molecular imaging of breast cancer. PMID- 22812695 TI - Reversal of paclitaxel resistance in epithelial ovarian carcinoma cells by a MUC1 aptamer-let-7i chimera. AB - The purpose of this study was to establish tumor tissue specific delivery of let 7i miRNA to reverse paclitaxel-induced chemoresistance. A chimera that combines MUC1 aptamer and let-7i miRNA was tested in OVCAR-3 ovarian cancer cells. Results demonstrated that the chimera can specifically be delivered into OVCAR-3 cells and the released let-7i significantly sensitized the role of paclitaxel in inhibiting cell proliferation, inducing cell apoptosis, and decreasing long-term cell survival. The chimera achieved reversal of chemoresistance through downregulation of cyclin D1, cyclin D2, Dicer 1, and PGRMC1 expressions. Our study indicated that this MUC1/let-7i chimera can specifically reverse chemoresistance to paclitaxel. PMID- 22812696 TI - Epoxidation of olefins with a silica-supported peracid. AB - Anhydrous [2-percarboxyethyl] functionalized silica (2a) is an advantageous oxidant for performing the epoxidation of olefins 1. Epoxides 3 do not undergo the ring-opening reactions catalyzed by the acidic silica surface, except for particularly activated cases such as styrene oxide. The hydrophilic and acidic character of the silica surface does not interfere with the directing effects exerted by allylic H-bond acceptor substituents. The alkenes 1 carrying hydroxyl groups react with silica-supported peracid 2a faster than unsubstituted alkenes, thus reversing the trend known for reactions with soluble peracids. These results are attributed to the H-bond interactions of substrate 1 with the silanol and carboxylic acid groups bonded to the silica surface. PMID- 22812697 TI - Improved assessment of multiple sclerosis lesion segmentation agreement via detection and outline error estimates. AB - BACKGROUND: Presented is the method "Detection and Outline Error Estimates" (DOEE) for assessing rater agreement in the delineation of multiple sclerosis (MS) lesions. The DOEE method divides operator or rater assessment into two parts: 1) Detection Error (DE) -- rater agreement in detecting the same regions to mark, and 2) Outline Error (OE) -- agreement of the raters in outlining of the same lesion. METHODS: DE, OE and Similarity Index (SI) values were calculated for two raters tested on a set of 17 fluid-attenuated inversion-recovery (FLAIR) images of patients with MS. DE, OE, and SI values were tested for dependence with mean total area (MTA) of the raters' Region of Interests (ROIs). RESULTS: When correlated with MTA, neither DE (rho = .056, p=.83) nor the ratio of OE to MTA (rho = .23, p=.37), referred to as Outline Error Rate (OER), exhibited significant correlation. In contrast, SI is found to be strongly correlated with MTA (rho = .75, p < .001). Furthermore, DE and OER values can be used to model the variation in SI with MTA. CONCLUSIONS: The DE and OER indices are proposed as a better method than SI for comparing rater agreement of ROIs, which also provide specific information for raters to improve their agreement. PMID- 22812698 TI - Multiattribute selection of acute stroke imaging software platform for Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) clinical trial. AB - BACKGROUND: The appropriateness of a software platform for rapid MRI assessment of the amount of salvageable brain tissue after stroke is critical for both the validity of the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) Clinical Trial of stroke thrombolysis beyond 4.5 hours and for stroke patient care outcomes. AIMS: The objective of this research is to develop and implement a methodology for selecting the acute stroke imaging software platform most appropriate for the setting of a multi-centre clinical trial. METHODS: A multi-disciplinary decision making panel formulated the set of preferentially independent evaluation attributes. Alternative Multi-Attribute Value Measurement methods were used to identify the best imaging software platform followed by sensitivity analysis to ensure the validity and robustness of the proposed solution. RESULTS: Four alternative imaging software platforms were identified. RApid processing of PerfusIon and Diffusion (RAPID) software was selected as the most appropriate for the needs of the EXTEND trial. A theoretically grounded generic multi-attribute selection methodology for imaging software was developed and implemented. CONCLUSIONS: The developed methodology assured both a high quality decision outcome and a rational and transparent decision process. This development contributes to stroke literature in the area of comprehensive evaluation of MRI clinical software. At the time of evaluation, RAPID software presented the most appropriate imaging software platform for use in the EXTEND clinical trial. The proposed multi-attribute imaging software evaluation methodology is based on sound theoretical foundations of multiple criteria decision analysis and can be successfully used for choosing the most appropriate imaging software while ensuring both robust decision process and outcomes. PMID- 22812699 TI - Academic achievement of adolescents born with extremely low birth weight. AB - AIM: To assess academic achievement, rates of learning disabilities (LD) and special education in extremely low birth weight (ELBW <1 kg) adolescents relative to normal birth weight (NBW) controls and to identify cognitive weaknesses. METHODS: Compared 181 ELBW adolescents born from 1992 to 1995 (mean age 14.8 years, mean BW 809 g, mean GA 26.4 weeks) and 115 NBW term controls. Measures included tests of IQ, reading and math achievement and executive function. Analyses included ANCOVA and logistic and linear regression. Covariates were sex, race and socioeconomic status. RESULTS: Extremely low birth weight adolescents had significantly lower scores on tests of IQ (87.1 vs. 96.4), achievement (88.6 vs. 95.5 reading; 81.3 vs. 93.2 math) and executive function than the NBW group (all p-values <0.001). ELBW also had higher rates of math LD, 51(50%) vs. 26 (28%), OR (95% CI) = 3.10 (1.65, 5.84), p < 0.001, and need for special education, 88 (49%) vs. 11(10%), OR (95% CI) = 11.78 (5.67, 24.47), p < 0.001. Measures of executive function were related to math independent of IQ. CONCLUSIONS: Extremely low birth weight adolescents born in the 1990s have poorer achievement and higher rates of math LD than NBW peers. The findings suggest a need for more intensive interventions addressing the specific cognitive vulnerabilities in this population. PMID- 22812700 TI - Removing the neglect from neglected tropical diseases: the Rwandan experience 2008-2010. AB - While there has been increasing recognition of the importance of neglected tropical diseases (NTDs), national scale action and funding remain limited. In 2007, a 3-year, $1 million per year programme was launched in Rwanda to address NTDs. While more than $100 million had flowed into Rwanda's health sector annually, not $1 was allocated for NTDs. This article describes the development of a national NTD strategy in Rwanda and outlines lessons learned, with particular regard to integrated approaches to NTD prevention. A baseline survey revealed that more than 65% of children had intestinal worms with high levels of concurrent multiple parasite infection. Within a year, mass treatment administration was provided for the first time. A repeat survey found that prevalence of soil-transmitted helminths and Schistosoma mansoni infection had been reduced significantly, including a reduction in prevalence of S. mansoni of 82% and of 72% in hookworm. Infection intensity and signs of early clinical morbidity also decreased significantly. Despite ongoing global neglect, the Rwandan NTD response presents a promising and unheralded success in science-based national public health action at scale. Looking forward, greater integration of the NTD response with water and sanitation activities are needed to consolidate impact and sustainably reduce the disease burden. PMID- 22812701 TI - A retrospective survey of the ocular histopathology of the pinniped eye with emphasis on corneal disease. AB - OBJECTIVE: A retrospective review of globes from 70 pinnipeds submitted to the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) describing the type and frequency of ocular disease. ANIMALS STUDIED: The study included 50 California sea lions, four animals listed only as 'sea lion', nine Northern elephant seals, five harbor seals, 1 Northern fur seal, and 1 Hooded seal. PROCEDURES: Globes were classified by microscopic findings. Categories were not mutually exclusive. RESULTS: The largest category was corneal disease (63 globes from 40 pinnipeds). The second largest was cataractous changes (35 globes from 23 pinnipeds). Additional ocular diseases included traumatic ocular injuries (nine globes from eight animals), phthisis bulbi (nine globes from eight pinnipeds), neoplasia (nine globes from six adult California sea lions), amyloid deposition in the corneal stroma, ciliary body, or both locations (five globes from four pinnipeds), and fungal disease (three globes from two pinnipeds). Pinnipeds with corneal disease were further categorized: stromal pathology (39 globes from 27 pinnipeds); epithelial pathology (37 globes from 27 pinnipeds); Descemet's pathology (11 globes from eight pinnipeds); endothelial attenuation or absence (33 globes from 22 pinnipeds); presence of retrocorneal membranes (15 globes from 10 pinnipeds); anterior synechia (eight globes from six animals), and keratitis (seven globes from five pinnipeds). CONCLUSIONS: This is the first report of ocular amyloid in pinniped eyes. All cases of neoplasia were in a pattern suggesting metastatic disease. In this study, there was a higher prevalence of ocular disease in captive pinnipeds, particularly in the posterior cornea. PMID- 22812702 TI - Perceived effectiveness of cessation advertisements: the importance of audience reactions and practical implications for media campaign planning. AB - Cessation television ads are often evaluated with measures of perceived effectiveness (PE) that gauge smokers' reactions to the ads. Although measures of PE have been validated for other genres of public service announcements, no studies to our knowledge have demonstrated the predictive validity of PE for cessation TV ads specifically. We analyzed data from a longitudinal Web survey of smokers in the United States to assess whether measures of PE for cessation TV ads are causally antecedent to cessation-related outcomes. These data consisted of baseline and 2-week follow-up surveys of 3,411 smokers who were shown a number of cessation TV ads and were asked to provide their appraisals of PE for those messages. We found that baseline PE for the ads was associated with increased negative feelings about smoking, increased outcome expectations about the benefits of quitting, increased consideration of the benefits of quitting, increased desire to quit, and increased intentions to quit smoking at follow-up. Results suggest that measures of PE for cessation TV ads can be powerful predictors of likely ad success. Hence, our findings support the use of PE in quantitative ad pretesting as part of a standard regimen of formative research for cessation television campaigns. PMID- 22812703 TI - The linker of the interferon response factor 3 transcription factor is not unfolded. AB - Interferon response factor 3 (IRF-3) is a transcription factor that plays an essential role in controlling the synthesis of interferon-beta (IFN-beta) and is a protein consisting of two well-defined domains, the N-terminal DNA-binding and the C-terminal dimerization domains, connected by a 75-residue linker, supposedly unfolded. However, it was not clear whether in intact IRF-3 this linker segment of the chain, which carries the nuclear export signal and includes a region of high helical propensity, remains unfolded. This has been investigated using nuclear magnetic resonance by ligating the (15)N-labeled linker to the unlabeled N-terminal and C-terminal domains. It was found that, while the linker alone is indeed in a completely unfolded state, when ligated to the C-terminal domain it shows some ordering, and this ordering becomes much more pronounced when the linker is also ligated to the N-terminal domain. Thus, in intact IRF-3, the linker represents a folded structural domain; i.e., IRF-3 is a three-domain globular protein. Light scattering studies of wild-type IRF-3 showed that these three domains are tightly packed, and therefore, the dimer of IRF-3, which is formed upon phosphorylation of its C-terminal domains following virus invasion, must be a rather rigid and compact construction. One would then expect that binding of such a dimer to its tandem recognition sites PRDIII and PRDI, which are located on opposing faces of the IFN-beta enhancer DNA, should result in deformation of the DNA. Analysis of the characteristics of binding of the monomeric and dimeric IRF-3 to the enhancer DNA indeed showed that formation of this complex requires considerable work for deformation of its components, most likely bending of the DNA. Such bending was confirmed by atomic force microscopy of dimeric IRF-3 bound to the PRDII-PRDI tandem recognition sites placed at the middle of a 300 bp DNA probe. Bending of DNA by IRF-3 must be significant in the assembly and function of the IFN-beta enhancer. PMID- 22812705 TI - Citrulline level is a potent indicator of acute rejection in the long term following pediatric intestinal/multivisceral transplantation. AB - Citrulline has been advocated as a marker for acute cellular rejection (ACR) in intestinal transplantation; however, its significance as a forewarning in the long-term follow-up remains unknown. This study aimed to investigate the association between citrulline levels and the grading of ACR to establish a cutoff point that accurately predicts ACR beyond 3 months posttransplant in the pediatric patient population. During a 16-year period (1995-2011), a total of 13 499 citrulline samples were prospectively collected from 111 consecutive pediatric intestinal/multivisceral transplant recipients: 2155 were obtained concurrently with intestinal biopsies. There were 185 ACR episodes observed among 74/111 (67%) patients (median follow-up: 4.4 years). Citrulline levels were inversely proportional to the severity of ACR. Negative predictive values for any type of ACR (cutoff, 20 MUmol/L) and moderate/severe ACR (cutoff, 10 MUmol/L) were 95% and 99%, respectively. When patients were divided according to graft size, diagnostic accuracy using the same cutoff was identical. Similarly, subgroup analysis by the timing of citrulline measurement prior to biopsy varying from 1 to 7 days demonstrated comparable results. Citrulline is a potent indicator as a danger signal for ACR, being an exclusionary, noninvasive biomarker with excellent negative predictive values in the long term after pediatric intestinal/multivisceral transplant. PMID- 22812704 TI - Continuing exposure to low-dose nonylphenol aggravates adenine-induced chronic renal dysfunction and role of rosuvastatin therapy. AB - BACKGROUND: Nonylphenol (NP), an environmental organic compound, has been demonstrated to enhance reactive-oxygen species (ROS) synthesis. Chronic exposure to low-dose adenine (AD) has been reported to induce chronic kidney disease (CKD). METHODS: In this study, we tested the hypothesis that chronic exposure to NP will aggravate AD-induced CKD through increasing generations of inflammation, ROS, and apoptosis that could be attenuated by rosuvastatin. Fifty male Wistar rats were equally divided into group 1 (control), group 2 (AD in fodder at a concentration of 0.25%), group 3 (NP: 2 mg/kg/day), group 4 (combined AD & NP), and group 5 (AD-NP + rosuvastatin: 20 mg/kg/day). Treatment was continued for 24 weeks for all animals before being sacrificed. RESULTS: By the end of 24 weeks, serum blood urea nitrogen (BUN) and creatinine levels were increased in group 4 than in groups 1-3, but significantly reduced in group 5 as compared with group 4 (all p < 0.05). Histopathology scorings of renal-parenchymal and tubular damages were significantly higher in group 4 than in groups 1-3, but remarkably lower in group 5 compared with group 4 (all p < 0.01). Both gene and protein levels of inflammation, oxidative stress, ROS, and cellular apoptosis were remarkably higher in group 4 compared with groups 1-3, but lowered in group 5 than in group 4 (all p < 0.001). Conversely, both gene and protein levels of anti-oxidants, anti-inflammation and anti-apoptosis were markedly increased in group 5 compared with group 4 (all p < 0.001). CONCLUSION: NP worsened AD-induced CKD that could be reversed by rosuvastatin therapy. PMID- 22812706 TI - Understanding the cell behavior on nano-/micro-patterned surfaces. AB - AIM: This article reports on studies conducted in the same laboratory on interactions between patterned substrates with different pattern dimensions and chemistries, and various types of cells. MATERIALS & METHODS: In order to compare the influence of various parameters, bone marrow stromal cells, retinal pigment epithelial cells, human corneal stromal cells (keratocytes), Saos-2 (human osteosarcoma cells), human microvascular endothelial cells and vascular smooth muscle cells were tested on surfaces with different physical patterns and chemical properties. RESULTS: It was observed that cell type and surface topography are more influential than surface chemistry in determining the alignment tendency of a cell on a substrate surface. Low walls (several microns high) could not confine cells into the microgrooves of the films but alignment was still possible if the cells had a natural alignment property. CONCLUSION: This information is very useful in designing tissue engineering scaffolds and in the long-term success of implants. PMID- 22812707 TI - Thiolated particles as effective intravesical drug delivery systems for treatment of bladder-related diseases. AB - AIM: To prove in vivo mucoadhesiveness of thiolated and well-established polymeric microparticles and nanoparticles (NPs) as a promising nanomedical tool for the treatment of bladder-related diseases. MATERIALS & METHODS: Spray drying and ionic gelation were used in order to generate microparticles and NPs. For particle detection, the fluorescent marker, fluorescein diacetate, was incorporated in microparticles and NPs, respectively. Mucoadhesive properties of the particles were pre-evaluated via rheological measurements and ex vivo in the porcine urinary bladder model to identify the most appropriate particles for in vivo application in female Sprague Dawley rats. RESULTS: Pretrials indicated that particles based on chitosan were most suitable as an intravesical drug delivery system for in vivo application. The retention time of thiolated chitosan NPs on the rat urinary bladder mucosa was approximately 170-fold higher in comparison with the pure fluorescent marker, fluorescein diacetate, having being applied as aqueous suspension without polymeric excipients. CONCLUSION: This advanced nanomedical tool based on thiolated chitosan seems to be a promising approach for the treatment of bladder-related diseases. PMID- 22812708 TI - Exploring the efficiency of gallic acid-based dendrimers and their block copolymers with PEG as gene carriers. AB - The synthesis of a new family of amino-functionalized gallic acid-triethylene glycol (GATG) dendrimers and their block copolymers with polyethylene glycol (PEG) has recently being disclosed. In addition, these dendrimers have shown potential for gene delivery applications, as they efficiently complex nucleic acids and form small and homogeneous dendriplexes. On this basis, the present study aimed to explore the interaction of the engineered dendriplexes with blood components, as well as their stability, cytotoxicity and ability to enter and transfect mammalian cells. Results show that GATG dendrimers can form stable dendriplexes, protect the associated pDNA from degradation, and are biocompatible with HEK-293T cells and erythrocytes. More importantly, dendriplexes are effectively internalized by HEK-293T cells, which are successfully transfected. Besides, PEGylation has a marked influence on the properties of the resulting dendriplexes. While PEGylated GATG dendrimers have improved biocompatibility, the long PEG chains limit their uptake by HEK-293T cells, and thus, their ability to transfect them. As a consequence, the degree of PEGylation in dendriplexes containing dendrimer/block copolymer mixtures emerges as an important parameter to be modulated in order to obtain an optimized stealth formulation able to effectively induce the expression of the encoded protein. PMID- 22812709 TI - Adjuvanticity and toxicity of cobalt oxide nanoparticles as an alternative vaccine adjuvant. AB - AIM: There are very few adjuvants licensed for use in human vaccination, and alum based adjuvants are the most widely used. Alum adjuvants predominantly boost Th2 immune responses and there is a need for new adjuvants that also stimulate Th1 immunity. We recently reported that cobalt oxide nanoparticles (Co(3)O(4)NPs) stimulate Th1-type immune responses in vivo. Here, we exploited this property to examine whether Co(3)O(4)NP could act as an adjuvant using the model antigen ovalbumin. MATERIALS & METHODS: Female C57BL/6 mice were immunized subcutaneously twice with ovalbumin plus adjuvant (Co(3)O(4)NPs or Imject(r) Alum) followed by intraperitoneal stimulation with soluble ovalbumin. RESULTS: Co(3)O(4)NPs induced a more balanced Th1- and Th2-type response, triggering higher specific Th1 dependent IgG2c production in addition to Th2-dependent IgG1 and less 'allergic' IgE production, and induced less inflammation at both the subcutaneous and intraperitoneal injection sites. DISCUSSION: Co(3)O(4)NPs could be a very useful adjuvant where both Th1 and Th2 responses are needed to clear pathogens. PMID- 22812710 TI - Spatial and temporal measurements of temperature and cell viability in response to nanoparticle-mediated photothermal therapy. AB - AIM: Nanoparticle-enhanced photothermal therapy is a promising alternative to tumor resection. However, quantitative measurements of cellular response to these treatments are limited. This article introduces a Bimodal Enhanced Analysis of Spatiotemporal Temperature (BEAST) algorithm to rapidly determine the viability of cancer cells in vitro following photothermal therapy alone or in combination with nanoparticles. MATERIALS & METHODS: To illustrate the capability of the BEAST viability algorithm, single wall carbon nanohorns were added to renal cancer (RENCA) cells in vitro and time-dependent spatial temperature maps measured with an infrared camera during laser therapy were correlated with post treatment cell viability distribution maps obtained by cell-staining fluorescent microscopy. CONCLUSION: The BEAST viability algorithm accurately and rapidly determined the cell viability as a function of time, space and temperature. PMID- 22812711 TI - Characterization and evaluation of BNIPDaoct-loaded PLGA nanoparticles for visceral leishmaniasis: in vitro and in vivo studies. AB - OBJECTIVE: To overcome the limitation of bisnaphthalimidopropyldiaaminooctane (BNIPDaoct) low physiological solubility and potentially increase its efficiency against visceral leishmaniasis (VL), a delivery system based on poly(d,l-lactide co-glycolide) (PLGA) nanoparticles was developed. MATERIALS & METHODS: BNIPDaoct PLGA nanoparticles were prepared by nanoprecipitation and characterized. Anti Leishmania activity was evaluated using in vitro and in vivo VL infection models. RESULTS: BNIPDaoct-PLGA nanoparticles were successfully produced and were sized at 156.0 +/- 2.8 nm with an encapsulation efficiency of approximately 85%. The PLGA nanoparticles reduced BNIPDaoct cellular toxicity, retained its in vitro anti-leishmanial activity and led to a significant reduction (~80%) in the parasite burden in the infected mice spleen when compared with the free drug or amphotericin B. In the liver the effect was less pronounced, with a 30-50% reduction observed between the nanoformulation and the BNIPDaoct per se or the amphotericin B, respectively. CONCLUSION: PLGA nanoparticles provide controlled and effective delivery of BNIPDaoct for treatment of VL. PMID- 22812712 TI - Targeting somatostatin receptors using in situ-bioconjugated fluorescent nanoparticles. AB - AIM: The author's group report, for the first time, on the development of a quantum dot (QD)-based fluorescent somatostatin (somatotropin release-inhibiting factor [SRIF]) probe that enables specific targeting of somatostatin receptors. Receptor-mediated endocytosis of SRIF was imaged using this probe. MATERIALS & METHODS: Biotinylated SRIF-analog (SRIF-B) and streptavidin (Sav)-coated QDs were used for the probe synthesis. A dye-labeled streptavidin complex was used to evaluate the effect of Sav binding on the activity of SRIF-B. RESULTS: A preconjugated probe of the form SRIF-B:Sav-QD, was inactive and unable to undergo receptor-mediated endocytosis. An alternative in situ bioconjugation strategy, where SRIF-B and Sav-QD were added in two consecutive steps, enabled visualization of the receptor-mediated endocytosis. The process of Sav binding appeared to be responsible for the inactivity in the first case. CONCLUSION: The in situ two-step bioconjugation strategy allowed QDs to be targeted to somatostatin receptors. This strategy should enable flexible fluorescent tagging of SRIF for the investigation of molecular trafficking in cells and targeted delivery in live animals. PMID- 22812713 TI - Ferrous centers confined on core-shell nanostructures for low-temperature CO oxidation. AB - A noble metal (NM) can stabilize monolayer-dispersed surface oxide phases with metastable nature. The formed "oxide-on-metal" inverse catalyst presents better catalytic performance than the NM because of the introduction of coordinatively unsaturated cations at the oxide-metal boundaries. Here we demonstrate that an ultrathin NM layer grown on a non-NM core can impose the same constraint on the supported oxide as the bulk NM. Cu@Pt core-shell nanoparticles (NPs) decorated with FeO patches use much less Pt but exhibit performance similar to that of Pt NPs covered with surface FeO patches in the catalytic oxidation of CO. The "oxide on-core@shell" inverse catalyst system may open a new avenue for the design of advanced nanocatalysts with decreased usage of noble metals. PMID- 22812714 TI - Measurement of salivary cortisol in 2012 - laboratory techniques and clinical indications. AB - The utility of measuring salivary cortisol has become increasingly appreciated since the early 1980s. Salivary cortisol is a measure of active free cortisol and follows the diurnal rhythm of serum or plasma cortisol. The saliva sample may be collected by drooling or through the use of absorbent swabs which are placed into the mouth until saturated. Salivary cortisol is therefore convenient for patients and research participants to collect noninvasively on an outpatient basis. Several assay techniques have been used to measure salivary cortisol, including radioimmunoassay and more recently liquid chromatography-tandem mass spectrometry. The analytical sensitivity varies between these assay methods, as does the potential for cross-reactivity with other steroids. The interpretation of salivary cortisol levels relies on rigorous standardization of sampling equipment, sampling protocols and assay technology with establishment of a local reference range. Clinically, the commonest use for salivary cortisol is measuring late-night salivary cortisol as a screening test for Cushing's syndrome. Several studies have shown diagnostic sensitivities and specificities of over 90%, which compares very favourably with other screening tests for Cushing's syndrome such as the 24-h urinary-free cortisol and the 1-mg overnight dexamethasone suppression test. There are emerging roles for the use of salivary cortisol in diagnosing adrenal insufficiency, particularly in conditions associated with low cortisol-binding globulin levels, and in the monitoring of glucocorticoid replacement. Finally, salivary cortisol has been used extensively as a biomarker of stress in a research setting, especially in studies examining psychological stress with repeated measurements. PMID- 22812715 TI - One-volt operation of high-current vertical channel polymer semiconductor field effect transistors. AB - We realize a vertical channel polymer semiconductor field effect transistor architecture by confining the organic material within gratings of interdigitated trenches. The geometric space savings of a perpendicular channel orientation results in devices sourcing areal current densities in excess of 40 mA/cm(2), using a one-volt supply voltage, and maintaining near-ideal device operating characteristics. Vertical channel transistors have a similar electronic mobility to that of planar devices using the same polymer semiconductor, consistent with a molecular reorientation within confining trenches we understand through X-ray scattering measurements. PMID- 22812716 TI - Synthesis, spectral, and electrochemical characterization of the first arsenic(V) phthalocyanines. AB - The first arsenic(V)-phthalocyanines, [As(tbpc)X(2)](+), where tbpc denotes tetra(tert-butyl)phthalocyaninate, C(48)H(48)N(8)(2-) and X = F, Cl, and Br) have been prepared through an appropriate oxidative addition process to a highly soluble arsenic(III) derivative, [As(tbpc)](+). Among them, [As(tbpc)F(2)](+) has been isolated as PF(6)(-) salt. Unlike conventional metal derivatives of phthalocyanines, they show a significantly red-shifted (by >1000 cm(-1)) Q-band and facile reduction of the macrocyclic ligand (redox potentials for [As(tbpc)F(2)](+) have been determined by cyclic voltammetry; 1.13 V vs ferricinium(+)/ferrocene (tbpc(-/2-)), -0.45 V (tbpc(2-/3-)), and -0.90 V (tbpc(3 /4-)), of which the values are anodically shifted by about 1 V) as compared to those of conventional phthalocyanines. Although the anomaly in their spectral and electrochemical properties is similar to that of the known antimony analogues, the arsenic-phthalocyanines have been found less stable. PMID- 22812717 TI - Levels of macrophage migration inhibitory factor and glucocorticoids in chronic wound patients and their potential interactions with impaired wound endothelial progenitor cell migration. AB - Macrophage migration inhibitory factor (MIF), a structurally and functionally unique pleiotropic mediator in inflammation and immune processes, was identified decades ago. There is now strong evidence that MIF promotes revascularization and is involved in wound healing processes. However, its exact role in wound healing is still a matter of debate. A cohort of 33 patients was recruited, including 14 patients with acute and 19 patients with chronic wounds. Both serum and wound fluid samples were collected from each patient, and MIF and cortisol concentrations were determined. To functionally underscore MIF's potential role in wound revascularization, a chemotaxis assay was adapted to test whether and to what extent serum samples and wound fluids of each group promote the chemotactic migration of endothelial progenitor cells (EPCs). MIF serum levels were significantly higher in chronic wound patients than in acute wound patients. Wound exudates of chronic wounds, however, contained a significantly lower concentration of MIF. In chronic wound patients, EPC migration might be delayed, as suggested by in vitro chemotaxis experiments. Despite the overall descriptive nature of this study, we conclude that MIF is correlated with occurrence of chronic wound. The increased MIF levels in the serum of chronic wound patients might be due to MIF's systemic effect of its proinflammatory activities, while its locally decreased levels in chronic wound exudates might be responsible for impaired recruitment of EPCs. Additional prospective data and detailed in vivo models are needed for a more comprehensive understanding of the role of MIF in chronic wound healing. PMID- 22812718 TI - Simulation analysis of contact angles and retention forces of liquid drops on inclined surfaces. AB - A simulation study of liquid drops on inclined surfaces is performed in order to understand the evolution of drop shapes, contact angles, and retention forces with the tilt angle. The simulations are made by means of a method recently developed for dealing with contact angle hysteresis in the public-domain Surface Evolver software. The results of our simulations are highly dependent on the initial contact angle of the drop. For a drop with an initial contact angle equal to the advancing angle, we obtain results similar to those of experiments in which a drop is placed on a horizontal surface that is slowly tilted. For drops with an initial contact angle equal to the mean between the advancing and the receding contact angles, we recover previous results of finite element studies of drops on inclined surfaces. Comparison with experimental results for molten Sn-Ag Cu on a tilted Cu substrate shows excellent agreement. PMID- 22812720 TI - Glossopharyngeal neuralgia secondary to vascular compression in a patient with multiple sclerosis: a case report. AB - INTRODUCTION: Glossopharyngeal neuralgia is an uncommon, painful syndrome, characterized by paroxysms of pain in the sensory distribution of the 9th cranial nerve. Idiopathic glossopharyngeal neuralgia may be due to compression of the glossopharyngeal nerve by adjacent vessels, while secondary glossopharyngeal neuralgia is associated with identifiable lesions affecting the glossopharyngeal nerve at different levels of its neuroanatomic pathway. Glossopharyngeal neuralgia is rare in the general population, but is more common in patients with multiple sclerosis. CASE PRESENTATION: A 56-year-old Caucasian woman with multiple sclerosis and migraine presented to our facility with intermittent lancinating pain to the right of her throat, tongue, and the floor of her mouth that had been occurring for the past year. The pain was intense, sharp, and stabbing, which lasted two to six seconds with radiation to the right ear. Initially, the attacks were infrequent, however, they had become more intense and frequent over time. Our patient reported weight loss, headache, painful swallowing, and the inability to maintain sleep due to painful attacks. A neurological examination revealed a right-handed woman with trigger points in the back of the tongue and throat on the right side. She also had dysphagia, hoarseness, and pain in the distribution of the right glossopharyngeal nerve. Mild right hemiparesis, hyperreflexia, dysmetria, and an ataxic gait were present. A magnetic resonance imaging scan of the brain was consistent with multiple sclerosis and magnetic resonance angiography demonstrated a loop of the posterior inferior cerebellar artery compressing the right glossopharyngeal nerve. She responded satisfactorily to carbamazepine. Microvascular decompression and Gamma Knife(r) radiosurgery were discussed in case of failure of the medical treatment; however, she declined these options. CONCLUSIONS: Glossopharyngeal neuralgia in multiple sclerosis may occur due to vascular compressive lesions and it should not be solely attributed to the underlying demyelinating process. Vascular compression of the glossopharyngeal nerve could independently cause glossopharyngeal neuralgia in patients with multiple sclerosis, and vascular imaging to exclude such a diagnosis is recommended. PMID- 22812719 TI - The ethics of research on deep brain stimulation for depression: decisional capacity and therapeutic misconception. AB - Research on deep brain stimulation (DBS) for treatment-resistant depression appears promising, but concerns have been raised about the decisional capacity of severely depressed patients and their potential misconceptions about the research. We assessed 31 DBS research participants with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a well-validated capacity measure, and with a scale to measure therapeutic misconception, which occurs when subjects do not recognize key differences between treatment and clinical research. Correlations with baseline depressive symptoms were explored. Subjects' performance on the MacCAT-CR was excellent, but therapeutic misconception was still apparent. A trend toward significance was found in the correlation between baseline depression ratings and total therapeutic misconception score. Responses to open-ended prompts revealed both reassuring and concerning statements related to expectations of risk, benefit, and individualization. Even severely depressed patients did not manifest impairments in their capacity to consent to DBS research. Therapeutic misconception, however, remained prevalent. PMID- 22812721 TI - Preparation and characterization of gelatin hydrogel support for immobilization of Candida rugosa lipase. AB - A series of gelatin hydrogels were prepared by crosslinking method using glutaraldehyde (GA). The hydrogels were characterized by gel formation, swelling/degradation tests, and FTIR analysis. The variations of swelling percentages (S%) with time, temperature, and pH were determined. It is found that the increasing amount of GA causes the decreasing in S% values from 366 to 213% and G-1 was found to be the most swollen hydrogel at pH 7.4 and 37 degrees C. Degradation tests of hydrogel samples were carried out and G-1 hydrogel, which contained the least amount of GA, degraded more rapidly than the others. G-2 hydrogel was chosen for immobilization studies and this procedure was carried out by activation of the hydrogel disc with N-(3-dimethylaminopropyl)-N ethylcarbodiimid (CDI) coupling agent. The kinetic parameters, K(m) and V(max), were calculated. K(m) values of free and immobilized lipases were found to be 0.290, 0.422 mM while V(max) values were calculated as 0.089, 0.080 mM.min(-1), respectively. For the free and immobilized system, the enzymes retained 32% and 92% of their initial activities, respectively, at the end of 48 days of storage. After using the mentioned immobilized system repeatedly 10 times, it retained 68% of its original activities. PMID- 22812722 TI - The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. AB - Fifty-three patients with resected pancreatic adenocarcinoma were studied to determine if adjuvant chemo-radiation causes severe lymphopenia and if this is associated with adverse outcomes. Total lymphocyte counts (TLC) were normal in 91% before adjuvant chemo-radiation. Two months later, TLC fell by 63% (p < .0001) with 45% of patients having TLC < 500 cells/mm(3). Median survival in patients with low TLC was 14 versus 20 months (p = .048). Multivariate analysis revealed a significant association between treatment related lymphopenia and survival (HR 2.2, p = .014). Adjuvant chemo-radiation induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma. PMID- 22812723 TI - Diameter modulation of vertically aligned single-walled carbon nanotubes. AB - We demonstrate wide-range diameter modulation of vertically aligned single-walled carbon nanotubes (SWNTs) using a wet chemistry prepared catalyst. In order to ensure compatibility to electronic applications, the current minimum mean diameter of 2 nm for vertically aligned SWNTs is challenged. The mean diameter is decreased to about 1.4 nm by reducing Co catalyst concentrations to 1/100 or by increasing Mo catalyst concentrations by five times. We also propose a novel spectral analysis method that allows one to distinguish absorbance contributions from the upper, middle, and lower parts of a nanotube array. We use this method to quantitatively characterize the slight diameter change observed along the array height. On the basis of further investigation of the array and catalyst particles, we conclude that catalyst aggregation-rather than Ostwald ripening dominates the growth of metal particles. PMID- 22812724 TI - Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor alpha1 subunit. AB - Autosomal dominant mutations S326fs328X and A322D in the GABA(A) receptor alpha1 subunit are associated with human absence epilepsy and juvenile myoclonic epilepsy, respectively. Because these mutations substantially reduce alpha1 subunit protein expression in vitro, it was hypothesized that they produce epilepsy by causing alpha1 subunit haploinsufficiency. However, in a mixed background strain of mice, alpha1 subunit deletion does not reduce viability or cause visually apparent seizures; the effects of alpha1 subunit deletion on electroencephalography (EEG) waveforms were not investigated. Here, we determined the effects of alpha1 subunit loss on viability, EEG spike-wave discharges and seizures in congenic C57BL/6J and DBA/2J mice. Deletion of alpha1 subunit caused strain- and sex-dependent reductions in viability. Heterozygous mice experienced EEG discharges and absence-like seizures within both background strains, and exhibited a sex-dependent effect on the discharges and viability in the C57BL/6J strain. These findings suggest that alpha1 subunit haploinsufficiency can produce epilepsy and may be a major mechanism by which the S326fs328X and A322D mutations cause these epilepsy syndromes. PMID- 22812725 TI - Sulfur fertilization and fungal infections affect the exchange of H(2)S and COS from agricultural crops. AB - The emission of gaseous sulfur (S) compounds by plants is related to several factors, such as the plant S status or fungal infection. Hydrogen sulfide (H(2)S) is either released or taken up by the plant depending on the ambient air concentration and the plant demand for S. On the contrary, carbonyl sulfide (COS) is normally taken up by plants. In a greenhouse experiment, the dependence of H(2)S and COS exchange with ambient air on the S status of oilseed rape (Brassica napus L.) and on fungal infection with Sclerotinia sclerotiorum was investigated. Thiol contents were determined to understand their influence on the exchange of gaseous S compounds. The experiment revealed that H(2)S emissions were closely related to pathogen infections as well as to S nutrition. S fertilization caused a change from H(2)S consumption by S-deficient oilseed rape plants to a H(2)S release of 41 pg g(-1) (dw) min(-1) after the addition of 250 mg of S per pot. Fungal infection caused an even stronger increase of H(2)S emissions with a maximum of 1842 pg g(-1) (dw) min(-1) 2 days after infection. Healthy oilseed rape plants acted as a sink for COS. Fungal infection caused a shift from COS uptake to COS releases. The release of S-containing gases thus seems to be part of the response to fungal infection. The roles the S-containing gases may play in this response are discussed. PMID- 22812726 TI - Modified anthropometry in prepubertal Israeli children while excluding the head's weight and height. AB - AIM: A methodological inadequacy in anthropometric measurements of children exists because of an age-dependent decelerating contribution of the head to body weight (Wt) and height (Ht). Hence, we aimed to assess the contribution of head measurements to anthropometry (Ht, Wt and BMI) in healthy prepubertal children. METHODS: This prospective study was conducted in 300 2- to 9-year-old typically growing children. Head-excluded (HE) Ht was determined by a stadiometer that measured the distance from the foot plate to the lower margin of protuberance occipitalis externa. Head's weight was calculated from the head volume using three different measurements of the head circumference. RESULTS: In the typically growing children, the HE/standard (STD) ratios for Wt and Ht increased significantly with age (p < 0.001 for both), but the HE/STD ratio for BMI did not increase with age. CONCLUSION: Measurement of body Wt and Ht while excluding the head's Wt and Ht provides a new dimension to standard anthropometry by eliminating the age-dependent head bias with its unique pattern of growth and minimal adipose tissue. PMID- 22812727 TI - Complex dynamical behavior in the highly photosensitive cerium-bromate-1,4 benzoquinone reaction. AB - Experimental and numerical investigations are carried out on the nonlinear dynamics of the cerium-bromate-1,4-benzoquinone reaction in which a unique kinetic feature is that the reduction of Ce(IV) is through bromide ions rather than by organic substrates. Nonlinear phenomena including both simple and sequential oscillations have been observed, and the system could oscillate for longer than a week. Significantly, fluorescent ceiling light with an intensity of less than 20 MUW/cm(2) exhibited strong influence on the frequency, lifetime, and complexity of the spontaneous oscillations. The transient oscillations lasted for a longer period of time at a low light intensity, were quenched by a moderate illumination, and then became long-lived again at a higher light intensity. Characterizations with (1)H NMR and GC/MS spectroscopy and ion selective electrode suggest that 2-bromo-1,4-benzoquinone is an important unstable intermediate product that undergoes photoaccelerated decomposition to produce hydroxy-1,4-benzoquinone and bromide ions. Simulations successfully reproduced the occurrence of oscillatory behavior in the studied system. PMID- 22812728 TI - 'I think my future will be better than my past': examining support group influence on the mental health of HIV-infected Rwandan women. AB - Urgent need exists for improved psychological services among HIV-infected women in post-genocide Rwanda. Psychological problems associated with trauma and sexual violence (i.e., depression, posttraumatic stress disorder [PTSD]) place women at increased risk for sexual risk behaviour, low health-seeking behaviour, delay of antiretroviral therapy (ART) and reduced ART adherence. We explored experiences of HIV-infected Rwandan women attending psychosocial support groups and their narratives about how participation affected their mental health and HIV treatment. Focus group discussions examined participants' reasons for support group attendance, perceived psychological benefit of support groups, influence on ART adherence, and other influences on health behaviors and attitudes. Rwandan women (aged 18-65) were randomly selected from 10 health clinic-facilitated support groups for HIV-infected trauma survivors in Kigali. Results identified positive psychological and physical changes as well as behaviour changes in relationships with men, which participants attributed to support group attendance. Data showed significant improvement in mental health, ART adherence and HIV serostatus disclosure resulting from group attendance. Participants acknowledged limitations of support groups with respect to addressing poverty and hunger. Implementing psychosocial support groups may leverage clinical outcomes and rejuvenate the well-being of HIV-infected women with interpersonal trauma and/or PTSD and depressive symptoms, particularly those from post-conflict countries. PMID- 22812729 TI - Influence of nutrient intake on antioxidant capacity, muscle damage and white blood cell count in female soccer players. AB - BACKGROUND: Soccer is a form of exercise that induces inflammatory response, as well as an increase in free radicals potentially leading to muscle injury. Balanced nutritional intake provides important antioxidant vitamins, including vitamins A, C and E, which may assist in preventing exercise-related muscle damage. The purpose of the present study was to determine the effect of macro/micronutrient intake on markers of oxidative stress, muscle damage, inflammatory and immune response in female soccer players. METHODS: Twenty-eight female players belonging to two soccer teams of the same professional soccer club participated in this study after being informed about the aims and procedures and after delivering written consent. Each team completed an 8-day dietary record and played one competition match the same week. Participants were divided into two groups: the REC group (who complied with recommended intakes) and the NO-REC group (who were not compliant). Laboratory blood tests were carried out to determine hematological, electrolytic and hormonal variables, as well as to monitor markers of cell damage and oxidative stress. Blood samples were obtained 24 h before, immediately after and 18 h after official soccer matches. Student t test or Mann-Whitney U-test was used to compare both groups throughout the match. RESULTS: At rest, we observed that the REC group had higher levels of total antioxidant status (TAS), glutathione peroxidase (GPx), and lower levels of creatine kinase (CK) and lactate dehydrogenase (LDH) in comparison to the NO-REC group. Immediately after the match, levels of TAS, GPx, superoxide dismutase (SOD), LDH and % lymphocytes were higher and the % of neutrophils were lower in the REC group compared to the NO-REC group. These differences were also maintained 18 h post-match, only for TAS and GPx. CONCLUSIONS: Our data reveal an association between nutritional intake and muscle damage, oxidative stress, immunity and inflammation markers. The benefit of the intake of specific nutrients may contribute to preventing the undesirable physiological effects provoked by soccer matches. PMID- 22812730 TI - Distinct features of fast oscillations in phasic and tonic rapid eye movement sleep. AB - Spatiotemporal activity patterns of neurones are organized by different types of coherent network oscillations. Frequency content and cross-frequency coupling of cortical oscillations are strongly state-dependent, indicating that different patterns of wakefulness or sleep, respectively, support different cognitive or mnestic processes. It is therefore crucial to analyse specific sleep patterns with respect to their oscillations, including interaction between fast and slow rhythms. Here we report the oscillation profile of phasic rapid eye movement (REM), a form of REM sleep which has been implicated in hippocampus-dependent memory processing. In all analysed frequency bands (theta, gamma and fast gamma, respectively) we find higher frequencies and higher power in phasic REM compared to tonic REM or wakefulness. Theta-phase coupling of fast oscillations, however, was highest in tonic REM, followed by phasic REM and wakefulness. Our data suggest different roles of phasic and tonic REM for information processing or memory formation during sleep. PMID- 22812731 TI - Sleep-disordered breathing in acute ischemic stroke and transient ischemic attack: effects on short- and long-term outcome and efficacy of treatment with continuous positive airways pressure--rationale and design of the SAS CARE study. AB - OBJECTIVES: Sleep-disordered breathing represents a risk factor for cardiovascular morbidity and mortality and negatively affects short-term and long term outcome after an ischemic stroke or transient ischemic attack. The effect of continuous positive airways pressure in patients with sleep-disordered breathing and acute cerebrovascular event is poorly known. The SAS CARE 1 study assesses the effects of sleep-disordered breathing on clinical evolution, vascular functions, and markers within the first three-months after an acute cerebrovascular event. The SAS CARE 2 assesses the effect of continuous positive airways pressure on clinical evolution, cardiovascular events, and mortality as well as vascular functions and markers at 12 and 24 months after acute cerebrovascular event. METHODS: SAS CARE 1 is an open, observational multicenter study in patients with acute cerebrovascular event acutely admitted in a stroke unit: a sample of 200 acute cerebrovascular event patients will be included. Vascular functions and markers (blood pressure, heart rate variability, endothelial function by peripheral arterial tonometry and specific humoral factors) will be assessed in the acute phase and at three-months follow-up. SAS CARE 2 will include a sample of patients with acute cerebrovascular event in the previous 60-90 days. After baseline assessments, the patients will be classified according to their apnea hypopnea index in four arms: non-sleep-disordered breathing patients (apnea hypopnea index <10), patients with central sleep disordered breathing, sleepy patients with obstructive apnea hypopnea index >=20, which will receive continuous positive airways pressure treatment, nonsleepy patients with obstructive sleep-disordered breathing (apnea hypopnea index >=20), which will be randomized to receive continuous positive airways pressure treatment or not. CONCLUSIONS: The SAS CARE study will improve our understanding of the clinical sleep-disordered breathing in patients with acute cerebrovascular event and the feasibility/efficacy of continuous positive airways pressure treatment in selected patients with acute cerebrovascular event and sleep disordered breathing. PMID- 22812902 TI - Adverse cutaneous drug reactions among hospitalized patients: five year surveillance. AB - CONTEXT: Cutaneous Adverse Drug Reactions (CADRs) are observed in 2-3% of hospitalized patients. The clinical presentation of the CADRs varies among different populations. OBJECTIVE: To study the CADRs in hospitalized patients and their outcome. MATERIALS AND METHODS: Patients hospitalized at our department between 2005 May and 2010 May were retrospectively reviewed for the diagnosis of CADRs. RESULTS: A total of 94 patients (3.3%) were diagnosed with CADR among 2801 hospitalized patients. Of them, 56 patients were female (59.6%) and 38 patients were male (40.4%). The culprit drugs were antibiotics (24.5%), non-steroid anti inflammatory drugs (NSAID) (22.4%), anticonvulsants (13.8%), antihypertensive agents (8.5%), paracetamol with or without pseudoephedrine or phenylephrine (6.4%), intravenous contrasts (3.2%), terbinafine (2.1%), biologic agents (2.1%) and various other medications (17.0%). The most common clinical type of CADRs was morbilliform exanthemas in 59.6% of the patients, followed by erythroderma (6.4%), drug reactions with eosinophilia and systemic symptoms (6.4%), lichenoid drug reaction (5.3%), urticaria and angioedema (4.3%), acute generalized exanthematous pustulosis (4.3%), drug-induced vasculitis (3.2%), drug induced psoriasis (2.1%), Stevens-Johnson syndrome/toxic epidermal necrolysis overlap (2.1%), psoriasiform drug reaction (2.1%). Fixed drug reaction, erythema multiforme, bullous drug reaction, drug induced panniculitis were observed in one each. No deaths occurred on the follow-up. Fever was observed in 35.1% of the patients. Eosinophilia was present in 51.1% of them. Latency period ranged between 0-15 days in 59 patients (62.8%), 15-30 days in 19 patients (20.2%), 30 90 days in 13 patients (13.8%), 90-120 days in three of them (3.2%). The latency for anticonvulsant drugs was statistically longer than the other group of drugs (p: 0.027). DISCUSSION AND CONCLUSIONS: CADRs were more common in women and most of them were caused by antimicrobial agents followed by NSAIDs and anticonvulsants. Latency period of anticonvulsants were longer than the other groups. PMID- 22812903 TI - The neuropathological consequences of CDKL5 mutation. PMID- 22812904 TI - Fluorophore and dye-assisted dispersion of carbon nanotubes in aqueous solution. AB - DNA short oligo, surfactant, peptides, and polymer-assisted dispersion of single walled carbon nanotube (SWCNTs) in aqueous solution have been intensively studied. It has been suggested that van der Waals interaction, pi-pi stacking, and hydrophobic interaction are major factors that account for the SWCNTs dispersion. Fluorophore and dye molecules such as Rhodamine B and fluorescein have both hydrophilic and hydrophobic moieties. These molecules also contain pi conjugated systems that can potentially interact with SWCNTs to induce its dispersion. Through a systematic study, here we show that SWCNTs can be dispersed in aqueous solution in the presence of various fluorophore or dye molecules. However, the ability of a fluorophore or dye molecule to disperse SWCNTs is not correlated with the stability of the fluorophore/dye-SWCNT complex, suggesting that the on-rate of fluorophore/dye binding to SWCNTs may dominate the efficiency of this process. We also examined the uptake of fluorophore molecules by mammalian cells when these molecules formed complexes with SWCNTs. The results can have potential applications in the delivery of poor cell-penetrating fluorophore molecules. PMID- 22812905 TI - The benefits of yoga for women veterans with chronic low back pain. AB - OBJECTIVES: Chronic low back (CLBP) pain is prevalent among military veterans and often leads to functional limitations, psychologic symptoms, lower quality of life, and higher health care costs. An increasing proportion of U.S. veterans are women, and women veterans may have different health care needs than men veterans. The purpose of this study was to assess the impact of a yoga intervention on women and men with CLBP. SUBJECTS/SETTING/INTERVENTION: VA patients with CLBP were referred by primary care providers to a clinical yoga program. DESIGN: Research participants completed a brief battery of questionnaires before their first yoga class and again 10 weeks later in a single-group, pre-post study design. OUTCOME MEASURES: Questionnaires included measures of pain (Pain Severity Scale), depression (CESD-10), energy/fatigue, and health-related quality of life (SF-12). Yoga attendance and home practice of yoga were also measured. Repeated measures analysis of variance was used to analyze group differences over time while controlling for baseline differences. RESULTS: The 53 participants who completed both assessments had a mean age of 53 years, and were well educated, 41% nonwhite, 49% married, and had varying employment status. Women participants had significantly larger decreases in depression (p=0.046) and pain "on average" (p=0.050), and larger increases in energy (p=0.034) and SF-12 Mental Health (p=0.044) than men who participated. The groups did not differ significantly on yoga attendance or home practice of yoga. CONCLUSIONS: These results suggest that women veterans may benefit more than men veterans from yoga interventions for chronic back pain. Conclusions are tentative because of the small sample size and quasi-experimental study design. A more rigorous study is being designed to answer these research questions more definitively. PMID- 22812906 TI - Metal-chelating polymers by anionic ring-opening polymerization and their use in quantitative mass cytometry. AB - Metal-chelating polymers (MCPs) are important reagents for multiplexed immunoassays based on mass cytometry. The role of the polymer is to carry multiple copies of individual metal isotopes, typically as lanthanide ions, and to provide a reactive functionality for convenient attachment to a monoclonal antibody (mAb). For this application, the optimum combination of chain length, backbone structure, end group, pendant groups, and synthesis strategy has yet to be determined. Here we describe the synthesis of a new type of MCP based on anionic ring-opening polymerization of an activated cyclopropane (the diallyl ester of 1,1-cyclopropane dicarboxylic acid) using a combination of 2 furanmethanethiol and a phosphazene base as the initiator. This reaction takes place with rigorous control over molecular weight, yielding a polymer with a narrow molecular weight distribution, reactive pendant groups for introducing a metal chelator, and a functional end group with orthogonal reactivity for attaching the polymer to the mAbs. Following the ring-opening polymerization, a two-step transformation introduced diethylenetriaminepentaacetic acid (DTPA) chelating groups on each pendant group. The polymers were characterized by NMR, size exclusion chromatography (SEC), and thermogravimetric analysis (TGA). The binding properties toward Gd(3+) as a prototypical lanthanide (Ln) ion were also studied by isothermal titration calorimetry (ITC). Attachment to a mAb involves a Diels-Alder reaction of the terminal furan with a bismaleimide, followed by a Michael addition of a thiol on the mAb, generated by mild reduction of a disulfide bond in the hinge region. Polymer samples with a number average degree of polymerization of 35, with a binding capacity of 49.5 +/- 6 Ln(3+) ions per chain, were loaded with 10 different types of Ln ions and conjugated to 10 different mAbs. A suite of metal-tagged Abs was tested by mass cytometry in a 10 plex single cell analysis of human adult peripheral blood, allowing us to quantify the antibody binding capacity of 10 different cell surface antigens associated with specific cell types. PMID- 22812907 TI - Timing of human chorionic gonadotrophin (hCG) hormone administration in IVF protocols using GnRH antagonists: a randomized controlled trial. AB - This randomized controlled trial investigated whether delaying human chorionic gonadotrophin hormone (hCG) administration within an IVF cycle impacts upon clinical outcomes. Participants included 125 women undergoing IVF/ICSI cycles at Leeds Centre for Reproductive Medicine. Subjects were aged 20-36 years, body mass index (BMI) 20-30 kg/m(2) with a normal FSH level (<8 IU/l). Administration of hCG took place 35-36 h prior to oocyte retrieval when there were >=3 follicles >=17 mm in diameter (Group A), delayed by 1 day (Group B) or 2 days (Group C). Outcomes included the number of oocytes retrieved per cycle, fertilization rate and live birth rate. On the day of oocyte retrieval, women in Groups B and C had significantly more mature follicles than Group A, although the number of oocytes retrieved did not differ (median = 12 in each group). Fertilization rates and embryo quality were comparable between groups. Pregnancies and live births per cycle were higher in Groups B and C (A = 30.8%, B = 54.1%, C = 38.7%; A = 17.9%, B = 27.0%, C = 25.8%), but did not reach statistical significance. Delaying hCG administration had no significant negative impact upon morphological quality of embryos, availability of surplus embryos for freezing or pregnancy outcomes. Postponing hCG may enable increased flexibility of cycle scheduling to avoid weekend procedures. PMID- 22812908 TI - Contact allergy to local anaesthetics-value of patch testing with a caine mix in the baseline series. AB - BACKGROUND: Contact allergy to local anaesthetics is relatively common. Patch testing with benzocaine in the European baseline series is recommended for diagnosis, even though a caine mix has been previously suggested to be superior. OBJECTIVES: To assess the frequency and patterns of contact allergy to local anaesthetics by using a caine mix (benzocaine, tetracaine, and cinchocaine) in the baseline series, and evaluate its efficiency as compared with benzocaine alone. METHODS: We reviewed the results of 2736 patch tests performed between 2000 and 2010, identifying patients with positive reactions to caine mix or to one of seven local anaesthetics. RESULTS: One hundred and twelve patients (4.1%) had at least one allergic reaction to local anaesthetics; 86 were tested with all seven local anaesthetics, resulting in 71 reactions in 53 patients. Cinchocaine gave the most reactions (50.7%); these occurred as a single reaction in 83.3% of patients, mostly with current or past relevance (97%). Benzocaine represented 22.5% of reactions, many of which were non-relevant (44%) or resulting from cross reactions with para-compounds. CONCLUSIONS: Almost 70% of allergic reactions to local anaesthetics would have been missed if benzocaine had been used as a screening allergen. This study supports a recommendation to replace benzocaine with a caine mix containing cinchocaine in the baseline patch test series. PMID- 22812909 TI - Ferroelectricity in Simple Binary ZrO2 and HfO2. AB - The transition metal oxides ZrO(2) and HfO(2) as well as their solid solution are widely researched and, like most binary oxides, are expected to exhibit centrosymmetric crystal structure and therewith linear dielectric characteristics. For this reason, those oxides, even though successfully introduced into microelectronics, were never considered to be more than simple dielectrics possessing limited functionality. Here we report the discovery of a field-driven ferroelectric phase transition in pure, sub 10 nm ZrO(2) thin films and a composition- and temperature-dependent transition to a stable ferroelectric phase in the HfO(2)-ZrO(2) mixed oxide. These unusual findings are attributed to a size-driven tetragonal to orthorhombic phase transition that in thin films, similar to the anticipated tetragonal to monoclinic transition, is lowered to room temperature. A structural investigation revealed the orthorhombic phase to be of space group Pbc2(1), whose noncentrosymmetric nature is deemed responsible for the spontaneous polarization in this novel, nanoscale ferroelectrics. PMID- 22812910 TI - Click-modified anandamide siRNA enables delivery and gene silencing in neuronal and immune cells. AB - Click chemistry of alkyne-modified RNA with different receptor ligand azides was used to prepare 3'-folate, 3'-cholesterol, and, as a new entity, 3'-anandamide modified RNA in high yields and excellent purity. The anandamide-modified RNA shows surprisingly high transfection properties and enables the delivery of siRNA even into difficult-to-transfect RBL-2H3 cells which model neuronal uptake. Furthermore, the system was employed in human immune cells (BJAB), demonstrating silencing effects similar to those of a cationic, benchmark transfection reagent. In addition, the anandamide conjugates were found to be nontoxic. The reported chemistry and the described properties of the anandamide siRNA extend the possibilities of using siRNA-based gene silencing in neuronal and immune cells. PMID- 22812911 TI - Assessment of identity development and identity diffusion in adolescence - Theoretical basis and psychometric properties of the self-report questionnaire AIDA. AB - BACKGROUND: In the continuing revision of Diagnostic and Statistical Manual (DSM V) "identity" is integrated as a central diagnostic criterion for personality disorders (self-related personality functioning). According to Kernberg, identity diffusion is one of the core elements of borderline personality organization. As there is no elaborated self-rating inventory to assess identity development in healthy and disturbed adolescents, we developed the AIDA (Assessment of Identity Development in Adolescence) questionnaire to assess this complex dimension, varying from "Identity Integration" to "Identity Diffusion", in a broad and substructured way and evaluated its psychometric properties in a mixed school and clinical sample. METHODS: Test construction was deductive, referring to psychodynamic as well as social-cognitive theories, and led to a special item pool, with consideration for clarity and ease of comprehension. Participants were 305 students aged 12-18 attending a public school and 52 adolescent psychiatric inpatients and outpatients with diagnoses of personality disorders (N = 20) or other mental disorders (N = 32). Convergent validity was evaluated by covariations with personality development (JTCI 12-18 R scales), criterion validity by differences in identity development (AIDA scales) between patients and controls. RESULTS: AIDA showed excellent total score (Diffusion: alpha = .94), scale (Discontinuity: alpha = .86; Incoherence: alpha = .92) and subscale (alpha = .73-.86) reliabilities. High levels of Discontinuity and Incoherence were associated with low levels in Self Directedness, an indicator of maladaptive personality functioning. Both AIDA scales were significantly different between PD patients and controls with remarkable effect sizes (d) of 2.17 and 1.94 standard deviations. CONCLUSION: AIDA is a reliable and valid instrument to assess normal and disturbed identity in adolescents. Studies for further validation and for obtaining population norms are in progress and may provide insight in the relevant aspects of identity development in differentiating specific psychopathology and therapeutic focus and outcome. PMID- 22812912 TI - Effect of different adhesion strategies on bond strength of resin composite to composite-dentin complex. AB - Service life of discolored and abraded resin composite restorations could be prolonged by repair or relayering actions. Composite-composite adhesion can be achieved successfully using some surface conditioning methods, but the most effective adhesion protocol for relayering is not known when the composite restorations are surrounded with dentin. This study evaluated the effect of three adhesion strategies on the bond strength of resin composite to the composite dentin complex. Intact maxillary central incisors (N=72, n=8 per subgroup) were collected and the coronal parts of the teeth were embedded in autopolymerized poly(methyl tfr54methacrylate) surrounded by a polyvinyl chloride cylinder. Cylindrical cavities (diameter: 2.6 mm; depth: 2 mm) were opened in the middle of the labial surfaces of the teeth using a standard diamond bur, and the specimens were randomly divided into three groups. Two types of resin composite, namely microhybrid (Quadrant Anterior Shine; AS) and nanohybrid (Grandio; G), were photo polymerized incrementally in the cavities according to each manufacturer's recommendations. The composite-enamel surfaces were ground finished to 1200-grit silicone carbide paper until the dentin was exposed. The surfaces of the substrate composites and the surrounding dentin were conditioned according to one of the following adhesion protocols: protocol 1: acid-etching (dentin) + silica coating (composite) + silanization (composite) + primer (dentin) + bonding agent (dentin + composite); protocol 2: silica coating (composite) + acid-etching (dentin) + silanization (composite) + primer (dentin) + bonding agent (dentin + composite); and protocol 3: acid-etching (dentin) + primer (dentin) + silanization (composite) + bonding agent (dentin + composite). Applied primer and bonding agents were the corresponding materials of the composite manufacturer. Silica coating (CoJet sand, 30 MUm) was achieved using a chairside air-abrasion device (distance: 10 mm; duration: four seconds in circular motion). After conditioning protocols, the repair resin was adhered to the substrate surfaces using transparent polyethylene molds (diameter: 3.6 mm) incrementally and photo polymerized. The substrate-adherend combinations were as follows: AS-AS, G-G, AS G. Shear force was applied to the adhesive interface in a Universal Testing Machine (crosshead speed: 1 mm/min). The types of failures were further evaluated and categorized as follows: 1) cohesive in the composite substrate and 2) adhesive at the interface. Bond strength values (MPa) were statistically analyzed using two-way analysis of variance and least significant difference post hoc tests (alpha=0.05). Significant effects of the adhesion strategy (p=0.006) and the composite type (p=0.000) were found. Interaction terms were not significant (p=0.292). Regardless of the substrate-adherend combination, protocol 1 (17-22 MPa) showed significantly higher results than did protocols 2 (15-17 MPa) and 3 (11-17 MPa) (p=0.028, p=0.002, respectively). The highest results were obtained from the G-G combination after all three protocols (17-22 MPa). The incidence of cohesive failures was more common when the substrate and the adherend were the same composite type (AS-AS: 87.5%, 87.5%, 75%; G-G: 100%, 75%, 50% for protocols 1, 2, and 3, respectively). When substrate and adherend were used interchangeably, adhesive failures were more frequent (25%, 50%, and 100% for protocol 1, 2, and 3, respectively). When the substrate and the adherend are of the same type, greater repair strength could be expected. In the repair of composites next to the dentin, depending on the composite type, conditioning the composite with silica coating and silanization after etching the dentin adds to the repair strength compared to the results obtained with silane application only. PMID- 22812913 TI - The Renalase Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmo Diet and cancer study. AB - BACKGROUND: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A > G and rs2296545 C > G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle aged Swedes. METHODS: The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmo Diet and Cancer" (MDC CC). The incidence of cardiovascular events (coronary events [n = 408], strokes [n = 330], heart failure [n = 190] and atrial fibrillation/flutter [n = 406]) was monitored for an average of approximately 15 years of follow-up. RESULTS: Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C > G and age with respect to BP/hypertension. CONCLUSIONS: Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C > G polymorphism, if any, could vary between different ages. PMID- 22812914 TI - Tear production in canine neonates--evaluation using a modified Schirmer tear test. AB - PURPOSE: The ability of human newborns to produce tears has been a subject of controversy in the literature since the mid-20th century, and there has been considerable debate as to whether they are able to produce tears. Recently, it was established that total tear secretion (reflex + basal) in full-term infants is similar to those of adults whereas both reflex and basal tear production is reduced in premature babies. The objectives of this study were to assess whether newborn dogs have measurable aqueous tear production at the fourth week of life and to evaluate a modified Schirmer tear test (mSTT) as a useful method for measuring neonatal tear production in dogs. METHODS: Thirty four-week-old healthy puppies from six litters were evaluated. A control group was composed of 10 normal adult dogs. The mSTT strips were obtained by cutting a 5 mm-wide strip in half (making two 2.5 mm-wide strips). The mSTT1 was performed in puppies and adult dogs. Values were compared using t-tests. RESULTS: In neonates, the average value for the mSTT1 was 13.6 +/- 3.07 (range = 7-19 mm/min), which was significantly lower in neonates than in adult dogs (23.25 +/- 3.5, range = 17-30 mm/min, P < 0.0001). CONCLUSIONS: Canine neonates do produce tears by the fourth week of life, which can be successfully measured with the mSTT. This report established for the first time that canine neonates have significantly reduced total (reflex + basal) tear secretion compared to adults. PMID- 22812915 TI - Identification of 5,7,3',4'-tetramethoxyflavone metabolites in rat urine by the isotope-labeling method and ultrahigh-performance liquid chromatography electrospray ionization-mass spectrometry. AB - 5,7,3',4'-Tetramethoxyflavone (TMF), one of the major polymethoxyflavones (PMFs) isolated from Kaempferia parviflor , has been reported possessing various bioactivities, including antifungal, antimalarial, antimycobacterial, and anti inflammatory activities. Although several studies on the TMF have been reported, the information about the metabolism of TMF and the structures of TMF metabolites is still not yet clear. In this study, an isotope-labeling method was developed for the identification of TMF metabolites. Three isotope-labeled TMFs (5,7,3',4' tetramethoxy[3'-D(3)]flavone, 5,7,3',4'-tetramethoxy[4'-D(3)]flavone, and 5,7,3',4'-tetramethoxy[5,4'-D(6)]flavone) were synthesized and administered to rats. The urine samples were collected, and the main metabolites were monitored by ultrahigh-performance liquid chromatography-electrospray ionization-mass spectrometry. Five TMF metabolites were unambiguously identified as 3'-hydroxy 5,7,4'-trimethoxyflavone, 7-hydroxy-5,3',4'-trimethoxyflavone sulfate, 7-hydroxy 5,3',4'-trimethoxyflavone, 4'-hydroxy-5,7,3'-trimethoxyflavone, and 5-hydroxy 7,3',4'-trimethoxyflavone. PMID- 22812916 TI - Adrian Barbul, MD: 2012 recipient of the Wound Healing Society's Lifetime Achievement Award. PMID- 22812917 TI - Superconductivity in films of Pb/PbSe core/shell nanocrystals. AB - Superconductivity in films of electronically coupled colloidal lead nanocrystals is reported. The coupling between particles is in situ controlled through the conversion of the oxides present on the surface of the nanoparticles to chalcogenides. This transformation allows for a 10(9)-fold increase in the conductivity. The temperature of the onset of the superconductivity was found to depend upon the degree of coupling of the nanoparticles in the vicinity of the insulator-superconductor transition. The critical current density of the best sample of Pb/PbSe nanocrystals at zero magnetic field was determined to be 4 * 10(3) A/cm(2). In turn, the critical field of the sample shows 50-fold enhancement compared to bulk Pb. PMID- 22812918 TI - Mode of delivery and neonatal outcome in uncomplicated monochorionic twin pregnancies. AB - OBJECTIVE: The association between of mode of delivery and perinatal morbidity in monochorionic (MC) twins is not clear. Thus there is no agreement regarding the optimal mode of delivery of MC twins. The aim of this study is to determine the impact of the mode of delivery on neonatal outcome of uncomplicated MC twins in a tertiary center with a strict policy of delivering MC twins by 37 weeks' gestation. METHODS: Retrospective analysis of all uncomplicated MC twin deliveries at a tertiary referral hospital during a 5-year period. Complicated MC pregnancies (fetal death, selective reduction, twin to twin transfusion syndrome, fetal growth restriction of one or both twins or major fetal anomalies) were excluded. Induction of labor or planned caesarean sections of uncomplicated MC pregnancies was conducted between 35 and 37 weeks of gestation. Neonatal outcomes of MC twins were compared according to the mode of delivery. Moreover, mode of delivery was compared with a control group of 1934 dichorionic (DC) twin pregnancies delivered during the same period. RESULTS: The rate of Caesarean section was 63.4% in uncomplicated MC/DA twins pregnancies and this was similar to our rate in DC twins (61%, p = 0.65). Multivariate analysis revealed that adverse neonatal outcome was significantly associated with gestational age at delivery, neonatal birth weight discordance and male gender but not with the intended or actual mode of delivery. CONCLUSION: Delivering MC twin pregnancies by 37 weeks' gestation is associated with similar rate of vaginal deliveries compared with DC twin pregnancies. The neonatal outcome was not affected by the mode of delivery, and therefore vaginal delivery seems safe in MC twins. PMID- 22812919 TI - The inclusion of women, girls and gender equality in National Strategic Plans for HIV and AIDS in southern and eastern Africa. AB - The global HIV and AIDS epidemics disproportionately affect women, particularly young women in southern and eastern Africa. UNAIDS, amongst other actors, has singled out National Strategic Plans for HIV and AIDS (NSPs) as a critical platform for ensuring that women and girls are meaningfully included in national HIV and AIDS responses. Despite this, there is little evidence as to how or whether NSPs integrate responses to women and girls. Using a collaboratively developed framework, we assessed how 20 countries in southern and eastern Africa integrated women and girls in their NSPs. We identified that in general there is poor inclusion, apart from access to post-exposure prophylaxis in the case of sexual violence and access to vertical transmission services. Drawing on Moser's distinction between women's practical and strategic interests, we suggest that overall women and girls are poorly included in NSPs, and where there are policies and programmes, there is an overwhelming focus on women's practical interests, without any consideration of women's strategic interests. We argue that this limits the potential of NSPs to be platforms for national responses that meaningfully seek to transform gender relations. PMID- 22812920 TI - Triangle pore arrays fabricated on Si (111) substrate by sphere lithography combined with metal-assisted chemical etching and anisotropic chemical etching. AB - The morphological change of silicon macropore arrays formed by metal-assisted chemical etching using shape-controlled Au thin film arrays was investigated during anisotropic chemical etching in tetramethylammonium hydroxide (TMAH) aqueous solution. After the deposition of Au as the etching catalyst on (111) silicon through a honeycomb mask prepared by sphere lithography, the specimens were etched in a mixed solution of HF and H2O2 at room temperature, resulting in the formation of ordered macropores in silicon along the [111] direction, which is not achievable by conventional chemical etching without a catalyst. In the anisotropic etching in TMAH, the macropores changed from being circular to being hexagonal and finally to being triangular, owing to the difference in etching rate between the crystal planes. PMID- 22812921 TI - Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System. AB - AIM: To determine the rate ratio of neuropsychiatric hospitalizations in new users of varenicline compared to new users of nicotine replacement therapy (NRT) patch in the Military Health System (MHS). DESIGN, SETTING AND PARTICIPANTS: Varenicline (n = 19,933) and NRT patch (n = 15,867) users who initiated therapy from 1 August 2006 to 31 August 2007 within the MHS were included in this retrospective cohort study. After matching according to propensity scores, 10,814 users remained in each cohort. The study population included those with and without a history of neuropsychiatric disease. MEASUREMENTS: Patients were followed for neuropsychiatric hospitalizations defined by primary neuropsychiatric discharge diagnosis using ICD-9 codes from in-patient administrative claims. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated after propensity score matching on exposure for socio-demographic factors, health-care utilization, comorbidities, medication history and neuropsychiatric history. FINDINGS: There was no increase in the rate of neuropsychiatric hospitalizations in patients treated with varenicline compared to NRT patch when followed for 30 days (propensity-score matched HR = 1.14, 95% CI: 0.56-2.34). Results were similar after 60 days of follow-up. CONCLUSIONS: There does not appear to be an increase in neuropsychiatric hospitalizations with varenicline compared with nicotine replacement therapy patch over 30 or 60 days after drug initiation. PMID- 22812922 TI - Chain transplantation: initial experience of a large multicenter program. AB - We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated by nondirected donors, were identified using a computer algorithm incorporating virtual cross-matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O-patients receiving a transplant (n = 90) was greater than the number of blood type O-non-directed donors (n = 32) initiating chains. We have 1-year follow up on the first 100 transplants. The mean 1-year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts. PMID- 22812923 TI - Protein-mediated efficient synergistic "antenna effect" in a ternary system in D2O medium. AB - A ternary system consisting of a protein, catechin (either + or - epimer), and Tb(III) in suitable aqueous buffer medium at physiological pH (= 6.8) has been shown to exhibit highly efficient "antenna effect". Steady state and time resolved emission studies of each component in the binary complexes (protein with Tb(III) and (+)- or (-)-catechin with Tb(III)) and the ternary systems along with the molecular docking studies reveal that the efficient sensitization could be ascribed to the effective shielding of microenvironment of Tb(III) from O-H oscillator and increased Tb-C (+/-) interaction in the ternary systems in aqueous medium. The ternary system exhibits protein-mediated efficient antenna effect in D(2)O medium due to synergistic ET from both the lowest pipi* triplet state of Trp residue in protein and that of catechin apart from protection of the Tb(III) environment from matrix vibration. The simple system consisting of (+)- or (-) catechin and Tb(III) in D(2)O buffer at pH 6.8 has been prescribed to be a useful biosensor. PMID- 22812924 TI - Association between the amount of right-to-left shunt and infarct patterns in patients with cryptogenic embolic stroke: a transcranial Doppler study. AB - BACKGROUND: Paradoxical embolism has been documented as a mechanism of cryptogenic embolic stroke. We investigated the frequency of right-to-left shunt in patients with cryptogenic embolic stroke and evaluated the factors associated with diffusion-weighted imaging (DWI) lesion pattern. METHODS: We analyzed data on 157 consecutive patients with acute ischemic stroke because of presumed cryptogenic embolism. Agitated saline transcranial Doppler study was conducted in all patients to detect right-to-left shunt. We evaluated the association of the amount (microemboli <20 vs. >=20) and activity (spontaneous vs. after Valsalva maneuver only) of right-to-left shunt with diffusion-weighted imaging lesion patterns. RESULTS: Right-to-left shunt was observed in 96 (61.1%) patients. The multiplicity and distribution of diffusion-weighted imaging lesions did not differ depending on the amount and activity of right-to-left shunt. However, the size of diffusion-weighted imaging lesions differed depending on the amount of right-to-left shunt (P = 0.019). Right-to-left shunt was more frequently observed in patients with small (<1 cm) infarcts than in those with a large infarct (66.7% vs. 45.9%), and most patients with a larger amount of right-to-left shunt were found to have small infarcts on diffusion-weighted imaging (80%). The clinical characteristics, including Framingham stroke risk strategy, did not differ between the groups. CONCLUSIONS: Our results indicate that the amount of right-to left shunt determines the Diffusion-weighted imaging lesion patterns and suggest that mechanisms of stroke other than paradoxical mechanism may play an important role in patients with large cryptogenic embolic stroke. PMID- 22812925 TI - Primary afterdischarge in organotypic hippocampal slice cultures: effects of standard antiepileptic drugs. AB - PURPOSE: In the hippocampus intense high frequency electrical stimulation induces a long-lasting rhythmic synchronization (primary afterdischarge). In order to examine the suitability of primary afterdischarges (PADs) in organotypic hippocampal slice cultures (OHSCs) as an in vitro model of evoked seizures, we have worked out in detail the sensitivity of PADs to standard antiepileptic drugs (AEDs) and compared the necessary concentrations to those that were effective in animal models of partial and generalized tonic-clonic seizures. METHODS: OHSCs were prepared according to the interface culture method from 8 to 11-day-old Wistar rats. A PAD in CA1 was elicited by stimulating the stratum radiatum with an intensity of two times that required to elicit a maximal population spike. The effects of carbamazepine, phenytoin, valproic acid, phenobarbital, diazepam, and ethosuximide on the duration and on frequency properties of PADs and the tonic like and clonic-like subdivisions of PADs were determined, and as a measure of the AEDs potency half maximal effective concentration (EC(50) ) values were calculated from concentration-response curves. KEY FINDING: Carbamazepine, phenytoin, valproic acid, phenobarbital, and diazepam reduced the durations of PADs and tonic-like and clonic-like subdivisions of PADs. The effects were concentration dependent and reversible. Ethosuximide was ineffective. The effects on subdivisions of PADs differed between AEDs. Carbamazepine and phenytoin shortened the tonic-like and clonic-like subdivisions at similar proportions, whereas phenobarbital, diazepam, and valproic acid preferentially shortened the clonic-like subdivision. Diazepam at low concentrations increased the duration of tonic-like subdivisions, an effect not seen with the other AEDs. The suppressive effects of AEDs on frequency properties of tonic-like and clonic-like subdivisions were variable and observed only at higher concentrations. SIGNIFICANCE: Carbamazepine and phenytoin were more effective in the PAD test in OHSCs than in the maximal electroshock and kindled seizures tests. The effectiveness of phenobarbital, diazepam, and valproic acid in the PAD test matched their effectiveness in the MES test and-with the exception of valproic acid and diazepam-in kindled seizures tests. Valproic acid was less effective in OHSCs than in the kindled seizure tests, and diazepam was more (generalized seizures) or less (focal seizures and afterdischarge durations) effective in this animal model than in OHSCs. We conclude that the PAD test in OHSCs is a suitable in vitro model of evoked seizures. The model could serve as an initial screen to identify the most promising leads for further evaluation and characterization in in vivo models of efficacy and toxicity. PMID- 22812926 TI - Visual signs and symptoms of dementia with Lewy bodies. AB - Dementia with Lewy bodies ('Lewy body dementia' or 'diffuse Lewy body disease') (DLB) is the second most common form of dementia to affect elderly people, after Alzheimer's disease. A combination of the clinical symptoms of Alzheimer's disease and Parkinson's disease is present in DLB and the disorder is classified as a 'parkinsonian syndrome', a group of diseases which also includes Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. Characteristics of DLB are fluctuating cognitive ability with pronounced variations in attention and alertness, recurrent visual hallucinations and spontaneous motor features, including akinesia, rigidity and tremor. In addition, DLB patients may exhibit visual signs and symptoms, including defects in eye movement, pupillary function and complex visual functions. Visual symptoms may aid the differential diagnoses of parkinsonian syndromes. Hence, the presence of visual hallucinations supports a diagnosis of Parkinson's disease or DLB rather than progressive supranuclear palsy. DLB and Parkinson's disease may exhibit similar impairments on a variety of saccadic and visual perception tasks (visual discrimination, space-motion and object-form recognition). Nevertheless, deficits in orientation, trail-making and reading the names of colours are often significantly greater in DLB than in Parkinson's disease. As primary eye-care practitioners, optometrists should be able to work with patients with DLB and their carers to manage their visual welfare. PMID- 22812927 TI - Hearing-aid counseling: comparison of single-session informational counseling with single-session performance-perceptual counseling. AB - OBJECTIVE: Hearing-aid counseling can improve outcome but programs are often too resource-intensive to be clinically practical. Here we examined the effectiveness of single-session informational counseling with single-session performance perceptual counseling. DESIGN: Two forms of counseling were compared: informational counseling (IC) and performance-perceptual counseling (PPC). IC focused on discussing communication strategies and tips for hearing-aid use. PPC addressed the discrepancy between measured and perceived ability to understand speech. Outcomes were measured eight-to-ten weeks post-counseling using quantitative and qualitative measures: Hearing handicap inventory, abbreviated profile of hearing aid benefit, psychosocial impact of assistive devices scale (PIADS), international outcome inventory for hearing aids, and a semi-structured exit interview. STUDY SAMPLE: Seventy-four hearing aid-users with symmetrical sensorineural hearing loss participated. RESULTS: Scores on the hearing questionnaires showed no change following either form of counseling. Scores on the PIADS improved for participants as a whole, and the semi-structured interview revealed increased hearing-aid use, better understanding and acceptance of hearing loss, increased use of communication strategies, and improved ability to explain hearing difficulties to others. CONCLUSIONS: A single session of hearing aid counseling can improve hearing-aid use and satisfaction. Open-ended interview and/or quality of life measures are more sensitive to these benefits than hearing questionnaires. PMID- 22812928 TI - Effects of trace water on charging of silica particles dispersed in a nonpolar medium. AB - This paper presents an investigation of the effects of trace water on the charging of silica (SiO(2)) particles dispersed in a nonpolar medium. There are a growing number of applications that seek to use electrostatic effects in apolar media to control particle movement and aggregation stability in such systems. One factor that is often overlooked in the preparation of nonpolar colloidal dispersions is the amount of water that is introduced to the system by hygroscopic particles and surfactants. The amount and location of this water can have significant effects on the electrical properties of these systems. For nonpolar surfactant solutions it has been shown that water can affect the conductivity, and it has been speculated that this is due to swelling of the polar cores of inverse micelles, increasing the fraction of them that are charged. Some studies have suggested that particle surface charging may also be sensitive to water content, but a clear mechanism for the process has not been fully developed. The situation with particles is further complicated by the fact that it is often unclear whether the water resides on the particle surfaces or in the polar cores of inverse micelles. The current work explores not only the effect of water content on reverse micelle and particle charging but seeks to differentiate between water bound to the particles and water located in the micelles. This is accomplished by measuring the solution conductivity and the electrophoretic mobility of silicon dioxide particles dispersed in solutions of Isopar-L and OLOA 11000. The water content is determined for both the dispersion and the supernatant after centrifuging the particles out. It is found that at equilibrium the majority of the water in the system adsorbs to the surface of the hygroscopic silica particles. In addition, the effect of water on particle electrophoretic mobility is found to be dependent on surfactant concentration. At small OLOA concentrations, additional water results in an increase in particle mobility due to increased particle charging. However, at large OLOA concentrations, additional water leads to a decrease in particle mobility, presumably as a result of increased electrostatic screening or neutralization. Thus, particle charging and electrophoretic mobility in an apolar surfactant solution are found to be highly sensitive to both the total water content in the system and to its concentration relative to the amount of surfactant present. PMID- 22812929 TI - Septic implantation syndrome in dogs and cats: a distinct pattern of endophthalmitis with lenticular abscess. AB - OBJECTIVE: To summarize the clinical and pathologic findings in a group of dogs and cats with progressive clinical ocular disease, which were diagnosed with suppurative endophthalmitis and lens capsule rupture. ANIMALS STUDIED: Twenty cats and forty-six dogs that underwent unilateral enucleation or evisceration for intractable uveitis and/or glaucoma. PROCEDURE: Biopsy submission requests and microscopic case material were evaluated for clinical and histological features, including history of ocular trauma, duration of ocular disease, pattern of inflammation, and the presence of intralenticular microorganisms. RESULTS: The median duration for cats and dogs was 6 and 5 weeks, respectively. A history of trauma was reported for four (20%) cats and 18 (39%) dogs. All confirmed cases of trauma-three in cats and 14 in dogs-were caused by a cat scratch. Microscopically, all cases had suppurative endophthalmitis centered on the lens, lens capsule rupture, cataract, and lenticular abscess. Infectious organisms were identified by Gram stain within the lens of 14 (70%) cats and 30 (65%) dogs. Gram positive cocci were seen most commonly. Male cats were overrepresented as compared to females. There were no apparent gender, age or breed predilections in dogs. CONCLUSIONS: A unique pattern of slowly progressive or delayed-onset endophthalmitis with lens capsule rupture, lenticular abscess, and frequently intralenticular microorganisms is associated with traumatic penetration of the globe and lens capsule. The term Septic Implantation Syndrome (SIS) is favored in lieu of 'phacoclastic uveitis' to avoid confusion with phacolytic uveitis and to clearly implicate the role of intralenticular microorganisms in the pathogenesis. PMID- 22812930 TI - Integrated analysis of hydrothermal flow through pretreatment. AB - BACKGROUND: The impact of hydrothermal flowthrough (FT) pretreatment severity on pretreatment and solubilization performance metrics was evaluated for three milled feedstocks (corn stover, bagasse, and poplar) and two conversion systems (simultaneous saccharification and fermentation using yeast and fungal cellulase, and fermentation by Clostridium thermocellum). RESULTS: Compared to batch pretreatment, FT pretreatment consistently resulted in higher XMG recovery, higher removal of non-carbohydrate carbon and higher glucan solubilization by simultaneous saccharification and fermentation (SSF). XMG recovery was above 90% for FT pretreatment below 4.1 severity but decreased at higher severities, particularly for bagasse. Removal of non-carbohydrate carbon during FT pretreatment increased from 65% at low severity to 80% at high severity for corn stover, and from 40% to 70% for bagasse and poplar.Solids obtained by FT pretreatment were amenable to high conversion for all of the feedstocks and conversion systems examined. The optimal time and temperature for FT pretreatment on poplar were found to be 16 min and 210 degrees C. At these conditions, SSF glucan conversion was about 85%, 94% of the XMG was removed, and 62% of the non carbohydrate mass was solubilized. Solubilization of FT-pretreated poplar was compared for C. thermocellum fermentation (10% inoculum), and for yeast-fungal cellulase SSF (5% inoculum, cellulase loading of 5 and 10 FPU/g glucan supplemented with beta-glucosidase at 15 and 30 U/g glucan). Under the conditions tested, which featured low solids concentration, C. thermocellum fermentation achieved faster rates and more complete conversion of FT-pretreated poplar than did SSF. Compared to SSF, solubilization by C. thermocellum was 30% higher after 4 days, and was over twice as fast on ball-milled FT-pretreated poplar. CONCLUSIONS: XMG removal trends were similar between feedstocks whereas glucan conversion trends were significantly different, suggesting that factors in addition to XMG removal impact amenability of glucan to enzymatic attack. Corn stover exhibited higher hydrolysis yields than bagasse or poplar, which could be due to higher removal of non-carbohydrate carbon. XMG in bagasse is more easily degraded than XMG in corn stover and poplar. Conversion of FT-pretreated substrates at low concentration was faster and more complete for C. thermocellum than for SSF. PMID- 22812931 TI - ENDOR evidence of electron-H2 interaction in a fulleride embedding H2. AB - An endofulleropyrrolidine, with H2 as a guest, has been reduced to a paramagnetic endofulleride radical anion. The magnetic interaction between the electron delocalized on the fullerene cage and the guest H2 has been probed by pulsed ENDOR. The experimental hyperfine couplings between the electron and the H2 guest were measured, and their values agree very well with DFT calculations. This agreement provides clear evidence of magnetic communication between the electron density of the fullerene host cage and H2 guest. The ortho-H2/para-H2 interconversion is revealed by temperature-dependent ENDOR measurements at low temperature. The conversion of the paramagnetic ortho-H2 to the diamagnetic para H2 causes the ENDOR signal to decrease as the temperature is lowered due to the spin catalysis by the paramagnetic fullerene cage of the radical anion fulleride. PMID- 22812932 TI - The subjective effects of cocaine: relationship to years of cocaine use and current age. AB - BACKGROUND: Little is known about whether the duration of cocaine use or an individual's age may influence the acute effects of cocaine, patterns of use, and specific treatment needs. OBJECTIVES: This post hoc analysis determined whether the duration of cocaine use or current age influenced the acute subjective response to cocaine. Data from four smoked cocaine self-administration laboratory studies were combined and analyzed to determine whether the subjective effects of a 25-mg smoked cocaine dose varied as a function of years of cocaine use or current age. METHODS: Thirty-six nontreatment-seeking healthy cocaine users (ages 32-49) were admitted to studies lasting from 12 to 105 days. Participants rated the subjective effects of each cocaine dose from 0 to 100 by completing a computerized self-report visual analogue scale (VAS). The main outcome measures were the change in VAS ratings between a baseline placebo dose and the first 25 mg dose of smoked cocaine. RESULTS: No significant relationship was found between the subjective effects of cocaine and years of cocaine use (mean 20.9, range 5 30) or current age (mean 41.1, range 32-49). CONCLUSION: Among long-term cocaine users between the ages of 32 and 49, the acute subjective effects of cocaine did not vary as a function of years of cocaine use or current age. SCIENTIFIC SIGNIFICANCE: These data fail to support the incentive sensitization theory for addiction by Robinson and Berridge, as cocaine "liking" and "wanting" remained the same regardless of age or years of cocaine use. PMID- 22812933 TI - Resident strategies for making a life in a nursing home: a qualitative study. AB - AIM: To identify strategies that older adults use to adapt to live in long-term care. BACKGROUND: The use of long-term care services has risen and this trend is expected to continue as the population reaches old age. Moving into a long-term care setting has been documented internationally as an overwhelming life change for many older adults. It has been observed that residents adjust differently over time, but the basis for these differences needs further exploration. DESIGN: A qualitative design using grounded theory method was employed. METHODS: A total of in-depth interviews were conducted in October 2008-February 2009 with a sample of 21 participants. Participants ranged in age from 65-93 years, 81% women and 19% men; mainly Caucasian with one African American and one Hispanic. Length of stay ranged from 3 days to over 9 years living in long-term care so that all stages of adjustment were included in the study. Ground theory method was used to analyse the data. FINDINGS: The results of this study yielded 21 facilitative strategies. The core category identified was personal resiliency, which served as the underpinning for the strategies used by the participants. Strategies were identified in making the decision to move into long-term care and in day-to-day living. CONCLUSION: Understanding the strategies that facilitate residents to make a successful transition to long-term care life will assist nurses to intervene in ways that are supportive. The strategies identified in this study may be used to develop interventions for residents that are having difficulty living in long-term care. Further exploration of how resiliency has an impact on strategies used by residents is clinically relevant, but further research is needed. PMID- 22813062 TI - Photo-Fenton reaction of graphene oxide: a new strategy to prepare graphene quantum dots for DNA cleavage. AB - Graphene quantum dots (GQDs) are great promising in various applications owing to the quantum confinement and edge effects in addition to their intrinsic properties of graphene, but the preparation of the GQDs in bulk scale is challenging. We demonstrated in this work that the micrometer sized graphene oxide (GO) sheets could react with Fenton reagent (Fe(2+)/Fe(3+)/H(2)O(2)) efficiently under an UV irradiation, and, as a result, the GQDs with periphery carboxylic groups could be generated with mass scale production. Through a variety of techniques including atomic force microscopy, X-ray photoelectron spectroscopy, gas chromatography, ultraperformance liquid chromatography-mass spectrometry, and total organic carbon measurement, the mechanism of the photo Fenton reaction of GO was elucidated. The photo-Fenton reaction of GO was initiated at the carbon atoms connected with the oxygen containing groups, and C C bonds were broken subsequently, therefore, the reaction rate depends strongly on the oxidization extent of the GO. Given the simple and efficient nature of the photo-Fenton reaction of GO, this method should provide a new strategy to prepare GQDs in mass scale. As a proof-of-concept experiment, the novel DNA cleavage system using as-generated GQDs was constructed. PMID- 22813063 TI - Gynecomastia: a rare complication of isoretinoin? AB - Isotretinoin is a retinoic acid derivative mostly used in the treatment of cystic acne vulgaris. The adverse effects of isotretinoin are well defined being the major limitation factor for its usage. The decrement of testosterone during isoretinoin treatment is defined in literature. We present a case with 20 years old man who developed gynecomastia after treatment with isotretinoin. To the best of our knowledge, this is the third report of the development of gynecomastia after isotretinoin treatment. PMID- 22813064 TI - Tilted face-centered-cubic supercrystals of PbS nanocubes. AB - We demonstrate a direct fabrication of PbS nanocube supercrystals without size selection pretreatment on the building blocks. Electron microscopic and synchrotron small angle X-ray scattering analyses confirm that nanocubes pack through a tilted face-centered-cubic (fcc) arrangement, that is, face-to-face along the <110>(super) direction, resulting in a real packing efficiency of as high as ~83%. This new type of superstructure consisting of nanocubes as building blocks, reported here for the first time, is considered the most stable surfactant-capped nanocube superstructure determined by far. PMID- 22813065 TI - Relationship between the neonatal white blood cell count and histologic chorioamnionitis in preterm newborns. AB - OBJECTIVE: The aim was to examine the relationship between neonatal white blood cell (WBC) count and the diagnosis of histologic chorioamnionitis (HCA). DESIGN: We measured WBC, a widely used marker of inflammation, to evaluate whether the values at birth were associated with HCA. SETTING: NICU, Department of Pediatrics of Padua University, Padua, Italy. SUBJECTS: WBC count was evaluated in 71 preterm neonates (<32 weeks of gestation) with HCA and in a control group without HCA on day 1, 3, and 6 after delivery. Logistic regression analysis and diagnostic accuracy analysis were used to assess the association between WBC counts and HCA. MAIN RESULTS: WBC levels were significantly higher in infants with HCA than in those without HCA (Median IQR, WBC (x10(9)/l): day 1, 13.2 (6.2 21.8) vs 8.1 (6-11.4), p < 0.001; day 3, 17.4 (11.4-26.9) vs 6.3 (5.2-8.3), p < 0.001; day 6, 18.4 (11.1-31) vs 6.5 (4.4-9), p < 0.0001). The neonatal WBC count on the third day of life was the most sensitive parameter associated with HCA (sensitivity: 0.80; specificity: 0.88). The cut-off value based on the ROC curve was 10 (x10(9)/l). CONCLUSIONS: WBC count in the third day of life is strongly associated with HCA. PMID- 22813066 TI - 'Slipping through the cracks': policy implications of delays in HIV treatment seeking. AB - Public health initiatives to 'test and treat' HIV-infected persons require understanding HIV care seeking. A study of 101 HIV-infected women receiving anti retroviral medications in Kampala, Uganda, examined barriers to HIV care. Participants entered HIV/AIDS care late, despite knowing their risk and having sought care for symptoms. Over half of the participants (51%) reported delays of up to 5 years from when they suspected they were infected to seeking an HIV test. Some women reported that they did not perceive a need to be tested because they 'knew' they had HIV due to their partner's death from AIDS. Once tested, delays in entering HIV specific care ranged from less than 6 months to over 5 years. The most common reason reported for entering HIV care was the occurrence of serious or persistent symptoms. Late presentation for HIV care in this cohort is due to the inability of the medical system to link women to appropriate care. Women 'slip through the cracks' of this system, despite their care seeking behaviours. The inability to provide linkage to care is a challenge at the health system level that threatens the success of 'test and treat' protocols. PMID- 22813068 TI - Semantic and phonological information in sentence recall: converging psycholinguistic and neuropsychological evidence. AB - We present one experiment and a neuropsychological case study to investigate to what extent phonological and semantic representations contribute to short-term sentence recall. We modified Potter and Lombardi's (1990) intrusion paradigm, in which retention of a list interferes with sentence recall such that on the list a semantically related lure is presented, which is expected to intrude into sentence recall. In our version, lure words are either semantically related to target words in the sentence or semantically plus phonologically related. With healthy participants, intrusions are more frequent when lure and target overlap phonologically in addition to semantically than when they solely overlap semantically. When this paradigm is applied to a patient with a phonological short-term memory impairment, both lure types induce the same amount of intrusions. These findings indicate that usually phonological information is retained in sentence recall in addition to semantic information. PMID- 22813067 TI - Identification of nephropathy candidate genes by comparing sclerosis-prone and sclerosis-resistant mouse strain kidney transcriptomes. AB - BACKGROUND: The genetic architecture responsible for chronic kidney disease (CKD) remains incompletely described. The Oligosyndactyly (Os) mouse models focal and segmental glomerulosclerosis (FSGS), which is associated with reduced nephron number caused by the Os mutation. The Os mutation leads to FSGS in multiple strains including the ROP-Os/+. However, on the C57Bl/6J background the mutation does not cause FSGS, although nephron number in these mice are equivalent to those in ROP-Os/+ mice. We exploited this phenotypic variation to identify genes that potentially contribute to glomerulosclerosis. METHODS: To identify such novel genes, which regulate susceptibility or resistance to renal disease progression, we generated and compared the renal transcriptomes using serial analysis of gene expression (SAGE) from the sclerosis-prone ROP-Os/+ and sclerosis resistant C57-Os/+ mouse kidneys. We confirmed the validity of the differential gene expression using multiple approaches. We also used an Ingenuity Pathway Analysis engine to assemble differentially regulated molecular networks. Cell culture techniques were employed to confirm functional relevance of selected genes. RESULTS: A comparative analysis of the kidney transcriptomes revealed multiple genes, with expression levels that were statistically different. These novel, candidate, renal disease susceptibility/resistance genes included neuropilin2 (Nrp2), glutathione-S-transferase theta (Gstt1) and itchy (Itch). Of 34 genes with the most robust statistical difference in expression levels between ROP-Os/+ and C57-Os/+ mice, 13 and 3 transcripts localized to glomerular and tubulointerstitial compartments, respectively, from micro-dissected human FSGS biopsies. Network analysis of all significantly differentially expressed genes identified 13 connectivity networks. The most highly scored network highlighted the roles for oxidative stress and mitochondrial dysfunction pathways. Functional analyses of these networks provided evidence for activation of transforming growth factor beta (TGFbeta) signaling in ROP-Os/+ kidneys despite similar expression of the TGFbeta ligand between the tested strains. CONCLUSIONS: These data demonstrate the complex dysregulation of normal cellular functions in this animal model of FSGS and suggest that therapies directed at multiple levels will be needed to effectively treat human kidney diseases. PMID- 22813069 TI - Do reading processes differ in transparent versus opaque orthographies? A study of acquired dyslexia in Welsh/English bilinguals. AB - In English, the relationship between the written and spoken forms of words is relatively opaque, leading to proposals that skilled reading requires two procedures: (a) a sublexical grapheme/phoneme conversion process allowing the correct reading of regular words (CAT) and new or pseudowords (ZAT); (b) a lexical process necessary to read irregular words accurately (TWO) and assumed to be the dominant process for familiar words. However, it has been argued that the sublexical process may be sufficient in highly transparent languages such as Welsh. If this is the case, damage to the sublexical process may lead to more severe deficits in transparent languages due to the lack of an alternative lexical process. To test this hypothesis, we compared Welsh and English oral reading and written-word recognition and comprehension in seven bilingual stroke participants with comparably impaired pseudoword reading in English and Welsh. Performance was remarkably similar across languages. Irrespective of the language tested, words were read more accurately than pseudowords. Lexical decision and word comprehension were as accurate in Welsh and in English, and when imageability effects were present they were of a similar size in both languages. This study does not support the hypothesis that orthographic transparency determines the nature of cognitive reading processes, but rather suggests that readers develop a sight vocabulary through reading experience irrespective of orthographic transparency. PMID- 22813070 TI - Selective impairment of masculine gender processing: evidence from a German aphasic. AB - The present single case study describes the performance of the German aphasic E.M. who exhibited a severe impairment of grammatical gender processing in masculine nouns but relatively spared performance regarding feminine and neuter ones. This error pattern was assessed with tests of gender assignment to orally or visually presented words, with oral or written responses, and with tests of gender congruency decision on noun phrases. The pattern occurred across tasks and modalities, thus suggesting a gender-specific impairment at a modality independent level of processing. It was sensitive to frequency, thus supporting the assumption that access to gender features as part of grammatical processing is frequency sensitive. Besides being the first description of a gender-specific impairment in an aphasic subject, the data therefore have implications regarding the modelling of representation and processing of grammatical gender information within the mental lexicon. PMID- 22813076 TI - Uptake of galaxolide, tonalide, and triclosan by carrot, barley, and meadow fescue plants. AB - Many xenobiotics entering wastewater treatment plants are known to be persistent during wastewater treatment and tend to adsorb to sewage sludge. The application of sewage sludge as fertilizer in agriculture may pose the risk of an incorporation of xenobiotics in the cultivated plants and, finally, an inclusion into the food chain. This study was performed to investigate the uptake of common sewage sludge contaminants, galaxolide, tonalide, and triclosan, by plants used for human consumption and livestock feeding. Barley, meadow fescue, and four carrot cultivars were sown and grown in spiked soils under greenhouse conditions. After harvesting the plants, roots and leaves were analyzed separately, and the respective bioconcentration factors were calculated. In carrots, a concentration gradient of the xenobiotics became evident that decreased from the root peel via root core to the leaves. A significant influence of the differing root lipid contents on the uptake rates cannot be supported by our data, but the crucial influence of soil organic carbon content was confirmed. Barley and meadow fescue roots incorporated higher amounts of the target substances than carrots, but translocation into the leaves was negligible. The results indicated that an introduction of persistent semi- and nonpolar xenobiotics into the food chain via edible plants like carrots could be of certain relevance when sludge is applied as fertilizer. Due to low rates found for the translocation of the xenobiotics into the aerial plant parts, the entrance pathway into food products via feeding livestock is less probable. PMID- 22813077 TI - Accommodating unwelcome guests in inorganic layered hosts: inclusion of chloranil in a layered double hydroxide. AB - The host-guest chemistry of most inorganic layered solids is limited to ion exchange reactions. The guest species are either cations or anions to compensate for the charge deficit, either positive or negative, of the inorganic layers. Here, we outline a strategy to include neutral molecules like ortho- and para chloranil, that are known to be good acceptors in donor-acceptor or charge transfer complexes, within the galleries of a layered solid. We have succeeded in including neutral ortho- and para-chloranil molecules within the galleries of an Mg-Al layered double hydroxide (LDH) by using charge-transfer interactions with preintercalated p-aminobenzoate ions as the driving force. The p-aminobenzoate ions are introduced in the Mg-Al LDH via ion exchange. The intercalated LDH can adsorb ortho- and para-chloranil from chloroform solutions by forming charge transfer complexes with the p-aminobenzoate anions present in the galleries. We use X-ray diffraction, spectroscopy, and molecular dynamics simulations to establish the nature of interactions and arrangement of the charge-transfer complex within the galleries of the layered double hydroxide. PMID- 22813078 TI - Immunisation status and its predictors among children of HIV-infected people in Kolkata. AB - World Health Organization and United Nations International Children's Emergency Fund have strongly recommended a sustained coverage of universal immunisation among all children against tuberculosis, polio, diphtheria, pertussis, tetanus and measles. In India, these vaccines under the universal immunisation programme are made available absolutely free of cost to all children through the public health system. Information regarding immunisation coverage among HIV exposed children in India is still very limited. The objective of this study was to estimate the proportion of children of people living with HIV who had been completely immunised by the age of 12 months and to find predictors of complete immunisation. A community-based cross-sectional survey was conducted in the Kolkata Metropolitan Area between 15 June and 14 September 2009 using a pre structured interview schedule. Data were analysed from 256 care-givers of children (85.5% response rate) whose parents were randomly selected from the Bengal Network of HIV-positive people. Multiple logistic regression was used to estimate and test associations of predictors with complete immunisation. The percentage of children of people living with HIV completely immunised at the age of 12 months was 73.0% (67.3% to 78.1%), which was not significantly different from that for all children at 12 months. Mothers having received antenatal care [OR (odds ratio): 7.29; 95% confidence intervals (CI): 2.39-22.25], mothers having postprimary education (OR: 3.37; 95% CI: 1.45-7.81), children of Hindu and Christian religion (OR: 3.74; 95% CI: 1.63-8.62), children not belonging to scheduled castes, tribes and 'other backward classes' (OR: 2.08; 95% CI: 1.02 4.25) were significant independent predictors of complete immunisation status of these children. This emphasises the imperative need for up-scaling of antenatal care among the pregnant mothers to ensure complete immunisation among their children. A special focus on girl child education should also be implemented to empower future mothers for a sustained improvement of child immunisation in the long-run. The current national immunisation programme should focus on the children from the Muslim community and those belonging to scheduled castes, tribes and other backward classes to improve coverage. PMID- 22813079 TI - Sport and exercise medicine and the Olympic health legacy. AB - London 2012 is the first Olympic and Paralympic Games to explicitly try and develop socioeconomic legacies for which success indicators are specified - the highest profile of which was to deliver a health legacy by getting two million more people more active by 2012. This editorial highlights how specialists in Sport and Exercise Medicine can contribute towards increasing physical activity participation in the UK, as well as how the National Centre for Sport and Exercise Medicine might be a useful vehicle for delivering an Olympic health legacy. Key challenges are also discussed such as acquisition of funding to support new physical activity initiatives, appropriate allocation of resources, and how to assess the impact of legacy initiatives. PMID- 22813080 TI - Upper-body kinematics in team-handball throw, tennis serve, and volleyball spike. AB - Overarm movements are essential skills in many different sport games; however, the adaptations to different sports are not well understood. The aim of the study was to analyze upper-body kinematics in the team-handball throw, tennis serve, and volleyball spike, and to calculate differences in the proximal-to-distal sequencing and joint movements. Three-dimensional kinematic data were analyzed via the Vicon motion capturing system. The subjects (elite players) were instructed to perform a team-handball jump throw, tennis serve, and volleyball spike with a maximal ball velocity and to hit a specific target. Significant differences (P < 0.05) between the three overarm movements were found in 17 of 24 variables. The order of the proximal-to-distal sequencing was equal in the three analyzed overarm movements. Equal order of the proximal-to-distal sequencing and similar angles in the acceleration phase suggest there is a general motor pattern in overarm movements. However, overarm movements appear to be modifiable in situations such as for throwing or hitting a ball with or without a racket, and due to differences at takeoff (with one or two legs). PMID- 22813082 TI - Synthesis of ultralong copper nanowires for high-performance transparent electrodes. AB - Cu nanowires hold great promise for the fabrication of low-cost transparent electrodes. However, their current synthesis is mainly performed in aqueous media with poor nanowire dispersibility. We report herein the novel synthesis of ultralong single-crystalline Cu nanowires with excellent dispersibility, providing an excellent candidate material for high-performance transparent electrode fabrication. PMID- 22813081 TI - Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials. AB - Liver transplant recipients are at high risk of developing acute and chronic renal failure. Moreover, introduction of the model for end-stage liver disease (MELD) score for primary allocation of liver grafts favors patients with pretransplant kidney dysfunction, which in turn have a higher risk of posttransplant renal failure. Calcineurin inhibitors (CNI) further increase the risk of renal failure and therefore sparing CNI with the use of mycophenolate mofetil (MMF) may improve renal function. MMF may either be used de novo in the immediate posttransplant period in combination with low-dose CNI (scenario 1) or patients that receive immunosuppression based on CNI may be converted to MMF in combination with minimization or elimination of CNI (scenario 2). Although many retrospective cohort studies and nonrandomized trials have implicated efficacy of this approach the evidence from randomized controlled studies has not been summarized. In the current review we report the results of a systematic review and meta-analysis of randomized controlled trials. PMID- 22813083 TI - Phase behavior, self-assembly, and emulsification of Tween 80/water mixtures with limonene and perfluoromethyldecalin. AB - The phase behavior, microstructure, and emulsification of polyoxyethylene (20) sorbitan monooleate (Tween 80), water, and d-limonene (LM) or perfluoromethyldecalin (PFMD) has been studied by small-angle X-ray scattering and polarizing optical microscopy. In the Tween 80/water binary system, a micellar solution (L(1)), a hexagonal (H(1)) phase, and a water-swellable isotropic surfactant liquid (L(2)) phase are successively formed at 25 degrees C. LM can be solubilized into all of the phases formed by Tween 80/water mixtures, whereas no solubilization of PFMD occurs. The L(2) phase was found by small-angle neutron scattering to be bicontinuous with low interfacial curvature. Added water swells and amplifies the pre-existing amphiphilic structure. The stability of oil-in-H(1) complex emulsions is found to be sensitive to changes in structure that accompany solubilization. PMID- 22813084 TI - Evaluation of the diagnostic algorithm consisting of enzyme immunoassay for toxins and polymerase chain reaction, for the diagnosis of Clostridium difficile associated diarrhoea. AB - A total of 1631 stool specimens were tested for Clostridium difficile toxins A and B using an enzyme immunoassay (EIA). C. difficile toxin was detected in 191 (11.7%, 191/1631) cases by EIA. Among the remaining 1440 cases, 102 cases in patients with either antibiotic-associated diarrhoea or hospitalized patients with unexplained leukocytosis (> 15,000/mm3) and fever (>= 38 degrees C) even though they did not meet the criteria for diarrhoea, were further assessed using a polymerase chain reaction (PCR) for the toxin B gene (tcdB). Thirty-four cases were tcdB-positive (33.3%, 34/102). A total of 225 cases (13.8%, 225/1631) had a stool test result positive for C. difficile toxins. Among these, 145 cases were diagnosed with C. difficile-associated diarrhoea (CDAD): 80.7% (117/145) using the EIA and 19.3% (28/145) using the PCR. In our study, the 2-test algorithm including EIA-toxin assay and PCR test made a more accurate diagnosis of CDAD. Furthermore, the application of clinical situations may be effective in the selection of patients who need confirmatory testing. PMID- 22813085 TI - Roy's adaptation model-guided education for adaptation to chronic obstructive pulmonary disease. AB - AIM: This article is a report of the effects of Roy's adaptation model-based patient education on physical and psychosocial adaptation of patients with chronic obstructive pulmonary disease. BACKGROUND: Patients with chronic obstructive pulmonary disease abound in Turkey, as they do worldwide. Patient education could help in the adaptation of patients with chronic obstructive pulmonary disease to the disease, as it has with other long-term diseases. DESIGN: The study adapted a quasi-experimental design, with a comparison between an intervention group and a control group. METHODS: Sixty-five patients with obstructive pulmonary disease participated in this study. The data were collected between December 2008-January 2010. The data collection tool comprised an adaptation of a Roy's adaptation model-based evaluation form and perceived social support from family and friends scale. The intervention group received oral and written education based on Roy's adaptation model, while the control group received a routine follow-up. Data were analysed with paired t-test and analysis of covariance (ancova). FINDINGS: The results indicate that education given according to Roy's adaptation model increases adaptation to disease in three modes (physiologic, self-concept and role-function mode). In addition, taking into account interdependence mode as Roy's adaptation model's fourth mode, a statistically significant increase was observed in social support from friends but not from family. CONCLUSION: The more intervention for improving interpersonal support - especially perceived as coming from family - the more using Roy's adaptation model to educate patients with chronic obstructive pulmonary disease could benefit them to increase adaptation to the disease. PMID- 22813086 TI - Young adults' favorable perceptions of snus, dissolvable tobacco products, and electronic cigarettes: findings from a focus group study. AB - OBJECTIVES: We explored young adults' perceptions of snus (spitless moist snuff packed in porous bags), dissolvable tobacco products, and electronic cigarettes and intention to try these products. METHODS: We conducted 11 focus group discussions involving a total of 66 young adults (18-26 years old) on these new tobacco products (e.g., harmfulness, potential as quit aids, intention to try) held between July and December 2010. We analyzed discussions using a thematic approach. RESULTS: Participants generally reported positive perceptions of the new products, particularly because they came in flavors. Few negative perceptions were reported. Although some participants believed these products were less harmful than cigarettes and helpful in quitting smoking, others thought the opposite, particularly regarding electronic cigarettes. Participants also commented that these products could be gateways to cigarette smoking. Half of the participants, including a mix of smokers and nonsmokers, admitted they would try these products if offered by a friend. CONCLUSIONS: Young adults perceive the new tobacco products positively and are willing to experiment with them. Eliminating flavors in these products may reduce young adults' intentions to try these products. PMID- 22813087 TI - e-Cigarette awareness, use, and harm perceptions in US adults. AB - OBJECTIVES: We estimated e-cigarette (electronic nicotine delivery system) awareness, use, and harm perceptions among US adults. METHODS: We drew data from 2 surveys conducted in 2010: a national online study (n = 2649) and the Legacy Longitudinal Smoker Cohort (n = 3658). We used multivariable models to examine e cigarette awareness, use, and harm perceptions. RESULTS: In the online survey, 40.2% (95% confidence interval [CI] = 37.3, 43.1) had heard of e-cigarettes, with awareness highest among current smokers. Utilization was higher among current smokers (11.4%; 95% CI = 9.3, 14.0) than in the total population (3.4%; 95% CI = 2.6, 4.2), with 2.0% (95% CI = 1.0, 3.8) of former smokers and 0.8% (95% CI = 0.35, 1.7) of never-smokers ever using e-cigarettes. In both surveys, non Hispanic Whites, current smokers, young adults, and those with at least a high school diploma were most likely to perceive e-cigarettes as less harmful than regular cigarettes. CONCLUSIONS: Awareness of e-cigarettes is high, and use among current and former smokers is evident. We recommend product regulation and careful surveillance to monitor public health impact and emerging utilization patterns, and to ascertain why, how, and under what conditions e-cigarettes are being used. PMID- 22813088 TI - Poverty, housing, and the rural slum: policies and the production of inequities, past and present. AB - We studied historical materials to examine the conditions that gave rise to California's rural slums, the consequences of their emergence, and how interpretations of housing, health, and welfare policies by government officials, and public health officials in particular, produced health inequities for residents of these communities. For more than a century, successive groups of immigrants and domestic migrant laborers have worked on California's farms and faced numerous challenges, among them a lack of safe and affordable housing, poor working conditions, and denial of public services. Although these experiences are not new, nor are they unique to agricultural workers, they illustrate a longer history in which inequities and injustices have been rooted in the exploitation and disposability of labor. Ameliorating or even redressing inequities will require understanding the social determinants of health through ecological approaches that can overcome the historical, social, and political causes of inequity. PMID- 22813089 TI - The return of rainbow diet pills. AB - The US Food and Drug Administration (FDA) has recently warned consumers about the risks of weight loss supplements adulterated with multiple pharmaceutical agents. Some of these supplements combine potent anorectics, such as amphetamines derivatives, with benzodiazepines, beta-blockers, and other medications to suppress the anorectics' adverse effects. These weight loss supplements represent the most recent generation of rainbow diet pills, named for their bright and varied colors, which date back more than 70 years. Beginning in the 1940s, several US pharmaceutical firms aggressively promoted rainbow pills to physicians and patients. By the 1960s the pills had caused dozens of deaths before the FDA began removing them from the US market. We used a variety of original resources to trace these deadly pills from their origins in the United States to their popularity in Spain and Brazil to their reintroduction to the United States as weight loss dietary supplements. PMID- 22813090 TI - Local public health systems and the incidence of sexually transmitted diseases. AB - OBJECTIVES: We examined the associations of local public health system organization and local health department resources with county-level sexually transmitted disease (STD) incidence rates in large US health jurisdictions. METHODS: We linked annual county STD incidence data (2005-2008) to local health department director responses (n = 211) to the 2006 wave of the National Longitudinal Study of Local Public Health Systems, the 2005 national Local Health Department Profile Survey, and the Area Resource File. We used nested mixed effects regression models to assess the relative contribution of local public health system organization, local health department financial and resource factors, and sociodemographic factors known to be associated with STD incidence to county-level (n = 307) STD incidence. RESULTS: Jurisdictions with local governing boards had significantly lower county-level STD incidence. Local public health systems with comprehensive services where local health departments shoulder much of the effort had higher county-level STD rates than did conventional systems. CONCLUSIONS: More integration of system partners in local public health system activities, through governance and interorganizational arrangements, may reduce the incidence and burden of STDs. PMID- 22813091 TI - Trends in Michigan early adolescent immunization: 2006-2008. AB - OBJECTIVES: We have described vaccine coverage of Michigan young adolescents immunized with tetanus, diphtheria, and pertussis; meningococcal conjugate; and human papillomavirus vaccines during 2006-2008. METHODS: We obtained data from the Michigan Care Improvement Registry, a state-based immunization information system that included more than 57 million vaccination records. We examined 3 overlapping cohorts of 11- and 12-year-old children (n > 350 000 in each) to assess temporal trends in vaccination coverage, characteristics of those immunized, funding sources, and vaccination sites. RESULTS: Vaccine uptake increased during 2006 through 2008, peaking in the summer months. More than half of children receiving more than 1 vaccine received the vaccines simultaneously. Older age, receipt of Medicaid, and prior completion of early childhood immunizations were associated with greater odds of vaccination. CONCLUSIONS: Vaccine coverage among Michigan young adolescents is increasing but continues to be relatively low. Coverage of 11- and 12-year-old children may improve with efforts to encourage vaccination at all health care visits, an increase in public funding in support of adolescent vaccination, and continued monitoring of adolescent vaccination levels through school-based assessments. PMID- 22813092 TI - Identifying the core elements of effective community health worker programs: a research agenda. AB - Community health workers (CHWs) are increasingly being incorporated into health programs because they are assumed to effectively deliver health messages in a culturally relevant manner to disenfranchised communities. Nevertheless, the role of CHWs-who they are, what they do, and how they do it-is tremendously varied. This variability presents a number of challenges for conducting research to determine the effectiveness of CHW programs, and translating research into practice. We discuss some of these challenges and provide examples from our experience working with CHWs. We call for future research to identify the "core elements" of effective CHW programs that improve the health and well-being of disenfranchised communities. PMID- 22813093 TI - The impact of oral health on the academic performance of disadvantaged children. AB - OBJECTIVES: We measured the impact of dental diseases on the academic performance of disadvantaged children by sociodemographic characteristics and access to care determinants METHODS: We performed clinical dental examinations on 1495 disadvantaged elementary and high school students from Los Angeles County public schools. We matched data with academic achievement and attendance data provided by the school district and linked these to the child's social determinants of oral health and the impact of oral health on the child's school and the parents' school or work absences. RESULTS: Students with toothaches were almost 4 times more likely to have a low grade point average. About 11% of students with inaccessible needed dental care missed school compared with 4% of those with access. Per 100 elementary and high school-aged children, 58 and 80 school hours, respectively, are missed annually. Parents averaged 2.5 absent days from work or school per year because of their children's dental problems. CONCLUSIONS: Oral health affects students' academic performance. Studies are needed that unbundle the clinical, socioeconomic, and cultural challenges associated with this epidemic of dental disease in children. PMID- 22813094 TI - Comparison of current US risk strategy to screen for hepatitis C virus with a hypothetical targeted birth cohort strategy. AB - OBJECTIVES: We compared the theoretical performance of a 1-time, birth cohort strategy with the currently recommended risk strategy for screening for hepatitis C virus (HCV) infection, which is undetected in an estimated 75% of 4 million affected people in the United States. METHODS: We applied current American Association for the Study of Liver Disease risk screening guidelines and a targeted birth cohort strategy to National Health and Nutrition Examination Survey data from 2003 to 2006 to estimate their performance in identifying HCV cases. RESULTS: Risk guidelines would recommend testing 25% of the US population aged 20 years or older and, if fully implemented, identify 82% of the projected HCV-exposed population. A targeted birth cohort (1946-1964) strategy would test 45% of the same population and identify 76% of the projected HCV population. CONCLUSIONS: In this ideal-world simulation, birth year and risk screening had similar theoretical performances for predicting HCV infection. However, actual implementation of risk screening has not achieved its theoretical performance, and birth cohort screening might increase HCV testing rates. PMID- 22813095 TI - Iridal coloboma induces dyscoria during miosis in FLS mice. AB - OBJECTIVE: Fatty liver Shionogi (FLS) mice exhibit characteristic retinochoroidal coloboma because of a failure in fusion of the embryonic optic fissure. However, the same pathogenesis should result in iridal coloboma that has not been reported in this strain. The purpose of this study was to describe the physiologic and morphometric changes in iridal tissue involved in ocular coloboma in FLS mice. PROCEDURES: The miotic response after light exposure was evaluated in three strains of live mice, and the shape and location of the pupil were judged macroscopically. Subsequently, macroscopic abnormalities in the anterior segment and fundus were observed postmortem in all mice. During miotic and mydriatic responses in the eyes of live male FLS mice with dyscoric and normal pupils, each iris was measured in four radial directions. The enucleated eyes were examined morphometrically and histologically in both sexes of FLS mice. RESULTS: Inferior corectopia upon light-induced miosis was clearly detected in live FLS mice. The deviated pupils were not round but oval-shaped. Clinical and postmortem examination revealed that all dyscoric eyes had hypoplastic and dysfunctional irides inferiorly in FLS mice. Histopathological examination confirmed that both the dilator and sphincter muscles and iris stroma were quantitatively diminished in the affected inferior iris. Meanwhile, the rate of fundus (retinochoroidal) coloboma in eyes exhibiting dyscoria was remarkably high, although some dyscoric eyes had no fundus coloboma. CONCLUSIONS: Fatty liver Shionogi mice had iridal coloboma, resulting in inferior corectopia upon light-induced miosis as an indicator of ocular coloboma. PMID- 22813097 TI - Hyperbaric oxygen therapy for the management of chronic wounds. AB - Wound healing is actually a complex, precisely coordinated interaction between inflammatory cells and mediators, establishing significant overlap between the phases of wound healing. Chronic wounds are defined as wounds that do not follow the well-defined stepwise process of physiologic healing. The true incidence and economic impact of chronic wounds are difficult to assess because of the wide range of causative diseases and available treatment options. Despite multiple simultaneous and sequential therapeutic approaches, chronic wounds are highly resistant to treatment and are often indolent or even slowly progressive. Hyperbaric oxygen therapy (HBOT) has been explored as a treatment modality for chronic wounds because of its potential to promote healing and reduce bioburden in the wound bed. Multiple potential beneficial effects for wound healing have been demonstrated in various laboratory studies and experimental animal models. In this manuscript, HBOT, its mechanism of action, adverse effects and usage in diabetic and nondiabetic chronic wounds have been reviewed. PMID- 22813096 TI - Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke? AB - BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1.56; 95% confidence interval 1.43-1.72; P < 0.001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1.31; 95% confidence interval 1.18-1.47; P = 0.006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1.01; 95% CI 0.90-1.14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment. PMID- 22813205 TI - Metabolomic fingerprinting employing DART-TOFMS for authentication of tomatoes and peppers from organic and conventional farming. AB - The rapidly growing demand for organic food requires the availability of analytical tools enabling their authentication. Recently, metabolomic fingerprinting/profiling has been demonstrated as a challenging option for a comprehensive characterisation of small molecules occurring in plants, since their pattern may reflect the impact of various external factors. In a two-year pilot study, concerned with the classification of organic versus conventional crops, ambient mass spectrometry consisting of a direct analysis in real time (DART) ion source and a time-of-flight mass spectrometer (TOFMS) was employed. This novel methodology was tested on 40 tomato and 24 pepper samples grown under specified conditions. To calculate statistical models, the obtained data (mass spectra) were processed by the principal component analysis (PCA) followed by linear discriminant analysis (LDA). The results from the positive ionisation mode enabled better differentiation between organic and conventional samples than the results from the negative mode. In this case, the recognition ability obtained by LDA was 97.5% for tomato and 100% for pepper samples and the prediction abilities were above 80% for both sample sets. The results suggest that the year of production had stronger influence on the metabolomic fingerprints compared with the type of farming (organic versus conventional). In any case, DART-TOFMS is a promising tool for rapid screening of samples. Establishing comprehensive (multi sample) long-term databases may further help to improve the quality of statistical classification models. PMID- 22813206 TI - Ab initio kinetics for thermal decomposition of CH3N*NH2, cis-CH3NHN*H, trans CH3NHN*H, and C*H2NNH2 radicals. AB - The thermal decomposition of the CH(3)N(*)NH(2), cis-CH(3)NHN(*)H, trans CH(3)NHN(*)H, and C(*)H(2)NNH(2) radicals, which are the four radical products from the H-abstraction reactions of monomethylhydrazine, were theoretically studied by using ab initio Rice-Ramsperger-Kassel-Marcus (RRKM) transition-state theory and master equation analysis. Various decomposition pathways were identified by using either the QCISD(T)/cc-pVinfinityZ//CASPT2/aug-cc-pVTZ or the QCISD(T)/cc-pVinfinityZ//B3LYP/6-311++G(d,p) quantum chemistry methods. The results reveal that the beta-scission of NH(2) to form methyleneimine is the predominant channel for the decomposition of the C(*)H(2)NNH(2) radical due to its small energy barrier of 13.8 kcal mol(-1). The high pressure limit rate coefficient for the reaction is fitted by 3.88 * 10(19)T(-1.672) exp(-9665.13/T) s(-1). In addition, the pressure dependent rate coefficients exhibit slight temperature dependence at temperatures of 1000-2500 K. The cis-CH(3)NHN(*)H and trans-CH(3)NHN(*)H radicals are the two distinct spatial isomers with an energy barrier of 26 kcal mol(-1) for their isomerization. The beta-scission of CH(3) from the cis-CH(3)NHN(*)H radical to form trans-diazene has an energy barrier of 35.2 kcal mol(-1), and the beta-scission of CH(3) from the trans-CH(3)NHN(*)H radical to form cis-diazene has an energy barrier of 39.8 kcal mol(-1). The CH(3)N(*)NH(2) radical undergoes the beta-scission of methyl hydrogen and amine hydrogen to form CH(2)?NNH(2), trans-CH(3)N?NH, and cis-CH(3)N?NH products, with the energy barriers of 42.8, 46.0, and 50.2 kcal mol(-1), respectively. The dissociation and isomerization rate coefficients for the reactions were calculated via the E/J resolved RRKM theory and multiple-well master equation analysis at temperatures of 300-2500 K and pressures of 0.01-100 atm. The calculated rate coefficients associated with updated thermochemical property data are essential components in the development of kinetic mechanisms for the pyrolysis and oxidation of MMH and its derivatives. PMID- 22813207 TI - A bidirectional S(E)' strategy for 1,5-syn and 1,5-anti stereocontrol toward the synthesis of complex polyols. AB - Studies report a bidirectional S(E)' strategy applicable for the stereocontrolled synthesis of nonracemic 1,5-syn and 1,5-anti diols and their derivatives. Nonracemic 1,3,2-diazaborolidine auxiliaries are incorporated by chemoselective tin-boron exchange to provide reactive allylic boranes. The convergent pathway utilizes sequential reactions with two aldehydes producing stereochemical outcomes from cyclic, closed, and open transition state preferences, respectively. Synthesis of fragment 16 of peloruside A is accomplished in four steps from readily available aldehydes 9 and 13. PMID- 22813208 TI - Extra-articular manifestations in a community-based sample of patients with rheumatoid arthritis: incidence and relationship to treatment with TNF inhibitors. AB - OBJECTIVES: To determine the incidence of severe extra-articular rheumatoid arthritis (ExRA) in a community-based cohort of RA patients, and to evaluate whether treatment with tumour necrosis factor (TNF) inhibitors has any effect on the risk of ExRA. METHODS: In a review of clinical records from 1 July 1997 to 31 December 2004, severe ExRA manifestations were classified according to predefined criteria. Patients were censored at the development of ExRA, death, emigration, or 31 December 2004. Exposure to anti-TNF treatment has continuously and independently been recorded as part of a regional follow-up system. RESULTS: During treatment with TNF inhibitors, there were two patients with new onset of ExRA in 408 person-years at risk (pyr) [0.49/100 pyr, 95% confidence interval (CI) 0.06-1.77]. Among those without anti-TNF treatment there were 63 patients with ExRA in 5425 pyr (1.16/100 pyr, 95% CI 0.89-1.49). The relative risk comparing those treated to those not treated with TNF inhibitors was 0.42 (95% CI 0.10-1.73). CONCLUSION: Our data show a lower incidence of ExRA in patients treated with TNF inhibitors but further studies with a larger sample size are needed for a more accurate estimate of the size of the effect. PMID- 22813209 TI - Prospective, randomized, controlled comparison of SYSTANE UD eye drops versus VISINE INTENSIV 1% EDO eye drops for the treatment of moderate dry eye. AB - PURPOSE: The aim of this prospective, randomized, clinical, single-center study was to compare the safety and efficacy of 2 ocular surface lubricant eye drops: preservative-free hydroxypropyl (HP)-Guar (SYSTANE UD((r))) eye drops versus preservative-free Tamarindus indica seed polysaccharide (TSP) 1% (VISINE INTENSIV 1% EDO((r))) eye drops. METHODS: Fifty-six eyes of 28 patients with moderate keratoconjunctivitis sicca (DEWS severity level 2) were enrolled in the trial. Patients were randomized for 2 treatment groups (SYSTANE UD eye drops vs. VISINE INTENSIV 1% EDO eye drops). The eye drops in both groups were applied 5 times per day for 3 months. Statistical analyses were performed using StatisticaTM software (Mann-Whitney U-test and Wilcoxon test). P-Values<0.05 were considered significant. RESULTS: After 3 months of treatment the patients of both groups had subjective benefit in the relief of symptoms of dry eye disease evaluated by the Ocular Surface Disease Index (OSDI) questionnaire score. Patients treated with HP Guar and TSP showed improvements in tear film stability measured by tear break-up time (TBUT), which are statistically significant in the HP-Guar group (P=0.02). CONCLUSIONS: The results of this clinical trial show improvements of symptoms and signs in patients with moderate dry eye after the consistent use of preservative free HP-Guar and TSP lubricant eye drops. Both artificial tear formulations produce amelioration in tear film stability improving eye conditions and patient quality of life. HP-Guar seems to be slightly more effective in improving ocular surface protection by decreasing tear film evaporation. PMID- 22813210 TI - Unwitnessed magnet ingestion in a 5 year-old boy leading to bowel perforation after magnetic resonance imaging: case report of a rare but potentially detrimental complication. AB - BACKGROUND: The ingestion of non-food items in children is a relatively common event, often unwitnessed, unknown, and unreported. For those children brought in for medical evaluation, less than 10% require intervention, and only 1% require surgery. This, however, is not the case for magnet ingestion. Magnets, in plurality, can become attracted to one another through intestinal walls, causing a variety of surgical emergencies. CASE PRESENTATION: We present a case of unwitnessed multiple magnet ingestion in a 5 year-old boy who presented to the emergency department with the atypical chief complaint of neck pain. The diagnostic work-up including a neck magnetic resonance imaging (MRI) potentially led to bowel perforations managed definitely by a subsequent exploratory laparotomy. The child had an uneventful postoperative recovery and was discharged to home upon surgical recovery. CONCLUSIONS: Institutions should make all possible efforts to attempt to prevent such potential life-threatening circumstances. We propose a screening tool that can further enhance the care of children who cannot or do not report unwitnessed magnetic ingestion prior to MRI evaluation. PMID- 22813211 TI - Protonation and complexation properties of polyaromatic terdentate six-membered chelate ligands. AB - The successive protonation steps occurring in 2,2';6',2"-terpyridine (L1) are characterized by a strong affinity for the first entering proton (DeltaG(connect)(H,L1) = -17 kJ/mol) followed by allosteric anticooperativity (DeltaE(interaction)(H,H,L1) = 6 kJ/mol), a behavior mirrored by 2,6 bis(azaindolyl)pyridine (L2) despite the extension of the chelate ring size from five members (L1) to six members (L2; DeltaG(connect)(H,L2) = -28 kJ/mol and DeltaE(interaction)(H,H,L2) = 7 kJ/mol). On the contrary, 2,6-bis(8 quinolinyl)pyridine (L3) is less eager for the initial protonation (DeltaG(connect)(H,L3) = -10 kJ/mol), but the fixation of a second proton in [H2L3]2+ is driven to completion by positive cooperativity (DeltaE(interaction)(H,H,L3) = -5 kJ/mol). Because of its unusual ability to adopt a cis-cis conformation with a large affinity for the entering protons, L2 has been selected for exploring the reactivity of a terdentate fused six-membered chelate with labile metallic cations possessing increasing electrostatic factors along the series Mz+ = Li+ < Mg2+ ~ Zn2+ < Y3+. Spectroscopic, thermodynamic, and structural studies demonstrate that covalency is crucial for stabilizing the complexes [Zn(L2)n]2+. With the highly charged Y3+ cation, hydrolysis drastically competes with ligand complexation, but anhydrous conditions restore sufficient selectivity for the successful coordination of neutral fused six-membered polyaromatic terdentate chelates with large 4f-block cations. PMID- 22813212 TI - Self-assembled extracellular macromolecular matrices and their different osteogenic potential with preosteoblasts and rat bone marrow mesenchymal stromal cells. AB - Extracellular environment is a physical support that is critical to cell adhesion, migration, and differentiation. In this work, cell-derived matrices (CDMs) were obtained by separately culturing fibroblasts, preosteoblasts, and chondrocytes. The cells were grown on a coverslip and subjected to decellularization using detergents and enzymes. The resulting matrices were named fibroblast-derived matrix (FDM), preosteoblast-derived matrix (PDM), and chondrocyte-derived matrix (CHDM). We hypothesize that the unique compositional and structural feature of each CDM provides cells with a distinct microenvironment capable of functioning as a different signaling cue in the regulation of preosteoblast and rat bone marrow mesenchymal stromal cell (BMSC) osteogenic differentiation. SEM images show that each cell type creates its unique surface texture in a fibrillar structure. Three major macromolecules, fibronectin, type I collagen, and laminin, were clearly identified using both immunofluorescence and Western blot, in which FDM exhibited a much stronger signal of each ECM component than that of PDM or CHDM. For early cell morphology, BMSCs on the CDMs were highly elongated in a spindle-like shape. Both preosteoblasts and BMSCs proliferated well on CDMs comparable to the control. Once preosteoblasts were cultured for 2 weeks, their osteogenic activity was significantly different depending on the type of CDM. Using Alizarin red and von Kossa staining, we found that the cells on the FDM were much more osteogenic than the other groups. Furthermore, FDM was the most effective in upregulating the osteogenic markers, such as alkaline phosphatase (ALP), osteopontin, osteocalcin, and type I collagen. In particular, we observed a 2.5-fold increase in ALP activity with FDM compared to that of control and CHDM. In stark contrast, CHDM was very poor in stimulating osteogenic differentiation of preosteoblasts. Interestingly, these results were reproducible with the use of BMSCs, which are much more heterogeneous in cell populations than preosteoblasts. CHDM was still very weak in triggering the osteogenesis of BMSCs, whereas both FDM and PDM were equally competitive. This study demonstrates that a combination of factors (surface texture and composition) shape a unique cellular microenvironment, which serves as a physical cue toward the osteogenic differentiation of preosteoblasts and BMSCs. PMID- 22813213 TI - Limits of detection and quantification in comprehensive multidimensional separations. 1. A theoretical look. AB - Comprehensive multidimensional separations (e.g., GC*GC, LC*LC, etc.) are increasingly popular tools for the analysis of complex samples, due to their many advantages, such as vastly increased peak capacity, and improvements in sensitivity. The most well-established of these techniques, GC*GC, has revolutionized analytical separations in fields as diverse as petroleum, environmental research, food and flavors, and metabolic profiling. Using multidimensional approaches, analytes can be quantified at levels substantially lower than those possible by one-dimensional techniques. However, it has also been shown that the modulation process introduces a new source of error to the measurement. In this work, we present the results of a study into the limits of quantification and detection (LOQ and LOD) in comprehensive multidimensional separations using GC*GC and the more popular "two-step" integration algorithm as an example. Simulation of chromatographic data permits precise control of relevant parameters of peak geometry and modulation phase. Results are expressed in terms of the dimensionless parameter of signal-to-noise ratio of the base peak (S/N(BP)) making them transportable to any result where quantification is performed using a two-step algorithm. Based on these results, the LOD is found to depend upon the modulation ratio used for the experiment and vary between a S/N(BP) of 10-17, while the LOQ depends on both the modulation ratio and the phase of the modulation for the peak and ranges from a S/N(BP) of 10 to 50, depending on the circumstances. PMID- 22813214 TI - Does everolimus increase donor-specific HLA antibodies in kidney transplant recipients? PMID- 22813215 TI - Comprehensive proteomic analysis of human dentin. AB - Proteomic analysis of the human body is a significant recent scientific endeavour. In this study, we investigated the proteomic profile of human dentin using modern analytical and mass spectrometric techniques. Five healthy permanent human molars from five adults were cut, pulverized, denaturated with guanidine buffer, and demineralized with EDTA buffer. The extracted proteins were analysed by gel electrophoresis (SDS-PAGE and two-dimensional gel electrophoresis), digested with trypsin, and separated by liquid chromatography/high-resolution tandem mass spectrometry. We identified 289 proteins with high confidence, 90 of which had not been previously detected in human dentin. Nine (currently hypothetical) proteins were identified for the first time in an actual human sample. The proteins have a variety of functions, including calcium-ion binding, formation of the extracellular matrix, formation of the cytoskeleton, cytoskeletal protein binding, immune response, and transport. In conclusion, this is the first use of two-dimensional electrophoresis for investigating human dentin. PMID- 22813216 TI - Does enamelin have pleiotropic effects on organs other than the teeth? Lessons from a phenotyping screen of two enamelin-mutant mouse lines. AB - We analyzed two mutant mouse lines, ATE1 and ATE2, that carry point mutations in the enamelin gene which result in premature stop codons in exon 8 and exon 7, respectively. Both mutant lines show amelogenesis imperfecta. To establish the effect of mutations within the enamelin gene on different organs, we performed a systematic, standardized phenotypic analysis of both mutant lines in the German Mouse Clinic. In addition to the initially characterized tooth phenotype that is present in both mutant lines, we detected effects of enamelin mutations on bone and energy metabolism, as well as on clinical chemical and hematological parameters. These data raise the hypothesis that enamelin defects have pleiotropic effects on organs other than the teeth. PMID- 22813217 TI - Novel nonsense mutation in MSX1 causes tooth agenesis with cleft lip in a Chinese family. AB - Tooth agenesis is one of the most common developmental disorders in humans. Previous studies have attributed non-syndromic tooth agenesis to mutations in several genes, including MSX1, PAX9, EDA, and AXIN2. In this study, we investigated a Chinese family with tooth agenesis combined with cleft lip. Genomic DNA was isolated from blood samples of all available family members. Candidate genes MSX1 and PAX9 were amplified by the PCR and directly sequenced. A novel heterozygous mutation at c.C565T, exon 2 of MSX1, was identified in affected members. To analyze the effect of the nonsense mutation on MSX1 expression, vectors containing wild-type and mutated MSX1 were constructed and transfected into COS7 cell lines. Real-time PCR showed that the mRNA expression of the mutated MSX1 was dramatically reduced compared with that of the wild-type MSX1. Our findings suggest that the nonsense mutation in MSX1 might have resulted in rapid degradation of the mutated transcript and caused the phenotype of tooth agenesis with cleft lip in the Chinese family. PMID- 22813218 TI - Cell proliferation and apoptosis in the fusion of human primary and secondary palates. AB - The markers of cell proliferation (Ki-67) and apoptosis [caspase-3, TdT-mediated biotin-dUTP nick-end labelling (TUNEL)] and the expression of syndecan-1 and heat shock protein 70 (Hsp70) were analyzed immunohistochemically in 11 developing human palates, from developmental weeks 6 to 10. During fusion of the primary palate, the proportion of proliferating cells decreased from 42 to 32% and the proportion of apoptotic cells decreased from 11 to 7% in the medial-edge epithelium. At later stages, the proportions of both types of cells decreased in the ectomesenchyme, except for proliferating cells in its non-condensing part. At developmental weeks 9-10, the epithelial seam in the secondary palate comprised 28% proliferative cells and 5% apoptotic cells. While condensing ectomesenchyme contained more apoptotic cells than proliferating cells, the opposite was observed for the non-condensing ectomesenchyme. Co-expression of syndecan-1 and Hsp70 was detected in cells budding from the epithelial seam. Our study indicates similar principles for human primary palate and secondary palate fusion, and parallel persistence of proliferation and apoptotic activity. While proliferation enables growth and fusion of different palatal primordia, apoptosis results in the removal of of large numbers epithelial cells at the fusion point. The disintegration of seam remnants seems to be executed through the processes of change in protein content and cell migration, probably leading to cell death as their final outcome. PMID- 22813219 TI - Expression of delta-like 1 homologue and insulin-like growth factor 2 through epigenetic regulation of the genes during development of mouse molar. AB - Delta-like 1 homolog (Dlk1) and insulin-like growth factor 2 (Igf2) are two of six well-studied mouse imprinted gene clusters that are paternally expressed. Their expression is also linked to their maternally expressed non-coding RNAs, encoded by Gene trap locus 2 (Gtl2) and Imprinted maternally expressed transcript (H19), co-located as imprinted gene clusters. Using deoxyoligonucleotide microarrays and real-time RT-PCR analysis we showed Dlk1 and Gtl2 to exhibit a time-course of expression during tooth development that was similar to that of Igf2 and H19. Western blot analysis of proteins encoded by Dlk1 and Igf2 suggested that the levels of these proteins reflected those of the corresponding mRNAs. Immunohistochemical studies of DLK1 in murine molars detected the protein in both epithelial and mesenchymal regions, in developing cusp mesenchyme, and in newly synthesized enamel and dentin tubules. IGF2 protein was detected primarily at prenatal stages, suggesting that it may be active before birth. Analysis of methylation of cytosine-phosphate-guanine (CpG) islands in both Dlk1 and Igf2 suggested the presence of an increasing fraction of hypermethylated bases with increasing time of development. The increased levels of hypermethylation coincided both with the diminished levels of expression of Dlk1 and Igf2 and with decreased levels of DLK1 and IGF2 proteins in the tooth germ, suggesting that their expression is regulated via methylation of CpG islands present in these genes. PMID- 22813220 TI - Identification of multipotent stem cells from adult dog periodontal ligament. AB - Periodontal diseases, which are characterized by destruction of the connective tissues responsible for restraining the teeth within the jaw, are the main cause of tooth loss. Periodontal regeneration mediated by human periodontal ligament stem cells (hPDLSCs) may offer an alternative strategy for the treatment of periodontal disease. Dogs are a widely used large-animal model for the study of periodontal-disease progression, tissue regeneration, and dental implants, but little attention has been paid to the identification of the cells involved in this species. This study aimed to characterize stem cells isolated from canine periodontal ligament (cPDLSCs). The cPDLSCs, like hPDLSCs, showed clonogenic capability and expressed the mesenchymal stem cell markers STRO-1, CD146, and CD105, but not CD34. After induction of osteogenesis, cPDLSCs showed calcium accumulation in vitro. Moreover, cPDLSCs also showed both adipogenic and chondrogenic potential. Compared with cell-free controls, more cementum/periodontal ligament-like structures were observed in CB-17/SCID mice into which cPDLSCs had been transplanted. These results suggest that cPDLSCs are clonogenic, highly proliferative, and have multidifferentiation potential, and that they could be used as a new cellular therapeutic approach to facilitate successful and more predictable regeneration of periodontal tissue using a canine model of periodontal disease. PMID- 22813221 TI - Initial responses of osteoblasts derived from human alveolar bone to various compressive forces. AB - Mechanical stress generated by orthodontic force is recognized as a major factor in the modulation of alveolar bone remodeling. During this process, osteoblasts play a crucial role, not only by participating in bone formation but also by promoting osteoclastogenesis. The aim of this study was to investigate how continuous compressive force (CF) affects human primary osteoblasts (HOBs) in terms of cell proliferation, apoptosis, and expression of interleukin-6 (IL-6) and chemokine CXC ligand 8 (CXCL8). Human primary osteoblasts, isolated from human mandibular bone pieces, were cultured with or without CF (1-4 g cm(-2)) for up to 72 h. Cell viability and proliferation were evaluated using the MTT assay. RT-PCR was used to determine the levels of expression of KI67 (a proliferation marker), BAX (a pro-apoptotic marker), BCL2 (an apoptotic inhibitor), IL6, and CXCL8 mRNAs, while a multiplexed bead immunoassay was used to measure the release of IL-6 and CXCL8. The results revealed that CF decreased cell viability and proliferation in a time- and force-dependent manner. After applying CF for 24 h, the mRNA expression of KI67 was markedly inhibited, whereas the mRNA expression of BAX and BCL2 was unaltered. In addition, CF enhanced the levels of IL6 and CXCL8 mRNAs in a force-dependent manner, whereas the levels of the corresponding proteins were reduced in the compressed HOBs. PMID- 22813222 TI - Effect of nicotine on growth and metabolism of Streptococcus mutans. AB - Streptococcus mutans is a key contributor to dental caries. Smokers have a higher number of caries-affected teeth than do nonsmokers, but the association among tobacco, nicotine, caries, and S. mutans growth has not been investigated in detail. Seven S. mutans strains--UA159, UA130, 10449, A32-2, NG8, LM7, and OMZ175 -were used in the present study. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), planktonic cell growth, biofilm formation, metabolism, and structure (determined using scanning electron microscopy) of the seven strains treated with different concentrations of nicotine (0-32 mg ml(-1)) were investigated. The MIC, MBC, and MBIC were 16 mg ml(-1) (0.1 M), 32 mg ml(-1) (0.2 M), and 16 mg ml(-1) (0.1 M), respectively, for most of the S. mutans strains. Growth of planktonic S. mutans cells was significantly repressed by 2.0-8.0 mg ml(-1) of nicotine. Biofilm formation and metabolic activity of S. mutans was increased in a nicotine-dependent manner up to 16.0 mg ml(-1) of nicotine. Scanning electron microscopy revealed that S. mutans treated with a high concentration of nicotine a had thicker biofilm and more spherical bacterial cells. In summary, nicotine enhances S. mutans biofilm formation and biofilm metabolic activity. These results suggest that smoking can increase the development of caries by fostering increased formation of S. mutans biofilm on tooth surfaces. PMID- 22813223 TI - Anterior and posterior neck muscle activation during a variety of biting tasks. AB - Bruxism may be involved in the aetiology of myofascial neck pain. The objective of this study was to test the hypothesis that anterior and posterior neck muscles co-contract during jaw clenching. Ten test subjects developed different feedback controlled submaximum bite forces in a variety of bite-force directions by means of bite-force transducers. The electromyographic activity of the sternocleidomastoid and supra/infrahyoidal muscles, and of the semispinalis capitis, semispinalis cervicis, and multifidi muscles was recorded by use of surface electrodes and intramuscular wire electrodes, respectively. For normalization of electromyography data, maximum voluntary contraction tasks of the neck muscles were conducted in eight different loading directions. The results confirmed co-contraction of the neck muscles in the range of 2-14% of the maximum voluntary contraction at a bite force ranging from 50 to 300 N. Significant activity differences were observed as a result of the different force levels and force directions exerted by the jaw muscles. Long-lasting tonic activation of specific neck muscles triggered by the jaw-clenching tasks was also detected. These findings support the assumption of a relationship between jaw clenching and the activity of the neck muscles investigated. The low level of co contraction activity, however, requires further study to elucidate possible pathophysiological interactions at the level of single motor units. PMID- 22813224 TI - Oral health-related perceptions, attitudes, and behavior in relation to oral hygiene conditions in an adolescent population. AB - The aim was to analyze oral health-related perceptions, attitudes, and behavior in relation to oral hygiene conditions among 19-yr-old Swedish subjects. A random sample of 506 individuals was clinically examined regarding oral hygiene conditions and provided questionnaire-based information on oral health-related perceptions, attitudes, and behaviors. Higher scores of plaque and gingivitis were significantly related to the following perceptions: (i) a less favorable oral health situation, (ii) a lower satisfaction with the esthetic appearance of the teeth, (iii) more frequent gingival bleeding during toothbrushing, (iv) less favorable self-care of the teeth, (v) a lower possibility to impact on own oral health, (vi) a lower importance of cleaning the teeth, and (vii) a lower importance of good oral health conditions. More favorable oral hygiene conditions and more positive perceptions, attitudes, and behaviors towards oral health were found among female subjects than among male subjects. In conclusion, adolescents with high scores of plaque and gingivitis had less positive perceptions, attitudes, and behaviors towards oral health than those with more favorable oral hygiene conditions. PMID- 22813225 TI - In situ effect of sodium fluoride or titanium tetrafluoride varnish and solution on carious demineralization of enamel. AB - This study evaluated the effect of titanium tetrafluoride (TiF(4)) formulations on enamel carious demineralization in situ. Thirteen subjects took part in this cross-over, split-mouth, double-blind study performed in three phases of 14 d each. In each subject, two sound and two predemineralized specimens of bovine enamel were worn intra-orally and plaque accumulation was allowed. One sound and one predemineralized specimen in each subject was treated once with sodium fluoride (NaF) varnish or solution (Treatment A); TiF(4) varnish or solution (Treatment B); or placebo varnish or no treatment (Treatment C). The initially sound enamel specimens were exposed to severe cariogenic challenge (20% sucrose, eight times daily for 5 min each time), whereas the predemineralized specimens were not. Eleven subjects were able to finish all experimental phases. The enamel alterations were quantified by surface hardness and transversal microradiography. Demineralization of previously sound enamel was reduced by all test formulations except for the NaF solution, while both TiF(4) formulations were as effective as NaF varnish. For the predemineralized specimens, enamel surface hardness was increased only by TiF(4) formulations, while subsurface mineral remineralization could not be seen in any group. Within the experimental protocol, TiF(4) was able to decrease enamel demineralization to a similar degree as NaF varnish under severe cariogenic challenges, while only TiF(4) formulations remineralized the enamel surface. PMID- 22813227 TI - Bioactive effects of a calcium/sodium phosphosilicate on the resin-dentine interface: a microtensile bond strength, scanning electron microscopy, and confocal microscopy study. AB - This study evaluated, through microtensile bond strength (MUTBS) testing, the bioactive effects of a calcium/sodium phosphosilicate (BAG) at the resin-dentine interface after 6 months of storage in phosphate buffer solution (PBS). Confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) were also performed. Three bonding protocols were evaluated: (i) RES-Ctr (no use of BAG), (ii) BAG containing adhesive (BAG-AD), and (iii) BAG/H (3) PO (4) before adhesive (BAG-PR). The dentin-bonded specimens were prepared for MUTBS testing, which was carried out after 24 h or 6 months of storage in PBS. Scanning electron microscopy ultramorphology analysis was performed after debonding. Confocal laser scanning microscopy was used to evaluate the morphological and nanoleakage changes induced by PBS storage. High MUTBS values were achieved in all groups after 24 h of storage in PBS. Subsequent to 6 months of storage in PBS the specimens created using the BAG-AD bonding approach still showed no significant reduction in MUTBS. Moreover, specimens created using the BAG-AD or the BAG-PR approach showed an evident reduction of nanoleakage after prolonged storage in PBS. The use of BAG-containing adhesive may enhance the durability of the resin dentine bonds through therapeutic/protective effects associated with mineral deposition within the bonding interface and a possible interference with collagenolytic enzyme activity (matrix metalloproteinases) responsible for the degradation of the hybrid layer. PMID- 22813226 TI - Counteractive effect of antacid suspensions on intrinsic dental erosion. AB - This in vitro study aimed to investigate the anti-erosive effect of antacid suspensions applied to enamel after exposure to hydrochloric acid (HCl). Ninety bovine enamel slabs were embedded, flattened, and polished. Reference areas were created and specimens were divided into six groups. They were exposed to 0.01 M HCl (pH 2) for 2 min, followed by immersion for 1 min in one of the following test suspensions: magnesium hydroxide, aluminum hydroxide, magnesium hydroxide/aluminum hydroxide, sodium alginate/sodium bicarbonate/calcium carbonate, or hydrated magnesium aluminate. Artificial saliva was used as a negative control. Specimens were subjected to a total of five cycles of erosion/antacid treatment. Enamel surface loss was measured (in micrometers) by optical profilometry. In addition, baseline and final surface microhardness (SMH) values of enamel were obtained. It was found that antacid suspensions significantly reduced enamel loss, and that similar protection was afforded by all formulations. No differences were observed between the final enamel SMH values among groups. Antacid suspensions counteracted HCl-induced enamel loss, although they were not effective in reducing enamel softening. Mouth rinsing with antacid suspensions after vomiting can potentially represent a promising strategy to counteract enamel loss caused by erosion. PMID- 22813228 TI - A Paced Auditory Serial Addition Task evokes stress and differential effects on masseter-muscle activity and haemodynamics. AB - This study aimed to determine autonomic and jaw-muscle activities, and haemodynamic responses, to acute experimental mental stress in humans. Eleven healthy men (25.2 +/- 3.0 years of age) and five healthy women (23.0 +/- 3.7 years of age) performed a standardized mental stress task, the Paced Auditory Serial Addition Task (PASAT). Autonomic function, such as heart rate variability (HRV), and haemodynamic changes were recorded simultaneously. The success rate of the PASAT decreased with increased pace and duration. Low-frequency (5.8 +/- 1.1 ms(2)) and high-frequency (5.3 +/- 0.6 ms(2)) components of HRV decreased during the PASAT (to 5.0 +/- 0.9 ms(2) and 4.6 +/- 1.1 ms(2), respectively) as an indication of acute stress. Oxygenated haemoglobin in the masseter muscle (14.6 +/- 2.2 10(4) units mm(-3)) remained at an elevated level during the PASAT (15.5 +/- 2.5 10(4) units mm(-3)), whereas deoxygenated haemoglobin (7.8 +/- 2.3 10(4) units mm(-3)) showed a consistent decrease (to 6.8 +/- 2.1 10(4) units mm(-3)). Total haemoglobin and jaw-muscle electromyographic (EMG) activity did not change during the PASAT. Thus, PASAT-induced mental stress changed the parasympathetic/sympathetic balance of the heart and had an acute influence on jaw-muscle haemodynamics, but not on jaw-muscle EMG activity. This non-invasive experimental set-up can be applied to study the effects of repeated or longer lasting mental stress in order to further the understanding of pathophysiological mechanisms in craniofacial pain conditions. PMID- 22813229 TI - Expression of SLC26A4/pendrin in ameloblasts. PMID- 22813231 TI - The effect of stimulation therapy and donepezil on cognitive function in Alzheimer's disease. A community based RCT with a two-by-two factorial design. AB - BACKGROUND: Progressive neurodegeneration in Alzheimer's disease (AD) induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD. METHOD: DESIGN: A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added. SETTING: Nine rural municipalities in Northern Norway. PARTICIPANTS: 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one year follow-up. INTERVENTIONS: In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period. MAIN OUTCOME: Changes in MMSE sum score.Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test. RESULTS: MMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo. CONCLUSION: In rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT00443014). EudraCT database (no 2004-002613-37). PMID- 22813232 TI - Synthesis strategy: building a culturally sensitive mid-range theory of risk perception using literary, quantitative, and qualitative methods. AB - AIM: This article presents a discussion of development of a mid-range theory of risk perception. BACKGROUND: Unhealthy behaviours contribute to the development of health inequalities worldwide. The link between perceived risk and successful health behaviour change is inconclusive, particularly in vulnerable populations. This may be attributed to inattention to culture. DATA SOURCES: The synthesis strategy of theory building guided the process using three methods: (1) a systematic review of literature published between 2000-2011 targeting perceived risk in vulnerable populations; (2) qualitative and (3) quantitative data from a study of Samoan Pacific Islanders at high risk of cardiovascular disease and diabetes. DISCUSSION: Main concepts of this theory include risk attention, appraisal processes, cognition, and affect. Overarching these concepts is health world view: cultural ways of knowing, beliefs, values, images, and ideas. This theory proposes the following: (1) risk attention varies based on knowledge of the health risk in the context of health-world views; (2) risk appraisals are influenced by affect, health-world views, cultural customs, and protocols that intersect with the health risk; (3) strength of cultural beliefs, values, and images (cultural identity) mediate risk attention and risk appraisal influencing the likelihood that persons will engage in health-promoting behaviours that may contradict cultural customs/protocols. IMPLICATIONS: Interventions guided by a culturally sensitive mid-range theory may improve behaviour-related health inequalities in vulnerable populations. CONCLUSIONS: The synthesis strategy is an intensive process for developing a culturally sensitive mid-range theory. Testing of the theory will ascertain its usefulness for reducing health inequalities in vulnerable groups. PMID- 22813233 TI - Dual-time scale photoinduced electron transfer from PbS quantum dots to a molecular acceptor. AB - A combination of picosecond and microsecond transient absorption dynamics reveals the involvement of two mechanisms by which 1,4-benzoquinone (BQ) induces the decay of the excited state of PbS quantum dots (QDs): (i) electron transfer to BQ molecules adsorbed to the surfaces of PbS QDs and (ii) collisionally gated electron transfer to freely diffusing BQ. Together, these two mechanisms quantitatively describe the quenching of photoluminescence upon addition of BQ to PbS QDs in dichloromethane solution. This work represents the first quantitative study of a QD-ligand system that undergoes both adsorbed and collisionally gated photoinduced charge transfer within the same sample. The availability of a collisionally gated pathway improves the yield of electron transfer from PbS QDs to BQ by an average factor of 2.5 over that for static electron transfer alone. PMID- 22813234 TI - Tracing the source of cooking oils with an integrated approach of using stable carbon isotope and fatty acid abundance. AB - We report a new approach to identify swill-cooked oils that are recycled from tainted food and livestock waste from commercial vegetable and animal oils by means of carbon isotope values and relative abundance of fatty acids. We test this method using 40 cooking oil samples of different types with known sources. We found significant differences in both total organic carbon isotope as well as compound-specific isotope values and fatty acid C(14)/C(18) ratios between commercial vegetable oils refined from C(3) plants (from -35.7 to -27.00/00 and from 0 to 0.15) and animal oils (from -28.3 to -14.30/00 and from 0.1 to 0.6). Tested swill-cooked oils, which were generally refined by mixing with animal waste illegally, fall into a narrow delta(13)C/fatty acid ratio distribution: from -25.9 to -24.10/00 and from 0.1 to 0.2. Our data demonstrate that the index of a cross-plotting between fatty acid delta(13)C values and C(14)/C(18) ratios can be used to distinguish clean commercial cooking oils from illegal swill cooked oils. PMID- 22813235 TI - Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: a phase IIb, randomized, controlled trial. AB - PURPOSE: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV), a novel high-affinity synaptic vesicle protein 2A ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels, in adult epilepsy patients with uncontrolled partial-onset seizures. METHODS: A phase IIb, double-blind, randomized, placebo-controlled, parallel-group, dose ranging study (N01114; NCT00175929) was conducted in patients aged 16-65 years. To be included in the study, patients were required to have experienced four or more partial-onset seizures during a 4-week prospective baseline, despite treatment with 1-2 concomitant antiepileptic drugs. Patients were randomized in a ratio of 1:1:1 to receive BRV 50 mg/day (BRV50), 150 mg/day (BRV150), or placebo. A 3-week up-titration period was followed by a 7-week maintenance period (total treatment period of 10 weeks). KEY FINDINGS: A total of 157 patients were randomized (intent-to-treat [ITT] population; BRV50 n = 53, BRV150 n = 52, placebo n = 52) and overall 148 (94.3%) completed the study. The percent reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week maintenance period (primary efficacy outcome) did not reach statistical significance (14.7% for BRV50 [p = 0.093] and 13.6% for BRV150 [p = 0.124]). However, during the entire 10-week treatment period a statistically significant difference was observed for both BRV groups (17.7% for BRV50 [p = 0.026] and 16.3% for BRV150 [p = 0.043]). The median percent reduction from baseline in partial-onset seizure frequency/week during the maintenance period was 38.2% for BRV50 (p = 0.017) and 30.0% for BRV150 (p = 0.113) versus 18.9% in the placebo group. During the treatment period, this was 34.9% for BRV50 (p = 0.004) and 28.3% for BRV150 (p = 0.070) compared with 16.3% for placebo. Fifty percent responder rates during the maintenance period were 23.1% for placebo compared with 39.6% for BRV50 (odds ratio [OR] 2.17, p = 0.077) and 33.3% for BRV150 (OR 1.66, p = 0.261). During the treatment period, 50% responder rates were 17.3% for placebo compared with 35.8% for BRV50 (OR 2.69, p = 0.038) and 30.8% for BRV150 (OR 2.15, p = 0.114). Nine patients were free from partial-onset seizures during the 10-week treatment period (five patients [9.4%] in the BRV50 group and three [5.8%] in the BRV150 group compared with one patient [1.9%] in the placebo group). Treatment-emergent adverse events (TEAEs) reported during the treatment period were mostly mild-to-moderate with similar incidence across treatment groups (BRV50 36/53, 67.9%; BRV150 35/52, 67.3%; placebo 37/52, 71.2%). The most frequently reported TEAEs in BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. SIGNIFICANCE: In this double-blind, placebo controlled, phase IIb study of adjunctive BRV (50 and 150 mg/day) in adults with uncontrolled partial-onset seizures, the primary efficacy analysis did not reach statistical significance; however, statistically significant differences compared with placebo were observed on several secondary efficacy outcomes. BRV was well tolerated. PMID- 22813236 TI - Plasmon-enhanced photocatalytic properties of Cu2O nanowire-Au nanoparticle assemblies. AB - Cu(2)O-Au nanocomposites (NCs) with tunable coverage of Au were prepared by a facile method of mixing gold nanoparticles (Au NPs) with copper(I) oxide nanowires (Cu(2)O NWs) in various ratios. These Cu(2)O-Au NCs display tunable optical properties, and their photocatalytic properties were dependent on the coverage density of Au NPs. The photocatalytic activity of Cu(2)O-Au NCs was examined by photodegradation of methylene blue. The presence of Au NPs enhanced the photodegradation efficiency of Cu(2)O NCs. The photocatalytic efficiency of Cu(2)O-Au NCs initially increased with the increasing coverage density of Au NPs and then decreased as the surface of Cu(2)O became densely covered by Au NPs. The enhanced photocatalytic efficiency was ascribed to enhanced light absorption (by the surface plasmon resonance) and the electron sink effect of the Au NPs. PMID- 22813237 TI - Comprehensive stroke units: a review of comparative evidence and experience. AB - BACKGROUND: Stroke unit care offers significant benefits in survival and dependency when compared to general medical ward. Most stroke units are either acute or rehabilitation, but comprehensive (combined acute and rehabilitation) model (comprehensive stroke unit) is less common. AIM: To examine different levels of evidence of comprehensive stroke unit compared to other organized inpatient stroke care and share local experience of comprehensive stroke units. METHODS: Cochrane Library and Medline (1980 to December 2010) review of English language articles comparing stroke units to alternative forms of stroke care delivery, different types of stroke unit models, and differences in processes of care within different stroke unit models. Different levels of comparative evidence of comprehensive stroke units to other models of stroke units are collected. RESULTS: There are no randomized controlled trials directly comparing comprehensive stroke units to other stroke unit models (either acute or rehabilitation). Comprehensive stroke units are associated with reduced length of stay and greatest reduction in combined death and dependency in a meta-analysis study when compared to other stroke unit models. Comprehensive stroke units also have better length of stay and functional outcome when compared to acute or rehabilitation stroke unit models in a cross-sectional study, and better length of stay in a 'before-and-after' comparative study. Components of stroke unit care that improve outcome are multifactorial and most probably include early mobilization. A comprehensive stroke unit model has been successfully implemented in metropolitan and rural hospital settings. CONCLUSIONS: Comprehensive stroke units are associated with reductions in length of stay and combined death and dependency and improved functional outcomes compared to other stroke unit models. A comprehensive stroke unit model is worth considering as the preferred model of stroke unit care in the planning and delivery of metropolitan and rural stroke services. PMID- 22813238 TI - Preparation and characterization of polymeric and lipid nanoparticles of pilocarpine HCl for ocular application. AB - Pilocarpine is used topically in the treatment of glaucoma. Various studies were performed to improve the bioavailability and prolong the residence time of drugs in ocular drug delivery. Drug loaded polymeric and lipid nanoparticles offer several favourable biological properties, such as biodegradability, nontoxicity, biocompatibility and mucoadhesiveness. Therefore, preparing positively-charged pilocarpine HCl-loaded polymeric and lipid nanoparticles was the purpose of this study. Nanoparticles were prepared by quasi-emulsion solvent evaporation technique. The non-biodegradable positively-charged polymer Eudragit((r)) RS 100 and semi-solid lipid excipient Gelucire((r)) 44/14 were used as a vehicle, the cationic lipid octadecylamine was used as a cationic agent. The formulations were evaluated in terms of particle size, size distribution, zeta potential measurement, thermal behavior (Differential Scanning Calorimetry DSC), entrapment efficacy and pH. Characterizations of nanoparticles were analyzed during the storage period of 6 months for stability tests. Polymeric and lipid nanoparticles could be prepared successfully promising their use for ophthalmic delivery. PMID- 22813341 TI - A layered approach to raising public awareness of macular degeneration in Australia. AB - Between 2007 and 2011, the Australian Macular Degeneration Foundation conducted a multifaceted campaign to increase public awareness of macular degeneration. Regular national polls conducted by an independent social research company have shown that awareness of macular degeneration increased from 47% to 80% in Australians aged 16 years or older and from 58% to 92% in those aged 50 years or older. The percentage of people aged 50 years or older who reported having had their macula checked in the 2 years prior to the survey increased from 33% to 70% from 2007 to 2011. Other measures, including analysis of Medicare data, have confirmed the success of the campaign. PMID- 22813343 TI - Tumor necrosis factor-alpha inhibits transforming growth factor-beta-stimulated myofibroblastic differentiation and extracellular matrix production in human gingival fibroblasts. AB - BACKGROUND: Fibroblasts play a critical role during wound healing and chronic inflammation through the synthesis and assembly of extracellular matrix (ECM) molecules. These responses may be modulated by soluble cytokines and growth factors present in tissues. In the present study, we evaluate whether transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF alpha) modulate myofibroblastic differentiation and the production of ECM components. METHODS: Primary cultures of human gingival fibroblasts (HGFs) were stimulated with recombinant TGF-beta1 and TNF-alpha. Protein levels of alpha smooth muscle actin (alpha-SMA), type I collagen, heat shock protein-47 (HSP-47), fibronectin (FN), ED-A-FN, and periostin and activation of the Smad pathway were evaluated through Western blot analysis. alpha-SMA and actin fibers were identified by immunofluorescence. TGF-beta1, TNF-alpha, and alpha-SMA were identified by immunohistochemistry in biopsies of inflamed human gingival tissues. TGF-beta1 activity was evaluated using a plasminogen activator inhibitor 1 (PAI-1) reporter transfected in HGFs. RESULTS: TGF-beta1 stimulated the differentiation of myofibroblasts as evidenced by strong expression of alpha-SMA and ED-A-FN. Moreover, TGF-beta1 induced the production of type I collagen, HSP 47, FN, and periostin. Costimulation with TNF-alpha and TGF-beta1 significantly reduced the expression of all the above-mentioned proteins. TNF-alpha also inhibited the activation of the Smad2/3 pathway and the activity of the PAI-1 reporter. CONCLUSIONS: TNF-alpha inhibits several cell responses induced by TGF beta1, including the differentiation of myofibroblasts, the activation of the Smad signaling pathway, and the production of key molecules involved in tissue repair, such as type I collagen, FN, and periostin. The interaction between cytokines may explain the delayed tissue repair observed in chronic inflammation of gingival tissues. PMID- 22813344 TI - Five-year changes in periodontal disease measures among postmenopausal females: the Buffalo OsteoPerio study. AB - BACKGROUND: Understanding of longitudinal characteristics of periodontal disease in older females is limited. This study examined 5-year changes in periodontal disease measures among postmenopausal females. METHODS: Participants were 1,025 postmenopausal, 53- to 83-year-old females who completed baseline (1997 to 2001) and 5-year follow-up (2002 to 2006) whole-mouth oral examinations in a study ancillary to the Women's Health Initiative. Periodontal disease was characterized using probing depth (PD), clinical attachment level (CAL), alveolar crest height (ACH), and tooth loss. Differences in measures between examinations were used to characterize patterns of change. RESULTS: Baseline prevalence of none/mild, moderate, and severe periodontal disease defined using criteria of the Centers for Disease Control and Prevention was 27%, 58%, and 15%, respectively. Tooth loss attributable to periodontitis occurred in 13% of females. Mean +/- SD changes in whole-mouth mean measures showed progression when based on ACH (-0.19 +/- 0.49 mm) yet relatively stable disease when based on PD (0.11 +/- 0.42 mm) and CAL (0.06 +/- 0.58 mm). Mean change in worst-site ACH was greater (P <0.001) in females with severe periodontitis and osteoporosis at baseline and with tooth loss during follow-up. Periodontal changes did not differ according to baseline age, hormone therapy use, smoking status, or age at menopause. CONCLUSIONS: Five year changes in periodontal measures among generally healthy postmenopausal females were, on average, small and did not suggest a consistent pattern of disease progression. Females with history of severe periodontitis or osteoporosis may experience accelerated oral bone loss despite stability or small improvement in routine probing measures. PMID- 22813345 TI - Effect of hydrosoluble chlorine-mediated antimicrobial photodynamic therapy on clinical parameters and cytokine profile in ligature-induced periodontitis in dogs. AB - BACKGROUND: Recently, a hydrosoluble chlorine composed of sodium salts chlorine e6, chlorine p6, and purpurine-5 has been shown to be a promising photosensitizer in antimicrobial photodynamic therapy (aPDT). The aim of this study is to evaluate the effects of adjunctive application of hydrosoluble chlorine-mediated aPDT compared with scaling and root planing (SRP) alone on clinical parameters and cytokine levels in gingival crevicular fluid of dogs with experimental periodontitis. METHODS: Periodontal disease was induced by placing silk ligatures around both maxillary and mandibular teeth. After establishment of attachment loss, full-mouth SRP was performed in all dogs. One day after SRP, each quadrant randomly received one of the following treatment modalities: hydrosoluble chlorine plus diode laser (wavelength 662 nm, power 100 mW, continuous mode, time of irradiation 20 seconds), hydrosoluble chlorine alone, laser alone, or no adjunctive treatment. The same adjunctive procedure was repeated 1 week later. Clinical parameters including periodontal probing depth, clinical attachment level, and bleeding on probing, as well as crevicular levels of interleukin-1beta and tumor necrosis factor-alpha, were evaluated at baseline, at 3 weeks, and at 3 months after treatment. RESULTS: After both 3 weeks and 3 months, all treatment groups showed significant improvement in all clinical and immunologic parameters (P <0.001). No significant differences were found between the four groups with regard to the measured parameters (P >0.05). CONCLUSION: Based on the results of this study, adjunctive use of hydrosoluble chlorine-mediated aPDT with the current setting has no additional effect on the clinical parameters or proinflammatory cytokine levels in ligature-induced periodontitis. PMID- 22813346 TI - Inferior alveolar neurosensory deficiency associated with placement of dental implants. AB - BACKGROUND: This study reports and analyzes a large series of patients with neurosensory deficiency related to the placement of dental implants (DIs) and resulting in liability claims (LCs). METHODS: From 1998 to 2009, there were 92 LCs related to persistent altered sensation post DI placements in Israel. Patients' demographics, year and source of LCs, interval between the procedure that resulted in a neurosensory deficiency and the LC, qualifications of the surgeon, preoperative imaging modality, DI length, available alveolar bone for DI placement, placement site, timing of DI placement (immediately after tooth extraction or after socket healing), and treatment after the diagnosis of neurosensory deficiency were recorded and analyzed. RESULTS: There were 21 cases during the first 5 years of the study (mean 4.2/year) and 63 cases (mean 12.6/year) over the following 5 years. Thirty LCs were issued during the second postoperative year and 15 LCs after >5 years. Most LCs (76%) involved procedures that were planned and performed according to radiographs and 24% after computed tomography. Sixty-five percent of the LCs were performed by general dental practitioners and 35% by specialists. More than one DI was performed during the surgical procedure that resulted in a neurosensory deficiency in 73 LCs (79.3%), and the DI was >10 mm in 55 (59.8%) cases. CONCLUSIONS: LCs for DIs that result in a neurosensory deficiency pose a legal risk to the practitioner long after the injury has occurred. PMID- 22813348 TI - Cortical excitability decreases in Lennox-Gastaut syndrome. AB - PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate cortical excitability changes in Lennox-Gastaut syndrome (LGS), anticipating we would find a marked increase in excitability compared to other patients with refractory epilepsies. METHODS: Eighteen patients with LGS were studied. Motor threshold (MT), short intracortical inhibition (paired pulse TMS at 2 and 5 msec interstimulus intervals [ISIs]), intracortical facilitation (10 and 15 msec ISIs), and long intracortical inhibition (100-300 msec ISIs) were measured. Results were compared to those of 20 patients with chronic refractory idiopathic generalized epilepsy (IGE), 20 patients with chronic refractory focal epilepsy, and 20 healthy nonepilepsy controls. KEY FINDINGS: A significant decrease in cortical excitability was observed in LGS compared to the other two groups with refractory epilepsy as evidenced by increased MT and intracortical inhibition at both short (2, 5 msec ISIs), and long (100-300 msec ISIs) as well as decreased intracortical facilitation (10, 15 msec ISIs), (p < 0.01; effect sizes ranging from 0.3 to 1.8). Cortical excitability was also lower in LGS compared to nonepilepsy controls (increased MT and decreased intracortical facilitation; p < 0.05; effect sizes ranging from 0.5 to 0.9). SIGNIFICANCE: Interictal cortical excitability is decreased in LGS; a feature that distinguishes it from other refractory epilepsy syndromes. This decrease may be an important mechanism for the neurobehavioral comorbidities associated with LGS. PMID- 22813350 TI - Risk factors for reported influenza and influenza-like symptoms in patients with rheumatoid arthritis. AB - OBJECTIVES: To determine the prevalence and predictors of influenza and influenza like symptoms in patients with rheumatoid arthritis (RA). METHOD: Questionnaires were sent to patients registered as having RA and they were asked to fill in per month any period and details of influenza-like symptoms and vaccination. An experienced rheumatologist assessed the level of disease activity and use of anti rheumatic medication. The prevalence of reported influenza (fever > 38 degrees C, headache, muscle soreness, and coughing and/or dyspnoea) and influenza-like symptoms was determined and risk factors were identified by logistic regression analysis. RESULTS: Of the 1692 patients approached, 783 (46%) patients were eligible for follow-up. Fifty per cent of the patients reported influenza-like symptoms, 5.9% had symptoms suggesting influenza, and 74% reported vaccination. The prevalence of influenza and influenza-like symptoms per month ranged from 0.0% to 2.3% and from 10.4% to 19.7%, respectively. Anti-tumour necrosis factors (anti-TNFs) [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.2-4.8] and body mass index (BMI) (OR 1.06, 95% CI 1.0-1.1) were independently associated with symptoms of influenza. A trend was found for patients not in remission, patients using leflunomide, and patients with previous lung conditions. Independent risk factors of influenza-like symptoms were age (OR 0.98, 95% CI 0.97-0.99), female gender (OR 1.8, 95% CI 1.3-2.5), influenza vaccination (OR 1.6, 95% CI 1.1-2.4), and previous lung condition (OR 1.7, 95% CI 1.2-2.4). CONCLUSIONS: In 2009-2010, the prevalence of reported influenza in patients with RA was 5.9%. Patients using anti-TNFs and with higher BMI seemed to be more at risk for influenza symptoms. Milder upper respiratory tract infections were reported more often by females, younger patients, and those vaccinated against influenza or with previous lung conditions. PMID- 22813351 TI - Liver transplantation using Chagas-infected donors in uninfected recipients: a single-center experience without prophylactic therapy. AB - Organ shortage is the first cause of death on liver transplant waiting lists. As a consequence, we recently decided to expand liver acceptance to those organs that could potentially transmit infectious diseases to their recipients. On January 2010, we initiated a prospective protocol using livers from Chagas infected donors for transplanting uninfected recipients without using prophylactic therapy. During a 13-month period, 9 of 37 (24%) liver transplants were performed within this protocol. After transplant, each recipient was sequentially and strictly monitored for infection transmission using the Strout method and promptly treated with benznidazole if this occurs. During follow-up, two patients died without Chagas infection and only two (donor-derived T. cruzi transmission rate: 2/9; 22%) patients developed donor-derived Chagas transmission without clinical symptoms. The median follow-up time of the seven live patients was 15 months (range: 13-20). At present, all are symptoms-free with excellent allograft function and without evidence of Chagas disease. In conclusion, we consider that Chagas-infected donors are a promising source of liver grafts that could reduce the growing mortality on liver waiting lists in America. Relevant data from larger prospective studies are required to confirm these preliminary excellent results. PMID- 22813353 TI - Physical characterization and reactivity of the uranyl peroxide [UO2(eta(2) O2)(H2O)2].2H2O: implications for storage of spent nuclear fuels. AB - The unusual uranyl peroxide studtite, [UO(2)(eta(2)-O(2))(H(2)O)(2)].2H(2)O, is a phase alteration product of spent nuclear fuel and has been characterized by solid-state cyclic voltammetry. The voltammogram exhibits two reduction waves that have been assigned to the U(VI/V) redox couple at -0.74 V and to the U(V/IV) redox couple at -1.10 V. This potential shows some dependence upon the identity of the cation of the supporting electrolyte, where cations with larger ionic radii exhibit more cathodic reduction potentials. Raman spectroelectrochemistry indicated that exhaustive reduction at either potential result in a product that does not contain peroxide linkers and is likely to be UO(2). On the basis of the reduction potentials, the unusual behavior of neptunium in the presence of studtite can be rationalized. Furthermore, the oxidation of other species relevant to the long-term storage of nuclear fuel, namely, iodine and iodide, has been explored. The phase altered product should therefore be considered as electrochemically noninnocent. Radiotracer studies with (241)Am show that it does not interact with studtite so mobility will not be retarded in repositories. Finally, a large difference in band gap energies between studtite and its dehydrated congener metastudtite has been determined from the electronic absorption spectra. PMID- 22813352 TI - ELISA-mimic screen for synthetic polymer nanoparticles with high affinity to target proteins. AB - Synthetic polymer nanoparticles (NPs) that display high affinity to protein targets have significant potential for medical and biotechnological applications as protein capture agents or functional replacements of antibodies ("plastic antibodies"). In this study, we modified an immunological assay (enzyme-linked immunosorbent assay: ELISA) into a high-throughput screening method to select nanoparticles with high affinity to target proteins. Histone and fibrinogen were chosen as target proteins to demonstrate this concept. The selection process utilized a biotinylated NP library constructed with combinations of functional monomers. The screen identified NPs with distinctive functional group compositions that exhibited high affinity to either histone or fibrinogen. The variation of protein affinity with changes in the nature and amount of functional groups in the NP provided chemical insight into the principle determinants of protein-NP binding. The NP affinity was semiquantified using the ELISA-mimic assay by varying the NP concentrations. The screening results were found to correlate with solution-based assay results. This screening system utilizing a biotinylated NP is a general approach to optimize functional monomer compositions and can be used to rapidly search for synthetic polymers with high (or low) affinity for target biological macromolecules. PMID- 22813349 TI - Quality indicators for colorectal cancer surgery and care according to patient-, tumor-, and hospital-related factors. AB - BACKGROUND: Colorectal cancer (CRC) care has improved considerably, particularly since the implementation of a quality of care program centered on national evidence-based guidelines. Formal quality assessment is however still needed. The aim of this research was to identify factors associated with practice variation in CRC patient care. METHODS: CRC patients identified from all cancer centers in South-West France were included. We investigated variations in practices (from diagnosis to surgery), and compliance with recommended guidelines for colon and rectal cancer. We identified factors associated with three colon cancer practice variations potentially linked to better survival: examination of >= 12 lymph nodes (LN), non-use and use of adjuvant chemotherapy for stage II and stage III patients, respectively. RESULTS: We included 1,206 patients, 825 (68%) with colon and 381 (32%) with rectal cancer, from 53 hospitals. Compliance was high for resection, pathology report, LN examination, and chemotherapy use for stage III patients. In colon cancer, 26% of stage II patients received adjuvant chemotherapy and 71% of stage III patients. 84% of stage US T3T4 rectal cancer patients received pre-operative radiotherapy. In colon cancer, factors associated with examination of >= 12 LNs were: lower ECOG score, advanced stage and larger hospital volume; factors negatively associated were: left sided tumor location and one hospital district. Use of chemotherapy in stage II patients was associated with younger age, advanced stage, emergency setting and care structure (private and location); whereas under-use in stage III patients was associated with advanced age, presence of comorbidities and private hospitals. CONCLUSIONS: Although some changes in practices may have occurred since this observational study, these findings represent the most recent report on practices in CRC in this region, and offer a useful methodological approach for assessing quality of care. Guideline compliance was high, although some organizational factors such as hospital size or location influence practice variation. These factors should be the focus of any future guideline implementation. PMID- 22813354 TI - Group B rotavirus infection in patients with acute gastroenteritis from India: 1994-1995 and 2004-2010. AB - Faecal specimens collected from 2101 patients with acute gastroenteritis from three cities (Pune, Alappuzha, Belgaum) in India during 1994-1995 and 2004-2010 were tested for group B rotavirus (RVB) by amplification of the NSP2 gene using RT-PCR. Seventy-five (3.6%) specimens were shown to contain RVB RNA. The positivity rate in Pune, Alappuzha and Belgaum was 4.1%, 7.3% and 4.1%, respectively, in the 2000s which was not significantly different from the detection rate in the 1990s in Pune (2.5%, P>0.05). RVB infections prevailed in adolescents and adults (62/1082, 5.7%) compared to children (13/1019, 1.3%, P<0.001) and were detected throughout the year. Phylogenetically, all strains clustered in an NSP2 lineage together with Indian-Bangladeshi RVB strains belonging to VP7 genotype G2. The study confirmed the occurrence of RVB infections in western India and reported for the first time circulation of RVB strains in southern India, suggesting that an increased awareness and monitoring for RVB infections is necessary in India. PMID- 22813355 TI - Structure and composition of insulin fibril surfaces probed by TERS. AB - Amyloid fibrils associated with many neurodegenerative diseases are the most intriguing targets of modern structural biology. Significant knowledge has been accumulated about the morphology and fibril-core structure recently. However, no conventional methods could probe the fibril surface despite its significant role in the biological activity. Tip-enhanced Raman spectroscopy (TERS) offers a unique opportunity to characterize the surface structure of an individual fibril due to a high depth and lateral spatial resolution of the method in the nanometer range. Herein, TERS is utilized for characterizing the secondary structure and amino acid residue composition of the surface of insulin fibrils. It was found that the surface is strongly heterogeneous and consists of clusters with various protein conformations. More than 30% of the fibril surface is dominated by beta sheet secondary structure, further developing Dobson's model of amyloid fibrils (Jimenez et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 9196-9201). The propensity of various amino acids to be on the fibril surface and specific surface secondary structure elements were evaluated. beta-sheet areas are rich in cysteine and aromatic amino acids, such as phenylalanine and tyrosine, whereas proline was found only in alpha-helical and unordered protein clusters. In addition, we showed that carboxyl, amino, and imino groups are nearly equally distributed over beta-sheet and alpha-helix/unordered regions. Overall, this study provides valuable new information about the structure and composition of the insulin fibril surface and demonstrates the power of TERS for fibril characterization. PMID- 22813356 TI - LXtoo: an integrated live Linux distribution for the bioinformatics community. AB - BACKGROUND: Recent advances in high-throughput technologies dramatically increase biological data generation. However, many research groups lack computing facilities and specialists. This is an obstacle that remains to be addressed. Here, we present a Linux distribution, LXtoo, to provide a flexible computing platform for bioinformatics analysis. FINDINGS: Unlike most of the existing live Linux distributions for bioinformatics limiting their usage to sequence analysis and protein structure prediction, LXtoo incorporates a comprehensive collection of bioinformatics software, including data mining tools for microarray and proteomics, protein-protein interaction analysis, and computationally complex tasks like molecular dynamics. Moreover, most of the programs have been configured and optimized for high performance computing. CONCLUSIONS: LXtoo aims to provide well-supported computing environment tailored for bioinformatics research, reducing duplication of efforts in building computing infrastructure. LXtoo is distributed as a Live DVD and freely available at http://bioinformatics.jnu.edu.cn/LXtoo. PMID- 22813357 TI - Skin sensitization study of bee venom (Apis mellifera L.) in guinea pigs and rats. AB - BACKGROUND: Bee venom (Apis mellifera L., BV) possessing a rich source of pharmacologically active substances has the potential to be used as a cosmetic ingredient for antiaging, antiinflammatory and antibacterial functions. The aim of this study was to assess the skin sensitization of BV on experimental animals using the Buehler test. MATERIALS AND METHODS: Guinea pigs were randomly allocated into three groups of BV-sensitization, positive control-sensitization, and ethyl alcohol-sensitization group for induction and challenge. On the other hand, two groups of rats were administered with BV at doses of 0 and 1500 mg/kg. Clinical signs, mortality and body weight changes were continually monitored during the study period. RESULTS: No treatment-related clinical signs or body weight changes were observed in both animal models. The average skin reaction evaluated by erythema and edema on the challenge sites, and sensitization rate in the BV-sensitization group of guinea pigs were substantially low compared with those in positive control group, representing a negligible sensitizing potential of BV. CONCLUSION: It was concluded that BV was well tolerated and exhibited no dermal irritation potential in guinea pigs and rats. Our findings may provide a developmental basis of BV for a cosmetic ingredient or external application for topical uses. PMID- 22813358 TI - The effectiveness of early intervention on paternal stress for fathers of premature infants admitted to a neonatal intensive care unit. AB - AIM: This article is a report of a study to evaluate the effectiveness of an intervention on fathering ability, perceived nurse's support and paternal stress after a preterm infant's admission to a neonatal intensive care unit. BACKGROUND: The birth of a premature infant who is admitted to a neonatal intensive care unit is a stressful experience. Due to the maternal postpartum practice in Taiwan, the father is the main visitor of the infant during the first few weeks, but interventions have rarely focused on the father. DESIGN: A historical comparison study. METHODS: Between August 2009-July 2010, 35 fathers in the comparison group received routine care; 34 fathers in the intervention group received a booklet designed for the fathers during their visits to the neonatal intensive care unit and nurses' guidance based on the contents of the booklet. Fathering ability, perceived nurse's support and paternal stress were measured. FINDINGS: The intervention group had a significantly higher fathering ability and perceived nurse support than the comparison group. In the intervention group, the increased fathering ability reduced paternal stress. After adjusting for severity of illness, an significant moderating effect of perceived nurse support on the relationship between fathering ability and paternal stress was found, accounting for 59.5% of variance. CONCLUSION: Designing a supportive intervention which provides informational, emotional, instrumental, and esteem support for the father can effectively empower his fathering ability and reduce his stress. The intervention should be initiated from the early admission of the premature infant to the neonatal intensive care unit. PMID- 22813359 TI - Guidelines for treatment of atopic eczema (atopic dermatitis) Part II. AB - The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. 'Eczema school' educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies. PMID- 22813360 TI - Physiologic changes during normal pregnancy and delivery. AB - The major adaptations of the maternal cardiovascular system that progress throughout gestation may unmask previously unrecognized heart disease and result in significant morbidity and mortality. Most of these changes are almost fully reversed in the weeks and months after delivery. Hemodynamic changes during pregnancy include increased blood volume, cardiac output (CO), and maternal heart rate; decreased arterial blood pressure; decreased systemic vascular resistance. CO increases up to 30% in the first stage of labor, primarily because of increased stroke volume; maternal pushing efforts in the second stage of labor can increase CO by as much as 50%. PMID- 22813361 TI - Cardiovascular imaging and diagnostic procedures in pregnancy. AB - Diagnostic imaging procedures, including echocardiography, chest radiography, angiography, CT, and cardiovascular MRI, may be indicated in pregnant patients. Concerns related to the safety of these tests must be balanced against the importance of accurate diagnosis and assessment of a pathologic state. Such a calculation requires an understanding of the normal physiology of pregnancy, manifestations of pre-existing cardiac disease in pregnant women, and signs and symptoms of nascent cardiovascular disease. Additionally cardiologists must understand indications for and limitations of each diagnostic imaging test, potential harmful effects of various modalities, and precautions that must be taken to protect the fetus. PMID- 22813362 TI - Chest pain syndromes in pregnancy. AB - Chest pain syndromes in pregnancy include numerous catastrophic cardiovascular events. Acute myocardial infarction, aortic dissection, pulmonary embolism, and amniotic fluid embolism are the most important causes of nonobstetric mortality and morbidity in pregnancy. Each of these could result in poor maternal and fetal outcomes if not diagnosed and treated in a timely fashion. However, their diagnosis and management is limited by fetal risks of diagnostic procedures, dangers of pharmacotherapy and interventions that have neither been widely studied nor validated. This article reviews the current literature on epidemiology, risk factors, pathogenesis, diagnosis, and management of 4 potentially lethal chest pain syndromes in pregnancy. PMID- 22813363 TI - Valvular heart disease and pregnancy. AB - Among women with valvular heart disease, those with mitral stenosis carry the greatest potential for problems during pregnancy. Asymptomatic women with aortic stenosis and only mild or moderate left ventricular outflow obstruction generally tolerate pregnancy well, as do those with regurgitant lesions. In Marfan syndrome, pregnancy should not be undertaken if the aortic root dimension exceeds 4 cm. Even if the aortic root is normal, a small increased risk of dissection is present. Women with well-functioning bioprosthetic valves and normal hemodynamics may safely undertake a pregnancy, although bioprostheses deteriorate rapidly in young people. PMID- 22813364 TI - Congenital heart disease in pregnancy. AB - Heart disease is a main cause of maternal mortality in the United States and the United Kingdom. Most deaths are from acquired conditions. However, due to the increased survival of children born with congenital heart disease (CHD) over the past 30 years, the population of adults with congenital heart disease in the U.S. now exceeds 1 million. Thus, there are now more adults with CHD than children with CHD. Many of these adult survivors of pediatric heart disease are of childbearing age and are considering pregnancy. This article reviews the literature concerning pregnancy and CHD. PMID- 22813365 TI - Anticoagulation in pregnancy. AB - Pregnancy-associated thrombosis is an important cause of morbidity and mortality during pregnancy. Anticoagulation therapy is an important component of the management of thrombotic complications in pregnancy but may result in fetal and maternal complications. Although evidence-based recommendations are available for the prevention and treatment of venous thromboembolism, the management of pregnant women with mechanical valves still presents a challenge, because there are no controlled clinical trials to provide guidelines for optimal antithrombotic therapy. This review presents information on anticoagulation therapy during pregnancy for thromboembolic prophylaxis in women with various cardiovascular disorders, focusing on patients with mechanical heart valves. PMID- 22813366 TI - Hypertension in pregnancy. AB - Hypertension in pregnancy is diagnosed on systolic blood pressure greater than or equal to 140 mm Hg and/or diastolic greater than or equal to 90 mm Hg. The classification systems separate chronic and gestational hypertension from preeclampsia. Significant uncertainty regarding optimal management is reflected in the differing major international society recommendations. Blood pressure treatment is designed to minimize maternal end-organ damage. Methyldopa, labetalol, hydralazine, and nifedipine are oral options; angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are contraindicated. Women with preeclampsia should be closely monitored and receive intravenous magnesium sulfate. PMID- 22813367 TI - Arrhythmias in pregnancy. AB - Pregnant women have an increased risk of having the usual arrhythmias seen in women of childbearing age. Most of these are benign sinus tachycardias or bradycardias or atrial and ventricular ectopic beats. Women who have had sustained supraventricular or ventricular tachycardias before pregnancy frequently develop them during pregnancy. These arrhythmias often have enough hemodynamic significance to decrease uterine blood flow, which adds a sense of urgency for treatment. The management is similar to that of nonpregnant women, with nuances important for the protection of the developing fetus. PMID- 22813368 TI - Peripartum cardiomyopathy. AB - In 1971, Demakis and colleagues established the term peripartum cardiomyopathy (PPCM) and defined it by criteria based on the clinical profile of their patients. With the recognition that these criteria are arbitrary and that PPCM often presents earlier in pregnancy, the definition of PPCM has been recently updated by a working group on PPCM of the European Society of Cardiology. This article discusses the cause, clinical presentation, prognosis, and treatment of PPCM, as well as other related topics. PMID- 22813369 TI - Pregnancy after cardiac transplantation. AB - More women are reporting pregnancy following heart transplantation. Although successful outcomes have been reported for the mother, transplanted heart, and newborn, such pregnancies should be considered high risk. Hypertension, preeclampsia, and infection should be treated. Vaginal delivery is recommended unless cesarean section is obstetrically necessary. Most outcomes are live births, and long-term follow-up of children show most are healthy and developing well. Maternal survival, independent of pregnancy-related events, should be part of prepregnancy counseling. PMID- 22813370 TI - Cardiopulmonary resuscitation in pregnancy. AB - Cardiac arrest in pregnancy is not only uncommon but also catastrophic. Early aggressive resuscitation by well-trained health care providers improves the chances of successful outcomes for both the patient and her fetus. Significant physiologic changes that occur normally in pregnancy require several modifications to standard cardiopulmonary resuscitation, and urgent cesarean delivery may be indicated to benefit both the mother and the infant. PMID- 22813371 TI - Cardiovascular drugs in pregnancy. AB - Cardiovascular drugs are used in pregnancy to treat maternal and fetal conditions. Mothers may also require drug therapy postpartum. Most cardiovascular drugs taken by pregnant women can cross the placenta and therefore expose the developing embryo and fetus to their pharmacologic and teratogenic effects. These effects are influenced by the intrinsic pharmacokinetic properties of a given drug and by the complex physiologic changes occurring during pregnancy. Many drugs are also transferred into human milk with potential adverse effects on the nursing infant. This article summarizes some of the literature concerning the risks and benefits of using cardiovascular drugs during pregnancy. PMID- 22813372 TI - Cardiovascular disease in pregnancy. Foreword. PMID- 22813373 TI - Cardiovascular disease in pregnancy. Preface. PMID- 22813389 TI - Influenza surveillance from November 2008 to 2011; including pandemic influenza A(H1N1)pdm09 in Bhutan. AB - OBJECTIVE: Describe the influenza A(H1N1) pandemic in Bhutan. DESIGN: Observational study from sentinel surveillance sites. SETTING: Bhutan remains isolated, with only one to two flights a day at the lone airport, no trains, and only three major roads that enter from India. MAIN OUTCOME MEASURES: PCR positive human respiratory samples. RESULTS: The first case of A(H1N1)pdm09 infection was detected in Bhutan in July 2009, 3 months after the virus was first reported in Mexico in April 2009. During the official WHO pandemic period (11 June 2009 to 8 August 2010), a total of 2149 samples were collected and tested by RT-PCR of which 22.7% (487) were confirmed A(H1N1)pdm09; H3N2, H1N1, and B were positive in 2.2%, 1.1%, and 7.2%, respectively. The highest rate of A(H1N1)pdm09 cases (57.4%) was detected in the 6-20 year-old age group. Importantly, Bhutan increased from 3 sentinel sites in April 2009 to 11 a year later, and in April 2010 established PCR capability for influenza. CONCLUSIONS: Despite relative isolation, the A(H1N1)pdm09 reached Bhutan within 3 months of identification in Mexico. The H1N1 pandemic has made Bhutan more prepared for epidemics in the future. PMID- 22813390 TI - The waiting game: the emergency patient as a customer. PMID- 22813392 TI - Is there a role for acetaminophen in the management of hyperthermia in poisoned patients? PMID- 22813393 TI - Development of emergency medicine in ethiopia. PMID- 22813394 TI - Emergency physician workload modeling. AB - BACKGROUND: A variety of models are used by hospitals, provincial governments, and departments of emergency medicine to "predict" the number of physician hours of coverage necessary to staff emergency departments. These models have arisen to meet specific requirements-some for the purpose of determining hourly rates of compensation, others to determine the amount of funding that will be provided to "purchase" physician coverage, and others to determine the number of hours of coverage necessary to maintain patient waits within "acceptable" limits. All such models have their strengths and weaknesses and have been criticized as not reflecting the "real" needs of any given department. OBJECTIVE: In the article that follows, a review of existing models is presented, annotating their strengths and weaknesses to derive the characteristics of an "ideal" workload model. CONCLUSION: None of the models currently used to measure emergency department workload can be relied on to accurately predict the number of staffed hours necessary. Models that may achieve this objective are suggested. PMID- 22813395 TI - Are patients willing to remove, and capable of removing, their own nonabsorbable sutures? AB - OBJECTIVES: Providing patients with instructions and equipment regarding self removal of nonabsorbable sutures could represent a new efficiency in emergency department (ED) practice. The primary outcome was to compare the proportion of patients successfully removing their own sutures when provided with suture removal instructions and equipment versus the standard advice and follow-up care. Secondary outcomes included complication rates, number of physician visits, and patient comfort level. METHODS: This prospective, controlled, single-blinded, pseudorandomized trial enrolled consecutive ED patients who met the eligibility criteria (age > 19 years, simple lacerations, nonabsorbable sutures, immunocompetent). The study group was provided with wound care instructions, a suture removal kit, and instructions regarding suture self-removal. The control group received wound care instructions alone. Outcomes were assessed by telephone contact at least 14 days after suturing using a standardized questionnaire. RESULTS: Overall, 183 patients were enrolled (93 in the intervention group; 90 in the control group). Significantly more patients performed suture self-removal in the intervention group (91.5%; 95% CI 85.4-97.5) compared to the control group (62.8%; 95% CI 52.1-73.6) (p < 0.001). Patients visited their physician less often in the intervention group (9.8%; 95% CI 3.3-16.2) compared to the control group (34.6%; 95% CI 24.1-45.2%) (p < 0.001). Complication rates were similar in both groups. CONCLUSION: Most patients are willing to remove, and capable of removing, their own sutures. Providing appropriate suture removal instructions and equipment to patients with simple lacerations in the ED appears to be both safe and acceptable. PMID- 22813396 TI - Compliance with the Canadian Association of Emergency Physicians' asthma clinical practice guidelines at a tertiary care emergency department. AB - INTRODUCTION: Although evidence-based clinical practice guidelines (CPGs) exist, emergency department (ED) asthma management remains highly variable. Our objective was to compare asthma management at a tertiary care ED with that advised by the Canadian Association of Emergency Physicians' (CAEP) asthma CPG and current best practice. METHODS: This medical record study enrolled patients between the ages of 19 and 60 years with a previous diagnosis of asthma who were seen for an acute asthma exacerbation at the Vancouver General Hospital ED in 2008. Standard methodology guidelines for medical record review were followed, including explicitly defined criteria and determination of interrater reliability. Primary outcomes were the proportion of cases with the following: objective assessment of severity using peak expiratory flow (PEF), use of systemic corticosteroids (SCSs) in the ED and at discharge, prescription for any inhaled corticosteroids (ICSs), and documentation of outpatient follow-up. RESULTS: A total of 204 patient encounters were enrolled. Kappa values for interrater assessment ranged from 0.93 to 1.00. Compliance with primary outcomes was as follows: measurement of PEF, 90% (95% CI 85-94); use of SCSs in the ED, 64% (95% CI 57-71); prescription of SCSs at discharge, 59% (95% CI 51-67); prescription of any ICS at discharge, 51% (95% CI 41-61); and documentation of outpatient follow-up, 78% (95% CI 71-84). CONCLUSIONS: This study indicates an improvement in ED asthma care compared to previously published studies; however, discordance still exists between asthma management at a tertiary care ED and the CAEP asthma CPG and current best practice. Further research is warranted to understand the reasons for this finding. PMID- 22813397 TI - Influence of publicly available online wait time data on emergency department choice in patients with noncritical complaints. AB - OBJECTIVES: Increased emergency department (ED) wait times lead to more patients who leave without being seen and decreased patient satisfaction. Many EDs post estimated wait times either online or in the ED to guide patient expectations. The objectives of this study were to assess patients' awareness of online wait time data and to investigate patients' willingness to use this information when choosing between two academic EDs in London, Ontario. METHODS: A prospective study was conducted over a 2-month period in a tertiary ED with online available wait times. Patients over 18 years of age assigned a Canadian Triage and Acuity Scale (CTAS) score of 3, 4, or 5 were approached by trained research assistants to complete a 15-item paper-based questionnaire. Multivariable logistic regression models were used to determine factors independently associated with the outcomes. RESULTS: A total of 1,211 patients completed the survey. Of these, 109 (9%) were aware that ED wait time information was available on the Internet; 544 (45%) reported that they would use the available data to make a decision on which ED to visit, and 536 (44%) indicated that they were more likely to go to the ED with a shorter wait time. Age, gender, household income, education, and Internet access were not associated with awareness of online ED wait times. Participants less than 40 years of age were more likely to use online wait time information. CONCLUSION: There is low awareness of the availability of ED wait time data published online in the study locaton. Future research may include the delivery of a public awareness strategy for ED wait time data and a re-evaluation of ED use and patient satisfaction following this. PMID- 22813398 TI - Review of the CATCH study: a clinical decision rule for the use of computed tomography in children with minor head injury. AB - CLINICAL QUESTION: In children with minor head trauma, which elements of the history and physical examination, combined as a clinical decision rule, can be used to rule out clinically significant brain trauma? ARTICLE CHOSEN: Osmond MH, Klassen TP, Wells GA, et al. CATCH: a clinical decision rule for the use of computed tomography in children with minor head injury. CMAJ 2010;182:341-48. OBJECTIVE: To prospectively derive a sensitive and reliable clinical decision rule for the use of computed tomography in children with minor head injury. PMID- 22813399 TI - Defining abnormal electrocardiography in adult emergency department syncope patients: the Ottawa Electrocardiographic Criteria. AB - BACKGROUND: Previous studies have indicated that the suboptimal performance of the San Francisco Syncope Rule (SFSR) is likely due to the misclassification of the "abnormal electrocardiogram (ECG)" variable. We sought to identify specific emergency department (ED) ECG and cardiac monitor abnormalities that better predict cardiac outcomes within 30 days in adult ED syncope patients. METHODS: This health records review included patients 16 years or older with syncope and excluded patients with ongoing altered mental status, alcohol or illicit drug use, seizure, head injury leading to loss of consciousness, or severe trauma requiring admission. We collected patient characteristics, 22 ECG variables, cardiac monitoring abnormalities, SFSR "abnormal ECG" criteria, and outcome (death, myocardial infarction, arrhythmias, or cardiac procedures) data. Recursive partitioning was used to develop the "Ottawa Electrocardiographic Criteria." RESULTS: Among 505 included patient visits, 27 (5.3%) had serious cardiac outcomes. We found that patients were at risk for cardiac outcomes within 30 days if any of the following were present: second-degree Mobitz type 2 or third-degree atrioventricular (AV) block, bundle branch block with first-degree AV block, right bundle branch with left anterior or posterior fascicular block, new ischemic changes, nonsinus rhythm, left axis deviation, or ED cardiac monitor abnormalities. The sensitivity and specificity of the Ottawa Electrocardiographic Criteria were 96% (95% CI 80-100) and 76% (95% CI 75-76), respectively. CONCLUSION: We successfully identified specific ED ECG and cardiac monitor abnormalities, which we termed the Ottawa Electrocardiographic Criteria, that predict serious cardiac outcomes in adult ED syncope patients. Further studies are required to identify which adult ED syncope patients require cardiac monitoring in the ED and the optimal duration of monitoring and to confirm the accuracy of these criteria. PMID- 22813400 TI - Iatrogenic bacterial meningitis: an unmasked threat. AB - Iatrogenic bacterial meningitis (IBM) is a rare but serious complication of neuraxial procedures, such as spinal and epidural anesthesia or lumbar puncture. We report a case of a 46-year-old female who presented to the emergency department with bacterial meningitis after spinal anesthesia. We review the existing literature outlining the pathogenesis, vector hypothesis, diagnosis, treatment, and prevention as they relate to IBM. We highlight the role of the emergency physician in the rapid diagnosis of this disease, and underscore the need for sterile technique when performing lumbar punctures. PMID- 22813401 TI - Amphiphiles based on D-glucose: efficient low molecular weight gelators. AB - A series of novel amphiphiles were synthesized based entirely on renewable resources. Besides their efficacy as supramolecular gelators in a wide variety of organic solvents and also water, their surface properties as surfactants and emulsifiers have been determined. A methodical study revealed that the length of the hydrocarbon chains has a dramatic and decisive influence on the thermal stabilities of the obtained hydrogels. PMID- 22813403 TI - Prevalence of metabolic syndrome in patients with angiographically proven coronary artery disease presenting to a tertiary care hospital in Delhi, India. AB - BACKGROUND: Coronary artery disease is fast emerging as the major concern for afflicting people across the globe. The Indian subcontinent is highly predisposed to this condition due to distinctive risk factor profile of this population. This fact has led to a condition where the current preventative and management protocols that have worked well in the non-Asian Indian Caucasian populations, have failed to bring about the anticipated control over the incidence and progression of CAD in Asian Indians. Metabolic syndrome has been identified as a major determinant of CAD in this population. MATERIALS AND METHODS: The prevalence of metabolic syndrome was determined in 431 patients undergoing coronary angiography through various diagnostic algorithms. The Asian modified diagnostic criteria were also implemented to estimate the metabolic syndrome prevalence in patients with different levels of stenosis. RESULTS: We observed a high incidence of metabolic syndrome in the patients with coronary artery disease. The prevalence of MS increased with increase in severity of coronary artery involvement. The IDF guideline with Asian modification was the most successful diagnostic algorithm. CONCLUSIONS: It is now imperative to acknowledge the unique pattern of CAD and risk factor profile prevalent among South Asians. This will facilitate more focused and individualized management protocols directed to this population. Metabolic syndrome is a major syndrome prevalent in this population. Hence, effective control of MS may help in reducing the morbidity and mortality due to CAD in a great way. PMID- 22813402 TI - Tumor stromal vascular endothelial growth factor A is predictive of poor outcome in inflammatory breast cancer. AB - BACKGROUND: Inflammatory breast cancer (IBC) is a highly angiogenic disease; thus, antiangiogenic therapy should result in a clinical response. However, clinical trials have demonstrated only modest responses, and the reasons for these outcomes remain unknown. Therefore, the purpose of this retrospective study was to determine the prognostic value of protein levels of vascular endothelial growth factor (VEGF-A), one of the main targets of antiangiogenic therapy, and its receptors (VEGF-R1 and -R2) in IBC tumor specimens. PATIENTS AND METHODS: Specimens from IBC and normal breast tissues were obtained from Algerian patients. Tumor epithelial and stromal staining of VEGF-A, VEGF-R1, and VEGF-R2 was evaluated by immunohistochemical analysis in tumors and normal breast tissues; this expression was correlated with clinicopathological variables and breast cancer-specific survival (BCSS) and disease-free survival (DFS) duration. RESULTS: From a set of 117 IBC samples, we evaluated 103 ductal IBC tissues and 25 normal specimens. Significantly lower epithelial VEGF-A immunostaining was found in IBC tumor cells than in normal breast tissues (P <0.01), cytoplasmic VEGF-R1 and nuclear VEGF-R2 levels were slightly higher, and cytoplasmic VEGF-R2 levels were significantly higher (P = 0.04). Sixty-two percent of IBC tumors had high stromal VEGF-A expression. In univariate analysis, stromal VEGF-A levels predicted BCSS and DFS in IBC patients with estrogen receptor-positive (P <0.01 for both), progesterone receptor-positive (P = 0.04 and P = 0.03), HER2+ (P = 0.04 and P = 0.03), and lymph node involvement (P <0.01 for both). Strikingly, in a multivariate analysis, tumor stromal VEGF-A was identified as an independent predictor of poor BCSS (hazard ratio [HR]: 5.0; 95% CI: 2.0-12.3; P <0.01) and DFS (HR: 4.2; 95% CI: 1.7-10.3; P <0.01). CONCLUSIONS: To our knowledge, this is the first study to demonstrate that tumor stromal VEGF-A expression is a valuable prognostic indicator of BCSS and DFS at diagnosis and can therefore be used to stratify IBC patients into low-risk and high-risk groups for death and relapses. High levels of tumor stromal VEGF-A may be useful for identifying IBC patients who will benefit from anti-angiogenic treatment. PMID- 22813404 TI - Taq1B polymorphism of cholesteryl ester transfer protein (CETP) in Egyptian patients with metabolic syndrome. AB - AIM: We aimed at evaluation of the possible association of cholesteryl ester transfer protein (CETP) Taq1B polymorphism with the components of metabolic syndrome in a cohort of Egyptian patients compared to their healthy counterparts. PATIENTS AND METHODS: Blood samples were collected for lipid profile, fasting glucose, insulin and routine biochemical tests. The Taq1B genotypes of CETP were determined using RFLP-PCR technique. RESULTS: The patients group showed a significantly higher B1B1 genotype and lower B2B2 genotype compared to the controls group. Serum HDL-C level was significantly higher in all subjects with the B2B2 genotype compared to those with B1B1 genotype. In the patients group, age positively correlated with cholesterol level, triglycerides, BMI and waist circumference. CONCLUSION: Egyptian patients affected with metabolic syndrome have a higher prevalence of B1B1 genotype that is associated with lower serum HDL C levels. PMID- 22813405 TI - Biliopancreatic diversion induces villi elongation and cholecystokinin and ghrelin increase. AB - INTRODUCTION: Factors leading to weight loss and weight stabilization after bariatric surgery are not fully understood. Our aim was to evaluate, in Sprague Dawley rats, the histological and gut hormonal changes after Larrad biliopancreatic diversion (Larrad-BPD). MATERIALS AND METHODS: Rats randomly underwent the following protocols: Larrad-BPD (n=4) versus pair fed (PF) (n=4). Weight and food intake were measured every day. By immunohistochemistry ghrelin was examined in the stomach, while cholecystokinin (CCK), glucagon-like-peptide-1 (GLP-1), peptide YY (PYY) and serotonin (5-HT) expression were analyzed in alimentary limb and ileum following or not the Larrad-BPD. RESULTS: Larrad-BPD rats exhibited significant (P<0.05) weight loss compared to PF rats. Villi enlongation was observed in Larrad-BPD rats. In residual stomach, ghrelin was diminished. In the alimentary limb, ghrelin and CCK positive cells were detected more than in the ileum of PF rats. GLP-1 expression was decreased and PYY expression was absent after Larrad-BPD compared with PF rats. DISCUSSION: Larrad BPD is followed by histological changes and a pleiotropic gut endocrine response aimed to compensate the reduction of intestinal area exposed to food. Until now, the hormones responsible for the intestinal hypertrophy have not been defined. PMID- 22813406 TI - Compare the effects of different visfatin concentration on cardiovascular risk factors, adiponectin and insulin resistance in patients with T2DM. AB - AIM: The discovery of new adipokine, visfatin can significantly enhance our knowledge of insulin resistance and diabetes mellitus. We explored the relation of visfatin concentrations to cardiovascular risk factors, adiponectin and insulin resistance criteria in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Fifty-eight patients with T2DM were recruited from the out patients clinic of Shariati Hospital. Laboratory and anthropometric measurements include FBG, OGTT, HbA1c, fasting serum visfatin, insulin and adiponectin, HOMA IR and hsCRP, weight, height, BMI and WHR were performed in all participants. All of the statistical data were analyzed using the SPSS15 software. RESULTS: The log(10)-transformed (log) plasma visfatin concentration was in significant positive correlation with age (r=0.286, p=0.033). Patients were divided in two groups by median log visfatin (0.85 ng/mL): group I had low values and group II had high values. In group I the log visfatin was in significant positive correlation with age (r=0.436, p=0.018) and in group II log visfatin was in significant negative correlation with FPG and HbA1c (r>0.4, p<0.05). CONCLUSION: In conclusion high circulating levels of visfatin could be in healthy relations with cardiovascular risk factors, insulin resistance status and adiponectin in diabetic patients. PMID- 22813407 TI - Association of nonalcoholic fatty liver disease with metabolic syndrome in Indian population. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), a common cause of cryptogenic cirrhosis is often associated with metabolic syndrome (MS) in the West. However, its association with MS in the Indian population is not well studied. AIMS: To evaluate the association NAFLD with MS using the modified ATP III criteria. PATIENTS AND METHODS: Seventy-six (62 men, mean age 40.05+/-11.4 years, range 18-66) apparently healthy subjects with fatty liver and histological evidence of NAFLD; with (64.5%) or without raised ALT, and 100 healthy controls were included in the study. The anthropometric measurements, metabolic parameters, tests of liver function and liver histology were studied. RESULTS: Twenty-one percent of the patients compared to 8% controls (p<0.01) had associated MS; according to ATP-III criteria while 42 and 12% were affected when the modified ATP-III criteria were used. About 35% of non-diabetic patients were insulin resistant with homeostatic model assessment-insulin resistance (HOMA-IR) cut-off set at 3. In patients, compared to controls, the mean BMI (25.2 vs. 22.7, p<0.01) and waist circumferences (92.9 cm vs. 80.8 cm, p<0.01) were higher. Seventy-nine percent of the patients and 44% of the controls were over weight. Stage 1 fibrosis was seen in 30 (39.5%), stage 2 in 10 (13.2%), stage 3 in 6 (7.9%) and stage 4 in 13 (17%) patients. CONCLUSIONS: Insulin resistance and obesity are associated in a proportion of Indian patients with NAFLD. However, the association with MS as defined by ATP-III in Indian patients is not strong compared to the West. It is likely that pathogenetic mechanisms unrelated to MS underlie development of NAFLD in a proportion of Indian patients. PMID- 22813408 TI - Metabolic syndrome: a clinic based rural study--are women at high risk? AB - BACKGROUND: Reports of urban based studies suggest an increase in the prevalence of MS worldwide along with diabetes, hypertension and atherogenic dyslipidemia. The supporting rural based studies on MS are few and prevalence of MS among women is underestimated. In this prospective study we have evaluated the clinic prevalence of metabolic syndrome among rural Indian population with special emphasis on prevalence in women. RESEARCH DESIGN AND METHOD: 2329 patients attending to diabetic centre were evaluated for the markers of MS. Anthropometric measurements, clinical assessment, capillary blood glucose and lipid profile (TC, HDL-C, TG, LDL-C, VLDL-C) were done and classified as per NCEP ATP III and NCEP ATP III modified for Asian guidelines. We compared the prevalence of MS between males and females for statistical significance by SPSS 16.0 statistical software. The level of significance was kept at <0.05. RESULTS: The Clinic prevalence of metabolic syndrome was 61.74% with 57.59% males and 69.66% females as per NCEP ATP III guidelines. 73.85% of the study population had MS, with 68.85% males and 83.39% females had MS as per modified Asian criteria. We could get a statistically significant variation between males and females in FBS, PPBS, SBP, DBP, TC, HDL-C, TG, LDL-C, VLDL-C, TC/HDL, LDL/HDL, BMI, W/H ratio and W/S ratio. CONCLUSION: Prevalence MS is increasing at an epidemic proportion bringing with it micro and macro vascular complications. Women are more prone to develop MS in rural population than the men and there is a statistically significant variation in the biochemical and anthropometric parameters. This is an era of 'gender equality'; here we see women over taking men in metabolic syndrome and its complications. PMID- 22813409 TI - Effect of vitamin D supplementation in type 2 diabetes patients with pulmonary tuberculosis. AB - AIM: Diabetes and vitamin D deficiency are widely prevalent in India. Studies have proven correlation between low vitamin D levels and pulmonary tuberculosis (PTB) and low vitamin D levels and insulin resistance. We evaluated the effects of vitamin D supplementation on type 2 diabetes mellitus patients with pulmonary tuberculosis (PTB). METHODS: Forty-five subjects (M:F=34:11) were screened. Inclusion criteria were age >15 years, newly diagnosed PTB cases with uncontrolled diabetes, serum vitamin D<20 ng/ml. The patients with vitamin D level<20 ng/ml were randomly assigned to 2 groups. Group 1 subjects received oral cholecalceferol (60,000 units/week) and calcium carbonate (1g/day) along with anti tubercular treatment (ATT), while group 2 subjects did not. Sputum was checked at interval of 2 weeks for 12 weeks. Primary end point was time to achieve sputum smear conversion. RESULTS: Fifteen patients having vitamin D>20 ng/ml were excluded. Age of the patients was 42.9+/-13.2 years and serum vitamin D levels were 18.4+/-15.3 ng/ml. Sputum smear conversion was 6 weeks in group 1 versus 8 weeks in group 2 (p=0.067). Glycated hemoglobin levels reduced from 11.1+/-1.3 to 7.7+/-0.9 in group 1 versus 10.3+/-1.2 to 7.8+/-1.1 (p>0.1). CONCLUSION: Vitamin D can serve as adjuvant treatment of tuberculosis in diabetics with vitamin D deficiency. Further studies are required to validate this observation and define a cut off for vitamin D level to prevent immunological alterations. PMID- 22813410 TI - Prevalence of metallo-beta-lactamase-producing Pseudomonas aeruginosa isolated from diabetic foot ulcer patients. AB - Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa strains have been reported to be an important cause of nosocomial infections. There is not enough information from India regarding their prevalence in diabetic foot ulcer (DFU) patients. The present study was undertaken over a period of two year from December 2008 to March 2011 to study the incidence of MBL producing P. aeruginosa isolated from 162 DFU patients with various grades of ulcer (Texas classification). Forty isolates of P. aeruginosa were obtained from patients. These isolates were subjected to susceptibility testing to anti-pseudomonal drugs as per Clinical Laboratory and Standards Institute (CLSI) guidelines, and were further screened for the production of MBL by disc potentiation testing using ethylenediaminetetraacetic acid (EDTA)-impregnated imipenem and meropenem discs. Of the 40 isolates of P. aeruginosa, 22 (55%) isolates were found resistant to carbapenems (imipenem) and 18 (81.1%) were found to be MBL producers using imipenem+(EDTA) and 15(68.1%) by meropenem+EDTA. This rapid dissemination of MBL producers is worrisome and necessitates the implementation of not just surveillance studies but also proper and judicious selection of antibiotics, especially carbapenems. PMID- 22813411 TI - Prevalence of metabolic syndrome and associated socioeconomic and demographic factors among Palestinian adults (20-65 years) at the Gaza Strip. AB - OBJECTIVES: Metabolic syndrome (MetS) is a multifaceted syndrome and has been described as a clustering of several risk factors for cardiovascular disease. This study was conducted to estimate the prevalence of MetS and its individual components among Palestinian adults, 20-65 years old in Gaza Strip. In addition to find any possible associations with socioeconomic and demographic factors. MATERIAL AND METHODS: The study sample included 230 adults aged 20-65 years. Data were collected by questionnaire interviews, anthropometrics, and biochemical analysis that included: serum glucose, total cholesterol, triglyceride, HDL, and LDL. MetS was defined according to the NCEP/ATP III diagnostic criteria. RESULTS: Overall prevalence of MetS was 23.0% among the study subjects, with no significant differences between males (18.1%) and females (28.1%). The prevalence of MetS increased significantly with age and was associated significantly with physical activity and martial status, while no significant associations were found with household income; geographical locality; smoking; watching TV; or family history. CONCLUSIONS: Age, sex, physical activity and marital status are risk factors independently associated with MetS in the Palestinian population at the Gaza Strip. National health awareness and preventive programs should be established aiming at decreasing of MetS trends in the Palestinian population at Gaza Strip. PMID- 22813412 TI - Energy metabolism and the metabolic syndrome: does a lower basal metabolic rate signal recovery following weight loss? AB - AIM: To determine whether basal metabolic rate (BMR) was causally related to MetS, and to study the role of gender in this relationship. METHODS: Seventy-two Caucasian subjects (43 women, 29 men) had changes in basal metabolic rate (BMR), carbohydrate oxidation rate (COR), fat oxidation rate (FOR) and prevalence of the metabolic syndrome (MetS) assessed in response to weight loss. RESULTS: There was a significant gender*MetS interaction in BMR at the start. Women with MetS had higher adjusted BMR, whilst men with MetS had lower adjusted BMR than their respective counterparts. Weight loss resulted in a significant decrease in fat mass (-5.2+/-0.31 kg, p=0.001), fat free mass (-2.3+/-0.27 kg, p=0.001), BMR ( 549+/-58 kJ/d, p=0.001) and a decreased proportion of MetS (22/72, chi(2)=0.005). Subjects who recovered from MetS after weight loss (RMS) had ~250 kJ/d significantly lower adjusted BMR compared to those who were never MetS (NMS, p=0.046) and those who still had MetS (MetS+, p=0.047). Regression analysis showed that change (Delta) in BMR was best determined by Deltaglucose*gender interaction (r(2)=23%), DeltaFOR (r(2)=20.3%), DeltaCOR (r(2)=19.4%) and Deltatriglycerides (r(2)=7.8%). CONCLUSIONS: There is a sexual dimorphism of BMR in MetS. Overall, the data support the notion that alterations in BMR may be central to the etiopathogenesis of MetS. PMID- 22813413 TI - Nuclear denotation and diabetes mellitus: a story. PMID- 22813414 TI - Thai ethnopharmacological herbs for diabetes treatment: data collection and informatics tracing for therapeutic property. AB - BACKGROUND: In the present day, the standard treatments for this medical disorder include diet modification, antidiabetic drug and insulin treatment. However, in additional to standard treatment, the role of complementary and alternative medicine (CAM) should be mentioned. OBJECTIVE: Here, the author reports on the important Thai herbs that are used as compositions for CAM regimen for diabetes mellitus. Further informatics approach is done to fulfill the existed usefulness of identified herbs. METHODS: The data from famous classical Thai CAM centers then details of detected herbal contents in the regimens were registered. The derived ethnopharmacological registered data on Thai herbs were further assessed for its clinical feasibility for usage in diabetes treatment by matching the reported literature in the public standard medical database. RESULTS: There are 7 identified herbs with 1 herb that has supportive evidence in the published literature for feasibility in using in diabetes treatment. CONCLUSION: There are many local Thai herbs that should be studied for its ethnopharmacological property for diabetes treatment. This is a preliminary for further research on diabetes treatment. PMID- 22813415 TI - DPP IV inhibitors: successes, failures and future prospects. AB - The dipeptidyl peptidase IV (DPP IV) enzyme is a novel target for the treatment of type 2 diabetes. Several DPP IV inhibitors are in the clinical development, since they are safe and tolerable with no increased risk of adverse events compared to placebo and have a low risk of hypoglycemia. They are flourishing as monotherapy and also in combination with commonly prescribed antidiabetic agents and are appropriate for once-daily oral dosing. However, further studies are needed to validate both long-term beta-cell preservation and the role of these agents in the management of diabetes. The present review gives an inside out of the DPP IV inhibitors for its success, failure and future prospects in the treatment of diabetes and associated complication. PMID- 22813416 TI - A new framework for childhood health promotion: the role of policies and programs in building capacity and foundations of early childhood health. AB - Although the connection between early life experiences and later health is becoming increasingly clear, what is needed, now, is a new organizing framework for childhood health promotion, grounded in the latest science. We review the evidence base to identify the steps in the overall pathway to ensuring better health for all children. A key factor in optimizing health in early childhood is building capacities of parents and communities. Although often overlooked, capacities are integral to building the foundations of lifelong health in early childhood. We outline a framework for policymakers and practitioners to guide future decision-making and investments in early childhood health promotion. PMID- 22813417 TI - Improving state health policy assessment: an agenda for measurement and analysis. AB - We examine the scope of inquiry into the measurement and assessment of the state public health policy environment. We argue that there are gains to be made by looking systematically at policies both within and across health domains. We draw from the public health and public policy literature to develop the concepts of interdomain and intradomain policy comprehensiveness and illustrate how these concepts can be used to enhance surveillance of the current public health policy environment, improve understanding of the adoption of new policies, and enhance evaluations of the impact of such policies on health outcomes. PMID- 22813418 TI - Can we finally make progress on sodium intake? PMID- 22813419 TI - A functional public health surveillance system. PMID- 22813420 TI - Seeing what you breathe: the Cleveland hazecam. PMID- 22813421 TI - Who profits from uncritical acceptance of biased estimates of vaccine efficacy and safety? PMID- 22813422 TI - Tobacco crop substitution: pilot effort in China. AB - In China, approximately 20 million farmers produce the world's largest share of tobacco. Showing that income from crop substitution can exceed that from tobacco growth is essential to persuading farm families to stop planting tobacco, grown abundantly in Yunnan Province. In the Yuxi Municipality, collaborators from the Yuxi Bureau of Agriculture and the University of California at Los Angeles School of Public Health initiated a tobacco crop substitution project. At 3 sites, 458 farm families volunteered to participate in a new, for-profit cooperative model. This project successfully identified an approach engaging farmers in cooperatives to substitute food crops for tobacco, thereby increasing farmers' annual income between 21% and 110% per acre. PMID- 22813423 TI - Reducing childhood obesity by eliminating 100% fruit juice. AB - The Healthy Hunger-Free Kids Act of 2010 presents an opportunity to change the nutritional quality of foods served in low-income childcare centers, including Head Start centers. Excessive fruit juice consumption is associated with increased risk for obesity. Moreover, there is recent scientific evidence that sucrose consumption without the corresponding fiber, as is commonly present in fruit juice, is associated with the metabolic syndrome, liver injury, and obesity. Given the increasing risk of obesity among preschool children, we recommend that the US Department of Agriculture's Child and Adult Food Care Program, which manages the meal patterns in childcare centers such as Head Start, promote the elimination of fruit juice in favor of whole fruit for children. PMID- 22813424 TI - Intracranial EEG in predicting surgical outcome in frontal lobe epilepsy. AB - PURPOSE: Surgery in frontal lobe epilepsy (FLE) has a worse prognosis regarding seizure freedom than anterior lobectomy in temporal lobe epilepsy. The current study aimed to assess whether intracranial interictal and ictal EEG findings in addition to clinical and scalp EEG data help to predict outcome in a series of patients who needed invasive recording for FLE surgery. METHODS: Patients with FLE who had resective surgery after chronic intracranial EEG recording were included. Outcome predictors were compared in patients with seizure freedom (group 1) and those with recurrent seizures (group 2) at 19-24 months after surgery. KEY FINDINGS: Twenty-five patients (16 female) were included in this study. Mean age of patients at epilepsy surgery was 32.3 +/- 15.6 years (range 12 70); mean duration of epilepsy was 16.9 +/- 13.4 years (range 1-48). In each outcome group, magnetic resonance imaging revealed frontal lobe lesions in three patients. Fifteen patients (60%) were seizure-free (Engel class 1), 10 patients (40%) continued to have seizures (two were class II, three were class III, and five were class IV). Lack of seizure freedom was seen more often in patients with epilepsy surgery on the left frontal lobe (group 1, 13%; group 2, 70%; p = 0.009) and on the dominant (27%; 70%; p = 0.049) hemisphere as well as in patients without aura (29%; 80%; p = 0.036), whereas sex, age at surgery, duration of epilepsy, and presence of an MRI lesion in the frontal lobe or extrafrontal structures were not different between groups. Electroencephalographic characteristics associated with lack of seizure freedom included presence of interictal epileptiform discharges in scalp recordings (31%; 90%; p = 0.01). Detailed analysis of intracranial EEG revealed widespread (>2 cm) (13%; 70%; p = 0.01) in contrast to focal seizure onset as well as shorter latency to onset of seizure spread (5.8 +/- 6.1 s; 1.5 +/- 2.3 s; p = 0.016) and to ictal involvement of brain structures beyond the frontal lobe (23.5 +/- 22.4 s; 5.8 +/- 5.4 s; p = 0.025) in patients without seizure freedom. The distribution of ictal onset patterns was similar in both groups, and fast rhythmic activity in the beta to gamma range was found in 57% of seizure-free patients compared to 70% of patients with recurrent seizures. Analysis of the temporal relation between first clinical alterations and EEG seizure onset did not reveal significant differences between both groups of patients. In multivariate analysis, resection in the left hemisphere (odds ratio [OR] 12.197 95% confidence interval [95% CI] 1.33-111.832; p = 0.027) and onset of seizure spread (odds ratio [OR] 0.733, 95% CI 0.549 0.978, p = 0.035) were independent predictors of ongoing seizures. SIGNIFICANCE: Widespread epileptogenicity as indicated by rapid onset of spread of ictal activity likely explains lack of seizure freedom following frontal resective surgery. The negative prognostic effect of surgery on the left hemisphere is less clear. Future study is needed to determine if neuronal network properties in this hemisphere point to intrinsic interhemispheric differences or if neurosurgeons are restrained by proximity to eloquent cortex. PMID- 22813425 TI - Vitamin A deficiency disrupts vaccine-induced antibody-forming cells and the balance of IgA/IgG isotypes in the upper and lower respiratory tract. AB - Vaccination by intranasal (IN) inoculation with a replication-competent virus forms the basis of licensed and novel candidate respiratory viral vaccines (e.g., the cold-adapted influenza virus vaccine). A positive global impact of vaccination depends on vaccine efficacy in developing countries where dietary deficiencies are commonplace. The current study was designed using Sendai virus (SeV) as a model respiratory viral vaccine to test antibody-forming cell (AFC) residence and isotype expression in the context of a vitamin A deficiency (VAD). Samples were taken 1 mo after vaccination when AFCs generally reach their peak in healthy animals. In control animals on a healthy diet, SeV induced an antibody response with a relative bias toward IgA in the upper respiratory tract (URT, as sampled by nasal wash), and IgG in the lower respiratory tract (LRT, as sampled by bronchoalveolar lavage [BAL]). In the context of VAD, the SeV-specific IgA antibodies in the nasal wash were significantly reduced in favor of enhanced IgG antibodies in the BAL. When AFCs were examined in diffuse nasal-associated lymphoid tissues (d-NALT), lungs, cervical lymph nodes (CLN), and mediastinal lymph nodes (MLN), a similar pattern emerged. AFCs were most frequent in the d NALT and most expressed IgA in control mice. In the context of VAD, these IgA producing AFCs were significantly reduced in number, skewing the natural balance of IgA and IgG. Taken together, the results show that the VAD diet, which is well known for its association with immune defects in the gut, significantly alters AFC induction and isotype expression in the respiratory tract. PMID- 22813426 TI - Years of potential life lost for six major enteric pathogens, Germany, 2004-2008. AB - In industrialized countries, acute infectious enteric diseases are usually mild, but they can also cause death. They do so, however, at different ages. Using 2004 2008 German notification data, we computed and compared crude and premature mortality [three different measures of years of potential life lost (YPLL)] of illnesses caused by Campylobacter spp., Listeria monocytogenes, norovirus, rotavirus, non-typhoidal Salmonella spp., and Shiga toxin-producing E. coli (STEC). Among ~1.5 million notified illnesses, those caused by norovirus were the most frequent. The highest annual mortality was registered for salmonellosis (0.55/1 000 000 population), but listeriosis accounted for the highest number of YPLL (n=4245). Disregarding death at advanced age (i.e. >70 years), STEC illness (n=757) and rotavirus gastroenteritis (n=648) ranked second and third, following listeriosis (n=2306). Routine surveillance captures only a fraction of all incident cases and deaths, under-ascertaining the true burden of disease. Weighting death by age permits a different view on the disease burden individual enteric pathogens cause and particularly underscores the public health importance of listeriosis prevention. PMID- 22813427 TI - The amyloid beta peptide: a chemist's perspective. Role in Alzheimer's and fibrillization. PMID- 22813428 TI - Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy. AB - Executive dysfunction occurs in a variety of patients who have sustained damage to the frontal lobes. In individuals with frontal lobe epilepsy (FLE) or after unilateral frontal lobe resection (FLR), a unique neuropsychological profile linking executive functions (EF) with the frontal lobe has been elusive, with conflicting findings in the literature. Some studies show greater risk of executive impairment with left-sided FLE or FLR, while others report greater risk for right-sided patients. Some studies report no relationship between FLE and EF impairment, while others show EF impairment regardless of side of seizure foci or surgery. In patients with temporal lobe epilepsy, executive dysfunction is associated with depressed mood possibly reflecting disruption of cortical-limbic pathways and/or frontal-striatal circuitry. Although not previously examined, depression level may affect executive functioning in those with FLE or FLR. We hypothesized that FLE patients with poor mood state would show greater executive dysfunction than FLE patients without poor mood state. The relationship among EF, side of surgery and depressed mood before and 8 months after unilateral FLR was evaluated in 64 patients using validated measures of EF and mood state (Beck Depression Inventory-II). Results indicated that individuals with depressed mood before surgery had greater difficulty on a task of mental flexibility compared to patients without preoperative depressed mood. Further, individuals with depressed mood before surgery had significant increases in perseverative responding and completed fewer categories on a card-sorting task after surgery compared to patients without preoperative depressed mood. Regression analyses showed that among side of surgery, seizure freedom status after surgery and depression status, only pre-surgical depression status explained a significant amount of variance in executive functioning performance after surgery. Results suggest that clinically elevated depressive symptoms before surgery are a risk factor for moderate declines in EF after surgery. Results may be attributable to reduced cognitive reserve in patients with depressive symptoms, or may reflect a common cause attributable to damage to unilateral dorsal and ventral lateral frontal lobe. PMID- 22813430 TI - Temporal event structure and timing in schizophrenia: preserved binding in a longer "now". AB - Patients with schizophrenia experience a loss of temporal continuity or subjective fragmentation along the temporal dimension. Here, we develop the hypothesis that impaired temporal awareness results from a perturbed structuring of events in time-i.e., canonical neural dynamics. To address this, 26 patients and their matched controls took part in two psychophysical studies using desynchronized audiovisual speech. Two tasks were used and compared: first, an identification task testing for multisensory binding impairments in which participants reported what they heard while looking at a speaker's face; in a second task, we tested the perceived simultaneity of the same audiovisual speech stimuli. In both tasks, we used McGurk fusion and combination that are classic ecologically valid multisensory illusions. First, and contrary to previous reports, our results show that patients do not significantly differ from controls in their rate of illusory reports. Second, the illusory reports of patients in the identification task were more sensitive to audiovisual speech desynchronies than those of controls. Third, and surprisingly, patients considered audiovisual speech to be synchronized for longer delays than controls. As such, the temporal tolerance profile observed in a temporal judgement task was less of a predictor for sensory binding in schizophrenia than for that obtained in controls. We interpret our results as an impairment of temporal event structuring in schizophrenia which does not specifically affect sensory binding operations but rather, the explicit access to timing information associated here with audiovisual speech processing. Our findings are discussed in the context of curent neurophysiological frameworks for the binding and the structuring of sensory events in time. PMID- 22813429 TI - Time, action and psychosis: using subjective time to investigate the effects of ketamine on sense of agency. AB - Sense of agency refers to the experience of initiating and controlling actions in order to influence events in the outside world. A disturbed sense of agency is found in certain psychiatric and neurological disorders, most notably schizophrenia. Sense of agency is associated with a subjective compression of time: actions and their outcomes are perceived as bound together in time. This is known as 'intentional binding' and, in healthy adults, depends partly on advance prediction of action outcomes. Notably, this predictive contribution is disrupted in patients with schizophrenia. In the present study we aimed to characterise the psychotomimetic effect of ketamine, a drug model for psychosis, on the predictive contribution to intentional binding. It was shown that ketamine produced a disruption that closely resembled previous data from patients in the early, prodromal, stage of schizophrenic illness. These results are discussed in terms of established models of delusion formation in schizophrenia. The link between time and agency, more generally, is also considered. PMID- 22813431 TI - A friendly version of the trier social stress test does not activate the HPA axis in healthy men and women. AB - The trier social stress test (TSST) is a well-established laboratory stressor leading to a robust activation of the hypothalamus-pituitary-adrenal (HPA) axis. Existing control conditions are often not adequate to investigate participants' behavior during the situation as participants are often left alone in the room. This present study aimed to evaluate a friendly version of the TSST as control condition, the friendly-TSST (f-TSST). We expected that the f-TSST would not activate the HPA axis or increase the negative affect (NA). Forty-eight healthy male and female students (24 males) aged between 18 and 30 years were randomly exposed to either the TSST or the f-TSST. The latter features a similar structure and similar cognitive demands as in the TSST, and a social interaction with a committee. The main difference lies in the friendly and warm behavior of the committee opposed to the neutral and reserved behavior in the TSST, typically inducing social-evaluative threat. Salivary cortisol, salivary alpha-amylase (sAA), and affect were measured to evaluate the stress response to the respective procedure. As expected, the f-TSST neither activated the HPA axis nor increased the NA. The TSST by contrast led to an increase in both measures. A comparable and significant increase in the sAA-concentrations occurred in both conditions. The f-TSST could be useful as a standardized control condition for future stress studies. On a conceptual level our data indicate that mere social performance in the absence of social-evaluative threat and performance pressure does not activate the HPA axis. PMID- 22813432 TI - Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations. AB - A novel use of external lubrication has been investigated in which magnesium stearate was applied directly to the roll surface during roller compaction. A scalable parameter; travelling roll distance per shot (D(pS)), has been defined which ensures that an equal amount of magnesium stearate is applied to the roll surface per rotation at any roll speed. It was found that a formulation containing 20% w/w of either the API Pravastatin or Ibipinabant required a smaller D(pS) than a placebo formulation in order to prevent roll adherence. The inherent adhesiveness, and hence the required amount of external magnesium stearate to prevent roll adhesion, will depend on the material properties of the formulation. The amount of magnesium stearate transferred from the roll surface to the ribbon was measured using inductively coupled plasma optical emission spectroscopy and was found to be less than 0.01% w/w. This is a significant reduction in magnesium stearate compared to the normal manufacturing procedure of blending 0.25-2.0% w/w within the formulation.The advantage of external lubrication during roller compaction is the significant reduction in magnesium stearate from the formulation which could lead to the production of tablets with superior mechanical properties and faster dissolution times. PMID- 22813434 TI - Metal coordination induced pi-extension and triplet state production in diketopyrrolopyrrole chromophores. AB - Triplet state photophysics has been generated in two distinct diketopyrrolopyrrole (DPP) chromophores terminated with either phenyl (1) or thienyl (2) spacers, when sandwiched between two Ir(III) complexes using bipyridyl linkers. Upon coordination of the bpy-DPP-bpy subunit resulting in its planarization, the pi-conjugation in the DPP chromophore formally extends and was manifested as a substantial red shift in the absorption and fluorescence profiles of 1 and 2. Low energy excitation of these dinuclear metal complexes produced strongly quenched singlet fluorescence, generated quite intense long-lived (tau ~ 3 MUs) absorption transients in the red, sensitized (1)O(2) photoluminescence centered at 1270 nm in aerated solutions, and yielded low temperature near-IR phosphorescence in 1 centered at 950 nm. PMID- 22813433 TI - Mechanism of interactions between calcium and viscous polysaccharide from the seeds of Plantago asiatica L. AB - The present study aimed at investigating the mechanism of interactions between calcium and the psyllium polysaccharide. Plantago asiatica L. crude polysaccharide (PLCP) was subjected to ethylenediaminetetraacetic acid (EDTA) to yield calcium-depleted polysaccharide named PLCP-E. There was essentially no difference in the structure between PLCP-E and PLCP. However, PLCP-E exhibited a much lower apparent viscosity compared to that of PLCP. PLCP was treated with sodium hydroxide to deplete ferulic acid. The resultant material was named PLCP FAS, which also exhibited lower viscosity. Adding Ca(2+) could both increase apparent viscosity of PLCP-E and PLCP-FAS, but only PLCP-E could keep the high viscosity when dialysis was carried out to remove free Ca(2+) in the solution. Thermal analysis showed that the thermal stability of the polysaccharide was reduced after EDTA chelation. Scanning electron microscopy (SEM) analysis showed that PLCP-E was flaky and curly aggregation, while PLCP was mostly filamentous in appearance. The results suggested that there are strong interactions between Ca(2+) and the polysaccharide. The interactions contributed to the high viscosity, weak gelling property, and thermal stability of the polysaccharide. PMID- 22813435 TI - Job strain associated CRP is mediated by leisure time physical activity: results from the MONICA/KORA study. AB - BACKGROUND: Psychological stress at work is considered a cardiac risk factor, yet whether it acts directly through neuroimmune processes, or indirectly by increasing behavioral risk factors, is uncertain. Cross-sectional associations between job strain and serum biomarkers of inflammation and endothelial dysfunction were investigated. Secondary analyses explored the role of psychosocial/cardiometabolic risk factors as mediators of job stress associated inflammation in healthy workers. METHODS: Information on risk factors was obtained in standardized personal interviews of a subcohort of working participants in the MONICA/KORA population (n = 951). Work stress was measured by the Karasek job strain index. Biomarkers were measured from non-fasting venous blood. Multivariate regression analyses were used to examine the association of job strain with inflammatory biomarkers. Mediation analysis (Sobel test) was used to determine the effect of psychosocial risk factors on the association between job strain and C-reactive protein (CRP). RESULTS: High job strain was reported by half (n = 482, 50.7%) of the study participants. While workers with high job strain were more likely to have adverse workplace conditions (competition with coworkers, job dissatisfaction and insecurity), sleeping problems, depressive symptoms, a Type A personality, and be physically inactive, no differences in cardiometabolic risk factors were detected. A strong and robust association between job strain and CRP was observed in age and sex adjusted models, as well as models adjusted for classic coronary heart disease risk factors (beta = 0.39, p = 0.006 and beta = 0.27, p = 0.03, respectively). Adjustment for physical activity abrogated this effect (beta = 0.23, p = 0.07), and a mediating effect of physical activity on stress-associated inflammation was demonstrated (p = 0.04). CONCLUSIONS: The analyses provide evidence for both a direct and an indirect effect of job strain on inflammation. PMID- 22813436 TI - Caffeine does not alter RPE or pain perception during intense exercise in active women. AB - Attenuated perceptions of exertion and leg pain are typically reported during exercise with caffeine ingestion, yet these responses are relatively unexplored in women. The primary aim of this study was to assess the effect of caffeine on rating of perceived exertion (RPE) and pain perception during a simulated time trial. Ten active women (age=22.1+/-1.9yr) completed an 8.2km "all out" time trial on each of 3days separated by at least 48h. Initially, a practice trial was completed, and participants refrained from products containing caffeine and lower body exercise for 24h prior to subsequent trials. During exercise, heart rate (HR), RPE, and leg pain were recorded. Using a double-blind, randomized crossover design, participants ingested anhydrous caffeine and glucose (each 6mg/kg bw+each 6mg/kg bw glucose) or placebo (each 6mg/kg bw of glucose) 1h pre-exercise. Despite not altering (P>0.05) RPE, HR, or leg pain, caffeine improved (P<0.05) cycling performance (17.7+/-1.0min versus 18.2+/-1.1min) and power output (121.6+/-17.5W versus 114.9+/-17.9W) versus placebo. Caffeine's ergogenic effects may be independent of changes in RPE or leg pain in active women performing a simulated time trial. PMID- 22813437 TI - Reductive eliminations from lambda3-iodanes: understanding selectivity and the crucial role of the hypervalent bond. AB - This computational study investigates the factors governing the selectivity of the reductive eliminations from rapidly equilibrating isomeric lambda(3)-iodanes derived from a diaryl iodonium salt and a nucleophile. The chemoselectivity is mainly determined by the partial charge at the ipso-carbon atom involved in the 3 center-4-electron bond. PMID- 22813438 TI - Severity of primary sclerosing cholangitis and ulcerative colitis: does liver transplantation protect against colectomy? PMID- 22813439 TI - Limited ability of the proton-pump inhibitor test to identify patients with gastroesophageal reflux disease. AB - BACKGROUND & AIMS: The efficacy of proton-pump inhibitor (PPI) therapy often is assessed to determine whether patients' symptoms are acid-related and if patients have gastroesophageal reflux disease (GERD), although the accuracy of this approach is questionable. We evaluated the diagnostic performance of the PPI test, in conjunction with other tests, for the diagnosis of GERD. METHODS: We analyzed data from the DIAMOND study, a multinational trial that compared the ability of the reflux disease questionnaire with that of symptom-based clinical diagnosis to identify GERD in primary care patients with frequent upper gastrointestinal symptoms. Patients (n = 308) were given placebo and further evaluated by endoscopy, wireless esophageal pH-metry, and symptom association monitoring. Those with GERD (n = 197) were identified based on the presence of reflux esophagitis, esophageal pH level less than 4 for more than 5.5% of 24 hours, or positive results from symptom association monitoring (or a positive result from the PPI test in patients with borderline levels of esophageal acidity). All patients then were given single-blind therapy with esomeprazole (40 mg once daily) for 2 weeks and symptoms were recorded daily. RESULTS: A positive response to the PPI test was observed in 69% of patients with GERD and in 51% of those without GERD. Response to placebo did not influence the diagnostic ability of the subsequent PPI test. More patients with reflux esophagitis had a positive result from the PPI test than patients without GERD (57% vs 35%; P = .002) or patients with GERD but no esophagitis. A clinical diagnosis by the primary care physician of an acid-related disease was not associated with response to PPIs. CONCLUSIONS: In a well-characterized population of primary care patients with frequent upper-gastrointestinal symptoms of any type, the PPI test has limited ability to identify patients with GERD, diagnosed by current standard tests. (ClinicalTrials.gov Number, NCT00291746.). PMID- 22813440 TI - Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. AB - Although tumor necrosis factor (TNF) antagonists have shown clear benefits over conventional treatments for inducing and maintaining clinical remission in both Crohn's disease and ulcerative colitis, a high proportion of patients lose response over time. Given the scarce alternative of treatments when treatment failure occurs, it is highly desirable to optimize both initial response and long term continuation of TNF antagonists. One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing antidrug antibodies accelerates drug clearance, leading to subtherapeutic drug concentrations and, ultimately, to treatment failure. However, other patient-related factors, such as sex and/or body size, and disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. Nevertheless, the evidence generated to date about these complex interactions is scarce, and further prospective studies evaluating their influence on the pharmacokinetics of TNF antagonists are needed. Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes. Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes. Therefore, incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time. PMID- 22813441 TI - Regression of hepatocellular carcinoma with right atrial extension after sorafenib and transarterial chemoembolization. PMID- 22813442 TI - Diffuse large B-cell lymphoma of the small bowel as an unusual cause for recurrent obscure gastrointestinal bleeding: diagnosis by video capsule endoscopy. PMID- 22813443 TI - Xanthomatosis coli. PMID- 22813444 TI - Fulminant amebic colitis with an atypical clinical presentation successfully treated by metronidazole. PMID- 22813445 TI - Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. AB - BACKGROUND & AIMS: Impaired accommodation and hypersensitivity to gastric distention are believed to be involved in the development of functional dyspepsia (FD). Buspirone, a 5-hydroxytryptamine 1A receptor agonist, relaxes the proximal stomach in healthy individuals. We studied the effects of buspirone on symptoms and mechanisms of FD. METHODS: We performed a randomized, double-blind, placebo controlled, crossover study of 17 patients (13 women; mean age, 38.5 +/- 2.4 years). The study included 2 treatment periods of 4 weeks each, separated by a 2 week washout period. In the first period, 7 participants were given buspirone (10 mg, 3 times daily for 4 weeks) and 10 were given placebo 15 minutes before meals; patients switched groups for the second period. We assessed meal-related symptoms and severity, along with gastric sensitivity, accommodation, and emptying (by using barostat and breath tests) before and after 4 weeks of treatment. RESULTS: Buspirone significantly reduced the overall severity of symptoms of dyspepsia (7.5 +/- 1.3 vs 11.5 +/- 1.2 for placebo; P < .005) and individual symptoms of postprandial fullness, early satiation, and upper abdominal bloating, whereas placebo had no significant effect (all P < .05). Buspirone did not alter the rate of gastric emptying of solids or sensitivity to gastric distention, but it significantly increased gastric accommodation, compared with placebo (229 +/- 28 vs 141 +/- 32 mL, respectively; P < .05), and delayed gastric emptying of liquids (half-life = 64 +/- 5 vs 119 +/- 24 minutes, respectively). Adverse events were similar when patients were given buspirone or placebo. CONCLUSIONS: In patients with FD, 4 weeks of administration of buspirone significantly improved symptoms and gastric accommodation, compared with placebo, whereas gastric emptying of liquids was delayed. PMID- 22813446 TI - Is the femtosecond laser worth it? PMID- 22813447 TI - Uveal melanoma trapped in the temple of doom. PMID- 22813448 TI - Aflibercept for age-related macular degeneration: a game-changer or quiet addition? AB - PURPOSE: To describe the pharmacokinetics, preclinical studies, and clinical trials of the newly approved anti-vascular endothelial growth factor (VEGF) drug aflibercept (Eylea (VEGF Trap-Eye); Regeneron; and Bayer). DESIGN: Review with editorial commentary. METHODS: A review of the medical literature and pertinent Internet postings combined with analysis of key studies with expert opinion regarding the use of aflibercept for the treatment of exudative age-related macular degeneration. RESULTS: Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity. Preclinical ophthalmologic studies demonstrated that aflibercept suppresses choroidal neovascularization in several animal models. The results of phase 1 and 2 trials showed excellent short-term suppression of choroidal neovascularization in patients with exudative age-related macular degeneration and suggested a longer durability of aflibercept compared with other anti-VEGF drugs. The pivotal phase 3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration 1 and 2 trials showed that monthly and bimonthly aflibercept were noninferior to monthly ranibizumab at preventing vision loss (< 15-letter loss) with comparable vision gains and safety. Year 2 treatment involved monthly pro re nata injections with required injections every 3 months and maintained vision gains from the first year, with an average of 4.2 injections of aflibercept and 4.7 injections of ranibizumab. CONCLUSIONS: Aflibercept promises to deliver excellent visual outcomes for exudative age-related macular degeneration patients while undergoing fewer injections compared with ranibizumab. With a wholesale cost of $1850 per dose, the cost per patient with aflibercept treatment promises to be lower than with ranibizumab. PMID- 22813449 TI - Use of topiramate and risk of glaucoma: a case-control study. PMID- 22813452 TI - Delayed- versus acute-onset endophthalmitis after cataract surgery. PMID- 22813453 TI - Immune ring formation associated with cytomegalovirus endotheliitis. PMID- 22813455 TI - A prospective study comparing EndoGlide and Busin glide insertion techniques in descemet stripping endothelial keratoplasty. PMID- 22813457 TI - Randomized double-masked controlled trial comparing pain scores with and without the use of supplementary 2% lidocaine gel in LASIK. PMID- 22813458 TI - Clinical significance of microbial growth on the surfaces of silicone tubes removed from dacryocystorhinostomy patients. PMID- 22813461 TI - Prevalence, seasonality, and peak age of infection of enteric adenoviruses in Japan, 1995-2009. AB - A total of 7185 faecal specimens collected from infants and children with gastroenteritis in seven different regions of Japan during 1995-2009 were examined for adenovirus by polymerase chain reaction. Adenovirus was detected in 568 (7.9%) patients. The adenovirus activity peak was in winter and spring seasons (December-March) during the study period in the Japanese paediatric population. During the last 15 years, adenovirus 41 was the most predominant strain in Japan. PMID- 22813462 TI - Deep understanding of the interaction between thienorphine and UDP glucuronosyltransferase (UGT) isoforms. AB - Thienorphine has been demonstrated to be a potent, long-acting partial opioid agonist. It is being developed as a good candidate to treat opioid dependence. The thienorphine's glucuronide was detected after thienorphine was incubated with human liver microsomes (HLMs). Recombinant UGT isoforms screening experiment and enzyme kinetic study showed that UGT1A1 completely contributed to the glucuronidation of thienorphine. Among the tested UGT isoforms, UGT1A3 and UGT2B7 were inhibited by thienorphine, with other UGT isoforms negligibly influenced. The inhibition type is competitive, and inhibition kinetic parameters (K(i)) were 1.65 and 5.27 MUM for UGT1A3 and UGT2B7, respectively. However, due to low plasma concentration of thienorphine, in vivo drug-drug interaction might not occur. PMID- 22813463 TI - Cigarette smoking as a risk factor for influenza-associated mortality: evidence from an elderly cohort. AB - BACKGROUND: The effects of individual lifestyle factors on the mortality risk after influenza infection have not been explored. OBJECTIVES: In this study, we assessed the modifying effects of cigarette smoking on mortality risks associated with influenza in a cohort of Hong Kong elders with a follow-up period of 1998 2009. METHODS: We used the Cox proportional hazards model with time-dependent covariates of weekly proportions of specimens positive for influenza (termed as influenza virus activity), to calculate the hazard ratio of mortality associated with a 10% increase in influenza virus activity for never, ex- and current smokers. Other individual lifestyle and socioeconomic factors as well as seasonal confounders were also added into the models. RESULTS: The overall hazard ratio associated with influenza was 1.028 (95% confidence interval, 1.006, 1.051) for all natural cause mortality and 1.035 (1.003, 1.068) for cardiovascular and respiratory mortality. We found that influenza-associated hazard ratio was greater in current and ex-smokers than in never smokers for mortality of all natural causes, cardiovascular and respiratory diseases. CONCLUSIONS: The findings suggest that smoking might increase influenza-associated mortality risks among elders. PMID- 22813466 TI - Obama, marriage equality, and the health of gay men. PMID- 22813465 TI - Neighborhood disparities in access to healthy foods and their effects on environmental justice. AB - Environmental justice is concerned with an equitable distribution of environmental burdens. These burdens comprise immediate health hazards as well as subtle inequities, such as limited access to healthy foods. We reviewed the literature on neighborhood disparities in access to fast-food outlets and convenience stores. Low-income neighborhoods offered greater access to food sources that promote unhealthy eating. The distribution of fast-food outlets and convenience stores differed by the racial/ethnic characteristics of the neighborhood. Further research is needed to address the limitations of current studies, identify effective policy actions to achieve environmental justice, and evaluate intervention strategies to promote lifelong healthy eating habits, optimum health, and vibrant communities. PMID- 22813467 TI - Of personal choice and level playing fields: why we need government policies on food content. PMID- 22813468 TI - AJPH supplement on military suicide. PMID- 22813470 TI - Biomedical and social dimensions of HIV prevention. PMID- 22813471 TI - The role of dental practices and dental science research in addressing systemic health conditions. PMID- 22813473 TI - Misdirected criticisms. PMID- 22813475 TI - Bossarte responds. PMID- 22813476 TI - Engaging individuals recently released from prison into primary care: a randomized trial. AB - OBJECTIVES: Individuals released from prison have high rates of chronic conditions but minimal engagement in primary care. We compared 2 interventions designed to improve primary care engagement and reduce acute care utilization: Transitions Clinic, a primary care-based care management program with a community health worker, versus expedited primary care. METHODS: We performed a randomized controlled trial from 2007 to 2009 among 200 recently released prisoners who had a chronic medical condition or were older than 50 years. We abstracted 12-month outcomes from an electronic repository available from the safety-net health care system. Main outcomes were (1) primary care utilization (2 or more visits to the assigned primary care clinic) and (2) emergency department (ED) utilization (the proportion of participants making any ED visit). RESULTS: Both groups had similar rates of primary care utilization (37.7% vs 47.1%; P = .18). Transitions Clinic participants had lower rates of ED utilization (25.5% vs 39.2%; P = .04). CONCLUSIONS: Chronically ill patients leaving prison will engage in primary care if provided early access. The addition of a primary care-based care management program tailored for returning prisoners reduces ED utilization over expedited primary care. PMID- 22813477 TI - Evidence in oral health promotion-implications for oral health planning. AB - I have explored the debates on evidence-based oral health promotion and examined the practicality of promoting oral health care within a whole system (social, cultural, and environmental) approach. The use of evidence-based decision-making in health services and planning is a viable mechanism to identify optimal health benefits; however, barriers to the effective adoption of evidence-based health practice, including barriers that apply to oral health promotion, have been identified. Evidence-based oral health promotion highlights the importance of examining health promotion activities within a defined social context-a departure from the focus on improving study designs and research methods. Thus, the basis for evidence in health activities is grounded in social and organizational systems. This could contribute to sustainable health efforts. PMID- 22813478 TI - Stability of lyophilized sucrose formulations of an IgG1: subvisible particle formation. AB - Eight lyophilized formulations of a IgG1 monoclonal antibody (MAb) were prepared containing increasing levels of sucrose. In addition, three of the formulations had sorbitol added at a level of 5% w/w relative to sucrose. The samples were stored for up to 4 weeks at 40 degrees C, which is well below the Tg. Upon reconstitution, the levels of subvisible particles were measured using microflow imaging (MFI). The formulation containing no sucrose contained exceedingly high levels of subvisible particles, accounting for as much as 25% of the weight of the protein. Addition of sucrose markedly decreased the number of subvisible particles, with the maximal sucrose:protein weight ratio being 2:1 (the highest level tested). Addition of sorbitol further decreased subvisible particle levels, even for formulations where the sucrose:protein ratio was relatively high. This suggests that even small amounts of a plasticizer like sorbitol can improve the storage stability of a lyophilized antibody formulation, probably by dampening beta-relaxations within the amorphous glass. PMID- 22813480 TI - Bandgap tuning in armchair MoS2 nanoribbon. AB - We report on the first-principles calculations of bandgap modulation in armchair MoS(2) nanoribbon (AMoS(2)NR) by transverse and perpendicular electric fields respectively. In the monolayer AMoS(2)NR case, it is shown that the bandgap can be significantly reduced and be closed by transverse field, whereas the bandgap modulation is absent under perpendicular field. The critical strength of transverse field for gap closure decreases as ribbon width increases. In the multilayer AMoS(2)NR case, in contrast, it is shown that the bandgap can be effectively reduced by both transverse and perpendicular fields. Nevertheless, it seems that the two fields exhibit different modulation effects on the gap. The critical strength of perpendicular field for gap closure decreases with increasing number of layers, while the critical strength of transverse field is almost independent of it. PMID- 22813481 TI - Browsed twig environmental DNA: diagnostic PCR to identify ungulate species. AB - Ungulate browsing can have a strong effect on ecological processes by affecting plant community structure and composition, with cascading effects on nutrient cycling and animal communities. However, in the absence of direct observations of foraging, species-specific foraging behaviours are difficult to quantify. We therefore know relatively little about foraging competition and species-specific browsing patterns in systems with several browsers. However, during browsing, a small amount of saliva containing buccal cells is deposited at the bite site, providing a source of environmental DNA (eDNA) that can be used for species identification. Here, we describe extraction and PCR protocols for a browser species diagnostic kit. Species-specific primers for mitochondrial DNA were optimized and validated using twigs browsed by captive animals. A time series showed that about 50% of the samples will amplify up to 12 weeks after the browsing event and that some samples amplify up to 24 weeks after browsing (12.5%). Applied to samples of natural browsing from an area where moose (Alces alces), roe deer (Capreolus capreolus), fallow deer (Cervus dama) and red deer (Cervus elaphus) are sympatric, amplification success reached 75%. This method promises to greatly improve our understanding of multispecies browsing systems without the need for direct observations. PMID- 22813482 TI - Group B streptococcal colonization and the risk of pre-eclampsia. AB - To determine if there was an association between recto-vaginal group B streptococcus (GBS) colonization and pre-eclampsia, two cross-sectional studies were conducted using statewide hospital databases. The first study analysed data from the state of Florida, USA, and included 190 645 women who were discharged in 2001. This dataset was used to generate the hypothesis that GBS colonization is associated with pre-eclampsia. The second study tested the GBS hypothesis using the records of 577 153 women who delivered in 2004 or 2005 in Texas, USA. Adjusted odds ratios (aOR) for the outcome of pre-eclampsia comparing GBS positive to GBS-negative women were calculated using logistic regression. The aOR for the association between GBS carriage and pre-eclampsia was 0.71 [95% confidence interval (CI) 0.65-0.77] in the Florida dataset. In the Texas dataset, the overall prevalence of GBS carriage was 14.1% while the overall prevalence of pre-eclampsia was 4.0%. GBS carriers were 31% less likely than non-carriers to have pre-eclampsia (aOR 0.69, 95% CI 0.66-0.72) in Texas. In two large statewide analyses, GBS carriage was inversely associated with pre-eclampsia. A sensitivity analysis revealed that misclassification of GBS status is not a likely explanation of our findings. PMID- 22813483 TI - The Bird ventilator. PMID- 22813485 TI - Ten caveats of interpreting correlation coefficient in anaesthesia and intensive care research. PMID- 22813484 TI - Confound those damned confounders. PMID- 22813486 TI - The interpretation of perioperative lactate abnormalities in patients undergoing cardiac surgery. AB - Hyperlactataemia and lactic acidosis are commonly encountered during and after cardiac surgery. Perioperative lactate production increases in the myocardium, skeletal muscle, lungs and in the splanchnic circulation during cardiopulmonary bypass. Hyperlactataemia has a bimodal distribution in the perioperative period. An early increase in lactate levels, arising intraoperatively or soon after intensive care unit admission, is a familiar and concerning finding for most clinicians. It is highly suggestive of tissue ischaemia and is associated with a prolonged intensive care unit stay, a prolonged requirement for respiratory and cardiovascular support and increased postoperative mortality. Its presence should prompt a thorough search for potential causes of tissue hypoxia. In contrast, late-onset hyperlactataemia, a less well recognised complication, occurs 4 to 24 hours after completion of surgery and is typically associated with preserved cardiac output and oxygen delivery. Risk factors for late-onset hyperlactataemia include hyperglycaemia, long cardiopulmonary bypass time and elevated endogenous catecholamines. Although patients with this complication may have a longer duration of ventilation and intensive care unit length of stay than those with normolactataemia, an association with increased mortality has not been demonstrated. The discovery of late-onset hyperlactataemia should not delay the postoperative progress of an otherwise stable patient following cardiac surgery. PMID- 22813487 TI - Epidural volume extension: a review. AB - Epidural volume extension is a technical modification of the combined spinal epidural block. It involves the epidural injection of normal saline or a small volume of local anaesthetic after an intrathecal injection, aiming to augment the post-spinal sensory level. Although the consequent sensory block augmentation has been adequately documented, the probable factors influencing epidural volume extension and its implications for clinical practice are not well defined. This article reviews published literature relating to the probable factors affecting epidural volume extension, its clinical implications, case reports of its successful clinical application and summarises its unexplored effects. PMID- 22813488 TI - Anaesthesia for robotic gynaecological surgery. AB - Robotic surgery is gaining widespread popularity due to advantages such as reduced blood loss, reduced postoperative pain, shorter hospital stay and better visualisation of fine structures. Robots are being used in urological, cardiac, thoracic, orthopaedic, gynaecological and general surgery. Robotic surgery received US Food and Drug Administration approval for use in gynaecological surgery in 2005. The various gynaecological robotic operations being performed are myomectomy, total and supracervical hysterectomy, ovarian cystectomy, sacral colpopexy, tubal reanastomosis, lymph node dissection, surgery of retroperitoneal ectopic pregnancy, Moskowitz procedure and endometriosis surgery. The anaesthetic considerations include difficult access to the patient intraoperatively, steep Trendelenburg position, long surgical duration and the impact of pneumoperitoneum. We highlight the complications encountered in these surgeries and methods to prevent these complications. Robotic gynaecological surgery can be safely performed after considering the physiological effects of the steep Trendelenburg position and of pneumoperitoneum. The benefits of the surgical procedure should be weighed against the risks in patients with underlying cardiorespiratory problems. PMID- 22813489 TI - Observations on the assessment and optimal use of videolaryngoscopes. AB - Due to the large number of videolaryngoscopes now available, it might be difficult for novice users to assess the various devices or use them optimally. We have collated the experiences of several airway management experts to assist in the assessment and optimal use of seven commonly used videolaryngoscopes. While all videolaryngoscopes have unique features, they can be broadly divided into those inserted via a midline approach over the tongue and those inserted laterally along the floor of the mouth. Videolaryngoscopes that are placed on the floor of the mouth displace the tongue antero-laterally and flatten the submandibular tissues. They generally require a conventional shaped bougie for tracheal intubation. Videolaryngoscopes that use the midline approach may have an in-built airway conduit for the tracheal tube or may require a 'J-shaped' stylet in the tracheal tube to negotiate the upper airway. This may cause difficulty when the tracheal tube is inserted through the glottis and the tip abuts the anterior wall of the subglottic space. Knowledge of the mechanism used by videolaryngoscopes to achieve laryngoscopy is essential for safe and successful tracheal intubation when using these devices. PMID- 22813491 TI - Ventilation - how often are we correct? AB - Traditional mechanical ventilation used tidal volumes (Vt) of between 10 to 15 ml/kg of body weight in order to achieve normal values of pH and partial pressure of carbon dioxide (PaCO2). Many clinicians today however, adopt lower volumes as a conservative 'safe' ventilation strategy in most mechanically ventilated patients. The method by which this is done varies between facilities, but anecdotally doctors use Vt of 6 to 8 ml/kg, and they commonly estimate these volumes at the bedside. This observational study was undertaken in a 23-bed level 3 intensive care unit at a metropolitan tertiary hospital in order to determine whether or not intensive care clinicians are accurately determining the Vt during mechanical ventilation which they purport to do. The primary outcome measure was the Vt being delivered at the time of observation. Thirty patients were recruited into the study, resulting in 55 observations of synchronised intermittent mandatory ventilation with autoflow mode ventilator settings. Although volumes between 6 to 8 ml/kg were recorded in 33 (60%) observations, more detailed exploration of the individual's clinical circumstances reflects that the actual dialled volumes were correct in all but two patients. Intensive care unit mortality was 13% (n=2) in those patients receiving higher than anticipated Vts (n=15). This study has demonstrated that while we achieve a protective ventilation strategy by adopting lower Vts in most mechanically ventilated patients, we should be constantly monitoring exactly what volume is being achieved, not just what is dialled up to be delivered. PMID- 22813490 TI - A comparison of pulse contour wave analysis and ultrasonic cardiac output monitoring in the critically ill. AB - Cardiac output (CO) is a key determinant of major organ blood flow and solute delivery to drug eliminating organs. As such, CO assessment is a key covariate in understanding altered drug handling in the critically ill. Newer minimally invasive devices are providing unique platforms for such an application, although comparison data are currently lacking. In this study we evaluated the Vigileo (Edwards Lifesciences, Irvine, CA, USA) and USCOM (USCOM Ltd, Sydney, NSW) devices in 62 critically ill patients requiring antibacterial therapy. The mean COVigileo and COUSCOM for the first paired measurements were 8.20+/-2.65 l/minute and 6.84+/-2.57 l/minute respectively (P <0.001). A significant correlation was evident in all patients (r=0.537, P <0.001) although the recorded bias was large (1.36+/-2.51 l/minute, limits of agreement -3.6 to+/-6.3 l/minute). The overall percentage error was 65%. There was an improved correlation in those admitted with sepsis (r=0.639, P <0.001), compared to trauma (r=0.373, P=0.066), although bias, precision and percentage error were similar in both subgroups. In 54 patients a second paired assessment was obtained at three hours. A weak, although significant correlation (r=0.377, P=0.005) was observed suggesting that gross trends over time were similar. In conclusion, our findings demonstrate poor agreement between these techniques suggesting that these devices are not simply interchangeable when assessing CO in a research or clinical setting. PMID- 22813492 TI - Cerebrospinal fluid volume and nerve root vulnerability during lumbar puncture or spinal anaesthesia at different vertebral levels. AB - Cerebrospinal fluid (CSF) and nerve root volumes within the lumbosacral dural sac were estimated at various vertebral levels, in an attempt to determine any possible relevance to the incidence of nerve root trauma during lumbar puncture or spinal anaesthesia. Magnetic resonance images from seven patients were studied. Volumes were calculated by semi-automatic threshold segmentation combined with manual editing of each slice. The mean dural sac volume from S1 to T12 was 42.8+/-5.8 ml and the mean CSF volume 34.3+/-5.1 ml with the mean root volume being 10.4+/-2.2 cm(3). The mean CSF volume per vertebral segment ranged from 4.3+/-0.7 ml at L5, to 5.8+/-2.5 ml at L1, with high inter-individual variability. The mean root volume ranged from 0.6+/-0.1 cm(3) at L5 to 2.4+/-0.5 cm(3) at T12. The conus medullaris was located at L1 in four of the five patients scanned at upper lumbar levels, and at the lower border of L2 in the other. Vulnerability to nerve root damage was expressed as the Vulnerability Index (%), being defined as the ratio of root volume to dural sac volume (CSF volume + root volume). The value ranged between 7 and 14% at L5, increasing rostrally to 30 to 43% at T12. Caution is obviously required in high punctures to avoid contact with the conus medullaris, but the cauda equina is also vulnerable to contact with more caudal punctures and had a Vulnerability Index of about 25% at L4, that increased rostrally. PMID- 22813493 TI - Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. AB - Critically ill patients receiving extracorporeal membrane oxygenation (ECMO) are often noted to have increased sedation requirements. However, data related to sedation in this complex group of patients is limited. The aim of our study was to characterise the sedation requirements in adult patients receiving ECMO for cardiorespiratory failure. A retrospective chart review was performed to collect sedation data for 30 consecutive patients who received venovenous or venoarterial ECMO between April 2009 and March 2011. To test for a difference in doses over time we used a regression model. The dose of midazolam received on ECMO support increased by an average of 18 mg per day (95% confidence interval 8, 29 mg, P=0.001), while the dose of morphine increased by 29 mg per day (95% confidence interval 4, 53 mg, P=0.021) The venovenous group received a daily midazolam dose that was 157 mg higher than the venoarterial group (95% confidence interval 53, 261 mg, P=0.005). We did not observe any significant increase in fentanyl doses over time (95% confidence interval 1269, 4337 ug, P=0.94). There is a significant increase in dose requirement for morphine and midazolam during ECMO. Patients on venovenous ECMO received higher sedative doses as compared to patients on venoarterial ECMO. Future research should focus on mechanisms behind these changes and also identify drugs that are most suitable for sedation during ECMO. PMID- 22813494 TI - Low-dose remifentanil infusion during ventilator weaning and tracheal extubation in postoperative intensive care unit patients sedated with propofol-remifentanil: a randomised clinical trial. AB - Discontinuation of sedatives for ventilator weaning and extubation can be associated with hyperdynamic responses, including hypertension and tachycardia. We examined the effects of a maintained low dose of remifentanil infusion on cardiovascular responses and coughing during extubation in postoperative intensive care unit patients sedated with propofol-remifentanil. Fifty patients who required mechanical ventilation after major abdominal surgery were randomised into remifentanil group (n=25) or control group (n=25). Sedation during mechanical ventilation was maintained with remifentanil and propofol via a target controlled infusion system. These drugs were titrated to the target sedation range, bispectral index values of 60 to 75 and Richmond Agitation Sedation Scale values of -3 to -2. When weaning was initiated, propofol was stopped in both groups. In the control group, remifentanil infusion was also stopped; in the remifentanil group, remifentanil infusion was maintained until extubation at a target effect site concentration of 1.0 ng/ml. Extubation was performed if the patient's respiratory, haemodynamic states were stable and if the patient was able to follow commands. Heart rate, mean arterial pressure and cough severity were evaluated. The mean arterial pressure, heart rate and cough severity did not differ between the two groups during extubation. The time from stopping of propofol infusion to extubation was significantly longer in the remifentanil group compared to that in the control group (P=0.020). Maintaining a low-dose remifentanil infusion during ventilator weaning, delayed tracheal extubation without any differences in haemodynamic changes or coughing in postoperative intensive care unit patients. PMID- 22813495 TI - The impact of clinical protocols in the management of severe sepsis: a prospective cohort study. AB - This study aimed to assess the availability of clinical protocols and their effect on compliance to the Surviving Sepsis Campaign bundles and on mortality in severe sepsis in ten Singaporean adult teaching intensive care units (ICU). The presence of 11 protocols in the ICUs, steps taken based on the Johns Hopkins University Quality and Safety Research Group's model to translate protocols into practice, and organisational characteristics were assessed. Clinical and research personnel recorded characteristics of patients with severe sepsis who were admitted in July 2009, the achievement of sepsis bundle targets and outcomes. Hospital mortality was 39% for 128 patients. Fewer than half of the ICUs had protocols for early goal-directed therapy, blood cultures, antibiotics, steroids, lung-protective ventilation and weaning. Compliance rates with the resuscitation and management bundles were 18 and 3% respectively. Units with protocols were generally not more likely to achieve associated bundle targets. Steps from the Johns Hopkins model to measure performance, engage teams and sustain and extend interventions were taken in fewer than half of the available protocols. However, on logistic regression analysis, the number of protocols available per ICU was independently and inversely associated with mortality. In conclusion, clinical protocols are infrequently available in Singapore's ICUs and when present do not generally improve compliance to the sepsis bundles. These protocols may, however, be a surrogate marker of the quality of care as they are independently associated with decreased mortality. The use of an integrated and multifaceted approach to translate protocols into practice should be considered. PMID- 22813496 TI - Assessment and perceptions of intensive care data quality, reporting and use: a survey of ICU directors. AB - It is becoming increasingly common for government bodies, healthcare providers, funders and consumers to seek measures of the quality of critical care. It is important to ensure the quality of intensive care unit (ICU) data is high so these stakeholders can confidently use quality of care measures in decision making. This paper aims to evaluate the quality of data collected for and submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database, and to investigate the perceptions of NSW ICU directors in relation to ICU data quality, reporting and usage. A survey tool was developed based on an existing framework that consisted of procedures for assessing data quality in medical registries. The survey was distributed to the directors of all NSW ICUs that submitted data in the 2007/2008 financial year. Overall, completeness of the data and its quality was perceived to be good. Participants were less likely to engage in activities involving the detection and correction of data errors, feedback of data or use of data for local purposes. A number of barriers and enablers to good quality ICU data as well as strategies to improve data quality were identified. Inadequate staff, training and resources for data collection were widespread concerns. NSW ICU directors believe more work is required to achieve high quality data and appropriate use of the data collected. Strategies targeting increased resources including updated technology and improved staffing and training, as well as low-cost solutions such as audit, feedback and clinician engagement, have been highlighted. PMID- 22813497 TI - The effect of hair colour on anaesthetic requirements and recovery time after surgery. AB - Patients with red hair are much more likely to have a variant of the melanocortin 1 receptor gene and this may affect sensitivity to general anaesthetics and pain response. We did a prospective, matched cohort study of 468 healthy adult patients undergoing general anaesthesia for elective surgery. All patients received an inhalational general anaesthetic. Anaesthetic drugs and doses used, hypnotic depth, recovery times, pain scores and quality of recovery scores were recorded. More men than women had red hair, so we did subgroup and multivariable analyses to account for this imbalance. There was no significant difference in recovery times, pain scores or quality of recovery scores in those with red hair. After adjusting for age, sex, American Society of Anesthesiologists physical status and duration of surgery, the recovery ratio for time to eye-opening in redheads was comparable to those with black or brown hair, 0.82 (0.57-1.19), P=0.30. We found no evidence that patient hair colour affects anaesthetic requirements or recovery characteristics in a broad range of surgical procedures. PMID- 22813498 TI - Comparison of evoked electromyography in three muscles of the hand during recovery from non-depolarising neuromuscular blockade. AB - The evoked electromyographic responses to supramaximal train of four stimulation of three muscles, all innervated by the ulnar nerve, were compared during recovery from non-depolarising neuromuscular blockade. The abductor digiti minimi was the most resistant to neuromuscular blockade (P <0.001) and the most repeatable (repeatability coefficient 4.4%) when compared with the adductor pollicis (5.9%) and the first dorsal interosseous (5.8%). The abductor digiti minimi had a bias of 0.1 compared to the adductor pollicis and first dorsal interosseous and its limits of agreement were more acceptable (-0.10 to 0.30) at a train of four ratio of 0.9. The electromyography train of four of the adductor pollicis and first dorsal interosseous at 0.8 is equivalent to an electromyography train of four of 0.9 at abductor digiti minimi. PMID- 22813499 TI - The development and preliminary evaluation of a proposed new scoring system for videolaryngoscopy. AB - Clear documentation of anaesthetic technique, difficulties and complications is an essential part of good anaesthetic practice, particularly in the area of airway management. The current convention of describing intubation using a videolaryngoscope only in terms of a Cormack and Lehane score is at best unhelpful and at worst dangerous. In an attempt to address the inadequacy of a Cormack and Lehane score to describe videoscopic intubation, we propose a three part scoring system: view, ease and device - the 'Fremantle Score'. Preliminary evaluation of this system in a diverse group of anaesthetists utilising four available videolaryngoscopes in a simulated normal and difficult airway manikin has demonstrated that the system is easy to use, easy to understand and relevant. In three of the eight device and manikin combinations studied, the videolaryngoscopic view correlated with the ease of intubation. This highlights the need for an alternative tool to describe intubation with a videolaryngoscope. We consider this development of a specific videoscopic scoring system a first step in better describing intubation by a videolaryngoscope and improving patient care. PMID- 22813500 TI - Audit of cardiac pathology detection using a criteria-based perioperative echocardiography service. AB - Transthoracic echocardiography is often used to screen patients prior to non cardiac surgery to detect conditions associated with perioperative haemodynamic compromise and to stratify risk. However, anaesthetists' use of echocardiography is quite variable. A consortium led by the American College of Cardiology Foundation has developed appropriate use criteria for echocardiography. At Joondalup Hospital in Western Australia, we have used these criteria to order echocardiographic studies in patients attending our anaesthetic pre-admission clinic. We undertook this audit to determine the incidence of significant echocardiographic findings using this approach. In a 22-month period, 606 transthoracic echocardiographic studies were performed. This represented 8.7% of clinic attendees and 1.7% of all surgical patients. In about two-thirds of the patients, the indication for echocardiography was identified on the basis of a telephone screening questionnaire. The most common indications were poor exercise tolerance (27.4%), ischaemic heart disease (20.9%) and cardiac murmurs (16.3%). Over 26% of patients studied had significant cardiac pathology (i.e. moderate or severe echocardiographic findings), most importantly moderate or severe aortic stenosis (8.6%), poor left ventricular function (7.1%), a regional wall motion abnormality (4.3%) or moderate or severe mitral regurgitation (4.1%). Using appropriate use criteria to guide ordering transthoracic echocardiography studies led to a high detection rate of clinically important cardiac pathology in our perioperative service. PMID- 22813502 TI - Gabapentin in the treatment of post-dural puncture headache: a case series. AB - Gabapentin has been reported to be useful in the management of epilepsy, neuropathic pain and post-dural puncture headache. Seventeen obstetric cases are presented in which gabapentin was used either as a primary therapy for the management of severe headache following a diagnosed dural puncture or as an analgesic adjunct in patients with dural puncture headache unresponsive to epidural blood patch. In our patients, analgesic therapy was essential to enable care of their newborns as other management options had failed or were unavailable. In nine patients we observed an excellent result with reduction of headache severity within 24 hours. Gabapentin appears potentially beneficial in the management of patients with post-dural puncture headaches. PMID- 22813501 TI - Long-term use of nerve block catheters in paediatric patients with cancer related pathologic fractures. AB - We report three cases of children with osteosarcoma and pathologic fractures treated with long-term continuous nerve blocks for preoperative pain control. One patient with a left distal femoral diaphysis fracture had a femoral continuous nerve block catheter for 41 days without complications. Another with a fractured left proximal femoral shaft had three femoral continuous nerve block catheters for 33, 26 and 22 days respectively. The third patient, whose right proximal humerus was fractured, had a brachial plexus continuous nerve block catheter for 36 days without complication. In our experience, prolonged use of continuous nerve block is safe and effective in children with pathologic fractures for preoperative pain control. PMID- 22813505 TI - Circumcision of neonates and children without appropriate anaesthesia is unacceptable practice. PMID- 22813507 TI - Persistent 'can't intubate, can't oxygenate' crisis despite reversal of rocuronium with sugammadex: the importance of timing. PMID- 22813508 TI - Likelihood of experiencing 'can't intubate, can't oxygenate'. PMID- 22813509 TI - Maskumm facemask scent bonds Humid-Vent filters to facemasks. PMID- 22813510 TI - Unilateral block after spinal anaesthesia for caesarean section. PMID- 22813511 TI - A potential technique for flexible scope-assisted intubation using an Ambu aScope 2TM inserted via a supraglottic airway device. PMID- 22813512 TI - The selective combined use of rocuronium and sugammadex would be particularly advantageous in replacing multiple boluses of succinylcholine. PMID- 22813513 TI - Anaesthetic management using high-frequency oscillatory ventilation for a patient with tracheal and bronchial stenoses. PMID- 22813514 TI - Bronchiolitis obliterans presenting as prolonged ventilator dependence in a patient with paraneoplastic pemphigus. PMID- 22813515 TI - The dRTA-rhabdomyolysis connection. PMID- 22813516 TI - Assessing neuromuscular function in patients who have received Botox injections. PMID- 22813517 TI - Scatter plot and correlation coefficient. PMID- 22813518 TI - A bedside placard significantly increases compliance with head of the bed elevation in the intensive care unit: a pilot study. PMID- 22813519 TI - Double kinking of a thoracic catheter within the epidural space. PMID- 22813520 TI - Measurement of indocyanine green plasma disappearance rate during running renal replacement therapy. PMID- 22813521 TI - A clear choice when seconds count. PMID- 22813522 TI - The use of internal laryngeal pressure to improve the laryngeal view in a patient with a difficult airway. PMID- 22813523 TI - Knowledge and perception about sepsis: a survey in Japan. PMID- 22813530 TI - The ability of clinical tests to diagnose stress fractures: a systematic review and meta-analysis. AB - STUDY DESIGN: Systematic literature review and meta-analysis. OBJECTIVES: To evaluate the diagnostic accuracy of clinical tests to identify stress fractures in the lower limb. BACKGROUND: Stress fractures are a bone-related overuse injury primarily occurring in the lower limb and commonly affecting running athletes and military personnel. Physical examination procedures and clinical tests are suggested for diagnosing stress fractures; however, data on the diagnostic accuracy of these tests have not been investigated through a systematic review of the literature. METHODS: A systematic review was conducted in 8 electronic databases to identify diagnostic accuracy studies, published between January 1950 and June 2011, that evaluated clinical tests against a radiological diagnosis of lower-limb stress fracture. Retrieved articles were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed where appropriate. RESULTS: Nine articles investigating 2 clinical procedures, therapeutic ultrasound (n = 7) and tuning fork testing (n = 2), met the study inclusion criteria. Meta-analysis was used to statistically analyze the data extracted from the ultrasound articles and demonstrated a pooled sensitivity of 64% (95% confidence interval [CI]: 55%, 73%), specificity of 63% (95% CI: 54%, 71%), positive likelihood ratio of 2.1 (95% CI: 1.1, 3.5), and negative likelihood ratio of 0.3 (95% CI: 0.1, 0.9). Tuning fork test data could not be pooled; however, sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio ranged from 35% to 92%, 19% to 83%, 0.6 to 3.0, and 0.4 to 1.6, respectively. CONCLUSION: The results of this systematic review do not support the specific use of ultrasound or tuning forks as standalone diagnostic tests for lower-limb stress fractures. As the overall diagnostic accuracy of the tests investigated is not strong, based on the calculated likelihood ratios, it is recommended that radiological imaging should continue to be used for the confirmation and diagnosis of stress fractures of the lower limb. LEVEL OF EVIDENCE: Diagnosis, level 1a-.J Orthop Sports Phys Ther 2012;42(9):760-771, Epub 19 July 2012. doi:10.2519/jospt.2012.4000. PMID- 22813533 TI - Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy. AB - We discuss possible aetiological factors, MRI evolution of injury and neuro developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes. PMID- 22813532 TI - Impact of visceral adipose tissue and subcutaneous adipose tissue on insulin resistance in middle-aged Japanese. AB - AIM: The enlargement of visceral adipose tissue (VAT) is considered to mediate the close relationship between obesity and insulin resistance. We aimed to determine whether a stronger association of VAT compared to subcutaneous adipose tissue (SAT) with insulin resistance could be confirmed and generalized in non diabetic Japanese men and women. METHODS: Participants were 912 non-diabetic Japanese (636 men and 276 women, mean age 52.4+/-7.0 years, and mean BMI 24.9+/ 3.1 kg/m(2)). VAT and SAT were measured through the use of computed tomography scanning. Homeostatic model for the assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI) were calculated based on results from the oral glucose tolerance test. RESULTS: For both genders, subjects in higher tertiles of SAT as well as VAT showed significantly higher levels of HOMA-IR and lower levels of Matsuda ISI (p<0.001). In multiple regression analyses with VAT and SAT included in the model, only VAT, but not SAT, was independently associated with Matsuda ISI in women (p<0.001), whereas both SAT and VAT were independently associated with HOMA-IR and with Matsuda ISI in men (p<0.001). When VAT and waist circumference were jointly included in the model, only VAT, but not waist circumference, was independently associated with Matsuda ISI in women (p<0.001) but not in men. CONCLUSION: VAT had a stronger association with insulin resistance than SAT or waist circumference in women but not in men. BMI showed a comparable association with insulin resistance to VAT in this population. PMID- 22813531 TI - Discovery of a Plasmodium falciparum glucose-6-phosphate dehydrogenase 6 phosphogluconolactonase inhibitor (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2 fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) that reduces parasite growth in vitro. AB - A high-throughput screen of the NIH's MLSMR collection of ~340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6 phosphate dehydrogenase (PfG6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum , the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1 ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC(50) = 889 nM). It is completely selective for the enzyme's human isoform, displays micromolar potency (IC(50) = 2.6 MUM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting PfG6PD in vivo are in progress. PMID- 22813534 TI - Immunosuppressant-related hip pain after orthotopic liver transplant. AB - OBJECTIVES: Immunosuppressant-related hip pain can greatly affect a patient's mobility and increase the number of total hip arthroplasties. We investigated risk factors and causes of hip pain after orthotopic liver transplant. MATERIALS AND METHODS: The medical records of 175 adult orthotopic liver transplant patients, who were followed-up for more than 2 years, were retrospectively reviewed. Data collected from the records included primary disease, medications, biochemical results, Child-Turcotte-Pugh score, death, rejection, and complications related to liver transplant. RESULTS: A total of 11 patients (6.3%) complained of hip pain, which was diagnosed as calcineurin-inhibitor-induced pain syndrome in 4 patients (2.3%), osteonecrosis of the femoral head in 3 patients (1.7%), and osteoporosis in 2 patients (1.1%). The incidence of calcineurin inhibitor-induced pain syndrome was related to the dosage of tacrolimus (P > .05) but independent of methylprednisolone use. The occurrence of osteonecrosis of the femoral head was independent of the dosage and early withdrawal of methylprednisolone (P > .05). Patients with methylprednisolone withdrawal within 6 months had significantly longer survival than those using methylprednisolone for more than 6 months (50 +/- 15 vs 41 +/- 18 mo; P = .007). CONCLUSIONS: Calcineurin-inhibitor-induced pain syndrome and osteonecrosis of the femoral head are main causes of hip pain in adult orthotopic liver transplant patients. Osteonecrosis of the femoral head was not common, but the incidence of hip pain owing to calcineurin-inhibitor-induced pain syndrome was relatively high in orthotopic liver transplant patients. Early withdrawal of methylprednisolone could benefit the patients' survival. PMID- 22813535 TI - The roles of whole body balance, shoe-floor friction and joint strength during maximum exertions: searching for the "weakest link". AB - Exerting manual forces is critical during occupational performance. Therefore, being able to estimate maximum force capacity is particularly useful for determining how these manual exertion demands relate to available capacity. To facilitate this type of prediction requires a complete understanding of how maximum force capacity is governed biomechanically. This research focused on identifying how factors including joint moment strength, balance and shoe-floor friction affected hand force capacity during pulling, pressing downward and pushing medially. To elucidate potential limiting factors, joint moments were calculated and contrasted with reported joint strength capacities, the balancing point within the shoe-floor interface was calculated and expressed relative to the area defined by the shoe-floor interface, and the net applied horizontal forces were compared with the available friction. Each of these variables were calculated as participants exerted forces in a series of conditions designed to systematically control or restrict certain factors from limiting hand force capacity. The results demonstrated that hand force capacity, in all tested directions, was affected by the experimental conditions (up to 300%). Concurrently, biomechanical measures reached or surpassed reported criterion thresholds inferring specific biomechanical limitations. Downward exertions were limited by elbow strength, whereas pulling exertions were often limited by balance along the anterior-posterior axis. No specific limitations were identified for medial exertions. PMID- 22813536 TI - Detection of varicella-zoster virus antigens in lesional skin of zosteriform lichen planus but not in that of linear lichen planus. AB - BACKGROUND: Distinctions between 'linear lichen planus' (LP) and 'zosteriform LP' are difficult to determine solely based on clinical findings. OBJECTIVE: The aim of this study is to determine whether the presence of the varicella-zoster virus (VZV) antigens could be used to differentiate the zosteriform LP from the linear LP. METHODS: We immunohistochemically investigated the presence of in vivo localization of VZV antigens in 8 LP lesions (zosteriform LP: n = 5, linear LP: n = 3). RESULTS: We describe 2 cases of zosteriform LP without apparent prior episodes of herpes zoster, in whom VZV antigens were detected in the eccrine epithelium. Further analysis showed that VZV antigens were exclusively detected in the eccrine epithelium in the zosteriform LP lesions, but not in the linear LP lesions. CONCLUSION: Etiological differences exist between zosteriform LP and linear LP. The presence of VZV antigens in lesional skin of the former indicates a possible triggering role of this virus in the pathogenesis of this variant. PMID- 22813537 TI - Three-dimensional knee kinematics by conventional gait analysis for eleven motor tasks of daily living: typical patterns and repeatability. AB - The availability of detailed knee kinematic data during various activities can facilitate clinical studies of this joint. To describe in detail normal knee joint rotations in all three anatomical planes, 25 healthy subjects (aged 22-49 years) performed eleven motor tasks, including walking, step ascent and descent, each with and without sidestep or crossover turns, chair rise, mild and deep squats, and forward lunge. Kinematic data were obtained with a conventional lower body gait analysis protocol over three trials per task. To assess the repeatability with standard indices, a representative subset of 10 subjects underwent three repetitions of the entire motion capture session. Extracted parameters with good repeatability included maximum and minimum axial rotation during turning, local extremes of the flexion curves during gait tasks, and stride times. These specific repeatable parameters can be used for task selection or power analysis when planning future clinical studies. PMID- 22813538 TI - A case of neonatal Marfan syndrome with good late follow-up: is it possible to avoid an early unfavourable outcome? AB - We report a case of a child with neonatal Marfan syndrome who was submitted for clinical and surgical treatment with good late outcome 9 years after the first cardiac operation. PMID- 22813539 TI - Electronic states of moire modulated Cu films. AB - We examined by low-energy electron diffraction and scanning tunneling microscopy the surface of thin Cu films on Pt(111). The Cu/Pt lattice mismatch induces a moire modulation for films from 3 to about 10 ML thickness. We used angle resolved photoemission spectroscopy to examine the effects of this structural modulation on the electronic states of the system. A series of hexagonal- and trigonal-like constant energy contours is found in the proximity of the Cu(111) zone boundaries. These electronic patterns are generated by Cu sp-quantum well state replicas, originating from multiple points of the reciprocal lattice associated with the moire superstructure. Layer-dependent strain relaxation and hybridization with the substrate bands concur to determine the dispersion and energy position of the Cu Shockley surface state. PMID- 22813540 TI - Social factors associated with alcohol consumption in the former Soviet Union: a systematic review. AB - AIMS: Alcohol consumption is a major cause of premature mortality in countries of the former Soviet Union (fSU). Despite the unique social profile of the region, we could find no published systematic review of studies of social factors and alcohol consumption in formerly Soviet countries. We aim to critically review the current evidence for social factors associated with alcohol consumption in the fSU and to identify key gaps in the literature. METHODS: We searched MEDLINE, EMBASE and Global Health databases for cross-sectional, case-control, longitudinal or qualitative studies of demographic, socio-economic, psycho-social and contextual factors associated with alcohol consumption, in any language, published from 1991 until 16 December 2011. Additional studies were identified from the references of selected papers and expert consultation. Our review followed PRISMA guidelines for the reporting of systematic reviews. RESULTS: Our search strategy resulted in 26 articles for review. Although there is strong evidence in the literature that males and smokers in the fSU are more likely to engage in hazardous alcohol consumption, findings regarding other social factors were mixed and there were almost no data on the association of contextual factors and alcohol consumption in this region. CONCLUSION: This review highlights the extremely limited amount of evidence for social factors associated with heavy alcohol consumption in the fSU. Given the unique social environment of countries of the fSU, future research should take these factors into account in order to effectively address the high levels of alcohol-related mortality in this region. PMID- 22813541 TI - Association between frequency of heavy episodic drinking and self-reported consequences: a cross-sectional study in a Swedish population. AB - AIMS: To describe perceived negative consequences (PNCs) of alcohol consumption related to the frequency of heavy episodic drinking (HED) in a Swedish population attending primary health care (PHC). METHODS: Data from a computer-based assessment, including questions about alcohol consumption and PNC, were collected from 28 PHC centres in Sweden. The analysis included 4559 responders. Risk ratios concerning PNC for different frequencies of HED were calculated. RESULTS: Engaging in HED once a month for women and two to three times a month for men significantly raised the proportion of individuals reporting PNC, compared with engaging in HED less than once a month. The men reported PNC of alcohol consumption to a higher degree than the women, and in general, the proportion of individuals reporting PNC was associated with the frequency of HED. CONCLUSION: Engaging in HED once a month for women and two to three times a month for men are critical levels regarding PNC of alcohol consumption. To identify a cut-off value for categorizing individuals as hazardous alcohol consumers due to the frequency of HED, further studies are needed. PMID- 22813543 TI - In vivo electrophysiological characterization of TASK-1 deficient mice. AB - BACKGROUND/AIMS: TASK-1 is a potassium channel predominantly expressed in heart and brain. We have previously shown that anesthetized TASK-1(-/-)mice have prolonged QT intervals in surface electrocardiograms (ECGs). In addition, heart rate variability quantified by time and frequency domain parameters was significantly altered in TASK-1(-/-) mice with a sympathetic preponderance. Aims of the present study were the analysis of QT intervals by telemetric ECGs, to determine potential influences of anesthesia and beta-adrenergic stimulation on repolarization in surface ECGs, to investigate in vivo electrophysiological parameters by intracardiac electrical stimulation and to quantify heart rate turbulence after ischemia/reperfusion or ventricular pacing in TASK-1(+/+) and TASK-1(-/-) mice. METHODS: Rate corrected QT intervals (QTc) were recorded in conscious mice by telemetry and in surface ECGs following administration of various anesthetics (tribromoethanol (Avertin((r))), pentobarbital and isoflurane). TASK-1(+/+) and TASK-1(-/-) mice were characterized by programmed electrical stimulation using an intracardiac octapolar catheter. The baroreceptor reflex was analyzed by heart rate turbulence (turbulence onset and slope) after ischemia/reperfusion and by stimulated premature ventricular contractions. RESULTS: Telemetric and surface ECGs in mice sedated with Avertin((r)) and pentobarbital, showed a significantly lengthened rate corrected QT interval in TASK-1(-/-) mice (telemetry: TASK-1(+/+) 43+/-3ms vs. TASK-1(-/-) 49+/-5ms, n=6, p<0.05; Avertin((r)): TASK-1(+/+) 36+/-8ms vs. TASK-1(-/-) 48+/-4ms, n=13/16, p<0.0001). The prolongation of the QT interval was most pronounced at lower heart rates. Isoflurane, known for its stimulatory effects on the TASK channel family, attenuated the rate corrected QT interval prolongation in TASK-1(-/-)mice. Intracardiac electrical stimulation revealed normal values for electrical conduction and refractoriness. No significant arrhythmias after atrial and ventricular burst stimulation were induced before and after adrenergic challenge in both genotypes. Turbulence onset after premature ventricular contraction was significantly altered in TASK-1(-/-) mice. CONCLUSION: TASK-1(-/-) mice exhibit a phenotype of QT prolongation, which distinct relation to heart rate. TASK-1 deficiency does neither alter key electrophysiological parameters nor increases atrial/ventricular vulnerability after electrical stimulation. The heart rate response after premature ventricular contractions is significantly abolished indicating a diminished baroreceptor reflex in TASK-1(-/-) mice. PMID- 22813542 TI - The impact of quadriceps femoris strength asymmetry on functional performance at return to sport following anterior cruciate ligament reconstruction. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the impact of quadriceps femoris (QF) muscle strength asymmetry at the time of return to sport on self-reported function and functional performance of individuals following anterior cruciate ligament reconstruction (ACLR). BACKGROUND: Evidence-based QF strength guidelines for return-to-sport decision making are lacking. Objective guidelines necessitate understanding the impact of QF strength deficits at the time of return to sport on function and performance. METHODS: Fifty-five individuals (mean age, 17.3 years) who were cleared for return to sport following primary ACLR (ACLR group) and 35 uninjured individuals (mean age, 17.0 years) in a control group participated in the study. QF strength (maximum voluntary isometric contraction) was assessed, and the quadriceps index (QI) was calculated [(involved strength/uninvolved strength) * 100%]. The ACLR group was further subdivided into 2 groups, based on the QI: high quadriceps (QI of 90% or greater) and low quadriceps (QI of less than 85%). The International Knee Documentation Committee Subjective Knee Evaluation Form score was used to assess self-reported function, and hop tests were used to assess functional performance. Multivariate analysis of variance and hierarchical regression analyses were performed. RESULTS: The individuals in the ACLR group were weaker, reported worse function, and performed worse on hop tests compared to those in the control group (P<.05). The low-quadriceps group demonstrated worse performance on the hop tests compared to the high-quadriceps group and the control group (P <=.016). Hop test performance did not differ between the high-quadriceps and control groups (P >=.14). QF strength predicted performance on the hop tests beyond graft type, presence of meniscus injury, knee pain, and knee symptoms. CONCLUSION: At the time of return to sport, individuals post-ACLR who had weaker QF (QI of less than 85%) demonstrated decreased function, whereas those with minimal QF strength deficits (QI of 90% or greater) demonstrated functional performance similar to uninjured individuals. QF strength deficits predicted hop test performance beyond the influences of graft type, presence of meniscus injury, knee pain, and knee symptoms. PMID- 22813544 TI - Overcoming the difficulties in collecting apoplastic fluid from rice leaves by the infiltration-centrifugation method. AB - Physiological and biochemical studies on the leaf apoplast have been facilitated by the use of the infiltration-centrifugation technique to collect intercellular washing fluid (IWF). However, this technique has been difficult to implement in rice (Oryza sativa L.) for various reasons. We compared the collection efficiency of leaf IWF between two types of rice varieties (Indica and Japonica), as well as between rice and other species (spinach, snap bean and wheat). Although the extraction of IWF in most species took only 2-3 min, it took up to 35 min in rice. The difficulty in infiltration with rice was ascribed to the small stomatal aperture and hydrophobicity of the leaves. In this study, we have established an improved method for collecting IWF and determining the apoplastic air and water volumes in rice leaves. We have shortened the infiltration time to 8 min via the following improvements: (i) infiltration under outdoor shade in the daytime to prevent stomatal closure and a rise in temperature of the infiltration medium; (ii) soaking of leaves in a surfactant solution to decrease the leaf hydrophobicity; and (iii) continuous pressurization using a sealant injector to facilitate the infiltration. The rapid collection of IWF achieved using this technique will facilitate study of the leaf apoplast in rice. PMID- 22813545 TI - Pleiotropic regulatory locus 2 exhibits unequal genetic redundancy with its homolog PRL1. AB - In plants, signaling leading to resistance against biotrophic pathogens is complex. Perception of pathogenic microbes by resistance (R) proteins is relayed though successive activities of downstream components, in a network that is not well understood. PLEIOTROPIC REGULATORY LOCUS 1 (PRL1) and >20 other proteins are members of the MOS4-associated complex (MAC), a regulatory node in defense signaling. Of all characterized MAC members, mutations in PRL1 cause the most severe susceptibility towards both virulent and avirulent microbial pathogens. Genetic suppressors of prl1 represent new signaling elements and may aid in further unraveling of defense mechanisms. Our identification and characterization of a dominant suppressor of prl1 revealed a regulatory, gain-of-function mutation in PLEIOTROPIC REGULATORY LOCUS 2 (PRL2), a close homolog of PRL1. Loss-of function mutants of PRL2 do not exhibit altered phenotypes; however, prl1 prl2 double mutants exhibit enhanced morphological defects consistent with unequal genetic redundancy between the homologs. Up-regulated gene expression mediated by the dominant prl2-1D allele completely suppresses disease susceptibility in the prl1 mutant background and also restores wild-type appearance, further supporting functional equivalence between the two PRL proteins. PMID- 22813546 TI - Evaluating systemic lupus erythematosus patients for lung involvement. AB - INTRODUCTION: We set out to determine the frequency of respiratory symptoms, abnormal lung function, and shrinking lung syndrome (SLS) among patients with systemic lupus erythematosus (SLE) and to determine correlates of SLS. METHODS: Consecutive adult patients who fulfilled the American College of Rheumatology classification criteria for SLE were enrolled. Demographics, clinical, and serologic characteristics were recorded; all patients underwent pulmonary function tests (PFT) and had either a chest X-ray or computed tomography scan. SLS was defined as dyspnea with restrictive lung physiology (defined as a forced vital capacity (FVC) <80% predicted in the absence of obstruction) who did not have any evidence of interstitial lung disease on chest imaging; controls were symptomatic patients with no restrictive physiology and the absence of interstitial changes on chest imaging. RESULTS: Sixty-nine out of 110 (63%) patients had respiratory symptoms, 73 (66%) patients had abnormal lung function, and 11 (10%) patients met the definition for SLS. In a multivariate model controlling for disease duration, a history of pleuritis, modified American College of Rheumatology total score, seropositivity for dsDNA and RNP antibodies, increased disease duration (odds ratio (OR) = 1.2; 95% confidence interval (CI) of 1.0-1.3, p = 0.04), seropositivity for anti-RNP (OR = 24.4; 95% CI of 1.6 384.0, p = 0.02), and a history of serositis were significantly associated with SLS when compared with symptomatic controls. CONCLUSION: Respiratory symptoms, abnormal lung function, and SLS are common in SLE. Clinicians should consider evaluation for SLS among symptomatic patients with long-standing disease and a history of pleuritis. PMID- 22813547 TI - Autoimmune disease. PMID- 22813561 TI - The IADSPG criteria for the diagnosis of GDM: has the pendulum swung too far to the other side? PMID- 22813562 TI - Prevalence of hypertension, control of blood pressure and treatment in hypertensive with type 2 diabetes in Hospital University Sains Malaysia. AB - AIMS: To determine the prevalence of hypertension, control of hypertension and patterns of antihypertensive medications in Malaysian type 2 diabetic patients who attended diabetes clinics in Hospital University Sains Malaysia (Tertiary Hospital). MATERIALS AND METHODS: The study design was observational prospective longitudinal follow-up study; the study was conducted with sample of 1077 type 2 diabetes mellitus outpatient recruited whom attended the diabetes clinics at Hospital Universiti Sains Malaysia (HUSM) in Kelantan. The study period was from January till December 2008. Blood pressure was defined as >130/80 or use of antihypertension medications. Demographic characteristics of patients, level of blood pressure control, use of antihypertensive medications and patterns of antihypertensive therapy. RESULTS: The prevalence of hypertension in Malaysian type 2 diabetic patients was 998 (92.7%),antihypertensive drugs were prescribed in 940 (94.2%) of hypertensive patients with type 2 diabetic mellitus. The achievement of blood pressure control (<=130/80 mmHg) was 471 (47.2%) %. The percentage of patients receiving one, two, three, and four drugs were 253 (25.3%), 311 (31.3%), 179 (17.9%), and 197 (19.7%) respectively. Calcium channel blockers were the most commonly prescribed antihypertensive agents 757 (75.7%) followed by Angiotensin-converting enzyme inhibitors 446 (44.6%), and Angiotensin receptor blockers 42.4 (42.4%). CONCLUSION: The prevalence of hypertension is high in Malaysian type 2 diabetic patients, hypertension was not controlled to the recommended levels of blood pressure in about one-half (52.8%) of diabetes patients. Calcium channel blockers were the most commonly prescribed antihypertensive agents. There is an urgent need to educate both patients and health care providers of importance of achieving target of treatment in order to reduce morbidity and mortality due to diabetes with hypertension. PMID- 22813563 TI - The impact of creatinine clearance on the outcome of diabetic foot ulcers in north Indian tertiary care hospital. AB - AIM: Wound healing has been reported to be poor in diabetic patients with impaired kidney functions that usually accompanies retinopathy and neuropathy. The insensitive foot is vulnerable to repeated trauma and development of ulcer precedes 70-80% of non-traumatic lower extremity amputation. The present study was aimed to study the impact of creatinine clearance (CCre) on the outcome of diabetic foot ulcers (DFU). MATERIALS AND METHODS: Data from 162 DFU patients admitted to Rajiv Gandhi Centre for Diabetes and Endocrinology of J.N. Medical College, Aligarh Muslim University, Aligarh, India, between December 2009 and March 2011 were analyzed. Detailed history and patient's profile, grade of DFU, co-morbidities and complications, laboratory data, microbiological profile and final outcome were collected. CCre was calculated according to MDRD formula. RESULTS: The study revealed that, DFU healing was worst in patients with decreased CCre than in those who had normal CCre. Other factors associated with poor outcome were, higher grade of ulcer, infection type (subcutaneous and osteomyelitis) and biofilm infection. Amputation rates were also found to be higher in those with poor renal functions. CONCLUSIONS: The results suggest that CCre is an important factor affecting wound healing in patients with DFUs. The automatic reporting of eGFR each time a serum creatinine concentration is requested will increase the awareness of significant kidney dysfunction in clinical practice especially in DFU patients and appropriate measures will improve the outcome. PMID- 22813564 TI - PONI and its association with oxidative stress in type I and type II diabetes mellitus. AB - OBJECTIVE: Paraoxonase (PON) is an antioxidant enzyme linked with cardiovascular disease (CVD), diabetes as it prevents LDL oxidation. The relation of PON with the other established risk factor of diabetic complications has not been looked into. RESEARCH DESIGN AND METHODS: 370 subjects were included in the study. Dividing into four group, i.e. group I included type II DM (n=220), group II was age matched control (n=100), group III were type I DM (n=25) and group IV (n=25) were age matched control group. The protocol of the study was approved by the ethical committee of the institute. SOD, GSH, PON (paraoxonase and arylesterase activity), GHb, and MDA were estimated. RESULTS: A highly significant decrease in paraoxonase and arylesterase activity was seen in the type II DM (p<0.0001) while in type I DM both the activity was not significant (p>0.05). Paraoxonase and arylesterase activity of PONI showed a negative significant correlated with MDA (r=-0.51, p<0.0001 and r=-0.23, p<0.001) in type II DM but was not correlated in type I DM. The GHb and MDA levels were significantly increased (p<0.0001) while the levels of SOD and GSH have been decreased in type I and type II DM. CONCLUSION: PONI is definitely associated with development of the complications of diabetes. This may be due to the role of it as an antioxidant. As it also show a negative correlation with MDA like the other antioxidants studied. PMID- 22813565 TI - Factor analysis of diabetic nephropathy in Chinese patients. AB - OBJECTIVE: To investigate factors related to albuminuria in diabetic nephropathy (DN). METHODS: Clinical data of 873 Chinese patients with type 2 diabetes were gathered retrospectively. Urinary albumin-creatinine-ratio was tested thrice for each patient before calculating its mean value for DN diagnosing and staging. Inter-relationship among variables was studied using factor analysis, and factor scores were compared and used as independent variables in regression models to identify the parameter clusters that predict the development and/or progression of DN. RESULTS: Factor analysis reduced 21 original variables to eight unique factors, representing obesity, glycemic, C peptide, lipids, time, renal, blood pressure and metabolism status. Logistic regression revealed that presence of hyperuricemia/gout (OR=1.821, 95%CI 1.224-2.707), time factor (OR=1.404, 95%CI 1.194-1.651) and blood pressure factor (OR=1.424, 95%CI 1.216-1.668) were positively associated with DN, while C peptide factor (OR=0.816, 95%CI 0.691 0.963) was negatively associated with DN. Ordinal regression revealed another positively related lipid factor (OR=1.237, 95%CI 1.060-1.445) besides those determined in Logistic regression. CONCLUSION: Hyperuricemia/gout, time, blood pressure and lipid factors are predictors of DN, while C peptide factor is negatively associated with the development and/or progression of DN. PMID- 22813566 TI - Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes. AB - Controversy exists regarding the effect of pregnancy on the development and course of diabetic nephropathy. This study followed 43 pregnant women with previous diabetes mellitus, 32 without nephropathy (Group I) and 11 with nephropathy (Group II). Urinary albumin excretion (UAE), serum creatinine (Cr) and creatinine clearance (CCr) in the pre-pregnancy (Pre-P), first trimester (1T), third trimester (3T) and 1 year postpartum (PP) were evaluated. In both groups there were an increase in 3T compared to Pre-P of CCr (137 vs. 98 ml/min and 110 vs. 81 ml/min, p=0.0001, respectively) and UAE (7.78 vs. 3.15 mg/24 h and 592 vs. 119 mg/24 h, p=0.0001, respectively). Increase of Cr in the PP compared to 1T in Group II (0.88 vs. 0.70 mg/dL, p=0.031) was observed. There were no difference in UAE, CCr and Cr in the PP when compared to pre-P as well variance over time between groups. Group II showed higher prevalence of chronic hypertension (72.7 vs. 21.9%, p=0.004), preeclampsia (63.6 vs. 6.3%, p=0.0003) and lower gestational age at birth (36 vs. 38 weeks, p=0.003). We conclude that pregnancy was not associated with development and progression of diabetic nephropathy in women with or without mild renal dysfunction. The presence of diabetic nephropathy was associated with increased risk of perinatal complications. PMID- 22813567 TI - Insulin resistance and alanine amino transaminase (ALT) levels in first degree relatives of type 2 diabetes mellitus. AB - INTRODUCTION: Insulin resistance is established as an independent predictor of a range of disorders such as obesity, hypertension, dyslipidemia, type 2 diabetes mellitus and atherosclerotic cardiovascular diseases. There is an association of hyperinsulinemia with hypertriglycerdemia, low level of HDL and high level of LDL. In nonalcoholic fatty liver disease, there is an elevation of ALT, raising the possibility that the prospective relationship between ALT and type 2 diabetes may reflect cross-sectional associations with insulin resistance or obesity. AIM AND OBJECTIVE: To find the significance of insulin resistance and alanine aminotransferase level in first degree relatives of type 2 diabetes mellitus. MATERIALS AND METHODS: The study included 50 first degree relatives of type 2 diabetes (25 men and 25 women) aged 20-60 years and 30 control of similar age. All cases were taken from SRM Medical College Hospital and Research Centre, Chennai. All the cases were analyzed for HOMA(IR), QUICKI, IR ratio, fasting glucose, insulin (ELISA), lipid profile and alanine aminotransferase. Student's 't' test was applied for statistical analysis. RESULT: The data show the significance of insulin resistance (HOMA(IR)) (2.76+/-1.46, 1.35+/-0.8, p<0.001) in the first degree relatives of type 2 diabetes mellitus when compared with controls respectively and increased level fasting plasma insulin (12.28+/-6.16, 6.12+/-3.04, p<0.001). In the lipid profile the total cholesterol and TAG are significant. No statistical significance was found in ALT (24.8+/-9.84, 20.08+/ 11.02). CONCLUSION: Results of the study conclude that there is a high prevalence of insulin resistance in the first degree relatives of type 2 diabetes mellitus. ALT levels in the first degree relatives of type 2 diabetes mellitus had increased levels of insulin resistance, the pathogenesis suggesting increase in ALT levels as seen in insulin resistance condition. In our study, ALT was not statistically significant. PMID- 22813568 TI - Shaddock peels (Citrus maxima) phenolic extracts inhibit alpha-amylase, alpha glucosidase and angiotensin I-converting enzyme activities: a nutraceutical approach to diabetes management. AB - In this study, the interactions of free and bound phenolic-rich extracts from shaddock peels (popular in folklore for the management of diabetes and hypertension) with alpha-amylase and alpha-glucosidase (key enzymes linked to type-2 diabetes) and angiotensin I-converting enzyme (ACE) (key enzyme linked to hypertension) were assessed. The free phenolics of shaddock (Citrus maxima) peels were extracted with 80% acetone, while the bound phenolics were extracted from the alkaline and acid hydrolyzed residue with ethyl acetate; and their interaction with the enzymes were assessed. The phenolic extracts inhibited alpha amylase, alpha-glucosidase and ACE enzyme activities in a dose-dependent manner; however, bound phenolics had significantly higher (P<0.05) alpha-amylase inhibitory activities, than free phenolics, which had significantly higher (P<0.05) ACE inhibitory activities. There was no significant difference (P>0.05) in their alpha-glucosidase inhibitory activities. The stronger inhibition of alpha-glucosidase when compared to alpha-amylase is of great pharmaceutical importance. The phenolic inhibited sodium nitroprusside induced lipid peroxidation in pancreas in a dose dependent manner. Therefore, free and bound phenolic extracts from shaddock peels could be used as nutraceutical for the management of hypertension and type-2 diabetes. PMID- 22813569 TI - Association of metabolic syndrome with carotid atherosclerosis in the young North Indian population. AB - BACKGROUND: Metabolic syndrome (MetS) and its components are associated with increased risk of stroke and cardiovascular disease. Relationship of MetS to carotid atherosclerosis has not been documented well in North Indian population. AIMS: (1) To determine the incidence of metabolic syndrome in asymptomatic healthy young North Indian population; (2) to evaluate individuals with MetS patients for carotid atherosclerosis by carotid duplex ultrasound examination; (3) to determine the significance of each component of MetS in relation to carotid atherosclerosis in these patients. METHODS: 440 individuals in the age group of 25-50 years, asymptomatic for cardiac or cerebrovascular disease were screened for metabolic syndrome. 162 patients from a hospital-based population fulfilled the criteria for MetS (as per NCEP ATP III criteria). Duplex ultrasound (DU) examination of extracranial carotid vessels was performed on all the subjects. 112 age- and sex-matched controls were screened, and they underwent DU examination for comparison. RESULTS: Hypertriglyceridemia was the commonest component seen in 79.6% of the MetS subjects, followed by central obesity seen in 74.6% subjects. Carotid atherosclerotic disease was observed in 21.6% of patients with MetS. Mild atherosclerosis (intima media thickness (IMT) >0.09 cm) was observed in 82.8% and 17.3% had plaques with mild stenosis (<50%) in the extracranial carotid arteries. Among patients of MetS with carotid atherosclerotic disease 82.6% had hypertriglyceridemia and 71.5% had 4 or more components for MetS. Among controls, five subjects (4.46%) had evidence of mild carotid atherosclerosis (IMT >0.09 cm) on DU. MetS was significantly associated with carotid DU abnormalities (increased IMT >0.09 cm) compared to controls (Fischer's exact test p<0.0001). Univariate analysis showed the relationship of hypertriglyceridemia to carotid atherosclerosis (p=0.03). On multivariate regression analysis none of the individual components of MetS contributed significantly to the presence of carotid atherosclerosis. CONCLUSIONS: MetS is common in asymptomatic healthy North Indian population, with hypertriglyceridemia being the commonest component of MetS in this population, which may be predictive of carotid atherosclerotic disease. Serum triglyceride estimation can serve as a screen for asymptomatic healthy subjects to select the target population for cerebrovascular disease prevention. PMID- 22813570 TI - Glycosylation, diabetes and dengue: effect on severity? AB - BACKGROUND: Co-presentation between dengue and diabetes mellitus (DM) can be expected. The author hereby assesses the effect of glycosylation process in poor glycemic control cases on the course of dengue infection. METHODS: The aim of this work is to assess the effect of glycosylation of CD61 on the pathogenesis of dengue hemorrhagic fever. The hypothetical bioinformatics approach is used in this research. RESULT: Significant change of similarity between CD61 and dengue NS1 after glycosylation can be detected. CONCLUSION: These findings might imply that immunomimicking process should be more difficult to occur. PMID- 22813571 TI - Metformin and insomnia: an interesting story. PMID- 22813572 TI - Overview of trans fatty acids: biochemistry and health effects. AB - Trans fatty acids (TFA) are unsaturated fatty acids that contain at least one non conjugated double bond in the trans configuration, resulting in a straighter shape. TFA present in our diet can either be industrially produced and ruminant or natural. The major process contributing to formation of industrial TFA is hydrogenation of vegetable oils. Thermal processes such as edible oil refining and frying also lead to the formation of TFA while, ruminant/natural TFA is formed in the rumen of ruminant animals through bio-hydrogenation. Industrial TFA poses severe effects on our health like cardiovascular problems, insulin resistance, infertility in women, compromised fetal development and cognitive decline. There are strict regulations for limiting/removing the TFA content from food supply across the world. However in India, there is scarcity of data on TFA content in foods and their consumption levels. Given the alarmingly rising trend of diabetes and cardiovascular disease in India, removal of TFA from the food supply along with generating awareness among the masses in this regard is of immense importance. PMID- 22813573 TI - Diabetic retinopathy: pathogenic mechanisms and current treatments. AB - Since diabetes is now a global epidemic, the incidence of retinopathy, a leading cause of blindness in patients aged 20-74 years, is also expected to rise to alarming levels. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure and possibly lipids. It is an unmet medical need that can lead to severe and irreversible loss of vision in people of working age worldwide. The aim of this review is to give an overview of the clinical and anatomical changes during the progression of retinopathy, the underlying pathogenic mechanisms that link hyperglycemia with retinal tissue damage, current treatments, and the emerging pharmacological therapies for this sight-threatening complication of diabetes. PMID- 22813574 TI - Walking strategies change with distance from hill transition and scale with hill angle. AB - Individuals must constantly modify their gait patterns to safely transition between different surfaces. The goal of the current study was to determine if gait changes could be detected two steps from a transition, and whether these changes scaled with the angle of the hill. We hypothesized that during the anticipation of uphill walking and the aftereffect of downhill walking, the magnitude of kinetic and electromyography changes would be greatest at steep hill angles and fewer steps from the transition. We collected force and electromyography data as participants walked on the level ground before an uphill ramp and after a downhill ramp. As hypothesized, there were significant main effects for both the number of steps and angle of the hill for the first vertical GRF peak, as well as lateral gastrocnemius and vastus lateralis activity. Overall, our results indicate that when transitioning to and from hills, anticipation and aftereffect responses occur at least two steps from the transition and are scaled to the angle of the hill. PMID- 22813575 TI - Loss of reliable temporal structure in event-related averaging of naturalistic stimuli. AB - To separate neural signals from noise, brain responses measured in neuroimaging are routinely averaged across space and time. However, such procedures may obscure some properties of neural activity. Recently, multi-voxel pattern analysis methods have demonstrated that patterns of activity across voxels contain valuable information that is concealed by spatial averaging. Here we show that temporal patterns of neural activity contain information that can discriminate different stimuli, even within brain regions that show no net activation to that stimulus class. Furthermore, we find that in many brain regions, responses to natural stimuli are highly context dependent. In such cases, prototypical event-related responses do not even exist for individual stimuli, so that averaging responses to the same stimulus within different contexts may worsen the effective signal-to-noise. As a result, analysis of the temporal structures of single events can reveal aspects of neural dynamics which cannot be detected using standard event-related averaging methods. PMID- 22813576 TI - Determination method for mono- and diethanolamine in workplace air by high performance liquid chromatography. AB - OBJECTIVES: The purpose of this research was to develop a simultaneous determination method for monoethanol-amine (MEA) and diethanolamine (DEA) in workplace air for risk assessment. METHODS: The characteristics of the proposed method, such as recovery, quantitation limit, reproducibility and storage stability of the samples, were examined. RESULTS: An air sampling cassette containing two sulfuric acid-treated glass fiber filters was chosen as the sampler. The MEA and DEA were extracted from the sampler filters, derivatized with 9-fluorenylmethyloxycarbonyl chloride and then analyzed by a high performance liquid Chromatograph equipped with a fluorescence detector or photo diode array detector. The overall recoveries from spiked samplers were 86-99 and 88-99% for MEA and DEA, respectively. The recovery after 5 days of storage in a refrigerator exceeded 95%. The overall limits of quantitation were 0.750 and 0.100 jug/sample for MEA and DEA, respectively. The relative standard deviations, which represent the overall reproducibility defined as precision, were 0.3-1.6 and 0.4-5.7% for MEA and DEA, respectively. CONCLUSIONS: The proposed method enables 4-h personal exposure monitoring of MEA and DEA at concentrations equaling 1/3,000-2 times the threshold limit value-time-weighted average (TLV TWA: 3 ppmfor MEA, 1 mg/m(3) for DEA) adopted by the American Conference of Governmental Industrial Hygienists and also by the Japan Society for Occupational Health. The method is useful for estimating worker exposure to MEA and DEA. PMID- 22813577 TI - Risk of stroke and atrial fibrillation after radiofrequency catheter ablation of typical atrial flutter. AB - BACKGROUND: Studies suggest that 18%-50% of the patients develop atrial fibrillation (AF) after typical atrial flutter (AFL) ablation. However, little data exist about the incidence of and risk factors for stroke and AF after successful ablation of typical AFL. OBJECTIVES: To determine the risk of stroke and AF after radiofrequency ablation of typical AFL. METHODS: A retrospective review of patients undergoing AFL ablation between 2002 and 2010 was performed to determine the incidence of and risk factors for stroke and AF after successful ablation of typical AFL. RESULTS: The study cohort consisted of 126 patients (age 66 +/- 10 years) with a mean follow-up of 40 +/- 30 months after ablation. Following successful AFL ablation, AF occurred in 46 patients (37%), with an incidence of 104 cases of documented AF per 1000 person-years after AFL ablation. Twenty patients (16%) developed new AF after AFL ablation. Stroke occurred in 8 patients (6%) during follow-up, with an incidence of 21 strokes per 1000 person years. Six of the 8 patients (75%) with strokes had documented AF occurrences after AFL ablation. The presence of AF after AFL ablation was the only risk factor associated with the risk for future stroke. CONCLUSIONS: Patients with typical AFL undergoing successful ablation are at an elevated risk for AF and stroke following the procedure. Because postprocedure AF is the only identifiable risk factor for stroke, rigorous monitoring of patients after typical AFL may help identify those patients who are at an increased risk for stroke. PMID- 22813578 TI - Heart to heart: cardiospheres for myocardial regeneration. AB - Cardiac regenerative therapies seek to grow new myocardium after "irreversible" injury such as myocardial infarction. Various cell types and delivery techniques have been used in experimental models of human disease and clinical trials. When selecting a candidate stem cell type for clinical use, multiple factors need to be taken into consideration. The ability to regenerate myocardium without potentiating arrhythmogenesis is a critical property. Skeletal myoblasts engraft, differentiate, and are arrhythmogenic; in contrast, bone marrow-derived cells do not engraft long-term and have not been associated with excess arrhythmias. Neither cell type, however, achieves true myocardial regeneration. Recognition of the existence of cardiac stem cells and of the ability of mature myocytes to reenter the cell cycle and proliferate has motivated the development of new approaches to cardiac regenerative medicine. Cardiosphere-derived cells decrease scar mass and regenerate viable myocardium both in animal models and in the CADUCEUS (Cardiosphere-Derived Cells For Heart Regeneration After Myocardial Infarction) clinical trial. Although cardiosphere-derived cells fulfill the criteria for stem cells, their stemness appears not to mediate the therapeutic benefit; instead, indirect mechanisms lead to proliferation of the host myocardium. Being of endogenous origin, the newly grown heart muscle is electrically and mechanically well integrated with preexisting myocardial tissue. We hypothesize that cardiac arrhythmias are less likely to complicate cell therapy when the mechanisms of benefit involve secondary proliferation of endogenous myocardium. Conversely, arrhythmias will more likely bedevil therapeutic approaches (such as transplantation of skeletal myoblasts or pluripotent stem cells) that lead to exogenous grafts within the heart, with the degree of coupling and the extent of inhomogeneity being critical determinants of the net effect. PMID- 22813579 TI - If the shoe fits: antitachycardia pacing in children and patients with congenital heart disease. PMID- 22813580 TI - Study of the N-terminal part of peptidic selective NPFF2 agonists. AB - Neuropeptide FF (NPFF) has been shown to act as an endogenous anti-analgesic peptide. In this paper, several peptide analogs of the selective ligand dNP(NMe)AFLFQPQRF-NH(2) modified in the putative address segment, were designed to be selective NPFF(2) receptor probes, synthesized and assayed. One peptide dA(NMe)AAFLFQPQRF-NH(2) displays a very high affinity for NPFF(2) receptors transfected in CHO cells, and a high selectivity versus NPFF(1) receptors. The exact residues carried in the N-terminal part of the ligands are not decisive to obtain a high affinity only the length of the peptide in itself seems important to create selectivity. PMID- 22813581 TI - K(+)-Cl(-) cotransporter 1 (KCC1) negatively regulates NGF-induced neurite outgrowth in PC12 cells. AB - Potassium chloride cotransporters (KCCs) mediate electroneutrally-coupled transport of K(+) and Cl(-), and play crucial roles in various cell functions including regulation of cell volume and homeostasis of cellular Cl(-)content. Four isoforms of KCCs (KCC1, 2, 3, and 4) have been identified. KCC1 is ubiquitously expressed, whereas KCC2 is mainly expressed in neuronal cells of central nervous system. KCC3 is highly expressed in heart, skeletal muscle, kidney, lung and placenta. KCC4 is mainly expressed in epithelial cells. In this study, we investigated roles of KCCs in NGF-induced neurite outgrowth of rat pheochromocytoma PC12 cells. The most abundantly expressed isoform in PC12 cells was KCC1. Inhibition of KCCs using [(dihydronindenyl)oxy] alkanoic acid (DIOA), an inhibitor of KCCs, enhanced the NGF-induced neurite outgrowth of PC12 cells in a dose-dependent manner. Treatment of PC12 cells with NGF significantly decreased mRNA expression of KCC1, whereas other isoforms, KCC2-4, showed no changes in their mRNA expression in response to NGF treatment. Knockdown of KCC1 using small interfering RNA (siRNA) enhanced the NGF-induced neurite outgrowth. These results suggest that KCC1 negatively regulates the NGF-induced neurite outgrowth of PC12 cells. PMID- 22813582 TI - Blood-brain barrier unlocked. AB - The brain is protected by a physiological blood-brain barrier (BBB) against toxins and some metabolites circulating in the blood. At the same time, the BBB limits penetration into the brain of many neuroactive drugs. Efficient ways to increase BBB permeability for delivery of drugs of different chemical nature into the brain are unknown. This work deals with delivery into the brain of 10(-2) M dopamine, a substance that does not penetrate the BBB under normal circumstances. It was studied in two independent experiments: (i) penetration of (3)H-labeled dopamine from its mixture with 10(-5) M H2O2 into hypothalamus and striatum structures of intact rat brain, and (ii) effect of unlabeled dopamine from a mixture with H(2)O(2) on the rat motor activity in a haloperidol catalepsy model. It was shown that (i) at the third minute after nasal application of the dopamine + H(2)O(2) mixture, the dopamine level increases 45-fold in the hypothalamus and almost 30-fold in the striatum and (ii) motility of animals in the catalepsy haloperidol model is recovered 90 sec after intranasal introduction of dopamine. No such effects were observed after replacement of H(2)O(2) by 0.9% NaCl solution. Thus, it was shown on the example of dopamine that its introduction into the nasal cavity simultaneously with H(2)O(2) provides for rapid delivery of the drug into the brain. These results expand our knowledge concerning the biological role of exoROS in modulating BBB permeability and may contribute to the development of a new therapeutic strategy for neurological diseases. PMID- 22813583 TI - Identification of new M23A mRNA of mouse aquaporin-4 expressed in brain, liver, and kidney. AB - Aquaporins (AQPs) belong to a transmembrane protein family of water channels that are permeable to water by the osmotic gradient. There are two isoforms of mouse AQP4 - M1 and M23. Their balance in the cell determines water permeability of the plasma membrane. These two isoforms are encoded by three mRNAs: M1 isoform is encoded by M1 mRNA and M23 isoform is encoded by M23 and M23X mRNAs. Here we found a new fourth mRNA of mouse AQP4 - M23A mRNA. The start of transcription is different for M23A mRNA from all the known AQP4 mRNAs. The 5'-untranslated region (5'-UTR) of M23A mRNA is encoded by four new exons (A, B, C, and D), which are located in the 5' region from exon-0 of the AQP4 gene. Alternative splicing between the exons-A, -B, -C, and -D leads to formation of multiple variants of M23A mRNA. We cloned six of these variants, all of which code full length M23 isoform of AQP4. Using RT-PCR we detected tissue-specific expression of the new M23A and already known M23, M23X, and M1 mRNAs. The M23A mRNA is expressed mostly in kidney, liver, and brain. Analysis of mRNA 5'-UTR structure showed low translation efficacy for M1 mRNA in comparison with high translation efficacy for M23A, M23X, and M23 mRNAs. We propose that AQP4 expression is controlled tissue specifically by independent promoters. Thus multiple AQP4 mRNAs may allow long term regulation of the balance between M1 and M23 AQP4 isoforms in the cell and thus water permeability of the plasma membrane. PMID- 22813584 TI - Classification of rhodopsin structures by modern methods of structural bioinformatics. AB - We report a classification of the crystallographic structures of bovine and squid rhodopsins corresponding to different stages of their photocycles. Using the resource Protein (Structure) Comparison, Knowledge, Similarity, and Information server (ProCKSI, http://www.procksi.net/), selected spatial structures were compared on the basis of classification schemes (dendrograms). To compare the spatial structures of transmembrane proteins, optimal consensus was developed from methods implemented in ProCKSI. Structures were also clustered using principal component analysis, resulting in good agreement with the classification based on the ProCKSI consensus method. Analysis of the results revealed the basic movements of individual transmembrane domains of these proteins that we were able to relate to different stages of the photoactivation of rhodopsin. A combination of methods identified in this study can be used as an up-to-date analytical tool to study the conformational dynamics of membrane receptors. PMID- 22813585 TI - Femtosecond charge separation in dry films of reaction centers of Rhodobacter sphaeroides and Chloroflexus aurantiacus. AB - In this work, the influence of the crystallographic water on electron transfer between primary donor P and acceptor B(A) was studied in reaction centers (RCs) of the purple bacterium Rhodobacter sphaeroides and the green bacterium Chloroflexus aurantiacus. For this purpose, time constants and oscillations of charge separation kinetics are compared between dry film RCs and RCs in glycerol water buffer at 90 K. A common result of the drying of Rba. sphaeroides and Cfx. aurantiacus RCs is slowing of the charge separation process, decrease in amplitude of the oscillatory components of the kinetics, and the depletion of its spectrum. Thus, the major time constant of stimulated emission decay of P* bacteriochlorophyll dimer at 940 nm is increased from 1.1 psec for water containing Rba. sphaeroides RCs to 1.9 psec for dry films of Rba. sphaeroides RCs. An analogous increase from 3.5 to 4.2 psec takes place in Cfx. aurantiacus RCs. In dry films of Rba. sphaeroides RCs, the amplitude of coherent oscillations of the absorption band of monomeric bacteriochlorophyll B(A)(-) at 1020 nm is 1.8 times less for the 130-cm(-1) component and 2.3 times less for the 32-cm(-1) component than the analogous amplitudes for water-containing RCs. Measurements in the analogous band of Cfx. aurantiacus RCs show that strong decrease (~5-10 times) of the B(A)(-) absorption band and strong slowing (from ~0.8 to ~3 psec) of B(A)(-) accumulation together with ~3-fold decrease in oscillation amplitude occurs on drying of these RCs. The overtones of the 32-cm(-1) component disappeared from the oscillations of the kinetics at 940 and 1020-1028 nm after drying of the Rba. sphaeroides and Cfx. aurantiacus RCs. The results are in agreement with the results for GM203L mutant of Rba. sphaeroides, in which the HOH55 water molecule is sterically removed, and with the results for dry films of pheophytin-modified RCs of Rba. sphaeroides R-26 and for YM210W and YM210L Rba. sphaeroides mutant RCs. The data are discussed in terms of the influence (or participation) of the HOH55 water molecule on electron transfer along the chain of polar atomic groups N-Mg(P(B))-N-C-N(HisM202)-HOH55-O=(B(A)) connecting P(B) and B(A) in Rba. sphaeroides RCs. PMID- 22813586 TI - Initiation of the 3':5'-AMP-induced protein kinase A Ialpha regulatory subunit conformational transition. Part I. A202 and A326 are critical residues. AB - Protein-ligand docking and molecular dynamics studies have shown that the key event initiated by 3':5'-AMP binding to the A- and B-domains of protein kinase A Ialpha regulatory subunit is formation of a hydrogen bond between 3':5'-AMP and A202(A326) (the residue in parentheses being from the B-domain). The A202(A326) amide group movement associated with the bond formation leads to reorganization of the phosphate binding cassette (PBC) (the short 3(10)-helix becomes the long alpha-helix). This process results in L203(L327) displacement and finally causes hinge (B-helix) rotation. The L203(L327) displacement and packing into the hydrophobic pocket formed by the PBC and beta2beta3-loop also depends on the beta2beta3-loop conformation. The correct conformation is maintained by R, I, E, but not K at position 209(333) of the A- and B-domains. So, the R209K and R333K mutants have problems with reaching B-conformation. The apo-form of the 3':5'-AMP binding domain also undergoes transition from H- to B-conformation. In this case, the movement of A202(A326) amide group seems to be a result of reorganization of the PBC into a more stable alpha-helix. PMID- 22813587 TI - Initiation of the 3':5'-AMP-induced protein kinase A Ialpha regulatory subunit conformational transition. Part II. Inhibition by Rp-3':5'-AMPS. AB - Protein-ligand docking and ab initio calculations have shown that the 3':5'-AMP phosphorothioate analog (Rp-3':5'-AMPS) blocks the A326 amide group displacement typical of transition from the H- to B-conformation within the B-domain of protein kinase A Ialpha R-subunit. This behavior of Rp-3':5'-AMPS leads to the inhibition of initial stages of hydrophobic relay operation. In accordance with the proposed hypothesis, Rp-3':5'-AMPS similarly to 3':5'-AMP forms a hydrogen bond with the amide group of A326; however, the properties of this bond together with the position of the sulfur atom prevent the movement of A326. Finally, the Rp-3':5'-AMPS-bound domain appears to be locked in the H-conformation, which is in agreement with the X-ray data. PMID- 22813588 TI - Correlation between biological activity and conformational dynamics properties of tetra- and pentapeptides derived from fetoplacental proteins. AB - In this work, using molecular dynamics simulation, we study conformational and dynamic properties of biologically active penta- and tetrapeptides derived from fetoplacental proteins such as alpha-fetoprotein, pregnancy specific beta1 glycoprotein, and carcinoembryonic antigen. Existence of correlation between flexibility of peptide backbone and biological activity of the investigated peptides was shown. It was also demonstrated that flexibility of peptide backbone depends not only on its length, but also on the presence of reactive functional groups in amino acid side chains that participate in intramolecular interactions. Peptides that demonstrate similar biological effects in regulation of proliferation of lymphocytes and expression of differentiation antigens on their surface (LDSYQCT, PYECE, YECE, and YVCE) are characterized by rigidity of their peptide backbone. Increased backbone flexibility in peptides PYQCE, YQCE, SYKCE, YQCT, YQCS, YVCS, YACS, and YACE is correlated with decreased biological activity. Conformational mobility of amino acid residues does not depend on physicochemical properties only, but also on intramolecular interactions. So, evolutionary restrictions should exist to maintain such interactions in the environment of functionally important sites. PMID- 22813589 TI - Processing character of the action of wheat endonucleases WEN1 and WEN2. Kinetic parameters. AB - The wheat seedling endonucleases WEN1 and WEN2 dependent on Mg(2+), Ca(2+), and S adenosyl-L-methionine (SAM) and sensitive to the substrate DNA methylation status have an expressed processing action. The enzymes hydrolyze DNA at a few subsequent stages: first, they split lambda phage DNA specifically at CNG-sites (WEN1) with liberation of large fragments; second, they hydrolyze these fragments to 120-140 bp oligonucleotides that finally are hydrolyzed to very short fragments and mononucleotides. Initial stages of DNA hydrolysis may proceed in the absence of Mg(2+), but subsequent hydrolysis stages are very strongly stimulated by Mg(2+). It cannot be ruled out that modulation of enzymatic activity with Mg(2+) and probably with DNA fragments formed is associated with reorganization of the structure of eukaryotic (wheat) endonucleases with respective changes in their catalytic properties and site specificity of action. Michaelis constant value for WEN1 endonuclease on hydrolysis of methylated lambda phage DNA containing Cm(5)CWGG and Gm(6)ATC sites is four-fold lower compared with that observed on hydrolysis of unmethylated lambda phage DNA. This may indicate that affinity of WEN1 enzyme to methylated DNA is higher than that to unmethylated DNA. In the presence of SAM, the Michaelis constant for WEN2 on the DNA hydrolysis stage characterized by formation of 120-140 bp fragments is decreased, but for WEN1 it is increased by 1.5-2.0-fold. This means that SAM inhibits WEN1 but stimulates WEN2. Thus, wheat endonucleases WEN1 and WEN2 differ significantly in affinities to substrate DNAs with different methylation status, in velocities of DNA hydrolysis, and time of production of DNA fragments of similar length. It seems that the investigated plant endonucleases can hydrolyze DNA in the nucleus as well to both large and very short fragments including mononucleotides, that is, in particular, essential for utilization of cell nucleic acid material during apoptosis. PMID- 22813590 TI - Isolation and properties of recombinant inulinases from Aspergillus sp. AB - The genes inuA and inu1, encoding two inulinases (32nd glycosyl hydrolase family) from filamentous fungi Aspergillus niger and A. awamori, were cloned into Penicillium canescens recombinant strain. Using chromatographic techniques, endoinulinase InuA (56 kDa, pI 3) and exoinulinase Inu1 (60 kDa, pI 4.3) were purified to homogeneity from the enzymatic complexes of P. canescens new transformants. The properties, such as substrate specificity, pH- and T-optima of activity, stability at different temperatures, influence of cations and anions on the catalytic activity, etc., of both recombinant inulinases were studied. PMID- 22813591 TI - Food protein fragments are regulatory oligopeptides. AB - Until recently food proteins were considered to be an energy source and a source of essential and nonessential amino acids required for protein synthesis and precursors of many vital biomolecules. However, we assumed earlier that food protein fragments might perform some regulatory functions. The theoretical justification for this assumption is advanced in this work. In the present work, the primary structures of protein fragments were compared with amino acid sequences of known natural regulatory oligopeptides in silico. It is shown that fragments formed as a result of animal food protein cleavage by proteolytic enzymes can exist in the gastrointestinal tract for a long time. Many of them are enzyme inhibitors, regulators of nervous, endocrine, and immune system, and possess antimicrobial and other activities. It has also been shown that the lifetime of fragments before their cleavage in the gastrointestinal tract could be enough for performing corrective functions. Thus, as a result of food protein fragmentation a dynamic pool of exogenous regulatory oligopeptides with functions changing as shorter fragments are generated may form. The detection of an endogenous-exogenous pool of regulatory molecules expands the significance and content of the Ashmarin-Obukhova hypothesis on a functional continuum of natural oligopeptides. The possible practical importance of these results is noted. PMID- 22813592 TI - Teichulosonic acid, an anionic polymer of a new class from the cell wall of Actinoplanes utahensis VKM Ac-674(T). AB - The cell wall of Actinoplanes utahensis VKM Ac-674(T) contains two anionic polymers: teichoic acid 1,3-poly(glycerol phosphate) that is widespread in cell walls of Gram-positive bacteria; and a unique teichulosonic acid belonging to a new class of bioglycans described only in microorganisms of the Actinomycetales order. The latter polymer contains residues of di-N-acyl derivative of sialic acid-like monosaccharide - 5,7-diamino-3,5,7,9-tetradeoxy-L-glycero-beta-L-manno non-2-ulosonic or pseudaminic acid (Pse) which bears the N-(3,4 dihydroxybutanoyl) group (Dhb) at C7. This polymer has irregular structure and consists of fragments of two types, which differ in substitution of the Dhb residues at O4 either with beta-D-glucopyranose or with beta-Pse residues. Most of the beta-Pse residues (~80%) are glycosylated at position 4 with alpha-D galactopyranose residues in both types of fragments. The glucose, galactose, and Dhb residues are partly O-acetylated. The structures of the polymers were established by chemical and NMR spectroscopy methods. PMID- 22813593 TI - Gene conversion in the mitochondrial genome on interspecific hybridization in voles of the Clethrionomys genus. AB - The phenomenon of interspecific hybridization accompanied by transfer of the mitochondrial genome from the northern red-backed vole (Clethrionomys rutilus) to the bank vole (Cl. glareolus) in northeastern Europe is well known already for 25 years. However, the possibility of recombination between homologous segments of maternal and paternal mtDNAs of the voles during fertilization was not previously studied. Analysis of data on variability of nucleotide sequences of the mitochondrial gene for cytochrome b in populations of red-backed and bank voles in the area of their sympatry has shown that as a result of interspecific hybridization, the mitochondrial gene pool of bank voles contains not only mtDNA haplotypes of red-backed vole females, but also mtDNA haplotypes of bank voles bearing short nucleotide tracts of red-backed vole mtDNA. This finding supports the hypothesis that an incomplete elimination of red-backed vole paternal mtDNA during the interspecific hybridization between bank vole females and red-backed vole males leads to the gene conversion of bank vole maternal mtDNA tracts by homologous ones of mtDNA of red-backed vole males. PMID- 22813594 TI - Interaction of nucleotide excision repair proteins with DNA containing bulky lesion and apurinic/apyrimidinic site. AB - The interaction of nucleotide excision repair (NER) proteins (XPC-HR23b, RPA, and XPA) with 48-mer DNA duplexes containing the bulky lesion-mimicking fluorescein substituted derivative of dUMP (5-{3-[6 (carboxyamidofluoresceinyl)amidocapromoyl]allyl}-2'-deoxyuridine-5' monophosphate) in a cluster with a lesion of another type (apurinic/apyrimidinic (AP) site) has been studied. It is shown that XPC-HR23b is modified to a greater extent by the DNA duplex containing an AP site opposite nucleotide adjacent to the fluorescein residue than by DNA containing an AP site shifted to the 3'- or 5'-end of the DNA strand. The efficiency of XPA modification by DNA duplexes containing both AP site and fluorescein residue is higher than that by DNA lacking the bulky lesion; the modification pattern in this case depends on the AP site position. In accordance with its major function, RPA interacts more efficiently with single-stranded DNA than with DNA duplexes, including those bearing bulky lesions. The observed interaction between the proteins involved in nucleotide excision repair and DNA structures containing a bulky lesion processed by NER and the AP site repaired via base excision repair may be significant for both these repair pathways in cells and requires the specific sequence of repair of clustered DNA lesions. PMID- 22813595 TI - A new viral vector exploiting RNA polymerase I-mediated transcription. AB - We have developed a new viral vector system exploiting RNA-polymerase I transcription. The vector is based on the crucifer-infecting tobacco mosaic virus (crTMV) cDNA inserted into the rRNA transcriptional cassette (promoter and terminator). To visualize reproduction of the vector, the coat protein gene was replaced with the gene encoding green fluorescent protein (GFP) resulting in a Pr(rRNA)-crTMV-GFP construct. Our results showed that agroinjection of Nicotiana benthamiana leaves with this vector results in GFP production from uncapped crTMV GFP RNA because RNA polymerase I mediates synthesis of rRNA lacking a cap. Coexpression of the crTMV 122 kDa capping protein gene and the silencing suppressor encoded by the tomato bushy stunt virus p19 gene stimulated virus directed GFP production more than 100-fold. We conclude that the Pol I promoter can be used to drive transcription in a transient expression system. PMID- 22813596 TI - Profiling and comparative analysis of glycoproteins in Hs578BST and Hs578T and investigation of prolyl 4-hydroxylase alpha polypeptide II expression and influence in breast cancer cells. AB - To identify potential cancer related glycoproteins in breast cancer cells, we enriched N-linked glycoproteins by lentil lectin from the human breast cancer cell line Hs578T and the normal breast cell line Hs578BST for proteomic comparison. Glycoproteins were separated and compared by two-dimensional electrophoresis. Twenty-four glycoproteins were identified that expressed remarkably differently, among which nine were involved in the progress of collagen synthesis. Prolyl 4-hydroxylase alpha polypeptide II (P4HA2) expression and influence in breast cancer was further investigated. Immunohistochemistry revealed that P4HA2 was upregulated in breast tumor cells compared with its adjacent normal tissues. Moreover, overexpression and RNA interference of P4HA2 showed that P4HA2 expression suppressed cell proliferation and migration in Hs578T in vitro. PMID- 22813597 TI - Expression of androgen receptor, estrogen receptors alpha and beta and aromatase in the fetal, perinatal, prepubertal and adult testes of the South American plains Vizcacha, Lagostomus maximus (Mammalia, Rodentia). AB - Androgens and androgen receptor play a critical role in spermatogenesis and fertility in mammals, and estrogens and their receptors contribute to regulation of testicular function through initiation and maintenance of spermatogenesis and germ cell division and survival. However, results from different species are still far from establishing a clear understanding of these receptors in the different cell types from the testis. We analyzed the expression of androgen receptor, estrogen receptors alpha and beta and aromatase protein by immunohistochemistry and real-time PCR, in relation to proliferation followed by the expression of proliferation cell nuclear antigen (PCNA) and germinal identity by VASA protein, in fetal, perinatal, prepubertal and adult testes of Lagostomus maximus, a rodent with sustained germ cell proliferation and an increasing number of OCT-4-expressing gonocytes in the developing ovary. AR expression was restricted to Leydig cells and peritubular cells before sexual maturity, at which point it also became expressed in Sertoli cells. ERalpha and ERbeta were expressed in seminiferous tubules and the interstitium, respectively, in both fetal and prepubertal testes. In adult testes, both ERalpha and ERbeta co localized in Leydig and peritubular cells. The aromatase enzyme, which converts androgenic precursors into estrogens, was detectable in all developmental stages analyzed and was restricted to Leydig cells. PCNA remained high until sexual maturity. ERalpha nuclear detection in germ cells and AR in Leydig cells in PCNA positive cells suggest the possibility of a stimulatory effect of estrogens on spermatogonia proliferation. This effect might explain the increase found in VASA expressing cells in the adult testis. PMID- 22813598 TI - Differential expression of the motin family in the peri-implantation mouse uterus and their hormonal regulation. AB - Increased vascular permeability and angiogenesis are hallmarks of the implantation process in the uterus. Angiomotin (Amot), which is a vascular angiogenesis-related protein, belongs to the motin family. There are two other members of the motin family, angiomotin-like 1 and 2 (Amotl1 and 2), which are also thought to be involved with angiogenesis. In the present study, the distribution of motin mRNAs in the mouse uterus during the peri-implantation period was investigated by in situ hybridization. Amot and Amotl1 were expressed in the stromal cells on days 3 and 4; expressions of Amotl2 during the same period were low. During the postimplantation period, Amot and Amotl1 were expressed in secondary decidual cells, while Amotl2 expression fell to an undetectable level. We also examined hormonal regulation of motin expression by steroid hormone treatment in ovariectomized mice. We found that expression of Amot was induced by P(4) in stromal cells. Additionally, Amotl1 expression was upregulated by both P(4) and estrogen (E(2)) in stromal cells, whereas E(2) increased this gene expression for only a limited time; after 12 h, expression dissipated. In contrast, P(4) regulated the expression of Amotl2 in stromal cells, while E(2) regulated its expression in luminal epithelium cells. Our results demonstrated that Amot, Amotl1, and Amotl2 were differentially expressed in uterine cells during the peri-implantation period, and that their expressions were differentially regulated by P(4) and E(2). PMID- 22813599 TI - Higher copy number variation and diverse X chromosome inactivation in parthenote derived human embryonic stem cells. AB - Parthenote-derived human embryonic stem cells (phESCs) have many advantages over conventionally derived human embryonic stem cells (hESCs), but a more thorough investigation of these cells is needed before they can be implemented in cell therapies. In this work, we used a Cytogenetics Whole-Genome Array to study the copy number variation (CNV) status in phESCs and hESCs. We also investigated X chromosome inactivation (XCI) and expression levels of marker genes in these cells. More CNVs were found in phESCs than in hESCs in the present study, and gene expression appeared to be associated with the gain or loss of CNVs. In addition, a variable XCI status and different expression pattern of paternally expressed imprinted gene were also found in phESCs. In conclusion, although phESCs had a similar pluripotent profile to conventionally derived hESCs, these cells differed in imprinted gene expression, XCI status and number of CNVs. Our work highlights the need for a deeper investigation to elucidate the genetic and epigenetic characteristics of these cells. PMID- 22813600 TI - Evidence for almost complete sex-reversal in bovine freemartin gonads: formation of seminiferous tubule-like structures and transdifferentiation into typical testicular cell types. AB - During mammalian sex determination of XY fetuses, SRY induces SOX9 in Sertoli cells, resulting in formation of testes with seminiferous tubules, interstitial Leydig cells and peritubular myoid cells. Meanwhile XX fetuses without SRY develop ovaries. In cattle, most XX heifers born with a male twin, so-called freemartins, develop nonfunctioning ovaries and genitalia with an intersex phenotype. Interestingly, freemartins sometimes develop highly masculinized gonads with seminiferous tubule-like structures despite the absence of SRY. However, in these cases, the degree of masculinization in each gonadal somatic cell type is unclear. Here, we report a rare case of a freemartin Japanese black calf with almost complete XX sexreversal. Gross anatomical analysis of this calf revealed the presence of a pair of small testis-like gonads with rudimentary epididymides, in addition to highly masculinized genitalia including a pampiniform plexus, scrotum and vesicular gland. Histological and immunohistochemical analyses of these masculinized gonads revealed well-defined seminiferous tubule-like structures throughout the whole gonadal parenchyma. In epithelia of these tubules, SOX9-positive supporting cells (i.e., Sertoli cells) were found to be arranged regularly along the bases of tubules, and they were also positive for GDNF, one of the major factors for spermatogenesis. 3beta-HSD positive cells (i.e., Leydig cells) and SMA-positive peritubular myoid cells were also identified around tubules. Therefore, for the first time, we found the transdifferentiation of ovarian somatic cells into all testicular somatic cell types in the XX freemartin gonads. These data strongly support the idea of a high sexual plasticity in the ovarian somatic cells of mammalian gonads. PMID- 22813601 TI - Knee and elbow 3D strength surfaces: peak torque-angle-velocity relationships. AB - Recognizing the importance of both the torque-angle and torque-velocity relations, three-dimensional (3D) human strength capabilities (i.e., peak torque as a function of both joint angle and movement velocity) have been increasingly reported. It is not clear, however, the degree to which these surfaces vary between joints, particularly between joints with similar biomechanical configurations. Thus, our goal was to compare 3D strength surfaces between the muscles about the elbow and knee hinge joints in men and women. Peak isometric and isokinetic strength was assessed in 54 participants (30 men) using the Biodex System 3 isokinetic dynamometer. Normalized peak torque surfaces varied significantly between flexion and extension (within each joint) and between joints; however, the normalized 3D torque surfaces did not differ between men and women. These findings suggest the underlying joint biomechanics are the primary influences on these strength surface profiles. Therefore, in applications such as digital human modeling, torque-velocity-angle relationships for each joint and torque direction must be uniquely represented to most accurately estimate human strength capability. PMID- 22813602 TI - A large intracardiac thrombus in a child with steroid-resistant nephrotic syndrome. AB - Intracardiac thrombus is a rare complication of nephrotic syndrome in children, and only a few cases have been reported. We report the case of a 3.5-year-old child diagnosed with Henoch-Schonlein Purpura and steroid-resistant nephrotic syndrome for 2 months. The patient had massive oedema but no cardiovascular instability. Echocardiography displayed a large thrombus within the right atrium and the patient was successfully managed with enoxoparine. PMID- 22813603 TI - Breathing not properly 10 years later: what we have learned and what we still need to learn. AB - Since the initial studies showing the usefulness of B-type natriuretic peptide for aiding in heart failure diagnosis, a vast number of other clinical applications for this neurohormone have emerged. In addition to refining our capabilities to diagnose and prognosticate in acute heart failure, natriuretic peptides are now being used in outpatient heart failure clinics, in screening programs, and in risk prediction algorithms in various settings. In just 10 years, B-type natriuretic peptide has gone from being an unknown biomarker to being one of the most useful in cardiology and beyond. In this perspective piece, the investigators review what we have learned about using natriuretic peptides over the past 10 years and the anticipated advances in their use over the next decade. PMID- 22813604 TI - Where genome meets phenome: rationale for integrating genetic and protein biomarkers in the diagnosis and management of dilated cardiomyopathy and heart failure. AB - This review provides the rationale for integrating genomic and protein biomarkers in the evolving diagnosis and management of dilated cardiomyopathy (DCM) and its causal pathway to heart failure (HF), with a larger objective to serve as a template for genomic and phenomic profiling of other cardiovascular disease. DCM is a major cause of HF and accounts for more than half of heart transplantation in adults and children worldwide. DCM may remain asymptomatic for years, but HF and/or arrhythmias, both late manifestations of the disease, ultimately cause significant morbidity and mortality. A significant proportion of DCM has a genetic etiology. DCM can also result from environmental injury such as infection, toxins, or catecholamine excess. While molecular genetic testing can identify those at risk for genetic DCM, epigenetic and sentinel phenomic staging can help to identify those at highest risk in need for intervention. Phenomic staging includes integrating clinical and imaging features, transcriptomics, higher order proteomics and metabolomics interactions, and epidemiological data. This principle can be applied in family members of patients with DCM, where genetic testing and clinical phenotyping are indicated. This will allow the design of specific interventions tailored to individuals sharing similar risks, to alter the natural history of DCM and obviate complications such as HF/arrhythmias. PMID- 22813605 TI - Prospective study on circulating MicroRNAs and risk of myocardial infarction. AB - OBJECTIVES: This study sought to explore the association between baseline levels of microRNAs (miRNAs) (1995) and incident myocardial infarction (1995 to 2005) in the Bruneck cohort and determine their cellular origin. BACKGROUND: Circulating miRNAs are emerging as potential biomarkers. We previously identified an miRNA signature for type 2 diabetes in the general population. METHODS: A total of 19 candidate miRNAs were quantified by real-time polymerase chain reactions in 820 participants. RESULTS: In multivariable Cox regression analysis, 3 miRNAs were consistently and significantly related to incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio: 2.69 [95% confidence interval: 1.45 to 5.01], p = 0.002), whereas miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio: 0.47 [95% confidence interval: 0.29 to 0.75], p = 0.002, and 0.56 [95% confidence interval: 0.32 to 0.96], p = 0.036). To determine their cellular origin, healthy volunteers underwent limb ischemia-reperfusion generated by thigh cuff inflation, and plasma miRNA changes were analyzed at baseline, 10 min, 1 h, 5 h, 2 days, and 7 days. Computational analysis using the temporal clustering by affinity propagation algorithm identified 6 distinct miRNA clusters. One cluster included all miRNAs associated with the risk of future myocardial infarction. It was characterized by early (1 h) and sustained activation (7 days) post-ischemia-reperfusion injury and consisted of miRNAs predominantly expressed in platelets. CONCLUSIONS: In subjects with subsequent myocardial infarction, differential co-expression patterns of circulating miRNAs occur around endothelium-enriched miR-126, with platelets being a major contributor to this miRNA signature. PMID- 22813606 TI - Small RNA biomarkers come of age. PMID- 22813607 TI - Modeling serum biomarkers S100 beta and neuron-specific enolase as predictors of outcome after out-of-hospital cardiac arrest: an aid to clinical decision making. AB - OBJECTIVES: The aim of this study was to determine the added value of the serum biomarkers S100 and neuron-specific enolase to clinical characteristics for predicting outcome after out-of-hospital cardiac arrest. BACKGROUND: Serum S100 beta (S100B) and neuron-specific enolase concentrations rise after brain injury. METHODS: A prolective observational study was conducted among all adult survivors of nontraumatic out-of-hospital cardiac arrest admitted to 1 hospital (April 3, 2008 to April 3, 2011). Three blood samples (on arrival and on days 1 and 3) were drawn for biomarkers, contingent on survival. Follow-up continued until in hospital death or discharge. Outcomes were defined as good (Cerebral Performance Category score 1 or 2) or poor (Cerebral performance category score 3 to 5). RESULTS: A total of 195 patients were included (65.6% men, mean age 73 +/- 16 years), with presenting rhythms of asystole in 61.5% and ventricular tachycardia or ventricular fibrillation in 24.1%. Only 43 patients (22.0%) survived to hospital discharge, 26 (13.3%) with good outcomes. Patients with good outcomes had significantly lower S100B levels at all time points and lower neuron-specific enolase levels on days 1 and 3 compared with those with poor outcomes. Independent predictors at admission of a good outcome were younger age, a presenting rhythm of ventricular tachycardia or ventricular fibrillation, and lower S100B level. Predictors on day 3 were younger age and lower day 3 S100B level. The area under the receiver-operating characteristic curve of the admission-day model was 0.932 with and 0.880 without biomarker data (p = 0.027 for the difference). CONCLUSIONS: Risk stratification after out-of-hospital cardiac arrest using both clinical and biomarker data is feasible. The biomarkers, although adding an ostensibly modest 5.2% to the area under the receiver-operating characteristic curve, substantially reduced the level of uncertainty in decision making. Nevertheless, current biomarkers cannot replace societal considerations in determining acceptable levels of uncertainty. (Protein S100 Beta as a Predictor of Resuscitation Outcome; NCT00814814). PMID- 22813608 TI - "Madam, methinks i see him living yet" (John Milton, 1644): predicting full recovery after out-of-hospital cardiac arrest. PMID- 22813609 TI - Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. AB - OBJECTIVES: This study was designed to explore the predictive value of the midregional fragment of pro-adrenomedullin (MR-proADM) in assessing the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). BACKGROUND: Midodrine hydrochloride is an important therapeutic option for children with POTS. However, there has not been any method to predict response to the drug. The MR-proADM is produced in equimolar amounts to adrenomedullin (ADM), and directly reflects levels of the rapidly degraded active peptide, ADM. METHODS: Fifty-seven children with POTS were designated as the POTS group. Twenty healthy children served as the control group. The children in the POTS group received midodrine hydrochloride treatment. The plasma concentration of MR-proADM was measured, using a sandwich immunoluminometric assay. A receiver-operating characteristic curve was used to explore the predictive value of MR-proADM. RESULTS: Plasma levels of MR-proADM were significantly higher in children with POTS (75.0 [62.5 to 96.0] pg/ml) than in the control group (58.5 [50.3 to 69.0] pg/ml). Plasma levels of MR-proADM in responders to midodrine hydrochloride was significantly higher than that of nonresponders (76.0 [66.0 to 91.0] pg/ml vs. 59.0 [54.0 to 65.5] pg/ml, p < 0.01]. A receiver-operating characteristic curve on the predictive value of MR proADM showed that the area under the curve was 0.879 with a 95% confidence interval of 0.761 to 0.997. Using a cutoff value for MR-proADM of 61.5 pg/ml produced both high sensitivity (100%) and specificity (71.6%) in predicting the efficacy of midodrine hydrochloride therapy for treating POTS. CONCLUSIONS: MR proADM can help guide midodrine hydrochloride therapy in the management of POTS in children. PMID- 22813610 TI - Peptides in postural orthostatic tachycardia syndrome: players or epiphenomena? PMID- 22813611 TI - Circulating apoptotic endothelial cells and apoptotic endothelial microparticles independently predict the presence of cardiac allograft vasculopathy. AB - OBJECTIVES: Maintenance of endothelial homeostasis may prevent the development of cardiac allograft vasculopathy (CAV). This study investigated whether biomarkers related to endothelial injury and endothelial repair discriminate between CAV negative and CAV-positive heart transplant recipients. BACKGROUND: CAV is the most important determinant of cardiac allograft survival and a major cause of death after heart transplantation. METHODS: Fifty-two patients undergoing coronary angiography between 5 and 15 years after heart transplantation were recruited in this study. Flow cytometry was applied to quantify endothelial progenitor cells (EPCs), circulating endothelial cells (CECs), and endothelial microparticles. Cell culture was used for quantification of circulating EPC number and hematopoietic progenitor cell number and for analysis of EPC function. RESULTS: The EPC number and function did not differ between CAV-negative and CAV positive patients. In univariable models, age, creatinine, steroid dose, granulocyte colony-forming units, apoptotic CECs, and apoptotic endothelial microparticles discriminated between CAV-positive and CAV-negative patients. The logistic regression model containing apoptotic CECs and apoptotic endothelial microparticles as independent predictors provided high discrimination between CAV positive and CAV-negative patients (C-statistic 0.812; 95% confidence interval: 0.692 to 0.932). In a logistic regression model with age and creatinine as covariates, apoptotic CECs (p = 0.0112) and apoptotic endothelial microparticles (p = 0.0141) were independent predictors (C-statistic 0.855; 95% confidence interval: 0.756 to 0.953). These 2 biomarkers remained independent predictors when steroid dose was introduced in the model. CONCLUSIONS: The high discriminative ability of apoptotic CECs and apoptotic endothelial microparticles is a solid foundation for the development of clinical prediction models of CAV. PMID- 22813612 TI - Prospective evaluation of pregnancy-associated plasma protein-a and outcomes in patients with acute coronary syndromes. AB - OBJECTIVES: This study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). BACKGROUND: PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality. METHODS: We measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 MUIU/ml was chosen from pilot work in this cohort. RESULTS: PAPP-A >6.0 MUIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 MUg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine. CONCLUSIONS: PAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications. PMID- 22813613 TI - Prognostic utility of neutrophil gelatinase-associated lipocalin in predicting mortality and cardiovascular events in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - OBJECTIVES: The aim of this study was to investigate the prognostic role of neutrophil gelatinase-associated lipocalin (NGAL) in a large population of patients with ST-segment elevation myocardial infarction. BACKGROUND: NGAL is a glycoprotein released by damaged renal tubular cells and is a sensitive maker of both clinical and subclinical acute kidney injury. New data have demonstrated that NGAL is also stored in granules of mature neutrophils, and recent data suggest that NGAL may also be involved in the development of atherosclerosis. NGAL is significantly increased in patients with myocardial infarction compared with patients with stable coronary artery disease and healthy subjects. However, the prognostic value of NGAL has never been studied in patients with myocardial infarction. METHODS: We included 584 consecutive ST-segment elevation myocardial infarction patients admitted to the heart center of Gentofte University Hospital, Denmark, and treated with primary percutaneous coronary intervention, from September 2006 to December 2008. Blood samples were drawn immediately before primary percutaneous coronary intervention. Plasma NGAL levels were measured using a time-resolved immunofluorometric assay. The endpoints were all-cause mortality (n = 69) and the combined endpoints (n = 116) of major adverse cardiac events (MACE) defined as cardiovascular mortality and admission due to recurrent myocardial infarction or heart failure. The median follow-up time was 23 months (interquartile range, 20 to 24 months). RESULTS: Patients with high NGAL (>75th percentile) had increased risk of all-cause mortality and MACE compared with patients with low NGAL (log-rank test, p < 0.001). After adjustment for confounding risk factors chosen by backward elimination by Cox regression analysis, high NGAL remained an independent predictor of all-cause mortality and MACE (hazard ratio: 2.00; 95% confidence interval: 1.16 to 3.44; p = 0.01 and hazard ratio: 1.51; 95% confidence interval: 1.00 to 2.30; p = 0.05, respectively). CONCLUSIONS: High plasma NGAL independently predicts all-cause mortality and MACE in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention. PMID- 22813614 TI - Elevated plasma levels of neuropeptide proenkephalin a predict mortality and functional outcome in ischemic stroke. AB - OBJECTIVES: The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease. BACKGROUND: The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders. METHODS: In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale). RESULTS: PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05). CONCLUSIONS: PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events. PMID- 22813615 TI - Subpulmonic obstruction by aneurysmal tricuspid valve tissue in a perimembranous ventricular septal defect. PMID- 22813616 TI - Imaging biomarkers of aortic disease: increased growth rates with eccentric systolic flow. PMID- 22813618 TI - Prospective validation of a predictive model that identifies homeless people at risk of re-presentation to the emergency department. AB - OBJECTIVE: To prospectively evaluate the accuracy of a predictive model to identify homeless people at risk of representation to an emergency department. METHODS: A prospective cohort analysis utilised one month of data from a Principal Referral Hospital in Melbourne, Australia. All visits involving people classified as homeless were included, excluding those who died. Homelessness was defined as living on the streets, in crisis accommodation, in boarding houses or residing in unstable housing. Rates of re-presentation, defined as the total number of visits to the same emergency department within 28 days of discharge from hospital, were measured. Performance of the risk screening tool was assessed by calculating sensitivity, specificity, positive and negative predictive values and likelihood ratios. RESULTS: Over the study period (April 1, 2009 to April 30, 2009), 3298 presentations from 2888 individuals were recorded. The homeless population accounted for 10% (n=327) of all visits and 7% (n=211) of all patients. A total of 90 (43%) homeless people re-presented to the emergency department. The predictive model included nine variables and achieved 98% (CI, 0.92-0.99) sensitivity and 66% (CI, 0.57-0.74) specificity. The positive predictive value was 68% and the negative predictive value was 98%. The positive likelihood ratio 2.9 (CI, 2.2-3.7) and the negative likelihood ratio was 0.03 (CI, 0.01-0.13). CONCLUSION: The high emergency department re-presentation rate for people who were homeless identifies unresolved psychosocial health needs. The emergency department remains a vital access point for homeless people, particularly after hours. The risk screening tool is key to identify medical and social aspects of a homeless patient's presentation to assist early identification and referral. PMID- 22813619 TI - Can a four-hour interactive workshop on the management of dental emergencies be effective in improving self reported levels of clinician proficiency? AB - BACKGROUND: Management of dental emergencies is a clinical problem facing many primary care providers who have often received little training in this area. AIM: This study evaluated the impact of a four-hour interactive workshop on clinicians' self reported proficiency in managing common dental emergencies. METHOD: A descriptive study design using a questionnaire type survey instrument was used to evaluate the effectiveness of a brief interactive workshop. RESULTS: The workshop positively impacted proficiency, especially in oral local anaesthesia, management of avulsed teeth and dental trauma. Open comments from participants focused on the lack of dental topics in professional training. RECOMMENDATIONS: Further education is required in the management of dental emergencies such as odontogenic infections, dental local anaesthesia, trauma, intra-oral haemorrhage and in dental nomenclature. CONCLUSIONS: An effective interactive workshop intervention employing blended instructional techniques may help improve the management of dental emergencies and patient outcomes. PMID- 22813621 TI - Testing the effects of educational toilet posters: a novel way of reducing haemolysis of blood samples within ED. AB - Haemolysed blood samples are an unnecessary burden on Emergency Departments (ED) as they increase workloads and drive down efficiencies. Little empirical data exists that demonstrates the effectiveness of educational posters displayed in staff toilet cubicles. This study explored the impact educational toilet posters have on reducing haemolysis rates within the ED. METHODS: A time series study of the clinical effect of educational toilet posters on reducing haemolysis rates throughout a 12 month period at the Gold Coast Hospital ED was undertaken. The GCH ED is a tertiary emergency service that has approximately 66,000 patient presentations per year. Data was collected prospectively. Analysis was undertaken to investigate the effects on total number of haemolysed samples and those clinically significant samples with a haemolytic index >3. Further investigation explored the specific effects on medical and nursing staff. RESULTS: Analysis undertaken using an independent t-test found that the pre-intervention data demonstrates a medium haemolysis rate of 4.92% (SD=1.04). This is a statistically significantly different (t=3.56, df=50, p=0.001) from the median post intervention data of 3.95% (SD=0.84). The difference of 0.97% (95%CI=0.42, 1.52) represents a 19.72% reduction in clinically significant haemolysed samples over the study period. CONCLUSION: This study reveals that the use of educational toilet posters had a positive impact on reducing the rates of haemolysed samples collected within the ED. This simple and cost effective educational initiative changed the behaviour of clinical staff. Further investigation is warranted to examine the impact of educational toilet posters on additional clinical scenarios. PMID- 22813620 TI - Characteristics of effective interventions supporting quality pain management in Australian emergency departments: an exploratory study. AB - BACKGROUND: It is well established that pain is the most common presenting complaint in Emergency Departments. Despite great improvements in available pain management strategies, patients are left waiting for longer than 60min for pain relief on arrival to the emergency department. The aim of this study was to describe interventions that lead to successful implementation of the National Health and Medical Research Council approved guidelines Acute Pain Management: Scientific Evidence (2nd Edition) that include specific recommendations for best practice pain management. METHODS: A two-phased, mixed-method, exploratory study of all 52 Australian hospital emergency departments participating in the National Emergency Care Pain Management Initiative incorporating interview and document analysis was undertaken. FINDINGS: Interventions used by clinicians to improve pain management included nurse initiated analgesia, intranasal fentanyl for paediatric patients and lignocaine, and facio illiaca block. Education formed a major part of the intervention and the development of a working group of key stakeholders was critical in the successful implementation of change. Staff perceptions of patients' pain level and attitudes toward pain assessment and pain management were identified as barriers. CONCLUSION: This study highlighted how an effective framework to plan and implement practice change and tailored interventions, including education and training systems and products using the best available evidence, best equipped clinicians to manage pain in the ED. PMID- 22813622 TI - Opportunistic childhood vaccinations in emergency--are we really missing anyone? AB - OBJECTIVES: Every health service presentation of a child should be considered an opportunity to ensure optimal immunisation. Measures to limit missed opportunities for vaccination in local emergency departments (ED) should reflect the scale of opportunity and parental support of immunisation service delivery strategies. METHODS: The vaccination status of every child aged less than seven years that presented to a tertiary hospital ED over a three month period was identified using the Australian Childhood Immunisation Register (ACIR). Contra indications to vaccination were determined from medical records. A telephone survey or posted survey was conducted with parents of eligible children to confirm ACIR status and whether they would have consented to receiving vaccinations during their presentation. ED records were reviewed for vaccination history recording and ACIR records were reviewed, after interview, to confirm parental reports that initial ACIR status was incorrect. RESULTS: Nine per cent (215/2399) of children were identified as incompletely vaccinated according to ACIR. Forty-seven children were excluded. Of the remaining 168 children, 95 parents (57%) participated. Thirty-eight children had no contra-indications and their parents would have consented to vaccination during their ED presentation. The vaccination status of 82% (78/95) was recorded in ED records, but was incorrect in 35 cases. Forty parents indicated that the ACIR record was incorrect and this was confirmed in 36 cases (90%). CONCLUSIONS: There were missed opportunities to vaccinate a small proportion of children in ED. Parents provided a more accurate timely history of immunisation status than ACIR and thus ED staff should ensure that parents are always asked whether their child is fully vaccinated and provide or encourage vaccination. PMID- 22813623 TI - Traumatic injury in Australia and New Zealand. AB - Injury is a leading cause of mortality, hospitalised morbidity and disability in Australia and New Zealand. Of the many public health challenges facing clinicians on a daily basis, traumatic injury is one of the most significant. A large spectrum of injury severity may result, ranging from minor injuries which require little medical intervention through to severe multisystem trauma, requiring definitive management by an experienced multidisciplinary team. An improved understanding of the incidence and prevalence of trauma can empower clinicians of all levels of experience to contribute to improving the trauma system they work in at a local level. This paper provides an overview of the history and epidemiology of traumatic injury in Australia and New Zealand. The reading of this article and completion of revision questions is equivalent to 2h of self directed learning. PMID- 22813624 TI - Lung cancer in the emergency department. AB - According to the World Health Organization lung cancer was the leading cause of cancer deaths in 2008. Patients with lung cancer present frequently to the emergency department. This article will outline Non-Small Cell Lung Cancer (NSCLC), patient presentation, and how to care for the patient with lung cancer in the emergency department (ED). PMID- 22813626 TI - Ab initio studies on the optical effects in the deep ultraviolet nonlinear optical crystals of the KBe2BO3F2 family. AB - Electronic structures of the deep ultraviolet nonlinear optical crystals of the KBe(2)BO(3)F(2) (KBBF) family, including KBBF, RbBe(2)BO(3)F(2) and CsBe(2)BO(3)F(2), have been investigated based on a plane-wave pseudopotential method. Their linear and nonlinear optical coefficients are also calculated, and are in good agreement with the experimental results. A real-space atom-cutting method is adopted to analyze the respective contributions of the alkali metal cations and anionic groups to optical response. The results show that the contributions of anionic groups to the nonlinear optical anisotropic responses are dominant, but the influence of the A-site alkali metal cations becomes slightly more pronounced with the increase of their radius. Moreover, the birefringence difference among these crystals strongly depends on the volume effect, i.e., the spatial density of the (BO(3))(3-) anionic groups. PMID- 22813627 TI - Disposition of diiosononyl phthalate and its effects on sexual development of the male fetus following repeated dosing in pregnant rats. AB - Pregnant Sprague-Dawley rats received 50, 250, and 500 mg/kg/day diisononyl phthalate (DiNP) from GD 12 to 19 via corn oil gavage to study the dose response for effects on fetal male rat sexual development as well as metabolite disposition in the dam and fetus. Monoisononyl phthalate (MiNP), mono(carboxy isooctyl) phthalate (MCiOP), mono(hydroxyl-isononyl) phthalate (MHiNP), mono(oxo isononyl) phthalate (MOiNP), and monoisononyl phthalate glucuronide (MiNP-G) were found in all measured tissues. MCiOP was the major metabolite, followed in decreasing order by MiNP, MHiNP, MOiNP, and MiNP-G. Percentage of dose absorbed decreased at 750 mg/kg/day. Testosterone concentration in the fetal testes was reduced at 250 and 750 mg/kg/day. Multinucleated germ cells were increased in the testes of rats at 250 and 750 mg/kg/day. The no observed effect level (NOEL) for this study was 50 mg/kg/day based on increased MNGs and reduced testes testosterone concentration in the fetal rat. PMID- 22813628 TI - Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression. AB - The embryonic stem cell test (EST) is based on compound-induced inhibition of cardiomyocyte differentiation of pluripotent stem cells. We examined the use of transcriptomics to assess concentration-effect relationships and performed potency ranking within a chemical class. Three embryotoxic phthalate monoesters, monobutyl phthalate (MBuP), monobenzyl phthalate (MBzP) and mono-(2-ethylhexyl) phthalate (MEHP) and the non-embryotoxic monomethyl phthalate (MMP) were studied for their effects on gene expression. Effects on gene expression were observed at concentrations that did not inhibit cardiomyocyte differentiation or induce cytotoxicity. The embryotoxic phthalate monoesters altered the expression of 668 commonly expressed genes in a concentration-dependent fashion. The same potency ranking was observed for morphology and gene expression (MEHP>MBzP>MBuP>MMP). These results indicate that integrating transcriptomics provides a sensitive method to measure the dose-dependent effects of phthalate monoester exposure and enables potency ranking based on a common mode of action within a class of compounds. Transcriptomic approaches may improve the applicability of the EST, in terms of sensitivity and specificity. PMID- 22813629 TI - Diversities of phthalate esters in suburban agricultural soils and wasteland soil appeared with urbanization in China. AB - The distribution of six priority phthalic acid esters (PAEs) in suburban farmland, vegetable, orchard and wasteland soils of Tianjin were obtained with gas chromatography-mass spectrometer analysis in 2009. Results showed that total PAEs varied from 0.05 to 10.4 MUg g(-1), with the median value as 0.32 MUg g(-1). Di-(2-ethylhexyl) phthalate and di-n-butyl phthalate are most abundant species. PAEs concentrations for the four types of soils exhibited decreasing order as vegetable soil > wasteland soil > farmland soil > orchard soil. PAEs exhibited elevated levels in more developed regions when compared with other studies. The agricultural plastic film could elevate the PAEs contents in soils. Principal component analysis indicated the emission from cosmetics and personal care products and plasticizers were important sources for PAEs in suburban soils in Tianjin. The higher PAEs contents in wasteland soils from suburban area should be paid more attention owing to large amounts of solid wastes appeared with the ongoing urbanization. PMID- 22813630 TI - Toxic effects of dietary hydrolysed lipids: an in vivo study on fish larvae. AB - We have previously described that fish larvae absorb a larger fraction of dietary monoacylglycerol than TAG. To investigate how dietary hydrolysed lipids affect a vertebrate at early life stages over time, we fed Atlantic cod (Gadus morhua) larvae six diets with different degrees of hydrolysed lipids for 30 d. The different diets had no effect on growth, but there was a positive correlation between the level of hydrolysed lipids in the diets and mortality. Important genes in lipid metabolism, such as PPAR, farnesoid X receptor (FXR) and stearoyl CoA desaturase (SCD), were regulated by the different diets. Genes involved in the oxidative stress response did not respond to the increased lipid hydrolysation in the diets. However, enterocyte damage was observed in animals fed diets with 2.7 % NEFA (diet 3) or more. It is thus possible that mortality was due to infections and/or osmotic stress due to the exposure of the subepithelial tissue. In contrast to earlier experiments showing a positive effect of dietary hydrolysed lipids, we have demonstrated a toxic effect of dietary NEFA on Atlantic cod larvae. Toxicity is not acute but needs time to accumulate. PMID- 22813631 TI - Is skin self-examination for cutaneous melanoma detection still adequate? A retrospective study. AB - OBJECTIVE: The aim of this retrospective study was to analyze the relationship between detection pattern, tumor thickness, patient demographics, and personal and family history of melanoma in the era of noninvasive diagnosis. METHODS: All patients with primary cutaneous melanoma who presented to the Department of Dermatology at the University of Florence between January 2000 and November 2010 were interviewed at the time of their final histopathological diagnoses of melanoma as part of their clinical record. The treating physician specifically questioned all patients about who had first detected or suspected the lesion that resulted in the histological diagnosis of melanoma. RESULTS: A total of 802 melanoma patients were analyzed. The spouse found approximately 16% of the melanomas, and a similar percentage was discovered by the general practitioner. The largest group of melanomas (36%) was discovered during regular annual skin examinations by dermatologists, while another large group (33%) were discovered by the patients themselves. The data that emerged from our study is that self detection was associated with a greater probability of having a thick melanoma and, therefore, a poor prognosis (odds ratio 1.56). CONCLUSIONS: Because the current mortality of melanoma is still stable, we are convinced that a new message should be introduced to encourage high-risk patients to have an annual skin examination as a rule. PMID- 22813632 TI - Structural studies of five novel bile acid-4-aminopyridine conjugates. AB - Synthesis and solid-state structural characterization of five bile acid amides of 4-aminopyridine (4-AP) are reported. Systematic crystallization experiments revealed a number of structural modifications and/or solvate/hydrate systems for these conjugates. Particularly, cholic acid conjugate exhibited five distinct structure modifications, including one anhydrous form, mono- and dihydrates, as well as ethanol and 2-butanol solvates. The obtained crystal forms were examined extensively with various analytical methods, including solid-state NMR, Raman, and IR spectroscopies, powder and single crystal X-ray diffraction methods, thermogravimetry, and differential scanning calorimetry. After releasing their crystal solvent molecules, the resulted non-solvated structure forms showed 50-75 degrees C higher melting points than corresponding bile acids, and thermal degradation occurred for all conjugates at about 300-330 degrees C. Moreover, the single crystal X-ray structure of the ursodeoxycholic acid-4-aminopyridine conjugate is reported. PMID- 22813640 TI - A decade of experience with a selective policy for direct to operating room trauma resuscitations. AB - BACKGROUND: The standard paradigm for acutely injured patients involves evaluation in an emergency department (ED). Our center has employed a policy for bypassing the ED and proceeding directly to the operating room (OR) based on prehospital criteria. METHODS: This is a retrospective analysis of all trauma patients admitted "direct to OR" (DOR) over 10 years. Demographics, injury patterns, prehospital, and in-hospital data were analyzed. RESULTS: There were 1,407 patients admitted as DOR resuscitations. Almost half (47%) had a penetrating mechanism, and 54% had chest or abdominal injury. The mean Injury Severity Score was 19, with altered mentation (Glasgow coma score [GCS] <9) in 20% and hypotension in 16%. Most patients (68%) required surgical intervention, and 33% required emergency surgery operations (abdominal [70%] followed by thoracic [22%] and vascular [4%]). The median time to intervention was 13 minutes. Mortality was significantly lower than predicted (5% vs 10%). Independent predictors of emergent surgical intervention were a penetrating truncal injury (odds ratio = 9.9), GCS <9 (odds ratio = 1.9), and hypotension (odds ratio = 1.8). DISCUSSION: Our DOR protocol identified a severely injured cohort at high risk for requiring surgery with improved observed survival. High yield triage criteria for DOR admission include a penetrating truncal injury, hypotension, and a severely altered mental status. PMID- 22813641 TI - Impact of jejunal pouch interposition reconstruction after proximal gastrectomy for early gastric cancer on quality of life: short- and long-term consequences. AB - BACKGROUND: Proximal gastrectomy with jejunal pouch interposition (JPI) reconstruction has been advocated as a function-preserving surgery in patients with early gastric cancer located in the upper third of the stomach. METHODS: This study clinically investigated 22 patients who underwent JPI reconstruction and 22 patients who underwent Roux-en-Y (RY) reconstruction after total gastrectomy for stage IA/IB gastric cancer. Patients in the 2 groups were compared to evaluate the short- and long-term postoperative outcomes. RESULTS: Morbidity and nutritional parameters were no different between the 2 groups. Although postoperative food intake volume was significantly superior in JPI patients than in RY patients 1 year postsurgery, the change in body weight was equal. JPI patients outperformed RY patients with a better quality of life (QOL) at 1 year postgastrectomy. However, 5 years after the surgery, both groups had a similar QOL except for fatigue. CONCLUSIONS: JPI reconstruction leads to better outcomes including QOL than RY reconstruction in the short term. However, this short-term positive impact of JPI decreases over time. PMID- 22813642 TI - Nuclear localization of DMP1 proteins suggests a role in intracellular signaling. AB - Dentin matrix protein 1 (DMP1) is highly expressed in odontoblasts and osteoblasts/osteocytes and plays an essential role in tooth and bone mineralization and phosphate homeostasis. It is debatable whether DMP1, in addition to its function in the extracellular matrix, can enter the nucleus and function as a transcription factor. To better understand its function, we examined the nuclear localization of endogenous and exogenous DMP1 in C3H10T1/2 mesenchymal cells, MC3T3-E1 preosteoblast cells and 17IIA11 odontoblast-like cells. RT-PCR analyses showed the expression of endogenous Dmp1 in all three cell lines, while Western-blot analysis detected a major DMP1 protein band corresponding to the 57 kDa C-terminal fragment generated by proteolytic processing of the secreted full-length DMP1. Immunofluorescent staining demonstrated that non-synchronized cells presented two subpopulations with either nuclear or cytoplasmic localization of endogenous DMP1. In addition, cells transfected with a construct expressing HA-tagged full-length DMP1 also showed either nuclear or cytoplasmic localization of the exogenous DMP1 when examined with an antibody against the HA tag. Furthermore, nuclear DMP1 was restricted to the nucleoplasm but was absent in the nucleolus. In conclusion, these findings suggest that, apart from its role as a constituent of dentin and bone matrix, DMP1 might play a regulatory role in the nucleus. PMID- 22813643 TI - Effects of both vitamin C and mechanical stimulation on improving the mechanical characteristics of regenerated cartilage. AB - The present work describes the influence of both vitamin C (VC) and mechanical stimulation on development of the extracellular matrix (ECM) and improvement in mechanical properties of a chondrocyte-agarose construct in a regenerating tissue disease model of hyaline cartilage. We used primary bovine chondrocytes and two types of VC, ascorbic acid (AsA) as an acidic form and ascorbic acid 2-phosphate (A2P) as a non-acidic form, and applied uniaxial compressive strain to the tissue model using a purpose-built bioreactor. When added to the medium in free-swelling culture conditions, A2P downregulated development of ECM and suppressed improvement of the tangent modulus more than AsA. By contrast, application of mechanical stimulation to the construct both increased the tangent modulus more than the free-swelling group containing A2P and enhanced the ECM network of inner tissue to levels nearly as high as the free-swelling group containing AsA. Thus, mechanical stimulation and strain appears to enhance the supply of nutrients and improve the synthesis of ECM via mechanotransduction pathways of chondrocytes. Therefore, we suggest that mechanical stimulation is necessary for homogenous development of ECM in a cell-associated construct with a view to implantation of a large-sized articular cartilage defect. PMID- 22813644 TI - Does wearing a prophylactic ankle brace during drop landings affect lower extremity kinematics and ground reaction forces? AB - The objective of the study was to determine if prophylactic ankle bracing worn by females during landings produces abnormal lower extremity mechanics. Angular kinematic and ground reaction force (GRF) data were obtained for 16 athletically experienced females who performed brace and no-brace drop landings. The brace condition displayed reduced in/external rotation and flexion displacements about the ankle and knee joints and increased vertical and mediolateral GRF peak magnitudes and rate of vertical GRF application (paired t test, P < .05). The ankle and knee joints landed in a less plantar flexed and more flexed position, respectively. No significant ab/adduction outcomes may have occurred due to interparticipant variability and/or a lack of brace restriction. Conclusion: During typical landings, this lace-up brace increases vertical GRF, decreases ankle and knee joint displacements of flexion and int/external rotation, but minimally affects ab/adduction displacements. PMID- 22813645 TI - Statistical considerations for the HPTN 052 Study to evaluate the effectiveness of early versus delayed antiretroviral strategies to prevent the sexual transmission of HIV-1 in serodiscordant couples. AB - The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: "immediate" (early) therapy with ART initiated upon enrollment plus HIV primary care, or "delayed" therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200-250 cells/mm(3), or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015. PMID- 22813646 TI - Prevalence of low ankle brachial index and its association with pulse pressure in an elderly Chinese population: a cross-sectional study. AB - BACKGROUND: We investigated the prevalence of low ankle brachial index (ABI) and the association of low ABI with pulse pressure among elderly community residents in China. METHODS: This population-based cross-sectional study was conducted in Beijing and recruited 2982 participants who were aged 60 years or older in 2007. Low ABI was defined as an ABI value less than 0.9 in either leg. Participants with or without stroke or coronary heart disease (CHD) were analyzed separately. The association between pulse pressure and low ABI was examined by using multiple logistic regression models. RESULTS: The prevalence of low ABI was 5.65% (4.24% among men and 6.52% among women; P = 0.0221) among participants without stroke or CHD and 10.91% (13.07% among men and 9.49% among women; P = 0.1328) among those with stroke or CHD. After adjusting for confounders, the odds ratio (95% CI) for each 5-mm Hg increase in pulse pressure was 1.19 (1.07, 1.33) and 1.10 (1.02, 1.20) for men and women, respectively, among participants without stroke or CHD and 1.17 (1.03, 1.34) and 1.15 (1.02, 1.30) for men and women with stroke or CHD. When pulse pressure was classified into quartiles and the lowest quartile was used as reference, the association between pulse pressure and low ABI remained positive in men and women. CONCLUSIONS: Low ABI was prevalent among elderly Chinese, and pulse pressure was positively associated with low ABI. PMID- 22813647 TI - Prevalence of atherosclerosis-related risk factors and diseases in the Philippines. AB - BACKGROUND: We conducted a survey in 2008 to measure the prevalence of lifestyle related diseases and risk factors in Philippine adults. METHODS: Stratified multistage sampling was used to cover the entire Philippine population of adults aged 20 years or older. Using health questionnaires, anthropometric measurements, and blood examinations, the prevalences of atherosclerosis-related risk factors and diseases were determined. Survey results were compared with those obtained in 2003. RESULTS: Out of 7700 eligible subjects, 64% to 93.7% responded to different survey items. Age-adjusted hypertension prevalence was 24.6% at a single visit and 20.6% when corrected for true prevalence. The prevalence of diabetes was 3.9% on the basis of fasting blood glucose (FBG), 5.2% by FBG and history, and 6.0% when 2-hour post-load plasma glucose level was determined. The prevalence of dyslipidemia was 72.0% and the prevalence of smoking was 31%. The prevalence of obesity was 4.9% by body mass index (BMI), and 10.2% and 65.6% by waist-hip ratio (WHR) in men and women, respectively. The prevalences of coronary, cerebrovascular, and peripheral arterial diseases were 1.1%, 0.9%, and 1.0%, respectively. CONCLUSIONS: The prevalences of risk factors for atherosclerosis were higher in 2008 than in 2003, although the increase in diabetes was not significant and smoking decreased. These findings indicate a need for active collaborative intervention by all government agencies and medical societies in the Philippines. PMID- 22813648 TI - Administration of perflutren contrast agents during transthoracic echocardiography is not associated with a significant increase in acute mortality risk. AB - BACKGROUND: Despite the 2008 revision of a previously issued black box warning of the US Food and Drug Administration against the use of perflutren ultrasound contrast agents, the warning still reports fatalities having occurred following their administration. We sought to assess 1-day mortality associated with contrast use across a wide range of clinical settings and co-morbidities. METHODS: We conducted a retrospective study involving 96,705 transthoracic echocardiograms (TTE) in 63,189 adults at our institution between July 2003 and June 2008. A contrast agent was used in 2,518 TTE during this time. The primary outcome was total mortality within 1 day of TTE. RESULTS: Death occurred in 10 patients (0.44%) in the contrast group and in 421 patients (0.69%) in the non contrast group (p = 0.14). In a multivariate model, use of contrast enhancement was not associated with increased mortality (p = 0.67) after adjustment for age, gender, race, patient location, ejection fraction, and the presence of various co morbidities. Cause of death analysis did not identify any cases where contrast played a likely role. CONCLUSION: Definity contrast use during TTE was not associated with increased acute mortality risk. Contrast administration during TTE should not be withheld when the additional information obtained could potentially improve patient management. PMID- 22813649 TI - Tissue-engineered devices in cardiovascular surgery. AB - Manufacturing life-long functional cardiovascular (CV) implants is the ultimate goal for researchers and clinicians in the cardiothoracic field. Tissue engineering (TE) is an opportunity to create ideal prostheses that are vital, growing, adaptive, autologous and functionally optimally performing. Today, initial translation from basic science to first clinical trials has begun. The article depicts the state of the art in TE techniques for CV products and describes milestones in the ongoing development of tissue-engineered myocardial, valvular and vascular devices from an experimental and clinical point of view. Artificial CV implants still reveal remarkable limitations but promising advances regarding optimal structural design, the prevention of intimal hyperplasia and the reduction of antigenicity and thrombogenicity. Where applicable, the implantation of vascularized autografts should still be preferred. Apart from that, decellularized allogen bioprostheses currently represent most promising matrix scaffolds that can be autologously cellularized in vitro prior to or in vivo after implantation. Capable biologic alternatives have been described like the decellularized porcine small intestinal submucosa. Rising evidence suggests that in vitro endothelialization might be the minimal requirement for improved long-term results of biological tissue-engineered CV grafts. PMID- 22813650 TI - Does milk fortification increase the risk of necrotising enterocolitis in preterm infants with congenital heart disease? AB - Prematurity and low birth weight adds to the risk of serious congenital heart disease in infants. It may also delay surgical intervention, especially when cardiopulmonary bypass is required, or where an aortopulmonary shunt is necessary to maintain adequate oxygenation. In this setting, neonatologists are faced with the challenge of accelerating the infant's growth to allow for early surgery. We describe the cases of two infants in whom an attempt to fortify the feeds was associated with necrotising enterocolitis, with a lethal outcome in one. The outcome suggests caution in fortifying feeds in premature infants with serious congenital heart disease. PMID- 22813651 TI - Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft. AB - The recognition and acceptance of the entity of antibody-mediated rejection (AMR) of solid organs has been slow to develop. Greatest acceptance and most information relates to cardiac transplantation. AMR is thought to represent antibody/complement mediated injury to the microvasculature of the graft that can result in allograft dysfunction, allograft loss, accelerated graft vasculopathy, and increased mortality. The morphologic hallmark is microvascular injury with immunoglobulin and complement deposition in capillaries, accumulation of intravascular macrophages, and in more severe cases, microvascular hemorrhage and thrombosis, with inflammation and edema of the affected organ. Understanding of the pathogenesis of AMR, criteria and methods for diagnosis, and treatment strategies are still in evolution, and will be addressed in this review. PMID- 22813652 TI - Regulation of the CD4+ T cell allo-immune response by endothelial cells. AB - Recent studies have revealed the presence of pro-inflammatory and/or regulatory CD4(+) T cells within allografts promoting either graft rejection or tolerance. Histological evidence has identified the microvascular endothelium as the primary site of allograft damage as it is the first site of encounter with the recipient's immune system. The initial view of the human endothelial cell inducing an effector Th1 response leading to graft rejection has been extended by recent results which demonstrate the endothelial cell ability to generate other CD4(+) T cell sub-populations including Th17 and Treg cells. In the transplantation setting, the allo-reactivity of the endothelium with the CD4(+) T cell populations is likely to depend upon multiple factors including the vascular origin of the endothelial cell, the cytokine environment, the presence or absence of pro-inflammatory stimuli including ligands of Toll like receptors and alloantibodies. This review provides an update on the characteristics of the endothelial cell activation of the CD4(+) T cell response and an analysis of the factors, which can modify this activity in favor of either graft rejection or tolerance. PMID- 22813653 TI - Psychiatric genetics research in Asia. PMID- 22813654 TI - Agonist treatment in opioid use: advances and controversy. AB - Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID- 22813655 TI - Sibling care, school performance, and depression among adolescent caretakers in Cambodia. AB - In many resource-poor countries, home-based care for young children is crucial. Yet little has been known about the negative impacts of sibling caretaking on mental health conditions of adolescent student caretakers. This study explored associations between sibling caretaking, school performance, and depression among 1943 students randomly selected from 11 junior high and high schools in Cambodia. The Asian Adolescent Depression Scale was used to measure depressive symptoms. In bivariate analyses, we used chi(2) test or Fisher's exact test for categorical variables and t-test or one-way analysis of variance for continuous variables. Multiple linear regression models were then constructed. Of total, 60.1% of our participants took care of their younger sibling(s) regularly during the past one year. The number of siblings under their care ranged from one to nine, and the time they spent for sibling care ranged from one to 10h per day. After adjustment, increased levels of depressive symptoms remained significantly associated among boys with sibling caretaking (p<0.001), as well as poor school performance (p=0.001) and perceived likelihood of dropping out of school in the near future (p=0.002). Among girls, increased levels of depressive symptoms retained their significant association with sibling caretaking (p<0.001); also poor school performance (p<0.001). Sibling care responsibility might have negative impact on school performance and the mental health condition of adolescent caretakers. PMID- 22813656 TI - Affect intensity and negative mood regulation (NMR) expectancies: a preliminary Indian study. AB - Individuals differ in the intensity with which they typically experience affect as well as in their beliefs regarding their ability to alleviate negative mood states. These variables have been implicated in a range of clinical problems. Most studies utilize a single index of affect intensity. The differential correlates of positive and negative affect intensity, their association with negative mood regulation expectancy and their role as predictors of psychological outcomes have been insufficiently explored. This study aimed at exploring the relationship of affect intensity variables with negative mood regulation (NMR) expectancy, their association with age and gender and examining the role of affect intensity and NMR expectancy as predictors of stress and well being in a community sample of Indian adults. The sample consisted of 206 participants aged between 20 and 60 years. Higher age was associated with higher NMR expectancy but lower positive affect intensity. Positive and negative affect intensity showed differential patterns of association with NMR expectancy. Higher negative affect intensity was associated with lower NMR expectancy whereas higher positive affect intensity was associated with higher NMR expectancy. Affect intensity and NMR expectancy variables jointly predicted 30-39% of variance in perceived stress and well being. Implications for further research are discussed. PMID- 22813657 TI - Association between MTHFR C677T and A1298C, and MTRR A66G polymorphisms and susceptibility to schizophrenia in a Syrian study cohort. AB - The folate-homocystiene metabolic pathway has been shown to be involved in the susceptibility for developing schizophrenia by several studies. In the present study we investigated the role of three common polymorphisms of the folate homocysteine metabolic pathway in an Arab population from Syria consisting of 85 schizophrenic patients and 126 healthy controls. The studied polymorphisms included the MTHFR C677T and A1298C, and MTRR A66G, all of which result into amino acid changes, and were previously shown to yield decreased enzymatic activity and alter plasma homocysteine concentration. While MTHFR C677T and A1298C polymorphisms were not previously studied in an Arab population with respect to the susceptibility for developing schizophrenia, the MTRR A66G was not previously investigated in any population around the world. Our results indicated a strong association between MTHFR A1298C and schizophrenia. The variant C allele frequency was significantly higher in the patients group (40% vs 29.4%, OR=1.6, 95% CI (1.06-2.41), p=0.023). A statistically significant association was found for MTHFR 677TT genotype under the recessive model in the male patients subgroup (OR=2.6, 95% CI (1.04-6.5), p=0.036), and MTHFR 677CT genotype under the overdominant model in the total patients group (OR=0.52 95% CI (0.29-0.92), p=0.024). No statistically significant association was found for MTRR A66G polymorphism on an individual basis. However, a borderline association was found for the CC/GG (C677T/A66G) compound genotype (OR=2.24, 95% CI (0.97-5.15), p=0.053). Our results support the hypothesis of association between schizophrenia and folate-homocystiene metabolic pathway genes. PMID- 22813658 TI - Factor structure and reliability of the 30-item Sinhala version of General Health Questionnaire (GHQ). AB - OBJECTIVE: To determine the factor structure and the reliability of the Sinhala version of the General Health Questionnaire-30 (GHQ-30). METHODS: This was a descriptive study including 368 patients with in the age range of 18-75 years, attending the Out Patient Department (OPD) of Colombo North Teaching Hospital, Ragama, Sri Lanka during the period between June 2009 and September 2010. Sinhala version of GHQ-30 was given to be completed by the participants. Each item of the GHQ was rated on a four-point scale (0-1-2-3). Factor analyses were performed by applying Generalized Least Squares method using oblimin rotation. The internal consistency was assessed by calculating Cronbach's alpha coefficient. RESULTS: Median age of the study population was 32.5 years (Inter quartile range [IQR]=21 years) and the median GHQ score was 9 (IQR 7). GHQ-30 produced a five factor solution which accounted for 51.6% of the total variance (TV). Factor I (Depression) accounted for 38% of TV, Factor II (Loss of confidence) 5%, Factor III (Insomnia) 4%, Factor IV (Social dysfunction) 2.7% and Factor V (Anxiety) 2%. The Cronbach's alpha coefficients of GHQ-30 was 0.94 indicating satisfactory internal consistency. CONCLUSIONS: GHQ-30 comprises five factors/subscales and it displayed adequate reliability for assessment of psychiatric disorders among Sinhala speaking primary care attendees in Sri Lanka. PMID- 22813659 TI - Suicidal risk and childhood adversity: a study of Indian college students. AB - BACKGROUND: The study was undertaken in response to reported increase in deaths due to suicide and suicidal behaviors in the youth. AIM: The objectives of the study were to assess childhood adversity and suicidal risk and to study the relationship between adverse childhood experiences and suicidal risk, in Indian students. METHOD: A cross sectional study design was conducted with 436 undergraduate students in the age range of 18-25. Suicidal risk was assessed using Scale for Suicidal Ideation and Beck's Hopelessness Scale. Parental Bonding Instrument and Early Trauma Inventory-Self Report (Short Form) were used to assess adverse childhood experiences. RESULTS: Suicidal risk in terms of suicidal ideation and hopelessness was reported by 15% and 9%, respectively. Physical abuse is the most common form of early trauma, experienced in both males and females. Males experienced significantly more traumatic experiences in all domains. Affectionless control, which is considered as the pathogenic form of parent child bonding, is widely reported. A moderate degree of association exists between suicidal risk and early exposure to trauma. Higher suicidal ideation, hopelessness and trauma are reported in respondents with affectionless parental control and neglectful parenting. CONCLUSION: The study provides evidence of correlation between suicidal risk and childhood adversity in the Indian setting. PMID- 22813660 TI - A preliminary study on the influence of glutathione S transferase T1 (GSTT1) as a risk factor for late onset Alzheimer's disease in North Indian population. AB - INTRODUCTION: Oxidative stress plays key role in pathogenesis of Alzheimer's disease. Glutathione S-transferases (GSTs), a family of phase-II isoenzymes, play a critical role in providing protection against electrophiles and products of oxidative stress. Among different classes of GSTs, GSTM1 (Mu) and GSTT1 (theta) are found to be genetically deleted which results in decreased expression of the concerned enzyme. This study aims at preliminary analysis of the frequency of deletion of GSTM1 and GSTT1 and their association with late-onset Alzheimer's disease. MATERIAL AND METHODS: In this study, association of the deletion type polymorphism of GST M1 and T1 as possible risk factors for dementia of Alzheimer's type was studied in 50 patients and 100 controls. Dementia was diagnosed by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scale. Genotyping was done by multiplex Polymerase Chain Reaction (PCR). Associations between null genotype of either GSTM1 and GSTT1 or both with Alzheimer's disease were analyzed by Chi-Square test. RESULTS: Deletion of GSTT1 was found significantly associated with Alzheimer's disease (chi(2)=5.08, p=0.02*). CONCLUSIONS: The odds of Alzheimer's disease in null GSTT1 is found to be increased by 2.47 times in comparison to positive GSTT1. PMID- 22813661 TI - Assessing social support among South Asians: the multidimensional scale of perceived social support. AB - The psychometric properties of the Multidimensional Scale of Perceived Social Support (MSPSS) of the Urdu (MSPSS-U) and Nepali (MSPSS-N) versions were investigated among Pakistani (n=148) and Nepalese (n=153) respondents living in Hong Kong. The factor analysis of the MSPSS-N conducted in this study confirmed the three factors of the original MSPSS, namely, Family, Friend, and Significant Others, while only two factors were extracted from the MSPSS-U (i.e., the Family and Friends subscales). With regard to construct validity, both the MSPSS-U and MSPSS-N were inversely correlated with depression, anxiety and stress as assessed by the Depression Anxiety Stress Scale (DASS-21). The internal reliability and construct validity of the MSPSS-U and MSPSS-N were also established and provided support for the validity of both versions as tools for measuring perceived social support among South Asian migrants. PMID- 22813662 TI - Identification of chromosome abnormalities in screening of a family with manic depression and psoriasis: predisposition to aneuploidy. AB - Cytogenetic analysis is an important stage in understanding the genetic background of manic depression (MD), and may provide a valuable clue to the identification of target loci and successful search for major genes. In order to identify chromosomal regions we aimed to detect the relationships between chromosomal aberrations (CAs) and immunological markers in a family with MD and psoriasis. We used the cell cultivation and conventional G-banding. We found predominantly numerical aberrations. The most common aneuploidy was chromosome 8, followed by chromosome 22, 21, 15, X and Y. However, structural aberrations consisted of duplications, deletions, translocations and breaks, with a focus on: loci on del(1)(q12-q23), del(1)(q21.1-q24), del(1)(q21.1-q23), del(10)(p11.2 pter), der(2)t(2;4)(p25;p12), t(2;22)(p14;p13), t(19;Y)? and dup(10)(q26). The susceptibility genes of MD or psoriasis may be located on these loci. Numerical sex CAs included 4(5.8%) with 45,X, 3(4.3%) with 47,XXY, and 4(5.8%) with structural chromosome X; del(X)(q13); del(X)(p11-pter) del(X)(q21.3) and inv(Y)(q11.2). We also conducted an immunological study. According results of this study, the percentage of CD2+, CD4+ and CD8+ lymphocytes of the father were significantly higher, whereas CD4+ lymphocytes were decreased in the mother, when compared the healthy persons. The percentage of CD4 level of the son was decreased, whereas CD8+ lymphocytes were higher. The CD4/CD8 ratio of the father and the son was found to be significantly high. These results may suggest that MD and psoriasis have a significant impact on both genetic and immunological parameters. PMID- 22813664 TI - Spirituality and psychiatry: special series. PMID- 22813663 TI - A synopsis of recent influential papers published in psychiatric journals (2010 2011) from the Arab world. AB - Six recent and influential papers that have appeared in the three leading psychiatry journals from the Arab region are summarized in this review. The first paper examined the prevalence of eating disorders (EDs) in rural and urban secondary school girls in Sharkia; more EDs were found among urban than rural population. The second study reported the high prevalence of Post Traumatic Stress Disorder (PTSD) in primary school children in Iraq in context of the present situation in Iraq dominated by violence creating a traumatizing atmosphere for the population, especially children. The third paper reported that substance dependent patients manifest elevated traits of impulsivity; emotionally driven impulsivity in particular predicted substance related problems. The fourth study reported significant cognitive impairments at illness onset in a large sample of patients with a first psychotic episode. The fifth paper, investigated the cultural imprint on symptom profile of mood disorders. Culture effect on mood disorder was more prominent in depression than in mania. The last article examined the relations between social circumstances, medical morbidity, locus of control and depression in elderly patients suffering from medical conditions. Overall, the papers describe a wide spectrum of research initiatives in the Arab World that are likely to have implications for global mental health. PMID- 22813666 TI - Adapting an evidence-based intervention to REACH Forgiveness for different religions and spiritualities. AB - The REACH Forgiveness intervention has been used in psychoeducational groups, couple and individual counseling and psychotherapy, and workbooks. It has been investigated in over 20 randomized clinical trials (RCTs) worldwide. It has been accommodated to treat Christians and shown to be effective in RCTs. But most research has established it to be effective when not accommodating it to religious or spiritual clientele. In this article, we will claim that it can be accommodated to a variety of religious clients. We describe guidelines about what is essential to the treatment and what might be effectively modified to be acceptable to religious and spiritual clients embracing a variety of beliefs and practices. PMID- 22813665 TI - Religion, spirituality and mental health in the West and the Middle East. AB - Research on religion, spirituality and mental health has been rapidly accumulating from Western countries and now increasingly from the Middle East. We review here the latest research on this topic from these two areas of the world, one largely Christian and the other largely Muslim, after discussing similarities and differences in these faith traditions. Contrary to popular thought, there is considerable overlap between these religious groups in beliefs, practices of worship, moral beliefs and values, and emphasis on family life (although also some distinct differences). Because of the similarity in belief and practice, it is not surprising that research on mental health and devout religious involvement in both these religious traditions has tended to produce similar results. Religious psychotherapies within these faith traditions have been developed and are now being refined and used in clinical trials to determine if integrating patients' religious resources into therapy is more or less effective than conventional therapies in relieving the symptoms of depression and anxiety. PMID- 22813667 TI - Yoga: a spiritual practice with therapeutic value in psychiatry. AB - Yoga is one of the spiritual practices derived from the orthodox school of Hindu philosophy. The practices were codified by Patanjali under the title of Ashtanga Yoga. Although Yoga was traditionally seen as a practice meant for achieving self realization, in recent years there has been significant attention given to the effects of yoga practices on physical and mental health. Yoga as a therapy has proven to be effective as a sole or additional intervention in several psychiatric disorders. CONCLUSIONS: The literature suggests that yoga can lead to significant symptomatic improvements in psychiatric disorders, along with neurobiological effects which may underlie these changes. This suggests that mental health professionals should be open to the potential benefits of spiritual practices for their patients, either as complementary interventions to modern treatments or as sole treatment in some disorders. PMID- 22813668 TI - The sense of the spirit as a form of conversation. AB - Experiential evidence suggests that the main features of spiritual experience are euphoria, and a feeling of the expansion and unification of consciousness. A way towards understanding this state and how it might arise comes from a consideration of a state in which these features are lacking. Such a state is borderline personality disorder, central to which is a "painful incoherence" that is not merely "psychological" but can be demonstrated neurophysiologically. The phenomena of the borderline syndrome can be understood as failure of proper maturation of the experience of "self," conceived as higher order consciousness in a notional hierarchy of consciousness. Spiritual experience is understood as a state "larger than self." Since both the achievement of a sense of the spirit and recovery from borderline personality disorder (BPD) involve an ascent in a hierarchy of consciousness, they may have a common basis. The approach to the development of self is derived from developmental observations which suggest that it depends upon a particular form of conversation, the first form of which is shown in the first months of life as a proto-conversation. It has the characteristics of an analogical relatedness. Symbolic play arising at the second year of life, shows a partial internalization of this relatedness. Symbolic play is accompanied by a quasi-inner conversation with an illusory other who is both self and the mothering figure. It is suggested that this is the embryonic form of the "conversations" of mystics in communion with self and God. PMID- 22813671 TI - Case of borderline personality disorder in a 23 year old male with history of Klinefelter syndrome. PMID- 22813669 TI - Treating a physician patient with psychosis. AB - The authors present a case of a psychotic female patient who is a former graduate of a locally prestigious medical school and has subsequently been diagnosed with schizophrenia. The patient entered treatment in an outpatient clinic following discharge from her 11th hospitalization. This hospitalization was initiated after the patient's physician friend had called the police and notified them that the patient was significantly disorganized to warrant further evaluation. Treatment was characterized by significant transference and counter-transference reactions amongst her clinicians - both treatment-promoting and treatment-interfering - based on her status as a physician. The problem of insight was a significant hurdle in the treatment of the patient as her medical knowledge of mental illness was substantially greater than her insight into her own mental illness. Throughout treatment, a number of medical-legal and ethical issues arose. Initially, the question was raised as to the legality of the actions by the patient's friend-having made a clinical assessment without having a clinical role in the patient's care. As the patient's clinical status improved and she sought to re-enter the medical field as a resident, new medical legal issues surfaced. What were the roles of the patient's treaters in maintaining confidentiality and simultaneously ensuring the safety of patients that the psychotic physician might care for? This case highlights the universality of psychiatric vulnerability. Insight in psychosis as well as the transference and counter-transference issues involved in caring for a psychotic physician are discussed. Additionally, a thorough medical-legal discussion addresses the various complexities of caring for a psychotic physician. PMID- 22813672 TI - Sleep disturbances with suicidal ideation have resisted for many years: lessons from a PTSD case. PMID- 22813673 TI - Efficacy of quetiapine in treatment-resistant panic disorder: a case report. PMID- 22813674 TI - AFPA and Vietnam psychiatric association hold psychiatry-training course in Ha Noi. PMID- 22813675 TI - Early career psychiatrists corner: third young psychiatrists' network meeting: stigma in YPs' perspective. PMID- 22813676 TI - Improving low-wage, midsized employers' health promotion practices: a randomized controlled trial. AB - BACKGROUND: The Guide to Community Preventive Services (Community Guide) offers evidence-based intervention strategies to prevent chronic disease. The American Cancer Society (ACS) and the University of Washington Health Promotion Research Center co-developed ACS Workplace Solutions (WPS) to improve workplaces' implementation of Community Guide strategies. PURPOSE: To test the effectiveness of WPS for midsized employers in low-wage industries. DESIGN: Two-arm RCT; workplaces were randomized to receive WPS during the study (intervention group) or at the end of the study (delayed control group). SETTING/PARTICIPANTS: Forty eight midsized employers (100-999 workers) in King County WA. INTERVENTION: WPS provides employers one-on-one consulting with an ACS interventionist via three meetings at the workplace. The interventionist recommends best practices to adopt based on the workplace's current practices, provides implementation toolkits for the best practices the employer chooses to adopt, conducts a follow-up visit at 6 months, and provides technical assistance. MAIN OUTCOME MEASURES: Employers' implementation of 16 best practices (in the categories of insurance benefits, health-related policies, programs, tracking, and health communications) at baseline (June 2007-June 2008) and 15-month follow-up (October 2008-December 2009). Data were analyzed in 2010-2011. RESULTS: Intervention employers demonstrated greater improvement from baseline than control employers in two of the five best-practice categories; implementing policies (baseline scores: 39% program, 43% control; follow-up scores: 49% program, 45% control; p=0.013) and communications (baseline scores: 42% program, 44% control; follow-up scores: 76% program, 55% control; p=0.007). Total best-practice implementation improvement did not differ between study groups (baseline scores: 32% intervention, 37% control; follow-up scores: 39% intervention, 42% control; p=0.328). CONCLUSIONS: WPS improved employers' health-related policies and communications but did not improve insurance benefits design, programs, or tracking. Many employers were unable to modify insurance benefits and reported that the time and costs of implementing best practices were major barriers. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT00452816. PMID- 22813677 TI - Facts up front versus traffic light food labels: a randomized controlled trial. AB - BACKGROUND: The U.S. food and beverage industry recently released a new front-of package nutrition labeling system called Facts Up Front that will be used on thousands of food products. PURPOSE: To test consumer understanding of the Facts Up Front system (Facts Up Front) compared to the Multiple Traffic Light system (Traffic Light). Facts Up Front displays grams/milligrams and percentage daily value information for various nutrients; Traffic Light uses an interpretive color coded scheme to alert consumers to low, medium, and high levels of certain nutrients. DESIGN: Participants in an Internet-based study were randomized to one of five front-of-package label conditions: (1) no label; (2) Traffic Light; (3) Traffic Light plus information about protein and fiber (Traffic Light+); (4) Facts Up Front; or (5) Facts Up Front plus information about "nutrients to encourage" (Facts Up Front+). SETTING/PARTICIPANTS: A total of 703 adults recruited through an online database in May 2011 participated in this study, and data were analyzed in June 2011. MAIN OUTCOME MEASURES: Total percentage correct quiz scores were generated reflecting participants' ability to compare two foods on nutrient levels, based on their labels, and to estimate amounts of saturated fat, sugar, sodium, fiber and protein in the foods. RESULTS: The front-of-package label groups outperformed the control group on nearly all of the nutrient quizzes (p<0.05). The control group did not differ from the Facts Up Front group on the saturated fat quiz, or from the Facts Up Front+ group on the sugars quiz. Those in the Traffic Light+ group had the best overall performance (>80% on all quizzes). CONCLUSIONS: Overall, those in the Traffic Light+ condition performed better than those in the Facts Up Front conditions on measures of nutrition knowledge and label perceptions. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT01626729. PMID- 22813680 TI - Correlates of preschool children's physical activity. AB - BACKGROUND: Physical activity is important for children's health, and identifying factors associated with their physical activity is important for future interventions and public health programs. PURPOSE: This study sought to identify multidimensional correlates of preschool children's physical activity. METHODS: The social-ecological model (SEM) was used to identify constructs potentially associated with preschool children's physical activity. Data were collected from 1004 preschool children, aged 3-5 years, and parents in 2008-2009, and analyzed in 2010-2011. Physical activity was measured over 8 days using ActiGraph accelerometers. Parents completed a comprehensive survey. Generalized linear modeling was used to assess associations between potential correlates and percentage of time spent in physical activity. RESULTS: Correlates of physical activity were found across all the domains of the SEM and varied between boys and girls and week and weekend days. Age was the only consistent correlate, with children spending approximately 10% less time in physical activity for each advancing year of age. Some modifiable correlates that were related to more than one physical activity outcome were rules restricting rough games inside and usual daily sleep time for boys. For girls, a preference to play inside/draw/do crafts rather than be active, and child constraints, was associated with more than one of the physical activity outcomes. A novel finding in this study is the counterintuitive association between parental rules restricting rough games inside and boys' higher physical activity participation levels. CONCLUSIONS: Potential strategies for promoting children's physical activity should seek to influence children's preference for physical activity and parent rules. Gender specific strategies also may be warranted. PMID- 22813678 TI - Federally qualified health centers and private practice performance on ambulatory care measures. AB - BACKGROUND: The 2010 Affordable Care Act relies on Federally Qualified Health Centers (FQHCs) and FQHC look-alikes (look-alikes) to provide care for newly insured patients, but ties increased funding to demonstrated quality and efficiency. PURPOSE: To compare FQHC and look-alike physician performance with private practice primary care physicians (PCPs) on ambulatory care quality measures. METHODS: The study was a cross-sectional analysis of visits in the 2006 2008 National Ambulatory Medical Care Survey. Performance of FQHCs and look alikes on 18 quality measures was compared with private practice PCPs. Data analysis was completed in 2011. RESULTS: Compared to private practice PCPs, FQHCs and look-alikes performed better on six measures (p<0.05); worse on diet counseling in at-risk adolescents (26% vs 36%, p=0.05); and no differently on 11 measures. Higher performance occurred in ACE inhibitors use for congestive heart failure (51% vs 37%, p=0.004); aspirin use in coronary artery disease (CAD; 57% vs 44%, p=0.004); beta-blocker use for CAD (59% vs 47%, p=0.01); no use of benzodiazepines in depression (91% vs 84%, p=0.008); blood pressure screening (90% vs 86%, p<0.001); and screening electrocardiogram (EKG) avoidance in low risk patients (99% vs 93%, p<0.001). Adjusting for patient characteristics yielded similar results, except that private practice PCPs no longer performed better on any measures. CONCLUSIONS: FQHCs and look-alikes demonstrated equal or better performance than private practice PCPs on select quality measures despite serving patients who have more chronic disease and socioeconomic complexity. These findings can provide policymakers with some reassurance as to the quality of chronic disease and preventive care at Federally Qualified Health Centers and look-alikes, as they plan to use these health centers to serve 20 million newly insured individuals. PMID- 22813679 TI - Parent and child screen-viewing time and home media environment. AB - BACKGROUND: Screen-viewing time has been associated with adverse health outcomes. Data on the predictors of youth screen-viewing time is predominately from older children in North America. Parental and home media environment factors that are associated with screen-viewing time could be targeted in interventions. PURPOSE: Examine if parental screen-viewing time and electronic media (access to game equipment, TVs, PCs, and laptops) environment factors were associated with Portuguese children's screen-viewing time and if associations differed by child age (<7 vs >=7 years); gender; or type of screen viewing. METHODS: Data are reported for 2965 families with children aged 3-10 years. Data were collected in 2009-2010 and analyzed in 2011. Outcomes were child spending >=2 hours watching TV and >=1 hour per day playing with combined other media. Exposures were mothers and fathers watching >=2 hours of TV and electronic media variables. RESULTS: Parental TV-viewing time was strongly associated with child weekday and weekend TV-viewing time across all four gender and age subgroups. Maternal TV-viewing time was a stronger predictor of child TV-viewing time than paternal TV-viewing time. There was very limited evidence that parental TV-viewing time was associated with combined other media time among boys or girls. Access to electronic game equipment increased the likelihood that children spent >1 hour using combined other media on weekdays and weekend days. CONCLUSIONS: Parental TV viewing time was associated with Portuguese children's TV-viewing time. The numbers of TVs in the household and electronic games equipment access were also associated with TV- and combined other media-viewing/usage time. PMID- 22813681 TI - Young children and parental physical activity levels: findings from the Canadian health measures survey. AB - BACKGROUND: Physical inactivity is a global public health concern. The relationship between dependent children in the home and parental physical activity has not been quantified using objective measures, nor has the relative association of the physical activity levels of mothers and fathers been examined. PURPOSE: To investigate the association of children of different ages in the home on two measures of parental physical activity: daily moderate-to-vigorous physical activity (MVPA) and likelihood of meeting the guideline of 150 minutes of MVPA per week accumulated in 10-minute bouts. METHODS: Data were from the 2007 2009 Canadian Health Measures Survey (n=2315), and analyses were conducted between February and December 2011. MVPA was measured directly using accelerometry. Linear (minutes of MVPA) and logistic (meeting physical activity guidelines) regression models were performed to determine if the presence, number of children, or the age of the youngest child at home was associated with parental physical activity. All models were adjusted for parental age, marital status, household income, employment, and BMI. RESULTS: Mothers whose youngest child was aged <6 years and fathers whose youngest was aged 6-11 years engaged in fewer minutes of daily MVPA than those without dependent children. Linear regression results identified that in comparison to those without children, women whose youngest child in the home was aged <6 years participated in 7.7 minutes less activity per day (p=0.007) whereas men engaged in 5.7 fewer minutes per day, or 54 and 40 minutes per week less, respectively. Similarly, logistic regression analyses indicated that both women and men were less likely to meet guidelines if their youngest child in the home was aged <6 years (OR=0.31, 95% CI=0.11, 0.87; OR=0.34, 95% CI=0.13, 0.93). CONCLUSIONS: The physical activity level of parents with young children present in the home was lower than that of those without children. Given the many physiologic, psychological, and social benefits of healthy active living, research efforts should continue to focus on strategies to encourage parents with young children to establish or re-engage in a physically active lifestyle, not only for their own health but to model healthy behavior for the next generation. PMID- 22813682 TI - An economic analysis of traditional and technology-based approaches to weight loss. AB - BACKGROUND: The financial burden and human losses associated with noncommunicable diseases necessitate cost-effective and efficacious interventions. PURPOSE: An economic analysis of the Lifestyle Education for Activity and Nutrition (LEAN) Study; an RCT that examined the efficacy of traditional and technology-based approaches to weight loss. METHODS: Economic analyses from an organizational perspective were conducted for four approaches: standard care control (SC); group weight-loss education (GWL); a multisensor armband (SWA); and the armband in combination with group weight-loss education (GWL+SWA). Data were collected in 2008-2009. Weight loss was the primary outcome. Total costs, costs per participant, costs per kilogram lost, and incremental cost-effectiveness ratios (ICERs) were calculated in 2010-2011. All costs are the actual expenses (i.e., staff time and materials) incurred by the LEAN study (except where noted) and reported in 2010 U.S. dollars. RESULTS: In the sample population of 197 sedentary, overweight, and obese adults (mean [+/-SD] age=46.9 +/- 0.8 years, BMI=33.3 +/- 5.2, weight=92.8 +/- 18.4 kg), the GWL+SWA was the most expensive intervention in costs/participant ($365/partic) while yielding the greatest weight loss/partic (6.59 kg). The GWL was next in cost/partic ($240), but the SWA was less expensive in cost/partic ($183) and more efficacious (3.55 vs 1.86 kg/partic). The SC did not achieve significant weight loss. The SWA was the most cost effective ($51/partic/kg lost), followed by the GWL+SWA ($55) and GWL alone ($129). The ICER suggests that for each additional kilogram lost, the GWL+SWA cost $60 more than the SWA alone. CONCLUSIONS: The SWA was the most cost effective intervention ($51/partic/kg lost). The addition of the GWL increased the efficacy of the SWA intervention but increased costs by $60/partic for each additional kilogram lost. The technology-based approaches were more cost effective and efficacious than traditional approaches in promoting weight loss via lifestyle changes in sedentary, overweight, and obese adults. PMID- 22813683 TI - Receipt of post-rape medical care in a national sample of female victims. AB - BACKGROUND: It is important for rape victims to receive medical care to prevent and treat rape-related diseases and injuries, access forensic exams, and connect to needed resources. Few victims seek care, and factors associated with post-rape medical care-seeking are poorly understood. PURPOSE: The current study examined prevalence and factors associated with post-rape medical care-seeking in a national sample of women who reported a most-recent or only incident of forcible rape, and drug- or alcohol-facilitated/incapacitated rape when they were aged >=14 years. METHODS: A national sample of U.S. adult women (N=3001) completed structured telephone interviews in 2006, and data for this study were analyzed in 2011. Logistic regression analyses examined demographic variables, health, rape characteristics, and post-rape concerns in relation to post-rape medical care seeking among 445 female rape victims. RESULTS: A minority of rape victims (21%) sought post-rape medical attention following the incident. In the final multivariate model, correlates of medical care included black race, rape-related injury, concerns about sexually transmitted diseases, pregnancy concerns, and reporting the incident to police. CONCLUSIONS: Women who experience rapes consistent with stereotypic scenarios, acknowledge the rape, report the rape, and harbor health concerns appear to be more likely to seek post-rape medical services. Education is needed to increase rape acknowledgment, awareness of post rape services that do not require formal reporting, and recognition of the need to treat rape-related health problems. PMID- 22813684 TI - Abuse against women, depression, and infant morbidity: a primary care cohort study in Brazil. AB - BACKGROUND: The relationship between abuse against women and maternal depression as risk factors for infant morbidity is unclear. PURPOSE: To describe the association of prenatal and postnatal abuse against women on infant physical morbidity and examine the potential mediating effect of maternal depression on these associations. METHODS: Prospective cohort study of 375 women from pregnancy (16th-36th week) to the fifth month postpartum, who attended 18 primary care units in Southern Brazil between 2006 and 2008. Abuse and depression were measured at the prenatal and postnatal interviews using standardized instruments. Infant outcomes were diarrhea and respiratory infection during the first 5 months after birth. Analyses were conducted in 2010. RESULTS: Overall, 35% of participants reported having suffered abuse during pregnancy and/or in the postnatal period. In addition, 10.1% reported infant diarrhea and 20.5% respiratory infection. Infants of mothers abused at the postnatal period were at increased risk for diarrhea (adjusted relative risk [RR]=2.20, 95% CI=1.15, 4.19) and for respiratory infection (adjusted RR=1.68, 95% CI=1.12, 2.52). There was no mediating effect of depression for either outcome. CONCLUSIONS: Postnatal abuse against women is associated with risk of infant diarrhea and respiratory infection. The current findings highlight the importance of getting abuse against women into the public health agenda. PMID- 22813685 TI - Television-viewing time and dietary quality among U.S. children and adults. AB - BACKGROUND: Greater TV-viewing time is generally associated with unhealthy dietary behaviors; however, few studies have examined associations between TV viewing time and composite measures of dietary quality. Most studies have focused on energy intake or intake of specific foods. But overall dietary quality is important to health and weight status. PURPOSE: To examine the relationship between TV-viewing time and dietary quality using a nationally representative U.S. sample. METHODS: Participants in the 2003-2006 National Health and Nutrition Examination Surveys were included (analyses conducted in Fall 2011). Dietary quality was determined by Healthy Eating Index (HEI)-2005 calculated from two 24 hour recalls. TV-viewing time was categorized as lower (<=1 hour/day); moderate (2-3 hours/day); and higher (>=4 hours/day; referent). Multivariate linear regression models were used to estimate the TV-viewing time and HEI-2005, adjusted for BMI (percentile for children aged 2-18 years); age; ethnicity; physical activity; and total energy intake. Analyses were conducted separately for gender-age groups (preschool=aged 2-5 years [n=1423]; school-aged=6-11 years [n=1749], adolescent=aged 12-18 years [n=3343], and adult=aged >=19 years [n=8222]). RESULTS: Lower TV-viewing time was associated with higher HEI-2005 (i.e., healthier diet) for all gender and age groups. Compared with higher TV viewing time, in each case, HEI-2005 was higher in groups with low TV-viewing time, ranging from 47.0-52.3 in <=1 hour/day to 44.7-48.9 in >=4 hours/day (all p<0.05). CONCLUSIONS: Less time spent watching TV was associated with better dietary quality in U.S. children and adults. PMID- 22813686 TI - Contribution of the school journey to daily physical activity in children aged 11 12 years. AB - BACKGROUND: Active travel is a possible method to increase physical activity in children, but the precise contribution of walking to school to daily physical activity is unclear. PURPOSE: To combine accelerometer and GPS data to quantify moderate-to-vigorous physical activity (MVPA) on the walk to and from school in relation to overall daily levels. METHODS: Participants were 141 children aged 11 12 years from the PEACH Project (Personal and Environmental Associated with Children's Health) in Bristol, England, measured between 2008 and 2009. Eighty four children met the inclusion criteria and were included in the final analysis. Accelerometers measured physical activity, GPS receivers recorded location, and mode of travel was self-reported. Data were analyzed between April and October 2011. Combined accelerometer and GPS data were mapped in a GIS. Minutes of MVPA were compared for school journeys taking place between 8:00 AM and 9:00 AM and between 3:00 PM and 5:00 PM and in relation to whole-day levels. RESULTS: Physical activity levels during journeys to and from school were highly similar, and contributed 22.2 minutes (33.7%) of total daily MVPA. In addition, MVPA on the journey did not differ between boys and girls, but because girls have lower levels of daily physical activity than boys, the journey contributed a greater proportion of their daily MVPA (35.6% vs 31.3%). CONCLUSIONS: The journey to and from school is a significant contributor to MVPA in children aged 11-12 years. Combining GPS and accelerometer data within a GIS is a useful approach to quantifying specific journeys. PMID- 22813687 TI - Diabetes prevention research: a systematic review of external validity in lifestyle interventions. AB - CONTEXT: Type 2 diabetes is a major contributor to disease burden globally. A number of systematic reviews support the efficacy of lifestyle interventions in preventing Type 2 diabetes in adults; however, relatively little attention has been paid to the generalizability of study findings. This study systematically reviews the reporting of external validity components and generalizability of diabetes prevention studies. EVIDENCE ACQUISITION: Lifestyle intervention studies for the prevention of Type 2 diabetes in adults with at least 6 months' follow up, published between 1990 and 2011, were identified through searches of major electronic databases. External validity reporting was rated using an assessment tool, and all analysis was undertaken in 2011. EVIDENCE SYNTHESIS: A total of 31 primary studies (n=95 papers) met the selection criteria. All studies lacked full reporting on external validity elements. Description of the study sample, intervention, delivery agents, and participant attrition rates were reported by most studies. However, few studies reported on the representativeness of individuals and settings, methods for recruiting settings and delivery agents, costs, and how interventions could be institutionalized into routine service delivery. It is uncertain to what extent the findings of diabetes prevention studies apply to men, socioeconomically disadvantaged individuals, those living in rural and remote communities, and to low- and middle-income countries. CONCLUSIONS: Reporting of external validity components in diabetes prevention studies needs to be enhanced to improve the evidence base for the translation and dissemination of these programs into policy and practice. PMID- 22813688 TI - Using International Classification of Diseases, 10th edition, codes to estimate abusive head trauma in children. AB - Passive surveillance using ICD codes for hospital discharges has been used to estimate the incidence of abusive head trauma (AHT) utilizing ICD-9-CM, but not ICD-10, codes. There have been no incidence estimates of AHT in Canada where ICD 10 codes have been used since 2002. The Discharge Abstract Database from the Canadian Institute of Health Information (CIHI) for 2002-2007 was used for analyses conducted in 2011. A case was defined by code combinations that indexed injury specificity (narrow or broad) and degree of certainty (presumptive or probable) that the injury was inflicted. Estimated incidences for the populations at risk in those aged <12 months and 12-23 months from 2002-2007 were determined. For those aged <12 months, the mean incidence for "narrow, presumptive" AHT was 13.0 (95% CIs=11.3, 14.9) per 100,000 person-years; for "broad, probable" it was 15.5 (13.6, 17.6) per 100,000 person-years. For those aged 12-23 months, the "narrow, presumptive" incidence was 2.4 (1.7, 3.3) and the "broad, probable" incidence was 2.8 (2.0, 3.8) per 100,000 person-years, respectively. Month and year of age patterns were similar to previous reports. ICD-10 codes can be used to estimate incidence of AHT. Narrower classifications provide estimates consistent with those from other surveillance programs in Canada and internationally. PMID- 22813689 TI - Thinking differently about cervical cancer screening in high-risk populations. PMID- 22813690 TI - Research to inform policy in diabetes prevention: a work in progress. PMID- 22813691 TI - Differential effects of exercise on cancer-related fatigue during and following treatment: a meta-analysis. AB - CONTEXT: Exercise-induced improvements in cancer-related fatigue may be moderated differentially in patients during and following treatment. These effects have not been reviewed systematically. In accordance with PRISMA guidelines, the population effect size for exercise training on cancer-related fatigue during and following treatment was estimated and the extent to which the effect is differentiated across the time course of treatment and recovery was determined. EVIDENCE ACQUISITION: Articles published before August 2011 were retrieved using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science databases. Seventy studies involving 4881 cancer patients during or following treatment were selected. Articles included a cancer-related fatigue outcome measured at baseline and post-intervention and randomized allocation to exercise or non-exercise comparison. From August to October 2011, Hedges' d effect sizes were computed, study quality was evaluated, and random effects models were used to estimate sampling error and population variance. EVIDENCE SYNTHESIS: Exercise significantly reduced cancer-related fatigue by a mean effect Delta (95% CI) of 0.32 (0.21, 0.43) and 0.38 (0.21, 0.54) during and following cancer treatment, respectively. During treatment, patients with lower baseline fatigue scores and higher exercise adherence realized the largest improvements. Following treatment, improvements were largest for trials with longer durations between treatment completion and exercise initiation, trials with shorter exercise program lengths, and trials using wait-list comparisons. CONCLUSIONS: Exercise reduces cancer related fatigue among patients during and following cancer treatment. These effects are moderated differentially over the time course of treatment and recovery. Exercise has a palliative effect in patients during treatment and a recuperative effect post-treatment. PMID- 22813693 TI - Commentary on the impact of a 25-cent-per-drink alcohol tax increase. PMID- 22813694 TI - Kinematic landing strategy transference in backward rotating gymnastic dismounts. AB - The aim of this study was to develop insight into the transference of kinematic landing strategies between back- ward rotating dismount skills. Female gymnasts performed backward rotating pike (N = 4 x 10 trials) and tuck dismounts skills (N = 4 x 10 trials) from the beam apparatus. Whole and lower body joint kinematic measures were quantified for the impact phase using an automatic motion analysis system (CODAMotion, Charnwood Dynamics Ltd.). Phase duration, whole body orientation and the mass center maximum z-displacement were similar (P < .01) between skills for individual gymnasts and the group. While skill differences in the hip joint motion profiles were notably larger (group root mean squared difference [RMSD]: 30.9%) than the ankle (group RMSD: 13.6%) and knee (group RMSD: 15.4%) joints, individual gymnast adjustments were made to the discrete joint kinematic measures. The use of a stable whole body orientation may provide important indicators of effective strategy transference between fundamental dismount skills. Further consideration of the joint strategy adjustments made according to the gymnast's performance level may, however, be warranted. PMID- 22813695 TI - High temperature extended x-ray absorption fine structure study of multiferroic BiFeO3. AB - Local atomic structure modifications around Fe atoms in polycrystalline multiferroic BiFeO(3) are studied by Fe K edge x-ray absorption spectroscopy as a function of temperature across the Neel temperature (T(N) = 643 K) in order to reveal local structure modifications related to the magnetic transition. This work demonstrates that on crossing T(N) the local structure around Fe shows peculiar changes: the Fe-O bond lengths get shorter, the ligand symmetry increases and the Fe-O bond length disorder (sigma(2)) deviates from Debye behaviour. These results suggest that the structural transition at the ferroelectric Curie temperature (T(C) = 1103 K) is anticipated by early local rearrangement of the structure starting already at T(N). PMID- 22813696 TI - Association of lower habitual physical activity level with mitochondrial and endothelial dysfunction in patients with stable coronary artery disease. AB - BACKGROUND: Exercise training improves endothelial function in patients with coronary artery disease (CAD) through unclear mechanisms. We hypothesized that mitochondrial dysfunction related to a lower habitual physical activity level (PAL) is associated with endothelial dysfunction. METHODS AND RESULTS: We assessed habitual PAL by a validated International Physical Activity Questionnaire, brachial flow-mediated dilation (FMD) and serum lactate, pyruvate, fasting glucose and lipid profiles in 105 CAD patients (age 68+/-10; 87% men). As defined by the lactate/pyruvate ratio (LP ratio) >=75(th) percentile of the age and sex-matched controls (ie, >=18), mitochondrial dysfunction was observed in 33/105 (31%) patients. With decreasing PAL tertiles, there were significant linear trends of lower FMD (P=0.004) and higher LP ratio (P=0.009). Multivariate logistic regression found that the lowest compared with the highest PAL tertile (adjusted odds ratio=3.78, P=0.02) had more patients with high LP ratio. After adjustment for cardiovascular risk factors and medications, the lowest compared to the highest PAL tertile had significantly lower FMD (absolute decrease 1.25%, P=0.03); and high LP ratio was associated with impaired FMD (absolute reduction 1.09%, P=0.03). CONCLUSIONS: In CAD patients, a lower level of habitual PAL is associated with impaired FMD and increased prevalence of mitochondrial dysfunction as defined by high LP ratio. Moreover, high LP ratio predicts a lower FMD, suggesting that the occurrence of mitochondrial dysfunction with lower habitual PAL is associated with endothelial dysfunction in CAD patients. PMID- 22813697 TI - Impact of functional, morphological and clinical parameters on epicardial adipose tissue in patients with coronary artery disease. AB - BACKGROUND: Because a close relationship between epicardial adipose tissue (EAT) and coronary artery disease (CAD) has been shown, the impact of functional, morphological and clinical parameters to identify potential determinants of EAT was investigated. METHODS AND RESULTS: Clinical and cardiac magnetic resonance parameters were determined and correlated to the amount of EAT in 158 patients with CAD and 40 healthy subjects. Patients with CAD and left ventricular function (LVEF) >=50% revealed significantly elevated EAT (36+/-11g/m2) compared to healthy controls (31+/-8g/m2) and to patients with LVEF <50% (26+/-8.0g/m2). In the whole study population, only LVEF (P=0.003), body mass index (BMI) (P=0.004) and left ventricular end diastolic diameter (LV-EDD) (P=0.004) remained significantly associated with EAT after multivariate analysis. Subgroup analysis in patients with CAD and LVEF >=50% showed that BMI (P=0.03) was the only correlate of EAT. However, in patients with CAD and LVEF <50%, indexed LV end diastolic mass (LV-EDMI) (P=0.003) and the extent of late gadolinium enhancement (LGE %) (P=0.03) remained significantly correlated with EAT in multivariate analysis. CONCLUSIONS: The amount and the determinants of EAT differ according to the LVEF in patients with CAD. Thus, different amounts of EAT reflect different stages of CAD underlining the complex interaction of EAT in the pathogenesis and progression of ischemic cardiomyopathy. PMID- 22813698 TI - An ultrastructural evidence for the expression of transient receptor potential ankyrin 1 (TRPA1) in astrocytes in the rat trigeminal caudal nucleus. AB - The transient receptor potential ankyrin 1 (TRPA1) is implicated in the mechanical and cold hyperalgesia following inflammation and nerve injury. Its expression has been presumed to be confined to primary afferent terminals. Here, we show that TRPA1 is expressed in astrocytes in the superficial laminae of the rat trigeminal caudal nucleus by use of electron microscopic immunoperoxidase and immunogold labeling techniques. Immunoreactivity for TRPA1 was consistently observed in somata and process of astrocytes and was weaker than that in presumed nociceptive primary afferent terminals, but increased significantly in the fine process of astrocyte in rats with experimental inflammation of the temporomandibular joint. Thus, we provide ultrastructural evidence that TRPA1 is expressed in astrocytes in the brain stem and propose a novel pathway of its involvement in the central mechanism of inflammatory hyperalgesia. PMID- 22813709 TI - A hydrogen peroxide electrode assay to measure thiol peroxidase activity for organoselenium and organotellurium drugs. AB - Molecular mimics of the enzyme glutathione peroxidase (GPx) are increasingly being evaluated as redox active drugs. Their molecular mechanism of action parallels that of the native enzyme; however, a major distinction is that GPx mimics can use alternative thiol substrates to glutathione. This generic thiol peroxidase activity implies that it is necessary to assess a GPx mimic's recognition of a range of cellular thiols in order to determine its potential therapeutic effects. We report an electrochemical assay that, by measuring the rate of decrease of the peroxide substrate, allows the activity of GPx mimics to be directly compared against an array of thiols. The derived pseudo zero-order rate constants, k(obs), for representative GPx mimics range between 0 and 6.6 min(-1) and can vary by more than an order of magnitude depending on the thiol electron donor. An additional advantage of the assay is that it enables synergistic interactions between GPx mimics and cellular proteins to be evaluated. Here we report that glutathione disulfide reductase, which is commonly used to evaluate GPx mimic activity, recognizes the GPx mimic ebselen as a substrate, increasing its apparent k(obs). Therefore, reports relying on glutathione disulfide reductase to evaluate GPx mimic activity may exaggerate drug antioxidant action. PMID- 22813710 TI - Enumeration and viability of rare cells in a microfluidic disk via positive selection approach. AB - Recent studies have shown that specific rare cells in the blood can serve as an indicator of cancer prognosis, among other purposes. This article demonstrates the concept of separating and detecting rare cells from peripheral blood mononuclear cells via an economical microfluidic disk with a model system. MCF7, labeled with magnetic beads, was used to simulate circulating tumor cells as a target. Jurkat clone E6-1 was used to simulate leukocytes or other cells abundant in human blood. A tailored multistage magnet maximized the magnetic field to ensure optimal trapping efficiency. Results indicate that the yield of detected MCF7 was consistent at approximately 80% when fewer than hundreds of MCF7 cells were mixed in greater than 1 million Jurkat cells. The 80% yield also held for 10 MCF7 in 100 million Jurkat (rarity of 10(7)). Compared with the results from autoMACS, the performance was at least 20% higher and was more independent of the number of Jurkat. The viability of the enriched cells was approximately 90 +/- 20%, showing that this method caused little damage to trapped cells. The microfluidic disk should be applicable for separation and detection of various rare cells, such as circulating tumor cells and circulating endothelial cells in human blood. PMID- 22813711 TI - A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. AB - Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE), an active metabolite. This study investigated the acute and chronic effects of Polygonum cuspidatum (PC), a resveratrol-rich nutraceutical, on the pharmacokinetics of CBZ in rats and the underlying mechanisms. Rats were orally administered CBZ (200 mg/kg) alone and coadministered with a single dose and the 7th dose of PC (2 g/kg) in a crossover design. The concentrations of CBZ and CBZE in serum and various tissues were determined by HPLC method. The results showed that PC significantly increased the AUC(0-t) of CBZ and CBZE, whereas the formation rate of CBZE was decreased. Tissue analysis showed that the concentrations of CBZ and CBZE in brain, liver and kidney were significantly increased by PC. Cell studies indicated that the efflux function of MRP 2 was inhibited by the serum metabolites of PC. In conclusion, PC markedly increased the systemic exposure and brain concentration of CBZ and CBZE through inhibiting the activities of CYP 3A and MRP 2. PMID- 22813712 TI - [Not Available]. AB - D Dosseh Ekoue, A Doleaglenou, Y-K Fortey, A-E Ayite Objective: to see whether there was a difference in therisk of local infection for surgical wounds in a tropical settingdepending on whether a wound was dressed or left open beyond 48hours post-operatively. METHOD: Over a four month period, 102 patients undergoingintra-abdominal surgery classified as clean or clean-contaminatedwere randomized into two equal groups. The "with dressing" groupunderwent a wound dressing change and re-application every two days.In the "without dressing" group, the wound wasleft open to the air after a first dressing change at 48 hours. RESULTS: There was no difference in post-operative temperaturecurve; post operative wound infection rate was 2% in eachgroup. Suture removal was performed two days earlier in the "withoutdressing" group and hospital stay was decreased by twodays. The expense of repeated dressing changes was also lessened. CONCLUSION: There is no benefit to leaving a wound dressingin place longer than 48 hours after surgery; costs related to prolongedhospitalization and expenses of dressing changes are decreased bya policy of leaving incisions undressed after 48 hours. PMID- 22813713 TI - Prevention of soya-induced enteritis in Atlantic salmon (Salmo salar) by bacteria grown on natural gas is dose dependent and related to epithelial MHC II reactivity and CD8alpha+ intraepithelial lymphocytes. AB - An experiment was carried out to study the preventive effect of bacterial meal (BM) produced from natural gas against plant-induced enteropathy in Atlantic salmon (Salmo salar). Salmon were fed a diet based on fish meal (FM) or seven diets with 200 g/kg solvent-extracted soyabean meal (SBM) to induce enteritis in combination with increasing levels of BM from 0 to 300 g/kg. Salmon fed a SBM containing diet without BM developed typical SBM-induced enteritis. The enteritis gradually disappeared with increasing inclusion of BM. By morphometry, no significant (P>0.05) differences in the size of stretches stained for proliferating cell nuclear antigen were found with 150 g/kg BM compared with the FM diet. Increasing BM inclusion caused a gradual decline in the number of cluster of differentiation 8 alpha positive (CD8alpha+) intraepithelial lymphocytes, and fish fed BM at 200 g/kg or higher revealed no significant difference from the FM diet. Histological sections stained with antibody for MHC class II (MHC II) showed that fish with intestinal inflammation had more MHC II reactive cells in the lamina propria and submucosa, but less in the epithelium and brush border, compared with fish without inflammation. There were no significant (P>0.05) differences in growth among the diets, but the highest levels of BM slightly reduced protein digestibility and increased the weight of the distal intestine. In conclusion, the prevention of SBM-induced enteritis by BM is dose dependent and related to intestinal levels of MHC II- and CD8alpha reactive cells. PMID- 22813715 TI - Incidence and clinical relevance of primary congenital anomalies of the coronary arteries in children and adults. AB - OBJECTIVES: To describe our experience in the management of coronary artery anomalies both in an adult and in a paediatric population and to compare the two groups for finding out differences in terms of angiographic incidence and treatment. PATIENTS AND METHODS: Databases at the Department of Cardiology of San Martino Adult's Hospital and of Gaslini Children's Hospital were searched for all patients with a diagnosis of coronary artery anomaly who underwent coronary angiography between 1994 and 2006. RESULTS: Coronary anomalies were diagnosed in 76 (1%) adult patients. Anomalous left circumflex artery was the commonest coronary anomaly (25%). Anomalous left coronary artery from pulmonary artery and myocardial bridges were the only anomalies responsible for angina-like symptoms. No patients except the one with anomalous left coronary artery from pulmonary artery needed surgical intervention. In the paediatric population, we found 28 (0.9%) patients with coronary anomalies. Anomalous left coronary artery from pulmonary artery was the most common anomaly (48%) and always required emergency surgical treatment; in addition there were two patients with stenosis of the left main coronary artery. CONCLUSION: Coronary artery anomalies may be associated with very acute, even life-threatening symptoms in children, whereas they are usually clinically silent and detected by accident on coronary angiography in adults. Recognition of coronary artery anomalies enables early treatment or close follow-up in children, whereas it could be useful in case of cardiac surgery in adults. PMID- 22813714 TI - Dermatoscopy as an adjunctive diagnostic tool in aquagenic syringeal acrokeratoderma. AB - Aquagenic syringeal acrokeratoderma (ASA) is a rare skin disorder of the palms and/or soles, characterized by whitish papules with occasional pruritus or pain sensation. Herein we report a 27-year-old man with a diagnosis of ASA based on clinical and histopathological features, and describe the dermatoscopic features consistent with threefold enlarged sweat duct pores compared with a normal looking palmar skin area. As far as we are aware, dermatoscopic features of ASA have not been reported so far. PMID- 22813716 TI - Effect of salt intake on bioavailability of mizoribine in healthy Japanese males. AB - Bioavailability of mizoribine in subjects with the concentrative nucleoside transporter 1 (CNT1, SLC28A1) 565-A/A allele is significantly lower than that in subjects with the SLC28A1 565-G/G allele. The aims of the present study were to investigate the cellular uptake of mizoribine in CNT1- and CNT2-expressing Madin Darby canine kidney type II (MDCKII) cells, and to evaluate the effect of salt intake on bioavailability of mizoribine in healthy Japanese volunteers with SLC28A1 565-A/A and -G/A alleles. Eight healthy males participated in the present study, and took 150 mg mizoribine concomitantly with/without 300 mg salt. Bioavailability of mizoribine was estimated by total cumulative urinary excretion of the drug. Mizoribine was taken up Na(+)-dependently into not only CNT1 expressing but also CNT2-expressing MDCKII cells, indicating that mizoribine is a substrate for both CNT1 and CNT2. Mean bioavailability of mizoribine taken with salt (83.8%) was significantly higher than that taken without salt (73.0%). These findings suggest that the salt intake is expected to improve the bioavailability of mizoribine in patients with insufficient intestinal absorption. PMID- 22813717 TI - Risk of insomnia attributable to beta-blockers in elderly patients with newly diagnosed hypertension. AB - Use of beta-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among beta-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with beta blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35-0.63) for non propranolol users, 0.31 (0.19-0.50) for bisoprolol, and 0.46 (0.33-0.66) for atenolol. Compared to the patients using non-selective beta-blockers, the adjusted odds ratio was 0.48 (0.36-0.34) for those using selective beta(1) blockers. Additionally, the adjusted odds ratio was 0.72 (0.53-0.96) for beta blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. beta-Blockers with high selectivity in beta(1)-receptors and/or low lipophilicity were associated with a lower risk of insomnia. PMID- 22813718 TI - Model-based dose selection for phase III rivaroxaban study in Japanese patients with non-valvular atrial fibrillation. AB - The global ROCKET AF phase III trial evaluated rivaroxaban 20 mg once daily (o.d.) for stroke prevention in atrial fibrillation (AF). Based on rivaroxaban pharmacokinetics in Japanese subjects and lower anticoagulation preferences in Japan, particularly in elderly patients, the optimal dose regimen for Japanese AF patients was considered. The aim of this analysis was dose selection for Japanese patients from a pharmacokinetic aspect by comparison of simulated exposure in Japanese patients with those in Caucasian patients. As a result of population pharmacokinetics-pharmacodynamics analyses, a one-compartment pharmacokinetic model with first-order absorption and direct link pharmacokinetic-pharmacodynamic models optimally described the plasma concentration and pharmacodynamic models (Factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest), which were also consistent with previous works. Steady-state simulations indicated 15 mg rivaroxaban o.d. doses in Japanese patients with AF would yield exposures comparable to the 20 mg o.d. dose in Caucasian patients with AF. In conclusion, in the context of the lower anticoagulation targets in Japanese practice, the population pharmacokinetic and pharmacodynamic modeling supports 15 mg o.d. as the principal rivaroxaban dose in J-ROCKET AF. PMID- 22813719 TI - The emerging role of human esterases. AB - In this review, novel aspects of the role of esterases, which contribute to the metabolism of 10% of therapeutic drugs, are described. Esterases hydrolyze the compounds that contain ester, amide, and thioester bonds, which cause prodrug activation or detoxification. Among esterases, carboxylesterases are well known to be involved in the hydrolysis of a variety of drugs. Additionally, other esterases have recently received attention for their pharmacological and toxicological roles. Arylacetamide deacetylase (AADAC) is involved in the hydrolysis of flutamide, phenacetin, and rifamycins. AADAC is associated with adverse drug reactions because the hydrolytic metabolites of flutamide and phenacetin appear to be associated with hepatotoxicity and nephrotoxicity/hematotoxicity, respectively. Paraoxonase and butyrylcholinesterase hydrolyze pirocarpine/simvastatin and succinylcholine/bambuterol, respectively. Although the esterases that hydrolyze the acyl-glucuronides of drugs have largely been unknown, we recently found that alpha/beta hydrolase domain containing 10 (ABHD10) is responsible for the hydrolysis of mycophenolic acid acyl-glucuronide in human liver. Because acyl glucuronides are associated with toxicity, ABHD10 might function as a detoxification enzyme. Thus, various esterases, which include enzymes that have not been known to hydrolyze drugs, are involved in drug metabolism with different substrate specificity. Further esterase studies should be conducted to promote our understanding in clinical pharmacotherapy and drug development. PMID- 22813720 TI - Hypothermia: a double-edged sword. AB - Therapeutic hypothermia is currently used to reduce neurological ischemic damage in postcardiac arrest patients. Nevertheless, it has been associated with relevant side effects such as infections, bleeding, hypotension and hyperkalemia. Although hypothermia-induced coronary spasm is rare, its occurrence needs to be considered attentively as it adds a high risk of ventricular arrhythmias and cardiac arrest in patients with already-existing critical heart conditions. PMID- 22813721 TI - Patient-centered care and emergency department utilization: a path analysis of the mediating effects of care coordination and delays in care. AB - Increased emergency department (ED) overcrowding has renewed interest in identifying remedies for unnecessary ED utilization. One potential remedy receiving more attention is patient-centered care. Relatively little is known, however, about how patient-centered care might decrease ED utilization. This study examined two mediating processes by which four dimensions of patient centered care may affect patients' reported ED visits. Cross-sectional path analysis of 8,140 chronically ill patients found that patients reporting higher levels of patient-centered care were less likely to have experienced problems of care coordination, and in turn were associated with decreased likelihood of having delayed care and fewer ED visits. These findings suggest that understanding how care is delivered, and not simply whether it is available or provided, is an important consideration in understanding ED utilization. Our findings suggest that fostering more fair and respectful relationships between patients and providers may be a particularly important way of reducing ED utilization. PMID- 22813722 TI - Freestanding inpatient rehabilitation facility performance following the 60 percent rule: a matter of fit. AB - The 60 percent rule has served as a controversial policy change within the postacute care sector since its revision in 2004, requiring inpatient rehabilitation facilities (IRFs) to admit no less than 60% of patients according to 1 of 13 specific conditions or else risk the loss of IRF designation according to Medicare's prospective payment system. Using a contingency theory framework, this study proposes that the 60 percent rule introduced considerable uncertainty into freestanding IRFs' operational environment, and as a result, IRFs' operational performance varied according to their "fit" between certain structural characteristics and the pervasive environmental uncertainty. The results suggest that operational performance, as measured by facility Malmquist Index scores, decreased on average for freestanding IRFs following the 60 percent rule's enforcement in 2005. In contrast, organizations possessing structural characteristics that better "fit" the heightened environmental uncertainty exhibited improved performance on average during the study's 6-year time period. PMID- 22813723 TI - Reliability and accuracy in three-dimensional gait analysis: a comparison of two lower body protocols. AB - The standard Plug-in-Gait (PiG) protocol used in three-dimensional gait analysis is prone to errors arising from inconsistent anatomical landmark identification and knee axis malalignment. The purpose of this study was to estimate the reliability and accuracy of a custom made lower body protocol (MA) compared with the PiG protocol. Twenty-five subjects volunteered to evaluate the intertrial reliability. In addition, intersession reliability was examined in 10 participants. An indirect indicator of accuracy according to the knee varus/valgus and flexion/extension range of motion (ROM) was used. Regarding frontal plane knee angles and moments as well as transverse plane motions in the knee and hip joint, the intersession errors were lower for the MA compared with the standard approach. In reference to the knee joint angle cross-talk, the MA produced 4.7 degrees more knee flexion/extension ROM and resulted in 6.5 degrees less knee varus/valgus ROM in the frontal plane. Therefore, the MA tested in this study produced a more accurate and reliable knee joint axis compared with the PiG protocol. These results are especially important for measuring frontal and transverse plane gait parameters. PMID- 22813724 TI - Prioritizing environmental risk of prescription pharmaceuticals. AB - Low levels of pharmaceutical compounds have been detected in aquatic environments worldwide, but their human and ecological health risks associated with low dose environmental exposure is largely unknown due to the large number of these compounds and a lack of information. Therefore prioritization and ranking methods are needed for screening target compounds for research and risk assessment. Previous efforts to rank pharmaceutical compounds have often focused on occurrence data and have paid less attention to removal mechanisms such as human metabolism. This study proposes a simple prioritization approach based on number of prescriptions and toxicity information, accounting for metabolism and wastewater treatment removal, and can be applied to unmeasured compounds. The approach was performed on the 200 most-prescribed drugs in the US in 2009. Our results showed that under-studied compounds such as levothyroxine and montelukast sodium received the highest scores, suggesting the importance of removal mechanisms in influencing the ranking, and the need for future environmental research to include other less-studied but potentially harmful pharmaceutical compounds. PMID- 22813726 TI - How similar are inbred rats? The influence of anatomical variations, shipment and sampling time on experimental surgery. AB - Variations among inbred rats in terms of anatomy and routine laboratory values can potentially blur surgical experimental results. Therefore, a retrospective analysis aiming at investigating hepatic and perihepatic anatomical variations, liver weight, body weight, liver weight/body weight ratio (LBWR), variations in routine laboratory values, and the influence of shipment and repeated sampling was performed. In our study, liver weight of rats seemed to be strain-specific. LBWR was weakly and negatively correlated with body weight in rats. A statistically significant difference in routine blood tests was found among normal rats grouped by different body weight or shipment. Weekly repeated sampling from the same rats revealed a statistically significant difference in a blood test. In conclusion, the fact that variation among rats or their environment can blur the results of a surgical experimental study should be kept in mind. PMID- 22813725 TI - An updated inhalation unit risk factor for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology studies. AB - The United States Environmental Protection Agency (USEPA) developed an inhalation unit risk factor (URF) of 4.3E-03 per MUg/m(3) for arsenic in 1984 for excess lung cancer mortality based on epidemiological studies of workers at two smelters: the Asarco smelter in Tacoma, Washington and the Anaconda smelter in Montana. Since the USEPA assessment, new studies have been published and exposure estimates were updated at the Asarco and Anaconda smelters and additional years of follow-up evaluated. The Texas Commission on Environmental Quality (TCEQ) has developed an inhalation URF for lung cancer mortality from exposures to arsenic and inorganic arsenic compounds based on a newer epidemiology study of Swedish workers and the updates of the Asarco and Anaconda epidemiology studies. Using a combined analysis approach, the TCEQ weighted the individual URFs from these three epidemiology cohort studies, to calculate a final inhalation URF of 1.5E-04 per MUg/m(3). In addition, the TCEQ also conducted a sensitivity analysis, in which they calculated a URF based on a type of meta-analysis, and these results compared well with the results of the combined analysis. The no significant concentration level (i.e., air concentration at 1 in 100,000 excess lung cancer mortality) is 0.067MUg/m(3). This value will be used to evaluate ambient air monitoring data so the general public in Texas is protected against adverse health effects from chronic exposure to arsenic. PMID- 22813727 TI - An evaluation of overnight fixation to facilitate neuropathological examination in Coroner's autopsies: our experience of over 200 cases. AB - AIMS: Following recent changes in Coroner's Rules, there has been a desire to examine brains at the time of autopsy, rather than after a prolonged period of immersion fixation. Examination of the fresh brain at postmortem can yield unsatisfactory results where detailed histological examination is required. We aim to provide a compromise, where detailed examination of the brain is possible, without the requirement for prolonged fixation, interference with funeral arrangements and delay in the Coronial process. METHODS: A retrospective audit of over 200 neuropathology cases requested by HM Coroner for the East Riding of Yorkshire between 2007 and 2010 was performed. The cases consisted of full neuropathology autopsies (n=212) and brains referred by general pathology colleagues (n=26). RESULTS: Of the 238 brains examined, approximately half (n=109) of the brains were sectioned fresh in the mortuary. The remaining brains (n=129) were immersion fixed overnight in 20% formalin prior to cutting and sampling for histology (n=127). The median time for reporting was 31 days (range 1-167; n=101) for brains requiring histology. This equates to a median turnaround time of 1 month for a neuropathological autopsy requiring detailed histology. In all cases, the report was prepared and available to HM Coroner in advance of the Inquest. CONCLUSIONS: This method provides reliable histological diagnoses in neuropathological autopsies and does not interfere with funeral arrangements for bereaved families following deaths falling under Coronial jurisdiction. In all cases, the body could be released to relatives, at Coroner's discretion, within two working days of the autopsy. PMID- 22813728 TI - High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas. AB - BACKGROUND AND AIMS: Molecular target therapy against L-type amino acid transporter 1 (LAT1) is unique and expected to be developed soon. LAT1 expression was investigated in pancreatic cancer as a prognostic predictor. METHODS: Surgically resected pancreatic ductal adenocarcinomas (PDAC, n=66) were investigated using immunohistochemistry. For reference, intraductal papillary mucinous carcinomas (IPMC, including intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia or with an associated invasive carcinoma, n=13) and adenomas (IPMA, including IPMN with low- and intermediate-grade dysplasia, n=5) were also examined. RESULTS: LAT1 expression scores increased from PDAC to IPMA to IPMC. Kaplan-Meier analysis showed significant differences between LAT1 high and -low scores in PDAC. Even in each Ki-67-labelling index (LI) low and high PDAC group (cut off 40%), high LAT1 expression could also predict poor prognosis. Multivariable analysis showed that LAT1 expression, Ki-67 LI, tumour differentiation and size were individual prognostic factors. CONCLUSIONS: LAT1 aberrant overexpression in PDAC predicts poor prognosis, independent of Ki-67 LI, and offers a potential target for future anticancer therapy with its inhibitors. PMID- 22813729 TI - Stromal invasion and micropapillary pattern in 212 consecutive surgically resected stage I lung adenocarcinomas: histopathological categories for prognosis prediction. AB - BACKGROUND AND AIM: It is of importance to search for prognostic indicators supplementing the tumour-node-metastasis stage for surgically resected early stage lung adenocarcinomas. The roles of stromal invasion and micropapillary pattern in categorising histopathology and predicting the prognosis of stage I lung adenocarcinomas are explored. METHODS: We retrospectively examined 212 consecutive surgically resected stage I lung adenocarcinomas to propose a new histopathology-based categorical classification. Category A tumours have pure lepidic growth pattern without stromal invasion (ie, adenocarcinoma in situ). Stromal invasion in the form of central fibrotic focus is absent in category B tumours and present in category C tumours. Category B is subclassified into B1, which has areas of lepidic growth, and B2, which does not. Category C is subclassified into C1, which has invasive tumour cells in the periphery of central fibrotic focus, and C2, which has invasive tumour cells in the centre of central fibrotic focus. Based on the absence or presence of micropapillary pattern, the C2 tumours are further subclassified into C2a and C2b, respectively. RESULTS: The 5-year recurrence-free probabilities for categories B1 (17 cases), B2 (10 cases), C1 (nine cases), C2a (114 cases) and C2b (62 cases) are 100%, 78.8%, 100%, 67.5% and 53.1%, respectively (p<0.001). CONCLUSIONS: Based on stromal invasion and micropapillary pattern, the histopathological categorical classification proposed here provides a concise and precise scheme for outcome prediction in early-stage lung adenocarcinomas. PMID- 22813730 TI - Faecal markers of gastrointestinal inflammation. AB - Gastrointestinal (GI) symptoms including abdominal pain, bloating and diarrhoea are a relatively common reason for consulting a physician. They may be due to inflammatory bowel disease (inflammatory bowel disease; Crohn's disease, ulcerative colitis and indeterminate colitis), malignancy (colorectal cancer), infectious colitis or irritable bowel syndrome (IBS). Differentiation between these involves the use of clinical, radiological, endoscopic and serological techniques, which are invasive or involve exposure to radiation. Serological markers include C-reactive protein, erythrocyte sedimentation rate and antibodies (perinuclear antineutrophil cytoplasm antibody and anti-Saccharomyces cerevisiae antibody). Faecal markers that can aid in distinguishing inflammatory disorders from non-inflammatory conditions are non-invasive and generally acceptable to the patient. As IBS accounts for up to 50% of cases presenting to the GI clinic and is a diagnosis of exclusion (Rome III criteria), any test that can reliably distinguish IBS from organic disease could speed diagnosis and reduce endoscopy waiting times. Faecal calprotectin, lactoferrin, M2-PK and S100A12 will be reviewed. PMID- 22813731 TI - Detection of Cu(I) and Zn(II) ions in colon tissues by multi-photon microscopy: novel marker of antioxidant status of colon neoplasm. AB - AIMS: Establishing probe-based analysis is important for developing multi-photon microscopy (MPM) to make an early diagnosis of colon neoplasm and assess its antioxidant status. Cu(I) and Zn(II) ions are trace elements which roll as cofactors of antioxidant, superoxide dismutase. However, there have been no reports on the features of MPM image using probe of Cu(I) and Zn(II) ions. Our main objective in this study was application of newly developed multi-photon probe (MP) probe on Cu(I) and Zn(II) ions as a tool to assess antioxidative status of colon neoplasm. METHODS: This study was a pilot study. Colon cancer cell lines (ACT116 and HT-29), NIH3T3 cells and tissues of normal colon mucosa and colon neoplasm obtained during colonoscopic biopsy from 17 patients were stained with MP probes for Cu(I) and Zn(II) (ACu1 and AZn1). Cu(I)/Zn(II) levels in the cells and tissues were determined by detecting MP-excited fluorescence by MPM. RESULTS: MPM images of cells stained with MP probes revealed that Cu(I) was more abundant in ACT116 and HT-29 cells than in NIH3T3 cells, while Zn(II) was more abundant in NIH3T3 cells than in ACT116 and HT-29 cells. Normal tissues had a defined texture, whereas adenoma/adenocarcinoma tissues were amorphous. The level of Cu(I) increased and that of Zn(II) decreased with the transition from normal to adenoma to adenocarcinoma tissue. CONCLUSION: MPM can be used to determine the relative Cu(I)/Zn(II) levels in cells and colon tissues by using ACu1 and AZn1 as MPM probes. These finding are new research tools for gastroenterologists to assess antioxidant status of colon neoplasm. PMID- 22813732 TI - Current issues in diagnostic breast pathology. AB - On behalf of the NHS Breast Screening Programme Pathology Coordinating Group we present recommendations for terminology and diagnostic criteria for a number of key areas of practice in breast pathology where terminology can be confusing and where accurate communication will ensure appropriate clinical management. These recommendations cover columnar cell lesions and the spectrum of changes that can be seen in these epithelial proliferations, lobular neoplasia, micrometastases and isolated tumour cells in axillary lymph nodes, the use of basal/myoepithelial markers in diagnostic practice and oestrogen receptor testing in ductal carcinoma in situ. PMID- 22813733 TI - Molecular architecture of the yeast monopolin complex. AB - The Saccharomyces cerevisiae monopolin complex directs proper chromosome segregation in meiosis I by mediating co-orientation of sister kinetochores on the meiosis I spindle. The monopolin subunits Csm1 and Lrs4 form a V-shaped complex that may directly crosslink sister kinetochores. We report here biochemical characterization of the monopolin complex subunits Mam1 and Hrr25 and of the complete four-protein monopolin complex. By purifying monopolin subcomplexes with different subunit combinations, we have determined the stoichiometry and overall architecture of the full monopolin complex. We have determined the crystal structure of Csm1 bound to a Mam1 fragment, showing how Mam1 wraps around the Csm1 dimer and alters the stoichiometry of kinetochore protein binding by Csm1. We further show that the kinase activity of Hrr25 is altered by Mam1 binding, and we identify Hrr25 phosphorylation sites on Mam1 that may affect monopolin complex stability and/or kinetochore binding in meiosis. PMID- 22813734 TI - Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. AB - AMPA receptor (AMPA-R) complexes consist of channel-forming subunits, GluA1-4, and auxiliary proteins, including TARPs, CNIHs, synDIG1, and CKAMP44, which can modulate AMPA-R function in specific ways. The combinatorial effects of four GluA subunits binding to various auxiliary subunits amplify the functional diversity of AMPA-Rs. The significance and magnitude of molecular diversity, however, remain elusive. To gain insight into the molecular complexity of AMPA and kainate receptors, we compared the proteins that copurify with each receptor type in the rat brain. This interactome study identified the majority of known interacting proteins and, more importantly, provides candidates for additional studies. We validate the claudin homolog GSG1L as a newly identified binding protein and unique modulator of AMPA-R gating, as determined by detailed molecular, cellular, electrophysiological, and biochemical experiments. GSG1L extends the functional variety of AMPA-R complexes, and further investigation of other candidates may reveal additional complexity of ionotropic glutamate receptor function. PMID- 22813735 TI - The Drosophila female aphrodisiac pheromone activates ppk23(+) sensory neurons to elicit male courtship behavior. AB - Females of many animal species emit chemical signals that attract and arouse males for mating. For example, the major aphrodisiac pheromone of Drosophila melanogaster females, 7,11-heptacosadiene (7,11-HD), is a potent inducer of male specific courtship and copulatory behaviors. Here, we demonstrate that a set of gustatory sensory neurons on the male foreleg, defined by expression of the ppk23 marker, respond to 7,11-HD. Activity of these neurons is required for males to robustly court females or to court males perfumed with 7,11-HD. Artificial activation of these ppk23(+) neurons stimulates male-male courtship even without 7,11-HD perfuming. These data identify the ppk23(+) sensory neurons as the primary targets for female sex pheromones in Drosophila. PMID- 22813736 TI - A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease. AB - Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid beta levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD. PMID- 22813737 TI - A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects. AB - The spinal muscular atrophy (SMA) protein, survival motor neuron (SMN), functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs). SMN has also been implicated in tissue-specific functions; however, it remains unclear which of these is important for the etiology of SMA. Smn null mutants display larval lethality and show significant locomotion defects as well as reductions in minor class spliceosomal snRNAs. Despite these reductions, we found no appreciable defects in the splicing of mRNAs containing minor-class introns. Transgenic expression of low levels of either wild-type or an SMA patient-derived form of SMN rescued the larval lethality and locomotor defects; however, snRNA levels were not restored. Thus, the snRNP biogenesis function of SMN is not a major contributor to the phenotype of Smn null mutants. These findings have major implications for SMA etiology because they show that SMN's role in snRNP biogenesis can be uncoupled from the organismal viability and locomotor defects. PMID- 22813738 TI - Voltage-dependent calcium channels at the plasma membrane, but not vesicular channels, couple exocytosis to endocytosis. AB - Although calcium influx triggers endocytosis at many synapses and non-neuronal secretory cells, the identity of the calcium channel is unclear. The plasma membrane voltage-dependent calcium channel (VDCC) is a candidate, and it was recently proposed that exocytosis transiently inserts vesicular calcium channels at the plasma membrane, thus triggering endocytosis and coupling it to exocytosis, a mechanism suggested to be conserved from sea urchin to human. Here, we report that the vesicular membrane, when inserted into the plasma membrane upon exocytosis, does not generate a calcium current or calcium increase at a mammalian nerve terminal. Instead, VDCCs at the plasma membrane, including the P/Q-type, provide the calcium influx to trigger rapid and slow endocytosis and, thus, couple endocytosis to exocytosis. These findings call for reconsideration of the vesicular calcium channel hypothesis. They are likely to apply to many synapses and non-neuronal cells in which VDCCs control exocytosis, and exocytosis is coupled to endocytosis. PMID- 22813739 TI - The Arabidopsis NPR1 protein is a receptor for the plant defense hormone salicylic acid. AB - Salicylic acid (SA) is an essential hormone in plant immunity, but its receptor has remained elusive for decades. The transcriptional coregulator NPR1 is central to the activation of SA-dependent defense genes, and we previously found that Cys(521) and Cys(529) of Arabidopsis NPR1's transactivation domain are critical for coactivator function. Here, we demonstrate that NPR1 directly binds SA, but not inactive structural analogs, with an affinity similar to that of other hormone-receptor interactions and consistent with in vivo Arabidopsis SA concentrations. Binding of SA occurs through Cys(521/529) via the transition metal copper. Mechanistically, our results suggest that binding of SA causes a conformational change in NPR1 that is accompanied by the release of the C terminal transactivation domain from the N-terminal autoinhibitory BTB/POZ domain. While NPR1 is already known as a link between the SA signaling molecule and defense-gene activation, we now show that NPR1 is the receptor for SA. PMID- 22813740 TI - Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. AB - Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements. PMID- 22813741 TI - Structure of a peptidoglycan amidase effector targeted to Gram-negative bacteria by the type VI secretion system. AB - The target range of a bacterial secretion system can be defined by effector substrate specificity or by the efficacy of effector delivery. Here, we report the crystal structure of Tse1, a type VI secretion (T6S) bacteriolytic amidase effector from Pseudomonas aeruginosa. Consistent with its role as a toxin, Tse1 has a more accessible active site than related housekeeping enzymes. The activity of Tse1 against isolated peptidoglycan shows its capacity to act broadly against Gram-negative bacteria and even certain Gram-positive species. Studies with intact cells indicate that Gram-positive bacteria can remain vulnerable to Tse1 despite cell wall modifications. However, interbacterial competition studies demonstrate that Tse1-dependent lysis is restricted to Gram-negative targets. We propose that the previously observed specificity for T6S against Gram-negative bacteria is a consequence of high local effector concentration achieved by T6S dependent targeting to its site of action rather than inherent effector substrate specificity. PMID- 22813742 TI - Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function. AB - FOXP3 is a key transcription factor for regulatory T cell function. We report the crystal structure of the FOXP3 coiled-coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or posttranslational modifications. Structure-guided mutagenesis revealed that FOXP3 coiled-coil mediated homodimerization is essential for Treg function in vitro and in vivo. In particular, we identified human FOXP3 K250 and K252 as key residues for the conformational change and stability of the FOXP3 dimer, which can be regulated by protein posttranslational modifications such as reversible lysine acetylation. These studies provide structural and mechanistic explanations for certain disease causing mutations in the coiled-coil domain of FOXP3 that are commonly found in IPEX syndrome. Overall, the regulatory machinery involving homooligomerization, acetylation, and heteroassociation has been dissected, defining atomic insights into the biological and pathological characteristics of the FOXP3 complex. PMID- 22813743 TI - Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility. AB - Translational control depends on phosphorylation of eIF2alpha by PKR-like ER kinase (PERK). To examine the role of PERK in cognitive function, we selectively disrupted PERK expression in the adult mouse forebrain. In the prefrontal cortex (PFC) of PERK-deficient mice, eIF2alpha phosphorylation and ATF4 expression were diminished and were associated with enhanced behavioral perseveration, decreased prepulse inhibition, reduced fear extinction, and impaired behavioral flexibility. Treatment with the glycine transporter inhibitor SSR504734 normalized eIF2alpha phosphorylation, ATF4 expression, and behavioral flexibility in PERK-deficient mice. Moreover, the expression levels of PERK and ATF4 were reduced in the frontal cortex of human patients with schizophrenia. Together, our findings reveal that PERK plays a critical role in information processing and cognitive function and that modulation of eIF2alpha phosphorylation and ATF4 expression may represent an effective strategy for treating behavioral inflexibility associated with several neurological disorders such as schizophrenia. PMID- 22813744 TI - The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2beta. AB - Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2beta on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2beta. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2beta in switching PICs from an open to a closed state at start codons. PMID- 22813745 TI - Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. AB - To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease. PMID- 22813747 TI - A developmental requirement for HIRA-dependent H3.3 deposition revealed at gastrulation in Xenopus. AB - Discovering how histone variants that mark distinct chromatin regions affect a developmental program is a major challenge in the epigenetics field. To assess the importance of the H3.3 histone variant and its dedicated histone chaperone HIRA, we used an established developmental model, Xenopus laevis. After the early rapid divisions exploiting a large maternal pool of both replicative H3.2 and replacement H3.3, H3.3 transcripts show a distinct peak of expression at gastrulation. Depletion of both H3.2 and H3.3 leads to an early gastrulation arrest. However, with only H3.3 depletion, defects occur at late gastrulation, impairing further development. Providing exogenous H3.3 mRNAs, but not replicative H3.2 mRNAs, rescues these defects. Notably, downregulation of the H3.3 histone chaperone HIRA similarly impairs late gastrulation, and we find a global defect in H3.3 incorporation into chromatin comparable to H3.3 depletion. We discuss how specific HIRA-dependent H3.3 deposition is required for chromatin dynamics during gastrulation. PMID- 22813746 TI - FoxM1 regulates mammary luminal cell fate. AB - Elevated expression of FoxM1 in breast cancer correlates with an undifferentiated tumor phenotype and a negative clinical outcome. However, a role for FoxM1 in regulating mammary differentiation was not known. Here, we identify another function of FoxM1, the ability to act as a transcriptional repressor, which plays an important role in regulating the differentiation of luminal epithelial progenitors. Regeneration of mammary glands with elevated levels of FoxM1 leads to aberrant ductal morphology and expansion of the luminal progenitor pool. Conversely, knockdown of FoxM1 results in a shift toward the differentiated state. FoxM1 mediates these effects by repressing the key regulator of luminal differentiation, GATA-3. Through association with DNMT3b, FoxM1 promotes methylation of the GATA-3 promoter in an Rb-dependent manner. This study identifies FoxM1 as a critical regulator of mammary differentiation with significant implications for the development of aggressive breast cancers. PMID- 22813748 TI - Highly canalized MinD transfer and MinE sequestration explain the origin of robust MinCDE-protein dynamics. AB - Min-protein oscillations in Escherichia coli are characterized by the remarkable robustness with which spatial patterns dynamically adapt to variations of cell geometry. Moreover, adaption, and therefore proper cell division, is independent of temperature. These observations raise fundamental questions about the mechanisms establishing robust Min oscillations, and about the role of spatial cues, as they are at odds with present models. Here, we introduce a robust model based on experimental data, consistently explaining the mechanisms underlying pole-to-pole, striped, and circular patterns, as well as the observed temperature dependence of the oscillation period. Contrary to prior conjectures, the model predicts that MinD and cardiolipin domains are not colocalized. The transient sequestration of MinE and highly canalized transfer of MinD between polar zones are the key mechanisms underlying oscillations. MinD channeling enhances midcell localization and facilitates stripe formation, revealing the potential optimization process from which robust Min-oscillations originally arose. PMID- 22813749 TI - Genome-wide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length. AB - Through alternative polyadenylation, human mRNAs acquire longer or shorter 3' untranslated regions, the latter typically associated with higher transcript stability and increased protein production. To understand the dynamics of polyadenylation site usage, we performed transcriptome-wide mapping of both binding sites of 3' end processing factors CPSF-160, CPSF-100, CPSF-73, CPSF-30, Fip1, CstF-64, CstF-64tau, CF I(m)25, CF I(m)59, and CF I(m)68 and 3' end processing sites in HEK293 cells. We found that although binding sites of these factors generally cluster around the poly(A) sites most frequently used in cleavage, CstF-64/CstF-64tau and CFI(m) proteins have much higher positional specificity compared to CPSF components. Knockdown of CF I(m)68 induced a systematic use of proximal polyadenylation sites, indicating that changes in relative abundance of a single 3' end processing factor can modulate the length of 3' untranslated regions across the transcriptome and suggesting a mechanism behind the previously observed increase in tumor cell invasiveness upon CF I(m)68 knockdown. PMID- 22813750 TI - Impact of metabolic syndrome independent of insulin resistance on the development of cardiovascular disease. AB - BACKGROUND: It is controversial as to whether metabolic syndrome is a predictor of cardiovascular disease (CVD) independent of insulin resistance (IR). The aim of this study was to determine the independent and combined effects of metabolic syndrome and IR on the incidence of CVD in a prospective cohort study. METHODS AND RESULTS: A total of 6,430 healthy subjects who underwent a health check-up were enrolled. Risk factors for atherosclerotic CVD (ASCVD) including ischemic heart disease (IHD) and stroke were measured. The prevalence of metabolic syndrome and IR were 24.4% and 25.6%, respectively. There were 644 incident cases (9.0%) of ASCVD diagnosed in the cohort. After adjusting for traditional confounders and IR, metabolic syndrome was related to the incidence of CVD. In the multivariate model, the hazard ratios (95% confidence intervals) of metabolic syndrome for IHD, stoke, and ASCVD were 1.66 (1.32-2.09), 1.60 (1.21-2.12), and 1.61 (1.36-1.90), respectively. The risk of IHD, stoke, and ASCVD increased with increasing number of metabolic syndrome components. Furthermore, the risk of CVD was stronger in those who had both metabolic syndrome and IR concurrently. CONCLUSIONS: Metabolic syndrome is related to the incidence of CVD independent of IR. Also, the combined effect of metabolic syndrome and IR contributes to the risk of CVD. PMID- 22813751 TI - Pulmonary vein fibrillation arising from an apicodorsal pulmonary vein. PMID- 22813752 TI - Brewing a perfect blend: the National Heart Association of Malaysia and the Japanese Circulation Society. PMID- 22813753 TI - Acute effect of front crawl sprint resisted swimming on the propulsive forces of the hand. AB - The purpose of the current study was to investigate the acute effect of sprint resisted front crawl swimming on the propulsive forces of the hand. Eight female swimmers swam 25 m with maximal intensity, with and without added resistance. A bowl with a capacity of 2.2, 4 and 6 L was used as low, moderate and high added resistance, respectively. The underwater motion of the swimmer's right hand was recorded using 4 cameras (60 Hz) and the digitization was undertaken using the Ariel Performance Analysis System. Repeated-measures ANOVA revealed that the velocity of the hand, the pitch and the sweepback angles of the hand, as well as the magnitude and the relative contribution of the drag and lift forces were not significantly modified and thus the magnitude of the resultant force did not change. Moreover, the magnitude of the effective force, as well as the angle formed between the resultant force and the axis of the swimming propulsion were not significantly affected. Thus, it could be concluded that resistance added as in this study did not alter the pattern of the propulsive hand forces associated with front crawl sprinting. PMID- 22813755 TI - Aging in the ferromagnetic phase of terbium. AB - We report on aging, rejuvenation and memory effects in the ferromagnetic phase of pure terbium. We have applied an experimental method specifically for investigating slow dynamics of spin glasses, because these effects cannot be interpreted as conventional diffusion after-effects. Results show that relaxation times of the magnetic response are widely distributed, and isothermal aging shifted the distribution towards longer durations. If the sample was heated/cooled after such isothermal aging, the relaxation times shortened as if aging was starting anew; the behavior resembles that in spin glasses. Uniform magnetization experiments indicate that, unlike rejuvenation in spin glasses, ferromagnetic correlations are not returned to disorder by thermal perturbations. In contrast with memory effects in spin glasses, the effects of isothermal aging cannot be recovered once these disappear, even if the system is returned to its initial temperature. The observed results can be explained as collective pinning of the domain walls for which the potential is given by a rugged temperature sensitive energy landscape. PMID- 22813754 TI - Identification of a Nfs1p-bound persulfide intermediate in Fe-S cluster synthesis by intact mitochondria. AB - Cysteine desulfurases generate a covalent persulfide intermediate from cysteine, and this activated form of sulfur is essential for the synthesis of iron-sulfur (Fe-S) clusters. In yeast mitochondria, there is a complete machinery for Fe-S cluster synthesis, including a cysteine desulfurase, Nfs1p. Here we show that following supplementation of isolated mitochondria with [(35)S]cysteine, a radiolabeled persulfide could be detected on Nfs1p. The persulfide persisted under conditions that did not permit Fe-S cluster formation, such as nucleotide and/or iron depletion of mitochondria. By contrast, under permissive conditions, the radiolabeled Nfs1p persulfide was greatly reduced and radiolabeled aconitase was formed, indicating transfer of persulfide to downstream Fe-S cluster recipients. Nfs1p in mitochondria was found to be relatively more resistant to inactivation by N-ethylmaleimide (NEM) as compared with a prokaryotic cysteine desulfurase. Mitochondria treated with NEM (1 mM) formed the persulfide on Nfs1p but failed to generate Fe-S clusters on aconitase, likely due to inactivation of downstream recipient(s) of the Nfs1p persulfide. Thus the Nfs1p-bound persulfide as described here represents a precursor en route to Fe-S cluster synthesis in mitochondria. PMID- 22813756 TI - Environmental analysis of raw cork extraction in cork oak forests in southern Europe (Catalonia--Spain). AB - Cork oak grows endemically in a narrow region bordering the western Mediterranean, and especially in the Iberian Peninsula. The importance of cork agro-forestry systems lies in the fact that a natural and renewable raw material cork - can be extracted sustainably without endangering the tree or affecting biodiversity. This paper describes an environmental analysis of the extraction of raw cork in cork oak forests in Catalonia, using data from five representative local forest exploitations. The evaluation was carried out using life cycle assessment (LCA) methodology, and all the forestry management required to obtain a tonne of raw cork was included. The aim of the study was to evaluate the environmental impacts - in terms of global warming, acidification, eutrophication, human toxicity, and so on - caused by cork extraction and determine the carbon dioxide balance of these forestry systems, with a tree lifespan of about 200 years. During the life cycle extraction of cork in Catalonia, 0.2 kg of CO(2) eq. was emitted per kg of raw cork extracted. Moreover, cork cannot be extracted without the tree, which will be fixing carbon dioxide throughout its technological useful life (200 years), despite the fact that the bark is removed periodically: every 13-14 years. If the emission from extraction and the carbon contained in the material is discounted, the carbon dioxide balance indicates that 18 kg of CO(2) are fixed per kg of raw cork extracted. Therefore, cork is a natural, renewable and local material that can replace other non-renewable materials, at local level, to reduce the environmental impacts of products, and particularly to reduce their carbon footprint. PMID- 22813757 TI - Environmental and economic analysis of application of water hyacinth for eutrophic water treatment coupled with biogas production. AB - The proliferation of water hyacinth is currently controlled by removing it from a water body and disposing it by landfill in China. Using water hyacinth to remove nutrients from water bodies and to produce biogas is another technically feasible option for the control of water hyacinth, but its environmental and economic performances are not well understood. This study collected data from an experimental biogas plant to develop a lifecycle analysis and a cost benefit analysis for the control of water hyacinth proliferation in a eutrophic lake in China. Comparison was made between the alternative option of using water hyacinth for biogas production and the current practice of disposing it in landfills. The results reveal that the biogas option is economically feasible with a positive energy balance. The removal of water hyacinth to produce biogas can contribute to water quality improvement and GHG emission reduction whose values, however, depend on the processing scale of the biogas plant. Since both the current approach and the biogas option can remove nutrients from water bodies, the additional value of water quality improvement resulting from the biogas option is only possible when the processing scale of the biogas plant is greater than the amount of water hyacinth disposed by landfill. The emission of methane deserves attention when water hyacinth is disposed by landfill. The biogas option can respond to China's policies on water pollution control, renewable energy development, and energy saving and emission reduction. PMID- 22813758 TI - Knowledge-driven institutional change: an empirical study on combating desertification in northern China from 1949 to 2004. AB - Understanding institutional changes is crucial for environmental management. Here we investigated how institutional changes influenced the process and result of desertification control in northern China between 1949 and 2004. Our analysis was based on a case study of 21 field sites and a meta-analysis of additional 29 sites reported in the literature. Our results show that imposed knowledge-driven institutional change was often perceived as a more progressive, scientific, and rational type of institutional change by entrepreneurs, scholars, experts, and technicians, while voluntary, knowledge-driven institutional change based on indigenous knowledge and experiences of local populations was discouraged. Our findings also demonstrate that eight working rules of imposed knowledge-driven institutional change can be applied to control desertification effectively. These rules address the issues of perception of potential gains, entrepreneurs' appeals and support, coordination of multiple goals, collaboration among multiple organizations, interest distribution and conflict resolution, incremental institutional change, external intervention, and coordination among the myriad institutions involved. Imposed knowledge-driven institutional change tended to be more successful when these rules were thoroughly implemented. These findings provide an outline for implementing future institutional changes and policy making to combat desertification and other types of ecological and environmental management. PMID- 22813759 TI - Seasonal variation in chemical properties and degradability by anaerobic digestion of landfill leachate at Benowo in Surabaya, Indonesia. AB - Seasonal variations in the physical and chemical characteristics of leachate taken from Benowo landfill in Indonesia, including factors likely to inhibit anaerobic digestion, were investigated to determine the impacts on the stability of anaerobic treatment. To evaluate the biodegradability of the leachate, a continuous experiment was conducted by changing the organic loading rate (OLR). Chemical oxygen demand (COD) ranged between 2621 and 16,832 mg L(-1), and COD in the dry season was twice the level in the rainy season owing to reduced rainwater input and significant evaporation. COD, pH, and the concentrations of ammonium ion, and metals in the leachate were within acceptable ranges for decomposition by anaerobic digestion. However, the Na(+) and Cl(-) in the leachate are high enough to inhibit anaerobic digestion. From chemical investigation of leachate at six monitoring wells in Benowo, food waste accumulation and seawater intrusion might cause high salinity in the leachate. In the continuous experiment, COD removal efficiency was maintained at 40% regardless of OLR, suggesting that at least 40% of the leachate contained biodegradable substances. Based on these results, issues surrounding the biological treatment of saline and refractory substances in landfill leachate were discussed. It is suggested that high salinity and refractory substances in the leachate are common issues during the leachate treatment by anaerobic digestion as the implications for similar landfills in other countries around the world. PMID- 22813760 TI - Enhancements in healthcare information technology systems: customizing vendor supplied clinical decision support for a high-risk patient population. AB - Healthcare organizations continue to adopt information technologies with clinical decision support (CDS) to prevent potential medication-related adverse drug events. End-users who are unfamiliar with certain high-risk patient populations are at an increased risk of unknowingly causing medication errors. The following case describes a heart transplant recipient exposed to supra-therapeutic concentrations of tacrolimus during co-administration of ritonavir as a result of vendor supplied CDS tools that omitted an interaction alert. After review of 4692 potential tacrolimus-based DDIs between 329 different drug pairs supplied by vendor CDS, the severity of 20 DDIs were downgraded and the severity of 62 were upgraded. The need for institution-specific customization of vendor-provided CDS is paramount to ensure avoidance of medication errors. Individualized care will become more important as patient populations and institutions become more specialized. In the future, vendors providing integrated CDS tools must be proactive in developing institution-specific and easily customizable CDS tools. PMID- 22813761 TI - Computerized clinical decision support for medication prescribing and utilization in pediatrics. AB - BACKGROUND AND OBJECTIVE: Accurate and informed prescribing is essential to ensure the safe and effective use of medications in pediatric patients. Computerized clinical decision support (CCDS) functionalities have been embedded into computerized physician order entry systems with the aim of ensuring accurate and informed medication prescribing. Owing to a lack of comprehensive analysis of the existing literature, this review was undertaken to analyze the effect of CCDS implementation on medication prescribing and use in pediatrics. MATERIALS AND METHODS: A literature search was performed using keywords in PubMed to identify research studies with outcomes related to the implementation of medication related CCDS functionalities. RESULTS AND DISCUSSION: Various CCDS functionalities have been implemented in pediatric patients leading to different results. Medication dosing calculators have decreased calculation errors. Alert based CCDS functionalities, such as duplicate therapy and medication allergy checking, may generate excessive alerts. Medication interaction CCDS has been minimally studied in pediatrics. Medication dosing support has decreased adverse drug events, but has also been associated with high override rates. Use of medication order sets have improved guideline adherence. Guideline-based treatment recommendations generated by CCDS functionalities have had variable influence on appropriate medication use, with few studies available demonstrating improved patient outcomes due to CCDS use. CONCLUSION: Although certain medication-related CCDS functionalities have shown benefit in medication prescribing for pediatric patients, others have resulted in high override rates and inconsistent or unknown impact on patient care. Further studies analyzing the effect of individual CCDS functionalities on safe and effective prescribing and medication use are required. PMID- 22813762 TI - Clinical documentation: composition or synthesis? AB - OBJECTIVE: To understand the nature of emerging electronic documentation practices, disconnects between documentation workflows and computing systems designed to support them, and ways to improve the design of electronic documentation systems. MATERIALS AND METHODS: Time-and-motion study of resident physicians' note-writing practices using a commercial electronic health record system that includes an electronic documentation module. The study was conducted in the general medicine unit of a large academic hospital. RESULTS: During the study, 96 note-writing sessions by 11 resident physicians, resulting in close to 100 h of observations were seen. Seven of the 10 most common transitions between activities during note composition were between documenting, and gathering and reviewing patient data, and updating the plan of care. DISCUSSION: The high frequency of transitions seen in the study suggested that clinical documentation is fundamentally a synthesis activity, in which clinicians review available patient data and summarize their impressions and judgments. At the same time, most electronic health record systems are optimized to support documentation as uninterrupted composition. This mismatch leads to fragmentation in clinical work, and results in inefficiencies and workarounds. In contrast, we propose that documentation can be best supported with tools that facilitate data exploration and search for relevant information, selective reading and annotation, and composition of a note as a temporal structure. CONCLUSIONS: Time-and-motion study of clinicians' electronic documentation practices revealed a high level of fragmentation of documentation activities and frequent task transitions. Treating documentation as synthesis rather than composition suggests new possibilities for supporting it more effectively with electronic systems. PMID- 22813776 TI - Seroepidemiology of Strongyloides stercoralis in Dhaka, Bangladesh. AB - Human strongyloidiasis is a neglected tropical disease with global distribution and this infection is caused by the parasitic nematode Strongyloides stercoralis. The aim of this study was to determine the prevalence of strongyloidiasis in Dhaka, Bangladesh. Sera from 1004 residents from a slum (group A) and 299 from city dwellers (group B) were tested for total IgG and IgG subclasses to Strongyloides antigen. There was a significant difference (P < 0.001) in IgG seroprevalence between group A (22%) and group B (5%). Reactive IgG subclasses (IgG1 and IgG4) were also higher in group A (P < 0.05). The seroprevalence of strongyloidiasis in group A increased with age but was unrelated to sex. The presence of reactive IgG to Strongyloides antigen had no correlation with either socio-economic or personal hygiene factors. However, a history of diarrhoea in a family member, in the past 6 months, but not in the respondents was associated with detection of antibodies to S. stercoralis (P < 0.01). None of the sera from either group had an HTLV-I reaction. This study demonstrates that strongyloidiasis is prevalent in Dhaka, especially among slum dwellers, but concurrent infection with HTLV-I was not found. Future epidemiological studies should identify individual risk factors and other communities at risk so that appropriate interventions can be planned. PMID- 22813777 TI - Evidence of a paucity of genes that interact with the mitochondrion on the X in mammals. AB - Mitochondria are essential organelles whose replication, development, and physiology are dependent upon coordinated gene interactions with both the mitochondrial and the nuclear genomes. The evolution of coadapted (CA) nuclear mitochondrial gene combinations would be facilitated if such nuclear genes were located on the X-chromosome instead of on the autosomes because of the increased probability of cotransmission. Here, we test the prediction of the CA hypothesis by investigating the chromosomal distribution of nuclear genes that interact with mitochondria. Using the online genome database BIOMART, we compared the density of genes that have a mitochondrion cellular component annotation across chromosomes in 16 vertebrates. We find a strong and highly significant genomic pattern against the CA hypothesis: nuclear genes interacting with the mitochondrion are significantly underrepresented on the X-chromosome in mammals but not in birds. We interpret our findings in terms of sexual conflict as a mechanism that may generate the observed pattern. Our finding extends single-gene theory for the evolution of sexually antagonistic genes to nuclear-mitochondrial gene combinations. PMID- 22813778 TI - Repeated evolution of identical domain architecture in metazoan netrin domain containing proteins. AB - The majority of proteins in eukaryotes are composed of multiple domains, and the number and order of these domains is an important determinant of protein function. Although multidomain proteins with a particular domain architecture were initially considered to have a common evolutionary origin, recent comparative studies of protein families or whole genomes have reported that a minority of multidomain proteins could have appeared multiple times independently. Here, we test this scenario in detail for the signaling molecules netrin and secreted frizzled-related proteins (sFRPs), two groups of netrin domain-containing proteins with essential roles in animal development. Our primary phylogenetic analyses suggest that the particular domain architectures of each of these proteins were present in the eumetazoan ancestor and evolved a second time independently within the metazoan lineage from laminin and frizzled proteins, respectively. Using an array of phylogenetic methods, statistical tests, and character sorting analyses, we show that the polyphyly of netrin and sFRP is well supported and cannot be explained by classical phylogenetic reconstruction artifacts. Despite their independent origins, the two groups of netrins and of sFRPs have the same protein interaction partners (Deleted in Colorectal Cancer/neogenin and Unc5 for netrins and Wnts for sFRPs) and similar developmental functions. Thus, these cases of convergent evolution emphasize the importance of domain architecture for protein function by uncoupling shared domain architecture from shared evolutionary history. Therefore, we propose the terms merology to describe the repeated evolution of proteins with similar domain architecture and discuss the potential of merologous proteins to help understanding protein evolution. PMID- 22813779 TI - Genes involved in the evolution of herbivory by a leaf-mining, Drosophilid fly. AB - Herbivorous insects are among the most successful radiations of life. However, we know little about the processes underpinning the evolution of herbivory. We examined the evolution of herbivory in the fly, Scaptomyza flava, whose larvae are leaf miners on species of Brassicaceae, including the widely studied reference plant, Arabidopsis thaliana (Arabidopsis). Scaptomyza flava is phylogenetically nested within the paraphyletic genus Drosophila, and the whole genome sequences available for 12 species of Drosophila facilitated phylogenetic analysis and assembly of a transcriptome for S. flava. A time-calibrated phylogeny indicated that leaf mining in Scaptomyza evolved between 6 and 16 million years ago. Feeding assays showed that biosynthesis of glucosinolates, the major class of antiherbivore chemical defense compounds in mustard leaves, was upregulated by S. flava larval feeding. The presence of glucosinolates in wild type (WT) Arabidopsis plants reduced S. flava larval weight gain and increased egg-adult development time relative to flies reared in glucosinolate knockout (GKO) plants. An analysis of gene expression differences in 5-day-old larvae reared on WT versus GKO plants showed a total of 341 transcripts that were differentially regulated by glucosinolate uptake in larval S. flava. Of these, approximately a third corresponded to homologs of Drosophila melanogaster genes associated with starvation, dietary toxin-, heat-, oxidation-, and aging-related stress. The upregulated transcripts exhibited elevated rates of protein evolution compared with unregulated transcripts. The remaining differentially regulated transcripts also contained a higher proportion of novel genes than the unregulated transcripts. Thus, the transition to herbivory in Scaptomyza appears to be coupled with the evolution of novel genes and the co-option of conserved stress-related genes. PMID- 22813781 TI - Association of macrophage migration inhibitory factor and mannose-binding lectin 2 gene polymorphisms in acute rheumatic fever. AB - BACKGROUND: Macrophage migration inhibitory factor and mannose-binding lectin-2 play important roles in the pathogenesis of several acute and chronic inflammatory/autoimmune disorders. The aim of the study was to investigate any possible association between migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms and acute rheumatic fever in children. Material and methods A total of 38 unrelated children with acute rheumatic fever and 40 age- and sex-matched healthy controls were analysed for codon 54 A/B polymorphism in mannose-binding lectin-2 gene and -173 G/C polymorphism in migration inhibitory factor gene by using the polymerase chain reaction method. RESULTS: Frequency of BB genotype of mannose-binding lectin-2 gene was higher in the patient group. Interestingly, children with acute rheumatic fever with AA genotype tended to have chorea compared with children with BB genotype. There was a statistically significant increase in frequency of the migration inhibitory factor -173 CC genotype in patients compared with the control subjects. CONCLUSION: The present study is the first to investigate the mannose-binding lectin-2 gene polymorphism in children with acute rheumatic fever. BB genotype of mannose-binding lectin-2 (codon 54) and CC genotype of migration inhibitory factor (-173) may have a role in the immunoinflammatory process of acute rheumatic fever. PMID- 22813782 TI - Acute toxicity of pinnatoxins E, F and G to mice. AB - The acute toxicities to mice of pinnatoxins E, F and G, members of the cyclic imine group of phycotoxins, by intraperitoneal injection and/or oral administration, have been determined. These substances were all very toxic by intraperitoneal injection, with LD(50) values between 12.7 and 57 MUg/kg. Pinnatoxin E was much less toxic by oral administration than by intraperitoneal injection, but this was not the case for pinnatoxin F. The median lethal doses of the latter substance by gavage and by voluntary intake were only 2 and 4 times higher than that by injection. The high oral toxicity of pinnatoxin F raises concerns as to the possibility of adverse effects of this substance in shellfish consumers, although it should be noted that no toxic effects in humans have been recorded with pinnatoxins or with any other compound of the cyclic imine group. PMID- 22813780 TI - Terbutaline impairs the development of peripheral noradrenergic projections: potential implications for autism spectrum disorders and pharmacotherapy of preterm labor. AB - Terbutaline, a beta2-adrenoceptor agonist, is used off-label for long-term management of preterm labor; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline's effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2-5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic beta2-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17-20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both beta1- and beta2-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline; methoxamine, which stimulates alpha1-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with beta2 adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder. PMID- 22813783 TI - Next-generation low-cost motion capture systems can provide comparable spatial accuracy to high-end systems. AB - The objective quantification of three-dimensional kinematics during different functional and occupational tasks is now more in demand than ever. The introduction of new generation of low-cost passive motion capture systems from a number of manufacturers has made this technology accessible for teaching, clinical practice and in small/medium industry. Despite the attractive nature of these systems, their accuracy remains unproved in independent tests. We assessed static linear accuracy, dynamic linear accuracy and compared gait kinematics from a Vicon MX20 system to a Natural Point OptiTrack system. In all experiments data were sampled simultaneously. We identified both systems perform excellently in linear accuracy tests with absolute errors not exceeding 1%. In gait data there was again strong agreement between the two systems in sagittal and coronal plane kinematics. Transverse plane kinematics differed by up to 3 degrees at the knee and hip, which we attributed to the impact of soft tissue artifact accelerations on the data. We suggest that low-cost systems are comparably accurate to their high-end competitors and offer a platform with accuracy acceptable in research for laboratories with a limited budget. PMID- 22813784 TI - Oculopalpebral dimensions of adult Nigerians: report from the Enugu normative ocular anthropometry study. AB - OBJECTIVE: To determine the normal oculopalpebral anthropometric measurements of a Nigerian adult population. SUBJECTS AND METHODS: A population-based prospective observational random survey was conducted in Enugu, South-Eastern Nigeria between January and April 2010. The participants were healthy adults comprising 248 males and 252 females aged 18-76 years. One thousand eyes were examined. Demographic data, and bilateral direct manual millimetre measurements of the horizontal palpebral fissure (HPF), vertical palpebral fissure (VPF), upper lid crease (ULC), brow height (BH), and margin reflex distance (MRD) were obtained from all participants. Data were categorised by demographic variables and analysed to yield frequencies, percentages and proportions. Between-gender comparisons, using the independent t test, were considered significant at p < 0.05. RESULTS: The mean age of the participants was 36.5 +/- 14.6 years. There was no significant difference between the genders in mean age (men: 37.3 +/- 15.7 vs. women: 35.8 +/ 13.3, p = 0.2302). The mean values of the parameters were (male, female) HPF: 32.8 +/- 2.0 vs. 32.6 +/- 3.0; VPF: 10.6 +/- 1.2 vs. 10.6 +/- 1.2; ULC: 8.2 +/- 2.5 vs. 7.9 +/- 2.2; BH: 13.1 +/- 2.4 vs. 13.6 +/- 2.7; and MRD: 4.1 +/- 0.5 vs. 4.2 +/- 0.8. Significant between-gender difference was observed only in BH measurements (p = 0.029) and variable trends with age. CONCLUSION: Oculopalpebral measurements of normal adult Nigerians in Enugu showed variations by age and gender. This may have implications for clinical evaluation and surgical management of oculopalpebral disorders in adult South-Eastern Nigerians. Future longitudinal studies are needed. PMID- 22813785 TI - Right- and left-subclavian vein port-a-cath systems: comparison of complications. AB - BACKGROUND: Central venous access systems are frequently used for delivery of medications; however, few studies have compared surgical and postoperative complications of right versus left access via the subclavian vein (SCV). The aim of this study was to compare the surgical and postoperative complications associated with Port-A-Cath system insertion via the right and left SCV. METHODS: The medical records of patients who received Port-A-Cath insertion via the SCV for parenteral chemotherapy between August 2004 and July 2008 were reviewed. The incidence of surgical and postoperative complications was compared between patients who received right- versus left-SCV Port-A-Cath insertion. RESULTS: A total of 1,848 patients were included in the study. Right-SCV catheterization was attempted in 1,029 (55.7%) patients and was successful in 866 (84.2%). Left-SCV catheterization was attempted in 819 (44.3%) patients and was successful in 651 (79.5%). The mean length of postoperative follow-up was 417.3 +/- 401.3 and 396.7 +/- 379.9 days for the right- and left-SCV groups, respectively. The incidence of SCV puncture failure was significantly lower in the right-SCV group (12.3%) compared with the left-SCV group (16.8%, p = 0.006). The incidence of catheter knotting at the ipsilateral brachiocephalic vein was also significantly lower in the right-SCV group (0.0%) compared with the left-SCV group (0.5%, p = 0.038), as was the incidence of catheter occlusion (1.0% for right SCV vs. 3.5% for left SCV, p = 0.001). CONCLUSION: These findings suggest that the right-SCV approach is superior to the left-SCV approach for Port-A-Cath insertion. PMID- 22813786 TI - The association of red cell distribution width with glycated hemoglobin among healthy adults without diabetes mellitus. AB - BACKGROUND: Red cell distribution width (RDW) and hemoglobin A1c (HbA1c) are both known to be predictive of future cardiovascular disease (CVD). OBJECTIVE: We hypothesized that RDW would be associated with HbA1c in adults without diabetes independent of fasting blood glucose (FBG). METHODS: This cross-sectional study included 15,343 nondiabetic adults, free of CVD, enrolled in NHANES 1999-2008. Adjusted means of RDW were calculated across HbA1c categories for the overall population. Multivariable regression analyses were performed analyzing the association between RDW and HbA1c for individuals with available data on FBG (n = 7,454). RESULTS: RDW significantly correlated with HbA1c (r = 0.27, p < 0.001; n = 15,343), with a gradual increase in adjusted mean RDW across HbA1c categories (12.59% +/- 0.02% in the group with HbA1c <=4.8% vs. 12.92% +/- 0.02% in the group with HbA1c >5.8%, p < 0.001 for trend). In regression analyses, RDW independently predicted HbA1c (beta-coefficient 0.034, 95% CI 0.026-0.042, p < 0.001). CONCLUSION: RDW significantly predicts HbA1c independent of FBG in healthy nondiabetic adults, suggesting the possibility of chronic hyperglycemia mediating the association between RDW and CVD. PMID- 22813787 TI - Intrathoracic impedance monitoring in patients with heart failure: correlation with dehydration and bleeding events. AB - BACKGROUND: Cardiac resynchronization therapy/defibrillators (CRTD) and implantable cardioverter defibrillators (ICD) with continuous intrathoracic impedance monitoring might provide an early warning of thoracic fluid retention. In contrast, volume loss events such as dehydration and bleeding are also common events in heart failure patients treated with diuretics and anticoagulants. The correlation between intrathoracic impedance and a volume loss event is not known. METHODS AND RESULTS: This study evaluated the association between intrathoracic impedance and volume loss events in 36 patients with chronic heart failure (New York Heart Association [NYHA] II, III and IV) who had received CRTD/ICD implantation. Elevation of thoracic impedance above the reference line was defined as a positive deviation of thoracic impedance (PDI). This study recorded 249 PDIs including 60 spike PDIs defined as over 5 ohms elevation from the reference line and 17 large PDIs as over 5 ohms elevation and continuing for at least 4 days. Clinically, 96 dehydration events and 2 bleeding events were observed over a 1-year period. The sensitivity and positive predictive value (PPV) for spike PDI was 31.6% and 51.7%, respectively, while those for large PDI were 17.3% and 100%, respectively. CONCLUSIONS: A large PDI reflected dehydration and bleeding events with a high PPV in severe heart failure patients. The large PDI criteria might therefore be useful for predicting volume loss events in chronic heart failure patients. PMID- 22813788 TI - Relationship between atrial fibrillation and sleep-disordered breathing. PMID- 22813789 TI - Impact of infantile short bowel syndrome on long-term health-related quality of life: a cross-sectional study. AB - BACKGROUND/PURPOSE: Studies on the long-term effects of short bowel syndrome (SBS) on the quality of life are scarce. Therefore, we determined health-related quality of life (HRQoL) in children and adolescents with a history of infantile SBS compared with that of same-aged controls drawn from the general population. METHODS: Cross-sectional assessment (2005-2007) of HRQoL in children with a history of infantile SBS treated in their first year of life, born between 1987 and 2002, using generic HRQoL measures was performed. Children aged 5 to 18 years and their parents filled out the Pediatric Quality of Life Inventory. Differences in scores between subjects and controls were analyzed using independent sample t tests. RESULTS: Thirty-one children with a history of SBS (19 girls and 12 boys; mean age, 11.8 +/- 4.2 years) participated, giving an overall response rate of 70%. The children and their parents reported significantly lower HRQoL than 275 healthy age-matched children and their parents (P < .05). CONCLUSIONS: Children with a history of infantile SBS have a lower HRQoL than healthy age-matched controls. This difference lasts beyond childhood and way beyond the period of intestinal rehabilitation early in life. These findings highlight the need for targeted interventions to address these dimensions of impaired HRQoL. PMID- 22813790 TI - Long-term disease-specific quality of life in children and adolescent patients with ARM. AB - BACKGROUND: The main aim of the present study was to investigate how fecal incontinence might influence different aspects of quality of life (QOL) in children and adolescents with anorectal malformations (ARMs). We considered both the influence of fecal incontinence at time 1 of the study and the influence of fecal incontinence at time 2 (4 years later) on QOL measured at time 2. METHODS: A total of 175 parents from the Italian Parents' and Patients' Association for Anorectal Malformations completed a questionnaire about fecal incontinence in their children at time 1 of the study. Four years later, 97 of these parents completed the Hirschsprung Disease/Anorectal Malformation Quality of Life questionnaire. Patient ages ranged from 4 to 17 years. Quality of life areas from the Hirschsprung Disease/Anorectal Malformation Quality of Life questionnaire were considered as outcome variables in a hierarchical regression analyses where fecal incontinence at time 1 and at time 2 served as predictors. RESULTS: The principal findings indicated that fecal incontinence at time 2 significantly predicted constipating diet, presence of diarrhea, urinary continence, social functioning, emotional functioning, body image, and physical symptoms, also when severity of the malformation was taken into account. CONCLUSIONS: It is extremely important that pediatric surgeons continue to promote effective bowel management programs and that they work with other specialists and support associations to offer emotional and psychological support to patients with ARM and their families. PMID- 22813791 TI - Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1. AB - BACKGROUND/PURPOSE: Increased glycolysis is among the biochemical characteristics of cancerous tissue. The glucose transporter isoform 1 (GLUT1) gene encodes a key factor for glucose transport into cancerous tissue. However, the expression and functional significance of GLUT1 in neuroblastoma have not been fully characterized. Therefore, we investigated the association of GLUT1 expression with clinical outcomes in patients with neuroblastoma using immunohistochemical staining for GLUT1 in neuroblastoma tissues. We also assessed the efficacy of glycolysis inhibition as an anticancer treatment in neuroblastoma cell lines with altered expression of GLUT1. METHODS: We obtained total RNA from cancerous tissue by microdissection in 47 patients with neuroblastoma. GLUT1 expression levels were evaluated by quantitative real-time polymerase chain reaction. We analyzed the association of GLUT1 expression levels with clinical outcomes. We also examined changes in GLUT1 expression and proliferative responses in vitro using 4 neuroblastoma cell lines treated with a glycolysis inhibitor, 3-Bromopyruvate acid. RESULTS: Elevated GLUT1 expression was associated with poor prognosis. Moreover, elevated GLUT1 expression independently predicted overall survival. Immunohistochemical analysis showed that GLUT1 expression tended to be localized to the centers of neuroblastoma cell nests. Our in vitro studies showed that 3 Bromopyruvate acid significantly suppressed the proliferation of neuroblastoma cells with high GLUT1 gene expression compared with those with low expression. CONCLUSION: Glycolysis inhibitors are a potential therapeutic option for treating aggressive tumors expressing GLUT1. PMID- 22813792 TI - Changing treatment and outcome of children with hepatoblastoma: analysis of a single center experience over the last 20 years. AB - BACKGROUND/PURPOSE: The aim of the study was to analyze changing management and survival of children with hepatoblastoma (HBL) treated in one center. MATERIALS AND METHODS: Over the last 20 years, 51 children with HBL were treated. Surgery was performed in 48 children (94.1%), conventional liver resection in 38 (of those, 2 received a rescue liver transplantation [LTx] for relapse), and total hepatectomy and primary LTx in 10 patients. The remaining 3 patients received only palliative treatment. Patient data were analyzed for survival with respect to PRETreatment EXTent of disease (PRETEXT), metastases, histopathology, conventional resection, and LTx. RESULTS: Survival of children with HBL treated with liver resection is 71% and 80% for primary LTx. Favorable prognostic factors for patient survival was tumor histology as epithelial-fetal subtype and mixed epithelial and mesenchymal type, without teratoid features, and good response to chemotherapy (necrosis, fibrosis). Unfavorable prognostic factors were small cells undifferentiated, transitional liver cell tumor, alpha-fetoprotein level above 1,000,000 IU/mL and below 100 IU/mL at diagnosis, lung metastases, and local recurrence after initial resection. Survival was related to PRETEXT stage. However, among patients with PRETEXT III and IV, LTx resulted in better survival. CONCLUSION: Liver transplantation is a good option for children with advanced HBL. Early referral of children with potentially unresectable tumors to centers where combined treatment (chemotherapy, surgery including LTx) is available is crucial. PMID- 22813793 TI - Transumbilical 1-port laparoscopic resection of benign ovarian tumor. AB - BACKGROUND/PURPOSE: We evaluated the effectiveness of transumbilical 1-port laparoscopic resection of benign ovarian tumors in children with limited working space. METHODS: This study involved 15 children and adolescents with benign ovarian tumors treated from January 2006 to December 2010. Preoperative evaluation included physical findings, tumor markers, and imaging studies. A single surgeon performed the procedure using a 10-mm 0 degrees operative laparoscope with a 5-mm working channel. The fallopian tube was suspended with transabdominal suspensory sutures passing through the mesosalpinx to expose the tumor and remove it after aspiration of the contents. The tumor was contained in the endobag and chopped into pieces before removal through the small umbilical wound. RESULTS: The patients' age ranged from 2 to 17 years (mean, 9.7 years). Tumor size ranged from 3.6 to 23 cm. Tumor markers including alpha-fetoprotein, beta-human chorionic gonadotropin, cancer antigen 125, and carcinoembryonic antigen were negative. The average operating time was 134 minutes. Except for 1 patient with associated encephalomyelitis, all patients were discharged within 3 days after surgery. Pathologic examination and follow-up studies revealed benign tumors, with no residual lesions in the abdomen or recurrence. CONCLUSIONS: Transumbilical 1-port laparoscopic resection is effective for resection of benign ovarian tumors in children, with a satisfactory cosmetic outcome. However, to prevent inadequate resection of a potential malignant lesion, thorough preoperative evaluation with physical signs, tumor markers, and imaging studies, as well as flexible intraoperative tactics, should be adopted. PMID- 22813794 TI - Median sternotomy for bilateral pulmonary metastasectomy in children. AB - BACKGROUND: Complete resection of metastatic pulmonary nodules in some children may increase survival. We present a series of 16 children who underwent median sternotomy for bilateral pulmonary metastasectomy from January 1, 1999, to December 31, 2010. METHODS: We reviewed the records of 16 children (3-18 years old, 12 boys, 4 girls) with bilateral pulmonary metastases who underwent median sternotomy with the intent of curative resection. All were treated with alternating single-lung ventilation and careful bilateral manual palpation for nodules. RESULTS: The mean number of lesions resected was 11.6 (range, 2-33). Two patients who were found to have lesions that were too numerous to count underwent biopsy only. There were no major complications, and median length of hospital stay was 4 days. One patient had postoperative atelectasis, and another had an air leak; both were discharged on the fifth postoperative day. Seven patients have since died, 2 of whom underwent further resection for recurrent disease, with a median survival of 30 months. Nine patients are currently alive with a median follow-up of 30 months, 2 of whom have recurrent disease. CONCLUSIONS: Median sternotomy allows excellent exposure of both lungs. In our series, there were no lesions that could not be resected because of inadequate exposure, including several in the left lower lobe posteriorly, and most patients were discharged within 4 days without major complications. In children with metastatic lung disease, median sternotomy is safe and avoids treatment delay and a second operation. PMID- 22813795 TI - Video-assisted thoracic surgery resection for pediatric mediastinal neurogenic tumors. AB - BACKGROUND/PURPOSE: Video-assisted thoracoscopic surgery (VATS) resection of mediastinal neurogenic tumors is still controversial in children. The aim of this study was to review the cases of VATS resection of such tumors in children from 3 institutions located in different countries. METHODS: This retrospective study included 17 children treated between July 1995 and February 2011. Medical charts were reviewed for collection of data on age, sex, histologic type of tumor, clinical manifestations, age and weight at surgery, tumor size, duration of thoracic drainage, surgical complications, tumor recurrence, and mortality. RESULTS: Thirteen (76.5%) males and 4 (23.5%) females were studied. Median age was 16 months (range, 10.6-60 months), and median weight was 11.9 kg (range, 9.3 27.4 kg). Ten children had neuroblastoma (58.8%), 4 had ganglioneuroma (23.5%), and 3 had ganglioneuroblastoma (17.7%). The median duration of the operation was 90 minutes (range, 45-180 minutes), with complete thoracoscopic resection in all cases. Two children (11.8%) developed Horner syndrome postoperatively. No deaths were reported, and no recurrence was noted during a median follow-up period of 16 months (range, 8.9-28.6 months). CONCLUSIONS: Video-assisted thoracoscopic surgery resection of mediastinal neurogenic tumors in children produced good results, with no recurrence and minimal postoperative complications. The major advantages of this approach are the avoidance of thoracotomy complications and the enhanced surgical accuracy provided by improved visualization. PMID- 22813796 TI - Prevention of postpneumonectomy syndrome in children with prophylactic tissue expander insertion. AB - INTRODUCTION: Postpneumonectomy syndrome (PPS) is an often life-threatening complication of pneumonectomy that occurs in up to 15% of children. This occurrence is higher than in adults, presumably because of more elastic tissues in younger patients. METHODS: We present a case series of 4 pediatric patients at Memorial Sloan Kettering Cancer Center, in whom prophylactic tissue expanders were inserted immediately after pneumonectomy. RESULTS: Insertion of the tissue expander and prevention of PPS was successful in all patients. The presence of the tissue expander did not result in infection in any patient. Our only complication was rupture of the tissue expander in 1 patient, but by the time of removal, a capsule had already formed within the lung and replacement was unnecessary. CONCLUSION: This case series, although limited in number and follow up, presents evidence that prophylactic tissue expander insertion appears to be a safe option for children requiring pneumonectomy. Its insertion at the time of pneumonectomy may prevent the devastating complications of PPS. Because it may result in a higher total number of procedures, the benefits must be weighed against the risks of insertion and decisions made for individual patients on a case-by-case basis. PMID- 22813797 TI - Surgical management of bronchopleural fistula in pediatric empyema and necrotizing pneumonia: efficacy of the serratus anterior muscle digitation flap. AB - PURPOSE: Surgical management of bronchopleural (B-P) fistula associated with thoracic empyema and necrotizing pneumonia is challenging. We evaluated the treatment and outcome of early surgical intervention with limited decortication and insertion of a serratus anterior muscle digitation flap. METHODS: A retrospective review during a 10-year period of children with empyema and B-P fistula secondary to necrotizing pneumonia was performed. During this period, 335 children with empyema were admitted, of which 20 developed a B-P fistula. All underwent a thoracotomy with insertion of a serratus anterior muscle digitation flap. RESULTS: Prethoracotomy chest computed tomographic scan was performed to define the pathologic characteristic. Streptococcus pneumoniae was identified by pus culture (n = 6) and by polymerase chain reaction (n = 4). The median postoperative time with pyrexia after surgical intervention was 2 days (range, 1 3 days). The median period of thoracostomy drain was 7 days (range, 5-15 days). Length of hospital stay was 21 days (range, 7-43 days). This parenchyma preserving technique was able to control the B-P fistula successfully in all cases. No reintervention was necessary in any case. Respiratory symptoms and radiology improved in all children on follow-up, except for 3 who required oral antibiotics for subsequent chest infections. CONCLUSION: Early surgical intervention with insertion of a serratus anterior muscle digitation flap is effective and safe and avoids morbidity associated with conservative management and necrotic lung resection surgery. PMID- 22813798 TI - Subspecialization may improve an esophageal atresia service but has not addressed declining trainee experience. AB - BACKGROUND: Subspecialization defined pediatric surgery using Alder Hey innovations in neonatal surgical units (Rickham) and anesthesia (Jackson-Rees). In neonatal surgery, United Kingdom subspecialization for cloacal extrophy and biliary atresia acknowledges their dependence on multidisciplinary management and the desirability of caseload for training. We phased in regional subspecialization for esophageal atresia (EA) repair and replacement surgery while trainee numbers increased nationally to reduce hours. We examined EA outcomes and training during subspecialization. METHODS: We analyzed EA cases (1999-2009) treated at Alder Hey Children's Hospital in two 5-year cohorts, the first early phase of incomplete subspecialization and the later near-total or "comprehensive" subspecialization phase. These periods approximated those before and after trainee numbers rose sharply to reduce working hours. RESULTS: Of 119 cases, 60 in the early cohort shared similar characteristics with the 59 in the later cohort. Near-complete subspecialization was achieved in the second 5 years with 97% of cases performed under a surgeon with an EA specialty interest; in the earlier cohort, 25% of surgeries were undertaken by surgeons without EA subspecialty interest. With near-complete subspecialization, pediatric intensive care unit stay fell from 5 (4-11) to 4 (2-7) days (median (IQR); P = .005), and approaches such as the Bianchi axillary repair and Bax single-stage jejunal interposition were introduced; hospital stay went from 25 (12-63) to 17 (13-28) days (P = .27), and deaths, from 6 to 3 children (P = .49). Mortality was 7.6% (9/119) compared with 14% (19/134) in our previous institutional series (chi(2) = 2.8, P = .09), and neonatal mortality fell from 6% to 0 (P = .008). Near doubling of trainee numbers accompanied an approximately 3-fold fall in repairs per trainee over the study. CONCLUSION: Near-complete subspecialization for EA coincided with reduced pediatric intensive care unit stay, successful introduction of cosmetic axillary approaches, and extension of our replacement service to offer all interposition types. It has not reversed the steep decline in trainee experience of EA that has been associated with the greater numbers of trainees that have been employed to reduce working hours. PMID- 22813799 TI - Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb-/- mouse embryos occurs in the absence of an endodermal plug. AB - PURPOSE: Duodenal atresia in humans has been hypothesized to arise from a failure of the duodenal lumen to recanalize after formation of an endodermal plug. Recently, mutations in the fibroblast growth factor receptor 2 gene (Fgfr2IIIb) have been shown to cause atretic defects of the duodenum in mice. However, work in rats suggests that murine species do not form an endodermal plug during normal duodenal development. These lines of data led us to hypothesize that mice are able to form a duodenal atresia in the absence of an endodermal plug. To test this hypothesis, we examined duodenal development in wild-type and Fgfr2IIIb-/- embryos. METHODS: Paraffin sections were generated for H&E, E-cadherin, or terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling staining from Fgfr2IIIb-/- and wild-type embryos between embryonic days (E) 10.5 and E14.5. Sections were photographed and reconstructed into 3-dimensional display using Adobe Photoshop and Amira Visage software. RESULTS: Normal mouse duodenum does not form an endodermal plug, although a plug does form in the pyloric region of the stomach at E14.5. Fgfr2IIIb-/- embryos experience significant apoptosis in the duodenal region at E10.5, followed by the disappearance of the endoderm in the atretic precursor by E11.5. Thereafter, the mesoderm of the atretic precursor involutes over the next 2 days in the absence of further apoptosis. Interestingly, an endodermal plug was not observed at any point during the formation of a duodenal atresia. CONCLUSIONS: These results suggest that duodenal atresia in the Fgfr2IIIb-/- model does not arise from persistence of an epithelial plug. Rather it appears to result from the loss of the endoderm because of apoptosis very early in development. PMID- 22813800 TI - The role of tissue plasminogen activator in the management of complex intra abdominal abscesses in children. AB - OBJECTIVE: The objective of this study is to assess the safety of fibrinolytic therapy using tissue plasminogen activator (tPA) in children with complex intra abdominal abscesses. SUMMARY BACKGROUND DATA: Intra-abdominal abscesses are common in children. Antibiotics and percutaneous drainage are the mainstays of treatment, but drainage may be less effective when the fluid is thick or septated. Fibrinolytic therapy using tPA is effective in a rat model of intra abdominal abscesses, has recently been reported for the treatment of intra abdominal abscesses in adults, and is commonly used in the treatment of empyema in children. METHODS: This is a retrospective review of all patients over a 10 year period who had intra-abdominal collections managed with tPA abscess drainage. RESULTS: Sixty-four children had a total of 66 drains placed and 92 doses of tPA. Appendicitis was the cause of the abscesses in 52 of 64 children. Mean length of stay pre-tPA was 11.7 +/- 7.63 days, mean time from drain insertion to tPA was 4.3 +/- 3.78 days, and mean time from tPA to discharge was 8.6 +/- 8.85 days. Thirty patients underwent an operation before tPA administration. No patients experienced bleeding complications, anastomotic or appendiceal stump leak, or wound dehiscence after the administration of tPA, and no patients had abnormalities in coagulation studies related to tPA administration. One child died of sepsis. CONCLUSIONS: Tissue plasminogen activator is safe for the management of thick or septated intra-abdominal abscesses in children. A prospective controlled study will be needed to evaluate the efficacy of this technique. PMID- 22813801 TI - Clostridium difficile infection in the pediatric surgery population. AB - PURPOSE: The incidence of Clostridium difficile-associated disease (CDAD) in the adult population doubled in the past decade, with increasing morbidity and mortality; however, little research has been performed in the pediatric population. We characterized C difficile infection in the pediatric population, with emphasis on the surgical population. METHODS: At a university-based children's hospital, we reviewed 231 patient (birth to 18 years of age) records containing a diagnosis of CDAD between January 1, 2002, and December 31, 2008. RESULTS: Clostridium difficile-associated disease incidence increased from 250 per 100,000 hospitalizations in 2002 to 580 per 100,000 hospitalizations in 2008. No fatalities or surgical interventions were attributable to CDAD. Eighty-seven percent of patients received antibiotics within 2 months of diagnosis. Fifty-two percent of patients underwent operative intervention within 2 months of diagnosis; of these, 89% percent received previous antibiotic therapy and 57% were immunosuppressed. The most common antecedent procedures were bone marrow biopsy and line placement for myelodysplastic diseases (40%), followed by renal transplant (11%). CONCLUSIONS: Pediatric CDAD incidence doubled during the study period but was not associated with death or operative intervention. A substantial number of CDAD cases were associated with previous operative procedures, particularly in immunosuppressed patients and those who received prior antibiotics. PMID- 22813802 TI - Heterotopic renal transplantation in piglets using vascular closure stapler metallic clips or conventional suturing techniques: comparison of vessel growth and macroscopical study. AB - BACKGROUND/PURPOSE: Our aim was to perform a macroscopic and imaging (ultrasonographic and angiographic) evaluation of vascular closure stapler (VCS) metallic clips for renal transplantation in growing piglets to assess their role for transplantation surgery in young children. If these techniques are to be useful, it is necessary to prove that their use avoids one of the main pitfalls of conventional sutures in this setting, namely lack of growth in the suture line. METHODS: Twenty-four piglets were used for this study. Animals were subjected to a heterotopic renal autotransplantation when they were 45 days old. The right kidney was moved from its normal location to the cranial area of the iliac fossa. The end-to-side anastomoses between the renal artery and vein and the aorta and vena cava, respectively, were performed using VCS metallic clips in 6 animals. Continuous polypropylene suturing was used in another 6 piglets, and continuous polyglycolic acid suture was used in 6 additional piglets. A control group of 6 animals without renal autotransplantation was also included in the study. All animals were allowed to grow for 6 months, during which time serial angiographic and ultrasonographic studies were carried out to assess the existence of vascular flow disturbances or stenosis. Similarly, angiographic measurements were obtained to document growth at the anastomotic site. Longitudinal growth was evaluated postmortem after the 6-month growing period. RESULTS: Angiography showed significant (P < .001) transverse growth in both arteries and veins belonging to the VCS clips, running absorbable suture, or control groups. No significant difference was observed among the 3 groups. Vascular growth in the running nonabsorbable suture (polypropylene) group, however, was significantly less than in the other 3 groups and did not significantly differ from baseline. Baseline luminal diameters at the anastomotic site as measured by angiography in the VCS group were 3.64 +/- 0.40 mm in the artery and 5.30 +/- 1.43 mm in the vein. After growth, these values increased to 6.87 +/- 0.90 mm and 11.27 +/- 2.53 mm, respectively. Significant longitudinal growth was evidenced macroscopically after 6 months in both aorta and vena cava in all groups. On the other hand, significant longitudinal growth in the renal artery and vein were only observed in the control, VCS, and absorbable suture groups. CONCLUSIONS: In this experimental setting, satisfactory macroscopic and angiographic vascular growth results were obtained using the VCS clips, suggesting that this suture could be the technique of choice in pediatric transplantation surgery. PMID- 22813803 TI - Bile duct anastomotic stricture after pediatric living donor liver transplantation. AB - BACKGROUND/PURPOSE: Hepaticojejunostomy is a well-accepted method, whereas duct to-duct anastomosis is gaining popularity for bile duct reconstruction in pediatric living donor liver transplantation (LDLT). Biliary complications, especially biliary anastomotic stricture (BAS), are not clearly defined. The aim of the present study is to determine the rate of BAS and its associated risk factors. METHODS: The study included 78 pediatric patients (<18 years old) who underwent LDLT during the period from end of September 1993 to end of November 2010. The diagnosis of BAS was based on clinical, biochemical, histologic, and radiologic results. RESULTS: All patients received left-side grafts. Thirteen patients (16.7%) developed BAS after LDLT. Among them, 3 patients (23.1%) had duct-to-duct anastomosis during LDLT. The median follow-up period for the BAS group and the non-BAS group was 57.8 and 79.5 months, respectively (P = .683). Ten of the patients with BAS required percutaneous transhepatic biliary drainage with or without dilatation for treating the stricture. Multivariable analysis showed that hepatic artery thrombosis and duct-to-duct anastomosis were 2 risk factors associated with BAS. CONCLUSION: In pediatric LDLT, hepaticojejunostomy is the preferred method for bile duct reconstruction, but more large-scale research needs to be done to reconfirm this result. PMID- 22813804 TI - Does obesity impact the pattern and outcome of trauma in children? AB - PURPOSE/BACKGROUND: Childhood obesity is pandemic condition. The effect of obesity on trauma outcomes in children has been relatively understudied. We conducted this study to ascertain the effects of obesity on the hospital outcome of injured children. METHODS: A retrospective cohort study of patients aged 2 to 18 years admitted to the King Abdul Aziz Medical City between May 2001 and May 2009 was conducted. Patients were categorized as lean (body mass index <95th percentile) and obese (body mass index >= 95th percentile). Groups were compared regarding admission demographics, mechanism of injury, pattern of injury, length of stay, intensive care unit admission, ventilation duration, types of procedures performed, injury severity score, and mortality. RESULT: Nine hundred thirty three patients were included, of those 55 (5.89%) children were obese. The obese children were older than nonobese (P = .001) and had a higher injury severity score (P = .001) and a lower pediatric trauma score (P = .00), heart rate (P = .0081), and respiratory rate (P = .000). There were no differences between groups with regard to sex, mechanism of injury, and surgical procedures. Obese children were more likely to have rib fractures (P = .02) and pelvic injuries (P = .033). There was no significant association between mortality and obesity (P = .42). CONCLUSION: Obesity does not seem to impact the severity of injury, mortality rate, types of injury, and procedure outcomes in children. Obese patients are more likely to have rib and pelvic injuries. PMID- 22813805 TI - Traumatic abdominal wall hernias: an emerging trend in handlebar injuries. AB - Handlebar injuries are well described in pediatric patients and are frequently associated with internal injuries, including the "classic" duodenal hematoma and solid organ injuries. Before this report, traumatic handlebar hernias were considered rare. They occur when the end of the handlebar (often bare or lacking protective equipment) applies a significant force to a focal area of the abdomen leading to a disruption in the underlying muscle fibers and fascia while sparing the overlying skin. Such nonpenetrating injuries may present with subtle clinical signs and should always be considered in the differential diagnosis. Imaging, with the use of computed tomographic scan or ultrasound will confirm the diagnosis as well as identify any associated injuries. The management plan usually requires surgical exploration and repair of the defect. The prognosis is favorable presuming that there is no significant underlying injury. In this report, we present a series of 5 patients with traumatic handlebar hernia-the most frequently-occurring injury in our series-and review concurrent associated injuries. PMID- 22813806 TI - How common is colonic elongation in children with slow-transit constipation or anorectal retention? AB - PURPOSE: Colonic elongation is reported as a possible cause for slow colonic transit, as it is observed in patients with slow-transit constipation (STC). This study aimed to determine the frequency of colonic elongation in children with STC or anorectal retention using radioimaging. We hypothesized that transverse colon elongation may occur in patients with STC, whereas sigmoid colon elongates in patients with anorectal retention. METHODS: Nuclear transit scintigraphy performed for chronic constipation (1999-2011) was analyzed qualitatively for elongated transverse colon or sigmoid colon. Three major colonic transit patterns were identified: slow transit in the proximal colon (STC), normal proximal colonic transit with anorectal retention (NT-AR), and rapid proximal transit +/- anorectal retention (RT). chi(2) Test was used for statistical analysis (P < .05 significant). RESULTS: From 1999 to 2011, 626 children had nuclear transit scintigraphy. Transverse colon elongation occurred more frequently in STC (73/322, or 23%) compared with NT-AR (9/127, or 7%) and RT (5/177, or 3%; P < .0001). Sigmoid colon elongation was equally common in NT-AR (8/127, or 6%) compared with RT (10/177, or 6%) and STC (14/322, or 4%; P < .9). CONCLUSION: Transverse colon elongation is more common in STC (23%), whereas sigmoid colon elongation is not more common in anorectal retention. Colonic elongation may be the cause or the result of the underlying slow colonic transit. PMID- 22813807 TI - The impact of transcutaneous electrical stimulation therapy on appendicostomy operation rates for children with chronic constipation--a single-institution experience. AB - PURPOSE: Appendicostomy for antegrade continence enema is a minimally invasive surgical intervention that has helped many children with chronic constipation. At our institution, since 2006, transcutaneous electrical stimulation (TES) has been trialed to treat slow-transit constipation (STC) in children. This retrospective audit aimed to determine if TES use affected appendicostomy-formation rates and to monitor changes in practice. We hypothesized that appendicostomy rates have decreased for STC but not for other indications. METHODS: Appendicostomy formation rate was determined for the 5 years before and after 2006. Children were identified as STC or non-STC from nuclear transit scintigraphy and patient records. RESULTS: Since 1999, 317 children were diagnosed with STC using nuclear transit scintigraphy with 121 during 2001 to 2005 (24.2/year) and 147 during 2006 to 2010 (29.4/year). Seventy-four children had appendicostomy formation. For 2001 to 2005, appendicostomy-formation rates for STC and non-STC children were similar: 5.4 per year (n = 27) and 4.8 per year (n = 24), respectively. For 2006 to 2010, appendicostomy-formation rates were 1.2 per year (n = 6) for STC and 3.2 per year (n = 16) for non-STC (chi(2), P = .04). CONCLUSION: Since 2006, appendicostomy-formation rates have significantly reduced in STC but not in non STC children at our institute, coinciding with the introduction of TES as an alternative treatment for STC. Transcutaneous electrical stimulation has not been tested on non-STC children in this period. PMID- 22813808 TI - Beneficial effects of (-)-epigallocatechin gallate on ischemia-reperfusion testicular injury in rats. AB - BACKGROUND/PURPOSE: The purpose of the study was to determine the effect of (-) epigallocatechin gallate (EGCG) on testicular ischemia-reperfusion injury in rats. METHODS: Forty male Wistar rats were assigned to 5 groups. A sham operation was performed on the animals in group 1. In group 2, after 4 hours of unilateral testicular ischemia, 4 hours of testicular reperfusion was performed with EGCG administered 1 hour before reperfusion. In group 3, the same surgical procedure as in group 2 was performed, but without EGCG. Serum superoxide dismutase activity, creatine kinase, and lactate dehydrogenase were then measured in blood samples from groups 1 to 3. In group 4, after 4 hours of unilateral testicular ischemia, testicular reperfusion was performed. In group 5, the same procedure as in group 4 was performed, but with EGCG administered 1 hour before reperfusion. For groups 4 and 5, bilateral orchiectomy was performed for histologic examination 4 weeks after reperfusion was started. RESULTS: Serum superoxide dismutase activity was significantly higher in group 2 than in group 3. The ratios of bilateral testicular weight, mean seminiferous tubule diameter, and germinal epithelial cell thickness were significantly higher in group 5 than in group 4. CONCLUSIONS: Therapy with EGCG before reperfusion might exert protective effects via antioxidant activities in a rat experimental model of testicular ischemia-reperfusion injury. PMID- 22813809 TI - Ramstedt and the centennial of pyloromyotomy. PMID- 22813810 TI - Novel report of an adrenal adenoma in a newborn. AB - An adrenal mass in a newborn usually suggests a diagnosis of neuroblastoma or hemorrhage. A 6-week-old girl was referred for evaluation of a left adrenal mass. The initial findings were most consistent with an adrenal hemorrhage. On surveillance imaging, the lesion was characterized as a complex cystic mass. The patient subsequently developed lesions in the right adrenal gland and liver as well as multiple cutaneous lesions. Although the contralateral adrenal and hepatic lesions resolved spontaneously, the left adrenal and cutaneous lesions persisted. Subsequent imaging revealed that the mural components of the left adrenal mass had increased in size, and at age 13 months, a laparoscopic left adrenalectomy was performed. A benign adrenal adenoma with myxoid changes was reported on surgical pathology. This is the first reported case in a newborn. PMID- 22813811 TI - Congenital Askin tumor with favorable outcome: case report and review of the literature. AB - Several disorders may present as cystic complex lesions of the fetal thorax, both with benign and malignant behavior. As a consequence, their detection may pose diagnostic, therapeutic, and parental counseling dilemmas. We describe a neonate with a congenital Askin tumor, diagnosed at the 37th week of gestation and treated after birth. Counseling and treatment challenges are discussed. PMID- 22813812 TI - Unilateral facial swelling in an infant. AB - The melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon, usually benign neoplasm which is most commonly found in the maxilla. We describe the case of a 6-month-old boy who was referred with a swiftly increasing swelling of the left cheek. After imaging and biopsy, MNTI was confirmed, and surgical resection was performed. Literature demonstrates that most MNTIs occur in the head and neck area and most of those occur in the maxilla. Although most cases are benign, 6.5% are malignant with metastatic disease. Treatment and outcome are discussed in detail. The case highlights the importance of making the diagnosis MNTI early on in order to achieve an optimal outcome. PMID- 22813813 TI - Portal teratoma causing obstructive jaundice in children: a rarity. AB - Teratoma in children is a common entity, usually occurring both in gonadal and extragonadal sites. Common extragonadal sites for teratoma in children are the sacrococcygeal region, retroperitoneum, and mediastinum. Various unusual extragonadal sites have been reported. However, teratoma in the hepatoduodenal ligament is a very rare occurrence. We herein report a case of a mature teratoma in the hepatoduodenal ligament in an 11-year-old child presenting with obstructive jaundice along with its surgical management and review of the literature. PMID- 22813814 TI - Partial internal biliary diversion for Alagille syndrome: case report and review of the literature. AB - This is a case report of the first patient with Alagille syndrome (AGS) to undergo a partial internal biliary diversion (PIBD) for the treatment of symptoms refractory to medical therapy. Alagille syndrome is a hereditary disease resulting in chronic cholestasis and hypercholesterolemia that can lead to severe and intractable pruritus and disfiguring and debilitating xanthomas. PIBD has proven to be an effective treatment option for other causes of cholestatic liver disease. This report reviews the immediate and 2-year follow-up of a patient after this surgical procedure. The results suggest that PIBD has potential to provide relief of intractable symptoms and improve the quality of life in patients with AGS while avoiding an external stoma. It does not, however, appear to prevent the progression of liver disease. Long-term follow-up is still needed. PMID- 22813815 TI - Isolated infantile myofibromatosis of the upper eyelid: uncommon localization and long-term results after surgical management. AB - Myofibroma, the most common juvenile fibrous disorder in infancy, usually manifests as a solitary soft tissue tumor and less commonly as simultaneous multiple tumors in both soft tissue and bones. Infantile myofibromatosis is well described in the head and neck, but cutaneous lesions rarely occur in the periorbit and orbit, where fast growth and bone damage can mimic malignant tumors. We describe a case of a solitary periorbital myofibroma in a newborn. Treatment consisted of partial excision of the tumor. Histologic and immunohistochemistry analyses provided the diagnosis of infantile myofibromatosis. The patient remains disease-free at 10 years of age, but with some visual impairment. Infantile myofibromatosis is an uncommon tumor with exceptional periorbital involvement. Differential diagnosis can be difficult when it is solely based on histologic assessment. Immunohistochemistry evaluation demonstrating cytoplasmic actin filaments in neoplastic spindle cells confirms the diagnosis. As soon as the diagnosis is made, chest and abdominal imaging must be performed to evaluate the overall prognosis and direct treatment. The treatment of choice is early conservative surgery to minimize functional and/or esthetic damage. Complete tumor excision is not always possible. Lengthy ophthalmologic monitoring is required to detect the onset of amblyopia. PMID- 22813816 TI - A unique presentation of a standard type C esophageal atresia in a very low-birth weight neonate. AB - Neonates with esophageal atresia and tracheoesophageal fistula usually present with inability to swallow immediately after birth often associated with respiratory distress. This is an unusual presentation of a very low-birth-weight neonate with a type C tracheoesophageal fistula that was fed for the first 4 days of life through an unintentional tracheogastric tube without incident. PMID- 22813817 TI - Extensive portal venous gas without obvious pneumatosis intestinalis in a preterm infant with necrotizing enterocolitis. AB - Portal venous gas is one of the classic radiologic features of necrotizing enterocolitis and is an uncommon isolated finding because it is most commonly seen in conjunction with pneumatosis intestinalis. In this case study, we present a preterm neonate with necrotizing enterocolitis who had extensive portal venous gas without obvious pneumatosis intestinalis. PMID- 22813818 TI - Sacral nerve stimulation is a valuable diagnostic tool in the management of anorectal and pelvic malformations. AB - BACKGROUND: We hypothesize that the current practice of sphincter assessment in anorectal malformations (ARMs) by direct muscle stimulation can be improved by sacral nerve stimulation (SNS). Focusing on the specific adjustments for infants, we highlight the anatomical and neurophysiologic basis of SNS and its further diagnostic and therapeutic implications. PATIENTS AND METHODS: We examined 20 patients: 12 patients with ARM, 3 with Hirschsprung disease, 3 with sacrococcygeal teratoma, and 2 with cloacal exstrophies. Under general anesthesia and ultrasound guidance, percutaneous needle electrodes were placed within the sacral neural foramina. Electrical stimulation was applied to assess the presence, pattern, and extent of the neuromuscular response of the external anal sphincter. RESULTS: We successfully modified the traditional method used in adults replacing radiographic controls by ultrasound guidance. In 20 SNS procedures with no complications, we found a muscle response on stimulation of the third and/or fourth sacral nerves in 18 of 20 patients (anal sphincter contraction and/or ipsilateral plantar flexion). CONCLUSION: We demonstrated the feasibility of SNS for intraoperative sphincter mapping and detection of primary innervation abnormalities in ARM as well as for the assessment of secondary deficits in postoperative follow-up. Sacral nerve stimulation broadens the spectrum of intraoperative information concerning the sacral innervation pattern by a direct assessment of the sacral nerves. Furthermore, electrophysiologic data may allow prospective criteria for sphincter function to be established. These may improve the accuracy of the present classification-based prognosis as well as the understanding of sphincter physiology in general. PMID- 22813819 TI - Chest wall reconstruction using implantable cross-linked porcine dermal collagen matrix (Permacol). AB - BACKGROUND/PURPOSE: Chest wall reconstruction in children is typically accomplished with either primary tissue repair or synthetic mesh prostheses. Primary tissue repair has been associated with high rates of scoliosis, whereas synthetic prostheses necessitate the placement of a permanent foreign body in growing children. This report describes the use of biologic mesh (Permacol; Covidien, Mansfield, MA) as an alternative to both tissue repair and synthetic prostheses in pediatric chest wall reconstruction. METHODS: A retrospective chart review was performed identifying patients undergoing chest wall reconstruction with biologic mesh at our tertiary referral children's hospital between 2007 and 2011. Data collection included patient demographics, indication for chest wall resection, number of ribs resected, the administration of postoperative radiation, length of follow-up, postoperative complications, and the degree of spinal angulation (preoperatively and at most recent follow-up). RESULTS: Five patients (age, 9.0-21.7 years; mean, 15.4 years) underwent resection for primary chest wall malignancy followed by reconstruction with biologic mesh (Permacol) during the study period. There were no postoperative mesh-related complications, and none of the patients developed clinically significant scoliosis (follow-up, 1.1-2.6 years; mean 1.9 years). CONCLUSION: Biologic mesh offers a safe and dependable alternative to both primary tissue repair and synthetic mesh in pediatric patients undergoing chest wall reconstruction. PMID- 22813820 TI - Tubularized incised plate urethroplasty with dorsal inlay graft prevents meatal/neourethral stenosis: a single surgeon's experience. PMID- 22813821 TI - The study by Shimotakahara et al evaluated urethral complications in patients undergoing tubularized incised plate (TIP) urethroplasty vs TIP with inlay grafting. PMID- 22813823 TI - Minimally invasive nephron-sparing surgery for unilateral Wilms tumor. AB - Minimally invasive surgery (MIS) for nephrectomy has been described since the early 1990s. More recently, MIS has been used for nephron-sparing surgery (NSS) when treating benign conditions. However, reports of NSS using MIS for malignant conditions are sparse. In this report, we describe our retroperitoneal laparoscopic approach for NSS for a localized Wilms tumor. PMID- 22813824 TI - Assessment of subtotal nasal reconstruction in a child after 6 years of follow up. AB - Nasal amputation in the child is infrequent, and the procedure is not clearly defined. Early reconstruction certainly improves the child's life and social integration. The major risk is unsatisfactory growth of the reconstructed nose, which may persuade some surgeons to postpone the operation. The evaluation of this nasal reconstruction in a 5-year-old boy who had undergone subtotal amputation of the nose after 6 years of follow-up tends to confirm the therapeutic choice of early nasal reconstruction in the child. The results were considered quite satisfactory esthetically and psychologically beneficial and are concordant with those of other studies. Early management allowed us to obtain an esthetically acceptable reconstruction with respect to growth, thereby enabling the child to resume his studies rapidly and to achieve good social integration. PMID- 22813825 TI - A very low-birth-weight infant with spontaneous perforation of a choledochal cyst and adjacent pseudocyst formation. AB - Spontaneous perforation of a choledochal cyst with ensuing pseudocyst formation is a very rare complication. We report the development of a pseudocyst adjacent to a choledochal cyst in a very low-birth-weight infant at 2 months of age. Elective excision of the choledochal cyst and biliary tract reconstruction were successfully performed 2 months later when the infant weighed 3 kg. Delayed primary repair may be a viable alternative treatment for low-birth-weight infants with choledochal cysts. PMID- 22813826 TI - Laparoscopic excision of a giant splenic vascular tumor. AB - The splenic vascular tumor referred to as a hemangioma is rare and typically presents as a small asymptomatic lesion. We report a case of a giant splenic cyst in a 13-year-old boy with abdominal distension. He underwent laparoscopic excision of the splenic cyst without complication. Pathology revealed a vascular tumor. At 15 months of follow-up, he continued to be asymptomatic, and abdominal ultrasound showed no recurrence of his disease. Laparoscopic excision of giant splenic cysts is a viable option in children, allowing for preservation of normal splenic tissue. PMID- 22813827 TI - Use of microcatheter for intraabdominal survey. AB - BACKGROUND: Laparoscopy is the most common procedure for minimally invasive intraabdominal surveys. Patients with pulmonary hypertension (PHTN) may need an alternate approach because the systemic absorption of carbon dioxide may lead to hypercapnia, acidemia, and increases in systemic and pulmonary pressures. We report a case of intraabdominal survey using a microcatheter trocar (Check-Flo Introducer) in a patient with a large adnexal mass and PHTN. CASE: An adolescent girl with severe PHTN and multiple cardiac anomalies presented with oligomenorrhea. During the course of workup, an ultrasound revealed an 8-cm simple cyst in the right adnexa, which required removal. The decision was made to proceed with cystectomy. The patient was not a candidate for laparoscopy, and an alternative method was used. The Check-Flo Introducer, a microcatheter trocar; crystalloid fluid infusion; and a 3-mm laparoscopic camera were used to survey the abdominal cavity, revealing a 10-cm simple paratubal cyst that could be safely drained and removed via a minilaparotomy incision. CONCLUSION: The microcatheter trocar is a useful and novel alternative in patients who cannot tolerate increases in intraabdominal pressure. PMID- 22813828 TI - Gastric hamartoma of the pylorus in an infant. AB - Gastric hamartomata, alternatively called adenomyomata, are rare, benign lesions of the gastric wall. They can present with a wide spectrum of symptomatology. Pure pyloric adenomyomata are exceedingly rare. We are reporting a 13-day-old infant with a gastric hamartoma at the pylorus presenting with gastric outlet obstruction mimicking infantile hypertrophic pyloric stenosis. PMID- 22813829 TI - Classical cloacal exstrophy with intravesical phallus. AB - Penile abnormalities such as epispadias, diphallia, asymmetry, and aphallia have been reported with cloacal exstrophy. The presence of intravesical phallus with cloacal exstrophy is presented with a review of literature. PMID- 22813830 TI - Unusual presentation of a cutaneous bronchogenic cyst in an asymptomatic neonate. AB - Cutaneous presentations of bronchogenic cysts are rare in all age groups. Previous reports of cutaneous manifestations of bronchogenic cysts have been described as nodular, adherent masses, most frequently with a suprasternal location. We report a unique presentation of an infant with a pedunculated, anterior chest wall mass, which was identified as a bronchogenic cyst. PMID- 22813831 TI - Clinical assessment of hand motor performance after acquired brain injury with dynamic computerized hand dynamometry: construct, concurrent, and predictive validity. AB - OBJECTIVE: To assess the construct, concurrent, and predictive validity of dynamic computerized hand dynamometry. DESIGN: Prospective correlational study between dynamometry and functional upper limb performance. SETTING: Hospital outpatient spasticity clinics. PARTICIPANTS: Adults with upper motor neuron syndrome affecting the upper limb after acquired brain injury (ABI) (n=38; median age, 50 y; range, 18-81 y) and healthy adult control participants (n=27; median age, 37 y; range, 22-62 y). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Dynamic computerized dynamometry elements of hand performance (isometric force, force velocity, isometric grip work, contraction and relaxation duration) and the Action Research Arm Test. RESULTS: Motor elements of hand performance objectively measured by the dynamic computerized dynamometry protocol achieved moderate to good validity when correlated with standardized measures of functional hand performance. Dynamic computerized dynamometry identified clear differences in hand performance between participants with and without ABI. Within the ABI group, dynamic computerized hand dynamometry achieved fair to moderate predictive validity with regards to whether a participant would be referred for botulinum toxin A injections. CONCLUSIONS: This study provides support for the construct, concurrent, and predictive validity of the dynamic computerized dynamometry protocol. PMID- 22813833 TI - Interjoint coordination and the personal lift-assist device. AB - It has been suggested that interjoint coordination may serve to reduce joint stress and muscular demand and to maintain balance during dynamic lifting tasks, thus having implications for safe lifting practices. Before recommending the use of an on-body ergonomic aid, the Personal Lift-Assist Device (PLAD), it is important to determine any effects this device may have on interjoint coordination. Principal component analyses were applied to relative phase angle waveforms, defining the hip-knee and lumbar spine-hip coordination of 15 males and 15 females during a repetitive lifting task. When wearing the PLAD, users lifted with more synchronous hip-knee and lumbar spine-hip coordination patterns (P < .01). Furthermore, increases in load caused less synchronized interjoint coordination at both the hip-knee and lumbar spine-hip during the up and down phases of the lift (P < .01) for all conditions. No significant main effects of sex or significant interactions were observed on any of the outcome variables. PMID- 22813832 TI - Telephone support oriented by accelerometric measurements enhances adherence to physical activity recommendations in noncompliant patients after a cardiac rehabilitation program. AB - OBJECTIVE: To assess the efficacy of a strategy, based on telephone support oriented by accelerometer measurements, on the adherence to physical activity (PA) recommendations in cardiac patients not achieving PA recommendations. DESIGN: Prospective and randomized study. SETTING: A cardiac rehabilitation program (CRP) at a clinic. PARTICIPANTS: Stable, noncompliant cardiac (coronary artery disease, heart failure, post-cardiovascular surgery) patients (weekly moderate-intensity PA <150 min) were randomly assigned to an intervention group (n=19) or a control group (n=10). INTERVENTIONS: The intervention group wore an accelerometer for 8 weeks. Every 15 days, feedback and support were provided by telephone. The control group wore the accelerometer during the 8th week of the intervention only. MAIN OUTCOME MEASURES: Active energy expenditure (EE) (in kilocalories) and the time spent doing light, moderate, or intense PA (minutes per week). RESULTS: In the intervention group, the time spent at moderate intensity PA increased from 95.6+/-80.7 to 137.2+/-87.5 min/wk between the 1st and 8th week (P=.002), with 36.8% of the sample achieving the target amount of moderate-intensity PA. During the 8th week, the EE averaged 543.7+/-144.1 kcal and 266.7+/-107.4 kcal in the intervention group and control group, respectively (P=.004). CONCLUSIONS: Telephone support based on accelerometer recordings appeared to be an effective strategy to improve adherence to PA in noncompliant patients. This intervention could be implemented after a CRP as an inexpensive, modern, and easy-to-use strategy. PMID- 22813834 TI - The impact of terminal complement blockade on the efficacy of induction with polyclonal rabbit antithymocyte globulin in living donor renal allografts. AB - BACKGROUND: Eculizumab, a potent inhibitor of terminal complement activation, appears promising in reducing early antibody-mediated rejection in positive crossmatch kidney transplantation. However, its concomitant use with polyclonal rabbit antithymocyte globulin (rATG) might reduce the efficacy of rATG. This study aimed to evaluate the effect of eculizumab on the efficacy of rATG in vivo and determine the role of complement in rATG-induced lymphocyte cell depletion. PATIENTS AND METHODS: Thirty-six kidney transplant recipients were classified into 3 groups according to induction regime: anti-IL-2 receptor antibody alone induction group (basiliximab, n=8); rATG induction (n=20), and rATG+eculizumab induction group (n=8). Peripheral blood T-cell subsets and NK cells were measured 3-4 days after transplant (after 3 doses of rATG). RESULTS: Compared to anti-IL-2 receptor antibody induction group, both groups treated with rATG demonstrated significant depletion of all T-cell subsets (CD3-positive cells) (P<0.0001 for rATG vs. anti-IL-2 receptor antibody induction group; P<0.001 for rATG+eculizumab vs. anti-IL-2 receptor antibody group). However, while T-cell counts were low in all rATG-treated patients, eculizumab treatment resulted in higher peripheral blood T-cell counts in rATG treated patients (P=0.005). Before induction, median total lymphocyte counts were normal for the three study groups. By 1, 4 months and 1 year, median the total lymphocyte count was normal for the anti-IL-2 receptor antibody group but was below normal range or at the lower edge of normality for rATG and rATG+eculizumab groups. CONCLUSIONS: This small-sample size study suggests that peripheral T cells are depleted by rATG in the presence of terminal complement inhibition. However, eculizumab appears to have a mild inhibitory effect on peripheral blood T-cell depletion by rATG in kidney transplant recipients. PMID- 22813835 TI - Myocardial infarction in a 17-year-old patient due to neurofibromatosis associated coronary aneurysm. AB - Neurofibromatosis is an autosomal dominant multi-system genetic disorder. Extra cardiac vascular manifestations of neurofibromatosis have been previously described in many reports. However, coronary arterial involvements have been rarely described. A 17-year-old girl with neurofibromatosis presented to our institute with subacute myocardial infarction. Coronary angiogram revealed an aneurysm with thrombus in the left anterior descending artery. PMID- 22813836 TI - Quantification of tibiofemoral shear and compressive loads using a MRI-based EMG driven knee model. AB - The purpose of this study is to describe an MRI-based EMG-driven knee model to quantify tibiofemoral compressive and shear forces. Twelve healthy females participated. Subjects underwent 2 phases of data collection: (1) MRI assessment of the lower extremity to quantify muscle volumes and patella tendon orientation and (2) biomechanical evaluation of a drop-jump task. A subject-specific EMG driven knee model that incorporated lower extremity kinematics, EMG, and muscle volumes and patella tendon orientation estimated from MRI was developed to quantify tibiofemoral shear and compressive forces. A resultant anterior tibial shear force generated from the ground reaction force (GRF) and muscle forces was observed during the first 30% of the stance phase of the drop-jump task. All of the muscle forces and GRF resulted in tibiofemoral compression, with the quadriceps force being the primary contributor. Acquiring subject-specific muscle volumes and patella tendon orientation for use in an EMG-driven knee model may be useful to quantify tibiofemoral forces in persons with altered patella position or muscle atrophy following knee injury or pathology. PMID- 22813837 TI - Effect of iron II on hydroxyapatite dissolution and precipitation in vitro. AB - The aim of this study was to evaluate the effect of iron II on the dissolution and precipitation of synthetic hydroxyapatite (HA). HA powder was suspended in solutions of iron (0.84 ug/ml, Fe0.84; 18.0 ug/ml, Fe18; 70.0 ug/ml, Fe70), fluoride (1,100 ug/ml, F1,100), and deionized water and submitted to pH cycling. After pH cycling, the samples were analyzed by infrared spectroscopy and X-ray diffraction. The concentrations of fluoride, calcium, phosphorus, and iron were also analyzed. The data were submitted to ANOVA, and analyzed by Tukey's test (p < 0.05). The infrared spectrum showed a reduction in all bands corresponding to phosphates and hydroxyls and an increase in the carbonate band in the groups with iron. The intensity of the phosphate bands increased and that of the hydroxyl bands decreased in the group F1,100. It was observed that there was a higher concentration of Ca in the group F1,100, with no significant difference between the groups Fe18 and Fe70 (p > 0.05). There was an increase in Fe concentration in the HA directly related to the Fe concentration of the treatment solutions. Results show that the presence of Fe causes the precipitation of apatite with high solubility. PMID- 22813838 TI - Prevalence and influence of hyperthyroidism on the long-term outcome of catheter ablation for drug-refractory atrial fibrillation. AB - BACKGROUND: Hyperthyroidism is usually regarded as a reversible cause of atrial fibrillation (AF); however, one-third of patients remain in AF despite euthyroid restoration. We hypothesized that a significant number of AF patients with hyperthyroidism (Hyperthyroid-AF) as well as those without (Non-thyroid-AF) would benefit from catheter ablation of AF (AF ablation). This study aimed to clarify the prevalence of hyperthyroidism in candidates for AF ablation and to compare the long-term outcome of AF ablation between the Hyperthyroid-AF and Non-thyroid AF groups. METHODS AND RESULTS: This study enrolled 337 consecutive patients with AF who underwent a first AF ablation that mainly involved extensive encircling pulmonary vein isolation. Sixteen (4.7%) patients had hyperthyroidism; the remaining 321 (95.3%) did not. In the Hyperthyroid-AF patients, a euthyroid state had been restored for at least 3 months before the ablation. During a mean follow up period of 4+/-1 years after ablation, AF recurred in 7 patients (44%) with Hyperthyroid-AF and in 139 patients (43%) with Non-thyroid-AF (P=0.91 by the log rank test). In the multivariate Cox regression models, the presence of hyperthyroidism was not associated with a higher risk of AF recurrence (hazard ratio, 0.87; 95% confidence interval, 0.40-1.88; P=0.73). CONCLUSIONS: In the AF ablation candidates without structural heart disease, hyperthyroidism was not rare. After euthyroid restoration on pharmacological treatment, hyperthyroidism was not associated with a higher risk of AF recurrence. PMID- 22813839 TI - Involvement of rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease. AB - BACKGROUND: Activation of Rho-kinase plays a central role in the pathogenesis of drug-eluting stents (DES)-induced coronary hyperconstricting responses in pigs in vivo has been previously demonstrated. In the present study, Rho-kinase activation involved in those responses in patients with coronary artery disease (CAD) is examined. METHODS AND RESULTS: In 24 patients with CAD who underwent coronary intervention with either DES or bare-metal stents (BMS), coronary vasomotor responses to intracoronary acetylcholine (ACh) before and after intracoronary pre-treatment with a Rho-kinase inhibitor, fasudil was examined. Coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT) was evaluated. QCA showed that the coronary vasoconstricting responses to ACh were significantly enhanced in the DES group compared with the BMS group both at the proximal and the distal segments adjacent to the stents (proximal: BMS -13.0+/-10.7% vs. DES 25.4+/-14.3%, P=0.036; distal: BMS -24.4+/-12.2% vs. DES -43.8+/-14.7%, P=0.003). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal 10.2+/-11.7%, distal 14.4+/-10.5% vs. before fasudil, both P<0.01). In the OCT imaging analysis, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. CONCLUSIONS: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD, suggesting the therapeutic importance of Rho kinase pathway. PMID- 22813840 TI - Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder. AB - OBJECTIVE: Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression. SUBJECTS AND METHODS: Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean+/-SD=39+/-12) years. Patients were prescribed paroxetine (n=11) or sertraline (n=13) for 4weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4weeks. RESULTS: Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group. CONCLUSION: Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order. PMID- 22813841 TI - Myelophil ameliorates brain oxidative stress in mice subjected to restraint stress. AB - We evaluated the pharmacological effects of Myelophil, a 30% ethanol extract of a mix of Astragali Radix and Salviae Radix, on oxidative stress-induced brain damage in mice caused by restraint stress. C57BL/6 male mice (eight weeks old) underwent daily oral administration of distilled water, Myelophil (25, 50, or 100mg/kg), or ascorbic acid (100mg/kg) 1h before induction of restraint stress, which involved 3h of immobilization per day for 21days. Nitric oxide levels, lipid peroxidation, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione redox system enzymes), and concentrations of adrenaline, corticosterone, and interferon-gamma, were measured in brain tissues and/or sera. Restraint stress-induced increases in nitric oxide levels (serum and brain tissues) and lipid peroxidation (brain tissues) were significantly attenuated by Myelophil treatment. Restraint stress moderately lowered total antioxidant capacity, catalase activity, glutathione content, and the activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase; all these responses were reversed by Myelophil. Myelophil significantly attenuated the elevated serum concentrations of adrenaline and corticosterone and restored serum and brain interferon-gamma levels. Moreover, Myelophil normalized expression of the genes encoding monoamine oxidase A, catechol-O methyltransferase, and phenylethanolamine N-methyltransferase, which was up regulated by restraint stress in brain tissues. These results suggest that Myelophil has pharmacological properties protects brain tissues against stress associated oxidative stress damage, perhaps in part through regulation of stress hormones. PMID- 22813842 TI - Variation in the major histocompatibility complex [MHC] gene family in schizophrenia: associations and functional implications. AB - Schizophrenia is a chronic debilitating neuropsychiatric disorder with a complex genetic contribution. Although multiple genetic, immunological and environmental factors are known to contribute to schizophrenia susceptibility, the underlying neurobiological mechanism(s) is yet to be established. The immune system dysfunction theory of schizophrenia is experiencing a period of renewal due to a growth in evidence implicating components of the immune system in brain function and human behavior. Current evidence indicates that certain immune molecules such as Major Histocompatibility Complex (MHC) and cytokines, the key regulators of immunity and inflammation are directly involved in the neurobiological processes related to neurodevelopment, neuronal plasticity, learning, memory and behavior. However, the strongest support in favor of the immune hypothesis has recently emerged from on-going genome wide association studies advocating MHC region variants as major determinants of one's risk for developing schizophrenia. Further identification of the interacting partners and receptors of MHC molecules in the brain and their role in down-stream signaling pathways of neurotransmission have implicated these molecules as potential schizophrenia risk factors. More recently, combined brain imaging and genetic studies have revealed a relationship between genetic variations within the MHC region and neuromorphometric changes during schizophrenia. Furthermore, MHC molecules play a significant role in the immune-infective and neurodevelopmental pathogenetic pathways, currently hypothesized to contribute to the pathophysiology of schizophrenia. Herein, we review the immunological, genetic and expression studies assessing the role of the MHC in conferring risk for developing schizophrenia, we summarize and discuss the possible mechanisms involved, making note of the challenges to, and future directions of, immunogenetic research in schizophrenia. PMID- 22813843 TI - Chest wall reconstruction: impact of Gore-Tex((r)) dual-mesh prosthesis on respiratory function. PMID- 22813844 TI - Chromosome evolution in Perissodactyla. AB - Comparative painting has provided a wealth of useful information and helped to reconstruct the pathways of karyotype evolution within major eutherian phylogenetic clades. New data have come from gene localizations, BAC mapping and high throughout sequencing projects that enrich and provide new details of genome evolution. Extensive research on perissodactyl genomes has revealed not only increased rates of chromosomal rearrangements, but also an exceptionally high number of centromere repositioning events in equids. Here were combined new physical mapping, comparative painting and genome sequencing data to refine the putative ancestral karyotype maps and to revise the previously proposed scenario of perissodactyl karyotype evolution. PMID- 22813845 TI - A capacitive electrode with fast recovery feature. AB - Capacitive electrodes (CEs) allow for acquiring biopotentials without galvanic contact, avoiding skin preparation and the use of electrolytic gel. The signal quality provided by present CEs is similar to that of standard wet electrodes, but they are more sensitive to electrostatic charge interference and motion artifacts, mainly when biopotentials are picked up through clothing and coupling capacitances are reduced to tens of picofarads. When artifacts are large enough to saturate the preamplifier, several seconds (up to tens) are needed to recover a proper baseline level, and during this period biopotential signals are irremediably lost. To reduce this problem, a CE that includes a fast-recovery (FR) circuit is proposed. It works directly on the coupling capacitor, recovering the amplifier from saturation while preserving ultra-high input impedance, as a CE requires. A prototype was built and tested acquiring ECG signals. Several experimental data are presented, which show that the proposed circuit significantly reduces record segment losses due to amplifier saturation when working in real environments. PMID- 22813846 TI - In vitro cytotoxicity evaluation of porous TiO2-Ag antibacterial coatings for human fetal osteoblasts. AB - Implant-associated infections (IAIs) may be prevented by providing antibacterial properties to the implant surface prior to implantation. Using a plasma electrolytic oxidation (PEO) technique, we produced porous TiO2 coatings bearing various concentrations of Ag nanoparticles (Ag NPs) (designated as 0 Ag, 0.3 Ag and 3.0 Ag) on a Ti-6Al-7Nb biomedical alloy. This study investigates the cytotoxicity of these coatings using a human osteoblastic cell line (SV-HFO) and evaluates their bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA). The release of Ag and the total amount of Ag in the coatings were determined using a graphite furnace atomic absorption spectrometry technique (GF-AAS) and flame-AAS, respectively. Cytotoxicity was evaluated using the AlamarBlue assay coupled with the scanning electron microscopy (SEM) observation of seeded cells and by fluorescence microscopy examination of the actin cytoskeleton and nuclei after 48 h of incubation. Antibacterial activity was assessed quantitatively using a direct contact assay. AlamarBlue viability assay, SEM and fluorescence microscopy observation of the SV-HFO cells showed no toxicity for 0 Ag and 0.3 Ag specimens, after 2, 5 and 7 days of culture, while 3.0 Ag surfaces appeared to be extremely cytotoxic. All Ag-bearing surfaces had good antibacterial activity, whereas Ag-free coatings showed an increase in bacterial numbers. Our results show that the 0.3 Ag coatings offer conditions for optimum cell growth next to antibacterial properties, which makes them extremely useful for the development of new antibacterial dental and orthopedic implants. PMID- 22813847 TI - Thermally responsive microcarriers with optimal poly(N-isopropylacrylamide) grafted density for facilitating cell adhesion/detachment in suspension culture. AB - Large-scale cell culture of anchorage-dependent cells based on microcarriers is a crucial method for industrial-scale cell culture and large-scale expansion of therapeutic cells. Previously, the authors developed temperature-responsive microcarriers bearing poly(N-isopropylacrylamide) (PIPAAm)-grafted chains on their outer surface for the non-invasive detachment of cultured cells through temperature reduction without proteolytic enzyme treatment. In this study, to further facilitate cell adhesion and thermally induced detachment efficiency, PIPAAm-grafted beads with various grafted amounts and various grafted PIPAAm chain densities were prepared. Contact angle measurements at different temperatures revealed that the magnitude of the contact angle change from 37 to 20 degrees C decreased with increasing brush density. Additionally, the amount of fibronectin adsorbed on the bead surface decreased with increasing brush density. Chinese hamster ovary (CHO-K1) cells adhered to the surface of PIPAAm grafted beads at 37 degrees C, and a negligible difference in the cell adhesive property was observed by varying the brush density of the PIPAAm-grafted beads. When the temperature was reduced to 20 degrees C, the adhering cells were found to detach themselves from the PIPAAm-grafted bead surfaces. Of particular interest, PIPAAm-grafted beads with intermediate brush density exhibited the highest efficiency of thermally induced cell detachment. Thus, the brush density of PIPAAm-grafted beads strongly affected the efficiency of thermally induced cell detachment. PMID- 22813848 TI - The use of layer by layer self-assembled coatings of hyaluronic acid and cationized gelatin to improve the biocompatibility of poly(ethylene terephthalate) artificial ligaments for reconstruction of the anterior cruciate ligament. AB - In this study layer by layer (LBL) self-assembled coatings of hyaluronic acid (HA) and cationized gelatin (CG) were used to modify polyethylene terephthalate (PET) artificial ligament grafts. Changes in the surface properties were characterized by scanning electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, and contact angle and biomechanical measurements. The cell compatibility of this HA-CG coating was investigated in vitro on PET films seeded with human foreskin dermal fibroblasts over 7days. The results of our in vitro studies demonstrated that the HA-CG coating significantly enhanced cell adhesion, facilitated cell growth, and suppressed the expression of inflammation-related genes relative to a pure PET graft. Furthermore, rabbit and porcine anterior cruciate ligament reconstruction models were used to evaluate the effect of this LBL coating in vivo. The animal experiment results proved that this LBL coating significantly inhibited inflammatory cell infiltration and promoted new ligament tissue regeneration among the graft fibers. In addition, the formation of type I collagen in the HA-CG coating group was much higher than in the control group. Based on these results we conclude that PET grafts coated with HA-CG have considerable potential as substitutes for ligament reconstruction. PMID- 22813849 TI - Preparation, mechanical property and cytocompatibility of poly(L-lactic acid)/calcium silicate nanocomposites with controllable distribution of calcium silicate nanowires. AB - How to accurately control the microstructure of bioactive inorganic/organic nanocomposites still remains a significant challenge, which is of great importance in influencing their mechanical strength and biological properties. In this study, using a combined method of electrospinning and hot press processing, calcium silicate hydrate (CSH) nanowire/poly(L-lactide) (PLLA) nanocomposites with controllable microstructures and tailored mechanical properties were successfully prepared as potential bone graft substitutes. The electrospun hybrid nanofibers with various degrees of alignment were stacked together in a predetermined manner and hot pressed into hierarchically structured nanocomposites. The relationship between the microstructure and mechanical properties of the as-prepared nanocomposites were systematically evaluated. The results showed that CSH nanowires in a PLLA matrix were able to be controlled from completely randomly oriented to uniaxially aligned, and then hierarchically organized with different interlayer angles, leading to corresponding nanocomposites with improved mechanical properties and varied anisotropies. It was also found that the bending strength of nanocomposites with 5 wt.% CSH nanowires (130 MPa) was significantly higher than that of pure PLLA (86 MPa) and other composites. The addition of CSH nanowires greatly enhanced the hydrophilicity and apatite-forming ability of PLLA films, as well as the attachment and proliferation of bone marrow stromal cells. The study suggested that a combination of electrospinning and hot pressing is a viable means to control the microstructure and mechanical properties, and improve the mineralization ability and cellular responses, of CSH/PLLA nanocomposites for potential bone repair applications. PMID- 22813851 TI - Plasma biomarkers of oxidative and AGE-mediated damage of proteins and glycosaminoglycans during healthy ageing: a possible association with ECM metabolism. AB - The aim of this study was to examine whether oxidative and AGE-mediated processes correlates with the metabolic changes of proteoglycans (PGs) and proteins during physiological ageing. The age and gender-associated changes of PGs metabolism were evaluated by plasma chondroitin sulfates (CS), dermatan sulfates (DS) and heparan sulfates and heparin (HS/H). We found a linear age-related decline in CS, DS and HS/H, the first one being the predominant plasma GAG during ageing. The possible deleterious effect of oxidative phenomenon on proteins' and proteoglycans' metabolism during ageing process was analyzed by plasma carbonyls (PCO) and thiols (PSH) as well as by total antioxidant capacity (TAS). An age dependent increase in PCO and decrease in PSH concentrations were found, both strongly correlated with decreasing with age plasma TAS. Intensity of glycation was assessed by circulating N(epsilon)-(carboxymethyl)lysine (CML) and endogenous secretory receptor for AGE (esRAGE), both of them founding associated with ageing. Moreover, all markers of oxidative and AGE-mediated damage correlated with CS and DS level and could be contributing factors to age-related changes of these GAG types. Thus, plasma CS and DS could become promising biomarkers of human ageing to date, owning to its close association with oxidative status and glycation processes. PMID- 22813850 TI - Focal adhesion kinase knockdown modulates the response of human corneal epithelial cells to topographic cues. AB - A rapidly expanding literature broadly documents the impact of biophysical cues on cellular behaviors. In spite of increasing research efforts in this field, the underlying signaling processes are poorly understood. One of the candidate molecules for being involved in mechanotransduction is focal adhesion kinase (FAK). To examine the role of FAK in the response of immortalized human corneal epithelial (hTCEpi) cells to topographic cues, FAK was depleted by siRNA transfection. Contrary to expectations, FAK knockdown resulted in an enhanced response with a greater number of hTCEpi cells aligned to the long axis of anisotropically ordered surface ridges and grooves. Both underlying topographic features and FAK depletion modulated the migration of corneal epithelial cells. The impact of FAK knockdown on both migration and alignment varied depending on the topographic cues to which the cells were exposed, with the most significant change observed on the biologically relevant size scale (400nm). Additionally, a change in expression of genes encoding perinuclear Nesprins 1 and 2 (SYNE1, 2) was observed in response to topographic cues. SYNE1/2 expression was also altered by FAK depletion, suggesting that these proteins might represent a link between cytosolic and nuclear signaling processes. The data presented here have relevance to our understanding of the fundamental processes involved in corneal cell behavior to topographic cues. These results highlight the importance of incorporating biophysical cues in the conduction of in vitro studies and into the design and fabrication of implantable prosthetics. PMID- 22813852 TI - Advancing age is associated with gene expression changes resembling mTOR inhibition: evidence from two human populations. AB - Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people. PMID- 22813853 TI - Two mechanisms underlying the loss of p16(Ink4a) function are associated with distinct tumorigenic consequences for WS MEFs escaping from senescence. AB - Werner syndrome (WS) mouse embryonic fibroblasts (MEFs) can spontaneously escape from senescence and become immortalized, either tumorigenic or non-tumorigenic. Our data revealed a single p53(N236S) point mutation in the tumorigenic cell lines, which was correlated with the down-regulation of p21(Waf1/Cip1). p16(Ink4a) expression was significantly decreased in all immortalized cell lines. Bisulfate sequencing indicated that the p16(Ink4a) gene was methylated in the tumorigenic cells. Exogenous overexpression of p21(Waf1/Cip1) demethylated p16(Ink4a) and restored its expression, which induced cell growth arrest and senescence. While in non-tumorigenic immortalized cells, the Ink4a loci and adjacent genomic DNA were found to be deleted. These data suggest that the loss of p16(Ink4a) function by either genomic DNA deletion or methylation have been adopted by senescent WS MEFs escaping from senescence, with distinct tumorigenic consequences. The fact that cells that had escaped senescence via the spontaneous biallelic deletion of the Ink4a loci could not form tumors suggests that the functional loss of p16(Ink4a)per se might not be sufficient for tumorigenesis; most likely, it is a byproduct and passenger mutation. The mutations in factors regulating p16(Ink4a) methylation might be the driver mutation. These findings shed light on the strategy of anti-aging by regulating p16(Ink4a) expression. PMID- 22813855 TI - Ecosystem service trends in basin-scale restoration initiatives: a review. AB - The integration of ecosystem services in ecological restoration projects presents an opportunity for enhancing benefits to human livelihood and funding sources as well as generating public support for such initiatives. This study reviewed the global trends in integrating ecosystem services in basin-scale restoration projects through bibliographic analysis. Few studies appear to incorporate ecosystem services, possibly due to the inconsistency and absence of the use of universally accepted classifications. Our review notes an increasing trend from 2006 onward toward the inclusion and citation of this concept, although its use is still limited. In this review, the supporting service was found to be the most cited (8), followed by regulatory (3), cultural (1) and provisioning (1) services. Identifying the number of services related to a restoration action was problematic when the services were not explicitly cited. We identify opportunities for increased integration of ecosystem services in basin-scale restoration projects, suggesting a conceptual framework following from new hierarchical maps. This is based on congruence between degrading processes or threat maps (e.g., thresholds of impacts) and ecosystem service maps. The resultant map will facilitate the targeting of threatened service supply at different scales from the basin scale to the scale of the restoration site. We urge the scientific community to standardize definitions and create methodologies and software tools that facilitate the incorporation of ecosystem services in large-scale restoration plans. PMID- 22813856 TI - Aggregating sustainability indicators: beyond the weighted sum. AB - Sustainability analysts and environmental decision makers often overcome the difficulty of interpreting comprehensive environmental profiles by aggregating the results using multi-criteria decision analysis (MCDA) methods. However, the wide variety of methodological approaches to weighting and aggregation introduces subjectivity and often uncertainty. It is important to select an approach that is consistent with the decision maker's information needs, but scant practical guidance is available to environmental managers on how to do this. In this paper, we aim to clarify the theoretical implications of an analyst's choice of MCDA method. By systematically examining the methodological decisions that must be made by the analyst at each stage of the assessment process, we aim to improve analysts' understanding of the relationship between MCDA theory and practice, and enable them to apply methods that are consistent with a decision maker's needs in any given problem context. PMID- 22813854 TI - Group V secretory phospholipase A2 enhances the progression of angiotensin II induced abdominal aortic aneurysms but confers protection against angiotensin II induced cardiac fibrosis in apoE-deficient mice. AB - Abdominal aortic aneurysms (AAAs) and heart failure are complex life-threatening diseases whose etiology is not completely understood. In this study, we investigated whether deficiency of group V secretory phospholipase A(2) (GV sPLA(2)) protects from experimental AAA. The impact of GV sPLA(2) deficiency on angiotensin (Ang) II-induced cardiac fibrosis was also investigated. Apolipoprotein E (apoE)(-/-) mice and apoE(-/-) mice lacking GV sPLA(2) (GV DKO) were infused with 1000 ng/kg per minute Ang II for up to 28 days. Increases in systolic blood pressure, plasma aldosterone level, and urinary and heart prostanoids were similar in apoE(-/-) and GV DKO mice after Ang II infusion. The incidence of aortic rupture in Ang II-infused GV DKO mice (10%) was significantly reduced compared with apoE(-/-) mice (29.4%). Although the incidence of AAA in GV DKO mice (81.3%) and apoE(-/-) mice (100%) was similar, the mean percentage increase in maximal luminal diameter of abdominal aortas was significantly smaller in GV DKO mice (68.5% +/- 7.7%) compared with apoE(-/-) mice (92.6% +/- 8.3%). Deficiency of GV sPLA(2) resulted in increased Ang II-induced cardiac fibrosis that was most pronounced in perivascular regions. Perivascular collagen, visualized by picrosirius red staining, was associated with increased TUNEL staining and increased immunopositivity for macrophages and myofibroblasts and nicotinamide adenine dinucleotide phosphate oxidase (NOX)-2 and NOX-4, respectively. Our findings indicate that GV sPLA(2) modulates pathological responses to Ang II, with different outcomes for AAA and cardiac fibrosis. PMID- 22813857 TI - Isotherm equilibria of Mn2+ biosorption in drinking water treatment by locally isolated Bacillus species and sewage activated sludge. AB - Manganese (Mn(2+)) is one of the inorganic contaminant that causes problem to water treatment and water distribution due to the accumulation on water piping systems. In this study, Bacillus sp. and sewage activated sludge (SAS) were investigated as biosorbents in laboratory-scale experiments. The study showed that Bacillus sp. was a more effective biosorbent than SAS. The experimental data were fitted to the Langmuir (Langmuir-1 & Langmuir-2), Freundlich, Temkin, Dubinin-Radushkevich (D-R) and Redlich-Peterson (R-P) isotherms to obtain the characteristic parameters of each model. Mn(2+) biosorption by Bacillus sp. was found to be significantly better fitted to the Langmuir-1 isotherm than the other isotherms, while the D-R isotherm was the best fit for SAS; i.e., the chi(2) value was smaller than that for the Freundlich, Temkin, and R-P isotherms. According to the evaluation using the Langmuir-1 isotherm, the maximum biosorption capacities of Mn(2+) onto Bacillus sp. and SAS were 43.5 mg Mn(2+)/g biomass and 12.7 mg Mn(2+)/g biomass, respectively. The data fitted using the D-R isotherm showed that the Mn(2+) biosorption processes by both Bacillus sp. and SAS occurred via the chemical ion-exchange mechanism between the functional groups and Mn(2+) ion. PMID- 22813864 TI - Metabolic and electrophysiological changes in the basal ganglia of transgenic Huntington's disease rats. AB - Huntington's disease (HD) is characterized by neuronal loss in the striatum, ultimately leading to an 'imbalance' in the electrical activity of the basal ganglia-thalamocortical circuits. To restore this 'imbalance' in HD patients, which is held responsible for (some) of the motor symptoms, different basal ganglia nuclei have been targeted for surgical therapies, such as ablative surgery and deep brain stimulation. However, evidence to target brain nuclei for surgical therapies in HD is lacking. We reasoned that a neuronal and metabolic mapping of the basal ganglia nuclei could identify a functional substrate for therapeutic interventions. Therefore, the aim of the present study was to investigate the metabolic and neuronal activity of basal ganglia nuclei in a transgenic rat model of HD (tgHD). Subjects were 10-12 month old tgHD rats and wildtype littermates. We examined the striatum, globus pallidus, entopeduncular nucleus, the subthalamic nucleus and substantia nigra at different levels. First, we determined the overall neuronal activity at a supracellular level, by cytochrome oxidase histochemistry. Secondly, we determined the subcellular metabolic activity, by immunohistochemistry for peroxisome proliferator-activated receptor-gamma transcription co-activator (PGC-1alpha), a key player in the mitochondrial machinery. Finally, we performed extracellular single unit recordings in the nuclei to determine the cellular activity. In tgHD rats, optical density analysis showed a significantly increased cytochrome oxidase levels in the globus pallidus and subthalamic nucleus when compared to controls. PGC-1alpha expression was only enhanced in the subthalamic nucleus and electrophysiological recordings revealed decreased firing frequency of the majority of the neurons in the globus pallidus and increased firing frequency of the majority of the neurons in the subthalamic nucleus. Altogether, our results suggest that the globus pallidus and subthalamic nucleus play a role in the neurobiology of HD and can be potential targets for therapeutic interventions. PMID- 22813865 TI - Spatiotemporal evolution of blood brain barrier damage and tissue infarction within the first 3h after ischemia onset. AB - Blood brain barrier (BBB) damage that occurs within the thrombolytic time window is increasingly appreciated to negatively impact the safety and efficacy profiles of thrombolytic therapy for ischemic stroke. However, the spatiotemporal evolution of BBB damage in this early stroke stage and the underlying mechanisms remain unclear. Here, we investigated the topographical distribution of BBB damage and its association with tissue injury within the first 3 h after ischemia onset and the roles of matrix metalloproteinase (MMP)-2/9 in this process. Rats were subjected to 1, 2, or 3 h of middle cerebral artery occlusion (MCAO) followed by 10 min reperfusion with fluorescence-labeled dextran as BBB permeability marker. Acute tissue infarction was evidenced by staining defect with triphenyltetrazolium chloride (TTC). Cerebral blood flow (CBF) was measured by magnetic resonance imaging. MMP-2/9 were assessed by gel and in situ zymography. After 2-h MCAO, dextran leakage was seen in the ischemic ventromedial striatum and the preoptic area which showed ~70% CBF reduction, and expanded to other MCA regions including the cortex after 3-h MCAO. Interestingly, high (2000 kDa) and low (70 kDa) molecular weight dextrans displayed almost identical leakage patterns. Different from BBB damage, tissue infarction was first seen in the ischemic dorsal striatum and the parietal/insular cortex which experienced ~90% CBF reduction. Increased gelatinolytic activity colocalized with dextran leakage, and MMP-2 was found to be the major enzymatic source on gelatin zymograms. Pretreatment with MMP inhibitor GM6001 significantly reduced dextran leakage induced by 2-h and 3-h MCAO. Taken together, our findings reveal substantial differences in the topographic distribution of BBB damage and tissue infarction within the first 3 h after MCAO onset. Unlike ischemic neuronal damage, BBB damage appears to develop faster in brain regions with moderately severe ischemia, and MMP-2 contributes to this early ischemic BBB damage. PMID- 22813866 TI - Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice. AB - Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 (hSOD1), models of familial amyotrophic lateral sclerosis. This denervation is especially marked in fast limb muscles, and precedes death of motor neuron somata. This study used mice that expressed yellow fluorescent protein (YFP) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle (epitrochleoanconeus, ETA) in presymptomatic and symptomatic hSOD1-G85R mice, compared to those in mice that express wild-type (wt) hSOD1. The percentage of endplates (identified using fluorescently-labeled alpha-bungarotoxin) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice, but fell to ~50% in symptomatic mice. The number of large diameter (>=4 MUm) axons in the ETA nerve also decreased as mice became symptomatic, and endplate innervation correlated best with the number of large diameter axons. Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2+ entry and vesicular exo/endocytosis. Most visible motor terminals (>90%) remained capable of responding to nerve stimulation in both pre- and symptomatic hSOD1-G85R mice, but with functional alterations. Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release, whereas symptomatic terminals exhibited increased acidification and reduced vesicular release. The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice. PMID- 22813867 TI - Binding of moesin and ezrin to membranes containing phosphatidylinositol (4,5) bisphosphate: a comparative study of the affinity constants and conformational changes. AB - The plasma membrane-cytoskeleton interface is a dynamic structure participating in a variety of cellular events. Moesin and ezrin, proteins from the ezrin/radixin/moesin (ERM) family, provide a direct linkage between the cytoskeleton and the membrane via their interaction with phosphatidylinositol 4,5 bisphosphate (PIP(2)). PIP(2) binding is considered as a prerequisite step in ERM activation. The main objective of this work was to compare moesin and ezrin interaction with PIP(2)-containing membranes in terms of affinity and to analyze secondary structure modifications leading eventually to ERM activation. For this purpose, we used two types of biomimetic model membranes, large and giant unilamellar vesicles. The dissociation constant between moesin and PIP(2) containing large unilamellar vesicles or PIP(2)-containing giant unilamellar vesicles was found to be very similar to that between ezrin and PIP(2)-containing large unilamellar vesicles or PIP(2)-containing giant unilamellar vesicles. In addition, both proteins were found to undergo conformational changes after binding to PIP(2)-containing large unilamellar vesicles. Changes were evidenced by an increased sensitivity to proteolysis, modifications in the fluorescence intensity of the probe attached to the C-terminus and in the proportion of secondary structure elements. PMID- 22813868 TI - Antibodies to wheat high-molecular-weight glutenin subunits in patients with celiac disease. AB - BACKGROUND: Wheat gluten comprises gliadins and glutenins. The high-molecular weight (HMW) glutenin subunits (GS)-1Dy10 are toxic for patients with celiac disease (CD). This study aimed to assess whether CD patients mount a serological response to HMW-GS-1Dy10. METHODS: Recombinant HMW-GS-1Dy10 was deamidated using human recombinant tissue transglutaminase. MALDI-TOF was performed to compare the level of deamidation of glutamine residues between material before and after treatment. Enzyme-linked immunosorbent assays were developed. Sera from patients with untreated CD and gastrointestinal disease controls were tested and receiver operator characteristics were used to calculate cutoffs. RESULTS: MALDI-TOF revealed a number of fragments matching known HMW-GS-1Dy10 sequences within both the deamidated and non-deamidated material. Evidence of deamidation of glutamine residues was found only within the human transglutaminase-treated material. Patients with untreated CD had significantly increased levels of serum antibodies to HMW-GS-1Dy10 compared to controls. Undeamidated HMW-GS-1Dy10 IgA antibodies had sensitivities and specificities of 72.5 and 78.26%, respectively. Deamidated HMW-GS-1Dy10 IgA antibodies had sensitivities and specificities of 76.8 and 65.2%. Undeamidated HMW-GS-1Dy10 IgG antibodies had sensitivities and specificities of 75.3 and 68.1%. Deamidated HMW-GS-1Dy10 IgG antibodies had sensitivities and specificities of 36.2 and 92.8%. CONCLUSION: Patients with untreated CD have raised antibody levels to HMW-GS-1Dy10, indicating the participation of these proteins in the adaptive immune response to gluten. Discrimination between CD patients and controls is not enhanced by deamidation of HMW-GS-1Dy10. Thus antibodies to these proteins are not useful markers for CD detection. PMID- 22813869 TI - Short-term heart rate variability--age dependence in healthy subjects. AB - Heart rate variability (HRV) analysis is an established method to characterize the autonomic regulation and is based mostly on 24h Holter recordings. The importance of short-term HRV (less than 30 min) for various applications is growing consistently. Major reasons for this are the suitability for ambulatory care and patient monitoring and the ability to provide an almost immediate test result. So far, there have been only a few studies that provided statistically relevant reference values for short-term HRV. In our study, 5 min short-term HRV indices were determined from 1906 healthy subjects. From these records, linear and nonlinear indices were extracted. To determine general age-related influences, HRV indices were compared from subjects aged 25-49 years with subjects aged 50-74 years. In a second approach, we examined the development of HRV indices by age in terms of age decades (25-34, 35-44, 45-54, 55-64 and 65-74 years). Our results showed significant variations of HRV indices by age in almost all domains. While marked dynamics in terms of parameter change (variability reduction) were observed in the first age decades, in particular the last two age decades showed certain constancy with respect to the HRV indices examined. PMID- 22813870 TI - Preliminary safety assessment of a membrane-bound delta 9 desaturase candidate protein for transgenic oilseed crops. AB - A gene encoding delta 9 desaturase (D9DS), an integral membrane protein, is being considered for incorporation into oilseed crops to reduce saturated fatty acids and thus improve human nutritional value. Typically, a safety assessment for transgenic crops involves purifying heterologously produced transgenic proteins in an active form for use in safety studies. Membrane-bound proteins have been very difficult to isolate in an active form due to their inherent physicochemical properties. Described here are methods used to derive enriched preparations of the active D9DS protein for use in early stage safety studies. Results of these studies, in combination with bioinformatic results and knowledge of the mode of action of the protein, along with a history of safe consumption of related proteins, provides a weight of evidence supporting the safety of the D9DS protein in food and feed. PMID- 22813871 TI - Narirutin fraction from citrus peels attenuates LPS-stimulated inflammatory response through inhibition of NF-kappaB and MAPKs activation. AB - In this study, we examined the regulatory activity of narirutin fraction from citrus peels on the production of inflammatory mediators managing acute or chronic inflammatory diseases in macrophages. Narirutin fraction inhibited the release, by lipopolysaccharide (LPS)-stimulated macrophages, of nitric oxide (NO) and prostaglandin E2 (PGE2) through suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. The release, by LPS stimulated macrophages, of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) was also reduced by narirutin fraction in a dose-dependent manner. Furthermore, narirutin fraction inhibited the LPS-mediated activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs), which are signaling molecules involved in production of pro-inflammatory factors. As a result of these properties, narirutin fraction has the potential to be used as a functional dietary supplement and effective anti-inflammatory agent. PMID- 22813872 TI - Heavy metals in raw, fried and grilled Mediterranean finfish and shellfish. AB - The effect of domestic pan-frying and grilling on Cd, Cr, Cu, Fe, Hg, Ni, Pb and Zn content of popular small Mediterranean finfish and shellfish was studied. The species selected -namely anchovy, bogue, hake, picarel, sardine, sand smelt, stripped mullet, Mediterranean mussel, shrimp and squid- are among the most commonly marketed and consumed in Greece and most of the Mediterranean countries. Both culinary practices examined resulted in increased metals concentrations compared to those of raw samples, the increment being inversely related to fish size and -in most cases- being more extended in pan-frying. The consumption of cooked seafood is expected to provide significant amounts of Fe and Zn followed, in decreasing order, by Cr, Cu and Ni. In addition, the estimation of (a) weekly intakes and (b) target hazard quotients for the toxic elements Cd, Hg and Pb revealed that the cooked fish and shellfish do not pose any health risk for the consumers. PMID- 22813873 TI - Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study. AB - BACKGROUND: To determine the normal range of left ventricular (LV) 2- dimensional (2-D) strain and vendor-specific differences, a multicenter prospective 2-D strain study endorsed by the Japanese Society of Echocardiography was conducted. METHODS AND RESULTS: 2-D speckle tracking analysis was performed on 817 healthy subjects (age range, 0-88 years); the images included 3 LV short axis and 3 apical views using an ultrasound system from 1 of the 3 different vendors (V(1), n=333; V(2), n=330; V(3), n=337). With the 2-D speckle tracking software from each vendor, radial, circumferential and longitudinal strain were measured using an 18-segment model. Inter-vendor variability was also assessed in a subset of subjects. The feasibility for 2-D strain measurements was different among the 3 vendors (V(1), 83%; V(2), 70%; V(3), 88%, P<0.01). The global radial (V(1), 54.6+/-12.6%; V(2), 36.3+/-8.2%; V(3), 51.4+/-8.0%), circumferential (V(1), 22.8+/-2.9%; V(2), -22.2+/-3.2%; V(3), -30.5+/-3.8%), and longitudinal (V(1), 21.3+/-2.1%; V(2), -18.9+/-2.5%; V(3), -19.9+/-2.4%) strain measurements were significantly different for each of the vendors. Segmental strain was also different between the 3 vendors. On inter-vendor analysis, vendor agreement ranged from mild to moderate. CONCLUSIONS: Reference values are provided for normal 2-D strain for 3 different ultrasound vendors. Due to a low inter-vendor agreement, 2-D strain data are not interchangeable when conducting a longitudinal follow-up or a cross-sectional assessment of LV function. PMID- 22813874 TI - Neurological benefit of therapeutic hypothermia following return of spontaneous circulation for out-of-hospital non-shockable cardiac arrest. AB - BACKGROUND: Although therapeutic hypothermia is an effective therapy for comatose adults experiencing out-of-hospital shockable cardiac arrest, there is insufficient evidence that is also applicable for those with out-of-hospital non shockable cardiac arrest. METHODS AND RESULTS: Of 452 comatose adults treated with therapeutic hypothermia after return of spontaneous circulation (ROSC) subsequent to an out-of-hospital cardiac arrest of cardiac etiology, 372 who had a bystander-witnessed cardiac arrest, target core temperature of 32-34 degrees C and cooling duration of 12-72 h were eligible for this study (75 cases of non shockable cardiac arrest, 297 cases of shockable cardiac arrest). The median collapse-to-ROSC interval was significantly longer in the non-shockable group than in the shockable group (30 min vs. 22 min, P=0.008), resulting in a significantly lower frequency of 30-day favorable neurological outcome in the non shockable group compared with the shockable group (32% vs. 66%, P<0.001). However, an analysis of data in quartiles assigned to varying lengths of collapse to-ROSC interval revealed a similar frequency of 30-day favorable neurological outcome among both groups when the collapse-to-ROSC interval was <=16 min (90% non-shockable group vs. 92% shockable group; odds ratio 0.80, 95% confidence interval 0.09-7.24, P=0.84). CONCLUSIONS: Post-ROSC cooling is an effective treatment for patients with non-shockable cardiac arrest when the time interval from collapse to ROSC is short. PMID- 22813875 TI - Prognostic value of normal stress-only technetium-99m myocardial perfusion imaging protocol. Comparison with standard stress-rest protocol. AB - BACKGROUND: Patients with a normal stress image on technetium-99m (Tc-99m) single-photon emission computed tomography (SPECT) have a good prognosis for diagnosing coronary artery disease. However, current guidelines recommend stress and rest imaging to confirm that a stress image is normal. METHODS AND RESULTS: We determined all-cause of cardiac events (acute coronary syndrome and sudden death) in 1,939 patients undergoing stress myocardial perfusion SPECT with Tc-99m radiotracers. Patients with an abnormal stress image were excluded, so we focused on 1,125 patients in whom the stress SPECT study was interpreted as normal. A stress-only protocol was used in 726 patients (adenosine=339; exercise=387), whereas 399 had both stress and rest imaging (adenosine=294; exercise=105). Mean follow-up was 1,252 days. At the end of follow-up, there were 39 cardiac events in the stress-only cohort and 19 in the stress-rest cohort. Kaplan-Meier analysis revealed that there were no differences for the entire cohort of cardiac events not only between the stress-only and stress-rest protocols but also for stressor modality, despite the fact that the stress-rest cohort showed higher coronary risk factors. CONCLUSIONS: Patients determined as having a normal SPECT on the basis of stress imaging alone have a similar cardiac event rate as those who have a normal SPECT on the basis of evaluation of both stress and rest images. This imaging strategy will significantly reduce radiation exposure in a substantial number of patients. PMID- 22813877 TI - A novel quantitative proteomics workflow by isobaric terminal labeling. AB - Quantification by series of b, y fragment ion pairs generated from isobaric labeled peptides in MS2 spectra has recently been considered an accurate strategy in quantitative proteomics. Here we developed a novel MS2 quantification approach named quantitation by isobaric terminal labeling (QITL) by coupling (18)O labeling with dimethylation. Trypsin-digested peptides were labeled with two (16)O or (18)O atoms at their C-termini in H(2)(16)O or H(2)(18)O. After blocking all epsilon-amino groups of lysines through guanidination, the N-termini of the peptides were accordingly labeled with formaldehyde-d(2) or formaldehyde. These indistinguishable, isobaric-labeled peptides in MS1 spectra produce b, y fragment ion pairs in the whole mass range of MS2 spectra that can be used for quantification. In this study, the feasibility of QITL was first demonstrated using standard proteins. An accurate and reproducible quantification over a wide dynamic range was achieved. Then, complex rat liver samples were used to verify the applicability of QITL for large-scale quantitative analysis. Finally, QITL was applied to profile the quantitative proteome of hepatocellular carcinoma (HCC) and adjacent non-tumor liver tissues. Given its simplicity, low-cost, and accuracy, QITL can be widely applied in biological samples (cell lines, tissues, and body fluids, etc.) for quantitative proteomic research. PMID- 22813876 TI - Proteome signatures of inflammatory activated primary human peripheral blood mononuclear cells. AB - Proteome profiling is the method of choice to identify marker proteins whose expression may be characteristic for certain diseases. The formation of such marker proteins results from disease-related pathophysiologic processes. In healthy individuals, peripheral blood mononuclear cells (PBMCs) circulate in a quiescent cell state monitoring potential immune-relevant events, but have the competence to respond quickly and efficiently in an inflammatory manner to any invasion of potential pathogens. Activation of these cells is most plausibly accompanied by characteristic proteome alterations. Therefore we investigated untreated and inflammatory activated primary human PBMCs by proteome profiling using a 'top down' 2D-PAGE approach in addition to a 'bottom up' LC-MS/MS-based shotgun approach. Furthermore, we purified primary human T-cells and monocytes and activated them separately. Comparative analysis allowed us to characterize a robust proteome signature including NAMPT and PAI2 which indicates the activation of PBMCs. The T-cell specific inflammation signature included IRF-4, GBP1 and the previously uncharacterized translation product of GBP5; the corresponding monocyte signature included PDCD5, IL1RN and IL1B. The involvement of inflammatory activated PBMCs in certain diseases as well as the responsiveness of these cells to anti-inflammatory drugs may be evaluated by quantification of these marker proteins. This article is part of a Special Issue entitled: Integrated omics. PMID- 22813878 TI - Proteomic analysis of Intercept-treated platelets. AB - In the past decades, transfusion medicine has been driven by the quest for increased safety against transfusion-transmitted infections, mainly by better donor selection and by the development of improved serological and nucleic-acid based screening assays. Recently, pathogen reduction technologies became available and started to be implemented in several countries, with the primary goal to fight against bacterial contamination of blood products, a rare but dramatic event against which there was no definitive measure. Though pathogen reduction technologies represent a quantum leap in transfusion safety, the biomedical efficacy of platelet concentrates (PCs) treated with various pathogen reduction techniques has been recently questioned by clinical studies. Here, a gel-based proteomic analysis of PCs (n=5), Intercept-treated or untreated, from pooled buffy-coat (10 donors per PC) at Days 1, 2 and 8, shows that the Intercept process that is the most widespread pathogen reduction technique to date, has relatively low impact on the proteome of treated platelets: the process induces modifications of DJ-1 protein, glutaredoxin 5, and G(i)alpha 2 protein. As for the impact of storage, chloride intracellular channel protein 4 (CLIC4) and actin increased independently of Intercept treatment during storage. Whereas alteration of the DJ-1 protein and glutaredoxin 5 points out an oxidative stress-associated lesion, modification of G(i)alpha2 directly connects a possible Intercept associated lesion to haemostatic properties of Intercept-treated platelets. This article is part of a Special Issue entitled: Integrated omics. PMID- 22813879 TI - Allergomic study of cypress pollen via combinatorial peptide ligand libraries. AB - Although Cupressus sempervirens (Cups) pollen represents one of the main aeroallergens in southern Europe, only two Cups allergens have yet been identified and reported: Cup s 1 and Cup s 3. The aim of this study was to identify allergens in cypress pollen using an immuno-proteomic approach. A sequential pollen protein extraction was developed and supplemented by a combinatorial peptide ligand library (CPLL) treatment to select low-abundance species. Control extracts and CPLL eluates have then been resolved by 1-DE and 2 DE gel electrophoresis, blotted and confronted with sera from cypress allergic patients. Extracted proteins including IgE-binding components were identified using nanoLC-MS/MS analysis. A total of 108 unique gene products were identified analyzing the eluates and control loaded onto 1-DE SDS-PAGE. Forty proteins were identified in control samples and 68 supplementary species upon CPLL treatment. Out of the 12 IgE-binding proteins characterized in 2-DE gels, 9 were already reported as allergens in various sources including the two major known allergens of Cupressaceae (groups 1 and 2). Three IgE-binding proteins, not previously reported as allergens, are newly described. The improvement in protein extraction combined with the enrichment of low-abundance species allowed us to extend the repertoire of potential cypress pollen allergens. PMID- 22813881 TI - Effect of high glucose on secreted proteome in cultured retinal pigmented epithelium cells: its possible relevance to clinical diabetic retinopathy. AB - Retinopathy has been observed in around quarter of diabetic patients. Diabetic retinopathy can result in poor vision and even blindness since high glucose has been evidenced to weaken retinal capillary leading to leakage of blood into the surrounding space. In the present study, a proteomics-based approach has been applied to analyze a model retinal pigmented epithelium cell line, ARPE-19, grown in mannitol-balanced 5.5mM, 25 mM and 100 mM D-glucose culture media and used as a model for hyperglycemia secretomic analysis. Totally, 55 differentially secreted proteins have been firmly identified representing 46 unique gene products. These secreted proteins mainly function in cytoskeleton-associated adhesion/junction (such as galectin-3-binding protein) and transport (multidrug resistance-associated protein 1). Additionally, the identified secreted markers including asialoglycoprotein receptor 1, lysophosphatidic acid receptor 3, moesin, MPP2, haptoglobin and cathepsin D were further validated in plasma samples coming from type 2 diabetic patients with retinopathy and healthy donors. In summary, we report a comprehensive retinal cell-based proteomic approach for the identification of potential secreted retinal markers-induced in high glucose conditions. Some of these identified secreted proteins have been validated in diabetic retinopathy plasma demonstrating the potentially utilizing of these markers in screening and treating diabetic retinopathy. PMID- 22813880 TI - An optimized isolation of biotinylated cell surface proteins reveals novel players in cancer metastasis. AB - Details of metastasis, the deadliest aspect of cancer, are unclear. Cell surface proteins play central roles in adhesive contacts between the tumor cell and the stroma during metastasis. We optimized a fast, small-scale isolation of biotinylated cell surface proteins to reveal novel metastasis-associated players from an isogenic pair of human MDA-MB-435 cancer cells with opposite metastatic phenotypes. Isolated proteins were trypsin digested and analyzed using LC-MS/MS followed by quantitation with the Progenesis LC-MS software. Sixteen proteins displayed over twofold expression differences between the metastatic and non metastatic cells. Interestingly, overexpression of most of them (14/16) in the metastatic cells indicates a gain of novel surface protein profile as compared to the non-metastatic ones. All five validated, differentially expressed proteins showed higher expression in the metastatic cells in culture, and four of these were further validated in vivo. Moreover, we analyzed expression of two of the identified proteins, CD109 and ITGA6 in 3-dimensional cultures of six melanoma cell lines. Both proteins marked the surface of cells derived from melanoma metastasis over cells derived from primary melanoma. The unbiased identification and validation of both known and novel metastasis-associated proteins indicate a reliable approach for the identification of differentially expressed surface proteins. PMID- 22813883 TI - Glycomics of pediatric and adulthood diseases of the central nervous system. AB - Glycosylation consists in the covalent linkage of a carbohydrate structure to membrane bound and secreted glycoconjugates. It is a common post-translational modification that serves multiple functions in cell differentiation, signaling and intercellular communication. Unlike DNA/RNA/protein, the addition of complex carbohydrates is not-template driven and it is conceivable that both genetics and environmental factors might interact to influence glycosylation machinery in several pathological processes. Over the last few decades, the recognition of Congenital Disorders of Glycosylation (CDG) as an increasing number of genetic diseases of glycosylation with almost constant nervous system involvement, dramatically illustrated the consequences of abnormal glycosylation as improper CNS development and function. In addition, CDG recognition contributed to postulate that aberrant glycosylation processes might play a role in multifactorial, complex CNS diseases. On this context, CNS glycomics explores the effects of possible aberrant glycosylation to identify potential glyco-biomarkers useful for the diagnosis and ultimately for potential intervention strategies in neurological diseases. Up to date, CNS glycomics is an emerging, still uncharted area because of the specificity of CNS glycosylation, the complexity of the neurological disorders and for the inaccessibility and invasiveness of disease relevant samples. Here we review current knowledge on clinical glycomics of nervous system diseases, starting with CDG to include those pediatric and adulthood neuropsychiatric diseases where some evidences suggest that multifactor determinants converge to dysregulate glycosylation. Conventional and mass spectrometry-based high throughput technology for glyco-biomarker detection in CNS diseases is reported. PMID- 22813882 TI - Microparticle content of plasma for transfusion is influenced by the whole blood hold conditions: pre-analytical considerations for proteomic investigations. AB - Microparticles (MPs) are shed from normal blood cells and may contribute to the coagulation potential of plasma. Transfusion of fresh frozen plasma (FFP) is used to correct coagulopathies and blood loss in trauma or major surgery. The role of MPs in FFP clinical efficacy is unknown. Regulations that govern the preparation of FFP vary in different countries. The aim of this study was to determine the effect of whole blood (WB)-hold conditions before FFP preparation on the MP profile. WB units were held at room temperature (RT) or combination of RT and refrigeration for up to 24h before FFP preparation. The MP content in thawed FFP was measured to reflect transfusion practice. The absolute number of MPs in FFP increased with longer WB hold time. Refrigeration of WB may also promote increased generation of MPs. In particular the number of platelet-derived and phosphatidylserine-containing MPs, which are known to have procoagulant properties, increased. Lipid peroxidation increased with longer WB-hold time. Donor-related factors appear to govern lipid peroxidation levels. Holistic proteomic and coagulant analyses of FFP MPs are warranted. Such information could guide the choice of the optimal handling conditions of WB and the most relevant quality control procedures for FFP. This article is part of a Special Issue entitled: Integrated omics. PMID- 22813884 TI - Alterations in gait initiation are present in those with posttraumatic ankle osteoarthritis: a pilot study. AB - The purpose of this investigation was to determine if stereotypical patterns of gait initiation are altered in those with posttraumatic ankle osteoarthritis. Ten subjects, five with unilateral ankle osteoarthritis and five uninjured controls, participated. Subjects completed the SF-36 and Ankle Osteoarthritis Scale to quantify self-reported disability as well as 10 dual-limb static stance trials and 10 gait initiation trials with each leg. Center of pressure outcomes were calculated for static balance trials while the peak center of pressure excursions were calculated for each phase of gait initiation. The results indicate greater self-reported disability (P < .05) and worse static postural control (P < .05) in the ankle osteoarthritis group. Nonstereotypical patterns were also observed during the first and third phases of gait initiation in those with ankle osteoarthritis. The results of this pilot study suggest that supraspinal motor control mechanisms may have changed in those with posttraumatic ankle osteoarthritis. PMID- 22813885 TI - Respiratory muscle fatigue following exercise in patients with interstitial lung disease. AB - BACKGROUND: It is not known whether respiratory muscle fatigue occurs as a consequence of exercise in patients with interstitial lung disease (ILD) and, if so, to what extent it is related to changes in dynamic lung volumes. OBJECTIVES: To assess the development of respiratory muscle fatigue in patients with ILD and relate it to the respiratory pattern during exercise. METHODS: Sixteen ILD patients (11 women) performed incremental, symptom-limited cycle ergometry with inspiratory capacity manoeuvres used to measure changes in end-expiratory lung volume (EELV). Twitch transdia-phragmatic pressure (TwPdi) and twitch gastric pressure (TwT10Pga), in response to magnetic stimulation, were used to assess the development of fatigue. RESULTS: TwPdi did not differ significantly before and after exercise (21.8 +/- 8 vs. 20.2 +/- 8 cm H2O; p = 0.10), while TwT10Pga fell from 28.6 +/- 18 to 25.2 +/- 14 cm H2O (p = 0.02). EELV fell from 2.18 +/- 0.65 to 1.91 +/- 0.59 liters following exercise (p = 0.04). The fall in TwT10Pga correlated with peak oxygen uptake at peak of exercise (r = -0.52, p = 0.041), increase in heart rate (r = 0.53, p = 0.032) and with the decrease of EELV during exercise (r = 0.57, p = 0.021). Abdominal muscle fatiguers (n = 9, 56%), defined as having a >=10% fall in TwT10Pga, had a fall in EELV of 22 +/- 22% compared to 0.7 +/- 8% in non-fatiguers (p = 0.016). CONCLUSION: Abdominal muscle fatigue develops during exercise in some ILD patients in association with increased expiratory muscle activity manifested by reduced EELV. PMID- 22813886 TI - Patient cost associated with filling a prescription for extended-duration venous thromboembolism (VTE) prophylaxis following surgery for gynecologic cancer. AB - OBJECTIVE: The primary purpose of this study was to determine the average patient cost for filling a prescription for extended-duration enoxaparin prophylaxis. METHODS: Women who underwent major abdominal/pelvic surgery for histologically confirmed gynecologic malignancy were included. Patients who underwent minimally invasive surgery, had benign disease or were on treatment for existing VTE were excluded. Pharmacy resource specialists electronically submitted test prescriptions to verify enoxaparin coverage in the outpatient setting prior to hospital discharge. Patient co-pay information collected included: the number of patients requiring prescription insurance prior authorization, those qualifying for the Lovenox Patient Assistance Program(r) (PAP) and insurance status. RESULTS: Three hundred and sixty-four patients were discharged with extended duration enoxaparin prophylaxis for 28 days between October 2009 and May 2011. The average patient cost to complete 28 days of enoxaparin prophylaxis was $62 (median $21, range $0-1210). Prior authorization was required for 32 patients (10%). Two patients (0.6%) qualified for the Lovenox Patient Assistance Program(r). A decrease in the average patient cost from $71 to $52 (median $30 to $10) was observed after generic enoxaparin approval in July 2011. CONCLUSION: Our results show that at least 90% of patients filled their prescription of extended duration enoxaparin prophylaxis after major abdominal surgery for cancer regardless of cost. PMID- 22813887 TI - Analysis of time-resolved interaction force mode AFM imaging using active and passive probes. AB - We present an in-depth analysis of time-resolved interaction force (TRIF) mode imaging for atomic force microscopy (AFM). A nonlinear model of an active AFM probe, performing simultaneous topography and material property imaging on samples with varying elasticity and adhesion is implemented in Simulink(r). The model is capable of simulating various imaging modes, probe structures, sample material properties, tip-sample interaction force models, and actuation and feedback schemes. For passive AFM cantilevers, the model is verified by comparing results from the literature. As an example of an active probe, the force sensing integrated readout and active tip (FIRAT) probe is used. Simulation results indicate that the active and damped nature of FIRAT provides a significant level of control over the force applied to the sample, minimizing sample indentation and topography error. Active tip control (ATC) preserves constant contact time during force control for stable contact while preventing the loss of material property information such as elasticity and adhesive force. Simulation results are verified by TRIF mode imaging of the samples with both soft and stiff regions. PMID- 22813888 TI - An annealing algorithm to correct positioning errors in ptychography. AB - Ptychography offers the possibility of improving the resolution of atomic-scale (electron and X-ray) transmission microscopy without any of the demands of high quality lenses: its resolution is in theory only limited by the effective synthetic numerical aperture determined by the angular size of the detector. However, it has been realised experimentally that a major weakness of the approach is that the obtainable resolution is only as good as the accuracy to which the illuminating beam can be moved relative to the specimen. This can be catastrophic in the electron case because of thermal drift and hysteresis in the probe scan coils. We present here a computationally efficient extension of the 'ePIE' ptychographic reconstruction algorithm for correcting these errors retrospectively. We demonstrate its effectiveness using simulations and results from visible light and electron beam experiments that show it can correct positioning errors tens of times larger than the pixel size in the resulting image. PMID- 22813889 TI - Caries is the main cause for dental pain in childhood: findings from a birth cohort. AB - AIM: The aim of the study was to evaluate the prevalence of dental pain in preschool children and its association with socioeconomic, demographic, clinical, and behavior variables. SUBJECTS AND METHODS: The study was nested in a population-based birth cohort from Pelotas, Brazil, started in 2004. A sample of 1,129 children aged 5 years was dentally examined, and their mothers were interviewed. Exploratory variables included demographics, socioeconomic status, mothers' oral health status and associated behaviors, and caries in primary teeth. Data were analyzed using multivariable Poisson regression. RESULTS: The prevalence of dental pain was 16.5% (95% CI: 14.4-18.8). Multivariate analysis showed that dark-skinned children (prevalence ratio, PR = 1.6, 95% CI: 1.1-2.4) from low socioeconomic level (PR 1.9, 1.2-3.0) whose mothers had less than 4 years of education (PR 1.9, 1.0-3.6), from mothers with less than 10 teeth in at least one arch (PR 1.7, 1.2-2.5) and less than 10 in two arches (PR 1.6, 1.0 2.6), and those with high caries prevalence at the age of 5 years (PR 4.8, 3.3 7.1) were more likely to experience dental pain. CONCLUSIONS: Unrestored caries is the main factor associated with dental pain in childhood. Socioeconomic aspects and family context in which dental pain occurs should also be taken into account when dental pain preventive measures are implemented. PMID- 22813890 TI - MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. AB - Cellular transcripts of all types, including coding messenger (m)RNAs and noncoding (nc)RNAs, are subject to extensive post-transcriptional regulation. Among the factors that elicit post-transcriptional control, microRNAs (miRNAs) have emerged as a major class of small regulatory RNAs. Since RNA-RNA interactions can be modeled computationally, several excellent programs have been developed to predict the interaction of miRNAs with target transcripts. However, many such predictions are not realized for different reasons, including absent or low-abundance expression of the miRNA in the cell, the existence of competing factors or conformational changes masking the microRNA site, and the possibility that target transcripts are not present in the prediction databases, as is the case for long ncRNAs. Here, we provide a systematic approach termed MS2-TRAP (tagged RNA affinity purification) for identifying miRNAs associated with a target transcript in the cellular context. We illustrate the use of this methodology by identifying microRNAs that associate with a long intergenic (li)ncRNA, based on the expression of the lincRNA tagged with MS2 RNA hairpins (lincRNA-p21-MS2) and the concomitant expression of a fusion protein recognizing the MS2 RNA hairpins, MS2-GST. After affinity pulldown of the ribonucleoprotein (RNP) complex comprising [MS2-GST/lincRNA-p21-MS2], the RNA in the pulldown material was isolated and reverse transcribed (RT). Subsequent assessment of the microRNAs present in the pulldown complex by using real-time quantitative (q)PCR analysis led to the identification of bona fide miRNAs that interact with and control the abundance of lincRNA-p21. We describe alternative designs and applications of this approach, and discuss its implications in deciphering post transcriptional gene regulatory schemes. PMID- 22813891 TI - Inferences from genomic models in stratified populations. AB - Unaccounted population stratification can lead to spurious associations in genome wide association studies (GWAS) and in this context several methods have been proposed to deal with this problem. An alternative line of research uses whole genome random regression (WGRR) models that fit all markers simultaneously. Important objectives in WGRR studies are to estimate the proportion of variance accounted for by the markers, the effect of individual markers, prediction of genetic values for complex traits, and prediction of genetic risk of diseases. Proposals to account for stratification in this context are unsatisfactory. Here we address this problem and describe a reparameterization of a WGRR model, based on an eigenvalue decomposition, for simultaneous inference of parameters and unobserved population structure. This allows estimation of genomic parameters with and without inclusion of marker-derived eigenvectors that account for stratification. The method is illustrated with grain yield in wheat typed for 1279 genetic markers, and with height, HDL cholesterol and systolic blood pressure from the British 1958 cohort study typed for 1 million SNP genotypes. Both sets of data show signs of population structure but with different consequences on inferences. The method is compared to an advocated approach consisting of including eigenvectors as fixed-effect covariates in a WGRR model. We show that this approach, used in the context of WGRR models, is ill posed and illustrate the advantages of the proposed model. In summary, our method permits a unified approach to the study of population structure and inference of parameters, is computationally efficient, and is easy to implement. PMID- 22813892 TI - DNA repair pathway choice is influenced by the health of Drosophila melanogaster. AB - In nature, individuals vary tremendously in condition and this may be an important source of variation in mutation rate. Condition is likely to affect cell state and thereby impact the amount of DNA damage sustained and/or the way it is repaired. Here, we focus on DNA repair. If low-condition individuals are less capable of devoting the same level of resources to accurate repair, they may suffer higher mutation rates. However, repair decisions are also governed by various aspects of cell physiology, which may render the prediction that "higher condition individuals use better repair mechanisms" too simplistic. We use a larval diet manipulation in Drosophila melanogaster to create high- and low condition individuals and then contrast their relative usage of three repair pathways [homologous recombination (HR), single-strand annealing (SSA), and nonhomologous end joining (NHEJ)] that differ in their mechanistic requirements and their mutational consequences. We find that low-condition flies are more likely than high-condition flies to use the most conservative of these three repair pathways, suggesting that physiological constraints on repair pathway usage may be more important than energetic costs. We also show that the repair differences between high- and low-condition flies resemble those between young and old flies, suggesting the underlying mechanisms may be similar. Finally, we observe that the effect of larval diet on adult repair increases as flies age, indicating that developmental differences early in life can have long-lasting consequences. PMID- 22813903 TI - Erythropoietin use and immunogenicity of hepatitis B virus vaccine in chronic kidney disease patients: a meta-analysis. AB - BACKGROUND: It is known that the immunogenicity of hepatitis B virus (HBV) vaccine is lower in uremic patients than healthy subjects. Numerous inherited or acquired factors have been implicated in this lowered response, and the high frequency of recombinant human erythropoietin use among patients on maintenance dialysis has been suggested to play a pivotal role. However, the impact of therapy with recombinant erythropoietin on the immune response to HBV vaccine in patients with chronic kidney disease (CKD) is not appropriately detailed. AIM: To evaluate the influence of human recombinant erythropoietin therapy on the immunological response to HBV vaccine in CKD patients by performing a systematic review of the literature with a meta-analysis of clinical studies. METHODS: We used the random-effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end-point of interest was the rate of patients showing seroprotective anti-hepatitis B titers at completion of a hepatitis B vaccine schedule among human erythropoietin users versus those who did not receive the drug in a CKD population. RESULTS: We identified 11 studies involving 862 unique patients with CKD. Aggregation of study results did not show a significant increase in response rates among erythropoietin user versus non-user patients (pooled odds ratio = 1.431; 95% CI 0.954; 2.146), according to a random-effects model. No heterogeneity was found, the p value was 0.1 for our test of study heterogeneity (Q = 14.147). Stratified analysis in various subgroups of interest did not significantly change these findings. CONCLUSIONS: Our meta-analysis showed no link between immunological response to HBV vaccine and therapy with human recombinant erythropoietin among individuals on long-term dialysis. We suggest the use of recombinant vaccine towards hepatitis B in patients on regular dialysis irrespective of erythropoietin treatment. PMID- 22813893 TI - Diversification of a protein kinase cascade: IME-2 is involved in nonself recognition and programmed cell death in Neurospora crassa. AB - Kinase cascades and the modification of proteins by phosphorylation are major mechanisms for cell signaling and communication, and evolution of these signaling pathways can contribute to new developmental or environmental response pathways. The Saccharomyces cerevisiae kinase Ime2 has been well characterized for its role in meiosis. However, recent studies have revealed alternative functions for Ime2 in both S. cerevisiae and other fungi. In the filamentous fungus Neurospora crassa, the IME2 homolog (ime-2) is not required for meiosis. Here we determine that ime-2 interacts genetically with a transcription factor vib-1 during nonself recognition and programmed cell death (PCD). Mutations in vib-1 (Deltavib-1) suppress PCD due to nonself recognition events; however, a Deltavib-1 Deltaime-2 mutant restored wild-type levels of cell death. A role for ime-2 in the post translational processing and localization of a mitochondrial matrix protein was identified, which may implicate mitochondria in N. crassa nonself recognition and PCD. Further, Deltavib-1 strains do not produce extracellular proteases, but protease secretion reverted to near wild-type levels in a Deltavib-1 Deltaime-2 strain. Mass spectrometry analysis revealed that the VIB-1 protein is phosphorylated at several sites, including a site that matches the IME-2 consensus. The genetic and biochemical data for ime-2 and vib-1 indicate that IME 2 is a negative regulator of VIB-1 and suggest parallel negative regulation by IME-2 of a cell death pathway in N. crassa that functions in concert with the VIB 1 cell death pathway. Thus, IME2 kinase function has evolved following the divergence of S. cerevisiae and N. crassa and provides insight into the evolution of kinases and their regulatory targets. PMID- 22813904 TI - Dual presence of Anaplasma phagocytophilum and its closely related Anaplasma sp. in ixodid ticks in Hokkaido, Japan, and their specific molecular detection. AB - Anaplasma phagocytophilum causes human granulocytic anaplasmosis (HGA) and tick borne fever in ruminants. A closely related and potentially novel Anaplasma sp. in Japan was recently characterized. The aims of the study were to provide molecular evidence for the presence of these 2 species in Japan, and to develop a reliable PCR method based on the nucleotide differences within the citrate synthase (gltA) gene. DNA samples from 182 ixodid ticks (134 Ixodes persulcatus, 35 Haemaphysalis douglasii and 13 I. ovatus) collected from 2 sites in Hokkaido, Japan, were screened for A. phagocytophilum and its closely related Anaplasma sp. (herein designated as Anaplasma sp. Japan) using 16S rRNA PCR, revealing a combined prevalence rate of 27.5% (50 samples). The positive samples were then used to evaluate a newly developed gltA-based nested PCR method. Selected positive samples were further characterized using the groEL gene for confirmation and phylogenetic analyses. Two groups of sequence results were obtained: those that had closer identities with (1) A. phagocytophilum (99.5-99.6% for 16S rRNA, 97.5% for gltA and 98.4% for groEL), and those that had closer identities with (2) Anaplasma sp. closely related to A. phagocytophilum in Japan (99.3% for 16S rRNA, 96.4-98.7% for gltA and 97.5-97.9% for groEL). The present study confirmed the distinct presence of A. phagocytophilum and its closely related Anaplasma sp. in Japan, and developed a new PCR detection method based on gltA that can distinguish the 2 organisms. PMID- 22813905 TI - Influence of protein expression system on elicitation of IgE antibody responses: experience with lactoferrin. AB - With increased interest in genetically modified (GM) crop plants there is an important need to understand the properties that contribute to the ability of such novel proteins to provoke immune and/or allergic responses. One characteristic that may be relevant is glycosylation, particularly as novel expression systems (e.g. bacterial to plant) will impact on the protein glycoprofile. The allergenicity (IgE inducing) and immunogenicity (IgG inducing) properties of wild type native human lactoferrin (NLF) from human milk (hm) and neutrophil granules (n) and a recombinant molecule produced in rice (RLF) have been assessed. These forms of lactoferrin have identical amino acid sequences, but different glycosylation patterns: hmNLF and nNLF have complex glycoprofiles including Lewis (Le)(x) structures, with particularly high levels of Le(x) expressed by nNLF, whereas RLF is simpler and rich in mannose residues. Antibody responses induced in BALB/c strain mice by intraperitoneal exposure to the different forms of lactoferrin were characterised. Immunisation with both forms of NLF stimulated substantial IgG and IgE antibody responses. In contrast, the recombinant molecule was considerably less immunogenic and failed to stimulate detectable IgE, irrespective of endotoxin and iron content. The glycans did not contribute to epitope formation, with equivalent IgE and IgG binding recorded for high titre anti-NLF antisera regardless of whether the immunising NLF or the recombinant molecule were used substrates in the analyses. These data demonstrate that differential glycosylation profiles can have a profound impact on protein allergenicity and immunogenicity, with mannose and Le(x) exhibiting opposing effects. These results have clear relevance for characterising the allergenic hazards of novel proteins in GM crops. PMID- 22813906 TI - Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. AB - High serum levels of p-cresol have been associated with cardiovascular diseases. This study investigated the effects of p-cresol on gap junctions in neonatal cultured cardiomyocytes. p-Cresol reduced the spontaneous contraction rates of cardiomyocytes, and caused irregular cardiomyocyte beating. Junctional connexin 43 (Cx43) plaques became smaller in size and the gap junction intercellular communication (GJIC) impaired. Moreover, p-cresol increased intracellular Ca(+2) levels, and induced Ca(+2)-dependent protein kinase Calpha (PKCalpha) activation. p-Cresol decreased P1 and P2 Cx43 levels, and increased non-phosphorylated S368 Cx43 levels. The above changes as well as Cx43 disassembly and GJIC decrease induced by p-cresol were prevented by the BAPTA-AM or PKCalpha inhibitor Go6976. These results suggest that PKCalpha mediates p-cresol-induced gap junction disassembly and GJIC dysfunction via S368-Cx43 serine dephosphorylation. This hypothesis was further confirmed in H9c2 cells by siRNA approach. SiRNA knockdown of PKCalpha prevented p-cresol-induced increase in nonphosphorylated Cx43. This finding supports the association of p-cresol and cardiovascular diseases. PMID- 22813910 TI - Dose pulmonary wedge resection for lung cancer always provide worse survival result than segmentectomy? PMID- 22813907 TI - Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats. AB - In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7 hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague-Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015-0.0072, for PCN 66 and 0.00029-0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO toxic equivalency factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity. PMID- 22813913 TI - Wedge bronchoplastic lobectomy. PMID- 22813914 TI - Can the success of transcatheter aortic valve implantation be increased? PMID- 22813916 TI - Expanding transcatheter aortic valve implantation to younger, lower-risk patients? PMID- 22813918 TI - Pulsatile biventricular assist device and an absent mitral valve. PMID- 22813919 TI - Online intervention engagement predicts smoking cessation. AB - OBJECTIVE: Instead of focusing on individual differences as predictors of quitting ("who they are"), this study focuses on actions ("what they do"). The purpose is to predict smoking abstinence in internet users who may become involved in social activities within the virtual community. METHODS: From March, 2009, to July, 2011, users of a web-based smoking cessation program in Germany made data available for a post-hoc evaluation study (n=13,174), including abstinence rates and online activities such as a) posting on a bulletin board after a smoke-free day, b) offering a donation, and c) posting messages throughout their course. RESULTS: Survival analyses for 70 days of self-reported non-smoking documented higher success rates for those who made use of one or more of the virtual community activities. Moreover, the effect of making an initial bulletin board entry on 10-week abstinence was mediated by offering a donation and posting messages throughout the course (R(2)=0.125). The indirect effect via donation was 0.10 (95% CI 0.06-0.14), and the indirect effect via message posting was 0.31 (95% CI 0.25-0.38). CONCLUSIONS: Virtual community activities predict smoking cessation. Shifting the focus from personality characteristics toward behavioral process variables such as intervention engagement might add more substance to smoking cessation studies. PMID- 22813920 TI - Adherence to and efficacy of home exercise programs to prevent falls: a systematic review and meta-analysis of the impact of exercise program characteristics. AB - OBJECTIVE: To determine whether adherence to home exercise interventions for the prevention of falls in older adults relates to home exercise program characteristics and intervention efficacy. METHODS: In Australia (2011) a systematic literature search of four databases was conducted. Randomized controlled trials were included. Random-effects meta-analysis of participant adherence rates was performed. Meta-regression analyses were used to determine the relationship between intervention program characteristics, intervention efficacy and adherence. RESULTS: Twenty-three studies met the inclusion criteria. The pooled estimate of participants who were fully adherent was 21% (95% Confidence Interval: 15%-29%, range: 0%-68%). Higher levels of full adherence were found in interventions containing balance or walking exercise, moderate home visit support, physiotherapist led delivery and no flexibility training. Higher levels of partial adherence were found in interventions containing home visit or telephone support, a participant health service recruitment approach and no group exercise training. Neither full nor partial adherence to prescribed home exercise program dosages was associated with intervention efficacy. CONCLUSION: Adherence to home exercise for the prevention of falls in older adults is low and may be affected by home exercise program characteristics. There is an absence of evidence to link adherence to intervention efficacy. PMID- 22813921 TI - Combined values of serum albumin, C-reactive protein and body mass index at dialysis initiation accurately predicts long-term mortality. AB - BACKGROUND: Protein-energy wasting and chronic inflammation are prevalent in patients with end-stage renal disease (ESRD). We investigated the combination of serum albumin, C-reactive protein (CRP) and body mass index (BMI) at initiation of hemodialysis therapy as a predictor of all-cause and cardiovascular disease (CVD) mortality in Japanese ESRD patients. METHODS: A total of 1,228 consecutive Japanese ESRD patients on hemodialysis therapy were enrolled and followed for up to 10 years. Patients were divided into quartiles according to levels of albumin, CRP and BMI. Furthermore, to clarify the joint role of these factors, albumin <3.5 g/dl, CRP >4.0 mg/l and BMI <19.6 were defined as risk factors using receiver operating characteristic analysis; thereafter, patients were divided into groups according to the positive number of these factors. RESULTS: Adjusted hazard ratios (HRs) for lower serum albumin, elevated CRP and lower BMI for 10 year all-cause mortality were 1.97, 3.13 and 2.61, respectively. Regarding the combination of these variables, adjusted HRs for mortality were 2.31, 4.28 and 8.07, respectively, in patients having any one factor, any two factors and all three factors. The C-index for an established risk model with these three positive markers was the most accurate for predicting mortality (0.768), as compared to other models with one or two markers. Similar results were seen for CVD mortality. CONCLUSIONS: Serum albumin, CRP and BMI at the start of hemodialysis therapy were able to individually stratify the risk of long-term mortality in ESRD patients. Furthermore, a combination of these variables could more accurately predict mortality. PMID- 22813922 TI - Evaluation of lumbar disc and spine morphology: long-term repeatability and comparison of methods. AB - Establishing the long-term repeatability of quantitative measures of lumbar intervertebral disc and spinal morphology is important for planning interventional studies. We aimed to examine this issue and to determine to what extent a smaller number of measurements per disc or vertebral level could be used to save operator time without compromising measurement precision. Twenty-one healthy male subjects were scanned at baseline and 1.5 years later. On sagittal MR-scans intervertebral disc cross-sectional area, anterior disc height, posterior disc height, intervertebral angle and intervertebral length were measured. The repeatability of the average value from all sagittal images or from 1, 3, 5 or 7 images centred at the spinous process was evaluated. Bland-Altman analysis showed all measurements to be repeatable between testing days. Intervertebral length was the most precise measurement (coefficients of variation [CVs] between 1.2% and 1.5%), followed by disc cross-sectional area (CVs between 2.9% and 3.6%). Variance component analysis showed that using 7 images, but not 1, 3 or 5 images, resulted in a similar level of measurement error as when measurements from all images were included. PMID- 22813923 TI - Is preterm delivery indicated in fetuses with gastroschisis and antenatally detected bowel dilation? AB - INTRODUCTION: Due to the controversy surrounding diagnostic ultrasound evaluations and elective preterm delivery of fetuses with gastroschisis, we sought to calculate the predictive value of bowel dilation in fetuses with gastroschisis and evaluate the effect of preterm delivery on neonatal outcomes. MATERIALS AND METHODS: Ultrasounds and medical records of 103 mother-infant pairs with fetal gastroschisis were reviewed. Eighty-nine pairs met the criteria. Intestinal complications, gestational age at delivery, birth weight, and number of abdominal surgeries were documented. RESULTS: Forty-eight fetuses (54%) had bowel dilation and 41 (46%) did not. The positive predictive value of bowel dilation for complicated gastroschisis was 21%. There were 50 (56%) preterm and 39 (44%) term deliveries. The mean birth weight was 2,114 g (SD = 507) and 2,659 g (SD = 687), p = 0.001. For infants delivered preterm, the mean number of postnatal abdominal surgeries was 2.1 (SD = 1.1) as compared to 1.3 (SD = 0.5) surgical procedures for those infants delivered at term gestation. This was not statistically significant. With respect to hospital stay for each group, the mean length of neonatal intensive care unit admission was 48 days (SD = 33) in the preterm group and 35 days (SD = 50) in the term group, which was not statistically significant. DISCUSSION: Ultrasound-detected bowel dilation was not predictive of important intestinal complications. Our data did not substantiate any benefit for elective preterm delivery of neonates with gastroschisis. PMID- 22813924 TI - Effect of safflower oil on the protective properties of the in situ formed salivary pellicle. AB - AIM: The prevalence of dental erosion is still increasing. A possible preventive approach might be rinsing with edible oils to improve the protective properties of the pellicle layer. This was tested in the present in situ study using safflower oil. METHODS: Pellicle formation was carried out in situ on bovine enamel slabs fixed buccally to individual upper jaw splints (6 subjects). After 1 min of pellicle formation subjects rinsed with safflower oil for 10 min, subsequently the samples were exposed in the oral cavity for another 19 min. Enamel slabs without oral exposure and slabs exposed to the oral cavity for 30 min without any rinse served as controls. After pellicle formation in situ, slabs were incubated in HCl (pH 2; 2.3; 3) for 120 s, and kinetics of calcium and phosphate release were measured photometrically (arsenazo III, malachite green). Furthermore, the ultrastructure of the pellicles was evaluated by transmission electron microscopy (TEM). RESULTS: Pellicle alone reduced erosive calcium and phosphate release significantly at all pH values. Pellicle modification by safflower oil resulted in an enhanced calcium loss at all pH values and caused an enhanced phosphate loss at pH 2.3. TEM indicated scattered accumulation of lipid micelles and irregular vesicle-like structures attached to the oil-treated pellicle layer. Acid etching affected the ultrastructure of the pellicle irrespective of oil rinsing. CONCLUSION: The protective properties of the pellicle layer against extensive erosive attacks are limited and mainly determined by pH. The protective effects are modified and reduced by rinses with safflower oil. PMID- 22813925 TI - Soluble extracellular domains of human SIRPalpha and CD47 expressed in Escherichia coli enhances the phagocytosis of leukemia cells by macrophages in vitro. AB - Signal regulatory protein (SIRP) alpha, a transmembrane protein belonging to the immunoglobulin superfamily, is a receptor for CD47. The interaction between SIRPalpha and CD47 plays an important role in regulating the phagocytosis of leukemia cells and leukemia stem cells (LSCs) by macrophages. Blocking antibodies against CD47 have been shown to promote phagocytosis of LSCs by macrophages. Here, we consider an alternative way to interrupt the interaction between CD47 and SIRPalpha. We expressed the extracellular domains of the human SIRPalpha (hSIRP(ext)) and the human CD47 (hCD47(ext)) in Escherichia coli as Trx fusion proteins, and purified them by using affinity chromatography. We show that the purified fusion protein Trx-SIRP(ext) could interact in vitro with Trx hCD47(ext). Moreover, Trx-SIRP(ext) could effectively bind to Jurkat T-ALL cells, which expressed CD47 at a high level. CD47(ext), on the other hand, bound to human macrophages. In vitro phagocytosis assay showed that these fusion proteins could enhance the phagocytosis of Jurkat cells by macrophage, with Trx-hSIRP(ext) showed a higher efficiency than Trx-CD47(ext). These results indicated that the soluble Trx-hSIRP(ext) and Trx-CD47(ext) polypeptides could be alternative molecules to interrupt CD47-SIRPalpha interaction between leukemia cells and macrophages, and might be potentially useful for the targeted therapy of leukemia. PMID- 22813926 TI - Relationships between fast bowling technique and ball release speed in cricket. AB - The aim of this study was to identify the key aspects of technique that characterize the fastest bowlers. Kinematic data were collected for 20 elite male fast bowlers with 11 kinematic parameters calculated, describing elements of fast bowling technique that have previously been linked to ball release speed. Four technique variables were identified as being the best predictors of ball release speed, explaining 74% of the observed variation in ball release speed. The results indicate that the fastest bowlers have a quicker run-up and maintain a straighter knee throughout the front foot contact phase. The fastest bowlers were also observed to exhibit larger amounts of upper trunk flexion up to ball release and to delay the onset of arm circumduction. This study identifies those technique variables that best explain the differences in release speeds among fast bowlers. These results are likely to be useful in both the coaching and talent identification of fast bowlers. PMID- 22813929 TI - A preliminary study of diagnostic color Doppler ultrasonography in equine superficial digital flexor tendonitis. AB - We hypothesized that semi-quantitative determinations of changeable blood flows in granulation and scar tissues during tendon healing could be helpful for differentiation between the acute phase rich in blood vessels and the remodeling phase with fewer vessels. Ten Thoroughbreds with injured superficial digital flexor tendon (SDFT) in a forelimb were used for evaluation of blood flows in the injured tendons of racehorses using color Doppler (CD) ultrasonography. Using longitudinal CD images, features of maximum color activities were defined. These were rhythmically blinking, tiny to small signals (grade 1), pulsatile expanded dots (grade 2), and dynamic streams (grade 3). Grade of color activity in CD ultrasonography could be useful for quantitative assessment of equine SDFT repair. PMID- 22813930 TI - Crystal structures of triosephosphate isomerase from methicillin resistant Staphylococcus aureus MRSA252 provide structural insights into novel modes of ligand binding and unique conformations of catalytic loop. AB - Staphylococcus aureus is one of the most dreaded pathogens worldwide and emergence of notorious antibiotic resistant strains have further exacerbated the present scenario. The glycolytic enzyme, triosephosphate isomerase (TIM) is one of the cell envelope proteins of the coccus and is involved in biofilm formation. It also plays an instrumental role in adherence and invasion of the bacteria into the host cell. To structurally characterize this important enzyme and analyze it's interaction with different inhibitors, substrate and transition state analogues, the present article describes several crystal structures of SaTIM alone and in complex with different ligands: glycerol-3-phosphate (G3P), glycerol 2-phosphate (G2P), 3-phosphoglyceric acid (3PG) and 2-phosphoglyceric acid (2PG). Unique conformations of the catalytic loop 6 (L6) has been observed in the different complexes. It is found to be in "almost closed" conformation in both subunits of the structure complexed to G3P. However L6 adopts the open conformation in presence of G2P and 2PG. The preference of the conformation of the catalytic loop can be correlated with the position of the phosphate group in the ligand. Novel modes of binding have been observed for G2P and 3PG for the very first time. The triose moiety is oriented away from the catalytic residues and occupies an entirely different position in some subunits. A completely new binding site for phosphate has also been identified in the complex with 2PG which differs substantially from the conventional phosphate binding site of the ligand in the crystal structures of TIM determined so far. PMID- 22813932 TI - Chemical composition and bioactivities of a water-soluble polysaccharide from the endodermis of shaddock. AB - The chemical composition of shaddock (Citrus paradisi) mainly consisted of polyphenols, proteins and polysaccharides. However, polysaccharides from shaddock materials have received much less consideration than polyphenols. Herein, a water soluble neutral polysaccharide from the endodermis of shaddock was isolated and showed good bioactivities. Crude polysaccharides from the endodermis of shaddock (EPS) was extracted with hot water and separated on a DEAE Sepharose FF gel filtration column to obtain NEPS. The IR and UV spectra of NEPS showed that NEPS was mainly composed of polysaccharide and there are no proteins existing in NEPS. The DPPH radical scavenging and reducing power of NEPS are much lower than those of crude EPS; however, Citrus flavonoids significantly improved the DPPH radical scavenging potential and reducing power of NEPS. The crude EPS (5mg/mL) showed a similar inhibitory effect (77.92+/-5.03%) with NEPS (5 mg/mL) (74.63+/-4.71%) on alpha-amylase. PMID- 22813931 TI - Microsporidian genome analysis reveals evolutionary strategies for obligate intracellular growth. AB - Microsporidia comprise a large phylum of obligate intracellular eukaryotes that are fungal-related parasites responsible for widespread disease, and here we address questions about microsporidia biology and evolution. We sequenced three microsporidian genomes from two species, Nematocida parisii and Nematocida sp1, which are natural pathogens of Caenorhabditis nematodes and provide model systems for studying microsporidian pathogenesis. We performed deep sequencing of transcripts from a time course of N. parisii infection. Examination of pathogen gene expression revealed compact transcripts and a dramatic takeover of host cells by Nematocida. We also performed phylogenomic analyses of Nematocida and other microsporidian genomes to refine microsporidian phylogeny and identify evolutionary events of gene loss, acquisition, and modification. In particular, we found that all microsporidia lost the tumor-suppressor gene retinoblastoma, which we speculate could accelerate the parasite cell cycle and increase the mutation rate. We also found that microsporidia acquired transporters that could import nucleosides to fuel rapid growth. In addition, microsporidian hexokinases gained secretion signal sequences, and in a functional assay these were sufficient to export proteins out of the cell; thus hexokinase may be targeted into the host cell to reprogram it toward biosynthesis. Similar molecular changes appear during formation of cancer cells and may be evolutionary strategies adopted independently by microsporidia to proliferate rapidly within host cells. Finally, analysis of genome polymorphisms revealed evidence for a sexual cycle that may provide genetic diversity to alleviate problems caused by clonal growth. Together these events may explain the emergence and success of these diverse intracellular parasites. PMID- 22813933 TI - Isolation and characterisation of carotenoproteins from deep-water pink shrimp processing waste. AB - The effect of barbel (Barbus callensis) trypsin on the recovery and characteristics of carotenoprotein from pink shrimp (Parapenaeus longirostris) waste was studied. The recovery of carotenoproteins was maximized by the hydrolysis of shrimp waste using 1.0 trypsin U/g of shrimp waste for 1h at 25 degrees C. Freeze dried partially purified carotenoproteins recovered contained 71.09+/-0.19% protein, 16.47+/-0.68% lipid, 7.78+/-0.12% ash, 1.79+/-0.04% chitin, 87.42+/-2.54MUg total astaxanthin/g of sample. Protein-pigment splitting, for astaxanthin recuperation, was carried out using barbel and bovine trypsins and the mixture of the two enzymes; then the protein was separated from the pigment by ultrafiltration. The hydrolysate obtained by treatment with the mixture of the two enzymes presented the best levels (p<0.05) of xanthophylls (80.15 MUg/g) and total protein (7.42 mg/g), respectively. Splitting the protein pigment complex allows studies on pigment absorption, stability and application. PMID- 22813934 TI - Contribution of hydrophobic interactions to the folding and fibrillation of histone H1 and its carboxy-terminal domain. AB - Histone H1 is involved in chromatin structure and gene regulation. H1 also performs functions outside cell nuclei, which may depend on its properties as a lipid-binding protein. The H1 CTD behaves as an intrinsically disordered protein (IDP) with coupled binding and folding. Here, we used neutral detergents and anionic SDS to study the contribution of hydrophobic interactions to the folding of the CTD. In the presence of neutral detergents, the CTD folded with proportions of secondary structure motifs similar to those observed in the DNA complexes. These results identify a folding pathway for the CTD based on hydrophobic interactions, and independent of charge compensation. The CTD is phosphorylated to different extents by cyclin-dependent kinases. The general effect of phosphorylation in the presence of detergents was a decrease in the alpha-helix content and an increase in that of the beta-structure. The greatest effect was observed in the fully phosphorylated CTD (three phosphate groups) in the presence of anionic SDS (7:1, detergent/CTD molar ratio); in these conditions, the CTD became an all-beta protein, with 83% beta-structure and no alpha-helix. The CTD in all-beta conformation readily formed ribbon-like fibers. The entire H1 also formed fibers when fully phosphorylated in the CTD. Fibers were of the amyloid type, as judged by strong birefringence in the presence of Congo red and thioflavin fluorescence enhancement. Amyloid fiber formation was only observed in SDS, suggesting that it requires the joint effects of partial charge neutralization and hydrophobic interactions, together with the all-beta potential provided by full phosphorylation. PMID- 22813935 TI - Serum levels of omentin in end-stage renal disease patients. AB - INTRODUCTION: Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis patients. Therefore, evaluation and prevention of cardiovascular diseases in end-stage renal disease (ESRD) patients are very important. The plasma level of omentin was found to be associated with different conditions such as insulin resistance. It is one of the novel adipokines synthesized mainly in the visceral adipose tissue. In this study, we aimed to investigate the level of omentin in patients with ESRD receiving hemodialysis. METHODS: The study population consisted of 59 adult chronic hemodialysis patients (30 women and 29 men) and age-matched control subjects were selected from apparently healthy subjects (28 participants; 14 women and 14 men). Blood samples were obtained before the dialysis session. Omentin concentrations were determined by using enzyme-linked immunosorbent assay. RESULTS: Plasma levels of omentin were found to be markedly higher in ESRD patients (606.6 +/- 313.0 ng/ml) than in the control group (357.5 +/- 147.4 ng/ml; p < 0.0001). Also, serum omentin levels were found to be correlated with creatinine (r = 0.333, p = 0.002). CONCLUSIONS: Omentin levels were found to be elevated in patients with ESRD receiving hemodialysis. To the best of our knowledge, this is the first clinical study that demonstrated the association between omentin and ESRD. PMID- 22813936 TI - Gentamicin pharmacokinetics and pharmacodynamics during short-daily hemodialysis. AB - BACKGROUND/AIMS: Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl(dial)) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. METHODS: Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl(dial) and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl(s)) and central volume of distribution (V(c)) and influence of urea removal estimates on Cl(dial) were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. RESULTS: A two compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl(s) and Cl(dial) were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl(s) and V(c). Predialysis every-other-day regimens were as effective (C(max) >=8 mg/l and AUC(48 h) >=140 mg.h/l) and less toxic (C(min) <2 mg/l and AUC(48 h) <240 mg.h/l) than postdialysis regimens. CONCLUSIONS: Estimated gentamicin Cl(dial) is higher than previous estimates with thrice weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD. PMID- 22813937 TI - Competing mortality contributes to excess mortality in patients with poor-risk lymph node-positive prostate cancer treated with radical prostatectomy. AB - BACKGROUND: Factors predicting survival in men with lymph node-positive prostate cancer are still poorly defined. PATIENTS AND METHODS: 193 prostate cancer patients with histopathologically proven lymph node involvement with a median follow-up of 7.3 years were studied. 94% of patients received immediate hormonal therapy. Kaplan-Meier curves were calculated to evaluate overall survival rates and compared with the log-rank test. Cumulative disease-specific and competing mortality rates were calculated by competing risk analysis and compared with the Pepe-Mori test. Cox proportional hazard models were used to determine the independent significance of predictors of all-cause mortality. RESULTS: Age (70 years or older vs. younger), Gleason score (8-10 vs. 7 or lower) and the number of involved nodes (3 or more vs. 1-2) were identified as independent predictors of all-cause mortality. When patients with 0-1 of these risk factors were compared with those with 2-3 risk factors, all-cause (rates after 10 years 21% vs. 71%, p < 0.0001), disease-specific (12 vs. 37%, p = 0.009) and competing mortality (9 vs. 33%, p = 0.02) differed significantly. CONCLUSIONS: Some of the excess mortality in patients with poor-risk lymph node-positive prostate cancer may be attributed to increased competing mortality, possibly caused by an interaction between comorbid diseases and hormonally treated persistent or progressive prostate cancer. PMID- 22813938 TI - Can the municipalities prevent medication of mental diseases? AB - BACKGROUND: In extension of a large municipality reform in 2007, which reduced the number of Danish municipalities from 275 to 98, it was the intention that the municipalities should assume responsibility for a part of the expenditure connected to secondary sector health care treatment. Furthermore, the municipalities were assigned the responsibility for--and equipped with a number of opportunities for--exerting primary preventive initiatives. AIM OF THE STUDY: To investigate, whether the municipalities by applying these opportunities have been able to prevent medication of mental diseases. Specifically, this is resolved by analysing whether there are significant relationships between measures of municipal policy opportunities and the proportion of population medicated for mental diseases. METHODS: We apply a variety of statistical regression models. Initially, simple linear regression is applied. Next, a Seemingly Unrelated Regression approach, which accounts for intra-municipal behavioural correlation, is brought in play. Finally, this approach is extended to regressions which are adjusted for spatial spillover effects. RESULTS: The initial simple linear specification indicates a potential significant relationship between municipal policy opportunities and medication. However, when applying a specification which is adjusted for intra-municipal correlation, this relationship vanishes. Finally, there seem to be indications of spatial spillover effects. Thus, the relationship between municipal preventive initiatives and medication seems to be a structural, intra-municipal relationship, rather than a cause-response effect. IMPLICATIONS FOR HEALTH POLICIES: Our results show that potential linkages between municipal preventive initiatives and medication for mental diseases are not of a simple nature. Specifically, sophisticated and targeted interventions are needed rather than broad and general public health initiatives. IMPLICATIONS FOR FURTHER RESEARCH: Though the approach is promising, the data underlying the study is at present relatively weak. Future studies should involve more variables as well as longer times series in order to obtain proper understandings of the potential linkages between municipal policy efforts and medication. PMID- 22813939 TI - Family leave after childbirth and the mental health of new mothers. AB - BACKGROUND: Recent studies indicate that short maternity leave, and, more generally, full-time maternal employment during the first year of life, detract from children's health, cognitive development, and behavioral outcomes. Much less is known, however, about how early parental employment affects the mental and physical health of the mothers themselves. AIMS OF THE STUDY: The purpose of this paper is to examine the association between short family leave length (less than 12 weeks of total leave after childbirth, less than 8 weeks of paid leave) and mental and physical health outcomes among new mothers. METHODS: Data come from the Early Childhood Longitudinal Study--Birth Cohort (ECLS-B), a nationally representative sample of 14,000 children born in 2001 and followed until kindergarten entry. We focus on a sample of ECLS-B mothers from the first wave of the survey who had worked during pregnancy and who had returned to work by the time of the first follow-up interview, which was conducted about 9 months after childbirth. When examining the effects of paternal leave, we further restrict this sample to mothers who were married at the time of the first follow-up interview. The maternal health outcomes of interest are measures of depression and overall health status. We use standard OLS and ordered probit models, as well as two-stage least squares and two-stage residual inclusion methods which address the potential endogeneity of family leave with respect to maternal health. RESULTS: Our findings from the OLS and ordered probit models indicate that, for mothers who worked prior to childbirth and who return to work in the first year, having less than 12 weeks of maternal leave and having less than 8 weeks of paid maternal leave are both associated with increases in depressive symptoms, and having less than 8 weeks of paid leave is associated with a reduction in overall health status. Findings from models that address the potential endogeneity of maternal leave generally support these results, and suggest that longer leave may improve the health of new mothers. DISCUSSION: Our findings suggest that longer leave after childbirth may benefit families. However, one potential drawback of using cross-sectional variation in state policies and community characteristics for identification is that these measures may be correlated with other unmeasured factors that directly influence family leave and maternal health. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: The mother's mental and physical health can be an important route through which infants are affected by parents' employment decisions. Our findings suggest that post-partum health services that target mothers' mental and physical health, and its effects on infants, may be useful. IMPLICATIONS FOR HEALTH POLICIES: Our findings suggest that policies that support longer family leave may benefit maternal mental health. IMPLICATIONS FOR FURTHER RESEARCH: Future research should examine how workplace and public policies related to maternal employment can be used to improve families' health outcomes. PMID- 22813940 TI - Mental disorders and earnings: results from the Nigerian National Survey of Mental Health and Well-Being (NSMHW). AB - BACKGROUND: Mental disorders are associated with a loss in earnings both at the individual and societal level. Very few studies have addressed the issue of the cost of mental illness in Sub-saharan Africa. These studies have been largely hospital based, localized, and have addressed only a few mental disorders using very small sample sizes. AIMS OF THE STUDY: To examine the impact of mental disorders on earnings of affected persons. METHODS: Mental disorders on and personal earnings were assessed in a representative sample of 1,889 Nigerians aged 18-64 years in an epidemiological survey. Version 3.0 of the World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was used to assess mental disorders. Respondents were also asked to report their personal earnings before tax in the past 12 months, while authors predicted personal earnings in the same period from information about 12 month and life time DSM IV mental disorders among respondents. RESULTS: A 12 month prevalence of Serious Mental Illness (SMI) was found in 0.5% of the sample while other 12 month disorders had a prevalence of 4.83%. The prevalence of other lifetime disorders was 4.14%. The mean annual impact of serious mental illness was 60,126 Naira (US$ 463). At the level of the society the annual impact was 21.6 billion Naira (US$ 166.2 million). DISCUSSION: Mental disorders have an enormous individual and societal financial burden. This impact appears more severe in males. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Mental disorders have enormous negative impacts on earnings both at the individual and societal level. This analysis highlights the financial value of lost earnings in the absence of such disorders. IMPLICATIONS FOR HEALTH POLICIES: An increase in spending on mental health based on proportionate economic burden of mental disorders may substantially reduce financial losses due to mental disorders. IMPLICATIONS FOR FURTHER RESEARCH: In the present study, only the indirect health care costs have been assessed. Future research should consider direct costs. PMID- 22813941 TI - Poverty and severe psychiatric disorder in the U.S.: evidence from the Medical Expenditure Panel Survey. AB - BACKGROUND: Previous studies have shown that persons with severe psychiatric disorders are more likely to be poor and face disparities in education and employment outcomes. Poverty rates, the standard measure of poverty, give no information on how far below the poverty line this group falls. AIMS OF THE STUDY: This paper compares the poverty rate, poverty depth (distance from the poverty line) and poverty severity (inequality of incomes below the poverty line) of households with and without a working-age member with severe psychiatric disorder in the United States using data from the 2007 Medical Expenditure Panel Survey (MEPS). METHODS: First, we perform multivariate analysis of the association between severe disorder and poverty depth using MEPS data. Second, we calculate poverty rates, depth, and severity for the subgroup of households having a member with disorder and compare to the subgroup of households without such a member. RESULTS: In multivariate regressions, the presence of a household member with severe psychiatric disorder predicts a 52-percentage point increase in poverty depth and 3.10 times the odds of being poor. Poverty rate, depth, and severity are significantly greater for households of persons with disorder. Mean total incomes are lower for households of persons with severe disorder compared to other households while mean health expenditures are similar. DISCUSSION: Severe psychiatric disorder is associated with greater depth of poverty and likelihood of being poor. We identify groups who are the most disadvantaged according to severity of income poverty among households with severe psychiatric disorder. These include households whose head has no high school education, who has been without work for the entire year, and who is black or Hispanic. While these characteristics are related to poverty for the overall sample, they correlate to heightened poverty severity when combined with severe disorder. Families face less severity than single persons but poverty rate, depth, and severity increase for both groups when combined with severe psychiatric disorder. Our study does not attempt to investigate the causes of poverty, focusing rather on improved poverty measurement. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: We find that households of persons with disorder have a lower standard of living and face more severe forms of poverty. This may affect the health of their members through reduced access to health inputs, including access to health care. IMPLICATIONS FOR HEALTH POLICIES: This paper shows that there is a strong association between severe psychiatric disorder and poverty, and points to a need to break this association. Both mental health policy and income assistance programs should consider using poverty rate, depth and severity measures to evaluate the economic benefits of current programs and target future programs to those facing the most severe poverty. IMPLICATIONS FOR FURTHER RESEARCH: The results point to the need for additional research in a number of areas: trends in poverty for households with severe psychiatric disorders over time; mobility and persistence of poverty for this group; and the association of severe disorder to other, non-monetary dimensions of poverty, such as a lack of social integration. PMID- 22813942 TI - Autobiographical memories of vomiting in people with a specific phobia of vomiting (emetophobia). AB - BACKGROUND: Vomiting is an almost universal phenomenon, but little is known about the aetiology of a specific phobia of vomiting (SPOV). The associations with vomiting during childhood and autobiographical memories may have relevance for our understanding of the development of SPOV and its treatment. METHOD: Two groups: (a) a group with SPOV (n = 94) and (b) a control group (n = 90) completed a self-report questionnaire assessing their lifetime memories of both their own vomiting and others vomiting. RESULTS: People with SPOV recalled the memories of their own and others vomiting experiences from an earlier age and rated them as significantly more distressing than the control group. There was no difference between the groups in the number of memories of their own vomiting recalled before the age at which vomiting became a problem. However, the SPOV group recalled more memories of others vomiting before the onset of the problem. After the age at which the phobia became a problem they recalled less memories of their own vomiting and more memories of others vomiting than the control group. They recalled significantly more memories of vomiting associated with inter-personal events, health or emotional or unrelated life events. CONCLUSIONS: Avoidance and hyper-vigilance for others vomiting after the onset of the phobia may have slightly reduced the risk of vomiting. There is some evidence for associative learning in SPOV with aversive consequences of vomiting and an unrelated life event. It suggests a model of autobiographical memories of vomiting that have lost a time perspective and context, which are being reactivated with cues for vomiting. The limitations of the study are those of memory biases in both groups. PMID- 22813943 TI - Clinical study monitoring the pH on tooth surfaces in patients with and without erosion. AB - The aim of this study was to compare tooth surface pH after drinking orange juice or water in 39 patients with dental erosion and in 17 controls. The following investigations were carried out: measurement of pH values on selected tooth surfaces after ingestion of orange juice followed by ingestion of water (acid clearance), measurement of salivary flow rate and buffering capacity. Compared with the controls, patients with erosion showed significantly greater decreases in pH after drinking orange juice, and the pH stayed lower for a longer period of time (p < 0.05). Saliva parameters showed no significant differences between the two patient groups except for a lower buffering capacity at pH 5.5 in the erosion group. PMID- 22813944 TI - Microarray and suppression subtractive hybridization analyses of gene expression in hybrid poplar (Populus alba * Populus tremula var. glandulosa) cell suspension cultures after exposure to NaCl. AB - The gene expression profiles of hybrid poplar (Populus alba * Populus tremula var. glandulosa) cells in suspension culture after exposure to salinity (NaCl) induced stress were examined by constructing two suppression subtractive hybridization (SSH) libraries. cDNA from non-treated cells was used as a driver and cDNA samples from cell suspension cultures exposed to 150 mM NaCl for 2 or 10 h were used as testers. Randomly selected clones from each SSH library were sequenced and 727 high-quality expressed sequence tags (ESTs) were obtained and analyzed. Four novel ESTs were identified. Between the two libraries, 542 unique SSH clones were selected for placement on a cDNA microarray. In total, 18 differentially expressed genes were identified with 4 and 12 genes being significantly differentially expressed 2 and 10 h after the treatment, respectively. Genes related to metabolism and protein synthesis and several genes whose protein products are implicated in salt or other abiotic stress-related responses were expressed in the salt-stressed cells. PMID- 22813945 TI - Mast cell sarcoma with megakaryocytic differentiation in a calf. AB - A case of mast cell sarcoma in a 5-month-old Holstein female calf is described. Macroscopically, enlargement of the spleen, lymph nodes, tonsils and kidneys was noted, and there were tumor masses in the neck region and on the pleura and peritoneum. The pericardium and uterine and ureter walls were also involved by tumor. Most neoplastic cells had eosinophilic granules, which were metachromatic and positive for naphthol AS-D chloroacetate esterase and tryptase, whereas smaller numbers of cells were positive for factor VIII-related antigen, a marker of megakaryocytes. Some of the predominant type of these tumor cells were found within the epithelia of the lungs, tonsils, gastrointestinal tract, liver, ureters, urinary bladder and uterus. Their normal counterparts were considered to be globule leukocytes. PMID- 22813946 TI - Improved RNA extraction method using the BioMasher and BioMasher power-plus. AB - The BioMasher is a disposable homogenizer that was developed to homogenize bovine brain tissue for bovine spongiform encephalopathy diagnosis. Capable of preventing the biohazard risk from infectious samples, it also prevents cross contamination among samples. The BioMasher is thus widely used in biochemical research, especially for RNA extraction. Here, we tested a novel BioMasher application for RNA extraction from animal and plant tissues. We also developed a grinding machine specific for the BioMasher, named the BioMasher Power-Plus. We developed RNA extraction protocols using the BioMasher combined with the BioMasher Power-Plus. We compared RNA extraction efficiency of the BioMasher with that of the FastPrep and the glass homogenizer. Though the RNA extraction efficiency by the BioMasher was nearly equivalent to that of the FastPrep and the glass homogenizer, sample preparation time was shorter for the BioMasher. The utility of RNA extraction by the BioMasher was examined in mouse, rat, and tomato tissue samples. In the rodent tissues, the highest extraction efficiency of total RNA was from liver, with lowest efficiency from fibrous tissues such as muscle. The quality of extracted total RNA was confirmed by agarose gel electrophoresis which produced highly visible clear bands of 18S and 28S rRNAs. Reproducibility among different operators in RNA extraction from tomato roots was improved by using the BioMasher Power-Plus. The BioMasher and BioMasher Power-Plus provide an effective and easy homogenization method for total RNA extraction from some rodent and plant tissues. PMID- 22813947 TI - Copy number variations in neurodevelopmental disorders. AB - Common neurodevelopmental disorders (including autism, speech and language delay, schizophrenia, epilepsy and intellectual disability) have complex aetiology, which is predominantly genomic, but also environmental in origin. They share a paradox, in that high heritability is matched by lowered fecundity, placing them under negative genetic selection. This implicates variants of recent origin, such as de novo mutations or common, very low-risk polymorphisms that escape negative selection. High or moderate risk variants have been discovered by chromosome analysis, genome sequencing and copy number variant (CNV) detection, including a 3Mb deletion causing 22q11.2 deletion syndrome (Velo-Cardio-Facial Syndrome) that has penetrance of up to 50% for schizophrenia. More recently, rare, recurrent and often de novo pathogenic CNVs, including deletions at NRXN1, 1q21.2, 15q11.2 and 15q13.3, 16p11.2 and duplications at VIPR2 and 16p13.11, have also been discovered. These have several unique features that differentiate them from Mendelian disease mutations in that they have incomplete penetrance, with moderate-to-high odds ratios for risk, and show diagnostic pleiotropy, increasing risk across the neurodevelopmental disorder spectrum. Some are also syndromic, with characteristic features such as facial dysmorphology, and other specific risks such as aortic dissection or obesity, implying that they might be better classified as distinct diagnoses. The discovery of pathogenic CNVs provide new opportunities for translation leading to patent benefit, including improvements in clinical genetic diagnosis and genetic counselling, the possibility of clinician decision-making tools for risk prediction, and the identification of drug targets and implementation of personalised medicine using stratification by genotype. PMID- 22813948 TI - Bioimpedance-based measurement method for simultaneous acquisition of respiratory and cardiac gating signals. AB - Respiratory and cardiac motion artefacts impair the quality and reliability of medical imaging, particularly in nuclear medicine. At worst, the interpretation of distorted images may lead to inadequate or unnecessary treatment. Image artefacts can be minimized by gating the image acquisition according to respiratory phase and cardiac contractions. However, currently there are no clinically established dual-gating methods in nuclear medicine imaging. The aim of this study is to validate a previously determined optimized bioimpedance measurement configuration against traditional respiratory and cardiac measurement systems in 12 volunteers. High agreement and excellent correlations (r = 0.944 0.999) were found between respiratory peak-to-peak amplitudes as well as temporal respiratory and cardiac intervals. Above all, good quality respiratory and cardiac gating signals were obtained from all test subjects with a fairly regular sinus rhythm. Importantly, both signals were acquired simultaneously with a single device. Due to the simplicity of this inexpensive method, the technique has high potential to be adopted for dual-gating in clinical practice in the future. PMID- 22813949 TI - Neutralization of tumor necrosis factor-alpha reduces renal fibrosis and hypertension in rats with renal failure. AB - BACKGROUND: Increased production of tumor necrosis factor-alpha (TNF-alpha) in chronic kidney disease may be involved in the progression of renal failure and injury, and cardiovascular disease. We investigated the effect of TNF-alpha neutralization on renal failure, inflammation and fibrosis, and blood pressure in rats with renal failure. METHODS AND RESULTS: Renal failure was induced by renal mass reduction and the animals were treated with PEG-sTNFR1, a pegylated form of soluble TNF type 1 receptor that neutralizes TNF-alpha, for 6 weeks. Systolic, diastolic and mean arterial pressures were higher in renal failure rats that were associated with increased serum creatinine, albuminuria and renal injury comprised of blood vessel media hypertrophy, focal and segmental glomerulosclerosis, tubular atrophy and interstitial inflammation and fibrosis. These changes were associated with greater levels of TNF-alpha, transforming growth factor (TGF)-beta1, nuclear transcription factor NF-KB and cytosolic phospho-IKB-alpha, and inflammatory markers expression (ICAM-1, VCAM-1 and MCP 1). Moreover, endothelin (ET)-1 production was also increased, whereas nitric oxide (NO) release was decreased. TNF-alpha neutralization reduced hypertension, albuminuria and renal inflammation and fibrosis, which were coupled to a reduction in renal NF-KB activation, inflammatory markers expression, TGF-beta1 and ET-1 production, and an increase in NO release. CONCLUSION: Neutralization of TNF-alpha in rats with renal failure decreases NF-KB activity that is associated with a reduction in renal TGF-beta1 and ET-1 production, and an improvement of NO release. These effects likely reduce renal inflammation and fibrosis, and blood pressure indicating a pivotal role for TNF-alpha, at least, in the progression of renal injury. PMID- 22813950 TI - Ultra-sensitive molecular MRI of cerebrovascular cell activation enables early detection of chronic central nervous system disorders. AB - Since endothelial cells can be targeted by large contrast-carrying particles, molecular imaging of cerebrovascular cell activation is highly promising to evaluate the underlying inflammation of the central nervous system (CNS). In this study, we aimed to demonstrate that molecular magnetic resonance imaging (MRI) of cerebrovascular cell activation can reveal CNS disorders in the absence of visible lesions and symptoms. To this aim, we optimized contrast carrying particles targeting vascular cell adhesion molecule-1 and MRI protocols through both in vitro and in vivo experiments. Although, pre-contrast MRI images failed to reveal the ongoing pathology, contrast-enhanced MRI revealed hypoperfusion triggered CNS injury in vascular dementia, unmasked amyloid-induced cerebrovascular activation in Alzheimer's disease and allowed monitoring of disease activity during experimental autoimmune encephalomyelitis. Moreover, contrast-enhanced MRI revealed the cerebrovascular cell activation associated with known risk factors of CNS disorders such as peripheral inflammation, ethanol consumption, hyperglycemia and aging. By providing a dramatically higher sensitivity than previously reported methods and molecular contrast agents, the technology described in the present study opens new avenues of investigation in the field of neuroinflammation. PMID- 22813951 TI - Neurocircuits underlying cognition-emotion interaction in a social decision making context. AB - Decision making (DM) in the context of others often entails complex cognition emotion interaction. While the literature suggests that the ventromedial prefrontal cortex (vmPFC), striatum, and amygdala are involved in valuation-based DM and hippocampus in context processing, how these neural mechanisms subserve the integration of cognitive and emotional values in a social context remains unclear. In this study we addressed this gap by systematically manipulating cognition-emotion interaction in a social DM context, when the participants played a card game with a hypothetical opponent in a behavioral study (n=73) and a functional magnetic-resonance-imaging study (n=16). We observed that payoff based behavioral choices were influenced by emotional values carried by face pictures and identified neurocircuits involved in cognitive valuation, emotional valuation, and concurrent cognition-emotion value integration. Specifically, while the vmPFC, amygdala, and ventral striatum were all involved in both cognitive and emotional domains of valuation, these regions played dissociable roles in social DM. The payoff-dependent responses in vmPFC and amygdala, but not ventral striatum, were moderated by the social context. Furthermore, the vmPFC, but not amygdala, not only encoded the opponent's gains as if self's losses, but also represented a "final common currency" during valuation-based decisions. The extent to which emotional input influenced choices was associated with the functional connectivity between the value-signaling amygdala and value integrating vmPFC, and also with the functional connectivity between the context setting hippocampus and value-signaling amygdala and ventral striatum. These results identify brain pathways through which emotion shapes subjective values in a social DM context. PMID- 22813953 TI - Distinct neural correlates underlying pretense and false belief reasoning: evidence from ERPs. AB - Two important milestones characterize the development of a theory of mind (ToM): The emergence of pretend play (PT) in which infants as young as 18 months separate the real world from fictional or imagined worlds. And the explicit understanding of false beliefs (FB) which develops around the age of about 4 years and demands a differentiation between mental states and reality. Although there is an outstanding debate about whether or not PT play involves metarepresentation understanding, to date, the neural correlates of FB and PT reasoning have not been investigated within one paradigm. The present study investigated PT and FB in comparison to reality understanding (RE) in an ERP paradigm presenting cartoon stories to 24 healthy adults. Results revealed a sequence of ERP components that distinguished between the conditions. PT compared to FB and RE was associated with a higher P2-amplitude at parieto-occipital sites and a late slow wave divergence (270-600 ms) at left frontal and left posterior positions. These components may indicate the processing of incongruity between the protagonist's knowledge and behavior and the identifying of the intentional character of the pretended action. In accordance with previous ERP studies on FB reasoning, we found late anterior activation (600-900 ms) for FB reasoning, probably indicating the decoupling mechanism involved in metarepresentation. These temporal and topographic differences indicate distinct underlying neural substrates for FB and PT processing, and do not support metarepresentational interpretations of PT. PMID- 22813952 TI - A robust method for investigating thalamic white matter tracts after traumatic brain injury. AB - Damage to the structural connections of the thalamus is a frequent feature of traumatic brain injury (TBI) and can be a key factor in determining clinical outcome. Until recently it has been difficult to quantify the extent of this damage in vivo. Diffusion tensor imaging (DTI) provides a validated method to investigate traumatic axonal injury, and can be applied to quantify damage to thalamic connections. DTI can also be used to assess white matter tract structure using tractography, and this technique has been used to study thalamo-cortical connections in the healthy brain. However, the presence of white matter injury can cause failure of tractography algorithms. Here, we report a method for investigating thalamo-cortical connectivity that bypasses the need for individual tractography. We first created a template for a number of thalamo-cortical connections using probabilistic tractography performed in ten healthy subjects. This template for investigating white matter structure was validated by comparison with individual tractography in the same group, as well as in an independent control group (N=11). We also evaluated two methods of masking tract location using the tract skeleton generated by tract based spatial statistics, and a cerebrospinal fluid mask. Voxel-wise estimates of fractional anisotropy derived from the template were more strongly correlated with individual tractography when both types of masking were used. The tract templates were then used to sample DTI measures from a group of TBI patients (N=22), with direct comparison performed against probabilistic tractography in individual patients. Probabilistic tractography often failed to produce anatomically plausible tracts in TBI patients. Importantly, we show that this problem increases as tracts become more damaged, and leads to underestimation of the amount of traumatic axonal injury. In contrast, the tract template can be used in these cases, allowing a more accurate assessment of white matter damage. In summary, we propose a method suitable for assessing specific thalamo-cortical white matter connections after TBI that is robust to the presence of varying amounts of traumatic axonal injury, as well as highlighting the potential problems of applying tractography algorithms in patient populations. PMID- 22813954 TI - Systemic inflammation in absence of gut bacterial translocation in C57BL/6 mice with cirrhosis. PMID- 22813955 TI - A 44-year-old Japanese female with recurrent pleuritis. PMID- 22813956 TI - History of frequent gum chewing is associated with higher unstimulated salivary flow rate and lower caries severity in healthy Chinese adults. AB - This was a single-center, prospective, cross-sectional study stratified by age and gender with the objective of determining the relationship between gum chewing history, salivary flow, and dental caries severity in adults. We enrolled 191 subjects aged 18-65 years who underwent assessments for gum chewing history, unstimulated salivary flow rate, salivary pH, and caries severity. Unstimulated salivary flow rate tended to decline with increasing age (p = 0.04), and significant differences in unstimulated salivary flow rate were also found for males (0.58 +/- 0.32 ml/min) versus females (0.48 +/- 0.30 ml/min) (p = 0.02). Weekly gum chewing frequency was greater in younger subjects (p = 0.001) while no age group differences were noted in pieces per day or chewing duration. Gum chewing habits were similar in males and females. A multivariate model demonstrated that only days per week chewing gum (p < 0.001) and gender (p = 0.007) were predictive of unstimulated salivary flow rate (R(2) = 0.40). Mean caries severity scores, assessed via ICDAS II and DMFT, increased with age. In multivariate analysis, age was positively associated with ICDAS (p = 0.001) and days per week chewing gum was negatively associated with ICDAS (p = 0.004), indicating that caries severity increased with age, and that days of chewing provided an inverse effect, with increased days of chewing being associated with decreased severity of caries. Overall, a history of frequent gum chewing is associated with higher unstimulated salivary flow rate and lower caries severity. PMID- 22813957 TI - Layered object models for image segmentation. AB - We formulate a layered model for object detection and image segmentation. We describe a generative probabilistic model that composites the output of a bank of object detectors in order to define shape masks and explain the appearance, depth ordering, and labels of all pixels in an image. Notably, our system estimates both class labels and object instance labels. Building on previous benchmark criteria for object detection and image segmentation, we define a novel score that evaluates both class and instance segmentation. We evaluate our system on the PASCAL 2009 and 2010 segmentation challenge data sets and show good test results with state-of-the-art performance in several categories, including segmenting humans. PMID- 22813958 TI - Accurate eye center location through invariant isocentric patterns. AB - Locating the center of the eyes allows for valuable information to be captured and used in a wide range of applications. Accurate eye center location can be determined using commercial eye-gaze trackers, but additional constraints and expensive hardware make these existing solutions unattractive and impossible to use on standard (i.e., visible wavelength), low-resolution images of eyes. Systems based solely on appearance are proposed in the literature, but their accuracy does not allow us to accurately locate and distinguish eye centers movements in these low-resolution settings. Our aim is to bridge this gap by locating the center of the eye within the area of the pupil on low-resolution images taken from a webcam or a similar device. The proposed method makes use of isophote properties to gain invariance to linear lighting changes (contrast and brightness), to achieve in-plane rotational invariance, and to keep low computational costs. To further gain scale invariance, the approach is applied to a scale space pyramid. In this paper, we extensively test our approach for its robustness to changes in illumination, head pose, scale, occlusion, and eye rotation. We demonstrate that our system can achieve a significant improvement in accuracy over state-of-the-art techniques for eye center location in standard low resolution imagery. PMID- 22813959 TI - Extended SRC: undersampled face recognition via intraclass variant dictionary. AB - Sparse Representation-Based Classification (SRC) is a face recognition breakthrough in recent years which has successfully addressed the recognition problem with sufficient training images of each gallery subject. In this paper, we extend SRC to applications where there are very few, or even a single, training images per subject. Assuming that the intraclass variations of one subject can be approximated by a sparse linear combination of those of other subjects, Extended Sparse Representation-Based Classifier (ESRC) applies an auxiliary intraclass variant dictionary to represent the possible variation between the training and testing images. The dictionary atoms typically represent intraclass sample differences computed from either the gallery faces themselves or the generic faces that are outside the gallery. Experimental results on the AR and FERET databases show that ESRC has better generalization ability than SRC for undersampled face recognition under variable expressions, illuminations, disguises, and ages. The superior results of ESRC suggest that if the dictionary is properly constructed, SRC algorithms can generalize well to the large-scale face recognition problem, even with a single training image per class. PMID- 22813960 TI - The contribution of vascular smooth muscle, elastin and collagen on the passive mechanics of porcine carotid arteries. AB - The main components responsible for the mechanical behavior of the arterial wall are collagen, elastin, and smooth muscle cells (SMCs) in the medial layer. We determined the structural and mechanical changes in porcine carotid arteries after administration of Triton(r) X-100, elastase, and collagenase using the inflation-deflation test. The arteries were intraluminarly pressurized from 0 to 200 mmHg, and the outer diameter of the artery was measured. The pressure-strain elastic modulus was determined based on the pressure/diameter ratio. The intima media thickness, wall thickness, thickness of the tunica adventitia layer, and the area fractions of SMCs, elastin, and collagen within the arterial wall (A(A)(SMC/elastin/collagen, wall)) were measured using stereological methods. The relative changes in the relevant components of the treated samples were as follows: the decrease in A(A)(SMC, wall) after administration of Triton(r) X-100 was 11% +/- 7%, the decrease in A(A)(elastin, wall) after administration of elastase was 40% +/- 22%, and the decrease in A(A)(collagen, wall) after the application of collagenase was 51% +/- 22%. The Triton(r) X-100 treatment led to a decrease in the SMC content that was associated with enlargement of the arterial wall (outer diameter) for pressures up to 120 mmHg, and with mechanical stiffening of the arterial wall at higher pressures. Elastase led to a decrease in the elastin content that was associated with enlargement of the arterial wall, but not with stiffening or softening. Collagenase led to a decrease in collagen content that was associated with a change in the stiffness of the arterial wall, although the exact contribution of mechanical loading and the duration of treatment (enlargement) could not be quantified. PMID- 22813962 TI - SnoN as a key regulator of the high glucose-induced epithelial-mesenchymal transition in cells of the proximal tubule. AB - BACKGROUND/AIMS: Ski-related protein N (SnoN) suppression is essential to transforming growth factor-beta1 induction and the epithelial-mesenchymal transition (EMT) in several cancer cells. The role of SnoN in diabetic nephropathy is unknown. We aimed to determine the role of SnoN in the EMT of proximal tubule cells (PTCs) maintained under high glucose conditions. METHODS: Immunohistochemistry, immunocytochemistry, Western blotting, small interfering RNA gene silencing, viral transduction and RT-PCR were used to assess changes in SnoN, E-cadherin, cytokeratin-18, alpha-smooth muscle actin and fibronectin expression using an in vivo streptozotocin-induced rat diabetic nephropathy model, and PTCs exposed to high glucose (25 mmol/l). RESULTS: High glucose induced EMT in vitro and in vivo. Exposure of PTCs to a high concentration of glucose suppressed SnoN expression in a time-dependent manner compared with normal glucose and high osmolarity-treated groups. SnoN gene silencing under high glucose conditions appears to enhance the transition of PTC phenotype. Conversely, ectopic expression of exogenous SnoN after transfection conferred tubular epithelial cell resistance to high glucose-induced EMT. CONCLUSION: SnoN plays a negative role in high glucose-induced EMT in PTCs. The effect of SnoN downregulation in vivo and in vitro suggests that SnoN may be a potential therapeutic target. PMID- 22813963 TI - Rhizobial extrachromosomal replicon variability, stability and expression in natural niches. AB - In bacteria, niche adaptation may be determined by mobile extrachromosomal elements. A remarkable characteristic of Rhizobium and Ensifer (Sinorhizobium) but also of Agrobacterium species is that almost half of the genome is contained in several large extrachromosomal replicons (ERs). They encode a plethora of functions, some of them required for bacterial survival, niche adaptation, plasmid transfer or stability. In spite of this, plasmid loss is common in rhizobia upon subculturing. Rhizobial gene-expression studies in plant rhizospheres with novel results from transcriptomic analysis of Rhizobium phaseoli in maize and Phaseolus vulgaris roots highlight the role of ERs in natural niches and allowed the identification of common extrachromosomal genes expressed in association with plant rootlets and the replicons involved. PMID- 22813964 TI - Effects of serum proteins on in vitro melamine-cyanurate crystal formation. AB - Melamine toxicity is recognized as a distinct form of renal failure due to occlusion of the renal tubules by the compound melamine and its deaminated derivative, cyanuric acid. The morphology of melamine-cyanurate crystals in vivo differs from that in vitro, being rounded in the former case but needle-like in the latter. The reasons for this difference in morphology between in vivo and in vitro crystals remain unknown. In the present study, we investigated the in vitro effects of several possible intra-renal factors, i.e., pH and serum and urinary proteins, on the morphology of melamine-cyanurate crystals in order to clarify what might be responsible for the formation of rounded urolites in vivo. We found that serum proteins, such as fetal bovine serum, bovine serum albumin and bovine gamma-globulin, can alter the morphology of melamine cyanurate, turning it into rounded crystals. The urinary protein beta-2-microglobulin had a less pronounced effect. The crystal morphology was unaffected by pH. Based on the present in vitro findings and known clinical data, we suggest a putative protein-related model for melamine-cyanurate formation in the kidney. PMID- 22813965 TI - Many faces of orexin/hypocretin. AB - Orexin/hypocretin (ORX/Hcrt) is a neuropeptide discovered in 1998 that is produced by a small group of neurons exclusively localized to the hypothalamus with extensive CNS wide projections. These neurons appear to regulate a wide range of homeostatic functions. Much innovative research has emerged in this field over the past decade, and several novel drug candidates targeting the ORX/Hcrt receptors are being pursued for a variety of disease states. This introduction is a brief overview of the outstanding research reports by leading experts in the field presented in this collection specifically compiled to provide comprehensive, most current reviews of the many functions of the ORX/Hcrt system. PMID- 22813966 TI - Overview of orexin/hypocretin system. AB - A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives. PMID- 22813967 TI - Hypocretins and the neurobiology of sleep-wake mechanisms. AB - In 1998, our group discovered a cDNA that encoded the precursor of two putative neuropeptides that we called hypocretins for their hypothalamic expression and their similarity to the secretin family of neuropeptides. In the past 15 years, numerous studies have placed the hypocretin system as an integrator of homeostatic functions with a crucial, nonredundant function as an arousal stabilizer. Here, we discuss some of the data that have accumulated over the years on the integrating capacity of these hypothalamic neurons and their role on sleep-to-wake transitions. PMID- 22813969 TI - Orexins, feeding, and energy balance. AB - In this chapter, we give an overview of the current status of the role of orexins in feeding and energy homeostasis. Orexins, also known as hypocretins, initially were discovered in 1998 as hypothalamic regulators of food intake. A little later, their far more important function as regulators of sleep and arousal came to light. Despite their restricted distribution, orexin neurons have projections throughout the entire brain, with dense projections especially to the paraventricular nucleus of the thalamus, the arcuate nucleus of the hypothalamus, and the locus coeruleus and tuberomammillary nucleus. Its two receptors are orexin receptor 1 and orexin receptor 2. These receptors show a specific and localized distribution in a number of brain regions, and a variety of different actions has been demonstrated upon their binding. Our group showed that through the autonomic nervous system, the orexin system plays a key role in the control of glucose metabolism, but it has also been shown to stimulate sympathetic outflow, to increase body temperature, heart rate, blood pressure, and renal sympathetic nerve activity. The well-known effects of orexin on the control of food intake, arousal, and wakefulness appear to be more extensive than originally thought, with additional effects on the autonomic nervous system, that is, to increase body temperature and energy metabolism. PMID- 22813970 TI - Orexin and natural reward: feeding, maternal, and male sexual behavior. AB - Orexin, also known as hypocretin, is a hypothalamic neuropeptide important for mediation of arousal and sleep as well as feeding and energy homeostasis. Recent studies have indicated that orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse. Based on those findings, it has been hypothesized that orexin is involved in control of other natural reward behaviors. This review will summarize studies that examine the role of orexin in motivation and reward associated with food intake, maternal behavior, and male sexual behavior. In particular for sexual behavior in male rats, we have recently shown that orexin cell-specific lesions do not impair sexual performance and motivation but disrupt conditioned responses associated with sexual reward. PMID- 22813968 TI - Respiration and autonomic regulation and orexin. AB - Orexin, a small neuropeptide released from neurons in the hypothalamus with widespread projections throughout the central nervous system, has broad biological roles including the modulation of breathing and autonomic function. That orexin activity is fundamentally dependent on sleep-wake state, and circadian cycle requires consideration of orexin function in physiological control systems in respect to these two state-related activity patterns. Both transgenic mouse studies and focal orexin receptor antagonism support a role for orexins in respiratory chemosensitivity to CO2 predominantly in wakefulness, with further observations limiting this role to the dark period. In addition, orexin neurons participate in the regulation of sympathetic activity, including effects on blood pressure and thermoregulation. Orexin is also essential in physiological responses to stress. Orexin-mediated processes may operate at two levels: (1) in sleep-wake and circadian states and (2) in stress, for example, the defense or "fight-or-flight" response and panic-anxiety syndrome. PMID- 22813972 TI - Hypocretin modulation of drug-induced synaptic plasticity. AB - The ventral tegmental area (VTA) is a brain region centrally involved in the development and expression of a variety of behaviors associated with drug use. Hypocretin (hcrt), also known as orexin, is a lateral hypothalamic neuropeptide that can be released into the VTA. An increasing number of studies show that hcrt in the VTA exerts modulatory effects on a variety of behaviors produced by drugs of abuse. Importantly, at a cellular level, acute application of hcrt in the VTA potentiates N-methyl-D-aspartate receptors expressed in VTA neurons and facilitates the plasticity induced by drugs of abuse. In this review, we discuss evidence that hcrt directly targets dopamine neurons by modulating excitatory synaptic activity and that hcrt action at excitatory synapses onto VTA dopamine neurons plays a central role in motivated behaviors. PMID- 22813974 TI - Orexin receptors as therapeutic drug targets. AB - Orexin (hypocretin) receptor antagonists stand as a model for the development of targeted CNS small-molecule therapeutics. The identification of mutations in the gene for the orexin 2 receptor responsible for canine narcolepsy, the demonstration of a hypersomnolence phenotype in hypocretin knockout mice and the disruption in orexin signaling in narcoleptic patients provides clear genetic proof of concept for targeting orexin-induced arousal for the treatment of insomnia. The full characterization of the genes encoding orexin and its two cognate receptors enabled the rapid development of in vitro and ex vivo assays with which to identify lead compound structures and to optimize potency and pharmacokinetic properties. Polysomnographic measures with cross-species translatability capable of measuring the sleep-promoting effects of orexin receptor antagonists from mice to man, and the existence of knockout models not only allow efficacy assessment but also the demonstration of mechanism of action. Focused efforts by a number of groups have identified potent compounds of diverse chemical structure with differential orexin receptor selectivity for either the orexin 1 receptor (OX1R) or the orexin 2 receptor (OX2R), or both. This work has yielded tool compounds that, along with genetic models, have been used to specifically define the role these receptors in mediating orexin-induced arousal and vigilance state control. Optimized dual receptor antagonists with favorable pharmacokinetic and safety profiles have now demonstrated efficacy in clinical development and represent a distinct mechanism of action for the treatment of insomnia relative to current standard of care. PMID- 22813976 TI - Meta-analysis of the influence of Parkin p.Asp394Asn variant on the susceptibility of Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The Parkin p.Asp394Asn variant (c.1281G>A) has been investigated as a potential genetic hallmark of PD, but studies investigating the association between the variant and PD have reported conflicting results. Therefore, we conducted this meta-analysis to assess whether pooled results show the association. We performed structured literature searches in MEDLINE, EMBASE, Cochrane Library, and China Academic Journals databases for studies addressing the association between Parkin p.Asp394Asn variant and PD. The meta-analysis was conducted in five genetic models: additive, dominant, recessive, heterozygous, and homozygous, with the odds ratio (OR) as the measure of association. When all 7 studies involving 2425 subjects (1213 cases and 1212 controls) were pooled into the analysis, there was no evidence for significant association between Parkin p. Asp394Asn variant and PD risk in additive genetic model (OR=1.06, 95% confidence interval (CI)=0.66 1.70, P=0.825). The OR for the dominant model was 1.07 (95% CI=0.69-1.67) while the OR for the recessive model was 0.84 (95% CI=0.16-4.35). The OR for the heterozygote was 1.08 (95% CI=0.73-1.60) while the OR for the homozygote was 0.85 (95% CI=0.16-4.61). Concluding, our study does not support an association between the Parkin p.Asp394Asn variant and PD risk. PMID- 22813973 TI - Orexin, stress, and anxiety/panic states. AB - A panic response is an adaptive response to deal with an imminent threat and consists of an integrated pattern of behavioral (aggression, fleeing, or freezing) and increased cardiorespiratory and endocrine responses that are highly conserved across vertebrate species. In the 1920s and 1940s, Philip Bard and Walter Hess, respectively, determined that the posterior regions of the hypothalamus are critical for a "fight-or-flight" reaction to deal with an imminent threat. Since the 1940s it was determined that the posterior hypothalamic panic area was located dorsal (perifornical hypothalamus: PeF) and dorsomedial (dorsomedial hypothalamus: DMH) to the fornix. This area is also critical for regulating circadian rhythms and in 1998, a novel wake-promoting neuropeptide called orexin (ORX)/hypocretin was discovered and determined to be almost exclusively synthesized in the DMH/PeF perifornical hypothalamus and adjacent lateral hypothalamus. The most proximally emergent role of ORX is in regulation of wakefulness through interactions with efferent systems that mediate arousal and energy homeostasis. A hypoactive ORX system is also linked to narcolepsy. However, ORX role in more complex emotional responses is emerging in more recent studies where ORX is linked to depression and anxiety states. Here, we review data that demonstrates ORX ability to mobilize a coordinated adaptive panic/defense response (anxiety, cardiorespiratory, and endocrine components), and summarize the evidence that supports a hyperactive ORX system being linked to pathological panic and anxiety states. PMID- 22813971 TI - Multiple roles for orexin/hypocretin in addiction. AB - Orexins/hypocretins are hypothalamic peptides involved in arousal and wakefulness, but also play a critical role in drug addiction and reward-related behaviors. Here, we review the roles played by orexins in a variety of animal models of drug addiction, emphasizing both commonalities and differences for orexin's involvement in seeking of the major classes of abused drugs, as well as food. One common theme that emerges is an involvement of orexins in drug seeking triggered by external stimuli (e.g., cues, contexts or stressors). We also discuss the functional neuronal circuits in which orexins are embedded, and how these circuits mediate addiction-related behaviors, with particular focus on the role of orexin and glutamate interactions within the ventral tegmental area. Finally, we attempt to contextualize the role of orexins in reward by discussing ways in which these peptides, expressed in only a few thousand neurons in the brain, can have such wide-ranging effects on behavior. PMID- 22813977 TI - Electrophysiological analysis of the interaction between the lateral septum and the central nucleus of the amygdala. AB - Evidence suggests that the lateral septum (LS) and the central nucleus of the amygdala (CeA) play opposing roles in the modulation of fear and anxiety. The current study examined the interaction of the two structures in the albino rat by electrically stimulating each and recording single-unit activity in the other. In each case, electrical stimulation consisted of 50 trains of 5 pulses 800MUA in amplitude, 0.1ms in duration with a .01s interval between pulses. Electrical stimulation of LS had a predominant inhibitory effect upon cells in CeA. Contrariwise, stimulation of CeA had a predominant excitatory effect on cells in LS. The results of the study suggest a possible regulatory, negative feedback model of the interaction between LS and CeA. PMID- 22813978 TI - Swimming exercise ameliorates depression-like behaviors induced by prenatal exposure to glucocorticoids in rats. AB - Prenatal exposure to glucocorticoids (GCs) leads to affective dysfunction in adulthood, which may be associated with the alterations in hypothalamic-pituitary adrenal (HPA) axis. Physical exercise has been shown to ameliorate depressive symptoms. The objectives of present study were to investigate whether prenatal exposure to GCs induces depression-like behaviors in adult offspring rats, and determine whether swimming exercise alleviates the depression-like behaviors induced by this paradigm. Pregnant rats received dexamethasone (DEX) (0.1mg/kg/day) in the last third of pregnancy or vehicle. DEX treatment reduced body weight in 1, 3, 6, 9-week old male offspring, and 3, 6, 9-week old female offspring. DEX treatment resulted in an elevated level of serum corticosterone in adult offspring (9weeks). Female and male adult offspring rats exhibited decreased number of poking into holes and rearing and decreased central distance traveled in open field test (OFT), and reduced sucrose consumption, suggesting prenatal DEX exposure increase depression-like behaviors in the adult offspring rats. Four-week swimming exercise reduced serum corticosterone levels, and alleviated the depressive behavior by reversing the decreased number of poking into holes and rearing as well as decreased central distance traveled, and reversing the reduced sucrose consumption in male and female adult offspring. These findings suggested prenatal exposure to GCs increase the activity of HPA axis and depression-like behaviors of adult offsprings. Swimming exercise decreases HPA activity and ameliorates depression in rats exposed to DEX prenatally. PMID- 22813979 TI - Basal ganglia circuits changes in Parkinson's disease patients. AB - Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects. PMID- 22813980 TI - Diagnosis and treatment of bladder endometriosis: state of the art. AB - BACKGROUND: The bladder is the most common affected site in urinary tract endometriosis, being diagnosed during gynecologic follow-up. The surgical urological treatment might lead to good results. STUDY OBJECTIVE: To define the state of the art in the diagnosis and treatment of bladder endometriosis. METHODS: We performed a literature review by searching the MEDLINE database for articles published between 1996 and 2011, limiting the searches to the words: urinary tract endometriosis, bladderendometriosis, symptoms, diagnosis and treatment. RESULTS: Deep pelvic endometriosis usually involves the urinary system, with the bladder being affected in 85% of cases. The diagnosis has to be considered as a step-by-step procedure. Currently, the treatment is usually surgical, consisting of either transurethral resection or partial cystectomy, and eventually associated with hormonal therapy. The hormonal therapy alone counteracts only the stimulus of endometriotic tissue proliferation, with no effects on the scarring caused by this tissue. The overall recurrence rate is about 30% for combined therapies and about 35% for the hormonal treatment alone. CONCLUSIONS: The bladder is the most common affected site in urinary tract endometriosis. Most of the time, this condition is diagnosed because of the complaint of urinary symptoms during gynecologic follow-up procedures for a deep pelvic endometriosis: a close collaboration between the gynecologist and the urologist is advisable, especially in highly specialized centers. The surgical urological treatment might lead to good results in terms of patients' compliance and prognosis. PMID- 22813981 TI - Within-session practice effects in patients referred for suspected dementia. AB - BACKGROUND: Practice effects are improvements in cognitive test performance associated with repeated administrations of same or similar measures and are traditionally seen as error variance. However, there is growing evidence that practice effects provide clinically useful information. METHODS: Within-session practice effects (WISPE) across 2 h were collected from 61 non-consecutive patients referred for suspected dementia and compared to the Mini Mental Status Examination (MMSE), a screening measure of dementia severity. RESULTS: In all patients, WISPE on two cognitive measures were significantly correlated with MMSE, even after controlling for baseline cognitive scores (partial r = 0.47, p < 0.001; partial r = 0.26, p = 0.046). In patients diagnosed with probable Alzheimer's disease, the trend was even stronger (partial r = 0.72, p < 0.01; partial r = 0.58, p = 0.046). In both groups, lower WISPE were associated with lower MMSE scores (i.e. greater dementia severity), even after controlling for initial cognitive scores. CONCLUSION: If future research validates these findings with longitudinal studies, then WISPE may have important clinical applications in dementia evaluations. PMID- 22813982 TI - Drug-induced effects on cardiovascular function in pentobarbital anesthetized guinea-pigs: invasive LVP measurements versus the QA interval. AB - INTRODUCTION: Evaluation of drug-related effects on cardiovascular function is part of the core battery described in the ICH S7A guideline. Anesthetized guinea pigs are excellent models for the evaluation of drug-induced prolongation of ventricular repolarization; however less information is available regarding other cardio-hemodynamic parameters in this model. The current study aimed to document cardio-hemodynamic responses in anesthetized guinea-pigs after administration of a number of reference drugs with known pharmacological actions. METHODS: Experiments were carried out in closed chest pentobarbital anesthetized female guinea-pigs. Compounds were administered intravenously while arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were measured continuously. The rate of LVP contraction (LV dP/dt(max)) was used to evaluate cardiac performance; and was compared to the QA interval; which has previously been proposed as an indirect measurement of cardiac function. RESULTS: Baseline values for heart rate and blood pressure were lower in anesthetized animals compared to literature data of conscious guinea-pigs. Heart rate increased after administration of adrenaline, isoprenaline and salbutamol, but not after L phenylephrine. Verapamil and amiodarone decreased heart rate and blood pressure. Zatebradine infusion led to a decrease in heart rate with minimal effects on blood pressure. Sodium nitroprusside (SNP) caused a reduction in mean blood pressure at higher doses followed by reflex tachycardia. Both adrenaline and L phenylephrine increased arterial blood pressure. Furthermore, adrenaline, isoprenaline and salbutamol increased LV dP/dt(max) and decreased the QA interval. L-phenylephrine increased LV dP/dt(max), but transiently prolonged the QA interval. Both verapamil and amiodarone decreased LV dP/dt(max) and prolonged the QA interval, whereas zatebradine did not affect this parameter. DISCUSSION: In addition to its utility for the assessment of test compounds on ventricular repolarization the pentobarbital anesthetized guinea-pig model shows promise for early stage cardio-hemodynamic screening. Furthermore, the QA interval shows potential for prediction of adverse effects on cardiac contractility. PMID- 22813983 TI - Effects of strength training on mechanomyographic amplitude. AB - The aim of the present study was to determine if the patterns of mechanomyographic (MMG) amplitude across force would change with strength training. Twenty-two healthy men completed an 8-week strength training program. During three separate testing visits (pre-test, week 4, and week 8), the MMG signal was detected from the vastus lateralis as the subjects performed isometric step muscle actions of the leg extensors from 10-100% of maximal voluntary contraction (MVC). During pre-testing, the MMG amplitude increased linearly with force to 66% MVC and then plateaued. Conversely, weeks 4 and 8 demonstrated an increase in MMG amplitude up to ~ 85% of the subject's original MVC before plateauing. Furthermore, seven of the ten force levels (30-60% and 80-100%) showed a significant decrease in mean MMG amplitude values after training, which consequently led to a decrease in the slope of the MMG amplitude/force relationship. The decreases in MMG amplitude at lower force levels are indicative of hypertrophy, since fewer motor units would be required to produce the same absolute force if the motor units increased in size. However, despite the clear changes in the mean values, analyses of individual subjects revealed that only 55% of the subjects demonstrated a significant decrease in the slope of the MMG amplitude/force relationship. PMID- 22813984 TI - Hearing preservation after cochlear implantation using deeply inserted flex atraumatic electrode arrays. AB - The aim of this study was to investigate hearing preservation in adults receiving cochlear implants with Flex arrays. Fifteen adults (19 ears) implanted with Flex EAS(r) (n = 4) or Flex Soft(r) (n = 15; MedEL, Innsbruck, Austria) were included in this retrospective study. The mean array insertion length was 25 +/- 0.9 mm (n = 19), and the mean cochlear coverage was 435 +/- 14.5 degrees (n = 19), with no difference between EAS and Soft arrays. Residual low-frequency hearing was preserved in all implanted ears but deteriorated [pure-tone average (125-1000 Hz) 55.1 +/- 2.90 dB before vs. 81.0 +/- 3.02 dB after surgery (n = 19, p < 0.01)]. Both Flex arrays allow deep insertion with reproducible hearing preservation. PMID- 22813985 TI - Medicare beneficiaries less likely to experience cost- and access-related problems than adults with private coverage. AB - The experiences of people covered by Medicare and those with private employer insurance can help inform policy debates over the federal budget deficit, Medicare's affordability, and the expansion of private health insurance under the Affordable Care Act. This article provides evidence that people with employer sponsored coverage were more likely than Medicare beneficiaries to forgo needed care, experience access problems due to cost, encounter medical bill problems, and be less satisfied with their coverage. Within the subset of beneficiaries who are age sixty-five or older, those enrolled in the private Medicare Advantage program were less likely than those in traditional Medicare to have premiums and out-of-pocket costs exceed 10 percent of their income. But they were also more likely than those in traditional Medicare to rate their insurance poorly and to report cost-related access problems. These results suggest that policy options to shift Medicare beneficiaries into private insurance would need to be attentive to potentially negative insurance experiences, problems obtaining needed care, and difficulties paying medical bills. PMID- 22813987 TI - Contribution of the MexXY multidrug efflux pump and other chromosomal mechanisms on aminoglycoside resistance in Pseudomonas aeruginosa isolates from canine and feline infections. AB - As study of multidrug efflux pumps is a crucial step for development of efflux pump inhibitors for treatment of Pseudomonas aeruginosa infection, the objective of this study was to examine the contribution of the MexXY multidrug efflux systems and other chromosomal mechanisms in aminoglycoside (AMG) resistance in P. aeruginosa isolated from dogs and cats. Thirteen Pseudomonas aeruginosa isolates from canine and feline infections were examined for contribution of the MexXY multidrug efflux pump and four other chromosomally-encoded genes including PA5471, galU, nuoG and rplY to AMG resistance. All the isolates were resistant to multiple AMGs and expressed mexXY. Deletion of mexXY caused 2- to 16-fold reduction in AMG MICs. Overproduction of MexXY did not fully account for the observed AMG resistance. No good correlations were detected between MexXY transcription level and AMG MICs. While no mutations were found in mexZ, PA5471 expression varied and its impact on MexXY expression and AMG resistance is diverse. No mutations were found in galU. Only two isolates carried a single base change G-367-T in rplY. Complete transcription of nuoG was detected in all the isolates. In conclusion, the MexXY multidrug efflux pump plays a role in AMG resistance in the dog and cat P. aeruginosa isolates, while disruption of nuoG, rplY and galU did not have a significant impact. These results indicate the existence of uncharacterized AMG-resistance mechanisms. PMID- 22813988 TI - Synthesis and studies on Cu(II), Co(II), Ni(II) complexes of Knoevenagel beta diketone ligands. AB - Transition metal complexes of various acetylacetone based ligands of the type ML [where M=Cu(II), Ni(II), Co(II); L=3-(aryl)-pentane-2,4-dione] have been synthesized. The structural features have been derived from their elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, (1)H NMR, Mass and ESR spectral studies. Conductivity measurements reveal that all the complexes are non-electrolytic in nature. Spectroscopic and other analytical data of the complexes suggest octahedral geometry for other metal(II) complexes. The redox behavior of the copper(II) complexes have been studied by cyclic voltammetry. The free ligands and their metal complexes have been screened for their in vitro biological activities against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus as well as the fungus Candida albicans by well diffusion method. The zone of inhibition value indicates that the most of the metal(II) complexes are found to possess increased activities compared to those of the free ligands. All synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation (SHG) efficiency of the ligands (L1-L3) was found to be considerable effect than that of urea and KDP (potassium dihydrogen phosphate). PMID- 22813989 TI - Selective quenching of benzimidazole derivatives by Cu2+ metal ion. AB - It is a very big challenge to develop a Cu(2+) selective fluorescent sensor with the ability to exclude the interference of some metal ions such as Fe(3+), Mg(2+), Ag(+), K(+) and Na(+). Herein, we report a fluorescence quenching of some benzimidazole derivatives (1-6) with Cu(2+) metal ion. These benzimidazole derivatives have been shown to bind copper ions resulting in quenching of its fluorescence. The response to Cu(2+) is rapid, selective and reversible upon addition of a copper chelator. These benzimidazole derivatives were characterized by (1)H, (13)C NMR mass and elemental analysis. XRD analysis was carried out for 1-(4-methylbenzyl)-2-p-tolyl-1H-benzo[d]imidazole. PMID- 22813990 TI - Synthesis, spectroscopic, photoluminescence properties and biological evaluation of novel Zn(II) and Al(III) complexes of NOON tetradentate Schiff bases. AB - Novel mononuclear Zn(II) and Al(III) complexes were synthesized from the reactions of Zn(OAc)(2).2H(2)O and anhydrous AlCl(3) with neutral N2O2 donor tetradentate Schiff bases; N,N'bis(salicylaldehyde)4,5-dimethyl-1,2 phenylenediamine (H(2)L(1)) and N,N'bis(salicylaldehyde)4,5-dichloro-1,2 phenylenediamine (H(2)L(2)). The new complexes were fully characterized by using micro analyses (CHN), FT-IR, (1)H NMR, UV-Vis spectra and thermal analysis. The analytical data have been showed that, the stoichiometry of the complexes is 1:1. Spectroscopic data suggested tetrahedral and square pyramidal geometries for Zn(II) and Al(III) complexes, respectively. The synthesized Zn(II), and Al(III) complexes exhibited intense fluorescence emission in the visible region upon UV excitation in methylene chloride solution at ambient temperature. This high fluorescence emission was assigned to the strong coordination of the ligands to the small and the highly charged Zn(II) and Al(III) ions. Such strong coordination seems to extend the pi-conjugation of the complexes. Thermal analysis measurements indicated that the complexes have good thermal stability. As a potential application the biological activity (e.g., antimicrobial action) of the prepared ligands and complexes was assessed by in-vitro testing of their effect on the growth of various strains of bacteria and fungi. PMID- 22813991 TI - Ligational behavior of Schiff bases towards transition metal ion and metalation effect on their antibacterial activity. AB - New Schiff bases pyrazine-2-carboxylicacid (phenyl-pyridin-2-yl-methylene) hydrazide (Hpch-bp) HL(1) and pyrazine-2-carboxylicacid (pyridin-2-ylmethylene) hydrazide (Hpch-pc) HL(2) derived from condensation of pyrazine carboxylic hydrazide (Hpch) with 2-benzoyl pyridine (bp) or pyridine 2-carbaldehyde (pc) and their transition metal complexes of type ML((1-2)2) have been synthesized, where M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Characterization of ligands and their metal complexes was carried out by elemental analysis, conductimetric studies, magnetic susceptibility, spectroscopic techniques (IR, UV-VIS, NMR, ESR, Mass) and thermogravimetric analysis. The physico-chemical studies revealed octahedral geometry or distorted octahedral geometry around metal ion. These azomethine Schiff base ligands acted as tridentate coordinating through carbonyl, azomethine and pyridine nitrogen present in the ligand. The thermodynamic and thermal properties of the complexes have been investigated and it was observed on the basis of these studies that thermal stability of complexes follows the order MnMn>Ni>Co>Zn. PMID- 22813993 TI - Anthropological universals and cultural specifics: conceptual and methodological challenges in cultural neuroscience. PMID- 22813992 TI - Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis. AB - Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders. PMID- 22813994 TI - Temporal and spatial dynamics of thalamus-evoked activity in the anterior cingulate cortex. AB - In the present study, multielectrode array (MEA) recording was used to illustrate the spatial-temporal progression of anterior cingulate cortex (ACC) activity following stimulation of the thalamus in a thalamocingulate pathway-preserved slice. The MEA was placed under the slice that contained the ACC, and 60 channels of extracellular local field potentials evoked by bipolar electrical stimulation within the thalamus were analyzed. Several distinct thalamic-evoked responses were identified. The early negative component (N1; amplitude, -35.7 +/- 5.9 MUV) emerged in layer VI near the cingulum 8.4 +/- 0.5 ms after stimulation. N1 progressed upward to layers V and II/III in a lateral-to-medial direction. Subsequently, a positive component (P; amplitude, 27.0 +/- 3.2 MUV) appeared 12.0 +/- 0.6 ms after stimulation in layer VI. At 26.8 +/- 1.1 ms, a second negative component (N2; amplitude, -20.9 +/- 2.7 MUV) became apparent in layers II/III and V, followed by a more ventrolateral component (N3; amplitude, -18.9 +/- 2.9 MUV) at 42.8 +/- 2.6 ms. These two late components spread downward to layer VI in a medial-to-lateral direction. The trajectory paths of the evoked components were consistently represented with varied medial thalamic stimulation intensities and sites. Both AMPA/kainate and N-methyl-D-aspartate-type glutamate receptors involved in monosynaptic and polysynaptic transmission participated in this thalamocortical pathway. Morphine mainly diminished the two negative synaptic components, and this suppressive effect was reversed by naloxone. The present study confirmed that functional thalamocingulate activity was preserved in the brain-slice preparation. The thalamus-evoked responses were activated and progressed along a deep surface-deep trajectory loop across the ACC layers. Glutamatergic neurotransmitters were crucially involved in information processing. Opioid interneurons may play a modulatory role in regulating the signal flows in the cingulate cortex. PMID- 22813995 TI - Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats. AB - Previous studies have shown that a 2-week treatment with 40 mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5 days) and chronic (4 weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a significant alteration in hippocampal levels, suggesting that treatment with running/CORT for 4 weeks may induce a change in central levels of hippocampal BDNF level, which may not lead to a significant change in peripheral levels. PMID- 22813996 TI - Focal electrical intracerebral stimulation of a face-sensitive area causes transient prosopagnosia. AB - Face perception is subtended by a large set of areas in the human ventral occipito-temporal cortex. However, the role of these areas and their importance for face recognition remain largely unclear. Here we report a case of transient selective impairment in face recognition (prosopagnosia) induced by focal electrical intracerebral stimulation of the right inferior occipital gyrus. This area presents with typical face-sensitivity as evidenced by functional neuroimaging right occipital face area (OFA). A face-sensitive intracerebral N170 was also recorded in this area, supporting its contribution as a source of the well-known N170 component typically recorded on the scalp. Altogether, these observations indicate that face recognition can be selectively impaired by local disruption of a single face-sensitive area of the network subtending this function, the right OFA. PMID- 22813998 TI - Motor resonance mechanisms are preserved in Alzheimer's disease patients. AB - This study aimed to better characterize the sensorimotor mechanisms underlying motor resonance, namely the relationship between motion perception and movement production in patients suffering from Alzheimer's disease (AD). This work first gives a kinematic description of AD patients' upper limb movements, then it presents a simple paradigm in which a dot with different velocities is moved in front of the participant who is instructed to point to its final position when it stopped. AD patients' actions, as well as healthy elderly participants, were similarly influenced by the dot velocity, suggesting that motor resonance mechanisms are not prevented by pathology. In contrast, only patients had anticipatory motor response: i.e. they started moving before the end of the stimulus motion, unlike what was requested by the experimenter. While the automatic imitation of the stimulus suggests an intact ability to match the internal motor representations with that of the visual model, the uncontrolled motion initiation would indicate AD patients' deficiency to voluntarily inhibit response production. These findings might open new clinical perspectives suggesting innovative techniques in training programs for people with dementia. In particular, the preservation of the motor resonance mechanisms, not dependent on conscious awareness, constitutes an intact basis upon which clinicians could model both physical and cognitive interventions for healthy elderly and AD patients. Furthermore, the evaluation of the inhibitory functions, less sensitive to the level of education than other methods, might be useful for screening test combined with the traditional AD techniques. However, further investigations to understand if this feature is specific to AD or is present also in other neurodegenerative diseases are needed. PMID- 22813997 TI - Connexin and AMPA receptor expression changes over time in the rat olfactory bulb. AB - Circadian rhythms affect olfaction by an unknown molecular mechanism. Independent of the suprachiasmatic nuclei, the mammalian olfactory bulb (OB) has recently been identified as a circadian oscillator. The electrical activity in the OB was reported to be synchronized to a daily rhythm and the clock gene, Period1, was oscillatory in its expression pattern. Because gap junctions composed of connexin36 and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) have been reported to work together to synchronize firing of action potentials in the OB, we hypothesized that circadian electrical oscillations could be synchronized by daily changes in the expression of connexins and AMPAR subunits (GluR1-4). We examined the OB for the presence of clock genes by polymerase chain reaction (PCR) and whether Period2, connexins, and AMPARs fluctuated across the light/dark cycle by quantitative PCR or SDS-PAGE/Western blot analysis. We observed significant changes in the messenger RNA and protein expression of our targets across 24 or 48 h. Whereas most targets were rhythmic by some measures, only GluR1 mRNA and protein were both rhythmic by the majority of our tests of rhythmicity across all time scales. Differential expression of these synaptic proteins over the light/dark cycle may underlie circadian synchronization of action potential firing in the OB or modify synaptic interactions that would be predicted to impact olfactory coding, such as alteration of granule cell inhibition, increased number of available AMPARs to bind glutamate, or an increased gap junction conductance between mitral/tufted cells. PMID- 22813999 TI - Epilepsy: Ever-changing states of cortical excitability. AB - It has been proposed that the underlying epileptic process is mediated by changes in both excitatory and inhibitory circuits leading to the formation of hyper excitable seizure networks. In this review we aim to shed light on the many physiological factors that modulate excitability within these networks. These factors have been discussed extensively in many reviews each as a separate entity and cannot be extensively covered in a single manuscript. Thus for the purpose of this work in which we aim to bring those factors together to explain how they interact with epilepsy, we only provide brief descriptions. We present reported evidence supporting the existence of the epileptic brain in several states; interictal, peri-ictal and ictal, each with distinct excitability features. We then provide an overview of how many physiological factors influence the excitatory/inhibitory balance within the interictal state, where the networks are presumed to be functioning normally. We conclude that these changes result in constantly changing states of cortical excitability in patients with epilepsy. PMID- 22814000 TI - Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein. AB - Synucleinopathies including Parkinson's disease (PD) are characterized by the accumulation of alpha-synuclein (alpha-syn) within neural cell bodies and their processes. Transgenic mice overexpressing human wild-type or mutant forms of alpha-syn under the control of different promoters were developed to analyse the underlying neuropathology of PD. One of the earliest clinical symptoms associated with PD is olfactory impairment. The generation of new neurons persists up to adulthood in mammals, in particular the olfactory bulb (OB). In order to assess this process in relation to alpha-syn accumulation, we used mice overexpressing human wild-type alpha-syn under the regulatable control (tet-off) of the calcium/calmodulin-dependent protein kinase IIalpha-promoter (CaMKII). We observed a decrease in OB neurogenesis in transgenic animals compared to controls using 5-bromo-2'-deoxyuridine (BrdU) to label newly generated cells (neuron specific nuclear protein; NeuN). After cessation of transgene expression we detected an increase in newly generated cells both in granular (GCL) and glomerular (GLOM) layers of the OB. This led to a rescue of newly generated neurons (BrdU(+)/NeuN(+)) within the GLOM with a distinct specificity for the dopaminergic subpopulation. In contrast, we did not detect a cell-specific rescue of neuronal cells in the GCL suggesting diverse effects of alpha-synucleinopathy in both interneuronal layers of the OB. Colabelling of BrdU with glial markers showed that a differentiation into neither astroglia nor microglia attributed to the observed phenotype in the GCL. In particular, BrdU(+) particles located within microglial cells were predominantly associated close to the membrane therefore the resembling phagocytosed nuclear fragments of BrdU(+) cells. Thus, our study further contributes insights into alpha-syn accumulation as a causative player in the impairment of adult neurogenesis and emphasizes its diverse role in cell renewal of distinct OB cell layers. PMID- 22814001 TI - The characterization of arachnoid cell transport II: paracellular transport and blood-cerebrospinal fluid barrier formation. AB - We used an immortalized arachnoid cell line to test the arachnoid barrier properties and paracellular transport. The permeabilities of urea, mannitol, and inulin through monolayers were 2.9 +/- 1.1 * 10(-6), 0.8 +/- .18 * 10(-6), 1.0 +/ .29 * 10(-6)cm/s. Size differential permeability testing with dextran clarified the arachnoidal blood-cerebrospinal fluid (CSF) barrier limit and established a rate of transcellular transport to be about two orders of magnitude slower than paracellular transport in a polyester membrane diffusion chamber. The theoretical pore size for paracellular space is 11A and the occupancy to length ratio is 0.8 and 0.72 cm(-1) for urea and mannitol respectively. The permeability of the monolayer was not significantly different from apical to basal and vice versa. Gap junctions may have a role in contributing to barrier formation. Although the upregulation of claudin by dexamethasone did not significantly alter paracellular transport, increasing intracellular cAMP decreased mannitol permeability. Calcium modulated paracellular transport, but only selectively with the ion chelator, EDTA, and with disruption of intracellular stores. The blood-CSF barrier at the arachnoid is anatomically and physiologically different from the vascular-based blood-brain barrier, but is similarly subject to modulation. We describe the basic paracellular transport characteristics of this CSF "sink" of the brain which will allow for a better description of mass and constitutive balance within the intracranial compartment. PMID- 22814002 TI - Triheteromeric N-methyl-D-aspartate receptors differentiate synaptic inputs onto pyramidal neurons in somatosensory cortex: involvement of the GluN3A subunit. AB - N-methyl-D-aspartate receptors (NMDARs) are glutamatergic by virtue of glutamate binding GluN2 subunits and glycinergic by virtue of glycine-binding GluN1 and GluN3 subunits. The existence, location, and functional-significance of NMDARs containing both GluN2 and GluN3 subunits have as yet remained unelucidated. Here we report on the discovery and characterization of a novel type of NMDARs, found at layer (L)1/primary whisker-motor-cortex inputs onto L5 pyramidal neurons in somatosensory cortex, that are distinct in structure and function from conventional GluN2A-containing NMDARs at thalamic/striatal (Str) inputs onto the same neurons. These receptors had a threshold-like activation at hyperpolarized holding-potentials with strong outward rectification of their current-voltage relationships unlike any known GluN1/GluN2-containing NMDARs. Pharmacology revealed a triheteromeric-receptor with features common to glutamate-activated GluN1/GluN2-containing and glycine-activated GluN1/GluN3-containing diheteromeric NMDARs. However, unlike GluN1/GluN3 receptors, NMDARs at L1 inputs were activated by glutamate and blocked by d-AP5, Ca(2+)-permeable, and more efficient at integrating and potentiating EPSPs selectively over Str inputs during high frequency stimulation while obviating the need for AMPAR-mediated depolarization. PMID- 22814003 TI - Prostate saturation biopsy following a first negative biopsy: state of the art. AB - INTRODUCTION: Saturation prostate biopsy (SPBx) has been initially introduced to improve prostate cancer (PCa) detection rate (DR) in the repeat setting. Nevertheless, the optimal number and the most appropriate location of the cores, together with the timing to perform a second PBx and the eventual modification of the PBx protocols according to the different clinical situations, are matters of debate. The aim of this review is to perform a critical analysis of the literature about the actual role of SPBx in the repeat setting. MATERIALS AND METHODS: We performed a systematic review of the literature since 1995 up to 2011. Electronic searches were limited to the English language, using the MEDLINE database. The key words 'saturation prostate biopsy' and 'repeated prostate biopsy' were used. RESULTS: SPBx improves PCa DR if clinical suspicion persists after previous biopsy with negative findings and provides an accurate prediction of prostate tumor volume and grade, even if the issue about the number and locations of the cores is still a matter of debate. CONCLUSIONS: At present, SPBx seems to be really necessary in men with persistent suspicion of PCa after negative initial biopsy and probably in patients with a multifocal high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. In the remaining situations, adopting an individualized scheme is preferable. PMID- 22814004 TI - L-NAME in the cardiovascular system - nitric oxide synthase activator? AB - L-arginine analogues are widely used inhibitors of nitric oxide synthase (NOS) activity both in vitro and in vivo, with N(omega)-nitro-L-arginine methyl ester (L-NAME) being at the head. On the one hand, acute and chronic L-NAME treatment leads to changes in blood pressure and vascular reactivity due to decreased nitric oxide (NO) bioavailability. However, lower doses of L-NAME may also activate NO production via feedback regulatory mechanisms if administered for longer time. Such L-NAME-induced activation has been observed in both NOS expression and activity and revealed considerable differences in regulatory mechanisms of NO production between particular tissues depending on the amount of L-NAME. Moreover, feedback activation of NO production by L-NAME seems to be regulated diversely under conditions of hypertension. This review summarizes the mechanisms of NOS regulation in order to better understand the apparent discrepancies found in the current literature. PMID- 22814005 TI - Prenatal tolerability of acetaminophen and other over-the-counter non-selective cyclooxygenase inhibitors. AB - Over-the-counter cyclooxygenase inhibitors are used to relief fever and various types of acute pain like headache, toothache, earache, sore throat, as well as postoperative and menstrual ones. They are also major ingredients in cold and flu mixtures. Unlike well-known organ toxicological profile, their prenatal toxicity was not fully established. For a long time, acetaminophen was considered as a relatively safe antipyretic and analgesic drug during pregnancy. However, a new data indicate that it may increase the risk of cryptorchidism and asthma during childhood as well as preeclampsia, preterm birth, maternal phlebothrombosis and pulmonary embolism. Contrary to acetaminophen, non-selective cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs - NSAID; i.e., diclofenac, ibuprofen, naproxen) may induce intrauterine growth retardation, ductus arteriosus constriction with secondary persistent pulmonary hypertension, reduced fetal renal perfusion that led to oligohydramion, prolonged pregnancy as well as increase prevalence of intracranial bleeding in newborns. Furthermore, a higher risk of miscarriage, stillbirth and some congenital malformations (cardiac and diaphragmatic defects, celosomy - gastroschisis and umbilical hernia) was reported for non-selective inhibitors, in particular high doses of acetylsalicylic acid (aspirin). PMID- 22814006 TI - Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. AB - BACKGROUND: Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. METHODS: One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. RESULTS: The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. CONCLUSIONS: The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. PMID- 22814007 TI - Baclofen influences acquisition and MMP-2, MMP-9 levels in the hippocampus of rats after hypoxia. AB - BACKGROUND: Baclofen, the agonist of GABA(B) receptors, influences hypoxia induced deficits in learning and memory processes. METHODS: We studied the effects of baclofen on acquisition in the passive avoidance test and in the Morris water maze in groups of rats without or after hypoxia as well as the influence of baclofen on MMP-2 and MMP-9 levels in the hippocampus. RESULTS: Even though baclofen itself impaired the acquisition in the passive avoidance, it improved the hypoxia-induced deficit of acquisition in the passive avoidance test and in the Morris water maze. There was a significant decrease in the level of the active form of MMP-2 as well as an increase in the level of pro-MMP-9 in the hippocampus of rats without hypoxia 30 min after the administration of baclofen. Furthermore, an elevated level of pro-MMP-9 was observed 30 min after hypoxia. Baclofen used before the deprivation of oxygen, decreased the level of the active form of MMP-2 and pro-MMP-9. CONCLUSIONS: These results show that MMP-2 and MMP-9 activities in the hippocampus can be regulated by baclofen in non-pathological conditions and very shortly after hypoxia induction. We suggest that the changes in MMP-2 and MMP-9 levels are the mechanism activities of baclofen in the acquisition process. PMID- 22814008 TI - Morphine-induced place preference affects mRNA expression of G protein alpha subunits in rat brain. AB - BACKGROUND: The conditioned place preference (CPP) test is an animal model serving to assess addictive potential of drugs in which environmental cues become associated with the subjective effects of drugs of abuse. Morphine, a known addictive drug, is an agonist of opioid receptors that couple to the G(i/o) family of guanine nucleotide-binding proteins (GP). We have recently found that chronic treatment with morphine affects mRNA levels of GPs that are not coupled to opioid receptors (OR). Therefore, in this study, we investigated the influence of morphine-induced CPP on mRNA expression of the Galpha subunits, G(i/o), G(s), G(q/11), and G(12), in the rat prefrontal cortex (PFC) and nucleus accumbens (NAc) using standard PCR techniques. METHODS: CPP and NO-CPP experiments were conducted; Wistar rats were either subjected to the standard CPP procedure or were injected with morphine (or saline) in their home cage. All rats were decapitated 24 h after the last injection. RESULTS: We found that mRNA levels of Galpha(q), Galpha(11) and Galpha(12) were increased after morphine in non conditioned treatment in the PFC but remained unchanged in the NAc. In rats showing conditioned place preference to morphine, levels of Galpha(i2) in the PFC and levels of Galpha(oA) in the NAc were diminished by ~58% and ~30%, respectively (p < 0.05 vs. saline), but levels of Galpha(s-l) in NAc were increased (~60%, p = 0.05). CONCLUSION: Our data indicate that only G(i/o) and G(s) were specifically changed in animals after morphine-induced CPP, thus suggesting that the effect was related to learning environmental cues associated with morphine. PMID- 22814009 TI - Citalopram decreases tryptophan 2,3-dioxygenase activity and brain 5-HT turnover in swim stressed rats. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their effects by increasing synaptic concentrations of serotonin (5-HT). The forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Rationale of the present study was to investigate the acute effects of citalopram on hepatic tryptophan metabolism and disposition in rats exposed to FST. METHODS: We investigated the effects of acute citalopram (20 mg/kg, ip) administration on rat's behavioral responses in FST paradigm, hepatic tryptophan 2,3-dioxygenase (TDO) activity, serum corticosterone levels and brain regional 5-HT metabolism. RESULTS: Citalopram administered to swim-stressed rats showed a decrease in FST induced increases in plasma corticosterone concentration and 5-HT turnover in hypothalamus, amygdala and hippocampus. The drug also decreases immobility and increases swimming during the FST. Citalopram administration to unstressed rats increases plasma corticosterone concentration but decreases 5-HT turnover in all three brain areas examined. CONCLUSIONS: Our findings support the hypothesis that acute citalopram administration increases tryptophan (by inhibiting TDO activity) availability for 5-HT synthesis and activates serotonergic neurotransmission in limbic brain areas in rats exposed to FST paradigm. The mechanism of action of citalopram in ameliorating social stress related depressive disorder in humans is discussed. PMID- 22814010 TI - Time course of zinc deprivation-induced alterations of mice behavior in the forced swim test. AB - BACKGROUND: Zinc is an important trace element essential for numerous bodily functions. It is believed that a deficiency of zinc can lead to various conditions, including depression, on which this study is focused. It is still not known if hypozincemia leads to the development of depression or whether zinc deficiency is a result of depression. It is hypothesized that zinc may be a therapeutic agent or supplement that would help to reverse the symptoms of this disease. METHODS: In the present study, the behavior of mice was assessed 2, 4, and 10 weeks following administration of a zinc deficient diet. To evaluate animal activity we used the forced swim test (FST). RESULTS: After 2-week zinc deprivation we demonstrated a significant reduction in the immobility time. However, after 4 and 10 weeks of zinc deprivation the mice exhibited an increased immobility time. There were no changes in locomotor activity at each time period. After 2-, 4- and 10-week zinc deprivation and the subsequent FST, serum zinc concentration was decreased and determined to be 59, 61 and 20%, respectively, compared with appropriate controls. The serum corticosterone concentration in mice after 2-, 4- and 10-week zinc deprivation and subjected to the FST was also assessed, whereby the differences between the control and experimental animals were demonstrated (increased by: 11, 97 and 225%, respectively). CONCLUSIONS: The obtained results indicate that zinc deprivation induced "pro-depressive" behavior (after the initial period of "antidepressive" behavior). This pro-depressive behavior correlates with enhanced serum corticosterone concentration. PMID- 22814011 TI - Pregabalin antinociception and its interaction with tramadol in acute model of pain. AB - BACKGROUND: The aim of present study was to investigate the antinociceptive effect of pregabalin and tramadol either alone and or in combination on acute model of pain. METHODS: The antinociceptive effect of intraperitoneal administration of pregabalin (1 to 400 mg/kg) and tramadol (10 to 80 mg/kg) or combination of them were measured after 30 and 60 min on hot-plate in terms of maximum possible effect (%MPE) in mice. RESULTS: Antinociceptive effect rose significantly for both pregabalin at doses 200 and 400 mg/kg and tramadol from 20 to 80 mg/kg in dose dependent manner. From linear equation the doses that increased antinociceptive effect by 50% (ED(50)) were 69 +/- 8.2 mg/kg for tramadol and 246 +/- 24 mg/kg for pregabalin. Unlike pregabalin, %MPE(30) (at 30(th) min) of tramadol was significantly higher than its %MPE(60). The interaction after co-administration of non analgesic dose of 10 mg/kg of pregabalin with low analgesic dose of 30 mg/kg of tramadol resulted super additive and %MPE(30) and %MPE(60) were increased compared to each drug alone. In all other combination groups, the interaction were sub-additive particularly when non analgesic doses of each drug (10 mg/kg) were co-administrated and %MPE was decreased significantly compared to that of each drug alone. CONCLUSION: Pregabalin revealed a comparative antinociceptive effect as similar to tramadol in acute model of pain, but interaction between these two drugs depends highly on their proportion in the combination. The analgesia may increase but adverse effects such as seizurogenic effect of tramadol can be reduced in clinical setting if right proportion is used. More studies are required to understand the mechanisms and clinical implication of such combinations. PMID- 22814012 TI - Deposition of ethyl glucuronide in WHP rat hair after chronic ethanol intake. AB - BACKGROUND: This study investigated the relationship between ethanol intake in rats and the resulting level of ethyl glucuronide (EtG) in rat hair. METHODS: Rats (n = 50) consumed a 10% ethanol solution for 4 weeks, then EtG was extracted from samples of their hair using a novel extraction procedure involving freezing and thawing. The EtG concentration was measured using gas chromatography and mass spectrometry. The animals voluntarily drank ethanol, with daily consumption in most rats exceeding 5 g/kg b.w. The silylated EtG was stable for at least 28 h. The limit of detection was 0.03 ng/mg, and the limit of quantification was 0.1 ng/mg. RESULTS: Hair samples from rats that consumed ethanol had EtG levels ranging from 0.17-20.72 ng/mg in female rats and 0.15-13.72 ng/mg in males. There was a correlation between the amount of alcohol consumed and the EtG levels in hair from female (p < 0.01), but not male, rats. CONCLUSION: The method presented allows detection and quantification of EtG in rat hair. We also observed differences in EtG deposition in male and female rats. PMID- 22814013 TI - Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine. AB - BACKGROUND: Cisplatin is a platinum derivative frequently used in the chemotherapy of different solid tumors. This biochemical and histologic study investigated a possible protective effect of mirtazapine with regard to cisplatin induced nephrotoxicity in the rat. METHODS: The animals were divided into 4 groups: 15 mg/kg mirtazapine + 10 mg/kg cisplatin, 30 mg/kg mirtazapine + 10 mg/kg cisplatin, only 10 mg/kg cisplatin and negative control (healthy) group. During 14 days, the treatment and treated control group took drugs, while the healthy animals were given distilled water on the same schedule. All animals were sacrificed by high-dose anesthesia at the end of the 14 days of treatment; their kidneys were removed and subjected to histologic and biochemical study. RESULTS: In both of the doses we used, mirtazapine decreased the levels of malondialdehyde, creatinine, blood urea nitrogen and myeloperoxidase activity when compared to cisplatin group. On the other hand, it increased total glutathione level in all doses. Slight histopathological findings were determined in mirtazapine groups when compared to cisplatin control group. CONCLUSION: In the light of our results and literature knowledge, we can conclude that the protective effect of mirtazapine in cisplatin toxicity originates from its own antioxidant activity. PMID- 22814014 TI - Comparison of the effects of valproic acid and levetiracetam on apoptosis in the human ovarian cancer cell line OVCAR-3. AB - BACKGROUND: We have previously shown that due to its cytotoxic and cytostatic activities, valproic acid (VPA), but not levetiracetam (LEV), may have potential as a drug for treating human ovarian cancer. In the present study, we compare apoptotic mechanisms including gene and protein expression in the human ovarian cancer cell line, OVCAR-3, following exposure to VPA and LEV. METHODS: Cells were cultured with VPA or LEV at concentrations between 0.1 mM and 10 mM. Apoptosis was assessed by DNA fragmentation assay and expression of apoptosis-regulatory genes determined by real-time PCR and confirmed by western blotting. Time dependent effects of VPA and LEV on activity of caspases (-3, -8 and -9) activity were evaluated by fluorescent assay and western blotting. RESULTS: Exposure to VPA at concentrations above 5 mM resulted in an increase in DNA fragmentation, modulated expression of genes and proteins associated with apoptosis and activated caspases cascade. Exposure to LEV, however, did not affect DNA fragmentation and modulation of the mechanisms of apoptosis was not observed in LEV-treated cells at all doses used. CONCLUSIONS: Exposure to high concentrations of VPA significantly stimulated apoptosis, by modulating the expression of genes and proteins responsible for cell death and also by activation of caspases cascade. Such effects were not observed with LEV. These data suggest that VPA should be seriously evaluated as an anti-cancer drug for ovarian cancer. PMID- 22814015 TI - Upregulation of intrinsic apoptotic pathway in NSAIDs mediated chemoprevention of experimental lung carcinogenesis. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of cyclooxygenase-2 (COX-2), which is overexpressed in cancer. The role of COX-2 and apoptosis were evaluated in 9,10-dimethylbenz(a)anthracene (DMBA)-induced lung cancer in rat and chemoprevention with indomethacin, a traditional NSAID and etoricoxib, a selective COX-2 inhibitor. METHODS: The animals were divided into Control, DMBA, DMBA+ indomethacin and DMBA+ etoricoxib groups. They received a single intratracheal instillation of DMBA while NSAIDs were given orally daily for 32 weeks. Besides morphology and histology of lungs, RT-PCR, western blots and immunohistochemistry were performed for the expression of apoptotic proteins and COX enzymes. Apoptosis was studied by DNA fragmentation and fluorescent staining. RESULTS: The occurrence of tumors and lesions was noted in the DMBA animals, besides constricted alveolar spaces and hyperplasia. COX-1 was found to be uniformly expressed while COX-2 level was raised significantly in DMBA group. The apoptotic proteins, apaf-1, caspase-9 and caspase-3 were highly diminished in DMBA group but restored to normal level in NSAIDs groups. Also, apoptosis was suppressed in carcinogen group by DNA fragmentation analysis and fluorescent staining of the lung cells while co-administration of NSAIDs along with DMBA led to the restoration of apoptosis. CONCLUSION: DMBA administration to the rats led to tumorigenesis in the lungs, had no effects on COX-1 expression, while elevating the COX-2 levels and suppressing apoptosis. The treatment with NSAIDs led to the amelioration of these effects. However, etoricoxib which is a COX-2 specific inhibitor, was found to be more effective than the traditional NSAID, indomethacin. PMID- 22814016 TI - Proton pump (H+/K+-ATPase) inhibitors weaken the protective effect of alendronate on bone mechanical properties in estrogen-deficient rats. AB - BACKGROUND: Alendronate can induce esophagitis and stomach ulceration requiring the concurrent use of drugs which decrease HCl production. The aim of the present study was to investigate the effect of concurrent administration of proton pump inhibitors, omeprazole or pantoprazole, and alendronate on the mechanical properties of long bones in bilaterally ovariectomized (OVX) rats. METHODS: The experiments were carried out on 3-month-old Wistar rats, divided into following groups: non-ovariectomized control rats, OVX control rats, OVX rats administered omeprazole or pantoprazole, OVX rats administered alendronate, OVX rats administered alendronate and omeprazole or pantoprazole. The drugs were administered to the rats for 28 days: alendronate at a dose of 3mg/kg po, omeprazole or pantoprazole at a dose of 3mg/kg ip. Mechanical properties of tibialmetaphysis, femoral diaphysis and femoral neck were assessed. Bone macrometric parameters, mass and mass of bone mineral were also examined in the tibia and femur. RESULTS: Estrogen deficiency caused development of osteopenia with significant worsening of bone mechanical properties. Alendronate counteracted the deleterious changes in bone mechanical properties of the tibial metaphysis and femoral neck induced by estrogen deficiency. Pantoprazole worsened mechanical properties of the tibia in estrogen-deficient rats. Omeprazole or pantoprazole administered concurrently with alendronate attenuated the effect of alendronate on mechanical properties of the tibial metaphysis and femoral neck in ovariectomized rats. The unfavorable effect of pantoprazole was stronger than that of omeprazole. CONCLUSION: Proton pump inhibitors weakened the protective effect of alendronate on bone mechanical properties in estrogen-deficient rats. PMID- 22814017 TI - Influence of short-term L-arginine supplementation on carbohydrate balance in rats with ischemia-reperfusion syndrome. AB - BACKGROUND: There are studies showing stimulative effect of arginine on insulin secretion. This mechanism is not fully explained. The effects of the impact of arginine on carbohydrate balance under the conditions of ischemia and reperfusion remain to be determined. The aim of this study is the evaluation of the influence of short-term L-arginine supplementation on the concentration of glucose and insulin in blood and insulin binding in rat skeletal muscle under the conditions of ischemia and reperfusion. METHODS: The study was conducted on male Wistar rats with average body mass 250 +/- 30 g. Animals were divided into four groups: Group I - control, Group II - placebo, Group III - L-arginine 500 mg/kg/24 h for 5 days, Group IV - L-arginine and L-NAME (75 MUmol/rat/24 h) for 5 days. Each group was divided into subgroups depending on duration of ischemia and reperfusion. Acute ischemia of hind limb was induced in each group by putting pneumatic tourniquet on the thigh. Blood samples and skeletal muscles were collected from the rats. Plasma concentrations of glucose and insulin were measured. Insulin binding to insulin receptors was determined in skeletal muscle. RESULTS: A clear reduction of insulin binding to receptor was found in the group of animals without ischemia and the group supplemented with L-arginine and subjected to 4-h ischemia and 30- and 120-min reperfusion. A significant increase in insulin level was found in groups of animals with L-arginine and/or L-NAME subjected to 4-h ischemia at all times of reperfusion. Supplementation with L-arginine and/or L NAME decreased levels of glucose in blood serum of animals undergoing ischemia reperfusion syndrome compared to the control and placebo groups. CONCLUSION: Under conditions of ischemia-reperfusion, short-term administration of L-arginine causes a decrease in insulin binding capacity of insulin receptors in skeletal muscle, an increase in insulin level and a decrease in the concentration of glucose in blood serum. PMID- 22814018 TI - Granulocyte colony-stimulating factor improves early remodeling in isoproterenol induced cardiac injury in rats. AB - BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has been used in some animal models and humans with well-established cardiovascular diseases. However, its effects in the initial stage of progressive non-ischemic heart failure are unknown. METHODS: Wistar rats (260-300 g) were divided into three groups: control (without any intervention), ISO (150 mg/kg isoproterenol hydrochloride sc, once a day for two consecutive days), and ISO-GCSF (50 MUg/kg/d G-CSF for 7 days beginning 24 h after the last administration of ISO). Echocardiography was performed at baseline and after 30 days of follow-up. Subsequently, animals were anesthetized for hemodynamic analysis. The left ventricle was removed for analysis of interstitial collagen deposition and cardiomyocyte hypertrophy. RESULTS: Isoproterenol led to left ventricular dilation (control, 7.7 +/- 0.14 mm; ISO, 8.7 +/- 0.16 mm; ISO-GCSF 7.8 +/- 0.09 mm; p < 0.05), myocardial fibrosis (control, 2.0 +/- 0.18%; ISO, 9.1 +/- 0.81%; ISO-GCSF 5.9 +/- 0.58%; p < 0.05) and cardiomyocyte hypertrophy (control, 303 +/- 10 MUm(2); ISO, 356 +/- 18 MUm(2); ISO-GCSF 338 +/- 11 MUm(2); p < 0.05). However, G-CSF partially prevented collagen deposition and left ventricular enlargement, with a slight effect on hypertrophy. Characterizing a compensated stage of disease, hemodynamic analysis did not change. CONCLUSION: G-CSF administered for 7 days was effective in preventing the onset of ventricular remodeling induced by high-dose isoproterenol with decreased collagen deposition and chamber preservation. PMID- 22814019 TI - Mechlorethamine (NTG) effects on the erythrocytic and leukocytic blood parameters during experimentally induced pleuritis in rats. AB - BACKGROUND: According to cytotoxic and mutagenic properties, nitrogranulogen (NTG) changes the character of inflammatory reactions. Our previous studies have shown that NTG can enhance immunological defense reactions, because of its high affinity to DNA, and causes disorders in the synthesis of acute phase proteins (e.g., haptoglobin, transferrin, fibrinogen and complement protein C3) [15]. The aim of the current studies was to determine the influence of three different NTG doses: 5 MUg/kg b.w. (body weight), 50 MUg/kg b.w. and 600 MUg/kg b.w. (cytotoxic dose) on the values of hematological blood parameters: RBC, HGB, HCT, RDW, MCV, MCH, MCHC, PLT, MPV, PCT, PDW, WBC, NEUT, LYMPH, MONO, EOS and BASO in pleuritis induced rats. METHODS: The animals were randomized into five groups: Group I - control group; Group II - IP (induced pleuritis) group; Group III - NTG5 group; Group IV - NTG50 group; Group V - NTG600 group. The blood was collected from all the groups at the 24(th) h, 48(th) h, and 72(nd) h after the initiation of the carrageenin-induced inflammatory reaction. RESULTS: These investigations have revealed that NTG administered at the dose of 5 MUg/kg b.w. caused the drop of the leukocyte and lymphocyte numbers and the rise of the neutrophil number at the 72(nd) h of the experimental-induced inflammatory reaction. Moreover, the dose of: 5 MUg/kg b.w. was an immunomodulatory property and it also increased the erythrocytic parameters. On the contrary, NTG applied at the doses of 50 MUg/kg and 600 MUg/kg b.w. contributed to the drop of both: the erythrocytic and leukocytic parameters during the whole time of the inflammatory reaction. CONCLUSIONS: The results suggest that nitrogranulogen affects the erythropoiesis. PMID- 22814020 TI - Effect of total and partial nephrectomy on the elimination of ciprofloxacin in humans. AB - BACKGROUND: Renal cell carcinoma (RCC) is the most common form of kidney cancer. Surgery is a standard procedure to resect the tumor during total (TN) or partial (nephron-sparing) nephrectomy (PN). Ciprofloxacin is most often administered at the usual intravenous dose of 100-400 mg/12 h. The application of such low doses of ciprofloxacin as 200 mg/24 h carries the risk of achieving subtherapeutic concentrations even in patients with limited renal function. The aim of the study was a comparison of concentrations and pharmacokinetics for ciprofloxacin at steady-state in patients after total and partial nephrectomy and evaluation of the effectiveness of the iv dose 200 mg/24 h against the theoretical value of MIC, 0.5 MUg/ml. METHODS: The research was carried out on two groups of patients after nephrectomy: total (group 1, n = 21; mean [SD], age, 62.9 [14.4] years; weight, 76.0 [14.6] kg; creatinine clearance, CL(CR), 90.7 [22.2] ml/min) and partial (group 2, n = 15; 61.7 [9.3] years; 87.8 [16.4] kg; CL(CR), 107.8 [36.4] ml/min). The patients were treated with ciprofloxacin in the dose of 200 mg/24 h (iv). Plasma concentrations of ciprofloxacin at steady state were measured with validated HPLC method with UV detection. RESULTS: The mean values of plasma concentrations of ciprofloxacin at steady state in group 1 and 2 were: C(ss)(max), 2.012 and 1.345; C(ss)(min), 0.437 and 0.244 MUg/ml, respectively. The main pharmacokinetic parameters for ciprofloxacin in group 1 and 2 were as follows: AUC((0-last)), 30.9 [17.9] and 19.5 [8.7] MUg h/ml; AUMC((0-last)), 177.91 [11.1] and 91.9 [66.5] MUg h(2)/ml; t(1/2beta), 13.9 [7.7] and 9.8 [3.3] h; MRT, 16.5 [12.1] and 9.77 [5.4] h; V(d), 115.0 [67.2] and 142.2 [78.7] l; CL, 6.2 [3.3] and 10.8 [5.7] l/h, respectively. With the assumed MIC = 0.5 MUg/ml, the values of C(ss)(max)/MIC < 10 and AUC/MIC < 125 were obtained in all the patients. CONCLUSION: In our patients we observed significant differences in some pharmacokinetic parameters of ciprofloxacin after two types of nephrectomy. PMID- 22814021 TI - Analysis of the role of Nrf2 in the expression of liver proteins in mice using two-dimensional gel-based proteomics. AB - BACKGROUND: The transcription factor Nrf2 regulates expression of multiple cellular defence proteins through the antioxidant response element (ARE). Nrf2 deficient mice (Nrf2(-/-)) are highly susceptible to xenobiotic-mediated toxicity, but it is not known whether this reflects low basal expression or reduced inducibility of Nrf2-regulated genes in response to chemical insults. METHODS: Wild type and Nrf2(-/-) mice were fed diet supplemented with the established Nrf2 inducer butylated hydroxyanisole (BHA) [0.5% (w/w)] for 14 days. To define the range of Nrf2-regulated proteins, both basally and following exposure to BHA, a comparison of the liver proteomes of Nrf2(-/-) and wild type mice was conducted. The two-dimensional gel electrophoresis (2-DE) technique and MALDI mass spectrometry were utilized in the attempt to define Nrf2-regulated proteins. RESULTS: Overall, 24 proteins were identified, which were regulated either basally (3 proteins), inducibly (16 proteins), or both (5 proteins). These included several well-established Nrf2-driven gene products e.g., aldo-keto reductase and glutathione transferases. Multiple consensus ARE/ARE-like sequences were found in the Nrf2-regulated genes. CONCLUSIONS: This study confirms the central role of Nrf2 in the induction of multiple defense proteins as well as its control in the constitutive expression of certain proteins. PMID- 22814022 TI - Potential hepato-protective effect of alpha-tocopherol or simvastatin in aged rats. AB - BACKGROUND: The effect of alpha-tocopherol or simvastatin treatment on antioxidant defense in liver of old rats was investigated. METHODS: Endogenous thiobarbituric acid reactive substances (TBARS) and total nitrite/nitrate (NO(2)/NO(3)) levels as well as non-enzymatic glutathione (GSH) and enzymatic antioxidants [glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) activities] were determined in the livers of young (3 months), aged (22 months), alpha-tocopherol- or simvastatin-treated aged rats. Serum lipid profile and liver function parameters were also assessed in these 4 groups. RESULTS: Both alpha-tocopherol and simvastatin almost equally restored the age-induced changes in liver TBARS and CAT activity, serum aspartate aminotransferase (GOT), alanine aminotransferase (GPT) and alkaline phosphatase (ALP). alpha-Tocopherol, but not simvastatin, tended to restore GST and GPX activities in livers of aged rats. Simvastatin, on the other hand, counteracted age-induced increases in serum cholesterol, TG, LDL, total hepatic NO(2)/NO(3) level, and preserved a normal liver function during aging. CONCLUSION: Thus, either drug may be beneficial, in spite of a mechanistic difference in the antioxidant effect of both of them, in alleviating age-induced liver injury. PMID- 22814023 TI - Involvement of NMDA receptors in the antidepressant-like action of adenosine. AB - BACKGROUND AND METHOD: In this work, the contribution of NMDA receptors to the antidepressant-like effect of adenosine in the forced swimming test (FST) was investigated. RESULTS: The pretreatment of mice with NMDA or D-serine was able to prevent the anti-immobility effect of either adenosine or MK-801 in the FST. In addition, the administration of a sub-effective dose of adenosine produced a synergistic effect with sub-effective doses of MK-801, ketamine and zinc chloride. Moreover, the immobility time of the mice treated with active doses of adenosine or N(6)-cyclohexyladenosine (CHA) plus MK-801 was not significantly different from that obtained with adenosine, CHA and MK-801 alone; by contrast, the combination between active doses of adenosine and CHA plus an active dose of the tricyclic antidepressant imipramine produced a greater effect in the FST than the administration of either drug alone. CONCLUSION: Together, the results suggest that the effect of adenosine in the FST is likely dependent on the inhibition of NMDA receptors mediated by the activation of adenosine A(1) receptors. PMID- 22814024 TI - Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction. AB - BACKGROUND: Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory skin disorders and, like other delayed-type hypersensitivity (DTH) reactions, affords immunity against tumor cells and microbes. CS response is a self-limiting reaction, and interleukin (IL)-10 is considered to be a natural suppressant of cutaneous inflammatory response. Recently, it has been demonstrated that major depression is related to activation of the inflammatory response and elevation of some parameters of cell-mediated immunity. It has been suggested that such activation of the immune system may play a role in etiology of depression. If this immunoactivation is involved in etiology of depression, one would expect that antidepressant agents may have negative immunoregulatory effects. To the best of our knowledge, the effect of antidepressants on contact hypersensitivity has not been studied. METHODS: The aim of the present study was to establish the effect of prolonged desipramine or fluoxetine treatment on CS reaction to picryl chloride. RESULTS: Antidepressants significantly suppressed CS reaction, fluoxetine by 53% whereas desipramine by 47% compared to positive control. Moreover, desipramine and fluoxetine decreased relative weight of auxillary lymph nodes. Desipramine decreased also relative weight of inguinal lymph nodes and spleens whereas desipramine and fluoxetine increased production of IL-10 in comparison to positive control. CONCLUSION: The observed effect of antidepressant drugs on CS reaction is consistent with the hypothesis that T-cell mediated immunity is targeted by antidepressants. PMID- 22814025 TI - Synergistic interaction of pregabalin with the synthetic cannabinoid WIN 55,212-2 mesylate in the hot-plate test in mice: an isobolographic analysis. AB - BACKGROUND: The aim of the study was to determine the type of interaction between pregabalin (a 3(rd)-generation antiepileptic drug) and WIN 55,212-2 mesylate (WIN - a highly potent non-selective cannabinoid CB1 and CB2 receptor agonist) administered in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice. METHODS: Linear regression analysis was used to evaluate the dose-response relationships between logarithms of drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, doses were calculated that increased the antinociceptive effect by 30% (ED(30) values) for pregabalin, WIN, and their combination. The type of interaction between pregabalin and WIN was assessed using the isobolographic analysis. RESULTS: Results indicated that both compounds produced a definite antinociceptive effect, and the experimentally-derived ED(30) values for pregabalin and WIN, when applied alone, were 29.4 mg/kg and 10.5 mg/kg, respectively. With isobolography, the experimentally derived ED(30 mix) value for the fixed ratio combination of 1:1 was 5.7 mg/kg, and differed significantly from the theoretically calculated ED(30 add) value of 19.95 mg/kg (p < 0.01), indicating synergistic interaction between pregabalin and WIN in the hot-plate test in mice. CONCLUSIONS: Isobolographic analysis demonstrated that the combination of WIN with pregabalin at a fixed ratio of 1:1 exerted synergistic interaction in the mouse model of acute thermal pain. If the results from this study could be adapted to clinical settings, the combination of WIN with pregabalin might be beneficial for pain relief in humans. PMID- 22814026 TI - Action of calcium antagonists and agonists on isolated human thoracic arteries used for coronary artery bypass grafting. AB - BACKGROUND: The goal of this study was to investigate the modulation of the contraction-relaxation effects in isolated human thoracic artery samples of three calcium-channel antagonists, amlodipine (CAS [88150-42-9]), cerebrocrast (CAS [118790-71-9]) and diltiazem (CAS [42399-41-7]), and two calcium-channel agonists, CGP 28392 (CAS [89289-93-0]) and benzimidazole derivative. To estimate the endothelial function of the artery samples, carbachol, an agonist of muscarinic receptors, was used. METHODS: The experiments were conducted on isolated human thoracic artery samples, and their isometric contractions were recorded using an i-FOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10(-7) to 10(-4) M) were established. RESULTS: Carbachol at concentrations of 10(-7) to 10(-6) M did not cause any relaxation of artery rings precontracted by 10(-4) M phenylephrine, and at concentrations of 10(-5) and 10(-4) M, isometric contractions increased by 7% and 20%, respectively. In response to amlodipine, cerebrocrast and CGP28392, the contraction of artery samples increased significantly, whereas diltiazem and benzimidazole derivative caused their relaxation by ~55%. CONCLUSION: The obtained data indicate that the endothelium of the thoracic artery, which is used for coronary artery bypass grafting, is damaged by and may have some influence on the inadequate response of 1,4-dihydropyrine type calcium-channel antagonists. PMID- 22814027 TI - Inhibition of voltage-gated K+ channels and Ca2+ channels by diphenidol. AB - BACKGROUND: Although diphenidol has long been deployed as an anti-emetic and anti vertigo drug, its mechanism of action remains unclear. In particular, little is known as to how diphenidol affects neuronal ion channels. Recently, we showed that diphenidol blocked neuronal voltage-gated Na(+) channels, causing spinal blockade of motor function, proprioception and nociception in rats. In this work, we investigated whether diphenidol could also affect voltage-gated K(+) and Ca(2+) channels. METHODS: Electrophysiological experiments were performed to study ion channel activities in two neuronal cell lines, namely, neuroblastoma N2A cells and differentiated NG108-15 cells. RESULTS: Diphenidol inhibited voltage-gated K(+) channels and Ca(2+) channels, but did not affect store operated Ca(2+) channels. CONCLUSION: Diphenidol is a non-specific inhibitor of voltage-gated ion channels in neuronal cells. PMID- 22814028 TI - Kynurenic acid enhances expression of p21 Waf1/Cip1 in colon cancer HT-29 cells. AB - BACKGROUND: Kynurenic acid (KYNA), a tryptophan metabolite, was found in the mucus of rat small intestine. However, its role in the gastrointestinal tract is still not fully elucidated. METHODS: To verify whether KYNA affects cell cycle regulators, the protein expression of cyclin-dependent kinase inhibitor p21 Waf1/Cip1 was investigated in colon adenocarcinoma HT-29 cells exposed to KYNA. MTT, BrdU assay and siRNA technology were used to evaluate the effect of KYNA on cancer cell proliferation. RESULTS: KYNA significantly enhanced the expression of p21 Waf1/Cip1. Importantly, the overexpression of this protein was involved in inhibition of proliferation and DNA synthesis in HT-29 cells. CONCLUSIONS: KYNA may be considered as a potential chemoprevention agent against colon cancer. PMID- 22814029 TI - CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells. AB - BACKGROUND: Cannabis is the most widely used illicit drug in the world that is often used by cancer patients in combination with conventional anticancer drugs. Multidrug resistance (MDR) is a major obstacle in the treatment of cancer. An extensively characterized mechanism of MDR involves overexpression of P glycoprotein (P-gp), which reduces the cellular accumulation of cytotoxic drugs in tumor cells. METHODS: Here we examined the role of cannabinoid receptors and transient receptor potential vanilloid type 1 (TRPV(1)) receptors in the effects of plant-derived cannabinoids on MDR1 mRNA expression in MDR CEM/VLB(100) cells which overexpress P-gp due to MDR1 gene amplification. RESULTS: We showed that both cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) (10 MUM) transiently induced the MDR1 transcript in P-gp overexpressing cells at 4 but not 8 or 48 h incubation durations. CBD and THC also concomitantly increased P-gp activity as measured by reduced accumulation of the P-gp substrate Rhodamine 123 in these cells with a maximal inhibitory effect observed at 4 h that slowly diminished by 48 h. CEM/VLB(100) cell lines were shown to express CB(2) and TRPV(1) receptors. Delta(9)-THC effects on MDR1 expression were mediated by CB(2) receptors. The effects of CBD were not mediated by either CB(2) or TRPV(1) receptors alone, however, required activation of both these receptors to modulate MDR1 mRNA expression. CONCLUSION: This is the first evidence that CB(2) and TRPV(1) receptors cooperate to modulate MDR1 expression. PMID- 22814030 TI - The reliability and validity of the mini-mental state examination in the elderly Croatian population. AB - AIM: The aim of this study was standardization and validation of the Mini-Mental State Examination (MMSE) in the general Croatian aging population. METHODS: Three hundred and forty-four participants underwent the MMSE test, 217 cognitively healthy subjects without neurological and psychiatric disorders and 127 patients with mild cognitive impairment (MCI) or dementia. RESULTS: The optimal cutoff point for screening of the general Croatian population (cognitively healthy vs. MCI and dementia) is 26/27; in the Croatian population aged >=65 years, the cutoff point is 24/25, whereas for screening of highly educated persons (>=14 years of education) aged >=65 years a higher cutoff point should be used (26/27). CONCLUSIONS: MMSE results when standardized and validated in a certain population might better contribute to recognition of the individuals at risk that should be directed to dementia outpatient clinics. PMID- 22814032 TI - Robust removal of short-duration artifacts in long neonatal EEG recordings using wavelet-enhanced ICA and adaptive combining of tentative reconstructions. AB - The goal of this paper is to describe a robust artifact removal (RAR) method, an automatic sequential procedure which is capable of removing short-duration, high amplitude artifacts from long-term neonatal EEG recordings. Such artifacts are mainly caused by movement activity, and have an adverse effect on the automatic processing of long-term sleep recordings. The artifacts are removed sequentially in short-term signals using independent component analysis (ICA) transformation and wavelet denoising. In order to gain robustness of the RAR method, the whole EEG recording is processed multiple times. The resulting tentative reconstructions are then combined. We show results in a data set of signals from ten healthy newborns. Those results prove, both qualitatively and quantitatively, that the RAR method is capable of automatically rejecting the mentioned artifacts without changes in overall signal properties such as the spectrum. The method is shown to perform better than either the wavelet-enhanced ICA or the simple artifact rejection method without the combination procedure. PMID- 22814031 TI - Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy. AB - Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT. PMID- 22814033 TI - Influence of angles of attack, frequency and kick amplitude on swimmer's horizontal velocity during underwater phase of a grab start. AB - The underwater phase of starts represents an important part of the performance in sprint swimming's events. Kinematics variables that swimmers have to take into account to improve their underwater phase of starts are unknown. The aim of this study was to determine the kinematics variables that improve performance during the underwater phase of grab starts. A three-dimensional analysis of the underwater phase of ten swimmers of national level was conducted. Stepwise multiple linear regressions identified the main kinematics variables that influence the horizontal velocity of the swimmer each 0.5 m in the range of 5 to 7.5 m. The results show that the kinematics parameters change during the range of 5 to 7.5 m of the underwater phase of the starts. For this population of swimmers, the results enable proposals of four principles to improve the underwater phase: i) to be streamlined at the beginning of the underwater gliding phase, ii) to start the dolphin kicking after 6 m, iii) to generate propulsive forces using only feet and legs during underwater undulatory swimming, iv) to improve the frequency of underwater undulatory swimming. PMID- 22814034 TI - The effect of superior semicircular canal dehiscence on intracochlear sound pressures. AB - Semicircular canal dehiscence (SCD) is a pathological opening in the bony wall of the inner ear that can result in conductive hearing loss. The hearing loss is variable across patients, and the precise mechanism and source of variability are not fully understood. Simultaneous measurements of basal intracochlear sound pressures in scala vestibuli (SV) and scala tympani (ST) enable quantification of the differential pressure across the cochlear partition, the stimulus that excites the cochlear partition. We used intracochlear sound pressure measurements in cadaveric preparations to study the effects of SCD size. Sound-induced pressures in SV and ST, as well as stapes velocity and ear canal pressure were measured simultaneously for various sizes of SCD followed by SCD patching. Our results showed that at low frequencies (<600 Hz), SCD decreased the pressure in both SV and ST, as well as differential pressure, and these effects became more pronounced as dehiscence size was increased. Near 100 Hz, SV decreased by about 10 dB for a 0.5-mm dehiscence and by 20 dB for a 2-mm dehiscence, while ST decreased by about 8 dB for a 0.5-mm dehiscence and by 18 dB for a 2-mm dehiscence. Differential pressure decreased by about 10 dB for a 0.5-mm dehiscence and by about 20 dB for a 2-mm dehiscence at 100 Hz. In some ears, for frequencies above 1 kHz, the smallest pinpoint dehiscence had bigger effects on the differential pressure (10-dB decrease) than larger dehiscences (less than 10 dB decrease), suggesting larger hearing losses in this frequency range. These effects due to SCD were reversible by patching the dehiscence. We also showed that under certain circumstances such as SCD, stapes velocity is not related to how the ear can transduce sound across the cochlear partition because it is not directly related to the differential pressure, emphasizing that certain pathologies cannot be fully assessed by measurements such as stapes velocity. PMID- 22814035 TI - Effects of refractive surgery in extreme altitude or space. PMID- 22814036 TI - Pseudo anterior capsule barrier for the management of posterior capsule rupture. AB - A technique that uses an implanted intraocular lens (IOL) to create a barrier for the management of posterior capsule rupture is described. When a rupture occurs, surgery is halted and a dispersive ophthalmic viscosurgical device (OVD) injected into the anterior chamber to prevent vitreous prolapse. The remaining nucleus is maneuvered into the anterior chamber away from the pupillary space. The posterior capsule tear is converted into a continuous curvilinear capsulorhexis where possible. Dissociated anterior vitrectomy is performed as indicated, keeping the large nuclear fragments trapped in the OVD-filled anterior chamber. An IOL is implanted in the capsular bag or sulcus with optic capture through the anterior capsulorhexis. Using reduced parameters, phacoemulsification of the remaining fragments is completed over the IOL, which functions as a barrier to seal off the vitreous cavity. Residual nuclear fragments and vitreous are cleared from beneath the optic by placing the vitreous cutter under the optic, recapturing the optic before the instruments are removed from the eye. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 22814037 TI - Ab externo scleral fixation of intraocular lens. AB - We describe an ab externo technique that facilitates IOL scleral fixation and reduces the risk associated with previous ab externo scleral fixation techniques. This technique uses a microvitreoretinal blade and an internal limiting membrane forceps to create sclerotomies and retrieve the suture, respectively. FINANCIAL DISCLOSURE: Dr. Cionni is a consultant to Morcher GmbH, Stuttgart, Germany. Dr. Crandall is a consultant to Alcon Laboratories, Inc., Ft. Worth, Texas, USA. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22814038 TI - Endoilluminated infusion cannula for anterior segment surgery. AB - An endoilluminated infusion cannula has been designed to enhance visualization when performing a bimanual anterior chamber vitrectomy. Although routinely used in posterior vitreous surgery, endoillumination has been sparingly described and used in complex anterior segment procedures. This instrument, with or without the use of triamcinolone staining, may add to the safety and efficacy when the cataract surgeon must perform an anterior vitrectomy. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 22814039 TI - Effect of corneal aberrations on intraocular lens power calculations. AB - PURPOSE: To use ray tracing to determine the influence of corneal aberrations on the prediction of the optimum intraocular lens (IOL) power for implantation in normal eyes and eyes with previous laser in situ keratomileusis (LASIK). SETTING: Hospital Universitario Virgen de la Arrixaca, Murcia, Spain. DESIGN: Case series. METHODS: The optimum IOL power was calculated by ray tracing using a patient customized eye model in cataract surgery cases. The calculation can be performed with or without inclusion of the patient's corneal aberrations. Standard predictions were also generated using current state-of-the-art IOL power calculation techniques. The results for all predictions were compared with the optimum IOL power after cataract surgery. RESULTS: For patients without previous LASIK (n = 18), the standard approaches and the ray-tracing procedure gave a similar mean absolute residual error and variance. The incorporation of corneal aberrations did not improve the accuracy of the ray-tracing prediction in these cases. For post-LASIK patients (n = 10), the ray-tracing prediction incorporating corneal aberrations generated the most accurate results. The difference between the prediction with and without considering corneal aberrations correlated with the amount of corneal spherical aberration (r(2) = 0.82), resulting in a difference of up to 3.00 diopters in IOL power in some cases. CONCLUSIONS: Ray tracing using patient-customized eye models was a robust procedure for IOL power calculation. The incorporation of corneal aberrations is crucial in post-LASIK eyes, primarily because of the elevated corneal spherical aberration. FINANCIAL DISCLOSURE: Mrs. Canovas and Dr. Artal hold a provisional patent application on the ray-tracing procedure. Mrs. Canovas is an employee of Abbott Medical Optics Groningen B.V. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22814040 TI - Clinical validation of an algorithm to correct the error in the keratometric estimation of corneal power in normal eyes. AB - PURPOSE: To validate clinically in a normal healthy population an algorithm to correct the error in the keratometric estimation of corneal power based on the use of a variable keratometric index of refraction (n(k)). SETTING: Medimar International Hospital (Oftalmar) and University of Alicante, Alicante, Spain. DESIGN: Case series. METHODS: Corneal power was measured with a Scheimpflug photography-based system (Pentacam software version 1.14r01) in healthy eyes with no previous ocular surgery. In all cases, keratometric corneal power was also estimated using an adjusted value of n(k) that is dependent on the anterior corneal radius (r(1c)) as follows: n(kadj) = -0.0064286 r(1c) +1.37688. Agreement between the Gaussian (P(c)(Gauss)) and adjusted keratometric (P(kadj)) corneal power values was evaluated. RESULTS: The study evaluated 92 eyes (92 patients; age range 15 to 64 years). The mean difference between P(c)(Gauss) and P(kadj) was -0.02 diopter (D) +/- 0.22 (SD) (P=.43). A very strong, statistically significant correlation was found between both corneal powers (r = .994, P<.01). The range of agreement between P(c)(Gauss) and P(kadj) was 0.44 D, with limits of agreement of -0.46 and +0.42 D. In addition, a very strong, statistically significant correlation of the difference between P(c)(Gauss) and P(kadj) and the posterior corneal radius was found (r = 0.96, P<.01). CONCLUSION: The imprecision in the calculation of corneal power using keratometric estimation can be minimized in clinical practice by using a variable keratometric index that depends on the radius of the anterior corneal surface. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814041 TI - Cataract surgery with trabecular micro-bypass stent implantation in patients with mild-to-moderate open-angle glaucoma and cataract: two-year follow-up. AB - PURPOSE: To assess the long-term safety and efficacy of a single trabecular micro bypass stent with concomitant cataract surgery versus cataract surgery alone for mild to moderate open-angle glaucoma. SETTING: Twenty-nine investigational sites, United States. DESIGN: Prospective randomized controlled multicenter clinical trial. METHODS: Eyes with mild to moderate glaucoma with an unmedicated intraocular pressure (IOP) of 22 mm Hg or higher and 36 mm Hg or lower were randomly assigned to have cataract surgery with iStent trabecular micro-bypass stent implantation (stent group) or cataract surgery alone (control group). Patients were followed for 24 months postoperatively. RESULTS: The incidence of adverse events was low in both groups through 24 months of follow-up. At 24 months, the proportion of patients with an IOP of 21 mm Hg or lower without ocular hypotensive medications was significantly higher in the stent group than in the control group (P=.036). Overall, the mean IOP was stable between 12 months and 24 months (17.0 mm Hg +/- 2.8 [SD] and 17.1 +/- 2.9 mm Hg, respectively) in the stent group but increased (17.0 +/- 3.1 mm Hg to 17.8 +/- 3.3 mm Hg, respectively) in the control group. Ocular hypotensive medication was statistically significantly lower in the stent group at 12 months; it was also lower at 24 months, although the difference was no longer statistically significant. CONCLUSIONS: Patients with combined single trabecular micro-bypass stent and cataract surgery had significantly better IOP control on no medication through 24 months than patients having cataract surgery alone. Both groups had a similar favorable long-term safety profile. FINANCIAL DISCLOSURE: Dr. Craven was an investigator in the clinical trial of the iStent. Dr. Katz is a consultant to Glaukos and was the medical monitor for the clinical trial of the iStent. Dr. Katz is a stockholder in Glaukos. Mr. Wells and Ms. Giamporcaro are employees of Glaukos. PMID- 22814042 TI - Complication rates of phacoemulsification and manual small-incision cataract surgery at Aravind Eye Hospital. AB - PURPOSE: To analyze the rate of intraoperative complications, reoperations, and endophthalmitis with phacoemulsification, manual small-incision cataract surgery (SICS), and large-incision extracapsular cataract extraction (ECCE). SETTING: Aravind Eye Hospital, Madurai, India. DESIGN: Retrospective cohort study. METHODS: This study comprised consecutive cataract surgeries performed during a 12-month period. All surgical complications and endophthalmitis cases were tabulated and analyzed for each of 4 surgeon groups (staff, fellows, residents, visiting trainees). Within each surgeon group, complication rates with phacoemulsification, manual SICS, and ECCE were compared. RESULTS: The surgical distribution was 20,438 (26%) phacoemulsification, 53,603 (67%) manual SICS, and 5736 (7%) ECCE. The overall intraoperative complication rate was 0.79% for staff, 1.19% for fellows, 2.06% for residents, and 5% for visiting trainees. Extracapsular cataract extraction had the highest overall rate of surgical complications (2.6%). The overall complication rate was 1.01% for manual SICS and 1.11% for phacoemulsification. However, the combined complication rate for trainees was significantly higher with phacoemulsification (4.8%) than with manual SICS (1.46%) (P<.001). The corrected distance visual acuity was better than 6/12 in 96% after phacoemulsification complications and 89% after manual SICS complications (P<.001). There were 27 cases (0.04%) of endophthalmitis but no statistical differences between surgical methods or surgeon groups. CONCLUSIONS: For staff surgeons experienced with both phacoemulsification and manual SICS, intraoperative complication rates were comparably low. However, for trainee surgeons, the complication rate was significantly higher with phacoemulsification, suggesting that manual SICS may be a safer initial procedure to learn for inexperienced cataract surgeons in the developing world. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814043 TI - Intracameral cefuroxime injection at the end of cataract surgery to reduce the incidence of endophthalmitis: French study. AB - PURPOSE: To determine whether an intracameral injection of cefuroxime at the end of cataract surgery decreases the incidence of postoperative endophthalmitis. SETTING: Dupuytren Hospital, Ophthalmology Department, Limoges, France. DESIGN: Clinical trials. METHODS: Patients having cataract surgery between April 2003 and June 2008 were included in a survey of operative-site infection. Intracameral cefuroxime injections started in June 2006. Preoperative data (beta-lactam allergy, a history of endophthalmitis, age, sex), intraoperative data (use of trypan blue, use of capsular ring or iris retractors, surgical time, senior or junior surgeon, corticosteroid injection, iris retractors), and the incidence of postoperative infections at 8 days and 1 month were prospectively collected. RESULTS: During the inclusion period, 5115 patients had cataract surgery; 2289 received cefuroxime and 2826 did not. The incidence of endophthalmitis was 35 (1.238%) of 2826 patients without intracameral cefuroxime and 1 (0.044%) of 2289 patients with intracameral cefuroxime; the difference was statistically significant (P<.0001). No intraoperative factor was significantly associated with postoperative infection. No allergic reaction was reported. CONCLUSION: Intracameral cefuroxime injection at the end of cataract surgery was safe and significantly decreased the incidence of endophthalmitis. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814044 TI - Simultaneous increases in multiple proinflammatory cytokines in the aqueous humor in pseudophakic glaucomatous eyes. AB - PURPOSE: To evaluate cytokine and growth factor levels in the aqueous humor in patients with open-angle glaucoma (OAG). SETTING: Kumamoto University Hospital, Kumamoto, Japan. DESIGN: Cross-sectional cohort study. METHODS: Aqueous humor samples were collected from cataract cases and OAG cases. Aqueous levels of cytokines and growth factors were determined by multiplex immunoassay. The data were analyzed using the Tukey-Kramer honestly-significant-difference test and multiple regression analyses. RESULTS: The study evaluated 52 cataract cases and 73 OAG cases. In the cataract cases, the mean interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tumor necrosis factor-alpha, epidermal growth factor, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, and VEGF levels (all pg/mL) were 21.4, 4.6, 829.4, 0.8, 0.5, 33.8, 1.6, and 77.9, respectively. In 23 phakic primary OAG (POAG) and 26 phakic exfoliation glaucoma cases, the corresponding values were 15.1 and 8.3, 15.2 and 12.3, 1142.5 and 1253.9, 0.3 and 0.5, 1.5 and 1.4, 57.7 and 58.0, 2.5 and 3.3, 37.4 and 59.7, respectively. In pseudophakic OAG cases, the IL-8 levels for exfoliation glaucoma (P=.0002) and MCP-1 for POAG (P=.0008) and exfoliation glaucoma (P<.0001) were significantly different compared with phakic OAG. Interleukin-6, IL-8, and MCP-1 levels were correlated (P<.0001). Multiple regression analyses showed the highest association of pseudophakic status with IL 8 and MCP-1 levels (P=.0002 and P<.0001, respectively). CONCLUSION: The OAG patients, especially those with pseudophakic eyes, had simultaneous cytokine level increases, suggesting the aqueous humor microenvironment is altered in pseudophakic glaucomatous eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814045 TI - Comparison of metal and flexible sub-Tenon cannulas. AB - PURPOSE: To compare metal posterior, flexible posterior, and flexible medium sub Tenon cannulas for akinesia and anesthesia. SETTING: King Khaled Specialist Eye Hospital, Riyadh, Saudi Arabia. DESIGN: Prospective blind randomized comparison. METHOD: Patients having cataract surgery under sub-Tenon block received a mixture of bupivacaine and lidocaine with hyaluronidase. The patients were divided into 3 groups based on whether a metal posterior sub-Tenon cannula, flexible posterior sub-Tenon cannula, or flexible medium sub-Tenon cannula was used. Pain during injection, akinesia, anesthesia, and complications were recorded. RESULTS: The study enrolled 159 patients. The akinesia score, superior oblique muscle activity, lid movements, and pain during injection were significantly lower in the metal posterior cannula group 2 minutes after injection (P=.002, P=.008, P=.097, and P=.001, respectively); there was no significant difference at 4 minutes, 6 minutes, 8 minutes, and 10 minutes. The incidence of intraoperative pain was low in all groups (P=.607). Chemosis was significantly less in the flexible posterior cannula group (P=.003); however, there was no significant difference in the site of chemosis (P=.460). There was no significant difference in the incidence, site, or severity of subconjunctival hemorrhage (P=.087, P=.072, and P=.331, respectively). No serious complications occurred. CONCLUSIONS: Rigid posterior, flexible posterior, and flexible medium cannulas produced effective and equivalent anesthesia. The flexible cannulas may be safer than the rigid cannulas. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814046 TI - Accommodative changes in anterior chamber depth in patients with high myopia. AB - PURPOSE: To study the accommodative changes in the central anterior chamber depth (ACD) in patients with high myopia using anterior segment optical coherence tomography (AS-OCT). SETTING: Cataract Surgery Department and Clinical & Functional Diagnostics Department, S. Fyodorov Eye Microsurgery Complex-Federal State Institution, Moscow, Russian Federation. DESIGN: Prospective case-control study. METHODS: The ACD measurements were obtained in the nonaccommodative state (baseline) and during accommodation using the Visante AS-OCT device. RESULTS: Thirty-six myopic eyes (36 patients; mean age 27 years; mean spherical equivalent (SE) -12.52 diopters [D]) and 31 emmetropic eyes (31 subjects; mean age 26 years; mean SE -0.39 D) were examined. At baseline, the mean ACD in both groups was similar. During accommodation, the mean maximum changes in the ACD were significantly less pronounced in the myopia group (-0.14 mm +/- 0.07 [SD]; range 0.03 to -0.29 mm) than in the emmetropia group (-0.22 +/- 0.08 mm; range -0.04 to -0.35 mm) (P<.0001). Ten patients in the myopia group had a critically shallow anterior chamber (ACD <2.8 mm) in the state of accommodation. CONCLUSIONS: Accommodative changes in the ACD were significantly less pronounced in eyes with high myopia than in emmetropic eyes. Still, the anterior chamber might become critically shallow during accommodation in some myopic eyes, and this should be taken into account when planning phakic intraocular lens implantation to correct high myopia. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814047 TI - Time course of refractive and corneal astigmatism after laser in situ keratomileusis for moderate to high astigmatism. AB - PURPOSE: To assess the time course of refractive and corneal astigmatism after laser in situ keratomileusis (LASIK) in eyes with moderate to high astigmatism. SETTING: Department of Ophthalmology, Kitasato University, Kanagawa, Japan. DESIGN: Retrospective case series. METHODS: Keratometric readings and corneal astigmatism were determined with an autokeratometer in consecutive patients who had LASIK for moderate to high astigmatism (>=2.00 diopters [D]). RESULTS: The study enrolled 48 eyes of 35 patients with a mean age of 34.0 years +/- 8.1 (SD), a mean spherical error of -5.10 +/- 2.11 D, and a mean cylindrical error of -2.74 +/- 0.99 D. Postoperatively, the mean spherical refraction changed significantly from 0.38 +/- 0.80 D at 1 week to -0.13 +/- 0.90 D at 1 year (P<.001, Wilcoxon signed-rank test). The mean cylindrical refraction showed no significant change ( 0.67 +/- 0.54 D at 1 week to -0.63 +/- 0.63 D at 1 year) (P=.54). There were significant increases in the flattest and steepest keratometry readings at 1 week and at 1 year. However, no significant change in corneal astigmatism was found at either time point (P=.10). CONCLUSIONS: After LASIK, there was significant refractive regression in the spherical component but not in the cylindrical component. This suggests that refractive regression occurs by corneal steepening in the spherical component and that astigmatic regression does not occur, even in moderately to highly astigmatic eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814048 TI - Consecutive myopia correction with transepithelial versus alcohol-assisted photorefractive keratectomy in contralateral eyes: one-year results. AB - PURPOSE: To compare the postoperative efficacy, safety, and higher-order aberrations (HOAs) between transepithelial photorefractive keratectomy (PRK) and alcohol-assisted PRK in contralateral eyes. SETTING: Private clinic, Utrecht, The Netherlands. DESIGN: Comparative case series. METHODS: Consecutive patients were randomized to have transepithelial PRK in 1 eye and alcohol-assisted PRK in the contralateral eye. In both eyes, aspheric treatments were planned with Custom Ablation Manager software and ablations performed with the Schwind Amaris system. Clinical outcomes were predictability, refraction, visual acuity, wavefront aberrations, and contrast and glare sensitivity. Paired t tests were applied for statistics. RESULTS: The study evaluated 66 eyes (33 patients). All patients completed the 1-year follow-up. At 1-year, 97% of eyes in both groups achieved an uncorrected distance visual acuity (UDVA) of 0.1 logMAR or better. No eye lost 2 or more lines of corrected distance visual acuity (CDVA); 97% of transepithelial PRK eyes and 91% of alcohol-assisted PRK eyes were within +/-0.50 diopter (D) of the targeted refraction. The postoperative mean spherical equivalent was +0.07 D +/- 0.23 (SD) and +0.01 +/- 0.27 D, respectively. CONCLUSIONS: The CDVA, UDVA, and safety outcomes between transepithelial PRK and alcohol-assisted PRK were comparable. Profiles for both techniques applied to regular corneas preserved the eye's natural HOAs. Transepithelial PRK is faster to perform and it is an all laser procedure, which might be less stressful for the patient. FINANCIAL DISCLOSURE: Mr. Ewering and Mr. Arba-Mosquera are employees of Schwind eye-tech solutions. Dr. Luger has no financial or proprietary interest in any material or method mentioned. PMID- 22814049 TI - Accelerated corneal crosslinking concurrent with laser in situ keratomileusis. AB - PURPOSE: To assess accelerated corneal collagen crosslinking (CXL) applied concurrently with laser in situ keratomileusis (LASIK) in a small group of patients. SETTING: Beyoglu Eye Research and Training Hospital, Istanbul, Turkey. DESIGN: Prospective pilot interventional case series. METHODS: In May 2010, patients had LASIK with concurrent accelerated CXL in 1 eye and LASIK only in the fellow eye to treat myopia or myopic astigmatism. The follow-up was 12 months. The attempted correction (spherical equivalent) ranged from -5.00 to -8.50 diopters (D) in the LASIK-CXL group and from -3.00 to -7.25 D in the LASIK-only group. Main outcome measures were manifest refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, and the endothelial cell count. RESULTS: Eight eyes of 3 women and 1 man (age 22 to 39 years old) were enrolled. At the 12-month follow-up, the LASIK-CXL group had a UDVA and manifest refraction equal to or better than those in the LASIK-only group. No eye lost 1 or more lines of CDVA at the final visit. The endothelial cell loss in the LASIK-CXL eye was not greater than in the fellow eye. No side effects were associated with either procedure. CONCLUSIONS: Laser in situ keratomileusis with accelerated CXL appears to be a promising modality for future applications to prevent corneal ectasia after LASIK treatment. The results in this pilot series suggest that evaluation of a larger study cohort is warranted. FINANCIAL DISCLOSURE: Drs. Yilmaz and Marshall are paid consultants to Avedro, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22814050 TI - Intrastromal corneal ring segments: effect of relationship between alignment and topographic keratometric meridians. AB - PURPOSE: To determine whether the keratometric and refractive surgical effects of paired intrastromal corneal ring segments (ICRS) depend on their alignment relative to steep and flat topographic meridians. SETTING: St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. DESIGN: Comparative case series. METHODS: Keratoconic patients who had two 0.3 mm Intacs ICRS inserted were retrospectively grouped depending on alignment of segments within 30 degrees either side of the steep (meridional group) or the flat (perpendicular group) topographic meridians, respectively, with the rest in the oblique group. Principal outcome measures were changes in visual acuity, refractive surgical effect, and keratometric surgical effect 4 months postoperatively. RESULTS: Forty eyes of 40 patients were included. There was a significant reduction in keratometric power (flattening) (P<.01) but not in refractive error in all 3 groups. The reduction in keratometric astigmatism was significantly greater in the perpendicular group (-2.67 diopters [D]) than in the meridional group (-0.65 D) (P=.03), with the oblique group (-0.9 D) in between (P=.12). The principal reduction was flattening orthogonal to the incision site, with relative steepening in the axis of ICRS alignment. In all groups, variations in the refractive surgical effect and keratometric surgical effect were very high. CONCLUSIONS: Placement of two 0.3 mm ICRS had a variable effect with limited predictability. There was predominant flattening of the cornea orthogonal to the axis of ICRS alignment. Irrespective of the location of preoperative steep and flat keratometric meridians, the maximum reduction in astigmatism occurred when the incision and the segments were placed along the flat topographic meridian. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814051 TI - Iris-fixated intraocular lens implantation to correct moderate to high myopia in Asian-Indian eyes: five-year results. AB - PURPOSE: To evaluate the efficacy, safety, predictability, and stability of iris fixated phakic intraocular lenses (pIOLs) to correct high myopia in an Asian Indian population. SETTING: Tertiary eyecare center. DESIGN: Interventional case series. METHODS: Eyes with myopia from -5.5 to -24.0 diopters (D) had pIOL implantation and were examined postoperatively at 1 day, 1 week, 1, 3, and 6 months, and yearly for 5 years. Parameters evaluated were postoperative uncorrected (UDVA) and corrected (CDVA) distance visual acuities, predictability, efficacy, stability of mean spherical equivalent (SE), and endothelial cell loss. RESULTS: The study enrolled 85 eyes (44 patients). The mean CDVA improved from 6/10 preoperatively to 6/7 postoperatively and the mean UDVA, from 6/319 to 6/9. Postoperatively, the mean SE was -0.63 +/- 0.55 D. Of the 51 eyes completing a 4 year follow-up; 19 (37.3%) had a mean SE of 0.50 D or less and 37 (72.5%) had a mean SE of 1.00 D or less. The CDVA improved 1 line or more in 35 eyes (68.6%); 14 eyes (27.5%) had postoperative CDVA similar to the preoperative CDVA. At 4 years, the safety index was 1.46 and the efficacy index, 0.96. Thirty-six eyes (70.6%) had a postoperative UDVA better than the preoperative CDVA. The mean endothelial cell loss at 1, 3, 6, 12, 24, 36, and 48 months was 4.3%, 5.7%, 7.1%, 7.6%, 8.7%, 9.2%, 11.07%, and 12.4% respectively. Twenty eyes (23.5%) had reenclavation for spontaneous or traumatic disenclavation. CONCLUSION: Postsurgical refractive outcomes of iris-fixated pIOL implantation for myopia were fairly predictable and stable in an Asian-Indian population. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814052 TI - Optimal parameters to improve the interface quality of the flap bed in femtosecond laser-assisted laser in situ keratomileusis. AB - PURPOSE: To analyze the interface quality of the anterior stroma after femtosecond laser flap creation using atomic force microscopy. SETTING: IRCCS Fondazione G.B. Bietti, Rome, Italy. DESIGN: Experimental study. METHODS: A 110 MUm depth flap was created in 20 human corneal tissues using a femtosecond laser platform (Intralase iFS). Tissues were divided into 4 groups of various cutting parameters: pulse energy and spot separation of 0.75 MUJ and 6 MUm (Group 1), 0.65 MUJ and 5 MUm (Group 2), 0.55 MUJ and 4 MUm (Group 3), and 0.45 MUJ and 4 MUm (Group 4). Four additional tissue sections were cut using a motorized microkeratome (Hansatome). Atomic force microscopy (Autoprobe CP) analysis was performed on the stromal bed of each sample. RESULTS: The corneal tissues treated with higher pulse energies and wider spot separations (Groups 1 and 2) showed a rougher stromal bed interface (root mean square [RMS] rough = 0.23 MUm +/- 0.008 (SD) and 0.24 +/- 0.009 MUm, respectively) than tissues in Groups 3 and 4 (RMS rough = 0.18 +/- 0.006 MUm and 0.18 +/- 0.008 MUm, respectively; P<.001, 1-way analysis of variance). The stromal surface quality of tissues treated with pulse energies of 0.55 MUJ or lower and 4 MUm spot separation compared favorably with that of tissues cut by the microkeratome (RMS rough = 0.17 +/- 0.006 MUm; P>.05, Tukey). CONCLUSIONS: The femtosecond stromal interface quality was improved with pulse energy lower and spot separations narrower than those currently used in the clinical setting. The flap interface smoothness created by the femtosecond laser was comparable to that created by the microkeratome. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814053 TI - Quantitative measurement of wound architecture in microincision cataract surgery. AB - PURPOSE: To evaluate whether changes in internal wound architecture after phacoemulsification can be measured quantitatively by analysis of scanning electron micrographs. SETTING: Baylor College of Medicine, Houston, Texas, USA. DESIGN: Experimental study. METHODS: Two comparative studies in human cadaver eyes were performed using coaxial small-incision cataract surgery (SICS), bimanual microincision cataract surgery (MICS), coaxial MICS, and a variety of phacoemulsification tips (MicroSurgical Technologies, Microphaco Tapered, Microtip Turbosonics, and Microphaco Mackool). After surgery, the cornea and scleral rims were harvested and digital scanning electron micrographs were taken. The internal corneal wound was analyzed using measurement software to determine the area of endothelial cell loss and length of Descemet membrane tears. RESULTS: Quantifiable differences were observed between combinations of techniques and tip designs. The mean area of endothelial cell loss was 2.93 +/- 0.31 mm(2) (SD) after coaxial MICS (n = 4) and 2.85 +/- 0.54 mm(2) after bimanual MICS (n = 4). However, after normalizing for differences in tip or sleeve diameter, the area of endothelial cell loss ranged from 1.4-fold to 1.7-fold less with coaxial SICS than with bimanual MICS with Microphaco Tapered, Microtip Turbosonics, and Microphaco Mackool tips. The mean total length of tearing was 1.38 +/- 0.38 mm for bimanual MICS (n = 4) and 0.84 +/- 0.61 mm for coaxial MICS (n = 4). CONCLUSION: The length and area of corneal wounds could be quantitated with accuracy and the measurements could be used to make quantifiable comparisons of phacoemulsification techniques and tips. FINANCIAL DISCLOSURE: Dr. Dimalanta is an employee of Alcon Research, Ltd. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22814054 TI - Effect of different femtosecond laser-firing patterns on collagen disruption during refractive lenticule extraction. AB - PURPOSE: To evaluate the changes in corneal collagen architecture subjected to different laser-firing patterns during refractive lenticule extraction. SETTING: Singapore Eye Research Institute, Singapore. DESIGN: Experimental study. METHODS: Refractive lenticule extraction was performed in rabbits without lenticule removal. Rabbits were divided into 4 groups that had incisions in the following firing patterns: (A) from periphery in (lenticule's posterior surface) and from center out (lenticule's anterior surface); (B) from center out and from center out; (C) from periphery in and from periphery in; and (D) from center out and from periphery in. The corneas were collected 18 hours postoperatively and were subjected to immunofluorescent staining of fibronectin, CD11b, and collagen type I. Ultrastructural analysis was performed using transmission electron microscopy (TEM). RESULTS: Refractive lenticule extraction-treated corneas showed no significant difference in fibronectin and CD11b expression. Similar expression patterns of collagen type I were observed in corneas that had femtosecond firing patterns A, B, and C; however, a discontinuous and relatively more intense staining pattern along the anterior plane of the lenticule was detected in corneas treated with pattern D. The TEM also showed a more disrupted collagen arrangement along the anterior incision site in pattern D-treated corneas. CONCLUSIONS: Differential laser firing patterns during refractive lenticule extraction resulted in different levels of collagen derangement along the anterior plane of the lenticule, with pattern D showing the most disrupted surface. Such disruption in the collagen architecture might affect postoperative visual recovery and refractive outcomes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814055 TI - Light scattering and light transmittance in intraocular lenses explanted because of optic opacification. AB - PURPOSE: To assess light scattering and light transmittance in intraocular lenses (IOLs) explanted because of optic opacification. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Poly(methyl methacrylate) (PMMA) IOLs with snowflake degeneration, hydrophilic acrylic IOLs with different calcification patterns, and 1 calcified silicone IOL explanted from an eye with asteroid hyalosis were studied with gross and light microscopy. Light scattering was measured with an EAS-1000 Scheimpflug camera. Light transmittance was measured with a Lambda 35 UV/Vis spectrophotometer (single-beam configuration with RSA-PE-20 integrating sphere). Analyses were performed at room temperature in the hydrated state and compared with controls. RESULTS: The study evaluated 8 PMMA IOLs, 22 hydrophilic acrylic IOLs, and 1 silicone IOL. Light scattering was as follows: 208 to 223 computer-compatible tapes (CCTs) for PMMA IOLs with snowflake degeneration (control = 9 CCTs); 90 to 227 CCTs for calcified hydrophilic acrylic IOLs (controls = 12 to 23 CCTs); 223 CCTs for the calcified silicone IOL (control = 5 CCTs). The mean light transmittance in the visible light spectrum was 81.08% to 97.10% for PMMA IOLs (control = 98.80%); 78.94% to 97.32% for hydrophilic acrylic IOLs (controls = 97.32% to 98.66%); 94.68% for the silicone IOL (control = 97.74%). CONCLUSION: Intraocular lens opacification led to very high levels of light scattering and a potential for decreased light transmittance, which play a role in the development of symptoms such as glare and halos, decreased contrast sensitivity, and eventually decreased visual acuity. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814056 TI - Visual stability of laser vision correction in an astronaut on a Soyuz mission to the International Space Station. AB - This report documents the effects of photorefractive keratectomy (PRK) in an astronaut during a 12-day Russian Soyuz mission to the International Space Station in 2008. Changing environmental conditions of launch, microgravity exposure, and reentry create an extremely dynamic ocular environment. Although many normal eyes have repeatedly been subject to such stresses, the effect on an eye with a relatively thin cornea as a result of PRK has not been reported. This report suggests that PRK is a safe, effective, and well-tolerated procedure in astronauts during space flight. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814057 TI - Capsule membrane growth complicating glaucoma and corneal decompensation after neodymium:YAG capsulotomy. AB - We report a case of progressive capsule membrane growth 4 months after neodymium:YAG capsulotomy for posterior capsule opacification. The clinical picture closely resembled epithelial ingrowth, but histology proved otherwise. Multiple operations were required to control glaucoma and capsule proliferation. However, the patient's visual potential was limited by corneal decompensation and glaucomatous damage. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814058 TI - Bilateral implantation of toric multifocal additive intraocular lenses in pseudophakic eyes. AB - A 41-year-old patient presented with hyperopia, astigmatism, and presbyopia for refractive treatment 6 years following cataract surgery. A toric multifocal additive intraocular lens with a near addition of +3.5 diopters (D) for sulcus implantation was chosen and implanted uneventfully. Follow-up examinations were performed from the first day until 9 months after surgery. A predictable refractive correction was seen, with a residual error of +0.125 D (spherical equivalent) in the right eye and emmetropia in the left eye. Monocular uncorrected distance visual acuity (UDVA) and uncorrected near visual acuity (UNVA) (40 cm) improved to 0.1 logMAR. It could not be improved further with near add spectacles. Binocular UDVA and UNVA were 0.0 logMAR and 0.1 logMAR (80 cm), respectively. Both additive IOLs remained centered and on axis during the follow up period. Spectacle independence was achieved, as was high patient satisfaction. FINANCIAL DISCLOSURE: The International Vision Correction Research Centre received research grants related to this publication from the following companies: Dr. Schmidt Intraocularlinsen GmbH, Rayner Intraocular Lenses, Ltd., and Carl Zeiss Meditec AG. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22814059 TI - Crisis management after incorrect intraocular lens insertion. PMID- 22814060 TI - Necessity of conjunctival flap in manual sutureless small-incision cataract surgery. PMID- 22814061 TI - Cataract Surgical Problem: August consultation #1. PMID- 22814070 TI - Role of intraocular pressure in wound closure at the end of phacoemulsification. PMID- 22814071 TI - Participation in the EUREQUO database report. PMID- 22814074 TI - Appearance and etiology of posterior capsule striae after intraocular lens implantation. PMID- 22814075 TI - Povidone-iodine for endophthalmitis prophylaxis. PMID- 22814077 TI - Brown discoloration of blue light-filtering intraocular lenses. PMID- 22814079 TI - Posterior capsule striae. PMID- 22814080 TI - Crosslinking and toric phakic IOL in keratoconus. PMID- 22814083 TI - A random change point model for cognitive decline in Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND: We present a random change point model to characterize decline in cognition among community-based elderly who developed Alzheimer's disease (AD) or amnestic mild cognitive impairment (MCI), and to examine how decline varies with age, sex, education, and APOE status. METHODS: Using longitudinal cohort data on cognitive function, we fit a piecewise linear trajectory with a random change point that allows different rates of cognitive decline before and after the change point. We estimated the change point that signals the onset of cognitive impairment, and examined the association of risk factors with the location of the change point as well as the rates of decline before and after the change point. RESULTS: Among participants who were dementia free at enrollment and developed incident AD, the change point occurred on average 5.7 years after enrollment and the rate of cognitive decline after the change point nearly quadrupled. Age, education, and APOE status play important but different roles in the timing of the onset of cognitive impairment and in the rates of decline before and after its onset. Results were similar among participants who were cognitively unimpaired at enrollment but later developed amnestic MCI or AD. CONCLUSIONS: The random change point model provides a more comprehensive understanding of the relation of risk factors with the onset of cognitive impairment and rates of decline before and after its onset. PMID- 22814084 TI - Horizontal transmission of Thelohania contejeani in the endangered white-clawed (Austropotamobius pallipes) and the invasive signal crayfish (Pacifastacus leniusculus). AB - The microsporidian parasite Thelohania contejeani causes porcelain disease and has been implicated in mass mortalities in populations of the endangered European crayfish Austropotamobius pallipes. However, the route of parasite transmission is not known. This paper investigates the horizontal transmission of T. contejeani between A. pallipes hosts as well as its transmissibility to the invasive signal crayfish (Pacifastacus leniusculus). Field collected juvenile A. pallipes and P. leniusculus were assigned to 1 of 3 experimental treatments; fed heavily infected A. pallipes tissue, exposed to water from tanks housing heavily parasitized A. pallipes, and a control group to provide an estimate of the baseline infection levels in the field. After 26 weeks, abdominal muscle samples were screened by PCR for T. contejeani. Infection was significantly higher in the treatment groups (83% in the cannibalism treatment, 42% in the water exposure treatment) than in the control group (4%), providing evidence for horizontal transmission of the parasite between A. pallipes hosts. Cannibalism and scavenging are common amongst crayfish, providing transmission opportunities in the field. The study also provides the first direct evidence for transmission of the parasite from an indigenous European crayfish species to the invasive signal crayfish, with 50% of P. leniusculus in each treatment, and 8% of control animals infected. We discuss the possibility that high density populations of the invasive signal crayfish may serve either as reservoirs or sinks for the parasite. PMID- 22814085 TI - Simple differentiation of avirulent and virulent strains of avian paramyxovirus serotype-1 (Newcastle disease virus) by PCR and restriction endonuclease analysis in Japan. AB - To differentiate the avirulent from virulent strains of avian paramyxovirus serotype-1 (APMV-1, Newcastle disease virus), PCR and restriction endonuclease analysis (REA) was employed. Primer sequences were used to amplify a 766-base pair fragment that included the fusion protein cleavage site. REA of PCR products generated by Hin1 I and Apa I enabled the differentiation of avirulent field and vaccine strains from more virulent field strains of APMV-1 in Japan. PMID- 22814086 TI - Construction of swine-specific CpG motif enriched plasmid and the study of its immunostimulatory effects both in vitro and in vivo. AB - A swine-specific CpG motif enriched plasmid (pUC18-CpG) was constructed in this study. Its immunostimulant property was tested in vitro via lymphocyte transformation assay using swine peripheral blood mononuclear cells (PBMCs). The recombinant plasmid showed higher Stimulation Index (SI) compared to the positive control (LPS). In a following animal experiment, pUC18-CpG was co-administered with a commercial swine FMD killed vaccine. Animals in the pUC18-CpG adjuvanted groups showed much higher antibody titers during the vaccination period. PMID- 22814087 TI - Large-scale serological survey of caprine arthritis-encephalitis virus (CAEV) in Korean black goats (Capra hircus aegagrus). AB - A national serological survey of caprine arthritis-encephalitis virus (CAEV) infection was conducted using an enzyme-linked immunosorbent assay (ELISA) and an agar gel immunodiffusion (AGID) test. A total of 658 black goats of various breeds were sampled from 59 farms in three regions of Korea. The CAEV-positive goats were predominantly detected in the Southern region (n=17) as compared with the Northern (n=1) and Central regions (n=0) (chi(2)=6.26, P=0.044). Among 658 goats tested, 18 were positive in both ELISA and AGID, indicating a CAEV prevalence of 2.73% (95% confidence interval: 1.74-4.28). These results indicate that CAEV is present in Korean black goats. PMID- 22814088 TI - Oxygenated drinking water enhances immune activity in pigs and increases immune responses of pigs during Salmonella typhimurium infection. AB - It has been considered that drinking oxygenated water improves oxygen availability, which may increase vitality and improve immune functions. The present study evaluated the effects of oxygenated drinking water on immune function in pigs. Continuous drinking of oxygenated water markedly increased peripheral blood mononuclear cell proliferation, interleukin-1beta expression level and the CD4(+):CD8(+) cell ratio in pigs. During Salmonella Typhimurium infection, total leukocytes and relative cytokines expression levels were significantly increased in pigs consuming oxygenated water compared with pigs consuming tap water. These findings suggest that oxygenated drinking water enhances immune activity in pigs and increases immune responses of pigs during S. Typhimurium Infection. PMID- 22814089 TI - Automatic seizure detection based on star graph topological indices. AB - The recognition of seizures is very important for the diagnosis of patients with epilepsy. The seizure is a process of rhythmic discharge in brain and occurs rarely and unpredictably. This behavior generates a need of an automatic detection of seizures by using the signals of long-term electroencephalographic (EEG) recordings. Due to the non-stationary character of EEG signals, the conventional methods of frequency analysis are not the best alternative to obtain good results in diagnostic purpose. The present work proposes a method of EEG signal analysis based on star graph topological indices (SGTIs) for the first time. The signal information, such as amplitude and time occurrence, is codified into invariant SGTIs which are the basis for the classification models that can discriminate the epileptic EEG records from the non-epileptic ones. The method with SGTIs and the simplest linear discriminant methods provide similar results to those previously published, which are based on the time-frequency analysis and artificial neural networks. Thus, this work proposes a simpler and faster alternative for automatic detection of seizures from the EEG recordings. PMID- 22814091 TI - Inhibition of TMV multiplication by siRNA constructs against TOM1 and TOM3 genes of Capsicum annuum. AB - The host proteins TOM1 and TOM3 associated with tonoplast membrane are shown to be required for efficient multiplication of Tobamoviruses. In this study, homologous of TOM1 and TOM3 genes were identified in pepper (Capsicum annuum) using specific primers. Their gene sequences have similarity to Nicotiana tabacum NtTOM1 and NtTOM3. Sequence alignment showed that CaTOM1 and CaTOM3 are closely related to TOM1 and TOM3 of N. tabacum and Solanum lycopersicum with 90% and 70% nucleotide sequence identities, respectively. RNA interference approach was used to suppress the TOM1 and TOM3 gene expression which in turn prevented Tobacco mosaic virus replication in tobacco. Nicotiana plants agro-infiltrated with siRNA constructs of TOM1 or TOM3 showed no mosaic or necrotic infection symptoms upon inoculation with TMV. The results indicated that silencing of TOM1 and TOM3 of pepper using the siRNA constructs is an efficient method for generating TMV resistant plants. PMID- 22814090 TI - A new finding concerning adenoviral-mediated gene transfer: a high-level, cell specific transgene expression in the neural stem cells of adult mice. AB - Adenoviruses are highly efficient vectors for gene transfer into brain cells. Restricting transgene expression to specific cell types and maintaining long-term expression are major goals for adenoviral-mediated gene transfer in the central nervous system. Human adenovirus type 5 (Ad5) mediated transgene expression is described under the control of the murine cytomegalovirus (mCMV) immediate-early promoter. It was found that the neural stem cells in the dentate subgranular zone were transduced preferentially, minimal neurons were transduced in the granule cell layer of the dentate gyrus, no EGFP was detected in the pyramidal cell layers of CAl to CA3 area and EGFP activity can be detected for 2 months after infection. Therefore, the mCMV-adenoviral vectors can be used both for studying the function of various genes in the differentiation of neural stem cells and, ultimately, for gene therapy or to modulate specific gene expression. PMID- 22814092 TI - Unusually large numbers needed to treat for radical prostatectomy in prostate cancer patients with PSA velocity <=2 ng/ml/year. AB - BACKGROUND: The numbers needed to treat (NNT) and the corresponding confidence intervals for patients with prostate cancer and defined annual PSA increases (PSA velocity, PSAV) have not been described previously. AIM: The objective of this study is to assess NNT, numbers needed to treat to harm and corresponding confidence intervals for radical prostatectomy (RP) in patients with prostate cancer defined as a PSAV <=2 ng/ml/year. METHODS: NNT following RP were estimated in risk groups defined by PSAV using mortality statistics and hazard ratios obtained in a noncontrolled trial. As no suited control group and no appropriate randomized trials were available for doing this calculation and as such trials are unlikely to become available in the near future we have calculated our NNTs as published previously by using relative risk reduction from an earlier randomized trial (RCT) comparing RP with watchful waiting (WW) [Can J Urol 2006;13(suppl 1):48-55]. RESULTS: For preoperative PSAV >2 ng/ml/year, NNT for RP were estimated at 25, whereas for preoperative PSAV <=2 ng/ml/year, the estimate was 618. The lower 95% confidence limits (NNTBl) were 9 and 126, respectively (treatment with benefit). The implications emerging from these findings are discussed by comparison with published NNT values from other RCTs. The lower 95% confidence limit for preoperative PSAV <=2 ng/ml/year was found to be large in comparison. CONCLUSION: The NNT estimate obtained here for PSAV >2 ng/ml/year and its lower 95% confidence interval is comparable to values in other studies on prostate cancer for therapies considered to be effective, while the estimated NNT for patients with PSAV <=2 ng/ml/year is large in comparison. We conclude that the benefits of RP for localized prostate cancer with preoperative PSAV <=2 ng/ml/year may be considered small. There are several limitations to our findings, the most important of which lies in the fact that while PSAV remains significantly associated with outcomes, the predictive value of PSA measurements is low. While PSAV >2 ng/ml/year clearly indicates a need for surgery, a PSAV <=2 ng/ml/year should imply further decision making. PMID- 22814093 TI - Delusions increase functional impairment in Alzheimer's disease. AB - BACKGROUND/AIMS: Delusions in Alzheimer's disease (AD) may be associated with functional impairment. No studies to date have used functional instruments sensitive to changes in frontal executive function, possibly underestimating the impact. METHODS: Patients with AD with and without delusions were administered cognitive tests and questionnaires to assess depression and quality of life. Caregivers were administered questionnaires to assess functional impairment, caregiver burden and behavioural symptoms. RESULTS: AD patients with delusions (n = 19) when compared to AD patients without delusions (n = 19) matched for age, education and global cognitive function were significantly more functionally impaired based on performance on the Disability Assessment for Dementia Scale (p < 0.005). CONCLUSION: AD patients with delusions have significantly worse functional performance. PMID- 22814094 TI - Biodynamic characteristics of upper limb reaching movements of the seated human under whole-body vibration. AB - Simulation of human movements is an essential component for proactive ergonomic analysis and biomechanical model development (Chaffin, 2001). Most studies on reach kinematics have described human movements in a static environment, however the models derived from these studies cannot be applied to the analysis of human reach movements in vibratory environments such as in-vehicle operations. This study analyzes three-dimensional joint kinematics of the upper extremity in reach movements performed in static and specific vibratory conditions and investigates vibration transmission to shoulder, elbow, and hand along the body path during pointing tasks. Thirteen seated subjects performed reach movements to five target directions distributed in their right hemisphere. The results show similarities in the characteristics of movement patterns and reach trajectories of upper body segments for static and dynamic environments. In addition, vibration transmission through upper body segments is affected by vibration frequency, direction, and location of the target to be reached. Similarities in the pattern of movement trajectories revealed by filtering vibration-induced oscillations indicate that coordination strategy may not be drastically different in static and vibratory environments. This finding may facilitate the development of active biodynamic models to predict human performance and behavior under whole body vibration exposure. PMID- 22814095 TI - Irregular primary otolith afferents from the guinea pig utricular and saccular maculae respond to both bone conducted vibration and to air conducted sound. AB - This study sought to identify in guinea pig the peripheral sense organ of origin of otolith irregular primary vestibular afferent neurons having a very sensitive response to both air-conducted sound (ACS) and bone-conducted vibration (BCV). Neurons responding to both types of stimuli were labelled by juxtacellular labelling by neurobiotin. Whole mounts of the maculae showed that some vestibular afferents activated by both ACS and BCV originate from the utricular macula and some from the saccular macula - there is no "afferent specificity" by one sense organ for ACS and the other for BCV - instead some afferents from both sense organs have sensitive responses to both stimuli. The clinical implication of this result is that differential evaluation of the functional status of the utricular and saccular maculae cannot rely on stimulus type (ACS vs BCV), however the differential motor projections of the utricular and saccular maculae allow for differential evaluation of each sense organ. PMID- 22814096 TI - On-line coordination in complex goal-directed movements: a matter of interactions between several loops. AB - Motor flexibility is the ability to rapidly modify behavior when unexpected perturbations occur. In goal directed movements, this process may be involved during the motor execution itself, by using on-line motor corrections, or off line, on a trial-by-trial basis. A consensus has emerged to describe and unify these two dependant processes within the framework of the internal models theory in which the cerebellum is involved in error processing. However, this general framework may be incomplete to describe on-line motor corrections when complex motor coordination is involved in the task. In particular, interaction torques existing between different effectors limit the independence between different controllers that could be considered to control various body parts. In addition, recent findings suggest that different (sub)-cortical loops may be involved during orienting responses to visual stimuli but also during on-line motor corrections following visual perturbations. The way these different loops with different dynamics interact but achieve the same motor goal is an important problem in motor control. The simplest organization may be sequential, as in the well-known stretch reflex. This implies that during on-line corrections, the nervous system may be involved in a distributed fashion and that motor plans and synergies depend both on anatomical and temporal constraints. More particularly, motor plans and synergies may be stored and may differ according to the (sub) cortical loops involved during the whole on-line correction process. Finally, questions concerning the independence (or not) of these loops remain unanswered. The case of strict independence would mean that between the various corrective loops, (i) error processing and (ii) motor plans/synergies would be different. By contrast, in a situation of dependency, it would probably mean that interactions would link lower (and faster) to upper (and longer) loops by informing these latter of the motor corrections sent by the former, similarly to an efference copy. PMID- 22814097 TI - ATP-induced currents carried through P2X7 receptor in rat myometrial cells. AB - OBJECTIVE: The functional significance of purinergic P2 receptors in the myometrium is unclear. We previously reported the ATP-induced ionic currents in rat myometrial cells, causing uterine contractility. The aim of this study is to determine the main P2X receptors that carry the adenosine triphosphate (ATP) induced currents. STUDY DESIGN: We cloned predominantly expressed P2X7 receptors from rat myometrium and transfected into cultured COS-7 cells. Reconstructed P2X7 receptor currents were characterized using the whole-cell patch clamp method. RESULTS: Extracellular ATP induced currents through P2X7 receptors with effective concentration (EC(50)) of 155 MUmol/L, without desensitization. The myometrial P2X7 receptor was permeable to multiple monovalent cations with conductances ranked as K(+)>Cs(+)>Li(+)>Na(+). It was activated by P2X receptor agonists, with effectiveness ranked as 2',3'-O-(4-benzoylbenzoyl)-ATP (Bz-ATP)>>ATP>alphabeta methylene ATP (alphabeta-MeATP)>2-methylthio ATP (2-MeSATP)>uridine triphosphate (UTP)>guanosine triphosphate (GTP)>adenosine diphosphate (ADP). These currents were blocked by selective P2X7 receptor antagonists and extracellular Mg(2+). CONCLUSION: P2X7 receptors carry ATP-induced currents in rat myometrial cells. PMID- 22814098 TI - Serum anti-Mullerian hormone levels affect the rate of ongoing pregnancy after in vitro fertilization. AB - We used logistic regression analysis to investigate the relationship between serum anti-Mullerian hormone (AMH) levels and the rate of ongoing pregnancy. Retrospective data were collected from 1043 women who had undergone their first cycle of in vitro fertilization (IVF), including 540 cycles of fresh embryo transfer and 503 cycles of frozen-thawed embryo transfer. The patients were divided into 4 groups based on the cutoff values from a receiver-operating characteristic curve: 0.0 to 12.4, 12.5 to 25.5, 25.6 to 44.1, and >44.2 pmol/L. After adjustment for multiple confounders, the serum AMH group was found to be significantly related to the rate of ongoing pregnancy in total cycles (0.0-12.4 vs 12.5-25.5 pmol/L; P = .0088, odds ratio, 1.909: vs 25.6-44.1 pmol/L; P = .0281, odds ratio, 2.109: vs >44.2 pmol/L; P = .0008, odds ratio, 2.840). In conclusion, there appears to be a significant relationship between serum AMH levels and the ongoing pregnancy rate in first IVF treatment cycles after adjustment for multiple confounders. PMID- 22814100 TI - Epab and Pabpc1 are differentially expressed during male germ cell development. AB - Modification of poly(A) tail length constitutes the main posttranscriptional mechanism by which gene expression is regulated during spermatogenesis. Embryonic poly(A)-binding protein (EPAB) and somatic cytoplasmic poly(A)-binding protein (PABPC1) are the 2 key proteins implicated in this pathway. In this study we characterized the temporal and spatial expression of Epab and Pabpc1 in immature (D6-D32) and mature (D88) mouse testis and in isolated spermatogenic cells. Both Epab and Pabpc1 expression increased during early postnatal life and reached their peak at D32 testis. This was due to an increase in both spermatogonia (SG) and spermatocytes. In the mature testis, the highest levels of Epab were detected in SG, followed by round spermatids (RSs), while the most prominent Pabpc1 expression was detected in spermatocytes and RSs. Our findings suggest that PABPC1 may play a role in translational regulation of gene expression by cytoplasmic polyadenylation, which occurs in spermatocytes, while both EPAB and PABPC1 may help stabilize stored polyadenylated messenger RNAs in RSs. PMID- 22814101 TI - Computational estimation of decline in sweating in the elderly from measured body temperatures and sweating for passive heat exposure. AB - Several studies reported the difference in heat tolerance between younger and older adults, which may be attributable to the decline in the sweating rate. One of the studies suggested a hypothesis that the dominant factor causing the decline in sweating was the decline in thermal sensitivity due to a weaker signal from the periphery to the regulatory centres. However, no quantitative investigation of the skin temperature threshold for activating the sweating has been conducted in previous studies. In this study, we developed a computational code to simulate the time evolution of the temperature variation and sweating in realistic human models under heat exposure, in part by comparing the computational results with measured data from younger and older adults. Based on our computational results, the difference in the threshold temperatures for activating the thermophysiological response, especially for sweating, is examined between older and younger adults. The threshold for activating sweating in older individuals was found to be about 1.5 degrees C higher than that in younger individuals. However, our computation did not suggest that it was possible to evaluate the central alteration with ageing by comparing the computation with the measurements for passive heat exposure, since the sweating rate is marginally affected by core temperature elevation at least for the scenarios considered here. The computational technique developed herein is useful for understanding the thermophysiological response of older individuals from measured data. PMID- 22814102 TI - S1, a novel pan-BH3 mimetic, induces apoptosis in Mcl-1-overexpressing cells through Bak. AB - Mcl-1, an anti-apoptotic Bcl-2 homolog that has a structurally divergent BH3 binding pocket, non-redundant action model, and unique characteristic of short life confers complete resistance to the BH3 mimetic ABT-737. Herein, we used S1, previously identified as a Mcl-1/Bcl-2 dual inhibitor and a pure BH3 mimetic, to explore the mechanism of Mcl-1's action and supply a strategy to challenge Mcl 1's protection. Apoptosis assay in SMMC-7721, HCT116, and K562 cells demonstrated that S1 can effectively challenge Mcl-1's anti-apoptotic effect. Notably, we discovered an unexpected dynamic change of Mcl-1 that directly correlates with resistance or commitment to apoptosis induced by both ABT-737 and S1. Co immunoprecipitation assays demonstrated that Mcl-1 increase results from Bim trafficking from Bcl-2 to Mcl-1, while subsequent Bak released by S1 determines Mcl-1 decrease and full-blown apoptosis. Further experiments using Bak shRNA testified that Bak accounts for S1-induced apoptosis and Mcl-1 decrease. Consistently, Bax-deficient DU145 cells are sensitive to S1, whereas Bak-mutant MKN-28 cells are significantly more resistant. The in vitro model could be extended to an in vivo mouse xenograft model in which Mcl-1 confers resistance by increased protein level, and the release of Bak could serve as a biomarker of apoptosis. PMID- 22814099 TI - Innate immunity, decidual cells, and preeclampsia. AB - Preeclampsia (PE) manifested by hypertension and proteinuria complicates 3% to 8% of pregnancies and is a leading cause of fetal-maternal morbidity and mortality worldwide. It may lead to intrauterine growth restriction, preterm delivery, and long-term sequelae in women and fetuses, and consequently cause socioeconomic burden to the affected families and society as a whole. Balanced immune responses are required for the maintenance of successful pregnancy. Although not a focus of most studies, decidual cells, the major resident cell type at the fetal-maternal interface, have been shown to modulate the local immune balance by interacting with other cell types, such as bone marrow derived-immune cells, endothelial cells, and invading extravillous trophoblasts. Accumulating evidence suggests that an imbalanced innate immunity, facilitated by decidual cells, plays an important role in the pathogenesis of PE. Thus, this review will discuss the role of innate immunity and the potential contribution of decidual cells in the pathogenesis of PE. PMID- 22814103 TI - Description of Sarcocystis turdusi sp. nov. from the common blackbird (Turdus merula). AB - Cysts of Sarcocystis species were found in 24 of 44 (54.5%) examined blackbirds (Turdus merula). Under the light microscope, only 1 morphological type of cyst was found in all birds investigated. Ribbon-shaped cysts were long (the largest fragment found amounted to 7 mm) and of different thickness (25-206 MUm). A cyst wall reached up to 3.5 MUm and had finger-like protrusions. Under the transmission electron microscope, a single cyst isolated from 1 blackbird was studied. The cyst wall was 2.5-4.4 MUm thick, had club- or irregularly-shaped and sometimes branched protrusions that differed in size. The content of cysts was divided into large chambers by septa. Orange segment-shaped cystozoites were 6.2 * 1.4 (5.5-7.2 * 1.2-1.5) MUm. This type of cyst wall has never been described in Sarcocystis species isolated from birds, thus far. The results of 18S rDNA, 28S rDNA and ITS-1 region sequences showed that S. turdusi was most closely related to S. columbae, S. calchasi, S. wobeseri, S. cornixi and Sarcocystis sp. ex Accipiter nisus parasitizing birds. Phylogenetic results suggest that predatory birds are the most probable definitive hosts of S. turdusi. PMID- 22814104 TI - Continuous ambulatory peritoneal dialysis-related peritonitis in an uremic outpatient: Achromobacter xylosoxidans. PMID- 22814105 TI - Oncostatin M inhibits TGF-beta1-induced CTGF expression via STAT3 in human proximal tubular cells. AB - Matricellular proteins play a critical role in the development of tubulointerstitial fibrosis and renal disease progression. Connective tissue growth factor (CTGF/CCN2), a CCN family member of matricellular proteins, represents an important mediator during development of glomerular and tubulointerstitial fibrosis in progressive kidney disease. We have recently reported that oncostatin M (OSM) is a potent inhibitor of TGF-beta1-induced CTGF expression in human proximal tubular cells (PTC). In the present study we examined the role of TGF-beta1- and OSM-induced signaling mechanisms in the regulation of CTGF mRNA expression in human proximal tubular HK-2 cells. Utilizing siRNA-mediated gene silencing we found that TGF-beta1-induced expression of CTGF mRNA after 2h of stimulation at least partially depends on SMAD3 but not on SMAD2. In contrast to TGF-beta1, OSM seems to exert a time dependent dual effect on CTGF mRNA expression in these cells. While OSM led to a rapid and transient induction of CTGF mRNA expression between 15 min and 1h of stimulation it markedly suppressed basal and TGF-beta1-induced CTGF mRNA levels thereafter. Silencing of STAT1 or STAT3 attenuated basal CTGF mRNA levels indicating that both STAT isoforms may be involved in the regulation of basal CTGF mRNA expression. However, knockdown of STAT3 but not STAT1 prevented OSM mediated suppression of basal and TGF-beta1-induced upregulation of CTGF mRNA expression. Together these results suggest that the inhibitory effect of OSM on TGF-beta1-induced CTGF mRNA expression is mainly driven by STAT3, thereby providing a signaling mechanism whereby OSM may contribute to tubulointerstitial protection. PMID- 22814106 TI - TGF-beta but not BMP signaling induces prechondrogenic condensation through ATP oscillations during chondrogenesis. AB - Although both TGF-beta and BMP signaling enhance expression of adhesion molecules during chondrogenesis, TGF-beta but not BMP signaling can initiate condensation of uncondensed mesenchymal cells. However, it remains unclear what causes the differential effects between TGF-beta and BMP signaling on prechondrogenic condensation. Our previous report demonstrated that ATP oscillations play a critical role in prechondrogenic condensation. Thus, the current study examined whether ATP oscillations are associated with the differential actions of TGF-beta and BMP signaling on prechondrogenic condensation. The result revealed that while both TGF-beta1 and BMP2 stimulated chondrogenic differentiation, TGF-beta1 but not BMP2 induced prechondrogenic condensation. It was also found that TGF-beta1 but not BMP2 induced ATP oscillations and inhibition of TGF-beta but not BMP signaling prevented insulin-induced ATP oscillations. Moreover, blockage of ATP oscillations inhibited TGF-beta1-induced prechondrogenic condensation. In addition, TGF-beta1-driven ATP oscillations and prechondrogenic condensation depended on Ca(2+) influx via voltage-dependent calcium channels. This study suggests that Ca(2+)-driven ATP oscillations mediate TGF-beta-induced the initiation step of prechondrogenic condensation and determine the differential effects between TGF-beta and BMP signaling on chondrogenesis. PMID- 22814107 TI - Cyclophilin A and viral infections. AB - Cyclophilin A (CyPA) is a peptidyl-prolyl cis/trans isomerase originally identified as the target of the immunosuppressive drug cyclosporine A. A number of reports have demonstrated that CyPA plays a critical role in the successful replication of viruses such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), etc. However, recent studies demonstrated that CyPA also possesses a repressive effect on the replication of some viruses like Influenza A virus and rotavirus. Moreover, CyPA could also regulate host IFN I response to viral infections. Together, these evidences showed diverse roles of CyPA in viral infection. PMID- 22814108 TI - AKT/SGK-sensitive phosphorylation of GSK3 in the regulation of L-selectin and perforin expression as well as activation induced cell death of T-lymphocytes. AB - Survival and function of T-lymphocytes critically depends on phosphoinositide (PI) 3 kinase. PI3 kinase signaling includes the PKB/Akt and SGK dependent phosphorylation and thus inhibition of glycogen synthase kinase GSK3alpha,beta. Lithium, a known unspecific GSK3 inhibitor protects against experimental autoimmune encephalomyelitis. The present study explored, whether Akt/SGK dependent regulation of GSK3 activity is a determinant of T cell survival and function. Experiments were performed in mutant mice in which Akt/SGK-dependent GSK3alpha,beta inhibition was disrupted by replacement of the serine residue in the respective SGK/Akt-phosphorylation consensus sequence by alanine (gsk3(KI)). T cells from gsk3(KI) mice were compared to T cells from corresponding wild type mice (gsk3(WT)). As a result, in gsk3(KI) CD4(+) cells surface CD62L (L-selectin) was significantly less abundant than in gsk3(WT) CD4(+) cells. Upon activation in vitro T cells from gsk3(KI) mice reacted with enhanced perforin production and reduced activation induced cell death. Cytokine production was rather reduced in gsk3(KI) T cells, suggesting that GSK3 induces effector function in CD8(+) T cells. In conclusion, PKB/Akt and SGK sensitive phosphorylation of GSK3alpha,beta is a potent regulator of perforin expression and activation induced cell death in T lymphocytes. PMID- 22814109 TI - Ligand binding induces a sharp decrease in hydrophobicity of folate binding protein assessed by 1-anilinonaphthalene-8-sulphonate which suppresses self association of the hydrophobic apo-protein. AB - High affinity folate binding protein (FBP) regulates as a soluble protein and as a cellular receptor intracellular trafficking of folic acid, a vitamin of great importance to cell growth and division. We addressed two issues of potential importance to the biological function of FBP, a possible decrease of the surface hydrophobicity associated with the ligand-induced conformation change of FBP, and protein-inter-protein interactions involved in self-association of hydrophobic apo-FBP. The extrinsic fluorescent apolar dye 1-anilinonaphthalene-8-sulphonate (ANS) exhibited enhanced fluorescence intensity and a blueshift of emission maximum from 510-520 nm to 460-470 nm upon addition of apo-FBP indicating binding to a strongly hydrophobic environment. Neither enhancement of fluorescence nor blueshift of ANS emission maximum occurred when folate-ligated holo-FBP replaced apo-FBP. The drastic decrease in surface hydrophobicity of holo-FBP could have bearings on the biological function of FBP since changes in surface hydrophobicity have critical effects on the biological function of receptors and transport proteins. ANS interacts with exposed hydrophobic surfaces on proteins and may thereby block and prevent aggregation of proteins (chaperone-like effect). Hence, hydrophobic interactions seemed to participate in the concentration-dependent self-association of apo-FBP which was suppressed by high ANS concentrations in light scatter measurements. PMID- 22814110 TI - Metabolic engineering of Rhizopus oryzae: effects of overexpressing pyc and pepc genes on fumaric acid biosynthesis from glucose. AB - Fumaric acid, a dicarboxylic acid used as a food acidulant and in manufacturing synthetic resins, can be produced from glucose in fermentation by Rhizopus oryzae. However, the fumaric acid yield is limited by the co-production of ethanol and other byproducts. To increase fumaric acid production, overexpressing endogenous pyruvate carboxylase (PYC) and exogenous phosphoenolpyruvate carboxylase (PEPC) to increase the carbon flux toward oxaloacetate were investigated. Compared to the wild type, the PYC activity in the pyc transformants increased 56%-83%, whereas pepc transformants exhibited significant PEPC activity (3-6 mU/mg) that was absent in the wild type. Fumaric acid production by the pepc transformant increased 26% (0.78 g/g glucose vs. 0.62 g/g for the wild type). However, the pyc transformants grew poorly and had low fumaric acid yields (<0.05 g/g glucose) due to the formation of large cell pellets that limited oxygen supply and resulted in the accumulation of ethanol with a high yield of 0.13-0.36 g/g glucose. This study is the first attempt to use metabolic engineering to modify the fumaric acid biosynthesis pathway to increase fumaric acid production in R. oryzae. PMID- 22814111 TI - A dextrocardia in a foetal Egyptian mummy? AB - Egyptian foetal mummies are rare archaeological artefacts. We report the case of a mummified foetus with a highly probable dextrocardia accurately depicted by computed tomography scan. PMID- 22814113 TI - Male and female Wistar rats differ in decision-making performance in a rodent version of the Iowa Gambling Task. AB - The Iowa Gambling Task (IGT) measures decision-making processes by simulating real-life decisions involving reward, punishment, and uncertainty of outcomes. In humans, men show more choices for the advantageous option than women. Here, we investigated sex differences in a rat model of the IGT (r-IGT). In our r-IGT mildly food-deprived rats learn to differentiate a long-term advantageous arm from a long-term disadvantageous arm differing in frequency and amount of sugar pellets as well as unpalatable but not uneatable quinine-treated sugar pellets. We also used a T-maze discrimination procedure in which rats learn to differentiate a high from a low reward arm to further explore sex differences in reward-related decision-making. In line with human data, male rats showed a stronger task progression of choices for the advantageous option than female rats. Furthermore, male rats showed more win-stay and less lose-shift behaviour in the advantageous arm as the task progressed than female rats. Whilst both male and female rats had a stronger preference for the high over the small reward arm in the T-maze, males increased this preference over sessions, whilst females did not. These data are discussed in relation to sex differences in processing rewards and punishments. PMID- 22814112 TI - Effects of novelty and methamphetamine on conditioned and sensory reinforcement. AB - BACKGROUND: Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light. METHODS: The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined. RESULTS: Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs. CONCLUSION: Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction. PMID- 22814114 TI - Despite higher glucocorticoid levels and stress responses in female rats, both sexes exhibit similar stress-induced changes in hippocampal neurogenesis. AB - Sex differences in stress reactivity may be one of the factors underlying the increased sensitivity for the development of psychopathologies in women. Particularly, an increased hypothalamic-pituitary-adrenal (HPA) axis reactivity in females may exacerbate stress-induced changes in neuronal plasticity and neurogenesis, which in turn may contribute to an increased sensitivity to psychopathology. The main aim of the present study was to examine male-female differences in stress-induced changes in different aspects of hippocampal neurogenesis, i.e. cell proliferation, differentiation and survival. Both sexes were exposed to a wide variety of stressors, where after differences in HPA-axis reactivity and neurogenesis were assessed. To study the role of oestradiol in potential sex differences, ovariectomized females received low or high physiological oestradiol level replacement pellets. The results show that females in general have a higher basal and stress-induced HPA-axis activity than males, with minimal differences between the two female groups. Cell proliferation in the dorsal hippocampus was significantly higher in high oestradiol females compared to low oestradiol females and males, while doublecortin (DCX) expression as a marker of cell differentiation was significantly higher in males compared to females, independent of oestradiol level. Stress exposure did not significantly influence cell proliferation or survival of new cells, but did reduce DCX expression. In conclusion, despite the male-female differences in HPA-axis activity, the effect of repeated stress exposure on hippocampal cell differentiation was not significantly different between sexes. PMID- 22814115 TI - Altered expression of glucocorticoid receptor and corticotropin-releasing factor in the central amygdala in response to elevated corticosterone. AB - The amygdala is not only a critical site for the generation of anxiety and fear, but is involved in the affective processing of sensory information including nociception. Previously, we demonstrated that the stress hormone corticosterone (CORT) localized to the central nucleus of the amygdala (CeA) induces anxiety like behavior and increases the sensitivity to visceral or somatic stimuli in rats. Here we test the hypothesis that exposure of the CeA to elevated CORT alters the expression of key receptors and ion channels that are implicated in anxiety and pain processing. PMID- 22814116 TI - alpha GABA(A) subunit-orexin receptor interactions activate learning/motivational pathways in the goldfish. AB - Orexins (ORXs) cross-talking with gamma-aminobutyric acid(A) receptor (GABA(A)R) is beginning to constitute a key neuronal signaling feature responsible for the successful promotion of sleep-wake cycle, feeding and motor behaviors plus reward/motivational activities. In this work, ORX-A and the two alpha GABA(A)R agonists (zolpidem, ZOL; diazepam, DZP) accounted for very great (p<0.001) increases of feeding while only DZP elicited great (p<0.01) levels of food intake in the goldfish (Carassius auratus). It was, however, T-maze and conditioned place preference (CPP) methods that allowed us to specifically establish learning/reward-related events operating in an ORX-A+GABA(A)R-dependent fashion in our experimental model. T-maze data showed that conditioned ORX-A treated-fish were capable of reaching the red/blue chamber and ingesting their food reward in a very greatly reduced latency time with respect to untreated conditioned fish while DZP and ZOL greatly and moderately (p<0.05) reduced their latency time, respectively. Regarding CPP study, conditioned ORX-A- and DZP-treated animals showed comparably greater preferences for the conditioned compartment that became even greater in ORX-A+DZP-treated fish. Surprisingly, ORX receptor expression of the telencephalon was preferentially activated by ORX-A treatments while diencephalic/mesencephalic structures and namely the tuberculum posterioris (TPp) were more sensitive to DZP especially following treatment with ORX-A+DZP. Overall, behavioral performances along with ORX receptor transcriptional properties tend to point to alpha GABA(A)R agonists as enhancers of palatability while the ORXergic system constitutes a crucial link between satiety-related and cognitive centers through the activation of TPp thus proposing this ascending dopaminergic system as a key target of learning/reward processes in fish. PMID- 22814117 TI - Modelling and prediction of 25-hydroxyvitamin D levels in Norwegian relapsing remitting multiple sclerosis patients. AB - BACKGROUND/AIM: 25-Hydroxyvitamin D (25(OH)D) levels are suggested to influence the susceptibility and risk of disease progression in multiple sclerosis (MS). Seasonal fluctuation of 25(OH)D levels may differ in magnitude between individuals. The purpose of this paper was to model the seasonal fluctuation of vitamin D in Norwegian MS patients and to examine to which extent one single 25(OH)D measurement predicts the level at other time points throughout the year. METHODS: During December 2004 and July 2008, 762 serum samples were collected from 92 Norwegian relapsing-remitting MS patients. Time series analysis and multivariate modelling techniques were used to model seasonal fluctuations and intra- and inter-individual variations in 25(OH)D values. RESULTS: Most patients reached their lowest 25(OH)D level in March/April and the highest in July/August. There were substantial intra-individual variations in the extent of seasonal fluctuation, with 36.6% of explainable variation in seasonally adjusted 25(OH)D levels (on a logarithmic scale) attributable to the patient level. The remaining 63.4% could be accounted for by sources of inter-individual variation. Both the total and inter-individual variabilities were lowest in February, and the prediction interval in this month was up to 26% narrower compared to other months. The prediction intervals would be at least 21% wider with only one observation available per patient. CONCLUSIONS: The seasonal fluctuations of 25(OH)D levels in Norwegian relapsing-remitting MS patients are subject to pronounced intra- and inter-individual variation. The most representative measurements of 25(OH)D levels are taken in February. PMID- 22814118 TI - The development of a CD-ROM: an aid to fetal cardiac diagnosis and counseling. AB - OBJECTIVE: Obstetric ultrasound allows for the fetal diagnosis of complex congenital heart disease, which once diagnosed is especially stressful for the affected parents. This study aimed to develop and pilot an educational CD-ROM for parents who had a fetal diagnosis of a congenital heart defect (CHD). MATERIAL AND METHODS: A CD-ROM was developed which included a brief description of a normal heart in text and cartoons, followed by one of five congenital heart abnormalities (again described in text and illustrated by cartoons highlighting the anatomy), the likely interventions (surgical or by catheter), and the local outcomes. A pilot study was conducted whereby parents were provided with the CD ROM and asked to complete a brief evaluation following the fetal diagnosis of a suspected CHD and subsequent to counseling by the pediatric cardiologist, but prior to the birth of the infant. The CD-ROM was to be viewed at the parents' convenience. The questionnaire was returned via postal mail. RESULTS: A CD-ROM covering five common congenital heart abnormalities was successfully developed and distributed to 20 parents. Fourteen responses were received. The feedback was favorable. The parents found the CD-ROM to be informative and easily understood and supplemented the information previously provided by the pediatric cardiologist. The diagrams were particularly helpful. CONCLUSION: An educational CD-ROM describing a cardiac abnormality of a fetus was successfully created and favorably received, complementing the earlier counseling given. Further development of the CD-ROM with modifications highlighting parental suggestions and to include other abnormalities will allow for a wider audience. PMID- 22814121 TI - WITHDRAWN: Functional implications of hypothalamic neurogenesis in the adult mammalian brain. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi 10.1016/j.ijdevneu.2012.07.003. The duplicate article has therefore been withdrawn. PMID- 22814119 TI - Coupling of pyrroloquinoline quinone dependent glucose dehydrogenase to (cytochrome c/DNA)-multilayer systems on electrodes. AB - The redox protein cytochrome c (cyt c) assembles into electro-active multilayers on gold electrodes by the help of deoxyribonucleic acid (DNA) as a negatively charged building block. The feasibility of this electro-active system as a novel interface for the immobilization of enzymes on electrodes is investigated in this study. Therefore the known reaction of cyt c and PQQ-GDH is confined to the immobilized state of both molecules. We find that electron-transfer from the substrate via PQQ-GDH and cyt c molecules, towards the electrode occurs; thus the system can be considered as an artificial signal chain. First, a monolayer of cyt c is prepared on a thiol-modified gold electrode and investigated with PQQ-GDH in solution. Cyclic voltammetric measurements prove that a small catalytic current occurs in the presence of the substrate. Next, both proteins are immobilized. We use the layer-by-layer deposition technique to assemble cyt c with DNA in multiple layers and a terminal layer of PQQ-GDH: (cyt c/DNA)(n)/PQQ-GDH. It is found that a catalytic current flows when glucose is present, proving that this system relies on inter-protein electron-transfer. The current intensity can be increased from 0.1nA, at the monolayer system, up to 3.7nA, at the (cyt c/DNA)(4)/PQQ-GDH electrode. This bi-protein multilayer system can follow different glucose concentrations in a linear dynamic range between 25nM and 0.5MUM at its pH optimum, i.e. pH 6. Therefore this system is of limited importance for sensing but it represents a new biomimetic signal chain by arranging proteins in multiple layers on electrodes, making direct electron exchange feasible. PMID- 22814123 TI - The eighth ETS special issue of Reproductive Toxicology. PMID- 22814124 TI - Size and sex matter: infection dynamics of an invading parasite (the pentastome Raillietiella frenatus) in an invading host (the cane toad Rhinella marina). AB - Correlations between host phenotype and vulnerability to parasites can clarify the processes that enhance rates of parasitism, and the effects of parasites on their hosts. We studied an invasive parasite (the pentastome Raillietiella frenatus, subclass Pentastomida, order Cephalobaenida) infecting a new host (the invasive cane toad Rhinella marina), in tropical Australia. We dissected toads over a 27-month period to investigate seasonal changes in pentastome population dynamics and establish which aspects of host phenotype are related to infection. Pentastome prevalence and intensity varied seasonally; male toads were 4 times more likely to be infected than were females; and prevalence was highest in hosts of intermediate body size. The strong sex effect may reflect habitat or dietary divergence between the sexes, resulting in males encountering parasites more often. The relationship between pentastome prevalence and host size likely reflects a role for acquired immunity in preventing re-infection. Infection did not influence host body condition (fatbody size), suggesting that R. frenatus does not impose high energy costs in cane toads. Infected toads had heavier spleens (likely an immune response to infection) and larger testes (perhaps since reproductively active hosts have altered microhabitat use and/or immunocompetence) than did uninfected conspecifics. Although experimental studies are required to identify the causal bases of such patterns, our data confirm that infection status within a population can be strongly linked to host phenotypic traits. PMID- 22814126 TI - Phenolics from Bidens bipinnata and their amylase inhibitory properties. AB - A new chlorinated flavonoid, 3, 6, 8-trichloro-5, 7, 3', 4'-tetrahydroxyflavone (1), a new biscoumaric acid derivative, 4-O-(2", 3"-O-diacetyl-6"-O-p-coumaroyl beta-D-glucopyranosyl)-p-coumaric acid (2), and 8, 3', 4'-trihydroxyflavone-7-O beta-D-glucopyranoside (3) together with twenty-four known compounds (4-27) were isolated from the whole plant of Bidens bipinnata. All chemical structures were established on the basis of UV-, MS- and NMR (1H, 13C, 1H-1H COSY, HMQC and HMBC) spectroscopic data. Some of the isolated compounds were tested for the inhibition of alpha-amylase. The result showed that isookanin (6) was a potent inhibitor of alpha-amylase (IC50=0.447 mg/ml). PMID- 22814127 TI - Central obesity, leptin and cognitive decline: the Sacramento Area Latino Study on Aging. AB - BACKGROUND/AIMS: Central obesity is a risk factor for cognitive decline. Leptin is secreted by adipose tissue and has been associated with better cognitive function. Aging Mexican Americans have higher levels of obesity than non-Hispanic Whites, but no investigations examined the relationship between leptin and cognitive decline among them or the role of central obesity in this association. METHODS: We analyzed 1,480 dementia-free older Mexican Americans who were followed over 10 years. Cognitive function was assessed every 12-15 months with the Modified Mini Mental State Exam (3MSE) and the Spanish and English Verbal Learning Test (SEVLT). RESULTS: For females with a small waist circumference (<=35 inches), an interquartile range difference in leptin was associated with 35% less 3MSE errors and 22% less decline in the SEVLT score over 10 years. For males with a small waist circumference (<=40 inches), an interquartile range difference in leptin was associated with 44% less 3MSE errors and 30% less decline in the SEVLT score over 10 years. There was no association between leptin and cognitive decline among females or males with a large waist circumference. CONCLUSION: Leptin interacts with central obesity in shaping cognitive decline. Our findings provide valuable information about the effects of metabolic risk factors on cognitive function. PMID- 22814128 TI - Differential diagnosis and treatment options for xanthogranulomatous cholecystitis. AB - OBJECTIVE: To describe the differential diagnosis and treatment options for xanthogranulomatous cholecystitis (XGC), the presentations and management of 68 patients were described. SUBJECTS AND METHODS: Demographical and clinical data from 68 cases of XGC treated between January 2004 and January 2010 were analyzed. Clinical characteristics, radiological and surgical findings, histopathological features and postoperative recoveries were recorded. Clinical features of laparoscopic cholecystectomy versus open surgery and XGC versus gallbladder (GB) cancer were compared. RESULTS: The CA19-9 levels of XGC and coexisting GB cancer were significantly different (p = 0.0034). In radiological findings, focal thickening of the GB wall was more frequent in coexisting GB cancer, early enhancement of the GB was observed more often in coexisting GB cancer, and lymph node enlargement was seen more often in coexisting GB cancer (p < 0.05). There were also significant differences between laparoscopic and open surgery for CA19 9, intramural hypoattenuated nodule, pericholecystic invasion, lymph node enlargement and maximum thickness, focal thickening, heterogeneous enhancement and early enhancement of the GB wall (p < 0.05). These findings were confirmed by multivariate analysis. CONCLUSIONS: Ultrasound, computed tomography scan and intraoperative frozen section were the helpful modalities for XGC diagnosis. CA19 9 (>37 kU/l), pericholecystic invasion, lymph node enlargement (>10 mm), and focal thickening and early enhancement of the GB wall were the criteria for open surgery. In some selected cases, laparoscopic cholecystectomy was preferable. PMID- 22814142 TI - Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus. AB - Previous studies have shown that several types of stem cells can differentiate into insulin-secreting islet beta-cells and that these cells can reduce blood glucose in some trials, but there has been no report of a long-term follow-up. We assessed the long-term effects of the use of autologous bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus (T2DM). Based on the willingness to receive implantation of bone marrow mononuclear cells, One hundred and eighteen patients with T2DM were divided into two groups; the patients in group I were treated with autologous bone marrow mononuclear cells and patients in group II were treated with insulin intensification therapy. Mononuclear cells from bone marrow were injected back into the patient's pancreas via a catheter. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 33 months, the occurrence of any side effects and the results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I and both the HbA1c and C-peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of autologous bone marrow mononuclear cells for the treatment of T2DM is safe and effective. This therapy can partially restore the function of islet beta-cells and maintain blood glucose homeostasis in a longer time. PMID- 22814143 TI - A case of zoledronate-induced tubulointerstitial nephritis with Fanconi syndrome. AB - A 54-year-old female underwent mastectomy in 1992 for breast cancer, but later developed liver metastasis in 2004, which was treated with docetaxel for a short period, and then discontinued due to nausea. Bone metastasis diagnosed in 2005 was treated with the combination of trastuzumab and zoledronate (4 mg/month) as well as radiotherapy. Progressive hypokalemia and renal dysfunction were observed since 2006 and the patient was admitted to our department in 2009 for further management of hypokalemia (serum potassium 2.2 mEq/L) and renal dysfunction (serum creatinine: 2.0 mg/dL). Accelerated potassium excretion and metabolic acidosis of the normal anion gap were observed and the patient was diagnosed with hypokalemia associated with renal tubular acidosis. Moreover, development of glucosuria, hypophosphatemia, hyperphosphaturia, hyponatremia, hypouricemia, and high beta2-microglobulin/NAG, together with histopathological findings compatible with renal tubular injury/interstitial nephritis on renal biopsy, allowed the diagnosis of Fanconi syndrome. Because the syndrome was considered to be induced by zoledronate based on the onset and clinical course, we stopped zoledronate. However, she continued the ambulatory chemotherapy with trastuzumab. This resulted in immediate and sustained improvement in renal function. To our knowledge, this is the first report of zoledronate-induced interstitial nephritis-Fanconi syndrome and indicates the close monitoring of renal function to avoid potential nephrotoxicity of zoledronate. PMID- 22814144 TI - Assessment of selected nutrient intake and adipocytokine profile among Saudi children and adults. AB - We report the dietary intake of selected nutrients in apparently healthy adults and children and its correlation with circulating levels of serum leptin and resistin. In this observational study, 47 Saudi children (mean age 13.1 +/- 2.8 year) and 47 adults (mean age 45.7 +/- 10.5 year) were recruited. Anthropometric data and lipid profile were obtained. Food intake was assessed by a food questionnaire and a 24-hour diet recall method. The dietary intake of selected nutrients was compared with the estimated average requirement (EAR) or adequate intake (AI) for establishing nutritional status. Results demonstrated that the levels of choline and calcium intake were significantly lower than the EAR in adults (p= 0.01 and 0.04, respectively) and relatively low in children. The level of manganese in adults was significantly higher (p= 0.02) than their AI level. The increasing levels of dietary vitamin B6 and B12 were associated with a significant increase in serum concentrations of leptin in adults and children (p=0.02). Overall, the dietary intakes of selected nutrients in Saudi adults and children were not adequate with most of them below cut-off EAR values except for essential amino acids. PMID- 22814145 TI - 25-hydroxyvitamin D level prediction models--is further optimization feasible? PMID- 22814125 TI - Lopinavir/ritonavir monotherapy after 24 weeks of second-line antiretroviral therapy in Africa: a randomized controlled trial (SARA). AB - BACKGROUND: Boosted protease inhibitor (bPI) monotherapy (bPImono) potentially has substantial cost, safety and operational benefits. It has never been evaluated as second-line antiretroviral therapy (ART) in Africa. METHODS: After 24 weeks of lopinavir/ritonavir-containing second-line therapy, DART participants were randomized to remain on combination therapy (CT), or change to bPImono maintenance (SARA trial; ISRCTN53817258). Joint primary end points were CD4(+) T cell changes 24 weeks later and serious adverse events (SAEs); retrospectively assayed viral load (VL) was a secondary end point. Analyses were intention-to treat. RESULTS: A total of 192 participants were randomized to CT (n=95) or bPImono (n=97) and followed for median 60 weeks (IQR 45-84). Participants received median 4.0 years (IQR 3.5-4.4) first-line ART. Median CD4(+) T-cell count at first-line failure was 86 cells/mm(3) (47-136), increasing to 245 cells/mm(3) (173-325) after 24-week induction when 77% had VL<50 copies/ml. Overall, 44 (23%) were receiving second-line therapy with bPI and nucleoside reverse transcriptase inhibitors (NRTI) only, and 148 (77%) with bPI plus non NRTI (NNRTI) with or without NRTI. At 24 weeks after randomization to CT versus bPImono, mean CD4(+) T-cell increase was 42 (CT, n=85) versus 49 cells/mm(3) (bPImono, n=88; adjusted difference 13 [95% CI -15, 43], P=0.37; non-inferior compared with predetermined non-inferiority margin [-33]). Virological suppression was greater for CT versus bPImono (trend P=0.009): 77% (70/91) versus 60% (56/94) were <50 copies/ml, and 5% (5) versus 14% (13) were >=1,000 copies/ml, respectively. A total of 0 (0%) versus 5 (5%) participants had major protease inhibitor mutations and 3 (3%) versus 0 (0%) new NNRTI/NRTI mutations were detected during follow-up. Two participants (1 CT and 1 bPImono) died >24 weeks after randomization, and 5 (2 CT and 3 bPImono) experienced SAEs (P=0.51). CONCLUSIONS: bPImono following a 24-week second-line induction was associated with similar CD4(+) T-cell response, but increased low-level viraemia, generally without protease inhibitor resistance. Longer-term trials are needed to provide definitive evidence about effectiveness in Africa. PMID- 22814146 TI - A functional neuroimaging study assessing gender differences in the neural mechanisms underlying the ability to resist impulsive desires. AB - There is ample evidence of gender differences in neural processes and behavior. Differences in reward-related behaviors have been linked to either temporary or permanent organizational influences of gonadal hormones on the mesolimbic dopamine system and reward-related activation. Still, little is known about the association between biological gender and the neural underpinnings of the ability to resist reward-related impulses. Here we assessed with functional magnetic resonance imaging which neural processes enable men and women to successfully control their desire for immediate reward when this is required by a higher-order goal (i.e., during a 'desire-reason dilemma'; Diekhof and Gruber, 2010). Thirty two participants (16 females) were closely matched for age, personality characteristics (e.g., novelty seeking) and behavioral performance in the 'desire reason task'. On the neural level, men and women showed similarities in the general response of the nucleus accumbens and of the ventral tegmental area to predictors of immediate reward, but they differed in additional brain mechanisms that enabled self-controlled decisions against the preference for immediate reward. Firstly, men exhibited a stronger reduction of activation in the ventral pallidum, putamen, temporal pole and pregenual anterior cingulate cortex during the 'desire-reason dilemma'. Secondly, connectivity analyses revealed a significant change in the direction of the connectivity between anteroventral prefrontal cortex and nucleus accumbens during decisions counteracting the reward related impulse when comparing men and women. Together, these findings support the view of a sexual dimorphism that manifested in the recruitment of gender specific neural resources during the successful deployment of self-control. PMID- 22814147 TI - Reduced audio-visual integration in synaesthetes indicated by the double-flash illusion. AB - It has been suggested that synaesthesia is the result of a hyper-sensitive multimodal binding-mechanism. To address the question whether multi-modal integration is altered in synaesthetes in general, grapheme-colour and auditory visual synaesthetes were studied using the double-flash illusion. This illusion is induced by a single light flash presented together with multiple beep sounds, which is then perceived as multiple flashes. By varying the separation of auditory and visual stimuli, the hypothesis of a widened temporal window of audio visual integration in synaesthetes was tested. As hypothesised, the results show differences between synaesthetes and controls concerning multisensory integration, but surprisingly other than expected synaesthetes perceive a reduced number of illusions and have a smaller time-window of audio-visual integration compared to controls. This indicates that they do not have a hyper-sensitive binding mechanism. On the contrary, synaesthetes seem to integrate even less than controls between vision and audition. PMID- 22814148 TI - On case-fatality rate: review and hypothesis. AB - The relationship between log cumulative number of patients (X) and that of deaths (Y) in an epidemic follows the equation logY = klogX - klogN(0), where k is a constant determining the slope and N(0) is the value of X when Y = 1. Diseases with k = 1 are Ebola hemorrhagic fever, avian influenza H5N1, cholera, and hand, foot, and mouth disease; those with k > 1 are the influenza H1N1 2009 pandemic in countries other than Mexico and the SARS epidemic in some countries; and those with k < 1 include the influenza H1N1 2009 pandemic in Mexico. Epidemics with k > 1 can be simulated by postulating two subpopulations (normal population [NP] and vulnerable population [VP]), where the epidemic proceeds at higher speed and at higher mortality in VP than in NP. Epidemics with k < 1 can be simulated by postulating coexisting high virulence virus (HVV) and low virulence virus (LVV), with the former being propagated at slower speed and with a higher mortality rate than the latter. An epidemic with k > 1 was simulated using parameters that are fractions of subpopulations NP or VP from the total population (f) and NP- or VP specific patient multiplication (M) and mortality (D) rates. An epidemic with k < 1 was simulated using parameters that are fractions of HVV- or LVV-infected human populations (f), and HVV- or LVV-specific M and D. PMID- 22814149 TI - Detection and serotyping of human adenoviruses from patients with influenza-like illness in mongolia. AB - Human adenoviruses (HAdVs) are responsible for approximately 5%-10% of acute respiratory infections. The serotypes of commonly detected respiratory HAdV in Asian countries are diverse. However, there are no well-documented reports of circulating HAdV serotypes in Mongolia. Between January 2010 and May 2011, 1,950 influenza-negative samples from patients with influenza-like illness, including eye swabs from patients with eye symptoms, were screened for HAdV, and 40 samples (2.1%) were positive for HAdVs. Among these 40 samples, 31 samples were positive for the hexon gene used in phylogenetic analysis, as determined by PCR. We identified 7 different serotypes. We constructed the phylogenetic trees of HAdV-B7 and HAdV-B3, the 2 most commonly detected serotypes in this study. All detected HAdV-B7 and -B3 Mongolian strains had identical sequences. HAdV-D8, known to be associated with epidemic keratoconjunctivitis (EKC), was detected from nasopharyngeal and eye swabs. There was no difference between the amino acid sequences of the hexon and fiber genes that may affect tissue tropism in Mongolian strains and those in EKC-causing strains. PMID- 22814150 TI - Effect of climatic conditions on epidemic patterns of influenza in Okinawa, Japan, during the pandemic of 2009: surveillance of rapid antigen test results. AB - Climatic conditions may have affected the incidence of influenza during the pandemic of 2009 as well as at other times. This study evaluated the effects of climatic conditions on influenza incidence in Okinawa, a subtropical region in Japan, during the 2009 pandemic using surveillance data from rapid antigen test (RAT) results. Weekly RAT results performed in four acute care hospitals in the Naha region of the Okinawa Islands from January 2007 to July 2011 were anonymously collected for surveillance of regional influenza prevalence. Intense epidemic peaks were noted in August 2009 and December 2009-January 2010 during the influenza pandemic of 2009. RAT positivity rates were lower during the pandemic period than during the pre- and post-pandemic periods. Lower ambient temperature was associated with higher influenza incidence during pre- and post pandemic periods but not during the pandemic of 2009. Lower relative humidity was associated with higher influenza incidence during the pandemic as well as during the other two periods. The association of climatic conditions and influenza incidence was less prominent during the pandemic of 2009 than during pre- and post-pandemic periods. PMID- 22814151 TI - Incidence of intussusception as studied from a hospital-based retrospective survey over a 10-year period (2001-2010) in Akita Prefecture, Japan. AB - One concern about rotavirus vaccines is its possible association with intussusception. Thus, it is necessary to determine the baseline incidence for intussusception in the first year of life in places where rotavirus vaccines are introduced. However, few safety data exist for the period at which the first dose of Rotarix and RotaTeq are allowed to administer in Japan. The first dose of Rotarix is scheduled to administer at 6-20 weeks of age and that of RotaTeq is scheduled to administer at 6-24 weeks of age; the upper limits for these vaccines is later than the upper limit recommended by the World Health Organization by 5 and 9 weeks, respectively. We performed a retrospective cross sectional study by reviewing medical charts of all hospitals that provided pediatric beds in Akita Prefecture, Japan, and identifying the cases of intussusception that met the Brighton criteria level 1 in these hospitals between January 2001 and December 2010. During this 10-year period, 122 children younger than 1 year of age were diagnosed with intussusception. The incidence of intussusception was estimated at 158 per 100,000 person-years among children younger than 1 year (95% confidence interval, 131-188), 10 per 100,000 person years for children aged 0-2 months, 165 for children aged 3-5 months, and 300 for children aged 6-8 months. This rapid and substantial increase in the incidence of intussusception during the first year of life should be considered when formulating the immunization schedule for administering rotavirus vaccines in Japan. PMID- 22814152 TI - Rapid identification of Mycobacterium tuberculosis in BACTEC MGIT960 cultures by in-house loop-medicated isothermal amplification. AB - Definitive diagnosis of tuberculosis (TB) by conventional culture, followed by bacterial identification based on biochemical tests is time-consuming and tedious. Simple loop-mediated isothermal amplification (LAMP) specific for Mycobacterium tuberculosis complex, targeting the M. tuberculosis 16S ribosomal RNA gene, termed TB-LAMP, was evaluated as an alternative for rapid culture confirmation. TB-LAMP was assessed for its ability to detect M. tuberculosis complex in BACTEC MGIT 960-positive cultures. Of the 103 cultures evaluated, 100 were identified to contain M. tuberculosis complex by TB-LAMP and had concordant results with standard biochemical tests of niacin accumulation, nitrate reductase, lack of heat-stable catalase, and susceptibility to para-nitrobenzoic acid. These results indicate that TB-LAMP in combination with BACTEC MGIT 960 is a specific, reliable, and technically feasible method for rapid and accurate identification of M. tuberculosis complex. PMID- 22814153 TI - An unusual case of fatal pericarditis due to Listeria monocytogenes. AB - Pericarditis due to Listeria monocytogenes is a very uncommon and serious disease. We describe a case of fatal subacute pericarditis that was caused by L. monocytogenes in a 61-year-old woman with Hodgkin's disease who was diagnosed in 1975 and considered cured. In addition, we review the literature on this condition. PMID- 22814154 TI - PCR-based detection of Leishmania DNA in skin samples of post kala-azar dermal leishmaniasis patients from an endemic area of Bangladesh. AB - Post kala-azar dermal leishmaniasis (PKDL) is a sequel of visceral leishmaniasis (VL) and PKDL patients are an important reservoir for anthroponotic transmission of VL. Therefore, diagnosis and treatment of PKDL is important for the kala-azar elimination program in South Asia, including Bangladesh. While definitive diagnosis of PKDL is still based on microscopy, despite the low sensitivity of this method of diagnosis, PCR for identification of kinetoplast DNA (kDNA) from Leishmania parasites is expected to be a rapid and sensitive diagnostic method. We attempted PCR-based diagnosis from skin biopsy specimens and compared PCR to other available detection methods in order to determine the acceptability and feasibility of the PCR diagnostic method in an endemic area of VL in Bangladesh. Both skin biopsy specimens and blood samples were collected from 110 patients suspected to have PKDL from 6 subdistrict health complexes in Mymensingh, Bangladesh. Using microscopy, we identified 32 samples (29.1%) that were positive for Leishmania. Immunochromatography tests indicated that 85 samples (77.3%) were positive for Leishmania. In contrast, a total of 104 (94.5%) samples tested positive using nested PCR, while unaffected portions of skin from PKDL patients tested negative. Sequencing analysis of the PCR products indicated that the amplified portion had more than 98% nucleotide sequence identity to the Leishmania donovani reference strain, D10. These findings indicate that the PCR method using a skin biopsy is highly sensitive and useful for confirmatory diagnosis of PKDL. PMID- 22814155 TI - Nosocomial infections in the general pediatric wards of a hospital in Turkey. AB - The aims of this study were to determine the prevalence, type, and clinical features of nosocomial infections (NIs), their etiological distribution, and the antibiotic resistance patterns of causative organisms in the general pediatric wards of a hospital in Turkey over a 3-year period. The Hospital Infection Control Committee NI surveillance reports were used as a database. NIs were detected in 171 (2.25%) of the 7,594 hospitalized patients. Some of these patients experienced more than 1 episode, and thus, the total NI episodes were 229. Patients' age varied from 1 to 144 months (mean +/- standard deviation, 14.5 +/- 23.6 months). The NI rate was 3.02%, and the NI density was 3.17/1,000 patient days. The most frequent NIs were lower respiratory system infections, blood stream infections, and urinary tract infections. Gram-negative organisms were the most frequently isolated agents. Of the 171 patients with NIs, 47 (27.5%) died. PMID- 22814156 TI - Relationship between stx genotype and Stx2 expression level in Shiga toxin producing Escherichia coli O157 strains. AB - To determine the expression level of Shiga toxin (Stx) 2-related toxins (Stx2 and Stx2c) produced by each of 33 Stx-producing Escherichia coli (STEC) O157 strains, stx2 and stx2c mRNAs (stx2-related mRNA) were measured using real-time PCR with primers that recognize sequences common to stx2 and stx2c. The amount of Stx2 and Stx2c protein was measured using a reversed passive latex agglutination (RPLA) kit. Expression of stx2-related mRNA was significantly higher in STEC O157 strains carrying the stx2 gene (i.e., stx2, stx1/stx2, or stx2/stx2c) than in most strains that carried the stx2c gene but not the stx2 gene (i.e., stx2c or stx1/stx2c). RPLA might not measure the precise amount of each toxin variant; nevertheless, stx2-inclusive strains had 40-fold higher mean toxin titers than did strains that carried the stx2c gene but not the stx2 gene, with the exception of 1 stx2c strain. Interestingly, 1 stx2c strain that was isolated from a patient with severe hemorrhagic diarrhea had the highest stx2 related mRNA expression and the highest toxin titer of all 33 STEC O157 strains. Taken together, these findings indicated that measurement of stx2-related mRNA expression could reflect differences in production levels of toxins among STEC strains. PMID- 22814157 TI - A superior test for diagnosis of Clostridium difficile-associated diarrhea in resource-limited settings. AB - In this prospective cohort study, we investigated the prevalence of Clostridium difficile-associated diarrhea (CDAD) in adult patients with nosocomial diarrhea by performing enzyme immunoassay (EIA) for detecting toxins A and B and polymerase chain reaction (PCR) for detecting the presence of the tcdB gene in stool samples. We determined the factors associated with CDAD, and the treatment outcome of CDAD from May 2010 to January 2011. A total of 175 stool samples were tested by EIA and PCR. In total, 26.9% patients tested positive for C. difficile: 12.6% by EIA and 24.0% by PCR. The kappa coefficient and total agreement of both the tests were 0.46 and 83.2%, respectively. Onset of diarrhea after antibiotic administration for 10 days or more (OR, 2.71; 95% CI, 1.14-6.44; P = 0.024) and leukocyte count >15,000 cells/mm(3) (OR, 3.12; 95% CI, 1.24-7.88; P = 0.016) were significantly associated with occurrence of CDAD. The non response rate to CDAD treatment was 24.1%, and the all-cause mortality rate was 31.9% in the CDAD group as against 35.9% in the non-CDAD group (P = 0.721). In our study, the performance of direct PCR of stool samples for detecting tcdB was better, with the number of positive results for stool toxins A and B being twofold higher than that in the case of EIA. Patients who have diarrhea after receiving antibiotics for 10 days or more or those who have a leukocyte count of >15,000 cells/mm(3) should be investigated for CDAD. PMID- 22814158 TI - Seasonal patterns of legionellosis in Saitama, 2005-2009. AB - Sporadic cases of legionellosis have increased in Saitama Prefecture. This study aimed to understand the characteristics and incidence of legionellosis in Saitama Prefecture by studying the corresponding data from Tokyo and all over Japan. We analyzed cases of legionellosis registered from 2005 through 2009 in the annual reports of the Infectious Disease Surveillance Center. There were two peaks in the incidence of legionellosis in Japan between June and November, and a trough between February and May every year. Similar seasonal characteristics were observed in both Tokyo and Saitama. Proper management of risk factors-such as cooling towers and other aerosol-generating devices, before and during the seasonal increase in these incidences-is essential as a prophylactic measure against legionellosis. PMID- 22814159 TI - Xenotropic murine leukemia virus-related virus proviral DNA not detected in blood samples donated in Japan. AB - The xenotropic murine leukemia virus-related virus (XMRV) was first described as a novel human gammaretrovirus in prostate tumor tissues and was reported to be found in blood, suggesting the possibility of XMRV transmission via blood transfusion. The gag and env regions of the XMRV proviral DNA that were detected 1,030 blood samples collected from the greater Tokyo area were examined by real time PCR analysis. However, XMRV infection was not found in the samples; this suggested that the risk of XMRV transmission via transfusion is very low in Japan. PMID- 22814160 TI - Molecular epidemiology of human metapneumovirus from 2009 to 2011 in Okinawa, Japan. AB - To clarify the molecular epidemiology of human metapneumovirus (HMPV) in Okinawa Prefecture, located in a subtropical region of Japan, we performed genetic analysis of the F gene in HMPV from patients with acute respiratory infection from January 2009 to December 2011. HMPV was detected in 18 of 485 throat swabs (3.7%). Phylogenetic analysis showed that 17 strains belonged to subgroup A2 and 1 strain belonged to subgroup B1. We did not observe seasonal prevalence of HMPV during the investigation period. A high level of sequence identity was observed in the strains belonging to subgroup A2 (>95%), and no amino acid substitution was found compared with other strains detected in Japan and other countries. The pairwise distance values among the present strains belonging to subgroup A2 were short. Our results suggest that the predominant HMPV strains belonging to A2 are highly homologous and seasonal epidemics were not seen in Okinawa during the investigation period. PMID- 22814161 TI - Molecular genotyping of Mycobacterium tuberculosis in Mie Prefecture, Japan, using variable numbers of tandem repeats analysis. AB - The variable numbers of tandem repeats (VNTR) analysis is a method frequently employed as a molecular epidemiological tool for Mycobacterium tuberculosis genetic fingerprinting. In this study, we characterized the population of M. tuberculosis circulating in Mie Prefecture, Japan, and assessed the utility of the proposed JATA12- and 15-VNTR analyses of 158 M. tuberculosis clinical isolates using 25 VNTR loci. The results revealed that the ancient Beijing sublineage is the most prevalent M. tuberculosis strain in Mie Prefecture, accounting for 85.0% of 113 Beijing lineage isolates. Our results also showed that JATA-VNTR using well-selected loci is as reliable as standardized 15-locus MIRU-VNTR. Furthermore, JATA15-VNTR analysis reliably improved the discriminatory power compared with basic JATA12-VNTR analysis. In summary, our data suggest that JATA-VNTR is a useful tool for discrimination of M. tuberculosis in areas where ancient Beijing strains are frequently isolated. PMID- 22814162 TI - Double oral administration of emtricitabine/tenofovir prior to virus exposure protects against highly pathogenic simian/human immunodeficiency virus infection in macaques. AB - In the absence of any effective vaccine against human immunodeficiency virus (HIV), current anti-retroviral drugs may be suitable for pre-exposure prophylaxis (PrEP). Previous large clinical trials showed that PrEP reduced HIV infection in high-risk populations. Emtricitabine/tenofovir (FTC/TDF) may be a suitable agent for PrEP. FTC/TDF PrEP efficacy was evaluated using a highly pathogenic simian/human immunodeficiency virus (SHIV) in a non-human primate model of AIDS, the SHIV-KS661c/cynomolgus monkey model. Double oral administration of FTC/TDF (20/30 mg/kg), at 24 h and a few minutes prior to exposure, completely protected 2/3 monkeys from infection. Interestingly, a single oral administration 2 weeks before viral exposure moderately rescued CD4 cells, although the data did not reach statistical significance. These results are consistent with previous primate studies and with recent clinical data. PMID- 22814164 TI - Geo-demographic factors affecting incidence of measles. PMID- 22814163 TI - Gender differences in Kaposi's sarcoma-associated herpesvirus infection in a population with schistosomiasis in rural China. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent of Kaposi's sarcoma (KS), a common cancer in patients with acquired immunodeficiency syndrome. The risk factors for KSHV infection have been extensively studied for Western countries but remain largely undefined for other parts of the world. Schistosomiasis, caused by Schistosoma japonicum infection, was recently identified as a cofactor for KSHV infection in rural Egypt. In this study, we examined the seroprevalence of KSHV in a population along the Yangtze River in China that has a high incidence of schistosomiasis. KSHV seroprevalence in subjects with schistosomiasis was slightly higher than that in subjects without schistosomiasis, but the difference was not statistically significant (8.4% versus 6.6%; P = 0.204). However, after adjusting for gender, KSHV seroprevalence in men with schistosomiasis was found to be significantly higher than that in men without schistosomiasis (8.4% versus 2.8%; odds ratio [OR], 3.170; 95% confidence interval [CI], 1.501-6.694; P = 0.002). Compared to men, women showed significantly higher seroprevalence of KSHV (5.9% versus 9.3%; OR, 1.621; 95% CI, 1.084-2.425; P = 0.019). PMID- 22814165 TI - Occurrence of toxigenic Vibrio cholerae in accessible water sources of cholera endemic foci in India. PMID- 22814166 TI - Log-log plot analysis of hand-foot-mouth disease severity in Beijing, 2009-2010. PMID- 22814167 TI - Molecular analysis of genome of the pandemic influenza A(H1N1) 2009 virus associated with fatal infections in Gunma, Tochigi, Yamagata, and Yamaguchi prefectures in Japan during the first pandemic wave. PMID- 22814168 TI - An outbreak of exanthematous disease due to coxsackievirus A9 in a nursery in Yamagata, Japan, from February to March 2012. PMID- 22814169 TI - Up-regulation of 2-oxoglutarate dehydrogenase as a stress response. AB - 2-Oxoglutarate dehydrogenase multienzyme complex (OGDHC) operates at a metabolic cross-road, mediating Ca(2+)- and ADP-dependent signals in mitochondria. Here, we test our hypothesis that OGDHC plays a major role in the neurotransmitter metabolism and associated stress response. This possibility was assessed using succinyl phosphonate (SP), a highly specific and efficient in vivo inhibitor of OGDHC. Animals exposed to toxicants (SP, ethanol or MnCl(2)), trauma or acute hypoxia showed intrinsic up-regulation of OGDHC in brain and heart. The known mechanism of the SP action as OGDHC inhibitor pointed to the up-regulation triggered by the enzyme impairment. The animal behavior and skeletal muscle or heart performance were tested to correlate physiology with the OGDHC regulation and associated changes in the glutamate and cellular energy status. The SP treated animals exhibited interdependent changes in the brain OGDHC activity, glutamate level and cardiac autonomic balance, suggesting the neurotransmitter role of glutamate to be involved in the changed heart performance. Energy insufficiency after OGDHC inhibition was detectable neither in animals up to 25 mg/kg SP, nor in cell culture during 24 h incubation with 0.1 mM SP. However, in animals subjected to acute ethanol intoxication SP did evoke energy deficit, decreasing muscular strength and locomotion and increasing the narcotic sleep duration. This correlated with the SP-induced decrease in NAD(P)H levels of the ethanol-exposed neurons. Thus, we show the existence of natural mechanisms to up regulate mammalian OGDHC in response to stress, with both the glutamate neurotransmission and energy production potentially involved in the OGDHC impact on physiological performance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 22814170 TI - Different PI 3-kinase inhibitors have distinct effects on endothelial permeability and leukocyte transmigration. AB - Endothelial cells play a central role in inflammatory responses, mediating leukocyte and solute traffic from blood vessels into the tissue, and are therefore key targets for anti-inflammatory therapies. Phosphoinositide 3-kinases (PI3Ks) are important signal transducers in inflammation and cancer, however there are 8 different PI3K catalytic isoforms, several of which have been shown to play distinct roles in cellular responses. Isoform-selective inhibitors have recently been described, but their effects on endothelial cell responses have not been compared. Here we compare the effects of the pan-PI3K inhibitor wortmannin with that of four more isoform-selective inhibitors, PI-103, TGX-221, AS604850 and IC87114, on endothelial cells stimulated with the pro-inflammatory cytokine TNFalpha. We find that PI-103 and wortmannin are most effective at reducing both endothelial permeability and leukocyte transendothelial migration (TEM), which correlates with a decrease in both the activity of the tyrosine kinase Pyk2 and its association with VE-cadherin. PI-103-related compounds are therefore likely to be good candidates for treating chronic inflammatory responses involving TNFalpha. PMID- 22814171 TI - Burst of succinate dehydrogenase and alpha-ketoglutarate dehydrogenase activity in concert with the expression of genes coding for respiratory chain proteins underlies short-term beneficial physiological stress in mitochondria. AB - Conditions for the realization in rats of moderate physiological stress (PHS) (30 120 min) were selected, which preferentially increase adaptive restorative processes without adverse responses typical of harmful stress (HST). The succinate dehydrogenase (SDH) and alpha-ketoglutarate dehydrogenase (KDH) activity and the formation of reactive oxygen species (ROS) in mitochondria were measured in lymphocytes by the cytobiochemical method, which detects the regulation of mitochondria in the organism with high sensitivity. These mitochondrial markers undergo an initial 10-20-fold burst of activity followed by a decrease to a level exceeding the quiescent state 2-3-fold by 120 min of PHS. By 30-60 min, the rise in SDH activity was greater than in KDH activity, while the activity of KDH prevailed over that of SDH by 120 min. The attenuation of SDH hyperactivity during PHS occurs by a mechanism other than oxaloacetate inhibition developed under HST. The dynamics of SDH and KDH activity corresponds to the known physiological replacement of adrenergic regulation by cholinergic during PHS, which is confirmed here by mitochondrial markers because their activity reflects these two types of nerve regulation, respectively. The domination of cholinergic regulation provides the overrestoration of expenditures for activity. In essence, this phenomenon corresponds to the training of the organism. It was first revealed in mitochondria after a single short-time stress episode. The burst of ROS formation was congruous with changes in SDH and KDH activity, as well as in ucp2 and cox3 expression, while the activity of SDH was inversely dependent on the expression of the gene of its catalytic subunit in the spleen. As the SDH activity enhanced, the expression of the succinate receptor decreased with subsequent dramatic rise when the activity was becoming lower. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaption and therapy. PMID- 22814172 TI - Enhanced biofilm formation and/or cell viability by polyamines through stimulation of response regulators UvrY and CpxR in the two-component signal transducing systems, and ribosome recycling factor. AB - We have reported that polyamines increase cell viability at the stationary phase of cell growth through translational stimulation of ribosome modulation factor, and SpoT and RpoZ proteins involved in the synthesis and function of ppGpp in Escherichia coli. Since biofilm formation is also involved in cell viability, we looked for proteins involved in biofilm formation and cell viability whose synthesis is stimulated by polyamines at the level of translation. It was found that the synthesis of response regulators UvrY and CpxR in the two-component signal transducing systems and ribosome recycling factor (RRF) was increased by polyamines at the level of translation. Polyamine stimulation of the synthesis of UvrY and RRF was dependent on the existence of the inefficient initiation codons UUG and GUG in uvrY and frr mRNA, respectively; and polyamine stimulation of CpxR synthesis was dependent on the existence of an unusual location of a Shine Dalgarno (SD) sequence in cpxR mRNA. Biofilm formation and cell viability in the absence of polyamines was increased by transformation of modified uvrY and cpxR genes, and cell viability by modified frr gene whose translation occurs effectively without polyamines. The results indicate that polyamines are necessary for both biofilm formation and cell viability. PMID- 22814173 TI - Concentration-response function for ozone and daily mortality: results from five urban and five rural U.K. populations. AB - BACKGROUND: Short-term exposure to ozone has been associated with increased daily mortality. The shape of the concentration-response relationship-and, in particular, if there is a threshold-is critical for estimating public health impacts. OBJECTIVE: We investigated the concentration-response relationship between daily ozone and mortality in five urban and five rural areas in the United Kingdom from 1993 to 2006. METHODS: We used Poisson regression, controlling for seasonality, temperature, and influenza, to investigate associations between daily maximum 8-hr ozone and daily all-cause mortality, assuming linear, linear-threshold, and spline models for all-year and season specific periods. We examined sensitivity to adjustment for particles (urban areas only) and alternative temperature metrics. RESULTS: In all-year analyses, we found clear evidence for a threshold in the concentration-response relationship between ozone and all-cause mortality in London at 65 ug/m3 [95% confidence interval (CI): 58, 83] but little evidence of a threshold in other urban or rural areas. Combined linear effect estimates for all-cause mortality were comparable for urban and rural areas: 0.48% (95% CI: 0.35, 0.60) and 0.58% (95% CI: 0.36, 0.81) per 10-ug/m3 increase in ozone concentrations, respectively. Seasonal analyses suggested thresholds in both urban and rural areas for effects of ozone during summer months. CONCLUSIONS: Our results suggest that health impacts should be estimated across the whole ambient range of ozone using both threshold and nonthreshold models, and models stratified by season. Evidence of a threshold effect in London but not in other study areas requires further investigation. The public health impacts of exposure to ozone in rural areas should not be overlooked. PMID- 22814174 TI - First report of glucose transporter 1 deficiency syndrome in Korea with a novel splice site mutation. AB - Glucose transporter type 1 deficiency syndrome (Glut-1DS) is caused by autosomal dominant haplodeficiency or autosomal recessive with homozygous mutation of the glucose transporter 1 (SLC2A1) gene and is characterized by severe seizures, developmental delay, ataxia and acquired microcephaly. We describe the first known Korean patient with glucose transporter 1 deficiency syndrome, who had a novel mutation in the splice site. The patient began having intractable seizures at 4 days of age that initially presented as eye blinking and apnea, evolving into generalized tonic seizures. A lumbar puncture revealed low glucose concentration in the cerebrospinal fluid (CSF) in the setting of normoglycemia (blood glucose, 106 mg/dl; CSF glucose 21 mg/dl, and CSF to blood glucose ratio 0.20). The results of a 3-O-methylglucose uptake study in erythrocytes (RBC) revealed that glucose uptake reduced to 48% of his parents in the patient. The patient responded to a ketogenic diet that was initiated at 4 months of age and currently is on the modified Atkins diet (MAD) without seizures. He does not require antiepileptic medication. We diagnosed the first Glut-1 patient in Korea with a novel splice site mutation on the basis of clinical features, deficient glucose uptake and a mutation in the SLC2A1 gene. PMID- 22814175 TI - Expressional and functional variation of horizontally acquired cellulases in the nematode Pristionchus pacificus. AB - Various whole genome-sequencing projects in the nematode phylum have revealed the widespread occurrence of horizontal gene transfer from different sources. Pristionchus pacificus was the first non-plant parasitic nematode that was found to contain cellulase genes in its genome and to have cellulolytic activity when grown in a monoxenic culture on Escherichia coli. The P. pacificus reference strain PS312 has seven cellulase genes, all of which were acquired by horizontal gene transfer. Previous phylogenomic studies indicated that the acquisition occurred at the base of the genus Pristionchus and was followed by rapid gene duplications and gene turnover. However, little was known about the protein domain architecture, gene expression and the functionality of individual proteins. Here, we analyzed the protein domain architecture, studied the expression at various developmentally stages and tried to induce cellulase gene expression by feeding nematodes with different polysaccharides. Only two of the encoded proteins, Ppa-CEL-2 and Ppa-CEL-3, have a carbohydrate-binding module. Interestingly, these were also the ones with developmental gene expression regulation. Ppa-cel-2 shows high expression in larval and adult stages but is only low expressed in eggs, while Ppa-cel-3 is highly upregulated in adult worms but hardly detectable in any other stage. Ppa-CEL-1, has a catalytic domain similar to Ppa-CEL-2 and Ppa-CEL-3, but lacks a carbohydrate-binding module. The other four cellulases have a very low transcriptional expression correlating with putative incompleteness of their catalytic domain. While, the expression of none of the genes is inducible by polysaccharides, zymographic studies and mass spectrometry indicate that Ppa-CEL-2 and Ppa-CEL-3 are the only two cellulases contributing to cellulase activity in carboxymethylcellulose. Thus, the cellulases of P. pacificus differ in their protein domain architecture, gene expression and functionality. These results indicate that horizontal gene transfer-acquired genes undergo rapid evolutionary changes that affect all aspects of their molecular biology. PMID- 22814177 TI - Treatment of haemoptysis in pulmonary atresia with tranexamic acid. AB - We report the case of a young woman with continuing haemoptysis, pulmonary atresia, previous shunt surgery, and pulmonary hypertension. She was not suitable for further surgery or for therapeutic embolisation of bronchial vessels. Treatment with tranexamic acid resolved the haemoptysis. PMID- 22814176 TI - Actin cross-linking domain of Aeromonas hydrophila repeat in toxin A (RtxA) induces host cell rounding and apoptosis. AB - The repeat in toxin (Rtx) of an environmental isolate ATCC 7966 of Aeromonas hydrophila consists of six genes (rtxACHBDE) organized in an operon similar to the gene organization found for the Rtx of the Vibrio species. The first gene in this operon (rtxA) encodes an exotoxin in vibrios, while other genes code for proteins needed for proper activation of RtxA and in secretion of this toxin from Vibrio cholerae. However, the RtxA of ATCC 7966, as well as from the clinical isolate SSU of A. hydrophila, was exclusively expressed and produced during co infection of this pathogen with the host, e.g., HeLa cells, indicating that rtxA gene expression required host cell contact. Within the RtxA, an actin cross linking domain (ACD) exists and to investigate the functionality of this domain, several truncated versions of ACD were generated to discern its minimal biological active region. Such genetically modified genes encoding ACD, which were truncated on either the NH(2) or the COOH terminal, as well as on both ends, were expressed from a bidirectional promoter of the pBI-enhanced green fluorescent protein (EGFP) vector in a HeLa-Tet-Off cell system. We demonstrated that only the full-length ACD of RtxA from A. hydrophila catalyzed the covalent cross-linking of the host cellular actin, whereas the ACD truncated on the NH(2), COOH or both ends did not exhibit such actin cross-linking characteristics. Further, we showed that the full-length ACD of A. hydrophila RtxA disrupted the actin cytoskeleton of HeLa cells, resulting in their rounding phenotype. Finally, our data provided evidence that the full-length ACD of RtxA induced host cell apoptosis. Our study is the first to report that A. hydrophila possesses a functional RtxA having an ACD that contributes to the host cell apoptosis, and hence could represent a potential virulence factor of this emerging human pathogen. PMID- 22814178 TI - The effect of valsartan versus non-RAAS treatment on autoregulation of cerebral blood flow. AB - BACKGROUND: Cerebral autoregulation (CA) is a protective mechanism which maintains the steadiness of the cerebral blood flow (CBF) through a broad range of systemic blood pressure (BP). Acute hypertension has been shown to reduce the cerebrovascular adaptation to BP variations. However, it is still unknown whether CA is impaired in chronic hypertension. This study evaluated whether a strict control of BP affects the CA in patients with chronic hypertension, and compared a valsartan-based regimen to a regimen not inhibiting the renin-angiotensin aldosterone system (non-RAAS). METHODS: Eighty untreated patients with isolated systolic hypertension were randomized to valsartan 320 mg or to a non-RAAS regimen during 6 months. The medication was upgraded to obtain BP <140/90 mm Hg. Continuous recordings of arterial BP and CBF velocity (transcranial Doppler) were performed during periods of 5 minutes, at rest, and at different levels of alveolar CO(2) pressure provided by respiratory maneuvers. The dominant frequency of CBF oscillations was determined for each patient. Dynamic CA was measured as the mean phase shift between BP and CBF by cross-spectral analysis in the medium frequency and in the dominant CBF frequency. RESULTS: Mean ambulatory 24-hour BP fell from 144/87 to 127/79 mm Hg in the valsartan group and from 144/87 to 134/81 mm Hg in the non-RAAS group (p = 0.13). Both groups had a similar reduction in the central BP and in the carotido-femoral pulse wave velocity. The average phase shift between BP fluctuations and CBF response at rest was normal at randomization (1.82 +/- 0.08 s), which is considered a preserved autoregulation and increased to 1.91 +/- 0.12 s at the end of study (p = 0.45). The comparison of both treatments showed no significant difference (-0.01 +/- 0.17 s vs. 0.16 +/ 0.16 s, p = 0.45) for valsartan versus non-RAAS groups. The plasmatic level of glycosylated hemoglobin decreased in the valsartan arm compared to the non-RAAS arm (-0.23 +/- 0.06 vs. -0.08 +/- 0.07%, p = 0.07). CONCLUSIONS: In elderly hypertensive men with isolated chronic systolic hypertension, CA seems efficient at baseline and is not significantly affected by 6 months of BP-lowering treatment. This suggests that the preventive effects of BP medication against stroke are not mediated through a restoration of the CA. PMID- 22814190 TI - Real-time, time-frequency mapping of event-related cortical activation. AB - Functional mapping of eloquent cortex is a common and necessary component of neurosurgical operative planning. Current electrical stimulation-based techniques are inefficient, can evoke seizures and are prone to false-negative results. Here, we present a novel cortical mapping system that extracts event-related neural activity from passive electrocorticographic recordings to quickly and accurately localize sensory and motor cortices using the precise temporal properties of spectral alteration. This procedure generates a robust functional motor and sensory cortical map in seconds, and usually with less than five to ten trial events. Our algorithm demonstrates high concordance with results derived using independent electrical cortical stimulation mapping. PMID- 22814191 TI - Change in total body water as a predictive tool for growth hormone treatment response. AB - BACKGROUND/AIMS: To investigate whether short-term changes in body composition as a result of growth hormone therapy could be used to predict its growth effect after 1 year in children with growth hormone deficiency (GHD) and children born small for gestational age (SGA). METHODS: 88 GHD children and 99 SGA children who started treatment with recombinant human growth hormone were included. Total body water (TBW) and height were measured. After 1 year, patients were divided into adequate and inadequate responders. RESULTS: In GHD and SGA children a sensitivity of 87 and 53%, respectively, and a specificity of 58 and 83%, respectively, were found. The positive predictive values for GHD and SGA children were 73 and 90%, respectively. The negative predictive values were 75 and 32%, respectively. CONCLUSION: Changes in body composition data measured by TBW are a valuable tool to correctly predict 75% of the GHD children and are only useful in SGA children when the change in TBW is above the cut-off value of 0.7 l/m(2). PMID- 22814192 TI - The computational fluid dynamics study of orientation effects of oar-blade. AB - The distribution of pressure coefficient formed when the fluid contacts with the kayak oar blade is not been studied extensively. The CFD technique was employed to calculate pressure coefficient distribution on the front and rear faces of oar blade resulting from the numerical resolution equations of the flow around the oar blade in the steady flow conditions (4 m/s) for three angular orientations of the oar (45 degrees , 90 degrees , 135 degrees ) with main flow. A three dimensional (3D) geometric model of oar blade was modeled and the k-epsilon turbulent model was applied to compute the flow around the oar. The main results reported that, under steady state flow conditions, the drag coefficient (Cd = 2.01 for 4 m/s) at 90 degrees orientation has the similar evolution for the different oar blade orientation to the direction of the flow. This is valid when the orientation of the blade is perpendicular to the direction of the flow. Results indicated that the angle of oar strongly influenced the Cd with maximum values for 90 degrees angle of the oar. Moreover, the distribution of the pressure is different for the internal and external edges depending upon oar angle. Finally, the difference of negative pressure coefficient Cp in the rear side and the positive Cp in the front side, contributes toward propulsive force. The results indicate that CFD can be considered an interesting new approach for pressure coefficient calculation on kayak oar blade. The CFD approach could be a useful tool to evaluate the effects of different blade designs on the oar forces and consequently on the boat propulsion contributing toward the design improvement in future oar models. The dependence of variation of pressure coefficient on the angular position of oar with respect to flow direction gives valuable dynamic information, which can be used during training for kayak competition. PMID- 22814193 TI - Leptin and cognition. AB - BACKGROUND: Leptin has been reported to have positive effects on cognition but has not been studied in a population-based sample or stratified by race or gender. METHODS: Leptin and fat mass were measured in 2,731 subjects, including 50% African Americans. Eight years later, subjects were administered the Montreal Cognitive Assessment (MoCA). Demographic factors and baseline measures, including a deficiency in leptin or levels in excess of what was predicted by fat, were investigated to see which predicted cognitive performance. RESULTS: There was a statistical trend for lower leptin levels to be associated with higher cognitive scores. Once stratified by race and gender, excessive leptin was associated with lower MoCA total scores and delayed recall domain score for black men, but white men demonstrated a reverse relationship. CONCLUSION: Excess leptin appears to have differential effects on delayed recall in black and white men. PMID- 22814194 TI - Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008. AB - BACKGROUND: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. METHODS: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. RESULTS: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). CONCLUSIONS: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly. PMID- 22814195 TI - Measurement of urinary 8-oxo-7,8-dihydro-2-deoxyguanosine in a novel point-of care testing device to assess oxidative stress in children. AB - BACKGROUND: 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), also known as 8-hydroxy 2'-deoxyguanosine (8-OHdG), is an oxidatively damaged nucleobases of DNA and is excreted into urine. Therefore, its urinary level is used as a sensitive marker for oxidative stress (OS). Although it can be measured by enzyme-linked immunosorbent assay (ELISA), its application to clinical pediatrics remains limited. Recently, a novel automatic analyzer (model no. ICR-001: Techno Medica Co., Ltd., Japan) has been developed for point-of-care testing (POCT) to measure urinary 8-oxodG. We verified the reliability of the value of urinary 8-oxodG measured by this novel analyzer and to set the age-related reference intervals. METHOD: We obtained random urine samples from 100 healthy Japanese adults and 157 healthy Japanese children aged 0-15years. Urinary 8-oxodG was determined using two methods: competitive immunochromatography using a novel automatic analyzer (ICR-001) and another was ELISA. RESULTS: Both urinary 8-oxodG and urinary creatinine measured by ICR-001 correlated well with those measured by ELISA (r(s)=0.945, p<0.0001) and an enzymatic method (r(s)=0.988, p<0.0001). Age related reference for 8-oxodG corrected by creatinine were highest in the youngest subjects and decreased until adolescence, consistent with published data by ELISA. CONCLUSION: A new automatic analyzer that measures urinary 8-oxodG can be used as a POCT for the assessment of OS levels in children. PMID- 22814196 TI - Serum vitamin B12 levels as indicators of disease severity and mortality of patients with acute-on-chronic liver failure. AB - BACKGROUND: The study was designed to investigate the association between vitamin B12 levels and patients with acute-on-chronic liver failure (AoCLF). In addition, we analyzed whether B12 is associated with mortality in the AoCLF patients. METHODS: One hundred five patients with AoCLF and 44 healthy controls (HCs) were prospectively studied. In all subjects, a blood sample was collected at admission to examine liver function, renal function, international normalized ratio and B12 levels. A total of 9 clinical chemistry and biochemical variables were analyzed for possible association with outcomes by using Cox proportional hazards and multiple regression models. RESULTS: AoCLF patients had significantly higher B12 levels at admission compared with HCs (AoCLF patients vs HCs, median 1218 pg/ml, mean 1736.2 pg/ml, SD, 1294.6 vs 504 pg/ml, 529.8 +/- 149.8 pg/ml, P<0.001). Elevated B12 levels were associated with increased severity of liver disease and 3-month mortality rate. Multivariate analysis demonstrated that B12 levels and the model for end-stage liver disease score were independent predictors for mortality (both P<0.001). CONCLUSION: B12 levels were significantly higher in AoCLF patients than in HCs and elevated B12 were associated with increased severity of disease. Moreover, B12 levels are an independent predicting factor for the 3-month mortality rate in AoCLF patients. PMID- 22814197 TI - High levels of cerebrospinal fluid free kappa chains predict conversion to multiple sclerosis. AB - BACKGROUND: A clinically isolated syndrome (CIS) may be the initial presentation of multiple sclerosis (MS). However, some CIS never develop MS. The identification of patients at risk of MS conversion is crucial as early treatment may improve their outcome. Free kappa chains (FKC) are increased in cerebrospinal fluid (CSF) of MS patients. We studied the accuracy of CSF FKC level measurement, using a new nephelometric test, to predict conversion of CIS patients to MS. METHODS: We calculated linearity and inter-assay variability of the FKC test for CSF values and quantified this protein in CSF from 25 patients with non inflammatory neurological diseases (NIND) and 78 consecutive CIS patients. We assessed whether high CSF FKC levels associate with CIS conversion to clinically definite MS, defined as the onset of new relapses during follow-up. RESULTS: Between 0.1 and 5mg/l the FKC test showed linearity of 0.98 and inter-assay correlation coefficient of =0.99. A cut-off value of 0.53 mg/l (mean+2SD of NIND group CSF FKC values) was calculated. CIS patients with CSF FKC above this value showed earlier conversion to MS in univariate and multivariate Cox analysis (HR=6.41; 95% CI=1.88-21.78, p=0.003). CONCLUSION: High CSF FKC levels accurately predict CIS patient conversion to MS. PMID- 22814198 TI - Genotoxicity testing of PLGA-PEO nanoparticles in TK6 cells by the comet assay and the cytokinesis-block micronucleus assay. AB - The in vitro genotoxicity of PLGA-PEO (poly-lactic-co-glycolic acid-polyethylene oxide copolymer) nanoparticles was assessed in TK6 cells using the comet assay as well as cytokinesis-block micronucleus (CBMN) assay. The cells were exposed to 0.12-75MUg/cm2 of PLGA-PEO nanoparticles during 2 and 24h for analysis in the comet assay, and to 3-75MUg/cm2 of these nanoparticles during 4, 24, 48 and 72h, respectively, for analysis in the CBMN assay. Two different protocols for treatment with cytochalasin B were used. We found that PLGA-PEO was neither cytotoxic (measured by relative cell growth activity and cytokinesis-block proliferation index (CBPI)), nor did it induce DNA strand-breaks (detected by the comet assay) or oxidative DNA lesions (measured by the comet assay modified with lesion-specific enzyme formamidopyrimidine-DNA-glycosylase). There were no statistically significant differences in the frequencies of micronucleated binucleated cells (MNBNCs) between untreated and treated cells in either of the conditions used. This suggests that PLGA-PEO did not have potential genotoxicity. However, using two experimental protocols of the micronucleus assay, PLGA-PEO nanoparticles showed a weak but significant increase in the level of MN in mononucleated cells, in cells treated for 48h with PLGA-PEO nanoparticles when cytochalasin B was added for the last 24h (1st protocol), and in cells treated for 24h with PLGA-PEO nanoparticles followed by washing of NPs and addition of cytochalasin B for another 24h (2nd protocol). It remains unclear whether the increase of MNMNC after treatment with PLGA-PEO nanoparticles is the effect of a possible, weak aneugenic potential or early effect of these particles, or due to another reason. These results suggest that aneugenicity in addition to clastogenicity may be considered as an important biomarker when assessing the genotoxic potential of polymeric nanoparticles. PMID- 22814199 TI - Integration of critically appraised topics into evidence-based physical therapist practice. AB - SYNOPSIS: Physical therapists frequently encounter situations that require complex differential-diagnosis decisions and the ability to consistently screen for serious pathology that may mimic a musculoskeletal complaint. By applying the evidence-based-practice process to diagnosis, screening, and referral, physical therapists can identify diagnostic and screening strategies that positively influence clinical decisions. A critically appraised topic document (a standard 1 page summary of the literature appraisal and clinical relevance in response to a specific clinical question) is a valuable tool in evidence-based practice. The creation of a critically appraised topic makes the educational process cumulative instead of duplicative, allowing the individual clinician to assimilate and consolidate knowledge after a search effort and improving search and appraisal skills. The purpose of this clinical commentary is as follows: (1) to describe the clinical reasoning process of 3 orthopaedic physical therapists that led to the development of specific clinical questions related to screening for nonmusculoskeletal pathology, (2) to describe the search and triage strategy that led each physical therapist to the current best evidence needed to rule out nonmusculoskeletal pathology in the patient, and (3) to discuss the advantages and disadvantages of a critically appraised topic, the implementation of this process, and the tailoring of search strategies to find diagnostic and screening strategies. PMID- 22814201 TI - Aorta-right atrial tunnel closure using the transcatheter technique: a case of a 3-year-old child. AB - Aorta-right atrial tunnel is a rare congenital defect. If it is not treated, critical complications can occur. Surgical closure is the treatment of choice, but with increasing experience in transcatheter techniques and the introduction of new occluder devices the percutaneous technique is now a successful modality for closure. In this paper, we report the case of a 3-year-old child with aorta right atrial tunnel whose defect was closed with the vascular plug 4 device. PMID- 22814200 TI - Exposure to tobacco smoke in utero and subsequent plasma lipids, ApoB, and CRP among adult women in the MoBa cohort. AB - BACKGROUND: Recent findings suggest that maternal smoking during pregnancy may play a role in the development of metabolic alterations in offspring during childhood. However, whether such exposure increases the risk of developing similar metabolic alterations during adulthood is uncertain. OBJECTIVE: We evaluated the association of in utero exposure to maternal tobacco smoke with plasma lipids, apolipoprotein B (apoB), and C-reactive protein (CRP) in adulthood. METHODS: The study was based on a subsample of the Norwegian Mother and Child Cohort Study (MoBa) and included 479 pregnant women with plasma lipids, apoB, and CRP measurements. Information on in utero exposure to tobacco smoke, personal smoking, and other factors were obtained from the women by a self completed questionnaire at enrollment, at approximately 17 weeks of gestation. RESULTS: Women exposed to tobacco smoke in utero had higher triglycerides [10.7% higher; 95% confidence interval (CI): 3.9, 17.9] and lower high-density lipoprotein cholesterol (HDL) (-1.9 mg/dL; 95% CI: -4.3, 0.5) compared with unexposed women, after adjusting for age, physical activity, education, personal smoking, and current body mass index (BMI). Exposed women were also more likely to have triglycerides >= 200 mg/dL [adjusted odds ratio (aOR) = 2.5; 95% CI: 1.3, 5.1] and HDL < 50 mg/dL (aOR = 2.3; 95% CI: 1.1, 5.0). Low-density lipoprotein cholesterol, total cholesterol, and apoB were not associated with the exposure. CRP was increased among exposed women; however, after adjustment for BMI, the association was completely attenuated. CONCLUSIONS: In this population, in utero exposure to tobacco smoke was associated with high triglycerides and low HDL in adulthood, 18-44 years after exposure. PMID- 22814202 TI - Decompression through tracheobronchial endoscopy of bronchial atresia presenting as massive pulmonary tumor: a new indication for fetoscopic surgery. AB - This is the first report of fetoscopy to successfully treat a case of bilobar bronchial atresia presenting in the form of a massive right lung tumor causing severe thoracic compression with mediastinal shift, pulmonary hypoplasia and eventually fetal hydrops. The presence of an echolucent tubular structure in the pulmonary hilum was identified as the intrapulmonary continuation of the interrupted main bronchus, and led to the diagnosis of main bronchial atresia. After extensive discussion and counseling, a fetoscopic operation was designed and indicated. The procedure consisted of a fetal tracheoscopy and access to the right main bronchus, which was perforated with a diode laser until a communication with the dead end of the intrapulmonary main bronchus was achieved. After the operation a significant reduction in size was observed, hydrops and mediastinal shift disappeared and O/E LHR increased to 85%. The fetus was born at term and lobectomy of two dysplastic pulmonary lobes was performed. The infant is developing well at 14 months of age. This report demonstrates that fetoscopic airway decompression can achieve fetal survival in the rare event of main bronchus atresia. PMID- 22814204 TI - Geometric effect of cell adhesive polygonal micropatterns on neuritogenesis and axon guidance. AB - Recent advances in nano- and micro-technology have made it possible to deliver surface-bound extracellular signaling cues to cultured neurons. In this study, we investigated the formation of neurites and axonal outgrowth using various types of polygonal micropatterns ('micropolygon arrays') on cell culture substrates and suggested a novel design principle of in vitro axon guidance. Ten different types of micropolygons (circle, triangle, square, pentagon, hexagon, stars and isosceles triangles) were printed on a culture substrate using micro-contact printing with a mixture of poly-l-lysine and laminin A chain synthetic peptide. E18 rat hippocampal neurons were cultured on the patterned substrates, and the relation between micropatterns and neurite outgrowth was analyzed. Micropolygon arrays had effects on the soma shape and neurite initiation. In the case of regular triangle patterns, neurons showed vertex preference in terms of neurite initiation: neurites were more frequently generated from the vertex region. In the case of isosceles triangles, a major neurite was formed from the sharpest vertex and axons were developed from the sharpest vertex. Thus, the direction of axon growth could be controlled by the orientation of the sharpest vertex in the isosceles triangles. This work suggests that the geometry of cell adhesive regions influences the development of a cultured neuron, and the structure of neural circuits can be designed by controlling axonal outgrowth with individual micropolygons. PMID- 22814203 TI - Computed tomography findings for intracerebral hemorrhage have little incremental impact on post-stroke mortality prediction model performance. AB - BACKGROUND: Stroke outcome studies often combine cases of intracerebral hemorrhage (ICH) and ischemic stroke (IS). These studies of mixed stroke typically ignore computed tomography (CT) findings for ICH cases, though the impact of omitting these traditional predictors of ICH mortality is unknown. We investigated the incremental impact of ICH CT findings on mortality prediction model performance. METHODS: Cases of ICH and IS (2000-2003) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Base models predicting 30-day mortality included demographics, stroke type, and clinical findings (National Institutes of Health Stroke Scale (NIHSS) +/- Glasgow Coma Scale (GCS)). The impact of adding CT data (volume, intraventricular hemorrhage, infratentorial location) was assessed with the area under the curve (AUC), unweighted sum of squared residuals (S), and integrated discrimination improvement (IDI). The model assessment was performed first for the mixed case of IS and ICH, and then repeated for ICH cases alone to determine whether any lack of improvement in model performance with CT data for mixed stroke type was due to IS cases naturally forming a larger proportion of the total sample than ICH. RESULTS: A total of 1,256 cases were included (86% IS, 14% ICH). Thirty-day mortality was 16% overall (11% for IS; 43% for ICH). When both clinical scales (NIHSS and GCS) were included, none of the model performance measures showed improvement with the addition of CT findings whether considering IS and ICH together (DeltaAUC: 0.002, 95% CI -0.01, 0.02; DeltaS: -3.0, 95% CI -9.1, 2.6; IDI: 0.017, 95% CI -0.004, 0.05) or considering ICH cases alone (DeltaAUC: 0.02, 95% CI -0.02, 0.08; DeltaS: -2.0, 95% CI -9.7, 3.4; IDI 0.065, 95% CI -0.03, 0.21). If NIHSS was the only clinical scale included, there was still no improvement in AUC or S when CT findings were added for the sample with IS/ICH combined (DeltaAUC: 0.005, 95% CI -0.01, 0.02; DeltaS: -5.0, 95% CI -11.6, 1.0) or for ICH cases alone (DeltaAUC: 0.05, 95% CI -0.002, 0.11; DeltaS: -4.2, 95% CI -11.5, 2.3). However, IDI was improved when NIHSS was the only clinical scale for IS/ICH combined (IDI: 0.029, 95% CI 0.002, 0.065) and ICH alone (IDI: 0.12, 95% CI 0.005, 0.26). CONCLUSIONS: Excluding ICH CT findings had only minimal impact on mortality prediction model performance whether examining ICH and IS together or ICH alone. These findings have important implications for the design of clinical studies involving ICH patients. PMID- 22814205 TI - Protective role of metabolism by intestinal microflora in butyl paraben-induced toxicity in HepG2 cell cultures. AB - Parabens are alkyl esters of p-hydroxybenzoic acid (BA), including methyl paraben (MP), ethyl paraben, propyl paraben (PP), and butyl paraben (BP). In the present study, possible role of metabolism by fecalase in BP-induced cytotoxicity was investigated in HepG2 cell cultures. As an intestinal bacterial metabolic system, a human fecalase prepared from human fecal specimen was employed. Among the parabens tested, cytotoxicity of BP was most severe. BA, the de-esterified metabolite, did not induce cytotoxicity when compared to other parabens. When BP was incubated with fecalase, it rapidly disappeared, in association with reduced cytotoxicity in HepG2 cells. In addition, BP incubated with fecalase significantly caused an increase in Bcl-2 expression together with a decrease in Bax expression and cleaved caspase-3. Moreover, anti-apoptotic effect by the incubation of BP with fecalase was also confirmed by the TUNEL assay. Furthermore, BP induced a sustained activation of the phosphorylation of JNK only when it was treated alone. Meanwhile, BP-induced cell death was reversed by the pre-incubation of BP with either fecalase or SP600125. Taken together, the findings suggested that metabolism of BP by human fecalase might have protective effects against BP-induced toxicity in HepG2 cells. PMID- 22814207 TI - Aldosterone induces kidney fibroblast proliferation via activation of growth factor receptors and PI3K/MAPK signalling. AB - BACKGROUND/AIMS: The mineralocorticoid hormone, aldosterone, has pro-fibrotic properties which can cause kidney damage. The severity of kidney interstitial fibrosis is dependent on the accumulation of fibroblasts, which result largely from local proliferation; however, it is unknown whether aldosterone stimulates kidney fibroblast proliferation. Therefore, we examined the effects of aldosterone on the proliferation of cultured kidney fibroblasts. METHODS: Uptake of (3)H-thymidine and cell number quantitation were used to determine the proliferative effects of aldosterone on a rat kidney fibroblast cell line (NRK49F cells) and interstitial fibroblasts extracted from mouse kidneys after unilateral ureter obstruction. The role of different mitogenic signalling pathways in aldosterone-induced proliferation was assessed using specific inhibitors of receptors and kinases. RESULTS: Physiological levels of aldosterone induced a doubling of proliferation of kidney fibroblasts (p < 0.0001), which was inhibited by pre-treatment with the mineralocorticoid receptor antagonist, eplerenone. Aldosterone-induced fibroblast proliferation was dependent upon the kinase activity of growth factor receptors [platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor]. Notably, PDGF ligands were not involved in aldosterone-induced PDGFR activation, indicating receptor transactivation. Aldosterone-induced fibroblast proliferation also required signalling via PI3K, JNK and ERK pathways, but not via the transforming growth factor-beta1 receptor. CONCLUSION: Aldosterone ligation of the mineralocorticoid receptor in kidney fibroblasts results in rapid activation of growth factor receptors and induction of PI3K/MAPK signalling, which stimulates proliferation. This suggests that increased levels of aldosterone during disease may promote the severity of kidney fibrosis by inducing fibroblast proliferation. PMID- 22814208 TI - Impact of beta-amyloid-specific florbetaben PET imaging on confidence in early diagnosis of Alzheimer's disease. AB - BACKGROUND: Early diagnosis of Alzheimer's disease (AD) may be corroborated by imaging of beta-amyloid plaques using positron emission tomography (PET). Here, we performed an add-on questionnaire study to evaluate the relevance of florbetaben imaging (BAY 949172) in diagnosis and consecutive management of probable AD patients. METHODS: AD patients with a clinical diagnosis in accordance with the NINCDS-ADRDA criteria or controls were imaged using florbetaben. Referring physicians were asked on a voluntary basis about their confidence in initial diagnosis, significance of PET imaging results, and their anticipated consequences for future patient care. RESULTS: 121 questionnaires for probable AD patients and 80 questionnaires for controls were evaluated. In 18% of patients who had initially received the diagnosis of probable AD, PET scans were rated negative, whereas in controls 18% of scans were positive. An increase in confidence in the initial diagnosis was frequently reported (80%). Imaging results had a significant impact on the intended patient care, as judged by the referring physicians; this was most prominent in those patients with a contradicting scan and/or a low confidence in the initial diagnosis. CONCLUSION: Florbetaben amyloid imaging increases the overall confidence in diagnosis of AD and may frequently influence clinical decisions and patient management. PMID- 22814209 TI - Lactational exposure to polybrominated diphenyl ethers and its relation to social and emotional development among toddlers. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants and are ubiquitous environmental contaminants. PBDEs have been linked to adverse neurodevelopment in animals and humans. OBJECTIVES: We investigated the association between breast milk PBDE levels and social and emotional development in toddlers. METHODS: The Pregnancy Infection and Nutrition (PIN) and PIN Babies studies followed a cohort of North Carolina pregnant women and their children through 36 months of age. Breast milk samples obtained at 3 months postpartum were analyzed for PBDEs. The Infant-Toddler Social and Emotional Assessment (ITSEA) was completed by mothers when children were approximately 30 months of age (n = 222). We assessed the relationship between breast milk concentrations of five PBDE congeners-BDEs 28, 47, 99, 100, and 153-and children's social and emotional development, adjusting for other factors. RESULTS: A small, imprecise, yet consistent positive association was apparent between BDEs 47, 99, and 100 and increased externalizing behaviors, specifically activity/impulsivity behaviors. Externalizing domain T-scores ranged from 30 to 87 with a mean of 47.8. Compared with those with BDE-47 concentrations below the median, adjusted externalizing behavior domain scores were 1.6 [95% confidence interval (CI): -1.2, 4.4] and 2.8 (95% CI -0.1, 5.7) points higher for children born to women with breast milk concentrations in the 3rd and 4th quartiles, respectively. PBDEs were not associated with other social and emotional developmental domains. CONCLUSIONS: Our results, although imprecise, suggest a subtle association between early-life PBDE exposure and increased activity/impulsivity behaviors in early childhood. Confirmation of these results is needed in other longitudinal studies. PMID- 22814210 TI - Regional brain metabolism and treatment response in panic disorder patients: an [18F]FDG-PET study. AB - BACKGROUND: Panic disorder (PD) is a common and often chronic psychiatric condition that can lead to considerable disability in daily life. Using [(18)F]fluorodeoxyglucose-PET, we examined brain baseline glucose metabolism in PD patients in comparison with normal controls and the changes in glucose metabolism after 12 weeks of escitalopram treatment. METHODS: Fifteen patients with PD were compared to 20 normal controls using [(18)F]FDG-PET at baseline and brain metabolism after 12 weeks of escitalopram treatment was compared to pretreatment in the patient group using voxel-based statistical analysis and post hoc region-of-interest analysis. RESULTS: Patients with PD showed decreased metabolism in both the frontal, right temporal, and left posterior cingulate gyruses. After 12 weeks of escitalopram treatment, treatment responders showed metabolic increases in global neocortical areas as well as limbic areas whereas nonresponders did not. CONCLUSION: Abnormal neocortical function appears to be associated with the pathophysiology of PD and escitalopram exerts its therapeutic action by modulating brain activity at the level of the neocortex and limbic system, notably the amygdala and parahippocampal gyrus. PMID- 22814211 TI - Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors. AB - Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA.CC(50)) was low. PMID- 22814212 TI - Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV. AB - We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56 MUM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections. PMID- 22814213 TI - The Tbx20 homolog Midline represses wingless in conjunction with Groucho during the maintenance of segment polarity. AB - The regulation of the segment polarity gene wingless is essential for the correct patterning of the Drosophila ectoderm. We have previously shown that the asymmetric activation of wingless downstream of Hedghog-signaling depends on the T-box transcription factors, midline and H15. Hedgehog activates wingless anterior to the Hedgehog domain. midline/H15 are responsible in part for repressing wingless in cells posterior to the Hedgehog expressing cells. Here, we show that Midline binds the Groucho co-repressor directly via the engrailed homology-1 domain and requires an intact engrailed-homology-1 domain to repress wingless. In contrast, the regulation of Serrate, a second target of midline repression, is not dependent on the engrailed-homology-1 domain. Furthermore, we identify a midline responsive region of the wingless cis-regulatory region and show that Midline binds to sequences within this region. Mutating these sequences in transgenic reporter constructs results in ectopic reporter expression in the midline-expression domain, consistent with wingless being a direct target of Midline repression. PMID- 22814214 TI - Distribution and clinical features of Paragonimiasis skrjabini in Three Gorges Reservoir Region. AB - Paragonimiasis has previously been reported in the Southwest Provinces of China, including Chongqing and Sichuan. The construction of Three Gorges Dam, which was begun in 1994, has resulted in substantial changes to the depth and the flow pattern of the Yangtze River. To investigate epidemiology of the paragonimiasis, 724 people aged 2-49 years were selected and examined for Paragonimus infection by intradermal test (IDT), and enzyme-linked immunosorbent assay (ELISA). A survey of eating habits was conducted face-to-face in 5 endemic counties. Freshwater crabs were collected from seven sites in the 5 counties to determine the rate of infection with Paragonimus metacercariae. Additionally, we analyzed 213 case reports from the region dated 2006 to 2009. According to the survey results, the prevalence of Paragonimus skrjabini infection in freshwater crab was 39.65%, and the human infection rates detected by IDT and ELISA were 14.36% (104/724) and 7.46% (54/724), respectively. These results show that the Three Gorges Reservoir is still an area of high paragonimiasis endemicity. The water level of the Yangtze River has risen to 175 m, and the area of water coverage in the region has increased to 1084 km(2). These conditions will favor the growth and expansion of the freshwater crab population. PMID- 22814215 TI - Cardiac troponin I after cardiopulmonary bypass in infants in comparison with older children. AB - OBJECTIVE: At the present time, there is a trend towards performing open heart surgery at a younger age. Myocardium of infants has been thought to be more vulnerable to cardiopulmonary bypass in comparison with adults. For this study, we evaluated the degree of myocardial injury by measurement of cardiac troponin levels in infants in comparison with older children for similar surgeries. METHODS: Serum was collected before bypass, after bypass, and daily after surgery and serum cardiac troponin I level (micrograms per litre). The demographic data, cardiac diagnoses, types of surgery performed, and peri-operative parameters were collected. RESULTS: Of the 21 children enrolled consecutively, five were infants. Among the 21 patients, four patients had post-operative peak troponin values greater than 100 (three were infants) and all four patients survived and had normal left ventricular systolic function upon discharge echocardiogram. The five infants had peak troponin levels of 222.3, 202, 129, 26.7, and 82.3. The post operative peak troponin levels were significantly higher in infants (mean 132.5 with a standard deviation of 81.6) than in the older children (mean 40.3 with a standard deviation of 33.4), although there was no significant difference in bypass time, bypass temperature, cross-clamp time, or the length of stay in the intensive care unit between the two age groups. CONCLUSIONS: Higher troponin release is seen in infants in comparison with older children after bypass for similar surgeries. A troponin level greater than 100 after bypass does not necessarily predict death or a severe cardiovascular event in the very young. PMID- 22814217 TI - Raman fingerprint of doping due to metal adsorbates on graphene. AB - The properties of single-layer graphene are strongly affected by metal adsorbates and clusters on graphene. Here, we study the effect of a thin layer of chromium (Cr) and titanium (Ti) metals on chemical vapor deposition (CVD)-grown graphene by using Raman spectroscopy and transport measurements. The Raman spectra and transport measurements show that both Cr and Ti metals affect the structure as well as the electronic properties of the CVD-grown graphene. The shift of peak frequencies, intensities and widths of the Raman bands are analyzed after the deposition of metal films of different thickness on CVD-grown graphene. The shifts in G and 2D peak positions indicate the doping effect of graphene by Cr and Ti metals. While p-type doping was observed for Cr-coated graphene, n-type doping was observed for Ti-coated graphene. The doping effect is also confirmed by measuring the gate voltage dependent resistivity of graphene. We have also found that annealing in Ar atmosphere induces a p-type doping effect on Cr- or Ti coated CVD-grown graphene. PMID- 22814216 TI - Risk factors associated with extended-spectrum beta-lactamase-producing Enterobacteriaceae nosocomial bloodstream infections in a tertiary care hospital: a clinical and molecular analysis. AB - AIM: To describe the risk factors and molecular epidemiology of nosocomial bloodstream infections caused by extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in a tertiary care hospital. METHODS: Patients with enterobacteria-positive blood cultures were included. ESBL expression in the isolates was detected using the combination disk method. Antimicrobial susceptibility testing was performed using the disk diffusion method. bla(SHV), bla(TEM), and bla(CTX-M) genes were identified in the isolated strains by PCR and sequencing. Klebsiella pneumoniae isolates were genotyped by PFGE. RESULTS: Of the 90 isolates recovered, half were found to express ESBLs. Twenty-eight (62%) of these isolates were K. pneumoniae, 8 (18%) were Escherichia coli, 6 (13%) were Enterobacter cloacae, and 3 (7%) were Serratia marcescens. Multivariate logistic regression analysis showed that the only independent risk factor associated with infection by ESBL-producing strains was use of broad-spectrum cephalosporins. None of the isolates was resistant to imipenem. The bla(SHV5) gene was detected in 84% of isolates, followed by bla(CTX-M15) (27%), bla(SHV2) (9%), and bla(SHV12) (7%). PFGE identified six clones among the 28 ESBL-producing K. pneumoniae isolates. CONCLUSIONS: ESBL-producing K. pneumoniae clones were detected throughout the hospital. Use of broad-spectrum cephalosporins is the most important risk factor associated with the proliferation of ESBL-producing strains. PMID- 22814218 TI - Can positive social exchanges buffer the detrimental effects of negative social exchanges? Age and gender differences. AB - BACKGROUND: Findings from existing research exploring whether positive social exchanges can help to offset (or 'buffer' against) the harmful effects of negative social exchanges on mental health have been inconsistent. This could be because the existing research is characterized by different approaches to studying various contexts of 'cross-domain' and 'within-domain' buffering, and/or because the nature of buffering effects varies according to sociodemographic characteristics that underlie different aspects of social network structure and function. OBJECTIVE: The purpose of this study was to examine whether the buffering effects of global perceptions of positive exchanges on the link between global negative exchanges and mental health varied as a function of age and gender. METHOD: We used a series of regressions in a sample of 556 Australian older adults (ages 55-94) to test for three-way interactions among gender, positive social exchanges, and negative social exchanges, as well as age and positive and negative social exchanges, in predicting mental health, controlling for years of education, partner status, and physical functioning. RESULTS: We found that positive exchanges buffered against negative exchanges for younger old adults, but not for older old adults, and for women, but not for men. CONCLUSIONS: Our findings are interpreted in light of research on individual differences in coping responses and interpersonal goals among late middle-aged and older adults. Our findings are in line with gerontological theories (e.g., socioemotional selectivity theory), and imply that an intervention aimed at using positive social exchanges as a means of coping with negative social exchanges might be more successful among particular populations (i.e., women, 'younger' old adults). PMID- 22814219 TI - Rate of force development as an adjunctive outcome measure for return-to-sport decisions after anterior cruciate ligament reconstruction. AB - STUDY DESIGN: Descriptive, prospective, longitudinal single-cohort study. OBJECTIVE: To investigate the rate of force development to 30% (RFD(30)), 50% (RFD(50)), and 90% (RFD(90)) of maximal voluntary isometric contraction (MVIC) as an adjunct outcome measure for determining readiness for return to sport following an anterior cruciate ligament (ACL) reconstruction. BACKGROUND: One criterion of full recovery following an ACL reconstruction is the ability to achieve 85% or 90% of the maximal strength of the contralateral limb. However, the time required to develop muscular strength in many types of daily and sports activities is considerably shorter than that required to achieve maximal strength. Therefore, in addition to maximal strength, neuromuscular functions such as RFD should also be considered in the definition of recovery. METHODS: Forty-five male professional soccer players who underwent an ACL reconstruction were recruited. Assessment with the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Tegner score, and KT1000 instrumented arthrometer was performed postinjury/prereconstruction and at 6 and 12 months after ACL reconstruction. MVIC, RFD(30), RFD(50), and RFD(90) testing was performed preinjury, as part of standard preseason assessment, and at 6 and 12 months post-ACL reconstruction. RESULTS: The average MVIC value 6 months postreconstruction was 97% of the preinjury average value. In contrast, at 6 months, the RFD(30), RFD(50), and RFD(90) values were 80% (P = .04), 77% (P = .03), and 63% (P = .007), respectively, of the preinjury values. The mean RFD values for the reconstructed knee attained or exceeded 90% of the preinjury mean values only at the 12-month post-ACL reconstruction assessment (RFD(30), P = .86; RFD(50), P = .51; RFD(90), P = .56). CONCLUSION: Despite the near recovery of MVIC strength to preinjury levels, there were still significant deficits in RFD at 6 months post-ACL reconstruction. An RFD similar to the preinjury RFD was achieved at 12 months post-ACL reconstruction, following a rehabilitation program focusing on muscle power. These results suggest that, following an ACL reconstruction, RFD criteria may be a useful adjunct outcome measure for the decision to return athletes to sports. J Orthop Sports Phys Ther 2012;42(9):772 780, Epub 19 July 2012. doi:10.2519/jospt.2012.3780. PMID- 22814220 TI - Biophysical and biological investigation of DNA nano-complexes with a non-toxic, biodegradable amine-modified hyperbranched polyester. AB - Designed for gene therapy of chronic diseases, HBP-DEAPA 60 is a non-toxic biodegradable amine modified hyperbranched polyester. This candidate was chosen from a series of hyperbranched polymers for further characterization as it showed the best transfection efficiency and fastest degradation rate. HBP-DEAPA 60/DNA complexes were investigated with regard to stability, uptake and formation to gain a better insight into HBP-DEAPA 60/DNA complex properties. We investigated HBP-DEAPA 60/DNA complex uptake into A 549 cells by FACS and CLSM. Their stability was investigated by a heparin displacement assay as well as by DNAse I assay. Morphology was shown by AFM. HBP-DEAPA 60/DNA complex formation was further characterized in terms of thermodynamic parameters. We studied the conformation of DNA in nano-complexes via circular dichroism (CD) spectroscopy for different NP ratios. Thermodynamic studies showed that binding enthalpies were endothermic; the nano-complex formation was entropically driven. Although PEI/DNA and HBP-DEAPA 60/DNA complexes showed similar behavior with regard to uptake, heparin stability, DNA helicality and their entropically driven complex formation they differ in their binding constant K(a) and in their ability to protect the DNA from DNAse. Concerning K(a) and DNAse stability, HBP-DEAPA/DNA complexes should be further optimized. This shows that different characterization studies are necessary to fully characterize polyplex stability and properties. PMID- 22814221 TI - A propofol microemulsion with low free propofol in the aqueous phase: formulation, physicochemical characterization, stability and pharmacokinetics. AB - The purpose of this study was to develop a propofol microemulsion with a low concentration of free propofol in the aqueous phase. Propofol microemulsions were prepared based on single-factor experiments and orthogonal design. The optimal microemulsion was evaluated for pH, osmolarity, particle size, zeta potential, morphology, free propofol in the aqueous phase, stability, and pharmacokinetics in beagle dogs, and comparisons made with the commercial emulsion, Diprivan((r)). The pH and osmolarity of the microemulsion were similar to those of Diprivan((r)). The average particle size was 22.6+/-0.2 nm, and TEM imaging indicated that the microemulsion particles were spherical in appearance. The concentration of free propofol in the microemulsion was 21.3% lower than that of Diprivan((r)). Storage stability tests suggested that the microemulsion was stable long-term under room temperature conditions. The pharmacokinetic profile for the microemulsion showed rapid distribution and elimination compared to Diprivan((r)). We conclude that the prepared microemulsion may be clinically useful as a potential carrier for propofol delivery. PMID- 22814222 TI - Aerosolized liposomal amphotericin B: prediction of lung deposition, in vitro uptake and cytotoxicity. AB - To predict the efficacy and toxicity of pulmonary administration of liposomal amphotericin B (L-AMB) for the treatment or the prevention of pulmonary invasive aspergillosis, a multistage liquid impinger was used to estimate the concentrations of drug that could be attained in different lung compartments after nebulization. The highest concentration of amphotericin B was found in the alveolar compartment, where it was calculated that the concentration in the lung surfactant could reach 54 MUM or more when 21.6 MUmoles of drug as liposomes was nebulized. The uptake and toxicity of L-AMB were studied in vitro using the A549 human lung epithelial cell line. Uptake was time and concentration-dependent and reached intracellular concentrations exceeding the minimal inhibitory concentrations for most Aspergillus species. The toxicity of L-AMB toward these cells, estimated by the MTT reduction assay, was reduced compared with the conventional form, deoxycholate amphotericin B (D-AMB), with an IC(50) value of about 120 MUM after 24 h of exposure for D-AMB, but only a 13% reduction in viability for 200 MUM L-AMB at 24 h. These results indicate that aerosol therapy with nebulized L-AMB could be efficient but that doses need to be carefully controlled to avoid toxicity. PMID- 22814223 TI - PEGylated-PLGA microparticles containing VEGF for long term drug delivery. AB - The potential of poly(lactic-co-glycolic) acid (PLGA) microparticles as carriers for vascular endothelial growth factor (VEGF) has been demonstrated in a previous study by our group, where we found improved angiogenesis and heart remodeling in a rat myocardial infarction model (Formiga et al., 2010). However, the observed accumulation of macrophages around the injection site suggested that the efficacy of treatment could be reduced due to particle phagocytosis. The aim of the present study was to decrease particle phagocytosis and consequently improve protein delivery using stealth technology. PEGylated microparticles were prepared by the double emulsion solvent evaporation method using TROMS (Total Recirculation One Machine System). Before the uptake studies in monocyte macrophage cells lines (J774 and Raw 264.7), the characterization of the microparticles developed was carried out in terms of particle size, encapsulation efficiency, protein stability, residual poly(vinyl alcohol) (PVA) and in vitro release. Microparticles of suitable size for intramyocardial injection (5 MUm) were obtained by TROMS by varying the composition of the formulation and TROMS conditions with high encapsulation efficiency (70-90%) and minimal residual PVA content (0.5%). Importantly, the bioactivity of the protein was fully preserved. Moreover, PEGylated microparticles released in phosphate buffer 50% of the entrapped protein within 4h, reaching a plateau within the first day of the in vitro study. Finally, the use of PLGA microparticles coated with PEG resulted in significantly decreased uptake of the carriers by macrophages, compared with non PEGylated microparticles, as shown by flow cytometry and fluorescence microscopy. On the basis of these results, we concluded that PEGylated microparticles loaded with VEGF could be used for delivering growth factors in the myocardium. PMID- 22814224 TI - pH sensitive polyelectrolyte complex of O-carboxymethyl chitosan and poly (acrylic acid) cross-linked with calcium for sustained delivery of acid susceptible drugs. AB - The present study investigates the ability of a polyelectrolyte complex, composed of O-carboxymethyl chitosan (O-CMC) and carbopol cross linked with calcium, as a pH-sensitive carrier for acid susceptible drugs. DSC studies were performed to confirm the formation of O-CMC-carbopol complex. Double endothermic peaks in thermogram of polyelectrolyte beads reflect the molecular changes brought in after cross-linking. FT-IR spectroscopy was used to reveal peak variation of the carboxylic groups as a function of pH 1.2 and pH 6.8. The formation of polyelectrolyte complex, on account of electrostatic interactions between the COO(-) group of carbopol and the NH(3)(+) group of O-CMC, was also confirmed by FT-IR studies. Swelling of the O-CMC-carbopol film showed a pH-dependent profile that was affected by calcium ion concentration. The swelling rate was more significant at intestinal pH because the ionization of carboxylic acid group on O CMC and carbopol creates electrostatic repulsion. Release behavior of drug is relative to the viscosity of solution and the ionic interaction between O-CMC and carbopol. Mucous glycoprotein assay revealed that ionization of carboxylic group on the beads at intestinal pH formed a strong hydrogen bond with mucin, which was responsible for the prominent mucoadhesive property thus prolonging the intestinal residence time. PMID- 22814225 TI - Single-pass intestinal perfusion to establish the intestinal permeability of model drugs in mouse. AB - The aim of the present work was to study the intestinal permeabilities (P(eff)) of five model drugs: furosemide, piroxicam, naproxen, ranitidine and amoxicillin in the in situ intestinal perfusion technique in mice and compare them with corresponding rat and human in vivo P(eff) values. The main experimental conditions were: mice CD1 30-35 g, test drug concentrations in perfusion experiments (the highest dose strength dissolved in 250 mL of PBS pH 6.2) and flow rate of 0.2 mL/min. The test compounds were assayed following a validated HPLC method. The effective permeability coefficients at steady-state were calculated after correcting the outlet concentration following the gravimetric correction method proposed by Sutton et al. (2001). The permeability coefficient values ranged from 0.1751+/-0.0756*10(-4) cm/s for ranitidine to 17.19+/-4.16*10( 4) cm/s for naproxen. The mouse method correctly assigned the BCS permeability classification of a given drug and a correlation between mouse permeability data and the fraction of an oral dose absorbed in humans was achieved (FA=1-exp( 34,745.P(eff(mouse))); R=0.9631). Based on the results obtained, we conclude that mouse can be considered a valuable tool in the evaluation of intestinal permeability in order to predict the extent of human gastrointestinal absorption following oral administration of a drug. PMID- 22814226 TI - Exploring the assembly process and properties of novel crosslinker-free hyaluronate-based polyelectrolyte complex nanocarriers. AB - The aim of this work was to study the formulation of pharmaceutically relevant polyelectrolyte complex nanoparticles (NPs) composed of hyaluronic acid (HA) and chitosan (CS) containing no crosslinkers. The influence of polymer mixing ratio, concentration and molecular weight as well as the type of counterion in chitosan salt on properties of the resulting NPs was examined. Formulations and their components were studied by laser light scattering, viscosity, infrared spectroscopy and microscopy. Physical stability, isoelectric points and cytotoxicity of selected NPs were determined. By appropriate modification of HA molecular weight, stable and non-sedimenting NPs were successfully formed. Sonication was found to be an effective method to reduce the molecular weight of HA from 2882+/-25 to 176+/-4 kDa with no chemical changes in the HA structure observed. High molecular weight CS formed micron-sized entities at all compositions investigated. Positively and negatively charged NPs were obtained depending on the mixing ratio of the polymers, with CS glutamate NPs yielding more negatively charged particles compared to CS chloride NPs. The smallest NPs (149+/-11 nm) were formed using HA with molecular weight of 176 kDa. Cytotoxicity of NPs was dependent on environmental pH but HA was found to exert cytoprotective effects on Caco-2 cells. PMID- 22814227 TI - Development of a new LDL-based transport system for hydrophobic/amphiphilic drug delivery to cancer cells. AB - Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol in the vascular system, play a key role in the delivery of hydrophobic/amphiphilic photosensitizers to tumor cells in photodynamic therapy of cancer. To make this delivery system even more efficient, we have constructed a nano-delivery system by coating of LDL surface by dextran. Fluorescence spectroscopy, confocal fluorescence imaging, stopped-flow experiments and flow-cytometry were used to characterize redistribution of hypericin (Hyp), a natural occurring potent photosensitizer, loaded in LDL/dextran complex to free LDL molecules as well as to monitor cellular uptake of Hyp by U87-MG cells. It is shown that the redistribution process of Hyp between LDL molecules is significantly suppressed by dextran coating of LDL surface. The modification of LDL molecules by dextran does not inhibit their recognition by cellular LDL receptors and U-87 MG cellular uptake of Hyp loaded in LDL/dextran complex appears to be similar to that one observed for Hyp transported by unmodified LDL particles. Thus, it is proposed that dextran modified LDL molecules could be used as a basis for construction of a drug transport system for targeted delivery of hydrophobic/amphiphilic drugs to cancer cells expressing high level of LDL receptors. PMID- 22814228 TI - A systematic review and meta-analysis of long-term development of early term infants. AB - BACKGROUND: Births between 37 0/7 and 38 6/7 weeks of gestation are newly defined as early term infants (ETIs), and are increasingly considered to be at higher risk of adverse outcomes than infants born at 39-41 weeks' gestation. To date, the long-term development of ETIs has not been systematically reviewed. OBJECTIVE: To assess the effect of being born early term on long-term developmental outcomes. METHODS: The literature of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, and abstracts from the Society of Pediatric Research were searched. If two or more studies regarding the same outcome were retrieved, a meta-analysis was conducted by RevMan 5. A sensitivity analysis was performed to assess the heterogeneity. RESULTS: Eleven studies involving 4 categories of long-term development were included. Compared with infants born at 39-41 weeks' gestation, ETIs had poorer outcomes in school performance, neurodevelopment, behavior and emotional status and long-term social outcomes. Meta-analyses showed that being born early term significantly increased the risk of cerebral palsy [relative risk, RR, 1.75 (95% confidence interval, CI, 1.32, 2.31)] and mathematical difficulties [RR 1.13 (95% CI 1.04, 1.21)]. The statistical test of heterogeneity for cerebral palsy was significant. Sensitivity analysis demonstrated that variations in follow-up periods were associated with heterogeneity. CONCLUSION: Emerging evidence suggests that ETIs are at risk of adverse long-term outcomes. Due to paucity and heterogeneity of the existing data, future research is needed to clarify the long-term risk of being born early term. PMID- 22814229 TI - Effects of chronic social isolation on Wistar rat behavior and brain plasticity markers. AB - Chronic stress is a contributing risk factor in the development of psychiatric illnesses, including depressive disorders. The mechanisms of their psychopathology are multifaceted and include, besides others, alterations in the brain plasticity. Previously, we investigated the effects of chronic social stress in the limbic brain structures of Wistar rats (hippocampus, HIPPO, and prefrontal cortex, PFC) and found multiple characteristics that resembled alterations described in some clinical studies of depression. We extended our investigations and followed the behavior of stressed animals by the open field test (OFT) and forced swimming test (FST), and the expression and polysialylation of synaptic plasticity markers, neural cell adhesion molecule (NCAM) and L1, in the HIPPO and PFC. We also determined the adrenal gland mass and plasma corticosterone (CORT) as a terminal part of the hypothalamic-pituitary-adrenal axis activity. Our data indicated that stressed animals avoided the central zone in the OFT and displayed decreased swimming, but prolonged immobility in the FST. The animals exhibited marked hypertrophy of the adrenal gland cortex, in spite of decreased serum CORT. Simultaneously, the stressed animals exhibited an increase in NCAM mRNA expression in the HIPPO, but not in the PFC. The synaptosomal NCAM of the HIPPO was markedly polysialylated, while cortical PSA-NCAM was significantly decreased. The results showed that chronic social isolation of Wistar rats causes both anxiety-like and depression-like behavior. These alterations are parallel with molecular changes in the limbic brain, including diminished NCAM sialylation in the PFC. Together with our previous results, the current observations suggest that a chronic social isolation model may potentially be used to study molecular mechanisms that underlie depressive symptomatology. PMID- 22814230 TI - Mechanism and stereoselectivity of HDAC I inhibition by (R)-9-hydroxystearic acid in colon cancer. AB - 9-Hydroxystearic acid (9-HSA) belongs to the endogenous lipid peroxidation by products that decrease in tumors, causing as a consequence the loss of one of the control mechanisms on cell division. It acts as a histone deacetylase (HDAC, E.C 3.5.1.98) inhibitor, and the interaction of the two enantiomers of 9-HSA with the catalytic site of the enzyme, investigated by using a molecular modelling approach, has been reported to be different. In this work we tested out this prediction by synthesizing the two enantiomers (R)-9-HSA (R-9) and (S)-9-HSA (S 9) starting from the natural source methyl dimorphecolate obtained from Dimorphotheca sinuata seeds and investigating their biological activity in HT29 cells. Both enantiomers inhibit the enzymatic activity of HDAC1, HDAC2 and HDAC3, R-9 being more active; R-9 and S-9 inhibitory effect induces an increase in histone H4 acetylation. We also demonstrate that the antiproliferative effect brought about by R-9 is more pronounced as well as we observe increase of p21 transcription and protein content, while the expression of cyclin D1 is decreased. Starting from these observations it can be hypothesized that the interaction of R-9 with HDAC1 induce conformational changes in the enzyme causing loss of its interaction with other proteins, like cyclin D1 itself. PMID- 22814231 TI - Non-formalin fixative versus formalin-fixed tissue: a comparison of histology and RNA quality. AB - Preanalytical handling of tissue samples can influence bioanalyte quality and ultimately outcome of analytical results. The aim of this study was to compare RNA quality, performance in real time RT PCR and histology of formalin-fixed tissue to that of tissue fixed and stabilized with a formalin-free fixative, the PAXgene Tissue System (PAXgene), in an animal model under highly controlled preanalytical conditions. Samples of rat liver, kidney, spleen, intestine, lung, heart muscle, brain, and stomach tissue were either fixed in formalin or fixed in PAXgene or fresh frozen in liquid nitrogen. RNA was extracted from all samples, examined for integrity in microcapillary electrophoresis, and used in a series of quantitative RT PCR assays with increasing amplicon length. Histology of paraffin embedded samples was determined by staining with hematoxylin and eosin. Histology of all formalin-fixed and PAXgene fixed samples was comparable. RNA with acceptable integrity scores could be isolated from all embedded tissues, 4.0 to 7.2 for formalin and 6.4 to 7.7 for PAXgene, as compared to 8.0 to 9.2 for fresh frozen samples. While RNA with acceptable RINs (RNA integrity number) could be isolated from formalin-fixed samples, in microcapillary electrophoresis this RNA separated with a slower migration rate and displayed diffuse, less focused peaks for ribosomal RNA as compared to RNA from frozen or PAXgene fixed samples. Furthermore, RNA from formalin-fixed tissues exhibited inhibition in quantitative RT PCR assays which increased with increasing amplicon length, while RNA from PAXgene fixed samples did not show such inhibition. In conclusion, our results demonstrate that excluding other preanalytical factors, PAXgene Tissue System preserves histology similarly to formalin, but unlike formalin, does not chemically modify RNA. RNA purified from PAXgene fixed tissues is of high integrity and performs as well as RNA from fresh frozen tissue in RT PCR regardless of amplicon length. PMID- 22814232 TI - Cutaneous collagenous vasculopathy: description of two new cases in elderly women and review of the literature. AB - Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy with characteristic histological findings. It was described in 2000, and 9 cases have since been described. Two women of 83 and 74 years consulted for long-standing telangiectasias. In case 1, they affected the limbs and trunk and in case 2 were located on the legs. Biopsies of these lesions showed dilated vascular structures whose walls were thickened due to deposition of eosinophilic hyaline material. The affected vessels were located in the superficial dermis in case 1, and in case 2 the reticular dermis was also affected. CCV is a microangiopathy of unknown etiology. Clinically it is indistinguishable from generalized essential telangiectasia and differs in its histology. CCV may be underdiagnosed, and some nonbiopsied cases of generalized essential telangiectasia may really be CCV. We contribute 2 new cases of this entity to help establish its clinical and epidemiological characteristics and make its etiology better known. PMID- 22814233 TI - Vaccine history: the past as prelude to the future. PMID- 22814234 TI - Xeroprotectants for the stabilization of biomaterials. AB - With the advancement of science and technology, it is crucial to have effective preservation methods for the stable long-term storage of biological material (biomaterials). As an alternative to cryopreservation, various techniques have been developed, which are based on the survival mechanism of anhydrobiotic organisms. In this sense, it has been found that the synthesis of xeroprotectants can effectively stabilize biomaterials in a dry state. The most widely studied xeroprotectant is trehalose, which has excellent properties for the stabilization of certain proteins, bacteria, and biological membranes. There have also been attempts to apply trehalose to the stabilization of eukaryotic cells but without conclusive results. Consequently, a xeroprotectant or method that is useful for the stable drying of a particular biomaterial might not necessarily be suitable for another one. This article provides an overview of recent advances in the use of new techniques to stabilize biomaterials and compare xeroprotectants with other more standard methods. PMID- 22814235 TI - Participant Retention in the Veterans Health Administration's MOVE! Weight management program, 2010. AB - INTRODUCTION: Participant retention is a frequent concern in structured weight management programs. Although research has explored participant characteristics influencing retention, little attention has been given to the influence of program characteristics. The objective of this study was to examine how program characteristics relate to participant retention in the Veterans Health Administration's weight-management program, MOVE! METHODS: We conducted semistructured interviews with coordinators of 12 MOVE! programs located throughout the United States, 5 with high participant retention rates and 7 with low rates. We transcribed and descriptively coded interviews and compared responses from high- and low-retention programs. RESULTS: Characteristics related to retention were provider knowledge of and referral to the program, reputation of the program within the medical facility, the MOVE! meeting schedule, inclusion of physical activity in group meetings, and involvement of the MOVE! physician champion. MOVE! introductory sessions, frequency of group meetings, and meeting topics were not related to retention. Coordinators described efforts to improve retention, including participant contracts and team competitions. Coordinators at 5 high-retention facilities and 1 low-retention facility discussed efforts to improve retention. CONCLUSION: Coordinators identified important program characteristics that could guide improvements to retention in group-based weight management programs. Training for providers is needed to assist with referral decisions, and program planners should consider incorporating physical activity in group meetings. PMID- 22814236 TI - Health care providers' advice to quit smoking, National Health Interview Survey, 2000, 2005, and 2010. AB - Although the prevalence of cigarette smoking has declined in the United States, little documentation exists to ascertain which health care providers (HCPs) promote smoking cessation. We used data from the 2000, 2005, and 2010 Cancer Control Supplement of the National Health Interview Survey to examine changes in the number of adults who received smoking cessation advice from their HCP. The percentage of smokers who received cessation advice was 53.3% in 2000, 58.9% in 2005, and 50.7% in 2010. To affect noticeably declining rates, HCPs should increase their efforts to advise smokers to quit. PMID- 22814237 TI - Small media and client reminders for colorectal cancer screening: current use and gap areas in CDC's Colorectal Cancer Control Program. AB - INTRODUCTION: CDC's Colorectal Cancer Control Program (CRCCP) funds 25 states and 4 tribal organizations to promote and increase colorectal cancer screening population-wide. The CRCCP grantees must use evidence-based strategies from the Guide to Community Preventive Services, including small media and client reminders. METHODS: To assess the existing resources and needs to promote colorectal cancer screening, we conducted 2 web-based surveys of CRCCP grantees and their community partners. Survey 1 sought to identify priority populations, the number and quality of existing colorectal cancer resources for different population subgroups, and the types of small media and client reminder they were most interested in using. Survey 2 assessed screening messages that were used in the past or might be used in the future, needs for non-English-language information, and preferences for screening-related terminology. RESULTS: In survey 1 (n = 125 from 26 CRCCPs), most respondents (83%) indicated they currently had some information resources for promoting screening but were widely dissatisfied with the quality and number of these resources. They reported the greatest need for resources targeting rural populations (62% of respondents), men (53%), and Hispanics (45%). In survey 2 (n = 57 from 25 CRCCPs), respondents indicated they were most likely to promote colorectal cancer screening using messages that emphasized family (95%), role models (85%), or busy lives (83%), and least likely to use messages based on faith (26%), embarrassment (25%), or fear (22%). Nearly all (85%) indicated a need for resources in languages other than English; 16 different languages were mentioned, most commonly Spanish. CONCLUSION: These findings provide the first picture of CRCCP information resources and interests, and point to specific gaps that must be addressed to help increase screening. PMID- 22814238 TI - Effect of casein kinase 1alpha activator pyrvinium pamoate on erythrocyte ion channels. AB - Pharmacological modification of protein kinase CK1 (casein kinase 1) has previously been shown to influence suicidal erythrocyte death or eryptosis, which is triggered by activation of Cl(-)-sensitive Ca(2+)-permeable cation channels. Ca(2+) entering through those channels stimulates cell membrane scrambling and opens Ca(2+)-activated K(+)-channels resulting in KCl exit and thus cell shrinkage. The specific CK1-inhibitor D4476 (1 uM) blunted, whereas the specific CK1 alphaactivator pyrvinium pamoate (10 uM) enhanced cell membrane scrambling. The substances were at least partially effective through modification of cytosolic Ca(2+)-activity. The present study explored, whether pyrvinium pamoate indeed influences Cl(-)-sensitive cation-channels in erythrocytes. As a result, removal of Cl(-)increased Fluo3-fluorescence (reflecting cytosolic Ca(2+) activity), triggered cell membrane scrambling (apparent from annexin-V-binding), and decreased forward scatter (pointing to cell shrinkage). Pyrvinium pamoate significantly augmented the effect of Cl(-)-removal on Fluo3 fluorescence and annexin-V-binding, but blunted the effect on forward scatter. According to whole cell patch clamp recording, Cl(-)removal activated a cation current, which was significantly enhanced by pyrvinium pamoate. Pyrvinium pamoate inhibited Ca(2+) activated K(+)-channels. Ca(2+)-ionophore ionomycin (1 uM) decreased forward scatter, an effect significantly blunted by pyrvinium pamoate. In conclusion, pyrvinium pamoate activates Cl(-)-sensitive Ca(2+)-permeable cation channels with subsequent Ca(2+)-entry and inhibits Ca(2+)-activated K(+)-channels thus blunting the stimulating effect of Ca(2+) on those channels, K(+)-exit and thus cell shrinkage. PMID- 22814239 TI - Red blood cell alterations in systemic sclerosis: a pilot study. AB - AIMS: The aim of this work was to investigate whether systemic oxidative imbalance that occurs in patients with systemic sclerosis affects red blood cell integrity. METHODS: Reactive oxygen species, intracellular content of total thiols and molecules involved in red blood cell aging (e.g., glycophorin A, band 3, CD47 and phosphatidylserine externalization), have been analyzed in erythrocytes from 39 patients with systemic sclerosis and 30 healthy donors by using flow and static cytometry. Analyses were carried out taking into account the two clinical subsets of scleroderma: diffuse cutaneous sclerosis and limited cutaneous sclerosis. RESULTS: A significant reduction (p<0.05) of intracellular total thiols and a significant loss (p<0.01) of glycophorin A, band 3 and CD47 was found in red blood cells from patients with limited cutaneous sclerosis. Conversely, a significant increase (p<0.01) of reactive oxygen species levels and CD47 expression was found in red blood cells from patients with diffuse cutaneous sclerosis. Phosphatidylserine externalization was significantly increased both in patients with limited and diffuse disease. Importantly, this increase was related with disease severity and nailfold capillaroscopy. CONCLUSIONS: Altogether these results suggest a reappraisal of the red blood cells as useful markers in the clinical management of the disease. PMID- 22814240 TI - Induction of programmed erythrocyte death by gambogic acid. AB - Gambogic acid, a xanthone from Garcinia hanburyi, stimulates apoptosis and has thus anticancer potency. Similar to apoptosis of nucleated cells, erythrocytes may undergo apoptosis-like suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Eryptosis could be triggered by increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)), ceramide formation, ATP-depletion and caspase activation. The present study explored, whether gambogic acid triggers eryptosis of human erythrocytes. [Ca(2+)](i )was estimated utilizing Fluo-3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, ceramide abundance utilizing antibodies, and cytosolic ATP with luciferin- luciferase. A 48 h exposure to gambogic acid (500 nM) significantly increased [Ca(2+)](i), stimulated ceramide formation, decreased forward scatter and increased annexin-V binding. Gambogic acid exposure was followed by a slight but significant increase of hemolysis. Gambogic acid did not significantly modify cytosolic ATP concentration. Removal of extracellular Ca(2+) slightly, but significantly blunted the effect of gambogic acid (500 nM) on annexin-V-binding. The present observations disclose a novel effect of gambogic acid, i.e. stimulation of suicidal death of human erythrocytes or eryptosis, paralleled by Ca(2+)-entry, ceramide formation, cell shrinkage and phosphatidylserine-exposure. PMID- 22814241 TI - NADPH oxidase 2-derived reactive oxygen species are involved in dysfunction and apoptosis of pancreatic beta-cells induced by low density lipoprotein. AB - BACKGROUND: Increased levels of plasma cholesterol are a common feature of patient of type 2 diabetes. However, the links between elevated levels of low density lipoprotein (LDL) and dysfunction of beta-cells are still unclear. METHODS: The apoE(-/-)mice were fed with a high-fat, cholesterol-rich diet for 8 weeks. Blood samples were collected from the mice for measurement of plasma glucose, lipids. The pancreas were embedded in OCT compound and frozen immediately in liquid nitrogen for further analysis. To examine the effects of LDL on beta-cell function, insulin content, cell apoptosis and ROS production were measured in pancreatic islets of apoE(-/-)mice and mouse pancreatic beta cell line NIT-1. Relative cell signal pathways were determined by Western blot. RESULTS: Decreased insulin content and increased apoptosis and ROS production were found in pancreatic islets of apoE(-/-)mice, accompanied by elevated plasma LDL. The ROS levels were significantly enhanced in NIT-1 cells exposed to LDL. Reduced insulin synthesis and glucose-stimulated insulin secretion and elevated apoptosis were reversed by suppression of NOX2 expression. Moreover, LDL induced dysfunction and apoptosis of pancreatic NIT-1 cells through JNK and p53 pathways, which were rescued by siRNA-mediated NOX2 reduction. CONCLUSIONS: NOX2-derived ROS may play a key role in LDL-induced dysfunction and apoptosis of pancreatic beta-cells through JNK and p53 pathways. PMID- 22814242 TI - Cellular heat acclimation regulates cell growth, cell morphology, mitogen activated protein kinase activation, and expression of aquaporins in mouse fibroblast cells. AB - The heat shock response has been extensively studied by a number of investigators to understand the molecular mechanism underlying the cellular response to severe heat stress (higher than 42 degrees C). But, body or tissue temperature increases by only a few degrees Celsius during physiological events. Therefore, the physiological cellular response to mild heat stress rather than severe heat stress is likely to be more important. Repeated exposure to hyperthermia for consecutive 5 days induces heat acclimation which is an adaptive physiological process in humans and animals. However, thus far, the effect of continuous exposure to heat stress on cells has not been fully evaluated. In this study, we investigated an adaptive physiological process that is induced in culture cells by continuous exposure to mild heat stress for 5 days. Exposure to heat activated p38-mitogen-activated protein kinase; inhibited cell growth without apoptosis; and increased the levels of HSPs and HSF-1 in mouse fibroblast cells. Interestingly, exposure to heat regulated the expression of aquaporins and induced morphological change. In a physiological sense, these results suggested that continuous exposure to mild heat stress for 5 days, in which heat acclimation is attained in humans and animals, might induce molecular adaptation to heat in cells. PMID- 22814243 TI - Upregulation of Na-coupled glucose transporter SGLT1 by Tau tubulin kinase 2. AB - The Tau-tubulin-kinase 2 (TTBK2) is a serine/threonine kinase expressed in various tissues including tumors. Up-regulation of TTBK2 increases resistance of tumor cells against antiangiogenic treatment and confers cell survival. Tumor cell survival critically depends on cellular uptake of glucose, which is partially accomplished by SGLT1 (SLC5A1) mediated Na(+)-coupled glucose transport. The present study explored whether TTBK2 participates in the regulation of SGLT1 activity. To this end, electrogenic glucose transport was determined in Xenopus oocytes expressing SGLT1 with or without wild-type TTBK2, truncated TTBK2([1-450]) or kinase inactive mutants TTBK2-KD and TTBK2-KD([1 450]). TTBK2, but not TTBK2([1-450]), TTBK2-KD or TTBK2-KD([1-450]), increased membrane carrier protein abundance and electrogenic glucose transport capacity in SGLT1-expressing Xenopus oocytes. Thus TTBK2 is a completely novel regulator of Na(+)-coupled glucose transport. PMID- 22814244 TI - Ballet injuries: injury incidence and severity over 1 year. AB - STUDY DESIGN: Prospective, descriptive single-cohort study. OBJECTIVE: To assess the incidence and severity of injuries to a professional ballet company over 1 year. METHODS: Data for an elite-level ballet company of 52 professional dancers were collected by an in-house medical team using a time-loss injury definition. RESULTS: A total of 355 injuries were recorded, with an overall injury incidence of 4.4 injuries per 1000 hours (female, 4.1; male, 4.8; P>.05) and a mean of 6.8 injuries per dancer (female, 6.3; male, 7.3; P>.05). Mean injury severity was 7 days (female, 4; male, 9; P<.05). Most injuries were classified as overuse (64%; female, 68%; male, 60%; P>.05); mean severity of injury was 3 days for females and 9 days for males (P<.05). The percentage of traumatic injuries was 32% for females and 40% for males (P<.05); the corresponding severity was 6 and 10 days, respectively (P<.05). CONCLUSION: The relatively high number of injuries reported and the resulting loss of dance time support the need to introduce interventions to reduce the risk of injury in professional dancers.J Orthop Sports Phys Ther 2012;42(9):781-790. Epub 19 July 2012. doi:10.2519/jospt.2012.3893. PMID- 22814245 TI - The effects of uni- and bilateral fatigue on postural and power tasks. AB - The aim of this study was to investigate the effects of unilateral and bilateral fatigue on both postural and power bipedal tasks. Ten healthy subjects performed two tasks: bipedal quiet standing and a maximal bipedal countermovement jumping before and after unilateral (with either the dominant or nondominant lower limb) and bilateral (with both lower limbs) fatigue. We employed two force plates (one under each lower limb) to measure the ground reaction forces and center of pressure produced by subjects during the tasks. To quantify the postural sway during quiet standing, we calculated the resultant center of pressure (COP) speed and COP area of sway, as well as the mean weight distribution between lower limbs. To quantify the performance during the countermovement jumping, we calculated the jump height and the peak force of each lower limb. We observed that both unilateral and bilateral fatigue affected the performance of maximal voluntary jumping and standing tasks and that the effects of unilateral and bilateral fatigue were stronger in the dominant limb than in the nondominant limb during bipedal tasks. We conclude that unilateral neuromuscular fatigue affects both postural and power tasks negatively. PMID- 22814246 TI - Charge fractionalization in biased bilayer graphene. AB - Fractional charge may arise when fermionic zero modes exist in a topological background field. In biased bilayer graphene (BBLG), the bias plays the role of the nontrivial background field. When semi-infinite BBLG with a zigzag edge is used, the dynamics induces an odd number of zero-energy modes, which, together with the conjugation symmetry between positive- and negative-energy states, are the requisite conditions for fractionalization. Exploiting the trigonal interaction to isolate a given zero-energy mode on the zigzag edge, we consider extended and localized modes (the latter being obtained from a localized wavepacket generated by prior irradiation of the sample with an electromagnetic vortex). The valley degeneracy is lifted by a layer asymmetry, while an edge induced spin polarization breaks the spin degeneracy. We describe scenarios for the detection of charge-1/2 edge states. PMID- 22814247 TI - Motor symptoms and schizophrenia. AB - Classical schizophrenia literature reports motor symptoms as characteristic of the disorder. After the introduction of neuroleptic drugs, the existence of genuine motor disorders was challenged. Renewed interest arose as symptoms were found in never-medicated patients. Reports focused on abnormal involuntary movements, parkinsonism, neurological soft signs, catatonia, negative symptoms, or psychomotor slowing. Since these syndromes refer to different concepts, however, the definitions are not congruent and the symptoms overlap. The prevalence rates of motor symptoms in schizophrenia are surprisingly high, and recent studies indicate a possible pathobiology. In particular, the development and maturation of the human motor system appears to be closely linked to the emergence of motor symptoms observed in schizophrenia. Post-mortem and neuroimaging results demonstrated aberrant structure and function of premotor and motor cortices, basal ganglia, thalamus, and the connecting white matter tracts. Animal models have focused on aberrant neurotransmission and genetic contributions. Findings of localized abnormal oligodendrocyte function and myelination point to the special role of the white matter in schizophrenia, and recent studies specifically found an association between motor abnormalities and white matter structure in schizophrenia. This review of the literature supports the idea that motor symptoms are closely related to the neurodevelopmental disturbances of schizophrenia and a distinct syndromal dimension with its own pathophysiology. PMID- 22814248 TI - Inhibitory effects of human immunodeficiency virus gp120 and Tat on CpG-A-induced inflammatory cytokines in plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs), not only inhibit viral replication, but also play an essential role in linking the innate and adaptive immune system. In this study, we explored the effects of human immunodeficiency virus (HIV) gp120 and tat on CpG-A-induced inflammatory cytokines in pDCs. The results provided fundamental insights into HIV pathogenesis that may hold promise for preventative and even curative strategies. pDCs were isolated using blood DC antigen 4 (BDCA 4) DC isolation kit, and the purity was analyzed using BDCA-2 antibody by flow cytometry. pDCs and peripheral blood mononuclear cells (PBMCs) were stimulated by either CpG-A (5 ug/ml), gp120 (0.5 ug/ml), tat (0.5 ug/ml), or CpG-A treatment combined with gp120 or tat. The production of type I interferons (IFNs) and other inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interlukine-6 (IL-6), and interferon-gamma-inducible protein-10 (IP-10) in the culture supernatant, was determined by enzyme-linked immunosorbent assay. The results showed that CpG-A induced high levels of type I IFNs and other inflammatory cytokines, including TNF-alpha, IL-6, and IP-10, in pDCs. Concomitant treatment with gp120 reduced the levels of IFN-alpha, IFN-beta, TNF alpha, IL-6, and IP-10 induced by CpG-A in pDCs by 79%, 53%, 60%, 50%, and 34%, respectively, while tat suppressed them by 88%, 66%, 71%, 64%, and 53%, respectively. Similar results were demonstrated in CpG-A-treated PBMCs. In conclusion, gp120 and tat are effective inhibitors of the CpG-A-mediated induction of type I IFNs and other inflammatory cytokines from pDCs and PBMCs. PMID- 22814249 TI - A proteomics study of auxin effects in Arabidopsis thaliana. AB - Many phytohormones regulate plant growth and development through modulating protein degradation. In this study, a proteome study based on multidimensional non-gel shotgun approach was performed to analyze the auxin-induced protein degradation via ubiquitin-proteasome pathway of Arabidopsis thaliana, with the emphasis to study the overall protein changes after auxin treatment (1 nM or 1 uM indole-3-acetic acid for 6, 12, or 24 h). More than a thousand proteins were detected by using label-free shotgun method, and 386 increased proteins and 370 decreased ones were identified after indole-3-acetic acid treatment. By using the auxin receptor-deficient mutant, tir1-1, as control, comparative analysis revealed that 69 and 79 proteins were significantly decreased and increased, respectively. Detailed analysis showed that among the altered proteins, some were previously reported to be associated with auxin regulation and others are potentially involved in mediating the auxin effects on specific cellular and physiological processes by regulating photosynthesis, chloroplast development, cytoskeleton, and intracellular signaling. Our results demonstrated that label free shotgun proteomics is a powerful tool for large-scale protein identification and the analysis of the proteomic profiling of auxin-regulated biological processes will provide informative clues of underlying mechanisms of auxin effects. These results will help to expand the understanding of how auxin regulates plant growth and development via protein degradation. PMID- 22814250 TI - Correlation between early subjective response to antipsychotics and the number of hospitalizations and hospitalization days in a period of 10-11 years in schizophrenia patients. AB - INTRODUCTION: Research into the significance of early subjective response to antipsychotic medication has so far only involved observation periods of up to 1 year. METHOD: The Drug Attitude Inventory (DAI-10) questionnaires, completed by patients with the diagnosis of schizophrenia in 1997-1998, were the bases for this study. In 2009, data on 36 patients (18 women and 18 men) with 10-11 years of follow-up information were found whose completed DAI questionnaires were on record in the hospital register. The data included the number of hospitalizations, which enabled to calculate the total number of days spent in hospital for each patient. Statistical analysis examined possible correlations between the DAI scale results and the number of hospitalizations in 1997/1998 2009 and the number of days spent in the hospital during that period of time. RESULTS: The total number of hospitalizations in the period of 11-12 years has shown no correlations with the results of the DAI-10 scale (p = 0.23). However, the number of days spent in hospital in the period of observation has shown a reverse correlation between the results of the DAI-10 scale in 1997-1998 and the number of days spent in hospital (p = 0.037). The higher the result of the DAI-10 scale was in 1997-1998 (indicating the absence of a dysphoric response to antipsychotic medications), the fewer days of hospitalization were found in the researched period. CONCLUSIONS: Early subjective response to antipsychotic drugs shows a relation to the number of days spent in hospital in the period of observation over 10 years. The data suggest that an early dysphoric response to antipsychotic medications is associated with more days spent in the hospital during subsequent years. PMID- 22814251 TI - Nucleolar exit of RNF8 and BRCA1 in response to DNA damage. AB - The induction of DNA double-strand breaks (DSBs) elicits a plethora of responses that redirect many cellular functions to the vital task of repairing the injury, collectively known as the DNA damage response (DDR). We have found that, in the absence of DNA damage, the DSB repair factors RNF8 and BRCA1 are associated with the nucleolus. Shortly after exposure of cells to gamma-radiation, RNF8 and BRCA1 translocated from the nucleolus to damage foci, a traffic that was reverted several hours after the damage. RNF8 interacted through its FHA domain with the ribosomal protein RPSA, and knockdown of RPSA caused a depletion of nucleolar RNF8 and BRCA1, suggesting that the interaction of RNF8 with RPSA is critical for the nucleolar localization of these DDR factors. Knockdown of RPSA or RNF8 impaired bulk protein translation, as did gamma-irradiation, the latter being partially countered by overexpression of exogenous RNF8. Our results suggest that RNF8 and BRCA1 are anchored to the nucleolus through reversible interactions with RPSA and that, in addition to its known functions in DDR, RNF8 may play a role in protein synthesis, possibly linking the nucleolar exit of this factor to the attenuation of protein synthesis in response to DNA damage. PMID- 22814252 TI - Dystroglycan is associated to the disulfide isomerase ERp57. AB - Dystroglycan (DG) is an extracellular receptor composed of two subunits, alpha-DG and beta-DG, connected through the alpha-DG C-terminal domain and the beta-DG N terminal domain. We report an alanine scanning of all DG cysteine residues performed on DG-GFP constructs overexpressed in 293-Ebna cells, demonstrating that Cys-669 and Cys-713, both located within the beta-DG N-terminal domain, are key residues for the DG precursor cleavage and trafficking, but not for the interaction between the two DG subunits. In addition, we have used immunprecipitation and confocal microscopy showing that ERp57, a member of the disulfide isomerase family involved in glycoprotein folding, is associated and colocalizes immunohistochemically with beta-DG in the ER and at the plasma membrane of 293-Ebna cells. The beta-DG-ERp57 complex also included alpha-DG. DG mutants, unable to undergo the precursor cleavage, were still associated to ERp57. beta-DG and ERp57 were also co-immunoprecipitated in rat heart and kidney tissues. In vitro, a mutant ERp57, mimicking the reduced form of the wild-type protein, interacts directly with the recombinant N-terminal domain of both alpha DG and beta-DG with apparent dissociation constant values in the micromolar range. ERp57 is likely to be involved in the DG processing/maturation pathway, but its association to the mature DG complex might also suggest some further functional role that needs to be investigated. PMID- 22814254 TI - The type of DUOX-dependent ROS production is dictated by defined sequences in DUOXA. AB - A deliberate generation of ROS is now recognized to be achieved by specific NADPH oxidases (NOX). Dual oxidases (DUOXs) are Ca(2+)-activated NOXs and operate as H(2)O(2)-generators in various tissues. A tight regulation is however required to avoid ROS overproduction that can rapidly be harmful to biological systems. DUOX activator (DUOXA) proteins act as organizing elements for surface expression and activity of the DUOX enzymes. To study DUOX activation by the maturation factors, chimeric DUOXA proteins were generated by replacing particular domains between DUOXA1 and DUOXA2. Their impact on DUOX function and membrane expression were explored in a reconstituted heterologous cell system composed of COS-7 cells. We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1 dependent H(2)O(2) generation. The NH(2)-terminal tail of DUOXA2 is critical to specify the type of ROS released by DUOX2, hydrogen peroxide or superoxide. Native DUOXA2 would constrain DUOX2 to produce H(2)O(2). However, alterations of the DUOXA2 NH(2)-terminal domain modify DUOX2 activity triggering superoxide leaking. Our results demonstrate that specific domains of the DUOX maturation factors promote the activation of DUOXs as well as the type of ROS generated by the oxidases. PMID- 22814253 TI - The neurogenic basic helix-loop-helix transcription factor NeuroD6 enhances mitochondrial biogenesis and bioenergetics to confer tolerance of neuronal PC12 NeuroD6 cells to the mitochondrial stressor rotenone. AB - The fundamental question of how and which neuronal specific transcription factors tailor mitochondrial biogenesis and bioenergetics to the need of developing neuronal cells has remained largely unexplored. In this study, we report that the neurogenic basic helix-loop-helix transcription factor NeuroD6 possesses mitochondrial biogenic properties by amplifying the mitochondrial DNA content and TFAM expression levels, a key regulator for mitochondrial biogenesis. NeuroD6 mediated increase in mitochondrial biogenesis in the neuronal progenitor-like PC12-NEUROD6 cells is concomitant with enhanced mitochondrial bioenergetic functions, including increased expression levels of specific subunits of respiratory complexes of the electron transport chain, elevated mitochondrial membrane potential and ATP levels produced by oxidative phosphorylation. Thus, NeuroD6 augments the bioenergetic capacity of PC12-NEUROD6 cells to generate an energetic reserve, which confers tolerance to the mitochondrial stressor, rotenone. We found that NeuroD6 induces an adaptive bioenergetic response throughout rotenone treatment involving maintenance of the mitochondrial membrane potential and ATP levels in conjunction with preservation of the actin network. In conclusion, our results support the concept that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronal differentiation with acquisition of adequate mitochondrial mass and energetic capacity to ensure energy demanding events, such as cytoskeletal remodeling, plasmalemmal expansion, and growth cone formation. PMID- 22814255 TI - Overexpression of lumican affects the migration of human colon cancer cells through up-regulation of gelsolin and filamentous actin reorganization. AB - Cell migration is a multistep process initiated by extracellular matrix components that leads to cytoskeletal changes and formation of different protrusive structures at the cell periphery. Lumican, a small extracellular matrix leucine-rich proteoglycan, has been shown to inhibit human melanoma cell migration by binding to alpha2beta1 integrin and affecting actin cytoskeleton organization. The aim of this study was to determine the effect of lumican overexpression on the migration ability of human colon adenocarcinoma LS180 cells. The cells stably transfected with plasmid containing lumican cDNA were characterized by the increased chemotactic migration measured on Transwell filters. Lumican-overexpressing cells presented the elevated filamentous to monomeric actin ratio and gelsolin up-regulation. This was accompanied by a distinct cytoskeletal actin rearrangement and gelsolin subcellular relocation, as observed under laser scaning confocal microscope. Moreover, LS180 cells overexpressing lumican tend to form podosome-like structures as indicated by vinculin redistribution and its colocalization with gelsolin and actin at the submembrane region of the cells. In conclusion, the elevated level of lumican secretion to extracellular space leads to actin cytoskeletal remodeling followed by an increase in migration capacity of human colon LS180 cells. These data suggest that lumican expression and its presence in ECM has an impact on colon cancer cells motility and may modulate invasiveness of colon cancer. PMID- 22814256 TI - Atorvastatin and simvastatin, but not pravastatin, up-regulate LPS-induced MMP-9 expression in macrophages by regulating phosphorylation of ERK and CREB. AB - Statins suppress expression of pro-inflammatory cytokines in endothelial cells, whereas they enhance it in immune cells. Pro-inflammatory cytokines and lipopolysaccharide (LPS) induce matrix metalloproteinase (MMP)-9 gene expression in macrophages, which has been linked to progress of various inflammatory diseases. The aim of this study was to identify effects of various statins on LPS induced MMP-9 gene expression in macrophages and microglia. MMP-9 expression was analyzed by real-time PCR or zymography. Effect of statins on activation of signaling pathways was analyzed by time-dependent phosphorylation of signaling molecules. Atorvastatin and simvastatin, but not pravastatin, up-regulated LPS induced MMP-9 expression in murine RAW 264.7 macrophages and BV2 microglia. The phosphorylation duration of extracellular signal regulated kinases was extended by simvastatin, but not by atorvastatin or pravastatin. The up-regulation of LPS induced MMP-9 gene expression by the statins was dependent on extracellular calcium ions and mediated by enhancing phosphorylation of cAMP-responsive element binding protein. Geranylgeranyl pyrophosphate, a precursor for cholesterol synthesis, could suppress up-regulation of LPS-mediated MMP-9 gene expression by atorvastatin and simvastatin. Atorvastatin and simvastatin-mediated up-regulation of LPS-induced MMP-9 gene expression in macrophages and microglia in vitro raises an important concern about use of the widely-prescribed statins in certain inflammatory conditions that are mediated by LPS. PMID- 22814257 TI - [EGFR-dependent impact of indol-3-carbinol on radiosensitivity of lung cancer cells]. AB - BACKGROUND: Indole-3-carbinol (I3C) is a naturally occurring phytochemical found in cruciferous vegetables. The aim of the present study is to investigate the influence of I3C on radiosensitivity in epidermal growth factor receptor (EGFR) positive and EGFR-negative lung cancer cell lines. METHODS: Human lung adenocarcinoma NIH-H1975 cells and human lung squamous carcinoma NIH-H226 and NIH H520 cells were routinely cultured in RPMI-1640. MTT assay and clonogenic assay were used to detect cell growth and survival, respectively. Western blot and RT PRC assay was employed to detect EGFR protein and mRNA expression. RESULTS: 5 MUmol/L of I3C significantly reduced radiosensitivity of EGFR-positive NIH-H1975 and NIH-H226 cells, but failed to affect radiosensitivity of EGFR-negative NIH H520 cells. Furthermore, I3C caused an increased expression of total EGFR and pEGFR (Y845) protein in NIH-H1975 and NIH-H226 cell lines, but not in NIH-H520 cell line. A reduction of EGFR expression by EGFR-siRNA significantly inhibited I3C-caused radioresistance in NIH-H1975 cells. CONCLUSIONS: Our data presented here for the first time demonstrate that I3C reduces radiosensitivity of lung cancer cells by mediating EGFR expression, indicating that EGFR may be an important target for I3C-mediated radioresistance in lung cancer. PMID- 22814258 TI - [Prognostic value of MACC1 and c-met expressions in non-small cell lung cancer]. AB - BACKGROUND: It has been proven that metastasis-associated in colon cancer 1 (MACC1) is a new gene that is related to the invasion and metastasis of tumors. MACC1 also regulates c-met expression. The aim of this study is to explore the expressions of MACC1 and hepatocyte growth factor receptor (c-met), and its relationship with invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC). METHODS: MACC1 and c-met expressions were detected in 103 cases of NSCLC and 40 cases of neighboring normal lung cancer tissue using immunohistochemistry. RESULTS: MACC1 and c-met expressions were significantly higher in lung cancer tissues than that in neighboring normal tissue (P<0.001). MACC1 and c-met expressions were associated with poor differentiation, advanced T stages, lymph node metastasis, and advanced TNM stages (P<0.05) of NSCLC, but not with sex, age, smoking, and histological classification (P>0.05). In addition, a positive correlation between MACC1 and c-met expressions was observed (r=0.403, P<0.001). The result from the Kaplan-Meier survival analysis showed that the five year survival rate in patients with positive MACC1 and c-met expressions was remarkanly lower than that in patients with negative expressions (P<0.05). The result from the Cox regression analysis showed that MACC1 expression was an independent prognostic factor for NSCLC (P=0.026). CONCLUSIONS: MACC1 and c-met have an important function in the differentiation, invasion, and metastasis of NSCLC. MACC1 and c-met have poor prognosis in patients with NSCLC. Moreover, MACC1 expression is an independent prognostic factor for NSCLC. PMID- 22814259 TI - [Correlation of aquaporin 3 expression with the clinicopathologic characteristics of non-small cell lung cancer]. AB - BACKGROUND: Lung cancer is a major health problem worldwide. The aim of this study is to investigate aquaporin 3 (AQP3) expression and its relationship with the clinicopathologic characteristics of non-small cell lung cancer (NSCLC). METHODS: AQP3 expression and the microvascular density (MVD) of tissue samples from 180 cases with NSCLC were detected by immunohistochemistry. RESULTS: AQP3 expression was negative in 25 (13.9%), positive in 67 (37.2%), and strongly positive in 88 (48.9%) of the 180 cases, which was significantly higher than that in the normal tissue (P<0.01). A significant correlation was found between AQP3 expression and MVD (P<0.01), whereas a high MVD was found among patients with strongly positive AQP3 expression. Male patients with positive or strongly positive AQP3 expression had significantly higher expression than female patients did (P=0.003). AQP3 expression was more significantly enhanced in adenocarcinoma than that in squamous cell carcinoma (P<0.001). Statistical analysis indicated that the positive rate of AQP3 expression in well-differentiated carcinoma was significantly higher than that in poorly differentiated tumors (P<0.001). Lymph node metastasis was positively correlated with high AQP3 expression (P=0.026). CONCLUSIONS: AQP3 expression was closely correlated with MVD in NSCLC, whereas high MVD was frequently found in tumors with high AQP3 expression. AQP3, as a therapeutic target for inhibiting high AQP3 expression in NSCLC tissues, may weaken cancer cell proliferation, invasion, and metastasis. PMID- 22814260 TI - [Survival and its influencing factors of the lung cancer patients with hospice service]. AB - BACKGROUND: Survival and the quality of life more comprehensively evaluates the survival conditions of cancer patients. This paper aims to analyze the survival time and quality of life (QOL) of hospice lung cancer patients and discusses the influencing factors to provide a basis for ameliorating their survival conditions. METHODS: Advanced lung cancer patients who are receiving hospice care in the Shengjing Hospital were retrospectively analyzed and followed-up. The data were analyzed using SPSS 13.0. The median survival of patients was determined using the Kaplan-Meier method, and their QOL were evaluated using the tumor patient's QOL scale. Finally, the relationship between the survival index and the various factors were determined. RESULTS: For 269 patients, the average QOL score was 28.76 and the median survival was 10 months. Awareness of their illness, pain relief, Karnofsky performance status (KPS) score, and nutritional status are the independent factors of QOL. Surgery, time of the occurrence of pain, pain relief, and KPS score are the independent factors of survival time. CONCLUSIONS: The survival of patients with advanced cancer is poor; hence, we should strengthen and improve hospice care in terms of the influencing factors to enhance the QOL of patients and prolong their survival. PMID- 22814261 TI - [Screening key genes associated with the development and progression of non-small cell lung cancer based on gene-enrichment analysis and meta-analysis]. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors; however, its causes are still not completely understood. This study was designed to screen the key genes and pathways related to NSCLC occurrence and development and to establish the scientific foundation for the genetic mechanisms and targeted therapy of NSCLC. METHODS: Both gene set enrichment analysis (GSEA) and meta-analysis (meta) were used to screen the critical pathways and genes that might be corretacted with the development and progression of lung cancer at the transcription level. RESULTS: Using the GSEA and meta methods, focal adhesion and regulation of actin cytoskeleton were determined to be the more prominent overlapping significant pathways. In the focal adhesion pathway, 31 genes were statistically significant (P<0.05), whereas in the regulation of actin cytoskeleton pathway, 32 genes were statistically significant (P<0.05). CONCLUSIONS: The focal adhesion and the regulation of actin cytoskeleton pathways might play important roles in the occurrence and development of NSCLC. Further studies are needed to determine the biological function for the positive genes. PMID- 22814262 TI - [Comparison of short-term effect of video-assisted thoracoscopic surgery lobectomy and thoracotomy lobectomy in the treatment of non-small cell lung cancer: a systematic review]. AB - BACKGROUND: Lung cancer is a common malignant tumor. The aim of this study is to assess the short-term effect of video-assisted thoracoscopic surgery lobectomy and thoracotomy lobectomy in the treatment of non-small cell lung cancer. METHODS: Cochrane Library, Embase, Pubmed, CBM, CNKI, VIP, and so on, were searched by computer. Randomized controlled trials comparing video-assisted thoracoscopic surgery lobectomy and thoracotomy lobectomy in the treatment of non small cell lung cancer were collected. Two reviewers independently assessed the quality of included studies and extracted data. We analyzed the data using Review Manager (Version 5.0). RESULTS: Five randomized controlled trials totaling 537 patients were included. The results of meta analysis were as follows: statistically significant difference was found in operating time (SMD=0.27, 95%CI: 0.10-0.44), chest tube drainage flow (SMD=-0.23, 95%CI: -0.45--0.01), postoperative hospital stay (SMD=-0.25, 95%CI: -0.46--0.05), and postoperative complications (SMD=0.51, 95%CI: 0.32-0.80). No statistically significant difference was found in the harvested lymph nodes (SMD=-0.01, 95%CI: -0.22-0.19) between video-assisted thoracoscopic surgery lobectomy and thoracotomy lobectomy in the treatment of non-small cell lung cancer. CONCLUSIONS: Compared with thoracotomy lobectomy in the treatment of non-small cell lung cancer, the amount of harvested lymph nodes was almost the same, but the amount of blood loss, operating time, chest tube drainage flow, and postoperative hospital stay were different. PMID- 22814263 TI - Lung cancer: microRNA and target database. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs that hybridize to mRNAs and induce either translation repression or mRNA cleavage. Recently, it has been reported that miRNAs could possibly play a critical role in cellular processes like regulation of cell growth, differentiation, and apoptosis, emphasizing their role in tumorigenesis. Likewise, several miRNA's are involved in lung cancer tumorigenesis. The present review puts forth a database of human miRNA's involved in lung cancer along with their target genes. It also provides sequences of miRNA's and their chromosomal locations retrieved from different databases like microCosm (218 microRNAs), PhenomiR (293 microRNAs), and mir2Disease (90 microRNAs) and target gene information such as the pathways like cell cycle regulation, angiogenesis, apoptosis etc. Though miRNA's are still to be explored, they hold a promise as therapeutic targets and diagnostic markers of cancer. PMID- 22814264 TI - [Progress of related targets in LKB1 signaling pathway for non-small cell lung cancer therapy]. PMID- 22814265 TI - [Protein kinase CK2 and human malignant tumors]. PMID- 22814266 TI - [Malignant peripheral nerve sheath tumor of the left lung: a case report]. PMID- 22814267 TI - Expansion of transducin subunit gene families in early vertebrate tetraploidizations. AB - Hundreds of gene families expanded in the early vertebrate tetraploidizations including many gene families in the phototransduction cascade. We have investigated the evolution of the heterotrimeric G-proteins of photoreceptors, the transducins, in relation to these events using both phylogenetic analyses and synteny comparisons. Three alpha subunit genes were identified in amniotes and the coelacanth, GNAT1-3; two of these were identified in amphibians and teleost fish, GNAT1 and GNAT2. Most tetrapods have four beta genes, GNB1-4, and teleosts have additional duplicates. Finally, three gamma genes were identified in mammals, GNGT1, GNG11 and GNGT2. Of these, GNGT1 and GNGT2 were found in the other vertebrates. In frog and zebrafish additional duplicates of GNGT2 were identified. Our analyses show all three transducin families expanded during the early vertebrate tetraploidizations and the beta and gamma families gained additional copies in the teleost-specific genome duplication. This suggests that the tetraploidizations contributed to visual specialisations. PMID- 22814269 TI - Sensory cilia in arthropods. AB - In arthropods, the modified primary cilium is a structure common to all peripheral sensory neurons other than photoreceptors. Since its first description in 1958, it has been investigated in great detail in numerous sense organs (sensilla) of many insect species by means of electron microscopy and electrophysiology. The perfection of molecular biological methods has led to an enormous advance in our knowledge about development and function of sensory cilia in the fruitfly since the end of the last century. The cilia show a wealth of adaptations according to their different physiological roles: chemoreception, mechanoreception, hygroreception, and thermoreception. Divergent types of receptors and channels have evolved fulfilling these tasks. The number of olfactory receptor genes can be close to 300 in ants, whereas in crickets slightest mechanical stimuli are detected by the interaction of extremely sophisticated biomechanical devices with mechanosensory cilia. Despite their enormous morphological and physiological divergence, sensilla and sensory cilia develop according to a stereotyped pattern. Intraflagellar transport genes have been found to be decisive for proper development and function. PMID- 22814268 TI - Whole-genome gene expression profiling reveals the major role of nitric oxide in mediating the cellular transcriptional response to ionizing radiation in normal human fibroblasts. AB - The indirect biological effects of ionizing radiation (IR) are thought to be mediated largely by reactive oxygen and nitrogen species (ROS and RNS). However, no data are available on how nitric oxide (NO) modulates the response of normal human cells to IR exposures at the level of the whole transcriptome. Here, we examined the effects of NO and ROS scavengers, carboxy-PTIO and DMSO, on changes in global gene expression in cultured normal human fibroblasts after exposures to gamma-rays, aiming to elucidate the involvement of ROS and RNS in transcriptional response to IR. We found that NO depletion dramatically affects the gene expression in normal human cells following irradiation with gamma-rays. We observed striking (more than seven-fold) reduction of the number of upregulated genes upon NO scavenging compared to reference irradiated cell cultures. NO scavenging in irradiated IMR-90 cells results in induction of p53 signaling, DNA damage and DNA repair pathways. PMID- 22814283 TI - Lumbar muscle activity during common lifts: a preliminary study using magnetic resonance imaging. AB - The purpose of this preliminary study was to assess lumbar multifidus, erector spinae, and quadratus lumborum muscle activity during lifts as measured by changes in transverse relaxation time (T2) from magnetic resonance imaging (MRI). Thirteen healthy adults performed dynamic squat, stoop, and asymmetric stoop lifts at a standard load, with each lift followed by MRI. Increase in T2 for the multifidus and erector spinae was greater for the stoop than squat. No difference in T2 increase was noted between the multifidus and erector spinae for the squat or stoop. Increase in T2 for the contralateral multifidus was less for the asymmetric stoop than stoop. Future research using MRI and other biomechanical techniques is needed to fully characterize lumbar muscle activity during lifts for various populations, settings, postures, and loads. PMID- 22814285 TI - Executive functions in patients with familial versus sporadic schizophrenia and their parents. AB - BACKGROUND: The aim of this study was to investigate the executive functions in patients with sporadic schizophrenia (SS) and familial schizophrenia (FS), and the executive functions in their parents. METHODS: The study included 30 patients with FS and their 37 parents with a positive family history of schizophrenia; 30 patients with SS and their 44 parents; 30 controls matched with the patients for gender, age and education, and 40 controls matched with the parents for gender, age and education (211 subjects in total). All the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I (SCID-I). The executive functions were assessed using the Verbal Fluency Test (VFT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test. RESULTS: Patients with FS and their parents, and patients with SS performed significantly worse than their controls on the VFT, TMT, WCST and the Stroop test. There were no statistically significant differences between parents of patients with SS and their controls on any of the tests except for the Stroop color score. FS parents performed significantly worse than SS parents on all tests. FS patients performed significantly worse than SS patients on the VFT, TMT, Stroop test. CONCLUSION: Previous studies that investigated the cognitive functions of relatives of patients with schizophrenia brought out inconsistent results. The present study investigated relatives with and without a family history of schizophrenia separately and found that executive functions were impaired only in parents with a positive family history of schizophrenia. These findings suggest that impairment in executive functions may represent a genetic endophenotype for schizophrenia. PMID- 22814284 TI - Measurement of segmental lumbar spine flexion and extension using ultrasound imaging. AB - STUDY DESIGN: Clinical measurement, technical note. OBJECTIVES: To describe a technique to measure interspinous process distance using ultrasound (US) imaging, to assess the reliability of the technique, and to compare the US imaging measurements to magnetic resonance imaging (MRI) measurements in 3 different positions of the lumbar spine. BACKGROUND: Segmental spinal motion has been assessed using various imaging techniques, as well as surgically inserted pins. However, some imaging techniques are costly (MRI) and some require ionizing radiation (radiographs and fluoroscopy), and surgical procedures have limited use because of the invasive nature of the technique. Therefore, it is important to have an easily accessible and inexpensive technique for measuring lumbar segmental motion to more fully understand spine motion in vivo, to evaluate the changes that occur with various interventions, and to be able to accurately relate the changes in symptoms to changes in motion of individual vertebral segments. METHODS: Six asymptomatic subjects participated. The distance between spinous processes at each lumbar segment (L1-2, L2-3, L3-4, L4-5) was measured digitally using MRI and US imaging. The interspinous distance was measured with subjects supine and the lumbar spine in 3 different positions (resting, lumbar flexion, and lumbar extension) for both MRI and US imaging. The differences in distance from neutral to extension, neutral to flexion, and extension to flexion were calculated. RESULTS: The measurement methods had excellent reliability for US imaging (intraclass correlation coefficient [ICC3,3] = 0.94; 95% confidence interval: 0.85, 0.97) and MRI (ICC3,3 = 0.98; 95% confidence interval: 0.95, 0.99). The distance measured was similar between US imaging and MRI (P>.05), except at L3-4 flexion-extension (P = .003). On average, the MRI measurements were 1.3 mm greater than the US imaging measurements. CONCLUSION: This study describes a new method for the measurement of lumbar spine segmental flexion and extension motion using US imaging. The US method may offer an alternative to other imaging techniques to monitor clinical outcomes because of its ease of use and the consistency of measurements compared to MRI. PMID- 22814286 TI - Type 2 diabetes mellitus in mice aggravates the renal impact of hemorrhagic shock. AB - The objectives of this study were to determine whether type 2 diabetic mice would exhibit a more severe renal impact of hemorrhagic shock (HS) based on a recently described model of acute kidney injury and to determine the impact of HS on renal responses to hypoxia. We induced HS or sham procedure in type 2 diabetic and obese db/db mice. Creatininemia, glomerular filtration rate, urine output, histologic injury score, and kidney inductible molecule 1 mRNA were used to investigate the renal impact of HS. Tissular hypoxia and its impact were quantified using pimonidazole immunostaining and mRNA of hypoxic inducible factor, vascular endothelial growth factor receptors 1 and 2, Tie-2, endothelial nitric oxide synthase, and inducible nitric oxide synthase. Diabetic mice exhibiting mild diabetic nephropathy express hypoxic signals at baseline. The renal impact of HS was more severe in diabetic mice, with a worsening of tissular hypoxia and an altered response to hypoxia. Furthermore, endothelial nitric oxide synthase was highly overexpressed in diabetic shocked mice when compared with nondiabetic shocked mice. Renal impact of HS in type 2 diabetic mice is more intense than in nondiabetic ones. Preexisting hypoxia during diabetes could result in a renal preconditioning that modifies endothelial and tissular responses to acute kidney injury. PMID- 22814288 TI - Anaphylactic shock decreases cerebral blood flow more than what would be expected from severe arterial hypotension. AB - The effects of acute reduction in arterial blood pressure in severe anaphylactic shock (AS) on cerebral blood flow are of paramount importance to be investigated. We studied cerebral circulation and oxygenation in a model of severe AS and compared it with a pharmacologically induced arterial hypotension of similar magnitude. Anaphylactic shock was induced by 1 mg intravenous ovalbumin (OVA) in sensitized rats. Rats were randomized to three groups: (i) no resuscitation (OVA; n = 10) (ii) intravenous volume expansion (10 mL in 10 min after OVA injection) (OVA + VE; n = 10); (iii) control hypotension (100 MUg of nicardipine followed by continuous infusion of 1 mg . 100 g . h intravenously; NICAR; n = 10). Mean arterial pressure (MAP), carotid blood flow (CBF), cardiac output, cerebral cortical blood flow (CCBF; estimated by laser Doppler technique), and cerebral tissue oxygen pressure (PtiO2) were recorded over the 15 min following AS induction in all three groups. Results are expressed as mean (SD). One minute after OVA or nicardipine injection, there was a rapid and significant 50% decrease in MAP from basal values. In the OVA group, AS severely altered systemic and cerebral hemodynamics in 5 min: 93% (SD, 4%) decrease in CBF, 66% (SD, 8%) in CCBF, and 44% (SD, 8%) in PtiO2; the decrease in CBF was significantly (P < 0.05) attenuated in the OVA + VE group; however, CCBF and PtiO2 were not statistically different in the OVA versus OVA + VE groups. On the contrary, nicardipine-induced hypotension had only a limited impact on CBF, cardiac output, CCBF, and PtiO2 for a similar MAP decrease. There was a linear relation between CCBF and blood pressure in the OVA (regression slope: 0.87 [SD, 0.06]; median r = 0.81) but not in the NICAR group (regression slope: 0.23 [SD, 0.32]; median r = 0.33). Anaphylactic shock resulted in severe impairment of cerebral blood flow and oxygenation, beyond what could be expected from the level of arterial hypotension. PMID- 22814287 TI - Role of non-muscle myosin light chain kinase in neutrophil-mediated intestinal barrier dysfunction during thermal injury. AB - Neutrophils and non-muscle myosin light chain kinase (nmMLCK) have been implicated in intestinal microvascular leakage and mucosal hyperpermeability in inflammation and trauma. The aim of this study was to characterize the role of nmMLCK in neutrophil-dependent gut barrier dysfunction following thermal injury, a common form of trauma that typically induces inflammation in multiple organs. Histopathological examination of the small intestine in mice after a full thickness burn revealed morphological evidence of mucosa inflammation characterized by neutrophil infiltration into the lamina propria, epithelial contraction, and narrow villi with blunt brush borders and loss of goblet cells. Compared with their wild-type counterparts, nmMLCK mice displayed diminished morphological abnormalities. Likewise, intravital microscopic studies showed significant leukocyte adhesion in intestinal microvessels after burn, a response that was blunted in the absence of nmMLCK. Functionally, thermal injury significantly increased the gut lumen-to-blood transport of fluorescein isothiocyanate-dextran (4 kd), and this hyperpermeability was attenuated by either neutrophil depletion or nmMLCK deficiency. Consistent with the in vivo observations, in vitro assays with Caco-2 epithelial cell monolayers revealed a decrease in transcellular electric resistance coupled with myosin light chain phosphorylation, actomyosin ring condensation, and claudin-1 internalization upon stimulation with fMLP (N-formyl-methionyl-leucyl-phenylalanine)-activated neutrophils. Pretreatment of the cells with the MLCK inhibitor ML-7 prevented the tight junction responses. Taken together, the results suggest that nmMLCK plays an important role in neutrophil-dependent intestinal barrier dysfunction during inflammatory injury. PMID- 22814289 TI - Acid-induced acute lung injury in mice is associated with P44/42 and c-Jun N terminal kinase activation and requires the function of tumor necrosis factor alpha receptor I. AB - Aspiration of hydrochloric acid (HCl)-containing gastric juice leads to acute lung injury (ALI) and hypoxemic respiratory failure due to an exuberant inflammatory response associated with pulmonary edema from increased vascular and epithelial permeability. The aim of this study was to determine the role and signaling mechanisms of tumor necrosis factor alpha (TNF-alpha) in experimental ALI from HCl aspiration using a combination of genetic animal models and pharmacologic inhibition strategies. To this end, HCl was instilled intratracheally to mice, followed by respiratory system elastance measurement, bronchoalveolar lavage, and lung tissue harvesting 24 h after injection. Hydrochloric acid instillation induced an inflammatory response in the lungs of wild-type mice, evidenced as increased bronchoalveolar lavage total cells, neutrophils, and total protein; histologic lung injury score; and respiratory system elastance, whereas TNF-alpha receptor I mRNA levels were maintained. These alterations could be prevented by pretreatment with etanercept or genetic deletion of the 55-kd TNF-alpha receptor I, but not by deletion of the TNF-alpha gene. Hydrochloric acid induced a 6-fold increase in apoptotic, caspase 3 positive cells in lung sections from wild-type mice, which was abrogated in mice lacking TNF-alpha receptor I. In immunoblotting and immunohistochemistry studies, HCl stimulated signaling via p44/42 and c-Jun N-terminal kinase, which was blocked in TNF-alpha receptor I knockout mice. In conclusion, ALI induced by HCl requires TNF-alpha receptor I function and associates with activation of downstream proinflammatory signaling pathways p44/42 and c-Jun N-terminal kinase. PMID- 22814290 TI - Time dependency and topography of hepatic nuclear factor kappaB activation after hemorrhagic shock and resuscitation in mice. AB - The leading causes of death in people aged 1 to 44 years are unintentional injuries with associated hemorrhagic shock. Hemorrhagic shock followed by resuscitation (H/R) activates the nuclear factor kappaB (NF-kappaB) pathway. To further address the association between liver damage and NF-kappaB activation, we analyzed the H/R-induced activation of NF-kappaB using cis-NF-kappaB reporter gene mice. In these mice, the expression of green fluorescent protein (GFP) is linked to the activation of NF-kappaB, and therefore tracing of GFP colocalizes NF-kappaB activation. Mice were hemorrhaged to a mean arterial blood pressure of 30mmHg for 90 min, followed by resuscitation. Six, 14, or 24 h after resuscitation, mice were killed. Compared with sham-operated mice, H/R led to a profound hepatic and cellular damage as measured by aspartate aminotransferase, creatine kinase, and lactate dehydrogenase levels, which was accompanied by an elevation in interleukin 6 levels and hepatic leukocyte infiltration. Interleukin 10 levels in plasma were elevated 6 h after H/R. Using serial liver sections, we found an association between necrotic areas, oxidative stress, and enhanced GFP positive cells. Furthermore, enhanced GFP-positive cells surrounded areas of necrotic liver tissue, predominantly in a penumbra-like-shape pericentrally. These results elucidate spatial relationship between oxidative stress, liver necrosis, and NF-kappaB activation, using an in vivo approach and therefore might help to further analyze mechanisms of NF-kappaB activation after resuscitated blood loss. PMID- 22814291 TI - Rearrangement of the myeloid/lymphoid leukemia gene in therapy-related myelodysplastic syndrome in patients previously treated with agents targeting DNA topoisomerase II. AB - BACKGROUND: Therapy-related acute myeloid leukemias (t-AML), with balanced translocations affecting the 11q23 point in the myeloid/lymphoid leukemia (MLL) gene, are one of the most serious complications of treatments with topoisomerase II inhibitors. However, only a few reports of t-AML exist. We aimed to study if these translocations are cumulative-dose-dependent, their frequency in therapy related myelodysplastic syndrome and the relationship between their presence, the type of therapy and the response criteria. METHODS: This retrospective study included 120 patients with various malignancies (108 non-Hodgkin's lymphoma, 8 Hodgkin's disease and 4 neuroblastoma) in remission, being treated with topoisomerase 2 inhibitors; 74 had been diagnosed with therapy-related myelodysplasia and 46 did not have dysplasia. All bone marrow biopsy samples were evaluated by fluorescence in situ hybridization for 11q23 point breakage in the MLL gene. RESULTS: MLL gene rearrangement frequency was 6% in dysplastic versus 2% in nondysplastic groups; p < 0.001. It was associated with a worse overall survival (mean 13 +/- 2 vs. 39 +/- 3 months, log-rank p value <0.0001). It was dose-dependent with a cut-off value of 290 mg/kg of topoisomerase II inhibitors as assessed by ROC curve (area under the curve 0.84 +/- 0.05, p < 0.0001). CONCLUSIONS: It is proposed that the MLL gene is etiopathogenetically relevant for hematological neoplasias transformation and survival. PMID- 22814292 TI - Pretreatment of leukemic cells with low-dose decitabine markedly enhances the cytotoxicity of gemtuzumab ozogamicin. PMID- 22814293 TI - Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation. PMID- 22814294 TI - Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. AB - Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1(WT)FBXW7(WT)), 38% single NOTCH1 mutant (NOTCH1(Single)FBXW7(WT)), 3% just FBXW7 mutant (NOTCH1(WT)FBXW7(MUT)) and 24% either double NOTCH1 mutant (NOTCH1(Double)FBXW7(WT)) or mutant in both genes (NOTCH1(MUT)FBXW7(MUT)), hereafter called as NOTCH1+/-FBXW7(Double). There was no difference between groups in early response to therapy, but NOTCH1+/-FBXW7(Double) patients were more likely to be associated with negative minimal residual disease (MRD) post induction than NOTCH1(WT)FBXW7(WT) patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1(WT)FBXW7(WT), NOTCH1(Single)FBXW7(WT) and NOTCH1+/ FBXW7(Double) patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1+/-FBXW7(Double) patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy. PMID- 22814295 TI - GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. PMID- 22814296 TI - IL-15-stimulated CD3/CD19-depleted stem-cell boosts in relapsed pediatric patients after haploidentical SCT. PMID- 22814297 TI - Manipulation of intraocular pressure for studying the effects on accommodation. AB - A reliable experimental system in which IOP can be manipulated or a rapid IOP change can be induced while simultaneously and continuously measuring IOP and the ocular accommodative changes would be useful for understanding the physiological effect of intraocular pressure (IOP) on the accommodative mechanism. In this study, an IOP perfusion and recording system was developed and tested using 13 enucleated pig eyes. The vitreous chamber of the pig eyes was cannulated with a needle connected to two fluid reservoirs at different heights. One reservoir was set to achieve one of three baseline pressures of 5.5 mmHg, 13.0 mmHg and 20.5 mmHg. The other reservoir was moved to achieve pressures of 1.5 mmHg, 3.0 mmHg, 4.5 mmHg and 6.0 mmHg higher than the baseline pressure. The height differential between the reservoirs determined the amplitude of IOP changes. Rapid IOP changes were induced by switching the reservoirs with a solenoid pinch-valve. Two needles, one each attached to a pressure transducer were inserted into the anterior chamber and vitreous chamber respectively. Custom developed software was used to measure the anterior chamber pressure and vitreous chamber pressure at 80 Hz. A high-resolution continuous A-scan ultrasound biometer (CUB) was used to dynamically measure changes in ocular biometry including anterior chamber depth (ACD), lens thickness (LT) and vitreous chamber depth (VCD) while the vitreous chamber pressure was manipulated. The changes in ACD, LT and VCD were analyzed as a function of the pressure change. Perfusion-induced axial biometric changes were quantified by the slopes of linear regression relationships. Both anterior chamber pressure and vitreous chamber pressure changed relatively systematically with the induced vitreous chamber pressure changes (anterior chamber: y = 0.863x + 0.030, r(2) = 0.983; vitreous chamber: y = 0.883x + 0.009, r(2) = 0.981). At perfusion pressures of 5.5, 13.0 and 20.5 mmHg, the slopes for ACD were -5.72, 2.75 and -2.36 MUm/mmHg, for LT were -3.31, -1.59 and -1.03 MUm/mmHg and for VCD were 19.05, 8.63 and 5.18 MUm/mmHg. The system was able to manipulate and monitor IOP while axial biometry changes were recorded. This system will allow the relationship between IOP and accommodation to be studied in non-human primate eyes. PMID- 22814298 TI - Sunitinib-sensitive suicidal erythrocyte death. AB - Sunitinib, a multikinase inhibitor, stimulates apoptosis and is thus utilized for the treatment of malignancy. Even though lacking mitochondria and nuclei, critical elements in apoptosis of nucleated cells, erythrocytes may undergo eryptosis, an apoptosis-like suicidal death, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Triggers of eryptosis include activation of Ca(2+) permeable cation channels with subsequent increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)), ceramide formation, ATP-depletion, stimulation of p38 kinase and caspase activation. The present study explored, whether sunitinib stimulates eryptosis. [Ca(2+)](i )was estimated from Fluo-3-fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, ceramide abundance from anti-ceramide antibody binding, and cytosolic ATP from luciferin-luciferase activity. A 48 h exposure to sunitinib (10 uM) significantly decreased forward scatter and increased annexin-V-binding, effects paralleled by significant increase of [Ca(2+)](i). Sunitinib exposure was followed by a slight but significant increase of hemolysis. Sunitinib induced annexin-V-binding was slightly, but significantly blunted by removal of extracellular Ca(2+), by p38 kinase inhibitor SB203580 (10 uM) and by the pancaspase inhibitor zVAD (10 uM). Sunitinib, however, did not significantly modify cytosolic ATP and ceramide abundance. The present observations reveal that sunitinib is able to trigger suicidal death in erythrocytes even in the absence of nuclei and mitochondria. PMID- 22814299 TI - Analysis of wastewater samples by direct combination of thin-film microextraction and desorption electrospray ionization mass spectrometry. AB - An analysis method for aqueous samples by the direct combination of C18/SCX mixed mode thin-film microextraction (TFME) and desorption electrospray ionization mass spectrometry (DESI-MS) was developed. Both techniques make analytical workflow simpler and faster, hence the combination of the two techniques enables considerably shorter analysis time compared to the traditional liquid chromatography mass spectrometry (LC-MS) approach. The method was characterized using carbamazepine and triclosan as typical examples for pharmaceuticals and personal care product (PPCP) components which draw increasing attention as wastewater-derived environmental contaminants. Both model compounds were successfully detected in real wastewater samples and their concentrations determined using external calibration with isotope labeled standards. Effects of temperature, agitation, sample volume, and exposure time were investigated in the case of spiked aqueous samples. Results were compared to those of parallel HPLC MS determinations and good agreement was found through a three orders of magnitude wide concentration range. Serious matrix effects were observed in treated wastewater, but lower limits of detection were still found to be in the low ng L(-1) range. Using an Orbitrap mass spectrometer, the technique was found to be ideal for screening purposes and led to the detection of various different PPCP components in wastewater treatment plant effluents, including beta-blockers, nonsteroidal anti-inflammatory drugs, and UV filters. PMID- 22814300 TI - Comparison of upper arm kinematics during a volleyball spike between players with and without a history of shoulder injury. AB - Volleyball players are at high risk of overuse shoulder injuries, with spike biomechanics a perceived risk factor. This study compared spike kinematics between elite male volleyball players with and without a history of shoulder injuries. Height, mass, maximum jump height, passive shoulder rotation range of motion (ROM), and active trunk ROM were collected on elite players with (13) and without (11) shoulder injury history and were compared using independent samples t tests (P < .05). The average of spike kinematics at impact and range 0.1 s before and after impact during down-the-line and cross-court spike types were compared using linear mixed models in SPSS (P < .01). No differences were detected between the injured and uninjured groups. Thoracic rotation and shoulder abduction at impact and range of shoulder rotation velocity differed between spike types. The ability to tolerate the differing demands of the spike types could be used as return-to-play criteria for injured athletes. PMID- 22814301 TI - Interventions to reduce or prevent obesity in pregnant women: a systematic review. AB - BACKGROUND: Around 50% of women of childbearing age are either overweight [body mass index (BMI) 25-29.9 kg/m(2)] or obese (BMI >= 30 kg/m(2)). The antenatal period provides an opportunity to manage weight in pregnancy. This has the potential to reduce maternal and fetal complications associated with excess weight gain and obesity. OBJECTIVES: To evaluate the effectiveness of dietary and lifestyle interventions in reducing or preventing obesity in pregnancy and to assess the beneficial and adverse effects of the interventions on obstetric, fetal and neonatal outcomes. DATA SOURCES: Major electronic databases including MEDLINE, EMBASE, BIOSIS and Science Citation Index were searched (1950 until March 2011) to identify relevant citations. Language restrictions were not applied. REVIEW METHODS: Systematic reviews of the effectiveness and harm of the interventions were carried out using a methodology in line with current recommendations. Studies that evaluated any dietary, physical activity or mixed approach intervention with the potential to influence weight change in pregnancy were included. The quality of the studies was assessed using accepted contemporary standards. Results were summarised as pooled relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous data. Continuous data were summarised as mean difference (MD) with standard deviation. The quality of the overall evidence synthesised for each outcome was summarised using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology and reported graphically as a two-dimensional chart. RESULTS: A total of 88 studies (40 randomised and 48 non-randomised and observational studies, involving 182,139 women) evaluated the effect of weight management interventions in pregnancy on maternal and fetal outcomes. Twenty-six studies involving 468,858 women reported the adverse effect of the interventions. Meta-analysis of 30 RCTs (4503 women) showed a reduction in weight gain in the intervention group of 0.97 kg compared with the control group (95% CI -1.60 kg to -0.34 kg; p = 0.003). Weight management interventions overall in pregnancy resulted in a significant reduction in the incidence of pre-eclampsia (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008) and shoulder dystocia (RR 0.39, 95% CI 0.22 to 0.70; p = 0.02). Dietary interventions in pregnancy resulted in a significant decrease in the risk of pre-eclampsia (RR 0.67, 95% CI 0.53 to 0.85; p = 0.0009), gestational hypertension (RR 0.30, 95% CI 0.10 to 0.88; p = 0.03) and preterm birth (RR 0.68, 95% CI 0.48 to 0.96; p = 0.03) and showed a trend in reducing the incidence of gestational diabetes (RR 0.52, 95% CI 0.27 to 1.03). There were no differences in the incidence of small for-gestational-age infants between the groups (RR 0.99, 95% CI 0.76 to 1.29). There were no significant maternal or fetal adverse effects observed for the interventions in the included trials. The overall strength of evidence for weight gain in pregnancy and birthweight was moderate for all interventions considered together. There was high-quality evidence for small-for-gestational-age infants as an outcome. The quality of evidence for all interventions on pregnancy outcomes was very low to moderate. The quality of evidence for all adverse outcomes was very low. LIMITATIONS: The included studies varied in the reporting of population, intensity, type and frequency of intervention and patient complience, limiting the interpretation of the findings. There was significant heterogeneity for the beneficial effect of diet on gestational weight gain. CONCLUSIONS: Interventions in pregnancy to manage weight result in a significant reduction in weight gain in pregnancy (evidence quality was moderate). Dietary interventions are the most effective type of intervention in pregnancy in reducing gestational weight gain and the risks of pre-eclampsia, gestational hypertension and shoulder dystocia. There is no evidence of harm as a result of the dietary and physical activity-based interventions in pregnancy. Individual patient data meta-analysis is needed to provide robust evidence on the differential effect of intervention in various groups based on BMI, age, parity, socioeconomic status and medical conditions in pregnancy. PMID- 22814302 TI - Efficacy of integuseal for surgical skin preparation in children and adolescents undergoing scoliosis correction. AB - STUDY DESIGN: Prospective randomized trial. OBJECTIVE: To explore the use of a microbial sealant applied before the surgical incision to reduce surgical site infection in patients with scoliosis. SUMMARY OF BACKGROUND DATA: The incidence of superficial or deep infections is reported in 2 groups of patients treated for neuromuscular or adolescent idiopathic scoliosis. Statistical analysis aimed to compare the effect of the use of a cyanoacrylate microbial sealant on infection rate. METHODS: From June 2010 to June 2011, 56 patients were prospectively enrolled in the study. Using a random number table, patients were assigned either to receive or not a sterile, film-forming cyanoacrylate liquid application (Integuseal). Epidemiological data and infection occurrence were compared in both groups. RESULTS: Statistical analysis comparing patients with neuromuscular scoliosis and adolescent idiopathic scoliosis showed that patients with neuromuscular scoliosis had more fused levels, increased intraoperative bleeding, and longer intraoperative time. Six patients had early postoperative infections of the posterior approach, which included 3 deep and 3 superficial infections. Five infections occurred in patients treated with Integuseal. Outcome was favorable in 6 cases after local wound debridement and antibiotics. Nonparametric statistical tests (Fisher exact test) showed no significant correlation (P = 0.096) between early postoperative infection occurrence and the use of Integuseal. CONCLUSION: Although microbial sealant may be a useful addition to a multimodal approach to minimize surgical site infection, there is currently insufficient evidence as to whether the use of microbial sealants reduces the risk of surgical site infection in patients undergoing scoliosis surgery. PMID- 22814303 TI - Real-time and spatial quantification using contrast-enhanced ultrasonography of spinal cord perfusion during experimental spinal cord injury. AB - STUDY DESIGN: Experimental study in male Wistar rats. OBJECTIVE: To quantify temporal and spatial changes simultaneously in spinal cord blood flow and hemorrhage during the first hour after spinal cord injury (SCI), using contrast enhanced ultrasonography (CEU). SUMMARY OF BACKGROUND DATA: Post-traumatic ischemia and hemorrhage worsen the primary lesions induced by SCI. Previous studies did not simultaneously assess temporal and spatial changes in spinal cord blood flow. METHODS: SCI was induced at Th10 in 12 animals, which were compared with 11 sham-operated controls. Spinal cord blood flow was measured in 7 adjacent regions of interest and in the sum of these 7 regions. Blood flow was quantified using CEU with intravenous microbubble injection. Spinal cord hemorrhage was measured on conventional B-mode sonogram slices. RESULTS: CEU allowed us to measure the temporal and spatial changes in spinal cord blood flow in both groups. In the SCI group, spinal cord blood flow was significantly decreased in the global region of interest (P = 0.0016), at the impact site (epicenter), and in the 4 regions surrounding the epicenter, compared with the sham group. The blood flow decrease was maximum at the epicenter. No statistically significant differences between the sham groups were found for the most rostral and caudal regions of interest. Hemorrhage size increased significantly with time (P < 0.0001), from 30.3 mm(2) (+/-2) after 5 minutes to 39.6 mm(2) (+/-2.3) after 60 minutes. CONCLUSION: CEU seems reliable for quantifying temporal and spatial changes in spinal cord blood flow. After SCI, bleeding occurs in the spinal cord parenchyma and increases significantly throughout the first hour. PMID- 22814304 TI - Outpatient surgery reduces short-term complications in lumbar discectomy: an analysis of 4310 patients from the ACS-NSQIP database. AB - STUDY DESIGN: Propensity score-adjusted prospective cohort study. OBJECTIVE: To compare the incidence of complications in patients undergoing single-level lumbar discectomy between the inpatient and outpatient settings, to determine baseline 30-day complication rates for lumbar discectomy, and to identify independent risk factors for complications. SUMMARY OF BACKGROUND DATA: Lumbar discectomy is the most common spinal procedure performed and can be done on an outpatient basis. Lower costs, greater patient satisfaction, and equivalent safety have been reported with outpatient surgery. METHODS: Patients undergoing lumbar discectomy between 2005 and 2010 were selected from The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Patient selection was based on a single primary current procedural terminology code. To ensure comparable inpatient and outpatient cohorts, patients with multilevel procedures were excluded. Thirty-day postoperative complications and preoperative patient characteristics were identified and compared. Propensity score matching and multivariate logistic regression analysis were used to adjust for selection bias and identify predictors of 30-day morbidity. RESULTS: Of the 4310 lumbar discectomy cases, 2658 (61.7%) underwent an inpatient hospital stay after surgery, whereas 1652 (38.3%) patients had outpatient surgery. Unadjusted overall complication rates (6.5% vs. 3.5%, P < 0. 0001) were higher in those undergoing inpatient surgery. After propensity score matching, overall complication rate was still higher with the inpatient cohort (5.4% vs. 3.5%, P = 0.0068). Adjusted comparison using multivariate logistic regression also demonstrated a significantly higher rate of complication for inpatients (odds ratio, 1.521; 95% confidence interval, 1.048-2.206). Age, diabetes, presence of preoperative wound infection, blood transfusion, operative time, and an inpatient hospital stay were all independent risk factors of short-term complication after lumbar discectomy. CONCLUSION: After adjusting for confounders using propensity score matching and multivariate logistic regression analysis, patients undergoing outpatient lumbar discectomy had lower overall complication rates than those treated as inpatients. Surgeons should consider outpatient surgery for lumbar discectomy in appropriate candidates. PMID- 22814305 TI - Neurological outcome and management of pedicle screws misplaced totally within the spinal canal. AB - STUDY DESIGN: This study reports 9 cases referred to our institution after surgical correction of adolescent idiopathic scoliosis and pedicle screws misplaced totally within the spinal canal. OBJECTIVE: To assess the neurological outcome associated with pedicle screws misplaced totally within the spinal canal. SUMMARY OF BACKGROUND DATA: The prevalence of neurological complications from misplaced pedicle screws might be under-reported, and optimal management of pedicle screws misplaced totally within the spinal canal remains unclear. METHODS: Nine cases with pedicle screws misplaced totally within the spinal canal during posterior surgery for adolescent idiopathic scoliosis were reviewed. All cases presented at least 1 medially misplaced pedicle screw, with spinal canal intrusion greater than pedicle screw diameter, that is, completely within the spinal canal. Percentage of spinal canal intrusion was measured from computed tomographic scans. RESULTS: Spinal canal intrusion varied from 21% to 61%. In 2 patients, misplacement of pedicle screws was recognized intraoperatively and all implants were removed. They both had motor deficits from which 1 patient recovered completely. Two patients had early postoperative postural headache that disappeared after removal of the misplaced screw. Five patients had uneventful early postoperative course. One of these developed a Brown-Sequard syndrome 2 years after surgery and underwent complete implant removal. Another patient developed left thoracic paresthesia 3 years after surgery, and complete implant removal was performed. Two neurologically intact patients had uneventful implant removal after infection. The last patient refused implant removal and remained asymptomatic 5 years after surgery. CONCLUSION: Improper pedicle screw placement can lead to neurological complications appearing early or late (after 2 yr). Late neurological complications were associated with screw loosening in 2 cases. The authors strongly recommend removal of any pedicle screw misplaced totally within the spinal canal due to the risk of early or late neurological complications, regardless of the severity of spinal canal intrusion. PMID- 22814306 TI - Does self-assessed physical capacity predict development of low back pain among health care workers? A 2-year follow-up study. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine the prognostic value of self-assessed physical capacity for the development of low back pain (LBP) among female health care workers without LBP. SUMMARY OF BACKGROUND DATA: High physical capacities in terms of strength, endurance, flexibility, and balance are assumed to prevent LBP among persons with high physical work demands. However, the few existing studies investigating this relationship show contrasting findings. METHODS: Female health care workers answered a questionnaire about physical capacity in 2004, and days with LBP in 2005 and 2006. The odds ratios (ORs) for developing nonchronic (1-30 d of the past 12 mo) and persistent (>30 d of the past 12 mo) LBP in 2006 from self-assessed physical capacity were investigated with multiadjusted logistic regressions among female health care workers without LBP in 2005 (n = 1612). RESULTS: Health care workers with low and medium physical capacity had increased risk of developing nonchronic LBP (OR = 1.52 [CI = 1.05-2.20] and OR = 1.37 [CI = 1.01-1.84], respectively), and health care workers with low physical capacity had an increased risk of developing persistent LBP (OR = 2.13 [CI = 1.15-3.96]), referencing those with high physical capacity. CONCLUSION: Self-assessed low physical capacity is a strong predictor for developing nonchronic and persistent LBP among pain-free female health care workers. Future intervention studies should investigate whether increased physical capacity, for example, through exercise training prevents development of LBP among female health care workers. PMID- 22814307 TI - Predictive value of marker half-life in relapsed and nonrelapsed nonseminomatous germ cell testicular tumor patients undergoing chemotherapy. AB - BACKGROUND: The aim of this study was to investigate the influence of a marker half-life (MHL) on relapse in nonseminomatous germ cell testicular tumor patients. METHODS: MHL was retrospectively analyzed in relapsed (n = 37) and nonrelapsed patients (n = 28) undergoing first-line chemotherapy (CT). Before CT and after the second cycle of CT, serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin levels were measured for MHL analysis. The International Germ Cell Cancer Collaborative Group risk classification system was used to assess the correlation between MHL and relapse. MHL was calculated according to a logarithmic formula. RESULTS: Median follow-up was 25 months (range, 6 to 96 mo). A statistically significant difference was not observed between initial AFP (P = 0.266) and beta-human chorionic gonadotropin (P=0.092) in both patient groups. MHL was statistically different between the relapsed and nonrelapsed patients with a good, intermediate, and poor prognosis, except for the half-life of AFP in patients with a poor prognosis. CONCLUSIONS: MHL is an indicator that predicted recurrence. Patients with an MHL longer than expected should be investigated to improve the effectiveness of treatment and should be treated with a recovery regimen. PMID- 22814308 TI - Phase I and pharmacokinetic study of IV vinflunine in combination with carboplatin in chemonaive patients with advanced non-small cell lung cancer. AB - OBJECTIVE: Vinflunine (VFL) (Javlor((r))), a novel fluorinated semisynthetic vinca alkaloid has shown significant antitumor activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose (RD) of VFL in combination with carboplatin in advanced NSCLC patients. METHODS: This phase I and pharmacokinetic study was designed to determine the maximum tolerated dose and to establish the RD of VFL in combination with carboplatin. Twenty-one chemonaive patients with advanced NSCLC were treated with a first-line chemotherapy of VFL and carboplatin both given on day 1 every 3 weeks with 3 dose levels. RESULTS: Five patients experienced a dose limiting toxicity consisting of constipation in 2 patients and febrile neutropenia in 2 patients. One patient experienced grade 3 abdominal pain concurrent with grade 4 neutropenia. The combination of VFL (320 mg/m(2)) and carboplatin AUC6 was defined as the maximum tolerated dose. The RD was established at the dose of VFL (320 mg/m(2)) combined with carboplatin AUC5. At the RD, 12 patients received a median number of 3 cycles of the combination. Neither VFL nor carboplatin seemed to be influencing the pharmacokinetics of the other. Among 19 patients evaluable for tumor response, 7 had a partial response and 7 experienced stable disease. CONCLUSIONS: The combination of VFL (320 mg/m(2)) and carboplatin AUC 5 given once every 3 weeks is established as the RD of the combination, which was shown to be active in these chemonaive NSCLC patients. PMID- 22814309 TI - Antiemetic control with palonosetron in patients with gastrointestinal cancer receiving a fluoropyrimidine-based regimen in addition to either irinotecan or oxaliplatin: a retrospective study. AB - BACKGROUND: For moderately emetogenic chemotherapy, palonosetron (PALO) is reported to provide complete control of chemotherapy-induced nausea and vomiting (CINV) in 69% of patients. Prior to August 2009, our gastrointestinal (GI) cancer patients receiving the moderately emetogenic compounds oxaliplatin or irinotecan plus a fluoropyrimidine regimen received ondansetron and dexamethasone orally on day 1 of chemotherapy for CINV prevention. Beginning in August of 2009, ondansetron was replaced by PALO 0.25 mg (intravenous push). METHODS: This is a single-institution retrospective study of GI cancer patients who received oxaliplatin or irinotecan plus a fluoropyrimidine. Failure of an antiemetic regimen was defined as grade >=1 vomiting or grade >=2 nausea (Common Terminology Criteria for Adverse Events, version 3) on days 1 through 5 following chemotherapy. Patients were divided for analysis into pre-PALO and post-PALO cohorts. Fisher's exact test compared cohort differences. RESULTS: A total of 305 patients were included in the study, with 157 patients in the pre-PALO cohort and 148 in the post-PALO cohort. For all patients, the risk of antiemetic failure was reduced from 50.3% [95% confidence interval (CI) 42.2-58.4%] to 28.4% (95% CI 21.3-36.4%) with PALO. This reduction in the relative risk of antiemetic failure was observed in all subgroups. CONCLUSION: The addition of PALO may provide increased control of CINV for the moderately emetogenic regimens of oxaliplatin or irinotecan plus a fluoropyrimidine in GI cancer patients. PMID- 22814310 TI - Antipsychotic response in the first week predicts later efficacy. AB - BACKGROUND AND AIMS: Time of onset of antipsychotic action is still a debated matter. We aimed to replicate and extend previous findings that early response can predict subsequent non-response. METHODS: 86 acutely psychotic patients treated with haloperidol were studied. RESULTS: A PANSS reduction <=16% at 1 week predicts non-response at 3 weeks of treatment (specificity 92%, sensitivity 82%). Conversely, a PANSS reduction >=23% at 1 week of treatment predicts response at 3 weeks, with a specificity of 84% and a sensitivity of 86%. CONCLUSION: Our results confirm that an early response to antipsychotic treatment accurately predicts the treatment effectiveness and extends it to a prediction performed as early as 1 week. PMID- 22814312 TI - From biomass to medicines. A simple synthesis of indolo[3,2-c]quinolines, antimalarial alkaloid isocryptolepine, and its derivatives. AB - Indolo[3,2-c]quinolines are pharmacologically attractive class of heterocyclic compounds. The method of their synthesis, based on transformation of furfural, which is a large-scale product of treatment of biomass including agricultural and forestry wastes, has been developed. This method was utilized for the total synthesis of antimalarial alkaloid isocryptolepine and its derivatives. PMID- 22814311 TI - Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. AB - Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (+/-s.d.) for the five typical patterns combined and for difficult cases were 0.77+/-0.07 and 0.38+/-0.14, respectively. Although 70% of the observers identified 12-65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92-100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55+/-0.06 and 0.08+/-0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance. PMID- 22814313 TI - Porous nanocubic Mn3O4-Co3O4 composites and their application as electrochemical supercapacitors. AB - A simple approach has been developed to fabricate ideal supercapacitors based on porous Mn(3)O(4)-Co(3)O(4) nanocubic composite electrodes. We can easily obtain porous corner-truncated nanocubic Mn(3)O(4)-Co(3)O(4) composite nanomaterials without any subsequent complicated workup procedure for the removal of a hard template, seed or by using a soft template. In such a composite, the porous Mn(3)O(4)-Co(3)O(4) enables a fast and reversible redox reaction to improve the specific capacitance. The porous nanocubic Mn(3)O(4)-Co(3)O(4) composite electrode can effectively transport electrolytes and shorten the ion diffusion path, which offers excellent electrochemical performance. These results suggest that such porous Mn(3)O(4)-Co(3)O(4) composite nanocubes are very promising for next generation high-performance supercapacitors. PMID- 22814314 TI - Muscle preactivation control: simulation of ankle joint adjustments at touchdown during running on uneven ground. AB - In locomotion, humans have to deal with irregularities in the ground. When they encounter uneven terrain with changes in vertical height, they adjust the geometry of their legs. Recent investigations have shown that the preactivation of the gastrocnemius muscle (GM) correlates with the ankle angle at touchdown, but it is as of yet unclear why these adjustments were achieved by the GM and not by the preactivation of the tibialis anterior (TA). To examine the differences between TA regulation and GM regulation regarding (1) ankle angle adjustment and (2) joint stiffness, we used a three-segment musculoskeletal model with two antagonistic muscles (GM, TA). During the GM regulation, the ankle angle was adjusted from 121 degrees to 109 degrees (dorsiflexion) by a 41% decrease in the GM activation. During the TA regulation, the activation of TA must be increased by about 52%. In addition, we found that the ankle stiffness was most sensitive to changes in activation of the GM and decreased by about 20% while adjusting the angle. In contrast, the ankle stiffness remains similar when using TA regulation. Thus, the GM regulation is more adequate for adjustment in the ankle joint, enabling sufficient regulation of angle and stiffness. PMID- 22814315 TI - Biological subtypes and survival outcomes in breast cancer patients with brain metastases (study of the Anatolian Society of Medical Oncology). AB - BACKGROUND: The aim of this study is to determine the relationship between the survival outcomes and biological subtype in breast cancer patients with brain metastases. METHODS: We retrospectively evaluated clinical data from 422 breast cancer patients with brain metastases between 2001 and 2011 from referral centers in Turkey. The study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression. RESULTS: Systemic treatment prolonged median overall survival (OS) after brain metastases in the entire group (14 vs. 3.2 months, p < 0.001). It also prolonged median OS after brain metastases in the triple negative (7.5 vs. 1.6 months, p = 0.010) and luminal A (14.3 vs. 7.1 months, p = 0.003) subgroups. The median OS for untreated patients, chemotherapy and/or hormonal therapy receiving patients, and chemotherapy and/or hormonal therapy plus targeted therapy receivers was 2, 5.8, and 17.7 months, respectively (p < 0.001), in the HER2-overexpressing subgroup. In the luminal B subgroup, it was 3.7, 5.3, and 15.4 months, respectively (p = 0.003). CONCLUSIONS: The use of systemic therapy improves OS after brain metastases in all biological subgroups. Targeted therapies also improve OS after brain metastases in HER2-positive patients. The combined use of targeted therapies and lapatinib are superior to single use and trastuzumab, respectively, in these patients. PMID- 22814316 TI - Matrix metalloproteinases in health and disease: insights from dermatopathology. AB - Matrix metalloproteinases, a group of over 26 zinc-dependent enzymes, share a similar structure to each other and functionally are capable of degrading almost every component of the extracellular matrix. They are essential to normal development during embryogenesis and extracellular matrix remodeling and, given this, understandably enough have been implicated in multiple pathologic processes that encompass the inflammatory and neoplastic spectrum of disease. This review attempts to define roles of matrix metalloproteinases of relevance in normal skin and to elucidate their roles in inflammatory dermatoses and benign and malignant neoplasms. PMID- 22814317 TI - Eosinophils in mycosis fungoides: an uncommon finding in the patch and plaque stages. AB - Early diagnosis of mycosis fungoides (MF) is one of the most challenging problems in dermatopathology, as the histopathologic features of inflammatory dermatoses and MF may show significant overlap. One criterion used to distinguish early MF (patch stage) from dermatitis, which may be currently underutilized, is the presence of eosinophils. A search was performed for cases with a preoperative diagnosis of MF, cutaneous T-cell lymphoma, or dermatitis, which included 29 cases "diagnostic" for MF, 25 cases "suspicious" for MF, and 55 cases of spongiotic dermatitis. We examined tissue sections blinded to diagnosis to obtain an exact eosinophil count. Twenty-nine cases were diagnostic for MF (12 patch, 9 plaque, and 8 tumor stage). The average eosinophil count for cases diagnostic for patch stage MF was 1 eosinophil in 10 (0.11) sections examined. For plaque MF, there was 1 eosinophil in 5 (0.24) sections examined. All tumor stage MF cases showed abundant eosinophils within each section. Twenty-five cases were suspicious for MF (15 patches, 9 plaques, and 1 folliculotropic). The average eosinophil count for the patch lesions was 1 eosinophil in 4 (0.25) sections examined and 2 eosinophils per section for plaque lesions. Forty-five of 55 cases of spongiotic dermatitis had at least scattered eosinophils (>3) in each section. Twenty-three (47%) had eosinophils around most postcapillary venules. Only 3 of 45 patients (6.6%) with biopsies diagnostic or suspicious for patch or plaque stage MF showed >3 eosinophils per tissue section, whereas 45 of 55 (81.8%) biopsies of spongiotic dermatitis had >3. The presence of eosinophils (>3 per tissue section) is statistically significant in differentiating cases diagnostic or suspicious for patch or plaque stage MF from dermatitis (P < 0.0001). Our data indicate that eosinophils are uncommon in cases of patch and plaque MF. When a pathologist is faced with evaluating a biopsy that lacks some of the criteria used to make the diagnosis of patch stage MF, yet demonstrates >3 eosinophils per tissue section, dermatitis is the likely diagnosis. However, in cases where fewer than 3 eosinophils are present in sections, patch stage MF cannot be excluded. PMID- 22814318 TI - Expression of CXCR4, E-cadherin, Bcl-2, and survivin in Merkel cell carcinoma: an immunohistochemical study using a tissue microarray. AB - Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy with a mortality rate exceeding that of melanoma. Although smaller studies of markers of progression have been performed, large-scale investigation has been difficult due to the rarity of this tumor. Investigation of 4 potential immunohistochemical progression markers using an MCC tissue microarray was performed. An immunohistochemical analysis of CXCR4, E-cadherin, Bcl-2, and Survivin was performed on a tissue microarray of two hundred twenty-seven 0.6-mm tumor cores-110 primary, 73 local/regional metastatic, and 44 distant metastatic from 87 patients, 23 of which were sampled 2 or more times. There was a statistically significant increase in immunoreactivity to CXCR4 and Survivin in local/regional nodal MCC metastases compared with primary and distant metastatic lesions. No significant differences by disease location were found for either Bcl 2 or E-cadherin. These results suggest a potential role for CXCR4 and Survivin in MCC tumor progression. However, previous data from other studies suggesting a role for Bcl-2 and E-cadherin in MCC progression are not confirmed in this larger sample. Further discovery of additional markers are needed to better characterize this rare but deadly malignancy. PMID- 22814319 TI - Acrokeratosis verruciformis of Hopf showing P602L mutation in ATP2A2 and overlapping histopathological features with Darier disease. AB - The relationship between acrokeratosis verruciformis (AKV) of Hopf and Darier disease (DD) has been debated for several decades. Both diseases are now thought to result from mutations in the same gene, that is, the ATP2A2 gene encoding the sarco (endo) plasmic reticulum Ca ATPase2 pump (SERCA2), although their histopathological features are different. We sought to detect possible overlapping histopathological features between AKV and DD. Fourteen members of a family affected by AKV were analyzed for the underlying molecular genetic derangement, and 3 cases were studied histopathologically using multiple step sections. A heterozygous P602L mutation in ATP2A2 was identified as the underlying cause in this family. This mutation and a heterozygous A698V were previously described in AKV. Both mutations were not among the 162 mutations in ATP2A2, which were reported to date in DD. The histopathological study demonstrated in several consecutive step sections of 2 of the 3 studied cases, foci of small suprabasal clefts with acantholytic keratinocytes, some of which were mildly dyskeratotic. These focal features were reminiscent of the basic histopathological characteristics of DD. These shared histopathological features of AKV with DD suggest that AKV and DD are allelic disorders with variable expression of the same disease, although identical mutations in ATP2A2 in AKV and DD were not reported to date. PMID- 22814320 TI - Necrobiotic xanthogranuloma associated with necrotizing scleritis. AB - A 57-year-old man presented to the ophthalmology clinic with a red right eye. He denied pain, diplopia, tearing, and blurred vision. His medical history included asymptomatic annular plaques on the trunk and extremities for at least a decade. Ophthalmological examination revealed a necrotizing scleritis of the right eye. Examination of the skin demonstrated variable sized annular plaques with central atrophy, some with prominent indurated border and yellow discoloration. No periorbital lesions were present. The ocular lesion rapidly progressed and areas of scleral melting developed in the right eye, which eventually required a scleral patch graft. The left eye also developed necrotizing scleritis with areas of scleral melting. Two sets of skin biopsies were performed a few weeks apart. An initial set of skin punch biopsies revealed extensive palisading granulomatous inflammation throughout the dermis, extending into the subcutis. The accompanying perivascular mononuclear infiltrate contained the collections of plasma cells. Scattered multinucleated giant cells were noted. The possibility of necrobiosis lipoidica diabeticorum was suggested. Subsequent skin biopsies showed more prominent and extensive necrobiosis, raising the possibility of necrobiotic xanthogranuloma. Protein electrophoresis was performed, which revealed an IgG lambda monoclonal protein. PMID- 22814321 TI - MSH6 mutation in a family affected by Muir-Torre syndrome. AB - Muir-Torre syndrome (MTS), a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome, or Lynch syndrome, is an autosomal dominantly inherited condition that combines at least one cutaneous sebaceous neoplasm and at least one visceral malignancy. Most patients (~90%) with MTS carry mutations in the MSH2 gene; less than 10% of the cases are associated with a mutation MLH1 gene, and only 3 MTS patients with a pathogenic MSH6 mutation have been previously documented. We report a family affected with MTS in which 3 members (father and 2 sons) were found to harbor a missense mutation c.2633T>C (p.V878A) in exon 4 of the MSH6 gene. PMID- 22814322 TI - Myxoinflammatory fibroblastic sarcoma of the face. AB - Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade tumor of modified fibroblasts, with tendency to local recurrence. This unusual entity typically presents as a slow-growing painless mass in the distal extremities of middle-aged subjects. A 48-year-old woman presented to our clinic with a painless subcutaneous mass in the right temporal region. Excisional biopsy made the rare diagnosis of MIFS. Histologic examination showed the unique features that characterize this lesion: a myxoid component with a superimposed inflammatory infiltrate and the presence of distinctive, large, and bizarre Reed-Stemberg-like cells. A second wide tumor bed resection was performed, achieving clear margins. No adjuvant therapy was administered, and the patient is free of disease at 18 months postoperatively. To the best of our knowledge, this is the first reported case of MIFS presenting in the face. This adds another possibility for differential diagnoses of soft tissue tumors of the face. PMID- 22814323 TI - To the editor. PMID- 22814324 TI - Numerous umbilicated papules on the trunk: multiple warty dyskeratoma. PMID- 22814325 TI - Well-differentiated malignant cylindroma. PMID- 22814326 TI - Congenital extrarenal malignant rhabdoid tumor in an infant with distal 22q11.2 deletion syndrome: the importance of SMARCB1. AB - Extrarenal rhabdoid tumor is a rare malignancy of infants and children, typically presenting in the soft tissue of deep, axial locations. We describe a rare dermal presentation of congenital extrarenal rhabdoid tumor in the left paraspinal region of a 6-month-old girl with germline deletion of chromosome 22q11.21q11.23. This case demonstrates that like other rhabdoid tumors, the SMARCB1 gene is also responsible for cutaneous extrarenal rhabdoid tumor oncogenesis. PMID- 22814327 TI - Reactivation of Chagas disease by immunosuppressive therapy in a patient with systemic lupus erythematosus: report of an exceptional case. AB - Chagas disease is a zoonosis caused by the protozoan Trypanosoma cruzi. It presents as a chronic evolution and produces high morbidity and mortality in countries where the disease is endemic, as in ours. The skin disease is very rare and results from the reactivation of latent disease as a result of immunosuppression, presenting with acute, atypical, and severe lesions. We describe the case of a patient who was unaware of being a carrier of Chagas disease and presented reactivation after immunosuppressive therapy instituted to treat her systemic lupus erythematosus. PMID- 22814328 TI - Impact of small variations in the delivered dose of rabbit antithymocyte induction therapy in kidney transplantation with early corticosteroid withdrawal. AB - BACKGROUND: Optimal dosing of rabbit antithymocyte globulin (rATG) induction therapy in kidney transplantation is not well defined. The impact of dosing from variations in dose rounding or single dose limits has not been studied. METHODS: This retrospective study of 242 adult renal transplant recipients receiving rATG induction and steroid-sparing maintenance therapy evaluates the effect of small changes in rATG induction dosing. The local protocol calls for four doses of rATG 1.5 mg/kg, approximated to the nearest 25 mg and limited to a max of 150 mg. Patients were stratified by total rATG dose received 5 to 6 mg/kg (n=151) and 6 mg/kg (n=91) or more. Incidence of biopsy-proven acute rejection, patient and graft survival, and allograft function were examined. RESULTS: Baseline and transplantation characteristics were similar between groups except for differences in mean weight (SD) (81 [17.3] vs. 76.3 [15.6]) and cumulative rATG dose received (451.8 [96.2] vs. 481.1 [93]) for patients in the 5- to 6-mg/kg group and 6-mg/kg or more group, respectively. Patients who received more rATG showed a significantly lower incidence of biopsy-proven acute rejection at last follow-up 11% (32/151) vs. 21.2% (10/91) among those who received only 5 to 6 mg/kg (P<0.042). Renal function (mean serum creatinine level) was similar at both 90 days and time of last follow-up. Safety review of leukopenia or thrombocytopenia did not differ. CONCLUSION: Small changes in total rATG induction administered seem to significantly impact the incidence of rejection. Adequate rATG dosing is associated with improved rejection-free graft survival and should be achieved for all patients; doses should be rounded up when appropriate or additional doses should be administered if necessary. PMID- 22814330 TI - Clinical relevance of anti-HLA donor-specific antibodies detected by Luminex assay in the development of rejection after renal transplantation. AB - BACKGROUND: The role of anti-human leukocyte antigen (HLA) donor-specific antibodies (DSA) detected by Luminex in the development of rejection is not fully understood. METHODS: A study including 369 patients who received transplants from deceased donors with a negative complement-dependent cytotoxicity crossmatch (XM) was performed. From the total of patients, 151 underwent a renal biopsy because of renal dysfunction, whereas the 218 remaining showed a stable renal function, and no rejection was assumed. Diagnosis and type of rejection was based in biopsy data. RESULTS: Patients with a positive virtual XMs showed more rejection episodes of any types when comparing with patients with negative virtual XMs (P<0.0001). Nevertheless, there were no significant differences between patients without anti-HLA antibodies and patients with anti-HLA no DSA. Allograft impairment was caused by a rejection episode in 84% (32/38) of patients with anti HLA-DSA but only in 30% (34/113) of patients without anti-HLA-DSA. Regarding the type of rejection detected in the biopsy, all the patients with de novo (after transplantation) anti-HLA-DSA were diagnosed as antibody-mediated rejection (AMR) or AMR+T-cell-mediated rejection, whereas most of the patients without anti-HLA DSA (68%) were diagnosed with T-cell-mediated rejection, and patients with preexistent anti-HLA-DSA showed a more homogeneous distribution of the different types of rejection. CONCLUSIONS: According to our results, patients with preformed or de novo anti-HLA-DSA showed the highest likelihood to suffer rejection episodes. Transplantation with preformed anti-HLA-DSA should be avoided, and an early detection of de novo HLA antibodies is important to treat patients before damage occurs in the graft. PMID- 22814329 TI - Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation. AB - BACKGROUND: Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT. METHODS: We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater. RESULTS: A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug. CONCLUSION: High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity. PMID- 22814331 TI - An isolated venous sac as a novel site for cell therapy in diabetes mellitus. AB - BACKGROUND: Transplanting pancreatic islets is of significant interest for type 1 diabetes mellitus. After intraportal injection of islets, inferior engraftment and eventual loss of transplanted islets constitute major limitations. Therefore, alternative approaches will be helpful. Here, we evaluated in animals whether an isolated venous sac would support survival of transplanted islets, along with correction of hyperglycemia. METHODS: Pancreatic islets isolated from adult Lewis rats were transplanted either into an isolated venous sac made from lumbar vein or into the portal vein of syngeneic rats. The integrity and vascular organization of the venous sac was determined by studies of the local microcirculation. The engraftment, survival, and function of transplanted islets were analyzed by histology, including endocrine function in situ and by glycemic control in rats with streptozotocin-induced diabetes. RESULTS: Transplanted islets showed normal morphology with insulin expression in isolated venous sac during the long term. Transplanted islets received blood supply from vasa vasorum and had access to drainage through venous tributaries in the venous sac. This resulted in restoration of euglycemia in diabetic rats. Removal of islet graft bearing venous sac in diabetic rats led to recurrence of hyperglycemia. By contrast, euglycemia was not restored in rats treated by intraportal transplantation of islets. CONCLUSIONS: We demonstrated that pancreatic islets successfully engrafted and functioned in the isolated venous sac with ability to restore euglycemia in diabetic rats. Therefore, the isolated venous sac offers a new site for transplantation of pancreatic islets. This would be clinically beneficial as an alternative to intrahepatic islet transplantation. PMID- 22814332 TI - Macroporous hydrogel micropillars for quantifying Met kinase activity in cancer cell lysates. AB - Overactive and overexpressed kinases have been implicated in the cause and progression of many cancers. Kinase inhibitors offer a targeted approach for treating cancers associated with increased or deregulated kinase activity. Often, however, cancer cells exhibit initial resistance to these inhibitors or evolve to develop resistance during treatment. Additionally, cancers of any one tissue type are typically heterogeneous in their oncogenesis mechanisms, and thus diagnosis of a particular type of cancer does not necessarily provide insight into what kinase therapies may be effective. For example, while some lung cancer cells that overexpress the epidermal growth factor receptor (EFGR) respond to treatment with EGFR kinase inhibitors, overexpression or hyperactivity of Met kinase correlates with resistance to EGFR kinase inhibitors. Here we describe a microfluidic-based assay for quantifying Met kinase activity in cancer cell lysates with the eventual goals of predicting cancer cell responsiveness to kinase inhibitors and monitoring development of resistance to these inhibitors. In this assay, we immobilized a phosphorylation substrate for Met kinase into macroporous hydrogel micropillars. We then exposed the micropillars to a cancer cell lysate and detected substrate phosphorylation using a fluorescently conjugated antibody. This assay is able to quantify Met kinase activity in whole cell lysate from as few as 150 cancer cells. It can also detect cells expressing overactive Met kinase in a background of up to 75% non-cancerous cells. Additionally, the assay can quantify kinase inhibition by the Met-specific kinase inhibitors SU11274 and PHA665752, suggesting predictive capability for cellular response to kinase inhibitors. PMID- 22814333 TI - The benefits of baseline glucocorticoid measurements: maximal cortisol production under baseline conditions revealed in male Richardon's ground squirrels (Urocitellus richardsonii). AB - Wildlife capture methods can make it impractical or impossible to obtain baseline plasma glucocorticoid (GC) levels, and the time of capture of individual animals is often unknown so there may be little uniformity in the duration of capture stress prior to blood collection. Although baseline samples are preferred, if seasonal changes in capture-stress GC levels closely reflect seasonal baseline changes, then capture-stress GC levels can be used to infer at least the direction of change in baseline levels; and if GC levels are relatively constant during long periods of capture, then lack of consistent capture durations are not problematic. These are empirical questions that need to be assessed for each species, and here we present our data for male Richardson's ground squirrels (Urocitellus richardsonii) sampled in prebreeding and postbreeding periods. We compared cortisol levels in blood samples taken within 3 min of capture (BASE), after 30 min of capture-stress (STRESS-1), and after >1.5h of capture-stress (STRESS-2). We found that STRESS-2 cortisol levels did not change in unison with BASE levels, nor were STRESS-2 levels always equal to STRESS-1 levels. The importance of obtaining a baseline sample was further highlighted by our finding that prebreeding BASE cortisol levels were elevated to capture-stress-induced levels, leaving the animals almost no ability to respond to the stress of capture. In contrast, BASE cortisol levels in postbreeding animals were low and most animals responded robustly to capture. Those postbreeding animals that did not respond had high corticosteroid binding globulin levels that buffered the animals against the increase in total cortisol. STRESS-2 cortisol levels were useful for revealing how animals respond to sustained capture-stress, and revealed the same substantial variation among individuals observed in STRESS-1 blood samples, but they missed dramatic changes in baseline levels that are important for understanding the full context of seasonal changes in the functioning of the HPA axis. PMID- 22814334 TI - Kinetics of GDF9 expression in buffalo oocytes during in vitro maturation and their associated development ability. AB - The capacity of fully grown oocytes to regulate their own microenvironment by secreted paracrine factors contribute to their developmental competence. In spite of growing evidence about the vital role of Growth Differentiation Factor 9 (GDF9) in determination of oocyte developmental competence, there is insufficient information about time dependent behavior of its expression during in vitro maturation (IVM) to have definite understanding about at what time point during IVM it plays most crucial role. The study reports the kinetics of GDF9 expression under four different IVM supplement conditions in buffalo oocytes and their concomitant development rate up to blastocyst. Oocytes matured under an ideal media condition with all supplements and those cultured with only FSH resulted in significantly higher cumulus expansion, nuclear maturation, cleavage and blastocyst rates. GDF9 expression at both mRNA and protein levels at different time points of IVM revealed that magnitude of mRNA abundance at 8h of IVM was most important towards imparting development competence to buffalo oocytes. Appearance of GDF9 protein in maturing oocytes was found asynchronous with mRNA appearance in the time course of IVM suggesting possible posttranscriptional regulation of this gene under dynamic oocyte cumulus cell communication process. Abundance of mature GDF9 protein at 16 h was most consistently related with all oocyte development parameters. PMID- 22814335 TI - Up-regulation of gonadotropin mRNA-expression at the onset of gametogenesis in the roach (Rutilus rutilus): evidence for an important role of brain-type aromatase (cyp19a1b) in the pituitary. AB - The present study characterized changes in key parameters of reproduction in adult roach (Rutilus rutilus) from Lake Grosser Mueggelsee (Berlin, Germany) during natural gametogenesis. Fish of both sexes were sampled in monthly intervals between April and August in order to cover the onset of gametogenesis. Investigated parameters included gonad histology, plasma levels of 17beta oestradiol (E2), testosterone (T), 11-ketotestosterone (11-KT), and 17,20beta dihydroxy-4-pregnen-3-one (17,20beta-P) as well as the expression of gonadotropin subunits in the pituitary. Furthermore, the mRNA-expression of brain-type aromatase (cyp19a1b), androgen receptor (ar), and estrogen receptor isoforms was studied at the pituitary level. The onset of gametogenesis - as indicated by follicles with cortical alveoli in females and first spermatogonia B in males - was observed in July, accompanied by a significant up-regulation of follicle stimulating hormone beta (fshbeta) mRNA in the pituitary in both sexes. On the other hand, luteinizing hormone beta (lhbeta) mRNA increased later on in August. In males, the increase of fshbeta mRNA in July coincided with a rise in plasma 11 KT concentrations. In females, E2 in plasma increased later, not until August, shortly before true vitellogenesis (late cortical alveoli stage). Expression of sex steroid receptors in the pituitary revealed only minor seasonal fluctuations. Most pronounced, ar mRNA displayed the highest level pre-spawning in both sexes. Interestingly, cyp19a1b mRNA-expression in the pituitary increased in parallel with fshbeta already before any changes in plasma E2 or T occurred. These data suggest an important role of pituitary FSH and aromatase at the onset of gametogenesis in the roach. PMID- 22814336 TI - Regulation of epithelial calcium transport by prolactin: from fish to mammals. AB - Among the reported ~300 biological actions, the established role of prolactin (PRL) is to act as a vertebrate hypercalcemic hormone that regulates epithelial calcium transport in several organs, such as the gills, intestine, and kidney. In fish, PRL stimulates the branchial calcium transport by increasing the activity of Ca(2+)-ATPase. Although this calciotropic hormone also induces hypercalcemia in amphibians, reptiles and birds, little has been known regarding the underlying mechanism. In contrast, the effects of PRL on the epithelial calcium transport in mammals are well documented. In rodents, PRL has been shown to stimulate the renal tubular calcium reabsorption and intestinal calcium absorption, the latter of which is mediated by the PRL-induced upregulation of calcium transporter gene expression and activities. Recently, we demonstrated that the duodenal calcium absorption in lactating rats was markedly enhanced by the suckling-induced PRL surge, presumably to provide calcium for milk production. The cellular and molecular mechanisms of the PRL-stimulated calcium transport in mammals have been elaborated in this review. PMID- 22814337 TI - Increase of carboxylesterase activity in Fasciola hepatica recovered from triclabendazole treated sheep. AB - In the present work, we evaluate in vivo the activity of carboxylesterase of Fasciola hepatica exposed to triclabendazole. We observed a statistically significant increase in enzyme activity at 24 and 48 h post treatment (P<0.01 and P<0.001, respectively). The zymogram of cytosolic fractions identified a protein of 170 kDa containing the carboxylesterase activity. The densitograms of the zymograms confirmed the phenomenon of enzyme induction under the experimental conditions of the assay. These results provide not only the understanding of the importance of this metabolic pathway in flukes but carboxylesterase would also be an enzyme that could participate more actively in the development of anthelmintic resistance at TCBZ. PMID- 22814338 TI - Parasite diversity and microsatellite variability in native and introduced populations of four Neogobius species (Gobiidae). AB - Species introduced into new areas often show a reduction in parasite and genetic diversity associated to the limited number of founding individuals. In this study, we compared microsatellite and parasite diversity in both native (lower Danube) and introduced populations of 4 Ponto-Caspian gobies, including those (1) introduced from within the same river system (middle Danube; Neogobius kessleri and N. melanostomus), and (2) introduced from a different river system (River Vistula; N. fluviatilis and N. gymnotrachelus). Microsatellite data confirmed the lower Danube as a source population for gobies introduced into the middle Danube. Both native and introduced (same river system) populations of N. kessleri and N. melanostomus had comparable parasite species richness and microsatellite diversity, possibly due to multiple and/or continual migration/introduction of new individuals and the acquisition of local parasites. Reduced parasite species richness and microsatellite diversity were observed in introduced (different river system) populations in the Vistula. A low number of colonists found for N. fluviatilis and N. gymnotrachelus in the Vistula potentially resulted in reduced introduction of parasite species. Insufficient adaptation of the introduced host to local parasite fauna, together with introduction into an historically different drainage system, may also have contributed to the reduced parasite fauna. PMID- 22814339 TI - Lower TCR repertoire diversity in Traj18-deficient mice. PMID- 22814340 TI - Immunological complications of obesity. AB - Current approaches for the treatment of obesity, including diet and lifestyle changes, have not been successful in curtailing the obesity epidemic. The higher incidence of inflammation-associated chronic disease and greater susceptibility to infection in obese people represents a growing health threat. Improved understanding of the immunological processes that regulate obesity may yield new treatments for obesity-associated disorders. PMID- 22814341 TI - Breaking the barrier: membrane fusion triggers innate antiviral immunity. AB - The sensing of viral infection by the innate immune system is dominated by the recognition of nucleic acids. New data now demonstrate that the fusion of viral and target-cell membranes leads to the activation of an immune response dependent on the adaptor STING. PMID- 22814342 TI - Hair follicles: gatekeepers to the epidermis. AB - Substantial depletion of Langerhans cells leads to their replenishment by bone marrow-derived precursors that access the epidermis through hair follicles, a site of crucial chemokine production. PMID- 22814343 TI - The yin-yang nature of CSF1R-binding cytokines. AB - Most myeloid cells express the growth-factor receptor CSF1R. Recognition of interleukin 34 by CSF1R is required for the development of tissue-resident Langerhans cells and microglia, which explains the independence of their growth from CSF1. PMID- 22814344 TI - Negative regulators take center stage. AB - The transcription factor Aiolos is upregulated in T lymphocytes in a manner dependent on the transcription factors STAT3 and AhR and leads to epigenetic silencing of the gene encoding interleukin 2. This acts as a cell-intrinsic safeguard mechanism for the differentiation of helper T cells into the TH17 subset. PMID- 22814352 TI - Disila-analogues of the synthetic retinoids EC23 and TTNN: synthesis, structure and biological evaluation. AB - Silicon chemistry offers the potential to tune the effects of biologically active organic molecules. Subtle changes in the molecular backbone caused by the exchange of a carbon atom for a silicon atom (sila-substitution) can significantly alter the biological properties. In this study, the biological effects of a two-fold sila-substitution in the synthetic retinoids EC23 (4 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid (4a)) and TTNN (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-naphthoic acid (7a)) as well as their corresponding analogues with an indane instead of a 1,2,3,4-tetrahydronaphthalene skeleton (compounds 5a and 8a) were investigated. Two-fold C/Si exchange in 4a, 5a, 7a and 8a leads to the silicon-analogues disila EC23 (4b), 5b, disila-TTNN (7b) and 8b, which contain a 1,2,3,4-tetrahydro-1,4 disilanaphthalene (4b, 7b) or 1,3-disilaindane skeleton (5b, 8b). Exchange of the SiCH(2)Si moiety of 5b for an SiOSi fragment leads to the disiloxane 6 (2-oxa-1,3 disilaindane skeleton). The EC23 derivative 5a, the TTNN derivative 8a and the silicon-containing analogues 4b, 5b, 6, 7b and 8b were synthesised, and the biological properties of the C/Si pairs 4a/4b, 5a/5b, 7a/7b and 8a/8b and compound 6 were evaluated in vivo using RAR isotype-selective reporter cells. EC23 (4a) and its derivatives disila-EC23 (4b), 5a, 5b and 6 are very potent RAR agonists, which are even more potent than the powerful reference compound TTNPB. Disila-substitution of EC23 (4a) and 5a leads to a moderate decrease in RARalpha activation, whereas the RARbeta,gamma activation is almost not affected. In contrast, two-fold C/Si exchange in the weak retinoid agonist TTNN (7a) and 8a resulted in considerably different effects: a significant increase (7a->7b) and almost no change (8a->8b) in transcription activation potential for all three RAR isotypes. Disila-TTNN (7b) can be regarded as a powerful RARbeta,gamma-selective retinoid. PMID- 22814351 TI - IL-12 family cytokines: immunological playmakers. AB - The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity. PMID- 22814353 TI - Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. AB - BACKGROUND: With widespread use of antiretroviral therapy (ART) and prolonged survival of HIV-infected children, toxicities like lipodystrophy are becoming more evident. Little is known about lipodystrophy in children in Uganda yet there is increased use of ART. The aim of this study was to determine the prevalence and factors associated with fat redistribution and metabolic abnormalities among HIV-infected children on highly active antiretroviral therapy (HAART) in Uganda. METHODS: A cross-sectional study of 364 HIV positive children aged between 2 and 18 years on ART were enrolled after consent and assent as appropriate. Sociodemographic, clinical and immunological data were collected and recorded in a questionnaire. Fat redistribution was assessed clinically for physical findings of lipohypertrophy and lipoatrophy. A fasting blood sample was taken for lipid profile and blood glucose analysis. Lipodystrophy was defined as presence of abnormal fat redistribution or metabolic abnormalities or both. The proportion of children with fat redistribution and metabolic abnormalities was calculated. We conducted multivariate analysis for factors associated with lipodystrophy among children with lipodystrophic features and those without. RESULTS: The median age of the participants was eight years (range 2 to 18), with 43% of these aged >= 10 years and a male to female ratio of 1.1:1. Majority (65%) had advanced HIV (WHO Stage III/IV) at ART initiation with a mean duration on ART of 3.8 years (+/- 1.2). The prevalence of fat redistribution and hyperlipidemia was 27.0% and 34.0%, respectively. None of the children had hyperglycaemia. Among the children with hyperlipidemia, 16.8% exhibited hypercholesterolemia and 83% had hypertriglyceridemia. Only 29% of children with fat redistribution had hyperlipidemia. We found significant association between fat redistribution and Tanner stages 2 to 5 OR=2.3 (95%CI 1.3 to 3.8), age >= 5 years OR=3.9 (95%CI 1.5 to 9.9) and d4T exposure OR=3.4 (95%CI 2.0 to 5.8). A Tanner stage 2 to 5 was independently associated with hyperlipidemia. No significant association was observed with HIV clinical stage and any of the anthropometric measurements. CONCLUSION: The prevalence of lipodystrophy is high among HIV-infected children on ART with a likelihood of developing fat redistribution and metabolic abnormalities increased during puberty. PMID- 22814354 TI - A oximato-bridged linear trinuclear [Mn(IV)Mn(III)Mn(IV)] single-molecule magnet. AB - The reaction of Mn(HCOO)(2).2H(2)O, (t)BuSaoH(2) (3,5-di-tert-butyl salicylaldoxime) and sodium azide in isopropanol leads to [NaMn(3)((t)BuSao)(6)] (1). Its structure can be described as a linear trinuclear cluster bridged by oximato ligands. Magnetic investigation revealed that the ferromagnetic coupling interaction is dominant in 1 leading to a ground-state spin S(T) = 5. 1 shows single-molecule magnet behaviour under zero or 1 kOe dc field with energy barrier U(eff) ~ 10 K. PMID- 22814355 TI - A comparison of treadmill and overground walking effects on step cycle asymmetry in young and older individuals. AB - Although lower limb strength becomes asymmetrical with age, past studies of aging effects on gait biomechanics have usually analyzed only one limb. This experiment measured how aging and treadmill surface influenced both dominant and nondominant step parameters in older (mean 74.0 y) and young participants (mean 21.9 y). Step cycle parameters were obtained from 3-dimensional position/time data during preferred-speed walking for 40 trials along a 10 m walkway and for 10 minutes of treadmill walking. Walking speed (young 1.23 m/s, older 1.24 m/s) and step velocity for the two age groups were similar in overground walking but older adults showed significantly slower walking speed (young 1.26 m/s, older 1.05 m/s) and step velocity on the treadmill due to reduced step length and prolonged step time. Older adults had shorter step length than young adults and both groups reduced step length on the treadmill. Step velocity and length of older adults' dominant limb was asymmetrically larger. Older adults increased the proportion of double support in step time when treadmill walking. This adaptation combined with reduced step velocity and length may preserve balance. The results suggest that bilateral analyses should be employed to accurately describe asymmetric features of gait especially for older adults. PMID- 22814356 TI - In vitro Antimicrobial Activity of SinuSurfTM. AB - BACKGROUND: Topical surfactant therapy has been found to be effective in the management of recalcitrant chronic rhinosinusitis. OBJECTIVE: To determine in vitro the antibacterial potential of SinuSurfTM, a previously commercially available sinonasal surfactant. METHODS: Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA) cultures were grown in the presence or absence of serial dilutions of mupirocin or gentamicin with and without SinuSurf and quantified by colony-forming units (CFUs). Biofilm formation was also assessed. Finally, bacterial growth was evaluated in sinus irrigation bottles inoculated with MRSA or PA and rinsed daily with SinuSurf. RESULTS: SinuSurf alone evinced a 3-log (1,000-fold) and 6-log (10(6)-fold) reduction in CFUs for MRSA and PA, respectively. The combination of SinuSurf with a 1:10 dilution mupirocin and 1:100 dilution gentamicin demonstrated complete bacterial eradication. Similar concentrations of antibiotic dilutions alone demonstrated bacterial growth. SinuSurf averaged an 83% MRSA and 76% PA reduction in biofilm formation. Bottle contamination evaluation demonstrated reduction of MRSA and PA (p < 0.05) with SinuSurf. CONCLUSION: Biofilms have been demonstrated in chronic rhinosinusitis patients and implicated in recalcitrant disease. Our in vitro data demonstrates the addition of SinuSurf improved the effectiveness of a lower concentration of topical antibiotics in biofilm mass and viability. PMID- 22814357 TI - Association of body image and health beliefs with health behaviors in patients with diabetes: a cross-sectional study. AB - PURPOSE: The purpose of this study was to investigate relationships between body image, health beliefs, and health behavior in patients with diabetes classified according to body mass index (BMI). METHODS: A cross-sectional study was conducted in a community hospital between January and April 2010. One-hundred sixty-eight patients with diabetes were enrolled. Main measure was the previously published and validated Health Belief Questionnaire. Data were analyzed and compared between two groups, one with BMI >= 24 Kg/m(2) and another with BMI < 24 Kg/m(2). RESULTS: Perceived body image affected health behavior of patients with BMI >= 24 Kg/m(2) but did not affect health behavior in patients with BMI < 24 Kg/m(2). Multivariate analysis found a positive association between health behavior and appearance evaluation and between health behavior and health evaluation in high BMI group. No significant association was found between body image and health behavior in the low BMI group. Patients with high BMI had lower body image than patients with low BMI as demonstrated by results of appearance evaluation, health evaluation, prevention behavior, and benefits. CONCLUSIONS: Perceived body image and health beliefs are associated with self-reported health behavior among patients with diabetes with BMI measurement greater than 24 Kg/m(2). Diabetes educators may apply the findings of this study and the Health Belief Questionnaire to instruct and monitor patients with diabetes about self management behaviors. PMID- 22814358 TI - The influence of diabetes on a clinician-rated assessment of depression in adults with type 1 diabetes. AB - PURPOSE: The purpose of the study was to examine the role of diabetes and diabetes-related distress within clinician-administered depression interviews of adults with type 1 diabetes. METHODS: This mixed-methods study coded responses to a structured clinical interview of depressive symptom severity administered to adults with type 1 diabetes (n = 34; 65% female; 56% white, 38% African American, 27% Hispanic). Pearson correlations and t tests assessed relationships between interview-based and self-reported ratings of diabetes-related distress and depression. RESULTS: Among participants endorsing depressive symptoms in the interview, 73% mentioned diabetes as a contributing factor. Themes emerged relating to (1) a link between diabetes symptoms and distress, including problems with appetite, sleep, concentration, and social relationships; (2) overlapping symptoms between diabetes and depression; and (3) the perceived interconnectedness of mood and blood glucose levels. Clinician-assessed depression ratings were strongly associated with self-reported ratings of depression and self-reported diabetes-related distress. Interview-based diabetes related distress was significantly associated with self-reported diabetes-related distress. Those with a diagnosis of major depressive disorder (44%) reported more diabetes-related distress. CONCLUSIONS: Results suggest that diabetes may influence the evaluation of depression, even in standardized clinical interviews administered by trained professionals, the gold standard of assessment. Findings highlight a need for improved conceptualization and measurement of distress in individuals with diabetes to distinguish between symptoms caused by illness burden and those indicating a psychiatric disorder. PMID- 22814359 TI - A role for the membrane proteome in human chronic kidney disease erythrocytes. AB - The molecular basis of the reduced half-life of chronic kidney disease (CKD) erythrocytes is unclear. The erythrocyte membrane plays a key role in the erythrocyte mechanical properties and survival. The aim of the present work is to uncover erythrocyte membrane proteins whose expression could be altered in CKD. The erythrocyte membrane subproteome was analyzed by a non-biased approach where the whole set of proteins was simultaneously investigated by 2D fluorescence difference gel electrophoresis without preselection of potential targets. Proteins significantly altered in CKD were identified by mass spectrometry (MS) and results validation was performed by Western blot and confocal microscopy. Nine differentially expressed spots among healthy individuals, non-dialyzed CKD and erythropoietin/dialysis-treated CKD patients were identified by MS/MS corresponding to 5 proteins (beta-adducin, HSP71/72, tropomodulin-1, ezrin, and radixin). Ezrin and radixin were higher in dialyzed CKD patients than in the other 2 groups. Beta-adducin was increased in CKD patients (dialyzed or not). Three spots were normalized in patients on the dialysis/erythropoietin combination compared with non-dialyzed CKD. Among these, a spot corresponding to tropomodulin 1, was found to be of higher abundance in non-dialyzed CKD patients compared with controls or dialyzed CKD. In conclusion, this study identifies changes in erythrocyte membrane proteins in CKD, which may be relevant for the pathogenesis of red cell abnormalities in uremia. PMID- 22814360 TI - Halomonas johnsoniae: review of a medically underappreciated genus of growing human importance. AB - The growing genus Halomonas includes bacteria favoring or tolerating high saline/halide and high-pH environments. Infections are rarely reported. A patient developed Halomonas johnsoniae (previously reported only as dialysis unit environmental contaminants) bacteremia. The medical community is alerted to the pathogenic potential of the genus, particularly in a dialysis setting. PMID- 22814361 TI - Measurement of colorectal cancer test use with medical claims data in a safety net health system. AB - BACKGROUND: Optimizing colorectal cancer (CRC) screening requires identification of unscreened individuals and tracking screening trends. A recent National Institutes of Health State of the Science Conference, "Enhancing Use and Quality of CRC Screening," cited a need for more population data sources for measurement of CRC screening, particularly for the medically underserved. Medical claims data (claims data) are created and maintained by many health systems to facilitate billing for services rendered and may be an efficient resource for identifying unscreened individuals. The aim of this study, conducted at a safety-net health system, was to determine whether CRC test use measured by claims data matches medical chart documentation. METHODS: The authors randomly selected 400 patients from a universe of 20,000 patients previously included in an analysis of CRC test use based on claims data 2002-2006 in Tarrant Co, TX. Claims data were compared with medical chart documentation by estimation of agreement and examination of test use over/underdocumentation. RESULTS: The authors found that agreement on test use was very good for fecal occult blood testing (kappa = 0.83, 95% confidence interval: 0.75-0.90) and colonoscopy (kappa = 0.91, 95% confidence interval: 0.85-0.96) and fair for sigmoidoscopy (kappa = 0.39, 95% confidence interval: 0.28-0.49). Over- and underdocumentations of the 2 most commonly used CRC tests--colonoscopy and fecal occult blood testing--were rare. CONCLUSIONS: Use of claims data by health systems to measure CRC test use is a promising alternative to measuring CRC test use with medical chart review and may be used to identify unscreened patients for screening interventions and track screening trends over time. PMID- 22814362 TI - Routine pneumococcal vaccination of children provokes new patterns of serotypes causing invasive pneumococcal disease in adults and children. AB - INTRODUCTION: Routine vaccination of infants with protein-conjugated 7-valent pneumococcal vaccine (PCV7) begun in 2000 initiated a sea change of prevalent serotypes (STs) in invasive pneumococcal disease (IPD). The authors investigated in 1 community all STs causing IPD during 5 years before (PRE) and 2, 5-year periods after (POST1 and POST2) its initiation and found that PCV7 adversely affected ST coverage of 23-valent pneumococcal polysaccharide vaccine (PPV23) among adults. METHODS: From 1996-2010, 620 consecutive Streptococcus pneumoniae IPD strains from adults (521) and children (99) hospitalized with IPD in Huntington, WV, were collected. Each strain was typed by Quellung reaction. The Marshall University Institutional Review Board approved this study. RESULTS: By 6 to 10 years after the initiation of PCV7, IPD in children decreased significantly, whereas IPD in adults increased significantly. In both adults and children, IPD due to PCV7 STs decreased significantly. In adults with IPD, PCV7 STs were replaced by several non-PCV7 STs including STs contained in PPV23 but not in PCV7 and STs not contained in either vaccine. IPD due to 4 nonsusceptible STs included in PCV7 decreased from PRE to POST1 and POST2. IPD due to nonsusceptible STs not included in PCV7 increased from PRE to POST1 and POST2. CONCLUSIONS: Routine PCV7 decreased IPD in children but not in adults. Predominant STs changed--children exhibited fewer PCV7 STs and adults exhibited fewer PCV7 and PPV23 STs--reducing vaccine coverage and increasing the risk of replacement STs causing IPD in adults. PMID- 22814363 TI - Differential diagnosis of acute pericarditis from normal variant early repolarization and left ventricular hypertrophy with early repolarization: an electrocardiographic study. AB - BACKGROUND: Differentiation of ST-segment elevation on electrocardiogram (ECG) from acute pericarditis (AP), normal variant early repolarization (ER) and early repolarization of left ventricular hypertrophy (ERLVH) can be problematic. Hence, the authors evaluated the accuracy of the ST/T ratio in ECG to more optimally differentiate between AP, ST-segment elevation, ER and ERLVH. METHODS: Between September 2006 and July 2010, 80 patients were enrolled in this study consisting of 25 individuals with AP, 27 with ER and 28 with ERLVH. Each ECG was analyzed in a systematic manner including the measurement of PR interval, QRS duration, QT segment duration, PR-segment deviation, ST-segment deviation and the height of T wave. The ratio of the height of ST segment to the height of T wave was measured in leads I, II, III, aVF and V2 through V6. RESULTS: The mean ages of the patients with AP, ER and ERLVH were 32 +/- 16.5, 36 +/- 15.4 and 53 +/- 16 years, respectively. The ratio of the amplitude of ST segment to the amplitude of the T wave in leads I, V4, V5 and V6 proved to be a significant discriminator at a value of >=0.25 (P < 0.05 for all). CONCLUSIONS: Leads I, V4, V5 and V6 can all be used to differentiate AP from ER and ERLVH. When ST elevation is present in lead I, the ST/T ratio has the best predictive value (0.82) to more accurately discriminate between AP, ER and ERLVH. PMID- 22814364 TI - Hapten facilitates food allergen-related intestinal hypersensitivity. AB - BACKGROUND: Haptens can bind to proteins to elicit antigenicity. Whether haptens play a role in the pathogenesis of food allergy remains to be investigated. This article aims to elucidate the role a hapten plays in food antigen-related T helper 2 (Th2) pattern inflammation in the intestine. METHODS: The effect of trinitrobenzene sulfonic acid (TNBS; as a hapten) on the properties of dendritic cells was assessed by a cell culture model. BALB/c mice were sensitized with a mixture of TNBS and ovalbumin (OVA; as a model antigen). Intestinal Th2 response, OVA-specific immunoglobulin E and histamine were analyzed with the mouse model. In addition to the infiltration of the intestinal inflammatory cells, cytokine expression profiles were determined. RESULTS: TNBS increased the expression of T cell immunoglobulin and mucin domain-4 and CD80 and decreased the levels of interleukin-12 in dendritic cells. Higher serum levels of OVA-specific immunoglobulin E, histamine expression and skewed antigen-specific Th2 polarization in the intestinal tissue were detected in mice sensitized with TNBS + OVA as compared with those treated with either OVA or TNBS alone. In addition, the TNBS-OVA-treated mice also showed an increased number of inflammatory cells, high levels of interleukin-4 and a decreased expression of interferon-gamma in the lamina propria mononuclear cells. CONCLUSIONS: Hapten TNBS can facilitate the initiation of food antigen-related Th2 pattern inflammation, such as food allergy, in the intestine. PMID- 22814365 TI - Facile and rapid DNA extraction and purification from food matrices using IFAST (immiscible filtration assisted by surface tension). AB - Extraction and purification of DNA is a prerequisite to detection and analytical techniques. While DNA sample preparation methods have improved over the last few decades, current methods are still time consuming and labor intensive. Here we demonstrate a technology termed IFAST (Immiscible Filtration Assisted by Surface Tension), that relies on immiscible phase filtration to reduce the time and effort required to purify DNA. IFAST replaces the multiple wash and centrifugation steps required by traditional DNA sample preparation methods with a single step. To operate, DNA from lysed cells is bound to paramagnetic particles (PMPs) and drawn through an immiscible fluid phase barrier (i.e. oil) by an external handheld magnet. Purified DNA is then eluted from the PMPs. Here, detection of Clostridium botulinum type A (BoNT/A) in food matrices (milk, orange juice), a bioterrorism concern, was used as a model system to establish IFAST's utility in detection assays. Data validated that the DNA purified by IFAST was functional as a qPCR template to amplify the bont/A gene. The sensitivity limit of IFAST was comparable to the commercially available Invitrogen ChargeSwitch(r) method. Notably, pathogen detection via IFAST required only 8.5 MUL of sample and was accomplished in five-fold less time. The simplicity, rapidity and portability of IFAST offer significant advantages when compared to existing DNA sample preparation methods. PMID- 22814366 TI - Serum thyroglobulin level measured after thyroxine withdrawal is useful to predict further recurrence in whole body scan-negative papillary thyroid cancer patients after reoperation. AB - The best treatment option for recurrent papillary thyroid carcinoma (PTC) is reoperation when the recurrent lesion is locoregional. The prognostic significance of serum thyroglobulin (Tg) levels before reoperation and the association between the outcome of reoperation and Tg level remain unclear. Our study aimed to determine the outcomes of patients who underwent reoperation and their association with serum Tg levels. We retrospectively studied 79 patients with PTC with locoregional recurrence whose whole-body scan results were negative for any recurrence but whose serum Tg levels were detectable after first-line treatment. All the patients underwent reoperation and follow-up examinations, which involved serial serum Tg measurements after thyroxine withdrawal (T4-off Tg), neck ultrasonography, chest computed tomography, and/or fluorodeoxyglucose positron emission tomography, to detect further recurrence. During the median follow-up duration of 89 months (range, 38-332 months), 30 patients (38.0%) experienced a second recurrence even after the reoperation. Among all patients, only 12 whose Tg levels decreased postoperatively to undetectable levels showed no recurrence. Most recurrences were detected in the patients with high T4-off Tg levels after the reoperation (T4-off Tg level (ng/mL), number of patients with recurrence, %: <1, 0/12, 0%; 1-10, 9/31, 33.3%; >10, 16/22, 72.7%; P < 0.001). In conclusion, recurrence occurred in 38.0% of the patients even after the reoperation. The postoperative T4-off Tg level was a good indicator of recurrence after the reoperation. Therefore, patients who experience recurrence should undergo follow-up examinations that involve routine measurements of T4-off Tg levels, especially when postreoperative values exceed 10 ng/mL. PMID- 22814367 TI - Cardiovascular therapy, diagnostic procedures, and control of risk factors in patients with diabetes or coronary artery disease in Poland: the Kardia-Pol registry. AB - INTRODUCTION: Diabetes mellitus (DM) and coronary artery disease (CAD) are associated with increased cardiovascular risk. OBJECTIVES: The aim of the study was to compare management of high-risk patients with DM and patients with CAD in Poland. PATIENTS AND METHODS: Randomly selected primary care offices enrolled patients aged 55 years and older, with DM and no documented CAD (n = 210) or with CAD and no documented DM (n = 186). RESULTS: Statins were given to 64% vs. 87% (P <0.05), acetylsalicylic acid (ASA) to 53% vs. 84% (P <0.05), and angiotensin converting enzyme inhibitors to 70% vs. 69% (P = 0.8) of the patients with DM and CAD, respectively. Screening tests to detect glucose abnormalities in patients with CAD or to detect CAD in patients with DM were not performed in 26% of patients with DM and 24% of those with CAD (P = 0.64). Mean systolic blood pressure was 136.8 +/- 13.6 vs. 131.7 +/- 15.8 mmHg (P = 0.001), diastolic blood pressure was 80.4 +/- 7.4 vs. 79.4 +/- 11.6 mmHg (P = 0.316), and total cholesterol was 196 +/- 42 vs. 183 +/- 42 mg/dl (P = 0.003) in patients with DM and CAD, respectively. The percentage of patients with blood pressure below 140/90 mmHg, total cholesterol below 175 mg/dl, and low-density lipoprotein (LDL) cholesterol below 100 mg/dl was 15% vs. 25% (P = 0.055), while the percentage of patients with blood pressure below 130/80 mmHg, total cholesterol below 175 mg/dl, and LDL cholesterol <70 mg/dl was 1% vs. 3% (P = 0.016) in the DM vs. CAD groups, respectively. CONCLUSIONS: Use of statins and ASA was more frequent in patients with CAD than in patients with DM. Control of risk factors in the study population was better in the CAD group but still unsatisfactory in most patients. PMID- 22814368 TI - Menstrual cycle effects on amygdala reactivity to emotional stimulation in premenstrual dysphoric disorder. AB - Premenstrual dysphoric disorder (PMDD) with luteal phase related anxiety and mood swings compromise quality of life in around 4% of reproductive women. While anxiety is related to amygdala function, prior studies on amygdala reactivity both in healthy controls and women with PMDD are inconsistent with respect to menstrual cycle effects. Here women with PMDD and healthy controls were exposed to emotional faces during the mid-follicular and late luteal phase, and mean blood-oxygen-level dependence (BOLD) signal changes in the amygdala were determined with functional magnetic resonance imaging (fMRI). Women with PMDD had enhanced bilateral amygdala reactivity in the follicular phase in comparison with healthy controls, but there was no difference between groups during the luteal phase. In contrast, healthy controls displayed higher left amygdala reactivity in the luteal than in their follicular phase. However, among women with PMDD follicular phase progesterone serum concentrations were positively correlated with bilateral amygdala reactivity while depression scores were positively correlated with right amygdala reactivity in the luteal phase. In addition, women with PMDD and high scores on trait anxiety had increased right amygdala reactivity in the luteal as compared to the follicular phase. Finally, amygdala reactivity was more prone to habituation in women with PMDD, as they had enhanced amygdala reactivity in comparison with controls at the first, but not the second scanning session. Thus, while the study failed to indicate increased luteal phase amygdala reactivity in women with PMDD, our findings suggest that anxiety proneness and progesterone levels modulate menstrual cycle related amygdala reactivity in women with PMDD. PMID- 22814369 TI - The forgotten griever: a nationwide follow-up study of mortality subsequent to the death of a sibling. AB - Previous findings have suggested that the loss of a family member is associated with mortality among bereaved family members. The least-studied familial relationship in the bereavement literature is that of siblings, although loss of a sibling may also involve health consequences. The authors conducted a follow-up study based on data from the Swedish total population register, covering the period 1981-2002. Using Cox regression, mortality risk ratios for bereaved and nonbereaved persons aged 18-69 years were estimated. All-cause mortality and cause-specific mortality (unnatural causes, natural causes, cardiovascular disease, cancer, suicide, accidents, and all other causes) were examined. In men, the mortality risk for bereaved persons versus nonbereaved persons was 1.26 (95% confidence interval: 1.22, 1.30), and in women it was 1.33 (95% confidence interval: 1.28, 1.39). An elevated mortality risk associated with a sibling's death was found in all age groups studied, but the association was generally stronger at younger ages and could be observed predominantly after more than 1 year of follow-up. There was also an increased mortality risk if the sibling had died from a discordant main cause, which may strengthen the possibility that the association observed is not due to confounding alone. PMID- 22814370 TI - Clinical usefulness of the Framingham cardiovascular risk profile beyond its statistical performance: the Tehran Lipid and Glucose Study. AB - The utility of a risk function in clinical practice is an important concept that has received insufficient attention. The authors evaluated the clinical usefulness of the Framingham risk function (FRF) for cardiovascular disease in a Middle Eastern population (2,640 men and 3,584 women aged 30-74 years) free of cardiovascular disease at baseline in 1999. They calculated the net benefit fraction for treatment of subjects with an estimated 10-year risk of >=10% and also >=20%, where the net benefit fraction is a weighted sum of true-positive and false-positive rates divided by incidence, as estimated by Kaplan-Meier analysis. The authors drew a decision curve by plotting the net benefit fraction against a wide range of risk thresholds for treatment. The cumulative incidence of cardiovascular disease was 7.6% and 12.3% in women and men, respectively. The FRF had a C index of 0.832 in women and 0.785 in men with a reasonable calibration. On the basis of the net benefit fraction, about 50% of the incidence in men and women could be appropriately treated by using the 10% threshold; however, the FRF was not useful at the 20% threshold, especially in women. In both genders, usefulness of the FRF was as good as the function derived directly from Tehrani data with the same variables; however, it could be useful in low thresholds for treatment. PMID- 22814371 TI - Invited commentary: Clinical usefulness of the Framingham cardiovascular risk profile beyond its statistical performance. AB - Framingham risk functions (FRFs) have been developed for over 50 years. There have been numerous applications of them and within the last few decades they have been used in drug treatment guidelines. The Adult Treatment Panel III explicitly used a coronary heart disease FRF in their guidelines for cholesterol drug treatment. Evaluation of these functions has traditionally involved discrimination and calibration measures. One major goal of the FRFs is to see if they are valid in non-Framingham settings. In this issue of the Journal, Khalili et al. (Am J Epidemiol. 2012;176(3):177-186) apply a recent global cardiovascular disease FRF to the data from their Tehran Lipid and Glucose Study and demonstrate that the cardiovascular disease FRF performs extremely well: as good as the best risk function generated from the Tehrani data. The FRF is transportable to the Tehrani data without need for any calibration adjustment. The investigators then move beyond the traditional discrimination and calibration evaluations, look for utility, and apply the decision theory concepts of net benefit fraction. This application makes assumptions about treatment guidelines. There are both useful and negative aspects of this application, and caution is advised against a too enthusiastic acceptance of it to evaluate prediction rules for primary prevention of cardiovascular disease. PMID- 22814372 TI - Identification and validation of reference genes to study the gene expression in Gluconacetobacter diazotrophicus grown in different carbon sources using RT-qPCR. AB - Gluconacetobacter diazotrophicus strain PAL5 is a nitrogen-fixing endophytic bacterium originally isolated from sugarcane and later on was found to colonize other plants such as rice, elephant grass, sweet potato, coffee, and pineapple. Currently, G. diazotrophicus has been considered a plant growth-promoting bacterium due to its characteristics of biological nitrogen fixation, phytohormone secretion, solubilization of mineral nutrients and antagonism to phytopathogens. Reverse transcription followed by quantitative real-time polymerase chain reaction (RT-qPCR) is a method applied for the quantification of nucleic acids because of its specificity and high sensitivity. However, the decision about the reference genes suitable for data validation is still a major issue, especially for nitrogen-fixing bacteria. To evaluate and identify suitable reference genes for gene expression normalization in the diazotrophic G. diazotrophicus, mRNA levels of fourteen candidate genes (rpoA, rpoC, recA, rpoD, fabD, gmk, recF, rho, ldhD, gyrB, gyrBC, dnaG, lpxC and 23SrRNA) and three target genes (matE, omp16 and sucA) were quantified by RT-qPCR after growing the bacteria in different carbon sources. The geNorm and Normfinder programs were used to calculate the expression stabilities. The analyses identified three genes, rho, 23SrRNA and rpoD, whose expressions were stable throughout the growth of strain PAL5 in the chosen carbon sources. In conclusion our results strongly suggest that these three genes are suitable to be used as reference genes for real-time RT-qPCR data normalization in G. diazotrophicus. PMID- 22814373 TI - Emerging modes of collective cell migration induced by geometrical constraints. AB - The role of geometrical confinement on collective cell migration has been recognized but has not been elucidated yet. Here, we show that the geometrical properties of the environment regulate the formation of collective cell migration patterns through cell-cell interactions. Using microfabrication techniques to allow epithelial cell sheets to migrate into strips whose width was varied from one up to several cell diameters, we identified the modes of collective migration in response to geometrical constraints. We observed that a decrease in the width of the strips is accompanied by an overall increase in the speed of the migrating cell sheet. Moreover, large-scale vortices over tens of cell lengths appeared in the wide strips whereas a contraction-elongation type of motion is observed in the narrow strips. Velocity fields and traction force signatures within the cellular population revealed migration modes with alternative pulling and/or pushing mechanisms that depend on extrinsic constraints. Force transmission through intercellular contacts plays a key role in this process because the disruption of cell-cell junctions abolishes directed collective migration and passive cell-cell adhesions tend to move the cells uniformly together independent of the geometry. Altogether, these findings not only demonstrate the existence of patterns of collective cell migration depending on external constraints but also provide a mechanical explanation for how large-scale interactions through cell cell junctions can feed back to regulate the organization of migrating tissues. PMID- 22814374 TI - Sumoylation of transcription factor MYB30 by the small ubiquitin-like modifier E3 ligase SIZ1 mediates abscisic acid response in Arabidopsis thaliana. AB - The phytohormone abscisic acid (ABA) plays an essential role in plant development and during the response of the plant to abiotic stress. In this study, we report that the R2R3-type transcription factor MYB30 is involved in the regulation of ABA signaling. Arabidopsis mutants lacking MYB30 are hypersensitive to ABA during germination and seedling growth. A K283R substitution in MYB30 blocks its SUMO E3 ligase SIZ1-mediated sumoylation in Arabidopsis protoplasts, indicating that MYB30 is sumoylated by SIZ1 and that K283 is the principal site for small ubiquitin-like modifier conjugation. Expression of MYB30(K283R) in myb30 partially rescues the mutant ABA-hypersensitive phenotype, but expression of wild type MYB30 complements the mutant phenotype. Overexpression of MYB30 in wild-type results in an ABA-insensitive phenotype, whereas overexpression of MYB30 in the siz1 mutant does not alter siz1 hypersensitivity to ABA. The siz1-2 myb30-2 double-mutant exhibits greater ABA sensitivity than either single mutant, but a mutation in the SIZ1-sumoylated ABI5 transcription factor suppresses the ABA hypersensitivity of myb30-2 to wild-type levels. Our results suggest that coordination of ABI5 and MYB30 sumoylation by SIZ1 may balance gene expression, which is required for regulation of ABA signaling during seed germination. PMID- 22814376 TI - Helioseismology challenges models of solar convection. PMID- 22814375 TI - Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc. AB - The finding that certain somatic cells can be directly converted into cells of other lineages by the delivery of specific sets of transcription factors paves the way to novel therapeutic applications. Here we show that human cord blood (CB) CD133(+) cells lose their hematopoietic signature and are converted into CB induced neuronal-like cells (CB-iNCs) by the ectopic expression of the transcription factor Sox2, a process that is further augmented by the combination of Sox2 and c-Myc. Gene-expression analysis, immunophenotyping, and electrophysiological analysis show that CB-iNCs acquire a distinct neuronal phenotype characterized by the expression of multiple neuronal markers. CB-iNCs show the ability to fire action potentials after in vitro maturation as well as after in vivo transplantation into the mouse hippocampus. This system highlights the potential of CB cells and offers an alternative means to the study of cellular plasticity, possibly in the context of drug screening research and of future cell-replacement therapies. PMID- 22814377 TI - Molecular basis of beta-amyloid oligomer recognition with a conformational antibody fragment. AB - Oligomers are intermediates of the beta-amyloid (Abeta) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other Abeta conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of Abeta oligomers, such as those formed by Abeta (1-40) and Abeta (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes Abeta residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with Abeta assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature Abeta fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of Abeta conformers. PMID- 22814378 TI - N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. AB - Protein N-terminal acetylation (Nt-acetylation) is an important mediator of protein function, stability, sorting, and localization. Although the responsible enzymes are thought to be fairly well characterized, the lack of identified in vivo substrates, the occurrence of Nt-acetylation substrates displaying yet uncharacterized N-terminal acetyltransferase (NAT) specificities, and emerging evidence of posttranslational Nt-acetylation, necessitate the use of genetic models and quantitative proteomics. NatB, which targets Met-Glu-, Met-Asp-, and Met-Asn-starting protein N termini, is presumed to Nt-acetylate 15% of all yeast and 18% of all human proteins. We here report on the evolutionary traits of NatB from yeast to human and demonstrate that ectopically expressed hNatB in a yNatB Delta yeast strain partially complements the natB-Delta phenotypes and partially restores the yNatB Nt-acetylome. Overall, combining quantitative N-terminomics with yeast studies and knockdown of hNatB in human cell lines, led to the unambiguous identification of 180 human and 110 yeast NatB substrates. Interestingly, these substrates included Met-Gln- N-termini, which are thus now classified as in vivo NatB substrates. We also demonstrate the requirement of hNatB activity for maintaining the structure and function of actomyosin fibers and for proper cellular migration. In addition, expression of tropomyosin-1 restored the altered focal adhesions and cellular migration defects observed in hNatB-depleted HeLa cells, indicative for the conserved link between NatB, tropomyosin, and actin cable function from yeast to human. PMID- 22814379 TI - Heterotrophic feeding as a newly identified survival strategy of the dinoflagellate Symbiodinium. AB - Survival of free-living and symbiotic dinoflagellates (Symbiodinium spp.) in coral reefs is critical to the maintenance of a healthy coral community. Most coral reefs exist in oligotrophic waters, and their survival strategy in such nutrient-depleted waters remains largely unknown. In this study, we found that two strains of Symbiodinium spp. cultured from the environment and acquired from the tissues of the coral Alveopora japonica had the ability to feed heterotrophically. Symbiodinium spp. fed on heterotrophic bacteria, cyanobacteria (Synechococcus spp.), and small microalgae in both nutrient-replete and nutrient depleted conditions. Cultured free-living Symbiodinium spp. displayed no autotrophic growth under nitrogen-depleted conditions, but grew when provided with prey. Our results indicate that Symbiodinium spp.'s mixotrophic activity greatly increases their chance of survival and their population growth under nitrogen-depleted conditions, which tend to prevail in coral habitats. In particular, free-living Symbiodinium cells acquired considerable nitrogen from algal prey, comparable to or greater than the direct uptake of ammonium, nitrate, nitrite, or urea. In addition, free-living Symbiodinium spp. can be a sink for planktonic cyanobacteria (Synechococcus spp.) and remove substantial portions of Synechococcus populations from coral reef waters. Our discovery of Symbiodinium's feeding alters our conventional views of the survival strategies of photosynthetic Symbiodinium and corals. PMID- 22814381 TI - Water and a protic ionic liquid acted as refolding additives for chemically denatured enzymes. AB - In this communication, we present the ability of water and a protic ionic liquid, triethyl ammonium phosphate (TEAP) to act as refolding additives for the urea induced chemical denaturated state of the two enzymes, alpha-chymotrypsin and succinylated Con A. We show that the enzymatic activity is regained and in certain circumstances enhanced. PMID- 22814380 TI - Integrating the landscape epidemiology and genetics of RNA viruses: rabies in domestic dogs as a model. AB - Landscape epidemiology and landscape genetics combine advances in molecular techniques, spatial analyses and epidemiological models to generate a more real world understanding of infectious disease dynamics and provide powerful new tools for the study of RNA viruses. Using dog rabies as a model we have identified how key questions regarding viral spread and persistence can be addressed using a combination of these techniques. In contrast to wildlife rabies, investigations into the landscape epidemiology of domestic dog rabies requires more detailed assessment of the role of humans in disease spread, including the incorporation of anthropogenic landscape features, human movements and socio-cultural factors into spatial models. In particular, identifying and quantifying the influence of anthropogenic features on pathogen spread and measuring the permeability of dispersal barriers are important considerations for planning control strategies, and may differ according to cultural, social and geographical variation across countries or continents. Challenges for dog rabies research include the development of metapopulation models and transmission networks using genetic information to uncover potential source/sink dynamics and identify the main routes of viral dissemination. Information generated from a landscape genetics approach will facilitate spatially strategic control programmes that accommodate for heterogeneities in the landscape and therefore utilise resources in the most cost-effective way. This can include the efficient placement of vaccine barriers, surveillance points and adaptive management for large-scale control programmes. PMID- 22814382 TI - The use of delta15N signatures of translocated macroalgae to map coastal nutrient plumes: improving species selection and spatial analysis of metropolitan datasets. AB - The definition of the spatial footprint of land-derived nutrient plumes is a key element to the design of initiatives to combat eutrophication in urbanised coastal regions. These plumes, however, are difficult to monitor because of their inherent high-frequency temporal and spatial variability. Biomonitoring with macroalgae provides time-integration of bioavailable nitrogen inputs through the measurement of delta15N signatures in tissues, and adequate spatial coverage through translocation to desirable monitoring locations. In this study, we used laboratory incubations to compare three different species of macroalgae as bioindicators, and a field experiment to investigate the applicability of the technique for the large-scale mapping of nutrient plumes. Cladophora valonioides was selected for the field experiment as it showed rapid changes in delta15N values in the laboratory incubations, was abundant in shallow depths making collection cost-efficient, and had tough thalli capable of withstanding deployment in open water. Ecklonia radiata also performed well in the laboratory incubations, but field harvest from subtidal depths was comparatively more expensive. Ulva lactuca had fragile thalli, and large nitrogen reserves that acted to mask the isotopic signal of newly acquired nitrogen. Cladophora valonioides was translocated to 246 sites covering an area of ~445 km2 along the highly urbanized temperate coast of Adelaide, South Australia. The resulting isotopic signatures of nitrogen in tissues were spatially interpolated to produce maps of land-derived nutrient plumes, to model probability and standard error in the predictive surface, and to optimize sampling design. PMID- 22814383 TI - Clinical trial results with the MED-EL fine structure processing coding strategy in experienced cochlear implant users. AB - OBJECTIVES: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. METHODS: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. RESULTS: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. CONCLUSIONS: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music. PMID- 22814385 TI - Cost-effectiveness analysis of goal-directed hemodynamic treatment of elderly hip fracture patients: before clinical research starts. AB - BACKGROUND: Health economic evaluations are increasingly used to make the decision to adopt new medical interventions. Before such decisions, various stakeholders have invested in clinical research. But health economic factors are seldom considered in research funding decisions. Cost-effectiveness analyses could be informative before the launch of clinical research projects, particularly when a targeted intervention is resource-intensive, total cost for the trial is very high, and expected gain of health benefits is uncertain. This study analyzed cost-effectiveness using a decision analytic model before initiating a large clinical research project on goal-directed hemodynamic treatment of elderly patients with hip fracture. METHODS: A probabilistic decision analytic cost-effectiveness model was developed; the model contains a decision tree for the postoperative short-term outcome and a Markov structure for long-term outcome. Clinical effect estimates, costs, health-related quality-of life measures, and long-term survival constituted model input that was extracted from clinical trials, national databases, and surveys. Model output consisted of estimated medical care costs related to quality-adjusted life-years. RESULTS: In the base case analysis, goal-directed hemodynamic treatment reduced average medical care costs by ?1,882 and gained 0.344 quality-adjusted life-years. In 96.5% of the simulations, goal-directed hemodynamic treatment is less costly and provides more quality-adjusted life-years. The results are sensitive to clinical effect size variations, although goal-directed hemodynamic treatment seems to be cost-effective even with moderate clinical effect. CONCLUSION: This study demonstrates that cost-effectiveness analysis is feasible, meaningful, and recommendable before launch of costly clinical research projects. PMID- 22814384 TI - Intralipid, a clinically safe compound, protects the heart against ischemia reperfusion injury more efficiently than cyclosporine-A. AB - BACKGROUND: We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening. METHODS: In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid (0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A (0.2 MUM, 0.8 MUM, and 1.5 MUM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B (Akt)/glycogen synthase kinase-3beta (GSK-3beta) were measured. The values are mean +/- SEM. RESULTS: Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo (infarct size/area at risk)%: 22.9 +/- 2.5% vs. 35.2 +/- 3.5%; P = 0.030, n = 7/group). Postischemic administration of intralipid at its optimal dose (1%) was more effective than cyclosporine-A (0.8 MUM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher (mmHg . beats/min: 12,740 +/- 675 [n = 7] vs. 9,203 +/- 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller (17.3 +/- 2.9 [n = 7] vs. 29.2 +/- 2.7 [n = 5], P = 0.014). Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening (calcium retention capacity = 280 +/- 8.2 vs. 260.3 +/- 2.9 nmol/mg mitochondria protein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt (6-fold) and GSK-3beta (5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases. CONCLUSIONS: Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery. PMID- 22814386 TI - Ventilation before paralysis: crossing the Rubicon, slowly. PMID- 22814387 TI - Ultrasound visualization of the superficial peroneal nerve in the mid-calf. PMID- 22814388 TI - Gender differences in trunk and pelvic kinematics during prolonged ergometer rowing in adolescents. AB - The trunk and pelvis kinematics of 20 healthy male and female adolescent rowers were recorded during an ergometer trial using an electromagnetic tracking system (Fastrak). The kinematics of each drive phase were collected during the 1st and 20th minute, respectively. The mean and range of the kinematics, stroke rate and stroke length were compared between genders and over time. Male rowers postured their pelvis with more posterior tilt and their thoracic spine in more flexion than female rowers (P < .05). Both genders postured their pelvis in more posterior pelvic rotation and upper trunk in more flexion over time. Male rowers were found to have a significantly shorter drive phase than female rowers (P = .001). Differences in trunk and pelvic kinematics between adolescent male and female rowers suggest potentially various mechanisms for biomechanical stress. Assessment and training of rowers should take gender differences into consideration. PMID- 22814389 TI - High-throughput fluorescence-based isolation of live C. elegans larvae. AB - For the nematode Caenorhabditis elegans, automated selection of animals of specific genotypes from a mixed pool has become essential for genetic interaction or chemical screens. To date, such selection has been accomplished using specialized instruments. However, access to such dedicated equipment is not common. Here we describe live animal fluorescence-activated cell sorting (laFACS), a protocol for automatic selection of live first larval stage (L1) animals using a standard FACS system. We show that FACS can be used for the precise identification of GFP-expressing and non-GFP-expressing subpopulations and can accomplish high-speed sorting of live animals. We have routinely collected 100,000 or more homozygotes from a mixed starting population within 2 h, and with greater than 99% purity. The sorted animals continue to develop normally, making this protocol ideally suited for the isolation of terminal mutants for use in genetic interaction or chemical genetic screens. PMID- 22814390 TI - Template-based protein structure modeling using the RaptorX web server. AB - A key challenge of modern biology is to uncover the functional role of the protein entities that compose cellular proteomes. To this end, the availability of reliable three-dimensional atomic models of proteins is often crucial. This protocol presents a community-wide web-based method using RaptorX (http://raptorx.uchicago.edu/) for protein secondary structure prediction, template-based tertiary structure modeling, alignment quality assessment and sophisticated probabilistic alignment sampling. RaptorX distinguishes itself from other servers by the quality of the alignment between a target sequence and one or multiple distantly related template proteins (especially those with sparse sequence profiles) and by a novel nonlinear scoring function and a probabilistic consistency algorithm. Consequently, RaptorX delivers high-quality structural models for many targets with only remote templates. At present, it takes RaptorX ~35 min to finish processing a sequence of 200 amino acids. Since its official release in August 2011, RaptorX has processed ~6,000 sequences submitted by ~1,600 users from around the world. PMID- 22814391 TI - Probing exchange kinetics and atomic resolution dynamics in high-molecular-weight complexes using dark-state exchange saturation transfer NMR spectroscopy. AB - We present the protocol for the measurement and analysis of dark-state exchange saturation transfer (DEST), a novel solution NMR method for characterizing, at atomic resolution, the interaction between an NMR-'visible' free species and an NMR-'invisible' species transiently bound to a very high-molecular-weight (>1 MDa) macromolecular entity. The reduced rate of reorientational motion in the bound state that precludes characterization by traditional NMR methods permits the observation of DEST. (15)N-DEST profiles are measured on a sample comprising the dark state in exchange with an NMR-visible species; in addition, the difference (DeltaR(2)) in (15)N transverse relaxation rates between this sample and a control sample comprising only the NMR-visible species is also obtained. The (15)N-DEST and DeltaR(2) data for all residues are then fitted simultaneously to the McConnell equations for various exchange models describing the residue specific dynamics in the bound state(s) and the interconversion rate constants. Although the length of the experiments depends strongly on sample conditions, approximately 1 week of NMR spectrometer time was sufficient for full characterization of samples of amyloid-beta (Abeta) at concentrations of ~100 MUM. PMID- 22814392 TI - An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. AB - Chloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca(2+) release channels. These RyR proteins play a major role in the regulation of Ca(2+) signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X linked intellectual disability (ID), atrial fibrillation, cardiomegaly, congestive heart failure (CHF), some somatic features and seizures. Functional studies of the H101Q variant indicated that it stimulated rather than inhibited the action of RyR channels, with channels remaining open for longer times and potentially amplifying Ca(2+) signals dependent on RyR channel activity. The overly active RyRs in cardiac and skeletal muscle cells and neuronal cells would result in abnormal cardiac function and trigger post-synaptic pathways and neurotransmitter release. The presence of both cardiomegaly and CHF in the two affected males and atrial fibrillation in one are consistent with abnormal RyR2 channel function. Since the dysfunction of RyR2 channels in the brain via 'leaky mutations' can result in mild developmental delay and seizures, our data also suggest a vital role for the CLIC2 protein in maintaining normal cognitive function via its interaction with RyRs in the brain. Therefore, our patients appear to suffer from a new channelopathy comprised of ID, seizures and cardiac problems because of enhanced Ca(2+) release through RyRs in neuronal cells and cardiac muscle cells. PMID- 22814393 TI - Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes. AB - Recent genome-wide association studies (GWASs) have identified >20 new loci associated with the susceptibility to psoriasis vulgaris (PsV) risk. We investigated the association of PsV and its main clinical subphenotypes with 32 loci having previous genome-wide evidence of association with PsV (P < 5e-8) or strong GWAS evidence (P < 5e-5 in discovery and P < 0.05 in replication sample) in a large cohort of PsV patients (n = 2005) and controls (n = 1497). We provide the first independent replication for COG6 (P = 0.00079) and SERPINB8 (P = 0.048) loci with PsV. In those patients having developed psoriatic arthritis (n = 955), we found, for the first time, a strong association with IFIH1 (P = 0.013). Analyses of clinically relevant PsV subtypes yielded a significant association of severity of cutaneous disease with variation at LCE3D locus (P = 0.0005) in PsV and nail involvement with IL1RN in purely cutaneous psoriasis (PsC, P = 0.007). In an exploratory analysis of epistasis, we replicated the previously described HLA-C-ERAP1 interaction with PsC. Our findings show that common genetic variants associated with a complex phenotype like PsV influence different subphenotypes of high clinical relevance. PMID- 22814395 TI - Can you blame cold feet on Epac (and Rap1A)? Focus on "cyclic AMP-Rap1A signaling activates RhoA to induce alpha(2C)-adrenoceptor translocation to the cell surface of microvascular smooth muscle cells". PMID- 22814394 TI - SJSZ glycoprotein (38 kDa) modulates expression of IL-2, IL-12, and IFN-gamma in cyclophosphamide-induced Balb/c. AB - OBJECTIVE: Cyclophosphamide (CTX) often results in immunosuppression and cytotoxic effects. The object of this study was to understand whether Styrax japonica Siebold et al. Zuccarini (SJSZ) glycoprotein prevents immunosuppression in CTX-induced Balb/c. METHODS: The mice were injected intraperitoneally with CTX (80 mg/kg, BW) for 1 week in the presence or absence of the SJSZ glycoprotein, and divided into five groups. Weights of the spleen and thymus, phagocytic macrophages, proliferation of splenocytes and thymocytes ([(3)H]-thymidine incorporation and expression of PCNA), natural killer (NK) cytotoxicity [MTT assay, perforin, and granzyme B], and cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-gamma] were evaluated using radioactivity, biochemical reactions, immunoblot analysis, and qRT-PCR. Activity of antioxidant enzymes [superoxide dismutase (SOD), glutathione dismutase (GPx) and catalase (CAT)] was also assessed. RESULTS: The results revealed that while the parameters assessed decreased with treatment with CTX alone, SJSZ glycoprotein (10 mg/kg, BW) in the presence of CTX significantly normalized the weights of spleen and thymus, the phagocytic effect of peritoneal macrophages, the activity of antioxidant enzymes, proliferation (splenocytes and thymocytes), NK cell cytotoxicity, and expression of IL-2, IL-12, and IFN-gamma. CONCLUSION: SJSZ glycoprotein can normalize activity of anti-oxidative enzymes and immune-related factors. PMID- 22814397 TI - Predicting kinase-substrate interactions in the era of proteomics: focus on "Identifying protein kinase target preferences using mass spectrometry". PMID- 22814396 TI - Sialofucosylated podocalyxin is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells. AB - Selectin-mediated interactions in the vasculature promote metastatic spread by facilitating circulating tumor cell binding to selectin-expressing host cells. Therefore, identifying the selectin ligand(s) on tumor cells is critical to the prevention of blood-borne metastasis. A current challenge is to distinguish between structures expressed by circulating tumor cells that can bind selectins in vitro from the functional ligands whose depletion suppresses selectin dependent binding under flow in vivo. Interestingly, podocalyxin (PODXL), which can bind E- and L-selectin, is upregulated in a number of cancers, including those of the breast, colon, and pancreas. In this work, we show that metastatic pancreatic cancer cells overexpress PODXL compared with nonmalignant pancreatic epithelial cells. We further demonstrate via tissue microarray that 69% of pancreatic ductal adenocarcinomas stain positive for PODXL. In cases of focal expression, positive staining is restricted to the invasive front of primary tumors. By combining immunoblot, immunodepletion, short-hairpin RNA-mediated gene silencing, and flow-based adhesion assays, we evaluated the functional role of sialofucosylated PODXL in selectin-mediated adhesion under flow. Our data indicate that sialofucosylated PODXL is a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells, as specific depletion of this molecule from the cell surface significantly interferes with selectin-dependent interactions. Cumulatively, these data support a correlation between sialofucosylated PODXL expression and enhanced binding to selectins by metastatic pancreatic cancer cells and offer additional perspective on the upregulation of PODXL in aggressive cancers. PMID- 22814398 TI - Shuttling glucose across brain microvessels, with a little help from GLUT1 and AMP kinase. Focus on "AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress". PMID- 22814399 TI - Regional differences in rat conjunctival ion transport activities. AB - Active ion transport and coupled osmotic water flow are essential to maintain ocular surface health. We investigated regional differences in the ion transport activities of the rat conjunctivas and compared these activities with those of cornea and lacrimal gland. The epithelial sodium channel (ENaC), sodium/glucose cotransporter 1 (Slc5a1), transmembrane protein 16 (Tmem16a, b, f, and g), cystic fibrosis transmembrane conductance regulator (Cftr), and mucin (Muc4, 5ac, and 5b) mRNA expression was characterized by RT-PCR. ENaC proteins were measured by Western blot. Prespecified regions (palpebral, fornical, and bulbar) of freshly isolated conjunctival tissues and cell cultures were studied electrophysiologically with Ussing chambers. The transepithelial electrical potential difference (PD) of the ocular surface was also measured in vivo. The effect of amiloride and UTP on the tear volume was evaluated in lacrimal gland excised rats. All selected genes were detected but with different expression patterns. We detected alphaENaC protein in all tissues, betaENaC in palpebral and fornical conjunctiva, and gammaENaC in all tissues except lacrimal glands. Electrophysiological studies of conjunctival tissues and cell cultures identified functional ENaC, SLC5A1, CFTR, and TMEM16. Fornical conjunctiva exhibited the most active ion transport under basal conditions amongst conjunctival regions. PD measurements confirmed functional ENaC-mediated Na(+) transport on the ocular surface. Amiloride and UTP increased tear volume in lacrimal gland excised rats. This study demonstrated that the different regions of the conjunctiva exhibited a spectrum of ion transport activities. Understanding the specific functions of distinct regions of the conjunctiva may foster a better understanding of the physiology maintaining hydration of the ocular surface. PMID- 22814400 TI - The dimeric platelet collagen receptor GPVI-Fc reduces platelet adhesion to activated endothelium and preserves myocardial function after transient ischemia in mice. AB - Platelets play a critical role in the pathophysiology of reperfusion, sepsis, and cardiovascular diseases. In a multiple step process, they adhere to activated endothelium and release proinflammatory cytokines thereby promoting the inflammatory process. Glycoprotein VI (GPVI) is the major collagen receptor on the platelet surface and triggers platelet activation and primary hemostasis. Activation of GPVI leads to stable platelet adhesion and degranulation of platelet granules. However, GPVI is critically involved in platelet adhesion to activated endothelium without exposure of subendothelial matrix. Earlier studies show that the soluble GPVI-Fc binds to collagen and protects mice from atherosclerosis and decreases neointima proliferation after arterial injury. Here, we show for the first time that recombinant GPVI-Fc binds to activated endothelium mainly via vitronectin and prevents platelet/endothelial interaction. Administration of GPVI-Fc reduced infarct size and preserved cardiac function in a mouse model of myocardial infarction. This process was associated with reduced GPVI-induced platelet degranulation and release of proinflammatory cytokines in vitro and in vivo. Taken together, administration of GPVI-Fc offers a novel strategy to control platelet-mediated inflammation and to preserve myocardial function following myocardial infarction. PMID- 22814401 TI - Quantification of low-polar small molecules using room temperature ionic liquids matrix-assisted desorption corona beam ionization. AB - A room temperature ionic liquids (RTILs) matrix-assisted desorption corona beam ionization (DCBI) technique was proposed. The quantification of the DCBI method for low-polar small molecules was improved greatly in terms of accuracy and precision. The thermal desorption processes of analytes in different liquid matrices under DCBI interrogation was investigated with thermal imaging and mass spectrometry simultaneously. When in a volatile liquid matrix, the analyte was not only desorbed thermally from the solid residue phase, but also desorbed along with evaporation of the matrix. The varying matrix evaporation speed and unstable sample introduction path clearly influence the quantitative result. With non volatile RTILs utilized as the matrix in the sample introduction, a micro slow release system (MSRS) is formed to relieve the fluctuation of analyte evaporation. With the RTILs matrix-assisted DCBI-MS technique, dramatic improvement of the quantification precision (RSD from about 20% to less than 3%) for model analytes was achieved. Seventeen small pharmaceutical and four pesticide molecules were detected successfully. With a shared mechanism, other thermal desorption and/or APCI-related ambient ionization techniques may also benefit from the RTILs matrix. PMID- 22814403 TI - Pulsatile stress, inflammation and change in arterial stiffness. AB - AIM: Understanding factors that contribute to changes in arterial stiffness over time is important as this may lead to therapies that can abrogate cardiovascular risk. We compared the contribution of pulsatile stress and inflammation to changes in arterial stiffness in middle-aged men using a 1-year follow-up study design. METHODS: Arterial stiffness was derived from brachial-ankle pulse wave velocity (baPWV) in 107 men (mean age 53+/-6 yrs) on two separate occasions. The changes in outcome variables were calculated as the difference between the first and second examinations (mean interval 403+/-122 days). Pulsatile stress was calculated as the product of heart rate and brachial pulse pressure. C-reactive protein (CRP), white blood cell count (WBC) and fibrinogen were measured as inflammatory markers. RESULTS: At baseline, baPWV was significantly correlated with pulsatile stress (r=0.37, p<0.01), WBC (r=0.19, p<0.05), HbA1c (r=0.39, p<0.01), HDL-C (r=.0.20, p<0.05), but not CRP (r= 0.06, p=0.56), or fibrinogen (r=0.12, p=0.21). The change in baPWV over 1 year was associated with the change in pulsatile stress (r=0.26, p<0.01) and HbA1c (r=0.19, p<0.05) over that same time period. Change in baPWV was not associated with the change in WBC (r=0.18, p=0.06) or CRP (r=0.05, p=0.62). CONCLUSIONS: These results demonstrate that both pulsatile stress and inflammation may be associated with arterial stiffness at any given moment in time, but change in pulsatile stress is a better predictor of change in arterial stiffness over time. PMID- 22814402 TI - Isolating, immunophenotyping and ex vivo stimulation of CD4+ and CD8+ gastric lymphocytes during murine Helicobacter pylori infection. AB - Helicobacter pylori infection is associated with severe chronic inflammation, yet the host immune response is rarely able to clear the bacterium. Thymus derived lymphocyte populations such as T helper 1, T helper 17, and T regulatory cells are known to play important roles in the chronicity of H. pylori infection as well as contributing to ongoing gastric pathology. It is yet to be established how these immune cell populations interact in the gastric environment during H. pylori infection. Mouse models of infection offer an opportunity to investigate these interactions in detail. Flow cytometric analysis provides excellent lymphocyte characterization due to its high specificity, sensitivity and potential to perform multiple simultaneous measurements. However, this requires a viable enriched single cell suspension after adequate tissue dissociation, which poses a challenge due to the heterogeneity of gastric tissue. We have evaluated several isolation techniques and have optimized a protocol to isolate and enrich lymphocytes from the H. pylori-infected murine stomach. EDTA/DTT followed by Collagenase IV digestion successfully dissociates an average of 1 * 107 cells per mouse. Further enrichment using Lympholyte M gradient yields on average 4 * 106 CD45+ lymphocytes per stomach. Following isolation we compared lymphocyte stimulation by CD3/CD28, phorbol 12-myristate 13-acetate (PMA) and ionomycin or H. pylori lysate and determined that CD3/CD28 effectively induces stimulation of IFNgamma and IL 17A, but impairs Foxp3 expression. Using an optimized protocol we observed a 2-fold increase of CD8+ IFNgamma-expressing lymphocytes localized specifically to the gastric compartment during H. pylori infection. The mechanisms of H. pylori immunopathogenesis are still considered enigmatic, therefore this optimized protocol can help delineate further novel immune cell targets that mediate H. pylori-induced pathology and identify the correlates of immunity for vaccine development. PMID- 22814404 TI - Insulin resistance and the development of cardiovascular disease in a Japanese community: the Hisayama study. AB - AIMS: Although several surrogate measures of insulin resistance have been proposed, their associations with cardiovascular disease (CVD) have not been evaluated sufficiently. METHODS: A total of 2,356 community-dwelling Japanese individuals aged 40 to 79 years who underwent a 75 g oral glucose tolerance test were followed up for 14 years. The status of insulin resistance was estimated by using the Matsuda index or homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: During follow-up, 260 subjects developed CVD. The age- and sex-adjusted hazard ratios of CVD significantly decreased with an increasing Matsuda index and rose with increasing HOMA-IR levels (both p for trend <0.05). After adjustment for age, sex, serum total cholesterol, electrocardiogram abnormalities, proteinuria, smoking habits, alcohol intake, and regular exercise, the risk of CVD was significantly lower in the third to fifth quintiles of the Matsuda index and higher in the fifth quintile of HOMA-IR values compared with the first quintile of the corresponding index (Matsuda index Q3: hazard ratio (HR)= 0.59 [95% confidence interval 0.40-0.87]; Q4: HR= 0.66 [0.45-0.97]; and Q5: HR= 0.67 [0.47-0.97]; HOMA-IR Q5: HR= 1.55 [1.05-2.29]); however, these associations were attenuated after further adjustment for the metabolic syndrome status. In regard to CVD subtypes, the risks for stroke and coronary heart disease significantly decreased with an increasing Matsuda index, while elevated HOMA-IR levels were a significant risk factor for stroke, but not for coronary heart disease. CONCLUSION: Our findings suggest that insulin resistance significantly increases the risk of incident CVD through metabolic syndrome in Japanese. PMID- 22814405 TI - Differences in the glycosylation of recombinant proteins expressed in HEK and CHO cells. AB - Glycosylation is one of the most common posttranslational modifications of proteins. It has important roles for protein structure, stability and functions. In vivo the glycostructures influence pharmacokinetics and immunogenecity. It is well known that significant differences in glycosylation and glycostructures exist between recombinant proteins expressed in mammalian, yeast and insect cells. However, differences in protein glycosylation between different mammalian cell lines are much less well known. In order to examine differences in glycosylation in mammalian cells we have expressed 12 proteins in the two commonly used cell lines HEK and CHO. The cells were transiently transfected, and the expressed proteins were purified. To identify differences in glycosylation the proteins were analyzed on SDS-PAGE, isoelectric focusing (IEF), mass spectrometry and released glycans on capillary gel electrophoresis (CGE-LIF). For all proteins significant differences in the glycosylation were detected. The proteins migrated differently on SDS-PAGE, had different isoform patterns on IEF, showed different mass peak distributions on mass spectrometry and showed differences in the glycostructures detected in CGE. In order to verify that differences detected were attributed to glycosylation the proteins were treated with deglycosylating enzymes. Although, culture conditions induced minor changes in the glycosylation the major differences were between the two cell lines. PMID- 22814406 TI - Serotonin and melatonin secretion and metabolism in patients with liver cirrhosis. AB - INTRODUCTION: Hepatic encephalopathy is one of the symptoms of liver failure. The exact causes of encephalopathy are complex and still unclear. Apart from elevated blood ammonia levels, the role of numerous other factors is being considered. OBJECTIVES: The aim of the study was to determine the serum level of serotonin and melatonin and the urinary excretion of their metabolites (5 hydroxyindoleacetic acid [5-HIAA] and 6-sulfatoxymelatonin [6-HMS]) in patients with various stages of liver cirrhosis. PATIENTS AND METHODS: The study comprised 75 patients with alcohol-induced liver cirrhosis and 25 healthy subjects (control group). Based on the Child-Pugh classification, 3 groups of 25 patients each were distinguished - group A, B, and C with grade A, B, and C of liver failure, respectively. Blood samples were drawn at fasting at 9 a.m., and 24-hour urine collection was performed. Immunoenzymatic assays were used to determine serum melatonin and serotonin levels as well as urine 5-HIAA and 6-HMS concentrations. RESULTS: Serum serotonin levels were 159.8 +/- 23.1 ng/ml in controls, 179.3 +/- 21.1 ng/ml in group A (P >0.05), 143.2 +/- 22.8 ng/ml in group B (P >0.05), and 114.5 +/- 37.6 ng/ml in group C (P <0.01). Serum melatonin levels were 10.6 +/- 1.7 in controls, 31.2 +/- 9.8 pg/ml in group A (P <0.01), 49.8 +/- 12.2 pg/ml in group B (P <0.001), and 94.8 +/- 22.6 pg/ml in group C (P <0.001). Urinary 5-HIAA excretion was 5.9 +/- 2.1 mg/24 h in controls, 5.9 +/- 1.9 mg/24 h in group A (P >0.05), 4.8 +/- 1.2 mg/24 h in group B (P >0.05), and 4.6 +/- 1.4 mg/24 h in group C (P <0.05). Urinary 6-HMS excretion was 26.6 +/- 15.1 MUg/24 h in controls, 23.2 +/- 7.9 MUg/24 h in group A (P >0.05), 18.3 +/- 10.6 MUg/24 h in group B (P >0.05), and 6.5 +/- 3.6 MUg/24 h in group C (P <0.001). CONCLUSIONS: Disturbances in serotonin and melatonin homeostasis observed in patients with liver cirrhosis may be associated with advanced encopaholopathy. PMID- 22814407 TI - Dual mechanism of protection by live attenuated Bordetella pertussis BPZE1 against Bordetella bronchiseptica in mice. AB - Bordetella bronchiseptica, a gram-negative bacterium, causes chronic respiratory tract infections in a wide variety of mammalian hosts, including man, and no human vaccine is currently available. Acellular pertussis vaccines protect poorly against B. bronchiseptica, although they contain cross-reactive antigens. We have recently developed Bordetella pertussis BPZE1, a novel, live attenuated pertussis vaccine, currently completing phase I clinical trials in humans, and found that it protects against both B. pertussis and Bordetella parapertussis in mice. Here, we show that a single nasal administration of BPZE1 protects mice against lethal infection with B. bronchiseptica. After challenge, the vaccinated animals displayed markedly reduced lung inflammation and tissue damage, decreased neutrophil infiltration and increased levels of CD4(+)CD25(+)FoxP3(+) regulatory T cells in the lungs compared to non-immunized mice. Depletion of these cells abolished BPZE1-induced protection, indicating that BPZE1 protects against lethal inflammation through the recruitment of regulatory T cells. In addition, the B. bronchiseptica load was significantly decreased in the vaccinated animals. Using passive transfer experiments, protection was found to be essentially cell mediated, and BPZE1-induced Th1 and Th17 T cells recognize whole B. bronchiseptica extracts, although the participation of antibodies in protection cannot be discounted. Thus, a single administration of BPZE1 can confer protection against B. bronchiseptica in mice by a dual mechanism. PMID- 22814408 TI - Oral immunization using live Lactococcus lactis co-expressing LACK and IL-12 protects BALB/c mice against Leishmania major infection. AB - Leishmaniasis is a parasitic disease affecting over 12 million individuals worldwide. Current treatments are laborious, expensive, cause severe side effects, and emerging drug resistance has been reported. While vaccination is the most cost-effective means to control infectious diseases there is no human vaccine currently available against Leishmania infections. Lactococcus lactis is a non-pathogenic, non-colonizing Gram-positive lactic acid bacterium commonly used in the dairy industry. Recently, L. lactis was used for the expression and delivery of biologically active molecules, such as antigens and cytokines, in mice and humans. In this study, we report the generation of L. lactis(alr-) strains solely expressing the protective Leishmania antigen, LACK, in the cytoplasm, secreted or anchored to the bacterial cell wall or co-expressing mouse IL-12. We show that oral immunization using live L. lactis, secreting both LACK and IL-12 was the only regimen that partially protected BALB/c mice against subsequent Leishmania major challenge. This highlights the importance of temporal and physical proximity of the delivered antigen and adjuvant for optimal immune priming by oral immunization since co-administration of L. lactis strains independently expressing secLACK and secIL-12 did not induce protective immunity. Protected animals displayed a delay in footpad swelling, which correlated with a significant reduction of parasite burden. Immunization with the L. lactis strain secreting both LACK and IL-12 induced an antigen-specific mucosal immune response and a LACK-specific T(H)1 immune response in splenocytes and mesenteric lymph node cells. Further, protection in immunized animals correlated with a strong Leishmania-specific T(H)1 immune response post-challenge, detectable in splenocytes and lymph node cells draining the site of infection. This report demonstrates the use of L. lactis as an oral live vaccine against L. major infection in susceptible BALB/c mice. The vaccine strains generated in this study provide the basis for the development of an inexpensive and safe oral live vaccine against the human parasite Leishmania. PMID- 22814409 TI - Health-related quality of life in the CDC Anthrax Vaccine Adsorbed Human Clinical Trial. AB - BACKGROUND: After the Department of Defense implemented a mandatory anthrax vaccination program in 1998 concerns were raised about potential long-term safety effects of the current anthrax vaccine. The CDC multicenter, randomized, double blind, placebo-controlled Anthrax Vaccine Adsorbed (AVA) Human Clinical Trial to evaluate route change and dose reduction collected data on participants' quality of life. Our objective is to assess the association between receipt of AVA and changes in health-related quality of life, as measured by the SF-36 health survey (Medical Outcomes Trust, Boston, MA), over 42 months after vaccination. METHODS: 1562 trial participants completed SF-36v2 health surveys at 0, 12, 18, 30 and 42 months. Physical and mental summary scores were obtained from the survey results. We used Generalized Estimating Equations (GEE) analyses to assess the association between physical and mental score difference from baseline and seven study groups receiving either AVA at each dose, saline placebo at each dose, or a reduced AVA schedule substituting saline placebo for some doses. RESULTS: Overall, mean physical and mental scores tended to decrease after baseline. However, we found no evidence that the score difference from baseline changed significantly differently between the seven study groups. CONCLUSIONS: These results do not favor an association between receipt of AVA and an altered health-related quality of life over a 42-month period. PMID- 22814410 TI - Carbon isotope fractionation of chlorinated ethenes during oxidation by Fe2+ activated persulfate. AB - The increased use of persulfate (S(2)O(8)(2-)) for in situ chemical oxidation to treat groundwater and soils contaminated by chlorinated hydrocarbon compounds (CHCs) requires unbiased methods to assess treatment performance. Stable carbon isotope analysis offers a potential tool for assessing the in situ treatment performance of persulfate at sites contaminated with CHCs. This study investigated the extent of C isotope fractionation during oxidation of tetrachloroethene (PCE), trichloroethene (TCE) and cis-dichloroethene (cis-DCE) by persulfate activated by ferrous ion (Fe(2+)). An average carbon isotope enrichment factor epsilon(bulk) of -4.90/00 for PCE, -3.60/00 for TCE and 7.60/00 for cis-DCE were obtained in batch experiments. Variations in the initial S(2)O(8)(2-)/Fe(2+)/CHC molar ratios did not result in any significant differences in carbon isotope fractionation. The occurrence of carbon isotope fractionation during oxidation and the lack of dependence of enrichment factors upon the S(2)O(8)(2-)/Fe(2+)/CHC molar ratio demonstrate that carbon isotope analysis can potentially be used at contaminated sites as an additional technique to estimate treatment efficacy during oxidation of CHCs by Fe(2+) activated persulfate. PMID- 22814411 TI - Thermodynamics of miracidial survival and metabolism. AB - Miracidia are short-lived, non-feeding (lecithotrophic) free-living stages of trematodes, whose survival is potentially influenced by temperature. Climate change may result in elevated temperatures affecting trematode transmission. Therefore understanding their thermobiology forms an important step in determining the future dynamics of parasite populations. An empirical relationship exists between the mean expected life span of lecithotrophic larvae and the half life of their population (t(0.5)) and therefore t(0.5) is a good indicator of glycogen utilization. In this study experimental data on the effects of temperature on miracidial survival were compiled from the scientific literature and evaluated in terms of metabolism using Q 10 and Arrhenius activation energy (E* or MU). Temperature poorly influenced survival/metabolism with all miracidia having distinct zone(s) of thermostability. Overall there were few differences in Q(10) and E* values between most species temperature ranges whilst there were only limited strain-specific variations in thermal responses of laboratory-maintained Schistosoma mansoni. Miracidia demonstrated a trend of greater thermal resistance than cercariae. In particular, comparative studies on 4 strains of the same species of miracidia and cercariae showed little correlation in thermal biology between the 2 life-history stages. The importance of these results for trematode transmission under global climate change is discussed. PMID- 22814412 TI - Fluid flow stress induced contraction and re-spread of mesenchymal stem cells: a microfluidic study. AB - Mesenchymal stem cells (MSCs), the multipotent progenitor cells, are sensitive to fluid shear stress (FSS). MSCs can migrate through the blood stream by intravasation into the circulatory system to transfer to distant positions through the blood stream. During the transferring process, MSCs may differentiate into cells of corresponding tissues for repair, or remain undifferentiated and initiate ectopic tissue formation, lipid accumulation, or calcification, which are closely related to the pathology of atherosclerosis. However, how the MSCs sense and respond to vascular FSS stimulation and lead to subsequent biological effects remains elusive. In this study, by using an in situ time-lapse microfluidic cell culture and observation system, we found that rat mesenchymal stem cells (rMSCs) presented a contraction and re-spread (CRS) process when they were initially subjected to a physiological FSS (1.3 Pa). Our subsequent studies demonstrated that integrin and cilia played key roles in sensing FSS. Calcium, F actin, and Rho-kinase were key molecules in the mechanotransduction of the CRS of the rMSCs. Our study revealed the immediate response of the rMSCs to FSS. It will be helpful for the understanding of MSC-related tissue repair and the role of MSCs in the initiation of atherosclerosis. PMID- 22814414 TI - Monascus-fermented red mold rice exhibits cytotoxic effect and induces apoptosis on human breast cancer cells. AB - Red mold rice (RMR) is a traditional food and folk medicine to Asian people and has recently become a popular health supplement. RMR has been shown to have some anticancer activities, although the mechanism for inducing cell death of human breast cancer cells is still not fully understood. In this study, bioactive extracts of RMR fermented by Monascus purpureus NTU 803 were analyzed for effects on apoptosis induction in human breast cancer cells. The RMR ethanol extract and ethyl acetate extract contain monacolin K, total phenols, and flavonoids, the three components that have been reported to have anticancer activity. Red mold rice extracts (RMRE) exhibited selective cytotoxic effect on MCF-7 cells. RMRE treatment induced apoptosis and cell cycle arrest at G2/M phase. Apoptosis was confirmed by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, the observation of characteristic chromatin condensation, nuclear DNA fragmentation, and poly(ADP-ribose) polymerase cleavage. Furthermore, the RMRE induced apoptosis in MCF-7 cells may occur through a mitochondria-dependent pathway while triggering an appropriate balance of bax/bcl-2 and activation of caspase-9 and caspase-3 in a time-dependent manner. To conclude, RMRE exhibits direct cytotoxic and proapoptotic effects on MCF-7 cells and could be considered as a potential functional food for breast cancer prevention. PMID- 22814413 TI - The chromatin code of fungal secondary metabolite gene clusters. AB - Secondary metabolite biosynthesis genes in fungi are usually physically linked and organized in large gene clusters. The physical linkage of genes involved in the same biosynthetic pathway minimizes the amount of regulatory steps necessary to regulate the biosynthetic machinery and thereby contributes to physiological economization. Regulation by chromatin accessibility is a proficient molecular mechanism to synchronize transcriptional activity of large genomic regions. Chromatin regulation largely depends on DNA and histone modifications and the histone code hypothesis proposes that a certain combination of modifications, such as acetylation, methylation or phosphorylation, is needed to perform a specific task. A number of reports from several laboratories recently demonstrated that fungal secondary metabolite (SM) biosynthesis clusters are controlled by chromatin-based mechanisms and histone acetyltransferases, deacetylases, methyltransferases, and proteins involved in heterochromatin formation were found to be involved. This led to the proposal that establishment of repressive chromatin domains over fungal SM clusters under primary metabolic conditions is a conserved mechanism that prevents SM production during the active growth phase. Consequently, transcriptional activation of SM clusters requires reprogramming of the chromatin landscape and replacement of repressive histone marks by activating marks. This review summarizes recent advances in our understanding of chromatin-based SM cluster regulation and highlights some of the open questions that remain to be answered before we can draw a more comprehensive picture. PMID- 22814416 TI - A new dawn in the sleep disorders pipeline? PMID- 22814415 TI - Acute and chronic cardioprotection by the enkephalin analogue, Eribis peptide 94, is mediated via activation of nitric oxide synthase and adenosine triphosphate regulated potassium channels. AB - BACKGROUND/AIMS: Eribis peptide 94 (EP 94) is a new enkephalin derivative which potently binds to the u- and delta-opioid receptor. In this study, we determined the effects of EP 94 and potential mechanism(s) involved in cardioprotection of the rat heart. METHODS AND RESULTS: An acute (5 and10 min into ischemia) and a chronic (24 h prior to ischemia) EP 94 administration produced a similar 30-40% reduction in infarct size/area at risk and the effects were blocked by the K(ATP) channel antagonists, HMR 1098 and 5-HD. The cardioprotective effects were blocked by a nonselective nitric oxide synthase (NOS) inhibitor (L-NAME) following acute administration and by a selective iNOS inhibitor (1400W) following chronic administration. CONCLUSION: These results suggest that EP 94 may have potential for the treatment of ischemic heart disease via a nitric oxide (NO)-K(ATP) mediated mechanism. PMID- 22814417 TI - Deal watch: Roche deal targets glutamate in neurodevelopmental disorders. PMID- 22814418 TI - Trial watch: Novel antimicrobial fights TB resistance. PMID- 22814419 TI - Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives. AB - Substitution at the 7-position of the chromen-4-one pharmacophore of 8 (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer. PMID- 22814420 TI - Incidence of aspirin hypersensitivity in patients with chronic rhinosinusitis and diagnostic value of urinary leukotriene E4. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD). OBJECTIVES: The aim of the study was to validate a simple measurement of urinary leukotriene E4 (uLTE4) excretion for the diagnosis of AERD in patients with CRS and indication for surgery. PATIENTS AND METHODS: Subjects requiring functional endoscopic sinus surgery (FESS) were recruited from the Department of Otolaryngology (n = 24). Before surgery, a standard oral placebo-controlled aspirin challenge was performed to diagnose aspirin hypersensitivity. Urine samples were collected on the placebo day and both before and within 2 to 4 hours after aspirin challenge for uLTE4 measurement. RESULTS: All patients with CRS had sinusitis confirmed by computed tomography. Previous ear, nose, and throat surgery was performed in 70% of the patients, NP was present in 86%, and asthma was diagnosed in 62.5%. AERD was diagnosed in 8 subjects (7 women and 1 man). Five of those patients had bronchoconstriction. At baseline, median uLTE4 was 7.5 times higher in AERD subjects than in the remaining patients. It increased almost 6-fold following the challenge, while remained unchanged in patients without aspirin hypersensitivity. Pretest uLTE4 had a sensitivity of 87.5% and specificity of 93.75% to diagnose aspirin hypersensitivity in patients with CRS. After the challenge, the values improved to 100% sensitivity and 93% specificity. CONCLUSIONS: Among CRS subjects requiring FESS, as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4. PMID- 22814421 TI - Antioxidant activity assay based on the inhibition of oxidation and photobleaching of L-cysteine-capped CdTe quantum dots. AB - Quantum dots (QDs) have recently been the focus of attention of many investigators for development of diagnostic tools in many research areas. In this work, we established a new QD-based assay to evaluate the antioxidant/polyphenolic activity. This assay is based on measurement of the inhibitory effect of the antioxidant/polyphenolic compounds on the UV-induced bleaching of CdTe QDs with L-cysteine capping. QDs exhibited excellent photostability without any UV exposure, while they bleached rapidly under UV irradiation. Generation of reactive oxygen species (ROS) under UV irradiation is probably the main cause of the photobleaching of QDs. By comparing the photostability of QDs in buffer solution in the absence and presence of sodium azide, as a known (1)O(2) quencher, the involvement of (1)O(2) in photobleaching of QDs was confirmed. The photobleaching effect induced by ROS could be reduced in the presence of antioxidant/polyphenolic compounds. We tested several antioxidant/polyphenolic compounds as well as known antioxidants such as trolox and 4 different types of tea. The results obtained by the QD-based assay revealed a very good correlation with the data acquired by Folin-Ciocalteu assay. Furthermore, a deeper understanding of the mechanism and the solution for photobleaching of QDs under UV irradiation might be very meaningful in promoting their clinical applications. PMID- 22814422 TI - Nitrite-generated nitric oxide to protect against intimal hyperplasia formation. AB - Vascular disease is a leading cause of morbidity and mortality worldwide. Current vascular therapeutic interventions directed at diseased vessels are restricted in long-term efficacy by the development of intimal hyperplasia and the reformation of flow-limiting disease. The vascular injury and inflammation that ensues from the intervention, especially in the setting of an existing atherosclerotic vascular disease, results in further endothelial dysfunction and subsequent smooth muscle cell proliferation and migration. Although the etiology of intimal hyperplasia is multifactorial, impaired nitric oxide (NO) signaling has been implicated. The vasoprotective properties of NO have been intensely studied, and many investigations have focused on harnessing this biological system for therapeutic benefit. Continued studies investigate the role of impaired NO signaling via the classical arginine/NO synthase (NOS)/NO pathway in the setting of intimal hyperplasia. Furthermore, the possible protective effects of nitrate and nitrite-generated NO via non-NOS-mediated pathways to limit vascular injury have been recently appreciated and will likely prove to be an important vasoregulatory and vasoprotective signaling pathway. PMID- 22814423 TI - MicroRNA-503 and the extended microRNA-16 family in angiogenesis. AB - MicroRNAs (miRs) are post-transcriptional inhibitory regulators of gene expression acting by direct binding to complementary messenger RNA (mRNA) transcripts. Recent studies have demonstrated that miRs are crucial determinants of endothelial cell behavior and angiogenesis. We have provided evidence of the prominent role of miR-503 in impairment of postischemic reparative angiogenesis in the setting of diabetes. Because miR-503 belongs to the miR-16 extended family of miRs, in this review, we describe the cardiovascular functions of miR-503 and other members of the miR-16 family and their impact on angiogenesis. PMID- 22814424 TI - Regulatory T cells and pulmonary hypertension. AB - Pulmonary hypertension (PH) is a disease of high lethality arising from numerous causes. For a significant subset of PH patients, autoimmune biomarkers or frank autoimmune disease are simultaneously present, but the extent to which lung inflammation contributes to PH is unknown. However, emerging experimental and clinical evidence suggests that immune dysregulation may lead to the propagation of vascular injury and PH. A recent preclinical study demonstrated that regulatory T cells are important mediators normally enlisted to control inflammation and that, if absent or dysfunctional, may predispose to the development of PH. PMID- 22814425 TI - MicroRNAs and aneurysm formation. AB - Aneurysms occur in large arteries and are characterized by pathological widening of the vessel and thinning of the vessel wall. In the past decade, microRNAs (miRs) have emerged as key regulators of biological processes, and they were recently shown to be involved in aneurysm formation. A few miRs have been proposed to play a role in aneurysm development, such as miR-21, miR-26, and miR 143/145. Several recent studies describe the involvement of miR-29 in aneurysm formation by post-transcriptionally repressing the expression of extracellular matrix proteins. Therapeutic inhibition of miR-29 using anti-miRs attenuates experimental aneurysm formation in mice. This review provides an overview of the upstream regulation of miR-29 as well as the downstream targets of miR-29. It also discusses the potential clinical use for miR-29 inhibitors and the role of other miRs involved in aneurysm formation. PMID- 22814426 TI - Aptamer binding and neutralization of beta1-adrenoceptor autoantibodies: basics and a vision of its future in cardiomyopathy treatment. AB - Autoantibodies directed against the second extracellular receptor loop of the beta(1) receptor (beta(1)-ECII-AABs) that belong to the superfamily of G protein coupled receptors have been frequently found in patients with idiopathic dilated cardiomyopathy, Chagas' cardiomyopathy, and peripartum cardiomyopathy and have been clearly evidenced to be related to disease pathogenesis. Consequently, specific proteins or peptides used as binders in immunoapheresis or as in vivo neutralizers of beta(1)-ECII-AABs have been suggested for patient treatment. Aptamers, which are target specifically selected short single- or double-stranded RNA or DNA sequences, are a recently introduced new molecule class applicable to bind and neutralize diverse molecule species, including antibodies. This article reviews selection technologies and characteristics of aptamers with respect to a single-stranded DNA aptamer recently identified as having a very high affinity against beta(1)-ECII-AABs. The potential of this aptamer for the elimination of beta(1)-ECII-AABs and in vivo neutralization is critically analyzed in view of its potential for future use in cardiomyopathy treatment. PMID- 22814427 TI - Prostaglandin I(2) analogues enhance already exuberant Th17 cell responses in systemic sclerosis. AB - OBJECTIVE: Among pleiotropic effects, the capacity of prostaglandin I(2) (PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI(2) analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell cultures were quantified by immunoassays. The frequencies of interleukin (IL)-17A, IL-22, interferon gamma (IFNgamma) and IL-4-producing CD4 T cells were assessed by multiparametric flow cytometry. Selective receptor antagonists, cytokine blocking antibodies and signalling protein inhibitors were used to identify the receptors and signalling pathways mediating PGI(2) analogue effects. RESULTS: Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI(2) analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNgamma production both in SSc and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased IL-23 production by monocytes, involved the IP prostacyclin receptor and required protein kinase A activation. Importantly, in vivo administration of iloprost in individuals with SSc presenting with digital ulcers resulted in a significant increase in the frequency of Th17 cells. CONCLUSIONS: These findings demonstrate that PGI(2) analogues affect Th cell differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell responses in SSc. The impact of these changes on the disease course needs to be taken into consideration and further exploited to improve SSc. PMID- 22814428 TI - Remote intracranial parenchymal hemorrhage in susceptibility-weighted imaging. PMID- 22814429 TI - Aromatic residue mutations reveal direct correlation between HIV-1 nucleocapsid protein's nucleic acid chaperone activity and retroviral replication. AB - The human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein plays an essential role in several stages of HIV-1 replication. One important function of HIV-1 NC is to act as a nucleic acid chaperone, in which the protein facilitates nucleic acid rearrangements important for reverse transcription and recombination. NC contains only 55 amino acids, with 15 basic residues and two zinc fingers, each having a single aromatic residue (Phe16 and Trp37). Despite its simple structure, HIV-1 NC appears to have optimal chaperone activity, including the ability to strongly aggregate nucleic acids, destabilize nucleic acid secondary structure, and facilitate rapid nucleic acid annealing. Here we combine single molecule DNA stretching experiments with ensemble solution studies of protein-nucleic acid binding affinity, oligonucleotide annealing, and nucleic acid aggregation to measure the characteristics of wild-type (WT) and aromatic residue mutants of HIV-1 NC that are important for nucleic acid chaperone activity. These in vitro results are compared to in vivo HIV-1 replication for viruses containing the same mutations. This work allows us to directly relate HIV 1 NC structure with its function as a nucleic acid chaperone in vitro and in vivo. We show that replacement of either aromatic residue with another aromatic residue results in a protein that strongly resembles WT NC. In contrast, single amino acid substitutions of either Phe16Ala or Trp37Ala significantly slow down NC's DNA interaction kinetics, while retaining some helix-destabilization capability. A double Phe16Ala/Trp37Ala substitution further reduces the latter activity. Surprisingly, the ensemble nucleic acid binding, annealing, and aggregation properties are not significantly altered for any mutant except the double aromatic substitution with Ala. Thus, elimination of a single aromatic residue from either zinc finger strongly reduces NC's chaperone activity as determined by single molecule DNA stretching experiments without significantly altering its ensemble-averaged biochemical properties. Importantly, the substitution of aromatic residues with Ala progressively decreases NC's nucleic acid chaperone activity while also progressively inhibiting viral replication. Taken together, these data support the critical role of HIV-1 NC's aromatic residues, and establish a direct and statistically significant correlation between nucleic acid chaperone activity and viral replication. PMID- 22814431 TI - Selection and characterisation of guanidine-resistant mutants of human enterovirus 71. AB - The replication of human enterovirus 71 (HEV71) in cell culture is inhibited by concentrations of guanidine that do not have an observable adverse effect on host cell metabolism. Although the HEV71 non-structural protein 2C is known to play an important role in viral RNA replication, its precise biochemical activities and structure have not been fully determined. Here we describe amino acid substitutions in HEV71 protein 2C that confer resistance to guanidine. Three guanidine-resistant virus populations were independently isolated and found to contain five mutations in protein 2C, one of which, A4657T (2C-M193L), was present in two of the independently selected populations. This mutation was introduced into a HEV71 infectious cDNA clone and was sufficient to confer complete resistance to growth inhibition in the presence of 4mM guanidine. In the first guanidine-resistant population selected, the 2C-M193L mutation occurred in association with an additional mutation, A4459G (2C-I127V), located in the putative cis-acting replication element (cre) of coding region 2C. This mutation conferred only partial guanidine resistance when introduced into the HEV71-26M infectious clone. When the 2C-I127V and 2C-M193L mutations were introduced into HEV71-26M together, the 2C-I127V mutation did not increase the level of guanidine resistance due to the 2C-M193L mutation alone. This study confirms that guanidine resistance can be readily selected in HEV71 and is attributable to mutations within protein 2C. PMID- 22814430 TI - RNA binding by the NS3 protease of the hepatitis C virus. AB - The hepatitis C virus (HCV) nonstructural protein 3 (NS3) is essential for the processing of the HCV polyprotein, the replication of HCV RNA, and to short circuit innate immunity signaling. NS3 contains an N-terminal domain with protease activity and a C-terminal domain with helicase activity. The two domains communicate with each other along with other HCV and cellular proteins. Herein we show that RNAs can bind directly to the active site cleft of the NS3 protease domain (NS3P) and inhibit proteolysis of peptide substrates. RNAs that are less apt to form intramolecular structures have a stronger inhibitory activity than RNAs with more stable base paired regions. Two mutations in the protease domain that resulted in decreased affinity to ssRNA were also defective in RNA-induced ATPase activity from the helicase domain of NS3. The coordinated effects on inhibition of protease activity and stimulation of ATPase activity raise the possibility that RNA serves as a regulatory switch for the two processes. PMID- 22814432 TI - Cellular RNA helicases and HIV-1: insights from genome-wide, proteomic, and molecular studies. AB - RNA helicases are ubiquitous in plants and animals and function in many cellular processes. Retroviruses, such as human immunodeficiency virus (HIV-1), encode no RNA helicases in their genomes and utilize host cellular RNA helicases at various stages of their life cycle. Here, we briefly summarize the roles RNA helicases play in HIV-1 replication that have been identified recently, in part, through genome-wide screenings, proteomics, and molecular studies. Some of these helicases augment virus propagation while others apparently participate in antiviral defenses against viral replication. PMID- 22814433 TI - Genetic profile characterization of ten X-STRs in a sample from Parana, Brazil. AB - This work reports the allele frequencies for ten X-STRs (DXS8378, DXS7132, DXS9898, DXS6809, DXS9902, DXS6789, DXS7133, DXS7423, GATA172D05, GATA31E08) in a sample of 800 individuals from Parana, Brazil. No deviations from the Hardy Weinberg equilibrium were observed. Linkage disequilibrium analysis did not reveal association between the X-STRs. High overall power of discrimination was obtained for female and male samples, and high probability of exclusion was observed in father/mother/daughter trios and father/daughter duos. Genetic comparisons revealed significant differences between Parana and other Brazilian populations. PMID- 22814434 TI - Cannabinoid receptor type 2 is time-dependently expressed during skin wound healing in mice. AB - Dynamic localization of CB2R and quantitative analysis of CB2R mRNA during skin wound healing in mice were performed. Co-localization of CB2R with F4/80 or alpha SMA was detected by double-color immunofluorescence microscopy. A total of 110 male mice were divided into control, injury, and postmortem groups. Sixty-five mice were sacrificed, followed by sampling at 0.5 h-21 days post-injury. Five mice without incision were used as control. The other 40 mice that received incised wound were sacrificed at 5 days after injury. The samples were collected at 0 h-3 days postmortem. In the uninjured controls, CB2R immunoreactivity was detected in the epidermis, hair follicles, sebaceous glands, dermomuscular layer, and vascular smooth muscle. In the incision groups, polymorphonulcear cells, macrophages, and myofibroblasts showed positive staining for CB2R. Morphometrically, the average ratios of CB2R-positive cells were more than 50 % at 5 days post-wounding, whereas it was <50 % at the other posttraumatic intervals. The average ratios of CB2R-positive macrophages maximized at 3 days post-wounding, and the average ratios of CB2R-positive myofibroblasts peaked at 5 days post-wounding. The relative quantity of CB2R mRNA expression maximized at posttraumatic 5 days in comparison with control as detected by real-time PCR, with an average ratio of >4.10, which was also confirmed by Western blotting. There was no significant change for CB2R protein within 6 h postmortem and for mRNA within 3 h postmortem as compared with the control group. In conclusion, dynamic distribution and expression of CB2R suggest that CB2R is involved in modulating macrophages and myofibroblasts in response to inflammatory event and repair process in mouse skin wound healing, and CB2R is available as a marker for wound age determination. PMID- 22814435 TI - Dissolution-guided wetting for microarray and microfluidic devices. AB - The trapping of air bubbles presents a substantial impediment for the user in the increasingly widespread use of lab-on-a-chip products having microcavities in the forms of microwells, traps, dead ends and corners. Here we demonstrate a simple, effective, and passive method to eliminate air bubbles by coating hydrophilized microarray and microfluidic devices with a monosaccharide such as D-glucose or D sorbitol, where the microcavities are filled with a conformal, elliptical, cone shaped monosaccharide solid. These devices were stored in air for up to 6 months with a complete rewetting of the microcavities by dissolution of the monosaccharide with an aqueous solution. PMID- 22814436 TI - The vascular barrier-protecting hawthorn extract WS(r) 1442 raises endothelial calcium levels by inhibition of SERCA and activation of the IP3 pathway. AB - WS(r) 1442 has been proven as an effective and safe therapeutical to treat mild forms of congestive heart failure. Beyond this action, we have recently shown that WS(r) 1442 protects against thrombin-induced vascular barrier dysfunction and the subsequent edema formation by affecting endothelial calcium signaling. The aim of the study was to analyze the influence of WS(r) 1442 on intracellular calcium concentrations [Ca(2+)](i) in the human endothelium and to investigate the underlying mechanisms. Using ratiometric calcium measurements and a FRET sensor, we found that WS(r) 1442 concentration-dependently increased basal [Ca(2+)](i) by depletion of the endoplasmic reticulum (ER) and inhibited a subsequent histamine-triggered rise of [Ca(2+)](i). Interestingly, the augmented [Ca(2+)](i) did neither trigger an activation of the contractile machinery nor led to a barrier breakdown (macromolecular permeability). It also did not impair endothelial cell viability. As assessed by patch clamp recordings, WS(r) 1442 did only slightly affect endothelial Na(+)/K(+)-ATPase, but increased [Ca(2+)](i) by inhibiting the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) and by activating the inositol 1,4,5-trisphosphate (IP(3)) pathway. Most importantly, WS(r) 1442 did not induce store-operated calcium entry (SOCE), but even irreversibly prevented histamine-induced SOCE. Taken together, WS(r) 1442 prevented the deleterious hyperpermeability-associated rise of [Ca(2+)](i) by a preceding, non-toxic release of Ca(2+) from the ER. WS(r) 1442 interfered with SERCA and the IP(3) pathway without inducing SOCE. The elucidation of this intriguing mechanism helps to understand the complex pharmacology of the cardiovascular drug WS(r) 1442. PMID- 22814438 TI - Selected adipokines and metabolic profiles in normal-weight women with abdominal obesity. AB - INTRODUCTION: Abdominal obesity (AO) is a risk factor of insulin resistance and its metabolic consequences. OBJECTIVES: The aim of the study was to assess the associations between adiponectin and visfatin levels, body fat (BF), abdominal and hip fat depots, blood lipid profile, insulin sensitivity surrogates, and AO. PATIENTS AND METHODS: The study included 145 healthy, premenopausal (aged 20-40 years), normal-weight women. Using the cut values of 80 cm waist circumference (WC) and 0.8 waist-to-hip ratio, we identified 38 and 68 women with AO, respectively. We assessed visfatin, adiponectin, blood lipid, glucose, and insulin levels. The body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: Regardless of the criteria used to diagnose AO, we found that women with AO were heavier (P = 0.01), had more deliveries (P = 0.03), and had lower high-density lipoprotein (HDL) cholesterol levels (P = 0.01) than women without AO. Serum visfatin and adiponectin levels, triglycerides, low-density lipoprotein (LDL) cholesterol, glucose, insulin, and indices of insulin sensitivity and resistance were comparable between the groups. AO was associated with higher diastolic blood pressure and higher total, abdominal (android), and hip (gynoid) fat as well as the android/BF ratio (all P <0.01). There was a positive correlation between glucose and WC (r = 0.206; P = 0.02). Adiponectin was positively associated with HDL cholesterol (r = 0.248; P = 0.008) and inversely with the android/BF ratio (r = -0.218; P = 0.009) and android/gynoid ratio (r = -0.201; P = 0.04). Visfatin inversely correlated with total (r = 0.251; P = 0.01) and LDL cholesterol (r = -0.181; P = 0.042). CONCLUSIONS: Normal weight women with AO have normal adiponectin and visfatin levels, higher diastolic blood pressure, and lower HDL cholesterol levels. The android/gynoid ratio and android/BF ratio are inversely correlated with adiponectin levels. PMID- 22814437 TI - Replacement of huntingtin exon 1 by trans-splicing. AB - Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a "gain-of-function" mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans-splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans-splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans. We detected the presence of the trans-spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans-spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre mRNA trans-splicing may be a promising approach for the treatment of HD and other dominant genetic disorders. PMID- 22814440 TI - Stereoselective glucuronidation of carvedilol in human liver and intestinal microsomes. AB - BACKGROUND AND PURPOSE: Carvedilol is used clinically as a beta-adrenoceptor antagonist for the treatment of chronic heart failure and is primarily metabolized into glucuronides by UDP-glucuronosyltransferase (UGT). In this study, the stereoselective glucuronidation of carvedilol by the human liver and intestinal microsomes was examined using racemate and enantiomers. METHODS: Carvedilol glucuronidation activities at substrate concentrations of 1-1,000 umol/l in human liver and intestinal microsomes were determined by high performance liquid chromatography with fluorescence detection, and the kinetic parameters were estimated. RESULTS: The activities of S-glucuronidation toward racemic and enantiomeric carvedilol in liver microsomes were higher than those of R-glucuronidation at all substrate concentrations examined. In intestinal microsomes, the activities of S-glucuronidation from racemic and enantiomeric carvedilol at <=100 umol/l substrates were higher than those of R glucuronidation, whereas the glucuronidation activities at >=200 umol/l substrates exhibited the opposite stereoselectivity (R > S) compared with those at <=100 umol/l substrates. The activities of R- and S-calvedilol glucuronidation from racemate and enantiomers in the liver and intestinal microsomes were decreased at substrate concentrations of >=100 or 200 umol/l, and the kinetics at substrate concentrations of 1-100 and 1-1,000 umol/l fitted with Michaelis-Menten and substrate inhibition models, respectively. The stereoselectivities of CL(int) values for carvedilol glucuronidation followed by Michaelis-Menten and substrate inhibition models were R < S for liver microsomes and R ~ S for intestinal microsomes. CONCLUSION: These findings demonstrate that the stereoselectivity of carvedilol glucuronidation was different between human liver and intestinal microsomes, and suggest that the difference is due to the tissue-specific expression of UGT isoforms involved in the glucuronidation of carvedilol. PMID- 22814441 TI - Silver nanoparticle aggregates on copper foil for reliable quantitative SERS analysis of polycyclic aromatic hydrocarbons with a portable Raman spectrometer. AB - Silver nanoparticle aggregates were synthesized on copper foil, which was used for the surface-enhanced Raman spectroscopy (SERS) detection of polycyclic aromatic hydrocarbons (PAHs) with a portable Raman spectrometer. Silver nanoparticle aggregates were prepared by immersing copper foil in the solution of Sn(2+) and AgNO(3) in a cyclic fashion. A four-cycle process was selected for the following experiments due to its high enhancement and relatively convenient experimental procedure. The substrate has greater temporal stability under continuous laser radiation, good uniformity and reproducibility, which indicated that the substrate could provide reliable measurements. The relationship between SERS intensity and concentrations of PAHs was studied. Quantitative analysis of PAHs in aqueous solution was further performed based on the prepared substrate. The log-log plot of normalized SERS intensity to PAHs concentration exhibited a good linear relationship, with the detection limits in the range of 5-500 MUg L( 1). Thus, due to the stability, reproducibility and quantitative results, the prepared substrate could be used as a potential SERS sensor for the analysis of environmental pollutants. PMID- 22814442 TI - Excess mortality associated with the 2009 A(H1N1)v influenza pandemic in Antananarivo, Madagascar. AB - It is difficult to assess the mortality burden of influenza epidemics in tropical countries. Until recently, the burden of influenza was believed to be negligible in Africa. We assessed the impact of the 2009 influenza epidemic on mortality in Madagascar by conducting Poisson regression analysis on mortality data from the deaths registry, after the first wave of the 2009 A(H1N1) virus pandemic. There were 20% more human deaths than expected in Antananarivo, Madagascar in November 2009, with excess mortality in the ?50 years age group (relative risk 1.41). Furthermore, the number of deaths from pulmonary disease was significantly higher than the number of deaths from other causes during this pandemic period. These results suggest that the A(H1N1) 2009 virus pandemic may have been accompanied by an increase in mortality. PMID- 22814444 TI - If exercise is medicine, who should be the prescriber? PMID- 22814443 TI - Cytochrome c-promoted cardiolipin oxidation generates singlet molecular oxygen. AB - The interaction of cytochrome c (cyt c) with cardiolipin (CL) induces protein conformational changes that favor peroxidase activity. This process has been correlated with CL oxidation and the induction of cell death. Here we report evidence demonstrating the generation of singlet molecular oxygen [O(2)((1)Delta(g))] by a cyt c-CL complex in a model membrane containing CL. The formation of singlet oxygen was directly evidenced by luminescence measurements at 1270 nm and by chemical trapping experiments. Singlet oxygen generation required cyt c-CL binding and occurred at pH values higher than 6, consistent with lipid-protein interactions involving fully deprotonated CL species and positively charged residues in the protein. Moreover, singlet oxygen formation was specifically observed for tetralinoleoyl CL species and was not observed with monounsaturated and saturated CL species. Our results show that there are at least two mechanisms leading to singlet oxygen formation: one with fast kinetics involving the generation of singlet oxygen directly from CL hydroperoxide decomposition and the other involving CL oxidation. The contribution of the first mechanism was clearly evidenced by the detection of labeled singlet oxygen [(18)O(2)((1)Delta(g))] from liposomes supplemented with 18-oxygen-labeled CL hydroperoxides. However quantitative analysis showed that singlet oxygen yield from CL hydroperoxides was minor (<5%) and that most of the singlet oxygen is formed from the second mechanism. Based on these data and previous findings we propose a mechanism of singlet oxygen generation through reactions involving peroxyl radicals (Russell mechanism) and excited triplet carbonyl intermediates (energy transfer mechanism). PMID- 22814445 TI - A neuroscience approach to managing athletes with low back pain. AB - Low back pain (LBP) is a common complaint within the athletic population and is commonly managed through a biomedical approach. The injured or damaged structure causing the LBP is identified and treated, and complete recovery from the episode is expected. Clinical experience shows us that often, athletes with LBP will not recover from their episode and may continue their sports participation despite persistent pain, or they may limit participation. Recent neuroscience research into the biology of pain suggests that clinicians involved in the management of athletes with LBP should embrace a biopsychosocial approach by engaging the brain and nervous system. This manuscript provides an overview of such a biopsychosocial approach, and presents information on the neurobiology of the athlete's pain experience. PMID- 22814446 TI - EMG of the hip adductor muscles in six clinical examination tests. AB - OBJECTIVES: To assess activation of muscles of hip adduction using EMG and force analysis during standard clinical tests, and compare athletes with and without a prior history of groin pain. STUDY DESIGN: Controlled laboratory study. PARTICIPANTS: 21 male athletes from an elite junior soccer program. MAIN OUTCOME MEASURES: Bilateral surface EMG recordings of the adductor magnus, adductor longus, gracilis and pectineus as well as a unilateral fine-wire EMG of the pectineus were made during isometric holds in six clinical examination tests. A load cell was used to measure force data. RESULTS: Test type was a significant factor in the EMG output for all four muscles (all muscles p < 0.01). EMG activation was highest in Hips 0 or Hips 45 for adductor magnus, adductor longus and gracilis. EMG activation for pectineus was highest in Hips 90. Injury history was a significant factor in the EMG output for the adductor longus (p < 0.05), pectineus (p < 0.01) and gracilis (p < 0.01) but not adductor magnus. For force data, clinical test type was a significant factor (p < 0.01) with Hips 0 being significantly stronger than Hips 45, Hips 90 and Side lay. BMI (body mass index) was a significant factor (p < 0.01) for producing a higher force. All other factors had no significant effect on the force outputs. CONCLUSIONS: Hip adduction strength assessment is best measured at hips 0 (which produced most force) or 45 degrees flexion (which generally gave the highest EMG output). Muscle EMG varied significantly with clinical test position. Athletes with previous groin injury had a significant fall in some EMG outputs. PMID- 22814447 TI - Asymmetry of the ULNT1 elbow extension range-of-motion in a healthy population: consequences for clinical practice and research. AB - OBJECTIVES: To investigate the effect of isolated muscular variance, side and hand dominance on elbow-extension range-of-motion (EE-ROM) of the median nerve upper limb neurodynamic test (ULNT1). This study analyzes these variables potential to influence ULNT1 EE-ROM symmetry and the possible consequences for clinical practice and research. STUDY DESIGN: Controlled laboratory study, cross sectional. BACKGROUND: No normative data exist to interpret correctly EE-ROM. Clinical interpretation is based on bilateral comparison. This procedure assumes natural EE-ROM symmetry, with lack of scientific evidence. METHODS: Nineteen participants with Langer's axillary arch (LAA), a muscular variant bridging the brachial plexus, were selected from 640 healthy volunteers, together with a matched control group. ULNT1 EE-ROM's were measured using the Vicon((r)) optoelectronic system. RESULTS: A full mixed model revealed no significant effects on EE-ROM for LAA and the variable side. Significant differences were found in EE-ROM between dominant and non-dominant sides (standard ULNT1 test position: 2.84 degrees +/- 1.60 degrees , p = 0.0004; ULNT1 with differentiating maneuver: 3.05 degrees +/- 1.98 degrees , p = 0.003). Approximately 30% of the subjects showed clinically detectable restriction (>=10 degrees ) of the dominant side EE-ROM. CONCLUSION: Hand dominance is significantly associated with restriction of EE-ROM, which results in a clinically detectable asymmetry. This compromises the clinical procedure of comparing the patient's EE-ROM to the opposite side. Erroneous conclusions could result in side to side analyses, if the effect is not taken into account in neurodynamic research. PMID- 22814448 TI - Electromyographic analysis of an eccentric calf muscle exercise in persons with and without Achilles tendinopathy. AB - OBJECTIVES: To compare surface electromyographic (EMG) activity of the gastrocnemius and soleus muscles between persons with and without Achilles tendinopathy (AT) during an eccentric muscle exercise in different knee joint positions. DESIGN: Repeated measures design. SETTING: Research laboratory. PARTICIPANTS: Participants (n = 18) diagnosed with AT and 18 control subjects were recruited. MAIN OUTCOME MEASURES: Gastrocnemius and soleus muscle activity was examined by surface (EMG) during extended and flexed knee joint conditions while performing the eccentric training technique. The EMG data were expressed as a percentage of a maximum voluntary contraction (MVC). RESULTS: EMG activity was notably higher (mean difference: 10%, effect size: 0.59) in those subjects with AT. Irrespective of the presence of AT, there was a significant interaction effect between muscle and joint position. The gastrocnemius muscle was significantly more active in the extended knee condition and soleus muscle activity was unchanged across joint positions. CONCLUSIONS: The results indicated that the presence of AT influenced calf muscle activity levels during performance of the eccentric exercise. There were differences in muscle activity during the extended and flexed knee conditions. This result does support performing Alfredson, Pietila, Jonsson, and Lorentzon (1998) eccentric exercise in an extended knee position but the specific effects of the knee flexed position on the Achilles tendon during eccentric exercise have yet to be determined, particularly in those with AT. PMID- 22814449 TI - Reproducibility of isokinetic knee eccentric and concentric strength indices in asymptomatic young adults. AB - OBJECTIVE: To assess the reproducibility of isokinetic eccentric and concentric knee extension and flexion strength indices obtained at two different angular velocities. DESIGN: Cohort study. SETTING: University human performance laboratory. PARTICIPANTS: 45 healthy physically active young adults (25 males). MAIN OUTCOME MEASURES: A non reciprocal protocol of concentric and eccentric contractions of the knee extensors and flexors was performed at 30 and 120 degrees /s. Strength indices evaluated included peak moment; dynamic control ratios; and the difference between eccentric and concentric ratio at the two angular velocities. RESULTS: No evidence for inter-test bias in any of the strength indices was noted. Measurement precision for peak moment, as quantified using ratio limits of agreement, suggest that scores may be expected to vary up to 15% for the knee extensors in both eccentric and concentric contraction modes. An error of up to 19% was calculated for the peak moment scores of the knee flexors. Intraclass correlation coefficients revealed fairly robust preservation of participants' rank order for the majority of strength indices (>0.85). CONCLUSION: Isokinetic-related indices of knee muscles performance enable an acceptable level of detection of expected changes in muscular strength parameters as a result of planned interventions. PMID- 22814450 TI - Taekwondo training improves the neuromotor excitability and reaction of large and small muscles. AB - OBJECTIVES: This study measured the neuromotor excitability and reaction time in professional and amateur Taekwondo (TKD) practitioners and compared them with non athletes. DESIGN: A cross-sectional cohort study design. SETTING: Exercise laboratory setting. PARTICIPANTS: 40 TKD practitioners (20 professionals, 20 amateurs) and 20 non-athletes. MAIN OUTCOME MEASURES: Neuromotor excitability (rheobase), premotor reaction time (PRT), total reaction time (TRT) and electromechanical delay (EMD) of rectus femoris (RF) and flexor pollicis brevis (FPB) in response to audio and visual stimuli were measured. The professional TKD practitioners have shorter TRT than non-athletes with sport-specific visual stimuli but they have longer PRT and TRT in response to audio stimuli than the amateur practitioners and non-athletes. RESULTS: The professional practitioners have longer EMD than the amateurs in responding to audio (p = 0.032) and sports specific visual stimuli (p = 0.03) in FPB. Professional practitioners have higher excitability in RF (p < 0.001) than the amateurs and non-athletes. CONCLUSION: We conclude that professional TKD practitioners have better neuromotor ability in both large and small muscles with faster reactions to sport-specific stimuli, suggesting a generalized training effect across muscles. They react slower to non sport specific stimuli, which suggested a decreased sensitivity to irrelevant sensory inputs after intensive TKD training. PMID- 22814451 TI - Running injuries and associated factors in participants of ING Taipei Marathon. AB - OBJECTIVES: To investigate the distribution of lower extremity running injuries and their associated factors. DESIGN: Descriptive and exploratory study. PARTICIPANTS: 1004 participants of the 2005 ING Taipei International Marathon. MAIN OUTCOME MEASURES: We used a self-developed questionnaire to collect data of previous running injuries and applied multivariate logistic regression modeling to examine relationships between these injuries and associated factors. RESULTS: Of the 893 valid questionnaires, 396 (44.4%) reported having previous lower extremity pain related to running. Knee joint pain was the most common problem (32.5%). Hip pain was associated with the racing group, training duration, and medial arch support. Use of knee orthotics (P = 0.002) and ankle braces (P = 0.007) was related to a higher rate of knee and ankle pain. Participants of the full marathon group who practiced on a synthetic track had a higher incidence of ankle pain. A training duration of >60 min was linked to an increased rate of foot pain (P = 0.003). CONCLUSION: Our data indicated that running injuries were associated with training duration and use of orthotics. Clinicians can use this information in treating or preventing running associated injuries and pain. PMID- 22814452 TI - Postural stability decreases in elite young soccer players after a competitive soccer match. AB - OBJECTIVE: To investigate the effects of an official soccer match on postural stability in youth elite soccer players. DESIGN: Single-group pre-post design. SETTING: Competitive soccer match. PARTICIPANTS: Twenty elite U-19 male soccer players (mean age: 17.7 +/- 1.0 years) of which 11 completed the full experimental set-up. MAIN OUTCOME MEASURES: Postural stability evaluated by unilateral stance tests for dominant and non-dominant lower limbs on a force plate under two visual conditions: eyes opened (EO) and eyes closed (EC). RESULTS: After the match, the centre of gravity (CoG) sway velocity with EO increased on the dominant and non-dominant limbs (median [interquartile range], 0.90 degrees /s [0.60-1.10] vs. 1.10 degrees /s [0.60-1.60]; and 0.70 degrees /s [0.50-0.90] vs 1.00 degrees /s [0.70-1.30]; respectively; p < 0.05). The CoG sway velocity with eyes closed did not change pre- to post-match. CONCLUSIONS: The soccer match decreased the postural stability only when the assessment was conducted with eyes open. PMID- 22814453 TI - The effect of heat applied with stretch to increase range of motion: a systematic review. AB - Application of heat to muscle is commonly advocated to enhance the efficacy of stretching. However, the effect of this combined therapy using different methods of heating, applied to different muscles, and after one or multiple treatments, is not known. To perform a systematic review to address the question: Does stretching augmented by heat application result in greater gains in range of motion (ROM) compared to stretch alone? The following databases were searched for original articles that evaluated our question: MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, SPORTDiscus and PEDro databases. After title and abstract screening followed by full-text screening, the quality of included articles was assessed and their data was abstracted. Screening, data abstraction and quality assessment was performed and consensus was achieved by two reviewers. Range of motion (ROM) data were synthesized by meta-analyses for overall effect and subgroup analysis according to muscle group, method of heat application, single or multiple treatments, and reported tightness of muscle. Twelve studies were included and reported the effects of stretch with or without heat on ROM of 352 participants. Heat applications included ultrasound, shortwave diathermy and hot packs. Meta-analyses and subgroup analyses demonstrated greater increases in ROM after heat and stretch (H + S) than heat alone. Subgroup analysis of muscle groups and the method of heat application showed some trends, but no significant differences. Multiple treatments (more so than single treatments) showed consistent treatment effects of H + S versus stretch alone amongst subgroups. Muscles described as tight did not show a greater treatment effect in response to H + S compared to muscles not reported as tight. Heating provides an added benefit on stretch related gains of ROM in healthy people. PMID- 22814454 TI - Achilles tendon tear following shock wave therapy for calcific tendinopathy of the Achilles tendon: a case report. AB - INTRODUCTION: Extracorporeal shock wave therapy (ESWT) is becoming a popular method for the treatment of musculoskeletal disorders. We herein report a case of Achilles tendon rupture possibly related to ESWT. CASE REPORT: A 49-year-old female was treated with a calcaneal osteotomy due to Haglund's disease on the right. However, she developed chronic calcific Achilles tendinopathy postoperatively, and during the following 2 year period after surgery she received various non-steroidal anti-inflammatory drugs and one injection of corticosteroids. She was subsequently treated with extracorporeal shock wave therapy (ESWT), but persistent pain, local swelling and redness over posterior right ankle were noted. Two months after ESWT she experienced an Achilles tendon tear and received Achilles tendon reconstruction. CONCLUSION: While ESWT is generally considered safe, physicians should be aware of potential major complications. PMID- 22814455 TI - The liver's imprint on CD8+ T cell priming. PMID- 22814456 TI - "Spoligoriftyping," a dual-priming-oligonucleotide-based direct-hybridization assay for tuberculosis control with a multianalyte microbead-based hybridization system. AB - We developed "spoligoriftyping," a 53-plex assay based on two preexisting methods, the spoligotyping and "rifoligotyping" assays, by combining them into a single assay. Spoligoriftyping allows simultaneous spoligotyping (i.e., clustered regularly interspaced short palindromic repeat [CRISPR]-based genotyping) and characterization of the main rifampin drug resistance mutations on the rpoB hot spot region in a few hours. This test partly uses the dual-priming oligonucleotide (DPO) principle, which allows simultaneous efficient amplifications of rpoB and the CRISPR locus in the same sample. We tested this method on a set of 114 previously phenotypically and genotypically characterized multidrug-resistant (MDR) Mycobacterium tuberculosis or drug-susceptible M. tuberculosis DNA extracted from clinical isolates obtained from patients from Bulgaria, Nigeria, and Germany. We showed that our method is 100% concordant with rpoB sequencing results and 99.95% (3,911/3,913 spoligotype data points) correlated with classical spoligotyping results. The sensitivity and specificity of our assay were 99 and 100%, respectively, compared to those of phenotypic drug susceptibility testing. Such assays pave the way to the implementation of locally and specifically adapted methods of performing in a single tube both drug resistance mutation detection and genotyping in a few hours. PMID- 22814457 TI - Clinical-epidemiological features of 13 cases of melioidosis in Brazil. AB - The aim of this work was to catalog the clinical and ecoepidemiological characteristics of melioidosis in Brazil. The clinical-epidemiological features of melioidosis in Ceara are similar to those in other regions where the disease is endemic. These findings support the inclusion of this Brazilian state as part of the zone of endemicity for melioidosis. PMID- 22814458 TI - Targeting both rs12979860 and rs8099917 polymorphisms with a single-tube high resolution melting assay for IL28b genotyping. AB - A rapid, duplex, high-resolution melting interleukin-28B gene (IL28B) genotyping assay, targeting both rs12979860 and rs8099917 polymorphisms, was developed and validated using 30 DNA samples from healthy volunteers. A linkage study on 300 healthy Singaporeans showed variable haplotypes. When the assay was applied to plasma DNA from 50 hepatitis C virus genotype-1 (HCV-1)-infected patients, five compound heterozygous types were detected. PMID- 22814459 TI - Analysis of borderline oxacillin-resistant Staphylococcus aureus (BORSA) strains isolated in Tunisia. AB - Twenty-three strains of Staphylococcus aureus with borderline resistance to oxacillin were studied. These strains were not detected by the cefoxitin test, tests for penicillin-binding protein 2a (PBP2a), mecA, and mecA(LGA251) were negative, and the strains were genetically unrelated. To detect all strains resistant to oxacillin, laboratories should routinely test for both cefoxitin and oxacillin. PMID- 22814460 TI - High metabolic potential may contribute to the success of ST131 uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) is the predominant cause of urinary tract infection in both hospital and community settings. The recent emergence of multidrug-resistant clones like the O25b:H4-ST131 lineage represents a significant threat to health, and numerous studies have explored the virulence potential of these organisms. Members of the ST131 clone have been described as having variable carriage of key virulence factors, and it has been suggested that additional unidentified factors contribute to virulence. Here we demonstrated that ST131 isolates have high metabolic potential and biochemical profiles that distinguish them from isolates of many other sequence types (STs). A collection of 300 UPEC isolates recovered in 2007 and 2009 in the Northwest region of England were subjected to metabolic profiling using the Vitek2 Advanced Expert System (AES). Of the 47 tests carried out, 30 gave a positive result with at least one of the 300 isolates examined. ST131 isolates demonstrated significant association with eight tests, including those for peptidase, decarboxylase, and alkalinization activity. Metabolic activity also correlated with antibiotic susceptibility profiles, with resistant organisms displaying the highest metabolic potential. This is the first comprehensive study of metabolic potential in the ST131 lineage, and we suggest that high metabolic potential may have contributed to the fitness of members of the ST131 clone, which are able to exploit the available nutrients in both the intestinal and urinary tract environments. PMID- 22814461 TI - Respiratory virus detection in immunocompromised patients with FilmArray respiratory panel compared to conventional methods. AB - Respiratory virus infections cause significant morbidity and mortality in immunocompromised patients. Timely diagnosis is needed to provide optimal clinical care. Diagnostic tests routinely available at most institutions are limited by poor sensitivity and a slow turnaround time. We collected 90 respiratory samples from 87 immunocompromised patients (56 bronchoalveolar lavage and 34 nasopharyngeal aspirate samples) in order to compare the performance of routine respiratory virus testing available at our institution to the FilmArray respiratory panel assay, a novel diagnostic tool which utilizes multiplex PCR to test for 21 respiratory pathogens with a 1-h turnaround time. Samples with discordant results and 13 samples with concordant results underwent further verification testing by laboratory-developed real-time PCR. The FilmArray assay identified viral pathogens in more samples than did clinical testing (30/90 versus 16/90; McNemar P = 0.001). Most of the additional viral pathogens identified by the FilmArray respiratory panel assay that were confirmed by verification testing were pathogens not assessed by routine clinical tests, including rhinovirus/enterovirus, human metapneumovirus, and coronavirus. The FilmArray respiratory panel assay allowed for increased identification of respiratory viral pathogens in this cohort of immunocompromised patients. PMID- 22814462 TI - Disk diffusion and MIC quality control ranges for BC-3205 and BC-3781, two novel pleuromutilin antibiotics. AB - MIC and disk diffusion quality control (QC) ranges were established for two new pleuromutilin antimicrobials (BC-3205 and BC-3781) in an eight-laboratory study performed according to Clinical and Laboratory Standards Institute M23-A3 guidelines. Staphylococcus aureus ATCC 29213 and 25923, Streptococcus pneumoniae ATCC 49619, and Haemophilus influenzae ATCC 4927 strains were evaluated. The proposed QC ranges would aid clinical laboratories in testing these compounds following their development for treatment of respiratory and cutaneous infections. PMID- 22814463 TI - Preadmission screening of adults highlights previously unrecognized carriage of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus in London: a cause for concern? AB - In the first study of its kind in the United Kingdom, we describe the colonization rate of ciprofloxacin-sensitive Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus (PVL-MRSA) in adult patients who were screened systematically at the time of hospital admission. We also describe the molecular characteristics of PVL-MRSA and antibiotic resistance phenotypes. A total of 55,760 specimens were screened for MRSA between April 2008 and December 2010. MRSA was identified in 1,998 specimens, and ciprofloxacin-susceptible (CSMRSA) isolates (385/1,998, or 19.3%) were subjected to PVL testing. Of these, 70 (18.1%) were identified as PVL-CSMRSA. During the study period, the MRSA colonization rate decreased from 4.6% to 2.8%. In contrast, the colonization rate of PVL-CSMRSA increased over time, rising from 0.075% in 2008 and 0.07% in 2009 to 0.22% in 2010. The mean patient age was 52 years (range, 18 to 90 years); over two-thirds were male. Seven different lineages of PVL-CSMRSA were identified. Over the 3 years, the Southwest Pacific clone (CC30) was dominant in our population. The CC5 clone was detected once in 2008 and not at all in 2009 but accounted for a third of all PVL-CSMRSA strains in 2010. This lineage was commonly associated with clindamycin resistance and, less frequently, tetracycline resistance. We conclude that there is hitherto unrecognized low level carriage of PVL-CSMRSA among patients being admitted to hospitals in northwest London. We observed the emergence of the CC5 clone in 2010 with associated clindamycin and tetracycline resistance. PMID- 22814465 TI - Variation-tolerant capture and multiplex detection of nucleic acids: application to detection of microbes. AB - In contrast to ordinary PCRs, which have a limited multiplex capacity and often return false-negative results due to target variation or inhibition, our new detection strategy, VOCMA (variation-tolerant capture multiplex assay), allows variation-tolerant, target-specific capture and detection of many nucleic acids in one test. Here we demonstrate the use of a single-tube, dual-step amplification strategy that overcomes the usual limitations of PCR multiplexing, allowing at least a 22-plex format with retained sensitivity. Variation tolerance was achieved using long primers and probes designed to withstand variation at known sites and a judicious mix of degeneration and universal bases. We tested VOCMA in situations where enrichment from a large sample volume with high sensitivity and multiplexity is important (sepsis; streptococci, enterococci, and staphylococci, several enterobacteria, candida, and the most important antibiotic resistance genes) and where variation tolerance and high multiplexity is important (gastroenteritis; astrovirus, adenovirus, rotavirus, norovirus genogroups I and II, and sapovirus, as well as enteroviruses, which are not associated with gastroenteritis). Detection sensitivities of 10 to 1,000 copies per reaction were achieved for many targets. VOCMA is a highly multiplex, variation-tolerant, general purpose nucleic acid detection concept. It is a specific and sensitive method for simultaneous detection of nucleic acids from viruses, bacteria, fungi, and protozoa, as well as host nucleic acid, in the same test. It can be run on an ordinary PCR and a Luminex machine and is suitable for both clinical diagnoses and microbial surveillance. PMID- 22814464 TI - Population dynamics among methicillin-resistant Staphylococcus aureus isolates in Germany during a 6-year period. AB - Methicillin-resistant Staphylococcus aureus (MRSA) originated from the health care setting but is now emerging in communities without health care contact (CA MRSA) or in livestock (LA-MRSA). The impact on the whole MRSA population was assessed in a German prospective multicenter study. Thirty-three laboratories consecutively collected up to 50 MRSA isolates from infection or carriage during two sampling periods in 2004 to 2005 and 2010 to 2011. Patient-related data were collected using a standardized questionnaire. Methicillin resistance was confirmed by the detection of mecA or its homologue mecA(LGA251). The spa type and major virulence factors were analyzed for each isolate. In total, 1,604 (2004 to 2005) and 1,603 (2010 to 2011) MRSA isolates were analyzed; one isolate from each sampling period harbored mecA(LGA251). LA-MRSA increased significantly (odds ratio [OR] = 22.67, 95% confidence interval [CI] = 8.51 to 85.49, P < 0.0005) and spread over Germany, originating from northwestern regions. Panton-Valentine leukocidin-positive CA-MRSA rose significantly, particularly in southern Germany, but the proportion in 2010 to 2011 remained low (2.7%, OR = 2.80, 95% CI = 1.54 to 5.34, P < 0.0005). The emerging MRSA clones changed the MRSA population in Germany during a 6-year period significantly. The ongoing epidemiological shift and changes of MRSA sources create a need for revision of guidelines for MRSA infection control and treatment. PMID- 22814466 TI - A longitudinal 6-year study of the molecular epidemiology of clinical campylobacter isolates in Oxfordshire, United kingdom. AB - Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST 283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity (P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST 460, ST-464, and ST-607) were associated with ciprofloxacin resistance (P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally. PMID- 22814467 TI - A swordless knight: epidemiology and molecular characteristics of the blaKPC negative sequence type 258 Klebsiella pneumoniae clone. AB - In June 2010, a bla(KPC)-negative, ertapenem-resistant ST-258 Klebsiella pneumoniae strain was isolated from a patient in the Laniado Medical Center (LMC). Our aims were (i) to describe its molecular characteristics and resistance mechanisms and (ii) to assess whether the bla(KPC)-negative ST-258 K. pneumoniae clone spreads as efficiently as its KPC-producing isogenic strain. In a prospective study, surveillance of all ertapenem-resistant, carbapenemase negative K. pneumoniae (ERCNKP) isolates was conducted from June 2010 to May 2011 at LMC (314 beds) and from July 2008 to December 2010 at the Tel Aviv Sourasky Medical Center (TASMC) (1,200 beds). Molecular typing was done by arbitrarily primed PCR, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). A total of 8 of 42 (19%) ERCNKP isolates in LMC and 1 of 32 (3.1%) in TASMC belonged to the ST-258 clone. These strains carried the bla(CTX-M-2) or the bla(CTX-M-25) extended-spectrum beta-lactamase (ESBL) gene. Sequencing of the ompK genes showed a frameshift mutation in the ompK35 gene. The fate of the bla(KPC)-carrying plasmid, pKpQIL, was determined by S1 analysis and by PCR of the Tn4401 transposon, repA, and the truncated bla(OXA-9). Plasmid analysis of the ERCNKP ST-258 isolates showed variability in plasmid composition and absence of the Tn4401 transposon and the pKpQIL plasmid. In addition, the ST-258 clone was identified in 35/35 (100%) of KPC-producing K. pneumoniae isolates but in none of 62 ertapenem-susceptible K. pneumoniae isolates collected in the two centers. Our results suggest that ERCNKP ST-258 evolved by loss of the bla(KPC) carrying plasmid pKpQIL. ERCNKP ST-258 appears to have low epidemic potential. PMID- 22814468 TI - Multilocus variable-number tandem-repeat analysis-confirmed emergence of a macrolide resistance-associated mutation in Mycoplasma pneumoniae during macrolide therapy for interstitial pneumonia in an immunocompromised child. AB - A child with Job's syndrome was treated for pneumonia due to Mycoplasma pneumoniae. A mixed population of wild-type bacteria and an A2059G mutant was detected during josamycin treatment failure. The same multilocus variable-number tandem-repeat analysis (MLVA) type (MLVA type I) was isolated before and after treatment failure. The child recovered after ciprofloxacin treatment. PMID- 22814469 TI - Development of an improved selective and differential medium for isolation of Salmonella spp. AB - We describe an improved selective, differential, and cost-effective medium, XA medium, which contains d-arabinose, to facilitate the selective isolation of Salmonella spp. The sensitivity and the specificity of XA medium were compared to those of xylose lysine desoxycholate agar (XLD) using stock cultures and naturally contaminated food samples. XA medium and XLD were evaluated with a total of 82 Salmonella and 69 non-Salmonella stock cultures. Of 82 strains of Salmonella spp. tested, 76 produced a characteristic black colony on XA medium and XLD. The remaining 6 strains belonged to Salmonella enterica serovars Berta (n = 1), Paratyphi A (n = 1), Gallinarum (n = 2), and Pullorum (n = 2). The sensitivities of XA medium and XLD were identical (92.7%). Citrobacter freundii (n = 21) and Proteus mirabilis (n = 21) stock cultures produced black colonies on XLD, whereas only 4 strains of P. mirabilis appeared as black colonies on XA medium. In the second phase of the study, a total of 180 food samples were cultured onto XA medium and XLD after selective enrichment. The sensitivities of XA medium and XLD were equal (100%), and a total of 6 Salmonella strains were isolated from the 180 food samples. The specificity of XA medium (92.0%) was superior to that of XLD (73.0%), with a total of 14 and 47 false-positive results found on XA medium and XLD, respectively. On the basis of its good specificity, XA medium is useful for the isolation of Salmonella spp. from food samples. PMID- 22814470 TI - Performance of clinical laboratories in South African parasitology proficiency testing surveys between 2004 and 2010. AB - Performance in proficiency testing (PT) schemes is an objective measure of a laboratory's best performance. We examined the performance of participants in two parasitology PT schemes in South Africa from 2004 through 2010. The average rates of acceptable scores over the period were 58% and 66% for the stool and blood parasite schemes, respectively. In our setting, participation in PT alone is insufficient to improve performance; a policy that provides additional resources and training seems necessary. PMID- 22814471 TI - Comparison of the BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay and the BD GeneOhm MRSA achromopeptidase assay with direct- and enriched-culture techniques using clinical specimens for detection of MRSA. AB - We evaluated the new, fully automated molecular BD Max methicillin-resistant Staphylococcus aureus (MRSA) assay for detection of methicillin-resistant S. aureus in a low-prevalence (4.1%) setting. Sensitivity, specificity, and positive and negative predictive values were 93.9%, 99.2%, 83.8%, and 99.7%, respectively. The assay reported fewer unresolved results than the BD GeneOhm MRSA ACP assay. PMID- 22814472 TI - Evaluation of Clearview Exact PBP2a, a new immunochromatographic assay, for detection of low-level methicillin-resistant Staphylococcus aureus (LL-MRSA). AB - We evaluated the performance of a new immunochromatographic assay (ICA), the Clearview Exact PBP2a, for rapid detection of penicillin-binding protein 2a (PBP2a) in a challenge set of Staphylococcus aureus strains showing MICs to oxacillin of <=16 mg/liter. The sensitivity and specificity of the ICA were 96.6% and 100%, respectively. PMID- 22814473 TI - Surface transport and stable trapping of particles and cells by an optical waveguide loop. AB - Waveguide trapping has emerged as a useful technique for parallel and planar transport of particles and biological cells and can be integrated with lab-on-a chip applications. However, particles trapped on waveguides are continuously propelled forward along the surface of the waveguide. This limits the practical usability of the waveguide trapping technique with other functions (e.g. analysis, imaging) that require particles to be stationary during diagnosis. In this paper, an optical waveguide loop with an intentional gap at the centre is proposed to hold propelled particles and cells. The waveguide acts as a conveyor belt to transport and deliver the particles/cells towards the gap. At the gap, the diverging light fields hold the particles at a fixed position. The proposed waveguide design is numerically studied and experimentally implemented. The optical forces on the particle at the gap are calculated using the finite element method. Experimentally, the method is used to transport and trap micro-particles and red blood cells at the gap with varying separations. The waveguides are only 180 nm thick and thus could be integrated with other functions on the chip, e.g. microfluidics or optical detection, to make an on-chip system for single cell analysis and to study the interaction between cells. PMID- 22814474 TI - The mechanics of stochastic slowdown in evolutionary games. AB - We study the stochastic dynamics of evolutionary games, and focus on the so called 'stochastic slowdown' effect, previously observed in Altrock et al. (2010) for simple evolutionary dynamics. Slowdown here refers to the fact that a beneficial mutation may take longer to fixate than a neutral one. More precisely, the fixation time conditioned on the mutant taking over can show a maximum at intermediate selection strength. We show that this phenomenon is present in the Prisoner's Dilemma, and also discuss counterintuitive slowdown and speedup in coexistence games. In order to establish the microscopic origins of these phenomena, we calculate the average sojourn times. This allows us to identify the transient states which contribute most to the slowdown effect, and enables us to provide an understanding of slowdown in the takeover of a small group of cooperators by defectors in the Prisoner's Dilemma: Defection spreads fast initially, but the final steps to takeover can be delayed substantially. The analysis of coexistence games reveals even more intricate non-monotonic behavior. In small populations, the conditional average fixation time can show multiple extrema as a function of the selection strength, e.g., slowdown, speedup, and slowdown again. We classify generic 2*2 games with respect to the possibility to observe non-monotonic behavior of the conditional average fixation time as a function of selection strength. PMID- 22814476 TI - A hybrid stochastic-deterministic computational model accurately describes spatial dynamics and virus diffusion in HIV-1 growth competition assay. AB - We present a new hybrid stochastic-deterministic, spatially distributed computational model to simulate growth competition assays on a relatively immobile monolayer of peripheral blood mononuclear cells (PBMCs), commonly used for determining ex vivo fitness of human immunodeficiency virus type-1 (HIV-1). The novel features of our approach include incorporation of viral diffusion through a deterministic diffusion model while simulating cellular dynamics via a stochastic Markov chain model. The model accounts for multiple infections of target cells, CD4-downregulation, and the delay between the infection of a cell and the production of new virus particles. The minimum threshold level of infection induced by a virus inoculum is determined via a series of dilution experiments, and is used to determine the probability of infection of a susceptible cell as a function of local virus density. We illustrate how this model can be used for estimating the distribution of cells infected by either a single virus type or two competing viruses. Our model captures experimentally observed variation in the fitness difference between two virus strains, and suggests a way to minimize variation and dual infection in experiments. PMID- 22814475 TI - Evolutionary shift dynamics on a cycle. AB - We present a new model of evolutionary dynamics in one-dimensional space. Individuals are arranged on a cycle. When a new offspring is born, another individual dies and the rest shift around the cycle to make room. This rule, which is inspired by spatial evolution in somatic tissue and microbial colonies, has the remarkable property that, in the limit of large population size, evolution acts to maximize the payoff of the whole population. Therefore, social dilemmas, in which some individuals benefit at the expense of others, are resolved. We demonstrate this principle for both discrete and continuous games. We also discuss extensions of our model to other one-dimensional spatial configurations. We conclude that shift dynamics in one dimension is an unusually strong promoter of cooperative behavior. PMID- 22814477 TI - Complex-linear invariants of biochemical networks. AB - The nonlinearities found in molecular networks usually prevent mathematical analysis of network behaviour, which has largely been studied by numerical simulation. This can lead to difficult problems of parameter determination. However, molecular networks give rise, through mass-action kinetics, to polynomial dynamical systems, whose steady states are zeros of a set of polynomial equations. These equations may be analysed by algebraic methods, in which parameters are treated as symbolic expressions whose numerical values do not have to be known in advance. For instance, an "invariant" of a network is a polynomial expression on selected state variables that vanishes in any steady state. Invariants have been found that encode key network properties and that discriminate between different network structures. Although invariants may be calculated by computational algebraic methods, such as Grobner bases, these become computationally infeasible for biologically realistic networks. Here, we exploit Chemical Reaction Network Theory (CRNT) to develop an efficient procedure for calculating invariants that are linear combinations of "complexes", or the monomials coming from mass action. We show how this procedure can be used in proving earlier results of Horn and Jackson and of Shinar and Feinberg for networks of deficiency at most one. We then apply our method to enzyme bifunctionality, including the bacterial EnvZ/OmpR osmolarity regulator and the mammalian 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase glycolytic regulator, whose networks have deficiencies up to four. We show that bifunctionality leads to different forms of concentration control that are robust to changes in initial conditions or total amounts. Finally, we outline a systematic procedure for using complex-linear invariants to analyse molecular networks of any deficiency. PMID- 22814478 TI - An analysis of non-response in a Swiss national survey. PMID- 22814479 TI - Socioeconomic position and later life prevalence of hypertension, diabetes and visual impairment in Nakuru, Kenya. AB - OBJECTIVES: We examined the extent to which the association between socioeconomic position (SEP) and later life prevalence of hypertension, diabetes and visual impairment in Nakuru, Kenya is mediated by health-related behaviour. METHODS: We used data from a community survey of 4,314 participants sampled from urban and rural areas in Nakuru, Kenya. Structural equation modelling was employed to estimate the direct and indirect--via health-related behaviour--effects of SEP on the three health outcomes. RESULTS: The accumulation of material resources was positively associated with hypertension and diabetes, whereas both education and material resources had a negative association with the prevalence of visual impairment. However, the observed health inequalities were not due to variation between SEP groups in health-related behaviour. CONCLUSIONS: The pattern of associations between education, material resources and the three health outcomes varied, suggesting that in Kenya, unlike the observed pattern of inequalities in high income countries, different dimensions of SEP provide different aspects of protection as well as risk. Smoking and alcohol use did not appear to mediate the observed associations, in contrast with countries past the epidemiologic transition. PMID- 22814480 TI - Multilateral, regional, and national determinants of policy adoption: the case of HIV/AIDS legislative action. AB - OBJECTIVES: This article examines the global legislative response to the HIV/AIDS epidemic with a particular focus on how policies were diffused internationally or regionally, or facilitated internally. METHODS: This article uses event history analysis combined with multinomial logit regression to model the legislative response of 133 countries. RESULTS: First, the results demonstrate that the WHO positively influenced the likelihood of a legislative response. Second, the article demonstrates that development bank aid helped to spur earlier legislative action. Third, the results demonstrate that developed countries acted earlier than developing countries. And finally, the onset and severity of the HIV/AIDS epidemic was a significant influence on the legislative response. CONCLUSION: Multilateral organizations have a positive influence in global policy diffusion through informational advocacy, technical assistance, and financial aid. It is also clear that internal stressors play key roles in legislative action seen clearly through earlier action being taken in countries where the shock of the onset of HIV/AIDS occurred earlier and earlier responses taken where the epidemic was more severe. PMID- 22814481 TI - Predicting ovarian aging: anti-Mullerian hormone. PMID- 22814482 TI - Poor results after surgery for rectovaginal endometriosis can be related to uterine adenomyosis. PMID- 22814483 TI - Blood pressure in ICSI-conceived adolescents. AB - STUDY QUESTION: Do young adolescents conceived by ICSI display a higher blood pressure than spontaneously conceived (SC) adolescents? SUMMARY ANSWER: In our study, 14-year-old male and female ICSI teenagers were not found to have increased blood pressure at rest. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Only limited data are available regarding the cardiovascular risk of children born after assisted conception and up till now, no data on the cardiovascular health in pubertal children conceived by ICSI have been published. In this study, resting blood pressure and blood pressure response to a psychological stressor were measured in a cohort of 14-year-old teenagers conceived by ICSI and compared the results with those of a group of SC peers. DESIGN: In this cross-sectional study, resting blood pressure measurements were available from 217 singleton ICSI children (116 boys, 101 girls) and 223 singleton control children born after spontaneous conception (115 boys, 108 girls). Continuous blood pressure measurements, performed during a psychological stress test, were available for only 67 ICSI and 38 SC children. PARTICIPANTS AND SETTING: The study group comprised adolescents conceived by ICSI predominantly because of male factor infertility and they were part of a previously published cohort followed since birth; controls were a cross-sectional sample of peers born to fertile parents and recruited from comparable schools as those attended by the ICSI teenagers. Response rates were 56% (tested/reached) in the ICSI group and 50% (agreed/eligible) in the SC group, but information regarding health could be obtained in 63 and 72% of the ICSI and SC children, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: ICSI girls had a comparable resting systolic (109 +/- 9 mmHg) and diastolic (64 +/- 6 mmHg) blood pressure in comparison with girls in the SC group (111 +/- 9 mmHg, P = 0.2 and 66 +/- 7 mmHg, P = 0.05), even after adjustment for age and height. After adjustment for current body characteristics, early life and parental background factors, systolic and diastolic blood pressure remained comparable in both groups. In ICSI boys, a slightly lower systolic (113 +/- 10 mmHg), but comparable diastolic (64 +/- 6 mmHg) resting blood pressure was found in comparison with the SC group (116 +/- 9 mmHg; P = 0.04 and 65 +/- 5 mmHg; P = 0.1). After adjustment for height and age, systolic and diastolic blood pressure were comparable in both groups (P = 0.7 and P = 0.6). After correction for current body characteristics, early life and parental factors, ICSI and SC boys still had comparable systolic (difference in ICSI versus SC: -1.1 mmHg; 95% CI: -3.8-1.6; P = 0.4) and diastolic (difference in ICSI versus SC: -1.2 mmHg; 95% CI: -3.2-0.7; P = 0.2) blood pressure measurements. In the small subsample of girls and boys with continuous blood pressure readings, the systolic and diastolic blood pressure response to the stress test was not significantly different between the ICSI and SC groups even after taking into account the baseline values. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Despite the rather low response rate in the ICSI group and the fact that no information on current health status could be obtained from more than a quarter of the eligible comparison group, the non-participating analysis in the ICSI as well in the SC group did not reveal differences between participating and non-participating children regarding clinical characteristics. The negative results for the sub analysis on blood pressure response to stress should be interpreted with caution, because these data were available for only a small number of children, and the analysis may be underpowered. This result can only rule out a large effect on blood pressure responsiveness to a psychological stressor. Although our sample size appears to be appropriate, our results need confirmation by others and in larger cohorts when more data become available. GENERALIZABILITY TO OTHER POPULATIONS: Our results are the first described ever in ICSI offspring, born to parents suffering from predominantly male factor infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Onderzoeksraad Vrije Universiteit Brussel and Wetenschappelijk Fonds Willy Gepts. Unconditional grants from MSD Belgium, Merck International, IBSA Institut Biochimique and Ferring International Center are kindly acknowledged. PMID- 22814484 TI - Surrogacy families 10 years on: relationship with the surrogate, decisions over disclosure and children's understanding of their surrogacy origins. AB - BACKGROUND: This study aimed to prospectively examine families created using surrogacy over a 10-year period in the UK with respect to intending parents' and children's relationship with the surrogate mother, parents' decisions over disclosure and children's understanding of the nature of their conception. METHODS: Semi-structured interviews were administered by trained researchers to intending mothers, intending fathers and children on four occasions over a 10 year period. Forty-two families (19 with a genetic surrogate mother) participated when the child was 1-year old and by age 10 years, 33 families remained in the study. Data were collected on the frequency of contact with the surrogate mother, relationship with the surrogate, disclosure of surrogacy to the child and the child's understanding of their surrogacy birth. RESULTS: Frequency of contact between surrogacy families and their surrogate mother decreased over time, particularly for families whose surrogate was a previously unknown genetic carrier (P < 0.001) (i.e. where they had met through a third party and the surrogate mother's egg was used to conceive the child). Most families reported harmonious relationships with their surrogate mother. At age 10 years, 19 (90%) children who had been informed of the nature of their conception had a good understanding of this and 13 of the 14 children who were in contact with their surrogate reported that they liked her. CONCLUSIONS: Surrogacy families maintained good relationships with the surrogate mother over time. Children felt positive about their surrogate mother and their surrogacy birth. The sample size of this study was small and further, larger investigations are needed before firm conclusions can be drawn. PMID- 22814485 TI - Effects of oral rehydration therapy on gastric volume and pH in patients with preanesthetic H2 antagonist. AB - Recent preanesthetic fasting practice allows patients to take clear fluids up to 2 h before surgery without taking any antacid for the prophylaxis of aspiration pneumonia; this practice is defined as oral rehydration therapy (ORT). It has been reported that with ORT the gastric volume may be significantly lower than that with a standard fasting regimen, although in a standard fasting regimen without preanesthetic antacid, gastric pH and volume values could be critical for causing aspiration pneumonia. In this study we compared gastric fluid status in patients with ORT and those with a standard fasting regimen; patients in both groups received a preanesthetic H(2) antagonist. One hundred and four patients were randomly assigned to either the ORT or standard fasting group, and all were given roxatidine 75 mg 2 h before surgery. After the induction of anesthesia, the gastric contents were collected via a gastric tube to measure gastric volume and pH. Neither gastric volume nor pH differed between the groups (ORT 9.6 +/- 8.2 ml and 5.6 +/- 1.7, respectively, vs. standard fasting 8.5 +/- 6.8 ml and 5.5 +/- 1.7, respectively). These data suggest that ORT may not reduce gastric volume in patients receiving a preanesthetic H(2) antagonist. PMID- 22814486 TI - Assessment of the effect of ribavirin on myeloid and plasmacytoid dendritic cells during interferon-based therapy of chronic hepatitis B patients. AB - The combination of ribavirin and peginterferon is the current standard of anti viral treatment for chronic HCV patients. However, little is known on the mode of action of ribavirin in the anti-viral treatment of HCV patients. To investigate the immunomodulatory mechanism of ribavirin, we studied peginterferon alone versus peginterferon and ribavirin in chronic HBV patients. The addition of ribavirin did not affect the number of myeloid dendritic cells (mDC) or plasmacytoid dendritic cells (pDC), nor did it enhance T-helper-1 cell activity or T-cell proliferation. In contrast, it increased upregulation of activation markers on mDC and pDC, which was sustained throughout treatment. However, the addition of ribavirin had no effect on IFNalpha production by pDC. Our findings demonstrate that, although ribavirin does not lead to a viral load decline, in vivo treatment with ribavirin affects the activation of pDC and mDC in chronic HBV patients. PMID- 22814487 TI - Brainstem auditory responses to resolved and unresolved harmonics of a synthetic vowel in quiet and noise. AB - OBJECTIVES: This study investigated speech auditory brainstem responses (speech ABR) with variants of a synthetic vowel in quiet and in background noise. Its objectives were to study the noise robustness of the brainstem response at the fundamental frequency F0 and at the first formant F1, evaluate how the resolved/unresolved harmonics regions in speech contribute to the response at F0, and investigate the origin of the response at F0 to resolved and unresolved harmonics in speech. DESIGN: In total, 18 normal-hearing subjects (11 women, aged 18-33 years) participated in this study. Speech ABRs were recorded using variants of a 300 msec formant-synthesized /a/ vowel in quiet and in white noise. The first experiment employed three variants containing the first three formants F1 to F3, F1 only, and F2 and F3 only with relative formant levels following those reported in the literature. The second experiment employed three variants containing F1 only, F2 only, and F3 only, with the formants equalized to the same level and the signal-to-noise ratio (SNR) maintained at -5 dB. Overall response latency was estimated, and the amplitude and local SNR of the envelope following response at F0 and of the frequency following response at F1 were compared for the different stimulus variants in quiet and in noise. RESULTS: The response at F0 was more robust to noise than that at F1. There were no statistically significant differences in the response at F0 caused by the three stimulus variants in both experiments in quiet. However, the response at F0 with the variant dominated by resolved harmonics was more robust to noise than the response at F0 with the stimulus variants dominated by unresolved harmonics. The latencies of the responses in all cases were very similar in quiet, but the responses at F0 due to resolved and unresolved harmonics combined nonlinearly when both were present in the stimulus. CONCLUSIONS: Speech ABR has been suggested as a marker of central auditory processing. The results of this study support earlier work on the differential susceptibility to noise of the F0 and F1 components of the evoked response. In the case of F0, the results support the view that in speech, the pitch of resolved harmonics and that of unresolved harmonics are processed in different but interacting pathways that converge in the upper brainstem. Pitch plays an important role in speech perception, and speech ABR can offer a window into the neural extraction of the pitch of speech and how it may change with hearing impairment. PMID- 22814488 TI - Cd(II)-triggered excimer-monomer conversion of a pyrene derivative: time dependent red-shift of monomer emission with cell staining application. AB - An efficient fluorescent probe (E)-N1-((E)-2-((pyren-7-yl)methyleneamino)ethyl) N2-((pyren-7-yl)methylene)ethane-1,2-diamine (L) has been synthesized by a facile one-step condensation reaction. L can selectively detect Cd(2+) in presence of other common metal ions in 0.1 M HEPES buffered DMSO-water (4 : 1, v/v) medium. The detection limit of Cd(2+) is 1.8 * 10(-8) M. Cd(2+) can effectively convert the excimer emission of L into its monomer emission which in turn exhibits a time dependent red-shift. PMID- 22814489 TI - Identification of mating type loci and development of SCAR marker genetically linked to the B3 locus in Pleurotus eryngii. AB - In order to estimate how diverse the mating types in Pleurotus eryngii from different regions are, pairings between monokaryons derived from inter- and intragroups were done. Sixteen and 15 alleles were identified at loci A and B from the 12 strains. In the P. eryngii KNR2312, widely used for commercial production, four mating loci, A3, A4, B3, and B4, were determined. Those loci, except A3, were found in 4 strains out of 12 strains. To improve breeding efficiency, especially in mating type determination, RAPD and BSA were performed to screen for a mating type specific marker. The SCAR marker 13- 2(2100) was developed based on the RAPD-derived sequence typing B3 locus. The sequence analysis of 13-2(2100) revealed that it contained a conserved domain, the STE3 superfamily, and consensus sequences like the TATA box and GC box. It seems likely that the SCAR marker region is a part of the pheromone receptor gene. PMID- 22814490 TI - The importance of weathered crude oil as a source of hydrocarbonoclastic microorganisms in contaminated seawater. AB - This study investigated the hydrocarbonoclastic microbial community present on weathered crude oil and their ability to degrade weathered oil in seawater obtained from the Gulf St. Vincent (SA, Australia). Examination of the native seawater communities capable of utilizing hydrocarbon as the sole carbon source identified a maximum recovery of just 6.6 * 10(1) CFU/ml, with these values dramatically increased in the weathered oil, reaching 4.1 * 10(4) CFU/ml. The weathered oil (dominated by >C30 fractions; 750,000 +/- 150,000 mg/l) was subject to an 8 week laboratory-based degradation microcosm study. By day 56, the natural inoculums degraded the soluble hydrocarbons (initial concentrations 3,400 +/- 700 mg/l and 1,700 +/- 340 mg/l for the control and seawater, respectively) to below detectable levels, and biodegradation of the residual oil reached 62% (254,000 +/ 40,000 mg/l) and 66% (285,000 +/- 45,000 mg/l) in the control and seawater sources, respectively. In addition, the residual oil gas chromatogram profiles changed with the presence of short and intermediate hydrocarbon chains. 16S rDNA DGGE sequence analysis revealed species affiliated with the genera Roseobacter, Alteromonas, Yeosuana aromativorans, and Pseudomonas, renowned oil-degrading organisms previously thought to be associated with the environment where the oil contaminated rather than also being present in the contaminating oil. This study highlights the importance of microbiological techniques for isolation and characterisation, coupled with molecular techniques for identification, in understanding the role and function of native oil communities. PMID- 22814491 TI - Analysis and quantification of ammonia-oxidizing bacteria community with amoA gene in sewage treatment plants. AB - The analysis and quantification of ammonia-oxidizing bacteria (AOB) is crucial, as they initiate the biological removal of ammonia-nitrogen from sewage. Previous methods for analyzing the microbial community structure, which involve the plating of samples or culture media over agar plates, have been inadequate because many microorganisms found in a sewage plant are unculturable. In this study, to exclusively detect AOB, the analysis was carried out via denaturing gradient gel electrophoresis using a primer specific to the amoA gene, which is one of the functional genes known as ammonia monooxygenase. An AOB consortium (S1 sample) that could oxidize an unprecedented 100% of ammonia in 24 h was obtained from sewage sludge. In addition, real-time PCR was used to quantify the AOB. Results of the microbial community analysis in terms of carbon utilization ability of samples showed that the aeration tank water sample (S2), influent water sample (S3), and effluent water sample (S4) used all the 31 substrates considered, whereas the AOB consortium (S1) used only Tween 80, D-galacturonic acid, itaconic acid, D-malic acid, and L-serine after 192 h. The largest concentration of AOB was detected in S1 (7.6 * 10(6) copies/microliter), followed by S2 (3.2 * 10(6) copies/microliter), S4 (2.8 * 10(6) copies/microliter), and S3 (2.4 * 10(6) copies/microliter). PMID- 22814492 TI - Synthesis and high expression of chitin deacetylase from Colletotrichum lindemuthianum in Pichia pastoris GS115. AB - A gene, ClCDA, encoding chitin deacetylase from Colletotrichum lindemuthianum, was optimized according to the codon usage bias of Pichia pastoris and synthesized in vitro by overlap extension PCR. It was secretorily expressed in P. pastoris GS115 using the constitutive expression vector pHMB905A. The expression level reached the highest with 110 mg/l culture supernatant after 72 h of methanol induction, which comprised 77.27 U/mg chitin deacetylase activity. SDS PAGE, mass spectrometry, and deglycosylation assays demonstrated that partial recombinant protein was glycosylated with an apparent molecular mass of 33 kDa. The amino acid sequences of recombinant proteins were confirmed by mass spectrometry. PMID- 22814493 TI - Draft genome database construction from four strains (NIES-298, FCY- 26, -27, and -28) of the cyanobacterium Microcystis aeruginosa. AB - Microcystis aeruginosa is a cyanobacterium that can form harmful algal blooms (HABs) producing toxic secondary metabolites. We provide here draft genome information of four strains of this freshwater cyanobacterium that was obtained by the Next Generation Sequencing approach to provide a better understanding of molecular mechanisms at the physiological and ecological levels. After gene assembly, genes of each strain were identified and annotated, and a genome database and G-browser of M. aeruginosa were subsequently constructed. Such genome information resources will enable us to obtain useful information for molecular ecological studies with a better understanding of modulating mechanisms of environmental factors associated with blooming. PMID- 22814494 TI - A novel Helicosporium isolate and its antimicrobial and cytotoxic pigment. AB - One Helicosporium strain, isolated from a wilted chestnut tree, evidenced in vitro antimicrobial activity against various types of bacteria and fungi, and generated a diffusible pigment. The antimicrobial compounds and the diffusible pigment of the Helicosporium sp. isolate were purified via solvent fractionation, column chromatography, and recycling preparative chromatography. Both the major antimicrobial compound and the diffusible pigment were identified as 2 methylresorcinol via nuclear magnetic resonance spectroscopy. Therefore, 2 methylresorcinol, a diffusible pigment generated by Helicosporium sp., appears to be an active antimicrobial principle. This pigment also exhibited considerable cytotoxicity against mammalian cells. PMID- 22814495 TI - Enhanced epsilon-poly-L-lysine production from Streptomyces ahygroscopicus by a combination of cell immobilization and in situ adsorption. AB - Epsilon-poly-L-lysine (epsilon-PL), produced by Streptomyces or Kitasatospora strains, is a homo-poly-amino acid of Llysine, which is used as a safe food preservative. The present study investigates the combined use of cell immobilization and in situ adsorption (ISA) to produce epsilon-PL in shaken flasks. Loofah sponge-immobilized Streptomyces ahygroscopicus GIM8 produced slightly more epsilon-PL than those immobilized on synthetic sponge, and sugarcane bagasse. Moreover, loofah sponge supported the maximum biomass. Hence, loofah sponge was chosen for cell immobilization. Meanwhile, the ion-exchange resin D152 was employed for ISA. The loofah sponge-immobilized cells produced 0.54 +/- 0.1 g/l epsilon-PL, which significantly increased to 3.64 +/- 0.32 g/l after combining with ISA through the addition of resin bags. The free cells with ISA using the dispersed resin yielded 2.73 +/- 0.26 g/l of epsilon-PL, an increase from 0.82 +/- 0.08 g/l. These data illustrate that the proposed combination method improved production most significantly compared with either immobilization or ISA only. Moreover, the immobilized cells could be repeatedly used and an epsilon-PL total amount of 8.05 +/- 0.84 g/l was obtained. The proposed combination method offers promising perspectives for epsilon-PL production. PMID- 22814496 TI - Enzymatic synthesis of puerarin glucosides using Leuconostoc dextransucrase. AB - Puerarin (P), an isoflavone derived from kudzu roots, has strong biological activities, but its bioavailability is often limited by its low water solubility. To increase its solubility, P was glucosylated by three dextransucrases from Leuconostoc or Streptococcus species. Leuconostoc lactis EG001 dextransucrase exhibited the highest productivity of puerarin glucosides (P-Gs) among the three tested enzymes, and it primarily produced two P-Gs with a 53% yield. Their structures were identified as alpha-D-glucosyl-(1-->6)-P (P-G) by using LC-MS or (1)H- or (13)C-NMR spectroscopies and alpha-D-isomaltosyl-(1-->6)-P (P-IG2) by using specific enzymatic hydrolysis, and their solubilities were 15- and 202-fold higher than that of P, respectively. P-G and P-IG2 are easily applicable in the food and pharmaceutical industries as alternative functional materials. PMID- 22814497 TI - Scale-up of an alkaline protease from Bacillus pumilus MTCC 7514 utilizing fish meal as a sole source of nutrients. AB - Fish meal grades SL1 and SL2 from Sardine (Sardinella longiceps) and NJ from Pink Perch (Nemipterus japonicas) were evaluated as a sole source of carbon and nitrogen in the medium for alkaline protease production by Bacillus pumilus MTCC 7514. The analysis of the fish meal suggests that the carbon and nitrogen contents in fish meal are sufficient to justify its choice as replacement for other nutrients. Protease production increased significantly (4,914 U/ml) in medium containing only fish meal, compared with the basal medium (2,646 U/ml). However, the elimination of inorganic salts from media reduced the protease productivity. In addition, all the three grades of fish meal yielded almost the same amounts of protease when employed as the sole source of carbon and nitrogen. Nevertheless, the best results were observed in fish meal SL1 medium. Furthermore, protease production was enhanced to 6,966 U/ml and 7,047 U/ml on scaling up from flask (4,914 U/ml) to 3.7 and 20 L fermenters, respectively, using fish meal (10 g/l). Similarly, the corresponding improvement in productivities over flask (102.38 U/ml/h) was 193.5 and 195.75 U/ml/h in 3.7 and 20 L fermenters, respectively. The crude protease was found to have dehairing ability in leather processing, which is bound to have great environmental benefits. PMID- 22814498 TI - Cloning of agarase gene from non-marine agarolytic bacterium Cellvibrio sp. AB - Agarase genes of non-marine agarolytic bacterium Cellvibrio sp. were cloned into Escherichia coli and one of the genes obtained using HindIII was sequenced. From nucleotide and putative amino acid sequences (713 aa, molecular mass; 78,771 Da) of the gene, designated as agarase AgaA, the gene was found to have closest homology to the Saccharophagus degradans (formerly, Microbulbifer degradans) 2-40 aga86 gene, belonging to glycoside hydrolase family 86 (GH86). The putative protein appears to be a non-secreted protein because of the absence of a signal sequence. The recombinant protein was purified with anion exchange and gel filtration columns after ammonium sulfate precipitation and the molecular mass (79 kDa) determined by SDS-PAGE and subsequent enzymography agreed with the estimated value, suggesting that the enzyme is monomeric. The optimal pH and temperature for enzymatic hydrolysis of agarose were 6.5 and 42.5 degrees C, and the enzyme was stable under 40 degrees C. LC-MS and NMR analyses revealed production of a neoagarobiose and a neoagarotetraose with a small amount of a neoagarohexaose during hydrolysis of agarose, indicating that the enzyme is a beta-agarase. PMID- 22814499 TI - Gene cloning and characterization of a cold-adapted esterase from Acinetobacter venetianus V28. AB - Acinetobacter venetians V28 was isolated from the intestine of righteye flounder, Poecilopsetta plinthus caught in Vietnam seawater, and the esterase gene was cloned using a shotgun method. The amino acid sequence deduced from the nucleotide sequence (1,017 bp) corresponded to a protein of 338 amino acid residues with a molecular weight of 37,186. The esterase had 87% and 72% identities with the lipases of A. junii SH205 and A. calcoaceticus RUH2202, respectively. The esterase contained a putative leader sequence, as well as the conserved catalytic triad (Ser, His, Asp), consensus pentapeptide GXSXG, and oxyanion hole sequence (HG). The protein from the strain V28 was produced in both a soluble and an insoluble form when the Escherichia coli cells harboring the gene were cultured at 18 degrees C. The maximal activity of the purified enzyme was observed at a temperature of 40 degrees C and pH 9.0 using p-NP-caprylate as substrate; however, relative activity still reached to 70% even at 5 degrees C with an activation energy of 3.36 kcal/mol, which indicated that it was a cold adapted enzyme. The enzyme was a nonmetalloprotein and was active against p nitrophenyl esters of C4, C8, and C14. Remarkably, this enzyme retained much of its activity in the presence of commercial detergents and organic solvents. This cold-adapted esterase will be applicable as catalysts for reaction in the presence of organic solvents and detergents. PMID- 22814500 TI - Functional expression of amylosucrase, a glucan-synthesizing enzyme, from Arthrobacter chlorophenolicus A6. AB - A gene (acas) designated as alpha-amylase was cloned from Arthrobacter chlorophenolicus A6. The multiple amino acid sequence analysis and functional expression of acas revealed that this gene really encoded an amylosucrase (ASase) instead of alpha-amylase. In fact, the recombinant enzyme exhibited typical ASase activity by showing both sucrose hydrolysis and glucosyltransferase activities. The purified enzyme has a molecular mass of 72 kDa and exhibits optimal hydrolysis activity at 45 degrees C and a pH of 8.0. The analysis of the oligomeric state of ACAS with gel permeation chromatography revealed that the ACAS existed as a monomer. PMID- 22814501 TI - Enhanced 2,3-butanediol production in recombinant Klebsiella pneumoniae via overexpression of synthesis-related genes. AB - 2,3-Butanediol (2,3-BD) is a major metabolite produced by Klebsiella pneumoniae KCTC2242, which is a important chemical with wide applications. Three genes important for 2,3-BD biosynthesis acetolactate decarboxylase (budA), acetolactate synthase (budB), and alcohol dehydrogenase (budC) were identified in K. pneumoniae genomic DNA. With the goal of enhancing 2,3-BD production, these genes were cloned into pUC18K expression vectors containing the lacZ promoter and the kanamycin resistance gene to generate plasmids pSB1-7. The plasmids were then introduced into K. pneumoniae using electroporation. All strains were incubated in flask experiments and 2,3-BD production was increased by 60% in recombinant bacteria harboring pSB04 (budA and budB genes), compared with the parental strain K. pneumoniae KCTC2242. The maximum 2,3-BD production level achieved through fedbatch fermentation with K. pneumoniae SGJSB04 was 101.53 g/l over 40 h with a productivity of 2.54 g/l.h. These results suggest that overexpression of 2,3-BD synthesisrelated genes can enhance 2,3-BD production in K. pneumoniae by fermentation. PMID- 22814502 TI - Effects of soil-plant interactive system on response to exposure to ZnO nanoparticles. AB - The ecotoxicological effects of nanomaterials on animal, plant, and soil microorganisms have been widely investigated; however, the nanotoxic effects of plant-soil interactive systems are still largely unknown. In the present study, the effects of ZnO nanoparticles (NPs) on the soil-plant interactive system were estimated. The growth of plant seedlings in the presence of different concentrations of ZnO NPs within microcosm soil (M) and natural soil (NS) was compared. Changes in dehydrogenase activity (DHA) and soil bacterial community diversity were estimated based on the microcosm with plants (M+P) and microcosm without plants (M-P) in different concentrations of ZnO NPs treatment. The shoot growth of M+P and NS+P was significantly inhibited by 24% and 31.5% relative to the control at a ZnO NPs concentration of 1,000 mg/kg. The DHA levels decreased following increased ZnO NPs concentration. Specifically, these levels were significantly reduced from 100 mg/kg in M-P and only 1,000 mg/kg in M+P. Different clustering groups of M+P and M-P were observed in the principal component analysis (PCA). Therefore, the M-P's soil bacterial population may have more toxic effects at a high dose of ZnO NPs than M+P's. The plant and activation of soil bacteria in the M+P may have a less toxic interactive effect on each of the soil bacterial populations and plant growth by the ZnO NPs attachment or absorption of plant roots surface. The soil-plant interactive system might help decrease the toxic effects of ZnO NPs on the rhizobacteria population. PMID- 22814504 TI - Genetic transformation of Geobacillus kaustophilus HTA426 by conjugative transfer of host-mimicking plasmids. AB - We established an efficient transformation method for thermophile Geobacillus kaustophilus HTA426 using conjugative transfer from Escherichia coli of host mimicking plasmids that imitate DNA methylation of strain HTA426 to circumvent its DNA restriction barriers. Two conjugative plasmids, pSTE33T and pUCG18T, capable of shuttling between E. coli and Geobacillus spp., were constructed. The plasmids were first introduced into E. coli BR408, which expressed one inherent DNA methylase gene (dam) and two heterologous methylase genes from strain HTA426 (GK1380-GK1381 and GK0343-GK0344). The plasmids were then directly transferred from E. coli cells to strain HTA426 by conjugative transfer using pUB307 or pRK2013 as a helper plasmid. pUCG18T was introduced very efficiently (transfer efficiency, 10(-5)-10(-3) recipient(-1)). pSTE33T showed lower efficiency (10(-7) 10(-6) recipient(-1)) but had a high copy number and high segregational stability. Methylase genes in the donor substantially affected the transfer efficiency, demonstrating that the host-mimicking strategy contributes to efficient transformation. The transformation method, along with the two distinguishing plasmids, increases the potential of G. kaustophilus HTA426 as a thermophilic host to be used in various applications and as a model for biological studies of this genus. Our results also demonstrate that conjugative transfer is a promising approach for introducing exogenous DNA into thermophiles. PMID- 22814503 TI - A fusion tag to fold on: the S-layer protein SgsE confers improved folding kinetics to translationally fused enhanced green fluorescent protein. AB - Genetic fusion of two proteins frequently induces beneficial effects to the proteins, such as increased solubility, besides the combination of two protein functions. Here, we study the effects of the bacterial surface layer protein SgsE from Geobacillus stearothermophilus NRS 2004/3a on the folding of a C-terminally fused enhanced green fluorescent protein (EGFP) moiety. Although GFPs are generally unable to adopt a functional confirmation in the bacterial periplasm of Escherichia coli cells, we observed periplasmic fluorescence from a chimera of a 150-amino-acid N-terminal truncation of SgsE and EGFP. Based on this finding, unfolding and refolding kinetics of different S-layer-EGFP chimeras, a maltose binding protein-EGFP chimera, and sole EGFP were monitored using green fluorescence as indicator for the folded protein state. Calculated apparent rate constants for unfolding and refolding indicated different folding pathways for EGFP depending on the fusion partner used, and a clearly stabilizing effect was observed for the SgsE_C fusion moiety. Thermal stability, as determined by differential scanning calorimetry, and unfolding equilibria were found to be independent of the fused partner. We conclude that the stabilizing effect SgsE_C exerts on EGFP is due to a reduction of degrees of freedom for folding of EGFP in the fused state. PMID- 22814505 TI - Survival of microorganisms on antimicrobial filters and the removal efficiency of bioaerosols in an environmental chamber. AB - Exposure to bioaerosols causes various adverse health effects including infectious and respiratory diseases, and hypersensitivity. Controlling exposure to bioaerosols is important for disease control and prevention. In this study, we evaluated the efficacies of various functional filters coated with antimicrobial chemicals in deactivating representative microorganisms on filters or as bioaerosols. Tested functional filters were coated with different chemicals that included (i) Ginkgo and sumac, (ii) Ag-apatite and guanidine phosphate, (iii) SiO2, ZnO, and Al2O3, and (iv) zeolite. To evaluate the filters, we used a model ventilation system (1) to evaluate the removal efficiency of bacteria (Escherichia coli and Legionella pneumophila), bacterial spores (Bacillus subtilis spore), and viruses (MS2 bacteriophage) on various functional filters, and (2) to characterize the removal efficiency of these bioaerosols. All experiments were performed at a constant temperature of 25 degrees C and humidity of 50%. Most bacteria (excluding B. subtilis) rapidly decreased on the functional filter. Therefore, we confirmed that functional filters have antimicrobial effects. Additionally, we evaluated the removal efficiency of various bioaerosols by these filters. We used a six-jet collision nebulizer to generate microbial aerosols and introduced it into the environmental chamber. We then measured the removal efficiency of functional filters with and without a medium-efficiency filter. Most bioaerosol concentrations did not significantly decrease by the functional filter only but decreased by a combination of functional and medium efficiency filter. In conclusion, functional filters could facilitate biological removal of various bioaerosols, but physical removal of these by functional was minimal. Proper use of chemical-coated filter materials could reduce exposure to these agents. PMID- 22814506 TI - Development of a qualitative dose indicator for gamma radiation using lyophilized Deinococcus. AB - The feasibility of using Deinococcus showing strong resistance to both desiccation and ionizing radiation as a dose indicator of gamma radiation exposure was evaluated. Three Deinococcus strains having different levels of radiation resistance, Deinococcus radiodurans (DRD), Deinococcus radiopugnans (DRP), and the DRD pprI mutant (DRM), were selected to develop an appropriate dose indicator for a broad range of exposures. DRD, DRP, and DRM cultures with different numbers of cells [~10(7) to 10(3) colony forming units (CFU)/100 microliter] were lyophilized and subjected to various doses of gamma radiation to determine a critical dose that inhibited bacterial growth completely. Finally, a combination of DRD at ~10(7) and ~10(6) CFU, DRP at ~10(5) CFU, and DRM at ~10(4) CFU successfully indicated exposure to 5, 10, 20, and 30 kGy of gamma radiation, respectively. This study shows the possibility of developing a qualitative indicator of radiation exposure using Deinococcus. PMID- 22814507 TI - Rapid detection and monitoring therapeutic efficacy of Mycobacterium tuberculosis complex using a novel real-time assay. AB - We combined real-time RT-PCR and real-time PCR (R/P) assays using a hydrolysis probe to detect Mycobacterium tuberculosis complex (MTBC)-specific 16S rRNA and its rRNA gene (rDNA). The assay was applied to 28 nonrespiratory and 207 respiratory specimens from 218 patients. Total nucleic acids (including RNA and DNA) were extracted from samples, and results were considered positive if the repeat RT-PCR threshold cycle was < or =35 and the ratio of real-time RT-PCR and real-time PCR load was > or =1.51. The results were compared with those from existing methods, including smear, culture, and real-time PCR. Following resolution of the discrepant results between R/P assay and culture, the overall sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) of all samples (including nonrespiratory and respiratory specimens) were 98.2%, 97.2%, 91.7%, and 99.4%, respectively, for R/P assay, and 83.9%, 89.9%, 72.3%, and 94.7%, respectively, for real-time PCR. Furthermore, the R/P assay of four patient samples showed a higher ratio before treatment than after several days of treatment. We conclude that the R/P assay is a rapid and accurate method for direct detection of MTBC, which can distinguish viable and nonviable MTBC, and thus may guide patient therapy and public health decisions. PMID- 22814508 TI - Soluble expression of OmpA from Haemophilus parasuis in Escherichia coli and its protective effects in the mouse model of infection. AB - Haemophilus parasuis causes contagious porcine Glasser's disease leading to severe losses in the swine industry. In this study, we established an efficient Escherichia colibased system for the expression of H. parasuis major outer membrane protein (MOMP) that has been known as a good vaccine candidate against Glasser's disease. Use of an E. coli-derived pelB leader sequence made it possible to produce recombinant MOMP (rMOMP) as the soluble forms without an additional refolding process. Using two different animal models, it was evaluated that the rMOMP was capable of inducing a significant immune response and providing protection against H. parasuis infection. PMID- 22814510 TI - Tumour immunology: Suppressing the rejection of pancreatic tumours. PMID- 22814511 TI - Hydration of isocyanates in an expandable, self-assembled capsule. AB - A self-assembled capsule facilitates reactions of isocyanates with water. The capsule provides an amphiphilic environment with hydrophobic aromatic ends and hydrophilic glycoluril units at the center. Reaction takes place in the narrow, cylindrical space to form the N,N-dialkylurea, which then appears in a longer capsule. PMID- 22814509 TI - Towards an HIV cure: a global scientific strategy. AB - Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community. PMID- 22814512 TI - Bangladesh anthrax outbreaks are probably caused by contaminated livestock feed. AB - In Bangladesh from 1 July to 30 September 2010 there were 104 animal cases of anthrax and 607 associated human cases. This investigation was conducted in Sirajganj district in December 2010, on eight farms where animal cases had occurred. Bacillus anthracis was recovered from soil samples and turbinate bones on six farms. Canonical single nucleotide polymorphism (SNP) analysis showed that all the isolates belonged to the major lineage A, sublineage A.Br.001/002 of China and South East Asia while a multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) with 15 VNTRs demonstrated three unique genotypes. The single nucleotide repeat (SNR) analyses showed two SNR types in 97 out of 99 isolates; nevertheless, due to its higher discriminatory power the presence of two isolates with different SNR-type polymorphisms were detected within two MLVA genotypes. The epidemic occurred during the monsoon season, a time of extensive flooding, suggesting that the source was contaminated feed, not grazing, which is supported by the genetic variance. PMID- 22814513 TI - Patient navigation and the quality of breast cancer care: an analysis of the breast cancer care quality indicators. AB - PURPOSE: Patient navigation programs are initiated to help guide patients through barriers in a complex cancer care system. We sought to analyze the impact of our patient navigator program on the adherence to specific Breast Cancer Care Quality Indicators (BCCQI). METHODS: A retrospective cohort of patients with stage I-III breast cancer seen the calendar year prior to the initiation of the patient navigation program were compared with patients treated in the ensuing two calendar years. Quality indicators deemed appropriate for analysis were those associated with overcoming barriers to treatment and those associated with providing health education and improving patient decision-making. RESULTS: A total of 134 consecutive patients between January 1, 2006 and December 31, 2006 and 234 consecutive patients between January 1, 2008 and December 31, 2009 were evaluated for compliance with the BCCQI. There was no significant difference in the mean age or race/ethnic distribution of the study population. In all ten BCCQI evaluated, there was improvement in the percentage of patients in compliance from pre and post implementation of a patient navigator program (range 2.5-27.0 %). Overall, compliance with BCCQI improved from 74.1 to 95.5 % (p < 0.0001). Indicators associated with informed decision-making and patient preference achieved statistical significance, while only completion axillary node dissection in sentinel node-positive biopsies in the process of treatment achieved statistical significance. CONCLUSIONS: The implementation of a patient navigator program improved breast cancer care as measured by BCCQI. The impact on disease-free and overall survival remains to be determined. PMID- 22814514 TI - The first impact factor for the Polish Archives of Internal Medicine--June 2012. PMID- 22814515 TI - Th1/Th2/Th17-related cytokines in the bronchoalveolar lavage fluid of patients with sarcoidosis: association with smoking. AB - INTRODUCTION: Sarcoidosis is a multiorgan granulomatous disease of unknown etiology. The predominance of Th1-related cytokines is observed in the bronchoalveolar fluid (BALF) in pulmonary sarcoidosis. Recently, Th17 cells have been postulated to be involved in the pathogenesis of sarcoidosis. Sarcoidosis is more prevalent in nonsmokers than in smokers. The exact effect of smoking on granulomatous inflammation in this disease remains unclear. OBJECTIVES: The aim of the study was to evaluate the Th1/Th2/Th17-related cytokine concentration in the BALF of patients with pulmonary sarcoidosis in relation to smoking status. PATIENTS AND METHODS: The study included 74 patients with confirmed pulmonary sarcoidosis. Data on smoking status were available for 61 patients (26 ever smokers, 35 never-smokers; mean 11 +/-9.1 pack-years in smokers). The concentrations of interleukin (IL) 17A (IL-17A), IL-10, IL-6, IL-4, and IL-2 as well as interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) were measured in BALF supernatants using a flow cytometry method--the Cytometric Bead Array. RESULTS: The median concentration of IL-6, IFN-gamma, and IL-17A (2.19 pg/ml, 1.28 pg/ml, and 6.08 pg/ml, respectively) did not differ significantly between smokers and nonsmokers. TNF-alpha, IL-10, IL-4 and IL-2 levels were below the detection limit in most patients. We observed a significant correlation between IFN-gamma concentration and the number of macrophages in BALF (r = 0.66, P <0.05) and between IL-17A and IL-6 levels (r = 0.94, P <0.05). CONCLUSIONS: We confirmed a significant role of IL-6, IFN-gamma, and IL-17A in the local inflammatory response in sarcoidosis. However, the interpretation of the limited number of cytokine measurements should be made with caution. Further studies are needed to explain the effect of smoking on the pathomechanism of inflammation in sarcoidosis. PMID- 22814516 TI - Transforming growth factor-beta1-induced expression of connective tissue growth factor is enhanced in bronchial fibroblasts derived from asthmatic patients. AB - INTRODUCTION: Bronchial asthma is accompanied by airway remodeling as well as increased secretion of cytokines, growth factors, and extracellular matrix proteins. Connective tissue growth factor (CTGF) has been suggested to contribute to many fibrotic disorders. However, the ability of human bronchial fibroblasts (HBFs) to express CTGF in response to transforming growth factor-beta1 (TGF beta1) has not been studied so far. OBJECTIVES: The aim of the study was to investigate whether HBFs are able to express CTGF when stimulated with TGF-beta1. PATIENTS AND METHODS: All experiments were conducted on in vitro cultures of HBFs isolated from bronchial biopsies obtained from 8 patients with asthma and from 5 nonasthmatic individuals. We performed an analysis of changes in mRNA expression for CTGF and alpha-smooth muscle actin and in protein expression for CTGF. RESULTS: We have shown for the first time that HBFs derived from asthmatic patients are capable of higher CTGF expression when stimulated with TGF-beta1 compared with HBFs isolated from nonasthmatic individuals. Moreover, this effect is significantly reduced after the Wnt signaling pathway activation. CONCLUSIONS: Our results point to a pleiotropic effect of TGF-beta1, the elevated levels of which are observed in the bronchoalveolar lavage fluid obtained from asthmatic patients. The structural cells of the bronchi, fibroblasts, stimulated with TGF beta1 begin to synthesize CTGF. Moreover, this process can be reversed by the GSK 3beta inhibitor, which activates the Wnt signaling pathway. Our model, based on in vitro primary cell cultures, may be a valuable experimental approach to study the mechanisms underlying bronchial wall remodeling, and in the future it may lead to the development of new therapeutic strategies in asthma. PMID- 22814517 TI - Comorbidities and the quality of life in hypertensive patients. AB - INTRODUCTION: An important factor influencing the perception of health-related quality of life (HRQoL) is the presence of chronic diseases, especially polymorbidity. However, little is known about how concurrent chronic diseases influence the HRQoL of hypertensive patients. OBJECTIVES: The primary aim of the study was to assess the relationship between comorbidities and different aspects of HRQoL in a large unselected cohort of patients undergoing treatment for hypertension. PATIENTS AND METHODS: A questionnaire-based study was conducted by 832 primary care physicians in a group of 12,525 unselected patients treated for hypertension for at least 3 months. HRQoL was evaluated using the Medical Outcomes Study 12-item Short-Form Health Survey (SF-12). RESULTS: Coexisting diseases were reported in 7986 patients (63.8%). Significantly lower HRQoL values were associated with coexisting diseases, especially obstructive respiratory disease, degenerative disc disease, radiculopathy, coronary artery disease, heart failure, stroke, diabetes, epilepsy, neurotic disorders, and mood disorders. The HRQoL of hypertensive patients decreased significantly with age and duration of antihypertensive therapy (>2 years). HRQoL values were higher for men and participants with higher education and lower for participants who were obese or had visceral obesity. Antihypertensive therapy was effective in 25.4% of the participants. CONCLUSIONS: Chronic diseases concomitant with arterial hypertension negatively affect all dimensions of the HRQoL. PMID- 22814518 TI - Neutrophil activation and B-cell stimulation in the pathogenesis of Felty's syndrome. AB - Felty's syndrome (FS) is a severe arthritic disorder that features chronic neutrophil activation and progresses to neutropenia and susceptibility to unabated infections. The life-threatening manifestations of FS have focused the attention of clinical experimenters who have made persistent efforts to find new and effective therapies. This review highlights important milestones in the research on FS and draws attention to recent studies on the antigen specificity of antibodies present in patients' sera. Recent data have indicated that immunoglobulins G (IgGs) in patients with FS bind selectively and specifically to deiminated histones and neutrophil extracellular chromatin traps (NETs). Deimination is the conversion of certain arginine residues in proteins to citrullines by the enzyme peptidylarginine deiminase 4. Earlier observations had indicated that IgGs in FS patients avidly bind to citrullinated peptides. These observations suggest that NETosis, the type of cell death that is defined by the release of NETs, provides autoantigens that stimulate B cell responses in this patient group. This insight parallels recent observations in other autoimmune conditions and lends support to the paradigm that NETosis plays a leading role in the pathogenesis of antiself immune responses. PMID- 22814519 TI - Role of mean platelet volume in acute exacerbation of chronic obstructive pulmonary disease. PMID- 22814520 TI - Comment on Peerbooms et al.: No positive bone healing after using platelet rich plasma in a skeletal defect. An observational prospective cohort study. PMID- 22814521 TI - Tracheostomy in children admitted to paediatric intensive care. AB - PURPOSE: Tracheostomy is a common intervention for adults admitted to intensive care; many are performed early and most are percutaneous. Our study aimed to elucidate current practice and indications for children in the UK admitted to paediatric intensive care and undergoing tracheostomy. DESIGN: A questionnaire covering unit guidelines, practice, and the advantages and disadvantages of tracheostomy was sent to all UK paediatric intensive care units (PICUs) participating in the Paediatric Intensive Care Audit Network (PICANet). These results were combined with data from PICANet on all children in the UK reported to have had a tracheostomy performed during a PICU admission between 2005 and 2009 inclusive. RESULTS: Over 5 years, 1613 children had tracheostomies performed during their PICU admission (2.05% of all admissions). The death rate was 5.58% with tracheostomy versus 4.72% overall, but differences were not significant when risk-adjusted using the Paediatric Index of Mortality 2 (PIM2). All 29 units participating in PICANet responded to the survey. Prolonged invasive ventilation was an indication for tracheostomy in 25/29 units, but the definition varied between 14 and 90 days, and most respondents considered timing on an individual basis. Children undergoing tracheostomy during PICU admission account for 9% of PICU bed days in the UK. CONCLUSIONS: In contrast with current adult UK practice, tracheostomy for children admitted to intensive care is infrequent, performed late following admission and usually surgical. Practice varies significantly. The death rate for children having a tracheostomy performed was not significantly higher than for children admitted to PICU who did not undergo tracheostomy. PMID- 22814522 TI - Enteroviral meningitis without pleocytosis in children. AB - OBJECTIVES: This study aims to describe the clinical characteristics of enteroviral meningitis in association with the absence of cerebrospinal fluid (CSF) pleocytosis. DESIGN: This was a retrospective analysis of databases of patients diagnosed with enteroviral meningitis by CSF reverse transcription-PCR testing. Presence of CSF non-pleocytosis at each age group was analysed by use of the two criteria. Clinical variables were compared with regard to the presence of CSF pleocytosis. Multiple logistic regression analysis was used to identify factors that were associated with CSF pleocytosis. SETTING: Two hospitals in South Korea, between January 2008 and August 2011. PATIENTS: 390 infants and children with enteroviral meningitis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Proportion of enteroviral meningitis without CSF pleocytosis. RESULTS: Among the 390 patients with enteroviral meningitis, 16-18% did not have CSF pleocytosis. In particular, CSF pleocytosis was not present in 68-77% of the neonates with enteroviral meningitis, demonstrating that the proportion of CSF pleocytosis decreased significantly with age (p<0.001). In multivariate models, younger age (adjusted OR 0.981; 95% CI 0.973 to 0.989), lower peripheral white blood cell count (adjusted OR 0.843; 95% CI 0.791 to 0.899), and shorter interval between onset and lumbar puncture (adjusted OR 0.527; 95% CI 0.315 to 0.882) were associated with the absence of CSF pleocytosis in enteroviral meningitis. CONCLUSIONS: This study demonstrated high proportion of non-pleocytic enteroviral meningitis in young infants and identified several clinical factors that contributed to the absence of CSF pleocytosis. We suggest that CSF enterovirus PCR testing is likely to detect more cases of enteroviral meningitis, especially in young infants. PMID- 22814524 TI - Highly sensitive optofluidic chips for biochemical liquid assay fabricated by 3D femtosecond laser micromachining followed by polymer coating. AB - The demand for increased sensitivity in the concentration analysis of biochemical liquids is a crucial issue in the development of lab on a chip and optofluidic devices. We propose a new design for optofluidic devices for performing highly sensitive biochemical liquid assays. This design consists of a microfluidic channel whose internal walls are coated with a polymer and an optical waveguide embedded in photostructurable glass. The microfluidic channel is first formed by three-dimensional femtosecond laser micromachining. The internal walls of the channel are then coated by the dipping method with a polymer that has a lower refractive index than water. Subsequently, the optical waveguide is integrated with the microfluidic channel. The polymer coating on the internal walls permits the probe light, which is introduced by the optical waveguide, to propagate along the inside of the microfluidic channel. This results in a sufficiently long interaction length between the probe light and a liquid sample in the channel and thus significantly improves the sensitivity of absorption measurements. Using the fabricated optofluidic chips, we analyzed protein in bovine serum albumin to concentrations down to 7.5 mM as well as 200 nM glucose-D. PMID- 22814525 TI - Large eyelid basal cell carcinoma with uniform and diffuse melanin deposition. PMID- 22814526 TI - Multimodal morphological and functional characterization of Malattia Leventinese. AB - BACKGROUND: To analyze the morphological and functional characteristics of malattia leventinese. METHODS: This was a chart review of patients with Malattia Leventinese. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). Microperimetry and Preferential Hyperacuity Perimeter (PHP) were performed in a subset of patients. RESULTS: Twelve eyes of six patients were included. BCVA ranged from 20/25 to 20/200. The largest drusen were round, not radially distributed, localized in the perimacular area and around the optic disc. The smallest drusen were not round, radially distributed, mostly localized temporally to the macula. FAF revealed an intense autofluorescence of large drusen. On both FA and ICGA, large round drusen turned to hyperfluorescent in the late phase, while small radial drusen progressively decreased their fluorescence. OCT showed the large round drusen as focal or diffuse deposition of hyperreflective material between the RPE and Bruch membrane within the macula, determining focal dome-shaped or diffuse RPE elevation respectively, and the small radial drusen, which ranged from irregular slight thickening of the RPE/Bruch membrane complex to sawtooth RPE elevation. In three patients (six eyes) that underwent microperimetry and PHP, there was a good correspondence between macular sensitivity and PHP score. Functional impairment correlated topographically to sub-RPE deposition of drusenoid material. CONCLUSIONS: In this series, large round drusen of Malattia Leventinese appeared similar to drusen in age-related macular degeneration, while small radial drusen of Malattia Leventinese shared similarities with early-onset cuticular drusen. PMID- 22814527 TI - Laser in situ keratomileusis enhancements with the Ziemer FEMTO LDV femtosecond laser following previous LASIK treatments. AB - BACKGROUND: The aim of this paper is to present the accuracy, predictability, and safety outcomes of LASIK enhancements performed with the FEMTO LDV femtosecond laser (Ziemer Ophthalmic Systems, Port, Switzerland) and the Allegretto Wave Concerto 500 Hz excimer laser (Wavelight AG, Erlangen, Germany), following previous LASIK treatments. METHODS: FEMTO LDV was used for flap creation in 85 previously LASIK-treated eyes of 62 patients. The intended flap thickness was 90 MUm in 81 eyes and 140 MUm in 4 eyes. The size of the suction ring was 9.0 mm in 72 eyes and 9.5 mm in 13 eyes. Flap dimensions were measured and correlated to preoperative characteristics. RESULTS: With the intended flap thickness of 90 MUm in previously LASIK-treated eyes, the actual flap thickness was 90.2 +/- 6.6 MUm (range 80-122), and the flap diameter was 9.2 +/- 0.2 mm (range 8.7-9.9). The mean hinge length was 4.0 +/- 0.2 mm (range 3.0-4.8). Flap thickness correlated positively with patient age and hinge length. Complications were reported in 12 eyes (14.1 %). Most of the complications were very mild, and none of them prevented further refractive laser treatment. One eye lost two Snellen lines of best spectacle-corrected visual acuity. CONCLUSIONS: Femtosecond LASIK enhancement is warranted only in rare cases. Surgical experience is needed and special caution must be practiced. For cases of a primary free cap, femtosecond LASIK is not recommended. PMID- 22814528 TI - Understanding behavioral intent to participate in shared decision-making in medically uncertain situations. AB - OBJECTIVE: This article describes the process undertaken to identify and validate behavioral and normative beliefs and behavioral intent based on the Theory of Reasoned Action (TRA) and applied to men between the ages of 45 and 70 in the context of their participation in shared decision-making (SDM) in medically uncertain situations. This article also discusses the preliminary results of the aforementioned processes and explores potential future uses of this information that may facilitate greater understanding, efficiency and effectiveness of clinician-patient consultations. MATERIALS AND METHODS: Twenty-five male subjects from the Philadelphia community participated in this study. Individual semi structure patient interviews were conducted until data saturation was reached. Based on their review of the patient interview transcripts, researchers conducted a qualitative content analysis to identify prevalent themes and, subsequently, create a category framework. Qualitative indicators were used to evaluate respondents' experiences, beliefs, and behavioral intent relative to participation in shared decision-making during medical uncertainty. RESULTS: Based on the themes uncovered through the content analysis, a category framework was developed to facilitate understanding and increase the accuracy of predictions related to an individual's behavioral intent to participate in shared decision-making in medical uncertainty. The emerged themes included past experience with medical uncertainty, individual personality, and the relationship between the patient and his physician. The resulting three main framework categories include 1) an individual's Foundation for the concept of medical uncertainty, 2) how the individual Copes with medical uncertainty, and 3) the individual's Behavioral Intent to seek information and participate in shared decision-making during times of medically uncertain situations. DISCUSSION: The theme of Coping (with uncertainty) emerged as a particularly critical behavior/characteristic amongst the subjects. By understanding a subject's disposition with regard to coping, researchers were better able to make connections between a subject's prior experiences, their knowledge seeking activities, and their intent to participate in SDM. Despite having information and social support, the subjects still had to cope with the idea of uncertainty before determining how to proceed with regard to shared decision-making. In addition, the coping category reinforced the importance of information seeking behaviors and preferences for shared decision-making. CONCLUSIONS: This study applies and extends the field of behavioral and health informatics to assist medical practice and decision-making in situations of medical uncertainty. More specifically, this study led to the development of a category framework that facilitates the identification of an individual's needs and motivational factors with regard to their intent to participate in shared decision-making in situations of medical uncertainty. PMID- 22814529 TI - Education and inequalities in risk scores for coronary heart disease and body mass index: evidence for a population strategy. AB - BACKGROUND: Concerns have been raised that education may have greater benefits for persons at high risk of coronary heart disease (CHD) than for those at low risk. METHODS: We estimated the association of education (less than high school, high school, or college graduates) with 10-year CHD risk and body mass index (BMI), using linear and quantile regression models, in the following two nationally representative datasets: the 2006 wave of the Health and Retirement Survey and the 2003-2008 National Health and Nutrition Examination Survey (NHANES). RESULTS: Higher educational attainment was associated with lower 10 year CHD risk for all groups. However, the magnitude of this association varied considerably across quantiles for some subgroups. For example, among women in NHANES, a high school degree was associated with 4% (95% confidence interval = 9% to 1%) and 17% (-24% to -8%) lower CHD risk in the 10th and 90th percentiles, respectively. For BMI, a college degree was associated with uniform decreases across the distribution for women, but with varying increases for men. Compared with those who had not completed high school, male college graduates in the NHANES sample had a BMI that was 6% greater (2% to 11%) at the 10th percentile of the BMI distribution and 7% lower (-10% to -3%) at the 90th percentile (ie, overweight/obese). Estimates from the Health and Retirement Survey sample and the marginal quantile regression models showed similar patterns. CONCLUSION: Conventional regression methods may mask important variations in the associations between education and CHD risk. PMID- 22814530 TI - Selective local nitrogen doping in a TiO2 electrode for enhancing photoelectrochemical water splitting. AB - Selective local N-doped TiO(2) electrodes were fabricated using a pulsed laser deposition method. Different from the uniform nitrogen-doping in TiO(2) electrodes showing the diminution of IPCE in the UV light region, the inner nitrogen-doped TiO(2) electrode uniquely enhanced IPCE in the UV light region significantly (up to 95% at 320 nm, 1.23 V vs. SHE). PMID- 22814531 TI - Myeloperoxidase and oxidative stress in rheumatoid arthritis. AB - OBJECTIVE: To determine whether MPO contributes to oxidative stress and disease activity in RA and whether it produces hypochlorous acid in SF. METHODS: Plasma and where possible SF were collected from 77 RA patients while 120 healthy controls supplied plasma only. MPO and protein carbonyls were measured by ELISAs. 3-Chlorotyrosine in proteins and allantoin in plasma were measured by mass spectrometry. RESULTS: Plasma MPO concentrations were significantly higher in patients with RA compared with healthy controls [10.8 ng/ml, inter-quartile range (IQR): 7.2-14.2; P<0.05], but there was no significant difference in plasma MPO protein concentrations between RA patients with high disease activity (HDA; DAS 28 >3.2) and those with low disease activity (LDA; DAS-28 <= 3.2) (HDA 27.9 ng/ml, 20.2-34.1 vs LDA 22.1 ng/ml, 16.9-34.9; P>0.05). There was a significant relationship between plasma MPO and DAS-28 (r=0.35; P=0.005). Plasma protein carbonyls and allantoin were significantly higher in patients with RA compared with the healthy controls. MPO protein was significantly higher in SF compared with plasma (median 624.0 ng/ml, IQR 258.4-2433.0 vs 30.2 ng/ml, IQR 25.1-50.9; P<0.0001). The MPO present in SF was mostly active. 3-Chlorotyrosine, a specific biomarker of hypochlorous acid, was present in proteins from SF and related to the concentration of MPO (r=0.69; P=0.001). Protein carbonyls in SF were associated with MPO protein concentration (r=0.40; P=0.019) and 3-chlorotyrosine (r=0.66; P=0.003). CONCLUSION: MPO is elevated in patients with RA and promotes oxidative stress through the production of hypochlorous acid. PMID- 22814533 TI - The changing landscape of traumatic brain injury research. PMID- 22814532 TI - Epileptic stimulus increases Homer 1a expression to modulate endocannabinoid signaling in cultured hippocampal neurons. AB - Endocannabinoid (eCB) signaling serves as an on-demand neuroprotective system. eCBs are produced postsynaptically in response to depolarization or activation of metabotropic glutamate receptors (mGluRs) and act on presynaptic cannabinoid receptor-1 to suppress synaptic transmission. Here, we examined the effects of epileptiform activity on these two forms of eCB signaling in hippocampal cultures. Treatment with bicuculline and 4-aminopyridine (Bic + 4-AP), which induced burst firing, inhibited metabotropic-induced suppression of excitation (MSE) and prolonged the duration of depolarization-induced suppression of excitation (DSE). The Homer family of proteins provides a scaffold for signaling molecules including mGluRs. It is known that seizures induce the expression of the short Homer isoform 1a (H1a) that acts in a dominant negative manner to uncouple Homer scaffolds. Bic + 4-AP treatment increased H1a mRNA. A group I mGluR antagonist blocked the Bic + 4-AP-evoked increase in burst firing, the increase in H1a expression, and the inhibition of MSE. Bic + 4-AP treatment reduced mGluR-mediated Ca(2+) mobilization from inositol trisphosphate-sensitive stores relative to untreated cells. Expression of H1a, but not a mutant form that cannot bind Homer ligands, mimicked Bic + 4-AP inhibition of MSE and mGluR mediated Ca(2+) mobilization. In cells expressing shRNA targeted to Homer 1 mRNA, Bic + 4-AP did not affect mGluR-mediated Ca(2+) release. Furthermore, knockdown of H1a prevented the inhibition of MSE induced by Bic + 4-AP. Thus, an epileptic stimulus increased H1a expression, which subsequently uncoupled mGluR-mediated eCB production. These results indicate that seizure activity modulates eCB mediated synaptic plasticity, suggesting a changing role for the eCB system following exposure to aberrant patterns of excitatory synaptic activity. PMID- 22814534 TI - Imaging neural correlates of mild cognitive impairment in Parkinson's disease. PMID- 22814535 TI - Being comatose: why definition matters. PMID- 22814536 TI - Is rivaroxaban safer and more effective than warfarin in patients with atrial fibrillation and stroke or TIA? PMID- 22814538 TI - Is neurology ready to see the light? PMID- 22814539 TI - Dag Aarsland: moving Parkinson's disease forward. PMID- 22814541 TI - Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. AB - Dementia is one of the most common and important aspects of Parkinson's disease and has consequences for patients and caregivers, and has health-related costs. Mild cognitive impairment is also common and frequently progresses to dementia. The underlying mechanisms of dementia associated with Parkinson's disease are only partly known and no mechanism-based treatments are available. Both dysmetabolism of alpha-synuclein and amyloid-protein and cholinergic deficits contribute to cognitive impairment in Parkinson's disease, and preliminary findings show that imaging and neurophysiological and peripheral biomarkers could be useful in diagnosis and prognosis. Rivastigmine is the only licensed treatment for dementia in Parkinson's disease, but emerging evidence suggests that memantine might also be useful. Whether these or other treatments can delay the progression from mild cognitive impairment to dementia in Parkinson's disease is a key research question. PMID- 22814542 TI - Advances and challenges in neurostimulation for headaches. AB - Many people who suffer from primary headache (ie, headache without an identifiable cause) are resistant or intolerant to available drugs. During the past decade, central and peripheral neurostimulation procedures have been investigated in such individuals--up to now, about 1200 worldwide. Techniques used range from invasive methods such as deep brain stimulation of the posterior hypothalamus, to minimally invasive percutaneous electrode implantation used in occipital nerve stimulation, or non-invasive methods such as transcranial magnetic stimulation. Although some of these procedures have been studied extensively, sham-controlled trials are sparse and the precise mode of action of such stimulation remains largely unknown. Nonetheless, occipital nerve stimulation and deep brain stimulation of the posterior hypothalamus seem to be effective in people with chronic cluster headache, and occipital nerve stimulation is promising in chronic migraine. Trial data for other techniques are scarce, but external and minimally invasive approaches should be privileged in future studies. PMID- 22814543 TI - Disorders of consciousness: responding to requests for novel diagnostic and therapeutic interventions. AB - Severe brain injury can leave patients with chronic disorders of consciousness. Because of impaired responsiveness, many of these patients have traditionally been regarded as unaware. However, findings from recent clinical studies herald a potential paradigm shift: functional imaging and neurophysiological studies have identified ways to assess awareness and have revealed astounding cases of awareness despite clinical unresponsiveness. Hence, diagnostic classifications have been rewritten, prognostic knowledge is improving, and therapeutic studies have regained momentum, showing for the first time some therapeutic effects on responsiveness. Clinicians must increasingly respond to requests by patients' families and surrogate decision makers to use novel techniques for diagnosis, prognosis, and treatment, and in doing so several ethical and social issues need to be considered. Such requests provide an opportunity for clinicians to learn about patients' values and preferences and to maintain clinical acumen for changes in patient status with the patients' best interests in mind. PMID- 22814544 TI - An assessment of changes in Kunzea ericoides var. microflora and other hydrothermal vegetation at the Wairakei-Tauhara geothermal field, New Zealand. AB - Hydrothermal ecosystems are of high conservation and scientific value, but they are sensitive to external perturbations that result from development. This study examines the composition of vegetation at four plots at the Wairakei-Tauhara geothermal field, New Zealand, using the Scott height-frequency method, ground temperatures at 0.1- and 1-m depth, soil pH, and photographic surveys. It highlights the response of plant communities, in particular that of Kunzea ericoides var. microflora, in terms of composition, structure, and biomass index values, measures changes in ground temperature, as well as provides baseline data against which to compare future changes. It was found that optimal growing conditions for K. ericoides var. microflora are at temperatures above background conditions with a slightly acidic pH. Plots with cooler, less acidic conditions support more diverse plant communities, which also promote the establishment of invasive species. This suggests that the largest threats to thermotolerant vegetation in New Zealand, including K. ericoides var. microflora, are further decreases in ground temperature because the establishment of invasive species may result in thermolerant vegetation being out-competed in hydrothermal ecosystems. Recognising and understanding the ecological diversity and dynamics of hydrothermal ecosystems, as well as acknowledging the competing interests between development and conservation, is key to the management and protection of these areas. PMID- 22814545 TI - The effectiveness of contrasting protected areas in preventing deforestation in Madre de Dios, Peru. AB - Accurate monitoring of the effectiveness of protected areas (PAs) in decreasing deforestation is increasingly important given the vital role of forest protection in climate change mitigation. Recent studies on PA effectiveness have used remote sensing imagery to compare deforestation rates within PAs to surrounding areas. However, remote-sensing data used in isolation provides limited information on the factors contributing to effectiveness. We used landscape-modelling techniques to estimate the effectiveness of ten PAs in Madre de Dios, Peru. Factors influencing PA effectiveness were investigated using in situ key-informant interviews. Although all of the PAs studied had positive effectiveness scores, those with the highest scores were ecotourism and conservation concessions, where monitoring and surveillance activities and good relations with surrounding communities were reported as possible factors in decreasing deforestation rates. Native community areas had the lowest scores, with deforestation mainly driven by internal resource use and population growth. Weak local governance and immigration were identified as underlying factors decreasing the effectiveness of protection, whereas good relations with surrounding communities and monitoring activity increased effectiveness. The results highlight the need to combine remote sensing with in situ information on PA management because identification of drivers and deterrents of deforestation is vital for improving the effectiveness of protection. PMID- 22814546 TI - The effects of local ecological knowledge, minimum-impact knowledge, and prior experience on visitor perceptions of the ecological impacts of backcountry recreation. AB - An on-site visitor survey instrument was developed to examine visitor perceptions of resource impacts resulting from backcountry hiking activities. The survey was conducted in the Bear Lake Corridor of Rocky Mountain National Park, CO and examined visitor characteristics that may influence visitor perceptions of specific resource conditions. Findings indicate that visitors are more perceptive of recreation-related resource impacts that are the result of undesirable behavior and, while visitors do perceive resource impacts, visitors tend to be more affected by crowding. Factors such as local ecological knowledge and knowledge of minimal-impact practices positively influence visitor perceptions of resource impacts. These findings support the use of visitor education on ecological knowledge and minimum-impact as a means of increasing visitor awareness of recreation impact issues. PMID- 22814547 TI - Artificial intelligence versus editorial art. PMID- 22814549 TI - Use of cone beam computed tomography and a laser intraoral scanner in virtual dental implant surgery: part 1. AB - OBJECTIVE: To describe a new procedure capable of coupling 2 data sets from cone beam computed tomography (CBCT) and an intraoral laser digital scanner to produce a stereolithographic model and surgical guide. METHODS: Use of DICOM (digital imaging and communications in medicine) format data obtained from CBCT scan images merged with standard triangulation language (STL) file data obtained from digital impressions using an intraoral laser scanner. The 2 data sets were electronically sent to a 3-dimensional imaging and technology software company over the Internet to fabricate a stereolithographic model of the jaws and surgical guide without the use of stone or plaster models obtained from traditional dental impressions. CONCLUSION: STL file data are able to accurately fabricate a stereolithographic model and surgical guide for implant surgery. PMID- 22814548 TI - Variations of vascular distribution in the mandibular anterior lingual region: a high risk of vascular injury during implant surgery. AB - PURPOSE: To clarify variations of vascular distribution around the mandibular anterior tooth lingual region, an area in which vascular injuries have often been reported during dental implant surgery. The reasons for such injuries in this region are discussed from an anatomical perspective. MATERIALS AND METHODS: Anatomical dissections were performed on 100 sides of 50 cadavers used for anatomy education. Ten sides of 5 cadavers were injected intravascularly with methyl methacrylate, and penetration of the mandible was closely evaluated. RESULTS: In the mandibular anterior tooth lingual region, both the sublingual and submental arteries showed various distribution patterns. Distal branches basically penetrated the bone. CONCLUSIONS: In the mandibular anterior tooth lingual region, the sublingual and submental arteries traveled from the vicinity of the mylohyoid muscle attachment along the bone surface in an anterosuperior direction. Many of these blood vessels penetrated the alveolar mucosa in the anterior tooth region, and many distal branches of the vessels also finally penetrated the bone. This seems to explain why many vascular injuries are encountered around the mandibular anterior tooth lingual region during implant surgery. PMID- 22814550 TI - Immediate rehabilitation of completely edentulous jaws with fixed prostheses supported by implants placed into fresh extraction sockets and in healed sites: a 4-year clinical evaluation. AB - PURPOSE: To evaluate the outcome of treatment in the rehabilitation of edentulous jaws with early loaded full-arch screw-retained prostheses after up to 4 years of function. METHODS: Patients with completely edentulous maxillae and/or mandibles, or presenting natural teeth with a poor or hopeless prognosis, received 6 implants each in the mandible and/or 8 in the upper jaw. All patients received a full-arch prosthetic reconstruction. RESULTS: A total of 19 patients were treated with a total of 164 implants. One hundred nineteen implants were placed immediately after tooth extraction, and 45 implants were placed in healed sites. Overall, 8 implants failed, leading to a 4-year cumulative survival rate of 95.1%. CONCLUSIONS: The rehabilitation of the edentulous maxilla and mandible with an early loaded prosthesis represents a viable alternative treatment to classic loading protocols. PMID- 22814551 TI - Oral squamous cell carcinoma arising around osseointegrated dental implants. AB - PURPOSE: This literature review investigates the occurrence of oral squamous cell carcinoma (OSCC) around osseointegrated dental implants (DI). METHODS: Databases were searched from 1989 up to and including November 2011. The eligibility criteria were as follows: (1) original studies, (2) clinical studies and case reports, (3) reference lists of the relevant original and review articles, (4) intervention: occurrence of OSSC around osseointegrated DI, and (5) articles published only in English language. RESULTS: Fourteen studies were included. In nine studies, the dental implant patients with diagnosed OSCC had previously been exposed to cancer. In five studies, the patients presented with a history of habitual tobacco smoking and alcohol consumption. CONCLUSION: OSCC is more likely to arise around osseointegrated DI in patients with a previous history of cancer. However, the role of other factors including tobacco and alcohol usage cannot be disregarded. PMID- 22814552 TI - Protocol for immediate implant replacement of infected teeth. AB - Extraction and immediate implant placement has become routine procedure due to reduced treatment time and the preservation of anatomical structures. However, in many cases, this technique involves teeth with different degrees of tissue compromise due to underlying infections. Until now, the degree of implant compromise has not been described, nor has a clinical management protocol been established for these cases. The aim of this article is to report the clinical results of a protocol used for immediate implant placement and provisionalization in infected extraction sockets. A classification of the implant surface compromise (in contact with previously infected tissue) is also described to facilitate the comparative analysis. It is possible to maintain the benefits of immediate implant placement and provisionalization in infected sites by applying a clinical protocol that considers antibiotic therapy, a thorough curettage of the infected tissue, antisepsis, and sufficient primary implant stability. PMID- 22814553 TI - Theoretical model for bone graft success. AB - Theoretical assumptions must correlate with clinical efficacy and good surgical outcomes to be of value to clinicians and patients. This article examines several common assumptions regarding the use of bone marrow aspirate to enhance bone grafting procedures. Contrary to these assumptions, evidence-based research suggests the following: (1) No more than 4 mL of bone marrow should be aspirated from a single donor site. Aspiration of more than that amount does not substantially increase the number of progenitor cells harvested but instead dilutes the concentration of progenitor cells with other nucleated cells from peripheral blood. (2) Bone marrow aspirate should not be concentrated using centrifuge technology. Rather than isolating desired cells, centrifuging concentrates all nucleated cells, increasing the overall metabolic activity to the detriment of the desired cells. (3) Increasing the volume of graft material brought to a graft site has the unwanted effect of increasing the diffusion distance for oxygen and nutrients and may lead to graft necrosis. (4) Histomorphometric analysis is the most effective method of evaluating bone graft outcomes because only such analysis allows for quantification of the percentage of bone and viable cells within a bone core biopsy. PMID- 22814554 TI - Novel implant design for initial stability of dental implants inserted in fresh extraction sockets: a preliminary study. AB - OBJECTIVES: To evaluate a novel implant design for immediate implantation. This implant presents a specially designed expanded diameter midcrestal "wing" thread, which is aimed to provide added bone contact for greater insertion torque and primary stability. METHODS: Mandibular premolars were extracted in 2 mongrel dogs, and immediate dental implants were inserted into the fresh extraction sockets. Implants were evaluated for stability using a resonance frequency analysis device immediately after insertion and after 4 and 8 weeks. Removal torque of 1 randomly selected implant in each hemimandible was measured as well. At 8 weeks, the remaining 6 implants were processed histologically. RESULTS: Mean implant stability quotient at implant placement was 64.38 (5.03) and 74.5 (3.08) at 8 weeks. Average removal torque immediately after implant placement was 49.65 (20.3) N.cm and 98.33 (12.34) N.cm at 8 weeks. The mean bone-to-implant contact value at 8 weeks was 38.89% (7.65%). CONCLUSIONS: The examined implant with the expanded diameter midcrestal "wing" thread showed good results of resonance frequency analysis and removal torque during the initial healing phase, and as such, it might be used for immediate implantation and loading. PMID- 22814555 TI - Evaluation of periimplant crevicular fluid prostaglandin E2 and matrix metalloproteinase-8 levels from health to periimplant disease status: a prospective study. AB - OBJECTIVE: To compare the levels of prostaglandin E2 (PGE2) and matrix metalloproteinases-8 (MMP-8) in periimplant crevicular fluid (PICF) after osseointegration and loading. MATERIALS AND METHODS: PICF was collected at the 3rd, 6th, 12th, and 18th months after implantation of 72 implants. PGE2 and MMP-8 levels besides clinical parameters were evaluated. RESULTS: Plaque and gingival index at the 6th, 12th, and 18th months presented higher values. Probing depth showed an increase after the 12th month. PGE2 presented a higher value at the 18th month. MMP-8 level demonstrated higher values after the sixth month. PGE2 and MMP-8 demonstrated positive correlations with gingival index and probing depth. CONCLUSION: The detection of PGE2 and MMP-8 in PICF serve to be useful for monitoring the course of periimplant disease. MMP-8 promises to be an early signal of periimplant inflammation. PMID- 22814556 TI - Probing and scaling instrumentation on implant abutment surfaces: an in vitro study. AB - PURPOSE: To investigate surface roughness on the apical collar of implant abutments caused by probing and scaling instruments. MATERIALS AND METHODS: Fourteen transmucosal abutments (BioHorizons, Atlanta, GA) and 4 instruments: UNC 15 metal probe, Periowise plastic probe, McCall SM 17/18 metal scaler, and universal plastic scaler were used to conduct the study. Four abutments were used for nontreated measures, and 10 abutments were treated with the 4 indicated instruments. Surface roughness was assessed with a contact profilometer. RESULTS: Analysis of variance showed significant differences in surface roughness between the treated and untreated surfaces (P < 0.0001). Add hoc analysis using Tukey Kramer honestly significant difference test showed no statistical differences between untreated measures and metal probe measures. On the other hand, statistical differences were noted between untreated measures with plastic probe measures (P = 0.05), plastic scaler measures (P = 0.05), and metal scaler measures (P = 0.05). The metal scaler measures were higher than plastic probe measures (P = 0.05) and plastic scaler measures (P = 0.05). CONCLUSIONS: Probing around implant abutments with a metal probe seems to have no effect on abutment surfaces. In contrast, instrumentation with scalers (metal and plastic) and plastic probe may cause surface roughness. PMID- 22814557 TI - Alveolar distraction osteogenesis in the human mandible: a clinical and histomorphometric study. AB - PURPOSE: To identify the quality of newly formed bone in the distraction region and to determine the percentage of mineralized bone formed in the distraction area. METHODS: Ten patients with vertically deficient mandibular alveolar ridges were treated by means of distraction osteogenesis. Four months after consolidation of distracted segments, a total of 40 dental implants were inserted in native bone and distracted bone. Bone biopsies were taken at the implant sites with trephine burrs for histological and histometric analyses. Four months after implant placement, abutments were connected, and prosthetic loading of the implants was started. RESULTS: The mean bone gain at the end of distraction was 7.2 +/- 0.8 mm. The cumulative success rate of implants 3 years after the onset of prosthetic loading was 100%. The newly formed bone consisted of woven bone reinforced by parallel-fibered bone with bone marrow spaces and the percentage of mineralized bone ranged from 50.56% to 76.88%. CONCLUSIONS: Alveolar distraction osteogenesis is able to produce adequate mature bone for the correction of mandibular bone deficits before dental implant insertion. PMID- 22814558 TI - Clinical and radiographic outcome of dental implants supporting fixed prostheses: the relevance of cortical bone formation. AB - PURPOSE: To evaluate the hard and the soft tissue parameters around implants supporting fixed prostheses over a period of 5 years and the possible association to the increase in periimplant bone density (IPBD). MATERIAL AND METHODS: A total of 39 dental implants placed in 29 patients were included in the study. Periimplant clinical (gingival index, probing depth, keratinized mucosa, sulcus fluid flow rate) and radiographic variables (bone loss, bone density) were collected, and the data analysis performed. RESULTS: Periimplant hard and soft tissue parameters remained stable throughout the follow-up period. Of the 39 implants, 20 demonstrated IPBD. The mean distance between first bone-to-implant contact and the microgap for implants with and without IPBD was significantly different at 1-year, 2-year, and 5-year follow-up. The evidence of IPBD demonstrated no influence on the periimplant soft tissue parameters. All mean values of bone density for implants with IPBD were higher than those for implants without IPBD throughout the whole observation period. CONCLUSION: All implants were clinically successful over the period of follow-up. IPBD might be more indicative of a stable periimplant bone level. PMID- 22814559 TI - A multicenter prospective study in type IV bone of a single type of implant. AB - PURPOSE: To analyze the success and survival rates of the Osstem GSII (Osstem, Busan, Korea) implant in type IV bone. MATERIALS: A prospective, multicenter (5 centers) study was conducted by examining the relationship between implant success and survival rates, and several patient and surgical parameters. The implants were placed in 82 patients who visited several nationwide dental hospitals and clinics between 2007 and 2008, followed by clinical and radiographic analyses. RESULTS: In type IV bone, the implant success and survival rates were 93.23% and 95.83%, respectively. The maxillary premolar and mandibular anterior tooth areas showed success rates of 100%. The most widely used implant diameter and length was 5.0 and 13 mm, respectively, but the diameter and length had no effect on success rates. However, success rates appeared to decrease with age. CONCLUSIONS: The results indicated that the Osstem GSII implant is highly effective in poor-quality type IV bone. PMID- 22814560 TI - An in vitro investigation concerning the bacterial leakage at implants with internal hexagon and Morse taper implant-abutment connections. AB - PURPOSE: To evaluate, in vitro, the leakage observed in internal hexagon and Morse taper implant-abutment connections. MATERIALS: Ten specimens with internal hexagon and 10 with Cone Morse connection were used. The inner parts of 5 implants, per group, were inoculated with Pseudomonas aeruginosa (PS) suspension and 5 implants, per group, with Aggregatibacter actinomycetemcomitans (AA). The penetration of bacterial suspension into the surrounding solution was determined by observation of turbidity of the broth. RESULTS: In the internal hexagon implants, bacterial contamination was found in 2 of 5 implant-abutment assemblies seeded with the PS, and in the assemblies seeded with AA, the contamination was found in 3 samples, with a total of leaked assemblies in this group in 5 of 10. In the Cone Morse implants, bacterial contamination was found in 2 of 5 implant abutment assemblies seeded with the PS, whereas in the assemblies seeded with AA, no contamination was found, with a total of leaked assemblies in 2 of 10. CONCLUSION: The data support a not significantly higher permeability to bacterial leakage and a lower infiltration rate of screw-retained abutment connections when compared to Cone Morse taper internal connections. PMID- 22814561 TI - Treatment planning of implants when 3 mandibular posterior teeth are missing: a 3-dimensional finite element analysis. AB - PURPOSE: To analyze the biomechanics of 3 designs of implant treatment for 3 teeth missing in posterior low arch quadrants. MATERIAL AND METHODS: A posterior portion of the human mandible missing 44, 45, 46 and three 4.1 * 10 mm threaded ITI implants with crowns were used to construct the finite element model. According to 3 implants being single, splinted or 2 implants support fixed partial denture (FPD) fixed in bone segments. Three implant support conditions were prepared with ANSYS 10.0. A load of 100 N was applied at the central fossa of the occlusal surfaces of the crowns at 45 degrees buccolingually along the triangular ridge of the buccal cusp. The von Mises stress and strain distributions in periimplant bone were observed. RESULTS: The results demonstrated that the von Mises stress in the supporting bone of the 2-implant supported FPD significantly increased compared with that in the 3-implant replacement. Meanwhile, when 3 implants were splinted, only the median implant had a decreased and more homogenous stress distribution, and the other implants did not exhibit significant differences when splinted. CONCLUSION: This study suggests that when space and cost permit, a 2-implant supported FPD should not be used, and 1 implant for each missing tooth being single is recommended. PMID- 22814562 TI - Retrospective clinical evaluation of tapered implants: 10-year follow-up of delayed and immediate placement of maxillary implants. AB - OBJECTIVES: To retrospectively evaluate the clinical outcome of tapered, multithreaded implants (Tapered Screw-Vent MTX; Zimmer Dental, Inc, Carlsbad, CA) with an emphasis on periimplant crestal bone status around those placed delayed and immediately in the posterior and anterior maxilla. METHODS: Chart reviews were performed on 46 patients who had been treated with 173 implants replacing one or more missing and/or unsalvageable teeth in the maxilla. Implant placement and loading was either immediate or delayed. Marginal bone changes were calculated using standardized radiographs taken at implant placement and during annual follow-up. RESULTS: After a mean follow-up of 119 to 121 months, implant survival rate was 99%, and implant success rate was 97%. No discernable bone loss was evident in 85.5% of the surviving implants. Crestal bone loss was observed in 14.5% of all surviving implants: 38.5% of implants immediately loaded and 29.9% of implants with delayed loading. Twenty-one implants exhibited 1 mm of bone loss, 3 implants lost 2 mm, and 1 implant lost 3 mm. Low-density maxillary jawbone and more extensive bone remodeling required around implants immediately placed into extraction sockets were the probable causes of observed bone loss in this study. CONCLUSIONS: Implants exhibited excellent long-term outcomes with little or no bone loss. PMID- 22814564 TI - [Coaching in primary care practices improves long-term weight loss]. PMID- 22814563 TI - [Undesired cutaneous adverse drug reactions: What is new?]. AB - New therapeutic agents, i.e., biologicals, may induce a variety of novel cutaneous adverse reactions (CAR), which hardly can be assigned to existing classification systems. Basing on clinical examples, we present a recently established classification system for CAR to novel drugs. In addition, management strategies for CAR to tumor necrosis factor-alpha antagonists and to epidermal growth factor receptor inhibitors are discussed. PMID- 22814565 TI - Spatio-temporal patterns of Campylobacter colonization in Danish broilers. AB - Despite a number of risk-factor studies in different countries, the epidemiology of Campylobacter colonization in broilers, particularly spatial dependencies, is still not well understood. A series of analyses (visualization and exploratory) were therefore conducted in order to obtain a better understanding of the spatial and temporal distribution of Campylobacter in the Danish broiler population. In this study, we observed a non-random temporal occurrence of Campylobacter, with high prevalence during summer and low during winter. Significant spatio-temporal clusters were identified in the same areas in the summer months from 2007 to 2009. Range of influence between broiler farms were estimated at distances of 9.6 km and 13.5 km in different years. Identification of areas and time with greater risk indicates variable presence of risk factors with space and time. Implementation of safety measures on farms within high-risk clusters during summer could have an impact in reducing prevalence. PMID- 22814566 TI - Four-level anterior cervical discectomies and cage-augmented fusion with and without fixation. AB - PURPOSE: Anterior cervical decompression and fusion is a well-established procedure for the treatment of cervical spinal canal stenosis. In this study, we evaluated the necessity of spinal instrumentation after four-level anterior cervical decompression and cage fusion. METHODS: From January 2006 until August 2008, 25 patients (8 females and 17 males) (mean age 63.9 +/- 7.9 years) suffering from spinal stenosis C3-C7 underwent anterior decompression and interbody fusion. The patients were divided into two groups. Four-level discectomy and cage fusion was performed in all patients. In group A including nine patients, posterior instrumentation with a lateral mass screw-rod system was added, while in group B including 16 patients, additional instrumentation was not performed. The mean duration of follow-up was 48.6 months (average 25-67 months). RESULTS: Clinically, the mean value for the Neck Disability Index improved from 40 +/- 23.25 at presentation to 16.31 +/- 15.09 at the final follow-up. The difference between the two groups was statistically not significant. Radiologically, the criteria for solid bony fusion were achieved successfully in all patients of group A, and in 87.5 % of patients in group B. The difference between the two groups was statistically not significant. The fused segment was then evaluated in the sagittal radiographs as regards the height and the lordosis angle. The loss in the height as well as the loss in the lordosis angle was more when posterior instrumentation was not added. However, the difference between the two groups was not statistically significant. CONCLUSION: Stand-alone intersomatic cage fusion is an acceptable line of treatment for four-level cervical disc disease, both clinically and radiologically. Although the addition of posterior instrumentation yields better radiological results, the difference does not reach the statistical significance level. PMID- 22814568 TI - Hydrosilane and bismuth-accelerated palladium catalyzed aerobic oxidative esterification of benzylic alcohols with air. AB - In a palladium-catalyzed oxidative esterification, hydrosilane can serve as an activator of palladium catalyst with bismuth, thus leading to a novel ligand- and silver-free palladium catalyst system for facile oxidative esterification of a variety of benzylic alcohols in good yields. PMID- 22814567 TI - Surgical techniques for sciatica due to herniated disc, a systematic review. AB - INTRODUCTION: Disc herniation with sciatica accounts for five percent of low-back disorders but is one of the most common reasons for spine surgery. The goal of this study was to update the Cochrane review on the effect of surgical techniques for sciatica due to disc herniation, which was last updated in 2007. MATERIALS AND METHODS: In April 2011, we conducted a comprehensive search in CENTRAL, MEDLINE, EMBASE, CINAHL, PEDRO, ICL, and trial registries. We also checked the reference lists and citation tracking results of each retrieved article. Only randomized controlled trials (RCT) of the surgical management of sciatica due to disc herniation were included. Comparisons including chemonucleolysis and prevention of scar tissue or comparisons against conservative treatment were excluded. Two review authors independently selected studies, assessed risk of bias of the studies and extracted data. Quality of evidence was graded according to the GRADE approach. RESULTS: Seven studies from the original Cochrane review were included and nine additional studies were found. In total, 16 studies were included, of which four had a low risk of bias. Studies showed that microscopic discectomy results in a significantly, but not clinically relevant longer operation time of 12 min (95% CI 2-22) and shorter incision of 24 mm (95% CI 7 40) compared with open discectomy, but did not find any clinically relevant superiority of either technique on clinical results. There were conflicting results regarding the comparison of tubular discectomy versus microscopic discectomy for back pain and surgical duration. CONCLUSIONS: Due to the limited amount and quality of evidence, no firm conclusions on effectiveness of the current surgical techniques being open discectomy, microscopic discectomy, and tubular discectomy compared with each other can be drawn. Those differences in leg or back pain scores, operation time, and incision length that were found are clinically insignificant. Large, high-quality studies are needed, which examine not only effectiveness but cost-effectiveness as well. PMID- 22814569 TI - Client characteristics and gender-specific correlates of testing HIV positive: a comparison of standalone center versus mobile outreach HIV testing and counseling in Botswana. AB - Using data from Botswana's largest HIV testing and counseling (HTC) provider, Tebelopele, we evaluate populations served and gender-specific correlates of testing HIV-positive among clients of two programs: standalone centers and outreach testing. Client records from January to June 2007 (n = 47,890) were evaluated by HTC program and gender. Bivariate and multivariate analyses were performed to identify demographic, testing, and risk-behavior variables associated with testing HIV-positive. Compared to outreach testing, standalone centers served proportionally more clients who were young, well-educated, unmarried, and HIV-infected; outreach testing reached an older, less-educated population. Age, educational attainment, marital status, couples testing, testing because of illness or discordant relationship, and nonuse of condoms (among young clients only) were consistently associated with testing HIV-positive, by HTC program and gender. Our evaluation suggests that Tebelopele standalone and outreach HTC programs serve different populations, and identifies strategies to reduce HIV infection risk and to improve uptake of HTC by HIV-infected, undiagnosed Batswana. PMID- 22814571 TI - Mobile phone-based antiretroviral adherence support in Vietnam: feasibility, patient's preference, and willingness-to-pay. AB - Feasibility of using mobile phone for antiretroviral treatment adherence support was assessed in a multi-site survey. Of 1,016 respondents, 84.5 % used mobile phones; 78.6 % found it effective for adherence aid, 44.8 % had privacy concerns, and 63.5 % expressed willingness-to-use the service. Willingness-to-pay was US$ 2.5/month. Text messaging (41.8 %) and direct calls by health workers (35.4 %) were preferred. Expressed preference for specific support service included direct counseling with physician (43.1 %), automated reminder for pills taking (29.1 %), regular information messages (21.3 %), and booking of clinic visits (16.5 %). These findings inform the design of adherence interventions using mobile phone in the Vietnamese setting. PMID- 22814570 TI - Labor force participation and health-related quality of life in HIV-positive men who have sex with men: the Multicenter AIDS Cohort Study. AB - Too many people with HIV have left the job market permanently and those with reduced work capacity have been unable to keep their jobs. There is a need to examine the health effects of labor force participation in people with HIV. This study presents longitudinal data from 1,415 HIV-positive men who have sex with men taking part in the Multicenter AIDS Cohort Study. Generalized Estimating Equations show that employment is associated with better physical and mental health quality of life and suggests that there may be an adaptation process to the experience of unemployment. Post hoc analyses also suggest that people who are more physically vulnerable may undergo steeper health declines due to job loss than those who are generally healthier. However, this may also be the result of a selection effect whereby poor physical health contributes to unemployment. Policies that promote labor force participation may not only increase employment rates but also improve the health of people living with HIV. PMID- 22814572 TI - Information properties of naturally-occurring proteins: Fourier analysis and complexity phase plots. AB - In previous work from this lab, the information in natural proteins was investigated with Ribonuclease A (RNase A) serving as the source. The signature traits were investigated at three structure levels: primary through tertiary. The present paper travels further by charting the primary structure information of about half a million molecules. This was feasible given abundant sequence archives for both living and viral systems. Notably, a method is presented for evaluating primary structure information, based on Fourier analysis and spectral complexity. Significantly, the results show certain complexity traits to be universal for living sources. Viruses, by contrast, encode protein collections which are case-specific and complexity-divergent. The results have ramifications for discriminating collections on the basis of sequence information. This discrimination offers new strategies for selecting drug targets. PMID- 22814573 TI - Influence of pH on the structure and oleic acid binding ability of bovine alpha lactalbumin. AB - The biological function of alpha-lactalbumin (alpha-LA) depends on its conformation. alpha-LA can adopt a stable intermediate state induced by heating or pH change. This intermediate state associates with oleic acid (OA) to form an anti-tumor complex. The effect of temperature on the formation the complex has been studied, whereas the effect of pH on complex formation remains unresolved. The effect of pH on tryptophan residues, hydrophobic clusters and secondary structure of Ca(2+)-depleted bovine alpha-LA (BLA) was studied by fluorescence spectroscopy and circular dichroism. BLA was found to adopt a more flexible conformation between pH 7.0 and 9.0 with buried hydrophobic clusters. The binding ability of alpha-LA towards OA and the anti-tumor activity of the corresponding complex were also studied. BLA was found to bind more OA over the pH range of 7.0 9.0 and the corresponding complexes showed a higher anti-tumor activity than those complexes formed under acidic conditions. Our study indicates that alkaline pH aided the formation of the complex as well as its anti-tumor activity. We also propose a possible characteristic structure that facilitates binding of OA. PMID- 22814575 TI - Intelligent data analysis to model and understand live cell time-lapse sequences. AB - BACKGROUND: One important aspect of cellular function, which is at the basis of tissue homeostasis, is the delivery of proteins to their correct destinations. Significant advances in live cell microscopy have allowed tracking of these pathways by following the dynamics of fluorescently labelled proteins in living cells. OBJECTIVES: This paper explores intelligent data analysis techniques to model the dynamic behavior of proteins in living cells as well as to classify different experimental conditions. METHODS: We use a combination of decision tree classification and hidden Markov models. In particular, we introduce a novel approach to "align" hidden Markov models so that hidden states from different models can be cross-compared. RESULTS: Our models capture the dynamics of two experimental conditions accurately with a stable hidden state for control data and multiple (less stable) states for the experimental data recapitulating the behaviour of particle trajectories within live cell time-lapse data. CONCLUSIONS: In addition to having successfully developed an automated framework for the classification of protein transport dynamics from live cell time-lapse data our model allows us to understand the dynamics of a complex trafficking pathway in living cells in culture. PMID- 22814576 TI - A single-cell drug efflux assay in bacteria by using a directly accessible femtoliter droplet array. AB - Active efflux of drugs, such as antibiotics, from a cell is one of the major mechanisms that cause multi-drug resistance in bacteria. Here we report a method to assess drug efflux activity in individual Escherichia coli cells enclosed and isolated in a directly accessible femtoliter droplet array with a fluorogenic compound. The inhibitory effect of a chemical compound on an exogenously expressed efflux pump system from pathogenic bacteria was easily detected at the single-cell level. We also present a proof-of-principle experiment to screen for the gene encoding a drug efflux pump by collecting individual droplets containing single cells in which the drug efflux activity was restored after introduction of the exogenous gene from pathogenic bacteria. Our approach will be a useful tool to screen novel pump inhibitors and efflux pump genes, and to overcome infectious diseases caused by multi-drug-resistant bacteria. PMID- 22814578 TI - A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications. AB - BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect. PMID- 22814577 TI - Exercise and diet-induced weight loss attenuates oxidative stress related coronary vasoconstriction in obese adolescents. AB - Obesity is a disease of oxidative stress (OS). Acute hyperoxia (breathing 100 % O(2)) can evoke coronary vasoconstriction by the oxidative quenching of nitric oxide (NO). To examine if weight loss would alter the hyperoxia-related coronary constriction seen in obese adolescents, we measured the coronary blood flow velocity (CBV) response to hyperoxia using transthoracic Doppler echocardiography before and after a 4-week diet and exercise regimen in 6 obese male adolescents (age 13-17 years, BMI 36.5 +/- 2.3 kg/m(2)). Six controls of similar age and BMI were also studied. The intervention group lost 9 +/- 1 % body weight, which was associated with a reduced resting heart rate (HR), reduced diastolic blood pressure (BP), and reduced RPP (all P < 0.05). Before weight loss, hyperoxia reduced CBV by 33 +/- 3 %. After weight loss, CBV only fell by 15 +/- 3 % (P < 0.05). In the control group, CBV responses to hyperoxia were unchanged during the two trials. Thus weight loss: (1) reduces HR, BP, and RPP; and (2) attenuates the OS-related coronary constrictor response seen in obese adolescents. We postulate that: (1) the high RPP before weight loss led to higher myocardial O(2) consumption, higher coronary flow and greater NO production, and in turn a large constrictor response to hyperoxia; and (2) weight loss decreased myocardial oxygen demand and NO levels. Under these circumstances, hyperoxia-induced vasoconstriction was attenuated. PMID- 22814579 TI - Expression and prognostic significance of Src family members in renal clear cell carcinoma. AB - BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer. PMID- 22814581 TI - Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit. AB - BACKGROUND: Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results. METHODS: We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 MUg dl(-1)) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 MUg dl(-1)). Stratification by PGII decreased the misclassification errors due to cancer induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: -1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: -1.07, 9.76). CONCLUSION: Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk. PMID- 22814580 TI - Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model. AB - BACKGROUND: This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia. METHODS: Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules. RESULTS: The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 MUg m(-2) tri-weekly, is G-CSF, 300 MUg, Q1D * 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 MUg, Q1D * 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per MUl) under Doc, 100-150 mg m(-2) tri-weekly. CONCLUSIONS: The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted. PMID- 22814588 TI - A mathematical solution and analysis of contaminant transport in a radial two zone confined aquifer. AB - An aquifer with a wellbore surrounded by a finite-thickness skin, such as a gravel pack, can be regarded as a radial two-zone system. In this study, a mathematical model is developed to describe contaminant transport in a radial two zone confined aquifer system. The solution of the model equations can be used to delineate contaminant transport in such a two-zone aquifer system and to investigate the skin effect on the temporal and spatial concentration distribution. The present solution is shown to reduce to an existing solution for transport in a homogeneous aquifer in the case when there is no wellbore skin. The results predicted from the solution indicate that the skin effect has a significant impact on the concentration distribution at early time. But an abrupt change in the spatial concentration distribution may occur at the interface of the skin zone and aquifer formation zone. The results from a sensitivity analysis reveal that dispersivity in the formation zone has a more significant effect on the concentration distribution than do the effects of skin thickness and dispersivity in the skin zone. PMID- 22814582 TI - Expression of oncogenic BARD1 isoforms affects colon cancer progression and correlates with clinical outcome. AB - BACKGROUND: Colon cancer predisposition is associated with mutations in BRCA1. BRCA1 protein stability depends on binding to BARD1. In different cancers, expression of differentially spliced BARD1 isoforms is correlated with poor prognosis and decreased patient survival. We therefore suspected a role of BARD1 isoforms in colon cancer. METHODS: We performed immunohistochemistry in 168 colorectal cancers, using four antibodies directed against differentially expressed regions of BARD1. We determined structure and relative expression of BARD1 mRNA isoforms in 40 tumour and paired normal peri-tumour tissues. BARD1 expression was correlated with clinical outcome. RESULTS: BARD1 isoforms were expressed in 98% of cases and not correlated with BRCA1. BARD1 mRNA isoforms were upregulated in all tumours as compared with paired normal peri-tumour tissues. Non-correlated expression and localisation of different epitopes suggested insignificant expression of full-length (FL) BARD1. Expression of N- and C terminal epitopes correlated with increased survival, but expression of epitopes mapping to the middle of BARD1 correlated with decreased survival. Middle epitopes are present in oncogenic BARD1 isoforms, which have pro-proliferative functions. Correlated upregulation of only N- and C-terminal epitopes reflects the expression of isoforms BARD1delta and BARD1phi. CONCLUSION: Our results suggest that BARD1 isoforms, but not FL BARD1, are expressed in colon cancer and affect its progression and clinical outcome. PMID- 22814589 TI - Ultrasound molecular imaging contrast agent binding to both E- and P-selectin in different species. AB - OBJECTIVES: Ultrasound molecular imaging is increasingly used in preclinical studies to measure the expression of vascular markers during inflammation process. In this context, a new ultrasound contrast agent functionalized with a recombinant P-selectin glycoprotein ligand-1 analogue (rPSGL-Ig) was developed (MBrPSGL-Ig). This agent was assayed in vitro and in vivo to evaluate its binding performance and potential to image expression of inflammatory markers E- and P selectin. Performance of this newly developed agent was compared with that of antibody (MBAb) or sialyl Lewis X (MBsLe) containing microbubbles and with control microbubbles (MBC). MATERIALS AND METHODS: The targeted ultrasound contrast agents were prepared by coupling biotin-conjugated ligands onto streptavidin-functionalized microbubbles. First, in vitro experiments were performed to measure the adhesion efficiency of these microbubble constructs under static or flow conditions (114 sec), on cell monolayer (human umbilical vein endothelial cells and bEnd.5), or coatings of E- or P-selectin of various animal species, respectively. Second, molecular imaging studies were performed in a rat inflammatory model 24 hours after intramuscular injection of lipopolysaccharide in the hind limb. Finally, immunohistochemistry staining of rat inflamed muscle tissue was performed to assess expression of E- and P selectin. RESULTS: Microbubbles functionalized with rPSGL-Ig (MBrPSGL-Ig) displayed firm in vitro binding on the coating of both recombinant E- or P selectin, with an efficiency similar to microbubbles comprising antibody specific for E-selectin (MBE) or P-selectin (MBP). In contrast, lower binding capacity was measured with MBsLe. At the surface of inflamed endothelial cells, MBrPSGL-Ig were able to interact specifically with E- and P-selectin. Binding specificity was demonstrated by performing blocking experiments with target-specific antibodies, resulting in an 80% to 95% decrease in binding. Ten minutes after microbubble injection, echo signal measured with MBrPSGL-Ig in the inflamed muscles was 20-fold higher compared with MBC. Moreover, the in vivo adhesion of MBrPSGL-Ig was 2- and 7-fold higher compared with P-selectin or E-selectin specific microbubbles, respectively. Immunohistochemistry revealed a temporal coexpression of E- and P-selectin in the vascular bed of inflamed rat muscle 24 hours after lipopolysaccharide injection. CONCLUSION: The molecular imaging study demonstrates that MBrPSGL-Ig provide imaging signal higher than those measured with antibody or sialyl Lewis X containing microbubbles. These results suggest that MBrPSGL-Ig is a powerful agent to image the expression of both E- and P selectin in the context of an inflammatory process. PMID- 22814590 TI - Assessment of preoperative magnetic resonance imaging staging in patients with hepatocellular carcinoma undergoing resection compared with the seventh American Joint Committee on Cancer System. AB - OBJECTIVES: The aim of this study was to compare the prognostic utility of a staging system using magnetic resonance imaging (MRI) with the seventh American Joint Committee on Cancer (AJCC) staging system in patients with hepatocellular carcinoma (HCC) who underwent hepatic resection. MATERIALS AND METHODS: A total of 175 consecutive patients with HCC who underwent curative hepatic resection after MRI between January 2000 and December 2007 were analyzed. In lieu of microvascular invasion, which is used by the AJCC staging system, we devised an MRI staging system in which a size criterion of 2 cm was used to differentiate between tumor stages 1 and 2. All patients were retrospectively staged using the seventh AJCC staging system and the preoperative MRI staging system. Differences in disease-free and overall survival rates between different stages by the MRI and AJCC staging systems were analyzed using the Kaplan-Meier method with log rank testing. The predictive accuracy of the 2 staging systems was directly compared using the time-dependent receiver operating characteristic curve analysis. RESULTS: Median follow-up period was 222.9 weeks. During the follow-up period, 74 (42.3%) patients experienced tumor recurrence and 22 (12.6%) died. The median disease-free survival and overall survival were 131.1 and 222.9 weeks, respectively. Both staging systems were excellent for the prediction of disease free survival across different tumor stages but failed to predict overall survival differences between stages 1 and 2. For disease-free and overall survivals, the time-dependent receiver operating characteristic curve analysis revealed no significant differences in predictive accuracy between the 2 staging systems. CONCLUSION: A preoperative MRI staging system using a size threshold instead of microvascular invasion may predict the prognosis of HCC patients undergoing hepatic resection as accurately as the seventh AJCC tumor-node metastasis staging system. PMID- 22814587 TI - Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. AB - Novel classes of small and long non-coding RNAs (ncRNAs) are being characterized at a rapid pace, driven by recent paradigm shifts in our understanding of genomic architecture, regulation and transcriptional output, as well as by innovations in sequencing technologies and computational and systems biology. These ncRNAs can interact with DNA, RNA and protein molecules; engage in diverse structural, functional and regulatory activities; and have roles in nuclear organization and transcriptional, post-transcriptional and epigenetic processes. This expanding inventory of ncRNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis. PMID- 22814591 TI - Involvement in research without compromising research quality. AB - Health research funders in the UK now ask applicants to state how their research will involve patients and members of the public. Such involvement can help with questions that researchers repeatedly face: about improving trial recruitment, response rates and follow-up. Patient and Public Involvement (PPI) in research is usually presented in the form of a ladder, from a low rung where studies are led by researchers with no patient involvement, to a high rung where studies are patient-led. This hierarchy does not sit well with many clinicians and academics whose expertise appears to have been downgraded. This article argues that research quality and relevance are optimised when patient expertise is integrated with researchers' and policy-makers' expertise, and each role acknowledged and valued, illustrated by an alternative model for PPI which places research and expertise at the centre of the involvement enterprise. PMID- 22814592 TI - Effect of triclosan-coated sutures on incidence of surgical wound infection after lower limb revascularization surgery: a randomized controlled trial. By Turtiainen et al. DOI:10.1007/s00268-012-1655-4. PMID- 22814593 TI - Influence of young age on outcome after esophagectomy for cancer. AB - BACKGROUND: The incidence of esophageal cancer has risen among all age groups. Controversy exists about the clinical presentation and prognosis of young patients. The aim of this study was to compare the clinicopathologic characteristics and outcomes after surgery between patients with esophageal cancer who were <50 years of age and those >=50 years of age. METHODS: Patients diagnosed with esophageal carcinoma who underwent esophagectomy between January 1990 and December 2010 in a single institution were selected from a prospective database. Patients aged <50 years at diagnosis (n = 163) were compared with those >=50 years (n = 1151) with respect to clinicopathologic stage and oncologic outcome. RESULTS: Younger patients had less co-morbidity (p < 0.001). There were no significantly differences in tumor localization, histology, differentiation, or TNM stage in the two groups. In both groups, 37 % of the patients underwent neoadjuvant chemo(radio)therapy. One or more nonsurgical complications developed in 53 % of the older group versus 42 % in the younger group (p = 0.012). In hospital mortality was 6.3 % for patients >=50 years compared to 1.8 % for younger patients (p = 0.021). The 5 year overall survival was significantly better for the younger patients than for those >=50 years (41 vs. 31 %, p < 0.001), but median disease-specific and disease-free survival did not differ between the groups (37 vs. 30 months, p = 0.140 and 49 vs. 28 months, p = 0.079, respectively). Multivariate analysis identified moderate, poorly, and undifferentiated tumors; tumor-positive resection margins (pR1-2); and TNM stage IIB-IV as independent predictors of disease-specific survival. CONCLUSIONS: A considerable proportion (12 %) of patients diagnosed with resectable esophageal carcinoma were <50 years. Phenotypic tumor characteristics and disease-specific survival were comparable for the two age groups. PMID- 22814594 TI - Measuring microtubule thickness: an exercise in cooperativity. AB - Doublecortin (DCX), a microtubule-associated protein, is essential for neuronal migration, although a clear mechanistic understanding of this requirement remains elusive. In this issue of Developmental Cell, Bechstedt and Brouhard (2012) report that DCX relies on cooperative binding and an affinity for growing microtubule ends to nucleate and stabilize 13-protofilament microtubules. PMID- 22814595 TI - The GAP between axon pruning and repulsion. AB - Stereotyped axonal pruning and growth cone repulsion, modulators of neuronal connectivity, share many ligands and receptors systems. Riccomagno et al. (2012) show in Cell that common ligands can link functionally specialized downstream pathways, demonstrating that the Rac GAP beta2-Chimaerin is needed in Semaphorin mediated axonal pruning but not growth cone repulsion. PMID- 22814596 TI - Sporoptosis: sowing the seeds of nuclear destruction. AB - What are the origins of programmed cell death (PCD)? In this issue of Developmental Cell, Eastwood et al. (2012) uncover an ancient developmental program of nuclear destruction in yeast, implying that some PCD mechanisms could have emerged from nonlethal processes before the divergence of fungi and metazoan. PMID- 22814597 TI - Calcineurin/NFATc signaling: role in postnatal beta cell development and diabetes mellitus. AB - Pancreatic islets are aggregates of endocrine cells required for blood glucose control and diabetes prevention after birth. In this issue of Developmental Cell, Goodyer et al. (2012) reveal a function of calcineurin, a calcium-activated serine/threonine phosphatase, in postnatal NFATc-regulated expression of genes that help beta cells to form insulin-containing vesicles and enter the cell cycle. PMID- 22814598 TI - Size doesn't matter! The importance of size variability in coated vesicles. AB - Coated vesicles are key components of the machinery of vesicular transport used by eukaryotic cells. In a recent story published in Science, Faini et al. (2012) report on the detailed 3D structure of a synthetically generated COPI vesicle coat obtained using cryoelectron tomography. PMID- 22814599 TI - Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin-protein interactions? AB - Caveolin proteins drive formation of caveolae, specialized cell-surface microdomains that influence cell signaling. Signaling proteins are proposed to use conserved caveolin-binding motifs (CBMs) to associate with caveolae via the caveolin scaffolding domain (CSD). However, structural and bioinformatic analyses argue against such direct physical interactions: in the majority of signaling proteins, the CBM is buried and inaccessible. Putative CBMs do not form a common structure for caveolin recognition, are not enriched among caveolin-binding proteins, and are even more common in yeast, which lack caveolae. We propose that CBM/CSD-dependent interactions are unlikely to mediate caveolar signaling, and the basis for signaling effects should therefore be reassessed. PMID- 22814600 TI - Neonatal beta cell development in mice and humans is regulated by calcineurin/NFAT. AB - Little is known about the mechanisms governing neonatal growth and maturation of organs. Here we demonstrate that calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling regulates neonatal pancreatic development in mouse and human islets. Inactivation of calcineurin b1 (Cnb1) in mouse islets impaired dense core granule biogenesis, decreased insulin secretion, and reduced cell proliferation and mass, culminating in lethal diabetes. Pancreatic beta cells lacking Cnb1 failed to express genes revealed to be direct NFAT targets required for replication, insulin storage, and secretion. In contrast, glucokinase activation stimulated Cn-dependent expression of these genes. Calcineurin inhibitors, such as tacrolimus, used for human immunosuppression, induce diabetes. Tacrolimus exposure reduced Cn/NFAT-dependent expression of factors essential for insulin dense core granule formation and secretion and neonatal beta cell proliferation, consistent with our genetic studies. Discovery of conserved pathways regulating beta cell maturation and proliferation suggests new strategies for controlling beta cell growth or replacement in human islet diseases. PMID- 22814601 TI - TGF-beta type II receptor/MCP-5 axis: at the crossroad between joint and growth plate development. AB - Despite its clinical significance, the mechanisms of joint morphogenesis are elusive. By combining laser-capture microdissection for RNA sampling with microarrays, we show that the setting in which joint-forming interzone cells develop is distinct from adjacent growth plate chondrocytes and is characterized by downregulation of chemokines, such as monocyte-chemoattractant protein-5 (MCP 5). Using in vivo, ex vivo, and in vitro approaches, we show that low levels of interzone-MCP-5 are essential for joint formation and contribute to proper growth plate organization. Mice lacking the TGF-beta-type-II-receptor (TbetaRII) in their limbs (Tgfbr2(Prx1KO)), which lack joint development and fail chondrocyte hypertrophy, show upregulation of interzone-MCP-5. In vivo and ex vivo blockade of the sole MCP-5 receptor, CCR2, led to the rescue of joint formation and growth plate maturation in Tgfbr2(Prx1KO) but an acceleration of growth plate mineralization in control mice. Our study characterized the TbetaRII/MCP-5 axis as an essential crossroad for joint development and endochondral growth. PMID- 22814602 TI - Hibris, a Drosophila nephrin homolog, is required for presenilin-mediated Notch and APP-like cleavages. AB - Drosophila Hibris (Hbs), a member of the Nephrin Immunoglobulin Super Family, has been implicated in myogenesis and eye patterning. Here, we uncover a role of Hbs in Notch (N) signaling and gamma-secretase processing. Loss of hbs results in classical N-signaling-associated phenotypes in Drosophila, including eye patterning, wing margin, and sensory organ specification defects. In particular, hbs mutant larvae display altered gamma-secretase-dependent Notch proteolytic processing. Hbs also interacts molecularly and genetically with Presenilin (Psn) and other components of the gamma-secretase complex. This Hbs function appears conserved, as mammalian Nephrin also promotes N signaling in mammalian cells. Our data suggest that Hbs is required for Psn maturation. Consistent with its role in Psn processing, Hbs genetically interacts with the Drosophila beta-amyloid protein precursor-like (Appl) protein, the homolog of mammalian APP, the cleavage of which is associated with Alzheimer's disease. Thus, Hbs/Nephrin appear to share a general requirement in Psn/gamma-secretase regulation and associated processes. PMID- 22814603 TI - Two forkhead transcription factors regulate the division of cardiac progenitor cells by a Polo-dependent pathway. AB - The development of a complex organ requires the specification of appropriate numbers of each of its constituent cell types, as well as their proper differentiation and correct positioning relative to each other. During Drosophila cardiogenesis, all three of these processes are controlled by jumeau (jumu) and Checkpoint suppressor homologue (CHES-1-like), two genes encoding forkhead transcription factors that we discovered utilizing an integrated genetic, genomic, and computational strategy for identifying genes expressed in the developing Drosophila heart. Both jumu and CHES-1-like are required during asymmetric cell division for the derivation of two distinct cardiac cell types from their mutual precursor and in symmetric cell divisions that produce yet a third type of heart cell. jumu and CHES-1-like control the division of cardiac progenitors by regulating the activity of Polo, a kinase involved in multiple steps of mitosis. This pathway demonstrates how transcription factors integrate diverse developmental processes during organogenesis. PMID- 22814604 TI - Separase sensor reveals dual roles for separase coordinating cohesin cleavage and cdk1 inhibition. AB - Complete dissociation of sister chromatid cohesion and subsequent induction of poleward movement of disjoined sisters are two essential events underlying chromosome segregation; however, how cells coordinate these two processes is not well understood. Here, we developed a fluorescence-based sensor for the protease separase that mediates cohesin cleavage. We found that separase undergoes an abrupt activation shortly before anaphase onset in the vicinity of chromosomes. This activation profile of separase depends on the abilities of two of its binding proteins, securin and cyclin B1, to inhibit its protease activity and target it to chromosomes. Subsequent to its proteolytic activation, separase then binds to and inhibits a subset of cyclin B1-cdk1, which antagonizes cdk1-mediated phosphorylation on chromosomes and facilitates poleward movement of sisters in anaphase. Therefore, by consecutively acting as a protease and a cdk1 inhibitor, separase coordinates two key processes to achieve simultaneous and abrupt separation of sister chromatids. PMID- 22814605 TI - Separase biosensor reveals that cohesin cleavage timing depends on phosphatase PP2A(Cdc55) regulation. AB - In anaphase, sister chromatids separate abruptly and are then segregated by the mitotic spindle. The protease separase triggers sister separation by cleaving the Scc1/Mcd1 subunit of the cohesin ring that holds sisters together. Polo-kinase phosphorylation of Scc1 promotes its cleavage, but the underlying regulatory circuits are unclear. We developed a separase biosensor in Saccharomyces cerevisiae that provides a quantitative indicator of cohesin cleavage in single cells. Separase is abruptly activated and cleaves most cohesin within 1 min, after which anaphase begins. Cohesin near centromeres and telomeres is cleaved at the same rate and time. Protein phosphatase PP2A(Cdc55) inhibits cohesin cleavage by counteracting polo-kinase phosphorylation of Scc1. In early anaphase, the previously described separase inhibition of PP2A(Cdc55) promotes cohesin cleavage. Thus, separase acts directly on Scc1 and also indirectly, through inhibition of PP2A(Cdc55), to stimulate cohesin cleavage, providing a feedforward loop that may contribute to a robust and timely anaphase. PMID- 22814606 TI - Golgin160 recruits the dynein motor to position the Golgi apparatus. AB - Membrane motility is a fundamental characteristic of all eukaryotic cells. One of the best-known examples is that of the mammalian Golgi apparatus, where constant inward movement of Golgi membranes results in its characteristic position near the centrosome. While it is clear that the minus-end-directed motor dynein is required for this process, the mechanism and regulation of dynein recruitment to Golgi membranes remains unknown. Here, we show that the Golgi protein golgin160 recruits dynein to Golgi membranes. This recruitment confers centripetal motility to membranes and is regulated by the GTPase Arf1. Further, during cell division, motor association with membranes is regulated by the dissociation of the receptor motor complex from membranes. These results identify a cell-cycle-regulated membrane receptor for a molecular motor and suggest a mechanistic basis for achieving the dramatic changes in organelle positioning seen during cell division. PMID- 22814607 TI - Chromatin-remodeling factor Brg1 is required for Schwann cell differentiation and myelination. AB - Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of transcription factors. How this is linked to chromatin changes is not well understood. Here we show that the glial transcription factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the transcription factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination. PMID- 22814608 TI - Let-7-complex microRNAs regulate the temporal identity of Drosophila mushroom body neurons via chinmo. AB - Many neural lineages display a temporal pattern, but the mechanisms controlling the ordered production of neuronal subtypes remain unclear. Here, we show that Drosophila let-7 and miR-125, cotranscribed from the let-7-Complex (let-7-C) locus, regulate the transcription factor chinmo to control temporal cell fate in the mushroom body (MB) lineage. We find that let-7-C is activated in postmitotic neurons born during the larval-to-pupal transition, when transitions among three MB subtypes occur. Loss or increase of let-7-C delays or accelerates these transitions, respectively, and leads to cell fate transformations. Consistent with our identification of let-7 and miR-125 sites in a recently identified ~6 kb extension of the chinmo 3' UTR, Chinmo is elevated in let-7-C mutant MBs. In addition, we show that let-7-C acts upstream of chinmo and that let-7-C phenotypes are caused by elevated chinmo. Thus, these heterochronic miRNAs, originally identified in C. elegans, underlie progenitor cell multipotency during the development of diverse bilateria. PMID- 22814609 TI - Eph/ephrin signaling in cancer: intricate, puzzling and ... fascinating! AB - The Eph receptor tyrosine kinases family and their membrane bound ligands, the ephrins, represents a complex signaling network of cell communication for cell sorting during tissue patterning in development and in the normal physiology and homeostasis of adult tissues. This molecular family has adapted to evolving tissue complexity in multicellular organisms through the emergence of more members and complex mechanisms of expression and signaling that result in the fine-tuning of cell positioning. Since their initial identification from an erythropoietin producing hepatocellular (Eph) carcinoma cell line in 1987, Eph/ephrin signaling has been a matter of intensive investigation for their plausible role in cancer. Similarly to their context dependent modus operandi in normal tissues, Eph/ephrin signaling in cancer is an intricate and puzzling network of events that tumors "manage" to their benefit in multiple aspects like cell adhesion to substrate, migration, invasion or growth. PMID- 22814610 TI - Time-series analysis of hepatitis A, B, C and E infections in a large Chinese city: application to prediction analysis. AB - Viral hepatitis is recognized as one of the most frequently reported diseases, and especially in China, acute and chronic liver disease due to viral hepatitis has been a major public health problem. The present study aimed to analyse and predict surveillance data of infections of hepatitis A, B, C and E in Wuhan, China, by the method of time-series analysis (MemCalc, Suwa-Trast, Japan). On the basis of spectral analysis, fundamental modes explaining the underlying variation of the data for the years 2004-2008 were assigned. The model was calculated using the fundamental modes and the underlying variation of the data reproduced well. An extension of the model to the year 2009 could predict the data quantitatively. Our study suggests that the present method will allow us to model the temporal pattern of epidemics of viral hepatitis much more effectively than using the artificial neural network, which has been used previously. PMID- 22814611 TI - [Treatment of proximal humerus fractures: relative position of different locking plates to the axillary nerve]. AB - OBJECTIVES: Placement of a proximal humerus locking plate through a percutaneous transdeltoid approach bears the advantages of a minimally invasive approach but may compromise the anterior branches of the axillary nerve. This anatomic study aimed to develop a risk profile for 6 types of modern proximal humerus locking plates as to their interference with the axillary nerve. MATERIALS AND METHODS: In this study six different implants (Arthrex(r), DePuy(r), Konigsee(r), Smith & Nephew(r), Stryker(r) and Synthes(r)) were placed on the intact proximal humerus of 33 embalmed cadaveric upper extremities and the relative positioning between the axillary nerve and the screw holes was determined. RESULTS: All locking plates displayed an area of risk which concerned 3 out of 7 (Arthrex(r)), 4 out of 10 (DePuy(r)), 2 out of 9 (Konigsee(r)), 3 out of 11 (Smith & Nephew(r)), 3 out of 11 (Stryker(r)) and 6 out of 12 (Synthes(r)) screw holes of the plate. CONCLUSIONS: Using the anterolateral percutaneous deltoid splitting approach the relative position of the axillary nerve to the holes of a specific implant is of relevance for avoidance of iatrogenic lesions to the nerve. PMID- 22814612 TI - Exploring anti-TB leads from natural products library originated from marine microbes and medicinal plants. AB - Multidrug-resistant tuberculosis (MDR-TB) and TB-HIV co-infection have become a great threat to global health. However, the last truly novel drug that was approved for the treatment of TB was discovered 40 years ago. The search for new effective drugs against TB has never been more intensive. Natural products derived from microbes and medicinal plants have been an important source of TB therapeutics. Recent advances have been made to accelerate the discovery rate of novel TB drugs including diversifying strategies for environmental strains, high throughput screening (HTS) assays, and chemical diversity. This review will discuss the challenges of finding novel natural products with anti-TB activity from marine microbes and plant medicines, including biodiversity- and taxonomy guided microbial natural products library construction, target- and cell-based HTS, and bioassay-directed isolation of anti-TB substances from traditional medicines. PMID- 22814613 TI - Chronic cavitating pulmonary aspergillosis with lung abscess. PMID- 22814614 TI - Is 46XX karyotype always a female? AB - A19-year-old man, from a middle east country was referred by his physician to the endocrine department for bilateral gynaecomastia, low libido and sparse facial hair. There was no history of any chronic illness, mumps or traumatic injury to testis. He had clinical features suggestive of gonadotropin deficiency which was confirmed on biochemical testing. On karyotype and fluorescent in situ hybridisation analysis, he was found to have 46XX(SRY+) karyotype. PMID- 22814615 TI - Oropharyngeal teratoma, a rare cause of airway obstruction in neonates. AB - Oropharyngeal teratomas are extremely rare congenital tumours, and because of their location in the upper airway they represent one of the most unusual causes of airway obstruction during the neonatal period. We report a 2-month-old girl who presented with repeated vomiting, failure to thrive and recurrent bouts of stridor and cyanosis since birth. On examination there was a mass originating from the oropharynx. The mass was excised under general anaesthesia by CO(2) laser. Histopathological examination revealed a teratoma of the oropharynx. We discuss the clinical presentation, diagnosis and treatment of this case as well as a review of the literature. PMID- 22814617 TI - Early illness recognition using in-home monitoring sensors and multiple instance learning. AB - BACKGROUND: Many older adults in the US prefer to live independently for as long as they are able, despite the onset of conditions such as frailty and dementia. Solutions are needed to enable independent living, while enhancing safety and peace of mind for their families. Elderly patients are particularly at-risk for late assessment of cognitive changes. OBJECTIVES: We predict early signs of illness in older adults by using the data generated by a continuous, unobtrusive nursing home monitoring system. METHODS: We describe the possibility of employing a multiple instance learning (MIL) framework for early illness detection. The MIL framework is suitable for training classifiers when the available data presents temporal or location uncertainties. RESULTS: We provide experiments on three datasets that prove the utility of the MIL framework. We first tuned our algorithms on a set of 200 normal/abnormal behavior patterns produced by a dedicated simulator. We then conducted two retrospective studies on residents from the Tiger Place aging in place facility, aged over 70, which have been monitored with motion and bed sensors for over two years. The presence or absence of the illness was manually assessed based on the nursing visit reports. CONCLUSIONS: The use of simulated sensor data proved to be very useful for algorithm development and testing. The results obtained using MIL for six Tiger Place residents, an average area under the receiver operator characteristic curve (AROC) of 0.7, are promising. However, more sophisticated MIL classifiers are needed to improve the performance. PMID- 22814618 TI - Discussing adolescent sexual health in African-American churches. AB - This study describes the ways in which two African-American churches discuss adolescent sexual health topics. Six focus groups were conducted in two churches in Flint, Michigan, that reported no formal sexual health programming for their congregants. Three themes emerged to highlight the different perspectives about the role of churches in adolescent sexual decision-making and sexual health education: (1) churches as sources of sexual information, (2) churches as complex communities, and (3) recommendations for sexual education in churches. Participant responses suggest that churches can and should serve a resource for sexual health information. Implications for practice and research are discussed. PMID- 22814619 TI - CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence. AB - Transforming growth factor-alpha (TGF-alpha)-induced proliferation and transforming growth factor-beta (TGF-beta)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC interacting transcriptional modulator, responds to TGF-alpha induction and TGF beta suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-alpha induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21(CIP1). CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC-HDAC1 complex formation. TGF-beta stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21(CIP1) suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21(CIP1) signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF alpha and TGF-beta-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome. PMID- 22814620 TI - TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. AB - Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAIL-induced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis. PMID- 22814621 TI - Prophylactic treatment with the BH3 mimetic ABT-737 impedes Myc-driven lymphomagenesis in mice. AB - As many oncogenic changes, such as Myc overexpression, promote apoptosis, the survival of emerging neoplastic clones may often initially depend upon endogenous levels of particular pro-survival members of the Bcl-2 protein family. Pertinently, we recently showed that in lymphoma-prone EMU-myc transgenic mice, which overexpress Myc in all B-lymphoid cells, endogenous Bcl-x(L) is critical for the survival, as well as the expansion of preneoplastic B-lymphoid cells and the development of malignant disease. This discovery raised the possibility that pharmacological blockade of Bcl-x(L) might impede Myc-driven lymphoma development. Indeed, we report here that treatment of preleukaemic EMU-myc transgenic mice with the Bcl-2 homology (BH)3 mimetic drug ABT-737, which inhibits Bcl-x(L), as well as Bcl-2 and Bcl-w, augmented apoptosis of preneoplastic B-lymphoid cells, reduced their numbers and greatly prolonged lymphoma-free survival. These findings reveal that BH3 mimetic drugs may provide a prophylactic strategy to prevent the development of certain tumours, particularly those driven by deregulated Myc expression. Moreover, such treatment may help in the management of patients with hereditary cancer syndromes and perhaps also in the prevention of tumour relapses. PMID- 22814622 TI - A variational approach to behavioral and neuroelectrical laws. AB - Variational methods play a fundamental and unifying role in several fields of physics, chemistry, engineering, economics, and biology, as they allow one to derive the behavior of a system as a consequence of an optimality principle. A possible application of these methods to a model of perception is given by considering a psychophysical law as the solution of an Euler-Lagrange equation. A general class of Lagrangians is identified by requiring the measurability of prothetic continua on interval scales. The associated Hamiltonian (the energy of the process) is tentatively connected with neurophysiological aspects. As an example of the suggested approach a particular choice of the Lagrangian, that is a sufficient condition to obtain classical psychophysical laws, while accounting for psychophysical adaptation and the stationarity of neuronal activity, is used to explore a possible relation between a behavioral law and a neuroelectrical ,response based on the Naka-Rushton model. PMID- 22814623 TI - A ventricular assist device as a bridge to recovery, decision making, or transplantation in patients with advanced cardiac failure. AB - Despite many advances in the management of patients with heart failure, acute cardiogenic shock and progressive congestive heart failure remain serious problems with dismal prognoses. Both temporary and permanent mechanical support has been gaining wide clinical application in this patient population. Although mechanical circulatory support technology is rapidly evolving, this approach is associated with multiple issues such as the optimal duration of temporary support, ideal timing to bridge these patients to a long-term device, and selection of the right device for the right patient. The currently available devices are categorized into two major groups: temporary and long-term devices (including destination therapy). Heart failure is a dynamic condition, and the therapeutic approach may need to be modified depending on the patient's condition. Furthermore, the patient's preexisting morbidity, age, socioeconomic status, and family support are confounding factors that need to be considered when making such decisions. Clinical trials including prospective studies, as well as meticulous analysis of existing data, may help develop universal guidelines to select the right device. This manuscript will review the most widely used ventricular assist devices. PMID- 22814624 TI - Intravenous pyogenic granuloma of the right adrenal gland: report of a case. AB - Pyogenic granuloma (PG) is a tumor-like lesion that typically arises on human skin. Intravenous pyogenic granuloma (IVPG) is the vascular counterpart, mostly observed in the venous structures of the neck and upper extremities. Chronic irritation of the skin, traumatic injury, and hormonal alterations seem to be implicated in the pathogenesis of PG. The incidence of PG, and IVPG, is very low in the reported scientific literature, and this underlines the need for understanding unresolved questions concerning the uncommon presentation, and correct diagnosis before surgical intervention. This report describes a case of IVPG diagnosed in a 55-year-old female that presented for observation of chronic abdominal pain associated with nausea and anorexia. A well-defined mass located in the right adrenal gland was documented by ultrasonography and finally confirmed by contrast enhanced CT of the abdomen. There were no radiological signs of liver, kidney, or vascular infiltration. The 35 * 22 mm adrenal gland lesion, suspected to be an adrenal gland tumor, was resected using a minimally invasive approach. Laparoscopic right adrenalectomy was successfully performed. The histology documented the typical morphological features of IVPG in the context of a normal right adrenal gland. This report describes and discusses the unusual presentation of intraabdominal IVPG located in the adrenal gland region together with a review of the current literature. PMID- 22814625 TI - An automated microfluidic device for assessment of mammalian cell genetic stability. AB - Single-cell transcriptome contains reliable gene regulatory relationships because gene-gene interactions only happen within a mammalian cell. While the study of gene-gene interactions enables us to understand the molecular mechanism of cellular events and evaluate molecular characteristics of a mammalian cell population, its complexity requires an analysis of a large number of single-cells at various stages. However, many existing microfluidic platforms cannot process single-cells effectively for routine molecular analysis. To address these challenges, we develop an integrated system with individual controller for effective single-cell transcriptome analysis. In this paper, we report an integrated microfluidic approach to rapidly measure gene expression in individual cells for genetic stability assessment of a cell population. Inside this integrated microfluidic device, the cells are individually manipulated and isolated in an array using micro sieve structures, then transferred into different nanoliter reaction chambers for parallel processing of single-cell transcriptome analysis. This device enables us to manipulate individual single cells into nanoliter reactor with high recovery rate. We have performed gene expression analysis for a large number of HeLa cells and 293T cells expanded from a single-cell. Our data shows that even the house-keeping genes are expressed at heterogeneous levels within a clone of cells. The heterogeneity of actin expression reflects the genetic stability, and the expression distribution is different between cancer cells (HeLa) and immortalized 293T cells. The result demonstrates that this platform has the potential for assessment of genetic stability in cancer diagnosis. PMID- 22814626 TI - Segmental bioelectrical impedance analysis: an update. AB - PURPOSE OF REVIEW: Bioelectrical impedance analysis is a popular, noninvasive and practical method for assessment of body composition. The last decade has seen the development of impedance analyzers designed to assess the composition of body segments as well as the whole body. This review outlines the theoretical basis for segmental impedance analysis, validity and use in practice. RECENT FINDINGS: Segmental impedance analysis tends to underestimate fat-free mass and overestimate fat mass when compared to reference techniques, although the magnitude of these differences can be small. Performance is improved with population-specific prediction equations; algorithms in-built into instrument firmware should not be relied upon. Prediction of whole-body composition from the sum of the individual segments, although theoretically preferable, shows little advantage over whole body wrist to ankle impedance approaches. Prediction of appendicular skeletal muscle mass, although promising, requires further research. The use of measured impedance data directly as indices of composition, rather than for prediction, has not found extensive application in nutritional research despite its success in other fields. SUMMARY: Segmental bioimpedance techniques have advanced substantially in recent years due to availability of simple-to-use analyzers and simplified measurement protocols. The method has been well validated and increasingly adopted in nutritional and clinical practice. Segmental impedance, like conventional whole body impedance approaches, provides indirect prediction of body composition whose accuracy is yet to achieve that of reference techniques such as magnetic reference imaging. This lack of accuracy, however, is outweighed by the method's practicality of use in many settings. PMID- 22814627 TI - The anaerobic threshold: over-valued or under-utilized? A novel concept to enhance lipid optimization! AB - PURPOSE OF REVIEW: The purpose of this article is to assess the value of the anaerobic threshold for use in clinical populations with the intent to improve exercise adaptations and outcomes. The anaerobic threshold is generally poorly understood, improperly used, and poorly measured. It is rarely used in clinical settings and often reserved for athletic performance testing. RECENT FINDINGS: Increased exercise participation within both clinical and other less healthy populations has increased our attention to optimizing exercise outcomes. Of particular interest is the optimization of lipid metabolism during exercise in order to improve numerous conditions such as blood lipid profile, insulin sensitivity and secretion, and weight loss. Numerous authors report on the benefits of appropriate exercise intensity in optimizing outcomes even though regulation of intensity has proved difficult for many. Despite limited use, selected exercise physiology markers have considerable merit in exercise intensity regulation. The anaerobic threshold, and other markers such as heart rate, may well provide a simple and valuable mechanism for regulating exercising intensity. SUMMARY: The use of the anaerobic threshold and accurate target heart rate to regulate exercise intensity is a valuable approach that is under-utilized across populations. The measurement of the anaerobic threshold can be simplified to allow clients to use nonlaboratory measures, for example heart rate, in order to self-regulate exercise intensity and improve outcomes. PMID- 22814628 TI - Vitreous hemorrhage secondary to optociliary shunt vessels from papilledema. AB - A 15-year-old adolescent girl with idiopathic intracranial hypertension was noted to have papilledema and optociliary shunt vessels. Medical management was controlling her symptoms, but vision deteriorated rapidly in the left eye secondary to a vitreous hemorrhage. Given the lack of any other cause for vitreous hemorrhage, it most likely originated from the shunt vessels. Optic nerve sheath fenestration was performed in an effort to promote regression of the papilledema and the shunt vessels. Our case illustrates a rare complication of optociliary shunt vessels in the setting of papilledema. PMID- 22814629 TI - Metformin is synthetically lethal with glucose withdrawal in cancer cells. PMID- 22814630 TI - Conditional grandmother effects on age at marriage, age at first birth, and completed fertility of daughters and daughters-in-law in historical Krummhorn. AB - Based on historical data pertaining to the Krummhorn population (eighteenth and nineteenth centuries, Germany), we compared reproductive histories of mothers according to whether the maternal grandmother (MGM) or the paternal grandmother (PGM) or neither of them was resident in the parents' parish at the time of the mother's first birth. In contrast to effects of PGMs, we discovered conditional differences in the MGM's effects between landless people and wealthier, commercial farmers. Our data indicate that the presence of the MGM only lowers the woman's age at marriage (AAM) and her age at the birth of her first child (AFB) in the case of landless families. However, among commercial farmers, who can generally be characterized by a lower AAM and AFB, we found opposite tendencies for the MGM's effect leading to a relatively small delay in AAM and AFB. Moreover, we also analyzed differences in the completed fertility (i.e., children ever born: CEB). Results indicate that landless families in general do have fewer CEB compared with commercial farmers except for those families in which the MGM has been present. Emphasizing that the adaptiveness of investment decisions should depend on the interaction of genetic, lineage-specific (intrinsic) and ecologically imposed (extrinsic) constraints, we conclude that kin strategies consequently address different fitness components under different conditions. PMID- 22814631 TI - Implantable cardiovascular sensors and computers: interventional heart failure strategies. AB - Despite evidence-based medical and pharmacologic advances the management of heart failure remains challenging, whether in the ambulatory setting where daily weight monitoring has failed, or in the inpatient setting where readmission rates and morbidity remains high. There is an urgent need to develop strategies to reduce hospitalizations and readmission rates for heart failure in general. There may be a shift in the paradigm with respect to the treatment of heart failure, which may usher in an era of invasive heart failure therapies and specialists. Experimental invasive devices and monitors have the potential to be game-changing therapies, and cardiac resynchronization therapy has evolved beyond just resynchronization and has the potential to provide important real-time hemodynamic feedback. PMID- 22814633 TI - [Psychodynamic therapy of depression]. PMID- 22814634 TI - [Deep brain stimulation for movement disorders]. AB - In the last 25 years deep brain stimulation (DBS) has increased the therapeutic options as well as the pathophysiological understanding of movement disorders (MDS) to an unforeseen extent. This paper covers the state of the art of DBS treatment of Parkinson's disease, tremors, dystonia and other rare forms of MDS and gives an short overview of the mechanisms of action of DBS. PMID- 22814635 TI - [Weaning from prolonged mechanical ventilation in neurological weaning units: an evaluation of the German Working Group for early Neurorehabilitation]. AB - BACKGROUND: A significant proportion of patients with long-term mechanical ventilation (MV) and difficult or prolonged weaning suffer from primary or secondary neurological conditions and concomitant functional disorders, in addition to respiratory problems. Therefore, these patients are treated in neurological weaning departments. MATERIAL AND METHODS: Using a questionnaire members of the German Working Group for early neurorehabilitation were interviewed with respect to the structure of weaning facilities, weaning strategies, patient characteristics and treatment outcome of patients admitted for weaning in 2009. RESULTS: In the year 2009 a total of 1,486 patients were admitted to 7 participating neurological weaning units. The primary diagnosis was a neurological condition in 97.5% of the patients. In 62.9% of the patients the neurological condition was considered to be primarily responsible for the MV, 22.8% demonstrated pulmonary factors and for 3.0% a cardiac condition was determined to be decisive. In 5.0% of the patients it was not possible to ascertain a single cause or factor. Weaning was successful in 69.8% of all cases, 64.9% (965 patients) were released from the facility without MV, 274 patients (18.4%) were released with MV, 61.3% of these (168 patients) were referred to other rehabilitation facilities or into the care of the family physician and 38.7% (106 patients) were transferred to other hospitals due to special medical problems. The total mortality rate was 16.6% (247 patients deceased). CONCLUSIONS: In this first comprehensive evaluation of German neurological weaning centers for patients with long-term MV, structures and treatment outcomes were compared with recent results from the literature. PMID- 22814636 TI - Bioavailability of chromium(III)-supplements in rats and humans. AB - Chromium(III) is long regarded as essential trace element but the biochemical function and even basic transport ways in the body are still unclear. For a more rational discussion on beneficial as well as toxic effects of Cr(III), we re investigated the bioavailability of the most important oral Cr supplements by using radiolabeled compounds and whole-body-counting in rats and in the first time also in humans. The apparent absorption of (51)Cr(III) from Cr-picolinate, Cr-nicotinate, Cr-phenylalaninate, Cr-proprionate, or Cr-chloride was generally low (0.04-0.24 %) in rats with slightly higher values for Cr-chloride and phenylalaninate. Taking a fast urine excretion into account, the true absorption of (51)Cr was clearly higher for CrPic(3) (0.99 %), probably indicating a different uptake mechanism of this rather stable organic Cr complex. The bioavailability of CrPic(3) and Cr(D: -Phen)(3), the leading compounds in actual investigations, was analysed also in human volunteer by intraindividual comparison. The apparent absorption (=Cr bioavailability) of (51)Cr from both compounds was substantially higher in humans (0.8-1 %) than in rats. Again, most of freshly absorbed CrPic(3) was excreted into the urine resulting in the same low whole-body retention after 7 days for both compounds. In summary, the bioavailability of Cr from pharmaceutical Cr compound is lower than hitherto assumed. Importantly, humans absorb Cr(III) clearly better than rats. The absorption mechanism of CrPic(3) seems to be different from ionic Cr(III) but, as only the same low amount of Cr is retained from this compound, it is also not more bioavailable than other Cr compounds. PMID- 22814637 TI - A modular synthesis of dithiocarbamate pendant unnatural alpha-amino acids. AB - Unnatural alpha-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to produce the corresponding dithiocarbamate pendant alpha-amino acids in high yields. PMID- 22814638 TI - Polyoxometalate-decorated nanoparticles. AB - Polyoxometalate cluster anions (POMs) control formation and morphology, and serve as protecting ligands, for structurally and compositionally diverse nanostructures. While numerous examples of POM-protected metal(0) nanoparticle syntheses and reactions can now be found in the literature, the use of POMs to prepare nano-scale analogs of binary inorganic materials, such as metal-oxides, sulfides and halides, is a relatively recent development. The first part of this critical review summarizes the use of POMs as protecting ligands for metal(0) nanoparticles, as well as their use as templates for the preparation of new inorganic materials. Here, key findings that reveal general trends are given additional emphasis. In the second part of the review, new information concerning the structure of POM-protected metal(0) nanoparticles is systematically developed. This information, obtained by the combined use of cryogenic transmission microscopy (cryo-TEM) and UV-vis spectroscopy, provides a new perspective on the formation and structure of POM-decorated nanoparticles, and on the rational design of catalytic and other functional POM-based nano-assemblies. PMID- 22814640 TI - Regulation, re-evaluation, and regenerative approaches. PMID- 22814641 TI - The origin of tears. II. The mucinic component in the XIX and XX centuries. PMID- 22814639 TI - The mediating roles of stress and maladaptive behaviors on self-harm and suicide attempts among runaway and homeless youth. AB - Runaway and homeless youth often have a constellation of background behavioral, emotional, and familial problems that contribute to stress and maladaptive behaviors, which, in turn, can lead to self-harming and suicidal behaviors. The current study examined the roles of stress and maladaptive behaviors as mediators between demographic and psychosocial background characteristics and self injurious outcomes through the lens of the stress process paradigm. The model was tested in a sample of runaway and homeless youth from Los Angeles County (N = 474, age 12-24, 41 % female, 17 % White, 32.5 % African American, 21.5 % Hispanic/Latino). Background variables (gender, age, sexual minority status, parental drug use history, and emotional distress) predicted hypothesized mediators of maladaptive behaviors and recent stress. In turn, it was hypothesized that the mediators would predict self-harming behaviors and suicide attempts in the last 3 months. Females and LGBT (lesbian, gay, bisexual, transgender) youth were more likely to have self-harmed and attempted suicide; younger participants reported more self-harming. The mediating constructs were associated more highly with self-harming than suicide attempts bivariately, although differences were modest. Maladaptive behaviors and recent stress were significant predictors of self-harm, whereas only recent stress was a significant predictor of suicide attempts. All background factors were significant predictors of recent stress. Older age, a history of parental drug use, and greater emotional distress predicted problem drug use. Males, younger participants, and participants with emotional distress reported more delinquent behaviors. Significant indirect effects on self-harming behaviors were mediated through stress and maladaptive behaviors. The hypothesized paradigm was useful in explaining the associations among background factors and self-injurious outcomes and the influence of mediating factors on these associations. PMID- 22814642 TI - Nuclear Factor-kappaB: central regulator in ocular surface inflammation and diseases. AB - The nuclear factor-kappaB (NF-kappaB) is a key transcription factor pathway that is responsible for many key biological processes, such as inflammation, apoptosis, stress response, corneal wound healing, angiogenesis, and lymphangiogenesis. Numerous recent studies have investigated NF-kappaB in the context of ocular surface disorders, including chemical injury, ultraviolet radiation-induced injury, microbial infections, allergic eye diseases, dry eye, pterygium, and corneal graft rejection. The purpose this article is to summarize key findings with regard to the pathways regulating NF-kappaB and processes governed by the NF-kappaB pathway. In the innate defense system, NF-kappaB is involved in signaling from the toll-like receptors 2, 3, 4, 5 and 7, which are expressed in conjunctival, limbal, and corneal epithelial cells. These determine the ocular responses to infections, such as those caused by Pseudomonas aeruginosa, Staphylococcus aureus, adenovirus, and herpes simplex-1 virus. Natural angiogenic inhibitors enhance NF-kappaB, and this may occur through the mitogen-activated protein kinases and peroxisome proliferator-activated receptor gamma. In alkali injury, inhibition of NF-kappaB can reduce corneal angiogenesis, suggesting a possible therapeutic strategy. The evaluation of NF-kappaB inhibitors in diseases is also discussed, including emodin, besifloxacin, BOL 303242-X (mapracorat), thymosin-beta4, epigallocatechin gallate, Perilla frutescens leaf extract and IKKbeta-targeting short interfering RNA. PMID- 22814643 TI - Goblet cells of the normal human bulbar conjunctiva and their assessment by impression cytology sampling. AB - Goblet cells of the conjunctiva are the main source of mucus for the ocular surface. The objectives of this review are to consider the goblet cells as assessed by various histological, cytological and electron microscopy methods, and to assess the consistency of published reports (over more than 25 years) of goblet cell density (GCD) from impression cytology specimens from nominally healthy human subjects. Reported GCD values have been notably variable, with a range from 24 to 2226 cells/mm2 for average values. Data analysis suggests that a high density of goblet cells should be expected for the healthy human conjunctiva, with a tendency toward higher values in samples taken from normally covered locations (inferior and superior bulbar conjunctiva) of the open eye (at 973 +/- 789 cells/ mm2) than in samples taken from exposed (interpalpebral) locations (at 427 +/- 376 cells/mm2). No obvious change in GCD was found with respect to age, perhaps because the variability of the data did not allow detection of any age-related decline in GCD. Analyses of published data from 33 other sources indicated a trend for GCD to be lower than normal across a spectrum of ocular surface diseases. PMID- 22814644 TI - Regenerative approaches as alternatives to donor allografting for restoration of corneal function. AB - A range of alternatives to human donor tissue for corneal transplantation are being developed to address the shortfall of good quality tissues as well as the clinical conditions for which allografting is contraindicated. Classical keratoprostheses, commonly referred to as artificial corneas, are being used clinically to replace minimal corneal function. However, they are used only as last resorts, as they are associated with significant complications, such as extrusion/rejection, glaucoma, and retinal detachment. The past few years have seen significant developments in technologies designed to replace part or the full thickness of damaged or diseased corneas with materials that encourage regeneration to different extents. This review describes selected examples of these corneal substitutes, which range from cell-based regenerative strategies to keratoprostheses with regenerative capabilities via tissue-engineered scaffolds pre-seeded with stem cells. It is unlikely that one corneal substitute will be best for all indications, but taken together, the various approaches may soon be able to supplement the supply of human donor corneas for transplantation or allow restoration of diseased or damaged corneas that cannot be treated by currently available techniques. PMID- 22814646 TI - How should we display our data? What is the best number? PMID- 22814645 TI - Glycomic analysis of tear and saliva in ocular rosacea patients: the search for a biomarker. AB - The purpose of this study was to study changes in glycosylation in tear and saliva obtained from control and ocular rosacea patients in order to identify potential biomarkers for rosacea. Tear fluid was collected from 51 subjects (28 healthy controls and 23 patients with ocular rosacea). Saliva was collected from 42 of the same subjects (25 controls and 17 patients). Pooled and individual samples were examined to determine overall glycan profiles and individual variations in glycosylation. O-and N- glycans were released from both patients and control subjects. Released glycans were purified and enriched by solid-phase extraction (SPE) with graphitized carbon. Glycans were eluted based on glycan size and polarity. SPE fractions were then analyzed by high-resolution mass spectrometry. Glycan compositions were assigned by accurate masses. Their structures were further elucidated by tandem mass spectrometric using collision induced dissociation (CID), and specific linkage information was obtained by exoglycosidase digestion. N- and O-glycans were released from 20-MUL samples without protein identification, separation, and purification. Approximately 50 N glycans and 70 O-glycans were globally profiled by mass spectrometry. Most N glycans were highly fucosylated, while O-glycans were sulfated. Normal tear fluid and saliva contain highly fucosylated glycans. The numbers of sulfated glycans were dramatically increased in tear and saliva of rosacea patients compared to controls. Glycans found in tear and saliva from roseatic patients present highly quantitative similarity. The abundance of highly fucosylated N-glycans in the control samples and sulfated O-glycans in ocular rosacea patient samples may lead to the discovery of an objective diagnostic marker for the disease. PMID- 22814647 TI - Pathway based microarray analysis, utilising enzyme compounds and cascade events. AB - BACKGROUND: Pathway based microarray analysis is an effort to integrate microarray and pathway data in a holistic analytical approach, looking for coordinated changes in the expression of sets of genes forming pathways. However, it has been observed that the results produced are often cryptic, with cases of closely related genes in a pathway showing quite variable, even opposing expression. OBJECTIVES: We propose a methodology to identify the state of activation of individual pathways, based on our hypothesis that gene members of many pathways or modules exhibit differential expression that results from their contribution to any combination of all their constituent pathways. Therefore, the observed expression of such a gene does not necessarily imply the activation state of a given pathway where its product participates, but reflects the net expression resulting from its participation in all its constituent pathways. METHODS: Firstly, in an effort to validate the hypothesis, we split the genes into two groups; single and multi-membership. We then determined and compared the proportion of differentially expressed genes in each group, for each experiment. In addition, we estimated the cumulative binomial probability of observing as many or more expressed genes in each group, in each experiment, simply by chance. Second, we propose a hill climbing methodology, aiming to maximise the agreement of gene expression per module. RESULTS: We detected more frequent expression of multi-membership genes and significantly lower probabilities of observing such a high proportion of differentially expressed multi-membership genes, as the one present in the dataset. The algorithm was able to correctly identify the state of activation of the KEGG glycolysis and gluconeogenesis modules, using a number of Saccharomyces cerevisiae datasets. We show that the result is equivalent to the best solution found following exhaustive search. CONCLUSIONS: The proposed method takes into account the multi-membership nature of genes and our knowledge of the competitive nature of our exemplar modules, revealing the state of activity of a pathway. PMID- 22814648 TI - Robotic implantation of deep brain stimulation leads, assisted by intra operative, flat-panel CT. AB - BACKGROUND: There are two mandatory skills in deep brain stimulation (DBS) neurosurgery: accuracy and control. METHOD: Frame-based robotic registration was performed. Prior to insertion into the skull, the guide tube's position was checked with flat-panel computed tomography (fpCT). After registration against the pre-operative plan, we measured and corrected the robotic arm's position so that the guide tube with the micro-electrode would follow the planned trajectory exactly. We then used fpCT again to check the DBS lead's final position. CONCLUSION: The combination of intra-operative fpCT with robotised surgery provides an appropriate, user-friendly solution to the key technical challenges in DBS lead implantation. PMID- 22814649 TI - Systematic comparison of tissue fixation with alternative fixatives to conventional tissue fixation with buffered formalin in a xenograft-based model. AB - In our study we systematically compared the alternative fixatives acidified formal alcohol (AFA), PAXgene(r), HOPE(r), and combinations of AFA or formalin with ultrasound treatment to standard (buffered) formalin fixation. We examined general morphology and detectability of protein structures by immunohistochemistry of the membrane receptors epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF-1R), and phosphorylated human epidermal growth factor receptor 2 (phospho-HER2). In order to allow for stringent comparability of different fixation techniques, we used matched mouse xenograft tumor samples from three different human cancer cell lines (colon, ovarian, and non-small cell lung cancer), either fixed conventionally with formalin or an alternative fixative. Tissue morphology after fixation with AFA and PAXgene(r) was comparable to formalin-fixed paraffin-embedded tissue (FFPET) morphology. Ultrasound fixations resulted in slightly inferior morphology and HOPE(r) fixation preserved morphology only poorly compared to FFPET in this system. None of the tested alternative fixatives enabled immunohistochemical detectability of all three targets in the same manner as FFPET. Pronounced staining was possible for EGFR and IGF-1R with all alternative fixatives but HOPE(r), and phospho-HER2 staining was only noteworthy with formalin-ultrasound fixed tissue. Therefore, the use of alternative fixatives comes with the need for careful validation of obtained IHC results individually for each target. PMID- 22814650 TI - Inhibitory antibodies in hemophilia A. AB - PURPOSE OF REVIEW: The review describes recent advances in our understanding of mechanisms leading to development of neutralizing antibodies following factor VIII (FVIII) replacement therapy for hemophilia A. Novel interventions with translational potential to lessen the incidence of these deleterious immune responses are discussed. RECENT FINDINGS: Genetic and environmental risk factors for inhibitor development, and cellular mechanisms leading to antibody production versus immune tolerance to FVIII, are increasingly coming into focus. Human and animal model studies are identifying T-cell and B-cell epitopes in FVIII and characterizing the presentation of naturally processed FVIII peptides on antigen presenting cells (APCs). Novel methods to promote immune tolerance include decreasing FVIII uptake by APCs, modifying co-stimulatory pathways, inducing regulatory T-cell production, and presenting FVIII antigen to immature dendritic cells in a tolerance-promoting manner. A complementary approach to reduce inhibitor incidence is the design of less immunogenic FVIII proteins through epitope modification. SUMMARY: Studies of FVIII immunogenicity are revealing mechanisms of anti-FVIII immune responses, suggesting new approaches to reduce the incidence of inhibitors. Rational design of FVIII variants is producing less immunogenic proteins targeted to specific patient sub-populations. Future therapies will likely involve administration of less immunogenic FVIII proteins under conditions that promote immune tolerance. PMID- 22814651 TI - Platelet mRNA: the meaning behind the message. AB - PURPOSE OF REVIEW: It is now well appreciated that megakaryocytes invest platelets with a diverse repertoire of messenger RNAs (mRNAs), which are competent for translation. Herein we describe what is currently known regarding the expression, function, and clinical significance of mRNAs in platelets. RECENT FINDINGS: Although mRNA was detected in platelets nearly 30 years ago, we are only beginning to understand the roles of mRNA in platelet biology and human disease. Recent studies have shown that megakaryocytes specifically sort, rather than randomly transfer, mRNA to platelets during thrombopoiesis. As a result, platelets are released into the circulation with thousands of mRNAs. The emergence of next-generation RNA sequencing has demonstrated that platelet mRNAs possess classic structural features, which include untranslated regions and open reading frames. There is also growing evidence that platelet mRNA expression patterns are altered in human disease. SUMMARY: Intense investigation of platelet mRNA has shed considerable light on predicted functions of platelets and identified previously unrecognized attributes of platelets. Lessons learned from platelet mRNA is presented in this review. PMID- 22814652 TI - Value of chiropractic services at an on-site health center. AB - OBJECTIVE: Chiropractic care offered at an on-site health center could reduce the economic and clinical burden of musculoskeletal conditions. METHODS: A retrospective claims analysis and clinical evaluation were performed to assess the influence of on-site chiropractic services on health care utilization and outcomes. RESULTS: Patients treated off-site were significantly more likely to have physical therapy (P < 0.0001) and outpatient visits (P < 0.0001). In addition, the average total number of health care visits, radiology procedures, and musculoskeletal medication use per patient with each event were significantly higher for the off-site group (all P < 0.0001). Last, headache, neck pain, and low back pain-functional status improved significantly (all P < 0.0001). CONCLUSIONS: These results suggest that chiropractic services offered at on-site health centers may promote lower utilization of certain health care services, while improving musculoskeletal function. PMID- 22814654 TI - Rare diseases: the bane of modern society and the quest for cures. AB - The enormous progress in the development of drugs for rare diseases may be attributed to advances in genomic technology, molecular profiling, improved target and biomarker selection, an improved understanding of the natural history and pathophysiology of several orphan diseases, use of integrated quantitative analysis techniques in drug development, and a favorable regulatory climate, but major challenges still remain. Most rare diseases manifest during childhood; about 30% of affected children die before their fifth birthday, and the health and economic burden on survivors can be tremendous. PMID- 22814657 TI - The future of orphan drug development. PMID- 22814658 TI - The current state of therapeutic drug trials in pregnancy. AB - The majority of pregnant women take prescription drugs during their pregnancy. Given the multitude of physiologic changes incumbent in pregnancy, accurate clinical trial data on drugs in pregnancy are crucial. This report summarizes the 264 registered clinical trials in the past two years. With many of these drug trials being pharmacokinetic and placebo-controlled studies, therapeutic drug trials are becoming more common. PMID- 22814659 TI - The challenges of orphan drugs and orphan diseases: real and imagined. AB - The Orphan Drug Act of 1983 in the United States and similar legislation in Europe in 1999 provided incentives for companies to develop and sell medicines for diseases with a small market. In this Commentary, we outline the European position on the regulation of orphan drugs and explain where it differs from the regulation in the United States. PMID- 22814660 TI - Ethical considerations in orphan drug approval and use. AB - The Orphan Drug Act seeks to meet a utilitarian goal of advancing therapeutic options for patients with rare diseases. However, data show that orphan drugs are often approved with more limited premarket testing than that carried out for nonorphan drugs and consequently expose patients to more risk and less certain efficacy. Therefore, the ethical principles of justice and beneficence may require attention to informed consent among patients receiving the drugs and greater investment in postmarket surveillance and confirmational testing. PMID- 22814661 TI - Modeling helps in understanding antidepressants. AB - The clinical pharmacology of antidepressant drugs is challenging to describe because of difficulties in describing the depressed state, the time course of response to a treatment intervention, and the frequent withdrawal of patients from clinical trials. Many of these challenges were addressed in a recent article by Russu et al. in this journal. PMID- 22814662 TI - Increased gray matter volume in the right angular and posterior parahippocampal gyri in loving-kindness meditators. AB - Previous voxel-based morphometry (VBM) studies have revealed that meditation is associated with structural brain changes in regions underlying cognitive processes that are required for attention or mindfulness during meditation. This VBM study examined brain changes related to the practice of an emotion-oriented meditation: loving-kindness meditation (LKM). A 3 T magnetic resonance imaging (MRI) scanner captured images of the brain structures of 25 men, 10 of whom had practiced LKM in the Theravada tradition for at least 5 years. Compared with novices, more gray matter volume was detected in the right angular and posterior parahippocampal gyri in LKM experts. The right angular gyrus has not been previously reported to have structural differences associated with meditation, and its specific role in mind and cognitive empathy theory suggests the uniqueness of this finding for LKM practice. These regions are important for affective regulation associated with empathic response, anxiety and mood. At the same time, gray matter volume in the left temporal lobe in the LKM experts appeared to be greater, an observation that has also been reported in previous MRI meditation studies on meditation styles other than LKM. Overall, the findings of our study suggest that experience in LKM may influence brain structures associated with affective regulation. PMID- 22814663 TI - Identification of the spinal pathways involved in the recovery of baroreflex control after spinal lesion in the rat using pseudorabies virus. AB - Neurons in the rostroventrolateral medulla (RVLM) mediate baroreflex regulation (BR) of spinal sympathetic preganglionic neurons. Previously, our laboratory has shown that recovery of BR occurs in the rat after spinal hemisection. (Zahner MR, Kulikowicz E, and Schramm LP. Am J Physiol Regul Integr Comp Physiol 301: R1584 R1590, 2011). The goal of these experiments was to determine whether the observed recovery of BR is mediated by the reorganization of ipsilateral pathways or by compensation by spared contralateral pathways. To determine this, we infected the left kidney in rats with the retrograde transynaptic tracer, pseudorabies virus (PRV), either 1 or 8 wk after left spinal hemisection at either T(3) or T(8), or after a sham lesion. In sham-lesioned rats, PRV infection of RVLM neurons was bilateral. In all rats with a left hemisection, regardless of the location of the lesion (T(3) or T(8)) or postlesion recovery time (1 or 8 wk), PRV infection of left RVLM neurons was significantly reduced compared with sham-lesioned rats (P < 0.05). In a separate group of rats, we performed BR tests by measuring responses of left renal sympathetic nerve activity to pharmacologically induced decreases and increases in arterial pressure. In rats with T(8) left hemisection and 8-wk recovery, BR was robust, and acute right upper thoracic hemisection abolished all BR of left renal sympathetic nerve activity. Collectively, these data suggest that the recovery of BR is not mediated by reorganization of ipsilateral bulbospinal connections, but instead by improved efficacy of existing contralateral pathways. PMID- 22814664 TI - Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule. AB - To elucidate the role of the insulin receptor (IR) on kidney nitric oxide generation and blood pressure (BP) control, we generated mice with targeted deletion of renal tubule IR using loxP recombination driven by a Ksp-cadherin promoter. Male knockout (KO) and wild-type (WT) littermates (~4 mo old) were transitioned through three 1-wk treatments: 1) low-NaCl diet (0.085%); 2) high NaCl diet (HS; 5%); and 3) HS diet plus 3 mM tempol, a superoxide dismutase mimetic, in the drinking water. Mice were then switched to medium-NaCl (0.5%) diet for 5 days and kidneys harvested under pentobarbital anesthesia. Twenty-four hour urinary nitrates plus nitrites were significantly higher in the WT mice under HS (2,067 +/- 280 vs. 1,550 +/- 230 nmol/day in WT and KO, respectively, P < 0.05). Tempol attenuated genotype differences in urinary nitrates plus nitrites. A rise in BP with HS was observed only in KO mice and not affected by tempol (mean arterial pressure, dark period, HS, 106 +/- 5 vs. 119 +/- 4 mmHg, for WT and KO, respectively, P < 0.05). Renal outer medullary protein levels of nitric oxide synthase (NOS) isoforms by Western blot (NOS1-3 and phosphorylated S1177-NOS3) revealed significantly lower band density for NOS1 (130-kDa isoform) in the KO mice. A second study, when mice were euthanized under HS conditions, confirmed significantly lower NOS1 (130 kDa) in the KO, with an even more substantial (>50%) reduction of the 160-kDa NOS1 isoform. These studies suggest that the loss of renal IR signaling impairs renal nitric oxide production. This may be important in BP control, especially in insulin-resistant states, such as the metabolic syndrome. PMID- 22814666 TI - Intrathecal melanin-concentrating hormone reduces sympathetic tone and blocks cardiovascular reflexes. AB - Melanin-concentrating hormone (MCH) is a neuropeptide that acts to increase feeding behavior and decrease energy expenditure. The role of MCH in central cardiorespiratory regulation is still poorly understood. Experiments were conducted on urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats (n = 22) to ascertain whether MCH modulates sympathetic vasomotor tone, as well as barosympathetic, chemosympathetic, and somatosympathetic reflexes at the level of the spinal cord. Intrathecal injection of 10 MUl of MCH produced a dose-dependent hypotension, bradycardia, and sympathoinhibition. Peak response was observed following administration of 1 mM MCH, causing a decrease in mean arterial pressure of 39 +/- 2 mmHg (P < 0.001), splanchnic sympathetic nerve activity of 78 +/- 11% (P < 0.001), and heart rate of 87 +/- 11 beats per minute (bpm) (P < 0.01). The two peaks of the somatosympathetic reflex were decreased by intrathecal MCH, 7 +/- 3% (P < 0.01) and 31 +/- 6% (P < 0.01), respectively, and the spinal component of the reflex was accentuated 96 +/- 23% (P < 0.05), with respect to the baseline for MCH, compared with the two peaks and spinal component of the somatosympathetic reflex elicited following saline injection with respect to the baseline for saline. MCH decreased the sympathetic gain to 120 s of hyperoxic hypercapnea (10% CO(2) in 90% O(2)) and to 10-12 s poikilocapneic anoxia (100% N(2)) from 0.74 +/- 0.14%/s to 0.23 +/- 0.04%/s (P < 0.05) and 16.47 +/- 3.2% to 4.35 +/- 1.56% (P < 0.05), respectively. There was a 34% decrease in gain and a 62% decrease in range of the sympathetic baroreflex with intrathecal MCH. These data demonstrate that spinal MCH blunts the central regulation of sympathetic tone and adaptive sympathetic reflexes. PMID- 22814665 TI - Activation of NTS A(1) adenosine receptors inhibits regional sympathetic responses evoked by activation of cardiopulmonary chemoreflex. AB - Previously we have shown that adenosine operating via the A(1) receptor subtype may inhibit glutamatergic transmission in the baroreflex arc within the nucleus of the solitary tract (NTS) and differentially increase renal (RSNA), preganglionic adrenal (pre-ASNA), and lumbar (LSNA) sympathetic nerve activity (ASNA>RSNA>=LSNA). Since the cardiopulmonary chemoreflex and the arterial baroreflex are mediated via similar medullary pathways, and glutamate is a primary transmitter in both pathways, it is likely that adenosine operating via A(1) receptors in the NTS may differentially inhibit regional sympathetic responses evoked by activation of cardiopulmonary chemoreceptors. Therefore, in urethane-chloralose-anesthetized rats (n = 37) we compared regional sympathoinhibition evoked by the cardiopulmonary chemoreflex (activated with right atrial injections of serotonin 5HT(3) receptor agonist phenylbiguanide, PBG, 1-8 MUg/kg) before and after selective stimulation of NTS A(1) adenosine receptors [microinjections of N(6)-cyclopentyl adenosine (CPA), 0.033-330 pmol/50 nl]. Activation of cardiopulmonary chemoreceptors evoked differential, dose dependent sympathoinhibition (RSNA>ASNA>LSNA), and decreases in arterial pressure and heart rate. These differential sympathetic responses were uniformly attenuated in dose-dependent manner by microinjections of CPA into the NTS. Volume control (n = 11) and blockade of adenosine receptor subtypes in the NTS via 8-(p-sulfophenyl)theophylline (8-SPT, 1 nmol in 100 nl) (n = 9) did not affect the reflex responses. We conclude that activation of NTS A(1) adenosine receptors uniformly inhibits neural and cardiovascular cardiopulmonary chemoreflex responses. A(1) adenosine receptors have no tonic modulatory effect on this reflex under normal conditions. However, when adenosine is released into the NTS (i.e., during stress or severe hypotension/ischemia), it may serve as negative feedback regulator for depressor and sympathoinhibitory reflexes integrated in the NTS. PMID- 22814668 TI - Synchronized activation of sympathetic vasomotor, cardiac, and respiratory outputs by neurons in the midbrain colliculi. AB - The superior and inferior colliculi are believed to generate immediate and highly coordinated defensive behavioral responses to threatening visual and auditory stimuli. Activation of neurons in the superior and inferior colliculi have been shown to evoke increases in cardiovascular and respiratory activity, which may be components of more generalized stereotyped behavioral responses. In this study, we examined the possibility that there are "command neurons" within the colliculi that can simultaneously drive sympathetic and respiratory outputs. In anesthetized rats, microinjections of bicuculline (a GABA(A) receptor antagonist) into sites within a circumscribed region in the deep layers of the superior colliculus and in the central and external nuclei of the inferior colliculus evoked a response characterized by intense and highly synchronized bursts of renal sympathetic nerve activity (RSNA) and phrenic nerve activity (PNA). Each burst of RSNA had a duration of ~300-400 ms and occurred slightly later (peak to peak latency of 41 +/- 8 ms) than the corresponding burst of PNA. The bursts of RSNA and PNA were also accompanied by transient increases in arterial pressure and, in most cases, heart rate. Synchronized bursts of RSNA and PNA were also evoked after neuromuscular blockade, artificial ventilation, and vagotomy and so were not dependent on afferent feedback from the lungs. We propose that the synchronized sympathetic-respiratory responses are driven by a common population of neurons, which may normally be activated by an acute threatening stimulus. PMID- 22814667 TI - Placental and vascular adaptations to exercise training before and during pregnancy in the rat. AB - Although exercise during pregnancy is generally recommended and thought to be beneficial to mother and fetus, the nature of the adaptations to exercise during pregnancy and how they may be beneficial remain poorly understood. Recent studies suggest that exercise may stimulate expression of several cytoprotective and pro angiogenic molecules such as heat shock proteins (HSP) and vascular endothelial growth factors (VEGF). We hypothesized that exercise training during pregnancy improves angiogenic balance, increases HSP expression, and improves endothelial function. Female rats were given access to an exercise wheel for 6 wk before and during pregnancy. On day 19 of pregnancy tissues were collected and snap frozen for later analysis. Western blots were performed in skeletal muscle and placenta. HSP 27 (3.7 +/- 0.36 vs. 2.2 +/- 0.38; P < 0.05), HSP 60 (2.2 +/- 0.73 vs. 0.49 +/- 0.08; P < 0.05), and HSP 90 (0.33 +/- 0.09 vs. 0.11 +/- 0.02; P < 0.05) were increased in the placentas of exercise-trained rats compared with sedentary controls. In addition, exercise training increased (P < 0.05) plasma free VEGF and augmented (P < 0.05) endothelium-dependent vascular relaxation compared with nonexercise control rats. The present data indicates chronic exercise training stimulates HSP expression in the placenta and that regular exercise training increases circulating VEGF in pregnant but not in nonpregnant rats. Although the present findings suggest that exercise before and during pregnancy may promote the expression of molecules that could attenuate placental and vascular dysfunction in complicated pregnancies, further studies are needed to determine the safety and effectiveness of exercise training as a therapeutic modality in pregnancy. PMID- 22814669 TI - Glucose oxidation and nonoxidative glucose disposal during prolonged fasts of the northern elephant seal pup (Mirounga angustirostris). AB - Elephant seal weanlings demonstrate rates of endogenous glucose production (EGP) during protracted fasts that are higher than predicted on the basis of mass and time fasting. To determine the nonoxidative and oxidative fate of endogenously synthesized glucose, substrate oxidation, metabolic rate, glycolysis, and EGP were measured in fasting weanlings. Eight weanlings were sampled at 14 days of fasting, and a separate group of nine weanlings was sampled at 49 days of fasting. Metabolic rate was determined via flow-through respirometry, and substrate-specific oxidation was determined from the respiratory quotient and urinary nitrogen measurements. The rate of glucose disposal (Glu((R)(d))) was determined through a primed, constant infusion of [3-(3)H]glucose, and glycolysis was determined from the rate of appearance of (3)H in the body water pool. Glu((R)(d)) was 1.41 +/- 0.27 and 0.95 +/- 0.21 mmol/min in the early and late fasting groups, respectively. Nearly all EGP went through glycolysis, but the percentage of Glu((R)(d)) oxidized to meet the daily metabolic demand was only 24.1 +/- 4.4% and 16.7 +/- 5.9% between the early and late fasting groups. Glucose oxidation was consistently less than 10% of the metabolic rate in both groups. This suggests that high rates of EGP do not support substrate provisions for glucose-demanding tissues. It is hypothesized that rates of EGP may be ancillary to the upregulation of the tricarboxylic acid cycle to meet high rates of lipid oxidation while mitigating ketosis. PMID- 22814671 TI - Differential regulation of sympathetic burst frequency and amplitude following acute hypoxia in humans. AB - Current evidence suggests that the persistent sympathetic nerve activity (SNA), commonly observed after exposure to hypoxia (HX), is mediated by chemoreceptor sensitization and or baroreflex resetting. Evidence in humans and animals suggests that these reflexes may independently regulate the frequency (gating) and amplitude (neuronal recruitment) of SNA bursts. In humans (n = 7), we examined the regulation of SNA following acute isocapnic HX (5 min; end-tidal P(O2) = 45 Torr) and euoxic hypercapnia (HC; 5 min; end-tidal P(CO2) = +10 from baseline). HX increased SNA burst frequency (21 +/- 7 to 28 +/- 8 bursts/min, P < 0.05) and amplitude (99 +/- 10 to 125 +/- 19 au, P < 0.05) as did HC (14 +/- 6 to 22 +/- 10 bursts/min, P < 0.05 and 100 +/- 12 to 133 +/- 29 au, P < 0.05, respectively). Burst frequency (26 +/- 7 bursts/min, P < 0.05), but not amplitude (97 +/- 12 au), remained elevated 10 min post-HX. The change in burst amplitude (but not frequency) was significantly related to the measured change in ventilation (r(2) = 0.527, P < 0.001). Both frequency and amplitude decreased during recovery following HC. These data indicate the differential regulation of pattern and magnitude of sympathetic outflow in humans with sympathetic persistence following HX being specific to burst frequency and not amplitude. PMID- 22814670 TI - CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis. AB - Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2- to 3-fold, CCL8 by 15-fold, CCL12 by 12- to 13-fold, and CXCL9 by 2- to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1- to 2-fold), CCL3 (2- to 3-fold) and CCL11 (2- to 3-fold); and at 30 days, CCL12 (20- to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4+ T cells at day 20, and CD4+ and CD8+ T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2- and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP. PMID- 22814672 TI - Editorial focus: oxygen sensors and mediators of the contractile responses of smooth muscle to hypoxia. Focus on: "Hydrogen sulfide mediates hypoxic vasoconstriction through a production of mitochondrial ROS in trout gills". PMID- 22814673 TI - Fusion and sorting of two parallel trains of droplets using a railroad-like channel network and guiding tracks. AB - We propose a robust droplet fusion and sorting method for two parallel trains of droplets that is relatively insensitive to frequency and phase mismatch. Conventional methods of droplet fusion require an extremely precise control of aqueous/oil flows for perfect frequency matching between two trains of droplets. In this work, by combining our previous two methods (i.e., droplet synchronization using railroad-like channels and manipulation of shape-dependent droplets using guiding tracks), we realized an error-free droplet fusion/sorting device for the two parallel trains of droplets. If droplet pairs are synchronized through a railroad-like channel, they are electrically fused and the fused droplets transit to a middle guiding track to flow in a middle channel; otherwise non-synchronized non-fused droplets will be discarded into the side waste channels by flowing through their own guiding tracks. The simple droplet synchronization, fusion, and sorting technology will have widespread application in droplet-based chemical or biological experiments, where two trains of the chemically or biologically treated or pre-formed droplets yield a train of 100% one-to-one fused droplets at the desired outlet channel by sorting all the non synchronized non-fused droplets into waste outlets. PMID- 22814674 TI - Operative treatment of chondral defects in the hip joint: a systematic review. AB - Young patients with cartilage defects in the hip present a complex problem for the treating physician with limited treatment modalities available. Cartilage repair/replacement techniques have shown promising results in other joints, however, the literature regarding the hip joint is limited. The purpose of the current study is to conduct a systematic review of clinical outcomes following various treatments for chondral lesions of the hip and define the techniques for the treatment of these cartilage defects. The full manuscripts of 15 studies were reviewed for this systematic review including case studies, case series, and clinical studies. A variety of techniques have been reported for the treatment of symptomatic chondral lesions in the hip. Microfracture, cartilage repair, autologous chondrocyte implantation, mosaicplasty, and osteochondral allografting have all been used in very limited case series. Although good results have been reported, most studies lack both a control group and a large number of patients. However, the reported results in this article do provide a good foundation for treatments and stimulant for further study in an inherently difficult to treat young patient population with articular cartilage defects in the hip. PMID- 22814675 TI - Micellar interpolyelectrolyte complexes. AB - Interpolyelectrolyte complexes (IPECs) are typically formed when two polyelectrolytes of opposite charge are mixed together in solution. We present an overview of different strategies for the preparation of micellar IPECs, i.e., structures where such IPEC domains form the core or the shell of micelles. In addition, vesicular architectures are considered, where the IPEC domain forms a membrane layer. One intriguing feature of IPECs is that their formation can be directed, their stability towards changes in pH or ionic strength can (to a certain extent) be predicted, and their size can be controlled. Especially the use of ionic/non-ionic block copolymers offers unique potential for the preparation of well-defined and sophisticated nanostructured materials. We also discuss possible applications, especially in the field of life sciences, including biocompatibility, the controlled uptake/release of guest substances, the immobilization of enzymes, or the controlled formation of inorganic/organic hybrid materials. PMID- 22814677 TI - Anti-proliferative effect of 23,24-dihydrocucurbitacin F on human prostate cancer cells through induction of actin aggregation and cofilin-actin rod formation. AB - PURPOSE: The cucurbitacins are a class of triterpenoid molecules that possess cytotoxic characteristics for plant defense against herbivore feeding. 23,24 dihydrocucurbitacin F (DHCF), a derivative of the cucurbitacin family, has been isolated as an active component from the root of Hemsleya amabilis (Cucurbitaceae), an ancient Chinese remedy for bacillary dysentery, gastroenteritis, and cancers. While the toxicity of other cucurbitacins has been explored in several cancers, little data exist on the effect of DHCF on human cancers, including prostate cancer (PCa). In this study, we explore the level and mechanisms of DHCF toxicity on human PCa cell lines. METHODS: Human PCa DU145, PC3, and LNCaP cells were treated with graded doses of DHCF in vitro, and anti proliferative, cytotoxic, and proteomic effects were determined using MTS assay, cell cycle analysis, immunofluorescent staining, and western blotting. RESULTS: DHCF inhibited cell growth and induced cell cycle arrest at G(2)/M phase, formation of binucleated cells, and increased levels of apoptosis in all PCa cell lines tested. G-actin depletion, actin aggregation, and rod-like actin fibers, with little effect on microtubule structure, were observed after DHCF treatment. Actin aggregation and cofilin-actin rod formation were highly correlated with rapid and persistent dephosphorylation of cofilin-1 (cofilin). DHCF treatment resulted in upregulation of p21(Cip1) and downregulation of cyclin A in all three PCa cell lines. CONCLUSIONS: The anti-proliferative activity of DHCF on human PCa cells may be brought about by inducing actin aggregation and cofilin-actin rod formation, leading to cell cycle arrest, cytokinesis failure, and apoptosis. PMID- 22814676 TI - Adipose tissue, hormones, and treatment of type 1 diabetes. AB - Type 1 diabetes (T1D) is a serious disease with increasing incidence worldwide, with fatal consequences if untreated. Traditional therapies require direct or indirect insulin replacement, which involves numerous limitations and complications. While insulin is the major regulator of blood glucose, recent reports demonstrate the ability of several extra-pancreatic hormones to decrease blood glucose and improve metabolic homeostasis. Such hormones mainly include adipokines originating from adipose tissue (AT), while specific factors from the gut and liver also contribute to glucose homeostasis. Correction of T1D with adipokines is progressively becoming a realistic option, with the potential to overcome many problems associated with insulin replacement. Several recent studies demonstrate insulin-independent reversal or amelioration of T1D through administration of specific adipokines. Our recent work demonstrates the ability of healthy AT to compensate for the function of endocrine pancreas in long-term correction of T1D. This review discusses the potential of AT-related therapies for T1D as viable alternatives to insulin replacement. PMID- 22814678 TI - Barbigerone, an isoflavone, inhibits tumor angiogenesis and human non-small-cell lung cancer xenografts growth through VEGFR2 signaling pathways. AB - PURPOSE: We previously reported that barbigerone (BA), an isoflavone isolated from Suberect Spatholobus, exhibited inhibitory effects on proliferation of many cancer cell lines in vitro. The objective of this study was to explore whether BA could effectively suppress tumor angiogenesis and tumor growth. METHODS: Zebrafish model and Matrigel assay were performed to access the anti-angiogenesis effects of BA. A549 and SPC-A1 tumor xenografts in mice models were used to examine the antitumor activity of BA. The anti-angiogenic effects and underlying mechanisms were also investigated using human umbilical vein endothelial cells (HUVECs) and A549 cells. RESULTS: In zebrafish model, 2.5 MUmol/L of BA significantly inhibited angiogenesis. Intravenous administration of BA effectively inhibited the tumor growth of A549 and SPC-A1 xenograft models in mice. The anti-angiogenic effect was indicated by CD31 immunohistochemical staining, Matrigel plug assay, and mouse aortic ring assay. BA could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and capillary-like tuber formation of HUVECs in a dose-dependent manner, suggesting that BA inhibited tumorigenesis by targeting angiogenesis. Western blots revealed that BA directly inhibited the phosphorylation of VEGFR2, followed by inhibiting the activations of its downstream protein kinases, including ERK, p38, FAK, AKT, and expression of iNOS, but had no effect on COX2. Additionally, BA could also down-regulate VEGF secretion in A549 cancer cells, which may correlate with the suppression of ERK, AKT activation, indicating that BA inhibits tumor angiogenesis and tumor growth through VEGFR2 signaling pathways. CONCLUSIONS: These findings suggest that BA may be a novel candidate in inhibiting tumor angiogenesis and NSCLC tumor growth. PMID- 22814681 TI - An innovative approach to the treatment of Gaucher disease and possibly other metabolic disorders of the brain. AB - The extraordinary benefit of enzyme replacement therapy (ERT) on the systemic manifestations of Gaucher disease was demonstrated in 1991. Since that time, investigators have devoted substantial effort to improve the delivery of enzymes to the brain because many hereditary metabolic disorders are characterized by extensive central nervous system involvement. Because the required supplemental enzyme is too large to cross the blood-brain barrier (BBB), ERT for central nervous system involvement was out of the question at that time. Several innovative strategies that have been reported to overcome this impediment are discussed. Recent investigations have provided additional insight concerning the pathogenesis of enzyme deficiency disorders. For many years it was presumed that alterations of the amino acid sequence of enzymes such as glucocerebrosidase reduced the catalytic activity of the enzyme. It has recently been shown that the decrease of glucocerebrosidase activity was the result of a quantitative loss of the amount of this enzyme. Significant increases of its activity were obtained with small molecule inhibitors of histone deacetylase that cross the BBB. The effect of such materials on neuronopathic Gaucher disease and other CNS metabolic disorders is discussed. PMID- 22814682 TI - Synthesis of selenium nano-composite (t-Se@PS) by surface initiated atom transfer radical polymerization. AB - Selenium nanostructures, which are otherwise susceptible to oxidative damage, were encapsulated with a thin layer of polystyrene. The thin layer of polystyrene was grafted onto the surfaces of selenium by a surface initiated atom transfer radical polymerization reaction. These encapsulated nanostructures demonstrate an enhanced resistance towards corrosion. PMID- 22814679 TI - Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases. AB - We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to alpha/beta-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to alpha/beta- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins. PMID- 22814683 TI - High risk of malignant mesothelioma and pleural plaques in subjects born close to ophiolites. AB - BACKGROUND: Ophiolites, a special sequence of geologic rock units, are known sources of naturally occurring asbestos. The aim of this study was to test whether the occurrence of malignant mesothelioma (MM) or pleural plaques (PPs) in the province of Sivas, Turkey, is determined by the proximity of the patient's birthplace to ophiolites and, if so, to establish the magnitude of the risk. METHODS: The birthplaces of patients with MM or PPs (cases) and patients with prostate or breast cancer (control subjects), diagnosed between 2000 and 2010 and identified through a mandatory cancer registry or from hospital records (PPs), were located on a geologic map, and the nearest distance to ophiolites was measured. The relation of MM or PPs with distance to ophiolites was analyzed by logistic regression. Samples of soil and house plaster were determined by x-ray diffraction. RESULTS: Patients with MM (n = 100) or PPs (n = 133) were born significantly nearer to ophiolites (median distance, 4.5 km for men, 0 km for women) than were patients with prostate cancer (n = 161) or breast cancer (n = 139) (median distance, 20 km for both). ORs were 1.6 (men) ( P < .001) and 2.0 (women) ( P < .001) for every 5-km decrease in the distance of birthplace to ophiolites for MM, compared with prostate and breast cancer, respectively. CONCLUSION: In this area without substantial industrial asbestos use, there is an association between the occurrence of mesothelioma (and of PPs) and the proximity of the subject's birthplace to ophiolites. PMID- 22814684 TI - Cone beam computed tomography in endodontics. AB - Cone beam computed tomography (CBCT) is a contemporary, radiological imaging system designed specifically for use on the maxillo-facial skeleton. The system overcomes many of the limitations of conventional radiography by producing undistorted, three-dimensional images of the area under examination. These properties make this form of imaging particularly suitable for use in endodontics. The clinician can obtain an enhanced appreciation of the anatomy being assessed, leading to an improvement in the detection of endodontic disease and resulting in more effective treatment planning. In addition, CBCT operates with a significantly lower effective radiation dose when compared with conventional computed tomography (CT). The purpose of this paper is to review the current literature relating to the limitations and potential applications of CBCT in endodontic practice. PMID- 22814685 TI - In vitro susceptibility of oral Candida albicans strains to different pH levels and calcium hydroxide saturated aqueous solution. AB - Candida albicans is present in the oral cavity and in the whole digestive tract of humans and other animals, being frequently related to endodontic treatment failure. The present study determined the incidence of C. albicans in the oral cavity and the susceptibility of isolates to different pH values and saturated calcium hydroxide aqueous solution at pH 12.5. Sixty-five patients attending the Endodontic Clinic at the Sagrado Coracao University participated in the study. The collected samples were cultivated in selective media for C. albicans and the isolates were tested in terms of resistance to both alkaline pH and saturated aqueous solution of calcium hydroxide. In relation to time variables, yeast viability was assessed by the Sabouraud's agar culture and fluorescein diacetate and ethidium bromide fluorescent staining method. Results from the different pHs and experimental times, including those from different techniques measuring fungal viability, were compared using the chi-square and Fisher's exact tests (alpha=0.05). The yeasts became completely inviable after 48 h of contact with the calcium hydroxide solution. On the other hand, when exposed to the alkaline culture broth, the yeasts were found to be viable at pHs 9.5 and 10.5 for up to 7 days. In conclusion, C. albicans can only be completely inhibited by direct contact with saturated calcium hydroxide aqueous solution after 48 h of exposure. PMID- 22814686 TI - Ex vivo accuracy of three electronic apex locators using different apical file sizes. AB - This study evaluated the accuracy of three electronic apex locators (Root ZX, Novapex, and Justy II) in root canal length determinations using different apical file sizes, considering the apical constriction (AC) and the major foramen (MF) as anatomic references. The diameter of the apical foramina of 40 single-rooted teeth was determined by direct visual measurement and the master apical file was established. Electronic measurements were then performed using 3 instruments: the selected master apical file (adjusted file), one size smaller (intermediate file), and two sizes smaller (misfit file). The distances from the tip of files fixed in the canals to the MF and to the AC were measured digitally. Precision at AC and at MF for the misfit, intermediate and adjusted apical files was as follows: 80%/88%/83% and 78%/83%/95% (Root ZX); 80%/85%/80% and 68%/73%/73% (Novapex); and 78%/80%/78% and 65%/78%/70% (Justy II). Considering the mean discrepancies, statistically significant differences were found only for the adjusted file at MF, with Root ZX presenting the best results at MF. The chi square test showed significant differences between the acceptable measurements at AC and at MF for the Justy II and Novapex (+/- 0.5 mm) regardless of file adjustment. Under the conditions of the present study, all devices provided acceptable electronic measurements regardless of file adjustment, except for Root ZX which had its performance improved significantly when the precisely fit apical file was used. Justy II and Novapex provided electronic measurements nearest to the AC. PMID- 22814687 TI - Interfacial adaptation of an epoxy-resin sealer and a self-etch sealer to root canal dentin using the System B or the single cone technique. AB - The aim of this laboratory study was to compare the interfacial adaptation of an epoxy-resin and a self-etch sealer in mesial root canals of mandibular molars filled using the System-B/Elements Obturation Unit. Sixty mesial root canals of mandibular molars were prepared using the K3 rotary system up to 35.04 instrument and then filled with the aid of the System-B/Elements Obturation Unit using either gutta-percha/ThermaSeal Plus (n=15) or Resilon/Real Seal SE (n=15). The single cone technique using both materials was used as control. The sealers were stained with Rhodamine B dye and the teeth were filled and sectioned at 2, 4 and 6 mm from the apex. The interfacial marginal adaptation of sealers was evaluated using confocal microscopy. Statistical analyses were performed by the Kruskall Wallis test (alpha=0.05). In general, microscopic analysis showed a quite regular gap distribution pattern at sealer-dentin interfaces, mainly for the two groups filled with Real Seal SE. This means that both nonbonding root-filling groups (ThermaSeal Plus) showed significantly higher amount of gap-free regions regardless of the filling technique (p<0.05). Better marginal adaptation was obtained with gutta-percha and epoxy resin-based sealer using either the system B or the single cone technique. PMID- 22814688 TI - Chitosan: effect of a new chelating agent on the microhardness of root dentin. AB - The effect of solutions of 0.2% chitosan, 15% EDTA and 10% citric acid on the microhardness of root dentin was evaluated comparatively in this study. Thirteen sound human maxillary central incisors were selected and decoronated at the cementoenamel junction. Ten roots were set into rapid polymerization acrylic resin and the root/resin block was fitted to the cutting machine to obtain slices from the cervical third. The first slice was discarded and the second slice was divided into four quadrants. Each quadrant was used to construct a sample, so that 4 specimens were obtained from each root slice, being one for each chelating solution to be tested: 15% EDTA, 10% citric acid, 0.2% chitosan and distilled water (control). The specimens were exposed to 50 MUL of the solution for 5 min, and then washed in distilled water. A microhardness tester (Knoop hardness) with a 10 g load was used for 15 s. Data were analyzed statistically by one-way ANOVA and Tukey-Kramer test (alpha=0.05). The other 3 roots had the canals instrumented and irrigated at the end of the biomechanical preparation with the test solutions, and then examined by scanning electron microscopy (SEM) for qualitative analysis. All solutions reduced the microhardness of root dentin in a way that was statistically similar to each other (p>0.05) but significantly different from the control (p>0.05). The SEM micrographs showed that the three solutions removed smear layer from the middle third of the root canal. In conclusion, 0.2% chitosan, 15% EDTA and 10% citric acid showed similar effects in reducing dentin microhardness. PMID- 22814689 TI - Adhesive bonding of resin cements to cast titanium with adhesive primers. AB - The purpose of this study was to evaluate the effects of adhesive primer applications on the bond strength of resin cements to cast titanium. Four adhesive primers - Metaltite, Metal Primer II, Alloy Primer and Ceramic Primer - and their respective resin cements - Bistite II DC, Link Max, Panavia F 2.0, RelyX Unicem and RelyX ARC - were tested. Cast plates were prepared from titanium ingots (n=6 specimens/cement) and had their surfaces airborne-particle abraded with Al2O3 (50 MU m). Three resin cement cylinders were built on each bonded titanium surface, using a cylindrical translucent tubing mold and were subjected to micro-shear testing. Data were analyzed statistically by two-way ANOVA and Tukey's post-hoc test (alpha=0.05). The application of Metal Primer II and Ceramic Primer resulted in significant higher bond strength for Link Max and RelyX Unicem resin cements, respectively, than nonuse of adhesive primers. Panavia F 2.0 and RelyX ARC yielded high bond strength means with or without adhesive primers. The use of adhesive primers might increase the bond strength to cast titanium depending on the resin cement used. PMID- 22814690 TI - Effect of bonding material, etching time and silane on the bond strength of metallic orthodontic brackets to ceramic. AB - The purpose of this study was to evaluate the bond strength of metallic orthodontic brackets to feldspathic ceramic with different etching times, bonding materials and with or without silane application. Cylinders of feldspathic ceramic were etched with 10% hydrofluoric acid for 20 or 60 s. For each etching time, half of the cylinders received two layers of silane. Metallic brackets were bonded to the cylinders using Transbond XT (3M Unitek) or Fuji Ortho LC (GC). Light-activation was carried out with total exposure time of 40 s using UltraLume 5. Shear bond strength testing was performed after 24 h storage. Data were submitted to three-way ANOVA and Tukey's test (alpha=0.05). The adhesive remnant index (ARI) was used to evaluate the amount of adhesive remaining on the ceramic surface at *8 magnification. Specimens etched for 60 s had significantly higher bond strength compared with 20 s. The application of silane was efficient in increasing the shear bond strength between ceramic and both fixed materials. Transbond XT showed significantly higher (p<0.05) bond strength than Fuji Orth LC. There was a predominance of ARI score 0 (clean ceramic failure surface) for all groups, with an increase in scores 1, 2 and 3 (adhesive material increasingly present on ceramic failure aspect) for the 60-s etching time. In conclusion, 60-s etching time, silane and Transbond XT improved significantly the shear bond strength of brackets to ceramic. PMID- 22814691 TI - Cigarette smoke inhalation influences bone healing of post-extraction tooth socket: a histometric study in rats. AB - The aim of this study was to evaluate, histometrically, the bone healing of the molar extraction socket just after cigarette smoke inhalation (CSI). Forty male Wistar rats were randomly assigned to a test group (animals exposed to CSI, starting 3 days before teeth extraction and maintained until sacrifice; n=20) and a control group (animals never exposed to CSI; n=20). Second mandibular molars were bilaterally extracted and the animals (n=5/group/period) were sacrificed at 3, 7, 10 and 14 days after surgery. Digital images were analyzed according to the following histometric parameters: osteoid tissue (OT), remaining area (RA), mineralized tissue (MT) and non-mineralized tissue (NMT) in the molar socket. Intergroup analysis showed no significant differences at day 3 (p>0.05) for all parameters. On the 7(th) day, CSI affected negatively (p<0.05) bone formation with respect to NMT and RA (MT: 36%, NMT: 53%, RA: 12%; and MT: 39%, NMT: 29%, RA: 32%, for the control and test groups, respectively). In contrast, no statistically significant differences (p>0.05) were found at days 10 and 14. It may be concluded that CSI may affect socket healing from the early events involved in the healing process, which may be critical for the amount and quality of new-bone formation in smokers. PMID- 22814692 TI - Supragingival plaque removal with and without dentifrice: a randomized controlled clinical trial. AB - The aim of this study was to compare the efficacy of dental plaque removal by brushing with and without conventional dentifrice. Twenty-four students aged 17 to 28 years participated in this randomized controlled clinical trial. Quadrants 1-3 or 2-4 were randomly allocated to the test group (brushing without dentifrice) or control group (brushing with dentifrice). After 72 h of cessation of oral hygiene, Quigley & Hein (Turesky) plaque index was assessed before and after brushing by a calibrated and blind examiner. Overtime and intergroup comparisons were performed by Student's paired sample t-test at 5% significance level. The results showed that both groups after toothbrushing presented statistically significant reductions in plaque, with no differences between them (from 3.06 +/- 0.54 to 1.27 +/- 0.26 versus from 3.07 +/- 0.52 to 1.31 +/- 0.23). A separate analysis of the buccal and lingual aspects also showed no significant differences between groups. It may be concluded that the use of a conventional dentifrice during toothbrushing does not seem to enhance plaque removal capacity. PMID- 22814693 TI - Reorganization of secondary and tertiary health care levels: impact on the outcomes of oral cancer screening in the Sao Paulo State, Brazil. AB - This study presents the strategies for prevention and early detection of oral cancer by means of screening in the elderly population of Sao Paulo, the richest and the most populous state of Brazil. This research was a retrospective longitudinal study based on the analysis of secondary data. The variables - number of participating cities, coverage of screening, and number of suspicious and confirmed cases of oral cancer - were divided into two periods: 2001-2004 and 2005-2008. Data were analyzed statistically by the chi-square test at 5% significance level. The implementation of a nationwide public oral health policy in 2004 and the reorganization of the secondary and tertiary health care were evaluated as mediator factors able to interfere in the achieved outcomes. From 2001 to 2008, 2,229,273 oral examinations were performed. There was an addition of 205 participating cities by the end of the studied period (p<0.0001). The coverage of oral cancer screening increased from 4.1% to 16% (p<0.0001). There was a decrease in the number of suspicious lesions (from 9% in 2005 to 5% in 2008) (p<0.0001) and in the rate of confirmed oral cancer cases per 100,000 examinations (from 20.89 in 2001 to 10.40 in 2008) (p<0.0001). After 8 years of screening, there was a decrease in the number of suspicious lesions and confirmed cases of oral cancer in the population. The reorganization of secondary and tertiary health care levels of oral care seems to have contributed to modify these numbers, having a positive impact on the outcomes of oral cancer screening in the Sao Paulo State. PMID- 22814694 TI - Behavioral problems and emotional stress in children with bruxism. AB - Bruxism has a multifactorial etiology, and psychosocial factors have been considered to increase the risk of occurrence of this parafunction. The aim of this study was to evaluate the behavior profile of a group of children diagnosed with bruxism. Eighty 7-11-year-old children of both genders (mean age 8.8 years) first recruited as eligible participants. Twenty-nine children (18 males and 11 females) whose parents/guardians reported to present frequent episodes of tooth grinding/clenching while awake or during sleep (at least 3 nights a week) in the previous 3 months were enrolled in the study. The diagnosis of bruxism was established based on the parents/guardians' report about the children's behavior, habits and possible discomforts in the components of the stomatognathic system allied to the presence of signs and symptoms such as pain on the masticatory muscles, masseter muscle hypertrophy, wear facets, fractures of restorations, dental impressions on the cheek mucosa and tongue. As part of the psychological evaluation, the Rutter's Child Behavior Scale-A2 was applied to the parents/caregivers (one for each child) and the Child Stress Scale was applied to the children. Data were analyzed descriptively based on the frequency of each studied variable. Twenty-four (82.76%) children needed psychological or psychiatric intervention; 17 of them presented neurotic disorders and 7 children presented antisocial disorders. Six (20.70%) children presented significant physical and psychological manifestations of stress. The findings of the present study suggest that behavioral problems and potential emotional problems can be risk factors to bruxism in children. PMID- 22814695 TI - Coronoid process hyperplasia: an unusual cause of mandibular hypomobility. AB - A large number of disorders affecting the masticatory system can cause restriction of mouth opening. The most common conditions related to this problem are those involving the temporomandibular joint (TMJ) and the masticatory muscles, when facial pain also is an usual finding. Congenital or developmental mandibular disorders are also possible causes for mouth opening limitation, although in a very small prevalence. Coronoid process hyperplasia (CPH) is an example of these cases, characterized by an excessive coronoid process growing, where mandibular movements become limited by the impaction of this structure on the posterior portion of the zygomatic bone. This condition is rare, painless, usually bilateral and progressive, affecting mainly men. Diagnosis of CPH is made based on clinical signs of mouth opening limitation together with imaging exams, especially panoramic radiography and computerized tomography (CT). Treatment is exclusively surgical. This paper presents a case of a male patient with bilateral coronoid process hyperplasia, initially diagnosed with bilateral disk displacement without reduction, and successfully treated with intraoral coronoidectomy. It is emphasized the importance of differential diagnosis for a correct diagnosis and, consequently, effective management strategy. PMID- 22814696 TI - The challenges of treating a fused tooth. AB - This paper describes and discusses the multidisciplinary treatment involving a permanent maxillary lateral incisor fused to a supernumerary tooth, both presenting pulp necrosis and periapical lesion. A 15-year-old male patient sought treatment complaining of pain, swelling and mobility on the maxillary right lateral incisor. After clinical and radiographic examination, root canal preparation was performed according to the crown-down technique and a calcium hydroxide dressing was placed for 15 days. The patient returned and the definitive endodontic filling was done with thermomechanical compaction of gutta percha and sealer. After 18 months, clinical and radiographic examinations were carried out and no pain or swelling was reported. Two years after endodontic treatment, the patient returned for periodontal and cosmetic treatments. Nine months later, a cone-beam computed tomography (CBCT) revealed that the previously detected periodontal defect and periapical lesion were persistent. Apical endodontic surgery was indicated. The supernumerary tooth was removed, the communicating distal surface was filled and the surgical site received bioactive glass and demineralized bovine organic bone. The pathological tissue was submitted to histopathological examination and the diagnosis was periapical cyst. One year after the apical endodontic surgery, CBCT showed bone formation at maxillary lateral incisor apical area. Two years after the surgery, the restoration was replaced due to aesthetic reasons and periapical radiograph showed success after 5 years of treatment. A correct diagnosis and establishment of an adequate treatment plan resulted in a successful management of the case. PMID- 22814697 TI - [The current situation with amendments to the scale of remuneration for physicians]. AB - The regulation for the scale of remuneration for physicians (GOA) is a Federal act which must be approved by the Federal Council. The structure and specification of the services in the current scales are out of date. The current performance ratings should be replaced by a strict economic analysis calculation model. This is the only way the Medical Council (BAK) can foresee that higher performance ratings for services can be enforced against the health insurance companies. PMID- 22814698 TI - Genetic identification of two sweet-potato-infecting begomoviruses in South Africa. AB - The complete genome sequences of two monopartite begomovirus isolates (genus Begomovirus, family Geminiviridae) that occurred either alone or in mixed infection in sweet potato (Ipomoea batatas) plants collected in Waterpoort, South Africa, are presented. One of the isolates corresponds to sweet potato mosaic associated virus (SPMaV; SPMaV-[ZA:WP:2011]), with which it shared 98.5 % nucleotide identity, whereas the second isolate corresponds to a new variant of sweet potato leaf curl Sao Paulo virus (SPLCSPV; SPLCSPV-[ZA:WP:2011]), with which it shared 91.4 % nucleotide identity. The phylogenetic and recombination relationships of these isolates to other monopartite Ipomoea-infecting begomoviruses were also investigated. SPLCSPV-[ZA:WP:2011] was found to be a natural recombinant of swepoviruses consisting of two distinct parental genomic sequences from SPLCSPV and sweet potato leaf curl Georgia virus (SPLCGV). PMID- 22814699 TI - Biology of fowl adenovirus type 1 infection of heterologous cells. AB - The JM1/1 strain of fowl adenovirus (FAV) serotype 1 isolated from gizzard erosion was used to investigate the biology of FAV in homologous (susceptible) and heterologous cells. The FAV JM1/1 strain is capable of efficient multiplication in primary chicken kidney (CK) cells, but not in Crandell-Rees feline kidney (CRFK) cells or Vero cells. FAV adsorption in heterologous cells was slightly higher than in CK cells. An early gene encoding a DNA-binding protein and a late gene encoding the hexon protein were expressed in CK cells. Only the early gene was expressed in Vero cells. Neither of these genes was expressed in CRFK cells. These results suggest that the virus was unable to multiply effectively due to suppression of viral gene expression in the heterologous cells used in this study. PMID- 22814700 TI - Expression of alternatively spliced variants of Na-Ca-exchanger-1 in experimental colitis: role in reduced colonic contractility. AB - Inflammation-induced colonic motility dysfunction is associated with a disturbance in Ca(2+) ion transporting mechanisms. The main objective of this study was to identify the types of Na-Ca-exchanger-1 (NCX-1) variants expressed in the rat colon, and how this was affected by colitis. In addition, the effect of colitis on the possible involvement of NCX-1 in the reduced carbachol-induced contraction of the rat colon was examined. Colitis was induced in male Sprague Dawley rats by intra-rectal instillation of trinitrobenzenesulphonic acid (TNBS). Animals were killed on day 5. Colitis was characterized by estimating myeloperoxidase (MPO) activity, body weight, and histological scores. NCX-1 mRNA and protein variants were confirmed by RT-PCR coupled nucleotide sequencing and by Western blot analysis, respectively. Contractility of the colon segments was studied using standard procedure. There was a significant reduction in body weight of TNBS-treated rats. A significant increase in MPO activity and infiltration of inflammatory cells were observed in the inflamed rat colon. RT PCR coupled nucleotide sequencing identified NCX-1.3 mRNA variant containing exons B and D. Western blot analysis confirmed 70 and 120 kDa molecular mass NCX 1 protein variants in rat colon. There was no significant difference (p > 0.05) in the level of NCX-1 protein variants in inflamed colon as compared to non colitis controls. Functional experiments demonstrated that NCX in reverse mode played a role in carbachol-induced contraction of colon, and this was not affected by colitis. These findings demonstrated expression of a NCX-1.3 mRNA splice variant, and 70 and 118 kDa protein variants. Inhibition of the reverse mode of NCX-1 was not different in reduced carbachol-induced contraction between the groups. These findings are interpreted to suggest that NCX-1, though expressed did not play a role in reduced contractility in experimental colitis. PMID- 22814702 TI - Macrophage oxysterols and their binding proteins: roles in atherosclerosis. AB - PURPOSE OF REVIEW: To offer a comprehensive review on the roles that oxysterols synthesized or engulfed by macrophages, or oxysterol-binding proteins in these cells, play in the development and progression of atherosclerotic lesions. RECENT FINDINGS: Oxysterols abundant within the plaque have the capacity to potentiate macrophage proinflammatory signaling and to induce cell death. These activities may contribute to formation of the complex lesion, expansion of the necrotic core, and to plaque rupture. On the contrary, several endogenous oxysterols generated by cholesterol hydroxylases act as ligands of liver X receptors, stimulate macrophage cholesterol efflux, repress proinflammatory signaling, and promote macrophage survival, counteracting lesion progression. Cytoplasmic oxysterol-binding proteins represent a family of sterol and phosphoinositide sensors that may contribute to the regulatory impact of these bioactive lipids on processes relevant in the context of atherogenesis. SUMMARY: The generation and deposition of oxysterols within the developing plaque is envisioned to modulate macrophage lipid metabolism, to affect the delicate balance of proinflammatory and anti-inflammatory processes, and to impact cell fate decisions, thus, determining whether the lesion remains benign or whether it develops into a hazardous, vulnerable plaque. PMID- 22814701 TI - Red blood cell lysate modulates the expression of extracellular matrix proteins in dermal fibroblasts. AB - During the early stage of wound healing process, blood clots can be served as a temporary extracellular matrix (ECM) to let skin cell migration and proliferation. The red blood cells are generally thought as inert bystanders in the early and inflammatory phase of wound healing. Here, we provide evidence that red blood cells (RBC) also play an important role in modulation of key ECM components such as type-I collagen, alpha-smooth muscle actin, fibronectin, and matrix metalloproteinases (MMPs). In this study, we used western blot analysis and showed a significant increase in the level of MMP-1, 2, 3. Furthermore, we found that RBC lysate significantly down-regulates type-I collagen and alpha smooth muscle actin while up-regulates fibronectin expression in dermal fibroblasts. To further explore the mechanism by which RBC lysate modulates MMP-1 expression, the effect of inhibitors for three MAPK signaling pathways on RBC inducing MMP-1 expression by dermal fibroblasts were tested. The result showed that the inhibitor of ERK1/2 could abrogate the stimulatory effect of RBC lysate on MMP-1 expression in dermal fibroblasts. Consistently, RBC treatment results in an increase of ERK1/2 phosphorylation in dermal fibroblast. In conclusion, these findings suggest that RBC lysate can modulate the expression of MMPs and key ECM components which are important in healing process. PMID- 22814703 TI - Apolipoprotein B100 autoimmunity and atherosclerosis - disease mechanisms and therapeutic potential. AB - PURPOSE OF REVIEW: Adaptive immune responses have been shown to play an important role in the atherosclerotic disease process and both pathogenic and protective immunity has been identified. Apolipoprotein (apo) B100 appears to be a key antigen and novel therapies modulating immune responses against apo B100 have shown promising results in experimental models. This review will discuss recent developments in the mechanistic understanding of apo B100 autoimmunity and approaches taken to use this knowledge for development of novel therapies. RECENT FINDINGS: It has recently been shown that not only apo B100 modified by oxidation but also nonmodified apo B100 is targeted by autoimmune responses. This implies that a corresponding set of regulatory T cells with the same antigen specificity must exist and that these cells under normal circumstances are able to prevent autoimmunity against LDL. Recent studies also suggest that the atheroprotective effect of apo B100 peptide immunization acts by re-enforcing the activity of such cells. SUMMARY: These novel findings suggest that aggravation of plaque inflammation may occur as a result of a local loss of tolerance against LDL in the plaque due to insufficient activity of regulatory T cells. Restoration of lost tolerance represents an interesting novel approach for treatment of cardiovascular disease. PMID- 22814704 TI - Inflammation in anxiety. AB - The idea of the existence of an interaction between the immune system and the central nervous system (CNS) has prompted extensive research interest into the subject of "Psychoneuroimmunology" taking the field to an interesting level where new hypotheses are being increasingly tested. Specifically, exactly how the cross talk of pathways and mechanisms enable immune system to influence our brain and behavior is a question of immense significance. Of particular relevance to this topic is the role of cytokines in regulating functions within the CNS that ultimately modulate behavior. Interestingly, psychological stress is reported to modulate cytokine production, suggesting potential relevance of this mediator to mental health. In fact, cytokine signaling in the brain is known to regulate important brain functions including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, as well as the neural circuitry of mood. It is rather obvious to expect an aberrant behavioral outcome as a result of a dysregulation in cytokine signaling which might lead to occurrence of depression, anxiety, and cognitive dysfunction. Thus, understanding the mechanisms by which the immune system influences behavior would reveal targets for potential therapeutic development as well as strategies for the prevention of neuropsychiatric diseases. To date, the presence of inflammatory responses and the crucial role of cytokines in depression have received most attention. However, considering a big socioeconomic impact due to an alarming increase in anxiety disorder patients, there is an urgent research need for a better understanding of the role of cytokines in anxiety. In this review, we discuss recent research on the role of neuroimmunology in anxiety. At the end, we offer an "oxidative stress theory," which we propose works perhaps as a "sensor of distress," the imbalance of which leads to neuroinflammation and causes anxiety disorders. Much research is needed to extensively test this theory keeping an open mind! PMID- 22814705 TI - Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization. AB - A recent study--comparing those with depression, somatization, comorbid depression+somatization, and controls--showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway-both centrally and peripherally-driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (gamma-mangostin), N-acetyl cysteine, and pamoic acid. PMID- 22814706 TI - Inflammation in schizophrenia. AB - Although there is no doubt that the dopaminergic neurotransmission is strongly involved in the pathophysiology of schizophrenia, the exact mechanism leading to dopaminergic dysfunction is still unclear. A disbalance in the immune response associated with a slight inflammatory process of the central nervous system (CNS) has been postulated. Such a mechanism is the basis for the "mild encephalitis" concept. A dysfunction in the activation of the type-1 immune response seems to be associated with decreased activity of the key enzyme of the tryptophan/kynurenine metabolism, indoleamine 2,3-dioxygenase (IDO). Theoretically, a decreased activity of IDO results in the increased production of kynurenic acid, an N-methyl-D-aspartate antagonist in the CNS, and a reduced glutamatergic neurotransmission in schizophrenia. Accordingly, in animal models of schizophrenia, increased levels of kynurenic acid in critical regions of the CNS were described, although studies of peripheral blood levels of kynurenic acid in schizophrenic patients showed controversial results. The immunological effects of a lot of existing antipsychotics, however, rebalance in part the immune imbalance and the overweight of the production of kynurenic acid. The inflammatory state in schizophrenia is associated with increased prostaglandin E(2) production and increased cyclooxygenase-2 (COX-2) expression. Growing evidence from clinical studies with COX-2 inhibitors points to favorable effects of anti-inflammatory therapy in schizophrenia, in particular in an early stage of the disorder. Further options for immunomodulating therapies in schizophrenia will be discussed. PMID- 22814707 TI - Inflammation in Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. The consistent findings obtained by various animal models of PD suggest that neuroinflammation is an important contributor to the pathogenesis of the disease and may further propel the progressive loss of nigral dopaminergic neurons. Furthermore, although it may not be the primary cause of PD, additional epidemiological, genetic, pharmacological, and imaging evidence support the proposal that inflammatory processes in this specific brain region are crucial for disease progression. Recent in vitro studies, however, have suggested that activation of microglia and subsequently astrocytes via mediators released by injured dopaminergic neurons is involved. However, additional in vivo experiments are needed for a deeper understanding of the mechanisms involved in PD pathogenesis. Further insight on the mechanisms of inflammation in PD will help to further develop alternative therapeutic strategies that will specifically and temporally target inflammatory processes without abrogating the potential benefits derived by neuroinflammation, such as tissue restoration. PMID- 22814708 TI - Treatment with Abeta42 binding D-amino acid peptides reduce amyloid deposition and inflammation in APP/PS1 double transgenic mice. AB - One of the two characteristic pathological hallmarks of Alzheimer's disease (AD) are neuritic plaques. The sequence of events leading to the extracellular deposition of amyloid beta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relationship between aggregation and deposition of Abeta by using peptides that bind to Abeta as antifibrillization treatments in APP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brain of these AD-model mice for 4 weeks with one of the three small D-amino acid peptides (i.e., D1, D3, or D3-FITC) that were designed to bind specifically to Abeta42, and examined the subsequent improvement in cognitive deficits after 3 weeks and analyzed amyloid deposition in the brain following the behavioral analysis. Cognitive deficits are similar comparing control and D3 treated mice, but D1-treated mice are slightly, but significantly, impaired. In contrast, there is a substantial improvement in the cognitive deficits in the animals treated with D3-FITC, compared to the other mice. In contrast, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3, compared to the other groups of mice. Furthermore, the amount of activated microglia and astrocytes surrounding Abeta deposits is dramatically reduced in both the D3- and D3-FITC-treated mice. Our findings demonstrate that treatments with a high-affinity Abeta-42-binding D-amino acid peptide significantly decrease Abeta deposits and the associated inflammatory response. Together, this suggests that aggregation likely plays an important role in the deposition of Abeta protein in APP/PS1 transgenic mice and that antiaggregation treatments with D-peptides may be successful in AD patients. PMID- 22814709 TI - Inflammation. Preface. PMID- 22814710 TI - An exploration of safety climate in nursing homes. AB - OBJECTIVES: Although nursing homes provide complex care requiring attention to safety, research on safety climate in nursing homes is limited. Our study assessed differences in attitudes about safety among nursing home personnel and piloted a new survey, specifically designed for the nursing home context. METHODS: Drawing on previous safety climate surveys for hospitals and nursing homes, researchers developed the Survey on Resident Safety in Nursing Homes and administered it March to June 2008 to frontline caregivers and managers in 8 randomly selected Massachusetts nursing homes. Our sample consisted of 751 employees, including all full-time, direct-care staff and managers from participating facilities. First, we performed factor analysis and determined Cronbach alphas for the Survey on Resident Safety in Nursing Homes. Then, we described facilities' safety climate and variation by personnel category and among facilities by calculating the proportion of responses that were strongly positive by item, personnel category, and nursing home. RESULTS: Of 432 respondents (57% response), 29% gave their nursing home an excellent rating overall. Scores varied by personnel category and home: 51% of senior managers gave an excellent safety grade versus 26% of nursing assistants; the range in top safety grades among nursing homes was 30 percentage points. CONCLUSIONS: Safety climate varied substantially among this small sample of nursing homes and by personnel category; managers had more positive perceptions about safety than frontline workers. Efforts to measure safety climate in nursing homes should include the full range of staff at a facility and comparisons among staff categories to provide a full understanding for decision making and to promote targeted response to improve resident safety. PMID- 22814711 TI - A neonate averted disaster. PMID- 22814712 TI - Improved proteomic analysis pipeline for LC-ETD-MS/MS using charge enhancing methods. AB - Electron transfer dissociation (ETD) is a useful and complementary activation method for peptide fragmentation in mass spectrometry. However, ETD spectra typically receive a relatively low score in the identifications of 2+ ions. To overcome this challenge, we, for the first time, systematically interrogated the benefits of combining ion charge enhancing methods (dimethylation, guanidination, m-nitrobenzyl alcohol (m-NBA) or Lys-C digestion) and differential search algorithms (Mascot, Sequest, OMSSA, pFind and X!Tandem). A simple sample (BSA) and a complex sample (AMJ2 cell lysate) were selected in benchmark tests. Clearly distinct outcomes were observed through different experimental protocol. In the analysis of AMJ2 cell lines, X!Tandem and pFind revealed 92.65% of identified spectra; m-NBA adduction led to a 5-10% increase in average charge state and the most significant increase in the number of successful identifications, and Lys-C treatment generated peptides carrying mostly triple charges. Based on the complementary identification results, we suggest that a combination of m-NBA and Lys-C strategies accompanied by X!Tandem and pFind can greatly improve ETD identification. PMID- 22814713 TI - Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. AB - We now recognize that the Epstein-Barr virus (EBV), which is a member of the gamma- herpesvirus family, plays a pivotal role in the development of several lymphomas and lymphoproliferative disorders that include B-cell, T-cell and NK cell processes. While over recent years, EBV associated lymphomas that arise in patients with known defects in cellular immunity are relatively well characterized, these diseases are becoming increasingly recognized in patients without overt immunodeficiency. Improved understanding of the biology of these lymphomas including elucidating the role that EBV plays in their pathogenesis has paved the way for improved therapies targeted at critical signaling pathways as well as the development of novel cellular therapies. In this review, we focus on recent progress that has been made in the biology and treatment of the rare EBV associated disorder lymphomatoid granulomatosis (LYG) and also discuss other EBV associated processes that occur in both immunocompetent and immunocompromised hosts. PMID- 22814715 TI - Join Us in Indy for AADE's 39th Annual Meeting and Exhibition. PMID- 22814716 TI - Who will be there? PMID- 22814720 TI - Integrin-linked kinase (ILK) expression correlates with tumor severity in clear cell renal carcinoma. AB - Integrin-linked kinase (ILK) is an unique intracellular serine/threonine kinase and adapter protein. When dysregulated, it has been associated with increased cell proliferation, anchorage-independent cell growth, evasion of apoptosis, angiogenesis, invasion of surrounding tissues, downregulation of E-cadherin expression, nuclear translocation of beta-catenin and metastasis, all features of tumoral malignancy. The objective of the present work was to evaluate the expression of ILK in clear cell renal carcinomas (CCRC) as a possible prognostic indicator. ILK immunoexpression was evaluated in a tissue microarray (TMA) with 45 human CCRCs. In addition, the apoptotic and proliferative indices and the immuno-expression of beta-catenin and E-cadherin were also evaluated. E-cadherin expression was significantly decreased in tumors with positive ILK expression in relation to those with negative immunoexpression (p = 0.011). ILK immunostaining was significantly increased in high-grade in comparison to low-grade CCRCs (p = 0.0008). ILK expression was also associated with increased proliferative index (p = 0.020), tumor size >7.0 cm (p = 0.018) and with renal vein and capsule invasion (p = 0.003 and p = 0.00). Finally, tumors stage I and II (noninvasive) presented significantly reduced ILK immunoexpression when compared to stage III (locally invasive) (p = 0.0028). ILK immunoexpression in CCRC increases with loss of intercellular adhesion, nuclear grading, increased proliferative index and Robson stage. Altogether, our data suggest a possible role for ILK in the progression of CRCC. PMID- 22814723 TI - Characteristics of subsolid pulmonary nodules showing growth during follow-up with CT scanning. AB - OBJECTIVE: The positive results of a screening CT scan trial are likely to lead to an increase in the use of CT scanning, and, consequently, an increase in the detection of subsolid nodules. Noninvasive methods including follow-up with CT scanning, to determine which nodules require invasive diagnosis and surgical treatment, should be defined promptly. METHODS: Between 2000 and 2008, from our database of . 60,000 examinations with CT scanning, we identified 174 subsolid nodules, which showed a ground-glass opacity area . 20% of the nodule and measured 2 cm in diameter, in 171 patients. We investigated the clinical characteristics and CT images of the subsolid nodules in relation to changes identified during the follow-up period. RESULTS: The nodule sizes ranged from 4 mm to 20 mm at the fi rst presentation. Nonsolid nodules numbered 98. During the follow-up period, 18 nodules showed resolution or shrinkage, and 41 showed growth of 2 mm or more in diameter. The time to 2-mm nodule-growth curves calculated by Kaplan-Meier methods indicated that the 2-year and 5-year cumulative percentages of growing nodules were 13% and 23% in patients with nonsolid nodules and 38% and 55% in patients with part-solid nodules, respectively. Multivariate analysis disclosed that a large nodule size ( . 10 mm) and history of lung cancer were significant predictive factors of growth in nonsolid nodules. CONCLUSIONS: An effective schedule for follow-up with CT scanning for subsolid nodules should be developed according to the type of subsolid nodule, initial nodule size, and history of lung cancer. PMID- 22814721 TI - The role of innate immunity in HBV infection. AB - Hepatitis B virus (HBV) infection is one of the main causes of chronic liver diseases. Whether HBV infection is cleared or persists is determined by both viral factors and host immune responses. It becomes clear that innate immunity is of importance in protecting the host from HBV infection and persistence. However, HBV develops strategies to suppress the antiviral immune responses. A combined therapeutic strategy with both viral suppression and enhancement of antiviral immune responses is needed for effective long-term clearance and cure for chronic HBV infection. We and others confirmed that bifunctional siRNAs with both gene silencing and innate immune activation properties are beneficial for inhibition of HBV and represent a potential approach for treatment of viral infection. Understanding the nature of liver innate immunity and their roles in chronic HBV progression and HBV clearance may aid in the design of novel therapeutic strategies for chronic HBV infection. PMID- 22814722 TI - Physical activity and mammographic breast density: a systematic review. AB - Studies show a protective relationship between physical activity and breast cancer risk across the life course from menarche to postmenopausal years. Mammographic breast density is a known and strong breast cancer risk factor. Whether the association of physical activity with breast cancer risk is mediated through mammographic breast density is poorly understood. This systematic review summarizes published studies that investigated the association between physical activity and mammographic breast density and discusses the methodological issues that need to be addressed. We included in this review studies that were published before October 31, 2011 that were accessible in full-text format and were published in English. We identified 20 studies through the PubMed Central, BioMed Central, Embase, and Scopus and using the search terms "physical activity and breast density" and "exercise and breast density" as well as through manual searches of the bibliographies of the articles identified in electronic searches. We found no evidence of association between physical activity and breast density across the studies by grouping them first by the timing of physical activity assessment (in adolescence, current/recent, past, and lifetime) and then by women's menopausal status (premenopausal and postmenopausal). Given the strength of the relationship between physical activity and breast cancer and the null findings of this review, it is unlikely that the effect of physical activity is mediated through an effect on breast density. PMID- 22814724 TI - Genome-based prediction of test cross performance in two subsequent breeding cycles. AB - Genome-based prediction of genetic values is expected to overcome shortcomings that limit the application of QTL mapping and marker-assisted selection in plant breeding. Our goal was to study the genome-based prediction of test cross performance with genetic effects that were estimated using genotypes from the preceding breeding cycle. In particular, our objectives were to employ a ridge regression approach that approximates best linear unbiased prediction of genetic effects, compare cross validation with validation using genetic material of the subsequent breeding cycle, and investigate the prospects of genome-based prediction in sugar beet breeding. We focused on the traits sugar content and standard molasses loss (ML) and used a set of 310 sugar beet lines to estimate genetic effects at 384 SNP markers. In cross validation, correlations >0.8 between observed and predicted test cross performance were observed for both traits. However, in validation with 56 lines from the next breeding cycle, a correlation of 0.8 could only be observed for sugar content, for standard ML the correlation reduced to 0.4. We found that ridge regression based on preliminary estimates of the heritability provided a very good approximation of best linear unbiased prediction and was not accompanied with a loss in prediction accuracy. We conclude that prediction accuracy assessed with cross validation within one cycle of a breeding program can not be used as an indicator for the accuracy of predicting lines of the next cycle. Prediction of lines of the next cycle seems promising for traits with high heritabilities. PMID- 22814725 TI - Development of flange and reticulate wall ingrowths in maize (Zea mays L.) endosperm transfer cells. AB - Maize (Zea mays L.) endosperm transfer cells are essential for kernel growth and development so they have a significant impact on grain yield. Although structural and ultrastructural studies have been published, little is known about the development of these cells, and prior to this study, there was a general consensus that they contain only flange ingrowths. We characterized the development of maize endosperm transfer cells by bright field microscopy, transmission electron microscopy, and confocal laser scanning microscopy. The most basal endosperm transfer cells (MBETC) have flange and reticulate ingrowths, whereas inner transfer cells only have flange ingrowths. Reticulate and flange ingrowths are mostly formed in different locations of the MBETC as early as 5 days after pollination, and they are distinguishable from each other at all stages of development. Ingrowth structure and ultrastructure and cellulose microfibril compaction and orientation patterns are discussed during transfer cell development. This study provides important insights into how both types of ingrowths are formed in maize endosperm transfer cells. PMID- 22814727 TI - Physiatry serves an important role in the acute care of patients: disability prevention! PMID- 22814726 TI - Prenatal diagnosis as a tool and support for eugenics: myth or reality in contemporary French society? AB - Today, French public debate and bioethics research reflect an ongoing controversy about eugenics. The field of reproductive medicine is often targeted as pre implantation genetic diagnosis (PGD), prenatal diagnosis, and prenatal detection are accused of drifting towards eugenics or being driven by eugenics considerations. This article aims at understanding why the charge against eugenics came at the forefront of the ethical debate. Above all, it aims at showing that the charge against prenatal diagnosis is groundless. The point of view presented in this article has been elaborated jointly by a geneticist and a philosopher. Besides a survey of the medical, bioethical, philosophical and social sciences literature on the topic, the methodology is founded on a joint analysis of geneticist's various consults. Evidence from office visits demonstrated that prenatal diagnosis leads to case-by-case decisions. As we have suggested, this conclusion does not mean that prenatal diagnosis is devoid of ethical issues, and we have identified at least two. The first is related to the evaluation of a decision to abort. The second line of ethical questions arises from the fact that the claim for "normality" hardly hides normative and ambiguous views about disability. As a conclusion, ethical dilemmas keep being noticeable in the field of reproductive medicine and genetic counselling, but an enquiry about eugenic tendencies probably does not allow us to understand them in the proper way. PMID- 22814728 TI - Shoulder injuries in the skeletally immature baseball pitcher and recommendations for the prevention of injury. AB - Since 1996, when the first article on pitch restriction recommendations was published, the number of research articles involving skeletally immature pitchers has increased. Potential shoulder injuries in this age group are proximal humeral epiphysiolysis, glenohumeral instability, rotator cuff dysfunction, and superior labrum anteroposterior lesions. Fatigue, improper biomechanics, and overuse are the most common reasons for these injuries. In the hopes of preventing injury to young pitchers, numerous organizations, including the USA Baseball Medical & Safety Advisory Committee, The American Sports Medicine Institute, Little League Baseball & Softball, and the Long Term Athlete Development Program for Baseball Canada, have developed recommendations on pitching restrictions that include limits on pitch count, pitches per week, pitches per season, and rest between pitching. Awareness by sports medicine providers, coaches, and parents/guardians of the most up-to-date recommendations on injury prevention and return to play guidelines should reduce the incidence of acute and chronic injuries in adolescent baseball pitchers. PMID- 22814729 TI - Ethical challenges of caring for VIPs in the rehabilitation setting. PMID- 22814730 TI - Use of medial branch blocks before radiofrequency ablation for lumbar facet joints. PMID- 22814731 TI - C6 radiculopathy: the initial presentation of fibromuscular dysplasia. PMID- 22814732 TI - Ultrasound evaluation of Baker cysts: diagnosis and management. PMID- 22814733 TI - Re: The ligament flavum at L4-5: relationship with anthropomorphic factors and clinical findings in older persons with and without spinal disorders. PMID- 22814735 TI - The complexities surrounding decisions related to prosthetic fitting in elderly dysvascular amputees. PMID- 22814736 TI - Effect of surface area and air-drying distance on shear bond strength of etch-and rinse adhesive. AB - We evaluated the effects of air-drying distance and bond surface area on the shear bond strength of a 2-step etch-and-rinse adhesive. A total of 120 bovine anterior teeth were equally divided into 6 main groups based on bonding surface area. The main groups were divided into sub-groups (n = 5) according to air drying distance. The shear strength was determined using a universal testing machine at a crosshead speed of 0.5 mm/min. The averaged results were subjected to two-way ANOVA and Tukey's test (alpha = 0.05). Two-way ANOVA testing identified no significant cross-product interactions (p > 0.05), but the main factors of area (p < 0.0001) and air-drying distance (p < 0.00001) significantly affected the mean bond strength. Shorter air-drying distances improved bond strength, and increased surface area decreased the bond strength. PMID- 22814737 TI - Effect of whitening toothpaste on titanium and titanium alloy surfaces. AB - Dental implants have increased the use of titanium and titanium alloys in prosthetic applications. Whitening toothpastes with peroxides are available for patients with high aesthetic requirements, but the effect of whitening toothpastes on titanium surfaces is not yet known, although titanium is prone to fluoride ion attack. Thus, the aim of the present study was to compare Ti-5Ta alloy to cp Ti after toothbrushing with whitening and conventional toothpastes. Ti-5Ta (%wt) alloy was melted in an arc melting furnace and compared with cp Ti. Disks and toothbrush heads were embedded in PVC rings to be mounted onto a toothbrushing test apparatus. A total of 260,000 cycles were carried out at 250 cycles/minute under a load of 5 N on samples immersed in toothpaste slurries. Surface roughness and Vickers microhardness were evaluated before and after toothbrushing. One sample of each material/toothpaste was analyzed by Scanning Electron Microscopy (SEM) and compared with a sample that had not been submitted to toothbrushing. Surface roughness increased significantly after toothbrushing, but no differences were noted after toothbrushing with different toothpastes. Toothbrushing did not significantly affect sample microhardness. The results suggest that toothpastes that contain and those that do not contain peroxides in their composition have different effects on cp Ti and Ti-5Ta surfaces. Although no significant difference was noted in the microhardness and roughness of the surfaces brushed with different toothpastes, both toothpastes increased roughness after toothbrushing. PMID- 22814738 TI - Erosive potential of different types of grape juices. AB - The purpose of the present study was to evaluate the erosive potential of different types (concentrated and powdered) and commercial brands of industrialised grape juices. The pH of all five fruit drinks was measured at two time points: immediately after preparation and 24 hours later. Sixty specimens of bovine enamel were randomly allocated and immersed in different types of grape juice (n = 10) for 10 minutes four times a day for fifteen days. The enamel alteration was analysed using surface Knoop microhardness (KHN) and surface roughness (Ra) tests at baseline and on the 5(th), 10(th) and 15(th) days of the experiment. Two way ANOVA, Tukey's post hoc and Pearson's correlation tests were used for statistical analysis (alpha = 5%). The grape juices presented pH values ranging from 2.9 to 3.5. All of the tested juices promoted significant enamel mineral loss (p < 0.05) on the first evaluation (5(th) day of immersion) and produced a significant increase in the mean roughness from the 10(th) day on when compared to the control group (p < 0.05). By the 15(th) day, all of the beverages had produced surface roughnesses that were significantly higher than that of the control group. The results suggest that all grape juices, regardless of their commercial presentation, present erosive potential. PMID- 22814739 TI - Severe complications in wound healing and fracture treatment in two brothers with congenital insensitivity to pain with anhidrosis. AB - Congenital insensitivity to pain with anhidrosis is an autosomal recessive disorder caused by mutations in the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene, which encodes the receptor for nerve growth factor. We report the clinical and radiological pitfalls in the diagnosis and treatment of two brothers, aged 5 and 8 years, with congenital insensitivity to pain with anhidrosis, the older brother having a proven NTRK1 mutation. In the neonatal period, both presented with recurrent episodes of fever of unknown origin, but their clinical problems changed later. In addition to severe mental retardation and self-harming behaviour, the older brother developed recurrent nonbacterial destructive infections of both the calcaneus and later the talus. No immunodeficiency was found. The younger brother had three complex fractures with a long history of healing problems: overwhelming production of callus, osteomyelitis and movement restrictions. He has less mental retardation than his older brother and shows no self-mutilation. PMID- 22814740 TI - Nonoriginal Malappropriate Eponymous Nomenclature: examples relevant to paediatric orthopaedics. AB - Eponyms are widely used in medicine and their use has been the subject of much debate recently. Advocates stress their historical significance, their ability to simplify complex terminology and their addition of character to science. Opponents cite the controversy among those eponyms and highlight the lack of both scientific and historical accuracy. The law of Nonoriginal Malappropriate Eponymous Nomenclature (NOMEN) suggests that no phenomenon is named after the individual(s) who originally described it. We aimed to determine whether this law is applicable to various clinical conditions and signs relevant to paediatric orthopaedics. We selected a series of 10 eponyms and performed a thorough literature review. In all cases, a description was identified preceding that from whom the disease received its eponymous name. We were also able to identify what we believe to be the earliest recorded description of each disease and sign. Our examples confirm the law of NOMEN in the field of paediatric orthopaedics. We suggest that irregularities in the descriptions and meanings of eponyms are identified and updated. PMID- 22814741 TI - Does the level of proximal femur rotation osteotomy influence the correction results in patients with cerebral palsy? AB - Proximal femur external rotation osteotomy is a common procedure used for the correction of increased femur anteversion and hip internal rotation in cerebral palsy (CP). Different levels of osteotomy have been used at the proximal femur, but there are no studies in the literature comparing the results in CP. Patients with spastic CP, Gross Motor Function Classification System (GMFCS) I-III, who had undergone a femoral rotational osteotomy from August 1998 to August 2007, and with complete documentation at gait laboratory were included in the study. Patients were divided into two groups according to the level of osteotomy at the proximal femur. Group A [Dynamic Compression Plate (DCP) group] included 24 patients (36 osteotomies), and the osteotomy in this group was performed below the lesser trochanter. In Group B (Blade Plate group), 29 patients (35 osteotomies) were included and the level of osteotomy was above the lesser trochanter. Age at surgery, sex distribution, follow-up time, previous surgical procedures, surgical procedures performed in the same session as femur osteotomy, GMFCS level, topographic classification, clinical findings (internal and external hip rotation, and femur anteversion), and hip rotation at kinematics were analyzed and the results were compared between groups. Groups A and B were matched in terms of the sex distribution, follow-up time, GMFCS levels, and severity of clinical findings and hip internal rotation at kinematics before surgery. The mean age of the patients at surgery was 9.24 years in group A and 12 years in group B, and this difference was significant on performing statistical analysis (P=0.004). The number of patients who had undergone previous hip adductors' tenotomy was higher in group B (P=0.036). Improvements in clinical and kinematics parameters were observed in both groups after femur osteotomy (P<0.001). The increase in hip external rotation at clinical examination and the reduction in hip internal rotation at kinematics did not show differences between groups A and B on performing statistical analysis. However, reduction of femoral anteversion (P=0.032) and hip internal rotation (P=0.002) were more remarkable in group B. In conclusion, reduction of hip internal rotation and femur anteversion at physical examination were more significant in patients with intertrochanteric osteotomies; however, improvement in kinematics was observed in both groups after surgical procedures. PMID- 22814743 TI - Hypertension and kidney disease: what do the data really show? AB - Hypertension is the most common co-morbidity in chronic kidney disease (CKD) and the optimal target BP to prevent CKD progression has been hotly debated. Prior recommendations by various groups for BP targets for CKD in the range of less than 130/80 mm Hg have been based on the assumed benefits of lower BP in this population with exceedingly high risk for cardiovascular disease (CVD). Although there is suggestive data that lower BP may be helpful in patients with proteinuria and CKD, studies not directly link a treatment-related reduction in proteinuria to a benefit in kidney outcomes. There are ongoing studies which will provide more data on BP targets in CKD. Based on the currently available data we recommend a BP goal of less than 140/90 mm Hg in all patients with CKD. PMID- 22814742 TI - Cyclin D1 degradation and p21 induction contribute to growth inhibition of colorectal cancer cells induced by epigallocatechin-3-gallate. AB - PURPOSE: The public has paid attention to green tea due to its health benefits. Epigallocatechin-3-gallate (EGCG), the major component of green tea, is well documented to induce apoptosis and cell cycle arrest in cancer cells by targeting multiple signal transduction pathways. However, the detailed mechanism(s) of action needs to be determined. METHODS: Cell growth was evaluated by MTT assay, cell cycle analysis, and caspase 3/7 activity. Protein expression was analyzed through Western blotting. Reverse transcription polymerase chain reaction was used for examining mRNA expression of p21 and cyclin D1. The promoter activity of p21 was assessed by the luciferase reporter system. RESULTS: We identified cyclin D1 and p21 as molecular targets of EGCG in human colorectal cancer cells. We observed that cyclin D1 was down-regulated, while p21 expression was up-regulated by EGCG in dose- and time-dependent manners. Furthermore, we found EGCG decreased cyclin D1 protein stability, therefore triggering ubiquitin-dependent proteasomal degradation. Meanwhile, EGCG increased p21 promoter activity, resulting in up regulation of p21 mRNA and protein, which was likely dependent on extracellular signal-regulated kinase (ERK), inhibitor of nuclear factor kappa-B kinase (IKK) and phosphoinositide 3-kinase (PI3 K). CONCLUSION: The data presented here details a novel mechanism by which EGCG inhibits cell growth of colorectal cancer cells. Namely, EGCG-induced cyclin D1 degradation and p21 transcriptional activation partially contribute to growth suppression in these cells. PMID- 22814744 TI - Enhanced performance of surface-modified TiO2 photocatalysts prepared via a visible-light photosynthetic route. AB - Benzene can be activated by visible light (lambda > 455 nm) in the presence of TiO(2), which leads to formation of carbonaceous polymeric deposits on the titania surface. These photosynthesized surface-modified materials exhibit enhanced photoactivity in degradation of phenolic compounds, particularly under visible light irradiation. PMID- 22814746 TI - Vascular hypoxic preconditioning relies on TRPV4-dependent calcium influx and proper intercellular gap junctions communication. AB - OBJECTIVE: We investigated the impact of hypoxia-reoxygenation on endothelial relaxation and aimed to clarify the role of transient receptor potential cation channels V4 (TRPV4) and gap junctions in the protective effect associated with hypoxic preconditioning on the vascular function. METHODS AND RESULTS: By mimicking ischemia-reperfusion in C57BL/6 male mice in vivo, we documented a reduced NO-mediated relaxation and an increased endothelium-derived hyperpolarization (EDH[F])-mediated relaxation. Hypoxic preconditioning, however, restored NO relaxation and further improved the EDH(F) response. We also examined specifically 2 major effectors of the EDH(F) pathway, transient receptor potential cation channels V4 and connexins. We found that in endothelial cells, expression and activity of transient receptor potential cation channels V4 were increased by hypoxic stimuli independently of preconditioning which was interestingly associated with an increase of structural caveolar component caveolin-1 at membrane locations. Gap junctions, however, seemed to directly support EDH(F)-driven preconditioning as connexin 40 and connexin 43 expression increased and as in vivo carbenoxolone treatment completely inhibited the EDH(F) pathway and significantly reduced the protection afforded by preconditioning for the concomitant NO-mediated relaxation. CONCLUSIONS: Our work provides evidence on how transient receptor potential cation channels V4 and connexins might participate in preserving vasorelaxation under hypoxia and restoring the NO mediated pathway in hypoxic preconditioning conditions pointing out caveolae as a common signaling location. PMID- 22814745 TI - Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. AB - OBJECTIVE: Cholesterol enrichment occurs in vivo when phagocytes ingest retained and aggregated lipoproteins, damaged or senescent cells, and related debris. We previously reported that enrichment of human monocyte/macrophages with unesterified cholesterol (UC) triggers the release of highly procoagulant microvesicles ([MVs], also called microparticles) through induction of apoptosis. We determined whether UC-induced MVs (UCMVs) might transmit endogenous danger signals and, if so, what molecular processes might be responsible for their production, recognition, and detoxification. METHODS AND RESULTS: Injection of UCMVs into rats provoked extensive leukocyte rolling and adherence to postcapillary venules in vivo. Likewise, exposure of mouse aortic explants or cultured human endothelial cells to UCMVs augmented the adhesion of human monocytes by several fold and increased endothelial cell intercellular adhesion molecule-1 via nuclear factor-kappaB activation. To explore molecular mechanisms, we found that UC enrichment of human monocytes, in the absence of other stimuli, induced mitochondrial complex II-dependent accumulation of superoxide and peroxides. A subset of these moieties was exported on UCMVs and mediated endothelial activation. Strikingly, aortic explants from mice lacking lectin-like oxidized low-density lipoprotein receptor-1, a pattern-recognition receptor, were essentially unable to respond to UCMVs, whereas simultaneously treated explants from wild-type mice responded robustly by increasing monocyte recruitment. Moreover, high-density lipoprotein and its associated enzyme paraoxonase-1 exerted unexpected roles in the detoxification of UCMVs. CONCLUSIONS: Overall, our study implicates MVs from cholesterol-loaded human cells as novel carriers of danger signals. By promoting maladaptive immunologic and thrombotic responses, these particles may contribute to atherothrombosis and other conditions in vivo. PMID- 22814748 TI - Lipid effects of peroxisome proliferator-activated receptor-delta agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome. AB - OBJECTIVE: Peroxisome proliferator-activated receptor-delta-induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. METHODS AND RESULTS: GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (-7.3%), triglycerides ( 16.9%), apoB (-14.9%), and free fatty acids (-19.4%). The exploratory study showed significant reductions in the concentration of very LDL (-19%), intermediate-density lipoprotein (-52%), and LDL (-14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). CONCLUSIONS: GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-delta being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients. PMID- 22814747 TI - Omega-3 fatty acids ameliorate atherosclerosis by favorably altering monocyte subsets and limiting monocyte recruitment to aortic lesions. AB - OBJECTIVE: Fish oil, containing omega-3 fatty acids, attenuates atherosclerosis. We hypothesized that omega-3 fatty acid-enriched oils are atheroprotective through alteration of monocyte subsets and their trafficking into atherosclerotic lesions. METHODS AND RESULTS: Low-density lipoprotein receptor knockout and apolipoprotein E(-/-) mice were fed diets containing 10% (calories) palm oil and 0.2% cholesterol, supplemented with an additional 10% palm oil, echium oil (containing 18:4 n-3), or fish oil. Compared with palm oil-fed low-density lipoprotein receptor knockout mice, echium oil and fish oil significantly reduced plasma cholesterol, splenic Ly6C(hi) monocytosis by ~50%, atherosclerosis by 40% to 70%, monocyte trafficking into the aortic root by ~50%, and atherosclerotic lesion macrophage content by 30% to 44%. In contrast, atherosclerosis and monocyte trafficking into the artery wall was not altered by omega-3 fatty acids in apolipoprotein E(-/-) mice; however, Ly6C(hi) splenic monocytes positively correlated with aortic root intimal area across all diet groups. In apolipoprotein E(-/-) mice, fish oil reduced the percentage of blood Ly6C(hi) monocytes, despite an average 2-fold higher plasma cholesterol relative to palm oil. CONCLUSIONS: The presence of splenic Ly6C(hi) monocytes parallels the appearance of atherosclerotic disease in both low-density lipoprotein receptor knockout and apolipoprotein E(-/-) mice. Furthermore, omega-3 fatty acids favorably alter monocyte subsets independently from effects on plasma cholesterol and reduce monocyte recruitment into atherosclerotic lesions. PMID- 22814749 TI - Vascular endothelial growth factor-induced osteopontin expression mediates vascular inflammation and neointima formation via Flt-1 in adventitial fibroblasts. AB - OBJECTIVE: Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation. METHODS AND RESULTS: In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis. CONCLUSIONS: These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases. PMID- 22814750 TI - Nonalcoholic fatty liver disease is associated with atherosclerosis in middle aged and elderly Chinese. AB - OBJECTIVE: To evaluate the associations between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis. METHODS AND RESULTS: A total of 8632 participants aged >= 40 years from Jiading district, Shanghai, were included in the present study. The presence of NAFLD was evaluated by ultrasonography. Carotid intima media thickness (CIMT) and brachial-ankle pulse wave velocity (ba-PWV) were measured in each participant. The prevalence of NAFLD was 30.0% in the total population, with 30.3% in men and 29.9% in women, respectively. Subjects with NAFLD had remarkably higher CIMT and ba-PWV compared with those without NAFLD (0.594 +/- 0.105 mm versus 0.578+/-0.109 mm, P<0.0001; 1665 +/- 424 cm/s versus 1558 +/- 430 cm/s, P<0.0001). Subjects with both NAFLD and metabolic syndrome had significantly higher CIMT and ba-PWV compared with those with neither or either of these 2 diseases after adjustment for age and sex (all P<0.05). Logistic regressions also revealed that NAFLD conferred 35% and 30% increased odds ratios of elevated CIMT and ba-PWV, independent of conventional risk factors and the presence of metabolic syndrome. CONCLUSIONS: NAFLD was associated with elevated CIMT and ba-PWV, independent of conventional cardiovascular disease risk factors and metabolic syndrome. The effects of NAFLD and metabolic syndrome on atherosclerosis might not fully overlap. PMID- 22814751 TI - ADP-stimulated activation of Akt during integrin outside-in signaling promotes platelet spreading by inhibiting glycogen synthase kinase-3beta. AB - OBJECTIVE: Integrins mediate platelet adhesion and transmit outside-in signals leading to platelet spreading. Phosphoinositide 3-kinases (PI3Ks) play a critical role in outside-in signaling and platelet spreading; however, the mechanisms of PI3K activation and function in outside-in signaling are unclear. We sought to determine the role of the Akt family of serine/threonine kinases and activation mechanisms of the PI3K/Akt pathway in outside-in signaling. METHODS AND RESULTS: Akt inhibitors and Akt3 knockout inhibited platelet spreading on fibrinogen, indicating that Akt is important in integrin outside-in signaling. Akt inhibitors and Akt3 knockout also diminished integrin-dependent phosphorylation of glycogen synthase kinase-3beta. Inhibition of glycogen synthase kinase-3beta reversed the inhibitory effects of Akt3 knockout and inhibitors of Akt or PI3K on platelet spreading, indicating that glycogen synthase kinase-3beta is a downstream target of Akt in outside-in signaling. Integrin-dependent activation of the PI3K-Akt pathway requires Src family kinase. Akt phosphorylation is also significantly inhibited in ADP receptor P2Y12 knockout platelets and further inhibited in P2Y12 knockout platelets treated with a P2Y1 antagonist. Consistently, P2Y12 knockout and P2Y1 inhibition together reduced platelet spreading. CONCLUSIONS: These results demonstrate that integrin outside-in signaling and platelet spreading requires Src family kinase-dependent and ADP receptor-amplified activation of the PI3K-Akt-GSK-3beta pathway. PMID- 22814752 TI - Vascular smooth muscle Emilin-1 is a regulator of arteriolar myogenic response and blood pressure. AB - OBJECTIVE: Emilin-1 is a protein of elastic extracellular matrix involved in blood pressure (BP) control by negatively affecting transforming growth factor (TGF)-beta processing. Emilin1 null mice are hypertensive. This study investigates how Emilin-1 deals with vascular mechanisms regulating BP. METHODS AND RESULTS: This study uses a phenotype rescue approach in which Emilin-1 is expressed in either endothelial cells or vascular smooth muscle cells of transgenic animals with the Emilin1(-/-) background. We found that normalization of BP required Emilin-1 expression in smooth muscle cells, whereas expression of the protein in endothelial cells did not modify the hypertensive phenotype of Emilin1(-/-) mice. We also explored the effect of treatment with anti-TGF-beta antibodies on the hypertensive phenotype of Emilin1(-/-) mice, finding that neutralization of TGF-beta in Emilin1 null mice normalized BP quite rapidly (2 weeks). Finally, we evaluated the vasoconstriction response of resistance arteries to perfusion pressure and neurohumoral agents in different transgenic mouse lines. Interestingly, we found that the hypertensive phenotype was coupled with an increased arteriolar myogenic response to perfusion pressure, while the vasoconstriction induced by neurohumoral agents remained unaffected. We further elucidate that, as for the hypertensive phenotype, the increased myogenic response was attributable to increased TGF-beta activity. CONCLUSIONS: Our findings clarify that Emilin-1 produced by vascular smooth muscle cells acts as a main regulator of resting BP levels by controlling the myogenic response in resistance arteries through TGF-beta. PMID- 22814753 TI - Progesterone and adipoQ receptor 11 links ras signaling to cardiac development in zebrafish. AB - OBJECTIVE: Progesterone and adipoQ receptor (PAQR) 10 and PAQR11 are 2 highly homologous genes involved in compartmentalized Ras signaling in the Golgi apparatus. The aim of this study was to investigate the physiological functions of PAQR10 and PAQR11. METHODS AND RESULTS: We used zebrafish as a model system to analyze the potential function of PAQR10/PAQR11. The expression profiles of PAQR10 and PAQR11 in zebrafish embryos are overlapping in many areas, but only PAQR11 is expressed in the developing heart. Knockdown of PAQR11 but not PAQR10 in zebrafish embryos causes cardiac developmental defects, including dilation of cardiac chambers, abnormal heart looping, disruption of atrioventricular cushion formation, heart edema, and blood regurgitation. PAQR11 knockdown markedly reduces the number and proliferation rate of cardiomyocytes and alters the morphology of myocardial cells during early heart development. The cardiac defects caused by PAQR11 knockdown can be phenocopied by MEK inhibitors and a dominant negative Ras. Furthermore, constitutively active Ras and especially a Golgi-localized but not a plasma membrane-localized Ras are able to rescue the cardiac defects caused by PAQR11 knockdown. CONCLUSIONS: This study not only provides in vivo evidence that PAQR11 plays a critical role in heart morphogenesis but also pinpoints the importance of compartmentalized Ras signaling during development. PMID- 22814755 TI - Characterization of an internal type-II NADH dehydrogenase from Chlamydomonas reinhardtii mitochondria. AB - Type-II NAD(P)H dehydrogenases form a multigene family that comprise six members in the green microalga Chlamydomonas. To date, only one enzyme (Nda2) located in the chloroplast has been characterized in this alga and demonstrated to participate in the reduction of the plastoquinone pool. We present here the functional characterization of Nda1. The enzyme is located on the inner face of the inner mitochondrial membrane. Its downregulation leads to a slight decrease of NADH:ferricyanide activity and of dark whole cell respiration. To determine whether the reduction of Nda1 combined with the lack of complex I would affect mitochondrial processes, double mutants affected in both Nda1 and complex I were isolated. Respiration and growth rates in heterotrophic conditions were significantly altered in the double mutants investigated, suggesting that Nda1 plays a role in the oxidation of matrix NADH in the absence of complex I. PMID- 22814756 TI - Comparative analyses of cytotoxicity and molecular mechanisms between platinum metallointercalators and cisplatin. AB - Platinum(II) metallointercalators of the type [Pt(I(L))(A(L))](2+), such as [(5,6 dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)](2+) (56MESS), are structurally different from cisplatin. This study, using a comparative transcriptomics approach, uncovered genomic expression patterns and molecular pathways that distinctively differentiated 56MESS and cisplatin in the eukaryote model organism Saccharomyces cerevisiae (yeast). Down-regulation of sulfur assimilation, cellular respiration, and energy metabolism were characteristics of 56MESS while up-regulation of these pathways and genes in cell cycle was the action of cisplatin. Furthermore, de novo purine biosynthesis and glycine metabolism were induced by 56MESS but suppressed by cisplatin. Different effects on intracellular concentrations of iron and copper were evident, with 56MESS more profoundly inducing genes controlling uptake of these ions than cisplatin. Finally, apart from 56MESS, additional metallointercalators including 56MEEN, 5MERR and 5MESS were subsequently identified to be more active in a cisplatin-resistant mouse leukaemia L1210cisR cell line than cisplatin, which provides multiple lead compounds for future drug development. PMID- 22814757 TI - Positive allosteric feedback regulation of the stringent response enzyme RelA by its product. AB - During the stringent response, Escherichia coli enzyme RelA produces the ppGpp alarmone, which in turn regulates transcription, translation and replication. We show that ppGpp dramatically increases the turnover rate of its own ribosome dependent synthesis by RelA, resulting in direct positive regulation of an enzyme by its product. Positive allosteric regulation therefore constitutes a new mechanism of enzyme activation. By integrating the output of individual RelA molecules and ppGpp degradation pathways, this regulatory circuit contributes to a fast and coordinated transition to stringency. PMID- 22814758 TI - Alveolar ridge preservation. A systematic review. AB - OBJECTIVE: The objective of this paper is to examine the effect of alveolar ridge preservation (ARP) compared to unassisted socket healing. METHODS: Systematic review with electronic and hand search was performed. Randomised controlled trials (RCT), controlled clinical trials (CCT) and prospective cohort studies were eligible. RESULTS: Eight RCTs and six CCTs were identified. Clinical heterogeneity did not allow for meta-analysis. Average change in clinical alveolar ridge (AR) width varied between -1.0 and -3.5 +/- 2.7 mm in ARP groups and between -2.5 and -4.6 +/- 0.3 mm in the controls, resulting in statistically significantly smaller reduction in the ARP groups in five out of seven studies. Mean change in clinical AR height varied between +1.3 +/- 2.0 and -0.7 +/- 1.4 mm in the ARP groups and between -0.8 +/- 1.6 and -3.6 +/- 1.5 mm in the controls. Height reduction in the ARP groups was statistically significantly less in six out of eight studies. Histological analysis indicated various degrees of new bone formation in both groups. Some graft interfered with the healing. Two out of eight studies reported statistically significantly more trabecular bone formation in the ARP group. No superiority of one technique for ARP could be identified; however, in certain cases guided bone regeneration was most effective. Statistically, significantly less augmentation at implant placement was needed in the ARP group in three out of four studies. The strength of evidence was moderate to low. CONCLUSIONS: Post-extraction resorption of the AR might be limited, but cannot be eliminated by ARP, which at histological level does not always promote new bone formation. RCTs with unassisted socket healing and implant placement in the ARP studies are needed to support clinical decision making. CLINICAL RELEVANCE: This systematic review reports not only on the clinical and radiographic outcomes, but also evaluates the histological appearance of the socket, along with site specific factors, patient-reported outcomes, feasibility of implant placement and strength of evidence, which will facilitate the decision making process in the clinical practice. PMID- 22814759 TI - Levels of salivary IgA in patients with minor recurrent aphthous stomatitis: a matched case-control study. AB - OBJECTIVES: Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disease. Despite plenty of studies on aetiopathogenesis of RAS, a definite cause is not clear. The objective of this study was to determine the potential changes of salivary IgA and salivary flow rate in patients affected with minor form of RAS. MATERIALS AND METHODS: Levels of salivary IgA in 33 patients with acute RAS (minor form) and 33 matched healthy controls were determined using enzyme-linked immunosorbent assay. Resting salivary flow rates were determined too. Both measurements, levels of salivary IgA and resting salivary flow rate, were performed again for each RAS patient in remission phase. RESULTS: Levels of salivary IgA were significantly increased in acute phase of RAS [median (interquartile range)-124.94 MUg/mL (106.22-136.31)] in comparison with the levels in healthy controls [88.92 MUg/mL (76.85-93.91; P < 0.001)] and with the levels in remission phase [102.4 MUg/mL (84.6-120.16; P = 0.01)]. Even in the disease-free period (remission phase), levels of salivary IgA remained significantly higher in comparison with the levels in healthy controls (P = 0.01). Salivary flow rates, on the other side, were not influenced by the disease state (RAS vs. healthy), phase (acute vs. remission) or even gender (males vs. females). CONCLUSION: Marked increase of salivary IgA in acute and remission phases of the minor RAS may suggest a potential role for this immunoglobulin in pathogenesis of the disease. CLINICAL RELEVANCE: Salivary IgA may be an important aetiological agent in the pathogenesis of RAS, and hence, its immunomodulation may help prevent the disease. PMID- 22814760 TI - Changes in mastication after an immediate loading implantation with complete fixed rehabilitation. AB - OBJECTIVE: This study aimed to measure modifications of mastication after immediate loading full-arch prosthesis (ILFAP) rehabilitation. MATERIALS AND METHOD: Fourteen patients were observed before and 6 months after ILFAP rehabilitation when masticating two natural, standardized foods (peanut and carrot) and three model foods with increasing hardness. The granulometry of the expectorated boluses from carrot and peanuts was characterized by median particle size (D50), determined at the natural point of swallowing. Chewing time (CT), number of chewing cycles (CC), and chewing frequency (CF) were video recorded. A self-assessment questionnaire for oral health-related quality of life [Geriatric Oral Health Assessment Index (GOHAI)] was also used. RESULTS: After ILFAP rehabilitation, the mean D50 values for carrot and peanuts were smaller [Repeated Model Procedures (RMP), F = 41, p < 0.001]. Mean CT and CC values recorded with the three model foods decreased, while CF increased regardless of the model food hardness (RMP, F = 14, F = 10, and F = 11, respectively, p < 0.001). The GOHAI score increased from 43 +/- 9 to 56 +/- 3 (t test, p < 0.001). CONCLUSION: ILFAP rehabilitation improves the ability to reduce the bolus particle size and the ability to discriminate between different food hardnesses in the 6 months post surgery period. CLINICAL RELEVANCE: This study encourages the clinical development of immediate loading implantation with a fixed full-arch prosthesis protocol. PMID- 22814761 TI - Color stability of white mineral trioxide aggregate. AB - OBJECTIVE: This study aims to evaluate the color stability of white mineral trioxide aggregate (WMTA) after irradiation with three different curing lights and with a fluorescent lamp in an oxygen-free environment. MATERIAL AND METHODS: Thirty samples of WMTA were divided into four experimental groups (three curing light and one fluorescent lamp) and one negative control group. The samples in the curing light groups were immersed in glycerine and were irradiated for 20, 60, and 120 s with a curing light. The samples in the fluorescent lamp group were immersed in glycerine and left on a laboratory shelf below a fluorescent lamp, whereas the negative control group was irradiated with a curing light without immersion in glycerine. A spectrophotometer was used to determine the color of each specimen before and after each light exposure and after 5 days. Data were analyzed using analysis of variance and Fisher's least significant difference test. RESULTS: All the groups showed discoloration except for the negative control group. At 20, 60, and 120 s, there were no significant differences between the Optilux and Bluephase groups (which were the darkest). The Demi group was the curing light experimental group that showed the lowest degree of discoloration (P = 0.0001). No differences were observed between the fluorescent lamp and the negative control groups. After 5 days, the fluorescent lamp group also showed darkening of the sample surface and there were no significant differences between this group and the other three experimental groups (P > 0.05). CONCLUSIONS: WMTA showed dark discoloration after irradiation with a curing light or fluorescent lamp in an oxygen-free environment. CLINICAL RELEVANCE: WMTA may cause tooth discoloration when it is used in a coronal position. PMID- 22814762 TI - Role of mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) in the recruitment of newcomer insulin granules in both first and second phases of glucose-stimulated insulin secretion in mouse islets. AB - AIMS/HYPOTHESIS: We have previously reported that the haplodeficient Munc13-1(+/ ) mouse exhibits impaired biphasic glucose-stimulated insulin secretion (GSIS), causing glucose intolerance mimicking type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can bypass these insulin-secretory defects in type 2 diabetes, but the mechanism of exocytotic events mediated by GLP-1 in rescuing insulin secretion is unclear. METHODS: The total internal reflection fluorescence microscopy (TIRFM) technique was used to examine single insulin granule fusion events in mouse islet beta cells. RESULTS: There was no difference in the density of docked granules in the resting state between Munc13-1(+/+) and Munc13-1(+/-) mouse islet beta cells. While exocytosis of previously docked granules in Munc13-1(+/-) beta cells is reduced during high-K(+) stimulation as expected, we now find a reduction in additional exocytosis events that account for the major portion of GSIS, namely two types of newcomer granules, one which has a short docking time (short-dock) and another undergoing no docking before exocytosis (no-dock). As mammalian homologue of Caenorhabditis elegans unc-13-1 (Munc13-1) is a phorbol ester substrate, phorbol ester could partially rescue biphasic GSIS in Munc13-1 deficient beta cells by enhancing recruitment of short-dock newcomer granules for exocytosis. The more effective rescue of biphasic GSIS by GLP-1 than by phorbol was due to increased recruitment of both short-dock and no-dock newcomer granules. CONCLUSIONS/INTERPRETATION: Phorbol ester and GLP-1 potentiation of biphasic GSIS are brought about by recruitment of distinct populations of newcomer granules for exocytosis, which may be mediated by Munc13-1 interaction with syntaxin-SNARE complexes other than that formed by syntaxin-1A. PMID- 22814763 TI - Deletion of protein kinase Cepsilon in mice has limited effects on liver metabolite levels but alters fasting ketogenesis and gluconeogenesis. AB - AIMS/HYPOTHESIS: Protein kinase Cepsilon (PKCepsilon) is emerging as a key mediator of lipid-induced insulin resistance in liver and hepatic lipid metabolism itself. We investigated whether PKCepsilon plays a role in other metabolic processes, to further examine its suitability as a therapeutic target. METHODS: We measured amino acid, organic acid and sugar levels by liquid and gas chromatography-mass spectrometry of liver extracts from chow and fat-fed wild type (WT) and PKCepsilon-deficient (Prkce(-/-)) mice. Fed and fasting glucose, ketone and fatty acid levels were measured in blood. Triacylglycerol levels and gluconeogenic and ketogenic enzyme expression were measured in liver. The effect of fasting on epididymal fat pad mass was also determined. RESULTS: Metabolomic analysis indicated that the short-term high-fat diet affected over 20 compounds, including a 50% reduction in the glucogenic amino acid alanine. Prkce deletion resulted only in a reduction of 4-hydroxyproline and aspartate and an increase in glutamate. However, upon fasting, Prkce(-/-) mice were better able to maintain blood glucose levels and also exhibited lower levels of the ketone beta hydroxybutyrate compared with WT mice. Upon fasting, Prkce deletion also resulted in lower liver and plasma lipids and a smaller reduction in fat pad mass. CONCLUSIONS/INTERPRETATION: Metabolomic analysis provided new insights into the effects of a high-fat diet on liver metabolite levels. Glucose homeostasis under fasting conditions is improved in Prkce(-/-) mice, which, in turn, may reduce the mobilisation of lipid from adipose tissue, reducing the availability of ketogenic substrate in the liver. Together with the protection against fat-diet-induced glucose intolerance previously observed in the fed state, these findings indicate PKCepsilon as a unique therapeutic target for the improvement of glucose homeostasis. PMID- 22814764 TI - Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes. AB - AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. METHODS: The biological actions of (pGlu Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. RESULTS: (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance. PMID- 22814766 TI - Improving general flexibility with a mind-body approach: a randomized, controlled trial using neuro emotional Technique(r). AB - General flexibility is a key component of health, well-being, and general physical conditioning. Reduced flexibility has both physical and mental/emotional etiologies and can lead to musculoskeletal injuries and athletic underperformance. Few studies have tested the effectiveness of a mind-body therapy on general flexibility. The aim of this study was to investigate if Neuro Emotional Technique(r) (NET), a mind-body technique shown to be effective in reducing stress, can also improve general flexibility. The sit-and-reach test (SR) score was used as a measure of general flexibility. Forty-five healthy participants were recruited from the general population and assessed for their initial SR score before being randomly allocated to receive (a) two 20-minute sessions of NET (experimental group); (b) two 20-minute sessions of stretching instruction (active control group); or (c) no intervention or instruction (passive control group). After intervention, the participants were reassessed in a similar manner by the same blind assessor. The participants also answered questions about demographics, usual water and caffeine consumption, and activity level, and they completed an anxiety/mood psychometric preintervention and postintervention. The mean (SD) change in the SR score was +3.1 cm (2.5) in the NET group, +1.2 cm (2.3) in the active control group and +1.0 cm (2.6) in the passive control group. Although all the 3 groups showed some improvement, the improvement in the NET group was statistically significant when compared with that of either the passive controls (p = 0.015) or the active controls (p = 0.021). This study suggests that NET could provide an effective treatment in improving general flexibility. A larger study is required to confirm these findings and also to assess longer term effectiveness of this therapy on general flexibility. PMID- 22814765 TI - Sulfur oxygenation in biomimetic non-heme iron-thiolate complexes. AB - The S-oxygenation of cysteine with dioxygen to give cysteine sulfinic acid occurs at the non-heme iron active site of cysteine dioxygenase. Similar S-oxygenation events occur in other non-heme iron enzymes, including nitrile hydratase and isopenicillin N synthase, and these enzymes have inspired the development of a class of [N(x)S(y)]-Fe model complexes. Certain members of this class have provided some intriguing examples of S-oxygenation, and this article summarizes these results, focusing on the non-heme iron(II/III)-thiolate model complexes that are known to react with O(2) or other O-atom transfer oxidants to yield sulfur oxygenates. Key aspects of the synthesis, structure, and reactivity of these systems are presented, along with any mechanistic information available on the oxygenation reactions. A number of iron(III)-thiolate complexes react with O(2) to give S-oxygenates, and the degree to which the thiolate sulfur donors are oxidized varies among the different complexes, depending upon the nature of the ligand, metal geometry, and spin state. The first examples of iron(II)-thiolate complexes that react with O(2) to give selective S-oxygenation are just emerging. Mechanistic information on these transformations is limited, with isotope labeling studies providing much of the current mechanistic data. The many questions that remain unanswered for both models and enzymes provide strong motivation for future work in this area. PMID- 22814768 TI - Sequence structure and intragenomic variability of ribosomal ITS2 in monozoic tapeworms of the genus Khawia (Cestoda: Caryophyllidea), parasites of cyprinid fish. AB - The sequence structure of the ribosomal internal transcribed spacer 2 (ITS2) was determined for six species of Khawia (Cestoda: Caryophyllidea), parasites of cyprinid fish in the Holarctic Region. Homologous intragenomic ITS2 structure was found in Khawia armeniaca, Khawia baltica, and Khawia rossittensis; whereas divergent intragenomic ITS2 copies were detected in Chinese, Japanese, and Slovak isolates of Khawia sinensis and in Khawia japonensis, both parasitic in common carp, and in Khawia saurogobii, recently described from Chinese lizard gudgeon in China. Despite distinct morphological differences between K. saurogobii and K. sinensis, both species display very high level of molecular homogeneity. Variation in number of short repetitive motifs [(GCCT)(n) (GCCC)(n)], [(GTG)(n)], [(ATAC)(n)], [ACGTGT (TCGTGT)(n)], [(GT)(n)], [(GT)(n)], and [(ACCT)(n) (GCCT)(n)] resulted in assortment of ITS2 sequences in four ITS2 variants in K. saurogobii from China, three in Chinese and Japanese isolates of K. sinensis, and five ITS2 variants in K. sinensis from Slovakia. In K. japonensis, the structure and arrangement of microsatellites was different from those of K. sinensis and K. saurogobii. The heterogeneity in the number of two microsatellite regions [(TG)(n); (TTG)(n)] divided ITS2 clones into two variants-first ITS2 variant (472 bp) with (TG)(5) and (TTG)(6), and second variant with (TG)(7) and (TTG)(2) (465 bp). Sequence identity of K. saurogobii with all but one (K. sinensis) congeneric species ranged between 49.5 and 69.2%, which corresponds to the interspecific differences. In contrast, sequence identity of K. saurogobii and K. sinensis (87.6-95.0%) failed into the range of intraspecific variation determined for K. sinensis samples. This close genetic similarity indicates that recently described K. saurogobii may have undergone morphological divergence as a result of ongoing sympatric speciation by host switching. PMID- 22814767 TI - Quantitative assessment of the associations between four polymorphisms (FokI, ApaI, BsmI, TaqI) of vitamin D receptor gene and risk of diabetes mellitus. AB - The vitamin D receptor (VDR) gene polymorphisms have been suggested to be involved in the development of diabetes mellitus, including type 1 diabetes (T1DM) and type 2 diabetes (T2DM). However, the results have been inconsistent. In this study, we performed a meta-analysis to investigate the associations. Literature was retrieved from PubMed, ISI Web of Science and Chinese databases. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated using a random or fixed effect model. 79 studies (FokI: 22 studies; BsmI: 25 studies; ApaI: 17 studies; TaqI: 15 studies) on T1DM and 44 studies (FokI: 10 studies; BsmI: 10 studies; ApaI: 14 studies; TaqI: 10 studies) on T2DM were included. The results indicated that BsmI polymorphism was associated with an increased risk of T1DM (B vs. b: OR 1.31, 95 % CI 1.10-1.55, P = 0.002), especially in East Asians (B vs. b: OR 2.57, 95 % CI: 1.55-4.24, P < 0.001); FokI polymorphism was associated with an increased risk of T2DM (f vs. F: OR 1.30, 95 % CI: 1.17-1.45, P < 0.001), especially in East Asians (f vs. F: OR 1.36, 95 % CI: 1.21-1.54, P < 0.001). However, no significant association was observed between ApaI or TaqI polymorphism and diabetes risk with the exception of significant association between ApaI polymorphism and T1DM risk in East Asians. Thus, the authors found BsmI polymorphism in the VDR gene may increase the risk of T1DM in East Asians and the FokI polymorphism may increase the risk of T2DM in East Asians. PMID- 22814769 TI - Giardia intestinalis: effects of Pulsatilla chinensis extracts on trophozoites. AB - Pulsatilla chinensis is a medicinal root plant that has been used to treat a wide range of disease conditions. Our study determined the antiprotozoal activity of various P. chinensis extracts and fractions against Giardia intestinalis including their effects on parasite growth, cell viability, adherence, and morphology. Ethyl acetate extracts (IC50 = 257.081 MUg/ml) were the most active to inhibit the growth of G. intestinalis followed by aqueous extract (PWE), saponins, and n-butanol extract. The PWE and ethyl acetate extract inhibited G. intestinalis trophozoites adherence after 3 h of incubation and killed almost 50 % of the parasite population in a time-dependent manner. Changes in morphology, presence of precipitates in the cytoplasm, dissolved cytoplasm with large vacuole, break of flagella and ventral disk, membrane blebs, and intracellular and nuclear clearance of the treated trophozoites were observed by scanning and transmission electron microscopy. We demonstrated that P. chinensis induced these changes in G. intestinalis morphology and consequently has potential therapeutic use against giardiasis. PMID- 22814770 TI - Tunga penetrans and further parasites in the giant anteater (Myrmecophaga tridactyla) from Minas Gerais, Brazil. AB - The Brazilian savannah-like area, the Cerrado region, covers large areas of the country and provides a habitat for a multitude of different animal species. The giant anteater (Myrmecophaga tridactyla) is geographically widespread and one of the typical inhabitants of the Cerrado. They are listed as vulnerable by the International Union for Conservation of Nature and Natural Resources. A population loss of at least 30 % over the past 10 years has been estimated based on local extinctions, habitat loss and deaths caused by fires, roadkills and hunting. Little is known about ecological and in particular parasitic conditions of this highly specialised insectivore species. During September and November 2010 we examined three roadkilled giant anteater for the presence of metazoan ecto- and endoparasites. Besides the cestode species Oochoristica tetragonocephala and the tick species Amblyomma nodosum, we found for the first time the flea Tunga penetrans. Beside morphological flea species identification, we compared a fragment of the 16S rRNA gene of eggs, a molecular method utilised for the first time in this combination. The identification of T. penetrans in M. tridactyla represents a new host record and expands the host and distribution range of the zoonotic flea species. PMID- 22814771 TI - Quantitative coronary arterial stenosis assessment by multidetector CT and invasive coronary angiography for identifying patients with myocardial perfusion abnormalities. AB - BACKGROUND: Semi-quantitative stenosis assessment by coronary CT angiography only modestly predicts stress-induced myocardial perfusion abnormalities. The performance of quantitative CT angiography (QCTA) for identifying patients with myocardial perfusion defects remains unclear. METHODS: CorE-64 is a multicenter, international study to assess the accuracy of 64-slice QCTA for detecting >=50% coronary arterial stenoses by quantitative coronary angiography (QCA). Patients referred for cardiac catheterization with suspected or known coronary artery disease were enrolled. Area under the receiver-operating-characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the most severe coronary artery stenosis in a subset of 63 patients assessed by QCTA and QCA for detecting myocardial perfusion abnormalities on exercise or pharmacologic stress SPECT. RESULTS: Diagnostic accuracy of QCTA for identifying patients with myocardial perfusion abnormalities by SPECT revealed an AUC of 0.71, compared to 0.72 by QCA (P = .75). AUC did not improve after excluding studies with fixed myocardial perfusion abnormalities and total coronary arterial occlusions. Optimal stenosis threshold for QCTA was 43% yielding a sensitivity of 0.81 and specificity of 0.50, respectively, compared to 0.75 and 0.69 by QCA at a threshold of 59%. Sensitivity and specificity of QCTA to identify patients with both obstructive lesions and myocardial perfusion defects were 0.94 and 0.77, respectively. CONCLUSIONS: Coronary artery stenosis assessment by QCTA or QCA only modestly predicts the presence and the absence of myocardial perfusion abnormalities by SPECT. Confounding variables affecting the relationship between coronary anatomy and myocardial perfusion likely account for some of the observed discrepancies between coronary angiography and SPECT results. PMID- 22814772 TI - Impact of ethnic variation and residential segregation on long-term survival following myocardial perfusion SPECT. AB - BACKGROUND: Ethnic characteristics of a neighborhood may impact upon all-cause mortality (ACM). It is not known whether this consideration remains a risk modifier among those being evaluated for CAD. METHODS: 6,477 pts (60 +/- 13 years, male 38%) residing in NYC with normal or abnormal stress SPECT studies were assessed for ACM during a mean follow-up of 9 +/- 3.8 years. Baseline CAD risk factors and ethnic characteristics of patient neighborhoods were considered. Zip-codes with >70% of one ethnicity was considered to be predominant of that ethnicity. RESULTS: There were 573 (20%) Hispanics (HS), 765 (27%) African Americans (AA), and 250 (30%) Caucasians (CC) residing in areas >70% of their own ethnicity. Compared to CC, the risk for ACM was lower in HS (hazard ratio (HR) 0.68, 95% CI 0.57-0.8, P < .0001) and similar among AA (HR 1.1, 95% CI 0.95-1.41, P = .2). Among HS, there was a lower ACM among those residing in HS areas compared to those residing in a non-HS areas (HR 0.7 95% CI 0.56-0.9, P = .03) despite a lower median household income ($27,838 +/- 3,328 vs $37,751 +/- 17,036; P < .0001). This survival difference was not seen in CC and AA. CONCLUSION: Among patients referred for nuclear SPECT studies for suspected CAD, HS ethnicity was an independent predictor of a favorable prognosis. Among HS, the ethnic characteristic of patients' neighborhoods was an independent predictor of ACM. These results imply that ethnic social support is a potentially powerful modifier of patient outcomes among certain patient groups. PMID- 22814773 TI - The prognosis of a normal Tl-201 stress-only SPECT MPI study. AB - BACKGROUND: Stress-only Tc-99m SPECT myocardial perfusion imaging (MPI) decreases test time and patient radiation exposure with a proven benign prognosis of a normal study. The imaging sequence of Tl-201 MPI always starts with the stress portion; therefore, no pre-test decisions are needed regarding the imaging sequence. The recent intermittent Tc-99m shortage afforded the unique opportunity to study an unselected group of patients undergoing Tl-201 imaging. METHODS: We retrospectively reviewed all the patients who had SPECT MPI with Tc-99m or Tl-201 over a 1-year period. When Tc-99m was not available, patients received Tl-201. All stress Tl-201 images were routinely processed, and if normal, rest imaging was not done. When Tc-99m was used, patients with lower pre-test probability were selected for a stress-first protocol. We compared the all-cause mortality of patients with normal Tl-201 studies to those with normal stress-only and rest stress Tc-99m studies using the Social Security Death Index. Unadjusted and risk adjusted survival analysis was performed. Specific causes of death (cardiac or non-cardiac) were determined by medical record review and contact with treating physicians. RESULTS: A total of 3,658 patients underwent stress MPI during this time period. Of the 1,215 patients who had Tl-201 MPI, 716 (67%) had a normal stress-only study. Out of 2,443 patients who underwent Tc-99m MPI, 70% had normal perfusion with 1,098 normal stress-only studies and 493 normal rest-stress studies. The average follow-up was 23.3 +/- 5.3 months. Unadjusted all-cause mortality at the end of follow-up was 7.1% in the Tl-201 stress-only group, 6.3% for Tc-99m stress-only patients, and 4.3% in the Tc-99m rest-stress cohort. After controlling for confounding variables, survival was similar in the three groups (HR 1.07, 95% CI 0.62-1.82, P = .82 for normal Tl-201 stress-only compared to normal Tc-99m rest-stress). The risk-adjusted 1-year survival was between 98.5 and 98.8% in the three groups. CONCLUSIONS: Normal stress-only Tl-201 SPECT MPI study has a similarly benign prognosis when compared to Tc-99m rest-stress and Tc 99m stress-only normal SPECT MPI studies. The stress-first design allowed for early triage of over 60% of patients and marked improvement in laboratory efficiency due to shortened test time. PMID- 22814774 TI - Optimizing outcomes during left main percutaneous coronary intervention with intravascular ultrasound and fractional flow reserve: the current state of evidence. AB - Percutaneous coronary intervention (PCI) is an evolving indication for the treatment of unprotected left main coronary arterial (UMLCA) stenoses in selected individuals. Intravascular ultrasound (IVUS)-guided PCI within the epicardial coronary tree has been shown to improve acute procedural results and subsequent clinical outcomes. Similarly, fractional flow reserve (FFR) is rapidly gaining popularity as a means to guide the coronary interventionalist to embark upon a "physiological-based" revascularization strategy. In light of the emergence of PCI for ULMCA stenoses, the lack of randomized trials has meant that there are no systematic guidelines that advocate the routine use of these adjunctive imaging techniques to optimize procedural and clinical outcomes. Given the potential dire clinical consequences of procedural failure during ULMCA PCI, in this review we systematically address the current level of evidence for the use of FFR and IVUS during the assessment for and undertaking of PCI for ULMCA stenoses. In lieu of the current available level of evidence, we recommend the use of FFR for the assessment of (angiographic indeterminate) isolated ostial or midshaft left main coronary arterial (LMCA) stenoses in patients who are considered more appropriate candidates for coronary arterial bypass grafting. In those patients with distal/bifurcation LMCA lesions and in those with diffuse/distal coronary arterial disease, we strongly recommend the liberal use of IVUS. Furthermore, in those patients considered likely candidates for ULMCA PCI, IVUS remains crucial for assessing the degree of lumen compromise and the extent, distribution, and morphology of plaque as well as for the immediate postprocedural quantification of stent deployment. PMID- 22814775 TI - Everolimus-eluting stent implantation for unprotected left main coronary artery stenosis. The PRECOMBAT-2 (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study. AB - OBJECTIVES: This study sought to evaluate the safety and efficacy of second generation drug-eluting stents (DES) for patients with unprotected left main coronary artery (ULMCA) stenosis. BACKGROUND: The clinical benefit of second generation DES for ULMCA stenosis has not been determined. METHODS: The authors assessed 334 consecutive patients who received everolimus-eluting stents (EES) for ULMCA stenosis between 2009 and 2010. The 18-month incidence rates of major adverse cardiac or cerebrovascular events (MACCE), including death, myocardial infarction (MI), stroke, or ischemia-driven target vessel revascularization (TVR), were compared with those of a randomized study comparing patients who received sirolimus-eluting stents (SES) (n = 327) or coronary artery bypass grafts (CABG) (n = 272). RESULTS: EES (8.9%) showed a comparable incidence of MACCE as SES (10.8%; adjusted hazard ratio [aHR] of EES: 0.84; 95% confidence interval [CI]: 0.51 to 1.40; p = 0.51) and CABG (6.7%, aHR of EES: 1.40; 95% CI: 0.78 to 2.54; p = 0.26). The composite incidence of death, MI, or stroke also did not differ among patients receiving EES (3.3%), SES (3.7%; aHR of EES: 0.63; 95% CI: 0.27 to 1.47; p = 0.29), and CABG (4.8%; aHR of EES: 0.67; 95% CI: 0.29 to 1.54; p = 0.34). However, the incidence of ischemia-driven TVR in the EES group (6.5%) was higher than in the CABG group (2.6%, aHR of EES: 2.77; 95% CI: 1.17 to 6.58; p = 0.02), but comparable to SES (8.2%, aHR of EES: 1.14; 95% CI: 0.64 to 2.06; p = 0.65). Angiographic restenosis rates were similar in the SES and EES groups (13.8% vs. 9.2%, p = 0.16). CONCLUSIONS: Second-generation EES had a similar 18-month risk of MACCE for ULMCA stenosis as first-generation SES or CABG. PMID- 22814776 TI - Drug-eluting stent for left main coronary artery disease. The DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. AB - OBJECTIVES: The aim of this study was to compare, in a large all-comers registry, major adverse cardiac and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in unprotected left main coronary artery (ULMCA) stenosis. BACKGROUND: Percutaneous coronary intervention with DES implantation in ULMCA has been shown to be a feasible and safe approach at midterm clinical follow-up. METHODS: All consecutive patients with ULMCA stenosis treated by PCI with DES versus CABG were analyzed in this multinational registry. A propensity score analysis was performed to adjust for baseline differences in the overall cohort. RESULTS: In total 2,775 patients were included: 1,874 were treated with PCI versus 901 with CABG. At 1,295 (interquartile range: 928 to 1,713) days, there were no differences, at the adjusted analysis, in the primary composite endpoint of death, cerebrovascular accidents, and myocardial infarction (MI) (adjusted hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.85 to 1.42; p = 0.47), mortality (adjusted HR: 1.16; 95% CI: 0.87 to 1.55; p = 0.32), or composite endpoint of death and MI (adjusted HR: 1.25; 95% CI: 0.95 to 1.64; p = 0.11). An advantage of CABG over PCI was observed in the composite secondary endpoint of MACCE (adjusted HR: 1.64; 95% CI: 1.33 to 2.03; p < 0.0001), driven exclusively by the higher incidence of target vessel revascularization with PCI. CONCLUSIONS: In our multinational all-comers registry, no difference was observed in the occurrence of death, cerebrovascular accidents, and MI between PCI and CABG. An advantage of CABG over PCI was observed in the incidence of MACCE, driven by the higher incidence of target vessel revascularization with PCI. PMID- 22814777 TI - Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]). AB - OBJECTIVES: This study sought to assess the effectiveness of a strategy of using drug-eluting stents (DES) with a different drug (switch) in patients with DES in stent restenosis (ISR). BACKGROUND: Treatment of patients with DES ISR remains a challenge. METHODS: The RIBS-III (Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent) study was a prospective, multicenter study that aimed to assess results of coronary interventions in patients with DES ISR. The use of a different DES was the recommended strategy. The main angiographic endpoint was minimal lumen diameter at 9-month follow-up. The main clinical outcome measure was a composite of cardiac death, myocardial infarction, and target lesion revascularization. RESULTS: This study included 363 consecutive patients with DES ISR from 12 Spanish sites. The different-DES strategy was used in 274 patients (75%) and alternative therapeutic modalities (no switch) in 89 patients (25%). Baseline characteristics were similar in the 2 groups, although lesion length was longer in the switch group. At late angiographic follow-up (77% of eligible patients, median: 278 days) minimal lumen diameter was larger (1.86 +/- 0.7 mm vs. 1.40 +/- 0.8 mm, p = 0.003) and recurrent restenosis rate lower (22% vs. 40%, p = 0.008) in the different-DES group. At the last clinical follow-up (99% of patients, median: 771 days), the combined clinical endpoint occurred less frequently (23% vs. 35%, p = 0.039) in the different-DES group. After adjustment using propensity score analyses, restenosis rate (relative risk: 0.41, 95% confidence interval [CI]: 0.21 to 0.80, p = 0.01), minimal lumen diameter (difference: 0.41 mm, 95% CI: 0.19 to 0.62, p = 0.001), and the event-free survival (hazard ratio: 0.56, 95% CI: 0.33 to 0.96, p = 0.038) remained significantly improved in the switch group. CONCLUSIONS: In patients with DES ISR, the implantation of a different DES provides superior late clinical and angiographic results than do alternative interventional modalities. PMID- 22814778 TI - Drug-eluting stent restenosis: a need for new technology? PMID- 22814779 TI - Time course of endothelium-dependent and -independent coronary vasomotor response to coronary balloons and stents. Comparison of plain and drug-eluting balloons and stents. AB - OBJECTIVES: This study sought to determine the time dependency of the endothelium dependent and -independent vascular responses after percutaneous coronary intervention (PCI) with drug-eluting (DEB) or plain balloons, bare-metal (BMS), and drug-eluting (DES) stents, or controls. BACKGROUND: Long-term endothelial dysfunction after DES implantation is associated with delayed healing and late thrombosis. METHODS: Domestic pigs underwent PCI using DEB or plain balloon, BMS, or DES. The dilated and stented segments, and the proximal reference segments of stents and control arteries were explanted at 5-h, 24-h, 1-week, and 1-month follow-up (FUP). Endothelin-induced vasoconstriction and endothelium-dependent and -independent vasodilation of the arterial segments were determined in vitro and were related to histological results. RESULTS: DES- and BMS-treated arteries showed proneness to vasoconstriction 5 h post-PCI. The endothelium-dependent vasodilation was profoundly (p < 0.05) impaired early after PCI (9.8 +/- 3.7%, 13.4 +/- 9.2%, 5.7 +/- 5.3%, and 7.6 +/- 4.7% using plain balloon, DEB, BMS, and DES, respectively), as compared with controls (49.6 +/- 9.5%), with slow recovery. In contrast to DES, the endothelium-related vasodilation of vessels treated with plain balloon, DEB, and BMS was increased at 1 month, suggesting enhanced endogenous nitric oxide production of the neointima. The endothelium independent (vascular smooth muscle-related) vasodilation decreased significantly at 1 day, with slow normalization during FUP. All PCI-treated vessels exhibited imbalance between vasoconstriction-vasodilation, which was more pronounced in DES and BMS-treated vessels. No correlation between histological parameters and vasomotor function was found, indicating complex interactions between the healing neoendothelium and smooth muscle post-PCI. CONCLUSIONS: Coronary arteries treated with plain balloon, DEB, BMS, and DES showed time-dependent loss of endothelial dependent and -independent vasomotor function, with imbalanced contraction/dilation capacity. PMID- 22814780 TI - Radiation exposure during percutaneous coronary interventions and coronary angiograms performed by the radial compared with the femoral route. AB - OBJECTIVES: This study aimed to compare radiation exposure of patients undergoing percutaneous coronary interventions (PCI) and coronary angiograms (CAG) accessed by the femoral route with the radial route (operator's choice). BACKGROUND: There are limited and contradictory data on the radiation exposure of patients during PCI and CAG performed by the radial route compared with the femoral route. METHODS: Data on the radiation exposure of patients from 3,973 PCI and CAG procedures between June 22, 2004, and December 31, 2008, were prospectively collected and analyzed. A prediction model was made for radiation exposure (dose area product in Gy.cm(2)) based upon the femoral access group, and the group of radial performed procedures was compared to assess differences between observed and expected radiation exposure. RESULTS: Median exposures of patients undergoing a PCI via the femoral route (n = 2,309) was 75 (interquartile range [IQR]: 44 to 135) Gy.cm(2) compared with 72 (IQR: 42 to 134) Gy.cm(2) for radial performed procedures (n = 1,212) (p = 0.30). Median exposure for CAGs was 44 (IQR: 31 to 69) Gy.cm(2) and 40 (IQR: 25 to 65) Gy.cm(2) for, respectively, femoral (n = 314) and radial performed procedures (n = 138), (p = 0.31). Also, the observed radiation exposure in patients undergoing radial PCI or CAGs was not higher than the expected exposure of patients as predicted by the femoral access-based prediction model (71.5 +/- 2.3 Gy.cm(2) vs. 79.9 +/- 1.8 Gy.cm(2,)). CONCLUSIONS: The study shows that even after correction for the complexity of the procedures, selected procedures performed by the radial route are not associated with higher radiation exposure of patients than selected procedures performed by the femoral route. PMID- 22814781 TI - Renal sympathetic denervation using an irrigated radiofrequency ablation catheter for the management of drug-resistant hypertension. AB - OBJECTIVES: This study sought to assess whether renal sympathetic denervation (RSDN) can be achieved using an off-the-shelf saline-irrigated radiofrequency ablation (RFA) catheter typically employed for cardiac tissue ablation. BACKGROUND: RSDN using a specialized solid-tip RFA catheter has recently been demonstrated to safely reduce systemic blood pressure in patients with refractory hypertension. For cardiac tissue ablation, RFA technology has evolved from nonirrigated to saline-irrigated ablation electrodes to improve both safety and effectiveness. METHODS: Ten patients with resistant hypertension underwent renal angiography, followed by bilateral RSDN with a saline-irrigated RFA catheter. Ambulatory blood pressure recordings (24 h) were obtained at baseline, 1, 3, and 6 months after the procedure. Repeat renal angiography was performed during follow-up to assess for arterial stenosis or aneurysm. In 5 patients, pre- and post-procedural serum measures of renal function and sympathetic activity were obtained: aldosterone; metanephrine; normetanephrine; plasma renin activity; and creatinine. RESULTS: Over a 6-month period: 1) the systolic/diastolic blood pressure decreased by -21/-11 mm Hg; 2) all patients experienced a decrease in systolic blood pressure of at least 10 mm Hg (range 10 to 40 mm Hg); 3) there was no evidence of renal artery stenosis or aneurysm at repeat angiography; and 4) there was a significant decrease in metanephrine (-12 +/- 4, p = 0.003), normetanephrine (-18 +/- 4, p = 0.0008), and aldosterone levels (-60 +/- 33 ng/l, p = 0.02) at 3 months. There was no significant change in plasma renin activity ( 0.2 mg/l/hod, p = 0.4). There was no significant change in serum creatinine (-1 mmol/l, p = 0.4). CONCLUSIONS: These data provide the proof-of-principle that RSDN can be performed using an off-the-shelf saline-irrigated RFA catheter. PMID- 22814782 TI - Renal denervation using an irrigated radiofrequency ablation catheter for management of drug-resistant hypertension: a demonstrated value? PMID- 22814784 TI - Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. AB - OBJECTIVES: In this study, a meta-analysis of observational studies was performed to compare the rate of recurrent neurological events (RNE) between transcatheter closure and medical management of patients with cryptogenic stroke/transient ischemic attack (TIA) and concomitant patent foramen ovale (PFO). BACKGROUND: A significant controversy surrounds the optimal strategy for treatment of cryptogenic stroke/TIA and coexistent PFO. METHODS: We conducted a MEDLINE search with standard search terms to determine eligible studies. RESULTS: Adjusted incidence rates of RNE were 0.8 (95% confidence interval [CI]: 0.5 to 1.1) events and 5.0 (95% CI: 3.6 to 6.9) events/100 person-years (PY) in the transcatheter closure and medical management arms, respectively. Meta-analysis of the limited number of comparative studies and meta-regression analysis suggested that the transcatheter closure might be superior to the medical therapy in prevention of RNE after cryptogenic stroke. Comparison of the anticoagulation and antiplatelet therapy subgroups of the medical arm yielded a significantly lower risk of RNE within patients treated with anticoagulants. Device-related complications were encountered at the rate of 4.1 (95% CI: 3.2 to 5.0) events/100 PY, with atrial arrhythmias being the most frequent complication. After transcatheter closure, RNE did not seem to be related to the pre-treatment shunt size or the presence of residual shunting in the follow-up period. Significant benefit of transcatheter PFO closure was apparent in elderly patients, patients with concomitant atrial septal aneurysm, and patients with thrombophilia. CONCLUSIONS: Rates of RNE with transcatheter closure and medical therapy in patients presenting with cryptogenic stroke or TIA were estimated at 0.8 and 5.0 events/100 PY. Further randomized controlled trials are needed to conclusively compare these 2 management strategies. PMID- 22814783 TI - Serious infection after acute myocardial infarction: incidence, clinical features, and outcomes. AB - OBJECTIVES: The aim of this study was to address the knowledge gap using the APEX AMI (Assessment of Pexelizumab in Acute Myocardial Infarction) trial database. We also assessed the association between serious infections and 90-day death or death/myocardial infarction (MI). BACKGROUND: Little is known about the incidence, location, etiological organisms, and outcomes of infection in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. METHODS: We analyzed data from 5,745 STEMI patients enrolled in the APEX-AMI trial. Detailed information on infection was collected for all patients. We described characteristics of patients according to infection and details of infection. Cox proportional hazards models were used to assess 90-day outcomes among patients with and without infections after adjusting for associated clinical variables and with infection as a time-dependent covariate. RESULTS: Overall, 138 patients developed a serious infection (2.4%), most of whom presented with a single-site infection. The median (25th, 75th percentile) time until diagnosis of infection was 3 (1, 6) days. The most commonly identified organism was Staphylococcus aureus, and the main location of infection was the bloodstream. These patients had more comorbidities and lower procedural success at index percutaneous coronary intervention than those without infections. Serious infection was associated with significantly higher rates of 90-day death (adjusted hazard ratio: 5.6; 95% confidence interval: 3.8 to 8.4) and death or MI (adjusted hazard ratio: 4.9; 95% confidence interval: 3.4 to 7.1). CONCLUSIONS: Infections complicating the course of patients with STEMI were uncommon but associated with markedly worse 90-day clinical outcomes. Mechanisms for early identification of these high-risk patients as well as design of strategies to reduce their risk of infection are warranted. PMID- 22814785 TI - Medical device innovation: prospective solutions for an ecosystem in crisis. Adding a professional society perspective. AB - Barriers to medical device innovation compromise timelines and costs from bench to bedside. Fragmented strategies by individual competitors are no longer sustainable. Pragmatically focused pre-competitive collaboration across stakeholders approaches innovation as an ecosystem. Desiloing experience and expertise encourages high-impact infrastructure efficiencies unique to pre competitive constructs. Alignment of processes and objectives across the regulatory, reimbursement, clinical research, and clinical practice enterprises, with particular attention to the total product life cycle and continuous accrual of safety information, promotes more predictable equipoise for speed of access relative to residual safety concerns. Professional societies are well positioned to convene pre-competitive dialogue, facilitate alignment, and add perspective to equipoise within the innovation ecosystem. PMID- 22814786 TI - Innovation at the Food and Drug Administration's Device Center. PMID- 22814787 TI - In-stent neoatherosclerosis: a cause of late stent thrombosis in a patient with "full metal jacket" 15 years after implantation: insights from optical coherence tomography. PMID- 22814788 TI - Appropriate use criteria (AUC) versus the heart team: to lump or to split. PMID- 22814789 TI - Suspected hypersensitivity reaction following drug-eluting stent implantation. Novel insights with optical coherence tomography. PMID- 22814790 TI - Aggregation induced ratiometric fluorescence change for a novel boron-based carbazole derivative. AB - Nanoparticles of a novel boron-based carbazole derivative have been reported. They exhibit efficient green fluorescence, aggregation induced ratiometric fluorescence change and green/blue fluorescent switching to sense VOCs. PMID- 22814792 TI - Stressors and rheumatoid arthritis: changes in stressors with advances in therapeutic agents. AB - The significance of evaluations of stressors in rheumatoid arthritis (RA) patients was investigated from the perspective of holistic medicine. The subjects were RA patients treated in the rheumatology outpatient clinic. They included 30 patients from 1987, 30 from 2002, and 137 from 2009. To investigate the specific causes of stress, the patients were asked the question, "What do you feel is your strongest stressor?" The same patients also underwent psychological testing and was examined the disease activity. Pain was the strongest stressor in RA patients in 1987, 2002, and 2009. However, the percentage of patients citing pain as their major stressor was decreasing with each year. CRP was significantly lower in 2009 than in 2002. CRP was also significantly lower in patients who used biologics than in patients who did not. In 2009, DAS28-CRP was significantly higher in patients whose largest stressor was pain than in patients whose largest stressor was another factor. In 2009, the values for both state anxiety and trait anxiety were significantly higher in patients who said that they had stressors than in those who said they did not. The strongest stressor in RA patients was pain. However, the percentage decreased over the years with lower disease activity from advances in therapeutic agents such as biologics. Meanwhile, stressors other than pain were the same or somewhat increased, and they were related to anxiety or depression. Understanding stressors in RA is thus important in treating RA patients. PMID- 22814791 TI - The factors considered as trigger for the attacks in patients with familial Mediterranean fever. AB - Although the inflammatory cascade of familial Mediterranean fever (FMF) is partially understood, triggering factors of those attacks has not been studied well. It is supposed that physical stresses such as cold exposure, tiredness and emotional stresses could provoke attacks. This study is aimed to survey the factors regarded as triggering the attacks in patients with FMF and their relationship with MEFV gene mutations. Clinical findings and genetic mutations (consist of M694V, M694I, M680I, V726A, E148Q) of patients were recorded. Patients were questioned about cold exposure, emotional stress, tiredness, long lasting standing, long-duration travel, starvation, high intake of food, trauma, and infection as triggering factors for the attacks with both serositis and musculoskeletal pain. The study is comprised of 275 FMF patients (male/female: 177/98). The most common triggering factors for the attacks with serositis were cold exposure (59.3 %), emotional stress (49.8 %), tiredness (40.0 %) and menstruation (33.7 % in females). Long-lasting standing (78.8 %), long-duration travel (64.1 %) and tiredness (47.8 %) were the triggering factors for the attacks with musculoskeletal symptoms. The relationships between MEFV mutations and triggering factors were found as M694V allele with starvation, E148Q allele with high intake of food and V726A allele with long-duration travel. The attacks with serositis seem to be triggered by those factors to which whole body exposed, whereas the attacks with musculoskeletal complaints seem to be triggered by those factors to which regional or local part of body exposed. Since the number of alleles was small, a clear conclusion for a relationship between a particular gene variant and a specific trigger was not made. PMID- 22814793 TI - Is RUNX3 a new player in the pathogenesis of ankylosing spondylitis? PMID- 22814794 TI - A four-time-recurring typical complete Kawasaki syndrome successfully treated with intravenous immunoglobulin: a case report with literature review. AB - Kawasaki syndrome (KS) typically strikes children younger than age 5 and presents with persistent high fever for at least 5 days combined with a heterogeneous polymorphous rash, extremity abnormalities, oropharyngitis, non-exudative conjunctivitis and cervical lymphadenitis. Treatment with high-dose intravenous immunoglobulin reduces substantially the risk of potential cardiovascular complications. For the first time, we report a child presenting all the clinical symptoms of KS, which recurred for 4 times in a period of 33 months. Each relapse was characterized by obstinate high fever combined with mucocutaneous signs and was each time successfully treated with intravenous immunoglobulin without the occurrence of any cardiovascular damage. PMID- 22814795 TI - Electric field effect on the zigzag (6,0) single-wall BC2N nanotube for use in nano-electronic circuits. AB - We have analyzed the effect of external electric field on the zigzag (6,0) single wall BC2N nanotube using density functional theory calculations. Analysis of the structural parameters indicates that the nanotube is resistant against the external electric field strengths. Analysis of the electronic structure of the nanotube indicates that the applied parallel electric field strengths have a much stronger interaction with the nanotube with respect to the transverse electric field strengths and the nanotube is easier to modulate by the applied parallel electric field. Our results show that the properties of the nanotube can be controlled by the proper external electric field for use in nano-electronic circuits. PMID- 22814796 TI - Perimenstrual headache in adolescence. AB - Headaches are a common complaint of childhood with the majority of the recurrent headaches seen by medical practitioners representing migraine. The incidence increases throughout adolescents as both boys and girls go through puberty. At this same time the ratio between girls and boys with migraine starts to become evident. This most likely etiology of these observations is the biological effects of hormonal progression and the expression of menstrual-related migraine. This development has begun to be delineated and this review will report on some of the advances toward this understanding. PMID- 22814797 TI - Magnetism in gold nanoparticles. AB - Gold nanoparticles currently elicit an intense and very broad research activity because of their peculiar properties. Be it in catalysis, optics, electronics, sensing or theranostics, new applications are found daily for these materials. Approximately a decade ago a report was published with magnetometry data showing that gold nanoparticles, most surprisingly, could also be magnetic, with features that the usual rules of magnetism were unable to explain. Many ensuing experimental papers confirmed this observation, although the reported magnetic behaviours showed a great variability, for unclear reasons. In this review, most of the experimental facts pertaining to "magnetic gold" are summarized. The various theories put forth for explaining this unexpected magnetism are presented and discussed. We show that despite much effort, a satisfying explanation is still lacking and that the field of hypotheses should perhaps be widened. PMID- 22814798 TI - Syntheses, structures and physical properties of transition metal-organic frameworks assembled from trigonal heterofunctional ligands. AB - Six novel metal-organic frameworks (MOFs), {Mn(bpydb)(bpyHdbH)}(n) (1) {[Co(2)(bpydb)(2)](H(2)O)(0.5)}(n) (2), {[Ni(0.5)(bpydbH)(H(2)O)](DMF)(2)}(n) (3), {[Cu(2)(bpydb)(2)](H(2)O)(0.5)}(n) (4), {Zn(bpyHdb)(2)}(n) (5) and {[Cd(0.5)(bpydb)(0.5)(DMF)](H(2)O)}(n) (6), were successfully synthesized by assembling transition metal salts with trigonal heterofunctional ligand 4,4' (4,4'-bipyridine-2,6-diyl) dibenzoic acid (bpydbH(2)) under hydrothermal and/or solvothermal conditions. Compound 1 features a rare 4-fold interpenetrating (3,5) connected framework with hms-type topology. Isostructural compounds 2 and 4, constructed by M(2)(COO)(4) secondary building units, exhibit a robust 3D framework with alb topological type in 2-fold interpenetrating mode. Compound 3 consists of 2D (4,4) networks, which are further assembled into the new topological framework with the symbol (5(3).6(2).8)(5(3).6(3))(2) through O-HO interactions. Compound 5 manifests a novel 4-connected interpenetrating framework, constructed by 2D (4,4) layers and interbedded N-HO interactions. Non interpenetrating honeycomb networks are observed in compound 6, and further packed into a 3D framework featuring 1D channels. The magnetic susceptibility of compound 2 indicates antiferromagnetic interactions between cobalt ions. The photoluminescent properties of 5 and 6 were investigated in the solid state at room temperature. PMID- 22814800 TI - Screening for intrauterine growth restriction in uncomplicated pregnancies: time for action. AB - A randomized clinical trial (RCT) noted that sonographic examination in the third trimester, in conjunction with delivery at term for abnormalities of fetal growth, significantly decreased the likelihood of small-for-gestational-age (SGA) neonates in uncomplicated pregnancies. We identified 15 characteristics of screening tests and attempted to determine if there is evidence to routinely obtain sonographic estimates of fetal weight in the third trimester and decrease rates of SGA. Of the 15 suggested characteristics, currently 10 (67%) are fulfilled, two are uncertain (sonographic examination is cost-effective or reliable), and one (the test must do its job) is possibly valid. Due to the lack of RCTs demonstrating reduction in morbidity, there is potential for lead-time and length bias. To observe a 36% decrease (from 4.1 to 2.6%) decrease in composite perinatal morbidity, 6000 women need to be randomized to at least two sonographic examinations in the third trimester versus routine prenatal care. Such an RCT is warranted and justified. PMID- 22814799 TI - Validation of a scoring system to identify women with near-miss maternal morbidity. AB - OBJECTIVE: To validate a five-factor scoring system that identifies parturients who experience near-miss morbidity. STUDY DESIGN AND SETTING: This study was conducted in an urban, tertiary care hospital over a 2-year period. A narrative case summary was prepared for women with high potential for significant obstetric morbidity. The summary was then reviewed by three physicians, and the extent of morbidity was assigned based on subjective assessment. The same cases were then scored using the proposed five-factor scoring system previously described by Geller et al. Test characteristics of the scoring system were assessed. RESULTS: Eight hundred fifteen cases with a high potential for significant morbidity were identified. Subjective review and the scoring system classified 4.5% and 4.2% as near-miss morbidity, respectively, with the scoring system having a corresponding sensitivity of 81.1% (95% confidence interval 64.8 to 92.0%) and a specificity of 99.5% (95% confidence interval 98.7 to 99.9%). CONCLUSION: The scoring system produced similar results to those obtained at its initial development and demonstrated acceptable sensitivity and specificity for identifying near-miss morbidity. PMID- 22814801 TI - Maternal antenatal treatments influence initial oral microbial acquisition in preterm infants. AB - OBJECTIVE: The purpose of this study was to analyze the association of maternal antenatal therapy on initial preterm infant oral microbial acquisition of gut metabolically important bacteria: Firmicutes, Bacteroidetes, Lactobacillus, Bifidobacterium, and Bacteroides species. STUDY DESIGN: Infant oral samples were collected prefeeding at 24 hours and analyzed using group-specific primers by real-time 16S rRNA quantitative polymerase chain reaction with analysis of variance and logistic regression to evaluate effect of antenatal exposure. RESULTS: Sixty-five infants < 34 weeks' gestational age (GA) were evaluated; mean GA was 28.6 +/- 2.6 (standard deviation) weeks. Infants unexposed to antenatal treatment (n = 5) acquired < 1% Firmicutes, which was composed of 100% Lactobacillus species with no detectable Bifidobacterium, Bacteroidetes, or Bacteroides species. Infants exposed to antibiotics (n = 7), acquired fivefold less total bacterial density (TBD) with 45% Firmicutes 1.3% Lactobacillus species, 23.5% Bacteroidetes and rare Bacteroides. Compared with unexposed infants, steroids (n = 26) or steroid and antibiotics (n = 27) exposure led to an eightfold increase in TBD with < 1% Lactobacillus species and Bacteroides species 100% and 30%, respectively (p < 0.04). Bifidobacterium was undetectable in all groups. CONCLUSION: Preterm infant exposure to routine maternal antenatal treatments influence early oral microbial acquisition during the primary hours related to establishment of gut commensal bacteria. PMID- 22814802 TI - Aggravation effect of isoflurane on Abeta(25-35)-induced apoptosis and tau hyperphosphorylation in PC12 cells. AB - Some anesthetics have been suggested to induce Alzheimer's disease (AD) neuro pathogenesis. Increasing evidence indicates that hyperphosphorylated tau plays a key role in the pathogenic events that occur in AD. Isoflurane has been shown to induce apoptosis, which leads to accumulation of amyloid-beta (Abeta). We set out to investigate whether isoflurane can induce apoptosis by increasing hyperphosphorylated tau in Abeta25-35-induced cells and the underlying mechanism. Cultured rat pheochromocytoma cells (PC12) were exposed to 20 mM Abeta25-35 alone or with 2% isoflurane for 6 h. The cell viability was determined by MTT assay, and the apoptosis rate was detected by flowcytometry. Western blotting and immunocytochemical staining were performed to observe the protein expression of Bcl-2 family, tau phosphorylation of different sites, tau protein kinases and phosphatases. Additionally, lithium chloride was administered to all above groups to investigate the changes of apoptosis rate and protein expression. The apoptosis rate was significantly increased in Abeta25-35 group compared with the others groups, which was accompanied by bcl-2 decline, and the phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) and tau of two sites increased. LiCl attenuated the cellular apoptosis by inhibition the level of tau phosphorylation. Isoflurane upregulated the level of phosphorylated GSK-3beta, which phosphorylate tau at different sites, and aggravated the apoptotic rate of the Abeta25-35 induced PC12 cells. It indicated that isoflurane-induced tau phosphorylation might play a role in the AD-like development. PMID- 22814803 TI - Protective effects of a novel synthetic alpha-lipoic acid-decursinol hybrid compound in experimentally induced transient cerebral ischemia. AB - Alpha-lipoic acid (ALA), a natural antioxidant, is widely used for the treatment of some diseases including diabetes, and decursinol (DA), a constituent of root of Angelica gigas Nakai, has some pharmacological activities including anti inflammatory function. In this study, we synthesized a novel synthetic alpha lipoic acid-decursinol (ALA-DA) hybrid compound, and compared neuroprotective effects of ALA, DA or ALA-DA against ischemic damage in the gerbil hippocampal CA1 region induced by 5 min of transient cerebral ischemia. In the 10 and 20 mg/kg ALA-, DA- and 10 mg/kg ALA-DA-pre-treated-ischemia-groups, there were no neuroprotective effects against ischemic damage 4 days after ischemic injury. However, 20 mg/kg ALA-DA pre-treatment protected pyramidal neurons from ischemic damage in the CA1 region. In addition, 20 mg/kg ALA-DA pre-treatment markedly decreased the activation of astrocytes and microglia in the CA1 region 4 days after ischemic injury. On the other hand, post-treatment with the same dosages of them did not show any neuroprotective effect against ischemic damage. In brief, these findings indicate that pre-treatment with ALA-DA, not ALA or DA alone, can protect neurons from ischemic damage in the hippocampus induced by transient cerebral ischemia via the decrease of glial activation. PMID- 22814804 TI - Are rehabilitation services for patients in UK eye clinics adequate? A survey of eye care professionals. AB - PURPOSE: The purpose of this study is to determine whether specific services such as emotional and family support are currently available in the United Kingdom for people with visual impairment. METHODS: A validated online survey was created and distributed to clinical staff in eye clinics (for example, ophthalmologists and optometrists) and rehabilitation staff (for example, social and rehabilitation workers) in the community, who worked with people with visual impairment. A total of 67 clinical and 42 rehabilitation staff completed the entire survey online. RESULTS: Only 67% of the respondents claimed their clinics provide emotional support and 44% of respondent's clinics provided family support. Clinical and rehabilitation staff have differences in opinion over what constitutes an essential service for a visually impaired patient. Rehabilitation staff considered emotional support and referral to social services as essential more often than clinical staff (P<0.05). There is some confusion over the type of personnel who provides each type of service, with some services showing substantial repetition. CONCLUSION: In the clinics sampled, there appears to be an underprovision of emotional support (attentive listening plus constructive suggestions) and family support (emotional support and advice for family members) for visually impaired patients in the United Kingdom. There also seems to be some discrepancy in services that eye care professionals feel are available and previous reports by visually impaired patients of the service they receive. There is a need to develop standardised pathways across the United Kingdom, to solve some of these issues. PMID- 22814805 TI - More on a patient-centric approach in the anti-VEGF therapy. PMID- 22814806 TI - Rituximab in IgG4-related inflammatory disease of the orbit and ocular adnexae. PMID- 22814807 TI - Hot, liquid glass injury as a novel mechanism for intraocular foreign body. AB - PURPOSE: To report the occurrence of a novel mechanism of IOFB with hot, liquefied glass injury. METHODS: Retrospective case series. RESULTS: Two patients suffered an injury to their eye with hot, liquefied glass. The ocular findings included a single scleral entry wound with multiple glass fragments located inside the eye. Fragments were found embedded in the retina, as well as mobile on the retinal surface. CONCLUSIONS: This distinctive mechanism involves an initial liquid state of glass causing injury, and results in multiple solidified glass IOFBs despite a single entrance wound. Though intraocular glass is typically inert, the unique characteristics of this injury may warrant a surgical approach. Surgical management proved successful in stabilizing vision and preventing further complications. PMID- 22814808 TI - Ciliary-body adenoma of the non-pigmented epithelium with rubeosis iridis treated with plaque brachytherapy and bevacizumab. PMID- 22814809 TI - Systemic toxicity of topical cyclopentolate eyedrops in a child. PMID- 22814810 TI - Time course of changes in ocular wavefront aberration after administration of eye ointment. AB - PURPOSE: To investigate the influence of an eye ointment on ocular aberration. DESIGN: Prospective, comparative study. METHODS: In 10 normal volunteers, ocular aberration was assessed before and 5, 30 min, 1, 2, 3, 6, and 12 h after administration of ofloxacin eye ointment. Ocular aberration was sequentially measured over a period of 10 s, and the root mean square (RMS) of the second-, third-, fourth-, and total higher-order aberrations (HOAs) were determined. From the sequential changes in total HOAs during 10 s, the fluctuation index (FI) and stability index (SI) were calculated. The obtained data were compared with those of another 17 normal volunteers who received timolol maleate gel-forming ophthalmic solution. RESULTS: No significant changes in second-order RMS were observed after administration of the ointment. HOAs such as third-, fourth-, and total higher-order RMS significantly changed during the study period (P<0.05, repeated-measures analysis of variance). The RMS of each HOA component significantly increased 5 min after administration compared with the baseline values (P<0.05, Dunnett test). FI also increased significantly 5 min after administration (P<0.05), but SI did not change significantly. When compared with the results of the gel-forming solution group, HOAs and FI showed significantly higher values at several time points during 6 h after application (P<0.05, Mann Whitney U-test). CONCLUSIONS: Administration of eye ointment significantly degrades optical quality of the eye by increasing and oscillating HOAs. These changes were more pronounced than those after instillation of gel-forming ophthalmic solution for at least several hours. PMID- 22814811 TI - Role of elective cesarean section in prevention of pelvic floor disorders. AB - PURPOSE OF REVIEW: The article reviews the current evidence and the role of elective Cesarean section in the prevention of pelvic floor disorders (PFDs). RECENT FINDINGS: Recent studies have revealed that operative vaginal delivery is an important risk factor for PFDs. The cause of PFD is multifactorial. Pregnancy itself also increases the PFDs. Elective Cesarean section carries diminished risk for stress urinary incontinence. Pelvic floor muscle training should be offered to all women in their first pregnancy as a preventive strategy. SUMMARY: The health provider should not offer elective Cesarean section to a pregnant woman without any prior risk of pelvic organ disorder for the prevention of urinary stress incontinence, anal incontinence, or pelvic organ prolapsus weighing the risks of Cesarean section. PMID- 22814812 TI - Adolescent endometriosis. AB - PURPOSE OF REVIEW: This review will address the recent literature regarding adolescent endometriosis. RECENT FINDINGS: An increasing body of literature suggests that there are symptoms of endometriosis present in adolescents. In addition, those teens with a history of dysmenorrhea severe enough to disrupt quality of life are more likely to be diagnosed with endometriosis. SUMMARY: The issues of endometriosis progression and early diagnosis remain key issues for the adolescent. PMID- 22814813 TI - Cigarette smoking associated with lung adenocarcinoma in situ in a large case control study (SFBALCS). AB - INTRODUCTION: Adenocarcinoma in situ (AIS), formerly bronchioloalveolar carcinoma, is an uncommon subtype of lung adenocarcinoma and accounts for approximately 3% to 4% of lung cancers. Compared with other lung cancer histologies, AIS patients are less likely to be smokers, yet associations with other lung cancer risk factors and differences by sex have not been determined. METHODS: A total of 338 AIS patients and frequency-matched controls from the parent study (cases = 6039, controls = 2073) were included in these analyses. Odds ratios and 95% confidence intervals as estimates of the relative risk were obtained from multivariable unconditional logistic regression analyses. RESULTS: Risk of AIS was associated with ever smoking (OR = 2.7, 95% confidence intervals: 2.1, 3.6), increased 20% to 30% for each 10-year increase in pack-years of smoking and decreased with increased years since quitting (p for trend <0.0001). There was no evidence that risk differed by sex but there was some suggestion that risk may differ by exposure to asbestos and by second-hand tobacco smoke exposure in whites. CONCLUSION: There is an association between AIS and smoking, which is smaller in magnitude than the association between other subtypes of non small-cell lung cancer and smoking. Our findings suggesting that effects may differ by exposure to asbestos and second-hand tobacco smoke should be interpreted conservatively and warrant validation and further evaluation in larger studies of AIS. PMID- 22814815 TI - Co-occurrence of fumonisins and deoxynivalenol in wheat and maize harvested in Serbia. AB - A survey was undertaken to determine total fumonisins (FUMs) and deoxynivalenol (DON) in wheat and maize. Out of 75 wheat samples, 50.7% contained FUMs in the span from 27 to 614 ng/g, while 65.3% contained DON in the span from 64 to 1,604 ng/g. Out of 24 maize samples, contents of FUMs in one and of DON in three samples were above the maximal limit. This is the one of rare reports of the natural co-occurrence of FUMs and DON in wheat and maize, and the first report of their correlation in different wheat cultivars. PMID- 22814814 TI - Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. AB - BACKGROUND: Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension. METHODS: We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N 5 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defi ned subgroups with a high 2-year mortality. Classifi cation and regression tree analysis was used to determine the incremental prognostic value of combined assessments. RESULTS: 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics 5 0.77 [95% CI 0.70 0.84] and 0.82 [95% CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics 5 0.68 [95% CI 0.60-0.76] and 0.74 [95% CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point. CONCLUSIONS: 6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values. PMID- 22814816 TI - Residues of HCHs and DDTs in soils and sediments of preconstructing urban wetland. AB - Residues of hexachlorohexanes isomers (HCHs) and dichlorodiphenyltrichloroethane and metabolites (DDTs) in the soils and sediments of Dayanghan Wetland in Wuhu, China were investigated. The concentrations of SigmaHCH in soils and sediments averaged 1.35 and 3.77 MUg/kg with the predominance of beta-HCH and delta-HCH, respectively. The concentrations of SigmaDDT in soils and sediments averaged of 7.80 and 2.80 MUg/kg, respectively, with the dominance of o, p'-DDT. The concentrations of HCHs in the soils and sediments and DDTs in the sediments were categorized as no pollution, but the level of DDTs in the soils was classified as low pollution. PMID- 22814817 TI - Stability of tandemly repetitive subelement PCR patterns in Trichophyton rubrum over serial passaging and with respect to drug pressure. AB - Trichophyton rubrum is the most significant agent of dermatomycoses worldwide, primarily causing tinea pedis and tinea unguium. PCR analysis of tandemly repetitive subelements (TRS) within the rDNA nontranscribed spacer region is a major tool for molecular typing of T. rubrum. The aim of this study was to investigate the stability of TRS PCR patterns by analyzing isogenic strains of T. rubrum. Twenty-seven groups of isogenic T. rubrum strains were examined, each composed of an original clinical isolate and its 3 subcultures, maintained on a drug-free medium, a medium containing fluconazole and itraconazole. TRS typing was performed for the original strains and their subcultures grown after 12 passages, at 4-week intervals, on respective media. To add more objectivity to the results, TRS typing for each of the isogenic strain was performed three times, using DNA isolated from three different colonies. Among 27 groups of isogenic strains, all but one were exclusively composed of strains with identical TRS-1 and TRS-2 PCR patterns. In one group, 3 isolates from the last, twelfth passage had identical TRS-1 PCR profiles (type 1), yet different TRS-2 PCR profiles, as compared with the original strain (type I vs. type II). The mechanism underlying the genotype switch was a deletion of a single repeat unit in the TRS-2 locus, as evidenced by sequence analysis. In the interpretation of TRS typing results, microevolutionary events need to be taken into account, urging drawing epidemiological conclusions with caution and in conjunction with other genotyping data and traditional contact tracing information. PMID- 22814819 TI - Limitations of in vitro assessments of the drug interaction potential of botanical supplements. AB - Although there are inherent and recognized limitations of in vitro screening methodologies to assess conventional drug-drug interactions (DDIs) per industry guidelines and those adopted by independent laboratories, further limitations are being appreciated which are unique to the evaluation of botanical products and potential DDIs in which they may participate. Among the larger issues faced are the uncertainty in assigning hepatic concentrations of multiple constituents and their potential metabolites, accounting for oral bioavailability, distribution, first-pass metabolism and active metabolites. Furthermore, the wide variability in the chemical composition of commercially available botanical supplement formulations continues to be a major concern, and manufacturing standards or enforcement thereof is essentially nonexistent in most countries. Differing formulations, unspecified product excipients, administration and absorption of the therapeutic ingredient(s) of a standardized dosage form, the very presence and/or concentration of one or more phytoconstituents within a supplement are typically unknown and nontarget entities. A further issue is the absence of authentic analytical standards, and the inability to accurately screen the entities as mixtures to even approximate typical scenarios, which may occur following the ingestion of dietary supplements, adds additional layers of complexity to experimental design and difficulty in interpreting experimental results. Multiple challenges exist in experimental methodologies employed in performing in vitro research with conventional pharmaceuticals and those unique to botanical extracts. These obstacles prevent the investigators from effectively utilizing high-throughput models to accomplish more than essentially "flag" suspected sources of drug interactions which must be further evaluated in vivo, at present, in order to confirm clinical significance. This review is intended to discuss the problems and challenges in evaluating botanical-drug interactions using in vitro methodologies. PMID- 22814818 TI - Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness. AB - Central corneal thickness (CCT) has become an endophenotype of major interest for the genetically complex disorder glaucoma. CCT has a high heritability, and thin CCT is an independent risk factor for the diagnosis and progression of open-angle glaucoma. Genome-wide association studies thus provide genetic loci associated with CCT and potentially related to open-angle glaucoma. The distribution of CCT and prevalence of glaucoma in population-based studies have demonstrated ethnic differences suggesting ethnic-dependent variations in the genetic determinants of CCT. We conducted a genome-wide association study in Caucasians (n = 3,931) from the Gutenberg Health Study (Germany) followed by replication of 30 genome-wide significant SNPs or SNPs of interest (P < 10(-5)) in the Rotterdam Study (The Netherlands, n = 1,418). In a combined analysis, we confirmed quantitative trait loci on chromosomes 9q34 and 16q24 for association with CCT. On chromosome 16q24, the locus is located in an intergenic region near the ZNF469 gene (top SNP: rs9938149, P = 1.45 * 10(-12)). ZNF469 missense mutation is involved in a syndrome with very thin cornea (brittle cornea syndrome). The second locus on chromosome 9q34 represents the intergenic region between the RXRA and COL5A1 gene (top SNP: rs3132306, P = 2.71 * 10(-10)). Collagen type 5 determines the diameter of the corneal collagen fibrils. In our Caucasian population-based GWA study, we reinforce the involvement of collagen-related genes influencing CCT in Caucasians. We could not confirm the collagen type 8 locus on chromosome 1 as reported in Asian studies. PMID- 22814820 TI - New xanthone glycosides from Comastoma pedunculatum. AB - Five new xanthone glycosides, comastomasides A-E (1-5), were isolated from aqueous ethanol extracts of the aerial portions of Comastoma pedunculatum. The structures of these compounds were elucidated by spectroscopic analysis methods. Compounds 1-5 were evaluated for their hepatoprotective activity and cytotoxicity against four human cancer cell lines by in vitro assays. Among them, compounds 3 and 5 exhibited potent hepatoprotective activity. However, none of the compounds displayed cytotoxic activity. PMID- 22814821 TI - Quorum quenching and antimicrobial activity of goldenseal (Hydrastis canadensis) against methicillin-resistant Staphylococcus aureus (MRSA). AB - The popular herbal remedy goldenseal (Hydrastis canadensis L.) is traditionally used to treat skin infections. With this study, we show activity of H. canadensis extracts in vitro against methicillin-resistant Staphylococcus aureus (MRSA). An extract from H. canadensis leaves demonstrated more potent antimicrobial activity than the alkaloid berberine alone (MICs of 75 ug/mL and 150 ug/mL, respectively). LC-MS detected alkaloids and efflux-pump inhibitory flavonoids in the extract, and the latter may explain the enhanced efficacy of the extract compared to berberine alone. We also show evidence of anti-virulence activity as a second mechanism by which H. canadensis acts against S. aureus. The H. canadensis leaf extract (but not the isolated alkaloids berberine, hydrastine, and canadine) demonstrated quorum quenching activity against several clinically relevant MRSA isolates (USA300 strains). Our data suggest that this occurs by attenuation of signal transduction through the AgrCA two-component system. Consistent with this observation, the extract inhibited toxin production by MRSA and prevented damage by MRSA to keratinocyte cells in vitro. Collectively, our results show that H. canadensis leaf extracts possess a mixture of constituents that act against MRSA via several different mechanisms. These findings lend support for the traditional application of crude H. canadensis extracts in the prevention of infection. PMID- 22814822 TI - Evaluation of the cytotoxic activity of some Brazilian medicinal plants. AB - Plants are promising sources of new bioactive compounds. The aim of this study was to investigate the cytotoxic potential of nine plants found in Brazil. The species studied were: Annona pickelii Diels (Annonaceae), Annona salzmannii A. DC. (Annonaceae), Guatteria blepharophylla Mart. (Annonaceae), Guatteria hispida (R. E. Fr.) Erkens & Maas (Annonaceae), Hancornia speciosa Gomes (Apocynaceae), Jatropha curcas L. (Euphorbiaceae), Kielmeyera rugosa Choisy (Clusiaceae), Lippia gracilis Schauer (Verbenaceae), and Hyptis calida Mart. Ex Benth (Lamiaceae). Different types of extractions from several parts of plants resulted in 43 extracts. Their cytotoxicity was tested against HCT-8 (colon carcinoma), MDA-MB 435 (melanoma), SF-295 (glioblastoma), and HL-60 (promielocitic leukemia) human tumor cell lines, using the thiazolyl blue test (MTT) assay. The active extracts were those obtained from G. blepharophylla, G. hispida, J. curcas, K. rugosa, and L. gracilis. In addition, seven compounds isolated from the active extracts were tested; among them, beta-pinene found in G. hispida and one coumarin isolated from K. rugora showed weak cytotoxic activity. In summary, this manuscript contributes to the understanding of the potentialities of Brazilian plants as sources of new anticancer drugs. PMID- 22814823 TI - Are statins more effective in male patients? PMID- 22814824 TI - Performance of computer-aided detection of pulmonary nodules in low-dose CT: comparison with double reading by nodule volume. AB - OBJECTIVE: To evaluate performance of computer-aided detection (CAD) beyond double reading for pulmonary nodules on low-dose computed tomography (CT) by nodule volume. METHODS: A total of 400 low-dose chest CT examinations were randomly selected from the NELSON lung cancer screening trial. CTs were evaluated by two independent readers and processed by CAD. A total of 1,667 findings marked by readers and/or CAD were evaluated by a consensus panel of expert chest radiologists. Performance was evaluated by calculating sensitivity of pulmonary nodule detection and number of false positives, by nodule characteristics and volume. RESULTS: According to the screening protocol, 90.9 % of the findings could be excluded from further evaluation, 49.2 % being small nodules (less than 50 mm(3)). Excluding small nodules reduced false-positive detections by CAD from 3.7 to 1.9 per examination. Of 151 findings that needed further evaluation, 33 (21.9 %) were detected by CAD only, one of them being diagnosed as lung cancer the following year. The sensitivity of nodule detection was 78.1 % for double reading and 96.7 % for CAD. A total of 69.7 % of nodules undetected by readers were attached nodules of which 78.3 % were vessel-attached. CONCLUSIONS: CAD is valuable in lung cancer screening to improve sensitivity of pulmonary nodule detection beyond double reading, at a low false-positive rate when excluding small nodules. KEY POINTS: * Computer-aided detection (CAD) has known advantages for computed tomography (CT). * Combined CAD/nodule size cut-off parameters assist CT lung cancer screening. * This combination improves the sensitivity of pulmonary nodule detection by CT. * It increases the positive predictive value for cancer detection. PMID- 22814825 TI - High-resolution CT of nontuberculous mycobacterium infection in adult CF patients: diagnostic accuracy. AB - OBJECTIVES: To determine the diagnostic accuracy of high-resolution computed tomography (HRCT) for the detection of nontuberculous mycobacterium infection (NTM) in adult cystic fibrosis (CF) patients. METHODS: Twenty-seven CF patients with sputum-culture-proven NTM (NTM+) underwent HRCT. An age, gender and spirometrically matched group of 27 CF patients without NTM (NTM-) was included as controls. Images were randomly and blindly analysed by two readers in consensus and scored using a modified Bhalla scoring system. RESULTS: Significant differences were seen between NTM (+) and NTM (-) patients in the severity of the bronchiectasis subscore [45 % (1.8/4) vs. 35 % (1.4/4), P = 0.029], collapse/consolidation subscore [33 % (1.3/3 vs. 15 % (0.6/3)], tree-in bud/centrilobular nodules subscore [43 % (1.7/3) vs. 25 % (1.0/3), P = 0.002] and the total CT score [56 % (18.4/33) vs. 46 % (15.2/33), P = 0.002]. Binary logistic regression revealed BMI, peribronchial thickening, collapse/consolidation and tree-in-bud/centrilobular nodules to be predictors of NTM status (R(2 )= 0.43). Receiver-operator curve analysis of the regression model showed an area under the curve of 0.89, P < 0.0001. CONCLUSION: In adults with CF, seven or more bronchopulmonary segments showing tree-in bud/centrilobular nodules on HRCT is highly suggestive of NTM colonisation. KEY POINTS: Lung function declines rapidly in cystic fibrosis patients with nontuberculous mycobacterium infection. High-resolution computed tomography can help identify nontuberculous mycobacterium in CF patients. Extensive collapse/consolidation and tree-in-bud/centrilobular nodules are predictive of NTM infection. Multiple bronchopulmonary segments showing tree-in bud/centrilobular nodules strongly suggest nontuberculous mycobacterium infection. PMID- 22814826 TI - Spectral CT imaging of myocardial infarction: preliminary animal experience. AB - OBJECTIVES: To evaluate the capability of spectral CT imaging to detect the different stages and angiogenesis of myocardial infarction (MI). METHODS: MI was surgically induced in 40 rabbits that were evenly divided into four stages of MI: 6 h (6H), 3 days (3D), 7 days (7D) and 14 days (14D). Spectral CT was performed at 10 s, 1 min and 3 min after intravenous contrast medium administration. CD31 immunohistochemistry was used for the microvessel density (MVD) measurement. Iodine concentrations in the myocardium were measured and normalised to the aorta as nIC. The relationships between infarcted myocardial nIC and MVD were analysed. RESULTS: The nIC of infarct myocardium decreased at 10 s and increased in late phase CT images. There were significant differences between the 6H and other groups (P ( 6H-3D ) = 0.01, P ( 6H-7D ) = 0.01, P ( 6H-14D ) = 0.00). There was a significant difference in the MVD of infarct myocardium between the two groups except in the 7D and 14D groups (P = 0.08). In the 10-s phase, the nIC of infarct myocardium was negatively correlated with MVD (r = -0.54, P = 0.00), whereas in the late phases, there was a positive correlation between them (r = 0.57, P = 0.00 in the 1-min phase, r = 0.48, P = 0.00 in the 3-min phase). CONCLUSION: Spectral CT imaging of the myocardium can be used to evaluate the different stages and angiogenesis of MI. PMID- 22814827 TI - The MRI features of histologically proven ovarian cystadenofibromas-an assessment of the morphological and enhancement patterns. AB - OBJECTIVES: To assess the morphological and enhancement features of histologically proven cystadenofibromas (CAFs) on magnetic resonance imaging (MRI). METHODS: Forty-seven histologically proven CAFs (42 benign, five borderline) were retrospectively reviewed. One benign CAF had a synchronous adenocarcinoma in the same ovary. The morphological, signal and enhancement characteristics on MRI were recorded. RESULTS: The mean long axis diameter of the CAFs was 80 mm. The contralateral ovary was abnormal in 45 % of cases. A solid component was seen in 85 %, which returned low T2-weighted signal in 75 % of CAFs. Septa were seen in 74 % and one CAF was purely cystic. The majority of solid components and septa demonstrated enhancement that was less than the myometrium. Wash-in rates (WIR) of the solid tissue were available for measurement in nine patients with an average WIR of 3.2 l/s. CONCLUSION: This is the largest series describing MRI appearances of histologically proven CAFs. They are typically complex adnexal lesions containing septa, cystic components and solid tissue. The majority of solid components demonstrate low T2 signal and minimal enhancement. Almost half of the cases have an abnormal contralateral ovary. PMID- 22814828 TI - Liver stiffness measured by magnetic resonance elastography as a risk factor for hepatocellular carcinoma: a preliminary case-control study. AB - OBJECTIVE: To examine if liver stiffness measured by magnetic resonance elastography (MRE) is a risk factor for hepatocellular carcinoma (HCC) in patients with chronic liver disease. METHODS: By reviewing the records of magnetic resonance (MR) examinations performed at our institution, we selected 301 patients with chronic liver disease who did not have a previous medical history of HCC. All patients underwent MRE and gadoxetic acid-enhanced MR imaging. HCC was identified on MR images in 66 of the 301 patients, who were matched to controls from the remaining patients without HCC according to age. MRE images were obtained by visualising elastic waves generated in the liver by pneumatic vibration transferred via a cylindrical passive driver. Risk factors of HCC development were determined by the odds ratio with logistic regression analysis; gender and liver stiffness by MRE and serum levels of aspartate transferase, alanine transferase, alpha-fetoprotein, and protein induced by vitamin K absence-II. RESULTS: Multivariate analysis revealed that only liver stiffness by MRE was a significant risk factor for HCC with an odds ratio (95 % confidence interval) of 1.38 (1.05-1.84). CONCLUSION: Liver stiffness measured by MRE is an independent risk factor for HCC in patients with chronic liver disease. PMID- 22814829 TI - Does the use of hormonal contraceptives cause microstructural changes in cerebral white matter? Preliminary results of a DTI and tractography study. AB - OBJECTIVE: To evaluate the effect of monophasic combined oral contraceptive pill (COCP) and menstrual cycle phase in healthy young women on white matter (WM) organization using diffusion tensor imaging (DTI). METHODS: Thirty young women were included in the study; 15 women used COCP and 15 women had a natural cycle. All subjects underwent DTI magnetic resonance imaging during the follicular and luteal phase of their cycle, or in different COCP cycle phases. DTI parameters were obtained in different WM structures by performing diffusion tensor fibre tractography. Fractional anisotropy and mean diffusivity were calculated for different WM structures. Hormonal plasma concentrations were measured in peripheral venous blood samples and correlated with the DTI findings. RESULTS: We found a significant difference in mean diffusivity in the fornix between the COCP and the natural cycle group. Mean diffusivity values in the fornix were negatively correlated with luteinizing hormone and estradiol blood concentrations. CONCLUSION: An important part in the limbic system, the fornix, regulates emotional processes. Differences in diffusion parameters in the fornix may contribute to behavioural alternations related to COCP use. This finding also suggests that the use of oral contraceptives needs to be taken into account when designing DTI group studies. PMID- 22814831 TI - The dependence of photocatalytic activity and photoinduced self-stability of photosensitive AgI nanoparticles. AB - AgI is instable under light irradiation owing to its photosensitive properties, while a supported Ag-AgI composite has been demonstrated to be a stable photocatalyst. However, seldom investigations have been focused on the photocatalytic activity (including deactivation) and photoinduced stability of the photosensitive AgI materials. In this study, the AgI nanoparticles were immobilized on the surface of Ag(8)W(4)O(16) nanorods by an anion-exchange route and their photocatalytic activities were evaluated by photocatalytic decomposition of methyl orange and phenol solutions under visible-light irradiation. A photoinduced self-stabilizing mechanism of the AgI nanoparticles was proposed to account for the formation of a stable Ag-AgI photocatalyst, namely, instable AgI can transform into a stable Ag-AgI photocatalyst after in situ formation of partial Ag on the surface of AgI nanoparticles. The photocatalytic performance of the immobilized AgI photocatalyst was greatly influenced by the formation of metallic Ag. With increasing repetitions of photocatalytic experiments, the initial deactivation was accompanied by the rapid increase of metallic Ag owing to the reduction of lattice Ag(+), while the subsequently stable activity corresponds to the formation of a stable Ag-AgI composite photocatalyst. Compared with the un-immobilized AgI photocatalyst, the immobilized AgI nanoparticles exhibited a higher and more stable photocatalytic performance. PMID- 22814830 TI - Radiographic features of multifocal endosteal thickening of the femur in patients on long-term bisphosphonate therapy. AB - OBJECTIVES: To describe the characteristics of multifocal endosteal thickening in patients on bisphosphonate therapy. METHOD: A retrospective study of 68 patients with atypical femoral fractures (as defined by ASBMR) whilst on bisphosphonate therapy was performed. Femoral radiographs were assessed for: focal endosteal thickening, number of lesions, lesion location, femoral bowing, periosteal beak and black line. Medical records were reviewed to obtain relevant clinical data. RESULTS: Forty-eight lesions with multifocal endosteal thickening were detected in seven patients (2 unilateral, 5 bilateral), affecting 11.8 % of femora. Location was mainly diaphyseal (95.8 %), upper (10.4 %), middle (58.3 %) and lower femur (31.3 %), involving the lateral (85.4 %), anterior (6.3 %), anterolateral (2.1 %) and posterior cortices (6.3 %). Femoral bowing was present in 85.7 %. Associated findings of a periosteal beak and/or a black line, seen in 14.6 %, were associated with increased fracture risk (100.0 % sensitivity, 93.2 % specificity). CONCLUSIONS: Multifocal endosteal thickening is a new finding seen in patients with low bone mineral density on bisphosphonate therapy. They are rare, frequently bilateral, predominantly diaphyseal in location involving the lateral cortex and often associated with bowing. Caution is advised when seen in association with periosteal beak and/or black line because of a high rate of progression to complete fracture. PMID- 22814832 TI - Vertically ordered Ni3Si2/Si nanorod arrays as anode materials for high performance Li-ion batteries. AB - In this paper, we have reported a novel hierarchical nanostructure made of vertically ordered Ni3Si2/Si nanorod arrays to moderate the notorious pulverization and capacity decay usually occurring in the silicon used as the anode materials in Li-ion batteries. During the lithiation and delithiation process, the amorphous Si (a-Si) layer acts as an active material and participates in the processes, whereas the Ni3Si2 nanorod arrays work as a mechanically stable supporter and fast charge transport pathway. In addition, they can afford sufficient interspace for expansion/contraction upon lithium insertion/extraction. These Ni3Si2/Si nanorod arrays anodes exhibit excellent cycling performance at high current rates of 1 C (4.2 A g-1), 2 C (8.4 A g-1), and 4 C (16.8 A g-1), respectively. A high and steady discharge capacity of over 2184 mA h g-1 can be achieved after 50 cycles with a high initial coulombic efficiency of 86.7%. The synthesis approach is simple, efficient and rich yielding, probably providing a new strategy for the application of silicon-based anode materials with enhanced performance. PMID- 22814833 TI - The deleterious effects of physical inactivity on elements of insulin resistance and metabolic syndrome in Central Africans at high cardiovascular risk. AB - AIM: We aimed to describe the physical activity and to investigate the association between classical hypertension, obesity, diabetes, and new inflammation, IDF-defined metabolic syndrome, insulin resistance CV risk factors. DESIGN: This was a cross-sectional study based on interviews and physical and biochemistry measurements among Central African patients. MEASUREMENTS: Waist circumference (WC), blood pressure, weight and height to calculate body mass index (BMI), fasting glucose, CRP, ERS, uric acid, cholesterol (C), LDL-C, HDL-C, triglycerides, elements of homeostatic model assessment (HOMA) including insulin, HOMA index, QUICKI, insulin sensitivity (%S), beta-cell function (%beta) and insulin resistance (IR). FINDINGS: Of the 60 patients included, 30 (50%) were physically inactive versus 30 (50%) active. In pooled analyses, in men and in women, there was significant and positive correlation between WC and seating/laying down position (WC=92.41+1.49 seating time in hours, R(2)=0.11; P<0.0001). The mean value of CRP and ERS were higher and those of all indices of HOMA were lower in inactive patients. The discriminant function for physical activity was Z (score=barycentre)=-7.36+1.013 HOMA index where -1.4 was the barycentre for active and +1.4 for inactive. HOMA index >2.42 was the optimal cut off value to detect physically inactive patients: sensitivity=93.3%, specificity=100%, area under ROC=0.991+/-0.01 95%=0.975-1.0; P<0.0001. CONCLUSION: The association between low-grade inflammation markers, insulin resistance and physical inactivity favours the hypothesis that a low-grade inflammatory status and enhanced insulin, sensitivity may constitute a part of the CV benefits from physical activity. PMID- 22814834 TI - Cardiovascular risk assessment in patients with type 2 diabetes mellitus and metabolic syndrome: role of biomarkers. AB - OBJECTIVES: Metabolic syndrome (MetS) and type 2 diabetes mellitus (DM) are associated with a high incidence of cardiovascular diseases. The aim of this study was to determine paraoxonase (PON), total sialic acid (TSA), and nitric oxide (NO) levels in addition to conventional risk markers in patients with DM, MetS and DM plus MetS. MATERIAL AND METHODS: The study has been carried out over 78 subjects which divided into four groups; control (n=18), DM (n=20), newly diagnosed MetS (n=20) and DM plus MetS patient groups (n=20). RESULTS: Both insulin and triglyceride concentrations were significantly higher in DM+MetS group than in control and DM groups and serum HDL-C concentrations were significantly lower in DM+MetS group than other groups. Patients with MetS had higher LDL-C, total cholesterol and hsCRP concentrations than in the other groups. Interestingly, in addition to body mass index and waist circumference values, LDL-C, total cholesterol and hsCRP concentrations were decreased in patients who have both DM and MetS. Serum NO and TSA levels were higher in MetS and DM+MetS groups compared to control subjects. Unexpectedly, PON activity has been found lower in control group when compared to other groups. CONCLUSIONS: Although there is no doubt that association of DM and MetS elevates the risk of cardiovascular disease, occurrence of DM in patients with undiagnosed MetS might be encouraging patients to change their life styles and dietary habits. PMID- 22814835 TI - Evaluation of the burden of type 2 diabetes mellitus in population of Puducherry, South India. AB - AIMS: To find out the prevalence of undiagnosed diabetes mellitus and the correlates among the adult population of Puducherry, South India. METHODS: In this population based cross-sectional study in the rural and urban field practice area of Mahatma Gandhi Medical College and Research Institute, Puducherry, by simple random sampling 1013 adults of 30 years and above, not on anti-diabetics drugs were included. Main outcome measures were the prevalence and correlates of undiagnosed diabetes mellitus among the adult population. Pre-designed and pre tested questionnaire was used to elicit the information on family and individual socio-demographic variables. Height, weight, waist and hip circumference, blood pressure were measured and venous blood was collected to measure fasting blood glucose and blood cholesterol. RESULTS: Overall, 10.3% study subjects were diagnosed as diabetic. In univariate analysis age, dilatory habit, tobacco addiction, body mass index, waist hip ratio, hypertension, and total blood cholesterol were found statistically significant. In multivariate logistic regression (LR method) analysis age, residence, education, dietary habit, tobacco addiction, body mass index, waist hip ratio and total blood cholesterol were statistically significant. CONCLUSIONS: In our study adults having increased age, urban residence, illiterate, non-vegetarian diet, tobacco addiction, obese and high total blood cholesterol were important correlates. PMID- 22814836 TI - The metabolic syndrome in a Congolese population and its implications for metabolic syndrome definitions. AB - AIM: Metabolic syndrome defined by International cut-off values are limited to detect people at high cardiometabolic risk in Central Africans in comparison with metabolic syndrome defined by ethnic-specific definition. We examined the relationship between metabolic syndromes, diabetes control, abdominal obesity, HDL-cholesterol groups and atherosclerotic complications. MATERIALS AND METHODS: A representative sample of type-2 diabetic central Africans from Kinshasa were studied. Outcome measures included control of diabetes, atherosclerosis, abdominal obesity, insulin resistance, total cholesterol, triglycerides, HDL cholesterol, metabolic syndromes and atherosclerosis. RESULTS: Of 1266 type-2 diabetic patients (48.8%), (61.8%), (27.1%) and (81%) had uncontrolled diabetes, atherosclerotics, metabolic syndrome (IDF/Europe), and metabolic syndrome (IDF/local) respectively. There was a significant U-shaped relationship between atherosclerotics complications, insulin resistance, delta postprandial glycaemia and HDL-cholesterol stratification. There was also a significant U-shaped relationship between cardiometabolic risk (P<0.01) and atherosclerotic complications. CONCLUSION: Type-2 diabetic Central Africans exhibit very high rates of uncontrolled diabetes, atherosclerotic complications and metabolic syndrome. Both, abdominal obesity, insulin resistance, low and very high HDL cholesterol levels are cardiometabolic risk factors. PMID- 22814837 TI - Optimal cut-off levels of body mass index and waist circumference in relation to each component of metabolic syndrome (MetS) and the number of MetS component. AB - AIMS: There is an ethnic difference of obesity index to diagnose metabolic syndrome. The authors explored the optimal cut-off levels for body mass index (BMI) and waist circumference (WC) in relation to each component of metabolic syndrome. MATERIALS AND METHODS: Receiver operating characteristics (ROC) analysis was used to determine the optimal cut-off levels for each component of metabolic syndrome. This study included 4572 workers aged 42.5+/-9.9 years. RESULTS: The optimal BMI cut-off values for diabetes mellitus, hypertension or dyslipidemia varied from 23.0 to 24.3 kg/m(2). As for WC, the optimal cut-off values varied from 83.0 to 83.7 cm. The optimal BMI cut-off values relating with one to three components of metabolic syndrome varied from 23.2 to 25.3 kg/m(2). As for WC, the optimal cut-off values varied from 83.0 to 85.0 cm. Pair-wise comparison of ROC curves showed that WC has an advantage in relation to metabolic syndrome and its components compared with BMI. By logistic regression analysis, odds ratios of obesity indices for hypertension, dyslipidemia or the number of metabolic component were all significantly increased. As for diabetes mellitus, odds ratios of BMI >=25 and WC >=85 significantly increased, respectively. CONCLUSIONS: Japanese criteria of obesity in metabolic syndrome in man may be appropriate for diabetes mellitus. Ethnic difference in criteria of obesity in Asian metabolic syndrome exists, and mutual comparisons in the prevalence of metabolic syndrome have a difficulty to conduct. PMID- 22814838 TI - Assessment of insulin resistance using surrogate markers in patients of metabolic syndrome. AB - BACKGROUND: Insulin resistance is defined as situation where there is insufficient biological or metabolic response to normal plasma levels of insulin. For precise quantification of insulin sensitivity, the euglycemic hyperinsulinemic clamp may be used, but it is expensive, invasive and used mainly in research settings. HOMA-IR (Homeostasis Model Assessment-Insulin Resistance) and ISI 0,120 (Insulin Sensitivity Index) are indirect markers of insulin resistance. The present study evaluated the usefulness of the surrogate markers for evaluation of Insulin resistance in clinical settings. METHOD: This study was carried out on 120 subjects. Of these, 60 subjects presenting with two or more features of metabolic syndrome (Hypertension, Obesity, Dyslipidemia, altered glucose tolerance) were included in the study group. Sixty age and sex matched healthy controls were selected with normal Body mass index. All the subjects underwent a standard Oral Glucose Tolerance Test. Plasma glucose and serum insulin were estimated using Glucose oxidase and ELISA principle respectively. HOMA-IR and ISI 0,120 were calculated using relevant formulae. RESULT: The HOMA IR values were significantly raised in suspected Insulin resistant subjects (6.74+/-1.24) as compared to healthy controls (0.82+/-0.017) (p=0.001). ISI 01,20 was significantly low in insulin resistant subjects (3.13+/-0.17) as compared to controls (20.60+/-0.37) (p<0.001). Insulin sensitivity index showed a significant negative correlation with HOMA-IR. A significant negative correlation was observed between serum cholesterol, serum LDL-cholesterol and ISI 0,120 indicating that dyslipidemia in metabolic syndrome may result from a decrease in Insulin sensitivity. CONCLUSION: HOMA-IR and ISI 0,120 are simple, convenient and sensitive estimates of insulin resistance adaptable for use in clinical practice as well as large-scale epidemiological studies. PMID- 22814839 TI - Influence of maternal diabetes on serum leptinemic and insulinemic status of the offspring: a case study of selected patients in a tertiary care hospital in Bangladesh. AB - INTRODUCTION: Leptin is now known to be an important hormone affecting intrauterine fetal growth. Since growth of fetus is also affected by the glycemic status of the mother. Serum leptin of infant is influenced by the maternal diabetic state. Investigation of cord blood leptin in babies of DM (Diabetes Mellitus) and GDM (Gestational Diabetes Mellitus) mothers (controlled blood glucose levels) may provide some indication about involvement of genetic factor in the development of leptin abnormalities in fetus. AIM: The study was taken to investigate whether cord blood insulin, c-peptide and leptin levels correlate with birth weight in offspring of DM mother. METHODS: Blood was drawn from umbilical cord of 30 babies from GDM mothers (GDM-babies), 45 babies from Type 2 DM Mothers (DM-babies), and 30 babies from ND (Nondiabetic) mothers (ND-babies) of term pregnancy. Weight, blood glucose, placenta, serum leptin and c-peptide of the babies were measured. RESULTS: Birth weight of GDM and DM babies were significantly higher compared to ND-babies. Glucose level in GDM babies was significantly higher than ND and DM babies. Leptin levels in GDM babies were significantly higher than that of ND and DM babies. Serum c-peptide in GDM babies was significantly higher than DM and ND babies. However, there was no significant difference in leptin-glucose ratio among the three groups. Irrespective of degree of hyperglycemia leptin is a major determinant of fetal growth. CONCLUSIONS: DM mother produces different insulinemic and leptinemic responses in the fetus indicating a possible genetic involvement. PMID- 22814840 TI - Metabolic syndrome--psycho neuropathogenesis and human brain evolution. AB - AIM: Metabolic syndrome (MS) is a major risk factor for coronary artery disease. Heightened hypothalamo-pituitary-adrenal axis activity is associated with pathogenesis of MS. Life style, food habits and physical activity also play critical role in the pathogenesis of MS. However, the precise neurophysiology behind chronic stress leading on to such effects is unknown. MATERIALS AND METHODS: Review of recent animal and human studies have shown the subtle differences in morphological changes associated with chronic stress between medial prefrontal cortex and amygdaloid complex. RESULT: The loss of dendritic spines in pyramidal neurons of medial prefrontal cortex, dendritic hypertrophy in basolateral amygdala and dendritic loss in central nucleus of amygdala causes increased basal output from amygdaloid complex to HPA axis and other targets whose networks are evolutionarily well conserved. CONCLUSION: The increased HPA axis activity, elevated blood pressure and appetite for high calorie diet leads to MS. The evolution of isocortex in primates and associated regression in size of limbic structures predisposed to increased synaptic noise in amygdaloid complex which in turn cause heighetened output from amygdala during chronic stress. PMID- 22814841 TI - Association of macrovascular complications of type 2 diabetes mellitus with serum magnesium levels. AB - BACKGROUND: Diabetes mellitus and its complications are a significant cause of morbidity and mortality worldwide. Micronutrients have been evaluated as potential preventive and therapeutic measures in diabetes. The present study evaluated serum magnesium levels in diabetic patients-uncomplicated and those with macrovascular complications. METHOD: This study was done on 150 subjects (60 normal, healthy controls and 90 diabetics). The 90 diabetic patients were selected in the following categories-30 patients without complications (Study Group I), 30 diabetic patients with coronary artery disease (Study Group II) and 30 diabetic patients with peripheral vascular disease (Study Group III). Plasma glucose, glycated hemoglobin and serum magnesium levels were estimated in all the patients. RESULTS: Fasting plasma glucose and glycated hemoglobin levels were significantly higher in all the 3 study groups as compared to the controls, however, serum magnesium levels were significantly lower (p<0.05). In diabetic patients with coronary atherosclerosis or peripheral vascular disease, a significant negative correlation was observed between serum magnesium and fasting plasma glucose and glycated hemoglobin indicating the role of hypomagnesemia in diabetic complications. CONCLUSION: Dietary supplementation with magnesium in addition to classical therapies for diabetes may help in prevention of diabetic complications. PMID- 22814842 TI - Diabetes and chronic oxidative stress. A perspective based on the possible usefulness of ozone therapy. AB - It is now well established that hyperglycemia, present in both type 1 and type 2 diabetes, causes a variety of biochemical derangements leading to a diffused vascular damage responsible for several pathologic manifestations. Although preclinical and clinical studies have been performed by an unreliable administration route, the correct approach of oxygen-ozonetherapy may break a vicious circle. Messengers, released by a precise interaction ex vivo of the patient's blood with an equivalent calculated dose of ozone (0.42-0.84 mM), react with a variety of cells after blood infusion and restore a number of functions went astray. This paper aims to open a debate on this new therapy for improving the prognosis of diabetes. PMID- 22814843 TI - "Annual cycle of availability of fruits", a geographical bound concern in planning for control of diabetes mellitus. AB - The glycemic control of diabetic patients seems to be a simple preventive practice but hard-to-do procedure for the diabetic patients. The unsuccessful control can be frequently seen. In this specific paper, the author hereby reports and discusses on "annual cycle of availability of fruits" and the observed poorly controlled diabetes from a setting in tropical Asia. This report can imply the geographical bound concern in planning for control of diabetes mellitus. PMID- 22814844 TI - Poor diabetic control after swine flu infection: a note. PMID- 22814845 TI - Effects of myogenin on expression of late muscle genes through MyoD-dependent chromatin remodeling ability of myogenin. AB - MyoD and myogenin (Myog) recognize sets of distinct but overlapping target genes and play different roles in skeletal muscle differentiation. MyoD is sufficient for near-full expression of early targets, while Myog can only partially enhance expression of MyoD-initiated late muscle genes. However, the way in which Myog enhances the expression of MyoD-initiated late muscle genes remains unclear. Here, we examine the effects of Myog on chromatin remodeling at late muscle gene promoters and their activation within chromatin environment. Chromatin immunoprecipitation (ChIP) assay showed that Myog selectively bound to the regulatory sequences of late muscle genes. Overexpression of Myog was found to overcome sodium butyrateinhibited chromatin at late muscle genes in differentiating C2C12 myoblasts, shifting the transcriptional activation of these genes to an earlier time period. Furthermore, overexpression of Myog led to increased hyperacetylation of core histone H4 in differentiating C2C12 myoblasts but not NIH3T3 fibroblasts, and hyperacetylated H4 was associated directly with the late muscle genes in differentiating C2C12, indicating that Myog can induce chromatin remodeling in the presence of MyoD. In addition, co-immunoprecipitation (CoIP) revealed that Myog was associated with the nuclear protein Brd4 in differentiating C2C12 myoblasts. Together, these results suggest that Myog enhances the expression of MyoD-initiated late muscle genes through MyoD dependent ability of Myog to induce chromatin remodeling, in which Myog-Brd4 interaction may be involved. PMID- 22814847 TI - Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer. AB - Lung cancer remains a global health problem with a high mortality rate. CpG island methylation is a common aberration frequently associated with gene silencing in multiple tumor types, emerging as a highly promising biomarker. The transmembrane protein with a single EGF-like and two follistatin domains (TMEFF2) is epigenetically silenced in numerous tumor types, suggesting a potential role as a potential tumor suppressor. However, the role of TMEFF2 in lung cancer remains to be fully elucidated. We explored the methylation status of TMEFF2 gene in 139 patients with non-small cell lung cancer (NSCLC) and the feasibility of detecting circulating methylated DNA as a screening tool for NSCLC using methylation-specific PCR in 316 patients and 50 age-matched health controls. TMEFF2 methylation in tumor tissues was found in 73 of the 139 NSCLCs (52.5%) and was related to gene expression. The frequency of TMEFF2 methylation was higher in females and never-smokers than in males and smokers with borderline significance (65.8% vs 47.8%, p = 0.06; 65.7% vs 48.1%, p = 0.07). Notably, in adenocarcinomas, TMEFF2 methylation was significantly more frequent in tumors without EGFR mutation than those with EGFR mutation (adjusted odds ratio = 7.13, 95% confidence interval = 2.05-24.83, P = 0.002). Furthermore, TMEFF2 methylation was exclusively detected in the serum of NSCLC patients at a frequency of 9.2% (29/316). These findings suggest that methylation-associated down-regulation of TMEFF2 gene may be involved in lung tumorigenesis and TMEFF2 methylation can serve as a specific blood-based biomarker for NSCLC. PMID- 22814846 TI - Over-expression of a RhoA-specific guanine nucleotide exchange factor, p190RhoGEF, in mouse dendritic cells negatively regulates cellular responses to bacterial lipopolysaccharide. AB - We studied the role of a RhoA-specific guanine nucleotide exchange factor (p190RhoGEF) in dendritic cells (DCs), using transgenic (TG) mice that over express a full gene of p190RhoGEF under the control of an invariant chain promoter. TG mice lacked localization of activated DCs to the T cell zone in the spleen and had reduced serum levels of IL-6 in response to lipopolysaccharide (LPS) injection. DCs from these mice also showed reduced surface expression of CD86, CD40, and CD205, but not MHCII, as well as a reduced capability to uptake antigen. Moreover, chemokine-driven migration and secretion of IL-6, but not of IL-12, were impaired after LPS-stimulation of TG DCs. Collectively, these results suggest that over-expressing p190RhoGEF negatively regulates conventional DC function in response to bacterial LPS infection. PMID- 22814848 TI - Reporting actionable research results: shared secrets can save lives. AB - In this Commentary, we describe a cryptographic method for returning research results to individuals who participate in clinical studies. Controlled use of this method, which relaxes the typical anonymization guarantee, can ensure that clinically actionable results reach participants while also addressing most privacy concerns. PMID- 22814850 TI - Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device. AB - Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because their concentrations in the bladder are low. A previous attempt to develop a drug delivery device for use in the bladder was unsuccessful, likely as a result of poor tolerability. A continuous lidocaine-releasing intravesical system (LiRIS) was designed to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. The 16 women with IC/BPS who were enrolled in the study met the National Institute of Diabetes and Digestive and Kidney Diseases criteria for bladder hemorrhages or Hunner's lesions. Subjects received either LiRIS 200 mg or LiRIS 650 mg for 2 weeks. Safety, efficacy, cystoscopic appearance of the bladder, and limited pharmacokinetic data were collected. Both doses were well tolerated, and clinically meaningful reductions were seen in pain, urgency, voiding frequency, and disease questionnaires. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner's lesions in five of six subjects with baseline lesions. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed. PMID- 22814852 TI - Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. AB - Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the inhibition of the plasma membrane Na(+)- and K(+)-dependent adenosine triphosphatase (Na(+)/K(+)-ATPase). CGs exacerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate syngeneic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin. PMID- 22814851 TI - Rapid evolution of HIV-1 to functional CD8+ T cell responses in humanized BLT mice. AB - The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV 1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens. PMID- 22814853 TI - HIV-1 reservoirs in breast milk and challenges to elimination of breast-feeding transmission of HIV-1. AB - By compensating for the relative immaturity of the neonatal immune system, breast milk and breast-feeding prevent deaths in children. Nevertheless, transmission of HIV-1 through breast-feeding is responsible for more than half of new pediatric HIV infections. Recent studies of possible HIV-1 reservoirs in breast milk shed new light on features that influence HIV-1 transmission through breast-feeding. The particular characteristics of breast milk CD4(+) T cells that distinguish them from circulating blood lymphocytes (high frequency of cell activation and expression of memory and mucosal homing markers) facilitate the establishment of HIV-1 replication. Breast milk also contains a plethora of factors with anti infectious, immunomodulatory, or anti-inflammatory properties that can regulate both viral replication and infant susceptibility. In addition, CD8(+) T lymphocytes, macrophages, and epithelial cells in breast milk can alter the dynamics of HIV-1 transmission. Even during efficient antiretroviral therapy, a residual stable, CD4(+) T cell-associated reservoir of HIV-1 is persistently present in breast milk, a likely source of infection. Only prophylactic treatment in infants--ideally with a long-acting drug, administered for the entire duration of breast-feeding--is likely to protect HIV-exposed babies against all forms of HIV transmission from breast milk, including cell-to-cell viral transfer. PMID- 22814854 TI - Primary care and behavioral health practice size: the challenge for health care reform. AB - INTRODUCTION: We investigated the size profile of US primary care and behavioral health physician practices since size may impact the ability to institute care management processes (CMPs) that can enhance care quality. METHOD: We utilized 2009 claims data from a nationwide commercial insurer to estimate practice size by linking providers by tax identification number. We determined the proportion of primary care physicians, psychiatrists, and behavioral health providers practicing in venues of >20 providers per practice (the lower bound for current CMP practice surveys). RESULTS: Among primary care physicians (n=350,350), only 2.1% of practices consisted of >20 providers. Among behavioral health practitioners (n=146,992) and psychiatrists (n=44,449), 1.3% and 1.0% of practices, respectively, had >20 providers. Sensitivity analysis excluding single physician practices as "secondary" confirmed findings, with primary care and psychiatrist practices of >20 providers comprising, respectively, only 19.4% and 8.8% of practices (difference: P<0.0001). In secondary analyses, bipolar disorder was used as a tracer condition to estimate practice census for a high-complexity, high-cost behavioral health condition; only 1.3-18 patients per practice had claims for this condition. CONCLUSIONS: The tax identification number method for estimating practice size has strengths and limitations that complement those of survey methods. The proportion of practices below the lower bound of prior CMP studies is substantial, and care models and policies will need to address the needs of such practices and their patients. Achieving a critical mass of patients for disorder-specific CMPs will require coordination across multiple small practices. PMID- 22814856 TI - Template-free synthesis of mesoporous N-doped SrTiO3 perovskite with high visible light-driven photocatalytic activity. AB - An effective, template-free synthesis methodology has been developed for preparing mesoporous nitrogen-doped SrTiO(3) (meso-STON) using glycine as both a nitrogen source and a mesopore creator. The N-doping, large surface area and developed porosity endow meso-STON with excellent activity in visible-light responsive photodegradation of organic dyes. PMID- 22814855 TI - Latent personality profiles and the relations with psychopathology and psychopathic traits in detained adolescents. AB - The present study constructed empirically derived subtypes of adolescent offenders based on general traits and examined their associations with psychopathology and psychopathic traits. The sample included 342 detained minors (172 boys and 170 girls; mean age 15.85 years, SD = 1.07) recruited in various Youth Detention Centers across the Flemish part of Belgium. All adolescents provided self-reports on the quick big five, the youth self report, and the youth psychopathic traits inventory to assess general traits, psychopathology, and psychopathic traits respectively. Latent class analyses based on general personality traits were performed and suggested three personality types, consisting of an emotionally labile, close-minded and goal-oriented class, an undercontrolled class, and an emotionally labile-careless class. These three personality types within detained minors showed particular constellations of general traits and differed meaningfully in terms of their mean-scores on externalizing psychopathology and psychopathy measures. PMID- 22814858 TI - Two ligand-functionalized Pb(II) metal-organic frameworks: structures and catalytic performances. AB - A microporous Pb(II) metal-organic framework (MOF) [PbL(2)].2DMF.6H(2)O (1) has been assembled from a N-oxide and amide doubly functionalized ligand HL (= N-(4 carboxyphenyl)isonicotinamide 1-oxide). Complex 1 features a three-dimensional (3D) framework possessing one-dimensional (1D) rhombic channels with dimensions of 13 * 13 A(2). The 3D framework is built up from 1D PbO(2) chains that link ligands in parallel fashion to construct single-wall channels. When recrystallizing 1 in a DMSO-DMF mixture (3 : 5 v/v), a new coordination polymer, [PbL(2)].DMF.2H(2)O (2), was obtained. Complex 2 is also a 3D framework containing 1D rectangular channels, but the channel dimensions become reduced in size to 13 * 8 A(2) due to reorganization of the Pb(ii) coordination environment. The PbO(2) chains in 2 are reformed to link ligands in a double-wall fashion, significantly reducing the channel size. Even though, the guest exchange study indicates that the DMF molecules in 2 could be replaced with benzene molecules when immersing in benzene solvent, showing single-crystal-to-single-crystal (SC SC) guest exchange in the solid state and leading to a daughter crystal [PbL(2)].0.5C(6)H(6).2H(2)O (2'). Desolvated 1 and 2 display preferential adsorption behaviors of water vapour over CO(2) due to the hydrophilic nature of the channels and the strong host-guest interactions. Catalytic tests indicate that desolvated 1 and 2 have size-selective catalytic activity towards the Knoevenagel condensation reaction. PMID- 22814857 TI - Low risk of thromboembolic complications with tranexamic acid after primary total hip and knee arthroplasty. AB - BACKGROUND: The use of antifibrinolytic medications in hip and knee arthroplasty reduces intraoperative blood loss and decreases transfusion rates postoperatively. Tranexamic acid (TXA) specifically has not been associated with increased thromboembolic (TE) complications, but concerns remain about the risk of symptomatic TE events, particularly when less aggressive chemical prophylaxis methods such as aspirin alone are chosen. QUESTIONS/PURPOSES: We determined whether the rate of symptomatic TE events differed among patients given intraoperative TXA when three different postoperative prophylactic regimens were used after primary THA and TKA. METHODS: We retrospectively reviewed 2046 patients who underwent primary THA or TKA and received TXA from 2007 to 2009. The three chemical regimens included aspirin alone, warfarin (target international normalized ratio, 1.8-2.2), and dalteparin. Primary outcome measures were venous TE events, including symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE), and arterioocclusive events, including myocardial infarction and cerebrovascular accident. Patients judged to be at high risk for TE due to recent cardiac stent placement or strong personal/family history of TE disease were excluded. RESULTS: For aspirin, warfarin, and dalteparin, the rates of symptomatic DVT (0.35%, 0.15%, and 0.52%, respectively) and nonfatal PE were similar (0.17%, 0.43%, and 0.26%, respectively). There were no fatal PE. Among the three groups, we found no difference in the rates of symptomatic DVT or PE with or without stratification by ASA score. CONCLUSIONS: A low complication rate was seen when using TXA as a blood conservation modality during primary THA and TKA with less aggressive thromboprophylactic regimens such as aspirin alone and dose-adjusted warfarin. PMID- 22814859 TI - A clinical prognostic model for the identification of low-risk patients with acute symptomatic pulmonary embolism and active cancer. AB - BACKGROUND: Physicians need a specific risk-stratification tool to facilitate safe and cost-effective approaches to the management of patients with cancer and acute pulmonary embolism (PE). The objective of this study was to develop a simple risk score for predicting 30-day mortality in patients with PE and cancer by using measures readily obtained at the time of PE diagnosis. METHODS: Investigators randomly allocated 1,556 consecutive patients with cancer and acute PE from the international multicenter Registro Informatizado de la Enfermedad TromboEmbolica to derivation (67%) and internal validation (33%) samples. The external validation cohort for this study consisted of 261 patients with cancer and acute PE. Investigators compared 30-day all-cause mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. RESULTS: In the derivation sample, multivariable analyses produced the risk score, which contained six variables: age > 80 years, heart rate >= 110/min, systolic BP < 100 mm Hg, body weight < 60 kg, recent immobility, and presence of metastases. In the internal validation cohort (n = 508), the 22.2% of patients (113 of 508) classified as low risk by the prognostic model had a 30-day mortality of 4.4% (95% CI, 0.6%-8.2%) compared with 29.9% (95% CI, 25.4%-34.4%) in the high-risk group. In the external validation cohort, the 18% of patients (47 of 261) classified as low risk by the prognostic model had a 30-day mortality of 0%, compared with 19.6% (95% CI, 14.3%-25.0%) in the high-risk group. CONCLUSIONS: The developed clinical prediction rule accurately identifies low risk patients with cancer and acute PE. PMID- 22814860 TI - Public awareness and use of direct-to-consumer personal genomic tests from four state population-based surveys, and implications for clinical and public health practice. AB - PURPOSE: Direct-to-consumer personal genomic tests are widely available, but population-based data are limited on awareness and use of these tests among the general public in the United States. METHODS: We assessed awareness and use of direct-to-consumer personal genomic tests in Connecticut, Michigan, Oregon, and Utah using the 2009 Behavioral Risk Factor Surveillance System and compared the state results to the 2008 national HealthStyles survey results. RESULTS: Awareness was the highest in Oregon (29.1%) and the lowest in Michigan (15.8%). Factors associated with awareness across all states and nationally were higher education, higher income, and increasing age, except among those 75 years or older. Less than 1% of respondents had used the tests, with about one-half to three-quarters of those sharing the results with a health-care provider. CONCLUSIONS: Awareness of direct-to-consumer genetic tests is greater in this study as compared with a related study conducted in 2006, whereas use is similarly low in both studies. The few respondents who reported using the tests often reported sharing their results with their health-care provider, indicating an important opportunity for health-care providers to offer patient education regarding these tests. Public health agencies have important roles in surveillance, education, and policy development on direct-to-consumer genomic tests. PMID- 22814861 TI - A case for reclassifying infiltrating gliomas in adults. PMID- 22814862 TI - Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT). AB - Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glioneuronal tumors included in the revised WHO classification of central nervous system tumors, showing partial histological similarities to pilocytic astrocytomas. To evaluate potential similarities at the molecular level between these tumors, we analysed a series of 10 RGNT for the presence of KIAA1549-BRAF fusions using interphase fluorescence in situ hybridisation. However, we found no cases showing KIAA1549-BRAF gene fusion or BRAF (V600E) mutation. Our data support the hypothesis that RGNT may represent a distinct entity among the glioneuronal tumors of the central nervous system, with molecular features different from pilocytic astrocytomas. PMID- 22814864 TI - Should we ban the use of colloids in patients with head injury? PMID- 22814863 TI - Estradiol effects on intracellular Ca(2+) homeostasis in bovine brain-derived endothelial cells. AB - Estrogens diversely affect various physiological processes by genomic or non genomic mechanisms, in both excitable and non-excitable cells. Additional to the trophic effects of estrogens promoting cell growth and differentiation, recent experimental evidence highlights their involvement in the regulation of intracellular Ca(2+) homeostasis. The effects of estrogens on excitable cells are well documented. However, these steroids also influence numerous physiological events in non-excitable cells, such as fibroblasts or vascular endothelial cells. We have focused our attention on an immortalized endothelial-like cell line derived from fetal bovine cerebellum. Estradiol (E(2)) effects on intracellular Ca(2+) homeostasis were tested by varying the exposure time to the hormone (8, 24, 48 h). Calcium measurements were performed with genetically encoded Ca(2+) probes (Cameleons) targeted to the main subcellular compartments involved in intracellular Ca(2+) homeostasis (cytosol, endoplasmic reticulum, mitochondria). Mitochondrial Ca(2+) uptake significantly decreased after 48-h exposure to E(2), whereas cytosolic and endoplasmic reticulum responses were unaffected. The effect of E(2) on mitochondrial Ca(2+) handling was blocked by ICI 182,780, a pure estrogen receptor antagonist, suggesting that the effect was estrogen-receptor mediated. To evaluate whether the decrease of Ca(2+) uptake affected mitochondrial membrane potential (DeltaPsim), cells were monitored in the presence of tetra-methyl-rhodamine-methylester; no significant changes were seen between cells treated with E(2) and controls. To investigate a mechanism of action, we assessed the possibile involvement of the permeability transition pore (PTP), an inner mitochondrial membrane channel influencing energy metabolism and cell viability. We treated cells with CyclosporinA (CsA), which binds to the matrix chaperone cyclophilin-D and regulates PTP opening. CsA reversed the effects of a 48-h treatment with E(2), suggesting a possible transcriptional modulation of proteins involved in the mitochondrial permeability transition process. PMID- 22814865 TI - Unless high-quality clinical data show they are safe, synthetic colloids should not be used in patients with head injury. PMID- 22814866 TI - Monitoring artifacts and large database research: what you don't know could hurt you. PMID- 22814867 TI - Computational tools for comparative phenomics: the role and promise of ontologies. AB - A major aim of the biological sciences is to gain an understanding of human physiology and disease. One important step towards such a goal is the discovery of the function of genes that will lead to a better understanding of the physiology and pathophysiology of organisms, which will ultimately lead to better diagnosis and therapy. Our increasing ability to phenotypically characterise genetic variants of model organisms coupled with systematic and hypothesis-driven mutagenesis is resulting in a wealth of information that could potentially provide insight into the functions of all genes in an organism. The challenge we are now facing is to develop computational methods that can integrate and analyse such data. The introduction of formal ontologies that make their semantics explicit and accessible to automated reasoning provides the tantalizing possibility of standardizing biomedical knowledge allowing for novel, powerful queries that bridge multiple domains, disciplines, species, and levels of granularity. We review recent computational approaches that facilitate the integration of experimental data from model organisms with clinical observations in humans. These methods foster novel cross-species analysis approaches, thereby enabling comparative phenomics and leading to the potential of translating basic discoveries from the model systems into diagnostic and therapeutic advances at the clinical level. PMID- 22814869 TI - New bis(aryloxy)-Ti(IV) complexes and their use for the selective dimerization of ethylene to 1-butene. AB - New titanium complexes of general formula [(ArO)(n)Ti(Oi-Pr)((4-n))] were synthesized and used as pre-catalysts for the selective dimerization of ethylene to 1-butene. The complexes were prepared in cyclohexane using [Ti(Oi-Pr)(4)] and one or two equivalents of the corresponding phenols (ArOH) at room temperature. In this work, both monodentate and chelating phenols were evaluated. For alkyl substituted phenols, it was demonstrated that large steric hindrance at both ortho and ortho' positions selectively yielded the mono-substituted complexes [(ArO)Ti(Oi-Pr)(3)]. Substitution at only one of the ortho positions allowed both the mono- and the di-substituted Ti complexes to be isolated. When a heteroatom was introduced on the phenol backbone, di-substitution systematically occurred except with phenols presenting a hemilabile -CH(2)NR(2) group at the ortho position. Upon activation with 3 equiv. of AlEt(3) at 20 bar and 60 degrees C, all the complexes selectively dimerized ethylene to 1-butene (>86% of butenes among which 99% of 1-butene). An increase of the steric bulk at the ortho position of the ligand or the introduction of a functional group led to decreased activity compared to [Ti(Oi-Pr)(4)]. PMID- 22814868 TI - Genomic analysis of the appearance of testicular oocytes in MRL/MpJ mice. AB - Mammals produce sperm or oocytes depending on their sex; however, newborn MRL/MpJ (MRL) male mice produce oocytes within their testes. We previously reported that one of the genes responsible for this phenotype is present on the MRL-type Y chromosome (Y(MRL)), and that multiple genes, probably autosomal, are also required for the development of this phenotype. In this study we focused on the autosomal genes and examined their relationship with this phenotype by analyzing the progeny from crosses between MRL mice and other strains. We first observed the male F1 progeny from the crosses between female A/J, C57BL/6 (B6), BALB/c, C3H/He, or DBA/2 mice and male MRL mice, and two consomic strains, male B6-Y(MRL) and MRL-Y(B6). Testicular oocytes that were morphologically similar to those of MRL mice were detected in all mouse strains except BALBMRLF1; however, the incidence of testicular oocytes was significantly lower than that in MRL mice. The appearance of testicular oocytes in MRL-Y(B6) mice indicates that this phenotype is strongly affected by genomic factors present on autosomes, and that there is at least one other causative gene on the MRL-type autosomes (MRL testicular oocyte production, mtop) other than that on Y(MRL). Furthermore, a quantitative trait locus (QTL) analysis using N2 backcross progeny from crosses between female MRLB6F1 and male MRL mice revealed the presence of susceptibility loci for the appearance of testicular oocytes at 8-17 cM on Chr 15. These findings demonstrate that the appearance of testicular oocytes is regulated by the genetic factors on Chr 15 and on Y(MRL). PMID- 22814870 TI - Slowed recovery of human photopic ERG a-wave amplitude following intense bleaches: a slowing of cone pigment regeneration? AB - We have used the post-bleach recovery of the ERG a-wave to estimate the time course of regeneration of cone pigment, following bleaching exposures far stronger than in a previous study. We recorded the photopic electroretinogram a wave from two subjects, in response to dim red flashes delivered following 1-min exposures to intensities ranging from 1.1 * 10(4) to 1.3 * 10(5) photopic cd m( 2). The measured response amplitudes were "linearized" to derive estimates of pigment level. These estimated pigment levels were found to increase at an initially linear rate, consistent with a "rate-limited" model of photopigment regeneration. The extracted time-course was similar to that previously reported in densitometric studies of cone pigment regeneration after similarly intense exposures. On the other hand, the rate of regeneration was slower than measured in the same subjects following less intense bleaches. These results are consistent with the notion that cone pigment regeneration is slowed following very strong bleaching exposures, possibly as a result of depletion of a pool of retinoid. PMID- 22814871 TI - Ambulatory arrhythmia monitoring in pregnant patients with palpitations. AB - OBJECTIVE To assess the frequency of rhythm disturbances (RDs) obtained following placement of a Holter monitor or an event loop recorder (ERT) in patients referred to cardiologists. STUDY DESIGN: Ninety-six gravidas were referred to the cardiology clinic for palpitations, syncope, or dizziness and had Holter monitoring or ERT after a baseline electroencephalogram. Arrhythmias were classified by severity. RESULTS: Gestational age at referral was 22.6 weeks +/- 8.3 days. Sixty-five patients had ERTs performed, and 19 had Holter monitors. Seventy-six percent had benign arrhythmias. In our ERT cohort, history of arrhythmias showed a fourfold increase in serious RD during gestation (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.1 to 20.3, p = 0.01); obesity (body mass index > 30) had a fourfold increased risk (OR 4.0, 95% CI 1.0 to 1, p = 0.03). Serious RD did not result in greater chance of cesarean delivery or induction of labor, or a newborn with arrhythmias. CONCLUSION: Most pregnant women with palpitations have benign arrhythmias. ERT appears to be a better method of diagnosis in pregnant women. PMID- 22814872 TI - Marinobufagenin predicts and resibufogenin prevents preeclampsia: a review of the evidence. AB - OBJECTIVE: The purpose of this review is to provide information detailing the existing evidence with regard to the hypothesis that marinobufagenin (MBG) is an important etiologic and predictive factor in preeclampsia (PE). In addition, evidence describing the role of the antagonist to MBG, resibufogenin (RBG), in the prevention and/or treatment of this disorder is provided. STUDY DESIGN: The studies outlined were performed in an animal model of PE, in in vitro experiments, and in human studies. RESULTS: Data have been obtained that strongly support the hypothesis that ~60 to 70% of PE patients demonstrate elevations in urinary and serum MBG levels. In the animal model, the entire syndrome can be prevented by the administration of RBG beginning early in pregnancy. CONCLUSION: Expanded human trials of MBG as a predictor of the later development of PE are warranted as are studies of the efficacy and safety of RBG as a preventative/therapy. PMID- 22814873 TI - What do you mean, a spot?: A qualitative analysis of patients' reactions to discussions with their physicians about pulmonary nodules. AB - BACKGROUND: More than 150,000 Americans each year are found to have a pulmonary nodule. Even more will be affected following the publication of the National Lung Screening Trial. Patient-doctor communication about pulmonary nodules can be challenging. Although most nodules are benign, it may take 2 to 3 years to rule out cancer. We sought to characterize patients' perceptions of communication with their providers about pulmonary nodules. METHODS: We conducted four focus groups at two sites with 22 adults with an indeterminate pulmonary nodule. Transcripts were analyzed using principles of grounded theory. RESULTS: Patients described conversations with 53 different providers about the pulmonary nodule. Almost all patients immediately assumed that they had cancer when first told about the nodule. Some whose providers did not discuss the actual cancer risk or explain the evaluation plan experienced confusion and distress that sometimes lasted for months. Patients were frustrated when their providers did not address their concerns about cancer or potential adverse effects of surveillance (eg, prolonged uncertainty, radiation exposure), which in some cases led to poor adherence to evaluation plans. Patients found it helpful when physicians used lay terms, showed the CT image, and quantified cancer risk. By contrast, patients resented medical jargon and dismissive language. CONCLUSIONS: Patients commonly assume that a pulmonary nodule means cancer. What providers tell (or do not tell) patients about their cancer risk and the evaluation plan can strongly influence patients' perceptions of the nodule and related distress. We describe simple communication strategies that may help patients to come to terms with an indeterminate pulmonary nodule. PMID- 22814874 TI - Short-peptide-based molecular hydrogels: novel gelation strategies and applications for tissue engineering and drug delivery. AB - Molecular hydrogels hold big potential for tissue engineering and controlled drug delivery. Our lab focuses on short-peptide-based molecular hydrogels formed by biocompatible methods and their applications in tissue engineering (especially, 3D cell culture) and controlled drug delivery. This feature article firstly describes our recent progresses of the development of novel methods to form hydrogels, including the strategy of disulfide bond reduction and assistance with specific protein-peptide interactions. We then introduce the applications of our hydrogels in fields of controlled stem cell differentiation, cell culture, surface modifications of polyester materials by molecular self-assembly, and anti degradation of recombinant complex proteins. A novel molecular hydrogel system of hydrophobic compounds that are only formed by hydrolysis processes was also included in this article. The hydrogels of hydrophobic compounds, especially those of hydrophobic therapeutic agents, may be developed into a carrier-free delivery system for long term delivery of therapeutic agents. With the efforts in this field, we believe that molecular hydrogels formed by short peptides and hydrophobic therapeutic agents can be practically applied for 3D cell culture and long term drug delivery in near future, respectively. PMID- 22814875 TI - Effect of Galla chinensis on the remineralization of two bovine root lesions morphous in vitro. AB - The present study aims to evaluate the effect of Galla chinensis compounds on the remineralization of two artificial root lesions morphous in vitro. Sixty bovine dentine blocks were divided into two groups and individually treated with two levels of demineralization solutions to form erosive and subsurface artificial carious lesions in vitro. Each group was then divided into three subgroups, each of which were treated with a remineralization solution (positive control), deionized water (negative control), or 4 000 mg?L(-1) aqueous solutions of Galla chinensis extract. The dentine blocks were then subjected to a pH-cycling regime for 7 days. During the first 4 days, the daily cycle included 21-h deal and 3-h demineralization applications. The dentine blocks were dealt with the entire day during the remaining 3 days. Two specimens from each of the treatment groups were selected and observed under a polarized light microscope. Data collected using a laser scanning confocal microscope were computerized and analyzed. Galla chinensis extract clearly enhanced the remineralization of both erosive lesion and subsurface lesion patterns in the specimens (P<0.05). The level of remineralization of the erosive lesion by Galla chinensis extract was lower than that of the subsurface lesion (P<0.05). In addition, the remineralization of the subsurface lesion by Galla chinensis extract was higher than that of the remineralization solution (P<0.05). No significant difference between the remineralization of erosive lesions by Galla chinensis extract and the remineralization solution was observed (P>0.05). So Galla chinensis extract has the potential to improve the remineralization of artificial root lesions under dynamic pH-cyclic conditions, indicating its potential use as a natural remineralization medicine. PMID- 22814876 TI - Transmission of endemic ST22-MRSA-IV on four acute hospital wards investigated using a combination of spa, dru and pulsed-field gel electrophoresis typing. AB - The transmission of meticillin-resistant Staphylococcus aureus (MRSA) between individual patients is difficult to track in institutions where MRSA is endemic. We investigated the transmission of MRSA where ST22-MRSA-IV is endemic on four wards using demographic data, patient and environmental screening, and molecular typing of isolates. A total of 939 patients were screened, 636 within 72 h of admission (on admission) and 303 >72 h after admission, and 1,252 environmental samples were obtained. Isolates were typed by spa, dru and pulsed-field gel electrophoresis (PFGE) typing. A composite dendrogram generated from the three sets of typing data was used to divide isolates into 'dendrogram groups' (DGs). Ten percent of patients (92/939) were MRSA-positive; 7 % (44/636) on admission and 16 % (48/303) >72 h after admission (p = 0.0007). MRSA was recovered from 5 % of environmental specimens (65/1,252). Most isolates from patients (97 %, 85/88) and the environment (97 %, 63/65) exhibited the ST22-MRSA-IV genotype. Four DGs (DG1, DG4, DG16 and DG17) accounted for 58 % of ST22-MRSA-IV isolates from patients. Epidemiological evidence suggested cross-transmission among 44/92 patients (48 %) but molecular typing confirmed probable cross-transmission in only 11 instances (13 %, 11/88), with the majority of cross-transmission (64 %; 7/11) occurring on one ward. In the setting of highly clonal endemic MRSA, the combination of local epidemiology, PFGE, spa and dru typing provided valuable insights into MRSA transmission. PMID- 22814877 TI - Role of fecal Clostridium difficile load in discrepancies between toxin tests and PCR: is quantitation the next step in C. difficile testing? AB - Direct tests for Clostridium difficile are 30-50 % more sensitive than tests for C. difficile toxins but the reasons for this discrepancy are incompletely understood. In addition to toxin degradation and strain differences, we hypothesized that C. difficile concentration could be important in determining whether toxins are detected in fecal samples. We performed standard curves on an FDA-approved real-time PCR test for the C. difficile tcdB gene (Xpert C. difficile/Epi, Cepheid) during a prospective comparison of a toxin immunoassay (Meridian Premier), PCR and toxigenic culture. Immunoassay-negative, PCR-positive samples were retested with a cell cytotoxin assay (TechLab). Among 107 PCR positive samples, 46 (43.0 %) had toxins detected by immunoassay and an additional 18 (16.8 %) had toxin detected by the cytotoxin assay yielding 64 (59.8 %) toxin-positive and 43 (40.2 %) toxin-negative samples. Overall, toxin negative samples with C. difficile had 10(1)-10(4) fewer DNA copies than toxin positive samples and most discrepancies between toxin tests and PCR were associated with a significant difference in C. difficile quantity. Of the toxin positive samples, 95 % had >= 4.1 log(10) C. difficile tcdB DNA copies/mL; 52 % of immunoassay-negative samples and 70 % of immunoassay and cytotoxin negative samples had <4.1 log(10) C. difficile tcdB DNA copies/mL. These findings suggest that fecal C. difficile concentration is a major determinant of toxin detection and C. difficile quantitation may add to the diagnostic value of existing test methods. Future studies are needed to validate the utility of quantitation and determine the significance of low concentrations of C. difficile in the absence of detectable toxin. PMID- 22814878 TI - Direct and trans-generational responses to food deprivation during development in the Glanville fritillary butterfly. AB - Life history characteristics and resulting fitness consequences manifest not only in an individual experiencing environmental conditions but also in its offspring via trans-generational effects. We conducted a set of experiments to assess the direct and trans-generational effects of food deprivation in the Glanville fritillary butterfly Melitaea cinxia. Food availability was manipulated during the final stages of larval development and performance was assessed during two generations. Direct responses to food deprivation were relatively minor. Food deprived individuals compensated, via increased development time, to reach a similar mass as adults from the control group. Delayed costs of compensatory growth were observed, as food-deprived individuals had either reduced fecundity or lifespan depending on the type of feeding treatment they had experienced (intermittent vs. continuous). Female food deprivation did not directly affect her offspring's developmental trajectory, but the way the offspring coped with food deprivation. Offspring of mothers from control or intermittent starvation treatments reached the size of those in the control group via increased development time when being starved. In contrast, offspring of mothers that had experienced 2 days of continuous food deprivation grew even larger than control animals, when deprived of food themselves. Offspring of food-deprived Glanville fritillary initially showed poor immune response to parasitism, but not later on in development. PMID- 22814879 TI - Observation of antinociceptive effects of oxymatrine and its effect on delayed rectifier K+ currents (Ik) in PC12 cells. AB - In order to observe antinociceptive effect of Oxymatrine (OMT) and its effect on voltage-activated K(+) channel, the acetic acid-induced abdominal contraction model of mouse was used to test the antinociceptive effect in vivo, and in vitro, the delayed rectifier K(+) currents (Ik) in PC12 cells (rat pheochromocytoma cells) was recorded using the automated patch-clamp method. The results indicated that after application of OMT, the number of acetic acid-induced animal abdominal contraction was significantly decreased, Ik in PC12 cells was significantly decreased, and showed a concentration-dependent manner. After application of OMT, both the activation and inactivation curves of Ik of PC12 cells were shifted to negative potentials. This study revealed that OMT showed antinociceptive effect in mice. The inhibition of voltage-activated K(+) channel might be one of mechanisms in which the enhanced both activation and inactivation of K(+) channel were involved and might play important roles. PMID- 22814880 TI - Role of somatodendritic and postsynaptic 5-HT1A receptors on learning and memory functions in rats. AB - Memory impairment is a major problem afflicting mankind. The association between memory functions and neurotransmitter functions is of great interest for understanding brain function. Serotonergic pathways play an important role in the modulation of memory functions but the importance of its receptor types and subtypes on memory functions is still unclear. Activation and blockade of various serotonin (5-HT) receptors has been reported to alter cognitive processes and 5 HT receptor antagonism could be beneficial in the treatment of cognitive diseases. The role of 5-HT on memory functions is complicated. Among the 5-HT receptors subtypes, 5-HT(1A) receptors are of special interest because these receptors are present in the brain areas involved in learning and memory functions such as hippocampus and cortex. The present study was therefore designed to investigate the effect of activation and blockade of somatodendritic and/or postsynaptic 5-HT(1A) receptor on learning and memory functions in rats using modified version of water maze. In this study, 8-OH-DPAT (8-hydroxy-2-(di-N propylamino) tetralin) at 0.3 mg/kg significantly enhanced learning acquisition (LA), short-term memory (STM) and long term memory (LTM) of rats pre-injected with saline suggesting that the activation of pre-synaptic 5-HT(1A) receptors by its agonist enhanced the memory functions of rats. Conversely, rats injected with 8-OH-DPAT at 1.0 mg/kg exhibited impaired LA and STM and had no effect on LTM. It was also shown in this study that blockade of 5-HT(1A) receptors by spiperone enhanced LA, had no effect on STM but impaired the LTM, which showed that the blockade of 5-HT(1A) receptors by its antagonist exerts different effect on different types of memory. This study suggests that 5-HT(1A) receptor could be used as a significant pharmacological target for the treatment of CNS diseases. Unraveling the role of serotonin in cognition and memory disorders could provide better therapy and it may lead to new insights in our understandings of learning and memory. PMID- 22814882 TI - Monitoring high-risk bladder cancer. AB - PURPOSE OF REVIEW: Monitoring high-risk nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) is challenging since currently used clinical and pathological risk parameters are not accurate enough to address the individual risk of progression. RECENT FINDINGS: In NMIBC, the use of urinary interleukin-2 and fluorescence in-situ hybridization predicts response to bacille calmette-guerin treatment. In both NMIBC and MIBC, the detection of circulating tumor cells at initial diagnosis allows improved monitoring since its presence is associated with higher tumor stages, concomitant carcinoma in situ and shorter time to recurrence. Molecular urine markers, such as fluorescence-in-situ hybridization, help to identify high-risk cases early on. In MIBC, serum C reactive protein and thrombocytosis have been recently incorporated into basic prognostic models and demonstrated an increase in the predictive accuracy of standard pathological risk factors. SUMMARY: New serological and urine-based markers have been identified for monitoring high-risk bladder cancer, and demand incorporation into established clinicopathological risk models to tailor surveillance regimens and provide improved prognostication for the need of adjuvant treatment. PMID- 22814881 TI - [Late impact of lambdacyhalothrin-treated nets on kdr allelic frequency in Anopheles gambiae s.s. (Diptera: Culicidae) from northern Cote-d'Ivoire]. AB - Nets treated with lambdacyhalothrin 15 mg a.i./m2 were distributed in four villages of Korhogo area in northern Cote-d'Ivoire, and four other villages without nets were followed as controls. Mosquitoes were collected every three months from June 1999 to August 2000 in the villages, and then tested to determine their genotypes for kdr mutation L1014F conferring cross-resistance to pyrethroids and DDT and for M and S molecular forms of Anopheles gambiae s.s. The frequencies of the resistant allele at kdr mutation L1014F locus were very high and they varied from 0.82 to 0.96. Before the trial, the genotypic frequencies of specimens at kdr locus did not show any significant difference. However, they significantly increased in mosquitoes from treated villages (0.94) compared to those from control villages (0.87) on month 14 (P = 0.013). No significant difference was observed between mosquitoes collected outside and inside the houses (P < 0.05). In contrary, a significant difference was observed before and after the trial between mosquitoes from villages with two cycles of rice cultivation per year and those from villages without rice cultivation (P = 0.008 and P = 0.012). Nine out of twelve populations of field mosquitoes showed Hardy Weinberg disequilibrium at kdr locus (P < 0.05). The S and M molecular forms of An. gambiae s.s. were sympatric in Korhogo area and the S form represents 97%. No hybrid between M and S forms was observed. All individuals of the M form were homozygote susceptible at kdr locus. PMID- 22814883 TI - Indication and timing of cystectomy in high-risk bladder cancer. AB - PURPOSE OF REVIEW: Although the conservative approach including Bacillus Calmette Guerin (BCG) therapy is considered as the first-line option in high-risk nonmuscle invasive bladder tumors, cystectomy is often required as an alternative treatment in the case of BCG failure. Considering all the parameters, including clinical data, endoscopic aspects and new biological markers, the question of the indication, and moreover timing, of cystectomy has become crucial. RECENT FINDINGS: In fact, the real positive effect of BCG remains controversial and its actual benefit in terms of survival is not evident. Therefore, early cystectomy for this population with high risk of progression and metastasis diffusion is clearly a radical approach which can lead to a reduction in specific mortality. Recent articles have studied the parameters involved in this issue to determine the exact timing of cystectomy. SUMMARY: To avoid delay of appropriate treatment, it is crucial to determine the non-BCG responder population. Unfortunately, no consensual marker is currently available. Nevertheless, multifocal tumors, associated carcinoma in situ, prostatic urethral involvement, tumoral size greater than 3 cm and depth of infiltration are useful parameters in clinical practice to propose early cystectomy. In the future, the crucial question of cystectomy timing may be answered by progress in molecular signatures for bladder cancers. PMID- 22814885 TI - H-bonds superstructures built by aquacomplexes and an azapurine derivative: a case of molecular recognition. AB - The crystal structures of six compounds involving the divalent cations of Mn, Zn and Cd, the anionic form of the heterocycle 4,6-dimethyl-1,2,3-triazolo[4,5 d]pyrimidin-5,7-dione (Hdmax) and bipyridyl based spacer ligands are reported. The most important feature of these structures is the presence, in all cases, of a topologically identical 1-D polymeric superstructure (tape), involving tetra- or hexaaqua complex cations and triazolopyrimidine anions, built through hydrogen bonds. Adding these results to others previously published, we may consider these tapes as robust supramolecular synthons where a defined/clear case of molecular recognition between these two moieties takes place. PMID- 22814884 TI - Pyrosequencing-based transcriptomic resources in the pond snail Lymnaea stagnalis, with a focus on genes involved in molecular response to diquat-induced stress. AB - Due to their ability to explore whole genome response to drugs and stressors, omics-based approaches are widely used in toxicology and ecotoxicology, and identified as powerful tools for future ecological risk assessment and environmental monitoring programs. Understanding the long-term effects of contaminants may indeed benefit from the coupling of genomics and eco evolutionary hypotheses. Next-generation sequencing provides a new way to investigate pollutants impact, by targeting early responses, screening chemicals, and directly quantifying gene expression, even in organisms without reference genome. Lymnaea stagnalis is a freshwater mollusk in which access to genomic resources is critical for many scientific issues, especially in ecotoxicology. We used 454-pyrosequencing to obtain new transcriptomic resources in L. stagnalis and to preliminarily explore gene expression response to a redox-cycling pesticide, diquat. We obtained 151,967 and 128,945 high-quality reads from control and diquat-exposed individuals, respectively. Sequence assembly provided 141,999 contigs, of which 124,387 were singletons. BlastX search revealed significant match for 34.6 % of the contigs (21.2 % protein hits). KEGG annotation showed a predominance of hits with genes involved in energy metabolism and circulatory system, and revealed more than 400 putative genes involved in oxidative stress, cellular/molecular stress and signaling pathways, apoptosis, and metabolism of xenobiotics. Results also suggest that diquat may have a great diversity of molecular effects. Moreover, new genetic markers (putative SNPs) were discovered. We also created a Ensembl-like web-tool for data-mining ( http://genotoul-contigbrowser.toulouse.inra.fr:9095/Lymnaea_stagnalis/index.html ). This resource is expected to be relevant for any genomic approach aimed at understanding the molecular basis of physiological and evolutionary responses to environmental stress in L. stagnalis. PMID- 22814886 TI - Impact of total PSA, PSA doubling time and PSA velocity on detection rates of 11C Choline positron emission tomography in recurrent prostate cancer. AB - PURPOSE: To evaluate the effect of total PSA (tPSA) and PSA kinetics on the detection rates of (11)C-Choline PET in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT). METHODS: We included 185 patients with BCR after RP (PSA >0.2 ng/ml) or after EBRT (ASTRO definition). After injection of 400 MBq 11C-Choline i.v., a scan was made using the ECAT HR + PET camera with CT fusion images or Siemens mCT PET/CT. Biopsy-proven histology, confirmative imaging (CT or bone scan) and/or clinical follow-up (PSA) were used as composite reference. Statistical analysis was performed using PASW Statistics 18. RESULTS: 11C-Choline PET was positive in 124/185 cases (65%) (in 22/61 (36%) after RP, 102/124 (82%) after EBRT). In 79 patients a local recurrence was identified, and 45 patients showed locoregional metastases on PET/CT. In 20 cases a proven false-negative PET scan was observed. Positive PET scans were confirmed by histology in 87/124 (70%) cases, by confirmatory imaging in 34/124 (28%) and by clinical follow-up after salvage treatment in 3 (2%) cases. The ROC analysis to detect a recurrence showed significant difference in area under the curve (AUC) of tPSA 0.721(p < 0.001) and PSA velocity 0.730 (p < 0.001). PSA doubling time showed no significant difference with an AUC of 0.542 (p = 0.354). Detection rates are <50% in tPSA <2 ng/ml and/or PSA velocity <1 ng/ml/year. CONCLUSIONS: Total serum PSA and PSA velocity have significant effect on the detection rates of 11C-Choline PET/CT in men with a BCR after RP or EBRT. PMID- 22814887 TI - The safety and feasibility of a less invasive distal femur closing wedge osteotomy technique: a cadaveric dissection study of the medial aspect of the distal femur. AB - PURPOSE: To investigate the feasibility and safety of a less invasive surgical approach to the distal medial aspect of the femur in supracondylar medial closing wedge osteotomy for the treatment of lateral compartment osteoarthritis of the knee. The aim of a less invasive approach is to minimize soft tissue disruption, reduce damage to neurovascular structures and thereby prevent muscle atrophy and optimize bone healing potential. METHODS: A human cadaver dissection study on the vascular and neural structures of the medial side of the distal femur was conducted. Surgical dissection (n = 4), cryomicrotomy and subsequent 3D reconstruction of the anatomy (n = 1), and surgical dissection after performance of a supracondylar osteotomy through a less invasive approach (n = 1) were performed in 6 legs in total. RESULTS: The surgical dissection and 3D reconstruction showed that a branch of the femoral artery, the distal genicular artery, supplies the distal area of the vastus medialis (VM) muscle. This artery has several branching patterns; crucial in the presented less invasive approach is its musculo-articular branch, which has an oblique course through the VM to the superomedial pole of the patella. The femoral nerve and saphenous nerve innervate the VM. These structures are at risk in the traditional subvastus approach, whereas no major damage was observed in the leg in which a less invasive approach was performed. CONCLUSIONS: In this cadaveric dissection study, a less invasive approach to the medial side of the distal femur proved to be feasible and safe. Damage to the VM and its neurovascular structures is minimized as compared to the traditional subvastus approach. PMID- 22814888 TI - New monoterpenes, diterpenes, and lignans from Abies recurvata. AB - From the aerial part of Abies recurvata, 62 miscellaneous chemical constituents were isolated including 6 new and 56 known ones. The new compounds comprised three monoterpenes, two diterpenes, and one lignan. Their chemical structures were characterized on the basis of various spectroscopic techniques. Dihydrodehydrodiconiferyl alcohol (35) showed the strongest inhibitory effects against lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells with an IC50 value of 66.4 uM. PMID- 22814889 TI - Triterpene acids from Euscaphis japonica and assessment of their cytotoxic and anti-NO activities. AB - Six new triterpenoids, euscaphic acids G-L (1-6), along with nine known triterpene acids, and two known lignans were isolated from the ethanolic extract of the twigs of Euscaphis japonica. This is the first report concerning 1alpha,3beta-dihydroxy-12-oleanen-28-oic acid isolated from a natural source. The structures of the new compounds were established by spectroscopic analysis. The cytotoxic and anti-NO production activities for the isolates are also evaluated and discussed; compound 1, hederagenin (11), and arjunic acid (12) showed significant cytotoxicity against NCI-H460 cells, HT-29 cells, and CEM cells (IC50 = 1.64 +/- 0.87, 2.11 +/- 1.54, 1.73 +/- 0.64 uM, respectively). Some of the isolated triterpenoids showed marginal inhibitions on NO production induced by LPS. PMID- 22814890 TI - Girls' experiences with violence: an analysis of violence against and by at-risk girls. AB - A growing body of work has emerged that examines crime and delinquency as gendered events. Given the prevalence of violence in the lives of women and girls, scholars have used various theoretical perspectives, including feminist pathways and "doing gender," to investigate the victimization-offending overlap. The authors contribute to this literature through an analysis of juvenile court records using a sample of at-risk girls. The authors identify the context of girls' experiences as victims of violence, perpetrators of violence, and both victims and perpetrators of violence. The authors conclude with epistemological thoughts regarding transdisciplinary research on girls' experiences with violence. PMID- 22814891 TI - Creating a more complete and current picture: examining police and prosecutor decision-making when processing sexual assault cases. AB - This study sought to identify factors that predicted outcomes for sexual assault cases involving female victims across several decision-making points and compare these findings to prior studies. The results indicate that there continues to be a high attrition rate in the handling of sexual assault cases. Only 9.7% of cases examined resulted in charges. In regards to processing decisions, most of the factors that predicted whether cases were founded, resulted in arrest, presented to the prosecution, or resulted in felony charges were extralegal factors. One factor appeared to influence several decision-making points: whether officers noted discrepancies in victim statements. PMID- 22814892 TI - Carrier-free, water dispersible and highly luminescent dye nanoparticles for targeted cell imaging. AB - We develop a new strategy of using surface functionalized small molecule organic dye nanoparticles (NPs) for targeted cell imaging. Organic dye (2-tert-butyl-9,10 di(naphthalen-2-yl)anthracene, TBADN) was fabricated into NPs and this was followed by surface modification with an amphipathic surfactant poly(maleic anhydride-alt-1-octadecene)-polyethylene glycol (C18PMH-PEG) through hydrophobic interactions to achieve good water dispersibility and bio-environmental stability. It should be noted that no additional inert materials were added as carriers, thus the dye-loading capacity of the resulting TBADN NPs is obviously higher than those of previously reported carrier-based structures. This would lead to much larger absorption and then much higher brightness. The resulting TBADN NPs possess comparable, if not higher, brightness than CdSe/ZnS quantum dots under the same conditions, with favorable biocompatibility. Significantly, TBADN NPs are readily conjugated with folic acid, and successfully applied in targeted cell imaging. These results show that water dispersible and highly stable organic NPs would be a promising new class of fluorescent probe for bioapplications in cellular imaging and labeling. This strategy may be straightforwardly extended to other organic dyes to achieve water dispersible NPs for cell imaging and drug delivery. PMID- 22814893 TI - Analgesic effect of a low-level laser therapy (830 nm) in early orthodontic treatment. AB - The aim of this study was to evaluate the pain sensation that orthodontic patients experience when elastic separators are placed between molars and premolars and to determine the degree of analgesic efficacy of low-level laser therapy (LLLT) compared to a placebo treatment. The study was conducted with 20 volunteers who were fitted with elastic separators between the maxillary molars and premolars. One quadrant was randomly chosen to be irradiated with an 830-nm laser, 100 mW, beam diameter of 7 mm, 250 mW/cm(2) applied for 20 s per point (5 J/cm(2)). Three points were irradiated in the buccal face and three were irradiated in the palate. The same procedure was applied in the contralateral quadrant with a placebo light. A visual analogue scale was used to assess pain 5 min, 6 h, 24 h, 48 h, and 72 h after placement of the separators. Maximum pain occurred 6-24 h after placement of the elastic separators. Pain intensity was significantly lower in the laser-treated quadrant (mean, 7.7 mm) than in the placebo-treated quadrant (mean, 14.14 mm; p = 0.0001). LLLT at these parameters can reduce pain in patients following placement of orthodontic rubber separators. PMID- 22814894 TI - Effects of low-intensity laser therapy on periodontal tissue remodeling during relapse and retention of orthodontically moved teeth. AB - This study was designed to investigate the effects of low-intensity laser therapy (LILT) on periodontal ligament (PDL) remodeling during relapse and retention after the completion of orthodontic movement. The maxillary central incisors (n = 104) of the 52 rats were randomly divided into five groups according to the treatment modality: baseline control group without any intervention (n = 8); relapse group without retainer after tooth movement (n = 24); retention group with fixed retainer after tooth movement (n = 24); lased relapse group without retainer after tooth movement and LILT (n = 24); lased retention group with retainer after tooth movement and LILT (n = 24). LILT was daily performed using a gallium-aluminum-arsenide diode laser in a biostimulation mode: wavelength of 780 nm, continuous waves at 70 mW output power, a preset low intensity of 1.75 W/cm(2) in contact mode, resulting in energy dose of 5 J/cm(2) per irradiation for 3 s. The animals were euthanized on days 1, 3, and 7 after removal of the orthodontic appliance. Real-time RT-PCR was performed for quantitative analysis of matrix metalloproteinases mRNA expression. Immunoreactivities of collagen and tissue inhibitor of metalloproteinase were observed on the compression and tension sides. LILT significantly facilitated the expression of five tested MMP mRNAs in both relapse and retention groups. TIMP-1 immunoreactivity was inhibited by LILT in both groups, whereas Col-I immunoreactivity was increased by LILT only in the retention group. These results indicate that LILT would act differently on the stability after orthodontic treatment according to additional retainer wearing or not. LILT when combined with a retainer on the moved teeth may shorten the retention period by accelerating periodontal remodeling in the new tooth position, whereas, LILT on the moved teeth left without any retainer would rather increase the rate of relapse after treatment. PMID- 22814895 TI - Clinical assessment of the efficacy of photodynamic therapy in the treatment of oral lichen planus. AB - The study objective was clinical assessment of the efficacy of photodynamic therapy (PDT) in the treatment of oral lichen planus (OLP). There were 23 patients aged 31-82 included in the study with oral lichen planus diagnosed clinically and histopathologically. In all patients photodynamic therapy was performed with the use of chlorin e6 (Photolon((r))), containing 20 % chlorin e6 and 10 % dimethyl sulfoxide as a photosensitizer. PDT was performed using a semiconductor laser, with power up to 300 mW and a wavelength of 660 nm. A series of illumination sessions was conducted with the use of superficial light energy density of 90 J/cm(2). Changes of lesion size were monitored at one, two, five, and ten PDT appointments from the series of ten according to the authors' own method. The sizes of clinical OLP lesions exposed to PDT were reduced significantly (on average by 55 %). The best effects were observed for the lesions on the lining mucosa (57.6 %). The therapy was statistically significantly less effective when masticatory mucosa was affected (reduction, 30.0 %). Due to substantial efficacy and noninvasiveness, PDT can be useful in the treatment of OLP lesions. PMID- 22814897 TI - Irradiation of 850-nm laser light changes the neural activities in rat primary visual cortex. AB - Although infrared laser was proven to be an alternative approach for neural stimulation, there is very little known about the neural response to infrared laser irradiation in visual cortex. This study is to investigate the effect of near-infrared laser irradiation on neural activities at the cortex level. A 850 nm pigtailed diode laser was applied to stimulate the rat primary visual cortex while the horizontal black and white stripe pattern was used as standard visual stimulation to evoke visual-evoked potential (VEP). Both amplitude and latency of VEP P100 was measured with or without infrared pulse stimulation applied in rat primary visual cortex. Paired t test and one-way analysis of variance were used to evaluate the impact of infrared irradiation and its pulse width on the amplitudes and latencies of P100, respectively. The results from our preliminary study revealed that, the pulsed near-infrared laser depressed the VEP amplitude and shortened the latency of P100; with the increment of pulse width of infrared irradiation, further decline of VEP amplitude and much shortened latency of P100 were observed. The present work suggests that near-infrared laser irradiation can alter the neural activities in primary visual cortex transiently, and could provide a novel contactless artificial neural stimulus to brain cortex with high spatial selectivity. PMID- 22814899 TI - Nitrate reduction with biotic and abiotic cathodes at various cell voltages in bioelectrochemical denitrification system. AB - Electrochemical treatment of nitrate ions was attempted using different catalysts on the cathode in bioelectrochemical denitrification systems. The carbon cathode coated by biofilm (biocathode) could remove 91 % of nitrate ions at 1.0 V, which was almost same as the Pt-coated electrode (90 %). The exchange current density of biocathode was 0.0083 A/m(2), which was almost 22 times higher than with an abiotic plain carbon cathode. The formation of intermediate products in nitrate reduction varied depending on the cell voltage. At 0.5 V, a large portion of nitrate was converted to ammonia, but at more increased cell voltage (0.7 and 1 V) a high amount of nitrite ions was found with little ammonia formation in cathodic solution. The maximum nitrate removal rate was 0.204 mg NO(3)-N/cm(2)d by biocathode, while plain carbon paper showed only 0.176 mg NO(3)-N/cm(2)d. Electrochemical analysis of chronoamperometry showed a higher stable current generation for biocathode (3.1 mA) and Pt-coated cathode (2.8 mA) as compared to plain carbon (0.6 mA) at 0.7 V of poised voltage. PMID- 22814896 TI - The adjunctive effect of photodynamic therapy for residual pockets in single rooted teeth: a randomized controlled clinical trial. AB - Residual pockets are challenging sites that require additional periodontal therapy. The aim of this study was to evaluate the effect of a single photodynamic therapy (PDT) as an adjunct to scaling and root planning (SRP) in residual pockets in single-rooted teeth. A blind, split-mouth, randomized controlled clinical trial was conducted in systemically healthy subjects presenting at least two residual pockets (probing pocket depth (PPD) >= 5 mm with bleeding on probing (BoP)) in single root teeth in supportive periodontal therapy. The selected sites were assigned to receive (1) PDT + SRP or (2) SRP. In sites treated by PDT as adjunctive to SRP, the laser system included a handheld battery-operated diode laser with a wavelength of 660 nm, a power output of 60 mW, and energy density of 129 J/cm(2), together with methylene blue as a photosensitizer (10 mg/ml). Clinical parameters were assessed at baseline and 3 months post-therapies. Clinical parameters improved significantly after both therapies (p < 0.05), whereas higher probing pocket depth reduction and clinical attachment level gain were observed in the PDT + SRP group at 3 months (p < 0.05). In addition, sites treated by the combined approach yielded a significant reduction in the number of sites with PPD <5 mm without BoP after 3 months compared to sites treated by conventional SRP alone (p < 0.05). PDT as an adjunctive to mechanical debridement demonstrated additional clinical benefits for residual pockets in single-rooted teeth and may be an alternative therapeutic strategy in supportive periodontal maintenance. PMID- 22814898 TI - Effect of laser and LED phototherapies on the healing of cutaneous wound on healthy and iron-deficient Wistar rats and their impact on fibroblastic activity during wound healing. AB - Iron deficiency impairs the formation of hemoglobin, red blood cells, as well the transport of oxygen. The wound healing process involves numerous functions, many of which are dependent on the presence of oxygen. Laser has been shown to improve angiogenesis, increases blood supply, cell proliferation and function. We aimed to study the effect of lambda660 nm laser and lambda700 nm light-emitting diode (LED) on fibroblastic proliferation on cutaneous wounds on iron-deficient rodents. Induction of iron anemia was carried out by feeding 105 newborn rats with a special iron-free diet. A 1 * 1 cm wound was created on the dorsum of each animal that were randomly distributed into seven groups: I, control anemic; II, anemic no treatment; III, anemic+L; IV, anemic+LED; V, healthy no treatment; VI, healthy+laser; VII, healthy+LED (n=15 each). Phototherapy was carried out using either a diode laser (lambda660 nm, 40 mW, 10 J/cm(2)) or a prototype LED device (lambda700 +/- 20 nm, 15 mW, 10 J/cm(2)). Treatment started immediately after surgery and was repeated at 48-h interval during 7, 14, and 21 days. After animal death, specimens were taken, routinely processed, cut, stained with hematoxylin eosin, and underwent histological analysis and fibroblast counting. Significant difference between healthy and anemic subjects on regards the number of fibroblast between treatments was seen (p<0.008, p<0.001). On healthy animals, significant higher count was seen when laser was used (p<0.008). Anemic subjects irradiated with LED showed significantly higher count (p<0.001). It is concluded that the use of LED light caused a significant positive biomodulation of fibroblastic proliferation on anemic animals and laser was more effective on increasing proliferation on non-anemics. PMID- 22814900 TI - Self-perceived burden as a mediator of depression symptoms amongst individuals living with a movement disorder. AB - OBJECTIVE: Movement disorders are chronic illnesses that can lead to functional impairment and psychological distress. This study examined the relations between functional impairment, depression, and anxiety in individuals with movement disorders, and whether these associations were mediated by feelings of self perceived burden. METHOD: This cross-sectional study sampled individuals (57 males and 57 females; mean age of 62) with chronic movement disorders from a movement disorders clinic. Patients completed measures of depression, anxiety, functional impairment, and self-perceived burden. RESULTS: Functional impairment was associated with depression, but not anxiety, and was mediated by self perceived burden for individuals with chronic movement disorders. CONCLUSIONS: Self-perceived burden may have an important role relative to individuals' adaptation to chronic illness with implications for future interventions. PMID- 22814902 TI - Novel water-soluble substituted pyrrolo[3,2-d]pyrimidines: design, synthesis, and biological evaluation as antitubulin antitumor agents. AB - PURPOSE: To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents. METHODS: Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel. RESULTS: Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI(50)) inhibitor of 8 tumor cell lines. CONCLUSION: We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization. PMID- 22814901 TI - Dedication to professor Leslie Z. Benet: 50 years of scientific excellence and still going strong! PMID- 22814903 TI - Penetration of fluorescein across the rabbit cornea from the endothelial surface. AB - PURPOSE: To model the kinetics of penetration of fluorescein across the cornea from the endothelial surface. METHODS: Rabbit corneas mounted in vitro were exposed to fluorescein at their endothelial surface. Trans-corneal fluorescence were acquired periodically for 6 h using a custom-built confocal microfluorometer. The profiles were then employed to fit a kinetic model for calculation of permeability and diffusion coefficients across the cellular layers and stroma, respectively. RESULTS: At the endothelium-stroma and stroma epithelium interfaces, the fluorescence profile exhibited sudden jumps. In each case, the fluorescence was higher at the stroma, indicating reduced partitioning of the dye into the lipid-rich cellular layers. The stroma did not swell significantly until 180 min of perfusion. The fluorescence profiles reached a pseudo-steady state at ~6 h. A transport model, which included convective and diffusive fluxes into the stroma, showed a good fit to the trans-corneal profiles at different time points. The estimated permeability coefficients for the cellular layers were close to the values reported previously, but the diffusion coefficient of fluorescein in the stroma was found to be smaller than the values obtained previously using Ussing chambers. CONCLUSIONS: The penetration of fluorescein could be modeled accurately by a combination of diffusion and convection. PMID- 22814907 TI - Decompression side tube-equipped double-balloon enteroscopy extends intubation depth and reduces patient discomfort. PMID- 22814904 TI - An overview of tubulin inhibitors that interact with the colchicine binding site. AB - Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs. PMID- 22814906 TI - Autologous dermal grafts for rectus sheath reconstruction and application in closure of ventral myofascial defects. AB - Ventral abdominal hernias pose a reconstructive challenge, with recurrence rates after primary closure exceeding 50 % and synthetic options at high risk for infection. We describe our experience with using autologous dermis, sourced from the redundant overlying abdominal skin, for reconstruction of ventral abdominal wall defects. We describe the surgical technique, applied anatomy and an analysis of short- and long-term outcomes. Twelve consecutive patients undergoing repair of medium-large size, reducible abdominal wall defects were recruited. The dermal graft technique was used in each case, utilizing an autologous running strip of abdominal skin for reconstruction. Both short- and long-term outcomes were assessed prospectively. Scores were given on a scale of 1-10, with 1 = least/worst and 10 = most/best. The described technique was successfully undertaken in all patients. Long-term follow-up demonstrated a 100 % resumption of normal activities, with an improvement in quality of life and physical activity scores postoperatively, and no recurrences. Short-term complications were notable, with five patients requiring postoperative intensive care unit admission, and seven patients requiring respiratory support. In conclusion, the use of autologous rectus sheath reinforcement may achieve good surgical outcomes and high patient satisfaction. While early respiratory complications should be noted, the potential utility of this technique is worthy of future investigation. PMID- 22814908 TI - Multicentric infantile myofibromatosis of the small bowel detected by video capsule endoscopy in a child. PMID- 22814909 TI - Rectal fistula due to ovarian teratoma. PMID- 22814910 TI - Complete endoscopic management of tubular esophageal duplication in a young woman. PMID- 22814911 TI - In vivo diagnosis and characterization of gastric Crohn's disease using endomicroscopy and virtual chromoendoscopy. PMID- 22814912 TI - Anterior spinal cord infarction with permanent paralysis following endoscopic ultrasound celiac plexus neurolysis. PMID- 22814913 TI - Fatal complication after endoscopic ultrasound-guided celiac plexus neurolysis. PMID- 22814914 TI - Serosal lacerations during colonoscopy - a rare complication. PMID- 22814915 TI - Gastric outlet obstruction secondary to percutaneous endoscopic gastrostomy tube placement. PMID- 22814916 TI - Gastric neuroendocrine tumor with extensive ossification. PMID- 22814917 TI - An unusual case of colorectal human papillomavirus infection. PMID- 22814918 TI - Sigmoid perforation caused by a migrated biliary stent and closed with clips. PMID- 22814919 TI - Endoscopic features of primary amyloidosis of the stomach. PMID- 22814920 TI - Assessing the value of information for water quality management: a watershed perspective from China. AB - To tackle China's pervasive water pollution, tremendous efforts are needed to achieve more and better information. However, resources for information collection (e.g., water quality monitoring, field experiments, etc.) are very limited for large watersheds with significant nonpoint source pollution. Thus, it is crucial to identify the priority of information acquisition. Based on the theory of value of information (VOI), a stochastic optimization approach was developed in this study to evaluate the importance of information. The approach was applied to several key polluted water bodies in China (e.g., Lake Taihu, Lake Chaohu, and Lake Dianchi). The major findings include: (1) because of the severe pollution and large uncertainty, the VOI for the targeted water bodies is substantial; (2) when the uncertainty is significant, a stricter regulation would result in a higher VOI, and therefore provide more incentives for data collection; (3) due to the interaction among different information sources, collecting multiple types of information simultaneously could be more valuable than collecting one after another; and (4) the importance of a specific type of information could vary significantly across watersheds. The proposed approach can be readily extended to more complex models and more sophisticated watershed cases. It could effectively support watershed management in China, as well as in other countries. PMID- 22814921 TI - Multistep, microvolume resin fractionation combined with 3D fluorescence spectroscopy for improved DOM characterization and water quality monitoring. AB - Conventionally, resin fractionation (RF) method has been widely used to characterize dissolved organic matter (DOM) found in different source waters based on general and broad DOM fractions grouping. In this study, a new refined method using multistep, microvolume resin fractionation combined with excitation emission matrix fluorescence spectroscopy (MSM-RF-EEMS) was developed for further isolation and characterization of subfractions within the primary DOM fractions separated from using the conventional RF method. Subsequently, its feasibility in indicating the occurrence of urban pollution in source waters was also assessed. Results from using the new MSM-RF-EEMS method strongly illustrated that several organic subfractions still exist within the regarded primary pure hydrophobic acid (HoA) fraction including the humic- and fulvic-like organic matters, tryptophan- and tyrosine-like proteins. It was found that by using the MSM-RF EEMS method, the organic subfractions present within the primary DOM fraction could be easily identified and characterized. Further validation on the HoA fraction using the MSM-RF-EEMS method revealed that the constant association of EEM peak T1 (tryptophan) fraction could specifically be used to indicate the occurrence of urban pollution in source water. The correlation analysis on the presence of EEM peak T2 (tyrosine) fraction could be used as a supplementary proof to further verify the presence of urban pollution in source waters. These findings on using the presence of EEM peaks T1 and T2 within the primary HoA fraction would be significant and useful for developing a sensory device for online water quality monitoring. PMID- 22814922 TI - [Supporting carers of persons suffering from an eating disorder]. AB - The purpose of this article is to describe the background and procedure of a skills training program provided for carers of patients suffering from anorexia or bulimia nervosa. Caring for someone suffering from an eating disorder is associated with psychological distress and may lead to unhelpful interactive behaviours that maintain the illness. Recent investigations in supporting carers, especially skills sharing workshops that target interpersonal maintaining factors are described. A 5-session training concept in teaching basic skills and information about eating disorders to carers in order to improve caregiving burden and reduce interpersonal maintaining factors like expressed emotions (EE) is currently examined in our department. Design and content will be described in detail. Carers' and sufferers' perceptions of the impact of the sessions and acceptance of the provided skills training are reported. PMID- 22814923 TI - [Subretinal hemorrhage. Natural course and staging]. AB - Subretinal hemorrhages are a complication of various diseases which arise from the choroidal or retinal circulation. Most commonly the underlying pathology is a choroidal neovascular membrane (CNV) especially in patients with age-related macular degeneration (AMD). Less common ocular diseases are those with non-AMD related CNV and retinal arterial macroaneurysms (RAM). Case studies have demonstrated a poor prognosis, however, a significant portion have favorable outcomes. Therefore, therapeutic decision-making is difficult. As a major difficulty in comparing different treatment modalities for submacular hemorrhages is the lack of a standardized definition of the extent of the hemorrhage. A classification for AMD-related subretinal hemorrhages including size, thickness and intraretinal location is suggested. PMID- 22814924 TI - [Subretinal surgery for massive hemorrhage]. AB - Subretinal massive hemorrhage due to exsudative age-related macular degeneration remains a challenging field for submacular surgery. While small hemorrhages can be easily displaced by various pneumatic techniques the correct strategy for massive subretinal bleeding is still under debate. This article reviews the different techniques for these severe cases and assesses the visual prognosis and potential complications. In general, invasive techniques for extraction of the neovascular membrane with or without macular translocation or retinal pigment epithelium (RPE) choroidal patch translocation have the potential to achieve visual improvement. However, the risk of severe visual loss due to subsequent complications has to be considered. Far better visual results with a significantly lower complication rate can be achieved by a 2-step strategy using rTPA-assisted dissolution of the hemorrhage and evacuation of the liquefied clot via a small retinotomy. PMID- 22814925 TI - [Massive subretinal hemorrhage and anticoagulants. An unfortunate combination?]. AB - Exudative age-related macular degeneration (ARMD) is one of the conditions which has been shown to be associated with a risk of massive subretinal hemorrhage. Patients with thick submacular hemorrhage complicating ARMD typically have a poor visual prognosis. Antiplatelet therapy with aspirin, clopidogrel or ticlopidine has significant benefits in the secondary prevention of fatal and non-fatal coronary and cerebrovascular events. Anticoagulation is frequently used in this elderly age group for a variety of other comorbidities including prosthetic heart valves, atrial fibrillation, ischemic heart disease, cerebrovascular disease and venous thromboembolism. However, it is a well established observation that the longer patients remain on anticoagulant therapy, the higher the cumulative risk of bleeding. Over the past years, there has been a rapidly growing body of literature concerning the risk of hemorrhagic ocular complications with ophthalmic surgery in patients receiving anticoagulant therapy. By contrast, there are still little data on the relationship between anticoagulation or antiplatelet therapy and spontaneous ocular hemorrhages and only few reports have focused on patients with ARMD. Just recently, several authors reported a strong association of anticoagulants and antiplatelet agents with the development of large subretinal hemorrhages in ARMD patients. Moreover, arterial hypertension is a high risk factor for large subretinal hemorrhages in ARMD patients receiving anticoagulants or antiplatelet agents. Physicians should be aware of an increased risk of extensive subretinal hemorrhage in ARMD patients when deciding on the initiation and duration of anticoagulant and antiplatelet therapy. PMID- 22814927 TI - [Central toxic keratopathy after photorefractive keratectomy]. AB - Central toxic keratopathy is a rare complication following laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) and may unfavorably influence best-corrected visual acuity and refraction. Because of the growing number of refractive surgical procedures worldwide there may be an increasing incidence of this disorder. A differentiation from an inflammatory or infectious etiology is necessary for the appropriate treatment. PMID- 22814928 TI - [Minimally invasive iridocorneal angle surgery]. AB - The classical filtration surgery with trabeculectomy or drainage of chamber fluid with episcleral implants is the most effective method for permanent reduction of intraocular pressure to lower and normal levels. Even though both operative procedures are well-established the high efficiency of the method causes potentially dangerous intraoperative as well as interoperative complications with a frequency which cannot be ignored. In the past this led to a search for low complication alternatives with non-penetrating glaucoma surgery (NPGS) and the search is still continuing. Trabecular meshwork surgery in particular with continuous development of new operation techniques steered the focus to a complication-poor and minimally invasive, gonioscopic glaucoma surgery. PMID- 22814930 TI - CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c Jun N terminal kinase activation independent from the interferon pathway. AB - CD40, a member of the tumor necrosis factor receptor family, and its ligand, CD40L (CD154), are important regulators of the antiviral immune response. CD40L is up-regulated on lymphocytes and CD40 on hepatocytes during infection with hepatitis C virus (HCV); we investigated the role of CD40 signaling during HCV replication in hepatocytes. Viral replication was studied in primary human hepatocytes (PHH) and Huh7.5 cells using the infectious HCV Japanese fulminate hepatitis 1 isolate (JFH1) culture system, and in coculture with HCV antigen specific CD8+ T cells. CD40L rapidly and transiently inhibits expression of the HCV nonstructural proteins NS3 and NS5A as well as HCV structural proteins core and E2 in Huh7.5 cells. Similarly, CD40L prevented replication of HCV in PHH, in synergy with interferon (IFN)-alpha. In Huh7.5 cells with replicating HCV, CD40L prevented production of infectious viral particles. When HCV antigen-specific CD8+ T cells were cocultured with HLA-A2-expressing Huh7 cells that had replicating virus, the T cells became activated, up-regulated CD40L, and inhibited HCV replication. Inhibition of CD40L partially prevented the antiviral activity of the CD8+ T cells. The antiviral effect of CD40L required activation of c-Jun N terminal kinases (JNK)1/2, but not induction of apoptosis or the JAK/STAT pathway that is necessary for the antiviral effects of IFNs. CONCLUSION: CD40 inhibits HCV replication by a novel, innate immune mechanism. This pathway might mediate viral clearance, and disruptions might be involved in the pathogenesis of HCV infection. PMID- 22814931 TI - Increased morbidity in combined abdominal sacrocolpopexy and abdominoplasty procedures. AB - INTRODUCTION AND HYPOTHESIS: This study was performed to determine whether abdominoplasty combined with abdominal sacrocolpopexy (ASC + A) increases perioperative morbidity compared with ASC alone. We hypothesized that patients undergoing combined procedures would have increased complications. METHODS: This was a multicenter, retrospective cohort study of all women undergoing ASC + A from 2002 to 2010 at Washington Hospital Center and Johns Hopkins University. We selected two women undergoing ASC alone for comparison with each ASC + A patient. Baseline demographics, surgical data, length of hospitalization, and perioperative complications were recorded. The primary outcome was any major complication within 6 weeks of surgery, including intraoperative complications, pulmonary embolism (PE), deep venous thrombosis (DVT), cardiac compromise, intensive care unit (ICU) admission, reoperation, and readmission. Surgical data and minor complications were also compared. RESULTS: Twenty-six ASC + A patients and 52 ASC patients were identified. There were no significant differences in baseline characteristics between groups. Patients with ASC + A had longer operating times (337 vs 261 min, p < 0.01), more intravenous fluid administration intraoperatively (4,665 vs 3181 ml, p < 0.01), and longer hospital stays (3.7 vs 2.7 days, p < 0.01). Major complications occurred in 23 % of the ASC + A group compared with 12 % of the ASC group (p = 0.20). The ASC + A group had greater declines in hematocrit levels and higher rates of PE, ICU admission, and blood transfusion, all of which were statistically significant. CONCLUSIONS: ASC + A increases length of stay and perioperative complications, such as PE, ICU admission, and blood transfusion, compared with ASC alone. Surgeons should consider recommending interval abdominoplasty due to increased morbidity risk with a combined procedure. PMID- 22814932 TI - What is the relationship between free flow and pressure flow studies in women? AB - INTRODUCTION AND HYPOTHESIS: The relationship between free flow (FFS) and pressure flow (PFS) voiding studies remains uncertain and the effect of a urethral catheter on flow rates has not been determined. The relationship between residuals obtained at FF and PFS has yet to be established. METHODS: This was a prospective cohort study based on 474 consecutive women undergoing cystometry using different sized urethral catheters at different centres. FFS and PFS data were compared for different conditions and the relationship of residuals analysed for FFS and PFS. The null hypothesis was that urethral catheters do not produce an alteration in maximum flow rates for PFS and FF studies. RESULTS: Urethral catheterisation results in lower flow rates (p < 0.01) and this finding is confirmed when flows are corrected for voided volume (p < 0.01). FFS and PFS maximum flow rates are lower in women with DO than USI (p < 0.01). A 6-F urethral catheter does not have a significantly greater effect than a 4.5-F urethral catheter. A mathematical model can be applied to transform FFS to PFS flow rates and vice versa. There was no significant difference between the mean residuals of the two groups (FFS vs PFS-two-tailed t = 0.54, p = 0.59). Positive residuals in FFS showed a good association with positive residuals in the PFS (r = 0.53, p < 0.01) CONCLUSIONS: Urethral catheterisation results in lower maximum flow rates. The relationship can be compared mathematically. The null hypothesis can be rejected. PMID- 22814933 TI - What information do UK speech and language therapists use when making oral versus nonoral feeding recommendations for adults with oropharyngeal dysphagia? AB - The current study explored what information UK speech and language therapists (SLTs) use when recommending oral versus nonoral feeding in adults with oropharyngeal dysphagia. This study differed from previous research on this topic by including a greater number of participants; focusing on UK-based clinicians; exploring whether different information was considered dependent on whether the person with oropharyngeal dysphagia had had a stroke, had motor neurone disease, or had dementia; and investigating how often videofluoroscopy was used when making these decisions. The current study surveyed UK-based SLTs via an online questionnaire. When asked to rate the ten most important factors involved when making oral versus nonoral decisions, UK SLTs chose 9 of the 13 factors chosen by US-based SLTs in an earlier study. Furthermore, the information considered important in oral versus nonoral decision-making varied depending on the diagnosis of the person with oropharyngeal dysphagia. Finally, the SLTs in the current study reported that they did not frequently use videofluoroscopy to make oral versus nonoral recommendations. PMID- 22814934 TI - Obstructed bilateral inguinal hernias after robotic-assisted laparoscopic ultra low anterior resection: an uncommon complication? PMID- 22814937 TI - Pebbles and PebbleJuggler: software for accurate, unbiased, and fast measurement and analysis of nanoparticle morphology from transmission electron microscopy (TEM) micrographs. AB - Pebbles is a user-friendly software program which implements an accurate, unbiased, and fast method to measure the morphology of a population of nanoparticles (NPs) from TEM micrographs. The morphological parameters of the projected NP shape are obtained by fitting intensity models to the TEM micrograph. Pebbles can be used either in automatic mode, where both fitting and validation are reliably carried out with minimal human intervention, and in manual mode, where the user has full control on the fitting and validation steps. Accuracy in diameter measurement has been shown to be ?1%. When operated in automatic mode, Pebbles can be very fast. The effective speed of 1 NP s-1 has been achieved in favorable cases (packed monolayer of NPs). Since Pebbles is based on a local modeling procedure, it successfully treats cases such as low contrast NPs, NPs with significant diffraction scattering, and inhomogeneous background which often make conventional thresholding procedures fail. Pebbles is accompanied by PebbleJuggler, a software program for the statistical analysis of the sets of best-fit NP models created by Pebbles. Effort has been devoted to make Pebbles and PebbleJuggler the most user-friendly and the least user-tedious we could. Pebbles and PebbleJuggler are available at http://pebbles.istm.cnr.it. PMID- 22814935 TI - Clinical utility of EEG in attention-deficit/hyperactivity disorder: a research update. AB - Psychiatric research applications of electroencephalography (EEG), the earliest approach to imaging human cortical brain activity, are attracting increasing scientific and clinical interest. For more than 40 years, EEG research has attempted to characterize and quantify the neurophysiology of attention deficit/hyperactivity disorder (ADHD), most consistently associating it with increased frontocentral theta band activity and increased theta to beta (theta/beta) power ratio during rest compared to non-ADHD controls. Recent reports suggest that while these EEG measures demonstrate strong discriminant validity for ADHD, significant EEG heterogeneity also exists across ADHD diagnosed individuals. In particular, additional studies validating the use of the theta/beta power ratio measure appear to be needed before it can be used for clinical diagnosis. In recent years, the number and the scientific quality of research reports on EEG-based neurofeedback (NF) for ADHD have grown considerably, although the studies reviewed here do not yet support NF training as a first-line, stand-alone treatment modality. In particular, more research is needed comparing NF to placebo control and other effective treatments for ADHD. Currently, after a long period of relative stasis, the neurophysiological specificity of measures used in EEG research is rapidly increasing. It is likely, therefore, that new EEG studies of ADHD using higher density recordings and new measures drawn from viewing EEG as a 3-dimensional functional imaging modality, as well as intensive re-analyses of existing EEG study data, can better characterize the neurophysiological differences between and within ADHD and non ADHD subjects, and lead to more precise diagnostic measures and effective NF approaches. PMID- 22814936 TI - Aldehyde dehydrogenase-2 activation during cardioplegic arrest enhances the cardioprotection against myocardial ischemia-reperfusion injury. AB - Ischemia/reperfusion damage is common during open-heart surgery. Activation of aldehyde dehydrogenase-2 can significantly reduce ischemia/reperfusion damage. We hypothesized that adding aldehyde dehydrogenase-2 agonist to regular cardioplegia solution would further ameliorate ischemia/reperfusion damage. Alda-1 was used as an aldehyde dehydrogenase-2 agonist. Cardioprotection by histidine-tryptophan ketoglutarate solution with and without Alda-1 was compared using an ex vivo perfused rat heart model of ischemia/reperfusion. Three groups of ex vivo rat hearts endured different treatments with variant ischemia or an ischemia/reperfusion time course: sham, no ischemia/reperfusion; histidine tryptophan-ketoglutarate; and histidine-tryptophan-ketoglutarate plus Alda-1. Aldehyde dehydrogenase-2 expressions and activities, oxidative parameters (including 4-hydroxy-2-nonenal-His adducts, malondialdehyde levels, and glutathione/oxidized glutathione ratios), myocardial protein carbonyl levels, coronary effluents creatine kinase isoenzyme MB levels, and heart function parameters were measured and compared. Alda-1 significantly elevated myocardium aldehyde dehydrogenase-2 activity (P < .01). Increased aldehyde dehydrogenase-2 activity in turn attenuated ischemia/reperfusion-induced elevation in cardiac aldehydes, creatine kinase isoenzyme MB leakage, and protein carbonyl formation (P < .01). The Alda-1 group also obtained higher glutathione/oxidized glutathione ratios (P < .01). Aldehyde dehydrogenase-2 activation alleviated ischemia/reperfusion-induced cardiomyocyte contractile function impairment as evidenced by improved maximal velocity of pressure development and decline, left ventricular developed pressure, and heart rate (P < .01). Alda-1 supplementation can significantly improve the cardioprotection effect of cardioplegia solution, possibly through activation of aldehyde dehydrogenase-2, to remove toxic aldehydes. This may aid in the identification of novel cardioplegia solutions. PMID- 22814938 TI - Nitric oxide modulated the expression of DREAM/calsenilin/KChIP3 in inflammatory pain of rats. AB - Downstream regulatory element antagonistic modulator (DREAM) is a critical transcriptional repressor for pain modulation. The role of nitric oxide (NO) plays in modulating DREAM pain pathway in the periphery is unclear. Therefore, we investigated the role of the NO in modulation of the expression of DREAM in formalin-induced rat inflammatory pain models. Male Sprague-Dawley rats were randomly distributed into four groups: the normal group, formalin test group, Nomega-nitro-L-arginine (l-NNA) group, and morphine group. One hundred microliters of 2.5 % formalin was injected into the plantar surface of the right hindpaw of rats. l-NNA (40 nmol/L) and morphine (40 nmol/L) were injected intrathecally in the hindpaw before formalin injection. The nociceptive behavioral reaction was recorded. After the formalin test, the expression of DREAM mRNA and protein in the spinal cord of the four groups were measured. The nociceptive reaction induced by injection of formalin exhibited two phases. Morphine and l-NNA significantly decreased pain scores of the second phase. The expression of DREAM was significantly increased in the rat spinal cord after formalin-induced pain. Morphine significantly upregulated the expression of DREAM, and the formalin-induced upregulation was significantly attenuated by l NNA. NO may play an important role in the DREAM pathway modulation of inflammatory pain. PMID- 22814939 TI - Over-expression of a cytosolic isoform of the HbCuZnSOD gene in Hevea brasiliensis changes its response to a water deficit. AB - Hevea brasiliensis is the main commercial source of natural rubber. Reactive oxygen species (ROS) scavenging systems are involved in various biotic and abiotic stresses. Genetic engineering was undertaken to study the strengthening of plant defences by antioxidants. To that end, Hevea transgenic plant lines over expressing a Hevea brasiliensis cytosolic HbCuZnSOD gene were successfully established and regenerated. Over-expression of the HbCuZnSOD gene was not clearly related to an increase in SOD activity in plant leaves. The impact of HbCuZnSOD gene over-expression in somatic embryogenesis and in plant development are presented and discussed. The water deficit tolerance of two HbCuZnSOD over expressing lines was evaluated. The physiological parameters of transgenic plantlets subjected to a water deficit suggested that plants from line TS4T8An displayed lower stomatal conductance and a higher proline content. Over expression of the HbCuZnSOD gene and activation of all ROS-scavenging enzymes also suggested that protection against ROS was more efficient in the TS4T8An transgenic line. PMID- 22814940 TI - Site-directed mutagenesis of a tetrameric dandelion polyphenol oxidase (PPO-6) reveals the site of subunit interaction. AB - Polyphenol oxidases (PPOs) catalyze the oxidation of ortho-diphenols to the corresponding quinones (EC 1.10.3.1). In plants PPOs appear in gene families, and the corresponding isoenzymes are located to the thylakoid lumen of chloroplasts. Although plant PPOs are often discussed with regard to their role in defense reactions, a common physiological function has not yet been defined. We analyzed a tetrameric PPO isoenzyme (PPO-6) from dandelion (Taraxacum officinale) heterologously expressed in Escherichia coli, and found it to display cooperativity in catalysis, a phenomenon that has rarely been shown for plant PPOs previously. The identification of a surface-exposed cysteine (197) through molecular modeling followed by site-directed mutagenesis proved this amino acid residue to stabilize the tetramer via a disulfide linkage. The C197S-mutein still forms a tetrameric structure but shows impaired enzymatic efficiency and cooperativity and a reduction in stability. These findings indicate that oligomerization may be a physiological requirement for PPO-6 stability and function in vivo and raise new questions regarding distinct functions for specific PPO isoenzymes in plants. PMID- 22814941 TI - Neonatal early-onset sepsis evaluations among well-appearing infants: projected impact of changes in CDC GBS guidelines. AB - OBJECTIVE: To determine (a) the proportion of asymptomatic infants born at >=35 weeks gestation evaluated for early-onset sepsis (EOS) and exposed to postnatal antibiotics; (b) reasons for and outcomes of the evaluations, and (c) anticipated changes when applying the Centers for Disease Control and Prevention (CDC) 2010 guidelines to this study population. STUDY DESIGN: Retrospective cohort study of infants born at >=35 weeks gestation in 2008-2009 in a large maternity center. RESULT: Out of the 7226 infants that met the study criteria: 1062 (14.7%) were evaluated for EOS and half of those evaluated, received empiric antibiotics. 70.4% of evaluations were performed owing to maternal intrapartum fever, but 23% were prompted by inadequate Group B Streptococcus (GBS) prophylaxis alone. Three cases of blood culture-proven infection were identified. CONCLUSION: Improved approaches are needed to identify asymptomatic infants who are at risk for EOS to decrease unnecessary evaluations and antibiotic exposure. Transition to the 2010 CDC GBS guidelines may eliminate a quarter of EOS evaluations among these infants. PMID- 22814943 TI - 3D characterization of pores in the cortical bone of human femur in the elderly at different locations as determined by synchrotron micro-computed tomography images. AB - Diaphysis, inferior, and lateral superior regions of the femoral neck are subjected to diverse mechanical loads. Using micro-CT based on synchrotron radiation, three-dimensional morphology and connectivity of the pore network are location dependent, underlying different remodeling mechanisms. INTRODUCTION: The three-dimensional (3D) morphology and connectivity of the pore network at various locations in human femurs subjected to diverse mechanical loads were assessed using micro-CT based on synchrotron radiation. METHODS: The cortex from 20 human femurs (mean age, 78.3 +/- 12.4 years) was taken from the diaphysis (D), the inferior (IN), and the lateral superior (LS) regions of the femoral neck. The voxel size of the 3D reconstructed image was 7.5 MUm. Cortical thickness and pore volume/tissue volume (Po.V/TV), pore diameter (Po.Dm) and spacing (Po.Sp) were determined. The pore surface/pore volume ratio (Po.S/Po.V), the number of pores (Po.N), the degrees of anisotropy (DA), and the connectivity density (ConnD), the degree of mineralization (DMB) were also determined. RESULTS: The characteristics of the pore network in femoral cortical bone were found to be location dependent. There was greater porosity, Po.Dm, and Po.N, and more large (180-270 MUm), extra large (270-360 MUm) and giant pores (>360 MUm) in the LS compared to the IN and D. The difference in porosity in between the periosteal and endosteal layers was mostly due to an increase of Po.Dm rather than Po.N. There was a lower DMB of bone in the LS, which is consistent with a higher remodeling rate. CONCLUSION: The results provide evidence for large variations in the structure of the internal pore network in cortical bone. These variations could involve different underlying remodeling mechanisms. PMID- 22814944 TI - Health-related quality of life in patients with osteoporosis in the absence of vertebral fracture: a systematic review. AB - To review whether osteoporosis in the absence of vertebral fracture (VFX) affects health-related quality of life (HRQoL), a systematic search of the main literature databases for HRQoL in patients with osteoporosis without VFX was undertaken. This was undertaken. This identified 1,327 articles as potentially relevant to the review. After screening of abstracts and reviewing 168 articles in detail, 27 were considered relevant. HRQoL data were extracted and collated into tables and, where possible, were converted into normative scores and further analysed. Data relating to the associations between HRQoL and bone mineral density (BMD) were also collated. Of the 27 articles included, only 5 directly compared osteoporosis without VFX with a control group (BMD T-score > -1.0, without VFX). Extracted raw data from 21 articles demonstrated that patients with osteoporosis without VFX had clinically relevant reductions in role physical, general health, vitality, mental health domains and the mental component summary score, using SF36. Using Qualeffo-41, pain and physical function were worse in these patients. Also, HRQoL was related to upper femur, but not lumbar spine BMD. HRQoL data in patients with osteoporosis without VFX are limited and variable but suggest that HRQoL is adversely affected by osteoporosis in the absence of VFX. The association of lower BMD and worse HRQoL suggests that more attention should be paid to HRQoL in those without VFX. Future studies are needed to investigate HRQoL in patients with osteoporosis in the absence of fracture, controlling for co-morbidities and social and economic status. PMID- 22814945 TI - Calcaneal ultrasound reference ranges for Australian men and women: the Geelong Osteoporosis Study. AB - Heel ultrasound is a more portable modality for assessing fracture risk than dual energy X-ray absorptiometry and does not use ionising radiation. Fracture risk assessment requires appropriate reference data to enable comparisons. This study reports the first heel ultrasound reference ranges for the Australian population. INTRODUCTION: This study aimed to develop calcaneal (heel) ultrasound reference ranges for the Australian adult population using a population-based random sample. METHODS: Men and women aged>=20 years were randomly selected from the Barwon Statistical Division in 2001-2006 and 1993-1997, respectively, using the electoral roll. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were measured at the heel using a Lunar Achilles Ultrasonometer. Gender-specific means and standard deviations for BUA, SOS and SI were calculated for the entire sample (men 20-93 years, n=1,104; women 20-92 years, n=914) and for participants aged 20-29 years (men, n=157; women, n=151). Associations between ultrasound measures and age were examined using linear regression. RESULTS: For men, mean+/-standard deviation BUA, SOS and SI were 118.7+/-15.8 dB/MHz, 1,577.0+/-43.7 m/s and 100.5+/-20.7, respectively; values for women were consistently lower (111.0+/-16.4 dB/MHz, P<0.001; 1,571.0+/-39.0 m/s, P=0.001; and 93.7+/-20.3, P<0.001, respectively). BUA was higher in young men compared with young women (124.5+/-14.4 vs 121.0+/-15.1 dB/MHz), but SOS (1,590.1+/-43.1 vs 1,592.5+/-35.0 m/s) and SI (108.0+/-19.9 vs 106.3+/-17.7) were not. The relationships between age and each ultrasound measure were linear and negative across the age range in men; associations were also negative in women but non-linear. CONCLUSION: These data provide reference standards to facilitate the assessment of fracture risk in an Australian population using heel ultrasound. PMID- 22814942 TI - Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage. AB - OBJECTIVE: To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants. STUDY DESIGN: Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort. RESULT: Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt. CONCLUSION: GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI. PMID- 22814946 TI - Dental calculus formation in children and adolescents undergoing hemodialysis. AB - BACKGROUND: This study aimed to determine whether dental calculus formation is really higher among patients with chronic kidney disease undergoing hemodialysis than among controls. Furthermore, the study evaluated correlations between dental calculus formation and dental plaque, variables that are related to renal disease and/or saliva composition. METHODS: The Renal Group was composed of 30 patients undergoing hemodialysis, whereas the Healthy Group had 30 clinically healthy patients. Stimulated whole saliva and parotid saliva were collected. Salivary flow rate and calcium and phosphate concentrations were determined. In the Renal Group the saliva collection was carried out before and after a hemodialysis session. Patients from both groups received intraoral exams, oral hygiene instructions, and dental scaling. Three months later, the dental calculus was measured by the Volpe-Manhold method to determine the rate of dental calculus formation. RESULTS: The Renal Group presented a higher rate of dental calculus formation (p < 0.01). Correlation was observed between rate of dental calculus formation and whole saliva flow rate in the Renal Group after a hemodialysis session (r = 0.44, p < 0.05). The presence of dental calculus was associated with phosphate concentration in whole saliva from the Renal Group (p < 0.05). CONCLUSION: In conclusion, patients undergoing hemodialysis presented accelerated dental calculus formation, probably due to salivary variables. PMID- 22814948 TI - Improving the carboxyamidomethyl ester for subtilisin A-catalysed peptide synthesis. AB - A series of novel glycine esters was evaluated for efficiency in subtilisin A CLEA-catalysed peptide synthesis. The reactivity of the easily accessible carboxyamidomethyl (Cam) ester was further enhanced by elongating it with an amino acid residue, thereby creating more recognition space for subtilisin A. PMID- 22814947 TI - Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. AB - Methylmalonic acidurias are a heterogeneous group of inborn errors of branched chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut degrees , cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients. PMID- 22814949 TI - Interactions between facial emotion and identity in face processing: evidence based on redundancy gains. AB - Interactions between the processing of emotion expression and form-based information from faces (facial identity) were investigated using the redundant target paradigm, in which we specifically tested whether identity and emotional expression are integrated in a superadditive manner (Miller, Cognitive Psychology 14:247-279, 1982). In Experiments 1 and 2, participants performed emotion and face identity judgments on faces with sad or angry emotional expressions. Responses to redundant targets were faster than responses to either single target when a universal emotion was conveyed, and performance violated the predictions from a model assuming independent processing of emotion and face identity. Experiment 4 showed that these effects were not modulated by varying interstimulus and nontarget contingencies, and Experiment 5 demonstrated that the redundancy gains were eliminated when faces were inverted. Taken together, these results suggest that the identification of emotion and facial identity interact in face processing. PMID- 22814950 TI - Extracting the stepping dynamics of molecular motors in living cells from trajectories of single particles. AB - Molecular motors are responsible of transporting a wide variety of cargos in the cytoplasm. Current efforts are oriented to characterize the biophysical properties of motors in cells with the aim of elucidating the mechanisms of these nanomachines in the complex cellular environment. In this study, we present an algorithm designed to extract motor step sizes and dwell times between steps from trajectories of motors or cargoes driven by motors in cells. The algorithm is based on finding patterns in the trajectory compatible with the behavior expected for a motor step, i.e., a region of confined motion followed by a jump in the position to another region of confined motion with similar characteristics to the previous one. We show that this algorithm allows the analysis of 2D trajectories even if they present complex motion patterns such as active transport interspersed with diffusion and does not require the assumption of a given step size or dwell period. The confidence on the step detection can be easily obtained and allows the evaluation of the confidence of the dwell and step size distributions. To illustrate the possible applications of this algorithm, we analyzed trajectories of myosin-V driven organelles in living cells. PMID- 22814951 TI - Intracranial clear cell meningioma in two children with blood relations: two case reports and literature review. AB - Intracranial clear cell meningioma (CCM) is very rare and often has an aggressive clinical course. The predilection site of intracranial CCM in children was cerebellopontine angle where represents challenging tumor resection because of the vicinity of brainstem, vertebral artery, and lower cranial nerve. Therefore, special consideration is required for this tumor.We report two cases with intracranial CCM in a family and reviewed the literature concerning pediatric intracranial CCM. Case 1 is a 4-year-old boy with a tumor at the right posterior fossa. Case 2 is an 8-year-old boy with a left basilar region tumor. Gross total resection and subtotal resection was achieved in case 1 and case 2, respectively. Case 1 had no tumor recurrence at 12 months after the operation. Case 2 received cyber-knife radiosurgery (CKS) after subtotal resection at 4 months, and the residual tumor had gradually shrunk. Comprehensive chromosomal number aberrations in both patients were revealed by array-comparative genomic hybridization, and loss of neurofibromatosis 2 (NF2) gene was the common genetic abnormality in the two patients.To the best of our knowledge, this is the first report concerned two patients with CCM in a family, and the findings in this article suggest that CKS is a safe and effective adjuvant therapy for residual CCM after operation and NF2 gene mutation plays a role in tumorigenesis of pediatric intracranial CCM. PMID- 22814952 TI - Rabi Rashidi (Rashidi Quarters): a late thirteen to early fourteenth century Middle Eastern Medical School. AB - INTRODUCTION: Following the Mongolian invasion of the Middle East in the thirteenth century, a regional power called the Ilkhanid emerged and was ruled by the heirs of Temujin from Mongolia. Embracing present-day Iran, Iraq, Afghanistan, Azerbaijan, areas of Russia, Turkey, and Pakistan, and nearby Middle Eastern territories, the Ilkhanid state patronized medicine and various other professions. Centered in Tabriz (Tauris), a city in the northwest of present-day Iran, was a non-profit-making educational and medical complex founded by Grand Minister Rashid al-Din Fazlollah Hamadani. METHODS: This paper reviews the literature regarding the rise and fall of the thirteenth century university and the Rabi Rashidi, emphasizing the structure of its medical school. CONCLUSIONS: The background training of Rashid al-Din and his keen interest in science turned this complex, Rabi Rashidi (literally meaning the Rashidi Quarters), into a cosmopolitan university that freely trained medical scholars nationally and internationally. The possibility that Rashid al-Din was inspired by university developments in Europe is discussed. PMID- 22814953 TI - Differential proliferative index of cancer stem-like cells in primary and recurrent medulloblastoma in human. AB - PURPOSE: Medulloblastoma is the most common malignant primitive neuroectodermal tumor found in children. It has a tendency to recur at a primary or distant site. The mechanism underlying the regulation of the recurrence of medulloblastoma remains largely unknown. Recently, several reports have described that cancer stem-like cells (CSCs) can be identified and isolated in medulloblastoma. The authors therefore attempted to demonstrate the correlation between the biological features of medulloblastoma's CSCs and its recurrence. METHODS: The data used were obtained in five consecutive patients with medulloblastomas who subsequently experienced tumor recurrence from 2004 to 2007. The authors performed the immunohistochemical assays to analyze the expression of CSC markers, proliferation features, and proliferative status of CSCs in primary and recurrent medulloblastoma. RESULTS: Of the five patients, two had recurrence at the primary site and three had a distant recurrence. CSC markers such as CD133(Prominin-1), DCX, PSA-NCAM, TUC-4, and nestin were expressed regardless of primary or recurrent medulloblastoma. All the five tumor specimens had a high proliferation index (PI). The PI was even higher in the group of patients after recurrence at a distant site (p<0.05), while the PI remained almost the same after primary recurrence. The Ki67/nestin-, Ki67/DCX-, and Ki67/TUC-4-positive cells were significantly increased in recurrent medulloblastoma at both the primary and distant sites, whereas CSCs in primary medulloblastoma showed much lower proliferative features (p<0.05). CONCLUSIONS: Our data suggest that tumorigenesis of medulloblastomas and their recurrence might be related to CSCs. More proliferating CSCs in medulloblastomas denote worse prognosis. PMID- 22814954 TI - Reduction in augmentation index after successful renal transplantation. AB - BACKGROUND: Patients of end stage renal disease (ESRD) have an increased risk of cardiovascular events. Arterial stiffness is an established independent predictor of cardiovascular morbidity and mortality in ESRD patients. Carotid femoral pulse wave velocity (c-f PWV) and augmentation index (AI) are the indices which are used for the noninvasive assessment of arterial stiffness. Renal transplantation (RT) as a treatment modality in ESRD patients is associated with improvement in cardiovascular survival. Whether this improvement is due to attenuation of arterial stiffness has been inadequately investigated. The present study was conducted in ESRD patients before and 3 months after RT to assess the reversibility of the abnormalities of vascular compliance that are known to be associated with adverse outcome. METHODS: Arterial stiffness indices (c-f PWV and AI) were measured using the principle of applanation tonometry with a SphygmoCor CvMS system (Atcor Medicals, Australia) in 23 ESRD patients (age: 35.9 +/- 9.3 years) before and 3 months after successful RT. RESULTS: After transplantation, augmentation index values reduced significantly as compared to their pre transplant values (27.7 +/- 11.3 % vs. 17.1 +/- 9.0 %; P < 0.0001), while the carotid femoral pulse wave velocity values did not differ significantly (8.7 +/- 2.0 vs. 8.6 +/- 3.2 m/s). The augmentation index was correlated with the biochemical parameters of serum creatinine (Pearson r = 0.3628; P = 0.0128) and calcium phosphate product (Pearson r = 0.3868; P = 0.0079). CONCLUSIONS: Restoration of renal function following successful RT is associated with differential effects on the two indices of arterial stiffness. The salient finding of our study is that 3 months after transplantation, functional changes in vasculature lead to a significant reduction in the augmentation index, while the pulse wave velocity may take longer to show an improvement. PMID- 22814955 TI - Virological responses of pegylated interferon alpha-2a treatment in hemodialysis patients infected with hepatitis C. AB - BACKGROUND: Hepatitis C is the most frequently encountered hepatic disease in dialysis patients. Data related to pegylated interferon alfa-2a (Peg-IFN-alpha 2a) use in hemodialysis patients with hepatitis C virus (HCV) are limited. The aim of this study was to evaluate the efficacy of Peg-IFN-alpha-2a among these patients. METHODS: Forty-one IFN-naive hemodialysis patients infected by HCV were assessed. All patients had positive anti-HCV antibody and positive HCV-RNA. Peg IFN-alpha-2a 135 mcg/week was given for 48 weeks. Biochemical and virological responses were evaluated at treatment weeks 12, 24, 48, and 72. RESULTS: Thirty eight of the 41 patients who completed the treatment enrolled in the study. Mean age of the 38 patients was 38.1 (range 23-65) years, and the study group was predominantly male (65.8 %). There was no statistically significant difference in mean age, gender, mean duration of hemodialysis, HCV infection, patient numbers with normal alanine aminotransferase (ALT) values and mean ALT, platelet, and HCV RNA values between patients who achieved sustained virological response (SVR) and those who did not. Only the Knodell histology activity index correlated with SVR (P = 0.048). Biochemical and virological response rates at the 12th week (early response) were 94.7 % and 60.5 %, respectively. The 34 (89.5 %) patients achieved biochemical response at the end of therapy (48th week); 24 (63.2 %) remained HCV RNA negative. At the 72nd week, biochemical and virological response rates were 84.2 % and 50 %, respectively. DISCUSSION: According to results of this study, patients achieved good sustained viral and biochemical response rates with Peg IFN-alpha-2a treatment. Histology activity index may be a predictor for SVR; but large randomized controlled trials are needed. Weekly 135 mcg dose of Peg-IFN alpha-2a for 48 weeks is an effective treatment in HCV-infected hemodialysis patients. PMID- 22814956 TI - Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease. AB - BACKGROUND: Chronic renal failure on dialysis can reduce the number of circulating endothelial progenitor cells (EPCs), but this biomarker has not been fully investigated in patients with chronic kidney disease (CKD). A link between CKD and increased mononuclear cell apoptosis (MCA) in circulation has been reported but the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1alpha, two angiogenesis factors, on circulating EPC levels in CKD has not been clarified. This study examined the relationships between the numbers of circulating EPCs and the severity of CKD, degree of MCA and serum levels of VEGF and SDF-1alpha in CKD patients. METHODS: The numbers of circulating EPCs (CD31/CD34+, CD62E/CD34+, KDR/CD34+, CXCR4/CD34+) were measured in 166 patients with varying degrees of CKD under regular treatment at an outpatient department and in 30 volunteer control subjects. RESULTS: CKD patients had significantly lower numbers of EPCs (p < 0.007), higher MCA in circulation and higher serum levels of VEGF and SDF-1 compared with the control subjects (all p < 0.001). Compared with patients with early CKD (stages I-III), patients with late CKD [stage IV-V or end-stage renal disease (ESRD)] had significantly lower numbers of EPCs (CXCR4/CD34+), higher MCA, and elevated serum levels of VEGF and SDF-1alpha (all p < 0.01). Serum VEGF level but not MCA or SDF-1alpha was strongly correlated with increased numbers of circulating EPCs. Multivariate analysis showed that ESRD along with lower serum albumin was independently predictive of lower numbers of circulating EPCs (p < 0.04). CONCLUSION: Circulating EPCs were markedly reduced in CKD patients. ESRD was strongly and independently predictive of decreased numbers of circulating EPCs. PMID- 22814957 TI - An evaluation of the effects of eyeball structure on ocular pulse amplitude in healthy subjects. AB - To evaluate the effects of eyeball structure on ocular pulse amplitude (OPA) measured using dynamic contour tonometer (DCT). In 86 eyes of 43 healthy subjects, we measured OPA and intraocular pressure (IOP) with DCT (DCT-IOP), IOP with Goldmann applanation tonometry (GAT-IOP), central corneal thickness (CCT), corneal thickness 2 mm (2 mmCT) and 4 mm (4 mmCT) apart from the center, corneal volume within a 3.5-mm radius from the corneal center, corneal curvature, anterior chamber depth, anterior chamber volume, and axial length (AL). OPA had a significant positive correlation with GAT-IOP (Pearson's r = 0.412, p < 0.001), DCT-IOP (r = 0.350, p < 0.001), and 4 mmCT (r = 0.244, p = 0.0231), and had a significant negative correlation with AL (r = -0.268, p = 0.0122). In a multiple linear regression analysis, AL and GAT-IOP were significantly associated with OPA. OPA measured with DCT is significantly influenced by several factors, such as IOP, peripheral corneal thickness (4 mmCT), and AL. PMID- 22814958 TI - Limbal stem cell deficiency in patients with inherited stem cell disorder of dyskeratosis congenita. AB - The aim of this study is to present the limbal stem cell deficiency (LSCD) cases with features resembling dyskeratosis congenita (DC), a heritable disease of stem cells principally caused by telomerase deficiency. The clinical, laboratory and molecular findings of four cases are presented. A complete systemic examination was performed in a standardized manner for each patient. Laboratory measurements included investigations of the tests used for screening DC. All eight known disease-causing genes in DC (DKC1, TERC, TERT, NOP10, NHP2, TINF2, C16orf57, and TCAB1) were screened for mutations. The family members of the cases were also assessed, when possible. In all four patients, multisystem involvement was present, along with the disorder affecting corneal LSCs. The affected tissues were mainly the skin and its adnexa, the oral cavity and the hematopoietic system, which are rapidly renewing tissues, consistent with the presence of a stem cell disorder. Similarly affected cases were seen in different generations in families, suggesting an underlying inherited disorder. No mutation was detected in any of the known disease-causing genes in these patients. Based on the presented cases and with the contribution of the review of previously reported DC cases available, we suggest that DC is one of the inherited causes of LSCD and that those cases presenting with LSCD might represent a subgroup of DC caused by mutations in an as yet undefined gene. PMID- 22814959 TI - Photodegradation of 4-tert octylphenol in aqueous solution promoted by Fe(III). AB - 4-Tert-octylphenol (4-t-OP), a kind of endocrine-disrupting compounds, is widely distributed in natural water surroundings but can hardly be biodegraded. The advanced oxidation processes (AOPs) have been proved to be an efficient method to degrade 4-t-OP. In this study, the photodegradation of 4-t-OP in aqueous solution promoted by Fe(III) and the photooxidation mechanism were investigated. The ferric perchlorate was added into the aqueous solution for the production of hydroxyl radical. The efficiency of mineralization was monitored by total organic carbon analyzer, and photooxidation products were determined by high-performance liquid chromatography and liquid chromatography-mass spectrometer. 4-t-OP (2.4 * 10(-5) M) in aqueous solution was completely degraded after 45 min in the presence of Fe(III) (1.2 * 10(-3) M) under UV irradiation (lambda = 365 nm). The optimal pH was 3.5. Higher Fe(III) concentration or lower initial 4-t-OP concentration led to increased photodegradation efficiency of 4-t-OP. The reaction was almost completely inhibited in the presence of 2-propanol. About 70 % mineralization of the solution was obtained after 50 h. The photooxidation product was supposed to be 4-tert-octyl catechol. 4-t-OP in aqueous solution can be degraded in the presence of Fe(III) under the solar irradiation. The photoinduced degradation is due to the reaction with hydroxyl radicals. It shows that the 4-t-OP is mineralized by the inducement of Fe(III) aquacomplexes, which exposes to solar light. Therefore, the results would provide useful information for the potential application of the AOPs to remove 4-t-OP in water surroundings. PMID- 22814960 TI - Coal fly ash as adsorptive material for treatment of a real textile effluent: operating parameters and treatment efficiency. AB - The experimental results performed after the application of one single-stage treatment by sorption onto coal fly ash are evaluated in order to decolorize a real textile effluent of a private company specializing in manufacturing of cotton fabrics (i.e., sorption performance applied for a real textile effluent collected after the fabric dyeing, rinsing, and final finishing steps). The experiments are focused on studying the effect of initial textile effluent pH, adsorbent dose, temperature and adsorption time, considered as operating parameters of sorption process for high pollutant removals (e.g., organic pollutants as dyes, phenols, polymeric, and degradation compounds), and decoloration. The results indicate high values of decoloration degree (55.42 83.00%) and COD removal (44.44-61.11%) when it is worked at pH <=2 with coal ash dose of 12-40 g/L, temperature higher than 20-25 degrees C, and continuous static operating regime (with an initial agitation step of 3-5 min). The treated textile effluent fulfills the quality demand, and is recyclable, inside reused or discharged after a stage of neutralization (standard pH of 6.5-8.5 for all textile effluent discharges). Also, the final effluent is able to follow the common path to the central biological treatment plant (i.e., a centralized treatment plant for all companies acting in the industrial site area with mechanical-biological steps for wastewater treatment) or may be directly discharged in the nearly watercourse. PMID- 22814962 TI - Cholangioscopy using a new type of cholangioscope for the diagnosis of biliary tract disease: a case series. AB - We present an initial report regarding the clinical usefulness of peroral cholangioscopy, using a new type of cholangioscope, the Polyscope. Peroral cholangioscopy was performed in four patients with strictures after orthotopic liver transplantation (OLT) which were suspected of being ischemic biliary lesions, in three with indeterminate biliary strictures, in three with suspected retained bile duct stones, and in two for evaluation of the intraductal spread of adenomatous tissue after an ampullectomy. In all cases peroral cholangioscopy was performed successfully without complications. On the basis of direct viewing and/or tissue sampling a correct diagnosis was reached in all cases: in all patients who underwent OLT the strictures were not ischemic; the indeterminate strictures were all benign; and, in patients with suspected stones, complete clearance was confirmed. Intraductal spread was confirmed in one patient and excluded in the other. In our experience, peroral cholangioscopy using a Polyscope is a safe and effective method for diagnosing bile duct lesions. PMID- 22814961 TI - Assessment of phytotoxicity of ZnO NPs on a medicinal plant, Fagopyrum esculentum. AB - Fagopyrum esculentum commonly named as buckwheat plant is pseudocereal food crops and healthy herbs but is not known as a bioindicator of environmental condition. In the present study, the effects of ZnO nanoparticles (NPs) and microparticles (MPs) on plant growth, bioaccumulation, and antioxidative enzyme activity in buckwheat were estimated under hydroponic culture. The significant biomass reduction at concentrations of 10-2,000 mg/L was 7.7-26.4 % for the ZnO NP and 11.4-23.5 % for the ZnO MP treatment, (p < 0.05). ZnO NPs were observed in root cells and root cell surface by scanning electron microscopy and transmission electron microscopy analysis. Zn bioaccumulation in plant increased with increasing treatment concentrations. The upward translocation (translocation factor <0.2) of Zn in plant was higher with the ZnO NP treatment than that with the ZnO MP treatment. Additionally, reactive oxygen species generation by ZnO NPs was estimated as the reduced glutathione level and catalase activity, which would be a predictive biomarker of nanotoxicity. The results are the first study to evaluate the phytotoxicity of ZnO NPs to medicinal plant. F. esculentum can be as a good indicator of plant species in NP-polluted environment. PMID- 22814963 TI - Differences in fecal androgen patterns of breeding and nonbreeding kori bustards (Ardeotis kori). AB - To better understand breeding conditions to promote reproduction in captive kori bustards, fundamental endocrine studies measuring fecal androgen metabolites in male and female kori bustards were conducted. Feces collected weekly from males and females were analyzed for testosterone using enzyme-linked immunoassay. Results from adult males (n = 5), adult females (n = 10), immature males (n = 10), and immature females (n = 10) revealed seasonally elevated testosterone concentrations in fertile, but not nonfertile adult males and females (P > 0.05). Adult females that were not maintained in a breeding group, or that did not produce eggs, did not demonstrate increases in testosterone compared to egg laying counterparts. In males, but not females, seasonal testosterone increases were accompanied by weight gain. Peaks in male fecal androgen metabolites ranged from 10- to 22-fold higher than nonbreeding season (181.5 +/- 19.1 vs. 17.0 +/- 0.94 ng/g; P < 0.05). Mean breeding season values for adult males were 83.6 +/- 6.1 ng/g vs. nonbreeding season values of 12.3 +/- 0.73 ng/g (P < 0.05). In females, average breeding season testosterone concentrations were approximately 4 fold higher than nonbreeding season (55.9 +/- 6.0 vs. 14.5 +/- 1.8 ng/g), with peaks 10- to 30-fold higher. Results show that noninvasive fecal androgen metabolite analysis can provide a means of predicting fertility potential of male and female kori bustards and might be utilized to assess effects of modifying captive environments to promote reproduction in this species. PMID- 22814964 TI - Treatment of tuberculosis with levofloxacin or moxifloxacin: report of 6 pediatric cases. AB - We report 6 pediatric cases of tuberculosis caused by Mycobacterium tuberculosis and treated them with levofloxacin or moxifloxacin in the mother-child unit of a university hospital in France between 2005 and 2011. We assess the clinical efficacy and safety of fluoroquinolones and the benefit-risk ratio for their use as second-line antituberculosis drugs in children and adolescents. PMID- 22814965 TI - Safety and immunogenicity of a quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine in infants and toddlers: three multicenter phase III studies. AB - BACKGROUND: Quadrivalent meningococcal conjugate vaccine (Menactra [MenACWY-D]), was licensed in the United States in 2005 to prevent meningococcal disease in adolescents and adults. The license was extended to children aged 2-10 years in 2007 and extended again in 2011 to infants aged 9 months and older based, in part, on results from 3 phase III studies presented herein. METHODS: The safety and immunogenicity of 2 doses of MenACWY-D was assessed in study-eligible children: dose 1 was administered at 9 months of age and dose 2 was administered 3 months later with or without routine childhood vaccines. RESULTS: Thirty days after vaccination, protective serum bactericidal assay-human complement titers >=1:8 for meningococcal serogroups A, C, Y and W-135 were achieved by 86-100% of children receiving 2 doses of MenACWY-D. When MenACWY-D was concomitantly administered with measles, mumps, rubella and varicella or heptavalent pneumococcal conjugate vaccine, 81-98% of participants achieved protective responses (serum bactericidal assay-human complement titers >=1:8 for all serogroups). All seroprotection rates were >91% when the protective titer was defined as serum bactericidal assay-human complement >=1:4. MenACWY-D did not interfere with measles, mumps, rubella or varicella vaccine responses (98-100% achieved protective titers). When heptavalent pneumococcal conjugate vaccine was given concomitantly with MenACWY-D, antipneumococcal antibody levels, although decreased, were protective for all serotypes by enzyme-linked immunosorbent assay (98-100% >= 0.35 MUg/mL) and opsonophagocytic assay (99-100% >= 1:8). Adverse events were generally mild and similar across groups. Serious adverse events were uncommon. CONCLUSIONS: MenACWY-D was safe and immunogenic when given in 2 doses to infants and toddlers; this vaccine can be given with other common childhood immunizations. PMID- 22814967 TI - Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors. AB - Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 +/- 0.85 umol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 +/- 0.58 and 4.57 +/- 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response. PMID- 22814966 TI - Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. AB - Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. CONCLUSION: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis. PMID- 22814968 TI - Effects of inbreeding on skeletal size and fluctuating asymmetry of Peromyscus polionotus mice. AB - Measurements of size and asymmetry in morphology might provide early indications of damaging effects of inbreeding or other genetic changes in conservation breeding programs. We examined the effects of inbreeding on size and fluctuating asymmetry (FA) in skull and limb bone measurements in experimental populations of three subspecies of Peromyscus polionotus mice that had previously been shown to suffer significant reductions in reproductive success when inbred. Inbreeding caused significant depression in mean size in two of the subspecies (P. p. rhoadsi and P. p. subgriseus), but the effects were smaller in the third (P. p. leucocephalus). Inbreeding caused an increase in FA of just one of eight bilateral traits in one subspecies (P. p. rhoadsi). Inbreeding depression in size was more easily detected than the effects of inbreeding on FA. FA may be much less sensitive to inbreeding and other stresses than are more direct measures of fitness such as reproductive output and body mass growth rate. Given the large sample sizes and statistical complexity required to assess changes to typically very small levels of FA in captive populations, FA will not likely provide a useful measure of inbreeding depression in captive populations. PMID- 22814970 TI - Fluorescence biosensing micropatterned surfaces based on immobilized human acetylcholinesterase. AB - Human acetylcholinesterase (AChE) is a widely studied target enzyme in drug discovery for Alzheimer's disease (AD). In this paper we report evaluation of the optimum structure and chemistry of the supporting material for a new AChE-based fluorescence sensing surface. To achieve this objective, multilayered silicon wafers with spatially controlled geometry and chemical diversity were fabricated. Specifically, silicon wafers with silicon oxide patterns (SiO(2)/Si wafers), platinum-coated silicon wafers with SiO(2) patterns (SiO(2)/Pt/Ti/Si wafers), and Pt-coated wafers coated with different thicknesses of TiO(2) and SiO(2) (SiO(2)/TiO(2)/Pt/Ti/Si wafers) were labelled with the fluorescent conjugation agent HiLyte Fluor 555. Selection of a suitable material and the optimum pattern thickness required to maximize the fluorescence signal and maintain chemical stability was performed by confocal laser-scanning microscopy (CLSM). Results showed that the highest signal-to-background ratio was always obtained on wafers with 100 nm thick SiO(2) features. Hence, these wafers were selected for covalent binding of human AChE. Batch-wise kinetic studies revealed that enzyme activity was retained after immobilization. Combined use of atomic-force microscopy and CLSM revealed that AChE was homogeneously and selectively distributed on the SiO(2) microstructures at a suitable distance from the reflective surface. In the optimum design, efficient fluorescence emission was obtained from the AChE-based biosensing surface after labelling with propidium, a selective fluorescent probe of the peripheral binding site of AChE. PMID- 22814969 TI - Quantitative profiling of oxylipins through comprehensive LC-MS/MS analysis: application in cardiac surgery. AB - Oxylipins, including eicosanoids, affect a broad range of biological processes, such as the initiation and resolution of inflammation. These compounds, also referred to as lipid mediators, are (non-) enzymatically generated by oxidation of polyunsaturated fatty acids such as arachidonic acid (AA). A plethora of lipid mediators exist which makes the development of generic analytical methods challenging. Here we developed a robust and sensitive targeted analysis platform for oxylipins and applied it in a biological setting, using high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) operated in dynamic multiple reaction monitoring (dMRM). Besides the well-described AA metabolites, oxylipins derived from linoleic acid, dihomo-gamma-linolenic acid, alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid were included. Our comprehensive platform allows the quantitative evaluation of approximately 100 oxylipins down to low nanomolar levels. Applicability of the analytical platform was demonstrated by analyzing plasma samples of patients undergoing cardiac surgery. Altered levels of some of the oxylipins, especially in certain monohydroxy fatty acids such as 12-HETE and 12-HEPE, were observed in samples collected before and 24 h after cardiac surgery. These findings indicate that this generic oxylipin profiling platform can be applied broadly to study these highly bioactive compounds in relation to human disease. PMID- 22814971 TI - Speciation of lead in seawater and river water by using Saccharomyces cerevisiae immobilized in agarose gel as a binding agent in the diffusive gradients in thin films technique. AB - Saccharomyces cerevisiae immobilized in agarose gel is proposed as a binding agent for the diffusive gradients in thin films (DGT) technique for determination of Pb in river water and seawater. DGT samplers were assembled with the proposed binding agent (25-mm disk containing 20%, m/v, S. cerevisiae and 3.0%, m/v, agarose) and a diffusive layer of cellulose (3MM Chr chromatography paper of 25 mm diameter). The effects of some DGT parameters (e.g., immersion time, ionic strength, and pH) were evaluated. Elution of Pb from the binding agent was effectively done with 1.75 mol L(-1) HNO(3). The deployment curve (between 2 and 24 h) was characterized by a significant uptake of Pb (346 ng Pb h(-1)) and good linear regression (R(2) = 0.9757). The experimental results are in excellent agreement with the predicted theoretical curve for mass uptake. Consistent results were found for solutions with ionic strengths of 0.005 mol L(-1) or greater and within a pH range of 4.5-8.5. Interferences from Cu (20:1), Mn (20:1), Fe (20:1), Zn (20:1), Ca (250:1), and Mg (250:1) in Pb retention were negligible. Determination of Pb in spiked river water samples (from the Corumbatai and Piracicaba rivers) performed using the proposed device was in agreement with total dissolved Pb, whereas measurements in seawater suggest that of the various species of Pb present in the samples, only cationic Pb species are adsorbed by the agarose-yeast gel disks. The in situ concentration of Pb obtained at two different sites of the Rio Claro stream (Corumbatai basin) were 1.13 +/- 0.01 and 1.34 +/- 0.04 MUg L(-1). For 72-h deployments, a detection limit of 0.75 MUg L(-1) was calculated. The combination of inductively coupled plasma optical emission spectroscopy and in situ deployments of DGT samplers during the 72-h period makes possible the determination of labile Pb in river water. PMID- 22814972 TI - Microwave-assisted extraction and determination of enrofloxacin and danofloxacin photo-transformation products in soil. AB - Here we describe the extraction from soil of the major photo-transformation products (PTPs) of enrofloxacin (ENR) and danofloxacin (DAN), two fluoroquinolones (FQs) widely used in veterinary medicine and of growing environmental concern, because their PTPs have been shown to retain high antibacterial activity. The microwave-assisted extraction (MAE) technique developed previously for determination of FQs, and based on use of an alkaline aqueous solution of Mg(2+) as a complexing agent for the analytes, was applied to agricultural soil samples fortified with different amounts of the PTPs and residues of the parent compounds (53-1000 ng g(-1) for ENR, 24-148 ng g(-1) for DAN). The PTPs, obtained by irradiation of thin layers of the two drugs, were, after extraction, separated and quantified by HPLC-FD. Good recovery (70-130%) and precision (RSDs 1-6% for repeatability and 9-22% for reproducibility) were obtained by use of the overall analytical procedure. The method was applied for the first time to study the in-soil lifecycle of ENR and DAN PTPs, generated in the matrix by irradiation under natural sunlight, at environmentally significant concentrations. Results indicated that soil-adsorbed FQ PTPs are themselves liable to photodegradation and have lifetimes comparable with those of parent compounds. PMID- 22814973 TI - [Longitudinal and specific analyses of physical performance in handball]. AB - BACKGROUND: Sports-specific, biomechanical measuring stations and measuring station trainings have become common practice in many forms of sports and are an essential element of the complex assessment of physical performance. In handball, however, there is still considerable research potential in this respect as well as in the systematic generation and acquisition of the requirements profile and progress of strain. OBJECTIVE: The prime objective of the longitudinal study was to determine the potential performance and development of handball players (3 rd league) in general and in terms of handball sport in particular. Another objective was to establish correlations between tests and indicators of performance in competitions. MATERIALS AND METHODS: 13 handball players (age: 26.5 +/- 3.6 years) were tested three times (before and after the pre-season preparation phase and at the end of the first half of the season) on two test days each. The examination was composed of sprint test (ST, day 1), handball specific complex test (HBKT, day 1) and assessment of treadmill diagnostics (LD, day 2). The surveyed parameters were lactate and heart rate (LD/HBKT) as well as time (ST, HBKT) and the number of errors (HBKT). RESULTS: The cardiac (Hfmax = 201 min-1) and metabolic strain (lactate = 17.8 mmol/L) in the HBKT were very high. In the preparatory phase, the average magnitudes of effect registered were at d = 0.31 (ST parameter), d = 0.68 (HBKT parameter) and d = 0.98 (LD parameter). The most significant improvements throughout the entire period of time were registered in the parameters v2 (LD; eta2 = 0.371), total goal-throwing time (HBKT; eta2 = 0.250), total penalty time (HBKT; eta2 = 0.236) and total round 2 (HBKT; eta2 = 0.227). In HBKT and LD, the performance level was stabilised by the end of the first half of the season. In terms of speed, however, there was a decline in performance abilities. The competition performance has its highest degree of correlation with cardial (defense: r = 0.656) and metabolic (offensive: r = -0.655) recuperativeness in HBKT. CONCLUSIONS: The findings of this longitudinal survey are on the one hand intended to make assessments of physical performance more efficient (isolated sprint test no longer required) and to improve data output (HBKT: throwing velocity; reference database). In this context, a more extensive consideration of indicators for competition performance and their correlation to specific parameters is recommendable. On the other hand, the applied training contents must be further optimised in terms of their severity and chronology. PMID- 22814974 TI - A rare genetic disorder causing persistent severe neonatal hypoglycaemia the diagnostic workup. AB - We report a case of familial glucocorticoid deficiency (FGD), a rare genetic autosomal-recessive disorder with typical hyperpigmentation of the skin and mucous membranes, severe hypoglycaemia, occasionally leading to seizures and coma, feeding difficulties, failure to thrive and infections. A newborn child was admitted, on his second day of life, to our neonatal intensive care unit because of seizures and respiratory insufficiency. Hyperpigmentation was not evident due to his Senegalese origin. The clinical presentation led us to consider a wide range of diagnostic hypothesis. Laboratory findings brought us to the diagnosis of FGD that was confirmed by molecular analysis showing an MC2R:p.Y254C mutation previously reported as causative of type 1 FGD and two novel heterozygous non synonymous single-nucleotide polymorphisms in exon 2 and 3 of melanocortin 2 receptor accessory protein-alpha, whose role in the disease is currently unknown. The importance of an early collection and storage of blood samples during hypoglycaemic event is emphasised. PMID- 22814975 TI - Sclerochoroidal calcification associated with Albright's hereditary osteodystrophy. AB - A 47-year-old woman presented with bilateral gradual loss of vision, ocular discomfort and seeing a black shadow in her right visual field over 6 months duration. Her medical history was extensive including: developmental delay, pseudohypoparathyroidism, hypertension, spinal stenosis, epilepsy and suspected idiopathic intracranial hypertension. Ocular examination revealed choroidal elevation in both eyes, which were highly ecogenic on ecography and confirmed to be calcifications of choroids on CT scan in her both eyes. She had subnormal vision and reduced colour vision in her both eyes. Electrodiagostic studies suggested rod dysfunction. She had typical features of Albright's hereditary dystrophy and was positive for the GNAS 1 mutation. She is currently being monitored by ophthalmologlists and is also under a medical team undergoing further assessment with regard to her treatment. PMID- 22814976 TI - Cryptogenic stroke in low-risk patients, consider a cardiac shunt at your peril. AB - Patent foramen ovale (PFO) as a cause of cryptogenic stroke from paradoxical embolisation remains a controversial issue. The optimal care between medical and surgical management of these patients for the attending clinician remains a conundrum. We report a case of cryptogenic stroke in a woman aged 59, with a PFO, concomitant venous thrombosis and cryptogenic stroke. The case highlights the difficulty in diagnosing and managing such patients, particularly as recent evidence challenges the clinical practice of percutaneous closure and pathophysiological rationale. PMID- 22814977 TI - Hand-biting and hand-waving paroxysms in epilepsy. AB - A 20-year-old ambidextrous female student with a 15-year history of refractory seizures was admitted to the epilepsy department for a second opinion on her diagnosis and treatment. She developed frequent motor paroxysms at the age of 4-5 years, which appeared resistant to antiepileptic therapy and which have continued to the present day. Over the last 8 years she also had five generalised tonic clonic seizures. There is a family history of epilepsy on the maternal side. The first type of episode is characterised by left-hand flickering, associated with head turning and loss of awareness. During the second type of attack the patient demonstrates vigorous hand biting which starts without warning. The patient appears disorientated subsequently. EEG telemetry was performed and confirmed the diagnosis of both epilepsy and non-epileptic attacks. Literature reports of the relevant cases are discussed. PMID- 22814978 TI - Successful salvage using combined radiation and ABMT for patients with recurrent CNS NGGCT following failed initial transplant. AB - Intracranial germ cell tumours (GCTs) are a rare and diverse group of tumours. Histology determines the type of treatment, natural history and prognosis. Germinoma GCTs account for the majority and are very radiosensitive. Conversely, non-germinoma GCTs (NGGCTs) are heterogeneous, relatively radioresistant and have a high risk of relapse despite multimodality therapy. Treatment of recurrence in these patients remains a therapeutic challenge. In this report we review the current literature for treatment of recurrent NGGCTs and present a case of recurrent NGGCT who relapsed despite autologous stem cell transplant (ASCT). The patient was successfully cured using multimodality therapy, consisting of repeat ASCT, intensity modulated radiation therapy and stereotactic radiosurgery. PMID- 22814979 TI - Pheochromocytoma presenting as acute decompensated heart failure reversed with medical therapy. AB - A 26-year-old woman presented to hospital with acute chest pain, hypertension, tachycardia and an elevated serum creatinine. She developed respiratory distress requiring endotracheal intubation and mechanical ventilation. She progressed to multiorgan failure due to decompensated congestive heart failure. Echocardiography demonstrated global hypokinesis and an ejection fraction of <10%. Her cardiac function improved with fluid resuscitation and beta blockade, and she was eventually discharged home. She was readmitted a few days later with pancreatitis after presenting with nausea, abdominal pain and hypertension. During hospitalisation she had paroxysms of headache, nausea and diaphoresis associated with hypertension and tachycardia. A CT scan of her abdomen revealed an adrenal mass and serum metanephrine studies confirmed the diagnosis of pheochromocytoma. After fluid resuscitation and sympathetic blockade her ejection fraction improved to 55%. The patient underwent an uneventful adrenalectomy and made a complete recovery. PMID- 22814980 TI - Posterior reversible encephalopathy syndrome postautologous peripheral stem cell transplantation for multiple myeloma. AB - This is a case of a 56-year-old lady with recent autologous peripheral stem cell transplantation for multiple myeloma. She was presented with a 48 h history of worsening headache, drowsiness, nausea/vomiting and some peripheral neurological symptoms. She developed status epilepticus, was intubated and transferred to intensive care unit. After full investigation with a CT head, CT cerebral angiogram, MRI brain and cerebral angiogram, she was diagnosed with posterior reversible encephalopathy syndrome (PRES) with the help of expert opinion, based on the clinical and radiological evidence. The MRI showed bilateral occipital signal changes suggestive of PRES. She was managed with nimodipine, phenytoin and clonazepam with good effect. Eventually extubated, she made good progress on the ward with no further seizure episodes. Functionally she did not appear to have any evidence of residual damage from the PRES. This case discusses PRES on a background of a haematological malignancy and its clinical features. PMID- 22814981 TI - Silicon granuloma mimicking lung cancer. AB - Silicon granuloma is one of the benign complications of breast implant failure but this is rarely reported. We report a 66-year-old lady presented to respiratory department with history of weight loss and a chest x-ray was highly suggestive of a lung malignancy. Further investigation including CT thorax and breast ultrasound suggested siliconoma that was later on confirmed on tissue biopsy. PMID- 22814982 TI - IVIG treatment for VZV-related acute inflammatory polyneuropathy in a child. AB - Acute inflammatory polyneuropathy is an inflammatory demyelinating disease triggered by an autoimmune mechanism. It follows an infection or an immunisation after a free interval of 2-30 days. We report a case of a 14-year-old boy who develops an acute rapidly progressive paraplegia, urine incontinence and positive Lasegue a week after a characteristic chickenpox rash. Spinal MRI showed diffuse thickening and leptomeningeal enhancement of cauda equina nerve roots. Intravenous immunoglobulins were given and yielded a dramatic clinical and radiological improvement. The patient was discharged without any clinical problems 1 month after the onset of symptoms. We performed a review of the literature, discussing the different forms of varicella-zoster virus-related central and peripheral nervous system complications and management strategies for acute postinfectious encephalomyelitis/radiculitis. PMID- 22814983 TI - Unusual cause of small bowel obstruction in an autistic child. PMID- 22814984 TI - A rare cause for superior vena cava obstruction. PMID- 22814985 TI - Cranial neuropathy because of IgG4-related pachymeningitis; intracranial and spinal mass lesions. PMID- 22814986 TI - Ophthalmic manifestations of atypical IgD multiple myeloma. AB - A previously healthy 32-year-old Caucasian female presented with sudden-onset horizontal diplopia following a paroxysm of coughing. She had recently sustained a pubic ramus fracture during an innocuous fall and had also noted a firm lump developing at the right side of her forehead. On examination, she had a right fronto-temporal mass. Visual acuities were 6/6 bilaterally. There was reduced abduction of the right eye, bilateral white, granular corneal opacities and evidence of bilateral optic disc swelling. Haematological investigations revealed normocytic anaemia, hypercalcaemia and raised erythrocyte sedimentation rate (ESR). CT showed lytic foci throughout the skull, ribs, scapulae, spine, pelvis and upper femora. Serum protein electrophoresis revealed immunoglobulin D (IgD) kappa paraproteinaemia; urine electrophoresis showed free light chain kappa and bone marrow biopsy demonstrated 87% plasma cells. A diagnosis of IgD multiple myeloma was made, with subsequent chemotherapeutic treatment and eventual autologous stem cell transplant resulting in resolution of neuro-ophthalmic manifestations and prolonged disease remission. PMID- 22814987 TI - Chronic left ventricular pseudo-aneurysm after posterior myocardial infarction. PMID- 22814988 TI - Bilateral facial palsy as a manifestation of Japanese encephalitis. AB - Japanese encephalitis is a cause of substantial morbidity and mortality, prevalent mainly in South East nations. It is caused by group B arbovirus and transmitted with bite of infected culex mosquitoes. The clinical features described are: headache, vomiting, altered sensorium, convulsions and both hypokinetic and hyperkinetic movement disorders. In this submission, we described a 68-year-old man suffering from Japanese encephalitis, who presented with bilateral facial palsy with encephalitic features. The bilateral facial palsy has not been reported previously in association with Japanese encephalitis. PMID- 22814989 TI - Bloody nipple discharge in infancy--report of two cases. AB - Bloody nipple discharge (BND) in infancy is an exceptionally rare finding. We report the cases of two children who are 9 and 29 months old. The first case presented with 1 month of bilateral intermittent blood-stained nipple discharge with no other symptoms. The second case presented with 15 days of intermittent right BND and a small palpable mass, without obvious signs of inflammation. The coagulation and hormonal tests were within the age-appropriate reference ranges. Ultrasound examination was normal. Cytological evaluation of nipple discharge showed no malignant cells. Both patients had spontaneous symptoms resolution. BND in paediatric age is usually benign and self-limited and often related to mammary duct ectasia. Unnecessary invasive procedures or treatments should be avoided. PMID- 22814990 TI - Radiotherapy is effective for a primary lung cancer invading the left atrium. AB - Atrial involvement is an uncommon feature of advanced non-small-cell lung cancer, occurring in up to 10% of patients with bronchogenic carcinoma. Additionally, cardiac metastases from other sources are documented in up to 7% of cancer patients at autopsy. Because atrial invasion can lead to systemic embolisation and/or outflow obstruction, it is treated regardless of the overall prognosis. While the gold standard treatment has historically been surgical resection, advances in radiotherapy allow for the safe treatment of cardiac disease. Here we present the case of a woman with pulmonary adenocarcinoma of the left lower lobe that progressed to invade the pulmonary vein and left atrium while maintained on standard chemotherapy. She was treated with intensity-modulated radiotherapy and had a complete response in terms of her atrial disease within 3 months. She suffered no acute toxicity or complications as a result of the radiation therapy. PMID- 22814991 TI - Polysling skin pressure necrosis--a complication of shoulder immobilisation. PMID- 22814992 TI - Application of ultrahigh-performance liquid chromatography coupled with mass spectrometry for analysis of lignans and quality control of Fructus Schisandrae chinensis. AB - Lignans in the drug Fructus Schisandrae chinensis (FSC) exhibit potent biological activities such as antihepatotoxic, antiasthmatic, and antigastric ulcer. An ultrahigh-performance liquid chromatography coupled with quadrupole time-of flight mass spectrometry method has been developed to evaluate the quality of FSC through simultaneous qualitative and quantitative analysis of 15 lignans, including schizandrin A, B, and C; schizandrol A and B; gomisin B, C, D, E, G, H, J, and N; tigloylgomisin H; and angeloylgomisin H. The compounds were separated on a Zorbax Eclipse Plus C(18) (2.1 * 100 mm, 1.8 MUm) column with a gradient elution of acetonitrile and 0.1% formic acid. Lignans were identified through their retention times, accurate mass data, and characteristic ions by comparison with a reference substance. All calibration curves showed perfect linear regression (r(2) > 0.99) within the test range. The limits of detection and quantitation fell in the ranges of 0.1-4 ng/mL for all the analytes with an injection of 10 MUL. Good results were obtained with respect to repeatability (relative standard deviation <4.6%) and recovery (85.58-105.82%). Meanwhile, the entire sample analysis time was less than 10 min. This developed method provided a new basis for the overall assessment of the quality of FSC. PMID- 22814993 TI - [Jakarta, Bangkok, Rio de Janeiro]. PMID- 22814994 TI - [Personal factors of the ICF]. AB - PURPOSE: The presentation aims at illustrating the draft proposal of personal factors of the ICF for German-speaking regions which has been published in 2010 by the working group ICF of Faculty II "Social Medicine and Rehabilitation" of the German Society for Social Medicine and Prevention, DGSMP. For this reason, each personal factor is illustrated by two examples. Thus, the benefit is intended to be convincing. METHODS: Applying a qualitative approach, the working group ICF consisting of members of various professions and institutions including a patients' representative selected for each item one example the factor serving as a facilitator and a second the factor serving as a barrier. RESULTS: The components of the personal factors, as proposed, are presented, each factor is accompanied by two examples. CONCLUSION: The presentation demonstrates the various possibilities of applying personal factors and intends to prove that the selection of items chosen makes sense. The process of a comprehensive discussion about the possible format of the component of personal factors in the ICF should lead to a further optimization of the proposal and the preparation of a discussion at an international level. PMID- 22814995 TI - Measuring skin conductance over clothes. AB - We propose a new method that measures skin conductance over clothes to nonintrusively monitor the changes in physiological conditions affecting skin conductance during daily activities. We selected the thigh-to-thigh current path and used an indirectly coupled 5-kHz AC current for the measurement. While varying the skin conductance by the Valsalva maneuver method, the results were compared with the traditional galvanic skin response (GSR) measured directly from the fingers. Skin conductance measured using a 5-kHz current displayed a highly negative correlation with the traditional GSR and the current measured over clothes reflected the rate of change of the conductance of the skin beneath. PMID- 22814996 TI - Generation and live imaging of an endogenous Cdx2 reporter mouse line. AB - To understand cell fate specification and maintenance during development, it is essential to visualize both lineage markers and cell behaviors in real time using endogenous markers to report cell fate. We have generated a reporter line in which eGFP is fused to the endogenous locus of Cdx2, a transcription factor essential for trophectoderm specification, allowing us to visualize cell fate decisions in the preimplantation mouse embryo. We used two-photon laser scanning microscopy to visualize expression of the endogenous Cdx2 fusion protein and show that Cdx2 undergoes phases of upregulation. Additionally, we show that as late as the 32-cell stage, outer trophectoderm cells may change their fates by migrating inward and losing Cdx2 expression. Furthermore, the tools and techniques we report allow for dual-colored imaging, which will greatly facilitate the study of not only preimplantation development, but later stages of development and tissues where Cdx2 plays an important role. PMID- 22814998 TI - Assessment of collateral circulation to the hand prior to radial artery harvest. AB - Assessment of collateral circulation to the hand is required prior to invasive procedures or harvesting of the radial artery (RA). A modified Allen's test (MAT) is commonly used to assess palmar arch collaterals. A variety of non-invasive methods including digital pressures, plethysmography, pulse oximetry and duplex ultrasonography are available to supplement physical examination. However, no consensus exists about the proper role of the MAT and the most appropriate non invasive test (NIT) in this situation. Interpretation of the MAT and NIT findings are also controversial. This paper reviews the anatomy and the physiologic basis for the MAT and various NITs, the pros and cons of various NITs and recommendations for the assessment of collateral circulation to the hand prior to interventions directed at the RA. PMID- 22814997 TI - Vitamin D status and functional performance in peripheral artery disease. AB - The clinical implications of low vitamin D in peripheral artery disease (PAD) are unknown. We hypothesized that among individuals with PAD, lower levels of 25 hydroxyvitamin D would be associated with poorer functional performance, more adverse calf muscle characteristics, and poorer peripheral nerve function. Participants were 402 men and women with PAD who underwent measurement of 25 hydroxyvitamin D (DiaSorin radioimmunoassay) along with 6-minute walk testing, measurement of walking velocity at usual and fastest pace, computed tomography measured calf muscle density, and peripheral nerve conduction velocity (NCV). Among PAD participants, 20.4% had 25-hydroxyvitamin D levels < 30 nmol/L, consistent with deficient vitamin D status. Adjusting for age, sex, and race, lower 25-hydroxyvitamin D levels were associated with poorer 6-minute walk performance (p trend = 0.002), slower usual-paced 4-meter walking velocity (p trend = 0.031), slower fast-paced 4-meter walking velocity (p trend = 0.043), and lower calf muscle density (p trend = 0.031). After additional adjustment for body mass index (BMI) and diabetes, none of these associations remained statistically significant. However, lower levels of 25-hydroxyvitamin D were associated with poorer peroneal NCV (p trend = 0.013) and poorer sural NCV (p trend = 0.039), even after adjusting for age, sex, race, BMI, comorbidities, smoking, physical activity, and other confounders. In conclusion, vitamin D deficiency is common among people with PAD encountered in clinical settings. After adjusting for BMI and diabetes mellitus, we found no significant associations of lower levels of 25 hydroxyvitamin D with poorer functional performance or calf muscle characteristics. Associations of low vitamin D levels with poorer peripheral nerve function require further study. PMID- 22814999 TI - Link between the renin-angiotensin system and insulin resistance: implications for cardiovascular disease. AB - The incidence of metabolic syndrome is rapidly increasing in the United States and worldwide. The metabolic syndrome is a complex metabolic and vascular disorder that is associated with inappropriate activation of the renin angiotensin-aldosterone system (RAAS) in the cardiovascular (CV) system and increased CV morbidity and mortality. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes nitric oxide (NO) production in the endothelium and glucose uptake in insulin-sensitive tissues. Angiotensin (Ang) II inhibits insulin-mediated PI3K pathway activation, thereby impairing endothelial NO production and Glut-4 translocation in insulin-sensitive tissues, which results in vascular and systemic insulin resistance, respectively. On the other hand, Ang II enhances insulin-mediated activation of the mitogen activated protein kinase (MAPK) pathway, which leads to vasoconstriction and pathologic vascular cellular growth. Therefore, the interaction of Ang II with insulin signaling is fully operative not only in insulin-sensitive tissues but also in CV tissues, thereby linking insulin resistance and CV disease. This notion is further supported by an increasing number of experimental and clinical studies indicating that pharmacological blockade of RAAS improves insulin sensitivity and endothelial function, as well as reduces the incidence of new onset diabetes in high-risk patients with CV disease. This article reviews experimental and clinical data elucidating the physiological and pathophysiological role of the interaction between insulin and RAAS in the development of insulin resistance as well as CV disease. PMID- 22815000 TI - The optimal measure of microvascular function with velocity time integral for cardiovascular risk prediction. AB - Recent evidence suggests that microvascular function may be important in cardiovascular risk prediction. One measure of microvascular function is hyperaemic velocity time integral (VTI). We assessed whether the VTI of more than one beat of reactive hyperaemia would provide a stronger correlate to traditional cardiovascular risk factors using a subset of subjects from the Firefighters and Their Endothelium (FATE) study. Vascular function was assessed by measurement of hyperaemic blood velocity with high-resolution ultrasound of the brachial artery. We evaluated three measures in the current analysis: the VTI of the first beat, average VTI of 10 beats, and maximum VTI of 10 beats post-cuff release. A total of 399 male subjects (45.5 +/- 10 years) were included in this analysis. Univariate correlations between the three end points and cardiovascular risk factors were calculated, and multivariable regression models constructed. Intra observer variability was approximately equal for all VTI end points (coefficient of variation: first = 1.6%, average = 1.4%, maximum = 1.4%). Univariate correlations between VTI and cardiovascular risk factors were similar across all three end points. In multivariable analyses, there were no differences in the relationships between cardiovascular risk factors and the various VTI end points (R(2) from 0.090 to 0.102). Age, systolic blood pressure, and BMI were predictors of the three VTI end points (p < 0.05). In conclusion, the first beat of reactive hyperaemia remains the suitable measure of microvascular function. PMID- 22815003 TI - Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. AB - BACKGROUND: Betablockade has been shown to have cardioprotective effects in patients under perioperative stress. Besides animal model of septic shock and a small cohort of septic patients, these benefits have not been studied in septic shock patients who require norepinephrine administration. METHODS: After correction of preload, an esmolol bolus (0.2-0.5 mg/kg) followed by continuous 24 h infusion was administered in septic patients with sinus or supraventricular tachycardia (HR > 120/min). Exclusion criteria were severe LV systolic dysfunction, atrioventricular blockade and norepinephrine infusion at rates over 0.5 mg/kg/min. Monitoring with echocardiography and pulmonary artery catheter before, at 2, 6, 12, 24 h following the start and 6 h after ceasing of the esmolol drip. Patients were maintained normovolemic throughout the study and adjustments of concomitant norepinephrine infusion rates were made as required. RESULTS: Ten septic patients (mean age 54.4 +/- 18.7), APACHE II 21.5 +/- 6.2, CRP 275 +/- 78 mg/l, procalcitonin 14.5 +/- 10.1 mg/l, were given esmolol drip of 212.5 +/- 63.5 mg/h at start to 272.5 +/- 89.5 mg/h at 24 h. Heart rate decreased from mean 142 +/- 11/min to 112 +/- 9/min (p < 0.001) with parallel insignificant reduction of cardiac index (4.94 +/- 0.76 to 4.35 +/- 0.72 l/min/m(2)). Stroke volume insignificantly increased from 67.1 +/- 16.3 ml to 72.9 +/- 15.3 ml. No parallel change of pulmonary artery wedge pressure was observed (15.9 +/- 3.2 to 15.0 +/- 2.4 mmHg) as well as no significant changes of norepinephrine infusion (0.13 +/- 0.17 to 0.17 +/- 0.19 mg/kg/min), DO(2), VO(2), OER or arterial lactate. CONCLUSIONS: Saving the heart 30 beats/min did not demonstrate adverse impact on global haemodynamics in rates above 110/min. Using well titratable betablocker seems to be safe and cardioprotective in septic shock patients with high cardiac output. PMID- 22815002 TI - Smoking and lung cancer: current trends in Austria. AB - BACKGROUND: Despite a recent decline in smoking behavior in many European countries, lung cancer rates remain high, especially in Central and Eastern Europe. This paper aims to describe trends in smoking behavior and lung cancer incidence and mortality, including histopathological classification of lung cancer, in a Central European country: Austria. METHODS: Using data from the Austrian Central Cancer Registry, we calculated age-standardized incidence, histopathology-specific incidence, and age-standardized and birth cohort-specific mortality rates for all lung cancer cases in Austria. Using national survey data, we estimated prevalence of smoking in the Austrian population. Our analysis covers the time period from 1970 to 2009. RESULTS: In 2009, lung cancer incidence rates were 41.3/100,000 and 18.5/100,000 and mortality rates were 36.3/100,000 and 14.5/100,000, for males and females, respectively. Male lung cancer rates declined but increased steadily in females over the past three decades. In 2009, the most common histological type is adenocarcinoma, which reflects a shift from predominantly squamous cell carcinoma and large cell carcinoma in the mid 1980s. In 2009, 27 % of men and 19 % of women were smokers, which represent a rise of smoking rates in women, especially in younger women, and a decline in the men. CONCLUSIONS: While in Austrian men the lung cancer rates, in accordance with their decreasing prevalence of smoking, declined over the past 30 years, the increasing smoking prevalence and lung cancer rates in women remain a public health concern. Antismoking laws and public health initiatives to curtail smoking habits are needed in Austria, especially targeting younger women. PMID- 22815004 TI - Human chorionic gonadotropin (hCG) plasma levels at oocyte retrieval and IVF outcomes. AB - PURPOSE: The aim of our study was to ascertain the influence of hCG levels at oocyte pick-up on IVF outcomes, and their relationship with clinical parameters. METHODS: A prospective study was performed including 473 women undergoing IVF, aged under 40 years. Blood samples to analyze hCG levels were obtained at the time of follicular aspiration, 36 h after the administration of 250 MUg of recombinant hCG. RESULTS: Neither the numbers of oocytes obtained or fertilized, nor the pregnancy rate, were correlated with hCG levels. Moreover, hCG values were very similar in women who did and did not become pregnant (123.3 +/- 48.7 and 117.5 +/- 44.7 mUI/mL). Cases in which no oocytes were recovered after follicular aspiration had similar hCG levels to those in which more than 1 oocyte was obtained. On the other hand, hCG levels were negatively related to body mass index, weight, and age. CONCLUSIONS: These data indicate that after the administration of 250 MUg of recombinant hCG, hCG levels are not responsible for failure to recover oocytes. Specifically, there was no correlation between plasma hCG levels and the number of oocytes obtained or other markers of IVF outcome. There was, however, an inverse relationship with BMI, body weight and age. PMID- 22815001 TI - [Therapy of castration-resistant prostate cancer]. AB - Within the last two years the therapy of castration resistant prostate cancer (CRPC) has made major advances. Both the COU-AA-301 phase III trial and the TROPIC trial showed a survival benefit for patients after docetaxel failure treated with abiraterone or cabazitaxel, respectively. With rising interest for chemotherapeutic options and novel drugs, our goal was to review within the context of a multidisciplinary team the available evidence and explore the standards for medical treatment of prostate cancer outside of clinical trials. From this background, we are carefully evaluating the current treatment recommendations, based on the available evidence, and highlight potential future treatment options but also discuss important clinical topics like treatment until progression versus the advantage of chemo holidays and definition of particular patient subgroups. Additionally, we focus on novel molecular entities, which will most likely be available in the near future, such as MDV3100 and Sipuleucel T. The role and importance of palliation with radiotherapy and proactive medical management of pain is also discussed, as well as new options for bone directed therapy. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists. PMID- 22815005 TI - Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis. AB - Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal alpha1-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered. PMID- 22815006 TI - [Clinical presentation of tuberculosis in routine practice]. AB - Since the beginning of the biologics era tuberculosis is known to be a potential life-threatening complication during treatment of patients with rheumatic diseases. National and international societies have developed recommendations for tuberculosis screening and treatment of patients at risk for development of tuberculosis. Owing to the relative rareness of overt tuberculosis in patients with rheumatic diseases, the experience of individual rheumatologists with this complication is limited. Therefore, we have analyzed the tuberculosis cases from 2006-2011 in our rheumatology referral center (treating more than 1,500 inpatient and 8,000 outpatient cases every year) to obtain a real-life picture more than 10 years after initiation of the first application of biologics outside of controlled clinical trials. We identified 4 cases that illustrate the difficulties of diagnosis and treatment. PMID- 22815007 TI - A guide to requesting outpatient and emergency radiographs. AB - Radiology is an important adjunct to clinical practice, but for many clinicians, requesting X-rays was something that was learnt on the job. This article provides guidelines on when and how to request X-rays for acute conditions such as head and cervical spine trauma, suspected rib and extremity fractures, low back pain and acute abdominal pain. We also highlight what to write in the request form, in order to obtain maximum value from the examination and allow the radiologist to generate a useful, accurate report. PMID- 22815008 TI - Improving mental health care for people with an intellectual disability in Singapore: bridging the health-social care divide. AB - Intellectual disability is known to be associated with a high incidence of psychiatric co-morbidity and problem behaviours. However, there are many challenges in trying to meet the mental health needs of people with an intellectual disability, and these are often not adequately addressed in Singapore's current healthcare system. This article outlines the present service provisions for this area in the country and details the importance of, as well as difficulties in the integration of health and social care measures in service development and delivery. PMID- 22815009 TI - Albert Calmette (1863-1933): originator of the BCG vaccine. PMID- 22815010 TI - Addiction in Singapore: changing patterns and evolving challenges. AB - Data from recent studies have shown an increase in substance use and addictive behaviours in Singapore. However, training and services still lag behind this trend, which means the provision of adequate treatment is lacking in spite of good evidence that treatment approaches for addiction disorders are effective. There is a need to train more manpower for this purpose, especially in primary healthcare. Another challenge is to ramp up services as quickly as possible to manage the growing number of addicts. Research should also focus on special populations, while public health education and national policies can be improved, particularly to curb binge drinking. We need to be open to the use of harm reduction therapies and substitution treatments, as addiction is a chronic relapsing disorder with significant health and psychosocial morbidity. PMID- 22815011 TI - Children with developmental and behavioural concerns in Singapore. AB - INTRODUCTION: Childhood developmental and behavioural disorders (CDABD) have been increasingly recognised in recent years. This study evaluated the profiles and outcomes of children referred for developmental and behavioural concerns to a tertiary child developmental centre in Singapore. This is the first such regional database. METHODS: Baseline information, obtained through a questionnaire, together with history at first consultation, provided information for referral, demographic and presentation profiles. Clinical formulations were then made. Definitive developmental and medical diagnoses, as well as outcomes based on clinical assessment and standardised testing, were recorded at one year post first consultation. RESULTS: Out of 1,304 referrals between January 1, 2003 and December 1, 2004, 45% were 2-4 years old and 74% were boys. The waiting time from referral to first consultation exceeded four months in 52% of children. Following clinical evaluation, 7% were found to be developmentally appropriate. The single most common presenting concern was speech and language (S&L) delay (29%). The most common clinical developmental diagnosis was autism spectrum disorder (ASD) (30%), followed by isolated S&L disorder, global developmental delay (GDD) and cognitive impairment (CI). Recommendations included S&L therapy (57%), occupational therapy (50%) and psychological/behavioural services (40%). At one year, ASD remained the most common definitive developmental diagnosis (31%), followed by S&L disorder, CI and GDD. Most were children with high-prevalence, low-moderate severity disorders who could potentially achieve fair-good prognosis with early intervention. CONCLUSION: Better appreciation of the profile and outcome of children with CDABD in Singapore could enable better resource planning for diagnosis and intervention. PMID- 22815012 TI - Application of a web-based cognitive-behavioural therapy programme for the treatment of selective mutism in Singapore: a case series study. AB - INTRODUCTION: Selective mutism (SM) is characterised by limited or a lack of speech in selected social settings. Recent reviews suggest that cognitive behavioural therapy (CBT) is an effective and promising treatment approach for SM. However, there is still a lack of studies documenting the applicability of CBT for SM in diverse populations. The goal of the present study was to examine the use of a web-based CBT programme ('Meeky Mouse') among Singaporean children diagnosed with SM. METHODS: Five children with SM (one boy and four girls aged 6 11 years) participated in the 14-week 'Meeky Mouse' programme, in addition to being prescribed with an unchanged dosage of fluoxetine 10-20 mg daily. The progress made by the children throughout the course of the programme was documented by the therapist. RESULTS: Post treatment, four out of the five children demonstrated improvements in the frequency of speech during therapy sessions at home, in school and at other social situations. CONCLUSION: Findings from the present study provide support for the use of a web-based CBT programme in improving speech and decreasing the severity of SM among affected children. PMID- 22815013 TI - Stigma and restriction on the social life of families of children with intellectual disabilities in Vietnam. AB - INTRODUCTION: Intellectual disabilities are as prevalent in East Asian countries as in the West (0.06%-1.3%). Widespread discrimination against intellectual disabilities in Asia may initiate stigma that places unfair restrictions on the social life of these individuals and their caregivers. We utilised established stigma frameworks to assess the extent to which a child's intellectual disability contributes to the social exclusion of caregivers in Vietnam. METHODS: A mixed quantitative and qualitative approach was employed to examine the experience of social life restriction among parents of children with intellectual disabilities. The child's disability level and restrictions on caregivers' social experiences were assessed among 70 mothers and fathers recruited from schools in Hue City, Vietnam. Qualitative responses describing social exclusion were also recorded. RESULTS: Caregivers reported elevated levels of social exclusion. As hypothesised, parents of children with greater intellectual disability experienced more restrictions on their social life (Beta = 0.79, 95% confidence interval 0.27-1.30, standard error = 0.26, p < 0.01). Qualitative analyses indicated that the threatening of core cultural norms (inability to be employed or married upsets community harmony) initiated labelling, social exclusion and efforts to keep the condition secret or withdraw from others. CONCLUSION: This study is among the first to demonstrate the impacts of intellectual disabilities on caregivers' social functioning in Asia. The findings illustrate how traditional Asian norms initiate stigma, which in turn restricts key social interactions among caregivers. Psycho-educational interventions may address the social domains in which caregivers are impacted and encourage sustained help seeking among caregivers for their children. PMID- 22815014 TI - The Modified Mini-Mental State Examination test: normative data for Singapore Chinese older adults and its performance in detecting early cognitive impairment. AB - INTRODUCTION: This study aimed to determine the stratified normative data by age and education for a modified version of the Mini-Mental State Examination (MMSE) test from a large sample of community-dwelling Chinese older adults in Singapore, and to examine the MMSE's value in detecting early cognitive impairment. METHODS: We studied 1,763 Chinese older adults with normal cognitive function and 121 Chinese older adults with early cognitive impairment (Clinical Dementia Rating global score 0.5). Normative MMSE values were derived for each of the 15 strata classified by age (three groups) and education level (five groups). Receiver operating characteristic curve analysis was conducted for the whole sample and each of the three education subgroups (no education, primary, secondary and above). RESULTS: Education level and age significantly influenced the normative values of MMSE total scores in Chinese older adults with normal cognitive function. For the purpose of detecting early cognitive impairment, an optimal balance between sensitivity (Se) and specificity (Sp) was obtained at a cutoff score of 25, 27 and 29 for each of the three education groups, respectively. For the whole sample, the optimal cutoff point was 26 (Se 0.61, Sp 0.84, area under curve 0.78). CONCLUSION: Age and education level must be taken into account in the interpretation of optimal cutoffs for the MMSE. Although widely used, the MMSE has limited value in detecting early cognitive impairment; tests with better performance should be considered in clinical practice. PMID- 22815015 TI - First presentation psychosis among the elderly in Singapore. AB - INTRODUCTION: In tandem with our ageing population, it is observed there is a growing trend of elderly patients presenting for the first time with psychotic symptoms. Clinical experience suggests differences in the phenomenology of late onset psychosis in our Asian context compared to studies done in the West. This study aimed to analyse the characteristics and psychopathology of first presentation psychosis in our local elderly and to determine the treatment outcome over a 12-month period. METHODS: A total of 64 subjects with first presentation psychosis were consecutively recruited. Those with a non-affective, non-organic psychotic disorder were evaluated using the Positive and Negative Symptoms Scale, the Clinical Global Impression Scale, Mini-Mental State Examination and the Beck's Depression Inventory. RESULTS: Of the 64 subjects recruited, 55 were enrolled in the study. 59.3% (n = 32) of the subjects were diagnosed to be suffering from very-late-onset schizophrenia-like psychosis, followed by delusional disorder in 31.5% (n = 17). The remaining 11.1% (n = 6) were diagnosed to have late-onset schizophrenia. The sample showed a high preponderance of women, with 88.9% reporting persecutory-type delusions. The majority of them were married and 80% of the subjects were living with relatives. Treatment was effective in ameliorating symptoms, but there was a high loss to follow-up of male subjects (81.8%). CONCLUSION: This descriptive study found sociodemographic and phenomenological similarities to other studies of late-onset psychosis in the West, except that social isolation and partition delusions were not prominent. PMID- 22815016 TI - Prevalence of depression among women attending a primary urban care clinic in Malaysia. AB - INTRODUCTION: Depression affects more women than men in Malaysia. The objective of this paper was to determine the prevalence of depression and its associated factors among women attending a government primary care clinic. METHODS: A cross sectional study was conducted in a government-funded primary care clinic in Malaysia. Consecutive adult female patients attending the clinic during the data collection period were invited to participate. The participants completed self administered questionnaires (including the validated Patient Health Questionnaire [PHQ-9], which was translated into the Malay language). RESULTS: A total of 895 female patients participated in the study (response rate 87.5%). The prevalence of depression (PHQ-9 scores >= 10) was 12.1%. Based on multiple logistic regression analysis, certain stressful life events were found to be associated with depression (p < 0.05). These factors, arranged from highest to lowest risk, were financial problems (odds ratio [OR] 3.7, 95% confidence interval [CI] 2.2 6.2), unhappiness in the parent-child relationship (OR 3.0, 95% CI 1.2-7.5), history of serious illness (OR 2.4, 95% CI 1.1-5.2), unhappiness in family relationships (OR 2.3, 95% CI 1.1-4.7) and unhappiness at work (OR 2.2, 95% CI 1.1-4.3) (p < 0.05). CONCLUSION: The prevalence of depression among participants in this study was clinically significant and corresponded with the findings of other international studies. Factors associated with depression need to be highlighted and addressed accordingly. Clinicians in Malaysia should be aware of this prevalence when making diagnoses in primary care. PMID- 22815017 TI - Evaluation of adherence and depression among patients on peritoneal dialysis. AB - INTRODUCTION: It is challenging for dialysis patients to maintain adherence to their medical regimen, and symptoms of depression are prevalent among them. Limited data is available about adherence and depression among patients receiving peritoneal dialysis (PD). This study aimed to examine the rates of treatment non adherence and depression in PD patients. METHODS: A total of 20 PD patients (response rate 71.4%; mean age 64.4 +/- 11.6 years) were assessed using the Beliefs about Medicines Questionnaire, Self Efficacy for Managing Chronic Disease Scale, Hospital Anxiety and Depression Scale (HAD) and Kidney Disease Quality of Life-Short Form. A self-reported adherence (PD exchanges, medication and diet) scale developed for the study was also included. Medical information (e.g. most recent biochemistry results) was obtained from chart review. RESULTS: The mean self-reported scores indicated an overall high level of adherence, although a significant proportion of patients were non-adherent. Among the latter, 20% of patients were non-adherent to medication and 26% to diet due to forgetfulness, while 15% and 26% of patients admitted to deliberate non-adherence to medication and diet, respectively. Treatment modality, employment, self-care status and self efficacy were associated with overall adherence. Using a cutoff point of 8 for HAD depression and anxiety subscales, 40% of patients were found to be depressed and 30% had symptoms of anxiety. CONCLUSION: This is the first study to document treatment adherence and depression among PD patients in Singapore. Findings of high prevalence of depression and anxiety, and reports of poor adherence warrant development of intervention programmes. PMID- 22815018 TI - Interpersonal problems among psychiatric outpatients and non-clinical samples. AB - INTRODUCTION: The aims of this study were two-fold; to investigate the validity and reliability of the Thai version of the Inventory of Interpersonal Problems (IIP) and to compare the characteristics of the interpersonal problems experienced in a non-clinical sample and psychiatric outpatients. METHODS: A total of 689 subjects (452 non-clinical sample and 237 psychiatric outpatients) completed the IIP-32 and IIP-64, Symptom checklist-90 (SCL-90) and 16 Personality Factor (16 PF) Questionnaire, after which a four-week retest was carried out. Cronbach's alpha was used for internal consistency and the intra-class correlation coefficient was used to determine test-retest reliability. Factor analysis of the IIP sub-scales and Pearson's correlation were used for construct and concurrent validity. RESULTS: Both versions of the IIP showed good internal consistency. Factor analysis revealed two factors that corresponded to the circumplex property. The expected correlation between the SCL-90 and 16 PF subscales reflected the level of concurrent validity. There was a significant difference in the cold, socially-inhibited and self-sacrificing subscales between the non-clinical and clinical samples, while major depressive disorder was found to have a significantly higher score in the subscales of the control dimension, i.e. the non-assertive, socially inhibited and self-sacrificing subscales, than the neurotic and non-clinical groups, whereas, the neurotic group differed from the normative sample in terms of the affiliation axis. CONCLUSION: The IIP-64 and IIP-32 demonstrated their reliability and are suitable for use in either clinical or non-clinical setting. PMID- 22815019 TI - Comparison of fasting blood sugar and serum lipid profile changes after treatment with atypical antipsychotics olanzapine and risperidone. AB - INTRODUCTION: This study aimed to compare the effects of the two most commonly prescribed atypical antipsychotics, olanzapine and risperidone, on fasting blood sugar and serum lipid profile of the recipients. METHODS: A randomised, comparative, open clinical study was conducted on 60 schizophrenic patients. The patients were divided into two groups, one receiving olanzapine and the other receiving risperidone. The patients were assessed for changes in fasting blood sugar and serum lipid profile (triglycerides [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very-low-density lipoprotein [VLDL] and total cholesterol) eight weeks after starting treatment. The number of patients positive for fasting blood sugar and lipid profile criteria of metabolic syndrome was calculated by applying the modified National Cholesterol Education Programme Adult Treatment Panel III guidelines (NCEP ATP III) criteria at eight weeks. RESULTS: Patients treated with olanzapine showed a highly significant increase in the observed parameters, whereas those treated with risperidone showed a significant increase in fasting blood sugar, HDL and LDL levels, and a highly significant increase in other parameters. Intergroup comparison was insignificant except for TG, VLDL and total cholesterol levels. More men as compared to women fulfilled the NCEP ATP III criteria for metabolic syndrome in both groups. CONCLUSION: Olanzapine has a higher propensity to cause derangement of some parameters of lipid profile than risperidone. These parameters include TG, VLDL and total cholesterol levels. PMID- 22815020 TI - Yes, children do die in Singapore: a seven-year analysis of paediatric mortality. PMID- 22815022 TI - The rising trend of myocardial infarction in young patients in Pakistan. PMID- 22815023 TI - Pituitary tumour presenting with psychotic symptoms without neurological signs. PMID- 22815028 TI - Breast carcinoma with asymptomatic metastasis to the gallbladder. AB - The biliary tract is an unusual site of metastasis from breast carcinoma, and this has rarely been reported in the literature. We report the case of a 42-year old woman diagnosed with invasive lobular carcinoma of the breast who underwent laparoscopic cholecystectomy for an incidental finding of gallbladder wall thickening on ultrasonography, which was subsequently confirmed to be consistent with metastasis from the breast primary. PMID- 22815029 TI - A case of Jikoshu-Kyofu treated with cognitive behavioural therapy. AB - Jikoshu-Kyofu (JKF) is a subtype of Taijin-Kyofu-Sho (TKS), a form of social anxiety first described in Japanese sufferers. Unlike the Diagnostic and Statistical Manual of Mental Disorders - 4th edition text revised definition of social anxiety disorder, TKS is characterised by a fear of offending others, whereas in the case of JKF, it is the fear of giving off a smell, thus causing offence. We describe the symptoms of JKF in a young woman who was treated with cognitive behavioural therapy (CBT). After only four sessions, the patient's anxiety ratings, as measured on the Social Phobia Inventory and Brief Social Phobia Scale, dropped considerably. This case illustrates the successful treatment of a patient with JKF-like symptoms using CBT. PMID- 22815030 TI - Three cases of permanent neonatal diabetes mellitus: genotypes and management outcome. AB - Neonatal diabetes mellitus (DM) is defined as insulin-requiring DM in the first six months of life. Unlike type 1 DM, it is a monogenic disorder resulting from a de novo mutation in the genes involved in the development of the pancreas, beta cell mass or secretory function. The majority of neonatal DM cases are caused by a heterozygous activating mutation in the KCNJ11 or ABCC8 genes that encode the Kir6.2 and SUR1 protein subunits, respectively, in the KATP channel. Sulphonylurea, a KATP channel inhibitor, can restore insulin secretion, hence offering an attractive alternative to insulin therapy. We report three cases of neonatal DM and their genetic mutations. Two patients were successfully switched over to sulphonylurea monotherapy with resultant improvement in the quality of life and a more stable blood glucose profile. Patients with neonatal DM should undergo genetic evaluation. For patients with KCNJ11 and ABCC8 gene mutation, oral sulphonylurea should be considered. PMID- 22815031 TI - Coexistence of occipital and infratorcular meningocele with cervical split cord anomaly. AB - In this case report, we present an 18-year-old girl with occipital and infratorcular meningocele and coexisting split cervical cord. She had been admitted into the hospital for cosmetic considerations due to an inborn swelling in the back of the head and neck. Her mental status and neurologic examination were surprisingly intact. We discuss a very rare case of meningocele associated with split cord anomaly in the light of the current literature. PMID- 22815032 TI - Congenital adrenal hyperplasia masquerading as periodic paralysis in an adolescent girl. AB - Congenital adrenal hyperplasia is an uncommon diagnosis in routine clinical practice. 21-hydroxylase deficiency, which is its most common subtype, may be diagnosed at birth in a female infant by virilisation or by features of salt wasting in both genders. However, other uncommon subtypes of this condition such as 17-alpha-hydroxylase deficiency, 11-beta-hydroxylase deficiency may present much later in adolescence or adulthood. A high index of suspicion is necessary when evaluating children with hypertension, hypokalaemia, metabolic alkalosis or sexual infantilism. PMID- 22815033 TI - Magnetic resonance imaging findings in adult-form myotonic dystrophy type 1. AB - The adult form of myotonic dystrophy type 1 is a neuromuscular disorder with multisystem involvement, including the central nervous system (CNS). The presenting clinical features of this condition include distal muscle weakness, myotonia, intellectual decline, cataract, frontal baldness and testicular atrophy. Magnetic resonance (MR) imaging shows characteristic white matter changes in the CNS. The clinical presentation, characteristic white matter changes in the brain on MR imaging and electromyographic findings aid in the diagnosis of this disorder. PMID- 22815034 TI - Aicardi syndrome. AB - Aicardi syndrome is a rare neurodevelopmental disease characterised by congenital chorioretinal lacunae, corpus callosum dysgenesis, seizures, polymicrogyria, cerebral callosum, chorioretinopathy and electroencephalogram abnormality. We present a case of Aicardi syndrome with callosal hypogenesis in a 4.5-month-old baby who presented with infantile spasms. Ophthalmoscopy revealed chorioretinal lacunae. The clinical and magnetic resonance imaging features were diagnostic of Aicardi syndrome. PMID- 22815035 TI - Primary idiopathic chylopericardium: a rare case with a synopsis of the literature. AB - Primary idiopathic chylopericardium is a rare clinical entity characterised by the collection of chyle within the pericardial cavity without a definitive cause. This case report describes the history, physical examination, evaluation, diagnosis and treatment of a 19-year-old boy with primary idiopathic chylopericardium. Radiological findings and biochemical analysis of the pericardial fluid following pericardiocentesis sustained this diagnosis. Initial conservative management failed, and the patient was surgically treated subsequently. He recovered well postoperatively and remained asymptomatic thereafter. Primary idiopathic chylopericardium is a rare pathology with very few cases reported till date, and the symptoms are commonly due to cardiac compression. Computed tomography of the chest and bipedal lymphoscintigraphy are considered the standard methods for accurate diagnosis, and in cases of failed medical treatment, open and thoracoscopic thoracic duct ligation with pericardiectomy have been described as the best surgical options. PMID- 22815036 TI - How can a hydrophobic MOF be water-unstable? Insight into the hydration mechanism of IRMOFs. AB - We report an ab initio molecular dynamics study of the hydration process in a model IRMOF material. At low water content (one molecule per unit cell), water physisorption is observed on the zinc cation but the free?bound equilibrium strongly favors the free state. This is consistent with the hydrophobic nature of the host matrix and its type-V isotherm observed in a classical Monte Carlo simulation. At higher loading, a water cluster can be formed at the Zn(4)O site and this is shown to stabilize the water-bound state. This structure rapidly transforms into a linker-displaced state, where water has fully displaced one arm of a linker and which corresponds to the loss of the material's fully ordered structure. Thus an overall hydrophobic MOF material can also become water unstable, a feature that has not been fully understood until now. PMID- 22815037 TI - Reply: To PMID 21994151. PMID- 22815038 TI - Revision otoplasty: an algorithm. AB - BACKGROUND: The purpose of this study was to propose a surgical algorithm for revision otoplasty, based on an evaluation of patient concerns, desires, and clinical findings. A series of instructive cases is presented. METHODS: Thirty six patients with an average age of approximately 15 years (range, 6 to 61 years), who underwent revision otoplasty between 2006 and 2011, were included. Demographic data, complications, indications for revision surgery, and operative details were retrieved from case notes and preoperative and postoperative photographs. Aesthetic outcomes were assessed by three independent plastic surgery consultants using a survey with 15 questions. RESULTS: Indications for revision otoplasty included recurrent prominence/undercorrection, distortion of scaphoid fossa, distortion of antihelical fold, hypertrophic conchal bowl, and telephone ear. The relevant surgical technique was performed according to the patient's concerns and aspirations in line with the proposed protocol of treatment and included the following: posterior suturing, conchal bowl reduction, reconstruction with conchal cartilage, or reconstruction with costal cartilage. CONCLUSIONS: Otoplasty is performed frequently in young patients, and unsuccessful surgery can have a negative impact on their quality of life. Suturing techniques are safer than sculpting techniques, which can cause permanent ear deformity. Complications after sculpting techniques can lead to ear reconstruction. The proposed algorithm for revision otoplasty addresses the whole variety of ear deformations, providing the surgical options available to address these abnormalities. PMID- 22815039 TI - Artificial niches: biomimetic materials for hematopoietic stem cell culture. AB - Hematopoietic stem cells (HSCs) are indispensable for the treatment of patients with hematological disorders such as leukemia. However, the amount of available transplantable HSCs is limited. Therefore, new approaches to multiply HSCs in the laboratory are needed. Promising biomimetic technologies for HSC expansion are currently developed. This feature article gives an insight into the significance of this approach and introduces the essential building blocks (cells, matrix, and scaffolds) of biomimetic materials. Some recent strategies are highlighted and the challenges and possible applications of such materials are discussed. PMID- 22815041 TI - A toolbox of geometric elements for labyrinth model design and analysis. AB - OBJECTIVES/HYPOTHESIS: To develop a toolbox of defined geometric shapes that can aid in the emulation of the architecture of the labyrinthine membranes. STUDY DESIGN: Analytical review of geometric shapes that are candidates for inclusion in the toolbox. METHODS: The mammalian labyrinth appears to have an overall tubular configuration. The bulges, bends and constrictions manifest by these chambers and conduits may be construed to be variations on an underlying core cylindrical structure. Four geometries that embrace the cylindrical shape are identified, namely the cylinder itself, the ellipsoid, the hyperboloid, and the torus. These can be exploited as model design tools and used to approximate the individual components of the labyrinth. RESULTS: A toolbox of geometric elements is identified for use in modeling the mammalian labyrinth. The toolbox includes cylindrical, ellipsoidal, hyperboloidal, and toroidal elements, their figures and mathematical definitions, as well as derivative characteristics that relate to contour and curvature. CONCLUSIONS: This analysis suggests that there is a heuristic value in considering the underlying structure of the mammalian labyrinth to be cylindrical. Four principal geometric shapes that are based on the cylinder have been identified for use in a toolbox of design elements. This toolbox can be used to model any mammalian labyrinth. PMID- 22815040 TI - Individual differences in cardiac vagal tone are associated with differential neural responses to facial expressions at different spatial frequencies: an ERP and sLORETA study. AB - A previous study has shown that greater cardiac vagal tone, reflecting effective self-regulatory capacity, was correlated with superior visual discrimination of fearful faces at high spatial frequency Park et al. (Biological Psychology 90:171 178, 2012b). The present study investigated whether individual differences in cardiac vagal tone (indexed by heart rate variability) were associated with different event-related brain potentials (ERPs) in response to fearful and neutral faces. Thirty-six healthy participants discriminated the emotion of fearful and neutral faces at broad, high, and low spatial frequencies, while ERPs were recorded. Participants with low resting heart rate variability-characterized by poor functioning of regulatory systems-exhibited significantly greater N200 activity in response to fearful faces at low spatial frequency and greater LPP responses to neutral faces at high spatial frequency. Source analyses-estimated by standardized low-resolution brain electromagnetic tomography (sLORETA)-tended to show that participants with low resting heart rate variability exhibited increased source activity in visual areas, such as the cuneus and the middle occipital gyrus, as compared with participants with high resting heart rate variability. The hyperactive neural activity associated with low cardiac vagal tone may account for hypervigilant response patterns and emotional dysregulation, which heightens the risk of developing physical and emotional problems. PMID- 22815042 TI - Glucose control in diabetes: the impact of racial differences on monitoring and outcomes. AB - Type 2 diabetes is the seventh leading cause of death in the US and is projected to increase in prevalence globally. Minorities are disproportionately affected by diabetes and data suggest that clinical outcomes consistently fall below American Diabetes Association recommendations. The purpose of this systematic review was to examine ethnic differences in self-monitoring and outcomes in adults with type 2 diabetes. Medline was searched for articles published between January 1990 and January 2012 by means of a reproducible strategy. Inclusion criteria included (1) published in English, (2) targeted African Americans, Hispanic, or Asian adults, ages 18+ years with type 2 diabetes, (3) cross-sectional, cohort, or intervention study, and (4) measured change in glycemic control, BP, lipids, or quality of life by race. Twenty-two papers met the inclusion criteria and were reviewed. Overall, significant racial differences and barriers were found in published studies in diabetes management as it pertains to self-monitoring and outcomes. African Americans tend to consistently exhibit worse outcomes and control when compared to other minority populations and non-Hispanic Whites. In conclusion, significant racial differences and barriers exist in diabetes management as it pertains to self-monitoring and outcomes when compared to non-Hispanic Whites. Explanatory and intervention studies are needed to determine the mechanisms and mediators of these differences and strategies to reduce these disparities. In addition, more research is needed to investigate the impact of racial differences in self-monitoring and outcomes on quality of life. PMID- 22815043 TI - Ginkgo biloba L. extract enhances the effectiveness of syngeneic bone marrow mesenchymal stem cells in lowering blood glucose levels and reversing oxidative stress. AB - Bone marrow mesenchymal stem cells (BMSCs) are potential therapy for diabetes. Owing to the oxidative stress caused by hyperglycemia, these transplanted BMSCs are with high rate of apoptotic death after transplantation. Ginkgo biloba L. extract (EGB) is a potent antioxidant which can remove free radicals. The study was to investigate whether EGB can protect BMSCs from oxidative stress in vitro and enhance the efficacy of BMSCs in lowering blood glucose levels after transplantation. BMSCs were cultured with H2O2, EGB, or H2O2 and EGB. Cell viability, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and cell death rates were determined. Diabetes was induced by single injection of streptozotocin (STZ) in male Wistar rats. Diabetic rats received EGB, BMSCs, or EGB/BMSCs. The serum levels of glucose, insulin, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), MDA, SOD, and GSH Px were determined. PKCalpha expression and NF-kappaB activation in kidney were determined. The MDA levels and cell death rates in BMSCs cultured with H2O2 and EGB were significantly lower; cell viability, SOD, and GSH-Px activities were significantly higher compared with those with H2O2 alone. Compared with diabetic rats receiving BMSCs, diabetic rats receiving EGB before BMSCs transplantation showed (1) significantly lower levels of blood glucose, serum MDA, IL-6, and TNF alpha, and higher levels of insulin, SOD, and GSH-Px activities; (2) significantly lower PKCalpha expression and NF-kappaB activation in the kidney. EGB administration before BMSC transplantation can enhance the effectiveness of BMSCs in lowering blood glucose levels and reversing oxidative stress in diabetic rats. PMID- 22815044 TI - Increased expression of pro-angiogenic factors and vascularization in thyroid hyperfunctioning adenomas with and without TSH receptor activating mutations. AB - Autonomously functioning thyroid nodules (AFTN) are known to receive an increased blood influx necessary to sustain their high rate of growth and hormone production. Here, we investigated the expression of hematic and lymphatic vases in a series of 20 AFTN compared with the contralateral non-tumor tissues of the same patients, and the transcript levels of proteins involved in the control of vascular proliferation, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF) and their receptors and the endothelial nitric oxide synthase (eNOS). In parallel, the expression of the differentiation markers sodium/iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (Tg), and TSH receptor (TSHR) was also investigated. The data were further analyzed comparing subgroups of tumors with or without mutations in the TSHR gene. Analysis by means of CD31 and D2-40 immunostaining showed in AFTN an increased number of hematic, but not lymphatic, vessels in parallel with an enhanced proliferation rate shown by increased Ki67 staining. Quantitative RT-PCR analysis revealed an increase of VEGF, VEGFR1 and 2, PDGF-A, PDGF-B, and eNOS expression in tumor versus normal tissues. Also, higher transcript levels of NIS, TPO, and Tg were detected. Comparison of the two subgroups of samples revealed only few differences in the expression of the genes examined. In conclusion, these data demonstrate an increased expression of angiogenesis-related factors associated with an enhanced proliferation of hematic, but not lymphatic, vessels in AFTNs. In this context, the presence of TSHR mutations may only slightly influence the expression of pro-angiogenic growth factors. PMID- 22815046 TI - Glycemic variability in gestational diabetes mellitus and its association with beta cell function. AB - Maternal hyperglycemia in gestational diabetes mellitus (GDM), especially hyperglycemic excursions, is associated with increased risks of adverse pregnancy outcomes. Continuous glucose monitoring (CGM) system (CGMS) is better than intermittent self-measurements in detecting detailed glucose profiles on the magnitude and duration of glucose fluctuations. Hyperglycemia resulted from impaired beta cell function. This study analyzed the characteristics of glycemic variability in GDM with 24-28 gestational weeks and its association with beta cell function. Thirty GDM with 24-28 gestational weeks (GDM group) were included in this study, and 20 normal gestational women (NGW group) and 20 normal glucose regulation non-pregnant women (NGRW group) were set as controls. The three groups were monitored using the CGMS for consecutive 72 h. The parameters of glycemic variability included the standard deviation of blood glucose (SDBG), mean of continuous 24-h blood glucose (MBG), mean amplitude of glycemic excursions (MAGEs), and mean of daily differences (MODDs). Homeostasis model assessments were applied to access the insulin resistance (HOMA-IR). The early insulinogenic index (DeltaI30/DeltaG30) and the area under the curve of insulin (AUCI180) derived from 75-g oral glucose tolerance test were applied to evaluate the early phase insulin secretion and second-phase insulin secretion, respectively. After CGM, MAGE and MBG value increased progressively from NGRW, NGW to GDM group (p < 0.05); MODD and SDBG values of GDM group were all higher than those of NGRW and NGW groups (p < 0.05), but there are no differences in MODD and SDBG between NGRW and NGW groups (p > 0.05). After comparison of beta cell function, DeltaI30/DeltaG30 decreased progressively from NGRW, NGW to GDM group (p < 0.05); HOMA-IR and AUCI180 increased progressively from NGRW, NGW to GDM group (p < 0.05). MAGE value was correlated with DeltaI30/DeltaG30 and HOMA-IR in GDM group (r = -0.78 and 0.65, respectively, p < 0.05). Multiple linear stepwise regression analysis showed that DeltaI30/DeltaG30 and HOMA-IR were the independent factors of MAGE (beta = -0.61, 0.34, respectively, p < 0.05). Glycemic variability in GDM was higher than in normal pregnant women, and glycemic variability evaluated by MAGE correlates well with impaired early-phase insulin secretion in GDM. Further large-scale studies are needed to formulate treatment strategies to make up for the impaired early-phase insulin secretion and flat glycemic variability, and analyze the association between pregnancy outcomes improvement and glycemic variability remission in GDM. PMID- 22815045 TI - Atrogin-1, MuRF-1, and sarcopenia. AB - Sarcopenia is one of the leading causes of disability in the elderly. Despite the growing prevalence of sarcopenia, the molecular mechanisms that control aging related changes in muscle mass are not fully understood. The ubiquitin proteasome system is one of the major pathways that regulate muscle protein degradation, and this system plays a central role in controlling muscle size. Atrogin-1 and MuRF-1 are two E3 ubiquitin ligases that are important regulators of ubiquitin-mediated protein degradation in skeletal muscle. In this review, we will discuss: (i) aging-related changes to skeletal muscle structure and function; (ii) the regulation of protein synthesis and protein degradation by IGF-1, TGF-beta, and myostatin, with emphasis on the control of atrogin-1 and MuRF-1 expression; and (iii) the potential for modulating atrogin-1 and MuRF-1 expression to treat or prevent sarcopenia. PMID- 22815047 TI - Atrial arrhythmias after pulmonary resection: the important role of pulmonary vein resection. AB - BACKGROUND: Atrial arrhythmias (AAs) remain one of the most common complications after pulmonary resection. The association between postoperative AAs and pulmonary vein (PV) resection has not previously been clearly elucidated. A retrospective study on this issue is reported. METHODS: A total of 125 patients were involved in this study and all the performed surgical procedures and all postoperative AAs were carefully reviewed and recorded. A univariate and multivariate analyses were utilized to clarify the effect of PV resection on postoperative AAs. RESULTS: The overall incidence of postoperative AAs was 14.4% (n = 18). A stepwise increase in the incidence of AAs was observed from none, to the inferior of PV resection only, superior PV resection only and up to both inferior and superior PV resection (0, 3.1, 14.3, and 38.5%, respectively; p = 0.000). During multivariate analysis, PV resection was identified as an independent risk factor for postoperative AAs when it was entered either as an ordinal or as a categorical variable. The area under the receiver operating characteristic curve of PV resection revealed 0.786 (95% confidence interval [CI], 0.685-0.887), which was significantly larger than the extent of pulmonary resection (0.724; 95% CI, 0.637-0.800; p = 0.015). CONCLUSION: PV resection plays an important role in the development of postoperative AAs after pulmonary resection and could be used as a good predictor for postoperative AAs. PMID- 22815049 TI - In utero exposure to antidepressants and the use of drugs for pulmonary diseases in children. AB - PURPOSE: The use of antidepressants during pregnancy is common. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases like asthma later in life. Serotonin reuptake inhibitors (SSRIs) as well tricyclic antidepressants (TCAs) are thought to be involved in the development of the respiratory rhythm generator (RRG) and the maturation of the formation of surfactant. In this study the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero were compared with non-exposed children. METHODS: The pharmacy prescription database IADB.nl was used for a cohort study in which the use of drugs for pulmonary disease in children after in utero exposure to antidepressants (TCAs, SSRIs) was compared with children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. RESULTS: A small though significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary disease was found after any time in utero exposure to SSRIs, adjusted for maternal use of antibiotics, of 1.17 (95 % CI 1.16-1.18). An increase was also seen when we looked specifically for the use of SSRIs in at least the first trimester (IRR = 1.18, 95 % CI 1.17 1.20). An increased IRR in the use of drugs for pulmonary disease was also seen when children were exposed to TCAs, but this was not statistically significant. However, in both groups our sample size was rather small. The effect size is modest and may also be confounded by maternal smoking. CONCLUSIONS: In utero exposure to SSRIs leads to a statistically significant increase in the use of drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. The increase in the use of drugs for pulmonary disease may also be related to other factors. Therefore, further study is recommended. PMID- 22815050 TI - Single ascending oral dose pharmacokinetics and pharmacodynamics study of EV-077: the specific inhibitor of prostanoid- and isoprostane-induced cellular activation. AB - PURPOSE: This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. METHODS: This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. RESULTS: Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t1/2z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (>90 %). All tested doses were well tolerated. CONCLUSIONS: Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min. PMID- 22815051 TI - Rapid and sensitive detection of auxins and flavonoids in plant samples by high performance liquid chromatography coupled with tandem mass spectrometry. AB - Simultaneous determination of indole-3-acetic acid and methyl indole-3-acetic acid ester in small amounts of plant tissue is essential for elucidating their mutual transformation mechanism and the in vivo function of methyl indole-3 acetic acid ester. Rapid quantification of flavonoids in the same sample is important for clarifying their roles in the transport of auxins and other phytohormones. Herein, we describe a simple method for the simultaneous determination of indole-3-acetic acid and its methyl ester in the roots of the Arabidopsis thaliana seedlings and a protocol for the rapid extraction and quantification of quercetin and kaempferol in these seedlings. High-performance liquid chromatography coupled with electrospray ionization time-of-flight tandem mass spectrometry was used for the detection of all the compounds. Negative data for indole-3-acetic acid and positive data for methyl indole-3-acetic acid ester were collected in two successive files with a single injection of the extracted sample. Under optimized conditions, the limit of detection for the four compounds was 2 ng/mL for indole-3-acetic acid, 0.5 ng/mL for methyl indole-3-acetic acid ester, 5 ng/mL for quercetin, and 1 ng/mL for kaempferol, respectively. Because of the high sensitivity of the assay, only 2-10 mg of the plant material was required to obtain quantitative results. PMID- 22815052 TI - Small-diameter tissue engineered vascular graft made of electrospun PCL/lecithin blend. AB - In this study, natural lecithin was incorporated into cholesterol-poly(epsilon caprolactone) (Chol-PCL) by solution blending in order to modify the performance of the hydrophobic and bio-inert PCL. The fibrous Chol-PCL/lecithin membranes were fabricated by electrospinning, and the surface morphology and properties were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, static water contact angle, and mechanical tensile testing. The blood compatibility of the scaffolds was evaluated by in vitro hemolysis assay. The cytocompatibility of the scaffolds was investigated by cell adhesion and proliferation using bone-marrow mesenchymal stem cells (MSCs). Subcutaneous implantation was also performed to evaluate the in vivo inflammatory reaction. The tubular tissue-engineered vascular graft (TEVG) was further constructed by rolling cell sheet comprising fibrous membrane and MSCs. Furthermore, endothelial cells (ECs) were seeded onto the lumen of the graft with the aim to form vascular endothelium. The preliminary results indicate that electrospun Chol-PCL/lecithin scaffolds show improved hemocompatibility and cytocompatibility compared with neat Chol-PCL, and combining the Chol-PCL/lecithin fibrous scaffold with MSCs and ECs with well controlled distribution is a promising strategy for constructing TEVGs. PMID- 22815053 TI - Examining church capacity to develop and disseminate a religiously appropriate HIV tool kit with African American churches. AB - Increasingly, African American churches have been called upon to assist in efforts to address HIV/AIDS in underserved communities. African Americans churches may be well-positioned to provide HIV education, screening, and support services, particularly if they are equipped with church-appropriate, easy-to deliver HIV tools that can be implemented through the naturalistic church environment. To inform the development of a church-based HIV tool kit, we examined church capacity with African American church leaders (N = 124 participants; n = 58 churches represented by senior pastors). Nearly all participants (96%) wanted to learn more about HIV and how to discuss it with their parishioners. Regarding church capacity, most of their representative churches held three regular services each week, facilitated various inreach and community outreach ministries, and had paid staff and computers. Also, many of their churches facilitated HIV/AIDS education/prevention and adolescent sex education activities. Guided by church capacity findings, an ecological framework, and a CBPR approach, we describe the resulting church-based HIV Tool Kit that "fits" naturalistically within a multilevel church infrastructure, builds upon churches' HIV-related experience, and equips faith leaders to efficiently promote HIV services with the communities they serve. PMID- 22815055 TI - Blunted response of pituitary type 1 and brown adipose tissue type 2 deiodinases to swimming training in ovariectomized rats. AB - Ovariectomy leads to significant increase in body weight, but the possible peripheral mechanisms involved in weight gain are still unknown. Since exercise and thyroid hormones modulate energy balance, we aimed to study the effect of swimming training on body weight gain and brown adipose tissue (BAT) type 2 iodothyronine deiodinase responses in ovariectomized (Ox) or sham-operated (Sh) rats. Rats were submitted to a period of 8-week training, 5 days per week with progressive higher duration of exercise protocol. Swimming training program did not totally prevent the higher body mass gain that follows ovariectomy in rats (16.5% decrease in body mass gain in Ox trained rats compared to 22% decrease in sham operated trained animals, in relation to the respective sedentary groups), but training of Ox animals impaired the accumulation of subcutaneous fat pads. Interestingly, swimming training upregulates pituitary type 1 (p<0.001 vs. all groups) and BAT type 2 iodothyronine deiodinases (p<0.05 vs. ShS and OxS) in sham operated but not in Ox rats, indicating an impaired pituitary and peripheral response to exercise in Ox rats. However, BAT mitochondrial O2 consumption significantly increased by swimming training in both sham and Ox groups, indicating that Ox BAT mitochondria responds normally to exercise stimulus, but does not result in a significant reduction of body weight. In conclusion, increased body mass gain produced by Ox is not completely impaired by 8 weeks of high intensity physical training, showing that these animals sustain higher rate of body mass gain independent of being submitted to higher energy expenditure. PMID- 22815054 TI - Adolescent criminal justice involvement and adulthood sexually transmitted infection in a nationally representative US sample. AB - Criminal justice involvement (CJI) disrupts social and sexual networks, and sexually transmitted infections (STIs) thrive on network disruption. Adolescent CJI may be a particularly important determinant of STI because experiences during adolescence influence risk trajectories into adulthood. We used Wave III (2001 2002: young adulthood) of the National Longitudinal Study of Adolescent Health (N = 14,322) to estimate associations between history of adolescent (younger than 18 years) CJI and adult STI risk. Respondents who reported a history of repeat arrest in adolescence, adolescent conviction, and arrest both as an adolescent and an adult (persistent arrest) had between two to seven times the odds of STI (biologically confirmed infection with chlamydia, gonorrhea, or trichomoniasis) in adulthood and between two to three times the odds of multiple partnerships and inconsistent condom use in the past year in adulthood. In analyses adjusting for sociodemographic and behavioral factors, history of having six or more adolescent arrests was associated with more than five times the odds of STI (adjusted odds ratio (AOR) 5.44, 95 % confidence interval (CI) 1.74-17.1). Both adolescent conviction and persistent CJI appeared to remain independent correlates of STI (conviction: AOR 1.90, 95 % CI 1.02-3.55; persistent CJI: AOR 1.60, 95 % CI 0.99 2.57). Adolescents who have repeat arrests, juvenile convictions, and persist as offenders into adulthood constitute priority populations for STI treatment and prevention. The disruptive effect of adolescent CJI may contribute to a trajectory associated with STI in adulthood. PMID- 22815056 TI - Mutations in Lyar and p53 are synergistically lethal in female mice. AB - BACKGROUND: Ly-1 antibody reactive clone (LYAR) is a nucleolar zinc finger protein that has been implicated in cell growth, self-renewal of embryonic stem cells, and medulloblastoma. To test whether LYAR is critical for cell growth and development, we generated Lyar mutant mice. METHODS: Mice carrying the mutant Lyar(gt) allele were generated from embryonic stem cells that contained a gene trap insertion in the Lyar gene. Phenotypic analyses were performed on Lyar mutant mice and mouse embryonic fibroblasts. Lyar(gt/gt) mice were crossed to mice lacking the p53 tumor suppressor protein and Lyar/p53 compound mutants scored for external abnormalities. RESULTS: Lyar(gt/gt) homozygotes are viable, fertile, and indistinguishable from wild type littermates. However, the growth of Lyar(+/gt) and Lyar(gt/gt) mouse embryonic fibroblasts (MEFs) was impaired, coincident with an increase in the steady-state level of p53 and a key p53 effector of growth arrest, p21, suggesting that a cellular stress response is triggered in the absence of a wild type level of LYAR. Remarkably, the majority of Lyar(+/gt) and Lyar(gt/gt) female mice lacking p53 mice failed to survive. The neural tube defect (NTD) exencephaly was observed in ~26% and ~61% of female Lyar(+/gt;) p53(-/-) and Lyar(gt/gt;) p53(-/-) embryos, respectively. CONCLUSIONS: Lyar/p53 mutant mice represent a new digenic model of NTDs. Furthermore, these studies identify Lyar as a novel candidate gene for a role in human NTDs. These results provide new data to support the idea that loss of a p53 mediated developmental checkpoint may increase the risk of NTDs owing to some germline mutations. PMID- 22815057 TI - Two types of laminolysis in adolescent athletes. AB - Bony defects in the spine are divided into three main types: spondylolysis, pediculolysis, and laminolysis. Lumbar spondylolysis is a well-known stress fracture that occurs frequently in adolescent athletes. Pediculolysis means stress fracture of the pedicle, which sometimes occurs subsequent to unilateral spondylolysis. Laminolysis is a rarely reported stress fracture similar to spondylolysis and pediculolysis that sometimes causes low back pain (LBP). However, its pathomechanism has not been elucidated. Recently, we encountered four adolescent athletes with symptomatic laminolysis. Mean age was 15.8 (range 15-17) years. All subjects reported severe LBP exacerbated by extension of the lumbar spine, and radiology revealed two types of laminolysis: hemilaminar type and intralaminar type. To elucidate the mechanisms of each type, we reviewed a biomechanical study, and found that the hemilaminar type was thought to be subsequent to contralateral spondylolysis, while the intralaminar type might be a result of a stress fracture due to repetitive extension loading. PMID- 22815058 TI - 5-HTTLPR polymorphism in bulimia nervosa: a multiple-model meta-analysis. AB - Several lines of research have found that genes in the serotonergic system may cause susceptibility to eating disorders (EDs). In particular, functional polymorphisms of the serotonin transporter gene (5-HTT) have been suspected to play a role in the pathogenesis of eating disorders. Several studies have examined the association between the 5-HTTLPR polymorphism and bulimia nervosa (BN). The results of these investigations have been unclear. The aims of this meta-analysis were to clarify the association between BN and 5-HTTLPR using statistical models not used by previous meta-analyses, and extend upon previous meta-analyses by including new samples. PsychINFO, ISI, and PubMed databases were searched for studies published up to May 2011. Ultimately, six case-control samples were included. Data were pooled using dominant and additive models. Both models showed a nonsignificant association between the 5-HTTLPR polymorphism and BN. However, this does not detract from recent research suggesting that the 5 HTTLPR polymorphism may be responsible for the phenotypic variability in the psychopathological symptoms observed in patients with BN. Future research should examine the association of BN with 5-HTTLPR using the recently proposed triallelic model. PMID- 22815059 TI - A novel anti-DR5 chimeric antibody and epirubicin synergistically suppress tumor growth. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumor cells. TRAIL receptor 2 (DR5) expression is high in tumor cells, transformed cells, and clinical tumor specimens and is low in most normal cells and tissues; therefore, DR5 is considered an attractive target for cancer therapy. In this study, HMCAZ5, a novel mouse-human chimeric antibody based on AD5-10, was generated and stably expressed in CHO-dhfr(-) cells. Highly purified HMCAZ5 exhibits a high affinity for the receptor that is equal to the parental mouse antibody, induces apoptosis in various cancer cells but not in normal hepatocytes, and elicits both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in various human cancer cells. The anthracycline anticancer drug epirubicin (EPB) synergizes the cytotoxicity of HMCAZ5 in cancer cells by upregulating DR5 expression on the cell surfaces, enhancing p53 expression, Bid cleavage, and JNK phosphorylation and downregulating c-FLIP expression and Akt phosphorylation. Moreover, HMCAZ5 alone suppresses tumor growth, and EPB augments the tumoricidal activity in human colorectal and hepatocellular tumor xenografts in athymic nude mice. These data suggest that the anti-DR5 chimeric antibody HMCAZ5 may have a clinical use and represents a useful immunological strategy, in combination with chemotherapy, for the treatment of cancer. PMID- 22815060 TI - Mouse model of primary biliary cirrhosis with progressive fibrosis: are we there yet? PMID- 22815061 TI - A peculiar cause of anaphylaxis: no more steak? The journey to discovery of a newly recognized allergy to galactose-alpha-1,3-galactose found in mammalian meat. AB - In recent years, a newly recognized allergic disease has been uncovered, and seemingly idiopathic causes of anaphylaxis now have an explanation. Individuals bitten by the lone star tick may develop IgE antibodies to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal). Upon exposure of sensitized subjects to mammalian meat containing alpha-gal on glycoproteins or glycolipids, delayed anaphylaxis may ensue, often three to six hours after ingestion.1 Many of these individuals have negative allergy skin prick tests to meat, further obscuring the diagnosis. With the recent development of IgE alpha-gal tests, the clinical diagnosis can be confirmed in the laboratory. PMID- 22815063 TI - Hiding behind the Hippocratic Oath. PMID- 22815062 TI - They don't know what they don't know: internal medicine residents' knowledge and confidence in urine drug test interpretation for patients with chronic pain. AB - BACKGROUND: Urine drug testing (UDT) can help identify misuse or diversion of opioid medications among patients with chronic pain. However, misinterpreting results can lead to false reassurance or erroneous conclusions about drug use. OBJECTIVE: To examine the relationship between resident physicians' knowledge about UDT interpretation and confidence in their ability to interpret UDT results. DESIGN: Cross-sectional survey. PARTICIPANTS: Internal medicine residents in a university health system in the Bronx, from 2010 to 2011. MAIN MEASURES: We assessed knowledge using a 7-item scale (UDT knowledge score), and confidence in UDT interpretation using a single statement ("I feel confident in my ability to interpret the results of urine drug tests"). We conducted chi square tests, t-tests, and logistic regression to determine the association between knowledge and confidence, and in exploratory analyses to examine whether resident characteristics (gender, training level, and UDT use) moderated the relationship between knowledge and confidence. KEY RESULTS: Among 99 residents, the mean UDT knowledge score was 3.0 out of 7 (SD 1.2). Although 55 (56 %) of residents felt confident in their ability to interpret UDT results, 40 (73 %) of confident residents had a knowledge score of 3 or lower. Knowledge score was not associated with confidence among the full sample or when stratified by training level or UDT use. The association between knowledge and confidence differed significantly by gender (interaction term p<0.01). Adjusting for training level and UDT use, knowledge was positively associated with confidence among females (AOR 1.79, 95 % CI: 1.06, 3.30), and negatively associated with confidence among males (AOR 0.47, 95 % CI: 0.23, 0.98). CONCLUSIONS: Despite poor knowledge about UDT interpretation, most resident physicians felt confident in their ability to interpret UDT results. Gender differences warrant further exploration, but even confident physicians who use UDT should evaluate their proficiency in interpreting UDT results. Educational initiatives should emphasize the complexities of UDT interpretation. PMID- 22815064 TI - Increased functional connectivity within medial temporal lobe in mild cognitive impairment. AB - Pathology at preclinical and prodromal stages of Alzheimer's disease (AD) may manifest itself as measurable functional change in neuronal networks earlier than detectable structural change. Functional connectivity as measured using resting state functional magnetic resonance imaging has emerged as a useful tool for studying disease effects on baseline states of neuronal networks. In this study, we use high resolution MRI to label subregions within the medial temporal lobe (MTL), a site of early pathology in AD, and report an increase in functional connectivity in amnestic mild cognitive impairment between entorhinal cortex and subregions of the MTL, with the strongest effect in the anterior hippocampus. However, our data also replicated the effects of decreased connectivity of the MTL to other nodes of the default mode network reported by other researchers. This dissociation of changes in functional connectivity within the MTL versus the MTL's connection with other neocortical structures can help enrich the characterization of early stages of disease progression in AD. PMID- 22815065 TI - Analogy as a strategy for supporting complex problem solving under uncertainty. AB - Complex problem solving in naturalistic environments is fraught with uncertainty, which has significant impacts on problem-solving behavior. Thus, theories of human problem solving should include accounts of the cognitive strategies people bring to bear to deal with uncertainty during problem solving. In this article, we present evidence that analogy is one such strategy. Using statistical analyses of the temporal dynamics between analogy and expressed uncertainty in the naturalistic problem-solving conversations among scientists on the Mars Rover Mission, we show that spikes in expressed uncertainty reliably predict analogy use (Study 1) and that expressed uncertainty reduces to baseline levels following analogy use (Study 2). In addition, in Study 3, we show with qualitative analyses that this relationship between uncertainty and analogy is not due to miscommunication-related uncertainty but, rather, is primarily concentrated on substantive problem-solving issues. Finally, we discuss a hypothesis about how analogy might serve as an uncertainty reduction strategy in naturalistic complex problem solving. PMID- 22815066 TI - Feeling the past: the absence of experimental evidence for anomalous retroactive influences on text processing. AB - In two self-paced reading experiments, we investigated the hypothesis that information moves backward in time to influence prior behaviors (Bem Journal of Personality and Social Psychology 100:407-425, 2011a). In two of Bem's experiments, words were presented after target pictures in a pleasantness judgment task. In a condition in which the words were consistent with the emotional valence of the picture, reaction times to the pictures were significantly shorter , as compared with a condition in which the words were inconsistent with the emotional valence of the picture. Bem Journal of Personality and Social Psychology 100:407-425, (2011a) interpreted these results as showing a "retroactive priming" effect resulting from precognition. To test the precognition hypothesis, we adapted a standard repetition priming paradigm from psycholinguistics. In the experiments, participants read a set of texts. In one condition, the participants read the same text twice. In other conditions, participants read two different texts. The precognition hypothesis predicts that readers who encounter the same text twice will experience reductions in processing load during their first encounter with the text. Hence, these readers' average reading times should be shorter than those of readers who encounter the target text only once. Our results indicated that readers processed the target text faster the second time they read it. Also, their reading times decreased as their experience with the self-paced reading procedure increased. However, participants read the target text equally quickly during their initial encounter with the text, whether or not the text was subsequently repeated. Thus, the experiments demonstrated normal repetition priming and practice effects but offered no evidence for retroactive influences on text processing. PMID- 22815067 TI - Acrodysostosis. AB - Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with "typical" acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis. In this review, we will first discuss the clinical, radiologic, and metabolic features of acrodysostosis, emphasizing evidence that several forms of the disease are likely to exist. Second, we will describe recent results explaining the pathogenesis of acrodysostosis with hormonal resistance (ADOHR). Finally, we will discuss the similarities and differences observed comparing patients with ADOHR and other diseases resulting from defects in the PTHR1 signaling pathway, in particular, pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism. PMID- 22815068 TI - Schizosaccharomyces pombe reporter strains for relative quantitative assessment of heterochromatin silencing. AB - The fission yeast Schizosaccharomyces pombe has been emerging as an important model organism for studying the formation and repression of heterochromatin. To enable simple and relative quantitative assessment of heterochromatin silencing, we have created bioluminescence-based reporter strains. A green-emitting click beetle luciferase (CBG68) gene was inserted within pericentromeric heterochromatin or at the silent mating-type locus via homologous recombination. In the same strains, a red-emitting click beetle luciferase (CBR) gene is expressed from the euchromatic leu1(+) locus and can be used as a reference in dual-colour assays. Our reporter strains are suitable for performing Chroma-GloTM assays, which can be carried out directly in the culture medium without prior cell lysis and in a multiwell format. Our reporter system reliably reflects the state of chromatin and can be easily adapted for use in high-throughput screening approaches. PMID- 22815069 TI - Determination of bromate in drinking water by ultraperformance liquid chromatography-tandem mass spectrometry. AB - Bromate is a byproduct formed as a result of disinfection of bromide-containing source water with ozone or hypochlorite. The International Agency for Research on Cancer has recognized bromate as a possible human carcinogen, thus it is essential to determine in drinking water. Present work highlights a development of sensitive and fast analytical method for bromate determination in drinking water by using ultraperformance liquid chromatography-tandem mass spectrometry. The quality parameters of the developed method were established, obtaining very low limit of detection (0.01 ng/mL), repeatability and reproducibility have been found to be less than 3% in terms of relative standard deviation when analyzing a bromate standard at 0.05 MUg/mL with 0.4 min analysis time. Developed method was applied for the analysis of metropolitan and bottled water from Saudi Arabia; 22 samples have been analyzed. Bromate was detected in the metropolitan water samples (from desalinization source) at concentrations ranging between 3.43 and 75.04 ng/mL and in the bottled water samples at concentrations ranging between 2.07 and 21.90 ng/mL. Moreover, in comparison to established analytical methods such as liquid chromatography-tandem mass spectrometry, the proposed method was found to be very sensitive, selective and rapid for the routine analysis of bromate at low level in drinking water. PMID- 22815070 TI - STRA6-catalyzed vitamin A influx, efflux, and exchange. AB - Vitamin A has diverse biological functions and is essential for human survival. STRA6 is the high-affinity membrane receptor for plasma retinol binding protein (RBP), the principle and specific carrier of vitamin A (retinol) in the blood. It was previously shown that STRA6 couples to lecithin retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP-I), but poorly to CRBP-II, for retinol uptake from holo-RBP. STRA6 catalyzes both retinol release from holo RBP, which is responsible for its retinol uptake activity, and the loading of free retinol into apo-RBP, which can cause retinol efflux. Although STRA6 catalyzed retinol efflux into apo-RBP can theoretically deplete cells of retinoid, it is unclear to what extent this efflux happens and in what context. We show here that STRA6 can couple strongly to both CRBP-I and CRBP-II for retinol efflux to apo-RBP. Strikingly, pure apo-RBP can cause almost complete depletion of retinol taken up by CRBP-I in a STRA6-dependent manner. However, if STRA6 encounters both holo-RBP and apo-RBP (as in blood), holo-RBP blocks STRA6 mediated retinol efflux by competing with apo-RBP's binding to STRA6 and by counteracting retinol efflux with influx. We also found that STRA6 catalyzes efficient retinol exchange between intracellular CRBP-I and extracellular RBP, even in the presence of holo-RBP. STRA6's retinol exchange activity may serve to refresh the intracellular retinoid pool. This exchange is also a previously unknown function of CRBP-I and distinguishes CRBP-I from LRAT. PMID- 22815071 TI - Calcium and phosphatidylserine inhibit lipid electropore formation and reduce pore lifetime. AB - Molecular dynamics simulations of electroporation of homogeneous phospholipid bilayers show that the pore creation time is strongly dependent on the magnitude of the applied electric field. Here, we investigated whether heterogeneous bilayers containing phospholipids with zwitterionic and anionic headgroups exhibit a similar dependence. To facilitate this analysis we divide the life cycle of an electropore into several stages, marking the sequence of steps for pore creation and pore annihilation (restoration of the bilayer after removal of the electric field). We also report simulations of calcium binding isotherms and the effects of calcium ions on the electroporation of heterogeneous lipid bilayers. Calcium binding simulations are consistent with experimental data using a 1:2 Langmuir binding isotherm. We find that calcium ions and phosphatidylserine increase pore creation time and decrease pore annihilation time. For all systems tested, pore creation time was inversely proportional to the bilayer internal electric field. PMID- 22815072 TI - Nitric oxide mediates TNF-alpha-induced apoptosis in the auditory cell line. AB - OBJECTIVES/HYPOTHESIS: Tumor necrosis factor-alpha (TNF-alpha) is released in a variety of pathological states in the inner ear. Inducible nitric oxide synthase (iNOS) can be induced by cytokines and other inflammatory factors, and is generally thought to be associated with inflammation and other pathological processes in the cochlea. The purpose of the present study was to reveal that TNF alpha could induce apoptosis in the auditory cell line and to investigate the role of nitric oxide (NO) in TNF-alpha-induced auditory cell death. STUDY DESIGN: Experimental study. METHODS: UB-OC1 cells and zebrafish were exposed to TNF alpha. Flow cytometry, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP biotin nick end labeling (TUNEL) assay, assay of mitochondrial membrane potential (MMP), and electron microscopy were used to show that TNF-alpha could induce apoptosis. Western blot was used to measure iNOS expression and mitogen-activated protein kinase pathway. RESULTS: Flow cytometric analysis, TUNEL assay, MMP, and electron microscopy all demonstrated that TNF-alpha could induce apoptosis in UB OC1 cells. TNF-alpha significantly increased NO generation and iNOS expression. Pretreatment with iNOS blocker NG-methyl-L-arginine (NMA) attenuated TNF-alpha induced cell death and caspase-3 activation. Also, TNF-alpha treatment increased p-p38 and p-ERK, and pretreatment of NMA reduced this increased expression of p p38 and p-ERK. CONCLUSIONS: TNF-alpha can induce apoptosis in the auditory cell line, and NO production in response to TNF-alpha is essential for apoptosis. PMID- 22815074 TI - BMP-2 tethered hydroxyapatite for bone tissue regeneration: coating chemistry and osteoblast attachment. AB - The goal of this study was to determine the effectiveness of using polyethyleneimine (PEI) and a polyethylene glycol (PEG) tether to bind human recombinant bone morphogenetic protein-2 (rhBMP-2) to hydroxyapatite (HAp) to enhance rhBMP-2 loading, alter its release properties, and enhance cellular interaction with the material. By using a branched PEI that was derived to express free thiols, rhBMP-2 was coated onto dense HAp surfaces at ~43 ng/cm(2). Using this novel attachment methodology, it was observed that the PEI-SH coating did not change the morphology of the HAp surfaces and that the amount of rhBMP-2 loaded was comparable to a direct adsorption method. In addition, it was also observed that the PEI and PEG tether significantly retained the rhBMP-2 to the HAp surface, inhibiting the burst release effect. Using human fetal osteoblast cells, the PEI- and PEG-tethered BMP-2 was also observed to increase cellular attachment by 10-fold when compared with uncoated HAp and adsorbed rhBMP-2. It was concluded from this study that PEI and PEG tether significantly reduce the initial burst release effect of rhBMP-2. It was also concluded that the rhBMP-2 conjugation to PEI and PEG tether promoted an increase in cellular attachment to the HAp surface. PMID- 22815076 TI - Funding boost is weak effort. PMID- 22815077 TI - Disease modifying drugs targeting beta-amyloid. AB - At this time there are no effective methods to alter the disease course in Alzheimer's disease. All FDA approved interventions are for symptomatic relief only. However, it is an exciting time as many agents in development have theorhetical potential to impact the disease course. This review discusses some of the agents that have been in clinical trials, particularly those that affect amyloid processing. Some agents have failed while others still provide hope. Since amyloid is the peptide most closely linked to disease pathogenesis, it is possible that some of the anti-amyloid agents will impact the disease progression in a meaningful way. PMID- 22815078 TI - STAM protocol in dementia: a multicenter, single-blind, randomized, and controlled trial. AB - BACKGROUND: The Sound Training for Attention and Memory in Dementia (STAM-Dem) is a manualized music-based protocol designed to be used in the rehabilitation of cognitive functions in elderly patients with dementia (PWD). METHOD: This was a multicenter, single-blind, randomized, and controlled trial that involved 51 PWD. The objective was to test the STAM-Dem efficacy. Patients in the experimental group followed the STAM-Dem for 2 weekly sessions of 45 minutes for 12 weeks (in addition to standard care). Those in the control group continued with the normal "standard care" provided. RESULTS: In the experimental group, the instruments immediate prose memory test (MPI), deferred prose memory test (MPD), attentional matrices, activities of daily living, Music Therapy Activity Scale (SVAM) and Geriatric Music Therapy Profile (GMP) increase significantly from pre to post test (P < .05). CONCLUSION: The protocol is feasible and data suggest that there was an effect on attentino (matrices) and prose memory skills (MPI and MPD). The effect size reveals a general improvement in the results of the experimental group. PMID- 22815079 TI - Anticholinesterase-induced symptoms improved by pacemaker implantation in patients with Alzheimer's disease: analysis of 6 cases. AB - Herein we describe 6 cases of patients with Alzheimer's disease presented with syncope, dizziness, and dyspnea soon after the initiation of cholinesterase inhibitor therapy. All patients had bradyarrhythmia on electrocardiogram (ECG). Two patients had complete atrioventricular block, 2 pateints had 2/1 type atrioventricular block, 1 patient had sinus bradycardia and hypersensitive carotid sinus syndrome, and 1 had sick sinus syndrome. All these patients were treated with pacemaker implantation and the cholinesterase inhibitor therapy continued. At 13-month follow-up, no syncope, dizziness, or dyspnea was reported. PMID- 22815080 TI - APOE genotype in the diagnosis of Alzheimer's disease in patients with cognitive impairment. AB - BACKGROUND: Although an association between the apolipoprotein E (APOE) epsilon4 allele and increased risk of Alzheimer's disease (AD) is established, the utility of APOE genotyping in the clinical diagnosis of AD is still under investigation. METHODS: Medical records of 89 patients with cognitive impairment and APOE genotype data underwent a retrospective review. RESULTS: Comparison of age, age at onset, education, Mini-Mental State Examination, months of follow-up, and family history of dementia did not reveal statistical difference among the patients with different APOE genotypes. The APOE epsilon4 carriers had a higher percentage of AD diagnoses after a median 16 months follow-up than non-APOE epsilon4 carriers. The APOE epsilon4 designation had a high sensitivity and high positive predictive value for the diagnosis of AD but a low negative predictive value and specificity. CONCLUSIONS: The APOE genotyping may be helpful in diagnosing AD especially in patients presenting with atypical features or early age of onset of dementia. PMID- 22815081 TI - Reorientation deficits are associated with amnestic mild cognitive impairment. AB - BACKGROUND/AIMS: Spatial memory can be impaired in amnestic mild cognitive impairment (aMCI). The present study investigates categorical spatial memory deficits using a virtual navigation-based reorientation task. METHODS: Twenty eight amnestic single domain and 23 amnestic multiple domain patients were compared with 53 healthy elderly controls on the performance of the virtual reorientation test (VReoT). RESULTS: The reorientation performance of participants in both aMCI groups was significantly worse than that of controls suggesting that VReoT detects spatial memory deficits. No significant difference emerged between the 2 groups of patients. A subsequent receiver-operating characteristic analysis showed that a score of 8 had a sensitivity of 80.4% and a specificity of 94.3% (area under the curve = 0.90). CONCLUSION: The VReoT seemed to be accurate in differentiating patients with aMCI from controls and may represent an evaluation supplement for spatial memory deficits in prodromal stages of Alzheimer's dementia. PMID- 22815082 TI - Development of an instrument to measure attitudes of physical therapy providers working with people with dementia. AB - BACKGROUND AND PURPOSE: This study investigated the factor structure of an instrument to measure attitudes and beliefs of how physical therapist (PT) practitioners perceive working with people with a dementia disorder. METHODS: A survey was mailed to every skilled nursing facility in Indiana (n = 495) for completion by a PT or physical therapist assistant. The survey was developed and included whether the severity of Alzheimer's disease (AD) impacts the attitudes of physical therapy practitioners. RESULTS: Of the 12 attitudinal questions, 11 were significant (P < .001) concerning how the severity of a diagnosis of AD (early, middle, and late) impacts attitudes of people in physical therapy practice. Principal component analysis identified 3 factors with Eigen values of 3.3 or higher accounting for 43% of the cumulative variance. These factors include professional competence, resources, and conscientiousness. CONCLUSION: This brief instrument could serve as an assessment tool to determine whether PT practitioners exhibit therapeutic nihilism when working with people with a dementia disorder. PMID- 22815083 TI - Anosognosia: patients' distress and self-awareness of deficits in Alzheimer's disease. AB - We aimed to study how patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) suffer from awareness of their deficits. Self-awareness was assessed using the Anosognosia Questionnaire for Dementia in 12 pairs of MCI outpatients and caregivers, 23 with mild AD, and 18 with moderate AD. The discrepancy between patient's and caregiver's evaluation (anosognosia) became greater as AD progressed. The predictors of patients' distress, shown by multiple linear regression analyses, were awareness of decline in intellectual or social functioning; self-awareness of deficits in remembering appointments in MCI; in remembering appointments, writing, mental calculation, and understanding the newspaper in mild AD; and in mental calculation and doing clerical work in moderate AD. Caregivers assumed the predictors of patients' distress differently: awareness of deterioration of memory in MCI and mild AD, and basic activities of daily living in moderate AD. Understanding patients' disability from patients' perspective is required for successful care. PMID- 22815084 TI - Validation of noninvasive body sensor network technology in the detection of agitation in dementia. AB - OBJECTIVE: Agitated behaviors are one of the most frequent reasons that patients with dementia are placed in long-term care settings. This study aims to validate the ability of a custom Body Sensor Network (BSN) to capture the presence of agitation against currently accepted subjective measures, the Cohen-Mansfield Agitation Inventory (CMAI) and the Aggressive Behavior Scale (ABS) and to discriminate between agitation and cognitive decline. METHODS: Six patients identified as being at high risk for agitated behaviors were enrolled in this study. The devices were applied at three sites for three hours while behaviors were annotated simultaneously and subsequently repeated twice for each enrolled subject. RESULTS: We found that the BSN was a valid measure of agitation based on construct validity testing and secondary validation using non-parametric ANOVAs. DISCUSSION: The BSN shows promise from these pilot results. Further testing with a larger sample is needed to replicate these results. PMID- 22815086 TI - Sources of uncertainty in cancer survivorship. AB - PURPOSE: Previous research has demonstrated the common experience of illness related uncertainty; however, little research has explored the specific sources of uncertainty throughout cancer survivorship. The purpose of this study is to investigate the experience of uncertainty for cancer survivors and their partners. Thus, the following research question is posed: What are the sources of uncertainty in cancer survivorship for survivors and partners? METHOD: One-on-one interviews were conducted with 35 cancer survivors and 25 partners. Constant comparative methodologies were used to analyze the data. RESULTS: Participants described medical, personal, and social sources of uncertainty that persisted throughout survivorship. Medical sources of uncertainty included questions about the cancer diagnosis, treatment and prognosis. Personal sources of uncertainty included ambiguous valued identities and career-related questions. Social sources of uncertainty included unclear communicative, relational and familial consequences of illness. CONCLUSION: Survivors and partners in this study experienced uncertainty that persisted long after the completion of cancer treatment. The participants also described sources of uncertainty unique to this illness context. These results have important implications for health care providers and intervention developers and imply that chronic uncertainty should be managed throughout survivorship. IMPLICATIONS FOR CANCER SURVIVORS: The sources of uncertainty described in the current study have important implications for cancer survivors' management of uncertainty. Cancer survivors and their family members must first know the common sources of uncertainty to adaptively adjust to an uncertain survivorship trajectory. The present investigation provides insight into the uncertainty experiences of cancer survivors and implies that continued care may improve well-being after the completion of cancer treatment. PMID- 22815088 TI - Reply: To PMID 22422600. PMID- 22815087 TI - Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca(2+) -permeable TRPC6 channels. AB - The standardized extract of the St. John's wort plant (Hypericum perforatum) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na(+) concentration through the activation of nonselective cationic TRPC6 channels. TRPC6 channels are also Ca(2+) -permeable, resulting in intracellular Ca(2+) elevations. Indeed, hyperforin activates TRPC6-mediated currents and Ca(2+) transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of nerve growth factor. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca(2+) transients and depolarizing inward currents sensitive to the TRPC channel blocker La(3+) , thus resembling the actions of the neurotrophin brain-derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John's wort are mediated by a mechanism similar to that engaged by BDNF. PMID- 22815090 TI - Atypical forms of the osmotic demyelination syndrome. AB - Osmotic demyelination syndrome (ODS) is the damage over the central nervous system caused by several electrolytes, metabolic and toxic disorders. We aimed to describe cases of unusual forms of ODS. In a 9-year period, 25 consecutive patients with ODS (15 men; mean age 42 years) were registered in our referral institution, among them, four (16 %) with atypical neuroimaging findings were abstracted for this communication. None of them presented cardiorespiratory arrest, head trauma, seizures, neuromyelitis optica spectrum or contact with toxic chemicals. Case 1 was a 33-year-old alcoholic man without hypertension or electrolyte imbalance, who presented a classic central pontine myelinolysis (CPM) and a hemorrhage within the pons. Case 2 was a 34-year-old alcoholic man with hypoglycemia and hyponatremia who presented CPM and diffuse bihemispheric extrapontine myelinolysis (EPM) after correction of serum sodium. Case 3 was a 52 year-old woman with mild hypokalemia and hyponatremia (inadequately corrected), who presented a peduncular and cerebellar EPM. Case 4 was a 67-year-old woman who had a suicidal attempt with antidepressants and carbamazepine without impaired consciousness, who complicated with mild hyponatremia associated with a classical CPM and a spinal cord EPM. Case 2 died and the rest remained with variable neurological impairments at last follow-up visit. With modern neuroimaging, the so-called atypical forms of ODS may not be as rare as previously thought; however, they could have a more adverse outcome than the classical ODS. PMID- 22815089 TI - Endogenous inhibitor proteins that connect Ser/Thr kinases and phosphatases in cell signaling. AB - Protein phosphatase activity acts as a primary determinant of the extent and duration of phosphorylation of cellular proteins in response to physiological stimuli. Ser/Thr protein phosphatase-1 (PP1) belongs to the PPP superfamily, and is associated with regulatory subunits that confer substrate specificity, allosteric regulation, and subcellular compartmentalization. In addition, all eukaryotic cells contain multiple heat-stable proteins that originally were thought to inhibit phosphatase catalytic subunits released from the regulatory subunits, as a fail-safe mechanism. However, discovery of C-kinase-activated PP1 inhibitor, Mr of 17 kDa (CPI-17) required fresh thinking about the endogenous inhibitors as specific regulators of particular phosphatase complexes, acting in addition to, not instead of, regulatory subunits. The cellular actions of the endogenous inhibitors are controlled by phosphorylation, connecting them to kinase pathways. More recent progress has unveiled additional functions of PP1 inhibitor-2 (I-2), including regulation of protein kinases. Transcriptional mechanisms govern the expression levels of CPI-17 in response to stimuli. If true for other inhibitor proteins, they have the potential of being diagnostic markers for pathological conditions. We discuss specific examples of PP1 inhibitor proteins regulating particular cellular functions and the rationale for incorporating phosphatase inhibitor proteins in development of new therapeutic strategies. PMID- 22815091 TI - A messy reality: an analysis of New Zealand's elective surgery scoring system via media sources, 2000-2006. AB - Waiting lists for elective procedures are a characteristic feature of tax-funded universal health systems. New Zealand has gained a reputation for its 'booking system' for waiting list management, introduced in the early-1990s. The New Zealand system uses criteria to 'score' and then 'book' qualifying patients for surgery. This article aims to (i) describe key issues focused on by the media, (ii) identify local strategies and (iii) present evidence of variation. Newspaper sources were searched (2000-2006). A total of 1199 booking system stories were identified. Findings demonstrate, from a national system perspective, the extraordinarily difficult nature of maintaining overall control and coordination. Equity and national consistency are affected when hospitals respond to local pressure by reducing access to elective treatment. Findings suggest that central government probably needs to be closely involved in local-level management and policy adjustments; that through the study period, the New Zealand system appears to have been largely out of the control of government; and that governments elsewhere may need to be cautious when considering developing similar systems. Developing and implementing scoring and booking systems may always be a 'messy reality' with unintended consequences and throwing regional differences in service management and access into stark relief. PMID- 22815092 TI - Aortico-left ventricular tunnel: the elusive diagnosis. AB - We present a case of an infant prenatally diagnosed with bilateral outflow-tract obstruction and severe aortic regurgitation who underwent cardiac transplantation at 45 days of life. Aortico-left ventricular tunnel was subsequently diagnosed on pathologic examination of the explant heart. Aortico-left ventricular tunnel is a rare congenital cardiac malformation and can remain undiagnosed if the clinician has a low level of suspicion. Aortico-left ventricular tunnel should be considered in any fetus or newborn with aortic regurgitation. PMID- 22815094 TI - Left-dominant double aortic arch in critical pulmonary stenosis and ventricular septal defect. PMID- 22815093 TI - Maternal environmental exposure, infant GSTP1 polymorphism, and risk of isolated congenital heart disease. AB - The GSTP1 gene, highly expressed early in fetal life, is the most abundant phase 2 xenobiotic metabolism enzyme in a human placenta. Fetal inherited GSTP1 Ile105Val polymorphism may modify the metabolism and excretion of xenobiotics from fetal tissue and increase the risk of congenital heart disease (CHD). This study aimed to analyze the joint effects of GSTP1 genetic polymorphism (Ile105Val) and maternal environmental exposure on CHD risk. Within a case control design, a total of 190 children with CHD (104 boys age 4 +/- 5.6 years) and 190 healthy children (114 newborn boys) were genotyped for the GSTP1 Ile105Val polymorphism. Mothers completed a structured questionnaire on the demographics as well as the preconceptional and lifestyle exposures. A higher frequency of mothers of children with CHD (38 %) reported a positive history of exposure to toxicants (occupational and environmental) than mothers of healthy children (23 %) (p = 0.0013). Logistic regression analysis showed that maternal occupational and environmental exposures increased the risk of CHD (odds ratio, 2.6; 95 % confidence interval, 1.6-4.2; p < 0.0001). No significant differences in Ile105Val genotype frequencies were observed between the children with CHD and the healthy children (p = 0.9). Furthermore, case-control analysis showed no evidence of significant interaction between the maternal exposures and GSTP1 polymorphism. Maternal exposure to toxicants increased the risk of children with CHD. However, fetal GSTP1 Ile105Val polymorphism did not increase the risk of CHD. PMID- 22815095 TI - Retrosigmoid approach to cerebellopontine angle tumor resection: surgical modifications. PMID- 22815096 TI - Measuring worksite health promotion programs: an application of structural equation modeling with ordinal data. AB - This paper presents a model for measuring the outcome of Worksite Health Promotion Programs through an application of Structural Equation Modeling with ordinal data. We model the function "being healthy" as a vector comprised of three latent or unobservable variables: Health Status, Lifestyle and Stress. Each variable can be measured only indirectly through a set of manifest or observable ordinal indicators. The objective is to derive and analyze the distributions, and changes in distributions over time, of the latent variables on an individual level. The model is analyzed empirically on data from three large Swedish manufacturing firms. PMID- 22815097 TI - How to use pharmacy claims data to measure patient nonadherence? The example of oral diabetics in therapy of type 2 diabetes mellitus. AB - INTRODUCTION: The purpose of this study was to describe the methodological framework underlying nonadherence (NA) measurement based on pharmacy claims data, its quantitative impact on the results of NA studies, and to identify those methodological categories most likely to explain diabetes-related clinical outcomes. We use the example of oral antidiabetics in the treatment of diabetes mellitus type 2; 113,108 patients derived from a German statutory health insurance fund were analyzed. METHODS: We identified 12 methodological categories as pervasive features in pharmacy claims data based NA analyses. The influence of the different methodological categories and their parameters on analysis results was tested using sensitivity analysis. To validate alternative methodological framework options, we performed multivariate logistical regression estimates using diabetes-related hospitalization/clinical events as a combined dichotomized dependent variable. RESULTS: The choice of parameters within the identified 12 methodological categories available has exceptional impact on the results of pharmacy data based claims NA analyses. When the full range of theoretically possible cases is considered in our sample, it can be seen that the resulting NA range is between 15.7% and 97.0%. The definition of the required daily dose, the decision to use either a prescription-/interval-based approach, and the classes of medication analyzed exert a notable influence on the study results. In our analysis, 69.4% of the 216 different study design options analyzed significantly explain the likelihood of diabetes-related clinical events. CONCLUSIONS: We recommend strongly that methodological transparency is awarded a much more important role in the conduct of NA analyses made on the basis of pharmacy claims data. PMID- 22815098 TI - The cost-effectiveness of treating chronic hepatitis B patients in a median endemic and middle income country. AB - BACKGROUND/AIMS: Chronic hepatitis B (CHB) infection is a serious public health problem due to its potential liver disease sequelae and highly expensive medical costs such as the need for liver transplantation. The aim of this study was to quantify the burden of active CHB in terms of mortality and morbidity, the eligibility of antiviral treatment and to assess various treatment scenarios and possible salvage combinations for cost-effectiveness. METHODS: A population cohort from a large data base of chronic hepatitis B patients was constructed and stratified according to 10-year age groups, the prevalence of HBsAg, HBV DNA level, ALT level, HBeAg status and the presence of cirrhosis. An age-specific Markov model for disease progression and cost-effectiveness analysis was constructed and calibrated for the specific population setting. RESULTS: Of about 3.2 million estimated HBsAg carriers, 25% are eligible for treatment. If the active cohort remains untreated, 31% will die due to liver related complications. Within a 20-year period, 11% will have developed decompensated cirrhosis, 12% liver cancer and 6% will need liver transplantation. Quality adjusted life years (QALYs) for the no treatment scenario ranged from 9.3 to 14.0. For scenarios with antiviral treatment, QALYs ranged from 9.9 to 14.5 for lamivudine, 13.0-17.5 for salvage therapy, and 16.6-19.0 for the third generation drugs entecavir and tenofovir. CONCLUSION: In a country with considerable amount of active CHB patients, monotherapy with a highly potent third generation drug has the most health-gain, and is cost-effective in both HBeAg-positive and negative in all stages of liver disease. PMID- 22815099 TI - Competition in prescription drug markets: the roles of trademarks, advertising, and generic names. AB - We take on two subjects of controversy among economists-advertising and trademarks-in the context of the market for generic drugs. We outline a model in which trademarks for drug names reduce search costs but increase product differentiation. In this particular framework, trademarks may not benefit consumers. In contrast, the generic names of drugs or "International Nonproprietary Names" (INN) have unquestionable benefits in both economic theory and empirical studies. We offer a second model where advertising of a brand-name drug creates recognition for the generic name. The monopoly patent-holder advertises less than in the absence of a competitive spillover. PMID- 22815100 TI - Dispersive liquid-liquid microextraction of organophosphorous pesticides using nonhalogenated solvents. AB - Dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography and mass spectrometry (GC-MS) was applied to the determination of five organophosphorous pesticides (OPPs) in water samples. The analytes included in this study were prophos, diazinon, chlorpyrifos methyl, fenchlorphos, and chlorpyrifos. The use of nonhalogenated solvents (cyclohexane, heptane, and octane) as extraction solvents was investigated using acetone, acetonitrile, or methanol, as dispersion solvents. The combination of less polar dispersion solvents (1-propanol and 2-propanol) and nonhalogenated extraction solvents was also studied in dispersive liquid-liquid microextraction for the first time. Several experimental conditions were tested (nature and volume of extraction solvents, nature and volume of dispersion solvents, salting-out effect) and the corresponding enrichment factors and recoveries were evaluated. The best microextraction condition was obtained using 50 MUL of cyclohexane and 0.3 mL of 1-propanol. The detection and quantification limits were in the low ppt range, with values between 3.3-8.0 ng/L and 11.0-26.6 ng/L, respectively. Relative standard deviations were between 6.6 and 13.1% for a fortification level of 500 ng/L. At the same fortification level, the relative recoveries (RR) of Alvito's dam water, Judeu's river water, and well water samples were in the range of 50.3 97.1%. PMID- 22815101 TI - Young adults' experience of living with neurofibromatosis type 1. AB - Neurofibromatosis Type 1 (NF1) may have many psychosocial consequences for affected adults. More knowledge is needed about the experience of psychosocial aspects in different stages of adulthood. This qualitative study aims to describe the experiences and concerns of persons living with NF1 in the early stages of adulthood. In semi-structured interviews, Norwegian adults with NF1 (n = 15) between 18 and 37 years of age described their experiences and concerns. Interview transcripts were analysed in a both concept and data driven way. Severity of NF1 was assessed from interview data. Our data indicate that many informants have more friends than in childhood, including friends with NF1. An important topic is whether or not to inform others about the NF1 diagnosis . Low self-confidence is common, often related to early school failure and bullying or to visible neurofibromas. The unpredictable development of NF1 causes much concern. The experience of NF1's impact seems less associated with the assessed severity than with social network, relation to the labour market, and psychological factors. PMID- 22815102 TI - Autophagy as a macrophage response to bacterial infection. AB - The macrophage is a key component of host defense mechanisms against pathogens. In addition to the phagocytosis of bacteria and secretion of proinflammatory mediators by macrophages, autophagy, a process involved in turnover of cellular material, is a recently identified component of the immune response to bacterial infection. Despite the bactericidal effect of autophagy, some species of intracellular bacteria are able to survive by using one or more strategies to avoid host autophagic attack. Here, we review the latest findings on the interactions between bacteria and autophagy in macrophages. PMID- 22815103 TI - Dyslexia in a second language?-a dynamic test of reading acquisition may provide a fair answer. AB - Dyslexia is hard to diagnose in a second language. Poor performance on a test of reading may be caused by poor language proficiency in the second language or by limited schooling rather than by poor reading ability per se. This confound was supported in a study of 88 adult second language learners and 65 native language speakers. The incidence of dyslexia in the second language learners varied widely depending on the measure of reading. In order to reduce language and schooling confounds, a dynamic test of acquisition of basic decoding ability was developed. In the dynamic test, participants are taught three novel letters and to synthesise the letter sounds into new words. Results from the study indicated that the dynamic test provided results in accordance with the current IDA definition of dyslexia, while significantly reducing the influence second language vocabulary and amount of schooling. With the dynamic measure, the same cut-off point between dyslexic and non-dyslexic performance appeared valid in both native language speakers and second language learners. PMID- 22815105 TI - Knowledge foundations for beginning reading teachers in EFL. AB - This study examined the knowledge that teachers need in order to become successful early reading teachers in English as a foreign language. The findings showed that in-service teachers had better content knowledge than pre-service teachers, although the results indicated overall low performance and insufficiently developed concepts about the structure of language, spelling rules, and academic terminology in both groups. PMID- 22815104 TI - Identifying students with dyslexia in higher education. AB - An increasing number of students with dyslexia enter higher education. As a result, there is a growing need for standardized diagnosis. Previous research has suggested that a small number of tests may suffice to reliably assess students with dyslexia, but these studies were based on post hoc discriminant analysis, which tends to overestimate the percentage of systematic variance, and were limited to the English language (and the Anglo-Saxon education system). Therefore, we repeated the research in a non-English language (Dutch) and we selected variables on the basis of a prediction analysis. The results of our study confirm that it is not necessary to administer a wide range of tests to diagnose dyslexia in (young) adults. Three tests sufficed: word reading, word spelling and phonological awareness, in line with the proposal that higher education students with dyslexia continue to have specific problems with reading and writing. We also show that a traditional postdiction analysis selects more variables of importance than the prediction analysis. However, these extra variables explain study-specific variance and do not result in more predictive power of the model. PMID- 22815106 TI - Evidence for a preserved sensitivity to orthographic redundancy and an impaired access to phonological syllables in French developmental dyslexics. AB - To evaluate the orthographic and phonological processing skills of developmental dyslexics, we (a) examined their abilities to exploit properties of orthographic redundancy and (b) tested whether their phonological deficit extends to spelling to-sound connections for large-grain size units such as syllables. To assess the processing skills in dyslexics, we utilized the illusory conjunction paradigm to investigate the nature of reading units in French dyslexic and control children matched in reading age. In control children, reading units were defined by both orthographic redundancy and phonological syllable information. In dyslexics, however, reading units were defined only by orthographic redundancy. Therefore, despite their impairment in reading acquisition, developmental dyslexics have the ability to encode and exploit letter frequency co-occurrences. In contrast, their access to phonological syllables from letters was impaired, suggesting that their phonological deficit extends to large grain-size phonological units. PMID- 22815107 TI - Do diagnosis-related groups explain variations in hospital costs and length of stay? Analyses from the EuroDRG project for 10 episodes of care across 10 European countries. PMID- 22815108 TI - How well do diagnosis-related groups explain variations in costs or length of stay among patients and across hospitals? Methods for analysing routine patient data. AB - We set out an analytical strategy to examine variations in resource use, whether cost or length of stay, of patients hospitalised with different conditions. The methods are designed to evaluate (i) how well diagnosis-related groups (DRGs) capture variation in resource use relative to other patient characteristics and (ii) what influence the hospital has on their resource use. In a first step, we examine the influence of variables that describe each individual patient, including the DRG to which the patients are assigned and a range of personal and treatment-related characteristics. In a second step, we explore the influence that hospitals have on the average cost or length of stay of their patients, purged of the influence of the variables accounted for in the first stage. We provide a rationale for the variables used in both stages of the analysis and detail how each is defined. The analytical strategy allows us (i) to identify those factors that explain variation in resource use across patients, (ii) to assess the explanatory power of DRGs relative to other patient and treatment characteristics and (iii) to assess relative hospital performance in managing resources and the characteristics of hospitals that explain this performance. PMID- 22815109 TI - Patient classification and hospital costs of care for acute myocardial infarction in nine European countries. AB - This study contributes to the literature on the performance of diagnosis-related groups (DRGs) for acute myocardial infarction (AMI) patients by evaluating in nine countries the factors--in addition to DRGs--that affect costs or length of stay and comparing the variation that can be explained with or without DRGs. We evaluate whether the existing DRGs for AMI patients would benefit from additional patient-related and treatment-related factors that are found in administrative data across countries. In most countries, the set of patient and quality variables performed better than the DRG variables. Our results suggest that DRG systems in all countries could be improved by including additional explanatory factors or by refining the existing DRGs. Our results suggest that for AMI and possibly for other related episodes, a refinement of DRGs to include information on patient severity, procedures and levels of complications could improve the ability of DRGs to explain resource use. It seems possible to improve DRG-like hospital payment systems through the inclusion of episode-specific variables. PMID- 22815110 TI - How well do diagnosis-related groups for appendectomy explain variations in resource use? An analysis of patient-level data from 10 European countries. AB - Appendectomy is a common and relatively simple procedure to remove an inflamed appendix, but the rate of appendectomy varies widely across Europe. This paper investigates factors that explain differences in resource use for appendectomy. We analysed 106,929 appendectomy patients treated in 939 hospitals in 10 European countries. In stage 1, we tested the performance of three models in explaining variation in the (log of) cost of the inpatient stay (seven countries) or length of stay (three countries). The first model used only the diagnosis-related groups (DRGs) to which patients were coded, the second model used a core set of general patient-level and appendectomy-specific variables, and the third model combined both sets of variables. In stage two, we investigated hospital-level variation. In classifying appendectomy patients, most DRG systems take account of complex diagnoses and comorbidities but use different numbers of DRGs (range: 2 to 8). The capacity of DRGs and patient-level variables to explain patient-level cost variation ranges from 34% in Spain to over 60% in England and France. All DRG systems can make better use of administrative data such as the patient's age, diagnoses and procedures, and all countries have outlying hospitals that could improve their management of resources for appendectomy. PMID- 22815111 TI - How well do diagnosis-related group systems group breast cancer surgery patients? Evidence from 10 European countries. AB - We analysed patient-level data (n = 72,235) from 563 hospitals in 10 European countries to assess the ability of national diagnosis-related group (DRG) systems to account for patient-level variation in cost or lengths of stay of breast cancer surgery patients against a standard set of patient characteristics, treatment and quality variables. We find that European DRG systems use very different types of classification variables and numbers of DRGs (range: 3-7) to classify these patients. In 6 of 10 countries, the set of patient characteristics, treatment and quality variables, which we were able to define across countries, perform better than the set of national DRGs in accounting for patient-level variation in resource consumption. Moreover, there appear to be factors that are consistently significant determinants of cost/length of stay of breast cancer surgery cases but are not, or at least not fully, considered in European DRG systems. Our results therefore raise concerns as to whether all systems rely on the most appropriate classification variables. In several countries, policymakers should reevaluate the appropriateness of their DRG algorithm for breast cancer surgery and of specific DRG weights. PMID- 22815112 TI - Diagnosis related groups and variations in resource use for child delivery across 10 European countries. AB - Childbirth is one of the main causes of hospitalisation for women, accounting for about 5% of hospital activity in most Organisation for Economic Co-operation and Development countries. We analysed the factors that explain variations in resource use for child delivery in ten European countries. We compared the performance of three models for explaining the variations in resource use (log cost or length of inpatient stay) at patient and hospital level. The first model used only the DRGs to which child deliveries were coded (M(D) ), the second used a set of 'patient-level' and delivery specific explanatory variables (M(P) ), and the third model combined both sets of variables (M(F) ). Countries vary both in the number of DRGs and the criteria used to classify cases of child delivery (range: 3-8) and in the percentage of deliveries classified as 'delivery without complication' (range: 53-90%). The capacity of DRGs and patient level variables to explain cost variation for child birth ranges from 48% in Sweden to over 70% in Spain. There is room for improving current DRG classification in most countries, but this does not necessary imply multiplying the groups and/or complicating criteria. Countries with a higher number of DRGs do not always perform better. PMID- 22815113 TI - DRGs in Europe: a cross country analysis for cholecystectomy. AB - Cholecystectomy is the surgical removal of the gallbladder. It is the most common method for treating symptomatic gallstones. Despite the existence of well established treatment guidelines, the rate of cholecystectomy varies widely across Europe. We analyse patients in 10 countries that had undergone surgery for the treatment of symptomatic gallstones. We test the performance of three models in explaining variation in the (log of) cost of the inpatient stay (seven countries) or length of stay (three countries). The first model includes only the diagnosis-related group (DRG) variables to which cholecystectomy patients were coded (M(D)), the second uses a core set of patient characteristics and episode specific explanatory variables (M(P)), and finally, the third model combines both sets of variables (M(F)). Countries vary both in the number of DRGs used to classify cholecystectomy patients (range: 2-8), and in the percentage of patients covered by a single DRG (range: 50%-92%). The ability of combining both DRGs and patient level variables to explain cost variation among patients ranges from 58% in Spain to over 81% in Finland. The comparison of models' performance suggests that incorporating relevant patient characteristics may significantly improve DRG systems. PMID- 22815114 TI - Why do patients having coronary artery bypass grafts have different costs or length of stay? An analysis across 10 European countries. AB - We analyse variations in cost or length of stay (LoS) for 66,587 patients from 10 European countries receiving a coronary artery bypass graft (CABG) procedure. In five of these countries, variations in cost are analysed using log-linear models. In the other five countries, negative binomial regression models are used to explore variations in LoS. We compare how well each country's diagnosis-related group (DRG) system and a set of patient-level characteristics explain these variations. The most important explanatory factors are the total number of diagnoses and procedures, although no clear effects are evident for our CABG specific diagnostic and procedural variables. Wound infections significantly increase LoS and costs in most countries. There is no evidence that countries using larger numbers of DRGs to group CABG patients are better at explaining variations in cost or LoS. However, refinements to the construction of DRGs to group CABG patients might recognise first and subsequent CABGs or other specific surgical procedures, such as multiple valve repair. PMID- 22815115 TI - Performance of 10 European DRG systems in explaining variation in resource utilisation in inguinal hernia repair. AB - By classifying hospital output into groups of patients with similar clinical characteristics and resource requirements, diagnosis-related groups (DRGs) are designed to be highly correlated with resource utilisation. Using a two-stage approach to control for variation within and between hospitals, we examine the ability of the diverse DRG systems in 10 European countries to explain variability in resource utilisation (costs or length of stay, LoS) for hospital patients undergoing surgical repair of inguinal hernia. Our national regression results suggest that DRGs are statistically significant in explaining cost/LoS variation in the absence of any other regressors and generally remain so in most countries when patient-level characteristics are added to the model. However patient-level characteristics, including those used in DRG assignment, are usually also statistically significant. In nine countries, where the number of relevant DRGs ranges from two (Poland) to seven (France), the inclusion of patient-level characteristics substantially improves model goodness-of-fit compared with that attained with DRGs alone. Only in Sweden is the converse true. If our analysis raises some concerns over the adequacy of DRGs to explain cost/LoS variation in inguinal hernia repair in nine of the 10 European countries, further research is required to consider whether future enhancements may be necessary. PMID- 22815116 TI - Do diagnosis-related groups appropriately explain variations in costs and length of stay of hip replacement? A comparative assessment of DRG systems across 10 European countries. AB - This paper assesses the variations in costs and length of stay for hip replacement cases in Austria, England, Estonia, Finland, France, Germany, Ireland, Poland, Spain and Sweden and examines the ability of national diagnosis related group (DRG) systems to explain the variation in resource use against a set of patient characteristic and treatment specific variables. In total, 195,810 cases clustered in 712 hospitals were analyzed using OLS fixed effects models for cost data (n=125,698) and negative binominal models for length-of-stay data (n=70,112). The number of DRGs differs widely across the 10 European countries (range: 2-14). Underlying this wide range is a different use of classification variables, especially secondary diagnoses and treatment options are considered to a different extent. In six countries, a standard set of patient characteristics and treatment variables explain the variation in costs or length of stay better than the DRG variables. This raises questions about the adequacy of the countries' DRG system or the lack of specific criteria, which could be used as classification variables. PMID- 22815117 TI - Patient classification systems and hospital costs of care for knee replacement in 10 European countries. AB - Knee replacement is a common surgical procedure performed to relieve pain and disability from degenerative osteoarthritis. This study evaluates the ability of ten European diagnosis-related group (DRG) systems to explain variations in costs or in length of stay for knee replacements. We assessed three different models in predicting variation of cost and length of stay. The first model, M(D), included only DRG groups as explanatory variables; the second, M(P), used a set of patient level variables; and the third, M(F), included all variables from both M(D) and M(P). The total number of DRGs used to group knee replacement is low, ranging from two to six. All DRG systems except one differentiate between primary knee replacement and revision surgery. Considerable differences exist in the rate of revision surgery. There is also high variation in mean cost (from ? 3809 to ? 8158) and in mean length of stay (LoS) (from 4.2 to 13.6 days). The explanatory power of DRGs varies from 21.5 to 72.5% with values of around 40% in most countries of the study. Findings suggest that DRG systems could be enhanced either by the inclusion of patient-level variables, by the use of measures of clinical outcome or by improving cost and administrative information. PMID- 22815118 TI - Patient classification and hospital costs of care for stroke in 10 European countries. AB - Stroke is a major cause of death and disability around the world, and the care of stroke patients ties up a great amount of resources in healthcare systems. Stroke severity and the given care may vary substantially between patients, and there is remarkable variation in both the costs and length of stay (LoS) of stroke patients. Using patient level data from 10 European countries on costs and LoS, we explored the ability of the diagnosis-related group (DRG) systems to explain variance in the costs and length of stay of stroke patients. In addition, we evaluated whether the existing DRGs for stroke patients would benefit from additional patient-related and treatment-related factors that are commonly found in the administrative databases across countries. Cost analyses were run using OLS fixed effects models, and LoS analyses with negative binomial models. The descriptive statistics showed that the stroke patients differ remarkably across countries. Large variations in the classification of stroke patients raise concerns about whether all systems rely on the most appropriate classification variables. In all the countries, the DRG classifications' performance could be improved with the introduction of the patient characteristics analysed here. PMID- 22815119 TI - Biomechanics and pathomechanisms of osteoarthritis. AB - Today, the most frequent chronic musculoskeletal disorder and the leading cause of disability in the elderly is osteoarthritis (OA). Approximately 43 million people in the United States and 15% of the world population are affected. Due to demographic changes, the incidence of OA is rapidly increasing, leading to an ascending socioeconomical and personal burden. Despite the exact cause of OA remains unknown, the pathogenic role of biomechanical dysfunction in OA is well established. For weight-bearing joints altered loading mechanisms, increased mechanical forces and changed biomechanics are significant contributing factors for initiation and progression of OA. Thus, OA is a disease of the whole joint, including muscles, tendons, ligaments, synovium and bone. This review focuses on the influence of biomechanics on the pathogenesis and progression of OA. We notably illustrate the pathological bioreactivity of soft tissues, subchondral bone and joint inflammation. Procedures, conservative or surgical, which actively alter the biomechanics of the lower limb, are promising strategies to treat symptoms as well as to influence disease progression in OA. PMID- 22815120 TI - Intraportal transplantation of human bone marrow mesenchymal stem cells in pigs with fulminant hepatic failure. PMID- 22815121 TI - Construction and hemocompatibility study of highly bioactive heparin functionalized surface. AB - A simple method is developed to construct anticoagulant surfaces via passive adsorption of heparin onto the protonated plasma-polymerized allylamine (PPAam) films from phosphate-buffered saline (PBS). These protonated PPAam surfaces are found to have high affinity to heparin. Importantly, the heparin-functionalized PPAam (Hep-PPAam) surfaces show good retention of heparin after long-term immersion in PBS. The Hep-PPAam surface prolongs the activated partial thromboplastin time for about 20 s as compared to 316L stainless steel even though the adsorption amount of heparin is only about 300 ng/cm(2). This indicates that the heparin bound to the protonated PPAam surfaces in this way maintains a high bioactivity. Blood platelet adhesion and activation on this surface is remarkably reduced and adsorption and activation of fibrinogen is inhibited. Thus, Hep-PPAam surface modification leads to a significant improve of the hemocompatibility. PMID- 22815122 TI - In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen. AB - The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlusTM. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l ( 1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID- 22815123 TI - Radionuclide therapy beyond radioiodine. AB - For decades, Iodine-131 has been used for the treatment of patients with thyroid cancer. In recent years, increasingly, other radiopharmaceuticals are in clinical use in the treatment of various malignant diseases. Although in principle these therapies-as in all applications of radionuclides-special radiation protection measures are required, a separate nuclear medicine therapy department is not necessary in many cases due to the lower or lack of gamma radiation. In the following article, four different radionuclide therapies are more closely presented which are emerging in the last years. One of them is the "Peptide Receptor Radionuclide Therapy," the so-called PRRT in which radiolabeled somatostatin (SST)-receptor(R) ligands are used in patients with neuroendocrine tumors. On the basis of radiolabeled antibodies against CD20-positive cells, the so-called radioimmunotherapy is used in the treatment of certain forms of malignant lymphoma. In primary or secondary liver tumors, the (90)Y-labeled particles can be administered. Last but not the least, the palliative approach of bone-seeking radiopharmaceuticals is noted in patients with painful bone metastases. PMID- 22815124 TI - The role of nuclear medicine in differentiated thyroid cancer. AB - In differentiated thyroid cancer (DTC) nuclear medicine is able to cover the spectrum from diagnosis and treatment to follow up keeping patient's management in one institution. Nowadays, DTC is often diagnosed per chance, presenting as small indolent nodule diagnosed on routinely performed ultrasound. Ultrasound and ultrasonography-guided fine-needle aspiration biopsy together with scintigraphy are probably the most adequate tools for diagnosis. After thyroidectomy, treatment with iodine-131 is routinely performed in a nuclear medicine therapy institution as a standard procedure in most of the cases with regard to histology. In case of iodine positive metastases, repeated therapies can be performed in order to reduce tumour burden. In the follow up of DTC thyroglobulin (tumour marker), ultrasound and diagnostic whole body scan are established procedures. With the development of SPECT/CT and PET/CT ((18)F-FDG, (68)Ga somatostatin receptor) combining functional and anatomic imaging the nuclear medicine spectrum has further increased. PMID- 22815125 TI - Intra-arterial dantrolene for refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Intravenous dantrolene has been used to prevent and treat cerebral vasospasm. We report a case of refractory cerebral vasospasm treated with intra arterial dantrolene after aneurysmal subarachnoid hemorrhage. METHODS: A 56-year old woman suffered a diffuse subarachnoid hemorrhage from a ruptured anterior communicating artery aneurysm which was successfully treated with coil embolization. She subsequently developed bilateral severe angiographic vasospasm which was treated with intra-arterial vasodilators. However, owing to the recurrence of vasospasm, intra-arterial dantrolene followed by balloon angioplasty was used. RESULTS: There was moderate improvement of the severe vasospasm in bilateral A1 segments of the anterior cerebral arteries after microcatheter-based intra-arterial infusion of 30 ml (1 mg/ml) dantrolene. Patient's hemodynamic parameters were monitored during and after the procedure and no significant changes were seen after dantrolene infusion. A follow up cerebral angiogram after 1 day demonstrated the persistence of therapeutic effect. CONCLUSION: Intra-arterial dantrolene induced a sustained improvement in cerebral vasospasm secondary to ruptured aneurysm. No significant side effects were observed during or after the infusion of the drug. PMID- 22815126 TI - Depression as a risk factor for dementia and mild cognitive impairment: a meta analysis of longitudinal studies. AB - BACKGROUND: This study examined whether depression was a risk factor for onset of dementia including Alzheimer's disease (AD), vascular dementia (VD) and any dementia, and mild cognitive impairment (MCI) by using a quantitative meta analysis of longitudinal studies. METHODS: EMBASE and MEDLINE were searched for articles published up to February 2011. All studies that examined the relationship between depression and the onset of dementia or MCI were included. Pooled relative risk was calculated using fixed-effects models. RESULTS: Twelve studies met our inclusion criteria for this meta-analysis. All subjects were without dementia or MCI at baseline. Four, two, five, and four studies compared the incidence of AD, VD, any dementia, and MCI between subjects with or without depression, respectively. After pooling all the studies, subjects with depression had higher incidence of AD (relative risk (RR):1.66, 95% confidence interval (CI): 1.29-2.14), VD (RR: 1.89, 95% CI: 1.19-3.01), any dementia (RR: 1.55, 95% CI: 1.31-2.83), and MCI (RR: 1.97, 95% CI: 1.53-2.54) than those without depression. CONCLUSIONS: The quantitative meta-analysis showed that depression was a major risk factor for incidence of dementia (including AD, VD, and any dementia) and MCI. PMID- 22815128 TI - Rationale for regenerative treatment in neonatology. PMID- 22815127 TI - Bearing the brunt: co-workers' experiences of work reintegration processes. AB - PURPOSE: Work disability research has found co-worker support to be a significant but under-recognised aspect of work reintegration (WR) processes. Although co workers work alongside returning workers, their practical contribution to WR success or failure is often invisible to others. This study aimed to gain further insight into the role and contribution of co-workers in WR interventions. METHOD: An exploratory qualitative pilot study was conducted in Toronto, Canada in 2011. Three focus groups were conducted with 13 co-workers, recruited for their direct experience of 'working alongside' a returning worker. An iterative data gathering and analysis process occurred. Themes were generated from categories in open ended interview questions and new issues arising from the data. FINDINGS: The findings detail co-workers' practical experiences of WR processes and their reflections on social and work conditions that impacted their participation. Co workers' capacity to support returning workers was related to the quality of the WR arrangements, the relationship with the returning worker, work culture, and the duration of the required support. Workplace privacy and confidentiality requirements were identified as a key challenge for co-worker participation. The effects on co-workers of WR processes ranged from the opportunity to learn new skills to disillusionment and withdrawal from the workplace. In worst case scenarios, 'ripple effects' including emotional distress, physical injury and termination of co-workers' employment had occurred. CONCLUSION: Co-workers are not a neutral party in WR procedures. Formalizing the co-worker role to include communication, consideration and recognition might improve co-workers' WR experiences. PMID- 22815129 TI - Oxygen saturation in pulse oximetry in hemoglobin anomalies. AB - Pulse oximetry is an essential diagnostic method in pediatric emergency medicine and pediatric intensive care. However, if undetected hemoglobin anomalies are the underlying cause measurements of low oxygen saturation can be interpreted incorrectly or may lead to unnecessary examinations. In 2 recently discovered hemoglobin anomalies, Hb Bonn and Hb Venusberg, this resulted in extensive and repeat cardiopulmonary examinations. This review aims to provide an overview of hemoglobin anomalies causing low oxygen saturation.We describe the methods required for differential diagnosis of hemoglobin anomalies, such as hemoglobin electrophoresis, High Performance Liquid Chromatography, hemoglobin gene sequencing and spectral photometry, and the difficulties with the interpretation of results. Furthermore, with a review of the literature we provide an extensive overview of hemoglobin anomalies which result in low oxygen saturation measurement in pulse oximetry. With the examples of Hb Bonn, a novel hemoglobin mutation of the proximal alpha1-globin, which results in false low pulse oximetry measurements of oxygen saturation, and Hb Venusberg, a low oxygen-affine hemoglobin mutation of the beta-globin, we highlight the difficulties arising from the respective case histories.In pediatric medicine, hemoglobin anomalies must be included in the diagnosis as a possible underlying cause of low oxygen saturation in case of ambiguous or conflicting pulse oximetry findings. PMID- 22815130 TI - Is measuring oxidative stress, inflammation and tissue damage induced by intravenous iron in a non-clinical model relevant to clinical practice? PMID- 22815131 TI - Anaphylaxis in children: current understanding and key issues in diagnosis and treatment. AB - Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. Since it is unpredictable and potentially fatal, prompt recognition and treatment are vital to maximize a positive outcome. The occurrence of anaphylaxis is increasing across all ages in the United States, with increased risk of worse outcome in teenagers/young adults and in those with comorbid conditions such as asthma. Gaps in the assessment of patient-specific risk factors, identification and prevention of triggers, recognition of signs/symptoms, and pharmacologic treatment of anaphylaxis have been identified at the physician and caregiver/patient level. A PubMed literature search (January 2000-December 2011) was conducted to identify publications on childhood anaphylaxis using the following terms: food allergy, food allergens, food hypersensitivity, epinephrine, epinephrine auto-injectors, anaphylactic triggers, and anaphylaxis. This review will critically appraise these key issues and highlight strategies that might result in improved management of anaphylaxis in children. PMID- 22815133 TI - The impact of cognitive deficit on self-reported car crashes in ultra octogenarian population: data of an Italian population-based study. AB - OBJECTIVE: To examine the usefulness of specific neurocognitive tests for predicting the crash involvement in ultra-octogenarian population. METHODS: A total of 800 subjects (mean age 82.4 + 3.1 years) underwent a battery of neuropsychological tests. Global intellectual functioning was assessed using the Mini Mental State Examination, mental flexibility and information processing speed were assessed using the Trail Making Test parts A and B (TMT-A and TMT-B), long-term memory was evaluated with the short story, and visuo-spatial skills were tested with Clock Drawing Test. One year after this evaluation, 343 (43%) participants have been interviewed by a telephone call to know if they were currently driving and if they had a car crash during this period. RESULTS: Two hundred ninety-seven subjects had their driving license renewed and completed the follow-up 1 year after. Data shows that less than 11% of this group had a car crash during the first year of observation (Crash Involved). Older subjects involved in a car crash showed significant worse performances on TMT-B (TMT-B pathological Crash Involved vs. Noncrash Involved 47% vs. 27%; p = 0.02) and on short story (short story pathological Crash Involved vs. Noncrash Involved 19% vs. 5%; p = 0.02). CONCLUSIONS: Trail Making test B and short story have been demonstrated to provide a predictive value of driving performance of older people. Therefore, we suggest that a simple and standardized battery of neuropsychological tests, lasting about 30 min and administered by an experienced staff, is a good diagnostic instrument for risk prevention of driving activity of older drivers. PMID- 22815132 TI - Deciphering the role of malin in the lafora progressive myoclonus epilepsy. AB - Lafora disease (LD) is a fatal, autosomal recessive neurodegenerative disorder that results in progressive myoclonus epilepsy. A hallmark of LD is the accumulation of insoluble, aberrant glycogen-like structures called Lafora bodies. LD is caused by mutations in the gene encoding the E3 ubiquitin ligase malin or the glucan phosphatase laforin. Although LD was first described in 1911, its symptoms are still lacking a consistent molecular explanation and, consequently, a cure is far from being achieved. Some data suggest that malin forms a functional complex with laforin. This complex promotes the ubiquitination of proteins involved in glycogen metabolism and misregulation of pathways involved in this process results in Lafora body formation. In addition, recent results obtained from both cell culture and LD mouse models have highlighted a role of the laforin-malin complex in the regulation of endoplasmic reticulum stress and protein clearance pathways. These results suggest that LD should be considered as a novel member of the group of protein clearance diseases such as Parkinson's, Huntington's, or Alzheimer's, in addition to being a glycogen metabolism disease. Herein, we review the latest results concerning the role of malin in LD and attempt to decipher its function. (c) 2012 IUBMB IUBMB Life, 64(10): 801-808, 2012. PMID- 22815135 TI - Child-Pugh score is altered by the albumin measurement method. PMID- 22815134 TI - Mercury concentrations in hair from neonatal and juvenile Steller Sea Lions (Eumetopias jubatus): implications based on age and region in this northern Pacific marine sentinel piscivore. AB - Mercury is a global contaminant of concern for the fetus and the neonate of piscivores. Methylmercury, produced within marine ecosystems, is of particular concern as a readily absorbed neurotoxicant transported across the blood brain barrier and transplacentally. In the North Pacific Ocean, Steller sea lions are broadly distributed apex predators and, as such, integrate complex food webs and the associated exposure and possible adverse effects of toxic and infectious agents. Hair, including lanugo, was examined using regional and age groupings to assess mercury concentrations in young Alaskan Steller sea lions. The highest concentrations of mercury occurred in the youngest animals, likely via in utero exposure. Based on the adverse developmental outcomes of methylmercury toxicity this specific cohort is of concern. Regionally, higher concentrations of mercury were observed in the endangered western population of Steller sea lions and mirrored patterns observed in human biomonitoring studies of Alaskan coastal communities. These data have broader implications with respect to human and ecosystem health as Steller sea lions rely on similar prey species and foraging areas as those targeted by commercial fisheries and subsistence users and are therefore valuable sentinels of marine ecosystem health. PMID- 22815136 TI - The AQC database represents a useful tool for quality control and scientific analysis of acute appendicitis. AB - PRINCIPLES: To ensure a high quality of care in surgery, many surgical departments in Switzerland are members of the working group for quality assurance in surgery (AQC). The purpose of this study was to assess the value of the AQC database as a tool for quality assurance and a source for scientific studies. We had two hypotheses. Firstly that the percentage of laparoscopic appendectomies would have increased over time without an increase in the complication rate and secondly that these procedures would primarily have been performed by residents. METHODS: All appendectomies performed at the Kantonsspital Olten between 2001 and 2006 were prospectively recorded in the AQC database. RESULTS: 684 appendectomies were performed. We recorded a clear increase in the use of laparoscopic interventions from 51 to 81%. Ninety three percent of these appendectomies were performed by residents or junior faculty members. The main complication were surgical site infection in 3.6% of the open procedures as compared to none in laparoscopic procedures (p <0.001). Intra-abdominal abscess formation was recorded in 2.7% of laparoscopic procedures as compared to 1.8% in open surgery (p = 0.608). The overall complication rate in the study was 5.4% with no statistical difference between open (6.5%) and laparoscopic (4.7%) surgery (p = 0.305). CONCLUSIONS: The study clearly shows that the AQC-database offers a wide variety of possibilities for quality assurance and scientific analyses. Our data demonstrate that laparoscopic procedures clearly increased from 2001 to 2006. Appendectomies were mainly performed by residents and junior faculty members. Laparoscopic appendectomy is a safe procedure with a low complication rate and should be applied as a teaching operation during the surgical training. PMID- 22815137 TI - Sorafenib combined with locoregional therapy prior to liver transplantation for hepatocellular carcinoma: an update on a previous case report. PMID- 22815138 TI - Physical properties, mechanical behavior, and electron microscopy study of a new alpha-TCP block graft with silicon in an animal model. AB - This study reports the characterization process and in vivo application of a new block bone graft of alpha-TCP with silicate in three different percentages in the aim of determining the influence of the silicate. Three groups of cylindrical implants (6 +/- 0.01 mm diameter, 8 +/- 0.01 mm length) with varying Si composition were studied: A: 3 wt % C(2) S; B: 1.5 wt % C(2) S; C: 100 wt % TCP-0 wt % C(2) S. These were implanted randomly in critical size defects in New Zealand rabbits. X-ray diffraction analysis was performed to determine the crystalline phases of the different compositions. Histomorphometric analysis produced one measurement of bone-to-implant contact. Comparing the alpha-TCPss ceramics, the trial found improved mechanical properties due to the silicon content in solid solution as well as densification. Previous studies have shown that the mechanical strengths of sintered ceramics correlate to densification as well as grain size and mechanical properties. Because of its mechanical and biological behavior, the study has shown alpha-TCP with C(2) S to be an alternative to other bone graft substitutes for use in bone reconstructive surgery in the fields of veterinary, medicine, and oral and maxillofacial surgery. PMID- 22815139 TI - Time-lapse microscopy of macrophages during embryonic vascular development. AB - BACKGROUND: Macrophages are present before the onset of blood flow, but very little is known about their function in vascular development. We have developed a technique to concurrently label both endothelial cells and macrophages for time lapse microscopy using co-injection of fluorescently conjugated acetylated low density lipoprotein (AcLDL) and phagocytic dye PKH26-PCL. RESULTS: We characterize double-labeled cells to confirm specific labeling of macrophages. Double-labeled cells circulate, roll along the endothelium, and extravasate from vessels. Most observed macrophages are integrated into the vessel wall, showing an endothelial-like morphology. We used transgenic quail that express a fluorescent protein driven by the endothelial-specific promoter Tie1 in conjugation with the phagocytic dye to analyze these cells. Circulating PKH26-PCL labeled cells are mostly Tie1-, but those which have integrated into the vessel wall are largely Tie1+. The endothelial-like phagocytic cells were generally stationary during normal vascular development. We, therefore, induced vascular remodeling and found that these cells could be recruited to sites of remodeling. CONCLUSIONS: The active interaction of endothelial cells and macrophages support the hypothesis that these cells are involved in vascular remodeling. The presence of phagocytic endothelial-like cells suggests either a myeloid-origin to certain endothelial cells or that circulating endothelial cells/hematopoietic stem cells have phagocytic capacity. PMID- 22815140 TI - Tuberculous cerebellar abscess in a child--role of 1H-magnetic resonance spectroscopy. PMID- 22815142 TI - Dopaminergic therapies modulate the T-CELL proteome of patients with Parkinson's disease. AB - Dopamine receptor agonists and L-dihydroxyphenylalanine (L-DOPA) counteract dopamine loss in the striatum and are therefore used in the treatment of Parkinson's disease (PD). T-Lymphocytes express some features of the dopaminergic system, and their function or activation might be regulated by dopaminergic treatments. Two-dimensional electrophoresis of total protein extract from T lymphocytes was performed to identify therapy-induced proteome changes in T-cells of 17 patients with PD. Specific protein level alterations were further validated by Western blotting. Of 17 enrolled patients, 11 were treated with different doses of L-DOPA; in this group, we found that the levels of two spots, corresponding to ATP synthase subunit beta and proteasome subunit beta type-2, correlated linearly with the L-DOPA daily dose. Moreover, we identified seven proteins (prolidase, actin-related protein 2, F-actin-capping protein subunit beta, tropomyosin alpha-3 chain, proteasome activator complex subunit 1, peroxiredoxin 6, and a glyceraldehyde-3-phosphate dehydrogenase isoform) whose levels were significantly different in patients treated with dopamine agonists. These findings demonstrate that dopaminergic stimulation has important effects on T-cell proteome in patients under long-term treatment. Therefore, therapies acting on the dopaminergic system may have additional effects on the immune system. PMID- 22815141 TI - Breast cancer survival in the US and Europe: a CONCORD high-resolution study. AB - Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment. PMID- 22815143 TI - A new massively parallel version of CRYSTAL for large systems on high performance computing architectures. AB - Fully ab initio treatment of complex solid systems needs computational software which is able to efficiently take advantage of the growing power of high performance computing (HPC) architectures. Recent improvements in CRYSTAL, a periodic ab initio code that uses a Gaussian basis set, allows treatment of very large unit cells for crystalline systems on HPC architectures with high parallel efficiency in terms of running time and memory requirements. The latter is a crucial point, due to the trend toward architectures relying on a very high number of cores with associated relatively low memory availability. An exhaustive performance analysis shows that density functional calculations, based on a hybrid functional, of low-symmetry systems containing up to 100,000 atomic orbitals and 8000 atoms are feasible on the most advanced HPC architectures available to European researchers today, using thousands of processors. PMID- 22815144 TI - [Not Available]. PMID- 22815145 TI - Development and application of a double-antigen sandwich enzyme-linked immunosorbent assay for detection of antibodies to porcine circovirus 2. AB - A double-antigen sandwich enzyme-linked immunosorbent assay (ELISA) is described for detection of porcine circovirus 2 (PCV2) antibodies using the well characterized recombinant PCV2 capsid protein. In a comparative test of 394 pig sera against an indirect immunofluorescence (IIF) test and a commercial ELISA kit (also based on the recombinant PCV2 capsid protein), the results showed that the diagnostic sensitivity, specificity, and accuracy of the assay were, respectively, 90.61, 94.02, and 91.62% compared with IIF and 94.38, 95.28, and 94.67% compared with the commercial ELISA kit. Assay of 12 PCV-free pigs over a 5 week period produced only PCV2-negative titers by all 3 methods. These results and the seroprofiles of 4 pig farms obtained by both the commercial ELISA kit and the double-antigen sandwich ELISA indicate that the sandwich ELISA is a reliable method for detection of antibodies to PCV2. Additionally, the method described here permits the use of undiluted test serum samples simultaneously loaded with horseradish peroxidase (HRP)-conjugated antigen into the test well, and the complete test procedure can be performed in less than 90 min. This double-antigen sandwich ELISA should be a useful tool to aid swine industry professionals in deciding the intervention strategies for the control of PCV2-associated diseases. PMID- 22815146 TI - Migration of the swine influenza virus delta-cluster hemagglutinin N-linked glycosylation site from N142 to N144 results in loss of antibody cross reactivity. AB - Routine antigenic characterization of swine influenza virus isolates in a high throughput serum neutralization (HTSN) assay found that approximately 20% of isolates were not neutralized by a panel of reference antisera. Genetic analysis revealed that nearly all of the neutralization-resistant isolates possessed a seasonal human-lineage hemagglutinin (HA; delta cluster). Subsequent sequencing analysis of full-length HA identified a conserved N144 residue present only in neutralization-resistant strains. N144 lies in a predicted N-linked glycosylation consensus sequence, i.e., N-X-S/T (where X is any amino acid except for proline). Interestingly, neutralization-sensitive viruses all had predicted N-linked glycosylation sites at N137 or N142, with threonine (T) occupying position 144 of HA. Consistent with the HTSN assay, hemagglutination inhibition (HI) and serum neutralization (SN) assays demonstrated that migration of the potential N-linked glycosylation site from N137 or N142 to N144 resulted in a >8-fold decrease in titers. These results were further confirmed in a reverse genetics system where syngeneic viruses varying only by predicted N-glycosylation sites at either N142 or N144 exhibited distinct antigenic characteristics like those observed in field isolates. Molecular modeling of the hemagglutinin protein containing N142 or N144 in complex with a neutralizing antibody suggested that N144-induced potential glycosylation may sterically hinder access of antibodies to the hemagglutinin head domain, allowing viruses to escape neutralization. Since N-linked glycosylation at these sites has been implicated in genetic and antigenic evolution of human influenza A viruses, we conclude that the relocation of the hemagglutinin N-linked glycosylation site from N142 to N144 renders swine influenza virus delta-cluster viruses resistant to antibody-mediated neutralization. PMID- 22815147 TI - Evaluation of an enzyme-linked immunosorbent assay based on crude Leishmania histone proteins for serodiagnosis of human infantile visceral leishmaniasis. AB - Human visceral leishmaniasis (VL) is routinely diagnosed by detecting IgG that specifically binds to Leishmania antigens. The enzyme-linked immunosorbent assay (ELISA) remains a widely used method. However, the biggest challenge remains the choice of antigen with the highest specificity and sensitivity. This study is aimed at assessing the diagnostic performances of crude Leishmania histone (CLH) protein-based ELISAs in Mediterranean VL patients. The CLH proteins were biochemically purified from promastigote nuclear extracts. Their reactivities were analyzed by Western blotting (WB) using rabbit polyclonal antibodies against Leishmania recombinant histones and sera from VL patients, respectively. Then, the diagnostic potential of CLH proteins was validated by the CLH-based ELISA using 42 infantile VL patients' sera and 70 control subjects. The CLH-based ELISA performance was compared to that of the soluble Leishmania antigen (SLA)- and the recombinant K39 (rK39)-based ELISAs. Analysis of the WB profile with the use of polyclonal antibodies confirmed the histone origin of low molecular mass proteins (12 to 16 kDa). All VL samples tested presented antibodies reacting against different antigen fractions; however, recognition patterns were different depending on the reactivity of each serum. CLH-based ELISA showed an excellent ability to discriminate between VL cases and healthy controls (97.6% sensitivity and 100% specificity). It had a diagnostic performance similar to that of rK39 based ELISA (97.6% sensitivity and 97.1% specificity, P = 0.5) and a better serodiagnosis accuracy than the SLA-based ELISA (85.7% sensitivity and 90% specificity, P < 0.05). Therefore, crude Leishmania histone extract could be a valuable antigen for clinical use. PMID- 22815148 TI - Direct human papillomavirus E6 whole-cell enzyme-linked immunosorbent assay for objective measurement of E6 oncoproteins in cytology samples. AB - A novel, whole-cell enzyme-linked immunosorbent assay (ELISA) based on a non-type specific anti-human papillomavirus (HPV) E6 antibody was tested on 182 residual cytological specimens. For samples with a designation of more severe than cervical intraepithelial neoplasia grade 3 (CIN3+), 83% tested positive for E6; in a subset with paired testing for E6 ELISA and HPV DNA, 72% tested E6 positive and 92% tested high-risk (HR)-HPV DNA positive (P = 0.2). Among the women with a less than CIN3 diagnosis, 31% and 47% tested positive for E6 and HR-HPV DNA, respectively (P = 0.0006). PMID- 22815149 TI - The pH-sensitive fusogenic 3-methyl-glutarylated hyperbranched poly(glycidol) conjugated liposome induces antigen-specific cellular and humoral immunity. AB - We examined the ability of a novel liposome, surface modified by 3-methyl glutarylated hyperbranched poly(glycidol) (MGlu-HPG), to enhance antigen-specific immunity in vitro and in vivo and to function as a vaccine carrier. Murine bone marrow-derived dendritic cells took up ovalbumin (OVA) encapsulated in MGlu-HPG modified liposomes more effectively than free OVA or OVA encapsulated in unmodified liposomes. Immunization of mice with OVA-containing MGlu-HPG-modified liposomes induced antigen-specific splenocyte proliferation and production of gamma interferon (IFN-gamma) more strongly than did immunization with free OVA or OVA encapsulated in unmodified liposomes. The immune responses induced by OVA encapsulated in MGlu-HPG-modified liposomes were significantly suppressed by addition of anti-major histocompatibility complex (MHC) class I and class II monoclonal antibodies, indicating the involvement of antigen presentation via MHC class I and II. Furthermore, delayed-type hypersensitivity responses and OVA specific antibodies were induced more effectively in mice immunized with OVA encapsulated by MGlu-HPG-modified liposomes than with unencapsulated OVA or OVA encapsulated in unmodified liposomes. These results suggested that MGlu-HPG modified liposomes effectively induced both cell-mediated and humoral immune responses. Collectively, this study is the first to demonstrate the induction of both cell-mediated and humoral immune responses in vivo by MGlu-HPG-modified liposomes. PMID- 22815150 TI - Device for carrying blood samples at 37 degrees C for cryoglobulin test. AB - To reliably transport blood samples for cryoglobulin analysis, we have created a sample transport device containing a mixture of two waxes that solidifies at 38 degrees C and maintains sample temperature at 38 degrees C. Samples arriving at the laboratory at 37 to 38 degrees C increased to 95% from 34% with the use of the device. PMID- 22815151 TI - Intestinal and systemic immune development and response to vaccination are unaffected by dietary (1,3/1,6)-beta-D-glucan supplementation in neonatal piglets. AB - Infants are susceptible to infections in early life and must rely on their innate immune system for protection. beta-Glucans potentiate immune responses. Therefore, we evaluated the influence of purified yeast (1,3/1,6)-beta-d-glucan (Wellmune WGP, here referred to as WGP) on the development of the gastrointestinal tract and the intestinal and systemic immune systems in neonatal piglets. Piglets were fed formula containing 0 (control), 1.8, 18, or 90 mg WGP/kg body weight (BW) and were vaccinated against human influenza. Piglets were euthanized at 7 or 21 days of age. Piglet weight and small intestinal length and weight were unaffected by dietary WGP. In addition, WGP did not affect ileal crypt depth, villus height, or ascending colon cuff depth. Immune parameters not affected by WGP supplementation included T cell phenotypes, cytokine gene expression, and cell proliferation. However, vaccination and developmental effects were seen. Overall, the doses of 1.8, 18, and 90 mg/kg BW of dietary WGP had no effect on intestinal or immune development and did not improve the antibody response to vaccination in neonatal piglets. PMID- 22815153 TI - Carotid artery stenting. AB - Atherosclerotic narrowing (stenosis) of the internal carotid artery accounts for about 10-15% of ischaemic strokes. Carotid endarterectomy (CEA) reduces the risk of stroke in patients with symptomatic stenosis and - to a lesser degree - with asymptomatic carotid stenosis. Endovascular treatment including balloon angioplasty and carotid artery stenting (CAS) has emerged as an alternative to CEA to treat carotid stenosis. The present review summarises the existing evidence on risks and benefits of CAS in comparison with CEA, with a focus on evidence from randomised clinical trials. Across all randomised trials, CEA was associated with a lower risk of peri-procedural stroke or death than CAS, while CAS had lower risks of myocardial infarction, cranial nerve palsy and access site haematoma. The increased stroke risk with CAS is mainly observed in elderly patients; therefore, CAS appears to be a safe option to CEA in younger patients. In the first few years following treatment, both procedures are equally effective in preventing ipsilateral recurrent strokes. Nevertheless, long-term follow-up of ongoing trials must be awaited to investigate whether a potential increase in recurrent stenosis following CAS might limit the long-term effectiveness in stroke prevention. The optimal treatment for asymptomatic carotid stenosis remains to be determined in ongoing clinical trials. PMID- 22815152 TI - Structural and immunological analysis of anthrax recombinant protective antigen adsorbed to aluminum hydroxide adjuvant. AB - New anthrax vaccines currently under development are based on recombinant protective antigen (rPA) and formulated with aluminum adjuvant. Because long-term stability is a desired characteristic of these vaccines, an understanding of the effects of adsorption to aluminum adjuvants on the structure of rPA is important. Using both biophysical and immunological techniques, we compared the structure and immunogenicity of freshly prepared rPA-Alhydrogel formulations to that of formulations stored for 3 weeks at either room temperature or 37 degrees C in order to assess the changes in rPA structure that might occur upon long-term storage on aluminum adjuvant. Intrinsic fluorescence emission spectra of tryptophan residues indicated that some tertiary structure alterations of rPA occurred during storage on Alhydrogel. Using anti-PA monoclonal antibodies to probe specific regions of the adsorbed rPA molecule, we found that two monoclonal antibodies that recognize epitopes located in domain 1 of PA exhibited greater reactivity to the stored formulations than to freshly prepared formulations. Immunogenicity of rPA-Alhydrogel formulations in mice was assessed by measuring the induction of toxin-neutralizing antibodies, as well as antibodies reactive to 12-mer peptides spanning the length of PA. Mice immunized with freshly prepared formulations developed significantly higher toxin-neutralizing antibody titers than mice immunized with the stored preparations. In contrast, sera from mice immunized with stored preparations exhibited increased reactivity to nine 12-mer peptides corresponding to sequences located throughout the rPA molecule. These results demonstrate that storage of rPA-Alhydrogel formulations can lead to structural alteration of the protein and loss of the ability to elicit toxin neutralizing antibodies. PMID- 22815154 TI - A retrospective study of SBRT of metastases in patients with primary sarcoma. AB - We retrospectively reviewed the results of stereotactic body radiotherapy (SBRT) in 46 patients with a total of 136 metastases from primary sarcoma. The purpose of this study was to evaluate the overall response rate and side effects of SBRT in metastatic sarcoma. The patients were treated at Karolinska University Hospital between 1994 and 2005, using 3D conformal multifield technique and a stereotactic body-frame. Prescribed doses ranged from 4 to 20 Gy per fraction in 1-5 fractions, with total doses of 10-48 Gy. All 46 patients were diagnosed with a primary sarcoma. The treated metastases were localized mainly in the lungs. A total number of 136 metastases were treated (1-14 per patient). Overall response rate (local control = CR, PR and SD) for each tumour was 88 % (119/135). Median follow-up was 21.8 months (range 2.7-112.8 months). Thirteen patients (31 %) were long-term survivors (>36 months), and 5 patients are still alive after last follow-up. Two cases of serious non-lethal side effects were seen, one patient had a colon perforation and another patient had contracture of the hip region. SBRT is a safe, convenient and effective non-invasive treatment with high local control for patients with metastatic sarcoma. PMID- 22815155 TI - Elevated expression of iASPP in head and neck squamous cell carcinoma and its clinical significance. AB - iASPP is shown to be elevated in several cancers. However, the role of iASPP in head and neck squamous cell carcinoma (HNSCC) remains unknown. We have investigated iASPP expression in HNSCC tissue and cell lines and evaluated its prognostic significance in HNSCC. The expression of iASPP in 109 primary HNSCC tissue specimens was examined by immunohistochemistry and its association with clinicopathological parameters and prognosis was analyzed. Additionally, expression status of iASPP in 16 paired HNSCC tissues and 7 HNSCC cell lines was evaluated by quantitative real-time PCR (qPCR) and immunoblotting. The protein and mRNA expression of iASPP were increased in HNSCC tissues and cell lines. Immunohistochemical staining indicated iASPP was detected in both cytoplasm and nucleus. Importantly, overexpression of cytoplasmic and nuclear iASPP was significantly associated with T classification (p = 0.002 and p = 0.033, respectively), clinical stage (p < 0.001 and p = 0.004), lymph node metastasis (p = 0.001 and p < 0.001), and recurrence (both p < 0.001). Survival analysis demonstrated high iASPP expression significantly correlated with shorter disease free survival (DFS) (both p < 0.001 for cytoplasmic and nuclear expression) and overall survival (OS) (both p < 0.001 for cytoplasmic and nuclear expression). Multivariate analysis revealed that cytoplasmic iASPP was the only independent prognostic factor for HNSCC patients. iASPP expression is elevated in HNSCC tissues and cell lines, which suggests iASPP may contribute to the malignant progression of HNSCC, and serves as a novel prognostic marker and a potential therapeutic target in HNSCC. PMID- 22815156 TI - C-KIT mutations were closely associated with the response to Imatinib in Chinese advanced gastrointestinal stromal tumor patients. AB - To investigate the correlation between C-KIT/PDGFRalpha mutations and Imatinib response or survival in Chinese advanced gastrointestinal stromal tumor (GIST) patients. Clinical data and paraffin-embedded tumor specimens were collected from 158 advanced GIST patients receiving first-line Imatinib. Mutation analyses of C KIT gene (Exons 9, 11, 13, and 17) and PDGFRalpha gene (exons 12 and 18) were performed by PCR amplification and Sanger sequencing. A total of 135 patients harboring C-KIT mutations (exon 11 mutation: 108; exon 9 mutation: 23; exon 13 mutation: 2; exon 17 mutation: 2) and one patients carrying PDGFRalpha mutation (exon 18) were found in this study. Twenty-two patients (13.9 %) with neither C KIT nor PDGFRalpha mutations were named as wild type. The response rate (64.7 vs. 36.4 %, P = 0.000) and median progression-free survival (28 vs. 8 months, P = 0.000) of mutant patients (n = 136) were significantly higher than those of wild type patients (n = 22). Moreover, the response rate and median progression-free survival in patients with exon 11 mutations (n = 108), exon 9 mutations (n = 23), and wild-type patients (n = 22) were 68.5, 47.8, and 36.4 % (P = 0.001), and 31 months, 13 months, and 8 months (P = 0.000), respectively. No significant differences of response rate or median progression-free survival were seen in patients with exon 11 deletion mutations, point mutations, and mixed-type mutations. C-KIT mutations were closely associated with Imatinib response and progression-free survival of Chinese advanced GIST patients. Other predictive markers for Imatinib would be further investigated. PMID- 22815157 TI - The effect of adherens junction components on keratinocyte adhesion in vitro: potential implications for sealing the skin-implant interface of intraosseous transcutaneous amputation prostheses. AB - Amputation places a significant burden on healthcare systems worldwide as patients suffer life-long complications associated with the stump-socket interface. Skin penetrating, osseointegrated implants like intraosseous transcutaneous amputation prostheses, could overcome this, however, they rely on the formation and maintenance of an infection-free seal at the skin-implant interface. Epithelial cell migration around transcutaneous implants creates downgrowth, which leads to infection and implant failure. Epithelial cells form cell-cell attachments via adherens junctions and desmosomes that prevent cell migration via contact inhibition. If epithelial cells formed cell-cell attachments with an implant surface, it could facilitate stronger cell attachment and prevent downgrowth. In adherens junctions, E-cadherin is essential in homotypic cell attachment. In this study, we have demonstrated that cell-cell adherens junctions can be formed on substrates adsorbed with E-cadherin. We have assessed the effects of two E-cadherin peptides and determined an optimal concentration for increasing cell attachment via adherens junctions. We have demonstrated that adsorption of 15 MUg/mL of the full extracellular domain of E cadherin to titanium alloy significantly increases metabolic activity, cell area, and attachment of murine keratinocytes in vitro, with a fourfold increase in attachment via adherens junctions at 24, 48, and 72 h. PMID- 22815159 TI - The relevance of rabies to today's military. PMID- 22815158 TI - Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells. AB - FK866 is a specific inhibitor of NAMPT and induces apoptosis of leukemic cells by depletion of intracellular NAD(+). Since up-regulation of NAMPT is associated with several cases of cancers, including leukemias, we asked whether in leukemic cells inhibition of NAMPT involves p53 pathway. We observed that FK866 induced apoptosis and reduced cell proliferation in NB-4, OCI-AML3 and MOLM-13 cell lines. In contrast, the leukemia cell lines, K-562 and Kasumi, containing nonfunctional p53 were relatively unaffected by FK866 treatment. Importantly, direct inhibition of sirtuins significantly reduced the viability of NB-4, OCI AML3 and MOLM-13 cell lines. Activation of p53 by FK866 involved increased acetylation of p53 at lysine 382 with subsequent increase in the expression of p21 and BAX. Further, knockdown of p53 attenuated the effects of FK866 on apoptosis and cell cycle arrest, which was partly associated with decreased expression of p21 and BAX. Our results suggest the role of p53 acetylation pathway in the anti-leukemic effect of FK866. PMID- 22815160 TI - Vector surveillance to determine species composition and occurrence of trypanosoma cruzi at three military installations in San Antonio, Texas. AB - Chagas disease, also known as American trypanosomiasis, is caused by the hemoflagellate protozoan Trypanosoma cruzi which is transmitted by blood-sucking triatomine bugs (Hemiptera: Reduviidae; Triatominae). The disease is endemic to south Texas, but exists almost exclusively as a zoonosis. Chagas disease has proven to be a serious public health threat to military working dogs. In 2007, seroprevalence of Chagas disease in military working dogs in San Antonio, Texas, reached 8%. A faunal survey was conducted at 3 San Antonio area military installations (Camp Bullis, Fort Sam Houston, and Lackland Air Force Base). A total of 140 triatomines representing 4 species (Triatoma gerstaeckeri, T. sanguisuga, T. lectularia, and T. indictiva) were collected. Trypanosoma cruzi infected bugs were only collected at Lackland Air Force Base, where the overall infection rate was 16%. The wood excavation technique developed during this study collected all life stages. Only 2 life stages (adult and 5th instar) were positive for T. cruzi. PMID- 22815161 TI - A field-expedient method for detection of leptospirosis causative agents in rodents. AB - We have developed a thermal-stable, pathogenic Leptospira TaqMan PCR assay intended to support pathogen surveillance in reservoir populations. The assay is packaged specifically for use with a portable, ruggedized, real-time PCR thermocycler. Limit of detection was established at <= 100 fg (20 organisms). Sensitivity and specificity were 100% concordant with conventional PCR results using a broad test panel of human pathogenic and nonpathogenic Leptospira, genetic near neighbors, and clinically significant organisms. In blind testing using a panel (n=50) of pathogenic Leptospira infected and noninfected Rattus species samples, assay sensitivity results were 100% concordant with conventional PCR. Tests performed under field conditions using wild-collected rodent kidney extracts demonstrated the mobility of the system. During field evaluation, samples were processed and analyzed in 3 hours. Thermal stabilized reagents allowed transportation, storage, and analyses under ambient temperatures. The system provides a promising aid in leptospirosis control programs. PMID- 22815162 TI - Military entomology in Operation Enduring Freedom, 2010-2011. PMID- 22815163 TI - A rapid and inexpensive bioassay to evaluate the decontamination of organophosphates. AB - An inexpensive and rapid bioassay using adult red flour beetles was developed for use in assessing the decontamination of environments containing organophosphates and related chemicals. A decontamination protocol was developed which demonstrated that 2 to 3 applications of 5% bleach solution were required to obtain nearly complete decontamination of malathion. The bioassay was also used to screen common household cleaners as potential decontaminating agents, but only 5% bleach was effective at improving survival of insects on steel plates treated with 25% malathion. A toxic degradation product (malaoxon) was detected using gas chromatography/mass spectrophotometry; this toxin affected the decontamination efficacy and resulted in continued toxicity to the beetles until subsequent decontaminations. The bioassay provides evidence to support the use of red flour beetles as a sensitive, less expensive method for determining safety levels of environments contaminated with malathion and other toxins, and may have application in the study of chemical warfare agents. PMID- 22815164 TI - Review of the Institute of Medicine report: long-term health consequences of exposure to burn pits in Iraq and Afghanistan. PMID- 22815165 TI - Hospitalization and medical evacuation of army personnel due to toxic inhalational exposure-Operations Iraqi Freedom and Enduring Freedom, 2001 through mid 2011. PMID- 22815166 TI - The impact of attachment style on posttraumatic stress disorder symptoms in postdeployed service members. AB - This study examined the effects of attachment style on self-reported posttraumatic stress disorder (PTSD) symptoms in a population of service members (N=561). Active duty, postdeployment service members completed anonymous questionnaires including 2 measures of adult attachment and the PTSD checklist military as a measure of PTSD symptoms. Results confirmed the central hypothesis that attachment style was related to reported PTSD symptoms. Secure attachment style was associated with less reported PTSD symptoms and therefore may be involved in mechanisms associated with protection from developing PTSD after experiencing wartime trauma. Results were consistent when tested across continuous and dichotomous assessments that captured diagnostic criteria. This study demonstrates a significant relationship between attachment style and PTSD symptoms within a military population, potentially providing the basis for future research in this area. PMID- 22815167 TI - A review of mechanics and injury trends among various running styles. AB - CONTEXT: Running related overuse injuries are a significant problem with half of all runners sustaining an injury annually. Many medical providers and coaches question how to advise their running clients to prevent injuries. Alternative running styles with a more anterior footstrike such as barefoot running, POSE running, and Chi running are becoming more popular. Little information, however, has been published comparing the mechanics and injury trends of different running styles. OBJECTIVE: The original purpose of this paper was to examine evidence concerning the biomechanics and injury trends of different running styles. Little to no injury data separated by running style existed. Therefore, we discuss the biomechanics of different running styles and present biomechanical findings associated with different running injuries. DATA SOURCES: English language articles published in peer reviewed journals were identified by searching PubMed, CINAHL, and SPORTDiscus databases. Nearly all of the studies identified by the search were observational studies. RESULTS: A more anterior initial foot contact present in barefoot or other alternative running styles may decrease or eliminate the initial vertical ground reaction peak or "impact transient," possibly reducing knee joint loads and injuries. A more anterior foot strike, however, may increase mechanical work at the ankle and tensile stress within the plantarflexors. Wearing minimal footwear may also increase contact pressure imposed on the metatarsals. CONCLUSION: More research is needed to determine which individuals with certain morphological or mechanical gait characteristics may benefit from alternative running styles that incorporate a more anterior initial foot contact with or without shoes. PMID- 22815169 TI - Risky business: challenges and successes in military radiation risk communication. AB - Given the general public's overall lack of knowledge about radiation and their heightened fear of its harmful effects, effective communication of radiation risks is often difficult. This is especially true when it comes to communicating the radiation risks stemming from military operations. Part of this difficulty stems from a lingering distrust of the military that harkens back to the controversy surrounding Veteran exposures to Agent Orange during the Vietnam War along with the often classified nature of many military operations. Additionally, there are unique military exposure scenarios, such as the use of nuclear weapons and combat use of depleted uranium as antiarmor munitions that are not found in the civilian sector. Also, the large, diverse nature of the military makes consistent risk communication across the vast and widespread organization very difficult. This manuscript highlights and discusses both the common and the distinctive challenges of effectively communicating military radiation risks, to include communicating through the media. The paper also introduces the Army's Health Risk Communication Program and its role in assisting in effective risk communication efforts. The authors draw on their extensive collective experience to share 3 risk communication success stories that were accomplished through the innovative use of a matrixed, team approach that combines both health physics and risk communication expertise. PMID- 22815168 TI - Clinical and electrodiagnostic abnormalities of the median nerve in US Army Dental Assistants at the onset of training. AB - PURPOSE/HYPOTHESIS: Dental personnel including dentists, dental hygienists, and dental assistants have been reported as having a high prevalence of upper extremity musculoskeletal disorders, including carpal tunnel syndrome. Previous research has not involved dental assistant students at the onset of dental training. Therefore, the purpose of this study was to determine the presence of median and ulnar neuropathies in US Army dental assistants at the onset of their training. NUMBER OF SUBJECTS: Fifty-five US Army Soldiers (28 female, 27 male) enrolled in the Dental Assistant (68E) course, volunteered to participate in the study. The mean age of the dental assistant students was 24+/-7.2 years (range 18 41 years). There were 45 right handed dental assistant students, and the mean length of time in the Army prior to dental training was 27 months (range 3-180 months). MATERIALS/METHODS: Subjects were evaluated during the first week of their 10-week dental assistant course. Subjects completed a history form, were interviewed, and underwent a physical examination. Electrophysiological status of the median and ulnar nerves of both upper extremities was obtained by performing motor and sensory nerve conduction studies. Descriptive statistics for subject demographics and nerve conduction study variables were calculated. RESULTS: Six of the 55 subjects (11%) presented with abnormal electrophysiologic values suggestive of median mononeuropathy at or distal to the wrist. Five of the subjects had abnormal electrophysiologic values in both hands. Five of these 6 subjects had clinical examination findings consistent with the electrophysiological findings. The ulnar nerve electrophysiologic assessment was normal in all subjects sampled. CONCLUSIONS: The prevalence of median mononeuropathies in this sample of Army dental assistants at the onset of training is greater than 5% prevalence reported in previous healthy populations and is less than 26% prevalence in previous research examining Army dental assistants with dental work experience. CLINICAL RELEVANCE: Median neuropathy at or distal to the wrist has been reported in dental personnel including dentists, dental hygienists, and dental assistants, and is also prevalent in this sample of dental assistants at the onset of training. Further long-term prospective research involving the impact of dental practice and techniques for reducing upper extremity injuries in dental professionals appears to be warranted. PMID- 22815170 TI - Summary of the Infectious Diseases and Disaster Response Conference in Abu Dhabi. PMID- 22815171 TI - Revolutionizing medicine in the 21st century through systems approaches. AB - Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term "personalized medicine", however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory-a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi-scale across all levels of biological organization and extremely heterogeneous in type - this enormous amount of data represents a striking signal-to-noise (S/N) challenge. The key to dealing with this S/N challenge is to take a "holistic systems approach" to disease as we will discuss in this article. PMID- 22815172 TI - Use of prevention and prevention plus weight management guidelines for youth with developmental disabilities living in group homes. PMID- 22815173 TI - Improving access to health care services for the medically underserved residents in a small lakeshore community in western Michigan. PMID- 22815174 TI - Personality traits, unmet expectations, and depressive symptoms in adoptive mothers. PMID- 22815175 TI - The effect of a safe zone on nurse distractions, interruptions, and medication administration errors. PMID- 22815176 TI - Validation of DNA methylation patterns: potential biomarker for heritable risk of preeclampsia. PMID- 22815177 TI - Meta-analysis of the relationship between coworker social support and burnout using a two-level hierarchical linear model. PMID- 22815178 TI - A structural model of quality of life in adults with type 2 diabetes. PMID- 22815179 TI - Attitudes, subjective norms, and intentions regarding infant feeding methods among black college students. PMID- 22815180 TI - A framework to evaluate the cultural appropriateness of intervention research. AB - Marked racial disparities exist in the prevalence, mortality, and treatment of asthma, between African American and White children and adolescents, despite increases in intervention trials to improve asthma outcomes. Yet, interventions to improve African American children's health must be culturally appropriate. To date, limited frameworks are available to decide whether an intervention tested with a targeted minority population employs a culturally appropriate design. In this article, we applied Bernal, Bonilla, and Bellido's ecological validity model to examine the cultural appropriateness of 12 randomized controlled trials of asthma self-management interventions published from 2000 to 2010. Most frequently met criteria were culturally appropriate methods of development and/or adaptation of interventions and inclusion of theoretical models. Least often met criteria were incorporating metaphors pertinent to participants and application of the language dimension. Based on this analysis, it is clear that an overarching framework is needed to guide the development of culturally targeted interventions. PMID- 22815183 TI - Vibrational frequency scale factors for density functional theory and the polarization consistent basis sets. AB - Calculated harmonic vibrational frequencies systematically deviate from experimental vibrational frequencies. The observed deviation can be corrected by applying a scale factor. Scale factors for: (i) harmonic vibrational frequencies [categorized into low (<1000 cm(-1)) and high (>1000 cm(-1))], (ii) vibrational contributions to enthalpy and entropy, and (iii) zero-point vibrational energies (ZPVEs) have been determined for widely used density functionals in combination with polarization consistent basis sets (pc-n, n = 0,1,2,3,4). The density functionals include pure functionals (BP86, BPW91, BLYP, HCTH93, PBEPBE), hybrid functionals with Hartree-Fock exchange (B3LYP, B3P86, B3PW91, PBE1PBE, mPW1K, BH&HLYP), hybrid meta functionals with the kinetic energy density gradient (M05, M06, M05-2X, M06-2X), a double hybrid functional with Moller-Plesset correlation (B2GP-PLYP), and a dispersion corrected functional (B97-D). The experimental frequencies for calibration were from 41 organic molecules and the ZPVEs for comparison were from 24 small molecules (diatomics, triatomics). For this family of basis sets, the scale factors for each property are more dependent on the functional selection than on basis set level, and thus allow for a suggested scale factor for each density functional when employing polarization consistent basis sets (pc-n, n = 1,2,3,4). A separate scale factor is recommended when the un-polarized basis set, pc-0, is used in combination with the density functionals. PMID- 22815181 TI - Multifunctional L1(0) -Mn(1.5)Ga films with ultrahigh coercivity, giant perpendicular magnetocrystalline anisotropy and large magnetic energy product. AB - A new kind of multifunctional L1(0) -Mn(1.5)Ga film is demonstrated for the first time. These MBE-grown epitaxial films exhibit pronounced magnetic properties at room temperature, including ultrahigh perpendicular coercivity up to 42.8 kOe, giant perpendicular magnetic anisotropy with a maximum of 21.7 Merg/cm(3) and large magnetic energy products up to 2.60 MGOe, which allow various applications in ultrahigh density recording, spintronics, and permanent magnets. PMID- 22815184 TI - Efficient regeneration potential is closely related to auxin exposure time and catalase metabolism during the somatic embryogenesis of immature embryos in Triticum aestivum L. AB - Regeneration of cultured tissue is a prerequisite of Agrobacterium- and biolistic mediated plant transformation. In this study, an efficient protocol for improving wheat (Triticum aestivum L.) immature embryo regeneration was developed. Based on the statistical analysis of embryogenic callus induction efficiency, green spot differentiation efficiency, and plant regeneration efficiency from five wheat accessions, improved culture conditions were found to be more effective for embryogenic callus production than the traditional conditions. Using semi quantitative reverse transcription polymerase chain reaction, a candidate gene, designated as TaCAT1, which encodes a catalase was identified to have a significant correlation with high-regeneration trait of wheat immature embryos. Three amino acid substitutions were found in TaCAT1 protein between high- and low regeneration wheat accessions. Hydrogen peroxide content in the cultured calli increased from day 5 to 15, and then decreased sharply on day 20, followed by a second peak on day 25 during regeneration stage. Furthermore, a 3,500-bp 5' flanking region upstream of the first codon ATG of TaCAT1 was isolated using inverse polymerase chain reaction. In silico, analysis revealed that the TaCAT1 promoter contained two regulatory motifs associated with responses to auxin. PMID- 22815185 TI - The future of osteoporosis treatment - a research update. AB - Osteoporosis is characterised by a progressive loss of bone mass and microarchitecture which leads to increased fracture risk. Some of the drugs available to date have shown reductions in vertebral and non-vertebral fracture risk. However, in the ageing population of industrialised countries, still more fractures happen today than are avoided, which highlights the large medical need for new treatment options, models, and strategies. Recent insights into bone biology, have led to a better understanding of bone cell functions and crosstalk between osteoblasts, osteoclasts, and osteocytes at the molecular level. In the future, the armamentarium against osteoporotic fractures will likely be enriched by (1.) new bone anabolic substances such as antibodies directed against the endogenous inhibitors of bone formation sclerostin and dickkopf-1, PTH and PTHrp analogues, and possibly calcilytics; (2.) new inhibitors of bone resorption such as cathepsin K inhibitors which may suppress osteoclast function without impairing osteoclast viability and thus maintain bone formation by preserving the osteoclast-osteoblast crosstalk, and denosumab, an already widely available antibody against RANKL which inhibits osteoclast formation, function, and survival; and (3.) new therapeutic strategies based on an extended understanding of the pathophysiology of osteoporosis which may include sequential therapies with two or more bone active substances aimed at optimising the management of bone capital acquired during adolescence and maintained during adulthood in terms of both quantity and quality. Finally, one of the future challenges will be to identify those patients and patient populations expected to benefit the most from a given drug therapy or regimen. The WHO fracture risk assessment tool FRAX(r) and improved access to bone mineral density measurements by DXA will play a key role in this regard. PMID- 22815186 TI - Polyurethane thermoplastic elastomers with inherent radiopacity for biomedical applications. AB - Synthesis and characterization of three different radiopaque thermoplastic polyurethane elastomers are reported. Radiopacity was introduced to the polyurethanes by incorporating an iodinated chain extender, namely, 4,4' isopropylidinedi-(2,6-diiodophenol) (IBPA), into the polymer chain during polyurethane synthesis. Radiopaque polyurethanes (RPUs) were synthesized by reacting 4,4'-methylenebis(phenyl isocyanate) (MDI), IBPA, and three different diols. The polyols used for the synthesis were polypropylene glycol, polycaprolactone diol, and poly(hexamethylene carbonate) diol. RPUs were characterized by infrared spectroscopy, contact angle measurements, thermogravimetry, dynamic mechanical analysis, energy dispersive X-ray analysis, gel permeation chromatography, X-ray fluorescence spectroscopy, and X radiography. X-ray images showed that all RPUs prepared using IBPA as the chain extender are highly radiopaque compared with an Aluminum wedge of equivalent thickness. Elemental analysis revealed that the polyurethanes contained 18-19% iodine in the polymer matrix. The RPUs developed have radiopacity equivalent to that of a polymer filled with 20 wt % barium sulfate. Results revealed that RPUs of wide range of properties may be produced by incorporating different diols as the soft chain segment. Cell culture cytotoxicity studies conducted using L929 cells by direct contact test and MTT assay proved that these RPUs are noncytotoxic in nature. PMID- 22815187 TI - Automated subcortical segmentation using FIRST: test-retest reliability, interscanner reliability, and comparison to manual segmentation. AB - Multiple techniques exist for the automated segmentation of magnetic resonance images (MRIs). The validity of these techniques can be assessed by evaluating test-retest reliability, interscanner reliability, and consistency with manual segmentation. We evaluate these measures for the FSL/FIRST subcortical segmentation tool. We retrospectively analyzed 190 MRI scans from 87 subjects with mood or anxiety disorders and healthy volunteers scanned multiple times on different platforms (N = 56) and/or the same platform (N = 45, groups overlap), and 146 scans from subjects who underwent both high-resolution and whole brain imaging in a single session, for comparison with manual segmentation of the hippocampus. The thalamus, caudate, putamen, hippocampus, and pallidum were reliably segmented in different sessions on the same scanner (Intraclass correlation coefficient (ICC) > 0.83 scanners and diagnostic groups pooled). In these regions, the range of between platform reliabilities were lower (0.527 < ICC < 0.953), although values below 0.7 were due to systematic differences between platforms or low reliability in the hippocampus between eight- and single channel coil platforms. Accumbens and amygdala segmentations were generally unreliable within and between scanning platforms. ICC values for hippocampal volumes between automated and manual segmentations were acceptable (ICC > 0.7, groups pooled), and both methods detected significant differences between genders. In addition, FIRST segmentations were consistent with manual segmentations (in a subset of images; N = 20) in the left caudate and bilateral putamen. This retrospective analysis assesses realistic performance of the algorithm in conditions like those found in multisite trials or meta-analyses. In addition, the inclusion of psychiatric patients establishes reliability in subjects exhibiting volumetric abnormalities, validating patient studies. PMID- 22815188 TI - Preoperative serum tissue polypeptide-specific antigen is a valuable prognostic marker in breast cancer. AB - Tissue polypeptide-specific antigen (TPS), a specific epitope structure of a peptide in serum associated with human cytokeratin 18, is linked to the proliferative activity of tumors. Here, we aimed to identify the association between the preoperative serum TPS level and outcome in breast cancer patients. We assayed preoperative serum TPS levels in 1,477 breast cancer patients treated between June 2000 and December 2006. The TPS level was measured with a one-step solid phase radiometric sandwich assay detecting the M3 epitope on cytokeratin 18 fragments. The cutoff value was 80 U/L. Among the 1,477 breast cancer patients examined, preoperative serum TPS level was elevated (>80 U/L) in 290 patients (19.6%). Age (>45 years), tumor size (>2 cm), nodal metastasis, negative progesterone receptor and human epidermal growth factor receptor 2 were associated with elevated TPS. Evidence of recurrence was observed in 229 patients (15.6%). Elevated TPS was associated with poor disease-free survival (p < 0.001) and overall survival (p < 0.001). In a multivariate analysis using the Cox proportional regression model, elevated TPS was an independent prognostic factor for disease-free survival (p = 0.001) and overall survival (p = 0.026). Furthermore, in subgroup analysis based on molecular subtype, the prognostic effect of preoperative TPS on survival (OS: HR 2.614, p = 0.003; DFS: HR 1.895, p = 0.001) was identified only in the luminal A subtype. Elevated preoperative serum TPS level is associated with poor breast cancer outcomes. Based on these findings, we conclude that preoperative TPS is a valuable biomarker for clinical use in predicting outcomes in breast cancer patients. PMID- 22815189 TI - Recombinantly produced cellobiose dehydrogenase from Corynascus thermophilus for glucose biosensors and biofuel cells. AB - Cellobiose dehydrogenase (CDH) is an emerging enzyme in the field of bioelectrocatalysis. Due to its flexible cytochrome domain, which acts as a built in redox mediator, CDH is capable of direct electron transfer (DET) to electrode surfaces. This rare property is employed in mediatorless "third generation" biosensors. The ability of Corynascus thermophilus CDH to oxidize glucose under physiological conditions makes it a promising candidate for miniaturized glucose biosensors or glucose powered biofuel cell anodes. We report for the first time the electrochemical application and characterization of a recombinantly produced CDH in a glucose biosensor. Recombinant CDH from C. thermophilus (rCtCDH) was expressed by the methylotrophic yeast Pichia pastoris (376 U L(-1) , 132 mg L(-1) ). A comparative characterization of rCtCDH and CtCDH shows identical pH optima, K(M) values and heme b midpoint potentials. In contrast, the specific activity of rCtCDH (2.84 U mg(-1) ) and consequently the turnover numbers were ~five-times lower than for CtCDH, which was caused by a sub-stoichiometric occupation of catalytic sites with flavin-adenin-dinukleotid (FAD). The performance of rCtCDH modified electrodes demonstrates the suitability for electrochemical studies. This opens the possibility to engineer the substrate specificity of C. thermophilus CDH for specific carbohydrates by rational engineering or directed evolution. PMID- 22815190 TI - Measurements of anisotropic (off-axis) friction-induced motion. PMID- 22815191 TI - Disparate profiles of dys-regulated miRNAs in activated hepatic stellate cells. PMID- 22815192 TI - Calculating pKa values for substituted phenols and hydration energies for other compounds with the first-order Fuzzy-Border continuum solvation model. AB - We have computed pK(a) values for 11 substituted phenol compounds using the continuum Fuzzy-Border (FB) solvation model. Hydration energies for 40 other compounds, including alkanes, alkenes, alkynes, ketones, amines, alcohols, ethers, aromatics, amides, heterocycles, thiols, sulfides, and acids have been calculated. The overall average unsigned error in the calculated acidity constant values was equal to 0.41 pH units and the average error in the solvation energies was 0.076 kcal/mol. We have also reproduced pK(a) values of propanoic and butanoic acids within about 0.1 pH units from the experimental values by fitting the solvation parameters for carboxylate ion carbon and oxygen atoms. The FB model combines two distinguishing features. First, it limits the amount of noise which is common in numerical treatment of continuum solvation models by using fixed-position grid points. Second, it uses either second- or first-order approximation for the solvent polarization, depending on a particular implementation. These approximations are similar to those used for solute and explicit solvent fast polarization treatment which we developed previously. This article describes results of using the first-order technique. This approximation places the presented methodology between the Generalized Born and Poisson Boltzmann continuum solvation models with respect to their accuracy of reproducing the many-body effects in modeling a continuum solvent. PMID- 22815193 TI - Intravascular ultrasound assessment of optimal stent area to prevent in-stent restenosis after zotarolimus-, everolimus-, and sirolimus-eluting stent implantation. AB - OBJECTIVES AND BACKGROUND: The impact of underexpansion and minimal stent area (MSA) criteria in the second generation drug-eluting stents (DES) has not been addressed yet. METHODS: Using intravascular ultrasound (IVUS), we assessed the optimal cut-off values of post-stenting MSA to prevent in-stent restenosis (ISR). Poststenting IVUS data and 9-month follow-up angiography were available in 912 patients with 990 lesions: 541 sirolimus-eluting stents (SES), 220 zotarolimus eluting stents (ZES) and 229 everolimus-eluting stents (EES). RESULTS: For the prediction of angiographic ISR, the MSA of each DES was measured. The poststenting MSA was 6.4 +/- 1.8 mm(2) in SES, 6.2 +/- 2.1 mm(2) in ZES and 6.2 +/- 2.1 mm(2) in EES. At the 9-months follow-up, the incidence of angiographic ISR was similar between SES (3.3%) vs. ZES (4.5%) vs. EES. (4.4%), (P = 0.53). Multivariable logistic regression analysis identified the post-stenting MSA as the only independent predictor of angiographic ISR in ZES (Odds ratio 0.722, 95% confidence interval 0.581-0.897, P = 0.001) and in EES (Odds ratio 0.595, 95% confidence interval 0.392-0.904, P = 0.015). The best MSA cut-off value was 5.5 mm(2) for the prediction of SES restenosis (sensitivity 72.2% and specificity 66.3%). For ZES, the optimal MSA predicting ISR was 5.3 mm(2) (sensitivity 56.7% and specificity 61.8%). For EES, the MSA <5.4 mm(2) predicted ISR (sensitivity 60.0% and specificity 60.0%). CONCLUSIONS: As a preventable mechanism of ISR, smaller stent area predicted angiographic restenosis of the second generation DES as well as the first generation. The optimal cut-off values of post-stenting MSA for preventing restenosis were similar between ZES vs. EES vs. SES. PMID- 22815196 TI - Middle airway obstruction--it may be happening under our noses. AB - BACKGROUND: Lower airway obstruction has evolved to denote pathologies associated with diseases of the lung, whereas, conditions proximal to the lung embody upper airway obstruction. This approach has disconnected diseases of the larynx and trachea from the lung, and removed the 'middle airway' from the interest and involvement of respiratory physicians and scientists. However, recent studies have indicated that dysfunction of this anatomical region may be a key component of overall airway obstruction, either independently or in combination with lung disease. New diagnostic modalities to effectively diagnose middle airway obstruction are being developed, and it has become feasible to identify and quantify middle airway obstruction. CONCLUSION: We, therefore, propose adding 'middle airway obstruction' to our nomenclature to embed it in diagnostic approaches, and to allow due emphasis on this neglected anatomical region. PMID- 22815195 TI - GSK3beta reduces risk of sporadic Parkinson's disease in ethnic Chinese. AB - Genetic variability of glycogen synthase kinase-3beta (GSK3beta) may be linked to Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3beta variation and PD in a Han Chinese population from mainland China. Using a case-control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3beta (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR = 0.82, 95% CI: 0.696-0.960, P = 0.014). Patients with CT + TT genotypes have a reduced risk of PD compared to those with CC genotype (OR = 0.61, 95% CI: 0.477 0.776, P = 6.09E-5). In addition, we demonstrated that CT + TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3beta reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3beta in PD. PMID- 22815194 TI - Endoplasmic reticulum enrollment in Alzheimer's disease. AB - Alzheimer's disease (AD) poses a huge challenge for society and health care worldwide as molecular pathogenesis of the disease is poorly understood and curative treatment does not exist. The mechanisms leading to accelerated neuronal cell death in AD are still largely unknown, but accumulation of misfolded disease specific proteins has been identified as potentially involved. In the present review, we describe the essential role of endoplasmic reticulum (ER) in AD. Despite the function that mitochondria may play as the central major player in the apoptotic process, accumulating evidence highlights ER as a critical organelle in AD. Stress that impairs ER physiology leads to accumulation of unfolded or misfolded proteins, such as amyloid beta (Abeta) peptide, the major component of amyloid plaques. In an attempt to ameliorate the accumulation of unfolded proteins, ER stress triggers a protective cellular mechanism, which includes the unfolded protein response (UPR). However, when activation of the UPR is severe or prolonged enough, the final cellular outcome is pathologic apoptotic cell death. Distinct pathways can be activated in this process, involving stress sensors such as the JNK pathway or ER chaperones such as Bip/GRP94, stress modulators such as Bcl-2 family proteins, or even stress effectors such as caspase-12. Here, we detail the involvement of the ER and associated stress pathways in AD and discuss potential therapeutic strategies targeting ER stress. PMID- 22815197 TI - Evolution of hippocampal shapes across the human lifespan. AB - Aberrant hippocampal morphology plays an important role in the pathophysiology of aging. Volumetric analysis of the hippocampus has been performed in aging studies; however, the shape morphometry--which is potentially more informative in terms of related cognition--has yet to be examined. In this paper, we employed an advanced brain mapping technique, large deformation diffeomorphic metric mapping (LDDMM), and a dimensionality reduction approach, locally linear diffeomorphic metric embedding (LLDME), to explore age-related changes in hippocampal shape as delineated from magnetic resonance (MR) images of 302 healthy adults aged from 18 to 94 years. Compared with the hippocampal volumes, the hippocampal shapes clearly showed the nonlinear trajectory of biological aging across the human lifespan, where the variation of hippocampal shapes by age was characterized by a cubic polynomial. By integrating of LDDMM and LLDME, we were also able to illustrate the average hippocampal shapes in each individual decade. In addition, LDDMM and LLDME facilitated the identification of 63 years as a threshold beyond which hippocampal morphological changes were accelerated. Adults over 63 years of age showed the inward-deformation bilaterally in the head of the hippocampi and the left subiculum regardless of hippocampal volume reduction when compared to adults younger than 63. Hence, we demonstrated that the shape of anatomical structures added another dimension of structural morphological quantification beyond the volume in understanding aging. PMID- 22815198 TI - Antinociceptive effects of a chloroform extract and the alkaloid dicentrine isolated from fruits of Ocotea puberula. AB - The present work describes the chemical characterization of a chloroform fraction (CF) obtained from an extract of Ocotea puberula (Lauraceae) fruits, and preliminary antinociceptive analysis of CF and the alkaloid dicentrine, isolated from this fraction. CF (30-300 mg/kg, p. o.) caused dose-related inhibition of abdominal constrictions caused by acetic acid and also inhibited both phases of formalin-induced nociception. However, hexane or ethyl acetate fractions did not produce any effect. Antinociception caused by CF (100 mg/kg, p. o.) in the acetic acid test was not affected either by caffeine, an adenosine receptor antagonist, or by naloxone, an opioid receptor antagonist, and neither was associated with nonspecific effects such as muscle relaxation or sedation. Furthermore, dicentrine (30-300 mg/kg, p. o.) produced dose-related inhibition of acetic acid induced pain without causing changes in the motor performance of mice. The results show, for the first time, that CF from Ocotea puberula fruits produced marked antinociception in different models of chemical pain, and this effect appears to be, at least in part, due to the presence of dicentrine. The mechanism by which CF and the alkaloid produced antinociception still remains unclear, but the adenosinergic or opioid system seems unlikely to be involved in this action. PMID- 22815199 TI - Prognostic value of arginase-II expression and regulatory T-cell infiltration in head and neck squamous cell carcinoma. AB - Tumor-infiltrating lymphocytes are present in a variety of tumors and play a central role in antitumor immune responses. Nevertheless, most cancers progress probably because tumors are only weakly immunogenic and develop multiple immunosuppressive mechanisms. In the present study, on head and neck squamous cell carcinoma, we found high intraepithelial infiltration of regulatory FOXP3(+) T cells, and relatively high levels of BDCA2(+) and FOXP3(+) cells in stromal (peripheral) regions of the tumors. Tumor-infiltrating (intraepithelial) FOXP3(+) T cells were significantly more frequent in patients with oropharynx and oral cavity squamous cell carcinoma and in patients without lymph node metastasis. Furthermore, arginase-II (ARG2) was expressed by 60%, inducible nitric oxide synthetase by 9%, cyclooxygenase-2 by 43%, and B-cell lymphoma 2 (BCL2) by 26% of tumors. Interestingly, the absence of ARG2 expression, enhanced stromal infiltration of CD11c(+) myeloid dendritic cells, and high numbers of FOXP3(+) T cells were each significantly associated with prolonged overall survival, and the latter two parameters were also confirmed by multivariate analysis. For disease-free survival, multivariate analysis revealed significant negative correlations with BCL2 and ARG2 expression by tumor cells. These findings shed new light on mechanisms of cancer progression, and provide rationales for therapeutic inhibition of immunosuppressive mechanisms in head and neck squamous cell carcinoma. PMID- 22815200 TI - Nanofluidic devices towards single DNA molecule sequence mapping. AB - Nanofluidics enables the imaging of stretched single molecules with potential applications for single molecule sequence mapping. Lab-on-a-chip devices for single cell trapping and lyzing, genomic DNA extraction from single cells, and optical mapping of genomic length DNA has been demonstrated separately. Yet the pursuit for applying DNA optical mapping to solve real genomics challenges is still to come. We review lab-on-a-chip devices from literature that could be part of a complete system for the sequence mapping of single DNA molecules. PMID- 22815201 TI - DSM-5 reduces the proportion of EDNOS cases: evidence from community samples. AB - OBJECTIVE: Eating Disorder Not Otherwise Specified (EDNOS) constitute the most common eating disorder among those seeking treatment at eating disorder facilities; they are even more common among persons with eating disorders the community. This study compares the impact of applying the revised diagnostic criteria proposed by the DSM-5 workgroup, and the broad categories for the diagnosis of eating disorders (BCD-ED) proposed by Walsh and Sysko on the prevalence of EDNOS. METHOD: In two nationwide epidemiological studies the prevalence of eating disorders among female high school (n = 2,028) and university students (n = 1,020) was examined using DSM-IV criteria. We used a two stage design, administering a questionnaire in the first stage and an interview in the second stage. RESULTS: In the combined samples 118 cases of eating disorders (DSM-IV) were detected, of which 86 were diagnosed as EDNOS (72.9%). Application of the DSM-5 criteria reduced the number of EDNOS cases to 60 (50.8%) or to 52 (44%), when using a BMI <18.5 as cutoff for "significantly low weight" criterion in AN; with the use of BCD-ED criteria, only 5 (4.2%) cases of EDNOS remained. DISCUSSION: Proposed criteria set for DSM-5 substantially reduce the number of EDNOS cases. However, the BCD-ED scheme further reduces its proportion, almost eliminating it. PMID- 22815202 TI - Amedeo Avogadro's cry: what is 1 ug of exosomes? PMID- 22815203 TI - Effect of DISC1 SNPs on brain structure in healthy controls and patients with a history of psychosis. AB - Disrupted-in-Schizophrenia-1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome-wide genotyping data for a Norwegian sample of healthy controls (n = 171) and patients with a history of psychosis (n = 184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (P(adjusted) = 0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (P(adjusted) = 0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype * case-control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings. PMID- 22815204 TI - A pressing matter--mediastinal fibrosis with near obliteration of the pulmonary arteries. AB - Idiopathic mediastinal fibrosis is a rare, histologically benign condition which often presents with symptoms attributable to compression of vital mediastinal structures. Diagnosis can be difficult and individualized treatments are required for patients, with possible intervention including pharmacotherapy, surgery, and percutaneous stenting. We present a case of idiopathic mediastinal fibrosis present in a 50-year-old woman as compression and near obliteration of the pulmonary arteries. A percutaneous approach was utilized with bilateral balloon expandable kissing stents simultaneous deployed from the main pulmonary artery to the right and left pulmonary arteries. There was instantaneous improvement in the pulmonary and systemic hemodynamics. Her immediate postprocedure course was complicated by reperfusion injury to the right lung, requiring intubation and ventilation. The patient made a full recovery and remains well at 6 months. Our case highlights the procedural and postprocedural difficulties that exist in such cases, and reinforces the value of endovascular stenting strategies in the management of patients with this rare condition. PMID- 22815205 TI - Choisyaternatine, a new alkaloid isolated from Choisya ternata. AB - One novel compound was isolated from the hexane extract of Choisya ternata Kunth. leaves, choisyaternatine (1), together with the known compounds tecleamaniensine A (2), lup-20(29)-en-3beta-ol (lupeol) (3), lup-20(29)-en-3beta,24-diol (4), beta sitosterol glucoside (5), and skimmianine (6), plus the following known compounds from the dichloromethane extract, choisyine (7) and 6-methoxy-7,8 methylenedioxycoumarin (8). Compounds 2-5 are reported for the first time in this species. The structures of isolated compounds were elucidated by extensive spectroscopic analyses and comparison with previously reported spectroscopic data. The structure of choisyaternatine was further confirmed based on X-ray data analysis. PMID- 22815206 TI - Loss in connectivity among regions of the brain reward system in alcohol dependence. AB - A recently developed measure of structural brain connectivity disruption, the loss in connectivity (LoCo), is adapted for studies in alcohol dependence. LoCo uses independent tractography information from young healthy controls to project the location of white matter (WM) microstructure abnormalities in alcohol dependent versus nondependent individuals onto connected gray matter (GM) regions. LoCo scores are computed from WM abnormality masks derived at two levels: (1) groupwise differences of alcohol-dependent individuals (ALC) versus light-drinking (LD) controls and (2) differences of each ALC individual versus the LD control group. LoCo scores based on groupwise WM differences show that GM regions belonging to the extended brain reward system (BRS) network have significantly higher LoCo (i.e., disconnectivity) than those not in this network (t = 2.18, P = 0.016). LoCo scores based on individuals' WM differences are also higher in BRS versus non-BRS (t = 5.26, P = 3.92 * 10(-6) ) of ALC. These results suggest that WM alterations in alcohol dependence, although subtle and spatially heterogeneous across the population, are nonetheless preferentially localized to the BRS. LoCo is shown to provide a more sensitive estimate of GM involvement than conventional volumetric GM measures by better differentiating between brains of ALC and LD controls (rates of 89.3% vs. 69.6%). However, just as volumetric measures, LoCo is not significantly correlated with standard metrics of drinking severity. LoCo is a sensitive WM measure of regional cortical disconnectivity that uniquely characterizes anatomical network disruptions in alcohol dependence. PMID- 22815207 TI - Early childhood infection of Kaposi's sarcoma-associated herpesvirus in Zambian households: a molecular analysis. AB - Sub-Saharan Africa is endemic for Kaposi's sarcoma-associated herpesvirus (KSHV) and there is a high rate of early childhood infection; however, the transmission sources are not well characterized. We examined household members as potential KSHV transmission sources to young children in the KSHV-endemic country of Zambia. To this end, we enrolled and followed Zambian households with at least one KSHV-seropositive child and collected longitudinal buccal swab samples. KSHV burden was evaluated and K1 sequences from the children were determined and analyzed for differences to K1 sequences from household members. The K1 sequences were also analyzed for evolution over time. We generated K1 sequences from 31 individuals across 16 households. Nine households contained multiple KSHV positive members, including at least one child. In six out of the nine households, the child had 100% sequence identity to all household members. However, in two households the child and mother had distinct K1 sequences. In the remaining household, the children were the only KSHV-infected individuals. Furthermore, we report that 1 out of 18 individuals had K1 sequence variation within the timespan analyzed. In our study, we provide evidence that (i) early childhood KSHV transmission occurs from both within and outside the household, (ii) intrahousehold transmission can occur via nonmaternal sources, (iii) viral shedding in the buccal cavity is highly variable and (iv) the dominant K1 sequence within an individual did not rapidly evolve over time. These results are important for developing KSHV intervention strategies. PMID- 22815208 TI - Efficacy of intranasal vaccination of field buffaloes against haemorrhagic septicaemia with a live gdhA derivative Pasteurella multocida B:2. AB - The efficacy of an intranasal haemorrhagic septicaemia vaccine containing live gdhA derivative Pasteurella multocida B:2 was tested in buffaloes in Sabah. Sixty buffaloes, kept grazing in the field with minimal human intervention were devided into three groups of 20 buffaloes per group. Buffaloes of group 1 were exposed intranasal to 5 ml vaccine containing 10(6) CFU/ml of live gdhA derivative P multocida B:2. Buffaloes of group 2 were not exposed to the vaccine but exposed to PBS and were allowed to commingle and graze in the same field as the buffaloes of group 1 while buffaloes of group 3 were similarly exposed to PBS and were grazing separately. Booster was on group 1, two weeks later. Twelve months after the first vaccination, three buffaloes from each group were brought into the experimental house and challenged subcutaneously with 10(9) CFU/ml of live wild type P multocida B:2. All challenged buffaloes of groups 1 and 2 survived with only mild, transient signs while all control unvaccinated buffaloes developed severe signs of haemorrhagic septicaemia and were euthanased between 28 hours and 38 hours postchallenge with signs and lesions typical of haemorrhagic septicaemia. These data showed that the gdhA mutant strain, given intranasally as two doses two weeks apart, successfully induced systemic immunity in exposed buffaloes and also led to spread of vaccine strain to the in-contact animals, where it acted as an effective live vaccine to protect both exposed buffaloes and in-contact buffaloes against challenge with the virulent parent strain. PMID- 22815209 TI - Multiphoton imaging of the dentine-enamel junction. AB - Multiphoton microscopy has been used to reveal structural details of dentine and enamel at the dentin-enamel junction (DEJ) based on their 2-photon excited fluorescence (2PEF) emission and second harmonic generation (SHG). In dentine tubule 2PEF intensity varies due to protein content variation. Intertubular dentin produces both SHG and 2PEF signals. Tubules are surrounded by a thin circular zone with a lower SHG signal than the bulk dentine and the presence of collagen fibers perpendicular to the tubule longitudinal axis is indicated by strong SHG responses. The DEJ appears as a low intensity line on the 2PEF images and this was never previously reported. The SHG signal is completely absent for enamel and aprismatic enamel shows a homogeneous low 2PEF signal contrary to prismatic enamel. The SHG intensity of mantle dentine is increasing from the dentine-enamel junction in the first 12 MUm indicating a progressive presence of fibrillar collagen and corresponding to the more external part of mantle dentine where matrix metallo-proteases accumulate. The high information content of multiphoton images confirms the huge potential of this method to investigate tooth structures in physiological and pathological conditions. PMID- 22815210 TI - Isotherm type shift of hydrophobic interaction adsorption and its effect on chromatographic behavior. AB - Adsorption isotherm type is a key factor in simulating chromatographic profiles. In this study, the adsorption isotherm type of pure bovine serum albumin (BSA) and immunoglobulin G (IgG) on hydrophobic interaction chromatography (HIC) media was found to shift from Freundlich to Langmuir with the increase of salt concentration. For BSA on butyl-, phenyl- and octyl-sepharose, the isotherm type shift occurred when the salt concentrations were higher than 1.8, 1.5 and 1.4 mol/L, respectively. For IgG, the turning points were 1.0 mol/L on phenyl sepharose and 0.9 mol/L on octyl-sepharose. Circular dichroism spectra and high performance size-exclusion chromatography found no obvious conformational change or oligomer formation for the proteins in the solutions with different salt concentrations. HIC profiles of BSA and IgG revealed that the isotherm type shift greatly affected the chromatographic behavior, because the original single peak was coincidentally split into two peaks at the salt concentrations over which the isotherm type shift occurred. Combining both the isotherm type shift and peak splitting phenomena, it was possible that the change of protein-protein repulsion among adsorbed protein molecules under different salt concentrations caused the abnormal behavior of adsorption isotherm and chromatographic profiles. PMID- 22815211 TI - Determination of isotoosendanin in rat plasma by liquid chromatography-tandem mass spectrometry: application to pharmacokinetics study. AB - A rapid, sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed and validated for the quantification of isotoosendanin, an important bioactive component isolated from Meliae cortex. A Capcell PAK C18 column (100 * 4.6 mm) was used for the chromatographic elution using methanol-10 mM ammonium acetate-formic acid (80:20:0.1, v/v/v) as mobile phase at the flow rate of 0.6 mL/min. MS-MS analysis was performed on a triple quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization source in positive ion mode. Extraction of isotoosendanin and genistein (internal standard, IS) from rat plasma was determined by precipitating protein treatment. Quantification was performed by MS in the multiple reaction monitoring mode with positive ionization at m/z 557 -> 437 for the analyte and m/z 271 -> 215 for IS, respectively. Linear isotoosendanin calibration curves were obtained between 2.0-2,000 ng/mL with a correlation coefficient greater than 0.99. Acceptable precision and accuracy were acquired for concentrations over the standard curve range. Satisfactory results were achieved for sensitivity, specificity, recovery, freeze/thaw and stability. This analytical method was successfully applied to determine the pharmacokinetic parameters of isotoosendanin after an oral administration of 200 mg/kg to rats. PMID- 22815212 TI - Semi-preparative enantiomeric separation of ofloxacin by HPLC. AB - A direct semi-preparative high performance liquid chromatography (HPLC) enantioseparation of ofloxacin was performed on chemically immobilized cyclodextrin derivative-mono (6A-azido-6A-deoxy)-per(p-chlorophenyl carbamoylated) beta-CD chiral stationary phase. Conditions for semi-preparative separations were established using a 250 * 4.6 mm i.d. column and subsequently extended to a 250 * 10.0 mm i.d. column that enabled separations on a milligram scale. Optimization of the chromatographic conditions (mobile phase and column load) with respect to better efficiency, resolution and peak retention resulted in a system capable of separating up to 304 mg of (-)-(S)-ofloxacin and 56 mg of (+)-(R)-ofloxacin of the racemate over 6 h. The purities of the separated enantiomers were determined by HPLC. Moreover, both separated enantiomers were characterized by mass spectrometry; then, the absolute configuration of the products was clearly confirmed by polarimetry. PMID- 22815213 TI - Associations between variability of risk factors and health outcomes in longitudinal studies. AB - Many statistical methods have been developed that treat within-subject correlation that accompanies the clustering of subjects in longitudinal data settings as a nuisance parameter, with the focus of analytic interest being on mean outcome or profiles over time. However, there is evidence that in certain settings, underlying variability in subject measures may also be important in predicting future health outcomes of interest. Here, we develop a method for combining information from mean profiles and residual variance to assess associations with categorical outcomes in a joint modeling framework. We consider an application to relating word recall measures obtained over time to dementia onset from the Health and Retirement Survey. PMID- 22815214 TI - A prognostic score based on clinical factors and biomarkers for advanced non small cell lung cancer. AB - AIMS: The objective of the present study is to determine the prognostic value of clinical variables and biomarkers in patients with advanced stages of NSCLC and establish a prognostic classification of these patients. METHODS: For 135 patients with advanced NSCLC we determined their clinical variables and their levels of CEA, CA 125, CYFRA 21-1, albumin, LDH, erythrosedimentation and leukocytes. RESULTS: Multivariate analysis identified PS (ECOG) >1, metastases, no anti-neoplastic treatment, CA 125 >35 U/mL, CYFRA 21-1 >3.3 ng/mL and leukocytes >10'000/uL, as independent prognostic factors for survival. Patients were classified into 3 groups according to the number of adverse prognostic factors (APF). One point was assigned for each APF, except for chemotherapy treatment. Patients with 0-1 APF represented our reference group: patients with 2 3 APF had HR=2.7 (95% CI: 1.5-4.6), while patients with 4-5 APF had HR=8.8 (95% CI: 4.6-16.8). This "score" maintained the differences between risk groups both in patients who received antineoplastic treatment and in those who did not. CONCLUSION: The application of a score that includes clinical data and biomarkers may improve the prognostic classification of NSCLC patients. PMID- 22815215 TI - Improved vaccines through targeted manipulation of the body's immunological risk assessment? AB - Recent advances have highlighted the outstanding role of the innate immune system for instructing adaptive immunity. Translating this knowledge into successful immunotherapies like vaccines, however, has proven to be a difficult task. This essay is based on the hypothesis that immune responses are tightly scaled to the infectious threat posed by a given microbial stimulus. A meticulous immunological risk-assessment process is therefore instrumental for eliciting well-balanced responses and maintaining immune homeostasis. The immune system makes fine distinctions, for example, between live and dead bacteria, or pathogenic and non pathogenic microorganisms. Here, I discuss recent evidence for some of the mechanisms underlying these distinctions and speculate on strategies for therapeutically targeting the immunological risk-assessment machinery. PMID- 22815217 TI - [NiCl2(dppp)]-catalyzed cross-coupling of aryl halides with dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphine. AB - We present a general approach to C-P bond formation through the cross-coupling of aryl halides with a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane by using [NiCl(2) (dppp)] as catalyst (dppp=1,3 bis(diphenylphosphino)propane). This catalyst system displays a broad applicability that is capable of catalyzing the cross-coupling of aryl bromides, particularly a range of unreactive aryl chlorides, with various types of phosphorus substrates, such as a dialkyl phosphite, diphenylphosphine oxide, and diphenylphosphane. Consequently, the synthesis of valuable phosphonates, phosphine oxides, and phosphanes can be achieved with one catalyst system. Moreover, the reaction proceeds not only at a much lower temperature (100-120 degrees C) relative to the classic Arbuzov reaction (ca. 160-220 degrees C), but also without the need of external reductants and supporting ligands. In addition, owing to the relatively mild reaction conditions, a range of labile groups, such as ether, ester, ketone, and cyano groups, are tolerated. Finally, a brief mechanistic study revealed that by using [NiCl(2) (dppp)] as a catalyst, the Ni(II) center could be readily reduced in situ to Ni(0) by the phosphorus substrates due to the influence of the dppp ligand, thereby facilitating the oxidative addition of aryl halides to a Ni(0) center. This step is the key to bringing the reaction into the catalytic cycle. PMID- 22815218 TI - Multicomponent reaction to construct spirocyclic oxindoles with a Michael (triple Michael)/cyclization cascade sequence as the key step. AB - Multicomponent cycloadditions with readily available isocyanides, allenoates, and isatylidene malononitriles are disclosed. This reaction, which does not require the aid of any catalyst, allows the efficient syntheses of spirocyclic oxindoles with excellent regioselectivity. Reactions with ethyl 2,3-butadienoate and various structurally diverse alpha- and gamma-substituted allenoates are also fully explored. Remarkably, we have shown that the usual three-component process can be further developed into an unprecedented four-component cycloaddition in the presence of water, which provides a new strategy to access highly unusual tricyclic oxindoles. From a synthetic point of view, this protocol is very interesting considering the high level of complexity reached in one step. The mechanism is thought to proceed by a triple Michael/cyclization process by using allenoate as a three carbon atom component (3 C). Furthermore, multicomponent reaction with gamma-substituted allenoate also results in a very interesting conversion. In such cases, the unusual cleavage of the "C=C" double bond of isatylidene malononitrile and one of the "C=C" double bonds of allenoate is always observed. PMID- 22815219 TI - FMO-MD simulations on the hydration of formaldehyde in water solution with constraint dynamics. AB - Full-quantum mechanical fragment molecular orbital-based molecular dynamics (FMO MD) simulations were applied to the hydration reaction of formaldehyde in water solution under neutral conditions. Two mechanisms, a concerted and a stepwise one, were considered with respect to the nucleophilic addition and the proton transfer. Preliminary molecular orbital calculations by means of polarized continuum model reaction field predicted that the hydration prefers a concerted mechanism. Because the calculated activation barriers were too high for free FMO MD simulations to give reactive trajectories spontaneously, a More O'Ferrall Jencks-type diagram was constructed from the statistical analysis of the FMO-MD simulations with constraint dynamics. The diagram showed that the hydration proceeds through a zwitterionic-like (ZW-like) structure. The free energy changes along the reaction coordinate calculated by means of the blue moon ensemble for the hydration and the amination of formaldehyde indicated that the hydration proceeds through a concerted process through the ZW-like structure, whereas the amination goes through a stepwise mechanism with a ZW intermediate. In inspection of the FMO-MD trajectories, water-mediated cyclic proton transfers were observed in both reactions on the way from the ZW-like structure to the product. These proton transfers also have an asynchronous character, in which deprotonation from the nucleophilic oxygen atom (or nitrogen atom for amination) precedes the protonation of the carbonyl oxygen atom. The results showed the strong advantage of the FMO-MD simulations to obtain detailed information at a molecular level for solution reactions. PMID- 22815220 TI - Cyclic and linear polyferrocenes with silicon and tin as alternating bridges. AB - The synthesis and characterization of ferrocene-based oligomers that contained two different elements (Si and Sn) as alternating bridges is described for the first time. The salt-metathesis reaction of R(2) Si[(C(5) H(4) )Fe(C(5) H(4) Li)](2) (R=Me, Et) with R'(2) SnCl(2) (R'=Me, nBu, tBu) afforded a mixture of oligomers (6(Me) SnMe(2), 6(Et) SnMe(2), 6(Me) SnnBu(2), 6(Et) SnnBu(2), 6(Me) SntBu(2), and 6(Et) SntBu(2)). These oligomers were characterized by (1) H, (13) C, (29) Si, and (119) Sn NMR spectroscopy and by mass spectrometry. MS (MALDI TOF) studies of 6(Et) SnMe(2) revealed the presence of linear (l) and cyclic (c) species that contained up to 20 ferrocene moieties. The molecular weights of the polymers were determined by gel-permeation chromatography (GPC) and by dynamic light scattering (DLS). GPC analysis revealed average molecular weights of 2100 6300 Da with respect to polystyrene as a standard. DLS analysis yielded very similar results. Some compounds, c-(6(Me) SnMe(2) )(1), c-(6(Me) SntBu(2))(2), c (6(Et) SnMe(2))(1), c-(6(Et) SntBu(2))(2), l-(6(Me) SnnBu(2) )(2), and l-(6(Me) SnnBu(2))(3), which contained up to six ferrocene moieties, were isolated in their pure form either by column chromatography or by crystallization. The Si- and Sn-bridged macrocycles that contained four ferrocene units (c-(6(Me) SntBu(2))(2) and c-(6(Et) SntBu(2))(2)) were structurally characterized by single crystal X-ray analysis. PMID- 22815222 TI - A systematic review and meta-analysis on the association between BDNF val(66)met and hippocampal volume--a genuine effect or a winners curse? AB - Inconsistenties have been reported with regard to an association between val(66)met, a polymorphism on the BDNF gene, and hippocampal volume. We performed a systematic review and a meta-analysis to determine the magnitude and direction of this putative association and estimated the potential influence of demographic, clinical, and methodological characteristics of studies. Tests of publication bias and time-related trends were performed and statistical power of the included studies was calculated. The literature search for MRI studies on differences in total hippocampal volume as a function of BDNF val(66)met returned 25 records that fulfilled our criteria (total N = 3,620). Meta-analysis showed that carriers of a met allele had lower hippocampal volumes relative to val/val homozygotes (d = 0.13, P = 0.02). Between-study heterogeneity in effect size estimates was substantial (Q = 54.47, P < .001) and this could not be explained by demographic, clinical, and methodological differences across studies. Funnel plot inspection and trim-and-fill estimations suggested evidence for publication bias and effect sizes decreased substantially over the years (Pearson's r = 0.54, P < .01). All included studies were underpowered. This meta-analysis shows that carriers of a met allele have lower total hippocampal volumes relative to val/val homozygotes. However, effect sizes converged closer to null with virtually each attempt at replication and were based on underpowered studies. Altogether, this may call into question whether the observed effect is a genuine biological effect of the met allele or whether it is subject to a winners curse, with large effect sizes found in a few early studies and increasingly smaller effect sizes in later studies. PMID- 22815223 TI - Executive performance is related to regional gray matter volume in healthy older individuals. AB - Individual differences in executive functioning and brain morphology are considerable. In this study, we investigated their interrelation in a large sample of healthy older individuals. Digit span, trail-making, and Stroop tasks were used to assess different executive subfunctions in 367 nondemented community dwelling individuals (50-81 years). Task performance was analyzed relative to brain structure using voxel-based morphometry, corrected for age and sex. Improved task performance was associated with increased local gray matter volume in task-specific patterns that showed partial, but not complete overlap with known task-specific functional imaging patterns. While all three tasks showed associations with prefrontal gray matter volume as expected for executive functioning, the strongest overlap between the three tasks was found in insular cortex, suggesting that it has a previously underestimated role for executive functions. The association between the insular cortex and executive functioning was corroborated using stereological region-of-interest measurement of insular volume in a subgroup of 93 subjects. Quantitatively, the volume of the single most strongly related region explained 2.4 +/- 1.1% of the variance in executive performance over and above the variance explained by age, which amounted to 7.4 +/- 4.1%. The age-independent peak associations between executive performance and gray matter described here occurred in regions that were also strongly affected by age-related gray matter atrophy, consistent with the hypothesis that age related regional brain volume loss and age-related cognitive changes are linked. PMID- 22815224 TI - Classification of samples into two or more ordered populations with application to a cancer trial. AB - In many applications, especially in cancer treatment and diagnosis, investigators are interested in classifying patients into various diagnosis groups on the basis of molecular data such as gene expression or proteomic data. Often, some of the diagnosis groups are known to be related to higher or lower values of some of the predictors. The standard methods of classifying patients into various groups do not take into account the underlying order. This could potentially result in high misclassification rates, especially when the number of groups is larger than two. In this article, we develop classification procedures that exploit the underlying order among the mean values of the predictor variables and the diagnostic groups by using ideas from order-restricted inference. We generalize the existing methodology on discrimination under restrictions and provide empirical evidence to demonstrate that the proposed methodology improves over the existing unrestricted methodology. The proposed methodology is applied to a bladder cancer data set where the researchers are interested in classifying patients into various groups. PMID- 22815225 TI - Genetics of dementia: update and guidelines for the clinician. AB - With increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X-linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia. PMID- 22815226 TI - Development of a sensitive GC-C-IRMS method for the analysis of androgens. AB - The administration of anabolic steroids is one of the most important issues in doping control and is detectable through a change in the carbon isotopic composition of testosterone and/or its metabolites. Gas chromatography-combustion isotope ratio mass spectrometry (GC-C-IRMS), however, remains a very laborious and expensive technique and substantial amounts of urine are needed to meet the sensitivity requirements of the IRMS. This can be problematic because only a limited amount of urine is available for anti-doping analysis on a broad spectrum of substances. In this work we introduce a new type of injection that increases the sensitivity of GC-C-IRMS by a factor of 13 and reduces the limit of detection, simply by using solvent vent injections instead of splitless injection. This drastically reduces the amount of urine required. On top of that, by only changing the injection technique, the detection parameters of the IRMS are not affected and there is no loss in linearity. PMID- 22815227 TI - Nanodiamond for intracellular imaging in the microorganisms in vivo. AB - Nanodiamond (ND) has great potential for bio labeling and drug delivery. In this work, the biocompatibility and bio labeling of ND are demonstrated via the interaction with cells and microorganisms, protists microorganisms Paramecium caudatum and Tetrahymena thermophile, in vitro and in vivo. We found the microorganism's living functions are not significantly affected by ND. The NDs were found entering the food vacuoles and later excreted by the microorganisms. The 5 nm ND was found more toxic compared to 100 nm ND, presumably due to the surface disordered carbons. Our results demonstrated nanodiamond can be used in bio imaging and matter delivery. PMID- 22815228 TI - Repeat balloon aortic valvuloplasty effectively delays surgical intervention in children with recurrent aortic stenosis. AB - OBJECTIVE: Balloon aortic valvuloplasty (BAV) is the primary therapy for congenital aortic stenosis (AS). Recurrent AS following initial BAV or initial surgical valvotomy (SV) may require a second BAV (BAV2). We sought to determine the longterm outcomes of BAV2. DESIGN: We reviewed all cases of BAV2, defined as BAV following primary BAV or SV between 1988 and 2009. Cases were reviewed for pre- and post-BAV2 echocardiographic and procedural details. SETTING: Tertiary care dedicated children's hospital. PATIENTS: Between 1985 and 2009, 43 patients underwent BAV2 (23 primary SV, 20 primary BAV) at median age 1.9 years (1 month 21 years) and median weight 15 (3.3-55) kg. INTERVENTIONS: BAV2 performed following primary SV or primary BAV. MAIN OUTCOME MEASURES: We evaluated the following endpoints: >= moderate AI post-BAV2, aortic valve replacement (AVR), additional BAV or SV post-BAV2, death and heart transplantation. RESULTS: The gradient decreased from 61.4 +/- 16.0 mm Hg to 26.0 +/- 13.6 post-BAV2 (P < 0.01). Gradient prior to BAV2 was higher in primary SV patients (66 +/- 13 mm Hg) than in primary BAV patients (56 +/- 18 mm Hg, P = 0.04). 24 patients had no further events after BAV2, while 19 patients (44%) experienced 23 events including: AVR (n = 8), SV (n = 6), BAV3 (n = 2), death (n = 5), and transplant (n = 1). Regression demonstrated that adverse events were associated with higher post-BAV2 gradient (P < 0.01). Repeat intervention on the aortic valve and AVR were associated with higher post BAV2 gradient (P = 0.04, P = 0.01). Prior to BAV2, 7 patients (17%) had AI > mild, compared to 21 (51%) patients after BAV2. Cox regression revealed that primary BAV was associated with development of AI > mild after BAV2 (P < 0.01). CONCLUSION: BAV2 is associated with decreased valve gradient, though with an increase in AI. However, residual AS, not AI, is associated with poor outcomes following BAV2. BAV2 effectively treats recurrent AS and postpones need for surgical intervention. PMID- 22815229 TI - Reading acquisition reorganizes the phonological awareness network only in alphabetic writing systems. AB - It is unknown how experience with different types of orthographies influences the neural basis of oral language processing. In order to determine the effects of alphabetic and nonalphabetic writing systems, the current study examined the influence of learning to read on oral language in English and Chinese speakers. Children (8-12 years olds) and adults made rhyming judgments to pairs of spoken words during functional magnetic resonance imaging (fMRI). Developmental increases were seen only for English speakers in the left hemisphere phonological network (superior temporal gyrus (STG), inferior parietal lobule, and inferior frontal gyrus). The increase in the STG was more pronounced for words with conflicting orthography (e.g. pint-mint; jazz-has) even though access to orthography was irrelevant to the task. Moreover, higher reading skill was correlated with greater activation in the STG only for English speaking children. The effects suggest that learning to read reorganizes the phonological awareness network only for alphabetic and not logographic writing systems because of differences in the principles for mapping between orthographic and phonological representations. The reorganization of the auditory cortex may result in better phonological awareness skills in alphabetic readers. PMID- 22815230 TI - The antioxidant and anticancer effects of wild carrot oil extract. AB - Daucus carota L. ssp. carota (Apiacea) is used in traditional medicine in Lebanon and in different regions throughout the world. The present study investigates the in vitro anticancer activities of Daucus carota oil extract (DCOE) on four human cancer cell lines as well as its in vitro antioxidant activity. DCOE was extracted from the dried umbels with 50:50 acetone-methanol. The oil extract was analyzed by gas chromatography-mass spectrometry and screened for its antioxidant properties in vitro using 1,1-diphenyl-2-picryl hydrazyl free radical scavenging assay (DPPH), ferrous ion chelating assay (FIC) and the ferric reducing antioxidant power assay (FRAP). The anticancer activity of the oil extract against human colon (HT-29, Caco-2) and breast (MCF-7, MDA-MB-231) cancer cell lines was evaluated using the trypan blue exclusion method and the WST-1 cell proliferation assay. DCOE exhibited antioxidant activity in all assays used. The FRAP value was 164 +/- 5.5 umol FeSO4 /g, and the IC50 values for DPPH and FIC assays were 2.1 +/- 0.03 mg/ml and 0.43 +/- 0.02 mg/ml, respectively. Also, DCOE demonstrated a significant increase in cell death and decrease in cell proliferation. The effect of DCOE on the cell lines exhibited time and dose dependent responses. The present study established that DCOE possesses both antioxidant and promising anticancer activities. PMID- 22815231 TI - Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors. AB - Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are highly expressed in rhabdomyosarcoma (RMS) cells. In tissue arrays of RMS tumor cores from 71 patients, 80% of RMS patients expressed high levels of Sp1 protein, whereas low expression of Sp1 was detected in normal muscle tissue. The non steroidal anti-inflammatory drug (NSAID) tolfenamic acid (TA) inhibited growth and migration of RD and RH30 RMS cell lines and also inhibited tumor growth in vivo using a mouse xenograft (RH30 cells) model. The effects of TA were accompanied by downregulation of Sp1, Sp3, Sp4 and Sp-regulated genes in RMS cells and tumors, and the role of Sp protein downregulation in mediating inhibition of RD and RH30 cell growth and migration was confirmed by individual and combined knockdown of Sp1, Sp3 and Sp4 proteins by RNA interference. TA treatment and Sp knockdown in RD and RH30 cells also showed that four genes that are emerging as individual drug targets for treating RMS, namely c-MET, insulin like growth factor receptor (IGFR), PDGFRalpha and CXCR4, are also Sp-regulated genes. These results suggest that NSAIDs such as TA may have potential clinical efficacy in drug combinations for treating RMS patients. PMID- 22815234 TI - Cannabidiol in inflammatory bowel diseases: a brief overview. AB - This minireview highlights the importance of cannabidiol (CBD) as a promising drug for the therapy of inflammatory bowel diseases (IBD). Actual pharmacological treatments for IBD should be enlarged toward the search for low-toxicityand low cost drugs that may be given alone or in combination with the conventional anti IBD drugs to increase their efficacy in the therapy of relapsing forms of colitis. In the past, Cannabis preparations have been considered new promising pharmacological tools in view of their anti-inflammatory role in IBD as well as other gut disturbances. However, their use in the clinical therapy has been strongly limited by their psychotropic effects. CBD is a very promising compound since it shares the typical cannabinoid beneficial effects on gut lacking any psychotropic effects. For years, its activity has been enigmatic for gastroenterologists and pharmacologists, but now it is evident that this compound may interact at extra-cannabinoid system receptor sites, such as peroxisome proliferator-activated receptor-gamma. This strategic interaction makes CBD as a potential candidate for the development of a new class of anti-IBD drugs. PMID- 22815232 TI - The mechanism of eukaryotic translation initiation: new insights and challenges. AB - Translation initiation in eukaryotes is a highly regulated and complex stage of gene expression. It requires the action of at least 12 initiation factors, many of which are known to be the targets of regulatory pathways. Here we review our current understanding of the molecular mechanics of eukaryotic translation initiation, focusing on recent breakthroughs from in vitro and in vivo studies. We also identify important unanswered questions that will require new ideas and techniques to solve. PMID- 22815233 TI - Global and regional alterations of hippocampal anatomy in long-term meditation practitioners. AB - Studies linking meditation and brain structure are still relatively sparse, but the hippocampus is consistently implicated as one of the structures altered in meditation practitioners. To explore hippocampal features in the framework of meditation, we analyzed high-resolution structural magnetic resonance imaging data from 30 long-term meditators and 30 controls, closely matched for sex, age, and handedness. Hippocampal formations were manually traced following established protocols. In addition to calculating left and right hippocampal volumes (global measures), regional variations in surface morphology were determined by measuring radial distances from the hippocampal core to spatially matched surface points (local measures). Left and right hippocampal volumes were larger in meditators than in controls, significantly so for the left hippocampus. The presence and direction of this global effect was confirmed locally by mapping the exact spatial locations of the group differences. Altogether, radial distances were larger in meditators compared to controls, with up to 15% difference. These local effects were observed in several hippocampal regions in the left and right hemisphere though achieved significance primarily in the left hippocampal head. Larger hippocampal dimensions in long-term meditators may constitute part of the underlying neurological substrate for cognitive skills, mental capacities, and/or personal traits associated with the practice of meditation. Alternatively, given that meditation positively affects autonomic regulation and immune activity, altered hippocampal dimensions may be one result of meditation-induced stress reduction. However, given the cross-sectional design, the lack of individual stress measures, and the limited resolution of brain data, the exact underlying neuronal mechanisms remain to be established. PMID- 22815235 TI - Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma. AB - In primary prostate cancer (PCa), a major cause of cancer-related death in men, the expression of various microRNAs (miRNAs) is deregulated. We previously detected several miRNAs, for example, miR-24 and miR-22, as significantly downregulated in PCa (Szczyrba et al., Mol Cancer Res 2010;8:529-38). An in silico search predicted that zinc finger protein 217 (ZNF217) and importin 7 (IPO7) were potential target genes of these miRNAs. Additionally, for two genes that are deregulated in PCa (heterogeneous nuclear ribonucleoprotein K, hnRNP-K, and vascular endothelial growth factor A, VEGF-A), we identified two regulatory miRNAs, miR-205 and miR-29b. The regulation of the 3'-untranslated regions of the four genes by their respective miRNAs was confirmed by luciferase assays. As expected, the upregulation of ZNF217, hnRNP-K, VEGF-A and IPO7 could be verified at the protein level in the PCa cell lines LNCaP and DU145. ZNF217 and IPO7, which had not yet been studied in PCa, were analyzed in more detail. ZNF217 mRNA is overexpressed in primary PCa samples, and this overexpression translates to an elevated protein level. However, IPO7 was upregulated at the protein level alone. The inhibition of ZNF217 and IPO7 by siRNA resulted in reduced proliferation of the PCa cell lines. ZNF217 could thus be identified as an oncogene that is overexpressed in PCa and affects the growth of PCa cell lines, whereas the function of IPO7 remains to be elucidated in greater detail. PMID- 22815236 TI - Robust analysis in joint models: an application to a study on muscular dystrophy. AB - Generalized partial ordinal models occur frequently in biomedical investigations where, along with ordinal longitudinal outcomes, there are time-dependent covariates that act nonparametrically. In these studies, an association between such outcomes and time to an event is of considerable interest to medical practitioners. The primary objective in the present article is to study the robustness of estimators of the parameters of interest in a joint generalized partial ordinal models and a time-to-event model, because in many situations, the estimators in such joint models are sensitive to outliers. A Monte Carlo Metropolis-Hastings Newton Raphson algorithm is proposed for robust estimation. A detailed simulation study was performed to justify the behavior of the proposed estimators. By way of motivation, we consider a data set concerning longitudinal outcomes of children involved in a study on muscular dystrophy. Our analysis revealed some interesting findings that may be useful to medical practitioners. PMID- 22815237 TI - Multimodality intracoronary imaging in spontaneous coronary artery dissection: impacts of intravascular ultrasound, optical coherence tomography, and coronary angioscopy. AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome and its etiology and pathogenesis have not been well understood. Intracoronary imaging modalities with intravascular ultrasound and optical coherence tomography would enable a precise diagnosis in this entity. Coronary angioscopy is also a unique tool for allowing direct visualization of the luminal surface of a vessel. We described an interesting case of SCAD documented with multimodality intracoronary imaging showing the presence of superficial lipid plaque nearby the coronary dissection entry point, which might have been associated with fragility of the arterial wall and the subsequent development of SCAD. PMID- 22815238 TI - Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study. AB - Pharmacometric characterization studies of liquiritigenin have historically overlooked its chiral nature. To achieve complete characterization, an analytical method enabling the detection and quantification of the individual enantiomers of racemic (+/-) liquiritigenin is necessary. Resolution of the enantiomers of liquiritigenin was achieved using a simple high-performance liquid chromatographic method. A Chiralpak(r) ADRH column was employed to perform baseline separation with UV detection at 210 nm.The standard curves were linear ranging from 0.5 to 100 ug/mL for each enantiomer. Limit of quantification was 0.5 ug/mL. The assay was applied successfully to stereoselective serum disposition of liquiritigenin enantiomers in rats. Liquiritigenin enantiomers were detected in serum as both aglycones and glucuronidated conjugates. Both unconjugated enantiomers had a serum half-life of ~15 min in rats. The volume of distribution (V(d) ) for S- and R-liquiritigenin was 1.49 and 2.21 L/kg, respectively. Total clearance (Cl(total) ) was 5.12 L/h/kg for S-liquiritigenin and 4.79 L/h/kg for R-liquiritigenin, and area under the curve (AUC(0-inf) ) was 3.95 ug h/mL for S-liquiritigenin and 4.23 ug h/mL for R-liquiritigenin. The large volume of distribution coupled with the short serum half-life suggests extensive distribution of liquiritigenin into tissues. PMID- 22815239 TI - Mangifera indica L. extract and mangiferin modulate cytochrome P450 and UDP glucuronosyltransferase enzymes in primary cultures of human hepatocytes. AB - The aqueous stem bark extract of Mangifera indica L. (MSBE) has been reported to have antioxidant, anti-inflammatory and analgesic properties. In previous studies, we showed that MSBE and mangiferin, its main component, lower the activity of some cytochrome P-450 (P450) enzymes in rat hepatocytes and human liver microsomes. In the present study, the effects of MSBE and mangiferin on several P450 enzymes and UDP-glucuronosyltransferases (UGTs) in human-cultured hepatocytes have been examined. After hepatocytes underwent a 48-h treatment with sub-cytotoxic concentrations of the products (50-250 ug/mL), a concentration dependent decrease of the activity of the five P450 enzymes measured (CYP1A2, 2A6, 2C9, 2D6 and 3A4) was observed. For all the activities, a reduction of at least 50% at the highest concentration (250 ug/mL) was observed. In addition, UGT activities diminished. MSBE considerably reduced UGT1A9 activity (about 60% at 250 ug/mL) and lesser effects on the other UGTs. In contrast, 250 ug/mL mangiferin had greater effects on UGT1A1 and 2B7 than on UGT1A9 (about 55% vs. 35% reduction, respectively). Quantification of specific mRNAs revealed reduced CYP3A4 and 3A5 mRNAs content, and an increase in CYP1A1, CYP1A2, UGT1A1 and UGT1A9 mRNAs. No remarkable effects on the CYP2A6, 2B6, 2C9, 2C19, 2D6 and 2E1 levels were observed. Our results suggest that the activity and/or expression of major P450 and UGT enzymes is modulated by MSBE and that potential herb-drugs interactions could arise after a combined intake of this extract with conventional medicines. Therefore, the potential safety risks of this natural product derived by altering the ADMET properties of co-administered drugs should be examined. PMID- 22815240 TI - Development and comparative assessment of Raman spectroscopic classification algorithms for lesion discrimination in stereotactic breast biopsies with microcalcifications. AB - Microcalcifications are an early mammographic sign of breast cancer and a target for stereotactic breast needle biopsy. Here, we develop and compare different approaches for developing Raman classification algorithms to diagnose invasive and in situ breast cancer, fibrocystic change and fibroadenoma that can be associated with microcalcifications. In this study, Raman spectra were acquired from tissue cores obtained from fresh breast biopsies and analyzed using a constituent-based breast model. Diagnostic algorithms based on the breast model fit coefficients were devised using logistic regression, C4.5 decision tree classification, k-nearest neighbor (k -NN) and support vector machine (SVM) analysis, and subjected to leave-one-out cross validation. The best performing algorithm was based on SVM analysis (with radial basis function), which yielded a positive predictive value of 100% and negative predictive value of 96% for cancer diagnosis. Importantly, these results demonstrate that Raman spectroscopy provides adequate diagnostic information for lesion discrimination even in the presence of microcalcifications, which to the best of our knowledge has not been previously reported. PMID- 22815241 TI - Body dysmorphic disorder in patients with obsessive-compulsive disorder: prevalence and clinical correlates. AB - BACKGROUND: The prevalence, sociodemographic aspects, and clinical features of body dysmorphic disorder (BDD) in patients with obsessive-compulsive disorder (OCD) have been previously addressed in primarily relatively small samples. METHODS: We performed a cross-sectional demographic and clinical assessment of 901 OCD patients participating in the Brazilian Research Consortium on Obsessive Compulsive Spectrum Disorders. We used the Structured Clinical Interview for DSM IV Axis I Disorders; Yale-Brown Obsessive-Compulsive Scale; Dimensional Yale Brown Obsessive-Compulsive Scale (DY-BOCS); Brown Assessment of Beliefs Scale; Clinical Global Impression Scale; and Beck Depression and Anxiety Inventories. RESULTS: The lifetime prevalence of BDD was 12.1%. The individuals with comorbid BDD (OCD-BDD; n = 109) were younger than were those without it. In addition, the proportions of single and unemployed patients were greater in the OCD-BDD group. This group of patients also showed higher rates of suicidal behaviors; mood, anxiety, and eating disorders; hypochondriasis; skin picking; Tourette syndrome; and symptoms of the sexual/religious, aggressive, and miscellaneous dimensions. Furthermore, OCD-BDD patients had an earlier onset of OC symptoms; greater severity of OCD, depression, and anxiety symptoms; and poorer insight. After logistic regression, the following features were associated with OCD-BDD: current age; age at OCD onset; severity of the miscellaneous DY-BOCS dimension; severity of depressive symptoms; and comorbid social phobia, dysthymia, anorexia nervosa, bulimia nervosa, and skin picking. CONCLUSIONS: Because OCD patients might not inform clinicians about concerns regarding their appearance, it is essential to investigate symptoms of BDD, especially in young patients with early onset and comorbid social anxiety, chronic depression, skin picking, or eating disorders. PMID- 22815242 TI - Avicenna's (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. AB - In this review, we introduce the traditional uses of saffron and its pharmacological activities as described by either Avicenna in Book II, Canon of Medicine (al-Qanun fi al-tib) or from recent scientific studies. Modern pharmacological findings on saffron are compared with those mentioned in Avicenna's monograph. A computerized search of published articles was performed using MEDLINE, Scopus and Web of Science databases as well as local references. The search terms used were saffron, Crocus sativus, crocin, crocetin, safranal, picrocrocin, Avicenna and 'Ibn Sina'. Avicenna described various uses of saffron, including its use as an antidepressant, hypnotic, anti-inflammatory, hepatoprotective, bronchodilatory, aphrodisiac, inducer of labour, emmenagogue and others. Most of these effects have been studied in modern pharmacology and are well documented. The pharmacological data on saffron and its constituents, including crocin, crocetin and safranal, are similar to those found in Avicenna's monograph. This review indicates that the evaluation of plants based on ethnobotanical information and ancient books may be a valuable approach to finding new biological activities and compounds. PMID- 22815243 TI - A novel application of contrast echocardiography to exclude active coronary perforation bleeding in patients with pericardial effusion. AB - Management of hemodynamically significant cardiac tamponade will most often require pericardial drainage. In the absence of hemodynamic evidence of tamponade, however, management of a pericardial effusion represents a clinical dilemma. Pericardial leakage of blood may be transient, and extravasation may have stopped by time of echocardiographic assessment. Besides its usefulness in ischemic heart disease, contrast echocardiography might be applied in the context of coronary perforations. We report the use of contrast echocardiography in four cases of coronary perforation without overt signs of cardiac tamponade as a tool to streamline decision making as to whether perform pericardiocentesis or not. Our series demonstrate the clinical utility and effectiveness of echocardiographic contrast imaging to confirm or exclude active bleeding into the pericardial space when not otherwise visible by conventional imaging measures. PMID- 22815244 TI - The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets. AB - SCOPE: Fumonisins (FB) are mycotoxins found in maize. The purpose of this study was to (i) determine the relationship between FB(1) , FB(2) , and FB(3) intake and urinary excretion in humans, (ii) validate a method to isolate urinary FB on C(18) -SPE cartridges for international shipment, and (iii) test the method using samples from Guatemala. METHODS AND RESULTS: Volunteers (n = 10) consumed 206 grams/day of tortillas and biscuits prepared from masa flour and a product containing maize flour. Volunteers estimated their daily urine output and samples were analyzed for FB(1) , FB(2) , and FB(3) and hydrolyzed FB(1) . Only FB(1) was detected in urine suggesting lower absorption of FB(2) and FB(3) . Excretion was highly variable peaking soon after consumption began and decreasing rapidly after consumption stopped. Within 5 days after consumption ended, FB(1) was not detected in urine. In a study with eight volunteers, the average total urinary FB(1) was 0.5% of the intake. FB(1) was detected in 61% (107/177) of the samples collected in Guatemala. CONCLUSION: The results support the use of urinary FB(1) to assess ongoing exposure in population-based studies. However, relating the FB(1) concentration in urine to dietary intake of FB by individual subjects will be complicated due to interindividual variability and the rapidity of clearance. PMID- 22815245 TI - An examination of the diagnostic efficiency of post-deployment mental health screens. AB - OBJECTIVE: To conduct a blinded study to examine the diagnostic efficiency of the Department of Defense (DoD) Post-Deployment Health Reassessment (PDHRA) screens for major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and alcohol abuse. METHOD: Participants were 148 post-deployed soldiers who were completing the PDHRA protocol. Soldiers' mean age was 27.7 (standard deviation = 6.6) years, and 89.0% were male. Mental health professionals blinded to the PDHRA screening results administered the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition directly after the PDHRA assessment protocol. RESULTS: All screens exhibited excellent negative predictive power. Sensitivity metrics were lower, consistent with the relatively low base rates observed for MDD (10.1%), PTSD (8.8%), and alcohol abuse (5.4%). Metrics obtained for the PTSD screen were consistent with previous research with a similar base rate. A two-item screen containing PTSD reexperiencing and hyperarousal symptom items revealed excellent psychometric properties (sensitivity = .92; specificity = .79). The alcohol abuse screen yielded high sensitivity (.86), but very poor precision; these metrics were somewhat improved when the screen was reduced to a single item. CONCLUSIONS: The PDHRA MDD, PTSD, and alcohol abuse screens appear to be functioning well in accurately ruling out these diagnoses, consistent with a population-level screening program. Cross validation of the current results is indicated. Additional refinement may yield more sensitive screening measures within constraints imposed by the low base rates in a typically healthy population. PMID- 22815246 TI - Mortality and the risk of malignancy in autoimmune liver diseases: a population based study in Canterbury, New Zealand. PMID- 22815247 TI - Personalized treatment of adult depression: medication, psychotherapy, or both? A systematic review. AB - BACKGROUND: Personalized medicine aims to identify which characteristics of an individual predict the outcome of a specific treatment, in order to get a better match between the individual and the treatment received. We conducted a systematic review and meta-analysis of randomized trials comparing two treatments directly in a group of patients with a specific characteristic. METHODS: We searched relevant studies from bibliographical databases and included trials comparing (1) medication with psychotherapy, (2) medication with combined treatment, and (3) psychotherapy with combined treatment, in specific target groups (a) with a predefined sociodemographic characteristic, (b) a specific type of depression, (c) a comorbid mental or somatic disorder, or (d) from a specific setting (outpatients, primary care). RESULTS: We included 52 studies with 4,734 depressed patients. In these studies, 20 characteristics of the target groups were examined. The results showed that medication is probably the best treatment for dysthymia, and combined treatments are more effective in depressed outpatients, as well as in depressed older adults. However, in order to examine the 20 characteristics in the three categories of comparisons, 254 studies would be needed for having sufficient statistical power to show an effect size of g = 0.5. Currently, only 20.1% of these studies have been conducted. CONCLUSIONS: Although a considerable number of studies have compared medication, psychotherapy, and combined treatments, and some preliminary results are useful for deciding which treatment is best for which patient, the development of personalized treatment of depression has only just begun. PMID- 22815248 TI - Protective effects of a purified saponin mixture from Astragalus corniculatus Bieb., in vivo hepatotoxicity models. AB - In this study, the in vivo effects of a purified saponin mixture (PSM), obtained from Astragalus corniculatus Bieb., were investigated using two in vivo hepatotoxicity models based on liver damage caused by paracetamol (PC) and carbon tetrachloride (CCl4 ). The effects of PSM were compared with silymarin. Male Wistar rats were challenged orally with 20% CCl4 or PC (2 g/kg) four days after being pre-treated with PSM (100 mg/kg) or silymarin (200 mg/kg). A significant decrease of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) activities and glutathione (GSH) levels and an increase of malondialdehyde (MDA) quantity was observed after CCl4 and PC administration alone. PSM pre-treatment decreased serum transaminases and LDH activities and MDA levels and increased the levels of cell protector GSH. Biotransformation phase I enzymes were also assessed in both models. In the CCl4 hepatotoxicity model, pre treatment with PSM or silymarin resulted in significantly increased activities of ethylmorphine-N-demethylase and aniline 4-hydroxylase activity and cytochrome P450, compared to the CCl4 only group. Neither silymarin nor PSM influenced PC biotransformation. Our results suggest that PSM, obtained from A. corniculatus, Bieb. showed in vivo hepatoprotective and antioxidant activities against CCl4 and PC-induced liver damage comparable to that of silymarin. PMID- 22815249 TI - Interpreting CARS images of tissue within the C-H-stretching region. AB - Single band coherent anti-Stokes Raman scattering (CARS) microscopy is one of the fastest implementation of nonlinear vibrational imaging allowing for video-rate image acquisition of tissue. This is due to the large Raman signal in the C-H stretching region. However, the chemical specificity of such images is conventionally assumed to be low. Nonetheless, CARS imaging within the C-H stretching region enables detection of single cells and nuclei, which allows for histopathologic grading of tissue. Relevant information such as nucleus to cytoplasm ratio, cell density, nucleus size and shape is extracted from CARS images by innovative image processing procedures. In this contribution CARS image contrast within the C-H-stretching region is interpreted by direct comparison with Raman imaging and correlated to the tissue composition justifying the use of CARS imaging in this wavenumber region for biomedical applications. PMID- 22815250 TI - Initial clinical experience with the Coherex FlatStentTM and FlatStentTM EF PFO closure system for in-tunnel PFO closure: results of the Coherex-EU study. AB - OBJECTIVE: The Coherex-EU Study evaluated the safety and efficacy of PFO closure utilizing novel in-tunnel PFO closure devices. BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) followed the development of transcatheter closure devices designed to patch atrial septal defects (ASDs). The Coherex FlatStentTM and FlatStentTM EF devices were designed specifically to treat PFO anatomy. METHODS: A total of 95 patients with a clinical indication for PFO closure were enrolled in a prospective, multicenter first in man study at six clinical sites. Thirty-six patients received the first-generation FlatStent study device, and 57 patients received the second-generation FlatStent EF study device, which was modified based on clinical experience during the first 38 cases. Two patients enrolled to receive the first generation did not receive a device. RESULTS: At 6 months post-procedure, 45% (17/38) of the intention-to-treat (ITT) cohort receiving the first-generation FlatStent device had complete closure, 26% (10/38) had a trivial residual shunt, and 29% (11/38) had a moderate to large residual shunt. In the ITT cohort receiving the second-generation FlatStent EF device, 76% (43/57) had complete closure, 12% (7/57) had a trivial shunt, and 12% had a moderate to large shunt. Five major adverse events occurred, all without sequelae. CONCLUSION: This initial study of the Coherex FlatStent/FlatStent EF PFO Closure System demonstrated the potential for in-tunnel PFO closure. The in tunnel Coherex FlatStent EF may offer an alternative to septal repair devices for PFO closure in appropriately selected patients; however, further investigation will be necessary to establish the best use of this device. PMID- 22815251 TI - Effects of physicochemical properties of carotenoids on their bioaccessibility, intestinal cell uptake, and blood and tissue concentrations. AB - SCOPE: Carotenoid bioavailability is affected by numerous factors. Our aim was to assess the involvement of known carotenoid physicochemical properties (e.g., hydrophobicity, van der Waals volume,...) on the transport of the main dietary carotenoids (beta-carotene, lycopene, lutein, and astaxanthin, from their food matrix to their main storage tissues. METHODS AND RESULTS: We used four complementary models: synthetic mixed micelles, an in vitro digestion procedure, Caco-2 cell monolayers, and a gavage experiment in rats. The efficiency with which pure carotenoids were incorporated into synthetic mixed micelles was related to their melting points (r = 0.99, p = 0.015). The efficiency with which pure carotenoids were transferred from dietary triglycerides into mixed micelles was related to carotenoid hydrophobicity (r = -1, p = 0.005). There was no relationship between the carotenoid physicochemical properties studied and their uptake efficiency by Caco-2. The postprandial plasma carotenoid response to carotenoid gavage was related to carotenoid hydrophobicity (r = -0.99, p = 0.006). Carotenoid adipose tissue response was not related to the carotenoid physicochemical properties studied. CONCLUSION: Thus, carotenoid hydrophobicity is important for bioaccessibility and postprandial blood response of carotenoids. In contrast, the carotenoid physicochemical properties studied are apparently not strong determinants of carotenoid uptake by enterocytes and adipose tissue. PMID- 22815252 TI - Sustained virologic response: is this equivalent to cure of chronic hepatitis C? PMID- 22815253 TI - Religious distress and coping with stressful life events: a longitudinal study. AB - OBJECTIVE(S): HYPOTHESIS: Religious strain would mediate the relationship between stress symptoms at baseline and stress symptoms 1 year later. METHOD: Seventy-nine people with a history of stressful life events (55 women, 23 men, one unknown gender, average age 58 years) from community churches reported stressful life events, spiritual adjustment, and posttraumatic stress symptoms at initial assessment and 1-year follow-up. RESULTS: Religious strain mediated the relationship between baseline and follow-up posttraumatic stress symptoms. CONCLUSIONS: Because religious distress contributed to prediction of stress symptoms over time, it appears that religious distress is related to adjustment to stressful life events. PMID- 22815254 TI - Attention bias of anxious youth during extended exposure of emotional face pairs: an eye-tracking study. AB - BACKGROUND: Previous studies demonstrate that anxiety is characterized by biased attention toward threats, typically measured by differences in motor reaction time to threat and neutral cues. Using eye-tracking methodology, the current study measured attention biases in anxious and nonanxious youth, using unrestricted free viewing of angry, happy, and neutral faces. METHODS: Eighteen anxious and 15 nonanxious youth (8-17 years old) passively viewed angry-neutral and happy-neutral face pairs for 10 s while their eye movements were recorded. RESULTS: Anxious youth displayed a greater attention bias toward angry faces than nonanxious youth, and this bias occurred in the earliest phases of stimulus presentation. Specifically, anxious youth were more likely to direct their first fixation to angry faces, and they made faster fixations to angry than neutral faces. CONCLUSIONS: Consistent with findings from earlier, reaction-time studies, the current study shows that anxious youth, like anxious adults, exhibit biased orienting to threat-related stimuli. This study adds to the existing literature by documenting that threat biases in eye-tracking patterns are manifest at initial attention orienting. PMID- 22815255 TI - EPSPS gene amplification in glyphosate-resistant Italian ryegrass (Lolium perenne ssp. multiflorum) from Arkansas. AB - BACKGROUND: Resistance to glyphosate in weed species is a major challenge for the sustainability of glyphosate use in crop and non-crop systems. A glyphosate resistant Italian ryegrass population has been identified in Arkansas. This research was conducted to elucidate its resistance mechanism. RESULTS: The investigation was conducted on resistant and susceptible plants from a population in Desha County, Arkansas (Des03). The amounts of glyphosate that caused 50% overall visual injury were 7 to 13 times greater than those for susceptible plants from the same population. The EPSPS gene did not contain any point mutation that has previously been associated with resistance to glyphosate, nor were there any other mutations on the EPSPS gene unique to the Des03 resistant plants. The resistant plants had 6-fold higher basal EPSPS enzyme activities than the susceptible plants, but their I(50) values in response to glyphosate were similar. The resistant plants contained up to 25 more copies of EPSPS gene than the susceptible plants. The level of resistance to glyphosate correlated with increases in EPSPS enzyme activity and EPSPS copy number. CONCLUSION: Increased EPSPS gene amplification and EPSPS enzyme activity confer resistance to glyphosate in the Des03 population. This is the first report of EPSPS gene amplification in glyphosate-resistant Italian ryegrass. Other resistance mechanism(s) may also be involved. PMID- 22815257 TI - Liquid-liquid/solid three-phase high-speed counter-current chromatography, a new technique for separation of polyphenols from Geranium wilfordii Maxim. AB - High-speed counter-current chromatography using a new liquid-liquid/solid three phase system was used for the separation of the polyphenols corilagin and geraniin from a crude extract of Geranium wilfordii Maxim in one step. The optimized three-phase system was composed of n-hexane/ethyl acetate/methanol/acetic acid/water and to which was added 10-MUm average diameter microspheres of cross-linked 12% agarose at the ratio of 0.2:10:2:1:5 and 0.1 g/mL, respectively. The purities of geraniin and corilagin were 82 and 90%, which were determined by HPLC at 280 nm. A 14.5 and 7 mg of geraniin and corilagin were purified from 160 mg crude extract with the yields of 70 and 78%, respectively. PMID- 22815256 TI - TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis. AB - Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. CONCLUSION: TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver. PMID- 22815258 TI - Metabolic labeling of DNA by purine analogues in vivo. PMID- 22815259 TI - Evaluating the feasibility of utilizing the small molecule phenamil as a novel biofactor for bone regenerative engineering. AB - Osteoblast cell adhesion and differentiation on biomaterials are important achievements necessary for implants to be useful in bone regenerative engineering. Recombinant bone morphogenetic proteins (BMPs) have been shown to be important for these processes; however, there are many challenges associated with the widespread use of these proteins. A recent report demonstrated that the small molecule phenamil, a diuretic derivative, was able to induce osteoblast differentiation and mineralization in vitro via the canonical BMP signalling cascade (Park et al., 2009). In this study, the feasibility of using phenamil as a novel biofactor in conjunction with a biodegradable poly(lactide-co-glycolide acid) (PLAGA) polymeric scaffold for engineering bone tissue was evaluated. The in vitro cellular behaviour of osteoblast-like MC3T3-E1 cells cultured on PLAGA scaffolds in the presence of phenamil at 10 MUM were characterized with regard to initial cell adhesion, proliferation, alkaline phosphatase (ALP) activity and matrix mineralization. The results demonstrate that phenamil supported cell proliferation, promoted ALP activity and facilitated matrix mineralization of osteoblast-like MC3T3-E1 cells. Moreover, in this study, we found that phenamil promoted integrin-mediated cell adhesion on PLAGA scaffolds. It was also shown that phenamil encapsulated within porous, microsphere PLAGA scaffolds retained its osteogenic activity upon release. Based on these findings, the small molecule phenamil has the potential to serve as a novel biofactor for the repair and regeneration of bone tissues. PMID- 22815260 TI - Aerosol delivery of trail pheromone disrupts the foraging of the red imported fire ant, Solenopsis invicta. AB - BACKGROUND: The fire ant, Solenopsis invicta, is one of the most aggressive and invasive species in the world. The trail pheromone Z,E-alpha-farnesene (91% purity) was prepared, and disruption of worker trail orientation was tested using an ethanol-based aerosol formulation presenting a single puff of this compound by airbrush and compressed air. Trail-following behaviour was recorded by overhead webcam and ants digitised before and after presentation of the aerosol treatment at four rates (1.6, 16, 160 and 1600 ng cm(-2)). RESULTS: Ants preferred 110 ng cm(-1) over 11, 1.1 and 0.11 ng cm(-1) for trail following. Within seconds of presentation of 1600 ng cm(-2), the highest dose tested, trail disruption was observed. Disruption was evident as reduced arrival success and reduction in the trail integrity statistic (r(2)), as well as increased deviation from the trail (deg). The distribution of walking track angles was also flattened. CONCLUSIONS: The feasibility of using aerosol for delivery of trail pheromone was demonstrated, but the need for high purity combined with the difficulty of commercial supply makes this technique impractical. However, the commercial production of Z,E-alpha-farnesene of high purity by industrial biotechnology or from (E)-nerolidol may be possible in future, which would facilitate further development of trail pheromone disruption of S. invicta. PMID- 22815261 TI - Ultrasound-assisted extraction, HPLC analysis, and antioxidant activity of polyphenols from unripe apple. AB - The polyphenols were extracted from the unripe apple assisted by a highly efficient and simple method of the ultrasound. Response surface methodology was used to investigate the effects of processing parameters, including ultrasound power, extraction time, temperature, and ethanol concentration on total polyphenols yield and polyphenols composition was analyzed by HPLC. Antioxidant activity of the polyphenols was evaluated as 2, 2-diphenyl-1-picrylhydracyl scavenging activity and inhibition activity of lipid peroxidation. The results showed that 10-100 times higher total polyphenols yield was obtained from the unripe apple than those from the reported apple pomace. The optimum extraction conditions were ultrasonic power of 519.39 W, extraction time of 30 min, extraction temperature 50 degrees C, ethanol concentration of 50% gave the total polyphenols yield of 13.26 +/- 0.56 mg GAE/g. HPLC analysis indicated that (-) epicatechin, procyanidin B2, chlorogenic acid, and procyanidin B1 were the predominant polyphenols in unripe apple, which contributed to the higher antioxidant activity to 2, 2-diphenyl-1-picrylhydracyl of unripe apple polyphenols than other apple polyphenols. The extracted polyphenols had higher ability to inhibit lipid peroxidation than butylated hydroxy toluene, which demonstrated that the unripe apple polyphenols have the potential to be used as a substitute of some synthetic antioxidants. PMID- 22815263 TI - Screening of radical scavengers in Scutellaria baicalensis using HPLC with diode array and chemiluminescence detection. AB - Scutellaria baicalensis Georgi is a well-known medical plant widely used as a famous traditional Chinese medicine. It has been reported that S. baicalensis can protect against oxidative stress and possess anti-inflammatory effect. In the present paper, an HPLC-diode array-chemiluminescence detection method for on-line detection was successfully developed to screen antioxidants in complex S. baicalensis extracts. Using the proposed approach, eight compounds in the S. baicalensis extracts were found to possess a potential antioxidant activity. Furthermore, the effects of purified compounds on protecting RAW 264.7 cells from hydrogen peroxide injury were also investigated in vitro to confirm the established method, which were consistent with the results of HPLC-diode array chemiluminescence detection method. These results demonstrated that this method was a useful technique for rapidly screening and identifying bioactive components from complex herbal medicines. PMID- 22815264 TI - Time-lapse microscopy and classification of 2D human mesenchymal stem cells based on cell shape picks up myogenic from osteogenic and adipogenic differentiation. AB - Current methods to characterize mesenchymal stem cells (MSCs) are limited to CD marker expression, plastic adherence and their ability to differentiate into adipogenic, osteogenic and chondrogenic precursors. It seems evident that stem cells undergoing differentiation should differ in many aspects, such as morphology and possibly also behaviour; however, such a correlation has not yet been exploited for fate prediction of MSCs. Primary human MSCs from bone marrow were expanded and pelleted to form high-density cultures and were then randomly divided into four groups to differentiate into adipogenic, osteogenic chondrogenic and myogenic progenitor cells. The cells were expanded as heterogeneous and tracked with time-lapse microscopy to record cell shape, using phase-contrast microscopy. The cells were segmented using a custom-made image processing pipeline. Seven morphological features were extracted for each of the segmented cells. Statistical analysis was performed on the seven-dimensional feature vectors, using a tree-like classification method. Differentiation of cells was monitored with key marker genes and histology. Cells in differentiation media were expressing the key genes for each of the three pathways after 21 days, i.e. adipogenic, osteogenic and chondrogenic, which was also confirmed by histological staining. Time-lapse microscopy data were obtained and contained new evidence that two cell shape features, eccentricity and filopodia (= 'fingers') are highly informative to classify myogenic differentiation from all others. However, no robust classifiers could be identified for the other cell differentiation paths. The results suggest that non-invasive automated time-lapse microscopy could potentially be used to predict the stem cell fate of hMSCs for clinical application, based on morphology for earlier time-points. The classification is challenged by cell density, proliferation and possible unknown donor-specific factors, which affect the performance of morphology-based approaches. PMID- 22815262 TI - Microarray analysis of Xenopus endoderm expressing Ptf1a. AB - Pancreas-specific transcription factor 1a (Ptf1a), a bHLH transcription factor, has two temporally distinct functions during pancreas development; initially it is required for early specification of the entire pancreas, while later it is required for proper differentiation and maintenance of only acinar cells. The importance of Ptf1a function was revealed by the fact that loss of Ptf1a leads to pancreas agenesis in humans. While Ptf1a is one of the most important pancreatic transcription factors, little is known about the differences between the regulatory networks it controls during initial specification of the pancreas as opposed to acinar cell development, and to date no comprehensive analysis of its downstream targets has been published. In this article, we use Xenopus embryos to identify putative downstream targets of Ptf1a. We isolated anterior endoderm tissue overexpressing Ptf1a at two early stages, NF32 and NF36, and compared their gene expression profiles using microarrays. Our results revealed that Ptf1a regulates genes with a wide variety of functions, providing insight into the complexity of the regulatory network required for pancreas specification. PMID- 22815265 TI - A simple gas chromatography method for the analysis of monoethanolamine in air. AB - A simple method determining airborne monoethanolamine has been developed. Monoethanolamine determination has traditionally been difficult due to analytical separation problems. Even in recent sophisticated methods, this difficulty remains as the major issue often resulting in time-consuming sample preparations. Impregnated glass fiber filters were used for sampling. Desorption of monoethanolamine was followed by capillary GC analysis and nitrogen phosphorous selective detection. Separation was achieved using a specific column for monoethanolamines (35% diphenyl and 65% dimethyl polysiloxane). The internal standard was quinoline. Derivatization steps were not needed. The calibration range was 0.5-80 MUg/mL with a good correlation (R(2) = 0.996). Averaged overall precisions and accuracies were 4.8% and -7.8% for intraday (n = 30), and 10.5% and -5.9% for interday (n = 72). Mean recovery from spiked filters was 92.8% for the intraday variation, and 94.1% for the interday variation. Monoethanolamine on stored spiked filters was stable for at least 4 weeks at 5 degrees C. This newly developed method was used among professional cleaners and air concentrations (n = 4) were 0.42 and 0.17 mg/m(3) for personal and 0.23 and 0.43 mg/m(3) for stationary measurements. The monoethanolamine air concentration method described here was simple, sensitive, and convenient both in terms of sampling and analytical analysis. PMID- 22815266 TI - Advances in molecular genetics of Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cells to fully colonize the gut during embryonic development. It is characterized by the absence of the enteric ganglia in a variable length of the intestine. Substantial progress has been made in understanding the genetic basis of HSCR with the help of advanced genetic analysis techniques and animal models. More than 11 genes have been found to be involved in the pathogenesis of HSCR. The RET gene is the most important susceptibility gene involved in HSCR with both coding and non- coding sequence mutations. Due to phenotypic diversity and genetic complexity observed in HSCR, mutational analysis has limited practical value in genetic counseling and clinical practice. In this review, we discuss the progress that has been made in understanding the molecular genetics of HSCR and summarize the currently identified genes as well as interactions between pathways and gene-modifying loci in HSCR. PMID- 22815267 TI - London 2012--what health impact? PMID- 22815268 TI - Skew-elliptical spatial random effect modeling for areal data with application to mapping health utilization rates. AB - Mixed models incorporating spatially correlated random effects are often used for the analysis of areal data. In this setting, spatial smoothing is introduced at the second stage of a hierarchical framework, and this smoothing is often based on a latent Gaussian Markov random field. The Markov random field provides a computationally convenient framework for modeling spatial dependence; however, the Gaussian assumption underlying commonly used models can be overly restrictive in some applications. This can be a problem in the presence of outliers or discontinuities in the underlying spatial surface, and in such settings, models based on non-Gaussian spatial random effects are useful. Motivated by a study examining geographic variation in the treatment of acute coronary syndrome, we develop a robust model for smoothing small-area health service utilization rates. The model incorporates non-Gaussian spatial random effects, and we develop a formulation for skew-elliptical areal spatial models. We generalize the Gaussian conditional autoregressive model to the non-Gaussian case, allowing for asymmetric skew-elliptical marginal distributions having flexible tail behavior. The resulting new models are flexible, computationally manageable, and can be implemented in the standard Bayesian software WinBUGS. We demonstrate performance of the proposed methods and comparisons with other commonly used Gaussian and non Gaussian spatial prior formulations through simulation and analysis in our motivating application, mapping rates of revascularization for patients diagnosed with acute coronary syndrome in Quebec, Canada. PMID- 22815269 TI - Molecular surveillance and phylogenetic analysis of Old World arenaviruses in Zambia. AB - In order to survey arenaviruses in the Republic of Zambia, we captured 335 rodents from three cities between 2010 and 2011. Eighteen Luna virus (LUNV) and one lymphocytic choriomeningitis virus (LCMV)-related virus RNAs were detected by one-step RT-PCR from Mastomys natalensis and Mus minutoides, respectively. Four LUNV strains and one LCMV-related virus were isolated, and the whole genome nucleotide sequence was determined by pyrosequencing. Phylogenetic analyses revealed that the LUNV clade consists of two branches that are distinguished by geographical location and that the LCMV-related virus belongs to the LCMV clade, but diverges from the typical LCMVs. Comparison of nucleoprotein amino acid sequences indicated that the LCMV-related virus could be designated a novel arenavirus, which was tentatively named as the Lunk virus. Amino acid sequences of the GP, NP, Z and L proteins showed poor similarity among the three Zambian arenavirus strains, i.e. Luna, Lunk and Lujo virus. PMID- 22815270 TI - The movement protein encoded by gene 3 of rice transitory yellowing virus is associated with virus particles. AB - Gene 3 in the genomes of several plant-infecting rhabdoviruses, including rice transitory yellowing virus (RTYV), has been postulated to encode a cell-to-cell movement protein (MP). Trans-complementation experiments using a movement defective tomato mosaic virus and the P3 protein of RTYV, encoded by gene 3, facilitated intercellular transport of the mutant virus. In transient-expression experiments with the GFP-fused P3 protein in epidermal leaf cells of Nicotiana benthamiana, the P3 protein was associated with the nucleus and plasmodesmata. Immunogold-labelling studies of thin sections of RTYV-infected rice plants using an antiserum against Escherichia coli-expressed His(6)-tagged P3 protein indicated that the P3 protein was located in cell walls and on virus particles. In Western blots using antisera against E. coli-expressed P3 protein and purified RTYV, the P3 protein was detected in purified RTYV, whilst antiserum against purified RTYV reacted with the E. coli-expressed P3 protein. After immunogold labelling of crude sap from RTYV-infected rice leaves, the P3 protein, as well as the N protein, was detected on the ribonucleocapsid core that emerged from partially disrupted virus particles. These results provide evidence that the P3 protein of RTYV, which functions as a viral MP, is a viral structural protein and seems to be associated with the ribonucleocapsid core of virus particles. PMID- 22815271 TI - Tat has a dual role in simian immunodeficiency virus transcription. AB - Tat has a pivotal role in human and simian immunodeficiency virus (HIV and SIV) replication because it stimulates transcription by binding to the trans-activator response (TAR) element. In addition, several other Tat functions have been proposed. Most studies have focused on HIV-1 Tat and much less is known about SIV Tat. An SIVmac239 variant was constructed previously in which the Tat-TAR transcription mechanism is functionally replaced by the doxycycline-inducible Tet On gene expression mechanism (SIV-rtTA). In this study, SIV-rtTA variants were used to analyse the functions of SIV Tat. It was shown that Tat-minus SIV-rtTA variants replicated efficiently in PM1 T-cells, ruling out an additional essential Tat function. Nevertheless, replication was suboptimal in other cells, and evolutionary pressure to repair Tat expression was documented. It was demonstrated that SIV-rtTA required Tat for optimal gene expression, despite the absence of the Tat-TAR axis. This Tat effect was lost upon replacement of the long terminal repeat promoter region by a non-related promoter. These results indicate that Tat can activate SIV transcription via TAR RNA and U3 DNA elements but has no other essential function in replication in cultured cells. The experiments were limited to cell lines and PBMCs, and did not exclude an accessory Tat function under specific conditions or in vivo. PMID- 22815272 TI - Permissive and restricted virus infection of murine embryonic stem cells. AB - Recent RNA interference (RNAi) studies have identified many host proteins that modulate virus infection, but small interfering RNA 'off-target' effects and the use of transformed cell lines limit their conclusiveness. As murine embryonic stem (mES) cells can be genetically modified and resources exist where many and eventually all known mouse genes are insertionally inactivated, it was reasoned that mES cells would provide a useful alternative to RNAi screens. Beyond allowing investigation of host-pathogen interactions in vitro, mES cells have the potential to differentiate into other primary cell types, as well as being used to generate knockout mice for in vivo studies. However, mES cells are poorly characterized for virus infection. To investigate whether ES cells can be used to explore host-virus interactions, this study characterized the responses of mES cells following infection by herpes simplex virus type 1 (HSV-1) and influenza A virus. HSV-1 replicated lytically in mES cells, although mES cells were less permissive than most other cell types tested. Influenza virus was able to enter mES cells and express some viral proteins, but the replication cycle was incomplete and no infectious virus was produced. Knockdown of the host protein AHCYL1 in mES cells reduced HSV-1 replication, showing the potential for using mES cells to study host-virus interactions. Transcriptional profiling, however, indicated the lack of an efficient innate immune response in these cells. mES cells may thus be useful to identify host proteins that play a role in virus replication, but they are not suitable to determine factors that are involved in innate host defence. PMID- 22815273 TI - Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor. AB - Dengue virus (DENV) causes dengue fever and dengue haemorrhagic fever/dengue shock syndrome, both considered major public-health problems worldwide. We generated a lethal DENV-2 strain (D220) by 10 additional cycles of subcutaneous inoculation of mice with supernatant from mosquito cells infected with the previously characterized strain D2S10, followed by harvesting of serum. D220 induces mortality at ten-fold lower doses than D2S10 in mice lacking only the alpha/beta interferon (IFN-alpha/beta) receptor in C57BL/6 or 129 backgrounds under both non-enhanced and antibody-enhanced conditions. Sequence analysis of the complete viral genome revealed five amino acid changes between D220 and D2S10, of which two (K122I in envelope and V115A in NS4B) appear to account for the observed phenotypic differences between the viruses. By causing mortality at lower doses in C57BL/6 mice lacking only the IFN-alpha/beta receptor, D220 constitutes an improved tool for study of DENV-induced pathogenesis, as well as for testing potential vaccines and antiviral drugs against DENV. PMID- 22815274 TI - Strain-dependent effects of PB1-F2 of triple-reassortant H3N2 influenza viruses in swine. AB - The PB1-F2 protein of the influenza A viruses (IAVs) can act as a virulence factor in mice. Its contribution to the virulence of IAV in swine, however, remains largely unexplored. In this study, we chose two genetically related H3N2 triple-reassortant IAVs to assess the impact of PB1-F2 in virus replication and virulence in pigs. Using reverse genetics, we disrupted the PB1-F2 ORF of A/swine/Wisconsin/14094/99 (H3N2) (Sw/99) and A/turkey/Ohio/313053/04 (H3N2) (Ty/04). Removing the PB1-F2 ORF led to increased expression of PB1-N40 in a strain-dependent manner. Ablation of the PB1-F2 ORF (or incorporation of the N66S mutation in the PB1-F2 ORF, Sw/99 N66S) affected the replication in porcine alveolar macrophages of only the Sw/99 KO (PB1-F2 knockout) and Sw/99 N66S variants. The Ty/04 KO strain showed decreased virus replication in swine respiratory explants, whereas no such effect was observed in Sw/99 KO, compared with the wild-type (WT) counterparts. In pigs, PB1-F2 did not affect virus shedding or viral load in the lungs for any of these strains. Upon necropsy, PB1 F2 had no effect on the lung pathology caused by Sw/99 variants. Interestingly, the Ty/04 KO-infected pigs showed significantly increased lung pathology at 3 days post-infection compared with pigs infected with the Ty/04 WT strain. In addition, the pulmonary levels of interleukin (IL)-6, IL-8 and gamma interferon were regulated differentially by the expression of PB1-F2. Taken together, these results indicate that PB1-F2 modulates virus replication, virulence and innate immune responses in pigs in a strain-dependent fashion. PMID- 22815275 TI - Characterization of epitope-tagged foot-and-mouth disease virus. AB - Foot-and-mouth disease (FMD) is a highly contagious and economically devastating disease of cloven-hoofed animals with an almost-worldwide distribution. Conventional FMD vaccines consisting of chemically inactivated viruses have aided in the eradication of FMD from Europe and remain the main tool for control in endemic countries. Although significant steps have been made to improve the quality of vaccines, such as improved methods of antigen concentration and purification, manufacturing processes are technically demanding and expensive. Consequently, there is large variation in the quality of vaccines distributed in FMD-endemic countries compared with those manufactured for emergency use in FMD free countries. Here, we have used reverse genetics to introduce haemagglutinin (HA) and FLAG tags into the foot-and-mouth disease virus (FMDV) capsid. HA- and FLAG-tagged FMDVs were infectious, with a plaque morphology similar to the non tagged parental infectious copy virus and the field virus. The tagged viruses utilized integrin-mediated cell entry and retained the tag epitopes over serial passages. In addition, infectious HA- and FLAG-tagged FMDVs were readily purified from small-scale cultures using commercial antibodies. Tagged FMDV offers a feasible alternative to the current methods of vaccine concentration and purification, a potential to develop FMD vaccine conjugates and a unique tool for FMDV research. PMID- 22815276 TI - Full genome analysis of group B rotaviruses from western India: genetic relatedness and evolution. AB - To date, full-genome sequences of only seven human group B rotavirus (RVBs) strains have been described. Such data on more RVBs are necessary to establish the evolutionary relationship and ecological features of RVBs from different geographical regions. The present study was aimed at determining the full-length sequences of all 11 genes of 13 human RVB strains detected during 1995-2010 in sporadic and outbreak cases of acute gastroenteritis from four different cities of western India. This study also included estimation of evolutionary rates and site-specific selection pressure analysis for all gene segments. Nucleotide/deduced amino acid sequence analyses of structural and non-structural genes showed 95.1-99.8/94.1-100 % identity with the counterparts of RVB strains isolated in India, Bangladesh and Myanmar. Phylogenetic analyses of all gene segments revealed formation of a monophyletic clade of the western Indian RVB strains, reflecting their highly conserved nature. All gene segments were also found to be under negative/purifying selection pressure. These data suggest that RVB is circulating in the natural host as a series of stable viral clones. Estimates of rates of nucleotide substitution in all RVBs ranged from 1.36 4.78*10(-3) substitutions per site per year. The rate for human RVB VP7 and NSP2 genes were comparable, respectively, with the evolution kinetics of genotype G9/G12 and N1 group A rotavirus strains. The time of the most recent common ancestor of the extant human RVBs was estimated to be during 1915-1974. Evolutionary and genetic analyses carried out in this study provide data that is useful for the elucidation of evolutionary relationship/timescale, stasis or dynamics existing in the RVB population. PMID- 22815277 TI - Network meta-analysis models to account for variability in treatment definitions: application to dose effects. AB - For a network meta-analysis, an interlinked network of nodes representing competing treatments is needed. It is often challenging to define the nodes as these typically refer to similar but rarely identical interventions. The objectives of this paper are as follows: (i) to present a series of network meta analysis models that account for variation in the definition of the nodes and (ii) to exemplify the models where variation in the treatment definitions relates to the dose. Starting from the model that assumes each node has a 'fixed' definition, we gradually introduce terms to explain variability by assuming that each node has several subnodes that relate to different doses. The effects of subnodes are considered monotonic, linked with a 'random walk', random but exchangeable, or have a linear pattern around the treatment mean effect. Each model can be combined with different assumptions for the consistency of effects and might impact on the ranking of the treatments. Goodness of fit, heterogeneity and inconsistency were assessed. The models are illustrated in a star network for the effectiveness of fluoride toothpaste and in a full network comparing agents for multiple sclerosis. The fit and parsimony measures indicate that in the fluoride network the impact of the dose subnodes is important whereas in the multiple sclerosis network the model without subnodes is the most appropriate. The proposed approach can be a useful exploratory tool to explain sources of heterogeneity and inconsistency when there is doubt whether similar interventions should be grouped under the same node. PMID- 22815279 TI - More on the management of ascites. PMID- 22815278 TI - Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia. AB - To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60 years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1-2 in 38 patients and grades 3-4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0 months (interquartile range 3.6-18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease ( p = 0.035) and initial daily dose of dasatinib (140 mg vs 100 mg, p = 0.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected 'real-life' population of elderly patients but were clinically manageable and did not seem to affect treatment results. PMID- 22815281 TI - Changes of postural steadiness following use of prefabricated orthotic insoles. AB - Orthoses are designed to assist a malaligned foot in adapting to the environment and reduce the frequency of injury. Literature is divided on the benefits of orthotics insoles for postural stability. The current study was conducted to determine the effect of prefabricated orthotic arch supports on postural stabilization. Twelve healthy young adults participated in this study and were tested with and without prefabricated orthotics. Different variables were computed from movement of center of pressure (COP) during orthotic use as suggested in the literature. The mean position of COP was significantly shifted forward and toward the dominant side. Neither the COP movement nor the velocity changes following the use of orthotics revealed significant differences. Mediolateral range of COP movement and the 95% confidence circle area of sway was significantly reduced (P = .022 and 0.048 respectively), but changes in 95% confidence circle and ellipse areas of fractal dimension were not significant (P = .053 and P = .057 respectively). In conclusion, orthotic insoles significantly improved postural sway initially by reducing mediolateral range of postural sway and 95% confidence circle area of sway at the cost of increased fractal dimension area variables and power. PMID- 22815282 TI - Effects of medially wedged foot orthoses on knee and hip joint running mechanics in females with and without patellofemoral pain syndrome. AB - We examined the effects of medially wedged foot orthoses on knee and hip joint mechanics during running in females with and without patellofemoral pain syndrome (PFPS). We also tested if these effects depend on standing calcaneal eversion angle. Twenty female runners with and without PFPS participated. Knee and hip joint transverse and frontal plane peak angle, excursion, and peak internal knee and hip abduction moment were calculated while running with and without a 6 degrees full-length medially wedged foot orthoses. Separate 3-factor mixed ANOVAs (group [PFPS, control] x condition [medial wedge, no medial wedge] x standing calcaneal angle [everted, neutral, inverted]) were used to test the effect of medially wedged orthoses on each dependent variable. Knee abduction moment increased 3% (P = .03) and hip adduction excursion decreased 0.6 degrees (P < .01) using medially wedged foot orthoses. No significant group x condition or calcaneal angle x condition effects were observed. The addition of medially wedged foot orthoses to standardized running shoes had minimal effect on knee and hip joint mechanics during running thought to be associated with the etiology or exacerbation of PFPS symptoms. These effects did not appear to depend on injury status or standing calcaneal posture. PMID- 22815285 TI - A critical role for Rictor in T lymphopoiesis. AB - Apart from a critical role for Notch and pre-TCR, the signaling pathway required for T lymphopoiesis is largely unknown. Given the potential link between Notch and mammalian target of rapamycin (mTOR) signaling in cancer cells, we used mice with conditional deletion of either Raptor or Rictor genes to determine potential contribution of the mTOR complex I and II in T lymphopoiesis. Our data demonstrated that targeted mutation of Rictor in the thymocytes drastically reduced the thymic cellularity, primarily by reducing proliferation of the immature thymocytes. Rictor deficiency caused a partial block of thymocyte development at the double-negative 3 stage. The effect of Rictor deficiency is selective for the T cell lineage, as the development of B cells, erythrocytes, and myeloid cells is largely unaffected. Analysis of bone marrow chimera generated from a mixture of wild-type and Rictor-deficient hematopoietic stem cells demonstrated that the function of Rictor is cell intrinsic. These data revealed a critical function of mTOR complex 2 in T lymphopoiesis. PMID- 22815286 TI - Endothelial CD47 promotes vascular endothelial-cadherin tyrosine phosphorylation and participates in T cell recruitment at sites of inflammation in vivo. AB - At sites of inflammation, endothelial adhesion molecules bind leukocytes and transmit signals required for transendothelial migration (TEM). We previously reported that adhesive interactions between endothelial cell CD47 and leukocyte signal regulatory protein gamma (SIRPgamma) regulate human T cell TEM. The role of endothelial CD47 in T cell TEM in vivo, however, has not been explored. In this study, CD47-/- mice showed reduced recruitment of blood T cells as well as neutrophils and monocytes in a dermal air pouch model of TNF-alpha-induced inflammation. Reconstitution of CD47-/- mice with wild-type bone marrow cells did not restore leukocyte recruitment to the air pouch, indicating a role for endothelial CD47. The defect in leukocyte TEM in the CD47-/- endothelium was corroborated by intravital microscopy of inflamed cremaster muscle microcirculation in bone marrow chimera mice. In an in vitro human system, CD47 on both HUVEC and T cells was required for TEM. Although previous studies showed CD47-dependent signaling required G(alphai)-coupled pathways, this was not the case for endothelial CD47 because pertussis toxin, which inactivates G(alphai), had no inhibitory effect, whereas G(alphai) was required by the T cell for TEM. We next investigated the endothelial CD47-dependent signaling events that accompany leukocyte TEM. Ab-induced cross-linking of CD47 revealed robust actin cytoskeleton reorganization and Src- and Pyk-2-kinase dependent tyrosine phosphorylation of the vascular endothelial-cadherin cytoplasmic tail. This signaling was pertussis toxin insensitive, suggesting that endothelial CD47 signaling is independent of G(alphai). These findings suggest that engagement of endothelial CD47 by its ligands triggers outside-in signals in endothelium that facilitate leukocyte TEM. PMID- 22815287 TI - Immune suppression and resistance mediated by constitutive activation of Wnt/beta catenin signaling in human melanoma cells. AB - Cancer-induced immunosuppression is a major problem reducing antitumor effects of immunotherapies, but its molecular mechanism has not been well understood. We evaluated immunosuppressive roles of activated Wnt/beta-catenin pathways in human melanoma for dendritic cells (DCs) and CTLs. IL-10 expression was associated with beta-catenin accumulation in human melanoma cell lines and tissues and was induced by direct beta-catenin/TCF binding to the IL-10 promoter. Culture supernatants from beta-catenin-accumulated melanoma have activities to impair DC maturation and to induce possible regulatory DCs. Those immunosuppressive culture supernatant activities were reduced by knocking down beta-catenin in melanoma cells, partly owing to downregulation of IL-10. Murine splenic and tumor infiltrating DCs obtained from nude mice implanted with human mutant beta-catenin overexpressed melanoma cells had less ability to activate T cells than did DCs from mice with control melanoma cells, showing in vivo suppression of DCs by activated Wnt/beta-catenin signaling in human melanoma. This in vivo DC suppression was restored by the administration of a beta-catenin inhibitor, PKF115-584. beta-catenin-overexpressed melanoma inhibited IFN-gamma production by melanoma-specific CTLs in an IL-10-independent manner and is more resistant to CTL lysis in vitro and in vivo. These results indicate that Wnt/beta-catenin pathways in human melanoma may be involved in immunosuppression and immunoresistance in both induction and effector phases of antitumor immunoresponses partly through IL-10 production, and they may be attractive targets for restoring immunocompetence in patients with Wnt/beta-catenin activated melanoma. PMID- 22815288 TI - Anti-peptidoglycan antibodies and Fcgamma receptors are the key mediators of inflammation in Gram-positive sepsis. AB - Gram-positive bacteria are an important public health problem, but it is unclear how they cause systemic inflammation in sepsis. Our previous work showed that peptidoglycan (PGN) induced proinflammatory cytokines in human cells by binding to an unknown extracellular receptor, followed by phagocytosis leading to the generation of NOD ligands. In this study, we used flow cytometry to identify host factors that supported PGN binding to immune cells. PGN binding required plasma, and plasma from all tested healthy donors contained IgG recognizing PGN. Plasma depleted of IgG or of anti-PGN Abs did not support PGN binding or PGN-triggered cytokine production. Adding back intact but not F(ab')2 IgG restored binding and cytokine production. Transfection of HEK293 cells with FcgammaRIIA enabled PGN binding and phagocytosis. These data establish a key role for anti-PGN IgG and FcgammaRs in supporting inflammation to a major structural element of Gram positive bacteria and suggest that anti-PGN IgG contributes to human pathology in Gram-positive sepsis. PMID- 22815289 TI - A genetically encoded IL-1beta bioluminescence resonance energy transfer sensor to monitor inflammasome activity. AB - Inflammation is fundamental for protecting the organism against infection and injury. However, a failure to control immune response results in chronic inflammation and several associated disorders such as pain and loss of function. Initiation of inflammation is orchestrated by cytokines, among which IL-1beta is particularly important. IL-1beta is synthesized as an inactive protein that has to be processed by the inflammasome to generate the mature bioactive form. Conventional techniques cannot monitor IL-1beta activation with high spatial and temporal resolution. In this study, we present a ratiometric biosensor that allows monitoring IL-1beta processing in real time, with a temporal resolution of seconds and with a single-cell spatial resolution. Using this sensor, to our knowledge, we describe for the first time the kinetic of the inflammasome activity in living macrophages. With this new probe, we also demonstrated that the pro-IL-1beta processing occurs all over the cytoplasm. PMID- 22815290 TI - The 3BP2 adapter protein is required for chemoattractant-mediated neutrophil activation. AB - 3BP2 is a pleckstrin homology and Src homology 2 domain-containing adapter protein mutated in cherubism, a rare autosomal-dominant human bone disorder. Previously, we have demonstrated a functional role for 3BP2 in peripheral B cell development and in peritoneal B1 and splenic marginal zone B cell-mediated Ab responses. In this study, we show that 3BP2 is required for G protein-coupled receptor-mediated neutrophil functions. Neutrophils derived from 3BP2-deficient (Sh3bp2-/-) mice failed to polarize their actin cytoskeleton or migrate in response to a gradient of chemotactic peptide, fMLF. Sh3bp2-/- neutrophils failed to adhere, crawl, and emigrate out of the vasculature in response to fMLF superfusion. 3BP2 is required for optimal activation of Src family kinases, small GTPase Rac2, neutrophil superoxide anion production, and for Listeria monocytogenes bacterial clearance in vivo. The functional defects observed in Sh3bp2-/- neutrophils may partially be explained by the failure to fully activate Vav1 guanine nucleotide exchange factor and properly localize P-Rex1 guanine nucleotide exchange factor at the leading edge of migrating cells. Our results reveal an obligate requirement for the adapter protein 3BP2 in G protein-coupled receptor-mediated neutrophil function. PMID- 22815291 TI - Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin. AB - Contact hypersensitivity (CHS) is a T cell response to hapten skin challenge of sensitized individuals proposed to be mediated by hapten-primed CD8 cytolytic T cells. Effector CD8 T cell recruitment into hapten challenge sites to elicit CHS requires prior CXCL1- and CXCL2-mediated neutrophil infiltration into the site. We investigated whether neutrophil activities directing hapten-primed CD8 T cell skin infiltration in response to 2,4-dinitro-1-fluorobenzene (DNFB) required Fas ligand (FasL) and perforin expression. Although DNFB sensitization of gld/perforin-/- mice induced hapten-specific CD8 T cells producing IFN-gamma and IL-17, these T cells did not infiltrate the DNFB challenge site to elicit CHS but did infiltrate the challenge site and elicit CHS when transferred to hapten challenged naive wild-type recipients. Hapten-primed wild-type CD8 T cells, however, did not elicit CHS when transferred to naive gld/perforin-/- recipients. Wild-type bone marrow neutrophils expressed FasL and perforin, and when transferred to sensitized gld/perforin-/- mice, they restored hapten-primed CD8 T cell infiltration into the challenge site and CHS. The FasL/perforin-mediated activity of wild-type neutrophils induced the expression of T cell chemoattractants, CCL1, CCL2, and CCL5, within the hapten-challenged skin. These results indicate FasL/perforin-independent functions of hapten-primed CD8 T cells in CHS and identify new functions for neutrophils in regulating effector CD8 T cell recruitment and immune responses in the skin. PMID- 22815292 TI - ICOS mediates the generation and function of CD4+CD25+Foxp3+ regulatory T cells conveying respiratory tolerance. AB - Costimulatory molecules like ICOS are crucial in mediating T cell differentiation and function after allergen contact and thereby strongly affect the immunologic decision between tolerance or allergy development. In this study, we show in two independent approaches that interruption of the ICOS signaling pathway by application of a blocking anti-ICOSL mAb in wild-type (WT) mice and in ICOS(-/-) mice inhibited respiratory tolerance development leading to eosinophilic airway inflammation, mucus hypersecretion, and Th2 cytokine production in response to OVA sensitization. Respiratory Ag application almost doubled the number of CD4(+)Foxp3(+) regulatory T cells (Tregs) in the lung of WT mice with 77% of lung derived Tregs expressing ICOS. In contrast, in ICOS(-/-) mice the number of CD4(+)CD25(+)Foxp3(+) Tregs did not increase after respiratory Ag application, and ICOS(-/-) Tregs produced significantly lower amounts of IL-10 than those of WT Tregs. Most importantly, in contrast to WT Tregs, ICOS(-/-) Tregs did not convey protection when transferred to "asthmatic" recipients demonstrating a strongly impaired Treg function in the absence of ICOS signaling. Our findings demonstrate a crucial role of ICOS for the generation and suppressive function of Tregs conveying respiratory tolerance and support the importance of ICOS as a target for primary prevention strategies. PMID- 22815293 TI - Childhood nutrition in predicting metabolic syndrome in adults: the cardiovascular risk in Young Finns Study. AB - OBJECTIVE: Our aim was to study the associations of childhood lifestyle factors (the frequency of consumption of vegetables, fruit, fish, and meat, butter use on bread, and physical activity) with the metabolic syndrome (MetS) in adulthood. RESEARCH DESIGN AND METHODS: The study cohort consisted of 2,128 individuals, 3 18 years of age at the baseline, with a follow-up time of 27 years. We used the average of lifestyle factor measurements taken in 1980, 1983, and 1986 in the analyses. Childhood dietary factors and physical activity were assessed by self reported questionnaires, and a harmonized definition of MetS was used as the adult outcome. RESULTS: Childhood vegetable consumption frequency was inversely associated with adult MetS (odds ratio [OR] 0.86 [95% CI 0.77-0.97], P = 0.02) in a multivariable analysis adjusted with age, sex, childhood metabolic risk factors (lipids, systolic blood pressure, insulin, BMI, and C-reactive protein), family history of type 2 diabetes and hypertension, and socioeconomic status. The association remained even after adjustment for adulthood vegetable consumption. Associations with the other childhood lifestyle factors were not found. Of the individual components of MetS, decreased frequency of childhood vegetable consumption predicted high blood pressure (0.88 [0.80-0.98], P = 0.01) and a high triglyceride value (0.88 [0.79-0.99], P = 0.03) after adjustment for the above mentioned risk factors. CONCLUSIONS: Childhood vegetable consumption frequency is inversely associated with MetS in adulthood. Our findings suggest that a higher intake of vegetables in childhood may have a protective effect on MetS in adulthood. PMID- 22815294 TI - IgA anti-transglutaminase autoantibodies at type 1 diabetes onset are less frequent in adult patients and are associated with a general celiac-specific lower immune response in comparison with nondiabetic celiac patients at diagnosis. AB - OBJECTIVE: To evaluate the celiac-associated humoral autoimmunity in child, adolescent, and adult patients at type 1 diabetes (DM1) onset and to determine whether DM1 celiac-specific humoral immunoreactivity occurs similarly to that in nondiabetic patients at celiac disease (CD) diagnosis. RESEARCH DESIGN AND METHODS: IgA anti-transglutaminase autoantibody (IgA-tTGAb) was detected in 654 new-onset DM1 sera. IgA-tTGAb(+) DM1 sera were subsequently analyzed for IgG-tTG, deamidated gliadin (DGP), and actin antibodies, and results were compared with those found in 83 screen-detected nondiabetic patients at CD diagnosis. RESULTS: A total of 12.8% DM1 sera were IgA-tTGAb(+), with a lower autoantibody frequency in adult patients aged >18 years (6.8 vs. 15.1%, aged <=18 years; P = 0.005). IgA tTGAb titers, IgG-tTGAb, and DGPAb frequency/titers and mean number of celiac autoantibody positivities per patient were significantly lower in IgA-tTGAb(+) DM1 compared with nondiabetic CD patients. CONCLUSIONS: Age of diabetes onset is negatively associated with risk of CD. The celiac-specific humoral immunoreactivity at DM1 onset is significantly lower compared with that found in nondiabetic patients at CD diagnosis. PMID- 22815295 TI - Continuing disparities in cardiovascular risk factors and complications between aboriginal and Anglo-Celt Australians with type 2 diabetes: the Fremantle Diabetes Study. AB - OBJECTIVE: To determine whether disparities in the nature and management of type 2 diabetes persist between Aboriginal and the majority Anglo-Celt patients in an urban Australian community. RESEARCH DESIGN AND METHODS: Baseline data from the observational Fremantle Diabetes Study collected from 1993 to 1996 (phase I) and from 2008 to 2011 (phase II) were analyzed. Patients characterized as Aboriginal or Anglo-Celt by self-report and supporting data underwent comprehensive assessment, including questionnaires, examination, and biochemical testing in a single laboratory. Generalized linear modeling with age/sex adjustment was used to examine differences in changes in variables in the two groups between phases I and II. RESULTS: The indigenous participants were younger at entry and at diabetes diagnosis than the Anglo-Celt participants in both phases. They were also less likely to be educated beyond primary level and were more likely to be smokers. HbA(1c) decreased in both groups over time (Aboriginal median 9.6% [interquartile range 7.8-10.7%] to 8.4% [6.6-10.6%] vs. Anglo-Celt median 7.1% [6.2-8.4%] to 6.7% [6.2-7.5%]), but the gap persisted (P = 0.65 for difference between phases I and II by ethnic group). Aboriginal patients were more likely to have microvascular disease in both phases. The prevalence of peripheral arterial disease (ankle-brachial index <=0.90 or lower-extremity amputation) increased in Aboriginal but decreased in Anglo-Celt participants (15.8-29.7 vs. 30.7-21.5%; P = 0.055). CONCLUSIONS: Diabetes management has improved for Aboriginal and Anglo Celt Australian patients, but disparities in cardiovascular risk factors and complications persist. PMID- 22815296 TI - Short- and long-term mortality after myocardial infarction in patients with and without diabetes: changes from 1985 to 2008. AB - OBJECTIVE: To study temporal trends in short- and long-term outcome after myocardial infarction (MI) according to diabetes status. RESEARCH DESIGN AND METHODS: We included all 14,434 consecutive patients admitted for ST-segment elevation MI or non-ST-segment elevation MI at our center between 1985 and 2008. The study patients were compared according to prevalent diabetes. Temporal trend analyses were performed by comparing decades of admission (1985-1989 vs. 1990 1999 vs. 2000-2008). RESULTS: A total of 2,015 (14%) of the patients had prevalent diabetes. The risk of presenting with diabetes increased from 8 to 17% from 1985 to 2008. Diabetic patients presented with a higher prevalence of cardiovascular risk factors. With time, the use of evidence-based therapies increased in both patients with and without diabetes. Diabetes is associated with a 1.5-fold increased risk of mortality at the 20-year follow-up. Ten-year mortality decreased over time in patients with diabetes, from 53% in 1985-1989 to 39% in 2000-2008 (adjusted hazard ratio 0.56 [95% CI 0.43-0.73]), and in those without diabetes, from 38% in 1985-1989 to 29% in 2000-2008 (0.66 [0.60-0.73]; P interaction = 0.83). Patients with diabetes benefitted from a higher 30-day and 10-year absolute survival increase. CONCLUSIONS: Temporal mortality reductions after MI between 1985 and 2008 were at least as high in patients with diabetes compared with those without diabetes. However, long-term mortality remained higher in diabetic patients. Awareness of the high-risk profile of diabetic patients is warranted and might stimulate optimal medical care and outcome. PMID- 22815297 TI - Growth-differentiation factor 15 predicts worsening of albuminuria in patients with type 2 diabetes. AB - OBJECTIVE: Development of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF 15 potential in nondiabetic subjects with hypertension (HT). RESEARCH DESIGN AND METHODS: Case and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition. RESULTS: Prior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885-1,546] vs. 948 pg/mL [660-1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1-7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1-3.5], P = 0.02) and improved prediction significantly. CONCLUSIONS: We identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects. PMID- 22815298 TI - Effect of pramlintide on prandial glycemic excursions during closed-loop control in adolescents and young adults with type 1 diabetes. AB - OBJECTIVE: Even under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions. RESEARCH DESIGN AND METHODS: Eight subjects (4 female; age, 15-28 years; A1C, 7.5 +/- 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-MUg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal. RESULTS: CLP was associated with overall delayed time to peak BG (2.5 +/- 0.9 vs. 1.5 +/- 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 +/- 42 vs. 113 +/- 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes. CONCLUSIONS: Pramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast. PMID- 22815299 TI - Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. AB - OBJECTIVE: There is a dearth of long-term data regarding patient and limb survival in patients with diabetic foot ulcers (DFUs). The purpose of our study was therefore to prospectively investigate the limb and person survival of DFU patients during a follow-up period of more than 10 years. RESEARCH DESIGN AND METHODS: Two hundred forty-seven patients with DFUs and without previous major amputation consecutively presenting to a single diabetes center between June 1998 and December 1999 were included in this study and followed up until May 2011. Mean patient age was 68.8 +/- 10.9 years, 58.7% were male, and 55.5% had peripheral arterial disease (PAD). Times to first major amputation and to death were analyzed with Kaplan-Meier curves and Cox multiple regression. RESULTS: A first major amputation occurred in 38 patients (15.4%) during follow-up. All but one of these patients had evidence of PAD at inclusion in the study, and 51.4% had severe PAD [ankle-brachial pressure index <=0.4]). Age (hazard ratio [HR] per year, 1.05 [95% CI, 1.01-1.10]), being on dialysis (3.51 [1.02-12.07]), and PAD (35.34 [4.81-259.79]) were significant predictors for first major amputation. Cumulative mortalities at years 1, 3, 5, and 10 were 15.4, 33.1, 45.8, and 70.4%, respectively. Significant predictors for death were age (HR per year, 1.08 [95% CI, 1.06-1.10]), male sex ([1.18-2.32]), chronic renal insufficiency (1.83 [1.25 2.66]), dialysis (6.43 [3.14-13.16]), and PAD (1.44 [1.05-1.98]). CONCLUSIONS: Although long-term limb salvage in this modern series of diabetic foot patients is favorable, long-term survival remains poor, especially among patients with PAD or renal insufficiency. PMID- 22815300 TI - Prognostic value of resting heart rate on cardiovascular and renal outcomes in type 2 diabetic patients: a competing risk analysis in a prospective cohort. AB - OBJECTIVE: Epidemiological studies and randomized clinical trials have demonstrated in various populations that resting heart rate (RHR) was an independent predictor of cardiovascular (CV) risk and all-cause mortality. However, few data specifically evaluated the relationship between RHR and long term CV and renal complications in a large population of type 2 diabetic (T2D) patients. RESEARCH DESIGN AND METHODS: We performed a single-center, prospective analysis in 1,088 T2D patients. RHR was determined at baseline by electrocardiogram. The primary outcome was a composite criterion of CV and renal morbi-mortality (CV death, nonfatal myocardial infarction and/or stroke, hospitalization for heart failure, renal replacement therapy), which was adjusted for death from non-CV cause as a competing event. The secondary outcome was a renal composite criterion (renal replacement therapy or doubling of baseline serum creatinine) adjusted for all-cause death as a competing event. RESULTS: During median follow-up of 4.2 years, 253 patients (23%) and 62 patients (6%) experienced the primary and secondary outcomes, respectively. In the subgroup of patients with CV disease history at baseline (n = 336), RHR was found to be associated with the incidence of primary outcome (P = 0.0002) but also with renal risk alone, adjusted for all-cause death as a competing event (secondary outcome; P < 0.0001). In patients without history of CV disease, no relation was found between RHR and the incidence of CV and/or renal events. CONCLUSIONS: In the real life setting, RHR constitutes an easy and less time-consuming factor that would permit identification of CV disease diabetic patients with an increased risk for long-term CV and renal complications. PMID- 22815302 TI - Migration of health workers in the Pacific Islands: a bottleneck to health development. AB - Human resources for health (HRH) are a crucial component of a well-functioning health system. Problems in the global HRH supply and distribution are an obstacle to achieving the health-related Millennium Development Goals and other health outcomes. The Pacific Island region, covering 20,000 to 30,000 islands in the South Pacific Ocean, is suffering a serious HRH crisis. Yet updated evidence and data are not available for the 22 Pacific Island Countries and Territories. The objective of this study was thus to explore the current HRH situation in the Pacific Island region, focusing particularly on the issue of health workforce migration. HRH trends and gaps differ by country, with some showing increases in HRH density over the past 20 years whereas others have made negligible progress. Currently, three Pacific Island countries are facing critical HRH shortages, a worsening of the situation from 2006, when HRH issues were first brought to widespread global attention. In this region, skilled personnel migration is a major issue contributing to the limited availability of HRH. Political commitment from source and destination countries to strengthen HRH would be a key factor toward increasing efforts to train new health personnel and to implement effective retention strategies. PMID- 22815303 TI - Recent resurgence of measles in a community with high vaccination coverage. AB - Even though 2-dose measles vaccination coverage rate was maintained at more than 95%, the largest measles outbreaks since 1996 still occurred in Wuhu city, P R China. A total of 916 cases were reported during 2005-2010. The annual incidence was 6.7 cases per 100,000 population with the peak incidence of 17.6 cases per 100,000 population in 2008. The highest age-specific incidence rate was 222.1 per 100,000 population and occurred in infants aged between 8 and 12 months; the second was 151.9 per 100,000 population in infants aged <8 months. Also, 200 cases occurred in those aged to 22 to 30 years old, accounting for 21.8% of total cases, with the age-specific incidence being 12.8 per 100,000 population. The characteristics related to age distribution have changed in recent measles outbreaks. It underlines the need for vaccination of susceptible young adults and timely administration of the first dose of the measles vaccine. PMID- 22815304 TI - Health changes in Sri Lanka: benefits of primary health care and public health. AB - The Democratic Socialist Republic of Sri Lanka is an island in the Indian Ocean that has achieved a unique status in the world with health indicators that are comparable with those of developed countries. This is illustrated, among others, by the reduction in both child and maternal mortality in the country. This achievement is the result of a range of long-term interventions, including providing education and health care free of charge, training of health care workers, developing public health infrastructure in rural areas, and adopting steps to improve sanitation, nutrition, and immunization coverage. PMID- 22815305 TI - Cause-specific mortality of psychiatric inpatients and outpatients in a general hospital in Korea. AB - This study aimed to examine the cause-specific excess mortality of psychiatric patients in a general hospital in Korea. Between January 1995 and December 2006, 29 986 patients presented to the outpatient clinic of a general hospital in Seoul, Korea, or were admitted to that hospital for psychiatric disorders. Their cause-specific mortality risk was compared with that of age-matched patients from the general Korean population. The mortality risk of psychiatric patients was 1.6 times higher than that of the general population. Inpatients, younger adults, and patients with alcohol use disorders or schizophrenia had the highest standardized mortality rates (SMRs). Alcohol use disorder was associated with extremely high SMRs of more than 20 for hematological disease and digestive system disease. Effective preventive measures are required to reduce the excess mortality of psychiatric patients, particularly alcohol-dependent patients and younger patients who have been admitted for general psychiatric care. PMID- 22815306 TI - Unhealthy lifestyle, poor mental health, and its correlation among adolescents: a nationwide cross-sectional survey. AB - OBJECTIVES: The objective was to study the relationship between mental health and lifestyles of adolescents using samples representative of Japanese adolescents nationwide. METHOD: The survey was conducted between December 2004 and January 2005 among students enrolled in randomly selected junior and senior high schools. Self-administered questionnaires addressed lifestyles, sleeping habits, and mental health status. Of 103 650 questionnaires collected, 85 158 were analyzed. RESULTS: Population characteristics associated with poor mental health were being female, being a senior high school student, skipping breakfast, not participating in extracurricular activities, not consulting parents about personal matters, parental smoking, students' smoking or alcohol use, poor subjective sleep assessment, and short or long sleeping duration. CONCLUSION: Smoking and anxiety disorders are associated with an elevation in acculturative stress in adolescents. Prepossessing adolescents are in subclinical depression. Results suggest that lifestyles approaches in preventions that target students can be effective in reaching high-risk populations. PMID- 22815307 TI - Lessons learned from the Great East Japan Earthquake: impact on child and adolescent health. AB - The Great East Japan Earthquake (the Tohoku Earthquake) was one of the most devastating natural disasters ever to hit Japan, and its social impact was so enormous that Japan may never be the same again. This was an unprecedented triple disaster: an earthquake followed by a devastating tsunami and, finally, the destruction of a major nuclear power plant with the leaking of large amounts of radiation. The destruction occurred despite the presence of a 10-m protection wall and the effects of the tsunami were seen as high as 40 m above sea level. About 78,000 residents from areas within a 20-km radius of the Fukushima Daiichi Nuclear Power Plant were evacuated together with another 10,000 residents from areas with elevated levels of radiation. In the afflicted area, 30% of the population was older than 60 years of age, but more than 60% of the deaths were in this age cohort. Children and adolescents younger than 19 years accounted for 6.5% of the deaths, and there were 229 survivors younger than 18 years who lost both their parents in the disaster and 1295 who lost one of their parents. The long-term psychological effects on children and adolescents remain uncertain. PMID- 22815308 TI - The association between drinking habits and family relationships in 3 villages of indigenous Taiwanese. AB - Although the vast majority of indigenous peoples in Taiwan consume alcohol, little is known about the relationship between alcoholic behavior and family relationships. A total of 471 residents from 3 villages in Alishan township in Taiwan were interviewed using a questionnaire that asked for demographic information and included the Family Function Scale and questions regarding the individual's consumption of alcohol. It was found that 50% of the participants drink alcohol, and 71% of their family members consume alcohol; 47% of the respondents indicated excessive alcohol consumption (ie, were heavy drinkers). When individuals are knowledgeable about alcohol-related health issues, their families generally function better (odds ratio = 2.56; 95% confidence interval = 1.38-4.74; P < .01). Those who were moderate and heavy drinkers were 2.5 and 3.0 times, respectively, more likely to have poor family relationships than those who were light drinkers. It is necessary to promote the reduction of alcohol consumption among indigenous peoples. PMID- 22815309 TI - Adult tobacco cessation in Cambodia: I. Determinants of quitting tobacco use. AB - This study determined factors associated with quitting tobacco in Cambodia, a country with a high prevalence of men who smoke and women who use smokeless tobacco. As part of a nationwide survey, face-to-face interviews were conducted with 5145 current and 447 former tobacco users who had quit for >= 2 years. Determinants of quitting in multivariate analyses were age >48 years, age at initiation >25 years, >= 7 years of education, income >= 1 US dollar per day, professional (odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.27-5.01) or labor (OR = 1.98, 95% CI = 1.10-3.56) occupations, and heart disease (OR = 1.94; 95% CI = 1.10, 3.42). Smokeless tobacco users were 10-fold less likely to quit (OR = 0.10; 95% = CI 0.05-0.20) than smokers. In conclusion, tobacco cessation among Cambodians was lower than in nations with decades of comprehensive tobacco control policies. Tobacco cessation programs and policies should include all forms of tobacco and target young to middle-aged users before onset of disease and premature death. PMID- 22815310 TI - Maternal return to paid work and breastfeeding practices in Bangkok, Thailand. AB - This study explored the association between mothers' work-related factors and breastfeeding practices in Bangkok, Thailand. Data were collected from 84 working mothers with a child aged 6 to 24 months who visited the breastfeeding mobile clinic at a nursery goods exhibition. Thai interviewers collected data using a structured questionnaire. Analysis of the data showed that exclusive breastfeeding for 3 months was 78.6%, and for 6 months it was 38.1%. Mothers who returned to work 3 months or more after giving birth exclusively breastfed more than the mothers who returned to work in less than 3 months (crude odds ratio [OR] = 4.26, 95% confidence interval [CI] = 1.39-13.05; adjusted OR = 4.15, 95% CI = 1.15-14.95). Moreover, mothers who worked at self-employed or family-owned businesses and some mothers working at private companies showed tendencies of returning to work in less than 3 months. Results suggest that longer maternity leave would help extend the duration of exclusive breastfeeding. In addition, the improvement of a breastfeeding supportive environment in the workplace would be valuable and may be an effective means to improve breastfeeding practices and infant health. PMID- 22815311 TI - Public health strategies to address Asian men's health needs. AB - Men's health discourse has been around for more than 2 decades. The higher mortality rates and the shorter life expectancy in Asian men compared with their women counterparts show the disadvantaged status of men's health. Thus, discussions on men's health should address their health needs and not be confined to sex-specific male urology and reproductive health. In Asia, assessing men's health needs is challenging because of the vast differences in the socioeconomic status and the diverse culture among its member countries. Although, the epidemiology of men's health provides the focus for what to address in improving men's health, having an optimal strategy requires the understanding of men's health-seeking behaviors and the social determinants surrounding them. Thus, public health approaches addressing health behaviors and health promotion in the society should be one of the keys in improving men's health status. Locally relevant information is needed to inform effective public health approaches. PMID- 22815312 TI - Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy. AB - There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage-specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have been shown to be regulated by estradiol. Because estradiol concentrations increase by ~50-fold during human pregnancy, it was hypothesized that the increasing estradiol concentrations during human pregnancy would result in induction of CYP2B6 activity. Hepatocytes from three female donors were treated with estradiol, and the EC(50) and E(max) were measured for CYP2B6 mRNA and bupropion hydroxylation activity. The measured values were used to predict the magnitude of CYP2B6 induction during human pregnancy. At 100 nM total estradiol, a concentration achievable during the third trimester of pregnancy, CYP2B6 activity was predicted to increase by 1.5-3-fold, based on increased CYP2B6 activity and mRNA. When the E(max) and EC(50) values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy. PMID- 22815313 TI - Acetylenic linkers in lead compounds: a study of the stability of the propargyl linked antifolates. AB - Propargyl-linked antifolates that target dihydrofolate reductase are potent inhibitors of several species of pathogenic bacteria and fungi. This novel class of antifolates possesses a relatively uncommon acetylenic linker designed to span a narrow passage in the enzyme active site and join two larger functional domains. Because the use of alkyne functionality in drug molecules is limited, it was important to evaluate some key physicochemical properties of these molecules and specifically to assess the overall stability of the acetylene. Herein, we report studies on four compounds from our lead series that vary specifically in the environment of the alkyne. We show that the compounds are soluble, chemically stable in water, as well as simulated gastric and intestinal fluids with half lives of approximately 30 min after incubation with mouse liver microsomes. Their primary in vitro route of metabolism involves oxidative transformations of pendant functionality with little direct alteration of the alkyne. Identification of several major metabolites indicated the formation of N-oxides; the rate of formation of these oxides was highly influenced by branching substitutions around the propargyl linker. On the basis of the lessons of these metabolic studies, a more advanced inhibitor was designed, synthesized, and shown to have increased (t(1/2) = 65 min) metabolic stability while maintaining potent enzyme inhibition. PMID- 22815314 TI - Voice hearing and pseudoseizures in a Maori teenager: an example of mate Maori and Maori traditional healing. AB - OBJECTIVE: The aim of this paper is to describe a Maori traditional healing approach to assessment and treatment of distressing psychiatric symptoms in a young man. METHOD: We describe the case of a 17 year old Maori male with voice hearing and pseudoseizures and the assessment and intervention by one of the authors (WN). We report on the young man's and his family's experience of this treatment. We outline concepts from a Maori world view that illuminate an indigenous rationale for this approach. RESULTS: A single session traditional Maori healing intervention was associated with immediate resolution of this young man's psychiatric symptoms and restoration of his sense of wellbeing, despite cessation of antipsychotic treatment. He and his family felt satisfied with the cultural explanation about the origin of his distress, which was congruent with their world view. He remained well at follow-up one year later. CONCLUSIONS: Collaboration between psychiatrists and traditional Maori healing practitioners can enhance the mental health care of Maori whaiora (service users) and their families. Indigenous research is required to further evaluate the acceptability and effectiveness of such joint approaches. PMID- 22815315 TI - Uroradiological screening for upper and lower urinary tract anomalies in patients with hypospadias: a systematic literature review. AB - INTRODUCTION: Hypospadias is associated with anomalies of the urinary tract, but the exact prevalence and significance of these anomalies are still controversial. OBJECTIVES: To assess the percentage of patients with hypospadias and associated urological anomalies, either requiring or not requiring medical or surgical attention. MATERIAL AND METHODS: We searched several databases using the following Mesh terms: hypospadias AND urination, ultrasonography, urinary tract/abnormalities, urinary bladder/radiography, ureteral obstruction, hydronephrosis or vesico-ureteral reflux. Type of uroradiological studies performed, type of urological anomalies, medical or surgical interventions, number of patients available, enrolled and undergoing uroradiological studies and number of patients with abnormal uroradiological exams were recorded. RESULTS: We found 24 studies. Four studies included 100% of available patients. In the other ones, the percentage of patients undergoing uroradiological screening varied from 12 to 82%. Frequency of anomalies varied from 0 to 56%. The most common anomalies were kidney position anomalies, vesico-ureteral reflux and hydronephrosis. CONCLUSIONS: The data published about screening patients with hypospadias for associated anomalies of their urinary tract are of poor quality. The clinical significance of the anomalies found is difficult to evaluate. We found no relationship between the severity of the hypospadias and associated anomalies of the upper or lower urinary tract. PMID- 22815316 TI - Prevalence of psychotic symptoms in the general population varies across 52 countries. PMID- 22815317 TI - The prognostic value of an increased mean platelet volume and platelet distribution width in the early phase of cerebral venous sinus thrombosis. AB - In this study, we aimed to investigate the value of mean platelet volume (MPV), platelet distribution width (PDW) and platelet count in cerebral venous sinus thrombosis (CVST) patients and in control subjects. Fifty-three patients with evidence of CVST and thirty-five controls with similar baseline characteristics were included in the study. CVST patients were further divided into two subgroups based on the presence or absence of parenchymal lesions in cranial MRI. Our analyses revealed a significant difference in MPV and PDW values between CVST patients with lesions and controls (P < 0.05). MPV and PDW values were significantly increased in CVST patients with brain parenchmal lesions, suggesting that MPV and PDW values can be used to predict the severity of CVST. PMID- 22815318 TI - Evaluation of children with chronic immune thrombocytopenic purpura and Evans syndrome treated with rituximab. AB - The primary objective was to evaluate the response rate of rituximab therapy for children with chronic immune thrombocytopenic purpura (ITP) and Evans syndrome (ES) and immune reconstitution of these children after rituximab therapy. Eleven patients with chronic ITP and 2 with ES between 6 and 18 years of age and platelet count less than 20 * 10(9)/L received rituximab. Overall response (OR) was defined as an increase in platelet count above 50 * 10(9)/L. The mean age of 13 children (9 girls, 4 boys) was 11.2 +/- 3.8 years (6-18). One of the patients with ES had been splenectomized; others were not. The patients mean follow-up time was 10.3 +/- 9.3 months after rituximab therapy. Two patients achieved complete response, 4 patients achieved partial response, and OR rate was 46% (6 of 13) after therapy. Seven patients have no response. In conclusion, rituximab may be considered prior to splenectomy in children with chronic ITP and ES with an acceptable toxicity profile. PMID- 22815320 TI - A case of pervasive refusal syndrome: a diagnostic conundrum. AB - A case is presented of an 11-year-old girl with pervasive refusal syndrome (PRS) who ultimately recovered acutely and completely after an 18-month paediatric hospitalisation. There was an apparent absence of previously proposed important aetiological factors in PRS, such as family pathology and markedly traumatic or abusive experiences, and her recovery was sudden and complete. The authors consider the differential diagnoses of PRS paying particular attention to the possibility of a conversion disorder or catatonia, given the absence of PRS in the North American literature. Consideration of catatonia is important as it has a diagnostic test and responds rapidly to appropriate treatment, in contrast to conventional treatment for PRS and conversion disorder. PMID- 22815321 TI - How effective is bipolar radiofrequency ablation for atrial fibrillation during concomitant cardiac surgery? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether, in patients undergoing cardiac surgery, concomitant bipolar radiofrequency ablation had an acceptable success rate to justify the additional procedure. Altogether 263 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The consensus in the literature was that bipolar radiofrequency ablation was highly successful in restoring sinus rhythm. One meta analysis of six non-randomized studies demonstrated that 76% of patients were in sinus rhythm compared with 16% in atrial fibrillation 3 months postoperatively. One randomized controlled trial found that the sinus rhythm conversion rate for any maze procedure was highly significant compared with the control group (P = 0.001). Another found that Cardioblate radiofrequency ablation was significantly better at restoring sinus rhythm at 1 year (75 vs 39% control, P = 0.019). Prospective studies showed a similar rate of sinus rhythm return at 1 year (89%). Notably some studies demonstrated a significant reduction in the New York Heart Association class when sinus rhythm was restored compared with those remaining in atrial fibrillation (P < 0.0001), demonstrating the value of this procedure beyond simply restoring sinus rhythm. In another study, the investigators found that both ablation and total procedure times were shorter with bipolar compared with monopolar ablation. These authors strongly recommend bipolar radiofrequency ablation due to a shorter procedure time, ability to avoid performing a standard left atriotomy and a greater guarantee of transmurality. With the current limited evidence, we conclude that bipolar radiofrequency ablation has a higher success rate in restoring sinus rhythm as an adjunct to cardiac surgery compared with no ablation for at least 1 year. The procedure had a high survival rate. There is randomized evidence to suggest the superiority of bipolar radiofrequency ablation over microwave ablation but limited evidence to suggest the superiority of bipolar over unipolar radiofrequency ablation. Factors found to be accurate predictors of ablation failure include a larger preoperative atrial diameter, permanent vs paroxysmal atrial fibrillation and longer duration of atrial fibrillation. PMID- 22815322 TI - Advanced heart failure in critical patients (INTERMACS 1 and 2 levels): ventricular assist devices or emergency transplantation? AB - OBJECTIVE: For patients in advanced heart failure, emergency transplantation or ventricular assist devices (VADs) are possible strategies. The aim of this single centre, retrospective study was to evaluate early and long-term results for these two strategies. METHODS: From 2005 to 2011, we analysed 49 INTERMACS level 1 and 2 patients, who were divided into the following two groups: group A comprised 26 patients on the waiting list for heart transplantation with urgent conditions; and group B comprised 23 patients who underwent VAD implantation as a bridge to candidacy. RESULTS: In group A, 25 patients underwent transplantation. In group B, 19 patients were supported with left VAD and four with biventricular VAD. Of these 23 patients, 13 underwent transplantation (mean time 279 +/- 196 days). The 30 day mortality was 42.3 and 4.3% in group A and B, respectively. Survival at 6 and 12 months was significantly better in group B than in group A (87 vs 53%, P = 0.018 at 6 months; and 77 vs 48%, P = 0.045 at 12 months). CONCLUSION: Improved outcomes may justify the use of mechanical assistance devices as a bridge to candidacy or bridge to transplantation in INTERMACS 1 and 2 patients in order to avoid high-risk transplants. Evaluation of long-term multicentre outcomes is needed to assess future strategies. PMID- 22815323 TI - Immediate postoperative inflammatory response predicts long-term outcome in lung transplant recipients. AB - OBJECTIVES: Although lung transplantation is an accepted therapy for end-stage disease, recipient outcomes continue to be hindered by early primary graft dysfunction (PGD) as well as late rejection and bronchiolitis obliterans syndrome (BOS). We have previously shown that the pro-inflammatory cytokine response following transplantation correlates with the severity of PGD. We hypothesized that lung-transplant recipients with an increased inflammatory response immediately following surgery would also have a greater incidence of unfavorable long-term outcomes including rejection, BOS and ultimately death. METHODS: A retrospective study of lung-transplant recipients (n = 19) for whom serial blood sampling of cytokines was performed for 24 h following transplantation between March 2002 and June 2003 at a single institution. Long-term follow-up was examined for rejection, BOS and survival. RESULTS: Thirteen single and six bilateral lung recipients were examined. Eleven (58%) developed BOS and eight (42%) did not. Subgroup analysis revealed an association between elevated IL-6 concentrations 4 h after reperfusion of the allograft and development of BOS (P = 0.068). The correlation between IL-6 and survival time was found to be significant (corr = -0.46, P = 0.047), indicating that higher IL-6 response had shorter survival following transplantation. CONCLUSIONS: An elevation in interleukin (IL)-6 concentration immediately following lung transplantation is associated with a trend towards development of bronchiolitis obliterans, rejection and significantly decreased survival time. Further studies are warranted to confirm the correlation between the immediate inflammatory response, PGD and BOS. Identification of patients at risk for BOS based on the cytokine response after surgery may allow for early intervention. PMID- 22815324 TI - A bulldog clamp that was forgotten during a coronary artery bypass operation 8 years ago. AB - Prevention of retained foreign bodies in the pericardial cavity is critical for patient safety. We report a patient with a bulldog clamp that was forgotten during a coronary artery bypass operation 8 years ago, which was detected by chance and removed. PMID- 22815325 TI - Experience with titanium devices for rib fixation and coverage of chest wall defects. AB - OBJECTIVES: To describe our experience with two new titanium-based devices for chest wall reconstruction and stabilization. METHODS: A retrospective analysis of 18 consecutive patients (multiple rib fractures n = 9, iatrogenic rib fracture n = 2, lung herniation n = 2, chest wall tumour n = 5) who underwent surgery for rib fractures or chest wall tumours requiring chest wall resection and reconstruction between October 2010 and March 2012 was conducted. Chest wall defects and rib fractures were fixed with titanium clips and bars or titanium plates and screws through a posterolateral thoracotomy. RESULTS: There were 12 males, and the median age was 61 years. There were no postoperative deaths. The only postoperative complication observed was a pleural effusion requiring drainage in one patient who had titanium clips for the fixation of multiple traumatic rib fractures. Median length of stay of the drain and median length of hospital stay were 3 days (range 1-6) and 4 days (range 2-42 days), respectively. The average follow-up period of operatively managed patients was 6 months, (range 2-14 months). Two cases of hardware failure occurred in two patients treated for a lung hernia with large chest wall defects involving the anterior costal margin with either devices. CONCLUSIONS: Titanium devices (clips and bars; screws and plates) are effective and safe for repair of rib fractures and large chest wall defect reconstruction with minimal complications and good long-term results. PMID- 22815327 TI - A video-assisted thoracic surgical lobectomy for a lung tumour with a rare anomalous pulmonary artery. AB - A detailed knowledge of anomalies of the anatomical course of the pulmonary vessels is extremely important for video-assisted thoracic surgery (VATS). Inadvertent vascular ligation and dissection are catastrophic for patients undergoing lobectomy. We describe a case with a rare anomaly of the left pulmonary artery and highlight the importance of identifying the courses of pulmonary vessels for VATS lobectomy. PMID- 22815326 TI - Incremental value of pocket-sized imaging device for bedside diagnosis of unilateral pleural effusions and ultrasound-guided thoracentesis. AB - OBJECTIVES: The present study aimed to assess the additional value of a pocket sized imaging device (PSID) as an adjunct to plain chest X-rays in the diagnosis of pleural effusion (PE), mainly for those requiring pleural thoracentesis. METHODS: We performed a thoracic ultrasound examination using a PSID in 73 patients with an abnormal chest X-ray diagnostic for unilateral PE. Abundant PE was defined as an interpleural distance between the diaphragm and visceral pleura (VP) of >= 30 mm at the apex of the 50 mm bisector line of the costodiaphragmatic recess at end expiration. RESULTS: According to PSID ultrasound evaluation, abundant PE was present in 46 patients (63%), while 27 (37%) patients showed the presence of mild PE or absence of PE. Thoracentesis was performed successfully and without procedure-induced complications in all 46 patients with abundant PE. Using the above-mentioned method, we obtained a high diagnostic accuracy (area under the curve = 0.99) and excellent sensitivity and specificity of 91.7 and 99.9%, respectively, to predict a PE >1000 ml, when VP was >6.3 cm. CONCLUSIONS: PSID is a useful tool that may integrate and complete the physical examination, also providing additional information to chest X-ray in the clinical management of patients with suspected PE. PSID evaluation can also increase the effectiveness and safety of thoracentesis. PMID- 22815329 TI - Cardiovascular drugs and cancer: of competing risk, smallpox, Bernoulli, and d'Alembert. PMID- 22815328 TI - Cardiac outcomes in adults with supravalvar aortic stenosis. AB - AIMS: Supravalvar aortic stenosis is a rare form of left ventricular outflow tract obstruction that is often progressive in childhood. Little data are available on outcomes in the adult population. Our aim was to define cardiac outcomes in adults with supravalvar aortic stenosis. METHODS AND RESULTS: This is a multicentre retrospective study of cardiac outcomes in adults (>=18 years) with supravalvar aortic stenosis. We examined: (i) adverse cardiac events (cardiovascular death, myocardial infarction, stroke, heart failure, sustained arrhythmias, and infective endocarditis) and (ii) the need for cardiac surgery in adulthood. One hundred and thirteen adults (median age at first visit 19 years; 55% with Williams-Beuren syndrome; 67% with surgical repair in childhood) were identified. Adults without Williams-Beuren syndrome had more severe supravalvar aortic stenosis and more often associated left ventricular outflow tract obstructions (P < 0.001). In contrast, mitral valve regurgitation was more common in patients with Williams-Beuren syndrome. Eighty-five per cent of adults (96/113) had serial follow-up information (median follow-up 6.0 years). Of these patients, 13% (12/96) had an adverse cardiac event and 13% (12/96) had cardiac operations (7 valve repair or replacements, 4 supravalvar aortic stenosis repairs, 1 other). Cardiac surgery was more common in adults without Williams Beuren syndrome (P = 0.007). Progression of supravalvar aortic stenosis during adulthood was rare. CONCLUSION: Adults with supravalvar aortic stenosis remain at risk for cardiac complications and reoperations, while progression of supravalvar aortic stenosis in adulthood is rare. Valve surgery is the most common indication for cardiac surgery in adulthood. PMID- 22815330 TI - Clinical update: Remaining challenges and opportunities for improvement in percutaneous transradial coronary procedures. AB - The adoption of transradial coronary angiography and coronary intervention is growing because of emerging data on its potential advantages over the femoral approach. As the adoption of radial procedures increases, it is important to understand the remaining challenges of both the technique and its implementation. In this review, we discuss four important issues related to transradial procedures--radial access site bleeding, radial artery injury and occlusion, radiation exposure, and implementation of a successful transradial primary percutaneous coronary intervention (PCI) programme. Although the radial artery is superficial and haemostasis can be achieved readily, access site bleeding can occur that, if left unchecked, can lead to forearm haematoma and, rarely, to compartment syndrome. Radial artery injury and occlusion are consequences of radial access, and randomized trials show that use of smaller diameter sheaths, adequate anticoagulation, and post-procedure 'patent' haemostasis reduce the risk of occlusion. The published literature demonstrates an association between transradial procedures and increased radiation exposure; therefore, reduction of radiation dosing during transradial procedures should be a priority for operators and catheterization laboratories. The potential reduction in mortality seen with transradial primary PCI must be balanced against the clinical imperative of timely reperfusion. Operators and catheterization laboratories should not begin a transradial primary PCI programme until sufficient radial experience has been gained in the elective setting. In addition, a protocol for femoral bailout should be considered to maintain door-to-reperfusion metrics. PMID- 22815331 TI - A health education pilot for Latina women with diabetes. AB - The purpose of this study was to develop and pilot test nutrition and physical activity educational tools for immigrant Latina women who have type 2 diabetes and low health literacy levels. Participants' ability to use the tools was assessed and a focus group was conducted (n=26). During two classes, the women were taught diabetes concepts related to nutrition and physical activity and were given a pedometer. The women recorded in a log vegetables consumed and steps taken. Nearly all participants (n=24) completed the nutrition log, and most used the pedometer (n=25) and completed the step log for 5 or more days (n=19). The women reported that the pedometer and logs helped them increase vegetable consumption and physical activity. Interventions for this population should use plain language, tools that are easy to use, and strategies that encourage behavioral change. PMID- 22815332 TI - Conventional case-cohort design and analysis for studies of interaction. AB - BACKGROUND: The case-cohort study design has received significant methodological attention in the statistical and epidemiological literature but has not been used as widely as other cohort-based sampling designs, such as the nested case-control design. Despite its efficiency and practicality for a wide range of epidemiological study purposes, researchers may not yet be aware of the fact that the design can be analysed using standard software with only minor adjustments. Furthermore, although the large number of options for design and analysis of case cohort studies may be daunting, they can be reduced to a few simple recommendations. METHODS: We review conventional methods for the design and analysis of case-cohort studies and describe empirical comparisons based on a study of radiation, gene polymorphisms and cancer in the Japanese atomic bomb survivor cohort. RESULTS: Stratified, as opposed to simple, random subcohort selection is recommended, especially for studies of gene-environment interaction, which are notorious for lacking statistical power. Methods based on the score unbiased exact pseudo-likelihood (or its analogue with stratified case-cohort data) are recommended for use in conjunction with the asymptotic variance estimator. CONCLUSIONS: We present an example of how to implement case-cohort analysis methods using SPSS, a popular statistical package that lacks some of the features necessary to directly adapt and implement published methods based on other software platforms. We also illustrate case-control analysis using Epicure, which provides greater risk-modelling flexibility than other software. Our conclusions and recommendations should help investigators to better understand and apply the case-cohort design in epidemiological research. PMID- 22815333 TI - Clinical, radiological and functional assessment of pulmonary status in patients with achalasia cardia before and after treatment. AB - OBJECTIVES: Patients with achalasia have respiratory symptoms due to chronic microaspiration. Achalasia can lead to radiological and functional changes in the lung. We studied the effect of either balloon dilatation or laparoscopic Heller's cardiomyotomy on the reversal of these changes in the lung. METHODS: Thirty patients with achalasia were included in this study. Oesophageal symptoms and pulmonary symptoms were recorded. Pulmonary function tests (PFTs) were done at baseline and at the end of 6 months. High-resolution computed tomography of the chest was performed prior to treatment and repeated 6 months after treatment if found abnormal at the initial evaluation. RESULTS: The mean age of the patients was 30.97 years and mean duration of symptoms was 22.5 months. Fifteen patients (50%) had respiratory symptoms, nocturnal cough being the commonest symptom in 13 (43.3%). Thirteen patients (43.3%) had parenchymal lung changes on high resolution computed tomography (HRCT). Eight patients (28.5%) had functional abnormalities in the lungs in the form of restrictive airway disease. Nineteen patients opted for Laparoscopic Heller's cardiomyotomy, while 11 patients underwent pneumatic dilatation. Six months after treatment, the respiratory symptoms resolved in all except two patients (13.3%). Four patients (66.6%) with active lung changes at HRCT showed resolution at 6 months. There was improvement in functional parameters on PFT evaluation with normalization of PFT in one patient. CONCLUSIONS: Pulmonary symptoms as well as radiological and functional abnormalities are common in patients with achalasia. Treatment in the form of pneumatic dilatation or Lap cardiomyotomy improves pulmonary symptoms. PMID- 22815334 TI - In pursuit of leanness: the management of appearance, affect and masculinities within a men's weight loss forum. AB - In a somatic society which promotes visible, idealized forms of embodiment, men are increasingly being interpellated as image-conscious body-subjects. Some research suggests that men negotiate appearance issues in complex and varied ways, partly because image concerns are conventionally feminized. However, little research has considered how overweight men construct body projects in the context of weight loss, or how men talk to each other about weight management efforts. Since sources of information and support for overweight men are now provided online, including dedicated weight loss discussion forums, our analysis focuses on one such forum, linked to a popular male-targeted magazine. We conducted a thematic analysis of selected extracts from seven threads on the forum. Our analysis suggests a widespread focus on appearance, as well as the use of emotion categories when describing difficult bodily experiences. Invariably, however, such talk was carefully constructed and constrained by hegemonic masculinities founded on discipline, work-orientation, pragmatism and self-reliance. The findings are discussed in relation to magazine masculinities and aesthetics, as well as literature on male embodiment. PMID- 22815335 TI - Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. AB - CONTEXT: Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. OBJECTIVE: Evaluation of the efficacy and tolerance of mitotane in CD patients. DESIGN AND SETTING: Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. MAIN OUTCOME MEASURE: Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). RESULTS: Remission was achieved in 48 (72%) of the 67 long term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5 +/- 8.9 mg/l, with a mean daily dose of 2.6 +/- 1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. CONCLUSION: Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients. PMID- 22815337 TI - Cardioprotective brain mechanisms. PMID- 22815338 TI - Platelet activation by an extracellular adherence protein from Staphylococcus aureus acting via modulation of sulfhydryl groups on platelets. PMID- 22815336 TI - Modulation of hippocampal dopamine metabolism and hippocampal-dependent cognitive function by catechol-O-methyltransferase inhibition. AB - Catechol-O-methyltransferase (COMT) catabolises the catecholamine neurotransmitters and influences cognitive function. COMT modulates dopamine levels in the prefrontal cortex and its action in this region is generally invoked to explain its effects on cognition. However, its role in other brain regions important for cognitive function remains largely unexplored. Here, we investigated COMT's impact on dopamine metabolism in the hippocampus and hippocampal-dependent behaviour. We examined the acute effects of a centrally acting COMT inhibitor, tolcapone (30 mg/kg i.p.), on dopamine metabolism in the rat dorsal hippocampus, assessed both in tissue homogenates and extracellularly, using in vivo microdialysis. Additionally, we investigated the effect of tolcapone on delayed-rewarded alternation and spatial novelty preference, behavioural tasks which are dependent on the dorsal hippocampus. Tolcapone significantly modulated dopamine metabolism in the dorsal hippocampus, as indexed by the depletion of extracellular homovanillic acid (HVA) and the accumulation of dihydroxyphenylacetic acid (DOPAC). Tolcapone also improved performance on the delayed-rewarded alternation and spatial novelty preference tasks, compared to vehicle-treated rats. Our findings suggest that COMT regulates dorsal hippocampal neurochemistry and modulates hippocampus-dependent behaviours. These findings support the therapeutic candidacy of COMT inhibition as a cognitive enhancer, and suggest that, in addition to the prefrontal cortex, the hippocampus might be a key region for mediating these effects. PMID- 22815339 TI - Insulin resistance and metabolic syndrome: mechanisms and consequences. PMID- 22815340 TI - Insulin resistance and coronary heart disease in nondiabetic individuals. AB - The goal of this review was to summarize evidence supporting the view that insulin resistance/compensatory hyperinsulinemia play an important role in the pathogenesis of coronary heart disease (CHD) in nondiabetic individuals. Results of case-control and epidemiological studies in nondiabetic individuals will be reviewed to examine the link between insulin resistance/compensatory hyperinsulinemia, associated abnormalities, and CHD. The primary focus of the review will be on the central role that dyslipidemia plays in the link between insulin resistance/compensatory hyperinsulinemia and CHD. Additional issues to be addressed include the following: (1) the relationship among obesity, insulin resistance, and CHD; (2) a listing of other abnormalities that contribute to risk of CHD in insulin-resistant individuals; and (3) discussion of the importance of differential tissue insulin sensitivity in the development of abnormalities that increase CHD risk in insulin-resistant, nondiabetic individuals. The information will reflect the author's decision as to what issues are believed to be of particular relevance or less well appreciated concerning the complex relationship between insulin resistance and CHD. Resistance to insulin-mediated glucose disposal and hyperinsulinemia is a common finding in apparently healthy individuals and is associated with a number of abnormalities that greatly increase risk of CHD. PMID- 22815341 TI - Glycation and insulin resistance: novel mechanisms and unique targets? AB - Multiple biochemical, metabolic, and signal transduction pathways contribute to insulin resistance. In this review, we present evidence that the posttranslational process of protein glycation may play a role in insulin resistance. The posttranslational modifications, the advanced glycation end products (AGEs), are formed and accumulated by endogenous and exogenous mechanisms. AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of tumor necrosis factor-alpha direct modification of the insulin molecule, thereby leading to its impaired action, generation of oxidative stress, and impairment of mitochondrial function, as examples. AGEs may stimulate signal transduction via engagement of cellular receptors, such as receptor for AGEs. AGE-receptor for AGE interaction perpetuates AGE formation and cellular stress via induction of inflammation, oxidative stress, and reduction in the expression and activity of the enzyme glyoxalase I that detoxifies the AGE precursor, methylglyoxal. Once set in motion, glycation-promoting mechanisms may stimulate ongoing AGE production and target tissue stresses that reduce insulin responsiveness. Strategies to limit AGE accumulation and action may contribute to the prevention of insulin resistance and its consequences. PMID- 22815342 TI - Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer. AB - Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index >= 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link. PMID- 22815344 TI - Smooth muscle phenotypic modulation--a personal experience. AB - The idea that smooth muscle cells can exist in multiple phenotypic states depending on the functional demands placed upon them has been around for >5 decades. However, much of the literature today refers to only recent articles, giving the impression that it is a new idea. At the same time, the current trend is to delve deeper and deeper into transcriptional regulation of smooth muscle genes, and much of the work describing the change in biology of the cells in the different phenotypic states does not appear to be known. This loss of historical perspective regarding the biology of smooth muscle phenotypic modulation is what the current article has tried to mitigate. PMID- 22815346 TI - Geographic differences in physical education and adolescent BMI: have legal mandates made a difference? AB - The school environment is an ideal setting for healthy weight programming with adolescents. The federal government has reinforced the importance of school-based health promotion. The current study examined the preliminary influence of the 2006 school wellness policy requirement of the Child Nutrition and WIC Reauthorization Act (CNWICRA) on adolescent Body Mass Index (BMI) and physical education participation. Nationally representative data from the 2003 and 2007 Youth Risk Behavior Surveillance Survey (YRBSS) were used. The authors examined BMI percentile and physical education participation based on survey year and geographic region. Results suggest a slight decrease in BMI with no changes in physical education participation. A main effect for geographic region was found for both physical education participation and BMI percentile, while a geographic region-by-survey year interaction was discovered when analyzing BMI percentiles. Results suggest a need for continued investigation and may inform future healthy weight programming and geographically tailored wellness policies. PMID- 22815343 TI - Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. AB - Obesity and its comorbidities, including type 2 diabetes mellitus and cardiovascular disease, are associated with a state of chronic low-grade inflammation that can be detected both systemically and within specific tissues. Areas of active investigation focus on the molecular bases of metabolic inflammation and potential pathogenic roles in insulin resistance, diabetes, and cardiovascular disease. An increased accumulation of macrophages occurring in obese adipose tissue has emerged as a key process in metabolic inflammation. Recent studies have also begun to unravel the heterogeneity of adipose tissue macrophages, and their physical and functional interactions with adipocytes, endothelial cells, and other immune cells within the adipose tissue microenvironment. Translating the information gathered from experimental models of insulin resistance and diabetes into meaningful therapeutic interventions is a tantalizing goal with long-term global health implications. In this context, ongoing clinical studies are testing the effects of targeting inflammation systemically on metabolic and cardiovascular outcomes. PMID- 22815347 TI - Asthma and adolescents: review of strategies to improve control. AB - One of every 10 adolescents in the United States has asthma. Adolescents who lack asthma control are at increased risk for severe asthma episodes and death. The National Heart, Lung, and Blood Institute 2007 asthma guidelines and research studies indicated that school nurses are instrumental in assisting adolescents to monitor their asthma, learn asthma self-management skills, and improve health outcomes. This integrative review examines the research from 2005 to 2011 to identify strategies for school nurses to employ with adolescents to foster self management skills. The research reviewed here supports the need for school nurses to engage adolescents with asthma to practice self-management behaviors. They should educate the adolescent for asthma, monitor how well the adolescent controls asthma, manage acute asthma episodes by using an asthma action plan, and coordinate care by obtaining written consent from parents to share health information with health care providers. PMID- 22815348 TI - Decreased microRNA-155 expression in ocular Behcet's disease but not in Vogt Koyanagi Harada syndrome. AB - PURPOSE: MicroRNAs (miRNAs) have emerged as a class of gene expression regulators involved in immune regulation. In the present study, we investigated the role of miRNA in two uveitis entities: Behcet's disease (BD) and Vogt Koyanagi Harada syndrome (VKH). METHODS: The expression of five miRNAs was studied in PBMCs, DCs, and CD4(+) T cells from BD patients with active and inactive uveitis, VKH patients with active uveitis, and healthy controls using real-time PCR. MiR-155 mimics and inhibitor were transfected to DCs to evaluate the effect on DC maturation and cytokine production by these cells and CD4(+) T cells. Luciferase reporter assays and Western blotting were performed to identify the target gene of miR-155. RESULTS: Only miR-155 expression was significantly decreased in PBMCs and DCs from BD patients with active uveitis and no differences were observed in the miRNA expression in cells from patients with VKH as compared with controls. Overexpression of miR-155 in DCs was shown to inhibit the production of IL-6 and IL-1beta, and to promote the expression of IL-10 by these cells. MiR-155 transfected DCs significantly inhibited intracellular IL-17 expression in allogeneic CD4(+) T cells; however, it did not influence the expression of cell surface markers CD80, CD40, CD83, CD86, and HLA-DR. Luciferase reporter assays revealed that TAB2 was a target gene of miR-155, which was confirmed by Western blotting. CONCLUSIONS: The present results suggest that miR-155 expression is decreased in active BD but not in VKH patients. Downregulated miR-155 may be involved in BD pathogenesis by targeting TAB2. PMID- 22815349 TI - Genetic, behavioral, and sociodemographic risk factors for second eye progression in age-related macular degeneration. AB - PURPOSE: This study was conducted to investigate the correlation of genetic, sociodemographic, and behavioral risk factors with second eye progression to end stage AMD. METHODS: One hundred and eight patients with end-stage AMD in one or both eyes were included in a retrospective time-to-event analysis of the onset of end-stage AMD in the second eye. Multivariate Cox regression survival analysis was performed for sex, age, smoking, body mass index (BMI), education, and 16 single nucleotide polymorphisms (SNPs) associated with AMD. RESULTS: Except for education, all sociodemographic and behavioral risk factors analyzed were significantly associated with a more rapid progression toward second eye involvement. Hazard ratios (HRs) were 2.6 (95% confidence interval [CI], 1.4-5.0) for female sex; 5.0 (95% CI, 2.0-12.5) for age >80; 2.2 (95% CI, 1.1-4.1) for BMI >30; and 4.4 (95% CI, 1.4-14.3) for >40 pack years, compared with the referent groups. Carriers of the lipoprotein lipase (LPL; rs12678919) risk alleles were at risk for more rapid progression to end-stage AMD in the second eye compared with the referent wild-type genotype (HR 2.0; 95% CI, 1.0-3.6). For complement factor I (CFI; rs10033900), homozygous carriers of the risk allele progressed faster than wild-type individuals (HR 2.2; 95% CI, 1.1-4.3). CONCLUSIONS: Sociodemographic, behavioral, and genetic risk factors are associated with the rate of second eye progression toward end-stage AMD. The findings of this study underline the importance of lifestyle factors and the complement pathway in AMD progression and suggest a role of the high-density-lipoprotein metabolism in second eye progression. PMID- 22815350 TI - Screening of ocular enterobacteriaceae isolates for presence of chromosomal blaNDM-1 and ESBL genes: a 2-year study at a tertiary eye care center. AB - PURPOSE: Since, to our knowledge, there are no reports on the prevalence of the blaNDM-1 gene among ocular isolates of Enterobacteriaceae, and only limited information on the prevalence of extended spectrum beta-lactamases (ESBLs) among ocular bacterial isolates are available, our study was undertaken. METHODS: A prospective study was done on 74 Enterobacteriaceae isolates from patients presenting with clinical suspicion of bacterial ocular infections during a period from January 2010-December 2011. All isolates were subjected to detection of ESBLs by double disc synergy and screened for the presence of CTX-M -I, II, III, and IV groups, and OXA, TEM, SHV, blaNDM-1 genes by PCR. RESULTS: Of 74 ocular Enterobacteriaceae isolates 57 (77%) were ESBL producers tested by the double disc diffusion test. PCR-based DNA sequencing of these 57 ocular isolates showed the presence of CTX-M-15 (14.0%), blaOXA-1 (5.2%), blaSHV-1 (8.7%), and blaTEM-1 (7.0%) types. The blaNDM-1 was absent among these ocular isolates. The most widely disseminated ESBL gene among ocular isolates was CTX-M-15. Phenotypic and genotypic results showed 100% correlation. CONCLUSIONS: To our knowledge, this is the first extensive study performed to genotype ESBL-producing ocular Enterobacteriaceae isolates. The isolation of ESBL-producing Enterobacteriaceae organisms predominantly from conjunctival specimens indicates community-acquired infections/colonization by these bacteria in the conjunctiva of the patients, and cases are not related to hospital-acquired infections because of the short stay of ophthalmic patients in the hospitals. A shift in the resistance rates of ceftazidime from 37.5% to 79.7% over the years proves the increase in drug resistance among ocular clinical isolates. PMID- 22815351 TI - Quantitative morphometry of perifoveal capillary networks in the human retina. AB - PURPOSE: To quantify the distribution and morphometric characteristics of capillary networks in the human perifovea. To determine correlations between the location of neuronal subcellular compartments and the morphometric features of regional capillary networks in the layered retina. METHODS: The perifoveal region, located 2 mm nasal to the fovea, was studied in 17 human donor eyes. Novel micropipette technology was used to cannulate the central retinal artery and label the retinal microcirculation using a phalloidin perfusate. gamma synuclein, Goalpha, and parvalbumin antibodies were also used to co-localize the nerve fiber layer (NFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL), and inner nuclear layer (INL). Confocal scanning laser microscopy was used for capillary imaging. Capillary diameter, capillary density, and capillary loop area measurements were compared between networks. RESULTS: Four capillary networks were identified in the following retinal layers: (1) NFL, (2) RGCL and superficial portion of IPL, (3) deep portion of IPL and superficial portion of INL, and (4) deep portion of INL. Laminar configurations were present in NFL and deep INL networks. Remaining networks demonstrated three-dimensional configurations. Capillary density was greatest in the networks serving the IPL. Capillary loop area was smallest in the two innermost networks. There was no difference in capillary diameter between networks. CONCLUSIONS: Capillary networks in the human perifovea are morphometrically heterogeneous. Morphometric features of regional capillary networks in the layered retina may serve a critical role in supporting neuronal homeostasis. Improved knowledge of these features may be important for understanding pathogenic mechanisms underlying retinal vascular diseases. PMID- 22815352 TI - Diagnostic ability of retinal nerve fiber layer thickness measurements and neurologic hemifield test to detect chiasmal compression. AB - PURPOSE: The purpose of the study was to investigate the diagnostic ability of the neurologic hemifield test (NHT) and retinal nerve fiber layer (RNFL) thickness measurements to detect chiasmal compression. METHODS: Thirty-seven patients with chiasmal compression, 35 patients with glaucoma, and 30 patients with glaucoma suspect were enrolled. The NHT score was established from a 30-2 visual field pattern deviation probability plot. Each test point value was calculated for a number that was inversely proportional to its pattern deviation probability. The NHT score was the absolute value of the difference in the sum of the point scores for two symmetrical regions of 16 points on either side of the vertical meridian. RNFL thickness was scored from 0 to 10 according to the pattern of RNFL loss and probability of abnormality. Solely present nasal or temporal RNFL defects were scored high, and exclusively appearing superior or nasal RNFL defects were scored low. The differences in the NHT and RNFL scores among the three groups were compared. Diagnostic ability was assessed by receiver operating characteristic (ROC) analysis. RESULTS: The NHT and RNFL scores were significantly higher in patients with chiasmal compression than in patients with glaucoma and glaucoma suspect. The area under the ROC curve (AROC) was 0.734 of the NHT score and 0.613 of the RNFL score. When AROC was calculated using the NHT and RNFL scores concurrently, AROC was increased to 0.807. CONCLUSIONS: The NHT score and RNFL score have diagnostic ability to detect chiasmal compression, and simultaneous assessment of NHT and RNFL scores improves the diagnostic power. PMID- 22815353 TI - Spread of the blaTEM-52 gene is mainly ensured by IncI1/ST36 plasmids in Escherichia coli isolated from cattle in France. PMID- 22815354 TI - Increase in fluoroquinolone non-susceptibility among clinical Streptococcus pyogenes in Belgium during 2007-10. AB - OBJECTIVES: To study the temporal evolution of fluoroquinolone non-susceptibility among Streptococcus pyogenes during 2007-10 in Belgium. METHODS: S. pyogenes (n = 4690) recovered from patients with tonsillopharyngitis or skin, wound or invasive infections were screened for fluoroquinolone non-susceptibility. A selection of fluoroquinolone-non-susceptible strains was investigated for resistance mechanisms: reserpine-sensitive efflux and mutations in topoisomerase genes parC and gyrA. Clonality was determined by emm typing. RESULTS: Fluoroquinolone non susceptibility (ciprofloxacin MIC >=2 mg/L) was identified in 535 (11.4%) of 4690 S. pyogenes recovered during 2007-10 in Belgium. The proportion of fluoroquinolone-non-susceptible S. pyogenes increased significantly from 4.3% (2008) to 10.9% (2009) to 21.6% (2010) and coincided with a significant increase in emm6 strains among fluoroquinolone-non-susceptible S. pyogenes. Ciprofloxacin MICs of 2-8 mg/L correlated with first-step ParC substitutions. Two high-level fluoroquinolone-resistant S. pyogenes strains (ciprofloxacin MICs 32 mg/L) showed second-step substitutions in GyrA (Ser-81->Phe or Tyr) in addition to first-step mutations in parC. Reserpine-sensitive efflux was not observed. CONCLUSIONS: We report an unprecedented increase in fluoroquinolone-non-susceptible S. pyogenes in Belgium, a country with high quinolone use, as well as emergence of two high level fluoroquinolone-resistant S. pyogenes strains with second-step mutations in gyrA, warning us of the need for more prudent use of fluoroquinolones and for continued resistance surveillance. PMID- 22815355 TI - Metabolite identification and molecular fingerprint prediction through machine learning. AB - MOTIVATION: Metabolite identification from tandem mass spectra is an important problem in metabolomics, underpinning subsequent metabolic modelling and network analysis. Yet, currently this task requires matching the observed spectrum against a database of reference spectra originating from similar equipment and closely matching operating parameters, a condition that is rarely satisfied in public repositories. Furthermore, the computational support for identification of molecules not present in reference databases is lacking. Recent efforts in assembling large public mass spectral databases such as MassBank have opened the door for the development of a new genre of metabolite identification methods. RESULTS: We introduce a novel framework for prediction of molecular characteristics and identification of metabolites from tandem mass spectra using machine learning with the support vector machine. Our approach is to first predict a large set of molecular properties of the unknown metabolite from salient tandem mass spectral signals, and in the second step to use the predicted properties for matching against large molecule databases, such as PubChem. We demonstrate that several molecular properties can be predicted to high accuracy and that they are useful in de novo metabolite identification, where the reference database does not contain any spectra of the same molecule. AVAILABILITY: An Matlab/Python package of the FingerID tool is freely available on the web at http://www.sourceforge.net/p/fingerid. CONTACT: markus.heinonen@cs.helsinki.fi. PMID- 22815356 TI - UniMoG--a unifying framework for genomic distance calculation and sorting based on DCJ. AB - SUMMARY: UniMoG is a software combining five genome rearrangement models: double cut and join (DCJ), restricted DCJ, Hannenhalli and Pevzner (HP), inversion and translocation. It can compute the pairwise genomic distances and a corresponding optimal sorting scenario for an arbitrary number of genomes. All five models can be unified through the DCJ model, thus the implementation is based on DCJ and, where reasonable, uses the most efficient existing algorithms for each distance and sorting problem. Both textual and graphical output is possible for visualizing the operations. AVAILABILITY AND IMPLEMENTATION: The software is available through the Bielefeld University Bioinformatics Web Server at http://bibiserv.techfak.uni-bielefeld.de/dcj with instructions and example data. CONTACT: rhilker@cebitec.uni-bielefeld.de. PMID- 22815357 TI - VegaMC: a R/bioconductor package for fast downstream analysis of large array comparative genomic hybridization datasets. AB - SUMMARY: Identification of genetic alterations of tumor cells has become a common method to detect the genes involved in development and progression of cancer. In order to detect driver genes, several samples need to be simultaneously analyzed. The Cancer Genome Atlas (TCGA) project provides access to a large amount of data for several cancer types. TGCA is an invaluable source of information, but analysis of this huge dataset possess important computational problems in terms of memory and execution times. Here, we present a R/package, called VegaMC (Vega multi-channel), that enables fast and efficient detection of significant recurrent copy number alterations in very large datasets. VegaMC is integrated with the output of the common tools that convert allele signal intensities in log R ratio and B allele frequency. It also enables the detection of loss of heterozigosity and provides in output two web pages allowing a rapid and easy navigation of the aberrant genes. Synthetic data and real datasets are used for quantitative and qualitative evaluation purposes. In particular, we demonstrate the ability of VegaMC on two large TGCA datasets: colon adenocarcinoma and glioblastoma multiforme. For both the datasets, we provide the list of aberrant genes which contain previously validated genes and can be used as basis for further investigations. AVAILABILITY: VegaMC is a R/Bioconductor Package, available at http://bioconductor.org/packages/release/bioc/html/VegaMC.html. CONTACT: morganella@unisannio.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22815358 TI - imDEV: a graphical user interface to R multivariate analysis tools in Microsoft Excel. AB - Interactive modules for Data Exploration and Visualization (imDEV) is a Microsoft Excel spreadsheet embedded application providing an integrated environment for the analysis of omics data through a user-friendly interface. Individual modules enables interactive and dynamic analyses of large data by interfacing R's multivariate statistics and highly customizable visualizations with the spreadsheet environment, aiding robust inferences and generating information-rich data visualizations. This tool provides access to multiple comparisons with false discovery correction, hierarchical clustering, principal and independent component analyses, partial least squares regression and discriminant analysis, through an intuitive interface for creating high-quality two- and a three dimensional visualizations including scatter plot matrices, distribution plots, dendrograms, heat maps, biplots, trellis biplots and correlation networks. AVAILABILITY AND IMPLEMENTATION: Freely available for download at http://sourceforge.net/projects/imdev/. Implemented in R and VBA and supported by Microsoft Excel (2003, 2007 and 2010). PMID- 22815359 TI - Quantifying uniformity of mapped reads. AB - We describe a tool for quantifying the uniformity of mapped reads in high throughput sequencing experiments. Our statistic directly measures the uniformity of both read position and fragment length, and we explain how to compute a P value that can be used to quantify biases arising from experimental protocols and mapping procedures. Our method is useful for comparing different protocols in experiments such as RNA-Seq. AVAILABILITY AND IMPLEMENTATION: We provide a freely available and open source python script that can be used to analyze raw read data or reads mapped to transcripts in BAM format at http://www.math.miami.edu/~vhower/ReadSpy.html. PMID- 22815360 TI - DanteR: an extensible R-based tool for quantitative analysis of -omics data. AB - MOTIVATION: The size and complex nature of mass spectrometry-based proteomics datasets motivate development of specialized software for statistical data analysis and exploration. We present DanteR, a graphical R package that features extensive statistical and diagnostic functions for quantitative proteomics data analysis, including normalization, imputation, hypothesis testing, interactive visualization and peptide-to-protein rollup. More importantly, users can easily extend the existing functionality by including their own algorithms under the Add On tab. AVAILABILITY: DanteR and its associated user guide are available for download free of charge at http://omics.pnl.gov/software/. We have an updated binary source for the DanteR package up on our website together with a vignettes document. For Windows, a single click automatically installs DanteR along with the R programming environment. For Linux and Mac OS X, users must install R and then follow instructions on the DanteR website for package installation. CONTACT: rds@pnnl.gov. PMID- 22815361 TI - Network inference using steady-state data and Goldbeter-Koshland kinetics. [corrected]. AB - MOTIVATION: Network inference approaches are widely used to shed light on regulatory interplay between molecular players such as genes and proteins. Biochemical processes underlying networks of interest (e.g. gene regulatory or protein signalling networks) are generally nonlinear. In many settings, knowledge is available concerning relevant chemical kinetics. However, existing network inference methods for continuous, steady-state data are typically rooted in statistical formulations, which do not exploit chemical kinetics to guide inference. RESULTS: Herein, we present an approach to network inference for steady-state data that is rooted in non-linear descriptions of biochemical mechanism. We use equilibrium analysis of chemical kinetics to obtain functional forms that are in turn used to infer networks using steady-state data. The approach we propose is directly applicable to conventional steady-state gene expression or proteomic data and does not require knowledge of either network topology or any kinetic parameters. We illustrate the approach in the context of protein phosphorylation networks, using data simulated from a recent mechanistic model and proteomic data from cancer cell lines. In the former, the true network is known and used for assessment, whereas in the latter, results are compared against known biochemistry. We find that the proposed methodology is more effective at estimating network topology than methods based on linear models. AVAILABILITY: mukherjeelab.nki.nl/CODE/GK_Kinetics.zip CONTACT: c.j.oates@warwick.ac.uk; s.mukherjee@nki.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22815362 TI - Cell-Dock: high-performance protein-protein docking. AB - SUMMARY: The application of docking to large-scale experiments or the explicit treatment of protein flexibility are part of the new challenges in structural bioinformatics that will require large computer resources and more efficient algorithms. Highly optimized fast Fourier transform (FFT) approaches are broadly used in docking programs but their optimal code implementation leaves hardware acceleration as the only option to significantly reduce the computational cost of these tools. In this work we present Cell-Dock, an FFT-based docking algorithm adapted to the Cell BE processor. We show that Cell-Dock runs faster than FTDock with maximum speedups of above 200*, while achieving results of similar quality. AVAILABILITY AND IMPLEMENTATION: The source code is released under GNU General Public License version 2 and can be downloaded from http://mmb.pcb.ub.es/~cpons/Cell-Dock. CONTACT: djimenez@ac.upc.edu or juanf@bsc.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22815363 TI - MolBioLib: a C++11 framework for rapid development and deployment of bioinformatics tasks. AB - SUMMARY: We developed MolBioLib to address the need for adaptable next-generation sequencing analysis tools. The result is a compact, portable and extensively tested C++11 software framework and set of applications tailored to the demands of next-generation sequencing data and applicable to many other applications. MolBioLib is designed to work with common file formats and data types used both in genomic analysis and general data analysis. A central relational-database-like Table class is a flexible and powerful object to intuitively represent and work with a wide variety of tabular datasets, ranging from alignment data to annotations. MolBioLib has been used to identify causative single-nucleotide polymorphisms in whole genome sequencing, detect balanced chromosomal rearrangements and compute enrichment of messenger RNAs (mRNAs) on microtubules, typically requiring applications of under 200 lines of code. MolBioLib includes programs to perform a wide variety of analysis tasks, such as computing read coverage, annotating genomic intervals and novel peak calling with a wavelet algorithm. Although MolBioLib was designed primarily for bioinformatics purposes, much of its functionality is applicable to a wide range of problems. Complete documentation and an extensive automated test suite are provided. AVAILABILITY: MolBioLib is available for download at: http://sourceforge.net/projects/molbiolib CONTACT: ohsumit@molbio.mgh.harvard.edu. PMID- 22815364 TI - Should we care about quality indicators for nursing journals? PMID- 22815365 TI - On the validity of the Trieste flatfish: dispelling the myth. PMID- 22815366 TI - Characterization of novel cytoplasmic PARP in the brain of Octopus vulgaris. PMID- 22815367 TI - Molecular characterization and expression of As-nurp1 gene from Artemia sinica during development and in response to salinity and temperature stress. AB - Nuclear protein 1 (NURP1) is a stress-related protein and closely related to diapause in the development of Artemia. In the present paper, the full-length 568 bp cDNA sequence of the nurp1 homolog of Artemia sinica (As-nurp1) was isolated by RACE technology for the first time. The putative As-nurp1 protein consists of 66 amino acids with a basic helix-loop-helix (bHLH) motif and a bipartite nuclear localization signal (NLS). Multiple sequence alignments revealed that the putative As-nurp1 protein sequence was relatively conserved across species, especially in the bHLH domain. The expression of As-nurp1 is widely distributed during A. sinica development. This is followed by a dramatic downregulation after diapause and is newly upregulated from the larval nauplius stage. Furthermore, As nurp1 transcripts are highly upregulated under conditions of high salinity and low temperature. These findings suggest that As-nurp1 is stress-related and may act as a protective factor in embryonic development. PMID- 22815368 TI - Annual variation in the timing of coral spawning in a high-latitude environment: influence of temperature. AB - This study was conducted at a high-latitude location (32 degrees N; Kochi, Japan), where annual seawater temperatures show large fluctuations due to the meandering of the Kuroshio Current, providing a unique opportunity to examine the influence of temperature on coral reproduction. Annual spawning of individual colonies of four reef coral species-two Acropora species (Acropora hyacinthus and A. japonica) and two faviid species (Favites pentagona and Platygyra contorta) was monitored in situ for 4 years in 2006-2009. The spawning of the four species always occurred around the last quarter moon in the local summer, July or August, irrespective of high annual variations in seawater temperatures (from 23.7 to 29.5 degrees C) and weather during the spawning period. However, the exact timing of spawning during the spawning period varied among the years and was correlated with the cumulative seawater temperature during the late period of gametogenesis (0-3 months before spawning). When seawater temperatures were higher, spawning occurred in the earlier spawning month (July) and vice versa, except in A. hyacinthus, which always spawned in July. In the case of the two Acropora species, higher (lower) temperatures led to spawning earlier (later) in the lunar cycle. Seawater temperature may have an influence on gametogenesis, causing the shift in spawning timing. PMID- 22815369 TI - Seasonal patterns of population structure in a colonial marine invertebrate (Bugula stolonifera, Bryozoa). AB - For sessile invertebrates, the degree to which dispersal mechanisms transport individuals away from their natal grounds can have significant ecological implications. Even though the larvae of the marine bryozoan Bugula stolonifera have limited dispersal potential, high levels of genetic mixing have been found within their conspecific aggregations. In this study, we investigated whether this high mixing within aggregations of B. stolonifera also resulted in high mixing between aggregations. Adult colonies were collected from five sites within and one site outside of Eel Pond, Woods Hole, Massachusetts, in August 2009 and genotyped at 10 microsatellite loci. Significant genotypic differentiation was found between most sites, suggesting limited connectivity across sites, even those separated by only 100 m. This investigation was extended to determine if low levels of genetic mixing throughout the reproductive season could result in increased homogeneity between sites. Four of the five sites in Eel Pond were sampled early, mid-, and late in the reproductive season in 2010, and again in early 2011. Inter- and intra-annual genotypic differentiation was then assessed within and between sites. Results from these analyses document that low levels of mixing could result in increased homogeneity between some aggregations, but that barriers to genetic exchange prevented mixing between most sites. Further, results from inter-annual comparisons within sites suggest that any potential homogeneity achieved throughout the reproductive season will likely be lost by the beginning of the next reproductive season due to the annual cycle of colony die-back and regrowth experienced by B. stolonifera colonies in Eel Pond. PMID- 22815370 TI - Comparative analysis of movement characteristics of lancelet and fish spermatozoa having different morphologies. AB - The movement characteristics of the sperm and their flagella obtained from a lancelet and 35 species from almost all orders of fishes were examined using high speed video microscopy. The aim was to clarify the relationship between the motility parameters of the spermatozoa having different morphologies and how these motility parameters affect the swimming speed of the spermatozoa. The motility parameters representing the flagellar waveform, the wavelength, and the amplitude were neither very different between the spermatozoa of the different species nor related to the swimming speed. In contrast, the beat frequency was remarkably changed in the different spermatozoa and was proportional to the swimming speed. The maximum shear angle of the flagellar wave, which is directly related to the maximum sliding displacement between the doublet microtubules, remained nearly constant while the beat frequency varied widely; therefore, the spermatozoa beat in the constant sliding displacement mode. An analysis of the relationship between swimming speed and flagellar length revealed that short flagella were at a disadvantage in developing swimming speed; however, so were extra-long flagella. The ratio of the swimming speed to the wave velocity calculated from the wavelength and the beat frequency depended on the distance from the glass surface. The swimming speeds calculated using the original resistive-force theory were greater than the measured values. To rationalize the measured values, the ratio between the normal and tangential drag coefficient in the resistive-force theory was corrected; namely, 1.99 at 1 MUm and 1.63 at 3 MUm from the glass surface. PMID- 22815371 TI - Effects of body size and shape on locomotion in the bat star (Patiria miniata). AB - Among taxa ranging from cnidarians to vertebrates, absolute speed of locomotion generally increases with increasing body size. Despite the unique mode of locomotion in echinoderms, crawling speed also appears to increase with increasing body size, at least in some species of asteroids and echinoids. We used an escape-response assay to assess how maximum crawling speed varied with body size in the bat star Patiria miniata. We also tested the effect of arm number on maximum crawling speed by comparing speeds of five- and six-armed individuals. Contrary to prior reports for a single sea urchin and sea star species, both absolute crawling speed and crawling speed relative to body size actually declined with increasing body mass, increasing arm length, and increasing oral surface area, in both five- and six-armed individuals. Arm number did not appear to have a significant effect on crawling speed. The reasons for this negative relationship between crawling speed and body size in P. miniata remain unclear, but we suspect that the disproportionate increase in body mass relative to total tube-foot cross-sectional area may make locomotion proportionally more difficult in larger-bodied sea stars. PMID- 22815372 TI - Hard and soft anatomy in two genera of Dondersiidae (Mollusca, Aplacophora, Solenogastres). AB - Phylogenetic relationships and identifications in the aplacophoran taxon Solenogastres (Neomeniomorpha) are in flux largely because descriptions of hard parts--sclerites, radulae, copulatory spicules--and body shape have often not been adequately illustrated or utilized. With easily recognizable and accessible hard parts, descriptions of Solenogastres are of greater use, not just to solenogaster taxonomists, but also to ecologists, paleontologists, and evolutionary biologists. Phylogenetic studies of Aplacophora, Mollusca, and the Lophotrochozoa as a whole, whether morphological or molecular, would be enhanced. As an example, morphologic characters, both isolated hard parts and internal anatomy, are provided for two genera in the Dondersiidae. Five species are described or redescribed and earlier descriptions corrected and enhanced. Three belong to Dondersia: D. festiva Hubrecht, D. incali (Scheltema), and D. namibiensis n. sp., the latter differentiated unambiguously from D. incali only by sclerites and copulatory spicules. Two species belong to Lyratoherpia: L. carinata Salvini-Plawen and L. californica (Heath). Notes are given for other species in Dondersiidae: L. bracteata Salvini-Plawen, Ichthyomenia ichthyodes (Pruvot), and Heathia porosa (Heath). D. indica Stork is synonymized with D. annulata. A cladistic morphological analysis was conducted to examine the utility of hard parts for reconstructing solenogaster phylogeny. Results indicate monophyly of Dondersia and Lyratoherpia as described here. PMID- 22815374 TI - Central corneal thickness and intraocular pressure in children undergoing congenital cataract surgery: a prospective, longitudinal study. AB - AIM: To investigate changes in central corneal thickness (CCT) and intraocular pressure (IOP) in children after congenital cataract surgery, as well as risk factors associated with these changes. METHODS: 37 eyes of 26 children with congenital cataract undergoing surgery were prospectively recruited. IOP and CCT measurements were performed before the surgery and 6, 12, 18, 24 and 36 months after the procedure. RESULTS: Among the 37 eyes, 15 became aphakic and 22 pseudophakic. Mean CCT significantly increased from 556.24 +/- 44.19 to 585.07 +/ 56.45 MUm (p=0.003) after 3 years, whereas mean IOP significantly increased from 12.05 +/- 2.3 to 13.89 +/- 2.96 mm Hg (p=0.037). Aphakic eyes underwent surgery at an early age (15.16 +/- 32.02 months) compared with pseudophakic eyes (71.48 +/- 53.14 months) (p<0.001). After 3 years, mean CCT change in aphakic eyes (56.10 +/- 46.97 MUm) was significantly higher than in pseudophakic eyes (12.71 +/- 38.41 MUm) (p=0.015). Age at the time of surgery was inversely correlated to CCT change (r=-0.34, p=0.04), but not to IOP change (r=-0.18, p=0.27). When surgery was performed between 0 and 1 year of age, mean CCT change at 3 years was 70.11 +/- 42.3 MUm, compared with 6.27 +/- 28.09, -17.0 +/- 8.04 and 48.33 +/- 34.99 MUm when surgeries were performed at 1-5, 5-10 and >10 years old, respectively (p<0.001). IOP change was not correlated to CCT change (r=0.31, p=0.06). CONCLUSIONS: CCT increases in eyes undergoing congenital cataract surgery, especially when the surgery is performed at an early age. PMID- 22815375 TI - Impact of coronary atherosclerosis on the efficacy of radiofrequency catheter ablation for atrial fibrillation. AB - AIMS: Coronary atherosclerosis has been associated with the development of atrial fibrillation (AF). However, little is known about the impact of coronary atherosclerosis on the outcome treatment of AF. The aim of this study was to investigate the impact of coronary atherosclerosis on the efficacy of radiofrequency catheter ablation (RFCA) for AF using multi-detector row computed tomography (MDCT). METHODS: In 125 consecutive patients undergoing RFCA for AF, a pre-procedural MDCT examination (coronary angiography and/or coronary calcium score) was performed to evaluate the presence and severity of coronary atherosclerosis. Furthermore, all patients underwent a comprehensive echocardiographic evaluation to measure the left atrial size and to rule out structural heart disease. After RFCA all patients were regularly evaluated at the outpatient clinic. RESULTS: After a mean follow-up of 12 +/- 3 months, 78 patients (62%) had maintained stable sinus rhythm and 47 patients (38%) had recurrence of AF. Left atrial volume index was a significant predictor of AF recurrence after RFCA. The presence of coronary atherosclerosis on MDCT did not influence the efficacy of RFCA for AF. CONCLUSIONS: The presence of coronary atherosclerosis on MDCT is not associated with a higher risk for AF recurrence after RFCA. PMID- 22815376 TI - Left ventricular chamber dimensions and wall thickness by cardiovascular magnetic resonance: comparison with transthoracic echocardiography. AB - AIMS: Cardiovascular magnetic resonance (CMR) is a reference standard imaging technique in assessment of cardiomyopathies due to the accurate measurement of cardiac volumes and mass. In clinical routine, transthoracic echocardiography (TTE) is the standard first-line technique and is commonly used for follow-up. In this study we examined how CMR-derived measurement of left ventricular (LV) chamber dimensions and wall thickness correspond to TTE. METHODS AND RESULTS: A total of 101 subjects underwent TTE and CMR (men, n = 67, mean age 62 +/- 9 years) and formed a normal group (n = 44), a group with dilated LV cavity (n = 33; LV internal dimensions in end-diastole >= 52 mm) and a group with increased LV wall thickness (n = 24; interventricular septum >= 12 mm, inferolateral wall both in end-diastole >= 12 mm). Standard TTE measurements of LV chamber and wall thickness were compared to CMR-derived values in the basal short-axis slice and the 3-chamber (3-CH) view. Interstudy reproducibility for CMR was done in 23 subjects. In all groups, there was a better agreement between TTE and 3-CH for all dimensions. The intraobserver and interobserver agreements were superior for 3-CH view. In addition, both CMR approaches showed sound interstudy reproducibility for all dimensions and in all groups. CONCLUSION: We demonstrate a good agreement between CMR and TTE in LV chamber dimension and wall thickness measurements. We propose that with CMR using a 3-CH approach is superior in reproducibility and closer in concordance with TTE-derived values. PMID- 22815377 TI - Comment on "Translational applications of flow cytometry in clinical practice". PMID- 22815378 TI - Comment on "Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGF-beta". PMID- 22815379 TI - Costs and benefits of immunity to worm infection. PMID- 22815380 TI - Pillars article: downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J. Exp. Med. 1991. 173: 159-166. AB - In the mouse, infection with Schistosoma mansoni results in an egg-producing infection and associated disease, whereas vaccination with attenuated larval stages produces a substantial and specific immunity in the absence of egg-induced pathology. Preliminary data showing enhanced interleukin-5 (IL-5) production by T cells from infected mice and interferon gamma (IFN-gamma) synthesis by cells from vaccinated animals (7), suggested differential CD4(+) subset stimulation by the different parasite stimuli. To confirem this hyposthesis, lymphocytes from vaccinated or infected animals were compared for their ability to produce IFN gamma and IL-2 (secreted by Th1 cells) as compared with IL-4 and IL-5 (characteristic Th2 cytokines). After stimulation with specific antigen or mitogen, T cells from vaccinated mice or prepatently infected animals responded primarily with Th1 lymphokines, whereas lymphocytes from patenly infected mice instead produced Th2 cytokines. The Th2 response in infected animals was shown to be induced by schistosome eggs and directed largely against egg antigens, whereas the Th1 reactivity in vaccinated mice was triggered primarily by larval anigens. Interestingly, Th1 responses in mice carrying egg-producing infections were found to be profoundly downregulated. Moreover, the injection of eggs into vaccinated mice resulted in a reduction of antigen and mitogen-stimulated Th1 function accompanied by a coincident expression of Th2 responses. Together, the data suggest that coincident with the induction of Th2 responses, murine schistosome infection results in an inhibition of potentially protective Th1 function. This previously unrecognized downregulation of Th1 cytokine production may be an important immunological consequence of helminth infection related to host adaptation. PMID- 22815381 TI - Incidence of genital warts in Sweden before and after quadrivalent human papillomavirus vaccine availability. AB - BACKGROUND: More than 90% of genital warts (GW) cases are caused by human papillomavirus (HPV) types 6 and 11. The introduction of HPV vaccines necessitates the estimation of the population-based incidence of GW immediately before and after vaccination uptake. METHODS: Incidence proportions were calculated using the entire population aged 10-44 years living in Sweden during 2006-2010. The Prescribed Drug Register and the National Patient Register were used to define GW episodes. Time trends were estimated using Poisson regression. RESULTS: In 2010, age-stratified incidence proportions of GW were highest for 20 year-old women (956 cases/100 000), while the incidence proportion among males was greatest at the slightly older age of 24 years (1137 cases/100 000). Crude rates were marginally higher among males than among females during 2006-2007 and appeared to later diverge. Between 2008 and 2010, the overall incidence appeared to increase among males, and the incidence among females declined. Females aged 17 and 18 years had a >25% decline in GW rates between 2006 and 2010, with significant decreases through the age of 25 years. CONCLUSIONS: This study provides a reasonable estimation of the incidence of GW in the Swedish population by use of register data, with results comparable to those from previous smaller studies. There was a downward trend of GW incidence among younger females between 2006 and 2010. PMID- 22815382 TI - Prenatal air pollution exposure induces neuroinflammation and predisposes offspring to weight gain in adulthood in a sex-specific manner. AB - Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pregnant mice were exposed to filtered air (FA) or diesel exhaust (DE) on embryonic days (E) 9-17. Prenatal DE induced a significant fetal brain cytokine response at E18 (46-390% over FA). As adults, offspring were fed either a low-fat diet (LFD) or high-fat diet (HFD) for 6 wk. Adult DE male offspring weighed 12% more and were 35% less active than FA male offspring at baseline, whereas there were no differences in females. Following HFD, DE males gained weight at the same rate as FA males, whereas DE females gained 340% more weight than FA females. DE-HFD males had 450% higher endpoint insulin levels than FA-HFD males, and all males on HFD showed decreased activity and increased anxiety, whereas females showed no differences. Finally, both DE males and females fed HFD showed increased microglial activation (30-66%) within several brain regions. Thus, prenatal air pollution exposure can "program" offspring for increased susceptibility to diet-induced weight gain and neuroinflammation in adulthood in a sex-specific manner. PMID- 22815383 TI - Plasmin-driven fibrinolysis facilitates skin tumor growth in a gender-dependent manner. AB - Rearrangement of the skin during wound healing depends on plasmin and plasminogen, which serve to degrade fibrin depositions in the provisional matrix and thereby facilitate keratinocyte migration. In the current study, we investigated whether plasmin and plasminogen likewise played a role during the development of skin cancer. To test this, we set up a chemically induced skin tumor model in a cohort of mice and found that skin tumor growth in Plg(-/-) male mice was reduced by 52% compared with wild-type controls. Histological analyses suggested that the growth-restricting effect of plasminogen deficiency was due to thrombosis and lost patency of the tumor vasculature, resulting in tumor necrosis. The connection between plasmin-dependent fibrinolysis, vascular patency, and tumor growth was further substantiated as the effect of plasminogen deficiency on tumor growth could be reverted by superimposing heterozygous fibrinogen deficiency on Plg(-/-) mice. Tumors derived from these Fib(-/+);Plg(-/ ) mice displayed a significantly decreased level of tumor thrombosis compared with Plg(-/-) mice. In summary, these data indicate that plasmin-driven fibrinolysis facilitates tumor growth by maintaining patency of the tumor vasculature. PMID- 22815384 TI - Isoflurane binds and stabilizes a closed conformation of the leukocyte function associated antigen-1. AB - We previously demonstrated that isoflurane targets lymphocyte function-associated antigen-1 (LFA-1), a critical adhesion molecule for leukocyte arrest. However, it remains to be determined how isoflurane interacts with the full ectodomain LFA-1 and modulates its conformation and function. Isoflurane binding sites on the full ectodomain LFA-1 were probed by photolabeling using photoactivatable isoflurane (azi-isoflurane). The adducted residues were determined by liquid chromatography/mass spectrometry analysis. Separately, docking simulations were performed to predict binding sites. Point mutations were introduced around isoflurane binding sites. The significance of isoflurane's effect was assessed in both intracellular adhesion molecule-1 (ICAM-1) binding assays and epitope mapping of activation-sensitive antibodies using flow cytometry. Two isoflurane binding sites were identified using photolabeling and were further validated by the docking simulation: one at the hydrophobic pocket in the ICAM-1 binding domain (the alphaI domain); the other at the betaI domain. Mutagenesis of the alpha'1 helix showed that isoflurane binding sites at the betaI domain were significantly important in modulating LFA-1 function and conformation. Epitope mapping using activation-sensitive antibodies suggested that isoflurane stabilized LFA-1 in the closed conformation. This study suggested that isoflurane binds to both the alphaI and betaI domains allosteric to the ICAM-1 binding site, and that isoflurane binding stabilizes LFA-1 in the closed conformation. PMID- 22815386 TI - Developing T-cell migration: role of semaphorins and ephrins. AB - Cell migration is a crucial event for normal T-cell development, and various ligand/receptor pairs have been implicated. Most of them, including chemokines and extracellular matrix proteins, have attractant properties on thymocytes. We discuss herein two further groups of ligand/receptor pairs, semaphorins/neuropilins and ephs/ephrins, which are constitutively expressed by thymocytes and thymic microenvironmental cells. Evidence shows that the corresponding interactions are relevant for developing T-cell migration, including the entry of bone marrow progenitor cells, migration of CD4/CD8-defined thymocyte subpopulations triggered by chemokines and/or extracellular matrix proteins, and thymocyte export. Conceptually, the data summarized here show that thymocyte migration results from a complex network of molecular interactions, which generate not only attraction, but also repulsion of migrating T-cell precursors. PMID- 22815385 TI - CD36 level and trafficking are determinants of lipolysis in adipocytes. AB - CD36 has been linked to the etiology of insulin resistance and inflammation. We explored its function in regulating adipose tissue lipolysis, which influences fat accumulation by liver and muscle and overall metabolism. Knockdown of CD36 in differentiated 3T3-L1 adipocytes decreased lipolysis in response to 10 MUM of the beta-adrenergic agonist isoproterenol (by 42%), 10 MUM of the adenyl cyclase activator forskolin (by 32%), and 500 MUM of the phosphodiesterase (PDE) inhibitor isobutylmethylxanthine (by 33%). All three treatments in the knockdown adipocytes were associated with significant decreases of cAMP levels and of the hormone-sensitive lipase (HSL) and perilipin phosphorylation. An important role for PDE was supported by the lack of inhibition of the lipolysis induced by the poorly hydrolyzable dibutyryl cAMP analog. An additional contributory mechanism was diminished activation of the Src-ERK1/2 pathway. Regulation of lipolysis and lipolytic signaling by CD36 was reproduced with adipose tissue from CD36(-/-) mice. The importance of surface CD36 in this regulation was suggested by the finding that the plasma membrane-impermeable CD36 inhibitor sulfo-N-succinimidyl oleate (20 MUM) decreased lipolysis. Interestingly, isoproterenol induced CD36 internalization, and this process was blocked by HSL inhibition, suggesting feedback regulation of adipocyte lipolysis via CD36 trafficking. PMID- 22815388 TI - Inspiratory-resistive loading increases the ventilatory response to arousal but does not reduce genioglossus muscle activity on the return to sleep. AB - Arousals from sleep are thought to predispose to obstructive sleep apnea by causing hyperventilation and hypocapnia, which reduce airway dilator muscle activity on the return to sleep. However, prior studies of auditory arousals have not resulted in reduced genioglossus muscle activity [GG-electromyogram (EMG)], potentially because airway resistance prior to arousal was low, leading to a small ventilatory response to arousal and minimal hypocapnia. Thus we aimed to increase the ventilatory response to arousal by resistive loading prior to auditory arousal and determine whether reduced GG-EMG occurred on the return to sleep. Eighteen healthy young men and women were recruited. Subjects were instrumented with a nasal mask with a pneumotachograph, an epiglottic pressure catheter, and intramuscular GG-EMG electrodes. Mask CO(2) levels were monitored. Three- to 15-s arousals from sleep were induced with auditory tones after resting breathing (No-Load) or inspiratory-resistive loading (Load; average 8.4 cmH(2)O.l(-1).s(-1)). Peak minute ventilation following arousal was greater after Load than No-Load (mean +/- SE; 8.0 +/- 0.6 vs. 7.4 +/- 0.6 l/min, respectively). However, the nadir end tidal partial pressure of CO(2) did not differ between Load conditions (43.1 +/- 0.6 and 42.8 +/- 0.5 mmHg, respectively), and no period of reduced GG activity occurred following the return to sleep (GG-EMG baseline, minimum after Load and No-Load = 2.9 +/- 1.2%, 3.1 +/- 1.3%, and 3.0 +/- 1.3% max, respectively). These findings indicate that the hyperventilation, which occurs following tone-induced arousal, is appropriate for the prevailing level of respiratory drive, because loading did not induce marked hypocapnia or lower GG muscle activity on the return to sleep. Whether similar findings occur following obstructive events in patients remains to be determined. PMID- 22815387 TI - Total sleep deprivation alters cardiovascular reactivity to acute stressors in humans. AB - Exaggerated cardiovascular reactivity to mental stress (MS) and cold pressor test (CPT) has been linked to increased risk of cardiovascular disease. Recent epidemiological studies identify sleep deprivation as an important risk factor for hypertension, yet the relations between sleep deprivation and cardiovascular reactivity remain equivocal. We hypothesized that 24-h total sleep deprivation (TSD) would augment cardiovascular reactivity to MS and CPT and blunt the MS induced forearm vasodilation. Because the associations between TSD and hypertension appear to be stronger in women, a secondary aim was to probe for sex differences. Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded during MS and CPT in 28 young, healthy subjects (14 men and 14 women) after normal sleep (NS) and 24-h TSD (randomized, crossover design). Forearm vascular conductance (FVC) was recorded during MS. MAP, FVC, and MSNA (n = 10) responses to MS were not different between NS and TSD (condition * time, P > 0.05). Likewise, MAP and MSNA (n = 6) responses to CPT were not different between NS and TSD (condition * time, P > 0.05). In contrast, increases in HR during both MS and CPT were augmented after TSD (condition * time, P <= 0.05), and these augmented HR responses persisted during both recoveries. When analyzed for sex differences, cardiovascular reactivity to MS and CPT was not different between sexes (condition * time * sex, P > 0.05). We conclude that TSD does not significantly alter MAP, MSNA, or forearm vascular responses to MS and CPT. The augmented tachycardia responses during and after both acute stressors provide new insight regarding the emerging links among sleep deprivation, stress, and cardiovascular risk. PMID- 22815389 TI - Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD. AB - Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 +/- 16%pred, body mass index [BMI] 26 +/- 4 kg/m(2)) and 15 controls (BMI 25 +/- 3 kg/m(2)) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers. Quadriceps function was assessed by isokinetic dynamometry, body composition by dual-energy X-ray absorptiometry, exercise capacity by an incremental load test, and physical activity level by accelerometry. Compared with controls, patients had comparable fat-free mass index, quadriceps strength, and fiber CSA, but quadriceps endurance was decreased by 29% (P = 0.002). Patients with COPD had a clear loss of muscle oxphen: a fiber type I-to-II shift, decreased levels of OXPHOS complexes IV and V subunits (47% and 31%, respectively; P < 0.05), a decreased ratio of 3-hydroxyacyl-CoA dehydrogenase/phosphofructokinase (PFK) enzyme activities (38%, P < 0.05), and decreased peroxisome proliferator-activated receptor-gamma coactivator-1alpha (40%; P < 0.001) vs. increased PFK (67%; P < 0.001) gene expression levels. Within the patient group, markers of oxphen were significantly positively correlated with quadriceps endurance and inversely with the increase in plasma lactate relative to work rate during the incremental test. Levels of protein carbonylation, tyrosine nitration, and malondialdehyde protein adducts were comparable between patients and controls. However, among patients, oxidative stress levels were significantly inversely correlated with markers of oxphen and quadriceps endurance. Reduced muscle endurance associated with underlying loss of muscle oxphen is already present in patients with mild-to-moderate COPD without muscle wasting. PMID- 22815390 TI - The single biopsy approach is reliable for the measurement of muscle protein synthesis rates in vivo in older men. AB - We aimed to assess the reliability of the single biopsy approach for calculating muscle protein synthesis rates compared with the well described sequential muscle biopsy approach following a primed continuous infusion of L-[ring (2)H(5)]phenylalanine and GC-MS analysis in older men. Two separate experimental infusion protocols, with differing stable isotope amino acid incorporation times, were employed consisting of n = 27 (experiment 1) or n = 9 (experiment 2). Specifically, mixed muscle protein FSR were calculated from baseline plasma protein enrichments and muscle protein enrichments obtained at 90 min or 50 min (1BX SHORT), 210 min or 170 min (1BX LONG), and between the muscle protein enrichments obtained at 90 and 210 min or 50 min and 170 min (2BX) of the infusion for experiments 1 and 2, respectively. In experiment 2, we also assessed the error that is introduced to the single muscle biopsy approach when nontracer naive subjects are recruited for participation in a primed continuous infusion of isotope-labeled amino acids. In experiment 1, applying the individual plasma protein enrichment values to the single muscle biopsy approach resulted in no differences in muscle protein FSR between the 1BX SHORT (0.031 +/- 0.003%.h(-1)), 1BX LONG (0.032 +/- 0.002%.h(-1)), or the 2BX approach (0.034 +/- 0.002%.h(-1)). A significant correlation in muscle protein FSR was observed only between the 1BX LONG and 2BX approach (r = 0.8; P < 0.001). Similar results were observed in experiment 2. In addition, using the single biopsy approach in nontracer naive state results in a muscle protein FSR that is negative for both the 1BX SHORT ( 0.67 +/- 0.051%.h(-1)) and 1BX LONG (-0.19 +/- 0.051%.h(-1)) approaches. This is the first study to demonstrate that the single biopsy approach, coupled with the background enrichment of L-[ring-(2)H(5)]-phenylalanine of mixed plasma proteins, generates data that are similar to using the sequential muscle biopsy approach in the elderly population. PMID- 22815398 TI - Effects of contrast and contrast adaptation on static receptive field features in macaque area V1. AB - The spatiotemporal features of the "static" receptive field (RF), as revealed with flashing bars or spots, determine other RF properties. We examined how some of these static RF features vary with contrast and contrast adaptation in area V1 of the anesthetized macaque monkey. RFs were mapped with light and dark flashing bars presented at three different contrasts, with the low and medium contrasts eliciting approximately 1/3 and 2/3 of the high-contrast response amplitude. The main results are as follows: 1) RF widths decreased when contrast decreased; however, the amount of decrease was less than that expected from an iceberg model and closer to the expectation of a contrast invariance of the RF width. 2) Area tuning experiments with drifting gratings showed an opposite effect of contrast: an increase in preferred stimulus diameter when contrast decreased. This implies that the effect of contrast on preferred stimulus size is not predictable from the static RF. 3) Contrast adaptation attenuated the effect of contrast on RF amplitude but did not significantly modify RF width. 4) RF subregion overlap was only marginally affected by changes in contrast and contrast adaptation; the classification of cells as simple and complex, when established from subregion overlap, appears to be robust with respect to changes in contrast and adaptation state. Previous studies have shown that the spatiotemporal features of the RF depend largely on the stimuli used to map the RF. This study shows that contrast is one elemental feature that contributes to the dynamics of the RF. PMID- 22815399 TI - Responsiveness to nicotine of neurons of the caudal nucleus of the solitary tract correlates with the neuronal projection target. AB - The caudal nucleus of the solitary tract (NTS) is the key integrating center of visceral sensory-motor signaling supporting autonomic homeostasis. Two key projections of this nucleus are the parabrachial nucleus (PbN) and the dorsal motor nucleus of the vagus (DMV). The PbN integrates and relays viscerosensory information primarily to the forebrain, supporting behavioral, emotional, and endocrine responses to visceral events, while the DMV contains parasympathetic preganglionic cholinergic motoneurons that support primarily gastrointestinal reflexes. Subsets of caudal NTS neurons express presynaptic and somatodendritic nicotinic acetylcholine receptors (nAChRs). However, the anatomical identification of nicotine-responsive caudal NTS neurons has not been determined. This study used in vivo and ex vivo fluorescent tracing and slice patch-clamp electrophysiological recordings from anatomically identified caudal NTS neurons to test the hypothesis that the responsiveness of these cells to nicotine correlates with the target of their axonal projections. The results demonstrate that the majority of glutamatergic terminals that synapse on PbN-projecting caudal NTS neurons are unaffected by nicotine. Moreover, only a fraction of these cells express somatodendritic nAChRs. In contrast, the majority of DMV-projecting caudal NTS neurons exhibit robust presynaptic and somatodendritic responsiveness to nicotine. However, PbN-projecting neurons also exhibit significantly lower background frequencies of glutamatergic miniature postsynaptic currents than DMV projecting neurons. Therefore, presynaptic unresponsiveness to nicotine may result from deficient glutamatergic innervation of PbN-projecting neurons. Nevertheless, the caudal NTS contains function-specific subsets of cells with target-specific responsiveness to nicotine. These results may support development of therapeutic strategies for selective targeting of specific autonomic pathways and impaired autonomic homeostasis. PMID- 22815400 TI - Intrinsic heterogeneity in oscillatory dynamics limits correlation-induced neural synchronization. AB - Synchronous neural oscillations are found throughout the brain and are thought to contribute to neural coding and the propagation of activity. Several proposed mechanisms of synchronization have gained support through combined theoretical and experimental investigation, including mechanisms based on coupling and correlated input. Here, we ask how correlation-induced synchrony is affected by physiological heterogeneity across neurons. To address this question, we examined cell-to-cell differences in phase-response curves (PRCs), which characterize the response of periodically firing neurons to weak perturbations. Using acute slice electrophysiology, we measured PRCs across a single class of principal neurons capable of sensory-evoked oscillations in vivo: the olfactory bulb mitral cells (MCs). Periodically firing MCs displayed a broad range of PRCs, each of which was well fit by a simple three-parameter model. MCs also displayed differences in firing rate-current relationships and in preferred firing rate ranges. Both the observed PRC heterogeneity and moderate firing rate differences (~10 Hz) separately reduced the maximum correlation-induced synchrony between MCs by up to 25-30%. Simulations further demonstrated that these components of heterogeneity alone were sufficient to account for the difference in synchronization among heterogeneous vs. homogeneous populations in vitro. Within this simulation framework, independent modulation of specific PRC features additionally revealed which aspects of PRC heterogeneity most strongly impact correlation-induced synchronization. Finally, we demonstrated good agreement of novel mathematical theory with our experimental and simulation results, providing a theoretical basis for the influence of heterogeneity on correlation-induced neural synchronization. PMID- 22815401 TI - Age-dependent adrenergic actions in the main olfactory bulb that could underlie an olfactory-sensitive period. AB - Many sensory systems are endowed with mechanisms of neural plasticity that are restricted to a sensitive period in the young developing animal. In this study, we performed experiments in slices of the main olfactory bulb (OB) from rats to examine possible age-dependent cellular mechanisms of plasticity in the olfactory system. We focused on the neurotransmitter norepinephrine (NE), shown to be important in different forms of olfactory learning, examining whether two specific cellular effects of NE previously observed in rats less than P14 extended to older animals. These included an acute reduction in GABAergic synaptic transmission from granule cells (GCs) onto output mitral cells (MCs) and an enhancement in gamma frequency (30-70 Hz) oscillations that persists long after removal of NE. We found that NE failed to reduce GC-to-MC transmission or enhance gamma oscillations in older rats at P18-23. The loss of NE actions on both phenomena appeared to reflect an age-dependent loss of function of alpha(2) adrenergic receptors. In addition, we found that NE induced an age-dependent enhancement of transient excitation in MCs, providing a mechanism to link the acute decrease in GC-to-MC inhibition to the long-term increase in gamma oscillations through increases in intracellular calcium. The age-dependent cellular mechanisms that we describe could underlie an olfactory-sensitive period in newborn rodents. PMID- 22815402 TI - Comparison of latency and rate coding for the direction of whisker deflection in the subcortical somatosensory pathway. AB - The response of many neurons in the whisker somatosensory system depends on the direction in which a whisker is deflected. Although it is known that the spike count conveys information about this parameter, it is not known how important spike timing might be. The aim of this study was to compare neural codes based on spike count and first-spike latency, respectively. We extracellularly recorded single units from either the rat trigeminal ganglion (primary sensory afferents) or ventroposteromedial (VPM) thalamic nucleus in response to deflection in different directions and quantified alternative neural codes using mutual information. We found that neurons were diverse: some (58% in ganglion, 32% in VPM) conveyed information only by spike count; others conveyed additional information by latency. An issue with latency coding is that latency is measured with respect to the time of stimulus onset, a quantity known to the experimenter but not directly to the subject's brain. We found a potential solution using the integrated population activity as an internal timing signal: in this way, 91% of the first-spike latency information could be recovered. Finally, we asked how well direction could be decoded. For large populations, spike count and latency codes performed similarly; for small ones, decoding was more accurate using the latency code. Our findings indicate that whisker deflection direction is more efficiently encoded by spike timing than by spike count. Spike timing decreases the population size necessary for reliable information transmission and may thereby bring significant advantages in both wiring and metabolic efficiency. PMID- 22815403 TI - Speed invariance of independent control of finger movements in pianists. AB - Independent control of finger movements characterizes skilled motor behaviors such as tool use and musical performance. The purpose of the present study was to identify the effect of movement frequency (tempo) on individuated finger movements in piano playing. Joint motion at the digits was recorded while 5 expert pianists were playing 30 excerpts from musical pieces with different fingering and key locations either at a predetermined normal tempo or as fast as possible. Principal component analysis and cluster analysis using an expectation maximization algorithm determined three distinct patterns of finger movement coordination for a keypress with each of the index, middle, ring, and little fingers at each of the two tempi. The finger kinematics of each coordination pattern was overall similar across the tempi. Tone sequences assigned into each cluster were also similar for both tempi. A linear regression analysis determined no apparent difference in the amount of movement covariation between the striking and nonstriking fingers at both metacarpo-phalangeal and proximal-interphalangeal joints across the two tempi, which indicated no effect of tempo on independent finger movements in piano playing. In addition, the standard deviation of interkeystroke interval across strokes did not differ between the two tempi, indicating maintenance of rhythmic accuracy of keystrokes. Strong temporal constraints on finger movements during piano playing may underlie the maintained independent control of fingers over a wider range of tempi, a feature being likely to be specific to skilled pianists. PMID- 22815405 TI - Reward processing: a global brain phenomenon? AB - Rewards and punishments (reinforcement) powerfully shape behavior. Accordingly, their neuronal representation is of significant interest, both for understanding normal brain-behavior relationships and the pathophysiology of disorders such as depression and addiction. A recent article by Vickery and colleagues (Neuron 72: 166-177, 2011) provides evidence that the neural response to rewards and punishments is surprisingly widespread, suggesting the need for examination of the specific roles of areas not commonly included in the canonical reward circuitry in processing reinforcement. PMID- 22815404 TI - Transduction in Drosophila olfactory receptor neurons is invariant to air speed. AB - In the vertebrate nose, increasing air speed tends to increase the magnitude of odor-evoked activity in olfactory receptor neurons (ORNs), given constant odor concentration and duration. It is often assumed that the same is true of insect olfactory organs, but this has not been directly tested. In this study, we examined the effect of air speed on ORN responses in Drosophila melanogaster. We constructed an odor delivery device that allowed us to independently vary concentration and air speed, and we used a fast photoionization detector to precisely measure the actual odor concentration at the antenna while simultaneously recording spikes from ORNs in vivo. Our results demonstrate that Drosophila ORN odor responses are invariant to air speed, as long as odor concentration is kept constant. This finding was true across a >100-fold range of air speeds. Because odor hydrophobicity has been proposed to affect the air speed dependence of olfactory transduction, we tested a >1,000-fold range of hydrophobicity values and found that ORN responses are invariant to air speed across this full range. These results have implications for the mechanisms of odor delivery to Drosophila ORNs. Our findings are also significant because flies have a limited ability to control air flow across their antennae, unlike terrestrial vertebrates, which can control air flow within their nasal cavity. Thus, for the fly, invariance to air speed may be adaptive because it confers robustness to changing wind conditions. PMID- 22815406 TI - Imaging neural circuit dynamics with a voltage-sensitive fluorescent protein. AB - Population signals from neuronal ensembles in cortex during behavior are commonly measured with EEG, local field potential (LFP), and voltage-sensitive dyes. A genetically encoded voltage indicator would be useful for detection of such signals in specific cell types. Here we describe how this goal can be achieved with Butterfly, a voltage-sensitive fluorescent protein (VSFP) with a subthreshold detection range and enhancements designed for voltage imaging from single neurons to brain in vivo. VSFP-Butterfly showed reliable membrane targeting, maximum response gain around standard neuronal resting membrane potential, fast kinetics for single-cell synaptic responses, and a high signal-to noise ratio. Butterfly reports excitatory postsynaptic potentials (EPSPs) in cortical neurons, whisker-evoked responses in barrel cortex, 25-Hz gamma oscillations in hippocampal slices, and 2- to 12-Hz slow waves during brain state modulation in vivo. Our findings demonstrate that cell class-specific voltage imaging is practical with VSFP-Butterfly, and expand the genetic toolbox for the detection of neuronal population dynamics. PMID- 22815407 TI - Division of labor in frontal eye field neurons during presaccadic remapping of visual receptive fields. AB - Our percept of visual stability across saccadic eye movements may be mediated by presaccadic remapping. Just before a saccade, neurons that remap become visually responsive at a future field (FF), which anticipates the saccade vector. Hence, the neurons use corollary discharge of saccades. Many of the neurons also decrease their response at the receptive field (RF). Presaccadic remapping occurs in several brain areas including the frontal eye field (FEF), which receives corollary discharge of saccades in its layer IV from a collicular-thalamic pathway. We studied, at two levels, the microcircuitry of remapping in the FEF. At the laminar level, we compared remapping between layers IV and V. At the cellular level, we compared remapping between different neuron types of layer IV. In the FEF in four monkeys (Macaca mulatta), we identified 27 layer IV neurons with orthodromic stimulation and 57 layer V neurons with antidromic stimulation from the superior colliculus. With the use of established criteria, we classified the layer IV neurons as putative excitatory (n = 11), putative inhibitory (n = 12), or ambiguous (n = 4). We found that just before a saccade, putative excitatory neurons increased their visual response at the RF, putative inhibitory neurons showed no change, and ambiguous neurons increased their visual response at the FF. None of the neurons showed presaccadic visual changes at both RF and FF. In contrast, neurons in layer V showed full remapping (at both the RF and FF). Our data suggest that elemental signals for remapping are distributed across neuron types in early cortical processing and combined in later stages of cortical microcircuitry. PMID- 22815408 TI - Motoneuron firing patterns underlying fast oscillations in phrenic nerve discharge in the rat. AB - Fast oscillations are ubiquitous throughout the mammalian central nervous system and are especially prominent in respiratory motor outputs, including the phrenic nerves (PhNs). Some investigators have argued for an epiphenomenological basis for PhN high-frequency oscillations because phrenic motoneurons (PhMNs) firing at these same frequencies have never been recorded, although their existence has never been tested systematically. Experiments were performed on 18 paralyzed, unanesthetized, decerebrate adult rats in which whole PhN and individual PhMN activity were recorded. A novel method for evaluating unit-nerve time-frequency coherence was applied to PhMN and PhN recordings. PhMNs were classified according to their maximal firing rate as high, medium, and low frequency, corresponding to the analogous bands in PhN spectra. For the first time, we report the existence of PhMNs firing at rates corresponding to high-frequency oscillations during eupneic motor output. The majority of PhMNs fired only during inspiration, but a small subpopulation possessed tonic activity throughout all phases of respiration. Significant time-varying PhMN-PhN coherence was observed for all PhMN classes. High-frequency, early-recruited units had significantly more consistent onset times than low-frequency, early/middle-recruited and medium frequency, middle/late-recruited PhMNs. High- and medium-frequency PhMNs had significantly more consistent offset times than low-frequency units. This suggests that startup and termination of PhMNs with higher firing rates are more precisely controlled, which may contribute to the greater PhMN-PhN coherence at the beginning and end of inspiration. Our findings provide evidence that near synchronous discharge of PhMNs firing at high rates may underlie fast oscillations in PhN discharge. PMID- 22815409 TI - Of bats and men. PMID- 22815410 TI - Antioxidant and renoprotective effects of paricalcitol on experimental contrast induced nephropathy model. AB - OBJECTIVES: The aim of the study was to assess the effect of paricalcitol on the experimental contrast-induced nephropathy (CIN) model. We hypothesised that paricalcitol may prevent CIN. METHODS: 32 Wistar albino rats were divided into four groups (n=8 each): control group, paricalcitol group, CIN group and paricalcitol plus CIN group. Paricalcitol (0.4 ug kg(-1) day(-1)) was given intraperitoneally for 5 consecutive days prior to induction of CIN. CIN was induced at day 4 by intravenous injection of indometacin (10 mg kg(-1)), Nomega nitro-L-arginine methyl ester (L-NAME, 10 mg kg(-1)) and meglumine amidotrizoate (6 ml kg(-1)). Renal function parameters, oxidative stress biomarkers, histopathological findings and vascular endothelial growth factor (VEGF) immunoexpression were evaluated. RESULTS: The paricalcitol plus CIN group had lower mean serum creatinine levels (p=0.034) as well as higher creatinine clearance (p=0.042) than the CIN group. Serum malondialdehyde and kidney thiobarbituric acid-reacting substances levels were significantly lower in the paricalcitol plus CIN group than in the CIN group (p=0.024 and p=0.042, respectively). The mean scores of tubular necrosis (p=0.024), proteinaceous casts (p=0.038), medullary congestion (p=0.035) and VEGF immunoexpression (p=0.018) in the paricalcitol plus CIN group were also significantly lower. CONCLUSION: This study demonstrates the protective effect of paricalcitol in the prevention of CIN in an experimental model. PMID- 22815412 TI - MRI as a reference standard for suspected scaphoid fractures. AB - OBJECTIVES: Some have suggested that MRI might be the best reference standard for a true fracture among patients with suspected scaphoid fractures. The primary aim of this study was to determine the rate of false-positive diagnosis of an acute scaphoid fracture in a cohort of healthy volunteers. METHODS: In a prospective study, 33 healthy volunteers were recruited and both wrists of each were scanned, except for 2 volunteers for whom only one wrist was scanned. To simulate the usual clinical context the 64 scans of healthy volunteers were mixed with 60 MRI scans of clinically suspected scaphoid fractures but normal scaphoid radiographs. These 124 MRI scans were blinded and randomly ordered. Five radiologists evaluated the MRI scans independently for the presence or absence of a scaphoid fracture and other injuries according to a standard protocol. RESULTS: To answer the primary question, only the diagnoses from the 64 scans of healthy volunteers were used. The radiologists diagnosed a total of 13 scaphoid fractures; therefore, specificity for diagnosis of scaphoid fracture was 96% (95% confidence interval: range 94-98%). The 5 observers had a moderate interobserver agreement regarding diagnosis of scaphoid fracture in healthy volunteers (multirater kappa=0.44; p<0.001). CONCLUSIONS: The specificity of MRI for scaphoid fractures is high (96%), but false-positives do occur. Radiologists have only moderate agreement when interpreting MRI scans from healthy volunteers. MRI is not an adequate reference standard for true fractures among patients with suspected scaphoid fractures. PMID- 22815413 TI - Olympic special feature editorial. PMID- 22815411 TI - Interobserver variation in parotid gland delineation: a study of its impact on intensity-modulated radiotherapy solutions with a systematic review of the literature. AB - OBJECTIVES: This study evaluates the interobserver variation in parotid gland delineation and its impact on intensity-modulated radiotherapy (IMRT) solutions. METHODS: The CT volumetric data sets of 10 patients with oropharyngeal squamous cell carcinoma who had been treated with parotid-sparing IMRT were used. Four radiation oncologists and three radiologists delineated the parotid gland that had been spared using IMRT. The dose-volume histogram (DVH) for each study contour was calculated using the IMRT plan actually delivered for that patient. This was compared with the original DVH obtained when the plan was used clinically. RESULTS: 70 study contours were analysed. The mean parotid dose achieved during the actual treatment was within 10% of 24 Gy for all cases. Using the study contours, the mean parotid dose obtained was within 10% of 24 Gy for only 53% of volumes by radiation oncologists and 55% of volumes by radiologists. The parotid DVHs of 46% of the study contours were sufficiently different from those used clinically, such that a different IMRT plan would have been produced. CONCLUSION: Interobserver variation in parotid gland delineation is significant. Further studies are required to determine ways of improving the interobserver consistency in parotid gland definition. PMID- 22815414 TI - Lower extremity and pelvic stress fractures in athletes. AB - Stress fractures occur following excessive use and are commonly seen in athletes, in whom the lower limbs are frequently involved. Delayed diagnosis and management of these injuries can result in significant long-term damage and athlete morbidity. A high index of suspicion may facilitate diagnosis, but clinical presentation may be non-specific. In this regard, imaging in the form of plain radiograph, CT, MRI and bone scintigraphy may be of value. This article reviews the incidence, presentation, radiological findings and management options for athletes with stress fractures of the lower limb. PMID- 22815415 TI - A physiotherapy perspective of musculoskeletal imaging in sport. AB - This paper presents a physiotherapy perspective on the role that imaging is now playing in the diagnosis and management of musculoskeletal and sporting injuries. Although the Royal College of Radiologists and the UK Chartered Society of Physiotherapy were founded in the latter part of the nineteenth century, it is 100 years later that developments in the UK NHS have led to increased roles for non-medical healthcare professionals and allied health professionals, such as physiotherapists, in an extended clinical role. Physiotherapists, perhaps because of their knowledge of clinical and applied anatomy, have keenly taken up the opportunities offered to request and interpret imaging in its various forms; the most commonly available are plain radiography, musculoskeletal ultrasound and MRI. This has meant taking formal courses under the auspices of universities with mentorship and tutoring within the clinical setting, which are part of a continuing professional development. The ability to request several forms of imaging has enhanced physiotherapy practice and has increased the appreciation of the responsibilities which accompany this new role. PMID- 22815416 TI - Imaging in sport and exercise medicine: "a sports physician's outlook and needs". AB - Sport and exercise medicine (SEM) is an exciting new medical specialty that thrives on interdisciplinary practice. The SEM physician will usually be found managing a wider, multidisciplinary team of specialists, orchestrating their various inputs to ensure that the most effective management plan is delivered to the patient. One key member of this team is the radiologist, with whom the SEM physician usually has a very close working relationship. Areas of SEM practice that commonly involve significant input from radiologists include the use of appropriate imaging to confirm an accurate diagnosis and to inform management planning (such as decisions on return to play in the elite athlete), various screening and pre-participation assessments and also technical assistance with certain procedures. This article discusses the relationship between the SEM physician and the radiologist across each of these areas, illustrating the important contribution made by imaging services to the specialty of SEM. PMID- 22815417 TI - Unsuspected cystic left upper quadrant mass. PMID- 22815418 TI - The diagnostic value of FDG-PET cannot be judged by iliac bone marrow biopsy. PMID- 22815420 TI - Oesophageal squamous cell carcinoma: relationship between fluorine-18 fludeoxyglucose positron emission tomography CT maximum standardised uptake value, metabolic tumour volume, and tumour, node and metastasis classification. AB - OBJECTIVES: We aimed to evaluate the relationships between primary tumour, maximum standardised uptake value, metabolic tumour volume and seventh edition American Joint Committee on Cancer (AJCC) classification in oesophageal squamous cell carcinoma (OSCC) patients. METHODS: Fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)-CT scans of 41 consecutive newly diagnosed OSCC patients were retrospectively reviewed. Maximum standard uptake value (SUV(max)) and metabolic tumour volume (MTV) were recorded. Two-tailed Spearman's correlation was used to analyse the relationships between the metabolic parameters and the AJCC staging system. RESULTS: Positive correlations were observed between SUV(max), MTV and tumour (T) stage, in addition to node (N) stage and AJCC stage. Both metabolic parameters were independent variables that significantly affected the N stage and AJCC stage, and SUV(max) was the only independent variable that significantly affected the T stage. CONCLUSION: The metabolic parameters derived from (18)F-FDG PET-CT were positively correlated with T, N and AJCC stage in primary OSCC. Our findings may suggest a complementary role of these parameters to seventh-edition AJCC staging in the prognostication of OSCC patients. PMID- 22815421 TI - Predicting portal hypertension as assessed by acoustic radiation force impulse: correlations with the Doppler ultrasound. AB - OBJECTIVE: The purpose of this study was to assess the value of acoustic radiation force impulse (ARFI) for evaluating portal hypertension by correlating the elasticity of liver cirrhosis, as measured by ARFI, with haemodynamic indices measured by Doppler ultrasound. METHODS: We evaluated the data of a total of 154 prospectively enrolled patients who underwent both duplex Doppler ultrasound and ARFI imaging. The duplex Doppler ultrasound indices, including the mean portal vein velocity, splenic index (SI) and splenoportal index (SPI) were evaluated to determine the statistical correlation with shear wave velocity (SWV) of ARFI. We also analysed the differences in the correlations between the SI, SPI and SWV of the group who had varices. The correlations were assessed with Spearman's rank correlation coefficients. RESULTS: There was an increase of SWV in parallel with the increase of the SI (rho=0.409, p<0.01) and SPI (rho=0.451, p<0.01). In the patient group who did not have varices (n=74), the Doppler indices were found to be more correlated with the SWV (SI: rho=0.447, SPI: rho=0.552, p<0.01). However, the group with varices showed no correlation between the SWV and the Doppler parameters. CONCLUSION: SWV of ARFI was well correlated statistically with Doppler parameters, but is of limited value in predicting portal hypertension directly owing to great variability of Doppler parameters. By evaluating the correlation between ARFI and Doppler ultrasound, we suggest that the SWV might be a non-invasive supplementary tool for predicting portal hypertension. PMID- 22815422 TI - Safety and efficacy of oral ivabradine as a heart rate-reducing agent in patients undergoing CT coronary angiography. AB - OBJECTIVE: To investigate the role of oral ivabradine as a heart rate reducing agent in patients undergoing CT coronary angiography (CTCA). Despite the routine use of beta-blockers prior to CTCA studies, it is not uncommon to have patients with heart rates persistently above the target range of 65 bpm. Ivabradine is a selective inhibitor of the I(f) current, which primarily contributes to sinus node pacemaker activity, and has no significant direct cardiovascular effects such as reduction of blood pressure, cardiac contractility or impairment of cardiac conduction. METHODS: We investigated 100 consecutive patients who had been referred for CTCA for the evaluation of suspected coronary artery disease (CAD). Patients were randomised to receive either of the following two pre medication protocols: oral metorprolol or oral ivabradine. RESULTS: Ivabradine was significantly more effective than metorprolol in lowering the heart rate; the mean percentage reduction in heart rate with ivabradine vs metorpolol was 23.89+6.95% vs 15.20+4.50%, respectively (p=0.0001). Metoprolol significantly lowered both systolic and diastolic blood pressure while ivabradine did not. The requirement of additional doses to achieve a target heart rate of <65 beats per min was also significantly more frequent with metoprolol. CONCLUSION: Ivabradine is a potentially attractive alternative to currently used drugs for reduction of heart rate in patients undergoing CTCA. PMID- 22815423 TI - Interobserver variation in clinical target volume and organs at risk segmentation in post-parotidectomy radiotherapy: can segmentation protocols help? AB - OBJECTIVE: A study of interobserver variation in the segmentation of the post operative clinical target volume (CTV) and organs at risk (OARs) for parotid tumours was undertaken. The segmentation exercise was performed as a baseline, and repeated after 3 months using a segmentation protocol to assess whether CTV conformity improved. METHODS: Four head and neck oncologists independently segmented CTVs and OARs (contralateral parotid, spinal cord and brain stem) on CT data sets of five patients post parotidectomy. For each CTV or OAR delineation, total volume was calculated. The conformity level (CL) between different clinicians' outlines was measured using a validated outline analysis tool. The data for CTVs were re-analysed after using the cochlear sparing therapy and conventional radiation segmentation protocol. RESULTS: Significant differences in CTV morphology were observed at baseline, yielding a mean CL of 30% (range 25 39%). The CL improved after using the segmentation protocol with a mean CL of 54% (range 50-65%). For OARs, the mean CL was 60% (range 53-68%) for the contralateral parotid gland, 23% (range 13-27%) for the brain stem and 25% (range 22-31%) for the spinal cord. CONCLUSIONS: There was low conformity for CTVs and OARs between different clinicians. The CL for CTVs improved with use of a segmentation protocol, but the CLs remained lower than expected. This study supports the need for clear guidelines for segmentation of target and OARs to compare and interpret the results of head and neck cancer radiation studies. PMID- 22815424 TI - Factors associated with patellofemoral pain syndrome: a systematic review. AB - This review systematically summarises factors associated with patellofemoral pain syndrome (PFPS). A systematic literature search was conducted. Studies including >=20 patients with PFPS that examined >=1 possible factor associated with PFPS were included. A meta-analysis was performed, clinical heterogeneous data were analysed descriptively. The 47 included studies examined 523 variables, eight were pooled. Pooled data showed a larger Q-angle, sulcus angle and patellar tilt angle (weighted mean differences (WMD) 2.08; 95% CI 0.64, 3.63 and 1.66; 95% CI 0.44, 2.77 and 4.34; 95% CI 1.16 to 7.52, respectively), less hip abduction strength, lower knee extension peak torque and less hip external rotation strength (WMD -3.30; 95% CI -5.60, -1.00 and -37.47; 95% CI -71.75, -3.20 and 1.43; 95% CI -2.71 to -0.16, respectively) in PFPS patients compared to controls. Foot arch height index and congruence angle were not associated with PFPS. Six out of eight pooled variables are associated with PFPS, other factors associated with PFPS were based on single studies. Further research is required. PMID- 22815425 TI - Why does exercise reduce falls in older people? Unrecognised contributions to motor control and cognition? PMID- 22815426 TI - High expression of lymphoid enhancer-binding factor-1 (LEF1) is a novel favorable prognostic factor in cytogenetically normal acute myeloid leukemia. AB - Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor of Wnt signaling. We recently showed that aberrant LEF1 expression induces acute myeloid leukemia (AML) in mice, and found high LEF1 expression in a subset of cytogenetically normal AML (CN-AML) patients. Whether LEF1 expression associates with clinical and molecular patient characteristics and treatment outcomes remained unknown. We therefore studied LEF1 expression in 210 adults with CN-AML treated on German AML Cooperative Group trials using microarrays. High LEF1 expression (LEF1high) associated with significantly better relapse-free survival (RFS; P < .001), overall survival (OS; P < .001), and event-free survival (EFS; P < .001). In multivariable analyses adjusting for established prognosticators, LEF1high status remained associated with prolonged RFS (P = .007), OS (P = .01), and EFS (P = .003). In an independent validation cohort of 196 CN-AML patients provided by the German-Austrian AML Study Group, LEF1high patients had significantly longer OS (P = .02) and EFS (P = .04). We validated the prognostic relevance of LEF1 expression by quantitative PCR, thereby providing a clinically applicable platform to incorporate this marker into future risk-stratification systems for CN-AML. Gene-expression profiling and immunophenotyping revealed up regulation of lymphopoiesis-related genes and lymphoid cell-surface antigens in LEF1high patients. In summary, we provide evidence that high LEF1 expression is a novel favorable prognostic marker in CN-AML. PMID- 22815427 TI - Pre-eclampsia. PMID- 22815428 TI - Kidney dialysis--the need for humanity. PMID- 22815430 TI - Treating Shiga toxin induced haemolytic uraemic syndrome. PMID- 22815431 TI - Vitamin D: some perspective please. PMID- 22815432 TI - Serco out of hours service in Cornwall was understaffed, finds watchdog. PMID- 22815433 TI - Almost a quarter of Royal College fellows say their hospitals cannot deliver continuity of care. PMID- 22815429 TI - Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. AB - OBJECTIVE: To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome. DESIGN: Multicentre retrospective case-control study. SETTING: 23 hospitals in northern Germany. PARTICIPANTS: 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome. MAIN OUTCOME MEASURES: Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death. RESULTS: 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P = 0.03), fewer deaths (0% v 5%, p = 0.029), required no abdominal surgery, and excreted E coli for a shorter duration. CONCLUSIONS: Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial. PMID- 22815434 TI - Countries contribute more to tackling HIV/AIDS than they get in aid, figures show. PMID- 22815435 TI - WHO workers are shot at during vaccination campaign in Pakistan. PMID- 22815436 TI - BMA drops plans for further industrial action over pensions. PMID- 22815437 TI - Genome sequence of a novel human pathogen, Aeromonas aquariorum. AB - Aeromonas aquariorum, a recently described species, is associated with a variety of human diseases. We present here the first genome sequence of A. aquariorum strain AAk1, which was isolated as the sole pathogen from the blood of a patient with septicemia and necrotizing fasciitis. PMID- 22815438 TI - Complete genome sequence of Bacillus anthracis H9401, an isolate from a Korean patient with anthrax. AB - Bacillus anthracis H9401 (NCCP 12889) is an isolate from a Korean patient with gastrointestinal anthrax. The whole genome of H9401 was sequenced. It is a circular chromosome containing 5,480 open reading frames (ORFs) and two plasmids, pXO1 containing 202 ORFs and pXO2 containing 110 ORFs. H9401 shows high pathogenicity and genome sequence similarity to Ames Ancestor. PMID- 22815439 TI - Complete genome sequence of Geobacillus thermoglucosidans TNO-09.020, a thermophilic sporeformer associated with a dairy-processing environment. AB - Thermophilic spore-forming bacteria are a common cause of contamination in dairy products. We isolated the thermophilic strain Geobacillus thermoglucosidans TNO 09.020 from a milk processing plant and report the complete genome of a dairy plant isolate consisting of a single chromosome of 3.75 Mb. PMID- 22815440 TI - Draft genome sequence of the antagonistic rhizosphere bacterium Serratia plymuthica strain PRI-2C. AB - Serratia plymuthica strain PRI-2C is a rhizosphere bacterial strain with antagonistic activity against different plant pathogens. Here we present the 5.39 Mb (G+C content, 55.67%) draft genome sequence of S. plymuthica strain PRI-2C with the aim of providing insight into the genomic basis of its antagonistic activity. PMID- 22815441 TI - Draft genome sequence of high-siderophore-yielding Pseudomonas sp. strain HYS. AB - We sequenced the genome of the high-siderophore-yielding strain Pseudomonas sp. HYS and then analyzed its iron acquisition systems. The 5.6-Mb draft genome sequence has a special pattern of pyoverdine synthesis clusters and contains an hmuRSTUV heme uptake cluster, which has a homolog only in some strains of the order Enterobacteriales. PMID- 22815442 TI - Complete genome sequence of Leptospirillum ferrooxidans strain C2-3, isolated from a fresh volcanic ash deposit on the island of Miyake, Japan. AB - A diazotrophic, acidophilic, iron-oxidizing bacterium, Leptospirillum ferrooxidans, known to be difficult to cultivate, was isolated from a fresh volcanic ash deposit on the island of Miyake, Japan. Here, we report the complete genome sequence of a cultured strain, C2-3. PMID- 22815443 TI - Whole-genome sequence of Staphylococcus aureus strain LCT-SA112. AB - Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. S. aureus is the most common species of Staphylococcus to cause staphylococcal infections, which are very common in clinical medicine. Here we report the genome sequence of S. aureus strain LCT-SA112, which was isolated from S. aureus subsp. aureus CGMCC 1.230. PMID- 22815444 TI - Genome sequence of Mycobacterium massiliense M18, isolated from a lymph node biopsy specimen. AB - Mycobacterium massiliense is a rapidly growing mycobacterial species. The pathogenicity of this subspecies is not well known. We report here the annotated genome sequence of M. massiliense strain M18, which was isolated from a lymph node biopsy specimen from a Malaysian patient suspected of having tuberculous cervical lymphadenitis. PMID- 22815445 TI - Complete genome sequences of Methylophaga sp. strain JAM1 and Methylophaga sp. strain JAM7. AB - Methylophaga sp. strains JAM1 and JAM7 have been isolated from a denitrification system. Strain JAM1 was the first Methylophaga strain reported to be able to grow under denitrifying conditions. Here, we report the complete genome sequences of the two strains, which allowed prediction of gene clusters involved in denitrification in strain JAM1. PMID- 22815446 TI - Draft genome sequence of the sulfur-oxidizing bacterium "Candidatus Sulfurovum sediminum" AR, which belongs to the Epsilonproteobacteria. AB - Sulfur-oxidizing bacteria are common microorganisms in a variety of sulfide-rich environments. They play important roles in the global sulfur cycle on earth. Here, we present a high-quality draft genome sequence of a sulfur-oxidizing bacterium, "Candidatus Sulfurovum sediminum" strain AR, which belongs to the class Epsilonproteobacteria and dominated an enrichment culture from a marine sediment collected off Svalbard, within the Arctic Circle. Its genome contains genes for sulfur oxidation and carbon fixation. The size of the draft genome is 2.12 Mb, and the G+C content is 39.4%. PMID- 22815447 TI - Draft genome sequence of Treponema sp. strain JC4, a novel spirochete isolated from the bovine rumen. AB - Morphologically and biochemically diverse members of the Treponema genus are present in the gastrointestinal tract of ruminants, yet very little is understood about their functional importance to this microbiome. Here we describe the annotated draft genome sequence of Treponema sp. strain JC4, a novel spirochete isolated from a bovine rumen sample. PMID- 22815448 TI - Complete genome sequences of probiotic strains Bifidobacterium animalis subsp. lactis B420 and Bi-07. AB - We present the complete genomes of Bifidobacterium animalis subsp. lactis B420 and Bi-07. Comparative genomic analysis with the type strain DSMZ10140 revealed 40 to 55 single nucleotide polymorphisms (SNPs) and an indel in a clustered regularly interspaced short palindromic repeat (CRISPR) locus. These genetic differences provide a molecular basis for strain typing within the two main phylogenetic groups of this monomorphic species. PMID- 22815449 TI - Genome sequences of two thermophilic Bacillus licheniformis strains, efficient producers of platform chemical 2,3-butanediol. AB - Both Bacillus licheniformis strains 10-1-A and 5-2-D are efficient producers of 2,3-butanediol. Here we present 4.3-Mb and 4.2-Mb assemblies of their genomes. The key genes for the regulation and metabolism of 2,3-butanediol production were annotated, which may provide further insights into the molecular mechanism for the production of 2,3-butanediol with high yield and productivity. PMID- 22815450 TI - Genome sequence of Micromonospora lupini Lupac 08, isolated from root nodules of Lupinus angustifolius. AB - Micromonospora strains have been isolated from diverse niches, including soil, water, and marine sediments and root nodules of diverse symbiotic plants. In this work, we report the genome sequence of Micromonospora lupini Lupac 08 isolated from root nodules of the wild legume Lupinus angustifolious. PMID- 22815451 TI - Draft genome sequence of Herbaspirillum lusitanum P6-12, an endophyte isolated from root nodules of Phaseolus vulgaris. AB - Herbaspirillum lusitanum strain P6-12 (DSM 17154) is, so far, the only species of Herbaspirillum isolated from plant root nodules. Here we report a draft genome sequence of this organism. PMID- 22815452 TI - Genome annotation of five Mycoplasma canis strains. AB - To understand its potential to cause invasive disease, the genome of Mycoplasma canis strain PG14(T) from a dog's throat was compared to those of isolates from the genital tract or brain of dogs. The average nucleotide identity between strain pairs is 98%, and their genome annotations are similar. PMID- 22815453 TI - Draft genome sequence of Arctic marine Bacterium Pseudoalteromonas issachenkonii PAMC 22718. AB - The psychrotolerant Pseudoalteromonas issachenkonii PAMC 22718 was isolated for its higher chitinase and protease activities from cold seawater in the Kara Sea, Arctic. Here, we present the draft genome sequence of PAMC 22718 to provide further information for the ecological function of the genus Pseudoalteromonas in a cold marine environment. PMID- 22815454 TI - Complete genome sequence of Mycobacterium intracellulare clinical strain MOTT 36Y, belonging to the INT5 genotype. AB - Here we report the complete genome sequence of the Mycobacterium intracellulare clinical strain MOTT-36Y, previously grouped into the INT5 genotype among the 5 genotypes of M. intracellulare. This genome sequence will serve as a valuable reference for understanding the disparity in virulence and epidemiologic traits between M. intracellulare-related strains. PMID- 22815455 TI - Genome sequence of Aerococcus viridans LL1. AB - Aerococcus viridans is a catalase-negative Gram-positive bacterium and has been described as an airborne organism widely distributed in the hospital environment or in clinical specimens. We isolated A. viridans strain LL1 from indoor dust samples collected by a patient. Here, we prepared a genome sequence for this strain consisting of 31 contigs totaling 1,994,039 bases and a GC content of 39.42%. PMID- 22815456 TI - Draft genome sequence of Streptomyces globisporus C-1027, which produces an antitumor antibiotic consisting of a nine-membered enediyne with a chromoprotein. AB - Streptomyces globisporus C-1027 is the producer of antitumor antibiotic C-1027, a nine-membered enediyne-containing compound. Here we present a draft genome sequence of S. globisporus C-1027 containing the intact biosynthetic gene cluster for this antibiotic. The genome also carries numerous sets of genes for the biosynthesis of diverse secondary metabolites. PMID- 22815457 TI - Genomic comparison of Rickettsia honei strain RBT and other Rickettsia Species. AB - Rickettsia honei strain RB(T) was isolated from a febrile patient on Flinders Island, Australia, in 1991 and has been demonstrated to be the agent of Flinders Island spotted fever, a disease transmitted to humans by ticks. The comparison of this 1.27-Mb genome with other Rickettsia genomes provides additional insight into the mechanisms of evolution in Rickettsia species. PMID- 22815458 TI - Genome of Helicobacter pylori strain XZ274, an isolate from a tibetan patient with gastric cancer in China. AB - The infection rate of Helicobacter pylori is high all over the world, especially in the Chinese Tibetan Plateau. Here, we report the genome sequence of Helicobacter pylori strain XZ274 isolated from a Tibetan patient with gastric cancer. The strain contains 1,634,138 bp with 1,654 coding sequences and a pXZ274 plasmid of 22,406 bp with 26 coding sequences. This is the first complete genome sequence of Helicobacter pylori from the Tibetan Plateau in China. PMID- 22815459 TI - Draft genome sequence of the plant growth-promoting bacterium Bacillus siamensis KCTC 13613T. AB - Bacillus siamensis KCTC 13613(T), a novel halophilic Bacillus species isolated from a salted Thai food, produced antimicrobial compounds against plant pathogens and promoted plant growth by volatile emission. We determined the 3.8-Mb genome sequence of B. siamensis KCTC 13613(T) to reveal the plant-beneficial effect at the genomic level. PMID- 22815460 TI - Genome sequence of Herbaspirillum sp. strain GW103, a plant growth-promoting bacterium. AB - Herbaspirillum sp. strain GW103 was isolated from rhizosphere soil of the reed Phragmites australis on reclaimed land. Here we report the 5.05-Mb draft genome sequence of the strain, providing bioinformation about the agronomic benefits of this strain, such as multiple traits relevant to plant root colonization and plant growth promotion. PMID- 22815461 TI - The evidence underpinning sports performance products: a systematic assessment. AB - BACKGROUND: To assess the extent and nature of claims regarding improved sports performance made by advertisers for a broad range of sports-related products, and the quality of the evidence on which these claims are based. METHODS: The authors analysed magazine adverts and associated websites of a broad range of sports products. The authors searched for references supporting the performance and/or recovery claims of these products. The authors critically appraised the methods in the retrieved references by assessing the level of evidence and the risk of bias. The authors also collected information on the included participants, adverse events, study limitations, the primary outcome of interest and whether the intervention had been retested. RESULTS: The authors viewed 1035 web pages and identified 431 performance-enhancing claims for 104 different products. The authors found 146 references that underpinned these claims. More than half (52.8%) of the websites that made performance claims did not provide any references, and the authors were unable to perform critical appraisal for approximately half (72/146) of the identified references. None of the references referred to systematic reviews (level 1 evidence). Of the critically appraised studies, 84% were judged to be at high risk of bias. Randomisation was used in just over half of the studies (58.1%), allocation concealment was only clear in five (6.8%) studies; and blinding of the investigators, outcome assessors or participants was only clearly reported as used in 20 (27.0%) studies. Only three of the 74 (2.7%) studies were judged to be of high quality and at low risk of bias. CONCLUSIONS: The current evidence is not of sufficient quality to inform the public about the benefits and harms of sports products. There is a need to improve the quality and reporting of research, a move towards using systematic review evidence to inform decisions. PMID- 22815462 TI - Antiemetic treatment for acute gastroenteritis in children: an updated Cochrane systematic review with meta-analysis and mixed treatment comparison in a Bayesian framework. AB - OBJECTIVE: To assess the evidence for the safety and effectiveness of antiemetics on gastroenteritis-induced vomiting in children and adolescents. DESIGN: Systematic review. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE searched from 1980 to March 2012. METHODS: Methods included comprehensive searches, data synthesis, meta-analysis and mixed treatment comparisons (MTC). REVIEW METHODS: Reference lists were checked, and missing or inconsistent data were sought from trial investigators. Randomised controlled trials comparing antiemetics in participants younger than 18 years and who were vomiting due to acute gastroenteritis. Four meta-analyses and three MTC were carried out. RESULTS: 10 trials (1479 participants) and five treatments were included: dexamethasone, dimenhydrinate, granisetron, metoclopramide and ondansetron. There was clear evidence that ondansetron (oral or intravenous) compared with placebo increased the proportion of patients with cessation of vomiting (orally administered) (RR 1.44, 95% CI 1.29 to 1.61), reduced the immediate hospital admission rate (orally administered) (RR 0.40, 95% CI 0.19 to 0.83) and the need for intravenous rehydration therapy (orally administered) (RR 0.41, 95% CI 0.29 to 0.59). No significant difference was noted in the revisit rates, but ondansetron was associated with an increase in episodes of diarrhoea. There was no evidence for the use of dexamethasone or metoclopramide and limited evidence that dimenhydrinate or granisetron increased the cessation of vomiting. The MTC analysis suggested that ondansetron was the most likely treatment to stop the child vomiting. Nine studies were carried out in secondary care and one in primary care. CONCLUSIONS: This systematic review used a method novel to this clinical area and found clear evidence that ondansetron was the most likely treatment to allow oral rehydration therapy to commence. Given the significance of these results, the authors urge healthcare policy makers to consider the wider use of ondansetron in secondary care. Furthermore, randomised controlled trials are needed to investigate the effectiveness of antiemetic treatment in primary care (including ambulatory care interventions). PMID- 22815463 TI - Correction. PMID- 22815464 TI - Observational evidence that urbanisation and neighbourhood deprivation are associated with escalation in chronic pharmacological pain treatment: a longitudinal population-based study in the Netherlands. AB - OBJECTIVE: To examine, in the light of the association between urban environment and poor mental health, whether urbanisation and neighbourhood deprivation are associated with analgesic escalation in chronic pharmacological pain treatment and whether escalation is associated with prescriptions of psychotropic medication. DESIGN: Longitudinal analysis of a population-based routine dispensing database in the Netherlands. SETTING: Representative sample of pharmacies, covering 73% of the Dutch nationwide medication consumption in the primary care and hospital outpatient settings. PARTICIPANTS: 449 410 patients aged 15-85 years were included, of whom 166 374 were in the Starter group and 283 036 in the Continuation group of chronic analgesic treatment. MAIN OUTCOME MEASURE: Escalation of analgesics (ie, change to a higher level of analgesic potency, classified across five levels) in association with urbanisation (five levels) and dichotomous neighbourhood deprivation was analysed over a 6-month observation period. METHODS: Ordered logistic multivariate model evaluating analgesic treatment. RESULTS: In both Starter and Continuation groups, escalation was positively associated with urbanisation in a dose-response fashion (Starter group: OR (urbanisation level 1 compared with level 5): 1.24, 95% CI 1.18 to 1.30; Continuation group: OR 1.18, 95% CI 1.14 to 1.23). An additional association was apparent with neighbourhood deprivation (Starter group: OR 1.07, 95% CI 1.02 to 1.11; Continuation group: OR 1.04, 95% CI 1.01 to 1.08). Use of somatic and particularly psychotropic co-medication was associated with escalation in both groups. CONCLUSIONS: Escalation of chronic analgesic treatment is associated with urban and deprived environments and occurs in a context of adding psychotropic medication prescriptions. These findings suggest that pain outcomes and mental health outcomes share factors that increase risk and remedy suffering. PMID- 22815465 TI - The optimal age of measles immunisation in low-income countries: a secondary analysis of the assumptions underlying the current policy. AB - OBJECTIVE: The current policy of measles vaccination at 9 months of age was decided in the mid-1970s. The policy was not tested for impact on child survival but was based on studies of seroconversion after measles vaccination at different ages. The authors examined the empirical evidence for the six underlying assumptions. DESIGN: Secondary analysis. DATA SOURCES AND METHODS: These assumptions have not been research issues. Hence, the authors examined case reports to assess the empirical evidence for the original assumptions. The authors used existing reviews, and in December 2011, the authors made a PubMed search for relevant papers. The title and abstract of papers in English, French, Portuguese, Spanish, German and Scandinavian languages were assessed to ascertain whether the paper was potentially relevant. Based on cumulative measles incidence figures, the authors calculated how many measles cases had been prevented assuming everybody was vaccinated at a specific age, how many 'vaccine failures' would occur after the age of vaccination and how many cases would occur before the specific age of vaccination. In the combined analyses of several studies, the authors used the Mantel-Haenszel weighted RR stratifying for study or age groups to estimate common trends. SETTING AND PARTICIPANTS: African community studies of measles infection. PRIMARY AND SECONDARY OUTCOMES: Consistency between assumptions and empirical evidence and the predicted effect on mortality. RESULTS: In retrospect, the major assumptions were based on false premises. First, in the single study examining this point, seronegative vaccinated children had considerable protection against measles infection. Second, in 18 community studies, vaccinated measles cases ('vaccine failures') had threefold lower case death than unvaccinated cases. Third, in 24 community studies, infants had twofold higher case death than older measles cases. Fourth, the only study examining the assumption that 'vaccine failures' lead to lack of confidence found the opposite because vaccinated children had milder measles infection. Fifth, a one-dose policy was recommended. However, the two randomised trials of early two dose measles vaccination compared with one-dose vaccination found significantly reduced mortality until 3 years of age. Thus, current evidence suggests that the optimal age for a single dose of measles vaccine should have been 6 or 7 months resulting in fewer severe unvaccinated cases among infants but more mild 'vaccine failures' among older children. Furthermore, the two-dose trials indicate that measles vaccine reduces mortality from other causes than measles infection. CONCLUSIONS: Many lives may have been lost by not determining the optimal age of measles vaccination. Since seroconversion continues to be the basis for policy, the current recommendation is to increase the age of measles vaccination to 12 months in countries with limited measles transmission. This policy may lead to an increase in child mortality. PMID- 22815466 TI - Feasibility and potential effectiveness of a non-pharmacological multidisciplinary care programme for persons with generalised osteoarthritis: a randomised, multiple-baseline single-case study. AB - OBJECTIVES: To evaluate the feasibility and potential effectiveness of a 12-week, non-pharmacological multidisciplinary intervention in patients with generalised osteoarthritis (GOA). DESIGN: A randomised, concurrent, multiple-baseline single case design. During the baseline period, the intervention period and the postintervention period, all participants completed several health outcomes twice a week on Visual Analogue Scales. SETTING: Rheumatology outpatient department of a specialised hospital in the Netherlands. PARTICIPANTS: 1 man and four women (aged 51-76 years) diagnosed with GOA. PRIMARY OUTCOME MEASURES: To assess feasibility, the authors assessed the number of dropouts and adverse events, adherence rates and patients' satisfaction. SECONDARY OUTCOME MEASURES: To assess the potential effectiveness, the authors assessed pain and self-efficacy using visual data inspection and randomisation tests. RESULTS: The intervention was feasible in terms of adverse events (none) and adherence rate but not in terms of participants' satisfaction with the intervention. Visual inspection of the data and randomisation testing demonstrated no effects on pain (p=0.93) or self efficacy (p=0.85). CONCLUSIONS: The results of the present study indicate that the proposed intervention for patients with GOA was insufficiently feasible and effective. The data obtained through this multiple-baseline study have highlighted several areas in which the therapy programme can be optimised. PMID- 22815467 TI - beta-Blocker treatment during pregnancy and adverse pregnancy outcomes: a nationwide population-based cohort study. AB - OBJECTIVE: To investigate the association between exposure to beta-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort. DESIGN: A population-based retrospective cohort study, using the Danish Fertility Database. The authors identified all pregnant women redeeming a prescription for beta blockers using the National Prescription Registry. Multivariate logistic regression models were used to assess the association between exposure and our outcomes. SETTING: Register-based survey. PARTICIPANTS: 911'685 births between 1995 and 2008 obtained from the Danish Fertility Database. OUTCOME MEASURES: Being born SGA was defined as having a birth weight below the 10th percentile for the corresponding gestational week. Preterm birth was defined as birth before the 37th gestational week. Perinatal mortality was defined as either death occurring within the first 28 days of life or stillbirth. Before 2004, fetal deaths were recorded as stillbirths if they occurred after 28 weeks of gestation, but since then stillbirth is recorded for deaths after 22 gestational weeks. RESULTS: The authors identified 2459 pregnancies exposed to beta-blockers. beta-Blocker exposure during pregnancy was found to be associated with increased risk of SGA (adjusted OR 1.97, 95% CI 1.75 to 2.23), preterm birth (adjusted OR 2.26, 95% CI 2.03 to 2.52) and perinatal mortality (adjusted OR 1.89, 95% CI 1.25 to 2.84). Analyses were adjusted for socioeconomic and maternal variables. The authors found similar risk profiles for pregnancies exposed to labetalol and for pregnancies exposed to other beta-blockers. CONCLUSIONS: The authors found that exposure to beta-blockers during pregnancy was associated with being born SGA, preterm birth and perinatal mortality. Our findings show that labetalol is not safer than other beta-blockers during pregnancy. PMID- 22815468 TI - Biomarkers of exposure to polycyclic aromatic hydrocarbons (PAHs) and DNA damage: a cross-sectional pilot study among roofers in South Florida. AB - OBJECTIVE: The main goal of this pilot study was to assess the technical and logistic feasibility of a future study. The research hypothesis is that occupational exposures to polycyclic aromatic hydrocarbons (PAHs) are associated with increased risk of DNA damage among roofers who work with hot asphalt. DESIGN: This is a cross-sectional pilot study. SETTING: The study included roofers from four different construction sites in Miami-Dade County, Florida. PARTICIPANTS: 19 roofers were recruited (six Hispanics and 13 African-Americans, all male), all of whom were eligible (no history of cancer and no history of chronic diseases of kidneys or liver). All participants provided pre-shift samples and 18 provided post-shift samples. Samples of one participant were excluded from the final analyses as they were considered unreliable. RESULTS: Levels of urinary PAH metabolites increased during 6 h of work. Linear regression models of post-shift metabolites included their pre-shift levels, post-shift urinary creatinine levels (for models of 1-OHPyr and 9-OHPhe), and skin burn due to contact with hot asphalt (for models of 1-OHPyr and 1-OHNap). Pre-shift levels of urinary 8-OHdG were not associated with any of the variables considered. For post-shift levels of 8-OHdG, however, post-shift 1-OHPyr (95% CI 0.091 to 0.788) and use of protective gloves (95% CI -1.57 to -0.61) during work explained 86.8% of its variation. Overall, highest levels of urinary PAH metabolites and of 8 OHdG were observed among workers who reported having skin burn and who did not use gloves during work. CONCLUSIONS: Urinary 1-OHPyr is a promising predictor of oxidative DNA damage among roofers. Work-related skin burn and use of protective gloves appear to influence PAH exposure and DNA damage levels in this group, suggesting the importance of dermal absorption. PMID- 22815469 TI - The organising vision for telehealth and telecare: discourse analysis. AB - OBJECTIVE: To (1) map how different stakeholders understand telehealth and telecare technologies and (2) explore the implications for development and implementation of telehealth and telecare services. DESIGN: Discourse analysis. SAMPLE: 68 publications representing diverse perspectives (academic, policy, service, commercial and lay) on telehealth and telecare plus field notes from 10 knowledge-sharing events. METHOD: Following a familiarisation phase (browsing and informal interviews), we studied a systematic sample of texts in detail. Through repeated close reading, we identified assumptions, metaphors, storylines, scenarios, practices and rhetorical positions. We added successive findings to an emerging picture of the whole. MAIN FINDINGS: Telehealth and telecare technologies featured prominently in texts on chronic illness and ageing. There was no coherent organising vision. Rather, four conflicting discourses were evident and engaged only minimally with one another's arguments. Modernist discourse presented a futuristic utopian vision in which assistive technologies, implemented at scale, would enable society to meet its moral obligations to older people by creating a safe 'smart' home environment where help was always at hand, while generating efficiency savings. Humanist discourse emphasised the uniqueness and moral worth of the individual and tailoring to personal and family context; it considered that technologies were only sometimes fit for purpose and could create as well as solve problems. Political economy discourse envisaged a techno economic complex of powerful vested interests driving commodification of healthcare and diversion of public funds into private business. Change management discourse recognised the complicatedness of large-scale technology programmes and emphasised good project management and organisational processes. CONCLUSION: Introduction of telehealth and telecare is hampered because different stakeholders hold different assumptions, values and world views, 'talk past' each other and compete for recognition and resources. If investments in these technologies are to bear fruit, more effective inter-stakeholder dialogue must occur to establish an organising vision that better accommodates competing discourses. PMID- 22815470 TI - Association between socioeconomic status and self-reported diabetes in India: a cross-sectional multilevel analysis. AB - OBJECTIVES: To quantify the association between socioeconomic status (SES) and type 2 diabetes in India. DESIGN: Nationally representative cross-sectional household survey. SETTING: Urban and rural areas across 29 states in India. PARTICIPANTS: 168 135 survey respondents aged 18-49 years (women) and 18-54 years (men). PRIMARY OUTCOME MEASURE: Self-reported diabetes status. RESULTS: Markers of SES were social caste, household wealth and education. The overall prevalence of self-reported diabetes was 1.5%; this increased to 1.9% and 2.5% for those with the highest levels of education and household wealth, respectively. In multilevel logistic regression models (adjusted for age, gender, religion, marital status and place of residence), education (OR 1.87 for higher education vs no education) and household wealth (OR 4.04 for richest quintile vs poorest) were positively related to self-reported diabetes (p<0.0001). In a fully adjusted model including all socioeconomic variables and body mass index, household wealth emerged as positive and statistically significant with an OR for self-reported diabetes of 2.58 (95% credible interval (CrI): 1.99 to 3.40) for the richest quintile of household wealth versus the poorest. Nationally in India, a one quintile increase in household wealth was associated with an OR of 1.31 (95% CrI 1.20 to 1.42) for self-reported diabetes. This association was consistent across states with the relationship found to be positive in 97% of states (28 of 29) and statistically significant in 69% (20 of 29 states). CONCLUSIONS: The authors found that the highest SES groups in India appear to be at greatest risk for type 2 diabetes. This raises important policy implications for addressing the disease burdens among the poor versus those among the non-poor in the context of India, where >40% of the population is living in poverty. PMID- 22815471 TI - An HIV/STI prevention intervention for internally displaced women in Leogane, Haiti: study protocol for an N-of-1 pilot study. AB - INTRODUCTION: Haiti has the highest HIV infection rate in the Western hemisphere, with approximately one in 50 people infected. The January 2010 earthquake led to the collapse of Haiti's social, economic and health infrastructure, exacerbating social and structural HIV risk factors. Internally displaced (ID) women are particularly at high risk for HIV infection due to breakdown of community networks, increased poverty and sexual violence. The authors present the rationale and study protocol for pilot-testing FASY (Famn an Aksyon Pou Sante Yo) (Women Taking Action For Their Health), a psychoeducational HIV/STI prevention intervention with ID women in Haiti. METHODS AND ANALYSIS: This is a single centre pragmatic N-of-1 pilot study. The target population is ID women in Leogane, Haiti. The authors aim to recruit 200 participants using purposive peer driven recruitment methods. ID women will be trained as community health workers to deliver the FASY intervention in Kreyol. Participants will conduct a pretest that involves an individual HIV/STI educational video-based component followed by a 6-week group programme of 2 h women's health meetings. The primary outcome is HIV knowledge; our prespecified index of clinically significant change is an effect size of 0.30. Secondary outcomes include: sexually transmitted infections knowledge, condom use, social support, resilient coping, depression and relationship control. Multivariate analysis of variance will be used to compare pretest and post-test differences across variables to assess if the intervention influenced primary or secondary outcomes. Significant multivariate analysis of variance will be followed up with both univariate tests and discriminant function analyses to understand significant effects. ETHICS AND DISSEMINATION: Research Ethics Board approval (2011-0033-E) was attained from the Women's College Hospital, University of Toronto, Toronto, Ontario, Canada. Trial results will be published according to the CONSORT statement, modified for the N-of-1 pilot study design, regardless of the outcomes. TRIAL REGISTRATION NUMBER: This study is registered at http://clinicaltrials.gov, registration number NCT01492829. PMID- 22815472 TI - UDP-glucose dehydrogenase polymorphisms from patients with congenital heart valve defects disrupt enzyme stability and quaternary assembly. AB - Cardiac valve defects are a common congenital heart malformation and a significant clinical problem. Defining molecular factors in cardiac valve development has facilitated identification of underlying causes of valve malformation. Gene disruption in zebrafish revealed a critical role for UDP glucose dehydrogenase (UGDH) in valve development, so this gene was screened for polymorphisms in a patient population suffering from cardiac valve defects. Two genetic substitutions were identified and predicted to encode missense mutations of arginine 141 to cysteine and glutamate 416 to aspartate, respectively. Using a zebrafish model of defective heart valve formation caused by morpholino oligonucleotide knockdown of UGDH, transcripts encoding the UGDH R141C or E416D mutant enzymes were unable to restore cardiac valve formation and could only partially rescue cardiac edema. Characterization of the mutant recombinant enzymes purified from Escherichia coli revealed modest alterations in the enzymatic activity of the mutants and a significant reduction in the half-life of enzyme activity at 37 degrees C. This reduction in activity could be propagated to the wild-type enzyme in a 1:1 mixed reaction. Furthermore, the quaternary structure of both mutants, normally hexameric, was destabilized to favor the dimeric species, and the intrinsic thermal stability of the R141C mutant was highly compromised. The results are consistent with the reduced function of both missense mutations significantly reducing the ability of UGDH to provide precursors for cardiac cushion formation, which is essential to subsequent valve formation. The identification of these polymorphisms in patient populations will help identify families genetically at risk for valve defects. PMID- 22815473 TI - Synergism of the two Myb domains of Tay1 protein results in high affinity binding to telomeres. AB - Double-stranded regions of the telomeres are recognized by proteins containing Myb-like domains conferring specificity toward telomeric repeats. Although biochemical and structural studies revealed basic molecular principles involved in DNA binding, relatively little is known about evolutionary pathways leading to various types of Myb domain-containing proteins in divergent species of eukaryotes. Recently we identified a novel type of telomere-binding protein YlTay1p from the yeast Yarrowia lipolytica containing two Myb domains (Myb1, Myb2) very similar to the Myb domain of mammalian TRF1 and TRF2. In this study we prepared mutant versions of YlTay1p lacking Myb1, Myb2, or both Myb domains and found that YlTay1p carrying either Myb domain exhibits preferential affinity to both Y. lipolytica (GGGTTAGTCA)(n) and human (TTAGGG)(n) telomeric sequences. Quantitative measurements of the protein binding to telomeric DNA revealed that the presence of both Myb domains is required for a high affinity of YlTay1p to either telomeric repeat. Additionally, we performed detailed thermodynamic analysis of the YlTay1p interaction with its cognate telomeric DNA, which is to our knowledge the first energetic description of a full-length telomeric-protein binding to DNA. Interestingly, when compared with human TRF1 and TRF2 proteins, YlTay1p exhibited higher affinity not only for Y. lipolytica telomeres but also for human telomeric sequences. The duplication of the Myb domain region in YlTay1p thus produces a synergistic effect on its affinity toward the cognate telomeric sequence, alleviating the need for homodimerization observed in TRF like proteins possessing a single Myb domain. PMID- 22815474 TI - Nuclear EGFR suppresses ribonuclease activity of polynucleotide phosphorylase through DNAPK-mediated phosphorylation at serine 776. AB - Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than two decades. Resistance of cancer to radiotherapy is frequently correlated with elevated EGFR expression, activity, and nuclear translocation. However, the role of nuclear EGFR (nEGFR) in radioresistance of cancers remains elusive. In the current study, we identified a novel nEGFR-associated protein, polynucleotide phosphorylase (PNPase), which possesses 3' to 5' exoribonuclease activity toward c-MYC mRNA. Knockdown of PNPase increased radioresistance. Inactivation or knock-down of EGFR enhanced PNPase-mediated c-MYC mRNA degradation in breast cancer cells, and also increased its radiosensitivity. Interestingly, the association of nEGFR with PNPase and DNA-dependent protein kinase (DNAPK) increased significantly in breast cancer cells after exposure to ionizing radiation (IR). We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. The phospho-mimetic S776D mutant of PNPase impaired its ribonuclease activity whereas the nonphosphorylatable S776A mutant effectively degraded c-MYC mRNA. Here, we uncovered a novel role of nEGFR in radioresistance, and that is, upon ionizing radiation, nEGFR inactivates the ribonuclease activity of PNPase toward c-MYC mRNA through DNAPK-mediated Ser-776 phosphorylation, leading to increase of c-MYC mRNA, which contributes to radioresistance of cancer cells. PMID- 22815475 TI - Methylation of lysine 9 in histone H3 directs alternative modes of highly dynamic interaction of heterochromatin protein hHP1beta with the nucleosome. AB - Binding of heterochromatin protein 1 (HP1) to the histone H3 lysine 9 trimethylation (H3K9me3) mark is a hallmark of establishment and maintenance of heterochromatin. Although genetic and cell biological aspects have been elucidated, the molecular details of HP1 binding to H3K9me3 nucleosomes are unknown. Using a combination of NMR spectroscopy and biophysical measurements on fully defined recombinant experimental systems, we demonstrate that H3K9me3 works as an on/off switch regulating distinct binding modes of hHP1beta to the nucleosome. The methyl-mark determines a highly flexible and very dynamic interaction of the chromodomain of hHP1beta with the H3-tail. There are no other constraints of interaction or additional multimerization interfaces. In contrast, in the absence of methylation, the hinge region and the N-terminal tail form weak nucleosome contacts mainly with DNA. In agreement with the high flexibility within the hHP1beta-H3K9me3 nucleosome complex, the chromoshadow domain does not provide a direct binding interface. Our results report the first detailed structural analysis of a dynamic protein-nucleosome complex directed by a histone modification and provide a conceptual framework for understanding similar interactions in the context of chromatin. PMID- 22815476 TI - A novel hydrogen sulfide-releasing N-methyl-D-aspartate receptor antagonist prevents ischemic neuronal death. AB - Physiological levels of H(2)S exert neuroprotective effects, whereas high concentrations of H(2)S may cause neurotoxicity in part via activation of NMDAR. To characterize the neuroprotective effects of combination of exogenous H(2)S and NMDAR antagonism, we synthesized a novel H(2)S-releasing NMDAR antagonist N ((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl) benzamide (S-memantine) and examined its effects in vitro and in vivo. S memantine was synthesized by chemically combining a slow releasing H(2)S donor 4 (3-thioxo-3H-1,2-dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na(2)S) or ACS48, but suppressed by memantine and S-memantine. S memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na(2)S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H(2)S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury. PMID- 22815477 TI - Meizothrombin is an unexpectedly zymogen-like variant of thrombin. AB - Thrombin is produced by the ordered action of prothrombinase on two cleavage sites in prothrombin. Meizothrombin, a proteinase precursor of thrombin, is a singly cleaved species that accumulates abundantly as an intermediate. We now show that covalent linkage of the N-terminal propiece with the proteinase domain in meizothrombin imbues it with exceptionally zymogen-like character. Meizothrombin exists in a slowly reversible equilibrium between two equally populated states, differing by as much as 140-fold in their affinity for active site-directed ligands. The distribution between the two forms, designated zymogen like and proteinase-like, is affected by Na(+), thrombomodulin binding, or active site ligation. In rapid kinetic measurements with prothrombinase, we also show that the zymogen-like form is produced following the initial cleavage reaction and slowly equilibrates with the proteinase-like form in a previously unanticipated rate-limiting step before it can be further cleaved to thrombin. The reversible equilibration of meizothrombin between zymogen- and proteinase like states provides new insights into its ability to selectively exhibit the anticoagulant function of thrombin and the mechanistic basis for its accumulation during prothrombin activation. Our findings also provide unexpected insights into the regulation of proteinase function and how the formation of meizothrombin may yield a long lived intermediate with an important regulatory role in coagulation. PMID- 22815478 TI - The binding site of the V-ATPase inhibitor apicularen is in the vicinity of those for bafilomycin and archazolid. AB - The investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning V(O) complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to (14)C labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the V(O) subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides. PMID- 22815479 TI - Uncovering principles that control septin-septin interactions. AB - Septins comprise a conserved family of GTPases important in cytokinesis. These proteins polymerize into filaments from rod-shaped heteromeric septin complexes. Septins interact with one another at two interfaces (NC and G) that alternate within the complex. Here, we show that small mutations at the N terminus greatly enhance the formation of SEPT2 homopolymers. Taking advantage of this mutation to examine polymer formation using SEPT2 alone, we show that both NC and G interfaces are required for filament formation. However, co-expression of wild type SEPT2 with SEPT2 containing mutations at either NC or G interfaces revealed that only the NC mutant suppressed filament formation. NC mutants are able to interact with one another at putative G interfaces, whereas G mutants fail to interact at NC interfaces. In addition, all promiscuous septin pairwise interactions occur at the G interface. These findings suggest that G interface interactions must occur before NC interactions during polymer formation. PMID- 22815480 TI - A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation. AB - Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM. Here, we report clinical and functional characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death. Diagnosed at age 5, the proband is family history-negative for HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which increased Ca(2+) sensitivity with no effect on the maximal contractile force generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% cTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100% cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The secondary structure of the cTnC mutant was evaluated by circular dichroism, which did not indicate global changes in structure. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. These results suggest that this mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. In summary, we report a novel mutation in the TNNC1 gene that is associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM. PMID- 22815481 TI - Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a critical role in beta cell survival under endoplasmic reticulum stress: promoting ubiquitination and degradation of C/EBP homologous protein (CHOP). AB - Lipotoxicity in pancreatic beta-cells, arising from excess free fatty acid induced endoplasmic reticulum (ER) stress response, has been recognized as a key pathogenic factor causing loss of beta-cell mass and contributing to type 2 diabetes. However, how the adaptive ER stress response causes cell death remains enigmatic. We report herein a critical role of cellular inhibitor of apoptosis protein-1 (cIAP1) in controlling beta-cell survival under ER stress. While both palmitate and palmitoleate induced an overt ER stress response, lipotoxicity was only observed in beta-cells exposed to palmitate but not palmitoleate. Interestingly, cells treated with palmitoleate exerted a sustainable level of cIAP1, whereas the protein quickly degraded following palmitate treatment. Enforced overexpression of cIAP1 prevented palmitate-induced cell death. In contrast, siRNA-mediated knockdown of cIAP1 in beta-cells or knock-out of cIap1 in mouse embryonic fibroblasts not only increased palmitate-induced apoptosis, but also committed cells to death in response to the nontoxic palmitoleate treatment. Of importance, we found that cIAP1 functions as an E3 ubiquitin ligase promoting ubiquitination and degradation of C/EBP homologous protein (CHOP), a key mediator of ER stress-induced cell death. These findings define a novel mechanism for beta-cell survival under ER stress and help to identify targets for therapeutic intervention against lipotoxicity in beta-cells. PMID- 22815482 TI - Mapping of the CD23 binding site on immunoglobulin E (IgE) and allosteric control of the IgE-Fc epsilonRI interaction. AB - IgE, the antibody that mediates allergic responses, acts as part of a self regulating protein network. Its unique effector functions are controlled through interactions of its Fc region with two cellular receptors, FcepsilonRI on mast cells and basophils and CD23 on B cells. IgE cross-linked by allergen triggers mast cell activation via FcepsilonRI, whereas IgE-CD23 interactions control IgE expression levels. We have determined the CD23 binding site on IgE, using a combination of NMR chemical shift mapping and site-directed mutagenesis. We show that the CD23 and FcepsilonRI interaction sites are at opposite ends of the Cepsilon3 domain of IgE, but that receptor binding is mutually inhibitory, mediated by an allosteric mechanism. This prevents CD23-mediated cross-linking of IgE bound to FcepsilonRI on mast cells and resulting antigen-independent anaphylaxis. The mutually inhibitory nature of receptor binding provides a degree of autonomy for the individual activities mediated by IgE-FcepsilonRI and IgE CD23 interactions. PMID- 22815483 TI - The p21-activated kinase PAK3 forms heterodimers with PAK1 in brain implementing trans-regulation of PAK3 activity. AB - p21-activated kinase 1 (PAK1) and PAK3 belong to group I of the PAK family and control cell movement and division. They also regulate dendritic spine formation and maturation in the brain, and play a role in synaptic transmission and synaptic plasticity. PAK3, in particular, is known for its implication in X linked intellectual disability. The pak3 gene is expressed in neurons as a GTPase regulated PAK3a protein and also as three splice variants which display constitutive kinase activity. PAK1 regulation is based on its homodimerization, forming an inactive complex. Here, we analyze the PAK3 capacity to dimerize and show that although PAK3a is able to homodimerize, it is more likely to form heterodimeric complexes with PAK1. We further show that two intellectual disability mutations impair dimerization with PAK1. The b and c inserts present in the regulatory domain of PAK3 splice variants decrease the dimerization but retain the capacity to form heterodimers with PAK1. PAK1 and PAK3 are co expressed in neurons, are colocalized within dendritic spines, co-purify with post-synaptic densities, and co-immunoprecipitate in brain lysates. Using kinase assays, we demonstrate that PAK1 inhibits the activity of PAK3a but not of the splice variant PAK3b in a trans-regulatory manner. Altogether, these results show that PAK3 and PAK1 signaling may be coordinated by heterodimerization. PMID- 22815484 TI - Role of phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase skeletal muscle- and kidney-enriched inositol polyphosphate phosphatase (SKIP) in myoblast differentiation. AB - Insulin-like growth factors (IGFs) are essential for the development, regeneration, and hypertrophy of skeletal muscles. IGF-II promotes myoblast differentiation through phosphatidylinositol 3-kinase (PI 3-kinase), Akt, and mTOR signaling. Here, we report that skeletal muscle- and kidney-enriched inositol polyphosphate phosphatase (SKIP) negatively regulates myogenesis through inhibition of IGF-II production and attenuation of the IGF-II-Akt-mTOR signaling pathway. We also demonstrate that SKIP expression, which was markedly elevated during differentiation, was controlled by MyoD in C2C12 cells. Expression of SKIP inhibited IGF-II at the transcription level. These results indicate that SKIP regulates MyoD-mediated muscle differentiation. Silencing of SKIP increased IGF II transcription and myoblast differentiation. Furthermore, knockdown of SKIP resulted in thick myotubes with a larger number of nuclei than that in control C2C12 cells. Taken together, these data indicate that SKIP controls the IGF-II-PI 3-kinase-Akt-mTOR auto-regulation loop during myogenesis. Our findings identify SKIP as a key regulator of muscle cell differentiation. PMID- 22815485 TI - Structural insights into the anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of ceftobiprole. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an antibiotic-resistant strain of S. aureus afflicting hospitals and communities worldwide. Of greatest concern is its development of resistance to current last-line-of-defense antibiotics; new therapeutics are urgently needed to combat this pathogen. Ceftobiprole is a recently developed, latest generation cephalosporin and has been the first to show activity against MRSA by inhibiting essential peptidoglycan transpeptidases, including the beta-lactam resistance determinant PBP2a, from MRSA. Here we present the structure of the complex of ceftobiprole bound to PBP2a. This structure provides the first look at the molecular details of an effective beta-lactam-resistant PBP interaction, leading to new insights into the mechanism of ceftobiprole efficacy against MRSA. PMID- 22815486 TI - Transcriptional co-activator p300 maintains basal hepatic gluconeogenesis. AB - A major cause of fasting hyperglycemia in diabetes mellitus is unregulated hepatic glucose production (HGP). Insulin suppresses HGP by phosphorylating CBP and disassembling the CREB-CBP complex from gluconeogenic genes. p300 is closely related to CBP; but in contrast to CBP, p300 binds constitutively to CREB due to the absence of phosphorylation site found in CBP. In a phosphorylation-competent p300(G442S) knock-in mouse model, we demonstrate that HGP is now exquisitely sensitive to insulin suppression. p300(G422S) and hepatic-deleted p300 mice exhibited significant lower blood glucose levels in the fasted and post-prandial states, indicating a role for p300 in maintaining basal HGP. PMID- 22815487 TI - BRAG2/GEP100/IQSec1 interacts with clathrin and regulates alpha5beta1 integrin endocytosis through activation of ADP ribosylation factor 5 (Arf5). AB - ADP ribosylation factors (Arfs) are small GTP-binding proteins known for their role in vesicular transport, where they nucleate the assembly of coat protein complexes at sites of carrier vesicle formation. Similar to other GTPases, Arfs require guanine nucleotide exchange factors to catalyze GTP loading and activation. One subfamily of ArfGEFs, the BRAGs, has been shown to activate Arf6, which acts in the endocytic pathway to control the trafficking of a subset of cargo proteins including integrins. We have previously shown that BRAG2 modulates cell adhesion by regulating integrin surface expression. Here, we show that, in addition to Arf6, endogenous BRAG2 also activates the class II Arfs, Arf4 and Arf5, and that surprisingly, it is Arf5 that mediates integrin internalization. We observed that cell spreading on fibronectin is enhanced upon inhibition of BRAG2 or Arf5 but not Arf6. Similarly, spreading in BRAG2-depleted cells is reverted by expression of a rapid cycling Arf5 mutant (T161A) but not by a corresponding Arf6 construct (T157A). We also show that BRAG2 binds clathrin and the AP-2 adaptor complex and that both BRAG2 and Arf5 localize to clathrin-coated pits at the plasma membrane. Consistent with these observations, depletion of Arf5, but not Arf6 or Arf4, slows internalization of beta1 integrins without affecting transferrin receptor uptake. Together, these findings indicate that BRAG2 acts at clathrin-coated pits to promote integrin internalization by activating Arf5 and suggest a previously unrecognized role for Arf5 in clathrin mediated endocytosis of specific cargoes. PMID- 22815488 TI - Multiple novel signals mediate thyroid hormone receptor nuclear import and export. AB - Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor alpha1 that is absent in thyroid hormone receptor beta1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor alpha1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the alpha-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor beta1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general. PMID- 22815489 TI - Factor h and properdin recognize different epitopes on renal tubular epithelial heparan sulfate. AB - During proteinuria, renal tubular epithelial cells become exposed to ultrafiltrate-derived serum proteins, including complement factors. Recently, we showed that properdin binds to tubular heparan sulfates (HS). We now document that factor H also binds to tubular HS, although to a different epitope than properdin. Factor H was present on the urinary side of renal tubular cells in proteinuric, but not in normal renal tissues and colocalized with properdin in proteinuric kidneys. Factor H dose-dependently bound to proximal tubular epithelial cells (PTEC) in vitro. Preincubation of factor H with exogenous heparin and pretreatment of PTECs with heparitinase abolished the binding to PTECs. Surface plasmon resonance experiments showed high affinity of factor H for heparin and HS (K(D) values of 32 and 93 nm, respectively). Using a library of HS like polysaccharides, we showed that chain length and high sulfation density are the most important determinants for glycosaminoglycan-factor H interaction and clearly differ from properdin-heparinoid interaction. Coincubation of properdin and factor H did not hamper HS/heparin binding of one another, indicating recognition of different nonoverlapping epitopes on HS/heparin by factor H and properdin. Finally we showed that certain low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on factor H binding to tubular HS. As a result, these heparinoids can control the alternative complement pathway. In conclusion, factor H and properdin interact with different HS epitopes of PTECs. These interactions can be manipulated with some low anticoagulant heparinoids, which can be important for preventing complement derived tubular injury in proteinuric renal diseases. PMID- 22815490 TI - Identification of the catalytic residues of sequence-specific and histidine-free ribonuclease colicin E5. AB - Colicin E5 cleaves tRNAs for Tyr, His, Asn and Asp in their anticodons to abolish protein synthesis in Escherichia coli. We previously showed how its C-terminal RNase domain, E5-CRD, recognizes the anticodon bases but the catalytic mechanism remained to be elucidated. Although the reaction products with 5'-OH and 2',3' cyclic phosphate ends suggested a similar mechanism to those of RNases A and T1, E5-CRD does not have the His residues necessary as a catalyst in usual RNases. To identify residues important for the catalytic reaction, mutants as to all residues within 5 A from the central phosphorus of the scissile phosphodiester bond were prepared. Evaluation of the killing activities of the mutant colicins and the RNase activities of the mutant E5-CRDs suggested direct involvement of Arg33, Lys25, Gln29 and Lys60 in the reaction. Particularly, Arg33 plays a critical role and Ile94 provides a structural support of Arg33. Crystal structure of the complex of E5-CRD(R33Q)/dGpdUp showed structural and binding functional integrity of this mutant protein, suggesting involvement of Arg33 in the catalytic reaction. The structure of the free E5-CRD, we also determined, showed great flexibility of a flap region, which facilitates the access of Lys60 to the substrate in an induced-fit manner. PMID- 22815491 TI - Stress-induced gist-based memory processing: a possible explanation for overgeneralization of fear in posttraumatic stress disorder. PMID- 22815492 TI - Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. AB - PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimer's disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid beta(42) (Abeta(42)) by the alpha7-nicotinic acetylcholine receptor (alpha7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Abeta(42)'s toxic cascade, decreasing phospho-tau and Abeta aggregates and reducing the dysfunction of alpha7nAChRs, NMDARs, and insulin receptors. PTI-125 prevents Abeta(42) signaling by drastically reducing its affinity for alpha7nAChRs and can even dissociate existing Abeta(42)-alpha7nAChR complexes. Additionally, PTI-125 prevents Abeta-induced inflammatory cytokine release by blocking FLNA recruitment to toll-like receptor 4, illustrating an anti inflammatory effect. PTI-125's broad spectrum of beneficial effects is demonstrated here in an intracerebroventricular Abeta(42) infusion mouse model of AD and in human postmortem AD brain tissue. PMID- 22815493 TI - Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. AB - During REM sleep the CNS is intensely active, but the skeletal motor system is paradoxically forced into a state of muscle paralysis. The mechanisms that trigger REM sleep paralysis are a matter of intense debate. Two competing theories argue that it is caused by either active inhibition or reduced excitation of somatic motoneuron activity. Here, we identify the transmitter and receptor mechanisms that function to silence skeletal muscles during REM sleep. We used behavioral, electrophysiological, receptor pharmacology and neuroanatomical approaches to determine how trigeminal motoneurons and masseter muscles are switched off during REM sleep in rats. We show that a powerful GABA and glycine drive triggers REM paralysis by switching off motoneuron activity. This drive inhibits motoneurons by targeting both metabotropic GABA(B) and ionotropic GABA(A)/glycine receptors. REM paralysis is only reversed when motoneurons are cut off from GABA(B), GABA(A) and glycine receptor-mediated inhibition. Neither metabotropic nor ionotropic receptor mechanisms alone are sufficient for generating REM paralysis. These results demonstrate that multiple receptor mechanisms trigger REM sleep paralysis. Breakdown in normal REM inhibition may underlie common sleep motor pathologies such as REM sleep behavior disorder. PMID- 22815494 TI - Cornichons modify channel properties of recombinant and glial AMPA receptors. AB - Ionotropic glutamate receptors, which underlie a majority of excitatory synaptic transmission in the CNS, associate with transmembrane proteins that modify their intracellular trafficking and channel gating. Significant advances have been made in our understanding of AMPA-type glutamate receptor (AMPAR) regulation by transmembrane AMPAR regulatory proteins. Less is known about the functional influence of cornichons-unrelated AMPAR-interacting proteins, identified by proteomic analysis. Here we confirm that cornichon homologs 2 and 3 (CNIH-2 and CNIH-3), but not CNIH-1, slow the deactivation and desensitization of both GluA2 containing calcium-impermeable and GluA2-lacking calcium-permeable (CP) AMPARs expressed in tsA201 cells. CNIH-2 and -3 also enhanced the glutamate sensitivity, single-channel conductance, and calcium permeability of CP-AMPARs while decreasing their block by intracellular polyamines. We examined the potential effects of CNIHs on native AMPARs by recording from rat optic nerve oligodendrocyte precursor cells (OPCs), known to express a significant population of CP-AMPARs. These glial cells exhibited surface labeling with an anti-CNIH-2/3 antibody. Two features of their AMPAR-mediated currents-the relative efficacy of the partial agonist kainate (I(KA)/I(Glu) ratio 0.4) and a greater than fivefold potentiation of kainate responses by cyclothiazide-suggest AMPAR association with CNIHs. Additionally, overexpression of CNIH-3 in OPCs markedly slowed AMPAR desensitization. Together, our experiments support the view that CNIHs are capable of altering key properties of AMPARs and suggest that they may do so in glia. PMID- 22815495 TI - Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases. AB - Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8(+/+) mice, in contrast to MMP8(-/-) mice, show no anti inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity. PMID- 22815496 TI - Critical-state dynamics of avalanches and oscillations jointly emerge from balanced excitation/inhibition in neuronal networks. AB - Criticality has gained widespread interest in neuroscience as an attractive framework for understanding the character and functional implications of variability in brain activity. The metastability of critical systems maximizes their dynamic range, storage capacity, and computational power. Power-law scaling a hallmark of criticality-has been observed on different levels, e.g., in the distribution of neuronal avalanches in vitro and in vivo, but also in the decay of temporal correlations in behavioral performance and ongoing oscillations in humans. An unresolved issue is whether power-law scaling on different organizational levels in the brain-and possibly in other hierarchically organized systems-can be related. Here, we show that critical-state dynamics of avalanches and oscillations jointly emerge in a neuronal network model when excitation and inhibition is balanced. The oscillatory activity of the model was qualitatively similar to what is typically observed in recordings of human resting-state MEG. We propose that homeostatic plasticity mechanisms tune this balance in healthy brain networks, and that it is essential for critical behavior on multiple levels of neuronal organization with ensuing functional benefits. Based on our network model, we introduce a concept of multi-level criticality in which power-law scaling can emerge on multiple time scales in oscillating networks. PMID- 22815497 TI - A retinal source of spatial contrast gain control. AB - Sensory cortex is able to encode a broad range of stimulus features despite a great variation in signal strength. In cat primary visual cortex (V1), for example, neurons are able to extract stimulus features like orientation or spatial configuration over a wide range of stimulus contrasts. The contrast invariant spatial tuning found in V1 neuron responses has been modeled as a gain control mechanism, but at which stage of the visual pathway it emerges has remained unclear. Here we describe our findings that contrast-invariant spatial tuning occurs not only in the responses of lateral geniculate nucleus (LGN) relay cells but also in their afferent retinal input. Our evidence suggests that a similar contrast-invariant mechanism is found throughout the stages of the early visual pathway, and that the contrast-invariant spatial selectivity is evident in both retinal ganglion cell and LGN cell responses. PMID- 22815498 TI - Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction. AB - Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation. PMID- 22815499 TI - Platelet-derived growth factor-BB restores human immunodeficiency virus Tat cocaine-mediated impairment of neurogenesis: role of TRPC1 channels. AB - Platelet-derived growth factor-BB (PDGF-BB) has been reported to provide tropic support for neurons in the CNS. However, whether PDGF-BB regulates neurogenesis, especially in the context of HIV-associated neurological disorder and drug abuse, remains essentially unknown. In this study, we demonstrate that pretreatment of rat hippocampal neuronal progenitor cells (NPCs) with PDGF-BB restored proliferation that had been impaired by HIV Tat-cocaine via the cognate receptors. We identify the essential role of transient receptor potential canonical (TRPC) channels in PDGF-BB-mediated proliferation. Parallel but distinct ERK/CREB, phosphatidylinositol 3-kinase/Akt signaling pathways with downstream activation of mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E-binding protein (4E-BP)-p70S6K and nuclear factor-kappaB were critical for proliferation. Blocking TRPC1 channel suppressed PDGF-mediated proliferation as well as PDGF-BB-induced ERK/CREB and mTOR/4E-BP p70S6K activation, thereby underscoring its role in this process. In vivo relevance of these findings was further corroborated in Tat transgenic mice wherein hippocampal injection of recombinant AAV2-PDGF-B restored impaired NPC proliferation that was induced by Tat-cocaine. Together, these data underpin the role of TRPC1 channel as a novel target that regulates cell proliferation mediated by PDGF-BB with implications for therapeutic intervention for reversal of impaired neurogenesis inflicted by Tat and cocaine. PMID- 22815500 TI - Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain. AB - The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1alpha (HIF-1alpha) and induction and recruitment to the cell membrane of the HIF-1alpha-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation. PMID- 22815501 TI - The influence of visual motion on motor learning. AB - How does visual perception shape the way we coordinate movements? Recent studies suggest that the brain organizes movements based on minimizing reaching errors in the presence of motor and sensory noise. We present an alternative hypothesis in which movement trajectories also result from acquired knowledge about the geometrical properties of the object that the brain is controlling. To test this hypothesis, we asked human subjects to control a simulated kinematic linkage by continuous finger motion, a completely novel experience. This paradigm removed all biases arising from influences of limb dynamics and past experience. Subjects were exposed to two different types of visual feedback; some saw the entire simulated linkage and others saw only the moving extremity. Consistent with our hypothesis, subjects learned to move the simulated linkage along geodesic lines corresponding to the geometrical structure of the observed motion. Thus, optimizing final accuracy is not the unique determinant of trajectory formation. PMID- 22815502 TI - TXNIP in Agrp neurons regulates adiposity, energy expenditure, and central leptin sensitivity. AB - Thioredoxin interacting protein (TXNIP) has recently been described as a key regulator of energy metabolism through pleiotropic actions that include nutrient sensing in the mediobasal hypothalamus (MBH). However, the role of TXNIP in neurochemically specific hypothalamic subpopulations and the circuits downstream from MBH TXNIP engaged to regulate energy homeostasis remain unexplored. To evaluate the metabolic role of TXNIP activity specifically within arcuate Agrp neurons, we generated Agrp-specific TXNIP gain-of-function and loss-of-function mouse models using Agrp-Ires-cre mice, TXNIP (flox/flox) mice, and a lentivector expressing the human TXNIP isoform conditionally in the presence of Cre recombinase. Overexpression of TXNIP in Agrp neurons predisposed to diet-induced obesity and adipose tissue storage by decreasing energy expenditure and spontaneous locomotion, without affecting food intake. Conversely, Agrp neuronal TXNIP deletion protected against diet-induced obesity and adipose tissue storage by increasing energy expenditure and spontaneous locomotion, also without affecting food intake. TXNIP overexpression in Agrp neurons did not primarily affect glycemic control, whereas deletion of TXNIP in Agrp neurons improved fasting glucose levels and glucose tolerance independently of its effects on body weight and adiposity. Bidirectional manipulation of TXNIP expression induced reciprocal changes in central leptin sensitivity and the neural regulation of lipolysis. Together, these results identify a critical role for TXNIP in Agrp neurons in mediating diet-induced obesity through the regulation of energy expenditure and adipose tissue metabolism, independently of food intake. They also reveal a previously unidentified role for Agrp neurons in the brain-adipose axis. PMID- 22815503 TI - Dissociable brain systems mediate vicarious learning of stimulus-response and action-outcome contingencies. AB - Two distinct strategies have been suggested to support action selection in humans and other animals on the basis of experiential learning: a goal-directed strategy that generates decisions based on the value and causal antecedents of action outcomes, and a habitual strategy that relies on the automatic elicitation of actions by environmental stimuli. In the present study, we investigated whether a similar dichotomy exists for actions that are acquired vicariously, through observation of other individuals rather than through direct experience, and assessed whether these strategies are mediated by distinct brain regions. We scanned participants with functional magnetic resonance imaging while they performed an observational learning task designed to encourage either goal directed encoding of the consequences of observed actions, or a mapping of observed actions to conditional discriminative cues. Activity in different parts of the action observation network discriminated between the two conditions during observational learning and correlated with the degree of insensitivity to outcome devaluation in subsequent performance. Our findings suggest that, in striking parallel to experiential learning, neural systems mediating the observational acquisition of actions may be dissociated into distinct components: a goal directed, outcome-sensitive component and a less flexible stimulus-response component. PMID- 22815505 TI - Adaptation paths to novel motor tasks are shaped by prior structure learning. AB - After extensive practice with motor tasks sharing structural similarities (e.g., different dancing movements, or different sword techniques), new tasks of the same type can be learned faster. According to the recent "structure learning" hypothesis (Braun et al., 2009a), such rapid generalization of related motor skills relies on learning the dynamic and kinematic relationships shared by this set of skills. As a consequence, motor adaptation becomes constrained, effectively leading to a dimensionality reduction of the learning problem; at the same time, adaptation to tasks lying outside the structure becomes biased toward the structure. We tested these predictions by investigating how previously learned structures influence subsequent motor adaptation. Human subjects were making reaching movements in 3D virtual reality, experiencing perturbations either in the vertical or in the horizontal plane. Perturbations were either visuomotor rotations of varying angle or velocity-dependent forces of varying strength. We found that, after extensive training with both kinematic or dynamic perturbations, adaptation to unpracticed, diagonal, perturbations happened along the previously learned structure (vertical or horizontal), and resulting adaptation trajectories were curved. This effect is robust, can be observed on the single-subject level, and occurs during adaptation both within and across trials. Additionally, we demonstrate that structure learning changes involuntary visuomotor reflexes and therefore is not exclusively a high-level cognitive phenomenon. PMID- 22815504 TI - Rit GTPase signaling promotes immature hippocampal neuronal survival. AB - The molecular mechanisms governing the spontaneous recovery seen following brain injury remain elusive, but recent studies indicate that injury-induced stimulation of hippocampal neurogenesis contributes to the repair process. The therapeutic potential of endogenous neurogenesis is tempered by the demonstration that traumatic brain injury (TBI) results in the selective death of adult-born immature neurons, compromising the cell population poised to compensate for trauma-induced neuronal loss. Here, we identify the Ras-related GTPase, Rit, as a critical player in the survival of immature hippocampal neurons following brain injury. While Rit knock-out (Rit(-/-)) did not alter hippocampal development, hippocampal neural cultures derived from Rit(-/-) mice display increased cell death and blunted MAPK cascade activation in response to oxidative stress, without affecting BDNF-dependent signaling. When compared with wild-type hippocampal cultures, Rit loss rendered immature (Dcx(+)) neurons susceptible to oxidative damage, without altering the survival of neural progenitor (Nestin(+)) cells. Oxidative stress is a major contributor to neuronal cell death following brain injury. Consistent with the enhanced vulnerability of cultured Rit(-/-) immature neurons, Rit(-/-) mice exhibited a significantly greater loss of adult born immature neurons within the dentate gyrus after TBI. In addition, post-TBI neuronal remodeling was blunted. Together, these data identify a new and unexpected role for Rit in injury-induced neurogenesis, functioning as a selective survival mechanism for immature hippocampal neurons within the subgranular zone of the dentate gyrus following TBI. PMID- 22815506 TI - Beta reactivity, prospective facilitation of executive processing, and its dependence on dopaminergic therapy in Parkinson's disease. AB - Oscillatory activity in the beta frequency band has been shown to be modulated during the preparation and execution of voluntary movements at both cortical and subcortical levels. The exaggeration of beta activity in the basal ganglia of patients with Parkinson's disease has heightened interest in this phenomenon. However, the precise function, if any, subserved by modulations in beta activity remains unclear. Here we test the hypothesis that beta reactivity can be dissociated from processing of specific actions and can index the salience of cues with respect to future behavior in a way that might help prospectively prioritize resources. To this end we used an experimental paradigm designed to dissociate salient warning cues from processing of specific motor or cognitive actions. We recorded local field potential activity from the subthalamic nucleus of humans undergoing functional neurosurgery for the treatment of Parkinson's disease, while the same patients were on or off the dopamine prodrug levodopa. In this way we demonstrate that beta reactivity is indeed dependent on the salience of cues with respect to future motor and cognitive action and is promoted by dopamine. The loss of normal beta encoding of saliency may underlie some of the motor and cognitive features of basal ganglia disorders such as Parkinson's disease. PMID- 22815507 TI - Morphine modulation of toll-like receptors in microglial cells potentiates neuropathogenesis in a HIV-1 model of coinfection with pneumococcal pneumoniae. AB - Chronic drug users account for a third of all cases of AIDS in the United States and the progression to AIDS dementia is accelerated in opiate drug abusers. Clinically, microglial activation better correlates with HIV-associated neurocognitive disorders (HAND) than productive HIV-1 infection in the CNS. Moreover, pneumococcal pneumonia is the most common opportunistic infection in individuals with HAND. We show that coinfection with Streptococcus pneumoniae may be a contributing factor in the increased prevalence of HAND in the opioid dependent population. To date, there have been no studies published implicating the Toll-like receptors (TLR) in the neurocognitive disorders associated with NeuroAIDS in the context of opportunistic infection. Our studies show for the first time, in a morphine-dependent model, synergistic increase and activation of TLR expression in the presence of HIV-1 protein TAT and S. pneumoniae with a significant increase in proinflammatory cytokines (IL-6, TNF-alpha) levels. Furthermore, concurrent increases in reactive oxygen species and nitric oxide production leading to increased caspase 3 activation are also observed in both murine and human microglial cells. These effects are recapitulated with TLR 2, 4, and 9 cognate ligands (Pam3CSK4, LPS, and CpG) and significantly attenuated in TLR 2 and 4 knock-out mice and TLR2/4 double knock-out mice. Therefor, our findings clearly suggest for the first time that activation of TLRs on microglia cells by morphine and TAT in the context of S. pneumoniae infection may be a potential mechanism for the increased prevalence of HAND in HIV-infected opioid dependent patients. PMID- 22815508 TI - Inhibitory networks of fast-spiking interneurons generate slow population activities due to excitatory fluctuations and network multistability. AB - Slow population activities (SPAs) exist in the brain and have frequencies below ~5 Hz. Despite SPAs being prominent in several cortical areas and serving many putative functions, their mechanisms are not well understood. We studied a specific type of in vitro GABAergic, inhibition-based SPA exhibited by C57BL/6 murine hippocampus. We used a multipronged approach consisting of experiment, simulation, and mathematical analyses to uncover mechanisms responsible for hippocampal SPAs. Our results show that hippocampal SPAs are an emergent phenomenon in which the "slowness" of the network is due to interactions between synaptic and cellular characteristics of individual fast-spiking, inhibitory interneurons. Our simulations quantify characteristics underlying hippocampal SPAs. In particular, for hippocampal SPAs to occur, we predict that individual fast-spiking interneurons should have frequency-current (f-I) curves that exhibit a suitably sized kink where the slope of the curve decreases more abruptly in the gamma frequency range with increasing current. We also predict that these interneurons should be well connected with one another. Our mathematical analyses show that the combination of synaptic and intrinsic conditions, as predicted by our simulations, promotes network multistability. Population slow timescales occur when excitatory fluctuations drive the network between different stable network firing states. Since many of the parameters we use are extracted from experiments and subsequent measurements of experimental f-I curves of fast spiking interneurons exhibit characteristics as predicted, we propose that our network models capture a fundamental operating mechanism in biological hippocampal networks. PMID- 22815509 TI - The ventral midline thalamus (reuniens and rhomboid nuclei) contributes to the persistence of spatial memory in rats. AB - The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: >500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks. PMID- 22815510 TI - Visuomotor functional network topology predicts upcoming tasks. AB - It is a vital ability of humans to flexibly adapt their behavior to different environmental situations. Constantly, the rules for our sensory-to-motor mappings need to be adapted to the current task demands. For example, the same sensory input might require two different motor responses depending on the actual situation. How does the brain prepare for such different responses? It has been suggested that the functional connections within cortex are biased according to the present rule to guide the flow of information in accordance with the required sensory-to-motor mapping. Here, we investigated with fMRI whether task settings might indeed change the functional connectivity structure in a large-scale brain network. Subjects performed a visuomotor response task that required an interaction between visual and motor cortex: either within each hemisphere or across the two hemispheres of the brain depending on the task condition. A multivariate analysis on the functional connectivity graph of a cortical visuomotor network revealed that the functional integration, i.e., the connectivity structure, is altered according to the task condition already during a preparatory period before the visual cue and the actual movement. Our results show that the topology of connection weights within a single network changes according to and thus predicts the upcoming task. This suggests that the human brain prepares to respond in different conditions by altering its large scale functional connectivity structure even before an action is required. PMID- 22815511 TI - Generation of spike latency tuning by thalamocortical circuits in auditory cortex. AB - In many sensory systems, the latency of spike responses of individual neurons is found to be tuned for stimulus features and proposed to be used as a coding strategy. Whether the spike latency tuning is simply relayed along sensory ascending pathways or generated by local circuits remains unclear. Here, in vivo whole-cell recordings from rat auditory cortical neurons in layer 4 revealed that the onset latency of their aggregate thalamic input exhibited nearly flat tuning for sound frequency, whereas their spike latency tuning was much sharper with a broadly expanded dynamic range. This suggests that the spike latency tuning is not simply inherited from the thalamus, but can be largely reconstructed by local circuits in the cortex. Dissecting of thalamocortical circuits and neural modeling further revealed that broadly tuned intracortical inhibition prolongs the integration time for spike generation preferentially at off-optimal frequencies, while sharply tuned intracortical excitation shortens it selectively at the optimal frequency. Such push and pull mechanisms mediated likely by feedforward excitatory and inhibitory inputs respectively greatly sharpen the spike latency tuning and expand its dynamic range. The modulation of integration time by thalamocortical-like circuits may represent an efficient strategy for converting information spatially coded in synaptic strength to temporal representation. PMID- 22815512 TI - Inactivation of basolateral amygdala specifically eliminates palatability-related information in cortical sensory responses. AB - Evidence indirectly implicates the amygdala as the primary processor of emotional information used by cortex to drive appropriate behavioral responses to stimuli. Taste provides an ideal system with which to test this hypothesis directly, as neurons in both basolateral amygdala (BLA) and gustatory cortex (GC)-anatomically interconnected nodes of the gustatory system-code the emotional valence of taste stimuli (i.e., palatability), in firing rate responses that progress similarly through "epochs." The fact that palatability-related firing appears one epoch earlier in BLA than GC is broadly consistent with the hypothesis that such information may propagate from the former to the latter. Here, we provide evidence supporting this hypothesis, assaying taste responses in small GC single neuron ensembles before, during, and after temporarily inactivating BLA in awake rats. BLA inactivation (BLAx) changed responses in 98% of taste-responsive GC neurons, altering the entirety of every taste response in many neurons. Most changes involved reductions in firing rate, but regardless of the direction of change, the effect of BLAx was epoch-specific: while firing rates were changed, the taste specificity of responses remained stable; information about taste palatability, however, which normally resides in the "Late" epoch, was reduced in magnitude across the entire GC sample and outright eliminated in most neurons. Only in the specific minority of neurons for which BLAx enhanced responses did palatability specificity survive undiminished. Our data therefore provide direct evidence that BLA is a necessary component of GC gustatory processing, and that cortical palatability processing in particular is, in part, a function of BLA activity. PMID- 22815513 TI - In vivo alterations in calcium buffering capacity in transgenic mouse model of synucleinopathy. AB - Abnormal accumulation of alpha-synuclein is centrally involved in the pathogenesis of many disorders with Parkinsonism and dementia. Previous in vitro studies suggest that alpha-synuclein dysregulates intracellular calcium. However, it is unclear whether these alterations occur in vivo. For this reason, we investigated calcium dynamics in transgenic mice expressing human WT alpha synuclein using two-photon microscopy. We imaged spontaneous and stimulus-induced neuronal activity in the barrel cortex. Transgenic mice exhibited augmented, long lasting calcium transients characterized by considerable deviation from the exponential decay. The most evident pathology was observed in response to a repetitive stimulation in which subsequent stimuli were presented before relaxation of calcium signal to the baseline. These alterations were detected in the absence of significant increase in neuronal spiking response compared with age-matched controls, supporting the possibility that alpha-synuclein promoted alterations in calcium dynamics via interference with intracellular buffering mechanisms. The characteristic shape of calcium decay and augmented response during repetitive stimulation can serve as in vivo imaging biomarkers in this model of neurodegeneration, to monitor progression of the disease and screen candidate treatment strategies. PMID- 22815514 TI - Sodium concentration coding gives way to evaluative coding in cortex and amygdala. AB - Typically, stimulus batteries used to characterize sensory neural coding span physical parameter spaces (e.g., concentration: from low to high). For awake animals, however, psychological variables (e.g., pleasantness/palatability) with complicated relationships to the physical often dominate neural responses. Here we pit physical and psychological axes against one another, presenting awake rats with a stimulus set including 4 NaCl concentrations (0.01, 0.1, 0.3, and 1.0 m) plus palatable (0.3 m sucrose) and aversive (0.001 m quinine) benchmarks, while recording the activity of neurons in two sites vital for NaCl taste processing, gustatory cortex (GC) and central amygdala (CeA). Since NaCl palatability (i.e., preference) follows a non-monotonic, "inverted-U-shaped" curve while concentration increases monotonically, this stimulus battery allowed us to test whether GC and CeA responses better reflect external or internal variables. As predicted, GC single-neuron and population responses reflected both parameters in separate response epochs: sodium concentration-related information appeared with the earliest taste-specific responses, giving way to palatability-related information, in an overlapping subset of neurons, several hundred milliseconds later. CeA single-neuron and population responses, meanwhile, contained only a brief period of concentration specificity, occurring just before palatability related information emerged (simultaneously with, or slightly later than, in GC). Thus, cortex and amygdala both prominently reflect NaCl palatability late in their responses; CeA neurons largely respond to either palatable or aversive stimuli, while GC responses tend to reflect the entire palatability spectrum in a graded fashion. PMID- 22815515 TI - The development of brain systems associated with successful memory retrieval of scenes. AB - Neuroanatomical and psychological evidence suggests prolonged maturation of declarative memory systems in the human brain from childhood into young adulthood. Here, we examine functional brain development during successful memory retrieval of scenes in children, adolescents, and young adults ages 8-21 via functional magnetic resonance imaging. Recognition memory improved with age, specifically for accurate identification of studied scenes (hits). Successful retrieval (correct old-new decisions for studied vs unstudied scenes) was associated with activations in frontal, parietal, and medial temporal lobe (MTL) regions. Activations associated with successful retrieval increased with age in left parietal cortex (BA7), bilateral prefrontal, and bilateral caudate regions. In contrast, activations associated with successful retrieval did not change with age in the MTL. Psychophysiological interaction analysis revealed that there were, however, age-relate changes in differential connectivity for successful retrieval between MTL and prefrontal regions. These results suggest that neocortical regions related to attentional or strategic control show the greatest developmental changes for memory retrieval of scenes. Furthermore, these results suggest that functional interactions between MTL and prefrontal regions during memory retrieval also develop into young adulthood. The developmental increase of memory-related activations in frontal and parietal regions for retrieval of scenes and the absence of such an increase in MTL regions parallels what has been observed for memory encoding of scenes. PMID- 22815516 TI - MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. AB - Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that affects approximately one in 10,000 female live births. Because mutations in the Mecp2 gene occur in the germ cells with onset of neurological symptoms occurring in early childhood, the role of MeCP2 has been ascribed to brain maturation at a specific developmental window. Here, we show similar kinetics of onset and progression of RTT-like symptoms in mice, including lethality, if MeCP2 is removed postnatally during the developmental stage that coincides with RTT onset, or adult stage. For the first time, we show that brains that lose MeCP2 at these two different stages are actively shrinking, resulting in higher than normal neuronal cell density. Furthermore, we show that mature dendritic arbors of pyramidal neurons are severely retracted and dendritic spine density is dramatically reduced. In addition, hippocampal astrocytes have significantly less complex ramified processes. These changes accompany a striking reduction in the levels of several synaptic proteins, including CaMKII alpha/beta, AMPA, and NMDA receptors, and the synaptic vesicle proteins Vglut and Synapsin, which represent critical modifiers of synaptic function and dendritic arbor structure. Importantly, the mRNA levels of these synaptic proteins remains unchanged, suggesting that MeCP2 likely regulates these synaptic proteins post transcriptionally, directly or indirectly. Our data suggest a crucial role for MeCP2 in post-transcriptional regulation of critical synaptic proteins involved in maintaining mature neuronal networks during late stages of postnatal brain development. PMID- 22815517 TI - The actin-binding protein Canoe/AF-6 forms a complex with Robo and is required for Slit-Robo signaling during axon pathfinding at the CNS midline. AB - Axon guidance is a key process during nervous system development and regeneration. One of the best established paradigms to study the mechanisms underlying this process is the axon decision of whether or not to cross the midline in the Drosophila CNS. An essential regulator of that decision is the well conserved Slit-Robo signaling pathway. Slit guidance cues act through Robo receptors to repel axons from the midline. Despite good progress in our knowledge about these proteins, the intracellular mechanisms associated with Robo function remain poorly defined. In this work, we found that the scaffolding protein Canoe (Cno), the Drosophila orthologue of AF-6/Afadin, is essential for Slit-Robo signaling. Cno is expressed along longitudinal axonal pioneer tracts, and longitudinal Robo/Fasciclin2-positive axons aberrantly cross the midline in cno mutant embryos. cno mutant primary neurons show a significant reduction of Robo localized in growth cone filopodia and Cno forms a complex with Robo in vivo. Moreover, the commissureless (comm) phenotype (i.e., lack of commissures due to constitutive surface presentation of Robo in all neurons) is suppressed in comm, cno double-mutant embryos. Specific genetic interactions between cno, slit, robo, and genes encoding other components of the Robo pathway, such as Neurexin-IV, Syndecan, and Rac GTPases, further confirm that Cno functionally interacts with the Slit-Robo pathway. Our data argue that Cno is a novel regulator of the Slit Robo signaling pathway, crucial for regulating the subcellular localization of Robo and for transducing its signaling to the actin cytoskeleton during axon guidance at the midline. PMID- 22815519 TI - Nonlinear computations underlying temporal and population sparseness in the auditory system of the grasshopper. AB - Sparse coding schemes are employed by many sensory systems and implement efficient coding principles. Yet, the computations yielding sparse representations are often only partly understood. The early auditory system of the grasshopper produces a temporally and population-sparse representation of natural communication signals. To reveal the computations generating such a code, we estimated 1D and 2D linear-nonlinear models. We then used these models to examine the contribution of different model components to response sparseness. 2D models were better able to reproduce the sparseness measured in the system: while 1D models only captured 55% of the population sparseness at the network's output, 2D models accounted for 88% of it. Looking at the model structure, we could identify two types of computation, which increase sparseness. First, a sensitivity to the derivative of the stimulus and, second, the combination of a fast, excitatory and a slow, suppressive feature. Both were implemented in different classes of cells and increased the specificity and diversity of responses. The two types produced more transient responses and thereby amplified temporal sparseness. Additionally, the second type of computation contributed to population sparseness by increasing the diversity of feature selectivity through a wide range of delays between an excitatory and a suppressive feature. Both kinds of computation can be implemented through spike-frequency adaptation or slow inhibition-mechanisms found in many systems. Our results from the auditory system of the grasshopper are thus likely to reflect general principles underlying the emergence of sparse representations. PMID- 22815518 TI - I(A) channels encoded by Kv1.4 and Kv4.2 regulate neuronal firing in the suprachiasmatic nucleus and circadian rhythms in locomotor activity. AB - Neurons in the suprachiasmatic nucleus (SCN) display coordinated circadian changes in electrical activity that are critical for daily rhythms in physiology, metabolism, and behavior. SCN neurons depolarize spontaneously and fire repetitively during the day and hyperpolarize, drastically reducing firing rates, at night. To explore the hypothesis that rapidly activating and inactivating A type (I(A)) voltage-gated K(+) (Kv) channels, which are also active at subthreshold membrane potentials, are critical regulators of the excitability of SCN neurons, we examined locomotor activity and SCN firing in mice lacking Kv1.4 (Kv1.4(-/-)), Kv4.2 (Kv4.2(-/-)), or Kv4.3 (Kv4.3(-/-)), the pore-forming (alpha) subunits of I(A) channels. Mice lacking either Kv1.4 or Kv4.2 alpha subunits have markedly shorter (0.5 h) periods of locomotor activity than wild-type (WT) mice. In vitro extracellular multi-electrode recordings revealed that Kv1.4(-/-) and Kv4.2(-/-) SCN neurons display circadian rhythms in repetitive firing, but with shorter periods (0.5 h) than WT cells. In contrast, the periods of wheel-running activity in Kv4.3(-/-) mice and firing in Kv4.3(-/-) SCN neurons were indistinguishable from WT animals and neurons. Quantitative real-time PCR revealed that the transcripts encoding all three Kv channel alpha subunits, Kv1.4, Kv4.2, and Kv4.3, are expressed constitutively throughout the day and night in the SCN. Together, these results demonstrate that Kv1.4- and Kv4.2 encoded I(A) channels regulate the intrinsic excitability of SCN neurons during the day and night and determine the period and amplitude of circadian rhythms in SCN neuron firing and locomotor behavior. PMID- 22815520 TI - Neural correlates of prior expectations of motion in the lateral intraparietal and middle temporal areas. AB - Successful decision making involves combining observations of the external world with prior knowledge. Recent studies suggest that neural activity in macaque lateral intraparietal area (LIP) provides a useful window into this process. This study examines how rapidly changing prior knowledge about an upcoming sensory stimulus influences the computations that convert sensory signals into plans for action. Two monkeys performed a cued direction discrimination task, in which an arrow cue presented at the start of each trial communicated the prior probability of the direction of stimulus motion. We hypothesized that the cue would either shift the initial level of LIP activity before sensory evidence arrived, or it would scale sensory responses according to the prior probability of each stimulus, manifesting as a change in slope of LIP firing rates. Neural recordings demonstrated a clear shift in the activity level of LIP neurons following the arrow cue, which persisted into the presentation of the motion stimulus. No significant change in slope of responses was observed, suggesting that sensory gain was not strongly modulated. To confirm the latter observation, middle temporal area (MT) neurons were recorded during a version of the cued direction discrimination task, and we found no change in MT responses resulting from the presentation of the directional cue. These results suggest that information about an immediately upcoming stimulus does not scale the sensory response, but rather changes the amount of evidence that must be accumulated to reach a decision in areas that are involved in planning action. PMID- 22815521 TI - Robustness of a rhythmic circuit to short- and long-term temperature changes. AB - Recent computational and experimental work has shown that similar network performance can result from variable sets of synaptic and intrinsic properties. Because temperature is a global perturbation that differentially influences every biological process within the nervous system, one might therefore expect that individual animals would respond differently to temperature. Nonetheless, the phase relationships of the pyloric rhythm of the stomatogastric ganglion (STG) of the crab, Cancer borealis, are remarkably invariant between 7 and 23 degrees C (Tang et al., 2010). Here, we report that, when isolated STG preparations were exposed to more extreme temperature ranges, their networks became nonrhythmic, or "crashed", in a reversible fashion. Animals were acclimated for at least 3 weeks at 7, 11, or 19 degrees C. When networks from the acclimated animals were perturbed by acute physiologically relevant temperature ramps (11-23 degrees C), the network frequency and phase relationships were independent of the acclimation group. At high acute temperatures (>23 degrees C), circuits from the cold acclimated animals produced less-regular pyloric rhythms than those from warm acclimated animals. At high acute temperatures, phase relationships between pyloric neurons were more variable from animal to animal than at moderate acute temperatures, suggesting that individual differences across animals in intrinsic circuit parameters are revealed at high temperatures. This shows that individual and variable neuronal circuits can behave similarly in normal conditions, but their behavior may diverge when confronted with extreme external perturbations. PMID- 22815522 TI - Determinants of taste preference and acceptability: quality versus hedonics. AB - Several methods exist for reliably determining the motivational valence of a taste stimulus in animals, but few to determine its perceptual quality independent of its apparent affective properties. Individual differences in taste preference and acceptability could result from variance in the perceptual qualities of the stimulus leading to different hedonic evaluations. Alternatively, taste perception might be identical across subjects, but the processing of the sensory signals in reward circuits could differ. Using an operant-based taste cue discrimination/generalization task involving a gustometer, we trained male Long-Evans rats to report the degree to which a test stimulus resembled the taste quality of either sucrose or quinine regardless of its intensity. The rats, grouped by a characteristic bimodal phenotypic difference in their preference for sucralose, treated this artificial sweetener as qualitatively different-compared to sucralose-avoiding rats, the sucralose preferring rats found the stimulus much more perceptually similar to sucrose. Although the possibility that stimulus palatability may have served as a discriminative cue cannot entirely be ruled out, the profile of results suggests otherwise. Subsequent brief-access licking tests revealed that affective licking responses of the same sucralose-avoiding and -preferring rats differed across concentration in a manner approximately similar to that found in the stimulus generalization task. Thus, the perceived taste quality of sucralose alone may be sufficient to drive the observed behavioral avoidance of the compound. By virtue of its potential ability to dissociate the sensory and motivational consequences of a given experimental manipulation on taste-related behavior, this approach could be interpretively valuable. PMID- 22815523 TI - Multilocus genetic composite reflecting dopamine signaling capacity predicts reward circuitry responsivity. AB - The objective of the study was to test the hypotheses that humans with genotypes putatively associated with low dopamine (DA) signaling capacity, including the TaqIA A1 allele, DRD2-141C Ins/Ins genotype, DRD4 7-repeat or longer allele, DAT1 10-repeat allele, and the Met/Met COMT genotype, and with a greater number of these genotypes per a multilocus composite, show less responsivity of reward regions that primarily rely on DA signaling. Functional magnetic resonance imaging (fMRI) paradigms were used to investigate activation in response to receipt and anticipated receipt of palatable food and monetary reward. DNA was extracted from saliva using standard methods. Participants were 160 adolescents (mean age = 15.3 years, SD = 1.07 years; mean body mass index = 20.8, SD = 1.9). The main outcome was blood oxygenation level-dependent activation in the fMRI paradigms. Data confirmed that these fMRI paradigms activated reward, attention, somatosensory, and gustatory regions. Individuals with, versus without, these five genotypes did not show less activation of DA-based reward regions, but those with the Met/Met versus the Val/Val COMT genotype showed less middle temporal gyrus activation and those with the DRD4-L versus the DRD4-S genotype showed less middle occipital gyrus activation in response to monetary reward. Critically, the multilocus composite score revealed that those with a greater number of these genotypes showed less activation in reward regions, including the putamen, caudate, and insula, in response to monetary reward. The results suggest that the multilocus genetic composite is a more sensitive index of vulnerability for low reward region responsivity than individual genotypes. PMID- 22815525 TI - Awaiting a new era of cancer immunotherapy. AB - A major challenge in cancer therapy is the lack of specificity for cancer cells. Antibody-based therapies have better specificity and, thus, improved efficacy over standard chemotherapy regimens. Monoclonal antibodies (mAb) constitute the most rapidly growing class of human therapeutics and are proven agents for recognizing and destroying malignant cells. However, the development of antibody therapies has focused only on targeting extracellular (cell-surface or secreted) proteins rather than intracellular targets (within cells, such as phosphatases and/or kinases and transcription factors), because antibodies are generally believed to be too large to enter cells, resulting in a large untapped source of intracellular therapeutic targets. Recently, we presented evidence that suggests that intracellular proteins with high expression in cancer cells are useful targets for mAb-based or vaccination immunotherapies, thus challenging current understanding. Here, we further discuss the concept and future uses of these immunotherapies against a large pool of intracellular oncoproteins for cancer therapy. This line of research has the potential to vastly expand the field of antibody therapy and usher in a new era of cancer vaccines. PMID- 22815527 TI - NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo. AB - Neuronal leucine-rich repeat protein-1 (NLRR1), a type-1 transmembrane protein highly expressed in unfavorable neuroblastoma, is a target gene of MYCN that is predominately expressed in primary neuroblastomas with MYCN amplification. However, the precise biological role of NLRR1 in cell proliferation and tumor progression remains unknown. To investigate its functional importance, we examined the role of NLRR1 in EGF and insulin growth factor-1 (IGF-1)-mediated cell viability. We found that NLRR1 positively regulated cell proliferation through activation of extracellular signal-regulated kinase mediated by EGF and IGF-1. Interestingly, EGF stimulation induced endogenous MYCN expression through Sp1 recruitment to the MYCN promoter region, which was accelerated in NLRR1 expressing cells. The Sp1-binding site was identified on the promoter region for MYCN induction, and phosphorylation of Sp1 was important for EGF-mediated MYCN regulation. In vivo studies confirmed the proliferation-promoting activity of NLRR1 and established an association between NLRR1 expression and poor prognosis in neuroblastoma. Together, our findings indicate that NLRR1 plays an important role in the development of neuroblastoma and therefore may represent an attractive therapeutic target for cancer treatment. PMID- 22815528 TI - Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. AB - Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2 feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (Rb) pathway. Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity. PMID- 22815529 TI - Hedgehog signaling regulates bladder cancer growth and tumorigenicity. AB - The role of Hedgehog (HH) signaling in bladder cancer remains controversial. The gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region of chromosome 9q, one copy of which is frequently lost in bladder cancer. Inconsistent with PTCH1 functioning as a classic tumor suppressor gene, loss-of-function mutations in the remaining copy of PTCH1 are not commonly found. Here, we provide direct evidence for a critical role of HH signaling in bladder carcinogenesis. We show that transformed human urothelial cells and many urothelial carcinoma cell lines exhibit constitutive HH signaling, which is required for their growth and tumorigenic properties. Surprisingly, rather than originating from loss of PTCH1, the constitutive HH activity observed in urothelial carcinoma cell lines was HH ligand dependent. Consistent with this finding, increased levels of HH and the HH target gene product GLI1 were found in resected human primary bladder tumors. Furthermore, on the basis of the difference in intrinsic HH dependence of urothelial carcinoma cell lines, a gene expression signature was identified that correlated with bladder cancer progression. Our findings therefore indicate that therapeutic targeting of the HH signaling pathway may be beneficial in the clinical management of bladder cancer. PMID- 22815531 TI - PERTINENT (a substudy of the EUROPA trial): a persistent legacy. PMID- 22815530 TI - Truncated DNMT3B isoform DNMT3B7 suppresses growth, induces differentiation, and alters DNA methylation in human neuroblastoma. AB - Epigenetic changes in pediatric neuroblastoma may contribute to the aggressive pathophysiology of this disease, but little is known about the basis for such changes. In this study, we examined a role for the DNA methyltransferase DNMT3B, in particular, the truncated isoform DNMT3B7, which is generated frequently in cancer. To investigate if aberrant DNMT3B transcripts alter DNA methylation, gene expression, and phenotypic character in neuroblastoma, we measured DNMT3B expression in primary tumors. Higher levels of DNMT3B7 were detected in differentiated ganglioneuroblastomas compared to undifferentiated neuroblastomas, suggesting that expression of DNMT3B7 may induce a less aggressive clinical phenotype. To test this hypothesis, we investigated the effects of enforced DNMT3B7 expression in neuroblastoma cells, finding a significant inhibition of cell proliferation in vitro and angiogenesis and tumor growth in vivo. DNMT3B7 positive cells had higher levels of total genomic methylation and a dramatic decrease in expression of the FOS and JUN family members that comprise AP1 transcription factors. Consistent with an established antagonistic relationship between AP1 expression and retinoic acid receptor activity, increased differentiation was seen in the DNMT3B7-expressing neuroblastoma cells following treatment with all-trans retinoic acid (ATRA) compared to controls. Our results indicate that DNMT3B7 modifies the epigenome in neuroblastoma cells to induce changes in gene expression, inhibit tumor growth, and increase sensitivity to ATRA. PMID- 22815532 TI - Chronic treatment with a broad-spectrum metalloproteinase inhibitor, doxycycline, prevents the development of spontaneous aortic lesions in a mouse model of vascular Ehlers-Danlos syndrome. AB - There is no proven therapy or prevention for vascular Ehlers-Danlos syndrome (vEDS), a genetic disorder associated with the mutation of procollagen type III and characterized by increased fragility of vascular and hollow organ walls. Heterozygous COL3A1-deficient (HT) mice recapitulate a mild presentation of one of the variants of vEDS: haploinsufficiency for collagen III. Adult HT mice are characterized by increased metalloproteinase (MMP) activity, reduced collagen content in the arterial walls, and spontaneous development of various severity lesions in aorta. We hypothesized that chronic treatment with a MMP inhibitor would increase collagen content and prevent the development of spontaneous aortic lesions. HT mice were treated since weaning with the broad-spectrum MMP inhibitor doxycycline added to food. At the age of 9 months MMP-9 expression was twice as high in the tunica media of aorta in untreated HT mice, whereas total collagen content was 30% lower (p < 0.01) and the cumulative score of aortic lesions was eight times higher than in wild-type (WT) mice (p < 0.01). After 9 months of doxycycline treatment, MMP-9 activity, collagen content, and lesions in the aortas of HT mice were at the level of those of WT mice (p > 0.05). In the mouse model of collagen III haploinsufficiency treatment with broad-spectrum MMP inhibitor that was started early in life normalized increased MMP activity, reduced aortic collagen content in adults, and prevented the development of spontaneous aortic lesions. Our findings provide experimental justification for the clinical evaluation of the benefit of doxycycline at least in the haploinsufficient variety of vEDS. PMID- 22815533 TI - Pharmacological properties and procognitive effects of ABT-288, a potent and selective histamine H3 receptor antagonist. AB - Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl) biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area. PMID- 22815534 TI - Rosiglitazone improves insulin sensitivity and baroreflex gain in rats with diet induced obesity. AB - Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulin-sensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 +/- 0.1 bpm/mm Hg; OR, 4.0 +/- 0.2 bpm/mm Hg; CON, 3.9 +/- 0.2 bpm/mm Hg; P < 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 +/- 0.9 mg/kg . min; OR, 22.2 +/- 1.2 mg/kg . min; CON, 17.7 +/- 0.8 mg/kg . min; P < 0.05), which were well correlated (r(2) = 0.49; P < 0.01). In OP rats, rosiglitazone dose-dependently improved (P < 0.05) insulin sensitivity (12.8 +/- 0.6 mg/kg . min at 3 mg/kg; 16.0 +/- 1.5 mg/kg . min at 6 mg/kg) and BRG (3.8 +/- 0.4 bpm/mm Hg at 3 mg/kg; 5.3 +/- 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r(2) = 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P < 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity. PMID- 22815535 TI - Antagonism of metabotropic glutamate 1 receptors attenuates behavioral effects of cocaine and methamphetamine in squirrel monkeys. AB - Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4 methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, food-reinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drug-reinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce species-typical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to investigate other mGluR1 antagonists for potential therapeutic value in psychostimulant abuse. PMID- 22815536 TI - Age-related declines in the fidelity of newly acquired category representations. AB - We present a theory suggesting that the ability to build category representations that reflect the nuances of category structures in the environment depends upon clustering mechanisms instantiated in an MTL-PFC-based circuit. Because function in this circuit declines with age, we predict that the ability to build category representations will be impaired in older adults. Consistent with this prediction, we find that older adults are impaired relative to younger adults at learning nuanced category structures that contain exceptions to the rule. Model based analysis reveals that this deficit arises from older adults' failure to engage clustering mechanisms to separate exception and rule-following items in memory. PMID- 22815537 TI - CREB selectively controls learning-induced structural remodeling of neurons. AB - The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning induced remodeling of neurons remains elusive. Using transgenic mice conditionally expressing a dominant-negative CREB (CREBS133A: mCREB) mutant, we found that inhibiting CREB function does not alter spine density, spine morphology, and levels of polymerized actin in naive CA1 neurons. CREB inhibition, however, impaired contextual fear conditioning and produced a learning-induced collapse of spines associated with a blockade of learning dependent increase in actin polymerization. Blocking mCREB expression with doxycycline rescued memory and restored a normal pattern of learning-induced spines, demonstrating that CREB controls structural adaptations of neurons selectively involved in memory formation. PMID- 22815538 TI - The visual orientation memory of Drosophila requires Foraging (PKG) upstream of Ignorant (RSK2) in ring neurons of the central complex. AB - Orientation and navigation in a complex environment requires path planning and recall to exert goal-driven behavior. Walking Drosophila flies possess a visual orientation memory for attractive targets which is localized in the central complex of the adult brain. Here we show that this type of working memory requires the cGMP-dependent protein kinase encoded by the foraging gene in just one type of ellipsoid-body ring neurons. Moreover, genetic and epistatic interaction studies provide evidence that Foraging functions upstream of the Ignorant Ribosomal-S6 Kinase 2, thus revealing a novel neuronal signaling pathway necessary for this type of memory in Drosophila. PMID- 22815539 TI - Quantitative valuation placed by children and teenagers on participation in two hypothetical research scenarios. AB - For paediatric medicine to advance, research must be conducted specifically with children. Concern about poor recruitment has led to debate about payments to child research participants. Although concerns about undue influence by such 'compensation' have been expressed, it is useful to determine whether children can relate the time and inconvenience associated with participation to the value of payment offered. This study explores children's ability to determine fair remuneration for research participation, and reviews payments to children participating in research. Forty children were interviewed before outpatient visits at two London Hospitals: Great Ormond Street Children's Hospital and the Whittington Hospital District General Hospital. Children were asked to value their involvement in two hypothetical research scenarios - the first an 'additional blood sample', the second also involving daily oral oil capsules taken for a fortnight before further venesection. Background knowledge about familiarity with money, and experience with hospitalisation was assessed. The mean valuation of involvement in the second scenario (L13.18) was higher than in the first (L2.84) (p<0.001). This higher valuation persisted when children were categorised into groups 'aged 12+' and 'below 12'. Those undergoing a blood test on the day placed a higher valuation on participation in the second scenario (L10.43, L21.67, p=0.044). These children aged 8-16 demonstrated the capacity to discern a fair valuation for participation in medical research. The monetary sums are influenced by the time and inconvenience involved in the research, and by the extent of recent experience with hospital procedures. The authors review current ethical thinking regarding payments to child research participants and suggest that a fair wage model might be an ethically acceptable way to increase participation of children in research. PMID- 22815540 TI - SWEET as sugar: new sucrose effluxers in plants. PMID- 22815541 TI - A putative nuclear CLE-like (CLEL) peptide precursor regulates root growth in Arabidopsis. PMID- 22815542 TI - Introduction and context: the past, present and future of CKD research. PMID- 22815543 TI - Estimating the financial cost of chronic kidney disease to the NHS in England. AB - BACKGROUND: Chronic kidney disease (CKD) is a major challenge for health care systems around the world, and the prevalence rates appear to be increasing. We estimate the costs of CKD in a universal health care system. METHODS: Economic modelling was used to estimate the annual cost of Stages 3-5 CKD to the National Health Service (NHS) in England, including CKD-related prescribing and care, renal replacement therapy (RRT), and excess strokes, myocardial infarctions (MIs) and Methicillin-Resistant Staphylococcus Aureus (MRSA) infections in people with CKD. RESULTS: The cost of CKD to the English NHS in 2009-10 is estimated at L 1.44 to L 1.45 billion, which is ~ 1.3% of all NHS spending in that year. More than half this sum was spent on RRT, which was provided for 2% of the CKD population. The economic model estimates that ~ 7000 excess strokes and 12 000 excess MIs occurred in the CKD population in 2009-10, relative to an age- and gender-matched population without CKD. The cost of excess strokes and MIs is estimated at L 174-L 178 million. CONCLUSIONS: The financial impact of CKD is large, with particularly high costs relating to RRT and cardiovascular complications. It is hoped that these detailed cost estimates will be useful in analysing the cost-effectiveness of treatments for CKD. PMID- 22815544 TI - Intra-individual variability of serum hepcidin-25 in haemodialysis patients using mass spectrometry and ELISA. AB - BACKGROUND: Measurement of serum hepcidin levels may provide a useful alternative to the current methods of determining iron status in chronic haemodialysis (HD) patients. However, the biological variability of this pivotal regulator of iron homeostasis is unclear, and the impact of inflammation, dialysis clearance and iron therapy on hepcidin variability has not been established. METHODS: Two independent studies in chronic HD patients were conducted; serum hepcidin levels were measured at the start of dialysis sessions in 20 UK patients and in 43 Dutch patients by mass spectrometry (MS). Samples from UK patients were also analysed by a competitive enzyme-linked immunosorbent assay (cELISA). Coefficient of variance (CV(1)) was calculated and potential factors affecting CV(1) were also examined. RESULTS: The median CV(1) (inter-quartile range) was 23% (17-28) for the UK MS, 26% (17-48) for the Dutch MS and 23% (17-39) for the UK cELISA. The CV(1) was similar in those patients receiving and those not receiving regular intravenous iron. The CV(1) was not associated with the degree of inflammation. Hepcidin levels were higher following an inter-dialytic period of 3 versus 2 days (P = 0.02). CONCLUSIONS: These findings suggest considerable variability of serum hepcidin levels in HD patients. Inflammation and the use of iron did not impact on the degree of variability, and hepcidin levels were higher after an inter dialytic period of 3 versus 2 days. These findings need to be taken into account in future studies assessing the utility of serum hepcidin as a guide to the use of iron or erythropoiesis-stimulating agents therapy. PMID- 22815545 TI - Adequacy of intermittent renal replacement techniques and survival of ICU patients with acute kidney injury. PMID- 22815546 TI - Pregnancy after renal transplantation: a review of registry and single-center practices and outcomes. AB - Registries from North America, Australia and Europe are rich sources of clinical data on pregnancy after kidney transplantation. Single-center reports of pregnancy outcomes are limited by small sample sizes but not by the potential reporting bias that can impact registry data. Despite the differences in data pools, the obstetric and graft outcomes reported by single centers and registries have been similar. The majority of pregnancies are successful in renal transplant patients, but the risk of complications like pre-eclampsia, low birth weight and premature birth is high. Pregnancy has no significant impact on graft function or survival when baseline function is normal. PMID- 22815547 TI - Development and neurodegeneration: turning HD pathogenesis on its head. PMID- 22815548 TI - Fluorodeoxyglucose F18 PET in progressive emotional dysprosody. PMID- 22815549 TI - Measures of growth in children at risk for Huntington disease. AB - OBJECTIVE: The effect of mHTT on human development was examined by evaluating measures of growth in children at risk for Huntington disease (HD). METHODS: Children at risk for HD with no manifest symptoms (no juvenile HD included) were enrolled and tested for gene expansion for research purposes only. Measurements of growth (height, weight, body mass index [BMI], and head circumference) in children tested as gene-expanded (n = 20, 7-18 years of age, CAG repeats >=39) were compared to those of a large database of healthy children (n = 152, 7-18 years of age). RESULTS: Gene-expanded children had significantly lower measures of head circumference, weight, and BMI. Head circumference was abnormally low even after correcting for height, suggesting a specific deficit in brain growth, rather than a global growth abnormality. CONCLUSIONS: These results indicate that, compared to a control population, children who were estimated to be decades from HD diagnosis have significant differences in growth. Further, they suggest that mHTT may play a role in atypical somatic, and in particular, brain development. PMID- 22815550 TI - Multifocal visual evoked potentials are influenced by variable contrast stimulation in MS. AB - OBJECTIVE: To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast. METHODS: In a cross sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels. RESULTS: Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p < 0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p < 0.0001 for 33.3% compared to 100%, and p < 0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p < 0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage). CONCLUSIONS: Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes. PMID- 22815551 TI - Racial disparities among Native Hawaiians and Pacific Islanders with intracerebral hemorrhage. AB - OBJECTIVES: To evaluate disparities in stroke risk factors and outcome among the Native Hawaiians and other Pacific Islanders (NHPI) in Hawaii who are hospitalized with intracerebral hemorrhage (ICH). METHODS: We performed a retrospective study on consecutive patients hospitalized for acute ICH at a single tertiary center on Oahu between 2004 and 2010. Clinical data were obtained from the Get With the Guidelines-Stroke database. Multivariable logistic regression was used to assess the predictors for young ICH (age <45). RESULTS: A total of 562 patients hospitalized for acute ICH (Asian 63%, NHPI 18%, white 16%, other 3%) were studied. The NHPI were younger (mean ages, NHPI 55 +/- 16 vs white 66 +/- 16 years, p < 0.0001), and had higher prevalence of diabetes (NHPI 35% vs white 20%, p = 0.01) and history of hypertension (NHPI 77% vs white 64%, p = 0.04) compared to white patients. Independent predictors for young ICH were NHPI race (odds ratio [OR] 3.55; 95% confidence interval [CI] 1.33-9.45), being transferred from another hospital (OR 2.03; 95% CI 1.05-3.93), hypertension (OR 0.49; 95% CI 0.27-0.91), previous stroke or TIA (OR 0.21; 95% CI 0.05-0.91), and dyslipidemia (OR 0.15; 95% CI 0.05-0.50). CONCLUSIONS: NHPI with ICH are younger and have higher burden of risk factors compared to white patients. Further studies controlling for socioeconomic modifiers are needed to determine factors contributing to the younger age at presentation in this racial group. PMID- 22815552 TI - The broader reach of racial disparities. PMID- 22815553 TI - Comment: serum ceramides--a new biomarker for preclinical AD? PMID- 22815554 TI - Syncope-like epileptic seizures in Panayiotopoulos syndrome. AB - OBJECTIVE: To describe the clinical features of syncope-like epileptic seizures (SLES) and their frequency in Panayiotopoulos syndrome (PS). METHODS: This was a 6-year prospective study of all children aged 1-15 years referred for an EEG. PS was defined by the occurrence of at least one autonomic seizure (AS) in a neurodevelopmentally normal child and at least one EEG with focal spikes. SLES were defined as self-terminating events of sudden loss of postural tone and unresponsiveness, occurring either concurrently with other ictal autonomic symptoms and signs that characterize PS (AS + SLES) or on their own (pure SLES). RESULTS: PS was diagnosed in 33 of 394 consecutive children with at least one afebrile seizure (8.4%). SLES occurred at least once in 17 of 33 children (51.5%); 12 presented SLES in all their AS, and 5 had also AS without SLES. Overall, 53 of 74 AS manifested with SLES (71.6%); 25 were AS + SLES and 28 were pure SLES. The latter occurred in 7 children suddenly and without premonition or obvious triggers while standing, sitting, lying down, or asleep, did not resolve in the horizontal position, and were not associated with stiffening or any involuntary movements, even when longer than a few minutes. Concurrent autonomic symptoms during AS + SLES included emesis, incontinence, mydriasis, miosis, and cardiorespiratory abnormalities. CONCLUSIONS: SLES is a common ictal manifestation of PS and should be considered in the differential diagnosis of suspected syncope, particularly when clinical signs are atypical for neurocardiogenic syncope and the EEG shows focal spikes. PMID- 22815555 TI - Spatial patterns of water diffusion along white matter tracts in temporal lobe epilepsy. AB - OBJECTIVES: Diffusion tensor imaging (DTI) tractography has shown tract-specific pathology in temporal lobe epilepsy (TLE). This technique normally yields a single value per diffusion parameter per tract, potentially reducing the sensitivity for the detection of focal changes. Our goal was to spatially characterize diffusion abnormalities of fasciculi carrying temporal lobe connections. METHODS: We studied 30 patients with drug-resistant TLE and 21 healthy control subjects. Twenty-four patients underwent DTI toward the end of video-EEG telemetry, with an average of 50 +/- 54 hours between the last seizure and DTI examination. After manual dissection of the uncinate and inferior longitudinal and arcuate bundle, they were spatially matched based on their distance to the temporal lobe, providing between-subject correspondence of tract segments. We evaluated point-wise differences in diffusion parameters along each tract at group and subject levels. RESULTS: Our approach localized increased mean diffusivity restricted to or more prominent within the ipsilateral temporal lobe. These abnormalities tapered off as tracts exited the temporal lobe. We observed that the shorter the interval between the last seizure and DTI, the higher the mean diffusivity (MD) of the ipsilateral tracts. Linear discriminant analysis of tract segments correctly lateralized 87% of patients. CONCLUSIONS: The centrifugal pattern of white matter diffusion abnormalities probably reflects astrogliosis and microstructure derangement related to seizure activity in the vicinity of the focus. The negative correlation between the interval from last seizure and MD suggests a role for postictal vasogenic edema. The ability to assess tracts segmentally may contribute to a better understanding of the extent of white matter pathology in epilepsy and assist in the presurgical evaluation of patients with TLE, particularly those with unremarkable conventional imaging results. PMID- 22815556 TI - Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To develop an evidence-based guideline assessing pharmacologic options for treating Huntington disease (HD) chorea. METHODS: We evaluated available evidence from a structured literature review performed through February 2011. RESULTS AND RECOMMENDATIONS: If HD chorea requires treatment, clinicians should prescribe tetrabenazine (up to 100 mg/day), amantadine (300-400 mg/day), or riluzole (200 mg/day) (Level B) for varying degrees of expected benefit. Occurrence of adverse events should be discussed and monitored, particularly depression/suicidality and parkinsonism with tetrabenazine and elevated liver enzymes with riluzole. Clinicians may also prescribe nabilone for modest decreases (1- to <2-point changes on the Unified Huntington's Disease Rating Scale [UHDRS] chorea score) in HD chorea (Level C), but information is insufficient to recommend long-term use, particularly given abuse potential concerns (Level U). Clinicians should not prescribe riluzole 100 mg/day for moderate (2- to < 3-point UHDRS chorea change) short-term benefits (Level B) or for any long-term (3-year) HD antichoreic goals (Level B). Clinicians may choose not to prescribe ethyl-EPA (Level B), minocycline (Level B), or creatine (Level C) for very important improvements (>3-point UHDRS chorea change) in HD chorea. Clinicians may choose not to prescribe coenzyme Q10 (Level B) for moderate improvements in HD chorea. Data are insufficient to make recommendations regarding the use of neuroleptics or donepezil for HD chorea treatment (Level U). PMID- 22815557 TI - Endothelial progenitor cells: a new key for endothelial dysfunction in migraine. AB - OBJECTIVE: We aimed to study endothelial function with biochemical and ultrasonographic markers and its relation with endothelial progenitor cells (EPCs) in patients with migraine. METHODS: We performed a case-control study including 47 patients with episodic migraine (International Headache Society 2004 criteria) and 23 control subjects. We analyzed flow-mediated dilation (FMD) in the dominant brachial artery, calcitonin gene-related peptide (CGRP), and vascular endothelial growth factor (VEGF) levels by ELISA, nitric oxide stable metabolites (NOx) by high-performance liquid chromatography, and EPCs in peripheral blood samples, obtained during interictal periods (n = 47) and migraine attacks (n = 19). Frequency, severity, duration of attacks, and time of evolution of migraine were also recorded. RESULTS: Patients with migraine showed lower numbers of EPCs than control subjects (9.4 +/- 5.0 vs 17.9 +/- 6.0 colony forming unit-endothelial cells [CFU-ECs]; p < 0.0001) and higher levels of CGRP (164.2 +/- 139.1 vs 37.1 +/- 38.5 pg/mL), VEGF (473.4 +/- 398.7 vs 72.6 +/- 56.6 pg/mL), and NOx (1225.2 +/- 466.1 vs 671.9 +/- 358.6 MUM) (all p < 0.05). During attacks, higher levels for CGRP (298.2 +/- 100.3 pg/mL) and NOx (1,656.8 +/- 259.5 MUM) and lower numbers of EPC (7.2 +/- 3.2 CFU-ECs) were observed (all p < 0.05). No changes were found for FMD in interictal periods or during headache. In relation to clinical parameters, EPCs decreased with the time of evolution of migraine (r = -0.592; p < 0.0001). CONCLUSIONS: Patients with migraine show reduced numbers of EPCs and increased levels of CGRP, NOx, and VEGF than control subjects. Furthermore, EPC counts decrease as migraine progresses in time. These findings suggest altered endothelial function in patients with migraine. PMID- 22815558 TI - Serum ceramides increase the risk of Alzheimer disease: the Women's Health and Aging Study II. AB - OBJECTIVES: Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all cause dementia and Alzheimer disease (AD). METHODS: Participants included 99 women without dementia aged 70-79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry. RESULTS: Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1-C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2-85.1) and 7.6-fold increased risk of AD (95% CI 0.9 62.1), respectively. The highest tertiles of ceramide d18:1-C24:0 (hazard ratio [HR] = 5.1, 95% CI 1.1-23.6) and lactosylceramide (HR = 9.8, 95% CI 1.2-80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD. CONCLUSIONS: Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies. PMID- 22815560 TI - Low-contrast multifocal visual evoked potentials: identifying more shades of gray in MS. PMID- 22815559 TI - Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. AB - OBJECTIVE: To present a new family with tyrosine hydroxylase deficiency (THD) that presented with a new phenotype of predominant, levodopa-responsive myoclonus with dystonia due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder. METHODS: We performed detailed clinical examination of the family and electrophysiology to characterize the myoclonus. We performed analysis of the TH gene and in silico prediction of the possible effect of nonsynonymous substitutions on protein structure. RESULTS: Electrophysiology suggested that the myoclonus was of subcortical origin. Genetic analysis of the TH gene revealed compound heterozygosity of a point mutation in the promoter region (c.1-71 C>T) and a novel nonsynonymous substitution in exon 12 (c.1282G>A, p.Gly428Arg). The latter is a novel variant, predicted to have a deleterious effect on the TH protein function and is the first pathogenic TH mutation in patients of African ancestry. CONCLUSION: We presented a THD family with predominant myoclonus-dystonia and a new genotype. It is important to consider THD in the differential diagnosis of myoclonus-dystonia, because early treatment with levodopa is crucial for these patients. PMID- 22815561 TI - C9ORF72 hexanucleotide repeat expansions in patients with ALS from the Coriell Cell Repository. PMID- 22815562 TI - Coevolution of white matter hyperintensities and cognition in the elderly. AB - OBJECTIVE: To investigate the effects of baseline white matter hyperintensity (WMH) and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function). METHODS: A total of 150 individuals including cognitively normal elderly individuals and those with Alzheimer disease and mild cognitive impairment completed serial episodic memory and executive function evaluations and serial MRI scans sufficient for longitudinal measurement of WMH (mean delay 4.0 years). Incident WMH voxels were categorized as extended (baseline WMH that grew larger) or emergent (newly formed WMH). We used a stepwise regression approach to investigate the effects of baseline WMH and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function). RESULTS: WMH burden significantly increased over time, and approximately 80% of incident WMH voxels represented extensions of existing lesions. Each 1 mL/y increase in WMH extension was associated with an additional 0.70 SD/y of subsequent episodic memory decrease (p = 0.0053) and an additional 0.55 SD/y of subsequent executive function decrease (p = 0.022). Emergent WMHs were not found to be associated with a change in cognitive measures. CONCLUSIONS: Aging-associated WMHs evolve significantly over a 4-year period. Most of this evolution represents worsening injury to the already compromised surround of existing lesions. Increasing WMH was also significantly associated with declining episodic memory and executive function. This finding supports the view that white matter disease is an insidious and continuously evolving process whose progression has clinically relevant cognitive consequences. PMID- 22815563 TI - (Computer) Vision without Sight. AB - Computer vision holds great promise for helping persons with blindness or visual impairments (VI) to interpret and explore the visual world. To this end, it is worthwhile to assess the situation critically by understanding the actual needs of the VI population and which of these needs might be addressed by computer vision. This article reviews the types of assistive technology application areas that have already been developed for VI, and the possible roles that computer vision can play in facilitating these applications. We discuss how appropriate user interfaces are designed to translate the output of computer vision algorithms into information that the user can quickly and safely act upon, and how system-level characteristics affect the overall usability of an assistive technology. Finally, we conclude by highlighting a few novel and intriguing areas of application of computer vision to assistive technology. PMID- 22815564 TI - Biochemical and molecular characterization of thermo-alkali tolerant xylanase producing bacteria from thermal springs of Manikaran. AB - One hundred ten alkalo-tolerant thermophilic bacteria were isolated from 17 samples (water and sediment) collected from Manikaran. Of 110 isolates, 70 showed the production of xylanases and were further screened for growth and production of xylanases at different temperature ranging from 40 to 75 degrees C. Eleven isolates that showed growth and xylanase production at temperatures >=50 degrees C were selected for quantitative estimation in modified Reese mineral liquid medium containing wheat bran. Maximum xylanase activity was produced by isolate H 7 followed by H-9 and R-9 and was statistically superior to other isolates. The microscopic observation showed that the isolates possessed the typical rod with endospore, characteristic of genus Bacillus. The isolates were found to be oxidase and catalase positive. Using BIOLOG Microlog 3 software, the isolates H7, H9 and R9 were identified as Paenibacillus ehemensis, Bacillus cereus/B. thuringiensis and B. subtilis respectively, based on utilization of 95 carbon sources. PCR-RFLP analysis of 16S rDNA indicated that the isolates were genetically different from each other. DNA sequencing of the three isolates and phylogenetic analysis revealed that all the isolates obtained from Manikaran thermal springs showed 97 to 100% similarity with the sequences within the GenBank. The closest phylogenetic neighbours according to the 16S rRNA gene sequence data for the three isolates H-7, H-9, and R-9 were Paenibacillus ehemensis, Bacillus cereus and Bacillus subtilis, respectively. PMID- 22815565 TI - DNA fingerprinting of Flavobacterium columnare using RAPD-PCR. AB - In the present study, DNA fingerprinting of eight strains of Flavobacterium columnare was done by random amplification of polymorphic DNA (RAPD) fingerprinting method. The strains were collected from Fish Health Management Division, Central Institute of Freshwater Aquaculture, Bhubaneswar, India. A total number of 160 primers were screened for RAPD-PCR, of which 10 primers yielded amplification with all the strains. The molecular weight of amplified bands varied from 0.29-2.63 Kb. The number of bands varied from 1 to 8. Unique band was seen with primer OPY-15 with molecular weight 0.75 Kb that can be used for epidemiological study. Genetic variability was investigated using NTSYS software. Highest genetic similarity was found between MS1 and MS3 followed by MS5 and MS7. Minimum genetic similarity was found between MS2 and MS8. Phylogenetic tree was constructed using UPGMA and neighbor joining methods. PMID- 22815566 TI - Novel heliobacteria of a few semi-arid tropical soils. AB - Out of forty rhizosphere soils collected from semi arid tropical regions of Andhra Pradesh, India, 30 gave positive enrichments for heliobacteria. These bacteria were recognized by the presence of bacteriochlorophyll-g together with endospores in the initial enrichments. Using group specific primers of 16S rRNA gene, ten monoheliobacterial cultures were sequenced. They were finally grouped into 3 clusters based on the 16S rRNA gene similarity. Based on a few phenotypic characters, in addition to genetic characterization, we identified them as potential novel species and the 16S rRNA gene sequences were deposited with EMBL. PMID- 22815567 TI - Optimization of biofloc production in Azospirillum brasilense (MTCC-125) and evaluation of its adherence with the roots of certain crops. AB - The phenomenon of flocculation in Azospirillum brasilense (MTCC-125) was studied under different combinations of carbon and nitrogen sources. Fructose and Potassium nitrate at a pH of 6.4 in the cultural medium favour a higher bio-floc production. The biofloc was studied for root adhesion and its survival efficiency in the rhizoplane and rhizosphere of certain crops such as sorghum and sunflower under dryland condition. It has been demonstrated that the flocculated cultures of Azospirillum were found to have maximum adhesion to the root surface and higher survival rate in the rhizoplane and rhizosphere under different moisture stressed conditions as compared to the log phase cells of Azospirillum. PMID- 22815568 TI - Development of mixed inoculum for methane enriched biogas production. AB - Inocula were collected from four different sources such as Jajmau tannery waste treatment plant (ITW), Jajmau municipal waste treatment (IMW), Unnao distillery (IDW) and a batch reactor, in which the sludge of a field scale biogas reactor was added to cow dung slurry to develop inoculum (IBS). A combination of these mixed inocula were used for biogas production at 35 degrees C in laboratory scale reactor (10 L capacity) and the average yield of biogas (0.547 Lg(-1) volatile solid (VS)) and methane (0.323 Lg(-1)VS) in 41 d was higher in case of mixed inoculum IMW (1) (IMW+IBS), with maximum methane content in biogas (68% during 27 30 d), as compared to other mixed inocula as well as control i.e. ITW (1) (ITW+IBS), IDW(1) (IDW+IBS) and IBS. The corresponding yields of gas were biogas (0.505, 0.536 and 0.456 Lg(-1)VS), methane (0.288, 0.305, and 0.245 Lg(-1)VS) where as, the corresponding maximum methane content in biogas was 62% during 29 33d, 64% during 29-33 d and 62% during 27-29 d in ITW(1), IDW(1) and IBS. PMID- 22815569 TI - Waste water treatment and metal (Pb(2+), Zn(2+)) removal by microalgal based stabilization pond system. AB - A case study was undertaken for the treatment of domestic wastewater generated at village of Sanghol, Distt. Fatehgarh Sahib, Punjab (India), using a schematic designed algal and duckweed based stabilization pond system, which is discussed here for winter months only (November to March) as there was no growth of duckweeds and only algae dominated the whole system. A proficient increase in pH and dissolved oxygen was observed after the treatment with reduction in chemical oxygen demand and biochemical oxygen demand by 93% and 79% respectively. Chlorella sp. was the dominating algal species in the stabilization pond water during entire period and was studied for its Zn(2+) and Pb(2+) metal removal efficiency. 60-70% removal of Zn(2+) was observed from culture medium containing 5-20 mg L(-1) Zn(2+), which declined to 42% at 50 mg L(-1). A constant decline in cell number from 538 * 10(5) to 8 * 10(5) cells ml(-1) was observed indicating zinc toxicity to Chlorella. Lead was maximally removed by 66.3% from culture medium containing 1 mg L(-1). The lead removal efficiency was 45 50 % at higher 5 to 20 mg L(-1) of external lead concentrations. The increase in cell number indicated no signs of Pb(2+) toxicity up to 20 mg L(-1). The maximum uptake (q(max)) by live Chlorella biomass for both Zn(2+) and Pb(2+) was 34.4 and 41.8 mg/g respectively. PMID- 22815570 TI - Production of feather hydrolysate by Elizabethkingia meningoseptica KB042 (MTCC 8360) in submerged fermentation. AB - A keratinolytic bacterium Elizabethkingia meningoseptica KB042 was isolated from dropped off feathers. The bacterium showed 82.50 +/- 0.3% feather degradation when grown on medium containing 10 g/l chicken feathers with initial pH 7.0 at 37 degrees C, 150 rpm in 6 days. The pH of the medium was increased up to 10.02 +/- 0.10 during 6 days of incubation. Soluble protein and amino acids concentration in the culture fluid was also found increased until the end of incubation. During the cultivation of strain KB042 on feather as sole source of carbon and nitrogen, the maximum cysteine release was noted on the 3rd day. Varying feather concentration 1.0-2.0% in basal medium resulted in soluble protein release between 1814.42 and 1954.61 MUg/ml. The amino acid concentration was found to be maximum, i.e. 937.85 +/- 11.9 MUg/ml in the cultures grown with 2% feather. The hydrolysate was also found rich in essential amino acids valine, tryptophan, threonine, leucine and cysteine and contains minor amount of methionine and arginine. These data indicate a potential biotechnology for biotransformation and utilization of feather keratin as a source of protein which can be used as animal feed after successful animal trials. PMID- 22815571 TI - Application of immobilized tannase from Aspergillus niger for the removal of tannin from myrobalan juice. AB - Tannase produced optimally on an agroresidue by an Aspergillus niger isolate under submerged fermentation immobilized on sodium alginate beads with 93.6% efficiency was applied for tannin removal from myrobalan/aonla (Phyllanthus emblica) juice. The pH and temperature optima of the immobilized enzyme were found to be 5.4 and 40 degrees C while the corresponding values of the soluble enzyme were 5.8 and 35 degrees C. Maximum tannin removal of 73.6% was obtained at 40 degrees C and 150 rpm in 180 min with 36.6 U/ml of immobilized enzyme while the same amount of the soluble enzyme removed 45.2% of tannin at 37 degrees C and 150 rpm in the same time period. The immobilized beads could be used repeatedly till 7th cycle with 77% efficiency. When preserved at 6 degrees C the beads retained 71.7% of enzyme activity after 60 days. Reduction in vitamin C content, which is responsible for antioxidant property of the fruit, was minimum at only 2% during the treatment. PMID- 22815572 TI - Differential temperature effect on the production of enhanced gamma linolenic acid in Mucor rouxii CFR-G15. AB - Mucor rouxii CFR-G15, a locally isolated phycomycetous fungus, on cultivation at room temperature produced more than 30% (w/w) lipid in their dry cell weight, in which 14.2% accounted to be GLA content of the total fatty acids. It was observed that when incubation temperature lowered at 14 degrees C, GLA content of the mycelium increased significantly (P<0.05) from 14.2% to 21.97%. In order to optimize the cultural conditions for high biomass and lipid production with high GLA content, the fungus was grown in association of two different temperatures and supply of additional glucose in culture medium. Maximum lipid and GLA were obtained 23.56 and 19.5% respectively, when the culture was grown at 28 degrees C for four days and followed by addition of glucose (5%), and lowered the incubation temperature to 14 degrees C for another four days. The presence of GLA in the oil obtained from M. rouxii CFR-G15 was confirmed by the gas chromatography-mass spectrometry. Gamma linolenic acid (GLA, n-6) is gaining importance in pharmaceutical and nutraceutical industries because of clinical evidence demonstrated that it has various beneficial effects in human health. In this paper temperature played a major role in enhancing the GLA content which has been described. PMID- 22815573 TI - Stabilization of dextransucrase from Leuconostoc mesenteroides NRRL B-640. AB - Stabilization of dextransucrase from Leuconostoc mesenteroides NRRL B-640 with various stabilizers at different temperatures was studied. Dextransucrase was stable at lower temperatures (10-30 degrees C) and lost the activity at above 30 degrees C. The salts such as CaCl(2), CoCl(2) and MgCl(2) enhanced the dextransucrase activity. A 22% higher dextransucrase activity was obtained by 4 mM CoCl(2). The dextransucrase activity was lost by 50% at 1 mM EDTA. Urea denatured the enzyme and caused 45%, 90% and 98% loss of activity in 30 min when treated with 1 M, 3 M, and 5 M urea concentrations, respectively. Amongst the stabilizers Tween 80, glycerol, PEG-8000, dextran (500 kDa) and glutaraldehyde, Tween 80 provided the maximum stability at 30 degrees C. In the presence of Tween 80 the enzyme lost only 8% activity at 30 degrees C in 20 h but, it lost 65% of activity with out any stabilizer. The enzyme lost 92% of activity with in 4 days at 30 degrees C and lost only 25% of activity at -20 degrees C after 14 days. PMID- 22815574 TI - Solanum melongena: A potential source of antifungal agent. AB - The antifungal activity of Solanum melongena leaf, extracted with petroleum ether, chloroform, methanol and water was evaluated against three human pathogenic dermatophytes namely Trichophyton mentagrophytes, T. rubrum and T. tonsurans and two opportunistic fungi Candida albicans and Trichosporon beigelii. Maximum yield of plant components was 4.32 g, extracted in water and minimum 1.07 g in petroleum ether from 150 g of dry plant material. Except water extract, all the extracts possessed significant antifungal property. All the test pathogens showed highest sensitivity towards chloroform extract, exhibiting maximum inhibition zone diameter of 50.0 mm in T. mentagrophytes and minimum 30.0 mm in C. albicans at 2 * 10(5) MUg/ml concentration. Chloroform extract at lower concentration 2.5 * 10(4) MUg/ml was inhibitory for all the test pathogens, exhibiting inhibition zone diameter 21.0 mm against T. tonsurans and 15.0 mm against C. albicans and T. beigelii. The activity of the different solvent extracts against the test pathogens in terms of inhibition zone diameter in decreasing order was as followsChloroform extract > Petroleum ether extract > Methanol extract for T. mentagrophytes, T. rubrum and T. tonsurans.Chloroform extract > Methanol extract > Petroleum ether extract for C. albicans and T. beigelii. PMID- 22815575 TI - Chemical constituents and antibacterial activity of the leaf essential oil of Feronia limonia. AB - The essential oil from the leaves of Feronia limonia was extracted and the chemical constituents and antibacterial activity were studied. The GC and GC-MS analyses revealed that the leaf essential oil of F. limonia contained fourteen compounds representing about 98.4% of the total oil. The major chemical compounds identified were Eudesma-4 (14).11-dine (46.3%), carvacrol (29.6%) and 1,5 cyclodecandine (13.4%). The essential oil was screened for its antibacterial activity against different clinically isolated Gram positive and Gram negative bacterial strains by disc diffusion and minimum inhibitory concentration assay. The essential oil exhibited moderate antibacterial activity against all the tested bacterial strains with MIC values ranging from 125 to 500 MUg/mL except Proteus mirabilis. PMID- 22815577 TI - High gravity fermentation of sugarcane molasses to produce ethanol: Effect of nutrients. AB - Fermentation efficiency of more than 85% was obtained by high gravity fermentation of 33-34 degrees Bx (spec. gravity ~1.134) molasses medium with certain nutrients, instead of generally employed medium containing ~16% (w/v) total sugar (spec. gravity ~1.090) for ethanol fermentation in distilleries to get maximum 80-85% conversion. The fermenting yeast, Saccharomyces, has varied capabilities, depending on the species and nutrition for fermenting the high solids medium. The fermentation period was reduced to 48 h; and the byproducts obtained were less in concentration, upon supplementation with nutrients (or osmoprotectants) like soy flour/wheat bran to the medium in the existing batch fermentation technology. This has been found partly due to improved yeast cell viability during fermentation. PMID- 22815576 TI - Antimicrobial endophytic fungal assemblages inhabiting bark of Taxus baccata L. of Indo-Burma mega biodiversity hotspot. AB - Fungal endophytes were isolated from inner bark of Taxus baccata L., an important source of potent anticancer drug taxol. Bark samples were collected from two locations of Arunachal Pradesh, India, part of the Indo-Burma mega biodiversity hotspot, during two seasons i.e. monsoon and winter. Altogether 77 fungal strains representing 18 genera were isolated from T. baccata bark during the present investigation. The colonizing frequency was recorded as 38.5% and the fungal community comprised of 78% of Hyphomycetes, 5.2% of Coelomycetes, 2.6% of Zygomycetes and Ascomycetes and 9.1% of sterile mycelia. Most common and frequently isolated genera were Fusarium, Penicillium and Aspergillus. Simpson and Shannon diversity indices indicated higher species diversity during monsoon than during winter seasons irrespective of the locations. The two locations harbored 5 to 37 endophyte species and the similarity index was low during winter and high during monsoon. Ethyl acetate extract of fermentation cultures of these fungi were tested for their antimicrobial activity against a panel of human pathogenic Gram-positive and Gram-negative bacteria and fungi. Fifteen fungal isolates out of the isolated strains displayed antimicrobial activity. An endophytic fungus, identified as Fusarium sp. displayed significant antimicrobial activity against all the test pathogens. PMID- 22815578 TI - Studies on production of alcoholic beverages from some tropical fruits. AB - The varieties of alcoholic beverages from watermelon; watermelon-banana and watermelon-pineapple mixtures were produced by using monoculture and mixed culture fermentation techniques. Three yeast species, namely, Saccharomyces cerevisiae, Kleochera apicalata, Torulospora delbruckii and four bacterial species Leuconostoc oenos, Lactobacillus Sp, Micrococcus luteus and Streptococcus lactis were identified during the study. The daily succession of these organisms in the various fermenting samples differed in cell mass and occurrence due to their different growth conditions and factors present. A higher bacterial load (3.9 +/- 0.2-4.4 +/- 0.3) log (cfu) ml(-1) than yeast (2.8 +/- 00-4.6 +/- 0.4) log (cfu) ml(-1) counts was observed in the mixed culture fermentation, while in the monoculture fermentation, a higher yeast load (4.3 +/- 0.3-4.7 +/- 0.2) log (cfu) ml(-1) than bacterial loads (2.7 +/- 0.1-4.1 +/- 0.3) log (cfu) ml(-1) counts was recovered. The results obtained from the present study indicated that monoculture-fermented beverages were of better quality as compared to the mixed culture fermented ones. The monoculture-fermented beverage from watermelon pineapple mixture was ranked as the best alcoholic beverage based on sensory evaluation score. PMID- 22815579 TI - In situ fermentation dynamics during production of gundruk and khalpi, ethnic fermented vegetable products of the Himalayas. AB - Gundruk is a fermented leafy vegetable and khalpi is a fermented cucumber product, prepared and consumed in the Himalayas. In situ fermentation dynamics during production of gundruk and khalpi was studied. Significant increase in population of lactic acid bacteria (LAB) was found during first few days of gundruk and khlapi fermentation, respectively. Gundruk fermentation was initiated by Lactobacillus brevis, Pediococcus pentosaceus and finally dominated by Lb. plantarum. Similarly in khalpi fermentation, heterofermentative LAB such as Leuconostoc fallax, Lb. brevis and P. pentosaceus initiated the fermentation and finally completed by Lb. plantarum. Attempts were made to produce gundruk and khalpi using mixed starter culture of LAB previously isolated from respective products. Both the products prepared under lab condition had scored higher sensory-rankings comparable to market products. PMID- 22815580 TI - Endophytic Penicillium citrinum Thom. from Scoparia dulcis Linn. AB - Scoparia dulcis of Scrophulariaceae is an annual herb distributed through out the tropics. Penicillium citrinum was obtained from apparently healthy roots, stem, leaves and fruits of this plant. Callus and multiple shoots produced during micropropagation from various explants were also symptomless but showed occurrence of Penicillium citrinum when cultured in Murashige & Skoog liquid medium for the production of secondary metabolites. PMID- 22815581 TI - Assessing the Zinc solubilization ability of Gluconacetobacter diazotrophicus in maize rhizosphere using labelled (65)Zn compounds. AB - Solubilization of insoluble zinc compounds like ZnCO(3) and ZnO by G. diazotrophicus was confirmed using radiotracers. The zinc compounds (ZnCO(3) and ZnO) were tagged with (65)Zn. (65)ZnCO(3) and (65)ZnO was effectively solubilized and the uptake of zn by the plants also more in G. diazotrophicus inoculated treatments compared to the uninoculated treatments. Three types of soils (Zn deficientsterile, Zn deficient-unsterile, and Zn sufficient-sterile) were used in experiment. Among the three soils, Zn deficient-unsterile soil registered maximum zinc solubilization compared to other two soils. This may be due to other soil microorganisms in unsterile soil. Application of ZnO with G. diazotrophicus showed better uptake of the nutrient. PMID- 22815582 TI - Morphological and genetic differentiation among four pigment producing Indian species of Phoma (Saccardo, 1899). AB - A PCR-based technique, involving the random amplification of polymorphic DNA (RAPD), was used for assessing genetic relatedness among isolates of the genus Phoma. Randomly Amplified Polymorphic DNA (RAPD) revealed the presence of interspecific genetic variation among the pigment producing isolates of Phoma and has shown distinct phylogenetic cluster. The major objective of the study was to study the genetic variation, if any. Study was aimed to differentiate four pigment producing species of Phoma based on morphological studies and molecular markers in general and RAPD in particular. We found that the test species of Phoma can be very well differentiated using molecular markers. Phoma sorghina was differentiated from P. exigua, P. fimeti and P. herbarum. RAPD profiles of P. herbarum and P. fimeti has shown the maximum similarity, which indicates the genetic relatedness among these two species which were considered earlier as distinct species based on morphological observation. PMID- 22815583 TI - Establishment of lacZ marked strain of phosphate solubilizing bacterium in the rhizosphere and its effect on plant growth in mungbean. AB - The establishment of lacZ marked strain of P-solubilizing bacterium Pseudomonas in the rhizosphere of mungbean (Vigna radiata) under pothouse conditions was studied. The lacZ marker was transferred to Pseudomonas P-36 on LB medium using donor strain of E. coli. The lacZ marked strain formed blue colonies on selective media and could be identified from soil on the basis of this character. The lacZ marked strain was able to survive in rhizosphere of mungbean under pothouse conditions and maintained a population of about 10(4) g(-1) of rhizosphere soils up to 60 days study period. Positive effect of inoculation with P-solubilizing bacterium on dry matter yield, P and N-uptake was observed using rock phosphate and single super phosphate as P sources with and without farmyard amendment. PMID- 22815584 TI - Optimization of extraction of beta-endoglucanase from the fermented bran of Aspergillus niger. AB - A local isolate of Aspergillus niger was cultivated under optimal growth conditions on wheat bran in solid state fermentation. beta-endoglucanase from fermented bran was separately extracted with different solvents to test recovery of enzyme. Among solvents tested, distilled water served the best leachate. Conditions were further optimized with this leachate. Two washes of fermented bran with the leachate for 30 min each under shaking conditions in a ratio of 1 g of wheat bran: 4 ml of distilled water together yielded maximum recovery of 16.7 U/g of wheat bran. PMID- 22815585 TI - Optimization of a protein extraction technique for fungal proteomics. AB - Protein extraction is a critical step in any proteomics study. Since most fungi possess a robust cell wall, efficient isolation of total proteins has become challenge to fungal proteomics. To circumvent this bottleneck of fungal proteomics, we standardized a protocol named as Mg/CHAPS extraction by comparing with an established method of protein extraction (Tris/EDTA extraction), using 2 DE and MALDI-TOF MS. Total mycelial proteins were isolated using both protocols from Magnaporthe grisea (causal agent of rice blast disease). Six hundred forty two proteins were resolved on two 2-DE gels corresponding to mycelial proteomes isolated by Mg/CHAPS and Tris/EDTA. Mycelial proteome extracted by Mg/CHAPS showed higher number protein spots than to Tris/EDTA. Quantitative analysis of mycelial proteome, histogram and MS analyses of a protein spot suggested that Mg/CHAPS extraction is more effective than the widely used protocol i.e. Tris/EDTA. PMID- 22815586 TI - Lignin peroxidases of some indigenous ligninolytic fungi: secretion and enzymatic characteristics. AB - Secretion and enzymatic characteristics of lignin peroxidases from Gloeophyllum sepiarium MTCC 1170, Cladosporium herbarum MTCC 346, Lenzites betulina MTCC 1183, Daedalea flavida MTCC 145, Hexagonia teruis MTCC 1119 and Coirolopsis floccosa MTCC 1177 ligninolytic fungal strains have been reported. Secretion of lignin peroxidase by these ligninolytic fungal strains have been found to be in the range of 0.86 to 3.0 enzyme unit per ml of the culture medium. The enzymatic characteristics like K(m), pH and temperature optima of all the lignin peroxidases of the above fungal strains have been determined using veratryl alcohol and H(2)O(2) as the variable substrates. The K(m) values using veratryl alcohol as the substrate were found to be 65.0 MUM, 58.5 MUM, 63.0 MUM, 54.5 MUM, 54.6 MUM and 61.0 MUM respectively. The K(m) values using H(2)O(2) as the substrate were found to be 88.0 MUM, 86.0 MUM, 71.0 MUM, 67.0 MUM, 80.0 MUM and 78.0 MUM respectively. The pH optima values for lignin peroxidases of the above ligninolytic fungal strains were found to be 2.5, 2.4, 2.4, 2.25, 2.5 and 2.8 respectively, where as the temperature optima values were 25 degrees C, 24 degrees C, 25 degrees C, 23 degrees C, 24 degrees C and 25 degrees C respectively. PMID- 22815587 TI - Fungal flora of Nigerian currency notes in circulation in Benin City, Nigeria. AB - A mycological survey of Nigerian currency (naira) notes in circulation in Benin City was undertaken to determine the fungal species present, so as to bring to light the health implications of their presence. A total of 84 naira notes comprising 20, 50, 100, 200 and 500 naira denominations were obtained randomly from a bank, commuter bus, food canteen, and open market. Four-day old Potato Dextrose Agar cultures of diluted water diffusate of the currency notes were examined under the microscope and fungi were isolated and identified. The isolated fungi and their frequencies of isolation were A. flavus (90.5), A. fumigatus (42.9), A. terreus (57.1), A. flavipes (26.2) A. niger (59.5), Candida albicans (92.3), Rhizopus sp (2.7), Penicillium sp (4.0), Fusarium sp (12.8), and Saccharomyces cerevisae (16.1%). The frequencies of fungi isolated from the various denominations varied significantly at 0.05 probability. While the 50 naira denomination had the highest colony count (mean of means = 41 colonies/ml) the 500 naira had the lowest colony count (mean of means =8.3 colonies/ml). The high occurrence of fungi in the currency notes is of public health concern. PMID- 22815588 TI - Marine blue green algae: Microorganism of bioactive potential. PMID- 22815592 TI - Siblings of Military Servicemembers: A Qualitative Exploration of Individual and Family Systems Reactions. AB - How does having a sibling in the military affect young adults? Despite increasing attention to the challenges faced by spouses and children of servicemembers, the siblings of servicemembers have been largely ignored. This qualitative investigation uses unstructured narratives to explore siblings' perceptions of changes in their lives and changes in the family of origin associated with having a family member enlist in the United States military. Thematic analyses revealed an acute period of conflict followed by reorganization, awareness of the parents' distress, changes in the emotional climate of the family, shifts in family roles, admiration for the military sibling, and increased meaning and purpose for the family following the servicemember's enlistment. Computer-assisted text analyses revealed both positive and negative emotional content associated with the siblings' military service. For professional psychologists who come into contact with siblings of servicemembers, it is important to recognize that military enlistment can have ripple effects and complicate other common individual and family stresses. More generally, it is important to provide siblings and the family of origin with information about what to expect during and after the servicemember's enlistment, especially since these families may lack support and contact from others going through similar transitions. PMID- 22815589 TI - The genus Cladosporium. AB - A monographic revision of the hyphomycete genus Cladosporium s. lat. (Cladosporiaceae, Capnodiales) is presented. It includes a detailed historic overview of Cladosporium and allied genera, with notes on their phylogeny, systematics and ecology. True species of Cladosporium s. str. (anamorphs of Davidiella), are characterised by having coronate conidiogenous loci and conidial hila, i.e., with a convex central dome surrounded by a raised periclinal rim. Recognised species are treated and illustrated with line drawings and photomicrographs (light as well as scanning electron microscopy). Species known from culture are described in vivo as well as in vitro on standardised media and under controlled conditions. Details on host range/substrates and the geographic distribution are given based on published accounts, and a re-examination of numerous herbarium specimens. Various keys are provided to support the identification of Cladosporium species in vivo and in vitro. Morphological datasets are supplemented by DNA barcodes (nuclear ribosomal RNA gene operon, including the internal transcribed spacer regions ITS1 and ITS2, the 5.8S nrDNA, as well as partial actin and translation elongation factor 1-alpha gene sequences) diagnostic for individual species. In total 993 names assigned to Cladosporium s. lat., including Heterosporium (854 in Cladosporium and 139 in Heterosporium), are treated, of which 169 are recognized in Cladosporium s. str. The other taxa are doubtful, insufficiently known or have been excluded from Cladosporium in its current circumscription and re-allocated to other genera by the authors of this monograph or previous authors. TAXONOMIC NOVELTIES: Cladosporium allicinum (Fr.: Fr.) Bensch, U. Braun & Crous, comb. nov., C. astroideum var. catalinense U. Braun, var. nov., Fusicladium tectonicola (Yong H. He & Z.Y. Zhang) U. Braun & Bensch, comb. nov., Septoidium uleanum (Henn.) U. Braun, comb. nov., Zasmidium adeniae (Hansf.) U. Braun, comb. nov., Zasmidium dianellae (Sawada & Katsuki) U. Braun, comb. nov., Zasmidium lythri (Westend.) U. Braun & H.D. Shin, comb. nov., Zasmidium wikstroemiae (Petch) U. Braun, comb. nov. PMID- 22815593 TI - Comparison of Overhauser DNP at 0.34 and 3.4 T with Fremy's Salt. AB - Dynamic nuclear polarization (DNP) is investigated in the liquid state using a model system of Fremy's salt dissolved in water. Nuclear magnetic resonance signal enhancements at 0.34 and 3.4 T of the bulk water protons are recorded as a function of the irradiation time and the polarizer concentration. The build-up rates are consistent with the T(1n) of the observed water protons at room temperature (for 9 GHz/0.34 T) and for about 50 +/- 10 degrees C at 94 GHz/3.4 T. At 94 GHz/3.4 T, we observe in our setup a maximal enhancement of -50 at 25 mM polarizer concentration. The use of Fremy's salt allows the determination of the saturation factors at 94 GHz by pulsed ELDOR experiments. The results are well consistent with the Overhauser DNP mechanism and indicate that higher enhancements at this intermediate frequency require higher sample temperatures. PMID- 22815595 TI - Preface to the first monograph. PMID- 22815594 TI - Alcohol industry influence on UK alcohol policy: A new research agenda for public health. AB - The British government has been criticised for according industry interests too much weight in alcohol policy-making. Consequently, it has been argued that alcohol strategy in the UK is built around policies for which the evidence base is weak. This has clear implications for public health. The purpose of this commentary is to map recent developments in UK alcohol policy and related debates within the alcohol policy literature, thus laying the foundations for a systematic examination of the influence of the alcohol industry on alcohol policy. It highlights the changing structure of the industry and summarises what is known about the positions and strategies of industry actors towards alcohol policy. In so doing, it aims to contribute not just to debates about alcohol policy, but to a broader understanding of health policy processes and the relationships between government and other stakeholders. It advances a new research agenda focused on the role of corporate actors in the field of alcohol policy and public health more broadly. PMID- 22815597 TI - Readers respond. PMID- 22815596 TI - Psychiatric Consequences of WTC Collapse and The Gulf War. AB - Along with political, economic, ethical, rehabilitative and military dimensions, psychopathological sequelae of war and terrorism also deserve our attention. The terrorist attack on the World Trade Centre ( W.T.C.) in 2001 and the Gulf War of 1990-91 gave rise to a number of psychiatric disturbances in the population, both adult and children, mainly in the form of Post-traumatic Stress disorder (PTSD). Nearly 75,000 people suffered psychological problems in South Manhattan alone due to that one terrorist attack on the WTC in New York and the Pentagon in Washington. In Gulf War I, morethat 1,00,000 US veterans reported a number of health problems on returning from war, whose claims the concerned government has denied in more than 90% cases. Extensive and comprehensive neurological damage to the brain of Gulf War I veterans has been reported by one study, as has damage to the basal ganglia in another, and Amyotrophic Lateral Sclerosis (ALS) in a third,possibly due to genetic mutations induced by exposure to biological and chemical agents, fumes from burning oil wells, landfills,mustard or other nerve gases. The recent Gulf War will no doubt give rise its own crop of PTSD and related disorders. In a cost-benefitanalysis of the post Gulf War II scenario, the psychopathological effects of war and terrorism should become part of the social audit any civilized society engages in. Enlightened public opinion must become aware of the wider ramifications of war and terrorism so that appropriate action plans can be worked out. PMID- 22815598 TI - Preface to the second monograph. PMID- 22815599 TI - Towards a suicide free society: identify suicide prevention as public health policy. AB - Suicide is amongst the top ten causes of death for all age groups in most countries of the world. It is the second most important cause of death in the younger age group (15-19 yrs.) , second only to vehicular accidents.Attempted suicides are ten times the successful suicide figures, and 1-2% attempted suicides become successful suicides every year. Male sex, widowhood, single or divorced marital status, addiction to alcohol ordrugs, concomitant chronic physical or mental illness, past suicidal attempt, adverse life events, staying in lodging homes or staying alone,or in areas with a changing population, all these conditions predispose people to suicides. The key factor probably is social isolation. An important WHO Study established that out of a total of 6003 suicides,98% had a psychiatric disorder. Hence mental health professionals havean important role to play in the prevention and management of suicide.Moreover, social disintegration also increases suicides, as was witnessed in the Baltic States following collapse of the Soviet Union. Hence, reducing social isolation, preventing social disintegration and treating mental disorders is the three pronged attack that must be the crux of any public health programme to reduce/prevent suicide. This requires an integrated effort on the part of mental health professionals (including crisis intervention and medication/psychotherapy), governmental measures to tackle poverty and unemployment, and social attempts toreorient value systems and prevent sudden disintegration of norms and mores. Suicide prevention and control is thus a movement which involves the state, professionals, NGOs, volunteers and an enlightened public.Further, the Global Burden of Diseases Study has projected a rise of more than 50% in mental disorders by the year 2020 (from 9.7% in 1990to 15% in 2020). And one third of this rise will be due to Major Depression. One of the prominent causes of preventable mortality issuicidal attempts made by patients of Major Depression. Therefore facilities to tackle this condition need to be set up globally on a warfooting by governments, NGOs and health care delivery systems, if morbidity and mortality of the world population has to be seriously controlled . The need, first of all, is to identify suicide prevention as public health policy, just as we think in terms of Malaria or Polio eradication, or have achieved smallpox eradication. PMID- 22815600 TI - Answering two serious charges on suicide prevention. PMID- 22815601 TI - 1) How do we account for deaths like Jnaneshwara's and Rama's? PMID- 22815602 TI - Readers respond. PMID- 22815603 TI - Preface to the third monograph. PMID- 22815605 TI - Readers respond. PMID- 22815604 TI - What shall we do about our concern with the most recent in psychiatric research? AB - Most clinicians and researchers are concerned with recent advances in psychiatry. This involves the danger whether something time-tested may get sidelined for extra-scientific reasons. That the pharmaceutical industry and superspecialist researcher may keep churning out new findings to impress audiences is only a partial truth. Research progresses by refutation and self-correction. Acceptance in science is always provisional; changing paradigms, frameworks of enquiry and raising new questions is integral to break through in scientific knowledge. Hence, there is in science a constant concern with the new. Moreover, the number of treatment non- responders to the time-tested swells with time, and researchers feel challenged to find ways and means of resolving their difficulties. Newer challenges need newer strategies. Obsession with the most recent can lead us astray, but a healthy evidence-based acceptance of the new is essential for advancement in psychiatric research. As indeed of research in all fields of medicine. And of science in general. The role of lithium and newer mood stabilizers in bipolar disorders are taken as examples to highlight this point. PMID- 22815606 TI - Preface to the fourth monograph. PMID- 22815607 TI - Replicative nature of Indian research, essence of scientific temper, and future of scientific progress. AB - A lot of Indian research is replicative in nature. This is because originality is at a premium here and mediocrity is in great demand. But replication has its merit as well because it helps in corroboration. And that is the bedrock on which many a fancied scientific hypothesis or theory stands, or falls. However, to go from replicative to original research will involve a massive effort to restructure the Indian psyche and an all round effort from numerous quarters.The second part of this paper deals with the essence of scientific temper,which need not have any basic friendship, or animosity, with religion, faith, superstition and other such entities. A true scientist follows two cardinal rules. He is never unwilling to accept the worth of evidence, howsoever damning to the most favourite of his theories. Second, and perhaps more important, for want of evidence, he withholds comment. He says neither yes nor no.Where will Science ultimately lead Man is the third part of this essay. One argument is that the conflict between Man and Science will continue tilleither of them is exhausted or wiped out. The other believes that it is Science which has to be harnessed for Man and not Man used for Science. And with the numerous checks and balances in place, Science will remain an effective tool for man's progress. The essential value-neutrality of Science will have to be supplemented by the values that man has upheld for centuries as fundamental, and which religious thought and moral philosophy have continuously professed. PMID- 22815608 TI - Some answers. PMID- 22815609 TI - Preface to the fifth monograph. PMID- 22815610 TI - Gandhi on religion, faith and conversion: secular blueprint relevant today. AB - Gandhi believed in judging people of other faiths from their stand point rather than his own. He welcomed contact of Hinduism with other religions, especially the Christian doctrines, for he did not want to be debarred from assimilating good anywhere else. He believed a respectful study of other's religion was a sacred duty and it did not reduce reverence for one's own. He was looking out for those universal principles which transcended religion as a dogma. He expected religion to take account of practical life, he wanted it to appeal to reason and not be in conflict with morality. He believed it was his right and duty to point out the defects of his own religion, but to desist from doing so with other's faith. He refused to abuse a man for his fanatical deeds for he tried to see them from the other person's point of view. He believed Jesus expressed the will and spirit of God but could not accept Jesus as the only incarnate son of God. If Jesus was like God or God himself, then all men were like God or God Himself. But neither could he accept the Vedas as the inspired word of God, for if they were inspired why not also the Bible and the Koran? He believed all great religions were fundamentally equal and that there should be innate respect for them, not just mutual tolerance. He felt a person wanting to convert should try to be a good follower of his own faith rather than seek goodness in change of faith. His early impressions of Christianity were unfortunate which underwent a change when he discovered the New Testament and the Sermon on the Mount, whose ideal of renunciation appealed to him greatly. He thought Parliament of Religions or International Fellowship of Religions could be based only on equality of status, a common platform. An attitude of patronising tolerance was false to the spirit of international fellowship. He believed that all religions were more or less true, but had errors because they came to us though imperfect human instrumentality. Religious symbols could not be made into a fetish to prove the superiority of one religion over another.In a multi-religious secular polity like that of India, Gandhi's ideas on religion and attitude toward other religions could serve as a secular blueprint to ponder over and implement. PMID- 22815611 TI - 1. Some answers. PMID- 22815613 TI - Preface to the sixth monograph. PMID- 22815612 TI - 2. Pandora's Box. PMID- 22815614 TI - The goal : health for all the commitment : all for health. AB - Primary Health Care was the means by which Health for All by the Year 2000 AD was to be achieved. And Health for All was possible only if All were mobilised for Health. This meant not just governments and medical establishments, but people themselves. Primary health care is essentially health care made universally accessible to individuals and families in the community by means acceptable to them, through their full participation and at a cost the community and country can afford. And in working for such positive health, the role of health experts or doctors is the same as that of a gardener faced with insects, moulds and weeds. Their work is never done. Primary health care is a health conscious people's movement. Its implementation depends on knowledge of proper disposal of services and a persistent demand from an active and quality conscious consumer the public. Strong political will, community participation and intersectoral coordination are its basic principles. However, the National Health Policy of India, 1983, was hardly debated in both houses when tabled. Both NHP 1983 and 2002 failed to confer the status of a Right to health, while most other nations are planning newer strategies to put Right to Health and Medical Services into practical use. Community participation in health is an aphorism that awaits genuine realisation in many countries of the world, notably of the third world. India, unfortunately, is no exception. Progressive Five Year Plans in India have reduced percentage spending over health as a part of GDP, which is an alarming state of affairs. Public awareness and activism alone can remedy this alarming condition. The people should not forget that health is not only a commodity that a benevolent government/ institution/ individual bestows on them. It has to be earned and maintained by the individual himself. Health problems cannot be solved in isolation. They will ultimately be part of our struggle for an egalitarian society, because better health care is a sign of a more evolved one. PMID- 22815615 TI - Readers respond. PMID- 22815616 TI - Psychiatry, science, religion and health. PMID- 22815618 TI - Profile in courage. PMID- 22815619 TI - What he meant to me. PMID- 22815620 TI - The Moral Dyad: A Fundamental Template Unifying Moral Judgment. PMID- 22815621 TI - The Associations between Structural Treatment Characteristics and Post-Treatment Functioning in Compulsory Residential Youth Care. AB - BACKGROUND: In 2005 a new compulsory residential treatment program was developed for adolescents in need for protection against themselves or their environment. OBJECTIVE: The aim of the present study was to examine the association of structural treatment characteristics of this new residential treatment program (i.e., duration of treatment, discharge status, and group composition in terms of sex) with post-treatment functioning. Additionally, the number of pre-treatment risk factors was included in the model. METHOD: A total of 301 adolescents (174 boys, 127 girls), with a mean age at time of admittance of 15.50 (SD = 1.26) participated in this study. The number of risk factors was derived from treatment files of the adolescents at time of entrance. Six months after discharge, adolescents participated in a telephone interview to measure ten post-treatment variables indicating how well they were doing. RESULTS: The results showed that duration of treatment was related to post-treatment living situation, in that adolescents who were in treatment for shorter durations were more likely to live on their own after treatment. For discharge status, findings suggested that adolescents who were regularly discharged had more frequent contact with their family; however, they also showed higher alcohol consumption 6 months after treatment. Group composition was related to the girls' official offending, indicating that girls placed in mixed-sex groups showed significantly fewer official police contacts than did girls in girls-only treatment groups. CONCLUSION: Overall, structural treatment characteristics were hardly related to the adolescents' functioning after treatment. Suggestions for future research are discussed. PMID- 22815622 TI - Generating Signals with Multiscale Time Irreversibility: The Asymmetric Weierstrass Function. AB - Time irreversibility (asymmetry with respect to time reversal) is an important property of many time series derived from processes in nature. Some time series (e.g., healthy heart rate dynamics) demonstrate even more complex, multiscale irreversibility, such that not only the original but also coarse-grained time series are asymmetric over a wide range of scales. Several indices to quantify multiscale asymmetry have been introduced. However, there has been no simple generator of model time series with "tunable" multiscale asymmetry to test such indices. We introduce an asymmetric Weierstrass function W(A) (constructed from asymmetric sawtooth functions instead of cosine waves) that can be used to construct time series with any given value of the multiscale asymmetry. We show that multiscale asymmetry appears to be independent of other multiscale complexity indices, such as fractal dimension and multiscale entropy. We further generalize the concept of multiscale asymmetry by introducing time-dependent (local) multiscale asymmetry and provide examples of such time series. The W(A) function combines two essential features of complex fluctuations, namely fractality (self-similarity) and irreversibility (multiscale time asymmetry); moreover, each of these features can be tuned independently. The proposed family of functions can be used to compare and refine multiscale measures of time series asymmetry. PMID- 22815623 TI - Modulation of matrix metalloproteinase activity by EDTA prevents posterior capsular opacification. AB - PURPOSE: To evaluate the effect of ethylenediaminetetraacetic acid (EDTA) on posterior capsular opacification (PCO) of rabbits and to assess its effect on intraocular tissues. METHODS: Modulation of matrix metalloproteinase (MMP) activity in the aqueous following cataract surgery in rabbits and its prevention by different doses of EDTA was determined by zymography. For evaluation of PCO, lensectomized rabbits were intracamerally injected with single dose of either 5 mg EDTA or normal saline. After one month, the degree of PCO was determined by slitlamp biomicroscopy, Miyake-Apple view, and histology of the lens capsule. The effect of EDTA on intra ocular pressure (IOP), corneal endothelial cells, and the retina was evaluated by tonometry, specular microscopy and scanning electron microscopy, and electroretinography. The concentration of EDTA in the aqueous was determined by high performance liquid chromatography (HPLC) at different time points. RESULTS: The MMP activity was significantly increased in the aqueous of the operated eyes, and EDTA reduced the degree of increase in a dose-dependent manner. EDTA treatment significantly reduced the degree of PCO (p<0.05). Histopathology of the lens capsule showed a reduction in the number of proliferating and migrating cells as well as MMP2 expression in the EDTA-treated eyes. EDTA treatment did not change the IOP; density, morphology and ultrastructure of the corneal endothelial cells; and electroretinography (ERG). EDTA was detectable in the aqueous humor up to 72 h following a single intracameral injection. CONCLUSIONS: EDTA reduces the degree of PCO by suppressing the MMP activity and it is not toxic to intra ocular structures at the concentration used. PMID- 22815624 TI - Fundus albipunctatus: novel mutations and phenotypic description of Israeli patients. AB - PURPOSE: To characterize the genetic defects associated with fundus albipunctatus (FAP) in patients in Israel. METHODS: Twenty patients with FAP from diverse ethnicities underwent ophthalmic and electroretinogram tests following the International Society for Clinical Electrophysiology of Vision protocol. Genomic DNA was extracted from peripheral blood. Mutation analysis of the 11-cis retinol dehydrogenase (RDH5) gene was performed with direct sequencing of PCR-amplified exons. RESULTS: Four novel RDH5 gene mutations were identified. Of them, the null mutations c.343C>T (p.R54X) and c.242delTGCC were most prevalent. Macular involvement was present in two patients who carry different mutation types. CONCLUSIONS: Mutation analysis of the RDH5 gene in the present series revealed four novel mutations and a previously reported one. No significant genotype phenotype correlation was found. PMID- 22815625 TI - Mutation screening of the PCDH15 gene in Spanish patients with Usher syndrome type I. AB - PURPOSE: PCDH15 codes for protocadherin-15, a cell-cell adhesion protein essential in the morphogenesis and cohesion of stereocilia bundles and in the function or preservation of photoreceptor cells. Mutations in the PCDH15 gene are responsible for Usher syndrome type I (USH1F) and non-syndromic hearing loss (DFNB23). The purpose of this work was to perform PCDH15 mutation screening to identify the genetic cause of the disease in a cohort of Spanish patients with Usher syndrome type I and establish phenotype-genotype correlation. METHODS: Mutation analysis of PCDH15 included additional exons recently identified and was performed by direct sequencing. The screening was performed in 19 probands with USH already screened for mutations in the most prevalent USH1 genes, myosin VIIA (MYO7A) and cadherin-23 (CDH23), and for copy number variants in PCDH15. RESULTS: Seven different point mutations, five novel, were detected. Including the large PCDH15 rearrangements previously reported in our cohort of patients, a total of seven of 19 patients (36.8%) were carriers of at least one pathogenic allele. Thirteen out of the 38 screened alleles carried pathogenic PCDH15 variants (34.2%). CONCLUSIONS: Five out of the seven point mutations reported in the present study are novel, supporting the idea that most PCDH15 mutations are private. Furthermore, no mutational hotspots have been identified. In most patients, detected mutations led to a truncated protein, reinforcing the hypothesis that severe mutations cause the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment. PMID- 22815626 TI - A selective inhibitor of the Rho kinase pathway, Y-27632, and its influence on wound healing in the corneal stroma. AB - PURPOSE: Our study examined the effect of a selective Rho kinase inhibitor, Y 27632, on corneal wound healing and potential stromal scarring after superficial keratectomy. METHODS: Rabbit keratocytes were induced into myofibroblasts by transforming growth factor beta1 (TGFbeta1) either with or without Y-27632. Then alpha-smooth muscle actin (alpha-SMA) was examined by immunohistochemistry and western blotting, and the contractility of the seeded collagen gels was measured. Y-27632 eye drops (or vehicle only) were administered to eyes after a superficial keratectomy, and the tissue was examined by immunohistochemistry for alpha-SMA, collagen types I, II, and III, and keratan sulfate. Electron microscopy was conducted with and without histochemical contrasting of sulfated proteoglycans. RESULTS: Spindle-like cells in culture constituted 99.5+/-1.1% with TGFbeta1 stimulation, but 3.5+/-1.0% after TGFbeta1 and Y-27632 treatment (p<0.01, n=6). alpha-SMA was seen in 4% of TGFbeta1-treated cells, but in only 0.3% of cells with Y-27632 added (p<0.01, n=6), which was confirmed by western blotting. Y 27632 also inhibited the TGFbeta1-induced contraction of seeded collagen gels. After superficial keratectomies, collagen type I and keratan sulfate were unchanged by Y-27632 application. Collagen type II was not detected in Y-27632 or vehicle-only corneas. With Y-27632 treatment, alpha-SMA expression increased and the collagen type III signal became in the weaker subepithelial area. Interestingly, bundles of aligned and uniformly spaced collagen fibrils were more prevalent in keratocytes in Y-27632-treated corneas, which is reminiscent of fibripositor-like structures that have been proposed as a mechanism of matrix deposition in embryonic connective tissues. CONCLUSIONS: Y-27632 inhibits keratocyte-to-myofibroblast transition, and its topical application after a superficial lamellar keratectomy elicits an altered wound healing response, with evidence of an embryonic-type deposition of collagen fibrils. PMID- 22815627 TI - Analysis of FOXD3 sequence variation in human ocular disease. AB - PURPOSE: The migratory neural crest cell population makes a significant contribution to the anterior segment structures of the eye. Consequently, several anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. The forkhead box D3 (FOXD3) gene encodes a forkhead transcription factor that plays an important role in neural crest specification in vertebrates and therefore may be involved in human eye disease. METHODS: We screened 310 probands with developmental ocular conditions for variations in FOXD3. RESULTS: Six nonsynonymous FOXD3 variants were identified. Four of these changes, c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), and c.818_829dup (p.Arg273_Gly276dup), affected conserved regions and were observed primarily in probands with aniridia or Peters anomaly; out of these four variants, one, p.Arg273_Gly276dup, was not detected in control populations and two, p.Pro120Leu and p.Asn173His, were statistically enriched in cases with aniridia or Peters anomaly. The p.Arg273_Gly276dup variant was seen in a proband with aniridia as well as two additional unrelated probands affected with anophthalmia or congenital cataracts. The p.Asn173His variant affects Helix 2 of the DNA-binding domain and was observed in two unrelated patients with Peters anomaly or aniridia; in both cases, one parent carried the same allele. CONCLUSIONS: FOXD3 variants increase the risk of anterior segment dysgenesis phenotypes in humans. The p.Asn173His mutation affects a residue in the forkhead domain that is 100% conserved among vertebrate orthologs and is predicted to participate in protein-protein interactions. Its phenotypic effects may be modulated by transcriptional cofactors which have yet to be identified. PMID- 22815628 TI - Mutation analysis of PAX6 in inherited and sporadic aniridia from northeastern China. AB - PURPOSE: Haplo-insufficiency at the paired box gene 6 (PAX6) locus causes aniridia,which is characterized by iris hypoplasia and other anterior and posterior eye defects leading to poor vision. This study aimed to identify novel PAX6 mutations that lead to familial and sporadic aniridia in northeastern China. METHODS: Two aniridia patients from a family and a sporadic patient underwent full ophthalmologic examinations. Genomic DNA was isolated from the affected individuals, 5 noncarriers in the family and 100 healthy normal controls. The coding regions and the adjacent intronic sequence of PAX6 were amplified by polymerase chain reaction (PCR) and direct bidirectional sequencing. RESULTS: A nonsense mutation in exon 9 (c.718C>T) was identified in the patients but not in any other unaffected families. A C>T substitution at codon 240 converts an arginine codon (CGA) to a termination codon (TGA).The same mutation was detected in the sporadic patient by chance. CONCLUSIONS: A mutation in the PAX6 gene was confirmed to be capable of causing the classic aniridia phenotype. This is the first report on the "hotspot" c.718C>T transition from northeastern Chinese families. PMID- 22815629 TI - Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes. AB - PURPOSE: To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta induced) gene that causes granular corneal dystrophy type 2 (GCD2). METHODS: We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors. RESULTS: We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another. CONCLUSIONS: GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary. PMID- 22815630 TI - Evaluation of NTF4 as a causative gene for primary open-angle glaucoma. AB - PURPOSE: The neurotrophin-4 (NTF4) gene has been recently implicated in primary open-angle glaucoma (POAG). In this study, we investigated the implication of NTF4 in POAG among three Chinese cohorts. METHODS: The coding regions and exon intron boundaries of NTF4 was sequenced in 950 unrelated Chinese subjects, including a Hong Kong cohort of 390 patients and 230 controls, a Shantou cohort of 130 patients, and a Beijing cohort of 200 patients. Constructs carrying the detected variants were generated using site-directed mutagenesis and transfected into HeLa cells, followed by solubility and migration analyses. RESULTS: Three variants were identified. p.Pro151Pro was detected in three POAG patients and one control subject. Two novel missense variants, p.Gly157Ala and p.Ala182Val, were identified each in one POAG patient from the Hong Kong cohort, but not in controls. Functional assays showed that the p.Gly157Ala mutant protein was less soluble in Triton X-100, and that migration of HeLa cells transfected with either mutant construct was less than cells transfected with the wildtype. CONCLUSIONS: The NTF4 variants p.Gly157Ala and p.Ala182Val have been shown to be functional mutations, occurring in 2 of a total of 720 Chinese POAG patients. NTF4 is functionally related to POAG pathogenesis but its mutation frequency is low. Therefore, NTF4 does not have a major contribution in the molecular genetics of POAG. PMID- 22815632 TI - COL1A2 polymorphic markers confer an increased risk of neovascular age-related macular degeneration in a Han Chinese population. AB - PURPOSE: We have previously documented that neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) have multiple different clinical and genetic characteristics. In this study, we investigated the association of rs42524 in the alpha-2 type I collagen (COL1A2) gene, which has been identified as a risk variant for intracranial aneurysm, with nAMD and PCV in a Han Chinese population. METHODS: The study prospectively recruited 195 patients with PCV, 136 patients with nAMD, and 181 control individuals. We genotyped the rs42524 polymorphism of COL1A2 using the Multiplex SNaPshot System and direct DNA sequencing. Genotype and allele frequencies were evaluated with PLINK software. RESULTS: The rs42524 polymorphism was modestly significantly associated with nAMD [minor allele: G, p(allelic)=0.04253, odds ratio=0.5285 (95% confidence interval: 0.2832-0.9866)], but not with PCV [minor allele: G, p(allelic)=0.4164, odds ratio=1.2110 (95% confidence interval: 0.7631-1.9210)]. The pvalues for the additive model were significant for nAMD but not for the dominant or recessive models. None of the models for PCV were statistically significant. The size of our sample cohort resulted in a post hoc power of more than 80% to detect associations of rs42524 with nAMD and PCV. CONCLUSIONS: The rs42524 polymorphism is a risk allele for nAMD in a Han Chinese population. rs42524 in COL1A2 confers different levels of susceptibility to nAMD and PCV. PMID- 22815631 TI - Spatial expression patterns of autophagy genes in the eye lens and induction of autophagy in lens cells. AB - PURPOSE: Mutation of the autophagy gene FYVE (named after the four cysteine-rich proteins: Fab 1 [yeast orthologue of PIKfyve], YOTB, Vac 1 [vesicle transport protein], and EEA1) and coiled coil containing 1 (fyco1) causes human cataract suggesting a role for autophagy in lens function. Here, we analyzed the range and spatial expression patterns of lens autophagy genes and we evaluated whether autophagy could be induced in lens cells exposed to stress. METHODS: Autophagy gene expression levels and their spatial distribution patterns were evaluated between microdissected human lens epithelium and fibers at the mRNA and protein levels by microarray data analysis, real-time PCR and western blot analysis. Selected autophagy protein spatial expression patterns were also examined in newborn mouse lenses by immunohistochemistry. The autophagosomal content of cultured human lens epithelial cells was determined by counting the number of microtubule-associated protein 1 light chain 3B (LC3B)-positive puncta in cells cultured in the presence or absence of serum. RESULTS: A total of 42 autophagy genes were detected as being expressed by human lens epithelium and fibers. The autophagosomal markers LC3B and FYCO1 were detected throughout the newborn mouse lens. Consistently, the autophagy active form of LC3B (LC3B II) was detected in microdissected human lens fibers. An increased number of LC3B-positive puncta was detected in cultured lens cells upon serum starvation suggesting induction of autophagy in lens cells under stress conditions. CONCLUSIONS: The data provide evidence that autophagy is an important component for the function of lens epithelial and fiber cells. The data are consistent with the notion that disruption of lens autophagy through mutation or inactivation of specific autophagy proteins could lead to loss of lens resistance to stress and/or loss of lens differentiation resulting in cataract formation. PMID- 22815633 TI - Topical steroid and non-steroidal anti-inflammatory drugs inhibit inflammatory cytokine expression on the ocular surface in the botulinum toxin B-induced murine dry eye model. AB - PURPOSE: To evaluate the effect of the topical steroid, fluorometholone, and the non-steroidal anti-inflammatory drugs (NSAIDs), nepafenac and ketorolac, on inflammatory cytokine expression of the ocular surface in the botulium toxin B induced murine dry eye model. METHODS: Topical artificial tears (0.5% carboxymethylcellulose sodium), 0.1% fluorometholone, 0.1% nepafenac, and 0.4% ketorolac were applied 3 times per day in a dry eye mouse model 1 week after intralacrimal botulium toxin B (BTX-B) or saline (sham) injection. Tear production and corneal fluorescein staining were evaluated in all groups before injection at baseline and at 3 time points up to 4 weeks after injection. The pro inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) were evaluated by immunohistochemistry. RESULTS: BTX-B-injected mice showed significantly decreased aqueous tear production and increased corneal fluorescein staining at the 1 and 2 week time points compared with normal control and saline-injected mice. In the BTX-B-injected mice, immunofluorescent staining for TNF-alpha and IL-1beta in corneal and conjunctival epithelial cells increased significantly at the 2 and 4 week time points compared to that of normal and saline-injected mice, and returned to normal levels at the 4 week time point. Topical fluorometholone significantly improved corneal surface staining in the BTX-B-injected mice after 1 week of treatment, and increased the tear production within 2 weeks, but without statistical significant difference. Topical fluorometholone significantly decreased the staining of TNF-alpha and IL-1beta in corneal and conjunctival epithelia after 1-week treatment. Topical artificial tears, 0.1% nepafenac, and 0.4% ketorolac did not show obvious effects on tear production, corneal surface staining, and levels of IL-1beta and TNF-alpha expression in normal, and BTX-B-injected dry eye mice. CONCLUSIONS: Topical fluorometholone caused suppression of inflammatory cytokine expression on the ocular surface in the Botulium toxin B-induced murine dry eye model, while topical NSAIDs demonstrated no clearly beneficial effects. PMID- 22815634 TI - Repression of genes involved in melanocyte differentiation in uveal melanoma. AB - PURPOSE: Uveal melanoma (UM) has been the subject of intense interest due to its distinctive metastatic pattern, which involves hematogenous dissemination of cancerous cells toward the liver in 50% of patients. To search for new UM prognostic markers, the Suppressive Subtractive Hybridization (SSH) technique was used to isolate genes that are differentially expressed between UM primary tumors and normal uveal melanocytes (UVM). METHODS: A subtracted cDNA library was prepared using cDNA from uncultured UM primary tumors and UVM. The expression level of selected genes was further validated by cDNA microarray, semi quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence analyses. RESULTS: One hundred-fifteen genes were identified using the SSH technique. Microarray analyses comparing the gene expression profiles of UM primary tumors to UVM validated a significant differential expression for 48% of these genes. The expression pattern of selected genes was then analyzed by semi-quantitative RT-PCR and was found to be consistent with the SSH and cDNA microarray findings. A down-regulation of genes associated with melanocyte differentiation was confirmed in UM primary tumors. Presence of undifferentiated cells in the UM was demonstrated by the expression of stem cell markers ATP-binding cassette sub-family G member 2 (ABCG2) and octamer-binding protein 4 (OCT4). CONCLUSIONS: We demonstrated that the SSH technique is efficient to detect differentially expressed genes between UM and UVM. The genes identified in this study represent valuable candidates for further functional analysis in UM and should be informative in studying the biology of this tumor. In addition, deregulation of the melanocyte differentiation pathway revealed the presence of UM cells exhibiting a stem cell-like phenotype. PMID- 22815635 TI - Structural features of isomerizable aspartyl residues in human alpha-crystallins. AB - PURPOSE: The aspartyl (Asp) residues 58 and 151 in alphaA-crystallin, and Asp36 and Asp62 in alphaB-crystallin in human lenses are known to be highly isomerized with aging. We investigate structural environments of these isomerizable aspartyl residues in alpha-crystallins of human lenses. METHODS: To perform limited proteolysis experiments of purified human alphaA- and alphaB-crystallins, endoproteinase Asp-N (EC 3.4.24.33), which selectively cleaves the peptide bonds at the amino side of aspartyl and cysteic acid residues, was employed. By proteolysis approach coupled with the time-of-flight mass spectrometry (TOF-MS) method, we determined the cleavage points along protein sequences. RESULTS: Proteolysis by endoproteinase Asp-N occurred preferentially at the site of isomerizable aspartyl residues in alphaA- and alphaB-crystallins. CONCLUSIONS: It is found that isomerizable aspartyl residues in alpha-crystallins in human lenses were located not only in the solvent accessible area but also at regions displaying inherent conformational flexibility. PMID- 22815637 TI - A multiphoton microscope platform for imaging the mouse eye. AB - PURPOSE: To demonstrate the ability of multiphoton microscopy to obtain full three-dimensional high-resolution images of the intact mouse eye anterior chamber without need for enucleation. METHODS: A custom multiphoton microscope was constructed and optimized for deep tissue imaging. Simultaneous two-photon autofluorescence (2PAF) and second harmonic generation (SHG) imaging were performed. A mouse holder and stereotaxic platform were designed to access different parts of the eye for imaging. A reservoir for keeping the eye moist was used during imaging sessions. RESULTS: Non-invasive multiphoton images deep inside the anterior chamber of the mouse eye were obtained without the need for enucleation. The iris, corneal epithelium and endothelium, trabecular meshwork region and conjunctiva were visualized by the 2PAF and SHG signals. Identification of the anatomy was achieved by the intrinsic properties of the native tissue without any exogenous labeling. Images as deep as 600 microns into the eye were clearly demonstrated. Full three-dimensional image reconstructions of the entire anterior chamber were performed and analyzed using custom software. CONCLUSIONS: Multiphoton imaging is a highly promising tool for ophthalmic research. We have demonstrated the ability to image the entire anterior chamber of the mouse eye in its native state. These results provide a foundation for future in vivo studies of the eye. PMID- 22815636 TI - Quiescent keratocytes fail to repair MMC induced DNA damage leading to the long term inhibition of myofibroblast differentiation and wound healing. AB - PURPOSE: The purpose of this study was to determine the acute and long-term effects of mitomycin C (MMC) on quiescent rabbit corneal keratocytes regarding cell proliferation, myofibroblast differentiation and DNA repair. METHODS: Quiescent keratocytes cultured in serum-free media were exposed to various concentrations of MMC and then treated with transforming growth factor-beta (TGFbeta). DNA damage was evaluated in both cultured keratocytes and live rabbit eyes following treatment with MMC. The long-term ability of quiescent keratocytes to repair MMC induced damage in vivo was evaluated in rabbits treated with MMC 2 months before 100 MUm deep lamellar keratectomy (LK) injury. RESULTS: MMC significantly blocked TGFbeta-induced cell proliferation and myofibroblast differentiation in cultured quiescent keratocytes and altered the transcriptional regulation of macrophage chemotactic protein-1 (MCP-1) and alpha smooth muscle actin (alphaSMA). MMC also induced phosphorylation of the nuclear histone marker of DNA damage, gammaH2AX (a member of the H2A histone family), without induction of cell cycle entry or immediate DNA repair measured by Comet assay. In live rabbits, 0.2 mg/ml MMC significantly induced gammaH2AX nuclear immunostaining (p<0.05) throughout the cornea and corneas receiving 0.2 mg/ml MMC treatment 2 months before LK injury showed complete absence of any corneal scarring. CONCLUSIONS: MMC induces DNA damage to quiescent corneal keratocytes, which remains unrepaired, resulting in abnormal cell replication and gene transcription that leads to long-term effects on corneal repair. Overall these findings suggest that there may be long-term and perhaps permanent consequences to the application of MMC as an anti-fibrotic therapy. PMID- 22815638 TI - TMEM126A mutation in a Moroccan family with autosomal recessive optic atrophy. AB - PURPOSE: Nonsyndromic autosomal recessive optic atrophy (arOA) is extremely rare and its existence was disputed until a locus, optic atrophy 6 (OPA6), was mapped to 8q. Recently, a second locus, OPA7, was found on 11q in several families from North Africa, with one presumably ancestral mutation of transmembrane protein 126A (TMEM126A). Here we report an independently ascertained large consanguineous family of Moroccan descent with three siblings affected with nonsyndromic arOA. METHODS: Assuming autosomal recessive inheritance, we identified a locus on 11q with homozygosity mapping, with a multipoint logarithm of the odds score of 3.84, and sequenced two candidate genes. Direct sequencing of the complete coding sequence of TMEM126A revealed mutation p.Arg55X, homozygous in all affected siblings and heterozygous in both unaffected parents. RESULTS: This mutation was identical to that recently reported in families from North Africa, consistent with a single ancestral origin. In contrast to the recently reported patients, however, the siblings reported in this study had a relatively mild clinical course, with sudden onset in adolescence in the proband. Interestingly, the proband, but not the other affected siblings, had sensory-motor axonal neuropathy with electrophysiological data strongly suggestive of focal demyelinating abnormalities. An unaffected sibling had transient loss of vision after exercise, i.e., Uhthoff's sign of optic neuropathy, and was found to be a heterozygous carrier of the mutation. CONCLUSIONS: Our results confirm genetic heterogeneity in arOA, illustrate clinical variability between families with the p.Arg55X mutation including the description of a mild phenotype in a heterozygote, and underscore the implication of mitochondrial proteins in optic and peripheral neuropathy. PMID- 22815640 TI - Comparison of single-step reverse transepithelial all-surface laser ablation (ASLA) to alcohol-assisted photorefractive keratectomy. AB - PURPOSE: To evaluate postoperative pain, corneal epithelial healing, development of corneal haze, refractive outcomes, and corneal aberrations in a novel one step, modified transepithelial photorefractive keratectomy (PRK), termed All surface laser ablation (ASLA), compared to conventional, alcohol-assisted PRK. MATERIALS AND METHODS: Sixty eyes of 30 myopic patients were prospectively recruited to a randomized fellow eye study. Patients underwent conventional alcohol-assisted PRK in one eye (control group) and ASLA-modified transepithelial PRK in the other (30 eyes in each treatment arm). Primary endpoints were postoperative pain and haze scores at 1 day, 3 days, 1 week, and 1, 3, 6, and 12 months. Secondary endpoints included visual acuity at 1, 3, 6, and 12 months, corneal aberrations at 3, 6, and 12 months, and early and late onset haze. Refractive predictability, safety, and efficacy of the two methods were considered. RESULTS: The average age of the cohort was 29 years (standard deviation [SD]: 9; range: 18-46), and the average spherical equivalent refractive error was -4.18 diopters (SD: 1.9). At 3 days after surgery, the average pain score was 64% lower in the ASLA group (P < 0.0005). At this point, 96% of ASLA eyes had no epithelial defect, whereas 43% in the alcohol-assisted group did not achieve complete epithelial healing, and required replacement of bandage contact lens. The haze level was consistently lower in the ASLA group at all time points from 1 to 6 months. CONCLUSION: This study shows that the ASLA technique may have a future role in refractive surgery, due to the fact that it offers faster epithelial healing, lower pain scores, and significantly less haze formation. PMID- 22815641 TI - Proposal of a novel classification of leukocorias. AB - BACKGROUND: To report a case series of nine patients presenting with leukocoria without lens opacification or retrolental abnormalities and to propose a novel classification for leukocoria. METHODS: An institutional and retrospective study including a case series of patients assisted in the Congenital Cataract Section of Federal University of Sao Paulo, Brazil, during the period between 2005 and 2010 with prelenticular leukocoria and clear lens. RESULTS: Nine patients younger than 4 years old presented with the diagnosis of unilateral prelenticular opacities without cataract formation. Echography in all patients revealed no posterior segment or lens abnormalities in the affected eye. Among the patients, three had idiopathic prelenticular membrane, two presented with juvenile xanthogranuloma with secondary pupillary membrane, one had persistent fetal pupillary membrane, one had prelenticular membrane due to congenital toxoplasmosis, one presented with pupillary membrane due to hyphema caused by iris hemangioma, and one had anterior segment persistent fetal vasculature. CONCLUSIONS: This case series of patients presented unilateral prelenticular leukocoria without lens opacification or posterior segment abnormalities. Several etiologies were associated with this condition. The correct diagnosis is important in order to avoid clear lens extraction. A new classification of leukocoria is proposed herein including: prelenticular leukocoria, lenticular leukocoria, retrolenticular leukocoria, and mixed presentation leukocoria. PMID- 22815639 TI - SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU). AB - PURPOSE: SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. METHODS: SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme linked immunosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. RESULTS: SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-gamma and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN gamma transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT/Def6 KO mice resembled their wild type (WT) controls, however, in the levels of their serum antibody against IRBP, the antigen presenting capacity of their dendritic cells, the proportion of cells expressing Foxp3 and the immunosuppressive activity of their T-regulatory cells. CONCLUSIONS: SLAT/Def6 KO mice exhibit reduced capacity to develop ocular inflammation and cellular activity when immunized with IRBP. Our study provides new data showing that SLAT/Def6 plays a major role in the T cell-mediated autoimmune processes that bring about the inflammatory eye disease, EAU. PMID- 22815642 TI - Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. AB - PURPOSE: The purpose of this study was to investigate the clinical outcomes of bromfenac ophthalmic solution 0.09% once daily (QD) and nepafenac 0.1% ophthalmic suspension three times daily following cataract extraction with posterior chamber intraocular lens implantation, specifically looking at any differences in Early Treatment Diabetic Retinopathy Study visual acuities, macular volume, and/or retinal thickness changes. METHODS: Subjects were randomly assigned to receive either bromfenac (n = 10) QD or nepafenac (n = 10) three times daily. Dosing began 3 days before cataract surgery, continuing to day 21 postsurgery. In addition to the investigated nonsteroidal antiinflammatory drug regimen, all subjects received antiinfective intraoperative and postoperative standard of care. Subjects were followed at 1 day and 1, 3, and 6 weeks postoperatively. Study visit assessments included best-corrected visual acuity, biomicroscopy, summed ocular inflammation score (anterior chamber cells and flare grading), intraocular pressure measurement, adverse event recording, and concomitant medication review. Optical coherence tomography was performed at 1, 3, and 6 weeks. RESULTS: Both treatment groups had similar baseline measurements. Outcomes for mean letters read (P = 0.318), mean change in macular volume (P = 0.665), and retinal thickness (P = 0.552) were not statistically different between the groups from baseline through week six, although independently only the bromfenac group demonstrated a statistically significant improvement in letters gained from baseline to week six (P = 0.040). In the same time period, mean macular volume and retinal thickening worsened in the nepafenac group, demonstrating a statistically significant increase (P = 0.006) at week six for macular volume when compared to baseline. One subject in the nepafenac group experienced recurrent inflammation at week six, was unmasked, and then rescued with bromfenac 0.09% QD and difluprednate 0.05% QD. CONCLUSION: Both bromfenac and nepafenac resulted in positive clinical outcomes of Early Treatment Diabetic Retinopathy Study visual acuities. Postoperative measurements of macular volume and retinal thickness of bromfenac subjects showed a trend toward improved vision, less retinal thickening, and more stable macular volumes overall. PMID- 22815643 TI - Intraocular pressure in Japanese diabetic patients. AB - BACKGROUND: To determine whether the intraocular pressure (IOP) in diabetic patients is significantly different from that in nondiabetic patients. METHODS: The medical records of all patients who were initially examined in the Department of Ophthalmology, Kansai Medical University, Takii Hospital were reviewed. At the initial examination, patients had a detailed interview and underwent a comprehensive ophthalmic examinations. All patients were over 20 years of age and did not have glaucoma. RESULTS: A total of 703 patients were evaluated. The mean (+/-standard error) IOP of the diabetic patients was 15.5 +/- 0.2 mmHg (n = 206), and was significantly higher than the 14.0 +/- 0.1 mmHg (n = 497) in the nondiabetic patients (P < 0.0001). The IOP was negatively correlated with age (r = -0.202; P = 0.024) in the diabetic patients and was weakly but significantly correlated with the glycosylated hemoglobin (HbA(1c)) level (r = 0.240; P = 0.015) in the group with diabetic retinopathy. CONCLUSION: The significantly higher IOP in diabetic patients and positive correlation of IOP with HbA(1c) levels in patients with diabetic retinopathy indicate that IOP in diabetic patients is higher, especially in those with poor control of diabetes. PMID- 22815645 TI - Thrombotic microangiopathy associated with use of interferon-beta. AB - Interferon-beta is widely used for the treatment of relapsing multiple sclerosis. The drug is usually well tolerated, but autoimmune adverse effects, including kidney disease, have been reported. Only a few cases of hemolytic uremic syndrome thrombotic microangiopathy associated interferon-alpha have been described so far, and even fewer with beta-interferon. We report a patient who developed thrombotic microangiopathy during treatment with interferon-beta and improved after discontinuation and steroid therapy. Complement cascade and antiphospholipid antibodies are investigated. The spectrum of renal diseases associated with interferon-beta treatment is also reviewed. PMID- 22815644 TI - Potential use of STAT3 inhibitors in targeted prostate cancer therapy: future prospects. AB - In 2012, prostate cancer will once again be the second-leading cause of cancer death of American males. Although initially treatable, prostate cancer can recur in a hormone refractory form that is not responsive to current available therapies. The mortality rate associated with hormone refractory prostate cancer is high, and there is an urgent need for new therapeutic agents to treat prostate cancer. A common feature of prostate cancer is the dependence on activated signal transducer and activator of transcription 3 (STAT3), a transcription factor, for survival. More important, inhibition of STAT3 has been shown to induce apoptosis in prostate cancer cells. In recent years, inhibitors of STAT3 have emerged as promising molecular candidates for targeted prostate cancer therapy. The aim of this review is to examine the role of STAT3 in prostate cancer and how inhibitors of STAT3 could advance the quest for treatment of the disease. Janus kinase 2 (JAK2)-targeted therapy appears very promising in the treatment of prostate cancer. It has been shown to decrease symptoms associated with myeloproliferative disorders and increase overall survival of patients compared with the best available therapy. In addition to improved outcome, many JAK2 inhibitors have been found to be tolerable with no adverse impact on quality of life. As such, JAK2 inhibitors may play an important role in the management of patients with prostate cancer. Current studies are evaluating the role of JAK2 inhibitors in solid tumors. Pending clinical trial results will determine the future direction of JAK2 inhibitors in the treatment of patients with prostate cancer. PMID- 22815646 TI - Impact of short-term antiretroviral therapy (START) on some fibrinolytic markers in HIV-infected Nigerian adults: preliminary findings from the START study. AB - BACKGROUND: Derangement in fibrinolytic markers can result in thrombosis and cardiovascular problems. Antiretroviral therapy (ART) has been reported to affect the levels of these markers. It is unclear how long a patient can be exposed to ART before the effect of the drugs on the fibrinolytic markers becomes noticeable; this short-term antiretroviral therapy (START) study aimed to answer this question. METHODS: Twenty human immunodeficiency virus (HIV)-positive subjects on ART and 20 controls (non-ART) were progressively monitored for three months. CD4 T-cell count was determined while D-dimer, t-PA, and PAI-1 parameters were determined. RESULTS: CD4 T-cell count increased from 192 MUL/mL at baseline to 323 MUL/mL at month 3 among patients on ART. D-dimer concentrations decreased from 301.0 MUL/mL at baseline to 172.0 MUL/mL at month 2, then increased to 226.0 MUL/mL at the end of the third month. The median baseline concentration of PAI-1 at the beginning of therapy was 14.0 MUg/mL, which increased progressively to 18.2 MUg/mL at the end of the third month. The baseline concentration of t-PA at the beginning of therapy was 5.15 MUg/mL. This progressively declined to 1.10 MUg/mL at the end of the first month and reached 1.45 MUg/mL and 1.5 MUg/mL at the end of the second and third months, respectively. D-dimer was positively and significantly correlated with CD4 cell counts in both AIDs-associated retrovirus (ARV) and non-ARV patients (r = -0.304, P < 0.01 vs r = -0.477, P < 0.001). t-PA was negatively correlated with CD4 T-lymphocytes in those undergoing ART (r = 0.294, P < 0.01). CONCLUSION: A progressive increase in PAI-1 and steady decline in t-PA concentrations within 3 months of commencement of ART could predispose patients to thrombotic disorders earlier than is expected. Pre-thrombotic assessment during therapy is therefore advocated. PMID- 22815647 TI - Quantifying the increasing use of anti-vascular endothelial growth factor therapy in ophthalmology. AB - INTRODUCTION: Bevacizumab (Avastin; Genetech Inc., South San Francisco, CA) and ranibizumab (Lucentis, Genetech Inc.) are two anti-Vascular Endothelial Growth Factor (VEGF) agents used in increasing amounts off-label to treat ocular conditions. To date, no study has quantified how far reaching these therapies have been in treating eye disease and compared their off-label use to the number of clinical trials performed. METHOD: A systematic search of Ovid MEDLINE using the keywords bevacizumab and ranibizumab limited to "Case Reports" was used as an index of the number of diseases treated. Each keyword was also limited to "Clinical Trials, All" and "Phase III Clinical Trials" to discern the quality of evidence for these uses. RESULTS: Bevacizumab has been utilized for the treatment of 58 different ocular conditions, but only 14 conditions were studied in a trial, and none were part of a phase III clinical trial. Ranibizumab has been used for 17 different eye conditions, with only 6 studied in a trial and only 1 disease, "wet" age-related macular degeneration reported in 4 phase III trials. In the case reports, there were 21 different adverse events ascribed to bevacizumab and 2 to ranibizumab with retinal pigment epithelial tears being the most common. CONCLUSION: Bevacizumab is one of the most far reaching drugs in ophthalmology and even medicine, but it is not yet supported by high quality evidence. The much higher cost of ranibizumab may be responsible for bevacizumab's popularity among eye specialists. Patients should be fully informed about the off-label use of bevacizumab and the associated risks with its use. PMID- 22815648 TI - A tale of two cultures: examining patient-centered care in a forensic mental health hospital. AB - Several questions remain unanswered regarding the extent to which the principles and practices of patient-centered care are achievable in the context of a forensic mental health hospital. This study examined patient-centered care from the perspectives of patients and providers in a forensic mental health hospital. Patient-centered care was assessed using several measures of complementary constructs. Interviews were conducted with 30 patients and surveys were completed by 28 service providers in a forensic mental health hospital. Patients and providers shared similar views of the therapeutic milieu and recovery orientation of services; however, providers were more likely to perceive the hospital as being potentially unsafe. Overall, the findings indicated that characteristics of patient-centered care may be found within a forensic mental health hospital. The principles of patient-centered care can be integrated into service delivery in forensic mental health hospitals, though special attention to providers' perceptions of safety is needed. PMID- 22815650 TI - Fast, slow, or not at all: the extracellular matrix controls movement of signaling molecules. PMID- 22815649 TI - Transport of fibroblast growth factor 2 in the pericellular matrix is controlled by the spatial distribution of its binding sites in heparan sulfate. AB - The heparan sulfate (HS) chains of proteoglycans are a key regulatory component of the extracellular matrices of animal cells, including the pericellular matrix around the plasma membrane. In these matrices they regulate transport, gradient formation, and effector functions of over 400 proteins central to cell communication. HS from different matrices differs in its selectivity for its protein partners. However, there has been no direct test of how HS in the matrix regulates the transport of its partner proteins. We address this issue by single molecule imaging and tracking in fibroblast pericellular matrix of fibroblast growth factor 2 (FGF2), stoichiometrically labelled with small gold nanoparticles. Transmission electron microscopy and photothermal heterodyne imaging (PHI) show that the spatial distribution of the HS-binding sites for FGF2 in the pericellular matrix is heterogeneous over length scales ranging from 22 nm to several um. Tracking of individual FGF2 by PHI in the pericellular matrix of living cells demonstrates that they undergo five distinct types of motion. They spend much of their time in confined motion (~110 nm diameter), but they are not trapped and can escape by simple diffusion, which may be slow, fast, or directed. These substantial translocations (um) cover distances far greater than the length of a single HS chain. Similar molecular motion persists in fixed cells, where the movement of membrane PGs is impeded. We conclude that FGF2 moves within the pericellular matrix by translocating from one HS-binding site to another. The binding sites on HS chains form non-random, heterogeneous networks. These promote FGF2 confinement or substantial translocation depending on their spatial organisation. We propose that this spatial organisation, coupled to the relative selectivity and the availability of HS-binding sites, determines the transport of FGF2 in matrices. Similar mechanisms are likely to underpin the movement of many other HS-binding effectors. PMID- 22815652 TI - The ethics of switch/simplify in antiretroviral trials: non-inferior or just inferior? PMID- 22815651 TI - Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. AB - Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following beta2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the beta-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that betaAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells. PMID- 22815653 TI - Effect of a community-based nursing intervention on mortality in chronically ill older adults: a randomized controlled trial. AB - BACKGROUND: Improving the health of chronically ill older adults is a major challenge facing modern health care systems. A community-based nursing intervention developed by Health Quality Partners (HQP) was one of 15 different models of care coordination tested in randomized controlled trials within the Medicare Coordinated Care Demonstration (MCCD), a national US study. Evaluation of the HQP program began in 2002. The study reported here was designed to evaluate the survival impact of the HQP program versus usual care up to five years post-enrollment. METHODS AND FINDINGS: HQP enrolled 1,736 adults aged 65 and over, with one or more eligible chronic conditions (coronary artery disease, heart failure, diabetes, asthma, hypertension, or hyperlipidemia) during the first six years of the study. The intervention group (n = 873) was offered a comprehensive, integrated, and tightly managed system of care coordination, disease management, and preventive services provided by community-based nurse care managers working collaboratively with primary care providers. The control group (n = 863) received usual care. Overall, a 25% lower relative risk of death (hazard ratio [HR] 0.75 [95% CI 0.57-1.00], p = 0.047) was observed among intervention participants with 86 (9.9%) deaths in the intervention group and 111 (12.9%) deaths in the control group during a mean follow-up of 4.2 years. When covariates for sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use were included, the adjusted HR was 0.73 (95% CI 0.55-0.98, p = 0.033). Subgroup analyses did not demonstrate statistically significant interaction effects for any subgroup. No suspected program-related adverse events were identified. CONCLUSIONS: The HQP model of community-based nurse care management appeared to reduce all-cause mortality in chronically ill older adults. Limitations of the study are that few low-income and non-white individuals were enrolled and implementation was in a single geographic region of the US. Additional research to confirm these findings and determine the model's scalability and generalizability is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071967. Please see later in the article for the Editors' Summary. PMID- 22815654 TI - Social entrepreneurship for sexual health (SESH): a new approach for enabling delivery of sexual health services among most-at-risk populations. PMID- 22815655 TI - Averting an impending storm: can we reengineer health systems to meet the needs of aging populations? PMID- 22815656 TI - Reduction in Clostridium difficile infection rates after mandatory hospital public reporting: findings from a longitudinal cohort study in Canada. AB - BACKGROUND: The role of public reporting in improving hospital quality of care is controversial. Reporting of hospital-acquired infection rates has been introduced in multiple health care systems, but its relationship to infection rates has been understudied. Our objective was to determine whether mandatory public reporting by hospitals is associated with a reduction in hospital rates of Clostridium difficile infection. METHODS AND FINDINGS: We conducted a longitudinal, population-based cohort study in Ontario (Canada's largest province) between April 1, 2002, and March 31, 2010. We included all patients (>1 y old) admitted to 180 acute care hospitals. Using Poisson regression, we developed a model to predict hospital- and age-specific monthly rates of C. difficile disease per 10,000 patient-days prior to introduction of public reporting on September 1, 2008. We then compared observed monthly rates of C. difficile infection in the post-intervention period with rates predicted by the pre-intervention predictive model. In the pre-intervention period there were 33,634 cases of C. difficile infection during 39,221,113 hospital days, with rates increasing from 7.01 per 10,000 patient-days in 2002 to 10.79 in 2007. In the first calendar year after the introduction of public reporting, there was a decline in observed rates of C. difficile colitis in Ontario to 8.92 cases per 10,000 patient-days, which was significantly lower than the predicted rate of 12.16 (95% CI 11.35-13.04) cases per 10,000 patient-days (p<0.001). Over this period, public reporting was associated with a 26.7% (95% CI 21.4%-31.6%) reduction in C. difficile cases, or a projected 1,970 cases averted per year (95% CI 1,476-2,500). The effect was specific to C. difficile, with rates of community-acquired gastrointestinal infections and urinary tract infections unchanged. A limitation of our study is that this observational study design cannot rule out the influence of unmeasured temporal confounders. CONCLUSIONS: Public reporting of hospital C. difficile rates was associated with a substantial reduction in the population burden of this infection. Future research will be required to discern the direct mechanism by which C. difficile infection rates may have been reduced in response to public reporting. Please see later in the article for the Editors' Summary. PMID- 22815658 TI - Investigating facets of personality in adult pathological gamblers with ADHD. AB - The present study explored facets of personality in a sample of pathological gamblers with ADHD (n = 52) and without ADHD (n = 43). Participants were assessed for psychopathology and gambling disorders using the Mini International Neuropsychiatric Interview, the National Opinion Research Center DSM Screen for Gambling Problems, and the Adult ADHD Self-Report Scale. Facets of personality were assessed using the NEO Personality Inventory-Revised. Group differences emerged across several facets of personality when analyzed using multivariate statistics. Although both groups experienced difficulties in several areas compared with norming data (e.g., greater depression, higher impulsivity, lower self-esteem and lower self-discipline), these facets of personality were more pronounced in pathological gamblers with ADHD. Most notable among these differences are tendencies for gamblers with ADHD to experience greater levels of emotional instability, interpersonal sensitivity and stress proneness. Pathological gamblers with ADHD also appear to experience lower self-esteem, greater difficulty being assertive and lower levels of self-discipline. Surprisingly, both groups were comparable on facets of impulsivity. These findings suggest that pathological gamblers diagnosed with adult ADHD may experience additional challenges compared with pathological gamblers without ADHD. PMID- 22815673 TI - Temperament clusters in a normal population: implications for health and disease. AB - BACKGROUND: The object of this study was to identify temperament patterns in the Finnish population, and to determine the relationship between these profiles and life habits, socioeconomic status, and health. METHODS/PRINCIPAL FINDINGS: A cluster analysis of the Temperament and Character Inventory subscales was performed on 3,761 individuals from the Northern Finland Birth Cohort 1966 and replicated on 2,097 individuals from the Cardiovascular Risk in Young Finns study. Clusters were formed using the k-means method and their relationship with 115 variables from the areas of life habits, socioeconomic status and health was examined. RESULTS: Four clusters were identified for both genders. Individuals from Cluster I are characterized by high persistence, low extravagance and disorderliness. They have healthy life habits, and lowest scores in most of the measures for psychiatric disorders. Cluster II individuals are characterized by low harm avoidance and high novelty seeking. They report the best physical capacity and highest level of income, but also high rate of divorce, smoking, and alcohol consumption. Individuals from Cluster III are not characterized by any extreme characteristic. Individuals from Cluster IV are characterized by high levels of harm avoidance, low levels of exploratory excitability and attachment, and score the lowest in most measures of health and well-being. CONCLUSIONS: This study shows that the temperament subscales do not distribute randomly but have an endogenous structure, and that these patterns have strong associations to health, life events, and well-being. PMID- 22815674 TI - Characterization of influenza hemagglutinin interactions with receptor by NMR. AB - In influenza, the envelope protein hemagglutinin (HA) plays a critical role in viral entry by first binding to sialic acid receptors on the cell surface and subsequently mediating fusion of the viral and target membranes. In this work, the receptor binding properties of influenza A HA from different subtypes (H1 A/California/04/09, H5 A/Vietnam/1205/04, H5 A/bar-headed goose/Qinghai/1A/05, and H9 A/Hong Kong/1073/99) have been characterized by NMR spectroscopy. Using saturation transfer difference (STD) NMR, we find that all HAs bind to the receptor analogs 2,3-sialyllactose and 2,6-sialyllactose, with subtle differences in the binding mode. Using competition STD NMR, we determine the receptor preferences for the HA subtypes. We find that H5-Qinghai and H9-Hong Kong HA bind to both receptor analogs with similar affinity. On the other hand, H1 exhibits a clear preference for 2,6-sialyllactose while H5-Vietnam exhibits a clear preference for 2,3-sialyllactose. Together, these results are interpreted within the context of differences in both the amino acid sequence and structures of HA from the different subtypes in determining receptor preference. PMID- 22815675 TI - Structural characterization of neutral and acidic glycolipids from Thermus thermophilus HB8. AB - The structural characterization of glycolipids from Thermus thermophilus HB8 was performed in this study. Two neutral and one acidic glycolipids were extracted and purified by the modified TLC-blotting method, after which their chemical structures were determined by chemical composition analysis, mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. The structure of one of the neutral glycolipids, NGL-A, was Galp(alpha1-6)GlcpNacyl(beta1-2)Glcp(alpha1 )acyl(2)Gro, and the other, NGL-C, was Galf(beta1-2)Galp(alpha1-6)GlcpNacyl(beta1 2)Glcp(alpha1-)acyl(2)Gro. The structure of NGL-C was identical to that reported previously [Oshima, M. and Ariga, T. (1976) FEBS Lett. 64, 440]. Both neutral glycolipids shared a common structural unit found in the Thermus species. The acyl groups found in NGL-A and NGL-C, iso-type pentadecanoxy and heptadecanoxy fatty acid, were also the same as those found in this species. In contrast, the acidic glycolipid, AGL-B, possessed the structure of N-(((GlcpNAc(alpha1 )acyl(2)Gro)P-2)GroA)alkylamine. The alkyl group in AGL-B was an iso-type heptadecanyl, suggesting that the iso-type structure of the long alkyl chain is responsible for the thermal stability of the bacteria. PMID- 22815676 TI - Alleviation of gut inflammation by Cdx2/Pxr pathway in a mouse model of chemical colitis. AB - Pregnane X Receptor (PXR), a master regulator of drug metabolism and inflammation, is abundantly expressed in the gastrointestinal tract. Baicalein and its O-glucuronide baicalin are potent anti-inflammatory and anti-cancer herbal flavonoids that undergo a complex cycle of interconversion in the liver and gut. We sought to investigate the role these flavonoids play in inhibiting gut inflammation by an axis involving PXR and other potential factors. The consequences of PXR regulation and activation by the herbal flavonoids, baicalein and baicalin were evaluated in vitro in human colon carcinoma cells and in vivo using wild-type, Pxr-null, and humanized (hPXR) PXR mice. Baicalein, but not its glucuronidated metabolite baicalin, activates PXR in a Cdx2-dependent manner in vitro, in human colon carcinoma LS174T cells, and in the murine colon in vivo. While both flavonoids abrogate dextran sodium sulfate (DSS)-mediated colon inflammation in vivo, oral delivery of a potent bacterial beta-glucuronidase inhibitor eliminates baicalin's effect on gastrointestinal inflammation by preventing the microbial conversion of baicalin to baicalien. Finally, reduction of gastrointestinal inflammation requires the binding of Cdx2 to a specific proximal site on the PXR promoter. Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions. PMID- 22815677 TI - Association between the ERCC5 Asp1104His polymorphism and cancer risk: a meta analysis. AB - BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair, removal of bulky lesions caused by environmental chemicals or UV light. Mutations in this gene cause a rare autosomal recessive syndrome, and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity phenotype and cancer risk. However, a series of epidemiological studies on the association between the ERCC5 Asp1104His polymorphism (rs17655, G>C) and cancer susceptibility generated conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: To derive a more precise estimation of the association between the ERCC5 Asp1104His polymorphism and overall cancer risk, we performed a meta-analysis of 44 published case-control studies, in which a total of 23,490 cases and 27,168 controls were included. To provide additional biological plausibility, we also assessed the genotype-gene expression correlation from the HapMap phase II release 23 data with 270 individuals from 4 ethnic populations. When all studies were pooled, we found no statistical evidence for a significantly increased cancer risk in the recessive genetic models (His/His vs. Asp/Asp: OR = 0.99, 95% CI: 0.92-1.06, P = 0.242 for heterogeneity or His/His vs. Asp/His + Asp/Asp: OR = 0.98, 95% CI: 0.93-1.03, P = 0.260 for heterogeneity), nor in further stratified analyses by cancer type, ethnicity, source of controls and sample size. In the genotype-phenotype correlation analysis from 270 individuals, we consistently found no significant correlation of the Asp1104His polymorphism with ERCC5 mRNA expression. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that it is unlikely that the ERCC5 Asp1104His polymorphism may contribute to individual susceptibility to cancer risk. PMID- 22815678 TI - Detection of quorum sensing signal molecules and identification of an autoinducer synthase gene among biofilm forming clinical isolates of Acinetobacter spp. AB - BACKGROUND: Quorum sensing is a term that describes an environmental sensing system that allows bacteria to monitor their own population density which contributes significantly to the size and development of the biofilm. Many gram negative bacteria use N-acyl-homoserine lactones as quorum sensing signal molecules. In this study, we sought to find out if the biofilm formation among clinical isolates of Acinetobacter spp. is under the control of autoinducing quorum sensing molecules. METHODOLOGY/PRINCIPAL FINDINGS: Biofilm formation among clinical isolates of Acinetobacter spp. was assessed and the production of signal molecules were detected with Chromobacterium violaceum CV026 biosensor system. Characterisation of autoinducers was carried out by mass spectrometric analysis. We have also reported the identification of an autoinducer synthase gene, abaIota among the isolates that produce quorum sensing signal molecules and have reported that the mutation in the abaI gene influences their biofilm forming capabilities. Using a microtitre-plate assay it was shown that 60% of the 50 Acinetobacter spp. isolates significantly formed biofilms. Further detection with the biosensor strain showed that some of these isolates produced long chain signal molecules. Mass spectrometric analysis revealed that five of these isolates produced N decanoyl homoserine lactone and two isolates produced acyl-homoserine lactone with a chain length equal to C(12). The abaIota gene was identified and a tetracycline mutant of the abaIota gene was created and the inhibition in biofilm formation in the mutant was shown. CONCLUSIONS/SIGNIFICANCE: These data are of great significance as the signal molecules aid in biofilm formation which in turn confer various properties of pathogenicity to the clinical isolates including drug resistance. The use of quorum sensing signal blockers to attenuate bacterial pathogenicity is therefore highly attractive, particularly with respect to the emergence of multi antibiotic resistant bacteria. PMID- 22815679 TI - Complexity and variability of gut commensal microbiota in polyphagous lepidopteran larvae. AB - BACKGROUND: The gut of most insects harbours nonpathogenic microorganisms. Recent work suggests that gut microbiota not only provide nutrients, but also involve in the development and maintenance of the host immune system. However, the complexity, dynamics and types of interactions between the insect hosts and their gut microbiota are far from being well understood. METHODS/PRINCIPAL FINDINGS: To determine the composition of the gut microbiota of two lepidopteran pests, Spodoptera littoralis and Helicoverpa armigera, we applied cultivation independent techniques based on 16S rRNA gene sequencing and microarray. The two insect species were very similar regarding high abundant bacterial families. Different bacteria colonize different niches within the gut. A core community, consisting of Enterococci, Lactobacilli, Clostridia, etc. was revealed in the insect larvae. These bacteria are constantly present in the digestion tract at relatively high frequency despite that developmental stage and diet had a great impact on shaping the bacterial communities. Some low-abundant species might become dominant upon loading external disturbances; the core community, however, did not change significantly. Clearly the insect gut selects for particular bacterial phylotypes. CONCLUSIONS: Because of their importance as agricultural pests, phytophagous Lepidopterans are widely used as experimental models in ecological and physiological studies. Our results demonstrated that a core microbial community exists in the insect gut, which may contribute to the host physiology. Host physiology and food, nevertheless, significantly influence some fringe bacterial species in the gut. The gut microbiota might also serve as a reservoir of microorganisms for ever-changing environments. Understanding these interactions might pave the way for developing novel pest control strategies. PMID- 22815680 TI - The sedative effect of non-alcoholic beer in healthy female nurses. AB - INTRODUCTION: The hop (Humulus lupulus L.), a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the alpha-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter acting in the central nervous system (CNS). OBJECTIVES: To analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population. METHODS: The experiment was conducted with healthy female nurses (n = 17) working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch(r)) after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0.0% alcohol) with supper for 14 days (treatment). Data were obtained in comparison with her own control group without consumption of beer during supper. RESULTS: Actigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p<=0.05) in the Treatment group (12.01+/-1.19 min) when compared to the Control group (20.50+/-4.21 min), as also did Total Activity (p<=0.05; Treatment group = 5284.78+/-836.99 activity pulses vs Control = 7258.78+/-898.89 activity pulses). In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI) decreased in the Treatment group (State Anxiety 18.09+/-3.8 vs Control 20.69+/-2.14). CONCLUSION: The moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism. PMID- 22815681 TI - Humans running in place on water at simulated reduced gravity. AB - BACKGROUND: On Earth only a few legged species, such as water strider insects, some aquatic birds and lizards, can run on water. For most other species, including humans, this is precluded by body size and proportions, lack of appropriate appendages, and limited muscle power. However, if gravity is reduced to less than Earth's gravity, running on water should require less muscle power. Here we use a hydrodynamic model to predict the gravity levels at which humans should be able to run on water. We test these predictions in the laboratory using a reduced gravity simulator. METHODOLOGY/PRINCIPAL FINDINGS: We adapted a model equation, previously used by Glasheen and McMahon to explain the dynamics of Basilisk lizard, to predict the body mass, stride frequency and gravity necessary for a person to run on water. Progressive body-weight unloading of a person running in place on a wading pool confirmed the theoretical predictions that a person could run on water, at lunar (or lower) gravity levels using relatively small rigid fins. Three-dimensional motion capture of reflective markers on major joint centers showed that humans, similarly to the Basilisk Lizard and to the Western Grebe, keep the head-trunk segment at a nearly constant height, despite the high stride frequency and the intensive locomotor effort. Trunk stabilization at a nearly constant height differentiates running on water from other, more usual human gaits. CONCLUSIONS/SIGNIFICANCE: The results showed that a hydrodynamic model of lizards running on water can also be applied to humans, despite the enormous difference in body size and morphology. PMID- 22815682 TI - Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. AB - Mesenchymal stromal cells (MSCs) are the leading cell candidates in the field of regenerative medicine. These cells have also been successfully used to improve skeletal muscle repair/regeneration; however, the mechanisms responsible for their beneficial effects remain to be clarified. On this basis, in the present study, we evaluated in a co-culture system, the ability of bone-marrow MSCs to influence C2C12 myoblast behavior and analyzed the cross-talk between the two cell types at the cellular and molecular level. We found that myoblast proliferation was greatly enhanced in the co-culture as judged by time lapse videomicroscopy, cyclin A expression and EdU incorporation. Moreover, myoblasts immunomagnetically separated from MSCs after co-culture expressed higher mRNA and protein levels of Notch-1, a key determinant of myoblast activation and proliferation, as compared with the single culture. Notch-1 intracellular domain and nuclear localization of Hes-1, a Notch-1 target gene, were also increased in the co-culture. Interestingly, the myoblastic response was mainly dependent on the paracrine release of vascular endothelial growth factor (VEGF) by MSCs. Indeed, the addition of MSC-derived conditioned medium (CM) to C2C12 cells yielded similar results as those observed in the co-culture and increased the phosphorylation and expression levels of VEGFR. The treatment with the selective pharmacological VEGFR inhibitor, KRN633, resulted in a marked attenuation of the receptor activation and concomitantly inhibited the effects of MSC-CM on C2C12 cell growth and Notch-1 signaling. In conclusion, this study provides novel evidence for a role of MSCs in stimulating myoblast cell proliferation and suggests that the functional interaction between the two cell types may be exploited for the development of new and more efficient cell-based skeletal muscle repair strategies. PMID- 22815684 TI - Desert springs: deep phylogeographic structure in an ancient endemic crustacean (Phreatomerus latipes). AB - Desert mound springs of the Great Artesian Basin in central Australia maintain an endemic fauna that have historically been considered ubiquitous throughout all of the springs. Recent studies, however, have shown that several endemic invertebrate species are genetically highly structured and contain previously unrecognised species, suggesting that individuals may be geographically 'stranded in desert islands'. Here we further tested the generality of this hypothesis by conducting genetic analyses of the obligate aquatic phreatoicid isopod Phreatomerus latipes. Phylogenetic and phylogeographic relationships amongst P. latipes individuals were examined using a multilocus approach comprising allozymes and mtDNA sequence data. From the Lake Eyre region in South Australia we collected data for 476 individuals from 69 springs for the mtDNA gene COI; in addition, allozyme electrophoresis was conducted on 331 individuals from 19 sites for 25 putative loci. Phylogenetic and population genetic analyses showed three major clades in both allozyme and mtDNA data, with a further nine mtDNA sub clades, largely supported by the allozymes. Generally, each of these sub-clades was concordant with a traditional geographic grouping known as spring complexes. We observed a coalescent time between ~2-15 million years ago for haplotypes within each of the nine mtDNA sub-clades, whilst an older total time to coalescence (>15 mya) was observed for the three major clades. Overall we observed that multiple layers of phylogeographic history are exemplified by Phreatomerus, suggesting that major climate events and their impact on the landscape have shaped the observed high levels of diversity and endemism. Our results show that this genus reflects a diverse fauna that existed during the early Miocene and appears to have been regionally restricted. Subsequent aridification events have led to substantial contraction of the original habitat, possibly over repeated Pleistocene ice age cycles, with P. latipes populations becoming restricted in the distribution to desert springs. PMID- 22815683 TI - A generative model for measuring latent timing structure in motor sequences. AB - Motor variability often reflects a mixture of different neural and peripheral sources operating over a range of timescales. We present a statistical model of sequence timing that can be used to measure three distinct components of timing variability: global tempo changes that are spread across the sequence, such as might stem from neuromodulatory sources with widespread influence; fast, uncorrelated timing noise, stemming from noisy components within the neural system; and timing jitter that does not alter the timing of subsequent elements, such as might be caused by variation in the motor periphery or by measurement error. In addition to quantifying the variability contributed by each of these latent factors in the data, the approach assigns maximum likelihood estimates of each factor on a trial-to-trial basis. We applied the model to adult zebra finch song, a temporally complex behavior with rich structure on multiple timescales. We find that individual song vocalizations (syllables) contain roughly equal amounts of variability in each of the three components while overall song length is dominated by global tempo changes. Across our sample of syllables, both global and independent variability scale with average length while timing jitter does not, a pattern consistent with the Wing and Kristofferson (1973) model of sequence timing. We also find significant day-to-day drift in all three timing sources, but a circadian pattern in tempo only. In tests using artificially generated data, the model successfully separates out the different components with small error. The approach provides a general framework for extracting distinct sources of timing variability within action sequences, and can be applied to neural and behavioral data from a wide array of systems. PMID- 22815685 TI - beta1 adrenergic receptor polymorphisms and heart failure: a meta-analysis on susceptibility, response to beta-blocker therapy and prognosis. AB - AIMS: The risk stratification of patients for heart failure (HF) remains a challenge, as well as the anticipation of the response to beta-blocker therapy. Since the pivotal role of beta1 adrenergic receptor (beta1-AR) in HF, many publications have studied the associations between the beta1-AR polymorphisms (Ser49Gly and Arg389Gly) and HF, with inconsistent results. Thus, we performed a meta-analysis of studies to evaluate the impact of beta1-AR polymorphisms on susceptibility to HF, the response to beta-blocker therapy and the prognosis of HF. METHODS AND RESULTS: Electronic databases were systematically searched before August 2011. We extracted data sets and performed meta-analysis with standardized methods. A total of 27 studies met our inclusion criteria. It was found that in East Asians, the Gly389 allele and Gly389 homozygotes significantly increased the HF risk, while the Gly389 allele and Gly389 homozygotes trended to decrease the risk of HF in whites. With the similar reduction of heart rate, overall, the Arg389 homozygotes showed a better response to beta-blocker therapy. Furthermore, the Arg389 homozygotes were significantly associated with better LVEF improvement in East Asians and a mixed population. And in white people, the Arg389 homozygotes made a greater LVESd/v improvement and trended to be associated with better LVEDd/v improvement. However, the prognosis of Arg389 homozygotes HF patients was similar to those with Gly389 carriers. The Ser49Gly polymorphism did not impact the risk or prognosis of HF. CONCLUSION: Based on our meta-analysis, the Gly389 allele and Gly389 homozygotes were risk factors in East Asians while trending to protect whites against HF. Furthermore, Arg389 homozygote is significantly associated with a favorable response to beta-blocker treatment in HF patients. However, neither of the two polymorphisms is an independent predictor of the prognosis of HF. PMID- 22815686 TI - Massive Trentepohlia-bloom in a glacier valley of Mt. Gongga, China, and a new variety of Trentepohlia (Chlorophyta). AB - Trentepohlia is a genus of subaerial green algae which is widespread in tropical, subtropical, and also temperate regions with humid climates. For many years, small-scale Trentepohlia coverage had been found on the rocks of some glacier valleys on the northern slopes of Mt. Gongga, China. However, since 2005, in the Yajiageng river valley, most of the rocks are covered with deep red coloured algal carpets, which now form a spectacular sight and a tourist attraction known as 'Red-Stone-Valley'. Based on morphology and molecular data, we have named this alga as a new variety: Trentepohlia jolithus var. yajiagengensis var. nov., it differs from the type variety in that its end cells of the main filament are often rhizoid, unilateral branches. This new variety only grows on the native rock, both global warming and human activity have provided massive areas of suitable substrata: the rocks surfaces of the Yajiageng river valley floodplain were re-exposed because of heavy debris flows in the summer of 2005; plus human activities such as tourism and road-building have also created a lot of exposed rock! In summer, the glaciers of the northern slopes of Mt. Gongga have brought to the valleys wet and foggy air, ideal for Trentepohlia growth. The cells of the new variety are rich in secondary carotenoids (astaxanthin?), which helps the algal cells resistance to strong ultraviolet radiation at high altitudes (they are only found on rock surfaces at alt. 1900-3900 m); the cells are also rich in oils, which gives them high resistance to cold dry winters. PMID- 22815687 TI - Hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor-1alpha-CXCR4 axis. AB - BACKGROUND: Cardiac progenitor cells (CPCs) have been shown to be suitable in stem cell therapy for resurrecting damaged myocardium, but poor retention of transplanted cells in the ischemic myocardium causes ineffective cell therapy. Hypoxic preconditioning of cells can increase the expression of CXCR4 and pro survival genes to promote better cell survival; however, it is unknown whether hypoxia preconditioning will influence the survival and retention of CPCs via the SDF-1alpha/CXCR4 axis. METHODS AND RESULTS: CPCs were isolated from adult mouse hearts and purified by magnetic activated cell sorting using c-kit magnetic beads. These cells were cultured at various times in either normoxic or hypoxic conditions, and cell survival was analyzed using flow cytometry and the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), CXCR4, phosphorylated Akt and Bcl-2 were measured by Western blot. Results showed that the expression of pro-survival genes significantly increased after hypoxia treatment, especially in cells cultured in hypoxic conditions for six hours. Upon completion of hypoxia preconditioning from c-kit+ CPCs for six hours, the anti-apoptosis, migration and cardiac repair potential were evaluated. Results showed a significant enhancement in anti-apoptosis and migration in vitro, and better survival and cardiac function after being transplanted into acute myocardial infarction (MI) mice in vivo. The beneficial effects induced by hypoxia preconditioning of c-kit+ CPCs could largely be blocked by the addition of CXCR4 selective antagonist AMD3100. CONCLUSIONS: Hypoxic preconditioning may improve the survival and retention of c kit+ CPCs in the ischemic heart tissue through activating the SDF-1alpha/CXCR4 axis and the downstream anti-apoptosis pathway. Strategies targeting this aspect may enhance the effectiveness of cell-based cardiac regenerative therapy. PMID- 22815688 TI - Early environment and neurobehavioral development predict adult temperament clusters. AB - BACKGROUND: Investigation of the environmental influences on human behavioral phenotypes is important for our understanding of the causation of psychiatric disorders. However, there are complexities associated with the assessment of environmental influences on behavior. METHODS/PRINCIPAL FINDINGS: We conducted a series of analyses using a prospective, longitudinal study of a nationally representative birth cohort from Finland (the Northern Finland 1966 Birth Cohort). Participants included a total of 3,761 male and female cohort members who were living in Finland at the age of 16 years and who had complete temperament scores. Our initial analyses (Wessman et al., in press) provide evidence in support of four stable and robust temperament clusters. Using these temperament clusters, as well as independent temperament dimensions for comparison, we conducted a data-driven analysis to assess the influence of a broad set of life course measures, assessed pre-natally, in infancy, and during adolescence, on adult temperament. RESULTS: Measures of early environment, neurobehavioral development, and adolescent behavior significantly predict adult temperament, classified by both cluster membership and temperament dimensions. Specifically, our results suggest that a relatively consistent set of life course measures are associated with adult temperament profiles, including maternal education, characteristics of the family's location and residence, adolescent academic performance, and adolescent smoking. CONCLUSIONS: Our finding that a consistent set of life course measures predict temperament clusters indicate that these clusters represent distinct developmental temperament trajectories and that information about a subset of life course measures has implications for adult health outcomes. PMID- 22815689 TI - Sarcoidosis and tuberculosis cytokine profiles: indistinguishable in bronchoalveolar lavage but different in blood. AB - BACKGROUND: The clinical, radiological and pathological similarities between sarcoidosis and tuberculosis can make disease differentiation challenging. A complicating factor is that some cases of sarcoidosis may be initiated by mycobacteria. We hypothesised that immunological profiling might provide insight into a possible relationship between the diseases or allow us to distinguish between them. METHODS: We analysed bronchoalveolar lavage (BAL) fluid in sarcoidosis (n = 18), tuberculosis (n = 12) and healthy volunteers (n = 16). We further investigated serum samples in the same groups; sarcoidosis (n = 40), tuberculosis (n = 15) and healthy volunteers (n = 40). A cross-sectional analysis of multiple cytokine profiles was performed and data used to discriminate between samples. RESULTS: We found that BAL profiles were indistinguishable between both diseases and significantly different from healthy volunteers. In sera, tuberculosis patients had significantly lower levels of the Th2 cytokine interleukin-4 (IL-4) than those with sarcoidosis (p = 0.004). Additional serum differences allowed us to create a linear regression model for disease differentiation (within-sample accuracy 91%, cross-validation accuracy 73%). CONCLUSIONS: These data warrant replication in independent cohorts to further develop and validate a serum cytokine signature that may be able to distinguish sarcoidosis from tuberculosis. Systemic Th2 cytokine differences between sarcoidosis and tuberculosis may also underly different disease outcomes to similar respiratory stimuli. PMID- 22815691 TI - Serum fetuin A and chemerin levels correlate with hepatic steatosis and regional adiposity in maintenance hemodialysis patients. AB - BACKGROUND: A deficiency of fetuin A is linked to cardiovascular calcification and mortality in dialysis patients. But, high levels of fetuin A and chemerin correlate with hepatic steatosis and regional adiposity in general population. The association between hepatic steatosis and fetuin A/chemerin levels in hemodialysis (HD) remains unclear. METHODS: We performed a cross-sectional, observational study; 216 prevalent HD patients from a single center were enrolled. Baseline serum fetuin A, chemerin levels, conicity index and anthropometric parameters were checked. Presence of hepatic steatosis was qualified by liver ultrasound and quantified by the hepato-renal index (HRI); central obesity defined by waist circumference (WC). ROC analyses and multivariate logistic regression analyses for prediction of hepatic steatosis and central obesity on the basis of fetuin A/chemerin levels, anthropometric parameters, and other relevant covariates were performed. RESULTS: Data from 103 women and 113 men (mean age 60+/-12 years) were analyzed. Eighty subjects had hepatic steatosis and their HRIs were significantly higher than those without hepatic steatosis (P<0.001). Serum fetuin A levels were positively associated with HRIs (P<0.001) and chemerin levels (P<0.001). Fetuin A, chemerin and WC were predictors for hepatic steatosis and central obesity by ROC curve. In multivariate logistic regression analysis, fetuin A and WC independently predicted hepatic steatosis defined by HRIs. And chemerin predicted central obesity and regional adiposity after covariate adjustments (all P<0.05). CONCLUSIONS: Serum fetuin A levels were higher in prevalent HD patients with hepatic steatosis, and positively correlated with chemerin levels. Chemerin levels predicted central obesity as well as regional adiposity in the HD patients. PMID- 22815690 TI - Roflumilast-N-oxide induces surfactant protein expression in human alveolar epithelial cells type II. AB - Surfactant proteins (SPs) are important lipoprotein complex components, expressed in alveolar epithelial cells type II (AEC-II), and playing an essential role in maintenance of alveolar integrity and host defence. Because expressions of SPs are regulated by cyclic adenosine monophosphate (cAMP), we hypothesized that phosphodiesterase (PDE) inhibitors, influence SP expression and release. Analysis of PDE activity of our AEC-II preparations revealed that PDE4 is the major cAMP hydrolysing PDE in human adult AEC-II. Thus, freshly isolated human AEC-II were stimulated with two different concentrations of the PDE4 inhibitor roflumilast-N oxide (3 nM and 1 uM) to investigate the effect on SP expression. SP mRNA levels disclosed a large inter-individual variation. Therefore, the experiments were grouped by the basal SP expression in low and high expressing donors. AEC-II stimulated with Roflumilast-N-oxide showed a minor increase in SP-A1, SP-C and SP D mRNA mainly in low expressing preparations. To overcome the effects of different basal levels of intracellular cAMP, cyclooxygenase was blocked by indomethacin and cAMP production was reconstituted by prostaglandin E2 (PGE2). Under these conditions SP-A1, SP-A2, SP-B and SP-D are increased by roflumilast-N oxide in low expressing preparations. Roflumilast-N-oxide fosters the expression of SPs in human AEC-II via increase of intracellular cAMP levels potentially contributing to improved alveolar host defence and enhanced resolution of inflammation. PMID- 22815693 TI - Adolescent bullying involvement and psychosocial aspects of family and school life: a cross-sectional study from Guangdong Province in China. AB - BACKGROUND: School bullying is an emerging problem in China. The present study aimed to measure the prevalence of bullying behaviors among Chinese adolescents and to examine the association of bullying and being bullied with family factors, school factors and indicators of psychosocial adjustment. METHODS: A cross sectional study was conducted. A total of 8,342 middle school students were surveyed in four cities in the Guangdong Province. Self-reports on bullying involvement and information regarding family factors, school factors and psychosocial adjustment were collected. Descriptive statistics and multi-level logistic regression analysis were used to evaluate the prevalence of school bullying and explore potentially influential factors. RESULTS: Of the total sample, 20.83% (1,738) reported being involved in bullying behaviors. Of the respondents, 18.99% were victims of bullying, 8.60% were bullies and 6.74% both bullied themselves and bullied others. Factors that were determined to be correlated with bullying behaviors included grade, parental caring, consideration of suicide, running away from home, time spent online per day and being in a physical fight. CONCLUSION: Bullying was determined to be prevalent among Chinese adolescents. Given the concurrent psychosocial adjustment, family and school factors associated with bullying, as well as the potential long-term negative outcomes for these youth, this issue merits serious attention, both for future research and preventive intervention. PMID- 22815692 TI - Regulation of inflammatory chemokine receptors on blood T cells associated to the circulating versus liver chemokines in dengue fever. AB - Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES(+) cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T helper/T-cytotoxic type-1 cell (Th1/Tc1)-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1beta but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3 expressing T cells and higher expression of CD29, CD44(HIGH) and CD127(LOW) markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response mediated by chemokines during dengue fever will be discussed. PMID- 22815694 TI - Gene silencing of Toll-like receptor 2 inhibits proliferation of human liver cancer cells and secretion of inflammatory cytokines. AB - BACKGROUND: Toll-like receptors (TLRs) are key factors in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. In the microenvironment of tumorigenesis, TLRs can promote inflammation and cell survival. Toll-like receptor 2/6 (TLR2/6) signaling in tumor cells is regarded as one of the mechanisms of chronic inflammation but it can also mediate tumor cell immune escape and tumor progression. However, the expression of TLR2 and its biological function in the development and progression of hepatocarcinoma have not been investigated. This study aimed to determine the expression of TLRs 1-10 in the established human hepatocellular carcinoma cell line BLE-7402, to investigate the biological effect of TLR2 on cell growth and survival. METHODS: TLR expression in BLE-7402 cells was assayed by RT-PCR, real time PCR and flow cytometry (FCM). To further investigate the function of TLR2 in hepatocarcinoma growth, BLE-7402 cells were transfected with recombinant plasmids expressing one of three forms of TLR2 siRNA (sh-TLR2 RNAi(A, B and C)). TLR2 knockdown was confirmed using RT-PCR, real-time PCR and fluorescence microscopy. Tumor cell proliferation was monitored by MTT assay and secreted cytokines in the supernatant of transfected cells were measured by bead-based FCM, the function of TLR2 siRNA was also investigated in vivo. RESULTS: The BLE-7402 cell line expressed TLRs 2 to 10 at both mRNA and protein levels. TLR2 was the most highly expressed TLR. While all the three siRNAs inhibited TLR2 mRNA and protein expression, sh-TLR2 RNAi(B) had the strongest knockdown effect. TLR2 knockdown with sh-TLR2 RNAi(B) reduced cell proliferation. Furthermore, secretion of IL-6 and IL-8 was also reduced. The result showed a drastic reduction in tumor volume in mice treated with sh-TLR2 RNAi(B). DISCUSSION: These results suggest that TLR2 knockdown inhibit proliferation of cultured hepatocarcinoma cells and decrease the secretion of cytokines. It is suggested that TLR2 silencing may worth further investigations for siRNA based gene therapy in treatment of hepatocarcinoma. PMID- 22815695 TI - How academics face the world: a study of 5829 homepage pictures. AB - It is now standard practice, at Universities around the world, for academics to place pictures of themselves on a personal profile page maintained as part of their University's web-site. Here we investigated what these pictures reveal about the way academics see themselves. Since there is an asymmetry in the degree to which emotional information is conveyed by the face, with the left side being more expressive than the right, we hypothesised that academics in the sciences would seek to pose as non-emotional rationalists and put their right cheek forward, while academics in the arts would express their emotionality and pose with the left cheek forward. We sourced 5829 pictures of academics from their University websites and found that, consistent with the hypotheses, there was a significant difference in the direction of face posing between science academics and English academics with English academics showing a more leftward orientation. Academics in the Fine Arts and Performing Arts however, did not show the expected left cheek forward bias. We also analysed profile pictures of psychology academics and found a greater bias toward presenting the left check compared to science academics which makes psychologists appear more like arts academics than scientists. These findings indicate that the personal website pictures of academics mirror the cultural perceptions of emotional expressiveness across disciplines. PMID- 22815696 TI - Thermal stress promotes host mitochondrial degradation in symbiotic cnidarians: are the batteries of the reef going to run out? AB - The symbiotic relationship between cnidarians and their dinoflagellate symbionts, Symbiodinium spp, which underpins the formation of tropical coral reefs, can be destabilized by rapid changes to environmental conditions. Although some studies have concluded that a breakdown in the symbiosis begins with increased reactive oxygen species (ROS) generation within the symbiont due to a decoupling of photosynthesis, others have reported the release of viable symbionts via a variety of host cell derived mechanisms. We explored an alternative model focused upon changes in host cnidarian mitochondrial integrity in response to thermal stress. Mitochondria are often likened to being batteries of the cell, providing energy in the form of ATP, and controlling cellular pathway activation and ROS generation. The overall morphology of host mitochondria was compared to that of associated symbionts under an experimental thermal stress using confocal and electron microscopy. The results demonstrate that hyperthermic stress induces the degradation of cnidarian host mitochondria that is independent of symbiont cellular deterioration. The potential sites of host mitochondrial disruption were also assessed by measuring changes in the expression of genes associated with electron transport and ATP synthesis using quantitative RT-PCR. The primary site of degradation appeared to be downstream of complex III of the electron transport chain with a significant reduction in host cytochrome c and ATP synthase expression. The consequences of reduced expression could limit the capacity of the host to mitigate ROS generation and maintain both organelle integrity and cellular energy supplies. The disruption of host mitochondria, cellular homeostasis, and subsequent cell death irrespective of symbiont integrity highlights the importance of the host response to thermal stress and in symbiosis dysfunction that has substantial implications for understanding how coral reefs will survive in the face of climate change. PMID- 22815697 TI - Adjusting brain dynamics in schizophrenia by means of perceptual and cognitive training. AB - BACKGROUND: In a previous report we showed that cognitive training fostering auditory-verbal discrimination and working memory normalized magnetoencephalographic (MEG) M50 gating ratio in schizophrenia patients. The present analysis addressed whether training effects on M50 ratio and task performance are mediated by changes in brain oscillatory activity. Such evidence should improve understanding of the role of oscillatory activity in phenomena such as M50 ratio, the role of dysfunctional oscillatory activity in processing abnormalities in schizophrenia, and mechanisms of action of cognitive training. METHODOLOGY/PRINCIPAL FINDINGS: Time-locked and non-time-locked oscillatory activity was measured together with M50 ratio in a paired-click design before and after a 4-week training of 36 patients randomly assigned to specific cognitive exercises (CE) or standard (comparison) cognitive training (CP). Patient data were compared to those of 15 healthy controls who participated in two MEG measurements 4 weeks apart without training. Training led to more time-locked gamma-band response and more non-time-locked alpha-band desynchronization, moreso after CE than after CP. Only after CE, increased alpha desynchronization was associated with normalized M50 ratio and with improved verbal memory performance. Thus, both types of cognitive training normalized gamma activity, associated with improved stimulus encoding. More targeted training of auditory-verbal discrimination and memory additionally normalized alpha desynchronization, associated with improved elaborative processing. The latter presumably contributes to improved auditory gating and cognitive function. CONCLUSIONS/SIGNIFICANCE: Results suggest that dysfunctional interplay of ocillatory activity that may contribute to auditory processing disruption in schizophrenia can be modified by targeted training. PMID- 22815698 TI - Effect of serotype on focus and mortality of invasive pneumococcal disease: coverage of different vaccines and insight into non-vaccine serotypes. AB - BACKGROUND: Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13). METHOD: Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients' diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5-64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines. RESULTS: The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines' coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals. CONCLUSION: Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss. PMID- 22815699 TI - Risk factors for preterm birth in an international prospective cohort of nulliparous women. AB - OBJECTIVES: To identify risk factors for spontaneous preterm birth (birth <37 weeks gestation) with intact membranes (SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women. DESIGN: Prospective international multicentre cohort. PARTICIPANTS: 3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%). RESULTS: Of the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant's not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07-6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB PPROM. CONCLUSION: The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes. TRIAL REGISTRATION: ACTR.org.au ACTRN12607000551493. PMID- 22815700 TI - Reduced retinal microvascular density, improved forepaw reach, comparative microarray and gene set enrichment analysis with c-jun targeting DNA enzyme. AB - Retinal neovascularization is a critical component in the pathogenesis of common ocular disorders that cause blindness, and treatment options are limited. We evaluated the therapeutic effect of a DNA enzyme targeting c-jun mRNA in mice with pre-existing retinal neovascularization. A single injection of Dz13 in a lipid formulation containing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N trimethylammonium methyl-sulfate and 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine inhibited c-Jun expression and reduced retinal microvascular density. The DNAzyme inhibited retinal microvascular density as effectively as VEGF-A antibodies. Comparative microarray and gene expression analysis determined that Dz13 suppressed not only c-jun but a range of growth factors and matrix degrading enzymes. Dz13 in this formulation inhibited microvascular endothelial cell proliferation, migration and tubule formation in vitro. Moreover, animals treated with Dz13 sensed the top of the cage in a modified forepaw reach model, unlike mice given a DNAzyme with scrambled RNA-binding arms that did not affect c Jun expression. These findings demonstrate reduction of microvascular density and improvement in forepaw reach in mice administered catalytic DNA. PMID- 22815701 TI - Transfer of Ho endonuclease and Ufo1 to the proteasome by the UbL-UbA shuttle protein, Ddi1, analysed by complex formation in vitro. AB - The F-box protein, Ufo1, recruits Ho endonuclease to the SCF(Ufo1) complex for ubiquitylation. Both ubiquitylated Ho and Ufo1 are transferred by the UbL-UbA protein, Ddi1, to the 19S Regulatory Particle (RP) of the proteasome for degradation. The Ddi1-UbL domain binds Rpn1 of the 19S RP, the Ddi1-UbA domain binds ubiquitin chains on the degradation substrate. Here we used complex reconstitution in vitro to identify stages in the transfer of Ho and Ufo1 from the SCF(Ufo1) complex to the proteasome. We report SCF(Ufo1) complex at the proteasome formed in the presence of Ho. Subsequently Ddi1 is recruited to this complex by interaction between the Ddi1-UbL domain and Ufo1. The core of Ddi1 binds both Ufo1 and Rpn1; this interaction confers specificity of SCF(Ufo1) for Ddi1. The substrate-shield model predicts that Ho would protect Ufo1 from degradation and we find that Ddi1 binds Ho, Ufo1, and Rpn1 simultaneously forming a complex for transfer of Ho to the 19S RP. In contrast, in the absence of Ho, Rpn1 displaces Ufo1 from Ddi1 indicating a higher affinity of the Ddi1-UbL for the 19S RP. However, at high Rpn1 levels there is synergistic binding of Ufo1 to Ddi1 that is dependent on the Ddi1-UbA domain. Our interpretation is that in the absence of substrate, the Ddi1-UbL binds Rpn1 while the Ddi1-UbA binds ubiquitin chains on Ufo1. This would promote degradation of Ufo1 and disassembly of SCF(Ufo1) complexes. PMID- 22815702 TI - Leukocyte telomere length in HIV-infected and HIV-exposed uninfected children: shorter telomeres with uncontrolled HIV viremia. AB - OBJECTIVES: Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging. METHODS: In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV-1-infected (HIV(+)) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV(-)) control children (n = 104) aged 0-19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV(+)/HEU children only, and c) HIV(+) children only. RESULTS: After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV(+) group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007). CONCLUSIONS: In this large study, group rates of LTL attrition were similar for HIV(+), HEU and HIV(-) children. No associations between children's LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition. PMID- 22815703 TI - Gemcitabine and irinotecan as first-line therapy for carcinoma of unknown primary: results of a multicenter phase II trial. AB - Metastatic carcinoma of unknown primary (CUP) has a very poor prognosis, and no standard first-line therapy currently exists. Here, we report the results of a phase II study utilizing a combination of gemcitabine and irinotecan as first line therapy. Treatment was with gemcitabine 1000 mg/m(2) and irinotecan 75 mg/m(2) weekly times four on a six week cycle (Cohort I). Due to excessive toxicity, the dose and schedule were modified as follows: gemcitabine 750 mg/m(2) and irinotecan 75 mg/m(2) given weekly times three on a four week cycle (Cohort II). The primary endpoint was the confirmed response rate (CR + PR). Secondary endpoints consisted of adverse events based upon the presence or absence of the UDP glucuronosyltransferase 1 family, polypeptide A1*28 (UGT1A1*28) polymorphism, time to progression, and overall survival. Thirty-one patients were enrolled with a median age of 63 (range: 38-94), and 26 patients were evaluable for efficacy. Significant toxicity was observed in Cohort 1, characterized by 50% (7/14) patients experiencing a grade 4+ adverse event, but not in cohort II. The confirmed response rate including patients from both cohorts was 12% (95% CI: 2 30%), which did not meet the criteria for continued enrollment. Overall median survival was 7.2 months (95% CI: 4.0 to 11.6) for the entire cohort but notably longer in cohort II than in cohort I (9.3 months (95% CI: 4.1 to 12.1) versus 4.0 months (95% CI: 2.2 to 15.6)). Gemcitabine and irinotecan is not an active combination when used as first line therapy in patients with metastatic carcinoma of unknown primary. Efforts into developing novel diagnostic and therapeutic approaches remain important for improving the outlook for this heterogeneous group of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00066781. PMID- 22815704 TI - T cell subsets in HIV infected patients after successful combination antiretroviral therapy: impact on survival after 12 years. AB - OBJECTIVES: Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up. METHODS: A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997-1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression. RESULTS: Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91-0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death. CONCLUSIONS: Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment. PMID- 22815705 TI - Complex patterns of human antisera reactivity to novel 2009 H1N1 and historical H1N1 influenza strains. AB - BACKGROUND: During the 2009 influenza pandemic, individuals over the age of 60 had the lowest incidence of infection with approximately 25% of these people having pre-existing, cross-reactive antibodies to novel 2009 H1N1 influenza isolates. It was proposed that older people had pre-existing antibodies induced by previous 1918-like virus infection(s) that cross-reacted to novel H1N1 strains. METHODOLOGY/PRINCIPAL FINDINGS: Using antisera collected from a cohort of individuals collected before the second wave of novel H1N1 infections, only a minority of individuals with 1918 influenza specific antibodies also demonstrated hemagglutination-inhibition activity against the novel H1N1 influenza. In this study, we examined human antisera collected from individuals that ranged between the ages of 1 month and 90 years to determine the profile of seropositive influenza immunity to viruses representing H1N1 antigenic eras over the past 100 years. Even though HAI titers to novel 2009 H1N1 and the 1918 H1N1 influenza viruses were positively associated, the association was far from perfect, particularly for the older and younger age groups. CONCLUSIONS/SIGNIFICANCE: Therefore, there may be a complex set of immune responses that are retained in people infected with seasonal H1N1 that can contribute to the reduced rates of H1N1 influenza infection in older populations. PMID- 22815706 TI - Evaluation of four different systems for extraction of RNA from stool suspensions using MS-2 coliphage as an exogenous control for RT-PCR inhibition. AB - Knowing when, and to what extent co-extracted inhibitors interfere with molecular RNA diagnostic assays is of utmost importance. The QIAamp Viral RNA Mini Kit (A); MagNA Pure LC2.0 Automatic extractor (B); KingFisher (C); and NucliSENS EasyMag (D) RNA extraction systems were evaluated for extraction efficiency and co purification of inhibitors from stool suspensions. Real-Time Reverse Transcriptase Polymerase Chain Reaction (rRT-PCR) of MS-2 coliphage spiked into each system's lysis buffer served as an external control for both. Cycle thresholds (Cts) of the MS2 were determined for RNA extracted from stool suspensions containing unknown (n = 93) or varying amounts of inhibitors (n = 92). Stool suspensions from the latter group were also used to determine whether MS-2 and enterovirus rRT-PCR inhibitions were correlated. Specifically 23 RNA extracts from stool suspensions were spiked with enterovirus RNA after extraction and 13 of these stool suspension were spiked with intact enterovirus before extraction. MS2 rRT-PCR inhibition varied for RNAs extracted by the different systems. Inhibition was noted in 12 (13.0%), 26 (28.3%), 7 (7.6%), and 7 (7.6%) of the first 93 RNA extracts, and 58 (63.0%), 55 (59.8%), 37 (40.2%) and 30 (32.6%) of the second 92 extracts for A, B, C, and D, respectively. Furthermore, enterovirus rRT-PCR inhibition correlated with MS2 rRT-PCR inhibition for added enterovirus RNA or virus particles. In conclusion, rRT-PCR for MS-2 RNA is a good predictor of inhibition of enterovirus RNA extracted from stool suspensions. EasyMag performed the best, however all four extraction methods were suitable provided that external controls identified problematic samples. PMID- 22815707 TI - A new body shape index predicts mortality hazard independently of body mass index. AB - BACKGROUND: Obesity, typically quantified in terms of Body Mass Index (BMI) exceeding threshold values, is considered a leading cause of premature death worldwide. For given body size (BMI), it is recognized that risk is also affected by body shape, particularly as a marker of abdominal fat deposits. Waist circumference (WC) is used as a risk indicator supplementary to BMI, but the high correlation of WC with BMI makes it hard to isolate the added value of WC. METHODS AND FINDINGS: We considered a USA population sample of 14,105 non pregnant adults (age >= 18) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 with follow-up for mortality averaging 5 yr (828 deaths). We developed A Body Shape Index (ABSI) based on WC adjusted for height and weight: ABSI = WC/(BMI(2/3)height(1/2)). ABSI had little correlation with height, weight, or BMI. Death rates increased approximately exponentially with above average baseline ABSI (overall regression coefficient of +33% per standard deviation of ABSI [95% confidence interval: +20%-+48%), whereas elevated death rates were found for both high and low values of BMI and WC. 22% (8%-41%) of the population mortality hazard was attributable to high ABSI, compared to 15% (3% 30%) for BMI and 15% (4%-29%) for WC. The association of death rate with ABSI held even when adjusted for other known risk factors including smoking, diabetes, blood pressure, and serum cholesterol. ABSI correlation with mortality hazard held across the range of age, sex, and BMI, and for both white and black ethnicities (but not for Mexican ethnicity), and was not weakened by excluding deaths from the first 3 yr of follow-up. CONCLUSIONS: Body shape, as measured by ABSI, appears to be a substantial risk factor for premature mortality in the general population derivable from basic clinical measurements. ABSI expresses the excess risk from high WC in a convenient form that is complementary to BMI and to other known risk factors. PMID- 22815708 TI - Arterial structure and function in mild primary hyperparathyroidism is not directly related to parathyroid hormone, calcium, or vitamin D. AB - OBJECTIVE: Elevated levels of calcium and parathyroid hormone (PTH), characteristics of primary hyperparathyroidism (PHPT), may be associated with cardiovascular morbidity and mortality in the general population. We evaluated the possible vascular effects of these risk factors in patients with mild PHPT by using standard methods and new imaging techniques. DESIGN: A prospective case control study. SUBJECTS AND METHODS: Forty-eight patients with mild PHPT without any known cardiovascular risk factors were studied at baseline and at one year after parathyroidectomy (PTX) in comparison with 48 healthy age- and gender matched controls. We measured biochemical variables, augmentation index (AIx), aortic pulse wave velocity (PWV(ao)), radial (IMT(rad)) and common carotid artery (IMT(cca)) intima media thicknesses, and the grayscale median (IM-GSM) of the latter. RESULTS: No significant differences were observed between PHPT patients and controls at baseline for AIx (28.6+/-12.2 vs. 27.7+/-12.8%), IMT(rad) (0.271+/-0.060 vs. 0.255+/-0.053 mm), IMT(cca) (0.688+/-0.113 vs. 0.680+/-0.135 mm), or IM-GSM (82.3+/-17.2 vs. 86.5+/-15.3), while PWV(ao) was slightly higher in patients (8.68+/-1.50 vs. 8.13+/-1.55, p<0.05). Systolic blood pressure (SBP), calcium, and PTH were higher in patients compared with controls, and decreased after PTX, while vitamin D was lower in patients and increased after PTX. While AIx, PWV(ao), IMT(rad), and IMT(cca) were related to SBP, neither correlated to vitamin D levels. Only PWV(ao) correlated weakly to plasma PTH (r = 0.29, p<0.01) and ionized calcium (r = 0.22, p<0.05) but showed no relation when age and SBP were adjusted for. CONCLUSION: We found normal arterial function despite high calcium, PTH, and low vitamin D levels, in patients with mild PHPT without cardiovascular risk factors. The cardiovascular risk associated with low vitamin D and/or high PTH and calcium levels may be explained by their coupling to blood pressure and other risk factors rather than direct effects on arterial structure. PMID- 22815709 TI - N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity. AB - The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (n = 7); 2--Nx+NAC (n = 6); 3--Nx+Gd (n = 7); 4- Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (ug/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (ug/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure. PMID- 22815710 TI - The irreversible loss of a decomposition pathway marks the single origin of an ectomycorrhizal symbiosis. AB - Microbial symbioses have evolved repeatedly across the tree of life, but the genetic changes underlying transitions to symbiosis are largely unknown, especially for eukaryotic microbial symbionts. We used the genus Amanita, an iconic group of mushroom-forming fungi engaged in ectomycorrhizal symbioses with plants, to identify both the origins and potential genetic changes maintaining the stability of this mutualism. A multi-gene phylogeny reveals one origin of the symbiosis within Amanita, with a single transition from saprotrophic decomposition of dead organic matter to biotrophic dependence on host plants for carbon. Associated with this transition are the losses of two cellulase genes, each of which plays a critical role in extracellular decomposition of organic matter. However a third gene, which acts at later stages in cellulose decomposition, is retained by many, but not all, ectomycorrhizal species. Experiments confirm that symbiotic Amanita species have lost the ability to grow on complex organic matter and have therefore lost the capacity to live in forest soils without carbon supplied by a host plant. Irreversible losses of decomposition pathways are likely to play key roles in the evolutionary stability of these ubiquitous mutualisms. PMID- 22815711 TI - Beyond captions: linking figures with abstract sentences in biomedical articles. AB - Although figures in scientific articles have high information content and concisely communicate many key research findings, they are currently under utilized by literature search and retrieval systems. Many systems ignore figures, and those that do not typically only consider caption text. This study describes and evaluates a fully automated approach for associating figures in the body of a biomedical article with sentences in its abstract. We use supervised methods to learn probabilistic language models, hidden Markov models, and conditional random fields for predicting associations between abstract sentences and figures. Three kinds of evidence are used: text in abstract sentences and figures, relative positions of sentences and figures, and the patterns of sentence/figure associations across an article. Each information source is shown to have predictive value, and models that use all kinds of evidence are more accurate than models that do not. Our most accurate method has an F1-score of 69% on a cross-validation experiment, is competitive with the accuracy of human experts, has significantly better predictive accuracy than state-of-the-art methods and enables users to access figures associated with an abstract sentence with an average of 1.82 fewer mouse clicks. A user evaluation shows that human users find our system beneficial. The system is available at http://FigureItOut.askHERMES.org. PMID- 22815712 TI - High-throughput multilocus sequence typing: bringing molecular typing to the next level. AB - Multilocus sequence typing (MLST) is a widely used system for typing microorganisms by sequence analysis of housekeeping genes. The main advantage of MLST in comparison to other typing techniques is the unambiguity and transferability of sequence data. However, a main disadvantage is the high cost of DNA sequencing. Here we introduce a high-throughput MLST (HiMLST) method that employs next-generation sequencing (NGS) technology (Roche 454), to generate large quantities of high-quality MLST data at low costs. The HiMLST protocol consists of two steps. In the first step MLST target genes are amplified by PCR in multi-well plates. During this PCR the amplicons of each bacterial isolate are provided with a unique DNA barcode, the multiplex identifier (MID). In the second step all amplicons are pooled and sequenced in a single NGS-run. The MLST profile of each individual isolate can be retrieved easily using its unique MID. With HiMLST we have profiled 575 isolates of Legionella pneumophila, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pneumoniae in mixed species HiMLST experiments. In conclusion, the introduction of HiMLST paves the way for a broad employment of the MLST as a high-quality and cost-effective method for typing microbial species. PMID- 22815713 TI - CACTI: free, open-source software for the sequential coding of behavioral interactions. AB - The sequential analysis of client and clinician speech in psychotherapy sessions can help to identify and characterize potential mechanisms of treatment and behavior change. Previous studies required coding systems that were time consuming, expensive, and error-prone. Existing software can be expensive and inflexible, and furthermore, no single package allows for pre-parsing, sequential coding, and assignment of global ratings. We developed a free, open-source, and adaptable program to meet these needs: The CASAA Application for Coding Treatment Interactions (CACTI). Without transcripts, CACTI facilitates the real-time sequential coding of behavioral interactions using WAV-format audio files. Most elements of the interface are user-modifiable through a simple XML file, and can be further adapted using Java through the terms of the GNU Public License. Coding with this software yields interrater reliabilities comparable to previous methods, but at greatly reduced time and expense. CACTI is a flexible research tool that can simplify psychotherapy process research, and has the potential to contribute to the improvement of treatment content and delivery. PMID- 22815714 TI - Expression of Ccl11 associates with immune response modulation and protection against neuroinflammation in rats. AB - Multiple sclerosis (MS) is a polygenic disease characterized by inflammation and demyelination in the central nervous system (CNS), which can be modeled in experimental autoimmune encephalomyelitis (EAE). The Eae18b locus on rat chromosome 10 has previously been linked to regulation of beta-chemokine expression and severity of EAE. Moreover, the homologous chemokine cluster in humans showed evidence of association with susceptibility to MS. We here established a congenic rat strain with Eae18b locus containing a chemokine cluster (Ccl2, Ccl7, Ccl11, Ccl12 and Ccl1) from the EAE- resistant PVG rat strain on the susceptible DA background and utilized myelin oligodendrocyte glycoprotein (MOG)-induced EAE to characterize the mechanisms underlying the genetic regulation. Congenic rats developed a milder disease compared to the susceptible DA strain, and this was reflected in decreased demyelination and in reduced recruitment of inflammatory cells to the brain. The congenic strain also showed significantly increased Ccl11 mRNA expression in draining lymph nodes and spinal cord after EAE induction. In the lymph nodes, macrophages were the main producers of CCL11, whereas macrophages and lymphocytes expressed the main CCL11 receptor, namely CCR3. Accordingly, the congenic strain also showed significantly increased Ccr3 mRNA expression in lymph nodes. In the CNS, the main producers of CCL11 were neurons, whereas CCR3 was detected on neurons and CSF producing ependymal cells. This corresponded to increased levels of CCL11 protein in the cerebrospinal fluid of the congenic rats. Increased intrathecal production of CCL11 in congenic rats was accompanied by a tighter blood brain barrier, reflected by more occludin(+) blood vessels. In addition, the congenic strain showed a reduced antigen specific response and a predominant anti-inflammatory Th2 phenotype. These results indicate novel mechanisms in the genetic regulation of neuroinflammation. PMID- 22815715 TI - Reaction networks as systems for resource allocation: a variational principle for their non-equilibrium steady states. AB - Within a fully microscopic setting, we derive a variational principle for the non equilibrium steady states of chemical reaction networks, valid for time-scales over which chemical potentials can be taken to be slowly varying: at stationarity the system minimizes a global function of the reaction fluxes with the form of a Hopfield Hamiltonian with hebbian couplings, that is explicitly seen to correspond to the rate of decay of entropy production over time. Guided by this analogy, we show that reaction networks can be formally re-cast as systems of interacting reactions that optimize the use of the available compounds by competing for substrates, akin to agents competing for a limited resource in an optimal allocation problem. As an illustration, we analyze the scenario that emerges in two simple cases: that of toy (random) reaction networks and that of a metabolic network model of the human red blood cell. PMID- 22815716 TI - MassTRIX reloaded: combined analysis and visualization of transcriptome and metabolome data. AB - Systems Biology is a field in biological science that focuses on the combination of several or all "omics"-approaches in order to find out how genes, transcripts, proteins and metabolites act together in the network of life. Metabolomics as analog to genomics, transcriptomics and proteomics is more and more integrated into biological studies and often transcriptomic and metabolomic experiments are combined in one setup. At a first glance both data types seem to be completely different, but both produce information on biological entities, either transcripts or metabolites. Both types can be overlaid on metabolic pathways to obtain biological information on the studied system. For the joint analysis of both data types the MassTRIX webserver was updated. MassTRIX is freely available at www.masstrix.org. PMID- 22815717 TI - Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. AB - Depending on the strength of signal dose, CD40 receptor (CD40) controls ERK-1/2 and p38MAPK activation. At low signal dose, ERK-1/2 is maximally phosphorylated but p38MAPK is minimally phosphorylated; as the signal dose increases, ERK-1/2 phosphorylation is reduced whereas p38MAPK phosphorylation is reciprocally enhanced. The mechanism of reciprocal activation of these two MAPKs remains un elucidated. Here, our computational model, coupled to experimental perturbations, shows that the observed reciprocity is a system-level behavior of an assembly of kinases arranged in two modules. Experimental perturbations with kinase inhibitors suggest that a minimum of two trans-modular negative feedback loops are required to reproduce the experimentally observed reciprocity. The bi-modular architecture of the signaling pathways endows the system with an inherent plasticity which is further expressed in the skewing of the CD40-induced productions of IL-10 and IL-12, the respective anti-inflammatory and pro inflammatory cytokines. Targeting the plasticity of CD40 signaling significantly reduces Leishmania major infection in a susceptible mouse strain. Thus, for the first time, using CD40 signaling as a model, we show how a bi-modular assembly of kinases imposes reciprocity to a receptor signaling. The findings unravel that the signalling plasticity is inherent to a reciprocal system and that the principle can be used for designing a therapy. PMID- 22815718 TI - The diagnostic accuracy of urine-based Xpert MTB/RIF in HIV-infected hospitalized patients who are smear-negative or sputum scarce. AB - BACKGROUND: Hospitals in sub-Saharan Africa are inundated with HIV-infected patients and tuberculosis (TB) is the commonest opportunistic infection in this sub-group. Up to one third of TB-HIV co-infected patients fail to produce a sputum sample (sputum scarce) and diagnosis is thus often delayed or missed. We investigated the sensitivity of urine-based methods (Xpert MTB/RIF, LAM strip test and LAM ELISA) in such patients. METHODOLOGY/PRINCIPAL FINDINGS: 281 HIV infected hospitalised patients with clinically suspected TB provided a spot urine sample. The reference standard was culture positivity for Mycobacterium tuberculosis on >=1 sputum or extra-pulmonary sample. MTB/RIF was performed using 1 ml of both unprocessed and, when possible, concentrated urine. Each unconcentrated urine sample was also tested using the Clearview LAM ELISA and Alere LAM strip test. 42% (116/242) of patients had culture-proven TB. 18% (20/54) were sputum scarce. In sputum-scarce patients, the sensitivity of urine MTB/RIF and LAM ELISA was 40% (95%CI: 22-61) and 60% (95%CI: 39-78), respectively. Urine MTB/RIF specificity was 98% (95%CI: 95-100). Combined sensitivity of urine LAM ELISA and MTB/RIF was better than MTB/RIF alone [MTB/RIF and LAM: 70% (95%CI: 48-85) vs. MTB/RIF: 40% (95%CI: 22-61), p = 0.03]. Significant predictors of urine MTB/RIF positivity were CD4<50 cells/ml (p = 0.001), elevated protein-to-creatinine ratio (p<0.001) and LAM ELISA positivity (p<0.001). Urine centrifugation and pelleting significantly increased the sensitivity of MTB/RIF over unprocessed urine in paired samples [42% (95%CI: 26 58) vs. 8% (95%CI: 0-16), p<0.001]. Urine MTB/RIF-generated C(T) values correlated poorly with markers of bacillary burden (smear grade and time-to positivity). CONCLUSIONS/SIGNIFICANCE: This preliminary study indicates that urine-based MTB/RIF, alone or in combination with LAM antigen detection, may potentially aid the diagnosis of TB in HIV-infected patients with advanced immunosuppression when sputum-based diagnosis is not possible. Concentration of urine prior to MTB/RIF-testing significantly improves sensitivity. PMID- 22815719 TI - Mechanical stretch and PI3K signaling link cell migration and proliferation to coordinate epithelial tubule morphogenesis in the zebrafish pronephros. AB - Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function "feeds back" to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology. PMID- 22815720 TI - Opportunities of habitat connectivity for tiger (Panthera tigris) between Kanha and Pench National Parks in Madhya Pradesh, India. AB - The Tiger (Panthera tigris) population in India has undergone a sharp decline during the last few years. Of the number of factors attributed to this decline, habitat fragmentation has been the most worrisome. Wildlife corridors have long been a subject of discussion amongst wildlife biologists and conservationists with contrasting schools of thought arguing their merits and demerits. However, it is largely believed that wildlife corridors can help minimize genetic isolation, offset fragmentation problems, improve animal dispersal, restore ecological processes and reduce man animal conflict. This study attempted to evaluate the possibilities of identifying a suitable wildlife corridor between two very important wildlife areas of central India--the Kanha National Park and the Pench National Park--with tiger as the focal species. Geographic Information System (GIS) centric Least Cost Path modeling was used to identify likely routes for movement of tigers. Habitat suitability, perennial water bodies, road density, railway tracks, human settlement density and total forest edge were considered as key variables influencing tiger movement across the Kanha-Pench landscape. Each of these variables was weighted in terms of relative importance through an expert consultation process. Using different importance scenarios, three alternate corridor routes were generated of which one was identified as the most promising for tiger dispersal. Weak links--where cover and habitat conditions are currently sub-optimal--were flagged on the corridor route. Interventions aimed at augmenting the identified corridor route have been suggested using accepted wildlife corridor design principles. The involvement of local communities through initiatives such as ecotourism has been stressed as a crucial long term strategy for conservation of the Kanha-Pench wildlife corridor. The results of the study indicate that restoration of the identified wildlife corridors between the two protected areas is technically feasible. PMID- 22815721 TI - Comparison of WTC dust size on macrophage inflammatory cytokine release in vivo and in vitro. AB - BACKGROUND: The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ~50 mm were recovered from rescue workers' lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways. METHODOLOGY/PRINCIPAL FINDINGS: Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM(10-53) or WTC-PM(2.5) at concentrations of 10, 50 or 100 ug/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM(10-53) and PM(2.5). GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM(10-53) and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM(10-53) consistently induced more cytokine release than WTC-PM(2.5) at 100 ug/mL. Individual baseline expression correlated with WTC-PM induced GM-CSF and MDC. CONCLUSIONS: WTC-PM(10-53) induced a stronger inflammatory response by human AM than WTC-PM(2.5). This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure. PMID- 22815722 TI - From single molecule fluctuations to muscle contraction: a Brownian model of A.F. Huxley's hypotheses. AB - Muscular force generation in response to external stimuli is the result of thermally fluctuating, cyclical interactions between myosin and actin, which together form the actomyosin complex. Normally, these fluctuations are modelled using transition rate functions that are based on muscle fiber behaviour, in a phenomenological fashion. However, such a basis reduces the predictive power of these models. As an alternative, we propose a model which uses direct single molecule observations of actomyosin fluctuations reported in the literature. We precisely estimate the actomyosin potential bias and use diffusion theory to obtain a brownian ratchet model that reproduces the complete cross-bridge cycle. The model is validated by simulating several macroscopic experimental conditions, while its interpretation is compatible with two different force-generating scenarios. PMID- 22815723 TI - Experimental design for parameter estimation of gene regulatory networks. AB - Systems biology aims for building quantitative models to address unresolved issues in molecular biology. In order to describe the behavior of biological cells adequately, gene regulatory networks (GRNs) are intensively investigated. As the validity of models built for GRNs depends crucially on the kinetic rates, various methods have been developed to estimate these parameters from experimental data. For this purpose, it is favorable to choose the experimental conditions yielding maximal information. However, existing experimental design principles often rely on unfulfilled mathematical assumptions or become computationally demanding with growing model complexity. To solve this problem, we combined advanced methods for parameter and uncertainty estimation with experimental design considerations. As a showcase, we optimized three simulated GRNs in one of the challenges from the Dialogue for Reverse Engineering Assessment and Methods (DREAM). This article presents our approach, which was awarded the best performing procedure at the DREAM6 Estimation of Model Parameters challenge. For fast and reliable parameter estimation, local deterministic optimization of the likelihood was applied. We analyzed identifiability and precision of the estimates by calculating the profile likelihood. Furthermore, the profiles provided a way to uncover a selection of most informative experiments, from which the optimal one was chosen using additional criteria at every step of the design process. In conclusion, we provide a strategy for optimal experimental design and show its successful application on three highly nonlinear dynamic models. Although presented in the context of the GRNs to be inferred for the DREAM6 challenge, the approach is generic and applicable to most types of quantitative models in systems biology and other disciplines. PMID- 22815724 TI - Resolving the stiffening-softening paradox in cell mechanics. AB - BACKGROUND: Despite their notorious diversity, biological cells are mechanically well characterized by only a few robust and universal laws. Intriguingly, the law characterizing the nonlinear response to stretch appears self-contradictory. Various cell types have been reported to both stiffen and soften, or "fluidize" upon stretch. Within the classical paradigm of cells as viscoelastic bodies, this constitutes a paradox. PRINCIPAL FINDINGS: Our measurements reveal that minimalistic reconstituted cytoskeletal networks (F-actin/HMM) exhibit a similarly peculiar response. A mathematical model of transiently crosslinked polymer networks, the so-called inelastic glassy wormlike chain (iGwlc) model, can simulate the data and resolve the apparent contradiction. It explains the observations in terms of two antagonistic physical mechanisms, the nonlinear viscoelastic resistance of biopolymers to stretch, and the breaking of weak transient bonds between them. CONCLUSIONS: Our results imply that the classical paradigm of cells as viscoelastic bodies has to be replaced by such an inelastic mechanical model. PMID- 22815725 TI - Interplay between path and speed in decision making by high-dimensional stochastic gene regulatory networks. AB - Induction of a specific transcriptional program by external signaling inputs is a crucial aspect of intracellular network functioning. The theoretical concept of coexisting attractors representing particular genetic programs is reasonably adapted to experimental observations of "genome-wide" expression profiles or phenotypes. Attractors can be associated either with developmental outcomes such as differentiation into specific types of cells, or maintenance of cell functioning such as proliferation or apoptosis. Here we review a mechanism known as speed-dependent cellular decision making (SdCDM) in a small epigenetic switch and generalize the concept to high-dimensional space. We demonstrate that high dimensional network clustering capacity is dependent on the level of intrinsic noise and the speed at which external signals operate on the transcriptional landscape. PMID- 22815726 TI - Role of demographic dynamics and conflict in the population-area relationship for human languages. AB - Many patterns displayed by the distribution of human linguistic groups are similar to the ecological organization described for biological species. It remains a challenge to identify simple and meaningful processes that describe these patterns. The population size distribution of human linguistic groups, for example, is well fitted by a log-normal distribution that may arise from stochastic demographic processes. As we show in this contribution, the distribution of the area size of home ranges of those groups also agrees with a log-normal function. Further, size and area are significantly correlated: the number of speakers p and the area a spanned by linguistic groups follow the allometric relation a proportional to p2, with an exponent z varying accross different world regions. The empirical evidence presented leads to the hypothesis that the distributions of p and a, and their mutual dependence, rely on demographic dynamics and on the result of conflicts over territory due to group growth. To substantiate this point, we introduce a two-variable stochastic multiplicative model whose analytical solution recovers the empirical observations. Applied to different world regions, the model reveals that the retreat in home range is sublinear with respect to the decrease in population size, and that the population-area exponent z grows with the typical strength of conflicts. While the shape of the population size and area distributions, and their allometric relation, seem unavoidable outcomes of demography and inter group contact, the precise value of z could give insight on the cultural organization of those human groups in the last thousand years. PMID- 22815727 TI - HIV model parameter estimates from interruption trial data including drug efficacy and reservoir dynamics. AB - Mathematical models based on ordinary differential equations (ODE) have had significant impact on understanding HIV disease dynamics and optimizing patient treatment. A model that characterizes the essential disease dynamics can be used for prediction only if the model parameters are identifiable from clinical data. Most previous parameter identification studies for HIV have used sparsely sampled data from the decay phase following the introduction of therapy. In this paper, model parameters are identified from frequently sampled viral-load data taken from ten patients enrolled in the previously published AutoVac HAART interruption study, providing between 69 and 114 viral load measurements from 3-5 phases of viral decay and rebound for each patient. This dataset is considerably larger than those used in previously published parameter estimation studies. Furthermore, the measurements come from two separate experimental conditions, which allows for the direct estimation of drug efficacy and reservoir contribution rates, two parameters that cannot be identified from decay-phase data alone. A Markov-Chain Monte-Carlo method is used to estimate the model parameter values, with initial estimates obtained using nonlinear least-squares methods. The posterior distributions of the parameter estimates are reported and compared for all patients. PMID- 22815728 TI - Birth weight, breast cancer and the potential mediating hormonal environment. AB - BACKGROUND: Previous studies have shown that woman's risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother's own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer. METHODS AND FINDINGS: Risk of breast cancer in relation to a first infant's birth weight, mother's own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6%) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2-5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2-5.6; P = 0.021). An infant's birth weight had a strong positive relationship with the mother's serum E3/AFP ratio and PAPP A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships. CONCLUSIONS: Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother's own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression. PMID- 22815730 TI - Egg speckling patterns do not advertise offspring quality or influence male provisioning in great tits. AB - Many passerine birds lay white eggs with reddish brown speckles produced by protoporphyrin pigment. However, the function of these spots is contested. Recently, the sexually selected eggshell coloration (SSEC) hypothesis proposed that eggshell color is a sexually selected signal through which a female advertises her quality (and hence the potential quality of her future young) to her male partner, thereby encouraging him to contribute more to breeding attempts. We performed a test of the SSEC hypothesis in a common passerine, the great tit Parus major. We used a double cross-fostering design to determine whether males change their provisioning behavior based on eggshell patterns they observe at the nest. We also tested the assumption that egg patterning reflects female and/or offspring quality. Because birds differ from humans in their color and pattern perception, we used digital photography and models of bird vision to quantify egg patterns objectively. Neither male provisioning nor chick growth was related to the pattern of eggs males observed during incubation. Although heavy females laid paler, less speckled eggs, these eggs did not produce chicks that grew faster. Therefore, we conclude that the SSEC hypothesis is an unlikely explanation for the evolution of egg speckling in great tits. PMID- 22815729 TI - Immunosignaturing can detect products from molecular markers in brain cancer. AB - Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer's disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naive brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O(6)-methyl-guanine DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients. PMID- 22815731 TI - Construction of whole genome radiation hybrid panels and map of chromosome 5A of wheat using asymmetric somatic hybridization. AB - To explore the feasibility of constructing a whole genome radiation hybrid (WGRH) map in plant species with large genomes, asymmetric somatic hybridization between wheat (Triticum aestivum L.) and Bupleurum scorzonerifolium Willd. was performed. The protoplasts of wheat were irradiated with ultraviolet light (UV) and gamma ray and rescued by protoplast fusion using B. scorzonerifolium as the recipient. Assessment of SSR markers showed that the radiation hybrids have the average marker retention frequency of 15.5%. Two RH panels (RHPWI and RHPWII) that contained 92 and 184 radiation hybrids, respectively, were developed and used for mapping of 68 SSR markers in chromosome 5A of wheat. A total of 1557 and 2034 breaks were detected in each panel. The RH map of chromosome 5A based on RHPWII was constructed. The distance of the comprehensive map was 2103 cR and the approximate resolution was estimated to be ~501.6 kb/break. The RH panels evaluated in this study enabled us to order the ESTs in a single deletion bin or in the multiple bins cross the chromosome. These results demonstrated that RH mapping via protoplast fusion is feasible at the whole genome level for mapping purposes in wheat and the potential value of this mapping approach for the plant species with large genomes. PMID- 22815732 TI - Effect of early detection and treatment on malaria related maternal mortality on the north-western border of Thailand 1986-2010. AB - INTRODUCTION: Maternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand. METHODS AND FINDINGS: All medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12(th) May 1986 to 31(st) December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150-230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200-780) in 1986-90 to 79 (40-170) in 2006-10, p<0.05. In migrants from adjacent Myanmar the decline in MMR was less significant: 588 (100 3260) to 252 (150-430) from 1996-2000 to 2006-2010. Mortality from P. falciparum malaria in pregnancy dropped sharply with the introduction of systematic screening and treatment and continued to decline with the reduction in the incidence of malaria in the communities. P. vivax was not a cause of maternal death in this population. Infection (non-puerperal sepsis and P. falciparum malaria) accounted for 39.7 (27/68) % of all deaths. CONCLUSIONS: Frequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P. falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai-Myanmar border. PMID- 22815733 TI - An Asian validation of the TIMI risk score for ST-segment elevation myocardial infarction. AB - BACKGROUND: Risk stratification in ST-elevation myocardial infarction (STEMI) is important, such that the most resource intensive strategy is used to achieve the greatest clinical benefit. This is essential in developing countries with wide variation in health care facilities, scarce resources and increasing burden of cardiovascular diseases. This study sought to validate the Thrombolysis In Myocardial Infarction (TIMI) risk score for STEMI in a multi-ethnic developing country. METHODS: Data from a national, prospective, observational registry of acute coronary syndromes was used. The TIMI risk score was evaluated in 4701 patients who presented with STEMI. Model discrimination and calibration was tested in the overall population and in subgroups of patients that were at higher risk of mortality; i.e., diabetics and those with renal impairment. RESULTS: Compared to the TIMI population, this study population was younger, had more chronic conditions, more severe index events and received treatment later. The TIMI risk score was strongly associated with 30-day mortality. Discrimination was good for the overall study population (c statistic 0.785) and in the high risk subgroups; diabetics (c statistic 0.764) and renal impairment (c statistic 0.761). Calibration was good for the overall study population and diabetics, with chi2 goodness of fit test p value of 0.936 and 0.983 respectively, but poor for those with renal impairment, chi2 goodness of fit test p value of 0.006. CONCLUSIONS: The TIMI risk score is valid and can be used for risk stratification of STEMI patients for better targeted treatment. PMID- 22815734 TI - Impact of perinatal dioxin exposure on infant growth: a cross-sectional and longitudinal studies in dioxin-contaminated areas in Vietnam. AB - Dioxin exposure levels remain elevated in residents living around former US Air Force bases in Vietnam, indicating potential adverse impacts on infant growth. In this study, 210 mother-infant pairs in dioxin-contaminated areas in Vietnam were recruited at the infants' birth and followed up for 4 months. Perinatal dioxin exposure levels were estimated by measurement of polychlorinated dibenzo-p dioxins/furans toxic equivalent (PCDDs/Fs-TEQ) in breast milk. The infants' size was measured at birth and 1 and 4 months after birth, and neurodevelopment was evaluated using the Bayley Scales III at 4 months of age. Among 4 dioxin groups (<25, 25-50, 50-75, >=75 percentile of PCDDs/Fs-TEQ), cross-sectional comparisons of body size and neurodevelopment scales and comparisons of longitudinally assessed body size were performed respectively. At birth, head circumference of girls in the >=75 percentile group was significantly larger than those in the <25 and 50-75 percentile groups. At 4 months of age, the weight and body mass index (BMI) of boys in the >=75 percentile group were significantly lower than those in the other groups. Increase in weight was significantly lower in the >=75 percentile group in both sexes from birth to 1 month but only in boys at 1-4 months of age. Estimated marginal mean values in a mixed model of weight and BMI during the first 4 months of life were significantly lower in the >=75 percentile group in boys. In girls, marginal mean values for head circumference were increased with increase in dioxin levels. Only in boys, cognitive, language, and fine motor scores in the >=75 percentile group were significantly lower than those in the other groups. These results suggested a considerable impact of perinatal dioxin exposure on infant growth, particularly in boys exposed to dioxins at high level of PCDDs/Fs-TEQ. PMID- 22815735 TI - Analysing the role of UVB-induced translational inhibition and PP2Ac deactivation in NF-kappaB signalling using a minimal mathematical model. AB - Activation of nuclear factor kappaB (NF-kappaB) by interleukin-1beta (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kappaB dependent resynthesis of its own inhibitor IkappaBalpha. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-kappaB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of IkappaBalpha recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKKbeta phosphorylation is shown to be a decisive process in IkappaBalpha degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of IkappaBalpha recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of IkappaBalpha. This shows that the processes leading to activation of transcription factor NF-kappaB upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting. PMID- 22815736 TI - A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII. AB - Hundreds of different human skeletal disorders have been characterized at molecular level and a growing number of resembling dysplasias with orthologous genetic defects are being reported in dogs. This study describes a novel genetic defect in the Brazilian Terrier breed causing a congenital skeletal dysplasia. Affected puppies presented severe skeletal deformities observable within the first month of life. Clinical characterization using radiographic and histological methods identified delayed ossification and spondyloepiphyseal dysplasia. Pedigree analysis suggested an autosomal recessive disorder, and we performed a genome-wide association study to map the disease locus using Illumina's 22K SNP chip arrays in seven cases and eleven controls. A single association was observed near the centromeric end of chromosome 6 with a genome wide significance after permutation (p(genome)= 0.033). The affected dogs shared a 13-Mb homozygous region including over 200 genes. A targeted next-generation sequencing of the entire locus revealed a fully segregating missense mutation (c.866C>T) causing a pathogenic p.P289L change in a conserved functional domain of beta-glucuronidase (GUSB). The mutation was confirmed in a population of 202 Brazilian terriers (p = 7,71*10(-29)). GUSB defects cause mucopolysaccharidosis VII (MPS VII) in several species and define the skeletal syndrome in Brazilian Terriers. Our results provide new information about the correlation of the GUSB genotype to phenotype and establish a novel canine model for MPS VII. Currently, MPS VII lacks an efficient treatment and this model could be utilized for the development and validation of therapeutic methods for better treatment of MPS VII patients. Finally, since almost one third of the Brazilian terrier population carries the mutation, breeders will benefit from a genetic test to eradicate the detrimental disease from the breed. PMID- 22815737 TI - Maximum diastolic potential of human induced pluripotent stem cell-derived cardiomyocytes depends critically on I(Kr). AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) hold promise for therapeutic applications. To serve these functions, the hiPSC-CM must recapitulate the electrophysiologic properties of native adult cardiomyocytes. This study examines the electrophysiologic characteristics of hiPSC-CM between 11 and 121 days of maturity. Embryoid bodies (EBs) were generated from hiPS cell line reprogrammed with Oct4, Nanog, Lin28 and Sox2. Sharp microelectrodes were used to record action potentials (AP) from spontaneously beating clusters (BC) micro-dissected from the EBs (n = 103; 37 degrees C) and to examine the response to 5 uM E-4031 (n = 21) or BaCl(2) (n = 22). Patch-clamp techniques were used to record I(Kr) and I(K1) from cells enzymatically dissociated from BC (n = 49; 36 degrees C). Spontaneous cycle length (CL) and AP characteristics varied widely among the 103 preparations. E-4031 (5 uM; n = 21) increased Bazett-corrected AP duration from 291.8+/-81.2 to 426.4+/-120.2 msec (p<0.001) and generated early afterdepolarizations in 8/21 preparations. In 13/21 BC, E-4031 rapidly depolarized the clusters leading to inexcitability. BaCl(2), at concentrations that selectively block I(K1) (50-100 uM), failed to depolarize the majority of clusters (13/22). Patch-clamp experiments revealed very low or negligible I(K1) in 53% (20/38) of the cells studied, but presence of I(Kr) in all (11/11). Consistent with the electrophysiological data, RT-PCR and immunohistochemistry studies showed relatively poor mRNA and protein expression of I(K1) in the majority of cells, but robust expression of I(Kr.) In contrast to recently reported studies, our data point to major deficiencies of hiPSC-CM, with remarkable diversity of electrophysiologic phenotypes as well as pharmacologic responsiveness among beating clusters and cells up to 121 days post differentiation (dpd). The vast majority have a maximum diastolic potential that depends critically on I(Kr) due to the absence of I(K1). Thus, efforts should be directed at producing more specialized and mature hiPSC-CM for future therapeutic applications. PMID- 22815738 TI - Gene Expression Commons: an open platform for absolute gene expression profiling. AB - Gene expression profiling using microarrays has been limited to comparisons of gene expression between small numbers of samples within individual experiments. However, the unknown and variable sensitivities of each probeset have rendered the absolute expression of any given gene nearly impossible to estimate. We have overcome this limitation by using a very large number (>10,000) of varied microarray data as a common reference, so that statistical attributes of each probeset, such as the dynamic range and threshold between low and high expression, can be reliably discovered through meta-analysis. This strategy is implemented in a web-based platform named "Gene Expression Commons" (https://gexc.stanford.edu/) which contains data of 39 distinct highly purified mouse hematopoietic stem/progenitor/differentiated cell populations covering almost the entire hematopoietic system. Since the Gene Expression Commons is designed as an open platform, investigators can explore the expression level of any gene, search by expression patterns of interest, submit their own microarray data, and design their own working models representing biological relationship among samples. PMID- 22815739 TI - Process-driven inference of biological network structure: feasibility, minimality, and multiplicity. AB - A common problem in molecular biology is to use experimental data, such as microarray data, to infer knowledge about the structure of interactions between important molecules in subsystems of the cell. By approximating the state of each molecule as "on" or "off", it becomes possible to simplify the problem, and exploit the tools of boolean analysis for such inference. Amongst boolean techniques, the process-driven approach has shown promise in being able to identify putative network structures, as well as stability and modularity properties. This paper examines the process-driven approach more formally, and makes four contributions about the computational complexity of the inference problem, under the "dominant inhibition" assumption of molecular interactions. The first is a proof that the feasibility problem (does there exist a network that explains the data?) can be solved in polynomial-time. Second, the minimality problem (what is the smallest network that explains the data?) is shown to be NP hard, and therefore unlikely to result in a polynomial-time algorithm. Third, a simple polynomial-time heuristic is shown to produce near-minimal solutions, as demonstrated by simulation. Fourth, the theoretical framework explains how multiplicity (the number of network solutions to realize a given biological process), which can take exponential-time to compute, can instead be accurately estimated by a fast, polynomial-time heuristic. PMID- 22815740 TI - Information processing in social insect networks. AB - Investigating local-scale interactions within a network makes it possible to test hypotheses about the mechanisms of global network connectivity and to ask whether there are general rules underlying network function across systems. Here we use motif analysis to determine whether the interactions within social insect colonies resemble the patterns exhibited by other animal associations or if they exhibit characteristics of biological regulatory systems. Colonies exhibit a predominance of feed-forward interaction motifs, in contrast to the densely interconnected clique patterns that characterize human interaction and animal social networks. The regulatory motif signature supports the hypothesis that social insect colonies are shaped by selection for network patterns that integrate colony functionality at the group rather than individual level, and demonstrates the utility of this approach for analysis of selection effects on complex systems across biological levels of organization. PMID- 22815741 TI - VAPC, an human endogenous inhibitor for hepatitis C virus (HCV) infection, is intrinsically unstructured but forms a "fuzzy complex" with HCV NS5B. AB - Nearly 200 million people are infected by hepatitis C virus (HCV) worldwide. For replicating the HCV genome, the membrane-associated machinery needs to be formed by both HCV non-structural proteins (including NS5B) and human host factors such as VAPB. Recently, the 99-residue VAPC, a splicing variant of VAPB, was demonstrated to inhibit HCV replication via binding to NS5B, thus acting as an endogenous inhibitor of HCV infection. So far, the structure of VAPC remains unknown, and its interaction with NS5B has not been biophysically characterized. In this study, we conducted extensive CD and NMR investigations on VAPC which led to several striking findings: 1) although the N-terminal 70 residues are identical in VAPC and VAPB, they constitute the characteristic beta-barrel MSP fold in VAPB, while VAPC is entirely unstructured in solution, only with helical like conformations weakly populated. 2) VAPC is indeed capable of binding to NS5B, with an average dissociation constant (Kd) of ~20 uM. Intriguingly, VAPC remains dynamic even in the complex, suggesting that the VAPC-NS5B is a "fuzzy complex". 3) NMR mapping revealed that the major binding region for NS5B is located over the C-terminal half of VAPC, which is composed of three discrete clusters, of which only the first contains the region identical in VAPC and VAPB. The second region containing ~12 residues appears to play a key role in binding since mutation of 4 residues within this region leads to almost complete loss of the binding activity. 4) A 14-residue mimetic, VAPC-14 containing the second region, only has a ~3-fold reduction of the affinity. Our study not only provides critical insights into how a human factor mediates the formation of the HCV replication machinery, but also leads to design of VAPC-14 which may be further used to explore the function of VAPC and to develop anti-HCV molecules. PMID- 22815742 TI - Neandertal humeri may reflect adaptation to scraping tasks, but not spear thrusting. AB - Unique compared with recent and prehistoric Homo sapiens, Neandertal humeri are characterised by a pronounced right-dominant bilateral strength asymmetry and an anteroposteriorly strengthened diaphyseal shape. Remodeling in response to asymmetric forces imposed during regular underhanded spear thrusting is the most influential explanatory hypothesis. The core tenet of the "Spear Thrusting Hypothesis", that underhand thrusting requires greater muscle activity on the right side of the body compared to the left, remains untested. It is unclear whether alternative subsistence behaviours, such as hide processing, might better explain this morphology. To test this, electromyography was used to measure muscle activity at the primary movers of the humerus (pectoralis major (PM), anterior (AD) and posterior deltoid (PD)) during three distinct spear-thrusting tasks and four separate scraping tasks. Contrary to predictions, maximum muscle activity (MAX) and total muscle activity (TOT) were significantly higher (all values, p<.05) at the left (non-dominant) AD, PD and PM compared to the right side of the body during spear thrusting tasks. Thus, the muscle activity required during underhanded spearing tasks does not lend itself to explaining the pronounced right dominant strength asymmetry found in Neandertal humeri. In contrast, during the performance of all three unimanual scraping tasks, right side MAX and TOT were significantly greater at the AD (all values, p<.01) and PM (all values, p<.02) compared to the left. The consistency of the results provides evidence that scraping activities, such as hide preparation, may be a key behaviour in determining the unusual pattern of Neandertal arm morphology. Overall, these results yield important insight into the Neandertal behavioural repertoire that aided survival throughout Pleistocene Eurasia. PMID- 22815743 TI - Candidatus Sodalis melophagi sp. nov.: phylogenetically independent comparative model to the tsetse fly symbiont Sodalis glossinidius. AB - Bacteria of the genus Sodalis live in symbiosis with various groups of insects. The best known member of this group, a secondary symbiont of tsetse flies Sodalis glossinidius, has become one of the most important models in investigating establishment and evolution of insect-bacteria symbiosis. It represents a bacterium in the early/intermediate state of the transition towards symbiosis, which allows for exploring such interesting topics as: usage of secretory systems for entering the host cell, tempo of the genome modification, and metabolic interaction with a coexisting primary symbiont. In this study, we describe a new Sodalis species which could provide a useful comparative model to the tsetse symbiont. It lives in association with Melophagus ovinus, an insect related to tsetse flies, and resembles S. glossinidius in several important traits. Similar to S. glossinidius, it cohabits the host with another symbiotic bacterium, the bacteriome-harbored primary symbiont of the genus Arsenophonus. As a typical secondary symbiont, Candidatus Sodalis melophagi infects various host tissues, including bacteriome. We provide basic morphological and molecular characteristics of the symbiont and show that these traits also correspond to the early/intermediate state of the evolution towards symbiosis. Particularly, we demonstrate the ability of the bacterium to live in insect cell culture as well as in cell-free medium. We also provide basic characteristics of type three secretion system and using three reference sequences (16 S rDNA, groEL and spaPQR region) we show that the bacterium branched within the genus Sodalis, but originated independently of the two previously described symbionts of hippoboscoids. We propose the name Candidatus Sodalis melophagi for this new bacterium. PMID- 22815744 TI - Mouse allergen, lung function, and atopy in Puerto Rican children. AB - OBJECTIVE: To examine the relation between mouse allergen exposure and asthma in Puerto Rican children. METHODS: Mus m 1, Der p 1, Bla g 2, and Fel d 1 allergens were measured in dust samples from homes of Puerto Rican children with (cases) and without (controls) asthma in Hartford, CT (n = 449) and San Juan (SJ), Puerto Rico (n = 678). Linear or logistic regression was used for the multivariate analysis of mouse allergen (Mus m 1) and lung function (FEV(1) and FEV(1)/FVC) and allergy (total IgE and skin test reactivity (STR) to >=1 allergen) measures. RESULTS: Homes in SJ had lower mouse allergen levels than those in Hartford. In multivariate analyses, mouse allergen was associated with higher FEV(1) in cases in Hartford (+70.6 ml, 95% confidence interval (CI) = 8.6-132.7 ml, P = 0.03) and SJ (+45.1 ml, 95% CI = -0.5 to 90.6 ml, P = 0.05). In multivariate analyses of controls, mouse allergen was inversely associated with STR to >=1 allergen in non sensitized children (odds ratio [OR] for each log-unit increment in Mus m 1 = 0.7, 95% CI = 0.5-0.9, P<0.01). In a multivariate analysis including all children at both study sites, each log-increment in mouse allergen was positively associated with FEV(1) (+28.3 ml, 95% CI = 1.4-55.2 ml, P = 0.04) and inversely associated with STR to >=1 allergen (OR for each log-unit increment in Mus m 1 = 0.8, 95% CI = 0.6-0.9, P<0.01). CONCLUSIONS: Mouse allergen is associated with a higher FEV(1) and lower odds of STR to >=1 allergen in Puerto Rican children. This may be explained by the allergen itself or correlated microbial exposures. PMID- 22815745 TI - The statistics of urban scaling and their connection to Zipf's law. AB - Urban scaling relations characterizing how diverse properties of cities vary on average with their population size have recently been shown to be a general quantitative property of many urban systems around the world. However, in previous studies the statistics of urban indicators were not analyzed in detail, raising important questions about the full characterization of urban properties and how scaling relations may emerge in these larger contexts. Here, we build a self-consistent statistical framework that characterizes the joint probability distributions of urban indicators and city population sizes across an urban system. To develop this framework empirically we use one of the most granular and stochastic urban indicators available, specifically measuring homicides in cities of Brazil, Colombia and Mexico, three nations with high and fast changing rates of violent crime. We use these data to derive the conditional probability of the number of homicides per year given the population size of a city. To do this we use Bayes' rule together with the estimated conditional probability of city size given their number of homicides and the distribution of total homicides. We then show that scaling laws emerge as expectation values of these conditional statistics. Knowledge of these distributions implies, in turn, a relationship between scaling and population size distribution exponents that can be used to predict Zipf's exponent from urban indicator statistics. Our results also suggest how a general statistical theory of urban indicators may be constructed from the stochastic dynamics of social interaction processes in cities. PMID- 22815746 TI - Prenatal treatment of mosaic mice (Atp7a mo-ms) mouse model for Menkes disease, with copper combined by dimethyldithiocarbamate (DMDTC). AB - Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a (mo-ms) recapitulates the Menkes phenotype and die about 15.75+/-1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl(2) (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76+/-25.3 days, whereas treatment with CuCl(2) alone (50 mg/kg) only leads to survival for about 21 days +/-5 days. These copper DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl(2) alone, a significant increase in the amount of copper was observed in the brain after prenatal copper DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans. PMID- 22815747 TI - Diarrhea outbreak during U.S. military training in El Salvador. AB - Infectious diarrhea remains a major risk to deployed military units worldwide in addition to their impact on travelers and populations living in the developing world. This report describes an outbreak of diarrheal illness in the U.S. military's 130(th) Maneuver Enhancement Brigade deployed in San Vicente, El Salvador during a training and humanitarian assistance mission. An outbreak investigation team from U.S. Naval Medical Research Unit-Six conducted an epidemiologic survey and environmental assessment, patient interviews, and collected stool samples for analysis in an at risk population of 287 personnel from May 31(st) to June 3(rd), 2011. Personnel (n = 241) completed an epidemiological survey (87% response rate) and 67 (27%) reported diarrhea and/or vomiting during the past two weeks. The median duration of illness was reported to be 3 days (IQR 2-4 days) and abdominal pain was reported among 30 (49%) individuals. Presentation to the medical aid station was sought by (62%) individuals and 9 (15%) had to stop or significantly reduce work for at least one day. Microscopy and PCR analysis of 14 stool samples collected from previously symptomatic patients, Shigella (7), Cryptosporidium (5), and Cyclospora (4) were the most prevalent pathogens detected. Consumption of food from on-base local vendors (RR = 4.01, 95% CI = 1.53-10.5, p-value <0.001) and arriving on base within the past two weeks (RR = 2.79, 95% confidence [CI] = 1.35-5.76, p-value = 0.001) were associated with increased risk of developing diarrheal disease. The risk of infectious diarrhea is great among reserve military personnel during two week training exercises. The consumption of local food, prepared without proper monitoring, is a risk factor for deployed personnel developing diarrheal illness. Additional information is needed to better understand disease risks to personnel conducting humanitarian assistance activities in the Latin America Region. PMID- 22815748 TI - Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer. AB - At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer. PMID- 22815749 TI - BF066, a novel dual target antiplatelet agent without significant bleeding. AB - In this study, we report BF066, a novel adenine derivative, inhibits platelet activation and thrombosis via the adenosine receptor (A(2A)) activation and phosphodiesterase (PDE) inhibition. BF066 inhibits platelet aggregation and ATP releasing induced by multiple platelet agonists in a dose-dependent manner. The inhibition of BF066 on ADP-induced aggregation is potentiated by adenosine and can be dramatically antagonized by the A(2A) antagonist SCH58261. BF066 also inhibits the PDE activity and platelet spreading on fibrinogen. In FeCl(3) injured mouse mesenteric arterial thrombosis model, BF066 prevents thrombus formation effectively, similar to clopidogrel. Intriguingly, at dose achieving similar antithrombotic effect compared to clopidogrel, BF066 does not increase bleeding significantly. Taken together, these results suggest that BF066 may be an effective and safe antiplatelet agent targeting both PDE and A(2A). Considering the successful use of combined antiplatelet therapy, BF066 may be further developed as a novel dual target antiplatelet agent. PMID- 22815750 TI - Hemoglobin interactions with alphaB crystallin: a direct test of sensitivity to protein instability. AB - As a small stress response protein, human alphaB crystallin, detects protein destabilization that can alter structure and function to cause self assembly of fibrils or aggregates in diseases of aging. The sensitivity of alphaB crystallin to protein instability was evaluated using wild-type hemoglobin (HbA) and hemoglobin S (HbS), the glutamate-6-valine mutant that forms elongated, filamentous aggregates in sickling red blood cells. The progressive thermal unfolding and aggregation of HbA and HbS in solution at 37 degrees C, 50 degrees C and 55 degrees C was measured as increased light scattering. UV circular dichroism (UVCD) was used to evaluate conformational changes in HbA and HbS with time at the selected temperatures. The changes in interactions between alphaB crystallin and HbA or HbS with temperature were analyzed using differential centrifugation and SDS PAGE at 37 degrees C, 50 degrees C and 55 degrees C. After only 5 minutes at the selected temperatures, differences in the aggregation or conformation of HbA and HbS were not observed, but alphaB crystallin bound approximately 6% and 25% more HbS than HbA at 37 degrees C, and 50 degrees C respectively. The results confirmed (a) the remarkable sensitivity of alphaB crystallin to structural instabilities at the very earliest stages of thermal unfolding and (b) an ability to distinguish the self assembling mutant form of HbS from the wild type HbA in solution. PMID- 22815751 TI - Clinical application of cine-MRI in the visual assessment of mitral regurgitation compared to echocardiography and cardiac catheterization. AB - BACKGROUND: Detecting and quantifying the severity of mitral regurgitation is essential for risk stratification and clinical decision-making regarding timing of surgery. Our objective was to assess specific visual parameters by cine magnetic resonance imaging (MRI) in the determination of the severity of mitral regurgitation and to compare it to previously validated imaging modalities: echocardiography and cardiac ventriculography. METHODS: The study population consisted of 68 patients who underwent a cardiac MRI followed by an echocardiogram within a median time of 2.0 days and 49 of these patients who had a cardiac catheterization, median time of 2.0 days. The inter-rater agreement statistic (Kappa) was used to evaluate the agreement. RESULTS: There was moderate agreement between cine MRI and Doppler echocardiography in assessing mitral regurgitation severity, with a kappa value of 0.47, confidence interval (CI) 0.29 0.65. There was also fair agreement between cine MRI and cardiac catheterization with a kappa value of 0.36, CI of 0.17-0.55. CONCLUSION: Cine MRI offers a reasonable alternative to both Doppler echocardiography and, to a lesser extent, cardiac catheterization for visually assessing the severity of mitral regurgitation with specific visual parameters during routine clinical cardiac MRI. PMID- 22815753 TI - Pineal photoreceptor cells are required for maintaining the circadian rhythms of behavioral visual sensitivity in zebrafish. AB - In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry)] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity. PMID- 22815754 TI - Job strain, job insecurity, and incident cardiovascular disease in the Women's Health Study: results from a 10-year prospective study. AB - OBJECTIVES: Research about work-related stressors and cardiovascular disease (CVD) has produced mixed findings. Moreover, a paucity of data exists regarding the long-term associations between job strain and job insecurity and CVD among women. METHODS: We used Cox proportional hazard models to examine the relationship between job strain, job insecurity, and incident CVD over 10 years of follow-up among 22,086 participants in the Women's Health Study (mean age 57+/ 5 years). RESULTS: During 10 years of follow-up there were 170 myocardial infarctions (MI), 163 ischemic strokes, 440 coronary revascularizations, and 52 CVD deaths. In models adjusted for age, race, education, and income, women with high job strain (high demand, low control) were 38% more likely to experience a CVD event than their counterparts who reported low job strain (low demand, high control; Rate Ratio (RR) = 1.38, 95% Confidence Interval (CI) = 1.08-1.77), and women with active jobs (high demand, high control) were 38% more likely to experience a CVD event relative to women who reported low job strain (95% CI = 1.07-1.77). Outcome-specific analyses revealed that high job strain predicted non fatal myocardial infarction (RR = 1.67, CI = 1.04-2.70), and coronary revascularization (RR = 1.41, CI = 1.05-1.90). No evidence of an association between job insecurity and long-term CVD risk was observed. CONCLUSION: High strain and active jobs, but not job insecurity, were related to increased CVD risk among women. Both job strain and job insecurity were significantly related to CVD risk factors. With the increase of women in the workforce, these data emphasize the importance of addressing job strain in CVD prevention efforts among working women. PMID- 22815752 TI - Concerted perturbation observed in a hub network in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease involving the alteration of gene expression at the whole genome level. Genome-wide transcriptional profiling of AD has been conducted by many groups on several relevant brain regions. However, identifying the most critical dys-regulated genes has been challenging. In this work, we addressed this issue by deriving critical genes from perturbed subnetworks. Using a recent microarray dataset on six brain regions, we applied a heaviest induced subgraph algorithm with a modular scoring function to reveal the significantly perturbed subnetwork in each brain region. These perturbed subnetworks were found to be significantly overlapped with each other. Furthermore, the hub genes from these perturbed subnetworks formed a connected hub network consisting of 136 genes. Comparison between AD and several related diseases demonstrated that the hub network was robustly and specifically perturbed in AD. In addition, strong correlation between the expression level of these hub genes and indicators of AD severity suggested that this hub network can partially reflect AD progression. More importantly, this hub network reflected the adaptation of neurons to the AD specific microenvironment through a variety of adjustments, including reduction of neuronal and synaptic activities and alteration of survival signaling. Therefore, it is potentially useful for the development of biomarkers and network medicine for AD. PMID- 22815756 TI - Infant rule learning: advantage language, or advantage speech? AB - Infants appear to learn abstract rule-like regularities (e.g., la la da follows an AAB pattern) more easily from speech than from a variety of other auditory and visual stimuli (Marcus et al., 2007). We test if that facilitation reflects a specialization to learn from speech alone, or from modality-independent communicative stimuli more generally, by measuring 7.5-month-old infants' ability to learn abstract rules from sign language-like gestures. Whereas infants appear to easily learn many different rules from speech, we found that with sign-like stimuli, and under circumstances comparable to those of Marcus et al. (1999), hearing infants were able to learn an ABB rule, but not an AAB rule. This is consistent with results of studies that demonstrate lower levels of infant rule learning from a variety of other non-speech stimuli, and we discuss implications for accounts of speech-facilitation. PMID- 22815757 TI - Capture, anesthesia, and disturbance of free-ranging brown bears (Ursus arctos) during hibernation. AB - We conducted thirteen immobilizations of previously collared hibernating two- to four-year-old brown bears (Ursus arctos) weighing 21-66 kg in central Sweden in winter 2010 and 2011 for comparative physiology research. Here we report, for the first time, an effective protocol for the capture and anesthesia of free-ranging brown bears during hibernation and an assessment of the disturbance the captures caused. Bears were darted in anthill, soil, or uprooted tree dens on eleven occasions, but two bears in rock dens fled and were darted outside the den. We used medetomidine at 0.02-0.06 mg/kg and zolazepam-tiletamine at 0.9-2.8 mg/kg for anesthesia. In addition, ketamine at 1.5 mg/kg was hand-injected intramuscularly in four bears and in six it was included in the dart at 1.1-3.0 mg/kg. Once anesthetized, bears were removed from the dens. In nine bears, arterial blood samples were analyzed immediately with a portable blood gas analyzer. We corrected hypoxemia in seven bears (PaO(2) 57-74 mmHg) with supplemental oxygen. We placed the bears back into the dens and antagonized the effect of medetomidine with atipamezole. Capturing bears in the den significantly increased the risk of den abandonment. One of twelve collared bears that were captured remained at the original den until spring, and eleven, left their dens (mean +/- standard deviation) 3.2+/-3.6 (range 0.5-10.5) days after capture. They used 1.9+/-0.9 intermediate resting sites, during 6.2+/-7.8 days before entering a new permanent den. The eleven new permanent dens were located 730+/-589 m from the original dens. We documented that it was feasible and safe to capture hibernating brown bears, although they behaved differently than black bears. When doing so, researchers should use 25% of the doses used for helicopter darting during the active period and should consider increased energetic costs associated with den abandonment. PMID- 22815758 TI - Dopamine receptor-interacting protein 78 acts as a molecular chaperone for CCR5 chemokine receptor signaling complex organization. AB - Chemokine receptors are members of the G protein-coupled receptor (GPCR) family. CCR5 and CXCR4 act as co-receptors for human immunodeficiency virus (HIV) and several efforts have been made to develop ligands to inhibit HIV infection by blocking those receptors. Removal of chemokine receptors from the cell surface using polymorphisms or other means confers some levels of immunity against HIV infection. Up to now, very limited success has been obtained using ligand therapies so we explored potential avenues to regulate chemokine receptor expression at the plasma membrane. We identified a molecular chaperone, DRiP78, that interacts with both CXCR4 and CCR5, but not the heterodimer formed by these receptors. We further characterized the effects of DRiP78 on CCR5 function. We show that the molecular chaperone inhibits CCR5 localization to the plasma membrane. We identified the interaction region on the receptor, the F(x)6LL motif, and show that upon mutation of this motif the chaperone cannot interact with the receptor. We also show that DRiP78 is involved in the assembly of CCR5 chemokine signaling complex as a homodimer, as well as with the Galphai protein. Finally, modulation of DRiP78 levels will affect receptor functions, such as cell migration in cells that endogenously express CCR5. Our results demonstrate that modulation of the functions of a chaperone can affect signal transduction at the cell surface. PMID- 22815759 TI - Conserved synthetic peptides from the hemagglutinin of influenza viruses induce broad humoral and T-cell responses in a pig model. AB - Outbreaks involving either H5N1 or H1N1 influenza viruses (IV) have recently become an increasing threat to cause potential pandemics. Pigs have an important role in this aspect. As reflected in the 2009 human H1N1 pandemia, they may act as a vehicle for mixing and generating new assortments of viruses potentially pathogenic to animals and humans. Lack of universal vaccines against the highly variable influenza virus forces scientists to continuously design vaccines a la carte, which is an expensive and risky practice overall when dealing with virulent strains. Therefore, we focused our efforts on developing a broadly protective influenza vaccine based on the Informational Spectrum Method (ISM). This theoretical prediction allows the selection of highly conserved peptide sequences from within the hemagglutinin subunit 1 protein (HA1) from either H5 or H1 viruses which are located in the flanking region of the HA binding site and with the potential to elicit broader immune responses than conventional vaccines. Confirming the theoretical predictions, immunization of conventional farm pigs with the synthetic peptides induced humoral responses in every single pig. The fact that the induced antibodies were able to recognize in vitro heterologous influenza viruses such as the pandemic H1N1 virus (pH1N1), two swine influenza field isolates (SwH1N1 and SwH3N2) and a H5N1 highly pathogenic avian virus, confirm the broad recognition of the antibodies induced. Unexpectedly, all pigs also showed T-cell responses that not only recognized the specific peptides, but also the pH1N1 virus. Finally, a partial effect on the kinetics of virus clearance was observed after the intranasal infection with the pH1N1 virus, setting forth the groundwork for the design of peptide-based vaccines against influenza viruses. Further insights into the understanding of the mechanisms involved in the protection afforded will be necessary to optimize future vaccine formulations. PMID- 22815760 TI - Protein surface matching by combining local and global geometric information. AB - Comparison of the binding sites of proteins is an effective means for predicting protein functions based on their structure information. Despite the importance of this problem and much research in the past, it is still very challenging to predict the binding ligands from the atomic structures of protein binding sites. Here, we designed a new algorithm, TIPSA (Triangulation-based Iterative-closest point for Protein Surface Alignment), based on the iterative closest point (ICP) algorithm. TIPSA aims to find the maximum number of atoms that can be superposed between two protein binding sites, where any pair of superposed atoms has a distance smaller than a given threshold. The search starts from similar tetrahedra between two binding sites obtained from 3D Delaunay triangulation and uses the Hungarian algorithm to find additional matched atoms. We found that, due to the plasticity of protein binding sites, matching the rigid body of point clouds of protein binding sites is not adequate for satisfactory binding ligand prediction. We further incorporated global geometric information, the radius of gyration of binding site atoms, and used nearest neighbor classification for binding site prediction. Tested on benchmark data, our method achieved a performance comparable to the best methods in the literature, while simultaneously providing the common atom set and atom correspondences. PMID- 22815755 TI - Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. AB - Failure of antiretroviral regimens containing elvitegravir (EVG) and raltegravir (RAL) can result in the appearance of integrase inhibitor (INI) drug-resistance mutations (DRMs). While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI) and reverse transcriptase inhibitor (RTI) DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point). Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48) typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs. PMID- 22815761 TI - A trans-Amazonian screening of mtDNA reveals deep intraspecific divergence in forest birds and suggests a vast underestimation of species diversity. AB - The Amazonian avifauna remains severely understudied relative to that of the temperate zone, and its species richness is thought to be underestimated by current taxonomy. Recent molecular systematic studies using mtDNA sequence reveal that traditionally accepted species-level taxa often conceal genetically divergent subspecific lineages found to represent new species upon close taxonomic scrutiny, suggesting that intraspecific mtDNA variation could be useful in species discovery. Surveys of mtDNA variation in Holarctic species have revealed patterns of variation that are largely congruent with species boundaries. However, little information exists on intraspecific divergence in most Amazonian species. Here we screen intraspecific mtDNA genetic variation in 41 Amazonian forest understory species belonging to 36 genera and 17 families in 6 orders, using 758 individual samples from Ecuador and French Guiana. For 13 of these species, we also analyzed trans-Andean populations from the Ecuadorian Choco. A consistent pattern of deep intraspecific divergence among trans Amazonian haplogroups was found for 33 of the 41 taxa, and genetic differentiation and genetic diversity among them was highly variable, suggesting a complex range of evolutionary histories. Mean sequence divergence within families was the same as that found in North American birds (13%), yet mean intraspecific divergence in Neotropical species was an order of magnitude larger (2.13% vs. 0.23%), with mean distance between intraspecific lineages reaching 3.56%. We found no clear relationship between genetic distances and differentiation in plumage color. Our results identify numerous genetically and phenotypically divergent lineages which may result in new species-level designations upon closer taxonomic scrutiny and thorough sampling, although lineages in the tropical region could be older than those in the temperate zone without necessarily representing separate species. In-depth phylogeographic surveys are urgently needed to avoid underestimating tropical diversity, and the use of mtDNA markers can be instrumental in identifying and prioritizing taxa for species discovery. PMID- 22815762 TI - Structural differences between human proteins and aero- and microbial allergens define allergenicity. AB - The current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature. To examine systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans using a variety of bioinformatic tools. Allergenicity was assessed based on IgE prevalences using publicly accessible databases and the literature. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. In contrast, 187 allergens showed no homology with any of the microbial genera studied. Interestingly, allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels with either parasite, including helminth, or human proteins. Our results suggest that allergenicity may be associated with the relative "uniqueness" of an antigen, i.e. immunogenicity, while similarity would lead to immunological tolerance. PMID- 22815763 TI - Climate change disproportionately increases herbivore over plant or parasitoid biomass. AB - All living organisms are linked through trophic relationships with resources and consumers, the balance of which determines overall ecosystem stability and functioning. Ecological research has identified a multitude of mechanisms that contribute to this balance, but ecologists are now challenged with predicting responses to global environmental changes. Despite a wealth of studies highlighting likely outcomes for specific mechanisms and subsets of a system (e.g., plants, plant-herbivore or predator-prey interactions), studies comparing overall effects of changes at multiple trophic levels are rare. We used a combination of experiments in a grassland system to test how biomass at the plant, herbivore and natural enemy (parasitoid) levels responds to the interactive effects of two key global change drivers: warming and nitrogen deposition. We found that higher temperatures and elevated nitrogen generated a multitrophic community that was increasingly dominated by herbivores. Moreover, we found synergistic effects of the drivers on biomass, which differed across trophic levels. Both absolute and relative biomass of herbivores increased disproportionately to that of plants and, in particular, parasitoids, which did not show any significant response to the treatments. Reduced parasitism rates mirrored the profound biomass changes in the system. These findings carry important implications for the response of biota to environmental changes; reduced top-down regulation is likely to coincide with an increase in herbivory, which in turn is likely to cascade to other fundamental ecosystem processes. Our findings also provide multitrophic data to support the general concern of increasing herbivore pest outbreaks in a warmer world. PMID- 22815764 TI - Exploration of the association rules mining technique for the signal detection of adverse drug events in spontaneous reporting systems. AB - BACKGROUND: The detection of signals of adverse drug events (ADEs) has increased because of the use of data mining algorithms in spontaneous reporting systems (SRSs). However, different data mining algorithms have different traits and conditions for application. The objective of our study was to explore the application of association rule (AR) mining in ADE signal detection and to compare its performance with that of other algorithms. METHODOLOGY/PRINCIPAL FINDINGS: Monte Carlo simulation was applied to generate drug-ADE reports randomly according to the characteristics of SRS datasets. Thousand simulated datasets were mined by AR and other algorithms. On average, 108,337 reports were generated by the Monte Carlo simulation. Based on the predefined criterion that 10% of the drug-ADE combinations were true signals, with RR equaling to 10, 4.9, 1.5, and 1.2, AR detected, on average, 284 suspected associations with a minimum support of 3 and a minimum lift of 1.2. The area under the receiver operating characteristic (ROC) curve of the AR was 0.788, which was equivalent to that shown for other algorithms. Additionally, AR was applied to reports submitted to the Shanghai SRS in 2009. Five hundred seventy combinations were detected using AR from 24,297 SRS reports, and they were compared with recognized ADEs identified by clinical experts and various other sources. CONCLUSIONS/SIGNIFICANCE: AR appears to be an effective method for ADE signal detection, both in simulated and real SRS datasets. The limitations of this method exposed in our study, i.e., a non-uniform thresholds setting and redundant rules, require further research. PMID- 22815765 TI - Distribution and radiosensitizing effect of cholesterol-coupled Dbait molecule in rat model of glioblastoma. AB - BACKGROUND: Glioma is the most aggressive tumor of the brain and the most efficient treatments are based on radiotherapy. However, tumors are often resistant to radiotherapy due to an enhanced DNA repair activity. Short and stabilized DNA molecules (Dbait) have recently been proposed as an efficient strategy to inhibit DNA repair in tumor. METHODOLOGY/PRINCIPAL FINDINGS: The distribution of three formulations of Dbait, (i) Dbait alone, (ii) Dbait associated with polyethylenimine, and (iii) Dbait linked with cholesterol (coDbait), was evaluated one day after intratumoral delivery in an RG2 rat glioma model. Dbait molecule distribution was assessed in the whole organ with 2D-FRI and in brain sections. CoDbait was chosen for further studies given its good retention in the brain, cellular localization, and efficacy in inducing the activation of DNA repair effectors. The radiosensitizing effect of coDbait was studied in four groups of rats bearing RG2-glioma: no treatment, radiotherapy only, coDbait alone, and CoDbait with radiotherapy. Treatment started 7 days after tumor inoculation and consisted of two series of treatment in two weeks: coDbait injection followed by a selective 6-Gy irradiation of the head. We evaluated the radiosensitizing effect using animal survival, tumor volume, cell proliferation, and vasculature characteristics with multiparametric MRI. CoDbait with radiotherapy improved the survival of rats bearing RG2-glioma by reducing tumor growth and cell proliferation without altering tumor vasculature. CONCLUSION/SIGNIFICANCE: coDbait is therefore a promising molecular therapy to sensitize glioma to radiotherapy. PMID- 22815766 TI - Acute coronary syndrome in patients with prior coronary artery bypass surgery: observations from a 20-year registry in a middle-eastern country. AB - OBJECTIVES: Clinical characteristics and trends in the outcome of acute coronary syndrome (ACS) in patients with prior coronary artery bypass graft surgery (CABG) are unclear. The aim of this study was to evaluate clinical characteristics, in hospital treatment, and outcomes in patients presented with ACS with or without a history of prior CABG over 2 decades. METHODS: Data were derived from hospital based study for collected data from 1991 through 2010 of patients hospitalized with ACS in Doha, Qatar. Data were analyzed according to their history of prior CABG. Baseline clinical characteristics, in-hospital treatment, and outcome were compared. RESULTS: A total 16,750 consecutive patients with ACS were studied, of which 693 (4.1%) had prior CABG. Patients with prior CABG were older (mean 60.5+/ 11 vs. 53+/-12 years; P = 0.001), more likely to be females and have more cardiovascular risk factors than the non-CABG group. Prior CABG patients had larger infarct size, were less likely to receive reperfusion therapy, early invasive therapy and more likely to receive evidence-based therapies when compared to non-CABG patients. In-hospital mortality and stroke rates were comparable between the 2 groups. Over 2 decades, there was reduction in the in hospital mortality rates and stroke rates in both groups (CABG, death; 13.2% to 4%, stroke; 1.9% to 0.0%, non-CABG, death; 10% to 3.2%, stroke 1.0% to 0.1%; all, p = 0.001). CONCLUSION: Significant reduction in-hospital morbidity and mortality among ACS patients with prior CABG over a 20-year period. PMID- 22815767 TI - Pharmacological inhibition of microsomal prostaglandin E synthase-1 suppresses epidermal growth factor receptor-mediated tumor growth and angiogenesis. AB - BACKGROUND: Blockade of Prostaglandin (PG) E(2) production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE(2) promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1beta) increased mPGES-1 expression, PGE(2) production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE(2) production, both in quiescent and in cells stimulated by IL-1beta. AF3485 abolished IL-1beta-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. CONCLUSION: Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE(2) mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth. PMID- 22815768 TI - Variable neuronal participation in stereotypic motor programs. AB - To what extent are motor networks underlying rhythmic behaviors rigidly hard wired versus fluid and dynamic entities? Do the members of motor networks change from moment-to-moment or from motor program episode-to-episode? These are questions that can only be addressed in systems where it is possible to monitor the spiking activity of networks of neurons during the production of motor programs. We used large-scale voltage-sensitive dye (VSD) imaging followed by Independent Component Analysis spike-sorting to examine the extent to which the neuronal network underlying the escape swim behavior of Tritonia diomedea is hard wired versus fluid from a moment-to-moment perspective. We found that while most neurons were dedicated to the swim network, a small but significant proportion of neurons participated in a surprisingly variable manner. These neurons joined the swim motor program late, left early, burst only on some cycles or skipped cycles of the motor program. We confirmed that this variable neuronal participation was not due to effects of the VSD by finding such neurons with intracellular recording in dye-free saline. Further, these neurons markedly varied their level of participation in the network from swim episode-to-episode. The generality of such unreliably bursting neurons was confirmed by their presence in the rhythmic escape networks of two other molluscan species, Tritonia festiva and Aplysia californica. Our observations support a view that neuronal networks, even those underlying rhythmic and stereotyped motor programs, may be more variable in structure than widely appreciated. PMID- 22815769 TI - Inter-identity autobiographical amnesia in patients with dissociative identity disorder. AB - BACKGROUND: A major symptom of Dissociative Identity Disorder (DID; formerly Multiple Personality Disorder) is dissociative amnesia, the inability to recall important personal information. Only two case studies have directly addressed autobiographical memory in DID. Both provided evidence suggestive of dissociative amnesia. The aim of the current study was to objectively assess transfer of autobiographical information between identities in a larger sample of DID patients. METHODS: Using a concealed information task, we assessed recognition of autobiographical details in an amnesic identity. Eleven DID patients, 27 normal controls, and 23 controls simulating DID participated. Controls and simulators were matched to patients on age, education level, and type of autobiographical memory tested. FINDINGS: Although patients subjectively reported amnesia for the autobiographical details included in the task, the results indicated transfer of information between identities. CONCLUSION: The results call for a revision of the DID definition. The amnesia criterion should be modified to emphasize its subjective nature. PMID- 22815770 TI - Rapid, long-distance dispersal by pumice rafting. AB - Pumice is an extremely effective rafting agent that can dramatically increase the dispersal range of a variety of marine organisms and connect isolated shallow marine and coastal ecosystems. Here we report on a significant recent pumice rafting and long-distance dispersal event that occurred across the southwest Pacific following the 2006 explosive eruption of Home Reef Volcano in Tonga. We have constrained the trajectory, and rate, biomass and biodiversity of transfer, discovering more than 80 species and a substantial biomass underwent a >5000 km journey in 7-8 months. Differing microenvironmental conditions on the pumice, caused by relative stability of clasts at the sea surface, promoted diversity in biotic recruitment. Our findings emphasise pumice rafting as an important process facilitating the distribution of marine life, which have implications for colonisation processes and success, the management of sensitive marine environments, and invasive pest species. PMID- 22815771 TI - Multivariate analyses to assess the effects of surgeon and hospital volume on cancer survival rates: a nationwide population-based study in Taiwan. AB - BACKGROUND: Positive results between caseloads and outcomes have been validated in several procedures and cancer treatments. However, there is limited information available on the combined effects of surgeon and hospital caseloads. We used nationwide population-based data to explore the association between surgeon and hospital caseloads and survival rates for major cancers. METHODOLOGY: A total of 11,677 patients with incident cancer diagnosed in 2002 were identified from the Taiwan National Health Insurance Research Database. Survival analysis, the Cox proportional hazards model, and propensity scores were used to assess the relationship between 5-year survival rates and different caseload combinations. RESULTS: Based on the Cox proportional hazard model, cancer patients treated by low-volume surgeons in low-volume hospitals had poorer survival rates, and hazard ratios ranged from 1.3 in head and neck cancer to 1.8 in lung cancer after adjusting for patients' demographic variables, co-morbidities, and treatment modality. When analyzed using the propensity scores, the adjusted 5-year survival rates were poorer for patients treated by low-volume surgeons in low-volume hospitals, compared to those treated by high-volume surgeons in high-volume hospitals (P<0.005). CONCLUSIONS: After adjusting for differences in the case mix, cancer patients treated by low-volume surgeons in low-volume hospitals had poorer 5-year survival rates. Payers may implement quality care improvement in low-volume surgeons. PMID- 22815772 TI - Using a data-constrained model of home range establishment to predict abundance in spatially heterogeneous habitats. AB - Mechanistic modelling approaches that explicitly translate from individual-scale resource selection to the distribution and abundance of a larger population may be better suited to predicting responses to spatially heterogeneous habitat alteration than commonly-used regression models. We developed an individual-based model of home range establishment that, given a mapped distribution of local habitat values, estimates species abundance by simulating the number and position of viable home ranges that can be maintained across a spatially heterogeneous area. We estimated parameters for this model from data on red-backed vole (Myodes gapperi) abundances in 31 boreal forest sites in Ontario, Canada. The home range model had considerably more support from these data than both non-spatial regression models based on the same original habitat variables and a mean abundance null model. It had nearly equivalent support to a non-spatial regression model that, like the home range model, scaled an aggregate measure of habitat value from local associations with habitat resources. The home range and habitat-value regression models gave similar predictions for vole abundance under simulations of light- and moderate-intensity partial forest harvesting, but the home range model predicted lower abundances than the regression model under high intensity disturbance. Empirical regression-based approaches for predicting species abundance may overlook processes that affect habitat use by individuals, and often extrapolate poorly to novel habitat conditions. Mechanistic home range models that can be parameterized against abundance data from different habitats permit appropriate scaling from individual- to population-level habitat relationships, and can potentially provide better insights into responses to disturbance. PMID- 22815773 TI - Altered microRNA expression in bovine subcutaneous and visceral adipose tissues from cattle under different diet. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of molecular regulators found to participate in numerous biological processes, including adipogenesis in mammals. This study aimed to evaluate the differences of miRNA expression between bovine subcutaneous (backfat) and visceral fat depots (perirenal fat) and the dietary effect on miRNA expression in these fat tissues. METHODOLOGY/PRINCIPAL FINDINGS: Fat tissues were collected from 16 Hereford*Aberdeen Angus cross bred steers (15.5 month old) fed a high-fat diet (5.85% fat, n = 8) or control diet (1.95% fat, n = 8). Total RNA from each animal was subjected to miRNA microarray analysis using a customized Agilent miRNA microarray containing 672 bovine miRNA probes. Expression of miRNAs was not equal between fat depots as well as diets: 207 miRNAs were detected in both fat depots, while 37 of these were found to be tissue specific; and 169 miRNAs were commonly expressed under two diets while 75 were diet specific. The number of miRNAs detected per animal fed the high fat diet was higher than those fed control diet (p = 0.037 in subcutaneous fat and p = 0.002 visceral fat). Further qRT-PCR analysis confirmed that the expression of some miRNAs was highly influenced by diet (miR-19a, -92a, -92b, -101, -103, -106, -142-5p, and 296) or fat depot (miR-196a and -2454). CONCLUSIONS/SIGNIFICANCE: Our results revealed that the miRNA may differ among adipose depots and level of fat in the diet, suggesting that miRNAs may play a role in the regulation of bovine adipogenesis. PMID- 22815775 TI - Evaluation of a gene-directed enzyme-product therapy (GDEPT) in human pancreatic tumor cells and their use as in vivo models for pancreatic cancer. AB - BACKGROUND: Gene-directed enzyme prodrug therapy (GDEPT) is a two-step treatment protocol for solid tumors that involves the transfer of a gene encoding a prodrug activating enzyme followed by administration of the inactive prodrug that is subsequently activated by the enzyme to its tumor toxic form. However, the establishment of such novel treatment regimes to combat pancreatic cancer requires defined and robust animal model systems. METHODS: Here, we comprehensively compared six human pancreatic cancer cell lines (PaCa-44, PANC-1, MIA PaCa-2, Hs-766T, Capan-2, and BxPc-3) in subcutaneous and orthotopical mouse models as well as in their susceptibility to different GDEPTs. RESULTS: Tumor uptake was 83% to 100% in the subcutaneous model and 60% to 100% in the orthotopical mouse model, except for Hs-766T cells, which did not grow orthotopically. Pathohistological analyses of the orthotopical models revealed an infiltrative growth of almost all tumors into the pancreas; however, the different cell lines gave rise to tumors with different morphological characteristics. All of the resultant tumors were positive for MUC-1 staining indicating their origin from glandular or ductal epithelium, but revealed scattered pan-cytokeratin staining. Transfer of the cytochrome P450 and cytosine deaminase suicide gene, respectively, into the pancreatic cancer cell lines using retroviral vector technology revealed high level infectibility of these cell lines and allowed the analysis of the sensitivity of these cells to the chemotherapeutic drugs ifosfamide and 5-fluorocytosine, respectively. CONCLUSION: These data qualify the cell lines as part of valuable in vitro and in vivo models for the use in defined preclinical studies for pancreas tumor therapy. PMID- 22815774 TI - Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a. AB - OBJECTIVE: The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis. DESIGN: URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a. RESULTS: IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27(Kip1) and p21(Cip1) and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity. CONCLUSIONS: URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease. PMID- 22815776 TI - Measuring health-related quality of life of HIV-positive adolescents in resource constrained settings. AB - BACKGROUND AND OBJECTIVES: Access to antiretroviral treatment among adolescents living with HIV (ALH) is increasing. Health-related quality of life (HRQOL) is relevant for monitoring the impact of the disease on both well-being and treatment outcomes. However, adequate screening tools to assess HRQOL in low resource settings are scarce. This study aims to fill this research gap, by 1) assessing the psychometric properties and reliability of an Eastern African English version of a European HRQOL scale for adolescents (KIDSCREEN) and 2) determining which version of the KIDSCREEN (52-, 27- and 10-item version) is most suitable for low-resource settings. METHODS: The KIDSCREEN was translated into Eastern African English, Luganda (Uganda) and Dholuo (Kenya) according to standard procedures. The reconciled version was administered in 2011 to ALH aged 13-17 in Kenya (n = 283) and Uganda (n = 299). All three KIDSCREEN versions were fitted to the data with confirmatory factor analysis (CFA). After comparison, the most suitable version was adapted based on the CFA outcomes utilizing the results of previous formative research. In order to develop a general HRQOL factor, a second-order measurement model was fitted to the data. RESULTS: The CFA results showed that without adjustments, the KIDSCREEN cannot be used for measuring the HRQOL of HIV-positive adolescents. After comparison, the most suitable version for low-resource settings--the 27-item version--was adapted further. The introduction of a negative wording factor was required for the Dholuo model. The Dholuo (CFI: 0.93; RMSEA: 0.039) and the Luganda model (CFI: 0.90; RMSEA: 0.052) showed a good fit. All cronbach's alphas of the factors were 0.70 or above. The alpha value of the Dholuo and Lugandan HRQOL second-order factor was respectively 0.84 and 0.87. CONCLUSIONS: The study showed that the adapted KIDSCREEN-27 is an adequate tool for measuring HRQOL in low-resource settings with high HIV prevalence. PMID- 22815777 TI - A least angle regression model for the prediction of canonical and non-canonical miRNA-mRNA interactions. AB - microRNAs (miRNAs) are short non-coding RNAs with regulatory functions in various biological processes including cell differentiation, development and oncogenic transformation. They can bind to mRNA transcripts of protein-coding genes and repress their translation or lead to mRNA degradation. Conversely, the transcription of miRNAs is regulated by proteins including transcription factors, co-factors, and messenger molecules in signaling pathways, yielding a bidirectional regulatory network of gene and miRNA expression. We describe here a least angle regression approach for uncovering the functional interplay of gene and miRNA regulation based on paired gene and miRNA expression profiles. First, we show that gene expression profiles can indeed be reconstructed from the expression profiles of miRNAs predicted to be regulating the specific gene. Second, we propose a two-step model where in the first step, sequence information is used to constrain the possible set of regulating miRNAs and in the second step, this constraint is relaxed to find regulating miRNAs that do not rely on perfect seed binding. Finally, a bidirectional network comprised of miRNAs regulating genes and genes regulating miRNAs is built from our previous regulatory predictions. After applying the method to a human cancer cell line data set, an analysis of the underlying network reveals miRNAs known to be associated with cancer when dysregulated are predictors of genes with functions in apoptosis. Among the predicted and newly identified targets that lack a classical miRNA seed binding site of a specific oncomir, miR-19b-1, we found an over-representation of genes with functions in apoptosis, which is in accordance with the previous finding that this miRNA is the key oncogenic factor in the mir 17-92 cluster. In addition, we found genes involved in DNA recombination and repair that underline its importance in maintaining the integrity of the cell. PMID- 22815778 TI - Species specific behavioural patterns (digging and swimming) and reaction to novel objects in wild type, Wistar, Sprague-Dawley and Brown Norway rats. AB - BACKGROUND: The purpose of the present study was to analyse species-specific forms of behaviour (digging and swimming) and response to novelty in laboratory rats and their wild type counterparts at a very early stage of laboratorization. Three behavioural phenomena were taken into account: burrowing, spontaneous swimming, and neophobic behaviour. PRINCIPAL FINDINGS: Wild-type rats and three strains of laboratory rats were involved in experiments: Warsaw-Wild-Captive Pisula-Stryjek (WWCPS), Wistar, Sprague-Dawley, and Brown Norway rats were compared in spontaneous swimming test, while WWCPS and Wistar rats were studied in burrowing and neophobia experiments. Wild rats were found to be faster at building tunnels than Wistar rats and at constructing more complex burrow systems. The experiment on neophobia showed that Wistar rats exhibited less neophobic responses and were more often trapped. WWCPS rats showed highly neophobic behaviour and were rarely trapped in this experiment. The experiment on swimming showed that WWCPS rats showed more complex water tank related activity than their laboratory counterparts. They swam and explored under surface environment. CONCLUSIONS: The three experiments showed profound behavioural differences in quasi-natural forms of behaviour between wild type rats (WWCPS) and three laboratory strains frequently used in behavioural studies. PMID- 22815779 TI - Do adolescent idiopathic scoliosis (AIS) neglect proprioceptive information in sensory integration of postural control? AB - INTRODUCTION: It has been reported that AIS rely much more on ankle proprioception to control the amplitude of the balance control commands as compared to age-matched healthy adolescents. Our hypothesis was that AIS do not neglect proprioceptive information to control posture probably because of their vestibular deficits. We investigated the proprioceptive contribution to postural control in AIS which expresses spinal deformity during a crucial transitional period of ontogenesis. METHODS: 10 adolescents with idiopathic scoliosis (AIS) with moderate spinal deformity (10 degrees < Cobb Angle >35 degrees ) and 10 control adolescents (CA) had to maintain vertical stance while very slow oscillations in the frontal plane (below the detection threshold of the semicircular canal system) were applied to the support with the eyes open and closed. Postural orientation and segmental stabilisation were analysed at head, shoulder, trunk and pelvis levels. RESULTS: Scoliosis did not affect vertical orientation control and segmental stabilization strategies. Vision improves postural control in both CA and AIS, which seem more dependent on visual cues than adults. CONCLUSIONS: AIS as CA were unable to control efficiently their postural orientation on the basis of the proprioceptive cues, the only sensory information available in the EC situation, whereas in the same condition healthy young adults present no difficulty to achieve the postural control. This suggests that AIS as CA transitory neglect proprioceptive information to control their posture. These results and previous studies suggest the existence of different afferent pathways for proprioceptive information subserving different parts in sensory integration of postural control. We conclude that the static proprioceptive system is not affected by the idiopathic scoliosis, while the dynamic proprioceptive system would be mainly affected. PMID- 22815780 TI - Synergistic effect between alcohol consumption and familial susceptibility on lung cancer risk among Chinese men. AB - We aimed to examine the effect of alcohol consumption on lung cancer risk stratified by smoking, and to explore whether the impact of alcohol was modified by familial susceptibility to cancer. We recruited 1208 male lung cancer incident cases and 1069 community referents during 2004-2006 and collected their lifetime history of alcohol consumption, cigarette smoking, and family cancer history. Unconditional multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (OR). We tested multiplicative-scale interaction between exposures of interest and examined the additive-scale interaction using synergy index. A moderate association between frequent alcohol consumption and lung cancer was observed among men who had family cancer history (OR = 4.22, 95%CI: 2.46-7.23) after adjustment of smoking and other confounders, while the alcohol effect among men without family history was weak (OR = 1.24, 95%CI: 0.95-1.63) and it became no excess in the never smokers. We observed a consistent synergistic effect between alcohol drinking and family cancer history for all lung cancers and the adenocarcinoma, while there was no multiplicative-scale interaction between the exposures of interest (likelihood ratio test for interaction, p>0.05). Our study revealed a possible synergistic effect between alcohol consumption and familial susceptibility for lung cancer risk; however, this observed possible association needs to be confirmed by future larger analytic studies with more never smoking cases. PMID- 22815781 TI - Systems biological approach of molecular descriptors connectivity: optimal descriptors for oral bioavailability prediction. AB - BACKGROUND: Poor oral bioavailability is an important parameter accounting for the failure of the drug candidates. Approximately, 50% of developing drugs fail because of unfavorable oral bioavailability. In silico prediction of oral bioavailability (%F) based on physiochemical properties are highly needed. Although many computational models have been developed to predict oral bioavailability, their accuracy remains low with a significant number of false positives. In this study, we present an oral bioavailability model based on systems biological approach, using a machine learning algorithm coupled with an optimal discriminative set of physiochemical properties. RESULTS: The models were developed based on computationally derived 247 physicochemical descriptors from 2279 molecules, among which 969, 605 and 705 molecules were corresponds to oral bioavailability, intestinal absorption (HIA) and caco-2 permeability data set, respectively. The partial least squares discriminate analysis showed 49 descriptors of HIA and 50 descriptors of caco-2 are the major contributing descriptors in classifying into groups. Of these descriptors, 47 descriptors were commonly associated to HIA and caco-2, which suggests to play a vital role in classifying oral bioavailability. To determine the best machine learning algorithm, 21 classifiers were compared using a bioavailability data set of 969 molecules with 47 descriptors. Each molecule in the data set was represented by a set of 47 physiochemical properties with the functional relevance labeled as (+bioavailability/-bioavailability) to indicate good-bioavailability/poor bioavailability molecules. The best-performing algorithm was the logistic algorithm. The correlation based feature selection (CFS) algorithm was implemented, which confirms that these 47 descriptors are the fundamental descriptors for oral bioavailability prediction. CONCLUSION: The logistic algorithm with 47 selected descriptors correctly predicted the oral bioavailability, with a predictive accuracy of more than 71%. Overall, the method captures the fundamental molecular descriptors, that can be used as an entity to facilitate prediction of oral bioavailability. PMID- 22815782 TI - Inferring proteolytic processes from mass spectrometry time series data using degradation graphs. AB - BACKGROUND: Proteases play an essential part in a variety of biological processes. Besides their importance under healthy conditions they are also known to have a crucial role in complex diseases like cancer. In recent years, it has been shown that not only the fragments produced by proteases but also their dynamics, especially ex vivo, can serve as biomarkers. But so far, only a few approaches were taken to explicitly model the dynamics of proteolysis in the context of mass spectrometry. RESULTS: We introduce a new concept to model proteolytic processes, the degradation graph. The degradation graph is an extension of the cleavage graph, a data structure to reconstruct and visualize the proteolytic process. In contrast to previous approaches we extended the model to incorporate endoproteolytic processes and present a method to construct a degradation graph from mass spectrometry time series data. Based on a degradation graph and the intensities extracted from the mass spectra it is possible to estimate reaction rates of the underlying processes. We further suggest a score to rate different degradation graphs in their ability to explain the observed data. This score is used in an iterative heuristic to improve the structure of the initially constructed degradation graph. CONCLUSION: We show that the proposed method is able to recover all degraded and generated peptides, the underlying reactions, and the reaction rates of proteolytic processes based on mass spectrometry time series data. We use simulated and real data to demonstrate that a given process can be reconstructed even in the presence of extensive noise, isobaric signals and false identifications. While the model is currently only validated on peptide data it is also applicable to proteins, as long as the necessary time series data can be produced. PMID- 22815783 TI - Mitochondrial genome variations in advanced stage endometriosis: a study in South Indian population. AB - BACKGROUND: Endometriosis is a chronic gynecological benign disease that shares several features similar to malignancy. Mitochondrial DNA (mtDNA) mutations have been reported in all most all types of tumors. However, it is not known as to whether mtDNA mutations are associated with endometriosis. METHODOLOGY: We sequenced the entire mitochondrial genome of analogous ectopic and eutopic endometrial tissues along with blood samples from 32 advanced stage endometriosis patients to analyze the role of somatic and germ-line mtDNA variations in pathogenesis of endometriosis. All ectopic tissues were screened for tumor specific mtDNA deletions and microsatellite instability (MSI). We also performed mtDNA haplogrouping in 128 patients and 90 controls to identify its possible association with endometriosis risk. PRINCIPAL FINDINGS: We identified 51 somatic (novel: 31; reported: 20) and 583 germ-line mtDNA variations (novel: 53; reported: 530) in endometriosis patients. The A13603G, a novel missense mutation which leads to a substitution from serine to glycine at the codon 423 of ND5 gene showed 100% incidence in ectopic tissues. Interestingly, eutopic endometrium and peripheral leukocytes of all the patients showed heteroplasmy (A/G; 40-80%) at this locus, while their ectopic endometrium showed homoplasmic mutant allele (G/G). Superimposition of native and mutant structures of ND5 generated by homology modeling revealed no structural differences. Tumor-specific deletions and MSI were not observed in any of the ectopic tissues. Haplogrouping analysis showed a significant association between haplogroup M5 and endometriosis risk (P: 0.00069) after bonferroni correction. CONCLUSIONS: Our findings substantiate the rationale for exploring the mitochondrial genome as a biomarker for the diagnosis of endometriosis. PMID- 22815784 TI - The role of place in shaping contraceptive use among women in Africa. AB - BACKGROUND: Contraceptive prevalence is low in the African region despite considerable family planning programmatic efforts. This study is the first to examine how community factors shape contraceptive use for married women in an entire region, comparing results across 21 African countries with a DHS in the last 5 years. The analysis builds on previous studies through an examination of the individual, household and community level factors that shape contraceptive use. METHODS: The data used in this analysis were from nationally representative Demographic and Health Surveys completed between 2005 and 2009. A separate multi level logistic model was fitted for the outcome of current modern contraceptive use in each country. RESULTS: After controlling for individual and household level factors, community level factors of demographics and fertility norms, gender norms and inequalities, and health knowledge remain significantly associated with contraceptive use, although the magnitude and direction of these community effects varied significantly across countries. CONCLUSIONS: The results highlight the importance of harnessing community level factors in planning interventions for increasing access to and utilization of modern contraceptive methods. PMID- 22815785 TI - Trait and state positive emotional experience in schizophrenia: a meta-analysis. AB - BACKGROUND: Prior meta-analyses indicated that people with schizophrenia show impairment in trait hedonic capacity but retain their state hedonic experience (valence) in laboratory-based assessments. Little is known about what is the extent of differences for state positive emotional experience (especially arousal) between people with schizophrenia and healthy controls. It is also not clear whether negative symptoms and gender effect contribute to the variance of positive affect. METHODS AND FINDINGS: The current meta-analysis examined 21 studies assessing state arousal experience, 40 studies measuring state valence experience, and 47 studies assessing trait hedonic capacity in schizophrenia. Patients with schizophrenia demonstrated significant impairment in trait hedonic capacity (Cohen's d = 0.81). However, patients and controls did not statistically differ in state hedonic (valence) as well as exciting (arousal) experience to positive stimuli (Cohen's d = -0.24 to 0.06). They also reported experiencing relatively robust state aversion and calmness to positive stimuli compared with controls (Cohen's d = 0.75, 0.56, respectively). Negative symptoms and gender contributed to the variance of findings in positive affect, especially trait hedonic capacity in schizophrenia. CONCLUSIONS: Our findings suggest that schizophrenia patients have no deficit in state positive emotional experience but impairment in "noncurrent" hedonic capacity, which may be mediated by negative symptoms and gender effect. PMID- 22815786 TI - Statins affect the presentation of endothelial chemokines by targeting to multivesicular bodies. AB - BACKGROUND: In addition to lowering cholesterol, statins are thought to beneficially modulate inflammation. Several chemokines including CXCL1/growth related oncogene (GRO)-alpha, CXCL8/interleukin (IL)-8 and CCL2/monocyte chemoattractant protein (MCP)-1 are important in the pathogenesis of atherosclerosis and can be influenced by statin-treatment. Recently, we observed that atorvastatin-treatment alters the intracellular content and subcellular distribution of GRO-alpha in cultured human umbilical vein endothelial cells (HUVECs). The objective of this study was to investigate the mechanisms involved in this phenomenon. METHODOLOGY/ PRINCIPAL FINDINGS: The effect of atorvastatin on secretion levels and subcellular distribution of GRO-alpha, IL-8 and MCP-1 in HUVECs activated by interleukin (IL)-1beta were evaluated by ELISA, confocal microscopy and immunoelectron microscopy. Atorvastatin increased the intracellular contents of GRO-alpha, IL-8, and MCP-1 and induced colocalization with E-selectin in multivesicular bodies. This effect was prevented by adding the isoprenylation substrate GGPP, but not the cholesterol precursor squalene, indicating that atorvastatin exerts these effects by inhibiting isoprenylation rather than depleting the cells of cholesterol. CONCLUSIONS/ SIGNIFICANCE: Atorvastatin targets inflammatory chemokines to the endocytic pathway and multivesicular bodies and may contribute to explain the anti-inflammatory effect of statins at the level of endothelial cell function. PMID- 22815787 TI - L1CAM binds ErbB receptors through Ig-like domains coupling cell adhesion and neuregulin signalling. AB - During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM. PMID- 22815788 TI - MicroRNA profiling in mucosal biopsies of eosinophilic esophagitis patients pre and post treatment with steroids and relationship with mRNA targets. AB - BACKGROUND: The characterization of miRNAs and their target mRNAs involved in regulation of the immune process is an area of intense research and relatively little is known governing these processes in allergic inflammation. Here we present novel findings defining the miRNA and mRNA transcriptome in eosinophilic esophagitis (EoE), an increasing recognized allergic disorder. METHODS: Esophageal epithelial miRNA and mRNA from five paired biopsies pre- and post treatment with glucocorticosteroids were profiled using Taqman and Affymetrix arrays. Validation was performed on additional paired biopsies, untreated EoE specimens and normal controls. Differentially regulated miRNAs and mRNAs were generated, within which miRNA-mRNA target pairs with high predicted confidence were identified. RESULTS: Compared to the post-glucocorticoid treated esophageal mucosa, of all the 377 miRNA sequences examined, 32 miRNAs were significantly upregulated and four downregulated in the pre-treated biopsies. MiR-214 was the most upregulated (150 fold) and miR-146b-5b, 146a, 145, 142-3p and 21 were upregulated by at least 10 fold. Out of 12 miRNAs chosen for validation by qRT PCR, five (miR-214, 146b-5p, 146a, 142-3p and 21) were confirmed and 11 shared the same trend. When the expression of the 12 miRNAs in the EoE mucosa was compared to unrelated normal mucosa, six (miR-214, 146b-5p, 146a, 21, 203, and 489) showed similar significant changes as in the paired samples and 10 of them shared the same trend. In the same five pairs of samples used to profile miRNA, 311 mRNAs were down-regulated and 35 were up-regulated in pre-treated EoE mucosa. Among them, 164 mRNAs were identified as potential targets of differentially regulated miRNAs. Further analysis revealed that immune-related genes, targeted and non-targeted by miRNAs, were among the most important genes involved in the pathogenesis of EoE. CONCLUSIONS: Our findings add to the accumulating body of data defining a regulatory role for miRNA in immune and allergic processes. PMID- 22815790 TI - Intraguild predation behaviour of ladybirds in semi-field experiments explains invasion success of Harmonia axyridis. AB - Harmonia axyridis has been introduced as a biological control agent in Europe and the USA. Since its introduction, it has established and spread, and it is now regarded as an invasive alien species. It has been suggested that intraguild predation is especially important for the invasion success of H. axyridis. The aim of this study was to compare the intraguild predation behaviour of three ladybird species (Coccinella septempunctata, Adalia bipunctata, and H. axyridis). Predation behaviour was investigated in semi-field experiments on small lime trees (Tilia platyphyllos). Two fourth-instar larvae placed on a tree rarely made contact during 3-hour observations. When placed together on a single leaf in 23% 43% of the observations at least one contact was made. Of those contacts 0%-27% resulted in an attack. Harmonia axyridis attacked mostly heterospecifics, while A. bipunctata and C. septempunctata attacked heterospecifics as often as conspecifics. In comparison with A. bipunctata and C. septempunctata, H. axyridis was the most successful intraguild predator as it won 86% and 44% of heterospecific battles against A. bipunctata and C. septempunctata respectively, whilst A. bipunctata won none of the heterospecific battles and C. septempunctata won only the heterospecific battles against A. bipunctata. Coccinella septempunctata dropped from a leaf earlier and more often than the other two species but was in some cases able to return to the tree, especially under cloudy conditions. The frequency with which a species dropped did not depend on the species the larva was paired with. The results of these semi-field experiments confirm that H. axyridis is a strong intraguild predator as a consequence of its aggressiveness and good defence against predation from heterospecific species. The fact that H. axyridis is such a strong intraguild predator helps to explain its successful establishment as invasive alien species in Europe and the USA. PMID- 22815789 TI - Myeloid suppressor cell depletion augments antitumor activity in lung cancer. AB - BACKGROUND: Myeloid derived suppressor cells (MDSC) are important regulators of immune responses. We evaluated the mechanistic role of MDSC depletion on antigen presenting cell (APC), NK, T cell activities and therapeutic vaccination responses in murine models of lung cancer. PRINCIPAL FINDINGS: Individual antibody mediated depletion of MDSC (anti-Gr1 or anti-Ly6G) enhanced the antitumor activity against lung cancer. In comparison to controls, MDSC depletion enhanced the APC activity and increased the frequency and activity of the NK and T cell effectors in the tumor. Compared to controls, the anti-Gr1 or anti-Ly6G treatment led to increased: (i) CD8 T cells, (ii) NK cells, (iii) CD8 T or NK intracytoplasmic expression of IFNgamma, perforin and granzyme (iv) CD3 T cells expressing the activation marker CD107a and CXCR3, (v) reduced CD8 T cell IL-10 production in the tumors (vi) reduced tumor angiogenic (VEGF, CXCL2, CXCL5, and Angiopoietin1&2) but enhanced anti-angiogenic (CXCL9 and CXCL10) expression and (vii) reduced tumor staining of endothelial marker Meca 32. Immunocytochemistry of tumor sections showed reduced Gr1 expressing cells with increased CD3 T cell infiltrates in the anti-Gr1 or anti-Ly6G groups. MDSC depletion led to a marked inhibition in tumor growth, enhanced tumor cell apoptosis and reduced migration of the tumors from the primary site to the lung compared to controls. Therapeutic vaccination responses were enhanced in vivo following MDSC depletion with 50% of treated mice completely eradicating established tumors. Treated mice that rejected their primary tumors acquired immunological memory against a secondary tumor challenge. The remaining 50% of mice in this group had 20 fold reductions in tumor burden compared to controls. SIGNIFICANCE: Our data demonstrate that targeting MDSC can improve antitumor immune responses suggesting a broad applicability of combined immune based approaches against cancer. This multifaceted approach may prove useful against tumors where MDSC play a role in tumor immune evasion. PMID- 22815792 TI - Evidence of multifractality from emerging European stock markets. AB - We test for the presence of multifractality in the daily returns of the three most important stock market indices from Central and Eastern Europe, Czech PX, Hungarian BUX and Polish WIG using the Empirical Mode Decomposition based Multifractal Detrended Fluctuation Analysis. We found that the global Hurst coefficient varies with the q coefficient and that there is multifractality evidenced through the multifractal spectrum. The exercise is replicated for the sample around the high volatility period corresponding to the last global financial crisis. Although no direct link has been found between the crisis and the multifractal spectrum, the crisis was found to influence the overall shape as quantified through the norm of the multifractal spectrum. PMID- 22815791 TI - Novel bacteriophages containing a genome of another bacteriophage within their genomes. AB - A novel bacteriophage infecting Staphylococus pasteuri was isolated during a screen for phages in Antarctic soils. The phage named SpaA1 is morphologically similar to phages of the family Siphoviridae. The 42,784 bp genome of SpaA1 is a linear, double-stranded DNA molecule with 3' protruding cohesive ends. The SpaA1 genome encompasses 63 predicted protein-coding genes which cluster within three regions of the genome, each of apparently different origin, in a mosaic pattern. In two of these regions, the gene sets resemble those in prophages of Bacillus thuringiensis kurstaki str. T03a001 (genes involved in DNA replication/transcription, cell entry and exit) and B. cereus AH676 (additional regulatory and recombination genes), respectively. The third region represents an almost complete genome (except for the short terminal segments) of a distinct bacteriophage, MZTP02. Nearly the same gene module was identified in prophages of B. thuringiensis serovar monterrey BGSC 4AJ1 and B. cereus Rock4-2. These findings suggest that MZTP02 can be shuttled between genomes of other bacteriophages and prophages, leading to the formation of chimeric genomes. The presence of a complete phage genome in the genome of other phages apparently has not been described previously and might represent a 'fast track' route of virus evolution and horizontal gene transfer. Another phage (BceA1) nearly identical in sequence to SpaA1, and also including the almost complete MZTP02 genome within its own genome, was isolated from a bacterium of the B. cereus/B. thuringiensis group. Remarkably, both SpaA1 and BceA1 phages can infect B. cereus and B. thuringiensis, but only one of them, SpaA1, can infect S. pasteuri. This finding is best compatible with a scenario in which MZTP02 was originally contained in BceA1 infecting Bacillus spp, the common hosts for these two phages, followed by emergence of SpaA1 infecting S. pasteuri. PMID- 22815793 TI - The genetics of reading disability in an often excluded sample: novel loci suggested for reading disability in Rolandic epilepsy. AB - BACKGROUND: Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating "pure" dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub phenotypes of RE. METHODS: We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus. RESULTS: In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD = 1.81), possibly because the replication sample did not have French Canadian representation. DISCUSSION: Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in "pure" dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci. PMID- 22815794 TI - Insertion of short amino-functionalized single-walled carbon nanotubes into phospholipid bilayer occurs by passive diffusion. AB - Carbon nanotubes have been proposed to be efficient nanovectors able to deliver genetic or therapeutic cargo into living cells. However, a direct evidence of the molecular mechanism of their translocation across cell membranes is still needed. Here, we report on an extensive computational study of short (5 nm length) pristine and functionalized single-walled carbon nanotubes uptake by phospholipid bilayer models using all-atom molecular dynamics simulations. Our data support the hypothesis of a direct translocation of the nanotubes through the phospholipid membrane. We find that insertion of neat nanotubes within the bilayer is a "nanoneedle" like process, which can often be divided in three consecutive steps: landing and floating, penetration of the lipid headgroup area and finally sliding into the membrane core. The presence of functional groups at moderate concentrations does not modify the overall scheme of diffusion mechanism, provided that their deprotonated state favors translocation through the lipid bilayer. PMID- 22815795 TI - Decreased expression of SATB2: a novel independent prognostic marker of worse outcome in laryngeal carcinoma patients. AB - BACKGROUND: To investigate the expression and role of special AT-rich sequence binding protein-2 (SATB2) in laryngeal squamous cell carcinoma (LSCC) tissue and cell line (HEp2), and to evaluate the clinical and prognostic significance of SATB2 protein in patients with LSCC. METHODS: The expression of SATB2 was examined in LSCC tissue and HEp2 cells by Western-blotting, Real-time PCR and immunohistochemical staining. Cell growth curve assay and colony formation assay were used to verify the effect of SATB2 on the proliferation and tumor progression ability of HEp2 cells. Tumor formation assay in nude mice was used to analyze the effect of SATB2 on the tumorigenicity of HEp2 cells. RESULTS: The status of SATB2 protein in carcinoma tissues is much lower than that in paracarcinoma tissues. The overall survival of the patients with high SATB2 expression was significantly higher than the low SATB2 expression group. Lower or negative SATB2 expression was significantly correlated with advanced clinical staging, histological grade and tumor recurrence. In vitro experiments demonstrated that over-expression of SATB2 in HEp2 cells inhibited cell proliferation and tumor progression ability, and down-regulation of SATB2 showed the opposite effects. Over-expression of SATB2 repressed the tumorigenicity of HEp2 cells by in vivo experiments. Moreover, multivariate analysis suggested that SATB2 expression might be an independent prognostic indicator for the survival of LSCC patients after curative surgery. CONCLUSIONS: SATB2 might involve in the development and progression of LSCC as a tumor suppressor, and thereby may be a valuable prognostic marker for LSCC patients. PMID- 22815796 TI - A fate map of the murine pancreas buds reveals a multipotent ventral foregut organ progenitor. AB - The definitive endoderm is the embryonic germ layer that gives rise to the budding endodermal organs including the thyroid, lung, liver and pancreas as well as the remainder of the gut tube. DiI fate mapping and whole embryo culture were used to determine the endodermal origin of the 9.5 days post coitum (dpc) dorsal and ventral pancreas buds. Our results demonstrate that the progenitors of each bud occupy distinct endodermal territories. Dorsal bud progenitors are located in the medial endoderm overlying somites 2-4 between the 2 and 11 somite stage (SS). The endoderm forming the ventral pancreas bud is found in 2 distinct regions. One territory originates from the left and right lateral endoderm caudal to the anterior intestinal portal by the 6 SS and the second domain is derived from the ventral midline of the endoderm lip (VMEL). Unlike the laterally located ventral foregut progenitors, the VMEL population harbors a multipotent progenitor that contributes to the thyroid bud, the rostral cap of the liver bud, ventral midline of the liver bud and the midline of the ventral pancreas bud in a temporally restricted manner. This data suggests that the midline of the 9.5 dpc thyroid, liver and ventral pancreas buds originates from the same progenitor population, demonstrating a developmental link between all three ventral foregut buds. Taken together, these data define the location of the dorsal and ventral pancreas progenitors in the prespecified endodermal sheet and should lead to insights into the inductive events required for pancreas specification. PMID- 22815797 TI - Immobilization of beta-galactosidase onto functionalized graphene nano-sheets using response surface methodology and its analytical applications. AB - BACKGROUND: beta-Galactosidase is a vital enzyme with diverse application in molecular biology and industries. It was covalently attached onto functionalized graphene nano-sheets for various analytical applications based on lactose reduction. METHODOLOGY/PRINCIPAL FINDINGS: Response surface methodology based on Box-Behnken design of experiment was used for determination of optimal immobilization conditions, which resulted in 84.2% immobilization efficiency. Native and immobilized functionalized graphene was characterized with the help of transmission and scanning electron microscopy, followed by Fourier transform infrared (FTIR) spectroscopy. Functionalized graphene sheets decorated with islands of immobilized enzyme were evidently visualized under both transmission and scanning electron microscopy after immobilization. FTIR spectra provided insight on various chemical interactions and bonding, involved during and after immobilization. Optimum temperature and energy of activation (E(a)) remains unchanged whereas optimum pH and K(m) were changed after immobilization. Increased thermal stability of enzyme was observed after conjugating the enzyme with functionalized graphene. SIGNIFICANCE: Immobilized beta-galactosidase showed excellent reusability with a retention of more than 92% enzymatic activity after 10 reuses and an ideal performance at broad ranges of industrial environment. PMID- 22815798 TI - Physalin F induces cell apoptosis in human renal carcinoma cells by targeting NF kappaB and generating reactive oxygen species. AB - BACKGROUND: The aim of this study was to determine the molecular mechanisms of physalin F, an effective purified extract of Physalis angulata L. (Solanacae), in renal carcinoma A498 cells. METHODOLOGY/PRINCIPAL FINDINGS: Physalin F was observed to significantly induce cytotoxicity of three human renal carcinoma A498, ACHN, and UO-31 cells in a concentration-dependent manner; this was especially potent in A498 cells. The physalin F-induced cell apoptosis of A498 cells was characterized by MTT assay, nuclear DNA fragmentation and chromatin condensation. Using flow cytometry analysis, physalin F induced A498 cell apoptosis as demonstrated by the accumulation of the sub-G1 phase in a concentration- and time-dependent manner. Moreover, physalin F-mediated accumulation of reactive oxygen species (ROS) caused Bcl-2 family proteins, Bcl 2, and Bcl-xL degradation, which led to disruption of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-3 and caspase-9 activity, which led to poly(ADP-ribose) polymerase cleavage. However, the antioxidant N acetyl-(L)-cysteine (NAC) and glutathione (GSH) resulted in the inhibition of these events and reversed physalin F-induced cell apoptosis. In addition, physalin F suppressed NF-kappaB activity and nuclear translocation of p65 and p50, which was reversed by NAC and GSH. CONCLUSION: Physalin F induced cell apoptosis through the ROS-mediated mitochondrial pathway and suppressed NF-kappaB activation in human renal cancer A498 cells. Thus, physalin F appears to be a promising anti-cancer agent worthy of further clinical development. PMID- 22815799 TI - Biodiversity assessment in incomplete inventories: leaf litter ant communities in several types of Bornean rain forest. AB - Biodiversity assessment of tropical taxa is hampered by their tremendous richness, which leads to large numbers of singletons and incomplete inventories in survey studies. Species estimators can be used for assessment of alpha diversity, but calculation of beta diversity is hampered by pseudo-turnover of species in undersampled plots. To assess the impact of unseen species, we investigated different methods, including an unbiased estimator of Shannon beta diversity that was compared to biased calculations. We studied alpha and beta diversity of a diverse ground ant assemblage from the Southeast Asian island of Borneo in different types of tropical forest: diperocarp forest, alluvial forest, limestone forest and heath forests. Forests varied in plant composition, geology, flooding regimes and other environmental parameters. We tested whether forest types differed in species composition and if species turnover was a function of the distance between plots at different spatial scales. As pseudo-turnover may bias beta diversity we hypothesized a large effect of unseen species reducing beta diversity. We sampled 206 ant species (25% singletons) from ten subfamilies and 55 genera. Diversity partitioning among the four forest types revealed that whereas alpha species richness and alpha Shannon diversity were significantly smaller than expected, beta-diversity for both measurements was significantly higher than expected by chance. This result was confirmed when we used the unbiased estimation of Shannon diversity: while alpha diversity was much higher, beta diversity differed only slightly from biased calculations. Beta diversity as measured with the Chao-Sorensen or Morisita-Horn Index correlated with distance between transects and between sample points, indicating a distance decay of similarity between communities. We conclude that habitat heterogeneity has a high influence on ant diversity and species turnover in tropical sites and that unseen species may have only little impact on calculation of Shannon beta diversity when sampling effort has been high. PMID- 22815800 TI - EEG dynamics reflect the distinct cognitive process of optic problem solving. AB - This study explores the changes in electroencephalographic (EEG) activity associated with the performance of solving an optics maze problem. College students (N = 37) were instructed to construct three solutions to the optical maze in a Web-based learning environment, which required some knowledge of physics. The subjects put forth their best effort to minimize the number of convexes and mirrors needed to guide the image of an object from the entrance to the exit of the maze. This study examines EEG changes in different frequency bands accompanying varying demands on the cognitive process of providing solutions. Results showed that the mean power of theta, alpha1, alpha2, and beta1 significantly increased as the number of convexes and mirrors used by the students decreased from solution 1 to 3. Moreover, the mean power of theta and alpha1 significantly increased when the participants constructed their personal optimal solution (the least total number of mirrors and lens used by students) compared to their non-personal optimal solution. In conclusion, the spectral power of frontal, frontal midline and posterior theta, posterior alpha, and temporal beta increased predominantly as the task demands and task performance increased. PMID- 22815801 TI - Treatment with antibiotics that interfere with peptidoglycan biosynthesis inhibits chloroplast division in the desmid Closterium. AB - Charophytes is a green algal group closely related to land plants. We investigated the effects of antibiotics that interfere with peptidoglycan biosynthesis on chloroplast division in the desmid Closterium peracerosum strigosum-littorale complex. To detect cells just after division, we used colchicine, which inhibits Closterium cell elongation after division. Although normal Closterium cells had two chloroplasts before and after cell division, cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division. The antibiotics bacitracin and vancomycin showed no obvious effect. Electron microscopic observation showed that irregular-shaped chloroplasts existed in ampicillin-treated Closterium cells. Because antibiotic treatments resulted in the appearance of long cells with irregular chloroplasts and cell death, we counted cell types in the culture. The results suggested that cells with one chloroplast appeared first and then a huge chloroplast was generated that inhibited cell division, causing elongation followed by cell death. PMID- 22815802 TI - Transcriptional profiling of Plasmodium falciparum parasites from patients with severe malaria identifies distinct low vs. high parasitemic clusters. AB - BACKGROUND: In the past decade, estimates of malaria infections have dropped from 500 million to 225 million per year; likewise, mortality rates have dropped from 3 million to 791,000 per year. However, approximately 90% of these deaths continue to occur in sub-Saharan Africa, and 85% involve children less than 5 years of age. Malaria mortality in children generally results from one or more of the following clinical syndromes: severe anemia, acidosis, and cerebral malaria. Although much is known about the clinical and pathological manifestations of CM, insights into the biology of the malaria parasite, specifically transcription during this manifestation of severe infection, are lacking. METHODS AND FINDINGS: We collected peripheral blood from children meeting the clinical case definition of cerebral malaria from a cohort in Malawi, examined the patients for the presence or absence of malaria retinopathy, and performed whole genome transcriptional profiling for Plasmodium falciparum using a custom designed Affymetrix array. We identified two distinct physiological states that showed highly significant association with the level of parasitemia. We compared both groups of Malawi expression profiles with our previously acquired ex vivo expression profiles of parasites derived from infected patients with mild disease; a large collection of in vitro Plasmodium falciparum life cycle gene expression profiles; and an extensively annotated compendium of expression data from Saccharomyces cerevisiae. The high parasitemia patient group demonstrated a unique biology with elevated expression of Hrd1, a member of endoplasmic reticulum-associated protein degradation system. CONCLUSIONS: The presence of a unique high parasitemia state may be indicative of the parasite biology of the clinically recognized hyperparasitemic severe disease syndrome. PMID- 22815803 TI - Serological evidence of Ebola virus infection in Indonesian orangutans. AB - Ebola virus (EBOV) and Marburg virus (MARV) belong to the family Filoviridae and cause severe hemorrhagic fever in humans and nonhuman primates. Despite the discovery of EBOV (Reston virus) in nonhuman primates and domestic pigs in the Philippines and the serological evidence for its infection of humans and fruit bats, information on the reservoirs and potential amplifying hosts for filoviruses in Asia is lacking. In this study, serum samples collected from 353 healthy Bornean orangutans (Pongo pygmaeus) in Kalimantan Island, Indonesia, during the period from December 2005 to December 2006 were screened for filovirus specific IgG antibodies using a highly sensitive enzyme-linked immunosorbent assay (ELISA) with recombinant viral surface glycoprotein (GP) antigens derived from multiple species of filoviruses (5 EBOV and 1 MARV species). Here we show that 18.4% (65/353) and 1.7% (6/353) of the samples were seropositive for EBOV and MARV, respectively, with little cross-reactivity among EBOV and MARV antigens. In these positive samples, IgG antibodies to viral internal proteins were also detected by immunoblotting. Interestingly, while the specificity for Reston virus, which has been recognized as an Asian filovirus, was the highest in only 1.4% (5/353) of the serum samples, the majority of EBOV-positive sera showed specificity to Zaire, Sudan, Cote d'Ivoire, or Bundibugyo viruses, all of which have been found so far only in Africa. These results suggest the existence of multiple species of filoviruses or unknown filovirus-related viruses in Indonesia, some of which are serologically similar to African EBOVs, and transmission of the viruses from yet unidentified reservoir hosts into the orangutan populations. Our findings point to the need for risk assessment and continued surveillance of filovirus infection of human and nonhuman primates, as well as wild and domestic animals, in Asia. PMID- 22815805 TI - Testing for the effects and consequences of mid paleogene climate change on insect herbivory. AB - BACKGROUND: The Eocene, a time of fluctuating environmental change and biome evolution, was generally driven by exceptionally warm temperatures. The Messel (47.8 Ma) and Eckfeld (44.3 Ma) deposits offer a rare opportunity to take a census of two, deep-time ecosystems occurring during a greenhouse system. An understanding of the long-term consequences of extreme warming and cooling events during this interval, particularly on angiosperms and insects that dominate terrestrial biodiversity, can provide insights into the biotic consequences of current global climatic warming. METHODOLOGY/PRINCIPAL FINDINGS: We compare insect-feeding damage within two middle Eocene fossil floras, Messel and Eckfeld, in Germany. From these small lake deposits, we studied 16,082 angiosperm leaves and scored each specimen for the presence or absence of 89 distinctive and diagnosable insect damage types (DTs), each of which was allocated to a major functional feeding group, including four varieties of external foliage feeding, piercing- and-sucking, leaf mining, galling, seed predation, and oviposition. Methods used for treatment of presence-absence data included general linear models and standard univariate, bivariate and multivariate statistical techniques. CONCLUSIONS/SIGNIFICANCE: Our results show an unexpectedly high diversity and level of insect feeding than comparable, penecontemporaneous floras from North and South America. In addition, we found a higher level of herbivory on evergreen, rather than deciduous taxa at Messel. This pattern is explained by a ca. 2.5-fold increase in atmospheric CO(2) that overwhelmed evergreen antiherbivore defenses, subsequently lessened during the more ameliorated levels of Eckfeld times. These patterns reveal important, previously undocumented features of plant-host and insect-herbivore diversification during the European mid Eocene. PMID- 22815804 TI - Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors. AB - The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis. PMID- 22815806 TI - Endothelin-1 in paraventricular nucleus modulates cardiac sympathetic afferent reflex and sympathetic activity in rats. AB - BACKGROUND: Cardiac sympathetic afferent reflex (CSAR) is a positive-feedback, sympathoexcitatory reflex. Paraventricular nucleus (PVN) is an important component of the central neurocircuitry of the CSAR. The present study is designed to determine whether endothelin-1 (ET-1) in the PVN modulates the CSAR and sympathetic activity, and whether superoxide anions are involved in modulating the effects of ET-1 in the PVN in rats. METHODOLOGY/PRINCIPAL FINDINGS: In anaesthetized Sprague-Dawley rats with cervical vagotomy and sinoaortic denervation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The CSAR was evaluated by the responses of the RSNA and MAP to epicardial application of capsaicin. Microinjection of ET-1 into the bilateral PVN dose-dependently enhanced the CSAR, increased the baseline RSNA and MAP. The effects of ET-1 were blocked by PVN pretreatment with the ET(A) receptor antagonist BQ-123. However, BQ-123 alone had no significant effects on the CSAR, the baseline RSNA and MAP. Bilateral PVN pretreatment with either superoxide anion scavenger tempol or polyethylene glycol-superoxide dismutase (PEG-SOD) inhibited the effects of ET-1 on the CSAR, RSNA and MAP. Microinjection of ET-1 into the PVN increased the superoxide anion level in the PVN, which was abolished by PVN pretreatment with BQ-123. Epicardial application of capsaicin increased superoxide anion level in PVN which was further enhanced by PVN pretreatment with ET-1. CONCLUSIONS: Exogenous activation of ET(A) receptors with ET-1 in the PVN enhances the CSAR, increases RSNA and MAP. Superoxide anions in PVN are involved in the effects of ET-1 in the PVN. PMID- 22815807 TI - Development and validation of a high throughput system for discovery of antigens for autoantibody detection. AB - An assay employing a panel of tumor-associated antigens has been validated and is available commercially (EarlyCDT(r)-Lung) to aid the early detection of lung cancer by measurement of serum autoantibodies. The high throughput (HTP) strategy described herein was pursued to identify new antigens to add to the EarlyCDT-Lung panel and to assist in the development of new panels for other cancers. Two ligation-independent cloning vectors were designed and synthesized, producing fusion proteins suitable for the autoantibody ELISA. We developed an abridged HTP version of the validated autoantibody ELISA, determining that results reflected the performance of the EarlyCDT assay, by comparing results on both formats. Once validated this HTP ELISA was utilized to screen multiple fusion proteins prepared on small-scale, by a HTP expression screen. We determined whether the assay performance for these HTP protein batches was an accurate reflection of the performance of R&D or commercial batches. A HTP discovery platform for the identification and optimal production of tumor-associated antigens which detects autoantibodies has been developed and validated. The most favorable conditions for the exposure of immunogenic epitopes were assessed to produce discriminatory proteins for use in a commercial ELISA. This process is rapid and cost-effective compared to standard cloning and screening technologies and enables rapid advancement in the field of autoantibody assay discovery. This approach will significantly reduce timescale and costs for developing similar panels of autoantibody assays for the detection of other cancer types with the ultimate aim of improved overall survival due to early diagnosis and treatment. PMID- 22815808 TI - Network analysis of rat spatial cognition: behaviorally-established symmetry in a physically asymmetrical environment. AB - BACKGROUND: We set out to solve two inherent problems in the study of animal spatial cognition (i) What is a "place"?; and (ii) whether behaviors that are not revealed as differing by one methodology could be revealed as different when analyzed using a different approach. METHODOLOGY: We applied network analysis to scrutinize spatial behavior of rats tested in either a symmetrical or asymmetrical layout of 4, 8, or 12 objects placed along the perimeter of a round arena. We considered locations as the units of the network (nodes), and passes between locations as the links within the network. PRINCIPAL FINDINGS: While there were only minor activity differences between rats tested in the symmetrical or asymmetrical object layouts, network analysis revealed substantial differences. Viewing 'location' as a cluster of stopping coordinates, the key locations (large clusters of stopping coordinates) were at the objects in both layouts with 4 objects. However, in the asymmetrical layout with 4 objects, additional key locations were spaced by the rats between the objects, forming symmetry among the key locations. It was as if the rats had behaviorally imposed symmetry on the physically asymmetrical environment. Based on a previous finding that wayfinding is easier in symmetrical environments, we suggest that when the physical attributes of the environment were not symmetrical, the rats established a symmetric layout of key locations, thereby acquiring a more legible environment despite its complex physical structure. CONCLUSIONS AND SIGNIFICANCE: The present study adds a behavioral definition for "location", a term that so far has been mostly discussed according to its physical attributes or neurobiological correlates (e.g.--place and grid neurons). Moreover, network analysis enabled the assessment of the importance of a location, even when that location did not display any distinctive physical properties. PMID- 22815810 TI - A new genus Bifidunguiglenea gen. nov. is erected for the species Glenea gestroi Gahan (Cerambycidae: Lamiinae: Saperdini). AB - Bifidunguigleneagen. nov. is erected for the species Glenea gestroi Gahan, 1894. Bifidunguiglenea gestroi (Gahan, 1894) comb. nov. is redescribed. The genitalia descriptions are reported for the first time and it is newly recorded from Thailand. PMID- 22815809 TI - Targeted inactivation of GPR26 leads to hyperphagia and adiposity by activating AMPK in the hypothalamus. AB - G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation. PMID- 22815811 TI - A role for PP1/NIPP1 in steering migration of human cancer cells. AB - Electrical gradients are present in many developing and regenerating tissues and around tumours. Mimicking endogenous electric fields in vitro has profound effects on the behaviour of many cell types. Intriguingly, specific cell types migrate cathodally, others anodally and some polarise with their long axis perpendicular to the electric vector. These striking phenomena are likely to have in vivo relevance since one of the determining factors during cancer metastasis is the ability to switch between attractive and repulsive migration in response to extracellular guidance stimuli. We present evidence that the cervical cancer cell line HeLa migrates cathodally in a direct current electric field of physiological intensity, while the strongly metastatic prostate cancer cell line PC-3-M migrates anodally. Notably, genetic disruption of protein serine/threonine phosphatase-1 (PP1) and its regulator NIPP1 decrease directional migration in these cell lines. Conversely, the inducible expression of NIPP1 switched the directional response of HeLa cells from cathodal to slightly anodal in a PP1 dependent manner. Remarkably, induction of a hyperactive PP1/NIPP1 holoenzyme, further shifted directional migration towards the anode. We show that PP1 association with NIPP1 upregulates signalling by the GTPase Cdc42 and demonstrate that pharmacological inhibition of Cdc42 in cells overexpressing NIPP1 recovered cathodal migration. Taken together, we provide the first evidence for regulation of directional cell migration by NIPP1. In addition, we identify PP1/NIPP1 as a novel molecular compass that controls directed cell migration via upregulation of Cdc42 signalling and suggest a way by which PP1/NIPP1 may contribute to the migratory properties of cancer cells. PMID- 22815812 TI - The pharmacological chaperone AT2220 increases recombinant human acid alpha glucosidase uptake and glycogen reduction in a mouse model of Pompe disease. AB - Pompe disease is an inherited lysosomal storage disease that results from a deficiency in the enzyme acid alpha-glucosidase (GAA), and is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. Recombinant human GAA (rhGAA) is the only approved enzyme replacement therapy (ERT) available for the treatment of Pompe disease. Although rhGAA has been shown to slow disease progression and improve some of the pathophysiogical manifestations, the infused enzyme tends to be unstable at neutral pH and body temperature, shows low uptake into some key target tissues, and may elicit immune responses that adversely affect tolerability and efficacy. We hypothesized that co-administration of the orally-available, small molecule pharmacological chaperone AT2220 (1-deoxynojirimycin hydrochloride, duvoglustat hydrochloride) may improve the pharmacological properties of rhGAA via binding and stabilization. AT2220 co-incubation prevented rhGAA denaturation and loss of activity in vitro at neutral pH and 37 degrees C in both buffer and blood. In addition, oral pre-administration of AT2220 to rats led to a greater than two fold increase in the circulating half-life of intravenous rhGAA. Importantly, co administration of AT2220 and rhGAA to GAA knock-out (KO) mice resulted in significantly greater rhGAA levels in plasma, and greater uptake and glycogen reduction in heart and skeletal muscles, compared to administration of rhGAA alone. Collectively, these preclinical data highlight the potentially beneficial effects of AT2220 on rhGAA in vitro and in vivo. As such, a Phase 2 clinical study has been initiated to investigate the effects of co-administered AT2220 on rhGAA in Pompe patients. PMID- 22815813 TI - Functional epistatic interaction between rs6046G>A in F7 and rs5355C>T in SELE modifies systolic blood pressure levels. AB - BACKGROUND: Although numerous genetic studies have been performed, only 0.9% of blood pressure phenotypic variance has been elucidated. This phenomenon could be partially due to epistatic interactions. Our aim was to identify epistatic interaction(s) associated with blood pressure levels in a pre-planned two-phase approach. METHODS AND RESULTS: In a discovery cohort composed of 3,600 French individuals, we found rs6046A allele in F7 associated with decreased blood pressure levels (P<=3.7*10(-3)) and rs5355T allele in SELE associated with decreased diastolic blood pressure levels (P = 5*10(-3)). Both variants interacted in order to influence blood pressure levels (P<=0.048). This interaction was replicated with systolic blood pressure in 4,620 additional European individuals (P = 0.03). Similarly, in this replication cohort, rs6046A was associated with decreased blood pressure levels (P<=8.5*10(-4)). Furthermore, in peripheral blood mononuclear cells of a subsample of 90 supposed healthy individuals, we found rs6046A positively associated with NAMPT mRNA levels (P<=9.1*10(-5)), suggesting an eventual involvement of NAMPT expression in blood pressure regulation. Confirming this hypothesis, further transcriptomic analyses showed that increased NAMPT mRNA levels were positively correlated with ICAM1, SELL, FPR1, DEFA1-3, and LL-37 genes expression (P<=5*10(-3)). The last two mRNA levels were positively associated with systolic blood pressure levels (P<=0.01) and explained 4% of its phenotypic variation. CONCLUSION: These findings reveal the importance of epistatic interactions in blood pressure genetics and give new insights for the role of inflammation in its complex regulation. PMID- 22815814 TI - A cross-platform comparison of genome-wide expression changes of laser microdissected lung tissue of C-Raf transgenic mice using 3'IVT and exon array. AB - Microarrays are widely used to study genome-wide gene expression changes in different conditions most notably disease, growth, or to investigate the effects of drugs on entire genomes. While the number and gene probe sequences to investigate individual gene expression changes differs amongst manufactures, the design for all of the probes is biased towards the 3' region. With the advent of exon arrays, transcripts of any known or predicted exon can be investigated to facilitate the study of genome-wide alternative splicing events. Thus, the use of exon arrays provides unprecedented opportunities in gene expression studies. However, it remains a major challenge to directly compare gene expression data derived from oligonucleotide to exon arrays. In the present study, genome-wide expression profiling of Laser Micro-dissected Pressure Catapulted (LMPC) samples of c-Raf mouse lung adenocarcinoma, dysplasia, unaltered transgenic and non transgenic tissues was performed using the Affymetrix GeneChip Mouse Genome 430 2.0 Array and whole genome Mouse Exon 1.0 ST Array. Based on individual group comparisons 52 to 83% of regulated genes were similar in direction, but fold changes of regulated genes disagreed when data amongst the two platforms were compared. Furthermore, for 27 regulated genes opposite direction of gene expression was observed when the two platforms were compared pointing to the need to assess alternative splicing events at the 3' end. Taken collectively, exon arrays can be performed even with laser microdissected samples but fold change gene expression changes differ considerably between 3'IVT array and exon arrays with alternative splicing events contributing to apparent differences in gene expression changes. PMID- 22815815 TI - Microarray analysis of rat sensory ganglia after local inflammation implicates novel cytokines in pain. AB - Inflammation plays a role in neuropathic pain conditions as well as in pain induced solely by an inflammatory stimulus. Robust mechanical hyperalgesia and allodynia can be induced by locally inflaming the L5 dorsal root ganglion (DRG) in rat. This model allows investigation of the contribution of inflammation per se to chronic pain conditions. Most previous microarray studies of DRG gene expression have investigated neuropathic pain models. To examine the role of inflammation, we used microarray methods to examine gene expression 3 days after local inflammation of the L5 DRG in rat. We observed significant regulation in a large number of genes (23% of observed transcripts), and examined 221 (3%) with a fold-change of 1.5-fold or more in more detail. Immune-related genes were the largest category in this group and included members of the complement system as well as several pro-inflammatory cytokines. However, these upregulated cytokines had no prior links to peripheral pain in the literature other than through microarray studies, though most had previously described roles in CNS (especially neuroinflammatory conditions) as well as in immune responses. To confirm an association to pain, qPCR studies examined these cytokines at a later time (day 14), as well as in two different versions of the spinal nerve ligation pain model including a version without any foreign immunogenic material (suture). Cxcl11, Cxcl13, and Cxcl14 were found to be significantly upregulated in all these conditions, while Cxcl9, Cxcl10, and Cxcl16 were upregulated in at least two of these conditions. PMID- 22815816 TI - Female rose bitterling prefer MHC-dissimilar males: experimental evidence. AB - The role of genetic benefits in female mate choice remains a controversial aspect of sexual selection theory. In contrast to "good allele" models of sexual selection, "compatible allele" models of mate choice predict that females prefer mates with alleles complementary to their own rather than conferring additive effects. While correlative results suggest complementary genetic effects to be plausible, direct experimental evidence is scarce. A previous study on the Chinese rose bitterling (Rhodeus ocellatus) demonstrated a positive correlation between female mate choice, offspring growth and survival, and the functional dissimilarity between the Major Histocompatibility Complex (MHC) alleles of males and females. Here we directly tested whether females used cues associated with MHC genes to select genetically compatible males in an experimental framework. By sequentially pairing females with MHC similar and dissimilar males, based on a priori known MHC profiles, we showed that females discriminated between similar and dissimilar males and deposited significantly more eggs with MHC dissimilar males. Notably, the degree of dissimilarity was an important factor for female decision to mate, possibly indicating a potential threshold value of dissimilarity for decision making, or of an indirect effect of the MHC. PMID- 22815817 TI - Female presence and estrous state influence mouse ultrasonic courtship vocalizations. AB - The laboratory mouse is an emerging model for context-dependent vocal signaling and reception. Mouse ultrasonic vocalizations are robustly produced in social contexts. In adults, male vocalization during courtship has become a model of interest for signal-receiver interactions. These vocalizations can be grouped into syllable types that are consistently produced by different subspecies and strains of mice. Vocalizations are unique to individuals, vary across development, and depend on social housing conditions. The behavioral significance of different syllable types, including the contexts in which different vocalizations are made and the responses listeners have to different types of vocalizations, is not well understood. We examined the effect of female presence and estrous state on male vocalizations by exploring the use of syllable types and the parameters of syllables during courtship. We also explored correlations between vocalizations and other behaviors. These experimental manipulations produced four main findings: 1) vocalizations varied among males, 2) the production of USVs and an increase in the use of a specific syllable type were temporally related to mounting behavior, 3) the frequency (kHz), bandwidth, and duration of syllables produced by males were influenced by the estrous phase of female partners, and 4) syllable types changed when females were removed. These findings show that mouse ultrasonic courtship vocalizations are sensitive to changes in female phase and presence, further demonstrating the context sensitivity of these calls. PMID- 22815818 TI - Cytoplasmic sulfurtransferases in the purple sulfur bacterium Allochromatium vinosum: evidence for sulfur transfer from DsrEFH to DsrC. AB - While the importance of sulfur transfer reactions is well established for a number of biosynthetic pathways, evidence has only started to emerge that sulfurtransferases may also be major players in sulfur-based microbial energy metabolism. Among the first organisms studied in this regard is the phototrophic purple sulfur bacterium Allochromatium vinosum. During the oxidation of reduced sulfur species to sulfate this Gammaproteobacterium accumulates sulfur globules. Low molecular weight organic persulfides have been proposed as carrier molecules transferring sulfur from the periplasmic sulfur globules into the cytoplasm where it is further oxidized via the "Dsr" (dissimilatory sulfite reductase) proteins. We have suggested earlier that the heterohexameric protein DsrEFH is the direct or indirect acceptor for persulfidic sulfur imported into the cytoplasm. This proposal originated from the structural similarity of DsrEFH with the established sulfurtransferase TusBCD from E. coli. As part of a system for tRNA modification TusBCD transfers sulfur to TusE, a homolog of another crucial component of the A. vinosum Dsr system, namely DsrC. Here we show that neither DsrEFH nor DsrC have the ability to mobilize sulfane sulfur directly from low molecular weight thiols like thiosulfate or glutathione persulfide. However, we demonstrate that DsrEFH binds sulfur specifically to the conserved cysteine residue DsrE-Cys78 in vitro. Sulfur atoms bound to cysteines in DsrH and DsrF were not detected. DsrC was exclusively persulfurated at DsrC-Cys111 in the penultimate position of the protein. Most importantly, we show that persulfurated DsrEFH indeed serves as an effective sulfur donor for DsrC in vitro. The active site cysteines Cys78 of DsrE and Cys20 of DsrH furthermore proved to be essential for sulfur oxidation in vivo supporting the notion that DsrEFH and DsrC are part of a sulfur relay system that transfers sulfur from a persulfurated carrier molecule to the dissimilatory sulfite reductase DsrAB. PMID- 22815819 TI - Loop 7 of E2 enzymes: an ancestral conserved functional motif involved in the E2 mediated steps of the ubiquitination cascade. AB - The ubiquitin (Ub) system controls almost every aspect of eukaryotic cell biology. Protein ubiquitination depends on the sequential action of three classes of enzymes (E1, E2 and E3). E2 Ub-conjugating enzymes have a central role in the ubiquitination pathway, interacting with both E1 and E3, and influencing the ultimate fate of the substrates. Several E2s are characterized by an extended acidic insertion in loop 7 (L7), which if mutated is known to impair the proper E2-related functions. In the present contribution, we show that acidic loop is a conserved ancestral motif in E2s, relying on the presence of alternate hydrophobic and acidic residues. Moreover, the dynamic properties of a subset of family 3 E2s, as well as their binary and ternary complexes with Ub and the cognate E3, have been investigated. Here we provide a model of L7 role in the different steps of the ubiquitination cascade of family 3 E2s. The L7 hydrophobic residues turned out to be the main determinant for the stabilization of the E2 inactive conformations by a tight network of interactions in the catalytic cleft. Moreover, phosphorylation is known from previous studies to promote E2 competent conformations for Ub charging, inducing electrostatic repulsion and acting on the L7 acidic residues. Here we show that these active conformations are stabilized by a network of hydrophobic interactions between L7 and L4, the latter being a conserved interface for E3-recruitment in several E2s. In the successive steps, L7 conserved acidic residues also provide an interaction interface for both Ub and the Rbx1 RING subdomain of the cognate E3. Our data therefore suggest a crucial role for L7 of family 3 E2s in all the E2-mediated steps of the ubiquitination cascade. Its different functions are exploited thank to its conserved hydrophobic and acidic residues in a finely orchestrate mechanism. PMID- 22815820 TI - Novel RNAi-mediated approach to G protein-coupled receptor deorphanization: proof of principle and characterization of a planarian 5-HT receptor. AB - G protein-coupled receptors (GPCRs) represent the largest known superfamily of membrane proteins extending throughout the Metazoa. There exists ample motivation to elucidate the functional properties of GPCRs given their role in signal transduction and their prominence as drug targets. In many target organisms, these efforts are hampered by the unreliable nature of heterologous receptor expression platforms. We validate and describe an alternative loss-of-function approach for ascertaining the ligand and G protein coupling properties of GPCRs in their native cell membrane environment. Our efforts are focused on the phylum Platyhelminthes, given the heavy health burden exacted by pathogenic flatworms, as well as the role of free-living flatworms as model organisms for the study of developmental biology. RNA interference (RNAi) was used in conjunction with a biochemical endpoint assay to monitor cAMP modulation in response to the translational suppression of individual receptors. As proof of principle, this approach was used to confirm the neuropeptide GYIRFamide as the cognate ligand for the planarian neuropeptide receptor GtNPR-1, while revealing its endogenous coupling to Galpha(i/o). The method was then extended to deorphanize a novel Galpha(s)-coupled planarian serotonin receptor, DtSER-1. A bioinformatics protocol guided the selection of receptor candidates mediating 5-HT-evoked responses. These results provide functional data on a neurotransmitter central to flatworm biology, while establishing the great potential of an RNAi-based deorphanization protocol. Future work can help optimize and adapt this protocol for higher-throughput platforms as well as other phyla. PMID- 22815821 TI - Innate immune activation by inhaled lipopolysaccharide, independent of oxidative stress, exacerbates silica-induced pulmonary fibrosis in mice. AB - Acute exacerbations of pulmonary fibrosis are characterized by rapid decrements in lung function. Environmental factors that may contribute to acute exacerbations remain poorly understood. We have previously demonstrated that exposure to inhaled lipopolysaccharide (LPS) induces expression of genes associated with fibrosis. To address whether exposure to LPS could exacerbate fibrosis, we exposed male C57BL/6 mice to crystalline silica, or vehicle, followed 28 days later by LPS or saline inhalation. We observed that mice receiving both silica and LPS had significantly more total inflammatory cells, more whole lung lavage MCP-1, MIP-2, KC and IL-1beta, more evidence of oxidative stress and more total lung hydroxyproline than mice receiving either LPS alone, or silica alone. Blocking oxidative stress with N-acetylcysteine attenuated whole lung inflammation but had no effect on total lung hydroxyproline. These observations suggest that exposure to innate immune stimuli, such as LPS in the environment, may exacerbate stable pulmonary fibrosis via mechanisms that are independent of inflammation and oxidative stress. PMID- 22815822 TI - Expression of mast cell proteases correlates with mast cell maturation and angiogenesis during tumor progression. AB - Tumor cells are surrounded by infiltrating inflammatory cells, such as lymphocytes, neutrophils, macrophages, and mast cells. A body of evidence indicates that mast cells are associated with various types of tumors. Although role of mast cells can be directly related to their granule content, their function in angiogenesis and tumor progression remains obscure. This study aims to understand the role of mast cells in these processes. Tumors were chemically induced in BALB/c mice and tumor progression was divided into Phases I, II and III. Phase I tumors exhibited a large number of mast cells, which increased in phase II and remained unchanged in phase III. The expression of mouse mast cell protease (mMCP)-4, mMCP-5, mMCP-6, mMCP-7, and carboxypeptidase A were analyzed at the 3 stages. Our results show that with the exception of mMCP-4 expression of these mast cell chymase (mMCP-5), tryptases (mMCP-6 and 7), and carboxypeptidase A (mMC-CPA) increased during tumor progression. Chymase and tryptase activity increased at all stages of tumor progression whereas the number of mast cells remained constant from phase II to III. The number of new blood vessels increased significantly in phase I, while in phases II and III an enlargement of existing blood vessels occurred. In vitro, mMCP-6 and 7 are able to induce vessel formation. The present study suggests that mast cells are involved in induction of angiogenesis in the early stages of tumor development and in modulating blood vessel growth in the later stages of tumor progression. PMID- 22815823 TI - Kinematic analysis quantifies gait abnormalities associated with lameness in broiler chickens and identifies evolutionary gait differences. AB - This is the first time that gait characteristics of broiler (meat) chickens have been compared with their progenitor, jungle fowl, and the first kinematic study to report a link between broiler gait parameters and defined lameness scores. A commercial motion-capturing system recorded three-dimensional temporospatial information during walking. The hypothesis was that the gait characteristics of non-lame broilers (n = 10) would be intermediate to those of lame broilers (n = 12) and jungle fowl (n = 10, tested at two ages: immature and adult). Data analysed using multi-level models, to define an extensive range of baseline gait parameters, revealed inter-group similarities and differences. Natural selection is likely to have made jungle fowl walking gait highly efficient. Modern broiler chickens possess an unbalanced body conformation due to intense genetic selection for additional breast muscle (pectoral hypertrophy) and whole body mass. Together with rapid growth, this promotes compensatory gait adaptations to minimise energy expenditure and triggers high lameness prevalence within commercial flocks; lameness creating further disruption to the gait cycle and being an important welfare issue. Clear differences were observed between the two lines (short stance phase, little double-support, low leg lift, and little back displacement in adult jungle fowl; much double-support, high leg lift, and substantial vertical back movement in sound broilers) presumably related to mass and body conformation. Similarities included stride length and duration. Additional modifications were also identified in lame broilers (short stride length and duration, substantial lateral back movement, reduced velocity) presumably linked to musculo-skeletal abnormalities. Reduced walking velocity suggests an attempt to minimise skeletal stress and/or discomfort, while a shorter stride length and time, together with longer stance and double-support phases, are associated with instability. We envisage a key future role for this highly quantitative methodology in pain assessment (associated with broiler lameness) including experimental examination of therapeutic agent efficacy. PMID- 22815824 TI - C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance. AB - Neurodegenerative disorders are growing burdens in modern societies because of increased life expectancy. Most neurodegenerative disorders commonly possess a similar neuropathological feature--the accumulation of abnormal protein aggregates or inclusions (misfolded proteins) in the brain. One of the main functions of endoplasmic reticulum (ER) is to initiate proper protein folding to facilitate protein secretion through the induction of unfolded protein response (UPR). C/EBP homologous protein (CHOP) induction has been demonstrated to be a signaling event underlying ER stress-induced cell apoptosis. In this study, we explored the role of CHOP in the hippocampal cell apoptosis and memory performance injury under an induced ER stress condition. Adult male wild type (C57BL/6J) and CHOP knockout (CHOP-/-) mice were intracerebroventricularly injected with tunicamycin. Tunicamycin can induce ER stress and cell apoptosis in mouse hippocampus. Compared with wild type mice, CHOP-/- mice showed an enhanced hippocampal cell apoptosis, worse performance in memory-related behavioral tests, and attenuated IRE-1 expression under tunicamycin treatment. The aggravated cell apoptosis and worse memory performance in CHOP-/- mice might be due to the deficiency of CHOP protein resulted in the impaired adaptive/pathological transcriptional response, the decreased IRE-1 and XBP-1 expressions, and the increased JNK phosphorylation to cope with ER stress. Taken together, these results suggest that CHOP may play a protective role in the hippocampal cell apoptosis and impairment of memory performance. PMID- 22815825 TI - Number conservation is related to children's prefrontal inhibitory control: an fMRI study of a piagetian task. AB - Although young children can accurately determine that two rows contain the same number of coins when they are placed in a one-to-one correspondence, children younger than 7 years of age erroneously think that the longer row contains more coins when the coins in one of the rows are spread apart. To demonstrate that prefrontal inhibitory control is necessary to succeed at this task (Piaget's conservation-of-number task), we studied the relationship between the percentage of BOLD signal changes in the brain areas activated in this developmental task and behavioral performance on a Stroop task and a Backward Digit Span task. The level of activation in the right insula/inferior frontal gyrus was selectively related to inhibitory control efficiency (i.e., the Stroop task), whereas the activation in the left intraparietal sulcus (IPS) was selectively related to the ability to manipulate numerical information in working memory (i.e., the Backward Digit Span task). Taken together, the results indicate that to acquire number conservation, children's brains must not only activate the reversibility of cognitive operations (supported by the IPS) but also inhibit a misleading length equal-number strategy (supported by the right insula/inferior frontal gyrus). PMID- 22815826 TI - Identification of potential small molecule binding pockets on Rho family GTPases. AB - Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (>100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism. PMID- 22815827 TI - Genomic organisation, embryonic expression and biochemical interactions of the zebrafish junctional adhesion molecule family of receptors. AB - The mammalian JAM family is composed of three cell surface receptors. Interactions between the proteins have well-characterised roles in inflammation and tight junction formation, but little is known about their function in early development. Recently, we identified a role for jamb and jamc in zebrafish myocyte fusion. Genome duplication in the teleost lineage raised the possibility that additional JAM family paralogues may also function in muscle development. To address this, we searched the zebrafish genome to identify potential paralogues and confirmed their homology, bringing the total number of zebrafish jam family members to six. We then compared the physical binding properties of each paralogue by surface plasmon resonance and determined the gene expression patterns of all zebrafish jam genes at different stages of development. Our results suggest a significant sub-functionalisation of JAM-B and JAM-C orthologues with respect to binding strength (but not specificity) and gene expression. The paralogous genes, jamb2 and jamc2, were not detected in the somites or myotome of wild-type embryos. We conclude that it is unlikely that the paralogues have a function in primary myogenesis. PMID- 22815828 TI - Examining inequities in incidence of catastrophic health expenditures on different healthcare services and health facilities in Nigeria. AB - OBJECTIVE: There is limited evidence about levels of socio-economic and other differences in catastrophic health spending in Nigeria and in many sub-Saharan African countries. The study estimated the level of catastrophic healthcare expenditures for different healthcare services and facilities and their distribution across socioeconomic status (SES) groups. METHODS: The study took place in four Local Government Areas in southeast Nigeria. Data were collected using interviewer-administered questionnaires administered to 4873 households. Catastrophic health expenditures (CHE) were measured using a threshold of 40% of monthly non-food expenditure. We examined both total monthly health expenditure and disaggregated expenditure by source and type of care. RESULTS: The average total household health expenditure per month was 2354 Naira ($19.6). For outpatient services, average monthly expenditure was 1809 Naira ($15.1), whilst for inpatient services it was 610 Naira ($5.1). Higher health expenditures were incurred by urban residents and the better-off SES groups. Overall, 27% of households incurred CHE, higher for poorer socioeconomic groups and for rural residents. Only 1.0% of households had a member that was enrolled in a health insurance scheme. CONCLUSION: The worse-off households (the poorest SES and rural dwellers) experienced the highest burden of health expenditure. There was almost a complete lack of financial risk protection. Health reform mechanisms are needed to ensure universal coverage with financial risk protection mechanisms. PMID- 22815829 TI - An IP-10 (CXCL10)-derived peptide inhibits angiogenesis. AB - Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP 10, spanning the alpha-helical domain residues 77-98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3 mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis. PMID- 22815830 TI - Accumulating microglia phagocytose injured neurons in hippocampal slice cultures: involvement of p38 MAP kinase. AB - In this study, microglial migration and phagocytosis were examined in mouse organotypic hippocampal slice cultures, which were treated with N-methyl-D aspartate (NMDA) to selectively injure neuronal cells. Microglial cells were visualized by the expression of enhanced green fluorescent protein. Daily observation revealed microglial accumulation in the pyramidal cell layer, which peaked 5 to 6 days after NMDA treatment. Time-lapse imaging showed that microglia migrated to the pyramidal cell layer from adjacent and/or remote areas. There was no difference in the number of proliferating microglia between control and NMDA treated slices in both the pyramidal cell layer and stratum radiatum, suggesting that microglial accumulation in the injured areas is mainly due to microglial migration, not to proliferation. Time-lapse imaging also showed that the injured neurons, which were visualized by propidium iodide (PI), disappeared just after being surrounded by microglia. Daily observation revealed that the intensity of PI fluorescence gradually attenuated, and this attenuation was suppressed by pretreatment with clodronate, a microglia toxin. These findings suggest that accumulating microglia phagocytosed injured neurons, and that PI fluorescence could be a useful indicator for microglial phagocytosis. Using this advantage to examine microglial phagocytosis in living slice cultures, we investigated the involvements of mitogen-activated protein (MAP) kinases in microglial accumulation and phagocytosis. p38 MAP kinase inhibitor SB203580, but not MAP kinase/extracellular signal-regulated kinase inhibitor PD98059 or c-Jun N terminal kinase inhibitor SP600125, suppressed the attenuation of PI fluorescence. On the other hand, microglial accumulation in the injured areas was not inhibited by any of these inhibitors. These data suggest that p38 MAP kinase plays an important role in microglial phagocytosis of injured neurons. PMID- 22815831 TI - Twist1 transcriptional targets in the developing atrio-ventricular canal of the mouse. AB - Malformations of the cardiovascular system are the most common type of birth defect in humans, frequently affecting the formation of valves and septa. During heart valve and septa formation, cells from the atrio-ventricular canal (AVC) and outflow tract (OFT) regions of the heart undergo an epithelial-to-mesenchymal transformation (EMT) and invade the underlying extracellular matrix to give rise to endocardial cushions. Subsequent maturation of newly formed mesenchyme cells leads to thin stress-resistant leaflets. TWIST1 is a basic helix-loop-helix transcription factor expressed in newly formed mesenchyme cells of the AVC and OFT that has been shown to play roles in cell survival, cell proliferation and differentiation. However, the downstream targets of TWIST1 during heart valve formation remain unclear. To identify genes important for heart valve development downstream of TWIST1, we performed global gene expression profiling of AVC, OFT, atria and ventricles of the embryonic day 10.5 mouse heart by tag-sequencing (Tag seq). Using this resource we identified a novel set of 939 genes, including 123 regulators of transcription, enriched in the valve forming regions of the heart. We compared these genes to a Tag-seq library from the Twist1 null developing valves revealing significant gene expression changes. These changes were consistent with a role of TWIST1 in controlling differentiation of mesenchymal cells following their transformation from endothelium in the mouse. To study the role of TWIST1 at the DNA level we performed chromatin immunoprecipitation and identified novel direct targets of TWIST1 in the developing heart valves. Our findings support a role for TWIST1 in the differentiation of AVC mesenchyme post EMT in the mouse, and suggest that TWIST1 can exert its function by direct DNA binding to activate valve specific gene expression. PMID- 22815832 TI - Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population. AB - BACKGROUND: Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs) of these genes and prostate cancer (PCa) in our Chinese population. METHODS: Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR) and 95% confidence intervals (95% CI) were evaluated by logistic regression. RESULTS: We observed significant associations between PCa risk and mTOR rs2295080 [P = 0.027, OR = 0.85, 95%CI = 0.74-0.98], and AKT2 rs7254617 (P = 0.003, OR = 1.35, 95%CI = 1.11 1.64). When estimated these two SNPs together, the combined genotypes with 2-4 risk alleles (rs2295080 T and rs7254617 A alleles) were associated with an increased risk of PCa compared with 0-1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2-4 risk alleles in advanced stage were significantly higher than in localized stage (P = 0.022), but there was no significant association in Gleason score and PSA level. CONCLUSION: Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2-4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers. PMID- 22815833 TI - Combined spatio-temporal impacts of climate and longline fisheries on the survival of a trans-equatorial marine migrant. AB - Predicting the impact of human activities and their derivable consequences, such as global warming or direct wildlife mortality, is increasingly relevant in our changing world. Due to their particular life history traits, long-lived migrants are amongst the most endangered and sensitive group of animals to these harming effects. Our ability to identify and quantify such anthropogenic threats in both breeding and wintering grounds is, therefore, of key importance in the field of conservation biology. Using long-term capture-recapture data (34 years, 4557 individuals) and year-round tracking data (4 years, 100 individuals) of a trans equatorial migrant, the Cory's shearwater (Calonectris diomedea), we investigated the impact of longline fisheries and climatic variables in both breeding and wintering areas on the most important demographic trait of this seabird, i.e. adult survival. Annual adult survival probability was estimated at 0.914+/-0.022 on average, declining throughout 1978-1999 but recovering during the last decade (2005-2011). Our results suggest that both the incidental bycatch associated with longline fisheries and high sea surface temperatures (indirectly linked to food availability; SST) increased mortality rates during the long breeding season (March-October). Shearwater survival was also negatively affected during the short non-breeding season (December-February) by positive episodes of the Southern Oscillation Index (SOI). Indirect negative effects of climate at both breeding (SST) and wintering grounds (SOI) had a greater impact on survival than longliner activity, and indeed these climatic factors are those which are expected to present more unfavourable trends in the future. Our work underlines the importance of considering both breeding and wintering habitats as well as precise schedules/phenology when assessing the global role of the local impacts on the dynamics of migratory species. PMID- 22815834 TI - Effects of hypoxia exposure on hepatic cytochrome P450 1A (CYP1A) expression in Atlantic croaker: molecular mechanisms of CYP1A down-regulation. AB - Hypoxia-inducible factor-alpha (HIF-alpha) and cytochrome P450 1A (CYP1A) are biomarkers of environmental exposure to hypoxia and organic xenobiotic chemicals that act through the aryl hydrocarbon receptor, respectively. Many aquatic environments heavily contaminated with organic chemicals, such as harbors, are also hypoxic. Recently, we and other scientists reported HIF-alpha genes are upregulated by hypoxia exposure in aquatic organisms, but the molecular mechanisms of hypoxia regulation of CYP1A expression have not been investigated in teleost fishes. As a first step in understanding the molecular mechanisms of hypoxia modulation of CYP1A expression in fish, we characterized CYP1A cDNA from croaker liver. Hypoxia exposure (dissolved oxygen, DO: 1.7 mg/L for 2 to 4 weeks) caused significant decreases in hepatic CYP1A mRNA and protein levels compared to CYP1A levels in fish held in normoxic conditions. In vivo studies showed that the nitric oxide (NO)-donor, S-nitroso-N-acetyl-DL-penicillamine, significantly decreased CYP1A expression in croaker livers, whereas the competitive inhibitor of NO synthase (NOS), N(omega)-nitro-L-arginine methyl ester, restored CYP1A mRNA and protein levels in hypoxia-exposed (1.7 mg DO/L for 4 weeks) fish. In vivo hypoxia exposure also markedly increased interleukin-1beta (IL-1beta, a cytokine), HIF-2alpha mRNA and endothelial NOS (eNOS) protein levels in croaker livers. Pharmacological treatment with vitamin E, an antioxidant, lowered the IL 1beta, HIF-2alpha mRNA and eNOS protein levels in hypoxia-exposed fish and completely reversed the down-regulation of hepatic CYP1A mRNA and protein levels in response to hypoxia exposure. These results suggest that hypoxia-induced down regulation of CYP1A is due to alterations of NO and oxidant status, and cellular IL-1beta and HIF-alpha levels. Moreover, the present study provides the first evidence of a role for antioxidants in hepatic eNOS and IL-1beta regulation in aquatic vertebrates during hypoxic stress. PMID- 22815835 TI - Looping mediated interaction between the promoter and 3' UTR regulates type II collagen expression in chondrocytes. AB - Type II collagen is the major component of articular cartilage and is mainly synthesized by chondrocytes. Repeated sub-culturing of primary chondrocytes leads to reduction of type II collagen gene (Col2a1) expression, which mimics the process of chondrocyte dedifferentiation. Although the functional importance of Col2a1 expression has been extensively investigated, mechanism of transcriptional regulation during chondrocyte dedifferentiation is still unclear. In this study, we have investigated the crosstalk between cis-acting DNA element and transcription factor on Col2a1 expression in primary chondrocytes. Bioinformatic analysis revealed the potential regulatory regions in the Col2a1 genomic locus. Among them, promoter and 3' untranslated region (UTR) showed highly accessible chromatin architecture with enriched recruitment of active chromatin markers in primary chondrocytes. 3' UTR has a potent enhancer function which recruits Lef1 (Lymphoid enhancer binding factor 1) transcription factor, leading to juxtaposition of the 3' UTR with the promoter through gene looping resulting in up-regulation of Col2a1 gene transcription. Knock-down of endogenous Lef1 level significantly reduced the gene looping and subsequently down-regulated Col2a1 expression. However, these regulatory loci become inaccessible due to condensed chromatin architecture as chondrocytes dedifferentiate which was accompanied by a reduction of gene looping and down-regulation of Col2a1 expression. Our results indicate that Lef1 mediated looping between promoter and 3' UTR under the permissive chromatin architecture upregulates Col2a1 expression in primary chondrocytes. PMID- 22815836 TI - Cord blood leptin levels of healthy neonates are associated with IFN-gamma production by cord blood T-cells. AB - Leptin is a hormone synthesized by adipocytes and other tissues, including the placenta, and it regulates food intake and energy expenditure, reproductive and immune functions. To investigate the role of leptin in neonatal immunity, we measured serum leptin and cytokine (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-10, IL 12) levels in the cord blood (cb) of 510 healthy neonates, 14 small for gestational age (SGA), 312 appropriately grown for gestational age (AGA) and 184 large for gestational age (LGA). Median serum leptin concentration in the whole sample was 11 ng/ml. In 11.2% neonates (1 SGA, 32 AGA, 24 LGA), leptin levels were >90th percentile (median 39 ng/ml). In 33.3% of those (3.72% of total sample) with the highest leptin levels (median 46 ng/ml), significantly elevated levels of serum IFN-gamma were also found (mean 27.11 pg/ml, range 17.5-38.5 pg/ml). In neonates with leptin levels ~50th percentile (median 12 ng/ml) or <10th percentile (median 1 ng/ml), serum IFN-gamma levels were negligible. All other cytokines measured, were < the assays' detection limits. To investigate whether leptin can independently influence cytokine gene expression by cb T-cells and monocytes (Mc), we cultured cb T-cells or Mc, isolated from randomly selected AGA neonates or adult peripheral blood, with leptin. This resulted in upregulation of IL-2, IFN-gamma and IL-4 gene expression in cb and adult T-cells and IL-10 expression mainly in cb-Mc. Significantly higher expression of IFN gamma occurred in female cb-T-cells cultured with leptin, compared with male cb-T cells. In conclusion, the concurrent presence of high concentrations in both leptin and IFN-gamma in cb of healthy infants, and leptin's ability to directly upregulate cytokine gene expression in cb T and Mc cells, indicate that abnormally high leptin levels can independently influence the immune system of healthy newborns, and may mediate gender differences in the development of a Th1 polarized immune response. PMID- 22815837 TI - Dietary fibre improves first-phase insulin secretion in overweight individuals. AB - Previous work has shown increased insulin sensitivity, increased hepatic insulin clearance and lower postprandial insulin responses following treatment with resistant starch, a type of dietary fibre. The objective of this study was to further explore the effects of resistant starch on insulin secretion. Twelve overweight (BMI 28.2+/-0.4 kg/m(2)) individuals participated in this randomized, subject-blind crossover study. Participants consumed either 40 g type 2 resistant starch or the energy and carbohydrate-matched placebo daily for four weeks. Assessment of the effect on insulin secretion was made at the end of each intervention using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT). Insulin and C-peptide concentrations were significantly higher during the FSIVGTT following the resistant starch compared with the placebo. Modelling of the data showed significantly improved first-phase insulin secretion with resistant starch. These effects were observed without any changes to either body weight or habitual food intake. This study showed that just four weeks of resistant starch intake significantly increased the first-phase insulin secretion in individuals at risk of developing type 2 diabetes. Further studies exploring this effect in individuals with type 2 diabetes are required. PMID- 22815838 TI - Wnt signaling enhances neurogenesis and improves neurological function after focal ischemic injury. AB - Stroke potently stimulates cell proliferation in the subventricular zone of the lateral ventricles with subsequent neuroblast migration to the injured striatum and cortex. However, most of the cells do not survive and mature. Extracellular Wnt proteins promote adult neurogenesis in the neurogenic niches. The aim of the study was to examine the efficacy of Wnt signaling on neurogenesis and functional outcome after focal ischemic injury. Lentivirus expressing Wnt3a-HA (LV-Wnt3a-HA) or GFP (LV-GFP) was injected into the striatum or subventricular zone of mice. Five days later, focal ischemic injury was induced by injection of the vasoconstrictor endothelin-1 into the striatum of the same hemisphere. Treatment with LV-Wnt3a-HA into the striatum significantly enhanced functional recovery after ischemic injury and increased the number of BrdU-positive cells that differentiated into mature neurons in the ischemic striatum by day 28. Treatment with LV-Wnt3a-HA into the subventricular zone significantly enhanced functional recovery from the second day after injury and increased the number of immature neurons in the striatum and subventricular zone. This was accompanied by reduced dissemination of the neuronal injury. Our data indicate that Wnt signaling appears to contribute to functional recovery after ischemic injury by increasing neurogenesis or neuronal survival in the striatum. PMID- 22815839 TI - Cranial irradiation alters dendritic spine density and morphology in the hippocampus. AB - Therapeutic irradiation of the brain is a common treatment modality for brain tumors, but can lead to impairment of cognitive function. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and number are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. To gain some insight into the temporal and sub region specific cellular changes in the hippocampus following brain irradiation, we investigated the effects of 10 Gy cranial irradiation on dendritic spines in young adult mice. One week or 1 month post irradiation, changes in spine density and morphology in dentate gyrus (DG) granule and CA1 pyramidal neurons were quantified using Golgi staining. Our results showed that in the DG, there were significant reductions in spine density at both 1 week (11.9%) and 1 month (26.9%) after irradiation. In contrast, in the basal dendrites of CA1 pyramidal neurons, irradiation resulted in a significant reduction (18.7%) in spine density only at 1 week post irradiation. Analysis of spine morphology showed that irradiation led to significant decreases in the proportion of mushroom spines at both time points in the DG as well as CA1 basal dendrites. The proportions of stubby spines were significantly increased in both the areas at 1 month post irradiation. Irradiation did not alter spine density in the CA1 apical dendrites, but there were significant changes in the proportion of thin and mushroom spines at both time points post irradiation. Although the mechanisms involved are not clear, these findings are the first to show that brain irradiation of young adult animals leads to alterations in dendritic spine density and morphology in the hippocampus in a time dependent and region specific manner. PMID- 22815840 TI - Regional intra-arterial vs. systemic chemotherapy for advanced pancreatic cancer: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To investigate the efficacy and safety of regional intra-arterial chemotherapy (RIAC) versus systemic chemotherapy for stage III/IV pancreatic cancer. METHODS: Randomized controlled trials of patients with advanced pancreatic cancer treated by regional intra-arterial or systemic chemotherapy were identified using PubMed, ISI, EMBASE, Cochrane Library, Google, Chinese Scientific Journals Database (VIP), and China National Knowledge Infrastructure (CNKI) electronic databases, for all publications dated between 1960 and December 31, 2010. Data was independently extracted by two reviewers. Odds ratios and relative risks were pooled using either fixed- or random-effects models, depending on I(2) statistic and Q test assessments of heterogeneity. Statistical analysis was performed using RevMan 5.0. RESULTS: Six randomized controlled trials comprised of 298 patients met the standards for inclusion in the meta analysis, among 492 articles that were identified. Eight patients achieved complete remission (CR) with regional intra-arterial chemotherapy (RIAC), whereas no patients achieved CR with systemic chemotherapy. Compared with systemic chemotherapy, patients receiving RIAC had superior partial remissions (RR = 1.99, 95% CI: 1.50, 2.65; 58.06% with RIAC and 29.37% with systemic treatment), clinical benefits (RR = 2.34, 95% CI: 1.84, 2.97; 78.06% with RAIC and 29.37% with systemic treatment), total complication rates (RR = 0.72, 95% CI: 0.60, 0.87; 49.03% with RIAC and 71.33% with systemic treatment), and hematological side effects (RR = 0.76, 95% CI: 0.63, 0.91; 60.87% with RIAC and 85.71% with systemic treatment). The median survival time with RIAC (5-21 months) was longer than for systemic chemotherapy (2.7-14 months). Similarly, one year survival rates with RIAC (28.6%-41.2%) were higher than with systemic chemotherapy (0% 12.9%.). CONCLUSION: Regional intra-arterial chemotherapy is more effective and has fewer complications than systemic chemotherapy for treating advanced pancreatic cancer. PMID- 22815841 TI - Learning impairment in honey bees caused by agricultural spray adjuvants. AB - BACKGROUND: Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. METHODOLOGY/PRINCIPAL FINDINGS: An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 ug organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. CONCLUSIONS/SIGNIFICANCE: A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions. Organosilicone spray adjuvants may therefore contribute to the ongoing global decline in honey bee health. PMID- 22815842 TI - Evolution of growth habit, inflorescence architecture, flower size, and fruit type in Rubiaceae: its ecological and evolutionary implications. AB - During angiosperm evolution, innovations in vegetative and reproductive organs have resulted in tremendous morphological diversity, which has played a crucial role in the ecological success of flowering plants. Morindeae (Rubiaceae) display considerable diversity in growth form, inflorescence architecture, flower size, and fruit type. Lianescent habit, head inflorescence, small flower, and multiple fruit are the predominant states, but arborescent habit, non-headed inflorescence, large flower, and simple fruit states occur in various genera. This makes Morindeae an ideal model for exploring the evolutionary appearances and transitions between the states of these characters. We reconstructed ancestral states for these four traits using a bayesian approach and combined nuclear/chloroplast data for 61 Morindeae species. The aim was to test three hypotheses: 1) self-supporting habit is generally ancestral in clades comprising both lianescent and arborescent species; 2) changes from lianescent to arborescent habit are uncommon due to "a high degree of specialization and developmental burden"; 3) head inflorescences and multiple fruits in Morindeae evolved from non-headed inflorescences and simple fruits, respectively. Lianescent habit, head inflorescence, large flower, and multiple fruit are inferred for Morindeae, making arborescent habit, non-headed inflorescence, small flower, and simple fruit derived within the tribe. The rate of change from lianescent to arborescent habit is much higher than the reverse change. Therefore, evolutionary changes between lianescent and arborescent forms can be reversible, and their frequency and trends vary between groups. Moreover, these changes are partly attributed to a scarcity of host trees for climbing plants in more open habitats. Changes from large to small flowers might have been driven by shifts to pollinators with progressively shorter proboscis, which are associated with shifts in breeding systems towards dioecy. A single origin of dioecy from hermaphroditism is supported. Finally, we report evolutionary changes from headed to non-headed inflorescences and multiple to simple fruits. PMID- 22815843 TI - Intracellular retention of ABL kinase inhibitors determines commitment to apoptosis in CML cells. AB - Clinical development of imatinib in CML established continuous target inhibition as a paradigm for successful tyrosine kinase inhibitor (TKI) therapy. However, recent reports suggested that transient potent target inhibition of BCR-ABL by high-dose TKI (HD-TKI) pulse-exposure is sufficient to irreversibly commit cells to apoptosis. Here, we report a novel mechanism of prolonged intracellular TKI activity upon HD-TKI pulse-exposure (imatinib, dasatinib) in BCR-ABL-positive cells. Comprehensive mechanistic exploration revealed dramatic intracellular accumulation of TKIs which closely correlated with induction of apoptosis. Cells were rescued from apoptosis upon HD-TKI pulse either by repetitive drug wash-out or by overexpression of ABC-family drug transporters. Inhibition of ABCB1 restored sensitivity to HD-TKI pulse-exposure. Thus, our data provide evidence that intracellular drug retention crucially determines biological activity of imatinib and dasatinib. These studies may refine our current thinking on critical requirements of TKI dose and duration of target inhibition for biological activity of TKIs. PMID- 22815844 TI - A 46,XY female DSD patient with bilateral gonadoblastoma, a novel SRY missense mutation combined with a WT1 KTS splice-site mutation. AB - Patients with Disorders of Sex Development (DSD), especially those with gonadal dysgenesis and hypovirilization are at risk of developing malignant type II germ cell tumors/cancer (GCC) (seminoma/dysgerminoma and nonseminoma), with either carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesion. In 10-15% of 46,XY gonadal dysgenesis cases (i.e., Swyer syndrome), SRY mutations, residing in the HMG (High Mobility Group) domain, are found to affect nuclear transport or binding to and bending of DNA. Frasier syndrome (FS) is characterized by gonadal dysgenesis with a high risk for development of GB as well as chronic renal failure in early adulthood, and is known to arise from a splice site mutation in intron 9 of the Wilms' tumor 1 gene (WT1). Mutations in SRY as well as WT1 can lead to diminished expression and function of SRY, resulting in sub-optimal SOX9 expression, Sertoli cell formation and subsequent lack of proper testicular development. Embryonic germ cells residing in this unfavourable micro-environment have an increased risk for malignant transformation. Here a unique case of a phenotypically normal female (age 22 years) is reported, presenting with primary amenorrhoea, later diagnosed as hypergonadotropic hypogonadism on the basis of 46,XY gonadal dygenesis with a novel missense mutation in SRY. Functional in vitro studies showed no convincing protein malfunctioning. Laparoscopic examination revealed streak ovaries and a normal, but small, uterus. Pathological examination demonstrated bilateral GB and dysgerminoma, confirmed by immunohistochemistry. Occurrence of a delayed progressive kidney failure (focal segmental glomerular sclerosis) triggered analysis of WT1, revealing a pathogenic splice-site mutation in intron 9. Analysis of the SRY gene in an additional five FS cases did not reveal any mutations. The case presented shows the importance of multi-gene based diagnosis of DSD patients, allowing early diagnosis and treatment, thus preventing putative development of an invasive cancer. PMID- 22815845 TI - Sorting the wheat from the chaff: identifying miRNAs in genomic survey sequences of Triticum aestivum chromosome 1AL. AB - Individual chromosome-based studies of bread wheat are beginning to provide valuable structural and functional information about one of the world's most important crops. As new genome sequences become available, identifying miRNA coding sequences is arguably as important a task as annotating protein coding sequences, but one that is not as well developed. We compared conservation-based identification of conserved miRNAs in 1.5* coverage survey sequences of wheat chromosome 1AL with a predictive method based on pre-miRNA hairpin structure alone. In total, 42 sequences expected to encode conserved miRNAs were identified on chromosome 1AL, including members of several miRNA families that have not previously been reported to be expressed in T. aestivum. In addition, we demonstrate that a number of sequences previously annotated as novel wheat miRNAs are closely related to transposable elements, particularly Miniature Inverted Terminal repeat Elements (MITEs). Some of these TE-miRNAs may well have a functional role, but separating true miRNA coding sequences from TEs in genomic sequences is far from straightforward. We propose a strategy for annotation to minimize the risk of mis-identifying TE sequences as miRNAs. PMID- 22815846 TI - Participation of myosin Va and Pka type I in the regeneration of neuromuscular junctions. AB - BACKGROUND: The unconventional motor protein, myosin Va, is crucial for the development of the mouse neuromuscular junction (NMJ) in the early postnatal phase. Furthermore, the cooperative action of protein kinase A (PKA) and myosin Va is essential to maintain the adult NMJ. We here assessed the involvement of myosin Va and PKA in NMJ recovery during muscle regeneration. METHODOLOGY/PRINCIPAL FINDINGS: To address a putative role of myosin Va and PKA in the process of muscle regeneration, we used two experimental models the dystrophic mdx mouse and Notexin-induced muscle degeneration/regeneration. We found that in both systems myosin Va and PKA type I accumulate beneath the NMJs in a fiber maturation-dependent manner. Morphologically intact NMJs were found to express stable nicotinic acetylcholine receptors and to accumulate myosin Va and PKA type I in the subsynaptic region. Subsynaptic cAMP signaling was strongly altered in dystrophic muscle, particularly in fibers with severely subverted NMJ morphology. CONCLUSIONS/SIGNIFICANCE: Our data show a correlation between the subsynaptic accumulation of myosin Va and PKA type I on the one hand and NMJ regeneration status and morphology, AChR stability and specificity of subsynaptic cAMP handling on the other hand. This suggests an important role of myosin Va and PKA type I for the maturation of NMJs in regenerating muscle. PMID- 22815847 TI - Breakdown of phylogenetic signal: a survey of microsatellite densities in 454 shotgun sequences from 154 non model eukaryote species. AB - Microsatellites are ubiquitous in Eukaryotic genomes. A more complete understanding of their origin and spread can be gained from a comparison of their distribution within a phylogenetic context. Although information for model species is accumulating rapidly, it is insufficient due to a lack of species depth, thus intragroup variation is necessarily ignored. As such, apparent differences between groups may be overinflated and generalizations cannot be inferred until an analysis of the variation that exists within groups has been conducted. In this study, we examined microsatellite coverage and motif patterns from 454 shotgun sequences of 154 Eukaryote species from eight distantly related phyla (Cnidaria, Arthropoda, Onychophora, Bryozoa, Mollusca, Echinodermata, Chordata and Streptophyta) to test if a consistent phylogenetic pattern emerges from the microsatellite composition of these species. It is clear from our results that data from model species provide incomplete information regarding the existing microsatellite variability within the Eukaryotes. A very strong heterogeneity of microsatellite composition was found within most phyla, classes and even orders. Autocorrelation analyses indicated that while microsatellite contents of species within clades more recent than 200 Mya tend to be similar, the autocorrelation breaks down and becomes negative or non-significant with increasing divergence time. Therefore, the age of the taxon seems to be a primary factor in degrading the phylogenetic pattern present among related groups. The most recent classes or orders of Chordates still retain the pattern of their common ancestor. However, within older groups, such as classes of Arthropods, the phylogenetic pattern has been scrambled by the long independent evolution of the lineages. PMID- 22815848 TI - Signal 3 cytokines as modulators of primary immune responses during infections: the interplay of type I IFN and IL-12 in CD8 T cell responses. AB - Signal 3 cytokines, such as IL-12 or type I IFN, support expansion and differentiation of CD8 T cells in vivo. If and how these two signal 3 cytokines compensate each other in T cell activation during different infections is so far unknown. Using CD8 T cells lacking receptors for IL-12, type I IFN or both, we show that the expansion of CD8 T cells depends on type I IFN (LCMV infection), type I IFN and IL-12 (Listeria and vesicular stomatitis virus infection) or is largely independent of the two cytokines (vaccinia virus infection). Furthermore, we show that CD8 T cells lacking IL-12 and type I IFN signals are impaired in cytokine production and cytolytic activity in the context of VSV and Listeria infection. These effector CD8 T cells fail to express KLRG1, thereby exhibiting a memory-like phenotype which correlated with lower expression of the transcription factor T-bet and higher expression of Eomes. This indicates that the variable interplay of both signal 3 cytokines is mandatory for cell fate decision of CD8 T cells in the context of different infections. Furthermore our results demonstrate that the pathogen-induced overall inflammatory milieu and not the antigen load and/or the quality of antigen presentation critically determine the signal 3 dependence of CD8 T cells. PMID- 22815849 TI - Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism. AB - Pantothenate kinase (PanK) phosphorylates pantothenic acid (vitamin B(5)) and controls the overall rate of coenzyme A (CoA) biosynthesis. Pank1 gene deletion in mice results in a metabolic phenotype where fatty acid oxidation and gluconeogenesis are impaired in the fasted state, leading to mild hypoglycemia. Inactivating mutations in the human PANK2 gene lead to childhood neurodegeneration, but Pank2 gene inactivation in mice does not elicit a phenotype indicative of the neuromuscular symptoms or brain iron accumulation that accompany the human disease. Pank1/Pank2 double knockout (dKO) mice were derived to determine if the mild phenotypes of the single knockout mice are due to the ability of the two isoforms to compensate for each other in CoA biosynthesis. Postnatal development was severely affected in the dKO mice. The dKO pups developed progressively severe hypoglycemia and hyperketonemia by postnatal day 10 leading to death by day 17. Hyperketonemia arose from impaired whole-body ketone utilization illustrating the requirement for CoA in energy generation from ketones. dKO pups had reduced CoA and decreased fatty acid oxidation coupled with triglyceride accumulation in liver. dKO hepatocytes could not maintain the NADH levels compared to wild-type hepatocytes. These results revealed an important link between CoA and NADH levels, which was reflected by deficiencies in hepatic oleate synthesis and gluconeogenesis. The data indicate that PanK1 and PanK2 can compensate for each other to supply tissue CoA, but PanK1 is more important to CoA levels in liver whereas PanK2 contributes more to CoA synthesis in the brain. PMID- 22815850 TI - Higher levels of ATGL are associated with exercise-induced enhancement of lipolysis in rat epididymal adipocytes. AB - BACKGROUND: In adipose cells, adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte triacylglyceride hydrolysis, thereby regulating both basal and hormone-stimulated lipolysis. However, little is known about the molecular mechanism(s) underlying habitual exercise-induced adaptive modulation of ATGL in white adipocytes via alteration in transcription regulator and lipolytic cofactors. METHODOLOGY/PRINCIPAL RESULTS: Male Wistar rats were randomly divided into 2 groups a sedentary control group (CG) and a habitual exercise group (EG). The EG was subjected to running on a treadmill set at 5 days per week for 9 weeks. The CG was not subjected to running on a treadmill. In the EG, levels of ATGL mRNA and protein were elevated with a significant increase in lipolysis compared with the CG, accompanied by a significant increase in associations of CGI-58 with ATGL protein. Under these conditions, an upregulation of peroxisome proliferation-activated receptorg-2 (PPARg-2) was observed. In the EG, the addition of rosiglitazone further significantly increased the levels of ATGL protein compared with the CG. However, attenuated levels of the ATGL protein in adipocytes were obtained by the addition of insulin, which is known to inhibit the expression of ATGL, in both types of groups. Actually, levels of plasma insulin were significantly reduced in the EG compared with the CG. CONCLUSIONS: These data suggest that elevated levels of ATGL are involved in the exercise induced enhancement of lipolysis in primary adipocytes. The exact mechanism(s) underlying this phenomenon is associated, at least in part, with upregulated transcriptional activation of PPARg-2. In addition, exercise-induced lower circulation levels of insulin also correlate with habitual exercise-induced higher levels of ATGL in primary adipocytes. PMID- 22815851 TI - Comparison of the predicted population coverage of tuberculosis vaccine candidates Ag85B-ESAT-6, Ag85B-TB10.4, and Mtb72f via a bioinformatics approach. AB - The Bacille-Calmette Guerin (BCG) vaccine does not provide consistent protection against adult pulmonary tuberculosis (TB) worldwide. As novel TB vaccine candidates advance in studies and clinical trials, it will be critically important to evaluate their global coverage by assessing the impact of host and pathogen variability on vaccine efficacy. In this study, we focus on the impact that host genetic variability may have on the protective effect of TB vaccine candidates Ag85B-ESAT-6, Ag85B-TB10.4, and Mtb72f. We use open-source epitope binding prediction programs to evaluate the binding of vaccine epitopes to Class I HLA (A, B, and C) and Class II HLA (DRB1) alleles. Our findings suggest that Mtb72f may be less consistently protective than either Ag85B-ESAT-6 or Ag85B TB10.4 in populations with a high TB burden, while Ag85B-TB10.4 may provide the most consistent protection. The findings of this study highlight the utility of bioinformatics as a tool for evaluating vaccine candidates before the costly stages of clinical trials and informing the development of new vaccines with the broadest possible population coverage. PMID- 22815852 TI - Systematic functional characterization of cytochrome P450 2E1 promoter variants in the Chinese Han population. AB - CYP2E1 promoter polymorphisms can lead to significant interindividual differences in expression of CYP2E1. Using a database of CYP2E1 gene polymorphisms established in 2010, our study aimed to functionally characterize the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in the Chinese Han population. Six novel SNPs and seven haplotypes with a frequency equal to or greater than 0.01 were constructed on a luciferase reporter system on the basis of site-directed mutagenesis. Dual luciferase reporter systems were used to analyze regulatory activity. The constructs including single novel SNP mutations exhibited insignificant change in luciferase activity, whereas, the activity produced by Haplo1(GTTGCTATAT), Haplo2 (CTTGCTATAT) and Haplo7 (GAGCTCACAT), containing a -333T>A polymorphism was significantly greater than for the wild type in Hep G2 cells (p<0.05), being 1.5 , 2.0- and 1.4- times greater respectively. These findings suggest the possibility of significant clinical prediction of adverse drug reaction and the facilitation of personalized medicine. PMID- 22815853 TI - Identification and characterization of the cognate anti-sigma factor and specific promoter elements of a T. tengcongensis ECF sigma factor. AB - Extracytoplasmic function (ECF) sigma factors, the largest group of alternative sigma factors, play important roles in response to environmental stresses. Tt RpoE1 is annotated as an ECF sigma factor in Thermoanaerobacter tengcongensis. In this study, we revealed that the Tt-tolB gene located downstream of the Tt-rpoE1 gene encoded the cognate anti-sigma factor, which could inhibit the transcription activity of Tt-RpoE1 by direct interaction with Tt-RpoE1 via its N-terminal domain. By in vitro transcription assay, the auto-regulation ability of Tt-RpoE1 was determined, and band shift assay showed that Tt-RpoE1 preferred to bind a fork-junction promoter DNA. With truncation or base-specific scanning mutations, the contribution of the nucleotides in -35 and -10 regions to interaction between Tt-RpoE1 and promoter DNA was explored. The promoter recognition pattern of Tt RpoE1 was determined as 5' tGTTACN(16)CGTC 3', which was further confirmed by in vitro transcription assays. This result showed that the Tt-RpoE1-recognized promoter possessed a distinct -10 motif (-13CGTC-10) as the recognition determinant, which is distinguished from the -10 element recognized by sigma(70). Site-directed mutagenesis in Region 2.4 of Tt-RpoE1 indicated that the "D" residue of DXXR motif was responsible for recognizing the -12G nucleotide. Our results suggested that distinct -10 motif may be an efficient and general strategy used by ECF sigma factors in adaptive response regulation of the related genes. PMID- 22815854 TI - Sexual compatibility among different host-originated isolates of Aphelenchoides besseyi and the inheritance of the parasitism. AB - Nine isolates of Aphelenchoides besseyi from two different hosts were studied. The isolates were identified at the species level according to morphometrics and fine structures observed under a scanning electron microscope. Two fern originated isolates, Fu, and Fm, one rice-originated isolate, Rl, were not able to reproduce from a single juvenile, based on at least 50 replicates. The other six isolates were able to develop into a small population when inoculated with a single juvenile, demonstrating parthenogenesis. Crosses between isolates were conducted. In a compatibility cross experiment, three fern-originated isolates were selfed and crossed reciprocally, and all nine crossings had viable offspring. When fern isolates were used as paternal lines, the only two successful crosses were with the Rd line, and as maternal lines, only the Ff x Re and Fu x Rn crosses had viable offspring. Rl was used as the maternal line and Fm as the paternal line to study the inheritance of the bird's-nest fern parasitism. Twenty of the 80 attempted crosses resulted in viable offspring and among these; six lines had the ability to parasitize on the bird's-nest fern. When the F(1) lines were back-crossed to the Rl maternal line, 20 viable offspring lines were obtained and among them 4 were able to parasitize bird's-nest fern. These results indicate that bird's-nest fern parasitism can be transferred to new generations by cross fertilization. PMID- 22815855 TI - Contribution of hypothermia and CB1 receptor activation to protective effects of TAK-937, a cannabinoid receptor agonist, in rat transient MCAO model. AB - BACKGROUND: Cannabinoid (CB) receptor agonists are expected to alleviate ischemic brain damage by modulating neurotransmission and neuroinflammatory responses via CB(1) and CB(2) receptors, respectively. In a previous study, TAK-937, a novel potent and selective CB(1) and CB(2) receptor agonist, was shown to exert significant cerebroprotective effects accompanied by hypothermia after transient middle cerebral artery occlusion (MCAO) in rats. Sustained hypothermia itself induces significant neuroprotective effects. In the present studies, we examined the relative contribution of hypothermia and CB(1) receptor activation to the cerebroprotective effects of TAK-937. METHODOLOGY/PRINCIPAL FINDINGS: Using a multichannel brain temperature controlling system we developed, the brain temperature of freely moving rats was telemetrically monitored and maintained between 37 and 38 degrees C during intravenous infusion of TAK-937 (100 ug/kg/h) or vehicle for 24 h after 2 h MCAO. AM251, a selective CB(1) receptor antagonist, was administered intraperitoneally at 30 mg/kg 30 min before starting intravenous infusion of TAK-937 (100 ug/kg/h) for 24 h. Rats were sacrificed and their brains were isolated 26 h after MCAO in both experiments. When the hypothermic effect of TAK-937 was completely reversed by a brain temperature controlling system, the infarct-reducing effect of TAK-937 was attenuated in part, but remained significant. On the other hand, concomitant AM251 treatment with TAK-937 completely abolished the hypothermic and infarct-reducing effects of TAK-937. CONCLUSIONS/SIGNIFICANCE: We conclude that the cerebroprotective effects of TAK 937 were at least in part mediated by induction of hypothermia, and mainly mediated by CB(1) receptor activation. PMID- 22815856 TI - Concordance of sleep and pain outcomes of diverse interventions: an umbrella review. AB - BACKGROUND/OBJECTIVE: Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep. METHODS: We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes. RESULTS: 151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092). CONCLUSIONS: Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain. PMID- 22815857 TI - Localization and expression of zonula occludins-1 in the rabbit corneal epithelium following exposure to benzalkonium chloride. AB - Preservatives are a major component of the ophthalmic preparations in multi-dose bottles. The purpose of this study was to investigate the acute effect of benzalkonium chloride (BAC), a common preservative used in ophthalmic preparations, on the localization and expression of zonula occludens (ZO)-1 in the rabbit corneal epithelium in vivo. BAC at 0.005%, 0.01%, or 0.02% was topically applied to one eye each of albino rabbits at 5 min intervals for a total of 3 times. The contralateral untreated eyes served as controls. The following clinical indications were evaluated: Schirmer test, tear break-up time (BUT), fluorescein and rose Bengal staining. The structure of central cornea was examined by in vivo confocal microscopy, and the corneal barrier function was evaluated by measurement of corneal transepithelial electrical resistance and permeability to carboxy fluorescein. Whole mount corneas were analyzed by using fluorescence confocal microscopy for the presence of ZO-1, 2, occludin, claudin 1, Ki67 and cell apoptosis in the epithelium. The expression of ZO-1 in the corneal epithelium was also examined by western blot and reverse transcription polymerase chain reaction analyses. Exposure to BAC resulted in higher rose Bengal staining scores while no significant changes in BUT, Schirmer and corneal florescein scores. It also induced corneal epithelial cell damage, dispersion of ZO-1 and ZO-2 from their normal locus at the superficial layer and disruption of epithelial barrier function. However, the amounts of ZO-1 mRNA and protein in the corneal epithelium were not affected by BAC treatment. Exposure to BAC can quickly impair the corneal epithelium without tear deficiency. BAC disrupts the tight junctions of corneal epithelium between superficial cells in the rabbit corneal epithelium in vivo. PMID- 22815858 TI - First insight into the kinome of human regulatory T cells. AB - Regulatory T cells (Tregs) are essential for controlling peripheral tolerance by the active suppression of various immune cells including conventional T effector cells (Teffs). Downstream of the T cell receptor (TCR), more than 500 protein kinases encoded by the human genome have to be considered in signaling cascades regulating the activation of Tregs and Teffs, respectively. Following TCR engagement, Tregs posses a number of unique attributes, such as constitutive expression of Foxp3, hyporesponsiveness and poor cytokine production. Furthermore, recent studies showed that altered regulation of protein kinases is important for Treg function. These data indicate that signaling pathways in Tregs are distinctly organized and alterations at the level of protein kinases contribute to the unique Treg phenotype. However, kinase-based signaling networks in Tregs are poorly understood and necessitate further systematic characterization. In this study, we analyzed the differential expression of kinases in Tregs and Teffs by using a kinase-selective proteome strategy. In total, we revealed quantitative information on 185 kinases expressed in the human CD4(+) T cell subsets. The majority of kinases was equally abundant in both T cell subsets, but 11 kinases were differentially expressed in Tregs. Most strikingly, Tregs showed an altered expression of cell cycle kinases including CDK6. Quantitative proteomics generates first comparative insight into the kinase complements of the CD4(+) Teff and Treg subset. Treg-specific expression pattern of 11 protein kinases substantiate the current opinion that TCR-mediated signaling cascades are altered in Tregs and further suggests that Tregs exhibit significant specificities in cell-cycle control and progression. PMID- 22815859 TI - Simulating molecular mechanisms of the MDM2-mediated regulatory interactions: a conformational selection model of the MDM2 lid dynamics. AB - Diversity and complexity of MDM2 mechanisms govern its principal function as the cellular antagonist of the p53 tumor suppressor. Structural and biophysical studies have demonstrated that MDM2 binding could be regulated by the dynamics of a pseudo-substrate lid motif. However, these experiments and subsequent computational studies have produced conflicting mechanistic models of MDM2 function and dynamics. We propose a unifying conformational selection model that can reconcile experimental findings and reveal a fundamental role of the lid as a dynamic regulator of MDM2-mediated binding. In this work, structure, dynamics and energetics of apo-MDM2 are studied as a function of posttranslational modifications and length of the lid. We found that the dynamic equilibrium between "closed" and "semi-closed" lid forms may be a fundamental characteristic of MDM2 regulatory interactions, which can be modulated by phosphorylation, phosphomimetic mutation as well as by the lid size. Our results revealed that these factors may regulate p53-MDM2 binding by fine-tuning the thermodynamic equilibrium between preexisting conformational states of apo-MDM2. In agreement with NMR studies, the effect of phosphorylation on MDM2 interactions was more pronounced with the truncated lid variant that favored the thermodynamically dominant closed form. The phosphomimetic mutation S17D may alter the lid dynamics by shifting the thermodynamic equilibrium towards the ensemble of "semi-closed" conformations. The dominant "semi-closed" lid form and weakened dependence on the phosphorylation seen in simulations with the complete lid can provide a rationale for binding of small p53-based mimetics and inhibitors without a direct competition with the lid dynamics. The results suggested that a conformational selection model of preexisting MDM2 states may provide a robust theoretical framework for understanding MDM2 dynamics. Probing biological functions and mechanisms of MDM2 regulation would require further integration of computational and experimental studies and may help to guide drug design of novel anti-cancer therapeutics. PMID- 22815860 TI - Genome-wide transcriptional profiles during temperature and oxidative stress reveal coordinated expression patterns and overlapping regulons in rice. AB - Genome wide transcriptional changes by cold stress, heat stress and oxidative stress in rice seedlings were analyzed. Heat stress resulted in predominant changes in transcripts of heat shock protein and heat shock transcription factor genes, as well as genes associated with synthesis of scavengers of reactive oxygen species and genes that control the level of sugars, metabolites and auxins. Cold stress treatment caused differential expression of transcripts of various transcription factors including desiccation response element binding proteins and different kinases. Transcripts of genes that are part of calcium signaling, reactive oxygen scavenging and diverse metabolic reactions were differentially expressed during cold stress. Oxidative stress induced by hydrogen peroxide treatment, resulted in significant up-regulation in transcript levels of genes related to redox homeostasis and down-regulation of transporter proteins. ROS homeostasis appeared to play central role in response to temperature extremes. The key transcription factors that may underlie the concerted transcriptional changes of specific components in various signal transduction networks involved are highlighted. Co-ordinated expression pattern and promoter architectures based analysis (promoter models and overrepresented transcription factor binding sites) suggested potential regulons involved in stress responses. A considerable overlap was noted at the level of transcription as well as in regulatory modules of differentially expressed genes. PMID- 22815862 TI - Antiretroviral treatment for HIV in rural Uganda: two-year treatment outcomes of a prospective health centre/community-based and hospital-based cohort. AB - BACKGROUND: In sub-Saharan Africa, a shortage of trained health professionals and limited geographical access to health facilities present major barriers to the expansion of antiretroviral therapy (ART). We tested the utility of a health centre (HC)/community-based approach in the provision of ART to persons living with HIV in a rural area in western Uganda. METHODS: The HIV treatment outcomes of the HC/community-based ART program were evaluated and compared with those of an ART program at a best-practice regional hospital. The HC/community-based cohort comprised 185 treatment-naive patients enrolled in 2006. The hospital cohort comprised of 200 patients enrolled in the same time period. The HC/community-based program involved weekly home visits to patients by community volunteers who were trained to deliver antiretroviral drugs to monitor and support adherence to treatment, and to identify and report adverse reactions and other clinical symptoms. Treatment supporters in the homes also had the responsibility to remind patients to take their drugs regularly. ART treatment outcomes were measured by HIV-1 RNA viral load (VL) after two years of treatment. Adherence was determined through weekly pill counts. RESULTS: Successful ART treatment outcomes in the HC/community-based cohort were equivalent to those in the hospital-based cohort after two years of treatment in on-treatment analysis (VL<=400 copies/mL, 93.0% vs. 87.3%, p = 0.12), and in intention-to-treat analysis (VL<=400 copies/mL, 64.9% and 62.0%, p = 0.560). In multivariate analysis patients in the HC/community-based cohort were more likely to have virologic suppression compared to hospital-based patients (adjusted OR = 2.47, 95% CI 1.01-6.04). CONCLUSION: Acceptable rates of virologic suppression were achieved using existing rural clinic and community resources in a HC/community based ART program run by clinical officers and supported by lay volunteers and treatment supporters. The results were equivalent to those of a hospital-based ART program run primarily by doctors. PMID- 22815861 TI - Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines. AB - Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER) positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel). We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK) were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in multidrug response in ER positive and ER negative breast cells. PMID- 22815863 TI - Digital transcriptome analysis of putative sex-determination genes in papaya (Carica papaya). AB - Papaya (Carica papaya) is a trioecious plant species that has male, female and hermaphrodite flowers on different plants. The primitive sex chromosomes genetically determine the sex of the papaya. Although draft sequences of the papaya genome are already available, the genes for sex determination have not been identified, likely due to the complicated structure of its sex-chromosome sequences. To identify the candidate genes for sex determination, we conducted a transcriptome analysis of flower samples from male, female and hermaphrodite plants using high-throughput SuperSAGE for digital gene expression analysis. Among the short sequence tags obtained from the transcripts, 312 unique tags were specifically mapped to the primitive sex chromosome (X or Y(h)) sequences. An annotation analysis revealed that retroelements are the most abundant sequences observed in the genes corresponding to these tags. The majority of tags on the sex chromosomes were located on the X chromosome, and only 30 tags were commonly mapped to both the X and Y(h) chromosome, implying a loss of many genes on the Y(h) chromosome. Nevertheless, candidate Y(h) chromosome-specific female determination genes, including a MADS-box gene, were identified. Information on these sex chromosome-specific expressed genes will help elucidating sex determination in the papaya. PMID- 22815864 TI - Dopamine D4 receptor activation increases hippocampal gamma oscillations by enhancing synchronization of fast-spiking interneurons. AB - BACKGROUND: Gamma oscillations are electric activity patterns of the mammalian brain hypothesized to serve attention, sensory perception, working memory and memory encoding. They are disrupted or altered in schizophrenic patients with associated cognitive deficits, which persist in spite of treatment with antipsychotics. Because cognitive symptoms are a core feature of schizophrenia it is relevant to explore signaling pathways that potentially regulate gamma oscillations. Dopamine has been reported to decrease gamma oscillation power via D1-like receptors. Based on the expression pattern of D4 receptors (D4R) in hippocampus, and pharmacological effects of D4R ligands in animals, we hypothesize that they are in a position to regulate gamma oscillations as well. METHODOLOGY/PRINCIPAL FINDINGS: To address this hypothesis we use rat hippocampal slices and kainate-induced gamma oscillations. Local field potential recordings as well as intracellular recordings of pyramidal cells, fast-spiking and non-fast spiking interneurons were carried out. We show that D4R activation with the selective ligand PD168077 increases gamma oscillation power, which can be blocked by the D4R-specific antagonist L745,870 as well as by the antipsychotic drug Clozapine. Pyramidal cells did not exhibit changes in excitatory or inhibitory synaptic current amplitudes, but inhibitory currents became more coherent with the oscillations after application of PD168077. Fast-spiking, but not non-fast spiking, interneurons, increase their action potential phase-coupling and coherence with regard to ongoing gamma oscillations in response to D4R activation. Among several possible mechanisms we found that the NMDA receptor antagonist AP5 also blocks the D4R mediated increase in gamma oscillation power. CONCLUSIONS/SIGNIFICANCE: We conclude that D4R activation affects fast-spiking interneuron synchronization and thereby increases gamma power by an NMDA receptor dependent mechanism. This suggests that converging deficits on fast-spiking interneurons may lead to decreased network function and thus aberrant gamma oscillations and cognitive decline in schizophrenia. PMID- 22815865 TI - Cerebrospinal fluid neopterin as marker of the meningo-encephalitic stage of Trypanosoma brucei gambiense sleeping sickness. AB - BACKGROUND: Sleeping sickness, or human African trypanosomiasis (HAT), is a protozoan disease that affects rural communities in sub-Saharan Africa. Determination of the disease stage, essential for correct treatment, represents a key issue in the management of patients. In the present study we evaluated the potential of CXCL10, CXCL13, ICAM-1, VCAM-1, MMP-9, B2MG, neopterin and IgM to complement current methods for staging Trypanosoma brucei gambiense patients. METHODS AND FINDINGS: Five hundred and twelve T. b. gambiense HAT patients originated from Angola, Chad and the Democratic Republic of the Congo (D.R.C.). Their classification as stage 2 (S2) was based on the number of white blood cells (WBC) (>5/uL) or presence of parasites in the cerebrospinal fluid (CSF). The CSF concentration of the eight markers was first measured on a training cohort encompassing 100 patients (44 S1 and 56 S2). IgM and neopterin were the best in discriminating between the two stages of disease with 86.4% and 84.1% specificity respectively, at 100% sensitivity. When a validation cohort (412 patients) was tested, neopterin (14.3 nmol/L) correctly classified 88% of S1 and S2 patients, confirming its high staging power. On this second cohort, neopterin also predicted both the presence of parasites, and of neurological signs, with the same ability as IgM and WBC, the current reference for staging. CONCLUSIONS: This study has demonstrated that neopterin is an excellent biomarker for staging T. b. gambiense HAT patients. A rapid diagnostic test for detecting this metabolite in CSF could help in more accurate stage determination. PMID- 22815866 TI - Longitudinal in vivo SPECT/CT imaging reveals morphological changes and cardiopulmonary apoptosis in a rodent model of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) has a complex pathogenesis involving both heart and lungs. Animal models can reflect aspects of the human pathology and provide insights into the development and underlying mechanisms of disease. Because of the variability of most animal models of PAH, serial in vivo measurements of cardiopulmonary function, morphology, and markers of pathology can enhance the value of such studies. Therefore, quantitative in vivo SPECT/CT imaging was performed to assess cardiac function, morphology and cardiac perfusion utilizing (201)Thallium ((201)Tl) in control and monocrotaline-treated rats. In addition, lung and heart apoptosis was examined with (99m)Tc-Annexin V ((99m)Tc-Annexin) in these cohorts. Following baseline imaging, rats were injected with saline or monocrotaline (50 mg/kg, i.p.) and imaged weekly for 6 weeks. To assess a therapeutic response in an established pulmonary hypertensive state, a cohort of rats received resveratrol in drinking water (3 mg/kg/day) on days 28-42 post-monocrotaline injection to monitor regression of cardiopulmonary apoptosis. PAH in monocrotaline-treated rats was verified by conventional hemodynamic techniques on day 42 (right ventricular systolic pressure (RSVP) = 66.2 mmHg in monocrotaline vs 28.8 mmHg in controls) and in terms of right ventricular hypertrophy (RV/LVS = 0.70 in monocrotaline vs 0.32 in controls). Resveratrol partially reversed both RVSP (41.4 mmHg) and RV/LVS (0.46), as well as lung edema and RV contractility +dP/dt(max). Serial (99m)Tc-Annexin V imaging showed clear increases in pulmonary and cardiac apoptosis when compared to baseline, which regressed following resveratrol treatment. Monocrotaline induced modest changes in whole-heart perfusion as assessed by (201)TI imaging and cardiac morphological changes consistent with septal deviation and enlarged RV. This study demonstrates the utility of functional in vivo SPECT/CT imaging in rodent models of PAH and further confirms the efficacy of resveratrol in reversing established monocrotaline-induced PAH presumably by attenuation of cardiopulmonary apoptosis. PMID- 22815867 TI - Genetic determinants for body iron store and type 2 diabetes risk in US men and women. AB - BACKGROUND: High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk. METHODOLOGY/PRINCIPAL FINDINGS: Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses' Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47*10(-6)), TF with transferrin (P = 0.0002 to 1.72*10(-10)); and HFE with ferritin (P = 0.017 to 1.6*10(-8)), sTfR (P = 0.007 to 7.9*10(-6)), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66-0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk. CONCLUSIONS/SIGNIFICANCE: The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study. PMID- 22815868 TI - Structural heterogeneity of terminal glycans in Campylobacter jejuni lipooligosaccharides. AB - Lipooligosaccharides of the gastrointestinal pathogen Campylobacter jejuni are regarded as a major virulence factor and are implicated in the production of cross-reactive antibodies against host gangliosides, which leads to the development of autoimmune neuropathies such as Guillain-Barre and Fisher Syndromes. C. jejuni strains are known to produce diverse LOS structures encoded by more than 19 types of LOS biosynthesis clusters. This study demonstrates that the final C. jejuni LOS structure cannot always be predicted from the genetic composition of the LOS biosynthesis cluster, as determined by novel lectin array analysis of the terminal LOS glycans. The differences were shown to be partially facilitated by the differential on/off status of three genes wlaN, cst and cj1144 45. The on/off status of these genes was also analysed in C. jejuni strains grown in vitro and in vivo, isolated directly from the host animal without passaging, using immunoseparation. Importantly, C. jejuni strains 331, 421 and 520 encoding cluster type C were shown to produce different LOS, mimicking asialo GM(1), asialo GM(2) and a heterogeneous mix of gangliosides and other glycoconjugates respectively. In addition, individual C. jejuni colonies were shown to consistently produce heterogeneous LOS structures, irrespective of the cluster type and the status of phase variable genes. Furthermore we describe C. jejuni strains (351 and 375) with LOS clusters that do not match any of the previously described LOS clusters, yet are able to produce LOS with asialo GM(2)-like mimicries. The LOS biosynthesis clusters of these strains are likely to contain genes that code for LOS biosynthesis machinery previously not identified, yet capable of synthesising LOS mimicking gangliosides. PMID- 22815869 TI - A comparison of gene region simulation methods. AB - BACKGROUND: Accurately modeling LD in simulations is essential to correctly evaluate new and existing association methods. At present, there has been minimal research comparing the quality of existing gene region simulation methods to produce LD structures similar to an existing gene region. Here we compare the ability of three approaches to accurately simulate the LD within a gene region: HapSim (2005), Hapgen (2009), and a minor extension to simple haplotype resampling. METHODOLOGY/PRINCIPAL FINDINGS: In order to observe the variation and bias for each method, we compare the simulated pairwise LD measures and minor allele frequencies to the original HapMap data in an extensive simulation study. When possible, we also evaluate the effects of changing parameters. HapSim produces samples of haplotypes with lower LD, on average, compared to the original haplotype set while both our resampling method and Hapgen do not introduce this bias. The variation introduced across the replicates by our resampling method is quite small and may not provide enough sampling variability to make a generalizable simulation study. CONCLUSION: We recommend using Hapgen to simulate replicate haplotypes from a gene region. Hapgen produces moderate sampling variation between the replicates while retaining the overall unique LD structure of the gene region. PMID- 22815870 TI - The aryl hydrocarbon receptor mediates leflunomide-induced growth inhibition of melanoma cells. AB - A novel role of the dihydroorotatedehydrogenase (DHODH) inhibitor leflunomide as a potential anti-melanoma therapy was recently reported (Nature 471:518-22, 2011). We previously reported that leflunomide strongly activates the transcriptional activity of the Aryl Hydrocarbon Receptor (AhR). We therefore tested whether the AhR regulates the anti-proliferative effects of leflunomide in melanoma. We first evaluated the expression of AhR in melanoma cells and found that AhR is highly expressed in A375 melanoma as well as in several other cancer cell types. To evaluate whether AhR plays a role in regulating the growth inhibitory effects of leflunomide in A375 cells, we generated a stable cell line from parental A375 cells expressing a doxycycline (DOX) inducible AhR shRNA. Using these cells in the absence or presence of DOX (normal AhR levels or AhR knockdown, respectively) we found that the anti-proliferative effects of leflunomide, but not its metabolite A771726, were strongly dependent upon AhR expression. It has been well established that supplementation of cells with exogenous uridine completely rescues the anti-proliferative effects due to DHODH inhibition. Thus, we performed uridine rescue experiments in A375 cells to determine whether the anti-proliferative effects of leflunomide are solely due to DHODH inhibition as previously reported. Interestingly, saturating levels of uridine only modestly rescued A375 cells from the anti-proliferative effects of both leflunomide and A771726, indicating additional mechanism(s), apart from DHODH inhibition are responsible for the anti-proliferative effects of leflunomide in melanoma cells. Uridine also did not rescue MDA-MB-435S melanoma cell proliferation after leflunomide treatment. Our results reveal that the AhR is a molecular target of leflunomide and support the feasibility of the clinical application of leflunomide for treating melanoma. Furthermore, analysis of expression data from 967 cancer cell lines revealed that AhR is expressed in multiple different cancer types supporting the intriguing possibility of targeting the AhR for therapy in a number of cancers. PMID- 22815871 TI - Faster, deeper, better: the impact of sniffing modulation on bulbar olfactory processing. AB - A key feature of mammalian olfactory perception is that sensory input is intimately related to respiration. Different authors have considered respiratory dynamics not only as a simple vector for odor molecules but also as an integral part of olfactory perception. Thus, rats adapt their sniffing strategy, both in frequency and flow rate, when performing odor-related tasks. The question of how frequency and flow rate jointly impact the spatio-temporal representation of odor in the olfactory bulb (OB) has not yet been answered. In the present paper, we addressed this question using a simulated nasal airflow protocol on anesthetized rats combined with voltage-sensitive dye imaging (VSDi) of odor-evoked OB glomerular maps. Glomerular responses displayed a tonic component during odor stimulation with a superimposed phasic component phase-locked to the sampling pattern. We showed that a high sniffing frequency (10 Hz) retained the ability to shape OB activity and that the tonic and phasic components of the VSDi responses were dependent on flow rate and inspiration volume, respectively. Both sniffing parameters jointly affected OB responses to odor such that the reduced activity level induced by a frequency increase was compensated by an increased flow rate. PMID- 22815872 TI - Development of multisensory reweighting is impaired for quiet stance control in children with developmental coordination disorder (DCD). AB - BACKGROUND: Developmental Coordination Disorder (DCD) is a leading movement disorder in children that commonly involves poor postural control. Multisensory integration deficit, especially the inability to adaptively reweight to changing sensory conditions, has been proposed as a possible mechanism but with insufficient characterization. Empirical quantification of reweighting significantly advances our understanding of its developmental onset and improves the characterization of its difference in children with DCD compared to their typically developing (TD) peers. METHODOLOGY/PRINCIPAL FINDINGS: Twenty children with DCD (6.6 to 11.8 years) were tested with a protocol in which visual scene and touch bar simultaneously oscillateded medio-laterally at different frequencies and various amplitudes. Their data were compared to data on TD children (4.2 to 10.8 years) from a previous study. Gains and phases were calculated for medio-lateral responses of the head and center of mass to both sensory stimuli. Gains and phases were simultaneously fitted by linear functions of age for each amplitude condition, segment, modality and group. Fitted gains and phases at two comparison ages (6.6 and 10.8 years) were tested for reweighting within each group and for group differences. Children with DCD reweight touch and vision at a later age (10.8 years) than their TD peers (4.2 years). Children with DCD demonstrate a weak visual reweighting, no advanced multisensory fusion and phase lags larger than those of TD children in response to both touch and vision. CONCLUSIONS/SIGNIFICANCE: Two developmental perspectives, postural body scheme and dorsal stream development, are provided to explain the weak vision reweighting. The lack of multisensory fusion supports the notion that optimal multisensory integration is a slow developmental process and is vulnerable in children with DCD. PMID- 22815873 TI - Microbial light-activatable proton pumps as neuronal inhibitors to functionally dissect neuronal networks in C. elegans. AB - Essentially any behavior in simple and complex animals depends on neuronal network function. Currently, the best-defined system to study neuronal circuits is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons is exactly known. Individual neurons can be activated by photostimulation of Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the importance of a particular neuron for the respective behavioral output of the network under study. In analogy, other excitable cells can be inhibited by expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent illumination with yellow light. However, inhibiting C. elegans neurons using NpHR is difficult. Recently, proton pumps from various sources were established as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3 (Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria maculans (Mac) can be utilized to effectively inhibit excitable cells in C. elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow or green light while the action spectrum of Mac is more blue-shifted, as analyzed by light-evoked behaviors and electrophysiology. This allows these tools to be combined in various ways with ChR2 to analyze different subsets of neurons within a circuit. We exemplify this by means of the polymodal aversive sensory ASH neurons, and the downstream command interneurons to which ASH neurons signal to trigger a reversal followed by a directional turn. Photostimulating ASH and subsequently inhibiting command interneurons using two-color illumination of different body segments, allows investigating temporal aspects of signaling downstream of ASH. PMID- 22815874 TI - Abundance and genetic diversity of microbial polygalacturonase and pectate lyase in the sheep rumen ecosystem. AB - BACKGROUND: Efficient degradation of pectin in the rumen is necessary for plant based feed utilization. The objective of this study was to characterize the diversity, abundance, and functions of pectinases from microorganisms in the sheep rumen. METHODOLOGY/PRINCIPAL FINDINGS: A total of 103 unique fragments of polygalacturonase (PF00295) and pectate lyase (PF00544 and PF09492) genes were retrieved from microbial DNA in the rumen of a Small Tail Han sheep, and 66% of the sequences of these fragments had low identities (<65%) with known sequences. Phylogenetic tree building separated the PF00295, PF00544, and PF09492 sequences into five, three, and three clades, respectively. Cellulolytic and noncellulolytic Butyrivibrio, Prevotella, and Fibrobacter species were the major sources of the pectinases. The two most abundant pectate lyase genes were cloned, and their protein products, expressed in Escherichia coli, were characterized. Both enzymes probably act extracellularly as their nucleotide sequences contained signal sequences, and they had optimal activities at the ruminal physiological temperature and complementary pH-dependent activity profiles. CONCLUSION/SIGNIFICANCE: This study reveals the specificity, diversity, and abundance of pectinases in the rumen ecosystem and provides two additional ruminal pectinases for potential industrial use under physiological conditions. PMID- 22815875 TI - Rosiglitazone improves survival and hastens recovery from pancreatic inflammation in obese mice. AB - Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin 3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice. PMID- 22815876 TI - A sparse neural code for some speech sounds but not for others. AB - The precise neural mechanisms underlying speech sound representations are still a matter of debate. Proponents of 'sparse representations' assume that on the level of speech sounds, only contrastive or otherwise not predictable information is stored in long-term memory. Here, in a passive oddball paradigm, we challenge the neural foundations of such a 'sparse' representation; we use words that differ only in their penultimate consonant ("coronal" [t] vs. "dorsal" [k] place of articulation) and for example distinguish between the German nouns Latz ([lats]; bib) and Lachs ([laks]; salmon). Changes from standard [t] to deviant [k] and vice versa elicited a discernible Mismatch Negativity (MMN) response. Crucially, however, the MMN for the deviant [lats] was stronger than the MMN for the deviant [laks]. Source localization showed this difference to be due to enhanced brain activity in right superior temporal cortex. These findings reflect a difference in phonological 'sparsity': Coronal [t] segments, but not dorsal [k] segments, are based on more sparse representations and elicit less specific neural predictions; sensory deviations from this prediction are more readily 'tolerated' and accordingly trigger weaker MMNs. The results foster the neurocomputational reality of 'representationally sparse' models of speech perception that are compatible with more general predictive mechanisms in auditory perception. PMID- 22815877 TI - Genistein affects histone modifications on Dickkopf-related protein 1 (DKK1) gene in SW480 human colon cancer cell line. AB - Genistein (GEN) is a plant-derived isoflavone and can block uncontrolled cell growth in colon cancer by inhibiting the WNT signaling pathway. This study aimed to test the hypothesis that the enhanced gene expression of the WNT signaling pathway antagonist, DKK1 by genistein treatment is associated with epigenetic modifications of the gene in colon cancer cells. Genistein treatment induced a concentration-dependent G2 phase arrest in the human colon cancer cell line SW480 and reduced cell proliferation. Results from several other human colon cancer cell lines confirmed the growth inhibitory effects of genistein. Overexpression of DKK1 confirmed its involvement in growth inhibition. Knockdown of DKK1 expression by siRNA slightly induced cell growth. DKK1 gene expression was increased by genistein in SW480 and HCT15 cells. DNA methylation at the DKK1 promoter was not affected by genistein treatment in all the cell lines tested. On the other hand, genistein induced histone H3 acetylation of the DKK1 promoter region in SW480 and HCT15 cells. This indicates that increased histone acetylation is associated with the genistein-induced DKK1 expression. The association between histone acetylation and DKK1 gene expression is confirmed by the histone deacetylase inhibitor trichostatin A (TSA) treatment. In conclusion, genistein treatment decreases cell growth and proliferation in colon cancer cell lines. The effect is associated with the increased DKK1 expression through the induction of histone acetylation at the DKK1 promoter region. PMID- 22815878 TI - Increased autophagy in placentas of intrauterine growth-restricted pregnancies. AB - BACKGROUND: Unexplained intrauterine growth restriction (IUGR) may be a consequence of placental insufficiency; however, its etiology is not fully understood. We surmised that defective placentation in IUGR dysregulates cellular bioenergic homeostasis, leading to increased autophagy in the villous trophoblast. The aims of this work were (1) to compare the differences in autophagy, p53 expression, and apoptosis between placentas of women with normal or IUGR pregnancies; (2) to study the effects of hypoxia and the role of p53 in regulating trophoblast autophagy; and (3) to investigate the relationship between autophagy and apoptosis in hypoxic trophoblasts. METHODOLOGY/PRINCIPAL FINDINGS: Compared with normal pregnant women, women with IUGR had higher placental levels of autophagy-related proteins LC3B-II, beclin-1, and damage-regulated autophagy modulator (DRAM), with increased p53 and caspase-cleaved cytokeratin 18 (M30). Furthermore, cytotrophoblasts cultured under hypoxia (2% oxygen) in the presence or absence of nutlin-3 (a p53 activity stimulator) had higher levels of LC3B-II, DRAM, and M30 proteins and increased Bax mRNA expression compared with controls cultured under standard conditions. In contrast, administration of pifithrin alpha (a p53 activity inhibitor) during hypoxia resulted in protein levels that were similar to those of the control groups. Moreover, cytotrophoblasts transfected with LC3B, beclin-1, or DRAM siRNA had higher levels of M30 compared with the controls under hypoxia. However, transfection with Bcl-2 or Bax siRNA did not cause any significant change in the levels of LC3B-II in hypoxic cytotrophoblasts. CONCLUSIONS/SIGNIFICANCE: Together, these results suggest that there is a crosstalk between autophagy and apoptosis in IUGR and that p53 plays a pivotal and complex role in regulating trophoblast cell turnover in response to hypoxic stress. PMID- 22815879 TI - STARS is essential to maintain cardiac development and function in vivo via a SRF pathway. AB - BACKGROUND: STARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein expressed early in cardiac development that acts as an acute stress sensor for pathological remodeling. However the role of STARS in cardiac development and function is incompletely understood. Here, we investigated the role of STARS in heart development and function in the zebrafish model and in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: Expression of zebrafish STARS (zSTARS) first occurs in the somites by the 16 somite stage [17 hours post fertilization (hpf)]. zSTARS is expressed in both chambers of the heart by 48 hpf, and also in the developing brain, jaw structures and pectoral fins. Morpholino-induced knockdown of zSTARS alters atrial and ventricular dimensions and decreases ventricular fractional shortening (measured by high-speed video microscopy), with pericardial edema and decreased or absent circulation [abnormal cardiac phenotypes in 126/164 (77%) of morpholino-injected embryos vs. 0/152 (0%) of control morpholino embryos]. Co-injection of zsrf (serum response factor) mRNA rescues the cardiac phenotype of zSTARS knockdown, resulting in improved fractional shortening and ventricular end-diastolic dimensions. Ectopic over expression of STARS in vitro activates the STARS proximal promoter, which contains a conserved SRF site. Chromatin immunoprecipitation demonstrates that SRF binds to this site in vivo and the SRF inhibitor CCG-1423 completely blocks STARS proximal reporter activity in H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study demonstrates for the first time that STARS deficiency severely disrupts cardiac development and function in vivo and revealed a novel STARS-SRF feed forward autoregulatory loop that could play an essential role in STARS regulation and cardiac function. PMID- 22815880 TI - Classification of different therapeutic responses of major depressive disorder with multivariate pattern analysis method based on structural MR scans. AB - BACKGROUND: Previous studies have found numerous brain changes in patients with major depressive disorder (MDD), but no neurological biomarker has been developed to diagnose depression or to predict responses to antidepressants. In the present study, we used multivariate pattern analysis (MVPA) to classify MDD patients with different therapeutic responses and healthy controls and to explore the diagnostic and prognostic value of structural neuroimaging data of MDD. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen patients with treatment-resistant depression (TRD), 17 patients with treatment-sensitive depression (TSD) and 17 matched healthy controls were scanned using structural MRI. Voxel-based morphometry, together with a modified MVPA technique which combined searchlight algorithm and principal component analysis (PCA), was used to classify the subjects with TRD, those with TSD and healthy controls. The results revealed that both gray matter (GM) and white matter (WM) of frontal, temporal, parietal and occipital brain regions as well as cerebellum structures had a high classification power in patients with MDD. The accuracy of the GM and WM that correctly discriminated TRD patients from TSD patients was both 82.9%. Meanwhile, the accuracy of the GM that correctly discriminated TRD or TSD patients from healthy controls were 85.7% and 82.4%, respectively; and the WM that correctly discriminated TRD or TSD patients from healthy controls were 85.7% and 91.2%, respectively. CONCLUSIONS/SIGNIFICANCE: These results suggest that structural MRI with MVPA might be a useful and reliable method to study the neuroanatomical changes to differentiate patients with MDD from healthy controls and patients with TRD from those with TSD. This method might also be useful to study potential brain regions associated with treatment response in patients with MDD. PMID- 22815881 TI - Sensitivity analysis of CLIMEX parameters in modelling potential distribution of Lantana camara L. AB - A process-based niche model of L. camara L. (lantana), a highly invasive shrub species, was developed to estimate its potential distribution using CLIMEX. Model development was carried out using its native and invasive distribution and validation was carried out with the extensive Australian distribution. A good fit was observed, with 86.7% of herbarium specimens collected in Australia occurring within the suitable and highly suitable categories. A sensitivity analysis was conducted to identify the model parameters that had the most influence on lantana distribution. The changes in suitability were assessed by mapping the regions where the distribution changed with each parameter alteration. This allowed an assessment of where, within Australia, the modification of each parameter was having the most impact, particularly in terms of the suitable and highly suitable locations. The sensitivity of various parameters was also evaluated by calculating the changes in area within the suitable and highly suitable categories. The limiting low temperature (DV0), limiting high temperature (DV3) and limiting low soil moisture (SM0) showed highest sensitivity to change. The other model parameters were relatively insensitive to change. Highly sensitive parameters require extensive research and data collection to be fitted accurately in species distribution models. The results from this study can inform more cost effective development of species distribution models for lantana. Such models form an integral part of the management of invasive species and the results can be used to streamline data collection requirements for potential distribution modelling. PMID- 22815882 TI - Recombinant lipidated HPV E7 induces a Th-1-biased immune response and protective immunity against cervical cancer in a mouse model. AB - The E7 oncoprotein of human papillomavirus (HPV) is an ideal target for developing immunotherapeutic strategies against HPV-associated tumors. However, because protein-based immunogens alone are poor elicitors of the cytotoxic T lymphocyte (CTL) responses, they have been difficult to exploit for therapeutic purposes. In this study, we report that a recombinant lipoprotein consisting of inactive E7 (E7m) biologically linked to a bacterial lipid moiety (rlipo-E7m) induces the maturation of mouse bone marrow-derived dendritic cells through toll like receptor 2 (TLR2), skews the immune responses toward the Th1 responses and induces E7-specific CTL responses. We further studied the ability of rlipo-E7m to provide protection against a TC-1 tumor cell challenge in an animal model. Mice prophylactically immunized with two 10-ug doses of rlipo-E7m were found to be free of TC-1 tumor growth. Experiments in a therapeutic immunization model showed that the tumor volume in mice receiving a single dose of rlipo-E7m was less than 0.01 cm(3) on day 40, whereas the tumor volume in mice treated with rE7m was 2.28+/-1.21 cm(3). The tumor volume of the entire control group was over 3 cm(3). In addition, we demonstrated that the CD8+ T cells play a major role in anti tumor immunity when administration of rlipo-E7m. These results demonstrate that rlipo-E7m could be a promising candidate for treating HPV-associated tumors. PMID- 22815883 TI - Retention in a NGO supported antiretroviral program in the Democratic Republic of Congo. AB - BACKGROUND: Retention of patients in ART care is a major challenge in sub-Saharan programs. Retention is also one of the key indicators to evaluate the success of ART programs. METHODS AND FINDINGS: A retrospective review of 1500 randomly selected medical charts of adult ART patients from a local non-governmental (NGO) supported ART program in the Democratic Republic of Congo (DRC). Retention was defined as any visit to the clinic in the 4 months prior to the abstraction date. Retention over time and across different sites was described. The relationship between patient characteristics and retention rates at 1 year was also examined. 1450 patients were included in the analysis. The overall retention rates were 81.4% (95% CI: 79.3-83.4), 75.2% (95% CI: 72.8-77.3), 65.0% (95% CI: 62.3-67.6) and 57.2% (95% CI: 54.0-60.3) at 6 months, 1 year, 2 years and 3 years respectively. The retention rates between sites varied between 62.1% and 90.6% at 6 months and between 55.5% and 86.2% at 1 year. During multivariable analysis weight below 50 kg (aHR: 1.33, 95%CI: 1.05-1.69), higher WHO stage at initiation (aHR: 1.22, 95%CI 0.85-1.76 for stage 3 and aHR: 2.98, 95%CI: 1.93-4.59 for stage 4), and male sex (aHR: 1.32, 95%CI: 1.05-1.65) remained as significant risk factors for attrition during the first year after ART initiation. Other independent risk factors were year of initiation (aHR: 1.73, 95%CI: 1.26-2.38 for the year 2007 and aHR: 3.06, 95%CI: 2.26-4.14 for the period 2008-2009), and site. CONCLUSIONS: Retention is a major problem in DRC, while coverage of patients on ART is still very low. With the flattening of funding for HIV care and treatment in sub-Saharan Africa, and with decreasing funding worldwide, maximizing retention during the much needed scaling-up will even be more important. PMID- 22815884 TI - R-Spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5. AB - The Wnt/beta-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/beta-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced beta catenin signaling. From this screen, we identified LGR4, then an orphan G protein coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced beta-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated beta-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4-/- crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications. PMID- 22815885 TI - Systematic analysis of FKBP inducible degradation domain tagging strategies for the human malaria parasite Plasmodium falciparum. AB - Targeted regulation of protein levels is an important tool to gain insights into the role of proteins essential to cell function and development. In recent years, a method based on mutated forms of the human FKBP12 has been established and used to great effect in various cell types to explore protein function. The mutated FKBP protein, referred to as destabilization domain (DD) tag when fused with a native protein at the N- or C-terminus targets the protein for proteosomal degradation. Regulated expression is achieved via addition of a compound, Shld-1, that stabilizes the protein and prevents degradation. A limited number of studies have used this system to provide powerful insight into protein function in the human malaria parasite Plasmodium falciparum. In order to better understand the DD inducible system in P. falciparum, we studied the effect of Shld-1 on parasite growth, demonstrating that although development is not impaired, it is delayed, requiring the appropriate controls for phenotype interpretation. We explored the quantified regulation of reporter Green Fluorescent Protein (GFP) and luciferase constructs fused to three DD variants in parasite cells either via transient or stable transfection. The regulation obtained with the original FKBP derived DD domain was compared to two triple mutants DD24 and DD29, which had been described to provide better regulation for C-terminal tagging in other cell types. When cloned to the C-terminal of reporter proteins, DD24 provided the strongest regulation allowing reporter activity to be reduced to lower levels than DD and to restore the activity of stabilised proteins to higher levels than DD29. Importantly, DD24 has not previously been applied to regulate proteins in P. falciparum. The possibility of regulating an exported protein was addressed by targeting the Ring-Infected Erythrocyte Surface Antigen (RESA) at its C-terminus. The tagged protein demonstrated an important modulation of its expression. PMID- 22815886 TI - Identification of distant Agouti-like sequences and re-evaluation of the evolutionary history of the Agouti-related peptide (AgRP). AB - The Agouti-like peptides including AgRP, ASIP and the teleost-specific A2 (ASIP2 and AgRP2) peptides have potent and diverse functional roles in feeding, pigmentation and background adaptation mechanisms. There are contradictory theories about the evolution of the Agouti-like peptide family as well the nomenclature. Here we performed comprehensive mining and annotation of vertebrate Agouti-like sequences. We identified A2 sequences from salmon, trout, seabass, cod, cichlid, tilapia, gilt-headed sea bream, Antarctic toothfish, rainbow smelt, common carp, channel catfish and interestingly also in lobe-finned fish. Moreover, we surprisingly found eight novel homologues from the kingdom of arthropods and three from fungi, some sharing the characteristic C-x(6)-C-C motif which are present in the Agouti-like sequences, as well as approximate sequence length (130 amino acids), positioning of the motif sequence and sharing of exon intron structures that are similar to the other Agouti-like peptides providing further support for the common origin of these sequences. Phylogenetic analysis shows that the AgRP sequences cluster basally in the tree, suggesting that these sequences split from a cluster containing both the ASIP and the A2 sequences. We also used a novel approach to determine the statistical evidence for synteny, a sinusoidal Hough transform pattern recognition technique. Our analysis shows that the teleost AgRP2 resides in a chromosomal region that has synteny with Hsa 8, but we found no convincing synteny between the regions that A2, AgRP and ASIP reside in, which would support that the Agouti-like peptides were formed by whole genome tetraplodization events. Here we suggest that the Agouti-like peptide genes were formed through classical subsequent gene duplications where the AgRP is the most distantly related to the three other members of that group, first splitting from a common ancestor to ASIP and A2, and then later the A2 split from ASIP followed by a split resulting in ASIP2 and AgRP2. PMID- 22815887 TI - Ovarian cancer gene therapy using HPV-16 pseudovirion carrying the HSV-tk gene. AB - Ovarian cancer is the leading cause of death from all gynecological cancers and conventional therapies such as surgery, chemotherapy, and radiotherapy usually fail to control advanced stages of the disease. Thus, there is an urgent need for alternative and innovative therapeutic options. We reason that cancer gene therapy using a vector capable of specifically delivering an enzyme-encoding gene to ovarian cancer cells will allow the cancer cell to metabolize a harmless prodrug into a potent cytotoxin, which will lead to therapeutic effects. In the current study, we explore the use of a human papillomavirus (HPV) pseudovirion to deliver a herpes simplex virus thymidine kinase (HSV-tk) gene to ovarian tumor cells. We found that the HPV-16 pseudovirion was able to preferentially infect murine and human ovarian tumor cells when administered intraperitoneally. Furthermore, intraperitoneal injection of HPV-16 pseudovirions carrying the HSV tk gene followed by treatment with ganciclovir led to significant therapeutic anti-tumor effects in murine ovarian cancer-bearing mice. Our data suggest that HPV pseudovirion may serve as a potential delivery vehicle for ovarian cancer gene therapy. PMID- 22815888 TI - Prevalence of DNA-HPV in male sexual partners of HPV-infected women and concordance of viral types in infected couples. AB - Investigation of HPV infection in men remains important due to its association with genital warts and anorectal cancer, as well as to the role men play in HPV transmission to their female sexual partners. Asymptomatic men (n = 43), whose sexual partners had presented cervical HPV infection, were enrolled in this study. Among the 43 men, 23 had their female partner included and tested for HPV DNA, totaling 23 couples. HPV-DNA was detected by PCR. Type specific PCR to detect HPV 16, 18, 31, 33, 45 and 6/11 was performed. At least one type of HPV was detected in 86.0% (37/43) of the male patients and more than one HPV type was identified in 39.5% (17/43) of the samples, including high and low risk HPV. HPV 16 proved to be the most prevalent viral type in both male and female samples. Concordance of at least one viral type was observed in 56.5% (13/23) of the couples. Among couples that have shown concordance of viral types, 84.6% (11/13) of the men had the same high risk viral type presented by the female sexual partner. These data suggest that HPV infected men is an important reservoir, contributing to a higher transmission to women and maintenance of infection, and consequently, a higher risk of developing cervical cancer. HPV vaccination in men will protect not only them but will also have implications for their sexual partners. PMID- 22815889 TI - Heterosexual men and women both show a hypothalamic response to the chemo-signal androstadienone. AB - The odorous steroid compound 4,16-androstadien-3-one (androstadienone), found in axillary sweat, was previously reported to evoke hypothalamic activation in heterosexual women, but not in heterosexual men. However, subjects were exposed to the pure crystalline form of androstadienone, which raised the question whether the observed hypothalamic response is physiologically relevant. Therefore, in the present study, we asked whether sexually dimorphic hypothalamic responses could be measured when subjects were exposed to lower, more physiologically relevant concentrations of androstadienone. A total of 21 women and 16 men, all heterosexual, participated in our functional magnetic resonance imaging study (fMRI). Three different concentrations of androstadienone diluted in propylene glycol (10 mM "high," 0.1 mM "medium" and 0.001 mM "low") were delivered to the subjects' nostrils using a computer-controlled stimulator. When exposed to the "high" androstadienone concentration, women showed stronger hypothalamic activation than men. By contrast, men showed more hypothalamic activation when exposed to the "medium" androstadienone concentrations in comparison to women. Thus, we replicated that smelling the chemo-signal androstadienone elicits a hypothalamic activation. However, this effect does not seem to be gender-specific, because androstadienone activated the hypothalamus in both men and women, suggesting that androstadienone exerts specific effects in heterosexual individuals of both sexes. PMID- 22815890 TI - Constructing endophenotypes of complex diseases using non-negative matrix factorization and adjusted rand index. AB - Complex diseases are typically caused by combinations of molecular disturbances that vary widely among different patients. Endophenotypes, a combination of genetic factors associated with a disease, offer a simplified approach to dissect complex trait by reducing genetic heterogeneity. Because molecular dissimilarities often exist between patients with indistinguishable disease symptoms, these unique molecular features may reflect pathogenic heterogeneity. To detect molecular dissimilarities among patients and reduce the complexity of high-dimension data, we have explored an endophenotype-identification analytical procedure that combines non-negative matrix factorization (NMF) and adjusted rand index (ARI), a measure of the similarity of two clusterings of a data set. To evaluate this procedure, we compared it with a commonly used method, principal component analysis with k-means clustering (PCA-K). A simulation study with gene expression dataset and genotype information was conducted to examine the performance of our procedure and PCA-K. The results showed that NMF mostly outperformed PCA-K. Additionally, we applied our endophenotype-identification analytical procedure to a publicly available dataset containing data derived from patients with late-onset Alzheimer's disease (LOAD). NMF distilled information associated with 1,116 transcripts into three metagenes and three molecular subtypes (MS) for patients in the LOAD dataset: MS1 (n1=80), MS2 (n2=73), and MS3 (n3=23). ARI was then used to determine the most representative transcripts for each metagene; 123, 89, and 71 metagene-specific transcripts were identified for MS1, MS2, and MS3, respectively. These metagene-specific transcripts were identified as the endophenotypes. Our results showed that 14, 38, 0, and 28 candidate susceptibility genes listed in AlzGene database were found by all patients, MS1, MS2, and MS3, respectively. Moreover, we found that MS2 might be a normal-like subtype. Our proposed procedure provides an alternative approach to investigate the pathogenic mechanism of disease and better understand the relationship between phenotype and genotype. PMID- 22815891 TI - Habitats as surrogates of taxonomic and functional fish assemblages in coral reef ecosystems: a critical analysis of factors driving effectiveness. AB - Species check-lists are helpful to establish Marine Protected Areas (MPAs) and protect local richness, endemicity, rarity, and biodiversity in general. However, such exhaustive taxonomic lists (i.e., true surrogate of biodiversity) require extensive and expensive censuses, and the use of estimator surrogates (e.g., habitats) is an appealing alternative. In truth, surrogate effectiveness appears from the literature highly variable both in marine and terrestrial ecosystems, making it difficult to provide practical recommendations for managers. Here, we evaluate how the biodiversity reference data set and its inherent bias can influence effectiveness. Specifically, we defined habitats by geomorphology, rugosity, and benthic cover and architecture criteria, and mapped them with satellite images for a New-Caledonian site. Fish taxonomic and functional lists were elaborated from Underwater Visual Censuses, stratified according to geomorphology and exposure. We then tested if MPA networks designed to maximize habitat richness, diversity and rarity could also effectively maximize fish richness, diversity, and rarity. Effectiveness appeared highly sensitive to the fish census design itself, in relation to the type of habitat map used and the scale of analysis. Spatial distribution of habitats (estimator surrogate's distribution), quantity and location of fish census stations (target surrogate's sampling), and random processes in the MPA design all affected effectiveness to the point that one small change in the data set could lead to opposite conclusions. We suggest that previous conclusions on surrogacy effectiveness, either positive or negative, marine or terrestrial, should be considered with caution, except in instances where very dense data sets were used without pseudo replication. Although this does not rule out the validity of using surrogates of species lists for conservation planning, the critical joint examination of both target and estimator surrogates is needed for every case study. PMID- 22815892 TI - Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3-5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using the well-established SOD1(G93A) mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1(G93A) mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. CONCLUSIONS/SIGNIFICANCE: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1(G93A) mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS. PMID- 22815893 TI - The inositol phosphatase SHIP-1 inhibits NOD2-induced NF-kappaB activation by disturbing the interaction of XIAP with RIP2. AB - SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a new inhibitory function for SHIP-1 in NOD2 signaling. NOD2 is a crucial cytoplasmic bacterial sensor that activates proinflammatory and antimicrobial responses upon bacterial invasion. We observed that SHIP-1 decreases NOD2-induced NF-kappaB activation in macrophages. This negative regulation relies on its interaction with XIAP. Indeed, we observed that XIAP is an essential mediator of the NOD2 signaling pathway that enables proper NF-kappaB activation in macrophages. Upon NOD2 activation, SHIP-1 C-terminal proline rich domain (PRD) interacts with XIAP, thereby disturbing the interaction between XIAP and RIP2 in order to decrease NF-kappaB signaling. PMID- 22815894 TI - A novel way to grow hemozoin-like crystals in vitro and its use to screen for hemozoin inhibiting antimalarial compounds. AB - BACKGROUND: Hemozoin crystals are normally formed in vivo by Plasmodium parasites to detoxify free heme released after hemoglobin digestion during its intraerythrocytic stage. Inhibition of hemozoin formation by various drugs results in free heme concentration toxic for the parasites. As a consequence, in vitro assays have been developed to screen and select candidate antimalarial drugs based on their capacity to inhibit hemozoin formation. In this report we describe new ways to form hemozoin-like crystals that were incidentally discovered during research in the field of prion inactivation. METHODS: We investigated the use of a new assay based on naturally occurring "self replicating" particles and previously described as presenting resistance to decontamination comparable to prions. The nature of these particles was determined using electron microscopy, Maldi-Tof analysis and X-ray diffraction. They were compared to synthetic hemozoin and to hemozoin obtained from Plasmodium falciparum. We then used the assay to evaluate the capacity of various antimalarial and anti-prion compounds to inhibit "self-replication" (crystallisation) of these particles. RESULTS: We identified these particles as being similar to ferriprotoporphyrin IX crystal and confirmed the ability of these particles to serve as nuclei for growth of new hemozoin-like crystals (HLC). HLC are morphologically similar to natural and synthetic hemozoin. Growth of HLC in a simple assay format confirmed inhibition by quinolines antimalarials at potencies described in the literature. Interestingly, artemisinins and tetracyclines also seemed to inhibit HLC growth. CONCLUSIONS: The described HLC assay is simple and easy to perform and may have the potential to be used as an additional tool to screen antimalarial drugs for their hemozoin inhibiting activity. As already described by others, drugs that inhibit hemozoin crystal formation have also the potential to inhibit misfolded proteins assemblies formation. PMID- 22815895 TI - Development of an all-in-one inducible lentiviral vector for gene specific analysis of reprogramming. AB - Fair comparison of reprogramming efficiencies and in vitro differentiation capabilities among induced pluripotent stem cell (iPSC) lines has been hampered by the cellular and genetic heterogeneity of de novo infected somatic cells. In order to address this problem, we constructed a single cassette all-in-one inducible lentiviral vector (Ai-LV) for the expression of three reprogramming factors (Oct3/4, Klf4 and Sox2). To obtain multiple types of somatic cells having the same genetic background, we generated reprogrammable chimeric mice using iPSCs derived from Ai-LV infected somatic cells. Then, hepatic cells, hematopoietic cells and fibroblasts were isolated at different developmental stages from the chimeric mice, and reprogrammed again to generate 2nd iPSCs. The results revealed that somatic cells, especially fetal hepatoblasts were reprogrammed 1200 times more efficiently than adult hepatocytes with maximum reprogramming efficiency reaching 12.5%. However, we found that forced expression of c-Myc compensated for the reduced reprogramming efficiency in aged somatic cells without affecting cell proliferation. All these findings suggest that the Ai-LV system enables us to generate a panel of iPSC clones derived from various tissues with the same genetic background, and thus provides an invaluable tool for iPSC research. PMID- 22815896 TI - Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. AB - The enormous bacterial load and mechanical forces in colon create a special requirement for protection of the epithelium. In the distal colon, this problem is largely solved by separation of the bacteria from the epithelium by a firmly attached inner mucus layer. In addition, an outer mucus layer entraps bacteria to be cleared by distal transport. The mucus layers contain a network of Muc2 mucins as the main structural component. Here, the renewal rate of the inner protective mucus layer was studied as well as the production and secretion of Muc2 mucin in the distal colon. This was performed by intraperitoneal injection of N azidoacetyl-galactosamine (GalNAz) that was in vivo incorporated during biosynthesis of O-glycosylated glycoproteins. The only gel-forming mucin produced in the colon is the Muc2 mucin and as it carries numerous O-glycans, the granulae of the goblet cells producing Muc2 mucin were intensely stained. The GalNAz labeled glycoproteins were first observed in the Golgi apparatus of most cells. Goblet cells in the luminal surface epithelium had the fastest biosynthesis of Muc2 and secreted material already three hours after labeling. This secreted GalNAz-labeled Muc2 mucin formed the inner mucus layer. The goblet cells along the crypt epithelium accumulated labeled mucin vesicles for a longer period and secretion of labeled Muc2 mucin was first observed after 6 to 8 h. This study reveals a fast turnover (1 h) of the inner mucus layer in the distal colon mediated by goblet cells of the luminal surface epithelium. PMID- 22815897 TI - Methods for detecting early warnings of critical transitions in time series illustrated using simulated ecological data. AB - Many dynamical systems, including lakes, organisms, ocean circulation patterns, or financial markets, are now thought to have tipping points where critical transitions to a contrasting state can happen. Because critical transitions can occur unexpectedly and are difficult to manage, there is a need for methods that can be used to identify when a critical transition is approaching. Recent theory shows that we can identify the proximity of a system to a critical transition using a variety of so-called 'early warning signals', and successful empirical examples suggest a potential for practical applicability. However, while the range of proposed methods for predicting critical transitions is rapidly expanding, opinions on their practical use differ widely, and there is no comparative study that tests the limitations of the different methods to identify approaching critical transitions using time-series data. Here, we summarize a range of currently available early warning methods and apply them to two simulated time series that are typical of systems undergoing a critical transition. In addition to a methodological guide, our work offers a practical toolbox that may be used in a wide range of fields to help detect early warning signals of critical transitions in time series data. PMID- 22815898 TI - HPV genotyping and site of viral integration in cervical cancers in Indian women. AB - Persistent HPV infection plays a major role in cervical cancer. This study was undertaken to identify HPV types in a cohort of Indian women with locally advanced cervical cancer as well as to determine the physical state and/or site of viral integration in the host genome. Pretreatment biopsies (n = 270) from patients were screened for HPV infection by a high throughput HPV genotyping assay based on luminex xMAP technology as well as MY09/11 PCR and SPF1/2 PCR. Overall HPV positivity was observed to be 95%, with HPV16 being most common (63%) followed by infection with HPV18. Integration status of the virus was identified using Amplification of Papillomavirus Oncogene Transcripts (APOT) assay in a subset of samples positive for HPV16 and/or HPV18 (n = 86) and with an adequate follow-up. The data was correlated with clinical outcome of the patients. Integration of the viral genome was observed in 79% of the cases and a preference for integration into the chromosomal loci 1p, 3q, 6q, 11q, 13q and 20q was seen. Clinical data revealed that the physical state of the virus (integrated or episomal) could be an important prognostic marker for cervical cancer. PMID- 22815899 TI - Smoking during pregnancy is associated with a decreased incidence of obstetric anal sphincter injuries in nulliparous women. AB - BACKGROUND: Smoking is a modifiable lifestyle factor that has been shown to be associated with adverse perinatal outcomes and to have adverse health and dose dependent connective tissue effects. The objective of this study was to examine whether smoking during pregnancy was associated with the incidence of obstetric anal sphincter injuries (OASIS) among six birthweight groups in singleton vaginal deliveries, considering nulliparous and multiparous women separately between 1997 and 2007 in Finland. METHODOLOGY: A retrospective population-based register study. Populations included women with spontaneous singleton vaginal deliveries, consisting of all 213,059 nulliparous and all 288,391 multiparous women. Incidence of OASIS (n = 2,787) between smoking status groups was adjusted using logistic regression analyses. PRINCIPAL FINDINGS: Of the nulliparous women, 13.1% were smokers, 3.6% had given up smoking during the first trimester of their pregnancy and 81.1% were non-smokers. Among these groups 0.7%, 0.9% and 1.1%, respectively suffered OASIS (p<=0.001). Nulliparous women who smoked had a 28% (95% CI 16-38%, p<=0.001) lower risk of OASIS compared to non-smokers, when adjusting for background variables. In multiparous women, the overall frequencies of OASIS were much lower (0.0-0.2%). A similar inverse relationship between OASIS rates and smoking was significant in pooled univariate analysis of multiparous women, but multivariate analysis revealed statistically insignificant results between non-smokers and smokers. CONCLUSIONS: Nulliparous women who were smokers had a 28% lower incidence of OASIS. However, smoking during pregnancy cannot be recommended since it has shown to be associated with other adverse pregnancy outcomes and adverse health effects. The observed association warrants clinical repetition studies and, if confirmed, also in vitro studies focusing on connective tissue properties at a molecular and cellular level. PMID- 22815900 TI - Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. AB - Non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) mutations attains a meaningful response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired resistance to EGFR-TKIs could affect long-term outcome in almost all patients. To identify the potential mechanisms of resistance, we established cell lines resistant to EGFR-TKIs from the human lung cancer cell lines PC9 and11-18, which harbored activating EGFR mutations. One erlotinib resistant cell line from PC9 and two erlotinib-resistant cell lines and two gefitinib-resistant cell lines from 11-18 were independently established. Almost complete loss of mutant delE746-A750 EGFR gene was observed in the erlotinib resistant cells isolated from PC9, and partial loss of the mutant L858R EGFR gene copy was specifically observed in the erlotinib- and gefitinib-resistant cells from 11-18. However, constitutive activation of EGFR downstream signaling, PI3K/Akt, was observed even after loss of the mutated EGFR gene in all resistant cell lines even in the presence of the drug. In the erlotinib-resistant cells from PC9, constitutive PI3K/Akt activation was effectively inhibited by lapatinib (a dual TKI of EGFR and HER2) or BIBW2992 (pan-TKI of EGFR family proteins). Furthermore, erlotinib with either HER2 or HER3 knockdown by their cognate siRNAs also inhibited PI3K/Akt activation. Transfection of activating mutant EGFR complementary DNA restored drug sensitivity in the erlotinib-resistant cell line. Our study indicates that loss of addiction to mutant EGFR resulted in gain of addiction to both HER2/HER3 and PI3K/Akt signaling to acquire EGFR-TKI resistance. PMID- 22815901 TI - Ultramarine, a chromoprotein acceptor for Forster resonance energy transfer. AB - We have engineered a monomeric blue non-fluorescent chromoprotein called Ultramarine (fluorescence quantum yield, 0.001; epsilon(585 nm), 64,000 M(-1) x cm(-1)) for use as a Forster resonance energy transfer acceptor for a number of different donor fluorescent proteins. We show its use for monitoring activation of caspase 3 in live cells using fluorescence lifetime imaging. Ultramarine has the potential to increase the number of cellular parameters that can be imaged simultaneously. PMID- 22815902 TI - Unique suites of trabecular bone features characterize locomotor behavior in human and non-human anthropoid primates. AB - Understanding the mechanically-mediated response of trabecular bone to locomotion specific loading patterns would be of great benefit to comparative mammalian evolutionary morphology. Unfortunately, assessments of the correspondence between individual trabecular bone features and inferred behavior patterns have failed to reveal a strong locomotion-specific signal. This study assesses the relationship between inferred locomotor activity and a suite of trabecular bone structural features that characterize bone architecture. High-resolution computed tomography images were collected from the humeral and femoral heads of 115 individuals from eight anthropoid primate genera (Alouatta, Homo, Macaca, Pan, Papio, Pongo, Trachypithecus, Symphalangus). Discriminant function analyses reveal that subarticular trabecular bone in the femoral and humeral heads is significantly different among most locomotor groups. The results indicate that when a suite of femoral head trabecular features is considered, trabecular number and connectivity density, together with fabric anisotropy and the relative proportion of rods and plates, differentiate locomotor groups reasonably well. A similar, yet weaker, relationship is also evident in the trabecular architecture of the humeral head. The application of this multivariate approach to analyses of trabecular bone morphology in recent and fossil primates may enhance our ability to reconstruct locomotor behavior in the fossil record. PMID- 22815903 TI - Pak1 regulates the orientation of apical polarization and lumen formation by distinct pathways. AB - The development of the basic architecture of branching tubules enclosing a central lumen that characterizes most epithelial organs crucially depends on the apico-basolateral polarization of epithelial cells. Signals from the extracellular matrix control the orientation of the apical surface, so that it faces the lumen interior, opposite to cell-matrix adhesion sites. This orientation of the apical surface is thought to be intrinsically linked to the formation of single lumens. We previously demonstrated in three-dimensional cyst cultures of Madin-Darby canine kidney (MDCK) cells that signaling by beta1 integrins regulates the orientation of the apical surface, via a mechanism that depends on the activity of the small GTPase Rac1. Here, we investigated whether the Rac1 effector Pak1 is a downstream effector in this pathway. Expression of constitutive active Pak1 phenocopies the effect of beta1 integrin inhibition in that it misorients the apical surface and induces a multilumen phenotype. The misorientation of apical surfaces depends on the interaction of active Pak1 with PIX proteins and is linked to defects in basement membrane assembly. In contrast, the multilumen phenotype was independent of PIX and the basement membrane. Therefore, Pak1 likely regulates apical polarization and lumen formation by two distinct pathways. PMID- 22815905 TI - Do chimpanzees use weight to select hammer tools? AB - The extent to which tool-using animals take into account relevant task parameters is poorly understood. Nut cracking is one of the most complex forms of tool use, the choice of an adequate hammer being a critical aspect in success. Several properties make a hammer suitable for nut cracking, with weight being a key factor in determining the impact of a strike; in general, the greater the weight the fewer strikes required. This study experimentally investigated whether chimpanzees are able to encode the relevance of weight as a property of hammers to crack open nuts. By presenting chimpanzees with three hammers that differed solely in weight, we assessed their ability to relate the weight of the different tools with their effectiveness and thus select the most effective one(s). Our results show that chimpanzees use weight alone in selecting tools to crack open nuts and that experience clearly affects the subjects' attentiveness to the tool properties that are relevant for the task at hand. Chimpanzees can encode the requirements that a nut-cracking tool should meet (in terms of weight) to be effective. PMID- 22815904 TI - Role of heat-stable enterotoxins in the induction of early immune responses in piglets after infection with enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) strains that produce heat-stable (ST) and/or heat-labile (LT) enterotoxins are cause of post-weaning diarrhea in piglets. However, the relative importance of the different enterotoxins in host immune responses against ETEC infection has been poorly defined. In the present study, several isogenic mutant strains of an O149:F4ac(+), LT(+) STa(+) STb(+) ETEC strain were constructed that lack the expression of LT in combination with one or both types of ST enterotoxins (STa and/or STb). The small intestinal segment perfusion (SISP) technique and microarray analysis were used to study host early immune responses induced by these mutant strains 4 h after infection in comparison to the wild type strain and a PBS control. Simultaneously, net fluid absorption of pig small intestinal mucosa was measured 4 h after infection, allowing us to correlate enterotoxin secretion with gene regulation. Microarray analysis showed on the one hand a non-toxin related general antibacterial response comprising genes such as PAP, MMP1 and IL8. On the other hand, results suggest a dominant role for STb in small intestinal secretion early after post weaning infection, as well as in the induced innate immune response through differential regulation of immune mediators like interleukin 1 and interleukin 17. PMID- 22815906 TI - Serum long-chain n-3 polyunsaturated fatty acids, mercury, and risk of sudden cardiac death in men: a prospective population-based study. AB - OBJECTIVES: Fish consumption has been associated with reduced risk of cardiovascular diseases (CVD), especially sudden cardiac death (SCD). Fish is the major source of long-chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid and docosahexaenoic acid. It is also a major source of methylmercury, which was associated with increased risk of CVD in this study population. Impact of interaction between long-chain n-3 PUFA and methylmercury on the SCD risk is unknown. METHODS: A total of 1857 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor study, aged 42-60 years and free of CVD at baseline in 1984-1989, were studied. Serum long-chain n 3 PUFA was used as the marker for long-chain n-3 PUFA intake and hair mercury as the marker for mercury exposure. RESULTS: During the mean follow-up of 20.1 years, 91 SCD events occurred. In the multivariate Cox proportional hazards regression models, serum long-chain n-3 PUFA concentration was not associated with the risk of SCD until hair mercury was accounted for; then the hazard ratio (HR) in the highest vs. lowest tertile was 0.54 [95% confidence interval (CI) 0.32 to 0.91, p for trend = 0.046]. When the analyses were stratified by hair mercury content, among those with lower hair mercury, each 0.5 percentage unit increase in the serum long-chain n-3 PUFA was associated with HR of 0.77 (95% CI 0.64 to 0.93), whereas no association was seen among those with higher hair mercury (p for interaction = 0.01). Among the individual long-chain n-3 PUFA, docosahexaenoic acid was most strongly associated with the risk. CONCLUSION: High exposure to mercury may reduce the benefits of long-chain n-3 PUFA on SCD. PMID- 22815907 TI - Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis. AB - Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFalpha, IL1beta and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNgamma in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs. PMID- 22815908 TI - Is payoff necessarily weighted by probability when making a risky choice? Evidence from functional connectivity analysis. AB - How people make decisions under risk remains an as-yet-unresolved but fundamental question. Mainstream theories about risky decision making assume that the core processes involved in reaching a risky decision include weighting each payoff or reward magnitude by its probability and then summing the outcomes. However, recently developed theories question whether payoffs are necessarily weighted by probability when making a risky choice. Using functional connectivity analysis, we aimed to provide neural evidence to answer whether this key assumption of computing expectations holds when making a risky choice. We contrasted a trade off instruction choice that required participants to integrate probability and payoff information with a preferential choice that did not. Based on the functional connectivity patterns between regions in which activity was detected during both of the decision-making tasks, we classified the regions into two networks. One network includes primarily the left and right lateral prefrontal cortices and posterior parietal cortices, which were found to be related to probability in previous reports, and the other network is composed of the bilateral basal ganglia, which have been implicated in payoff. We also found that connectivity between the payoff network and some regions in the probability network (including the left lateral prefrontal cortices and bilateral inferior parietal lobes) were stronger during the trade-off instruction choice task than during the preferential choice task. This indicates that the functional integration between the probability and payoff networks during preferential choice was not as strong as the integration during trade-off instruction choice. Our results provide neural evidence that the weighting process uniformly predicted by the mainstream theory is unnecessary during preferential choice. Thus, our functional integration findings can provide a new direction for the investigation of the principles of risky decision making. PMID- 22815909 TI - IRF7 regulates TLR2-mediated activation of splenic CD11c(hi) dendritic cells. AB - Members of the Interferon Regulatory Factor (IRF) family of transcription factors play an essential role in the development and function of the immune system. Here we investigated the role of IRF7 in the functional activation of conventional CD11c(hi) splenic dendritic cells (cDCs) in vitro and in vivo. Using mice deficient in IRF7, we found that this transcription factor was dispensable for the in vivo development of cDC subsets in the spleen. However, IRF7-deficient cDCs showed enhanced activation in response to microbial stimuli, characterised by exaggerated expression of CD80, CD86 and MHCII upon TLR2 ligation in vitro. The hyper-responsiveness of Irf7(-/-) cDC to TLR ligation could not be reversed with exogenous IFNalpha, nor by co-culture with wild-type cDCs, suggesting an intrinsic defect due to IRF7-deficiency. Irf7(-/-) cDCs also had impaired capacity to produce IL-12p70 when stimulated ex vivo, instead producing elevated levels of IL-10 that impaired their capacity to drive Th1 responses. Finally, analysis of bone marrow microchimeric mice revealed that cDCs deficient in IRF7 were also hyper-responsive to TLR2-mediated activation in vivo. Our data suggest a previously unknown function for IRF7 as a component of the regulatory network associated with cDC activation and adds to the wide variety of situations in which these transcription factors play a role. PMID- 22815910 TI - Vitamin E isoforms differentially regulate intercellular adhesion molecule-1 activation of PKCalpha in human microvascular endothelial cells. AB - AIMS: ICAM-1-dependent leukocyte recruitment in vivo is inhibited by the vitamin E isoform d-alpha-tocopherol and elevated by d-gamma-tocopherol. ICAM-1 is reported to activate endothelial cell signals including protein kinase C (PKC), but the PKC isoform and the mechanism for ICAM-1 activation of PKC are not known. It is also not known whether ICAM-1 signaling in endothelial cells is regulated by tocopherol isoforms. We hypothesized that d-alpha-tocopherol and d-gamma tocopherol differentially regulate ICAM-1 activation of endothelial cell PKC. RESULTS: ICAM-1 crosslinking activated the PKC isoform PKCalpha but not PKCbeta in TNFalpha-pretreated human microvascular endothelial cells. ICAM-1 activation of PKCalpha was blocked by the PLC inhibitor U73122, ERK1/2 inhibitor PD98059, and xanthine oxidase inhibitor allopurinol. ERK1/2 activation was blocked by inhibition of XO and PLC but not by inhibition of PKCalpha, indicating that ERK1/2 is downstream of XO and upstream of PKCalpha during ICAM-1 signaling. During ICAM-1 activation of PKCalpha, the XO-generated ROS did not oxidize PKCalpha. Interestingly, d-alpha-tocopherol inhibited ICAM-1 activation of PKCalpha but not the upstream signal ERK1/2. The d-alpha-tocopherol inhibition of PKCalpha was ablated by the addition of d-gamma-tocopherol. CONCLUSIONS: Crosslinking ICAM-1 stimulated XO/ROS which activated ERK1/2 that then activated PKCalpha. ICAM-1 activation of PKCalpha was inhibited by d-alpha-tocopherol and this inhibition was ablated by the addition of d-gamma-tocopherol. These tocopherols regulated ICAM-1 activation of PKCalpha without altering the upstream signal ERK1/2. Thus, we identified a mechanism for ICAM-1 activation of PKC and determined that d-alpha-tocopherol and d-gamma-tocopherol have opposing regulatory functions for ICAM-1-activated PKCalpha in endothelial cells. PMID- 22815911 TI - A global view of the oncogenic landscape in nasopharyngeal carcinoma: an integrated analysis at the genetic and expression levels. AB - Previous studies have reported that the tumour cells of nasopharyngeal carcinoma (NPC) exhibit recurrent chromosome abnormalities. These genetic changes are broadly assumed to lead to changes in gene expression which are important for the pathogenesis of this tumour. However, this assumption has yet to be formally tested at a global level. Therefore a genome wide analysis of chromosome copy number and gene expression was performed in tumour cells micro-dissected from the same NPC biopsies. Cellular tumour suppressor and tumour-promoting genes (TSG, TPG) and Epstein-Barr Virus (EBV)-encoded oncogenes were examined. The EBV encoded genome maintenance protein EBNA1, along with the putative oncogenes LMP1, LMP2 and BARF1 were expressed in the majority of NPCs that were analysed. Significant downregulation of expression in an average of 76 cellular TSGs per tumour was found, whilst a per-tumour average of 88 significantly upregulated, TPGs occurred. The expression of around 60% of putative TPGs and TSGs was both up and down-regulated in different types of cancer, suggesting that the simplistic classification of genes as TSGs or TPGs may not be entirely appropriate and that the concept of context-dependent onco-suppressors may be more extensive than previously recognised. No significant enrichment of TPGs within regions of frequent genomic gain was seen but TSGs were significantly enriched within regions of frequent genomic loss. It is suggested that loss of the FHIT gene may be a driver of NPC tumourigenesis. Notwithstanding the association of TSGs with regions of genomic loss, on a gene by gene basis and excepting homozygous deletions and high-level amplification, there is very little correlation between chromosomal copy number aberrations and expression levels of TSGs and TPGs in NPC. PMID- 22815912 TI - Using DNA barcoding to assess Caribbean reef fish biodiversity: expanding taxonomic and geographic coverage. AB - This paper represents a DNA barcode data release for 3,400 specimens representing 521 species of fishes from 6 areas across the Caribbean and western central Atlantic regions (FAO Region 31). Merged with our prior published data, the combined efforts result in 3,964 specimens representing 572 species of marine fishes and constitute one of the most comprehensive DNA barcoding "coverages" for a region reported to date. The barcode data are providing new insights into Caribbean shorefish diversity, allowing for more and more accurate DNA-based identifications of larvae, juveniles, and unknown specimens. Examples are given correcting previous work that was erroneous due to database incompleteness. PMID- 22815913 TI - Methylomic analysis identifies frequent DNA methylation of zinc finger protein 582 (ZNF582) in cervical neoplasms. AB - BACKGROUND: Despite of the trend that the application of DNA methylation as a biomarker for cancer detection is promising, clinically applicable genes are few. Therefore, we looked for novel hypermethylated genes for cervical cancer screening. METHODS AND FINDINGS: At the discovery phase, we analyzed the methylation profiles of human cervical carcinomas and normal cervixes by methylated DNA immunoprecipitation coupled to promoter tiling arrays (MeDIP-on chip). Methylation-specific PCR (MSP), quantitative MSP and bisulfite sequencing were used to verify the methylation status in cancer tissues and cervical scrapings from patients with different severities. Immunohistochemical staining of a cervical tissue microarray was used to confirm protein expression. We narrowed to three candidate genes: DBC1, PDE8B, and ZNF582; their methylation frequencies in tumors were 93%, 29%, and 100%, respectively. At the pre validation phase, the methylation frequency of DBC1 and ZNF582 in cervical scraping correlated significantly with disease severity in an independent cohort (n = 330, both P<0.001). For the detection of cervical intraepithelial neoplasia 3 (CIN3) and worse, the area under the receiver operating characteristic curve (AUC) of ZNF582 was 0.82 (95% confidence interval= 0.76-0.87). CONCLUSIONS: Our study shows ZNF582 is frequently methylated in CIN3 and worse lesions, and it is demonstrated as a potential biomarker for the molecular screening of cervical cancer. PMID- 22815914 TI - Can falls risk prediction tools correctly identify fall-prone elderly rehabilitation inpatients? A systematic review and meta-analysis. AB - BACKGROUND: Falls of elderly people may cause permanent disability or death. Particularly susceptible are elderly patients in rehabilitation hospitals. We systematically reviewed the literature to identify falls prediction tools available for assessing elderly inpatients in rehabilitation hospitals. METHODS AND FINDINGS: We searched six electronic databases using comprehensive search strategies developed for each database. Estimates of sensitivity and specificity were plotted in ROC space graphs and pooled across studies. Our search identified three studies which assessed the prediction properties of falls prediction tools in a total of 754 elderly inpatients in rehabilitation hospitals. Only the STRATIFY tool was assessed in all three studies; the other identified tools (PJC FRAT and DOWNTON) were assessed by a single study. For a STRATIFY cut-score of two, pooled sensitivity was 73% (95%CI 63 to 81%) and pooled specificity was 42% (95%CI 34 to 51%). An indirect comparison of the tools across studies indicated that the DOWNTON tool has the highest sensitivity (92%), while the PJC-FRAT offers the best balance between sensitivity and specificity (73% and 75%, respectively). All studies presented major methodological limitations. CONCLUSIONS: We did not identify any tool which had an optimal balance between sensitivity and specificity, or which were clearly better than a simple clinical judgment of risk of falling. The limited number of identified studies with major methodological limitations impairs sound conclusions on the usefulness of falls risk prediction tools in geriatric rehabilitation hospitals. PMID- 22815915 TI - Prediction of chemical-protein interactions network with weighted network-based inference method. AB - Chemical-protein interaction (CPI) is the central topic of target identification and drug discovery. However, large scale determination of CPI is a big challenge for in vitro or in vivo experiments, while in silico prediction shows great advantages due to low cost and high accuracy. On the basis of our previous drug target interaction prediction via network-based inference (NBI) method, we further developed node- and edge-weighted NBI methods for CPI prediction here. Two comprehensive CPI bipartite networks extracted from ChEMBL database were used to evaluate the methods, one containing 17,111 CPI pairs between 4,741 compounds and 97 G protein-coupled receptors, the other including 13,648 CPI pairs between 2,827 compounds and 206 kinases. The range of the area under receiver operating characteristic curves was 0.73 to 0.83 for the external validation sets, which confirmed the reliability of the prediction. The weak-interaction hypothesis in CPI network was identified by the edge-weighted NBI method. Moreover, to validate the methods, several candidate targets were predicted for five approved drugs, namely imatinib, dasatinib, sertindole, olanzapine and ziprasidone. The molecular hypotheses and experimental evidence for these predictions were further provided. These results confirmed that our methods have potential values in understanding molecular basis of drug polypharmacology and would be helpful for drug repositioning. PMID- 22815916 TI - Transcriptional response of peripheral blood mononuclear cells from cattle infected with Mycobacterium bovis. AB - Mycobacterium bovis is the causative agent of most cases of bovine tuberculosis. The identification of bTB biomarkers in specific stages of the disease will contribute to a better understanding of the immunopathology associated with tuberculosis and will enable their use in disease diagnosis and prognosis. The aim of this study was to evaluate the gene expression profile induced after specific stimulation of bovine peripheral blood mononuclear cells from cattle infected with M. bovis using the Affymetrix(r) GeneChip(r) Bovine Genome Array. A total of 172 genes showed differential expression profile that was statistically significant with log2-fold change >2.5 and <-2.5. Twenty-four out of these genes were upregulated and 148 were downregulated in bovine peripheral blood mononuclear cells of M. bovis-infected cattle. The highest differentially expressed genes were related to immune and inflammatory responses, apoptosis, endocytosis, cellular trafficking and genes encoding proteins involved in cellular matrix degradation. Microarray results were confirmed in another group of infected cattle by RT-qPCR for the CD14, IL-1R, THBS1, MMP9 and FYVE genes. This study confirms previous findings that have shown that M. bovis infection in cattle results in the downregulation of immune response-related genes. Moreover, it validates the use of microarray platforms in combination with RT-qPCR to identify biomarkers of bovine tuberculosis. In addition, we propose CD14, IL-1R, THBS1, MMP9 and FYVE as potential biomarkers of bovine tuberculosis. PMID- 22815917 TI - Epidemiological characteristics and underlying risk factors for mortality during the autumn 2009 pandemic wave in Mexico. AB - BACKGROUND: Elucidating the role of the underlying risk factors for severe outcomes of the 2009 A/H1N1 influenza pandemic could be crucial to define priority risk groups in resource-limited settings in future pandemics. METHODS: We use individual-level clinical data on a large series of ARI (acute respiratory infection) hospitalizations from a prospective surveillance system of the Mexican Social Security medical system to analyze clinical features at presentation, admission delays, selected comorbidities and receipt of seasonal vaccine on the risk of A/H1N1-related death. We considered ARI hospitalizations and inpatient deaths, and recorded demographic, geographic, and medical information on individual patients during August-December, 2009. RESULTS: Seasonal influenza vaccination was associated with a reduced risk of death among A/H1N1 inpatients (OR = 0.43 (95% CI: 0.25, 0.74)) after adjustment for age, gender, geography, antiviral treatment, admission delays, comorbidities and medical conditions. However, this result should be interpreted with caution as it could have been affected by factors not directly measured in our study. Moreover, the effect of antiviral treatment against A/H1N1 inpatient death did not reach statistical significance (OR = 0.56 (95% CI: 0.29, 1.10)) probably because only 8.9% of A/H1N1 inpatients received antiviral treatment. Moreover, diabetes (OR = 1.6) and immune suppression (OR = 2.3) were statistically significant risk factors for death whereas asthmatic persons (OR = 0.3) or pregnant women (OR = 0.4) experienced a reduced fatality rate among A/H1N1 inpatients. We also observed an increased risk of death among A/H1N1 inpatients with admission delays >2 days after symptom onset (OR = 2.7). Similar associations were also observed for A/H1N1-negative inpatients. CONCLUSIONS: Geographical variation in identified medical risk factors including prevalence of diabetes and immune suppression may in part explain between-country differences in pandemic mortality burden. Furthermore, access to care including hospitalization without delay and antiviral treatment and are also important factors, as well as vaccination coverage with the 2008-09 trivalent inactivated influenza vaccine. PMID- 22815918 TI - The impact of small molecule binding on the energy landscape of the intrinsically disordered protein C-myc. AB - Intrinsically disordered proteins are attractive therapeutic targets owing to their prevalence in several diseases. Yet their lack of well-defined structure renders ligand discovery a challenging task. An intriguing example is provided by the oncoprotein c-Myc, a transcription factor that is over expressed in a broad range of cancers. Transcriptional activity of c-Myc is dependent on heterodimerization with partner protein Max. This protein-protein interaction is disrupted by the small molecule 10058-F4 (1), that binds to monomeric and disordered c-Myc. To rationalize the mechanism of inhibition, structural ensembles for the segment of the c-Myc domain that binds to 1 were computed in the absence and presence of the ligand using classical force fields and explicit solvent metadynamics molecular simulations. The accuracy of the computed structural ensembles was assessed by comparison of predicted and measured NMR chemical shifts. The small molecule 1 was found to perturb the composition of the apo equilibrium ensemble and to bind weakly to multiple distinct c-Myc conformations. Comparison of the apo and holo equilibrium ensembles reveals that the c-Myc conformations binding 1 are already partially formed in the apo ensemble, suggesting that 1 binds to c-Myc through an extended conformational selection mechanism. The present results have important implications for rational ligand design efforts targeting intrinsically disordered proteins. PMID- 22815919 TI - Predictive sequence analysis of the Candidatus Liberibacter asiaticus proteome. AB - Candidatus Liberibacter asiaticus (Ca. L. asiaticus) is a parasitic gram-negative bacterium that is closely associated with Huanglongbing (HLB), a worldwide citrus disease. Given the difficulty in culturing the bacterium and thus in its experimental characterization, computational analyses of the whole Ca. L. asiaticus proteome can provide much needed insights into the mechanisms of the disease and guide the development of treatment strategies. In this study, we applied state-of-the-art sequence analysis tools to every Ca. L. asiaticus protein. Our results are available as a public website at http://prodata.swmed.edu/liberibacter_asiaticus/. In particular, we manually curated the results to predict the subcellular localization, spatial structure and function of all Ca. L. asiaticus proteins (http://prodata.swmed.edu/liberibacter_asiaticus/curated/). This extensive information should facilitate the study of Ca. L. asiaticus proteome function and its relationship to disease. Pilot studies based on the information from our website have revealed several potential virulence factors, discussed herein. PMID- 22815920 TI - Alterations in mouse hypothalamic adipokine gene expression and leptin signaling following chronic spinal cord injury and with advanced age. AB - Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions. PMID- 22815921 TI - Planktonic aggregates of Staphylococcus aureus protect against common antibiotics. AB - Bacterial cells are mostly studied during planktonic growth although in their natural habitats they are often found in communities such as biofilms with dramatically different physiological properties. We have examined another type of community namely cellular aggregates observed in strains of the human pathogen Staphylococcus aureus. By laser-diffraction particle-size analysis (LDA) we show, for strains forming visible aggregates, that the aggregation starts already in the early exponential growth phase and proceeds until post-exponential phase where more than 90% of the population is part of the aggregate community. Similar to some types of biofilm, the structural component of S. aureus aggregates is the polysaccharide intercellular adhesin (PIA). Importantly, PIA production correlates with the level of aggregation whether altered through mutations or exposure to sub-inhibitory concentrations of selected antibiotics. While some properties of aggregates resemble those of biofilms including increased mutation frequency and survival during antibiotic treatment, aggregated cells displayed higher metabolic activity than planktonic cells or cells in biofilm. Thus, our data indicate that the properties of cells in aggregates differ in some aspects from those in biofilms. It is generally accepted that the biofilm life style protects pathogens against antibiotics and the hostile environment of the host. We speculate that in aggregate communities S. aureus increases its tolerance to hazardous environments and that the combination of a biofilm-like environment with mobility has substantial practical and clinical importance. PMID- 22815922 TI - Effects of body mass index on task-related oxygen uptake and dyspnea during activities of daily life in COPD. AB - BACKGROUND: Patients with COPD use a higher proportion of their peak aerobic capacity during the performance of domestic activities of daily life (ADLs) compared to healthy peers, accompanied by a higher degree of task-related symptoms. To date, the influence of body mass index (BMI) on the task-related metabolic demands remains unknown in patients with COPD. Therefore, the aim of our study was to determine the effects of BMI on metabolic load during the performance of 5 consecutive domestic ADLs in patients with COPD. METHODOLOGY: Ninety-four COPD patients and 20 healhty peers performed 5 consecutive, self paced domestic ADLs putting on socks, shoes and vest; folding 8 towels; putting away groceries; washing up 4 dishes, cups and saucers; and sweeping the floor for 4 min. Task-related oxygen uptake and ventilation were assessed using a mobile oxycon, while Borg scores were used to assess task-related dyspnea and fatigue. PRINCIPAL FINDINGS: 1. Relative task-related oxygen uptake after the performance of domestic ADLs was increased in patients with COPD compared to healthy elderly, whereas absolute oxygen uptake is similar between groups; 2. Relative oxygen uptake and oxygen uptake per kilogram fat-free mass were comparable between BMI groups; and 3. Borg symptom scores for dyspnea en fatigue were comparable between BMI groups. CONCLUSION: Patients with COPD in different BMI groups perform self paced domestic ADLs at the same relative metabolic load, accompanied by comparable Borg symptom scores for dyspnea and fatigue. PMID- 22815923 TI - Measuring animal welfare within a reintroduction: an assessment of different indices of stress in water voles Arvicola amphibius. AB - Reintroductions are an increasingly common conservation restoration tool; however, little attention has hitherto been given to different methods for monitoring the stress encountered by reintroduced individuals. We compared ten potential measures of stress within four different categories (neuroendocrine, cell function, body condition and immune system function) as proxies for animal welfare in water voles being reintroduced to the Upper Thames region, Oxfordshire, UK. Captive-bred voles were assessed pre-release, and each month post-release for up to five months. Wild-born voles were captured in the field and assessed from two months post-release. Plasma corticosteroid, hydration and body condition of captive-bred voles differed between their pre-release measures and both their first ("short-term") recapture, and their final recapture ("long term" release), however only body condition and immunocompetence measured using the Nitroblue Tetrazolium (NBT) test were significantly different post-release between the first and last recaptures. Captive-bred animals had lower fat reserves, higher weight/length ratios and better immunocompetence (NBT) than did wild-born voles. Captive-bred males had higher ectoparasite burdens compared to wild-born males and, as reintroduction site quality decreased, became less hydrated. These observations indicate that some methods can identify changes in the stress response in individuals, highlighting areas of risk in a reintroduction programme. In addition, a single measure may not provide a full picture of the stress experienced; instead, a combination of measures of different physiological systems may give a more complete indication of stress during the reintroduction process. We highlight the need to monitor stress in reintroductions using measures from different physiological systems to inform on possible animal welfare improvements and thus the overall success rate of reintroductions. PMID- 22815924 TI - TAGCNA: a method to identify significant consensus events of copy number alterations in cancer. AB - Somatic copy number alteration (CNA) is a common phenomenon in cancer genome. Distinguishing significant consensus events (SCEs) from random background CNAs in a set of subjects has been proven to be a valuable tool to study cancer. In order to identify SCEs with an acceptable type I error rate, better computational approaches should be developed based on reasonable statistics and null distributions. In this article, we propose a new approach named TAGCNA for identifying SCEs in somatic CNAs that may encompass cancer driver genes. TAGCNA employs a peel-off permutation scheme to generate a reasonable null distribution based on a prior step of selecting tag CNA markers from the genome being considered. We demonstrate the statistical power of TAGCNA on simulated ground truth data, and validate its applicability using two publicly available cancer datasets: lung and prostate adenocarcinoma. TAGCNA identifies SCEs that are known to be involved with proto-oncogenes (e.g. EGFR, CDK4) and tumor suppressor genes (e.g. CDKN2A, CDKN2B), and provides many additional SCEs with potential biological relevance in these data. TAGCNA can be used to analyze the significance of CNAs in various cancers. It is implemented in R and is freely available at http://tagcna.sourceforge.net/. PMID- 22815925 TI - Mitochondrial reactive oxygen species modulate mosquito susceptibility to Plasmodium infection. AB - BACKGROUND: Mitochondria perform multiple roles in cell biology, acting as the site of aerobic energy-transducing pathways and as an important source of reactive oxygen species (ROS) that modulate redox metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that a novel member of the mitochondrial transporter protein family, Anopheles gambiae mitochondrial carrier 1 (AgMC1), is required to maintain mitochondrial membrane potential in mosquito midgut cells and modulates epithelial responses to Plasmodium infection. AgMC1 silencing reduces mitochondrial membrane potential, resulting in increased proton leak and uncoupling of oxidative phosphorylation. These metabolic changes reduce midgut ROS generation and increase A. gambiae susceptibility to Plasmodium infection. CONCLUSION: We provide direct experimental evidence indicating that ROS derived from mitochondria can modulate mosquito epithelial responses to Plasmodium infection. PMID- 22815926 TI - Neuroprotective effects of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats. AB - Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury. PMID- 22815927 TI - Role of the adiponectin binding protein, T-cadherin (Cdh13), in allergic airways responses in mice. AB - Adiponectin is an adipose derived hormone that declines in obesity. We have previously shown that exogenous administration of adiponectin reduces allergic airways responses in mice. T-cadherin (T-cad; Cdh13) is a binding protein for the high molecular weight isoforms of adiponectin. To determine whether the beneficial effects of adiponectin on allergic airways responses require T-cad, we sensitized wildtype (WT), T-cadherin deficient (T-cad(-/-)) and adiponectin and T cad bideficient mice to ovalbumin (OVA) and challenged the mice with aerosolized OVA or PBS. Compared to WT, T-cad(-/-) mice were protected against OVA-induced airway hyperresponsiveness, increases in BAL inflammatory cells, and induction of IL-13, IL-17, and eotaxin expression. Histological analysis of the lungs of OVA challenged T-cad(-/-) versus WT mice indicated reduced inflammation around the airways, and reduced mucous cell hyperplasia. Combined adiponectin and T-cad deficiency reversed the effects of T-cad deficiency alone, indicating that the observed effects of T-cad deficiency require adiponectin. Compared to WT, serum adiponectin was markedly increased in T-cad(-/-) mice, likely because adiponectin that is normally sequestered by endothelial T-cad remains free in the circulation. In conclusion, T-cad does not mediate the protective effects of adiponectin. Instead, mice lacking T-cad have reduced allergic airways disease, likely because elevated serum adiponectin levels act on other adiponectin signaling pathways. PMID- 22815928 TI - Evolutionary diversification of banded tube-dwelling anemones (Cnidaria; Ceriantharia; Isarachnanthus) in the Atlantic Ocean. AB - The use of molecular data for species delimitation in Anthozoa is still a very delicate issue. This is probably due to the low genetic variation found among the molecular markers (primarily mitochondrial) commonly used for Anthozoa. Ceriantharia is an anthozoan group that has not been tested for genetic divergence at the species level. Recently, all three Atlantic species described for the genus Isarachnanthus of Atlantic Ocean, were deemed synonyms based on morphological simmilarities of only one species: Isarachnanthus maderensis. Here, we aimed to verify whether genetic relationships (using COI, 16S, ITS1 and ITS2 molecular markers) confirmed morphological affinities among members of Isarachnanthus from different regions across the Atlantic Ocean. Results from four DNA markers were completely congruent and revealed that two different species exist in the Atlantic Ocean. The low identification success and substantial overlap between intra and interspecific COI distances render the Anthozoa unsuitable for DNA barcoding, which is not true for Ceriantharia. In addition, genetic divergence within and between Ceriantharia species is more similar to that found in Medusozoa (Hydrozoa and Scyphozoa) than Anthozoa and Porifera that have divergence rates similar to typical metazoans. The two genetic species could also be separated based on micromorphological characteristics of their cnidomes. Using a specimen of Isarachnanthus bandanensis from Pacific Ocean as an outgroup, it was possible to estimate the minimum date of divergence between the clades. The cladogenesis event that formed the species of the Atlantic Ocean is estimated to have occured around 8.5 million years ago (Miocene) and several possible speciation scenarios are discussed. PMID- 22815929 TI - Fasciculation and guidance of spinal motor axons in the absence of FGFR2 signaling. AB - During development, fibroblast growth factors (FGF) are essential for early patterning events along the anterior-posterior axis, conferring positional identity to spinal motor neurons by activation of different Hox codes. In the periphery, signaling through one of four fibroblast growth factor receptors supports the development of the skeleton, as well as induction and maintenance of extremities. In previous studies, FGF receptor 2 (FGFR2) was found to interact with axon bound molecules involved in axon fasciculation and extension, thus rendering this receptor an interesting candidate for the promotion of proper peripheral innervation. However, while the involvement of FGFR2 in limb bud induction has been extensively studied, its role during axon elongation and formation of distinct nervous projections has not been addressed so far. We show here that motor neurons in the spinal cord express FGFR2 and other family members during the establishment of motor connections to the forelimb and axial musculature. Employing a conditional genetic approach to selectively ablate FGFR2 from motor neurons we found that the patterning of motor columns and the expression patterns of other FGF receptors and Sema3A in the motor columns of mutant embryos are not altered. In the absence of FGFR2 signaling, pathfinding of motor axons is intact, and also fasciculation, distal advancement of motor nerves and gross morphology and positioning of axonal projections are not altered. Our findings therefore show that FGFR2 is not required cell-autonomously in motor neurons during the formation of initial motor projections towards limb and axial musculature. PMID- 22815930 TI - Magnetic catechol-chitosan with bioinspired adhesive surface: preparation and immobilization of omega-transaminase. AB - The magnetic chitosan nanocomposites have been studied intensively and been used practically in various biomedical and biological applications including enzyme immobilization. However, the loading capacity and the remained activity of immobilized enzyme based on existing approaches are not satisfied. Simpler and more effective immobilization strategies are needed. Here we report a simple catechol modified protocol for preparing a novel catechol-chitosan (CCS)-iron oxide nanoparticles (IONPs) composites carrying adhesive moieties with strong surface affinity. The omega-transaminase (omega-TA) was immobilized onto this magnetic composite via nucleophilic reactions between catechol and omega-TA. Under optimal conditions, 87.5% of the available omega-TA was immobilized on the composite, yielding an enzyme loading capacity as high as 681.7 mg/g. Furthermore, the valuation of enzyme activity showed that omega-TA immobilized on CCS-IONPs displayed enhanced pH and thermal stability compared to free enzyme. Importantly, the immobilized omega-TA retained more than 50% of its initial activity after 15 repeated reaction cycles using magnetic separation and 61.5% of its initial activity after storage at 4 degrees C in phosphate buffered saline (PBS) for 15 days. The results suggested that such adhesive magnetic composites may provide an improved platform technology for bio-macromolecules immobilized. PMID- 22815931 TI - Amniotic mesenchymal stem cells enhance wound healing in diabetic NOD/SCID mice through high angiogenic and engraftment capabilities. AB - Although human amniotic mesenchymal stem cells (AMMs) have been recognised as a promising stem cell resource, their therapeutic potential for wound healing has not been widely investigated. In this study, we evaluated the therapeutic potential of AMMs using a diabetic mouse wound model. Quantitative real-time PCR and ELISA results revealed that the angiogenic factors, IGF-1, EGF and IL-8 were markedly upregulated in AMMs when compared with adipose-derived mesenchymal stem cells (ADMs) and dermal fibroblasts. In vitro scratch wound assays also showed that AMM-derived conditioned media (CM) significantly accelerated wound closure. Diabetic mice were generated using streptozotocin and wounds were created by skin excision, followed by AMM transplantation. AMM transplantation significantly promoted wound healing and increased re-epithelialization and cellularity. Notably, transplanted AMMs exhibited high engraftment rates and expressed keratinocyte-specific proteins and cytokeratin in the wound area, indicating a direct contribution to cutaneous closure. Taken together, these data suggest that AMMs possess considerable therapeutic potential for chronic wounds through the secretion of angiogenic factors and enhanced engraftment/differentiation capabilities. PMID- 22815932 TI - DSP-PP precursor protein cleavage by tolloid-related-1 protein and by bone morphogenetic protein-1. AB - Dentin sialoprotein (DSP) and phosphophoryn (PP), acidic proteins critical to dentin mineralization, are translated from a single transcript as a DSP-PP precursor that undergoes specific proteolytic processing to generate DSP and PP. The cleavage mechanism continues to be controversial, in part because of the difficulty of obtaining DSP-PP from mammalian cells and dentin matrix. We have infected Sf9 cells with a recombinant baculovirus to produce large amounts of secreted DSP-PP(240), a variant form of rat DSP-PP. Mass spectrometric analysis shows that DSP-PP(240) secreted by Sf9 cells undergoes specific cleavage at the site predicted from the N-terminal sequence of PP extracted from dentin matrix: SMQG(447)?D(448)DPN. DSP-PP(240) is cleaved after secretion by a zinc-dependent activity secreted by Sf9 cells, generating DSP(430) and PP(240) products that are stable in the medium. DSP-PP processing activity is constitutively secreted by Sf9 cells, but secretion is diminished 3 days after infection. Using primers corresponding to the highly conserved catalytic domain of Drosophila melanogaster tolloid (a mammalian BMP1 homolog), we isolated a partial cDNA for a Spodopotera frugiperda tolloid-related-1 protein (TLR1) that is 78% identical to Drosophila TLR1 but only 65% identical to Drosophila tolloid. Tlr1 mRNA decreased rapidly in Sf9 cells after baculovirus infection and was undetectable 4d after infection, paralleling the observed decrease in secretion of the DSP-PP(240) processing activity after infection. Human BMP1 is more similar to Sf9 and Drosophila TLR1 than to tolloid, and Sf9 TLR1 is more similar to BMP1 than to other mammalian homologs. Recombinant human BMP1 correctly processed baculovirus-expressed DSP PP(240) in a dose-dependent manner. Together, these data suggest that the physiologically accurate cleavage of mammalian DSP-PP(240) in the Sf9 cell system represents the action of a conserved processing enzyme and support the proposed role of BMP1 in processing DSP-PP in dentin matrix. PMID- 22815933 TI - Molecular characterization of NAD+-dependent DNA ligase from Wolbachia endosymbiont of lymphatic filarial parasite Brugia malayi. AB - The lymphatic filarial parasite, Brugia malayi contains Wolbachia endobacteria that are essential for development, viability and fertility of the parasite. Therefore, wolbachial proteins have been currently seen as the potential antifilarial drug targets. NAD(+)-dependent DNA ligase is characterized as a promising drug target in several organisms due to its crucial, indispensable role in DNA replication, recombination and DNA repair. We report here the cloning, expression and purification of NAD(+)-dependent DNA ligase of Wolbachia endosymbiont of B. malayi (wBm-LigA) for its molecular characterization. wBm-LigA has all the domains that are present in nearly all the eubacterial NAD(+) dependent DNA ligases such as N-terminal adenylation domain, OB fold, helix hairpin-helix (HhH) and BRCT domain except zinc-binding tetracysteine domain. The purified recombinant protein (683-amino acid) was found to be biochemically active and was present in its native form as revealed by the circular dichroism and fluorescence spectra. The purified recombinant enzyme was able to catalyze intramolecular strand joining on a nicked DNA as well as intermolecular joining of the cohesive ends of BstEII restricted lamda DNA in an in vitro assay. The enzyme was localized in the various life-stages of B. malayi parasites by immunoblotting and high enzyme expression was observed in Wolbachia within B. malayi microfilariae and female adult parasites along the hypodermal chords and in the gravid portion as evident by the confocal microscopy. Ours is the first report on this enzyme of Wolbachia and these findings would assist in validating the antifilarial drug target potential of wBm-LigA in future studies. PMID- 22815934 TI - The LKB1 tumor suppressor controls spindle orientation and localization of activated AMPK in mitotic epithelial cells. AB - Orientation of mitotic spindles plays an integral role in determining the relative positions of daughter cells in a tissue. LKB1 is a tumor suppressor that controls cell polarity, metabolism, and microtubule stability. Here, we show that germline LKB1 mutation in mice impairs spindle orientation in cells of the upper gastrointestinal tract and causes dramatic mislocalization of the LKB1 substrate AMPK in mitotic cells. RNAi of LKB1 causes spindle misorientation in three dimensional MDCK cell cysts. Maintaining proper spindle orientation, possibly mediated by effects on the downstream kinase AMPK, could be an important tumor suppressor function of LKB1. PMID- 22815935 TI - Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson's disease. AB - The use of human embryonic stem cells (hESCs) to repair diseased or injured brain is promising technology with significant humanitarian, societal and economic impact. Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. The generation of this cell type will fulfill a currently unmet therapeutic need. We report on the isolation and perpetuation of a midbrain-specified self-renewable human neural stem cell line (hNSCs) from hESCs. These hNSCs grew as a monolayer and uniformly expressed the neural precursor markers nestin, vimentin and a radial glial phenotype. We describe a process to direct the differentiation of these hNSCs towards the DA lineage. Glial conditioned media acted synergistically with fibroblastic growth factor and leukemia inhibitory factor to induce the expression of the DA marker, tyrosine hydroxylase (TH), in the hNSC progeny. The glial-derived neurotrophic factor did not fully mimic the effects of conditioned media. The hNSCs expressed the midbrain-specific transcription factors Nurr1 and Pitx3. The inductive effects did not modify the level of the glutamic acid decarboxylase (GAD) transcript, a marker for GABAergic neurons, while the TH transcript increased 10 fold. Immunocytochemical analysis demonstrated that the TH-expressing cells did not co-localize with GAD. The transplantation of these DA-induced hNSCs into the non-human primate MPTP model of PD demonstrated that the cells maintain their DA induced phenotype, extend neurite outgrowths and express synaptic markers. PMID- 22815936 TI - Whole-genome synthesis and characterization of viable S13-like bacteriophages. AB - BACKGROUND: Unprecedented progresses in high-throughput DNA sequencing and de novo gene synthesis technologies have allowed us to create living organisms in the absence of natural template. METHODOLOGY/PRINCIPAL FINDINGS: The sequence of wild-type S13 phage genome was downloaded from GenBank. Two synonymous mutations were introduced into wt-S13 genome to generate m1-S13 genome. Another mutant, m2 S13 genome, was obtained by engineering two nonsynonymous mutations in the capsid protein coding region of wt-S13 genome. A chimeric phage genome was designed by replacing the F capsid protein open reading frame (ORF) from phage S13 with the F capsid protein ORF from phage G4. The whole genomes of all four phages were assembled from a series of chemically synthesized short overlapping oligonucleotides. The linear synthesized genomes were circularized and electroporated into E.coli C, the standard laboratory host of S13 phage. All four phages were recovered and plaques were visualized. The results of sequencing showed the accuracy of these synthetic genomes. The synthetic phages were capable of lysing their bacterial host and tolerating general environmental conditions. While no phenotypic differences among the variant strains were observed when grown in LB medium with CaCl(2), the S13/G4 chimera was found to be much more sensitive to the absence of calcium and to have a lower adsorption rate under calcium free condition. CONCLUSIONS/SIGNIFICANCE: The bacteriophage S13 and its variants can be chemically synthesized. The major capsid gene of phage G4 is functional in the phage S13 life cycle. These results support an evolutional hypothesis which has been proposed that a homologous recombination event involving gene F of quite divergent ancestral lineages should be included in the history of the microvirid family. PMID- 22815938 TI - Making robust policy decisions using global biodiversity indicators. AB - In order to influence global policy effectively, conservation scientists need to be able to provide robust predictions of the impact of alternative policies on biodiversity and measure progress towards goals using reliable indicators. We present a framework for using biodiversity indicators predictively to inform policy choices at a global level. The approach is illustrated with two case studies in which we project forwards the impacts of feasible policies on trends in biodiversity and in relevant indicators. The policies are based on targets agreed at the Convention on Biological Diversity (CBD) meeting in Nagoya in October 2010. The first case study compares protected area policies for African mammals, assessed using the Red List Index; the second example uses the Living Planet Index to assess the impact of a complete halt, versus a reduction, in bottom trawling. In the protected areas example, we find that the indicator can aid in decision-making because it is able to differentiate between the impacts of the different policies. In the bottom trawling example, the indicator exhibits some counter-intuitive behaviour, due to over-representation of some taxonomic and functional groups in the indicator, and contrasting impacts of the policies on different groups caused by trophic interactions. Our results support the need for further research on how to use predictive models and indicators to credibly track trends and inform policy. To be useful and relevant, scientists must make testable predictions about the impact of global policy on biodiversity to ensure that targets such as those set at Nagoya catalyse effective and measurable change. PMID- 22815937 TI - Sequence-based polymorphisms in the mitochondrial D-loop and potential SNP predictors for chronic dialysis. AB - BACKGROUND: The mitochondrial (mt) displacement loop (D-loop) is known to accumulate structural alterations and mutations. The aim of this study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) within the D loop among chronic dialysis patients and healthy controls. METHODOLOGY AND PRINCIPAL FINDINGS: We enrolled 193 chronic dialysis patients and 704 healthy controls. SNPs were identified by large scale D-loop sequencing and bioinformatic analysis. Chronic dialysis patients had lower body mass index, blood thiols, and cholesterol levels than controls. A total of 77 SNPs matched with the positions in reference of the Revised Cambridge Reference Sequence (CRS) were found in the study population. Chronic dialysis patients had a significantly higher incidence of 9 SNPs compared to controls. These include SNP5 (16108Y), SNP17 (16172Y), SNP21 (16223Y), SNP34 (16274R), SNP35 (16278Y), SNP55 (16463R), SNP56 (16519Y), SNP64 (185R), and SNP65 (189R) in D-loop of CRS. Among these SNPs with genotypes, SNP55-G, SNP56-C, and SNP64-A were 4.78, 1.47, and 5.15 times more frequent in dialysis patients compared to controls (P<0.05), respectively. When adjusting the covariates of demographics and comorbidities, SNP64-A was 5.13 times more frequent in dialysis patients compared to controls (P<0.01). Furthermore, SNP64-A was found to be 35.80, 3.48, 4.69, 5,55, and 4.67 times higher in female patients and in patients without diabetes, coronary artery disease, smoking, and hypertension in an independent significance manner (P<0.05), respectively. In patients older than 50 years or with hypertension, SNP34-A and SNP17-C were found to be 7.97 and 3.71 times more frequent (P<0.05) compared to patients younger than 50 years or those without hypertension, respectively. CONCLUSIONS AND SIGNIFICANCE: The results of large-scale sequencing suggest that specific SNPs in the mtDNA D-loop are significantly associated with chronic dialysis. These SNPs can be considered as potential predictors for chronic dialysis. PMID- 22815939 TI - Two unique ligand-binding clamps of Rhizopus oryzae starch binding domain for helical structure disruption of amylose. AB - The N-terminal starch binding domain of Rhizopus oryzae glucoamylase (RoSBD) has a high binding affinity for raw starch. RoSBD has two ligand-binding sites, each containing a ligand-binding clamp: a polyN clamp residing near binding site I is unique in that it is expressed in only three members of carbohydrate binding module family 21 (CBM21) members, and a Y32/F58 clamp located at binding site II is conserved in several CBMs. Here we characterized different roles of these sites in the binding of insoluble and soluble starches using an amylose-iodine complex assay, atomic force microscopy, isothermal titration calorimetry, site directed mutagenesis, and structural bioinformatics. RoSBD induced the release of iodine from the amylose helical cavity and disrupted the helical structure of amylose type III, thereby significantly diminishing the thickness and length of the amylose type III fibrils. A point mutation in the critical ligand-binding residues of sites I and II, however, reduced both the binding affinity and amylose helix disruption. This is the first molecular model for structure disruption of the amylose helix by a non-hydrolytic CBM21 member. RoSBD apparently twists the helical amylose strands apart to expose more ligand surface for further SBD binding. Repeating the process triggers the relaxation and unwinding of amylose helices to generate thinner and shorter amylose fibrils, which are more susceptible to hydrolysis by glucoamylase. This model aids in understanding the natural roles of CBMs in protein-glycan interactions and contributes to potential molecular engineering of CBMs. PMID- 22815940 TI - Reduced susceptibility to colitis-associated colon carcinogenesis in mice lacking plasma membrane-associated sialidase. AB - Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and change their conformation, intermolecular interactions, and/or half-life. Thus, sialidases are believed to modulate the function of sialoglycoconjugates by desialylation. We previously reported that the membrane associated mammalian sialidase NEU3, which preferentially acts on gangliosides, is involved in cell differentiation, motility, and tumorigenesis. The NEU3 gene expression is aberrantly elevated in several human cancers, including colon, renal, prostate, and ovarian cancers. The small interfering RNA-mediated knock down of NEU3 in cancer cell lines, but not in normal cell-derived primary cultures, downregulates EGFR signaling and induces apoptosis. Here, to investigate the physiological role of NEU3 in tumorigenesis, we established Neu3 deficient mice and then subjected them to carcinogen-induced tumorigenesis, using a sporadic and a colitis-associated colon cancer models. The Neu3-deficient mice showed no conspicuous accumulation of gangliosides in the brain or colon mucosa, or overt abnormalities in their growth, development, behavior, or fertility. In dimethylhydrazine-induced colon carcinogenesis, there were no differences in the incidence or growth of tumors between the Neu3-deficient and wild-type mice. On the other hand, the Neu3-deficient mice were less susceptible than wild-type mice to the colitis-associated colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. These results suggest that NEU3 plays an important role in inflammation-dependent tumor development. PMID- 22815941 TI - The structure and usage of female and male mouse ultrasonic vocalizations reveal only minor differences. AB - Ultrasonic vocalizations (USV) of mice are increasingly recognized as informative dependent variables in studies using mouse models of human diseases. While pup vocalizations primarily serve to re-establish contact with the mother, adult male "songs" were considered to be courtship signals. Alternatively, mouse USVs may generally function as territorial signals. To distinguish between these two hypotheses, we compared the structure and usage of adult male and female USVs in staged resident-intruder encounters. If calls function primarily as courtship signals, males should respond stronger than females, specifically when presented with a female intruder. Refuting this hypothesis, we found that in response to female intruders, females called more than males (228+/-32 calls/min vs. 71+/-15 calls/min), and males called more to female than to male intruders (14+/-7.5 calls/min). There were no significant differences in the acoustic characteristics of the calls given by females and males. To control for the influence of the intruder's behavior on calling, we repeated the experiments using anaesthetized intruders. Again, females produced more calls to female than male intruders (173+/-17 calls/min vs. 71+/-15 calls/min), while males called more in response to female than male intruders (39+/-17 calls/min), and there were no acoustic differences in female and male calls. The vocal activity did not differ significantly with regard to intruder state (awake or anaesthetized), while the acoustic structure exhibited significant differences. Taken together, our findings support the view that calls do not mainly function as courtship signals, although they might serve both a territorial (sex-independent) and a courtship function. The comparison of responses to awake vs. anaesthetized intruders suggests that the latter are sufficient to elicit vocal activity. The subtle acoustic differences, however, indicate that the subject differentiates between intruder states. PMID- 22815942 TI - Selective attention increases choice certainty in human decision making. AB - Choice certainty is a probabilistic estimate of past performance and expected outcome. In perceptual decisions the degree of confidence correlates closely with choice accuracy and reaction times, suggesting an intimate relationship to objective performance. Here we show that spatial and feature-based attention increase human subjects' certainty more than accuracy in visual motion discrimination tasks. Our findings demonstrate for the first time a dissociation of choice accuracy and certainty with a significantly stronger influence of voluntary top-down attention on subjective performance measures than on objective performance. These results reveal a so far unknown mechanism of the selection process implemented by attention and suggest a unique biological valence of choice certainty beyond a faithful reflection of the decision process. PMID- 22815943 TI - Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI. AB - A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1alpha (SDF-1alpha) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd induced circulating EPCs or plasma SDF-1alpha. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI. PMID- 22815944 TI - Induction of Fas mediated caspase-8 independent apoptosis in immune cells by Armigeres subalbatus saliva. AB - BACKGROUND: It is widely recognized that the introduction of saliva of bloodsucking arthropods at the site of pathogen transmission might play a central role in vector-borne infections. However, how the interaction between salivary components and the host immune system takes place and which physiological processes this leads to has yet to be investigated. Armigeres subalbatus is one of the prominent types of mosquitoes involved in the transmission of parasitic and viral diseases in humans and animals. METHODOLOGY/PRINCIPAL FINDINGS: Using murine peritoneal macrophages and lymphocytes, and human peripheral mononuclear cells (PBMCs), this study shows that saliva of the female Ar. subalbatus induces apoptosis via interaction with the Fas receptor within a few hours but without activating caspase-8. The process further activates downstream p38 MAPK signaling, a cascade that leads to the induction of apoptosis in capase-3 dependent manner. We further illustrate that Ar. subalbatus saliva suppresses proinflammatory cytokines without changing IL-10 levels, which might happen as a result of apoptosis. CONCLUSIONS: Our study shows for the first time that saliva induced apoptosis is the leading phenomenon exerted by Ar.subalbatus that impede immune cells leading to the suppression of their effecter mechanism. PMID- 22815945 TI - Hydrogen sulfide inhibits the development of atherosclerosis with suppressing CX3CR1 and CX3CL1 expression. AB - Hydrogen sulfide, as a novel gaseous mediator, has been suggested to play a key role in atherogenesis. However, the precise mechanisms by which H(2)S affects atherosclerosis remain unclear. Therefore, the present study aimed to investigate the potential role of H(2)S in atherosclerosis and the underlying mechanism with respect to chemokines (CCL2, CCL5 and CX3CL1) and chemokine receptors (CCR2, CCR5, and CX3CR1) in macrophages. Mouse macrophage cell line RAW 264.7 or mouse peritoneal macrophages were pre-incubated with saline or NaHS (50 uM, 100 uM, 200 uM), an H(2)S donor, and then stimulated with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS). It was found that NaHS dose-dependently inhibited IFN gamma or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages. Overexpression of cystathionine gamma-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages. The inhibitory effect of H(2)S on CX3CR1 and CX3CL1 expression was mediated by modulation of proliferators-activated receptor-gamma (PPAR-gamma) and NF-kappaB pathway. Furthermore, male apoE(-/-) mice were fed a high-fat diet and then randomly given NaHS (1 mg/kg, i.p., daily) or DL-propargylglycine (PAG, 10 mg/kg, i.p., daily). NaHS significantly inhibited aortic CX3CR1 and CX3CL1 expression and impeded aortic plaque development. NaHS had a better anti atherogenic benefit when it was applied at the early stage of atherosclerosis. However, inhibition of H(2)S formation by PAG increased aortic CX3CR1 and CX3CL1 expression and exacerbated the extent of atherosclerosis. In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo. In conclusion, these data indicate that H(2)S hampers the progression of atherosclerosis in fat-fed apoE(-/-) mice and downregulates CX3CR1 and CX3CL1 expression on macrophages and in lesion plaques. PMID- 22815946 TI - Fractal dimension and vessel complexity in patients with cerebral arteriovenous malformations. AB - The fractal dimension (FD) can be used as a measure for morphological complexity in biological systems. The aim of this study was to test the usefulness of this quantitative parameter in the context of cerebral vascular complexity. Fractal analysis was applied on ten patients with cerebral arteriovenous malformations (AVM) and ten healthy controls. Maximum intensity projections from Time-of-Flight MRI scans were analyzed using different measurements of FD, the Box-counting dimension, the Minkowski dimension and generalized dimensions evaluated by means of multifractal analysis. The physiological significance of this parameter was investigated by comparing values of FD first, with the maximum slope of contrast media transit obtained from dynamic contrast-enhanced MRI data and second, with the nidus size obtained from X-ray angiography data. We found that for all methods, the Box-counting dimension, the Minkowski dimension and the generalized dimensions FD was significantly higher in the hemisphere with AVM compared to the hemisphere without AVM indicating that FD is a sensitive parameter to capture vascular complexity. Furthermore we found a high correlation between FD and the maximum slope of contrast media transit and between FD and the size of the central nidus pointing out the physiological relevance of FD. The proposed method may therefore serve as an additional objective parameter, which can be assessed automatically and might assist in the complex workup of AVMs. PMID- 22815947 TI - Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by the inheritance of one mutant copy of the huntingtin gene. Mutant huntingtin protein (mHtt) contains an expanded polyglutamine repeat region near the N-terminus. Cleavage of mHtt releases an N-terminal fragment (N-mHtt) which accumulates in the nucleus. Nuclear accumulation of N-mHtt has been directly associated with cellular toxicity. Decreased transcription is among the earliest detected changes that occur in the brains of HD patients, animal and cellular models of HD. Transcriptional dysregulation may trigger many of the perturbations that occur later in disease progression. An understanding of the effects of mHtt may lead to strategies to slow the progression of HD. Current models of N-mHtt-mediated transcriptional dysregulation suggest that abnormal interactions between N-mHtt and transcription factors impair the ability of these transcription factors to associate at N-mHtt-affected promoters and properly regulate gene expression. We tested various aspects of the current models using two N-mHtt-affected promoters in two cell models of HD using overexpression of known N-mHtt-interacting transcription factors, promoter deletion and mutation analyses and in vitro promoter binding assays. Consequently, we proposed a new model of N-mHtt-mediated transcriptional dysregulation centered on the presence of N-mHtt at promoters. In this model, N-mHtt interacts with multiple partners whose presence and affinity for N-mHtt influence the severity of gene dysregulation. We concluded that simultaneous interaction of N-mHtt with multiple binding partners within the transcriptional machinery would explain the gene-specificity of N-mHtt-mediated transcriptional dysregulation, as well as why some genes are affected early in disease progression while others are affected later. Our model explains why alleviating N-mHtt-mediated transcriptional dysregulation through overexpression of N-mHtt-interacting proteins has proven to be difficult and suggests that the most realistic strategy for restoring gene expression across the spectrum of N mHtt affected genes is by reducing the amount of soluble nuclear N-mHtt. PMID- 22815948 TI - Constitutive gene expression in monocytes from chronic HIV-1 infection overlaps with acute Toll-like receptor induced monocyte activation profiles. AB - Elevated TLR expression/signalling in monocyte/macrophages has been shown to mediate systemic immune activation, a hallmark of progressive HIV-1 infection. Here we show, via differential gene expression comparisons, the presence of a constitutive in vivo TLR-like gene activation signature in steady-state circulating monocytes from chronically HIV-1 infected subjects. The TLR2-like gene signature was defined as an 82 gene subset of the 376 genes constitutively modulated in in vivo HIV-1 monocytes, based on their overlap with de novo TLR2 induced genes in uninfected subjects' monocytes following acute ex vivo stimulation with Staphylococcus Aureus Cowan (SAC). Additional comparison of in vivo gene networks with available datasets from acute TLR activations in M/M expanded the overlap to 151-gene concordance among the 376 differential genes with emphasis on ERK/MAPK, TNF/IL6 (NFkappaB) and p53 gene networks. TLR2 stimulation of monocytes from HIV-1 infected subjects resulted in further upregulation of inflammatory genes indicative of a sustained transcriptional potential upon stimulation. In summary, our data support the presence of a sustained TLR-like gene activation profile in circulating monocyte from steady state viremia in HIV-1 infected subjects. PMID- 22815949 TI - Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpalpha+ dendritic cells: a murine model. AB - Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8alpha( )Sirpalpha(+) cDCs, but not the major subset, CD8alpha(+)Sirpalpha(-) cDCs can selectively capture blood-borne antigens and crucially contribute to the self tolerance. In the present study, we further demonstrated that Sirpalpha(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpalpha(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpalpha(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpalpha(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpalpha(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpalpha(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance. PMID- 22815950 TI - Were multiple stressors a 'perfect storm' for northern Gulf of Mexico bottlenose dolphins (Tursiops truncatus) in 2011? AB - An unusual number of near term and neonatal bottlenose dolphin (Tursiops truncatus) mortalities occurred in the northern Gulf of Mexico (nGOM) in 2011, during the first calving season after two well documented environmental perturbations; sustained cold weather in 2010 and the Deepwater Horizon oil spill (DWHOS). Preceding the stranding event, large volumes of cold freshwater entered the nGOM due to unusually large snowmelt on the adjacent watershed, providing a third potential stressor. We consider the possibility that this extreme cold and freshwater event contributed to the pattern of perinatal dolphin strandings along the nGOM coast. During the 4-month period starting January 2011, 186 bottlenose dolphins, including 46% perinatal calves (nearly double the percentage for the same time period from 2003-2010) washed ashore from Louisiana to western Florida. Comparison of the frequency distribution of strandings to flow rates and water temperature at a monitoring buoy outside Mobile Bay, Alabama (the 4(th) largest freshwater drainage in the U.S.) and along the nGOM coast showed that dolphin strandings peaked in Julian weeks 5, 8, and 12 (February and March), following water temperature minima by 2-3 weeks. If dolphin condition was already poor due to depleted food resources, bacterial infection, or other factors, it is plausible that the spring freshet contributed to the timing and location of the unique stranding event in early 2011. These data provide strong observational evidence to assess links between the timing of the DWHOS, other local environmental stressors, and mortality of a top local predator. Targeted analyses of tissues from stranded dolphins will be essential to define a cause of death, and our findings highlight the importance of considering environmental data along with biological samples to interpret stranding patterns during and after an unusual mortality event. PMID- 22815951 TI - Staphylococcus aureus isolates encode variant staphylococcal enterotoxin B proteins that are diverse in superantigenicity and lethality. AB - Staphylococcus aureus produces superantigens (SAgs) that bind and cross-link T cells and APCs, leading to activation and proliferation of immune cells. SAgs bind to variable regions of the beta-chains of T cell receptors (Vbeta-TCRs), and each SAg binds a unique subset of Vbeta-TCRs. This binding leads to massive cytokine production and can result in toxic shock syndrome (TSS). The most abundantly produced staphylococcal SAgs and the most common causes of staphylococcal TSS are TSS toxin-1 (TSST-1), and staphylococcal enterotoxins B and C (SEB and SEC, respectively). There are several characterized variants of humans SECs, designated SEC1-4, but only one variant of SEB has been described. Sequencing the seb genes from over 20 S. aureus isolates show there are at least five different alleles of seb, encoding forms of SEB with predicted amino acid substitutions outside of the predicted immune-cell binding regions of the SAgs. Examination of purified, variant SEBs indicates that these amino acid substitutions cause differences in proliferation of rabbit splenocytes in vitro. Additionally, the SEBs varied in lethality in a rabbit model of TSS. The SEBs were diverse in their abilities to cause proliferation of human peripheral blood mononuclear cells, and differed in their activation of subsets of T cells. A soluble, high-affinity Vbeta-TCR, designed to neutralize the previously characterized variant of SEB (SEB1), was able to neutralize the variant SEBs, indicating that this high-affinity peptide may be useful in treating a variety of SEB-mediated illnesses. PMID- 22815952 TI - Global analysis of the small RNA transcriptome in different ploidies and genomic combinations of a vertebrate complex--the Squalius alburnoides. AB - The Squalius alburnoides complex (Steindachner) is one of the most intricate hybrid polyploid systems known in vertebrates. In this complex, the constant switch of the genome composition in consecutive generations, very frequently involving a change on the ploidy level, promotes repetitive situations of potential genomic shock. Previously in this complex, it was showed that in response to the increase in genome dosage, triploids hybrids could regulate gene expression to a diploid state. In this work we compared the small RNA profiles in the different genomic compositions interacting in the complex in order to explore the miRNA involvement in gene expression regulation of triploids. Using high throughput arrays and sequencing technologies we were able to verify that diploid and triploid hybrids shared most of their sequences and their miRNA expression profiles were high correlated. However, an overall view indicates an up regulation of several miRNAs in triploids and a global miRNA expression in triploids higher than the predicted from an additive model. Those results point to a participation of miRNAs in the cellular functional stability needed when the ploidy change. PMID- 22815953 TI - The bitter truth about morality: virtue, not vice, makes a bland beverage taste nice. AB - To demonstrate that sensory and emotional states play an important role in moral processing, previous research has induced physical disgust in various sensory modalities (visual, tactile, gustatory, and olfactory modalities, among others) and measured its effects on moral judgment. To further assess the strength of the connection between embodied states and morality, we investigated whether the directionality of the effect could be reversed by exposing participants to different types of moral events prior to rating the same neutral tasting beverage. As expected, reading about moral transgressions, moral virtues, or control events resulted in inducing gustatory disgust, delight, or neutral taste experiences, respectively. Results are discussed in terms of the relation between embodied cognition and processing abstract conceptual representations. PMID- 22815954 TI - Daily scheduled high fat meals moderately entrain behavioral anticipatory activity, body temperature, and hypothalamic c-Fos activation. AB - When fed in restricted amounts, rodents show robust activity in the hours preceding expected meal delivery. This process, termed food anticipatory activity (FAA), is independent of the light-entrained clock, the suprachiasmatic nucleus, yet beyond this basic observation there is little agreement on the neuronal underpinnings of FAA. One complication in studying FAA using a calorie restriction model is that much of the brain is activated in response to this strong hunger signal. Thus, daily timed access to palatable meals in the presence of continuous access to standard chow has been employed as a model to study FAA in rats. In order to exploit the extensive genetic resources available in the murine system we extended this model to mice, which will anticipate rodent high fat diet but not chocolate or other sweet daily meals (Hsu, Patton, Mistlberger, and Steele; 2010, PLoS ONE e12903). In this study we test additional fatty meals, including peanut butter and cheese, both of which induced modest FAA. Measurement of core body temperature revealed a moderate preprandial increase in temperature in mice fed high fat diet but entrainment due to handling complicated interpretation of these results. Finally, we examined activation patterns of neurons by immunostaining for the immediate early gene c-Fos and observed a modest amount of entrainment of gene expression in the hypothalamus of mice fed a daily fatty palatable meal. PMID- 22815955 TI - FAST-SeqS: a simple and efficient method for the detection of aneuploidy by massively parallel sequencing. AB - Massively parallel sequencing of cell-free, maternal plasma DNA was recently demonstrated to be a safe and effective screening method for fetal chromosomal aneuploidies. Here, we report an improved sequencing method achieving significantly increased throughput and decreased cost by replacing laborious sequencing library preparation steps with PCR employing a single primer pair designed to amplify a discrete subset of repeated regions. Using this approach, samples containing as little as 4% trisomy 21 DNA could be readily distinguished from euploid samples. PMID- 22815956 TI - Amniotic fluid cathelicidin in PPROM pregnancies: from proteomic discovery to assessing its potential in inflammatory complications diagnosis. AB - BACKGROUND: Preterm prelabor rupture of membranes (PPROM) complicated by microbial invasion of the amniotic cavity (MIAC) leading to histological chorioamnionitis (HCA) significantly impacts perinatal morbidity. Unfortunately, no well-established tool for identifying PPROM patients threatened by these disorders is available. METHODOLOGY/PRINCIPAL FINDINGS: We performed an unbiased exploratory analysis of amniotic fluid proteome changes due to MIAC and HCA. From among the top five proteins that showed the most profound and significant change, we sought to confirm results concerning cathelicidin (P49913, CAMP_HUMAN), since an ELISA kit was readily available for this protein. In our exploratory proteomic study, cathelicidin showed a ~6-fold higher concentration in PPROM patients with confirmed MIAC and HCA. We verified significantly higher levels of cathelicidin in exploratory samples (women without both MIAC and HCA: median 1.4 ng/ml; women with both conditions confirmed: median 3.6 ng/ml; p = 0.0003). A prospective replication cohort was used for independent validation and for assessment of cathelicidin potential to stratify women with MIAC leading to HCA from women in whom at least one of these conditions was ruled out. We confirmed the association of higher amniotic fluid cathelicidin levels with MIAC leading to HCA (the presence of both MIAC and HCA: median 3.1 ng/ml; other women: median 1.4 ng/ml; p<0.0001). A cathelicidin concentration of 4.0 ng/ml was found to be the best cut off point for identifying PPROM women with both MIAC and HCA. When tested on the validation cohort, a sensitivity of 48%, a specificity of 90%, a likelihood ratio of 5.0, and an area under receiver-operating characteristic curve of 71% were achieved for identification of women with MIAC leading to HCA. CONCLUSIONS: Our multi-stage study suggests cathelicidin as a candidate marker that should be considered for a panel of amniotic fluid proteins permitting identification of PPROM women with MIAC leading to HCA. PMID- 22815957 TI - Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses. AB - An infection represents a highly dynamic process involving complex biological responses of the host at many levels. To describe such processes at a global level, we recorded gene expression changes in mouse lungs after a non-lethal infection with influenza A virus over a period of 60 days. Global analysis of the large data set identified distinct phases of the host response. The increase in interferon genes and up-regulation of a defined NK-specific gene set revealed the initiation of the early innate immune response phase. Subsequently, infiltration and activation of T and B cells could be observed by an augmentation of T and B cell specific signature gene expression. The changes in B cell gene expression and preceding chemokine subsets were associated with the formation of bronchus associated lymphoid tissue. In addition, we compared the gene expression profiles from wild type mice with Rag2 mutant mice. This analysis readily demonstrated that the deficiency in the T and B cell responses in Rag2 mutants could be detected by changes in the global gene expression patterns of the whole lung. In conclusion, our comprehensive gene expression study describes for the first time the entire host response and its kinetics to an acute influenza A infection at the transcriptome level. PMID- 22815958 TI - Central but not systemic administration of ghrelin induces wakefulness in mice. AB - Ghrelin is a brain-gut peptide hormone widely known for its orexigenic and growth hormone-releasing activities. Findings from our and other laboratories indicate a role of ghrelin in sleep regulation. The effects of exogenous ghrelin on sleep wake activity in mice are, however, unknown. The aim of the present study was to determine the sleep-modulating effects of ghrelin after central and systemic administrations in mice. Sleep-wake activity after intracerebroventricular (i.c.v.) administration of 0.2, 1 and 5 ug ghrelin and intraperitoneal injections of 40, 100, and 400 ug/kg ghrelin prior to light onset were determined in C57BL/6 mice. In addition, body temperature, motor activity and 1-hour food intake was measured after the systemic injections. Sleep effects of systemic ghrelin (40 and 400 ug/kg) injected before dark onset were also determined. I.c.v. injection of ghrelin increased wakefulness and suppressed non-rapid-eye-movement sleep and electroencephalographic slow-wave activity in the first hour after injections. Rapid-eye-movement sleep was decreased for 2-4 hours after each dose of ghrelin. Sytemic administration of ghrelin did not induce changes in sleep-wake activity in mice at dark or light onset. Motor activity and body temperature remained unaltered and food intake was significantly increased after systemic injections of ghrelin given prior the light period. These findings indicate that the activation of central, but not peripheral, ghrelin-sensitive mechanisms elicits arousal in mice. The results are consistent with the hypothesis that the activation of the hypothalamic neuronal circuit formed by ghrelin, orexin, and neuropeptide Y neurons triggers behavioral sequence characterized by increased wakefulness, motor activity and feeding in nocturnal rodents. PMID- 22815959 TI - Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI treatment. Here, we show that the proliferation of the gefitinib-resistant NSCLC cell lines H460 and A549 is reduced by the small molecule SecinH3 which indirectly attenuates EGFR activation by inhibition of cytohesins, a class of recently discovered cytoplasmic EGFR activators. SecinH3 and gefitinib showed a synergistic antiproliferative effect, which correlated with a profound inhibition of Akt activation and survivin expression. Treating mice bearing H460 xenografts with SecinH3 showed the antiproliferative and pro-apoptotic effect of SecinH3 in vivo. Our data suggest that targeting the EGFR indirectly by inhibiting its cytoplasmic activators, the cytohesins, has the potential to improve the treatment of primarily EGFR-TKI resistant lung cancers. PMID- 22815960 TI - Electrophysiological correlates of object location and object identity processing in spatial scenes. AB - The ability to quickly detect changes in our surroundings has been crucial to human adaption and survival. In everyday life we often need to identify whether an object is new and if an object has changed its location. In the current event related potential (ERP) study we investigated the electrophysiological correlates and the time course in detecting different types of changes of an objects location and identity. In a delayed match-to-sample task participants had to indicate whether two consecutive scenes containing a road, a house, and two objects, were either the same or different. In six randomly intermixed conditions the second scene was identical, one of the objects had changed its identity, one of the objects had changed its location, or the objects had switched locations. The results reveal different time courses for the processing of identity and location changes in spatial scenes. Whereas location changes elicited a posterior N2 effect, indicating early mismatch detection, followed by a P3 effect reflecting post-perceptual processing, identity changes elicited an anterior N3 effect, which was delayed and functionally distinct from the N2 effect found for the location changes. The condition in which two objects switched position elicited a late ERP effect, reflected by a P3 effect similar to that obtained for the location changes. In sum, this study is the first to cohesively show different time courses for the processing of location changes, identity changes, and object switches in spatial scenes, which manifest themselves in different electrophysiological correlates. PMID- 22815961 TI - The role of activity in synaptic degeneration in a protein misfolding disease, prion disease. AB - In chronic neurodegenerative diseases associated with aggregates of misfolded proteins (such as Alzheimer's, Parkinson's and prion disease), there is an early degeneration of presynaptic terminals prior to the loss of the neuronal somata. Identifying the mechanisms that govern synapse degeneration is of paramount importance, as cognitive decline is strongly correlated with loss of presynaptic terminals in these disorders. However, very little is known about the processes that link the presence of a misfolded protein to the degeneration of synapses. It has been suggested that the process follows a simple linear sequence in which terminals that become dysfunctional are targeted for death, but there is also evidence that high levels of activity can speed up degeneration. To dissect the role of activity in synapse degeneration, we infused the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of mice with prion disease and assessed synapse loss at the electron microscopy level. We found that injection of BoNT/A in naive mice caused a significant enlargement of excitatory presynaptic terminals in the hippocampus, indicating transmission impairment. Long-lasting blockade of activity by BoNT/A caused only minimal synaptic pathology and no significant activation of microglia. In mice with prion disease infused with BoNT/A, rates of synaptic degeneration were indistinguishable from those observed in control diseased mice. We conclude that silencing synaptic activity neither prevents nor enhances the degree of synapse degeneration in prion disease. These results challenge the idea that dysfunction of synaptic terminals dictates their elimination during prion-induced neurodegeneration. PMID- 22815962 TI - Stress-induced susceptibility to sudden cardiac death in mice with altered serotonin homeostasis. AB - In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT(1A) receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5 HT(1A) receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress. PMID- 22815963 TI - Activity-dependent subcellular cotrafficking of the small GTPase Rem2 and Ca2+/CaM-dependent protein kinase IIalpha. AB - BACKGROUND: Rem2 is a small monomeric GTP-binding protein of the RGK family, whose known functions are modulation of calcium channel currents and alterations of cytoskeletal architecture. Rem2 is the only RGK protein found predominantly in the brain, where it has been linked to synaptic development. We wished to determine the effect of neuronal activity on the subcellular distribution of Rem2 and its interacting partners. RESULTS: We show that Rem2 undergoes activity-and N Methyl-D-Aspartate Receptor (NMDAR)-dependent translocation in rat hippocampal neurons. This redistribution of Rem2, from a diffuse pattern to one that is highly punctate, is dependent on Ca(2+) influx, on binding to calmodulin (CaM), and also involves an auto-inhibitory domain within the Rem2 distal C-terminus region. We found that Rem2 can bind to Ca(2+)/CaM-dependent protein kinase IIalpha (CaMKII) a in Ca(2+)/CaM-dependent manner. Furthermore, our data reveal a spatial and temporal correlation between NMDAR-dependent clustering of Rem2 and CaMKII in neurons, indicating co-assembly and co-trafficking in neurons. Finally, we show that inhibiting CaMKII aggregation in neurons and HEK cells reduces Rem2 clustering, and that Rem2 affects the baseline distribution of CaMKII in HEK cells. CONCLUSIONS: Our data suggest a novel function for Rem2 in co-trafficking with CaMKII, and thus potentially expose a role in neuronal plasticity. PMID- 22815964 TI - Shifting preference between oviposition vs. host-feeding under changing host densities in two aphelinid parasitoids. AB - Destructive host-feeding is common in hymenopteran parasitoids. Such feeding may be restricted to host stages not preferred for oviposition. However, whether this is a fixed strategy or can vary according to resource levels or parasitoid needs is less clear. We tested the trade-off between host feeding and oviposition on two whitefly parasitoids under varying host densities. Females of two aphelinid parasitoids, Eretmocerus hayati and Encarsia sophia were exposed to nine different densities of their whitefly host, Bemisia tabaci, in single-instar tests to identify their functional response. Mixed-instar host choice tests were also conducted by exposing whiteflies at four densities to the parasitoids. We hypothesized that the parasitoid females can detect different host densities, and decide on oviposition vs. host-feeding accordingly. The results showed that both Er. hayati and En. sophia females tended to increase both oviposition and host feeding with increased host density within a certain range. Oviposition reached a plateau at lower host density than host-feeding in Er. hayati, while En. sophia reached its oviposition plateau at higher densities. At low densities, Er. hayati parasitized most on first and second (the optimal ones), and fed most on third nymphal instars (the suboptimal one) of the whitefly host as theory predicts, while at high densities, both parasitism and host-feeding occurred on first and second instars which are preferred for oviposition. En. sophia parasitized most on third and fourth (the optimal ones), while fed on first instars (the suboptimal one) at low densities, and utilized third and fourth instars for both at high densities. In conclusion, oviposition vs. host-feeding strategy of parasitoid females was found to vary at different host densities. The balance between reserving optimal hosts for oviposition or using them for host-feeding depended on parasitoid life history and the availability of host resources. PMID- 22815965 TI - Is Fitts' law continuous in discrete aiming? AB - The lawful continuous linear relation between movement time and task difficulty (i.e., index of difficulty; ID) in a goal-directed rapid aiming task (Fitts' law) has been recently challenged in reciprocal performance. Specifically, a discontinuity was observed at critical ID and was attributed to a transition between two distinct dynamic regimes that occurs with increasing difficulty. In the present paper, we show that such a discontinuity is also present in discrete aiming when ID is manipulated via target width (experiment 1) but not via target distance (experiment 2). Fitts' law's discontinuity appears, therefore, to be a suitable indicator of the underlying functional adaptations of the neuro-muscular skeletal system to task properties/requirements, independently of reciprocal or discrete nature of the task. These findings open new perspectives to the study of dynamic regimes involved in discrete aiming and sensori-motor mechanisms underlying the speed-accuracy trade-off. PMID- 22815966 TI - Skin and bones: the contribution of skin tone and facial structure to racial prototypicality ratings. AB - Previous research reveals that a more 'African' appearance has significant social consequences, yielding more negative first impressions and harsher criminal sentencing of Black or White individuals. This study is the first to systematically assess the relative contribution of skin tone and facial metrics to White, Black, and Korean perceivers' ratings of the racial prototypicality of faces from the same three groups. Our results revealed that the relative contribution of metrics and skin tone depended on both perceiver race and face race. White perceivers' racial prototypicality ratings were less responsive to variations in skin tone than were Black or Korean perceivers' ratings. White perceivers ratings' also were more responsive to facial metrics than to skin tone, while the reverse was true for Black perceivers. Additionally, across all perceiver groups, skin tone had a more consistent impact than metrics on racial prototypicality ratings of White faces, with the reverse for Korean faces. For Black faces, the relative impact varied with perceiver race: skin tone had a more consistent impact than metrics for Black and Korean perceivers, with the reverse for White perceivers. These results have significant implications for predicting who will experience racial prototypicality biases and from whom. PMID- 22815967 TI - Biologging, remotely-sensed oceanography and the continuous plankton recorder reveal the environmental determinants of a seabird wintering hotspot. AB - Marine environments are greatly affected by climate change, and understanding how this perturbation affects marine vertebrates is a major issue. In this context, it is essential to identify the environmental drivers of animal distribution. Here, we focused on the little auk (Alle alle), one of the world's most numerous seabirds and a major component in Arctic food webs. Using a multidisciplinary approach, we show how little auks adopt specific migratory strategies and balance environmental constraints to optimize their energy budgets. Miniature electronic loggers indicate that after breeding, birds from East Greenland migrate >2000 km to overwinter in a restricted area off Newfoundland. Synoptic data available from the Continuous Plankton Recorder (CPR) indicate that this region harbours some of the highest densities of the copepod Calanus finmarchicus found in the North Atlantic during winter. Examination of large-scale climatic and oceanographic data suggests that little auks favour patches of high copepod abundance in areas where air temperature ranges from 0 degrees C to 5 degrees C. These results greatly advance our understanding of animal responses to extreme environmental constraints, and highlight that information on habitat preference is key to identifying critical areas for marine conservation. PMID- 22815968 TI - Migration routes and strategies in a highly aerial migrant, the common swift Apus apus, revealed by light-level geolocators. AB - The tracking of small avian migrants has only recently become possible by the use of small light-level geolocators, allowing the reconstruction of whole migration routes, as well as timing and speed of migration and identification of wintering areas. Such information is crucial for evaluating theories about migration strategies and pinpointing critical areas for migrants of potential conservation value. Here we report data about migration in the common swift, a highly aerial and long-distance migrating species for which only limited information based on ringing recoveries about migration routes and wintering areas is available. Six individuals were successfully tracked throughout a complete migration cycle from Sweden to Africa and back. The autumn migration followed a similar route in all individuals, with an initial southward movement through Europe followed by a more southwest-bound course through Western Sahara to Sub-Saharan stopovers, before a south-eastward approach to the final wintering areas in the Congo basin. After approximately six months at wintering sites, which shifted in three of the individuals, spring migration commenced in late April towards a restricted stopover area in West Africa in all but one individual that migrated directly towards north from the wintering area. The first part of spring migration involved a crossing of the Gulf of Guinea in those individuals that visited West Africa. Spring migration was generally wind assisted within Africa, while through Europe variable or head winds were encountered. The average detour at about 50% could be explained by the existence of key feeding sites and wind patterns. The common swift adopts a mixed fly-and-forage strategy, facilitated by its favourable aerodynamic design allowing for efficient use of fuel. This strategy allowed swifts to reach average migration speeds well above 300 km/day in spring, which is higher than possible for similar sized passerines. This study demonstrates that new technology may drastically change our views about migration routes and strategies in small birds, as well as showing the unexpected use of very limited geographical areas during migration that may have important consequences for conservation strategies for migrants. PMID- 22815969 TI - To beg, or not to beg? That is the question: mangabeys modify their production of requesting gestures in response to human's attentional states. AB - BACKGROUND: Although gestural communication is widespread in primates, few studies focused on the cognitive processes underlying gestures produced by monkeys. METHODOLOGY/PRINCIPAL FINDINGS: The present study asked whether red capped mangabeys (Cercocebus torquatus) trained to produce visually based requesting gestures modify their gestural behavior in response to human's attentional states. The experimenter held a food item and displayed five different attentional states that differed on the basis of body, head and gaze orientation; mangabeys had to request food by extending an arm toward the food item (begging gesture). Mangabeys were sensitive, at least to some extent, to the human's attentional state. They reacted to some postural cues of a human recipient: they gestured more and faster when both the body and the head of the experimenter were oriented toward them than when they were oriented away. However, they did not seem to use gaze cues to recognize an attentive human: monkeys begged at similar levels regardless of the experimenter's eyes state. CONCLUSIONS/SIGNIFICANCE: These results indicate that mangabeys lowered their production of begging gestures when these could not be perceived by the human who had to respond to it. This finding provides important evidence that acquired begging gestures of monkeys might be used intentionally. PMID- 22815970 TI - Home-based aerobic interval training improves peak oxygen uptake equal to residential cardiac rehabilitation: a randomized, controlled trial. AB - Aerobic capacity, measured as the peak oxygen uptake, is a strong predictor of survival in cardiac patients. Aerobic interval training (AIT), walking/running four times four minutes at 85-95% of peak heart rate, has proven to be effective in increasing peak oxygen uptake in coronary heart disease patients. As some patients do not attend organized rehabilitation programs, home-based exercise should be an alternative. We investigated whether AIT could be performed effectively at home, and compared the effects on peak oxygen uptake with that observed after a standard care, four-week residential rehabilitation. Thirty patients undergoing coronary artery bypass surgery were randomized to residential rehabilitation or home-based AIT. At six months follow-up, peak oxygen uptake increased 4.6 (+/-2.7) and 3.9 (+/-3.6) mL.kg(-1) min(-1) (both p<0.005, non significant between-group difference) after residential rehabilitation and AIT, respectively. Quality of life increased significantly in both groups, with no statistical significant difference between groups. We found no evidence for a different treatment effect between patients randomized to home-based AIT compared to patients attending organized rehabilitation (95% confidence interval -1.8, 3.5). AIT patients reported good adherence to exercise training. Even though these first data indicate positive effects of home-based AIT in patients undergoing coronary artery bypass surgery, more studies are needed to provide supporting evidence for the application of this rehabilitation strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00363922. PMID- 22815971 TI - Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population. AB - BACKGROUND: It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer. METHODOLOGY AND PRINCIPAL FINDINGS: Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage. CONCLUSIONS AND SIGNIFICANCE: Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results. PMID- 22815972 TI - Assessment of strain-specific PrP(Sc) elongation rates revealed a transformation of PrP(Sc) properties during protein misfolding cyclic amplification. AB - Prion replication is believed to consist of two components, a growth or elongation of infectious isoform of the prion protein (PrP(Sc)) particles and their fragmentation, a process that provides new replication centers. The current study introduced an experimental approach that employs Protein Misfolding Cyclic Amplification with beads (PMCAb) and relies on a series of kinetic experiments for assessing elongation rates of PrP(Sc) particles. Four prion strains including two strains with short incubation times to disease (263K and Hyper) and two strains with very long incubation times (SSLOW and LOTSS) were tested. The elongation rate of brain-derived PrP(Sc) was found to be strain-specific. Strains with short incubation times had higher rates than strains with long incubation times. Surprisingly, the strain-specific elongation rates increased substantially for all four strains after they were subjected to six rounds of serial PMCAb. In parallel to an increase in elongation rates, the percentages of diglycosylated PrP glycoforms increased in PMCAb-derived PrP(Sc) comparing to those of brain derived PrP(Sc). These results suggest that PMCAb selects the same molecular features regardless of strain initial characteristics and that convergent evolution of PrP(Sc) properties occurred during in vitro amplification. These results are consistent with the hypothesis that each prion strain is comprised of a variety of conformers or 'quasi-species' and that change in the prion replication environment gives selective advantage to those conformers that replicate most effectively under specific environment. PMID- 22815973 TI - An international reference consensus genetic map with 897 marker loci based on 11 mapping populations for tetraploid groundnut (Arachis hypogaea L.). AB - Only a few genetic maps based on recombinant inbred line (RIL) and backcross (BC) populations have been developed for tetraploid groundnut. The marker density, however, is not very satisfactory especially in the context of large genome size (2800 Mb/1C) and 20 linkage groups (LGs). Therefore, using marker segregation data for 10 RILs and one BC population from the international groundnut community, with the help of common markers across different populations, a reference consensus genetic map has been developed. This map is comprised of 897 marker loci including 895 simple sequence repeat (SSR) and 2 cleaved amplified polymorphic sequence (CAPS) loci distributed on 20 LGs (a01-a10 and b01-b10) spanning a map distance of 3, 863.6 cM with an average map density of 4.4 cM. The highest numbers of markers (70) were integrated on a01 and the least number of markers (21) on b09. The marker density, however, was lowest (6.4 cM) on a08 and highest (2.5 cM) on a01. The reference consensus map has been divided into 20 cM long 203 BINs. These BINs carry 1 (a10_02, a10_08 and a10_09) to 20 (a10_04) loci with an average of 4 marker loci per BIN. Although the polymorphism information content (PIC) value was available for 526 markers in 190 BINs, 36 and 111 BINs have at least one marker with >0.70 and >0.50 PIC values, respectively. This information will be useful for selecting highly informative and uniformly distributed markers for developing new genetic maps, background selection and diversity analysis. Most importantly, this reference consensus map will serve as a reliable reference for aligning new genetic and physical maps, performing QTL analysis in a multi-populations design, evaluating the genetic background effect on QTL expression, and serving other genetic and molecular breeding activities in groundnut. PMID- 22815974 TI - Neuronal mechanisms of voice control are affected by implicit expectancy of externally triggered perturbations in auditory feedback. AB - Accurate vocal production relies on several factors including sensory feedback and the ability to predict future challenges to the control processes. Repetitive patterns of perturbations in sensory feedback by themselves elicit implicit expectations in the vocal control system regarding the timing, quality and direction of perturbations. In the present study, the predictability of voice pitch-shifted auditory feedback was experimentally manipulated. A block of trials where all pitch-shift stimuli were upward, and therefore predictable was contrasted against an unpredictable block of trials in which the stimulus direction was randomized between upward and downward pitch-shifts. It was found that predictable perturbations in voice auditory feedback led to a reduction in the proportion of compensatory vocal responses, which might be indicative of a reduction in vocal control. The predictable perturbations also led to a reduction in the magnitude of the N1 component of cortical Event Related Potentials (ERP) that was associated with the reflexive compensations to the perturbations. We hypothesize that formation of expectancy in our study is accompanied by involuntary allocation of attentional resources occurring as a result of habituation or learning, that in turn trigger limited and controlled exploration related motor variability in the vocal control system. PMID- 22815975 TI - Limited fitness advantages of crop-weed hybrid progeny containing insect resistant transgenes (Bt/CpTI) in transgenic rice field. AB - BACKGROUND: The spread of insect-resistance transgenes from genetically engineered (GE) rice to its coexisting weedy rice (O. sativa f. spontanea) populations via gene flow creates a major concern for commercial GE rice cultivation. Transgene flow to weedy rice seems unavoidable. Therefore, characterization of potential fitness effect brought by the transgenes is essential to assess environmental consequences caused by crop-weed transgene flow. METHODOLOGY/PRINCIPAL FINDINGS: Field performance of fitness-related traits was assessed in advanced hybrid progeny of F(4) generation derived from a cross between an insect-resistant transgenic (Bt/CpTI) rice line and a weedy strain. The performance of transgene-positive hybrid progeny was compared with the transgene-negative progeny and weedy parent in pure and mixed planting of transgenic and nontransgenic plants under environmental conditions with natural vs. low insect pressure. Results showed that under natural insect pressure the insect-resistant transgenes could effectively suppress target insects and bring significantly increased fitness to transgenic plants in pure planting, compared with nontransgenic plants (including weedy parent). In contrast, no significant differences in fitness were detected under low insect pressure. However, such increase in fitness was not detected in the mixed planting of transgenic and nontransgenic plants due to significantly reduced insect pressure. CONCLUSIONS/SIGNIFICANCE: Insect-resistance transgenes may have limited fitness advantages to hybrid progeny resulted from crop-weed transgene flow owning to the significantly reduced ambient target insect pressure when an insect-resistant GE crop is grown. Given that the extensive cultivation of an insect-resistant GE crop will ultimately reduce the target insect pressure, the rapid spread of insect-resistance transgenes in weedy populations in commercial GE crop fields may be not likely to happen. PMID- 22815976 TI - Human albumin prevents 6-hydroxydopamine-induced loss of tyrosine hydroxylase in in vitro and in vivo. AB - Human albumin has recently been demonstrated to protect brain neurons from injury in rat ischemic brain. However, there is no information available about whether human albumin can prevent loss of tyrosine hydroxylase (TH) expression of dopaminergic (DA) neurons induced by 6-hydroxydopamine (6-OHDA) toxicity that is most commonly used to create a rat model of Parkinson's disease (PD). In the present study, two microliters of 1.25% human albumin were stereotaxically injected into the right striatum of rats one day before or 7 days after the 6 OHDA lesion in the same side. D-Amphetamine-induced rotational asymmetry was measured 7 days, 3 and 10 weeks after 6-OHDA lesion. We observed that intrastriatal administration of human albumin significantly reduced the degree of rotational asymmetry. The number of TH-immunoreactive neurons present in the substantia nigra was greater in 6-OHDA lesioned rats following human albumin treatment than non-human albumin treatment. TH-immunoreactivity in the 6-OHDA lesioned striatum was also significantly increased in the human albumin-treated rats. To examine the mechanisms underlying the effects of human albumin, we challenged PC12 cells with 6-OHDA as an in vitro model of PD. Incubation with human albumin prevented 6-OHDA-induced reduction of cell viability in PC12 cell cultures, as measured by MTT assay. Furthermore, human albumin reduced 6-OHDA induced formation of reactive oxygen species (ROS) and apoptosis in cultured PC12 cells, as assessed by flow cytometry. Western blot analysis showed that human albumin inhibited 6-OHDA-induced activation of JNK, c-Jun, ERK, and p38 mitogen activated protein kinases (MAPK) signaling in PC12 cultures challenged with 6 OHDA. Human albumin may protect against 6-OHDA toxicity by influencing MAPK pathway followed by anti-ROS formation and anti-apoptosis. PMID- 22815977 TI - Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7-/- mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin 1beta (IL-1beta) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1beta expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation. PMID- 22815978 TI - Systemic effects of ingested Lactobacillus rhamnosus: inhibition of mast cell membrane potassium (IKCa) current and degranulation. AB - Exposure of the intestine to certain strains lactobacillus can have systemic immune effects that include the attenuation of allergic responses. Despite the central role of mast cells in allergic disease little is known about the effect of lactobacilli on the function of these cells. To address this we assessed changes in rat mast cell activation following oral treatment with a strain of Lactobacillus known to attenuate allergic responses in animal models. Sprague Dawley rats were fed with L. rhamnosus JB-1 (1*10(9)) or vehicle control for 9 days. Mediator release from peritoneal mast cells (RPMC) was determined in response to a range of stimuli. Passive cutaneous anaphylaxis (PCA) was used to assess mast cell responses in vivo. The Ca(2+) activated K(+) channel (KCa3.1) current, identified as critical to mast cell degranulation, was monitored by whole cell patch-clamp. L. rhamnosus JB-1 treatment lead to significant inhibition of mast cell mediator release in response to a range of stimuli including IgE mediated activation. Furthermore, the PCA response was significantly reduced in treated rats. Patch-clamp studies revealed that RPMC from treated animals were much less responsive to the KCa3.1 opener, DCEBIO. These studies demonstrate that Ingestion of L. rhamnosus JB-1 leads to mast cell stabilization in rats and identify KCa3.1 as an immunomodulatory target for certain lactobacilli. Thus the systemic effects of certain candidate probiotics may include mast cell stabilization and such actions could contribute to the beneficial effect of these organisms in allergic and other inflammatory disorders. PMID- 22815979 TI - Simulating the cortical 3D visuomotor transformation of reach depth. AB - We effortlessly perform reach movements to objects in different directions and depths. However, how networks of cortical neurons compute reach depth from binocular visual inputs remains largely unknown. To bridge the gap between behavior and neurophysiology, we trained a feed-forward artificial neural network to uncover potential mechanisms that might underlie the 3D transformation of reach depth. Our physiologically-inspired 4-layer network receives distributed 3D visual inputs (1(st) layer) along with eye, head and vergence signals. The desired motor plan was coded in a population (3(rd) layer) that we read out (4(th) layer) using an optimal linear estimator. After training, our network was able to reproduce all known single-unit recording evidence on depth coding in the parietal cortex. Network analyses predict the presence of eye/head and vergence changes of depth tuning, pointing towards a gain-modulation mechanism of depth transformation. In addition, reach depth was computed directly from eye-centered (relative) visual distances, without explicit absolute depth coding. We suggest that these effects should be observable in parietal and pre-motor areas. PMID- 22815980 TI - A pseudo-tRNA modulates antibiotic resistance in Bacillus cereus. AB - Bacterial genomic islands are often flanked by tRNA genes, which act as sites for the integration of foreign DNA into the host chromosome. For example, Bacillus cereus ATCC14579 contains a pathogenicity island flanked by a predicted pseudo tRNA, tRNA(Other), which does not function in translation. Deletion of tRNA(Other) led to significant changes in cell wall morphology and antibiotic resistance and was accompanied by changes in the expression of numerous genes involved in oxidative stress responses, several of which contain significant complementarities to sequences surrounding tRNA(Other). This suggested that tRNA(Other) might be expressed as part of a larger RNA, and RACE analysis subsequently confirmed the existence of several RNA species that significantly extend both the 3' and 5'-ends of tRNA(Other). tRNA(Other) expression levels were found to be responsive to changes in extracellular iron concentration, consistent with the presence of three putative ferric uptake regulator (Fur) binding sites in the 5' leader region of one of these larger RNAs. Taken together with previous data, this study now suggests that tRNA(Other) may function by providing a tRNA like structural element within a larger regulatory RNA. These findings illustrate that while integration of genomic islands often leaves tRNA genes intact and functional, in other instances inactivation may generate tRNA-like elements that are then recruited to other functions in the cell. PMID- 22815982 TI - On the blink: the importance of target-distractor similarity in eliciting an attentional blink with faces. AB - Temporal allocation of attention is often investigated with a paradigm in which two relevant target items are presented in a rapid sequence of irrelevant distractors. The term Attentional Blink (AB) denotes a transient impairment of awareness for the second of these two target items when presented close in time. Experimental studies reported that the AB is reduced when the second target is emotionally significant, suggesting a modulation of attention allocation. The aim of the present study was to systematically investigate the influence of target distractor similarity on AB magnitude for faces with emotional expressions under conditions of limited attention in a series of six rapid serial visual presentation experiments. The task on the first target was either to discriminate the gender of a neutral face (Experiments 1, 3-6) or an indoor/outdoor visual scene (Experiment 2). The task on the second target required either the detection of emotional expressions (Experiments 1-5) or the detection of a face (Experiment 6). The AB was minimal or absent when targets could be easily discriminated from each other. Three successive experiments revealed that insufficient masking and target-distractor similarity could account for the observed immunity of faces against the AB in the first two experiments. An AB was present but not increased when the facial expression was irrelevant to the task suggesting that target distractor similarity plays a more important role in eliciting an AB than the attentional set demanded by the specific task. In line with previous work, emotional faces were less affected by the AB. PMID- 22815981 TI - Ancient migratory events in the Middle East: new clues from the Y-chromosome variation of modern Iranians. AB - Knowledge of high resolution Y-chromosome haplogroup diversification within Iran provides important geographic context regarding the spread and compartmentalization of male lineages in the Middle East and southwestern Asia. At present, the Iranian population is characterized by an extraordinary mix of different ethnic groups speaking a variety of Indo-Iranian, Semitic and Turkic languages. Despite these features, only few studies have investigated the multiethnic components of the Iranian gene pool. In this survey 938 Iranian male DNAs belonging to 15 ethnic groups from 14 Iranian provinces were analyzed for 84 Y-chromosome biallelic markers and 10 STRs. The results show an autochthonous but non-homogeneous ancient background mainly composed by J2a sub-clades with different external contributions. The phylogeography of the main haplogroups allowed identifying post-glacial and Neolithic expansions toward western Eurasia but also recent movements towards the Iranian region from western Eurasia (R1b L23), Central Asia (Q-M25), Asia Minor (J2a-M92) and southern Mesopotamia (J1 Page08). In spite of the presence of important geographic barriers (Zagros and Alborz mountain ranges, and the Dasht-e Kavir and Dash-e Lut deserts) which may have limited gene flow, AMOVA analysis revealed that language, in addition to geography, has played an important role in shaping the nowadays Iranian gene pool. Overall, this study provides a portrait of the Y-chromosomal variation in Iran, useful for depicting a more comprehensive history of the peoples of this area as well as for reconstructing ancient migration routes. In addition, our results evidence the important role of the Iranian plateau as source and recipient of gene flow between culturally and genetically distinct populations. PMID- 22815983 TI - The molecular effects of a polymorphism in the 5'UTR of solute carrier family 44, member 5 that is associated with birth weight in Holsteins. AB - Dystocia is a major problem for the dairy cattle industry, and the observed high rates of this condition stem from genetic selection to increase subsequent milk production of the calving female. Because smaller birth size does not adversely affect subsequent milk production, selecting for cows with a smaller birth size would reduce dystocia rates and be beneficial for both the cattle and the farmers. To identify genes that regulate birth weight, we conducted a genome-wide association study using 1151 microsatellite markers and identified a single nucleotide polymorphism (SNP) associated with birth weight: A-326G in the 5' untranslated region (UTR) of solute carrier family 44, member 5 (SLC44A5). Cows with higher birth weights carried the A polymorphism in the SLC44A5 5' UTR, and the presence of the A polymorphism correlated with a high rate of dystocia. Luciferase assays and quantitative polymerase chain reaction (QPCR) assays revealed that SLC44A5 transcripts with the A polymorphism are expressed at lower levels than those carrying the G polymorphism. SLC44A5 encodes a choline transporter-like protein, and choline is a component of the major phospholipids of cell membranes. Uptake studies in HeLa cells demonstrated that SLC44A5 knockdown reduces choline efflux, whereas SLC44A5 overexpression resulted in the opposite effect. Furthermore, cell viability assays indicated that SLC44A5 knockdown increased cell proliferation, whereas SLC44A5 overexpression repressed proliferation. Taken together, our results suggest that calves with reduced SLC44A5 expression are larger due to enhanced cell proliferation. This study provides novel insights into the molecular mechanisms that control birth weight in Holsteins and suggests that SLC44A5 may serve as a potential target for preventing dystocia. PMID- 22815984 TI - No difference in keratin thickness between inner and outer foreskins from elective male circumcisions in Rakai, Uganda. AB - It has been hypothesized that increased HIV acquisition in uncircumcised men may relate to a more thinly keratinized inner foreskin. However, published data are contradictory and potentially confounded by medical indications for circumcision. We tested the hypothesis that the inner foreskin was more thinly keratinized than the outer foreskin using tissues from 19 healthy, HIV-uninfected men undergoing routine prophylactic circumcision in Rakai, Uganda. Sections from 3 foreskin anatomic sites (inner, outer, and frenar band) were snap-frozen separately. Two independent laboratories each separately stained, imaged, and measured keratin thicknesses in a blinded fashion. There was no significant difference in keratin thickness between the inner (mean = 14.67+/-7.48 um) and outer (mean = 13.30+/ 8.49 um) foreskin, or between the inner foreskin and the frenar band (mean = 16.91+/-12.42 um). While the frenar band showed the greatest intra-individual heterogeneity in keratin thickness, there was substantial inter-individual variation seen in all regions. Measurements made by the two laboratories showed high correlation (r = 0.741, 95% CI, 0.533-0.864). We conclude that, despite inter- and intra-individual variability, keratin thickness was similar in the inner and outer foreskin of healthy Ugandan men, and that reduced keratin thickness is not likely to make the inner foreskin more susceptible to HIV acquisition. PMID- 22815985 TI - The dynamic changes of DNA methylation and histone modifications of salt responsive transcription factor genes in soybean. AB - Epigenetic modification contributes to the regulation of gene expression and plant development under salinity stress. Here we describe the identification of 49 soybean transcription factors by microarray analysis as being inducible by salinity stress. A semi-quantitative RT-PCR-based expression assay confirmed the salinity stress inducibility of 45 of these 49 transcription factors, and showed that ten of them were up-regulated when seedlings were exposed to the demethylation agent 5-aza-2-deoxycytidine. Salinity stress was shown to affect the methylation status of four of these ten transcription factors (one MYB, one b ZIP and two AP2/DREB family members) using a combination of bisulfite sequencing and DNA methylation-sensitive DNA gel blot analysis. ChIP analysis indicated that the activation of three of the four DNA methylated transcription factors was correlated with an increased level of histone H3K4 trimethylation and H3K9 acetylation, and/or a reduced level of H3K9 demethylation in various parts of the promoter or coding regions. Our results suggest a critical role for some transcription factors' activation/repression by DNA methylation and/or histone modifications in soybean tolerance to salinity stress. PMID- 22815986 TI - Retro-nasal aroma release is correlated with variations in the in-mouth air cavity volume after empty deglutition. AB - We hypothesized that interindividual differences in motor activities during chewing and/or swallowing were determining factors for the transfer of volatile aroma from the in-mouth air cavity (IMAC) toward the olfactory mucosa. In our first experiment, we looked for changes in IMAC volume after saliva deglutition in 12 healthy subjects. The mean IMAC volume was measured after empty deglutition using an acoustic pharyngometer device. Based on the time course of the IMAC volume after swallowing, we discerned two groups of subjects. The first group displayed a small, constant IMAC volume (2.26 mL +/-0.62) that corresponded to a high tongue position. The second group displayed a progressive increase in IMAC (from 6.82 mL +/-2.37 to 22.82 mL +/-3.04) that corresponded to a progressive lowering of the tongue to its resting position. In our second experiment, we investigated the relationship between IMAC volume changes after deglutition and the level of aroma release at the nostril. For this purpose, the release of menthone was measured at the nostril level in 25 subjects who consumed similar amounts of a mint tablet. The subjects were separated into two groups corresponding to two levels of menthone release: high (H) and low (L). The mean volume of IMAC was measured during and after empty deglutition. Group H displayed a small, constant amplitude of IMAC volume change after deglutition, while Group L displayed a progressive increase in IMAC. It is likely that Group H continuously released the aroma through the veloglossal isthmus as the mint was consumed, while Group L trapped the aroma in the oral cavity and then released it into the nasal cavity upon swallowing. These results show that the in vivo aroma release profile in humans depends closely on the different motor patterns at work during empty deglutition. PMID- 22815987 TI - Prostate specific membrane antigen (PSMA) regulates angiogenesis independently of VEGF during ocular neovascularization. AB - BACKGROUND: Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF). While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA) is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies. METHODOLOGY/PRINCIPAL FINDINGS: Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature. CONCLUSIONS/SIGNIFICANCE: Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may represent a novel therapeutic strategy for treatment of angiogenesis-based ocular diseases. PMID- 22815988 TI - MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor. AB - Constitutive androstane receptor (CAR) is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK)-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4 carboxamide 1-beta-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes. PMID- 22815989 TI - Randomized Polypill crossover trial in people aged 50 and over. AB - BACKGROUND: A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone. Its efficacy in reducing cholesterol and blood pressure is uncertain. METHODS: We conducted a randomized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50+ without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs. Participants took the Polypill (amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg and simvastatin 40 mg) each evening for 12 weeks and a placebo each evening for 12 weeks in random sequence. The mean within-person differences in blood pressure and low density lipoprotein (LDL) cholesterol at the end of each 12 week period were determined. RESULTS: 84 out of 86 participants completed both treatment periods. The mean systolic blood pressure was reduced by 17.9 mmHg (95% CI, 15.7-20.1) on the Polypill, diastolic blood pressure by 9.8 mmHg (8.1-11.5), and LDL cholesterol by 1.4 mmol/L (1.2 1.6), reductions of 12%, 11%, and 39% respectively. The results were almost identical to those predicted; 18.4 mmHg, 9.7 mmHg, and 1.4 mmol/L respectively. CONCLUSION: The Polypill resulted in the predicted reductions in blood pressure and LDL cholesterol. Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN36672232. PMID- 22815990 TI - Microbial community analysis of a coastal salt marsh affected by the Deepwater Horizon oil spill. AB - Coastal salt marshes are highly sensitive wetland ecosystems that can sustain long-term impacts from anthropogenic events such as oil spills. In this study, we examined the microbial communities of a Gulf of Mexico coastal salt marsh during and after the influx of petroleum hydrocarbons following the Deepwater Horizon oil spill. Total hydrocarbon concentrations in salt marsh sediments were highest in June and July 2010 and decreased in September 2010. Coupled PhyloChip and GeoChip microarray analyses demonstrated that the microbial community structure and function of the extant salt marsh hydrocarbon-degrading microbial populations changed significantly during the study. The relative richness and abundance of phyla containing previously described hydrocarbon-degrading bacteria (Proteobacteria, Bacteroidetes, and Actinobacteria) increased in hydrocarbon contaminated sediments and then decreased once hydrocarbons were below detection. Firmicutes, however, continued to increase in relative richness and abundance after hydrocarbon concentrations were below detection. Functional genes involved in hydrocarbon degradation were enriched in hydrocarbon-contaminated sediments then declined significantly (p<0.05) once hydrocarbon concentrations decreased. A greater decrease in hydrocarbon concentrations among marsh grass sediments compared to inlet sediments (lacking marsh grass) suggests that the marsh rhizosphere microbial communities could also be contributing to hydrocarbon degradation. The results of this study provide a comprehensive view of microbial community structural and functional dynamics within perturbed salt marsh ecosystems. PMID- 22815991 TI - Resource use and costs associated with coeliac disease before and after diagnosis in 3,646 cases: results of a UK primary care database analysis. AB - BACKGROUND: Despite the considerable health impact of coeliac disease (CD), reliable estimates of the impact of diagnosis on health care use and costs are lacking. AIMS: To quantify the volume, type and costs, in a United Kingdom primary care setting, of healthcare resources used by individuals diagnosed with CD up to ten years before and after diagnosis, and to estimate medical costs associated with CD. METHODS: A cohort of 3,646 CD cases and a parallel cohort of 32,973 matched controls, extracted from the General Practice Research Database (GPRD) over the period 1987-2005 were used i) to evaluate the impact of diagnosis on the average resource use and costs of cases; ii) to assess direct healthcare costs due to CD by comparing average resource use and costs incurred by cases vs. controls. RESULTS: Average annual healthcare costs per patient increased by L310 (95% CI L299, L320) after diagnosis. CD cases experienced higher healthcare costs than controls both before diagnosis (mean difference L91; 95% CI: L86, L97) and after diagnosis (mean difference L354; 95% CI: L347, L361). These differences were driven mainly by higher test and referral costs before diagnosis, and by increased prescription costs after diagnosis. CONCLUSIONS: This study shows significant additional primary care costs associated with coeliac disease. It provides novel evidence that will assist researchers evaluating interventions in this area, and will challenge policymakers, clinicians, researchers and the public to develop strategies that maximise the health benefits of the resources associated with this disease. PMID- 22815992 TI - An infinitesimal model for quantitative trait genomic value prediction. AB - We developed a marker based infinitesimal model for quantitative trait analysis. In contrast to the classical infinitesimal model, we now have new information about the segregation of every individual locus of the entire genome. Under this new model, we propose that the genetic effect of an individual locus is a function of the genome location (a continuous quantity). The overall genetic value of an individual is the weighted integral of the genetic effect function along the genome. Numerical integration is performed to find the integral, which requires partitioning the entire genome into a finite number of bins. Each bin may contain many markers. The integral is approximated by the weighted sum of all the bin effects. We now turn the problem of marker analysis into bin analysis so that the model dimension has decreased from a virtual infinity to a finite number of bins. This new approach can efficiently handle virtually unlimited number of markers without marker selection. The marker based infinitesimal model requires high linkage disequilibrium of all markers within a bin. For populations with low or no linkage disequilibrium, we develop an adaptive infinitesimal model. Both the original and the adaptive models are tested using simulated data as well as beef cattle data. The simulated data analysis shows that there is always an optimal number of bins at which the predictability of the bin model is much greater than the original marker analysis. Result of the beef cattle data analysis indicates that the bin model can increase the predictability from 10% (multiple marker analysis) to 33% (multiple bin analysis). The marker based infinitesimal model paves a way towards the solution of genetic mapping and genomic selection using the whole genome sequence data. PMID- 22815993 TI - BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. AB - BACKGROUND: K-RAS mutation poses a particularly difficult problem for cancer therapy. Activating mutations in K-RAS are common in cancers of the lung, pancreas, and colon and are associated with poor response to therapy. As such, targeted therapies that abrogate K-RAS-induced oncogenicity would be of tremendous value. METHODS: We searched for small molecule kinase inhibitors that preferentially affect the growth of colorectal cancer cells expressing mutant K RAS. The mechanism of action of one inhibitor was explored using chemical and genetic approaches. RESULTS: We identified BAY61-3606 as an inhibitor of proliferation in colorectal cancer cells expressing mutant forms of K-RAS, but not in isogenic cells expressing wild-type K-RAS. In addition to its anti proliferative effects in mutant cells, BAY61-3606 exhibited a distinct biological property in wild-type cells in that it conferred sensitivity to inhibition of RAF. In this context, BAY61-3606 acted by inhibiting MAP4K2 (GCK), which normally activates NFkappabeta signaling in wild-type cells in response to inhibition of RAF. As a result of MAP4K2 inhibition, wild-type cells became sensitive to AZ 628, a RAF inhibitor, when also treated with BAY61-3606. CONCLUSIONS: These studies indicate that BAY61-3606 exerts distinct biological activities in different genetic contexts. PMID- 22815994 TI - Diverging trends in recent population-based survival rates in oesophageal and gastric cancer. AB - BACKGROUND: Survival trends in oesophageal and gastric cancer need to be updated. A nationwide Swedish population-based study in 1961-2009 was based on registry data. METHODOLOGY/PRINCIPAL FINDINGS: Relative survival rate, i.e. the ratio of the observed to the expected survival, adjusted for age, sex, and calendar period, and presented with 95% confidence intervals (CI), was the main outcome measure. The expected survival was calculated using the corresponding Swedish general population with no exclusions. The relative survival rates in oesophageal and gastric cardia adenocarcinoma have improved since the 1990s (p for trend <0.001), but not in oesophageal squamous cell carcinoma or gastric non-cardia adenocarcinoma. The relative 5-year survival rates during the two recent periods 1990-1999 and 2000-2008 were 12.5% (95%CI 10.1%-14.9%) and 10.3% (95%CI 8.5 12.0%) for oesophageal squamous cell carcinoma, 12.5% (95%CI 10.1%-14.9%) and 14.6% (95%CI 12.6-16.6%) for oesophageal adenocarcinoma, 11.1% (95%CI 9.6%-12.6%) and 14.3% (95%CI 12.3-16.3%) for gastric cardia adenocarcinoma, and 20.2% (95%CI 19.2%-21.1%) and 19.0% (95%CI 17.7-20.2%) for gastric non-cardia adenocarcinoma. The 3-year survival in tumour stage III in 2004-2008 was about 25% for all four tumour types. CONCLUSIONS/SIGNIFICANCE: The survival in oesophageal and cardia adenocarcinoma is increasing, but the lack of such increase in oesophageal squamous cell carcinoma and gastric non-cardia adenocarcinoma is a concern. PMID- 22815995 TI - Barriers to HIV testing in Cote d'Ivoire: the role of individual characteristics and testing modalities. AB - BACKGROUND: Expanding HIV testing requires a better understanding of barriers to its uptake. We investigated barriers to HIV testing in Cote d'Ivoire, taking into account test circumstances (client vs. provider-initiated). METHODS: We used data from the 2005 nationally representative Demographic and Health Survey conducted in Cote d'Ivoire. Socio-demographic characteristics, sexual behaviour and knowledge and attitudes toward HIV/AIDS associated with recent (<2 years) HIV testing were identified using gender-specific univariate and multivariate logistic regressions. Among women, differential effects of barriers to testing according to test circumstance (whether they have been offered for a prenatal test or not) were assessed through interaction tests. RESULTS: Recent HIV testing was reported by 6.1% of men and 9.5% of women (including 4.6% as part of antenatal care). Among men, having a low socioeconomic status, having a low HIV related knowledge level and being employed [compared to those inactive: adjusted Odds Ratio (aOR) 0.46; 95% confidence interval (CI) 0.25-0.87] were associated with lower proportions of recent HIV testing. Among women without a prenatal HIV testing offer, living outside the capital (aOR 0.38; CI 0.19-0.77) and reporting a unique lifetime sexual partner constituted additional barriers to HIV testing. By contrast, among women recently offered to be tested in prenatal care, none of these variables was found to be associated with recent HIV testing. CONCLUSIONS: Various dimensions of individuals' characteristics constituted significant barriers to HIV testing in Cote d'Ivoire in 2005, with gender specificities. Such barriers are substantially reduced when testing was proposed in the framework of antenatal care. This suggests that provider-initiated testing strategies may help overcome individual barriers to HIV testing. PMID- 22815996 TI - Exploring IRES region accessibility by interference of foot-and-mouth disease virus infectivity. AB - Translation initiation of picornavirus RNA is driven by an internal ribosome entry site (IRES) element located upstream of the initiator codon. RNA structure organization as well as RNA-protein interaction plays a fundamental role in internal initiation. IRES activity has been mainly analyzed in the context of reporter genes, lacking regions of the viral genome potentially affecting translation efficiency. With the aim to understand the vulnerability of the IRES and translation start region to small molecules in the context of the viral genome, we designed a set of customized RNase-resistant 2'O-methyl antisense oligoribonucleotides (2'OMe AONs) based on RNA structure data. These AONs were then used to monitor their capacity to interfere viral RNA translation, and thus, to inhibit virus yield. Foot-and-mouth disease virus (FMDV) RNA translation can be initiated at two in-frame AUG codons. We show here that a 2'OMe AON complementary to AUG2 inhibited viral multiplication more efficiently than the one that targeted AUG1. Furthermore, the response of the viral RNA to AONs targeting the IRES region denoted important differences between tissue culture cells and cell-free systems, reinforcing the need to analyze viral RNA response in living cells. Importantly, we have identified four specific motifs within the IRES element that are targets for viral inhibitors both in tissue culture cells and in cell-free systems. The identified targets define accessible regions to small molecules, which disturb either the RNA structural organization or the RNA protein interactions needed to initiate translation in FMDV RNA. PMID- 22815998 TI - Complement inhibitors from scabies mites promote streptococcal growth--a novel mechanism in infected epidermis? AB - BACKGROUND: Scabies is highly prevalent in socially disadvantaged communities such as indigenous populations and in developing countries. Generalized itching causes discomfort to the patient; however, serious complications can occur as a result of secondary bacterial pyoderma, commonly caused by Streptococcus pyogenes (GAS) or Staphylococcus aureus. In the tropics, skin damage due to scabies mite infestations has been postulated to be an important link in the pathogenesis of disease associated with acute rheumatic fever and heart disease, poststreptococcal glomerulonephritis and systemic sepsis. Treatment of scabies decreases the prevalence of infections by bacteria. This study aims to identify the molecular mechanisms underlying the link between scabies and GAS infections. METHODOLOGY/PRINCIPAL FINDINGS: GAS bacteria were pre-incubated with blood containing active complement, phagocytes and antibodies against the bacteria, and subsequently tested for viability by plate counts. Initial experiments were done with serum from an individual previously exposed to GAS with naturally acquired anti-GAS antibodies. The protocol was optimized for large-scale testing of low opsonic whole blood from non-exposed human donors by supplementing with a standard dose of heat inactivated human sera previously exposed to GAS. This allowed an extension of the dataset to two additional donors and four proteins tested at a range of concentrations. Shown first is the effect of scabies mite complement inhibitors on human complement using ELISA-based complement activation assays. Six purified recombinant mite proteins tested at a concentration of 50 ug/ml blocked all three complement activation pathways. Further we demonstrate in human whole blood assays that each of four scabies mite complement inhibitors tested increased GAS survival rates by 2-15 fold. CONCLUSIONS/SIGNIFICANCE: We propose that local complement inhibition plays an important role in the development of pyoderma in scabies infested skin. This molecular link between scabies and bacterial infections may provide new avenues to develop alternative treatment options against this neglected disease. PMID- 22815997 TI - Autophagy in idiopathic pulmonary fibrosis. AB - BACKGROUND: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis. METHODS: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-beta(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model. RESULTS: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-beta(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-beta(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of a-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin 1, leads to the opposite effect on fibroblast expression of a-smooth muscle actin and fibronectin. CONCLUSION: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-beta(1) may represent a mechanism for the promotion of fibrogenesis in IPF. PMID- 22815999 TI - Effective control of Schistosoma haematobium infection in a Ghanaian community following installation of a water recreation area. AB - BACKGROUND: Urogenital schistosomiasis caused by Schistosoma haematobium was endemic in Adasawase, Ghana in 2007. Transmission was reported to be primarily through recreational water contact. METHODS: We designed a water recreation area (WRA) to prevent transmission to school-aged children. The WRA features a concrete pool supplied by a borehole well and a gravity-driven rainwater collection system; it is 30 m(2) and is split into shallow and deep sections to accommodate a variety of age groups. The WRA opened in 2009 and children were encouraged to use it for recreation as opposed to the local river. We screened children annually for S. haematobium eggs in their urine in 2008, 2009, and 2010 and established differences in infection rates before (2008-09) and after (2009 10) installation of the WRA. After each annual screening, children were treated with praziquantel and rescreened to confirm parasite clearance. PRINCIPAL FINDINGS: Initial baseline testing in 2008 established that 105 of 247 (42.5%) children were egg-positive. In 2009, with drug treatment alone, the pre-WRA annual cumulative incidence of infection was 29 of 216 (13.4%). In 2010, this incidence rate fell significantly (p<0.001, chi-squared) to 9 of 245 (3.7%) children after installation of the WRA. Logistic regression analysis was used to determine correlates of infection among the variables age, sex, distance between home and river, minutes observed at the river, low height-for-age, low weight-for age, low Body Mass Index (BMI)-for-age, and previous infection status. CONCLUSION/SIGNIFICANCE: The installation and use of a WRA is a feasible and highly effective means to reduce the incidence of schistosomiasis in school-aged children in a rural Ghanaian community. In conjunction with drug treatment and education, such an intervention can represent a significant step towards the control of schistosomiasis. The WRA should be tested in other water-rich endemic areas to determine whether infection prevalence can be substantially reduced. PMID- 22816000 TI - Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compartments. AB - BACKGROUND: The clinical syndrome associated with secondary syphilis (SS) reflects the propensity of Treponema pallidum (Tp) to escape immune recognition while simultaneously inducing inflammation. METHODS: To better understand the duality of immune evasion and immune recognition in human syphilis, herein we used a combination of flow cytometry, immunohistochemistry (IHC), and transcriptional profiling to study the immune response in the blood and skin of 27 HIV(-) SS patients in relation to spirochetal burdens. Ex vivo opsonophagocytosis assays using human syphilitic sera (HSS) were performed to model spirochete-monocyte/macrophage interactions in vivo. RESULTS: Despite the presence of low-level spirochetemia, as well as immunophenotypic changes suggestive of monocyte activation, we did not detect systemic cytokine production. SS subjects had substantial decreases in circulating DCs and in IFNgamma-producing and cytotoxic NK-cells, along with an emergent CD56-/CD16+ NK cell subset in blood. Skin lesions, which had visible Tp by IHC and substantial amounts of Tp-DNA, had large numbers of macrophages (CD68+), a relative increase in CD8+ T-cells over CD4+ T-cells and were enriched for CD56+ NK-cells. Skin lesions contained transcripts for cytokines (IFN-gamma, TNF-alpha), chemokines (CCL2, CXCL10), macrophage and DC activation markers (CD40, CD86), Fc-mediated phagocytosis receptors (FcgammaRI, FcgammaR3), IFN-beta and effector molecules associated with CD8 and NK-cell cytotoxic responses. While HSS promoted uptake of Tp in conjunction with monocyte activation, most spirochetes were not internalized. CONCLUSIONS: Our findings support the importance of macrophage driven opsonophagocytosis and cell mediated immunity in treponemal clearance, while suggesting that the balance between phagocytic uptake and evasion is influenced by the relative burdens of bacteria in blood and skin and the presence of Tp subpopulations with differential capacities for binding opsonic antibodies. They also bring to light the extent of the systemic innate and adaptive immunologic abnormalities that define the secondary stage of the disease, which in the skin of patients trends towards a T-cell cytolytic response. PMID- 22816001 TI - Fine scale spatiotemporal clustering of dengue virus transmission in children and Aedes aegypti in rural Thai villages. AB - BACKGROUND: Based on spatiotemporal clustering of human dengue virus (DENV) infections, transmission is thought to occur at fine spatiotemporal scales by horizontal transfer of virus between humans and mosquito vectors. To define the dimensions of local transmission and quantify the factors that support it, we examined relationships between infected humans and Aedes aegypti in Thai villages. METHODOLOGY/PRINCIPAL FINDINGS: Geographic cluster investigations of 100-meter radius were conducted around DENV-positive and DENV-negative febrile "index" cases (positive and negative clusters, respectively) from a longitudinal cohort study in rural Thailand. Child contacts and Ae. aegypti from cluster houses were assessed for DENV infection. Spatiotemporal, demographic, and entomological parameters were evaluated. In positive clusters, the DENV infection rate among child contacts was 35.3% in index houses, 29.9% in houses within 20 meters, and decreased with distance from the index house to 6.2% in houses 80-100 meters away (p<0.001). Significantly more Ae. aegypti were DENV-infectious (i.e., DENV-positive in head/thorax) in positive clusters (23/1755; 1.3%) than negative clusters (1/1548; 0.1%). In positive clusters, 8.2% of mosquitoes were DENV infectious in index houses, 4.2% in other houses with DENV-infected children, and 0.4% in houses without infected children (p<0.001). The DENV infection rate in contacts was 47.4% in houses with infectious mosquitoes, 28.7% in other houses in the same cluster, and 10.8% in positive clusters without infectious mosquitoes (p<0.001). Ae. aegypti pupae and adult females were more numerous only in houses containing infectious mosquitoes. CONCLUSIONS/SIGNIFICANCE: Human and mosquito infections are positively associated at the level of individual houses and neighboring residences. Certain houses with high transmission risk contribute disproportionately to DENV spread to neighboring houses. Small groups of houses with elevated transmission risk are consistent with over-dispersion of transmission (i.e., at a given point in time, people/mosquitoes from a small portion of houses are responsible for the majority of transmission). PMID- 22816002 TI - Seroprevalence and risk factors for Taenia solium cysticercosis in rural pigs of northern Peru. AB - Taenia solium is a cestode parasite that causes cysticercosis in both humans and pigs. A serological survey was undertaken to assess the seroprevalence and risk factors associated with porcine cysticercosis in the rural district of Morropon, Peru. Pigs aged between 2 and 60 months were assessed by the Enzyme-linked Immunoelectrotransfer blot (EITB) assay to determine their serological status against porcine cysticercosis in a cross-sectional study. A total of 1,153 pigs were sampled. Porcine seroprevalence was 45.19% (42.31-48.06). The information about the animals and households was analyzed and risk factors associated with seroprevalence were determined by a multivariate logistic regression analysis. In the porcine population, the risk of being seropositive increased by 7% with every month of age (OR 1.07, 95% CI 1.05-1.09), and by 148% for pigs living in East Morropon (OR 2.48, 95% CI 1.82-3.37). Whereas, the presence of latrines in a household decreased the risk of being seropositive by 49% (OR 0.51; 95% CI 0.39 0.67). Sex and rearing system did not represent either risk or protective factors associated with the seroprevalence of porcine cysticercosis. The findings of this study could be used for further development of control programs that might focus on similar population groups within rural communities of developing countries where cysticercosis is endemic. PMID- 22816003 TI - TNF-alpha involvement in insulin resistance induced by experimental scorpion envenomation. AB - BACKGROUND: Scorpion venom induces systemic inflammation characterized by an increase in cytokine release and chemokine production. There have been few experimental studies assessing the effects of scorpion venom on adipose tissue function in vivo. METHODOLOGY/PRINCIPAL FINDINGS: To study the adipose tissue inflammation (ATI) induced by Androctonus australis hector (Aah) venom and to assess possible mechanisms of ATI, mice (n = 6, aged 1 month) were injected with Aah (0.45 mg/kg), toxic fraction of Aah (FTox-G50; 0.2 mg/kg) or saline solution (control). Inflammatory responses were evaluated by ELISA and cell sorting analyses in adipose tissue 45 minutes and 24 hours after injection. Quantitative real-time PCR was used to assess the regulation of genes implicated in glucose uptake. The titers of selected inflammatory cytokines (IL-1beta, IL-6 and TNF alpha) were also determined in sera and in insulin target tissues. The serum concentration of IL-1beta rose 45 minutes after envenomation and returned to basal level after 24 hours. The pathophysiological effects of the venom after 24 hours mainly involved M1-proinflammatory macrophage infiltration in adipose tissue combined with high titers of IL-1beta, IL-6 and TNF-alpha. Indeed, TNF alpha was strongly induced in both adipose tissue and skeletal muscle. We studied the effects of Aah venom on genes implicated in insulin-stimulated glucose uptake. Insulin induced a significant increase in the expression of the mRNAs for hexokinase 2 and phosphatidylinositol 3-kinase in both skeletal muscle and adipose tissue in control mice; this upregulation was completely abolished after 24 hours in mice envenomed with Aah or FTox-G50. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that Aah venom induces insulin resistance by mechanisms involving TNF-alpha-dependent Map4k4 kinase activation in the adipose tissue. PMID- 22816005 TI - Podoconiosis in East and West Gojam Zones, northern Ethiopia. AB - BACKGROUND: Podoconiosis is a neglected tropical disease (NTD) that is prevalent in red clay soil-covered highlands of tropical Africa, Central and South America, and northern India. It is estimated that up to one million cases exist in Ethiopia. This study aimed to estimate the prevalence of podoconiosis in East and West Gojam Zones of Amhara Region in northern Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional household survey was conducted in Debre Eliyas and Dembecha woredas (districts) in East and West Gojam Zones, respectively. The survey covered all 17,553 households in 20 kebeles (administrative subunits) randomly selected from the two woredas. A detailed structured interview was conducted on 1,704 cases of podoconiosis identified in the survey. RESULTS: The prevalence of podoconiosis in the population aged 15 years and above was found to be 3.3% (95% CI, 3.2% to 3.6%). 87% of cases were in the economically active age group (15-64 years). On average, patients sought treatment five years after the start of the leg swelling. Most subjects had second (42.7%) or third (36.1%) clinical stage disease, 97.9% had mossy lesions, and 53% had open wounds. On average, patients had five episodes of acute adenolymphangitis (ALA) per year and spent a total of 90 days per year with ALA. The median age of first use of shoes and socks were 22 and 23 years, respectively. More men than women owned more than one pair of shoes (61.1% vs. 50.5%; chi(2) = 11.6 p = 0.001). At the time of interview, 23.6% of the respondents were barefoot, of whom about two-thirds were women. CONCLUSIONS: This study showed high prevalence of podoconiosis and associated morbidities such as ALA, mossy lesions and open wounds in northern Ethiopia. Predominance of cases at early clinical stage of podoconiosis indicates the potential for reversing the swelling and calls for disease prevention interventions. PMID- 22816004 TI - Primary vaccination with low dose live dengue 1 virus generates a proinflammatory, multifunctional T cell response in humans. AB - The four dengue virus serotypes (DENV-1-DENV-4) have a large impact on global health, causing 50-100 million cases of dengue fever annually. Herein, we describe the first kinetic T cell response to a low-dose DENV-1 vaccination study (10 PFU) in humans. Using flow cytometry, we found that proinflammatory cytokines, IFNgamma, TNFalpha, and IL-2, were generated by DENV-1-specific CD4(+) cells 21 days post-DENV-1 exposure, and their production continued through the latest time-point, day 42 (p<0.0001 for all cytokines). No statistically significant changes were observed at any time-points for IL-10 (p = 0.19), a regulatory cytokine, indicating that the response to DENV-1 was primarily proinflammatory in nature. We also observed little T cell cross-reactivity to the other 3 DENV serotypes. The percentage of multifunctional T cells (T cells making >= 2 cytokines simultaneously) increased with time post-DENV-1 exposure (p<0.0001). The presence of multifunctional T cells together with neutralizing antibody data suggest that the immune response generated to the vaccine may be protective. This work provides an initial framework for defining primary T cell responses to each DENV serotype and will enhance the evaluation of a tetravalent DENV vaccine. PMID- 22816006 TI - Difficult colon polypectomy. AB - Colorectal cancer (CRC) is one of the leading causes of death from cancer in the world. We now know that 90% of CRC develop from adenomatous polyps. Polypectomy of colon adenomas leads to a significant reduction in the incidence of CRC. At present most of the polyps are removed endoscopically. The vast majority of colorectal polyps identified at colonoscopy are small and do not pose a significant challenge for resection to an appropriately trained and skilled endoscopist. Advanced polypectomy techniques are intended for the removal of difficult colon polyps. We have defined a "difficult polyp" as any lesion that due to its size, shape or location represents a challenge for the colonoscopist to remove. Although many "difficult polyps" will be an easy target for the advanced endoscopist, polyps that are larger than 15 mm, have a large pedicle, are flat and extended, are difficult to see or are located in the cecum or any angulated portion of the colon should be always considered difficult. Although very successful, advanced resection techniques can potentially cause serious, even life-threatening complications. Moreover, post polypectomy complications are more common in the presence of difficult polyps. Therefore, any endoscopist attempting advanced polypectomy techniques should be adequately supervised by an expert or have an excellent training in interventional endoscopy. This review describes several useful tips and tricks to deal with difficult polyps. PMID- 22816007 TI - Use of portal pressure studies in the management of variceal haemorrhage. AB - Portal hypertension occurs as a complication of liver cirrhosis and complications such as variceal bleeding lead to significant demands on resources. Endoscopy is the gold standard method for screening cirrhotic patients however universal endoscopic screening may mean a lot of unnecessary procedures as the presence of oesophageal varices is variable hence a large time and cost burden on endoscopy units to carry out both screening and subsequent follow up of variceal bleeds. A less invasive method to identify those at high risk of bleeding would allow earlier prophylactic measures to be applied. Hepatic venous pressure gradient (HVPG) is an acceptable indirect measurement of portal hypertension and predictor of the complications of portal hypertension in adult cirrhotics. Varices develop at a HVPG of 10-12 mmHg with the appearance of other complications with HPVG > 12 mmHg. Variceal bleeding does not occur in pressures under 12 mmHg. HPVG > 20 mmHg measured early after admission is a significant prognostic indicator of failure to control bleeding varices, indeed early transjugular intrahepatic portosystemic shunt (TIPS) in such circumstances reduces mortality significantly. HVPG can be used to identify responders to medical therapy. Patients who do not achieve the suggested reduction targets in HVPG have a high risk of rebleeding despite endoscopic ligation and may not derive significant overall mortality benefit from endoscopic intervention alone, ultimately requiring TIPS or liver transplantation. Early HVPG measurements following a variceal bleed can help to identify those at risk of treatment failure who may benefit from early intervention with TIPS. Therefore, we suggest using HVPG measurement as the investigation of choice in those with confirmed cirrhosis in place of endoscopy for intitial variceal screening and, where indicated, a trial of B-blockade, either intravenously during the initial pressure study with assessment of response or oral therapy with repeat HVPG six weeks later. In those with elevated pressures, primary medical prophylaxis could be commenced with subsequent close monitoring of HVPG thus negating the need for endoscopy at this point. All patients presenting with variceal haemorrhage should undergo HVPG measurement and those with a gradient greater than 20 mmHg should be considered for early TIPS. By introducing portal pressure studies into a management algorithm for variceal bleeding, the number of endoscopies required for further intervention and follow up can be reduced leading to significant savings in terms of cost and demand on resources. PMID- 22816008 TI - Stenosis in gastric bypass: Endoscopic management. AB - Gastric bypass is a treatment option for morbid obesity. Stenosis of the gastrojejunal anastomosis is a recognized complication. The pathophysiological mechanisms involved in the formation of stenosis are not well known. Gastrojejunal strictures can be classified based on time of onset, mechanism of formation, and endoscopic aspect. Diagnosis is usually obtained by endoscopy. The two main treatment alternatives for stomal stricture are: endoscopic dilatation (balloon or bouginage) and surgical revision (open or laparoscopic). Both techniques of dilation [through-the-scope (TTS) balloon dilators, Bougienage dilators] are considered safe, effective, and do not require hospitalization. The optimal technique for dilation of stomal strictures remains to be determined, but many authors prefer the use of TTS balloon catheters. Most patients can be successfully treated with 1 or 2 sessions. The need for reconstructive surgery of a stomal stricture is extremely rare. PMID- 22816009 TI - What are the latest developments in colorectal endoscopic submucosal dissection? AB - Endoscopic submucosal dissection (ESD) enables direct submucosal dissection so that even large early-stage gastrointestinal tumors can be resected en bloc. ESD has recently been applied to the colorectum since it was originally developed for use in the stomach. However, colorectal ESD is technically more difficult with an increased risk of perforation compared with gastric ESD. In addition, this procedure is seldom performed in Western countries. Consequently, further technical advances and the availability of a suitable clinical training system are required for the extensive use of colorectal ESD. In this topic highlight, we review the most recent developments in colorectal ESD. PMID- 22816010 TI - Possibilities of interventional endoscopic ultrasound. AB - Since endoscopic ultrasound (EUS) was developed in the 1990s, EUS has become widely accepted as an imaging tool. EUS is categorized into radial and linear in design. Radial endoscopes provide cross-sectional imaging of the mediastinum, gastrointestinal tract, liver, spleen, kidney, adrenal gland, and pancreas, which has highly accuracy in the T and N staging of esophageal, lung, gastric, rectal, and pancreatic cancer. Tumor staging is common indication of radial-EUS, and EUS staging is predictive of surgical resectability. In contrast, linear array endoscope uses a side-viewing probe and has advantages in the ability to perform EUS-guides fine needle aspiration (EUS-FNA), which has been established for cytologic diagnosis. For example, EUS-FNA arrows accurate nodal staging of esophageal cancer before surgery, which provides more accurate assessment of nodes than radial-EUS imaging alone. EUS-FNA has been also commonly used for diagnose of pancreatic diseases because of the highly accuracy than US or computed tomography. EUS and EUS-FNA has been used not only for TNM staging and cytologic diagnosis of pancreatic cancer, but also for evaluation of chronic pancreatitis, pancreatic cystic lesions, and other pancreatic masses. More recently, EUS-FNA has developed into EUS-guided fine needle injection including EUS-guided celiac plexus neurolysis, celiac plexus block, and other "interventional EUS" procedures. In this review, we have summarized the new possibilities offered by "interventional EUS". PMID- 22816011 TI - Endoscopic ultrasound guided biliary drainage. AB - Endoscopic retrograde cholangio-pancreatography is the most appropriate technique for treating common bile duct and pancreatic duct stenosis secondary to benign and malignant diseases. Even if the procedure is performed by skillful endoscopist, there are patients in whom endoscopic stent placement is not possible. Common causes of failure include complex peri-papillary diverticula, prior surgery procedures, tumor involvement of the papilla, biliary sphincter stenosis, and impacted stones. Percutaneous trans-hepatic biliary drainage (PTBD) and surgical intervention carry morbidity and mortality. Recently endoscopic ultrasonography-guided biliary drainage has been reported as an alternative technique. Endoscopic ultrasonography-guided biliary drainage using either direct access or a rendezvous technique has attracted attention as an alternative procedure to PTBD, with a technical success between 75%-100% and with low complication rate. We have reviewed published data on EUS guided biliary drainage procedures with the aim of summarizing the efficacy and safety of this promising method. PMID- 22816012 TI - Endoscopic management of esophageal varices. AB - The rupture of gastric varices results in variceal hemorrhage, which is one the most lethal complications of cirrhosis. Endoscopic therapies for varices aim to reduce variceal wall tension by obliteration of the varix. The two principal methods available for esophageal varices are endoscopic sclerotherapy (EST) and band ligation (EBL). The advantages of EST are that it is cheap and easy to use, and the injection catheter fits through the working channel of a diagnostic gastroscope. Endoscopic variceal ligation obliterates varices by causing mechanical strangulation with rubber bands. The following review aims to describe the utility of EBL and EST in different situations, such as acute bleeding, primary and secondary prophylaxis. PMID- 22816013 TI - A study of the changes in the cause of peptic ulcer bleeding. AB - AIM: To clarify the frequency of and changes in the cause of peptic ulcer bleeding. METHODS: This study retrospectively evaluated the out- and inpatients who underwent endoscopy between 2002 to 2008. The subjects were patients presenting with peptic ulcer bleeding. The details of these patients were obtained from their endoscopic reports and medical records. RESULTS: The rates of Helicobacter pylori (H. pylori) infection were significantly low (P = 0.039), while the proportion of nonsteroidal antiinflammatory drugs (NSAIDs) users and vascular disease significantly increased over the period studied (P = 0.034 and P = 0.04, respectively). However, there was no significant difference in the proportion of low-dose aspirin users (P = 0.832). CONCLUSION: It's found that the primary cause of peptic ulcer bleeding changed from H. pylori infection to use of NSAIDs over the 7-year period of study. It seems that the number of low-dose aspirin users has increased with the increase in the proportion of vascular disease. It is necessary to take measures to prevent peptic ulcer bleeding among NSAIDs and low dose aspirin users. PMID- 22816014 TI - Role of endoscopic ultrasound and endoscopic retrograde cholangiopancreatography in isolated pancreatic metastasis from lung cancer. AB - A case is reported of a 50-year-old woman with a history of small-cell lung cancer admitted with pancreatic head lesions, discovered during investigation for obstructive jaundice. Endoscopic ultrasound assisted fine needle aspiration of the pancreatic mass was consistent with small cell carcinoma, presenting as an isolated metastasis from the previously diagnosed lung cancer. Endoscopic retrograde cholangiopancreatography (ERCP) showed extrinsic compression and a bile duct stricture, requiring sphincterotomy and stent insertion. This case highlights that acute pancreatitis and biliary obstruction can occur as a manifestation of small cell lung cancer metastasizing to the pancreas. EUS is a safe, low risk and rapid diagnostic tool in such cases, and ERCP with stenting offers a safe and effective treatment option. PMID- 22816015 TI - Acute inflammation occurring in gastric aberrant pancreas followed up by endoscopic ultrasonography. AB - We describe a case of gastric aberrant pancreas with acute pancreatitis followed up with subsequent endoscopic ultrasound. A 20-year-old woman known to have aberrant pancreas in the stomach was admitted to our hospital because of severe epigastralgia. Laboratory tests showed slight C reactive protein elevation without hyperamylasemia. Esophagogastroduodenoscopy revealed a swollen submucosal lesion (SML) to a greater degree compared with the previous findings. Subsequent endoscopic ultrasonography (EUS) revealed a swollen lesion of 35 mm in diameter. The internal echo-pattern was more hypoechoic than in the previous EUS. The border between the fourth layer (muscularis propria) and the SML was unclear. The anechoic lumen in the mass, considered as the ductal lumen, was dilated. Based on these results, we diagnosed the patient as having acute inflammation, resembling pancreatitis, in the aberrant pancreas. PMID- 22816016 TI - A case of chronic pancreatitis in which endoscopic ultrasonography was effective in the diagnosis of a pseudoaneurysm. AB - Endoscopic ultrasonography (EUS) was performed on a patient being treated for chronic pancreatitis because a submucosal tumor was observed in the stomach during gastrointestinal endoscopy. As internal pulsatile blood flow on Doppler was present, the diagnosis of an aneurysm was made. The pseudoaneurysm of the left gastric artery was embolized with histoacryl and lipiodol and the splenic artery was embolized with coils at the location of the pseudoaneurysm to prevent hemorrhage. Follow up EUS confirmed the cessation of blood flow from the pseudoaneurysm. Clinicians encountering a gastric submucosal tumor-like protrusion in a patient with chronic pancreatitis should use EUS to investigate the possibility of a pseudoaneurysm, which must be treated as quickly as possible once identified. PMID- 22816017 TI - Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective MU-delta agonists. AB - Research in the opioid field has relied heavily on the use of standard agonist ligands such as morphine, [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin (DAMGO), U69593, bremazocine, [d-Pen(2)d-Pen(5)]enkephalin (DPDPE), and deltorphin-II as tools for investigating the three major types of opioid receptors, MOP (MU), KOP (kappa), and DOP (delta), that mediate antinociception. The functional selectivity of these ligands has been based on the assumption that opioid receptors exist as homomers. As numerous studies in cultured cells have suggested that opioid receptors can associate both as homomers and heteromers, we have investigated the selectivity of these standard ligands using intracellular calcium release and [(35)S]GTPgammaS assays in HEK-293 cells that contain singly and coexpressed opioid receptors. The present study reveals that morphine and DAMGO, traditionally classified as MU selective agonists, selectively activate MU-delta heteromeric opioid receptors with greater efficacy than homomeric opioid receptors. Moreover, standard ligands that have been widely employed as kappa- and delta-selective agonists display little or no differences in the activation of homomeric and heteromeric opioid receptors. The far-reaching implications of these results are discussed. PMID- 22816018 TI - Normal mode gating motions of a ligand-gated ion channel persist in a fully hydrated lipid bilayer model. AB - We have previously used molecular modeling and normal-mode analyses combined with experimental data to visualize a plausible model of a transmembrane ligand-gated ion channel. We also postulated how the gating motion of the channel may be affected by the presence of various ligands, especially anesthetics. As is typical for normal-mode analyses, those studies were performed in vacuo to reduce the computational complexity of the problem. While such calculations constitute an efficient way to model the large scale structural flexibility of transmembrane proteins, they can be criticized for neglecting the effects of an explicit phospholipid bilayer or hydrated environment. Here, we show the successful calculation of normal-mode motions for our model of a glycine alpha-1 receptor, now suspended in a fully hydrated lipid bilayer. Despite the almost uniform atomic density, the introduction of water and lipid does not grossly distort the overall gating motion. Normal-mode analysis revealed that even a fully immersed glycine alpha-1 receptor continues to demonstrate an iris-like channel gating motion as a low-frequency, high-amplitude natural harmonic vibration consistent with channel gating. Furthermore, the introduction of periodic boundary conditions allows the examination of simultaneous harmonic vibrations of lipid in synchrony with the protein gating motions that are compatible with reasonable lipid bilayer perturbations. While these perturbations tend to influence the overall protein motion, this work provides continued support for the iris-like motion model that characterizes gating within the family of ligand-gated ion channels. PMID- 22816019 TI - ACS chemical neuroscience molecule spotlight on Telcagepant (MK-0974). AB - Telcagepant (MK-0974) is a novel calcitonin gene-related peptide (CGRP) receptor antagonist currently undergoing clinical trials for migraine (http://www.merck.com/research/pipeline/home.html). MK-0974 is currently being studied in phase III clinical trials. PMID- 22816021 TI - Characterization of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as novel leads to development of mu opioid receptor selective antagonists. AB - As important pharmacological probes, highly selective opioid receptor antagonists are essential in opioid receptor structural characterization and opioid agonist functional studies. At present, a nonpeptidyl, highly selective, and reversible mu opioid receptor antagonist is still not available. Among a series of novel naltrexamine derivatives that have been designed and synthesized following molecular modeling studies, two compounds, NAP and NAQ, were identified as leads based on the results of in vitro and in vivo pharmacological assays. Both of them displayed high binding affinity and selectivity to the mu opioid receptor. Further pharmacokinetic and functional characterization revealed that NAP seems to be a peripheral nervous system agent while NAQ seems to be a central one. Such characteristics provide two distinguished potential application routes for these two agents and their derivatives. These results also supported our hypothesis that they may serve as leads to develop more potent and selective antagonists for the mu opioid receptor. PMID- 22816020 TI - Hydrogels in spinal cord injury repair strategies. AB - Nowadays there are at present no efficient therapies for spinal cord injury (SCI), and new approaches have to be proposed. Recently, a new regenerative medicine strategy has been suggested using smart biomaterials able to carry and deliver cells and/or drugs in the damaged spinal cord. Among the wide field of emerging materials, research has been focused on hydrogels, three-dimensional polymeric networks able to swell and absorb a large amount of water. The present paper intends to give an overview of a wide range of natural, synthetic, and composite hydrogels with particular efforts for the ones studied in the last five years. Here, different hydrogel applications are underlined, together with their different nature, in order to have a clearer view of what is happening in one of the most sparkling fields of regenerative medicine. PMID- 22816022 TI - Discovery of 3-substituted aminocyclopentanes as potent and orally bioavailable NR2B subtype-selective NMDA antagonists. AB - A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner. PMID- 22816023 TI - Modulation of adenosine receptors by [60]fullerene hydrosoluble derivative in SK N-MC cells. AB - The most known fullerenes are spherical carbon compounds composed of 60 carbon atoms. C(60) fullerenes have shown biochemical and biomedical properties in the last years such as as blockade of apoptosis and neuroprotection. The nucleoside adenosine has a neuroprotective role mainly due to inhibition of glutamate release, which is a neurotransmitter related to excitotoxicity and cell death. In the present work, we have determined the presence of adenosine receptors in SK-N MC cells, a neuroepithelioma human cell line, and analyzed the effect of fullerenes in these receptors by using radioligand binding, immunoblotting, and quantitative real time PCR assays. Results demonstrated that SK-N-MC cells endogenously express adenosine receptors. Fullerene exposure of these cells did not affect cell viability measured by MTT reduction assay. However, adenosine A(1) and A(2A) receptors were both increased in SK-N-MC cells after treatment. These results suggest for the first time the modulation of adenosine receptors after C(60) fullerenes exposure. PMID- 22816024 TI - Visualization of the cocaine-sensitive dopamine transporter with ligand conjugated quantum dots. AB - The presynaptic dopamine (DA) transporter is responsible for DA inactivation following release and is a major target for the psychostimulants cocaine and amphetamine. Dysfunction and/or polymorphisms in human DAT (SLC6A3) have been associated with schizophrenia, bipolar disorder, Parkinson's disease, and attention-deficit hyperactivity disorder (ADHD). Despite the clinical importance of DAT, many uncertainties remain regarding the transporter's regulation, in part due to the poor spatiotemporal resolution of conventional methodologies and the relative lack of efficient DAT-specific fluorescent probes. We developed a quantum dot-based labeling approach that uses a DAT-specific, biotinylated ligand, 2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (IDT444), that can be bound by streptavidin-conjugated quantum dots. Flow cytometry and confocal microscopy were used to detect DAT in stably and transiently transfected mammalian cells. IDT444 is useful for quantum-dot-based fluorescent assays to monitor DAT expression, function, and plasma membrane trafficking in living cells as evidenced by the visualization of acute, protein-kinase-C (PKC)-dependent DAT internalization. PMID- 22816025 TI - Glycemia management in critical care patients. AB - Over the last decade, the approach to clinical management of blood glucose concentration (BGC) in critical care patients has dramatically changed. In this editorial, the risks related to hypo, hyperglycemia and high BGC variability, optimal BGC target range and BGC monitoring devices for patients in the intensive care unit (ICU) will be discussed. Hypoglycemia has an increased risk of death, even after the occurrence of a single episode of mild hypoglycemia (BGC < 80 mg/dL), and it is also associated with an increase in the ICU length of stay, the major determinant of ICU costs. Hyperglycemia (with a threshold value of 180 mg/dL) is associated with an increased risk of death, longer length of stay and higher infective morbidity in ICU patients. In ICU patients, insulin infusion aimed at maintaining BGC within a 140-180 mg/dL target range (NICE-SUGAR protocol) is considered to be the state-of-the-art. Recent evidence suggests that a lower BGC target range (129-145 mg/dL) is safe and associated with lower mortality. In trauma patients without traumatic brain injury, tight BGC (target < 110 mg/dL) might be associated with lower mortality. Safe BGC targeting and estimation of optimal insulin dose titration should include an adequate nutrition protocol, the length of insulin infusion and the change in insulin sensitivity over time. Continuous glucose monitoring devices that provide accurate measurement can contribute to minimizing the risk of hypoglycemia and improve insulin titration. In conclusion, in ICU patients, safe and effective glycemia management is based on accurate glycemia monitoring and achievement of the optimal BGC target range by using insulin titration, along with an adequate nutritional protocol. PMID- 22816026 TI - Over expression of resistin in adipose tissue of the obese induces insulin resistance. AB - AIM: To compare resistin mRNA expression in subcutaneous adipose tissue (SAT) and its correlation with insulin resistance (IR) in postmenopausal obese women. METHODS: A total of 68 postmenopausal women (non obese = 34 and obese = 34) were enrolled for the study. The women of the two groups were age matched (49-70 years). Fasting blood samples were collected at admission and abdominal SAT was obtained during surgery for gall bladder stones or hysterectomy. Physical parameters [age, height, weight, body mass index (BMI)] were measured. Biochemical (plasma insulin and plasma glucose) parameters were estimated by enzymatic methods. RNA was isolated by the Trizol method. SAT resistin mRNA expression was done by real time- reverse transcription polymerase chain reaction (RT-PCR) by using Quanti Tect SYBR Green RT-PCR master mix. Data was analyzed using independent Student's t test, correlation and simple linear regression analysis. RESULTS: The mean weight (52.81 +/- 8.04 kg vs 79.56 +/- 9.91 kg; P < 0.001), BMI (20.23 +/- 3.05 kg/m(2)vs 32.19 +/- 4.86 kg/m(2); P < 0.001), insulin (8.47 +/- 3.24 MUU/mL vs 14.67 +/- 2.18 MUU/mL; P < 0.001), glucose (97.44 +/- 11.31 mg/dL vs 109.67 +/- 8.02 mg/dL; P < 0.001) and homeostasis model assessment index (2.01 +/- 0.73 vs 3.96 +/- 0.61; P < 0.001) were significantly higher in postmenopausal obese women compared to postmenopausal non obese women. The mean serum resistin level was also significantly higher in postmenopausal obese women compared to postmenopausal non obese women (9.05 +/- 5.15 vs 13.92 +/- 6.32, P < 0.001). Furthermore, the mean SAT resistin mRNA expression was also significantly (0.023 +/- 0.008 vs 0.036 +/- 0.009; P < 0.001) higher and over expressed 1.62 fold (up-regulated) in postmenopausal obese women compared to postmenopausal non obese women. In postmenopausal obese women, the relative SAT resistin mRNA expression showed positive (direct) and significant correlation with BMI (r = 0.78, P < 0.001) and serum resistin (r = 0.76, P < 0.001). Furthermore, the SAT resistin mRNA expression in postmenopausal obese women also showed significant and direct association (r = 0.45, P < 0.01) with IR, while in postmenopausal non obese women it did not show any association (r = -0.04, P > 0.05). CONCLUSION: Increased SAT resistin mRNA expression probably leads to inducing insulin resistance and thus may be associated with obesity-related disorders in postmenopausal obese women. PMID- 22816027 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion: The University of Arizona early experience. AB - AIM: To evaluate the safety and effectiveness of our new cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) program. METHODS: Retrospective review of patients with gastrointestinal malignancies who were suitable candidates for CRS and HIPEC between 12/1/2009 and 10/1/2010. All clinicopathologic data were reviewed with a special focus on the surgical outcome and the postoperative morbidity and mortality. RESULTS: Fourteen patients were identified. Median age was 64 years; seven were female. The primary tumors were: colonic (29%), appendiceal (36%), peritoneal mesothelioma (14%), gastric (7%), adenocarcinoma of unknown primary (7%), and gastrointestinal stromal tumor (7%). Eleven patients (79%) received CRS/HIPEC, three for palliation. Three patients that did not undergo CRS/HIPEC had an average peritoneal cancer index (PCI) of 25. The eight patients that underwent curative CRS/HIPEC had an average PCI of 10 and a completeness of cytoreduction score of 0 (87.5%) or 1 (12.5%). Postoperative morbidity was 36%; the worst adverse event was Grade 3 ileus. Mortality rate was 0%. CONCLUSION: CRS with HIPEC is safe and feasible at tertiary institutions with fledgling programs. PCI is an accurate predictor of surgical outcomes. PMID- 22816028 TI - Virtual modeling of robot-assisted manipulations in abdominal surgery. AB - AIM: To determine the effectiveness of using multidetector computed tomography (MDCT) data in preoperative planning of robot-assisted surgery. METHODS: Fourteen patients indicated for surgery underwent MDCT using 64 and 256-slice MDCT. Before the examination, a specially constructed navigation net was placed on the patient's anterior abdominal wall. Processing of MDCT data was performed on a Brilliance Workspace 4 (Philips). Virtual vectors that imitate robotic and assistant ports were placed on the anterior abdominal wall of the 3D model of the patient, considering the individual anatomy of the patient and the technical capabilities of robotic arms. Sites for location of the ports were directed by projection on the roentgen-positive tags of the navigation net. RESULTS: There were no complications observed during surgery or in the post-operative period. We were able to reduce robotic arm interference during surgery. The surgical area was optimal for robotic and assistant manipulators without any need for reinstallation of the trocars. CONCLUSION: This method allows modeling of the main steps in robot-assisted intervention, optimizing operation of the manipulator and lowering the risk of injuries to internal organs. PMID- 22816029 TI - Pentoxifylline improves liver regeneration through down-regulation of TNF-alpha synthesis and TGF-beta1 gene expression. AB - AIM: To investigate the mechanism of pentoxifylline (PTX) improvement in liver regeneration. RESULTS: Rats were randomized into 4 groups: Control rats; Sham - sham-operation rats; Saline - 70% hepatectomy plus saline solution; PTX - 70% hepatectomy plus PTX. At 2 and 6 h after hepatectomy, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor (TNF)-alpha and interleukin-6 (IL 6) serum and hepatic tissue levels were determined. Tumor growth factor (TGF) beta1 gene expression in liver tissue was evaluated 24 h after hepatectomy by quantitative reverse transcriptase polymerase chain reaction analysis. Proliferation was analyzed by mitotic index and proliferating cell nuclear antigen (PCNA) staining 48 h after hepatectomy. RESULTS: TNF-alpha and IL-6 serum levels increased at 2 and 6 h after hepatectomy. At 2 h after hepatectomy serum PTX was reduced but not hepatic levels of TNF-alpha and IL-6. A decrease in liver TGF-beta1 gene expression and an increase in mitotic index and PCNA after hepatectomy were observed in the PTX treatment group in comparison to the saline group. CONCLUSION: PTX improves liver regeneration by a mechanism related to down regulation of TNF-alpha production and TGF-beta1 gene expression. PMID- 22816030 TI - Postoperative pneumoperitoneum after colorectal surgery: Expectant vs surgical management. AB - Postoperative pneumoperitoneum poses a clinical dilemma. Depending on the cause, its management includes a spectrum from simple observation and supportive care to surgical exploration. The aim of this paper is to present four clinical cases and propose an algorithm for the management of postoperative pneumoperitoneum based on available literature. The causes, diagnosis and possible complications arising from pneumoperitoneum will also be discussed. Three of the four cases presented were successfully managed conservatively and one had an exploratory laparotomy with negative findings. In such scenarios, it is important to consider the nonsurgical causes of pneumoperitoneum, which include pseudopneumoperitoneum, thoracic, abdominal, gynecological and idiopathic. These causes do not always require emergent exploratory laparotomy. The surgical team needs to consider the history, physical exam and diagnostic workup of the patient. If a patient presents with peritoneal signs, then exploratory laparotomy is a must. Since 10% of the cases of pneumoperitoneum are caused by nonsurgical entities, managed expectantly, a negative exploratory laparotomy and its associated risks are avoided. PMID- 22816031 TI - Solitary rectal cap polyp: Case report and review of the literature. AB - Rectal bleeding combined with the presence of a rectal mass has been traditionally associated with the presence of malignant disease. Cap polyposis is a relatively young and still undefined rare entity which mainly involves the rectosigmoid. It is characterized by the presence of inflammatory polyps. In this case report, we present a patient who was diagnosed with a solitary cap polyp of the rectum during the investigation of a bleeding rectal mass. The patient's age and the absence of family history were not in favor of malignancy, despite the strong initial clinical impression. After confirmation of the diagnosis, the patient underwent a snare excision and remains asymptomatic. Cap polyposis, although rare, should be suspected and, when diagnosed, should be treated according to location, number of polyps and severity of symptoms. PMID- 22816032 TI - Evaluation of different antiretroviral drug protocols on naturally infected feline immunodeficiency virus (FIV) cats in the late phase of the asymptomatic stage of infection. AB - The aim of this study was to evaluate the efficacy of the antiretrovirals: Zidovudine (ZDV) alone; ZDV + Recombinant Human Interferon-alpha (rHuIFN-alpha); ZDV + Lamivudine (3TC) and ZDV + valproic acid (Valp) on naturally feline immunodeficiency virus (FIV)-infected cats, in the late phase of the asymptomatic stage of infection. The follow-up was performed over one year, through clinical evaluation and the determination of viral loads and CD4+/CD8+ ratios. Neurological signs were studied by visual and auditory evoked potentials (VEP, AEP) and the responses were abnormal in 80% of the FIV-infected cats. After one year, an improvement in VEP and AEP was observed in the ZDV + Valp group and a worsening in the group receiving ZDV + rHuIFN-alpha. The CD4+/CD8+ ratio showed a significant increase (both intra and inter-groups) only in ZDV and ZDV + 3TC, between their pre-treatment and one year values, as well as among the other groups. Viral load only showed a significant decrease in ZDV and ZDV + 3TC groups, when comparing the values at one year of treatment vs. pre-treatment values and when the different groups were compared. In addition, the viral load decrease was significantly more pronounced in the ZDV + 3TC vs. ZDV group. We conclude that ZDV and ZDV + 3TC produce significant reductions in viral load and stimulate a recovery of the CD4+/CD8+ ratio, compared with the other protocols. It is clear that the addition of 3TC resulted in a greater reduction in viral load than use of ZDV as a single drug. Therefore, the combination ZDV + 3TC could be more effective than the sole use of ZDV. PMID- 22816033 TI - Analysis of sequence polymorphism and population structure of tomato chlorotic dwarf viroid and potato spindle tuber viroid in viroid-infected tomato plants. AB - The sequence polymorphism and population structure of Tomato chlorotic dwarf viroid (TCDVd) (isolate Trust) and Potato tuber spindle viroid (PSTVd) (isolate FN) in tomato plants were investigated. Of the 9 and 35 TCDVd clones sequenced from 2 different TCDVd-infected plants, 2 and 4 sequence variants were identified, respectively, leading to a total of 4 sequence variants of 360 nucleotides in length. Variant I was identical to AF162131, the first TCDVd sequence to be reported, and the rest exhibited 1 to 3 nucleotide differences, all in the T(R) domain, from AF162131/variant I. Of the 33 and 29 PSTVd clones sequenced from 2 different PSTVd-infected plants, 8 and 9 sequence variants were found, respectively, leading to a total of 15 variants ranging in length from 356 to 359 nucleotides. The variant I was identical to EF044303, a PSTVd reported in Russia. The rest exhibited 1 to 11 nucleotide differences scattering in all five domains from EF044303/variant I. The results demonstrated for the first time that TCDVd, like many other viroids including PSTVd, exists in host plants as a collective group comprised of various sequence variants. However, in comparison to PSTVd, TCDVd is less polymorphic in tomato plants as fewer variants and lower haplotype/nucleotide diversities were observed. PMID- 22816034 TI - Administration of Fozivudine tidoxil as a single-agent therapeutic during acute feline immunodeficiency virus infection does not alter chronic infection. AB - Initiating combination antiretroviral therapy (ART) during acute HIV infection has been correlated with decreased viral set point and improved lymphocyte function. However, the long term effects of single-agent therapy administered only during the acute stage of infection (interrupted treatment) remain largely uncharacterized. In this study we provide longitudinal data using the feline immunodeficiency virus (FIV) model for HIV infection. Infected cats were treated with a prophylactic single-agent therapy, Fozivudine tidoxil (FZD), for six weeks, starting one day before infection. The initial acute infection study, reported elsewhere, demonstrated a decrease in plasma- and cell-associated viremia at two weeks post-infection (PI) in FZD-treated cats as compared to placebo-treated cats. We hypothesized that this early alteration in plasma- and cell-associated viremia would alter the virus set point and ultimately affect the outcome of chronic infection. Here we provide data at one, two and three years PI for plasma- and/or cell-associated viremia, total lymphocyte counts and CD4:CD8 ratios. There was no difference in viremia or cell counts between treated and nontreated groups at all time points tested. Contrary to our hypothesis, these results suggest that treatment with a single agent anti-retroviral drug during acute lentivirus infection does not significantly alter viral load and immune function during the chronic, asymptomatic stage of infection. PMID- 22816035 TI - Application of live-cell RNA imaging techniques to the study of retroviral RNA trafficking. AB - Retroviruses produce full-length RNA that serves both as a genomic RNA (gRNA), which is encapsidated into virus particles, and as an mRNA, which directs the synthesis of viral structural proteins. However, we are only beginning to understand the cellular and viral factors that influence trafficking of retroviral RNA and the selection of the RNA for encapsidation or translation. Live cell imaging studies of retroviral RNA trafficking have provided important insight into many aspects of the retrovirus life cycle including transcription dynamics, nuclear export of viral RNA, translational regulation, membrane targeting, and condensation of the gRNA during virion assembly. Here, we review cutting-edge techniques to visualize single RNA molecules in live cells and discuss the application of these systems to studying retroviral RNA trafficking. PMID- 22816038 TI - Information processing capacity of dynamical systems. AB - Many dynamical systems, both natural and artificial, are stimulated by time dependent external signals, somehow processing the information contained therein. We demonstrate how to quantify the different modes in which information can be processed by such systems and combine them to define the computational capacity of a dynamical system. This is bounded by the number of linearly independent state variables of the dynamical system, equaling it if the system obeys the fading memory condition. It can be interpreted as the total number of linearly independent functions of its stimuli the system can compute. Our theory combines concepts from machine learning (reservoir computing), system modeling, stochastic processes, and functional analysis. We illustrate our theory by numerical simulations for the logistic map, a recurrent neural network, and a two dimensional reaction diffusion system, uncovering universal trade-offs between the non-linearity of the computation and the system's short-term memory. PMID- 22816036 TI - Recent progress in studies of arterivirus- and coronavirus-host interactions. AB - Animal coronaviruses, such as infectious bronchitis virus (IBV), and arteriviruses, such as porcine reproductive and respiratory syndrome virus (PRRSV), are able to manifest highly contagious infections in their specific native hosts, thereby arising in critical economic damage to animal industries. This review discusses recent progress in studies of virus-host interactions during animal and human coronavirus and arterivirus infections, with emphasis on IBV-host cell interactions. These interactions may be directly involved in viral replication or lead to the alteration of certain signaling pathways, such as cell stress response and innate immunity, to facilitate viral replication and pathogenesis. PMID- 22816037 TI - Mechanisms of coronavirus cell entry mediated by the viral spike protein. AB - Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S) mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes-A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses. PMID- 22816039 TI - Targeting JNK for therapeutic depletion of stem-like glioblastoma cells. AB - Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells. PMID- 22816040 TI - Ultraviolet shadowing of RNA can cause significant chemical damage in seconds. AB - Chemical purity of RNA samples is important for high-precision studies of RNA folding and catalytic behavior, but photodamage accrued during ultraviolet (UV) shadowing steps of sample preparation can reduce this purity. Here, we report the quantitation of UV-induced damage by using reverse transcription and single nucleotide-resolution capillary electrophoresis. We found photolesions in a dozen natural and artificial RNAs; across multiple sequence contexts, dominantly at but not limited to pyrimidine doublets; and from multiple lamps recommended for UV shadowing. Irradiation time-courses revealed detectable damage within a few seconds of exposure for 254 nm lamps held at a distance of 5 to 10 cm from 0.5-mm thickness gels. Under these conditions, 200-nucleotide RNAs subjected to 20 seconds of UV shadowing incurred damage to 16-27% of molecules; and, due to a 'skin effect', the molecule-by-molecule distribution of lesions gave 4-fold higher variance than a Poisson distribution. Thicker gels, longer wavelength lamps, and shorter exposure times reduced but did not eliminate damage. These results suggest that RNA biophysical studies should report precautions taken to avoid artifactual heterogeneity from UV shadowing. PMID- 22816042 TI - Tuning charge and spin excitations in zigzag edge nanographene ribbons. AB - Graphene and its quasi-one-dimensional counterpart, graphene nanoribbons, present an ideal platform for tweaking their unique electronic, magnetic and mechanical properties by various means for potential next-generation device applications. However, such tweaking requires knowledge of the electron-electron interactions that play a crucial role in these confined geometries. Here, we have investigated the magnetic and conducting properties of zigzag edge graphene nanoribbons (ZGNRs) using the many-body configuration interaction (CI) method on the basis of the Hubbard Hamiltonian. For the half-filled case, the many-body ground state shows a ferromagnetic spin-spin correlation along the zigzag edge, which supports the picture obtained from one-electron theory. However, hole doping reduces the spin and charge excitation gap, making the ground state conducting and magnetic. We also provide a two-state model that explains the low-lying charge and spin excitation spectrum of ZGNRs. An experimental setup to confirm the hole-mediated conducting and magnetic states is discussed. PMID- 22816041 TI - Evolution of cariogenic character in Streptococcus mutans: horizontal transmission of glycosyl hydrolase family 70 genes. AB - Acquisition of the ability to produce polysaccharides from sucrose, i.e. the gtf gene encoding glucosyltransferase (GTF), is the key evolutionary event enabling dental biofilm formation by streptococci. To clarify the ancestry of streptococcal GTFs, time of its occurrence, and order of specific events, we investigated the distribution of GTFs among bacteria by phylogenetic analysis of the glycosyl hydrolase family 70 enzymes. We found that streptococcal GTFs were derived from other lactic acid bacteria such as Lactobacillus and Leuconostoc, and propose the following evolutionary model: horizontal gene transfer via transposons occurred when streptococci encountered lactic acid bacteria contained in fermented food. Intra-genomic gene duplication occurred by a secondary selection pressure such as consumption of refined sugar. Our findings concerning this evolution in Streptococcus mutans provide an important background for studies of the relationship between the historical spread of dental caries and anthropological factors. PMID- 22816044 TI - Adult neurological handicap: new insight from neurogenesis. PMID- 22816043 TI - Crystal structure of graphite under room-temperature compression and decompression. AB - Recently, sophisticated theoretical computational studies have proposed several new crystal structures of carbon (e.g., bct-C(4), H-, M-, R-, S-, W-, and Z carbon). However, until now, there lacked experimental evidence to verify the predicted high-pressure structures for cold-compressed elemental carbon at least up to 50 GPa. Here we present direct experimental evidence that this enigmatic high-pressure structure is currently only consistent with M-carbon, one of the proposed carbon structures. Furthermore, we show that this phase transition is extremely sluggish, which led to the observed broad x-ray diffraction peaks in previous studies and hindered the proper identification of the post-graphite phase in cold-compressed carbon. PMID- 22816045 TI - Adult neurogenesis in the central and peripheral nervous systems. AB - Neurogenesis occurs during embryonic development and continues throughout adulthood. Although spontaneous adult neurogenesis is restricted to selective germinal regions, including the subventricular zone and dentate gyrus of the hippocampus, neural stem cells (NSCs) are widely distributed in the central and peripheral nervous systems. Besides their ability to integrate into existing neural networks during physiological conditions, NSCs also proliferate and differentiate in response to injury, thus promising the potential use of endogenous NSCs for the treatment of neuropathological conditions. In this review, we discuss recent progress in the understanding of adult neurogenesis in the brain and peripheral nervous system. PMID- 22816046 TI - Modulation of alpha 1 adrenergic receptors on urinary bladder in rat spinal cord injury model. AB - PURPOSE: Whereas many studies have focused on the vesical changes of the alpha1 adrenergic receptor (AR) subtypes in partial outlet obstruction, few studies have addressed the modulation of the alpha1 AR subtypes after spinal cord injury (SCI). Therefore, we studied the modulation of the alpha1 ARs in urinary bladder in a rat SCI model. METHODS: Four weeks after a SCI, the whole vesical bodies from eight female Sprague-Dawley rats and from eight controls were harvested. The total RNA was extracted from the samples and was used to prepare cDNA. We developed standard plasmid constructs of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and three alpha1 ARs (alpha1a, alpha1b, and alpha1d) to convert the cycle threshold (Ct) values from real-time polymerase chain reaction (RT-PCR) into subtype mRNA concentrations. The detected Ct values of 16 samples from RT-PCR were interpolated into the standard plasmid curves. RESULTS: All serially diluted standard samples showed very good linearity. The mRNA expression of GAPDH was higher in the SCI group, whereas the mRNA expression of all alpha1 ARs was lower in the SCI group than in the control animals. The alpha1a, alpha1b, and alpha1d mRNA expression in the controls was 81.7%, 3.3%, and 15.1%, respectively, whereas the alpha1a, alpha1b, and alpha1d mRNA expression in the SCI group was 33.5%, 5.2%, and 60.9%, respectively. CONCLUSIONS: SCI moderates the alpha1 AR mRNA subtypes in the urinary bladder. The relatively increased alpha1d or decreased alpha1a AR mRNA expression may be a therapeutic candidate for controlling the symptoms of neurogenic bladder after SCI. PMID- 22816047 TI - Function of the Cold Receptor (TRPM8) Associated with Voiding Dysfunction in Bladder Outlet Obstruction in Rats. AB - PURPOSE: Bladder outlet obstruction (BOO) causes storage and voiding dysfunction in the lower urinary tract. We investigated the expression of transient receptor potential cation channel subfamily M member 8 (TRPM8) to evaluate the relationship between TRPM8 expression and overactive bladder (OAB) in a rat model of BOO. METHODS: Fifty female Sprague-Dawley rats were divided into 4 groups; normal (n=10), normal-menthol (n=10), BOO (n=15), BOO-menthol (n=15). After 3 weeks, cystometry was performed by infusing physiological saline and menthol (3 mM) into the bladder at a slow infusion rate. The histological changes and expression of TRPM8 in the bladder were investigated by Masson's trichrome staining, immunofluorescence and reverse transcription-polymerase chain reaction. RESULTS: Cystometry showed that the intercontraction interval (ICI; 428.2+/-23.4 vs. 880.4+/-51.2, P<0.001), micturition pressure (MP; 25.7+/-1.01 vs. 71.80+/ 3.01, P<0.001), and threshold pressure (2.9+/-0.25 vs. 9.2+/-1.58, P<0.01) were significantly increased in BOO rats. The bladder wall was significantly dilated compared with the control. Detrusor muscle hypertrophy and a thick mucosa layer were observed in BOO bladder. After menthol treatment, ICIs were decreased and MPs were increased in the menthol treatment groups. TRPM8-positive cells and mRNA were predominantly increased in the bladder and dorsal root ganglia of all groups compared with the normal group. CONCLUSIONS: Increased bladder wall thickness and proportion of collagen probably affect voiding dysfunction. Furthermore, an increase of TRPM8 expression in BOO may induce entry of Ca(2+) from the extracellular space or stores. The increase of Ca(2+) probably causes contraction of smooth muscle in BOO. However, OAB symptoms were not observed after menthol treatment although the expression of TRPM8 was abundant in the bladder epithelium after menthol treatment. Although OAB in BOO models may be caused by complex pathways, regulation of TRPM8 presents possibilities for OAB treatment. PMID- 22816048 TI - Psychometric Properties of the Korean Version of the Overactive Bladder Questionnaire (OAB-q) in a Korean Population. AB - PURPOSE: Psychometric properties of the overactive bladder questionnaire (OAB-q) were recently examined. However, since the cross-cultural adaptation of a non English version of the OAB-q has never been demonstrated, we evaluated the psychometric properties of a Korean version of the OAB-q in a Korean population with OAB. METHODS: A prospective cohort study involving 116 women with 58 OAB and 58 control subjects was performed and convergent validity was assessed. Total and subscale OAB-q scores of the control and OAB groups were compared to their sensitivity to score changes before and after administering anti-cholinergic medication for 12 weeks. Short form 36 and King's health questionnaire (KHQ) were also used for comparison or correlation. RESULTS: Assessment of face validity showed that the Korean version of the OAB-q was reasonable with OAB-q subscale scores being significantly different between the control and patient groups. Significant correlation (range, -0.29 to -0.81) was found between the OAB-q scores and KHQ results for the OAB patients. Cronbach's alpha coefficients (range, 0.77 to 0.95) indicated excellent internal consistency and test-retest analysis involving 35 OAB patients showed that each questions as well as subscale scores were reproducible. Each score of OAB-q also showed statistically significant sensitivity to changes following anti-muscarinic treatment for OAB (n=27, P<0.001 except for social, P=0.059). CONCLUSIONS: The Korean version of the OAB-q is a valid and reliable instrument to measure outcomes in Korean patients with OAB. PMID- 22816049 TI - Prevalence of stress urinary incontinence in women with multiple sclerosis. AB - PURPOSE: The purpose of this study was to determine the prevalence of stress urinary incontinence (SUI) in women with multiple sclerosis (MS) and to what degree these women are bothered by their SUI, since there is a paucity of literature regarding the nature of SUI in this unique population of women. METHODS: We conducted a prospective Institutional Review Board approved study. Women scheduled for outpatient follow-up appointments at a dedicated MS center were asked to complete a questionnaire regarding urinary incontinence. Urgency urinary incontinence (UUI) and SUI were defined as an answer of slightly, moderately or greatly to the Urogenital Distress Inventory (UDI-6) question #2 and question #3, respectively. Impact of SUI on physical activity was determined by Incontinence Impact Questionnaire (IIQ-7) question #2. RESULTS: A total of 55.9% (80/143) women had SUI, 70.6% (101/143) women had UUI, and 44.8% (64/143) women had mixed urinary incontinence. The mean age was 45.8 years old (range, 20 to 72 years). Women with SUI were significantly older (mean, 47.2 vs. 41.9; P=0.023) and there was a trend towards a greater body mass index (mean, 29.3 vs. 26.5; P=0.057). Women with SUI had significantly higher IIQ-7 scores compared to women without SUI (P<0.001). Impact of urinary incontinence on physical activity was also found to be significantly greater in women with SUI (mean IIQ-7 question #2, 0.96 vs. 0.35; P<0.001). CONCLUSIONS: The prevalence of SUI in women with MS is 55.9% and the presence of SUI has a significant impact on their quality of life. A comprehensive urologic evaluation of a woman with MS should include assessment of SUI. PMID- 22816050 TI - Short-term Effect of Radical Hysterectomy with or without Adjuvant Radiation Therapy on Urodynamic Parameters in Patients with Uterine Cervical Cancer. AB - PURPOSE: Lower urinary tract dysfunction is the most common complication after radical pelvic surgery. The aims of this study were to assess the effect of radical hysterectomy (RH) on the storage function of the lower urinary tract and to evaluate the impact of radiation therapy (RT) on postoperative urodynamic parameters. METHODS: This was a retrospective review of preoperative and postoperative urodynamic variables, which were prospectively collected. All women from 2006 to 2008, who underwent RH for uterine cervical cancer with a stage of 1A to 2B with or without adjuvant RT were enrolled. All patients were divided into two groups: group 1, without RT, and group 2, with adjuvant RT. Urodynamic studies were performed before, 10 days after, and 6 months after RH. RESULTS: A total of 42 patients with a mean (+/-standard error) age of 51.9 (+/-12.3) years were analyzed. There were no significant differences in age, body mass index or clinical stage between the two groups. On the 10th postoperative day, all parameters were decreased except postvoid residual volume. In comparison with group 2 (n=14), group 1 (n=28) showed a significant increase in bladder compliance. At 6 months postoperatively, bladder compliance in group 1 had increased four times or more compared with that on postoperative 10 days. However, it had increased only 2.5 times in group 2 at the same time point (P<0.001). CONCLUSIONS: The results of our study suggest that adjuvant RT after RH might result in a deterioration of bladder compliance. It is highly suggested that practitioners pay attention to low bladder compliance, especially in patients who have adjuvant RT after RH. PMID- 22816051 TI - Perineum-based Pediculated Scrotal Flap for Reconstructive Urethral Surgery. AB - Herein, we describe a perineum-based pediculated scrotal flap procedure for urethral reconstruction. A scrotal tubular flap was used as a substitute to correct a proximal penile urethral stricture in case 1. In case 2, a scrotal island patch was performed to treat an iatrogenic penile urethral injury. In both cases, the urethral catheter was removed on postoperative day 14 with simultaneous normal voiding cystourethrography. The excellent axial vascularization of this perineum-based pediculated scrotal flap procedure allows successful urethral reconstruction, regardless of extension, location, and etiology. PMID- 22816052 TI - New hope for wound healing after bowel resection. PMID- 22816053 TI - Good Post-operative Results Depend on Strict Patient Selection and Strict Operative Procedure. PMID- 22816054 TI - T3 subdivision correlation with nodal or distant metastasis in colorectal cancer; is it practically useful? PMID- 22816056 TI - Adipose-tissue-derived Stem Cells Enhance the Healing of Ischemic Colonic Anastomoses: An Experimental Study in Rats. AB - PURPOSE: This experimental study verified the effect of adipose-tissue-derived stem cells (ASCs) on the healing of ischemic colonic anastomoses in rats. METHODS: ASCs were isolated from the subcutaneous fat tissue of rats and identified as mesenchymal stem cells by identification of different potentials. An animal model of colonic ischemic anastomosis was induced by modifying Nagahata's method. Sixty male Sprague-Dawley rats (10-week-old, 370 +/- 50 g) were divided into two groups (n = 30 each): a control group in which the anastomosis was sutured in a single layer with 6-0 polypropylene without any treatment and an ASCtreated group (ASC group) in which the anastomosis was sutured as in the control group, but then ASCs were locally transplanted into the bowel wall around the anastomosis. The rats were sacrificed on postoperative day 7. Healing of the anastomoses was assessed by measuring loss of body weight, wound infection, anastomotic leakage, mortality, adhesion formation, ileus, anastomotic stricture, anastomotic bursting pressure, histopathological features, and microvascular density. RESULTS: No differences in wound infection, anastomotic leakage, or mortality between the two groups were observed. The ASC group had significantly more favorable anastomotic healing, including less body weight lost, less ileus, and fewer ulcers and strictures, than the control group. ASCs augmented bursting pressure and collagen deposition. The histopathological features were significantly more favorable in the ASC group, and microvascular density was significantly higher than it was in the control group. CONCLUSION: Locally-transplanted ASCs enhanced healing of ischemic colonic anastomoses by increasing angiogenesis. ASCs could be a novel strategy for accelerating healing of colonic ischemic risk anastomoses. PMID- 22816057 TI - Comparison of Long-term Clinical Outcomes according to the Change in the Rectocele Depth between Transanal and Transvaginal Repairs for a Symptomatic Rectocele. AB - PURPOSE: This study was aimed to compare the results of a transanal repair with those of a transvaginal levatorplasty and to determine the long-term clinical outcomes according to the change in the depth of the rectocele after the procedure. METHODS: Of 50 women who underwent a rectocele repair from March 2005 to February 2007, 26 women (group A) received a transanal repair, and 24 (group B) received a transvaginal repair with or without levatorplasty. At 12 months after the procedures, 45 (group A/B, 22/23 women) among the 50 women completed physiologic studies, including anal manometry and defecography, and clinical outcome measurements. The variations of the clinical outcomes with changes in the depth of the rectocele were also evaluated in 42 women (group A/B, 20/22) at the median follow-up of 50 months. RESULTS: On the defecographic findings, the postoperative depth of the rectocele decreased significantly in both groups (group A vs. B, 1.91 +/- 0.20 vs. 2.25 +/- 0.46, P = 0.040). At 12 months after surgery, 17 women in each group (group A/B, 77/75%) reported improvement of their symptoms. However, only 11 and 13 women (group A/B, 55/59%) of groups A and B, respectively, maintained their improvement at the median follow-up of 50 months. Better results were reported in patients with a greater change in the depth of their rectocele (>=4 cm) after the procedure (P = 0.001) CONCLUSION: In both procedures, clinical outcomes might become progressively worse as the length of the follow-up is increased. PMID- 22816055 TI - A comprehensive review of inflammatory bowel disease focusing on surgical management. AB - The two main diseases of inflammatory bowel disease are Crohn's disease and ulcerative colitis. The pathogenesis of inflammatory disease is that abnormal intestinal inflammations occur in genetically susceptible individuals according to various environmental factors. The consequent process results in inflammatory bowel disease. Medical treatment consists of the induction of remission in the acute phase of the disease and the maintenance of remission. Patients with Crohn's disease finally need surgical treatment in 70% of the cases. The main surgical options for Crohn's disease are divided into two surgical procedures. The first is strictureplasty, which can prevent short bowel syndrome. The second is resection of the involved intestinal segment. Simultaneous medico-surgical treatment can be a good treatment strategy. Ulcerative colitis is a diffuse nonspecific inflammatory disease that involves the colon and the rectum. Patients with ulcerative colitis need surgical treatment in 30% of the cases despite proper medical treatment. The reasons for surgical treatment are various, from life-threatening complications to growth retardation. The total proctocolectomy (TPC) with an ileal pouch anal anastomosis (IPAA) is the most common procedure for the surgical treatment of ulcerative colitis. Medical treatment for ulcerative colitis after a TPC with an IPAA is usually not necessary. PMID- 22816058 TI - The influence of nutritional assessment on the outcome of ostomy takedown. AB - PURPOSE: Ostomy takedown is often considered a simple procedure without intention; however, it is associated with significant morbidity. This study is designed to evaluate factors predicting postoperative complications in the ostomy takedown in view of metabolism and nutrition. METHODS: A retrospective, institutional review-board-approved study was performed to identify all patients undergoing takedown of an ostomy from 2004 to 2010. RESULTS: Of all patients (150), 48 patients (32%; male, 31; female, 17) had complications. Takedown of an end-type ostomy showed a high complication rate; complications occurred in 55.9% of end-type ostomies and 15.7% of loop ostomies (P < 0.001). Severe adhesion was also related to a high rate of overall complication (41.3%) (P = 0.024). In preoperative work-up, ostomy type was not significantly associated with malnutrition status. However, postoperatively severe malnutrition level (albumin <2.8 mg/dL) was statistically significant in increasing the risk of complications (72.7%, P = 0.015). In particular, a significant postoperative decrease in albumin (>1.3 mg/dL) was associated with postoperative complications, particularly surgical site infection (SSI). Marked weight loss such as body mass index downgrading may be associated with the development of complications. CONCLUSION: A temporary ostomy may not essentially result in severe malnutrition. However, a postoperative significant decrease in the albumin concentration is an independent risk factor for the development of SSI and complications. PMID- 22816059 TI - Appendicitis during Pregnancy: The Clinical Experience of a Secondary Hospital. AB - PURPOSE: Appendicitis is the most common condition leading to an intra-abdominal operation for a non-obstetric problem in pregnancy. The aim of this study was to examine our experience and to analyze the clinical characteristics and the pregnancy outcomes for appendicitis during pregnancy that was reported in Korea. METHODS: We reported 25 cases of appendicitis during pregnancy that were treated at Good Moonhwa Hospital from January 2004 to March 2010. We also analyzed appendicitis during pregnancy reported in Korea between 1970 and 2008 by a review of journals. RESULTS: The incidence of acute appendicitis during pregnancy was one per 568 deliveries. The mean age was 27.92 years old, the gestational stage at the onset of symptoms was the first trimester in 10 patients (40%), the second trimester in 14 patients (56%), and the third trimester in 1 patient (4%). Among the 25 cases, 21 were treated with an open appendectomy and 4 with laparoscopic appendectomies. The postoperative complications were 2 wound infections and 1 spontaneous abortion. CONCLUSION: Our experience demonstrated that appendectomies on pregnant patients can be successfully performed at secondary hospitals. PMID- 22816060 TI - Does t3 subdivision correlate with nodal or distant metastasis in colorectal cancer? AB - PURPOSE: We analyzed the clinical data of T3 colorectal cancer patients to assess whether T3 subdivision correlates with node (N) or metastasis (M) staging and stage-independent factors. METHODS: Five hundred fifty-five patients who underwent surgery for primary colorectal cancer from January 2003 to December 2009 were analyzed for T3 subdivision. T3 subdivision was determined by the depth of invasion beyond the outer border of the proper muscle (T3a, <1 mm; T3b, 1 to 5 mm; T3c, >5 to 15 mm; T3d, >15 mm). We investigated the correlation between T3 subdivision and N, M staging and stage-independent prognostic factors including angiolymphatic invasion (ALI), venous invasion (VI) and perineural invasion (PNI). RESULTS: The tumors of the 555 patients were subclassified as T3a in 86 patients (15.5%), T3b in 209 patients (37.7%), T3c in 210 patients (37.8%) and T3d in 50 patients (9.0%). The nodal metastasis rates were 39.5% for T3a, 56.5% for T3b, 75.7% for T3c and 74.0% for T3d. The distant metastasis rates were 7.0% for T3a 9.1% for T3b, 27.1% for T3c and 40.0% for T3d. Both N and M staging correlated with T3 subdivision (Spearman's rho = 0.288, 0.276, respectively; P < 0.001). Other stage-independent prognostic factors correlated well with T3 subdivision (Spearman's rho = 0.250, P < 0.001 for ALI; rho = 0.146, P < 0.001 for VI; rho = 0.271, P < 0.001 for PNI). CONCLUSION: Subdivision of T3 colorectal cancer correlates with nodal and metastasis staging. Moreover, it correlates with other prognostic factors for colorectal cancer. PMID- 22816061 TI - Treatment of a recurrent rectourethral fistula by using transanal rectal flap advancement and fibrin glue: a case report. AB - Rectourethral fistulas (RUFs) in adults are rare and could result from complicated trauma, and prostatic or rectal surgery. RUFs have been treated initially by using primary repair and omental interposition with or without a colostomy during surgery. Recurrent RUFs require complex surgery, such as a low rectal resection and coloanal anastomosis, an interposition flap of the datos muscle or gracilis muscle, and others. Recently, transanal rectal flap advancement and fibrin glue injection have provided an effective occlusion of RUFs. However, no reports about this technique exist for cases of recurrent RUFs. We report a case of a recurrent RUF successfully repaired by using transanal rectal flap advancement combined with fibrin glue injection into the fistula tract. The postoperative course was uneventful without complications. At the 1 year follow-up, no complications such as urethral stricture or recurrence existed, and voiding was normal without anal incontinence. PMID- 22816062 TI - A case of rectal cancer in a patient with neurofibromatosis type 1. AB - A rectal cancer was found in a 67-year-old man with a history of neurofibromatosis type 1. A low anterior resection was performed, and he received concurrent chemoradiation for 6 months. Twelve months after the surgery, a tumor was found at the anastomotic site by positron emission tomography-computed tomography and colonoscopy and was mistaken as anastomotic site recurrence. The tumor was confirmed as an inflammatory myofibroblastic tumor through transanal excision. PMID- 22816063 TI - Physician-Researchers' Experiences of the Consent Process in the Sociocultural Context of a Developing Country. AB - Background: International guidelines for medical research involving human subjects maintain the primacy of informed consent while recognizing cultural diversity. Methods: This article draws on empirical data obtained from interviews with physician-researchers in teaching hospitals of Lahore, Pakistan, to identify social and cultural factors that affect the consent process for participants in research. Results: This article presents variable findings with regards to communication, comprehension, and decision making. While some physicians consider that social factors such as lack of education, a patriarchal family system, and skepticism about research can make patients dependent on either the physician researcher or the family, others believe that patients do make independent decisions. Conclusions: In light of the findings, the article ends with a recommendation for communication and decision making that is sensitive to the local sociocultural environment while at the same time meeting the ethical imperative of respect for persons. PMID- 22816064 TI - Reconstruction options for acetabular revision. AB - This article summarizes reconstruction options available for acetabular revision following total hip arthroplasty. A thoughtful methodology to the evaluation and treatment of patients with implant failure after joint replacement is essential to guarantee accurate diagnoses, appropriate triage to reconstruction options, and optimal clinical outcomes. In the majority of patients who undergo acetabular revision, factors such as bone loss and pelvic discontinuity provide a challenge in the selection and implementation of the proper reconstruction option. With advanced evaluation algorithms, imaging techniques, and implant designs, techniques have evolved to rebuild the compromised acetabulum at the time of revision surgery. However, clinical outcomes data for these techniques continue to lag behind the exponential increase in revision hip arthroplasty cases predicted to occur over the next several years. We encourage those involved in the treatment of patients undergoing hip replacement surgery to participate in well-designed clinical studies to enhance evidence-based knowledge regarding revision acetabular reconstruction options. PMID- 22816066 TI - Giant pseudomeningocele after spinal surgery: A case report. AB - Very few reports have described giant pseudomeningoceles >= 8 cm in diameter. We report this case of the biggest giant pseudomeningocele at the unusual cervicothoracic level. A 59 year old man who underwent cervicothoracic laminectomy had a giant pseudomeningocele detected and the lesion gradually grew to about 15 cm in diameter by 2 years postoperatively. Cerebrospinal fluid leak closure was performed and the postoperative course was favorable. We present this case, review the literature and discuss the size and portion, mechanism of formation, symptoms and treatments of giant pseudomeningocele. PMID- 22816065 TI - Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus. AB - Osteochondral lesions of the talus are common injuries in the athletic patient. They present a challenging clinical problem as cartilage has a poor potential for healing. Current surgical treatments consist of reparative (microfracture) or replacement (autologous osteochondral graft) strategies and demonstrate good clinical outcomes at the short and medium term follow-up. Radiological findings and second-look arthroscopy however, indicate possible poor cartilage repair with evidence of fibrous infill and fissuring of the regenerative tissue following microfracture. Longer-term follow-up echoes these findings as it demonstrates a decline in clinical outcome. The nature of the cartilage repair that occurs for an osteochondral graft to become integrated with the native surround tissue is also of concern. Studies have shown evidence of poor cartilage integration, with chondrocyte death at the periphery of the graft, possibly causing cyst formation due to synovial fluid ingress. Biological adjuncts, in the form of platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have been investigated with regard to their potential in improving cartilage repair in both in vitro and in vitro settings. The in vitro literature indicates that these biological adjuncts may increase chondrocyte proliferation as well as synthetic capability, while limiting the catabolic effects of an inflammatory joint environment. These findings have been extrapolated to in vitro animal models, with results showing that both PRP and BMAC improve cartilage repair. The basic science literature therefore establishes the proof of concept that biological adjuncts may improve cartilage repair when used in conjunction with reparative and replacement treatment strategies for osteochondral lesions of the talus. PMID- 22816067 TI - USING LIVED EXPERIENCES OF ADULTS TO UNDERSTAND CHRONIC PAIN: SICKLE CELL DISEASE, AN EXEMPLAR. AB - Healthcare provision pertaining to painful, chronic conditions can best be optimized by developing positive healthcare provider (HCP)-patient relationships that minimize fragmented care. Nurses, with their holistic, humanistic approach provide a multidimensional focus that fosters individualized and effective outcomes for chronic events. The chronic pain phenotype is subjective, difficult to assess, define and effectively manage. Individuals with one such chronic syndrome, sickle cell disease (SCD), are living longer with pain that is poorly defined and inadequately managed. In addition to using quantitative assessment, clinicians and researchers must use substantive qualitative inquiry to understand the pain from the individual's perspective, define, and appropriately manage the pain. Combined quantitative and qualitative inquiry can help clinicians and researchers gain insights into pain experiences. This manuscript summarizes the importance of including a narrative (qualitative) inquiry, to offer a holistic, comprehensive and humanistic approach to understanding chronic pain from the individual's perspective and subsequently positively impacting care delivery. All nurses in the academy-educators, clinicians and researches need to include a qualitative approach to care delivery, investigation and evaluation of the phenomenon pain, and intentionally demonstrate care. The experiences of individuals with chronic sickle cell disease (SCD) pain are used as an exemplar. PMID- 22816068 TI - Etv5, a transcription factor with versatile functions in male reproduction. AB - Transcription factors govern diverse aspects of cell growth and differentiation as major switches of gene expression. Etv5, a member of the E26 transformation specific family of transcription factors, has many stories to share when it comes to reproduction. Etv5 deficient mice show complex infertility phenotypes both in males and females. In males, the infertility phenotype exhibited by Etv5 deficiency is sexually dimorphic, and it involves both somatic cells and germ cells. In Etv5(-/-) female mice, the problem is more complicated by hormonal involvement. This review synthesizes old and new information on this versatile transcription factor-from the inadvertent discovery of its role in the testes to its newly discovered role in maintaining spermatogonial stem cells. PMID- 22816069 TI - Fertility preservation in women with cancer. AB - Fertility preservation (FP) is an effort to retain the fertility of cancer patients, and as an emerging discipline, it plays a central role in cancer care. Because of improvement in diagnostic and therapeutic strategies, an increasingly large number of patients are surviving with cancer. FP specialists should make an effort to spread the significance of FP among reproductive women with cancer and provide appropriate education both for associated physicians and for cancer patients who wish to preserve their fertility. Physicians who take part in the initial diagnosis and management of cancer should consider the importance of early referral of young cancer patients to FP specialists and take care of those patients by providing timely information and appropriate counseling. Individualized treatment strategies should be delivered depending on the patient's situation with appropriate team approach. PMID- 22816070 TI - Array comparative genomic hybridization screening in IVF significantly reduces number of embryos available for cryopreservation. AB - OBJECTIVE: During IVF, non-transferred embryos are usually selected for cryopreservation on the basis of morphological criteria. This investigation evaluated an application for array comparative genomic hybridization (aCGH) in assessment of surplus embryos prior to cryopreservation. METHODS: First-time IVF patients undergoing elective single embryo transfer and having at least one extra non-transferred embryo suitable for cryopreservation were offered enrollment in the study. Patients were randomized into two groups: Patients in group A (n=55) had embryos assessed first by morphology and then by aCGH, performed on cells obtained from trophectoderm biopsy on post-fertilization day 5. Only euploid embryos were designated for cryopreservation. Patients in group B (n=48) had embryos assessed by morphology alone, with only good morphology embryos considered suitable for cryopreservation. RESULTS: Among biopsied embryos in group A (n=425), euploidy was confirmed in 226 (53.1%). After fresh single embryo transfer, 64 (28.3%) surplus euploid embryos were cryopreserved for 51 patients (92.7%). In group B, 389 good morphology blastocysts were identified and a single top quality blastocyst was selected for fresh transfer. All group B patients (48/48) had at least one blastocyst remaining for cryopreservation. A total of 157 (40.4%) blastocysts were frozen in this group, a significantly larger proportion than was cryopreserved in group A (p=0.017, by chi-squared analysis). CONCLUSION: While aCGH and subsequent frozen embryo transfer are currently used to screen embryos, this is the first investigation to quantify the impact of aCGH specifically on embryo cryopreservation. Incorporation of aCGH screening significantly reduced the total number of cryopreserved blastocysts compared to when suitability for freezing was determined by morphology only. IVF patients should be counseled that the benefits of aCGH screening will likely come at the cost of sharply limiting the number of surplus embryos available for cryopreservation. PMID- 22816071 TI - Function of the pentose phosphate pathway and its key enzyme, transketolase, in the regulation of the meiotic cell cycle in oocytes. AB - OBJECTIVE: Previously, we identified that transketolase (Tkt), an important enzyme in the pentose phosphate pathway, is highly expressed at 2 hours of spontaneous maturation in oocytes. Therefore, this study was performed to determine the function of Tkt in meiotic cell cycle regulation, especially at the point of germinal vesicle breakdown (GVBD). METHODS: We evaluated the loss-of function of Tkt by microinjecting Tkt double-stranded RNAs (dsRNAs) into germinal vesicle-stage oocytes, and the oocytes were cultured in vitro to evaluate phenotypic changes during oocyte maturation. In addition to maturation rates, meiotic spindle and chromosome rearrangements, and changes in expression of other enzymes in the pentose phosphate pathway were determined after Tkt RNA interference (RNAi). RESULTS: Despite the complete and specific knockdown of Tkt expression, GVBD occurred and meiosis was arrested at the metaphase I (MI) stage. The arrested oocytes exhibited spindle loss, chromosomal aggregation, and declined maturation promoting factor and mitogen-activated protein kinase activities. The modified expression of two enzymes in the pentose phosphate pathway, Prps1 and Rbks, after Tkt RNAi and decreased maturation rates were amended when ribose-5-phosphate was supplemented in the culture medium, suggesting that the Tkt and pentose phosphate pathway are important for the maturation process. CONCLUSION: We concluded that Tkt and its associated pentose phosphate pathway play an important role in the MI-MII transition of the oocytes' meiotic cell cycle, but not in the process of GVBD. PMID- 22816072 TI - Stimulated intrauterine insemination in women with unilateral tubal occlusion. AB - OBJECTIVE: To investigate the value of stimulated intrauterine insemination (IUI) in women with unilateral tubal occlusion. METHODS: Superovulation and IUI was performed during 2003-2010 and the medical records were reviewed retrospectively. Thirty-seven infertile women (52 cycles) with unilateral tubal occlusion diagnosed by hysterosalpingography and without other causes of infertility were selected. One-hundred fourteen patients with unexplained infertility served as a control group (182 cycles). The main outcome was the clinical pregnancy rate per cycle. RESULTS: The pregnancy rate per cycle was similar, 17.3% for the unilateral tubal occlusion group and 16.5% for the unexplained infertility group. The rate of miscarriage (11.1% vs. 23.3%) and ectopic pregnancy (11.1% vs. 6.7%) was similar between the two groups. The pregnancy rate was higher in patients with proximal occlusion (25.0%) compared with distal occlusion (13.9%) or unexplained infertility, but not statistically significant. CONCLUSION: Stimulated IUI can be suggested as the initial treatment option in women with unilateral proximal or distal tubal occlusion. PMID- 22816073 TI - Effects of hypoxia inducible factors-1alpha on autophagy and invasion of trophoblasts. AB - OBJECTIVE: This study was undertaken to determine the effect of hypoxia inducible factor (HIF)-1alpha on the cell death, autophagy, and invasion of trophoblasts. METHODS: To understand the effect of HIF-1alpha, we inhibited HIF-1alpha using siRNA under normoxia and hypoxia conditions. Invasion assay and zymography were performed to determine changes in the invasion ability of HIF-1alpha. Western blotting and immunofluorescence were performed to determine some of the signal events involved in apoptosis and autophagy. RESULTS: There was no difference in cell death through the inhibition of HIF-1alpha expression by siRNA; however, the expression of LC3 and autophagosome formation increased. On the other hand, autophagy was increased, and the invasive ability of trophoblast cells decreased according to the inhibition of HIF-1alpha expression by siRNA. These experimental results mean that HIF-1alpha genes regulate the invasive ability of trophoblasts by increasing autophagy. CONCLUSION: This study contributes important data for understanding the mechanism of early pregnancy implantation and the invasive ability of trophoblasts by defining the relationship between the roles of HIF 1alpha and autophagy. PMID- 22816074 TI - Prooxidant-antioxidant balance and malondialdehyde over time in adult rats after tubal sterilization and vasectomy. AB - OBJECTIVE: Sterilization (tubal sterilization and vasectomy) is a widely applied contraceptive method worldwide. Although most studies have described sterilization as a safe method, there are reports of tubal ligation (TL) and vasectomy complications. The aim of this study was to evaluate the effects of TL and vasectomy on the serum oxidative stress, specifically prooxidant-antioxidant balance (PAB) and malondialdehyde (MDA) levels, over time. METHODS: Male and female rats were classified into vasectomy, sham-vasectomy, TL, and sham-TL groups, respectively. The PAB and MDA levels were measured on days 15 and 45 and months 3 and 6 after the intervention. For female rats, blood sampling was performed during the diestrous phase and estradiol and progesterone were also measured. RESULTS: Serum PAB and MDA increased after TL (p<0.05). Vasectomy increased serum MDA remarkably after 45 days, 3 months, and 6 months (p<0.05). After vasectomy, serum PAB also increased although not significantly. Serum estradiol and progesterone decreased remarkably in the TL group compared to the sham group (p<0.05). CONCLUSION: Bilateral TL and vasectomy both increase the serum oxidative stress; however the imbalance after TL was very noticeable. As for the TL, the reduction of serum estrogen levels can be involved in this imbalance. Complications followed by TL or vasectomy could be due to increased levels of oxidants. Thus, prescribing antioxidants during and or after surgery may be a solution. PMID- 22816075 TI - Lin28 regulates the expression of neuropeptide Y receptors and oocyte-specific homeobox genes in mouse embryonic stem cells. AB - OBJECTIVE: Lin28 has been known to control the proliferation and pluripotency of embryonic stem cells. The purpose of this study was to determine the downstream effectors of Lin28 in mouse embryonic stem cells (mESCs) by RNA interference and microarray analysis. METHODS: The control siRNA and Lin28 siRNA (Dharmacon) were transfected into mESCs. Total RNA was prepared from each type of transfected mESC and subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis to confirm the downregulation of Lin28. The RNAs were labeled and hybridized with an Affymetrix Gene-Chip Mouse Genome 430 2.0 array. The data analysis was accomplished by GenPlex 3.0 software. The expression levels of selected genes were confirmed by quantitative real-time RT-PCR. RESULTS: According to the statistical analysis of the cDNA microarray, a total of 500 genes were altered in Lin28-downregulated mESCs (up-regulated, 384; down regulated, 116). After differentially expressed gene filtering, 31 genes were selected as candidate genes regulated by Lin28 downregulation. Among them, neuropeptide Y5 receptor and oocyte-specific homeobox 5 genes were significantly upregulated in Lin28-downregulated mESCs. We also showed that the families of neuropeptide Y receptor (Npyr) and oocyte-specific homeobox (Obox) genes were upregulated by downregulation of Lin28. CONCLUSION: Based on the results of this study, we suggest that Lin28 controls the characteristics of mESCs through the regulation of effectors such as the Npyr and Obox families. PMID- 22816076 TI - Respiratory response to microinjections of GABA and penicillin into various parts of the ventral respiratory group. AB - Experiments on rats showed that local injection of GABA (10(-4) M) into the rostral and caudal compartments of the ventral respiratory groups decreased the respiratory rhythm, but increased lung ventilation (especially injection into the rostral part). Penicillin (10(-7) M) injected into the rostral division increased the tidal volume and practically did not change the respiratory rate, but its injection into the caudal part reduced the tidal volume and increased respiratory rate. These results indicate that GABAergic mechanisms including GABA(A) sites play an ambiguous role in the regulation of respiration at the level of the rostral and caudal parts of the ventral respiratory group. PMID- 22816077 TI - Behavioral effects of original tetrapeptide, an analog of N-terminal nociceptin fragment. AB - The study examined the effect of an analog to N-terminal nociceptin fragment AcOH*Phe-Gly-Gly-Phe-NH(2) on the behavior of albino rats. This tetrapeptide (5 MUg/kg intraperitoneally) significantly enhanced motor and exploratory activity in mature rats and in 42-day pups and produced opposite effects in 21-day rat pups, which attests to the complex dynamics of maturation of nervous structures involved in the realization of nociceptin action. PMID- 22816078 TI - Effect of single and repeated injections of selective D2-antagonist clebopride on maternal behavior of albino rats. AB - This study examined the effect of clebopride at low concentration that did not modify the motor activity on the parental care in female albino rats. Single injection of the drug attenuated the parental care reactions on postinjection minute 20, but not one day thereafter. The daily injection of the drug during the post partum period (1-6 days) resulted in significantly more pronounced and stable effects. The data obtained substantiated the views on the major contribution of D(2)-receptors in the development of behavioral manifestations of puerperal depression. PMID- 22816079 TI - Activity of the inflammatory process in different types of unstable atherosclerotic plaques. AB - Inflammatory biomarkers and chemoattractants characteristic and important for different types (lipid; inflammatory erosive; degenerative necrotic) of unstable plaques in coronary arteries were identified and studied in male patients with coronary atherosclerosis without acute coronary syndrome we studied. Among the three types of unstable plaques, elevated concentrations of IL-1beta, IL-6, IL-8, IL-18 and monocyte chemotactic protein-1 were characteristic of not only inflammatory erosive type, but also lipid type compared with degenerative necrotic type. Thus, intensification of the inflammatory process plays an important role in the development of not only inflammatory and destructive, but also of lipid type of unstable atherosclerotic plaques. PMID- 22816080 TI - Mechanisms for vascular effects of androgens in normotensive and hypertensive rats. AB - Castration had no effect on baseline BP and vascular sensitivity to acetylcholine and deficiency of nitric oxide and prostacyclin in normotensive specimens. Castration of hypertensive specimens decreased BP and potentiated the hypotensive effects of acetylcholine, but did not modulate vascular sensitivity to the blockade of nitric oxide and prostacyclin synthesis. The removal of the testicles abolished the pressor influence of glybenclamide in hypertensive and, particularly, in normotensive males. These data indicate that the non-endothelial vascular effects of androgens (i.e., stimulation of K(ATP) channels) predominate under normal conditions. The activating effects of androgens on K(ATP) channels decrease during hypertension, which is accompanied by inhibition of endothelium dependent vasorelaxation. The production of nitric oxide and prostacyclin remains unchanged under these conditions. Our results suggest that endothelium-derived hyperpolarizing factor is involved in these processes. PMID- 22816081 TI - Effect of taurine on the proteomic profile of the cytosolic and microsomal fractions of rat hepatocytes during ontogeny. AB - The proteomic features of the cytosolic and microsomal fractions of rat hepatocytes were studied during long-term dietary consumption of taurine (12 months) as a modulator of energy homeostasis. We identified proteomic markers of the effect of taurine on regulation of cell homeostasis. A protein with unknown biological function was revealed. PMID- 22816082 TI - Heterogeneity of left ventricular cardiomyocytes from rat heart. AB - Contractile cardiomyocytes in various parts of the heart differ in shape, size, ploidy, and other parameters. However, it is not known whether their population is heterogeneous within each heart chamber. In this paper, dry weight and ploidy of cardiomyocytes were estimated in different parts of rat left ventricle. It was found that the dry weight of cardiomyocytes in medial part of left ventricular anterior wall is higher than in other parts of the ventricle. Cardiomyocyte ploidy is the same in different regions of the left ventricle. PMID- 22816083 TI - Theory of intercellular communication in the development of endothelial dysfunction. AB - Activation of intracellular signaling and blebbing of the plasma membrane lead to rafting and clustering of membrane receptors. Lymphocyte with high receptor density at the cell pole interacts with endothelial cells, which leads to their hyperactivation. In this case, lymphocyte getting a response from the endothelial cell can release membrane particles, which interact with endothelial receptors and penetrate through gaps between endothelial cells forming aseptic inflammation and causing atherogenesis. Endotheliocytes also contribute to generation of active membrane microparticles. Hyperactivation of endothelial cells and constant stimulation by the lymphocytes and microparticles trigger programmed cell death resulting in exfoliation of the endothelial cell. The endothelial defect is replaced by endothelial cells of the vascular wall (in case of mild endothelial dysfunction) or by progenitor endothelial cells (in case of severe dysfunction). PMID- 22816084 TI - Absolute bioavailability of himantane in rabbits. AB - Pharmacokinetic parameters of himantane and its metabolites in the blood plasma of rabbits were compared after single administration of himantane solution in a dose of 25 mg intravenously and 100 mg orally. It was established that the original substance is characterized by low absolute bioavailability (7.95%). Himantane is subjected to first-pass effect and is extensively metabolized in the liver to metabolites with m/z 266 and 250. PMID- 22816085 TI - Changes in electrokinetic properties of erythrocytes under the influence of pentoxifylline and new hemorheologically active substances. AB - We studied the impact of compounds RU-1202 and SUM-55 on electrophoretic mobility of "young" and "old" erythrocytes fractionated in a density gradient. The test compounds are shown to increase electrophoretic mobility of erythrocytes, compound SUM-55 being superior to the reference drug pentoxifylline. PMID- 22816086 TI - Study of wound-healing activity of bioregulators isolated from eye tissues and bovine serum in the model of experimental corneal injury in rabbits in vivo. AB - We compared wound-healing activity of bioregulators isolated from cattle cornea, serum, and retinal pigment epithelium on in vivo model of experimental corneal injury in rabbits. Bioregulators were instilled into the eye as solutions at a concentration corresponding to 10(-12) mg protein/ml. The animals were sacrificed on day 21 after injury and the corneas were examined histologically. The best wound-healing effect was produced by bioregulators isolated from the cornea and serum and instilled successively into rabbit eyes with an interval of 15-20 min twice a day: multicellular epithelium was observed in the wound, and slight inflammation, in the stroma. PMID- 22816087 TI - Effect of regular physical training on hemopoiesis in experimental animals. AB - Regular physical activity of moderate intensity over a long period (swimming at water temperature of 33-35 degrees C without load, 2 h per day, 5 days a week for 4 months) activated hemopoiesis in mice: stimulation of myelopoiesis in the bone marrow and increase in the percentage of erythropoietic elements in the spleen were observed. In the peripheral blood, the relative content of lymphocytes increased, that of granulocytes decreased, and plasma cells appeared. Stimulation of erythropoiesis in the spleen can be partially responsible for suppression of immune responses during physical exercise. PMID- 22816088 TI - In vitro expression of vascular endothelial growth factor and its receptors by placental macrophages. AB - The expression of VEGF and membrane-bound and soluble forms of the VEGF-R1 receptor in cultured placental macrophages (trimesters I and III of pregnancy) was studied by flow cytometry, cytometric bead array, and ELISA. Nearly all population of placental macrophages (98%) was capable of producing VEGF during the early and late gestational periods. However, the expression of cellular VEGF R1 varied from 3.4 to 92%. VEGF secretion was relatively low in the first and third trimesters (0.5 and 1.1 pg/10(5) cells, respectively). Cultured placental macrophages produced soluble receptor sVEGF-R1 in the first and third trimesters (86.4 and 36.4 pg/10(5) cells, respectively). Stimulation with LPS was followed by a 4-fold increase in sVEGF-R1 secretion. Our results indicate that placental macrophages are involved in the autocrine and paracrine regulation in chorionic villi. The data suggest that these cells have a physiological and pathogenetic role in gestation. PMID- 22816089 TI - Telomere lengthening in CD8(+)cells in polyclonal in vitro stimulation is associated with an increase in protein content of catalytic subunit of telomerase (hTERT). AB - Culturing of polyclonally activated T lymphocytes for 7 days in vitro leads to telomere lengthening in CD8(+), but not CD4(+)lymphocytes. Under these conditions, CD8(+)lymphocytes more intensively express telomerase catalytic subunit protein (hTERT) and divide more often than CD4(+)lymphocytes. It changes the ratio of CD4(+)and CD8(+)subpopulations in favor of the latter by the end of culturing. PMID- 22816090 TI - Structural and functional changes in pulmonary macrophages and lungs of mice infected with influenza virus A/H5N1 A/goose/Krasnoozerskoye/627/05. AB - C57Bl/6 mice were intranasally infected with influenza virus A/H5N1 A/goose/Krasnoozerskoye/627/05. The mortality rate of animals reached 70% on day 14 of the disease. The lungs of animals were characterized by necroses, destruction of vessels, hemorrhagic and thrombotic complications, edematous syndrome, and early fibrosis of the interstitium. On days 6-10 after infection, fibrosis was found in the zones of postnecrotic inflammatory infiltration. The expression of lysozyme and myeloperoxidase by pulmonary macrophages was initially increased, but decreased on day 10 of the study. The number of cathepsin D expressing macrophages was elevated up to the 10th day of examination. PMID- 22816091 TI - New adamantane derivatives can overcome resistance of influenza A(H1N1)pdm2009 and A(H3N2) viruses to remantadine. AB - New adamantane derivatives with amino acid residues and other bifunctional compounds were synthesized and their antiviral activity towards influenza A(H1N1)pdm and A(H3N2) viruses was studied. Some of these adamantane derivatives completely suppressed replication of remantadine-resistant influenza A virus strains. PMID- 22816092 TI - Expression of TLR9 and BD-2 protein genes in corneal cells of mice of different strains with herpetic keratitis. AB - The dynamics of gene expression of two proteins, TLR9 (one of the key receptors recognizing CpG repeats of herpes virus DNA) and beta-defensin 2 (antibacterial peptide), was studied on the model of herpetic keratitis in C57Bl/6 and BALB/c mice. New data on differences in TLR9 gene expression in mice of the two strains infected with the virus were obtained. Reduced TLR9 gene expression in the cornea of C57Bl/6 mice was associated with their high sensitivity to infection caused by herpes simplex 1 virus. PMID- 22816093 TI - Modification of the testicular function in laboratory male mice during social interactions: effect of female presence. AB - The count of spermatozoa in both caudal epididymides, percentage of abnormal spermatozoon heads and of mobile spermatozoa, body weight, weights of the testes and caudal epididymides were evaluated in adult inbred males (PT and CBA/Lac) kept with females for 5 days. Male mice of the same genotypes and age separated from females served as controls. In males kept with females, the weights of the testes increased in PT male mice, the percentage of rapidly mobile spermatozoa increased in CBA/Lac mice, and body weights decreased in males of both genotypes. The morphometric and spermatogenic parameters in laboratory mice were modulated by the presence of a female, but the effect was determined by the male genotype. PMID- 22816094 TI - Analysis of expression of genes involved in immune response modulation in silent multipotent mesenchymal stromal cells. AB - The expression of some genes modulating the immune response was studied in multipotent mesenchymal stromal cells (MMSC) from the bone marrow of a healthy donor. Non-activated MMSC expressed IL-6 and IL-10, complement H factor, macrophage growth factor, prostaglandin E2 synthase, and indoleamine-2,3 dioxygenase. The expression of all these genes was higher in female MMSC. A close inverse relationship between IL-6 expression in MMSC and male donor age, close relationship between body weight index and fibroblast CFU concentration in female donor bone marrow and between indoleamine-2,3-dioxygenase and macrophage growth factor in MMSC from these donors were detected. The expression of the analyzed genes was higher in MMSC of donors who had no antibodies to cytomegalovirus, herpes simplex virus, and Epstein-Barr virus in the blood. The results demonstrate the MMSC regulation of immune reactions by MMSC at the cell and organism levels. PMID- 22816095 TI - Serum immunoglobulin free light chains in patients with monoclonal gammapathies. AB - Serum concentrations of kappa- and lambda-free light chains and their ratios were compared in 126 patients with monoclonal gammapathies (age 23-80 years) and 60 normal subjects (25-82 years). The main group included patients with intact immunoglobulin multiple myeloma, Bence Jones multiple myeloma, nonsecreting multiple myeloma, plasmocytoma, and monoclonal gammapathy of unknown origin. The accuracy of the method was evaluated by the analysis of 3 serum specimens with different concentrations of kappa- and lambda-free light chains. The variability of the method did not surpass the coefficient of variations permissible for this kind of analysis (10%). The new immunochemical method is characterized by high analytical sensitivity 100-fold surpassing that of electrophoretic methods. High concentrations of free light chains were most often found in the sera of patients with multiple myeloma with intact immunoglobulin secretion, Bence Jones multiple myeloma, and plasmocytoma. The diagnostic sensitivity of measurements of serum free light chains by the immunoturbidimetric method attained 90.5%. Combination of this method with serum protein electrophoresis and immunofixation resulted in detection of monoclonal gammapathy in 98.8% cases. These data indicate high specificity and analytical and diagnostic sensitivity of the immunoturbidimetric method for measurement of serum free light chains. PMID- 22816096 TI - Molecular cellular mechanisms of peptide regulation of melatonin synthesis in pinealocyte culture. AB - The effects of epithalone and vilone peptides on the synthesis of melatonin and factors involved in this process, arylalkylamine-N-acetyltransferase (AANAT) enzyme and pCREB transcription protein, were studied in rat pinealocyte culture. Epithalone stimulated AANAT and pCREB synthesis and increased melatonin level in culture medium. Simultaneous addition of norepinephrine and peptides into the culture potentiated the expression of AANAT and pCREB. PMID- 22816097 TI - Proliferative activity and viability of fibroblast and glioblastoma cell on various types of carbon nanotubes. AB - The effects of single-walled and multiwalled carbon nanotubes on proliferative activity and viability of human embryo fibroblasts and glioblastoma cells were studied. Low cytotoxic activity of single-walled carbon tubes was demonstrated. Possible mechanisms of nanotube effects on cell growth are discussed. PMID- 22816098 TI - Pharmacology of somatrotropin pegylated by electron-beam synthesis nanotechnology. AB - Pharmacological characteristics of somatotropin pegylated using electron-beam synthesis nanotechnology (PEG-STH) were studied. Oral PEG-STH stimulated the intensity of protein and lipid metabolism and endochondral bone growth without modifying the processes of periosteal and endosteal bone formation. Specific activity of this substance administered orally significantly surpassed that of parenteral non-modified growth hormone. PMID- 22816099 TI - Physiological and biomechanical characteristics of the kick and goal techniques of football players. AB - Physiological and biomechanical characteristics of the kick and goal technique in football were studied in athletes of different qualification. The formation of technological skills of football players kicking the ball from the standard position requires coordinated movements and high differentiation of muscular activity. PMID- 22816100 TI - Effect of esophagoplasty on structural reorganization of colon transplant. AB - We studied ultrastructural reorganization of the colon transplant in delayed period after esophagoplasty. It was found that during functioning of the artificial esophagus, a complex of adaptive and pathologic processes occurs in the mucosa. Focal sclerosis of the mucosa and slight epithelial degeneration with hyperplasia and hypersecretion of goblet cells were found in biopsy specimens with stenosis of the anastomosis. In case of colonopathy of the transplant, more pronounced epithelial degeneration and proliferation accompanied by abundant polymorphocellular stromal infiltration were seen. Deformation of the transplant was characterized by progressive atrophic and sclerotic reorganization of the mucosa. Goblet cells with ultrastructural signs of hypersecretion predominated in the population of epithelial cells of the colon transplant; oligomucus and poorly differentiated cell and colonocytes with signs of alteration and degenerative changes in cytoplasmic organelles were also found. PMID- 22816101 TI - Response of glandular organs to experimental macroglossia. AB - Response of glandular organs to tongue enlargement was studied in 16 outbred male rats; each of them received injections of hydrophobic polyacrylamide gel (0.05 ml) in midline of the tongue. Changes in the studied glandular organs of external secretion (salivary glands) and internal secretion (thyroid and adrenal glands) were morphometrically detected. PMID- 22816102 TI - Expression of renal crystallization inhibitors in experimental nephrolithiasis. AB - The expression of renal inhibitors of crystallization (Tamm-Horsefall protein, osteopontin, bikunin) in experimental nephrolithiasis was studied in rats receiving 1% ethylene glycol solution for drinking for 3 weeks. The expression of Tamm-Horsefall protein increased, while osteopontin and bikunin expression decreased in experimental nephrolithiasis. PMID- 22816103 TI - Role of sexually-transmitted infections in the structural and functional reorganization of the prostate. AB - Intracellular reorganization of secretory epitheliocytes in the main, intermediate, and periurethral prostatic glands was studied in chronic prostatitis under conditions of sexually-transmitted infections. The destructive and autophagic processes in the secretory epitheliocytes were stimulated by persistence of microorganisms, Mycoplasmataceae (mainly mycoplasmas and ureaplasmas) and Chlamydia trachomatis, in the prostatic terminal compartments, epithelial layer, and epitheliocytes. Significant intracellular reorganization of smooth-muscle cells was found: focal destruction of ultrastructures (mainly in the perinuclear zone) and lythic changes in the myofilaments (focal and diffuse). PMID- 22816104 TI - Experimental morphological study of the effects of subchondral tunnelization and bone marrow stimulation on articular cartilage regeneration. AB - The articular cartilage was studied under conditions of experimental osteoarthrosis with tunnelization of the subchondral zone and injection of autologous bone marrow into the channels. Histomorphological studies showed that tunnelization of the subchondral zone with injection of autologous bone marrow into the channels stimulated reparative regeneration of the chondral tissue by inhibiting destruction of the joints. PMID- 22816105 TI - Exploring the coordination chemistry of isomerizable terpyridine derivatives for successful analyses of cis and trans isomers by travelling wave ion mobility mass spectrometry. AB - The photochemical cis-trans isomerization of the 4-{4-[2-(pyridin-4 yl)ethenyl]phenyl}-2,2':6',2''-terpyridine ligand (vpytpy) was investigated by UV vis, NMR and TWIM-MS. Ion mobility mass spectrometry was performed pursuing the quantification of the isomeric composition during photolysis, however an in source trans-to-cis isomerization process was observed. In order to overcome this inherent phenomenon, the isomerization of the vpytpy species was suppressed by complexation, reacting with iron(II) ions, and forming the [Fe(vpytpy)(2)](2+) complex. The strategy of "freezing" the cis-trans isomerizable ligand at a given geometric conformation was effective, preventing further isomerization, thus allowing the distinction of each one of the isomers in the photolysed mixture. In addition, the experimental drift times were related to the calculated surface areas of the three possible cis-cis, cis-trans and trans-trans iron(II) complex isomers. The stabilization of the ligand in a given conformation also allows us to obtain the cis-cis and cis-trans complexes exhibiting the ligand in the metastable cis-conformation, as well as in the thermodynamically stable trans conformation. PMID- 22816106 TI - A renaissance for PD in acute kidney injury. PMID- 22816107 TI - [Not Available]. PMID- 22816108 TI - [Not Available]. PMID- 22816109 TI - [Not Available]. PMID- 22816110 TI - [Being a physician... "getting close to retirement"]. PMID- 22816111 TI - [LX anniversary of the Sociedad Espanola de Medicina Interna (Spanish Society of Internal Medicine)]. PMID- 22816112 TI - Risky research: The sky's the limit. PMID- 22816113 TI - Bibliography. Services, research and outcomes. Current world literature. PMID- 22816114 TI - Oral absorption enhancement: taking the next steps in therapeutic delivery. PMID- 22816115 TI - Realizing the potential of therapeutic stem cells with effective delivery. PMID- 22816116 TI - The 12th Conference on the Formulation and Delivery of Bioactives. AB - The effective delivery of bioactives (drugs) to the brain is a major challenge. Compared with the research intensity on the discovery of new drugs to treat neurological disorders, the effort on delivery of these therapies is limited. A second significant challenge is the delivery of large molecules, for example oligopeptides, proteins and oligonucleotides. These were the topics for discussion at the multidisciplinary 12th Conference on the Formulation and Delivery of Bioactives. PMID- 22816117 TI - Therapeutic Particles and Biomaterials Technology Laboratory at the University of Kansas. AB - Novel technologies to enhance therapeutic delivery and biomaterial performance are fundamental to the development of improved products with fewer unwanted side effects. The Therapeutic Particles and Biomaterials Technology Laboratory at The University of Kansas (KS, USA) works at the interface of medicine and engineering to develop novel materials that enhance therapeutic delivery in a variety of biomedical applications. Research areas include aerosol drug delivery, targeted nanoparticles for drug and contrast agent delivery, biomaterials for tissue engineering and polymer therapeutics. The lab works with industry, academia and law firms through a variety of mechanisms such as fee-for-service, contract research and collaboration. Ultimately, the group aims to develop materials and drug delivery platforms that are fundamentally unique yet simple solutions to improve human health. PMID- 22816118 TI - Osmotic-driven release of papaverine hydrochloride from novel poly(decane-co tricarballylate) elastomeric matrices. AB - BACKGROUND: We have recently reported on the synthesis, characterization and biocompatibility of a novel family of visible-light photocrosslinked poly(diol-co tricarballylate) elastomers intended for use in drug delivery and tissue engineering applications. In this work, the osmotic-driven controlled release of the water-soluble drug, papaverine hydrochloride, from poly(decane-co tricarballylate) elastomeric cylindrical monoliths is reported. We also examined the influence of various parameters such as the degree of prepolymer acrylation, crosslinking density and the incorporation of osmotic excipients such as trehalose on the release kinetics of the drug. RESULTS: The release rate of papaverine hydrochloride was found to decrease in dissolution media of higher osmotic activity as an indication of the predominant involvement of the osmotic driven release mechanism from the elastomeric devices. The drug release rate was also found to be dependent on the degree of macromer acrylation. Furthermore, it was found that coformulating papaverine hydrochloride with trehalose increases the release rate without altering the linear nature of the drug release kinetics. CONCLUSIONS: A new delivery vehicle composed of biodegradable poly(decane-co tricarballylate) elastomers was demonstrated to be a promising and effective matrix for linear, constant and controllable osmotic-driven release of drugs. PMID- 22816119 TI - Physicochemical principles of controlled release solid dispersion containing a poorly water-soluble drug. AB - BACKGROUND: The aim of this study was to investigate the physicochemical properties of polyethylene oxide (PEO)-based controlled release solid dispersions (CR-SDs) containing aceclofenac, Gelucire 44/14, poloxamer 407 and pH modifier (Na2CO3). RESULTS: The immediate release solid dispersions containing the pH modifier greatly enhanced the drug dissolution rate to approximately 100%, while the CR-SDs with PEO showed controlled release. A bigger droplet size and a higher surface charge for the CR-SDs were observed compared with the immediate release solid dispersions. The pH modifier played an important role in modulating the release rate of the drug through changes in the drug crystallinity and the hydrogen-bonding interaction, as well as the microenvironmental pH. Near-infrared images revealed a modulation of the PEO concentration to preserve the pH modifier within the system for controlled release of the drug. CONCLUSION: The dissolution process of PEO-based solid dispersions containing a water-insoluble drug was governed by the changing net effect of the microenvironmental pH, the surface charge, the particle size and the release rate of the pH modifier, as well as the function of PEO in controlling drug release. PMID- 22816120 TI - Effect of lipid matrix on repaglinide-loaded solid lipid nanoparticles for oral delivery. AB - AIM: To study the effect of different types of lipid on the entrapment efficiency (EE) and physical stability of repaglinide (RG)-loaded solid lipid nanoparticles (SLNs). RG-loaded SLNs were prepared by modified solvent injection method using stearic acid (RSA), glycerol monosteratae (RGM), glyceryl behenate (RGB) and tristearin (RTS). Poloxamer F68 was used as a stabilizer. RESULTS: SLNs were characterized by particle size, zeta-potential, EE, in vitro release, solid-state properties (differential scanning calorimetry, transmission electron microscopy and electron diffraction) and stability at 30 degrees C/65% relative humidity for 3 months. The mean particle size and zeta-potential of RG-loaded SLNs prepared with different lipids in varying concentrations ranged from 150 to 355 nm and 21.04 +/- 3.10 to -30.54 +/- 2.76 mV, respectively. CONCLUSION: EE was found to vary with lipids in the following order: RSA < RGM < RGB < RTS. Tristearin prepared SLNs showed a significant prolonged drug release up to 24 h. Differential scanning calorimetry and electron diffraction microphotograph results indicated that RG entrapped in the SLNs existed in an amorphous or molecular state. SLNs prepared with stearic acid, glycerol monostearate and glyceryl behenate after storage showed significant increases in particle size, polydispersity index and EE. The SLNs prepared with tristearin were stable. PMID- 22816121 TI - Restoration of rat colonic epithelium after in situ intestinal instillation of the absorption promoter, sodium caprate. AB - BACKGROUND: Sodium caprate (C10) is an oral absorption promoter that is currently in clinical trials as a component of solid dosage forms for poorly permeable small molecules and peptides. Clinical data with zoledronic acid tablets suggest that significant delivery along with acceptable safety can be achieved from a once-a-week dosing regime. C10 has surfactant-like properties at the high doses used in vivo and therefore we examined its effects on rat intestinal epithelium following intestinal instillation. RESULTS: Addition of 100 mM concentrations of C10 with the paracellular flux marker, fluorescein isothiocyanate-dextran 4 kDa, permitted a bioavailability of 33% to be achieved. When C10 was added 10, 30 and 60 min in advance of fluorescein isothiocyanate-dextran 4 kDa, enhancement still occurred, but was progressively reduced. Histology revealed that the permeability increase was likely related in part to superficial epithelial damage caused in the first few minutes of exposure, which was rapidly repaired within 30-60 min. CONCLUSIONS: Design of optimized dosage forms containing C10 should corelease the payload and promoter close to the epithelium in high concentrations. While C10 induces some epithelial damage, its remarkable capacity for epithelial repair may render this effect insignificant in vivo. PMID- 22816122 TI - Nanotechnology and therapeutic delivery: a drug regulation perspective. AB - Nanotechnology is expected to contribute to the therapeutic delivery field in the coming decade. Although the US FDA has multiple guidance documents in place to deal with novel drug products, nanoparticles may produce issues that have not been previously encountered with small drug molecules. This regulatory focus highlights some current guidance documents and thinking of the FDA as applied to nanoparticles used for therapeutic delivery. PMID- 22816123 TI - Nucleic acid therapeutics: concepts for targeted delivery to solid tumors. AB - Solid tumors form a heterogeneous group of diseases, although common features such as hyperproliferation, overexpression of certain growth factor receptors and deregulated vessel formation including leaky vasculature give the opportunity to target macromolecular drug and nucleic acid carriers to tumor tissue. Similar to other macromolecular drugs, nucleic acid carriers have to be designed to enable tumor targeting after systemic injection. Chemical modification of nucleic acids makes them resistant towards enzymatic degradation. Cationic lipids or polycations condense nucleic acids into small, virus-like structures and the surface modification with hydrophilic polymers allows passive accumulation in tumor tissue; tumor cell binding ligands allow cellular targeting. To avoid toxic side effects, biodegradable and biocompatible carriers were designed. The design of thermoresponsive gene carriers allowed their selective tumor accumulation by locoregional hyperthermia. As a therapeutic concept, tumor-specific delivery of antitumoral RNA was realized in an orthotopic brain tumor model. The combination of gene- and radio-therapy enabled selective accumulation of radionuclides in tumors and boosted antitumoral effects. Hence, combining a smart delivery concept for nucleic acids with a suitable therapeutic strategy will allow successful treatment of otherwise incurable malignant diseases. PMID- 22816124 TI - Efficient, specific and targeted delivery of genes to the lung. AB - Many inherited and acquired pulmonary disorders without satisfactory therapies may be amenable to gene therapy. Despite numerous advances, efficient delivery and expression of the therapeutic transgene at physiological levels for phenotypic correction of disease has proved elusive. This article focuses on various strategies aimed at achieving targeted delivery to the lungs. Both physical methods and biological targeting have been successfully applied in various gene delivery systems. Targeting of different cell types has been achieved by pseudotyping of viral vectors with capsids from different serotypes and modification of nonviral vectors with targeting ligands. Both classes of vectors are discussed with respect to their gene delivery and expression efficiencies, longevity of expression and immunogenicity. Moreover, gene therapy clinical trials for different lung diseases are discussed. PMID- 22816125 TI - Nanoparticulate strategies for effective delivery of poorly soluble therapeutics. AB - The pharmacological activity of a drug molecule depends on its ability to dissolve and interact with its biological target, either through dissolution and absorption, or through dissolution and receptor interaction. The low bioavailability that characterizes poorly water-soluble drugs is usually attributed to the dissolution kinetic profile. Novel strategies to effectively deliver these drugs include nanoparticulate approaches that either increase the surface area of the drug or improve the solubility characteristics of the drug. Nanosizing approaches are based on the production of drug nanocrytals dispersed in an aqueous surfactant solution, whereas other possibilities include drug loading in nanoparticles. Promising nanoparticulate approaches include the development of lipid-based nanocarriers to increase drug solubility followed by enhanced bioavailability. To select the best approach there are, however, some critical considerations to take into account, for example the physicochemical properties of the drug, the possibility to scale-up the production process, the toxicological considerations of the use of solvents and cosolvents, the selection of an environmentally sustainable methodology and the development of a more patient-friendly dosage form. This article addresses these relevant questions and provides feasible examples of novel strategies with respect to relevant administration routes. PMID- 22816126 TI - Applications of capsule dosing techniques for use in dry powder inhalers. AB - Dry powder inhaler (DPI) devices that utilize two-piece capsules as the dose holding system can require specialized dosing equipment to fill the capsules. Such products are known as 'premetered' because they contain previously measured doses in a dose carrier (the capsule). The capsule is either inserted into the device during manufacture or by the patient prior to use. The dose is inhaled directly from the device/premetered unit by the patient. Regardless of DPI design, the most crucial attributes are the reproducibility of the discharged dose and the particle size distribution of the drug within that dose. Filling inhalation powders into capsules often requires specialized equipment in order to handle the very low weights that are often contained in each dose. The equipment typically needs to incorporate in-process checks to confirm the filling process has been correctly performed, with the ability to reject any under- or over filled capsules, in line with established quality criteria. In the majority of cases, such processing equipment is maintained in a temperature and humidity controlled environment to avoid moisture uptake and potential powder aggregation and, in particular, to ensure the powder is free flowing on introduction into the capsule. This ensures that the emitted dose is maximized and controlled according to industry guidelines and that the fine particle fraction provides an optimum clinical benefit. Several methods of dosing precise doses of powder into capsules are available and include dosator technology and tamp processes, as well as equipment that utilize the 'pepper-shaker' or 'pepper-pot' principle for the accurate dispensing of powders. This article reviews the suitability of each method with respect to dosing inhalation powder into capsules for use in DPI devices, and discusses why the pepper-pot principle could offer a number of clear benefits. PMID- 22816127 TI - Cancer gene therapies come of age. PMID- 22816128 TI - Nano drug-delivery systems in cancer therapy: gains, pitfalls and considerations in DMPK and PD. PMID- 22816129 TI - First World Conference on Nanomedicine and Drug Delivery. AB - The Institute of Holistic Medical Sciences (IHMS), Kottayam, Kerala, India, the Institute of Macromolecular Science and Engineering (IMSE), Kottayam, Kerala, India and Mathew Ayurveda und Venen Klinik (MUVK), Klagenfurt, Austria, have jointly conducted a 3-day world conference on nanomedicine and drug delivery (WCN 2010) in Kottayam, Kerala, India from 16-18 April 2010. Nanomedicine is defined as the application of nanotechnology to achieve breakthroughs in healthcare. It exploits the improved and often novel physical, chemical and biological properties of materials at the nanometer scale. It has the potential to enable early detection and prevention and to improve diagnosis, treatment and follow-up of diseases. Nanomedicine is a very special area of nanotechnology because it is an extremely large field ranging from in vivo and in vitro diagnostics to therapy including targeted delivery and regenerative medicine; it interfaces nanomaterials (e.g., surfaces and particles) or analytical instruments with 'living' human material (cells, tissue and body fluids) and it creates new tools and methods that impact significantly on existing practices. PMID- 22816130 TI - Nanomedicines for delivery of therapeutic proteins and biopharmaceuticals. AB - Biopharmaceuticals are a class of therapeutics including recombinant therapeutic proteins, engineered antibodies and genetic material. They are attractive from a medical point of view, but technologically they face major challenges. The delivery of biopharmaceuticals still prevents them from reaching their maximum pharmacodynamic potential, owing to their physicochemical properties, poor stability, permeability and biodistribution. In our research group we have been involved with inter-related projects that intend to optimize strategies to improve the bioavailability of biopharmaceutical drugs after administration. One of the most employed drugs has been insulin, the oldest therapeutic protein, as well as siRNA and gene silencing genetic material. We are interested in formulating such drugs in polymeric nanoparticles, because they encompass an array of advantages compared with classical dosage forms. We also look for tools to correlate in vitro and in vivo absorption rates of biopharmaceuticals, in a rational chronologic sequence of manufacturing parameters, preclinical assessments and requirements for marketing approval. PMID- 22816131 TI - Optimum conditions of ultrasound-mediated destruction of bubble liposome for siRNA transfer in bladder cancer. AB - BACKGROUND: We investigated the effectiveness of ultrasound-mediated destruction of bubble liposome (UBL) for siRNA transfer by observing reduction in the luciferase activity of human bladder tumor RT-112 cells transfected with the luciferase gene (RT-112Luc) following luciferase siRNA transfer into the cells. RESULTS: siRNA was transferred to 26% of RT-112Luc cells by UBL and the luciferase activity of RT-112Luc cells was significantly suppressed by UBL using the luciferase siRNA, compared with that using nonspecific siRNA in vitro (p = 0.036). The luciferase activity of RT-112Luc tumor was suppressed by UBL using luciferase siRNA compared with that using nonspecific siRNA 2 days after the in vivo treatment. CONCLUSION: This study showed that UBL is suitable for siRNA transfer to mammalian cells. PMID- 22816132 TI - Antinuclear antibodies with nucleosome-restricted specificity for targeted delivery of chemotherapeutic agents. AB - Circulating antinuclear autoantibodies (ANAs) are well known to accompany various pathological conditions and can be artificially induced by immunization. Research and clinical data permit us to hypothesize a definite connection between cancer and ANAs. Based on the available data, my group's research suggested that exogenous ANAs may be used as anticancer therapeutics. Among these ANAs, nucleosome-specific ANAs may be particularly useful. Advances in cancer immunotherapy with monoclonal antibodies re-emphasized the role of humoral immunity in neoplasia control. The development of a universal antibody targeting diverse cancers is of clear importance. We showed that certain natural ANAs recognize the surface of numerous tumor cells but not normal cells via cell surface-bound nucleosomes originating from the apoptotically dying neighboring tumor cells, mediate antibody-dependent cellular cytotoxicity of tumor cells in vitro and inhibit the development of murine tumor in syngeneic mice. A single monoclonal antinuclear nucleosome-specific autoantibody, mAb 2C5, specifically recognizes multiple unrelated human tumor cell lines and accumulates at a high tumor-to-normal cell ratio in various human tumors in nude mice. Immunotherapy with mAb 2C5 resulted in significant suppression of the growth of several human tumors. In addition, mAb 2C5, when used in subtherapeutic quantities, can serve as a highly efficient specific ligand to target various drug- or diagnostic agent loaded pharmaceutical nanocarriers, such as liposomes and polymeric micelles, to various tumors. Here, the data (accumulated predominantly in our laboratory over several years) on mAb 2C5-mediated tumor targeting of chemotherapeutic agents is reviewed. PMID- 22816133 TI - Nanoparticle delivery strategies to target doxorubicin to tumor cells and reduce side effects. AB - Doxorubicin (DOX) is one of the most active anticancer drugs, while its cumulative dose-dependent side effects compromise the anticancer efficacy. Nanoparticles, an emerging platform for cancer therapy, have been shown to increase intracellular uptake of DOX with reduced side effects compared with conventional DOX formulations. While large numbers of clinical and preclinical studies have been published, the purpose of this review is to draw attention to the developments of DOX-loaded nanoparticles for cancer therapy, with special a focus on enhanced intracellular uptake and reduced side-effects strategies. PMID- 22816135 TI - Nanoparticle-assisted combination therapies for effective cancer treatment. AB - Combination chemotherapy and nanoparticle drug delivery are two areas that have shown significant promise in cancer treatment. Combined therapy of two or more drugs promotes synergism among the different drugs against cancer cells and suppresses drug resistance through distinct mechanisms of action. Nanoparticle drug delivery, on the other hand, enhances therapeutic effectiveness and reduces side effects of the drug payloads by improving their pharmacokinetics. These two active research fields have been recently merged to further improve the efficacy of cancer therapeutics. This review article summarizes the recent efforts in developing nanoparticle platforms to concurrently deliver multiple types of drugs for combination chemotherapy. We also highlight the challenges and design specifications that need to be considered in optimizing nanoparticle-based combination chemotherapy. PMID- 22816136 TI - Harnessing traditional Chinese medicine to improve cancer therapy: issues for future development. AB - Traditional Chinese medicine (TCM) has recently yielded a number of chemical compounds with clinically significant anticancer activity. The theory of TCM formulas, however, unlike Western medicine, is based on the interactions of the various Chinese medicinal materials in the body, rather than the activity of a single purified chemical compound. Mechanisms for the possible synergistic anticancer effects of components in TCM formulas have recently been postulated. Advanced research on the clinical effects of TCM formulas, however, has been hampered by inconsistent dosage formulations and unreliable quality control. Scientific challenges in dosage formulation and methods for ensuring quality control of TCM products will be discussed. PMID- 22816134 TI - Advances in image-guided intratumoral drug delivery techniques. AB - Image-guided drug delivery provides a means for treating a variety of diseases with minimal systemic involvement while concurrently monitoring treatment efficacy. These therapies are particularly useful to the field of interventional oncology, where elevation of tumor drug levels, reduction of systemic side effects and post-therapy assessment are essential. This review highlights three such image-guided procedures: transarterial chemoembolization, drug-eluting implants and convection-enhanced delivery. Advancements in medical imaging technology have resulted in a growing number of new applications, including image guided drug delivery. This minimally invasive approach provides a comprehensive answer to many challenges with local drug delivery. Future evolution of imaging devices, image-acquisition techniques and multifunctional delivery agents will lead to a paradigm shift in patient care. PMID- 22816137 TI - Steroid-coupled liposomes for targeted delivery to tumor. AB - The steroidal receptors play a key role in protein synthesis and maintain the homeostasis in normal and diseased state, including tumorigenesis at the target tissues when overactivated. Thus steroidal receptors may act as potential targets for selective delivery of different therapeutic agents as they are overexpressed by a number of endocrinal tumors. The selective delivery of these agents may be a better treatment strategy for endocrinal cancer as it may also result in cytosolic and nuclear delivery of cytotoxic agents. In this review, the targeting potential of steroidal receptors for the drug or bioactive(s) delivery is discussed. The ligands that have been proven to be effective for specific steroidal receptors can be used as vectors for carrying the drug or drug-delivery system to the desired site of drug action in an optimum concentration. This strategy will not only minimize the undesired side effects associated with nonspecific delivery of drug, but will also maximize the drug utilization. Ligand conjugated liposomes as a carrier of bioactives prevent passive diffusion of the encapsulated drug to normal cells, increase the time of circulation and reduce the undesirable side effects of a drug. PMID- 22816138 TI - Working collectively for real change. PMID- 22816139 TI - Drug delivery systems using polymer nanoassemblies for cancer treatment. PMID- 22816140 TI - Interview with John Patton. PMID- 22816141 TI - Antiretroviral nanoparticles: an extended drug delivery modality. AB - The antiretroviral nanoparticle formulation laboratory at Creighton University School of Pharmacy & Health Professions is lead by Chris Destache. Over the past 4 years, this laboratory has been investigating the use of antiretroviral nanoparticles as a sustained drug delivery method for HIV-1-infected patients. PMID- 22816142 TI - Recent advances in the use of encapsulated cells for effective delivery of therapeutics. AB - Cell encapsulation can be defined as a living cell approach for the long-term delivery of therapeutic products. It consists of the immobilization of therapeutically active cells within a general polymer matrix that permits the ingress of nutrients and oxygen and the egress of therapeutic protein products but impedes the immune contact of the enclosed cells. In recent decades many attempts have evaluated the potential of this technology to release therapeutic agents for the treatment of different pathologies and disorders. At present, cell encapsulation may be used as a technological platform to improve knowledge and clinical use of stem cells. This review describes the main issues related to this cell-based approach and summarizes some of the most interesting therapeutic applications. PMID- 22816143 TI - Advances in effective vaccine development against hepatitis B: focus on mucosal vaccine delivery strategies. AB - Hepatitis B virus causes chronic necroinflammatory liver disease, which is known as hepatitis B. This inflammatory condition may further aggravate liver cirrhosis or hepatocellular carcinoma. Currently available conventional hepatitis B vaccine contains one of the viral envelope proteins, hepatitis B surface antigen, which develops a humoral immune response and hence protects against the infection. However, it fails in developing the desired cellular immune response, which is one of the most important bioresponses contributing to virus elimination from infected hepatocytes. At the same time, moderate humoral response developed following conventional vaccination do not protect the mucosal surfaces through serosal response. The mucosa is a predominant entry site for most of the infectious pathogens. Several strategies, including the use of adjuvants, development of surface functionalized novel antigen carriers and mucosal immunization for example, have been explored to investigate their role in addressing the limitations associated with the current hepatitis B vaccine. This review focuses on recent advances that have been made in order to develop an effective vaccine against hepatitis B. PMID- 22816144 TI - Peptides for specific intracellular delivery and targeting of nanoparticles: implications for developing nanoparticle-mediated drug delivery. AB - The use of peptides to mediate the delivery and uptake of nanoparticle (NP) materials by mammalian cells has grown significantly over the past 10 years. This area of research has important implications for the development of new therapeutic materials and for the emerging field of NP-mediated drug delivery. In this review, we highlight recent advances in the delivery of various NPs by some of the more commonly employed cellular delivery peptides and discuss important related factors such as NP-peptide bioconjugation, uptake efficiency, intracellular fate and toxicity. We also highlight various demonstrations of therapeutic applications of NP-peptide conjugates where appropriate. The paper concludes with a brief forward-looking perspective discussing what can be expected as this field develops in the coming years. PMID- 22816145 TI - Formulation strategies for sustained release of proteins. AB - Proteins constitute an increasing proportion of the drugs in development. The barriers to their entry into the blood stream and rapid clearance means that they often have to be injected several times a day, affecting patient compliance. This paper reviews the major technologies enabling the development of injectable sustained-release products and formulation strategies to maintain protein integrity and modify release rates. Whilst many injectable sustained-release products are on the market, these are all delivering small molecular weight drugs and peptides. This is due to the manufacturing processes that denature and degrade the proteins upon encapsulation and release into the body. Formulation strategies are discussed and a number of new technologies reviewed that are able to overcome the issues with conventional manufacturing processes. The reliance of many processes on organic solvents has prevented their application to the development of injectable sustained release protein products. The development of entirely solvent free and aqueous methods of manufacture of these products has meant that numerous sustained-release protein products are close to reaching the market. PMID- 22816147 TI - Understanding conflict management. PMID- 22816146 TI - Finance for nurse managers. PMID- 22816148 TI - Best carotid artery treatment approach may depend on age. The stroke-prevention methods include stents and surgery. PMID- 22816149 TI - Ablation vs. medication for atrial fibrillation. There are many things to consider when choosing a treatment. PMID- 22816150 TI - Weight loss may reverse arterial damage. But experts warn against "fads" and recommend cutting back on fat. PMID- 22816151 TI - Reducing your salt intake could lower your heart disease risks. Research shows that even modest reductions can also boost the effectiveness of antihypertensive medications. PMID- 22816152 TI - A potent alternative to clopidogrel emerges. Prasugrel appears to lower heart attack risk for patients with acute coronary syndrome. PMID- 22816153 TI - Factors of metabolic syndrome linked to plaque progression. The individual components appear to be the culprits, rather than the presence of the syndrome itself. PMID- 22816154 TI - My doctor wanted me to start taking Evista (raloxifene hydrochloride) for osteoporosis, but I'm worried because the drug is linked to a risk of blood clots. I have mild hypertension that I manage with medications, diet and exercise. Do you think the drug is safe? PMID- 22816155 TI - For many years I have been diagnosed with cardiomyopathy and an ever-decreasing ejection fraction. My cardiologist says there is no cure, but I have seen some encouraging stories about stem cell therapy. What would it take to become a candidate for such therapy? PMID- 22816156 TI - I have heard conflicting advice regarding coffee and caffeine through the years. I had heard caffeine can contribute to high blood pressure, but I just recently read where coffee drinkers who have atrial fibrillation (as I do) have fewer serious rhythm disturbances. What's your advice? PMID- 22816157 TI - Percarditis proves a mysterious but usually manageable condition. Inflammation of the heart's outer lining can be guided by imaging and often be managed by medication only. PMID- 22816158 TI - Stroke surgery may be safe for some kidney patients. But experts warn that benefits should be weighed against the risks. PMID- 22816159 TI - There's no such thing as overweight and heart healthy. Research shows that carrying extra pounds, even with normal blood pressure and cholesterol levels, can pose a cardiac risk. PMID- 22816160 TI - Know the risks and benefits of antidepressant use. Recent research has raised concerns about their effect on cardiac risks. PMID- 22816161 TI - Small device may offer big boost to heart failure survival. Implantable cardioverter-defibrillators are now routinely recommended for many heart failure patients. PMID- 22816162 TI - Ablation before ICD implantation can reduce painful shocks. Patients at risk for multiple episodes of ventricular tachycardia most likely to benefit. PMID- 22816163 TI - I take medications for blood pressure, cholesterol and other conditions. I have a two-part question: are there any long-term problems from taking a dozen or so pills a day, and has there been much progress in developing a "polypill" that combines several drugs into a single pill? PMID- 22816164 TI - I've read about "body-mass index" and "waist-to-hip ration" as measures of health and heart health risks, along with some others. I wonder if one is better than another for gauging whether my weight and fitness levels are okay. I'm 64 and was recently diagnosed with atrial fibrillation. PMID- 22816165 TI - A friend of mine was diagnosed with pulmonary edema and was prescribed a diuretic. I'm a heart attack survivor and I currently take a diuretic (among other drugs). What exactly is pulmonary edema, and am I protected since I take a diuretic? PMID- 22816166 TI - [Phase II multi-center randomized clinical trial on the use of synthetic absorbable sutures to prevent wound infection in surgery]. PMID- 22816167 TI - A consensus document requesting the Medical Council of India to take action on the issue of boundary violations in doctor-patient relationships. PMID- 22816168 TI - Overcoming shortage of doctors in rural areas: lessons from Tamil Nadu. PMID- 22816169 TI - Molecular and genetic basis of stress. PMID- 22816170 TI - India's health workforce: current status and the way forward. PMID- 22816171 TI - Rifaximin and lubiprostone: the best options for treating irritable bowel syndrome? PMID- 22816172 TI - Good preparation shown to be highly significant in screening colonoscopy. PMID- 22816173 TI - New procedure could provide a new treatment for locally advanced pancreatic cancer. PMID- 22816174 TI - A review of literature on the adverse effects of hyperthyroidism on the heart functional behavior. AB - Thyroid hormones play an important role on the physiological chemistry of heart and vascular systems in healthy subjects. Any thyroid disorders accompanied with alteration of effective concentration of thyroid hormones cause heart dysfunctions. Thyrotoxicosis is a term given for the clinical manifestation of hyperthyroidism which can invoke heart and vascular abnormalities through the mechanism at heart muscle cells nuclear level. Thyrotoxicosis can play positive roles for heart disorders including atrial fibrillation, left ventricular hypertrophy and right ventricular systolic dysfunction, which are considered as major risk factors for heart abnormalities. Miscalculation of heart dysfunctions related thyrotoxicosis in cardiovascular patients might be avoided through careful laboratory measurements of T4 and T3 to exclude any possible thyroid hormone-related heart diseases. PMID- 22816175 TI - Effect of field history on the cereal leafminer Syringopais temperatella Led. (Lepidoptera: Scythrididae) and its preference to different wheat and barley cultivars. AB - Due to the importance of wheat and barley production in Jordan, prevention of the cereal leafminer, Syringopais temperatella Led. (Lepidoptera: Scythrididae) is of vital importance. The insect is a severe pest and plays an important role in limiting the production of these crops. The use of insecticides is neither economic nor sustainable, so that there is an urgent need to initiate a viable alternative to chemical control. Therefore, this study aimed at investigating the effect of crop rotation on S. temperatella and its preference to different wheat and barley cultivars. The field history experiment was conducted using five different crop rotations. For the preference experiments in the laboratory, two major experimental groups were conducted. The first was set up to measure the consumed leaf area and the second one to record the number of larval attaches. Each group consisted of four different subgroups; 6 wheat cultivars, 6 barley cultivars, two and one cultivar of each crop. The results indicated that the infestation percentage and number of larvae were significantly the lowest in the crop rotation, wheat/chickpea/wheat while the highest were recorded for barley/barley/barley. The preference results showed that wheat cultivar, Horani Nawawi is significantly the most preferred while Horani 27 is the least cultivar. In case of barley, Mutah was the most preferred cultivar and the least preference was recorded for Athroh. Also, wheat was significantly less preferred than barley. The wheat cultivars, Sham, Em-Qees and Acsad 65 had the highest number of attaches and Deer Alla the least. In contrast, the barley cultivar, Acsad 176 had the highest and Athroh and Rum 1 had the least attaches. Barley cultivars had higher attaches than wheat ones. There was a positive relation between the infestation percent and number of larvae, as well as the consumed area and number of attaches in all of the four subgroups. In conclusion, the crop rotation, wheat/chickpea/wheat should be followed and there is a preference variation among the tested wheat and barley cultivars. PMID- 22816176 TI - Demographics of patients with surgical and nonsurgical cystic echinococcosis in East Azerbaijan from 2001 to 2012. AB - Echinococcosis is very frequent helminthic infection in human being. The disease is endemic in Iran and particularly in its northwestern region, East Azerbaijan. The objective of this study was to study demographics of patients with cystic echinococcosis in East Azerbaijan; as well as to repot the sites of involvements. In this cross-sectional study, 318 patients with surgical and nonsurgical cystic echinococcosis were recruited from three referral centers in Tabriz within a 10 year period of time. The patients' demographics (age and gender) and the site of infection were investigated. Among the patients, females were predominant (57.5 vs. 42.5%). The mean age of patients was 32.59 +/- 18.47 (range: < 1-87) years and the most frequently age group was 20-30 years (23.6%), followed by the age groups of 30-40 years (21.7%), 10-20 years (14.2%), 40-50 years (11.9%), 50-60 years (11.3%), < 1 year (6%), 60-70 years (4.7%), 1-10 years (4.1%) and finally, > 70 years (2.5%). The lung was the most frequently infected organ (48.1%), followed by the liver (28.9%), gallbladder (3.5%), spleen and kidney (each one in 2.2%), abdomen, intestine, pleura, bronchus and mediastinum (each one in 1.6%), chest wall and heart (each one in 1.3%), brain, pericardium, facial sinus, pancreas and esophagus (each one in 0.6%) and the ovary, uterus, axillary region, pelvis and femur (each one in 0.3%). In conclusion, this study showed that the patients with hydatid cysts in East Azerbaijan Province are mainly females in the age group of 20-40 years. The lung and liver are the major sites of infection in these patients. PMID- 22816177 TI - Agronomic importance of first development of chickpea (Cicer arietinum L.) under semi-arid conditions: II. Seed imbibition. AB - Due to the slowness growth and weakness of the first developments of chickpea (Cicer arietinum L.), it could not combated with weeds and easily caught up by Ascochyta blight (Ascochyta rabiei (Pass) Labr.) disease. Additionally, due to biotic and abiotic stress factors, esp. at the late sowing, important seed yield losses could be happened. To be able to avoid from them is only possible to accelerate of its first development as possible as. So, one of the best solutions to is to use chemical compounds such as Humic Acid (HA) known soil regulator under the semi-arid conditions. With this aim this research was performed in a Randomized Complete Block Design (RCBD) with four replications under semi-arid field conditions during (2008/2009) and (2009/2010) in Turkiye. Two cultivars (V1 = Gokce and V2 = Ispanyol) and four seed imbibition methods (A0 = 0, A1 = Tap Water, A2 = 1/2 Tap Water + 1/2 Humic acid (HA), A3 = Full HA, as w/w) and seven yield components Plant Height (PH), Number of Branches per Plant (NBP), Number of Pods per Plant (NPP), First Pod Height (NFP), Number of Seeds per Pod (NSP), Seed Weight per Plant (SWP) and 100-Seed weight (HSW) were investigated. The PH and FPH were affected the A0, the NBP, NPP and NSP were affected the A2 and the SWP and HSW were given the varied but not clear responses according to varieties for all the parameters in A1. The A0 and A1 were encouraged the germination and top soil of the plant but, the A2 to A3 were encouraged root system's development. It was concluded that the A2 is a promising method which makes the maximum and positive effect to the first development of the chickpea agronomy under the semi arid conditions. PMID- 22816178 TI - Histopathological effects of short and long-term treatment of Orchis antolica crude root extract on female albino rats fertility and pregnancy. AB - The present study has investigated the effects of Orchis antolica (dose of 400 mg/kg/Body Wight) on female rats reproductive system for two time periods 4 and 12 weeks. Forty adult female Sprague-Dawley rats were divided into two treatment and two control groups of 10 rats each. The two treated groups received 400 mg/kg/body weight of Orchis antolica for two periods of 4 and 12 weeks. Female rats were allowed mating with untreated males when treatment ended. Pregnancy parameters such as: total number of pregnancy, body weight, reproductive organ weight, number of implantation sites, number of resorption sites and number of viable fetuses. The significance of these results was calculated using student's "t" and Chi- square tests. Treatment with Orchis antolica for 4 weeks did not have any significant effects on most parameters investigated except for a slight increase in the relative ovarian and embryo weights. Orchis antolica for 12 weeks induces a significant increased in the percentage of pregnancies and the number of implantation sites when compared with controls. Further, an increase in ovarian weights and in viable fetuses count was also observed. Histological sections of treated female ovaries were found to have an empty blood vessels within the cortical and modularly regions. We also noted an increased in the developing follicles at primary and secondary stages in addition to an absence of degenerative areas and increased cellularity in medulla. Long-term treatment with Orchis antolica might lead to diversified positive effects on fertility and pregnancy in female rats. PMID- 22816179 TI - Agronomic importance of first development of chickpea (Cicer arietinum L.) under semi-arid conditions: I. Effect of powder humic acid. AB - Due to slow growth and weakness of the first development of chickpea (Cicer arietinum L.) plant could not combatted with weeds and easily get caught up by Ascochyta blight (Ascochyta rabiei (Pass) Labr.) disease; esp. under the late sowing and semi-arid conditions, due to effect of biotic and abiotic stress factors, significant yield losses could be arised. To be able to avoid from them is only possible to accelerate the first development of this crop. So, one of the best solutions is to use of "soil conditioner" chemical compounds such as HA at optimum dose. With this aim, it was established in order to find out the optimum dose range of HA. Three doses (D0 = 0 g, D1 = 100 g and D2 = 200 g), four varieties (V1 = Er-99, V2 = Gokce, V3 = ILC-482 and V4 = Australia) and five yield components Plant Height (PH), First pod height (FPH), Number of Branches per Plant (NBP), Number of Pods per Plant (NPP) and Number of seeds per pod (NSP) were investigated. Obtained results are: Recommended (Optimum) HA doses and interactions were ranged and found as (V4 > V2 = V3 > V1); (D2 > D0 = D1); (D1 x V4) for the PH and FPH, (D2 x V3) for the NBP and (D1 x V3) for the NPP, respectively. It was concluded that when the recommended HA dose applied, it was seen that the first development has been clearly accelerated and increased under the semi-arid conditions in terms of investigated traits and cultivars. PMID- 22816180 TI - Mushroom poisoning: a case report from Jordan. AB - An eight years male child with his family ate fresh mushroom at lunch time from back garden at their home in a village in the North of Jordan. By the evening approximately six hours later all started feeling nausea, abdominal cramps and vomiting they rushed to nearest primary health care center. After getting general medical medication they were transfer to a referral hospital at city of Irbid. The boy got deteriorated with diarrhea in addition to the previous gastrointestinal complains and died on third day. The message from this case is to ascertain in the public opinion that unknown type of mushroom even eaten previously could be poisonous and fetal. PMID- 22816181 TI - Plant pathogenic bacteria are not that dependent on their siderophores as mammalian pathogenic bacteria for their virulence. PMID- 22816182 TI - [Gender differences in the relationship between sleep and depression among elderly people residing at home]. AB - OBJECTIVES: To investigate gender differences in the relationship between sleep and depression in the elderly. METHODS: Residents of a village in Kumamoto Prefecture, Japan (563 people) aged > or =65 years were given a self-administered questionnaire survey between June and July 2010. To evaluate levels of sleep and depression, the Pittsburgh Sleep Quality Index (PSQI) and the Geriatric Depression Scale-Short Form (GDS-SF) were used. Adjustment factors assessed age, income, residence status, social role, medical history, nursing situation, and cognitive function. As with previous studies, respondents were evaluated as having a disturbed sleep or depression if the sum of their PSQI and GDS-SF scores was 6 or more. We examined the relationship between sleep and depression using multiple logistic regression analysis, with presence of depression in each gender introduced as a dependent variable. Given that some degree of correlation was expected among adjustment factors in the model, we constructed a model that introduced the adjustment factors stepwise to confirm the robustness of the model and any effect of multicollinearity. RESULTS: Overall (n=424), a significant relationship was found between disturbed sleep and depression in all models. The odds ratio was 1.92 (95% confidence interval: 1.11-3.32) in the final model, controlling all adjustment factors. In men (n=198), although the relationship between disturbed sleep and depression was significant before adjustment, no significance was observed after adjustment. In women (n=226), however, a significant relationship was observed between disturbed sleep and depression in both models. After the introduction of all variables as adjustment factors, the odds ratio was 2.28 (95% confidence interval: 1.11-4.69). CONCLUSION: Our findings suggest a significant relationship between disturbed sleep and depression in elderly women, but not in men. While the reasons for this gender difference are unclear at present, various factors, such as the endocrine system, are likely to be involved. Future studies should take this gender difference into account in order to enact more effective measures for preventing depression in the elderly. PMID- 22816183 TI - [Factors associated with delay in seeking medical treatment in pulmonary tuberculosis patients in Japan]. AB - OBJECTIVES: As the number of tuberculosis (TB) cases has decreased, early diagnosis of TB has become more difficult. Delayed diagnosis of TB may lead to worsening of the affected individual's condition and may spread the disease in the community. The purpose of this study was to find factors associated with patient delay in seeking treatment after developing symptoms of TB. METHODS: Structured interviews were conducted with adult TB patients from 17 health centers registered under the national Japanese TB surveillance system from January 1, 2010 to November 30, 2010. The questionnaire used for the interview included items on symptoms, type of coping behavior from the time of onset of symptoms to the time of the first hospital visit, recognition of and experience with TB, priorities in terms of health behavior, and demographic characteristics of the patients. RESULTS: Among the 60 patients interviewed, only 53 patients' data were analyzed. Seven patients were excluded from analysis because they had no symptoms, were non-Japanese, had extrapulmonary tuberculosis, or were undergoing retreatment. The mean age of the patients was 60.2 +/- 19.2 (mean +/- SD) years. Twenty-two patients (41.5%) visited a hospital after a gap of more than two months from the time of onset of their symptoms (hereafter referred to as "patient delay"). Factors associated with patient delay were presence of sputum and hemoptysis, positive sputum smear, low priority given to health, lack of a family physician, lack of consultation, taking over-the-counter drugs, and disliking hospital visits. CONCLUSION: Factors associated with patients' seeking medical treatment more than two months after developing symptoms of TB included taking over-the-counter drugs disliking hospital visits and not consulting health professionals or the people around them. In order to prevent patient delay, our findings suggest the following actions. Health care professionals need to provide information about symptoms of tuberculosis and the merits of early hospital visits to patients. It is also necessary for health care professionals in public health centers, etc., to communicate the need to have people available whom patients can consult regarding their symptoms and receive appropriate advices or secure appropriate treatment when they have symptoms of tuberculosis. PMID- 22816184 TI - [Professional mental health support provided by local government to families of people with schizophrenia in need of treatment]. AB - OBJECTIVES: The purpose of this study was to describe the content of interventions provided by mental health professionals working for local government in Japan to families of people with schizophrenia in need of treatment. METHODS: The study was designed to be qualitative and descriptive. The subjects were ten local prefectural or municipal government professionals in the Kanto region who worked as psychiatric social workers or public health nurses and who had five or more years of experience in their professions. In semi-structured interviews, subjects were asked to choose one case from their experience of assisting both persons with schizophrenia and their families who contacted them for consultation, in which they believed that they were able to successfully assist the family in bringing the untreated person with schizophrenia or person who had discontinued treatment to hospital. Interview questions focused on the professionals' assistance to the families. The interview data were transcribed, coded by type of assistance rendered, and categorized by commonalities for comparison. RESULTS: Six major categories and nineteen subcategories were extracted through the data analysis process, which focused on support for the families of people with schizophrenia that helped the latter engage in treatment. The six major categories were "Make a tentative intervention plan", "Establish relationship with family", "Wait for the family members to make their decision to hospitalize the person", "Stand by the family members and support their decision to persuade the person to receive treatment" "Make pre-hospitalization arrangements" and "Provide continual support for families and the patient after hospitalization". CONCLUSION: The most important forms of support for families were assistance in persuading the person with schizophrenia to receive treatment and in making their own decision to bring the person to inpatient treatment. This support can lead to better patient-family relationships in the future and to better prognoses. The results of this study will contribute to improving the quality of professional support for families who are trying to make decisions regarding treatment of their relatives with schizophrenia. PMID- 22816185 TI - [Polio virus detection in stool by the pathogen surveillance system of Japan. An observational study]. AB - OBJECTIVES: To examine the applicability of data on polio virus detection in stool by the Pathogen Surveillance System of Japan (PSSJ) for the evaluation of polio virus retention status in a regional community after oral polio vaccination (OPV). METHODS: (1) Data for the city of Kobe (part of the PSSJ data): Cases of polio virus detection in stool reported to Kobe City Public Health Center from January 1, 2000 to June 30, 2010 were examined regarding time duration from vaccination to detection as well as age and gender. (2) PSSJ data: Cases of polio virus detection in stool reported to PSSJ from January 1, 2000 to December 31, 2010 were examined regarding the serological types of the virus as well as age and gender. A logistic regression analysis was used to derive odds ratios for the relationship between age and serological type of polio virus in stool. RESULTS: Thirty-one cases (33 stool samples) were identified in the Kobe city data. Of these, 96.8% were in children two years old or younger and 54.8% were girls. The time duration between vaccination and detection of all the cases was within two months from vaccination. From the PSSJ data, 852 cases were identified. Of these, 97.3% were two years old or younger and 54.6% were girls. The proportion of serological types was different by age group: for those under one year old, the type 1 virus accounted for 33.2%; type 2, 44.8%; and type 3, 22.0%. In the one year old or older age group, these types accounted for 22.8%, 27.6% and 49.6%, respectively. Notably, the type 3 virus was detected more for the older age group. (odds ratio 3.4, 95% confidence interval 2.5-4.6). CONCLUSION: The duration before detection and the serological types of polio virus in stool from the PSSJ and Kobe City data are consistent with the results of the prior studies that have evaluated the shedding of polio virus in stool after the administration of OPV. Since the PSSJ data are collected from a relatively wide range of samples, we conclude that the PSSJ data accurately represent polio virus retention status in a regional community after OPV. The current situation of polio virus shedding in stool cannot be ignored, and further consideration needs to be given to improving the accuracy of the PSSJ data, because Japan is to switch over to inactive polio vaccines in the near future. PMID- 22816186 TI - [Relationships of the stages of behavior change in dietary habits of the mothers of school-age children with the breakfast intake of the children and the health associated behavior of the family]. AB - OBJECTIVES: We aimed to clarify the relationships of the different stages of behavior change in dietary habits followed by the mothers of school-age children with the actual breakfast intake of these children and the health-associated behavior of the family. METHODS: We carried out a questionnaire-based survey of 1949 children at 18 elementary schools and of 881 families with children attending seven elementary schools in Kagoshima prefecture. We were supplied with information about children's breakfast intake and content on the day they took the survey and information about mothers' breakfast intake and the stage of behavior change in dietary habits to which they belonged, for which five stages were defined using the stage-of-change model. RESULTS: The collection rates were 83.3% and 83.1% among children and mothers respectively. Of the children, 83.1% ate breakfast every day, while 15.1% were not in the habit of having breakfast. Furthermore, 98.6% children had eaten breakfast on the day of the survey, but 15.1% had eaten only staple foods such as rice or bread; only 34.0% children combined staple foods, a main dish, and vegetables/fruits in their breakfast. Regarding dietary stage, 28.1% of the mothers belonged to the "maintenance" stage; 24.0%, the "action" stage; 6.9%, the "preparation" stage; 9.8%, the "contemplation" stage; and 5.7%, the "precontemplation" stage. Mothers belonging to the first two stages constituted the "action group," because they were already taking care of their dietary habits, and mothers belonging to the latter three stages constituted the "no-action group", because they were not taking care of their dietary habits. The mothers who could provide no answers to the question constituted the "no-answer group" (25.5%). A comparison of the three groups revealed that mothers belonging to the no-answer group had more children who went without breakfast than the action group (P = 0.000). The children of mothers belonging to the no-action group (P = 0.003) and the no-answer group (P = 0.036) were not in general eating vegetables/fruits in their breakfast, in contrast with the action group. Furthermore, in the case of families with mothers belonging to the no-action and no-answer groups, the families did not often talk about diet, and the incidence of smokers among the fathers was high. CONCLUSION: In this study, the breakfast habits of children and the health behavior of families differed by stage of dietary behavior change to which the mother belonged. PMID- 22816187 TI - [Risk factors for falls and survival after falling in elderly people in a community]. AB - OBJECTIVES: The purpose of this study was to assess the risk factors associated with falls and to examine the effects of falls on survival of elderly people in a community. METHODS: A questionnaire survey was conducted in 16,462 urban elderly dwellers aged 65 years or more in City A in September 2001. A follow-up survey was carried out in September 2004. We analyzed the data of 8,285 subjects who answered both questionnaires and had not relocated by August 2007. Baseline assessments of health and functioning were carried out in 2001. Falls experienced during the 1-year period before September 2004 were recorded, and the deaths were recorded until August 2007. Statistical analysis was performed using a logistic regression model and Cox's proportional hazards analysis. RESULTS: A total of 6,420 subjects (3,127 men and 3,293 women) who had provided complete answers about their falls were included in the analyses. Of these, 27.8% of women and 16.4% of men had experienced falls, while 6.2% of women and 2.1% of men had experienced falls that caused fractures. We found that the likelihood of fall, with or without fracture development, was greater in women than in men (P < 0.001). The rate of falls tended to increase with age in both women and men. Risk factors associated with falls, in addition to age and gender, were pain (odds ratio [OR], 1.75), lack of instrumental activities of daily living (IADL; OR, 1.45), poor self-rated health status (OR, 1.42), and presence of disease (OR, 1.35). Risk factors associated with falls that caused fracture were pain (OR, 1.85) and lack of IADL (OR, 1.61). Cox's proportional hazards analysis showed a significant increase in mortality in both men and women who had experienced falls than in those who had not (hazard ratio [HR], 1.94, 1.43). CONCLUSION: Aging, pain and disease, lack of IADL, and poor self-rated health status were all significant risk factors for falls in elderly people, and a fall was related to subsequent mortality. PMID- 22816188 TI - [Relationship between personal trust and parental feelings of parents of children aged 3 years. Differences between the characteristics of fathers and mothers]. AB - OBJECTIVES: In modern society, which is said to lack human relationships, an individual's personal ability to build relationships has gained great importance. The purpose of this study was to define the relationship between the parental feelings of parents of children aged 3 years and a personal trust (PT) scale developed by the author. We also clarified the differences between fathers and mothers with regard to PT. METHODS: The study sample comprised 329 parents (134 fathers, 195 mothers) of children who underwent the health examination for children aged 3 years in 2008 in City A, Japan. We distributed questionnaire forms to the participants before the examination and collected the completed forms on the day of the health examination. The PT scale consists of 3 subscales: (1) strategic trust for building bonds (ST), (2) universal trust toward the general public (UT), and (3) trust toward specific persons (TS). First, subscale scores were summed up for fathers and mothers. Next, confounding factors were investigated by comparing the median subscale scores obtained for different demographic groups. Next, we performed logistic regression analysis to investigate the influence of PT, which was evaluated using the 3 subscales, on parental feelings. RESULTS: We identified the confounding factors by comparing the median scores of each subscale for different demographic groups. A group of parents whose birthplace was City A had a high ST score. Next, compared to unemployed mothers, working mothers had higher ST and TS scores. Furthermore, mothers of male children had higher ST scores than those of female children. We performed multivariate logistic regression analysis to investigate the psychological parental variables affected by PT calculated using each of the subscales. The results indicated the ST and TS scores affects parental feelings of fathers. However, the UT scores had no effect on parental feelings of fathers. In the case of mothers, the ST, TS, and UT scores affects parental feelings but the ST scores had no effect on parental feelings after adjusting for confounding factors. CONCLUSION: The PT scale reflected the socializing patterns of parents with various communities. We confirmed that PT promoted parental happiness and buffered parenting-related stress. However, there was a difference between the characteristics of fathers and mothers in relationships between parental feelinfs and PT. For example, in the case of fathers, there was no significant relationship between parental feelings and UT. PMID- 22816189 TI - [Possibilities for detection of homebound elderly people through the welfare commissioner (Minsei-iin)]. AB - OBJECTIVES: The purposes of this study were (1) to evaluate the percentage of homebound elderly people that could actually be detected through commissioners who consciously tried to detect and provide information regarding these people, and (2) to identify difficulties that commissioners experienced when attempting to detect and provide information about such people. METHODS: This study was conducted in one of the districts of a city in Kanto area. The percentage of detection of homebound elderly people was calculated by following the 3 steps described below. First, the number of homebound elderly people was estimated by using the probability sample survey on elderly people living in the district. Second, detection and information activities were conducted by the commissioner in the district over a 2-month period. Finally, the detection rate through the commissioner's efforts was calculated. The detection rate was calculated by dividing the number of homebound elderly people detected through commissioners by the estimated number of homebound elderly people in the district. The difficulties that commissioners experienced were analyzed by using the KJ method to analyze qualitative data obtained from focus group interview surveys for commissioners. RESULTS: The commissioners actually detected and reported 1.4% of homebound elderly people. The difficulties in detection and reporting included the lack of opportunities for detection and hesitation in providing information about homebound elderly people. CONCLUSION: Although the commissioners are not completely responsible for detection of homebound elderly people, the rate of detection through these commissioners can be higher. To improve this rate of detection, the commissioner's other responsibilities need to be limited and the anonymity of the commissioners who provided information regarding homebound elderly people should be restricted to avoid harming their relationships with the elderly. PMID- 22816190 TI - [Isolation of Legionella species from hot springs used for foot-soaking]. AB - OBJECTIVES: We aimed to investigate the presence of Legionella species in hot spring baths for feet, which have been rapidly increasing in number in Japan in recent years. METHODS: The investigations were conducted between March 2009 and November 2011, and hot springs throughout the country were sampled. Legionella isolates were confirmed on the basis of the method described in the "Manual for the countermeasure to legionellosis, 3rd Edition." In this method, the samples were concentrated and smeared on GVPCalpha agar medium after acid treatment and cultured for 7 days at 36 degrees C. Gram-negative rods that required L-cysteine were determined to be Legionella species. After the first identification using Duopath Legionella (Merck Ltd. Japan), isolates were identified on the basis of agglutination reaction of an immune serum or genetic examination. RESULTS: Legionella was isolated from 56 of the 196 samples (28.6%) and was confirmed to widely inhabit hot-spring baths from Hokkaido to Kyushu. The isolation rates were the highest (40.9%) in facilities installed around railway stations, including those on platforms. The average microbial density of Legionella species per 100 ml of hot spring water was 1.0 x 10(1) CFU, with a maximum value of 1.0 x 10(4) CFU, although the microbial density in most of the samples (34 samples; 60.7%) was less than 10(2) CFU. Legionella pneumophila was the dominant strain, and 16 strains (23.9%) of serogroup 1 were isolated. In addition, 7 strains (10.4%) of Legionella londiniensis and 4 strains (6.0%) of Legionella rubrilucens were isolated. CONCLUSION: Legionella species inhabit approximately 30% of all hot springs for foot-soaking in the country. Although the number of viable organisms is small, the dominant presence of Legionella pneumophila, a major pathogen responsible for legionnaire's disease, raises the possibility of legionnaire's disease in users of these hot springs. Therefore, each institute should understand the present distribution of Legionella species in these hot springs and undertake appropriate sanitary measures. PMID- 22816191 TI - [Investigation of the operational readiness of a public health center, municipality, and home-visit nursing care station in Ibaraki Prefecture for disaster management in the event of an earthquake]. PMID- 22816192 TI - A critique of race-based and genomic medicine. AB - Now that a composite human genome has been sequenced (HGP), research has accelerated to discover precise genetic bases of several chronic health issues, particularly in the realms of cancer and cardiovascular disease. It is anticipated that in the future it will be possible and cost effective to regularly sequence individual genomes, and thereby produce a DNA profile that potentially can be used to assess the health risks for each person with respect to certain genetically predisposed conditions. Coupled with that enormous diagnostic power, it will then depend upon equally rapid research efforts to develop personalized courses of treatment, including that of pharmaceutical therapy. Initial treatment attempts have been made to match drug efficacy and safety to individuals of assigned or self-identified groups according to their genetic ancestry or presumed race. A prime example is that of BiDil, which was the first drug approved by the US FDA for the explicit treatment of heart patients of African American ancestry. This race-based approach to medicine has been met with justifiable criticism, notably on ethical grounds that have long plagued historical applications and misuses of human race classification, and also on questionable science. This paper will assess race-based medical research and practice in light of a more thorough understanding of human genetic variability. Additional concerns will be expressed with regard to the rapidly developing area of pharmacogenomics, promoted to be the future of personalized medicine. Genomic epidemiology will be discussed with several examples of on going research that hopefully will provide a solid scientific grounding for personalized medicine to build upon. PMID- 22816193 TI - Physiological dysregulation and somatic decline among elders: modeling, applying and re-interpreting allostatic load. AB - Mortality rates continue to decline among post-reproductive individuals. This makes understanding long-term physiological responses to stress increasingly important. Allostatic load (AL) was developed to assess detrimental effects on the soma of responding to multiple stressors over a lifetime. AL arises from developmental experiences, genetic predispositions, environmental, psychosocial, life style and other stressors. In early life stress responsive systems are initiated that produce hormones that maintain the soma through continual allostatic responses. Later in life, systems designed to mitigate stressors may fail or be compromised, promoting unwanted somatic changes and dysregulation. This places a load on the regulatory system that impedes day-to-day stress responses, predisposing to cellular damage and degenerative diseases. Here we review 44 peer-reviewed 2005-2010 publications reportedly examining relationships between AL and risk factors, chronic diseases, morbidity and mortality in samples of elderly adults. The sum of results suggests that AL does assess aspects of physiological dysregulation and somatic decline, predicts detrimental age-related declines, and is associated with negative sociocultural attributes and psychological outcomes. Such consistent results and wide application of AL, while it is still being modeled and re-interpreted, suggest its perceived usefulness as a research and clinical tool. AL provides a possible biomarker of senescence, assessing it over the life span will aid in predicting future negative health outcomes. PMID- 22816194 TI - The role of motor and nutritional individuality in childhood obesity. AB - Nutritional and motor individuality vary significantly among human subjects, and their mutal relationship is decisive for a desirable energy balance and turnover with regard to body composition, physical fitness level and health. Early establishment of optimal individualities, with regard to genetic, epigenetic and other factors which influence the organism early in life is desirable for a positive life-long health prognosis and life expectancy. Approaches for the evaluation of both nutritional and motor individualities have been elaborated as an important starting point for their positive development and eventual modification. This should aim to achieve not only prevention of diseases, but also to improve health prevention and achieving the status of "positive health". PMID- 22816195 TI - Data analysis strategies for reducing the influence of the bias in cross-cultural research. AB - In cross-cultural research, researchers have to adjust the constructs and associated measurement instruments that have been developed in one culture and then imported for use in another culture. Importing concepts from other cultures is often simply reduced to language adjustment of the content in the items of the measurement instruments that define a certain (psychological) construct. In the context of cross-cultural research, test bias can be defined as a generic term for all nuisance factors that threaten the validity of cross-cultural comparisons. Bias can be an indicator that instrument scores based on the same items measure different traits and characteristics across different cultural groups. To reduce construct, method and item bias,the researcher can consider these strategies: (1) simply comparing average results in certain measuring instruments; (2) comparing only the reliability of certain dimensions of the measurement instruments, applied to the "target" and "source" samples of participants, i.e. from different cultures; (3) comparing the "framed" factor structure (fixed number of factors) of the measurement instruments, applied to the samples from the "target" and "source" cultures, using explorative factor analysis strategy on separate samples; (4) comparing the complete constructs ("unframed" factor analysis, i.e. unlimited number of factors) in relation to their best psychometric properties and the possibility of interpreting (best suited to certain cultures, applying explorative strategy of factor analysis); or (5) checking the similarity of the constructs in the samples from different cultures (using structural equation modeling approach). Each approach has its advantages and disadvantages. The advantages and lacks of each approach are discussed. PMID- 22816196 TI - The nutritional dual-burden in developing countries--how is it assessed and what are the health implications? AB - This paper focuses on the phenomenon of the nutritional dual-burden in the developing world. Nutritional dual-burden is defined as the coexistence of under and-over nutrition in the same population/group, the same household/family, or the same person. In this paper we aim: a) to describe the different types of nutritional dual-burden, b) to identify the anthropometric indicators generally used to classify the nutritional dual-burden, c) to focus our attention on a dual burden group (the Maya from Merida, Yucatan, Mexico), d) to illustrate problems in the categorization of the dual-burden, and e) to suggest possible health implications. Our results show that, for our sample, the prevalence of individual dual-burden among children is very low, but is very high among the mothers and for mother-child pairs (household dual-burden). Most importantly, the criteria used to assess the nutritional status of the individuals and of the families will play an important role in the estimated prevalence of nutritional dual-burden, and this will have practical impacts for health intervention programs. PMID- 22816197 TI - The Selska valley Study of Health and Aging: unraveling senescence, stress and frailty. AB - In this project we use an age-stratified sample of 100 men and 100 women aged 55 years and older who were residents of the Selska valley in order to explore two health indices, allostatic load (AL), and frailty. AL assesses lifelong stress responses using commonly assessed and clinically meaningful aspects of physiology; our frailty index assesses current somatic well-being using 5 aspects of functioning. Both correlate with clinical morbidity, self-reported health, life style, health history, and well-being. Our research site includes 9 villages located in the isolated Selska valley. Given their relative isolation, residents of this region provide a natural experimental setting for assessing stress, frailty, morbidity, and senescence in a local isolate. This isolated alpine setting provides numerous advantages for continuing research on health, disease and senescence. Our fieldwork protocols include detailed health demographic and SES interviews, measurement of blood pressure, anthropometry, walking speed, strength/endurance, and collection of blood and saliva samples for determinations of hormones, plasma proteins, and lipids. In this paper, we present one segment of data for 41 participants on self-report health and use of prescription medications during our 2008-2010 survey. In general, most participants rate themselves as being in good to excellent health (34/41 = 85%). However, over 66% are taking medications for a chronic condition, with about 25% taking 4 or more medications. PMID- 22816198 TI - Inheritance of dermatoglyphic asymmetry in 500 Indian pedigrees: complex segregation analysis. AB - The major aim of this study is to determine the mode of inheritance of asymmetry of quantitative dermatoglyphic traits based on principal factors through the application of complex segregation (genetic model fitting) analyses on a large ethnically homogeneous sample of 500 Indian pedigrees (2435 individuals) of two generations. By segregation analysis of the traits- PC1_FA both Mendelian and Environmental models were rejected (< 0.001) with the General model, i.e. that despite presence of significant inheritance (rejection of Environmental model), the nature of inheritance is more complex, than Mendelian one. Although a little genetic effect was observed due to familial correlations on asymmetry traits, no evidence was found of major gene contribution to be involved, but this does not contradict the notion postulated by several earlier authors that asymmetry (fluctuating) provides a measure of developmental instability in human. PMID- 22816199 TI - Prevalence and tracking of weight disorders in Italian primary school students: a three-year follow-up. AB - Obesity has been widely described as the latest epidemic, and in some areas obesity co-exists with undernutrition. The purpose of this study was to assess the variability of weight status of a cohort of 279 Italian primary school students followed longitudinally for three years. Overweight was the most common weight status disorder in both sexes and generally prevailed in females. Underweight was also more frequent in females than males, while males generally showed a higher incidence of obesity. Overweight showed the highest stability in females. In males, tracking of overweight was 62.5%, while that of normal weight was 89.36%. Overweight tracks through the three consecutive years in a high percentage of both sexes. In the whole sample (regardless of sex and weight category), overweight shows the highest increase over the three-year period. This study provides public health professionals with useful data for policy planning in regard to childhood obesity. PMID- 22816200 TI - Relationships between cognitive and motor abilities in female children aged 10-14 years. AB - The aim of the study was to determine cognitive and motor status factors in female children aged 10-14 years and to identify developmental and/or integration functions according to age. The study included a sample of 162 female schoolchildren aged 10-14 years divided into two groups: 84 girls aged 10-12 (X 11.26, SD 0.68) years and 78 girls aged 13-14 (X 13.52, SD 0.63) years. Study results showed a statistically significant between-group difference in the overall system of variables (MANOVA), with the level of significance determined for each individual variable (ANOVA). The older group of subjects showed significantly superior results in comparison with the younger group in the motor tests assessing flexibility, agility, psychomotor speed, explosive strength of throwing type and repetitive strength of the trunk, as well as in the test assessing cognitive functioning. Qualitative differences between the two age groups (prepubertal and pubertal) were determined by use of the matrix of variable inter-correlations factorized by the procedure of principal components that were then transformed to promax solution. The results thus obtained indicated cognitive functioning to take significant part in the motor efficacy of girls aged 10-14 years. In the younger age group (10-12 years), cognitive functioning was related to the motor system that integrates muscle tone regulation and agility/coordination. In the older age group (13-14 years), cognitive functioning was involved in the formation of the first and third factor isolated, i.e. in the factor regulating coordination and intensity of energy mobilization of lower extremities (general motor efficiency) and, to a lesser extent, in third factor regulation the intensity of energy mobilization of upper extremities and trunk strength. PMID- 22816201 TI - High school students' body weight control: differences between athletes and non athletes. AB - Due to chronic dissatisfaction with body weight in youth, efforts to lose weight often lead to pathological dietary behaviours. Regular and heavy sports activity may contribute to the optimization of body weight, not only by elevating the energy utilization but also by increasing the health consciousness and the tendency to self-monitor. Research generally finds a beneficial role of extracurricular sports activity in body weight control. Therefore, we aim to analyze how regular, heavy sports activity (more precisely, competitive sports) may contribute to body weight control among two groups of youth: athletes and non athletes. Our study was carried out using 347 adolescents; among them there were 91 athletes and 259 controls. The subjects completed self-administered questionnaires concerning their body weight control and dietary habits. We found that girls were less satisfied with their body weight and reported dieting more frequently with a greater emphasis on healthy dieting than boys. Sport influenced these strong gender differences only regarding healthy dieting, young male athletes laid a larger emphasis on healthy diets than their non-athlete counterparts, therefore their attitude became similar to that of female athletes and non-athletes. We conclude that despite the normal weight in high school students, episodes of dieting that might contribute to eating disorders were quite frequent. This was not influenced by the students' extracurricular sports activity. A greater monitoring of male athletes' and their friend's diet draw attention to the need for developing health education programs specific to boys. PMID- 22816202 TI - The determination of blood pressure, anger expression and body mass index in adolescents in Turkey: a pilot study. AB - This study was planned to determine whether there is a correlation between blood pressure, anger expression and body mass index of 16-18 year-old-adolescents. A descriptive-correlation design was used in this study. The study population comprised 276 students from 4 public high school. A questionnaire form and Anger Expression Inventory were used, and measures of systolic and diastolic blood pressure, height and weight measures were noted to the questionnaire form. The systolic blood pressure of 3.3% of the adolescents and the diastolic blood pressure of 4.7% of the adolescents was found hypertensive. Anger-in score was 15.42 +/- 3.78; anger-out score was 17.70 +/- 4.55 and anger-control score was 19.39 +/- 4.53. Body mass index of 67.8% of the adolescents was found within the normal range and 7. 6% of students were obese. A positive correlation was found between anger-control and systolic blood pressure (r = 0.13; p < 0.05), body mass index and systolic blood pressure (r = 0.24; p < 0.01), body mass index and diastolic blood pressure (r = 0.16; p < 0.01) and anger-in and body mass index (r = 0.17; p < 0.01) of adolescents. As a conclusion, this study provided findings related to the importance of determination of blood pressure, anger expression and body mass index in school health studies. PMID- 22816203 TI - Relationship between the training of young recruits and values of bite forces. AB - Analysis of masticatory function is the basis of clinical work in almost all fields of dentistry. Bite forces are the expression and measure of masticatory function. Physical training has an effect on the development of functional ability, motoric ability of the organism and the formation of desired physical proportions. The purpose of this study was to examine the association between physical fitness and bite force values. Because of strictly defined regulations in the army with regard to training and nutrition, Croatian Army recruits were ideal examinees for this examination. The examinees were 135 recruits. Bite forces were measured on three places (area of the central incisors, left and right in the area of the first molars) before and after three-months of training. Of all the examinees, 108 had increased their body weight, 12 had decreased it and 15 had not changed their body weight. The median of measured forces in the recruits prior to training was 291 N in the right (lateral quadrant), 285.5 N in the left lateral quadrant and 205 N in the anterior area. After training the median of measured forces in the right quadrant was 312 N, in the left 313 N and in the anterior area 216 N Greater bite forces after training on all measured places were statistically proved. Increased activity of masticatory muscles can have the same effect on the values of bite forces as bite training. There are few data on the correlation between physical muscles and values of bite forces. The results of those studies are doubtful. In this study, after three months of conditional training, the body mass of the recruits had increased and they expressed greater values of bite forces. However, correlation between body mass and bite forces cannot be proved with certainty. PMID- 22816204 TI - The training and employment of teachers of physical education and sports in Turkey. AB - This paper examines the phenomenon of training teachers of Physical Education and Sports (PES) in Turkey with respect to its dimensions of student quotas, graduates, and employment; and performs analytical evaluations through the numeric data. In the last five years, the number of labor force participants in PES teaching posts was 14,459 on average and the average employment volume was 10.29%, which means that a great number of graduates have accumulated against employment. Thus, this indicates that no realistic planning was done in the past years "so as to create a supply-demand equilibrium between training and employment of PES teachers". PMID- 22816205 TI - The negative effect of heavy work life during adolescence on height development of young males. AB - The aim of this study was to determine the physical development level of post adolescent automotive repair workers who had been employed in heavy work during adolescence, a critical developmental period. Young workers (Group 1, N = 106, Mean age = 18.33, SD = 0.65) employed an average of 6 years in workshops in the capital of Turkey, Ankara. For the control group, two groups of the same age but having a difference in terms of socioeconomic status were chosen. The first one of these was comprised of individuals who had the same socioeconomic status as the laborers (Group 2, N = 106, Mean age = 18.33, SD = 0.65) but were not laborers. The second control group was composed of individuals from the higher socioeconomic levels of society (Group 3, N = 100, Mean Age = 18.45 SD = 0.63). Weight, height and measures were taken from the individuals and the body mass index (kg/m2) was calculated. The results of the analysis show that, although all the variables of the labor group were lower than Group 2, the difference is only significant for the height variable (p < 0.05). These findings reveal that, having completed a critical developmental period such as adolescence after being employed in heavy work, the automotive repair youngsters are prone to chronic developmental retardation. PMID- 22816206 TI - Presenteeism towards absenteeism: manual work versus sedentary work, private versus governmental--a Croatian review. AB - The research objectives were to find out the extent of presenteeism and absenteeism in manual workers and whether it differs in clerks that perform sedentary jobs. For that purpose 121 manual workers of "3.maj" were polled, of whom 61 are employed by the shipyard in state ownership and 60 are sub-contracted workers. Also 120 clerks were interviewed, 60 postal employees of "Telecom" Zadar and 60 of the police administration. The Stanford Presenteeism Scale (SPS-6), the internationally recognized questionnaire for assessing presenteeism was used as well as the Rijeka Presenteeism Scale (RPS-6), the new questionnaire compiled for this research, and also the Rijeka Absenteeism Scale (RAS-6). The results have shown that in our country the RPS-6 test is adequate for assessment of presenteeism with high reliability for this type of testing, Crombach's alpha = 0.757. The RAS-6 test has shown a low level of reliability and so have our questions on absenteeism which therefore cannot be considered an official scale. All four groups of employees have shown high positive presenteeism with no considerable differences, p = 0.3610, p > 0.05. Only when the question referred to one's performing efficient work with maximum care there were considerable differences p = 0.023, p < 0.05. The research has shown that the use of SPS-6 is not suitable in our parts probably because of cross-cultural differences, reasoning and speech differences. The research has also shown that the notion presenteeism as a positive presenteeism has to be distinguished from the "sickness-presenteeism" for which the SPS-6 scale could conditionally be suitable, which showed medium presenteeism in our workers, but that cannot be considered reliable due to low correlations. To conclude, although the workers show good, positive presenteeism the working conditions are to be further enhanced as well as the contact with the company management, to maintain such presenteeism and not to exhaust the worker's positive energy. PMID- 22816207 TI - Health-related quality of life and metabolic control in children with type 1 diabetes mellitus in Bosnia and Herzegovina. AB - The primary objective of the study was to examine the relationship between generic and disease-specific HRQOL scores and metabolic control in children with Type 1 Diabetes Mellitus (T1DM). This cross-sectional study included 65 consecutive children between ages 5 and 18 years with T1DM. According to their values of glycosylated hemoglobin (HbA(1C)), the children were assigned to one of two groups. In Group 1 (N = 21) were the children with HbA(1C) values < 8% (good to moderate metabolic control) and Group 2 (N = 44) were children with > 8% (poor metabolic control). To evaluate generic and disease-specific HRQOL scores in children with T1DM in relation to metabolic control, we used the PedsQL 4.0 Generic Core Scales and the PedsQL 3.0 Diabetes Module. The patients in Group 1, by pediatric patient self-report and parent proxy-report, had statistically better disease-specific HRQOL scores on the diabetes symptoms, treatment barriers, treatment adherence and worry domains in comparison with Group 2. We also found significant correlations between the total generic HRQOL scores and HbA(1C) for both parent proxy-reports' Spearman's coefficient of rank correlation rho = -0.257; p = 0.0412 and pediatric patients' Spearman's coefficient of rank correlation rho = -0.269; p = 0.0313. The current findings suggest that poor glycemic control in children with T1DM is associated with lower generic and disease-specific HRQOL scores in developing and transitional countries. PMID- 22816208 TI - Current status of iodine intake in Croatia--the results of 2009 survey. AB - In 1996, due to persistence of mild to moderate iodine deficiency, new law on obligatory salt iodination with 25 mg of potassium iodide (KI) per kg of salt was implemented in Croatia. Along with a new law, a new program for monitoring of iodine prophylaxis was implemented. Investigations of goiter and iodine intake performed in 2002, demonstrated sufficient iodine intake in Croatia with overall median of urinary iodine concentration (UIC) for schoolchildren in Croatia of 140 microg/L. In 2002, thyroid volumes (TV) measured by ultrasound in schoolchildren from all four geographic regions of Croatia were for the first time within the normal range according to ICCIDD reference values. Nowadays, Croatia is internationally recognized as iodine sufficient country. The aim of the present study was to assess current status of iodine intake in Croatia. The investigation was carried out in 2009. A total of 386 schoolchildren aged 7-10 years from all four major geographic regions of Croatia, 103 euthyroid pregnant women and 36 women of child-bearing age from Zagreb, the capital, were included in the survey. Urinary iodine concentration (UIC) was measured in all participants. Thyroid volumes were measured by ultrasound in schoolchildren from the capital of Zagreb (N = 101) and the village of Rude (N = 56). In the time period 2002-2009, the content of KI was analyzed in 384 salt samples from Croatian salt plants and samples of imported salt. An overall median UIC for schoolchildren in Croatia was 248 microg/L. Median UIC in pregnant women was 159 microg/L, with 50% of samples below and under 150 microg/L. Median UIC in women of child-bearing age was 136 microg/L. Thyroid volumes in schoolchildren were within the normal range according to the new reference values. Mean value of KI/kg of salt in samples from Croatian salt plants was 25.5 mg/kg and 24.9 mg/kg in samples of imported salt. A total of 72/384 (18.8%) of salt samples didn't corresponded to the Croatian law on obligatory salt iodination. Presented data indicate sufficient iodine intake of the Croatian population. Current medians of UIC in schoolchildren in Croatia are significantly higher than medians measured in 2002. This indicates that other potential sources of iodine are present in Croatian diet that may contribute to overall iodine intake. Due to rising medians of UIC in schoolchildren in Croatia, it is important to conduct nutrition studies to identify potential sources of "silent prophylaxis" in order to avoid iodine excess. PMID- 22816209 TI - Effect of LGG yoghurt on Streptococcus mutans and Lactobacillus spp. salivary counts in children. AB - The aim of this study was to establish effect of 14 day consumption of commercially available yoghurt containing Lactobacillus rhamnosus ATCC53103 - LGG (Bioaktiv LGG, Dukat, Croatia) on Streptococcus mutans and Lactobacillus spp. salivary counts in children. Twenty five patients, 6-10 yr old participated in the study. At the inclusion in the study caries risk for every patient was evaluated. The saliva samples were tested with chair side kits for saliva buffer capacity (CRT buffer, Vivadent, Schaan, Liechtenstein), S. Mutans and Lactobacillus counts (CRT bacteria test, Vivadent, Schaan, Liechtenstein). Seven, 14 and 30d after yoghurt consumption saliva samples were tested again with CRT buffer and CRT bacteria tests. Obtained data were analyzed using chi2 and Kruskal Wallis tests. Results showed significant increase in saliva buffer capacity 30d after yoghurt consumption. S. Mutans salivary counts were significantly decreased after 30d. Significant differences in Lactobacillus counts were not observed. It could be concluded that daily consumption of yoghurt containing LGG have an inhibitory effect on oral pathogenic bacteria and may be beneficial in caries prevention. PMID- 22816210 TI - Descriptive epidemiology of cutaneous squamous cell carcinoma in Croatia. AB - The aim of the study was to investigate the squamous cell carcinoma (SCC) incidence in Croatia in the 2003-2005 period. The cases of SCC were retrospectively studied. Data were collected from University Department of Dermatology and Venereology, Zagreb University Hospital Center and National Cancer Registry. In the study period, there were 1,860 cases of SCC (934 men and 926 women). The crude incidence rate for the Croatian population of 100,000 was 14.6 for men and 13.4 for women. The age-standardized incidence rate (adjusted for the world standard population) was 8.9 for men and 5.2 for women. The head was almost exclusive localization of SCC in both sexes. The highest SCC incidence was recorded in Zadar County. These results will serve for the SCC trend monitoring in Croatia and Europe in the forthcoming years. PMID- 22816211 TI - Blood pressure trends and hypertension among rural and urban Jat women of Haryana, India. AB - Hypertension is an important public health problem and the major causes of cardiovascular morbidity and mortality among aged and elderly population in India. The present study is an attempt to assess age related trends of blood pressure and prevalence of hypertension in rural and urban women as well as correlation of blood pressure with obesity indicators (WC, BMI, and WHR). Data for present cross-sectional study were collected by purposive sampling method from six hundred Jat women (300 rural and 300 urban), aged 40 to 70 years. Karl Pearson's correlation coefficient (r) was employed to find the relationship between blood pressure and obesity indicators. The results revealed an age associated increase in mean values of systolic and diastolic blood pressure in rural and urban women. Urban women showed significantly higher overall mean value of systolic (mm of Hg) (133.93 vs. 130.79, p < 0.001), diastolic blood pressure (mm of Hg) (84.34 vs. 82.81, p < 0.01) and pulse rate (81.72 +/- 6.27 vs. 80.94 +/- 9.06, p > 0.05) as compared to rural women. The overall prevalence of hypertension was found to be 9% in rural and 26.66% in urban women as per JNC VII criteria. Increased prominence of hypertension among urban Jat women may be attributed to their modern lifestyle having more stress, less manual work and faulty dietary habits. There was a very low awareness of hypertension in the rural subjects (37%) than their urban (72%) counterparts. Rural and urban women revealed a positive and significant association of systolic blood pressure with body mass index, whereas only urban women displayed positive correlation of waist circumference with systolic (r = 0.183**) and diastolic (r = 0.151**) blood pressure. PMID- 22816212 TI - Quantitative analysis of troponin I serum values in patients with acute cholecystitis. AB - The diagnosis and staging of acute cholecystitis, upon a lot of diagnostic methods and some scoring systems, is still a great clinical problem. The aim of the study was to investigate if serum Troponin I is elevated in patients with acute cholecystitis. Following informed consent, 65 patients with clinical and laboratory signs of acute cholecystitis were enrolled. All patients had measured serum Troponin I level and an abdominal ultrasound was done before definitive treatment was performed. Increased serum Troponin I level was found in most patients with severe form of acute cholecystitis (p < 0.00001). It reached sensitivity of 94.5% and specificity of 57.1% of this test. In multiple regression analysis Troponin I significantly correlated (p < 0.05) with the serum aspartate aminotransferase (r = 0.27), gamma-glutamyl transferase (r = 0.25) and gallbladder wall (> 6 mm) thickness (r = 0.58). Our study confirms that in most patients with severe and acute cholecystitis, serum Troponin I is increased. Troponin I level is in a lower range than it would be in patients with cardiac muscle damage or necrosis. Measuring serum Troponin I is a fast, reliable and widely performed test that could, with other routinely measured parameters, help in early diagnosis of the severe form of acute cholecystitis. PMID- 22816213 TI - Spinal anesthesia at the L2-3 and L3-4 levels: comparison of analgesia and hemodynamic response. AB - Aim of this study was to evaluate level of analgesia and hemodynamic response to spinal anesthesia obtained by administering 15 mg 0.5% isobaric bupivacaine at L2 3 vs. L3-4 interspace for inguinal herniorrhaphy, since studies comparing analgesia and hemodynamic response at the L2-3 vs. L3-4 interspaces are lacking. In a prospective, randomized clinical study that encountered 72 patients undergoing elective inguinal herniorrhaphy randomly allocated in to two equal groups L2-3 (N = 36) and L3-4 (N = 36) according to lumbar interspace where intrathecal injection of bupivacaine was administered. Analgesia was evaluated by intraoperative "rescue" fentanyl requirements, the absence of pain and the maximal visual analogue scale (VAS) scores reached per patient during the operation. The severity of intraoperative pain was quantified by a 10 cm VAS scale (VAS 0: no pain to 10: worst pain imaginable) every 5 minutes after skin incision until the end of the operation. VAS > 3 was treated with intravenous fentanyl 25 microg. Hemodynamic response was monitored and evaluated, heart rate was continuously monitored as well as, baseline systolic, diastolic and mean arterial pressure prior to induction and every 5 minute after applying spinal anesthesia until surgical completion. Intraoperative fentanyl requirements were significantly higher in group L3-4 (L2-3 0%, 97.5% confidence interval [CI] 0.0 0.11 vs. L3-4 17%, 95% CI 0.07-0.32, p = 0.025). Absence of pain was significantly higher in L2-3 group at the beginning of the operation (L2-3 89%, 95% CI 0.74-0.96 vs. L3-4 67%, 95% CI 0.50-0.79, p = 0.047). The maximal VAS scores reached per patient during the operation in L2-3 group were lower then in L3-4 group (L2-3 median [M] 0, range [R] 0-3, L3-4 M 0, R 0-8, p = 0.014). There were no significant differences (p > 0.05) in the incidence of hypotension (L2-3 19%, 95% CI 0.09-0.35 vs. L3-4 17%, 95% CI 0.07-0.32) and bradycardia (L2-3 19%, 95% CI 0.09-0.35 vs. L3-4 8%, 95% CI 0.02-0.23). Spinal anesthesia with isobaric bupivacaine administered in L2-3 interspace for inguinal herniorrhaphy provides superior analgesia and equal hemodynamic stability as compared to neuroaxial anesthesia administered in the L3-4 interspace. PMID- 22816214 TI - Psychological status and recurrent aphthous ulceration. AB - Recurrent aphthous ulceration (RAU) are a disease of an unknown etiology and mediated through T-cell lymphocytes. Evidence suggests that RAU is connected with chronic bowel disease, haematinic deficiencies, AIDS, food hypersensitivity and severe stress. The aim of this study was to determine whether differences in anxiety and depression could be seen in patients with RAU during acute phase and remision period and in comparison to the healthy controls. There were 30 patients with RAU (age range 36.27 +/- 15.308) and 30 controls aged 29.83 +/- 9.082. Every participant with RAU fullfilled STAI and Beck Depression Inventory II test during acute phase and during remission period as well as controls. Statistical analysis was performed by use of descriptive statistics and t-test. There are no differences in the level of depression and stress between the two phases of the RAU (acute versus remission period) as well as in comparison to the controls. Patients with acute RAU are more anxious than patients with RAU during remission period. We might conclude that psychological disturbances do not preceed the development of RAU and that the patients with acute RAU are more anxious when compared to the condition when they do not have RAU due to the discomfort they experience. PMID- 22816215 TI - Long-term functional outcomes after 10 years of bilateral cochlear implantat use. AB - The aims were to determine the benefit of bilateral cochlear implantation in a 20 years old patient implanted in Croatia on hearing and speech development. The male patient, after 10 years of deafness, got cochlear implants Med-EL Combi 40+ on both sides in one-stage surgery. The etiology of his deafness was posttraumatic meningitis. Auditory capacity and speech recognition tests were performed for both ears separately and together Average hearing level on the right ear with right cochlear implant switched on started at 62 dB 1 month after the cochlear implantation and was on 55 dB after 10 years. Average hearing level on the left ear with left cochlear implant switched on started at 55 dB 1 month after the cochlear implantation and was on 32 dB after 10 years. Average hearing level on the both ears with 2 cochlear implants switched on started at 35 dB 1 month after the cochlear implantation and was on 27 dB after 10 years. Long-term functional outcomes with bilateral cochlear implantation provides advantages over unilateral implantation including improved hearing level, speech perception in noise and improved sound localization. PMID- 22816216 TI - Influence of hyperbaric oxygen treatment on myogenic transcriptional factors of denervated rat muscle. AB - The aim of this study was to determine whether hyperbaric oxygen (HBo2) treatment influences the expression of transcriptional myogenic factors in denervated rat's extensor digitorum longus muscle. Thus, expressing regulatory myogenic factors MyoD and myogenin were analyzed in denervated muscles (up to 30 days). Second group of denervated rats were afterwards treated with HBO2. Normal, innervated muscles were used as controls. Western blot analysis showed a significant upregulation of MyoD and myogenin proteins in denervated muscle during this period. Denervated muscles of rats exposed to HBO2 treatment had also significant upregulation of both transcriptional factors but the treatment had not altered their expression. The immunohistochemical analysis showed MyoD and myogenin protein expression through this period in the denervated, untreated muscles and in denervated muscles of rats treated with HBO2, too. One month denervation caused a reduction in muscle fiber cross-sectional area. The treatment with HBO2 had not reduced the degree of atrophy. The protocol of hyperbaric oxygenation (HBO) applied in this study had no beneficial effect either on transcriptional myogenic factors or on atrophy of denervated rat muscle. PMID- 22816217 TI - Optical aspect of deformation analysis in the bone-denture complex. AB - The aim of this study was to register and measure any deformation of mandible models under load. The method for full field measurement of strain is done by using the ARAMIS three-dimensional image correlation system. The system uses two digital cameras that provide a synchronized stereo view of the specimen and the results show the complete strain field during the tests. The biggest deformation values were just under the working force of the biggest intensity 500 N, and for the region of the lower second premolar the deformation is 625 microm. The following study is presented that highlight the use of stereometric measuring system for modern research. It is shown that this measuring methodology can capture the trends of the experiments. PMID- 22816218 TI - Measurement of spinal sagittal curvatures using the laser triangulation method. AB - The purpose of the first part of the study was to establish the variability of repeated measurements in different measuring conditions. In the second part, we performed in a large number of patients, a measurement of thoracic kyphosis and lumbar lordosis and compared them to age, gender, and level of nourishment. In the first part, measurements were performed on a plastic model of the back of a patient with a rigid and a normal spine. In the second part, 250 patients participated in the study (126 men and 124 women). For measuring spinal curvatures we used an apparatus for laser triangulation constructed at the Faculty of Mechanical Engineering, University of Ljubljana. A comparison of 30 repeated measurements was shown as the average value +/- 2 SD which included 95% of the results. Thirty repeated readings of one 3D measurement: thoracic kyphosis 41.2 degrees +/- 0.6 degrees, lumbar lordosis 4.4 degrees +/- 1.2 degrees; 30 measurements on a plastic model: thoracic kyphosis 36.8 degrees +/- 1.2 degrees, lumbar lordosis 30.9 degrees +/- 2.0 degrees; 30 measurements on a patient with a rigid spine: thoracic kyphosis 41.5 degrees +/- 2.4 degrees, lumbar lordosis 4.0 degrees +/- 1.8 degrees; 30 measurements on a patient with a normal spine: thoracic kyphosis 48.8 degrees +/- 7.4 degrees, lumbar lordosis 21.1 degrees +/- 4.4 degrees. The average size of thoracic kyphosis in 250 patients was 46.8 degrees (SD 10.1 degrees) and lumbar lordosis 31.7 degrees (SD 12.5 degrees). The angle size was statistically significantly correlated to gender (increased thoracic kyphosis and lumbar lordosis in women) and body mass index (increased thoracic kyphosis and lumbar lordosis in more nourished patients). Age was not significantly correlated to the observed angles. During measurements of the spinal angles it was important to pay attention to relaxation and the patient's position as well as to perform more measurements providing the average value. The age and the level of nourishment influence the size of the sagittal spinal angles. In the observed sample the effect of age was not confirmed. PMID- 22816219 TI - Isolated capitellum humeri fractures in adults. AB - From 2003 through 2009 we treated 35 patients who suffered from an isolated capitellum humerus fracture whom we treated with osteosynthesis. Patients who presented with concomitant fractures were not included. Thirty-four patients were categorized as Type I (Hahn-Steinthal) while one patient was Type IV (McKee). We describe the mechanism of injury and compared our results with works available in the literature. The average age of our patients was 38.6 years which was much younger than many articles about this type of injury found in the literature. The ratio of women to men in our study was 20:15. The surgical treatment was performed with various methods including: Kirschner wires, AO screws, Herbert screws and TwinFix screws. We discuss type of injury, days after injury operative treatment is performed, type of osteosynthesis used, the surgical approaches used for our treatment of capitellum humeri fractures, possible complications and our postoperative treatment. Results at the conclusion of treatment were excellent. Range of motion, shown in detail for each patient, was measured preoperatively, 1 month and 3 months postoperatively. We concluded that the major factors in successful treatment are how quickly the surgical treatment is performed after injury and early postoperative rehabilitation. PMID- 22816220 TI - Intercondylar notch width and inner angle of lateral femoral condyle as the risk factors for anterior cruciate ligament injury in female handball players in Herzegovina. AB - The principal purpose of this prospective study was to examine intercondylar notch size and the value of inner angle of lateral femoral condyle as the risk factors for noncontact anterior cruciate ligament ACL injury and than to correlate them to the physical values of the athletes such as body mass index (BMI), hight, wight, etc. There are indentified two type of risk factors, external include shoes-surface interaction, type of playing surface, weather conditions and internal include anatomic, neuromuscular, biomechanical and hormonal factors that may predispose female athlets to noncontact injury of ACL. Among anatomic factors, intercondylar notch stenosis and larger inner angle of lateral condyle of femur as the factors which can cause impigement of ACL, were related to an increased risk of injury of ACL. In this study were included 51 female athlete. In the study group there were 24 female handball players with ACL tear and in control group there were 27 female handball players without any type of injury of the knee, who are practicing handball on a daily basis for at least for two years. In the first step, were gathered clinical data performed by orthopaedic surgeon. In the second step, the femoral notch width and the inner angle of lateral condyle of femur were measured on coronal MR-images. Study has shown that value of inner angle of lateral condyle of femur was significantly higher in athletes with ACL tear compared to those without. Value of width of intercondylar notch was statisticaly smaller in athletes with ACL tear, compared to those without. In the conclusion the inner angle of lateral femoral condyle is better predicting factor for ACL tear in young female handball players compared to intercondylar notch width. PMID- 22816221 TI - Results of the surgical reconstruction of the anterior cruciate ligament. AB - Results of the surgical reconstruction of the anterior cruciate ligament (ACL), using as a graft fourfold hamstring tendons (gracilis and semitendinosus) and middle third of the patellar ligament, were compared. In all patients that were participating in this study clinical examination and magnetic resonance showed ACL rupture, and apart from the choice of the graft, surgical technique was identical. We evaluated 112 patients with implemented patellar ligament graft and fourfold hamstring tendons graft six months after the procedure. Both groups were similar according to age, sex, activity level, knee instability level and rehabilitation program. The results showed that there was no significant difference between groups regarding Lysholm Knee score, IKDC 2000 score, activity level, musculature hypotrophy, and knee joint stability 6 months after the surgery. Anterior knee pain incidence is significantly higher in the group with patellar ligament graft (44% vs. 21%). Both groups had a significant musculature hypotrophy of the upper leg of the knee joint that was surgically treated, six months after the procedure. Both grafts showed good subjective and objective results. PMID- 22816222 TI - Measuring improvement following total hip and knee arthroplasty using the SF-36 Health Survey. AB - The aim of this study was to evaluate the impact of total hip or knee arthroplasty upon quality of life in elderly patients. The study was carried out at the Clinic for Orthopaedic Surgery Lovran on 74 total hip arthroplasty and 70 total knee arthroplasty patients. All patients had completed the Medical Outcomes Study 36-Item Short Form in the week having preceded their surgery and then again postoperatively, 2 years after. The data obtained were statistically processed at the level of physical function, role limitations due to physical problems, role limitations due to emotional problems, social function, mental health, energy or vitality, pain and general health perception, and change in health. The primary total hip arthroplasty patients showed significant improvement at all levels measured. Similarly, the primary total knee arthroplasty patients expressed significant improvement according to all the parameters but the mental health assessment. Comparison of outcomes between the two assessment groups of patients resulted in slightly superior quality of life outcomes in total hip arthroplasty patients. It can be concluded that total hip or knee arthroplasty significantly enhances the health related quality of life in elderly patients. PMID- 22816224 TI - Oral health awareness in Croatian and Italian urban adolescents. AB - Purpose of this study was to investigate and compare differences in oral health awareness between Croatian and Italian urban adolescents. The sample consisted of primary school last grade students aged between 13 and 15 years, 300 children from Zagreb (Croatia) and 298 children from Bari (Italy). Oral health awareness was evaluated using a self-administered standardized questionnaire. Self perception of oral health proved to be different between the two groups (p < 0.001). The Croatians reported that their oral health was "excellent" or "very good" more often than the Italians (68.6% vs. 50.2%). The reasons given for visiting a dentist were different (p < 0.001). The Italians cleaned their teeth more often than the Croatians ("two or more times a day", 83.1% vs. 72.2%, p < 0.003). Wooden toothpicks were preferred by the Croatians (p < 0.001), while floss was preferred by the Italians (p = 0.03). The awareness regarding the use of fluoridated toothpaste was higher in the Italian group (95.6% vs. 72.5%, p < 0.001). The Croatians were consuming sweetened foods more often than the Italians (p < 0.001). Croatian adolescents reported more indicators of a lower level of oral health awareness than the Italians, while on the contrary Croatians had higher esteem of their oral health. Defining national preventive strategies is essential for improving adolescents' attitudes toward oral health in both countries, particularly in Croatia. PMID- 22816223 TI - Oral hygiene and gingival health in patients with fixed prosthodontic appliances- a 12-month follow-up. AB - The aim of this study was to assess and observe the oral hygiene and gingival condition in patients before and after fixed prosthodontic therapy through a 12 month period in combination with oral hygiene instructions. It was also analysed how factors, such as type of fixed prosthodontic appliance, constructive material, the position of a fixed partial denture (FPD) in the mouth, age and gender influenced oral hygiene. The dental arches were divided into three segments each and teeth and gingiva were examined using the Plaque and Gingiva Index by Silness and Loe, and for the mineralized deposits assessment the Calculus Index by Green and Vermillion was employed. The preliminary examination was conducted before the prosthodontic therapy, and the reexaminations were carried out 14 days, 1, 6 and 12 months after crown and/or FPD placement. A total of 93 subjects from the original study group of 146 patients attended all clinical examinations, while the rest was excluded. The sample consisted of 60 women, 33 men at age between 21 and 95 (average 51.8). A total of 39 patients had single crowns (C), 50 FPDs and 5 C+FPD. The frequency of plaque found during the preliminary visit was higher than that found in the other periods (p < 0.001). Patients with C showed better oral hygiene levels than patients with FPDs or C+FPDs (p = 0.001). Our results revealed no significant difference in oral hygiene status among patients with FPDs made of different materials (p = 0.083). The worst hygiene levels were found in patients with fixed prosthodontic appliances in both jaws (p = 0.012). Younger patients showed better hygiene levels than the older ones (p = 0.002). Our research showed that appropriate educational and motivational measures can lead to improved oral hygiene, even after FPD placement. Presumably, the oral health in a group of adult patients can be kept acceptable by providing a prophylactic oral hygiene program. PMID- 22816225 TI - Cathepsin D and its prognostic value in neuroepithelial brain tumors. AB - Expression of Cathepsin D (Cath D) in some primary neuroepithelial brain tumors and its prognostic value were studied. The research included 65 samples of human primary neuroepithelial brain tumors. There were 50 glial tumors (10 diffuse astrocytomas (DA), 15 anaplastic astrocytomas (AA), 25 glioblastomas (GB), 15 embryonic tumors (15 medulloblastomas (MB) as well as 5 samples of normal brain tissue. Immunohistochemical method was applied to monitor diffuse positive reaction in the cytoplasm of brain tumor cells, endothelial cells and tumor stromal cells and showed diffuse positive reaction for Cath D in the cytoplasm of brain tumor cells, endothelial cells and stromal cells in all analyzed samples of DA, AA, GB and MB as well as in microglial cells, neurons and in endothelial cells in all analyzed samples of normal brain tissue. Qualitative analysis of Cath D expression in the cytoplasm of brain tumor cells and endothelial cells as well as the percentage of brain tumor cells, endothelial cells and stromal cells immunopositive for Cath D showed that there was difference between analyzed brain tumor groups, but according to statistical tests the difference was not statistically significant. Survival correlated with the percentage of stromal cells immunopositive for Cath D. Survival prognosis was influenced by the percentage of stromal cells immunopositive for Cath D and tumor grade. The obtained results singled out the percentage of stromal cells immunopositive for Cath D as an independent parameter. The results of this research on the prognostic value of Cath D in some primary brain tumors of neuroepithelial origin indicate that there is real possibility to use Cath D as an independent prognostic factor in human glioma progression and thus open up possibilities for further scientific research. PMID- 22816226 TI - Phyllodes tumors and fibroadenoma common beginning and different ending. AB - Phyllodes tumors and fibroadenomas are the most common benign breast tumors. They arise from intralobular fibrous tissue as a unique lesion and after a period of time they differentiate in two direction: to fibroadenoma and to phyllodes tumors. Fibroadenomas grow up to 2-3 cm and then stop growing but phyllodes tumors grow continually and sometimes are to 40 cm big. Both these lesions have two components, epithelial and stromal. Clinically fibroadenomas are well circumscibed, hard, oval, movable lesions. They can be solitary, multiple, unilateral and bilateral. They are hormone dependent changes, because they change their own consistency during menstrual cycle and gravidity. The most commonly used histological classification is in two types: pericanalicular and intracanalicular type. Phyllodes tumors make about 1% of all breast tumors. This tumor has many synonyms. It starts as fibroadenoma in intralobular stromal component. It has continuous growth and biologically it can be benign, borderline and malignant. The first description is from Miller (1838). The main goal is to find the divergence point when the developing is direct to fibroadenoma or phyllodes tumor. The second goal is to investigate the fate of epithelial and stromal component in these two lesions. Retrospective analysis is made of all fibroadenomas and phyllodes tumors in Pathology Department of Medical Center "Bezanijska kosa" in the period from 1998 to 2006. In this period, 2919 women were operated for breast changes. 343 fibroadenoma (24, 4%), were diagnosed, benign phyllodes tumor in 95 women (6.7%) and malignant phyllodes in 4 cases or 0.2%. All slides from these patients were analysed for many different histological parameters and immunohistological investigation for steroid receptors was also used, c-erbB2 (Her2/Neu), PCNA (proliferative cellular nuclear antigen) and Ki-67, androgen receptor and p53. All data were statistically investigated (Odds ratio, confidence interval, Fisher exact test, Wilcoxon sum test and Kendall test). It was concluded that fibroadenomas and phyllodes tumors arise from intralobular fibrous tissue, both changes have very close histology in the beginning and divergent growth starts later. Differences are present in stromal component. Phyllodes tumor has two component stroma. Stromal cells in phyllodes tumors are more PCNA positive than in fibroadenomas, also Ki-67 and androgen receptors are more positive in phyllodes tumors. Histologically phyllodes tumors have perforated capsule with finger like projections. These data determine surgical procedure, wide excision in phyllodes and simple excision in fibroadenomas. PMID- 22816227 TI - The efficacy and safety of solifenacin in patients with overactive bladder syndrome. AB - The aim of the randomised, double blind, placebo controlled study was to evaluate the efficacy, tolerability and safety of solifenacin, a once-daily M3 selective receptor antagonist, in patients with overactive bladder syndrome. Following a single blind 2-week placebo run in period, patients who complained from symptoms of OAB for at least 6 months, were randomized to 4 weeks of solifenacin in 5 mg once daily doses or placebo. 171 patients were enrolled in the study and 157 patients completed the study. Patients with solifenacin had significantly improved micturitions per 24 hours after first week of treatment (1.75 +/- 0.63 vs. 2.64 +/- 0.48, p < 0.001), and after four weeks (1.56 +/- 0.58 vs. 2.71 +/- 0.45, p < 0.001) compared to placebo group. The mean number of urgency episodes per 24 hours had significantly decreased in patients with solifenacin compared to placebo after first week (5.75 +/- 1.43 vs. 6.65 +/- 0.65, p < 0.001), and after four weeks of treatment (5.77 +/- 1.33 vs. 6.54 +/- 0.50, p < 0.001). Solifenacin was also significantly more effective than placebo in reducing the mean number of episodes of severe urgency from baseline to end point (5.83 +/- 1.16 vs. 6.48 +/- 0.50, p < 0.001). Compared with changes obtained with placebo, episodes of urinary frequency were significanlty reduced after first week (0.3 vs. -0.5, p < 0.001) and four weeks check up periods in patients treated with solifenacin (0.19 vs. -0.15, p < 0.001). Episodes of nocturia was significantly reduced in patients treated with solifenacin after first week (0.3 vs. -0.5, p < 0.001), and after four weeks treatment period (0.45 vs. -0.50, p < 0.001). The number of incontinence episodes was also significantly decreased in solifenacin group compared to placebo group after first week (1.06 +/- 0.57 vs. 2.74 +/- 0.47, p < 0.001) and four weeks check up (0.96 +/- 0.57 vs. 2.75 +/- 0.43, p < 0.001). The most common adverse effects with solifenacin were dry mouth and constipation. Adverse effects were mild or moderate severity. The discontinuation rate owing to adverse effects was 4.5%-6.7% with solifenacin and 3.8%-6.1% with placebo, respectively. According to subjective estimation, significant improvement was achieved in 71 (92.21%) of patients treated with solifenacin and in 68 (85%) patients treated with placebo there was no change in OAB symptoms compared to baseline values. UDI score was significantly improved after solifenacin (22.26 +/ 5.91 vs. 29.61 +/- 8.45, p < 0.001) compared to placebo. IIQ score was significantly decreased in patients with solifenacin (36.25 +/- 10.34 vs. 46.86 +/- 6.81, p < 0.001) compared to placebo. In conclusion, solifenacin is a safe and effective treatment alternative for patients with overactive bladder symptoms. PMID- 22816228 TI - Multiple identification processes on the Island of Korcula (nested identities). AB - The aim of this paper is to investigate the ways contemporary identification processes on the island of Korcula take place. The changes in the political situation during 1990s, as well as contemporary context of the accession of the Republic of Croatia into European integration, provided the new "arena" for the expression of different identifications. The positioning of identities into the wider context, either on vertical or horizontal level, is also important in these processes. The research was carried out at all the major settlements on the island of Korcula by qualitative methodological tools and ethnographic approach. The results indicate the existence of nested identities on the island of Korcula (ranging from supranational (European) to national and regional and finally to diverse local identifications and their situational and dynamic character. The nested identities on the island of Korcula demonstrate their mutual compatibility and the fact that not only identities of the higher order (regional, for example) comprise the identities of the lower order (local, for example); the reverse process also takes place. The members of seemingly close and similar island communities in fact have very differentiated local identifications that are very often equally important or even more important than identities of the higher order, such as national. PMID- 22816229 TI - Citta Vecchia and Lesina--everlasting animosity on the Island of Hvar. AB - This paper is focused on the manifestations of inter-community animosities and campanilistic rivalries in the treatise Faria - Citta Vecchia e non Lesina. Pietro Hektorovich - Cittavecchiano e non Lesignano (1873) written by Hvar's scientist and historian Sime Ljubic (1822-1896). In his scientific argumentation we can find descriptions and comparisons that are more typical of creating stereotype views and campanilistic rivalry, than they are for a scientific discourse. This treatise is a confirmation of the oldest campanilism on the island that still exists between Stari Grad and Hvar, two largest island's towns. PMID- 22816230 TI - Croatian Muslims--immigrant community of indigenous Europeans. AB - Subject of this paper is muslim population in Croatia. Its unique position as community of muslim immigrants with indigenous European origin give us plenty of research opportunities. Long history of contacts between muslims and christians on Croatian-Bosnian border evolved in many ways and resulted with today's reality that muslims are part of Croatian society. In modern age, since austrian occupation of Bosnia in 1878. bosnian muslims came to Croatia as workers, refugees, members of state apparatus, students etc. Their descendants are now Croatian citizens in third and fourth generation. Muslims managed to establish formal islamic community. On the personal level, they mix their feeling of belonging with feeling of origin. They act as equal part of Croatian society on whole range of social levels. PMID- 22816231 TI - Cyber anthropology or anthropology in cyberspace. AB - As a variety of anthropology, cyber anthropology is considered to be the fastest growing sub branch in the science. It is based on synergic effects of multimedia systems and hypermedia, using their comparative advantages. One of the least researched fields of cyber anthropology is the relationship of individuals and social groups with a multimedia document in terms of their perception of such subject. This is because the foundation of social-informatics perception in the society is created based on the evidence of a real life, whereas here the perception is established at the level of virtual, i.e. online life. The rhetorical question here is whether an identical content causes the same or different user reactions, depending on whether it was perceived offline or online, i.e. to what extend does the medium (and not the information content) dictate the user perception. In this respect the research titled "Perception of online museum content creators and actual habits of Croatian online museum visitors" can be a "case study" for the impact of "cyber potential" on the classic anthropological paradigm. PMID- 22816232 TI - A probable case of Hand-Schueller-Christian's disease in an Egyptian mummy revealed by CT and MR investigation of a dry mummy. AB - The challenging mission of paleopathologists is to be capable to diagnose a disease just on the basis of limited information gained by means of one or more paleodiagnostic techniques. In this study a radiologic, anthropologic and paleopathologic analysis of an ancient Egyptian mummy through X-rays, CT and MR was conducted. An Ancient Egyptian mummy ("Mistress of the house", Archeological Museum, Zagreb, Croatia) underwent digital radiography, computed tomography and magnetic resonance imaging employing 3-dimensional ultra-short-echo time (UTE) sequence, that allows to image ancient dry tissue. Morphological observations on the skull and pelvis, the stages of epiphyseal union and dental wear indicated that the remains are those of a young adult male. Multiple osseous lytic lesions were observed throughout the spine as well as on the frontal, parietal, and occipital bone, orbital wall and the sella turcica of the sphenoid. Considering the sex and age of the individual and the features of the lesions, the authors propose the diagnosis of Hand-Schueller-Christian's disease. This is the first study to have effectively used MR images in the differential diagnosis of a disease. It also confirmed the CT value in revealing central nervous system involvement just by detecting skeletal lesions. Although the mummy was previously dated to 3rd century B.C. based on the properties of the sarcophagi, the sex of the mummy suggests that it was most probably transferred into these sarcophagi in later times. The mummification techniques used and radiometric data (C14) dated it to 900-790. B.C. PMID- 22816233 TI - The trend of parasitic diseases among the population of Osjecko-baranjska County during the period 1996-2010--Croatia. AB - Our manuscript shows infestation of the different population (by age groups, and by sex) with endoparasites and ectoparasites from 1996 till 2010, through seasons (spring, summer, autumn, winter).Parasitological examinations which were done at "Public health Institute" of Osjecko-baranjska county, and which were done at total of 3667 patients, were the methods of direct parasitological diagnostic for proof of parasitic elements in clinical samples, and the methods of indirect parasitological diagnostic, serological examination for proof of antibodies to antigens in the serum of the patients or of the asymptomatic parasite carriers. Development of causers of the diseases (parasites) is depending on the season. Results of our researches were processed with statistical program called Statistica 8.0 (StatSoft. Inc 1984-2008). From statistical parameters arithmetic middle (x), standard deviation (s), and standard error of the arithmetic middle (sx), are shown. Testing of the significance of differences between independent samples was done with t-test (ANOVA), and is shown in the chart using the appropriate letters (a,b,c). Determined parameters of total infestation and endoparasitic infestation, and total infestation and ectoparasitic infestation show statistically significant difference on the risk level of 0.05 regardless of the age or the sex group of the population of Osjecko-baranjska county. Determined parameters of monitoring infestation (endoparasitosis and ectoparasitosis) have shown statistically significant difference on the risk level of 0.05. PMID- 22816234 TI - Organization of the "Marine Colony" for children with tuberculosis in Rijeka (Croatia): entanglement between medicine and politics. AB - Tuberculosis was a major public health concern in the beginning of the 20th century. Since medications were not available at the time, therapy in general was based on health education, healing effects of climate, nutrition and rest. The Marine Colony was founded in 1924 in Rijeka, a city with turbulent political history, by the Antitubercular Consortium which was part of a planned program for the fight against tuberculosis on a national level in the whole of Italy. The Colony in Rijeka, Croatia specialised in care of children with clinical tuberculosis or under greater risk of developing disease. This article gives an overview of the medical treatment provided for children in Colony, as well as pointing out the political-agenda at that period. PMID- 22816235 TI - The role of IgG avidity in diagnosis of cytomegalovirus infection in newborns and infants. AB - To evaluate the value of IgG avidity in diagnosis of congenital cytomegalovirus (CMV) infection in newborns and infants we collected serum samples from 40 infants under 12 months of age with suspected congenital CMV infection. Sera were tested for IgM, IgG and IgG avidity. For 25 of them, virus isolation and/or polymerase chain reaction (PCR) on urine specimens were performed. Thirteen (32.5%) patients showed the presence of CMV IgM antibodies, 3 (7.5%) had equivocal IgM result, and 24 (60.0%) patients had IgG antibodies only. Using IgG avidity, CMV infection (low avidity index-AI) was documented in 61.5% IgM positive and 54.2% IgM negative patients. Eight of nine (88.8%) IgM positive patients were positive either on virus isolation or PCR. In IgM negative patients, 46.6% urine cultures were positive for CMV and 66.6% were PCR positive. According to age, IgG avidity demonstrated acute/recent primary CMV infection in 58.8% patients younger than three months compared with 91.7% and 81.8% in 3-6 and 6-12 months old babies, respectively. In conclusion, IgG avidity is useful in diagnosis of CMV infection either in IgM positive or IgM negative children older than 3 months of age. In infants less than 3 months, transplacentally derived maternal IgG antibodies of high avidity influence on the IgG avidity result. In these children, CMV infection should be confirmed by direct virologic methods such as virus isolation or PCR. PMID- 22816236 TI - Implant prosthetic rehabilitation of the patients with mandibular resection following oral malignoma surgery. AB - Patient underwent mandibular resection due to surgical therapy of oropharingeal malignoma. Facial asymmetry and cosmetic distortion are frequent consequences of such interventions, which may also include deviation and intrusion of the mandible, motor and sensory disorders, abnormal intermaxillary relations and malocclusion. Implant-supported prosthesis could be an optimal solution to prosthodontic treatment of such patients. However, there is a problem in determination of stable (interocclusal) intermaxillary relations. This article describes the choice of therapy and procedures undertaken in prosthetic rehabilitation of a patient who underwent mandibular resection and radiotherapy with supported prosthesis retained with four implants. PMID- 22816237 TI - Prosthetic rehabilitation of a patient with mandibular resection prosthesis using mini dental implants (MDIs)--case report. AB - Physical disfigurement and functional impairments associated with facial trauma are a challenge to a prosthodontist, because even novel sophisticated surgical reconstructive techniques fail to provide adequate support for dental resection prosthesis. Therefore, different endosseous implants are often used as prosthesis supporting elements. Manufacturers of dental implants have recently presented mini dental implants (MDIs) with diameter of only 1.8-2.4 mm. These implants allow very suitable prosthetic solutions within the range of their indications due to good osseointegration success rates, simple surgical technique, and immediate loading possibility. In this report, a case was presented for prosthetic rehabilitation including implantation of two Sendax type (IMTEC, Ardmore, Oklahoma, USA) MDIs in mental region, to obtain better retention and stability of the mandibular resection prosthesis and to improve function, phonation and aesthetics. The use of these implants, among aforementioned preferences, is also very cost-effective, so this implantation possibility should be taken into consideration during prosthetic treatment planning. PMID- 22816238 TI - Voice rehabilitation of Broca's aphasia following total laryngectomy. AB - Total laryngectomy, as a consequence of carcinoma of the larynx, results in loss of speech function. Cerebrovascular stroke is the leading cause of reduced speech production ability, and thereby communication difficulties. The case is presented of a 60-year-old male patient who suffered stroke five years after a total laryngectomy. Speech rehabilitation was hampered due to the depressive state of the patient. Although contraindicated, the secondary voice prosthesis was implanted. Only at that moment the patient showed willingness and motivation for speech rehabilitation. The aim of this presentation is to demonstrate that not all neurological disorders are contraindicated for implantation of voice prostheses. PMID- 22816239 TI - Giant basal cell carcinoma of the forehead: a case report. AB - Giant basal cell carcinoma (GBCC) is defined as a tumor 5cm or greater in diameter. They present less than 1% of all basal cell carcinomas. We present a case of an 85-year-old male patient with a giant ulcerating tumor of the left forehead (measuring 7x6 cm). Under local anesthesia tumor was surgically excised. No involvement of the underlying periostal or bone structure was noted. Pathohystological exam revealed the giant basal cell carcinoma, with free surgical margins. Giant basal cell carcinomas are rare tumors and are usually result of a long duration and patient neglect. In comparison to the ordinary basal cell carcinoma these tumors have a higher metastatic potential. Surgical resection with negative surgical margin is the best possible treatment option. PMID- 22816240 TI - A battery in the stenotic esophagus of a child with a congenital tracheoesophageal fistula. AB - A case of a three-year-old male child who was admitted to our hospital with the suspicion that he had swallowed a battery approximately one hour before admittance. The parents believed that it was a button-shaped lithium battery approximately 12 mm in diameter. A chest X-ray was taken immediately, and a battery was identified in the esophagus at the fifth thoracic vertebra. By reviewing the child's medical history, we found that the child had had surgery the day after birth due to congenital atresia of the esophagus and a tracheoesophageal fistula type III b. An esophagoscopy was performed one hour after admittance, and the battery was found to be partially past the scar from the first surgery. Because of that, the battery was pushed further toward the stomach, out of fear that retrieving the battery through the scarred section of the child's esophagus could damage the stenotic wall. Upon the next X-ray of the abdomen, the battery was observed in the stomach. The child was monitored, and X rays were taken over the next several days. The battery was evacuated in stool eight days after it had been ingested. PMID- 22816241 TI - Dermatomyositis as paraneoplastic syndrome of peritoneal and ovarian relapse after long-term complete remission in patient with metastatic bilateral breast cancer. AB - Dermatomyositis is a rare disease characterised by inflammatory muscle affection and characteristic cutaneous changes. When occuring in a patient with cancer, dermatomyositis may indicate recurrence or progression and poor outcome. Herein, the treatment of metastatic breast cancer, metastatic pattern, characteristics of long-term survivors, and link between dermatomyositis and breast cancer are discussed and the literature reviewed. We report a 57-year old female patient with metastatic bilateral breast cancer whose ovarian and peritoneal relapse after long-term remission was disclosed by occurence of paraneoplastic dermatomyositis. The patient previously had a 15-year long disease free-period after primary treatment for breast cancer before onset of pulmonary dissemination. Following antracycline-based chemotherapy, the complete remission lasting another 15 years was accomplished. Dermatomyositis had been resolved upon induction of second-line taxane-based chemotherapy. After completion of six cycles of gemcitabine and paclitaxel chemotherapy, check-up revealed further progression. The patient subsequently underwent six cycles of third-line CAP chemotherapy (cyclofosfamide, doxorubicine, cisplatin) but disease progressed and oral capecitabine chemotherapy was initiated. The patient received four cycles of capecitabine followed by further vast progression and finally expired following massive pulmonary embolism. Our case stresses the need of thorough staging and check-up when dermatomyositis arises in patients with breast cancer, regardless of previous stable long-term complete remission. Furthermore, we believe that treatment with curative intent in young patients with metastatic breast cancer, who have good performance statuses and no comorbidities is required, because it is more likely to produce long-term complete remission. However, following disease relapse a poor outcome can be expected. PMID- 22816242 TI - Extramedullary plasmacytoma imitating neoplasm of the gallbladder fossa after cholecystectomy. AB - Extramedullary plasmacytomas are plasma cell tumors that arise outside of the bone marrow. They account for approximately 3% of plasma cell neoplasms and are most frequently located in the head and neck region. Five months after undergoing cholecystectomy, a 69-year-old patient presented with the pain under the right costal margin and a 12 kg weight loss. Computed tomography of the abdomen demonstrated irregular, vascular mass in the gallbladder fossa that dents towards the duodenum and the pylorus and lowers caudally to the hepatic flexure. His laboratory tests indicated normocytic anemia and showed elevated sedimentation rate. During operative procedure, a tumorous mass in the gallbladder fossa was found, inseparable of the peritoneum of the hepatoduodenal ligament and the IVb liver segment. Histopathological examination and immunohistochemical staining determined the diagnosis of the plasmacytoma. Total resection of the tumor was achieved and after 24-month follow-up patient showed no signs of local recurrence or dissemination of the disease. PMID- 22816243 TI - Perforated ascending colon cancer presenting as colocutaneous fistula with abscess to the anterior abdominal wall at the site of a cholecystectomy scar treated with biologic mesh. AB - Ascending colon cancer as a colocutaneous fistula to the abdominal wall at the site of a previous postoperative scar is extremely rare. A 69 year old male presented with five day history of pain and foul smelling discharge from right subcostal scar from elective cholecystectomy performed 8 years ago. Last three days, he had fever up to 39 degrees C, with mild pain in right upper abdominal quadrant without vomiting, diarrhea, bloody stools or weight loss. Computed tomography, with peroral contrast, revealed extralumination into abdominal wall with several fistulas reaching the skin. Emergency median laparotomy found infiltrating tumor of ascending colon into abdominal wall. A right hemicolectomy and complete thickness abdominal wall excision (7 x 10 cm) was performed. The abdominal wall defect was too extensive for primary closure and two 20 x 20 cm moist gauzes were placed to cover the defect and were fixed with stitches to the skin. On second postoperative day, due to contamination, porcine dermal collagen implant was placed intraperitoneally. Such emergency presentations and therapeutic options are discussed. PMID- 22816244 TI - Severe traumatic brain injury after the assault with an axe handle. AB - Traumatic brain injuries represent a major cause of death and disability. We present a case of a 47-year-old patient who sustained a severe brain injury after being assaulted with a handle of an axe. The patient underwent numerous surgeries by various specialists during several months. Following a few failed attempts to cover the skull defects, the vacuum-assisted closure system had been utilized with great success in healing of her complex head wound. Traumatic brain injury requires great effort and collaboration in order to rehabilitate people to the most independent level of functioning possible. PMID- 22816245 TI - Emergency contraception: can we benefit from lessons learned? AB - The aim of the paper was to evaluate current emergency contraception (EC) methods and policies in order to implement lessons learned and maximize potential population impact while introducing dedicated EC pills in Croatia. Literature search for potential reasons for EC failing to show positive population impact and detecting actionable points to be implemented in national guidelines. Six potential reasons for ECs failure to show population impact were evaluated and four actionable points were detected: low use of EC compared to the numbers of risk events, low awareness on EC in general population, differences in efficacy of EC methods and EC vailability. In order to ensure EC's population impact in Croatia it is of a critical relevance to establish continuous education programs for population of women at risk. When recommending an EC method, superior efficacy must be a key decision-making criteria therefore cooper IUD and ulipristal acetate should be our primary options. Counseling is a critical step to ensure maximal efficacy of the EC method, but also to encourage future use of regular contraceptives. Finally, national ECP dispension protocol is needed to close the loop from effective women screening, prompt yet appropriate ECP administration/dispensing towards structured follow up after EC pills intake. PMID- 22816246 TI - Determination of vitamins D2 and D3 in infant formula and adult nutritionals by ultra-pressure liquid chromatography with tandem mass spectrometry detection (UPLC-MS/MS): First Action 2011.12. AB - The method for the "Determination of Vitamins D2 and D3 in Infant Formula and Adult Nutritionals by Ultra-Pressure Liquid Chromatography with Tandem Mass Spectrometry Detection (UPLC-MS/MS)" was adopted as AOAC Official First Action during the "Standards Development and International Harmonization: AOAC INTERNATIONAL Mid-Year Meeting" held June 29, 2011. During the meeting, an Expert Review Panel (ERP) evaluated the available validation information against standard method performance requirements (SMPRs) articulated by stakeholders. The method, approved by the ERP, is applicable for the determination of vitamin D (total vitamins D2 and D3). A range of products had been tested during a single laboratory validation study. The products included butter, National Institute of Standards and Technology SRM 1849, eggs, cheese, yogurt, ready-to-eat cereal, bread, mushrooms, and tuna. The testing of the method established linearity in the range of 0.005-50 microg/mL. The recovery range was 93.4-100.9% for vitamin D2 and 102.4-106.2% for vitamin D3. The LOD and LOQ for vitamin D2 were reported as 0.20 and 0.61 microgl100 g, respectively; for vitamin D3, the reported values were 0.47 and 1.44 microg/100 g, respectively. The method met the SMPRs set by the Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN). It was, therefore, decided that the method was appropriate for Official First Action Method status. PMID- 22816247 TI - Simultaneous determination of vitamins D2 and D3 by LC-MS/MS in infant formula and adult nutritionals: First Action 2011.13. AB - During the "Standards Development and International Harmonization: AOAC INTERNATIONAL Mid-Year Meeting" held on June 29, 2011, an Expert Review Panel (ERP) on behalf of AOAC INTERNATIONAL adopted the method "Simultaneous Determination of Vitamins D2 and D3 by LC-MS/MS in Infant Formula and Adult Nutritionals" as an AOAC Official First Action method. Vitamins D2 and D3 are extracted from the sample using pentane-ether; the extract is collected and dried under nitrogen. Vitamin D is separated from interfering compounds using UPLC, and quantitated using tandem mass spectrometry (MS/MS). Preliminary data showed the intermediate precision ranged from 3.34-8.05% and an accuracy range of 98.5-111% over the samples tested for vitamin D3. For vitamin D2, the intermediate precision ranged from 2.37-5.45% and accuracy ranged from 96.4-104% over the four matrixes evaluated. The analytical range for the method is bounded by the concentrations of the working standards, 21-270 ng/mL, and is equivalent to 0.168 2.16 mcg/100 g in ready-to-feed product. The practical method quantitation limit is 0.168 mcg/100 g product with method detection limit of 60 ng/100 g product. The ERP reviewed the data and determined that the performance characteristics of the method met the standard method performance requirements, and therefore the method was granted First Action status. PMID- 22816248 TI - Application of inductively coupled plasma/mass spectrometry for the measurement of chromium, selenium, and molybdenum in infant formula and adult nutritional products: First Action 2011.19. AB - An inductively coupled plasma/MS method was developed for the simultaneous determination of Cr, Se, and Mo in infant formula and other nutritional products. All samples were digested using a closed vessel microwave oven system, together with Ni and Te internal standards. The practical quantitation limits for Cr, Se, and Mo were 0.4, 0.2, and 0.4 ng/mL, respectively; dilution factors were 250 for powders and 50 for liquids. The Cr, Se, and Mo concentrations in 10 nutritional products were within specification limits; within-day and day-to-day (6 independent days) precision values were <5% RSD. For two control samples, the observed precision was < or = 2% RSD over 10 independent days. Cr, Se, and Mo results were within the certified limits in three National Institute of Standards and Technology standard reference materials. The average sample spike recoveries for 10 nutritional products ranged from 93 to 107%. Robustness studies showed a minimal effect from concomitant easily ionized element concentrations. However, the choice of internal standard and matrix-matching carbon content were critical to obtaining accurate Se results. All indications are that this method would be a suitable candidate as a global reference method for the determination of these trace elements in infant formula, adult nutritionals, and other nutritional PMID- 22816249 TI - Analysis of 5'-mononucleotides in infant formula and adult/pediatric nutritional formula by liquid chromatography: First Action 2011.20. AB - A method for the routine determination of 5'-mononucleotides (uridine 5' monophosphate, inosine 5'-monophosphate, adenosine 5'-monophosphate, guanosine 5' monophosphate, and cytidine 5'-monophosphate) in infant formula and adult nutritionals is described. After sample dissolution and addition of internal standard, potential interferences were removed by anion-exchange SPE followed by HPLC-UV analysis. Single-laboratory validation performance parameters include recovery (92-101%) and repeatability (1.0-2.3% RSD). The method was approved for Official First Action status by an AOAC expert review panel. PMID- 22816250 TI - HILIC-MS/MS method for the quantitation of nucleotides in infant formula and adult nutritional formula: First Action 2011.21. AB - Official Method 2011.21 is for the quantitation of the following nucleotides: adenosine 5'-monophosphate (AMP), guanosine 5'-monophosphate (GMP), uridine 5' monophosphate (UMP), cytidine 5'-monophosphate (CMP), and inosine 5' monophosphate (IMP) in infant formula and adult/pediatric nutritional formula. It uses hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS). Preparation of the internal standards was conducted using centrifugal ultrafiltration and the standards are AMP- (13)C10, (15)N5; GMP (13)C10, (15)N5; UMP-(13)C9, (15)N2; and15 CMP- (13)C9, (15)N3. Data were collected by using multiple reaction monitoring of the product ions of protonated molecules of the five nucleotides generated by positive-electrospray ionization. The HILIC conditions were conducted with ammonium formate (30 mmol/L) in water (pH 2.5, adjusted with formic acid) and methanol. The LOD and LOQ of the standard solution were 0.005-0.01 and 0.01-0.03 microg/mL, respectively. Recovery data were collected for intraday and interday testing and ranged from 98.1 to 108.9% with an RSD of 0.7-5.4%. The analytical range of the method is between 0.04 to 5 microg/mL for standard solution. PMID- 22816251 TI - Chemometrics in pharmaceutical analysis. PMID- 22816252 TI - Chemometrics in pharmaceutical analysis: an introduction, review, and future perspectives. AB - Chemometrics is the application of statistical and mathematical methods to analytical data to permit maximum collection and extraction of useful information. The utility of chemometric techniques as tools enabling multidimensional calibration of selected spectroscopic, electrochemical, and chromatographic methods is demonstrated. Application of this approach mainly for interpretation of UV-Vis and near-IR (NIR) spectra, as well as for data obtained by other instrumental methods, makes identification and quantitative analysis of active substances in complex mixtures possible, especially in the analysis of pharmaceutical preparations present in the market. Such analytical work is carried out by the use of advanced chemical instruments and data processing, which has led to a need for advanced methods to design experiments, calibrate instruments, and analyze the resulting data. The purpose of this review is to describe various chemometric methods in combination with UV-Vis spectrophotometry, NIR spectroscopy, fluorescence spectroscopy, electroanalysis, chromatographic separation, and flow-injection analysis for the analysis of drugs in pharmaceutical preparations. Theoretical and practical aspects are described with pharmaceutical examples of chemometric applications. This review will concentrate on gaining an understanding of how chemometrics can be useful in the modern analytical laboratory. A selection of the most challenging problems faced in pharmaceutical analysis is presented, the potential for chemometrics is considered, and some consequent implications for utilization are discussed. The reader can refer to the citations wherever appropriate. PMID- 22816253 TI - Comparative analysis of chiral drugs in view of chemometrics. AB - With the development of methods for obtaining chiral compounds as potential drugs, there is also need to develop analytical methods for the separation of both enantiomers. Keeping in mind that the physical and chemical properties of both enantiomers are identical, their different nature will only be revealed in a chiral environment that is appropriately designed. Physicochemical systems can be used to predict the differences in biological activity of both enantiomers. The complexity of the problem requires the use of additional tools, which are various chemometric methods. This paper reviews the application of chemometry in the analysis of chiral drugs and discusses the effects of a combination of chromatographic, electrophoretic, and spectroscopic analysis (UV-Vis absorption spectroscopy, and near-IR spectroscopy aided by cyclodextrin inclusion complexes) with chemometrics for improving the methods of enantioseparation (experimental design), explaining the mechanisms of behavior and chiral recognition (quantitative structure-enantioselective retention relationships) and indicating chiral purity (enantiomeric excess). PMID- 22816255 TI - Artificial neural networks: theoretical background and pharmaceutical applications: a review. AB - In recent times, there has been a growing interest in artificial neural networks, which are a rough simulation of the information processing ability of the human brain, as modern and vastly sophisticated computational techniques. This interest has also been reflected in the pharmaceutical sciences. This paper presents a review of articles on the subject of the application of neural networks as effective tools assisting the solution of various problems in science and the pharmaceutical industry, especially those characterized by multivariate and nonlinear dependencies. After a short description of theoretical background and practical basics concerning the computations performed by means of neural networks, the most important pharmaceutical applications of neural networks, with suitable references, are demonstrated. The huge role played by neural networks in pharmaceutical analysis, pharmaceutical technology, and searching for the relationships between the chemical structure and the properties of newly synthesized compounds as candidates for drugs is discussed. PMID- 22816254 TI - Feature selection methods in QSAR studies. AB - A quantitative structure-activity relationship (QSAR) relates quantitative chemical structure attributes (molecular descriptors) to a biological activity. QSAR studies have now become attractive in drug discovery and development because their application can save substantial time and human resources. Several parameters are important in the prediction ability of a QSAR model. On the one hand, different statistical methods may be applied to check the linear or nonlinear behavior of a data set. On the other hand, feature selection techniques are applied to decrease the model complexity, to decrease the overfitting/overtraining risk, and to select the most important descriptors from the often more than 1000 calculated. The selected descriptors are then linked to a biological activity of the corresponding compound by means of a mathematical model. Different modeling techniques can be applied, some of which explicitly require a feature selection. A QSAR model can be useful in the design of new compounds with improved potency in the class under study. Only molecules with a predicted interesting activity will be synthesized. In the feature selection problem, a learning algorithm is faced with the problem of selecting a relevant subset of features upon which to focus attention, while ignoring the rest. Up to now, many feature selection techniques, such as genetic algorithms, forward selection, backward elimination, stepwise regression, and simulated annealing have been used extensively. Swarm intelligence optimizations, such as ant colony optimization and partial swarm optimization, which are feature selection techniques usually simulated based on animal and insect life behavior to find the shortest path between a food source and their nests, recently are also involved in QSAR studies. This review paper provides an overview of different feature selection techniques applied in QSAR modeling. PMID- 22816256 TI - Chemometric and statistical evaluation of calibration curves in pharmaceutical analysis -- a short review on trends and Recommendations. AB - The calibration of an analytical method is a very important part of its development, and only the proper statistical and chemometric evaluation of the results, together with understanding this process, allows good results. The purpose of this minireview is to call the reader's attention to the major problems in calibration: curvilinearity, heteroscedasticity, presence of outliers, transformation of results, and distribution and autocorrelation of residuals. The common misunderstandings and mistakes are emphasized to inform the reader. Additionally, the computational package "quantchem" for GNU R environment, allowing full and automatic calibration evaluation, is presented. PMID- 22816257 TI - Topological indexes and QSRR methodology in pharmaceutical and chemical analysis. AB - This paper presents an assessment of the possibility of using topological indexes and related structural descriptors in TLC, HPLC, GC, micellar electrokinetic capillary chromatography (MEKC), and capillary zone electrophoresis (CZE) techniques. Every work quoted is a new aspect of the use of topological indexes. Data from the scientific literature indicate that the topological indexes discussed can be used to predict and describe retention and lipophilic parameters obtained by TLC, HPLC, GC, MEKC, and CZE for different classes of organic compounds including drugs. The results presented indicate that the topological indexes and other structural descriptors have significance in analytical investigations of organic compounds. This review indicates that further investigations on the application of the topological indexes in TLC, HPLC, GC, MEKC, and CZE are justifiable. PMID- 22816258 TI - Application of chemometrically processed thermogravimetric data for identification of baclofen-excipient interactions. AB - Studies are constantly being conducted on the elaboration of efficient methods to confirm the compatibility of active pharmaceutical ingredients (APIs) and excipients, since medicinal products, apart from their APIs, also contain numerous excipients that not only have important functions in pharmaceutical preparations but can also initiate or participate in interactions with drug substances, which eventually lead to a decline in drug quality. With this in mind, research was undertaken to evaluate two of the most often applied pattern recognition methods, hierarchical cluster analysis (HCA) and principal component analysis (PCA), as supporting techniques in the identification of potential physicochemical interactions that may occur during the preformulation of solid dosage forms. The investigation performed with the use of baclofen and selected excipients has shown that with thermogravimetric analysis, HCA and PCA fulfill their role as supporting techniques in the interpretation of the data obtained. Based on these methods, it is possible to detect incompatibilities between baclofen and excipients, and the data obtained concur strongly with the results of differential scanning calorimetry and IR spectrometry analyses. PMID- 22816259 TI - Chemometric processing of pharmaceutical essential oil fingerprints -- comparison of GC, HPLC, TLC, IR spectroscopy, and differential scanning calorimetry. AB - Fifteen essential oils of pharmaceutical grade were fingerprinted by five techniques: TLC, GC, HPLC, attenuated total reflectance FTIR spectroscopy, and differential scanning calorimetry (DSC). Denoising and baseline removal was found to be a crucial step for correct comparative analysis. Standardization of the signal was not necessary in the presented case; however, it should be considered and checked in each case. Due to small variance explained by first two principal components (below 50%) and outlying observations, the main analysis was performed by Euclidean dendrograms. It was found that almost all techniques besides DSC find real chemical similarities; however, DSC can be used as an additional tool. The similarities among the five techniques were also compared and discussed. PMID- 22816260 TI - Detection of drug active ingredients by chemometric processing of solid-state NMR spectrometry data -- the case of acetaminophen. AB - This paper presents a preliminary study in building discriminant models from solid-state NMR spectrometry data to detect the presence of acetaminophen in over the-counter pharmaceutical formulations. The dataset, containing 11 spectra of pure substances and 21 spectra of various formulations, was processed by partial least squares discriminant analysis (PLS-DA). The model found coped with the discrimination, and its quality parameters were acceptable. It was found that standard normal variate preprocessing had almost no influence on unsupervised investigation of the dataset. The influence of variable selection with the uninformative variable elimination by PLS method was studied, reducing the dataset from 7601 variables to around 300 informative variables, but not improving the model performance. The results showed the possibility to construct well-working PLS-DA models from such small datasets without a full experimental design. PMID- 22816261 TI - Application of curve resolution algorithms in the study of drug photodegradation kinetics -- the example of moclobemide. AB - The photodegradation of moclobemide was studied in methanolic media. Ultra-HPLC (UHPLC)/MS/MS analysis proved decomposition to 4-chlorobenzamide as a major degradation product and small amounts of Ro 16-3177 (4-chloro-N-[2-[(2 hydroxyethyl)amino] ethyl]benzamide) and 2-[(4-chlorobenzylidene)amino]-N-[2 ethoxyethenyl]ethenamine. The methanolic solution was investigated spectrophotometrically in the UV region, registering the spectra during 30 min of degradation. Using reference spectra and a multivariate chemometric method (multivariate curve resolution-alternating least squares), the spectra were resolved and concentration profiles were obtained. The obtained results were in good agreement with a quantitative approach, with UHPLC-diode array detection as the reference method. PMID- 22816262 TI - Chemometric exploration of the dependencies between molecular modeling descriptors and analytical chemistry data of antihistaminic drugs. AB - The relationships between experimental and computational descriptors of antihistamine drugs were studied using principal component analysis (PCA). Empirical data came from UV and IR spectroscopic measurements. Nonempirical data, such as structural molecular descriptors and chromatographic data, were obtained from HyperChem software. Another objective was to test whether the parameters used as independent variables (nonempirical and empirical-spectroscopic) could lead to attaining classification similar to that developed on the basis of the chromatographic parameters. To arrive at the answer to the question, a matrix of 18x49 data, including HPLC and UV and IR spectroscopic data, together with molecular modeling studies, was evaluated by the PCA method. The obtained clusters of drugs were consistent with the drugs' chemical structure classification. Moreover, the PCA method applied to the HPLC retention data and structural descriptors allowed for classification of the drugs according to their pharmacological properties; hence it may potentially help limit the number of biological assays in the search for new drugs. PMID- 22816263 TI - Reflectance near-infrared spectroscopic method with a chemometric technique using partial least squares multivariate calibration for simultaneous determination of chondroitin, glucosamine, and ascorbic acid. AB - A reflectance near-infrared (RNIR) spectroscopy method was developed for simultaneous determination of chondroitin (CH), glucosamine (GO), and ascorbic acid (AS) in capsule powder. A simple preparation of the sample was done by grinding, sieving, and compression of the powder sample for improving RNIR spectra. Partial least squares (PLS-1 and PLS-2) was successfully applied to quantify the three components in the studied mixture using information included in RNIR spectra in the 4240-9780 cm(-1) range. The calibration model was developed with the three drug concentrations ranging from 50 to 150% of the labeled amount. The calibration models using pure standards were evaluated by internal validation, cross-validation, and external validation using synthetic and pharmaceutical preparations. The proposed method was applied for analysis of two pharmaceutical products. Both pharmaceutical products had the same active principle and similar excipients, but with different nominal concentration values. The results of the proposed method were compared with the results of a pharmacopoeial method for the same pharmaceutical products. No significant differences between the results were found. The standard error of prediction was 0.004 for CH, 0.003 for GO, and 0.005 for AS. The correlation coefficient was 0.9998 for CH, 0.9999 for GO, and 0.9997 for AS. The highly accurate and precise RNIR method can be used for QC of pharmaceutical products. PMID- 22816264 TI - Development and optimization of an HPLC analysis of citalopram and its four nonchiral impurities using experimental design methodology. AB - In this study, the RP-HPLC method was investigated for the separation of citalopram and its four impurities by use of statistical experimental design. Initially, the influence of different experimental conditions (buffer pH, flow rate, and column temperature) on the chromatographic behavior of citalopram and its four impurities was investigated by use of partial least squares regression (PLSR) and multilayer perceptron (MLP) artificial neural networks (ANNs) trained by back-propagation. The developed models and the corresponding response surface plots were used to select the optimal HPLC conditions, buffer pH 7.0, flow rate 1.0 mL/ min, and column temperature 25 degrees C, for an efficient separation of citalopram and its four impurities. The elaborated HPLC method was found to be linear, specific, sensitive, precise, accurate, and robust. Retention times of citalopram and its impurities, obtained with the developed HPLC method, and the computed molecular parameters of the examined compounds were used in a quantitative structure retention relationship (QSRR) study. The PLSR and ANN algorithms were applied for the development of the QSRR methods. The MLP-two layers-ANN-QSRR model with root mean square error of prediction 0.105 and r(2) (observed versus predicted) 0.978 was selected. Since many different reaction conditions are applied for the synthesis of citalopram, different impurities and degradation products can be formed. Therefore, the developed QSRR model can be extended to the prediction of the retention times with the other citalopram impurities, degradation products, and metabolites. PMID- 22816265 TI - Quantitative determination of prednisone in tablets by infrared attenuated total reflection and Raman spectroscopy. AB - The quantification of prednisone in tablets was performed using partial least squares (PLS) models based on FTIR-attenuated total reflection (ATR) and FT-Raman spectra. To compare the predictive ability of these models, the relative standard error of prediction (RSEP) values were calculated. In the case of prednisone determination from the FT-Raman data, RSEP values of 3.1 and 3.2% for the calibration and validation data sets were obtained. For FTIR-ATR models, which were constructed using five spectra for each sample, these errors amounted to 2.6 and 2.9%, respectively. Four commercial products containing 1, 5, 10, and 20 mg prednisone/tablet were quantified. Concentrations derived from the elaborated models correlated strongly with the results of reference analyses and with the declared values (in parentheses). The analyses gave recoveries of 100.0-101.6% (100.1-103.0%) and 98.1-103.2% (100.4-102.9%) for FTIR-ATR and FT-Raman data, respectively. A successful quantification of prednisolone in tablets containing 5 mg active ingredient/tablet was also performed using the PLS model, which was based on FTIR-ATR spectra, with a recovery of 99.8 (98.8%). Both reported spectroscopic techniques can be used as fast and convenient alternatives to the standard pharmacopeial methods of prednisone and prednisolone quantification in solid dosage forms. However, in the case of FTIR-ATR spectroscopy, it is necessary to repeat measurements several times to obtain sufficiently low quantification errors. PMID- 22816266 TI - A new application of continuous wavelet transform to overlapping chromatograms for the quantitative analysis of amiloride hydrochloride and hydrochlorothiazide in tablets by ultra-performance liquid chromatography. AB - A new application of continuous wavelet transform (CWT) to overlapping peaks in a chromatogram was developed for the quantitative analysis of amiloride hydrochloride (AML) and hydrochlorothiazide (HCT) in tablets. Chromatographic analysis was done by using an ACQUITY ultra-performance LC (UPLC) BEH C18 column (50 x 2.1 mm id, 1.7 pm particle size) and a mobile phase consisting of methanol 0.1 M acetic acid (21 + 79, v/v) at a constant flow rate of 0.3 mL/min with diode array detection at 274 nm. The overlapping chromatographic peaks of the calibration set consisting of AML and HCT mixtures were recorded rapidly by using an ACQUITY UPLC H-Class system. The overlapping UPLC data vectors of AML and HCT drugs and their samples were processed by CWT signal processing methods. The calibration graphs for AML and HCT were computed from the relationship between concentration and areas of chromatographic CWT peaks. The applicability and validity of the improved UPLC-CWT approaches were confirmed by recovery studies and the standard addition technique. The proposed UPLC-CWT methods were applied to the determination of AML and HCT in tablets. The experimental results indicated that the suggested UPLC-CWT signal processing provides accurate and precise results for industrial QC and quantitative evaluation of AML-HCT tablets. PMID- 22816267 TI - Simultaneous determination of saponins and a flavonoid from aerial parts of Zygophyllum coccineum L. AB - Triterpenoid saponins are a class of glycosides with a wide range of bioactivities, which make them interesting research candidates. Zygophyllum coccineum is an Egyptian desert plant rich in triterpenoid saponins. Reviewing the relevant literature, no data concerning the HPLC or ultra-performance LC (UPLC) analysis of Zygophyllum content were found. This paper presents two methods, HPLC-UV and UPLC-UV-evaporative light scattering detector (ELSD)/MS, for the simultaneous determination of 10 compounds in the alcohol extract of Z. coccineum. The HPLC method uses a C18 column and water-acetonitrile (both containing 0.1% trifluoroacetic acid) gradient system. The separation was achieved within 32 min. The developed UPLC method simultaneously detects and quantifies the 10 compounds using an Acquity UPLC BEH Shield RP18 column and reagent alcohol-acetonitrile (80/20, v/v) and water (both containing 0.5% formic acid) gradient system within 14 min with UV, ELS, and MS detectors. The methods were used to analyze another species, Z. simplex, and results revealed a great variation between the secondary metabolite pattern of both species. PMID- 22816268 TI - Influence of extraction methodologies on the analysis of five major volatile aromatic compounds of citronella grass (Cymbopogon nardus) and lemongrass (Cymbopogon citratus) grown in Thailand. AB - This paper deals with the systematic comparison of extraction of major volatile aromatic compounds (VACs) of citronella grass and lemongrass by classical microhydrodistillation (MHD), as well as modern accelerated solvent extraction (ASE). Sixteen VACs were identified by GC/MS. GC-flame ionization detection was used for the quantification of five VACs (citronellal, citronellol, geraniol, citral, and eugenol) to compare the extraction efficiency of the two different methods. Linear range, LOD, and LOQ were calculated for the five VACs. Intraday and interday precisions for the analysis of VACs were determined for each sample. The extraction recovery, as calculated by a spiking experiment with known standards of VACs, by ASE and MHD ranged from 64.9 to 91.2% and 74.3 to 95.2%, respectively. The extraction efficiency of the VACs was compared for three solvents of varying polarities (hexane, dichloromethane, and methanol), seven different temperatures (ranging from 40 to 160 degrees C, with a gradual increment of 20 degrees C), five time periods (from 1 to 10 min), and three cycles (1, 2, and 3 repeated extractions). Optimum extraction yields of VACs were obtained when extractions were carried out for 7 min with dichloromethane and two extraction cycles at 120 degrees C. The results showed that the ASE technique is more efficient than MHD, as it results in improved yields and significant reduction in extraction time with automated extraction capabilities. PMID- 22816269 TI - Fast screening for antioxidant properties of flavonoids from Pterogyne nitens using electrochemical methods. AB - A fast, low-cost, convenient, and especially sensitive voltammetric screening approach for the study of the antioxidant properties of isoquercitrin and pedalitin from Pterogyne nitens is suggested in this work. These flavonoids were investigated for their redox properties using cyclic voltammetry in nonaqueous media using N,N-dimethylformamide and tetrabutylammonium tetrafluorborate as the supporting electrolyte, a glassy carbon working electrode, A6(see symbol in text)AgCI reference electrode, and Pt bare wire counter electrode. The comparative analysis of the activity of rutin has also been carried out. Moreover, combining HPLC with an electrochemical detector allowed qualitative and quantitative detection of micromolecules (e.g., isoquercitrin and pedalitin) that showed antioxidant activities. These results were then correlated to the inhibition of beta-carotene bleaching determined by TLC autographic assay and to structural features of the flavonoids. PMID- 22816270 TI - Evaluation of the VITEK 2 Gram-negative (GN) microbial identification test card: collaborative study. AB - A collaborative study was conducted to evaluate the performance of the VITEK 2 Gram-negative (GN) Identification card for use with the VITEK 2 automated microbial identification system. The GN test card is used in the identification of fermenting and nonfermenting Gram-negative bacilli, including the select agent organisms Brucella melitensis, Francisella tularensis, Burkholderia mallei, B. pseudomallei, and Yersinia pestis. The VITEK 2 GN card is based on 47 biochemical tests measuring carbon source utilization, inhibition and resistance, and enzymatic activities. A total of 20 laboratories representing government, industry, and private testing facilities throughout the United States participated. In this study, 720 Gram-negative inclusivity isolates were analyzed by the GN Identification method. Of the 720 well-characterized isolates, 707 were identified correctly, 0 were misidentified, 0 were unidentified, and 13 were not characterized as a Gram-negative organism. Additionally, 120 isolates exclusive of fermenting and nonfermenting Gram-negative bacilli were screened by Gram stain. A total of 117 isolates were correctly excluded. Three organisms were incorrectly characterized by Gram stain procedures, resulting in incorrect analysis and misidentification by VITEK 2 GN. The VITEK 2 GN identification method is an acceptable automated method for the rapid identification of Gram negative bacteria. PMID- 22816271 TI - Validation of the Soleris E. coli method for detection and semi-quantitative determination of Escherichia coli in foods. AB - The performance of the Soleris E. coli method was compared with that of the ISO 7251 most probable number (MPN) and detection reference methods for Escherichia coli. The Soleris E. coli method is a growth-based, rapid, automated system composed of temperature-controlled incubation chambers and photodiode-based optical detection devices for measurement of color changes in a prepared medium vial. A dilution of the test sample homogenate is inoculated directly into the vial. Products of E. coli metabolism alter the color of the medium over time, and this change is monitored by the Soleris instrument. The test is used in a dilute to-specification or specification monitoring manner in which the result is positive or negative around a desired cutoff (in CFU/g) determined by the dilution and volume of sample homogenate added to the vial. Alternatively, the test is used for zero tolerance determinations (e.g., absence in 25 g) by performing an off-line pre-enrichment step followed by transfer of a portion of the pre-enrichment culture to the Soleris vial. Six E. coli strains originating from food sources were inoculated individually into six food commodities: frozen green beans, Echinacea powder, cocoa powder, sweetened condensed milk, pasteurized liquid egg, and shredded mozzarella cheese. Uninoculated samples were included in each trial. The results obtained by the ISO 7251 detection method and the Soleris E. coli method were shown to be in agreement by Chi-square analysis when the presence of E. coli was determined in 25 g of sample. Results from the Soleris E. coli dilute-to-specification method and the ISO 7251 MPN method were found to be in agreement by probability of detection statistical analysis. In inclusivity testing, 52 of 53 E. coli strains were detected within 24 h. Only a non-thermoduric strain of serotype O157:H43 was not detected. In exclusivity testing, all 31 strains tested produced negative results. Results of ruggedness experiments show that accurate results can be obtained even when the operating temperature of the Soleris instrument is set beyond normal tolerances. The internal and independent laboratory studies demonstrated that the Soleris E. coli method could be successfully utilized as an alternative to the reference methods, with a significant time savings of 2 to 3 days. PMID- 22816272 TI - Determination of paralytic shellfish toxins in shellfish by receptor binding assay: collaborative study. AB - A collaborative study was conducted on a microplate format receptor binding assay (RBA) for paralytic e shellfish toxins (PST). The assay quantifies the composite PST toxicity in shellfish samples based on the ability of sample extracts to compete with (3)H saxitoxin (STX) diHCl for binding to voltage-gated sodium channels in a rat brain membrane preparation. Quantification of binding can be carried out using either a microplate or traditional scintillation counter; both end points were included in this study. Nine laboratories from six countries completed the study. One laboratory analyzed the samples using the precolumn oxidation HPLC method (AOAC Method 2005.06) to determine the STX congener composition. Three laboratories performed the mouse bioassay (AOAC Method 959.08). The study focused on the ability of the assay to measure the PST toxicity of samples below, near, or slightly above the regulatory limit of 800 (microg STX diHCl equiv./kg). A total of 21 shellfish homogenates were extracted in 0.1 M HCl, and the extracts were analyzed by RBA in three assays on separate days. Samples included naturally contaminated shellfish samples of different species collected from several geographic regions, which contained varying STX congener profiles due to their exposure to different PST-producing dinoflagellate species or differences in toxin metabolism: blue mussel (Mytilus edulis) from the U.S. east and west coasts, California mussel (Mytilus californianus) from the U.S. west coast, chorito mussel (Mytilus chiliensis) from Chile, green mussel (Perna canaliculus) from New Zealand, Atlantic surf clam (Spisula solidissima) from the U.S. east coast, butter clam (Saxidomus gigantea) from the west coast of the United States, almeja clam (Venus antiqua) from Chile, and Atlantic sea scallop (Plactopecten magellanicus) from the U.S. east coast. All samples were provided as whole animal homogenates, except Atlantic sea scallop and green mussel, from which only the hepatopancreas was homogenized. Among the naturally contaminated samples, five were blind duplicates used for calculation of RSDr. The interlaboratory RSDR of the assay for 21 samples tested in nine laboratories was 33.1%, yielding a HorRat value of 2.0. Removal of results for one laboratory that reported systematically low values resulted in an average RSDR of 28.7% and average HorRat value of 1.8. Intralaboratory RSDr based on five blind duplicate samples tested in separate assays, was 25.1%. RSDr obtained by individual laboratories ranged from 11.8 to 34.9%. Laboratories that are routine users of the assay performed better than nonroutine users, with an average RSDr of 17.1%. Recovery of STX from spiked shellfish homogenates was 88.1-93.3%. Correlation with the mouse bioassay yielded a slope of 1.64 and correlation coefficient (r(2)) of 0.84, while correlation with the precolumn oxidation HPLC method yielded a slope of 1.20 and an r(2) of 0.92. When samples were sorted according to increasing toxin concentration (microg STX diHCl equiv./kg) as assessed by the mouse bioassay, the RBA returned no false negatives relative to the 800 microg STX diHCl equiv./kg regulatory limit for shellfish. Currently, no validated methods other than the mouse bioassay directly measure a composite toxic potency for PST in shellfish. The results of this interlaboratory study demonstrate that the RBA is suitable for the routine determination of PST in shellfish in appropriately equipped laboratories. PMID- 22816273 TI - Determination of wine aroma compounds by dehydration followed by GC/MS. AB - A new extraction method for the analysis of the volatile fraction of white and red wines has been developed and validated. A dehydration step with MgSO4 separated an aroma compounds-rich alcoholic-glycerine layer. Spiked samples showed good recoveries in the range between 75 and 120% with CVmax% of 17, except for 2-phenylethanol and y-butyrolactone for which recoveries in red wines were under 60%, and for monoethylsuccinate, where recoveries averaged 50 and 60% in white and red wines, respectively. Method repeatability and intermediate precision showed good CVmax% with minimum and maximum values between 7.7 and 24, and between 18.7 and 25.0, respectively. The average determination coefficients were greater than 0.99 with CVmax% of 13. The instrumental LOD and LOQ were, in all cases, under 0.05 mg/L, except for 2,3 butanediol (0.20 mg/L). Overall, the presence of wine matrix affected aroma compounds responses in GC/MS analysis. These observations indicate that the use of a matrix-matched calibration curve is mandatory to obtain reliable quantitative data. PMID- 22816274 TI - Identification of Ensis siliqua samples and establishment of the catch area using a species-specific microsatellite marker. AB - European Council Regulation 104/2000 states that fishery products must be labeled to indicate commercial designation of species, the production method, and the catch area. Therefore, traceability of seafood implies knowledge of the species offered to retail and their origin. Ensis siliqua is a bivalve intensively fished in Europe and sold in fresh and canned forms. Although several published methods clearly differentiate Ensis genus species, none of those assess the origin of the commercial samples. In the present study, a microsatellite marker (Esi-UDC3055F) was developed to establish the catch area of E. siliqua samples. Amplification yielded a fragment of 275 or 302 base pairs, depending on whether they were Iberian or Irish populations. The usefulness of this method was also assessed in commercial samples. The results of this study provide a reliable methodology for the identification of catch area in European E. siliqua commercial samples. The coupling of this methodology with existing techniques for razor clam species identification provides a powerful tool for traceability and labeling enforcement. PMID- 22816275 TI - Determination of insoluble, soluble, and total dietary fiber (CODEX definition) by enzymatic-gravimetric method and liquid chromatography: collaborative study. AB - A method for the determination of insoluble (IDF), soluble (SDF), and total dietary fiber (TDF), as defined by the CODEX Alimentarius, was validated in foods. Based upon the principles of AOAC Official Methods 985.29, 991.43, 2001.03, and 2002.02, the method quantitates water-insoluble and water-soluble dietary fiber. This method extends the capabilities of the previously adopted AOAC Official Method 2009.01, Total Dietary Fiber in Foods, Enzymatic-Gravimetric Liquid Chromatographic Method, applicable to plant material, foods, and food ingredients consistent with CODEX Definition 2009, including naturally occurring, isolated, modified, and synthetic polymers meeting that definition. The method was evaluated through an AOAC/AACC collaborative study. Twenty-two laboratories participated, with 19 laboratories returning valid assay data for 16 test portions (eight blind duplicates) consisting of samples with a range of traditional dietary fiber, resistant starch, and nondigestible oligosaccharides. The dietary fiber content of the eight test pairs ranged from 10.45 to 29.90%. Digestion of samples under the conditions of AOAC 2002.02 followed by the isolation, fractionation, and gravimetric procedures of AOAC 985.29 (and its extensions 991.42 and 993.19) and 991.43 results in quantitation of IDF and soluble dietary fiber that precipitates (SDFP). The filtrate from the quantitation of water-alcohol-insoluble dietary fiber is concentrated, deionized, concentrated again, and analyzed by LC to determine the SDF that remains soluble (SDFS), i.e., all dietary fiber polymers of degree of polymerization = 3 and higher, consisting primarily, but not exclusively, of oligosaccharides. SDF is calculated as the sum of SDFP and SDFS. TDF is calculated as the sum of IDF and SDF. The within-laboratory variability, repeatability SD (Sr), for IDF ranged from 0.13 to 0.71, and the between-laboratory variability, reproducibility SD (SR), for IDF ranged from 0.42 to 2.24. The within-laboratory variability Sr for SDF ranged from 0.28 to 1.03, and the between-laboratory variability SR for SDF ranged from 0.85 to 1.66. The within-laboratory variability Sr for TDF ranged from 0.47 to 1.41, and the between-laboratory variability SR for TDF ranged from 0.95 to 3.14. This is comparable to other official and approved dietary fiber methods, and the method is recommended for adoption as Official First Action. PMID- 22816276 TI - Determination of the isoflavone genistein in soybeans by high-performance liquid chromatography following cloud point extraction. AB - A simple and sensitive method has been developed for preconcentration and determination of genistein in soybeans. This method is based on cloud point extraction (CPE) of genistein from soybeans using ethylene glycol monoalkyl ether (Genapol X-080) as a nonionic surfactant. The concentration of extracted genistein was determined by HPLC with a UV detector. Optimum experimental conditions were established. With 5% Genapol X-080 (v/v), a liquid/solid ratio of 25:1 mL/g, and ultrasonic-assisted extraction at 40 degrees C for 45 min, the extraction percentage of genistein reached its highest value. The preconcentration factor for genistein was about 16.5. The RSD for seven replicate measurements and the LOD were +/- 4.45% and 15.0 ng/mL, respectively. CPE is simple, inexpensive, and suitable for extraction of genistein from soybean. It uses environmentally friendly surfactants and offers a convenient alternative to more conventional extraction systems. PMID- 22816277 TI - SDIX RapidChek Listeria F.A.S.T. environmental test system for the detection of Listeria species on environmental surfaces. AB - The SDIX RapidChek Listeria F.A.S.T. test system was validated against the U.S. Department of Agriculture-Food Safety and Inspection Service (USDA-FSIS) cultural reference method for the detection of Listeria species on stainless steel, plastic, rubber, and painted concrete. The SDIX method uses a proprietary RapidChek Listeria enrichment media for a one-step, 24-40 h enrichment at 30 degrees C, and detects Listeria on an immunochromatographic lateral flow device in 10 min. Different Listeria species were used to spike each of the environmental surfaces. Environmental surfaces were spiked at levels ranging from 50 to 400 CFU/surface (1 in.2 swabs for painted concrete, 4 in.(2) for sponge). A total of 120 spiked samples were tested by the SDIX method at 24 and 40 h and the cultural reference method. Total confirmed positives were 49, 54, and 48 for the SDIX 24 h method, the SDIX 40 h method, and the USDA-FSIS cultural reference method, respectively. Nonspiked samples from all environmental surfaces were reported as negative for Listeria spp. by all methods. The overall Chi square was 0.017 (P = 0.104) and 0.611 (P= 0.566) after a 24 and 40 h enrichment, respectively, indicating that the test method was equivalent in performance to the reference method at both enrichment times. The SDIX method was evaluated for the detection of 50 Listeria and 35 non-Listeria bacterial strains. All 50 Listeria strains were detected by the method (100% sensitivity). Five out of 35 non-Listeria species gave light test signals when grown in nonselective broth culture and tested undiluted. However, when grown in the RapidChek Listeria F.A.S.T. proprietary media, only one bacterial strain (Staphylococcus aureus) was detected, giving a very low test signal (97% specificity). The method was shown to be robust toward several alterations in testing and storage conditions. PMID- 22816278 TI - RAZOR EX anthrax air detection system. AB - The RAZOR EX Anthrax Air Detection System, developed by Idaho Technology, Inc. (ITI), is a qualitative method for the detection of Bacillus anthracis spores collected by air collection devices. This system comprises a DNA extraction kit, a freeze-dried PCR reagent pouch, and the RAZOR EX real-time PCR instrument. Each pouch contains three assays, which distinguish potentially virulent B. anthracis from avirulent B. anthracis and other Bacillus species. These assays target the pXO1 and pXO2 plasmids and chromosomal DNA. When all targets are detected, the instrument makes an "anthrax detected" call, meaning that virulence genes of the anthrax bacillus are present. This report describes results from AOAC Method Developer (MD) and Independent Laboratory Validation (ILV) studies, which include matrix, inclusivity/exclusivity, environmental interference, upper and lower LOD of DNA, robustness, product consistency and stability, and instrument variation testing. In the MD studies, the system met the acceptance criteria for sensitivity and specificity, and the performance was consistent, stable, and robust for all components of the system. For the matrix study, the acceptance criteria of 95/96 expected calls was met for three of four matrixes, clean dry filters being the exception. Ninety-four of the 96 clean dry filter samples tested gave the expected calls. The nucleic acid limit of detection was 5-fold lower than AOAC's acceptable minimum detection limit. The system demonstrated no tendency for false positives when tested with Bacillus cereus. Environmental substances did not inhibit accurate detection of B. anthracis. The ILV studies yielded similar results for the matrix and inclusivity/exclusivity studies. The ILV environmental interference study included environmental substances and environmental organisms. Subsoil at a high concentration was found to negatively interfere with the pXO1 reaction. No interference was observed from the environmental organisms. The nucleic acid LOD, however, was 10 times higher (1 pg/reaction, equivalent to about 200 spores) than that found in the MD study. These results indicate that the RAZOR System is a sensitive and specific system that accurately identifies B. anthracis in aerosol matrixes and in the presence of interfering substances, and that the method can be performed by an independent laboratory and achieve similar results. PMID- 22816279 TI - Determination of some trace elements in food and soil samples by atomic absorption spectrometry after coprecipitation with holmium hydroxide. AB - The determination of trace elements in food and soil samples by atomic absorption spectrometry was investigated. A coprecipitation procedure with holmium hydroxide was used for separation-preconcentration of trace elements. Trace amounts of copper(II), manganese(II), cobalt(II), nickel(ll), chromium(lll), iron(Ill), cadmium(ll), and lead(ll) ions were coprecipitated with holmium hydroxide in 2.0 M NaOH medium. The optimum conditions for the coprecipitation process were investigated for several commonly tested experimental parameters, such as amount of coprecipitant, effect of standing time, centrifugation rate and time, and sample volume. The precision, based on replicate analysis, was lower than 10% for the analytes. In order to verify the accuracy of the method, the certified reference materials BCR 141 R calcareous loam soil and CRM 025-050 soil were analyzed. The procedure was successfully applied for separation and preconcentration of the investigated ions in various food and soil samples. An amount of the solid samples was decomposed with 15 mL concentrated hydrochloric acid-concentrated nitric acid (3 + 1). The preconcentration procedure was then applied to the final solutions. The concentration of trace elements in samples was determined by atomic absorption spectrometry. PMID- 22816280 TI - Synthesis and application of glutaric dihydrazide modified multiwalled carbon nanotubes for selective solid-phase extraction and preconcentration of Cu(II), Zn(II), Ni(II), and Fe(III). AB - An SPE method for selective separation-preconcentration of Cu(ll), Zn(II), Ni(II), and Fe(III) on multiwalled carbon nanotubes (MWCNTs) modified by glutaric dihydrazide prior to flame atomic absorption spectrometric determination was investigated. The adsorption was achieved quantitatively on MWCNTs at pH 5.0, and then the retained metal ions on the adsorbent were eluted with 1 M HNO3. The effects of analytical parameters including pH of the solution, eluent type, sample volume, and matrix ions were investigated for optimization of the presented procedure. The adsorption capacity of the adsorbent at optimum conditions was found to be 33.6, 29.2, 22.1, and 36.0 mg/g for Cu(ll), Zn(ll), Ni(ll), and Fe(lll), respectively. The LOD values of the method were 0.21, 0.11, 0.24, and 0.27 microg/L for Cu(ll), Zn(ll), Ni(ll), and Fe(lll), respectively. The RSDs were lower than 3.01%. The method was applied for the determination of analytes in soil, river water, and wastewater samples with satisfactory results. PMID- 22816281 TI - Fractional-continuous wavelet transforms and ultra-performance liquid chromatography for the multicomponent analysis of a ternary mixture containing thiamine, pyridoxine, and lidocaine in ampules. AB - New chemometric approaches based on the application of partial least squares (PLS) and principal component regression (PCR) algorithms with fractional wavelet transform (FWT) and continuous wavelet transform (CWT) are proposed for the spectrophotometric multicomponent determination of thiamine hydrochloride (B1), pyridoxine hydrochloride (B6), and lidocaine hydrochloride (LID) in ampules without any separation step. In this study PLS and PCR techniques were applied to the raw spectral data, FWT-coefficients, and FWT-CWT-coefficients. These calibration models were labeled as Raw-PLS and Raw-PCR, FWT-PLS and FWT-PCR, and FWT-CWT-PLS and FWT-CWT-PCR, respectively. A new ultra-performance liquid chromatographic (UPLC) method was developed for the comparison of the results obtained by applying the chemometric calibration methods. Chromatographic separation and determination of B1, B6, and LID in ampules were performed on an Acquity UPLC BEH C18 column (50x2.1 mm id, 1.7 pm particle size) using gradient elution with a mobile phase consisting of methanol and 0.01 M HCI at a constant flow rate of 0.6 mL/min. These combined chemometric calibrations and UPLC were validated by analyzing various ternary mixtures, B1, B6, and LID. The proposed chemometric approaches (signal processing-multivariate calibrations) and UPLC method were applied to the quantitative multicomponent analysis of marketed ampules containing the vitamins B1 and B6 with LID. PMID- 22816282 TI - A simple method for the determination of malachite green and leucomalachite green residues in fish by a modified QuEChERS extraction and LC/MS/MS. AB - A simple method using LC/MS/MS was developed and validated to determine residues of malachite green (MG) and leucomalachite green (LMG) in fish fillet. A modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) technique was used to perform the sample preparation. The optimal extraction and cleanup conditions were established using an experimental design. The validation parameters obtained to determine both MG and LMG complied with the requirements established by regulatory agencies for the presence of such substances in fish, which establish that the method must attain, at least, a minimum required performance limit of 2 ng/g. The accuracy values ranged between 95 and 107%, and the precision values were lower than 11.2%. The method was used in the analysis of tilapia samples (n = 20) commercialized in Campinas, SP, Brazil. None of the samples presented detectable levels of MG or LMG residues. PMID- 22816283 TI - Rapid determination of nitroimidazole residues in honey by liquid chromatography/tandem mass spectrometry. AB - We developed a rapid and efficient means of determining residues of four nitroimidazoles-i.e., dimetridazole, ipronidazole, metronidazole, and ronidazole and three hydrophilic metabolites- i.e., 2-hydroxymethyl-1-methyl-5 nitroimidazole, 1 -methyl-2-(2'-hydroxyisopropyl)-5-nitroimidazole, and 1-(2 hydroxyethyl)-2-hydroxymethyl-nitroimidazole--in honey. We applied a QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) procedure improved to suit a nitroimidazole analysis, which is fast (approximately 30 min) and uses less organic solvent. The procedure involves initial single-phase extraction of 5 g of honey with acetonitrile containing 1% acetic acid, followed by liquid-liquid partitioning involving the addition of 5 g sodium chloride, 1.5 g trisodium citrate dihydrate, and 4 g magnesium sulfate. Moreover, matrix from honey was reduced by an SPE method with an alumina-N cartridge. The samples were analyzed using LC/MS/MS. Chromatographic separation of these nitroimidazoles and metabolites was performed in the gradient mode on a pentafluorophenylpropyl bonded silica column (150x2.0 mm, 3 pm particle size) at 40 degrees C. The mobile phase consisted of a 0.01% acetic acid solution and acetonitrile, and the flow rate was 0.2 mL/min. The method was validated using honey spiked with these nitroimidazoles from 0.1 to 0.5 microg/kg. The overall recovery of the seven nitroimidazoles ranged from 76.1 to 98.5%; intra- and interassay CV values were <9.5 and <14.2%, respectively. The LOQ ranged from 0.1 to 0.5 microg/kg. LC/MS/MS coupled with the QuEChERS method showed good potential as a method for determining nitroimidazole residues in honey. PMID- 22816284 TI - Preface. An international journal for communications and reviews covering all aspects of natural products research. PMID- 22816285 TI - Distribution of drimane sesquiterpenoids and tocopherols in liverworts, ferns and higher plants: Polygonaceae, Canellaceae and Winteraceae species. AB - The liverwort, Porella vernicosa complex produces a very hot tasting polygodial, a drimane-type sesquiterpene dialdehyde. The same compound has been isolated from two ferns, Thelypteris hispidula and Blechnum fluviatile, as well as from the higher plants Polygonum hydropiper, P. hydropiper f. purpurascens (Polygonaceae), Cinnamosma, Caspicodendron, Canella and Warburgia species (Canellaceae), and Pseudowintera colorata, Tasmannia lanceolata, Drimys and Zygogynum species (Winteraceae). In addition, the liverworts and higher plants which elaborate polygodial and its related pungent drimane dials contain a small amount of alpha tocopherol, gamma-tocopherol or delta-tocotrienol. The present paper gives the results of a comparative study on the drimane-type sesquiterpenoids in some liverworts, ferns and higher plants, and the role of tocopherols in these plant groups. PMID- 22816286 TI - A novel isopimarane diterpenoid with acetylcholinesterase inhibitory activity from Nepeta sorgerae, an endemic species to the Nemrut Mountain. AB - From the dichloromethane extract of Nepeta sorgerae, the isolation and structure elucidation are now reported of a new isopimarane diterpenoid, named sorgerolone, and two known triterpenoids, oleanolic acid and ursolic acid. Antioxidant activity of the extracts and the isolated terpenoids was determined by the DPPH free radical scavenging and lipid peroxidation inhibition (beta-carotene bleaching) methods. Anticholinesterase activity of the extracts and isolates was investigated by Ellman's method against AChE and BChE enzymes. Although the antioxidant activity results were low, the AChE enzyme inhibition of the extracts and terpenoids was very promising. PMID- 22816287 TI - Synthesis of taxane ABC tricyclic skeleton from lycoctonine. AB - A new conversional synthesis of the ABC ring system of taxoids from the C19 diterpenoid alkaloid lycoctonine was developed in 6 steps with 2% overall yield. The distinctive features of the conversion include pinacol rearrangement, enlargement of ring B, and opening of a four-membered ring. PMID- 22816288 TI - Two antiproliferative saponins of Tarenna grevei from the Madagascar dry forest [1]. AB - Antiproliferative bioassay-guided fractionation of the ethanol extract of the endemic Malagasy Rubiaceous plant Tarenna grevei led to the isolation of two new antiproliferative oxygenated oleanane triterpene saponins. The structures of the two active compounds were elucidated as 23-hydroxylongispinogenin 3-O-beta-D glucopyranoside (1) and longispinogenin 3-O-beta-D-glucopyranosyl (1 --> 2)-beta D-glucopyranoside (3) by analyses of their spectral data including 1D- and 2D-NMR spectroscopy and chemical evidence. Compounds 1 and 3 displayed moderate antiproliferative activity against the A2780 ovarian cancer cell line with IC50 values of 7.6 and 4 microM, respectively. PMID- 22816289 TI - Revisit to 25R/25S stereochemical analysis of spirostane-type steroidal sapogenins and steroidal saponins via 1H NMR chemical shift data. AB - An approach based on the difference (deltaab = deltaa - deltab) between 1H NMR chemical shifts (deltaa, deltab) of the geminal protons of oxymethylene (H2-26) (delta(ab) = < 0.2 for 25R; delta(ab) = > 0.5 for 25S) is proposed for ascertaining 25R/25S orientation of the 27-methyl group for (22R)-spirostane-type steroidal sapogenins and steroidal saponins. These studies suggested the 25R orientation of the 27-Me group for the steroidal saponins isolated by Temraz et al. from Tribulus alatus. PMID- 22816290 TI - Structure-cardiac activity relationship of C19-diterpenoid alkaloids. AB - Thirty three C19-diterpenoid alkaloids, twenty-two prepared from known C19 diterpenoid alkaloids and eleven isolated from Aconitum and Delphinium spp. were evaluated for their cardiac activity in the isolated bullfrog heart assay. Among them, eleven compounds exhibited cardiac activity, with average rate of amplitude increase in the range of 16-118%. Compound 7, mesaconine (17), hypaconine (25), and beiwutinine (26) exhibited strong cardiac activities relative to the reference drug. The structure-activity relationship data acquired indicated that an alpha-hydroxyl group at C-15, a hydroxyl group at C-8, an alpha-methoxyl or hydroxyl group at C-1, and a secondary amine or N-methyl group in ring A are important structure features necessary for the cardiac activities of the aconitine-type C19-diterpenoid alkaloids without any ester groups. In addition, an alpha-hydroxyl group at C-3 is also helpful for the cardiac activity of these alkaloids. PMID- 22816291 TI - Unusual reactions of a 7,17-seco-type C19-diterpenoid alkaloid derived from deltaline. AB - Treatment of a 7,17-seco-type C19-diterpenoid alkaloid (3), prepared from deltaline (8), with triethylamine in either DMF or TEG (triethylene glycol) at 120 degrees C provided two interesting compounds 6 and 7. The structures of compounds 3, 6, and 7 were established based on extensive interpretations of their 1D and 2D NMR data. Compound 6, a lycoctonine-type C19-diterpenoid alkaloid, can be transformed from alkaloid 3 via Grob fragmentation, Prins reaction, and intramolecular disproportionation. The mechanism of the formation of compound 6 was confirmed by deuteration experiments. Product 7 was formed through a pinacol-like rearrangement of alkaloid 3. PMID- 22816292 TI - Cytotoxic and anti-HIV phenanthroindolizidine alkaloids from Cryptocarya chinensis. AB - Bioassay-guided fractionation of the cytotoxic ethanol extract of Cryptocarya chinensis has led to the isolation of 11 compounds, including two phenanthroindolizidine alkaloids [(-)-antofine (1) and dehydroantofine (2)], five pavine alkaloids (3-7), and four proaporphine alkaloids (8-11). The structures of the isolated compounds were determined by means of NMR spectroscopic methods, and supported by HRMS and optical rotation data. Compounds 1 and 2 showed cytotoxic activity against four cancer cell lines, L1210, P388, A549, and HCT-8, with 1 being the most potent against A549 and HCT-8 with EC50 values of 0.002 and 0.001 microg/mL, respectively. In addition, 2 is first reported to exhibit significant anti-HIV activity. PMID- 22816293 TI - New indole alkaloid from Peschiera affinis (Apocynaceae). AB - A new indole alkaloid of the pyridocarbazole type, named 6N-hydroxy-olivacine, and two known compounds, 2N-oxide-olivacine and olivacine, were isolated from roots of Peschiera affinis. The structures of the compounds were determined by spectroscopic {IR and extensive NMR (COSY, HMQC, HMBCand NOESY)} and EIMS analysis. PMID- 22816294 TI - Indole alkaloids from Vinca major and V. minor growing in Turkey. AB - A new indole alkaloid, 11-hydroxypolyneuridine, was isolated from Vinca major subsp. major L. and the known indole alkaloids vallesiachotamine and isovallesiachotamine from Vinca minor L. This is the first report on the alkaloids of both Vinca species growing in Turkey; vallesiachotamine and isovallesiachotamine were isolated from a Vinca species for the first time. V. minor may be considered as a new source for these two alkaloids due to their occurrence in high amount in the aerial parts of the plant. The alkaloid extracts of the two Vinca species were found to have high lipid peroxidation inhibitory and DPPH radical scavenging activities. Anticholinesterase activity of the extracts was also very strong. PMID- 22816295 TI - Determination of the absolute configuration of 19-OH-(-)-eburnamonine using a combination of residual dipolar couplings, DFT chemical shift predictions, and chiroptics. AB - 19-OH-(-)-eburnamonine 1 is a new indole alkaloid isolated from Bonafusia macrocalyx. A natural derivative from (-)-eburnamonine for which absolute configuration and conformation has been determined by making use of residual dipolar couplings enhanced NMR, circular dichroism spectra and high-level computations. PMID- 22816296 TI - Unusual nitrogenous derivatives from Alstonia. AB - Five new nitrogenous compounds were isolated from the Malayan Alstonia angustifolia and their structures determined based on interpretation of spectroscopic data. PMID- 22816297 TI - Photoactivated [3+2] addition of 6,7-seco-angustilobine B to fullerene [C60]. AB - A synthesis of a new alkaloid-fullerene conjugate (1) is reported. The reaction was carried out by photoinduced [3+2] cycloaddition of the Alstonia indole alkaloid, 6,7-seco-angustilobine B (2), to fullerene[C60] (3) under aerobic conditions. The major monoaddition photoadduct (1) was characterized unambiguously by UV, IR, MALDI-TOFMS and NMR experiments. A mechanism highlighted by sequential photoinduced electron transfer andradical recombination pathways is also proposed. No significant enhancement in inhibition against M. tuberculosis H37Rv was observed for 1 compared with its parent compounds 2 and 3. PMID- 22816298 TI - Flavone C-glycosides from Anthurium andraeanum. AB - We describe here the isolation of three flavone 6-C-glycosides from the leaves of Anthurium andraeanum, The two new flavones were identified through detailed spectroscopic analysis as 4"'-(3,4-dimethoxycinnamoyl)-embinin (2) and 4"' ferruloyl-embinin (3). PMID- 22816299 TI - LC-PDA-ESI/MS identification of the phenolic components of three compositae spices: chamomile, tarragon, and Mexican arnica. AB - Chamomile (Matricaria chamomilla L.), tarragon (Artemisia dracunculus L.) and Mexican arnica (Heterotheca inuoides) are common compositae spices and herbs found in the US market. They contain flavonoids and hydroxycinnamates that are potentially beneficial to human health. A standardized LC-PDA-ESI/MS profiling method was used to identify 51 flavonoids and 17 hydroxycinnamates. Many of the identifications were confirmed with authentic standards or through references in the literature or the laboratory's database. More than half of the phenol compounds for each spice had not been previously reported. The phenolic profile can be used for plant authentication and to correlate with biological activities. PMID- 22816300 TI - Cinnamoylphenethyl amides from Polygonum hyrcanicum possess anti-trypanosomal activity. AB - A methanolic extract from aerial parts of Polygonum hyrcanicum (Polygonaceae) showed high activity against Trypanosoma brucei rhodesiense (IC50 = 3.7 microg/mL). Bioassay-guided fractionation of the extract resulted in isolation of cinnamoylphenethyl amides, including N-trans-caffeoyltyramine (1), N-trans-p coumaroyltyramine (7), and N-trans-feruloyltyramine (8) as the main active constituents (IC50s ranging from 2.2 to 13.3 microM). Some structurally related, but less active compounds, such as cannabisin B (2), tyrosol (3), p-coumaric acid (4), ferulic acid (5), and N-cis-feruloyltyramine (6) were also identified, along with N-trans-3,4-dimethoxycinnamoyldopamine (9). Cytotoxicity of the active compounds in L6 cells was determined, and selectivity indices (SI) of 7.9 to 33.4 were calculated. PMID- 22816301 TI - Comparative study of the in vitro bioactivities of Bupleurum rigidum and B. fruticescens. AB - Decoctions of the aerial parts of either Bupleurum rigidum or B. fruticescens are equally used in certain parts of Spain for the treatment of topical and musculoskeletal inflammations. In the present paper, their phytochemical profile and pharmacological value has been compared. After chromatographic and spectral analyses we could establish the presence of rutin and absence of chlorogenic acid in B. fruticescens, whilst the contrary applies to B. rigidum, providing a means to chemically differentiate extracts and dry materials from the two species. Their free radical scavenging and antiperoxidative activities were similar, with B. fruticescens being more active overall. The infusions of both Bupleurum species also showed similar anti-inflammatory activity when tested by NF-kappaB assay (40% and 42% at 60 microg x mL(-1)), as well as in a hexosaminidase exocytosis assay (30% at 50 microg x mL(-1)). Antimigratory effects on rat melanoma B16F10 showed significant activity for both infusions, with B. rigidum twice as potent as B. fruticescens, the activity of the latter not being fully explained by its content of rutin. Taking all these results together, we can conclude that, in the selected experimental models, there exist an in vitro bioequivalence of the infusions from both species, which is in agreement with the majority of ethnopharmacological reports. PMID- 22816303 TI - Saracoside: a new lignan glycoside from Saraca indica, a potential inhibitor of DNA topoisomerase IB. AB - Chemical investigation of the stem bark of Saraca indica has resulted in the isolation of a new lignan glycoside, saracoside, along with four known lignan glycosides lyoniside, icariside E3, (+)5'-methoxyisolarciresinol-9'-O-beta-D glucopyranoside and nudiposide, and a phenolic glucopyranoside, 3,4,5 trimethoxyphenyl-beta-D-glucopyranoside, which has been isolated for the first time from this species. The isolated lignan glycosides exhibit potent DNA topoisomerase IB inhibitory activity. PMID- 22816302 TI - Influence of nutrient medium composition on in vitro growth, polyphenolic content and antioxidant activity of Alchemilla mollis. AB - Alchemilla mollis (Buser) Rothm. (Rosaceae) is a high-mountain medicinal plant growing in the Balkan Peninsula, with only one population in Bulgaria. Alchemilla plants (Lady's mantle) are commonly used in traditional medicine for treatment of many gynecological diseases. The commercial drugs "Herba Alchemillae" induce a rapid regeneration of skin epithelium and have styptic and anti-inflammatory actions. Because of the high content of phenolic compounds (tannins and flavonoids) and the ecological plasticity of the species, field cultivation or in vitro biomass production of A. mollis are possible alternatives to its collection from nature. Four MS based nutrient media differing in the concentration of the minerals and supplemented with alpha-naphthaleneacetic acid (NAA) and benzylaminopurine (BAP) were tested in order to examine their influence on the shoot multiplication effectiveness and the antioxidant activity of A. mollis, and also the possible relation between these parameters under the conditions of in vitro culture. The cultures grown for two months on these media differed significantly in their multiplication rates (p < 0.001), as well as in their morphological features--height, leaf color and root development. Methanol extracts of in vitro cultivated and ex vitro adapted and acclimated on Vitosha Mt. (1500 m a. s. l.) plants were analyzed for tannin and flavonoid content and for free radical scavenging activity. The contents of flavonoids and tannins in the in vitro cultures of A. mollis cultivated on the four tested media differed significantly (p < 0.05). The highest flavonoid content was found in the shoots cultivated on the control MS medium, as well as in the ex vitro adapted plants. The antioxidant activity of the in vitro cultures correlated positively with the concentrations of the PGRs in the respective media, and the ex vitro adapted plants had the highest antioxidant activity (IC50 13.1 +/- 1.9 microg/mL) commensurable with that of the commercial antioxidant butylated hydroxytoluene (BHT) used as a positive control, with an IC50 of 12.65 microg/mL. PMID- 22816304 TI - Secondary metabolite production by the basidiomycete, Lentinus strigellus, under different culture conditions. AB - The basidiomycete Lentinus strigellus was cultivated in three different culture media and the secondary metabolites produced under different culture conditions were isolated and identified. When cultivated in a liquid medium with peptone, L. strigellus afforded the benzopyrans, 2,2-dimethyl-6-methoxychroman-4-one, 4 hydroxy-2,2-dimethyl-6-methoxychromane and (3R,4S)-3,4-dihydroxy-2,2-dimethyl-6 methoxychromane. The indole alkaloid echinuline and the anthraquinone fiscione, both unprecedented for the genus Lentinus, were isolated from the mycelium of the fungus. When cultured in Czapek medium enriched with potato broth, the fungus afforded the same benzopyrans except (3S,4S)-3,4-dihydroxy-2,2-dimethyl-6 methoxychromane. Panepoxydone and isopanepoxydone were also isolated when the microorganism was grown in Czapek medium. PMID- 22816305 TI - Phenylethanoid glycosides isolated from Paraboea paniculata. AB - Phytochemical studies of the leaves and rhizomes of Paraboea pa niculata (Gesneriaceae) are reported for the first time. Three phenylethanoid glycosides were isolated and characterized as 3,4-dihydroxyphenethyl-(3"-O-beta-D apiofuranosyl)-beta-D-glucopyranoside, calceoralarioside E, and acteoside. These isolates exhibited weak cytotoxic activity against the K-562 cell line with a 50% of cell killing rate of 40.18 microM, 27.05 microM, and 27.24 microM, respectively. In the DPPH free radical scavenging assay, their IC50 values were determined as 75.89 microM, 25.00 microM, and 26.04 microM, respectively. PMID- 22816306 TI - Villarinol, a new alkenoyloxyalkenol derivative from the endemic Philippine Rubiaceae species Villaria odorata. AB - Villarinol (1), a new alkenoyloxy alkenol metabolite, has been isolated from the dichloromethane extract of Villaria odorata, an endemic Rubiaceae Philippine plant, along with the known compounds stigmasterol and 4-hydroxybenzaldehyde. The structure of 1 was elucidated on the basis of spectroscopic and spectrometric studies. The extracts of V. odorata exhibited moderate inhibition against Mycobacterium tuberculosis H37Rv, based on the colorimetric microplate alamar blue assay. PMID- 22816307 TI - Isolation and characterization of new ceramides from aerial parts of Lepidaploa cotoneaster. AB - Two new ceramides were isolated from the bulbs of Lepidaploa cotoneaster (Willd. ex Spreng.) H. Rob. [Vernonia cotoneaster (Willd. ex Spreng.) Less.)], in addition to germanicol, beta-sitosterol, stigmasterol, 3-beta-O-beta-D glucopyranosyl-sitosterol, lupeol, lupeoyl acetate and tiliroside. The structures of the new compounds were elucidated by spectral techniques (MS, 1H NMR, 13C NMR, HSQC, HMBC, DEPT, and TOCSY) and were compared with data reported in literature, and were established as 2S*,2'R*,3S*,4R*,11E)-N-[2'-hydroxyhenicosanoyl]-2-amino nonadec-11-ene-1,3,4-triol (1) and (2S*,2'R*,3S*,4R*,8E)-N-[2' hydroxytricosanoyl]-2-amino-nonadec-8-ene-1,3,4-triol (2). To establish the structure and to locate the double bond, the methyl ester of the fatty acid and dimethyl disulfide (DMDS) derivatives were prepared for both ceramides. PMID- 22816308 TI - Cis-aconitic anhydride ethyl ester and phenolic compounds from the seeds of Alisma orientale. AB - From the seeds of Alisma orientale, cis-aconitic anhydride ethyl ester and cis 2,4,5-trihydroxycinnamic acid were isolated, together with nine known phenolic compounds and a megastigmane sesquiterpene. All compounds are reported for the first time from Alisma species. PMID- 22816310 TI - Structural characterization and biological effects of constituents of the seeds of Alpinia katsumadai (Alpina Katsumadai Seed). AB - Alpinia katsumadai Hayata (Zingiberaceae) has been used as an anti-emetic medicine and to treat gastric disorders in Oriental Medicine. Previous phytochemical investigations of this plant have resulted in the isolation of various diarylheptanoids, kavalactones, flavonoids, stilbenes, monoterpenes, and sesquiterpenes. Some of these compounds have antioxidant, anti-emetic, antiviral, and cytoprotective effects. This review paper discusses the structural characterization of the chemical constituents of A. katsumadai, as well as the biological activity of pure constituents of this plant material. PMID- 22816309 TI - Suppression of nitric oxide synthase by thienodolin in lipopolysaccharide stimulated RAW 264.7 murine macrophage cells. AB - The measurement of nitric oxide in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells is used as a model for evaluating the anti-inflammatory or chemopreventive potential of substances. Thienodolin, isolated from a Streptomyces sp. derived from Chilean marine sediment, inhibited nitric oxide production in LPS-stimulated RAW 264.7 cells (IC50 = 17.2 +/- 1.2 microM). At both the mRNA and protein levels, inducible nitric oxide synthase (iNOS) was suppressed in a dose-dependent manner. Mitogen-activated protein kinases (MAPKs), one major upstream signaling pathway involved in the transcription of iNOS, were not affected by treatment of thienodolin. However, the compound blocked the degradation of IkappaBa resulting in inhibition of NF-kappaB p65 nuclear translocation, and inhibited the phosphorylation of signal transducers and activators of transcription 1 (STAT1) at Tyr701. This study supports further exploration of thienodolin as a potential therapeutic agent with a unique mechanistic activity. PMID- 22816311 TI - Inventory, constituents and conservation of biologically important Sumatran plants. AB - An inventory of Sumatran medicinal plants, and reports on their chemistry and conservation carried out in the last three decades are reviewed. PMID- 22816312 TI - Herbal medicine in healthcare--an overview. AB - It is generally accepted by all concerned that modern pharmaceuticals will remain out of reach of many people and 'health for all' may only be realized by the use of adequately assessed herbal products. Mankind has been using herbal medicine for healing right from the beginning of human civilization. With the advent of 'modern medicine' herbal products have been looked down upon, especially by western societies. Yet, in recent times, use of herbal medicine for heathcare has increased steadily all over the world. However, serious concerns are being realized regarding the safety, claimed efficacy and quality of herbal products used as herbal medicine, nutraceuticals, health food and cosmetics. Although herbal products are generally considered safe due to their age-old usage, significant side effects have been reported for many herbal products, including herbal medicine. Accidental contamination and intentional adulteration are considered as primary reasons for the side effects. The historical perspective and the philosophy of herbal medical practice along with its present status in the light of present day science have been reviewed and included in the present article. Assurance of safety by identification of contaminants and assessment of toxicity has been outlined. Assessment of claimed efficacy of herbal medicine is difficult due to its holistic approach. Practical ways of assessing efficacy of herbal medicine by adapting the methodologies used for modern pharmaceutical are described. The maintenance of standard of herbal medicine has been stressed and pragmatic approaches of assuring quality of herbal medicine by using modern tools of fingerprinting the chemical profile of herbal medicine are discussed. As much of the traditional herbal medical knowledge is scattered around the world at the family and community levels, and more so in the indigeneous people, the knowledge base is continuously being lost and so needs immediate documentation. Difficulties in documentation due to concerns of Intellectual Property Rights (IPR) have been highlighted. PMID- 22816313 TI - Apathy, cognitive dysfunction and impaired social cognition in a patient with bilateral thalamic infarction. AB - We describe the case of a patient with bilateral thalamic lesions due to brain infarcts in the paramedian thalamic artery territories. The patient demonstrated symptoms of apathy (e.g., loss of initiative and interest in others, poor motivation, flattened affect). Neuropsychological assessment 3 and 5 years post infarct revealed severe deficits in verbal and non-verbal immediate and delayed memory, attention, and executive functioning, with minimal improvement over time. Also, he demonstrated difficulties in social cognition (i.e., perception of facial expressions of others and of sarcasm). These findings are discussed and interpreted in light of current theories regarding the neurobiological substrate of apathy. PMID- 22816314 TI - What's wrong with the debate on mesh surgery? AB - There is an increasingly acrimonious debate surrounding the use of anchored mesh in prolapse surgery. It is evident that clinicians and researchers working with this technology are under pressure from the public, from lawyers, regulators and colleagues. There is a risk that rapidly changing societal standards, championed by colleagues, lawyers and bureaucrats, will interfere with professional independence to such a degree that an entire new technology is lost before there has been time for clinical research to assess risks and benefits properly, before we learn which patients stand to benefit most, and before we get a chance to optimise implant design. PMID- 22816315 TI - Stem cell research and therapy in the Islamic republic of Iran: pioneering in the Islamic world. AB - In the early 2000s, the Iranian stem cell research and technology had a relatively strong start that benefited from religious blessings, political and public support, as well as scientific endeavors on the part of non-governmental and public research organizations and universities. Later on, it developed a dynamic niche market of public, private start-up, and spin-off companies and organizations that pioneered in the Islamic world in terms of ISI papers, clinical trials, and cell therapy. However, at present, it faces new challenges stemming from the insufficient finance and a comprehensive law and regulation structure to keep its momentum. To remedy this situation, the scientific community and other stakeholders need to have a series of shared long-time goals and try to build consensus on how to achieve them through nationally approved policy documents. PMID- 22816316 TI - Rare disasters and risk attitudes: international differences and implications for integrated assessment modeling. AB - Evaluation of public policies with uncertain economic outcomes should consider society's preferences regarding risk. However, the preference models used in most integrated assessment models, including those commonly used to inform climate policy, do not adequately characterize the risk attitudes revealed by typical investment decisions. Here, we adopt an empirical approach to risk preference description using international historical data on investment returns and the occurrence of rare economic disasters. We improve on earlier analyses by employing a hierarchical Bayesian inference procedure that allows for nation specific estimates of both disaster probabilities and preference parameters. This provides a stronger test of the underlying investment model than provided by previous calibrations and generates some compelling hypotheses for further study. Specifically, results suggest that society is substantially more averse to risk than typically assumed in integrated assessment models. In addition, there appear to be systematic differences in risk preferences among nations. These results are likely to have important implications for policy recommendations: higher aversion to risk increases the precautionary value of taking action to avoid low probability, high-impact outcomes. However, geographically variable attitudes toward risk indicate that this precautionary value could vary widely across nations, thereby potentially complicating the negotiation of transboundary agreements focused on risk reduction. PMID- 22816317 TI - Structural and theoretical basis for ligand exchange on thiolate monolayer protected gold nanoclusters. AB - Ligand exchange reactions are widely used for imparting new functionality on or integrating nanoparticles into devices. Thiolate-for-thiolate ligand exchange in monolayer protected gold nanoclusters has been used for over a decade; however, a firm structural basis of this reaction has been lacking. Herein, we present the first single-crystal X-ray structure of a partially exchanged Au(102)(p MBA)(40)(p-BBT)(4) (p-MBA = para-mercaptobenzoic acid, p-BBT = para-bromobenzene thiol) with p-BBT as the incoming ligand. The crystal structure shows that 2 of the 22 symmetry-unique p-MBA ligand sites are partially exchanged to p-BBT under the initial fast kinetics in a 5 min timescale exchange reaction. Each of these ligand-binding sites is bonded to a different solvent-exposed Au atom, suggesting an associative mechanism for the initial ligand exchange. Density functional theory calculations modeling both thiol and thiolate incoming ligands postulate a mechanistic pathway for thiol-based ligand exchange. The discrete modification of a small set of ligand binding sites suggests Au(102)(p-MBA)(44) as a powerful platform for surface chemical engineering. PMID- 22816318 TI - Ischemia-reperfusion increases transfection efficiency of intracoronary adenovirus type 5 in pig heart in situ. AB - Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia. Fluoroscopically guided angioplasty balloon catheters occluded the coronary artery in Yorkshire pigs and delivered adenoviral type 5 vector encoding the luciferase gene (Ad5Luc, 10(11) viral particles). TE (luciferase activity) was minimal and was not augmented by IC co-administration of 50 MUg/min sodium nitroprusside to nonischemic myocardium. Two (but not one) 3-min episodes of occlusion tended to increase luciferase activity (p=0.06), and luciferase activity was further increased by IC co-administration of nitroglycerin (p<0.001). After 75 min of coronary artery occlusion, luciferase activity was greater than with shorter periods of ischemia, and was significantly greater in the ischemia-reperfused zone compared to the border zone 3 and 14 days after infusion; there was no transfection in nonischemic myocardium. IC delivery of Ad5Luc into post-ischemic myocardium caused no local inflammation or hemodynamic instability. We conclude that the uptake of IC Ad5 to ischemic reperfused myocardium validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients following myocardial ischemia. PMID- 22816319 TI - Two-dimensional boron monolayer sheets. AB - Boron, a nearest-neighbor of carbon, is possibly the second element that can possess free-standing flat monolayer structures, evidenced by recent successful synthesis of single-walled and multiwalled boron nanotubes (MWBNTs). From an extensive structural search using the first-principles particle-swarm optimization (PSO) global algorithm, two boron monolayers (alpha(1)- and beta(1) sheet) are predicted to be the most stable alpha- and beta-types of boron sheets, respectively. Both boron sheets possess greater cohesive energies than the state of-the-art two-dimensional boron structures (by more than 60 meV/atom based on density functional theory calculation using PBE0 hybrid functional), that is, the alpha-sheet previously predicted by Tang and Ismail-Beigi and the g(1/8)- and g(2/15)-sheets (both belonging to the beta-type) recently reported by Yakobson and co-workers. Moreover, the PBE0 calculation predicts that the alpha-sheet is a semiconductor, while the alpha(1)-, beta(1)-, g(1/8)-, and g(2/15)-sheets are all metals. When two alpha(1) monolayers are stacked on top each other, the bilayer alpha(1)-sheet remains flat with an optimal interlayer distance of ~3.62 A, which is close to the measured interlayer distance (~3.2 A) in MWBNTs. PMID- 22816320 TI - Rapid climate change and the rate of adaptation: insight from experimental quantitative genetics. AB - Evolution proceeds unceasingly in all biological populations. It is clear that climate-driven evolution has molded plants in deep time and within extant populations. However, it is less certain whether adaptive evolution can proceed sufficiently rapidly to maintain the fitness and demographic stability of populations subjected to exceptionally rapid contemporary climate change. Here, we consider this question, drawing on current evidence on the rate of plant range shifts and the potential for an adaptive evolutionary response. We emphasize advances in understanding based on theoretical studies that model interacting evolutionary processes, and we provide an overview of quantitative genetic approaches that can parameterize these models to provide more meaningful predictions of the dynamic interplay between genetics, demography and evolution. We outline further research that can clarify both the adaptive potential of plant populations as climate continues to change and the role played by ongoing adaptation in their persistence. PMID- 22816367 TI - Compensation through increased functional connectivity: neural correlates of inhibition in old and young. AB - With increasing age, people experience more difficulties with suppressing irrelevant information, which may have a major impact on cognitive functioning. The extent of decline of inhibitory functions with age is highly variable between individuals. In this study, we used ERPs and phase locking analyses to investigate neural correlates of this variability in inhibition between individuals. Older and younger participants performed a selective attention task in which relevant and irrelevant information was presented simultaneously. The participants were split into high and low performers based on their level of inhibition inefficiency, that is, the slowing of RTs induced by information that participants were instructed to ignore. P1 peak amplitudes were larger in low performers than in high performers, indicating that low performers were less able to suppress the processing of irrelevant stimuli. Phase locking analyses were used as a measure of functional connectivity. Efficient inhibition in both age groups was related to the increased functional connectivity in the alpha band between frontal and occipito-parietal ROIs in the prestimulus interval. In addition, increased power in the alpha band in occipito-parietal ROIs was related to better inhibition both before and after stimulus onset. Phase locking in the upper beta band before and during stimulus presentation between frontal and occipito-parietal ROIs was related to a better performance in older participants only, suggesting that this is an active compensation mechanism employed to maintain adequate performance. In addition, increased top-down modulation and increased power in the alpha band appears to be a general mechanism facilitating inhibition in both age groups. PMID- 22816366 TI - Anti-Candida albicans action of the glyco-protein complex purified from metabolites of gut bacterium Raoultella ornithinolytica isolated from earthworms Dendrobaena veneta. AB - AIMS: The aim of our research was to isolate the compounds from the metabolites of Raoultella ornithinolytica with the activity against Candida albicans and to analyse the action of the compounds on the metabolic activity and morphology of the fungus cells. METHODS AND RESULTS: The effect of active protein fractions on the cell morphology, growth, and metabolic activity of C. albicans was analysed under a light microscope with Nomarski contrast and after staining with calcofluor-white. The LIVE/DEAD Yeast Viability Kit F-7030 FUN 1 was used for determination of C. albicans metabolic activity. The biomolecules obtained after isolation by ion exchange chromatography were further fractionated by Sephadex G 50 medium gel filtration. Then, after molecular sieve, the fractions were analysed by FTIR and SERS Spectroscopy. A subfraction was isolated from the antifungal protein fraction above 100 kDa. The active subfraction identified as the glyco-protein complex caused a decrease in the metabolic activity and morphological changes of C. albicans cells. CONCLUSIONS: The glyco-protein complex obtained from metabolites of bacteria Raoultella ornithinolytica possesses antifungal activity against C. albicans and shows minimal toxicity (1%) against fibroblasts. SIGNIFICANCE AND IMPACT OF THE STUDY: Studies on the glyco protein complex obtained from earthworm gut bacteria R. ornithinolytica can lead to their application in biological fungicide and pharmaceutical industry. PMID- 22816368 TI - Does this ring a bell? Music-cued retrieval of semantic knowledge and metamemory judgments. AB - Failed knowledge recall attempts are sometimes accompanied by a strong feeling of imminent success, giving rise to a "tip-of-the-tongue" (TOT) experience. Similar to successful retrieval (i.e., the Know state, K), a TOT commences with strong cue familiarity but involves only partial retrieval of related information. We sought to characterize the cognitive processes and temporal dynamics of these retrieval states and to extend the applicability of previous findings about TOT to the auditory modality. Participants heard 3-sec initial segments of popular songs and were asked to recall their names. EEG was recorded while participants indicated their retrieval state via button press. Stimulus-locked analyses revealed a significant early left fronto-central difference between TOT and K, at 300-550 msec postcue onset. Post hoc analysis revealed that, in this time window, TOT also differed from DK (Don't Know) responses, which themselves were similar to the K responses. This finding indicates that neural processes, which may reflect strategy selection, ease of semantic processing, familiarity-related processes, or conflict monitoring, are indicative of the fate of our knowledge judgments long before we actually execute them. PMID- 22816369 TI - Increased absorption of mangiferin in the gastrointestinal tract and its mechanism of action by absorption enhancers in rats. AB - The therapeutic efficiency of mangiferin is restricted by its low intestinal permeability. In order to improve the oral absorption of mangiferin, potential of enhancers, including TPGS, sodium deoxycholate and Carbopol 974P, were investigated in a series of in vivo experiments. After administration of mangiferin at a dose of 30 mg/kg combining with sodium deoxycholate, the bioavailability of mangiferin increased four-fold, and this may be due to sodium deoxycholate weakening the compactness between lecithin molecules and increased the paracellular permeability. When Carbopol 974P (100 mg/kg) was combined with mangiferin, the oral bioavailability of it increased seven-fold compared with the control group, and this may be related to the mucoadhesive properties of Carbopol 974P and paracellular drug permeation. However, following coadministration of TPGS (50 mg/kg), the oral absorption of mangiferin increased slightly compared with that of the control group (p > 0.05). The increased oral absorption by the three coexcipients was in the order of Carbopol 974P > sodium deoxycholate > TPGS. The absolute bioavailability of mangiferin in the three different doses following oral administration were evaluated based on the AUC(0-t) of the intravenous dose and there was no increase from low doses to high doses (25 mg/kg to 100 mg/kg). The above results show that the low absorption of mangiferin was due to presence of a narrow absorption window, which may also exist in these compounds, which have structures similar to mangiferin including three fused aromatic rings with polyphenolic hydroxyl groups. Bioadhesion polymers are effective enhancers of the absorption of mangiferin in the gastrointestinal tract. PMID- 22816370 TI - Consistency of the automatic algorithm in detecting complex fractionated electrograms using an electroanatomical navigation system. AB - BACKGROUND: The different settings of the automatic algorithm in the Carto system (Carto XP, Biosense Webster, Diamond Bar, CA, USA) used for detecting complex fractionated electrograms (CFEs) during atrial fibrillation (AF) may influence the identification of the fragmented electrograms. OBJECTIVES: We aimed to evaluate the impact of the different parameters on the detection of CFEs and the efficacy of the substrate modification after pulmonary vein isolation (PVI). METHODS: A total of 1,159 electrograms were analyzed from 11 consecutive patients (age = 56 +/- 12 years). The effect of the different algorithm factors, such as the high-voltage thresholds (0.12, 0.25, 0.5, 20 mV), detection algorithms (average complex interval [ACI] vs interval confidence level), and recording duration (2.5 seconds vs 5 seconds), on the disparities of the CFEs was investigated. RESULTS: The proportion of the different grades of CFEs depended on the detection algorithm and recording duration. The high-voltage threshold would not affect the consistency of the CFEs irrespective of the different settings of the detection algorithm or recording duration. High-grade CFEs were most consistent with an ACI algorithm and recording duration of 5 seconds (Cronbach's alpha = 0.952). Ablation consisting of a PVI and high-grade CFE sites converted AF directly to sinus rhythm in eight of 11 patients or into atrial tachycardia in one of 11. CONCLUSIONS: The distribution and consistency of the CFE detection depended on the detection algorithm and recording duration, but not on the high voltage threshold. Under the ACI algorithm and a recording duration of 5 seconds, high-grade CFE sites remained highest consistency. PMID- 22816371 TI - Effectiveness of aripiprazole in adolescents and young adults with schizophrenia spectrum disorders: comparison of first-episode to recurrent psychosis. AB - AIMS: The study aims to determine the clinical outcomes of aripiprazole treatment in adolescents and young adults with schizophrenia spectrum disorders. METHODS: This was a 24-week, observational, prospective study. Patients with schizophrenia spectrum disorders were prescribed a daily dose of 5 mg to 30 mg of aripiprazole. Effectiveness was assessed by the change from baseline in psychotic symptoms and quality of life. RESULTS: Forty-two patients with a mean age of 18.1 +/- 3.7 years were recruited. Eighteen were experiencing the first episode of psychosis (FEP), whereas the remaining 24 were non-FEP. Psychotic symptoms, but not quality of life, improved globally from baseline scores by the endpoint of the study (effect size = 0.44). Compared with non-FEP patients, FEP patients had greater improvements (effect size = 0.45) in some clinical outcome dimensions during the 24-week aripiprazole treatment. CONCLUSION: We observed significant improvements of medium effect sizes in psychotic symptoms of patients with schizophrenia spectrum disorders within a naturalistic clinical setting, especially for FEP patients. PMID- 22816372 TI - Use of a laboratory only score system to define trajectories and outcomes of older people admitted to the acute hospital as medical emergencies. AB - AIM: Increasing numbers of older people are admitted to hospital as medical emergencies. They are a heterogeneous population with uncertain trajectories and outcomes. Our aim was to retrospectively characterize subgroups of older inpatients based on their acuity trajectories. METHODS: This was a single-center patient series from St James's Hospital Dublin, Ireland (2002-2010). The Medical Admissions Risk System (MARS) score was used to classify a sample of 14,607 patients aged >= 65 years, from admission to end of episode, into four trajectory groups: (i) static high acuity (group 1); (ii) static low acuity (group 2); (iii) inpatient deterioration (group 3); and (iv) inpatient improvement (group 4). K means cluster analysis was used for the classification. RESULTS: Group 1 (4.1%): median length of stay (LOS) 7.4 days, 23.6% used intensive care, mortality rate 79.2%; sepsis and renal failure were the dominant features. Group 2 (76.6%): median LOS 8.0 days, 5.2% used intensive care, mortality rate 9.5%; younger age, low comorbidity and diseases of non-vital organs were predominant. Group 3 (7.6%): median LOS 17.2 days, 17.4% used intensive care, mortality rate 76.1%; high comorbidity and sepsis/respiratory disease featured. Group 4 (11.7%): median LOS 12.1 days, 12.8% used intensive care, mortality rate 22.7%; sepsis and renal/metabolic disease were frequent, and comorbidity levels were intermediate. CONCLUSIONS: In older acute medical inpatients, the outcome seemed more driven by specific diagnoses (such as sepsis and renal failure) and comorbidity, than by age. Using the MARS score to retrospectively categorize older inpatients might help to understand their heterogeneity and promote the design of appropriate care pathways. PMID- 22816373 TI - Missing the handoff: post-hospitalization follow-up care among rural Medicare beneficiaries with diabetes. AB - INTRODUCTION: Diabetes is a condition that requires adequate care to ensure ideal outcomes. One need is for proper post-discharge follow-up care to reduce unnecessary hospital re-admissions. This care is more difficult in US rural areas due to lower physician and resource availability. The purpose of this analysis was to examine US urban-rural differences in 30 day post-discharge physician follow-up care. METHODS: This analysis utilized data from 2005 Medicare claims files, merged with county-level information from the area resource file. Beneficiaries with diabetes and with a hospitalization served as the study population. Differences in hospitalization rates and 30 day physician follow-up care were estimated across levels of rurality. Multi-level multivariate models estimated the factors that significantly contributed to obtaining such care. RESULTS: Approximately 90% of the study population had a follow-up physician visit within 30 days; this rate was lower among rural beneficiaries. Adjusted estimates indicated that beneficiaries in rural areas were not less likely to obtain a follow-up visit. Factors associated with obtaining a follow up included having addition comorbidities, being female or White, and living in the US Northeast. CONCLUSIONS: This analysis found evidence that rural Medicare beneficiaries were less likely to obtain post-discharge physician follow-up visits within 30 days. The adjusted result indicate that other factors such as personal demographic and illness characteristics are more predictive of this behavior than the rural location itself. More research is needed to identify why these specific factors are associated with visit behavior, and how to design interventions to improve these rates. PMID- 22816374 TI - Seizure outcome after extratemporal epilepsy surgery in childhood. AB - AIM: The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures. METHOD: In this retrospective cohort study, children with drug-resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008. RESULTS: Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo-18y 7mo). The aetiology was identified as focal cortical dysplasia (n=37), low-grade tumour (n=22), tuberous sclerosis (n=9), or non-specific (n=12). Children were followed for a median of 3 years 1 month (range 8mo-10y 7mo) after surgery. Overall, at last follow-up, 50% of the children had been completely seizure free since surgery (Engel class Ia); of these 40 individuals, 15 had discontinued all antiepileptic drugs. Several presurgical factors were associated with a favourable outcome. However, after controlling for confounding factors, aetiology appeared to be the only determinant of long-term seizure outcome as non-specific lesion pathology was associated with seizure recurrence (hazard ratio 10.43; 95% confidence interval 3.26-33.39). INTERPRETATION: In 50% of cases, children with surgically treated drug-resistant extratemporal epilepsies have an excellent long-term outcome. The aetiology of the epileptogenic lesion appears to be the only significant determinant of surgical outcome in this population of children. It is difficult to correctly identify non-specific pathology on presurgical magnetic resonance imaging. PMID- 22816375 TI - Serum carcinoembryonic antigen correlates with severity of idiopathic pulmonary fibrosis. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is the commonest idiopathic interstitial pneumonia and carries a poor prognosis. Epidemiological evidence suggests that patients with IPF have an increased risk of developing lung cancer. Carcinoembryonic antigen (CEA) has a close association with epithelial malignancy. The aim of this study was to evaluate serum CEA concentrations in patients with IPF and to perform correlation with pulmonary function. METHODS: Serum CEA concentrations were measured by two-site sequential chemiluminescent immunometric assay in 41 non-smoking patients with IPF. Patients with a history of gastrointestinal tract malignancy or other disorder known to be associated with raised serum CEA were excluded. RESULTS: A total of 41 patients were evaluated. The mean (+/-standard deviation) age of patients was 73 +/- 7 years. The mean (+/-standard deviation) forced vital capacity was 88 +/- 20% of predicted, and the mean (+/-standard deviation) diffusing factor for carbon monoxide (DLco) was 52 +/- 19% of predicted. Twenty-one (51%) patients had a serum CEA concentration higher than upper limit of the normal range (0-5 ng/mL). CEA concentration was significantly negatively correlated with lung function (P = 0.005; R(2) = 0.20 for forced vital capacity and P = 0.006; R(2) = 0.20 for DLco). Raised CEA level also correlated significantly with the extent of fibrosis. A lung biopsy specimen from a patient with IPF demonstrated strong staining for CEA in metaplastic epithelium lining the honeycombed cysts and respiratory bronchioles. CONCLUSIONS: Serum CEA concentration is elevated in approximately half of patients with IPF and is correlated with disease severity. Immunohistochemical staining reveals that CEA localizes to metaplastic epithelium lining honeycombed bronchioles. PMID- 22816376 TI - HIV testing in U.S. emergency departments: at the crossroads. PMID- 22816377 TI - Partial agonist of benzodiazepine receptors Ro 19-8022 elicits withdrawal symptoms after short-term administration in immature rats. AB - Repeated administration of partial agonist of benzodiazepine receptors Ro 19-8022 (a derivative of quinolizine class) does not elicit withdrawal in adult rats. Our older data demonstrated that single injection of Ro 19-2088 to immature rats induces increased sensitivity to convulsant action of pentylenetetrazol as a withdrawal phenomenon. To know if repeated administration of the partial agonist has the same effect we injected rats at postnatal days 7 to 11 with an anticonvulsant dose of Ro 19-8022 (0.5 mg/kg i.p.) and tested them 24 h, 48 h and 4 days after the last injection. Repeated administration of Ro 19-8022 resulted also in an increased sensitivity to convulsant action of pentylenetetrazol in immature rats (higher incidence and severity of seizures). This effect was significant 24 h after the last injection but only outlined 48 h after administration. No signs of hypersensitivity were seen at 4-day interval. There is a difference between immature and adult brain in an appearance of withdrawal symptom after administration of the partial agonist of benzodiazepine receptors Ro 19-8022. PMID- 22816378 TI - Quantification of AAV particle titers by infrared fluorescence scanning of coomassie-stained sodium dodecyl sulfate-polyacrylamide gels. AB - Adeno-associated virus (AAV)-based vectors have gained increasing attention as gene delivery vehicles in basic and preclinical studies as well as in human gene therapy trials. Especially for the latter two-for both safety and therapeutic efficacy reasons-a detailed characterization of all relevant parameters of the vector preparation is essential. Two important parameters that are routinely used to analyze recombinant AAV vectors are (1) the titer of viral particles containing a (recombinant) viral genome and (2) the purity of the vector preparation, most commonly assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by silver staining. An important, third parameter, the titer of total viral particles, that is, the combined titer of both genome-containing and empty viral capsids, is rarely determined. Here, we describe a simple and inexpensive method that allows the simultaneous assessment of both vector purity and the determination of the total viral particle titer. This method, which was validated by comparison with established methods to determine viral particle titers, is based on the fact that Coomassie Brilliant Blue, when bound to proteins, fluoresces in the infrared spectrum. Viral samples are separated by SDS-PAGE followed by Coomassie Brilliant Blue staining and gel analysis with an infrared laser-scanning device. In combination with a protein standard, our method allows the rapid and accurate determination of viral particle titers simultaneously with the assessment of vector purity. PMID- 22816380 TI - Odontogenic infections: an 8-year epidemiologic analysis in a dental emergency outpatient care unit. AB - OBJECTIVES: The purpose of this investigation was to analyze epidemiological patterns, clinical features and the management of odontogenic infections in patients undergoing treatment in a dental emergency outpatient care unit. STUDY DESIGN: A retrospective analysis of 58 161 case records of patients presenting to an emergency outpatient unit in Hamburg, Germany between 2000-2007 was performed. From this pool, patients with odontogenic infections were identified using an ICD 10 code, analyzing age, gender, medical co-morbidities, duration of pain, ratio of infiltrates/abscesses, affected teeth, management of infection and administered antibiotics. RESULTS: Of the 58 161 patients, 5357 (9.2%) were identified as having odontogenic infections, with 2689 (50.2%) inflammatory infiltrates and 2668 (49.8%) abscesses. Mean age was 34.8 +/- 16.8 years. As the primary site of odontogenic infection, the most significantly affected teeth were the maxillary and mandibular first molars. Patients in age-group 20-29 years (25.1%) utilized the emergency care unit more frequently than other age groups. Clindamycin was the most frequently administered antibiotic. CONCLUSIONS: Early recognition, diagnosis and management of odontogenic infections are requisite for avoiding or minimizing the development of potential complications. Strategies and evidence-based protocols should be developed within the dental ambulatory care sector, advancing interdisciplinary cooperation between general dentists and oral or maxillofacial surgeons. PMID- 22816379 TI - Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-beta-associated neuropathology in Alzheimer mice. AB - Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of beta amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-beta (Abeta) levels/beta-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1*10(6) cells/MUL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Abeta levels/beta-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level. PMID- 22816381 TI - The activities and participation categories of the ICF Core Sets for multiple sclerosis from the patient perspective. AB - PURPOSE: To validate the activities and participation components of The International Classification of Functioning, Disability and Health (ICF). METHODS: In this cross-sectional study, 113 Finnish community-dwelling persons with MS were assessed using a semi-structured interview provided by the Canadian Occupational Performance Measure (COPM) to capture participants' self-perceived problems in everyday activities and participation. Problems were linked to the ICF categories. RESULTS: Participants identified 527 of the most important occupational performance problems. They covered all chapters of the ICF Activities and Participation components. Forty-one categories out of a total 53 ICF activities and participation categories of the Comprehensive ICF Core Set and four out of five categories of the Brief ICF Core Set were reported on by the participants. The most common category in this sample, 'd920 Recreation and leisure' (145 problems/27.5%), is not included in the Brief ICF Core Set. CONCLUSIONS: Most, but not all, ICF activities and participation categories of the ICF Core Sets for MS could be confirmed from the perspective of persons with MS. It is worth considering to add category 'd920 Recreation and leisure' to the Brief ICF Core Set. PMID- 22816382 TI - Education and employment characteristics of nurse preceptors. AB - BACKGROUND: Nurse preceptors are vital linchpins, supporting the transition of new graduates to practicing registered nurses (RNs). This research clarifies similarities and differences among preceptors and nonpreceptors in an established statewide preceptor program. METHODS: A secondary analysis of relicensure data from all nurses working in Vermont hospitals in two years (2005 and 2009) was undertaken. RESULTS: There were no statistical differences by basic degree type, highest degree, RN experience, years in the current job, job satisfaction, and intention to leave. Statistically significant differences that persisted over time included: (1) being less likely to be employed per diem; (2) work site population density; and (3) being more likely to be enrolled in nursing education programs. CONCLUSION: Given the lack of obvious identifiers, organizations would benefit from a systemized approach to preceptor identification and development. Regulators, who hold the clear social and legal mandate for patient safety, must also be an enabling force toward change. PMID- 22816383 TI - Barriers to advanced practice registered nurse scope of practice: issue analysis. AB - Advanced practice registered nurses (APRNs) have the unique potential to affect the changing needs of health care in the United States, but are restricted in care provision by varying state regulations and reimbursement policies. Although research shows APRN care to be safe, cost-effective, and of high quality, most medical professional organizations continue to oppose the removal of scope-of practice barriers, citing patient safety concerns. Nursing organizations at the state and national levels have already begun to invest the time and resources needed for policy change. However, empirical evidence of APRN quality of care must be shared with policymakers, funding entities, and the public. Additionally, support must be garnered from the public and other health care disciplines. Scope of-practice policy change will occur through the emergence of strong individuals within nursing professional organizations and the joining together of organizations to form one voice. PMID- 22816384 TI - Staff practice, attitudes, and knowledge/skills regarding evidence-based practice before and after an educational intervention. AB - BACKGROUND: Today's clinicians have different levels of knowledge and skill related to evidence-based practice, depending on their educational background, level of experience, and interest. This multidisciplinary study assessed nurses' baseline and posteducation practice, attitudes, and knowledge/skills regarding evidence-based practice. METHODS: A descriptive pre- and postsurvey design study evaluated clinical staff's practice, attitudes, and knowledge/skills regarding evidence-based practice with the Clinical Effectiveness and Evidence-Based Practice Questionnaire. RESULTS: A total of 327 participants (24%) completed the presurvey and 282 (20%) completed the postsurvey. No statistically significant changes were found in practice, attitudes, and knowledge/skills after the online education. In the multivariate analysis, online education was not a significant predictor of practice, attitudes, or knowledge/skills regarding evidence-based practice; graduate educational degree, formal evidence-based practice classes, and registered nurse status were statistically significant positive predictors. CONCLUSION: Administering self-learning online modules may not be the most effective method for expanding evidence-based practice abilities and knowledge/skills of nurses. PMID- 22816385 TI - Effect of biofield therapy in the human brain. AB - OBJECTIVES: The effects of Okada Purifying Therapy (OPT), a form of subtle energy (biofield) therapy that originated in Japan, were investigated. Electroencephalograms and the Profile of Mood States scores were measured using a crossover design during OPT and placebo sessions. PARTICIPANTS: Nineteen (19) healthy Japanese adults (mean age+/-standard deviation: 40.8+/-11.2 years; 10 females) with no previous experience of biofield therapy participated in this study. METHODS: Each session lasted 15 minutes. A single-blind, randomized design with a protocol consisting of regular cycles with eyes open followed by eyes closed was used. The power spectral value was calculated in theta (4.0-7.9 Hz), alpha (8.0-12.9 Hz), and beta (13.0-29.9 Hz) frequency ranges. RESULTS: The power spectral value of the alpha band at F(p1), F(p2), F(7), F(z), F(8), C(3), C(z), C(4), and P(z) increased significantly in the OPT session compared with the placebo session. Mood state was improved after both sessions, and no significant difference was found between the two sessions. CONCLUSIONS: OPT was more effective in increasing alpha waves in the frontal and central cortex than a placebo treatment. PMID- 22816386 TI - A facile solution-phase approach to transparent and conducting ITO nanocrystal assemblies. AB - Monodisperse 11 nm indium tin oxide (ITO) nanocrystals (NCs) were synthesized by thermal decomposition of indium acetylacetonate, In(acac)(3), and tin bis(acetylacetonate)dichloride, Sn(acac)(2)Cl(2), at 270 degrees C in 1 octadecene with oleylamine and oleic acid as surfactants. Dispersed in hexane, these ITO NCs were spin-cast on centimeter-wide glass substrates, forming uniform ITO NC assemblies with root-mean-square roughness of 2.9 nm. The assembly thickness was controlled by ITO NC concentrations in hexane and rotation speeds of the spin coater. Via controlled thermal annealing at 300 degrees C for 6 h under Ar and 5% H(2), the ITO NC assemblies became conductive and transparent with the 146 nm-thick assembly showing 5.2 * 10(-3) Omega.cm (R(s) = 356 Omega/sq) resistivity and 93% transparency in the visible spectral range--the best values ever reported for ITO NC assemblies prepared from solution phase processes. The stable hexane dispersion of ITO NCs was also readily spin-cast on polyimide (T(g) ~360 degrees C), and the resultant ITO assembly exhibited a comparable conductivity and transparency to the assembly on a glass substrate. The reported synthesis and assembly provide a promising solution to the fabrication of transparent and conducting ITO NCs on flexible substrates for optoelectronic applications. PMID- 22816387 TI - Ir-catalyzed direct borylation at the 4-position of pyrene. AB - The first direct borylation of a C-H bond at the 4-position of pyrene was achieved using [Ir(COD)Cl](2)/dtbpy as the catalyst precursor and B(2)pin(2) as the boron source. The position-related photophysical properties of pyrene derivatives are reported. PMID- 22816388 TI - Impaired neutralizing activity by transplacental measles antibodies in infants born to HIV-1-infected mothers. AB - AIM: Growing numbers of newborns are saved from HIV infection through increased access to mother-to-child transmission prevention programmes. The maternally derived humoral immunity of these children might be impaired, both in terms of quantity and in terms of quality, with consequences for the timing of immunization against measles. METHODS: A cell-ELISA technique compared the neutralizing activity on Edmonston strain measles virus of sera from 1- to 4 month-old infants. Ten serum specimens came from noninfected infants of HIV infected mothers and another 10 from infants of healthy mothers. The sera were matched for the level of conventional ELISA measles antibodies. RESULTS: Reflecting infection of the Vero cells by non-neutralized virus, optical density values were significantly higher for the sera from the children of the HIV infected mothers than for those of the noninfected mothers (p < 0.001). CONCLUSION: Maternally derived protection against measles may be impaired by the mother's HIV infection, relating to the quality rather than to the quantity of transplacental antibodies. Selective, early immunization with live attenuated measles vaccine should be evaluated in noninfected children of HIV-1-infected mothers. PMID- 22816389 TI - Living with polio and postpolio syndrome in the United Kingdom. AB - The term Postpolio Syndrome (PPS) is used to describe new and late manifestations of poliomyelitis that occur later in life in polio survivors. Polio had been eradicated in the United Kingdom (UK) and most of Europe, although this is not the case in all countries. Research in this area has tended to focus upon the impact of polio and PPS on health status and functional health rather than its overall effect on people's lives. This study's two main aims were to explore the ways in which polio and PPS in the UK has affected the respondents' lives and to ascertain their views about how the quality of life could be improved. The two questions were as follows: (1) How has the health of people with polio and PPS affected their quality of life? (2) What would people with polio and PPS change to improve their quality of life? Deductive content analysis using existing qualitative data from a cross-sectional survey of 336 returned questionnaires from persons with polio and PPS was carried out. The average age of the participants was 54 years. Our research found that polio survivors valued social occupations and participation in family life. Our research has also shown that healthcare professionals still do not understand polio and PPS and this lack of understanding influences their clients' quality of life. Finances and accessibility of environments also influence participation in chosen occupations. Rehabilitation programmes for people with polio and PPS need to be targeted towards maintaining and improving accessible environments and participation in chosen occupations, and healthcare professionals need to ensure that persons with polio and PPS are referred to persons with specific expertise in this area. PMID- 22816425 TI - In vitro photodynamic therapy against Foncecaea pedrosoi and Cladophialophora carrionii. AB - Photodynamic therapy (PDT) has been originally developed for cancer treatment, but recently, it has been successfully employed against microorganisms, including fungi. Chromoblastomycosis is a subcutaneous fungal infection that is recalcitrant to conventional antifungal drug therapy. The most frequent species involved are Foncecaea pedrosoi and Cladophialophora carrionii. The present study aimed to verify the efficacy in vitro of PDT employing methylene blue (MB) as a photosensitiser and Light emmiting diode (LED) (InGaAl) as the light source. Methylene blue at the concentrations of 16, 32 and 64 MUg/mL and LED (InGalP) were employed for 15 min against spores of two isolates of F. pedrosoi and two isolates of C. carrionii. The spores were plated on Sabouraud Dextrose agar and the number of colony forming units was counted after 7-10 days of incubation at 37 degrees C. The PDT with MB and LED was efficient in reducing the growth of all samples tested. Better results were obtained for the concentration of 32 MUg/mL of MB. The treatment proved to be highly effective in killing the samples of F. pedrosoi and Cladophialophora pedrosoi tested in vitro. PDT arises as a promising alternative for the treatment of this subcutaneous infection. PMID- 22816426 TI - Community residential segregation and the local supply of federally qualified health centers. AB - OBJECTIVE: To examine associations between community residential segregation by income and race/ethnicity, and the supply of federally qualified health centers (FQHCs) in urban areas. DATA SOURCES AND STUDY SETTING: Area Resource File (2000 2007) linked with 2000 U.S. Census on U.S. metropolitan counties (N = 1,786). STUDY DESIGN: We used logistic and negative binomial regression models with state level fixed effects to examine how county-level characteristics in 2000 are associated with the presence of FQHCs in 2000, and with the increase in FQHCs from 2000 to 2007. Income and racial/ethnic residential segregation were measured by poverty and the non-white dissimilarity indices, respectively. Covariates included measures of federal criteria for medically underserved areas/populations. PRINCIPAL FINDINGS: Counties with a high non-white dissimilarity index and a high percentage of minorities were more likely to have an FQHC in 2000. When we examined the addition of new FQHCs from 2000 to 2007, the effects of both poverty and non-white dissimilarity indices were positive and significant. CONCLUSIONS: Residential segregation likely produces geographic segregation of health services, such that provider maldistribution may explain the association between residential segregation and FQHC supply. Metropolitan areas that fail to achieve greater integration of poor and minority communities may require FQHCs to compensate for provider shortages. PMID- 22816427 TI - High prevalence of sarcopenia and reduced leg muscle mass in Japanese patients immediately after a hip fracture. AB - AIM: Sarcopenia-related falls and fractures are becoming an emerging problem as a result of rapid aging worldwide. We aimed to investigate the prevalence of sarcopenia by estimating the muscle mass of the arms and legs of patients with and without hip fracture. METHODS: This cross-sectional study examined 357 patients immediately after a hip fracture (the HF group) and in 2511 patients from an outpatient clinic who did not have a hip fracture (the NF group) at single institution in Japan. We carried out whole-body dual energy X-ray absorptiometry to analyze body composition with skeletal muscle mass index (SMI; lean mass/height(2)) and bone mineral density (BMD). We carried out stepwise logistic regression analysis to determine the factors associated with a hip fracture. RESULTS: Lower appendicular SMI (P < 0.001), leg SMI (P < 0.001), and higher prevalence of sarcopenia (P < 0.001) were observed in the HF group after controlling for age and sex. The arm SMI was similar in both groups (P > 0.95). In multivariate analysis, the presence of sarcopenia, older age and lower BMD were associated with the occurrence of a hip fracture (OR 1.476, P = 0.002; OR 1.103, P < 0.001; OR 0.082, P < 0.001; respectively). CONCLUSION: This study showed a higher prevalence of sarcopenia and more reduced leg muscle mass in patients after a hip fracture than in the outclinic patients who did not have hip fractures. The results imply sarcopenia can be a risk factor for a hip fracture. PMID- 22816428 TI - Functional atrial undersensing associated with switching to a tracking mode of pacing. AB - We have previously demonstrated that contemporary St. Jude devices (pacemakers and implantable cardioverter-defibrillators [ICDs]; St. Jude Medical, Sylmar, CA, USA) are designed to generate an extended postventricular atrial refractory period (PVARP) of 475 ms at the termination of conventional automatic mode switching (AMS) in response to atrial tachyarrhythmias . This response may cause functional atrial undersensing . A similar PVARP response unrelated to conventional AMS was found in four St. Jude devices (three ICDs and one pacemaker) whenever a nontracking pacing mode switched to a tracking DDD(R) mode. PVARP extension and functional atrial undersensing were observed when the VOO, VVI, and the DDI(R) modes (unrelated to conventional AMS) switched to the DDD(R) mode . In one patient the switch from the OOO mode (in the programmed noise reversion mode) to the DDD mode occurred after cessation of electromagnetic interference disturbing the ventricular channel. In this case PVARP extension was seen only in the corresponding markers because no P waves occurred coincidentally with the extended PVARP. The PVARP extension caused by a mode switch to the tracking function was designed to prevent sensing of a retrograde P wave on the first cycle of the reestablished tracking mode. The observed functional atrial undersensing is a normal manifestation of device function and must not be misinterpreted as a true atrial undersensing problem. PMID- 22816429 TI - Cadmium toxicity is alleviated by AtLCD and AtDCD in Escherichia coli. AB - AIMS: Arabidopsis thaliana l- and d-cysteine desulfhydrases (AtLCD and AtDCD) are two important H(2) S-generating enzymes. This study determined the effects of H(2) S derived from AtLCD and AtDCD on cadmium (Cd) toxicity in Escherichia coli. METHODS AND RESULTS: AtLCD and AtDCD were cloned into pET28a vectors and transformed into wild-type E. coli strain BL21(DE3), named BL21(LCD) and BL21(DCD). In the induced BL21(LCD) and BL21(DCD) compared with wild type, significantly higher H(2) S generation rates were observed. Additionally, higher survival rates, reduced contents of malondialdehyde (MDA) and hydrogen peroxide (H(2) O(2)), decreased activities of superoxide dismutase and catalase under 220 MUmol l(-1) Cd stress were noted. We obtained similar results in the wild type treated with NaHS, a H(2) S donor. The above changes were substantially counteracted by the mixture of ammonia and pyruvic acid potassium (NH(3) + C(3) H(3) KO(3)), a synthetic inhibitor of H(2) S. CONCLUSIONS: AtLCD and AtDCD catalyse the H(2) S production, generating an ameliorating effect against Cd induced oxidative stress and resulting in E. coli resistance to Cd toxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: H(2) S as a gasotransmitter is certified to have an ameliorating effect against Cd toxicity, thus providing information for further research regarding the role of H(2) S in regulating resistance to the heavy metal stress in organisms. PMID- 22816430 TI - Chimeric anti-podoplanin antibody suppresses tumor metastasis through neutralization and antibody-dependent cellular cytotoxicity. AB - Podoplanin is a platelet aggregation-inducing factor associated with tumor metastasis, malignant progression, and cancer stem cells. We produced a rat-human chimeric anti-podoplanin mAb, NZ-8, from rat anti-podoplanin mAb (NZ-1). Although both NZ-1 and NZ-8 possess high binding affinities and high neutralizing activities of platelet aggregation, the antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity of NZ-8 were much higher than NZ-1. Furthermore, both NZ-1 and NZ-8 inhibited the growth of podoplanin-expressing tumors in vivo. Both NZ-1 and NZ-8 also suppressed hematogenous metastasis of podoplanin-expressing tumors. These results suggest that anti-podoplanin mAbs suppressed hematogenous metastasis by both neutralization and antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity activities. Targeting therapy to podoplanin-expressing tumors should be useful as a novel immunotherapy. PMID- 22816431 TI - Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases. AB - BACKGROUND: Congenital erythropoietic porphyria (CEP) is an autosomal recessive cutaneous porphyria caused by decreased activity of uroporphyrinogen III synthase (UROS). Its predominant characteristics include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. Due to its rarity and genetic heterogeneity, clinical phenotypes are unclear and its impact on health-related quality of life (HRQoL) has not been previously assessed. OBJECTIVES: To define comprehensively CEP phenotypes and assess their impact on HRQoL, and to correlate these factors with laboratory parameters. METHODS: A single observer assessed patients with CEP from four European countries. RESULTS: Twenty-seven unrelated patients with CEP, aged between 7.6 and 65 years, participated in the study. The patients came from the U.K. (17), France (4), Switzerland (4) and Germany (2). Additional data were obtained for two deceased patients. Newly characterized features of CEP include acute-onset cutaneous and noncutaneous symptoms immediately following sunlight exposure, and pink erythematous facial papules. There was a lack of consistent genotype-phenotype correlation in CEP. The main poor prognostic factors in CEP are the early age of disease onset and haematological complications. CONCLUSIONS: CEP is a multisystem disease; cutaneous, ocular, oral and skeletal manifestations also contribute to disease severity and impact on HRQoL, in addition to the haematological complications. The rarity of the disease can lead to delayed diagnosis. The lack of consistent genotype-phenotype correlation in CEP suggests a contribution to phenotype from other factors, such as environment, patients' photoprotective behaviour and genes other than UROS. There is currently an unmet need for multidisciplinary management of patients with CEP. PMID- 22816432 TI - Examining the effects of mass media campaign exposure and interpersonal discussions on youth's drug use: the mediating role of visiting pro-drug websites. AB - To extend past research on interpersonal communication and campaign effects, we hypothesized that anti-drug mass media campaign message exposure indirectly affects visiting anti- and pro-drug websites through targeted parent-child and friend-to-friend communication against drugs, as well as through having drug related discussions during organized group activities. Second, we posited that engaging in anti-drug interpersonal communication indirectly affects adolescents' drug use through two intervening variables: visiting anti-drug websites and visiting pro-drug websites. Using self-reported longitudinal data from 2,749 youth, we found that as youth reported higher levels of anti-drug mass media campaign message exposure, they were more likely to talk to friends about the bad consequences of drugs, how to avoid drugs, and anti-drug ads. In turn, however, they were more likely to visit pro-drug websites, and subsequently, to smoke cigarettes. PMID- 22816433 TI - Factors affecting early psychiatric intervention for patients with first-episode psychosis in Japan. AB - AIM: The present study aimed to clarify the factors affecting early psychiatric intervention for patients with first-episode psychosis in Japan. METHODS: A postal questionnaire survey was conducted in 346 members of the Association of Family of Psychosis Patients, in Mie, Japan. RESULTS: The questionnaire was completed by 138 respondents. The mean interval between a suspected first episode of psychosis and the first visit to a medical institution was 18.4 months (SD: 40.0, range: 0-336 months). Forty-five respondents consulted a family member first and required a mean duration of 9.8 months (SD: 11.2) before their first visit; this was significantly shorter than those who did not. Eighteen respondents consulted their class teacher at school first and required a mean duration of 40.2 months (SD: 63.0) before their first visit; this was significantly longer (P < 0.05) than those who did not. When loss of sleep or appetite was present, the mean duration before their first visit was 9.3 months (SD: 12.1), which was significantly shorter (P < 0.05) than the time required by those who did not. Logistic regression analysis using the first episode-first visit interval as an independent variable, and independent variables such as age, gender of the patient and family member, and loss of sleep, revealed that variables relating to the respondent's notion about the psychosis were mitigating factors (e.g. 'prejudice-causing' and 'nothing to do with me'). CONCLUSION: Prejudice towards psychosis and poor awareness about mental illnesses are two factors that may affect early psychiatric intervention. PMID- 22816434 TI - Sensibility assessment of the HIV Disability Questionnaire. AB - PURPOSE: Our purpose was to assess the sensibility of the human immunodeficiency virus (HIV) Disability Questionnaire (HDQ), the first HIV-specific disability questionnaire. METHODS: We administered the HDQ, a sensibility questionnaire and a structured qualitative interview to 22 adults living with HIV and five experienced clinicians. We considered the HDQ sensible if median scores on the sensibility questionnaire were >=5 for adults living with HIV and >=4 for clinicians for at least 80% of the items. We analyzed the interview data using directed qualitative content analytical techniques. RESULTS: Questionnaire scores were >=5 for 88% (15/17) of the items and >=4 for 100% (17/17) of the items for adults living with HIV and clinicians, respectively. The interview analysis indicated participants felt the HDQ possessed face and content validity in all disability dimensions, had adequate response options, was easy to complete, and adequately captured the episodic nature of disability. Participants had mixed responses about the questionnaire title and provided recommendations to refine item wording and response options. CONCLUSIONS: The HDQ appears sensible for use with adults living with HIV. Next steps include further measurement property assessment. The HDQ may be used by rehabilitation clinicians and researchers to assess disability experienced by adults living with HIV. IMPLICATIONS FOR REHABILITATION: * As people with HIV infection live longer, individuals may face a range of health-related challenges due to the disease, concurrent health conditions and the potential adverse effects of treatment. Together, these health related challenges may be termed disability. * The HIV Disability Questionnaire (HDQ) is the first HIV-specific instrument developed to describe the presence, severity and episodic nature of the disability experienced by adults living with HIV. The HDQ is comprised of four domains including symptoms and impairments, uncertainty about future health, difficulties carrying out day-to-day activities, and challenges to social inclusion. * The HDQ appears sensible for use with adults living with HIV, possessing face and content validity and ease of use in all four domains as well as describing the daily episodic nature of disability. * The HDQ may be used by rehabilitation clinicians and researchers to assess disability experienced by adults living with HIV. PMID- 22816435 TI - The impact of protein glycosylation on Flo11-dependent adherence in Saccharomyces cerevisiae. AB - Fungal cell adhesion molecules are critical for the attachment of cells to each other and to surfaces and in pathogens contribute to virulence. Fungal adhesins are typically heavily glycosylated. The impact of protein glycosylation on the function and regulation of adhesion glycoproteins is not clear. We examined the role of protein glycosylation on the adherence properties of the major adhesion molecule Muc1/Flo11 in the budding yeast Saccharomyces cerevisiae. Using a conditional mutant required for an early step in protein glycosylation, pmi40 101, we show that the glycosylation of Flo11 is required for invasive growth and biofilm/mat formation. Underglycosylated Flo11 was not defective in cell-surface localization or binding to wild-type cells in trans. However, wild-type Flo11 was defective for binding to the surface of cells undergoing a glycosylation stress. Shed Flo11 and other shed glycoproteins (Msb2 and Hkr1) were extremely stable with half-lives on the order of days. The glycosylation of Flo11 contributed to its stability. Moreover, the overall balance between Flo11 production, shedding, and turnover favored accumulation of the shed protein over time. Our findings may be applicable to fungal adhesion molecules in other species including pathogens. PMID- 22816436 TI - Association of depressiveness with chronic facial pain: a longitudinal study. AB - OBJECTIVE: Depression and pain are often co-morbid. Temporomandibular disorders (TMD) include facial pain as one main symptom. Reports are lacking on the association between chronic facial pain and earlier depressiveness. The aim of the study was to investigate whether depressiveness increases the risk for chronic facial pain in a longitudinal population-based study. MATERIALS AND METHODS: Subjects included in the Northern Finland Birth Cohort 1966 (n = 5696) answered a questionnaire on facial pain and depressiveness using the Symptom Checklist-25 depression sub-scale at the age of 31 years. In addition, reported depression diagnosed by a doctor was enquired about. Three years later a sub sample of the cohort, including 63 cases with chronic facial pain and 85 pain free controls, was formed based on the question concerning facial pain. RESULTS: Of the chronic facial pain cases 17.5% and of the pain-free controls 7.1% were depressive 3 years earlier at baseline (p = 0.050, chi(2) test, crude OR = 2.8, 95% CI = 1.0-8.0). Of the chronic facial pain cases 6.3% and of the pain-free controls 1.2% reported having had diagnosed depression (p = 0.085, crude OR = 5.7, 95% CI = 0.6-52.2). After adjusting the gender, the association between depressiveness reported at the baseline and chronic facial pain was significant (OR = 4.2, 95% CI = 1.1-16.2). When widespread pain was included in the analysis, the association was not significant. CONCLUSIONS: Depressiveness increases the risk for chronic facial pain in a 3-year follow-up. This association seems to be mediated through widespread pain. PMID- 22816437 TI - Cervical cancer trends in the United States: a 35-year population-based analysis. AB - PURPOSE: To analyze trends in invasive cervical cancer incidence by age, histology, and race over a 35-year period (1973-2007) in order to gain insight into changes in the presentation of cervical cancer. METHODS: Data from the nine Surveillance, Epidemiology, and End Results (SEER) registries that continuously collected information on invasive cervical cancer were analyzed for trends. Standardized to the 2000 U.S population, annual age-adjusted incidence rates were estimated by race and histologic subtype. Histologic subtype was classified into squamous, adenocarcinoma, and adenosquamous. RESULTS: Overall incidence rates for invasive cervical cancer decreased by 54% over the 35 years, from 13.07/100,000 (1973-1975) to 6.01/100,000 (2006-2007), and the incidence rates declined by 51% and 70.2%, respectively, among whites and blacks. The incidence rates for squamous carcinoma decreased by 61.1% from 10.2/100,000 (1973-1975) to 3.97/100,000 (2006-2007). Incidence rates for adenosquamous cell carcinomas decreased by 16% from 0.27/100,000 (1973-1975) to 0.23/100,000 (2006-2007), and incidence rates for adenocarcinomas increased by 32.2% from 1.09/100,000 (1973 1975) to 1.44/100,000 (2006-2007). This increase in adenocarcinomas was due to an increase in incidence in white women; a decrease in incidence was observed for black women. CONCLUSIONS: Although marked reductions in the overall and race specific incidence rates of invasive cervical cancer have been achieved, they mask important variation by histologic subtype. These findings suggest that alternatives to Pap smear-based screening, such as human papillomavirus (HPV) testing and HPV vaccination, need to be prioritized if adenocarcinomas of the cervix are to be controlled. PMID- 22816438 TI - Non-native plants and soil microbes: potential contributors to the consistent reduction in soil aggregate stability caused by the disturbance of North American grasslands. AB - * Soil aggregate stability is an important ecosystem property that is altered by anthropogenic disturbance. Yet, the generalization of these alterations and the identification of the main contributors are limited by the absence of cross-site comparisons and the application of inconsistent methodologies across regions. * We assessed aggregate stability in paired remnant and post-disturbance grasslands across California, shortgrass and tallgrass prairies, and in manipulative experiments of plant composition and soil microbial inoculation. * Grasslands recovering from anthropogenic disturbance consistently had lower aggregate stability than remnants. Across all grasslands, non-native plant diversity was significantly associated with reduced soil aggregate stability. A negative effect of non-native plants on aggregate stability was also observed in a mesocosm experiment comparing native and non-native plants from California grasslands. Moreover, an inoculation study demonstrated that the degradation of the microbial community also contributes to the decline in soil aggregate stability in disturbed grasslands. * Anthropogenic disturbance consistently reduced water stable aggregates. The stability of aggregates was reduced by non-native plants and the degradation of the native soil microbial community. This latter effect might contribute to the sustained decline in aggregate stability following anthropogenic disturbance. Further exploration is advocated to understand the generality of these potential mechanisms. PMID- 22816439 TI - Comparison of 5-year outcomes between pedicle screw and hybrid constructs in adolescent idiopathic scoliosis. AB - OBJECT: Pedicle screw fixation has been theorized to provide better correction of scoliotic deformity, but controversy over the benefits of pedicle screw-only constructs remains, and the longer-term impact of pedicle screw fixation as compared with hybrid constructs is unclear. In this study, a retrospective review of a prospectively collected database was conducted to determine the longer-term impact of pedicle screw fixation as compared with hybrid constructs in patients with adolescent idiopathic scoliosis (AIS). METHODS: The authors retrospectively reviewed a multicenter database of pediatric patients (ages <= 18) from 1995 to 2006 and identified 127 patients with Lenke Type 1-4 AIS curves with a minimum 5 years of follow-up. Patients were divided into 2 cohorts based on whether they had undergone pedicle screw fixation or fixation with hybrid constructs. RESULTS: The mean main thoracic curvature of 56.1 degrees +/- 13.0 degrees , which corrected to 14.9 degrees +/- 9.3 degrees , translated into a mean correction of 73% (p < 0.01). The curve was 19.4 degrees +/- 10.6 degrees at 2-year follow-up and 20.5 degrees +/- 10.4 degrees at 5 years. When comparing preoperative parameters between the groups, differences were noted in the magnitude of the main thoracic curve (p = 0.04), flexibility of the main thoracic curve (p = 0.02), coronal balance (p = 0.04), T2-12 kyphosis (p = 0.02), and sex (p = 0.02). The pedicle screw cohort had fewer spinal segments instrumented (p < 0.01), fewer anterior releases performed (p = 0.02), and fewer thoracoplasties performed (p < 0.01). By 5 years of follow-up, significant differences were apparent between the two cohorts with respect to upper thoracic curvature (p = 0.01), T2-12 (p = 0.02) and T5-12 (p = 0.02) kyphosis, lumbar lordosis (p < 0.01), and sagittal balance (p = 0.01). CONCLUSIONS: Although some preoperative differences did exist, outcomes were comparable between hybrid and screw constructs at 2 and 5 years. However, hybrid constructs required more concurrent anterior releases and thoracoplasties to achieve similar results. PMID- 22816440 TI - A single spinal lesion arising from an intradural meningioma contiguous with an extradural lymphoma. AB - The authors describe here a unique case of contiguous, synchronous meningioma and lymphoma in the spinal column. Both tumors were present at the same vertebral level, one intradural and the other extradural. A patient presented with bilateral leg pain, acute weakness, and sensory loss in the lower extremities. Magnetic resonance imaging revealed an intradural mass at T6-7 with ambiguous boundaries relative to the thecal sac and compressing the spinal cord. The patient underwent resection of the epidural and intradural mass at T6-7. Histopathology revealed the epidural specimen to be a double-hit B-cell lymphoma and the intradural mass to be a transitional meningioma. Postoperatively, the patient did well, with an immediate return of strength and sensation. A postoperative MR image showed complete resection of the intradural mass. The authors suggest that biopsy may be prudent in patients with known systemic lymphoma presenting with a spinal lesion that has unclear boundaries relative to the thecal sac prior to commencing radiation and chemotherapy. PMID- 22816441 TI - A randomized, controlled trial of four ablative fractionated lasers for photoaging: a quadrant study. AB - BACKGROUND: Fractionated technology has revolutionized laser therapy. With the success of initial devices, several fractionated lasers have appeared on the market. Claims of superiority have made device choice difficult for physicians and patients. MATERIALS AND METHODS: Twelve subjects were treated with fractionated ablative lasers (10,600-nm carbon dioxide and 2790-nm yttrium scandium gallium garnet) in this institutional review board-approved trial. Each face was divided into four quadrants, and each quadrant was randomly treated using one of four lasers. Clinical experience was used to optimize settings. Two patients submitted biopsies from each quadrant immediately after treatment. Patients and blinded investigators assessed pain during treatment and post treatment improvement in photoaging (measured by rhytides, lentigines, texture, and pore size) using a five-point scale. RESULTS: All devices resulted in statistical improvement in photoaging in all patients, but no device was statistically significantly superior. No statistically significant difference was found in pain scores. All patients reported satisfaction 1 month after treatment. Three patients experienced adverse reactions. Histologically, there were no statistically significant differences between devices. CONCLUSIONS: Fractionated ablative lasers reliably result in improvement in photoaging. Despite marketing claims, no statistically significant differences were found in outcomes, pain during treatment, or histologic findings. Even with experienced users, significant adverse reactions are possible. PMID- 22816442 TI - Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization. AB - Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases. PMID- 22816443 TI - Growth in transitional countries: the long-term impact of under-nutrition on health. AB - CONTEXT: Despite significant economic development in many parts of the world, upwards of 150 million children are short for their age. Epidemiologic and clinical data suggest that stunting increases the risk for nutrition-related chronic diseases (NRCD), a particular problem for transitional countries as dietary and environmental shifts that accompany development are also reported to increase the risk for NRCD. OBJECTIVE AND METHODS: This paper reviews studies on the causes and long-term effects of poor nutrition as well as data from clinical studies of growth retardation and metabolism and body composition that may explain the link between poor growth and later risk for NRCD. RESULTS: Growth retardation is the physical outcome of a complex interaction of socio- economic factors during key periods of development. Growth-retarded children may present with metabolic or body fat distribution profiles that predispose them to NRCD, a risk factor that may be compounded by consuming a diet consistent with the 'nutrition transition'. CONCLUSION: It is important to continue studying the long term physiological changes following recovery from under-nutrition, especially in countries undergoing a 'nutrition transition'. Estimates suggest that, within 20 30 years, ~ 2/3 of the world population will reside in urban areas. The potential economic fallout of continued poor nutrition, poor growth and changing diets and activity patterns will be great given the healthcare costs and social problems associated with NRCD. PMID- 22816444 TI - Direct asymmetric allylic alkenylation of N-itaconimides with Morita-Baylis Hillman carbonates. AB - The asymmetric allylic alkenylation of Morita-Baylis-Hillman (MBH) carbonates with N-itaconimides as nucleophiles has been developed using a commercially available Cinchona alkaloid catalyst. A variety of multifunctional chiral alpha methylene-beta-maleimide esters were attained in moderate to excellent yields (up to 99%) and good to excellent enantioselectivities (up to 91% ee). The origin of the regio- and stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed regio- and enantioselectivity. PMID- 22816445 TI - Measuring patient satisfaction with the Polish version of the Newcastle Satisfaction with Nursing Scale. AB - The measurement of patients' satisfaction is increasingly becoming legal and ethical duty of healthcare providers worldwide. Till now, there were no validated, widely available Polish scales to assess patients' satisfaction with nursing care. The aim of this study was to assess the experiences and satisfaction with nursing care of patients hospitalized in surgical and nonsurgical wards in Poland using Polish version of the Newcastle Satisfaction with Nursing Scale. This is a multicentre, cross-sectional, descriptive study. Eight hospitals were qualified to participate in a convenience manner. The correlations between variables were analysed using the Mann-Whitney or the Kruskal-Wallis tests. In the case of a significant correlation, the Dunn's test was used to conduct multiple comparisons for the group of variables. A significance of alpha = 0.05 was assumed for the tests. A total 918 patients participated in the study, and 787 (85.72%) questionnaires were correctly filled out. The average result on the 'experience' scale was 73.22 (Me 73.07) and on the 'satisfaction' scale, 74.98 (Me 76.31). Education levels did not affect the experiences of nursing care levels p = 0.2204 and satisfaction with nursing care p = 0.1075. Patient age had a statistically significant impact on the results of the 'experiences of nursing care' scale p = 0.0005 and the 'satisfaction with nursing' scale p = 0.0194. The experiences of nursing care (p = 0.0002) and patients satisfaction (p = 0.0000) were significantly higher in surgical wards than in nonsurgical wards. The experiences of nursing care were significantly lower in the university hospital than in provincial hospitals (p = 0.0374) and district hospitals (p = 0.0183). A comparison of patient satisfaction with nursing in various hospitals shows that patients were most satisfied in district hospitals (average 78.10, Me 82.89), followed by provincial hospitals (average 72.11, Me 76.31) and the university hospital (average 70.64, Me 71.05). PMID- 22816446 TI - Evaluation of polymorphisms in the sulfonamide detoxification genes CYB5A and CYB5R3 in dogs with sulfonamide hypersensitivity. AB - BACKGROUND: Delayed hypersensitivity (HS) reactions to potentiated sulfonamide antimicrobials occur in both dogs and humans, and involve an intermediate hydroxylamine metabolite that is detoxified by cytochrome b(5) and NADH cytochrome b(5) reductase. HYPOTHESIS/OBJECTIVES: We hypothesized that polymorphisms in the genes (CYB5A and CYB5R3) encoding these 2 enzymes would be associated with risk of sulfonamide HS in dogs. ANIMALS: A total of 18 dogs with delayed HS to potentiated sulfonamide antimicrobials and 16 dogs that tolerated (TOL) a therapeutic course of these drugs without adverse effect. METHODS: CYB5A and CYB5R3 were sequenced from canine liver, and the promoter, exons, and 3' untranslated regions of both genes were resequenced from genomic DNA obtained from all dogs. RESULTS: Multiple polymorphisms were found in both genes. When controlled for multiple comparisons, the 729GG variant in CYB5R3 was significantly overrepresented in dogs with sulfonamide HS (78% of dogs), compared to TOL dogs (31%; P = .003). CONCLUSIONS AND CLINICAL IMPORTANCE: The CYB5R3 729GG variant may contribute to the risk of sulfonamide HS in dogs. Functional characterization of this polymorphism, as well as genotyping in a larger number of HS and TOL dogs, is warranted. PMID- 22816447 TI - Outcomes for whites and blacks at hospitals that disproportionately care for black Medicare beneficiaries. AB - OBJECTIVE: Hospital care for blacks is concentrated among a small number of hospitals and whether they have worse outcomes across common medical conditions is unknown. DATA SOURCE: We used the 2007 100% Medicare file to calculate 30- and 90-day mortality rates for white and black patients admitted for acute myocardial infarction (AMI), congestive heart failure (CHF), or pneumonia. STUDY DESIGN: We ranked all hospitals in the country by their proportion of discharged black patients and identified the top 10 percent of these hospitals as black serving. We examined race-specific adjusted mortality rates and adjusted for differences in hospital characteristics. PRINCIPAL FINDINGS: At 30 days, black-serving hospitals had, compared with nonblack-serving hospitals, similar mortality for AMI, lower mortality for CHF, and higher mortality for pneumonia. At 90 days, mortality was higher at black-serving hospitals for both AMI and pneumonia and comparable for CHF compared with nonblack-serving hospitals. White patients had worse outcomes at black-serving hospitals for two conditions at 30 days and all three conditions at 90 days. Blacks also had worse outcomes at black-serving hospitals. CONCLUSIONS: Hospitals with a high proportion of black patients had worse outcomes than other hospitals for both their white and black elderly patients. PMID- 22816448 TI - Galactose half-life is a useful tool in assessing prognosis of chronic liver disease in children. AB - In children, optimal timing of liver transplantation (LT) is crucial, but reliable prognostic tools for chronic liver diseases are scarce. We assessed the predictive value of galactose half-life (Gal1/2) for LT or death. A retrospective search of hospital database 2003-2010 revealed 92 consecutive children with chronic liver disease (36 biliary atresia) whose liver function was assessed with Gal1/2 measurement. Gal1/2, follow-up data, and liver biochemistry were recorded and pediatric/model for end-stage liver disease (P/MELD) scores calculated. Patients listed for LT or those who died within 1 year of the Gal1/2 measurement (Group 1) were compared to those surviving without listing (Group 2). Predictive value of Gal1/2 and P/MELD for listing for LT was assessed with area under the receiver operating characteristic curve (AUROC) analysis. Group 1 had markedly increased median Gal1/2 [17.0 (interquartile range 12.5-28.5) min] and higher P/MELD [13 (-1-23)] compared with group 2, [10.5 (9.5-12.5) min and -1 (-8-8); P < 0.001 for both]. Both Gal1/2 and P/MELD (P < 0.001) predicted listing or death with respective AUROCs of 0.808 (95% CI 0.704-0.913) and 0.780 (0.676-0.890), and 85% sensitivity and 69% specificity for Gal1/2>=12.0 min. Gal1/2 is a useful tool when evaluating 1-year prognosis in children with chronic liver disease. PMID- 22816484 TI - Where is the initiation of atrial fibrillation? PMID- 22816485 TI - Drivers of cyanobacterial diversity and community composition in mangrove soils in south-east Brazil. AB - Cyanobacteria act as primary producers of carbon and nitrogen in nutrient-poor ecosystems such as mangroves. This important group of microorganisms plays a critical role in sustaining the productivity of mangrove ecosystems, but the structure and function of cyanobacteria assemblages can be perturbed by anthropogenic influences. The aim of this work was to assess the community structure and ecological drivers that influence the cyanobacterial community harboured in two Brazilian mangrove soils, and examine the long-term effects of oil contamination on these keystone species. Community fingerprinting results showed that, although cyanobacterial communities are distinct between the two mangroves, the structure and diversity of the assemblages exhibit similar responses to environmental gradients. In each ecosystem, cyanobacteria occupying near-shore areas were similar in composition, indicating importance of marine influences for structuring the community. Analysis of 16S rRNA sequences revealed the presence of diverse cyanobacterial communities in mangrove sediments, with clear differences among mangrove habitats along a transect from shore to forest. While near-shore sites in both mangroves were mainly occupied by Prochlorococcus and Synechococcus genera, sequences retrieved from other mangrove niches were mainly affiliated with uncultured cyanobacterial 16S rRNA. The most intriguing finding was the large number of potentially novel cyanobacteria 16S rRNA sequences obtained from a previously oil-contaminated site. The abundance of cyanobacterial 16S rRNA sequences observed in sites with a history of oil contamination was significantly lower than in the unimpacted areas. This study emphasized the role of environmental drivers in determining the structure of cyanobacterial communities in mangrove soils, and suggests that anthropogenic impacts may also act as ecological filters that select cyanobacterial taxa. These results are an important contribution to our understanding of the composition and relative abundance of previously poorly described cyanobacterial assemblages in mangrove ecosystems. PMID- 22816486 TI - Delay of flower senescence by bacterial endophytes expressing 1-aminocyclopropane 1-carboxylate deaminase. AB - AIMS: The ability of 1-aminocyclopropane-1-carboxylate (ACC) deaminase-containing plant growth-promoting bacterial (PGPB) endophytes Pseudomonas fluorescens YsS6 and Pseudomonas migulae 8R6, their ACC deaminase minus mutants and the rhizospheric plant growth-promoting bacterium Pseudomonas putida UW4 to delay the senescence of mini carnation cut flowers was assessed. METHODS AND RESULTS: Fresh cut flowers were incubated with either a bacterial cell suspension, the ethylene precursor ACC, the ethylene inhibitor l-alpha-(aminoethoxyvinyl)-glycine or 0.85% NaCl at room temperature for 11 days. Levels of flower senescence were recorded every other day. To verify the presence of endophytes inside the plant tissues, scanning electron microscopy was performed. Among all treatments, flowers treated with wild-type ACC deaminase-containing endophytic strains exhibited the most significant delay in flower senescence, while flowers treated with the ACC deaminase minus mutants senesced at a rate similar to the control. Flowers treated with Ps. putida UW4 senesced more rapidly than untreated control flowers. CONCLUSION: The only difference between wild-type and mutant bacterial endophytes was ACC deaminase activity so that it may be concluded that this enzyme is directly responsible for the significant delay in flower senescence. Despite containing ACC deaminase activity, Ps. putida UW4 is not taken up by the cut flowers and therefore has no effect on prolonging their shelf life. SIGNIFICANCE AND IMPACT OF THE STUDY: The world-wide cut flower industry currently uses expensive and potentially environmentally dangerous chemical inhibitors of ethylene to prolong the shelf life of cut flowers. The use of PGPB endophytes with ACC deaminase activity has the potential to replace the chemicals that are currently used by the cut flower industry. PMID- 22816487 TI - Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi center study in Japan. AB - The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5-30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m(2) daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m(2) and experienced no dose limiting toxicity during the first cycle. Thirty-four patients received 20 mg/m(2) . Grade 3 or greater non-hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m(2) , complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4-8), and duration of remission was 474+ days (range 294-598+). The 2-year rate of acute myeloid leukemia-free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high-risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003). PMID- 22816489 TI - A comparison of survey techniques on sensitive sexual behavior in Italy. AB - This article compares two national surveys carried out through the most commonly used procedures in Italy: CATI (computer-assisted telephone interviews) and SAQ FI (self-answered questionnaires following interviews). Both surveys ask two identical questions concerning sensitive sexual behavior: early age at first intercourse and same-sex attraction. The SAQ-FI survey had both unit non-response and item non-response rates much lower than the CATI survey. Moreover, in the CATI survey, the groups with highest item non-response rates were also the groups with the lowest proportions of early intercourse and homosexual attraction. In addition, a differential analysis of the respondents produced diverse results for the two surveys. This is especially true of results by gender for same-sex attraction: Such behavior is more common among men (3.1%) than women (2.9%), according to the CATI survey, whereas the opposite is true of the SAQ-FI survey (6.1% of men vs. 7.7% women). In Italy at the beginning of the 21st century, CATI surveys reveal a lower level of early intercourse and same-sex attraction than SAQ-FI surveys. This article argues that the CATI survey underestimates the true level of these sensitive sexual behaviors in the Italian population. PMID- 22816488 TI - A novel primer set for multilocus phylogenetic inference in East African cichlid fishes. AB - The cichlid fishes in the East African Great Lakes are a prime model system for the study of adaptive radiation. Therefore, the availability of an elaborate phylogenetic framework is an important prerequisite. Previous phylogenetic hypotheses on East African cichlids are mainly based on mitochondrial and/or fragment-based markers, and, to date, no taxon-rich phylogeny exists that is based on multilocus DNA sequence data. Here, we present the design of an extensive new primer set (24 nuclear makers) for East African cichlids that will be used for multilocus phylogenetic analyses in the future. The primers are designed to work for both Sanger sequencing and next-generation sequencing with the 454 technology. As a proof of principle, we validate these primers in a phylogenetically representative set of 16 cichlid species from Lake Tanganyika and main river systems in the area and provide a basic evaluation of the markers with respect to marker length and diversity indices. PMID- 22816490 TI - Analysis of 303 Ro/SS-A antibody-positive patients: is this antibody a possible marker for malignancy? AB - BACKGROUND: The risk of cancer in patients with autoimmune diseases has been investigated in several studies. Ro/SS-A antibodies are frequent and specific autoantibodies among patients with various autoimmune diseases. OBJECTIVES: To assess the risk of cancer in individuals with positive Ro/SS-A antibodies and to analyse their clinical and laboratory characteristics. METHODS: Consecutive patients (n = 303) with Ro/SS-A antibody positivity were collected during 11 years in our outpatient clinic for autoimmune diseases and were retrospectively analysed. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for all cancers were calculated. In addition, we identified further clinical and laboratory characteristics of Ro/SS-A antibody-positive patients indicating the development or existence of a malignancy. RESULTS: Fifty (16.5%) patients were diagnosed with malignancies. Ro/SS-A antibody was strongly associated with malignant diseases (SIR 2.6, 95% CI 1.9-6.1), particularly melanoma (SIR 33.3, 95% CI 5.2-188.6), T-cell lymphoma (SIR 16.7, 95% CI 2.9-128.9), non-Hodgkin lymphoma (SIR 10.6, 95% CI 1.5-78.9) and breast carcinoma (SIR 4.98, 95% CI 1.3 28.3). Logistic regression modelling revealed that Ro/SS-A antibody-positive patients aged 55 years or older, presenting with fever, anaemia and cutaneous lupus erythematosus, have a greater probability of developing cancer and are considered high-risk patients, as compared with Ro/SS-A antibody-positive patients with none of the mentioned clinical criteria. CONCLUSIONS: In our cohort of Ro/SS-A antibody-positive patients, an overall increased risk of malignancy was noticed. Regular screening tests including imaging and laboratory values are justified in Ro/SS-A antibody-positive patients who exhibit the mentioned clinical criteria. PMID- 22816491 TI - Multidrug-resistant coagulase-negative Staphylococci in food animals. AB - AIMS: To study the antimicrobial resistance of coagulase-negative staphylococci (CoNS) in animals. METHODS AND RESULTS: In the present study, a total of 87 CoNS recovered from food animals were characterized by antimicrobial susceptibility testing, resistance gene identification and conjugation. Of the seven species studied, Staphylococcus lentus, Staphylococcus sciuri, Staphylococcus xylosus and Staphylococcus haemolyticus accounted for over 96% of the isolates. In addition to beta-lactam resistance (100%), high percentages of CoNS were resistant to tetracycline (67.8%), erythromycin (36.7%), clindamycin (27.5%) and quinopristin/dalfopristin (14.9%). Importantly, 47 (54%) isolates were resistant to at least three antimicrobial classes, including six CoNS resistant to six antimicrobial classes. The common genes for the above-mentioned resistance phenotypes were mec(A), tet(M), erm(A) and vga(A)(LC) , which were identified from 68.7%, 61%, 56.2% and 69.2% of the isolates, respectively. tet(M) was conjugatively transferable from 10 tetracycline-resistant CoNS to a Enterococcus strain, underlining the potential of antimicrobial resistance transfer from Staphylococcus to the commensal bacteria in human. CONCLUSIONS: Multidrug resistance and resistance to non-beta-lactam antimicrobials are common in CoNS in animals. SIGNIFICANCE AND IMPACT OF THE STUDY: The data improve our understanding on the extent to which CoNS contribute to the dissemination of antimicrobial resistance in the food production environment. PMID- 22816492 TI - Associations between gastric sensorimotor function, depression, somatization, and symptom-based subgroups in functional gastroduodenal disorders: are all symptoms equal? AB - BACKGROUND: Previous work indicated that psychosocial factors (depression and somatization) are more strongly associated with symptom severity and weight loss in functional dyspepsia (FD) than gastric sensorimotor function. However, there is conflicting evidence regarding the association of these etiopathogenetic factors with Rome III symptom-based subgroups in FD [epigastric pain syndrome (EPS), postprandial distress syndrome (PDS)]. We aimed to test whether gastric sensitivity and emptying, depression, and somatization are differentially associated with empirically derived functional gastroduodenal disorders (FGD) symptom factors in one comprehensive model. METHODS: In 259 tertiary care FD patients, we studied gastric sensorimotor function with barostat and gastric emptying breath test. Depression, somatization, and FGD symptoms were measured using self-report questionnaires. Confirmatory factor analysis (CFA) on 7 FGD symptoms was used to determine the fit of a latent variable structure based on Rome III symptom-based subgroups. Structural equation modeling (SEM) was used to test the putative relationships of the symptom factors with gastric sensorimotor function, depression, and somatization. KEY RESULTS: The results of the CFA show a good fit [C(min) /DF = 1.54, CFI(comparative fit index) = 0.97] for the three factor solution based on Rome III subgroups. The SEM also fitted the data well (C(min) /DF = 1.24, CFI = 0.98) and demonstrated that gastric sensitivity and depression are associated with PDS and nausea and vomiting. Gastric emptying is uniquely associated with EPS and somatization is strongly associated with all three symptom factors. CONCLUSIONS & INFERENCES: Confirmatory factor analysis confirms the existence of three FGD symptom factors, corresponding to Rome III symptom-based subgroups. The SEM results suggest that different psychobiological mechanisms may play a role in these subgroups. PMID- 22816493 TI - Comparing errors in Medicaid reporting across surveys: evidence to date. AB - OBJECTIVE: To synthesize evidence on the accuracy of Medicaid reporting across state and federal surveys. DATA SOURCES: All available validation studies. STUDY DESIGN: Compare results from existing research to understand variation in reporting across surveys. DATA COLLECTION METHODS: Synthesize all available studies validating survey reports of Medicaid coverage. PRINCIPAL FINDINGS: Across all surveys, reporting some type of insurance coverage is better than reporting Medicaid specifically. Therefore, estimates of uninsurance are less biased than estimates of specific sources of coverage. The CPS stands out as being particularly inaccurate. CONCLUSIONS: Measuring health insurance coverage is prone to some level of error, yet survey overstatements of uninsurance are modest in most surveys. Accounting for all forms of bias is complex. Researchers should consider adjusting estimates of Medicaid and uninsurance in surveys prone to high levels of misreporting. PMID- 22816494 TI - Prospective study of thrombospondin-1 mimetic peptides, ABT-510 and ABT-898, in dogs with soft tissue sarcoma. AB - BACKGROUND: Exposure to anti-angiogenic thrombospondin-1 (TSP-1) mimetic peptides (MPs) has resulted in sporadic anti-tumor activity in humans and dogs. HYPOTHESIS: Novel TSP-1 MPs formulations will be safe, tolerated, and clinically active in soft tissue sarcoma (STS) in dogs. ANIMALS: Sixty-two client-owned dogs with measurable STS were enrolled, excluding hemangiosarcoma. METHODS: A prospective, single agent, multicenter, open-label study assessing ABT-510 bolus, ABT-898 bolus, or ABT-898 depot formulations of TSP-1 in dogs. Endpoints included tolerability, antitumor activity, and the assessment of ability of clinical covariates and circulating endothelial cells (CEC) concentration to predict tumor response. RESULTS: Two non-dose-limiting toxicoses possibly attributed to treatment were observed (keratitis and osteoarthritis). Antitumor activity (10/44 = 23% responses) was observed in study subjects who received treatment for >28 days (n = 44) including both partial (7) and minimal responses (3). Responses were disproportionately seen in dogs receiving ABT-898 formulations (9/28 = 32%) versus those receiving ABT-510 (1/16 = 6%; P < .045). Disease stabilization for >84 days was also documented (8/44 = 18%). Slow rates of tumor progression before study entry correlated with anti-tumor activity in treated dogs, whereas no significant association was found between changes in total CEC concentration and tumor response (P = .28) or time to progression (P = .42). CONCLUSIONS AND CLINICAL IMPORTANCE: Safely achieved antitumor activity was documented with TSP-1 MPs in dogs with STS. The most notable activity was achieved with the ABT-898 formulations. PMID- 22816495 TI - Sunlight-induced reduction of ionic Ag and Au to metallic nanoparticles by dissolved organic matter. AB - Despite the possible occurrence of metal nanoparticles in the environment due to the discharge of engineered nanoparticles and the natural transformation of metal ions into metal nanoparticles, little is known about the transformation mechanism, fates, behaviors, and effects of these nanoparticles in the environment. Here, we show that dissolved organic matter (DOM) in environmental waters can mediate the reduction of ionic Ag and Au to their metallic nanoparticles under natural sunlight, suggesting that this process may be general for metals with high reduction potential. We demonstrated that the reduction was mediated by superoxide from photoirradiation of the phenol group in DOM, and the dissolved O(2) significantly enhanced the formation of Ag nanoparticles. These results imply that previous knowledge about O(2)-induced dissolution and its effect on persistence of Ag nanoparticles should be reconsidered in a sunlit DOM rich aqueous environment. This study can also shed light on understanding possible natural sources of Ag and Au nanoparticles in the aquatic environment, which is possibly critical in the supergene enrichment of Ag and Au. PMID- 22816496 TI - Influence of adhesive point dimension and splint type on splint rigidity- evaluation by the dynamic Periotest method. AB - AIM: To evaluate the influence of adhesive point dimension and splint type on the rigidity of wire-composite splints in vitro. MATERIALS AND METHODS: A custom-made artificial model was used. The two central incisors served as injured teeth (degrees of loosening III and II) and the two lateral incisors as non-injured teeth (physiological mobility). Horizontal and vertical tooth mobilities were investigated before and after splinting with the Periotest((r)) method; the percent change was taken as the relative splint effect. Teeth were splinted with three types of wire-composite splints: Dentaflex (0.45 mm), Strengtheners (0.8 * 1.8 mm), and Dentaflex completely covered with composite. Four adhesive point dimensions (2, 3, 4, and 5 mm) were evaluated. Normal distribution was tested with the Kolmogorov-Smirnov test. Differences were evaluated with the anova and post hoc tests for pair-wise comparisons. Significance level was set at 0.05. RESULTS: The adhesive point dimension did not influence splint rigidity, in general ( P = 0.288). Significant effects were found in non-injured teeth with the Dentaflex ( P < 0.001) and in injured teeth with the Strengtheners ( P < 0.001). The Strengtheners splint rigidity increased significantly with increasing adhesive point dimensions. The three splints showed significantly different effects at 5-mm adhesive point dimension ( P < 0.001). CONCLUSION: Splint rigidity for injured teeth was influenced by adhesive point dimension only when splinting with Strengtheners. We recommend adapting splint rigidity by selecting different wires and reducing the adhesive point dimension to a minimum. Dentaflex can be used for flexible splinting, Strengtheners, and composite covered Dentaflex for rigid splinting. PMID- 22816497 TI - Electronic media and the journal. PMID- 22816499 TI - Effect of temperature on the degree of conversion and working time of dual-cured resin cements exposed to different curing conditions. AB - OBJECTIVES: This study evaluated the degree of conversion (DC) and working time (WT) of two commercial, dual-cured resin cements polymerized at varying temperatures and under different curing-light accessible conditions, using Fourier transformed infrared analysis (FTIR). MATERIALS AND METHODS: Calibra (Cal; Dentsply Caulk) and Variolink II (Ivoclar Vivadent) were tested at 25 degrees C or preheated to 37 degrees C or 50 degrees C and applied to a similar temperature surface of a horizontal attenuated-total-reflectance unit (ATR) attached to an infrared spectrometer. The products were polymerized using one of four conditions: direct light exposure only (600 mW/cm(2)) through a glass slide or through a 1.5- or 3.0-mm-thick ceramic disc (A2 shade, IPS e.max, Ivoclar Vivadent) or allowed to self-cure in the absence of light curing. FTIR spectra were recorded for 20 min (1 spectrum/s, 16 scans/spectrum, resolution 4 cm(-1)) immediately after application to the ATR. DC was calculated using standard techniques of observing changes in aliphatic-to-aromatic peak ratios precuring and 20-min postcuring as well as during each 1-second interval. Time-based monomer conversion analysis was used to determine WT at each temperature. DC and WT data (n=6) were analyzed by two-way analysis of variance and Tukey post hoc test (p=0.05). RESULTS: Higher temperatures increased DC regardless of curing mode and product. For Calibra, only the 3-mm-thick ceramic group showed lower DC than the other groups at 25 degrees C (p=0.01830), while no significant difference was observed among groups at 37 degrees C and 50 degrees C. For Variolink, the 3-mm-thick ceramic group showed lower DC than the 1-mm-thick group only at 25 degrees C, while the self-cure group showed lower DC than the others at all temperatures (p=0.00001). WT decreased with increasing temperature: at 37 degrees C near 70% reduction and at 50 degrees C near 90% for both products, with WT reduction reaching clinically inappropriate times in some cases (p=0.00001). CONCLUSION: Elevated temperature during polymerization of dual-cured cements increased DC. WT was reduced with elevated temperature, but the extent of reduction might not be clinically acceptable. PMID- 22816500 TI - Functional and aesthetic guidelines for stress-reduced direct posterior composite restorations. AB - Amalgam has been used in the restoration of structurally compromised posterior teeth for many years. When placing large amalgam restorations, replacement of weak cusps with restorative material is recommended to prevent tooth fracture. This recommendation can be modified with new guidelines using modern adhesive techniques. Semidirect and indirect inlay/onlay composite restorations have progressively replaced amalgam restorations over the past 20 years. Lately, single visit direct resin-bonded composite (RBC) restorations have also been used as a viable alternative to conventional indirect restorations. This paper is intended to introduce a step-by-step protocol for the direct restoration of structurally compromised posterior teeth using RBCs with stress-reducing protocols. PMID- 22816502 TI - Sapflow+: a four-needle heat-pulse sap flow sensor enabling nonempirical sap flux density and water content measurements. AB - * To our knowledge, to date, no nonempirical method exists to measure reverse, low or high sap flux density. Moreover, existing sap flow methods require destructive wood core measurements to determine sapwood water content, necessary to convert heat velocity to sap flux density, not only damaging the tree, but also neglecting seasonal variability in sapwood water content. * Here, we present a nonempirical heat-pulse-based method and coupled sensor which measure temperature changes around a linear heater in both axial and tangential directions after application of a heat pulse. By fitting the correct heat conduction-convection equation to the measured temperature profiles, the heat velocity and water content of the sapwood can be determined. * An identifiability analysis and validation tests on artificial and real stem segments of European beech (Fagus sylvatica L.) confirm the applicability of the method, leading to accurate determinations of heat velocity, water content and hence sap flux density. * The proposed method enables sap flux density measurements to be made across the entire natural occurring sap flux density range of woody plants. Moreover, the water content during low flows can be determined accurately, enabling a correct conversion from heat velocity to sap flux density without destructive core measurements. PMID- 22816503 TI - Provision of Kangaroo Mother Care: supportive factors and barriers perceived by parents. AB - BACKGROUND: Kangaroo Mother Care (KMC) supports parents' role at the neonatal intensive care unit (NICU). To enhance parents' provision of KMC, it is essential to obtain knowledge of what parents perceive as supportive factors and barriers regarding their opportunities to perform KMC. AIM: To identify factors that parents of preterm infants perceived as supportive factors or barriers for their performance of KMC and to explore the timing of and reasons for parents' discontinuation of KMC. METHODS: A descriptive study performed at two NICUs in Sweden with 76 mothers and 74 fathers of preterm infants born at gestational ages ranging from 28 to 33 weeks. Data on infant characteristics were obtained from the infants' medical records. A questionnaire, based on scientific literature and the researchers' clinical experience, was completed by the mothers and the fathers separately, shortly after the infant's discharge from the hospital. The data were analyzed with qualitative content analysis and descriptive statistic. RESULTS: Four categories were identified in parents' responses regarding support and barriers for their performance of KMC: Parent related factors, Time, Infants related factors and The NICU and home environment. The hospital staff and environment were described by the parents as both supportive and barriers for their application of KMC. Some mothers described the infants' feeding process as an obstacle to KMC. Sleeping with the infant skin-to-skin in the same position throughout the night could be difficult, as an uncomfortable sleeping position caused insufficient sleep. A majority of both mothers and fathers continued providing their infant with KMC to some extent after discharge. CONCLUSION: Interventions for enhancing parents' opportunities for performing KMC should address both hospital staff attitudes and practices and the NICU environment. PMID- 22816504 TI - Malignant cytology in washings of Mohs micrographic surgery instruments. PMID- 22816505 TI - A case of latent tuberculosis reactivation in a patient treated with ustekinumab without concomitant isoniazid chemoprophylaxis in the PEARL trial. PMID- 22816506 TI - Human papillomavirus vaccine for women over forty: it's not just for kids. PMID- 22816508 TI - Degradation of chloroaromatics: structure and catalytic activities of wild-type chlorocatechol 2,3-dioxygenases and modified ones. AB - To improve the efficiency and to investigate the molecular determinants that direct substrate specificity of chlorocatechol 2,3-dioxygenase CbzE(GJ31) , several mutant enzymes were constructed. Loci for substitutions of amino acids were selected by sequence comparisons as well as by homology modelling of known chlorocatechol 2,3-dioxygenases (CbzE(BASF) , CbzE(SK1) and CbzE(16-6A)). Activity measurements with various catechols showed that most of the modifications influenced activity only to a minor degree. The amino acid at position 154 seems to be located at a non-important position in the enzyme with minor extension into the substrate tunnel. Similarly, the change of related amino acids such as D95E and Y223F did not influence the catalysis since both residues are far away from the catalytic centre and the substrate tunnel. Even the modification of isoleucine to threonine in position 310, located at the outer substrate tunnel, showed a significant alteration of activities. Position 196 seems to be of higher relevance since the modification of valine to alanine, i.e. the reduction of the side-chain, produced much alteration. The amino acid is located at the interface of inner to outer substrate tunnel. CbzE(V196A) showed high relative k(cat) for 3-chlorocatechol. A pronounced increase in activity for 3-chlorocatechol resulted by the change from alanine to valine and from aspartic acid to glycine laying in the outer substrate tunnel at position 211 and 212 respectively. PMID- 22816507 TI - Testing for urinary tract colonization before high-dose corticosteroid treatment in acute multiple sclerosis relapses: prospective algorithm validation. AB - BACKGROUND AND PURPOSE: To evaluate a dipstick algorithm for urinary tract colonization, prior to high-dose corticosteroid treatment in acute relapses of multiple sclerosis (MS). METHODS: Prospective cohort study of 267 consecutive patients with MS relapses requiring corticosteroid treatment in a hospital-based, ambulatory, acute MS relapse clinic. A total of 18 participants met the exclusion criteria, leaving 249 for analysis. Main outcome measures were urinary dipstick sensitivity, specificity, positive predictive value, negative predictive value and safety of antibiotic co-treatment with high-dose corticosteroids. RESULTS: Significant bacteriuria (>=10(5) colonies ml) rate in this population was 11% (95% CI, 7.1-14.9). Specificity and sensitivity of positive leucocyte esterase or nitrite were 78% and 65%. Negative predictive value of urine dipstick was 96%. No clinical adverse events occurred in the 3% (95% CI, 0.9-5.1) of patients with a false-negative dipstick. Eighteen per cent of patients were unnecessarily treated with antibiotics for 48 h. CONCLUSION: Urinary dipstick testing allows for rapid and safe management of patients suffering from an acute MS relapse. The algorithm is conservative, and future work is needed to reduce the false-positive rate. PMID- 22816509 TI - Therapeutic effect of surfactant inhalation during warm ischemia in an isolated rat lung perfusion model. AB - Warm ischemia-reperfusion injury related to donation after cardiac death donors is a crucial and inevitable issue. As surfactant function is known to deteriorate during warm ischemia, we hypothesized that surfactant inhalation during warm ischemia would mitigate warm ischemia-reperfusion injury. We used an isolated rat lung perfusion model. The rats were divided into three groups: sham, control, and surfactant. In the control and surfactant groups, cardiac arrest was induced by ventricular fibrillation. Ventilation was restarted 110 min later; subsequently, the lungs were flushed, and heart and lung block was recovered. In the surfactant group, a natural bovine surfactant Surfacten((r)) was inhaled for 3 min at the end of warm ischemia. Then, the lungs were reperfused for 80 min. Surfactant inhalation significantly improved graft functions, effectively increased lung tissue ATP levels, and significantly decreased mRNA levels of IL-6 and IL-6/IL-10 ratio at the end of reperfusion. Histologically, lungs in the surfactant group showed fewer signs of interstitial edema and hemorrhage, and significantly less neutrophilic infiltration than those in the control group. Our results indicated that surfactant inhalation in the last phase of warm ischemia maintained lung tissue energy levels and prevented cytokine production, resulting in the alleviation of warm ischemia-reperfusion injury. PMID- 22816510 TI - Obesity prevention: the impact of local health departments. AB - OBJECTIVE: To examine the association between bodyweight status and provision of population-based prevention services. DATA SOURCES: The National Association of City and County Health Officials 2005 Profile survey data, linked with two cross sections of the Behavioral Risk Factor Surveillance System (BRFSS) survey in 2004 and 2005. STUDY DESIGN: Multilevel logistic regressions were used to examine the association between provision of obesity-prevention services and the change in risk of being obese or morbidly obese among BRFSS respondents. The estimation sample was stratified by sex. Low-income samples were also examined. Falsification tests were used to determine whether there is counterevidence. PRINCIPAL FINDINGS: Provision of population-based obesity-prevention services within the jurisdiction of local health departments and specifically those provided by the local health departments are associated with reduced risks of obesity and morbid obesity from 2004 to 2005. The magnitude of the association appears to be stronger among low-income populations and among women. Results of the falsification tests provide additional support of the main findings. CONCLUSIONS: Population-based obesity-prevention services may be useful in containing the obesity epidemic. PMID- 22816511 TI - Consecutive natural influenza a virus infections in sentinel mallards in the evident absence of subtype-specific hemagglutination inhibiting antibodies. AB - Dabbling ducks, particularly Mallards (Anas platyrhynchos) have been frequently and consistently reported to play a pivotal role as a reservoir of low pathogenic avian influenza viruses (AIV). From October 2006 to November 2008, hand-raised Mallard ducks kept at a pond in an avifaunistically rich area of Southern Germany served as sentinel birds in the AIV surveillance programme in Germany. The pond was regularly visited by several species of dabbling ducks. A flock of sentinel birds, consisting of the same 16 individual birds during the whole study period, was regularly tested virologically and serologically for AIV infections. Swab samples were screened by RT-qPCR and, if positive, virus was isolated in embryonated chicken eggs. Serum samples were tested by the use of competitive ELISA and hemagglutinin inhibition (HI) assay. Sequences of full-length hemagglutinin (HA) and neuraminidase (NA) genes were phylogenetically analysed. Four episodes of infections with Eurasian-type AIV occurred in August (H6N8), October/November (H3N2, H2N3) 2007, in January (H3N2) and September (H3N8) 2008. The HA and NA genes of the H3N2 viruses of October 2007 and January 2008 were almost identical rendering the possibility of a re-introduction of that virus from the environment of the sentinel flock highly likely. The HA of the H3N8 virus of September 2008 belonged to a different cluster. As a correlate of the humoral immune response, titres of nucleocapsid protein-specific antibodies fluctuated in correlation with the course of AIV infection episodes. However, no specific systemic response of hemagglutination inhibiting antibodies could be demonstrated even if homologous viral antigens were used. Besides being useful as early indicators for the circulation of influenza viruses in a specific region, the sentinel ducks also contributed to gaining insights into the ecobiology of AIV infection in aquatic wild birds. PMID- 22816512 TI - Quantifying and mapping ecosystem services supplies and demands: a review of remote sensing applications. AB - Ecosystems provide services necessary for the livelihoods and well-being of people. Quantifying and mapping supplies and demands of ecosystem services is essential for continuous monitoring of such services to support decision-making. Area-wide and spatially explicit mapping of ecosystem services based on extensive ground surveys is restricted to local scales and limited due to high costs. In contrast, remote sensing provides reliable area-wide data for quantifying and mapping ecosystem services at comparatively low costs, and with the option of fast, frequent, and continuous observations for monitoring. In this paper, we review relevant remote sensing systems, sensor types, and methods applicable in quantifying selected provisioning and regulatory services. Furthermore, opportunities, challenges, and future prospects in using remote sensing for supporting ecosystem services' quantification and mapping are discussed. PMID- 22816513 TI - Structural effects of an atomic-level layer of water molecules around proteins solvated in supra-molecular coarse-grained water. AB - Atomistic molecular dynamics simulations of proteins in aqueous solution are still limited to the multinanosecond time scale and multinanometer range by computational cost. Combining atomic solutes with a supra-molecular solvent model in hybrid fine-grained/coarse-grained (FG/CG) simulations allows atomic detail in the region of interest while being computationally more efficient. A recent comparison of the properties of four proteins in CG water versus FG water showed the preservation of the secondary and tertiary structure with a computational speed-up of at least an order of magnitude. However, an increased occurrence of hydrogen bonds between side chains was observed due to a lack of hydrogen-bonding partners in the supra-molecular solvent. Here, the introduction of a FG water layer around the protein to recover the hydrogen-bonding pattern of the atomistic simulations is studied. Three layer thicknesses of 0.2, 0.4, and 0.8 nm are considered. A layer thickness of 0.8 nm is found sufficient to recover the behavior of the proteins in the atomistic simulations, whereas the hybrid simulation is still three times more efficient than the atomistic one and the cutoff radius for nonbonded interactions could be increased from 1.4 to 2.0 nm. PMID- 22816515 TI - Bolivian health providers' attitudes toward alternative technologies for cervical cancer prevention: a focus on visual inspection with acetic acid and cryotherapy. AB - BACKGROUND: Little is known about health providers' attitudes toward visual inspection with acetic acid (VIA) and cryotherapy in the prevention of cervical cancer, as most research in Latin America and the Caribbean (LAC) has examined attitudes of the general population. This study describes attitudes of Bolivian health professionals toward new technologies for cervical cancer prevention, focusing on VIA and cryotherapy. METHODS: Between February 2011 and March 2012, we surveyed 7 nurses and 35 physicians who participated in 5-day workshops on VIA and cryotherapy conducted in Bolivia. Multiple choice and open-ended questions were used to assess participants' acceptability of these procedures and the feasibility of their implementation in the context of perceived barriers for the early detection of cervical cancer in this country. RESULTS: Most believed that cultural factors represent the main barrier for the early detection of cervical cancer (70%), although all stated that VIA and cryotherapy would be accepted by women, citing the advantages of VIA over cytology for this belief. Most also believed their colleagues would accept VIA and cryotherapy (71%) and that VIA should replace Pap testing (61%), reiterating the advantages of VIA for these beliefs. Those who believed the contrary expressed a general resistance to change associated with an already existing cytology program and national norms prioritizing Pap testing. CONCLUSIONS: Most participants had favorable attitudes toward VIA and cryotherapy; however, a sizable minority cited challenges to their adoption by colleagues and believed VIA should not replace cytology. This report can inform the development of strategies to expand the use of alternative cervical cancer screening methods in LAC and Bolivia. PMID- 22816517 TI - The hair dye allergy self-test: considerations for treating physicians. PMID- 22816516 TI - Ordered arrays of native chromatin molecules for high-resolution imaging and analysis. AB - Individual chromatin molecules contain valuable genetic and epigenetic information. To date, there have not been reliable techniques available for the controlled stretching and manipulation of individual chromatin fragments for high resolution imaging and analysis of these molecules. We report the controlled stretching of single chromatin fragments extracted from two different cancerous cell types (M091 and HeLa) characterized through fluorescence microscopy and atomic force microscopy (AFM). Our method combines soft lithography with molecular stretching to form ordered arrays of more than 250,000 individual chromatin fragments immobilized into a beads-on-a-string structure on a solid transparent support. Using fluorescence microscopy and AFM, we verified the presence of histone proteins after the stretching and transfer process. PMID- 22816518 TI - Ehrlichia muris infection in a dog from Minnesota. PMID- 22816519 TI - A novel foil flip-over system as the final layer in wound closure: excellent cosmetic results and patient comfort. AB - BACKGROUND: Wound closure after excision is commonly done with sutures or staples. A new sutureless innovative wound closure system is available for sutureless skin closure. OBJECTIVE: To evaluate wound healing, patient comfort, and cosmetic results of a foil flip-over system for excision of small skin lesion. MATERIALS AND METHODS: Patients presenting to the department of Dermatology of Erasmus University Medical Center, Rotterdam, The Netherlands for skin surgery during a 1.5-year period were prospectively studied. Key outcome measures were wound healing, patient comfort, and cosmetic results. Three independent physicians scored photographs of the scars. Evaluation tools used were comfort and body image questionnaires and visual analogue scales. RESULTS: Ninety-six patients with 103 lesions were included in our study. The surgeon scored wound healing as excellent or good in 96%. No wound infections occurred. Ninety-two percent of patients scored removal of the system as comfortable. Median patient grade of scar after 1 month was 8 out of 10 points (interquartile range [IQR] 7-9). Median independent physician grade of photographs of the scars was 7.7 (IQR 7.1-8.0). CONCLUSION: Sutureless foil flip-over is promising, with excellent patient comfort characteristics and good to excellent cosmetic results. PMID- 22816520 TI - Low-temperature perception leading to gene expression and cold tolerance in higher plants. AB - Plant species exhibit a range of tolerances to low temperatures, and these constitute a major determinant of their geographical distribution and use as crops. When tolerance is insufficient, either chilling or freezing injuries result. A variety of mechanisms are employed to evade the ravages of extreme or sub-optimal temperatures. Many of these involve cold-responsive gene expression and require that the drop in temperature is first sensed by the plant. Despite intensive research over the last 100 yr or longer, we still cannot easily answer the question of how plants sense low temperature. Over recent years, genomic and post-genomic approaches have produced a wealth of information relating to the sequence of events leading from cold perception to appropriate and useful responses. However, there are also crucial and significant gaps in the pathways constructed from these data. We describe the literature pertaining to the current understanding of cold perception, signalling and regulation of low-temperature responsive gene expression in higher plants, raising some of the key questions that still intrigue plant biologists today and that could be targets for future work. Our review focuses on the control of gene expression in the pathways leading from cold perception to chilling and freezing tolerance. PMID- 22816521 TI - Downregulation of antigen-presenting cells in tonsil and lymph nodes of porcine reproductive and respiratory syndrome virus-infected pigs. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) can persist in different organs of infected pigs, which suggests a failure in the immune response. Antigen-presenting cells (APCs) play a pivotal role in the induction of effective T- and B-cell responses. In this study, we investigated the changes in the different APC subpopulations and T- and B-cell counts in the tonsil, retropharyngeal and mediastinal lymph nodes of pigs experimentally infected with a European PRRSV field isolate. Our results demonstrated that the expression of S100, SWC3, HLA-DR molecule and CD3 was diminished in the studied organs throughout the study, observing a significant negative correlation between viral antigen and HLA-DR expression in both retropharyngeal and mediastinal lymph nodes. In contrast, lambda-light chains showed an increase during the study. Taking all into account, after PRRSV infection, no enhancement in the number of APCs and T cells was observed, suggesting an impairment of the immune function which may allow the persistence of PRRSV into the organism. PMID- 22816522 TI - Which antithyroid drug regimen in paediatric Graves' disease? PMID- 22816523 TI - Surgical prevention and management of vascular complications of kidney transplantation. AB - The main surgical changes in kidney procurement, preparation, and transplantation procedures occurred 20 years ago and were undertaken despite the inability to design randomized studies. The objective was to assess the evolution of vascular complications after kidney transplantation in a setting of surgical preventive measures in a historical series. A monocentric series of 3129 consecutive kidney transplantations performed over 3 decades was reviewed. The occurrence of arterial or venous thromboses, stenoses, and aneurysms was analyzed in relation with kidney procurement, preparation, and transplantation techniques. Vascular complications occurred in 13.5% of the recipients with a mean 3-year decrease in kidney graft function. The transplantation of a right kidney without renal vein extension, multiple renal arteries, ex vivo vascular repairs, and end-to-end arterial anastomoses were the unfavorable surgical vascular factors. It was possible to manage Transplant Renal Artery Stenosis (TRAS) nonsurgically in 80% of the cases. The prevention of vascular complications begins from the time of organ procurement by skilled surgeons. The aims of organ preparation are to evaluate the vascular risk, select the organs, and to simplify the anatomical constraints of vascular implantations. The three surgical steps of kidney transplantation are determinant in postoperative vascular complications and the duration of graft function. PMID- 22816524 TI - Assessing county-level water footprints of different cellulosic-biofuel feedstock pathways. AB - While agricultural residue is considered as a near-term feedstock option for cellulosic biofuels, its sustainability must be evaluated by taking water into account. This study aims to analyze the county-level water footprint for four biofuel pathways in the United States, including bioethanol generated from corn grain, stover, wheat straw, and biodiesel from soybean. The county-level blue water footprint of ethanol from corn grain, stover, and wheat straw shows extremely wide variances with a national average of 31, 132, and 139 L of water per liter biofuel (L(w)/L(bf)), and standard deviation of 133, 323, and 297 L(w)/L(bf), respectively. Soybean biodiesel production results in a blue water footprint of 313 L(w)/L(bf) on the national average with standard deviation of 894 L(w)/L(bf). All biofuels show a greater green water footprint than the blue one. This work elucidates how diverse spatial resolutions affect biofuel water footprints, which can provide detailed insights into biofuels' implications on local water sustainability. PMID- 22816525 TI - Improved cloning efficiency and developmental potential in bovine somatic cell nuclear transfer with the oosight imaging system. AB - In somatic cell nuclear transfer (SCNT) procedures, exquisite enucleation of the recipient oocyte is critical to cloning efficiency. The purpose of this study was to compare the effects of two enucleation systems, Hoechst staining and UV irradiation (hereafter, irradiation group) and Oosight imaging (hereafter, Oosight group), on the in vitro production of bovine SCNT embryos. In the Oosight group, the apoptotic index (2.8 +/- 0.5 vs. 7.3 +/- 1.2) was lower, and the fusion rate (75.6% vs. 62.9%), cleavage rate (78.0% vs. 63.7%), blastocyst rate (40.2% vs. 29.2%), and total cell number (128.3+/-4.8 vs. 112.2 +/- 7.6) were higher than those in the irradiation group (all p<0.05). The overall efficiency after SCNT was twice as high in the Oosight group as that in the irradiation group (p<0.05). The relative mRNA expression levels of Oct4, Nanog, Interferon tau, and Dnmt3A were higher and those of Caspase-3 and Hsp70 were lower in the Oosight group compared with the irradiation group (p<0.05). This is the first report to show the positive effect of the Oosight imaging system on molecular gene expression in the SCNT embryo. The Oosight imaging system may become the preferred choice for enucleation because it is less detrimental to the developmental potential of bovine SCNT embryos. PMID- 22816526 TI - Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series. AB - BACKGROUND AND PURPOSE: The autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. The disease, first described in Canadian families from Quebec, is characterized by cerebellar ataxia, pyramidal tract involvement and peripheral neuropathy. METHODS: Analysis of SACS gene allowed the identification of 14 patients with ARSACS from 13 unrelated Italian families. Clinical phenotype, gene mutations and magnetic resonance imaging (MRI) findings were analysed. RESULTS: We found 16 novel SACS gene mutations, including a large in-frame deletion. The age at onset was in infancy, but one patient presented the first symptoms at age 32. Progression of the disease was variable, and increased muscle tone was mostly recognized in later stages. Structural MRI showed atrophy of the superior cerebellar vermis, a bulky pons exhibiting T2-hypointense stripes, identified as the corticospinal tract (CST), thinning of the corpus callosum and a rim of T2-hyperintensity around the thalami in 100% of cases. The presence of iron or other paramagnetic substances was excluded. Diffusion tensor imaging (DTI) revealed grossly over-represented transverse pontine fibres (TPF), which prevented reconstruction of the CST at this level (100% of cases). In all patients, significant microstructural alterations were found in the supratentorial white matter of forceps, cingulum and superior longitudinal fasciculus. CONCLUSIONS: Our findings further enlarge the genetic spectrum of SACS mutations and widen the study of clinical phenotype. MRI characteristics indicate that pontine changes and supratentorial abnormalities are diagnostic. The over-representation of TPF on DTI suggests a developmental component in the pathogenesis of the disease. PMID- 22816527 TI - Meaningful use of electronic health record systems and process quality of care: evidence from a panel data analysis of U.S. acute-care hospitals. AB - OBJECTIVE: To estimate the incremental effects of transitions in electronic health record (EHR) system capabilities on hospital process quality. DATA SOURCE: Hospital Compare (process quality), Health Information and Management Systems Society Analytics (EHR use), and Inpatient Prospective Payment System (hospital characteristics) for 2006-2010. STUDY SETTING: Hospital EHR systems were categorized into five levels (Level_0 to Level_4) based on use of eight clinical applications. Level_3 systems can meet 2011 EHR "meaningful use" objectives. Process quality was measured as composite scores on a 100-point scale for heart attack, heart failure, pneumonia, and surgical care infection prevention. Statistical analyses were conducted using fixed effects linear panel regression model for all hospitals, hospitals stratified on condition-specific baseline quality, and for large hospitals. PRINCIPAL FINDINGS: Among all hospitals, implementing Level_3 systems yielded an incremental 0.35-0.49 percentage point increase in quality (over Level_2) across three conditions. Hospitals in bottom quartile of baseline quality increased 1.16-1.61 percentage points across three conditions for reaching Level_3. However, transitioning to Level_4 yielded an incremental decrease of 0.90-1.0 points for three conditions among all hospitals and 0.65-1.78 for bottom quartile hospitals. CONCLUSIONS: Hospitals transitioning to EHR systems capable of meeting 2011 meaningful use objectives improved process quality, and lower quality hospitals experienced even higher gains. However, hospitals that transitioned to more advanced systems saw quality declines. PMID- 22816528 TI - The implications of age and comorbidity on survival following epithelial ovarian cancer: summary and results from a Centers for Disease Control and Prevention study. AB - BACKGROUND: Advances in treatment have improved ovarian cancer survival for most women, although less for the elderly. We report on this disparity and add further evidence about the relationship among age, comorbidity, and survival after ovarian cancer. METHODS: To examine age and comorbidity, Centers for Disease Control and Prevention (CDC)-funded cancer registries examined 2367 women residing in New York and Northern California diagnosed with epithelial ovarian cancer (1998-2000). Subjects were identified through tumor registries, treatment data were supplemented with physician survey, and comorbidity was identified through hospital discharge database linkages. Proportional hazards modeling was used to estimate the risk of death by age and comorbidity, adjusting for clinical and sociodemographic factors. RESULTS: Crude survival at 1 year and 3 years was 71.9% and 50.1%, respectively. Within stage, age-specific survival rates were lower in the oldest groups, particularly for those with advanced disease. For age 75+, 3-year survival was 13% vs. 50% in those <35 (stage IV). For all stages, women without comorbidity had higher survival rates than those with comorbidity. Older age and comorbidity were both associated with advanced stage and less aggressive treatment. The adjusted risk of death was 40%, and it was 80% higher for the 65-74 and 75+ groups, respectively, compared to women 35-64 (p<0.00). Comorbidity increased the risk of death by 40% (p<0.00). CONCLUSIONS: This study confirmed the independent adverse effects of age and comorbidity on survival following ovarian cancer. As the population ages, the co-occurrence of ovarian cancer and comorbidity will increase. Further work identifying critical conditions that impact survival could potentially inform complex treatment decisions. PMID- 22816529 TI - Monte Carlo studies on the interfacial properties and interfacial structures of ternary symmetric blends with gradient copolymers. AB - Using Monte Carlo simulation methods, the effects of the comonomer sequence distribution on the interfacial properties (including interfacial tension, interfacial thickness, saturated interfacial area per copolymer, and bending modulus) and interfacial structures (including chain conformations and comonomer distributions of the simulated copolymers at the interfaces) of a ternary symmetric blend containing two immiscible homopolymers and one gradient copolymer are investigated. We find that copolymers with a larger composition gradient width have a broader comonomer distribution along the interface normal, and hence more pronouncedly enlarge the interfacial thickness and reduce the interfacial tension. Furthermore, the counteraction effect, which arises from the tendency of heterogeneous segments in gradient copolymers to phase separate and enter their miscible phases to reduce the local enthalpy, decreases the stretching of copolymers along the interface normal direction. As a result, copolymers with a larger width of gradient composition can occupy a larger interfacial area and form softer monolayers at saturation and are more efficient in facilitating the formation of bicontinuous microemulsions. Additionally, chain length ratio, segregation strength, and interactions between homopolymers and copolymers can alter the interfacial character of gradient copolymers. There exists a strong coupling between the comonomer sequence distribution, chain conformation, and interfacial properties. Especially, bending modulus is mainly determined by the complicated interplay of interfacial copolymer density and interfacial chain conformation. PMID- 22816530 TI - Nanoscale strontium titanate photocatalysts for overall water splitting. AB - SrTiO(3) (STO) is a large band gap (3.2 eV) semiconductor that catalyzes the overall water splitting reaction under UV light irradiation in the presence of a NiO cocatalyst. As we show here, the reactivity persists in nanoscale particles of the material, although the process is less effective at the nanoscale. To reach these conclusions, Bulk STO, 30 +/- 5 nm STO, and 6.5 +/- 1 nm STO were synthesized by three different methods, their crystal structures verified with XRD and their morphology observed with HRTEM before and after NiO deposition. In connection with NiO, all samples split water into stoichiometric mixtures of H(2) and O(2), but the activity is decreasing from 28 MUmol H(2) g(-1) h(-1) (bulk STO), to 19.4 MUmol H(2) g(-1) h(-1) (30 nm STO), and 3.0 MUmol H(2) g(-1) h(-1) (6.5 nm STO). The reasons for this decrease are an increase of the water oxidation overpotential for the smaller particles and reduced light absorption due to a quantum size effect. Overall, these findings establish the first nanoscale titanate photocatalyst for overall water splitting. PMID- 22816531 TI - Emotion regulation and risk taking: predicting risky choice in deliberative decision making. AB - Only very recently has research demonstrated that experimentally induced emotion regulation strategies (cognitive reappraisal and expressive suppression) affect risky choice (e.g., Heilman et al., 2010). However, it is unknown whether this effect also operates via habitual use of emotion regulation strategies in risky choice involving deliberative decision making. We investigated the role of habitual use of emotion regulation strategies in risky choice using the "cold" deliberative version of the Columbia Card Task (CCT; Figner et al., 2009). Fifty three participants completed the Emotion Regulation Questionnaire (ERQ; Gross & John, 2003) and--one month later--the CCT and the PANAS. Greater habitual cognitive reappraisal use was related to increased risk taking, accompanied by decreased sensitivity to changes in probability and loss amount. Greater habitual expressive suppression use was related to decreased risk taking. The results show that habitual use of reappraisal and suppression strategies predict risk taking when decisions involve predominantly cognitive-deliberative processes. PMID- 22816532 TI - Cutaneous Mycobacterium haemophilum infection in a patient receiving infliximab for psoriasis. PMID- 22816533 TI - Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized double-blind placebo-controlled study. AB - OBJECTIVES: Pioglitazone is an insulin sensitizer used for the management of type 2 diabetes mellitus (T2DM). It has been shown to reduce testosterone level in patients with polycystic ovarian syndrome. However, its effect on testosterone in men has not been studied. RESEARCH DESIGN AND METHODS: A randomized, double blind, placebo-controlled trial with 6 months follow-up. Fifty (25 in each group) eugonadal men (well virilized and total testosterone >= 12 nm) with T2DM, aged 30 55 year and HbA1c of <= 7.5% were randomly assigned to receive pioglitazone 30 mg per day or placebo along with existing glimepiride and metformin therapy. RESULTS: As compared to placebo, 6 months of pioglitazone therapy in patients with T2DM resulted in significant reduction in mean total testosterone level (16.1 to 14.9 vs 17.1 to 17.0 nm; P = 0.031), calculated free testosterone (P = 0.001) and bioavailable testosterone (P = 0.000) despite significant increase in sex hormone-binding globulin (P = 0.000). Plasma androstenedione (?(4) ) level increased (1.5 to 1.9 vs 1.7 to 1.7 ng/ml; P = 0.051) following pioglitazone therapy. The decrease in testosterone was independent of change in body weight, body fat and HbA1c. CONCLUSION: Pioglitazone therapy significantly decreases total, free and bioavailable testosterone in eugonadal men with T2DM. The effects of these alterations need to be determined by further long-term studies. PMID- 22816534 TI - P-wave morphology: underlying mechanisms and clinical implications. AB - Increasing awareness of atrial fibrillation (AF) and its impact on public health revives interest in identification of noninvasive markers of predisposition to AF and ECG-based risk stratification. P-wave duration is generally accepted as the most reliable noninvasive marker of atrial conduction, and its prolongation has been associated with history of AF. However, patients with paroxysmal AF without structural heart disease may not have any impressive P-wave prolongation, thus suggesting that global conduction slowing is not an obligatory requirement for development of AF. P-wave morphology is therefore drawing increasing attention as it reflects the three-dimensional course of atrial depolarization propagation and detects local conduction disturbances. The factors that determine P-wave appearance include (1) the origin of the sinus rhythm that defines right atrial depolarization vector, (2) localization of left atrial breakthrough that defines left atrial depolarization vector, and (3) the shape and size of atrial chambers. However, it is often difficult to distinguish whether P-wave abnormalities are caused by atrial enlargement or interatrial conduction delay. Recent advances in endocardial mapping technologies have linked certain P-wave morphologies with interatrial conduction patterns and the function of major interatrial conduction routes. The value of P-wave morphology extends beyond cardiac arrhythmias associated with atrial conduction delay and can be used for prediction of clinical outcome of a wide range of cardiovascular disorders, including ischemic heart disease and congestive heart failure. PMID- 22816535 TI - The year of 2011 in electrocardiology. PMID- 22816536 TI - Multicenter automatic defibrillator implantation trial: reduce inappropriate therapy (MADIT-RIT): background, rationale, and clinical protocol. AB - The implantable cardioverter defibrillator (ICD) is highly effective in reducing mortality due to cardiac arrhythmias in high-risk cardiac patients. However, inappropriate therapies caused predominantly by supraventricular tachyarrhythmias (SVTs) remain a significant side effect of ICD therapy despite medical treatment, affecting 8-40% of patients. The MADIT-RIT is a global, prospective, randomized, nonblinded, three-arm, multicenter clinical investigation to be performed in the Unites States, Europe, Canada, Israel and Japan, and will utilize approximately 90 centers with plan to enroll 1500 patients programmed to three treatment arms. The objective of the MADIT-RIT trial is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-Arm B) and/or long delay in combination with detection enhancements (MADIT-RIT-Arm C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT-Arm A) during postimplant follow-up of patients with indication for primary prevention device therapy. This paper describes design and analytic plan for the MADIT-RIT trial. PMID- 22816537 TI - Enhancing the reliability in the noninvasive measurement of the his bundle magnetic field using a novel signal averaging methodology. AB - BACKGROUND: Extraction of the weak electrical activity of the "His Bundle" (HB) by noninvasive methods has not been very successful in the past. The study reassesses the use of signal averaged magnetocardiography (SAMCG), overcoming some of the limitations in earlier studies including in the signal averaging methodology. METHODS: SAMCG on healthy subjects (14 male and 1 female) were performed using R-peak as the fiducial point in all cases and also using QRS onset as the fiducial point in select cases. RESULTS: A conspicuous feature (H) with a magnitude up to 200 femto Tesla (fT) attributed to the HB activity was observed in the PR segment at several spatial positions on the thorax, with onset at 35-50 ms before the QRS-onset (V) in 15 out of 18 trials constituting 83% of cases studied. The QRS-onset as the fiducial point resolved the feature better compared to the conventionally used R-peak, especially in trials exhibiting spread in heart rate (HR). This is attributed to the fluctuations in Q(on) RD (the time interval between QRS-onset and R-peak) compared to the temporal stability of the H-V duration. conclusions: SAMCG reveals a well-resolved H feature. The double hump morphology of the feature extended at least up to a frequency of 150 Hz. The importance of the choice of QRS-onset as the fiducial point is unequivocally demonstrated, illustrated by measurements on subjects exhibiting considerable heart rate variability. The latter has a general validity and should be applicable to SAECG as well. PMID- 22816538 TI - Relation between beat-to-beat QT interval variability and T-wave amplitude in healthy subjects. AB - OBJECTIVES: Elevated beat-to-beat QT interval variability (QTV) has been associated with increased cardiovascular morbidity and mortality.The aim of this study was to investigate interlead differences in beat-to-beat QTV of 12-lead ECG and its relationship with the T wave amplitude. METHODS: Short-term 12-lead ECGs of 72 healthy subjects (17 f, 38 +/- 14 years; 55 m, 39 +/- 13 years) were studied. Beat-to-beat QT intervals were extracted separately for each lead using a template matching algorithm. We calculated the standard deviation of beat-to beat QT intervals as a marker of QTV as well as interlead correlation coefficients. In addition, we measured the median T-wave amplitude in each lead. RESULTS: There was a significant difference in the standard deviation of beat-to beat QT intervals between leads (minimum: lead V(3) (2.58 +/- 1.36 ms), maximum: lead III (7.2 +/- 6.4 ms), ANOVA: P < 0.0001). Single measure intraclass correlation coefficients of beat-to-beat QT intervals were 0.27 +/- 0.18. Interlead correlation coefficients varied between 0.08 +/- 0.33 for lead III and lead V(1) and 0.88 +/- 0.09 for lead II and lead aVR. QTV was negatively correlated with the T-wave amplitude (r =-0.62, P < 0.0001). There was no significant affect of mean heart rate, age or gender on QT variability (ANOVA: P > 0.05). CONCLUSIONS: QTV varies considerably between leads in magnitude as well as temporal patterns. QTV is increased when the T wave is small. PMID- 22816539 TI - Evaluation of 5-year risk of cardiovascular events in patients after acute myocardial infarction using synchronization of 0.1-Hz rhythms in cardiovascular system. AB - BACKGROUND: Synchronization between 0.1-Hz rhythms in cardiovascular system is deteriorated at acute myocardial infarction (AMI) leading to a disruption of natural functional couplings within the system of autonomic regulation. OBJECTIVE: This study evaluates the prognostic value of autonomic regulation indices for the 5-year risk of fatal and nonfatal cardiovascular events in patients after AMI. METHODS AND RESULTS: We studied 125 patients (53 [42%] female) after AMI aged between 30 and 83 years. The period of observation was 5 years with checkpoints at the first week after AMI and after each year after AMI. We compared the prognostic value of established clinical characteristics and degree S of synchronization between 0.1-Hz rhythms in heart rate and microcirculation for evaluation of the 5-year risk of mortality and recurrent myocardial infarction (MI) in patients after AMI. Acute heart failure Killip 2-4 at AMI and S < 20% at the first week after AMI were identified as the most important factors for evaluation of the risk of 5-year mortality in patients after AMI (chi(2) = 14.2, P = 0.003). Sensitivity and specificity of low S (<20%) at the first week after AMI were 76% and 43%, respectively. For evaluation of the 5-year risk of recurrent MI index S had no advantage over established clinical characteristics. CONCLUSION: The value of S below 20% in patients with AMI is a sensitive marker of high risk of mortality during the subsequent five years. It is characterized by better prognostic value than most of established clinical characteristics. PMID- 22816540 TI - T-wave amplitude is related to physical fitness status. AB - BACKGROUND: Abnormalities in repolarization may reflect underlying myocardial pathology and play a prominent role in arrhythmogenesis The T-wave amplitude has been associated with cardiovascular outcome in patients with acute myocardial infarction (MI) Additionally, T-wave amplitude is considered a predictor of arrhythmias, as well as being related to an individual's inflammatory status. The combined influence of different variables, such as inflammation, cardiovascular risk factors and physical fitness status, on the T-wave amplitude has not been evaluated to date. The aim of this study was to identify factors that affect the T-wave amplitude. METHODS: Data from 255 consecutive apparently healthy individuals included in the Tel Aviv Medical Center Inflammation Survey (TAMCIS) were reviewed. All patients had undergone a physical examination and an exercise stress test, and different inflammatory and metabolic biomarkers (fibrinogen, potassium, and high-sensitivity C-reactive protein) were measured. RESULTS: Multivariate stepwise analysis revealed that the body mass index and the resting heart rate were significantly associated with the T-wave amplitude (beta=-0.34, P < 0.001; beta=-0.19, P = 0.03, respectively) in males, while the recovery rate and the usage of statins significantly affected the T-wave amplitude in females (beta= 0.36, P = 0.002; beta= 0.35, P = 0.002, respectively). Inflammatory variables had no significant affect on the T-wave amplitude of either gender. CONCLUSIONS: In conclusion, the T-wave amplitude is linked to an individual's physical fitness and not to his/her inflammatory status. PMID- 22816541 TI - Heart rate variability assessment of the effect of physical training on autonomic cardiac control. AB - BACKGROUND: The effect of exercise interventions on autonomic nervous system (ANS) control of the heart by heart rate variability (HRV) is often investigated in just one position. It was hypothesized that results of exercise-induced changes on ANS are dependent on body position and that it is possible to distinguish between exercise induced changes in vagal and sympathetic influence by taking measurements in different body positions. METHODS: One hundred eighty three (male = 100, female = 83) healthy volunteers, between 18 and 22 years, participated in a prospective twelve week medium to high intensity exercise intervention study with a self-control design. The influence of the exercise intervention was investigated on supine, rising, and standing as well as on the orthostatic response. Time domain, frequency domain and nonlinear (Poincare) HRV analysis were performed. RESULTS: The exercise intervention lead to a significant increase (P < 0.05) in vagal influence during supine, rising, and standing. Sympathetic control in the supine position was decreased and increased during rising and standing. In the initial orthostatic response to rising from the supine position, the exercise intervention lead to increased (P < 0.05) vagal withdrawal as well as increased sympathetic control. The orthostatic response measured as the difference between standing and supine indicated only an exercise induced increase in sympathetic control. CONCLUSIONS: Exercise-induced changes in sympathetic and parasympathetic ANS control differ, depending on posture and period of measurement. Exercise induced changes in parasympathetic and sympathetic outflow, respectively, can be extracted from measurements from supine, through the orthostatic response, to standing, thereby detecting changes in ANS that are otherwise obscured. PMID- 22816542 TI - The significance of heart rate turbulence in predicting major cardiovascular events in patients after myocardial infarction treated invasively. AB - INTRODUCTION: The role of heart rate turbulence (HRT) related to baroreflex sensitivity in predicting mortality after myocardial infarction (MI) has been confirmed by several investigators. However, the significance of HRT in predicting major adverse cardiovascular events (MACE) following acute MI is unknown. PURPOSE: To analyze the prognostic value of HRT and other independent risk factors associated with autonomic regulation of MACE. METHODS: HRT was assessed based on 24-hour Holter recordings in 500 patients (pts) with acute MI treated invasively (352 M, aged 60.58 years). Turbulence onset (TO,%), slope (TS, ms/RR interval) and timing (TT) were calculated. TO >= 0, TS <= 2.5 and TT >= 10 were considered abnormal; classic and own categories were defined. Time domain heart rate variability (HRV) parameters were also calculated. Within 30.1 +/- 15.1 months of follow-up, MACE occurred in 116 pts. RESULTS: Abnormal TO, TS, and TT were significantly more frequent in patients with MACE (P < 0.05 for each parameter, classic and own categories). In long-term follow-up, the largest differences in MACE were observed in patients with own category comprising abnormal TO, TS, and TT. Combining HRT parameters with SDNN (total HRV index) augmented their predictive value. Independent risk factors for MACE were TT, SDNN and rMSSD (a parasympathetic activity index) (HR 2.44, 1.71 and 1.69 respectively; P < 0.05). CONCLUSION: Abnormal HRT distinguishes patients at risk of MACE after MI. Own category encompassing three abnormal HRT parameters best differentiates patients at risk of MACE. Turbulence timing is a strong independent risk factor for MACE following MI. PMID- 22816543 TI - High-risk electrocardiographic parameters are ubiquitous in patients with ischemic cardiomyopathy. AB - BACKGROUND: The electrocardiogram (ECG) can be used to predict cardiovascular risk; however, like all risk factors with imperfect specificity, studies in low risk populations have been plagued by poor predictive accuracy. Although predictive accuracy might be improved among cohorts with a higher likelihood of cardiovascular events, this would also affect the prevalence of abnormal parameters and their exclusions. METHOD: To determine the magnitude of these changes in a cohort with ischemic cardiomyopathy we analyzed 15 previously validated high-risk parameters from the resting and ambulatory ECG in subjects enrolled in the Prediction of Arrhythmic Events with Positron Emission Tomography (PAREPET) study (n = 198). RESULTS: Using the published exclusion criteria from the validation studies (i.e., atrial fibrillation, persistent pacing, prolonged QRS), only 4 high-risk ECG parameters (27%) could be evaluated in all subjects and only 42% of subjects could have all 15 ECG parameters assessed. Nevertheless, almost every subject (97%) had at least one abnormal parameter. On average, there were 3.4 +/- 1.8 (range, 0-8) high-risk ECG parameters per subject among the 11.7 +/- 4.5 (range, 4-15) parameters that could be assessed. CONCLUSIONS: Thus, 34% of all assessable parameters were abnormal. In conclusion, a significant proportion of ECG parameters cannot be assessed in patients with ischemic cardiomyopathy, but high-risk results are ubiquitous. The influence of these issues will be clarified when the results of the PAREPET study are available to actually determine the predictive value of these parameters on cause-specific mortality in a high-risk cohort. PMID- 22816544 TI - P-wave morphologic characteristics predict cardiovascular events in a community dwelling population. AB - BACKGROUND: There have been few reports on the relationship between P-wave characteristics and long-term cardiovascular events. METHODS: A nested case control study was conducted as part of the Jichi Medical School cohort study, which enrolled 12,490 subjects in a community-dwelling population. The mean follow-up period was 10.7 years. The P-wave characteristics of 526 patients who suffered cardiovascular events (fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, and sudden death) within the follow-up period (case group) were compared with those of 1578 matched controls (control group). The P-wave morphology was classified as normal, deflected, and notched type in precordial leads. A broad P wave was defined as a maximum P-wave duration of more than 120 ms in any of the 12 leads. RESULTS: The mean age was 64 +/- 8 years and the percentage of males was 54% in both groups. A notched P wave at baseline was observed in 10.1% of the case group and 6.0% of the control group (P = 0.001). A notched P wave was a significant predictor of cardiovascular events after adjustment for covariates (odds ratio = 1.59; 95% confidence interval = 1.08 2.33). Among the patients with left ventricular hypertrophy as evaluated by the Sokolow-Lyon criteria or Cornell product criteria, there was no significant difference in cardiovascular events between those with and those without a notched P wave, but in the absence of left ventricular hypertrophy, patients with a notched P wave suffered more cardiovascular events than those without a notched P wave by each criteria. CONCLUSION: P-wave morphologic characteristics were effective for predicting cardiovascular events. PMID- 22816545 TI - Risk stratification for serious arrhythmic events using nonsustained ventricular tachycardia and heart rate turbulence detected by 24-hour holter electrocardiograms in patients with left ventricular dysfunction. AB - BACKGROUND: Previous studies have described the clinical usefulness of the presence of nonsustained ventricular tachycardia (NSVT) and defined heart rate turbulence (HRT) in stratifying patients at risk. We prospectively assessed whether HRT can facilitate the predictive accuracy of NSVT for identifying patients at risk for serious arrhythmic events in patients with left ventricular (LV) dysfunction. METHODS: We enrolled 299 consecutive patients with LV dysfunction (ejection fraction <= 40%) including ischemic (n = 184) and nonischemic causes (n = 115). The presence of NSVT was assessed on Holter electrocardiograms (ECGs). HRT was simultaneously measured from Holter ECGs, assessing two parameters: turbulence onset (TO) and turbulence slope (TS). HRT was considered positive when both TO and TS were abnormal. The end point was defined as of sudden cardiac death (SCD) and sustained ventricular tachyarrhythmias (VTs). RESULTS: NSVT was documented in 93 patients (32.7%). For HRT assessment, 17 patients (5.6%) were not utilized. Of 282 patients, 68 (24.1%) were HRT positive. During follow-up of 960 +/- 444 days, 14 patients (5.0%) reached the end point. NSVT, HRT, and diabetes were significantly associated with the end point. On multivariate analysis, NSVT had the strongest value for the end point, with an HR of 4.4 (95%CI, 1.4-14.3; P = 0.0138). When NSVT combined with HRT, the predictive accuracy is more increased, with an HR of 8.2 (95%CI, 2.9 23.3; P < 0.0001). The predictive values of the combination were higher than single use of NSVT or HRT. CONCLUSIONS: HRT can facilitate the predictive accuracy of NSVT for identifying patients at risk for serious arrhythmic events in patients with LV dysfunction. PMID- 22816546 TI - Optimal QT/JT interval assessment in patients with complete bundle branch block. AB - BACKGROUND: Prolonged ventricular repolarization duration confers increased risk for malignant ventricular arrhythmias. We sought to clarify the optimal method of QT/JT interval assessment in patients with complete bundle branch block (BBB). METHODS: Study patients (n = 71) were dual-chamber device recipients with baseline left or right BBB who preserved intrinsic ventricular activation during incremental atrial pacing. Patients were classified according to the presence or not of structural heart disease. The former group received chronic amiodarone therapy. QT and JT intervals were recorded at baseline heart rate of 51 +/- 4 beats/min and during atrial pacing at 60, 80, and 100 beats/min. We used linear mixed-effects models to assess the effect of heart rate on the derived QTc and JTc values with the use of six different heart rate correction formulae. RESULTS: Heart rate had a significant effect on the QTc and the JTc intervals regardless of the correction formula used (P < 0.001 for all formulae). The formula of Hodges demonstrated the least variability in QTc and JTc measurements across the different heart rates in both patients groups without (F = 15.05 and F = 13.53, respectively) and with structural heart disease (F = 5.71 and F = 7.69, respectively), followed by the Nomogram and Framingham methods, whereas the uncorrected QT and JT intervals showed comparable heart rate-dependency. The application of Bazett's JTc and QTc led to the most pronounced interval variations in any case with BBB. CONCLUSIONS: The Hodges, Nomogram and Framingham correction methods provide best assessment of QT/JT intervals in BBB, whereas Bazett's formula exaggerates heart rate-dependency of ventricular repolarization intervals. PMID- 22816547 TI - The presence of giant epsilon waves in a patient with arrhythmogenic right ventricular cardiomyopathy. AB - Epsilon wave, which is a major diagnosis criterion for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD/C), is defined as small amplitude potentials. The present case is a 49-year-old man with a history of syncope and palpitations for 6 months. The ECG documented ventricular tachycardia (VT) when the patient has palpitations. However, there has been a giant epsilon wave in sinus rhythm. Electroanatomic mapping also has a prominent double potential identified on ABL catheter. The amplitude of epsilon wave reached 0.9 mV, which might be the maximum epsilon wave until now. PMID- 22816548 TI - Complete heart block following a blow on the chest by a soccer ball: a rare manifestation of commotio cordis. AB - Commotio cordis is a rare type of blunt cardiac injury in which low impact chest trauma causes sudden cardiac arrest, usually occurs from being struck by a projectile during sports. The most common arrhythmia during commotio cordis is ventricular fibrillation, although complete heart block and an idioventricular rhythm have also been reported. We describe a case of a young patient who presented with a persistent third-degree atrioventricular block and a left bundle branch block, following blunt chest trauma, as a result of blow by soccer ball and subsequently needed a permanent pacemaker. PMID- 22816549 TI - Wolff-Parkinson-White syndrome and acute pulmonary embolism: a case report. AB - A 48-year-old woman admitted to the emerhency departments due to sudden onset of dyspnea. The diagnosis of pulmonary embolism (PE) was made and thrombolytic therapy was started. Baseline ECG showed signs of right ventricular overload and after thrombolysis, short PR, wide QRS, and delta wave indicating Wolf-Parkinson White (WPW) pattern were appeared. In this case report, we discuss ECG of patient with PE mimicknig WPW. PMID- 22816550 TI - Vasospastic angina with J-wave pattern and polymorphic ventricular tachycardia effectively treated with quinidine. AB - BACKGROUND: Myocardial ischemia during coronary spasm may generate malignant ventricular arrhythmias. The J-wave pattern was suggested to be a marker of a disorder associated with life-threatening arrhythmias. RESULTS: We report the case of a patient with vasospastic angina and J-wave pattern in inferior and lateral leads associated with polymorphic ventricular tachycardia which was effectively treated only with quinidine-vasodilating drugs were not able to prevent the arrhythmia although they were effective in preventing ischemic events. CONCLUSION: The J-wave pattern in inferolateral leads may be a sign of electrical vulnerability to lethal ventricular arrhythmia in patients suffering from vasospastic angina--quinidine can effectively prevent such arrhythmias in these patients. PMID- 22816551 TI - Determination of integron frequency by a polymerase chain reaction-restriction fragment length polymorphism method in multidrug-resistant Escherichia coli, which causes urinary tract infections. AB - The purpose of this study was to determine the presence of integrons in Escherichia coli, which cause urinary tract infections, and to define the association between integrons and antimicrobial susceptibility. Susceptibility of 200 isolates from urine samples of patients suffering from urinary tract infections to 13 antibiotics was determined by the Kirby-Bauer disk diffusion method. The existence of class1 and 2 integrons in resistant isolates was assessed by polymerase chain reaction-restriction fragment length polymorphism and sequencing. Antibiotic resistance patterns were observed as follows: amoxicillin 78%, tetracycline 76.1%, co-trimoxazole 67.7%, cephalotin 60%, nalidixic acid 57.4%, chloramphenicol 49%, gentamicin 46.4%, ceftazidim 38.1%, ciprofloxacin 36.2%, nitrofurantoin 33.5%, amikacin 32.1%, norfloxacin 36.1%, and imipenem 27.1%. Of 200 isolates, 155 (77.5%) were multidrug resistant (MDR). The existence of integrons was confirmed in 50.3% of isolates. Three class 1 integron types, aadA2 being the most frequently found, and four class 2 integron types are described. Significant association between resistance to gentamicin, co trimoxazole, cephalotin, ceftazidim, imipenem, chloramphenicol, and nalidixic acid with the existence of integrons was observed. Multidrug resistance suggests that the strategy for treatment of patients with E.coli infections needs to be revised. Furthermore, it was shown that integrons may be partly responsible for multidrug resistance. Imipenem and norfloxacin were the most effective antibiotics against isolates. PMID- 22816552 TI - The role of automobiles for the future of aluminum recycling. AB - To reach required product qualities with lowest costs, aluminum postconsumer scrap is currently recycled using strategies of downgrading and dilution, due to difficulties in refining. These strategies depend on a continuous and fast growth of the bottom reservoir of the aluminum downgrading cascade, which is formed by secondary castings, mainly used in automotive applications. A dynamic material flow model for the global vehicle system was developed to assess the likelihood, timing, and extent of a potential scrap surplus. The results demonstrate that a continuation of the above-mentioned strategies will lead to a nonrecyclable scrap surplus by around 2018 +/- 5 if no additional measures are taken. The surplus could grow to reach a level of 0.4-2 kg/cap/yr in 2050, corresponding to a loss of energy saving potential of 43-240 TWh/yr electricity. Various intervention options for avoiding scrap surplus are discussed. Effective strategies need to include an immediate and rapid penetration of dramatically improved scrap sorting technologies for end-of-life vehicles and other aluminum applications. PMID- 22816553 TI - Perception of picky eating among children in Singapore and its impact on caregivers: a questionnaire survey. AB - BACKGROUND: Picky eating is relatively common among infants and children, often causing anxiety for parents and caregivers. The purpose of this study was to determine the key aspects of picky eating and feeding difficulties among children aged 1 to 10 years in Singapore and the impact on their parents or caregivers. METHODS: In this survey, 407 parents or grandparents who are the primary caregivers of children aged 1 to 10 years in Singapore were interviewed via telephone using a structured questionnaire of 36 questions. Respondents were randomly selected from the Singapore Residential Telephone Directory to meet a pre-set interlocked quota of race, sex, and age to represent the population. Quantitative data collected included demographics, body weight and height, respondents' perceptions of the duration of picky eating, the child's eating habits and perceived health status, respondents' attitudes towards picky eating, coping strategies and the impact on family relationships. Bonferroni z-test and t test were used to indicate significance across groups or demographics, while Pearson correlation coefficient was used to measure the strength of association between variables. RESULTS: One-half of the respondents reported that the child was 'all the time' (25.1%) or sometimes (24.1%) a picky eater. When aided with a list of typical behaviours, the respondent-reported prevalence of picky eating or feeding difficulties occurring 'all the time' increased to 49.6%. The highest number of respondents first noticed the child's picky eating behaviours or feeding difficulties as early as 1 year (20.0%). Children 3 to 10 years [p = 0.022], children of professional respondents (p = 0.019), and children with a family history of picky eating (p = 0.03) were significantly more likely to be picky eaters. Overall, all 'picky eating' and all 'feeding difficulty' behaviours occurring 'all the time' were significantly associated with caregiver stress when feeding (p = 0.000026 and p = 0.000055, respectively) and with a negative impact on family relationships (p = 0.011 and p = 0.00000012, respectively). CONCLUSIONS: The perceived prevalence and duration of picky eating behaviours and feeding difficulties are high. The impact on the respondent and family relationships appears to be significant in Singapore. Parental concerns about picky eating should be adequately assessed and managed in routine clinic consultations. PMID- 22816554 TI - Synthesis, isolation, characterization, and reactivity of high-energy stereogenic at-Ru carbenes: stereochemical inversion through olefin metathesis and other pathways. AB - The synthesis, isolation, purification (routine silica gel chromatography), and spectroscopic characterization of high-energy endo stereogenic-at-Ru complex isomers, generated by ring-opening/cross-metathesis (ROCM) reaction of the corresponding exo carbenes, are disclosed. We provide experimental evidence showing that an endo isomer can undergo thermal or Bronsted acid-catalyzed polytopal rearrangement, causing conversion to the energetically favored exo carbene. PMID- 22816555 TI - Effects of population size and isolation on heterosis, mean fitness, and inbreeding depression in a perennial plant. AB - * In small isolated populations, genetic drift is expected to increase chance fixation of partly recessive, mildly deleterious mutations, reducing mean fitness and inbreeding depression within populations and increasing heterosis in outcrosses between populations. * We estimated relative effective sizes and migration among populations and compared mean fitness, heterosis, and inbreeding depression for eight large and eight small populations of a perennial plant on the basis of fitness of progeny produced by hand pollinations within and between populations. * Migration was limited, and, consistent with expectations for drift, mean fitness was 68% lower in small populations; heterosis was significantly greater for small (mean = 70%, SE = 14) than for large populations (mean = 7%, SE = 27); and inbreeding depression was lower, although not significantly so, in small (mean = -0.29%, SE = 28) than in large (mean = 0.28%, SE = 23) populations. * Genetic drift promotes fixation of deleterious mutations in small populations, which could threaten their persistence. Limited migration will exacerbate drift, but data on migration and effective population sizes in natural populations are scarce. Theory incorporating realistic variation in population size and patterns of migration could better predict genetic threats to small population persistence. PMID- 22816556 TI - Human placenta-derived mesenchymal stem cells with silk fibroin biomaterial in the repair of articular cartilage defects. AB - Cartilage tissue engineering requires a porous biodegradable scaffold and nonimmunogenic cells with chondrogenic potential. In this study, the ability of the placenta-derived mesenchymal stem cells (PMSCs) to grow on silk fibroin (SF) biomaterial was determined, and the potential of a SF biomaterial serving as a delivery vehicle for human PMSCs in a rabbit articular cartilage defects model was evaluated. Human PMSCs were maintained in vitro in an allogeneic mixed lymphocyte reactions (MLR) system to investigate the suppressive effects on T cell proliferation. A total of 12 healthy adult New Zealand rabbits were implanted with a PMSC/SF biomaterial complex after articular cartilage defects of the femoral condyle in the knee were established. The repair of the articular cartilage defects was observed after 4 weeks, 8 weeks, and 12 weeks. Results from the MLR indicated that human PMSCs inhibited rabbit T cell responses. Knee damage was repaired by the newly formed hyaline cartilage, and within 12 weeks there was neither degeneration nor infiltration with lymphocytes or leukocytes, and no silk fibroin biomaterial residue was detected. In conclusion, the silk fibroin biomaterial can be applied as a new scaffold for cartilage tissue engineering, and implantation of human PMSCs on the cartilage can enhance repair of articular cartilage defects in a rabbit model. PMID- 22816557 TI - Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study. AB - Kidney transplant recipients who switched from a calcineurin inhibitor (CNI) to belatacept demonstrated higher calculated glomerular filtration rates (cGFRs) at 1 year in a Phase II study. This report addresses whether improvement was sustained at 2 years in the long-term extension (LTE). Patients receiving cyclosporine or tacrolimus were randomized to switch to belatacept or continue CNI. Of 173 randomized patients, 162 completed the 12-month main study and entered the LTE. Two patients (n = 1 each group) had graft loss between Years 1 2. At Year 2, mean cGFR was 62.0 ml/min (belatacept) vs. 55.4 ml/min (CNI). The mean change in cGFR from baseline was +8.8 ml/min (belatacept) and +0.3 ml/min (CNI). Higher cGFR was observed in patients switched from either cyclosporine (+7.8 ml/min) or tacrolimus (+8.9 ml/min). The frequency of acute rejection in the LTE cohort was comparable between the belatacept and CNI groups by Year 2. All acute rejection episodes occurred during Year 1 in the belatacept patients and during Year 2 in the CNI group. There were more non-serious mucocutaneous fungal infections in the belatacept group. Switching to a belatacept-based regimen from a CNI-based regimen resulted in a continued trend toward improved renal function at 2 years after switching. PMID- 22816558 TI - Sirenomelia: case reports and current concepts of pathogenesis. AB - We present 2 cases of sirenomelia and highlight the recent theories about its pathogenesis. Both cases had a large aberrant abdominal umbilical artery (AAUA) arising from the aorta, suggesting vascular steal as the pathophysiology. However, the bilateral upper limb defects noted in 1 case, the reported 10% association of holoprosencephaly and anencephaly, and the reports of sirenomelia with normal umbilical arteries point to the alternative caudal dysgenesis (CD) theory. This proposes that an insult at the early blastogenic stage interferes with the formation of the notochord, resulting in abnormal development of caudal structures, an AAUA, and occasional neural tube defects. We have also analyzed the implications of the similarities between sirenomelia/CD and the VATER association; the increased risk of CD but not sirenomelia in infants of diabetic mothers; the fact that sirenomelia, holoprosencephaly, and the VATER association are all more common in monozygotic twins; the experimental production of sirenomelia in mice; and the possible genetic implications of the co-occurrence of sirenomelia and CD. PMID- 22816559 TI - Covalent assembly of gold nanoparticles: an application toward transistor memory. AB - This work reports a versatile approach utilizing covalent assembly of functionalized gold nanoparticles for organic field-effect transistor (OFET) based memory devices. 11-Mercapto-1-undecanol functionalized gold nanoparticles (AuNPs) having size of 5 +/- 0.5 nm were synthesized and immobilized onto SiO(2) substrate through covalent binding using a functionalized polymer as a surface modifier. The pentacene OFET-based memory devices utilizing such covalently bound gold nanoparticles with nanoparticle density of 5 * 10(11) cm(-2) exhibited a large memory window (7.7 V), high on/off ratio between memory states (10(5)), and long retention time (>10,000 s). The present synthetic route for memory devices incorporating covalently immobilized gold nanoparticles has several advantages such as solution processable, enhanced device stability, low-cost, and low temperature process and will be a step toward realization for low-cost, lightweight, flexible, logic display driver, and flash memory applications. PMID- 22816560 TI - Frequencies of falls and associated features at different stages of Parkinson's disease. AB - BACKGROUND AND PURPOSE: To examine the frequencies and clinical characteristics of fallers and non-fallers at different stages of Parkinson's disease (PD). METHODS: The sample consisted of 232 patients in an unselected cross-sectional cohort of patients with PD, 207 newly diagnosed and drug naive patients and 175 controls. The examinations included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr, Schwab and England, and Mini-Mental State Examination. According to item 13 of the UPDRS, the participants were classified as fallers, rare-fallers and non-fallers. RESULTS: In the cross-sectional study cohort, 19% of the patients were classified as fallers and 25% as rare-fallers. Higher scores on activity of daily living (UPDRS ADL score) and motor complications (UPDRS complication of therapy score) were significantly and independently associated with falling. In the cohort of newly diagnosed patients with PD 2% were classified as fallers and 15% as rare-fallers. In the age- and sex-matched control group, none were fallers, and only 2% were rare-fallers. Patients with tremor-dominated PD subtype in both study populations did not fall. CONCLUSIONS: Falls are a markedly increasing problem in patients with PD as the disease progresses. Healthcare workers should ask patients about falling, and specially focus on patients with motor complications or postural instability and gait disability-dominated subtype of parkinsonism. PMID- 22816561 TI - Measures of social deprivation that predict health care access and need within a rational area of primary care service delivery. AB - OBJECTIVE: To develop a measure of social deprivation that is associated with health care access and health outcomes at a novel geographic level, primary care service area. DATA SOURCES/STUDY SETTING: Secondary analysis of data from the Dartmouth Atlas, AMA Masterfile, National Provider Identifier data, Small Area Health Insurance Estimates, American Community Survey, Area Resource File, and Behavioural Risk Factor Surveillance System. Data were aggregated to primary care service areas (PCSAs). STUDY DESIGN: Social deprivation variables were selected from literature review and international examples. Factor analysis was used. Correlation and multivariate analyses were conducted between index, health outcomes, and measures of health care access. The derived index was compared with poverty as a predictor of health outcomes. DATA COLLECTION/EXTRACTION METHODS: Variables not available at the PCSA level were estimated at block level, then aggregated to PCSA level. PRINCIPAL FINDINGS: Our social deprivation index is positively associated with poor access and poor health outcomes. This pattern holds in multivariate analyses controlling for other measures of access. A multidimensional measure of deprivation is more strongly associated with health outcomes than a measure of poverty alone. CONCLUSIONS: This geographic index has utility for identifying areas in need of assistance and is timely for revision of 35-year-old provider shortage and geographic underservice designation criteria used to allocate federal resources. PMID- 22816562 TI - Perforation of transverse colon by intra-operative cardiac pacing wires. PMID- 22816563 TI - Engraftment defect of cytokine-cultured adult human mobilized CD34(+) cells is related to reduced adhesion to bone marrow niche elements. AB - In vitro exposure of haematopoietic stem and progenitor cells (HSPC) to cytokines in expansion or gene therapy protocols reduces homing and engraftment in vivo. We have previously reported that this is related in part to altered tissue specificity of short-term homing, leading to loss of cells in non-haematopoietic tissues. Here we demonstrate that defective engraftment persists when cultured HSPC are transplanted by intrabone injection. Changes in engraftment function occur within 24 h of cytokine exposure, and are evident when engraftment is analysed solely in the injected bone. A novel ex vivo model of the bone marrow was developed, in which the attachment of infused HSPC in rodent long bones is reduced following culture with cytokines. Finally, cultured HSPC demonstrated reduced adhesion to N-cadherin, osteopontin and vascular cell-adhesion molecule 1, ligands present in bone marrow niches. These changes in adhesive function occur rapidly, and are not related to downregulation of the relevant receptors. Our findings suggest that cytokine exposure of adult human HSPC results in altered adhesion within bone marrow niches, further leading to reduced engraftment potential in vivo. PMID- 22816598 TI - Laparoscopic ischemic conditioning of the stomach prior to esophagectomy. AB - Several complications after esophagectomy with gastric pull-up are associated with ischemia within the gastric conduit. The aim of this study is to assess the feasibility of laparoscopic ischemic preconditioning of the stomach prior to thoracotomy, esophagectomy, and gastric pull-up with an intrathoracic anastomosis. A retrospective review of 24 consecutive patients between October 2008 and July 2011 with esophageal adenocarcinoma (stage I-III) undergoing laparoscopic gastric ischemic conditioning prior to esophagectomy was conducted. Conditioning included laparoscopic ligation of the left and short gastric arteries, celiac node dissection, and jejunostomy tube placement. Formal resection and reconstruction was then performed 4-10 days later. Of the 24 patients, 88% received neoadjuvant chemotherapy/radiation therapy. Twenty-three of the 24 patients underwent successful laparoscopic ischemic conditioning and subsequent esophagectomy. Total mean number of lymph nodes harvested was 21.8 (+/ 8.0), and a mean of 5.3 (+/-2.4) celiac lymph nodes identified. There were no conversions to an open procedure. Length of stay was 3.8 (+/-4.8) days with a median length of stay of 2 (1-24) days. Three patients experienced anastomotic leak, six patients experience delayed gastric emptying, and two patients developed anastomotic stricture. There were no surgical site infections. R0 resection was achieved in all patients who underwent laparoscopic ischemic conditioning followed by esophagectomy. Laparoscopic ischemic conditioning of the gastric conduit has been shown to be feasible and safe. PMID- 22816564 TI - The nonnucleoside reverse transcription inhibitor MIV-160 delivered from an intravaginal ring, but not from a carrageenan gel, protects against simian/human immunodeficiency virus-RT Infection. AB - We previously showed that a carrageenan (CG) gel containing 50 MUM MIV-150 (MIV 150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p>0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, >80% protection was observed (p<0.03). MIV-160 is a related NNRTI with a similar IC(50), greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV 160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo. PMID- 22816599 TI - Effects of caesarean section on serum levels of NT-proBNP. AB - OBJECTIVE: To determine the effects of delivery by caesarean on serum levels of N terminal fragment of precursor protein brain-type natriuretic peptide (NT proBNP). METHODS: Serum NT-proBNP levels were determined longitudinally at 24 and 36 weeks of gestation (GW) and on post-partum day 3 and month 1 (PPD3 and PPM1, respectively) in 78 women with normotensive singleton pregnancies. Thirty-nine women underwent caesarean delivery. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were determined on PPD3. Effects of maternal demographic characteristics on NT-proBNP levels were also analysed. RESULTS: NT proBNP levels (pg/ml) either in pregnancy or on PPM1 did not differ between women with vaginal and caesarean deliveries (44 +/- 24 vs 41 +/- 30, 24 GW; 37 +/- 22 vs 29 +/- 22, 36 GW; 43 +/- 28 vs 39 +/- 24, PPM1, respectively). Levels on PPD3 were significantly higher (94 +/- 105 vs 247 +/- 186, P < 0.0001) in women with caesarean delivery. Among women with caesarean delivery, a larger rise of NT proBNP on PPD3 occurred in nulliparous than in multiparous women (319 +/- 232 vs 185 +/- 107, P = 0.023), while no rise occurred among multiparous women with vaginal delivery (108 +/- 115 vs 47 +/- 27). NT-proBNP levels on PPD3 were significantly and negatively correlated with PRA, PAC and maternal weight loss after childbirth on PPD3. These 3 variables on PPD3 were significantly lower in women undergoing caesarean than vaginal delivery (0.8 +/- 0.4 vs 1.9 +/- 1.4 ng/ml/h for PRA; 70 +/- 38 vs 136 +/- 88 pg/ml for PAC; 2.7 +/- 1.2 vs 4.3 +/- 1.1 kg for weight loss, each P < 0.0001). CONCLUSIONS: The transient post-partum rise in serum NT-proBNP may reflect transient volume overload after parturition and is remarkable in nulliparous women, especially after caesarean section. PMID- 22816600 TI - Influence of severe sarcopenia on cardiovascular risk factors in nonobese men. AB - BACKGROUND: It is unknown whether severe sarcopenia produces unfavorable effects on cardiovascular risk factors. To examine the influence of severe and moderate sarcopenia on selected cardiovascular risk factors, 687 men were screened; those exhibiting clinically relevant diseases and higher body fat percentage (>25% fat) were excluded. A total of 410 men aged 40-76 years (mean age 56.0 years) were used for data analyses. METHODS: Sarcopenia was defined as a skeletal muscle mass (SM) index (muscle mass/height squared) of 1-2 standard deviations (SD) below (moderate) or <2 SDs below (severe) the mean for young adult men. Ultrasound measured subcutaneous fat and muscle thicknesses were used to estimate the SM, percent body fat, and fat-free mass. Serum total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels were determined using fasting blood samples. Systolic blood pressure and diastolic blood pressure were also measured. RESULTS: HDL-C was similar among the groups, but TC was lower in severe and moderate sarcopenia groups compared to the normal group. As a result, the TC:HDL-C ratio was lower in the moderate and severe sarcopenia groups than in the normal group. After adjusting for age, body mass index (BMI), waist circumference, and percent body fat, HDL-C was lower in both sarcopenia groups compared to the normal group, but other parameters were similar among the groups. A low prevalence of high HDL-C and high prevalence of moderate HDL-C were observed in the severe and the moderate sarcopenia groups. CONCLUSION: Our results suggest that moderate and severe sarcopenia may influence the HDL-C level, although the values are still maintained in the clinically normal range. PMID- 22816601 TI - The RxLR effector Avh241 from Phytophthora sojae requires plasma membrane localization to induce plant cell death. AB - * The Phytophthora sojae genome encodes hundreds of RxLR effectors predicted to manipulate various plant defense responses, but the molecular mechanisms involved are largely unknown. Here we have characterized in detail the P. sojae RxLR effector Avh241. * To determine the function and localization of Avh241, we transiently expressed it on different plants. Silencing of Avh241 in P. sojae, we determined its virulence during infection. Through the assay of promoting infection by Phytophthora capsici to Nicotiana benthamiana, we further confirmed this virulence role. * Avh241 induced cell death in several different plants and localized to the plant plasma membrane. An N-terminal motif within Avh241 was important for membrane localization and cell death-inducing activity. Two mitogen activated protein kinases, NbMEK2 and NbWIPK, were required for the cell death triggered by Avh241 in N. benthamiana. Avh241 was important for the pathogen's full virulence on soybean. Avh241 could also promote infection by P. capsici and the membrane localization motif was not required to promote infection. * This work suggests that Avh241 interacts with the plant immune system via at least two different mechanisms, one recognized by plants dependent on subcellular localization and one promoting infection independent on membrane localization. PMID- 22816602 TI - Imbalanced shift of cytokine expression between T helper 1 and T helper 2 (Th1/Th2) in intestinal mucosa of patients with post-infectious irritable bowel syndrome. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder. The post-infectious IBS (PI-IBS) occurs in IBS patients with a history of intestinal infection preceding the onset of symptoms. However, the underlying cause of PI-IBS is not fully understood, and the purpose of this study was to investigate the immune regulatory mechanism of PI-IBS. METHODS: Participants enrolled in this study were divided into three groups including PI-IBS patients (n = 20), IBS patients without a history of infection (non-PI-IBS, n = 18), and healthy controls (n = 20). The expression levels of the Th1-derived cytokines IFN gamma and IL-12, and the Th2-derived cytokines IL-4 and IL-10 in the mucosal specimens, and in the ascending colon, the descending colon, and the rectal segments were measured by RT-PCR and western blot. RESULTS: The IFN-gamma mRNA levels in the intestinal mucosa were significantly higher in the PI-IBS group than in the non-PI-IBS or control group (both P < 0.05), but there was no difference between the non-PI-IBS and control groups. A trend toward IFN-gamma protein upregulation was found in the PI-IBS group, while the IL-12 and IL-4 mRNA and protein levels were not different between any groups. The IL-10 mRNA and protein levels in the PI-IBS group were both significantly lower than in the non PI-IBS or control groups (P < 0.05, respectively), but there was no difference between the non-PI-IBS and control groups. There were no differences in the cytokine mRNA and protein levels among the ascending colon, the descending colon, and the rectum of all groups. CONCLUSIONS: An increase in IFN-gamma levels and a decrease in IL-10 levels were found in the intestinal mucosa of PI-IBS patients, suggesting that the infection may affect the Th1/Th2 balance. Thus, the dysregulation of the immune response is likely an important cause of IBS. PMID- 22816603 TI - Pediatric incidental brain tumors: a growing treatment dilemma. AB - OBJECT: Rising numbers of MRI studies performed during evaluations for pediatric disorders have contributed to a significant increase in the number of incidentally found brain tumors. Currently, there is very little literature on the nature of and the preferred treatment for these incidental brain tumors. In this paper the authors review their experience diagnosing and treating these lesions in children as well as the current literature on this topic. METHODS: Records from 2 centers were reviewed for incidentally found brain tumors, treatment approaches, and outcomes for both surgical and nonsurgical cohorts. RESULTS: Forty-seven children (30 males and 17 females) with a mean age of 8.6 years were found to have incidental brain lesions suspected to be neoplasms. Twenty-five underwent surgery and 22 were observed. Two children in the observation group required surgery at a later stage. Tumor pathology in 24 patients was benign. Only 3 patients had high-grade tumors. All nonsurgically treated lesions were presumed to be low-grade tumors and were followed up for 25 +/- 20 months. CONCLUSIONS: The discovery of incidental brain tumors on MRI in children poses an increasing challenge. Additional studies are needed to determine the significance as well as the optimal management strategies in this situation. PMID- 22816604 TI - Interrater reliability of Engel, International League Against Epilepsy, and McHugh seizure outcome classifications following vagus nerve stimulator implantation. AB - OBJECT: Interrater reliability as measured by the kappa (kappa) statistic is a widely used and valuable tool to measure the robustness of a scoring system. Seizure frequency reduction is a central outcome measure following vagus nerve stimulation (VNS). A specific VNS scoring system has been proposed by McHugh, but its interrater reliability has not been tested. The authors assessed its interrater reliability and compared it with that of the Engel and International League Against Epilepsy (ILAE) systems. METHODS: Using the Engel, ILAE, and McHugh scoring systems, 3 observers independently rated the medical records of children who had undergone vagus nerve stimulator implantation between January 2001 and April 2011 at the Southampton University Hospital. The interrater agreements were then calculated using the kappa statistic. RESULTS: Interrater reliability for the McHugh scale (kappa0.693) was very good and was superior to those of the Engel (kappa0.464) and ILAE (kappa0.491) systems for assessing outcome in patients undergoing VNS. CONCLUSIONS: The authors recommend considering the McHugh scoring system when assessing outcomes following VNS. PMID- 22816605 TI - Bifrontal encephalogaleosynangiosis for children with moyamoya disease. AB - OBJECT: Several operative techniques have been reported to increase the cerebral blood flow (CBF) of the anterior cerebral artery (ACA) territory in patients with moyamoya disease. However, the optimal procedure has not yet been determined. This study compared the efficacy of performing bifrontal encephalogaleosynangiosis (EGS) using a craniotomy with performing EGS using bur holes. METHODS: The authors retrospectively analyzed surgical results of pediatric patients with moyamoya disease treated using encephaloduroarteriosynangiosis (EDAS) and bifrontal EGS with a craniotomy, or EGS with bur holes, for the purpose of improving the ischemia of the ACA territory. Patients' demographic data, clinical presentations, surgical therapies, and clinical outcomes were reviewed. RESULTS: Nine patients underwent EDAS with bifrontal EGS using a craniotomy. Three patients underwent EDAS with EGS using bur holes for 5 cerebral hemispheres (1 bur hole in 2 hemispheres, 2 bur holes in 2 hemispheres, and 3 bur holes in 1 hemisphere). The mean follow-up period was 46.8 months (range 7-96 months). Preoperative symptoms improved in all patients in each group. The collateral circulation in the ACA territory made by EGS was divided into 3 groups according to postoperative angiography results: Group A (revascularization of more than two-thirds of the ACA territory), Group B (revascularization between one-third and two-thirds), and Group C (revascularization less than one-third). Of 5 hemispheres treated with EGS using bur holes, 1 was evaluated as Group B and 4 as Group C. Of 18 hemispheres treated with bifrontal EGS using a craniotomy, 8 were evaluated as Group A, 7 as Group B, and 3 as Group C. The patients who underwent bifrontal EGS using a craniotomy showed significantly better revascularization than those who underwent EGS using bur holes (p = 0.0065). Cerebral blood flow in the ACA territory improved in 13 (92.9%) of 14 hemispheres in patients treated with bifrontal EGS. In contrast, only 3 (60%) of 5 hemispheres demonstrated an increase of CBF in patients treated with EGS using bur holes. A trend was demonstrated for better improvement with bifrontal EGS (p = 0.08). CONCLUSIONS: Encephaloduroarteriosynangiosis with bifrontal EGS using a craniotomy demonstrated better revascularization and improvement of CBF in the ACA territory than with EGS using bur holes. Bifrontal EGS using a craniotomy is considered to be a simple, safe, and effective surgical procedure for improvement of the ischemia of the ACA territory in pediatric patients with moyamoya disease. PMID- 22816606 TI - Basilar invagination. PMID- 22816607 TI - Intracranial pediatric aneurysms: endovascular treatment and its outcome. AB - OBJECT: The aim of this study was to analyze the location, clinical presentation, and morphological characteristics of pediatric aneurysms and the safety, feasibility, and durability of endovascular treatment. METHODS: The authors conducted a retrospective study of all cases involving patients 18 years old or younger who underwent endovascular treatment for pediatric aneurysms at their institution between July 1998 and July 2010. The clinical presentation, aneurysm location, endovascular management, and treatment outcome were studied. RESULTS: During the study period, 23 pediatric patients (mean age 13 years, range 2 months 18 years) were referred to the authors' department and underwent endovascular treatment for aneurysms. The aneurysms were saccular in 6 cases, dissecting in 4, infectious in 5, and giant partially thrombosed lesions in 8. Fourteen of the aneurysms were ruptured, and 9 were unruptured. Thirteen were in the anterior circulation and 10 in the posterior circulation. The most common location in the anterior circulation was the anterior communicating artery; in the posterior circulation, the most common location was the basilar artery. Saccular aneurysms were the most common type in the anterior circulation; and giant partially thrombosed and dissecting aneurysms were the most common types in the posterior circulation. Coil embolization was performed in 7 cases, parent vessel sacrifice in 10, flow reversal in 3, glue embolization in 2, and stent placement in 1. Immediate angiographic cure was seen in 21 (91%) of 23 patients. Complications occurred in 4 patients, 3 of whom eventually had a good outcome. No patient died. Overall, a favorable outcome was seen in 22 (96%) of 23 patients. Follow-up showed stable occlusion of aneurysms in 96% of the patients. CONCLUSIONS: Pediatric aneurysms are rare. Their clinical presentation varies from intracranial hemorrhage to mass effect. They may also be found incidentally. Among pediatric patients with aneurysms, giant aneurysms are relatively common. Endovascular management is associated with low rates of complications and is a safe, durable, and effective treatment for pediatric aneurysms. PMID- 22816608 TI - Dorzolamide-induced relaxation of intraocular porcine ciliary arteries in vitro depends on nitric oxide and the vascular endothelium. AB - PURPOSE: Carbonic anhydrase inhibitors (CAIs) are used to reduce aqueous production in glaucoma, which includes a direct effect on the ciliary body. However, CAIs also affect ciliary blood flow, but the mechanisms of action of CAIs on the tone of intraocular ciliary arteries supplying the ciliary body have not been studied in detail. MATERIALS AND METHODS: The intraocular part of porcine ciliary arteries was isolated and mounted in a wire myograph system for isometric tension recordings. After contraction with the thromboxane analogue U46619, the vasorelaxing effect of the CAIs acetazolamide, brinzolamide and dorzolamide was studied. Subsequently, the involvement of the carbonic anhydrase reaction and nitric oxide (NO) in dorzolamide-induced vasorelaxation was characterized. RESULTS: All CAIs induced relaxation of contracted ciliary arteries, but the effect of dorzolamide was most pronounced. Dorzolamide-induced relaxation was unaffected by changes in pH and CO(2), and by removal of substrates to the carbonic anhydrase enzyme, but was abolished after inhibition of NO synthase and guanylyl cyclase and after removal of the vascular endothelium. CONCLUSIONS: Dorzolamide-induced vasorelaxation of ciliary arteries is independent of changes in the substances involved in the carbonic anhydrase reaction, but depends on NO and the vascular endothelium. The mechanism of action of dorzolamide in ocular disease may involve an effect on vascular tone mediated by NO. PMID- 22816609 TI - The future of occupational hygiene education and research. PMID- 22816610 TI - Leptin-mediated modulation of steroidogenic gene expression in hypoxic zebrafish embryos: implications for the disruption of sex steroids. AB - Hypoxia can impair reproduction of fishes through the disruption of sex steroids. Here, using zebrafish (Danio rerio) embryos, we investigated (i) whether hypoxia can directly affect steroidogenesis independent of pituitary regulation via modulation of steroidogenic gene expression, and (ii) the role of leptin in hypoxia-induced disruption of steroidogenesis. Exposure of fertilized zebrafish embryos to hypoxia (1.0 mg O(2) L(-1)) from 0-72 h postfertilization (hpf), a developmental window when steroidogenesis is unregulated by pituitary influence, resulted in the up-regulation of cyp11a, cyp17, and 3beta-hsd and the down regulation of cyp19a. Similar gene expression patterns were observed for embryos exposed to 10 mM cobalt chloride (CoCl(2), a chemical inducer of hypoxia inducible factor 1, HIF-1), suggesting a regulatory role of HIF-1 in steroidogenesis. Testosterone (T) and estradiol (E2) concentrations in hypoxic embryos were greater and lesser, respectively, relative to the normoxic control, thus leading to an increased T/E2 ratio. Expression of the leptin-a gene (zlep-a) was up-regulated upon both hypoxia and CoCl(2) treatments. Functional assays suggested that under hypoxia, elevated zlep-a expression might activate cyp11a and 3beta-hsd and inhibit cyp19a. Overall, this study indicates that hypoxia, possibly via HIF-1-induced leptin expression, modulates sex steroid synthesis by acting directly on steroidogenic gene expression. PMID- 22816611 TI - Acute myeloid leukemia with 11q23/MLL rearrangement after 'FCR' regimen for chronic lymphocytic leukemia. PMID- 22816612 TI - Synthetic procedure for N-Fmoc amino acyl-N-sulfanylethylaniline linker as crypto peptide thioester precursor with application to native chemical ligation. AB - N-sulfanylethylanilide (SEAlide) peptides 1, obtainable using Fmoc-based solid phase peptide synthesis (Fmoc SPPS), function as crypto-thioesters in native chemical ligation (NCL), yielding a wide variety of peptides/proteins. Their acylating potential with N-terminal cysteinyl peptides 2 can be tuned by the presence or absence of phosphate salts, leading to one-pot/multifragment ligation, operating under kinetically controlled conditions. SEAlide peptides have already been shown to be promising for use in protein synthesis; however, a widely applicable method for the synthesis of N-Fmoc amino acyl-N sulfanylethylaniline linkers 4, required for the preparation of SEAlide peptides, is unavailable. The present study addresses the development of efficient condensation protocols of 20 naturally occurring amino acid derivatives to the N sulfanylethylaniline linker 5. N-Fmoc amino acyl aniline linkers 4 of practical use in NCL chemistry, except in the case of the proline- or aspartic acid containing linker, were successfully synthesized by coupling of POCl(3)- or SOCl(2)-activated Fmoc amino acid derivatives with sodium anilide species 6, without accompanying racemization and loss of side-chain protection. Furthermore, SEAlide peptides 7 possessing various C-terminal amino acids (Gly, His, Phe, Ala, Asn, Ser, Glu, and Val) were shown to be of practical use in NCL chemistry. PMID- 22816613 TI - Detection of significant coronary artery stenosis with cardiac dual-source computed tomography angiography in heart transplant recipients. AB - Present study evaluates clinical feasibility of cardiac dual-source computed tomography angiography (DSCTA) to detect significant coronary stenosis because of chronic allograft vasculopathy (CAV) after heart transplantation (HTX). An overall of 51 consecutive heart transplant recipients (43 men, 8 women, mean age: 52.3 +/- 13.6 years) underwent DSCTA 1 +/- 2 days before annual routine invasive coronary angiography (ICA). Three patients were excluded from further analysis. Total 714/717 (99.6%) segments in remaining 48 patients were depicted in diagnostic image quality by DSCTA with three vessel segments in two patients being additionally excluded because of motion artefacts. On a segment-based analysis, sensitivity, specificity, and diagnostic accuracy (DA) for detection of significant stenosis were calculated as 100%, 98.9% and 98.9% respectively. On a patient-based evaluation, sensitivity, specificity and DA were 100%, 86.0% and 93.0% respectively for remaining 46 patients. Negative predictive value (NPV) was 100%. DSCTA enables diagnosis and especially the exclusion of significant coronary artery stenosis in patients after HTX with a high NPV. The low rate of excluded vessel segments compared with former studies indicates improvement in image acquisition and robustness of latest scanner technology and thus may make subsequent annual invasive coronary angiography unnecessary. PMID- 22816614 TI - Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups. AB - The prognostic relevance of CRLF2 -rearrangements in childhood acute B-cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+ , 15 IGH@-CRLF2+ ), 76 from the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not statistically different: 0.37 +/- 0.06 vs. 0.25 +/- 0.08 (P = 0.194). In contrast, 0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the different prognosis of IGH@-CRLF2+ patients could be related to the different structures of the applied treatment protocols. PMID- 22816615 TI - Methodological concerns regarding 'Assessment of von Willebrand disease as a risk factor for primary postpartum haemorrhage'. PMID- 22816616 TI - Device diagnosis of pacemaker-mediated tachycardia: true or false? PMID- 22816617 TI - A FILAMENTOUS FLOWER orthologue plays a key role in leaf patterning in opium poppy. AB - The plant-specific YABBY genes were initially defined by their roles in determining abaxial/adaxial cell fate in lateral organs of eudicots, and repressing meristematic genes in differentiating tissues such as leaves. In Arabidopsis thaliana FILAMENTOUS FLOWER (FIL) is also required for inflorescence and floral meristem establishment and flower development in a pathway involving the floral transition and identity genes. Here we describe the characterization of a FIL orthologue from the basal eudicot, Papaver somniferum (the opium poppy), and demonstrate a role for the gene in patterning the highly lobed leaf of the poppy. Silencing of PapsFIL using viral-induced gene silencing resulted in leaves of reduced laminar area, more pronounced margin serration and, in some cases, leaf bifurcation. In contrast, the gene does not appear to affect the development of the flower, and these variations in function are discussed in relation to its taxonomic position as a basal eudicot and its determinate growth habit. PMID- 22816618 TI - Quantitative characterization of nanoparticles in blood by transmission electron microscopy with a window-type microchip nanopipet. AB - Transmission electron microscopy (TEM) is a unique and powerful tool for observation of nanoparticles. However, due to the uneven spatial distribution of particles conventionally dried on copper grids, TEM is rarely employed to evaluate the spatial distribution of nanoparticles in aqueous solutions. Here, we present a microchip nanopipet with a narrow chamber width for sorting nanoparticles from blood and preventing the aggregation of the particles during the drying process, enabling quantitative analysis of their aggregation/agglomeration states and the particle concentration in aqueous solutions. This microchip is adaptable to all commercial TEM holders. Such a nanopipet proves to be a simple and convenient sampling device for TEM image based quantitative characterization. PMID- 22816619 TI - Presence of high-risk human papillomavirus genotype and human immunodeficiency virus DNA in anal high-grade and low-grade squamous intraepithelial lesions. AB - Human immunodeficiency virus type 1 (HIV)-infected individuals are at risk for anal cancer, which is caused by human papillomavirus (HPV). The relationship between HIV and HPV that leads to anal cancer remains unclear. Recent data, however, suggest that the continued persistence of HIV DNA in patients treated with combined antiretroviral therapy leads to progression of HIV disease and other HIV-associated complications. Therefore, we investigated the relationship among anal low- and high-grade squamous intraepithelial lesions (LGSIL/HGSIL), high-risk HPV genotypes, and high HIV DNA copy numbers. Anal cytology specimens were assayed for HPV genotype and HIV DNA copy number. High-risk HPV genotypes (odds ratio OR: 3.73; 95% confidence interval CI: 1.08-12.91; p=0.04) and high HIV DNA copy numbers (OR(per 100 HIV DNA copies): 1.13; 95% CI: 1.01-1.27, p=0.04) were both associated with LGSIL/HGSIL. When considering both high-risk HPV genotypes and HIV DNA copy numbers in predicting LGSIL/HGSIL, HIV DNA copy number was significant (OR(per 100 HIV DNA copies): 1.09; 95% CI: 0.96-1.23, p=0.04) but not high-risk HPV genotypes (OR: 2.30, p=0.28), which did not change when adjusted for nadir CD4 cell count and HIV RNA levels. The findings warrant further investigation of HIV DNA and its relationship with HPV in LGSIL/HGSIL pathogenesis. PMID- 22816620 TI - Succession of N cycling processes in biological soil crusts on a Central European inland dune. AB - Biological soil crusts (BSCs) are microbial assemblages that occur worldwide and facilitate ecosystem development by nitrogen (N) and carbon accumulation. N turnover within BSC ecosystems has been intensively studied in the past; however, shifts in the N cycle during BSC development have not been previously investigated. Our aim was to characterise N cycle development first by the abundance of the corresponding functional genes (in brackets) and second by potential enzyme activities; we focussed on the four processes: N fixation (nifH), mineralisation as proteolysis and chitinolysis (chiA), nitrification (amoA) and denitrification (nosZ). We sampled from four phases of BSC development and from a reference located in the rooting zone of Corynephorus canescens, on an inland dune in Germany. BSC development was associated with increasing amounts of chlorophyll, organic carbon and N. Potential activities increased and were highest in developed BSCs. Similarly, the abundance of functional genes increased. We propose and discuss three stages of N process succession. First, the heterotrophic stage (mobile sand without BSCs) is dominated by mineralisation activity. Second, during the transition stage (initial BSCs), N accumulates, and potential nitrification and denitrification activity increases. Third, the developed stage (established BSCs and reference) is characterised by the dominance of nitrification. PMID- 22816650 TI - The clinical characteristics of gastroesophageal reflux disease in patients with laryngeal symptoms who are referred to gastroenterology. AB - The prevalence of gastroesophageal reflux disease (GERD) has increased recently in Asia-Pacific countries. However, little is known about its prevalence and clinical characteristics in GERD patients with atypical symptoms in Asia. The aim of this study was to investigate the clinical characteristics of GERD in patients who had laryngeal symptoms in Korea. Data were gathered retrospectively from patients who presented with atypical symptoms, such as throat discomfort, globus pharyngeus, hoarseness, and chronic cough. They underwent a 24-hour ambulatory intraesophageal pH monitoring and filled in a validated reflux questionnaire. Overall, 128 patients (36 men and 92 women) with laryngeal symptoms were included. Of these 128, 43 patients (34%) had erosive esophagitis or pathological reflux from 24-hour ambulatory pH monitoring, and 24 (19%) had a positive Bernstein test or positive symptom index from 24-hour pH monitoring. Sixty-one patients (48%) had no evidence of reflux esophagitis on upper endoscopy and pathological acid reflux on 24-hour pH monitoring. Fifty-six patients (44%) had weekly heartburn or regurgitation. Typical symptoms and dyspepsia were significantly more common in patients with GERD who had laryngeal symptoms than non-GERD. Fifty-two percent of patients had laryngeal symptoms that were associated with GERD. The presence of typical reflux symptoms and dyspepsia are risk factors for GERD in patients who present with laryngeal symptoms. PMID- 22816651 TI - Reentrant nematic phenomenon in a new class of low molar mass, single-component liquid crystals. AB - We report the observation of reentrant nematic behavior in a relatively new class of compounds, namely, dimerlike mesogens that are made by covalently linking nematogenic cyanobiphenyl and nonmesogenic N-(n-alkyl)salicylaldimine segments through a central flexible spacer of varying length and parity. The existence of reentrant phenomenon in this class of mesogens, evidenced indubitably by means of several complementary studies, appears to be crucially dependent on the length of the terminal alkyl tail and parity of the spacer. PMID- 22816652 TI - Role of subcutaneous adipose tissue in metabolic complications of obesity. PMID- 22816654 TI - Electrocatalytic oxidation of glucose by rhodium porphyrin-functionalized MWCNT electrodes: application to a fully molecular catalyst-based glucose/O2 fuel cell. AB - This paper details the electrochemical investigation of a deuteroporphyrin dimethylester (DPDE) rhodium(III) ((DPDE)Rh(III)) complex, immobilized within a MWCNT/Nafion electrode, and its integration into a molecular catalysis-based glucose fuel cell. The domains of present (DPDE)Rh(I), (DPDE)Rh-H, (DPDE)Rh(II), and (DPDE)Rh(III) were characterized by surface electrochemistry performed at a broad pH range. The Pourbaix diagrams (plots of E(1/2) vs pH) support the stability of (DPDE)Rh(II) at intermediate pH and the predominance of the two electron redox system (DPDE)Rh(I)/(DPDE)Rh(III) at both low and high pH. This two electron system is especially involved in the electrocatalytic oxidation of alcohols and was applied to the glucose oxidation. The catalytic oxidation mechanism exhibits an oxidative deactivation coupled with a reductive reactivation mechanism, which has previously been observed for redox enzymes but not yet for a metal-based molecular catalyst. The MWCNT/(DPDE)Rh(III) electrode was finally integrated in a novel design of an alkaline glucose/O(2) fuel cell with a MWCNT/phthalocyanin cobalt(II) (CoPc) electrode for the oxygen reduction reaction. This nonenzymatic molecular catalysis-based glucose fuel cell exhibits a power density of P(max) = 0.182 mW cm(-2) at 0.22 V and an open circuit voltage (OCV) of 0.64 V. PMID- 22816653 TI - Postnatal alteration of collapsin response mediator protein 4 mRNA expression in the mouse brain. AB - Collapsin response mediator protein 4 (CRMP4) is a molecular marker for immature neurons but only limited information is available on the spatiotemporal gene expression changes of Crmp4 in the developing rodent. In the present study, the variation of CRMP4 mRNA expression in the mouse brain was investigated from postnatal day (PD) 0 (the day of birth) to adulthood by in situ hybridization. The hybridization signals were broadly detected on PD0 and regional changes in expression during development were noted. Expression patterns of CRMP4 mRNA were classified into the following three types: (i) signals that were strongest on PD0 or PD7, weak or undetectable on PD14, and absent in adulthood: this pattern was observed in most brain areas; (ii) signals that were first detected on PD0 or PD7 and persisted into adulthood: this pattern was seen in the dentate gyrus and subventricular zone of the olfactory bulb (OB); and (iii) signals that were strongest on PD0 and decreased gradually with age but were still detectable in adulthood: this pattern was identified for the first time in the mitral cell layer of the OB. Analysis using quantitative real-time RT-PCR confirmed higher expression of CRMP4 mRNA in the OB than in other adult brain regions. The persistence of CRMP4 mRNA in the adult OB, including the mitral cell layer, suggests the possibility of both neurogenetic and non-neurogenetic functional roles of CRMP4 in this region. PMID- 22816655 TI - Reduction in cholesterol absorption in Caco-2 cells through the down-regulation of Niemann-Pick C1-like 1 by the putative probiotic strains Lactobacillus rhamnosus BFE5264 and Lactobacillus plantarum NR74 from fermented foods. AB - Hypercholesterolaemia is a major risk factor related to atherosclerosis, and it may be influenced by our diet. This study addresses the impact of Lactobacillus rhamnosus BFE5264 (isolated from Maasai fermented milk) and Lactobacillus plantarum NR74 (from Korean kimchi) on the control of cholesterol absorption through down-regulation of Niemann-Pick C1-like 1 (NPC1L1) expression. Caco-2 enterocytes were treated with the live, heat-killed (HK) bacteria, bacterial cell wall extracts and metabolites; mRNA level and protein expression were measured. Caco-2 cells showed lower NPC1L1 expression in the presence of the live test strains than the control, elucidating down-regulation of cholesterol uptake, and were compared well with the positive control, L. rhamnosus GG. This effect was also observed with HK bacteria and cell wall fractions but not with their metabolites. The potential of some Lactobacillus strains associated with traditional fermented foods to suppress cholesterol uptake and promote its efflux in enterocytes has been suggested from these data. PMID- 22816656 TI - Oxidative stress is associated with C-reactive protein in nondiabetic postmenopausal women, independent of obesity and insulin resistance. AB - OBJECTIVE: Oxidative stress is associated with obesity, metabolic syndrome and inflammation, suggesting it could be an early event in the pathology of chronic diseases. We tested the hypothesis that elevated levels of oxidative stress markers are associated with increased C-reactive protein (CRP) and that this is independent of obesity and insulin resistance. RESEARCH DESIGN AND METHODS: This study was cross-sectional designed and nondiabetic postmenopausal women (n = 1821) with CRP levels <=10 mg/l was enrolled. The CRP levels were categorized into quartiles from the lowest to the highest concentrations (Q1-Q4). The degree of insulin resistance was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR). We measured oxidative stress using urinary 8-epi prostaglandin F2alpha (8-epi-PGF2alpha) and plasma oxidized low-density lipoprotein (ox-LDL). RESULTS: After adjustments for age and lifestyle habits, including smoking and drinking, we found higher body mass index (BMI) and HOMA-IR scores in Q2 and Q3 vs Q1. The Q4 BMI and HOMA-IR scores were higher than all other quartiles. The plasma ox-LDL was higher in Q4 than in Q1. Urinary 8-epi PGF2alpha was higher in Q3 and Q4 than in Q1 or Q2. Urinary 8-epi-PGF2alpha positively correlated with CRP (r = 0.235, P < 0.001), whereas no correlation was found between ox-LDL and CRP. Multiple linear regression analyses of BMI and HOMA IR showed that the association between urinary 8-epi-PGF2alpha and CRP levels remained significant (P < 0.001). CONCLUSIONS: Oxidative stress measured by increased concentration of urine 8-epi-PGF2alpha is strongly associated with CRP levels. This finding was independent of obesity and insulin resistance in nondiabetic postmenopausal women. PMID- 22816657 TI - Systematic review of the impact of urinary tract infections on health-related quality of life. AB - What's known on the subject? and What does the study add? Values for equivalent health states can vary substantially depending on the measure used and method of valuation; this has a direct impact on the results of economic analyses. To date, the majority of existing economic evaluations that include UTI as a health state refer to an analysis in which the Index of Well Being was used to estimate the quality of life experienced by young women with UTIs. Currently, there are no validated methods or filters for systematically searching for the type of generic quality of life data required for decision analytic models. This study is the only systematic review of quality of life in people with UTI in the literature. Twelve studies were identified which report quality of life using a variety of generic methods; the results of these papers were summarized in a way that is useful for a health researcher seeking to populate a decision model, design a clinical study or assess the effect of UTI on quality of life relative to other conditions. One research group provided previously unpublished data from a large cohort study; these scores were mapped to EuroQol 5-Dimension values using published algorithms and probabilistic simulations. The aim of this review was to identify studies that have evaluated the impact of symptomatic urinary tract infection (UTI) and UTI-associated bacteraemia on quality of life, and to summarize these data in a way that is useful for a health researcher seeking to populate a cost-utility model, design a clinical study or assess the effect of UTIs on quality of life relative to other conditions. We conducted a systematic search of the literature using MEDLINE, EMBASE, the NHS Economic Evaluations database, Health Technology Assessment database, Health Economics Evaluations database, Cost-Effectiveness Analysis Registry and EuroQol website. Studies that reported utility values for symptomatic UTI or UTI-associated bacteraemia derived from a generic QoL measurement tool or expert opinion were included. Studies using disease-specific instruments were excluded. Twelve studies were identified that included a generic measure of health-related quality of life for patients with UTIs. These measures included: the short-form (SF)-36 and SF-12 questionnaires; the Health Utilities Index Mark 2; Quality of Well Being; the Index of Well Being, standard gamble; the Health and Activity Limitation Index; and expert opinion. The authors of studies using either of the SF questionnaires were contacted for additional data. One research group provided previously unpublished data from a large cohort study; these scores were mapped to EuroQol 5 Dimension (EQ-5D) values using published algorithms and probabilistic simulations. The present review provides health researchers with several sources from which to select utility values to populate cost-utility models. It also shows that very few studies have measured quality of life in patients with UTI using generic preference-based measures of health and none have evaluated the impact of this health state on quality of life in children. Future studies ought to consider the inclusion of commonly used preference-based measures of health, such as the EQ-5D, in all patient populations experiencing symptomatic UTI or UTI related complications. PMID- 22816660 TI - Methacholine is more sensitive than mannitol for evaluation of bronchial hyper responsiveness in youth athletes with exercise-induced bronchoconstriction. PMID- 22816659 TI - Samter's triad and eicosanoid imbalance in children with recurrent nasal polyps. PMID- 22816661 TI - Phospholipid bilayer-perturbing properties underlying lysis induced by pH sensitive cationic lysine-based surfactants in biomembranes. AB - Amino acid-based surfactants constitute an important class of natural surface active biomolecules with an unpredictable number of industrial applications. To gain a better mechanistic understanding of surfactant-induced membrane destabilization, we assessed the phospholipid bilayer-perturbing properties of new cationic lysine-based surfactants. We used erythrocytes as biomembrane models to study the hemolytic activity of surfactants and their effects on cells' osmotic resistance and morphology, as well as on membrane fluidity and membrane protein profile with varying pH. The antihemolytic capacity of amphiphiles correlated negatively with the length of the alkyl chain. Anisotropy measurements showed that the pH-sensitive surfactants, with the positive charge on the alpha amino group of lysine, significantly increased membrane fluidity at acidic conditions. SDS-PAGE analysis revealed that surfactants induced significant degradation of membrane proteins in hypo-osmotic medium and at pH 5.4. By scanning electron microscopy examinations, we corroborated the interaction of surfactants with lipid bilayer. We found that varying the surfactant chemical structure is a way to modulate the positioning of the molecule inside bilayer and, thus, the overall effect on the membrane. Our work showed that pH-sensitive lysine-based surfactants significantly disturb the lipid bilayer of biomembranes especially at acidic conditions, which suggests that these compounds are promising as a new class of multifunctional bioactive excipients for active intracellular drug delivery. PMID- 22816662 TI - Association of sequence variation in the CX3CR1 gene with geographic atrophy age related macular degeneration in a Greek population. AB - PURPOSE: To explore the association of two single nucleotide polymorphisms (SNPs) in the CX3CR1 gene with grades of age-related macular degeneration (AMD) in a population-based setting. METHODS: The Thessaloniki Eye study is a cross sectional population-based epidemiologic study of chronic eye diseases in Thessaloniki, Greece. A total of 371 subjects were included and classified according to their AMD status. Subjects with AMD Grades 0-1 (n = 188) were compared to those with AMD Grades 2-3 (n = 138), to those with AMD Grade 4 (geographic atrophy) (n = 20) and to those with AMD Grade 5 (neovascular AMD) (n = 25) with regard to the presence of CX3CR1 polymorphisms (V249I and T280M). Polychotomous logistic regression analysis adjusted for age, gender, and smoking was conducted and the log-additive allelic model was preferred. RESULTS: Participants with AMD Grade 4 were approximately three times more likely to carry the VI249 and nine times more likely to carry the II249 alleles, compared to those with AMD Grades 0-1, whereas those with AMD Grades 2-3 or Grade 5 did not differ. The T280M polymorphism was not associated with either AMD Grades 2-3 or AMD Grades 4 or 5. CONCLUSION: In this Greek population, after adjusting for known risk factors, increased risk of geographic atrophy (GA) AMD among the carriers of the V249I polymorphism in the CX3CR1 gene was found. Our study failed to reveal any association with the T280M polymorphism reported in previous studies. Additional studies in different ethnic populations using standardized methodology are needed in order to confirm this association. PMID- 22816664 TI - Prototropic interactions of pyrimidine nucleic acid bases with acridine: a spectroscopic investigation. AB - In this article, we have investigated the interactions of three pyrimidine nucleic acid bases, cytosine (C), thymine (T), and uracil (U) with acridine (Acr), an N-heterocyclic DNA intercalator, through the changes in photophysics of Acr inside SDS micelles. Fluorescence of AcrH(+)* at 478 nm and its lifetime are quenched on addition of C, T, and U, while a concomitant increment of Acr* is observed only with C. However, the relative amplitude of Acr* increases with a simultaneous decrease in AcrH(+)* only with C. The fluorescence quenching of AcrH(+)* is explained by photoinduced electron transfer (PET), while changes in the relative contributions of Acr* and AcrH(+)* with C are due to associated excited-state proton transfer (ESPT). The rate of electron transfer (kET) is maximum for T, followed by U and C. The associated ESPT from AcrH(+)* is the reason behind the reduced efficiency of PET with C. The lack of proton transfer with T and U as well as the higher kET for T compared to U are explained by keto enol tautomerization and subtle changes in the structure and geometry of the pyrimidine bases. PMID- 22816663 TI - The mercury resistance (mer) operon in a marine gliding flavobacterium, Tenacibaculum discolor 9A5. AB - Genes conferring mercury resistance have been investigated in a variety of bacteria and archaea but not in bacteria of the phylum Bacteroidetes, despite their importance in many environments. We found, however, that a marine gliding Bacteroidetes species, Tenacibaculum discolor, was the predominant mercury resistant bacterial taxon cultured from a salt marsh fertilized with mercury contaminated sewage sludge. Here we report characterization of the mercuric reductase and the narrow-spectrum mercury resistance (mer) operon from one of these strains - T. discolor 9A5. This mer operon, which confers mercury resistance when cloned into Flavobacterium johnsoniae, encodes a novel mercury responsive ArsR/SmtB family transcriptional regulator that appears to have evolved independently from other mercury-responsive regulators, a novel putative transport protein consisting of a fusion between the integral membrane Hg(II) transporter MerT and the periplasmic Hg(II)-binding protein MerP, an additional MerP protein, and a mercuric reductase that is phylogenetically distinct from other known mercuric reductases. PMID- 22816665 TI - Design of beta-amino acid with backbone-side chain interactions: stabilization of 14/15-helix in alpha/beta-peptides. AB - A new C-linked carbo-beta-amino acid, (R)-beta-Caa((r)), having a carbohydrate side chain with D-ribo configuration, was prepared from D-glucose by inverting the C-3 stereocenter to introduce constraints/interactions. From the NMR studies it was inferred that the new monomer may participate in additional electrostatic interactions, facilitating and enhancing novel folds in oligomeric peptides derived from it. The alpha/beta-peptides, synthesized from alternating L-Ala and (R)-beta-Caa((r)), have shown the presence of 14/15-helix by NMR (in CDCl(3), methanol-d(3) and CD(3)CN), CD and MD calculations. The hybrid peptides showed the presence of electrostatic interactions involving the intraresidue amide proton and the C3-OMe, which helped in the stabilization of the NH(i)...CO(i-4) H bonds and adoption of 14/15-helix. The importance of such additional interactions has been well defined in recent times to stabilize the folding in a variety of peptidic foldamers. These observations suggest and emphasize that the side chain backbone interactions are crucial in the stabilization of the desired folding propensity. The designed monomer thus enlarges the opportunities for the synthesis of peptides with novel conformations and expands the repertoire of the foldamers. PMID- 22816666 TI - Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation. AB - Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B-cell-specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B-cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL-10 production in primary stimulated B cells. In addition, B-cell co-cultures with pre-activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T-cell-dependent immunoglobulin production. Sotrastaurin did not inhibit B-cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B-cell functions in a dose-dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T-cell-dependent B-cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B-lymphocyte function and activation. PMID- 22816668 TI - Field application of the Nanoparticle Emission Assessment Technique (NEAT): task based air monitoring during the processing of engineered nanomaterials (ENM) at four facilities. AB - In early 2006, the National Institute for Occupational Safety and Health created a field research team whose mission is to visit a variety of facilities engaged in the production, handling, or use of engineered nanomaterials (ENMs) and to conduct initial emission and exposure assessments to identify candidate sites for further study. To conduct the assessments, the team developed the Nanoparticle Emission Assessment Technique (NEAT), which has been used at numerous facilities to sample multiple engineered nanomaterials. Data collected at four facilities, which volunteered to serve as test sites, indicate that specific tasks can release ENMs to the workplace atmosphere and that traditional controls such as ventilation can be used to limit exposure. Metrics such as particle number concentration (adjusted for background), airborne mass concentration, and qualitative transmission electron microscopy were used to determine the presence, nature, and magnitude of emissions and whether engineered nanomaterials migrated to the workers' breathing zone. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a PDF file containing information on facilities, a description of processes/tasks, existing controls, and sampling strategy, and a PDF file containing TEM images according to facility and task.]. PMID- 22816669 TI - Significance of mediastinal adenopathy in childhood acute lymphoblastic leukemia: prognostic impact and association with clinicodemographic factors. PMID- 22816667 TI - Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. AB - BACKGROUND: Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease. CASE PRESENTATION: We describe a case of type 2 AIH with serological positivity for PBC-specific anti mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later. CONCLUSION: This is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage. PMID- 22816672 TI - Using robots to understand social behaviour. AB - A major challenge in studying social behaviour stems from the need to disentangle the behaviour of each individual from the resulting collective. One way to overcome this problem is to construct a model of the behaviour of an individual, and observe whether combining many such individuals leads to the predicted outcome. This can be achieved by using robots. In this review we discuss the strengths and weaknesses of such an approach for studies of social behaviour. We find that robots-whether studied in groups of simulated or physical robots, or used to infiltrate and manipulate groups of living organisms-have important advantages over conventional individual-based models and have contributed greatly to the study of social behaviour. In particular, robots have increased our understanding of self-organization and the evolution of cooperative behaviour and communication. However, the resulting findings have not had the desired impact on the biological community. We suggest reasons for why this may be the case, and how the benefits of using robots can be maximized in future research on social behaviour. PMID- 22816673 TI - Expression of breast cancer anti-estrogen resistance 1 in relation to vascular endothelial growth factor, p53, and prognosis in esophageal squamous cell cancer. AB - The purpose of this study was to clarify the role of breast cancer anti-estrogen resistance 1 (BCAR1) expression in relation to vascular endothelial growth factor (VEGF), p53, and proliferation in esophageal squamous cell cancer (ESCC). Expression of BCAR1, VEGF, p53, and the ki-67 proliferative index were examined by tissue microarray and immunohistochemistry in 106 specimens with ESCC and matched adjacent normal tissues. Among them, 40 cases were simultaneously examined by Western blot. Both Western blot and immunohistochemistry showed that BCAR1 expression was substantially higher in ESCC than in adjacent normal tissues (P < 0.001). BCAR1 expression was significantly connected with degree of tumor differentiation, with poorly differentiated tumors showing higher BCAR1 expression (P < 0.001). BCAR1 expression was significantly and positively correlated with VEGF and p53 expression levels (r= 0.541, P < 0.001; r= 0.374; P < 0.001) but not proliferative index (r= 0.44; P= 0.066). Additionally, a significant relationship was also observed between VEGF and p53 (r= 0.321; P= 0.001). Kaplan-Meier survival analysis revealed that patients with high BCAR1 expression had significantly shorter survival times than those with low BCAR1 expression levels (median survival 40 months vs. 27 months, P= 0.09). Multivariate analysis also revealed that levels of BCAR1 expression (hazard ratio 2.250, P= 0.015) was a significant and independent prognostic indicator. High expression of BCAR1 is associated with elevated VEGF and p53 expression levels, as well as poor prognosis in ESCC. Therefore, BCAR1 may be a potential candidate for predicting prognosis and a new therapy target for ESCC. PMID- 22816674 TI - Efficacy evaluation of products for treatment of bleeding episodes. PMID- 22816670 TI - Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study. AB - OBJECTIVES: To compare the concentrations of high-energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). METHODS: We used in vivo phosphorus-31 magnetic resonance spectroscopy ((31) P-MRS) at 3 Tesla to measure phosphocreatine (PCr), beta-nucleoside triphosphate (beta-NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. RESULTS: Analysis of covariance, including age as a covariate, revealed differences in PCr (p=0.037), Pi (p=0.017), and PCr/Pi (p=0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post-hoc Tukey-Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p=0.038) and medicated BD (24%; p=0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p=0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p=0.013) and with medicated BD (39%; p=0.002). No differences in beta-NTP or pH were observed. CONCLUSIONS: Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD. PMID- 22816675 TI - Fluorous affinity chromatography for enrichment and determination of perfluoroalkyl substances. AB - The adsorption behavior of four perfluoroalkyl acids, including the environmentally relevant perfluorooctanoic acid, has been investigated on a straight-chain perfluorohexyl adsorbent. The aim of this study was to probe the potential of perfluorinated materials for the analysis and enrichment of perfluoroalkyl analytes. Water/acetonitrile mixtures, to which formic acid had been added (generally, 0.1%), were employed as mobile phases. For all perfluorinated acids, a U-shaped retention profile was observed by changing the amount of acetonitrile in the mobile phase. This behavior has been correlated to the excess adsorption of the organic component on the adsorbent surface. The concept of perfluoromethylene selectivity has been defined as the ability of a chromatographic system to discriminate between molecules that differ by a single perfluoromethylene group. The contribution to the Gibbs free energy of phase transfer for the passage of a perfluoroalkyl carbon from the mobile to the stationary phase has been evaluated. This information, in addition to the traditional van't Hoff analysis, has also been used to estimate the analogous contribution for the transfer of a carboxylic unit. Finally, insights into the retention mechanisms of perfluoroalkyl acids on straight-chain perfluorohexyl sorbents are discussed. PMID- 22816676 TI - Is ablation of atrial flutter always safe? AB - BACKGROUND: Radiofrequency ablation of typical atrial flutter is largely used and is considered as safe. The purpose of the study was to evaluate the prevalence and the causes of severe adverse event (AE) following atrial flutter ablation. METHODS: Ablation of typical flutter was performed by conventional method with an 8-mm-tip electrode catheter, a maximum power of 70 W, and a maximum target temperature of 70 degrees for 60 seconds in 883 patients, (685 males and 198 females aged from 18 to 93 years [64 +/- 11.5]; 664 had heart disease [HD]). RESULTS: AE occurred in 44 patients (5%). AE was life threatening in 14 patients: poorly tolerated bradycardia (transient complete atrioventricular block [AVB] or sinus bradycardia [SB] <40 beats per minute) associated with cardiac shock and acute renal failure in five patients, tamponade (n = 1), bleeding leading to death (n = 1), various AE-related deaths (n = 2), ventricular tachycardia-related death (n = 1), definitive complete AVB (n = 3), and right coronary artery occlusion-related complete AVB (n = 1). Less serious AE occurred in 30 patients: transitory major SB or second- or third-degree AVB (n = 23), bleeding (n = 4), transient ischemic attack (n = 1), and various AE (n = 2). Most of the bradycardia was related to beta-blockers or other antiarrhythmic drugs used to slow atrial flutter. Factors of AE were female gender (36% vs 22%, P < 0.02) and the presence of ischemic (P < 0.03) or valvular HD (P < 0.01). CONCLUSIONS: AE following atrial flutter ablation occurred in 5% of patients. Most of them are avoidable by control of anticoagulants and arrest of rate-control drugs used to slow the rate of atrial flutter. PMID- 22816677 TI - Calcium rubies: a family of red-emitting functionalizable indicators suitable for two-photon Ca2+ imaging. AB - We designed Calcium Rubies, a family of functionalizable BAPTA-based red fluorescent calcium (Ca(2+)) indicators as new tools for biological Ca(2+) imaging. The specificity of this Ca(2+)-indicator family is its side arm, attached on the ethylene glycol bridge that allows coupling the indicator to various groups while leaving open the possibility of aromatic substitutions on the BAPTA core for tuning the Ca(2+)-binding affinity. Using this possibility we now synthesize and characterize three different CaRubies with affinities between 3 and 22 MUM. Their long excitation and emission wavelengths (peaks at 586/604 nm) allow their use in otherwise challenging multicolor experiments, e.g., when combining Ca(2+) uncaging or optogenetic stimulation with Ca(2+) imaging in cells expressing fluorescent proteins. We illustrate this capacity by the detection of Ca(2+) transients evoked by blue light in cultured astrocytes expressing CatCh, a light-sensitive Ca(2+)-translocating channelrhodopsin linked to yellow fluorescent protein. Using time-correlated single-photon counting, we measured fluorescence lifetimes for all CaRubies and demonstrate a 10-fold increase in the average lifetime upon Ca(2+) chelation. Since only the fluorescence quantum yield but not the absorbance of the CaRubies is Ca(2+)-dependent, calibrated two-photon fluorescence excitation measurements of absolute Ca(2+) concentrations are feasible. PMID- 22816679 TI - Phytosterol supplementation does not affect plasma antioxidant capacity in patients with metabolic syndrome. AB - Several studies have observed decreased levels of lipophilic antioxidants after supplementation with phytosterols and stanols. The aim of this study was to examine the effect of phytosterol supplementation on plasma total antioxidant capacity in patients with metabolic syndrome. In a parallel arm, randomized placebo-controlled design, 108 patients with metabolic syndrome were assigned to consume yogurt beverage which provided 4 g of phytosterols per day or yogurt beverage without phytosterols. The duration of the study was 2 months and the patients in both groups followed their habitual westernized type diet. Blood samples were drawn at baseline and after 2 months, and the total antioxidant capacity of plasma was measured using the ferric reducing antioxidant power of plasma and oxygen radical absorbance capacity assays. After 2 months of intervention, plasma total antioxidant capacity did not differ between and within the intervention and the control groups. Phytosterol supplementation does not affect plasma antioxidant status. PMID- 22816678 TI - Synergistic protection against hyperoxia-induced lung injury by neutrophils blockade and EC-SOD overexpression. AB - BACKGROUND: Oxygen may damage the lung directly via generation of reactive oxygen species (ROS) or indirectly via the recruitment of inflammatory cells, especially neutrophils. Overexpression of extracellular superoxide dismutase (EC-SOD) has been shown to protect the lung against hyperoxia in the newborn mouse model. The CXC-chemokine receptor antagonist (Antileukinate) successfully inhibits neutrophil influx into the lung following a variety of pulmonary insults. In this study, we tested the hypothesis that the combined strategy of overexpression of EC-SOD and inhibiting neutrophil influx would reduce the inflammatory response and oxidative stress in the lung after acute hyperoxic exposure more efficiently than either single intervention. METHODS: Neonate transgenic (Tg) (with an extra copy of hEC-SOD) and wild type (WT) were exposed to acute hyperoxia (95% FiO2 for 7 days) and compared to matched room air groups. Inflammatory markers (myeloperoxidase, albumin, number of inflammatory cells), oxidative markers (8 isoprostane, ratio of reduced/oxidized glutathione), and histopathology were examined in groups exposed to room air or hyperoxia. During the exposure, some mice received a daily intraperitoneal injection of Antileukinate. RESULTS: Antileukinate-treated Tg mice had significantly decreased pulmonary inflammation and oxidative stress compared to Antileukinate-treated WT mice (p < 0.05) or Antileukinate-non-treated Tg mice (p < 0.05). CONCLUSION: Combined strategy of EC SOD and neutrophil influx blockade may have a therapeutic benefit in protecting the lung against acute hyperoxic injury. PMID- 22816681 TI - Anammox bacterial abundance, activity, and contribution in riparian sediments of the Pearl River estuary. AB - The hypothesis of an anammox hotspot in river riparian zones was put forward based on our investigation on freshwater ecotones for over 25 years and previous anammox research. Here we used a complementary array of methods including isotope pairing technique, quantitative PCR assays, and 16S rRNA and hydrazine synthase gene (hzsB) clone libraries to document the spatiotemporal evidence for a high abundance zone of anammox bacteria in river riparian sediment with observed abundance of 1.3-12 * 10(6) (summer) and 1.4-20 * 10(8) (winter) hydrazine synthase gene copies g(-1), which is the highest abundance in natural environments recorded so far. Meanwhile high anammox bacterial biodiversity were detected with 'Brocadia' and 'Kuenenia' dominating. However, the high anammox bacterial abundances were not related with high activities and contributions for nitrogen gas generation. The anammox activities ranged from 0.07 to 0.15 nmol N cm(-3) h(-1) (summer) to 1.0-2.6 nmol N cm(-3) h(-1) (winter) with high temporal heterogeneity. The retrieval of archaeal and bacterial amoA sequences indicated that nitrifying microbes might be the major source of nitrite for anammox bacteria in winter, while in summer the anaerobic nitrate reduction is more likely the main source. On the basis of (15)N tracing technology, it was estimated that a total loss of 0.67-9.62 g N m(-2) yr(-1) is linked to anammox in the riparian zone while denitrification contributed 96.2-170.3 g N m(-2) yr(-1) in Pearl River riparian sediments. PMID- 22816680 TI - Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen-specific cellular immunity. AB - Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have completed the investigational therapy; autologous lymphocytes were collected from all of the patients. Thirteen patients have successfully completed SCT and 11 have undergone ALI. Six patients tested have demonstrated CTA up-regulation in either unfractionated bone marrow (n = 4) or CD138+ cells (n = 2). CTA (CTAG1B)-specific T cell response has been observed in all three patients tested and persists following SCT. Epigenetic induction of an adaptive immune response to cancer testis antigens is safe and feasible in MM patients undergoing SCT. PMID- 22816682 TI - Parent-child relationships of boys in different offending trajectories: a developmental perspective. AB - BACKGROUND: This study tested the theoretical assumption that transformations of parent-child relationships in late childhood and adolescence would differ for boys following different offending trajectories. METHODS: Using longitudinal multiinformant data of 503 boys (ages 7-19), we conducted Growth Mixture Modeling to extract offending trajectories. Developmental changes in child reports of parent-child joint activities and relationship quality were examined using Latent Growth Curves. RESULTS: Five offending trajectories were found: non-offenders, moderate childhood offenders, adolescent-limited offenders, serious childhood offenders, and serious persistent offenders. Non-offenders reported high and stable levels of relationship quality between age 10 and 16. Adolescent-limited offenders reported a similarly high relationship quality as non-offenders at ages 7 and 10, but a lower and decreasing relationship quality in adolescence. Compared with non-offenders, serious persistent offenders reported poorer parent child relationship quality at all ages, and a decreasing relationship quality in adolescence. Serious persistent offenders and adolescent-limited offenders reported similar levels and changes in parent-child relationship quality in adolescence. Although serious persistent offenders reported fewer joint activities at age 10 and 13 than non-offenders, a similar linear decrease in joint activities in early to middle adolescence was found for boys in each trajectory. CONCLUSION: Developmental changes in parent-child relationship quality differ for different types of offenders. This finding has scientific and practical implications. PMID- 22816683 TI - Cyclic transmembrane charge transport mediated by low-potential pyrylium ions. AB - We have investigated the capacity of a series of N-dialkylaminophenyl-substituted pyrylium and thiopyrylium ions to act as photosensitizers and redox mediators between reactants separated by bilayer membranes. These studies were prompted by earlier results indicating that simple trimethy- and triphenyl-substituted analogues could promote efficient photosensitized transmembrane redox between vectorially organized reactants by an electroneutral e(-)/OH(-) antiport mechanism. Unlike the dyes used in the earlier studies, the ions investigated herein absorb strongly throughout the visible absorption region and are therefore potentially useful in solar photoconversion processes. We demonstrate that these ions can carry out cyclic electron transport between phase-separated electron donors and occluded Co(bpy)(3)(3+) in several transversely organized vesicles. The quantum yields obtained were relatively low, but were independent of the membrane microviscosity, suggesting that transmembrane diffusion was not rate limiting. Triphenylpyrylium and triphenylthiopyrylium ions were shown to be capable of acting as combined photosensitizers/redox relays, apparently by direct oxidation of either solvent (water) or buffer (acetate) ions from their triplet excited state. These reactions did not require addition of separate photosensitizers and electron donors; as such, they represent a minimal photochemical scheme for effecting transmembrane charge separation. The low potential visible-absorbing pyrylium ions were unable to function in this dual capacity, consistent with thermodynamic limitations. However, redox titrations established that the pyranyl radicals of these dyes should be capable of reducing H(+) to H(2) in weakly acidic solutions. Consistent with their strongly reducing nature, these dyes were shown to be capable of forming methyl viologen radical in photoinitiated transmembrane redox reactions. PMID- 22816721 TI - More sports injuries, please! PMID- 22816722 TI - AMPK vs mTORC1 signaling: genuine exercise effects of differentiated exercise in humans. Response to letter to editor by Dr A. K. Yamada. PMID- 22816723 TI - Exertional heat stroke and the intestinal microbiome. PMID- 22816724 TI - Retraction: "Cable wakeboarding, a new trendy sport: analysis of injuries with regard to injury prevention" publishedby M. D. Schofer, S.A. Hrabal, N. Timmesfeld, S. Fuchs-Winkelmann, T. Patzer in Scandinavian Journal of Medicine& Science in Sports, Early View, 15 July 2010 (DOI: 10.1111/j.1600 0838.2010.01158.x). PMID- 22816726 TI - Permanent pacemaker-related upper extremity deep vein thrombosis: a series of 20 cases. AB - BACKGROUND: Upper extremity deep vein thrombosis (DVT) has become a common occurrence nowadays due to emergence of multiple newer risk factors, such as implantation of permanent pacemaker (PPM) and implantable cardioverter defibrillators. We are reporting 20 cases of upper extremity DVT related to PPM implantation. METHODS AND RESULT: All the patients presented within 6 months, with unilateral upper extremity swelling (90%), pain (45%), erythema (15%), and other less frequent features. Venography established the diagnosis in all the cases. Considering the distribution of possible risk factors of venous thrombosis among our patients, diabetes was the most frequent (present in 45%) followed by smoking (35%), hypertension (30%), obesity with body mass index >=30 (30%), history of acute myocardial infarction (25%), chronic obstructive pulmonary disease (20%), and history of congestive cardiac failure (15%). Antiplatelets were not found protective against the development of this situation. There was no statistically significant difference in respect to venous access, number of leads, use of previous temporary pacing lead, or poor left ventricular systolic function (ejection fraction <=40%) among the six patients who presented with complete occlusion of subclavian vein compared to the rest of the 14 patients who had partial occlusion. There were complete resolutions of symptom in 85% of patients after 6 months of anticoagulation therapy in the form of initial intravenous unfractinated heparin followed by oral warfarin. CONCLUSION: Anticoagulation with warfarin for 6 months with initial intravenous unfractionated heparin was a safe and effective mode of therapy in most of the patients with PPM related upper extremity DVT. PMID- 22816725 TI - Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression. AB - OBJECTIVES: In a well-defined sample, we sought to determine which clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M). METHODS: We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder. RESULTS: Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n=21) was strongly associated with repeat episodes of H/M [hazard ratio (HR)=2.01, 95% confidence interval (CI): 1.06-3.83, p=0.03]. Those with treatment-associated episodes (n=12) were less likely to experience subsequent episodes of H/M, although this was not significant in the multivariate model (HR=0.25, 95% CI: 0.06-1.05, p=0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode. CONCLUSIONS: A family history of bipolar disorder influences the course of illness, even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes. PMID- 22816727 TI - Modular design of domain assembly in porous coordination polymer crystals via reactivity-directed crystallization process. AB - The mesoscale design of domain assembly is crucial for controlling the bulk properties of solids. Herein, we propose a modular design of domain assembly in porous coordination polymer crystals via exquisite control of the kinetics of the crystal formation process. Employing precursors of comparable chemical reactivity affords the preparation of homogeneous solid-solution type crystals. Employing precursors of distinct chemical reactivity affords the preparation of heterogeneous phase separated crystals. We have utilized this reactivity-directed crystallization process for the facile synthesis of mesoscale architecture which are either solid-solution or phase-separated type crystals. This approach can be also adapted to ternary phase-separated type crystals from one-pot reaction. Phase-separated type frameworks possess unique gas adsorption properties that are not observed in single-phasic compounds. The results shed light on the importance of crystal formation kinetics for control of mesoscale domains in order to create porous solids with unique cooperative functionality. PMID- 22816729 TI - Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, placebo-controlled trial. AB - OBJECTIVE: Glycaemic control in patients with type 2 diabetes (T2DM) is often not achieved or not sustained using monotherapy such as metformin, necessitating the addition of other antihyperglycaemic agents. Linagliptin, a dipeptidyl peptidase 4 inhibitor, is licensed for 5 mg once-daily dosing. As metformin is administered twice daily, a fixed-dose combination of these compounds would require twice daily administration of linagliptin. This study evaluated whether 2.5 mg twice daily dosing of linagliptin has comparable efficacy and safety to 5 mg once-daily dosing when given in addition to metformin twice daily in patients with inadequate glycaemic control. METHODS: A total of 491 T2DM patients with glycated haemoglobin (HbA1c) 7.0-10.0% were randomised (5:5:1) to double-blind treatment with linagliptin 2.5 mg twice daily, 5 mg once daily or placebo, respectively, in addition to continuing metformin twice daily (>=1500 mg/day or maximally tolerated dose). The primary endpoint was change from baseline in HbA1c after 12 weeks. ClinicalTrials.gov, NCT01012037. RESULTS: Mean baseline HbA1c for all patients was 7.97%. After 12 weeks, linagliptin 2.5 mg twice daily and 5 mg once daily both significantly reduced HbA1c (placebo-adjusted changes from baseline 0.74% (95% CI -0.97, -0.52) and -0.80% (95% CI -1.02, -0.58), respectively, both p<0.0001). The treatment difference (twice daily-once daily) between the linagliptin regimens was 0.06 (95% CI -0.07, 0.19), the upper bound of which was less than the predefined noninferiority margin (0.35%). The overall incidence of adverse events with linagliptin 2.5 mg twice daily, 5 mg once daily and placebo was 43.0%, 34.8%, and 38.6% respectively. Hypoglycaemia was rare (3.1% with linagliptin 2.5 mg twice daily, 0.9% with 5 mg once daily, 2.3% with placebo) with no severe episodes. Study limitations include duration, patient population (mainly white) and absence of postprandial glucose data. CONCLUSIONS: Linagliptin 2.5 mg twice daily had non-inferior HbA1c-lowering effects after 12 weeks compared to 5 mg once daily, with comparable safety and tolerability, in T2DM patients inadequately controlled with metformin. PMID- 22816728 TI - A magic pill? A qualitative analysis of patients' views on the role of antidepressant therapy in inflammatory bowel disease (IBD). AB - BACKGROUND: Studies with healthy volunteers have demonstrated that antidepressants can improve immunoregulatory activity and thus they may have a potential to positively impact the disease course in inflammatory bowel disease (IBD), a chronic and incurable condition. However, patients' views on the role of antidepressants in the management of their IBD are unknown. Thus, this study aimed to explore patients' experiences and opinions regarding the effect of antidepressants on IBD course before possibly undertaking future treatment trials with antidepressants. METHODS: Semi-structured in-depth interviews with open ended questions were conducted with a randomly selected sample of IBD patients recruited at the Australian public hospital IBD clinic and currently receiving antidepressants. A qualitative content analysis was undertaken to summarise patients' responses. A Visual Analogue Scale was used to provide a quantitative assessment of patients' experiences with antidepressants. RESULTS: Overall, 15 IBD sufferers currently on antidepressants (nine females, six males) were interviewed. All 15 reported a positive response to antidepressants reporting they improved their quality of life, with minimal side-effects. Five patients (33.3%) felt the antidepressant had specifically improved their IBD course. Three patients noted how they believed the reduction in feelings of stress mediated the positive influence of the antidepressant on IBD course. Ten patients (66.7%) felt the antidepressants had not specifically influenced their IBD. Nine patients (60.0%) had a generally positive attitude towards antidepressants, four patients (26.7%) were ambivalent, and two patients (13.3%) held a negative view towards antidepressants. Twelve patients (80.0%) stated that they would be willing to participate in clinical trials. CONCLUSIONS: Antidepressants seem to be well tolerated by IBD patients. One third of patients reported an observable improvement of their IBD under the influence of this treatment. The positive attitude towards antidepressants in these participants may make the conduct of clinical trials to further assess for any specific role on IBD course feasible. However, due to a small sample size, a qualitative nature of this study and in light of the results of studies on other populations indicating reluctance to taking antidepressants at least in some patients, these results should be interpreted with caution until confirmed in quantitative studies. PMID- 22816730 TI - Synthesis and herbicidal activity of 2-(substituted phenoxyacetoxy)alkyl-5,5 dimethyl-1,3,2-dioxaphosphinan-2-one. AB - A series of 2-(substituted phenoxyacetoxy)alkyl-5,5-dimethyl-1,3,2 dioxaphosphinan-2-ones IIa-s were designed and synthesized on the basis of the previous work for the modification of alkylphosphonates I, and their structures were confirmed by (1)H NMR, (31)P NMR, (13)C NMR, IR, MS, and elemental analysis. Their herbicidal activities against seven species of weeds were evaluated in a greenhouse. A part of the title compounds such as IIa-g, IIk, IIo, and IIr exhibited significant postemergence herbicidal activity against Abutilon theophrasti, Brassica juncea, Amaranthus retroflexus, and Eclipta prostrate at a dosage of 150 g ai/ha. Structure-activity relationship analyses indicated that the introduction of a phosphorus-containing heterocyclic ring had a favorable effect on herbicidal activity, and their herbicidal activity could be further increased by a reasonable combination of X, Y, and R in parent structure II. It could be found that the title compounds IIa 2-[(2,4 dichlorophenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2-dioxaphosphinan-2-one and IIr 2-[(4-chloro-2-methyl-phenoxy)acetoxy](methyl)methyl-5,5-dimethyl-1,3,2 dioxaphosphinan-2-one possess high activity and a broad spectrum against all of the test broadleaf weeds with 70-100% inhibition effect at a dosage of 75 g ai/ha, and the title compounds IIa and IIr are safe for corn and wheat at a dosage of 150 g ai/ha. Furthermore, the title compound IIa possesses low rat toxicity. These results suggest that the title compounds IIa and IIr could be potential and selective postemergence herbicides for further development. PMID- 22816732 TI - High-dose statin therapy does not induce insulin resistance in patients with familial hypercholesterolemia. AB - BACKGROUND: Insulin resistance is thought to play a pathophysiological role in the development of atherosclerosis. Decreased adiponectin levels are associated with hyperinsulinemia, insulin resistance, and coronary artery disease. Patients with familial hypercholesterolemia (FH) develop premature atherosclerosis and should be insulin resistant and have low adiponectin levels. METHODS: A total of 51 homozygous FH (HoFH) and 20 heterozygous FH (HeFH) patients were studied before and after statin therapy. Twenty normocholesterolemic subjects were controls. Fasting lipograms, glucose, insulin, proinsulin, adiponectin, and high sensitivity C-reactive protein (hsCRP) were measured. Insulin resistance was calculated with the homeostasis model assessment (HOMA-IR) formula. Carotid intima media thickness (CIMT) was measured as a subclinical marker of atherosclerosis. RESULTS: On multiple regression analysis, the major determinant of insulin resistance measured by HOMA-IR was body mass index (BMI) (r=0.54; P=0.004). On simple linear regression, the highest correlation was with BMI (r=0.39; P=0.0002). Log hsCRP correlated with BMI (r=0.35; P<0.002) and insulin resistance (r=0.22; P=0.05). Low-density lipoprotein cholesterol (LDL-C) and CIMT did not correlate with insulin resistance. Unexpectedly, adiponectin levels were highest in HoFH patients and correlated with LDL-C (r=0.34; P=0.001). No change in the degree of IR was observed with statin therapy. CONCLUSIONS: FH patients are not insulin resistant and do not have low adiponectin levels. There was no significant change in insulin resistance with high-dose statin therapy. PMID- 22816733 TI - Salivary secretion effects of the antipsychotic drug olanzapine in an animal model. AB - OBJECTIVE: Olanzapine, introduced as an alternative to clozapine in schizophrenia therapy, is thought to display a receptor affinity similar to that of clozapine. Antipsychotics are well-known xerogenic drugs. However, clozapine exerts both antagonistic and agonistic salivary effects ('clozapine-induced sialorrhea'), the latter probably via muscarinic M1 type of receptor. We hypothesise that olanzapine also has dual salivary effects. MATERIAL AND METHODS: Effects of intravenous olanzapine were examined in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). Secretion was evoked reflexly, and by intravenous methacholine and the tachykinin substance P. RESULTS: At 0.01-1 mg kg(-1), olanzapine dose dependently reduced secretion in response to methacholine or reflex stimulus but not that to substance P. At 10 mg kg(-1), olanzapine evoked a long-lasting secretion, independent of the autonomic innervation as well as of alpha- and beta-adrenergic receptors and muscarinic receptors. The secretion was reduced, but not abolished, by a substance P receptor antagonist. CONCLUSIONS: Like clozapine, olanzapine evoked secretion. The response to olanzapine was greater and, in contrast to clozapine, involved non-traditional gland receptors (such as substance P receptors). The findings imply that olanzapine plays an excitatory role via tachykinin receptors in humans. PMID- 22816731 TI - Glutaredoxin 1 protects dopaminergic cells by increased protein glutathionylation in experimental Parkinson's disease. AB - AIMS: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. RESULTS: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knock-down sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. INNOVATION: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. CONCLUSIONS: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2. PMID- 22816735 TI - Comparison of rapid methods for detection of Giardia spp. and Cryptosporidium spp. (oo)cysts using transportable instrumentation in a field deployment. AB - Reliable, sensitive, quantitative, and mobile rapid screening methods for pathogenic organisms are not yet readily available, but would provide a great benefit to humanitarian intervention units in disaster situations. We compared three different methods (immunofluorescent microscopy, IFM; flow cytometry, FCM; polymerase chain reaction, PCR) for the rapid and quantitative detection of Giardia lamblia and Cryptosporidium parvum (oo)cysts in a field campaign. For this we deployed our mobile instrumentation and sampled canal water and vegetables during a 2 week field study in Thailand. For purification and concentrations of (oo)cysts, we used filtration and immunomagnetic separation. We were able to detect considerably high oo(cysts) concentrations (ranges: 15-855 and 0-240 oo(cysts)/liter for Giardia and Cryptosporidium, respectively) in 85 to 300 min, with FCM being fastest, followed by PCR, and IFM being slowest due to the long analysis time per sample. FCM and IFM performed consistently well, whereas PCR reactions often failed. The recovery, established by FCM, was around 30% for Giardia and 13% for Cryptosporidium (oo)cysts. It was possible to track (oo)cysts from the wastewater further downstream to irrigation waters and confirm contamination of salads and water vegetables. We believe that rapid detection, in particular FCM-based methods, can substantially help in disaster management and outbreak prevention. PMID- 22816734 TI - Production of highly concentrated, heat-stable hepatitis B surface antigen in maize. AB - Plant-based oral vaccines are a promising emergent technology that could help alleviate disease burden worldwide by providing a low-cost, heat-stable, oral alternative to parenterally administered commercial vaccines. Here, we describe high-level accumulation of the hepatitis B surface antigen (HBsAg) at a mean concentration of 0.51%TSP in maize T1 seeds using an improved version of the globulin1 promoter. This concentration is more than fourfold higher than any previously reported lines. HBsAg expressed in maize seeds was extremely heat stable, tolerating temperatures up to 55 degrees C for 1 month without degradation. Optimal heat stability was achieved after oil extraction of ground maize material, either by supercritical fluid extraction or hexane treatment. The contributions of this material towards the development of a practical oral vaccine delivery system are discussed. PMID- 22816736 TI - The effects of cranio-cervical flexion on activation of swallowing-related muscles. AB - We tested the effects of cranio-cervical flexion (CCF) on activation of swallowing-related muscles while swallowing liquid in a sample of 45 healthy volunteers. Activation following CCF movement was examined across two positions (supine and sitting) and, three pressure levels and two different postures were examined in each condition, respectively. When CCF was applied, activation of swallowing-related muscles was significantly increased compared to the neutral neck position, and such findings were found across both the supine and sitting positions. Also in the supine position, when the pressure level of the stabilizer was escalated, there was a significant difference in the activity of the swallowing-related muscles compared to the baseline level. In conclusion, our results suggest that CCF may be a viable method to enhance the effectiveness of swallowing-related muscles by changing neck position. When CCF is applied, the stability of the deep flexor muscles must be secured first after which superficially located muscles may better assist swallowing with less effort. PMID- 22816737 TI - High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma. AB - Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B-cell lymphomas (P < 0.00001). The presence of unmutated IGHV, genomic complexity, 17p13-TP53 deletion and 8q-MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studies narrowed down a commonly deleted region of 2.7 Mb in 7q32.1-q32.2 spanning a region between the SND1 and COPG2 genes. High-throughput sequencing analysis of the 7q32-deleted segment did not identify biallelic deletions/insertions or clear pathogenic gene mutations, but detected six nucleotide changes in IRF5 (n = 2), TMEM209 (n = 2), CALU (n = 1) and ZC3HC1 (n = 1) not found in healthy individuals. Comparative expression analysis found a fourfold down-regulation of IRF5 gene in lymphomas with 7q32 deletion versus non deleted tumours (P = 0.032). Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased proliferation and increased apoptosis in vitro, and impaired lymphoma development in vivo. These results show that cryptic deletions, insertions and/or point mutations inactivating genes within 7q32 are not common in SMZL, and suggest that IRF5 may be a haploinsufficient tumour suppressor in this lymphoma entity. PMID- 22816738 TI - Single cell matrix-assisted laser desorption/ionization mass spectrometry imaging. AB - Application of mass spectrometry imaging (MS imaging) analysis to single cells was so far restricted either by spatial resolution in the case of matrix-assisted laser desorption/ionization (MALDI) or by mass resolution/mass range in the case of secondary ion mass spectrometry (SIMS). In this study we demonstrate for the first time the combination of high spatial resolution (7 MUm pixel), high mass accuracy (<3 ppm rms), and high mass resolution (R = 100,000 at m/z = 200) in the same MS imaging measurement of single cells. HeLa cells were grown directly on indium tin oxide (ITO) coated glass slides. A dedicated sample preparation protocol was developed including fixation with glutaraldehyde and matrix coating with a pneumatic spraying device. Mass spectrometry imaging measurements with 7 MUm pixel size were performed with a high resolution atmospheric-pressure matrix assisted laser desorption/ionization (AP-MALDI) imaging source attached to an Exactive Orbitrap mass spectrometer. Selected ion images were generated with a bin width of Deltam/z = +/-0.005. Selected ion images and optical fluorescence images of HeLa cells showed excellent correlation. Examples demonstrate that a lower mass resolution and a lower spatial resolution would result in a significant loss of information. High mass accuracy measurements of better than 3 ppm (root-mean-square) under imaging conditions provide confident identification of imaged compounds. Numerous compounds including small metabolites such as adenine, guanine, and cholesterol as well as different lipid classes such as phosphatidylcholine, sphingomyelin, diglycerides, and triglycerides were detected and identified based on a mass spectrum acquired from an individual spot of 7 MUm in diameter. These measurements provide molecularly specific images of larger metabolites (phospholipids) in native single cells. The developed method can be used for a wide range of detailed investigations of metabolic changes in single cells. PMID- 22816766 TI - Polymer-metal complexes in polyelectrolyte multilayer films as catalysts for oxidation of toluene. AB - We report on the binding of metal ions (Me(2+); Co(2+) and Cu(2+)) with weak polyelectrolyte multilayers (PEMs), as well as on catalytic activity of PEM Me(2+) films for oxidation of toluene. Using several types of PEM films constructed using branched polyethyleneimine (BPEI) or quaterinized poly-4 vinylpyridines (QPVPs) as polycations and poly(acrylic acid) (PAA) or poly(styrene sulfonate) (PSS) as polyanions, we found that binding of Co(2+) and Cu(2+) ions with a PEM matrix can occur both through coordination to polycationic amino groups and/or ionic binding to polyacid groups. The amount of metal ions loaded within the film increased linearly with film thickness and was strongly dependent on polyelectrolyte type, film assembly pH, and fraction of permanent charge in polymer chains. Among various PEM-Me(2+) systems, BPEI/PAA-Co(2+) films assembled at pH 8.5 show the best catalytic performance, probably because of the preservation of high mobility of Co(2+) ions coordinated to amino groups of BPEI in these films. With BPEI/PAA-Co(2+) films, we demonstrated that films were highly permeable to reagents and reaction products within hundreds of nanometers of the film bulk; i.e., film catalytic activity increased linearly with layer number up to 30 bilayers and slowed for thicker films. PMID- 22816767 TI - The PtdIns3P-binding protein Phafin 2 mediates epidermal growth factor receptor degradation by promoting endosome fusion. AB - Phosphatidylinositol 3-phosphate (PtdIns3P) orchestrates endosomal cargo transport, fusion and motility by recruiting FYVE or PX domain-containing effector proteins to endosomal membranes. In an attempt to discover novel PtdIns3P effectors involved in the termination of growth factor receptor signalling, we performed an siRNA screen for epidermal growth factor (EGF) degradation, targeting FYVE and PX domain proteins in the human proteome. This screen identified several potential regulators of EGF degradation, including HRS (used as positive control), PX kinase, MTMR4 and Phafin2/PLEKHF2. As Phafin2 has not previously been shown to be required for EGF receptor (EGFR) degradation, we performed further functional studies on this protein. Loss of Phafin2 was found to decrease early endosome size, whereas overexpression of Phafin2 resulted in enlarged endosomes. Moreover, both the EGFR and the fluid-phase marker dextran were retained in abnormally small endosomes in Phafin2-depleted cells. In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1. PMID- 22816768 TI - Bioavailability, distribution, and antioxidative effects of selected triterpenes in mice. AB - This study analyzed the content of eight triterpenes (oleanolic acid, ursolic acid, arjunolic acid, asiatic acid, boswellic acid, corosolic acid, madecassic acid, and maslinic acid) in ten vegetables and eight fruits. These compounds at 0.5% were supplied to mice for 4 or 8 weeks. The bioavailability, tissue distribution, and antioxidative protection of these triterpenes were examined. Results showed that triterpenes were detected in eight vegetables and six fruits. Basil and brown mustard contained seven test triterpenes, in the range of 14-102 mg/100 g dry weight. The level of each triterpene in plasma, brain, heart, liver, kidney, colon, and bladder increased as the feeding period was increased from 4 weeks to 8 weeks (P < 0.05). Renal homogenates from mice with triterpene intake had greater antioxidative effects against glucose-induced glutathione loss and malondialdehyde and oxidized glutathione production when compared with those from control groups (P < 0.05). These data support that these triterpenes were absorbed and deposited in their intact forms, which in turn exerted in vivo antioxidative protection. PMID- 22816769 TI - Do globins in microaerophilic Campylobacter jejuni confer nitrosative stress tolerance under oxygen limitation? AB - The microaerophilic pathogen Campylobacter jejuni possesses inducible systems for resisting NO. Two globins--Cgb (a single-domain globin) and Ctb (a truncated globin)--are up-regulated in response to NO via the positively acting transcription factor NssR. Our aims were to determine whether these oxygen binding globins also function in severely oxygen-limited environments, as in the host. At growth-limiting oxygen transfer rates, bacteria were more S nitrosoglutathione (GSNO) sensitive, irrespective of the presence of Cgb, Ctb, or NssR. Pregrowth of cells with GSNO enhanced GSNO resistance, even in nssR and cgb mutants, but transcriptomic profiling of oxygen-limited, NO-exposed cells failed to reveal the NssR regulon. Nevertheless, globin expression in an Escherichia coli mutant lacking the NO-detoxifying flavohemoglobin Hmp showed that Cgb and Ctb consume NO aerobically or anoxically and offer some protection to respiratory inhibition by NO. The constitutively expressed nitrite reductase NrfA does not provide resistance under oxygen-limited conditions. We, therefore, hypothesize that, although Cgb and NrfA can detoxify NO, even anoxically, they are neither up regulated nor functional under physiologically relevant oxygen-limited conditions and, second, responses to NO do not stem from trancriptional regulation. PMID- 22816771 TI - Simulating adsorption of organic pollutants on finite (8,0) single-walled carbon nanotubes in water. AB - Understanding the mechanism and thermodynamics of the adsorption of chemicals on carbon nanotubes (CNTs) is important to risk assessment and pollution control of both CNTs and chemicals. We computed the adsorption of cyclohexane, benzene derivatives, and polycyclic aromatic hydrocarbons (PAHs) on (8,0) single-walled carbon nanotubes by the M05-2X of density functional theory. The computed adsorption energies (E(a)) in the aqueous phase are lower than those in the gaseous phase, indicating that the adsorption in the aqueous phase is more favorable. The contribution of pi-pi interactions and the enhancing effect of a NO(2) substituent on the adsorption were quantified. For a hypothetical aromatic with the same hydrophobicity (logK(OW)) to cyclohexane, pi-pi interactions contribute ca. 24% of the total interactions as indicated by E(a). -NO(2) enhances the pi-pi interactions due to its electron withdrawing effects, and contributes 24% to the value of E(a). Simple linear regression showed the computed Gibbs free energy changes for the adsorption correlate significantly with the experimental values (r = 0.97, p < 0.01). The correlation together with the computed thermodynamic parameters may be employed to predict the adsorption affinity of other chemicals. The study may pave a new way for evaluating/predicting the adsorption affinity of organic compounds on SWNTs and probing the adsorption mechanisms. PMID- 22816772 TI - Rh-catalyzed borylation of N-adjacent C(sp3)-H bonds with a silica-supported triarylphosphine ligand. AB - Direct C(sp(3))-H borylation of amides, ureas, and 2-aminopyridine derivatives at the position alpha to the N atom, which gives the corresponding alpha aminoalkylboronates, has been achieved with a heterogeneous catalyst system consisting of [Rh(OMe)(cod)]2 and a silica-supported triarylphosphine ligand (Silica-TRIP) that features an immobilized triptycene-type cage structure with a bridgehead P atom. The reaction occurs not only at terminal C-H bonds but also at internal secondary C-H bonds under mild reaction conditions (25-100 degrees C, 0.1-0.5 mol % Rh). PMID- 22816773 TI - Effects of intrauterine infection or inflammation on fetal lung development. AB - 1. Intrauterine infection or inflammation is common in cases of preterm birth. Preterm infants are at risk of acute respiratory distress as a result of lung immaturity; evidence of exposure to infection and/or inflammation before birth is associated with a reduced risk of neonatal respiratory distress syndrome (RDS). Experimentally induced intrauterine inflammation or infection in sheep causes a precocious increase in pulmonary surfactant in the preterm lungs that improves preterm lung function, consistent with the reduced risk of RDS in human infants exposed to infection and/or inflammation before birth. 2. The effects of intrauterine inflammation on fetal lung development appear to result from direct action of proinflammatory stimuli within the lungs rather than by systemic signals, such as the classical glucocorticoid-mediated lung maturation pathway. However, paracrine and/or autocrine production and/or metabolism of glucocorticoids in fetal lung tissue may occur as a result of inflammation induced changes in the expression of 11beta-hydroxysteroid dehydrogenase (types 1 and 2). 3. Likely candidates that mediate inflammation-induced surfactant production by the preterm lung include prostaglandin E2 and/or other arachidonic acid metabolites. Intrauterine inflammation induces the expression of enzymes responsible for prostaglandin production in fetal lung tissue. Inhibition of prostaglandin production prevents, at least in part, the effects of inflammation on fetal lungs. 4. Our experiments are identifying mechanisms of surfactant production by the preterm lungs that may be exploited as novel therapies for preventing respiratory distress in preterm infants. Elucidation of the effects of inflammation on the fetal lungs and other organs will allow more refined approaches to the care of preterm infants exposed to inflammation in utero. PMID- 22816774 TI - The growth and osteoclastogenic effects of fibroblasts isolated from keratocystic odontogenic tumor. AB - OBJECTIVES: To investigate the growth characteristics and effects on osteoclastogenesis in fibroblasts isolated from keratocystic odontogenic tumor (KCOT) fibrous capsule. MATERIALS AND METHODS: Fibroblasts isolated from KCOT fibrous capsule and normal gingival mucosa were cultured in vitro. Their colony forming units and proliferative activity were investigated, and the osteoclastogenic effects were also observed by a co-culture system with osteoclast precursor cell line Raw264.7. The mRNA of several genes related to bone resorption (IL-6, VEGF, COX-2, and M-CSF) was analyzed by real-time PCR. RESULTS: Keratocystic odontogenic tumor fibroblasts developed fewer CFU and had longer population doubling time than gingival fibroblasts (P < 0.05). In contrast to gingival fibroblasts, KCOT fibroblasts expressed less IL-6, COX-2, and M-CSF (P < 0.05); however, the Raw264.7 co-cultured with KCOT fibroblasts developed more osteoclast-like cells and expressed higher level of nfatc1 than that co cultured with gingival fibroblasts. Increased COX-2 expression and VEGF expression were detected in KCOT fibroblasts and Raw264.7 co-culture system (P < 0.05). CONCLUSION: Although KCOT fibroblasts showed lower level of cell proliferation than gingival fibroblasts, higher osteoclastogenic ability was detected when co-cultured with Raw264.7. These results suggest that the cell-cell interaction in the co-culture system, possibly by increasing COX-2 and VEGF expression, may be responsible for the increased osteoclastogenic effects of KCOT fibroblasts. PMID- 22816775 TI - Homogeneous assay for detection of active Epstein-Barr nuclear antigen 1 by thrombin activity modulation. AB - Epstein-Barr virus (EBV) has been associated with several malignancies as Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease. In those diseases, Epstein-Barr nuclear antigen 1 (EBNA-1) is constitutively expressed. Here, we reported an innovative system to detect active EBNA-1 protein in a homogeneous assay. The system is based on the modulation of thrombin activity by a self-complementary single stranded DNA (scssDNA), which was designed and synthesized to mimic the palindromic target sites of EBNA-1 in the EBV genome. This model system showed a limit of detection of 3.75 ng mL(-1) of active EBNA-1 protein with a dynamic detection range from 3.75 to 250 ng mL(-1) with a correlation coefficient of 0.997. This new homogeneous assay for active EBNA-1 protein detection and quantification provides a very useful tool for rapid screening of EBNA-1 blockers in biomedical research. PMID- 22816776 TI - Bacterial RNA extraction and purification from whole human blood using isotachophoresis. AB - We demonstrate a novel assay for physicochemical extraction and isotachophoresis based purification of 16S rRNA from whole human blood infected with Pseudomonas putida . This on-chip assay is unique in that the extraction can be automated using isotachophoresis in a simple device with no moving parts, it protects RNA from degradation when isolating from ribonuclease-rich matrices (such as blood), and produces a purified total nucleic acid sample that is compatible with enzymatic amplification assays. We show that the purified RNA is compatible with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and demonstrate a clinically relevant sensitivity of 0.03 bacteria per nanoliter using RT-qPCR. PMID- 22816777 TI - Building blocks for the development of an interface for high-throughput thin layer chromatography/ambient mass spectrometric analysis: a green methodology. AB - Interfacing thin layer chromatography (TLC) with ambient mass spectrometry (AMS) has been an important area of analytical chemistry because of its capability to rapidly separate and characterize the chemical compounds. In this study, we have developed a high-throughput TLC-AMS system using building blocks to deal, deliver, and collect the TLC plate through an electrospray-assisted laser desorption ionization (ELDI) source. This is the first demonstration of the use of building blocks to construct and test the TLC-MS interfacing system. With the advantages of being readily available, cheap, reusable, and extremely easy to modify without consuming any material or reagent, the use of building blocks to develop the TLC-AMS interface is undoubtedly a green methodology. The TLC plate delivery system consists of a storage box, plate dealing component, conveyer, light sensor, and plate collecting box. During a TLC-AMS analysis, the TLC plate was sent to the conveyer from a stack of TLC plates placed in the storage box. As the TLC plate passed through the ELDI source, the chemical compounds separated on the plate would be desorbed by laser desorption and subsequently postionized by electrospray ionization. The samples, including a mixture of synthetic dyes and extracts of pharmaceutical drugs, were analyzed to demonstrate the capability of this TLC-ELDI/MS system for high-throughput analysis. PMID- 22816779 TI - Clinical pharmacokinetic assessment of an anti-MAdCAM monoclonal antibody therapeutic by LC-MS/MS. AB - Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been shown to be a viable tool for preclinical pharmacokinetic (PK) analysis of monoclonal antibody (mAb) therapeutics. This work describes free and total PK assays for the mAb PF 00547,659 in serum of ulcerative colitis patients in a First-In-Human study [Vermeire, S. et al. Gut2011, 60 (8), 1068-1075]. The assay to measure free PF 00547,659 used immuno-enrichment with a biotinylated anti-idiotypic antibody and streptavidin magnetic beads. The total assay used enrichment by protein G magnetic beads. Following elution of PF-00547,659 from the beads, addition of an extended sequence stable isotope labeled peptide and trypsin digestion, a proteotypic peptide derived from the CDR region of the light chain of PF 00547,659 was quantified by LC-MS/MS. The free assay had a calibration range from 7.03 ng/mL to 450 ng/mL. The assay was precise and accurate with interbatch imprecision <16.5%, and interbatch inaccuracy <13.7% at all concentrations investigated during assay qualification. Results from LC-MS/MS methodologies are compared with historical immunoassay data originally acquired during the course of the clinical study. PK parameter estimates were highly correlated between the two analytical approaches. This work provides precedence that immunoaffinity LC MS/MS can effectively be used to measure the serum concentrations of mAb therapeutics in clinical studies. PMID- 22816778 TI - Selective imaging of active pharmaceutical ingredients in powdered blends with common excipients utilizing two-photon excited ultraviolet-fluorescence and ultraviolet-second order nonlinear optical imaging of chiral crystals. AB - Second order nonlinear optical imaging of chiral crystals (SONICC) and two-photon excited fluorescence measurements [both autofluorescence and two-photon excited UV-fluorescence (TPE-UVF)] were assessed for the selective detection of APIs relative to common pharmaceutical excipients. Active pharmaceutical ingredients (APIs) compose only a small percentage of most tabulated formulations, yet the API distribution within the tablet can affect drug release and tablet stability. Complementary measurements using either UV-SONICC (266 nm detection) or TPE-UVF were shown to generate signals >50-fold more intense for a model API (griseofulvin) than those produced by common pharmaceutical excipients. The combined product of the measurements produced signals >10(4)-fold greater than the excipients studied. UV-SONICC or TPE-UVF produced greater selectivity than analogous measurements with visible-light detection, attributed to the presence of aromatic moieties within the API exhibiting strong one and two photon absorption at ~266 nm. Complementary SONICC and fluorescence measurements allowed for the sensitive detection of the three-dimensional distribution of tadalafil within a Cialis tablet to a depth of >140 MUm. PMID- 22816780 TI - Detection of inflammation in vivo by surface-enhanced Raman scattering provides higher sensitivity than conventional fluorescence imaging. AB - The detection of inflammatory changes is a key aim for the early diagnosis and treatment of several autoimmune, infectious, and metastatic diseases. While surface-enhanced Raman scattering (SERS) has the capability to provide noninvasive, in vivo imaging at sufficient depth to achieve this goal, this approach has not been exploited in the study of inflammation. SERS-active nanoparticles were coded with a unique Raman signal that was protected under a wide range of conditions and stimuli. To detect early-stage inflammation, gold nanoparticle clusters containing Raman-active molecules were conjugated to intercellular adhesion molecule 1- (ICAM-1-) specific monoclonal antibodies. SERS allowed noninvasive measurement of ICAM-1 expression in vivo with twice the sensitivity of two-photon fluorescence. This is the first time SERS has been used for in vivo detection of inflammation and is a major advance in the ever-growing toolkit of approaches for use in noninvasive, next-generation in vivo imaging. PMID- 22816781 TI - Rapid identification of long-chain polyunsaturated fatty acids in a marine extract by HPLC-MS using data-dependent acquisition. AB - The collision-induced dissociation (CID) of a range of deprotonated fatty acid standards was studied using linear ion trap mass spectrometry. Neutral losses of 78, 98, and 136 Da were consistently observed for fatty acids with five or more double bonds. Comparison of the MS/MS spectra of docosahexaenoic acid (DHA) and universally (13)C-labeled DHA allowed the molecular formulas for these neutral losses to be determined as C(6)H(6), C(5)H(6)O(2), and C(8)H(8)O(2). Knowledge of fatty acid fragmentation processes was then applied to identify fatty acids from a sea anemone, Aiptasia pulchella, and dinoflagellate symbiont, Symbiodinium sp. extract. Using HPLC-MS, fatty acids were separated and analyzed by tandem mass spectrometry in data-dependent acquisition mode. Neutral loss chromatograms for 78, 98, and 136 Da allowed the identification of long-chain fatty acids with five or more double bonds. On the basis of precursor ion m/z ratios, chain length and degree of unsaturation for these fatty acids were determined. The application of this technique to an Aiptasia sp.-Symbiodinium sp. lipid extract enabled the identification of the unusual, long-chain fatty acids 24:6, 26:6, 26:7, 28:7, and 28:8 during a single 40 min HPLC-MS analysis. PMID- 22816783 TI - Polydispersity characterization of lipid nanoparticles for siRNA delivery using multiple detection size-exclusion chromatography. AB - The development of lipid nanoparticle (LNP) based small interfering RNA (siRNA) therapeutics presents unique pharmaceutical and regulatory challenges. In contrast to small molecule drugs that are highly pure and well-defined, LNP drug products can exhibit heterogeneity in size, composition, surface property, or morphology. The potential for batch heterogeneity introduces a complexity that must be confronted in order to successfully develop and ensure quality in LNP pharmaceuticals. Currently, there is a lack of scientific knowledge in the heterogeneity of LNPs as well as high-resolution techniques that permit this evaluation. This article reports a size-exclusion chromatography (SEC) method that permits the high-resolution analysis of LNP size distribution in its native solution condition. When coupled with multiple detection systems including UV vis, multi-angle light scattering, and refractive index, on-line characterization of the distributions in size, molecular weight, and siRNA cargo loading of LNPs could be achieved. Six LNPs with sizes in the rang of 60-140 nm were evaluated and it was found that the SEC separation is efficient, highly reproducible, and can be broadly applied to a diverse range of LNPs. A comparison between the current SEC method and asymmetric field flow fractionation (FFF) shows that the current method provides similar size distribution results on LNPs compared to FFF. Two representative LNPs with similar bulk properties were evaluated in-depth using the SEC method along with two other sizing techniques-dynamic light scattering and cryo-TEM. Profound differences in batch polydispersity were observed between them. Despite the similarity in the particle assembly process, it was found that one LNP (A) possessed a narrow size and molecular weight distribution while the other (B) was polydisperse. The present results suggest that LNP drug products are highly complex and diverse in nature, and care should be taken in examining and understanding them to ensure quality and consistency. The method developed here can not only serve as a method for understanding LNP product property, permitting control on product quality, but also could serve as a potential manufacturing method for product purification. Understandings obtained in this work can help to facilitate the development of LNPs as a well defined pharmaceutical product. PMID- 22816782 TI - Neutrophil chemotaxis within a competing gradient of chemoattractants. AB - The dynamics of neutrophil chemotaxis under competing chemoattractant gradients was studied using a microfluidic platform. This microfluidic platform, which establishes a stable and dynamic gradient of chemoattractants across a cell culture chamber, enabled the investigation of human neutrophil migration patterns in the presences of four different chemoattractants (leukotriene B(4), chemokine C-X-C motif ligands 2 and 8, and fMLP) and competing gradients of all pairwise combinations. The migration patterns for individual cells were tracked and quantitatively analyzed, and the results suggest a hierarchy among these chemoattractants of fMLP > CXCL8 > CXCL2 > leukotriene B(4). In all conditions, over 60% of neutrophils exposed to a competing gradient move toward the stronger signal though the weaker chemoattractant still influences neutrophil motility. These results yield insight about how each chemoattractant contributes to overall neutrophil chemotaxis within complex physiological environments. PMID- 22816784 TI - Correlation of stoichiometries for Rb+ extraction determined by mass spectrometry and electrochemistry at liquid|liquid interfaces. AB - The electrochemical extraction of rubidium at micro water|1,2-dichloroethane (w|DCE) and water|room-temperature ionic liquid (w|RTIL) interfaces housed at the tip of a 25-MUm capillary using octyl(phenyl)-N,N diisobutylcarbamoylmethylphosphine oxide (CMPO) in the TRans Uranic EXtraction (TRUEX) process, was examined. Rubidium is of great interest in a modern spent nuclear fuel cycle as well as toward myocardial perfusion imaging utilizing (82)Sr/(82)Rb isotopic generators. The ligand-to-metal stoichiometry (n:1) and overall complexation constant (beta) for interfacial complexation reactions induced by an applied potential were determined by the interfacial electrochemistry. One stoichiometry, n = 2, was observed at the w|DCE interface with beta = 3.3 * 10(4). In the w|RTIL system, two rubidium salt solutions were employed: RbNO(3) and RbNO(3) plus Rb(2)SO(4). The former demonstrated a stoichiometry of n = 2 and beta = 2.4 * 10(6), while the latter showed n = 4 and beta = 3.3 * 10(12). These stoichiometries of the reaction were confirmed by electrospray ionization mass spectrometry, using an emulsion generated by shaking water and DCE phases containing the dissolved metal and ligand, respectively. Both RbCMPO(+) and RbCMPO(2)(+) complexes were observed. The influence of ion pair interactions in this system will be discussed. PMID- 22816785 TI - Detection of DNA adducts originating from 1-methoxy-3-indolylmethyl glucosinolate using isotope-dilution UPLC-ESI-MS/MS. AB - 1-Methoxy-3-indolylmethyl (1-MIM) glucosinolate, present at substantial levels in several food crops (e.g., broccoli and cabbage), forms DNA adducts in vitro and is mutagenic to bacterial and mammalian cells after activation by the plant enzyme myrosinase. Moreover, a breakdown product, 1-MIM alcohol, is metabolized to a secondary reactive intermediate by some mammalian sulfotransferases (SULTs). First, we incubated herring-sperm DNA with 1-MIM glucosinolate in the presence of myrosinase. We identified and synthesized the predominant adducts, N(2)-(1-MIM) dG and N(6)-(1-MIM)-dA, and developed an UPLC-ESI-MS/MS method for their specific detection using isotopic dilution. Second, we demonstrated both DNA adducts in target cells (Salmonella typhimurium TA100 and Chinese hamster V79) of standard mutagenicity tests treated with 1-MIM glucosinolate/myrosinase as well as in 1 MIM alcohol-treated Salmonella and V79 cells engineered for expression of human SULT1A1. Similar excesses of N(2)-(1-MIM)-dG over N(6)-(1-MIM)-dA adducts were found in all cellular models independent of the test compound (1-MIM glucosinolate or alcohol), whereas dA adducts predominated in the cell-free system. Finally, we detected both DNA adducts in colon tissue of a mouse orally treated with 1-MIM glucosinolate. We are going to use this specific and sensitive method for investigating genotoxic risks of food-borne exposure to 1-MIM glucosinolate in animal and human studies. PMID- 22816786 TI - Multiplexed fluorescence resonance energy transfer aptasensor between upconversion nanoparticles and graphene oxide for the simultaneous determination of mycotoxins. AB - We presented a new aptasensor for mycotoxins, which was based on multiplexed fluorescence resonance energy transfer (FRET) between multicolor upconversion fluorescent nanoparticles (UCNPs) as donors and graphene oxide (GO) as the entire and effective acceptor. BaY(0.78)F(5):Yb(0.2), Er(0.02) and BaY(0.78)F(5):Yb(0.7), Tm(0.02) upconversion nanoparticles were synthesized and functionalized, respectively, with immobilized ochratoxin A (OTA)-aptamers and fumonisin B(1) (FB(1))-aptamers. On the basis of the strong pi-pi stacking effect between the nucleobases of the aptamers and the sp(2) atoms of GO, the aptamer modified-UCNPs can be brought in close proximity to the GO surface. The strong upconversion fluorescence both of BaY(0.78)F(5):Yb(0.2), Er(0.02) and BaY(0.78)F(5):Yb(0.2), Tm(0.02) can be completely quenched by the GO, because of a good overlap between the fluorescence emission of multicolor UCNPs and the absorption spectrum of GO. In contrast, in the presence of OTA and FB(1), the aptamers preferred to bind to their corresponding mycotoxins, which led to changes in the formation of aptamers, and therefore, aptamer modified-UCNPs were far away from the GO surface. Our study results showed that the fluorescence intensity of BaYF(5):Yb Er and BaYF(5):Yb Tm were related to the concentration of OTA and FB(1). We therefore developed a sensitive and simple platform for the simultaneous detection of OTA and FB(1) with multicolor UCNPs and GO as the FRET pair. The aptasensor provided a linear range from 0.05 to 100 ng.mL(-1) for OTA and 0.1 to 500 ng.mL(-1) for FB(1); the detection limit of OTA was 0.02 ng.mL(-1) and FB(1) was 0.1 ng.mL(-1). As a practical application, the aptasensor was used to monitor OTA and FB(1) level in naturally contaminated maize samples with the results consistent with that of a classic ELISA method. More importantly, the novel multiplexed FRET was established for the first time based on multiplexed energy donors to the entire energy acceptor; this work was expected to open up a new field of FRET system applications for various targets. PMID- 22816787 TI - Venous thromboembolism and coagulation activity in patients with immune thrombocytopenia treated with thrombopoietin receptor agonists. PMID- 22816788 TI - Understanding ligand interaction with different structures of G-quadruplex DNA: evidence of kinetically controlled ligand binding and binding-mode assisted quadruplex structure alteration. AB - The study of ligand interaction with G-quadruplex DNA is an active research area, because many ligands are shown to bind G-quadruplex structures, showing anticancer effects. Here, we show, for the first time, how fluorescence correlation spectroscopy (FCS) can be used to study binding kinetics of ligands with G-quadruplex DNA at the single molecule level. As an example, we study interaction of a benzo-phenoxazine ligand (Cresyl Violet, CV) with antiparallel and (3 + 1) hybrid G-quadruplex structures formed by human telomeric sequence. By using simple modifications in FCS setup, we describe how one can extract the reaction kinetics from diffusion-coupled correlation curves. It is found that the ligand (CV) binds stronger, by an order of magnitude, to a (3 + 1) hybrid structure, compared to an antiparallel one. Ensemble-averaged time-resolved fluorescence experiments are also carried out to obtain the binding equilibrium constants (K) of ligand-quadruplex interactions in bulk solution for the first time, which are found to match very well with FCS results. Global analysis of FCS data provides association (k(+)) and dissociation (k(-)) rates of the ligand in the two structures. Results indicate that stronger ligand binding to the (3 + 1) hybrid structure is controlled by the dissociation rate, rather than the association rate of ligand in the quadruplexes. Circular dichroism (CD) and induced-CD spectra show that the ligand not only binds at different conformations in the quadruplexes, but also induces antiparallel structure to form a mixed-type hybrid structure in Na(+) solution. However, in K(+) solution, the ligand stabilizes the (3 + 1) hybrid structure. Molecular docking studies predict the possible differences in binding sites of the ligand inside two quadruplexes, which strongly support the experimental observations. Results suggest that different binding modes of the ligand to the quadruplex structures actually assist the alteration of structures differently. PMID- 22816789 TI - Molecular characterization of central neurocytomas: potential markers for tumor typing and progression. AB - Central neurocytomas (CNs) are rare intraventricular tumors presenting a favorable prognosis after surgery. Their transcriptomic profile is poorly characterized. We performed a microarray transcriptomic study to search for molecular markers that might improve diagnostic accuracy. Microarray analysis was performed on five CNs (3 primary and 2 recurrent CNs) using CodeLink human whole genome bioarrays, and the gene expression in CNs was compared with that in four pineal parenchymal tumors, consisting of two pineocytomas (PCs) and two pineoblastomas (PBs), other periventricular tumors which may present neuronal differentiation. We identified genes that were highly expressed in CNs compared to normal brain and might be candidates for the molecular typing of CNs. Several genes are part of the Wnt/beta-catenin and sonic hedgehog signaling pathways or mainly linked to calcium function or maintenance of neural progenitors. Moreover, several genes are overexpressed in both CNs and PCs and/or PBs such as INSM1 and NEUROD4, involved in neural or neuroendocrine differentiation. The overexpression of eight candidate genes in CNs (CHRDL2, IGF2, KiSS-1, CAL2, NTS, NHLH1, RGS16 and SCGN) was confirmed by real-time RT-PCR. Of the genes overexpressed in the recurrent CNs compared to the primary CNs, AQP5, KiSS-1, FZD7, AURKB, UBE2C and PTTG1 are genes which may be involved in tumor progression. Our study shows the potential involvement of various genes in the pathogenesis of CNs. These genes could be potential candidate markers for improving the characterization of CNs and some could be involved in CN tumorigenesis. PMID- 22816790 TI - Uptake of natural and synthetic estrogens by maize seedlings. AB - Runoff from manure-fertilized crop fields constitutes a significant source of natural estrogens (e.g., estradiol [17beta-E2] and estrone [E1]) and synthetic estrogen mimics (e.g., zeranol [alpha-ZAL] and zearalanone [ZAN]) in the environment. However, processes such as sorption to and uptake by plants may inhibit the environmental mobility of hormonally active compounds. Sorption to dried root tissue was assessed in batch sorption tests, and resulting sorption isotherms were nonlinear at aqueous concentrations below 0.1 MUM and linear above that limit. To evaluate the role of crop plants in the environmental fate of such compounds, we exposed hydroponic solutions containing 2 MUM 17beta-E2, E1, alpha ZAL, or ZAN to maize seedlings. After 22 days of exposure, alpha-ZAL and ZAN concentrations decreased by more than 96%, and 17beta-E2 and E1 were undetectable. The decrease in alpha-ZAL and ZAN concentrations in maize-exposed solutions was initially slow, but the observed uptake exceeded that predicted by sorption alone within 3 d. All four estrogens were detected in root tissues at concentrations up to 0.19 MUmol g(-1), with concentrations peaking after 1-3 days of exposure. Only 17beta-E2 and alpha-ZAL were detected in shoots, and maximum concentrations were measured after 2 days for 17beta-E2 (0.02 MUmol g(-1)) and 16 days for alpha-ZAL (0.8 nmol g(-1)). Concentrations measured in root and shoot tissues were 82% or less than those predicted by a partition-limited uptake model, which is attributed to transformation and possibly irreversible binding processes. PMID- 22816791 TI - Understanding complex interactions using social network analysis. AB - AIMS AND OBJECTIVES: The aim of this paper is to raise the awareness of social network analysis as a method to facilitate research in nursing research. BACKGROUND: The application of social network analysis in assessing network properties has allowed greater insight to be gained in many areas including sociology, politics, business organisation and health care. However, the use of social networks in nursing has not received sufficient attention. DESIGN: Review of literature and illustration of the application of the method of social network analysis using research examples. METHODS: First, the value of social networks will be discussed. Then by using illustrative examples, the value of social network analysis to nursing will be demonstrated. RESULTS: The method of social network analysis is found to give greater insights into social situations involving interactions between individuals and has particular application to the study of interactions between nurses and between nurses and patients and other actors. CONCLUSION: Social networks are systems in which people interact. Two quantitative techniques help our understanding of these networks. The first is visualisation of the network. The second is centrality. Individuals with high centrality are key communicators in a network. RELEVANCE TO CLINICAL PRACTICE: Applying social network analysis to nursing provides a simple method that helps gain an understanding of human interaction and how this might influence various health outcomes. It allows influential individuals (actors) to be identified. Their influence on the formation of social norms and communication can determine the extent to which new interventions or ways of thinking are accepted by a group. Thus, working with key individuals in a network could be critical to the success and sustainability of an intervention. Social network analysis can also help to assess the effectiveness of such interventions for the recipient and the service provider. PMID- 22816792 TI - Isomerizing olefin metathesis as a strategy to access defined distributions of unsaturated compounds from fatty acids. AB - The dimeric palladium(I) complex [Pd(MU-Br)(t)Bu(3)P](2) was found to possess unique activity for the catalytic double-bond migration within unsaturated compounds. This isomerization catalyst is fully compatible with state-of-the-art olefin metathesis catalysts. In the presence of bifunctional catalyst systems consisting of [Pd(MU-Br)(t)Bu(3)P](2) and NHC-indylidene ruthenium complexes, unsaturated compounds are continuously converted into equilibrium mixtures of double-bond isomers, which concurrently undergo catalytic olefin metathesis. Using such highly active catalyst systems, the isomerizing olefin metathesis becomes an efficient way to access defined distributions of unsaturated compounds from olefinic substrates. Computational models were designed to predict the outcome of such reactions. The synthetic utility of isomerizing metatheses is demonstrated by various new applications. Thus, the isomerizing self-metathesis of oleic and other fatty acids and esters provides olefins along with unsaturated mono- and dicarboxylates in distributions with adjustable widths. The cross metathesis of two olefins with different chain lengths leads to regular distributions with a mean chain length that depends on the chain length of both starting materials and their ratio. The cross-metathesis of oleic acid with ethylene serves to access olefin blends with mean chain lengths below 18 carbons, while its analogous reaction with hex-3-enedioic acid gives unsaturated dicarboxylic acids with adjustable mean chain lengths as major products. Overall, the concept of isomerizing metatheses promises to open up new synthetic opportunities for the incorporation of oleochemicals as renewable feedstocks into the chemical value chain. PMID- 22816794 TI - Two types of two-component gels formed from pseudoenantiomeric ethynylhelicene oligomers. AB - Two-component gels formed from pseudoenantiomeric ethynylhelicene oligomers in toluene exhibited two different properties depending on difference in numbers of helicenes in the two components. The combinations (M)-5/(P)-4, (M)-6/(P)-4, and (M)-7/(P)-4, which contained oligomers with comparable numbers of helicenes, formed transparent gels (Type I gels). The combinations (M)-6/(P)-3, (M)-7/(P)-3, and (M)-8/(P)-3, which contained oligomers with considerably different numbers of helicenes, formed turbid gels (Type II gels). Negative Cotton effects were observed for the Type I gels in the region between 350 and 450 nm, and were positive for the Type II gels, despite the use of (M)-oligomers for the longer components. UV/vis exhibited absorption maxima at 350 nm for the Type I gels and at 338 nm for the Type II gels. Different behaviors in gel formation processes were observed by fluorescence studies. Atomic force microscopy analysis showed fiber structures of 25-50 nm diameter for Type I gels and bundles of 100-150 nm diameter for Type II gels. The stoichiometry in gel formation also differed: The Type I gels showed 1:1 stoichiometry of the two components; the Type II gels showed no 1:1 stoichiometry, likely 1:2 stoichiometry. Using the Type I and II gels, two-layer gel systems were constructed. PMID- 22816793 TI - Sensitive and high resolution localization and tracking of membrane proteins in live cells with BRET. AB - Peripheral and integral membrane proteins can be located in several different subcellular compartments, and it is often necessary to determine the location of such proteins or to track their movement in living cells. Image-based colocalization of labeled membrane proteins and compartment markers is frequently used for this purpose, but this method is limited in terms of throughput and resolution. Here we show that bioluminescence resonance energy transfer (BRET) between membrane proteins of interest and compartment-targeted BRET partners can report subcellular location and movement of membrane proteins in live cells. The sensitivity of the method is sufficient to localize a few hundred protein copies per cell. The spatial resolution can be sufficient to determine membrane topology, and the temporal resolution is sufficient to track changes that occur in less than 1 second. BRET requires little user intervention, and is thus amenable to large-scale experimental designs with standard instruments. PMID- 22816795 TI - Heterogeneous photochemistry of oxalic acid on Mauritanian sand and Icelandic volcanic ash. AB - Teragram quantities of crustal and volcanic aerosol are released into the atmosphere on an annual basis. Although these substrates contain photoactive metal oxides, little is known about the role that they may play in catalyzing the heterogeneous phototransformation of semivolatile organic species. In the present study, we have investigated oxalic acid photochemistry at the surface of Fe(2)O(3), TiO(2), Mauritanian sand, and Icelandic volcanic ash in the presence and absence of oxygen using a photochemical Knudsen cell reactor. Illumination of all sample types resulted in the production of gas-phase CO(2). In the case of Mauritanian sand, the production of gas-phase CO(2) scaled with the loss of surface oxalic acid. In the absence of oxygen, the production of CO(2) by the sand and ash films scaled with the absorption spectrum of iron oxalate, which suggests that the reaction is at least in part iron-mediated. The presence of oxygen suppressed CO(2) production at the Fe(2)O(3) surface, enhanced CO(2) production at the Mauritanian sand surface, and did not have a net effect upon CO(2) production at the Icelandic ash surface. These different oxygen dependencies imply that oxalic acid photochemistry at the authentic surfaces under study was not solely iron-mediated. Experiments at the TiO(2) surface, which showed enhanced CO(2) production from oxalic acid in the presence of oxygen, suggest that Ti-mediated photochemistry played an important role. In summary, these results provide evidence that solid-phase aerosol photochemistry may influence the atmospheric lifetime of oxalic acid in arid regions, where its removal via wet deposition is insignificant. PMID- 22816796 TI - Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature. AB - AIMS: Angiotensin-II receptor 1 antagonists (AT1-antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1-antagonist treatment during the second or third trimester of pregnancy. METHODS: Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1 antagonist fetopathy were: oligo-/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death. RESULTS: In 5/29 (17%) prospectively enrolled cases with AT1-antagonist exposure beyond the first trimester oligo-/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo-/anhydramnios was reversible after AT1-antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive. CONCLUSIONS: Our survey suggests that the risk increases with duration of AT1-antagonist treatment into late pregnancy and oligo-/anhydramnios may be reversible after AT1 antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1-antagonist fetopathy. AT1-antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1-antagonist exposure should be considered. PMID- 22816797 TI - Implementation of complex adaptive chronic care: the Patient Journey Record system (PaJR). AB - BACKGROUND: The Patient Journey Record system (PaJR) is an application of a complex adaptive chronic care model in which early detection of adverse changes in patient biopsychosocial trajectories prompts tailored care, constitute the cornerstone of the model. AIMS: To evaluate the PaJR system's impact on care and the experiences of older people with chronic illness, who were at risk of repeat admissions over 12 months. DESIGN: Community-based cohort study - random assignment into intervention and usual care group, with process and outcome evaluation. STUDY POPULATION: Adult and older patients with multiple morbidity, one or more chronic diseases with one or more overnight hospitalizations, and seven or more general practice visits in the past 6 months. COMPLEX INTERVENTION: PaJR lay care guides/advocates call patients and their caregivers. The care guides summarize their semi-structured conversations about health concerns and well-being. Predictive modelling and rules-based algorithms trigger alerts in relation to online call summaries. Alerts are acted upon according to agreed guidelines. ANALYSIS: Descriptive and comparative statistics. OUTCOMES: Impact on unplanned emergency ambulatory care sensitive admissions (ACSC) with an overnight stay; sensitivity of alerts and predictions; rates of care guides-supported activities. FINDINGS: Five part-time lay care guides and a care manager monitored 153 intervention patients for 500 person months with 5050 phone calls. The 153 patients in the intervention group were comparable to the 61 controls. The intervention group reported in 50% of calls that their health limited their social activities; and one-third of calls reported immediate health concerns. Predictive analytics were highly sensitive to risk of hospitalization. ACSC admissions were reduced by 50% compared to controls across the sites. DISCUSSION: The initial implementation of a complex patient-centred adaptive chronic care model using lay care guides, supported by machine learning, appeared sensitive to risk of hospitalization and capable of stabilizing illness journeys in older patients with multi-morbidity. CONCLUSION: Actions based on alerts produced in this study appeared to significantly reduce hospitalizations. This paves the way for further testing of the model. PMID- 22816798 TI - Pathology Harmony moves on: progress on implementation in haematology. PMID- 22816799 TI - Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases. AB - Th17 lymphocyte and its relative cytokines have been shown to play an important role in autoimmune thyroid diseases (AITD). The aim of this study was to investigate the association between IL-17A and IL-17F gene polymorphisms and two main types of AITD, Graves' disease (GD) and Hashimoto's thyroiditis (HT). Whole blood specimens and clinical data were collected from 508 AITD patients (326 with GD and 182 with HT) and 224 age- and gender-matched healthy controls, respectively. IL-17A (rs2275913, rs8193037, rs3819025) polymorphism was determined using DNA sequencing method and IL-17F/rs763780 polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR -RFLP). The results indicated that the frequencies of IL-17F/rs763780 genotypes in patients with GD and HT differed significantly from their controls (P = 0.013 and P = 0.005, respectively); the G allele frequencies were also significantly higher in the patient groups than the control groups (P = 0.002 and 0.001, respectively). For IL-17A/rs2275913 and rs8193037 SNP, no significant difference was observed in patients with either GD or HT compared to the control groups (P>0.05). Interestingly, for rs3819025, the frequency of A allele was lower in patients with GD than controls (P = 0.011). The frequencies of haplotype AGGG and GGGG in patients with GD and HT were significantly higher than in controls (P = 0.012, P = 0.019, P = 0.017 and P = 0.029, respectively). In conclusion, the results indicate that IL-17F/rs763780 polymorphisms may affect the susceptibility to AITD, and IL-17A/rs3819025 SNP is likely a protective factor to GD in the Chinese population. PMID- 22816800 TI - Development and external validation of lymph node density cut-off points in prospective series of radical cystectomy and pelvic lymph node dissection. AB - OBJECTIVE: To identify lymph node density thresholds and their prognostic role in patients who underwent radical cystectomy and pelvic lymph node dissection, and to validate findings in an external series. METHODS: Between May 2001 and September 2009, data from 750 radical cystectomies carried out at "Regina Elena" National Cancer Institute (Rome, Italy) were collected in a prospectively maintained database. Once patients who had undergone neoadjuvant treatments and those who had undergone salvage radical cystectomy were excluded from the 210 pN+ patients, 156 patients with urothelial carcinoma were selected for analysis. Optimal cut-off points for age, lymph node count and lymph node density were identified by considering these variables as continuous. External validation of findings was carried out by using data of 154 pN+ patients selected from two prospective series. RESULTS: The optimal identified cut-off points were 11% and 30% for lymph node density, nine and 30 nodes for lymph node count, and 73 years for age. Median cancer-specific survival of patients were significantly different in patients with lymph node density <12%, between 12% and 30%, and >30% (71 months, 24 months and 11 months, respectively; P < 0.001). Cancer-specific survival was independently predicted by lymph node density cut-off points (12-30% vs <12%: hazard ratio 1.51, P = 0.047; >30% vs <12%: hazard ratio 2.89, P < 0.001). In the external series, the prognostic effect of lymph node density according to tertiary distribution of risk based on these lymph node density cut off points was confirmed at Cox multivariable analysis (12-30% vs <12%: hazard ratio 1.5, P = 0.048; >30% vs <12%: hazard ratio 2.5, P = 0.004). CONCLUSIONS: Lymph node density is the strongest predictor of cancer-specific survival. Identified lymph node density thresholds have shown to be independent predictors of cancer-specific survival in the external validation series. PMID- 22816801 TI - Germination dramatically increases isoflavonoid content and diversity in chickpea (Cicer arietinum L.) seeds. AB - The effect of germination on bioactive components in legume seeds was investigated in terms of the antioxidant capacity and total phenolic contents. Germination increased the total phenolic content and antioxidant capacity of most seeds. Particularly in chickpea seeds, the isoflavone contents increased by over 100 fold, mainly due to the increase of formononetin and biochanin A level. As a result, these two compounds were conveniently isolated from the germinated seeds in preparative scale and structurally confirmed by UV-vis, ESI-MS, and (1)H NMR spectroscopies. Isoflavonoid fingerprints analyzed by HPLC-PDA and LC-ESI-MS demonstrated that germination could significantly increase isoflavonoids diversity. Twenty-five isoflavonoids were detected and identified tentatively. These include 20 isoflavones, 2 isoflavanones, and 3 pterocarpan phytoalexins. Total isoflavonoid content of germinated chickpea was approximately 5-fold of that of germinated soybean. Our findings suggest that the germinated chickpea seeds could serve as a promising functional food rich in isoflavonoids. PMID- 22816865 TI - Prescribing for pain--how do nurses contribute? A national questionnaire survey. AB - AIMS AND OBJECTIVES: To provide information on the profile and practice of nurses in the UK who prescribe medication for pain. BACKGROUND: Pain is widely under reported and under-treated and can have negative consequences for health and psychosocial well-being. Indications are that nurses can improve treatment and access to pain medications when they prescribe. Whilst nurses working in many practice areas treat patients with pain, little is known about the profile, prescribing practice or training needs of these nurses. DESIGN: A descriptive questionnaire survey. METHOD: An online questionnaire was used to survey 214 nurses who prescribed for pain in the UK between May and July 2010. Data were analysed using descriptive statistics and non-parametric tests. RESULTS: Half the participants (50%) worked in primary care, 32% in secondary care and 14% worked across care settings. A range of services were provided, including general practice, palliative care, pain management, emergency care, walk-in-centres and out-of-hours. The majority (86%) independently prescribed 1-20 items per week. Non-opioid and weak opioids analgesics were prescribed by most (95%) nurses, whereas fewer (35%) prescribed strong opioids. Training in pain had been undertaken by 97% and 82% felt adequately trained, although 28% had problems accessing training. Those with specialist training prescribed a wider range of pain medications, were more likely to prescribe strong opioids and were more often in pain management roles. CONCLUSION: Nurses prescribe for pain in a range of settings with an emphasis on the treatment of minor ailments and acute pain. A range of medications are prescribed, and most nurses have access to training. RELEVANCE TO CLINICAL PRACTICE: The nursing contribution to pain treatment must be acknowledged within initiatives to improve pain management. Access to ongoing training is required to support nurse development in this area of practice to maximise benefits. PMID- 22816866 TI - A unique approach to development of near-infrared fluorescent sensors for in vivo imaging. AB - Near-infrared (NIR) fluorescent sensors have emerged as promising molecular tools for imaging biomolecules in living systems. However, NIR fluorescent sensors are very challenging to be developed. Herein, we describe the discovery of a new class of NIR fluorescent dyes represented by 1a/1c/1e, which are superior to the traditional 7-hydroxycoumarin and fluorescein with both absorption and emission in the NIR region while retaining an optically tunable hydroxyl group. Quantum chemical calculations with the B3LYP exchange functional employing 6-31G(d) basis sets provide insights into the optical property distinctions between 1a/1c/1e and their alkoxy derivatives. The unique optical properties of the new type of fluorescent dyes can be exploited as a useful strategy for development of NIR fluorescent sensors. Employing this strategy, two different types of NIR fluorescent sensors, NIR-H(2)O(2) and NIR-thiol, for H(2)O(2) and thiols, respectively, were constructed. These novel sensors respond to H(2)O(2) or thiols with a large turn-on NIR fluorescence signal upon excitation in the NIR region. Furthermore, NIR-H(2)O(2) and NIR-thiol are capable of imaging endogenously produced H(2)O(2) and thiols, respectively, not only in living cells but also in living mice, demonstrating the value of the new NIR fluorescent sensor design strategy. The new type of NIR dyes presented herein may open up new opportunities for the development of NIR fluorescent sensors based on the hydroxyl functionalized reactive sites for biological imaging applications in living animals. PMID- 22816867 TI - Bayesian analysis of the geographical variation of type 1 diabetes mellitus in under 15 yr olds in northeast Spain, 1991-2009. AB - OBJECTIVE: High variability has been observed in type 1 diabetes mellitus (DM1) incidence rates (IRs) in childhood. The aim of this study was to characterize DM1 in Aragon and to identify variations in the geographical pattern by gender. METHODS: A descriptive and ecological study was conducted to determine geographical variations in the DM1 incidence for the period 1991-2009. The source of information was the registry of DM1. To determine data completeness, a capture recapture analysis was performed. Cases were georeferenced according to the Basic Healthcare Area (BHA) of residence. IRs for both genders, age group, 5 yr of diagnosis, and 95% confidence intervals (95% CIs) were calculated. Geographical pattern was studied applying Bayesian statistical model. The standardized incidence ratios (SIRs), smoothed SIR, and the posteriori risk probability (PRP) were represented cartographically for BHA stratified by gender. RESULTS: The completeness was 93.5%. The global IR was 19.2 cases/10(5) person-years (95% CI: 17.6-20.8), boys 21.4 (95% CI: 19.0-23.8) and girls 16.8 (95% CI: 14.7-19.1). The age-specific rates were significantly lower in the 0-4 year age group with respect to the groups of 5-9 and 10-14 years. For boys, areas with a statistically significant excess of risk were found in the north [smoothed SIR: 118-167.9 and PRP of what the smoothed SIR would be greater than 100 (PRP) above 0.8] and below average risk in the south (smoothed SIR: 65.9-79.1 and PRP less than 0.2). CONCLUSIONS: DM1 IR presented a north-south geographical pattern in boys. This pattern was not observed in girls or when both genders were considered together. Later studies should include gender as an essential variable. PMID- 22816868 TI - From DTCA-PD to patient information to health information: the complex politics and semantics of EU health policy. AB - RATIONALE, AIMS AND OBJECTIVES: Between 2001 and 2011 the pharmaceutical industry, supported by DG Enterprise, was engaged in an ongoing campaign to repeal/amend the European Union (EU) ban on direct-to-consumer advertising of prescription drugs (DTCA-PD). As it became increasingly clear that the ban would not be repealed, DTCA-PD supporters tried to shift the debate away from advertising and towards the provision of 'patient information' and the rights of patients to access such information. Meanwhile, a variety of national and European health organizations, supported by DG SANCO, sought to maintain the ban and oppose the industry-supported 'patient information' campaign. Instead, they promoted a concept of 'health information' that included all aspects of citizens' health, not just pharmaceuticals. This article aims to analyse the transition from DTCA-PD to patient information to health information and examine its implications for EU health policy as a complex policy space. METHODS: The article examines the emergence and development of EU health policy and the evolution of the DTCA-PD debate through the lens of complexity theory. It analyses the nature of the semantic, political and policy transition and asks why it occurred, what it tells us about EU health policy and future EU health legislation and how it may be understood from a complexity perspective. RESULTS AND CONCLUSIONS: The article concludes that the complexity framework is ideally suited for the field of public health and, in particular, the DTCA-PD debate. Having successfully shifted the policy-focus of the debate to patients' rights and health information, opponents of the legislation are likely to face their next battle in the realm of cyberspace, where regulatory issues change the nature of advertising. PMID- 22816869 TI - DNA-vaccine platform development against H1N1 subtype of swine influenza A viruses. AB - Swine influenza virus (SIV) is an important viral pathogen in pig populations. However, commercial vaccines cannot provide complete protection with induced humoral immunity only, and require frequent updates to fight against current isolates. DNA vaccination is an effective means of eliciting both arms of the immune system, the humoral and cellular immune responses. In this study, DNA vector pcDNA3.1 was inserted with a chimeric intron downstream of the CMV promoter region followed by a Kozak sequence to enhance the expression of gene inserts. The C-terminal of the VP22 gene (VP22c), encoding the tegument protein of bovine herpesvirus-1, was fused separately to the N-terminal of four quadruplicated epitopes: two B-cell epitopes (HA91-108 and M2e), and two T-cell epitopes (NP366-374 and NP380-393), which were conserved, at least among the three SIV subtypes prevailing in pig populations in North America. Linker -KK- was used to space between each copy of the two B-cell epitopes, and -RVKR- was used for the two T-cell epitopes, in order to enhance the presentation of epitopes to the immune system. The expression of epitopes was confirmed in in vitro transfection of 293FT cells, and higher percentages of epitope-positive cells were achieved from the plasmids containing VP22c than those without. After the DNA plasmids were administered to mice intramuscularly in combination or separately, or boosted with recombinant proteins of quadruplicated epitopes fused to VP22c, the vaccine stimulated the desired epitope-specific humoral immunity to the two B-cell epitopes, and cellular immunity to the epitope NP380-393. Our results indicate that plasmids with quadruplicated epitopes fused to the VP22c may be a potential vehicle in developing epitopes as vaccines against SIV. PMID- 22816870 TI - Unrestrained computation of free energy along a path. AB - We apply the adaptive biasing potential (ABP) method to optimize the principal curve defining a conformational transition between two known end states and to subsequently compute the one-dimensional potential of mean force as a function of arc length along the principal curve. This approach allows the use of the ABP method in a collective variable space of arbitrary dimension and offers several advantages over line-search methods. First, configurations are neither generated along an initial path for the transition nor equilibrated during evolution of the path. Second, and most importantly, the powerful sampling provided by the ABP serves to accelerate the dynamics during the optimization and computation of the free energy. Finally, the free energy is formulated as a potential of mean force that captures changes in the reaction channel along the principal curve, in contrast to the free energy profile evaluated from the local free-energy gradient in restrained path optimization methods. We first demonstrate the ABP formulation of path optimization using a two-dimensional potential surface and then with a more complex system of Src protein tyrosine kinase. The method is shown to be efficient and robust in the case of rugged, free-energy landscapes. PMID- 22816872 TI - Fate of zinc oxide nanoparticles during anaerobic digestion of wastewater and post-treatment processing of sewage sludge. AB - The rapid development and commercialization of nanomaterials will inevitably result in the release of nanoparticles (NPs) to the environment. As NPs often exhibit physical and chemical properties significantly different from those of their molecular or macrosize analogs, concern has been growing regarding their fate and toxicity in environmental compartments. The wastewater-sewage sludge pathway has been identified as a key release pathway leading to environmental exposure to NPs. In this study, we investigated the chemical transformation of two ZnO-NPs and one hydrophobic ZnO-NP commercial formulation (used in personal care products), during anaerobic digestion of wastewater. Changes in Zn speciation as a result of postprocessing of the sewage sludge, mimicking composting/stockpiling, were also assessed. The results indicated that "native" Zn and Zn added either as a soluble salt or as NPs was rapidly converted to sulfides in all treatments. The hydrophobicity of the commercial formulation retarded the conversion of ZnO-NP. However, at the end of the anaerobic digestion process and after postprocessing of the sewage sludge (which caused a significant change in Zn speciation), the speciation of Zn was similar across all treatments. This indicates that, at least for the material tested, the risk assessment of ZnO NP through this exposure pathway can rely on the significant knowledge already available in regard to other "conventional" forms of Zn present in sewage sludge. PMID- 22816871 TI - Observational study on safety and tolerability of duloxetine in the treatment of female stress urinary incontinence in German routine practice. AB - AIMS: To evaluate the safety and tolerability of duloxetine during routine clinical care in women with stress urinary incontinence (SUI) in Germany, and in particular, to identify previously unrecognized safety issues as uncommon adverse reactions, and the influence of confounding factors present in clinical practice on the safety profile of duloxetine. METHODS: Office-based urologists, gynaecologists and primary care physicians were asked to document women newly started on treatment for moderate to severe symptoms of SUI. Six thousand eight hundred and fifty-four patients from urologist/gynaecologist practices and 5879 primary care patients were assessed. In a two-armed, observational study with parallel 12 week (urologists and gynaecologists) or 24 week (primary care physicians) design, patients were treated with duloxetine or other conservative treatment. The main outcome measure was the occurrence of adverse events (AEs). RESULTS: Baseline characteristics differed slightly between patient groups and studies. Duloxetine doses in most patients were lower than recommended. Overall, AE frequency with duloxetine was lower than in controlled studies (15.9% (95% CI 14.9, 16.9) and 9.1% (95% CI 8.2, 10.0) in the 12 and 24 week treatment groups, respectively), but exhibited a similar qualitative spectrum. In the logistic regression models, the following factors were associated with greater AE risk: investigator specialization (gynaecologist vs. urologist and primary care physician), initial duloxetine dose (80 vs. 20 mg day(-1) ) and use of any concomitant medication. Within the 24 week study, a positive screen for depressive disorder was surprisingly common, but no case of attempted suicide was reported in either study. CONCLUSIONS: Our results from German clinical practice show that women with SUI were often treated with duloxetine doses lower than recommended. This was associated with a low incidence of AEs. Suicide attempts were not reported. PMID- 22816873 TI - Control of enzyme-solid interactions via chemical modification. AB - Electrostatic forces could contribute significantly toward enzyme-solid interactions, and controlling these charge-charge interactions while maintaining high affinity, benign adsorption of enzymes on solids is a challenge. Here, we demonstrate that chemical modification of the surface carboxyl groups of enzymes can be used to adjust the net charge of the enzyme and control binding affinities to solid surfaces. Negatively charged nanosolid, alpha-Zr(HPO(4))(2).H(2)O (abbreviated as alpha-ZrP) and two negatively charged proteins, glucose oxidase (GO) and methemoglobin (Hb), have been chosen as model systems. A limited number of the aspartate and glutamate side chains of these proteins are covalently modified with tetraethylenepentamine (TEPA) to convert these negatively charged proteins into the corresponding positively charged ones (cationized). Cationized proteins retained their structure and activities to a significant extent, and the influence of cationization on binding affinities has been tested. Cationized GO, for example, showed 250-fold increase in affinity for the negatively charged alpha-ZrP, when compared to that of the unmodified GO, and cationized Hb, similarly, indicated 26-fold increase in affinity. Circular dichroism spectra showed that alpha-ZrP-bound cationized GO retained native-like structure to a significant extent, and activity studies showed that cationized GO/alpha-ZrP complex is ~2.5-fold more active than GO/alpha-ZrP. Cationized Hb/alpha-ZrP retained ~75% of activity of Hb/alpha-ZrP. Therefore, enzyme cationization enhanced affinities by 1-2 orders of magnitude, while retaining considerable activity for the bound biocatalyst. This benign, chemical control over enzyme charge provided a powerful new strategy to rationally modulate enzyme-solid interactions while retaining their biocatalytic properties. PMID- 22816874 TI - Risk of arterial thrombosis in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. PMID- 22816875 TI - Chemotherapy increases amenability of surgical resection in congenital glioblastoma. AB - Brain tumors presenting in infancy, especially during the first 6 months of life, are often very large and highly vascular. It is generally accepted that gross total resection of the tumor affords the best outcome to the patient. However, tumor resection is frequently very challenging due to the risk of significant bleeding. We report two cases of congenital glioblastoma whose initial surgery was hampered by tumor hypervascularity and excessive blood loss, resulting in subtotal resection. Subsequent carboplatin-based chemotherapy led to a significant reduction in tumor size and vascularity, enabling safe gross total resection at second-look surgery. Based on these findings and a review of the literature, we recommend cytoreductive chemotherapy following diagnostic biopsy for infants presenting with large, highly vascular tumors, such as congenital glioblastoma, in lieu of aggressive upfront surgery, to increase the feasibility and facilitate safe gross total excision at second-look surgery. PMID- 22816876 TI - Rapid estimation of glucosinolate thermal degradation rate constants in leaves of Chinese kale and broccoli (Brassica oleracea) in two seasons. AB - Kinetic modeling was used as a tool to quantitatively estimate glucosinolate thermal degradation rate constants. Literature shows that thermal degradation rates differ in different vegetables. Well-characterized plant material, leaves of broccoli and Chinese kale plants grown in two seasons, was used in the study. It was shown that a first-order reaction is appropriate to model glucosinolate degradation independent from the season. No difference in degradation rate constants of structurally identical glucosinolates was found between broccoli and Chinese kale leaves when grown in the same season. However, glucosinolate degradation rate constants were highly affected by the season (20-80% increase in spring compared to autumn). These results suggest that differences in glucosinolate degradation rate constants can be due to variation in environmental as well as genetic factors. Furthermore, a methodology to estimate rate constants rapidly is provided to enable the analysis of high sample numbers for future studies. PMID- 22816877 TI - Control of a tyrosyl radical mediated protein cross-linking reaction by electrostatic interaction. AB - Herein, we demonstrate the control of protein heteroconjugation via a tyrosyl coupling reaction by using electrostatic interaction. Aspartic acid and arginine were introduced to a tyrosine containing peptide tag (Y-tag) to provide electrostatic charge. Designed negatively or positively charged Y-tags were tethered to the C-terminus of Escherichia coli alkaline phosphatase (BAP) and streptavidin (SA), and these model proteins were subjected to horseradish peroxidase (HRP) treatment. The negatively charged Y-tags showed low reactivity due to repulsive interactions between the Y-tags with the negatively charged BAP and SA. In contrast, the positively charged Y-tags showed high reactivity, indicating that the electrostatic interaction between Y-tags and proteins significantly affects the tyrosyl radical mediated protein cross-linking. From the heteroconjugation reaction of BAP and SA, the SA with the positively charged Y-tags exhibited favorable cross-linking toward negatively charged BAP, and the BAP-SA conjugates prepared from BAP with GY-tag (GGGGY) and SA with RYR-tag (RRYRR) had the best performance on a biotin-coated microplate. Encompassing the reactive tyrosine residue with arginine residues reduced the reactivity against HRP, enabling the modulation of cross-linking reaction rates with BAP-GY. Thus, by introducing a proper electrostatic interaction to Y-tags, it is possible to kinetically control the heteroconjugation behavior of proteins, thereby maximizing the functions of protein heteroconjugates. PMID- 22816878 TI - The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy. AB - BACKGROUND: Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), supplemented by a short-acting beta2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use. METHODS: Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMARTTM, Turbuhaler(r)) 160/4.5 MUg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol. RESULTS: Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0-10.1% of days post-index for all regimens compared with 2.5-3.4% of days with budesonide/formoterol maintenance and reliever therapy. CONCLUSIONS: Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS. TRIAL REGISTRATION: These studies do not have registration numbers as they were conducted before clinical trial registration was required. PMID- 22816881 TI - Efficacy and safety of acitretin in three fixed doses of 25, 35 and 50 mg in adult patients with severe plaque type psoriasis: a randomized, double blind, parallel group, dose ranging study. AB - BACKGROUND: Acitretin is available for use in psoriasis since the late 1980s; however, there is no consensus on its optimum effective dose with acceptable side effects. OBJECTIVE: To evaluate the efficacy and safety of acitretin in three fixed doses in adult patients with severe plaque type psoriasis. METHODS: This was a randomized, double blind, parallel group, dose ranging study. The study included patients of either gender (age range, 18-65 years) with severe chronic plaque type psoriasis. Of the 80 patients screened, 61 were randomly assigned to three groups: group A - 20 patients (acitretin 25 mg/day), group B - 20 patients (acitretin 35 mg/day) and group C - 21 patients (acitretin 50 mg/day) for 12 weeks. Forty-eight patients completed the study. The main outcome measure was change in Psoriasis Area Severity Index (PASI) score between the three groups from baseline to 12 weeks. RESULTS: After 12 weeks of therapy, the percentage reduction in the PASI score was 54%, 76% and 54% in acitretin 25, 35 and 50 mg/day group respectively. PASI 75 was achieved in 47%, 69% and 53% patients in acitretin 25, 35 and 50 mg/day groups respectively. The majority of adverse events were mucocutaneous, mild-to-moderate severity and dose dependent. CONCLUSIONS: Acitretin 35 mg/day was observed to be more efficacious compared to 25 mg/day and 50 mg/day dosing, whereas its safety profile is better than 50 mg/day dosing in the management of severe plaque type psoriasis in adult patients. PMID- 22816880 TI - Progression of diffuse esophageal spasm to achalasia: incidence and predictive factors. AB - The progression of certain primary esophageal motor disorders to achalasia has been documented; however, the true incidence of this decay is still elusive. This study aims to evaluate: (i) the incidence of the progression of diffuse esophageal spasm to achalasia, and (ii) predictive factors to this progression. Thirty-five patients (mean age 53 years, 80% females) with a manometric picture of diffuse esophageal spasm were followed for at least 1 year. Patients with gastroesophageal reflux disease confirmed by pH monitoring or systemic diseases that may affect esophageal motility were excluded. Esophageal manometry was repeated in all patients. Five (14%) of the patients progressed to achalasia at a mean follow-up of 2.1 (range 1-4) years. Demographic characteristics were not predictive of transition to achalasia, while dysphagia (P= 0.005) as the main symptom and the wave amplitude of simultaneous waves less than 50 mmHg (P= 0.003) were statistically significant. In conclusion, the transition of diffuse esophageal spasm to achalasia is not frequent at a 2-year follow-up. Dysphagia and simultaneous waves with low amplitude are predictive factors for this degeneration. PMID- 22816962 TI - Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease. AB - The experimental models of Heymann nephritis (HN) and slowly progressive Heymann nephritis (SPHN) give us rare opportunities to investigate the etiologies and pathogenesis of two immunopathological processes in rats leading to: (1) autoimmune disease, where the autoimmune disease HN and SPHN is initiated and maintained by cross-reactive pathogenic IgG autoantibodies (aabs) directed against the renal proximal convoluted tubules' brush border (BB) cells - where the nephritogenic antigen (ag) is produced and localized - damaging and releasing BB associated nephritogenic ag into the circulation which in turn contributes to continuation of the autoimmune disease; and (2) immune complex glomerulonephritis, where the glomerular injury is initiated, proceeding into a chronic progressive disease by depositing immune complexes (ICs) - made up of a glomerular epithelial cell produced endogenous nephritogenic ag and the developing pathogenic IgG aab directed against the nephritogenic ag, and complement components - on the epithelial side of the glomerular basement membrane. We also observed how the normally functioning immune system is able to avert autoimmune disease developments by circulating specific non-pathogenic IgM aabs clearing the system of intracytoplasmic ags released from cells at the end of their life spans or following damage by toxic agents. We also described how an autoimmune disease SPHN can be prevented and when present terminated by the implementation of a new vaccination technique we have developed and call modified vaccination technique. By increasing the specific IgM aab production against the native nephritogenic ag - by injecting ICs made up of: [nephritogenic ag X homologous anti-nephritogenic ag IgM ab] in slight ag excess into SPHN rats - pathogenic IgG aab producing native and modified nephritogenic ags were removed from the circulation and termination of the autoimmune disease causing immune events was achieved. Even though HN and SPHN are not well-known disease models, their studies are important because the etiologies and pathogenesis of two conditions - that can also occur in humans, namely autoimmune diseases and membranous glomerulonephritis - can be simultaneously investigated. PMID- 22816879 TI - Small molecule tools for functional interrogation of protein tyrosine phosphatases. AB - The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signalling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes and autoimmune disorders, as well as neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored as a result of a lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We highlight the current challenges to and opportunities for developing PTP-specific small molecule agents. We also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC-PTP, SHP2, lymphoid-specific tyrosine phosphatase, haematopoietic protein tyrosine phosphatase, CD45, PTPbeta, PTPgamma, PTPRO, Vaccinia H1-related phosphatase, mitogen-activated protein kinase phosphatase-1, mitogen-activated protein kinase phosphatase-3, Cdc25, YopH, mPTPA and mPTPB. PMID- 22816963 TI - Glycated albumin is lower in infants than in adults and correlated with both age and serum albumin. AB - BACKGROUND: Glycated albumin (GA) reflects glycemic control in patients with neonatal diabetes mellitus (NDM). However, GA in NDM patients is apparently low in relation to glycemia. OBJECTIVE: To establish the reference intervals for GA in healthy infants. SUBJECTS AND METHODS: Fifty-eight healthy, full-term newborn infants were used to define the GA reference values and to investigate its relationship to plasma glucose (PG) and serum albumin. The infants were categorized into three groups according to age: group A, 5 (4-6) median (range) d: n = 18; group B, 33 (30-38) d: n = 19; and group C, 181 (50-352) d: n = 21. We also studied 212 non-diabetic adults [group D, 53 (28-78) yr old] and the 5 NDM patients previously reported for GA comparisons. RESULTS: In the infants, GA was strongly positively correlated with logarithmic transformation of age [log (age)] (p = 0.831, p < 0.0001). The GA in groups A, B, C, and D were 7.3 +/- 1.0%, 8.6 +/- 1.1%, 10.9 +/- 0.8%, and 14.0 +/- 1.1%, respectively. The GA was more strongly positively correlated with serum albumin (r = 0.768, p < 0.0001) than with PG (r = 0.596, p < 0.0001). When GA levels were compared with the age dependent reference values, GA in the transient NDM patient was normalized although GA in the four permanent NDM patients decreased but remained high after insulin therapy. CONCLUSIONS: This study showed that the reference range for GA in infants is lower than that of adults and increases with age, with which we confirmed that GA in the NDM patients reflected the clinical course. Consequently, GA in NDM patients should be compared with the age-based reference values to assess the accurate glycemic status. PMID- 22816965 TI - 5HT(6) receptor antagonists: a patent update. Part 1. Sulfonyl derivatives. AB - INTRODUCTION: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5HT receptors (5HT(6)Rs) are highly attractive as important biological targets with enormous clinical importance. Among this subclass, 5HT(6)R is the most recently discovered group. Available biological data clearly indicate that 5HT(6)R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease and Alzheimer's disease. Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential. AREAS COVERED: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents (see issue 20(7), 2010). Here, the main focus is on small molecule compounds - 5HT(6) antagonists - which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic within the field of 5HT(6) ligands, having an obvious pharmaceutical potential in terms of related patents, a comprehensive search through several key patent collections have been provided. The authors describe the reported chemical classes and scaffolds in sufficient detail to provide a valuable insight in the 5HT(6)R chemistry and pharmacology. The review consists of two core parts with separate sections arranged in accordance with the main structural features of 5HT(6)R ligands. EXPERT OPINION: Recent progress in the understanding of the 5HT(6) receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Heterocycles with sulfonyl group and without any basic center provide sufficient supramolecular interactions and show high antagonistic activity against 5HT(6)R. PMID- 22816969 TI - A new African fossil caprin and a combined molecular and morphological Bayesian phylogenetic analysis of caprini (Mammalia: Bovidae). AB - Given that most species that have ever existed on Earth are extinct, no evolutionary history can ever be complete without the inclusion of fossil taxa. Bovids (antelopes and relatives) are one of the most diverse clades of large mammals alive today, with over a hundred living species and hundreds of documented fossil species. With the advent of molecular phylogenetics, major advances have been made in the phylogeny of this clade; however, there has been little attempt to integrate the fossil record into the developing phylogenetic picture. We here describe a new large fossil caprin species from ca. 1.9-Ma deposits from the Middle Awash, Ethiopia. To place the new species phylogenetically, we perform a Bayesian analysis of a combined molecular (cytochrome b) and morphological (osteological) character supermatrix. We include all living species of Caprini, the new fossil species, a fossil takin from the Pliocene of Ethiopia (Budorcas churcheri), and the insular subfossil Myotragus balearicus. The combined analysis demonstrates successful incorporation of both living and fossil species within a single phylogeny based on both molecular and morphological evidence. Analysis of the combined supermatrix produces superior resolution than with either the molecular or morphological data sets considered alone. Parsimony and Bayesian analyses of the data set are also compared and shown to produce similar results. The combined phylogenetic analysis indicates that the new fossil species is nested within Capra, making it one of the earliest representatives of this clade, with implications for molecular clock calibration. Geographical optimization indicates no less than four independent dispersals into Africa by caprins since the Pliocene. PMID- 22816970 TI - Oops! PMID- 22816971 TI - Alkylresorcinols in Latvian and Finnish breads. AB - The alkylresorcinol (AR) content and relative homologue composition were determined in 9 Latvian and 11 Finnish soft breads. ARs were extracted with hot 1 propanol and quantified, using a gas chromatography-mass spectrometry method. The total AR content (MUg/g dry matter) varied from 560 to 840 in rye breads, from 500 to 700 in Finnish mixed rye and wheat flour breads, from 200 to 300 in Latvian mixed rye and wheat flour breads and from 25 to 30 in white wheat breads. Rye and white wheat breads in the two countries varied only slightly in AR content, but there were wide variations in AR content in mixed flour breads. The AR contents in soft breads could be indicators of bran or fibre content, but not of whole-grain flour content. PMID- 22816972 TI - Palladium-catalyzed C(sp3)-H arylation of diarylmethanes at room temperature: synthesis of triarylmethanes via deprotonative-cross-coupling processes. AB - Although metal-catalyzed direct arylation reactions of non- or weakly acidic C-H bonds have recently received much attention, chemists have relied heavily on substrates with appropriately placed directing groups to steer reactivity. To date, examples of intermolecular arylation of unactivated C(sp(3))-H bonds in the absence of a directing group remain scarce. We report herein the first general, high-yielding, and scalable method for palladium-catalyzed C(sp(3))-H arylation of simple diarylmethane derivatives with aryl bromides at room temperature. This method facilitates access to a variety of sterically and electronically diverse hetero- and nonheteroaryl-containing triarylmethanes, a class of compounds with various applications and interesting biological activity. Key to the success of this approach is an in situ metalation of the substrate via C-H deprotonation under catalytic cross-coupling conditions, which is referred to as a deprotonative-cross-coupling process (DCCP). Base and catalyst identification were performed by high-throughput experimentation (HTE) and led to a unique base/catalyst combination [KN(SiMe(3))(2)/Pd-NiXantphos] that proved to efficiently promote the room-temperature DCCP of diarylmethanes. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of substrates that are known to undergo O-, N-, enolate-, and C(sp(2))-H arylation. PMID- 22816973 TI - Simulating geriatric home safety assessments in a three-dimensional virtual world. AB - Virtual worlds could offer inexpensive and safe three-dimensional environments in which medical trainees can learn to identify home safety hazards. Our aim was to evaluate the feasibility, usability, and acceptability of virtual worlds for geriatric home safety assessments and to correlate performance efficiency in hazard identification with spatial ability, self-efficacy, cognitive load, and presence. In this study, 30 medical trainees found the home safety simulation easy to use, and their self-efficacy was improved. Men performed better than women in hazard identification. Presence and spatial ability were correlated significantly with performance. Educators should consider spatial ability and gender differences when implementing virtual world training for geriatric home safety assessments. PMID- 22816974 TI - The brave new world of GEC evaluation: the experience of the Rhode Island Geriatric Education Center. AB - In 2007, the Health Resources Services Administration introduced new mandates that raised the standards on program evaluation for Geriatric Education Centers. Described in this article are the primary and secondary evaluation efforts undertaken for one program within the Rhode Island Geriatric Education Center (RIGEC), the findings from these efforts, and the modifications to assessment that ensued in response to the increased accountability requirements. The evaluation focused on RIGEC's series of continuing education, day-long workshops for health and social service professionals, the completion of all seven of which leads to a Certificate in Interdisciplinary Practice in Geriatrics. PMID- 22816975 TI - Getting to know you: using documentary video-making to challenge ageist stereotypes. AB - The article theorizes that augmenting traditional humanities course work with documentary video-making can enhance and motivate learning. The English class profiled focused on aging and the lives of elders in an adult daycare center and a retirement community. Students documented elders' stories in video over 15 weeks. The instructor's goal was to use the immediacy of video to challenge and dismantle ageist stereotypes. Documentary video-making is a simple, and enticing, technology that gives students a powerful tool for getting to know elders. Scholarship on classroom uses of digital video-making is discussed, and critical comments from the five reflective essays students wrote during the semester are used to track changes in student perceptions of elders. PMID- 22816976 TI - Raising awareness of assistive technology in older adults through a community based, cooperative extension program. AB - The Fashion an Easier Lifestyle with Assistive Technology (FELAT) curriculum was developed as a needs-based, community educational program provided through a state Cooperative Extension Service. The overall goal for participants was to raise awareness of assistive technology. Program evaluation included a postassessment and subsequent interview to determine short-term knowledge gain and longer term behavior change. The sample consisted of mainly older, married females. The FELAT program was effective at raising awareness and increasing knowledge of assistive technology, and for many participants, the program acted as a catalyst for planning to or taking action related to assistive technology. PMID- 22816977 TI - The longitudinal elderly person shadowing program: outcomes from an interprofessional senior partner mentoring program. AB - The University of Saskatchewan's Longitudinal Elderly Person Shadowing (LEPS) is an interprofessional senior mentors program (SMP) where teams of undergraduate students in their first year of medicine, pharmacy, and physiotherapy; 2nd year of nutrition; 3rd year nursing; and 4th year social work partner with community dwelling older adults. Existing literature on SMPs provides little information on the sustainability of attitudinal changes toward older adults or changes in interprofessional attitudes. LEPS students completed Polizzi's Aging Semantic Differential and the Interdisciplinary Education Perception Scale. Perceptions of older men and women improved significantly and changes were sustained after one year. However, few changes were seen in interprofessional attitudes. PMID- 22816978 TI - Paradigms in the gerontology classroom: connections and challenges to learning. AB - The article explores paradigms for approaching course content to be studied in the classroom. These paradigms, or global views about what is of interest or importance and ways of knowing, relate to key questions in gerontology, such as what is the relevant domain/content to be studied, what is the central level of analysis or action, what are appropriate ways to gain knowledge, and how do we best address the challenges related to aging? For interdisciplinary gerontology programs, the discussion of paradigms raises the question of whether learning effectiveness and student satisfaction may suffer when the students are unaware of their own budding gerontological paradigms or when an instructor's paradigm remains unarticulated or differs from those of students. This article discusses selected paradigms inherent within gerontology education/training programs and their diverse foci, two emerging paradigms of gerontology, and potential steps to clarify these paradigms in the classroom. PMID- 22816979 TI - Evaluation and feedback for effective clinical teaching in postgraduate medical education: validation of an assessment instrument incorporating the CanMEDS roles. AB - BACKGROUND: Providing clinical teachers in postgraduate medical education with feedback about their teaching skills is a powerful tool to improve clinical teaching. A systematic review showed that available instruments do not comprehensively cover all domains of clinical teaching. We developed and empirically test a comprehensive instrument for assessing clinical teachers in the setting of workplace learning and linked to the CanMEDS roles. METHODS: In a Delphi study, the content validity of a preliminary instrument with 88 items was studied, leading to the construction of the EFFECT (evaluation and feedback for effective clinical teaching) instrument. The response process was explored in a pilot test and focus group research with 18 residents of 6 different disciplines. A confirmatory factor analyses (CFA) and reliability analyses were performed on 407 evaluations of 117 supervisors, collected in 3 medical disciplines (paediatrics, pulmonary diseases and surgery) of 6 departments in 4 different hospitals. RESULTS: CFA yielded an 11 factor model with a good to excellent fit and internal consistencies ranged from 0.740 to 0.940 per domain; 7 items could be deleted. CONCLUSION: The model of workplace learning showed to be a useful framework for developing EFFECT, which incorporates the CanMEDS competencies and proved to be valid and reliable. PMID- 22816980 TI - How we conduct ongoing programmatic evaluation of our medical education curriculum. AB - Evaluation of undergraduate medical education programs is necessary to meet accreditation standards; however, implementation and maintenance of an adequate evaluation process is challenging. A curriculum evaluation committee (CEC) was established at the Penn State University College of Medicine in 2000 to complement the already established activities of the Office of the Vice Dean for Medical Education and the Committee on Undergraduate Medical Education. Herein, we describe the methodology used by the CEC at our academic medical center and outcomes attributable to the curriculum evaluation process that was enacted. Strengths of our process include ongoing, regular assessments that guarantee a course is reviewed at least every two years and a feedback loop whereby course directors are held accountable for implementing changes when necessary. Our evaluative process has proven effective, sustainable, and has identified additional areas for curricular improvements. PMID- 22816981 TI - Non conventional mutations associated with myeloproliferative disorders are absent in splanchnic venous thrombosis cases. PMID- 22816982 TI - Low-dose acyclovir prophylaxis for bortezomib-induced herpes zoster in multiple myeloma patients. PMID- 22816984 TI - Contact dermatitis to ophthalmic solutions. AB - Periorbital and eyelid dermatitis is a recalcitrant and often distressing condition. Allergic contact dermatitis to ophthalmic solutions is an important cause of periorbital and eyelid dermatitis. In this review article, we discuss the allergens involved, the difficulties in patch testing, and the recommended concentrations and vehicles for patch testing. PMID- 22816983 TI - Comparative protein interactomics of neuroglobin and myoglobin. AB - Neuroglobin is a hypoxia-inducible O(2)-binding protein with neuroprotective effects in cell and animal models of stroke and Alzheimer's disease. The mechanism underlying neuroglobin's cytoprotective action is unknown, although several possibilities have been proposed, including anti-oxidative and anti apoptotic effects. We used affinity purification-mass spectrometry methods to identify neuroglobin-interacting proteins in normoxic and hypoxic murine neuronal (HN33) cell lysates, and to compare these interactions with those of a structurally and functionally related protein, myoglobin. We report that the protein interactomes of neuroglobin and myoglobin overlap substantially and are modified by hypoxia. In addition, neuroglobin-interacting proteins include partners consistent with both anti-oxidative and anti-apoptotic functions, as well as with a relationship to several neurodegenerative diseases. PMID- 22816985 TI - Quality of life in patients with pemphigus receiving adjuvant therapy. AB - BACKGROUND: Pemphigus has a strong effect on patients' quality of life (QOL). AIM: To analyze QOL and psychological well-being within patient groups, subdivided according to their different adjuvant treatments. METHODS: All adult patients with pemphigus enrolled in the study were assessed using the Short Form (SF)-36, the Skindex-29, and the General Health Questionnaire (GHQ)-12 for health status, effect of dermatology-specific aspects, and the presence of psychological comorbidity, respectively. The study population was subdivided into the following treatment groups: (i) those who were untreated or were treated only with corticosteroids (CS) at a dose of <= 5 mg/day (no adjuvant treatment, NAT); and patients receiving or not receiving CS <= 5 mg/day who also received either (ii) azathioprine (AZ), (iii) cyclophosphamide (CY), (iv) mycophenolate mofetil (MM) or (v) rituximab (RTX). RESULTS: In total, 113 patients were recruited. There were no significant differences between the treatment subgroups in either the SF 36 or Skindex-29 results. However, for the GHQ, there were large differences in QOL scores between patients scoring > 4 points (GHQ+) and those scoring < 4 points (GHQ-), especially for the more 'physical' components of QOL. The overall observed proportion of GHQ+ patients was 33.6%. CONCLUSIONS: We found no significant differences in QOL impairment between the treatment subgroups; however, we observed a strong association between psychiatric morbidity and poorer QOL within each of the treatment groups. This should be of concern for dermatologists, as psychiatric morbidity is associated with poor treatment adherence and dissatisfaction with care. PMID- 22816986 TI - MBTPS2 mutation in a British pedigree with keratosis follicularis spinulosa decalvans. AB - Keratosis follicularis spinulosa decalvans (KFSD; OMIM 308800) is an X-linked disorder characterized by widespread hyperkeratotic follicular papules (including keratosis pilaris-like lesions), facial erythema, hypotrichosis and scarring alopecia. KFSD results from mutations in the MBTPS2 gene. Mutations in this gene also underlie ichthyosis follicularis, alopecia and photophobia syndrome. We report a British pedigree with KFSD resulting from the mutation p.Asn508Ser. This particular mutation has been reported in three other pedigrees with KFSD (Dutch, American, British) and is the only pathogenic mutation reported in this disorder to date. However, the same mutation has also been reported in a Chinese pedigree with IFAP syndrome, highlighting the clinical heterogeneity and overlapping molecular pathology of these two disorders. PMID- 22816987 TI - Psoriatic onycho-pachydermo-periostitis progressing to generalized pustular psoriasis. PMID- 22816988 TI - Multiple blue nodules. PMID- 22816989 TI - Phylogenetic diversity of Aeromonas from "alheira," a traditional Portuguese meat product. AB - "Alheira" is a traditional smoked meat sausage produced in the north of Portugal, representing an important economic resource for the region. This meat product has been subjected to research studies with the aim of detecting the presence of common foodborne pathogens, but, to our knowledge, isolation of emerging foodborne Aeromonas from alheira has never been previously described. Present work attempts to evaluate the Aeromonas species diversity of 84 isolates of Aeromonas spp. collected from 32 alheira samples. All presumptive Aeromonas isolates were subjected to genotyping by enterobacterial repetitive intergenic consensus-polymerase chain reaction analysis. The isolates presenting a different pattern were subjected to gyrB gene sequencing for species classification, and the species A. hydrophila, A. salmonicida, A. caviae, A. media, and A. allosaccharophila were identified. The Aeromonas species diversity found has not been previously described in any other meat product evaluated in previous studies. It is also important to highlight the presence of A. hydrophila and A. caviae because they were previously associated with illness in humans, including gastroenteritis. PMID- 22816990 TI - Pressure-induced phase transition in N-H...O hydrogen-bonded molecular crystal oxamide. AB - The effect of high pressure on the structural stability of oxamide has been investigated in a diamond anvil cell by Raman spectroscopy up to ~14.6 GPa and by angle-dispersive X-ray diffraction (ADXRD) up to ~17.5 GPa. The discontinuity in Raman shifts around 9.6 GPa indicates a pressure-induced structural phase transition. This phase transition is confirmed by the change of ADXRD spectra with the symmetry transformation from P1 to P1. On total release of pressure, the diffraction pattern returns to its initial state, implying this transition is reversible. We discuss the pressure-induced variations in N-H stretching vibrations and the amide modes in Raman spectra and propose that this phase transition is attributed to the distortions of the hydrogen-bonded networks. PMID- 22816991 TI - Silver nanoparticle-algae interactions: oxidative dissolution, reactive oxygen species generation and synergistic toxic effects. AB - The short-term toxicity of citrate-stabilized silver nanoparticles (AgNPs) and ionic silver Ag(I) to the ichthyotoxic marine raphidophyte Chattonella marina has been examined using the fluorometric indicator alamarBlue. Aggregation and dissolution of AgNPs occurred after addition to GSe medium while uptake of dissolved Ag(I) occurred in the presence of C. marina. Based on total silver mass, toxicity was much higher for Ag(I) than for AgNPs. Cysteine, a strong Ag(I) ligand, completely removed the inhibitory effects of Ag(I) and AgNPs on the metabolic activity of C. marina, suggesting that the toxicity of AgNPs was due to the release of Ag(I). Synergistic toxic effects of AgNPs/Ag(I) and C. marina to fish gill cells were observed with these effects possibly attributable to enhancement in the generation of reactive oxygen species by C. marina on exposure of the organism to silver. PMID- 22816992 TI - A diabetes awareness campaign prevents diabetic ketoacidosis in children at their initial presentation with type 1 diabetes. AB - OBJECTIVE: To evaluate the effect of a diabetes awareness campaign on the incidence of diabetic ketoacidosis (DKA) at the first presentation of type 1 diabetes in children (0-18 yr). METHODS: This study was a controlled population intervention study with a 2-yr baseline period and a 2-yr intervention period. Data were collected on all children presenting with their initial diagnosis of type 1 diabetes [pH, bicarbonate, base excess, blood glucose level (BGL), urea, and creatinine] at Gosford, Newcastle, and Sydney (Sydney Children's Hospital and Royal North Shore Hospital). During the intervention period, diabetes education occurred in the intervention region (Gosford). Child care centers, schools, and doctor's offices were offered education and posters about the symptoms of type 1 diabetes. Doctor's offices were given glucose and ketone testing equipment. The control regions (Newcastle and Sydney) did not receive any educational intervention or test equipment. DKA was defined as pH < 7.3 or bicarbonate < 15 mmol/L. RESULTS: In Gosford, the proportion of children presenting in DKA decreased from 37.5% (15/40) during the 2-yr baseline period to 13.8% (4/29) during the 2-yr intervention (p < 0.03). There was no significant change in the control regions during the same time periods, 37.4% (46/123) and 38.6% (49/127), respectively. In Gosford, the average BGL at presentation was 27.5 mmol/L during the baseline and 21.2 mmol/L during the intervention (p < 0.01). CONCLUSION: During the diabetes awareness campaign, the rate of DKA at initial diagnosis of type 1 diabetes in children decreased by 64%. PMID- 22816993 TI - Inactivation of vaccinia virus by natural sunlight and by artificial UVB radiation. AB - This study determined the sensitivity of vaccinia virus, an orthopox virus commonly used as a surrogate for variola virus (etiological agent of smallpox), exposed to UVB radiation emitted by a solar simulator, or to direct natural sunlight. The data obtained indicate that: (1) the virucidal effect of natural sunlight can be mimicked adequately by an artificial light source with similar spectral characteristics in the UVB, (2) viral sensitivity to UVB or to solar radiation can be correlated with experimental data previously obtained with UVC, (3) the correlation factor between virus inactivation by solar radiation (measured at 300 +/- 5 nm) and by UVC (254 nm) is between 33 and 60, and (4) the sensitivity of viruses either dry on glass surfaces or in liquid suspension is similar when in the presence of similar amounts of cellular debris and growth media. The findings reported in this study should assist in estimating the threat posed by the persistence of virus during epidemics or after an accidental or intentional release. PMID- 22816994 TI - Mechanical bowel preparation for esophagocoloplasty in children: is it really necessary? AB - Esophagocoloplasty is a commonly performed procedure for esophageal replacement in children. Traditionally, mechanical bowel preparation (MBP) is performed before this operation. However, this practice has been questioned, initially in adults and now in children. The aim of this study was to evaluate the influence of MBP on esophagocoloplasty in a series of children. Data collected from 164 patients who underwent esophagocoloplasty in the Pediatric Surgery Division, University of Sao Paulo Medical School, from February 1978 to July 2011 were reviewed for postoperative complications. In 134 patients, at least one kind of MBP was performed before the surgery (PREP group). MBP was omitted in 30 patients (NO-PREP group). There was no statistical difference between the groups in the rates of evisceration, colocolic, or cologastric anastomotic dehiscence and death. However, in the NO-PREP group, the incidence of cervical leakage (6.6%) was significantly decreased in comparison with the classical PREP group (25.3%) (P= 0.03). The results of this study suggest that the omission of MBP has a positive impact on the incidence of postoperative complications in esophagocoloplasty. PMID- 22817101 TI - Anterior migration of prosthesis following cervical arthroplasty. AB - We present a case of anterior migration of prosthesis that presented acutely several weeks following cervical arthroplasty. The implant was subsequently removed and the level fused. The cause of this unusual complication is speculated. PMID- 22817103 TI - Phenomena associated with sick leave among primary care patients with Medically Unexplained Physical Symptoms: a systematic review. AB - OBJECTIVE: To explore and synthesize the literature on phenomena associated with sick leave among patients with Medically Unexplained Physical Symptoms (MUPS). DESIGN: A systematic review of the literature was undertaken in three phases: (1) a search of the following databases: Medline, Embase, Psych Info, Cochrane Collaboration Library, Digital Dissertations, DiVA, SweMed +, NORART, and ISI Web of Science, (2) selection of studies based on pre-specified inclusion criteria was undertaken, extracting study design and results, (3) quality assessment was undertaken independently by two reviewers. Due to heterogeneity in study designs, populations, interventions, and outcome measures, a mixed research synthesis approach was used. Results were assessed in a pragmatic and descriptive way; textual and numerical data were extracted from the included studies, and classified into patient- and doctor-related factors. RESULTS: Sixteen studies were included. With regard to patients, an association was found between sick leave and psychiatric comorbidity as well as total symptom burden. With regard to doctors, knowledge of the patient, sympathy, and trust appeared to increase the probability of the patient being sick-listed. None of the interventions in the educational programmes aiming to improve doctors' management of MUPS patients succeeded in lowering sick leave. IMPLICATIONS: Despite MUPS being a leading cause of sickness absence, the review identified only a small number of studies concerning phenomena associated with sick leave. The authors did not identify any studies regarding the impact of the working conditions on sick leave among MUPS patients. This is an important area for further studies. PMID- 22817104 TI - Creation of high-refractive-index amorphous titanium oxide thin films from low fractal-dimension polymeric precursors synthesized by a sol-gel technique with a hydrazine monohydrochloride catalyst. AB - Amorphous titanium dioxide (TiO(2)) thin films exhibiting high refractive indices (n ~ 2.1) and high transparency were fabricated by spin-coating titanium oxide liquid precursors having a weakly branched polymeric structure. The precursor solution was prepared from titanium tetra-n-butoxide (TTBO) via the catalytic sol gel process with hydrazine monohydrochloride used as a salt catalyst, which serves as a conjugate acid-base pair catalyst. Our unique catalytic sol-gel technique accelerated the overall polycondensation reaction of partially hydrolyzed alkoxides, which facilitated the formation of liner polymer-like titanium oxide aggregates having a low fractal dimension of ca. (5)/(3), known as a characteristic of the so-called "expanded polymer chain". Such linear polymeric features are essential to the production of highly dense amorphous TiO(2) thin films; mutual interpenetration of the linear polymeric aggregates avoided the creation of void space that is often generated by the densification of high fractal-dimension (particle-like) aggregates produced in a conventional sol-gel process. The mesh size of the titanium oxide polymers can be tuned either by water concentration or the reaction time, and the smaller mesh size in the liquid precursor led to a higher n value of the solid thin film, thanks to its higher local electron density. The reaction that required no addition of organic ligand to stabilize titanium alkoxides was advantageous to overcoming issues from organic residues such as coloration. The dense amorphous film structure suppressed light scattering loss owing to its extremely smooth surface and the absence of inhomogeneous grains or particles. Furthermore, the fabrication can be accomplished at a low heating temperature of <80 degrees C. Indeed, we successfully obtained a transparent film with a high refractive index of n = 2.064 (at lambda = 633 nm) on a low-heat-resistance plastic, poly(methyl methacrylate), at 60 degrees C. The result offers an efficient route to high refractive-index amorphous TiO(2) films as well as base materials for a wider range of applications. PMID- 22817102 TI - The effect of a pre- and post-operative orthogeriatric service on cognitive function in patients with hip fracture. The protocol of the Oslo Orthogeriatrics Trial. AB - BACKGROUND: Hip fractures mainly affect older people. It is associated with high morbidity and mortality, and in particular a high frequency of delirium. Incident delirium following hip fracture is associated with an increased risk of dementia in the following months, but it is still not firmly established whether this is an association or a causal relationship. Orthogeriatric units vary with respect to content and timing of the intervention. One main effect of orthogeriatric care may be the prevention of delirium, especially if preoperative and postoperative care are provided. Thus, the aim of Oslo Orthogeriatric Trial, is to assess whether combined preoperative and postoperative orthogeriatric care can reduce the incidence of delirium and improve cognition following hip fracture. METHODS/DESIGN: Inclusion and randomisation will take place in the Emergency Department, as soon as possible after admission. All patients with proximal femur fractures are eligible, irrespective of age, pre-fracture function and accommodation, except if the fracture is caused by a high energy trauma or the patient is terminally ill. The intervention is pre-and post-operative orthogeriatric care delivered on a dedicated acute geriatric ward. The primary outcome measure is a composite endpoint combining the Clinical Dementia Rating Scale (CDR) and the 10 word memory task at four months after surgery. Secondary outcomes comprise incident delirium, length of stay, cognition, mobility, place of residence, activities of daily living and mortality, measured at 4 and 12 months after surgery. We have included 332 patients in the period 17th September 2009 to 5th January 2012. DISCUSSION: Our choice of outcome measures and our emphasis of orthogeriatric care in the preoperative as well as the postoperative phase will enable us to provide new knowledge on the impact of orthogeriatric care on cognition. TRIALS REGISTRATION: ClinicalTrials.gov NCT01009268. PMID- 22817106 TI - Implementation of the Chinese national microscopy centre policy: health facility survey in Shandong Province. AB - OBJECTIVE: In compliance with Chinese national policy, Shandong province set up microscopy centres (MCs) in one-third of all township hospitals where sputum smear microscopy is performed. We assessed the centres' performance and any factors influencing it. METHODS: A cross-sectional, structured, facility-based questionnaire survey was conducted in 2006, collecting data from all 113 counties with established MCs as well as tuberculosis (TB) routine reporting data from the county TB dispensary. RESULTS: One hundred and thirteen of 142 counties in Shandong had established 497 MCs. The centres identified 3.3% of smear-positive patients in the province. Sixty-six percentage of MCs did not identify any patients with TB; only 5% identified more than 10. Poor performance arose from low quality of staff training in township hospitals, but inappropriate geographical provision of services was the main cause of low additional case finding. CONCLUSION: The MC policy did not achieve its goal of improving TB case finding in Shandong. PMID- 22817107 TI - Secondary intention healing in skin surgery: our own experience and expanded indications in hidradenitis suppurativa, rhinophyma and non-melanoma skin cancers. AB - BACKGROUND: There are many situations in integument surgery in which secondary intention healing (SIH) may bring results comparable or even superior to those obtained with primary intention healing. OBJECTIVE: To present our own methods of employing SIH in surgical treatment of different skin lesions. Moreover, to delineate the extended indications for SIH as a first-line method of wound treatment. METHODS: Between 1999 and 2009, we conducted 236 operations followed by SIH in the group of 195 patients. Two independent investigators and the patients carried out post-operative assessment (at 12 months) of both cosmetic and functional results of operations (data for 142 patients). Moreover, at 3 and 12 months, patients were asked for self-evaluation of the outcomes of surgical procedures using the visual analogue scale (VAS). RESULTS: The most frequent indications for SIH were defects after the excision of non-melanoma skin cancers and hidradenitis suppurativa lesions. Depending on localization, the mean extent of the post-operative wounds prepared for SIH ranged from 0.8to 85.7 cm(2). The healing lasted 2-12 weeks. The most important factor was the size of the wound (r = 0.59; P < 0.001). The assessment at 12 months revealed that cosmetic/functional outcomes were evaluated as 'good' or 'excellent' in 89/83% and 72/70% cases, according to patients and physicians respectively. VAS showed that evaluation scores at 3 months post-surgery were significantly lower than at 12 months (P < 0.0001). CONCLUSION: SIH is a safe and efficient form of treatment for various post-operative skin defects. In certain areas of the body, SIH shows favourable cosmetic and functional effects. In these cases, it may even be regarded as the method of choice. PMID- 22817109 TI - The evolution of experience-mediated plasticity in mate preferences. AB - Experience of sexual signals can alter mate preferences and influence the course of sexual selection. Here, we examine the patterns of experience-mediated plasticity in mate preferences that can arise in response to variation in the composition of mates in the environment. We use these patterns to test hypotheses about potential sources of selection favouring experience-mediated plasticity. We manipulated signal experience of female Enchenopa treehoppers (Hemiptera: Membracidae) in a vibrational playback experiment with the following treatments: silence; two types of non-preferred signals; preferred signals; and a mixture of preferred and non-preferred signals. This experiment revealed plasticity in mate preference selectivity, with greatest selectivity in the mixed signal treatment, followed by the preferred signal treatment. We found no plasticity in peak preference. These results suggest that females have been selected to adjust preference selectivity according to the variability of potential mates in their social environment, as well as to the presence/absence of preferred mates. We discuss how experience-mediated plasticity in mate preferences can influence the strength of selection on male signals and can result in evolutionary dynamics between variation in preferences and signals that either promote the maintenance of variation or facilitate rapid trait fixation. PMID- 22817110 TI - Acute hyperkalemia detected by alert from implantable cardioverter-defibrillator. AB - Two cases of implantable cardioverter-defibrillator lead impedance changes that corresponded with changes in serum potassium are described. In the first case, an audible lead alert was triggered due to a significant change in lead impedance caused by hyperkalemia. In the second case, a patient was admitted with hyperkalemia and renal failure. Device interrogation revealed a change in lead impedance corresponding to changes in serum potassium. As devices and leads become more sophisticated, their role for monitoring parameters and triggering alerts may expand to include electrolyte and other metabolic changes. PMID- 22817111 TI - Suite of tools for statistical N-gram language modeling for pattern mining in whole genome sequences. AB - Genome sequences contain a number of patterns that have biomedical significance. Repetitive sequences of various kinds are a primary component of most of the genomic sequence patterns. We extended the suffix-array based Biological Language Modeling Toolkit to compute n-gram frequencies as well as n-gram language-model based perplexity in windows over the whole genome sequence to find biologically relevant patterns. We present the suite of tools and their application for analysis on whole human genome sequence. PMID- 22817112 TI - Controlled chemical doping of semiconductor nanocrystals using redox buffers. AB - Semiconductor nanocrystal solids are attractive materials for active layers in next-generation optoelectronic devices; however, their efficient implementation has been impeded by the lack of precise control over dopant concentrations. Herein we demonstrate a chemical strategy for the controlled doping of nanocrystal solids under equilibrium conditions. Exposing lead selenide nanocrystal thin films to solutions containing varying proportions of decamethylferrocene and decamethylferrocenium incrementally and reversibly increased the carrier concentration in the solid by 2 orders of magnitude from their native values. This application of redox buffers for controlled doping provides a new method for the precise control of the majority carrier concentration in porous semiconductor thin films. PMID- 22817113 TI - Case reports: medical students priced out of the market. PMID- 22817114 TI - Protein phosphatase-1M and Rho-kinase affect exocytosis from cortical synaptosomes and influence neurotransmission at a glutamatergic giant synapse of the rat auditory system. AB - Protein phosphatase-1M (PP1M, myosin phosphatase) consists of a PP1 catalytic subunit (PP1c) and the myosin phosphatase target subunit-1 (MYPT1). RhoA activated kinase (ROK) regulates PP1M via inhibitory phosphorylation of MYPT1. Using multidisciplinary approaches, we have studied the roles of PP1M and ROK in neurotransmission. Electron microscopy demonstrated the presence of MYPT1 and ROK in both pre- and post-synaptic terminals. Tautomycetin (TMC), a PP1-specific inhibitor, decreased the depolarization-induced exocytosis from cortical synaptosomes. trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride, a ROK-specific inhibitor, had the opposite effect. Mass spectrometry analysis identified several MYPT1-bound synaptosomal proteins, of which interactions of synapsin-I, syntaxin-1, calcineurin-A subunit, and Ca(2+) /calmodulin-dependent kinase II with MYPT1 were confirmed. In intact synaptosomes, TMC increased, whereas Y27632 decreased the phosphorylation levels of MYPT1(Thr696) , myosin-II light chain(Ser19) , synapsin-I(Ser9) , and syntaxin 1(Ser14) , indicating that PP1M and ROK influence their phosphorylation status. Confocal microscopy indicated that MYPT1 and ROK are present in the rat ventral cochlear nucleus both pre- and post-synaptically. Analysis of the neurotransmission in an auditory glutamatergic giant synapse demonstrated that PP1M and ROK affect neurotransmission via both pre- and post-synaptic mechanisms. Our data suggest that both PP1M and ROK influence synaptic transmission, but further studies are needed to give a full account of their mechanism of action. PMID- 22817116 TI - Japanese Society for Dialysis Therapy: clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C. PMID- 22817117 TI - 2011 Japanese Society for Dialysis Therapy guidelines for the treatment of hepatitis C virus infection in dialysis patients. PMID- 22817115 TI - A strategy based on protein-protein interface motifs may help in identifying drug off-targets. AB - Networks are increasingly used to study the impact of drugs at the systems level. From the algorithmic standpoint, a drug can "attack" nodes or edges of a protein protein interaction network. In this work, we propose a new network strategy, "The Interface Attack", based on protein-protein interfaces. Similar interface architectures can occur between unrelated proteins. Consequently, in principle, a drug that binds to one has a certain probability of binding to others. The interface attack strategy simultaneously removes from the network all interactions that consist of similar interface motifs. This strategy is inspired by network pharmacology and allows inferring potential off-targets. We introduce a network model that we call "Protein Interface and Interaction Network (P2IN)", which is the integration of protein-protein interface structures and protein interaction networks. This interface-based network organization clarifies which protein pairs have structurally similar interfaces and which proteins may compete to bind the same surface region. We built the P2IN with the p53 signaling network and performed network robustness analysis. We show that (1) "hitting" frequent interfaces (a set of edges distributed around the network) might be as destructive as eleminating high degree proteins (hub nodes), (2) frequent interfaces are not always topologically critical elements in the network, and (3) interface attack may reveal functional changes in the system better than the attack of single proteins. In the off-target detection case study, we found that drugs blocking the interface between CDK6 and CDKN2D may also affect the interaction between CDK4 and CDKN2D. PMID- 22817118 TI - Immunoadsorption in dermatology. AB - Immunoadsorption (IA) has been successfully used in a large variety of autoantibody-mediated disorders. In dermatology, IA is increasingly applied as adjuvant treatment for severe and/or refractory autoimmune bullous diseases. These disorders are characterized by autoantibodies against structural proteins of the skin and/or mucous membranes and include, among others, pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid. Autoimmune blistering diseases are associated with a high mortality (pemphigus) or morbidity (bullous pemphigoid) and in particular in pemphigus diseases, treatment is challenging. The pathogenetic role of autoantibodies in most of the immunobullous diseases has been clearly demonstrated, therefore, removal of these autoantibodies is a rational therapeutic approach. IA has been shown to effectively lower the serum autoantibodies and to lead to rapid clinical responses. Most recently, IA has been successfully applied in patients with severe atopic dermatitis and high total serum IgE levels. Here, the different treatment protocols, clinical efficacy, and adverse events are summarized. PMID- 22817119 TI - Hemodialysis vascular access dysfunction: molecular mechanisms and treatment. AB - Hemodialysis vascular access complications are one of the main causes associated with an increase in morbidity and hospitalization in hemodialysis (HD) patients. The most common cause of vascular access dysfunction is venous stenosis as a result of venous neointimal hyperplasia within the peri-anastomotic region (arteriovenous [AV] fistula) or at the graft-vein anastomosis. There have been few studies regarding effective therapeutic interventions for HD vascular dysfunction at the present time, despite the magnitude of the clinical problem. This review will focus initially on the pathology and pathogenesis of HD vascular access dysfunction in the setting of both native AV fistula and polytetrafluoroethylene (PTFE) graft, then experimental and clinical therapies that could potentially be used in the setting of HD vascular access dysfunction. PMID- 22817120 TI - Occult hepatitis B virus infection in hemodialysis patients: a concept for consideration. AB - Hemodialysis patients potentially have an increased risk of infection with parenterally transmitted viral agents due to an impaired host immune response and multiple transfusion requirements. Viral hepatitis is considered as a problem for hemodialysis patients because 1.9% of all deaths among this population are related to the consequence of viral hepatitis. Hepatitis B virus (HBV) is one of the most important causes of transmitted infections by the parenteral route in hemodialysis patients. Occult HBV infection is characterized by presence of HBV infection without detectable hepatitis B surface antigen (HBsAg), which harbors potential risk of HBV transmission through hemodialysis. There are conflicting reports on the prevalence of occult HBV infection (OBI) in hemodialysis patients. Considering the importance of occult HBV infection in hemodialysis patients and the growing evidence on this subject, the purpose of this review is to provide comprehensive information on OBI prevalence in hemodialysis patients and highlight the most important points in this issue. PMID- 22817121 TI - Effects of in-center nocturnal versus conventional hemodialysis on endothelial dysfunction. AB - Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage renal disease who undergo hemodialysis and endothelial dysfunction is an early key step in the development of atherosclerosis. The aim of this study was to investigate the effect of thrice-weekly in-center nocturnal hemodialysis (INHD, 8 h per session and three sessions per week) and conventional hemodialysis (CHD, 4 h per session and three sessions per week) on endothelial dysfunction in patients with end-stage renal disease. 32 INHD and 58 matched CHD patients were enrolled, baseline and 12-month measures of blood pressure (BP), serum calcium and phosphorus, serum intact PTH (iPTH) and brachial artery flow mediated dilation (FMD) were collected and analyzed. Baseline characteristics were similar between groups except that serum phosphorus and calcium * phosphorus were higher in the INHD group. At the 12-month follow-up, there was a significant increase in FMD (6.0 +/- 1.5% to 7.1 +/- 1.8%, P < 0.01) in INHD patients. Multivariate analysis showed that FMD was inversely correlated with systolic BP (SBP) (beta = -0.485, P < 0.01), diastolic BP (DBP) (beta = -0.428, P < 0.01), iPTH (beta = -0.405, P < 0.01) and serum phosphorus level (beta = -0.375, P < 0.01). There was no significant change in FMD in the CHD group. Compared with CHD, INHD improves endothelial function, and control of serum phosphorus is associated with the improvement of endothelial function. PMID- 22817122 TI - Randomized crossover study of the efficacy and safety of sevelamer hydrochloride and lanthanum carbonate in Japanese patients undergoing hemodialysis. AB - Insufficient control of serum calcium and phosphate levels in patients undergoing hemodialysis is associated with increased mortality. As commonly used calcium containing phosphate binders can cause arterial calcification, newly developed calcium-free phosphate binders, such as sevelamer hydrochloride (SH) and lanthanum carbonate (LC), have received much attention. We assessed the efficacy and safety of SH and LC treatment in Japanese patients undergoing hemodialysis in a prospective randomized open blinded endpoint (PROBE) crossover study. Forty-two patients were randomized to receive SH or LC for 13 weeks, with the dosages adjusted every 2 weeks, followed by treatment with the other drug for another 13 weeks. The average daily doses of SH and LC were 2971 +/- 1464 mg and 945 +/- 449 mg, respectively. The mean dosage ratio of SH to LC was 3.05, which was maintained throughout the treatment period. SH and LC were similarly effective at controlling serum calcium and phosphate levels in the majority of patients (78 93%). A few serious adverse events (AEs) involving the biliary system occurred during the LC treatment period, but they were not considered to be treatment induced. Although the incidence of constipation, the most common treatment related AE, was higher during the SH period (27% vs. 5%; P < 0.05), no difference was observed in total treatment-related AEs. This study demonstrates that SH and LC are comparable treatments for controlling serum phosphate and calcium levels, and that both compounds are safe and well-tolerated in Japanese patients undergoing hemodialysis. PMID- 22817123 TI - Capillary electrophoretic profile of beta2-microglobulin intermediate associated with hemodialysis. AB - We previously identified an intermediate beta(2)-microglobulin (I-beta(2) m), which is an amyloidogenic beta(2) m variant, via capillary electrophoresis (CE) and reported hemodialysis (HD)-associated variations in the serum concentrations of each beta(2) m component, including that found in the rebound phase. Recent research has indicated that I-beta(2) m can bind, via the SO(3)(-) moiety, with glycosaminoglycan or proteoglycan, which are major components of interstitial tissue. Because alterations in I-beta(2) m are likely to be important in view of the possible accumulation of amyloidogenic precursor proteins in the interstitial space, we studied the I-beta(2) m profile as related to HD. We used CE to determine the I-beta(2) m profile both at the start and at the end of HD and during the rebound phase in 12 HD patients. We found both an unfolded beta(2) m and a destructured I-beta(2) m. More important, two peaks appeared in the rebound phase, one suggesting a refolding and one suggesting an irreversible destruction. Given that the intercompartmental transfer coefficient for beta(2) m is 1.0, our results indicated concomitant processes occurring after HD: refolding of the beta(2) m conformation and trapping of destructured I-beta(2) m in the extravascular space. Because the trapping of destructured I-beta(2) m supposedly leads to accumulation of beta(2) m in the interstitial space, we have proposed a new concept-a "shuttle" concept-for amyloid formation from beta(2) m in the HD setting. PMID- 22817124 TI - Perilipin-1 in hemodialyzed patients: association with history of coronary heart disease and lipid profile. AB - Perilipin-1 surrounds lipid droplets in both adipocytes and in atheroma plaque foam cells and controls access of lipases to the lipid core. In hemodialysis (HD) patients, dyslipidemia, malnutrition, inflammation and atherosclerosis are common. Thirty-six HD patients and 28 healthy volunteers were enrolled into the study. Ten HD patients suffered from coronary heart disease (CHD). Perilipin-1, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol (HDL-C), body mass index, albumin, geriatric nutritional risk index, normalized protein catabolic rate, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured. Perilipin-1 did not differ between HD patients and healthy volunteers. IL-6 and TNF-alpha were higher in HD patients. The evaluated nutritional markers and the markers of inflammation did not differ between HD patients with high perilipin-1 levels and HD patients with low perilipin-1 levels. Regarding the lipid profile, only HDL-C differed between HD patients with high perilipin-1 levels and HD patients with low perilipin-1 levels, and it was higher in the first subgroup. Perilipin-1 was significantly higher in HD patients without CHD. Perilipin-1 is detectable in the serum of HD patients and it is associated with increased HDL-C and decreased incidence of CHD. PMID- 22817125 TI - High correlation between clearance of renal protein-bound uremic toxins (indoxyl sulfate and p-cresyl sulfate) and renal water-soluble toxins in peritoneal dialysis patients. AB - Peritoneal dialysis (PD) is characterized by a slow continuous removal of solutes. Traditionally, dialysis adequacy is quantified by referring to the kinetics of urea nitrogen (UN) and creatinine (Cr) clearance. The efficacy of middle molecular substances and protein-bound solutes as markers for peritoneal dialysis adequacy is not clear. The aim of this cross-sectional study was to investigate correlations between the clearance of indoxyl sulfate (IS), p-cresyl sulfate (PCS), UN, and Cr in the peritoneum and kidneys and to compare the overall clearances of IS and PCS between non-anuric and anuric groups in PD patients. We recruited a total of 175 patients who had been undergoing continuous ambulatory PD (CAPD) or automated PD (APD) for at least 4 months. We measured total IS and PCS concentrations in serum, dialysate, and urine samples. Free IS and PCS concentrations were measured in all serum samples. IS and PCS clearances via both kidney and peritoneum were measured. The mean concentration of IS in the urine samples was 9.2-fold higher than that in the dialysate samples, and concentration of PCS in the urine samples was 8.5-fold higher than that in the dialysate samples. Peritoneal UN and Cr clearances were not correlated with peritoneal PCS clearance (P > 0.05) but were mildly correlated with peritoneal IS clearance. The peritoneal IS and PCS clearances in the different peritoneal equilibration test groups were similar. The renal UN and Cr clearances were strongly correlated with renal PCS and IS clearances (P > 0.89, P < 0.001). In addition, non-anuric patients showed better elimination of total PCS (10.3 mg/day [range, 1.6-19.8] vs. 5.2 mg/day [range, 0-14]; P < 0.001] and IS (37.9 mg/day [range, 25.6-56.7] vs. 24.8 mg/day [range, 17.1-41.6]; P < 0.001) than anuric patients. This cross-sectional study showed that peritoneal clearance of water soluble solutes is not correlated with that of PCS but is mildly correlated with that of IS. However, the renal clearances of IS and PCS show strong positive correlation with the renal clearances of UN and Cr. This study confirms the important role of residual renal function in the removal of protein-bound uremic toxins. PMID- 22817126 TI - Role of apheresis and dialysis in pediatric living donor liver transplantation: a single center retrospective study. AB - In the field of pediatric living donor liver transplantation, the indications for apheresis and dialysis, and its efficacy and safety are still a matter of debate. In this study, we performed a retrospective investigation of these aspects, and considered its roles. Between January 2008 and December 2010, 73 living donor liver transplantations were performed in our department. Twenty seven courses of apheresis and dialysis were performed for 19 of those patients (19/73; 26.0%). The indications were ABO incompatible-liver transplantation in 11 courses, fluid management in seven, acute liver failure in three, renal replacement therapy in two, endotoxin removal in two, cytokine removal in one, and liver allograft dysfunction in one. Sixteen courses of apheresis and dialysis were performed prior to liver transplantation for 14 patients. The median IgM antibody titers before and after apheresis for ABO blood type-incompatible liver transplantation was 128 and eight, respectively (P < 0.05). Eleven courses of apheresis and dialysis were performed post liver transplantation for 10 patients. The median PaO2/FiO2 ratio before and after dialysis for fluid overload was 159 and 339, respectively (P < 0.05). No bleeding or technical complications attributable to apheresis and dialysis occurred. The 1-year survival rate of the patients was 100%. Apheresis and dialysis in pediatric living donor liver transplantation are effective for antibody removal in ABO-incompatible liver transplantation, and fluid management for acute respiratory failure. PMID- 22817127 TI - Sarcomatoid carcinoma in the native kidney of a renal transplant recipient. PMID- 22817128 TI - Methoxy polyethylene glycol-epoetin beta (CERA) induced restless legs syndrome. PMID- 22817129 TI - Immunosuppressant and infliximab-resistant generalized pustular psoriasis successfully treated with granulocyte and monocyte adsorption apheresis. PMID- 22817132 TI - Good practice in postoperative and procedural pain management, 2nd edition. PMID- 22817133 TI - Accidental and experimentally induced 5-fluorouracil toxicity in dogs. AB - OBJECTIVE: To summarize the literature involving 5-fluorouracil (5-FU) toxicosis in dogs. ETIOLOGY: 5-Fluorouracil's mechanism of action revolves around the metabolism of 5-FU into fluorouridine triphosphate which then interferes with RNA synthesis and function as well as the inhibition of thymidylate synthase which ultimately impairs DNA stability. Toxicity of 5-FU is the most pronounced on rapidly dividing cells. Toxicity manifests itself mainly in the neurologic, gastrointestinal, respiratory, or hematopoietic systems. DIAGNOSIS: History of accidental exposure to 5-FU-containing products. THERAPY: Therapy for 5-FU toxicosis involves typical decontamination procedures and symptomatic therapy for the subsequent toxicity. Seizure control and treatment of the severe gastrointestinal signs that follow are the primary goals in the acute setting. As the disease progresses, management of the sequelae to bone marrow suppression and pulmonary complications are essential. PROGNOSIS: The prognosis for dogs with ingestion of 5-FU is dependent on the amount consumed, with severe intoxication carrying a poor prognosis. Toxic doses can be as little as 5 mg/kg, and doses >=40 mg/kg are reported to be uniformly fatal. PMID- 22817134 TI - New fluorescent and colorimetric probe for cyanide: direct reactivity, high selectivity, and bioimaging application. AB - Taking advantage of the special nucleophilicity of cyanide, a new ratiometric fluorescent and colorimetric probe (Coum-1) was designed by tuning the pi conjugated bridge to affect the intramolecular charge transfer efficiency. Upon the addition of CN(-) anion, the probe displayed very large blue-shift in both fluorescence (90 nm) and absorption (90 nm) spectra, with the detection limit of 800 nM. Other anions gave nearly no interference. Furthermore, Coum-1 was successfully applied to the fluorescent microscopic imaging for the detection of CN(-) in HeLa cells. PMID- 22817135 TI - UV/TiO2 photocatalytic degradation of xanthene dyes. AB - UV/titanium dioxide (TiO(2)) degradation of two xanthene dyes, erythrosine B (Ery) and eosin Y (Eos), was studied in a photocatalytic reactor. Photocatalysis was able to degrade 98% of Ery and 73% of Eos and led to 65% of chemical oxygen demand removal. Experiments in buffered solutions at different initial pH values reveal the pH dependence of the process, with better results obtained under acidic conditions due to the electrostatic attraction caused by the opposite charges of TiO(2) (positive) and of anionic dyes (negative). Batch activity tests under methanogenic conditions showed the high toxicity exerted by the dyes even at low concentrations (~85% with initial concentration of 0.3 mmol L(-1)), but the end products of photocatalytic treatment were much less toxic toward methanogenic bacteria, as detoxification of 85 +/- 5% for Eos and 64 +/- 7% for Ery were obtained. In contrast, the dyes had no inhibitory effect on the biogenic carbon biodegradation activity of aerobic biomass, obtained by respirometry. The results demonstrate that photocatalysis combining UV/TiO(2) as a pretreatment followed by an anaerobic biological process may be promising for the treatment of wastewaters produced by many industries. PMID- 22817136 TI - Anaphylaxis induced by ingestion of raw garlic. AB - Patients allergic to garlic often present dermatitis, rhinitis, asthma, and urticaria after ingestion of garlic, contact with garlic, or exposure to garlic dust. Garlic-related anaphylaxis is rare, and the impact of heating on garlic allergens is not very clear. We report a case of anaphylaxis induced by ingestion of raw rather than cooked garlic with manifestations different from previous reports, and we hypothesized that heating could reduce the allergenicity of garlic. Serum total immunoglobulin E (IgE) and specific IgE were tested using the Phadia CAP System FEIA (Phadia, Uppsala, Sweden). Protein extracts from raw and cooked garlic were analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. Serum-specific IgE for garlic was 8.16 kUA/L. IgE banding proteins could only be detected in raw garlic extract, because allergens in garlic were mostly degraded into small fragments after heating, as shown in SDS-PAGE profile. In conclusion, raw garlic could induce life-threatening anaphylaxis. However, most of its allergens are heat labile, and patients allergic to garlic might tolerate the cooked one well. PMID- 22817137 TI - Postprandial improvement in insulin sensitivity after a single exercise session in adolescents with low aerobic fitness and physical activity. AB - The purpose of this study was to determine the acute and residual impact of a single exercise bout on meal glucose control in adolescents with habitually low physical activity. Twelve adolescents (seven females/five males, 14 +/- 2 yr) completed three trials. One trial [No Exercise (No Ex)] was completed after refraining from vigorous activity for >= 3 d. On the other two trials, a 45-min aerobic exercise bout at 75% peak heart rate was performed either 17-h Prior Day Exercise (Prior Day Ex) trial or 1-h Same Day Exercise (Same Day Ex) trial before consuming the test meal (2803 kJ, 45/40/15% energy as carbohydrate/fat/protein, respectively). Compared to No Ex, insulin sensitivity (SI) (minimal model analysis) was increased by 45% (p < 0.03) and 78% (p < 0.01) on the Prior Day Ex and Same Day Ex trials, respectively. This improvement in glucose control was supported by corresponding reductions in the net area under the curve for glucose, insulin, and c-peptide, although there was no change in postprandial suppression of fatty acids. These results show that SI is improved with a single bout of moderate intensity exercise in adolescents with habitually low physical activity and that the residual beneficial effect of exercise lasts at least 17 h. This finding highlights the plasticity of exercise responses in youth and the importance of daily exercise for metabolic health. PMID- 22817138 TI - Cyber-support: an analysis of online self-help forums (online self-help forums in bipolar disorder). AB - BACKGROUND: The Internet is becoming increasingly important in psychiatry and psychotherapy. AIMS: The objective of this study was to evaluate if and how online self-help forums are used by patients with bipolar disorders, their relatives and treating professionals. METHODS: A total of 2400 postings in two online forums were analysed qualitatively and quantitatively. RESULTS: "Disclosure", "friendship" and "online-group cohesion" were the main self-help mechanisms. The topics most discussed were "social network", "symptoms of the illness" and "medication". Factor analyses revealed three factors concerning self help mechanisms: "group cohesion", "emotional support" and "exchange of information", as well as three factors concerning fields of interest: "illness related aspects", "social aspects" and "financial and legal issues". CONCLUSION: We infer that the main interest in participating in online forums for patients with bipolar disorders and their relatives is to share emotions and to discuss their daily struggles with the illness. Our study also reveals that social networking is very important for patients coping with bipolar disorders. Psycho educative programmes should focus on those aspects. PMID- 22817261 TI - No use for waist-for-height ratio in addition to body mass index to identify children with elevated blood pressure. AB - BACKGROUND: In children, waist-for-height ratio (WHtR) has been proposed to identify subjects at higher risk of cardiovascular diseases. The utility of WHtR to identify children with elevated blood pressure (BP) is unclear. Design. Cross sectional population-based study of schoolchildren. METHODS: Weight, height, waist circumference and BP were measured in all sixth-grade schoolchildren of the canton de Vaud (Switzerland) in 2005/06. WHtR was computed as waist [cm]/height [cm]. Elevated BP was defined according to sex-, age- and height-specific US reference data. The area under the receiver operating characteristic curve (AUC) statistic was computed to compare the ability of body mass index (BMI) z-score and WHtR, alone or in combination, to identify children with elevated BP. RESULTS: 5207 children participated (76% response) [2621 boys, 2586 girls; mean (+/- SD) age, 12.3 +/- 0.5 years; range: 10.1-14.9]. The prevalence of elevated BP was 11%. Mean WHtR was 0.44 +/- 0.05 (range: 0.29- 0.77) and 11% had high WHtR (> 0.5). BMI z-score and WHtR were strongly correlated (Spearman correlation coefficient r = 0.76). Both indices were positively associated with elevated BP. AUCs for elevated BP was relatively low for BMI z-score (0.62) or for WHtR (0.62), and was not substantially improved when both indices were considered together (0.63). CONCLUSIONS: The ability of BMI z-score or WHtR to identify children aged 10-14 with elevated BP was weak. Adding WHtR did not confer additional discriminative power to BMI alone. These findings do not support the measurement of WHtR in addition to BMI to identify children with elevated BP. PMID- 22817263 TI - Significant reduction of fluoroscopy in pediatric catheter ablation procedures: long-term experience from a single center. AB - BACKGROUND: Traditionally fluoroscopy has been used for navigation of catheters during electrophysiological procedures. Recent advances in electroanatomic mapping technologies resulted in a decrease and even in elimination of fluoroscopy exposure during these procedures. METHODS: Electrophysiological procedures were performed with the use EnSite NavXTM or VelocityTM (St. Jude Medical, St. Paul, MN, USA) systems. Following construction of the right atrial geometry, other relevant geometries were formed (right ventricle, coronary sinus, or left atrium). Fluoroscopy was used in patients with complex congenital heart disease, in younger children, and during transseptal punctures. Cryoablation or radiofrequency was used for catheter ablation. RESULTS: A total of 305 patients underwent catheter ablation for various supraventricular and ventricular tachyarrhythmia substrates using EnSite system guidance. No fluoroscopy was used in 191 (63%) of these cases. The mean fluoroscopy time in the rest of the procedures was 13.9 +/- 11.6 minutes (0.2-60 minutes). The mean procedure time was 184 +/- 71 minutes. No complications were noted except for temporary diaphragmatic paralysis in one patient and temporary AV block in another patient following cryoablation. Acute success rate in achieving complete elimination of arrhythmia substrates was 95% (290/305). The recurrence rate was (31/271) 11.4% at a mean follow-up time of 42 +/- 23 months. CONCLUSIONS: Fluoroscopy can be significantly decreased or even eliminated in the majority of catheter ablation procedures. Long-term results demonstrate that this can be done efficiently and safely. PMID- 22817262 TI - Quetiapine prevents oligodendrocyte and myelin loss and promotes maturation of oligodendrocyte progenitors in the hippocampus of global cerebral ischemia mice. AB - White matter impairment is a feature of vascular depression. The anti-psychotic quetiapine has been shown to enhance the therapeutic effects of anti-depressants on vascular depression, but the mechanism remains unknown. In this study, we found that 2 weeks of treatment with quetiapine prior to bilateral carotid artery occlusion and reperfusion, in an animal model of vascular depression, resulted in reduced myelin breakdown and oligodendrocyte loss compared to placebo-treated mice on post-operative day (POD) 7. For late stage of recovery (POD40), quetiapine treatment resulted in enhanced oligodendrocyte maturation relative to placebo. The results suggest that quetiapine is a potential intervention for oligodendrocyte damage and this may contribute to its anti-depressant effects through white matter protection in vascular depression. PMID- 22817264 TI - Electrophilic fluorination of organoplatinum(II) iodides: iodine and platinum atoms as competing fluorination sites. AB - A series of diphosphine Pt(II) aryl iodo complexes were reacted with XeF(2) to cleanly produce the corresponding Pt(II) difluoro complexes and free iodoarenes. However, when aryl ligands bearing fluoro substituents in the ortho positions were used, the formation of the corresponding Pt(II) aryl fluoro complexes was observed in the reaction with XeF(2). In the case of the Pt-C(6)F(5) complex, the products of the fluoride-for-iodide exchange were the only products observed by means of (31)P and (19)F NMR spectroscopy. The experimental and theoretical studies suggest that the formation of iodine-fluorine bond may accompany this transformation. The plausible "I-F" species could be trapped by electron-richer organoplatinum complexes to give a Pt(IV) transient which subsequently eliminates the corresponding aryl iodide. Hence, in some cases a pathway involving an attack of XeF(2) at the iodo ligand of Pt(II) aryl iodo complexes to generate I-F species can be operative in addition to or instead of the XeF(2) attack at the metal center. Our DFT studies demonstrate that the electrophilic attacks of XeF(2) at both sites, platinum and iodide, can be competitive. PMID- 22817265 TI - Identification of amino acid residues important for the function of Agrobacterium tumefaciens Irr protein. AB - The key amino acid residues that influence the function of the Agrobacterium tumefaciens iron response regulator protein (Irr(At) ) were investigated. Several Irr(At) mutant proteins containing substitutions in amino acids corresponding to candidate metal- and haem-binding sites were constructed. The ability of the mutant proteins to repress the promoter of the membrane bound ferritin (mbfA) gene was investigated using a promoter-lacZ fusion assay. A single mutation at residue H94 significantly decreased the repressive activity of Irr(At) . Multiple mutation analysis revealed the importance of H45, H65, the HHH motif (H92, H93 and H94) and H127 for the repressor function of Irr(At) . H94 is essential for the iron responsiveness of Irr(At) . Furthermore, the Irr(At) mutant proteins showed differential abilities to complement the H(2) O(2) -hyper-resistant phenotype of an irr mutant. PMID- 22817266 TI - Transient severe non-proliferative retinopathy in an adolescent with type 1 diabetes and chronic myeloid leukemia. AB - The onset of diabetic retinopathy correlates with the long-term quality of glycemic control. A 17-yr-old adolescent with type 1 diabetes presented unexpectedly with acute non-proliferative retinopathy despite good glycemic control. Two months later chronic myeloid leukemia (CML) was diagnosed. Chemotherapy was initiated and within a few weeks the patient was in full remission concerning leukemia. Retinopathy completely resolved within 8 months. The patient was in good metabolic control throughout the course. To our knowledge, this is the first report of CML-triggered retinopathy in a well controlled diabetic adolescent. In case of unexpected retinopathy in patients with type 1 diabetes, other potential causes of retinopathy should be considered. PMID- 22817267 TI - PAMAM dendrimer-baculovirus nanocomplex for microencapsulated adipose stem cell gene therapy: in vitro and in vivo functional assessment. AB - The present study aims to develop a new stem cell based gene delivery system consisting of human adipose tissue derived stem cells (hASCs) genetically modified with self-assembled nanocomplex of recombinant baculovirus and PAMAM dendrimer (Bac-PAMAM) to overexpress the vascular endothelial growth factor (VEGF). Cells were enveloped into branched PEG surface functionalized polymeric microcapsules for efficient transplantation. In vitro analysis confirmed efficient transduction of hASCs expressing 7.65 +/- 0.86 ng functionally active VEGF per 10(6) microencapsulated hASCs (ASC-VEGF). To determine the potential of the developed system, chronically infarcted rat hearts were treated with either empty microcapsules (MC), microencapsulated hASCs expressing MGFP reporter protein (MC+ASC-MGFP), or MC+ASC-VEGF, and analyzed for 10 weeks. Post transplantation data confirmed higher myocardial VEGF expressions with significantly enhanced neovasculature in the MC+ASC-VEGF group. In addition, the cardiac performance, as measured by percentage ejection fraction, also improved significantly in the MC+ASC-VEGF group (48.6 +/- 6.1%) compared to that in MC+ASC MGFP (38.8 +/- 5.3%) and MC groups (31.5 +/- 3.3%). Collectively, these data demonstrate the feasibility of this system for improved stem cell therapy applications. PMID- 22817268 TI - Physician perceptions of the role and value of basic science knowledge in daily clinical practice. AB - BACKGROUND: The role of basic science education in a clinical setting remains unclear. Research to understand how academic clinicians perceive and use this part of their education can aid curricular development. AIMS: To assess physician's attitudes toward the value of science knowledge in their clinical practice. METHODS: Academic physicians from three medical schools completed a questionnaire about the utility of basic science education in core clinical tasks and in practice-based learning and improvement. RESULTS: A total of 109 clinical faculty returned the survey. Overall, 89% of the respondents indicated that basic science education is valuable to their clinical practice. When asked about the utility of basic science information in relation to direct patient care, greater than 50% of the doctors felt they use this when diagnosing and communicating with patients. This rose to greater than 60% when asked about choosing treatment options for their patients. Individuals also responded that basic science knowledge is valuable when developing evidence-based best practices. Specifically, 89% felt that they draw upon this information when training students/residents and 84% use this information when reading journal articles. CONCLUSIONS: This study shows that basic science education is perceived by responding academic physicians to be important to their clinical work. PMID- 22817269 TI - Situational judgement tests for medical students: really the best way to determine your future? PMID- 22817270 TI - The normal-mode entropy in the MM/GBSA method: effect of system truncation, buffer region, and dielectric constant. AB - We have performed a systematic study of the entropy term in the MM/GBSA (molecular mechanics combined with generalized Born and surface-area solvation) approach to calculate ligand-binding affinities. The entropies are calculated by a normal-mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with distances larger than 8-16 A to the ligand, including a 4 A shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the whole protein within statistical uncertainty (1-2 kJ/mol). We have also tested to use a distance-dependent dielectric constant in the minimization and frequency calculation (epsilon = 4r), but it typically gives slightly different entropies and poorer binding affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 A) and epsilon =1. Such an approach also gives an improved precision for the calculated binding free energies. PMID- 22817271 TI - Incidence and causes of perioperative endotracheal reintubation in children: a review of 28,208 anesthetics. AB - OBJECTIVES/AIM: To determine the incidence, risk factors, and causes of endotracheal reintubation in children and identify methods to reduce the occurrence. BACKGROUND: Reintubation during the perioperative period is a serious and potentially preventable adverse event that can result in significant morbidity. METHODS: A total of 28,208 anesthetics were delivered to pediatric patients at our institution between May 2006 and May 2009. Reintubations were identified with our quality assurance (QA) surveillance database coupled with chart review by our QA nurse. Cases were classified as planned versus inadvertent extubations, and adverse events were assessed. RESULTS: We discovered 27 cases of reintubation with an incidence of 9.6 : 10,000 anesthetics. Reintubated patients were found to be younger than the general population (P = 0.001) with a high rate of comorbid disease. While most reintubations could be attributed to respiratory causes, 30% were attributed to inadvertent displacement of the endotracheal tube. No mortalities were seen, but 22% of patients needed resuscitative medications and 7% received chest compressions. Of the patients who failed planned extubations, 53% were left intubated with an average duration of postoperative intubation of 2.4 +/- 1.9 days. CONCLUSIONS: The incidence of endotracheal reintubation in children is low, but can result in significant morbidity. Because of the high frequency of inadvertent extubation, a significant number of reintubations could be prevented with greater care during transfer of patients with endotracheal tubes, and in procedures near the airway. Increased vigilance in younger children is also recommended as children under 3 years old required the majority of the reintubations. PMID- 22817272 TI - Genetic dissection of growth, wood basic density and gene expression in interspecific backcrosses of Eucalyptus grandis and E. urophylla. AB - BACKGROUND: F1 hybrid clones of Eucalyptus grandis and E. urophylla are widely grown for pulp and paper production in tropical and subtropical regions. Volume growth and wood quality are priority objectives in Eucalyptus tree improvement. The molecular basis of quantitative variation and trait expression in eucalypt hybrids, however, remains largely unknown. The recent availability of a draft genome sequence (http://www.phytozome.net) and genome-wide genotyping platforms, combined with high levels of genetic variation and high linkage disequilibrium in hybrid crosses, greatly facilitate the detection of quantitative trait loci (QTLs) as well as underlying candidate genes for growth and wood property traits. In this study, we used Diversity Arrays Technology markers to assess the genetic architecture of volume growth (diameter at breast height, DBH) and wood basic density in four-year-old progeny of an interspecific backcross pedigree of E. grandis and E. urophylla. In addition, we used Illumina RNA-Seq expression profiling in the E. urophylla backcross family to identify cis- and trans-acting polymorphisms (eQTLs) affecting transcript abundance of genes underlying QTLs for wood basic density. RESULTS: A total of five QTLs for DBH and 12 for wood basic density were identified in the two backcross families. Individual QTLs for DBH and wood basic density explained 3.1 to 12.2% of phenotypic variation. Candidate genes underlying QTLs for wood basic density on linkage groups 8 and 9 were found to share trans-acting eQTLs located on linkage groups 4 and 10, which in turn coincided with QTLs for wood basic density suggesting that these QTLs represent segregating components of an underlying transcriptional network. CONCLUSION: This is the first demonstration of the use of next-generation expression profiling to quantify transcript abundance in a segregating tree population and identify candidate genes potentially affecting wood property variation. The QTLs identified in this study provide a resource for identifying candidate genes and developing molecular markers for marker-assisted breeding of volume growth and wood basic density. Our results suggest that integrated analysis of transcript and trait variation in eucalypt hybrids can be used to dissect the molecular basis of quantitative variation in wood property traits. PMID- 22817273 TI - Costing a pilot complex community-based childhood obesity intervention. AB - BACKGROUND: Childhood obesity has significant impact on future health and economic consequences. Evidence of effectiveness of interventions is developing, although little is known about costs. Therefore, the direct costs to health care and other public sector agencies of a pilot community-based childhood obesity treatment programme were estimated. METHODS: The present study comprised a retrospective review of resource use of an intervention drawing resources from local government and primary care sectors and delivered across multiple settings. Ninety-six children, aged 8-16 years old; body mass index (BMI) >98th centile; mean BMI SD 3.1 and low quality of life scores attended a 12-month programme delivered by nonhealth professionals. Direct costs to health care and other public sector agencies were assessed. RESULTS: Total programme direct costs were L82,380 (?94,736, $123,569) in the base case or L120,474 (?138,546, $180,713) when venues were treated as real additional costs, and varied only slightly with the number of participants in the programme. Costs per participant were L858 (?987, $1287) in the base case or L1255 (?1443, $1883) when venues were treated as additional costs. Costs per participant were sensitive to the number of participants, varying between L691 (?795, $1037) and L2026 (?2330, $3039) when venue costs were zero and between L1009 (?1160, $1514) and L2978 (?3425, $4467) with venue costs added. CONCLUSIONS: It is possible to provide a community-based service at reasonable cost, and probably less than for health professional delivered services. Further work is required to assess the possible effects of the programme on wider service resource use, on users' costs and on programme effectiveness. PMID- 22817274 TI - Decongestion improves cell-mediated immunity in postmastectomy arm lymphoedema: a pilot study. AB - BACKGROUND: Chronic lymphoedematous limbs have an increased propensity for infections and primary or secondary malignant tumours. It has been attributed to suppressed delayed-type hypersensitivity measured in lymphoedemas related to Stewart-Treves syndrome, Kaposi's sarcoma or breast cancer treatment. Cell mediated immunity is an effective defence mechanism against bacteria, fungi, viruses and tumour cells. OBJECTIVE: We aimed to examine whether decongestive lymphoedema therapy could improve cell-mediated immunity in breast cancer treatment-related lymphoedema (BCRL). METHODS: Eight women with unilateral BCRL were included in this study. At baseline, tuberculin skin test (TST) was performed on the volar surfaces of the forearms of the affected and non-affected sides using 0.5, 1 and 5 tuberculin units in the form of three consecutive injections with 3-cm spaces in-between, and arm volumes were measured using the Kuhnke's disc model. Decongestive lymphatic therapy was given to swollen arms in 10 consecutive working days. At the end of intensive decongestion, TST on affected side and bilateral volumetry were repeated. RESULTS: Baseline test using undiluted (5 units) and fivefold diluted (1 unit) tuberculin solutions has shown significant differences (P < 0.05) between the mean sizes (11.81 +/- 2.32 and 7.75 +/- 1.92; 7.12 +/- 1.12 and 5.12 +/- 0.91 respectively) in favour to healthy arms. Post therapeutically, the mean sizes were significantly increased (P < 0.05) in the dilutions of 1 : 1 and 1 : 5 (7.75 +/- 1.92 and 10.56 +/- 1.23 mm, 5.12 +/- 0.91 and 5.93 +/- 1.74 mm respectively). CONCLUSION: Significant increase in TST sizes suggests that decongestive lymphatic therapy is able to partially restore impaired cellular immune function in BCRL. PMID- 22817275 TI - Residual risk of transfusion-transmitted infection with human immunodeficiency virus, hepatitis C virus, and hepatitis B virus in Korea from 2000 through 2010. AB - BACKGROUND: Despite screening blood donations with advanced technologies and improved donor screening, the risk of transfusion-transmitted infections persists. This risk is mainly due to blood donations collected during the window period. A precise estimate of the transfusion risk of viral infection will help to determine the effect of new and current safety measures and to prioritize and allocate limited resources. Therefore, we estimated the risk of transfusion transmitted viral infection in blood donations collected in Korea from 2000 to 2010. METHODS: Blood donations collected at 16 blood centers were tested for HIV, HCV, and HBV to estimate the residual risk of transfusion-transmitted viral infection. The residual risk was calculated in two-year periods using the incidence/window model. The incidence rates for HIV/HCV and the confirmed positive rate for HIV/HCV in first-time and repeat donors were compared. RESULTS: The residual risks for HIV in 2004/2005 and 2009/2010 were 1 in 1,080,244 and 1 in 1,356,547, respectively. The risks for HCV in 2000/2001 and 2009/2010 were 1 in 81,431 and 1 in 2,984,415, and the risks for HBV in 2000/2001 and 2009/2010 were 1 in 45,891 and 1 in 43,666. These estimates indicate that the residual risks for HCV in Korea have declined 36.6-fold, and those for HIV and HBV have not improved significantly, compared to previous estimates. The odds ratios for HCV and HBV positivity in first-time donors compared to repeat donors were 11.8 and 19.6, respectively. CONCLUSIONS: The residual risk of HCV declined over the last decade due to improved screening reagents, implementation of the nucleic acid amplification test, and tight application of strict donor selection procedures. Current residual risk estimates for HIV and HCV in Korea are extremely low, but the risk for HBV is still high; therefore, urgent measures should focus on decreasing the residual risk of HBV. Despite the introduction of more sensitive assays in blood screening, several other factors may influence the actual residual risk of transfusion-transmitted infection. A continuous monitoring of residual risk of transfusion-transmitted infection is crucial in managing blood safety. PMID- 22817276 TI - Tornadoes, sepsis, and goal-directed therapy in dogs. PMID- 22817277 TI - Theoretical prediction of spin-crossover temperatures in ligand-driven light induced spin change systems. AB - Spin-crossover compounds exhibit two alternative spin states with distinctive chemical and physical properties, a particular feature that makes them promising materials for nanotechnological applications as memory or display devices. A key parameter that characterizes these compounds is the spin-crossover temperature, T(1/2), defined as the temperature with equal populations of high and low-spin species. In this study, a theoretical/computational approach is described for the calculation of T(1/2) for the trans-[Fe(styrylpyridine)(4)(NCX)(2)] (X = S, Se, and BH(3), styrylpyridine in the trans configuration) ligand driven light-induced spin change (LD-LISC) complexes. In all cases, the present calculations provide an accurate description of both structural and electronic properties of the LD LISC complexes and, importantly, predict spin-crossover temperatures in good agreement with the corresponding experimental data. Fundamental insights into the dependence of T(1/2) on the nature of the axial ligands are obtained from the direct analysis of the underlying electronic structure in terms of the relevant molecular orbitals. PMID- 22817278 TI - Field-effect transistors based on silicon nanowire arrays: effect of the good and the bad silicon nanowires. AB - Aligned arrays of silicon nanowires (aa-Si NWs) allow the exploitation of Si NWs in a scalable way. Previous studies explored the influence of the Si NWs' number, doping density, and diameter on the related electrical performance. Nevertheless, the origin of the observed effects still not fully understood. Here, we aim to provide an understanding on the effect of channel number on the fundamental parameters of aa-Si NW field effect transistors (FETs). Toward this end, we have fabricated and characterized 87 FET devices with varied number of Si NWs, which were grown by chemical vapor deposition with gold catalyst. The results show that FETs with Si NWs above a threshold number (n > 80) exhibit better device uniformity, but generally lower device performance, than FETs with lower number of Si NWs (3 <= n < 80). Complementary analysis indicates that the obtained discrepancies could be explained by a weighted contribution of two main groups of Si NWs: (i) a group of gold-free Si NWs that exhibit high and uniform electrical characteristics; and (ii) a group of gold-doped Si NWs that exhibit inferior electrical characteristics. These findings are validated by a binomial model that consider the aa-Si NW FETs via a weighted combination of FETs of individual Si NWs. Overall, the obtained results suggest that the criterions used currently for evaluating the device performance (e.g., uniform diameter, length, and shape of Si NWs) do not necessarily guarantee uniform or satisfying electrical characteristics, raising the need for new growth processes and/or advanced sorting techniques of electrically homogeneous Si NWs. PMID- 22817279 TI - Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? AB - Oxidative stress has long been linked to neuronal cell death that is associated with certain neurodegenerative conditions. Whether it is a primary cause or merely a downstream consequence of the neurodegenerative and aging process is still an open question. Mitochondria are deeply involved in the production of reactive oxygen species through the electron carriers of the respiratory chain and their role in neurodegenerative diseases is discussed here. Moreover, the input of new technological approaches in the study of oxidative stress response or in the evidence of an oxidative stress component in neurodegeneration is reviewed in this paper. PMID- 22817280 TI - Preparation of new magnetic nanocatalysts based on TiO2 and ZnO and their application in improved photocatalytic degradation of dye pollutant under visible light. AB - Photocatalytic degradation of methyl orange (MO) as a model of an organic pollution was accomplished with magnetic and porous TiO(2)/ZnO/Fe(3)O(4)/PANI and ZnO/Fe(3)O(4)/PANI nanocomposites under visible light irradiation. The structures of nanocomposites were characterized by various techniques including UV-Vis absorption spectroscopy, XRD, SEM, EDS, BET and TGA. Optical absorption investigations show two lambda(max) at 450 and 590 nm for TiO(2)/ZnO/Fe(3)O(4)/PANI nanocomposites respectively possessing optical band gaps about 2.75 and 2.1 eV smaller than that of the neat TiO(2) and ZnO nanoparticles. Due to these optical absorptions, the nanocomposites can be considered promising candidates as visible light photocatalysts to produce more electron-hole pairs. The degradation of MO, extremely increased using polymeric photocatalysts and decolorization in the presence of visible light achieved up to 90% in less than 20 min in comparison with the neat nanoparticles (about 10%). All these advantages promise a bright future for these composites as useful photocatalysts. The degradation efficiency of MO using stable nanocomposites was still over 70% after ten times reusing. The highest decolorizing efficiencies were achieved with 0.75 g L(-1) of catalyst and 10 mg L(-1) of MO at natural pH under visible light irradiation in less than 20 min. PMID- 22817281 TI - Limitation of pro- and anti-inflammatory cytokine analysis to discriminate biological stress effects in patients suffering from chronic psychological distress. AB - BACKGROUND: Research endeavors aiming to evaluate the effect of prolonged psychological distress on the immune system have been pursed over the past decades. Due to the complexity of the two systems involved, the mental and immune status, a large number of questions still remains to be addressed. AIM: In the present study, we aimed to test if chronic distress is associated with pro- and anti-inflammatory cytokine levels in a well-defined study cohort. METHODS: We recruited 42 inpatients suffering from post-traumatic embitterment disorder (PTED), a condition that has been demonstrated to cause intense and persistent psychological distress. Study participants completed established questionnaires to evaluate stress perception, depression and quality of life before and after psychotherapy, aiming to improve stress coping. Venous blood samples to detect serum levels of pro- and anti-inflammatory cytokines [interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma] were obtained pre- and post-treatment. RESULTS: The psychological assessments showed an increase of quality of life, a decrease of perceived stress and depressive symptoms, between the two groups. These findings are not associated with significant alterations of the cytokine levels before and after treatment. CONCLUSIONS: In our study, the psychological treatment of inpatients suffering from chronic psychological distress does not result in changes in cytokine levels. Further research with a broader analysis of immune markers and enhanced detection methods may be required to unveil psycho-immunological association in PTED patients. PMID- 22817282 TI - Changes in oxidative stress in renal graft patients receiving calcineurin inhibitors: cyclosporine versus tacrolimus. AB - OBJECTIVES: The effects of calcineurin inhibitors on oxidative stress after renal transplant are obscure. This study sought to investigate the changes in plasma oxidative stress and lipid levels in patients receiving cyclosporine or tacrolimus before and after renal transplant for 6 months. MATERIALS AND METHODS: Twenty-one patients and 15 healthy controls were involved in our study. Twelve of the patients were treated with cyclosporine and 9 were treated with tacrolimus. Plasma malondialdehyde, nitrite/nitrate, vitamin C, vitamin E, and plasma glutathione levels, as well as total cholesterol and triglyceride levels, were evaluated before and after transplant for 6 months. RESULTS: Before the transplant, patients had higher malondialdehyde and plasma glutathione levels than did healthy controls (3.76 +/- 0.79 nmol/mL vs 3.21 +/- 0.57 nmol/mL; P < .05, and 66.6 +/- 23.2 MUmol/L vs 43.3 +/- 26.9 MUmol/L; P < .05). In the overall group of patients, a significant increase in malondialdehyde levels was detected 3 and 6 months after transplant (3.76 +/- 0.79 nmol/mL vs 4.38 +/- 0.87 nmol/mL in the third month; P = .02; and 3.76 +/- 0.79 nmol/mL vs 4.28 +/- 0.69 nmol/mL in the sixth month; P = .04). A significant reduction in plasma glutathione levels 1 month after transplant and nitrite/nitrate levels 6 months after transplant was found. No changes in vitamin C and vitamin E levels were detected before and after transplant. After 3 and 6 months of transplant, cyclosporine treated patients had higher levels of total cholesterol and triglycerides when compared with tacrolimus-treated patients. CONCLUSIONS: An enhancement in plasma malondialdehyde levels was found after transplant at 6-month follow-up. However, no significant change in vitamin C, vitamin E, nitrite/nitrate levels between patients and controls was recorded. Although both calcineurin inhibitors showed similar effects on oxidative stress, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides. PMID- 22817283 TI - Phrenic nerve pacing during atrial ablation: a stimulus plan that works. PMID- 22817323 TI - Facilitating medical students to undertake research. PMID- 22817324 TI - Age-related modulation of gamma-secretase activity in non-human primate brains. AB - Age-dependent accumulation of the amyloid-beta peptide (Abeta) in the brain is a pre-condition for development of Alzheimer's disease. A relative increase in the generation of longer Abeta species such as Abeta42 and Abeta43 is critical for Abeta deposition, but the underlying mechanism remains unresolved. Here, we performed a cell-free assay using microsome fractions of temporal cortex tissues from 42 cynomolgus monkeys and found that Abeta40-generating gamma-secretase activity (gamma40) decreased with age, whereas Abeta42-generating gamma-secretase activity (gamma42) was unaltered. In ELISAs, more than 80% of monkeys over 20 years old showed evidence of Abeta accumulation in the temporal cortex. The ratio of gamma42 to gamma40 increased with age and correlated with the level of accumulated Abeta. These results suggest that gamma-secretase activity undergoes age-related, non-genetic modulation and that this modulation may cause Abeta accumulation in aging brains. Similar modulation may predispose aged human brains to Alzheimer's disease. PMID- 22817325 TI - A mononuclear Fe(III) single molecule magnet with a 3/2<->5/2 spin crossover. AB - The air stable complex [(PNP)FeCl(2)] (1) (PNP = N[2-P(CHMe(2))(2)-4 methylphenyl](2)(-)), prepared from one-electron oxidation of [(PNP)FeCl] with ClCPh(3), displays an unexpected S = 3/2 to S = 5/2 transition above 80 K as inferred by the dc SQUID magnetic susceptibility measurement. The ac SQUID magnetization data, at zero field and between frequencies 10 and 1042 Hz, clearly reveal complex 1 to have frequency dependence on the out-of-phase signal and thus being a single molecular magnet with a thermally activated barrier of U(eff) = 32 36 cm(-1) (47-52 K). Variable-temperature Mossbauer data also corroborate a significant temperature dependence in delta and DeltaE(Q) values for 1, which is in agreement with the system undergoing a change in spin state. Likewise, variable-temperature X-band EPR spectra of 1 reveals the S = 3/2 to be likely the ground state with the S = 5/2 being close in energy. Multiedge XAS absorption spectra suggest the electronic structure of 1 to be highly covalent with an effective iron oxidation state that is more reduced than the typical ferric complexes due to the significant interaction of the phosphine groups in PNP and Cl ligands with iron. A variable-temperature single crystal X-ray diffraction study of 1 collected between 30 and 300 K also reveals elongation of the Fe-P bond lengths and increment in the Cl-Fe-Cl angle as the S = 5/2 state is populated. Theoretical studies show overall similar orbital pictures except for the d(z(2)) orbital, which has the most sensitivity to change in the geometry and bonding, where the quartet ((4)B) and the sextet ((6)A) states are close in energy. PMID- 22817327 TI - Patient education on the benefit and risks of medications goes beyond metformin. PMID- 22817326 TI - Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions. AB - In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance. PMID- 22817328 TI - Association of 1936A > G in AKAP10 (A-kinase anchoring protein 10) and blood pressure in Polish full-term newborns. AB - OBJECTIVE: The 1936G AKAP10 allele is associated with increased adult basal heart rate (HR) and decreased variability, markers of low cholinergic/vagus sensitivity associated with hypertension. Blood pressure (BP) values in newborns are important measurable markers of cardiovascular risk later in life. The question was whether decreased vagal function-related 1936A > G AKAP10 is associated with newborn BP. STUDY DESIGN: 114 healthy Polish newborns born after 37th gestational week to healthy women with uncomplicated pregnancies. At birth, newborn cord blood obtained for isolation of genomic DNA. BP and HR measured on days 1 and 3 after delivery. RESULTS: Diastolic BP on day 3 and absolute and relative differences between diastolic BP values, as well as between mean BP values on day 3 and on day 1 after birth, in carriers of 1936G AKAP10 allele, were significantly higher as compared with wild-type homozygotes. CONCLUSION: Results demonstrate possible association between 1936G AKAP10 variant and BP in Polish newborns. PMID- 22817329 TI - Insight into the dynamics of lanthanide-DTPA complexes as revealed by oxygen-17 NMR. AB - DTPA chelates of various diamagnetic and paramagnetic lanthanide(III) metal ions, as well as the chemically similar DTPA chelate of Y(3+), were studied in aqueous solution by variable temperature (17)O NMR with the aim of characterizing their internal dynamics. As a consequence of poor chemical shift dispersion and fast quadrupole relaxation, no dynamic exchange process could be detected for the diamagnetic complexes nor for the Sm-DTPA complex. In contrast, the spectra recorded for the Eu-DTPA complex show chemical exchange due to the well-known racemization process and, at high temperature, feature signal broadening that reveals a fluxional process involving the interchange of the coordinated and noncoordinated oxygen atoms of the carboxylate groups. The spectra recorded for the Pr-DTPA complex feature coalescence events due to such a fluxional process, which is ascribable to the rotation of the carboxylate groups. The activation free energy barriers determined experimentally are remarkably lower than the calculated activation barriers recently reported for the rotation of the carboxylate groups of various Ln-DOTA complexes. Furthermore, the smallest activation free energy measured for the Pr-DTPA complex, about 45 kJ mol(-1), is significantly lower than the activation free energy characterizing the racemization process. The fluxional behavior of the carboxylate groups is, however, not expected to significantly affect the residence time of the water molecule coordinated to the metal ion. PMID- 22817331 TI - The role of oxygen-associated therapies for the healing of chronic wounds, particularly in patients with diabetes. AB - This paper discusses the role of molecular oxygen as an aid to wound healing, and the potential value of the three major therapies which allow the delivery of oxygen to the wound site: Hyperbaric Oxygen Therapy (HBOT), Topical Oxygen Therapy (TOT) and a new sterile wound dressing, OxyzymeTM. We summarize studies which have been undertaken using these interventions, and discuss their reported effect on chronic, non-healing wounds, in particular, on ulcers associated with Diabetes. The main conclusions drawn from the studies reviewed indicate that therapeutic oxygen can be used as an aid to the healing of chronic wounds; and benefits are clearly evident with the use of both HBOT and TOT. There is also potential for the use of a new, portable, topical oxygen delivery system, oxyzyme. However its use is still embryonic and studies on its effectiveness are limited. More robust measures of its efficacy are urgently needed. PMID- 22817330 TI - AB-QTL analysis reveals new alleles associated to proline accumulation and leaf wilting under drought stress conditions in barley (Hordeum vulgare L.). AB - BACKGROUND: Land plants have evolved several measures to maintain their life against abiotic stresses. The accumulation of proline is the most generalized response of plants under drought, heat or salt stress conditions. It is known as an osmoprotectant which also acts as an instant source of energy during drought recovery process. But, both its role and genetic inheritance are poorly understood in agriculture crops. In the present work, advanced backcross quantitative trait locus (AB-QTL) analysis was performed to elucidate genetic mechanisms controlling proline accumulation and leaf wilting in barley under drought stress conditions. RESULTS: The analysis revealed eight QTL associated to proline content (PC) and leaf wilting (WS). QTL for PC were localized on chromosome 3H, 4H, 5H and 6H. The strongest QTL effect QPC.S42.5H was detected on chromosome 5H where drought inducible exotic allele was associated to increase PC by 54%. QTL effects QPC.S42.3H, QPC.S42.4H and QPC.S42.6H were responsible to heighten PC due to the preeminence of elite alleles over the exotic alleles which ranged from 26% to 43%. For WS, QTL have been localized on chromosome 1H, 2H, 3H and 4H. Among these, QWS.S42.1H and QWS.S42.4H were associated to decrease in WS due to the introgression of exotic alleles. In addition, two digenic epistatic interaction effects were detected for WS where the additive effect of exotic alleles imparted a favorable increase in the trait value. CONCLUSIONS: The present data represents a first report on whole-genome mapping of proline accumulation and leaf wilting in barley. The detected QTL are linked to new alleles from both cultivated and wild accessions which bring out an initial insight on the genetic inheritance of PC and WS. These QTL alleles are fixed in the isogenic background of Scarlett, which will allow for positional cloning of underlying genes and to develop drought resilient barley cultivars. PMID- 22817332 TI - Series of new D-A-pi-A organic broadly absorbing sensitizers containing isoindigo unit for highly efficient dye-sensitized solar cells. AB - In this work, six new D-A-pi-A sensitizers (ID1-ID6), with triarylamine as the electron donor; isoindigo as a auxiliary electron withdrawing unit; thiophene, furan, and benzene as the linker; and cyanoacrylic acid as the anchoring group, were synthesized through simple synthetic procedures and with low cost. Their absorption spectra were broad with long wavelength absorption maximum approximately at 589 nm and the absorption onset at 720 nm on the TiO(2) film. Electrochemical experiments indicate that the HOMO and LUMO energy levels can be conveniently tuned by alternating the donor moiety and the linker. All of these dyes performed as sensitizers for the DSSCs test under AM 1.5 similar experimental conditions, and a maximum overall conversion efficiency of 5.98% (J(sc) = 14.77 mA cm(-2), V(oc) = 644 mV, ff = 0.63) is obtained for ID6-based DSSCs when TiO(2) films were first immersed for 6 h in 20 mM CDCA ethanol solution followed by 12 h of dipping in the dye CH(2)Cl(2) solution. Electrochemical impedance measurement data implies that the electron lifetime can be increased by coadsorption of CDCA, which leads to a lower rate of charge recombination and thus improved V(oc). PMID- 22817333 TI - Hydroxyurea is associated with reductions in hypercoagulability markers in sickle cell anemia. PMID- 22817334 TI - Clinical judgment in psychiatry. Requiem or reveille? AB - BACKGROUND: There is increasing awareness of a crisis in psychiatric research and practice. Psychopathology and clinical judgment are often discarded as non scientific and obsolete methods. Yet, in their everyday practice, psychiatrists use observation, description and classification, test explanatory hypotheses, and formulate clinical decisions. AIM: The aim of this review was to examine the clinical judgment in psychiatry, with special reference to clinimetrics, a domain concerned with the measurement of clinical phenomena that do not find room in customary taxonomy. METHODS: A MEDLINE search from inception to August 2011 using the keywords "clinical judgment" and "clinimetric" in relation to psychiatric illness for articles in English language was performed. It was supplemented by a manual search of the literature. Choice of items was based on their established or potential incremental increase in clinical information compared with use of standard diagnostic criteria. The most representative examples were selected. RESULTS: Research on clinical judgment has disclosed several innovative assessment strategies: the use of diagnostic transfer stations instead of diagnostic endpoints using repeated assessments, subtyping versus integration of different diagnostic categories, staging, macro-analysis, extension of clinical information beyond symptomatic features. Evidence-based medicine does not appear to provide an adequate scientific background for challenges of clinical practice in psychiatry and needs to be integrated with clinical judgment. CONCLUSIONS. A renewed interest in clinical judgment may yield substantial advances in clinical assessment and treatment. A different clinical psychiatry is available and can be practiced now. PMID- 22817335 TI - Iron induces hepatocytes death via MAPK activation and mitochondria-dependent apoptotic pathway: beneficial role of glycine. AB - In the present study we investigated the beneficial role of glycine in iron (FeSO4) induced oxidative damage in murine hepatocytes. Exposure of hepatocytes to 20 MUM FeSO4 for 3 hours enhanced reactive oxygen species (ROS) generation and induced alteration in biochemical parameters related to hepatic oxidative stress. Investigating cell signalling pathway, we observed that iron (FeSO4) intoxication caused NF-kappaB activation as well as the phosphorylation of p38 and ERK MAPKs. Iron (FeSO4) administration also disrupted Bcl-2/Bad protein balance, reduced mitochondrial membrane potential, released cytochrome c and induced the activation of caspases and cleavage of PARP protein. Flow cytometric analysis also confirmed that iron (FeSO4) induced hepatocytes death is apoptotic in nature. Glycine (10 mM) supplementation, on the other hand, reduced all the iron (FeSO4) induced apoptotic indices. Combining, results suggest that glycine could be a beneficial agent against iron mediated toxicity in hepatocytes. PMID- 22817336 TI - Osteomyelitis of a long bone due to Fusobacterium nucleatum and Actinomyces meyeri in an immunocompetent adult: a case report and literature review. AB - BACKGROUND: Fusobacterium species are uncommon causes of osteomyelitis. These organisms are normal flora of the oral cavity. Therefore, they mostly cause osteomyelitis of the head and neck. Hematogenous osteomyelitis at distant sites other than the head and neck has rarely been reported in pediatric or immunocompromised patients. Here, we report the first case of osteomyelitis of a long bone combined with a muscle abscess due to Fusobacterium nucleatum in an otherwise healthy adult. CASE PRESENTATION: A 59-year-old Korean man was admitted for pain and swelling of the right lower leg, which had been persistent for two weeks. Magnetic resonance imaging showed osteomyelitis of the right fibula with a surrounding muscle abscess of the right lower leg. Incision and drainage was performed, and repetitive tissue cultures grew F. nucleatum. In this patient, it was presumed that recurrent periodontitis caused hematogenous seeding of F. nucleatum to a distant site leading to osteomyelitis with a muscle abscess. The patient was successfully treated with intravenous ampicillin-sulbactam for three weeks and oral amoxicillin-clavulanate for eight weeks. He also underwent repeated surgical drainage. He has no evidence of recurrence after seven months of follow-up. CONCLUSIONS: Clinicians should be aware that F. nucleatum could be the etiologic agent of hematogenous osteomyelitis of a long bone in an immunocompetent patient. PMID- 22817337 TI - Effects of oat beta-glucan on the macrophage cytokine response to herpes simplex virus 1 infection in vitro. AB - Oat beta-glucan can counteract the increased risk for Herpes Simplex Virus 1 (HSV 1) infection in mice, the effects of which have, at least in part, been attributed to macrophages. However, the specific responses of macrophages to oat beta-glucan treatment in this model have yet to be elucidated. We examined the effects of varying doses of oat beta-glucan on the pro-inflammatory cytokine response in both peritoneal and lung macrophages with and without exposure to HSV 1 infection in vitro. Peritoneal and lung macrophages were obtained from mice and cultured with varying concentrations of oat beta-glucan (0 (control), 10, 100, and 1,000 MUg) for 24 h and supernatants were collected. A standardized dose of HSV-1 was added for a second 24 h incubation period after which supernatants were again collected. Samples were analyzed for interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) using enzyme linked immunosorbent assay (ELISA). In most cases, oat beta-glucan resulted in a dose-dependent increase in pro-inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) in lung and peritoneal macrophages with and without exposure to HSV-1 infection. When comparing across macrophage source, this response was greater for IL-1beta and IL 6 in peritoneal macrophages and for TNF-alpha in lung macrophages. This may be a mechanism for the decreased risk for HSV-1 infection following oat beta-glucan feedings in mice. PMID- 22817338 TI - A prospective observational quality improvement study of the sustained effects of a program to reduce unplanned extubations in a pediatric intensive care unit. AB - BACKGROUND: The use of endotracheal intubation is routine in the care of critically ill children. Unplanned extubation exposes the patient to morbidity and mortality over and above that associated with the patient's underlying disease. All unplanned extubations are unacceptable because of their potential for causing unnecessary harm to the patient. OBJECTIVE: To prospectively determine whether a quality improvement program adopted 9 years ago has continued to be successful in maintaining a low rate of unplanned extubation in our pediatric intensive care unit (PICU). DESIGN: Prospective, observational study. SETTING: 10-bed PICU in an urban, county, teaching hospital. PATIENTS: All intubated pediatric patients in the PICU from February 15, 2009 to February 14, 2010. INTERVENTION: None. MEASUREMENTS AND RESULTS: Prior to the implementation of the program in 2000, our PICU had an unplanned extubation rate of 6.4 unplanned extubations per 100 ventilated days. After implementation of the quality improvement program, the rate of unplanned extubation decreased to 1.0 unplanned extubation per 100 ventilated days. In this study, we reevaluated the unplanned extubation rate 9 years after the implementation of the quality improvement program. We found that the rate had remained unchanged (P > 0.05): 1.5 unplanned extubations per 100 ventilated days as compared to 1.0 unplanned extubation per 100 ventilated days. There were no significant differences (P > 0.05) in age, weight, endotracheal tube size, duration of intubation or rate of unplanned extubation. LIMITATIONS: In this study, no randomization took place, in which one group was not subject to the quality improvement program. We did not account for potential changes in severity of illness or staffing issues. CONCLUSIONS: In the 9 years since implementation, our program has remained successful in decreasing unplanned extubations. It is important to periodically reevaluate quality improvement programs to determine whether they have continued to achieve their intended goals. The initiative is reported here using the Standards for Quality Improvement Reporting Excellence (SQUIRE). PMID- 22817339 TI - Method for assessing IFN-gamma responses in guinea pigs during TB vaccine trials. AB - AIMS: We sought to develop a new method that enables the assessment of the immune response of guinea pigs during TB vaccine evaluation studies, without the need to cull or anaesthetize animals. METHOD AND RESULTS: Guinea pigs were vaccinated with five different formulations of oral BCG. One week prior to challenge with Mycobacterium bovis, blood (50-200 MUl) was taken from the ears of vaccinated subjects. Host RNA was isolated and amplified following antigenic restimulation of PBMCs for 24 h with 30 MUg of bovine PPD. The up- or down-regulation of gamma interferon (IFN-gamma), a key cytokine involved in protection against tuberculosis, was assessed using real-time PCR. The relative expression of prechallenge IFN-gamma mRNA in the vaccinated groups (n=5) correlated (P<0.001) with protection against M. bovis challenge. CONCLUSION: We have demonstrated that it is possible to take blood samples and track IFN-gamma responses in guinea pigs that then go on to be exposed to M. bovis, thus providing prechallenge vaccine uptake information. SIGNIFICANCE AND IMPACT OF THE STUDY: This methodology will also be applicable for tracking the immune responses of vaccinated guinea pigs over time that then go on to be challenged with M. tuberculosis during human TB vaccine evaluation studies. PMID- 22817340 TI - Evaluation of a portable ambulatory prototype for automated overnight closed-loop insulin delivery in young people with type 1 diabetes. AB - OBJECTIVE: To evaluate an ambulatory, portable prototype, overnight automated closed-loop (CL) system and to explore optimal time of CL initiation. METHODS: We performed a randomized crossover study and compared automated overnight glucose control started at the time of an evening-meal or at bedtime. Eight young people with type 1 diabetes (T1D) on insulin pump therapy [M = 4; age = 14.3 (1.7) yr; HbA1c = 8.2 (1.3)%; mean (SD)] were studied on two occasions at clinical research facility. A standardized self-selected evening meal [70 (11)g CHO] and snack [22 (4)g CHO] accompanied by prandial insulin boluses were given at 18:00 and 21:00 hours, respectively. In random order, automated CL was started at 18:00 or 21:00 hours and ran until 8:00 hours the next day. Basal insulin delivery was automatically adjusted by a model predictive control algorithm based on real-time continuous glucose monitor readings. RESULTS: Overnight plasma glucose levels (between 21:00 and 08:00 hours) were within the target range (71-145 mg/dL) for 82 (59, 98)% of time when CL started at 18:00 hours and 64 (48, 70)% when CL started at 21:00 hours [median (IQR), p = 0.036]. Time spent above 180 mg/dL [8 (0, 17) vs. 13 (3, 26)%, p = 0.310] or below 70 mg/dL [0 (0,7) vs. 0 (0, 8)%, p = 1.000] did not differ between the two occasions. Mean overnight glucose [121 (14) vs. 137 (13) mg/dL, p = 0.731) was also similar. Overnight insulin infusion rates were comparable [0.8 (0.5, 1.3) vs. 0.8 (0.6, 1.4) U/h, p = 0.263]. No interruptions to CL delivery were observed. CONCLUSION: Automated CL delivery can be applied reliably and safely to control glucose levels overnight in young people with T1D. Tighter glucose levels may be achieved with an earlier time of CL initiation. PMID- 22817341 TI - Photoinduced CC-coupling reactions of rigid diastereomeric benzophenone methionine dyads. AB - The reactions of ketone/methionine systems are widely used as efficient and selective sources of biorelevant radical species. In this study, we address intramolecular variants of this couple with respect to its photosynthetic utility and as a mechanistic model of underlying elementary reaction steps of biological importance, especially with respect to the study of photoinitiated electron transport in complex peptides. The outcomes of this study are two-fold: (1) steady-state irradiation of sterically constrained benzophenone/methionine dyads afforded stable photocyclization products with high yield and product selectivity. (2) Mechanistic insights into the triplet-triggered product formation were obtained from an analysis of the flash photolysis results and the molecular structure of the stable product formed upon irradiation. Time-resolved experiments identified (net) hydrogen-atom transfer from the methionine as the mechanism of the triplet quenching and the resulting biradicals as the major precursor of the isolated stable product. Both the analyses of triplet quenching and stable-product formation in the diastereomeric pairs point to effects of chiral center configuration, i.e., significant stereoselectivity is observed for all elementary steps. The underlying stereochemical restraints were quantitatively addressed by means of molecular dynamics simulations. PMID- 22817342 TI - Genome-wide microarray comparison reveals downstream genes of Pax6 in the developing mouse cerebellum. AB - The Pax6 transcription factor is expressed in cerebellar granule cells and when mutated, as in the Sey/Sey mouse, produces granule cells with disturbed survival and migration and with defects in neurite extension. The impact of Pax6 on other genes in the context of cerebellar development has not been identified. In this study, we performed transcriptome comparisons between wildtype and Pax6-null whole cerebellar tissue at embryonic day (E) 13.5, 15.5 and 18.5 using Affymetrix arrays (U74Av2). Statistical analyses identified 136 differentially regulated transcripts (FDR 0.05, 1.2-fold change cutoff) over time in Pax6-null cerebellar tissue. In parallel we examined the Math1-null granuloprival cerebellum and identified 228 down-regulated transcripts (FDR 0.05, 1.2-fold change cutoff). The intersection of these two microarray datasets produced a total of 21 differentially regulated transcripts. For a subset of the identified transcripts, we used qRT-PCR to validate the microarray data and demonstrated the expression in the rhombic lip lineage and differential expression in Pax6-null cerebellum with in situ hybridisation analysis. The candidate genes identified in this way represent direct or indirect Pax6-downstream genes involved in cerebellar development. PMID- 22817381 TI - Preprocedural ventricular rate predicts subsequent sick sinus syndrome after ablation for long-standing persistent atrial fibrillation. AB - BACKGROUND: Concealed sick sinus syndrome may become manifest after restoration of sinus rhythm by ablation in patients with long-standing persistent atrial fibrillation (AF). The purpose of this study was to investigate the association between the preprocedural ventricular rate during AF and sinus node function in patients with long-standing persistent AF. METHODS: Consecutive patients (n = 102) who underwent ablation for long-standing persistent AF were enrolled. We measured the ventricular rate during AF before ablation in the absence of antiarrhythmic drugs. Sinus node function was assessed by electrophysiological study and serial Holter recordings after ablation. RESULTS: Patients in the lowest quartile of ventricular rate during AF had longer corrected sinus node recovery time (1.06 +/- 1.39 seconds) than those in the other quartiles (0.54 +/- 0.31 seconds; P = 0.006) and lower mean heart rate on 24-hour Holter recording 3 months after ablation (68 +/- 9 beats/min vs 75 +/- 10 beats/min, P = 0.01). During a mean follow-up of 23 +/- 10 months, sick sinus syndrome necessitating permanent pacemaker implantation developed in five (5%) patients, and multivariate analysis revealed that a low ventricular rate during AF rate was an independent risk factor for sick sinus syndrome (odds ratio = 0.90 for a 1 beat/min increase in AF rate, P = 0.04). CONCLUSIONS: A low preprocedural ventricular rate during AF indicates the existence of sinus node dysfunction after restoration of sinus rhythm by ablation in patients with long-standing persistent AF. PMID- 22817382 TI - Twelve tips for supporting student learning in multidisciplinary clinical placements. AB - Healthcare profession students participate in a range of clinical placements within multidisciplinary health care settings. Often these placements offer students opportunities to participate in activities with staff and/or students from other healthcare disciplines. Although health service staff generally recognise the importance of clinical placements for student learning, they sometimes feel overwhelmed by workload and resource constraints. As a consequence, the potential of the clinical team to contribute to student learning may not be fully realised. A key element of successful clinical placement programs across all healthcare disciplines is a coordinated approach to the development and management of complex university/health service partnerships. Explicit mechanisms to support clinical team members in their teaching roles can also contribute to develop and sustain staff capacity for student supervision, as appropriate recognition of clinical staff contributes to student learning. Twelve tips are offered for consideration by universities, health services and clinical staff when planning and implementing student clinical placements in multidisciplinary healthcare settings. PMID- 22817383 TI - Design, construction and validation of a nose-only inhalation exposure system to measure infectivity of filtered bioaerosols in mice. AB - AIMS: The aim of this project was to validate a method to deliver a reproducible, selected dose of infective bioaerosol through a respiratory protective technology to an animal that exhibits a proportional clinical response. METHODS AND RESULTS: The Controlled Aerosol Test System (CATS) was designed to generate and condition a viable infective aerosol, pass it through a treatment technology and thence to the breathing zone of a mouse constrained in a Nose-Only Inhalation Exposure System (NOIES). A scanning mobility particle sizer and impingers at sampling ports were used to show that viability is preserved and particle size distribution (PSD) is acceptably uniform throughout the open CATS, including the 12 ports of the NOIES, and that a particle filter used caused the expected attenuation of particle counts. CONCLUSIONS: Controlled Aerosol Test System delivers uniformly to mice constrained in the NOIES a selectable dose of viral bioaerosol whose PSD and viable counts remain consistent for an hour. SIGNIFICANCE AND IMPACT OF THE STUDY: This study's characterization of CATS provides a new test system in which a susceptible small-animal model can be used as the detector in a quantitative method to evaluate the ability of respiratory protective technologies to attenuate the infectivity of an inspired pathogenic aerosol. This provides a major improvement over the use of viable bioaerosol collectors (e.g. impactors and impingers), which provide data that are difficult to relate to the attenuation of pathogenicity. PMID- 22817384 TI - First principles simulations of the electrochemical lithiation and delithiation of faceted crystalline silicon. AB - Silicon is of significant interest as a next-generation anode material for lithium-ion batteries due to its extremely high capacity. The reaction of lithium with crystalline silicon is known to present a rich range of phenomena, including electrochemical solid state amorphization, crystallization at full lithiation of a Li(15)Si(4) phase, hysteresis in the first lithiation-delithiation cycle, and highly anisotropic lithiation in crystalline samples. Very little is known about these processes at an atomistic level, however. To provide fundamental insights into these issues, we develop and apply a first principles, history-dependent, lithium insertion and removal algorithm to model the process of lithiation and subsequent delithiation of crystalline Si. The simulations give a realistic atomistic picture of lithiation demonstrating, for the first time, the amorphization process and hinting at the formation of the Li(15)Si(4) phase. Voltages obtained from the simulations show that lithiation of the (110) surface is thermodynamically more favorable than lithiation of the (100) or (111) surfaces, providing an explanation for the drastic lithiation anisotropy seen in experiments on Si micro- and nanostructures. Analysis of the delithiation and relithiation processes also provides insights into the underlying physics of the lithiation-delithiation hysteresis, thus providing firm conceptual foundations for future design of improved Si-based anodes for Li ion battery applications. PMID- 22817385 TI - Transmembrane semaphorin5B is proteolytically processed into a repulsive neural guidance cue. AB - Developing neuronal growth cones respond to a number of post-transcriptionally modified guidance cues to establish functional neural networks. The Semaphorin family has well-established roles as both secreted and transmembrane guidance cues. Here, we describe the first evidence that a transmembrane Semaphorin, Semaphorin 5B (Sema5B), is proteolytically processed from its transmembrane form and can function as a soluble growth cone collapsing guidance cue. Over expression of A Disintegrin and Metalloprotease (ADAM)-17, results in an enhanced release of the Sema5B ectodomain, while removal of a predicted ADAM-17 cleavage site prevents its release. In contrast, knockdown of ADAM-17 does not significantly reduce Sema5B release, indicating there are additional unknown compensating proteases. This modulation of the transmembrane Sema5B to a diffusible cue represents a sophisticated method to regulate neuronal guidance in vivo. PMID- 22817386 TI - Transplanting of mesenchymal stem cells may affect proliferation and function of CD4(+)T cells in experimental autoimmune encephalomyelitis. AB - OBJECTIVES: To research the effects of transplanting mesenchymal stem cells on the development of experimental autoimmune encephalomyelitis and the mechanism behind it. MATERIALS AND METHODS: An experimental autoimmune encephalomyelitis animal model was induced by injection of the MOG peptide, and mesenchymal stem cell injection was done 20 and 22 days after experimental autoimmune encephalomyelitis induction. Clinical scores were recorded daily to evaluate developing experimental autoimmune encephalomyelitis. The frequency of CD4(+)CD25(+)Foxp3(+)T cells in the spleen, the thymus, and the lymph nodes were analyzed by flow cytometry, and Foxp3, TGF-beta1, and IL-10 mRNA were detected by reverse-transcription-polymerase chain reaction. RESULTS: Transplant of mesenchymal stem cells on experimental autoimmune encephalomyelitis mice led to a decreased clinical score, an up-regulation of CD4(+)CD25(+)Foxp3(+)T cells, Foxp3, TGF-beta1, and IL-10 mRNA in the spleen, the lymph nodes, and the thymus as compared with experimental autoimmune encephalomyelitis mice. CONCLUSIONS: Transplant of mesenchymal stem cells may prevent developing experimental autoimmune encephalomyelitis and might be an available method in therapy of multiple sclerosis. Mesenchymal stem cells transplant may affect proliferation and function of CD4(+)T cells in experimental autoimmune encephalomyelitis, and CD4(+)CD25(+)Foxp3(+)T cell, Foxp3, TGF-beta1, and IL-10 may be involved in this process. PMID- 22817388 TI - Resistant and refractory hypertension: reflections on pathophysiology and terminology. PMID- 22817387 TI - Epidemiology of diabetic retinopathy and maculopathy in Africa: a systematic review. AB - AIM: To summarize findings from studies reporting the prevalence and incidence of diabetic retinopathy and diabetic maculopathy in African countries in light of the rising prevalence of diabetes mellitus. METHODS: Using a predefined search strategy, we systematically searched MEDLINE, EMBASE, Science Citation index and Conference Proceedings Citation index, African Index Medicus and the grey literature database 'OpenSIGLE' for studies published between January 1990 and February 2011. Included studies reported prevalence or incidence of diabetic retinopathy or diabetic maculopathy of subjects with diabetes resident in African countries. RESULTS: Sixty-two studies from 21 countries were included: three population-based surveys; two cohort studies; five case-control studies; 32 diabetes clinic-based, nine eye clinic-based and 11 other hospital-based surveys. Included studies varied considerably in terms of patient selection, method of assessing the eye and retinopathy classification. In population-based studies, the reported prevalence range in patients with diabetes for diabetic retinopathy was 30.2 to 31.6%, proliferative diabetic retinopathy 0.9 to 1.3%, and any maculopathy 1.2 to 4.5%. In diabetes clinic-based surveys, the reported prevalence range for diabetic retinopathy was 7.0 to 62.4%, proliferative diabetic retinopathy 0 to 6.9%, and any maculopathy 1.2 to 31.1%. No obvious association between prevalence and income level of the country was detected. CONCLUSIONS: Large, community-based cross-sectional and cohort studies are needed to investigate rates and determinants of prevalence of diabetic retinopathy, incidence and progression in Africa. Consensus is needed on the most appropriate methods of identification and classification of retinopathy for research and clinical practice. Estimates of prevalence of diabetic retinopathy, proliferative diabetic retinopathy and maculopathy are comparable with recent European and American studies. PMID- 22817390 TI - A nonsense mutation in the tyrosinase gene causes albinism in water buffalo. AB - BACKGROUND: Oculocutaneous albinism (OCA) is an autosomal recessive hereditary pigmentation disorder affecting humans and several other animal species. Oculocutaneous albinism was studied in a herd of Murrah buffalo to determine the clinical presentation and genetic basis of albinism in this species. RESULTS: Clinical examinations and pedigree analysis were performed in an affected herd, and wild-type and OCA tyrosinase mRNA sequences were obtained. The main clinical findings were photophobia and a lack of pigmentation of the hair, skin, horns, hooves, mucosa, and iris. The results of segregation analysis suggest that this disease is acquired through recessive inheritance. In the OCA buffalo, a single base substitution was detected at nucleotide 1,431 (G to A), which leads to the conversion of tryptophan into a stop codon at residue 477. CONCLUSION: This premature stop codon produces an inactive protein, which is responsible for the OCA buffalo phenotype. These findings will be useful for future studies of albinism in buffalo and as a possible model to study diseases caused by a premature stop codon. PMID- 22817391 TI - PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. AB - BACKGROUND: There are ethnic differences in the genetic risk factors for venous thrombosis (VT). The genetic causes of VT in the Chinese population are not fully understood. OBJECTIVES: To identify possible common abnormal factors that could contribute to thrombosis susceptibility. METHODS/RESULTS: We measured the levels of nine types of plasma coagulation factor, three types of anticoagulation factor and two types of fibrinolytic factor in 310 VT patients. Factor V activity was higher in 32 cases. Eleven of the 32 cases also had low protein C (PC) or protein S (PS) activities, indicating PC or PS deficiency. No other abnormalities were observed in the other 21 cases. All of the samples were sensitive to activated PC inactivation. Therefore, the abnormal factor involved may be FV inactivator or its cofactor rather than FV itself. Resequencing identified a common PROC c.574_576del variant in 10 of the 32 subjects. In a case-control study, this variant was detected in 68 of the 1003 patients and in 25 of the 1031 controls. It had an adjusted odds ratio of 2.71 (95% confidence interval [CI] 1.68-4.36). PC amidolytic activities of most variant carriers were similar to those of non carriers, but the mean anticoagulant activity was only 72.7 U dL(-1). Expression studies in vitro showed that the anticoagulant activity of the mutant PC was 43.6% of that of the wild-type PC. CONCLUSIONS: We identified what is, so far, the most common genetic risk factor for VT in the Chinese population, with its prevalence being approximately 2.36%. PMID- 22817392 TI - Novel layer-by-layer procedure for making nylon-6 nanofiber reinforced high strength, tough, and transparent thermoplastic polyurethane composites. AB - We highlight a novel composite fabrication method based on solution casting, electrospinning, and film stacking for preparing highly transparent nylon-6 nanofiber reinforced thermoplastic polyurethane (TPU) composite films. The procedure is simple and can be extended to the other thermoplastics. The morphology of fiber/matrix interface and the properties of composite films were also investigated. The method led to a significant reinforcement in mechanical properties of TPU like tensile strength, E modulus, strain, and toughness just using very small amounts of nylon fibers (about 0.4-1.7 wt %; 150-300 nm diameter). The enhanced mechanical properties were achieved without sacrificing optical properties like transparency of TPU. PMID- 22817393 TI - A simple scoring system for the diagnosis of palmo-plantar pigmented skin lesions by digital dermoscopy analysis. AB - BACKGROUND: Many research groups have recently developed equipments and statistical methods enabling pattern classification of pigmented skin lesions. To differentiate between benign and malignant ones, the mathematical extraction of digital patterns together with the use of appropriate statistical approaches is a challenging task. OBJECTIVE: To design a simple scoring model that provides accurate classification of benign and malignant palmo-plantar pigmented skin lesions, by evaluation of parameters obtained by digital dermoscopy analysis (DDA). PATIENTS AND METHODS: In the present study we used a digital dermoscopy analyser to evaluate a series of 445 palmo-plantar melanocytic skin lesion images (25 melanomas 420 nevi). Area under the receiver operator curve, sensitivity and specificity were calculated to evaluate the diagnostic performance of our scoring model for the differentiation of benign and malignant palmo-plantar melanocytic lesions. RESULTS: Model performance reached a very high value (0.983). The DDA parameters selected by the model that proved statistically significant were: area, peripheral dark regions, total imbalance of colours, entropy, dark area and red and blue multicomponent. When all seven model variables were used in a multivariate mode, setting sensitivity at 100% to avoid false negatives, we estimated a minimum specificity of about 80%. CONCLUSIONS: Simplicity of use and effectiveness of implementation are important requirements for the success of quantitative methods in routine clinical practice. Scoring systems meet these requirements. Their outcomes are accessible in real time without the use of any data processing system, thus allowing decisions to be made quickly and effectively. PMID- 22817394 TI - Non-steady peristaltic propulsion with exponential variable viscosity: a study of transport through the digestive system. AB - A theoretical study is presented for transient peristaltic flow of an incompressible fluid with variable viscosity in a finite length cylindrical tube as a simulation of transport in physiological vessels and biomimetic peristaltic pumps. The current axisymmetric analysis is qualitatively similar to two dimensional analysis but exhibits quantitative variations. The current analysis is motivated towards further elucidating the physiological migration of gastric suspensions (food bolus) in the human digestive system. It also applies to variable viscosity industrial fluid (waste) peristaltic pumping systems. First, an axisymmetric model is analysed in the limit of large wavelength ([Formula: see text]) and low Reynolds number ([Formula: see text]) for axial velocity, radial velocity, pressure, hydromechanical efficiency and stream function in terms of radial vibration of the wall ([Formula: see text]), amplitude of the wave ([Formula: see text]), averaged flow rate ([Formula: see text]) and variable viscosity ([Formula: see text]). Subsequently, the peristaltic flow of a fluid with an exponential viscosity model is examined, which is based on the analytical solutions for pressure, wall shear stress, hydromechanical efficiency and streamline patterns in the finite length tube. The results are found to correlate well with earlier studies using a constant viscosity formulation. This study reveals some important features in the flow characteristics including the observation that pressure as well as both number and size of lower trapped bolus increases. Furthermore, the study indicates that hydromechanical efficiency reduces with increasing magnitude of viscosity parameter. PMID- 22817395 TI - Comments on "Studies of the mortality of atomic bomb survivors, report 14, 1950 2003: an overview of cancer and noncancer diseases" (Radiat Res 2012; 177:229 43). PMID- 22817396 TI - Methods to assess seasonal effects in epidemiological studies of infectious diseases--exemplified by application to the occurrence of meningococcal disease. AB - Seasonal variation in occurrence is a common feature of many diseases, especially those of infectious origin. Studies of seasonal variation contribute to healthcare planning and to the understanding of the aetiology of infections. In this article, we provide an overview of statistical methods for the assessment and quantification of seasonality of infectious diseases, as exemplified by their application to meningococcal disease in Denmark in 1995-2011. Additionally, we discuss the conditions under which seasonality should be considered as a covariate in studies of infectious diseases. The methods considered range from the simplest comparison of disease occurrence between the extremes of summer and winter, through modelling of the intensity of seasonal patterns by use of a sine curve, to more advanced generalized linear models. All three classes of method have advantages and disadvantages. The choice among analytical approaches should ideally reflect the research question of interest. Simple methods are compelling, but may overlook important seasonal peaks that would have been identified if more advanced methods had been applied. For most studies, we suggest the use of methods that allow estimation of the magnitude and timing of seasonal peaks and valleys, ideally with a measure of the intensity of seasonality, such as the peak to-low ratio. Seasonality may be a confounder in studies of infectious disease occurrence when it fulfils the three primary criteria for being a confounder, i.e. when both the disease occurrence and the exposure vary seasonally without seasonality being a step in the causal pathway. In these situations, confounding by seasonality should be controlled as for any confounder. PMID- 22817397 TI - Cone-beam computed tomography study of root and canal morphology of mandibular premolars in a western Chinese population. AB - BACKGROUND: Traditional radiography is limited in its ability to give reliable information on the number and morphology of root canals. The application of cone beam computed tomography (CBCT) provides a non-invasive three-dimensional confirmatory diagnosis as a complement to conventional radiography. The aim of this study was to evaluate the root and canal morphology of mandibular premolars in a western Chinese population using CBCT scanning. METHODS: The sample included 149 CBCT images comprising 178 mandibular first premolars and 178 second premolars. The tooth position, number of roots and canals, and canal configuration according to Vertucci's classification were recorded. RESULTS: The results showed that 98% of mandibular first premolars had one root and 2% had two roots; 87.1% had one canal, 11.2% had two canals and 0.6% had three canals. The prevalence of C-shaped canals was 1.1%. All mandibular second premolars had one root; 97.2% had one canal and 2.2% had two canals. The prevalence of C-shaped canals was 0.6%. CONCLUSIONS: The prevalence of multiple canals in mandibular first premolars was mainly of Type V, and mandibular second premolars had a low rate of canal variation in this western Chinese population. Root canal bifurcation occurred at the middle or apical third in most bicanal mandibular premolars. CBCT scanning can be used in the management of mandibular premolars with complex canal morphology. PMID- 22817398 TI - Adiabatic quantum dynamics of CH(X2Pi) + H(2S) reactions on the CH2(X3A") surface and role of the excited electronic states. AB - We present the Born-Oppenheimer (BO) quantum mechanical (QM) dynamics of the CH decay (d) CH(X2Pi) + H(2S) -> C(3P) + H2(X1Sigma(g)(+)) and of the H exchange reaction (e) CH(X2Pi) + H'(2S) -> CH'(X2Pi) + H(2S) on the CH2 X3A" adiabatic potential energy surface (PES) of Harding et al. (J. Phys. Chem. 1993, 97, 5472). A thorough analysis of the correlation diagram of the four lowest CH2 electronic states, as well as Renner-Teller and spin-orbit nonadiabatic test calculations on the X3A", a1A', and b1A" coupled PESs, validate the X3A" BO results, confirming that these reactions occur essentially on the uncoupled X3A" ground surface. We consider the CH molecule in the ground vibrational state and in the four lowest rotational states j0. Thus, we obtain initial-state resolved reaction probabilities, cross sections, and rate constants by propagating coupled-channel real wave packets and performing flux analyses. If J is the total angular momentum quantum number and K is its projection along the body-fixed z axis, CH + H gives essentially the C + H2 products via a barrierless K-inhibited insertion, CH2 resonances at low J, and large cross sections near the threshold. These cross sections decrease strongly with collision energy and depend slightly on j0. On the other hand, the small cross sections obtained for the (e) channel are nearly independent of energy. From initial-state resolved rate constants and Boltzmann populations at temperature T, we obtain QM thermal rate constants from 100 to 400 K: at 300 K, k(d) = (9.57 +/- 0.96) * 10(-11) and k(e) = (1.41 +/- 0.14) * 10( 11) cm(3) s(-1) for (d) and (e) reactions, respectively. The k(d) value is in good agreement with previous quasi-classical trajectory (QCT) results on the same PES, but it is larger than that observed at 297 K by a factor of 7. On the contrary, and in agreement with the small role of CH2 excited electronic states, X3A" QCT and experimental rate constants agree at high temperatures. Thus, the discrepancy obtained at room T between theory and experiment should be due to an experimental error or to some theoretical effects that we have not been considered in this work. At the present state of the art, an experimental error is more likely and suggests a new measurement of the rate constant. PMID- 22817399 TI - 2-O-Methyl- and 3,6-di-O-methyl-cellulose from natural cellulose: synthesis and structure characterization. AB - For the first time, 2-O-methyl- (2MC) and 3,6-di-O-methyl-cellulose (36MC) were synthesized via 3-O-allyl- and 3-O-methyl-cellulose, respectively. Position 6 of 3-O-allyl- and 3-O-methyl-cellulose was protected with the 4-methoxytrityl groups. The reaction time and temperature were optimized to achieve a high regioselectivity at C-6 and to prevent the introduction of the 4-methoxytrityl group at C-2 of the polymer. It was found that the substituent at C-3 of 3-O functionalized celluloses influenced the reactivity of the hydroxyl group at C-6. The structure was characterized by means of (1)H and (13)C NMR spectroscopy of the acetates of 2MC and 36MC. 2MC and 36MC were soluble in water and did not show thermoreversible gelation. PMID- 22817400 TI - Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine. AB - BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, characterised by thickening of the wall of the right hemicolon with calcification of mesenteric veins. However, the aetiology remains unknown. AIM: To investigate the possible association of herbal medicines with IMP. METHOD: The clinical data of four of our own patients were collected. Furthermore, we searched for previous reports about similar patients with detailed descriptions of herbal prescriptions that they had taken. We compared herbal ingredients to identify the toxic agent as a possible aetiological factor. RESULTS: Clinical data on a total of 25 patients were summarised. Mean age was 61.8 years and there was female predominance (6 men and 19 women). The used Kampo prescription, the number of cases, and the mean duration of use were as follows: kamisyoyosan in 12 cases for 12.8 years, inshin-iseihaito in 5 cases for 13.4 years, orengedokuto in 4 cases for 14.3 years, inchinkoto in 1 case for 20 years, kamikihitou in 1 case for 19 years, seijobofuto in 1 case for 10 years and gorinsan in 1 case for an unknown duration. Only one ingredient, sansisi, was common to the herbal medicines of all 25 patients. This crude drug called geniposide in English is a major constituent of the Gardenia fruits. CONCLUSION: The long-term use of geniposide in herbal medicines appears to be associated with mesenteric phlebosclerosis. PMID- 22817401 TI - Correlation between cognitive ability measured by response time of 1-back task and changes of SpO2 by supplying three different levels of oxygen in the elderly. AB - AIM: This study investigated the correlation between response time of the 1-back task and changes of blood oxygen saturation (SpO2 ) by supplying three different levels of oxygen (21%, 1 L/min; 93%, 1 L/min; 93%, 5 L/min) in the elderly. METHODS: A total of 17 older adults (mean age 72.9 +/- 4.7 years) participated in the experiment. A 1-back task was used as a cognitive task. The experiment consisted of three phases, which included the adaptation phase (3 min) after oxygen administration, the control phase (2 min) that maintained a stable condition before the task, and the task phase (2 min) where the 1-back task was carried out. SpO2 was measured during each phase. RESULTS: As concentration level and supply of oxygen increased, SpO2 increased and response time of the 1-back task decreased. CONCLUSION: Highly concentrated oxygen administration can increase SpO2 in the elderly and an increase in cognitive performance, such as a decrease in response time, can be observed. PMID- 22817403 TI - Ca2+-dependent ion channels underlying spontaneous activity in insect circadian pacemaker neurons. AB - Electrical activity in the gamma frequency range is instrumental for temporal encoding on the millisecond scale in attentive vertebrate brains. Surprisingly, also circadian pacemaker neurons in the cockroach Rhyparobia maderae (Leucophaea maderae) employ fast spontaneous rhythmic activity in the gamma band frequency range (20-70 Hz) together with slow rhythmic activity. The ionic conductances controlling this fast spontaneous activity are still unknown. Here, Ca(2+) imaging combined with pharmacology was employed to analyse ion channels underlying spontaneous activity in dispersed circadian pacemakers of the adult accessory medulla, which controls circadian locomotor activity rhythms. Fast spontaneous Ca(2+) transients in circadian pacemakers accompany tetrodotoxin (TTX)-blockable spontaneous action potentials. In contrast to vertebrate pacemakers, the spontaneous depolarisations from rest appear to be rarely initiated via TTX-sensitive sustained Na(+) channels. Instead, they are predominantly driven by mibefradil-sensitive, low-voltage-activated Ca(2+) channels and DK-AH269-sensitive hyperpolarisation-activated, cyclic nucleotide gated cation channels. Rhythmic depolarisations activate voltage-gated Na(+) channels and nifedipine-sensitive high-voltage-activated Ca(2+) channels. Together with Ca(2+) rises, the depolarisations open repolarising small conductance but not large-conductance Ca(2+) -dependent K(+) channels. In contrast, we hypothesise that P/Q-type Ca(2+) channels coupled to large conductance Ca(2+) -dependent K(+) channels are involved in input-dependent activity. PMID- 22817404 TI - Basal exit site of clinical ventricular tachycardia is an independent predictor of antitachycardia pacing failure in implantable cardioverter-defibrillators recipients. AB - BACKGROUND: Little is known about predictors of antitachycardia pacing (ATP) failure in implantable cardioverter defibrillator (ICD) recipients. Distance between the stimulation site and the ventricular tachycardia (VT) site of origin may critically affect ATP effectiveness. We hypothesized that ATP may be less effective in ICD patients who had basal VT than in those who had apical VT. METHODS: We reviewed data from 52 patients with sustained monomorphic VT and left ventricular disease referred for ICD implantation. ATP was delivered exclusively at the right ventricular apex. The clinical VTs site of origin (basal, midventricular, or apical) was determined in each patient, using 12-lead electrocardiogram. VTs episodes treated with ATP during the 1-year follow-up were studied. ATP success rate (%), defined as the ratio between the number of successful ATP sequences and the number of delivered ATP sequences, was determined in each patient. RESULTS: VT exit site was apical in 19 patients (36%), basal in 18 patients (35%), and midventricular in 15 patients (29%). In those 52 patients, 1,393 ATP sequences, delivered to treat 761 VT episodes, were analyzed. ATP success rate was found to be associated with the VT site of origin (median [interquartile range]): basal (33%[11-67]), midventricular (50%[37-100]), apical (100%[41-100]) (P = 0.027). Multivariate analysis identified basal VT site of origin as an independent predictor of ATP failure (P = 0.023). CONCLUSION: ATP is less effective in ICD patients who had basal VT than in those who had apical VT before ICD implantation. PMID- 22817402 TI - Mechanism of interleukin-1beta induced-increase in mouse intestinal permeability in vivo. AB - Interleukin-1beta (IL-1beta) has been shown to play an essential role in mediating intestinal inflammation of Crohn's disease and other inflammatory conditions of the gut. Previous studies from our laboratory have shown that IL 1beta causes an increase in intestinal tight-junction permeability in Caco-2 monolayers in vitro. However, the IL-1beta effect on the intestinal epithelial barrier in vivo remains unclear. AIMS: the major aims of this study were to examine the effect of IL-1beta on mouse intestinal epithelial barrier in vivo and to delineate the mechanisms involved using an in vivo model system consisting of a recycling perfusion of mouse small intestine. Intraperitonial injection of IL 1beta at varying doses (0-10 MUg) caused a concentration-dependent increase in mouse intestinal permeability to the paracellular marker dextran (10 KD), and the maximal increase in dextran flux occurred at IL-1beta dose of 5 MUg. IL-1beta treatment caused an increase in myosin light-chain kinase (MLCK) mRNA and protein expression in the small intestinal tissue starting at 24 h, which continued up to 72 h. Additionally, IL-1beta did not cause an increase in intestinal permeability in MLCK-deficient mice (C57BL/6 MLCK(-/-)). MLCK inhibitor ML-7 (2 mg/kg body weight) also inhibited the IL-1beta-induced increase in small intestinal permeability. The IL-1beta-induced increase in mouse intestinal permeability was associated with an increase in NF-kappaB activation. The intestinal tissue specific silencing of NF-kappaB p65 inhibited the IL-1beta-induced increase in intestinal permeability and increase in MLCK expression. These data show for the first time that IL-1beta causes an increase in mouse intestinal permeability in vivo. These data suggested that the mechanism of IL-1beta-induced increase in mouse intestinal permeability in vivo involved NF-kappaB p65-induced activation of the mouse enterocyte MLCK gene. PMID- 22817451 TI - Simple monitoring of cancer cells using nanoparticles. AB - Here we present a new strategy for a simple and fast detection of cancer circulating cells (CTCs) using nanoparticles. The human colon adenocarcinoma cell line (Caco2) was chosen as a model CTC. Similarly to other adenocarcinomas, colon adenocarcinoma cells have a strong expression of EpCAM, and for this reason this glycoprotein was used as the capture target. We combine the capturing capability of anti-EpCAM functionalized magnetic beads (MBs) and the specific labeling through antibody-modified gold nanoparticles (AuNPs), with the sensitivity of the AuNPs-electrocatalyzed hydrogen evolution reaction (HER) detection technique. The fully optimized process was used for the electrochemical detection of Caco2 cells in the presence of monocytes (THP-1), other circulating cells that could interfere in real blood samples. Therefore we obtained a novel and simple in situ like sensing format that we applied for the rapid quantification of AuNPs-labeled CTCs in the presence of other human cells. PMID- 22817452 TI - Reduced spread of Campylobacter jejuni in broiler chickens by stimulating the bird's natural barriers. AB - AIM: We have tested the effect of feed structure and feeding regime to prevent the spread of the zoonotic pathogen Campylobacter jejuni in broiler chicken flocks. METHODS AND RESULTS: Birds were offered two types of feed, control diet and a diet supplemented with 15% oat/barley hulls for structure. In addition, the birds were either fed ad libitum or intermittent. One bird in each treatment group was infected with a three-strain-mix of Camp. jejuni, and the spread of Camp. jejuni within the group was investigated. Feed structure increased the gizzard weight, delayed the spread of Camp. jejuni within the group and reduced the relative amount of Camp. jejuni in the caecum compared with the control diet. CONCLUSIONS: Our results show that stimulating the bird's natural barriers is a novel and promising intervention strategy to reduce the spread of Camp. jejuni in chicken flocks. SIGNIFICANCE AND IMPACT OF THE STUDY: Preventing Camp. jejuni in broiler chicken flocks is essential to ensure food safety because this bacterium is transferred to chicken carcasses during the slaughter process and readily survive in unprocessed poultry products. We have evaluated a novel approach for stimulation of the bird's natural barriers in the upper digestive tract with promising results. PMID- 22817453 TI - Physical activity level and body composition among adults with type 1 diabetes. AB - AIMS: Physical activity is part of a healthy lifestyle and contributes to prevent weight gain and cardiometabolic disorders. Adults with Type 1 diabetes are at risk of weight gain attributable to various factors, including a high prevalence of sedentary lifestyle related to fear of exercise-induced hypoglycaemia. This project aims to observe the association between physical activity level and body composition in adults with Type 1 diabetes. METHODS: Cross-sectional study; 75 adults with and 75 adults without diabetes (52% men; 41.8 +/- 11.8 years old) wore a motion sensor for 1 week and performed a cardiorespiratory fitness test on an ergocycle (VO(2peak)). Body composition was assessed by dual energy X-ray absorptiometry and circumferences measures. RESULTS: Mean body composition was not different between the two groups. VO(2peak) was lower among the group with diabetes than the control subjects (29.3 +/- 9.2 vs. 33.5 +/- 9.0 ml kg(-1) min( 1); P = 0.005), but their physical activity level (ratio total/resting energy expenditure) was similar (1.68 +/- 0.37 vs. 1.65 +/- 0.26; P = 0.572). In both groups, having an active lifestyle (physical activity level >= 1.7) compared with a more sedentary lifestyle (physical activity level < 1.7) was associated with lower BMI and percentage of total and truncal fat mass (P <= 0.030 to P <= 0.001). Among adults with diabetes, physical activity level was not associated with diabetes treatment (insulin doses) and control (HbA(1c) and hypoglycaemia) or cardiovascular risk factors (blood pressure and lipid profile). CONCLUSION: As in the population without diabetes, an active lifestyle is associated with a better body composition profile in adults with Type 1 diabetes. PMID- 22817454 TI - Structure of human DNA polymerase iota and the mechanism of DNA synthesis. AB - Cellular DNA polymerases belong to several families and carry out different functions. Highly accurate replicative DNA polymerases play the major role in cell genome replication. A number of new specialized DNA polymerases were discovered at the turn of XX-XXI centuries and have been intensively studied during the last decade. Due to the special structure of the active site, these enzymes efficiently perform synthesis on damaged DNA but are characterized by low fidelity. Human DNA polymerase iota (Pol iota) belongs to the Y-family of specialized DNA polymerases and is one of the most error-prone enzymes involved in DNA synthesis. In contrast to other DNA polymerases, Pol iota is able to use noncanonical Hoogsteen interactions for nucleotide base pairing. This allows it to incorporate nucleotides opposite various lesions in the DNA template that impair Watson-Crick interactions. Based on the data of X-ray structural analysis of Pol iota in complexes with various DNA templates and dNTP substrates, we consider the structural peculiarities of the Pol iota active site and discuss possible mechanisms that ensure the unique behavior of the enzyme on damaged and undamaged DNA. PMID- 22817455 TI - Ribosomal proteins: structure, function, and evolution. AB - The question concerning reasons for the variety of ribosomal proteins that arose for more than 40 years ago is still open. Ribosomes of modern organisms contain 50-80 individual proteins. Some are characteristic for all domains of life (universal ribosomal proteins), whereas others are specific for bacteria, archaea, or eucaryotes. Extensive information about ribosomal proteins has been obtained since that time. However, the role of the majority of ribosomal proteins in the formation and functioning of the ribosome is still not so clear. Based on recent data of experiments and bioinformatics, this review presents a comprehensive evaluation of structural conservatism of ribosomal proteins from evolutionarily distant organisms. Considering the current knowledge about features of the structural organization of the universal proteins and their intermolecular contacts, a possible role of individual proteins and their structural elements in the formation and functioning of ribosomes is discussed. The structural and functional conservatism of the majority of proteins of this group suggests that they should be present in the ribosome already in the early stages of its evolution. PMID- 22817456 TI - Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis. AB - p21(Waf1) was identified as a protein suppressing cyclin E/A-CDK2 activity and was originally considered as a negative regulator of the cell cycle and a tumor suppressor. It is now considered that p21(Waf1) has alternative functions, and the view of its role in cellular processes has begun to change. At present, p21(Waf1) is known to be involved in regulation of fundamental cellular programs: cell proliferation, differentiation, migration, senescence, and apoptosis. In fact, it not only exhibits antioncogenic, but also oncogenic properties. This review provides a contemporary understanding of the functions of p21(Waf1) depending on its intracellular localization. On one hand, when in the nucleus, it serves as a negative cell cycle regulator and tumor suppressor, in particular by participating in the launch of a senescence program. On the other hand, when p21(Waf1) is localized in the cytoplasm, it acts as an oncogene by regulating migration, apoptosis, and proliferation. PMID- 22817457 TI - Mechanism of intermolecular interactions of microsomal cytochrome P450s CYP17 and CYP21 involved in steroid hormone biosynthesis. AB - Protein-protein interactions play a significant role in regulation of functional activity of cytochrome P450s. The aim of the present study was to elucidate the molecular interactions between steroidogenic enzymes CYP17 and CYP21 localized in endoplasmic reticulum membranes of adrenal cortex and involved in biosynthesis of corticosteroid hormones. In the present work, we demonstrate for the first time the direct interaction at molecular level between highly purified human recombinant cytochrome P450s in a mixed reconstituted system. The dependence of the interaction between CYP17 and CYP21 on concentration of the redox-partner - NADPH-cytochrome P450 reductase - is demonstrated, and it is shown that electrostatic interactions play a crucial role in the interaction between CYP17 and CYP21. PMID- 22817458 TI - Activity of nucleoside diphosphate kinase alpha (NDPK alpha) capable of binding to outer mitochondrial membrane accounts for less than 10% of total NDPK activity present in cytoplasm of liver cells. AB - During incubation of a constant volume of rat liver cytosol with an increasing quantity of mitochondrial protein in the presence of 3.3 mM MgCl(2), the binding of nucleoside diphosphate kinase (NDPK) from the cytosol to mitochondrial membranes is described by a saturation curve. The highest bound NDPK activity accounts for less than 9% of the added activity. Analysis of the results suggests that only one NDPK isozyme is bound to the membranes. Western blotting showed it to be NDPK alpha, a homolog of human NDPK-B. Substrates of NDPK, hexokinase, and glycerol kinase, as well as N,N'-dicyclohexylcarbodiimide and palmitate, did not influence the association of NDPK with mitochondrial membranes. We conclude that the sites of NDPK binding to the outer mitochondrial membrane are not identical to those of hexokinase and glycerol kinase. PMID- 22817459 TI - Rapid and massive green fluorescent protein production leads to formation of protein Y-bodies in plant cells. AB - Although high level of recombinant protein production can be achieved via transient expression in plant cells, the mechanism by which tolerance to the presence of recombinant protein is acquired remains unclear. Here we show that green fluorescent protein (GFP) encoded by an intron-optimized tobacco mosaic viral vector formed large membraneless GFP bodies called Y-bodies that demonstrated mainly perinuclear localization. The Y-bodies were heterogeneous in size, approaching the size of the cell nucleus. Experiments with extracted GFP and live cell imaging showed that Y-bodies included actively fluorescent, non aggregated, tightly packed GFP molecules. The plant cells probably formed Y bodies to exclude the recombinant protein from normal physiological turnover. PMID- 22817460 TI - Structure of a peptidoglycan-related polysaccharide from Providencia alcalifaciens O45. AB - A polysaccharide was isolated from the opportunistic human pathogen Providencia alcalifaciens O45:H26 by extraction with aqueous phenol and studied by sugar and methylation analyses along with (1)H and (13)C NMR spectroscopy, including two dimensional ROESY and H-detected (1)H,(13)C HSQC experiments. The polysaccharide contains N-acetylglucosamine and N-acetylmuramic acid (D-GlcpNAc3Rlac) amidated with L-alanine and has the following structure: ->4)-beta-D-GlcpNAc-(1->4)-beta-D GlcpNAc3(Rlac-L-Ala)-(1->. The polysaccharide possesses a remarkable structural similarity to the bacterial cell wall peptidoglycan. It is not unique to the strain studied but is common to strains of at least four P. alcalifaciens O serogroups (O3, O24, O38, and O45). No evidence was obtained that the polysaccharide is associated with the LPS, and hence it might represent a bacterial capsule component. PMID- 22817461 TI - Comparison of experimental and theoretical data on hydrogen-deuterium exchange for ten globular proteins. AB - The number of protons available for hydrogen-deuterium exchange was predicted for ten globular proteins using a method described elsewhere by the authors. The average number of protons replaced by deuterium was also determined by mass spectrometry of the intact proteins in their native conformations. Based on these data, we find that two models proposed earlier agree with each other in estimation of the number of protons replaced by deuterium. Using a model with a probability scale for hydrogen bond formation, we estimated a number of protons replaced by deuterium that is close to the experimental data for long-term incubation in D(2)O (24 h). Using a model based on estimations with a scale of the expected number of contacts in globular proteins there is better agreement with the experimental data obtained for a short period of incubation in D(2)O (15 min). Therefore, the former model determines weakly fluctuating parts of a protein that are in contact with solvent only for a small fraction of the time. The latter model (based on the scale of expected number of contacts) predicts either flexible parts of a protein chain exposed to interactions with solvent or disordered parts of the protein. PMID- 22817462 TI - Hybrid system based on quantum dots and photosystem 2 core complex. AB - We show that semiconductor nanocrystals (quantum dots, QD) can be used to increase the absorption capacity of pigment-protein complexes. In a mixture of photosystem 2 core complex (PS2) and QD, the fluorescence of the latter decreases several-fold due to the transfer of the absorbed energy to the PS2 core complex. We discuss Forster's inductive-resonance mechanism as a possible way of energy transfer in donor-acceptor pairs QD-PS2 core complex. Calculations based on the experimental data show that the enhancement of PS2 fluorescence and the rate of Q(A) reduction increase up to 60% due to efficient energy migration from QD to PS2. PMID- 22817463 TI - Two-stage method for purification of ceruloplasmin based on its interaction with neomycin. AB - A two-stage chromatography that yields highly purified ceruloplasmin (CP) from human plasma and from rat and rabbit serum is described. The isolation procedure is based on the interaction of CP with neomycin, and it provides a high yield of CP. Constants of inhibition by gentamycin, kanamycin, and neomycin of oxidase activity of CP in its reaction with p-phenylenediamine were assayed. The lowest K(i) for neomycin (11 uM) corresponded to the highest specific adsorption of CP on neomycin-agarose (10 mg CP/ml of resin). Isolation of CP from 1.4 liters of human plasma using ion-exchange chromatography on UNO-Sphere Q and affinity chromatography on neomycin-agarose yields 348 mg of CP with 412-fold purification degree. Human CP preparation obtained with A(610)/A(280) ~ 0.052 contained neither immunoreactive prothrombin nor active thrombin. Upon storage at 37 degrees C under sterile conditions, the preparation remained stable for two months. Efficient preparation of highly purified CP from rat and rabbit sera treated according to a similar protocol suggests the suitability of our method for isolation of CP from plasma and serum of other animals. The yield of CP in three separate purifications was no less than 78%. PMID- 22817464 TI - Hemostatic interference of Indian king cobra (Ophiophagus hannah) Venom. Comparison with three other snake venoms of the subcontinent. AB - Unlike Naja naja, Bungarus caeruleus, Echis carinatus, and Daboia/Vipera russellii venoms, Ophiophagus hannah venom is medically ignored in the Indian subcontinent. Being the biggest poisonous snake, O. hannah has been presumed to inject several lethal doses of venom in a single bite. Lack of therapeutic antivenom to O. hannah bite in India makes any attempt to save the victim a difficult exercise. This study was initiated to compare O. hannah venom with the above said venoms for possible interference in hemostasis. Ophiophagus hannah venom was found to actively interfere in hemostatic stages such as fibrin clot formation, platelet activation/aggregation, and fibrin clot dissolution. It decreased partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin clotting time (TCT). These activities are similar to that shown by E. carinatus and D. russellii venoms, and thus O. hannah venom was found to exert procoagulant activity through the common pathway of blood coagulation, while N. naja venom increased aPTT and TCT but not PT, and hence it was found to exert anticoagulant activity through the intrinsic pathway. Venoms of O. hannah, E. carinatus, and D. russellii lack plasminogen activation property as they do not hydrolyze azocasein, while they all show plasmin-like activity by degrading the fibrin clot. Although N. naja venom did not degrade azocasein, unlike other venoms, it showed feeble plasmin-like activity on fibrin clot. Venom of E. carinatus induced clotting of human platelet rich plasma (PRP), while the other three venoms interfered in agonist-induced platelet aggregation in PRP. Venom of O. hannah least inhibited the ADP induced platelet aggregation as compared to D. russellii and N. naja venoms. All these three venoms showed complete inhibition of epinephrine-induced aggregation at varied doses. However, O. hannah venom was unique in inhibiting thrombin induced aggregation. PMID- 22817465 TI - SkQ1 slows development of age-dependent destructive processes in retina and vascular layer of eyes of wistar and OXYS rats. AB - We show the development of clearly pronounced age-related pathological changes in eye tissues of Wistar and OXYS rats. Photoreceptor cells were virtually absent in all OXYS rats in the age of 24 months. Massive accumulations of lipofuscin granules were detected in the pigmented epithelium cells. Flattening, overgrowing, and degradation of endothelial cells of choriocapillaries were also observed. Along with these changes, vessels without signs of degradation were detected in the pigmented epithelium. In 24-month-old Wistar rats these changes were local and were seen in only some of the animals. The mitochondria-targeted antioxidant SkQ1 (the rats were given SkQ1 daily with food at the dose of 250 nmol/kg for 5 months, starting from the age of 19 months) prevented the development of these pathological changes in both Wistar and OXYS rats. The data were subjected to mathematical processing and statistical analysis. PMID- 22817466 TI - Nanoantibodies for detection and blocking of bioactivity of human vascular endothelial growth factor A(165). AB - Nanoantibodies (single-domain antibodies, nanobodies) derived from noncanonical single-chain immunoglobulins provide an attractive tool for in vitro and in vivo diagnostics as well as for development of targeted drugs for clinical use. Nanoantibodies against several clinically important targets have been developed and are actively investigated. However, no development of nanoantibodies against vascular endothelial growth factor VEGF-A(165) has been reported. We describe here the generation of nanoantibodies derived from single-chain Bactrian camel immunoglobulins directed against VEGF-A(165). We demonstrate that these nanoantibodies are suitable for enzyme-linked immunoassay to quantify human VEGF A(165) as well as for blocking its activity. Our results provide a basis for diagnostic kit development for quantification of VEGF-A(165), which emerges as a biomarker useful in various pathological conditions. In addition, the nanoantibodies might be used for development of therapeutic molecules targeting VEGF-A(165)-dependent pathological neoangiogenesis. PMID- 22817467 TI - Mitochondria-targeted antioxidant SkQR1 ameliorates gentamycin-induced renal failure and hearing loss. AB - The influence of the mitochondria-targeted antioxidant SkQR1 on gentamycin induced nephrotoxicity and ototoxicity has been analyzed. SkQR1 reduces the death of kidney epithelium cells and decreases the severity of renal failure caused by gentamycin application and also lowers the animals' mortality. Treatment with SkQR1 also decreases gentamycin-induced hearing loss. Mitochondria-targeted antioxidants, such as SkQR1, are new promising agents for preventing negative consequences of therapy with antibiotics. PMID- 22817468 TI - Cerebral ischemia-reperfusion induces GAPDH S-nitrosylation and nuclear translocation. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme, plays an important role in glycolysis. It was reported that GAPDH undergoes S nitrosylation, which facilitated its binding to Siah1 and resulted in nuclear translocation and cell apoptosis. The results of this study show that GAPDH S nitrosylation, Siah1 binding, translocation to nucleus, and concomitant neuron death occur during the early stages of reperfusion in the rat four-vessel occlusion ischemic model. N-Methyl-D-aspartate receptor antagonist MK801, neuronal nitric oxide synthase inhibitor 7-nitroindazole, or monoamine oxidase-B inhibitor (R)-(-)-deprenyl hydrochloride could inhibit GAPDH S-nitrosylation and translocation and exert neuroprotective effects. PMID- 22817469 TI - Phosphatase activity in barley proteins tightly bound to DNA and its development dependent changes. AB - The tightly bound proteins (TBPs), a protein group that remains attached to DNA either covalently or noncovalently after deproteinization, have been found in numerous eukaryotic species. Some TBPs isolated from mammalian and yeast cells possess phosphatase or kinase activity. The aim of this study was to characterize further TBPs in barley (Hordeum vulgare) cells. The spectra of TBPs varied in different organs of barley shoots (first leaves, coleoptile, and roots) and at different developmental stages of the plant. Some barley TBPs manifested phosphatase, probably Ser/Thr or dual Ser/Thr/Tyr activity. MALDI-TOF mass spectrometry of barley TBPs identified several proteins involved in chromatin rearrangement and regulation processes, including transcription factors, serpins, protein phosphatases and protein kinases, RNA helicases, and DNA topoisomerase II. PMID- 22817470 TI - Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. AB - BACKGROUND: Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers. OBJECTIVE: To quantify bleeding in warfarin-anticoagulated and DE anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh-frozen plasma (FFP). METHODS: CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents. RESULTS: PCC (14.3 IU kg(-1) ), but not rFVIIa (3 mg kg(-1) ) or FFP (12 mL kg(-1) ), normalized blood loss and bleeding time in mice with warfarin-induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg(-1) ) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg(-1) DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE treated mice. CONCLUSIONS: Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in DE induced coagulopathy. PMID- 22817471 TI - Advanced material modelling in numerical simulation of primary acetabular press fit cup stability. AB - Primary stability of artificial acetabular cups, used for total hip arthroplasty, is required for the subsequent osteointegration and good long-term clinical results of the implant. Although closed-cell polymer foams represent an adequate bone substitute in experimental studies investigating primary stability, correct numerical modelling of this material depends on the parameter selection. Material parameters necessary for crushable foam plasticity behaviour were originated from numerical simulations matched with experimental tests of the polymethacrylimide raw material. Experimental primary stability tests of acetabular press-fit cups consisting of static shell assembly with consecutively pull-out and lever-out testing were subsequently simulated using finite element analysis. Identified and optimised parameters allowed the accurate numerical reproduction of the raw material tests. Correlation between experimental tests and the numerical simulation of primary implant stability depended on the value of interference fit. However, the validated material model provides the opportunity for subsequent parametric numerical studies. PMID- 22817473 TI - Correction to first total synthesis of protoapigenone and its analogues as potent cytotoxic agents. PMID- 22817472 TI - Brain transcriptome variation among behaviorally distinct strains of zebrafish (Danio rerio). AB - BACKGROUND: Domesticated animal populations often show profound reductions in predator avoidance and fear-related behavior compared to wild populations. These reductions are remarkably consistent and have been observed in a diverse array of taxa including fish, birds, and mammals. Experiments conducted in common environments indicate that these behavioral differences have a genetic basis. In this study, we quantified differences in fear-related behavior between wild and domesticated zebrafish strains and used microarray analysis to identify genes that may be associated with this variation. RESULTS: Compared to wild zebrafish, domesticated zebrafish spent more time near the water surface and were more likely to occupy the front of the aquarium nearest a human observer. Microarray analysis of the brain transcriptome identified high levels of population variation in gene expression, with 1,749 genes significantly differentially expressed among populations. Genes that varied among populations belonged to functional categories that included DNA repair, DNA photolyase activity, response to light stimulus, neuron development and axon guidance, cell death, iron binding, chromatin reorganization, and homeobox genes. Comparatively fewer genes (112) differed between domesticated and wild strains with notable genes including gpr177 (wntless), selenoprotein P1a, synaptophysin and synaptoporin, and acyl-CoA binding domain containing proteins (acbd3 and acbd4). CONCLUSIONS: Microarray analysis identified a large number of genes that differed among zebrafish populations and may underlie behavioral domestication. Comparisons with similar microarray studies of domestication in rainbow trout and canids identified sixteen evolutionarily or functionally related genes that may represent components of shared molecular mechanisms underlying convergent behavioral evolution during vertebrate domestication. However, this conclusion must be tempered by limitations associated with comparisons among microarray studies and the low level of population-level replication inherent to these studies. PMID- 22817474 TI - Stronger and faster degradable biobased poly(propylene sebacate) as shape memory polymer by incorporating boehmite nanoplatelets. AB - Boehmite (BM) nanoplatelets were adopted to compound with fully biobased poly(propylene sebacate) (PPSe) to form the shape memory composites. The PPSe/BM composites kept excellent shape memory properties as previously reported PPSe. Compared to neat PPSe, the composites possess much higher mechanical properties above the melting point and faster biodegradation rate, which was demonstrated via tensile test at elevated temperature and in vitro degradation experiments in phosphate buffer saline (PBS), respectively. The obviously improved mechanical properties at elevated temperature are attributed to the uniform dispersion of the reinforcing boehmite nanoplatelets, which was facilitated by the interfacial interaction between BM and PPSe as revealed by FTIR, XPS, and XRD results. The faster degradation is correlated to accelerated hydrolysis by basic boehmite with surface aluminols. The potential biocompatibility, as substantiated by the outstanding cell viability and cell attachment, together with the realization of transformation temperature close to body temperature makes the PPSe/BM composites suitable for the biomedical applications, such as stents, in human body. PMID- 22817475 TI - Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma. AB - BACKGROUND: The formation of metastases and the efficacy of systemic therapies in cutaneous malignant melanoma (CMM) depend on the characteristics of the tumour cells and the host immune response. Aberrant expression of metallothionein (MT) has been observed in several types of cancers with poor prognoses. OBJECTIVE: To perform an immunohistochemical study on primary CMM comparing the MT expression of tumours without metastases (n = 23) to that of samples with haematogenous metastases (n = 23) and to examine the correlation between MT staining and immunological markers relevant in CMM progression. METHODS: The immunohistochemical labelling of different tumour sections was analysed using tissue microarrays for the evaluation of the suitability of this method in future studies. RESULTS: Our results suggest that MT overexpression is significantly more frequent in primary CMM with haematogenous metastases (P = 0.018) and that the overexpression is independent of the Breslow tumour thickness (R = 0.102, P = 0.501). Interestingly, MT overexpression of the tumour cells was correlated with the presence of tumour-infiltrating CD68(+) macrophages (P = 0.003), a known predictive factor for melanoma progression, thereby suggesting a role for MT in the development of a defective host immune response. Furthermore, the presence of CD163(+) macrophages infiltrating the tumours correlated with metastasis formation (P < 0.001), whereas the presence CD1a(+) dendritic cells surrounding the tumours was associated with a lower risk of haematogenous spread (P = 0.003). CONCLUSION: Our results demonstrate that MT may represent a suitable prognostic factor that can characterize the metastasising ability of CMM and the tumour promoting host immune response. PMID- 22817476 TI - Bicyclo[3.2.0]heptane mechanophores for the non-scissile and photochemically reversible generation of reactive bis-enones. AB - Force-induced transformations of polymer-bound functionalities have the potential to produce a rich array of stress-responsive behavior. One area of particular interest is the activation of non-scissile mechanophores in which latent reactivity can be unveiled that, under the appropriate conditions, could lead to constructive bond formation in materials exposed to typically destructive stress. Here, the mechanical activation of a bicyclo[3.2.0]heptane (BCH) mechanophore is demonstrated via selective labeling of bis-enone products. BCH ring-opening produces large local elongation (>4 A) and products that are reactive to conjugate additions under mild conditions. Subsequent photocyclization regenerates the initial BCH functionality, providing switchable structure and reactivity along the polymer backbone in response to stress and visible light. PMID- 22817477 TI - Functional complementation of Drosophila itpr mutants by rat Itpr1. AB - The Drosophila inositol 1,4,5-trisphosphate receptor (IP(3)R) and mammalian type 1 IP(3)Rs have 57-60% sequence similarity and share major domain homology with each other. Mutants in the single Drosophila IP(3)R gene, itpr, and Itpr1 knockout mice both exhibit lethality and defects in motor coordination. Here the authors show that the rat type-1 IP(3)R, which is the major neuronal isoform, when expressed in the pan-neuronal domain in Drosophila, functionally complements Drosophila IP(3)R function at cellular and systemic levels. It rescues the established neuronal phenotypes of itpr mutants in Drosophila, including wing posture, flight, electrophysiological correlates of flight maintenance, and intracellular calcium dynamics. This is the first in vivo demonstration of functional homology between a mammalian and fly IP(3)R. This study also paves the way for cellular and molecular analyses of the spinocerebellar ataxias in Drosophila, since SCA15/16 is known to be caused by heterozygosity of human ITPR1. PMID- 22817478 TI - Serum lactate and procalcitonin measurements in emergency room for the diagnosis and risk-stratification of patients with suspected infection. AB - OBJECTIVE: To study the contribution of lactate and procalcitonin (PCT) serum measurements for the diagnosis and the risk-stratification of patients with suspected infection presenting to the ED. METHODS: Single-center one year observational study on 462 consecutive patients. Multivariate analysis to assess variables associated with sepsis, severe sepsis, septic shock and severe outcome. RESULTS: Multivariate analysis (Odds ratio [95% CI]), showed that PCT was the best independent variable to identify sepsis (3.98 [2.60-6.10]), while lactate was the best to diagnose severe sepsis (10.88 [6.51-18.19]). Patients with both lactate above 2 mmol.L(-1) and PCT above 0.8 ng.mL(-1) had an enhanced risk of severe outcome. CONCLUSIONS: the dosages of lactate and PCT are complementary for the diagnosis and risk-stratification of patients evaluated in the ED for suspected infection. PMID- 22817479 TI - Sustaining surveillance: evaluating syndromic surveillance in the Pacific. AB - Prior to the 2009 H1N1 pandemic, the Pacific Island Countries and Territories (PICTs) had agreed to develop a standardised, simple syndromic surveillance system to ensure compliance with International Health Regulations requirements (rapid outbreak detection, information sharing and response to outbreaks). In October 2010, the new system was introduced and over the next 12 months implemented in 20 of 22 PICTs. An evaluation was conducted to identify strengths and weaknesses of the system, ease of use and possible points for improvement. An in-country quantitative and qualitative evaluation in five PICTs identified that the most important determinants of the system's success were: simplicity of the system; support from all levels of government; clearly defined roles and responsibilities; feedback to those who collect the data; harmonisation of case definitions; integration of data collection tools into existing health information systems; and availability of clinical and epidemiological advice from external agencies such as the World Health Organization and the Secretariat of the Pacific Community. Regional reporting of alerts, outbreaks and outbreak updates has dramatically increased since implementation of the system. This syndromic system will assist PICTs to detect future influenza pandemics and other emerging infectious diseases and to rapidly contain outbreaks in the Pacific. PMID- 22817480 TI - High-throughput quantitative real-time polymerase chain reaction array for absolute and relative quantification of rhesus macaque types I, II, and III interferon and their subtypes. AB - Rhesus macaques provide a valuable research and preclinical model for cancer and infectious diseases, as nonhuman primates share immune pathways with humans. Interferons (IFNs) are key cytokines in both innate and adaptive immunity, so a detailed analysis of gene expression in peripheral blood and tissues may shed insight into immune responses. Macaques have 18 IFN genes, of which 14 encode for 13 distinct IFN-alpha subtypes, and one for IFN-beta. Here, we developed a high throughput array to evaluate each of the IFN-alpha subtypes, as well as IFN-beta, IFN-gamma and 2 subtypes of IFN-lambda. With this array, expression of each IFN species may be quantified as relative to a reference (housekeeping) gene (DeltaCq) or fitted to its own 4-point standard curve for absolute quantification (copy number per mass unit RNA). After validating the assay with IFN complementary DNA, we determined the IFN expression profile of peripheral blood mononuclear cells from 3 rhesus macaques in response to TLR agonists, and demonstrated that the profiles are consistent among animals. Furthermore, because the IFN expression profiles differ depending on the TLR stimuli, they suggest different biological functions for many of the IFN species measured, including individual subtypes of IFN-alpha. PMID- 22817524 TI - Safety of the open-irrigated ablation catheter for radiofrequency ablation: safety analysis from six clinical studies. AB - BACKGROUND: The open-irrigated catheter is used most frequently for atrial and ventricular radiofrequency ablation (RFA), and is often considered as the standard by which new ablation systems are compared. But few data have been published concerning its safety. This report provides a comprehensive safety analysis of the use of an open-irrigated catheter for RFA of atrial flutter, ventricular tachycardia, and atrial fibrillation in 1,275 patients in six rigorously monitored, prospective, multicenter studies. METHODS: This analysis is of data from six studies conducted as part of both Food and Drug Administration mandated investigational device exemption studies and postapproval studies. The six studies span a period of more than 10 years. All serious RFA complications and vascular access complications that occurred within seven days postprocedure were included. RESULTS: The number of patients who experienced any acute serious RFA complication in these studies combined was 4.9% (63/1,275). The two earliest studies were conducted when the open-irrigated catheter was first introduced, and accounted for 55.6% of the complications. In the first atrial flutter ablation study, RFA complications decreased by 60% (15.4%-6.2%) after a proctoring program was initiated during the study. For all studies, vascular access complications ranged between from 0.5%-4.7%, and no stroke or transient ischemic attack was reported within 7 days postprocedure. No significant pulmonary vein stenosis was reported from the atrial fibrillation studies. CONCLUSION: A proctoring program, careful fluid management, and absence of char and coagulum contributed to the safe use of the open-irrigated RFA catheter. PMID- 22817481 TI - Suppressing inflammation by inhibiting the NF-kappaB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia. AB - BACKGROUND AND PURPOSE: Angiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti-inflammatory effect contributes to the neuroprotection induced by Ang-(1-7) in a rat model of permanent middle cerebral artery occlusion (pMCAO). EXPERIMENTAL APPROACH: We infused Ang-(1-7), Mas receptor antagonist A-779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague-Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty-four hours after pMCAO, the neuroprotective effect of Ang-(1-7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF-kappaB was assessed by Western blot and immunohistochemistry analysis. The level of COX-2 was tested by Western blot analysis and concentrations of pro-inflammatory cytokines were measured by elisa. KEY RESULTS: Infusion of Ang-(1-7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF-kappaB activity, which was accompanied by a reduction of pro-inflammatory cytokines and COX-2 in the peri-infarct regions. These effects of Ang-(1-7) were reversed by A-779 but not by PD123319. Additionally, infusion of A-779 alone increased oxidative stress levels and enhanced NF-kappaB activity, which was accompanied by an up-regulation of pro-inflammatory cytokines and COX 2. CONCLUSION AND IMPLICATIONS: Our findings indicate that suppressing NF-kappaB dependent pathway via Mas receptor may represent one mechanism that contributes to the anti-inflammatory effects of Ang-(1-7) in rats with pMCAO. PMID- 22817525 TI - Review article: overlap syndromes and autoimmune liver disease. AB - BACKGROUND: Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the family of autoimmune liver diseases, whereby the result of immune-mediated liver injury gives rise to varied clinical presentations. Some patients demonstrate a phenotype whereby there is evidence of either PBC or PSC together with overlapping features of AIH. Due to an absence of well-validated diagnostic criteria and a lack of large therapeutic trials, treatment of overlap conditions is empiric and extrapolated from data derived from the primary autoimmune liver diseases. AIMS: To review overlaps in the context of autoimmune liver diseases. METHODS: General and specific review of published articles using PubMed, Medline and Ovid search engines, alongside pre-existing clinical management protocols, guidelines, and the authors' own knowledge of the published literature. RESULTS: The challenges in diagnosis, clinical presentation, determining natural history and outcome of overlaps are presented, as well as present-day management suggestions, some based on evidence, others on consensus and opinion. CONCLUSIONS: Overlapping autoimmune features, be they clinical, serological, histological or radiological are not infrequent, but appropriate diagnosis remains hindered by a lack of standardised diagnostic criteria. Optimum care for those with suspected overlap should thus focus on attention to detail over the fundamental aspects of timely secure diagnosis of the dominant disease entity. Clinicians should counsel patients carefully with regard to the risks and benefits of treatment, bearing in mind the paucity of randomised and controlled outcome data for medical interventions. PMID- 22817526 TI - Emerging Pseudoterranova decipiens (Krabbe, 1878) problems in Baltic cod, Gadus morhua L., associated with grey seal colonization of spawning grounds. PMID- 22817527 TI - Risk factors for unexpected death from suffocation in elderly patients hospitalized for pneumonia. AB - AIM: Unexpected death from suffocation as a result of ortholaryngeal mucinous secretions or vomitus during recovery from pneumonia is devastating for patients, their families and medical professionals. This study aimed to determine the risk factors for unexpected death from suffocation in elderly patients hospitalized for pneumonia. METHODS: This study was carried out with patients aged 65 years and older that were hospitalized for pneumonia and died of any cause. Unexpected death from suffocation was defined as: (i) being in the recovery stage of pneumonia; (ii) presenting stable vital signs a week before death; (iii) dying within 24 h after suffocation; and (iv) aspiration confirmed by transtracheal suction. The clinical features and courses, and methods of feeding were retrospectively analyzed. RESULTS: A total of 11 patients that had an unexpected death from suffocation and 62 patients who died of other causes were enrolled. There were significantly more patients that received tube feeding after admission (continuation and introduction) among the patients who had died of suffocation (63.6%) than in those who had died of other causes (12.9%; P < 0.001). A multiple logistic regression analysis showed that tube feeding after admission was strongly associated with unexpected death from suffocation (adjusted odds ratio 9.536, P = 0.047) after adjusting for sex, age, level of serum albumin, PaO2 /FIO2 ratio, the pneumonia severity score and performance status. CONCLUSION: A continuation of tube feeding after admission is thus considered to be a significant predictor of unexpected death from suffocation in elderly patients with pneumonia. PMID- 22817528 TI - Seasonality of viral infections: mechanisms and unknowns. AB - Seasonality is a long-recognized attribute of many viral infections of humans, but the mechanisms underlying seasonality, particularly for person-to-person communicable diseases, remain poorly understood. Better understanding of drivers of seasonality could provide insights into the relationship between the physical environment and infection risk, which is particularly important in the context of global ecological change in general, and climate change in particular. In broad terms, seasonality represents oscillation in pathogens' effective reproductive number, which, in turn, must reflect oscillatory changes in infectiousness, contact patterns, pathogen survival, or host susceptibility. Epidemiological challenges to correct identification of seasonal drivers of risk include failure to adjust for predictable correlation between disease incidence and seasonal exposures, and unmeasured confounding. The existing evidence suggests that the seasonality of some enteric and respiratory viral pathogens may be driven by enhanced wintertime survival of pathogens, and also by increased host susceptibility resulting from relative 'wintertime immune suppression'. For vector-borne diseases and zoonoses, environmental influences on vector or reservoir abundance, and vector biting rates, are probably more important. However, numerous areas of uncertainty exist, making this an exciting area for future research. PMID- 22817529 TI - Spin-orbit treatment of UV-vis absorption spectra and photophysics of rhenium(I) carbonyl-bipyridine complexes: MS-CASPT2 and TD-DFT analysis. AB - The lowest-lying spectral transitions in [ReX(CO)(3)(bpy)] (X = Cl, Br, I; bpy = 2,2'-bipyridine) complexes were calculated by means of spin-orbit time-dependent density functional theory (SO-TD-DFT) and spin-orbit multistate complete active space second-order perturbation theory (SO-MS-CASPT2). Computational results are compared with absorption spectra measured in different solvents and used to qualitatively explain the temperature dependence of the phosphorescence decay parameters that were measured for the whole series of complexes. Spin-orbit excited-state calculations interpret their electronic absorption spectra as arising from a bunch of spin mixed states with a singlet component of only 50-90% (depending on the halide), and attribute the phosphorescence decay to thermal population of spin-mixed states with a substantial singlet character. PMID- 22817530 TI - Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study. AB - BACKGROUND: Chronic kidney disease progression has been linked to pro inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem. OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development. DESIGN AND METHODS: A retrospective case control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD. RESULTS: Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance. CONCLUSION: Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD. PMID- 22817531 TI - Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3beta and CREB through PI3-K/Akt pathways. AB - Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK-3beta) and cAMP response element-binding protein (CREB) through phosphatidylinositol 3-kinase (PI3-K)-dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four-vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK-3beta and CREB appear to play a critical role in resveratrol neuroprotection through the PI3-K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK-3beta and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3-K, compromised the neuroprotective effect of resveratrol and decreased the level of p-Akt, p-GSK-3beta and p-CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro survival states of Akt, GSK-3beta and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3-K/Akt signaling pathway, subsequently downregulating expression of GSK-3beta and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats. PMID- 22817532 TI - What is "phenoptosis" and how to fight it? AB - Phenoptosis is the death of an organism programmed by its genome. Numerous examples of phenoptosis are described in prokaryotes, unicellular eukaryotes, and all kingdoms of multicellular eukaryotes (animals, plants, and fungi). There are very demonstrative cases of acute phenoptosis when actuation of a specific biochemical or behavioral program results in immediate death. Rapid (taking days) senescence of semelparous plants is described as phenoptosis controlled by already known genes and mediated by toxic phytohormones like abscisic acid. In soya, the death signal is transmitted from beans to leaves via xylem, inducing leaf fall and death of the plant. Mutations in two genes of Arabidopsis thaliana, required for the flowering and subsequent formation of seeds, prevent senescence, strongly prolonging the lifespan of this small semelparous grass that becomes a big bush with woody stem, and initiate substitution of vegetative for sexual reproduction. The death of pacific salmon immediately after spawning is surely programmed. In this case, numerous typical traits of aging, including amyloid plaques in the brain, appear on the time scale of days. There are some indications that slow aging of higher animals and humans is also programmed, being the final step of ontogenesis. It is assumed that stepwise decline of many physiological functions during such aging increases pressure of natural selection on organisms stimulating in this way biological evolution. As a working hypothesis, the biochemical mechanism of slow aging is proposed. It is assumed that mitochondria-generated reactive oxygen species (ROS) is a tool to stimulate apoptosis, an effect decreasing with age the cell number (cellularity) of organs and tissues. A group of SkQ-type substances composed of plastoquinone and a penetrating cation were synthesized to target an antioxidant into mitochondria and to prevent the age-linked rise of the mitochondrial ROS level. Such targeting is due to the fact that mitochondria are the only cellular organelles that are negatively charged compared to the cytosol. SkQs are shown to strongly decrease concentration of ROS in mitochondria, prolong lifespan of fungi, invertebrates, fish, and mammals, and retard appearance of numerous traits of aging. Clinical trials of SkQ1 (plastoquinonyl decyltriphenylphosphonium) have been successfully completed so that the Ministry of Health of the Russian Federation recommends drops of very dilute (0.25 uM) solution of this antioxidant as a medicine to treat the syndrome of dry eye, which was previously considered an incurable disease developing with age. These drops are already available in drugstores. Thus, SkQ1 is the first mitochondria-targeted drug employed in medical practice. PMID- 22817533 TI - Classification of phenoptotic phenomena. AB - Phenoptosis is defined as the programmed death of an organism. In a more detailed formulation of the concept, it is the death of an individual caused by its own actions or by actions of close relatives (and not by accidents or age-independent diseases), which is determined by genes that are favored by natural selection and in certain cases increase the evolvability of organisms. This category of phenomena cannot be justified in terms of individual selection and needs always a justification in terms of supra-individual selection. Four types of phenoptosis are proposed (A, obligatory and rapid; B, obligatory and slow; C, optional; D, indirect). Examples of each type and subtype are given. The classification is discussed in its meaning and implications, and compared with another classification of end life types largely based on the classical concept of senescence. PMID- 22817534 TI - Adaptive aging in the context of evolutionary theory. AB - Compelling evidence for an adaptive origin of aging has clashed with traditional evolutionary theory based on exclusively individual selection. The consensus view has been to try to understand aging in the context of a narrow, restrictive evolutionary paradigm, called the Modern Synthesis, or neo-Darwinism. But neo Darwinism has shown itself to be inadequate in other ways, failing to account for stable ecosystems, for the evolution of sex and the maintenance of diversity and the architecture of the genome, which appears to be optimized for evolvability. Thus aging is not the only reason to consider overhauling the standard theoretical framework. Selection for stable ecosystems is rapid and efficient, and so it is the easiest modification of the neo-Darwinian paradigm to understand and to model. Aging may be understood in this context. More profound and more mysterious are the ways in which the process of evolution itself has been transformed in a bootstrapping process of selection for evolvability. Evolving organisms have learned to channel their variation in ways that are likely to enhance their long-term prospects. This is an expanded notion of fitness. Only in this context can the full spectrum of sophisticated adaptations be understood, including aging, sex, diversity, ecological interdependence, and the structure of the genome. PMID- 22817535 TI - Demographic evidence for adaptive theories of aging. AB - Pleiotropic theories for the evolutionary origins of senescence have been ascendant for forty years (see, for example, G. Williams (1957) Evolution, 11, 398-411; T. Kirkwood (1977) Nature, 270, 301-304), and it is not surprising that interpreters of demographic data seek to frame their results in this context. But some of that evidence finds a much more natural explanation in terms of adaptive aging. Here we re-interpret the 1997 results of the Centenarian Study in Boston, which found in their sample of centenarian women an excess of late childbearing. The finding was originally interpreted as a selection effect: a metabolic link between late menopause and longevity. But we demonstrate that this interpretation is statistically strained, and that the data in fact indicate a causal link: bearing a child late in life induces a metabolic response that promotes longevity. This conclusion directly contradicts some pleiotropic theories of aging that postulate a "cost of reproduction", and it supports theories of aging as an adaptive genetic program. PMID- 22817536 TI - On the programmed/non-programmed aging controversy. AB - The programmed vs. non-programmed aging controversy has now existed in some form for at least 150 years. For much of the XX century, it was almost universally believed that evolution theory prohibited programmed (adaptive) aging in mammals and there was little direct experimental or observational evidence favoring it. More recently, multiple new evolutionary mechanics concepts that support programmed aging and steadily increasing direct evidence favoring it overwhelmingly support the existence of programmed aging in humans and other organisms. This issue is important because the different theories suggest very different mechanisms for the aging process that in turn suggest very different paths toward treating and preventing age-related diseases. PMID- 22817537 TI - Can kin selection facilitate the evolution of the genetic program of senescence? AB - The theory of adaptive senescence, or phenoptosis ("altruistic suicide" of the organism), implies that mutations enhancing mortality growth with age ("senescence genes") can be favored by selection under some circumstances, although the nature of these circumstances and the frequency of their occurrence are not clear. Here I demonstrate by means of computer simulation that senescence genes can spread in the population's gene pool via the mechanism of kin selection if two conditions are met. First, the population must have high viscosity (low intermixing), which provides positive correlation between spatial proximity of individuals and their relatedness, an important precondition for kin selection. Second, prior to acquisition of the senescence genes, there must be a sufficiently fast decline in the reproductive potential with age, while viability should decrease slower or remain constant. These conditions are probably met in some territorial and social species with severe competition for social rank and mating partners. PMID- 22817538 TI - The phenoptosis problem: what is causing the death of an organism? Lessons from acute kidney injury. AB - Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death. PMID- 22817539 TI - Testing predictions of the programmed and stochastic theories of aging: comparison of variation in age at death, menopause, and sexual maturation. AB - One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8-13% for age at menarche, 7-11% for age at menopause, and 16-21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche. PMID- 22817540 TI - Phenoptosis in yeasts. AB - The current view on phenoptosis and apoptosis as genetic programs aimed at eliminating potentially dangerous organisms and cells, respectively, is given. Special emphasis is placed on apoptosis (phenoptosis) in yeasts: intracellular defects and a plethora of external stimuli inducing apoptosis in yeasts; distinctive morphological and biochemical hallmarks accompanying apoptosis in yeasts; pro- and antiapoptotic factors involved in yeast apoptosis signaling; consecutive stages of apoptosis from external stimulus to the cell death; a prominent role of mitochondria and other organelles in yeast apoptosis; possible pathways for release of apoptotic factors from the intermembrane mitochondrial space into the cytosol are described. Using some concrete examples, the obvious physiological importance and expediency of altruistic death of yeast cells is shown. Poorly known aspects of yeast apoptosis and prospects for yeast apoptosis study are defined. PMID- 22817542 TI - Cellularity loss and Dilman's problem: an in silico study. AB - We assume that prolonged trends of increasing concentration of hormones could be a consequence of deterioration of functioning of glands producing inhibitors of their synthesis. Such deterioration would result from loss of cellularity of the glands. Experiments in silico carried out using the model at http://www.winmobile.biz/monstr/ show that, in principle, the diversity of hormonal effects that accompany phenoptosis of multicellular organisms can be provided with a simple "software mechanism". This mechanism is based on the gradual loss of cellularity as a result of continuous run of apoptosis in some cells of the glands due to natural fluctuations in levels of intracellular inducers of apoptosis. The main practical sense of our work lies in the illustration of the fact that substances inhibiting cellularity loss can theoretically be effective suppressors of hormonal changes characteristic for aging. PMID- 22817541 TI - Superoxide scavenging activity of plastoquinone derivative 10-(6' plastoquinonyl)decyltriphenylphosphonium (SkQ1). AB - The plastoquinone derivative 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) has the ability to scavenge superoxide anion radical. This ability is manifested both in vitro and in vivo in experiments with the bacterium Escherichia coli. The protective effect of SkQ1 in vivo significantly exceeds that of ascorbic acid. PMID- 22817543 TI - Longevity and mitochondrial membrane potential. AB - In Saccharomyces cerevisiae yeast cells a decrease in the mitochondrial membrane potential caused by protonophores or by a loss of mitochondrial DNA leads to an increase in longevity (replicative life span). The loss of mitochondrial DNA also activates retrograde signaling that results in certain changes in transcription. Recently, Miceli and coauthors ((2011) Front. Genet., 2, 102) showed that retrograde response is triggered by a drop in the membrane potential. Independently, it has been shown that retrograde response activates autophagic mitochondrial degradation (mitophagy). Together, it suggests that activation of selective mitophagy increases lifespan by protecting cells from accumulation of damaged mitochondria in cells. Low concentrations of protonophores can be beneficial by increasing the accuracy of the mitophagosomal degradation of mitochondria with deleterious mutations in their DNA. PMID- 22817544 TI - Phenoptosis, another specialized neologism, or the mark of a widespread revolution? AB - The classical approach of evolutionism is based on the concept of the survival of the fittest individuals. More and more data indicate that natural selection often acts with supra-individual mechanisms favoring genes and actions harmful for the individual. The most striking type of cases is when an individual kills himself or his offspring by actions genetically determined or favored. The neologism "phenoptosis" describes these events and implicates that they are not evolutionary anomalies but physiological phenomena determined by natural selection. The most important and familiar kind of phenoptosis, the "slow phenoptosis" or aging, which is currently considered an inevitable and scarcely changeable event, is transformed by this different interpretation into a function, in principle modifiable and manageable. Perhaps, the neologism "phenoptosis" will represent, together with the term supra-individual selection, the mark of a vital enrichment of evolutionism, conceived in broader terms of which the individual selection is just a particular case, and will be referred to as the brand and the standard for the start of a new era. PMID- 22817546 TI - Mechanical properties of thin glassy polymer films filled with spherical polymer grafted nanoparticles. AB - It is commonly accepted that the addition of spherical nanoparticles (NPs) cannot simultaneously improve the elastic modulus, the yield stress, and the ductility of an amorphous glassy polymer matrix. In contrast to this conventional wisdom, we show that ductility can be substantially increased, while maintaining gains in the elastic modulus and yield stress, in glassy nanocomposite films composed of spherical silica NPs grafted with polystyrene (PS) chains in a PS matrix. The key to these improvements are (i) uniform NP spatial dispersion and (ii) strong interfacial binding between NPs and the matrix, by making the grafted chains sufficiently long relative to the matrix. Strikingly, the optimal conditions for the mechanical reinforcement of the same nanocomposite material in the melt state is completely different, requiring the presence of spatially extended NP clusters. Evidently, NP spatial dispersions that optimize material properties are crucially sensitive to the state (melt versus glass) of the polymeric material. PMID- 22817545 TI - Composition and organization of active centromere sequences in complex genomes. AB - BACKGROUND: Centromeres are sites of chromosomal spindle attachment during mitosis and meiosis. While the sequence basis for centromere identity remains a subject of considerable debate, one approach is to examine the genomic organization at these active sites that are correlated with epigenetic marks of centromere function. RESULTS: We have developed an approach to characterize both satellite and non-satellite centromeric sequences that are missing from current assemblies in complex genomes, using the dog genome as an example. Combining this genomic reference with an epigenetic dataset corresponding to sequences associated with the histone H3 variant centromere protein A (CENP-A), we identify active satellite sequence domains that appear to be both functionally and spatially distinct within the overall definition of satellite families. CONCLUSIONS: These findings establish a genomic and epigenetic foundation for exploring the functional role of centromeric sequences in the previously sequenced dog genome and provide a model for similar studies within the context of less-characterized genomes. PMID- 22817547 TI - Update: Percentage of young persons with a driver's license continues to drop. AB - In two previous studies, we have shown that in several countries, including the United States, the percentage of young persons with a driver's license has recently decreased substantially. In this update, we extend the analysis for the United States--originally performed for 1983 and 2008-through 2010 by using driver-license and general-population data from the Federal Highway Administration and the U.S. Census Bureau. The results indicate that the general trend continues. For example, the percentages of persons 19 years of age with a driver's license in 1983, 2008, and 2010 were 87.3, 75.5, and 69.5, respectively. PMID- 22817548 TI - Suicide by motor vehicle "accident" in Queensland. AB - OBJECTIVE: Around the world, a substantial proportion of motor vehicle crash deaths are recognized as "hidden" suicides. This project sought to progress understandings of drivers who used a motor vehicle to die by suicide in Queensland, Australia, during the period 1990 to 2007. METHODS: Data for this study were derived from the Queensland Suicide Register and forensic crash investigation case records. Analysis focused on life circumstances and events preceding the death, physical and mental illnesses, past suicidality, and indication of suicide intent (e.g., suicide notes or statements). RESULTS: Compared to cases using other methods, confirmed driver suicides were more likely to be males aged between 25 and 44 years who were employed at the time of death. A large proportion of driver suicides had consumed alcohol immediately prior to the crash and experienced a number of life events, including relationship conflict, legal or criminal issues, and financial problems. CONCLUSION: These exploratory results indicate the need to educate crash investigators about the characteristics of those who use a motor vehicle to die. Improving the information available on the mental and physical health and background life related factors of crash victims can help coroners and researchers determine whether these deaths were intentional. Further investigation is needed in order to formulate intervention strategies for those who may be vulnerable to driver suicide. PMID- 22817550 TI - An investigation of the risk factors causing severe injuries in crashes involving gravel trucks. AB - OBJECTIVE: Gravel trucks that transport heavy materials such as gravel, sand, dirt, or crushed rock require great skill and attention for safe driving, especially when they carry excessive loads or drive at unwarranted speeds that tend to cause serious accidents. Very few studies in the past have attempted to examine the effect of risk factors on the severity of injury associated with gravel truck crashes. This study intends to assess the impact of risk factors on the severity of injury associated with gravel truck crashes. METHODS: Factors that contribute to 2 severity levels of fatalities or injuries and property damage only were examined by using the binary logit model. This article also estimates the effects of risk factors on various types of crashes involving gravel trucks; for example, head-on, angle, sideswipe, and rear-end. RESULTS: Some factors associated with lack of driver awareness, geometric improvements to roads or intersections, and the desire to achieve higher salaries by making more runs in a day were found to have a significant effect on causing severe injuries in gravel truck accidents. CONCLUSIONS: Some policy recommendations to prevent gravel truck-involved crashes that resulted in serious injuries include mandating gravel truck operators and companies to strictly enforce the maximum legal driving hours and improve the wage system of a low pay base and high-bonus by runs, in addition to a required driver training program, mandating gravel truck drivers to attend a traffic safety program for the education and awareness of risky driving behaviors--for example, overloading, speeding, and prolonged driving--before obtaining a professional driver's license. PMID- 22817549 TI - Identifying work-related motor vehicle crashes in multiple databases. AB - OBJECTIVE: To compare and estimate the magnitude of work-related motor vehicle crashes in Utah using 2 probabilistically linked statewide databases. METHODS: Data from 2006 and 2007 motor vehicle crash and hospital databases were joined through probabilistic linkage. Summary statistics and capture-recapture were used to describe occupants injured in work-related motor vehicle crashes and estimate the size of this population. RESULTS: There were 1597 occupants in the motor vehicle crash database and 1673 patients in the hospital database identified as being in a work-related motor vehicle crash. We identified 1443 occupants with at least one record from either the motor vehicle crash or hospital database indicating work-relatedness that linked to any record in the opposing database. We found that 38.7 percent of occupants injured in work-related motor vehicle crashes identified in the motor vehicle crash database did not have a primary payer code of workers' compensation in the hospital database and 40.0 percent of patients injured in work-related motor vehicle crashes identified in the hospital database did not meet our definition of a work-related motor vehicle crash in the motor vehicle crash database. Depending on how occupants injured in work-related motor crashes are identified, we estimate the population to be between 1852 and 8492 in Utah for the years 2006 and 2007. CONCLUSIONS: Research on single databases may lead to biased interpretations of work-related motor vehicle crashes. Combining 2 population based databases may still result in an underestimate of the magnitude of work-related motor vehicle crashes. Improved coding of work-related incidents is needed in current databases. PMID- 22817551 TI - Effects of obesity on seat belt fit. AB - INTRODUCTION: Obesity has been shown to increase the risks of some types of injury in crashes. One way in which obesity may increase injury risk is by changing the routing of the belt relative to the underlying skeletal structures. METHODS: Belt fit was measured in a laboratory study of 54 men and women, 48 percent of whom were obese, defined by body mass index (BMI) of 30 kg/m(2) or greater. Test conditions included a wide range of upper and lower belt anchorage locations and ranges of seat height, seat cushion angle, and seat back angle spanning the conditions in a large fraction of front and rear seats in passenger cars and light trucks. In some conditions, foot position was restricted to simulate the typical situation in the second row of a small sedan. RESULTS: Across individuals, an increase in BMI of 10 kg/m(2) was associated with a lap belt positioned 43 mm further forward and 21 mm higher relative to the anterior superior iliac spines of the pelvis. Each 10 kg/m(2) increase in BMI was associated with an increase in lap belt webbing length of 130 mm. The worsening of lap belt fit with restricted foot position was slightly greater for obese participants. Obesity was associated with a more-inboard shoulder belt routing across a wide range of upper belt anchorage locations, and the shoulder belt webbing length between the D-ring and latch plate increased by an average of 60 mm with each 10 kg/m(2) increase in BMI. DISCUSSION AND CONCLUSIONS: The results suggest that obesity effectively introduces slack in the seat belt system by routing the belt further away from the skeleton. Particularly in frontal crashes, but also in rollovers and other scenarios, this slack will result in increased excursions and an increased likelihood and severity of contacts with the interior. The higher routing of the lap belt with respect to the pelvis also increases the likelihood of submarining in frontal crashes. PMID- 22817552 TI - A brief educational program improves awareness regarding whiplash prevention among a cohort of vehicle fleet managers in British Columbia, Canada. AB - OBJECTIVE: Previous research indicates that most vehicle occupants are unaware that a correctly adjusted, well-designed vehicular head restraint provides substantial protection against whiplash injuries. This study examined whether a brief educational intervention could improve awareness regarding whiplash injuries and prevention strategies among a cohort of vehicle fleet managers. METHODS: A brief written survey was administered prior to, and approximately 1 h after a 30-min presentation on whiplash injury and prevention measures, which was delivered at a regional fleet manager meeting held in British Columbia, Canada (n = 27 respondents). RESULTS: Respondents had low baseline knowledge levels regarding the causes, consequences, and prevention of whiplash. Following the presentation, however, respondents improved awareness in all of these domains and, most important, reported an increased motivation to implement changes based on this newly acquired knowledge. CONCLUSIONS: These results indicate that improved education practices and social marketing tools are potentially valuable to increase awareness among relevant stakeholders. PMID- 22817553 TI - Motion of the head and neck of female and male volunteers in rear impact car-to car impacts. AB - OBJECTIVES: The objectives of this study were to quantify and compare dynamic motion responses between 50th percentile female and male volunteers in rear impact tests. These data are fundamental for developing future occupant models for crash safety development and assessment. METHODS: High-speed video data from a rear impact test series with 21 male and 21 female volunteers at 4 and 8 km/h, originally presented in Siegmund et al. (1997), were used for further analysis. Data from a subset of female volunteers, 12 at 4 km/h and 9 at 8 km/h, were extracted from the original data set to represent the 50th percentile female. Their average height was 163 cm and their average weight was 62 kg. Among the male volunteers, 11 were selected, with an average height of 175 cm and an average weight of 73 kg, to represent the 50th percentile male. Response corridors were generated for the horizontal and angular displacements of the head, T1 (first thoracic vertebra), and the head relative to T1. T-tests were performed with the statistical significance level of .05 to quantify the significance of the differences in parameter values for the males and females. RESULTS: Several differences were found in the average motion response of the male and female volunteers at 4 and 8 km/h. Generally, females had smaller rearward horizontal and angular motions of the head and T1 compared to the males. This was mainly due to shorter initial head-to-head restraint distance and earlier head-to-head restraint contact for the females. At 8 km/h, the female volunteers showed 12 percent lower horizontal peak rearward head displacement (P = .018); 22 percent lower horizontal peak rearward head relative to T1 displacement (P = .018); and 30 percent lower peak head extension angle (P = .001). The females also had more pronounced rebound motion. CONCLUSIONS: This study indicates that there may be characteristic differences in the head-neck motion response between 50th percentile males and females in rear impacts. The exclusive use of 50th percentile male rear impact dummies may thus limit the assessment and development of whiplash prevention systems that adequately protect both male and female occupants. The results of this study could be used in the development and evaluation of a mechanical and/or computational average-sized female dummy model for rear impact safety assessment. These models are used in the development and evaluation of protective systems. It would be of interest to make further studies into seat configurations featuring a greater head-to-head restraint distance. PMID- 22817554 TI - Front versus rear seat placement of children aged 12 or younger within vehicles: a rural/urban comparison in North Dakota. AB - OBJECTIVE: Research has shown that rear-seated children are 36 to 40 percent safer than front-seated children. Because of the substantial differences in traffic safety culture that appear to exist in rural areas and the limited research regarding seat placement and rurality, this study seeks to contribute to the safety literature by determining at what rate children are riding in the front seat and whether differences exist between rural and urban areas in regards to child front seat placement. METHODS: Current child placement frequencies within vehicles were ascertained through direct observations of morning child drop-offs at randomly selected urban and rural elementary schools in eastern North Dakota during November and December of 2009, with a focus on children aged 12 or younger. Two observers wearing orange safety vests and carrying observation sheets were stationed at each elementary school a minimum of 45 min prior to each school's designated start time. Based on the vehicles that entered the school's parking lot/drop-off circle and from which a minimum of one child exited, observers were instructed to record vehicle type, presence of children in the front seat appearing to be younger than 13 years old, availability of room in the back seat, and placement of other children in the vehicle. RESULTS: During November and December of 2009 a total of 537 vehicles were observed at urban schools and 150 vehicles were observed at rural schools. Of the 537 vehicles observed at urban schools, 28.7 percent had children seated in the front seat, whereas 41.3 percent of the 150 vehicles observed at rural schools had front seated children. Significant urban/rural differences exist in child seat placement, with vehicles in rural areas much more likely to be carrying front seated children than vehicles in urban areas. CONCLUSIONS: Based on a sample of vehicles observed at urban and rural elementary schools in North Dakota, the results of this study indicate that there are significant rural/urban differences in child seat placement. PMID- 22817555 TI - A methodology to estimate the kinematics of pediatric occupants in frontal impacts. AB - OBJECTIVE: The goal of this article is to propose a new methodology to estimate the sagittal plane displacement of the head, spine, and pelvis of a 6-year-old (6YO) occupant during a high-speed frontal impact. Research has shown major discrepancies between the spinal kinematics of current pediatric anthropomorphic test devices and humans during frontal impacts. This article provides an estimation of the kinematics of a pediatric subject that may assist in the development of physical and computational models of a 6YO occupant in high-speed frontal impacts. METHODS: This article presents data on 4 different experimental data sets corresponding to noninjurious low-speed (nominally 9 km/h) frontal impacts involving pediatric and adult volunteers and to low-speed (9 km/h) and high-speed (40 km/h) frontal impacts with postmortem human subjects (PMHS). Kinematic data from each subject were first normalized to the size of a 50th percentile within its age group. Two already published and commonly used scaling methods (mass scaling and the Society of Automotive Engineers [SAE] scaling methods) were assessed using volunteer data. A new scaling method based on energy considerations was developed. RESULTS: Both the mass scaling and the SAE scaling methods failed to predict the actual pediatric displacement at 9 km/h. The newly proposed method substantially improved the prediction of the pediatric kinematics at low speed and it was applied to the high-speed PMHS data to provide an approximation of the displacements of the head, thoracic spine, and pelvis of a 6YO occupant in a 40 km/h frontal impact. CONCLUSIONS: A new scaling method based on energy conservation improved the prediction of the displacement of the pediatric head, thoracic spine, and pelvis at 9 km/h. This method was then applied to the response of the PMHS in a high-speed impact to provide an approximation of the 6YO kinematics in a 40 km/h frontal impact. The article also discusses the limitations of the method, which failed to completely describe the kinematics of pediatric occupants. PMID- 22817556 TI - Pedestrian headform testing: inferring performance at impact speeds and for headform masses not tested, and estimating average performance in a range of real world conditions. AB - OBJECTIVE: Tests are routinely conducted where instrumented headforms are projected at the fronts of cars to assess pedestrian safety. Better information would be obtained by accounting for performance over the range of expected impact conditions in the field. Moreover, methods will be required to integrate the assessment of secondary safety performance with primary safety systems that reduce the speeds of impacts. Thus, we discuss how to estimate performance over a range of impact conditions from performance in one test and how this information can be combined with information on the probability of different impact speeds to provide a balanced assessment of pedestrian safety. METHOD: Theoretical consideration is given to 2 distinct aspects to impact safety performance: the test impact severity (measured by the head injury criterion, HIC) at a speed at which a structure does not bottom out and the speed at which bottoming out occurs. Further considerations are given to an injury risk function, the distribution of impact speeds likely in the field, and the effect of primary safety systems on impact speeds. These are used to calculate curves that estimate injuriousness for combinations of test HIC, bottoming out speed, and alternative distributions of impact speeds. RESULTS: The injuriousness of a structure that may be struck by the head of a pedestrian depends not only on the result of the impact test but also the bottoming out speed and the distribution of impact speeds. Example calculations indicate that the relationship between the test HIC and injuriousness extends over a larger range than is presently used by the European New Car Assessment Programme (Euro NCAP), that bottoming out at speeds only slightly higher than the test speed can significantly increase the injuriousness of an impact location and that effective primary safety systems that reduce impact speeds significantly modify the relationship between the test HIC and injuriousness. CONCLUSIONS: Present testing regimes do not take fully into account the relationship between impact severity and variations in impact conditions. Instead, they assess injury risk at a single impact speed. Hence, they may fail to differentiate risks due to the effects of bottoming out under different impact conditions. Because the level of injuriousness changes across a wide range of HIC values, even slight improvements to very stiff structures need to be encouraged through testing. Indications are that the potential of autonomous braking systems is substantial and needs to be weighted highly in vehicle safety assessments. PMID- 22817557 TI - The effect on road safety of a modal shift from car to bicycle. AB - OBJECTIVE: To describe and apply a method to assess the effect on road safety of a modal shift from cars to bicycles. METHOD: Ten percent of all car trips shorter than 7.5 km were assumed to be replaced by bicycle trips. Single-vehicle and multivehicle crashes involving cars and/or bicycles were considered. The safety of car occupants and cyclists was taken into account as well as the safety of other road users involved in such crashes. The computations were carried out by age and gender. Assuming constant risk (casualties per distance traveled), the expected number of accidents is proportional to the mobility shift. Several types of risk were considered: the risk of being injured as a car driver or cyclist and the risk of being involved as a car driver or cyclist in a crash in which another road user is injured. RESULTS: The results indicated that the total gain of the modal shift was negative for fatalities, which means that there was a net increase in the number of fatalities. The modal shift was advantageous for young drivers and disadvantageous for elderly drivers. In addition, it was more positive for males than for females. The turning point was around the age of 35. For hospitalized casualties, due to the strong influence of the many hospitalized cyclists in nonmotorized vehicle crashes, there was a strong negative overall effect, and the modal shift resulted in a positive effect for 18- and 19-year-old males only. Overall, a small increase (up to 1%) in the number of cyclist fatalities and a greater increase of 3.5 percent in the number of inpatients was expected. The increase in casualties was mainly due to the proportion of single vehicle bicycle crashes with serious injuries in relation to the total number of injured cyclists. The effect of the modal shift was shown to depend on age and gender, resulting in fewer casualties for younger drivers and for women. CONCLUSIONS: It is possible to provide a first approximation of the effect on road safety of a mobility shift from cars to bicycles. This approximation indicates that, in general, road safety does not benefit from this modal shift. The effect differs for gender and age groups. Elderly drivers are safer inside a car than on a bicycle. For the number of hospitalized casualties, the modal shift increases the number of casualties for practically all ages and both genders. PMID- 22817558 TI - Challenges in evaluating the decade of action for road safety in developing countries: a survey of traffic fatality reporting capacity in the Eastern Mediterranean region. AB - OBJECTIVE: The United Nations have proclaimed the "Decade of Action for Road Safety 2011-2020" to reduce traffic fatalities worldwide, particularly in low- and middle-income countries (LMICs). It is estimated that the LMICs in the Eastern Mediterranean Region (EMR) have the highest traffic fatality rates. This study evaluated the capacity of current traffic fatality reporting in the EMR to indicate the impact of future interventions. METHODS: The World Health Organization's (WHO) SMART (specific, measurable, achievable, realistic, timely) criteria for indicators were used to assess traffic fatality reporting in the 17 LMICs in the EMR. RESULTS: Official statistics accounted for less than 60 percent of estimated fatalities in 12 of the 17 EMR countries. Police data were the main source of reporting for 11 LMICs, only 3 had a specific traffic fatality surveillance system, the standard definition of fatality was used for 7 LMICs, local fatality distributions were available for 5 LMICs, multiple data sets were available for 6 LMICs, and only 7 regularly published fatality data. CONCLUSIONS: These reporting problems could easily undermine the evaluation of any future preventive efforts in the EMR. International cooperation and financial assistance from experienced high-income countries, focusing on building capacity, might be useful in strengthening the current reporting systems in LMICs in the EMR. PMID- 22817559 TI - Metaproterenol, isoproterenol, and their bisdimethylcarbamate derivatives as human cholinesterase inhibitors. AB - Metaproterenol and isoproterenol are bronchodilators that provide a structural basis for many other bronchodilators currently in use. One of these structurally related bronchodilators is terbutaline; it is administered as a prodrug, bambuterol, and is metabolized (bioconverted) into terbutaline by butyrylcholinesterase (BChE). The metabolism rate can be affected by BChE gene polymorphism in the human population and BChE stereoselectivity. The aim of our study was to investigate inhibition of human BChE and acetylcholinesterase (AChE) with metaproterenol, isoproterenol, and newly synthesized racemic bisdimethylcarbamate derivatives of metaproterenol (metacarb) and isoproterenol (isocarb) and their (R)-enantiomers to see if their bioconversion is affected by BChE inhibition in the same way as that for bambuterol. Metacarb and isocarb proved to be selective BChE inhibitors, as they progressively inhibited AChE 960 to 80 times more slowly than BChE(UU). All studied cholinesterases displayed poor affinity for metaproterenol and isoproterenol, yet BChE(UU) had an affinity about five times higher than that of AChE. PMID- 22817560 TI - Structure and macroscopic tackiness of ultrathin pressure sensitive adhesive films. AB - Ultrathin layers of the statistical copolymer P(nBA-stat-MA) with a majority of n butyl acrylate (nBA) and a minority of methyl acrylate (MA) are characterized with respect to the film morphology and the mechanical response in a probe tack test. The probed copolymer can be regarded as a model system of a pressure sensitive adhesive (PSA). The films are prepared by spin-coating which enables an easy thickness control via the polymer concentration of the solution. The film thickness is determined with x-ray reflectivity (XRR) and white light interferometry (WLI). Grazing incidence small angle x-ray scattering (GISAXS) provides detailed and statistically significant information about the film morphology. Two types of lateral structures are identified and no strong correlation of these structures with the PSA film thickness is observed. In contrast, prominent parameters of the probe tack test, such as the stress maximum and the tack energy, exhibit an exponential dependence on the film thickness. PMID- 22817561 TI - Increased production of nitric oxide correlates with tumor growth in Algerian patients with nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is thought to arise because of chronic inflammation. The correlation between nitric oxide (NO) production, a biomarker of inflammation and NPC development remains unexplored. To investigate this question, we performed a profile analysis on plasma collected from untreated, treated, remissive, cured and relapsing patients. Nitrites were measured to assess NO activity. We observed that increased nitrites concentrations in untreated and relapsing patients associated with tumor development. Moreover, nitrites levels were similar in remissive, cured and healthy individuals. Altogether, our results suggest that NO might be an interesting blood biomarker to monitor tumor growth in NPC patients. PMID- 22817604 TI - Monosaccharide composition of the outer membrane lipopolysaccharide and O-chain from the freshwater cyanobacterium Microcystis aeruginosa NIES-87. AB - AIMS: Bacterial lipopolysaccharide (LPS) protruding from the outermost layer of the outer membrane is expected to play an important role in cell physiology by interacting with molecules in the extracellular milieu; however, the structural and functional characteristics of these components in cyanobacteria remain largely unknown. We isolated water-soluble fractions of LPS and O-chain from the bloom-forming freshwater cyanobacterium Microcystis aeruginosa NIES-87 and identified their monosaccharide compositions. METHODS AND RESULTS: SDS-PAGE followed by silver staining demonstrated that the isolated total LPS was the smooth type with different numbers of repeating sugar units in the O-chain region. GC/MS analysis after acid hydrolysis, reduction and acetylation treatments indicated that the neutral monosaccharide components of the total LPS include glucose, rhamnose, mannose, galactose and xylose (in decreasing order of weight percentage), while only glucose was detected in the purified O-chain fraction. MALDI-TOF MS analysis suggested that the O-chain fraction is composed of repeating glucose and methylated glucose disaccharide units. CONCLUSIONS: Our results indicate that the monosaccharide composition of M. aeruginosa O-chain is relatively simple. SIGNIFICANCE AND IMPACT OF THE STUDY: Although further studies are necessary, these findings provide fundamental information for understanding the structural and functional properties of cyanobacterial LPS and O-chain. PMID- 22817605 TI - Conflicting results of pacing maneuvers during supraventricular tachycardia. PMID- 22817608 TI - Human Toll-like receptor 8 can be cool too: implications for foreign RNA sensing. AB - Recent advances in our understanding of foreign nucleic acid sensing indicate an important role for the human Toll-like receptor (TLR) 8 in the initiation of immune responses to certain pathogens. However, TLR8, far too often grouped together with TLR7 for its common ability to detect RNA, has a function on its own in the initiation of specific proinflammatory responses to viruses and bacteria. Here, we present an overview of what is currently known of human TLR8 biology, from genetic regulation to its function in innate immunity, and discuss how TLR8 could present novel therapeutic opportunities in viral and cancer diseases. PMID- 22817606 TI - Rosuvastatin prevents angiotensin II-induced vascular changes by inhibition of NAD(P)H oxidase and COX-1. AB - BACKGROUND AND PURPOSE: NAD(P)H oxidase and COX-1 participate in vascular damage induced by angiotensin II. We investigated the effect of rosuvastatin on endothelial dysfunction, vascular remodelling, changes in extracellular matrix components and mechanical properties of small mesenteric arteries from angiotensin II-infused rats. EXPERIMENTAL APPROACH: Male rats received angiotensin II (120 ng.kg-1 .min-1 , subcutaneously) for 14 days with or without rosuvastatin (10 mg.kg-1 .day-1 , oral gavage) or vehicle. Vascular functions and morphological parameters were assessed by pressurized myography. KEY RESULTS: In angiotensin II-infused rats, ACh-induced relaxation was attenuated compared with controls, less sensitive to L-NAME, enhanced by SC-560 (COX-1 inhibitor) or SQ 29548 (prostanoid TP receptor antagonist), and normalized by the antioxidant ascorbic acid or NAD(P)H oxidase inhibitors. After rosuvastatin, relaxations to ACh were normalized, fully sensitive to L-NAME, and no longer affected by SC-560, SQ-29548 or NAD(P)H oxidase inhibitors. Angiotensin II enhanced intravascular superoxide generation, eutrophic remodelling, collagen and fibronectin depositions, and decreased elastin content, resulting in increased vessel stiffness. All these changes were prevented by rosuvastatin. Angiotensin II increased phosphorylation of NAD(P)H oxidase subunit p47phox and its binding to subunit p67phox, effects inhibited by rosuvastatin. Rosuvastatin down-regulated vascular Nox4/NAD(P)H isoform and COX-1 expression, attenuated the vascular release of 6-keto-PGF1alpha , and enhanced copper/zinc-superoxide dismutase expression. CONCLUSION AND IMPLICATIONS: Rosuvastatin prevents angiotensin II induced alterations in resistance arteries in terms of function, structure, mechanics and composition. These effects depend on restoration of NO availability, prevention of NAD(P)H oxidase-derived oxidant excess, reversal of COX-1 induction and its prostanoid production, and stimulation of endogenous vascular antioxidant defences. PMID- 22817607 TI - Randomized controlled trial of postoperative exercise rehabilitation program after lumbar spine fusion: study protocol. AB - BACKGROUND: Lumbar spine fusion (LSF) effectively decreases pain and disability in specific spinal disorders; however, the disability rate following surgery remains high. This, combined with the fact that in Western countries the number of LSF surgeries is increasing rapidly it is important to develop rehabilitation interventions that improve outcomes. METHODS/DESIGN: In the present RCT-study we aim to assess the effectiveness of a combined back-specific and aerobic exercise intervention for patients after LSF surgery. One hundred patients will be randomly allocated to a 12-month exercise intervention arm or a usual care arm. The exercise intervention will start three months after surgery and consist of six individual guidance sessions with a physiotherapist and a home-based exercise program. The primary outcome measures are low back pain, lower extremity pain, disability and quality of life. Secondary outcomes are back function and kinesiophobia. Exercise adherence will also be evaluated. The outcome measurements will be assessed at baseline (3 months postoperatively), at the end of the exercise intervention period (15 months postoperatively), and after a 1 year follow-up. DISCUSSION: The present RCT will evaluate the effectiveness of a long-term rehabilitation program after LSF. To our knowledge this will be the first study to evaluate a combination of strength training, control of the neutral lumbar spine position and aerobic training principles in rehabilitation after LSF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00834015. PMID- 22817609 TI - Proliferation signal inhibitors in the treatment of lupus nephritis: preliminary experience. AB - AIM: Proliferation signal inhibitors (PSI) have demonstrated efficacy in prevention and treatment in an animal model of lupus nephritis (LN) but there are no data regarding the use of PSI in human LN. We report here our experience of using PSI treatment in seven patients with severe proliferative lupus nephritis. METHODS: This is a retrospective study on patients with proliferative lupus nephritis who had received PSI treatment. RESULTS: Seven patients were included. Two patients had concomitant membranous lupus nephropathy. The indications for PSI included mycophenolate mofetil intolerance (n = 4), history of malignancy (n = 2) and leucopoenia (n = 1). Five patients were given PSI when disease was active. Two had treatment discontinued because of acute cholecystitis and leucopoenia, respectively. In the other three patients combined steroid and PSI treatment as induction therapy led to improvements in serology, renal function and proteinuria. In two patients treated with PSI and low-dose steroid as maintenance immunosuppression, both maintained stable lupus serology, renal function and proteinuria over 18 months. Side-effects included dyslipidemia and oral ulcers. CONCLUSION: Proliferation signal inhibitors warrants further investigation as an alternative immunosuppressive treatment in lupus nephritis. PMID- 22817611 TI - Two concise enantioselective total syntheses of (-)-glabrescol implicate alternative biosynthetic pathways starting from squalene. AB - The C(2)-symmetric (-)-glabrescol was synthesized in two steps from (10S,11R) dihydroxy-10,11-dihydrosqualene or squalene with 50% or 10% overall yields, respectively. These highly efficient and biomimetic syntheses employed a base promoted middle-to-terminal double epoxide-opening cascade, which constructs the five tetrahydrofuran rings in glabrescol in one operation. PMID- 22817610 TI - Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. AB - AIM: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome. METHODS: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS. RESULTS: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted. CONCLUSION: The 26-year-old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population. PMID- 22817612 TI - Five models of players' rule behavior for game balance. AB - We present a five-part model of players' rule behaviors in a multiplayer online game (utilization, emergence, usefulness, usefulness-balance, and balance usefulness). The model was identified through a pilot study involving nine expert players. The model fitness was then verified in a main experiment involving eighteen regular players. Our results showed that the utilization (4 players) and emergence (4 players) models were most frequently used, followed by the balance usefulness (3 players), usefulness (3 players), and usefulness-balance (2 players) models. The coding scheme for this research was built from video observations and a literature review. We suggest this model is applicable for the implementation of a human-like virtual character's artificial intelligence algorithm in the game editors and the server loader for quality assurance. PMID- 22817613 TI - Updated thresholds for serum alanine aminotransferase level in a large-scale population study composed of 34 346 subjects. AB - BACKGROUND: The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently. AIM: To identify modulating factors for serum ALT levels and to refine its ULN threshold. METHODS: We enrolled 34 346 consecutive subjects who completed the health check-up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population. RESULTS: A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high-density lipoprotein-cholesterol, triglyceride, hepatitis B virus surface antigen, anti-hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut-off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets. CONCLUSIONS: The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels. PMID- 22817614 TI - The development of a supportive care needs assessment tool for Indigenous people with cancer. AB - BACKGROUND: Little is known about the supportive care needs of Indigenous people with cancer and to date, existing needs assessment tools have not considered cultural issues for this population. We aimed to adapt an existing supportive care needs assessment tool for use with Indigenous Australians with cancer. METHODS: Face-to-face interviews with Indigenous cancer patients (n = 29) and five focus groups with Indigenous key-informants (n = 23) were conducted to assess the face and content validity, cultural acceptability, utility and relevance of the Supportive Care Needs Survey - Short Form 34 (SCNS-SF34) for use with Indigenous patients with cancer. RESULTS: All items from the SCNS-SF34 were shortened and changed to use more appropriate language (e.g. the word 'anxiety' was substituted with 'worry'). Seven questions were omitted (e.g. items on death and future considerations) as they were deemed culturally inappropriate or irrelevant and 12 items were added (e.g. accessible transport). Optional instructions were added before the sexual items. The design and response format of the SCNS-SF34 was modified to make it easier to use for Indigenous cancer patients. Given the extensive modifications to the SCNS-SF34 and the liklihood of a different factor structure we consider this tool to be a new tool rather than a modification. The Supportive care needs assessment tool for Indigenous people (SCNAT-IP) shows promising face and content validity and will be useful in informing services where they need to direct their attention for these patients. CONCLUSIONS: Indigenous people with cancer have language, customs and specific needs that are not accommodated within the standard SCNS-SF34. Our SCNAT-IP improves acceptability, relevance and face validity for Indigenous-specific concerns. Our SCNAT-IP will allow screening for supportive care needs that are specific to Indigenous cancer patients' and greatly inform targeted policy development and practice. PMID- 22817615 TI - Total synthesis of 2''',5'''-diepisilvestrol and its C1''' epimer: key structure activity relationships at C1''' and C2'''. AB - The first total synthesis of the low-abundance natural product 2''',5''' diepisilvestrol (4) is described. The key step involved a Mitsunobu coupling between cyclopenta[b]benzofuran phenol 7 and dioxane lactol 6. Deprotection then gave a 1:2.6 ratio of natural product 2''',5'''-diepisilvestrol (4) and its C1 epimer 1''',2''',5'''-triepisilvestrol (15) in 50% overall yield. An in vitro protein translation inhibition assay showed that 2''',5'''-diepisilvestrol (4) was considerably less active than episilvestrol (2), while the unnatural isomer 1''',2''',5'''-triepisilvestrol (15) was essentially inactive, showing that the configuration at C1''' and C2''' has a large effect on the biological activity. PMID- 22817617 TI - Beetle-inspired bidirectional, asymmetric interlocking using geometry-tunable nanohairs. AB - We present bidirectional, asymmetric interlocking behaviors between tilted micro- and nanohair arrays inspired from the actual wing locking device of beetles. The measured shear adhesion force between two identical tilted microhair arrays (1.5 MUm radius, 30 MUm height) turned out to be higher in the reverse direction than that in the angled direction, suggesting that the directionality of beetle's microtrichia may play a critical role in preventing the elytra from shifting along the middle of insect body. Furthermore, we observed dramatic enhancement of shear adhesion using asymmetric interlocking of various nanohair arrays (tilting angle, delta < 40 degrees ). A maximum shear locking force of ~60 N/cm(2) was measured for the nanohair arrays of 50 nm radius and 1 MUm height with a hysteresis as high as ~3. A simple theoretical model was developed to describe the measured asymmetric adhesion forces and hysteresis, in good agreement with the experimental data. PMID- 22817618 TI - Improving oversight of innovative medical interventions in Texas, USA. PMID- 22817616 TI - Prenatal polychlorinated biphenyl exposure is associated with decreased gestational length but not birth weight: archived samples from the Child Health and Development Studies pregnancy cohort. AB - BACKGROUND: Polychlorinated biphenyls (PCBs), known endocrine disruptors, were banned in 1979 but persist in the environment. Previous studies are inconsistent regarding prenatal exposure to PCBs and pregnancy outcomes. We investigated associations between prenatal exposure to PCBs and gestational length and birth weight. METHODS: In a sample of 600 infants (born between 1960 and 1963) randomly selected from Child Health and Development Studies participants followed through adolescence we measured 11 PCB congeners in maternal post partum sera (within three days of delivery). Length of gestation was computed from the reported first day of the last menstrual period (LMP) and delivery date. Linear regression was used to estimate associations between PCB exposure and gestational age and birth weight, adjusting for potential confounders. PCBs were grouped according to hypothesized biological action (1b (sum of weak phenobarbital inducers), 2b (sum of limited dioxin activity), and 3 (sum of CYP1A and CYP2b inducers)) or degree of ortho- substitution (mono, di, tri). Secondary analyses examined associations between total PCB exposure and exposure to individual congeners. RESULTS: Each unit increase in mono-ortho substituted PCBs was associated with a 0.30 week decrease (95% confidence interval (CI) -0.59, -0.016), corresponding to a 2.1 (95% CI -4.13, -0.11) day decrease in length of gestation. Similar associations were estimated for di-ortho substituted PCBs, (1.4 day decrease; (95% CI -2.9, 0.1)) and group 3 PCBs (0.84 day decrease; (95% CI -1.8, 0.11). We found similar associations in congener specific analyses and for the sum of congeners. CONCLUSIONS: Our study provides new evidence that PCB exposure shortens length of gestation in humans. This may have public health implications for population exposures. PMID- 22817619 TI - A decade of cell therapy clinical trials (2000-2010). PMID- 22817622 TI - A new factory for insulin-producing cells: the gut? PMID- 22817623 TI - Conference scene: Trends in the stem cells marketplace: report from the SSCN Conference 2012. PMID- 22817624 TI - Cell therapy with adipose tissue-derived stem/stromal cells for elastase-induced pulmonary emphysema in rats. AB - AIMS: The purpose of this study was to elucidate the mechanism underlying the effects of adipose tissue-derived stem/stromal cell (ASC) transplantation on porcine pancreatic elastase-induced emphysema. MATERIALS & METHODS: ASCs (2.5 * 10(6)) were transplanted into pancreatic elastase (250 U/kg)-treated rats, after which gas exchange and growth factor/cytokine levels in lung tissue were determined. RESULTS: ASC transplantation restored pulmonary function (arterial oxygen tension and alveolar-arterial oxygen tension difference) almost to that of normal animals. Enlargement of the alveolar airspaces was inhibited. HGF and CINC 1 levels were significantly higher in the ASC group even at 2 weeks after transplantation. Sponge implantation with CINC-1 induced neovascular formation with increased HGF. In vitro secretion of HGF and CINC-1 from ASCs was promoted in the presence of IL-1beta. CONCLUSION: Not only HGF, but also CINC-1, secreted from transplanted and viable ASCs presumably contributed to lung repair through angiogenesis. PMID- 22817625 TI - Decision-making in stem cell trials for spinal cord injury: the role of networks and peers. AB - AIMS: The purpose of this study was to characterize the self-perceived role of professionals and personal caregivers in decision-making about participation in stem cell clinical trials by individuals in early post-spinal cord injury time points. MATERIALS & METHODS: Data were obtained from focus groups and semi structured individual interviews from two networks: healthcare professionals (e.g., physicians, allied healthcare workers) and personal contacts (family and friends). We transcribed audio-recorded data in extenso and analyzed transcripts using the qualitative method of constant comparison. RESULTS: Results from more than 60 h of data suggest that adequate decision support is difficult to achieve for individuals during the subacute phase of injury. Three major obstacles prevent this goal: the personal dimensions of risk; limited insights into the pathophysiology and recovery process; and deference of each network to the other. CONCLUSION: The data suggest that novel strategies for decision-making processes, such as those involving peer support, are needed to enrich the knowledge base of all stakeholders. The results further underscore the importance of the role that both the academic and private sector play in ensuring the protection of human subjects in these trials. PMID- 22817626 TI - Controlled release of thymosin beta4 from injected collagen-chitosan hydrogels promotes angiogenesis and prevents tissue loss after myocardial infarction. AB - AIMS: Acute myocardial infarction (MI) leads to fibrosis and severe left ventricular wall thinning. Enhancing vascularization within the infarct reduces cell death and maintains a thick left ventricular wall, which is essential for proper cardiac function. Here, we evaluated the controlled delivery of thymosin beta4 (Tbeta4), which supports cardiomyocyte survival by inducing vascularization and upregulating Akt activity, in the treatment of MI. MATERIALS & METHODS: We injected collagen-chitosan hydrogel with controlled release of Tbeta4 into the infarct after performing left anterior descending artery ligation in rats. RESULTS: Tbeta4-encapsulated hydrogel (thymosin) significantly reduced tissue loss post-MI (13 +/- 4%), compared with 58 +/- 3% and 30 +/- 8% tissue loss for no treatment (MI only) and Tbeta4-free hydrogel (control). Significantly more Factor VIII-positive blood vessels with diameter >50 um were in the thymosin group compared with both MI only and control (p < 0.0001), showing Tbeta4-induced vascularization. Wall thickness was positively correlated with the mature blood vessel density (r = 0.9319; p < 0.0001). CONCLUSION: Controlled release of Tbeta4 within the infarct enhances angiogenesis and presence of cardiomyocytes that are necessary for cardiac repair. PMID- 22817628 TI - Impact of inflammation on the osteoarthritic niche: implications for regenerative medicine. AB - Osteoarthritis (OA) is the most common form of arthritis worldwide and is the sixth leading cause of disability. It costs the UK economy approximately 1% of gross national product per annum. With an aging population, the cost of chronic conditions such as OA continues to rise. Historically, treatments for OA have been limited to painkillers, physiotherapy and joint injections. When these fail, patients are referred for joint replacement surgery. With the advent of tissue engineering strategies aimed at generating new bone and cartilage for repair of osteochondral defects, there has been considerable interest in exploiting these techniques to devise new treatments for OA. To date, little consideration has been given to the OA niche and attendant inflammatory milieu for any regenerative skeletal strategy. This review highlights the importance of understanding the osteoarthritic niche in order to modify existing tissue engineering and regenerative medicine strategies for the future treatment of OA. PMID- 22817629 TI - Cellular cardiomyoplasty: current state of the field. AB - Cellular cardiomyoplasty employs stem cell therapy to regenerate myocardium. Characterized by their potential for proliferation, differentiation and capacity for self-renewal, stem cells are ideally suited for use in regenerative medicine. Supplementing traditional therapeutic modalities aimed at the palliation of congestive heart failure, cellular cardiomyoplasty is an innovative approach aimed at producing functional, viable myocardium following an acute infarction. The primary focus is to prevent the onset of congestive heart failure; however, potential applications aimed at reversing ischemic heart disease are concurrently in development. After decades of research, cellular cardiomyoplasty has moved beyond traditional in vitro and animal models; it is currently being implemented in clinical trials. Despite this monumental advance, certain limitations remain inherent in this process, preventing stem cell therapy from reaching its full potential. On a cellular level, stem cell retention and viability postimplantation continues to be problematic. Solutions under investigation include pioneering advances in cell delivery, in vitro pretreatment, and tissue engineering. Moreover, questions surrounding optimal cell type and cellular mechanisms concerning cellular cardiomyoplasty remain unanswered. Clarification of these issues is essential to ensure continued progression of this new technology. Stem cell therapy has been highly successful within the in vitro and in vivo environment. However, as clinical trials abound, cellular cardiomyoplasty must transition from an experimental concept to an effective therapeutic treatment. This process is hindered by discordance between scientific accrue and practical applicability. This review will provide a comprehensive summary of current innovations on cellular cardiomyoplasty, and future prospects. There will be a particular emphasis on the clinical aspects of stem cell therapy in an attempt to bridge the gap between science and medicine. Overcoming this barrier will render cellular cardiomyoplasty accessible to patients on a global basis. PMID- 22817630 TI - Pluripotent stem cell-derived pancreatic beta-cells: potential for regenerative medicine in diabetes. AB - Diabetes mellitus, which affects 346 million people, is one of the leading causes of death worldwide. Pancreatic beta-cells, existing in the islets of Langerhans, play central roles in the progression of diabetes. An efficient strategy to produce functional pancreatic beta-cells is important for both transplantation therapy and disease modeling of diabetes. Human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, provide unlimited starting materials to generate differentiated cells for regenerative studies. Significant progress has been made in human embryonic/induced pluripotent stem cell differentiation in the last several years. However, efficient generation of mature pancreatic beta-cells with complete functional capabilities has not yet been accomplished. Here, we review recent successes as well as the technical and theoretical challenges in the use of pluripotent stem cell-derived pancreatic beta-cells for disease modeling and replacement therapy of diabetes. PMID- 22817627 TI - The role of small molecules in musculoskeletal regeneration. AB - The uses of bone morphogenetic proteins and parathyroid hormone therapeutics are fraught with several fundamental problems, such as cost, protein stability, immunogenicity, contamination and supraphysiological dosage. These downsides may effectively limit their more universal use. Therefore, there is a clear need for alternative forms of biofactors to obviate the drawbacks of protein-based inductive factors for bone repair and regeneration. Our group has studied small molecules with the capacity to regulate osteoblast differentiation and mineralization because their inherent physical properties minimize limitations observed in protein growth factors. For instance, in general, small molecule inducers are usually more stable, highly soluble, nonimmunogenic, more affordable and require lower dosages. Small molecules with the ability to induce osteoblastic differentiation may represent the next generation of bone regenerative medicine. This review describes efforts to develop small molecule based biofactors for induction, paying specific attention to their novel roles in bone regeneration. PMID- 22817631 TI - US FDA outreach to the regenerative medicine community: challenges and opportunities. AB - Advances in the field of regenerative medicine have yielded novel approaches to developing treatments for currently unmet medical needs. The regenerative medicine field is diverse, spanning many research and clinical disciplines; no single society or organization fully represents regenerative medicine. The US FDA maintains an active dialog with a variety of stakeholders to keep abreast of the latest available science, to anticipate regulatory challenges posed by the latest scientific developments and to educate stakeholders about regulatory expectations for product development. The diversity of stakeholders in this field makes this dialog challenging. This article provides an overview of some of the FDA's current outreach activities in this area. The FDA welcomes opportunities to enhance its interactions with the regenerative medicine community. PMID- 22817632 TI - Local and global returns from research in stem cells: the case of the California Institute for Regenerative Medicine. AB - As of July 2010, the California Institute for Regenerative Medicine (CA, USA) had awarded US$1.1 billion to over 50 institutions which obtained $884.3 million in matching funds. Those grants have one-time and ongoing economic impacts: the former during the disbursement of the funds locally, while the latter result from structural changes and are global. For the period 2006-2014, one-time impacts in California (USA) are 24,000 jobs/year and $201 million in tax revenues for California ($362 million for the federal government). A grantee developed an inhibitor to treat polycythemia vera and primary myelofibrosis. The patients in remission who will return to work will cause an average increase of $94.4 million in California's annual personal income ($560.9 million for the USA) and tax revenues of $46.7 million over 10 years. The annual decrease in direct healthcare costs in California is $2.1 million. Grantees concentrate in two clusters--San Francisco and San Diego--strengthening California's leadership in stem cell research. PMID- 22817634 TI - Do immunological, endocrine and metabolic traits fall on a single Pace-of-Life axis? Covariation and constraints among physiological systems. AB - Variation in demographic and physiological attributes of life history is thought to fall on one single axis, a phenomenon termed the Pace-of-Life. A slow Pace-of Life is characterized by low annual reproduction, long life span and low metabolic rate, a fast Pace-of-Life by the opposite characteristics. The existence of a single axis has been attributed to constraints among physiological mechanisms that are thought to restrict evolutionary potential. In that case, physiological traits should covary in the same fashion at the levels of individual organisms and species. We examined covariation at the levels of individual and subspecies in three physiological systems (metabolic, endocrine and immune) using four stonechat subspecies with distinct life-history strategies in a common-garden set-up. We measured basal metabolic rate, corticosterone as endocrine measure and six measures of constitutive immunity. Metabolic rate covaried with two indices of immunity at the individual level, and with corticosterone concentrations and one index of immunity at the subspecies level, but not with other measures. The different patterns of covariation among individuals and among subspecies demonstrate that links among physiological traits are loose and suggest that these traits can evolve independent of each other. PMID- 22817635 TI - Vascular endothelial growth factor-D: signaling mechanisms, biology, and clinical relevance. AB - Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that promotes growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis), and can induce remodeling of large lymphatics. VEGF-D enhances solid tumor growth and metastatic spread in animal models of cancer, and in some human cancers VEGF-D correlates with metastatic spread, poor patient outcome, and, potentially, with resistance to anti-angiogenic drugs. Hence, VEGF D signaling is a potential target for novel anti-cancer therapeutics designed to enhance anti-angiogenic approaches and to restrict metastasis. In the cardiovascular system, delivery of VEGF-D in animal models enhanced angiogenesis and tissue perfusion, findings which have led to a range of clinical trials testing this protein for therapeutic angiogenesis in cardiovascular diseases. Despite these experimental and clinical developments, our knowledge of the signaling mechanisms driven by VEGF-D is still evolving--here we explore the biology of VEGF-D, its signaling mechanisms, and the clinical relevance of this growth factor. PMID- 22817636 TI - Genetic modifiers of comatose mutations in Drosophila: insights into neuronal NSF (N-ethylmaleimide-sensitive fusion factor) functions. AB - By the middle of the 20th century, development of powerful genetic approaches had ensured that the fruit fly would remain a model organism of choice for genetic and developmental studies. But in the 1970s, a few pioneering groups turned their attention to the prospect of using the fly for neurophysiological experiments. They proposed that in a poikilothermic organism such as Drosophila, temperature sensitive or "ts" mutations in proteins that controlled nerve function would translate to a "ts" paralytic phenotype. This was by no means an obvious or even a likely assumption. However, following directed screens these groups soon reported dramatic demonstrations of reversible ts paralysis in fly mutants. Resultantly, these "simple" experiments led to the isolation of a number of conditional mutations including shibire, paralytic, and comatose. All have since been cloned and have enabled deep mechanistic insights into synaptic transmission and nerve conduction. comatose (comt) mutations, for example, were found to map to missense changes in dNSF1, a neuron-specific fly homolog of mammalian NSF (N ethylmaleimide-sensitive fusion factor). Studies on comt were also some of the first to discriminate between nuanced models of NSF function during presynaptic transmitter release that have since been borne out by experiments in multiple preparations. Here, the authors present an overview of NSF function as it is understood today, with an emphasis on contributions from Drosophila beginning with experiments carried out by Obaid Siddiqi in the Benzer laboratory. The authors also outline initial results from a genetic screen for phenotypic modifiers of comt that hold the promise of further elucidating NSF function at the synapse. Over the years, the neuromuscular system of Drosophila has served as a uniquely accessible model to unravel mechanisms underlying synaptic transmission. To this day, ts paralysis remains one of the most emphatic demonstrations of nerve function in an intact organism. PMID- 22817637 TI - The prescription rate of antibacterial agents in dogs in Norway - geographical patterns and trends during the period 2004-2008. AB - The aim of the present study was to describe the prescription rate and patterns of antibacterial agents in the Norwegian dog population in relation to time and place during 2004-2008. Prescription data were collected from the Norwegian prescription database (NorPD), whereas an estimate of the dog population was obtained from the Norwegian Kennel Club (NKK). Maps of the geographical prescription rate patterns were generated in the software ArcGIS 9.2. This study indicates an increased usage of antibacterial agents in dogs in Norway during the study period in which antibacterial agents for systemic use and especially the combination amoxicillin and clavulanic acid accounted for the major part. Among antibacterial agents defined as critically important for human medicine, an increase was observed in the prescription rate of quinolones. The geographical prescription rate patterns were stable during the study period, which indicated that the identified increase in usage of antimicrobial agents occurred all over the country, but that there were regional differences in the prescribing behaviour. Prescription data from the NorPD of antibacterial agents to dogs can be used as a basis to perform a risk-based sampling approach to detect emerging antimicrobial resistance in the dog population. PMID- 22817639 TI - Functional lateralization in auditory cortex under informational masking and in silence. AB - The N(1) m is an evoked magnetic field in auditory cortex that is automatically elicited by tones in silence but not in the context of multiple other tones: when listeners are unaware of a tone stream because of informational masking, no N(1) m-like activity is observed. In contrast, N(1) m-like activity is evoked when listeners are aware of the regular tone stream in the same context but in another trial. Here we compared this awareness-related negativity (ARN) with the automatic N(1) m. First, we evaluated whether stimulus lateralization by ear or interaural time differences modulates hemispheric lateralization of the response, as a putative marker of sensory processing. Second, we evaluated the stimulus independent hemispheric balance thought to indicate higher level cortical processing. The results dissociate three, partly overlapping, time intervals: the P(1) m (45-85 ms) was evoked by missed and detected target tones alike. Subsequent negative activity was only observed when listeners indicated awareness of the target stream inside the multi-tone masker. In the N(1) m time interval (75-175 ms), hemispheric balance of the ARN and N(1) m was modulated by stimulus lateralization. In the subsequent time interval (175-275 ms), auditory-cortex activity was generally right-lateralized in silence and balanced under informational masking, but was not modulated by stimulus lateralization. These results suggest that the same auditory-cortex activity that varies with perceptual awareness also shows sensory response features. This is in accordance with models for visual perception, suggesting that sensory competition determines whether midlevel visual responses occur automatically or vary with perceptual state. PMID- 22817638 TI - Glutamate transporter-dependent mTOR phosphorylation in Muller glia cells. AB - Glu (glutamate), the excitatory transmitter at the main signalling pathway in the retina, is critically involved in changes in the protein repertoire through the activation of signalling cascades, which regulate protein synthesis at transcriptional and translational levels. Activity-dependent differential gene expression by Glu is related to the activation of ionotropic and metabotropic Glu receptors; however, recent findings suggest the involvement of Na+-dependent Glu transporters in this process. Within the retina, Glu uptake is aimed at the replenishment of the releasable pool, and for the prevention of excitotoxicity and is carried mainly by the GLAST/EAAT-1 (Na+-dependent glutamate/aspartate transporter/excitatory amino acids transporter-1) located in Muller radial glia. Based on the previous work showing the alteration of GLAST expression induced by Glu, the present work investigates the involvement of GLAST signalling in the regulation of protein synthesis in Muller cells. To this end, we explored the effect of D-Asp (D-aspartate) on Ser-2448 mTOR (mammalian target of rapamycin) phosphorylation in primary cultures of chick Muller glia. The results showed that D-Asp transport induces the time- and dose-dependent phosphorylation of mTOR, mimicked by the transportable GLAST inhibitor THA (threo-beta-hydroxyaspartate). Signalling leading to mTOR phosphorylation includes Ca2+ influx, the activation of p60src, phosphatidylinositol 3-kinase, protein kinase B, mTOR and p70S6K. Interestingly, GLAST activity promoted AP-1 (activator protein-1) binding to DNA, supporting a function for transporter signalling in retinal long-term responses. These results add a novel receptor-independent pathway for Glu signalling in Muller glia, and further strengthen the critical involvement of these cells in the regulation of glutamatergic transmission in the retina. PMID- 22817640 TI - atBioNet--an integrated network analysis tool for genomics and biomarker discovery. AB - BACKGROUND: Large amounts of mammalian protein-protein interaction (PPI) data have been generated and are available for public use. From a systems biology perspective, Proteins/genes interactions encode the key mechanisms distinguishing disease and health, and such mechanisms can be uncovered through network analysis. An effective network analysis tool should integrate different content specific PPI databases into a comprehensive network format with a user-friendly platform to identify key functional modules/pathways and the underlying mechanisms of disease and toxicity. RESULTS: atBioNet integrates seven publicly available PPI databases into a network-specific knowledge base. Knowledge expansion is achieved by expanding a user supplied proteins/genes list with interactions from its integrated PPI network. The statistically significant functional modules are determined by applying a fast network-clustering algorithm (SCAN: a Structural Clustering Algorithm for Networks). The functional modules can be visualized either separately or together in the context of the whole network. Integration of pathway information enables enrichment analysis and assessment of the biological function of modules. Three case studies are presented using publicly available disease gene signatures as a basis to discover new biomarkers for acute leukemia, systemic lupus erythematosus, and breast cancer. The results demonstrated that atBioNet can not only identify functional modules and pathways related to the studied diseases, but this information can also be used to hypothesize novel biomarkers for future analysis. CONCLUSION: atBioNet is a free web-based network analysis tool that provides a systematic insight into proteins/genes interactions through examining significant functional modules. The identified functional modules are useful for determining underlying mechanisms of disease and biomarker discovery. It can be accessed at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm. PMID- 22817641 TI - SPI-1 encoded genes of Salmonella Typhimurium influence differential polarization of porcine alveolar macrophages in vitro. AB - BACKGROUND: Within the last decade, macrophages have been shown to be capable of differentiating toward a classically activated phenotype (M1) with a high antimicrobial potential or an alternatively activated phenotype (M2). Some pathogens are capable of interfering with differentiation in order to down regulate the anti-microbial activity and enhance their survival in the host. RESULTS: To test this ability in Salmonella enterica serovar Typhimurium, we infected porcine alveolar macrophages with wild-type Salmonella Typhimurium and its isogenic mutants devoid of two major pathogenicity islands, SPI-1 and SPI-2. The induction of genes linked with M1 or M2 polarization was determined by quantification of gene expression by RT-qPCR. The DeltaSPI-1 mutant induced a high, dose-dependent M1 response but a low M2 response in infected macrophages. On the other hand, wild-type Salmonella Typhimurium induced a low M1 response but a high, dose-dependent M2 response in infected macrophages. The response to DeltaSPI-2 mutant infection was virtually the same as the wild-type strain. CONCLUSIONS: We therefore propose that Salmonella Typhimurium DT104 studied here can polarize macrophages towards the less bactericidal M2 phenotype and that this polarization is dependent on the type III secretion system encoded by SPI-1. PMID- 22817642 TI - Cognitive and behavioral features of c9FTD/ALS. AB - Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders. PMID- 22817643 TI - First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5-HT3 and D3 receptors. AB - BACKGROUND AND PURPOSE: Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. EXPERIMENTAL APPROACH: Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. KEY RESULTS: Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pK(i) values for 19 receptors and analysed for correlation. Our results indicated that 5-HT(3) receptors have an enhancing effect on gamma oscillations whereas dopamine D(3) receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT(3) , D(3) and 5-HT(2C) receptors were applied and revealed that 5-HT(3) receptors indeed enhanced the gamma power whereas D(3) receptors reduced it. As predicted, 5-HT(2C) receptors had no effects on gamma oscillations. CONCLUSION AND IMPLICATIONS: Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT(3) and dopamine D(3) receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. PMID- 22817644 TI - Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients. AB - AIM: To investigate whether gut bacteria translocation occurs in end-stage renal disease patients and contributes to microinflammation in end-stage renal disease (ESRD). METHODS: The subjects were divided into two groups: nondialysed ESRD patients (n = 30) and healthy controls (n = 10). Blood samples from all participants were subjected to bacterial 16S ribosomal DNA amplification and DNA pyrosequencing to determine the presence of bacteria, and the alteration of gut microbiomes were examined with the same methods. High-sensitive C-reactive protein and interleukin-6 were detected. Plasma D-lactate was tested for gut permeability. RESULTS: Bacterial DNAs were detected in the blood of 20% (6/30) of the ESRD patients. All the observed genera in blood (Klebsiella spp, Proteus spp, Escherichia spp, Enterobacter spp, and Pseudomonas spp) were overgrown in the guts of the ESRD patients. Plasma D-lactate, High-sensitive C-reactive protein, and interleukin-6 levels were significantly higher in patients with bacterial DNA than those without. The control group showed the same results as that of patients without bacterial DNA. CONCLUSION: Bacterial translocation occurs in ESRD patients and is associated with microinflammation in end stage renal disease. PMID- 22817645 TI - Cognitive aging affects motor performance and learning. AB - Substantial evidence indicates that declines in cognitive and motor functioning are often observed when we age. The interdependence of cognition and behavior has been reported in a wide range of studies. However, research on the cognitive motor associations in aging has been lacking. We review behavioral and neural characteristics of cognitive aging in relation to motor aging and aim to elucidate their interrelationships in an aging context. From a developmental view, we propose an integrative concept focusing on the dynamics of cognitive functioning, motor performance and skill acquisition. In the framework, representations and motor learning potential are closely related. and supported by distributed neural systems, which are less susceptible to functional declines in the aging process. Mostly supported by high-level areas, control processes, motor learning efficiency and motor performance are closely related. As high level areas are more vulnerable during aging, control processes, motor learning efficiency and motor performance are substantially affected when one approaches late adulthood. Practical implications and future research directions are discussed. PMID- 22817646 TI - Educational attainment is associated with atrial fibrillation symptom severity. AB - BACKGROUND: Atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice, is often managed with a rhythm control strategy. Despite the emphasis on symptom relief as the motivation for a rhythm controlling strategy in AF, it remains unclear what factors affect the patient's experienced severity of AF symptoms. We hypothesize that demographic variables may affect AF symptom severity as many AF symptoms (palpitations, dyspnea, fatigue) are nonspecific and may require particular patient insight. METHODS: We assessed demographic variables, cardiac and noncardiac comorbidities, AF burden, and AF-specific self reported symptom severity in a cohort of 300 outpatients with AF presenting to outpatient electrophysiology clinics. RESULTS: In unadjusted analyses, decreased educational attainment, unemployed working status, and non-Caucasian race were associated with worsened AF symptom severity. After adjusting for potential confounders, the association of decreased educational attainment with worsened AF symptom severity persisted. CONCLUSIONS: Possible links between these demographic features and AF symptom severity are socioeconomic status and health literacy. Further study into the relationship between educational attainment and AF symptom severity is warranted. PMID- 22817647 TI - Identification and quantification of 1-hydroxybutene-2-yl mercapturic acid in human urine by UPLC- HILIC-MS/MS as a novel biomarker for 1,3-butadiene exposure. AB - 1,3-Butadiene (BD) is a Class 1 carcinogen present at workplaces, in polluted air, in automobile exhaust, and in tobacco smoke. 2-Hydroxybutene-1-yl mercapturic acid (2-MHBMA) is a urinary metabolite often measured as a biomarker for exposure to BD. Here, we show for the first time that an additional MHBMA isomer is present at significant amounts in human urine, 1-hydroxybutene-2-yl mercapturic acid (1-MHBMA). For its quantification, a highly sensitive UPLC-HILIC MS/MS method was developed and validated. Analyzing urinary samples of 183 volunteers, we demonstrate that 1-MHBMA is a novel and potentially more reliable biomarker for BD exposure than the commonly analyzed 2-MHBMA. PMID- 22817648 TI - Clinical features of the hospitalized patients with 2009 pandemic influenza A (H1N1) in Santa Fe, Argentina. AB - BACKGROUND: During 2009 occurred the emergence and global spread of a novel influenza A (H1N1) virus. We describe the clinical and epidemiologic features of hospitalized patients who survived and patients who died because of pandemic 2009 influenza A (H1N1) infection reported in Santa Fe, Argentina, from May to July 2009. METHODS: Using medical charts, we collected data on 242 patients who were hospitalized with confirmed laboratory results (defined as positive by specific PCR for pandemic 2009 influenza A H1N1). RESULTS: During the study period, there were 242 cases of hospitalization or death. Of the 242, 46% were admitted to an intensive care unit (ICU) and 33.5% died. The mean age was 27.8 years for surviving and 39.6 for those who died. Twenty-eight percent of hospitalizations involved persons under the age of 15 years; 33% of the patients were between the age of 15 and 44 years; and only 3.3% were 65 years of age or older. Sixty-seven percent had an underlying medical conditions, including diabetes, obesity, heart and lung diseases, and pregnancy. Of the 242 patients, 68% had findings consistent with pneumonia. Treatment with oseltamivir was administered to 227 (93.8%) patients from which 38 received oseltamivir within 48 hours after the onset of symptoms. CONCLUSIONS: The pandemic strain caused severe illness, including pneumonia and acute respiratory distress syndrome, and resulted in ICU admissions in 46% of patients and death in 33.5%. The mean age of hospitalized infected cases was lower than is common with seasonal influenza. Underlying medical conditions were common in the 67% the evaluated patients. Patients who died had a higher prevalence of comorbidities (86.4%) than those who survived (57%), suggesting that the presence of chronic illness may increase the likelihood of death. However, the severe illness was also identified among young, healthy persons. PMID- 22817649 TI - Direct patterning of conductive polymer domains for photovoltaic devices. AB - We report a simple approach to control the morphology of polymer/fullerene solar cells based on electron-beam patterning of polymer semiconductors. This process generates conductive nanostructures or microstructures through an in situ cross linking reaction, where the size, shape, and density of polymer domains are all tunable parameters. Cross-linked polymer structures are resistant to heat and solvents, so they can be incorporated into devices that require thermal annealing or solution-based processing. We demonstrate this method by building "gradient" and nanostructured poly(3-hexylthiophene)/fullerene solar cells. The power conversion efficiency of these model devices improves with increasing interfacial area. The flexible methodology can be used to study the effects of active layer design on optoelectronic function. PMID- 22817650 TI - Social implications of smartphone use: Korean college students' smartphone use and psychological well-being. AB - The purpose of this study is to explore the relationship between motives of smartphone use, social relation, and psychological well-being. The correlation analysis shows that the motives of smartphone use were positively related to bonding relations but negatively related to bridging relations. The hierarchical multiple regression analysis finds the associations among motives of smartphone use, social relations, perceived social support, and variables of psychological well-being. The results demonstrate that needs for caring for others were negatively related to loneliness and depression and positively related to self esteem. However, the communication motives are not a significant predictor to determine self-esteem, loneliness, and depression. In addition, bonding and bridging social relations and social support significantly increase self-esteem and decrease loneliness and depression. PMID- 22817652 TI - Variations in connectivity in the sensorimotor and default-mode networks during the first nocturnal sleep cycle. AB - The function of sleep in humans has been investigated using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging recordings to provide accurate sleep scores with spatial precision. Recent studies have demonstrated that spontaneous brain oscillations and functional connectivity dissociate during nonrapid eye movement (NREM) sleep; this leads to spontaneous cognitive processes, such as memory consolidation and emotional modulation. However, variations in network connectivity across the sleep stages or between sleep/wake transitions require further elucidation. We observed changes in the connectivity of the sensorimotor and default-mode networks (DMN) mediated by midnight sleep among 18 healthy participants. The results indicated that (1) functional connectivity in both networks showed increasing dissociation as NREM sleep deepened, whereas hyperconnectivity occurred during rapid eye movement (REM) sleep; and (2) compared with connectivity before sleep, the DMN presented a comparable connectivity pattern immediately after awakening, whereas the connectivity of the sensorimotor network remained disrupted. These findings showed that connectivity patterns dissociate and reconnect coherently in both cortical networks during NREM and REM sleep, respectively. After the person awakened, the DMN connectivity was re-established before the sensorimotor reconnection. These dynamic sleep-related dissociations and reconnections between sleep/wake conditions might provide the key to understanding cognitive modulations in sleep. If so, connectivity changes might serve as an alternative indicator beyond the EEG signature to unveil the spontaneous processes that occur during sleep. PMID- 22817651 TI - Temporary clamping of drain combined with tranexamic acid reduce blood loss after total knee arthroplasty: a prospective randomized controlled trial. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with a significant blood loss. Several methods have been reported to reduce postoperative blood loss and avoid homologous blood transfusions. In this study, we investigated the efficacy of temporary clamping of the drain either or not in combination with tranexamic acid administration for controlling blood loss after TKA. METHODS: The prospective, randomized, and double-blinded study was conducted in our institute. Total of 240 patients, who diagnosed primary osteoarthritis and scheduled to undergo a primary TKA,,were randomized into one of the four groups: Group A or control group, the drain was not clamped and the patient received a placebo; Group B, the drain was not clamped and the patient received tranexamic acid; Group C, the drain was clamped and the patient received a placebo; and Group D, the drain was clamped and the patient received tranexamic acid. The volume of drained blood at 48 hours postoperatively, the decreasing of hemoglobin (Hb) level at 12 hours postoperatively and the number of patients requiring blood transfusion were recorded and compared. RESULTS: The mean postoperative volumes of drained blood and the amount of blood transfusion in the three study groups (group B, C and D) were significantly lower than those in the control group (p < 0.05), which group D had the lowest values. Furthermore, group B and D could maintain the Hb level better than group A and C (p < 0.001). In terms of blood transfusions rate, although the patients in group D required transfusion less than group A and C (p < 0.05), there was no significant difference between group D and B. The relative risks for transfusion requirement were 4.4 for group A, 1.4 for group B and 3.0 for group C when compared to group D. CONCLUSIONS: The clamping of drain combined with tranexamic acid administration could reduce postoperative blood loss and blood transfusion after TKA, significantly greater than using tranexamic acid or drain clamping alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01449552. PMID- 22817653 TI - Ectoparasite fitness in auxiliary hosts: phylogenetic distance from a principal host matters. AB - We studied reproductive performance in two flea species (Parapulex chephrenis and Xenopsylla ramesis) exploiting either a principal or one of eight auxiliary host species. We predicted that fleas would produce more eggs and adult offspring when exploiting (i) a principal host than an auxiliary host and (ii) an auxiliary host phylogenetically close to a principal host than an auxiliary host phylogenetically distant from a principal host. In both flea species, egg production per female after one feeding and production of new imago after a timed period of an uninterrupted stay on a host differed significantly between host species. In general, egg and/or new imago production in fleas feeding on an auxiliary host was lower than in fleas feeding on the principal host, except for the auxiliary host that was the closest relative of the principal host. When all auxiliary host species were considered, we did not find any significant relationship between either egg or new imago production in fleas exploiting an auxiliary host and phylogenetic distance between this host and the principal host. However, when the analyses were restricted to auxiliary hosts belonging to the same family as the principal host (Muridae), new imago production (for P. chephrenis) or both egg and new imago production (for X. ramesis) in an auxiliary host decreased significantly with an increase in phylogenetic distance between the auxiliary and principal host. Our results demonstrated that a parasite achieves higher fitness in auxiliary hosts that are either the most closely related to or the most distant from its principal host. This may affect host associations of a parasite invading new areas. PMID- 22817654 TI - Determination of rituximab dose according to immunologic risk in ABO-incompatible kidney transplantation. AB - The adequate rituximab (RTX) dosage in ABO-incompatible transplantation (ABO-IKT) remains undetermined. We used two kinds of RTX dosage groups [low RTX (100 mg/m(2)) and typical RTX (375 mg/m(2)) dosage groups] according to immunologic risks and investigated the change of B-cell, anti-ABO antibodies, and the clinical outcome in ABO-IKT according to the RTX dose. Fifteen patients with high immunologic risk [panel reactive antibody (PRA) > 50%, retransplant, AB to O transplant] were assigned to typical RTX group and 17 patients without risk were assigned to low RTX group. We compared the changes of B-cell, anti-ABO antibody titer, required number of plasmapheresis (PP), and the clinical outcome after transplantation between the two groups. After infusion of RTX, peripheral blood B cell counts were successfully depleted to <1% in both groups. Before kidney transplantation (KT), the minimal number of PP to achieve the target titer (1:16) (2.6 +/- 2.7 vs. 2.2 +/- 2.5; p = 0.66) and the titer reduction rate of anti-ABO antibodies did not differ between the two groups (low RTX: 1.52 +/- 1.21 vs. typical RTX: 1.53 +/- 1.20, p = 0.94). After KT, anti-ABO antibody titer was suppressed less than 1:32 in both groups up to posttransplant 1 year. The allograft function and infectious complication did not differ between the two groups as well. In ABO-IKT, low RTX is comparable with typical RTX dosing with respect to B-cell depletion, antibody rebound suppression, the effect on clinical outcome in patients with low immunologic risk. PMID- 22817655 TI - Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study. AB - BACKGROUND: Few large population-based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients. AIMS: To investigate if cirrhotic patients have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients. METHODS: Using the National Health Insurance Research Database, a nationwide population-based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log-rank test was used to analyse differences in accumulated PUB-free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients. RESULTS: During the 7-year follow-up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log-rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37-5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro-oesophageal variceal bleeding and use of nonsteroidal anti-inflammatory drugs were risk factors for PUB in cirrhotic patients. CONCLUSION: Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication. PMID- 22817656 TI - Genome-wide CNV analysis replicates the association between GSTM1 deletion and bladder cancer: a support for using continuous measurement from SNP-array data. AB - BACKGROUND: Structural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance. RESULTS: 773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package. CONCLUSIONS: This study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms. PMID- 22817657 TI - NH4OAc promoted cyclocondensation of 3-(o-allylphenyl)pentane-1,5-diones: synthesis of tetracyclic benzofused 1-azahomoisotwistanes. AB - A facile two-step synthetic route for preparing the novel tetracyclic skeleton of benzofused 2,6-diaryl-1-azahomoisotwistanes 2 had been developed. The route was carried out by a one-pot tandem cross-coupling reaction of o-allylbenzaldehydes 1 with aryl methyl ketones 3, and NH(4)OAc mediated the cascade cyclocondensation reaction of the resulting 1,5-diketones 4 with the 3-o-allylphenyl group in good yield in two steps. PMID- 22817658 TI - Prospects and applications of nanobiotechnology: a medical perspective. AB - BACKGROUND: Nanobiotechnology is the application of nanotechnology in biological fields. Nanotechnology is a multidisciplinary field that currently recruits approach, technology and facility available in conventional as well as advanced avenues of engineering, physics, chemistry and biology. METHOD: A comprehensive review of the literature on the principles, limitations, challenges, improvements and applications of nanotechnology in medical science was performed. RESULTS: Nanobiotechnology has multitude of potentials for advancing medical science thereby improving health care practices around the world. Many novel nanoparticles and nanodevices are expected to be used, with an enormous positive impact on human health. While true clinical applications of nanotechnology are still practically inexistent, a significant number of promising medical projects are in an advanced experimental stage. Implementation of nanotechnology in medicine and physiology means that mechanisms and devices are so technically designed that they can interact with sub-cellular (i.e. molecular) levels of the body with a high degree of specificity. Thus therapeutic efficacy can be achieved to maximum with minimal side effects by means of the targeted cell or tissue specific clinical intervention. CONCLUSION: More detailed research and careful clinical trials are still required to introduce diverse components of nanobiotechnology in random clinical applications with success. Ethical and moral concerns also need to be addressed in parallel with the new developments. PMID- 22817659 TI - Invariant NKT cells increase drug-induced osteosarcoma cell death. AB - BACKGROUND AND PURPOSE: In osteosarcoma (OS) patients, only a limited number of drugs are active and the regimens currently in use include a combination of at least two of these drugs: doxorubicin, cisplatin, methotrexate and ifosfamide. Today, 30-40% of patients still die of OS highlighting the urgent need for new treatments. Invariant NKT (iNKT) cells are a lymphocyte lineage with features of both T and NK cells, playing important roles in tumour suppression. Our aim was to test whether the cytoxicity induced by cisplatin, doxorubicin and methotrexate against OS cells can be enhanced by iNKT cell treatment. EXPERIMENTAL APPROACH: iNKT cells were purified from human peripheral blood mononuclear cells by cell sorting (Valpha24Vbeta11(+) cells) and used as effector cells against OS cells (U2-OS, HOS, MG-63). Cell death (calcein-AM method), perforin/granzyme B and Fas/FasL expressions were determined by flow cytometry. CD1d expression was analysed at both the gene and protein level. KEY RESULTS: iNKT cells were cytotoxic against OS cells through a CD1d-dependent mechanism. This activity was specific for tumour cells, because human CD1d(+) mesenchymal stem cells and CD1d( ) osteoblasts were not affected. iNKT cell treatment enhanced drug-induced OS cell death in a concentration-dependent manner and this effect was reduced in CD1d-silenced OS cells. CONCLUSION AND IMPLICATIONS: iNKT cells kill malignant, but not non-malignant, cells. iNKT cell treatment enhances the cytotoxicity of anti-neoplastic drugs against OS cells in a CD1d-dependent manner. The present data encourage further studies on the use of iNKT cells in OS therapy. PMID- 22817660 TI - Indian hedgehog gene transfer is a chondrogenic inducer of human mesenchymal stem cells. AB - INTRODUCTION: To date, no single most-appropriate factor or delivery method has been identified for the purpose of mesenchymal stem cell (MSC)-based treatment of cartilage injury. Therefore, in this study we tested whether gene delivery of the growth factor Indian hedgehog (IHH) was able to induce chondrogenesis in human primary MSCs, and whether it was possible by such an approach to modulate the appearance of chondrogenic hypertrophy in pellet cultures in vitro. METHODS: First-generation adenoviral vectors encoding the cDNA of the human IHH gene were created by cre-lox recombination and used alone or in combination with adenoviral vectors, bone morphogenetic protein-2 (Ad.BMP-2), or transforming growth factor beta-1 (Ad.TGF-beta1) to transduce human bone-marrow derived MSCs at 5 * 102 infectious particles/cell. Thereafter, 3 * 105 cells were seeded into aggregates and cultured for 3 weeks in serum-free medium, with untransduced or marker gene transduced cultures as controls. Transgene expressions were determined by ELISA, and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy. RESULTS: IHH, TGF-beta1 and BMP 2 genes were equipotent inducers of chondrogenesis in primary MSCs, as evidenced by strong staining for proteoglycans, collagen type II, increased levels of glycosaminoglycan synthesis, and expression of mRNAs associated with chondrogenesis. IHH-modified aggregates, alone or in combination, also showed a tendency to progress towards hypertrophy, as judged by the expression of alkaline phosphatase and stainings for collagen type X and Annexin 5. CONCLUSION: As this study provides evidence for chondrogenic induction of MSC aggregates in vitro via IHH gene delivery, this technology may be efficiently employed for generating cartilaginous repair tissues in vivo. PMID- 22817662 TI - Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease. AB - Although CSs (corticosteroids) demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and AHR (airway hyper-responsiveness) despite optimal treatment with these agents, probably due to progressive airway remodelling. Identifying novel therapies that can target airway remodelling and/or airway reactivity may improve symptom control in these patients. We have demonstrated previously that the anti-fibrotic hormone RLN (relaxin) can reverse airway remodelling (epithelial thickening and subepithelial fibrosis) and AHR in a murine model of AAD (allergic airways disease). In the present study, we compared the effects of RLN with a CS (methylprednisolone) on airway remodelling and AHR when administered independently or in combination in the mouse AAD model. Female mice at 6-8 weeks of age were sensitized and challenged to OVA (ovalbumin) over a 9-week period and treated with methylprednisolone, RLN, a combination of both treatments or vehicle controls. Methylprednisolone was administered intraperitoneally on the same day as nebulization for 6 weeks, whereas recombinant human RLN-2 was administered via subcutaneously implanted osmotic mini-pumps from weeks 9-11. RLN or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; whereas RLN but not methylprednisolone significantly decreased epithelial thickness and AHR. Additionally, combination therapy with CS and RLN more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that RLN can modulate a broader range of airway remodelling changes and AHR than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis. PMID- 22817661 TI - Leishmania amazonensis fails to induce the release of reactive oxygen intermediates by CBA macrophages. AB - CBA mouse macrophages effectively control Leishmania major infection, yet are permissive to Leishmania amazonensis. It has been established that some Leishmania species are destroyed by reactive oxygen species (ROS). However, other species of Leishmania exhibit resistance to ROS or even down-modulate ROS production. We hypothesized that L. amazonensis-infected macrophages reduce ROS production soon after parasite-cell interaction. Employing a highly sensitive analysis technique based on chemiluminescence, the production of superoxide (O(. )(2)) and hydrogen peroxide (H(2)O(2)) by L. major- or L. amazonensis-infected CBA macrophages were measured. L. major induces macrophages to release levels of (O(.-)(2)) 3.5 times higher than in uninfected cells. This (O(.-)(2)) production is partially dependent on NADPH oxidase (NOX) type 2. The level of accumulated H(2)O(2) is 20 times higher in L. major-than in L. amazonensis-infected cells. Furthermore, macrophages stimulated with L. amazonensis release amounts of ROS similar to uninfected cells. These findings support previous studies showing that CBA macrophages are effective in controlling L. major infection by a mechanism dependent on both (O(.-)(2)) production and H(2)O(2) generation. Furthermore, these data reinforce the notion that L. amazonensis survive inside CBA macrophages by reducing ROS production during the phagocytic process. PMID- 22817663 TI - Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia. AB - Dichlorvos [2,2-dichlorovinyl dimethyl phosphate] is one of the most common in use organophosphate (OP) in developing nations. Previous studies from our lab have shown chronic Dichlorvos exposure leads to neuronal cell death in rats. However, the extent of damage caused by Dichlorvos to other cells of the central nervous system (CNS) is still not clear. Microglial cells are the primary threat sensors of CNS which become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by increased cellular damage in the affected regions. Using rat primary microglial cultures, here we show that Dichlorvos exposure can activate and induce apoptotic cell death in microglia. We observed significant up-regulation of pro-inflammatory molecules like nitric oxide, TNF-alpha, and IL-1beta when microglia were treated with Dichlorvos (10 MUM). Significant up-regulation of CD11b, microglial specific activation marker, was also observed after 24 h of Dichlorvos treatment. The activated microglial cells eventually undergo cell death after 48 h of Dichlorvos treatment. The DNA fragmentation pattern of Dichlorvos treated microglia along with increased expression of Bax in mitochondria, cytochrome c release from mitochondria, and caspase-3 activation led us to assume that microglia were undergoing apoptosis. Thus, the present study showed that Dichlorvos can induce microglial activation and ultimately apoptotic cell death. These findings gave new perspective to the current knowledge of Dichlorvos (OPs) mediated CNS damage and presents microglial activation as a potential therapeutic target for preventing the OP induced neuronal damage. PMID- 22817664 TI - Short-term effect of low-intensity, pulsed, electromagnetic fields on gait characteristics in older adults with low bone mineral density: a pilot randomized controlled trial. AB - AIM: To evaluate the short-term effects of a 10-min exposure to low-intensity, pulsed, electromagnetic fields (PEF) on gait characteristics in older adults with low bone mineral density. METHODS: In a single-center, double-blind, randomized controlled trial, community-dwelling older adults aged >= 70 years were randomized (3:2 ratio) to receive a 10-min treatment with PEF (mean intensity 1.5 mW) or placebo. The following gait parameters were assessed at baseline and just after the intervention/placebo with the GAITRite Portable Walkway system: self selected gait speed (cm/s), stride length (cm), support base (cm) and double support phase (s). RESULTS: In the intervention group (25 patients), both self selected gait speed and stride length increased significantly from baseline, whereas the double support phase decreased. In the placebo group, all gait parameters except for support base remained unchanged. The mean percent increase (+/- standard deviation) of self-selected gait speed was significantly (P = 0.010) greater in the intervention group (20.1 +/- 15.6) compared with the placebo group (10.5 +/- 13.1), whereas no significant difference in the mean percent variation of the other parameters was found between the two groups. During the intervention, no adverse event was observed. A similar proportion of patients in the two groups reported one fall in the 30 days after the intervention/placebo. CONCLUSIONS: This is the first randomized-controlled trial showing the potential beneficial effects of PEF on gait characteristics in older adults. Further phase III randomized trials are warranted to establish their potential benefits (e.g. fall prevention) on fall-related health outcomes in elderly patients. PMID- 22817665 TI - Pancreatic juice cytology of serous cystic neoplasms communicating with the pancreatic duct: diagnostic pitfalls in this rare entity. PMID- 22817666 TI - Acute tubulointerstitial nephritis, treatment with steroid and impact on renal outcomes. AB - BACKGROUND: The use and timing of steroids in the management of acute tubulointerstitial nephritis (ATIN) remains debatable. AIMS: To determine the incidence and aetiology of ATIN in our unit, and to examine trends in the use of steroids and their impact on renal outcomes. METHODS: Patients with a histological diagnosis of ATIN over a 9-year period were identified and divided into steroid-treated (StG) and steroid-naive groups (SnG). Mean change in estimated glomerular filtration rate (eGFR) was determined. RESULTS: Forty-nine patients had ATIN as their main diagnosis, 67% of cases were drug-induced, and proton pump inhibitors (PPI) were the second commonest implicated drug category. Majority (75%) of patients received steroids, and eGFR improved to a significantly greater degree in these steroid-treated patients (3.4-fold improvement vs 2.0-fold in SnG; P < 0.05, unpaired t-test). Despite comparable eGFR at presentation (StG: 11.7; SnG: 15.4), steroid-treated patients were less likely to receive dialysis, although not significantly so (OR 0.27; 95% CI 0.06 1.15, P = 0.066, chi-squared test). However, there was no significant relation between the degree of eGFR improvement and delay in starting steroids (Pearson r = -0.25, P > 0.45), and no difference in eGFR at the time of last follow-up (StG: 33 +/- 3; SnG: 32 +/- 7; P > 0.9, unpaired t-test). CONCLUSION: StG patients had a greater degree of improvement in renal function, but with no correlation between degree of improvement in eGFR and delay in starting steroids, and similar eGFR values at final follow-up. PPI were the second commonest drug category among drug-induced cases. PMID- 22817668 TI - Failure to deliver ICD shocks after a failed discharge despite redetection of rapid ventricular tachycardia? What is the cause? PMID- 22817667 TI - Cost effectivenes of erlotinib versus chemotherapy for first-line treatment of non small cell lung cancer (NSCLC) in fit elderly patients participating in a prospective phase 2 study (GFPC 0504). AB - BACKGROUND: The median age of newly diagnosed patients with non-small cell lung cancer (NSCLC) is 67 years, and one-third of patients are older than 75 years. Elderly patients are more vulnerable to the adverse effects of chemotherapy, and targeted therapy might thus be a relevant alternative. The objective of this study was to assess the cost-effectiveness of erlotinib followed by chemotherapy after progression, compared to the reverse strategy, in fit elderly patients with advanced NSCLC participating in a prospective randomized phase 2 trial (GFPC0504). METHODS: Outcomes (PFS and overall survival) and costs (limited to direct medical costs, from the third-party payer perspective) were prospectively collected until second progression. Costs after progression and health utilities (based on disease states and grade 3-4 toxicities) were derived from the literature. RESULTS: Median overall survival, QALY and total costs for the erlotinib-first strategy were respectively 7.1 months, 0.51 and 27 734 ?, compared to 9.4 months, 0.52 and 31 688 ? for the chemotherapy-first strategy. The Monte Carlo simulation demonstrates that the two strategies do not differ statistically. CONCLUSION: In terms of cost effectiveness, in fit elderly patients with NSCLC, erlotinib followed by chemotherapy compares well with the reverse strategy. PMID- 22817669 TI - Correlation between emergency room visits for influenza-like illness during the influenza A (H1/N1) pandemic in children and adults. AB - Surveillance of incident influenza-like illness (ILI) was implemented in two children and adult medical emergency departments during the influenza A (H1/N1) pandemic to assess correlations in the daily number of ILI-related emergency room visits (ERV) between these departments. A total of 7165 ILIs in children and 610 ILIs in adults were observed. We noticed a high linear correlation between the number of ERV involving ILI on day D in the pediatric department and the number of ERV because of ILI 2 days later in adults (R = 0.82, P < 10(-4)). Therefore, the rate of adult ILI-related ERV might be anticipated based on the rate of pediatric ERV. PMID- 22817670 TI - Modulating gas sensing properties of CuO nanowires through creation of discrete nanosized p-n junctions on their surfaces. AB - We report significant enhancement of CuO nanowire (NW) sensing performance at room temperature through the surface functionalization with SnO(2) nanocrystals (NCs). The sensitivity enhancement can be as high as ~300% for detecting 1% NH(3) diluted in air. The improved sensitivity could be attributed to the electronic interaction between p-type CuO NWs and n-type SnO(2) NCs due to the formation of nanosized p-n junctions, which are highly sensitive to the surrounding gaseous environment and could effectively manipulate local charge carrier concentration. Our results suggest that the NC-NW structure is an attractive candidate for practical sensing applications, in view of its outstanding room-temperature sensitivity, excellent dynamic properties (rapid response and quick recovery), and flexibility in modulating the sensing performance (e.g., by adjusting the coverage of SnO(2) NCs on CuO NWs and doping of SnO(2) NCs). PMID- 22817671 TI - The integrated model of smartphone adoption: hedonic and utilitarian value perceptions of smartphones among Korean college students. AB - This study aims to propose an integrated model of smartphone adoption that incorporates social influences (SIs), perceived technicality, as well as hedonic and utilitarian attitudes into the technology acceptance model. The proposed model was empirically evaluated by using survey data collected from 239 Korean college students to investigate their perception and attitudes toward smartphone adoption intention. Our results show that users' attitudes and their adoption intention are highly influenced by SI and positive self-image. This implies that a smartphone is a symbolic product that can signal affiliation and enhance the users' status in a group. The results also indicate that hedonic enjoyment is equally important as utilitarian usefulness in predicting the adoption intention, and the two variables mediate the relationships between SI, positive self-image, perceived technicality, and the intention to use. Consequently, the results reveal that smartphones are convergent media that can be viewed as both task oriented and entertainment-oriented devices. PMID- 22817672 TI - Preventing hypothermia in elective arthroscopic shoulder surgery patients: a protocol for a randomised controlled trial. AB - BACKGROUND: Patients having arthroscopic shoulder surgery frequently experience periods of inadvertent hypothermia. This common perioperative problem has been linked to adverse patient outcomes such as myocardial ischaemia, surgical site infection and coagulopathy. International perioperative guidelines recommend patient warming, using a forced air warming device, and the use of warmed intraoperative irrigation solutions for the prevention of hypothermia in at-risk patient groups. This trial will investigate the effect of these interventions on patients' temperature, thermal comfort, and total recovery time. METHOD/DESIGN: The trial will employ a randomised 2 x 2 factorial design. Eligible patients will be stratified by anaesthetist and block randomised into one of four groups: Group one will receive preoperative warming with a forced air warming device; group two will receive warmed intraoperative irrigation solutions; group three will receive both preoperative warming and warmed intraoperative irrigation solutions; and group four will receive neither intervention. Participants in all four groups will receive active intraoperative warming with a forced air warming device. The primary outcome measures are postoperative temperature, thermal comfort, and total recovery time. Primary outcomes will undergo a two-way analysis of variance controlling for covariants such as operating room ambient temperature and volume of intraoperative irrigation solution. DISCUSSION: This trial is designed to confirm the effectiveness of these interventions at maintaining perioperative normothermia and to evaluate if this translates into improved patient outcomes. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12610000591055. PMID- 22817673 TI - Cis- and trans-acting genetic factors contribute to heterogeneity in the rate of crossing over between the Drosophila simulans clade species. AB - In the genus Drosophila, variation in recombination rates has been found within and between species. Genetic variation for both cis- and trans-acting factors has been shown to affect recombination rates within species, but little is known about the genetic factors that affect differences between species. Here, we estimate rates of crossing over for seven segments that tile across the euchromatic length of the X chromosome in the genetic backgrounds of three closely related Drosophila species. We first generated a set of Drosophila mauritiana lines each having two semidominant visible markers on the X chromosome and then introgressed these doubly marked segments into the genetic backgrounds of its sibling species, Drosophila simulans and Drosophila sechellia. Using these 21 lines (seven segments, three genetic backgrounds), we tested whether recombination rates within the doubly marked intervals differed depending on genetic background. We find significant heterogeneity among intervals and among species backgrounds. Our results suggest that a combination of both cis- and trans-acting factors have evolved among the three D. simulans clade species and interact to affect recombination rate. PMID- 22817676 TI - Human induced pluripotent stem cells differentiated into chondrogenic lineage via generation of mesenchymal progenitor cells. AB - Human induced pluripotent stem cells (hiPSCs) exhibit pluripotency, proliferation capability, and gene expression similar to those of human embryonic stem cells (hESCs). hESCs readily form cartilaginous tissues in teratomas in vivo; despite extensive effort, however, to date no efficient method for inducing mature chondrocytes in vitro has been established. hiPSCs can also differentiate into cartilage in vivo by teratoma formation, but as with hESCs, no reliable system for in vitro chondrogenic differentiation of hiPSCs has yet been reported. Here, we examined the chondrogenic differentiation capability of hiPSCs using a multistep culture method consisting of embryoid body (EB) formation, cell outgrowth from EBs, monolayer culture of sprouted cells from EBs, and 3 dimensional pellet culture. In this culture process, the cell density of monolayer culture was critical for cell viability and subsequent differentiation capability. Monolayer-cultured cells exhibited fibroblast-like morphology and expressed markers for mesenchymal stem cells. After 2-3 weeks of pellet culture, cells in pellets exhibited a spherical morphology typical of chondrocytes and were surrounded by extracellular matrix that contained acidic proteoglycans. The expression of type II collagen and aggrecan in pellets progressively increased. Histological analysis revealed that over 70% of hiPSC-derived pellets successfully underwent chondrogenic differentiation. Using the same culture method, hESCs showed similar histological changes and gene expression, but differentiated slightly faster and more efficiently than hiPSCs. Our study demonstrates that hiPSCs can be efficiently differentiated into the chondrogenic lineage in vitro via generation of mesenchymal progenitor cells, using a simplified, multistep culture method. PMID- 22817677 TI - A prognostic model for patients with hepatocellular carcinoma within the Milan criteria undergoing non-transplant therapies, based on 1106 patients. AB - BACKGROUND: The Milan criteria are used to select candidates with small hepatocellular carcinoma (HCC) for liver transplantation. Due to severe shortage of donors, majority of patients within the Milan criteria need to seek alternative treatments. AIM: To propose a prognostic model for these patients undergoing non-transplant therapies. METHODS: A total of 1106 HCC patients, who were within the Milan criteria and received non-transplant therapies were retrospectively analysed. Patients were randomly assigned to the derivation and validation set according to treatments. A prognostic model was constructed from independent predictors of survival identified in the multivariate Cox model of the derivation set and was confirmed in the validation set. RESULTS: In the Cox model, serum bilirubin >=1.5 mg/dL [risk ratio (RR): 1.525, P = 0.016], alpha fetoprotein (AFP) >=100 ng/mL (RR: 1.728, P < 0.001), mild ascites (RR: 1.705, P = 0.025) and moderate/severe ascites (RR: 4.163, P < 0.001) were independent predictors of poor survival in the derivation set (n = 553). A prognostic model with a total of 0-4 points was derived with the sum of three variables: 1 point each for bilirubin >=1.5 mg/dL, AFP >=100 ng/mL and mild ascites, and 2 points for moderate/severe ascites. This scoring system accurately predicted the survival in the validation set (n = 553; P < 0.001). The model consistently discriminated the survival in patients stratified by curative and noncurative treatments (both P values <0.001). CONCLUSION: The newly proposed prognostic scoring model, based on serum bilirubin and AFP level, and severity of ascites, is informative to predict the survival in non-transplant HCC patients within the Milan criteria. PMID- 22817678 TI - Attitudes towards preconception care in Maltese women with type 1 diabetes mellitus. AB - INTRODUCTION: The aim of this study was to assess the level of knowledge and awareness related to preconception care among Maltese women of reproductive age with type 1 diabetes mellitus (T1DM). METHODS: Thirty-seven T1DM women, aged 12 30 years, were self-administered a questionnaire related to diabetes self management and preconception care. The participants then underwent an educational intervention and re-took the same questionnaire. RESULTS: Before the intervention, 26 participants (70%) claimed they did not have any knowledge about the preconception care of diabetes. Of the remaining 11 participants, the main reported source of information about diabetes care was the diabetologist (n = 8; 6.7%). The response rate was 70% (26 out of 37 participants completed the questionnaire after the educational intervention). Six of the participants who initially reported no preconception care knowledge claimed an increased awareness after the event. There was a statistically significant increase in the knowledge scores after the intervention. CONCLUSION: It is evident that there is a lack of awareness of the importance of pre-pregnancy planning to avoid pregnancy-related complications with diabetes. This emphasizes the need for more education and it is imperative for healthcare professionals to address these issues with adolescent female patients. PMID- 22817679 TI - Canada's highest court unchains injection drug users; implications for harm reduction as standard of healthcare. AB - North America's only supervised injection facility, Insite, opened its doors in September of 2003 with a federal exemption as a three-year scientific study. The results of the study, evaluated by an independent research team, showed it to be successful in engaging the target group in healthcare, preventing overdose death and HIV infections while increasing uptake and retention in detox and treatment. The research, published in peer-reviewed medical and scientific journals, also showed that the program did not increase public disorder, crime or drug use. Despite the substantial evidence showing the effectiveness of the program, the future of Insite came under threat with the election of a conservative federal government in 2006. As a result, the PHS Community Services Society (PHS), the non-profit organization that operates Insite, launched a legal case to protect the program. On 30 September 2011, Supreme Court of Canada ruled in favour of Insite and underscored the rights of people with addictions to the security of their person under section 7 of the Charter of Rights and Freedoms (Charter of Rights). The decision clears the ground for other jurisdictions in Canada, and perhaps North America, to implement supervised injection and harm reduction where it is epidemiologically indicated. The legal case validates the personhood of people with addictions while metaphorically unchaining them from the criminal justice system. PMID- 22817680 TI - Roles of iron acquisition systems in virulence of extraintestinal pathogenic Escherichia coli: salmochelin and aerobactin contribute more to virulence than heme in a chicken infection model. AB - BACKGROUND: Avian pathogenic Escherichia coli (APEC) and uropathogenic E. coli (UPEC) are the two main subsets of extraintestinal pathogenic E. coli (ExPEC). Both types have multiple iron acquisition systems, including heme and siderophores. Although iron transport systems involved in the pathogenesis of APEC or UPEC have been documented individually in corresponding animal models, the contribution of these systems during simultaneous APEC and UPEC infection is not well described. To determine the contribution of each individual iron acquisition system to the virulence of APEC and UPEC, isogenic mutants affecting iron uptake in APEC E058 and UPEC U17 were constructed and compared in a chicken challenge model. RESULTS: Salmochelin-defective mutants E058DeltairoD and U17DeltairoD showed significantly decreased pathogenicity compared to the wild type strains. Aerobactin defective mutants E058DeltaiucD and U17DeltaiucD demonstrated reduced colonization in several internal organs, whereas the heme defective mutants E058DeltachuT and U17DeltachuT colonized internal organs to the same extent as their wild-type strains. The triple mutant DeltachuTDeltairoDDeltaiucD in both E058 and U17 showed decreased pathogenicity compared to each of the single mutants. The histopathological lesions in visceral organs of birds challenged with the wild-type strains were more severe than those from birds challenged with DeltairoD, DeltaiucD or the triple mutants. Conversely, chickens inoculated with the DeltachuT mutants had lesions comparable to those in chickens inoculated with the wild-type strains. However, no significant differences were observed between the mutants and the wild-type strains in resistance to serum, cellular invasion and intracellular survival in HD-11, and growth in iron-rich or iron-restricted medium. CONCLUSIONS: Results indicated that APEC and UPEC utilize similar iron acquisition mechanisms in chickens. Both salmochelin and aerobactin systems appeared to be important in APEC and UPEC virulence, while salmochelin contributed more to the virulence. Heme bounded by ChuT in the periplasm appeared to be redundant in this model, indicating that other periplasmic binding proteins likely contributed to the observed no phenotype for the heme uptake mutant. No differences were observed between the mutants and their wild-type parents in other phenotypic traits, suggesting that other virulence mechanisms compensate for the effect of the mutations. PMID- 22817682 TI - Positive feedback regulation of Akt-FMRP pathway protects neurons from cell death. AB - J. Neurochem. (2012) 123, 226-238. ABSTRACT: Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up-regulated FMRP expression was abolished by pre-treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B-cell lymphoma-extra large (Bcl-xL). However, over-expression of FMRP using enhanced green fluorescent protein (eGFP)-FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl-xL production. The pro-survival role of Akt dependent up-regulation of FMRP in glutamate-stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury. PMID- 22817681 TI - Gene expression profiling and functional analysis of angiogenic markers in murine collagen-induced arthritis. AB - INTRODUCTION: Dysregulated angiogenesis is implicated in the pathogenesis of rheumatoid arthritis (RA). To provide a more profound understanding of arthritis associated angiogenesis, we evaluated the expression of angiogenesis-modulating genes at onset, peak and declining phases of collagen-induced arthritis (CIA), a well-established mouse model for RA. METHODS: CIA was induced in DBA/1 mice with type II collagen. Functional capillary density in synovial tissue of knee joints was determined by intravital fluorescence microscopy. To assess the ability of arthritic joint homogenates to induce angiogenesis, an endothelial chemotaxis assay and an in vivo matrigel plug assay were employed. The temporal expression profile of angiogenesis-related genes in arthritic paws was analysed by quantitative real-time RT-PCR using an angiogenesis focused array as well as gene specific PCR. Finally, we investigated the therapeutic effect of a monoclonal antibody specifically blocking the binding of VEGF to neuropilin (NRP)-1. RESULTS: Although arthritic paw homogenates displayed angiogenic activity in vitro and in vivo, and synovia of arthritic paws appeared highly vascularised on histological examination, the functional capillary density in arthritic knee synovia was significantly decreased, whereas capillary diameter was increased. Of the 84 genes analysed, 41 displayed a differential expression in arthritic paws as compared to control paws. Most significant alterations were seen at the peak of clinical arthritis. Increased mRNA expression could be observed for VEGF receptors (Flt-1, Flk-1, Nrp-1, Nrp-2), as well as for midkine, hepatocyte growth factor, insulin-like growth factor-1 and angiopoietin-1. Signalling through NRP-1 accounted in part for the chemotactic activity for endothelial cells observed in arthritic paw homogenates. Importantly, therapeutic administration of anti-NRP1B antibody significantly reduced disease severity and progression in CIA mice. CONCLUSIONS: Our findings confirm that the arthritic synovium in murine CIA is a site of active angiogenesis, but an altered balance in the expression of angiogenic factors seems to favour the formation of non-functional and dilated capillaries. Furthermore, our results validate NRP-1 as a key player in the pathogenesis of CIA, and support the VEGF/VEGF receptor pathway as a potential therapeutic target in RA. PMID- 22817683 TI - Synthesis of alpha,alpha-difluoroethyl aryl and heteroaryl ethers. AB - Fluorine plays a critical role in modern medicinal chemistry due to its unique properties, and new methods for its incorporation into target molecules are of high interest. An efficient new method for the preparation of aryl-alpha,alpha difluoroethyl ethers (4) via addition of aryl and heteroaryl alcohols (1) to commercially available 2-bromo-1,1-difluoroethene (2) and subsequent hydrogenolysis is presented. This procedure is an attractive alternative to existing methods that employ harshly reactive fluorinating systems such as xenon difluoride and hydrogen fluoride. PMID- 22817684 TI - Concurrent influenza virus infection and tuberculosis in patients hospitalized with respiratory illness in Thailand. AB - Thailand, where influenza viruses circulate year-round, is one of 22 WHO designated high-burden countries for tuberculosis (TB). Surveillance for hospitalized respiratory illness between 2003 and 2011 revealed 23 (<1% of 7180 tested) with concurrent influenza and TB. Only two persons were previously known to have TB suggesting that acute respiratory illness may bring patients to medical attention and lead to TB diagnosis. Influenza/TB was not associated with higher disease severity or mortality. PMID- 22817686 TI - A validated survival score for patients with metastatic spinal cord compression from non-small cell lung cancer. AB - BACKGROUND: This multicenter study aimed to create and validate a scoring system for survival of patients with metastatic spinal cord compression (MSCC) from non small cell lung cancer (NSCLC). METHODS: The entire cohort of 356 patients was divided in a test group (N = 178) and a validation group (N = 178). In the test group, nine pre-treatment factors including age, gender, Eastern Cooperative Oncology Group performance status (ECOG-PS), number of involved vertebrae, pre radiotherapy ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, and the time developing motor were retrospectively analyzed. RESULTS: On multivariate analysis, survival was significantly associated with ECOG-PS, pre-radiotherapy ambulatory status, visceral metastases, and the time developing motor deficits. These factors were included in the scoring system; the score for each factor was determined by dividing the 6-month survival rate (in %) by 10. The risk score represented the sum of the scores for each factor. According to the risk scores, which ranged from 6 to 19 points, three prognostic groups were designed. The 6-month survival rates were 6% for 6-10 points, 29% for 11-15 points, and 78% for 16-19 points (p < 0.001). In the validation group, the 6-month survival rates were 4%, 24%, and 76%, respectively (p < 0.001). CONCLUSIONS: Since the survival rates of the validation group were similar to those of the test group, this score can be considered reproducible. The scoring system can help when selecting the individual treatment for patients with MSCC from NSCLC. A prospective confirmatory study is warranted. PMID- 22817685 TI - The autophagic inhibitor 3-methyladenine potently stimulates PKA-dependent lipolysis in adipocytes. AB - BACKGROUND AND PURPOSE The class III PI3K inhibitor, 3-methyladenine (3-MA), is commonly used to selectively block autophagy. Recent findings suggest a strong relationship between autophagy and lipid turnover. Here, we explore the effect of 3-MA on adipocyte lipolysis. EXPERIMENTAL APPROACH Assays were performed in 3T3 L1 cells. Cells were treated with 3-MA and wortmannin, a pan PI3K and autophagy inhibitor. Pharmacological and genetic manipulation of endogenous autophagic and lipolytic pathways was used to ascertain the contribution of 3-MA to the observed effects on lipolysis. KEY RESULTS 3T3-L1 cells that were exposed to 3-MA showed a consistent increase in lipolysis, approximately 50% over basal levels. The effect of 3-MA was not secondary to autophagic inhibition as treatment of 3T3-L1 cells with wortmannin yielded no such changes. Dosing and time course experiments showed that 3-MA's ability to activate lipolysis was more sensitive than its inhibitory effect on autophagy. Knockdown of adipose triglyceride lipase (ATGL) negated the stimulatory effect of 3-MA by >90%, indicating that 3-MA enhanced ATGL-dependent hydrolysis of triacylglycerols. Additionally, the lipolytic effect of 3-MA was dependent on the activation of PKA and 3-MA induced a rapid and potent elevation of intracellular cAMP levels in adipocytes. CONCLUSIONS AND IMPLICATIONS Cumulatively, we show that 3-MA potently modulated a cellular mechanism and its underlying signalling pathways not associated with autophagy. Furthermore, we describe a novel stimulatory effect on a major signalling pathway. Our findings provide valuable information to studies employing 3-MA as a specific inhibitor for PI3K and autophagy. PMID- 22817688 TI - Atonement. PMID- 22817687 TI - Cervical squamous intraepithelial lesions and associated cervical infections in an HIV-positive population in Rural Mpumalanga, South Africa. AB - BACKGROUND: The incidences of genital human papillomavirus (HPV) infection, associated squamous intraepithelial lesions and cervical squamous cell carcinoma are significantly increased in HIV-positive women. The role of other cervicovaginal infections in the acquisition of the HPV infection, cervical carcinogenesis and genital HIV infection remains largely speculative. METHODS: A retrospective study was conducted including 1087 HIV-positive women in rural Mpumalanga province, South Africa, for the period 1 May 2009 to 31 August 2010. For each patient, the age at first presentation, cervical cytological diagnosis, subsequent follow-up cytology and histology, and microscopically visible infections (including endemic Bilharzia) were tabulated and statistically analysed. RESULTS: The prevalence of low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), squamous cell carcinoma, atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude HSIL (ASC-H) in the study population were 22.1%, 30.9%, 0.6%, 13.5% and 4.0%, respectively. LSIL, HSIL and squamous cell carcinoma were diagnosed, respectively, at the average ages of 35.7, 37.9 and 37.2 years. Four patients with cervical intraepithelial neoplasia grade 1 (CIN1), 32 with CIN2/CIN3 and two with cervical squamous cell carcinoma were also diagnosed with Bilharzia. Of the other infections only bacterial vaginosis had a positive statistical correlation with HPV-induced cervical abnormalities (LSIL, HSIL or squamous cell carcinoma). CONCLUSION: This study confirms the high prevalence of progressive HPV-associated cervical disease in a rural Southern African HIV-positive population, which is at least equal to or worse than in other African HIV-positive studies. The high incidence of Bilharzia infection in those cases that underwent cervical cone excision suggests a possible relationship with progressive HPV disease and cervical carcinogenesis. Bacterial vaginosis (perhaps in combination with Bilharzia) may compromise the normal barriers against HPV and HIV infection. PMID- 22817689 TI - Living behind dikes: mimicking flooding experiences. AB - Delta areas like the Netherlands are threatened by global climate change. Awareness is, however, rather low. Our research objective was to investigate whether coping responses to flooding risks could be enhanced in a virtual environment (VE). A laboratory experiment was conducted in which participants were exposed to a simulated dike breach and consequent flooding of their virtual residence. We tested the hypothesis that an interactive 3D flood simulation facilitates coping responses compared to noninteractive film and slide simulations. Our results showed that information search, the motivation to evacuate, and the motivation to buy flood insurance increased after exposure to the 3D flood simulation compared to the film and slide simulations. Mediation analyses revealed that some of these presentation mode effects were mediated by a greater sense of being present in the VE. Implications to use high-end flood simulations in a VE to communicate real-world flooding risks and coping responses to threatened residents will be discussed. PMID- 22817690 TI - Scale-dependent effects of habitat area on species interaction networks: invasive species alter relationships. AB - BACKGROUND: The positive relationship between habitat area and species number is considered a fundamental rule in ecology. This relationship predicts that the link number of species interactions increases with habitat area, and structure is related to habitat area. Biological invasions can affect species interactions and area relationships. However, how these relationships change at different spatial scales has remained unexplored. We analysed understory plant-pollinator networks in seven temperate forest sites at 20 spatial scales (radius 120-2020 m) to clarify scale-associated relationships between forest area and plant-pollinator networks. RESULTS: The pooled data described interactions between 18 plant (including an exotic) and 89 pollinator (including an exotic) species. The total number of species and the number of interaction links between plant and pollinator species were negatively correlated with forest area, with the highest correlation coefficient at radii of 1520 and 1620 m, respectively. These results are not concordant with the pattern predicted by species-area relationships. However, when associations with exotic species were excluded, the total number of species and the number of interaction links were positively correlated with forest area (the highest correlation coefficient at a radius of 820 m). The network structure, i.e., connectance and nestedness, was also related to forest area (the highest correlation coefficients at radii of 720-820 m), when associations with exotics were excluded. In the study area, the exotic plant species Alliaria petiolata, which has invaded relatively small forest patches surrounded by agricultural fields, may have supported more native pollinator species than initially expected. Therefore, this invasive plant may have altered the original relationships between forest area and plant-pollinator networks. CONCLUSIONS: Our results demonstrate scale-dependent effects of forest area on the size and structure of plant-pollinator networks. We also suggest that a single exotic plant species can impact plant-pollinator networks, even in temperate continental habitats. PMID- 22817691 TI - Repeatability of gingival crevicular fluid collection and quantification, as determined through its alkaline phosphatase activity: implications for diagnostic use. AB - BACKGROUND AND OBJECTIVE: In spite of four decades of studies on gingival crevicular fluid, no data have been reported on the repeatability of gingival crevicular fluid collection and the subsequent quantification procedures. The present study reports, for the first time, on the repeatability and method error of gingival crevicular fluid collection and quantification, as determined through its alkaline phosphatase (ALP) activity. Diagnostic considerations are then explored. MATERIAL AND METHODS: Twenty-seven healthy subjects (17 women and 10 men; mean age +/- SD, 21.2 +/- 4.8 years) with optimal periodontal status were enrolled according to a blind prospective design. The gingival crevicular fluid was collected at baseline, and after 1 d, 1 wk and 3 mo. At each clinical session, two consecutive rounds of gingival crevicular fluid collection were made from each of the four maxillary incisors, allowing the recovery of resting and flow gingival crevicular fluid. The total ALP activities were determined spectrophotometrically, and repeatability and method errors for the resting, flow and overall (resting + flow) gingival crevicular fluid ALP activities were calculated, relative to the corresponding baseline levels. RESULTS: No significant differences were seen over time, although the flow gingival crevicular fluid ALP activity was generally lower than that for the resting gingival crevicular fluid. The method errors ranged from 40 to 58%, with the flow and overall gingival crevicular fluid activities showing the highest and lowest errors, respectively. CONCLUSION: Reliable use of the gingival crevicular fluid ALP collection and quantification, both in research and diagnosis on an individual basis, should take into account relevant errors, and variations are to be considered as true only above relevant thresholds. PMID- 22817692 TI - Air pollution and lung health: an epilogue. PMID- 22817693 TI - Cyberbullying definition among adolescents: a comparison across six European countries. AB - Several criteria have been proposed for defining cyberbullying to young people, but no studies have proved their relevance. There are also variations across different countries in the meaning and the definition of this behavior. We systematically investigated the role of five definitional criteria for cyberbullying, in six European countries. These criteria (intentionality, imbalance of power, repetition, anonymity, and public vs. private) were combined through a set of 32 scenarios, covering a range of four types of behaviors (written-verbal, visual, exclusion, and impersonation). For each scenario, participants were asked whether it was cyberbullying or not. A randomized version of the questionnaire was shown to 295 Italian, 610 Spanish, 365 German, 320 Sweden, 336 Estonian, and 331 French adolescents aged 11-17 years. Results from multidimensional scaling across country and type of behavior suggested a clear first dimension characterized by imbalance of power and a clear second dimension characterized by intentionality and, at a lower level, by anonymity. In terms of differences across types of behaviors, descriptive frequencies showed a more ambiguous role for exclusion as a form of cyberbullying, but general support was given to the relevance of the two dimensions across all the types of behavior. In terms of country differences, French participants more often perceived the scenarios as cyberbullying as compared with those in other countries, but general support was found for the relevance of the two dimensions across countries. PMID- 22817695 TI - [Since a change has to be made]. PMID- 22817694 TI - Vascular endothelial growth factor C enhances cervical cancer migration and invasion via activation of focal adhesion kinase. AB - Vascular endothelial growth factor C (VEGF-C) is correlated positively with clinical cervical cancer metastasis and survival. Previously we showed that VEGF C directly activated actin-binding protein moesin, leading to the formation of membrane protrusions. However, whether VEGF-C alters cervical cancer cell adhesion to the extra-cellular matrix is currently unknown. In this study, we investigated the effects of VEGF-C on the formation of focal adhesion complexes, which provide anchoring sites for cell attachment to the extracellular matrix. On cultured cervical carcinoma cell line SiHa cells, VEGF-C enhanced focal adhesion kinase (FAK) phosphorylation. As a result, VEGF-C led to increased formation of focal adhesion complexes and enhanced migration and invasion, which was reversed by siRNA abrogating FAK. VEGF-C resulted in increased interaction of its receptor Flt-4 with non-receptor tyrosine kinase c-Src, leading to c-Src phosphorylation. The specific inhibitor of c-Src kinase, PP2, or the transfection with specific c Src siRNA largely impaired VEGF-C-enhanced FAK phosphorylation, suggesting that Flt-4/c-Src cascade plays a central role in these processes. These results implied that VEGF-C promotes cervical cancer metastasis by activation of FAK protein through Flt-4/c-Src pathway. PMID- 22817696 TI - Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project. AB - BACKGROUND: There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. METHODS/DESIGN: Semi structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. DISCUSSION: To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version. PMID- 22817697 TI - Divergent behavior of glycosylated threonine and serine derivatives in solid phase peptide synthesis. AB - Solid phase peptide coupling of glycosylated threonine derivatives was systematically evaluated. In contrast to glycosylated serine derivatives which are highly prone to epimerization, glycosylated threonine derivatives produce only negligible amounts of epimerization. Under forcing conditions, glycosylated threonine analogs undergo beta-elimination, rather than epimerization. Mechanistic studies and molecular modeling were used to understand the origin of the differences in reactivity. PMID- 22817698 TI - Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. AB - INTRODUCTION: The purpose of this investigation was to evaluate the efficacy of cisplatin chemotherapy in BRCA1 mutation carriers with metastatic breast cancer. METHODS: In a phase II, open-label study, 20 patients with metastatic breast cancer who carried a mutation in BRCA1 were treated with cisplatin 75 mg/m2 intravenously every 3 weeks as part of a 21-day cycle for 6 cycles. Restaging studies to assess response were performed after cycles 2 and 6, and every three months thereafter. RESULTS: Between July 2007 and January 2009, 20 patients were enrolled. Baseline characteristics were as follows: 65% had prior adjuvant chemotherapy, 55% had prior chemotherapy for metastatic breast cancer; mean age was 48 years (ranges 32 to 70); 30% estrogen receptor (ER) or progesterone receptor (PR)+, 70% ER/PR/Human Epidermal Growth Factor Receptor 2 (HER2)- and 0% HER2+. Overall response rate was 80%; nine patients experienced a complete clinical response (45%) and seven experienced a partial response (35%). Overall survival was 80% at one year, 60% at two years and 25% at three years. Four of the 20 patients are alive four years after initiating treatment. The median time to progression was 12 months. The median survival from the start of cisplatinum treatment was 30 months. Cisplatin-related adverse events, including nausea (50%), anemia (5%) and neutropenia (35%) were mostly mild to moderate in severity. CONCLUSIONS: This phase II study demonstrates that cisplatin chemotherapy has high activity in women with a BRCA1 mutation and metastatic breast cancer and is generally well tolerated. TRIAL REGISTRATION: This trial is registered retrospectively on the clinical trials website ClinicalTrials.gov. The identifier is NCT01611727. PMID- 22817699 TI - Better adherence to a transdermal tulobuterol patch than inhaled salmeterol in elderly chronic obstructive pulmonary disease patients. AB - BACKGROUND: Inhaled long-acting beta2-agonists (LABA) are often poorly adhered to by elderly patients with chronic obstructive pulmonary disease (COPD). We hypothesized that older age and compromised cognitive function might contribute to poor adherence to inhaled medications among COPD patients, and that transdermally delivered medications could improve adherence, exercise tolerance and quality of life (QOL). OBJECTIVE: To compare adherence and effects on health outcomes between transdermal and inhaled LABA. METHODS: A total of 44 treatment naive, elderly Japanese patients with moderate-to-severe COPD were treated with a transdermal tulobuterol patch (TP; 2 mg, once a day) or inhaled salmeterol (50 ug, twice a day) in a randomized crossover manner. The primary outcomes were adherence to the LABA medications and changes in QOL measured by the St George's Respiratory Questionnaire. Secondary outcomes were changes in 6-min walk distance (6MWD) and spirometric values. RESULTS: The overall adherence rate was 90.3 +/- 1.6% for TP and 75.5 +/- 2.9% for salmeterol (P < 0.001). Adherence to salmeterol was correlated with age and Mini-Mental State Examination (MMSE) score (P < 0.05 and P < 0.01, respectively), although that to TP was relatively constant regardless of age and MMSE score. 6MWD and QOL were significantly improved from baseline after TP, but not after salmeterol treatment (P < 0.05). Similar degrees of increase in spirometric values occurred after treatment with TP and salmeterol. CONCLUSIONS: Adherence levels were higher overall with TP than with inhaled salmeterol, and more stable across age groups and MMSE levels. TP might be a favorable treatment option for COPD patients with poor adherence to an inhaled LABA. PMID- 22817700 TI - Early pharmacotherapy with fluoxetine rescues dendritic pathology in the Ts65Dn mouse model of down syndrome. AB - Down syndrome DS is a genetic pathology characterized by brain hypotrophy and severe cognitive impairment. Although defective neurogenesis is an important determinant of mental disability, a severe dendritic pathology appears to be an equally important factor. A previous study showed that fluoxetine, a selective serotonin reuptake inhibitor, fully restores neurogenesis in the Ts65Dn mouse model of DS. The goal of the current study was to establish whether fluoxetine also restores dendritic development. In mice aged 45 days, treated with fluoxetine in the postnatal period P3-P15, we examined the dendritic arbor of the granule cells of the dentate gyrus (DG). The granule cells of trisomic mice had a severely hypotrophic dendritic arbor, fewer spines and a reduced innervation than euploid mice. Treatment with fluoxetine fully restored all these defects. In Ts65Dn mice, we found reduced levels of serotonin that were restored by treatment. Results show that a pharmacotherapy with fluoxetine is able to rescue not only the number of granule neurons but also their "quality" in terms of correct maturation and connectivity. These findings strongly suggest that fluoxetine may be a drug of choice for the improvement of the major defects in the DS brain and, possibly, of mental retardation. PMID- 22817701 TI - Nanoparticle assembly for sensitive DNA detection using SERRS. AB - SERRS (surface-enhanced resonance Raman scattering) is a vibrational technique, whereby a relatively weak Raman scattering effect is enhanced through the use of a visible chromophore and a roughened metal surface. The direct analysis of DNA by SERRS requires the modification of a nucleic acid sequence to incorporate a chromophore, and adsorption of the modified sequence on to a roughened metal surface. Aggregated metallic nanoparticles are commonly used in the analysis of dye-labelled DNA by SERRS, allowing for detection levels that rival those gained from standard fluorescence-based techniques. In the present paper, we report on how SERRS can be exploited for the analysis of clinically relevant DNA samples. We also report on the ability of nanoparticles to aggregate as the result of a biologically significant event, as opposed to the use of an external charge modifying agent. The self-assembly of metallic nanoparticles is shown to be a promising new technique in the move towards extremely sensitive methods of DNA analysis by SERRS. PMID- 22817702 TI - Nanomechanics of superbugs and superdrugs: new frontiers in nanomedicine. AB - The alarming rise in drug-resistant hospital 'superbugs' and the associated increase in fatalities is driving the development of technologies to search for new antibiotics and improve disease diagnostics. One of the most successful drug targets is the bacterial cell wall, an evolutionary feature of virtually all prokaryotes and vital for their survival by providing mechanical strength. The recent discovery of bacterial cytoskeletal proteins analogous to the key force bearing machinery in eukaryotes also provides new opportunities for drug discovery, but little is known about their mechanical role in bacteria. In the present short article, I review recent developments in the field of nanotechnology to investigate the mechanical mechanisms of action of potent antibiotics on cell wall and cytoskeletal targets with unprecedented spatial, temporal and force resolution and the development of a new generation of nanomechanical devices to detect pathogens for point-of-care diagnostics. PMID- 22817703 TI - Advances in TERS (tip-enhanced Raman scattering) for biochemical applications. AB - TERS (tip-enhanced Raman scattering) provides exceptional spatial resolution without any need for labelling and has become a versatile tool for biochemical analysis. Two examples will be highlighted here. On the one hand, TERS measurements on a single mitochondrion are discussed, monitoring the oxidation state of the central iron ion of cytochrome c, leading towards a single protein characterization scheme in a natural environment. On the other hand, a novel approach of single molecule analysis is discussed, again based on TERS experiments on DNA and RNA, further highlighting the resolution capabilities of this method. PMID- 22817704 TI - Building droplet-based microfluidic systems for biological analysis. AB - In the present paper, we review and discuss current developments and challenges in the field of droplet-based microfluidics. This discussion includes an assessment of the basic fluid dynamics of segmented flows, material requirements, fundamental unit operations and how integration of functional components can be applied to specific biological problems. PMID- 22817705 TI - Solid-state nanopores for biosensing with submolecular resolution. AB - Biological cell membranes contain various types of ion channels and transmembrane pores in the 1-100 nm range, which are vital for cellular function. Individual channels can be probed electrically, as demonstrated by Neher and Sakmann in 1976 using the patch-clamp technique [Neher and Sakmann (1976) Nature 260, 799-802]. Since the 1990s, this work has inspired the use of protein or solid-state nanopores as inexpensive and ultrafast sensors for the detection of biomolecules, including DNA, RNA and proteins, but with particular focus on DNA sequencing. Solid-state nanopores in particular have the advantage that the pore size can be tailored to the analyte in question and that they can be modified using semi conductor processing technology. This establishes solid-state nanopores as a new class of single-molecule biosensor devices, in some cases with submolecular resolution. In the present review, we discuss a few of the most important recent developments in this field and how they might be applied to studying protein protein and protein-DNA interactions or in the context of ultra-fast DNA sequencing. PMID- 22817706 TI - Functional self-assembling polypeptide bionanomaterials. AB - Bionanotechnology seeks to modify and design new biopolymers and their applications and uses biological systems as cell factories for the production of nanomaterials. Molecular self-assembly as the main organizing principle of biological systems is also the driving force for the assembly of artificial bionanomaterials. Protein domains and peptides are particularly attractive as building blocks because of their ability to form complex three-dimensional assemblies from a combination of at least two oligomerization domains that have the oligomerization state of at least two and three respectively. In the present paper, we review the application of polypeptide-based material for the formation of material with nanometre-scale pores that can be used for the separation. Use of antiparallel coiled-coil dimerization domains introduces the possibility of modulation of pore size and chemical properties. Assembly or disassembly of bionanomaterials can be regulated by an external signal as demonstrated by the coumermycin-induced dimerization of the gyrase B domain which triggers the formation of polypeptide assembly. PMID- 22817707 TI - Quantum dot-nucleic acid/aptamer bioconjugate-based fluorimetric biosensors. AB - Over the last 10 years, fluorescent semiconductor QD (quantum dot)-biomolecule conjugates have emerged as a powerful new sensing platform showing great potential in a wide range of applications in biosensing, environmental monitoring and disease diagnosis. The present mini-review is a brief account of the recent developments in QD-NA (nucleic acid), particularly NA aptamer, conjugate-based biosensors using the FRET (Forster resonance energy transfer) readout mechanism. It starts with a brief introduction to the NA aptamer and QD-FRET, followed by example approaches to compact QD-DNA conjugates, target readout strategies and sensing performance, and concludes with challenges and outlook for the QD NA/aptamer bioconjugate sensors. PMID- 22817708 TI - Twice is better: highlights of the second meeting focused on tau biology and pathology. AB - It is an exciting time for tau researchers as it is now generally accepted that abnormal tau species are required to mediate the toxic effects of amyloid beta peptide oligomers in Alzheimer's disease. Tau may play multiple roles in neurophysiology and there may be further pathologically relevant tau alterations, besides hyperphosphorylation and aggregation. The recent Biology and Pathology of Tau and its Role in Tauopathies II meeting explored these various aspects of tau, and presentations at the meeting, described in the following articles in this issue of Biochemical Society Transactions, are outlined in the present paper. PMID- 22817709 TI - Degradation of tau protein by autophagy and proteasomal pathways. AB - Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin-proteasome system) and the ALS (autophagy lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies. PMID- 22817710 TI - Looking for novel functions of tau. AB - The lack or excess of the protein tau can be deleterious for neurons. The absence of tau can result in retarded neurogenesis and neuronal differentiation, although adult mice deficient in tau are viable, probably because of the compensation of the loss of tau by other MAPs (microtubule-associated proteins). On the contrary, the overexpression of tau can be toxic for the cell. One way to reduce intracellular tau levels can be achieved by its secretion through microvesicles to the extracellular space. Furthermore, tau can be found in the extracellular space because of the neuronal cell death occurring in neurodegenerative disorders such as Alzheimer's disease. The presence of toxic extracellular tau could be the mechanism for the spreading of tau pathology in these neurodegenerative disorders. PMID- 22817711 TI - Potential neuroprotective strategies against tauopathy. AB - Tauopathies are neurodegenerative diseases, including AD (Alzheimer's disease) and FTLD-T (tau-positive frontotemporal lobar degeneration), with shared pathology presenting as accumulation of detergent-insoluble hyperphosphorylated tau deposits in the central nervous system. The currently available treatments for AD address only some of the symptoms, and do not significantly alter the progression of the disease, namely the development of protein aggregates and loss of functional neurons. The development of effective treatments for various tauopathies will require the identification of common mechanisms of tau neurotoxicity, and pathways that can be modulated to protect against neurodegeneration. Model organisms, such as Caenorhabditis elegans, provide methods for identifying novel genes and pathways that are involved in tau pathology and may be exploited for treatment of various tauopathies. In the present paper, we summarize data regarding characterization of MSUT2 (mammalian suppressor of tau pathology 2), a protein identified in a C. elegans tauopathy model and subsequently shown to modify tau toxicity in mammalian cell culture via the effects on autophagy pathways. MSUT2 represents a potential drug target for prevention of tau-related neurodegeneration. PMID- 22817712 TI - Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. AB - Neurons within the brains of those with AD (Alzheimer's disease) and related neurodegenerative disorders, collectively termed 'tauopathies', contain fibrillar inclusions composed of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes MTs (microtubules). Tau hyperphosphorylation and aggregation probably result in reduced MT binding that could affect axonal transport and neuronal function. A possible therapeutic strategy to overcome a loss of tau function in tauopathies is administration of MT-stabilizing agents, such as those used in the treatment of cancer. However, these drugs elicit severe side effects, and most existing MT-stabilizing compounds have poor BBB (blood-brain barrier) permeability, which renders them unsuitable for tauopathy treatment. We identified EpoD (epothilone D) as a brain penetrant MT-stabilizing agent with preferred pharmacokinetic and pharmacodynamic properties. EpoD was evaluated for its ability to compensate for tau loss-of function in an established Tg (transgenic) mouse model, using both preventative and interventional dosing paradigms. EpoD at doses much lower than previously used in human cancer patients caused improved axonal MT density and decreased axonal dystrophy in the tau Tg mice, leading to an alleviation of cognitive deficits. Moreover, EpoD reduced the extent of tau pathology in aged tau Tg mice. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a viable drug candidate for the treatment of AD and related tauopathies. PMID- 22817713 TI - Tau oligomers and tau toxicity in neurodegenerative disease. AB - AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-positive pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course analysis and antibody labelling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labelling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the molecular chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease. PMID- 22817714 TI - Copy number variations involving the microtubule-associated protein tau in human diseases. AB - Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism. PMID- 22817715 TI - Tau alternative splicing in familial and sporadic tauopathies. AB - Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies. PMID- 22817716 TI - The self-perpetuating tau truncation circle. AB - Pathological truncations of human brain proteins represent the common feature of many neurodegenerative disorders including AD (Alzheimer's disease), Parkinson's disease and Huntington's disease. Protein truncations significantly change the structure and function of these proteins and thus can engender their pathological metamorphosis. We have shown previously that truncated forms of tau protein are contained in the core of the paired helical filaments that represent the main constituent of neurofibrillary pathology. Recently, we have identified truncated tau species of a different molecular signature. We have found that tau truncation is not produced by a random process, but rather by highly specific proteolytic cleavage and/or non-enzymatic fragmentation. In order to characterize the pathophysiology of AD-specific truncated tau species, we have used a transgenic rat model for AD expressing human truncated tau. Expression of the tau protein induces the formation of novel truncated tau species that originate from both transgenic human tau and endogenous rat tau proteins. Moreover, these truncated tau proteins are found exclusively in the misfolded fraction of tau, suggesting that they actively participate in the tau misfolding process. These findings corroborate further the idea that the appearance of truncated tau species starts a self-perpetuating cycle of further tau protein truncation leading to and accelerating tau misfolding and formation of neurofibrillary pathology. PMID- 22817717 TI - The role of MAPT sequence variation in mechanisms of disease susceptibility. AB - The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse group of neurodegenerative dementias and movement disorders. The genomic architecture in the region spanning the MAPT locus contains a ~1.8 Mb block of linkage disequilibrium characterized by two major haplotypes: H1 and H2. Recent studies have established strong genetic association between the MAPT locus and neurodegenerative disease and uncovered haplotype-specific differences in expression and alternative splicing of MAPT transcripts. Integrating genetic association data and gene expression data to understand how non-coding genetic variation at a gene locus affects gene expression and leads to susceptibility to disease is a high priority in disease genetics, and the MAPT locus provides an excellent paradigm for this. In the absence of protein-coding changes caused by haplotype sequence variation, altered levels of protein expression or altered ratios of isoform expression are excellent candidate mechanisms to link the MAPT genetic disease association with biological function. The use of novel transgenic and endogenous genetic models are required to understand the role of MAPT sequence variation in mechanisms of disease susceptibility. PMID- 22817718 TI - What is the pathological significance of tau oligomers? AB - Insoluble aggregates of the microtubule-associated protein tau characterize a number of neurodegenerative diseases collectively termed tauopathies. These aggregates comprise abnormally hyperphosphorylated and misfolded tau proteins. Research in this field has traditionally focused on understanding how hyperphosphorylated and aggregated tau mediates dysfunction and toxicity in tauopathies. Recent findings from both Drosophila and rodent models of tauopathy suggest that large insoluble aggregates such as tau filaments and tangles may not be the key toxic species in these diseases. Thus some investigators have shifted their focus to study pre-filament tau species such as tau oligomers and hyperphosphorylated tau monomers. Interestingly, tau oligomers can exist in a variety of states including hyperphosphorylated and unphosphorylated forms, which can be both soluble and insoluble. It remains to be determined which of these oligomeric states of tau are causally involved in neurodegeneration and which signal the beginning of the formation of inert/protective filaments. It will be important to better understand this so that tau-based therapeutic interventions can target the most toxic tau species. PMID- 22817719 TI - Towards understanding the phosphorylation code of tau. AB - We describe our efforts to combine in vitro enzymatic reactions with recombinant kinases to phosphorylate the neuronal tau protein, and NMR spectroscopy to unravel the resulting phosphorylation pattern in both qualitative and quantitative manners. This approach, followed by functional assays with the same samples, gives access to the complex phosphorylation code of tau. As a result, we propose a novel hypothesis for the link between tau (hyper)phosphorylation and aggregation. PMID- 22817720 TI - Luminescent conjugated poly- and oligo-thiophenes: optical ligands for spectral assignment of a plethora of protein aggregates. AB - The deposition of protein aggregates in various parts of our body gives rise to several devastating diseases, and the development of probes for the selective detection of aggregated proteins is crucial to advance our understanding of the pathogenesis underlying these diseases. LCPs (luminescent conjugated polythiophenes) are fluorescent probes that bind selectively to protein aggregates. The conjugated thiophene backbone is flexible and offers a connection between the conformation and the emission properties, hence binding of LCPs gives the molecule a spectral fingerprint. The present review covers the utilization of LCPs to study the heterogeneity of protein aggregates. It emphasizes specifically the introduction of well-defined probes called LCOs (luminescent conjugated oligothiophenes) and reports how these molecules can be used for real-time in vivo imaging of cerebral plaques as well as for spectral discrimination of protein aggregates and detection of early species in the fibrillation pathway of amyloid beta-peptide. PMID- 22817721 TI - The relationship between subcortical tau pathology and Alzheimer's disease. AB - The stepwise progression of tau pathology [NFTs (neurofibrillary tangles) and NTs (neuropil threads)] in AD (Alzheimer's disease) is generally assumed to begin in the transentorhinal region (entorhinal stage) from which it progresses to the hippocampus (limbic stage) and to neocortical regions (neocortical stage). This stepwise progression is reflected in the NFT Braak stages. However, it has been shown recently that tau pathology is frequently seen in subcortical nuclei, in particular the LC (locus coeruleus) in over 90% of individuals under 30 years of age, suggesting that AD-associated tau pathology begins in the LC and not in the transentorhinal region. On the other hand, only minimal amounts of tau pathology are seen in the LC in cases with considerable entorhinal tau pathology, while the severity of tau pathology in the LC significantly increases with increasing NFT Braak stages. These findings suggest that the LC becomes increasingly involved during AD progression rather than representing the site initially affected. Further studies are warranted to answer the question of whether tau pathology in the LC of young individuals is associated with AD or whether it rather reflects non-specific neuronal damage. PMID- 22817722 TI - Pharmacological chaperones increase the cell-surface expression of intracellularly retained mutants of the melanocortin 4 receptor with unique rescuing efficacy profiles. AB - Mutated versions of membrane proteins often fail to express at the plasma membrane, but instead are trapped in the secretory pathway, resulting in disease. The retention of these mutant proteins is thought to result from local misfolding, which prevents export from the ER (endoplasmic reticulum), targeting the receptor for degradation via the ER-associated quality control system. The rhodopsin-like G-protein-coupled MC4R (melanocortin 4 receptor) is an example of such a membrane protein. Over 100 natural MC4R mutations are linked with an obese phenotype and to date represent the most common monogenic cause of severe early onset obesity. More than 80% of these mutations result in a substantial proportion of MC4R being retained intracellularly. If these receptors were expressed at the plasma membrane, many could be functional, as mutations often occur in regions distinct from those associated with ligand or G-protein binding. Our aim is to show proof of concept that selective compounds can rescue the function of MC4R mutants by increasing their cell-surface expression, and further to this, examine whether the rescue profile differs between mutants. Whole-cell ELISA and 96-well fluorescence-based assays with N-terminally HA (haemagglutinin) tagged and C-terminally mCherry-tagged mutant MC4Rs were used to screen a number of novel MC4R-selective compounds. A total of four related compounds increased the cell-surface expression of wild-type and three intracellularly retained mutant MC4Rs, thus acting as pharmacological chaperones. There appears to be a unique rescue efficacy profile for each compound that does not correlate with potency, suggesting distinct receptor conformations induced by the different mutations. A degree of functionality of V50M and S58C was also rescued following relocation to the cell surface. PMID- 22817723 TI - Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. AB - The quality control of protein homoeostasis deteriorates with aging, causing the accumulation of misfolded proteins and neurodegeneration. Thus, in AD (Alzheimer's disease), soluble oligomers, protofibrils and fibrils of the Abeta (amyloid beta-peptide) and tau protein accumulate in specific brain regions. This is associated with the progressive destruction of synaptic circuits controlling memory and higher mental function. The primary signalling mechanisms that (i) become defective in AD to alter the normal proteostasis of Abeta and tau, and (ii) initiate a pathophysiological response to cause cognitive decline, are unclear. The IIS [insulin/IGF-1 (insulin-like growth factor 1)-like signalling] pathway is mechanistically linked to longevity, protein homoeostasis, learning and memory, and is emerging to be central to both (i) and (ii). This pathway is aberrantly overactivated in AD brain at the level of increased activation of the serine/threonine kinase Akt and the phosphorylation of its downstream targets, including mTOR (mammalian target of rapamycin). Feedback inhibition of normal insulin/IGF activation of the pathway also occurs in AD due to inactivation of IRS-1 (insulin receptor substrate 1) and decreased IRS-1/2 levels. Pathogenic forms of Abeta may induce aberrant sustained activation of the PI3K (phosphoinositide 3-kinase)/Akt signal in AD, also causing non-responsive insulin and IGF-1 receptor, and altered tau phosphorylation, conformation and function. Reducing IIS activity in animal models by decreasing IGF-1R levels or inhibiting mTOR activity alters Abeta and tau protein homoeostasis towards less toxic protein conformations, improves cognitive function and extends healthy lifespan. Thus normalizing IIS dysfunction may be therapeutically relevant in abrogating Abeta and tau proteotoxicity, synaptic dysfunction and cognitive decline in AD. PMID- 22817724 TI - Exploiting amyloid: how and why bacteria use cross-beta fibrils. AB - Many bacteria produce protein fibrils that are structurally analogous to those associated with protein misfolding diseases such as Alzheimer's disease. However, unlike fibrils associated with disease, bacterial amyloids have beneficial functions including conferring stability to biofilms, regulating development or imparting virulence. In the present review, we consider what makes amyloid fibrils so suitable for these roles and discuss recent developments in the study of bacterial amyloids, in particular the chaplins from Streptomyces coelicolor. We also consider the broader impact of the study of bacterial amyloids on our understanding of infection and disease and on developments in nanotechnology. PMID- 22817725 TI - Prion processing: a double-edged sword? AB - The events leading to the degradation of the endogenous PrP(C) (normal cellular prion protein) have been the subject of numerous studies. Two cleavage processes, alpha-cleavage and beta-cleavage, are responsible for the main C- and N-terminal fragments produced from PrP(C). Both cleavage processes occur within the N terminus of PrP(C), a region that is significant in terms of function. alpha Cleavage, an enzymatic event that occurs at amino acid residues 110 and 111 on PrP(C), interferes with the conversion of PrP(C) into the prion disease associated isoform, PrP(Sc) (abnormal disease-specific conformation of prion protein). This processing is seen as a positive event in terms of disease development. The study of beta-cleavage has taken some surprising turns. beta Cleavage is brought about by ROS (reactive oxygen species). The C-terminal fragment produced, C2, may provide the seed for the abnormal conversion process, as it resembles in size the fragments isolated from prion-infected brains. There is, however, strong evidence that beta-cleavage provides an essential process to reduce oxidative stress. beta-Cleavage may act as a double-edged sword. By beta cleavage, PrP(C) may try to balance the ROS levels produced during prion infection, but the C2 produced may provide a PrP(Sc) seed that maintains the prion conversion process. PMID- 22817726 TI - Choosing and using Drosophila models to characterize modifiers of Huntington's disease. AB - HD (Huntington's disease) is a fatal inherited gain-of-function disorder caused by a polyQ (polyglutamine) expansion in the htt (huntingtin protein). Expression of mutant htt in model organisms is sufficient to recapitulate many of the cellular defects found in HD patients. Many groups have independently developed Drosophila models of HD, taking advantage of its rapid life cycle, carefully annotated genome and well-established molecular toolkits. Furthermore, unlike simpler models, Drosophila have a complex nervous system, displaying a range of carefully co-ordinated behaviours which offer an exquisitely sensitive readout of neuronal disruption. Measuring HD-associated changes in behaviour in Drosophila therefore offers a window into the earliest stages of HD, when therapeutic interventions might be particularly effective. The present review describes a number of recently developed Drosophila models of HD and offers practical guidance on the advantages and disadvantages of various experimental approaches that can be used to screen these models for modifiers of mutant htt-mediated toxicity. PMID- 22817727 TI - Alternatively folded proteins with unexpected beneficial functions. AB - HAMLET (human alpha-lactalbumin made lethal to tumour cells) and its related partially unfolded protein-fatty acid complexes are novel biomolecular nanoparticles that possess relatively selective cytotoxic activities towards tumour cells. One of the key characteristics is the requirement for the protein to be partially unfolded, hence endowing native proteins with additional functions in the alternatively folded states. Beginning with the history of its discovery and development, the cellular targets that appear to be strongly correlated with tumour cell death are introduced in the present article. PMID- 22817728 TI - Oestrogen-dependent regulation of miRNA biogenesis: many ways to skin the cat. AB - The steroid hormone oestrogen is central to normal female physiology, reproduction and behaviour, through its effects on cellular processes including cell proliferation and cell survival. The effects of oestrogen are mediated by nuclear ERs (oestrogen receptors). ER status is important for the development, progression and treatment of breast cancer. miRNAs (microRNAs) are small non coding RNAs that bind the 3'-UTR (untranslated region) of target mRNAs to reduce their stability and/or translation. miRNAs participate in oestrogen signalling by regulating oestrogen-responsive genes and pathways. Interestingly expression and maturation of miRNAs can also be regulated by ER signalling at multiple levels. In addition to regulating the expression of miRNAs at the transcriptional level, ER appears to be able to regulate the biogenesis of miRNAs. In the present review, we summarize recent findings on miRNA biogenesis and describe various mechanisms by which oestrogen signalling can modulate the production of miRNAs. PMID- 22817729 TI - Intronic microRNAs: a crossroad in gene regulation. AB - Most human genes transcribed by RNA Pol II (polymerase II) contain short exons separated by long tracts of non-coding intronic sequences. In addition to their role in generating proteomic diversity through the process of alternative splicing, intronic sequences host many ncRNAs (non-coding RNAs), involved in various gene regulation processes. miRNAs (microRNAs) are short ncRNAs that mediate either mRNA transcript translational repression and/or degradation. Between 50 and 80% of miRNAs are encoded within introns of host mRNA genes. This observation suggests that there is co-regulation between the miRNA biogenesis and pre-mRNA splicing processes. The present review summarizes current advances in this field and discusses possible roles for intronic co-transcriptional cleavage events in the regulation of human gene expression. PMID- 22817730 TI - Pleiotropy of microRNA-192 in the kidney. AB - Diverse aetiologies result in significant deviation from homoeostasis in the kidney, leading to CKD (chronic kidney disease). CKD progresses to end-stage renal disease principally as a result of renal fibrosis, although the molecular mechanisms underlying this fibrotic process are still poorly understood. miRNAs (microRNAs) are a recently discovered family of endogenous short single-stranded RNAs that regulate global gene expression at the post-transcriptional level. The recent findings from our laboratory and others discussed in the present review outline pleiotropic roles for miR-192 in renal homoeostasis and in the fibrotic kidney. We describe miR-192-driven anti-and pro-fibrotic effects via the repression of ZEB1 and ZEB2 (zinc finger E-box-binding homeobox proteins 1 and 2), resulting in changes in extracellular matrix deposition and cell differentiation. PMID- 22817731 TI - BRCA1 exon 11 alternative splicing, multiple functions and the association with cancer. AB - BRCA1 (breast cancer early-onset 1) alternative splicing levels are regulated in a cell-cycle- and cell-type-specific manner, with splice variants being present in different proportions in tumour cell lines as well as in normal mammary epithelial cells. The importance of this difference in the pathogenesis of breast cancer has yet to be determined. Developing an understanding of the impact of BRCA1 isoform ratio changes on cell phenotype will be of value in breast cancer and may offer therapeutic options. In the present paper, we describe the splicing isoforms of BRCA1 exon 11, their possible role in cancer biology and the importance of maintaining a balanced ratio. PMID- 22817732 TI - Human papillomavirus gene expression is controlled by host cell splicing factors. AB - HPVs (human papillomaviruses) infect stratified epithelia and cause a variety of lesions ranging from benign warts to invasive tumours. The virus life cycle is tightly linked to differentiation of the keratinocyte it infects: papillomaviruses modulate host gene expression to ensure efficient virus replication. For example, the viral transcription factor E2 can directly up regulate, in an epithelial differentiation-dependent manner, cellular SRSFs [SR (serine/arginine-rich) splicing factors] that control constitutive and alternative splicing. Changes in alternative splicing and the mechanisms controlling this for viral mRNAs have been the subject of intense exploration. However, to date experiments have only been carried out in model systems because the genetic systems suitable for studying alternative splicing of viral RNAs in the context of the virus life cycle are relatively recent and technically challenging. Now using these life cycle-supporting systems, our laboratory has identified SR proteins as important players in differentiation-dependent regulation of HPV gene expression. Better understanding of the role of cellular factors in regulating the virus life cycle is needed as it may help development of novel diagnostic approaches and antiviral therapies in the future. PMID- 22817733 TI - UPF1 involvement in nuclear functions. AB - UPF1 (up-frameshift 1) is a protein conserved in all eukaryotes that is necessary for NMD (nonsense-mediated mRNA decay). UPF1 mainly localizes to the cytoplasm and, via mechanisms that are linked to translation termination but not yet well understood, stimulates rapid destruction of mRNAs carrying a PTC (premature translation termination codon). However, some studies have indicated that in human cells UPF1 has additional roles, possibly unrelated to NMD, which are carried out in the nucleus. These might involve telomere maintenance, cell cycle progression and DNA replication. In the present paper, we review the available experimental evidence implicating UPF1 in nuclear functions. The unexpected view that emerges from this literature is that the nuclear functions primarily stem from UPF1 having an important role in DNA replication, rather than NMD affecting the expression of proteins involved in these processes. Our bioinformatics survey of the interaction network of UPF1 with other human proteins, however, highlights that UPF1 also interacts with proteins associated with nuclear RNA degradation and transcription termination; therefore suggesting involvement in processes that could also impinge on DNA replication indirectly. PMID- 22817734 TI - How does Tra2beta protein regulate tissue-specific RNA splicing? AB - The splicing regulator protein Tra2beta is conserved between humans and insects and is essential for mouse development. Recent identification of physiological RNA targets has started to uncover molecular targets and mechanisms of action of Tra2beta. At a transcriptome-wide level, Tra2beta protein binds a matrix of AGAA rich sequences mapping frequently to exons. Particular tissue-specific alternatively spliced exons contain high concentrations of high scoring Tra2beta binding sites and bind Tra2beta strongly in vitro. These top exons were also activated for splicing inclusion in cellulo by co-expression of Tra2beta protein and were significantly down-regulated after genetic depletion of Tra2beta. Tra2beta itself seems to be fairly evenly expressed across several different mouse tissues. In the present paper, we review the properties of Tra2beta and its regulated target exons, and mechanisms through which this fairly evenly expressed alternative splicing regulator might drive tissue-specific splicing patterns. PMID- 22817735 TI - Terminal loop-mediated control of microRNA biogenesis. AB - Regulation of miRNA (microRNA) biogenesis shapes the profiles of miRNAs in the living cell, contributing to cell identity and function. Importantly, aberrant miRNA levels have been linked to a variety of human pathological states. In recent years, a number of proteins have been shown to regulate the miRNA biogenesis at the level of Drosha and Dicer cleavage. A large proportion of these factors regulate miRNA production through binding to the TL (terminal loop) regions of miRNA progenitors. In the present paper, we review the current knowledge about pri-miRNA (primary miRNA) and pre-miRNA (precursor miRNA) TL involvement in the regulation of miRNA biogenesis. PMID- 22817736 TI - Adaptation to stress in yeast: to translate or not? AB - For most eukaryotic organisms, including Saccharomyces cerevisiae, the rapid inhibition of protein synthesis forms part of a response to stress. In order to balance the changing conditions, precise stress-specific alterations to the cell's proteome are required. Therefore, in the background of a global down regulation in protein synthesis, specific proteins are induced. Given the level of plasticity required to enable stress-specific alterations of this kind, it is surprising that the mechanisms of translational regulation are not more diverse. In the present review, we summarize the impact of stress on translation initiation, highlighting both the similarities and distinctions between various stress responses. Finally, we speculate as to how yeast cells generate stress responsive programmes of protein production when regulation is focused on the same steps in the translation pathway. PMID- 22817737 TI - MicroRNA expression profiling of human islets from individuals with and without type 2 diabetes: promises and pitfalls. AB - Recent studies in mouse, involving the beta-cell-specific deletion of Dicer1, have highlighted the crucial role of miRNAs (microRNAs) in regulating insulin secretion and consequently Type 2 diabetes. Identifying the individual miRNAs involved in human islet dysfunction may be of diagnostic and therapeutic interest. miRNA expression profiling of human islets isolated from donors with and without Type 2 diabetes may represent one of the first steps in the discovery of these specific miRNAs. The present review discusses some of the potential pitfalls and promises of such an approach. PMID- 22817738 TI - Mechanisms of Drosophila Dscam mutually exclusive splicing regulation. AB - Alternative splicing of pre-mRNA is a major mechanism to increase protein diversity in higher eukaryotes. Dscam, the Drosophila homologue of human DSCAM (Down's syndrome cell adhesion molecule), generates up to 38016 isoforms through mutually exclusive splicing in four variable exon clusters. This enormous molecular diversity is functionally important for wiring of the nervous system and phagocytosis of invading pathogens. Current models explaining this complex splicing regulation include a default repressed state of the variable exon clusters to prevent the splicing together of adjacent exons, the presence of RNA secondary structures important for the release of one specific variable exon from the repressed state and combinatorial interaction of RNA-binding proteins for choosing a specific exon. PMID- 22817739 TI - Cytoplasmic mRNA 3' tagging in eukaryotes: does it spell the end? AB - Although functional RNA is generally protected against degradation, defects or irregularity during RNA biogenesis lead to rapid degradation. Cellular surveillance mechanisms therefore need to distinguish aberrant, erroneous, damaged or aging transcripts from normal RNAs in order to maintain fidelity and control of gene expression. The detection of defects seems to be primarily based on functionality or aberrant rates of a given step in RNA biogenesis, allowing efficient detection of many different errors without recognition of their specific nature. We propose that the addition of non-templated nucleotides to the 3' end of mRNAs and small non-coding RNAs, 3' tagging, is the primary means by which malfunctioning RNAs are labelled, promoting their functional repression and degradation. However, the addition of non-templated nucleotides to transcripts can have diverse effects which vary with location, length, substrate and sequence. PMID- 22817740 TI - Defining the roles and interactions of PTB. AB - PTB (polypyrimidine tract-binding protein) is an abundant and widely expressed RNA-binding protein with four RRM (RNA recognition motif) domains. PTB is involved in numerous post-transcriptional steps in gene expression in both the nucleus and cytoplasm, but has been best characterized as a regulatory repressor of some ASEs (alternative splicing events), and as an activator of translation driven by IRESs (internal ribosome entry segments). We have used a variety of approaches to characterize the activities of PTB and its molecular interactions with RNA substrates and protein partners. Using splice-sensitive microarrays we found that PTB acts not only as a splicing repressor but also as an activator, and that these two activities are determined by the location at which PTB binds relative to target exons. We have identified minimal splicing repressor and activator domains, and have determined high resolution structures of the second RRM domain of PTB binding to peptide motifs from the co-repressor protein Raver1. Using single-molecule techniques we have determined the stoichiometry of PTB binding to a regulated splicing substrate in whole nuclear extracts. Finally, we have used tethered hydroxyl radical probing to determine the locations on viral IRESs at which each of the four RRM domains bind. We are now combining tethered probing with single molecule analyses to gain a detailed understanding of how PTB interacts with pre-mRNA substrates to effect either repression or activation of splicing. PMID- 22817741 TI - The role of microRNA in the response to cisplatin treatment. AB - Resistance to the cytotoxic effects of cisplatin can be mediated through changes in a wide variety of cellular processes and signalling pathways. The discovery of microRNAs as regulators of protein expression through the targeting of mRNA has led to a number of studies on the effect of cisplatin treatment on microRNA expression, and the ability of microRNAs to modulate cisplatin resistance. PMID- 22817742 TI - SAFB1- and SAFB2-mediated transcriptional repression: relevance to cancer. AB - SAFB1 (scaffold attachment factor B1) and a second family member SAFB2, are multifunctional proteins implicated in a variety of cellular processes including cell growth, apoptosis and stress response. Their potential function as tumour suppressors has been proposed based on well-described roles in tran-scriptional repression. The present review summarizes the current knowledge of SAFB1 and SAFB2 proteins in transcriptional repression with relevance to cancer. PMID- 22817743 TI - SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases. AB - SRPK1 (serine-arginine protein kinase 1) is a protein kinase that specifically phosphorylates proteins containing serine-arginine-rich domains. Its substrates include a family of SR proteins that are key regulators of mRNA AS (alternative splicing). VEGF (vascular endothelial growth factor), a principal angiogenesis factor contains an alternative 3' splice site in the terminal exon that defines a family of isoforms with a different amino acid sequence at the C-terminal end, resulting in anti-angiogenic activity in the context of VEGF165-driven neovascularization. It has been shown recently in our laboratories that SRPK1 regulates the choice of this splice site through phosphorylation of the splicing factor SRSF1 (serine/arginine-rich splicing factor 1). The present review summarizes progress that has been made to understand how SRPK1 inhibition may be used to manipulate the balance of pro- and anti-angiogenic VEGF isoforms in animal models in vivo and therefore control abnormal angiogenesis and other pathophysiological processes in multiple disease states. PMID- 22817744 TI - Form and function of eukaryotic unstable non-coding RNAs. AB - Unstable non-coding RNAs are produced from thousands of loci in all studied eukaryotes (and also prokaryotes), but remain of largely unknown function. The present review summarizes the mechanisms of eukaryotic non-coding RNA degradation and highlights recent findings regarding function. The focus is primarily on budding yeast where the bulk of this research has been performed, but includes results from higher eukaryotes where available. PMID- 22817745 TI - BLF1, the first Burkholderia pseudomallei toxin, connects inhibition of host protein synthesis with melioidosis. AB - Melioidosis is a disease caused by infection with Burkholderia pseudomallei. The molecular basis for the pathogenicity of B. pseudomallei is poorly understood. However, recent work has identified the first toxin from this bacterium and shown that it inhibits host protein synthesis. Here, we review the illness that is potentially associated with biological warfare, the pathogen and its deadly molecular mechanism of action, as well as therapeutic developments that may follow. PMID- 22817746 TI - The increasing functional repertoire of U1 snRNA. AB - Splicing is a key process for mRNA maturation, particularly in higher eukaryotes where most protein-coding transcripts contain multiple introns. It is achieved by the concerted action of five snRNAs (small nuclear RNAs) and hundreds of accessory proteins that form the spliceosome. Although snRNAs are present in equal amounts in the spliceosome, there is an overall excess of U1 in human cells. This finding led to the opinion that U1 might be involved in processes other than splicing. Research has shown that this is indeed the case and some examples found from studies in human cell systems are described briefly in the present review. PMID- 22817747 TI - Comparison of the yeast and human nuclear exosome complexes. AB - Most RNAs in eukaryotic cells are produced as precursors that undergo processing at the 3' and/or 5' end to generate the mature transcript. In addition, many transcripts are degraded not only as part of normal recycling, but also when recognized as aberrant by the RNA surveillance machinery. The exosome, a conserved multiprotein complex containing two nucleases, is involved in both the 3' processing and the turnover of many RNAs in the cell. A series of factors, including the TRAMP (Trf4-Air2-Mtr4 polyadenylation) complex, Mpp6 and Rrp47, help to define the targets to be processed and/or degraded and assist in exosome function. The majority of the data on the exosome and RNA maturation/decay have been derived from work performed in the yeast Saccharomyces cerevisiae. In the present paper, we provide an overview of the exosome and its role in RNA processing/degradation and discuss important new insights into exosome composition and function in human cells. PMID- 22817748 TI - The role of mammalian poly(A)-binding proteins in co-ordinating mRNA turnover. AB - The function of cytoplasmic PABPs [poly(A)-binding proteins] in promoting mRNA translation has been intensively studied. However, PABPs also have less clearly defined functions in mRNA turnover including roles in default deadenylation, a major rate-limiting step in mRNA decay, as well as roles in the regulation of mRNA turnover by cis-acting control elements and in the detection of aberrant mRNA transcripts. In the present paper, we review our current understanding of the complex roles of PABP1 in mRNA turnover, focusing on recent progress in mammals and highlighting some of the major questions that remain to be addressed. PMID- 22817749 TI - The mystery of mitochondrial RNases. AB - The central dogma states that DNA is transcribed to generate RNA and that the mRNA components are then translated to generate proteins; a simple statement that completely belies the complexities of gene expression. Post-transcriptional regulation alone has many points of control, including changes in the stability, translatability or susceptibility to degradation of RNA species, where both cis- and trans-acting elements will play a role in the outcome. The present review concentrates on just one aspect of this complicated process, which ultimately regulates the protein production in cells, or more specifically what governs RNA catabolism in a particular subcompartment of human cells: the mitochondrion. PMID- 22817750 TI - Role of splice variants in the metastatic progression of prostate cancer. AB - AS (alternative splicing) and its role in disease, especially cancer, has come to forefront in research over the last few years. Alterations in the ratio of splice variants have been widely observed in cancer. Splice variants of cancer associated genes have functions that can alter cellular phenotype, ultimately altering metastatic potential. As metastases are the cause of approximately 90% of all human cancer deaths, it is crucial to understand how AS is dysregulated in metastatic disease. We highlight some recent studies into the relationship between altered AS of key genes and the initiation of prostate cancer metastasis. PMID- 22817751 TI - Analysis of urinary microRNAs in chronic kidney disease. AB - Kidney biopsy is the gold-standard diagnostic test for intrinsic renal disease, but requires hospital admission and carries a 3% risk of major complications. Current non-invasive prognostic indicators such as urine protein quantification have limited predictive value. Better diagnostic and prognostic tests for chronic kidney disease patients are a major focus for industry and academia, with efforts to date directed largely at urinary proteomic approaches. microRNAs constitute a recently identified class of endogenous short non-coding single-stranded RNA oligonucleotides that regulate gene expression post-transcriptionally. Quantification of urinary microRNAs offers an alternative approach to the identification of chronic kidney disease biomarkers. PMID- 22817752 TI - The control of histone gene expression. AB - Histone proteins are essential for the packaging of DNA into chromosomes. Histone gene expression is cell-cycle-regulated and coupled to DNA replication. Control of histone gene expression occurs at the transcriptional and post-transcriptional level and ensures that a fine balance between histone abundance and DNA replication is maintained for the correct packaging of newly replicated DNA into chromosomes. In the present paper, we review histone gene expression, highlighting the control mechanisms and key molecules involved in this process. PMID- 22817753 TI - Extracellular small RNAs: what, where, why? AB - miRNAs (microRNAs) are a class of small RNA that regulate gene expression by binding to mRNAs and modulating the precise amount of proteins that get expressed in a cell at a given time. This form of gene regulation plays an important role in developmental systems and is critical for the proper function of numerous biological pathways. Although miRNAs exert their functions inside the cell, these and other classes of RNA are found in body fluids in a cell-free form that is resistant to degradation by RNases. A broad range of cell types have also been shown to secrete miRNAs in association with components of the RISC (RNA-induced silencing complex) and/or encapsulation within vesicles, which can be taken up by other cells. In the present paper, we provide an overview of the properties of extracellular miRNAs in relation to their capacity as biomarkers, stability against degradation and mediators of cell-cell communication. PMID- 22817754 TI - The roles of miRNAs in wing imaginal disc development in Drosophila. AB - During development, it is essential for gene expression to occur in a very precise spatial and temporal manner. There are many levels at which regulation of gene expression can occur, and recent evidence demonstrates the importance of mRNA stability in governing the amount of mRNA that can be translated into functional protein. One of the most important discoveries in this field has been miRNAs (microRNAs) and their function in targeting specific mRNAs for repression. The wing imaginal discs of Drosophila are an excellent model system to study the roles of miRNAs during development and illustrate their importance in gene regulation. This review aims at discussing the developmental processes where control of gene expression by miRNAs is required, together with the known mechanisms of this regulation. These developmental processes include Hox gene regulation, developmental timing, growth control, specification of SOPs (sensory organ precursors) and the regulation of signalling pathways. PMID- 22817755 TI - Deadenylation of cytoplasmic mRNA by the mammalian Ccr4-Not complex. AB - The Ccr4-Not complex is one of the major deadenylase factors present in eukaryotic cells. This multi-subunit protein complex is composed of at least seven stably associated subunits in mammalian cells including two enzymatic deadenylase subunits: one DEDD (Asp-Glu-Asp-Asp)-type deadenylase (either CNOT7/human Caf1/Caf1a or CNOT8/human Pop2/Caf1b/Calif) and one EEP (endonuclease exonuclease-phosphatase)-type enzyme (either CNOT6/human Ccr4/Ccr4a or CNOT6L/human Ccr4-like/Ccr4b). Here, the role of the human Ccr4-Not complex in cytoplasmic deadenylation of mRNA is discussed, including the mechanism of its recruitment to mRNA and the role of the BTG/Tob proteins. PMID- 22817756 TI - Long non-coding RNAs and human disease. AB - The central dogma of molecular biology states that DNA is transcribed into RNA, which in turn is translated into proteins. We now know, however, that as much as 50% of the transcriptome has no protein-coding potential, but rather represents an important class of regulatory molecules responsible for the fine-tuning of gene expression. Although the role of small regulatory RNAs [microRNAs and siRNAs (small interfering RNA)] is well defined, another much less characterized category of non-coding transcripts exists, namely lncRNAs (long non-coding RNAs). Pervasively expressed by eukaryotic genomes, lncRNAs can be kilobases long and regulate their targets by influencing the epigenetic control, chromatin status, mRNA processing or translation capacity of their targets. In the present review, I outline the potential mechanisms of action of lncRNAs, the cellular processes that have been associated with them, and also explore some of the emerging evidence for their involvement in common human disease. PMID- 22817757 TI - Non-coding RNAs in Saccharomyces cerevisiae: what is the function? AB - New sequencing technologies and high-resolution microarray analysis have revealed genome-wide pervasive transcription in many eukaryotes, generating a large number of RNAs with no coding capacity. The focus of current debate is whether many of these ncRNAs (non-coding RNAs) are functional, and if so, what their function is. In this review, we describe recent discoveries in the field of ncRNAs in the yeast Saccharomyces cerevisiae. Newly identified ncRNAs in this budding yeast, their functions in gene regulation and possible mechanisms of action are discussed. PMID- 22817759 TI - Atypical vitelliform macular dystrophy misdiagnosed as chronic central serous chorioretinopathy: case reports. AB - BACKGROUND: To report two cases of atypical vitelliform macular dystrophy misdiagnosed as chronic central serous chorioretinopathy. CASE PRESENTATION: Two patients with incidentally discovered abnormalities of the retina without specific symptoms were referred to our hospital for consultation. Bilateral macula atrophic lesions were observed and optical coherence tomography revealed serous retinal detachment in the macula. Fluorescein angiography showed multiple leakages around the central hypofluorescent area and indocyanine green angiography showed partially dilated choroidal vessels. Fundus autofluorescence (FAF) showed a decreasing pattern of autofluorescence in the subretinal fluid area, and increasing autofluorescence at the border of the serous retinal detachment. Both patients were diagnosed with chronic central serous chorioretinopathy. Photodynamic therapy and intravitreal bevacizumab injection were administered for engorged choroidal vessels during follow-up, but neither patient showed improvement in symptoms or ophthalmologic findings. Based on re evaluation by fundus photography, optical coherence tomography, fluorescein angiography, and comparison of the results of FAF with the first visit, vitelliform macular dystrophy was suspected and a definite diagnosis was made by electrooculography and genetic testing. CONCLUSION: In patients with continuous serous retinal detachment without response to photodynamic therapy or intravitreal bevacizumab injection, careful fundus exam and FAF can be used to diagnose atypical vitelliform macular dystrophy. PMID- 22817758 TI - Comparison of oral microbiota in tumor and non-tumor tissues of patients with oral squamous cell carcinoma. AB - BACKGROUND: Bacterial infections have been linked to malignancies due to their ability to induce chronic inflammation. We investigated the association of oral bacteria in oral squamous cell carcinoma (OSCC/tumor) tissues and compared with adjacent non-tumor mucosa sampled 5 cm distant from the same patient (n = 10). By using culture-independent 16S rRNA approaches, denaturing gradient gel electrophoresis (DGGE) and cloning and sequencing, we assessed the total bacterial diversity in these clinical samples. RESULTS: DGGE fingerprints showed variations in the band intensity profiles within non-tumor and tumor tissues of the same patient and among the two groups. The clonal analysis indicated that from a total of 1200 sequences characterized, 80 bacterial species/phylotypes were detected representing six phyla, Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Actinobacteria and uncultivated TM7 in non-tumor and tumor libraries. In combined library, 12 classes, 16 order, 26 families and 40 genera were observed. Bacterial species, Streptococcus sp. oral taxon 058, Peptostreptococcus stomatis, Streptococcus salivarius, Streptococcus gordonii, Gemella haemolysans, Gemella morbillorum, Johnsonella ignava and Streptococcus parasanguinis I were highly associated with tumor site where as Granulicatella adiacens was prevalent at non-tumor site. Streptococcus intermedius was present in 70% of both non-tumor and tumor sites. CONCLUSIONS: The underlying changes in the bacterial diversity in the oral mucosal tissues from non-tumor and tumor sites of OSCC subjects indicated a shift in bacterial colonization. These most prevalent or unique bacterial species/phylotypes present in tumor tissues may be associated with OSCC and needs to be further investigated with a larger sample size. PMID- 22817760 TI - Identification of an OPR protein involved in the translation initiation of the PsaB subunit of photosystem I. AB - Genetic analysis of mutants deficient in the biosynthesis of the photosystem I complex has revealed several nucleus-encoded factors that act at different post transcriptional steps of chloroplast gene expression. Here we have identified and characterized the gene affected in the tab 1-F15 mutant, which is specifically deficient in the translation of the photosystem I reaction center protein PsaB as the result of a single nucleotide deletion. This gene encodes Tab 1, a 1287 amino acid protein that contains 10 tandem 38-40 amino acid degenerate repeats of the PPPEW/OPR (octatricopeptide repeat) family, first described for the chloroplast translation factor Tbc2. These repeats are involved in the binding of Tab 1 to the 5'-untranslated region of the psaB mRNA based on gel mobility shift assays. Tab 1 is part of a large family of proteins in Chlamydomonas that are also found in several bacteria and protozoans, but are rare in land plants. PMID- 22817761 TI - Balanced ultrafiltration: inflammatory mediator removal capacity. AB - Ultrafiltration with a hemoconcentrator may remove excess fluid load and alleviate tissue edema and has been universally adopted in extracorporeal circulation protocols during pediatric cardiac surgery. Balanced ultrafiltration is advocated to remove inflammatory mediators generated during surgery. However, whether balanced ultrafiltration can remove all or a portion of the inflammatory mediator load remains unclear. The inflammatory mediator removal capacity of zero balanced ultrafiltration was measured during pediatric extracorporeal circulation in vitro. Extracorporeal circulation was composed of cardiotomy reservoir, D902 Lilliput 2 membrane oxygenator, and Capiox AF02 pediatric arterial line filter. The Hemoconcentrator BC 20 plus was placed between arterial purge line and oxygenator venous reservoir. Fresh donor human whole blood was added into the circuit and mixed with Ringer's solution to obtain a final hematocrit of 24-28%. After 2 h of extracorporeal circulation, zero-balanced ultrafiltration was initiated and arterial line pressure was maintained at approximately 100 mmHg with Hoffman clamp. The rate of ultrafiltration (12 mL/min) was controlled by ultrafiltrate outlet pressure. Identical volume of plasmaslyte A was dripped into the circuit to maintain stable hematocrit during the 45 min of the experiment. Plasma and ultrafiltrate samples were drawn every 5 min, and concentrations of inflammatory mediators including interleukin-1beta (IL-1beta), IL-6, IL-10, neutrophil elastase (NE), and tumor necrosis factor-alpha (TNF-alpha) were measured. All assayed inflammatory mediators were detected in the ultrafiltrate, demonstrating that the ultrafiltrator may remove inflammatory mediators. However, dynamic observations suggested that the concentration of NE was highest among the five inflammatory mediators in both plasma and ultrafiltrate (P < 0.001). IL 1beta had the lowest concentration in plasma, whereas the concentration of TNF alpha was the lowest in ultrafiltrate (P < 0.001). Concentrations of all inflammatory mediators in the ultrafiltrate did not increase linearly compared with those in plasma. The respective ultrafiltrate to plasma concentration and amount ratios indicated that the total removal effect of hemoconcentrator on the inflammatory mediators was 4.17 +/- 2.68% for IL-1beta, 0.64 +/- 0.69% for IL-6, 0.24 +/- 0.18% for IL-10, 2.84 +/- 1.65% for NE, and 0.51 +/- 0.81% for TNF alpha, respectively. Balanced ultrafiltration may selectively remove inflammatory mediators from serum. Respective ratios of inflammatory mediators in ultrafiltrate compared with plasma, as well as total amount of inflammatory mediators in the ultrafiltrate suggest that balanced ultrafiltration removes a limited portion of the total inflammatory mediator load. PMID- 22817762 TI - Simulation of longitudinal exposure data with variance-covariance structures based on mixed models. AB - Longitudinal data are important in exposure and risk assessments, especially for pollutants with long half-lives in the human body and where chronic exposures to current levels in the environment raise concerns for human health effects. It is usually difficult and expensive to obtain large longitudinal data sets for human exposure studies. This article reports a new simulation method to generate longitudinal data with flexible numbers of subjects and days. Mixed models are used to describe the variance-covariance structures of input longitudinal data. Based on estimated model parameters, simulation data are generated with similar statistical characteristics compared to the input data. Three criteria are used to determine similarity: the overall mean and standard deviation, the variance components percentages, and the average autocorrelation coefficients. Upon the discussion of mixed models, a simulation procedure is produced and numerical results are shown through one human exposure study. Simulations of three sets of exposure data successfully meet above criteria. In particular, simulations can always retain correct weights of inter- and intrasubject variances as in the input data. Autocorrelations are also well followed. Compared with other simulation algorithms, this new method stores more information about the input overall distribution so as to satisfy the above multiple criteria for statistical targets. In addition, it generates values from numerous data sources and simulates continuous observed variables better than current data methods. This new method also provides flexible options in both modeling and simulation procedures according to various user requirements. PMID- 22817763 TI - A clinico-radiological phenotype of voltage-gated potassium channel complex antibody-mediated disorder presenting with seizures and basal ganglia changes. AB - In childhood, central nervous system (CNS) presentations associated with antibodies to voltage-gated potassium channel (VGKC) complex include limbic encephalitis, status epilepticus, epileptic encephalopathy, and autistic regression. We report the cases of two individuals (a 6-year-old male and an 11 year-old female) who presented with an acute-onset explosive seizure disorder with positive VGKC complex antibodies and bilateral basal ganglia changes on magnetic resonance imaging (MRI). Both patients made a complete clinical recovery, without immunotherapy, with resolution of the MRI changes and normalization of the antibody levels. Extended antibody testing, including testing for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein 2, and contactin-2 was negative. This could suggest that the clinico radiological phenotype in our patients may in fact be associated with a novel autoreactive target(s) within the VGKC complex, as may be the case in other children with VGKC complex-mediated CNS disorders. PMID- 22817764 TI - Two canine malignant vascular tumours with features of human retiform haemangioendothelioma. AB - Within the human medical literature, retiform haemangioendothelioma (RHE) is an established and well-recognized histopathological variant of endothelial tumours, but to date RHE has not been reported in animals. These tumours are characterized by the presence of elongate, arborizing vascular channels lined by neoplastic endothelium with prominent, often bulging ('hobnail') nuclei supported by a dense collagenous matrix and accompanied by abundant lymphoplasmacytic inflammation. Immunohistochemically, the neoplastic cells typically express endothelial markers such as von Willebrand factor and CD31. Human RHEs are categorized as low-grade malignancies. This report describes two canine vascular tumours with features consistent with RHE. In both cases there was suspected or known widespread tumour metastasis. PMID- 22817765 TI - Is chest tube insertion with ultrasound guidance safe in patients using clopidogrel? AB - BACKGROUND AND OBJECTIVE: Drainage of the pleural space is a common procedure. The safety of chest tube insertion in patients using clopidogrel has not been investigated. METHODS: Ultrasound-guided chest tube insertions performed on 24 patients who were being actively treated with clopidogrel were retrospectively reviewed. RESULTS: No excessive bleeding occurred in any of these patients. CONCLUSIONS: Given the known effects of clopidogrel on platelet function, these results were interpreted as indicating that clopidogrel therapy is a relative but not an absolute contraindication to chest tube insertion, if an experienced operator places a small-bore tube under ultrasound guidance. PMID- 22817766 TI - Incidence and risk factors for infection in oral cancer patients undergoing different treatments protocols. AB - BACKGROUND: Over the past decade, advances in cancer treatments have been counterbalanced by a rising number of immunosuppressed patients with a multitude of new risk factors for infection. Hence, the aim of this study was to determine risk factors, infectious pathogens in blood and oral cavity of oral cancer patients undergoing different treatment procedures. METHODS: The present prospective cohort analysis was conducted on the patients undergoing treatment in the radiotherapy unit of Regional Cancer Institute, Pt. B.D. Sharma University of Health Sciences, Rohtak, Haryana, during the period of January 2007 to October 2009. Total 186 patients with squamous cell carcinoma of oral cavity were analyzed in the study. Based on treatment procedures patients were divided into three groups, group I were under radiotherapy, group II under chemotherapy and group III were of radio chemotherapy together. Clinical isolates from blood and oral cavity were identified by following general microbiological, staining and biochemical methods. The absolute neutrophile counts were done by following the standard methods. RESULTS: Prevalent bacterial pathogens isolated were Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, Klebsiella pneumonia, Proteus mirabilis, Proteus vulgaris and the fungal pathogens were Candida albicans, Aspergillus fumigatus. The predominant gram negative bacteria, Pseudomonas aeruginosa and Klebsiella pneumonia were isolated from blood of radiotherapy and oral cavity of chemotherapy treated cases respectively. The predominance of gram positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis) were observed in blood of chemotherapy, radio chemotherapy cases and oral cavity of radiotherapy, radio chemotherapy treated cases. Our study also revealed the presence of C. albicans fungi as most significant oral cavity pathogens in radiotherapy and radio chemotherapy cases. CONCLUSION: Gram positive bacteria and Gram negative were reported from the blood of all the three groups of patients. Oral mucositis played a significant role in oral cavity infection and make patients more prone to C. albicans infection. PMID- 22817767 TI - Adnexal torsion in children and adolescents: new trends to conservative surgical approach -- our experience and review of literature. AB - The purpose of this study is to discuss the surgical treatment for ovarian torsion in children and adolescents with a focus on the procedures of adnexal conservation surgery and its frequency in the literature of the last 10 years. We retrospectively reviewed the medical charts of 127 operative ovarian lesions including 30 ovarian torsions (23.6%) treated in two pediatric centers over a 10 year period. Age at presentation, presenting symptoms, diagnostic studies, surgical procedure and pathological findings were analyzed. Mean age was 13.7 years. Conservative surgery has been performed in 46.7% of the cases and laparoscopic approach in 40%. Ovarian torsion occurred in 56.7% on ovaries with functional lesion, in 23.3% on normal adnexa and in 20% on ovaries with benign neoplasm. The article includes a literature review (2000-2010) and a statistical analysis which shows a slow increase in conservative surgery from 28 to 45%. Laparoscopic surgery accounts for 23.5%. Literature review shows 40.5% normal adnexa, 33.2% non-neoplastic lesions, 25.3% benign neoplasms and 1% malignant neoplasms. The surgical treatment of children and adolescents presenting adnexal torsion should be practiced as an emergency and it should be more conservative as possible in order to maximize the future reproductive potential. PMID- 22817769 TI - Predictors of patrol officer interest in cybercrime training and investigation in selected United States police departments. AB - Cybercrime has created substantial challenges for law enforcement, particularly at the local level. Most scholars and police administrators believe that patrol officers need to become more effective first responders to cybercrime calls. The evidence illustrates, however, that many patrol officers are neither adequately prepared nor strongly interested in taking an active role in addressing cybercrime at the local level. This study, therefore, examined the factors that predicted patrol officer interest in cybercrime training and investigations in two southeastern U.S. cities. The study specifically examined the relationship between demographics, cybercrime exposure, computer training, computer proficiency, Internet and cybercrime perceptions, and views on policing cybercrime with officer interest in cybercrime investigation training and conducting cybercrime investigations in the future. Officer views on policing cybercrime, particularly whether they valued cybercrime investigations and believed that cybercrime would dramatically change policing, along with their computer skills, were the strongest predictors of interest in cybercrime efforts. Officers who had received previous computer training were less interested in additional training and conducting investigations. These findings support the argument that more command and departmental meetings focusing on the value of investigating these types of crime need to be held in order to increase officer interest. PMID- 22817768 TI - Voluntary intravenous self-administration of alcohol detects an interaction between GABAergic manipulation and GABRG1 polymorphism genotype: a pilot study. AB - BACKGROUND: Operant responding paradigms quantify a subject's motivation for reward, but such studies employing ingested alcohol cannot assure the same incremental increase in brain exposure to alcohol across subjects because of substantial variability in absorption kinetics. We developed a human progressive ratio (PR) paradigm using the computer-assisted self-infusion of ethanol (CASE) system that overcomes such variability and conducted a pilot study to assess its utility for detecting an interaction of subjects' GABRA2 or GABRG1 genotype and pretreatment with 1 mg of lorazepam (LZ) vs. placebo on their willingness to work for alcohol rewards. METHODS: Twenty healthy, nondependent drinkers, aged 21 to 27, were balanced on rs279871 and rs2350439 single nucleotide polymorphisms in the GABRA2 and GABRG1 genes, respectively. Subjects worked for alcohol, with water as an alternative reinforcer (AR), using a progressive schedule of a task that required constant attention and adapted to both fatigue and drug effects. Testing began 1 hour after pretreatment with 1 mg LZ or placebo in a crossover design. RESULTS: The CASE system performed well, and the constant attention task was perceived as work by all subjects. GABRA2 homozygosity did not significantly predict either breakpoint or cumulative work, whereas a significant GABRG1 genotype by LZ pretreatment interaction for cumulative work was detected (p = 0.04). Breakpoint revealed a weak trend toward pretreatment drug effects (p = 0.11), and a somewhat stronger interaction of LZ pretreatment with GABRG1 genotype (p = 0.06). GABRG1 status revealed a more complex relationship with respect to motivation for alcohol with and without LZ pretreatment; AG and GG individuals worked more for alcohol under both pretreatment conditions, while AA individuals worked more for the AR. CONCLUSIONS: The CASE PR paradigm shows promise as a laboratory method for use in drug development and phenotyping studies. PMID- 22817770 TI - Psychometric properties of the German version of the MacNew heart disease health related quality of life questionnaire. AB - BACKGROUND: There is a lack of German-language, disease-specific health related quality of life instruments applicable in cardiac rehabilitation. The purpose of this project was to investigate the psychometric properties of the German version of the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) in patients undergoing cardiac rehabilitation. METHODS: The MacNew was filled out by 5692 inpatients. We analysed acceptance (number of missing values), ceiling and floor effects, reliability (Cronbach's alpha), factor structure (confirmatory factor analysis), construct validity (correlation with a generic health-related quality of life instrument), and sensitivity to change. RESULTS: Two items had more than 7% missing data. We observed neither floor nor ceiling effects. Cronbach's alpha of the scales ranged from 0.78 (physical scale) to 0.95 (global scale). Confirmatory factor analysis failed to reproduce the proposed factor structure (CFI = 0.882; TLI = 0.871; RMSEA = 0.074). We therefore drafted our own model (CFI = 0.932; TLI = 0.921; RMSEA = 0.064), and observed a correlation pattern largely conforming to the hypotheses with a generic health-related quality of life instrument. The effect sizes we noted between the start and end of rehabilitation fell between 0.66 and 0.74; at the 6-month follow-up they ranged from 0.69 to 0.92. CONCLUSIONS: The German version of the MacNew Heart Disease Health-related Quality of Life Questionnaire is a suitable instrument with which to measure the impairment experienced by individuals with heart disease during inpatient cardiologic rehabilitation. The social and the global scale must be interpreted cautiously. PMID- 22817772 TI - Immunolocalization of keratin-associated beta-proteins (beta-keratins) in scales of the reptiles Sphenodon punctatus indicates that different beta-proteins are present in beta- and alpha-layers. AB - The present ultrastructural immunocytochemical study analyzes the localization of keratin-associated beta-proteins (beta-keratins) in the epidermis of the ancient reptile Sphenodon punctatus, a relict species adapted to mid-cold conditions. The epidermis comprises two main layers, indicated as beta- and alpha-keratin layers. The beta-layer contains small beta-proteins (beta-keratins) identified by using three different antibodies while the alpha-layer is poorly or not labeled for these proteins. Using other two antibodies directed against specific amino acid sequences identified in beta-proteins of lizard it results that a high-glycine beta-protein (HgG5) is specific for the beta-layer. Another antibody that recognizes glycine-cysteine medium-rich beta-proteins (HgGC10) immuno-stains beta and alpha-layers. This pattern of distribution suggests that both beta- and alpha-layers contain beta-proteins of different types that associate and replace intermediate-filament alpha-keratins during the terminal differentiation of keratinocytes. Therefore the different epidermal layers of the epidermis in S. punctatus, characterized by a specific cytology, material properties and consistency appear to derive from the prevalent type of beta-proteins synthesized in each epidermal layer and not from the alternation between beta- and alpha keratins. The present observations are discussed in comparison to previous results from lizard epidermis and indicate that beta-keratins correspond to keratin-associated proteins that through their internal beta-pleated region are capable to form filaments in addition to intermediate filaments keratins. PMID- 22817771 TI - Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer. AB - INTRODUCTION: Molecular apocrine is a subtype of estrogen receptor (ER)-negative breast cancer that is characterized by a steroid-response gene signature. We have recently identified a positive feedback loop between androgen receptor (AR) and extracellular signal-regulated kinase (ERK) signaling in this subtype. In this study, we investigated the transcriptional regulation of molecular apocrine genes by the AR-ERK feedback loop. METHODS: The transcriptional effects of AR and ERK inhibition on molecular apocrine genes were assessed in cell lines. The most regulated gene in this process, prolactin-induced protein (PIP), was further studied using immunohistochemistry of breast tumors and xenograft models. The transcriptional regulation of PIP was assessed by luciferase reporter assay and chromatin immunoprecipitation. The functional significance of PIP in cell invasion and viability was assessed using siRNA knockdown experiments and the mechanism of PIP effect on integrin-beta1 signaling was studied using immunoblotting and immunoprecipitation. RESULTS: We found that PIP is the most regulated molecular apocrine gene by the AR-ERK feedback loop and is overexpressed in ER-/AR+ breast tumors. In addition, PIP expression is regulated by AR-ERK signaling in xenograft models. These observations are explained by the fact that PIP is a target gene of the ERK-CREB1 pathway and is also induced by AR activation. Furthermore, we demonstrated that PIP has a significant functional role in maintaining cell invasion and viability of molecular apocrine cells because of a positive regulatory effect on the Integrin-ERK and Integrin-Akt signaling pathways. In fact, PIP-knockdown markedly decreases the phosphorylation of ERK, Akt, and CREB1. Importantly, PIP knockdown leads to a marked reduction of integrin-beta1 binding to ILK1 and ErbB2 that can be reversed by the addition of fibronectin fragments. CONCLUSIONS: We have identified a novel feedback loop between PIP and CREB1 mediated through the Integrin signaling pathway. In this process, PIP cleaves fibronectin to release fragments that activate integrin signaling, which in turn increases PIP expression through the ERK-CREB1 pathway. In addition, we demonstrated that PIP expression has a profound effect on cell invasion and the viability of molecular apocrine cells. Therefore, PIP signaling may be a potential therapeutic target in molecular apocrine breast cancer. PMID- 22817774 TI - Biomimetic synthesis and proposal of relative and absolute stereochemistry of heronapyrrole C. AB - The first synthesis of (-)-heronapyrrole C, the enantiomer of a unique farnesylated 2-nitropyrrole natural product is described. With none of the chiral centers of heronapyrrole C originally assigned, we proposed the most likely natural configuration on the basis of a putative biosynthetic pathway. The key step of the synthesis is a biomimetic polyepoxide cyclization cascade to establish the bis-THF moiety. Thus, (-)-heronapyrrole C is synthesized in eight steps from commercially available starting materials. PMID- 22817775 TI - Intra-atrial conduction block mimicking atrioventricular nodal block after multiple catheter ablation procedures for atrial tachycardia in a patient with cardiomyopathy. AB - A 42-year-old woman with a history of cardiomyopathy and multiple ablation procedures for atrial tachycardia developed intra-atrial conduction block that mimicked atrioventricular (AV) nodal block during radiofrequency ablation at the cavotricuspid isthmus. She was treated with atrial pacing (from the coronary sinus), which overcame intra-atrial conduction block and resulted in AV nodal conduction. PMID- 22817776 TI - Lower extremity ulceration caused by medical scooter injury: a case series. AB - The motorized mobility scooter (MMS) provides considerable benefits to patients with mobility limitations. Nevertheless, safety concerns related to MMS use are an issue. With increased use because of increased life expectancy and chronic illness, there are a growing number of reports of MMS-related injuries, ranging from lacerations and contusions to fatalities. Comorbidities may also exacerbate wound care. Prevention of these injuries is greatly needed. The author presents 5 patients with lower-extremity ulceration caused by MMS injuries. To prevent these injuries, health care providers must carefully evaluate and monitor patients. Clinicians and MMS manufacturers also need to educate and train patients on the safe use of MMS devices, including the regular use of footwear. PMID- 22817777 TI - Association of FTO gene variants with body composition in UK twins. AB - The association of FTO gene variants with body mass index (BMI) and other obesity characteristics is well established. However, uncertainties remain whether the association is present only in young populations and whether it is attributable to body fat mass specifically. We aimed to clarify these two questions in a large sample (N= 4,523 individuals) of middle-aged and older (range 40-80 years) British female twins. The women were assessed for BMI, waist and hip circumference, total lean (LBM) and fat (FBM) body mass. Since the majority of FTO association signals have been reported in a haploblock bordering 52,355 52,408 kb (on chromosome 16q12.2), we examined five genotyped and 43 imputed SNPs mapped to this block. Canonical correlation and other association analyses showed significant and consistent association between the selected SNP and studied body composition phenotypes, with p-values reaching p= 0.000004. Of particular interest, in addition to the expected significant associations between FTO variants and FBM, we also identified significant associations with LBM. These results suggest that the association between FTO variants and body composition phenotypes is present across a wide range of ages, and that FTO appears primarily to affect the amount of body soft tissue, influencing both fat and lean mass. PMID- 22817779 TI - Flood protection diversification to reduce probabilities of extreme losses. AB - Recent catastrophic losses because of floods require developing resilient approaches to flood risk protection. This article assesses how diversification of a system of coastal protections might decrease the probabilities of extreme flood losses. The study compares the performance of portfolios each consisting of four types of flood protection assets in a large region of dike rings. A parametric analysis suggests conditions in which diversifications of the types of included flood protection assets decrease extreme flood losses. Increased return periods of extreme losses are associated with portfolios where the asset types have low correlations of economic risk. The effort highlights the importance of understanding correlations across asset types in planning for large-scale flood protection. It allows explicit integration of climate change scenarios in developing flood mitigation strategy. PMID- 22817778 TI - Prenatal alcohol exposure, attention-deficit/hyperactivity disorder, and sluggish cognitive tempo. AB - BACKGROUND: Children with heavy prenatal alcohol exposure often meet criteria for attention-deficit/hyperactivity disorder (ADHD). ADHD research has examined subtype differences in symptomatology, including sluggish cognitive tempo (SCT). This construct is defined by behavioral symptoms including hypoactivity and daydreaming and has been linked to increased internalizing behaviors. The current study examined whether similar findings are displayed in children with prenatal alcohol exposure. METHODS: As part of a multisite study, caregivers of 272 children (8 to 16 years) completed the SCT Scale and Child Behavior Checklist (CBCL). Four groups were included: alcohol-exposed children with ADHD (ALC+; n = 75), alcohol-exposed children without ADHD (ALC-; n = 35), nonexposed children with ADHD (ADHD; n = 60), and nonexposed children without ADHD (CON; n = 102). SCT and CBCL scores were analyzed using 2 (exposure) * 2 (ADHD) analyses of variance. Pearson's correlations measured the relationships between SCT, CBCL, and Full Scale IQ (FSIQ). Discriminant function analysis examined whether SCT items could accurately classify groups. RESULTS: Analyses revealed significant main effects of exposure and ADHD on SCT and internalizing and externalizing scores and significant interaction effects on SCT and internalizing scores. SCT significantly correlated with internalizing, externalizing, and attention ratings in all groups and with FSIQ in ALC+. Discriminant function analysis indicated that specific SCT items could distinguish ALC- from CON. CONCLUSIONS: Alcohol exposed children exhibited elevated SCT scores. Elevations were related to increased parent ratings of internalizing and externalizing behaviors and attention. These findings are observed in alcohol-exposed children regardless of ADHD symptoms and specific SCT items proved useful in distinguishing exposed children, suggesting clinical utility for this measure in further defining the neurobehavioral profile related to prenatal alcohol exposure. PMID- 22817780 TI - Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation. AB - Percutaneous femoral venoarterial (VA) or jugular venovenous (VV) extracorporeal membrane oxygenation (ECMO) can result in delivery of hypoxic blood to the brain, coronaries, and upper extremities. Additionally, VA-ECMO by percutaneous femoral artery cannulation may compromise perfusion to the lower limbs. Use of near infrared spectroscopy (NIRS) detects regional ischemia and warns of impending hypoxic damage. We report the first known series with standardized monitoring of this parameter in adults on ECMO. This is an institutional review board-approved single institution retrospective review of patients with NIRS monitoring on ECMO from July 2010 until June 2011. Patients were analyzed for drops in NIRS tracings below 40 or >25% from baseline. VA-ECMO and VV-ECMO were initiated by percutaneous cannulation of the femoral vessels and the internal jugular vein, respectively. Sensors were placed on the patients' foreheads and on the lower limbs. NIRS tracings were recorded, analyzed, and correlated with clinical events. Twenty patients were analyzed (median age: 47.5 years): 17 patients were placed on VA-ECMO, and three patients on VV-ECMO. The median duration on ECMO was 7 days (range 2-26). One hundred percent of patients had a significant drop in bilateral cerebral oximetry tracings resulting in hemodynamic interventions, which involved increasing pressure, oxygenation, and/or ECMO flow. In 16 patients (80%), these interventions corrected the underlying ischemia. Four patients (20%) required further diagnostic intervention for persistent decreased bilateral and/or unilateral cerebral oximetry tracings, and were found to have a cerebrovascular accident (CVA). Six (30%) patients had persistent unilateral lower limb oximetry events, which resolved upon placement or replacement of a distal perfusion cannula. No patient was found to have either lower limb ischemia or a CVA with normal NIRS tracings. Use of NIRS with ECMO is important in detecting ischemic cerebral and peripheral vascular events. This allows for potential correction of the underlying process, thus preventing permanent ischemic damage. PMID- 22817781 TI - The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on imaging in Barrett's Esophagus. PMID- 22817782 TI - What is a defiant polyp and how good are we at removing them? PMID- 22817783 TI - Endoscopic sclerotherapy for the treatment of weight regain after Roux-en-Y gastric bypass: outcomes, complications, and predictors of response in 575 procedures. AB - BACKGROUND: Weight regain after Roux-en-Y gastric bypass (RYGB) is common. Endoscopic sclerotherapy is increasingly used to treat this weight regain. OBJECTIVES: To report safety, outcomes, durability, and predictors of response to sclerotherapy in a large prospective cohort. DESIGN: Retrospective analysis of a prospective cohort study of patients with weight regain after RYGB. PATIENTS: A total of 231 consecutive patients undergoing 575 sclerotherapy procedures between September 2008 and March 2011. INTERVENTIONS: Single or multiple sclerotherapy procedures to inject sodium morrhuate into the rim of the gastrojejunal anastomosis. MAIN OUTCOME MEASUREMENTS: We report weight loss, complications, and predictors of response. We also used Kaplan-Meier survival analysis and log-rank test to compare time to continuation of weight regain after sclerotherapy in patients undergoing a single versus multiple sclerotherapy procedures. RESULTS: At 6 and 12 months from the last sclerotherapy procedure, weight regain stabilized in 92% and 78% of the cohort, respectively. Those who underwent 2 or 3 sclerotherapy sessions had significantly higher rates of weight regain stabilization than those who underwent a single session (90% vs 60% at 12 months; P = .003). The average weight loss at 6 months from the last sclerotherapy session for the entire cohort was 10 lb (standard deviation 16), representing 18% of the weight regained after RYGB. A subset of 73 patients (32% of the cohort) had greater weight loss at 6 months (26 lb, standard deviation 12), representing 61% of the weight regained. Predictors of a favorable outcome included greater weight regain and the number of sclerotherapy procedures. Bleeding was reported in 2.4% of procedures and transient diastolic blood pressure increases in 15%, without adverse health outcomes. No GI perforations were reported. CONCLUSIONS: Endoscopic sclerotherapy appears to be a safe and effective tool for the management of weight regain after RYGB. PMID- 22817784 TI - Feasibility and preliminary accuracy of high-resolution imaging of the liver and pancreas using FNA compatible microendoscopy (with video). AB - BACKGROUND: EUS-guided FNA is one of the few techniques that can obtain cells and tissue from the liver and pancreas. However, the technique remains vulnerable to poor specimen quality and sampling error. OBJECTIVE: To evaluate the ability of a high-resolution microendoscope (HRME) to visualize the cellular and architectural features of normal and malignant liver and pancreatic tissue ex vivo, to assess the ability of endosonographers to identify normal and neoplastic tissue by using HRME images, and to demonstrate preliminary technical feasibility of in vivo HRME imaging via EUS fine-needle puncture (FNP). DESIGN: Ex vivo pilot feasibility study in human tissue; in vivo swine model. SETTING: Two academic medical centers. PATIENTS: Co-registered HRME images and biopsies were obtained from surgically resected hepatic and pancreatic tissues from 44 patients. INTERVENTION: Images were divided into training (12 images) and test (80 images) sets containing a range of normal and pathologic conditions for each organ. After viewing the training sets, 9 endosonographers attempted to distinguish malignant tissue from normal or benign lesions in the test sets, each of which contained 40 unique images with individual diagnoses from pathology. MAIN OUTCOME MEASUREMENTS: Image acquisition feasibility, ex vivo and in vivo. Ability of endosonographers to recognize features of normal/benign or malignant tissue from the liver and pancreas. RESULTS: Overall, the 9 endosonographers achieved median accuracy figures of 85% in the liver and 90% in the pancreas. The endosonographers with prior experience in reading HRME images achieved accuracy rates between 90% and 95%. Technical feasibility of HRME imaging through a 19 gauge EUS-FNP needle was demonstrated in an in vivo swine model. LIMITATIONS: Ex vivo study. CONCLUSION: High-resolution microendoscopy allows real-time imaging of cellular-level morphology and tissue architecture in the liver and pancreas. The technique appears to have a short learning curve, after which endosonographers achieved high accuracy rates in distinguishing malignant tissue from normal and benign pathology in both organs. Translating this imaging platform to the in vivo setting appears technically feasible. PMID- 22817785 TI - Flow, firmness, or FNA? Is enhanced EUS fantastic or just fancy? PMID- 22817786 TI - Assessment of the technical performance of the flexible 19-gauge EUS-FNA needle. AB - BACKGROUND: A needle made of nitinol has been developed with enhanced flexibility to overcome the limitations of the currently available 19-G EUS-FNA needles. OBJECTIVE: Evaluate the ability to perform transduodenal FNAs, procure histologic specimens, and undertake therapeutic interventions using the flexible 19-G needle. DESIGN: Prospective cohort study. SETTING: Tertiary-care academic medical center. PATIENTS: Consecutive patients with subepithelial masses, pancreatic head or uncinate lesions, or lesions adjacent to the pancreatic head, and patients undergoing therapeutic intervention. INTERVENTIONS: Perform tissue acquisition and interventions with the flexible 19-G FNA needle. MAIN OUTCOME MEASURES: Evaluate the ability to perform transduodenal passes with the flexible 19-G FNA needle. Also, assess the utility of the needle to yield both cytologic and histologic samples and to perform therapeutic interventions. RESULTS: Of the 50 patients enrolled, tissue acquisition was undertaken in 38 and therapeutic intervention in 12. Of 38 patients from whom tissue was procured, 32 tissue samples were from pancreatic head/uncinate or peripancreatic masses and 6 were from subepithelial masses. Tissue acquisition, which included transduodenal passes, was successful and adequate for cytologic assessment in all 38 patients (100%). Satisfactory histologic specimens were procured from 36 of 38 (94.7%) patients. An onsite diagnosis was established in 35 of 38 (92.1%) patients. In 3 patients with indeterminate/suspicious lesions, a definitive diagnosis was established at histology. A mean of 1.45 +/- 0.79 passes per patient was performed. All 12 therapeutic interventions were successful (100%) and included pseudocyst drainage in 5, pelvic abscess drainage in 2, fiducial placement in 2, celiac plexus neurolysis in 2, and cholangiogram in 1. Needle dysfunction or procedural complications were not encountered. LIMITATIONS: Single-center study with limited power. CONCLUSIONS: Preliminary data suggest that the flexible 19-G needle can be used for procuring cytologic aspirates and histologic specimens and to undertake therapeutic interventions even by the transduodenal route. Confirmatory studies are required in a larger cohort of patients with varied pathologic conditions to validate these findings. PMID- 22817787 TI - Enteroscopic and radiologic diagnoses, treatment, and prognoses of small-bowel tumors. AB - BACKGROUND: Small-bowel tumors (SBTs) represent a diagnostic challenge. OBJECTIVE: To evaluate the usefulness of contrast-enhanced CT (CECT), fluoroscopic enteroclysis (FE), videocapsule endoscopy (VCE), and double-balloon endoscopy (DBE) and the outcome after treatment. DESIGN: Single-center, retrospective study. SETTING: Tertiary-care referral hospital. PATIENTS: Between June 2003 and May 2011, 159 consecutive patients with SBTs (93 malignant and 66 benign) were enrolled. MAIN OUTCOME MEASUREMENTS: Comparison of diagnostic yields among CECT, FE, VCE, and DBE and the prognosis. RESULTS: CECT and FE had significantly lower diagnostic yields of SBTs <= 10 mm, but VCE and DBE had high yields of SBTs regardless of size. CECT had a significantly lower diagnostic yield of epithelial tumors compared with subepithelial tumors. When stratified by the site, the diagnostic yield of VCE for SBTs located only in the distal duodenum/the proximal jejunum (73%) was significantly lower than that for SBTs located in other areas (90%). Comparisons among the 4 methods revealed that VCE and DBE had significantly higher diagnostic yields than CECT, and DBE had significantly higher diagnostic yields than VCE, but a combination of CECT and VCE had a diagnostic yield similar to that of DBE. The histologic diagnostic yield of SBTs by DBE was 92%, and 25% of SBTs were enteroscopically treated. Metastatic tumors had the poorest overall survival, followed by adenocarcinomas and malignant lymphomas. LIMITATIONS: Retrospective comparative study. CONCLUSION: For the detection of SBTs, a combination screening method by using VCE and CECT is recommended. DBE is useful for histologic diagnosis and endoscopic treatment. PMID- 22817788 TI - Receipt of colonoscopy is key to reduction of colorectal cancer mortality. PMID- 22817789 TI - Inspection on instrument insertion during colonoscopy: a randomized controlled trial. AB - BACKGROUND: Polyps seen and not removed during colonoscope insertion are sometimes unable to be found during withdrawal. OBJECTIVE: To investigate the impact of additional inspection during instrument insertion on adenoma detection in sedated patients undergoing routine screening or surveillance colonoscopy. DESIGN: Randomized, controlled trial. SETTING: University hospital and associated ambulatory surgery center. PATIENTS: Patients undergoing elective screening or surveillance colonoscopy. INTERVENTION: Patients were randomized to undergo colonoscopy with 3 minutes of dedicated inspection time during insertion plus 6 minutes during withdrawal versus 9 minutes of inspection on instrument withdrawal. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was the adenoma detection rate (proportion of patients with adenomas) between patients in whom inspection for adenomas was performed partly on instrument insertion compared with patients for whom inspection was performed entirely on withdrawal. RESULTS: There was no difference in the proportion of patients with 1 or more adenomas between the inspection on insertion group (52%) and the inspection on withdrawal group (58%). There were no significant differences in total procedure time, time taken to remove polyps, sedation doses, or after-procedure pain between groups. LIMITATIONS: Single-center study with two endoscopists. CONCLUSION: Inspection during colonoscope insertion offered no additional benefit compared with an equivalent period of inspection performed entirely during withdrawal. These results do not support an additional role for routine inspection during colonoscope insertion. PMID- 22817791 TI - Cytopathology: a dying art or something that a gastroenterologist should know? PMID- 22817790 TI - On-demand endoscopic CO2 insufflation with feedback pressure regulation during natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy induces minimal hemodynamic and respiratory changes. AB - BACKGROUND: Endoscopic insufflation has been associated with marked increase in intra-abdominal pressure (IAP) and hemodynamic and respiratory changes during transgastric surgery. OBJECTIVE: To investigate the hemodynamic and respiratory effects during intraperitoneal cavity exploration through 3 different natural orifice transluminal endoscopic surgery (NOTES) access locations compared with laparoscopy. DESIGN AND SETTING: Survival experiments using 40 female pigs randomized to transgastric, transcolonic, transvaginal, and laparoscopic peritoneoscopy. INTERVENTIONS: On-demand endoscopic insufflation of CO(2) with feedback pressure regulation was used in NOTES with a maximum pressure of 14 mm Hg. In the laparoscopy group, the IAP was maintained at 14 mm Hg. NOTES procedures were performed by an endoscopist (with the assistance of a gynecologist in the transvaginal group and a second endoscopist in the transgastric and transrectal groups) and laparoscopy by 2 surgeons. MAIN OUTCOME MEASUREMENTS: Invasive hemodynamic and respiratory data. Blood samples were drawn for gas analyses. RESULTS: All experiments except one in the transrectal group were completed. The IAP was significantly lower in all NOTES groups compared with the laparoscopy group. A significant increase in mean systemic arterial blood pressure was observed in the laparoscopy group at 15 and 30 minutes of intraperitoneal cavity exploration, but it remained unchanged during all NOTES procedures. An increase in airway pressures was observed at 15 and 30 minutes of peritoneoscopy in the animals undergoing laparoscopy, whereas those parameters remained unchanged in the NOTES groups. The laparoscopy group showed a significant impairment in pulmonary gas exchange (decrease in Pao(2), increase in Paco(2), and decrease in arterial pH) after 30 minutes of peritoneoscopy, whereas only a slight increase in Paco(2) was observed in the transrectal and transvaginal groups. LIMITATIONS: Healthy animal model. CONCLUSION: On-demand endoscopic insufflation of CO(2) with feedback pressure regulation can minimize the risk of hemodynamic and respiratory compromise caused by acute changes in IAP. PMID- 22817792 TI - Anorectal bleeding: etiology, evaluation, and management (with videos). PMID- 22817793 TI - Capillary hemangioma of the esophagus in a patient with systemic sclerosis and gastric antral vascular ectasia. PMID- 22817794 TI - Gastric lymphoepithelioma-like carcinoma mimicking a subepithelial lesion treated by endoscopic submucosal dissection. PMID- 22817795 TI - Helicobacter heilmannii gastritis in a young patient with a pet. PMID- 22817796 TI - A case of celiac artery dissection diagnosed with EUS. PMID- 22817797 TI - Covered esophageal self-expandable metal stents in the nonoperative management of postoperative colorectal anastomotic leaks. PMID- 22817798 TI - Prospective evaluation of spiral overtube-assisted ERCP in patients with surgically altered anatomy. PMID- 22817799 TI - Clinical outcomes of endoscopic submucosal dissection for rectal tumor close to the dentate line. PMID- 22817800 TI - Endoscopic resection is the criterion standard of treatment for patients with early squamous cell neoplasia of the esophagus. PMID- 22817801 TI - Submucosal gland tumor spreading in mucosal squamous cell carcinoma: a concern for radiofrequency ablation? PMID- 22817802 TI - EUS-guided rendezvous instead of precut techniques as a rescue measure when selective biliary cannulation fails: is it replacement or misplacement? PMID- 22817804 TI - Guidewire cannulation and the risk of post-ERCP pancreatitis. PMID- 22817806 TI - Peroral direct cholangioscopy in patients with altered GI anatomy: proceed with extreme caution! PMID- 22817808 TI - Ocular toxicity of authentic lunar dust. AB - BACKGROUND: Dust exposure is a well-known occupational hazard for terrestrial workers and astronauts alike and will continue to be a concern as humankind pursues exploration and habitation of objects beyond Earth. Humankind's limited exploration experience with the Apollo Program indicates that exposure to dust will be unavoidable. Therefore, NASA must assess potential toxicity and recommend appropriate mitigation measures to ensure that explorers are adequately protected. Visual acuity is critical during exploration activities and operations aboard spacecraft. Therefore, the present research was performed to ascertain the ocular toxicity of authentic lunar dust. METHODS: Small (mean particle diameter = 2.9 +/- 1.0 MUm), reactive lunar dust particles were produced by grinding bulk dust under ultrapure nitrogen conditions. Chemical reactivity and cytotoxicity testing were performed using the commercially available EpiOcularTM assay. Subsequent in vivo Draize testing utilized a larger size fraction of unground lunar dust that is more relevant to ocular exposures (particles <120 MUm; median particle diameter = 50.9 +/- 19.8 MUm). RESULTS: In vitro testing indicated minimal irritancy potential based on the time required to reduce cell viability by 50% (ET50). Follow-up testing using the Draize standard protocol confirmed that the lunar dust was minimally irritating. Minor irritation of the upper eyelids was noted at the 1-hour observation point, but these effects resolved within 24 hours. In addition, no corneal scratching was observed using fluorescein stain. CONCLUSIONS: Low-titanium mare lunar dust is minimally irritating to the eyes and is considered a nuisance dust for ocular exposure. No special precautions are recommended to protect against ocular exposures, but fully shielded goggles may be used if dust becomes a nuisance. PMID- 22817811 TI - Brucellosis: a neglected but existing threat to travelers and laboratory personnel in Taiwan. PMID- 22817809 TI - Transcript profiling reveals complex auxin signalling pathway and transcription regulation involved in dedifferentiation and redifferentiation during somatic embryogenesis in cotton. AB - BACKGROUND: Somatic embryogenesis (SE), by which somatic cells of higher plants can dedifferentiate and reorganize into new plants, is a notable illustration of cell totipotency. However, the precise molecular mechanisms regulating SE remain unclear. To characterize the molecular events of this unique process, transcriptome analysis, in combination with biochemical and histological approaches, were conducted in cotton, a typical plant species in SE. Genome-wide profiling of gene expression allowed the identification of novel molecular markers characteristic of this developmental process. RESULTS: RNA-Seq was used to identify 5,076 differentially expressed genes during cotton SE. Expression profile and functional assignments of these genes indicated significant transcriptional complexity during this process, associated with morphological, histological changes and endogenous indole-3-acetic acid (IAA) alteration. Bioinformatics analysis showed that the genes were enriched for basic processes such as metabolic pathways and biosynthesis of secondary metabolites. Unigenes were abundant for the functions of protein binding and hydrolase activity. Transcription factor-encoding genes were found to be differentially regulated during SE. The complex pathways of auxin abundance, transport and response with differentially regulated genes revealed that the auxin-related transcripts belonged to IAA biosynthesis, indole-3-butyric acid (IBA) metabolism, IAA conjugate metabolism, auxin transport, auxin-responsive protein/indoleacetic acid induced protein (Aux/IAA), auxin response factor (ARF), small auxin-up RNA (SAUR), Aux/IAA degradation, and other auxin-related proteins, which allow an intricate system of auxin utilization to achieve multiple purposes in SE. Quantitative real-time PCR (qRT-PCR) was performed on selected genes with different expression patterns and functional assignments were made to demonstrate the utility of RNA-Seq for gene expression profiles during cotton SE. CONCLUSION: We report here the first comprehensive analysis of transcriptome dynamics that may serve as a gene expression profile blueprint in cotton SE. Our main goal was to adapt the RNA-Seq technology to this notable development process and to analyse the gene expression profile. Complex auxin signalling pathway and transcription regulation were highlighted. Together with biochemical and histological approaches, this study provides comprehensive gene expression data sets for cotton SE that serve as an important platform resource for further functional studies in plant embryogenesis. PMID- 22817812 TI - Effect of growth hormone therapy on Taiwanese children with growth hormone deficiency. AB - BACKGROUND/PURPOSE: Human growth hormone (GH) has been successfully used in children with GH deficiency (GHD). However, there are few published data on the effect of GH in Taiwanese children with GHD. METHODS: We performed a retrospective cohort study to identify factors influencing the effect of GH therapy on ethnic Chinese children with GHD in Taiwan. Idiopathic GHD can be classified into isolated GHD (IGHD) and multiple pituitary hormone deficiency (MPHD). The study looked at the effect of GH on the auxological, biochemical, and imaging parameters of 51 patients (13 girls and 38 boys) in three different diagnostic groups: MPHD (n = 12), IGHD (n = 8), and transient GHD (TGHD; n = 31). TGHD is defined as a GH peak >10 MUg/L in re-evaluation by two GH stimulation tests approximately 6 months after discontinuation of GH therapy. RESULTS: The height velocity for first-year GH therapy was 7.61 +/- 1.46, 8.14 +/- 1.92, and 9.99 +/- 2.75 cm/y in the TGHD, IGHD, and MPHD groups, respectively. After post hoc comparison, the MPHD group had a significantly accelerated height velocity in the first year compared to the TGHD group. Correlation analysis showed that a change in height standard deviation score (SDS) in the first year had a significant negative correlation with the following variables: peak GH (r = 0.52, p < 0.001), pretreatment height SDS (r = -0.49, p < 0.001), and height target height (Ht-TH) SDS (r = -0.49, p < 0.001). Change in height SDS in the first 2 years had a significantly negative correlation with peak GH (r = -0.51, p < 0.001), insulin-like growth factor-1 SDS (r = -0.35, p = 0.022), height SDS (r = -0.60, p < 0.001), difference between bone age and chronological age (r = 0.46, p = 0.001), and Ht-TH SDS (r = -0.50, p = 0.001). After using multiple linear regression, the pretreatment GH peak value was found to be significantly associated with height increments after 1 year of GH treatment (B = -0.07, p = 0.014). CONCLUSION: The administration of GH to children with GHD results in a pronounced acceleration in linear growth during the first year of treatment, especially in those with MPHD. The diagnosis of GHD requires comprehensive auxological, biochemical, and brain magnetic resonance imaging assessment. We also suggest that patients with GHD, specifically IGHD, must undergo a re evaluation of GH secretion after completion of GH therapy. PMID- 22817813 TI - Factors associated with development of complications among adults with influenza: a 3-year prospective analysis. AB - BACKGROUND/PURPOSE: This prospective study aimed to describe the clinical features, as well as outcomes, of adult patients with influenza of different severity, and to determine the predictors for development of complications. METHODS: From December 2006 to March 2009, four types of diagnostic tests were given to both in- and outpatients with influenza-like illness (ILI). Confirmed cases were categorized into three groups (uncomplicated, moderately complicated, and severely complicated) for analysis using a proportional odds logistic regression model. RESULTS: A total of 206 laboratory-confirmed cases of influenza were identified out of 360 enrolled patients with ILI. Among 30 patients (14.6%) classified as complicated cases due to development of pneumonia (n=28) and viral encephalopathy (n=2), 16 were hospitalized in general wards (moderately complicated) and 14 required admission to intensive care units (severely complicated). Complicated patients were less likely to have classic symptoms of ILI than uncomplicated patients. By multivariate analysis, the presence of coronary artery disease, systemic corticosteroid use, impaired renal function and delayed hospital visit were independently associated with development of complications. CONCLUSION: Our study results may help clinicians to identify patients at high risk for complicated influenza, to provide timely antiviral therapy and optimal clinical care. PMID- 22817814 TI - Clinical features and major histocompatibility complex genes as potential susceptibility factors in pediatric immune thrombocytopenia. AB - BACKGROUND/PURPOSE: Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder with diverse response rates to treatments that include corticosteroids, intravenous immunoglobulins (IVIG), and splenectomy. The predisposing causes of this autoimmune disorder, one of which is immunogenetic susceptibility, have not been fully determined. We investigated whether clinical features and human leukocyte antigen (HLA) genotypes influence the occurrence, treatment response, and disease duration of childhood ITP in Taiwan. METHODS: We performed HLA genotyping of 70 Taiwanese children with ITP and of 70 healthy controls and compared the data. Demographic data were also collected and evaluated. RESULTS: The frequencies of heterozygous HLA-A11 and the HLA-Cw1 allele were both significantly decreased in the ITP group (p = 0.0160 and p = 0.0089, respectively), whereas the frequency of heterozygous HLA-DQ5 was significantly increased in the ITP group (p = 0.0057). Patients with HLA-DRB1*11 or -DRB1*15 were more likely to respond poorly to corticosteroids than IVIG (p = 0.0446 and p = 0.0008, respectively). In addition, we observed a positive association between HLA-A11 homozygosity and the development of persistent or chronic ITP [odds ratio (OR) = 6.3165, p = 0.0479]. The presence of HLA-DRB1*08 was, however, negatively correlated with the development of persistent or chronic ITP (OR = 0.1729, p = 0.0657). Children with antecedent of preceding illness (API) and with a younger age of onset were more likely to experience a better treatment response and shorter course of ITP. CONCLUSION: We suggest that API, age of onset, and particular HLA class I and class II alleles, may be involved in and influence the occurrence and disease duration of childhood ITP, as well as responses to different therapeutic approaches. PMID- 22817815 TI - Clinical and genetic analysis of four Taiwanese families with autosomal dominant hereditary spastic paraplegia. AB - BACKGROUND/PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Defects in the SPG4 and SPG3A genes are the two leading causes of HSPs with autosomal dominant inheritance (AD-HSPs). The purpose of this study was to investigate the clinical features and associated genetic mutations in Taiwanese families with AD-HSP. METHODS: Four kindreds with AD-HSP were recruited, and clinical data were collected from the affected individuals. Genetic studies were conducted in the following order: sequence analysis of the SPG4 gene (SPAST) exons, multiplex ligation-dependent probe amplification to detect genetic rearrangements in SPAST, and sequence analysis of the SPG3A gene exons. RESULTS: Four different SPAST mutations were detected, including a novel small deletion, a missense mutation, and two gross deletions involving exon 17. Although all symptomatic cases manifested as uncomplicated phenotypes, considerable intrakindred and interkindred variations in terms of age at onset, rate of progression, and severity of disease were observed. CONCLUSION: Mutation patterns and phenotypic expressivity are heterogeneous in Taiwanese patients with SPG4-related HSP. Genetic rearrangements could be a significant cause of SPG4-related HSP in the Taiwanese population. Assessment of the large deletions that could present in SPAST is warranted when direct sequencing is uninformative. PMID- 22817816 TI - Clinical symptoms are not reliable in the diagnosis of lower urinary tract dysfunction in women. AB - BACKGROUND/PURPOSE: The pathophysiology of female lower urinary tract symptoms (LUTS) may involve bladder, urethral, and pelvic floor dysfunctions. This study analyzed the relationship between clinical symptoms and lower urinary tract dysfunctions (LUTD) in women. METHODS: A total of 1605 consecutive women were included. LUTS were classified as storage, voiding, pain, and postmicturition symptoms. All patients underwent videourodynamic study (VUDS) and the final diagnosis of LUTD was made based on VUDS findings. Patients were stratified into three major disorder groups: sensory, motor, and bladder outlet disorders. The main symptoms and associated symptoms were used for analysis in varying LUTD. RESULTS: Normal tracing was found in 272 patients (16.9%), sensory bladder disorders in 459 (28.6%), motor bladder disorders in 560 (34.9%), and bladder outlet disorders were found in 314 patients (19.6%). Frequent urination was the main symptom in patients with normal, bladder oversensitivity, interstitial cystitis, and idiopathic detrusor overactivity (DO). In patients with voiding dysfunction due to detrusor underactivity, bladder neck dysfunction and urethral stricture, dysuria was the most common symptom. However, 707 (44%) of overall women had both storage and voiding symptoms. DO was present in 533 women and in 149 (66%) of 212 with bladder outlet obstruction. However, DO was only found in 42.5% of women with urgency and in 69.4% of women with urgency incontinence based on reported LUTS. CONCLUSION: Storage and voiding symptoms are common in women with LUTD. The differential diagnosis of LUTD in women cannot be based on LUTS alone. PMID- 22817817 TI - Comparison of clinical and microbiological features of vulvovaginitis in prepubertal and pubertal girls. AB - BACKGROUND/PURPOSE: Vulvovaginitisis the most common gynecological problem of childhood. The aim of the study was to determine and compare clinical and microbiological features of vulvovaginitis in prepubertal and adolescent girls. METHODS: In this retrospective study, the records of patients who were diagnosed with vulvovaginitis between January 2005 and December 2010 in the pediatric outpatient clinic at Fatih University Hospital were retrieved. Information regarding age, symptoms, history of antibiotic use within 1 month prior to presentation, findings on urinalysis, serum antistreptolysin-O levels, and results of urine/vaginal cultures was collected. RESULTS: The records of 112 patients were evaluated, 72 of which were prepubertal (64.2%) and 40 were pubertal (35.7%) at the time of diagnosis. Thirty-eight prepubertal patients (52.7%) had a positive result on vaginal culture, the most commonly encountered microorganism being group A beta-hemolytic streptococcus (15.2%). Culture positivity rate in the pubertal group was 47.5% (19 patients), with Candida albicans being the most frequently isolated microorganism (27.5%). CONCLUSION: The etiopathogenesis and culture results differ between prepubertal and adolescent girls with vulvovaginitis, which should be taken into consideration in the treatment approach of this disorder. PMID- 22817818 TI - Oculopharyngeal muscular dystrophy --an under-diagnosed disease in China? Report a China-born Chinese with PABPN1 mutation and epidemiology review of the literature. AB - BACKGROUND/PURPOSE: Most reports about oculopharyngeal muscular dystrophy (OPMD) have been contributed by occidental countries, and most of the victims of this disease are racially white. In contrast, this disorder is rarely seen in Asians and has only one African report. Consequently, OPMD has been regarded as a disease of the Western world. The purpose of this paper is to challenge the accuracy of this concept. METHODS: In a Chinese immigrant family, 3 patients manifesting signs related to OPMD were examined. Electromyography, nerve conduction studies, muscle biopsy and genetic analysis were performed on the proband. All the 322 papers about OPMD were reviewed and their country of origin was labeled to perceive the approximate prevalence of OPMD. Countries were categorized into groups according to the continents to which they belonged. RESULTS: The proband's muscle histopathology showed small angulated fiber with rimmed vacuoles, ultrastructural pathology exposed filamentous intranuclear inclusions, and genetic analysis of the polyadenylate binding protein nuclear 1(PABPN1) gene revealed 13 GCG trinucleotide repeats in one allele (GCG)13 while being normal in the other. The survey of the country of origin of OPMD reports showed that 80% of these papers were contributed by occidental countries and that the number of publications of OPMD among countries of Americas and Asia were unequal, when compared to those of European countries, which were fairly proportioned. An epidemiologic review of the literature is presented and the prevalence of OPMD is discussed. CONCLUSION: This is a China-born Chinese patient with both morphologically and genetically proven of OPMD. The very low OPMD report rate in developing countries of East Asia is due to the unfamiliarity of medical workers to OPMD and the unavailability of medical supplies to confirm the diagnosis. In addition, the present and previous reports provide clear evidence that OPMD in these areas is underdiagnosed. PMID- 22817819 TI - A Lemierre syndrome variant caused by Klebsiella pneumoniae. AB - Lemierre syndrome is an extremely rare disease characterized by oropharyngeal infection, septicemia, internal jugular vein thrombosis, and skip lesions. The most common causative pathogen is Fusobacterium necrophorum. We reported a 45 year-old woman who presented with left neck painful swelling and septicemia. Magnetic resonance imaging of the head and neck demonstrated venous thrombosis extending from the left internal jugular vein to the sigmoid sinus. During admission we discovered that the patient had uncontrolled diabetes mellitus. We also found a metastatic lesion through chest radiography. Klebsiella pneumoniae was cultivated from both blood samples and pus from deep neck spaces. Surgical drainage, early and adequate antibiotic treatment, anticoagulation, and strict control of blood glucose led to the patient's complete recovery. Because Lemierre syndrome is a forgotten disease in the era of antibiotics, awareness of the signs and symptoms of this disease is important because of its associated high mortality rate. This case illustrated that the presence of K pneumoniae can lead to Lemierre syndrome. PMID- 22817820 TI - Tongue base hamartoma in a child. PMID- 22817822 TI - Re: Beat Roth, Frederic D. Birkhauser, Pascal Zehnder, et al. Parenteral nutrition does not improve postoperative recovery from radical cystectomy: results of a prospective randomised trial. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2012.05.052. PMID- 22817823 TI - Development of rapid preexcited ventricular response to atrial fibrillation in a patient with intermittent preexcitation. AB - Intermittent preexcitation during sinus rhythm is indicative of an accessory pathway at a very low risk for sudden death. We present the case of a 49-year-old man with intermittent preexcitation who subsequently developed rapid atrial fibrillation with a shortest preexcited R-R interval of 230 milliseconds. Electrophysiology study showed intermittent preexcitation at baseline and 1:1 anterograde accessory pathway conduction to 220 milliseconds in the presence of 1 mcg/min isoproterenol infusion. The pathway was successfully ablated at the lateral mitral annulus. Accessory pathways highly sensitive to catecholamines may show intermittent preexcitation at baseline with potential for rapid conduction during atrial fibrillation and sudden death. PMID- 22817825 TI - Copper catalyzed oxidative esterification of aldehydes with alkylbenzenes via cross dehydrogenative coupling. AB - Copper(II) as the catalyst in a cross dehydrogenative coupling (CDC) reaction has been demonstrated for the synthesis of benzylic esters using aldehydes and alkylbenzenes as coupling partners. PMID- 22817824 TI - Wound healing activities of different extracts of Centella asiatica in incision and burn wound models: an experimental animal study. AB - BACKGROUND: The efficacy of Centella asiatica for incision and burn wounds are not fully understood. Here, we report the wound healing activities of sequential hexane, ethyl acetate, methanol, and water extracts of Centella asiatica in incision and partial-thickness burn wound models in rats. METHODS: Male Sprague Dawley rats weighing 250-300 g were randomly divided into incision and burn wound groups. Each group was stratified into seven subgroups: (1) untreated; (2) NSS-; (3) Tween 20(r)- (vehicle control); (4) hexane extract-; (5) ethyl acetate extract-; (6) methanol extract-; and (7) aqueous extract-treated groups. The test substances were applied topically once daily. The tensile strength of the incision wound was measured on the seventh day after wound infliction. The general appearance and degree of wound healing of the burn wound were assessed on Days 3, 7, 10 and 14 after burn injury and prior to histopathological evaluation. RESULTS: On the seventh day after wound infliction, the tensile strength of incision wound in all extract-treated groups was significantly higher than that of the vehicle control (Tween 20(r)), but comparable to the NSS-treated group. The degrees of healing in the burn wound with the four extracts were significantly higher than that of the control on Days 3, 10 and 14. Histopathological findings on Day 14 after burn injury revealed prominent fibrinoid necrosis and incomplete epithelialization in the control and untreated groups, whereas fully developed epithelialization and keratinization were observed in all extract-treated groups. Analysis by thin layer chromatography demonstrated that the phyto-constituents beta-sitosterol, asiatic acid, and asiaticoside and madecassocide were present in the hexane, ethyl acetate and methanol extracts, respectively. CONCLUSIONS: All extracts of Centella asiatica facilitate the wound healing process in both incision and burn wounds. Asiatic acid in the ethyl acetate extract seemed to be the most active component for healing the wound. PMID- 22817826 TI - Is obesity development associated with dietary sugar intake in the U.S.? AB - OBJECTIVE: In the public health arena, a single component of total dietary intake, such as sugar intake, has been questioned as the health risk of obesity. This study aimed to investigate if the uptrend of obesity prevalence in the USA is associated with dietary sugar intake when other dietary intakes are controlled. METHODS: In this cross-sectional study, National Health and Nutrition Examination Surveys I (1971-1975, n = 20 195) and III (1988-1994, n = 28 663) were investigated. Multivariate predictive models were used to determine if body mass index was predicted by the daily intakes of total energy, carbohydrate (CHO), and total sugars and the percentages of energy from CHO, fat, total sugar, and added sugars. RESULTS: From 1970 through 1990, the contribution of sugars to total CHO intake decreased in the 1 to 18 y and >=19 y subgroups, and the contribution of added sugars to the total energy intake did not change. Multivariate predictive models identified energy intake as a positive predictor, CHO as a negative predictor, and total sugar intake as a non-predictor for body mass index in the 1 to 18 y and >=19 y age subgroups. Daily energy intake was positively predicted by CHO and fat intakes but not with total and added sugar intakes in the two age subgroups. CONCLUSION: Energy intake was the primary contributor to body mass index in all age groups in this study. The major energy sources of children and adolescents differed from those of adults. The implicated associations between energy and macronutrient intakes indicate that keeping energy balance is the primary strategy to avoid obesity. PMID- 22817827 TI - Effect of Ala54Thr polymorphism of FABP2 on anthropometric and biochemical variables in response to a moderate-fat diet. AB - OBJECTIVE: To analyze the effect of the fatty acid-binding protein (FABP2) gene Ala54Thr polymorphism on anthropometric and biochemical variables in response to a moderate-fat diet in overweight or obese subjects. METHODS: One hundred nine subjects with a body mass index >= 25 kg/m(2) were studied. Participants underwent a dietary intervention that consisted of 30% fat (saturated fat <7% of total calories), 15% protein, and 55% carbohydrates. The FABP2 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Anthropometric and biochemical data were measured at baseline, 1 mo, and 2 mo of nutritional intervention. RESULTS: The mean age was 38.6 +/- 11.3 y and the mean body mass index 32.7 +/- 6.1 kg/m(2), with 20 men (18%) and 89 women (82%). Fifty three patients (48.6%) had genotype Ala54Ala (wild-type group) and 56 patients had genotype Ala54Thr/Thr54Thr (51.4%, mutant group). At baseline, no significant difference was found between the FABP2 genotypes groups, except for the carbohydrate intake and resting metabolic rate, which were higher in the Ala54Thr/Thr54Thr group (P < 0.05). At 2 mo, participants had lost 6.8% of their initial weight. The Ala54Thr/Thr54Thr group compared with the Ala54Ala group showed significant decreases in the parameters of weight (-7.5 versus -4.2 kg), body mass index (-2.1 versus -1.2 kg/m(2)), waist circumference (-7.6 versus -5.2 cm), waist-to-hip ratio (-0.04 versus -0.02), and C-reactive protein (-1.4 versus -0.76 mg/L), respectively (P < 0.05). After the resting metabolic rate was adjusted, the decreases in waist circumference, waist-to-hip ratio, and C reactive protein remained significant between the two groups. CONCLUSIONS: This study showed that the Thr54 allele carriers responded better to a moderate-fat diet. PMID- 22817828 TI - Effect of a phytopharmaceutical medicine, Ginko biloba extract 761, in an animal model of Parkinson's disease: therapeutic perspectives. AB - Ginkgo Biloba extract 761 (EGb 761) is a patented and well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract contains two main groups of active compounds, flavonoids (24%) and terpenoids (6%). EGb 761 is used clinically to treat dementia and vaso-occlusive and cochleovestibular disorders. This extract has neuroprotective effects, exerted probably by means of its antioxidant function. Parkinson's disease (PD) is a neurodegenerative disorder that affects 2% of the population older than 60 y. It produces a progressive loss of dopaminergic neurons and depletion of dopamine (DA), leading to movement impairment. The production of reactive oxygen species, which act as mediators of oxidative damage, is linked to PD. This disease is routinely treated with the DA precursor, L-3,4-dihydroxyphenylalanine. However, this produces severe side effects, and its neurotoxic properties can be due to a free radical production. Thus, administration of antioxidant drugs might be used to prevent neuronal death produced by oxidative mechanisms. The use of synthetic antioxidants has decreased because of their suspected activity as carcinogenic promoters. We describe the studies related to the antioxidant effect of EGb 761 in an animal model of PD. It has been shown that EGb761 can provide a neuroprotective/neurorecovery effect against the damage to midbrain DA neurons in an animal model of PD. EGb 761 also has been found to lessen the impairment of locomotion, correlating with an increase of DA and other morphologic and biochemical parameters related to its antioxidant effect in an animal model of PD. These studies suggest it as an alternative in the future treatment of PD. PMID- 22817829 TI - A novel hybrid adenoretroviral vector with more extensive E3 deletion extends transgene expression in submandibular glands. AB - Salivary glands are an attractive target for gene transfer. Salivary epithelial cells are considered to be highly differentiated and have low rates of cell division (~6 months), affording the opportunity to obtain relatively long-term transgene expression in the absence of genomic integration. Here, we report a novel modified hybrid adenoretroviral vector, which provides stable transgene expression in salivary epithelial cells in vivo for up to 6 months in the absence of genomic integration. This modified hybrid vector, Ad(DeltaE1/3)LTR(2)EF1alpha hEPO, encodes human erythropoietin (hEPO) and differs from a previously developed hybrid vector, AdLTR(2)EF1alpha-hEPO, by having more extensive E3 gene deletion. Following direct salivary gland gene transfer by retroductal cannulation, rats transduced with Ad(DeltaE1/3)LTR(2)EF1alpha-hEPO had sustained, elevated serum hEPO levels and hematocrits for 6 months (length of experiment), as compared with ~2 months for animals administered the AdLTR(2)EF1alpha-hEPO vector. Immunohistochemistry demonstrated that this novel vector could transduce both acinar and ductal cells. Interestingly, the Ad(DeltaE1/3)LTR(2)EF1alpha-hEPO vector evoked much weaker local (salivary gland) immune responses than seen after AdLTR(2)EF1alpha-hEPO vector delivery, which likely permits its significantly lengthened transgene expression in this tissue. PMID- 22817830 TI - Developmental expression and function of DKKL1/Dkkl1 in humans and mice. AB - BACKGROUND: Experiments were designed to identify the developmental expression and function of the Dickkopf-Like1 (DKKL1/Dkkl1) gene in humans and mice. METHODS: Mouse testes cDNA samples were collected at multiple postnatal times (days 4, 9, 18, 35, and 54, as well as at 6 months) and hybridized to Affymetrix mouse whole genome Genechips. To further characterize the homologous gene DKKL1 in human beings, the expression profiles between human adult testis and foetal testis were compared using Affymetrix human Genechips. The characteristics of DKKL1/Dkkl1 were analysed using various cellular and molecular biotechnologies. RESULTS: The expression of Dkkl1 was not detected in mouse testes on days 4 or 9, but was present on days 18, 35, and 54, as well as at 6 months, which was confirmed by RT-PCR and Western blot results. Examination of the tissue distribution of Dkkl1 demonstrated that while Dkkl1 mRNA was abundantly expressed in testes, little to no expression of Dkkl1 was observed in the epididymis or other tissues. In an in vitro fertilization assay, a Dkkl1 antibody was found to significantly reduce fertilization. Human Genechips results showed that the hybridization signal intensity of DKKL1 was 405.56-fold higher in adult testis than in foetal testis. RT-PCR analysis of multiple human tissues indicated that DKKL1 mRNA was exclusively expressed in the testis. Western blot analysis also demonstrated that DKKL1 was mainly expressed in human testis with a molecular weight of approximately 34 kDa. Additionally, immunohistochemical staining showed that the DKKL1 protein was predominantly located in spermatocytes and round spermatids in human testes. An examination of the expression levels of DKKL1 in infertile male patients revealed that while no DKKL1 appeared in the testes of patients with Sertoli cell only syndrome (SCOS) or cryptorchidism, DKKL1 was observed with variable expression in patients with spermatogenic arrest. CONCLUSIONS: These results, together with previous studies, suggest that DKKL1/Dkkl1 may play an important role in testicular development and spermatogenesis and may be an important factor in male infertility. PMID- 22817831 TI - Descemet's stripping automated endothelial keratoplasty: the tenuous relationship between donor thickness and postoperative vision. AB - PURPOSE: To determine whether preoperative donor thickness has a relationship with postoperative visual acuity after Descemet's stripping automated endothelial keratoplasty (DSAEK). DESIGN: Retrospective correlation and comparative analysis of an interventional case series. PARTICIPANTS: A total of 418 eyes of 292 patients undergoing DSAEK surgery for Fuchs' endothelial dystrophy without visual loss from comorbidities. METHODS: Descemet's stripping automated endothelial keratoplasty was performed in 548 eyes with Fuchs' dystrophy, and preoperative graft thickness (GT) was recorded. After exclusion of patients with confounding variables that would affect postoperative visual acuity, postoperative best spectacle-corrected visual acuity (BSCVA) was measured at 6 months in 418 eyes. Pearson's correlation analysis was performed between preoperative GT and BSCVA. Cases were split into deciles on the basis of GT and BSCVA and then compared with 1-way analysis of variance (ANOVA) and chi-square test. MAIN OUTCOME MEASURES: Best spectacle-corrected visual acuity at 6 months postoperatively. RESULTS: Mean GT of the series was 162.9+/-29.0 MUm (range, 80-265 MUm), and mean Snellen BSCVA was 20/28 with a range of 20/16 to 20/70. There was a weak correlation between GT and BSCVA that was significant (R = 0.236, P<0.001) but only accounted for 5% of the visual outcome (R(2) = 0.056). Visual outcome was best within the thinnest decile group of 45 donors (GT range, 80-124), with a mean Snellen BSCVA of 20/25 (range, 20/20-20/50), and worst within the thickest decile group of 41 donors (GT range, 200-265), with a mean Snellen BSCVA of 20/33 (range, 20/20-20/70). Post hoc comparison of BSCVA between the thickest and thinnest groups was significant (P = 0.006). CONCLUSIONS: Preoperative GT may have a small effect on visual outcome in the extremes of thickness, but not in the common range of 100 to 200 MUm. Donor thickness has a tenuous relationship with visual outcome, accounting for only 5% of the variance in vision between patients, and should play a minimal role in surgical planning. PMID- 22817832 TI - A one-year follow-up study on the incidence and risk of endophthalmitis after pyogenic liver abscess. AB - PURPOSE: Although endophthalmitis secondary to pyogenic liver abscess (PLA) is becoming a globally emerging infectious disease, population-based investigations evaluating the relationship between PLA and endogenous endophthalmitis remain scarce. This study aimed to investigate the incidence and risk of endogenous endophthalmitis in patients with PLA compared with unaffected individuals by using a nationwide, population-based dataset. DESIGN: Retrospective, cohort study. PARTICIPANTS AND CONTROLS: This study used data sourced from Taiwan's National Health Insurance Research Database. In total, 12 727 patients with PLA were included in the study group and 63 635 matched subjects were randomly extracted as a comparison group. METHODS: Stratified Cox proportional hazards regressions were performed to assess the effect of PLA on the hazard of developing endogenous endophthalmitis. MAIN OUTCOME MEASURES: The incidence and risk of endogenous endophthalmitis between the study group and comparison group. RESULTS: Of the total sample, 148 subjects (0.10%) were diagnosed with endophthalmitis during the 1-year follow-up period. Endophthalmitis was found in 106 patients (0.84%) with PLA and 42 comparison patients (0.07%). After adjusting for patient monthly income, geographic location, and urbanization level, those suffering from PLA were found to have a greater likelihood of developing endophthalmitis during the 1-year follow-up period than comparison patients (hazard ratio [HR], 12.83; 95% confidence interval, 8.94-18.41). Stratification did not reveal any large differences in the adjusted HRs for endophthalmitis between PLA patients suffering from diabetes and those in whom diabetes was absent. We further analyzed the etiology of cases with endogenous endophthalmitis in this investigation and found Klebsiella pneumonia to be the causative organism among 75.5% of the cases but only 33.4% of the comparison group. CONCLUSIONS: We found that the incidence and risk of developing endophthalmitis was significantly higher among patients with PLA compared with matched controls irrespective of diabetes status. PMID- 22817833 TI - Improved vision-related function after ranibizumab for macular edema after retinal vein occlusion: results from the BRAVO and CRUISE trials. AB - PURPOSE: To examine the impact of intravitreal ranibizumab on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) through 6 months in patients with macular edema (ME) secondary to branch or central retinal vein occlusion (RVO). DESIGN: Two multicenter, double-masked trials, which enrolled participants with ME secondary to branch or central RVO: the RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) trial or the Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE) trial. PARTICIPANTS: Three hundred ninety-seven BRAVO and 392 CRUISE patients. METHODS: Patients were randomized 1:1:1 to monthly sham, 0.3-mg, or 0.5-mg injections of ranibizumab for 6 months. MAIN OUTCOME MEASURES: Although visual acuity was the main outcome measure for the trials, mean change from baseline in NEI VFQ-25 scores at month 6 was a secondary outcome measure. RESULTS: In BRAVO, among the 132, 134, and 131 patients randomized, respectively, to sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab, the study eye was the worse seeing eye in 121 (91.7%), 118 (88.1%), and 125 (95.4%) patients and 123 (93.2%), 128 (95.5%), and 125 (95.4%), respectively, had a 6-month follow-up visit. In CRUISE, among the 130, 132, and 130 patients randomized, respectively, to sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 117 (90.0%), 123 (93.2%), and 120 (92.3%) patients and 115 (88.5%), 129 (97.7%), and 119 (91.5%), respectively, had a 6-month follow-up visit. In both trials, patients treated with ranibizumab reported greater mean improvements in visual function, with substantial differences observed as early as month 1, including the NEI VFQ-25 composite score and near and distance activities subscales, compared with sham patients. P values for comparisons with sham for the composite score and these 2 subscales were <0.05. CONCLUSIONS: These results from the BRAVO and CRUISE trials indicate that patients with ME from RVOs treated with monthly ranibizumab report greater improvements in vision-related function compared with sham-treated patients through 6 months, even when a majority of patients present with RVOs in the worse-seeing eye. PMID- 22817837 TI - Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models. AB - The aim of our study was to enhance the bioavailability of ranolazine by using herbal-bioenhancer quercetin in rats and to study the role of P-glycoprotein (P gp) in vitro models. In single dose study (SDS), rats were divided into four groups, Group I was treated with 0.5% sodium carboxy methyl cellulose (SCMC), Group II was treated with ranolazine (14 mg/kg), Group III was treated with quercetin (20 mg/kg) and Group IV was treated with both ranolazine and quercetin. The blood samples were collected at 0.5, 1, 2, 3, 4, 6, 8 and 12 h, and the concentration of ranolazine in the plasma was estimated by reverse phase high performance liquid chromatography (RP-HPLC) method. In multiple dose study (MDS), rats were treated with same drugs for 7 days. On 8th day, the concentration of ranolazine in plasma was estimated. In vitro study performed on the rat and chick intestinal sacs to study the intestinal transport of ranolazine in the presence and absence of quercetin and verapamil (P-gp-inhibitor). Quercetin increased the peak concentration (Cmax) of ranolazine from 254 +/- 8.45 to 324 +/- 10.21 and 331 +/- 9.65 ng/mL in SDS and MDS, respectively. Quercetin also increased area under the curve (AUC) of ranolazine from 1565.12 +/- 52.24 to 2016.98 +/- 142.65 and 2070.85 +/- 271.60 ng/mL/h in SDS and MDS, respectively. The transport of ranolazine from mucosal side to serosal side was increased in presence of quercetin. Quercetin is an inhibitor of CYP3A4 and P-gp. So it increased the AUC and Cmax of ranolazine. PMID- 22817834 TI - Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: relationship with spatial impairment. AB - Both cholinergic and GABAergic projections from the rostral basal forebrain contribute to hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in codistributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase [ChAT] immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 [GAD67] immunopositive) neurons, and total (neuronal nuclei [NeuN] immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline. PMID- 22817838 TI - Individual interferon regulatory factor-3 thiol residues are not critical for its activation following virus infection. AB - The interferon regulatory factor (IRF)-3 transcription factor plays a central role in the capacity of the host to mount an efficient innate antiviral immune defense, mainly through the regulation of type I Interferon genes. A tight regulation of IRF-3 is crucial for an adapted intensity and duration of the response. Redox-dependent processes are now well known to regulate signaling cascades. Recent reports have revealed that signaling molecules upstream of IRF 3, including the mitochondrial antiviral-signalling protein (MAVS) and the TNF receptor associated factors (TRAFs) adaptors, are sensitive to redox regulation. In the present study, we assessed whether redox regulation of thiol residues contained in IRF-3, which are priviledged redox sensors, play a role in its regulation following Sendai virus infection, using a combination of mutation of Cysteine (Cys) residues into Alanine and thiols alkylation using N-ethyl maleimide. Alkylation of IRF-3 on Cys289 appears to destabilize IRF-3 dimer in vitro. However, a detailed analysis of IRF-3 phosphorylation, dimerization, nuclear accumulation, and induction of target gene promoter in vivo led us to conclude that IRF-3 specific, individual Cys residues redox status does not play an essential role in its activation in vivo. PMID- 22817842 TI - Sleep EEG as a potential marker of alcoholism predisposition-commentary on "Adolescence and parental history of alcoholism: insights from the sleep EEG". PMID- 22817843 TI - Risk factors for contacts between wild boar and outdoor pigs in Switzerland and investigations on potential Brucella suis spill-over. AB - BACKGROUND: Due to the parallel increase of the number of free-ranging wild boar and domestic pigs reared outdoor, the risk that they interact has become higher. Contacts with wild boar can be the origin of disease outbreaks in pigs, as it has been documented for brucellosis in some European countries. This study aimed at quantifying the occurrence of contacts between wild boar and outdoor domestic pigs in Switzerland, and identifying risk factors for these contacts. Furthermore, exposed pigs were tested for pathogen spill-over, taking Brucella suis as an example because B. suis is widespread in Swiss wild boar while domestic pigs are officially free of brucellosis. RESULTS: Thirty-one percent of the game-wardens and 25% of the pig owners participating to a country-wide questionnaire survey reported contacts, including approaches of wild boar outside the fence, intrusions, and mating. Seventeen piggeries (5%) reported the birth of cross-bred animals. Risk factors for contacts identified by a uni- and multivariable logistic regression approach were: distance between pig enclosure and buildings, proximity of a forest, electric fences, and fences <= 60 cm. Pigs of the Mangalitza breed were most at risk for mating with wild boar (births of cross-bred animals). Blood and tissues of 218 outdoor pigs from 13 piggeries were tested for an infection with Brucella suis, using rose bengal test, complement fixation test, and an IS711-based real-time PCR. One piggery with previous wild boar contacts was found infected with B. suis, however, epidemiological investigations failed to identify the direct source of infection. CONCLUSIONS: Results show that interactions between wild boar and outdoor pigs are not uncommon, pointing at the existing risk of pathogen spill-over. Provided data on risk factors for these interactions could help the risk-based implementation of protection measures for piggeries. The documentation of a brucellosis outbreak in pigs despite the freedom-of-disease status underlines the importance of improving pathogen surveillance strategies and increasing disease awareness of farmers and veterinary practitioners. PMID- 22817841 TI - Transcriptional integration of mitochondrial biogenesis. AB - Gene regulatory factors encoded by the nuclear genome are essential for mitochondrial biogenesis and function. Some of these factors act exclusively within the mitochondria to regulate the control of mitochondrial transcription, translation, and other functions. Others govern the expression of nuclear genes required for mitochondrial metabolism and organelle biogenesis. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators play a major role in transducing and integrating physiological signals governing metabolism, differentiation, and cell growth to the transcriptional machinery controlling mitochondrial functional capacity. Thus, the PGC-1 coactivators serve as a central component of the transcriptional regulatory circuitry that coordinately controls the energy-generating functions of mitochondria in accordance with the metabolic demands imposed by changing physiological conditions, senescence, and disease. PMID- 22817845 TI - Modeling extreme risks in ecology. AB - Extreme risks in ecology are typified by circumstances in which data are sporadic or unavailable, understanding is poor, and decisions are urgently needed. Expert judgments are pervasive and disagreements among experts are commonplace. We outline approaches to evaluating extreme risks in ecology that rely on stochastic simulation, with a particular focus on methods to evaluate the likelihood of extinction and quasi-extinction of threatened species, and the likelihood of establishment and spread of invasive pests. We evaluate the importance of assumptions in these assessments and the potential of some new approaches to account for these uncertainties, including hierarchical estimation procedures and generalized extreme value distributions. We conclude by examining the treatment of consequences in extreme risk analysis in ecology and how expert judgment may better be harnessed to evaluate extreme risks. PMID- 22817844 TI - Novel HER2 aptamer selectively delivers cytotoxic drug to HER2-positive breast cancer cells in vitro. AB - BACKGROUND: Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers. METHODS: In this paper, we developed a new HER2 aptamer (HB5) by using systematic evolution of ligands by exponential enrichment technology (SELEX) and exploited its role as a targeting ligand for delivering doxorubicin (Dox) to breast cancer cells in vitro. RESULTS: The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD) of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer doxorubicin complex (Apt-Dox) was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2 positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2 positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells. CONCLUSIONS: The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells. PMID- 22817846 TI - Ultrasonography as a non-invasive tool for detection of nonalcoholic fatty liver disease in overweight/obese Egyptian children. AB - INTRODUCTION: Liver biopsy, although a gold standard in diagnosis of nonalcoholic fatty liver disease (NAFLD), is an invasive and expensive tool. AIM: To assess the diagnostic accuracy of abdominal ultrasound in detecting NAFLD among a group of overweight/obese children having one or more liver abnormality (clinical hepatomegaly, raised ALT or echogenic liver parenchyma by ultrasound). METHODS: Seventy-eight overweight/obese children were referred to the Pediatric Hepatology Unit, Cairo University Pediatric Hospital, Egypt, for assessment for hepatic abnormalities. Out of the 78 children, 34 had one or more abnormality in the form of clinical hepatomegaly, raised alanine aminotransferase (ALT) and/or echogenic liver parenchyma by ultrasound. All 34 cases underwent liver biopsy for evaluation for NAFLD. RESULTS: Histological NAFLD was detected in 15 cases; 8 simple steatosis and 7 nonalcoholic steatohepatitis (NASH). Sonographic evaluation of hepatic parenchymal echogenicity revealed: 11 with grade 1 echogenicity, 12 with grade 2 and 9 with grade 3 while only 2 had normal liver echopattern. Ultrasonography was 100% sensitive and 100% specific in detecting histological NAFLD, while the positive predictive value (PPV) was 47% and negative predictive value (NPV) was 11%. After consolidating the included children into 2 groups: the first including normal and grade 1 echogenicity and the second including grades 2 and 3, the sensitivity of ultrasonography in detecting histological NAFLD was still 100%, while negative predictive value increased to 100% with an accuracy of 82%. CONCLUSION: We conclude that ultrasonography is an important non invasive tool in assessment for NAFLD. Normal or grade 1 hepatic echogenicity can soundly exclude histological NAFLD and obviates the need for liver biopsy. PMID- 22817847 TI - Characterization of a computed tomography iterative reconstruction algorithm by image quality evaluations with an anthropomorphic phantom. AB - OBJECTIVE: This study aims to investigate the consequences on dose and image quality of the choices of different combinations of NI and adaptive statistical iterative reconstruction (ASIR) percentage, the image quality parameters of GE CT equipment. METHODS: An anthropomorphic phantom was used to simulate the chest and upper abdomen of a standard weight patient. Images were acquired with tube current modulation and different values of noise index, in the range 10-22 for a slice thickness of 5mm and a tube voltage of 120 kV. For each selected noise index, several image series were reconstructed using different percentages of ASIR (0, 40, 50, 60, 70, 100). Quantitative noise was assessed at different phantom locations. Computed tomography dose index (CTDI) and dose length products (DLP) were recorded. Three radiologists reviewed the images in a blinded and randomized manner and assessed the subjective image quality by comparing the image series with the one acquired with the reference protocol (noise index 14, ASIR 40%). The perceived noise, contrast, edge sharpness and overall quality were graded on a scale from -2 (much worse) to +2 (much better). RESULTS: A repeatable trend of noise reduction versus the percentage of ASIR was observed for different noise levels and phantom locations. The different combinations of noise index and percentage of ASIR to obtain a desired dose reduction were assessed. The subjective image quality evaluation evidenced a possible dose reduction between 24 and 40% as a consequence of an increment of ASIR percentage to 50 or 70%, respectively. CONCLUSION: These results highlighted that the same patient dose reduction can be obtained with several combinations of noise index and percentages of ASIR, providing a model with which to choose these acquisition parameters in future optimization studies, with the aim of reducing patient dose by maintaining image quality in diagnostic levels. PMID- 22817848 TI - Evaluation of colonic lesions and pitfalls in CT colonography: a systematic approach based on morphology, attenuation and mobility. AB - Computed tomographic colonography is a reliable technique for the detection and classification of neoplastic and non-neoplastic lesions of the colon. It is based on a thin-section CT dataset of the cleansed and air-distended colon, acquired in prone and supine position. Two-dimensional and 3D projections are used in combination for image interpretation. The evaluation of CT colonography datasets is based on two steps, lesion perception to detect a polyp candidate and image interpretation to correctly characterize colonic filling defects. A thorough knowledge of the morphologic and attenuation characteristics of common colonic lesions and artifacts facilitates characterization of the findings. The purpose of this review article is to give an overview of the key CT colonographic imaging criteria to correctly characterize common colorectal lesions and to identify typical pitfalls and pseudolesions. PMID- 22817849 TI - An investigation into the variables associated with length of hospital stay related to primary cleft lip and palate surgery and alveolar bone grafting. AB - This retrospective study evaluated variables associated with length of stay (LOS) in hospital for 406 admissions of primary cleft lip and palate and alveolus surgery between January 2007 and April 2009. Three patients were treated as day cases, 343 (84%) stayed one night, 48 (12%) stayed 2 nights and 12 (3%) stayed > 2 nights. Poisson regression analysis showed that there was no association between postoperative LOS and age, distance travelled, diagnosis and type of operation, with a p value > 0.2 for all variables. 60/406 patients stayed 2 nights or more postoperatively mostly due to poor pain control and inadequate oral intake. Patients with palate repair were more likely to have postoperative LOS > 1 night, compared to patients with lip repair, p value = 0.011. Four patients (1%), all of whom had undergone cleft palate surgery, were readmitted within 4 weeks of the operation due to respiratory obstruction or haemorrhage. Using logistic regression, evidence showed that these readmissions were related to a longer original postoperative LOS. This study shows that length of stay for primary cleft lip, palate and alveolus surgery can in most cases be limited to one night postoperatively, provided that adequate support can be provided at home. PMID- 22817850 TI - Validating and updating a risk model for pneumonia - a case study. AB - BACKGROUND: The development of risk prediction models is of increasing importance in medical research - their use in practice, however, is rare. Among other reasons this might be due to the fact that thorough validation is often lacking. This study focuses on two Bayesian approaches of how to validate a prediction rule for the diagnosis of pneumonia, and compares them with established validation methods. METHODS: Expert knowledge was used to derive a risk prediction model for pneumonia. Data on more than 600 patients presenting with cough and fever at a general practitioner's practice in Switzerland were collected in order to validate the expert model and to examine the predictive performance of it. Additionally, four modifications of the original model including shrinkage of the regression coefficients, and two Bayesian approaches with the expert model used as prior mean and different weights for the prior covariance matrix were fitted. We quantify the predictive performance of the different methods with respect to calibration and discrimination, using cross validation. RESULTS: The predictive performance of the unshrinked regression coefficients was poor when applied to the Swiss cohort. Shrinkage improved the results, but a Bayesian model formulation with unspecified weight of the informative prior lead to large AUC and small Brier score, naive and after cross validation. The advantage of this approach is the flexibility in case of a prior data conflict. CONCLUSIONS: Published risk prediction rules in clinical research need to be validated externally before they can be used in new settings. We propose to use a Bayesian model formulation with the original risk prediction rule as prior. The posterior means of the coefficients, given the validation data showed best predictive performance with respect to cross-validated calibration and discriminative ability. PMID- 22817852 TI - Diabetes mellitus presents one of the most serious health problems in the United States and around the world. Introduction. PMID- 22817851 TI - CD4(+) CD25(high) Foxp3(+) cells increased in the peritoneal fluid of patients with endometriosis. AB - PROBLEM: To evaluate CD4(+) CD25(high) Foxp3(+) cells and IL-6, IL-10, IL-17, and TGF-beta in the peritoneal fluid of women with endometriosis. METHOD OF STUDY: A total of ninety-eight patients were studied: endometriosis (n = 70) and control (n = 28). First, peritoneal fluid lymphocytes were isolated, and CD4(+) CD25(high) cells were identified using flow cytometry. Then, RT-PCR was performed to verify Foxp3 expression in these cells. Also, IL-6, IL-10, IL-17, and TGF-beta concentration was determined. RESULTS: Of all the lymphocytes in the peritoneal fluid of women with endometriosis, 36.5% (median) were CD4(+) CD25(high) compared to only 1.15% (median) in the control group (P < 0.001). Foxp3 expression was similarly elevated in patients with the disease compared to those without (median, 50 versus 5; P < 0.001). IL-6 and TGF-beta were higher in endometriosis group (IL-6: 327.5 pg/mL versus 195.5 pg/mL; TGF-beta: 340 pg/mL versus 171.5 pg/mL; both P < 0.001). IL-10 and IL-17 showed no significant differences between the two groups. CONCLUSION: The peritoneal fluid of patients with endometriosis had a higher percentage of CD4(+) CD25(high) Foxp3(+) cells and also higher levels of IL-6 and TGF-beta compared to women without the disease. These findings suggest that CD4(+) CD25(high) Foxp3(+) cells may play a role in the pathogenesis of endometriosis. PMID- 22817853 TI - Diabetic neuropathy: is pain God's greatest gift to mankind? AB - Diabetic neuropathy is common and it has been estimated that around 40% of older type 2 diabetic patients have risk factors for foot ulceration. It is the loss of the "gift of pain" that results in the development of what should be preventable foot lesions in many patients. As neuropathy is silent in up to 50% of patients, all diabetic patients should receive an annual screening by careful examination of the lower limbs for evidence of any sensory loss or peripheral vascular disease. Similarly, it must be remembered when treating neuropathic foot lesions that patients will willingly weight-bear on plantar ulcers: suitable offloading is therefore the first-line treatment for such lesions. PMID- 22817854 TI - Diabetic foot ulcerations: biomechanics, charcot foot, and total contact cast. AB - Diabetes is the seventh leading cause of death in the United States; approximately 6% of the US population has been diagnosed with diabetes. Fifteen percent of all people with diabetes will develop a foot ulceration, and 14% to 20% of them will require an amputation. During the past 25 years, much has been learned and written about lower extremity complications associated with diabetes. The single most significant discovery relative to diabetic foot ulceration is the role of peripheral sensory neuropathy. Once the correlation between the absence of sensation and foot breakdown was made, treatment algorithms began to develop. For the first time, the concept of biomechanics and the role of weight-bearing stress were considered when applying different treatments to the patient with a diabetic foot ulcer. Wound classification systems developed to aid the physician in treating what had been a very frustrating group of patients; those with diabetic foot ulcerations. From that, a myriad of treatments developed. In fact, the technology of wound management became a billion dollar business and, to this day, continues to present the clinician with unending options to effectively manage and heal wounds on the diabetic lower extremity. PMID- 22817855 TI - Wound care: biofilm and its impact on the latest treatment modalities for ulcerations of the diabetic foot. AB - Biofilm is an increasingly important topic of discussion in the care of the chronic diabetic foot wound. Treatment modalities have focused on biofilm reduction or eradication through debridement techniques, topical therapies, negative pressure therapy, and ultrasound. In addition, advanced wound healing modalities, such as bioengineered alternative tissues, require optimal wound bed preparation with specific consideration of biofilm reduction before their application. Although fundamental principles of diabetic wound care still apply, critical thought must be given to biofilm before implementing a treatment plan for the closure of these complex wounds. PMID- 22817856 TI - Diabetic foot infections: the role of microbiology and antibiotic treatment. AB - Diabetes mellitus is a major risk factor for the development of foot infections. Among the risk factors that contribute to the development of diabetic foot infections are local neuropathy, vascular changes and depressed local host defenses. The microbiology of these infections is often complex and can be polymicrobial. Treatment of these infections depends on the severity and extent of infection. Treatment should involve a multi-disciplinary team approach involving surgeons and infectious disease specialists. The current recommendations for treatment are primarily based on expert opinion and consensus rather than clinical trials. No single agent or combination of agents has been shown to be superior to others. The aim of this review is to provide valid options of therapy, especially with regard to newer agents that are currently available for treatment of both soft tissue infections and osteomyelitis. PMID- 22817857 TI - Renal failure: implications of chronic kidney disease in the management of the diabetic foot. AB - Foot complications are common in patients with diabetes, however, chronic kidney disease has emerged as an independent risk factor for development of foot lesions in the diabetic population. Apart from peripheral arterial disease, infection, and neuropathy, which are classic factors contributing to development of foot lesions, skin disorders specific to renal failure, impaired wound healing from uremia, and psychosocial issues offer further compounded risk. Consequently, there are high ulceration and amputation rates that are associated with increased morbidity and mortality. In recent studies, foot-care programs with a multidisciplinary approach within dialysis units have demonstrated improved outcomes. PMID- 22817858 TI - Diabetic vascular disease: characteristics of vascular disease unique to the diabetic patient. AB - Diabetes is a cardiovascular disease affecting almost every arterial vascular bed with significant consequences. Vascular disease is one part of a triopathy of complications that singularly but most commonly in combination makes the diabetic patient uniquely susceptible to lower extremity complications. The other two conditions are neuropathy and an altered response to infection. Diabetic peripheral arterial disease has a predilection for the smaller below knee tibial/peroneal arteries and there is no microvascular occlusive arterial disease affecting the diabetic foot. Microvascular dysfunction is not an occlusive phenomenon and supports an aggressive approach to treating existing macrovascular atherogenic occlusive disease complicating diabetic wounds of all extremities. Individualized, patient-centered treatment utilizing all available endovascular and open revascularization options best ensures the highest quality outcomes at a cost our healthcare system can afford. PMID- 22817859 TI - Endovascular therapy: is it effective in the diabetic limb? AB - Reducing the risk of lower extremity amputation in diabetics is a top priority. To make progress in this area, we must bring all options to bear in the treatment of diabetic peripheral vascular disease. The "endovascular promise" of lower morbidity, while attaining the primary clinical goal (in this case, limb salvage), was late to arrive in the treatment of the ischemic diabetic lower extremity. This is due to complex and severe lesion morphologies requiring treatment, as well as the complexity of the vascular disease and the clinical scenario in diabetic critical limb ischemia. Although not without remaining challenges, significant strides have been made in the last 5 years that have increased the role of endovascular therapy in this setting. PMID- 22817860 TI - Surgical bypass: when is it best and do angiosomes play a role? AB - The etiology of foot lesions in diabetics is multifactorial. Arterial insufficiency, neuropathy, and susceptibility to infection are major factors contributing to the formation of nonhealing diabetic foot lesions. These factors lead to a 15% ulceration rate in diabetics with 20% resulting in amputation. This amputation rate, 4.1 per 1,000 per year, represents a risk 40 times greater for diabetics, with a subsequent second amputation in 60% by 5 years. Conversely, more than half of all lower-extremity amputations are performed in diabetic patients. Therefore, the primary goal in diabetic lower-extremity care is to heal foot ulcerations and prevent amputations and major disabilities. Lower-extremity revascularization is a major facet of achieving the goal of healing and amputation prevention. Due to the severity, distribution, and complexity of diabetic vascular disease, surgical bypass continues to play a role in attaining this goal. Surgical bypass might be the best option for diabetic patients with significant tissue loss or to revascularize the appropriate angiosome of the foot and maximize healing potential. In order to offer surgical bypass to these patients, innovative techniques might need to be considered, including venous patches and cuffs, heparin-bonded grafts, and adjunctive distal arteriovenous fistulas. PMID- 22817861 TI - Diabetic revascularization: endovascular versus open bypass--do we have the answer? AB - Diabetes is an independent risk factor for peripheral arterial disease and, when advanced peripheral arterial disease develops in the setting of diabetes, it portends a greatly increased threat to both life and limb. The management of severe limb ischemia in diabetic patients, particularly those with tissue loss and infection, remains a major surgical challenge in the new millennium. However, advances in multidisciplinary care, including an aggressive revascularization approach, can avoid major amputation in a large percentage of patients. The unique pattern of lower extremity atherosclerosis in diabetes is a critical determinant of the revascularization strategy. Most diabetics with critical ischemia have popliteal/tibial occlusions requiring below-the-knee intervention or bypass grafting. Bypass surgery with vein to crural or pedal arteries remains the gold standard of revascularization, but may be limited by patient risk, conduit availability, and a suitable target. Infrapopliteal angioplasty can have acceptable results for suitable lesions, particularly when there is not extensive tissue loss in the foot. However, restenosis rates after endovascular intervention in these vessels are high, and recent advances in drug-eluting balloons and stents have promise but remain largely unproven. There is limited high-quality evidence to support treatment choices in this arena, with only one randomized clinical trial to date. The available data suggest that patients with life expectancy of at least 2 years and more extensive disease have superior outcomes with open reconstruction. A selective revascularization strategy is advocated, using autogenous vein bypass as the initial approach in a significant percentage of patients, based on its greater overall efficacy and proven durability. However, endovascular therapies have an important role in current practice, which will increase further if restenosis can be overcome. Vascular specialists should understand and be able to apply both types of interventions to optimize patient outcomes. PMID- 22817862 TI - Amputation in the diabetic to maximize function. AB - For the patient facing a major lower extremity amputation, the surgeon's goal should be to salvage a residual limb with the maximum amount of function. This requires coordinating length with the available prosthetics and tenodesing muscle to optimize joint motion and maintain muscle tone. This article explains a systematic approach to major lower extremity amputation. We believe outcomes can be improved through careful preoperative evaluation and optimization of biomechanics, blood flow, and infection. Thoughtful planning and the creative use of remaining viable tissue can give most amputees a highly functional lower extremity. PMID- 22817863 TI - Prevention: can we stop problems before they arise? AB - It is estimated that 50% of diabetic ulcerations and amputations can be prevented by identifying the at-risk foot and implementing preventative strategies. Patients with diabetes mellitus (DM) should be screened and placed in the appropriate risk category. Risk factors for the development of ulcer in several prospective studies include neuropathy, deformity, limited joint mobility, vascular disease, and history of previous ulceration or amputation. Early identification of the at-risk foot and placing the patient in the appropriate risk category is essential to prevention. Once the at-risk foot is identified, abnormal foot pressures should be reduced or eliminated using several treatment options. Repetitive, moderate mechanical stress (the pressure time integral) is often the initial mechanism of injury in the formation and/or recurrence of diabetic foot ulcers. Once conservative treatment options to off load the foot have failed, surgery should be considered. There are patients with diabetic foot ulcers for whom a combination of surgery (intrinsic off loading) and extrinsic off loading is better than either method alone. These difficult wounds are characterized by a combination of variables acting singularly or together, such as neuropathy, rigid deformity, limited joint mobility, and activity level. Our experience dictates, patients with rigid deformity and limited joint mobility get caught in the cycle of repetitive stress and cannot break the cycle until the etiology of the structural deformity is addressed surgically and preventative strategies for off loading, temperature monitoring, and activity level are implemented. If a structural deformity exists, the deformity will delay or prevent healing of the ulcer. Once the ulcer is healed, the likelihood for recurrence is high unless the deformity is corrected. When a structural deformity exists, the patient should be referred for evaluation and possible prophylactic surgery. PMID- 22817865 TI - Normal anatomy by three-dimensional ultrasound in the second and third trimesters. AB - Fetal brain is rapidly developing and changing its appearance week by week during pregnancy. It is quite difficult to observe detailed structure of the brain by conventional transabdominal sonography. Transvaginal high-resolution ultrasound and three-dimensional (3D) ultrasound have been establishing sonoembryology in the first trimester as well as neurosonography. It is possible to observe the whole brain structure by magnetic resonance imaging in the latter half of pregnancy but transvaginal high-resolution 3D ultrasound is also a powerful modality for understanding brain anatomy. As for brain vascularization, main arteries and veins have been demonstrated and evaluated in various central nervous system conditions. Transvaginal high-resolution 3D ultrasound can demonstrate even cerebral fine vascular anatomy such as medullary vessels and it is greatly expected to estimate neurological prognosis in relation to vascular development during the fetal period. PMID- 22817864 TI - The ubiquitin-proteasome system in glioma cell cycle control. AB - A major determinant of cell fate is regulation of cell cycle. Tight regulation of this process is lost during the course of development and progression of various tumors. The ubiquitin-proteasome system (UPS) constitutes a universal protein degradation pathway, essential for the consistent recycling of a plethora of proteins with distinct structural and functional roles within the cell, including cell cycle regulation. High grade tumors, such as glioblastomas have an inherent potential of escaping cell cycle control mechanisms and are often refractory to conventional treatment. Here, we review the association of UPS with several UPS-targeted proteins and pathways involved in regulation of the cell cycle in malignant gliomas, and discuss the potential role of UPS inhibitors in reinstitution of cell cycle control. PMID- 22817866 TI - Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome. AB - BACKGROUND: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5 HT7) receptors; the underlying mechanisms are unknown. METHODS: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. RESULTS: Application of 5-HT or 8-OH-DPAT (a mixed 5 HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY 100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. CONCLUSIONS: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS. PMID- 22817867 TI - The monoamine stabilizer (-)-OSU6162 attenuates voluntary ethanol intake and ethanol-induced dopamine output in nucleus accumbens. AB - BACKGROUND: New medications for alcohol use disorder (AUD) are needed. Long-term alcohol consumption leads to a dysregulated dopamine system. A novel approach to normalize these dysregulations might be treatment with "monoamine stabilizers," a novel class of compounds characterized by the ability to either suppress, stimulate, or not influence dopamine activity depending on the prevailing dopaminergic tone. METHODS: The effects of the monoamine stabilizer (-)-OSU6162 (OSU6162) on voluntary ethanol intake and ethanol withdrawal symptoms were evaluated in rats voluntarily consuming ethanol for at least 3 months before testing. Furthermore, effects of OSU6162 on ethanol seeking behavior were evaluated with the progressive ratio and cue-induced reinstatement paradigms. Finally, the interaction of OSU6162 with ethanol on dopamine output and metabolism was studied with microdialysis. RESULTS: The OSU6162 attenuated several ethanol-mediated behaviors, including voluntary ethanol consumption, ethanol withdrawal symptoms, operant ethanol self-administration under progressive ratio schedule, and cue-induced reinstatement of ethanol seeking in rats that had voluntarily consumed ethanol for at least 3 months before treatment. In addition, OSU6162 blunted ethanol-induced dopamine output in nucleus accumbens of ethanol-naive rats. CONCLUSIONS: These results highlight the ability of OSU6162 to stabilize dopamine activity depending on the prevailing dopaminergic tone and indicate that OSU6162 might decrease ethanol intake by attenuating the acute rewarding properties of ethanol. In addition, OSU6162 might have potential to prevent relapse triggered by alcohol craving, alcohol related cues, and or an urge to relieve abstinence symptoms. The present study is to our knowledge the first indicating that OSU6162 might serve as a novel medication for AUD. PMID- 22817869 TI - Is there a future for prenyltransferase inhibitors in cancer therapy? AB - It has been over 20 years since it was first recognized that the function of both normal and oncogenic Ras is dependent on the post-translational modification termed farnesylation. Since that time, intense effort has been expended on the development of farnesyltransferase inhibitors as novel anticancer agents. Over 70 clinical trials have now been conducted, with limited efficacy demonstrated. Here we provide an update of the most recently published clinical trials, discuss the use of the RASGRP1/APTX two-gene expression screen to select patients with acute myeloid leukemia for therapy, and report on the latest discoveries related to the targets of prenyltransferase inhibitors. PMID- 22817868 TI - Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the kappa opioid agonist Salvinorin A in humans. AB - BACKGROUND: Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)-a highly selective agonist at the kappa opiate receptor-is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans. METHODS: In a 3 day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia. RESULTS: SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects. CONCLUSIONS: SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with kappa opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects. PMID- 22817871 TI - Activation of farnesoid X receptor increases the expression of cytokine inducible SH2-containing protein in HepG2 cells. AB - Cytokine inducible SH2-containing protein (CISH), which negatively regulates cytokine signaling by inhibiting JAK2/STAT5 activity, is regarded as a therapeutic target for inflammatory diseases. Farnesoid X receptor (FXR), a ligand-activated transcription factor, has been proposed to play a protective function in the inflammatory responses. However, the role of FXR in modulation of CISH expression is unknown. In the present study, we for the first time identified that in human hepatoma cell line HepG2 the activation of FXR by the natural agonist chenodeoxycholic acid (CDCA) and the synthetic specific agonist GW4064 upregulated CISH at both transcriptional and translational levels, and inhibited interleukin (IL)6-induced STAT5 activation. Moreover, the in vivo experiment demonstrated that gavaging mice with CDCA increased CISH expression and reduced basal STAT5 phosphorylation in liver tissues. Reporter assay showed that FXR agonists enhanced the transcriptional activity of CISH promoter. These data suggest that FXR may serve as a novel molecular target for manipulating CISH expression in hepatocytes. FXR-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases. PMID- 22817872 TI - Different radiolabelling methods alter the pharmacokinetic and biodistribution properties of plasminogen activator inhibitor type 2 (PAI-2) forms. AB - INTRODUCTION: Tumour-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, and it is recognised as having strong prognostic relevance as well as being a therapeutic target. The specific uPA inhibitor plasminogen activator inhibitor type-2 (PAI-2, SerpinB2) specifically targets cell bound uPA and is internalised. Furthermore, preclinical studies have established the "proof-of-principle" of uPA-targeting by PAI-2-cytotoxin conjugates in human carcinoma models. However, these studies also suggest that PAI-2 is rapidly cleared via the renal system with low total dose reaching the tumour. In this study, a comparative single photon emission computed tomography (SPECT) and biodistribution (BD) analysis of different forms of PAI-2 labelled with the radioisotopes iodine-123 ((123)I) and technetium-99m ((99m)Tc) was undertaken. METHODS: The pharmacokinetic (PK) properties and BD of wild-type, DeltaCD-loop and PEGylated DeltaCD-loop PAI-2 labelled with the commonly used diagnostic SPECT radioisotopes (99m)Tc or (123)I were compared in mouse models of human prostate carcinoma. Whole body SPECT imaging was also performed. RESULTS: Both wild-type and the shorter but active DeltaCD-loop form of PAI-2 (123)I labelled indirectly via conjugation to free amine groups (termed (123)I-Bn-PAI-2) exhibited low tumour uptake, rapid excretion and similar PK profiles. Preliminary studies with a short branched-chain PEGylated (123)I-Bn-PAI-2 DeltaCD-loop indicated an increase in blood retention time and tumour uptake. All (123)I-Bn labelled radiotracers were largely excreted through the kidneys. By comparison, both wild-type (123)I-PAI-2 (labelled directly via tyrosine residues) and (99m)Tc PAI-2 displayed different PK/BD patterns compared to (123)I-Bn-PAI-2, suggesting greater liver based catabolism and thus slower elimination. SPECT imaging mimicked the BD results of all radiotracers. CONCLUSION: The different labelling methods gave distinct PAI-2 BD and tumour uptake profiles, with radioiodination resulting in the best non-tumour organ clearance profiles. Preliminary analyses with short branched-chain PEGylated (123)I-Bn-PAI-2 DeltaCD-loop suggest that further investigations with other PEGylation reagents are required to optimise this approach for tumour imaging. These findings impact on the use of PAI-2 for drug delivery and/or diagnostic development. PMID- 22817873 TI - 177Lu-nimotuzumab. PMID- 22817874 TI - Association between white matter fiber integrity and subclinical psychotic symptoms in schizophrenia patients and unaffected relatives. AB - In this study, we investigate whether aberrant integrity of white matter (WM) fiber tracts represents a genetically determined biological marker of schizophrenia (SZ), and its relation with clinical symptoms. We collected brain DTI data from 28 SZ patients, 18 first-degree relatives and 22 matched controls and used voxel-based analysis with tract-based spatial statistics (TBSS) in order to compare fractional anisotropy (FA) between groups. Mean voxel-based FA values from the entire skeleton of each group were compared. We did a multiple regression analysis, followed by single post-hoc contrasts between groups. FA values were extracted from the statistically significant areas. The results showed significantly smaller FA values for SZ patients in comparison with controls in cortico-spinal tracts, in commissural fibers, in thalamic projections, in association fibers and in cingulum bundles. A significant increase of FA in SZ patients in comparison with healthy controls was only found in the arcuate fasciculus. Relatives had intermediate values between patients and controls which were deemed significant in the comparison to patients and controls in association fibers, arcuate fasciculus and cingulum bundles. Lower FA values in association fibers were significantly associated with predisposition toward hallucinations (in SZ patients and relatives), with higher PANSS scores of positive symptoms and with duration of illness (SZ patients). Our results suggest that clinical and subclinical presentations of psychotic symptoms are associated with aberrant integrity of multiple WM tracts. This association may represent an endophenotype of schizophrenia, since it is present in unaffected relatives as well. Such endophenotypes may serve as quantitative traits for future genetic studies and as candidate markers for early and preclinical identification of subjects at risk. PMID- 22817875 TI - Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein. AB - OBJECTIVE: Severe mental disorder and cardiovascular disease (CVD) are often associated, and inflammation is implicated in both disorders. We investigated whether there is a relationship between CVD risk factors and inflammation in schizophrenia or bipolar disorder, and if second generation antipsychotics (SGA) interact. METHODS: We included 361 patients in a naturalistic cross-sectional study, 235 subjects on current SGA treatment and 126 subjects not treated with SGA as controls. Cardiovascular parameters were measured and current medication recorded. Fasting plasma levels of the following cytokines were measured: high sensitivity CRP (hsCRP), soluble tumor necrosis factor receptor 1 (sTNF-R1), osteoprotegerin (OPG), soluble CD40 ligand (sCD40L), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (vWf) and interleukin-6 (IL-6). RESULTS: In this relatively young sample of patients with a mean age of 33.3years, the following CVD risk factors were associated with elevated inflammation markers after adjusting for confounders: BMI, triglycerides and glucose with hsCRP (p=0.041-0.001), HDL-cholesterol and triglycerides with sTNF R1 (p=0.009-0.001) and triglycerides with vWf (p=0.004). In patients treated with SGA, elevated hsCRP was significantly associated with high BMI (p=0.012), and with high glucose levels (p=0.003). CONCLUSION: Several CVD risk factors are associated with elevated levels of inflammation markers in young patients with severe mental illness. The interaction between SGA and CVD risk factors on hsCRP levels might indicate a specific inflammatory activation related to SGA induced overweight and hyperglycemia. This suggests that hsCRP could be a valuable marker for future cardiovascular events, particularly in patients treated with SGA. PMID- 22817876 TI - Multilocus sequence analysis reveals multiple symbiovars within Mesorhizobium species. AB - The genus Mesorhizobium includes species nodulating several legumes, such as chickpea, which has a high agronomic importance. Chickpea rhizobia were originally described as either Mesorhizobium ciceri or M. mediterraneum. However, rhizobia able to nodulate chickpea have been shown to belong to several different species within the genus Mesorhizobium. The present study used a multilocus sequence analysis approach to infer a high resolution phylogeny of the genus Mesorhizobium and to confirm the existence of a new chickpea nodulating genospecies. The phylogenetic structure of the Mesorhizobium clade was evaluated by sequence analysis of the 16S rRNA gene, ITS region and the five core genes atpD, dnaJ, glnA, gyrB, and recA. Phylogenies obtained with the different genes are in overall good agreement and a well-supported, almost fully resolved, phylogenetic tree was obtained using the combined data. Our phylogenetic analyses of core genes sequences and their comparison with the symbiosis gene nodC, corroborate the existence of one new chickpea Mesorhizobium genospecies and one new symbiovar, M. opportunistum sv. ciceri. Furthermore, our results show that symbiovar ciceri spreads over six species of mesorhizobia. To our knowledge this study shows the most complete Mesorhizobium multilocus phylogeny to date and contributes to the understanding of how a symbiovar may be present in different species. PMID- 22817877 TI - Natrinema salaciae sp. nov., a halophilic archaeon isolated from the deep, hypersaline anoxic Lake Medee in the Eastern Mediterranean Sea. AB - Two halophilic archaea, strains MDB25(T) and MDB20, were isolated from a sample of the brine from Lake Medee, at a depth of 3050 m, in the Mediterranean Sea. Cells of the organisms were Gram-negative, non-motile and pleomorphic, and colonies were red pigmented. Strains MDB25(T) and MDB20 showed optimum growth at 45 degrees C, in 2.6-3.4M NaCl and at pH 7.0-8.0. The major polar lipids of the two strains were phosphatidylglycerol (PG1 and PG2), phosphatidylglycerol phosphate methyl ester (PGP-Me) and mannose-2,6-dissulfate (1->2)-glucose glycerol diether (S(2)-DGD). Menaquinone MK-8 and MK-8(H(2)) were the major respiratory quinones. The DNA G+C content of strain MDB25(T) was 63.0%. The strains were facultatively anaerobic but grew better under aerobic conditions, nitrate served as electron acceptor. Analysis of the almost complete 16S rRNA gene sequence indicated that the strains MDB25(T) and MDB20 represented a member of the genus Natrinema in the family Halobacteriaceae. Both strains formed a distinct cluster and were most closely related to Natrinema ejinorense JCM 13890(T) and Haloterrigena longa JCM 13562(T) (98.0% and 97.9% sequence similarity, respectively). Based on 16S rRNA gene sequence analysis, DNA-DNA hybridization results, physiological and biochemical characteristics we describe a new species represented by strain MDB25(T) (=DSM 25055(T) =JCM 17869(T)) for which we propose the name Natrinema salaciae sp. nov. PMID- 22817878 TI - 2011 Pediatric Rheumatology Symposium sponsored by the American College of Rheumatology Miami, FL, USA. 2-5 June 2011. Abstracts. PMID- 22817879 TI - High glucose potentiates and renin-angiotensin blockade downregulates LPS-induced tissue factor expression in human mononuclear cells. AB - BACKGROUND: Intimate links connect tissue factor (TF), the principal initiator of the clotting cascade, to inflammation, a cross-talk amplified by locally generated Angiotensin (ANG) II, the effector arm of the Renin Angiotensin System (RAS). The RAS, in turn, plays a pathophysiological role in diabetes, a proinflammatory state to which elevated glucose, the disease hallmark, contributes by activating key signalling pathways and increasing the cellular content of RAS components. AIMS: To evaluate the effect of high glucose concentrations on TF antigen (Ag) expression and procoagulant activity (PCA) in lipopolysaccharide(LPS)-primed human mononuclear cell(MNC)s and to test whether pharmacological RAS blockade modifies that pattern. METHODS: LPS-activated MNCs exposed to increasing D-glucose (from 5.5 to 50mM) in absence or presence of aliskiren, a renin inhibitor, zofenopril, an ANG converting enzyme inhibitor, and olmesartan, an ANGII type I receptor blocker. PCA was assessed by one-stage clotting assay and TF antigen expression by ELISA. RESULTS: Increasing ambient glucose (range 5.5-50mM) potentiated LPS-induced PCA and TF Ag expression. Aliskiren, zofenopril and olmesartan downregulated those responses but the efficacy of the former decreased by ascending drug concentration while both zofenopril and olmesartan showed an opposite behaviour. TF Ag expression modulation by RAS blockade was stronger in 50 than 5mM ambient glucose. CONCLUSIONS: High glucose potentiates the procoagulant action of LPS in human MNCs and RAS blockers downregulate that response possibly as a reflection of the underlying involvement of the system in that mechanism. PMID- 22817880 TI - Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience. AB - BACKGROUND: Patients with locally advanced or recurrent rectal cancer often require multimodality treatment. Intraoperative radiation therapy (IORT) is a focal approach which aims to improve local control. METHODS: We retrospectively reviewed 42 patients treated with IORT following definitive resection of a locally advanced or recurrent rectal cancer from 2000-2009. All patients were treated with the Intrabeam(r) Photon Radiosurgery System (PRS). A dose of 5 Gy was prescribed to a depth of 1 cm (surface dose range: 13.4-23.1, median: 14.4 Gy). Median survival times were calculated using Kaplan-Meier analysis. RESULTS: Of 42 patients, 32 had recurrent disease (76%) while 10 had locally advanced disease (24%). Eighteen patients (43%) had tumors fixed to the sidewall. Margins were positive in 19 patients (45%). Median follow-up after IORT was 22 months (range 0.2-101). Median survival time after IORT was 34 months. The 3-year overall survival rate was 49% (43% for recurrent and 65% for locally advanced patients). Local recurrence was evaluable in 34 patients, of whom 32% failed. The 1-year local recurrence rate was 16%. Distant metastasis was evaluable in 30 patients, of whom 60% failed. The 1-year distant metastasis rate was 32%. No intraoperative complications were attributed to IORT. Median duration of IORT was 35 minutes (range: 14-39). Median discharge time after surgery was 7 days (range: 2-59). Hydronephrosis after IORT occurred in 10 patients (24%), 7 of whom had documented concomitant disease recurrence. CONCLUSIONS: The Intrabeam(r) PRS appears to be a safe technique for delivering IORT in rectal cancer patients. IORT with PRS marginally increased operative time, and did not appear to prolong hospitalization. Our rates of long-term toxicity, local recurrence, and survival rates compare favorably with published reports of IORT delivery with other methods. PMID- 22817881 TI - The long-term changes of hard palatal bony cleft defects after palatoplasty in unilateral complete cleft lip and palate. AB - There have been few long-term studies regarding the change of bony cleft defects in cleft lip and palate after palatoplasty. The purpose of this study was to evaluate the regenerated bone formed in bony cleft defects and the change in bony cleft width after palatoplasty using computed tomography (CT). Thirty non syndromic unilateral complete cleft lip and palate patients were retrospectively reviewed. The patients underwent palatoplasty at an average age of 14.32 months. CT was performed at an average age of 9.8 years. The authors evaluated the regenerated bone volume ratio, remnant bony cleft area ratio and change in bony cleft width at the posterior nasal spine. The relative locations of the regenerated bone lesion and the bony cleft to the hard palate were measured. Regenerated bone was observed in all patients. The average regenerated bone volume ratio was 61.1%, and the largest regenerated bone was usually located in the anterior half of the hard palate. The average remnant bony cleft area ratio was 7.6%, and the widest bony cleft was usually located in the anterior 1/3 and the posterior 1/3. The remnant bony cleft and non-regenerated bone lesion were rarely located in the middle 1/3. The bony cleft width at the posterior nasal spine decreased significantly after palatoplasty. Hard palatal bony cleft defects after palatoplasty were decreased by regenerated bone, and possibly by the contracting force of the scar at the midline of the hard palate, and the continuous pressure of the surrounding tissues. PMID- 22817882 TI - An ideal surgical technique for postaxial polysyndactyly of the toes. PMID- 22817883 TI - Scarless lymphatic venous anastomosis for latent and early-stage lymphoedema using indocyanine green lymphography and non-invasive instruments for visualising subcutaneous vein. AB - BACKGROUND: Lymphoedema can be treated conservatively or surgically. Early treatment is important, but the surgical indication and the effect of surgery on pain in lymphoedema-affected limbs have not been described. The objective of this study was to examine the effect of low-invasive scarless lymphatic venous anastomosis (LVA) for early or latent lymphoedema. METHODS: LVA was performed in six patients (eight legs) with leg lymphoedema between April 2010 and March 2011. Lymphoedema was stage 0 (defined as subclinical) in three patients (five legs) and stage 1 in three patients (three legs). Subjective symptoms, circumference of the affected leg and a lymphoscintigram were evaluated before and 6 months after surgery. Preoperatively, subcutaneous lymph vessels and veins were identified non invasively using ICG lymphoscintigraphy and non-invasive instruments for visualising subcutaneous vein, AccuVein system, through the skin. These vessels and veins were secured with vessel loops passed underneath and side-to-side anastomosed under a surgical microscope. RESULTS: Subjective symptoms improved after surgery in all patients. The leg circumference improved in stage 1 cases, which all had an increased circumference before surgery. Lymph retention was observed on preoperative lymphoscintigraphy in all six patients and was improved after surgery in all cases. CONCLUSIONS: Scarless LVA performed through a small incision improves abnormal lymph circulation and subjective symptoms in cases of early lymphoedema, in which the limb circumference has just started to increase, and latent lymphoedema, in which the circumference has not increased, but abnormal findings on lymphoscintigraphy or subjective symptoms are present. PMID- 22817884 TI - Science for sale: academic meets industry. AB - As research becomes increasingly interdisciplinary and the lines between academic and industrial pursuits blur, scientists on both sides of the fence are developing outsourcing models to build innovative collaborations and open funding opportunities. PMID- 22817885 TI - Transcription, splicing, and release: are we there yet? AB - A systematic analysis of LPS-induced gene expression in macrophages by Bhatt et al. demonstrates that inflammatory responses are governed primarily at the level of transcription initiation. Unexpectedly, full-length nascent RNAs that contain introns appear to accumulate on chromatin, presumably to complete processing, prior to release of functional mRNA for export to the cytoplasm. PMID- 22817886 TI - Unfolding the bridge between transcription and translation. AB - Transcription antiterminator RfaH alternates between closed (inactive) and open (activated) conformation. In this issue of Cell, Burmann et al. show that opening is accompanied by dramatic all-alpha to all-beta refolding of its C-terminal domain. Each of the folds has a distinct function: all-alpha-fold acts as a specificity determinant, directing RfaH to a small subset of operons, whereas the all-beta-fold recruits ribosome, thereby coupling RfaH-stimulated transcription to translation. PMID- 22817887 TI - The split personality of CENP-A nucleosomes. AB - The composition and structure of centromeric nucleosomes, which contain the histone H3 variant CENP-A, is intensely debated. Two independent studies in this issue, in yeast and human cells, now suggest that CENP-A nucleosomes adopt different structures depending on the stage of the cell cycle. PMID- 22817888 TI - The dawn of virtual cell biology. AB - To fulfill systems biology's promise of providing fundamental new insights will require the development of quantitative and predictive models of whole cells. In this issue, Karr et al. present the first integrated and dynamic computational model of a bacterium that accounts for all of its components and their interactions. PMID- 22817889 TI - A landscape of driver mutations in melanoma. AB - Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic UV light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), three of which-RAC1, PPP6C, and STK19-harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. PMID- 22817890 TI - The origin and evolution of mutations in acute myeloid leukemia. AB - Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse. PMID- 22817891 TI - Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. AB - Macrophages respond to inflammatory stimuli by modulating the expression of hundreds of genes in a defined temporal cascade, with diverse transcriptional and posttranscriptional mechanisms contributing to the regulatory network. We examined proinflammatory gene regulation in activated macrophages by performing RNA-seq with fractionated chromatin-associated, nucleoplasmic, and cytoplasmic transcripts. This methodological approach allowed us to separate the synthesis of nascent transcripts from transcript processing and the accumulation of mature mRNAs. In addition to documenting the subcellular locations of coding and noncoding transcripts, the results provide a high-resolution view of the relationship between defined promoter and chromatin properties and the temporal regulation of diverse classes of coexpressed genes. The data also reveal a striking accumulation of full-length yet incompletely spliced transcripts in the chromatin fraction, suggesting that splicing often occurs after transcription has been completed, with transcripts retained on the chromatin until fully spliced. PMID- 22817892 TI - An alpha helix to beta barrel domain switch transforms the transcription factor RfaH into a translation factor. AB - NusG homologs regulate transcription and coupled processes in all living organisms. The Escherichia coli (E. coli) two-domain paralogs NusG and RfaH have conformationally identical N-terminal domains (NTDs) but dramatically different carboxy-terminal domains (CTDs), a beta barrel in NusG and an alpha hairpin in RfaH. Both NTDs interact with elongating RNA polymerase (RNAP) to reduce pausing. In NusG, NTD and CTD are completely independent, and NusG-CTD interacts with termination factor Rho or ribosomal protein S10. In contrast, RfaH-CTD makes extensive contacts with RfaH-NTD to mask an RNAP-binding site therein. Upon RfaH interaction with its DNA target, the operon polarity suppressor (ops) DNA, RfaH CTD is released, allowing RfaH-NTD to bind to RNAP. Here, we show that the released RfaH-CTD completely refolds from an all-alpha to an all-beta conformation identical to that of NusG-CTD. As a consequence, RfaH-CTD binding to S10 is enabled and translation of RfaH-controlled operons is strongly potentiated. PAPERFLICK: PMID- 22817893 TI - Cell-cycle-coupled structural oscillation of centromeric nucleosomes in yeast. AB - The centromere is a specialized chromosomal structure that regulates chromosome segregation. Centromeres are marked by a histone H3 variant. In budding yeast, the histone H3 variant Cse4 is present in a single centromeric nucleosome. Experimental evidence supports several different models for the structure of centromeric nucleosomes. To investigate Cse4 copy number in live yeast, we developed a method coupling fluorescence correlation spectroscopy and calibrated imaging. We find that centromeric nucleosomes have one copy of Cse4 during most of the cell cycle, whereas two copies are detected at anaphase. The proposal of an anaphase-coupled structural change is supported by Cse4-Cse4 interactions, incorporation of Cse4, and the absence of Scm3 in anaphase. Nucleosome reconstitution and ChIP suggests both Cse4 structures contain H2A/H2B. The increase in Cse4 intensity and deposition at anaphase are also observed in Candida albicans. Our experimental evidence supports a cell-cycle-coupled oscillation of centromeric nucleosome structure in yeast. PMID- 22817894 TI - Cell-cycle-dependent structural transitions in the human CENP-A nucleosome in vivo. AB - In eukaryotes, DNA is packaged into chromatin by canonical histone proteins. The specialized histone H3 variant CENP-A provides an epigenetic and structural basis for chromosome segregation by replacing H3 at centromeres. Unlike exclusively octameric canonical H3 nucleosomes, CENP-A nucleosomes have been shown to exist as octamers, hexamers, and tetramers. An intriguing possibility reconciling these observations is that CENP-A nucleosomes cycle between octamers and tetramers in vivo. We tested this hypothesis by tracking CENP-A nucleosomal components, structure, chromatin folding, and covalent modifications across the human cell cycle. We report that CENP-A nucleosomes alter from tetramers to octamers before replication and revert to tetramers after replication. These structural transitions are accompanied by reversible chaperone binding, chromatin fiber folding changes, and previously undescribed modifications within the histone fold domains of CENP-A and H4. Our results reveal a cyclical nature to CENP-A nucleosome structure and have implications for the maintenance of epigenetic memory after centromere replication. PMID- 22817895 TI - Structure of the rigor actin-tropomyosin-myosin complex. AB - Regulation of myosin and filamentous actin interaction by tropomyosin is a central feature of contractile events in muscle and nonmuscle cells. However, little is known about molecular interactions within the complex and the trajectory of tropomyosin movement between its "open" and "closed" positions on the actin filament. Here, we report the 8 A resolution structure of the rigor (nucleotide-free) actin-tropomyosin-myosin complex determined by cryo-electron microscopy. The pseudoatomic model of the complex, obtained from fitting crystal structures into the map, defines the large interface involving two adjacent actin monomers and one tropomyosin pseudorepeat per myosin contact. Severe forms of hereditary myopathies are linked to mutations that critically perturb this interface. Myosin binding results in a 23 A shift of tropomyosin along actin. Complex domain motions occur in myosin, but not in actin. Based on our results, we propose a structural model for the tropomyosin-dependent modulation of myosin binding to actin. PMID- 22817896 TI - The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. AB - RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of beta-amyloids, as shown by Thioflavin T (ThT) and Congo red (CR) binding, circular dichroism, infrared spectroscopy, X ray diffraction, and solid-state NMR. Structured amyloid cores are mapped in RIP1 and RIP3 that are flanked by regions of mobility. The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure, whereas necrosis is partially inhibited by ThT, CR, and another amyloid dye, HBX. Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. The current study provides insight into the structural changes that occur when RIP kinases are triggered to execute different signaling outcomes and expands the realm of amyloids to complex formation and signaling. PMID- 22817897 TI - Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. AB - Wnt signaling is involved in self-renewal and maintenance of hematopoietic stem cells (HSCs); however, the particular role of noncanonical Wnt signaling in regulating HSCs in vivo is largely unknown. Here, we show Flamingo (Fmi) and Frizzled (Fz) 8, members of noncanonical Wnt signaling, both express in and functionally maintain quiescent long-term HSCs. Fmi regulates Fz8 distribution at the interface between HSCs and N-cadherin(+) osteoblasts (N-cad(+)OBs that enrich osteoprogenitors) in the niche. We further found that N-cad(+)OBs predominantly express noncanonical Wnt ligands and inhibitors of canonical Wnt signaling under homeostasis. Under stress, noncanonical Wnt signaling is attenuated and canonical Wnt signaling is enhanced in activation of HSCs. Mechanistically, noncanonical Wnt signaling mediated by Fz8 suppresses the Ca(2+)-NFAT- IFNgamma pathway, directly or indirectly through the CDC42-CK1alpha complex and also antagonizes canonical Wnt signaling in HSCs. Taken together, our findings demonstrate that noncanonical Wnt signaling maintains quiescent long-term HSCs through Fmi and Fz8 interaction in the niche. PMID- 22817898 TI - A whole-cell computational model predicts phenotype from genotype. AB - Understanding how complex phenotypes arise from individual molecules and their interactions is a primary challenge in biology that computational approaches are poised to tackle. We report a whole-cell computational model of the life cycle of the human pathogen Mycoplasma genitalium that includes all of its molecular components and their interactions. An integrative approach to modeling that combines diverse mathematics enabled the simultaneous inclusion of fundamentally different cellular processes and experimental measurements. Our whole-cell model accounts for all annotated gene functions and was validated against a broad range of data. The model provides insights into many previously unobserved cellular behaviors, including in vivo rates of protein-DNA association and an inverse relationship between the durations of DNA replication initiation and replication. In addition, experimental analysis directed by model predictions identified previously undetected kinetic parameters and biological functions. We conclude that comprehensive whole-cell models can be used to facilitate biological discovery. PMID- 22817899 TI - Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. AB - Meiotic recombination and de novo mutation are the two main contributions toward gamete genome diversity, and many questions remain about how an individual human's genome is edited by these two processes. Here, we describe a high throughput method for single-cell whole-genome analysis that was used to measure the genomic diversity in one individual's gamete genomes. A microfluidic system was used for highly parallel sample processing and to minimize nonspecific amplification. High-density genotyping results from 91 single cells were used to create a personal recombination map, which was consistent with population-wide data at low resolution but revealed significant differences from pedigree data at higher resolution. We used the data to test for meiotic drive and found evidence for gene conversion. High-throughput sequencing on 31 single cells was used to measure the frequency of large-scale genome instability, and deeper sequencing of eight single cells revealed de novo mutation rates with distinct characteristics. PMID- 22817900 TI - Systematic functional prioritization of protein posttranslational modifications. AB - Protein function is often regulated by posttranslational modifications (PTMs), and recent advances in mass spectrometry have resulted in an exponential increase in PTM identification. However, the functional significance of the vast majority of these modifications remains unknown. To address this problem, we compiled nearly 200,000 phosphorylation, acetylation, and ubiquitination sites from 11 eukaryotic species, including 2,500 newly identified ubiquitylation sites for Saccharomyces cerevisiae. We developed methods to prioritize the functional relevance of these PTMs by predicting those that likely participate in cross regulatory events, regulate domain activity, or mediate protein-protein interactions. PTM conservation within domain families identifies regulatory "hot spots" that overlap with functionally important regions, a concept that we experimentally validated on the HSP70 domain family. Finally, our analysis of the evolution of PTM regulation highlights potential routes for neutral drift in regulatory interactions and suggests that only a fraction of modification sites are likely to have a significant biological role. PMID- 22817901 TI - Functional interplay between caspase cleavage and phosphorylation sculpts the apoptotic proteome. AB - Caspase proteases are principal mediators of apoptosis, where they cleave hundreds of proteins. Phosphorylation also plays an important role in apoptosis, although the extent to which proteolytic and phosphorylation pathways crosstalk during programmed cell death remains poorly understood. Using a quantitative proteomic platform that integrates phosphorylation sites into the topographical maps of proteins, we identify a cohort of over 500 apoptosis-specific phosphorylation events and show that they are enriched on cleaved proteins and clustered around sites of caspase proteolysis. We find that caspase cleavage can expose new sites for phosphorylation, and, conversely, that phosphorylation at the +3 position of cleavage sites can directly promote substrate proteolysis by caspase-8. This study provides a global portrait of the apoptotic phosphoproteome, revealing heretofore unrecognized forms of functional crosstalk between phosphorylation and caspase proteolytic pathways that lead to enhanced rates of protein cleavage and the unveiling of new sites for phosphorylation. PMID- 22817902 TI - Snapshot: endogenous RNAi [corrected] pathways. PMID- 22817903 TI - Two-handed endoscopic-directed vestibular nerve sectioning: case series and review of the literature. AB - OBJECT: Vestibular nerve sectioning is an accepted surgical treatment option for patients with medically refractory Meniere disease. In this paper the authors introduce and evaluate a 2-handed endoscopic-directed technique for vestibular nerve section. METHODS: Eleven patients underwent a retrosigmoid craniectomy for endoscopic-directed vestibular nerve sectioning as treatment for intractable vertigo associated with Meniere disease. In all patients, identification and dissection of the cranial nerve VII/VIII complex was performed entirely under endoscopic guidance. The authors used the specially designed Frazee II neuroendoscope, consisting of a traditional endoscope lens with a microsuction attachment. RESULTS: Vestibular nerve sectioning was completed in all 11 patients. Postoperative improvement in vertiginous episodes was achieved in 10 patients (91%). Auditory function was noted to be worse postoperatively in only 1 patient (9%). The same patient also developed a House-Brackmann Grade III facial nerve palsy, which improved gradually over time. There were no further complications, including no delayed CSF leaks. CONCLUSIONS: The endoscopic directed approach represents a safe and effective method for performing vestibular nerve sectioning. Until now, the endoscope has been used primarily as an adjunct to the operating microscope in surgery at the cerebellopontine angle. In addition, previous endoscopic techniques typically require a third hand to manipulate the endoscope. With the 2-handed endoscopic-directed technique, however, the endoscope is used as the primary means of visualization, and the unique design of this endoscope allows for a bimanual procedure without the requirement of a cosurgeon. Advantages of using this technique compared with the microscope include superior brightness at close distances, greater depth of field, increased maneuverability within small regions, and an improved ability to visualize objects not in a direct line of sight. Among other things, this allows for minimally invasive openings, decreased cerebellar retraction, and better identification of nerve cleavage planes and vascular anatomy. PMID- 22817904 TI - Identification of high-risk carotid artery stenosis: motion of intraplaque contents detected using B-mode ultrasonography. AB - OBJECT: Identification of the risk of rupture and vulnerability of arterial plaque is not yet clearly understood. The aim of this study was to assess the clinical features of the motion of intraplaque contents (MIC) detected by B-mode ultrasonography. The MIC is characterized by the peculiar movement of the intraplaque contents that is not synchronized with the heartbeat; however, the movement of the carotid artery (CA) wall depends on the heartbeat. METHODS: From January 2008 to November 2010, 1798 consecutive patients with transient ischemic attacks (TIAs) or acute ischemic stroke underwent CA ultrasonography for the examination of the MIC. Patients with CA stenosis greater than 50% were followed up until they underwent carotid endarterectomy or CA angioplasty and stent placement. If neither of these procedures were used, the patients were followed up at 90 days. Chi-square and Mann-Whitney tests were performed to compare the categorical and continuous demographic data and risk factors. The effect of the MIC on the rate of recurrent cerebral ischemia was examined using Kaplan-Meier and univariate Cox regression analyses. RESULTS: One hundred and fifteen patients had CA stenosis greater than 50%. Among these 115 patients, 58 with a total of 59 CA stenoses had MIC. Twenty-four recurrent ischemic events were associated with MIC, whereas only 6 such events occurred in the absence of MIC. The MIC decreased event-free survival (log-rank test = 15.8, p < 0.001); univariate Cox analysis confirmed that MIC increased the risk of a recurrent ischemic event (HR 5.12, 95% CI 2.08-12.58; p < 0.001). CONCLUSIONS: The MIC is one of the findings of vulnerable plaques. The MIC is more useful in predicting the recurrence of TIAs or ischemic events in patients with symptomatic CA stenosis. PMID- 22817905 TI - Clinical outcomes following brachialis to anterior interosseous nerve transfers. AB - The surgical management of lower brachial plexus injuries remains a challenging problem. Although nerve transfers have improved clinical outcomes following brachial plexus injuries, the majority of work has focused on upper trunk injuries. Complete lower plexus injuries often lack suitable donors for either nerve or tendon transfers. The authors describe their experience with isolated lower trunk injuries utilizing the nerve to the brachialis to reinnervate the anterior interosseous nerve. PMID- 22817906 TI - Improvements in site-specific quality of life 6 months after endoscopic anterior skull base surgery: a prospective study. AB - OBJECT: Endoscopic skull base surgery (ESBS) is a minimal-access technique that provides an alternative to traditional approaches. Patient-reported outcomes are becoming increasingly important in measuring the success of surgical interventions. Endoscopic skull base surgery may lead to improvements in quality of life (QOL) since natural orifices are used to reach the pathology; however, sinonasal QOL may be negatively affected. The purpose of this study was to assess the impact of ESBS on both site-specific QOL, using the Anterior Skull Base Questionnaire (ASBQ), and sinonasal-related QOL, using the Sino-Nasal Outcome Test (SNOT-22). METHODS: Consecutive patients from a tertiary referral center who were undergoing ESBS were prospectively enrolled in this study. All patients completed the ASBQ and SNOT-22 preoperatively as well as at regular intervals after ESBS. RESULTS: Sixty-six patients were included in the study, and 57.6% of them had pituitary adenoma. There was no significant decline or improvement in the ASBQ-measured QOL at 3 and 6 weeks after ESBS, but there were significant improvements at 12 weeks and 6 months postoperatively (p < 0.05). Improvements were noted in all but one ASBQ subdomain at 12 weeks and 6 months postsurgery (p < 0.05). Preoperative QOL was significantly worse in patients who had undergone revision surgery and significantly improved postoperatively in patients who underwent gross-total resection (p < 0.05). Scores on the SNOT-22 worsened at 3 weeks postoperatively and returned to baseline thereafter. The presence of a nasoseptal flap or a graft-donor site did not contribute to a decreased QOL. CONCLUSIONS: Endoscopic skull base surgery is associated with an improvement in postoperative site-specific QOL as compared with the preoperative QOL. Short-term improvements are greater if gross-total resection is achieved. Sinonasal QOL transiently declines and then returns to preoperative baseline levels. Endoscopic skull base surgery is a valuable tool in the neurosurgical management of anterior skull base pathology, leading to improvements in site-specific QOL. PMID- 22817907 TI - The utility of surgical lung biopsy in immunocompromised children. AB - OBJECTIVE: To determine the utility of lung biopsy in immunocompromised pediatric patients with suspected infectious lung disease and to evaluate the risks and benefits of biopsy in the era of minimally invasive thoracic surgery. STUDY DESIGN: We reviewed charts for 50 immunocompromised patients who underwent surgical lung biopsy between January 2000 and July 2011 at a free-standing, tertiary care, urban children's hospital. The primary outcome variable was "benefit from biopsy," defined as change in therapy based on biopsy results. The secondary outcome variable was survival to discharge. The chi(2) analysis was used for categorical variables and Student t test for continuous variables. RESULTS: Biopsy provided a definitive histopathologic or microbiologic diagnosis in 25 patients (50%), the most common diagnosis being fungal infection (22%). Diagnostic and nondiagnostic biopsy results yielded benefit in 25 surviving patients (50%) for whom the biopsy results were used to tailor treatment. Taking more than one biopsy specimen did not improve diagnostic yield. Six patients (12%) had a major morbidity including reinsertion of chest tube after initial chest tube removal (3), prolonged air leak (1), and a new requirement for mechanical ventilation postoperatively (2). Two patients died postoperatively, but the mortalities were not clearly related to surgery. Underlying diagnoses included hematologic malignancy (64%), primary immunodeficiency (12%), organ transplant recipient (12%), and solid malignancy (10%). Twelve patients (24%) had undergone stem cell transplantation. CONCLUSION: Lung biopsy in immunocompromised pediatric patients alters therapy in 50% of cases, but predictably carries identifiable morbidities. This study is limited by its retrospective nature. PMID- 22817908 TI - High risk blood pressure and obesity increase the risk for left ventricular hypertrophy in African-American adolescents. AB - OBJECTIVE: To examine the relative effects of high blood pressure (HBP) and obesity on left ventricular mass (LVM) among African-American adolescents; and if metabolic or inflammatory factors contribute to LVM. STUDY DESIGN: Using a 2 * 2 design, African-American adolescents were stratified by body mass index percentile (body mass index <95th percentile = non-obese; >= 95th percentile = obese) and average blood pressure (BP) (normal BP <120/80 mm Hg; HBP >= 120/80). Glucose, insulin, insulin resistance, lipids, and inflammatory cytokines were measured. From echocardiography measures of LVM, calculated LVM index (LVMI) >= 95th percentile defined left ventricular hypertrophy (LVH). RESULTS: Data included 301 adolescents (48% female), mean age 16.2 years, 51% obese, and 29% HBP. LVMI was highest among adolescents with both obesity and HBP. The multiplicative interaction of obesity and HBP on LVH was not significant (OR = 2.35, P = .20) but the independent additive associations of obesity and HBP with log-odds of LVH were significant; obesity OR = 3.26, P < .001; HBP OR = 2.92, P < .001. Metabolic and inflammatory risk factors were associated with obesity, but had no independent association with LVMI. Compared with those with average systolic BP (SBP) <75th percentile, adolescents with SBP from the 75th percentile to 90th percentile had higher LVMI (33.2 vs 38.7 g/m(2.7), P < .001) and greater LVH (18% vs 43%, P < .001), independent of obesity. CONCLUSIONS: Prevalence of LVH is highest among African-American adolescents with average BP >= 120/80 mm Hg and obesity. There also is an independent association of LVMI with BP, beginning at the 75th SBP percentile. PMID- 22817909 TI - Acute onset of a hemorrhagic rash in an otherwise well-appearing infant. PMID- 22817910 TI - [Acute gastric volvulus: the importance of early diagnosis]. PMID- 22817911 TI - Hippocampal magnetization transfer ratio at 3T: validation of automated postprocessing and comparison of quantification metrics. AB - BACKGROUND: To investigate the reliability of a novel magnetization transfer ratio (MTR) postprocessing technique for the hippocampus using histogram analysis, and compare results to more established volumetric measurements. This study is conducted in healthy volunteers as a precursor to future applications regarding progressive neurologic diseases, such as Alzheimer's disease. METHODS: Eight healthy subjects were scanned twice with interval of 1 week using quantitative magnetic resonance imaging (MRI). Automated pixel-wise analysis was performed for the hippocampal regions of each patient. Reliability was assessed using intraclass correlation coefficients (ICCs), coefficients of variation (COVs), and instrumental standard deviation (ISD). RESULTS: Reliable metrics were 25th percentile, median, 75th percentile, peak location, and mean approach (ranges: ICC = .93-.96, COV = 2.71-3.88%, ISD .78-1.01). Histogram peak height had ICC below .7, and a COV above 10%. Volumetric measurements had (ICC = .95 .97, COV = 1.43-3.39%). CONCLUSION: Excellent scan-rescan reproducibility (ICC > .9, COV < 10%) was observed for specific MTR histogram metrics and the mean MTR approach. These results are comparable to the volumetric approach. Future studies can examine the possibility that MTR changes precede morphological changes as this study suggests that both MTR and volumetric measurements of the hippocampus can be used as reliable imaging tools. PMID- 22817914 TI - Multidrug resistance determinants from NDM-1-producing Klebsiella pneumoniae in the USA. PMID- 22817912 TI - Defining the subcellular sites of innate immune signal transduction. AB - Innate immune activation by microbial detection receptors is a complex process involving at least 100 proteins and multiple signaling pathways. Although there continues to be a need to identify additional regulators of host-microbe interactions, a larger conceptual challenge is our lack of understanding of how the known regulators interact in space and time. This review offers a framework to explain the long appreciated (but poorly understood) observation that innate immune signaling pathways are activated from multiple organelles. Using the Toll like receptors (TLRs) and the retinoic acid-inducible gene 1 protein (RIG-I)-like receptors (RLRs) as examples, I propose that the receptors do not necessarily define the sites of signaling. Rather, a structurally unrelated class of proteins called 'sorting adaptors' functions in this capacity. PMID- 22817913 TI - Association of hemoglobin concentration and mortality in critically ill patients with severe traumatic brain injury. AB - INTRODUCTION: The critical care management of traumatic brain injury focuses on preventing secondary ischemic injury. Cerebral oxygen delivery is dependent upon the cerebral perfusion pressure and the oxygen content of blood, which is principally determined by hemoglobin. Despite its importance to the cerebral oxygen delivery, the precise hemoglobin concentration to provide adequate oxygen delivery to injured neuronal tissue in TBI patients is controversial with limited evidence to provide transfusion thresholds. METHODS: We conducted a retrospective cohort study of severe TBI patients, investigating the association between mean 7 day hemoglobin concentration and hospital mortality. Demographic, physiologic, intensive care interventions, clinical outcomes and daily hemoglobin concentrations were recorded for all patients. Patients were all cared for at a tertiary, level 1 trauma center in a mixed medical and surgical intensive unit. Patients were divided into quartiles based on their mean 7-day hemoglobin concentration: < 90 g/L, 90 - 99 g/L, 100 - 109 g/L and > 110 g/L. Multivariable log-binomial regression was used to model the association between mean daily hemoglobin concentration and hospital mortality. RESULTS: Two hundred seventy three patients with traumatic brain injury were identified and 169 were included in the analysis based on inclusion/exclusion criteria. Of these, 77% of the patients were male, with a mean age of 38 (SD 17) years and a median best GCS of 6 (IQR 5 - 7). One hundred fifteen patients (68%) received a red blood cell (RBC) transfusion. In RBCs administered in the ICU, the median pre-transfusion hemoglobin was 79 g/L (IQR 73 - 85). Thirty-seven patients (22%) died in hospital. Multivariable analysis revealed that mean 7-day hemoglobin concentration < 90 g/L was independently associated with an increased risk of hospital mortality (RR 3.1, 95% CI 1.5 - 6.3, p = 0.03). Other variables associated with increased mortality on multivariable regression were insertion of external ventricular drain, age and decreased GCS. Red blood cell transfusion was not associated with mortality following multivariable adjustment. CONCLUSIONS: A mean 7-day hemoglobin concentration of < 90g/L is associated with increased hospital mortality in patients with severe traumatic brain injury. PMID- 22817915 TI - Stearidonic acid acts in synergism with amphotericin B in inhibiting Candida albicans and Candida dubliniensis biofilms in vitro. PMID- 22817916 TI - Escherichia coli ST502 and Klebsiella pneumoniae ST11 sharing an IncW plasmid harbouring the bla(KPC-2) gene in an Intensive Care Unit patient. PMID- 22817917 TI - Class 1 integron gene cassettes in multidrug-resistant Gram-negative bacteria in southern China. AB - Non-duplicate multidrug-resistant Gram-negative bacteria (n=1447) isolated from January 2008 to December 2009 were investigated for the presence of integrons as well as characterisation of gene cassettes. Among 825 strains carrying the class 1 integrase gene intI1, 461 gene cassette-positive isolates were found. Thirty eight distinct gene cassette arrays were identified by restriction fragment length polymorphism (RFLP) and DNA sequencing analyses. In addition, several novel gene cassette arrays detected in this study were reported for the first time in some species: one in Escherichia coli, six in Klebsiella pneumoniae, six in Enterobacter cloacae, three in Enterobacter aerogenes, one in Proteus mirabilis, one in Acinetobacter spp., one in Stenotrophomonas maltophilia and one in Pseudomonas putida. Among them, three cassettes, including HAD-like, DeltaMFS 1 and qnrVC-like genes, were originally detected in integrons. PMID- 22817918 TI - Multidrug-resistant Corynebacterium striatum endocarditis successfully treated with daptomycin. PMID- 22817919 TI - Seventeenth International Conference on Flow Injection Analysis. PMID- 22817920 TI - Flow-injection analysis as a tool for determination of pharmaceutical residues in aqueous environment. AB - Numerous reported applications of flow-injection analytical methods in pharmaceutical analysis concern quality control of pharmaceutical preparations, investigation of dissolution of particular formulations and process control of production of pharmaceuticals. In recent decades an important environmental problem is increasing level of pharmaceutical residues in aqueous environment. The analytical determination of those residual compounds requires of the use a very selective method of a very low limit of detection. Appropriate selection of extraction and preconcentration methods for on-line sample processing and suitable detection allows the development of flow-injection analysis methods for such analyses. Especially satisfactory for this purpose is the application of a measuring system combining flow-injection systems for on-line sample processing with liquid chromatography. PMID- 22817921 TI - Analytical applications of emulsions and microemulsions. AB - Dispersion systems like emulsions and microemulsions are able to solubilize both polar and non-polar substances due to the special arrangement of the oil and aqueous phases. The main advantages of using emulsions or microemulsions in analytical chemistry are that they do not require the previous destruction of the sample matrix or the use of organic solvents as diluents, and behave similarly to aqueous solutions, frequently allowing the use of aqueous standard solutions for calibration. However, it appears that there are many contradictory concepts and misunderstandings often related to terms definition when referring to such systems. The main aim of this review is to outline the differences between these two aggregates and to give an overview of the most recent advances on their analytical applications with emphasis on the potentiality of the on-line emulsification processes. PMID- 22817922 TI - On-line cleavage of disulfide bonds by soluble and immobilized tris-(2 carboxyethyl)phosphine using sequential injection analysis. AB - Reduction of disulfide bonds is - in many cases - a critical pretreatment step for the determination of thiols in real samples. This study reports the first systematic investigation of the potentials of the on-line reduction of disulfide bonds under flow conditions in a sequential injection setup. One of the most promising reducing agents, tris-(2-carboxyethyl)phosphine (TCEP) was selected for this purpose while the Ellman's disulfide (DTNB) was used as model compound. The study involved the investigation of several parameters that affected the kinetics and efficiency of the reaction, including stopped-flow experiments. Both soluble and immobilized TCEP on agarose beads were examined. The results confirmed that both forms of TCEP can be used as an advantageous on-line reducing reagent for disulfide bonds under flow conditions. PMID- 22817924 TI - Critical approach to flow injection gradient titration as a calibration method. AB - An attempt was made to demonstrate that flow injection gradient titration should not be considered as classical titration but rather as the indirect calibration method. This was shown experimentally by exploiting indirect spectrophotometric determination of chlorite ions in the presence of iron(II) in an acid environment with measurement of absorbance for the coloured Fe(II)/o-phenanthroline complex at 512nm. In such an analytical system, the peaks of a cut-off profile were obtained with two characteristic points corresponding to equivalent amounts of analyte and reagent, and peak widths were used as the analytical signal. The only difference between the approach presented and the classical flow injection titration procedure was not fundamental but of a technical nature and consisted in the fact that a sample loop of relatively great volume instead of a mixing chamber was installed into the flow injection system. The analytical performance of the developed calibration procedure is also presented and discussed. PMID- 22817923 TI - beta-Galactosidase activity in mixed micelles of imidazolium ionic liquids and sodium dodecylsulfate: A sequential injection kinetic study. AB - An automated methodology for the kinetic study of beta-galactosidase activity in sodium dodecylsulfate (SDS)/ionic liquid (IL) mixed micelles was developed. The main objective of the work was the evaluation of mixed micelles as reaction media for the industrial synthesis of glyco-oligossacharides. Enzyme activity was evaluated by means of a model reaction with the fluorescent substrate 4 methylumbelliferyl-alpha-d-galactopyranoside (MUG). The assay was implemented in a sequential injection analysis (SIA) system and enzyme activity was studied in SDS/bmim [BF(4)] and SDS/hmim [Cl] mixed micelles with variable concentrations of both components. In order to perform a critical evaluation of the obtained results, CMC and average micellar size of SDS/hmim [Cl] mixed micelles were evaluated by fluorescence and dynamic light scattering, respectively. In the micelle characterization assays it was observed that the CMC of the mixed micelles increased with hmim [Cl] concentration up to 1molL(-1). In the presence of higher IL concentrations there were no evidences of micelle formation. Regarding micellar size, it was maximum for an IL concentration of 0.09molL(-1). The kinetic assays evidenced that SDS/bmim [BF(4)] and SDS/hmim [Cl] mixed micellar systems can led to an increase of enzyme activity. This increase is dependent on the variation of the average micellar size that occurs with the increase of IL concentration up to 0.09molL(-1). It was also noticed that the most promising systems are those incorporating SDS and IL in concentrations under 50mmolL(-1) and 0.5molL(-1), respectively(.) These results evidenced that the studied ILs can modify the physico-chemical properties of the surfactant solution in a favourable way regarding beta-galactosidase activity being an important achievement for the future implementation of industrial processes catalyzed by this enzyme, mainly the synthesis of glyco-oligossacharides. Indeed, surfactant/IL mixed micelles proved to be an interesting alternative to conventional organic solvents in this field enabling the implementation of the processes in a relatively hydrophobic media with enhanced enzyme activity. PMID- 22817925 TI - Theoretical and experimental examination of recovery in the context of trueness of analytical results. AB - In the report of the International Union of Pure and Applied Chemistry (IUPAC) estimation of analyte recovery (RV) is recommended as one of the ways for assessment of trueness of analytical results. RV is usually estimated with the use of samples spiked with known amount of analyte. However, neither the IUPAC guidelines, nor the available literature take into consideration various effects of different nature that may occur along the sample preparation steps prior and during measurements. Hence, in this work the attempt was made to classify these effects and to evaluate their influence on the analyte recovery. For this purpose a mathematical model has been developed, enabling to judge usefulness of the recovery test in objective estimation of trueness, and the results predicted by the model were checked experimentally. Trueness was estimated on the basis of analytical results obtained by both interpolative and extrapolative ways. The experiments were performed with the use of a dedicated flow injection system coupled to UV/VIS spectrometer and covered determination of chromium(III) as chromium(III) nitrate at a wavelength of 590nm. PMID- 22817926 TI - Simultaneous determination of vanadium(IV) and vanadium(V) by flow injection analysis using kinetic spectrophotometry with Xylenol Orange. AB - A flow injection method of analysis has been developed for the simultaneous determination of V(IV) and V(V) using the difference in the rate of complex formation between vanadium in two different oxidation states and Xylenol Orange in acidic media. The proposed method used a spectrophotometric detector equipped with two flow cells aligned with the same optical path to yield two successive peaks per each sample injection. V(IV) and V(V) were determined by solving simultaneous equations in two unknowns, the concentrations of V(IV) and V(V), obtained from measurements of the two peak heights. The detection limit calculated as 3sigma of noise signals was 0.01MUg/mL for both V(IV) and V(V). The relative standard deviations for V(IV) and V(V) at the 1MUg/mL level were 1.6 and 2.4%, respectively. The sample throughput was found to be about 19h(-1). The proposed method was successfully applied to the simultaneous determination of V(IV) and V(V) in synthetic scrubbing solutions used in desulphurization with reasonable accuracy. PMID- 22817927 TI - Simultaneous injection effective mixing flow analysis of urinary albumin using dye-binding reaction. AB - A new four-channel simultaneous injection effective mixing flow analysis (SIEMA) system has been assembled for the determination of urinary albumin. The SIEMA system consisted of a syringe pump, two 5-way cross connectors, four holding coils, five 3-way solenoid valves, a 50-cm long mixing coil and a spectrophotometer. Tetrabromophenol blue anion (TBPB) in Triton X-100 micelle reacted with albumin at pH 3.2 to form a blue ion complex with a lambda(max) 625nm. TBPB, Triton X-100, acetate buffer and albumin standard solutions were aspirated into four individual holding coils by a syringe pump and then the aspirated zones were simultaneously pushed in the reverse direction to the detector flow cell. Baseline drift, due to adsorption of TBPB-albumin complex on the wall of the hydrophobic PTFE tubing, was minimized by aspiration of Triton X 100 and acetate buffer solutions between samples. The calibration graph was linear in the range of 10-50MUg/mL and the detection limit for albumin (3sigma) was 0.53MUg/mL. The RSD (n=11) at 30MUg/mL was 1.35%. The sample throughput was 37/h. With a 10-fold dilution, interference from urine matrix was removed. The proposed method has advantages in terms of simple automation operation and short analysis time. PMID- 22817928 TI - Evaluation of acetylcysteine promoting effect on CdTe nanocrystals photoluminescence by using a multipumping flow system. AB - A simple and straightforward quantification method integrated in a fully automated multi-pumping flow system (MPFS) using water-soluble mercaptopropionic acid (MPA)-capped CdTe quantum dots (QDs) was implemented for the fluorescence quantification of N-acetyl-L-cysteine (NAC) in pharmaceutical formulations. The developed approach was based on NAC ability to establish surface interactions that result in enhanced nanocrystals fluorescence intensity, proportional to analyte concentration. Size and concentration of QDs, ageing, composition, concentration and pH of the buffer solution revealed to have a noticeable effect on the enhancing efficiency affecting sensitivity and linear working range of the methodology. Under the optimal conditions, a linear working range was obtained for NAC concentrations ranging from 50 to 750MUmolL(-1) (r=0.9978), with good precision (r.s.d.<1.6%; n=5) and a sampling rate of about 75hr(-1). The detection limit (LOD) was approximately 1.6MUmolL(-1). The method was applied to pharmaceutical preparations and the results revealed good agreement with those obtained by the reference procedure with relative deviations between -2.1 and +4.2%. Advantages of the new procedure include speed, low consumption of reagents, minor waste generation, requiring also much less work than the recommended HPLC method. The mechanism for luminescence enhancement of CdTe QDs is discussed. FT-IR spectra revealed that sulphydryl groups of NAC have a high affinity with the nanocrystals. PMID- 22817929 TI - Stepwise injection spectrophotometric determination of epinephrine. AB - Simple, rapid and fully automated methods for the manual and automated spectrophotometric determination of epinephrine have been developed by using schemes of stepwise injection (SWIA) and sequential injection analysis (SIA) implemented in the same manifold. The determination is based on the formation of reduced form of 18-molybdodiphosphate heteropoly anion by its reaction with epinephrine. Using of the reaction vessel in the general SWIA configuration instead of a holding and reaction coil in the SIA manifold provides several essential advantages, including higher sensitivity and lower reagent consumption. The linear dependence of the analytical signal on the epinephrine concentration was preserved over the range of 1.5-30, 3.0-30, and 1.5-25MUmolL(-1) by using of SWIA, SIA and spectrophotometric analysis, respectively. The relative standard deviation for the SWIA determination of 10MUmolL(-1) epinephrine was 1.8% (n=10). PMID- 22817930 TI - Application of direct-injection detector integrated with the multi-pumping flow system to photometric stop-flow determination of total iron. AB - A novel direct-injection detector (DID) integrated with multi-pumping flow system (MPFS) for the photometric determination of iron is proposed. Paired emitter detector diodes have been used as a photometric detection system. The sample and reagent were injected using appropriate solenoid pulse micro-pumps directly into the detection chamber where effective mixing occured. The use of proposed stop flow detector considerably simplified the analytical procedure. The potassium thiocyanate has been chosen as a chromogenic reagent for photometric Fe(III) detection. The total volume of reagent and sample/standard solutions involved in the detection process was adjusted to the volume of the reaction-detection chamber. Calibration graph was found to be linear in the range up to 10mgL(-1). The detection limit (3s(b)/S) was 0.15mgL(-1). The repeatability (R.S.D.), calculated from 10 analyses of sample containing 5mgL(-1) Fe(III), was 1.5% and the sample throughput 180 determinations per hour. The consumption of sample and reagent was 20MUL each with the waste generation at the level of 0.24mL. The applicability of the proposed method to the determination of total iron in groundwater samples has been proved. The analytical parameters are compared to those obtained exploiting the MPFS system with typical configuration containing a confluence point and reaction coil. PMID- 22817931 TI - On-line preconcentration and determination of lead and cadmium by sequential injection/anodic stripping voltammetry. AB - The highly sensitive determination of lead (Pb(II)) and cadmium (Cd(II)) ions, with a limit of detection of 0.01MUgL(-1) for Pb(II) and Cd(II), by on-line preconcentration and anodic stripping voltammetry (ASV) controlled by a sequential injection analysis (SIA) system is reported here. The SIA system consisted of a syringe pump, an 8-port selection valve and a 6-port switching valve and was incorporated with a bismuth coated screen-printed carbon nanotube electrode (Bi-SPCNTE). The preconcentration of metal ions was performed by solid phase extraction using an Analig TE-05 chelating resin mini-column on a switching valve. The metal ions collected were then eluted from the resin with 1M hydrochloric acid (HCl), deposited on the electrode surface at -1.3V vs. Ag/AgCl and then measured with ASV. The pH of the sample, eluent volume, flow rate, concentration of the bismuth plating solution and the square-wave voltammetric parameters were optimized. Under the optimum conditions, an enrichment factor of 11.9-fold and 6.6-fold for Pb(II) and Cd(II) ions, respectively, was attained. Detection of Pb(II) and Cd(II) had two different linear ranges (0.5-15MUgL(-1) and 15-70MUgL(-1)). PMID- 22817932 TI - Improvement of copper FAAS determination conditions via preconcentration procedure with the use of salicylaldoxime complex trapped in polymer matrix. AB - The paper presents application of a new resin dedicated to copper(II) flow injection on-line preconcentration prior its flame atomic absorption spectrometric (FAAS) determination. The new sorbent, obtained by suspension polymerization technique, was styrene-divinylbenzene copolymer modified with 5 dodecylsalicylaldoxime-copper(II) complex. In flow mode leaching of initially imprinted Cu(II) ions from polymer beads was effective with 1% (v/v) nitric acid, however for elution of ions retained on the sorbent during the loading process sufficient efficiency was obtained for 0.5% (v/v) nitric acid. The most effective copper(II) sorption was observed within sample pH ca. 6.3 at flow rate 7.5mLmin( 1). Furthermore, preconcentration studies of Cu(II) ions realized in the presence of popular foreign ions like Cd(II), Pb(II), Zn(II), Ni(II), Mn(II), Co(II) did not reveal significant interference. The expected effect of Cu(II)-imprinting was confirmed by higher tolerance level for interferents ions concentration for the new sorbent than for the control polymer. It was found that alkaline metals ions and humic acid had the most relevant influence on copper(II) uptake. Accuracy of the evaluated method was assessed for analysis of water samples (tap and mineral water, river water, artesian water) and certified water reference materials compare them to results obtained by inductively plasma mass spectrometry. The satisfactory relative error values obtained with use of standard addition calibration method, confirms the feasibility of this method for Cu(II) determination in water samples. Application of 120s sorption time enabled to obtain 74-fold enrichment factor and limit of detection (3sigma) equal to 0.4MUgL(-1). PMID- 22817933 TI - Application of multiwall carbon nanotubes impregnated with 5 dodecylsalicylaldoxime for on-line copper preconcentration and determination in water samples by flame atomic absorption spectrometry. AB - The paper presents application of multiwall carbon nanotubes (MWCNTs) modified with 5-dodecylsalicylaldoxime to copper(II) flow-injection on-line preconcentration and flame atomic absorption spectrometric (FAAS) determination. Two new sorbents were obtained by impregnation of MWCNTs with Cu(II)-LIX 622((r)) complex, however in the first case modification was preceded by carbon wall activation via oxidization (Cu-LIX-CNT-A sorbent), and in the second one no surface activation was performed (Cu-LIX-CNT sorbent). It was found that effective leaching of initially introduced copper and Cu(II) retained in preconcentration process could be realized with the use 7% and 5% (v/v) nitric acid, for particular sorbents. Testing the influence of loading solution pH and rate of loading on sorption it was found out that optimal range of loading solution pH was about 4.5-6.3 for activated and 6.15-6.25 for non-activated CNT. Investigation of sorption kinetics showed that the process can be described by pseudo-second order reaction model. Sorption equilibrium conditions (90% sorption) for LIX-CNT-A and LIX-CNT were obtained after 8-15min, respectively and maximum sorption capacity for the new sorbents amounted to 18.1mgg(-1) and 31.6mgg(-1), respectively. For the examined sorbents enrichment factors increased with extension of loading time up to 180s: linearly for activated and non linearly for non-activated MWCNTs. Influence of potential interferents such as Cd(II), Zn(II), Fe(III), Mg(II) and Ca(II) ions on copper(II) sorption on the new CNT materials was examined individually and with the use of 2(5-2) factorial design. The study revealed significant interference from iron, magnesium and calcium ions at relatively high concentrations. Applicability of the proposed sorbents was tested for Cu(II) determination in various kinds of water samples and the results were compared with those obtained with the use of ICP MS as a reference technique. Copper(II) determination in two certified reference materials: waste water (EU-H-3) and ground (ES-H-2) water was performed in order to assess trueness of the evaluated preconcentration procedures. Satisfactory values of relative errors were obtained for both procedures. PMID- 22817934 TI - Automated total and radioactive strontium separation and preconcentration in samples of environmental interest exploiting a lab-on-valve system. AB - A novel lab-on-valve system has been developed for strontium determination in environmental samples. Miniaturized lab-on-valve system potentially offers facilities to allow any kind of chemical and physical processes, including fluidic and microcarrier bead control, homogenous reaction and liquid-solid interaction. A rapid, inexpensive and fully automated method for the separation and preconcentration of total and radioactive strontium, using a solid phase extraction material (Sr-Resin), has been developed. Total strontium concentrations are determined by ICP-OES and (90)Sr activities by a low background proportional counter. The method has been successfully applied to different water samples of environmental interest. The proposed system offers minimization of sample handling, drastic reduction of reagent volume, improvement of the reproducibility and sample throughput and attains a significant decrease of both time and cost per analysis. The LLD of the total Sr reached is 1.8ng and the minimum detectable activity for (90)Sr is 0.008Bq. The repeatability of the separation procedure is 1.2% (n=10). PMID- 22817935 TI - Determination of total protein content in white wines by solid phase spectrometry in a SI-LOV system. AB - Although present at low concentration in wine samples, proteins, have considerable technological importance, due to their capability of haze formation. The present work presents a methodology for the quantification of total protein in white wine in a sequential injection lab-on-valve system, exploiting the bead injection concept for solid phase extraction with spectrophotometric detection. The method is based on the retention of the proteins in the solid support, NTA (nitrilotriacetic acid) superflow beads, charged by Cu(2+). The change in the absorbance is monitored at 500nm at the surface of the beads after addition of the Folin-Ciocalteu's reagent (FCr). The developed method presented a sample consumption of 400MUL per assay and a consumption of FCr and Cu(2+) solution of 25MUL and 100MUL per assay, respectively. It was possible to achieve a linear range up to 0.30g/L with a limit of detection and quantification of 0.03 and 0.10g/L, respectively. The proposed method was successfully applied to white wine samples. PMID- 22817936 TI - Application of DV-SIA manifold for determination of thiocyanate ions in human saliva samples. AB - An automated, simple and inexpensive double-valve sequential injection analysis (DV-SIA) spectrophotometic method with online liquid-liquid extraction, for the determination of thiocyanate has been developed. The method has been based on the formation of an ion associate between thiocyanate and Astra Phloxine in acidic medium, and the subsequent extraction with amylacetate. The absorbance of the extracted ion associate was measured at 550nm. The calibration function was linear in the range 0.05-0.50mmolL(-1) and the regression equation was A=(1.887+/ 0.053) [SCN(-)mmolL(-1)]+(0.037+/-0.014) with a correlation coefficient of 0.995. The precision of the proposed method was evaluated by the relative standard deviation (RSD) values at two concentration levels: 0.20 and 0.50mmolL(-1). The obtained results were 1.0 and 2.8%, respectively, for the intra-day precision, and 4.2 and 3.8%, respectively for the inter-day precision. The calculated detection limit was 0.02mmolL(-1). The developed method has been successfully applied for determining thiocyanate ions in human saliva samples. PMID- 22817937 TI - Towards the development of a miniaturized fiberless optofluidic biosensor for glucose. AB - A miniaturized fiberless optical sensor integrated in an automated sequential injection (SI) manifold for mesofluidic handling of sample, conditioning and regeneration solutions is herein proposed for monitoring glucose (as a model analyte) in human serum. The optofluidic biosensor capitalizes on the co immobilization of Prussian Blue (PB) and glucose oxidase (GOx) on a polyester film working concomitantly as a chemo- and bioreceptor. The oxidation of beta glucose at the receptor surface by GOx yields hydrogen peroxide whereby reoxidizing the reduced form of PB (the so-called Prussian White) so as to generate a deep blue color. The change in the optical properties of the film was continuously monitored by red paired emitter-detector diodes (PEDDs). A full factorial design followed by a Doehlert matrix-based response surface was exploited for multivariate optimization of the optofluidic PB-GOx-PEDD biosensor. The most significant variables influencing sensor's response were the current powering the light emitting diode (LED) emitter and the surface concentration of GOx. The optosensor was proven rugged as the response varies by merely 5% from the optimal value whenever the GOx concentration increases or decreases by 17% or the current powering the LED by 18.5%. Under the optimized physicochemical conditions, the limits of detection and quantification at the 3s(blank) and 10s(blank) levels, respectively, were estimated to be 23.8MUmolL(-1) and 79.3MUmolL(-1), respectively, with a dynamic working range spanning from 0.1 to 2.5mmolL(-1) of glucose. The trueness of the biosensor measurements was assessed with certified pathological and physiological human serum materials and compared against the spectrophotometric Trinder method. The devised enzymatic biosensor is affordable (less than 0.2?), sturdy, and versatile inasmuch as the chemical composition of the receptor and pair of LEDs might be customized at will. PMID- 22817938 TI - Low-cost optical detectors and flow systems for protein determination. AB - Two miniature, fibreless, compact and highly integrated flow-through optoelectronic detectors dedicated for photometric and fluorimetric determination of proteins have been developed. Both detectors operating according to paired emitter-detector-diode methodology are constructed only of light emitting diodes and therefore their total cost is extremely low. The photometric detector is dedicated for protein determination according to Bradford method based on detection of protein adduct with Coomassie Brilliant Blue. The fluorimetric detector allows determination of proteins after reaction with fluorescamine. Both developed detectors have been incorporated into economic flow systems constructed of microsolenoid valves and pumps. The resulting multicommutated/multipumping flow analysis systems enable detection of albumins and globulins at ppm levels, thus they are useful for protein determination in diluted samples of physiological fluids. PMID- 22817939 TI - Serum alkaline phosphatase assay with paired emitter detector diode. AB - A simple multicommutated flow system based on optoelectronic detector, three valves and peristaltic pump only has been developed for photometric determination of alkaline phosphatase activity in human serum. A miniaturized, compact flow through detector dedicated to selective photometric detection of product formed in the course of the enzyme assay has been constructed using two paired light emitting diodes. The proposed analytical procedure based on kinetic methodology of enzyme activity detection and stopped-flow methodology of two-point measurements eliminates interferences caused by intense color of real samples and impurities present in commercial reagents. After optimization the system allows reproducible, mechanized analysis of human serum in relatively short time (8-9 samples per hour). Volume of serum required for single determination is 0.05mL only. The system validated with real clinical samples is useful for determination of enzyme activity in human serum at physiological and pathological levels. PMID- 22817940 TI - Performance of an organic photodiode as an optical detector and its application to fluorometric flow-immunoassay for IgA. AB - The performance of an organic thin film photodiode (OPD), fabricated from a hetero-junction comprised of two layers of C(60) and a phthalocyanine-Cu(II) complex was evaluated by detecting the chemiluminescence generated from the reaction of luminol with horseradish peroxidase in the presence of H(2)O(2), and the fluorescence from resorufin, as an optical detector. The photocurrent of the OPD was linear with respect to the power of light from a commercial LED. The sensitivity of the OPD was sufficient for detecting chemiluminescence with a power 0.1MUW/cm(2). The OPD was successfully used in a flow-immunoassay for IgA, a marker of human stress, in which a sandwich immunoassay was carried out on the microchip and the fluorescence from resorufin, produced by the enzymatic reaction, was detected. The detection limits for resorufin and IgA were 5.0MUM and 16ng/mL, respectively. The photosensitivity of the OPD remained relatively constant for a minimum of one year. PMID- 22817941 TI - Cadmium determination in natural water samples with an automatic multisyringe flow injection system coupled to a flow-through screen printed electrode. AB - Heavy metals, as cadmium, attract a rising attention in environmental studies due to their increasing release by human activities and acute toxicity. In situ analytical methods are needed to minimize current uncertainties caused by the transport and conservation of samples. Here, we present the completely automatic determination of Cd in natural waters using a newly developed screen printed electrode sensor (SPE), inserted in a homemade purpose-built flow cell coupled to a Multi-Syringe Flow Injection Analysis system (MSFIA). The working electrode of SPEs was constituted by a carbon film modified with Nafion. Cd was plated on an in situ bismuth film and determined using Square Wave Anodic Stripping Voltammetry. Different chemical conditions of deposition and stripping were studied. A sample/acetic buffer mixture was found to be a well suited medium to form the Bi film and perform the analysis. Cd was quantified via calibration by on line standard additions. The limit of detection was found to be 0.79MUgL(-1), well below the limit stipulated by the European directive (5MUgL(-1)). Good sample throughput (14h(-1)) and low consumption of reagent and sample (1.3mL) were also obtained in line with previous works in Cd flow analysis. PMID- 22817942 TI - Tyrosinase biosensor for benzoic acid inhibition-based determination with the use of a flow-batch monosegmented sequential injection system. AB - Amperometric tyrosinase based biosensor for benzoic acid determination with the use of a flow-batch monosegmented sequential injection system is proposed. The functioning of the biosensor is based on the inhibition effect of benzoic acid on the biocatalytic activity of tyrosinase, polyphenol oxidase. In the biosensor, tyrosinase is entrapped in titania gel modified with multiwalled carbon nanotubes (MWCNT) and Nafion. The procedure of optimization of experimental conditions affecting the biosensor response, as well as its analytical characteristics and results of the approach verification using synthetic samples and a reference material are presented. The developed biosensor exhibits linear range up to 2.46MUM, good sensitivity toward benzoic acid (1.06MUAMUM(-1)) and low detection limit (0.03MUM). The approach has been applied to benzoic acid determination in a real beverage sample giving the result consistent with that obtained using the HPLC method. PMID- 22817943 TI - Potentiometric determination of tolterodine in batch and flow injection conditions. AB - Two new ion-selective electrodes of the plastic membrane type for the determination of Tolterodine (Tol) were prepared. These electrodes depend on the incorporation of the ion-exchangers of the above mentioned drug with phosphotungestic acid (PTA) or Silicotungestic acid (STA) in a PVC matrix. A comparative study is made between the performance characteristics of electrodes containing ion-exchanger in batch and FIA conditions. The usable concentration range of the electrodes was found to be (1.0*10(-5)-1.0*10(-2) and 5.0*10(-5) 1.0*10(-2)M) in batch and FIA conditions, respectively. The electrodes have nearly the same usable concentration, pH range and exhibited high selectivity toward Tol in the presence of many inorganic cations and can be used in biological fluids such as urine and plasma. The dissolution profile of the investigated drug as well as its assay in pure and pharmaceutical preparations was performed, and the results were relatively accurate and precise as indicated by the recovery values and coefficients of variation. PMID- 22817944 TI - Flow injection catalase activity measurement based on gold nanoparticles/carbon nanotubes modified glassy carbon electrode. AB - Amperometric flow injection method of hydrogen peroxide analysis was developed based on catalase enzyme (CAT) immobilization on a glassy carbon electrode (GC) modified with electrochemically deposited gold nanoparticles on a multiwalled carbon nanotubes/chitosan film. The resulting biosensor was applied to detect hydrogen peroxide with a linear response range 1.0*10(-7)-2.5*10(-3)M with a correlation coefficient 0.998 and response time less than 10s. The optimum conditions of film deposition such as potential applied, deposition time and pH were tested and the flow injection conditions were optimized to be: flow rate of 3ml/min, sample volume 75MUl and saline phosphate buffer of pH 6.89. Catalase enzyme activity was successfully determined in liver homogenate samples of rats, raised under controlled dietary plan, using a flow injection analysis system involving the developed biosensor simultaneously with spectrophotometric detection, which is the common method of enzymatic assay. PMID- 22817945 TI - A dual-electrode flow sensor fabricated using track-etched microporous membranes. AB - A new dual-electrode flow sensor has been fabricated by piling the microporous membrane electrodes which have 7-10MUm thickness. The electrode was prepared by sputtering of platinum onto both sides of the membrane filter which contain a smooth flat surface as well as cylindrical pores with uniform diameters. The electrolysis is performed when the sample solution flows through the membrane electrode, and a generated analyte on the first working electrode is instantaneously transported to the surface of second working electrode which is located at the downstream of the first one. In this case, the sample solution surely flows through the pores of the membrane filters. As the result, highly efficient electrolysis was achieved at each electrode, and the collection efficiency values as high as 100% were obtained in the wide range of flow rate. Good responses to the injections of sample solutions were also confirmed in the FIA system. PMID- 22817946 TI - Indirect method for spectrophotometric determination of ascorbic acid in pharmaceutical preparations with 2,4,6-tripyridyl-s-triazine by flow-injection analysis. AB - A flow-injection indirect spectrophotometric method for the determination of ascorbic acid (AA) in pharmaceutical preparations is proposed. The method is based on the reduction of iron(III) to iron(II) by the AA, and by the subsequent reaction of the produced iron(II) with 2,4,6-tripyridyl-s-triazine (TPTZ) in buffered medium (pH=3.6) to form a coloured complex (lambda(max)=593nm). The three-line manifold with one reaction coil was used. The linear range of the method is from 0.08 to 10MUM of ascorbic acid, with the detection limit 24nM of AA. The proposed method is simple, rapid (sampling rate of 180 samples per hour), sensitive and reproducible (RSD 0.8%, n=100). The proposed method is very selective, because only the reducing substances with standard (formal) potentials lower than 0.6V would have the thermodynamic predisposition to interfere in the proposed method. Tested reducing substances (thiol compounds) did not give serious errors when present at the same concentrations as the ascorbic acid. The proposed method can be applied for the determination of AA in pharmaceutical preparations, down to picomolar quantity. PMID- 22817947 TI - Flow injection determination of hydrogen peroxide using catalytic effect of cobalt(II) ion on a dye formation reaction. AB - A novel flow injection photometric method was developed for the determination of hydrogen peroxide in rainwater. This method is based on a cobalt(II)-catalyzed oxidative coupling of 3-methyl-2-benzothiazolinone hydrazone (MBTH) with N-ethyl N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline (DAOS) as a modified Trinder's reagent to produce intensely colored dye (lambda(max)=530nm) in the presence of hydrogen peroxide at pH 8.4. In this method, 1,2-dihydroxy-3,5-benzenedisulfonic acid (Tiron) acted as an activator for the cobalt(II)-catalyzed reaction and effectively increased the peak height for hydrogen peroxide. The linear calibration graphs were obtained in the hydrogen peroxide concentration range 5*10(-8) to 2.2*10(-6)mol dm(-3) at a sampling rate of 20h(-1). The relative standard deviations for ten determinations of 2.2*10(-6) and 2*10(-7)mol dm(-3) hydrogen peroxide were 1.1% and 3.7%, respectively. The proposed method was successfully applied to the determination of hydrogen peroxide in rainwater samples and the analytical results agreed fairly well with the results obtained by different two reference methods; peroxidase method and hydrogen peroxide electrode method. PMID- 22817948 TI - A non-extractive sequential injection method for determination of molybdenum. AB - A non-extractive sequential injection spectrophotometric method for the determination of molybdenum has been developed. The method is based on the reaction between the thiocyanate complex of molybdenum and the polymethine dye (2 [2-(4-dipropylamino-phenyl)-vinyl]-1,3,3-trimethyl-3H-indolium chloride) in a hydrochloric acid medium. The calibration plot in the SIA system was linear from 0.080mgL(-1) to 1.92mgL(-1) of Mo; LOD was 0.021mgL(-1). The method was applied for the determination of molybdenum in spiked drinking water and mineral water. PMID- 22817949 TI - Fluorimetric determination of thiabendazole residues in mushrooms using sequential injection analysis. AB - Thiabendazole is a benzimidazole fungicide of general use that is specifically used to control mushroom diseases, mainly cobweb diseases, which is caused by members of the genus Cladobotryum. Although this compound is legislated and its maximum residue limit established at 60mgkg(-1) by Codex Alimentarius, there is almost a complete absence of analytical methods available for its determination in mushrooms. Here, we propose an automated method, using Sequential Injection Analysis with fluorescence detection (lambda(exc)/lambda(em)=305/345nm) for the determination of thiabendazole in mushrooms. We have developed a flow-through optosensor using C(18) silica gel as solid support placed in the flow-cell where the determination is performed. This method presents a detection limit of 0.5mgkg(-1), and recovery experiments have been carried out in different kinds of mushrooms at levels below the legislated maximum residue limit, demonstrating that the proposed analytical method fulfils the requirements for its applications in quality control of mushrooms. PMID- 22817950 TI - Analysis of Bisphenol A in milk by using a multicommuted fluorimetric sensor. AB - Bisphenol A (BPA) is a polyphenol widely used in industry as an intermediate in the production of polycarbonate plastics and epoxy resins, which are applied to produce plastic food containers, inner surface coating of food and beverage cans. Hence, BPA can migrate from these containers and cans with epoxy coating into foods. It is dangerous taking into account that BPA is considered as a potential endocrine disruptor, which mimics the action of the hormone estrogen. The method here proposed for the determination of BPA involves the implementation of solid phase spectroscopy (SPS) in an automatic flow system. With this purpose, the measurement of the native fluorescence of BPA, retained on C(18) silica gel together with the implementation of multicommutation have been employed for its determination in different types of milk. The analytical measurements were made at 271/305nm (lambda(ex)/lambda(em)) obtaining a detection limit (LOD) of 0.06ngmL(-1). The pre-cleaning procedure and the posterior extraction with C(18) applied to the samples allowed the removal of proteins and the extraction of BPA from the matrix, respectively. The method showed an RSD lower than 6.0% (n=10). BPA was determined in powdered milk, infant formula and pure liquid milk samples, being found in five samples at levels lower than the maximum residue limit (MRL) established by the European Union. In addition, a recovery study has been carried out where values close to 100% were observed in all cases, so demonstrating that the proposed analytical method fulfills the requirements for its application in quality control analyses. PMID- 22817951 TI - Chemiluminometric determination of phenothiazines by means of a combined multi commutated/multi-pumped flow assembly. AB - A rapid, sensitive and fully automated chemiluminometric method is described for determination of five phenothiazine derivatives, namely, trifluoperazine, fluphenazine, perphenazine, thioridazine and chlorpromazine. The method is based on the chemiluminescence (CL) induced by the oxidation of drugs with Ce(IV) in nitric acid. A flow manifold based on the association of multi-commutation and multi-pumping flow methodologies is proposed. The active operated solenoid devices consisted of a micro-pump (propelling 50MUL per stroke) and a six ports solenoid valve. Reconfiguration of the flow manifold was performed by using software settings, without physical alteration of the instrument manifold. It permits the design of flexible miniaturized networks for flow analysis based on a time-pulse-counting strategy. The proposed method allows the determination of the drugs at the ngmL(-1) level with a sample throughput of 38h(-1) (chlorpromazine) and 40h(-1) (trifluoperazine, fluphenazine, perphenazine, and thioridazine). The method was successfully applied to the determination of the phenothiazine derivatives in pharmaceuticals formulations. PMID- 22817952 TI - Chemiluminometric determination of captopril in a multi-pumping flow system. AB - In this work, a simple, versatile and fully automated analytical methodology for the chemiluminometric determination of captopril - an angiotensin II-converting enzyme (ACE) inhibitor - in pharmaceutical formulations, is proposed. The developed methodology was based on the enhancement by captopril of the chemiluminescence emission of tris(2,2'-bipyridyl)ruthenium(II). In sulphuric acid medium tris(2,2'-bipyridyl)ruthenium(II) was oxidized by cerium(IV) and converted into a reactive oxidant specie [Ru(bpy)(3)](3+), which was subsequently reduced with captopril in order to yield a significant enhancement of the original chemiluminescence emission that was directly related to captopril concentration. The analytical process was implemented by resorting to an automated multi-pumping flow system (MPFS) that enabled the establishment of multiple reaction interfaces, which, in combination with the created pulsed flowing stream assured a fast and reproducible sample/reagent mixing and reaction development essential to guarantee the generation and subsequent measurement of the short-lived species involved in the chemiluminescent process. The developed system employed three solenoid micro-pumps as the only flow manifold active components. These assured the insertion, propelling and commuting of all solutions. The automatic actuation of the solenoid micro-pumps provided an easily programmed, operated and controlled analytical flow system, exhibiting high versatility, efficiency and compactness at a low cost. Under the optimized experimental conditions, the proposed method allowed the determination of captopril for concentrations between 2*10(-3) and 1.5*10(-1)mmolL(-1) (r=0.9996, n=6) and a sampling frequency of about 58 determinations per hour, producing 620MUL of waste per determination. The results obtained for pharmaceutical formulations were statistically comparable to those provided by the reference procedure with a relative deviation between -2.32 and 1.39%. The possible mechanism of the chemiluminescence reaction was also discussed in this work. PMID- 22817953 TI - Determination of the flavonoids/antioxidant levels in Cirsium oleraceum and Cirsium rivulare extracts with cerium(IV)-rhodamine 6G chemiluminescence detection. AB - The determination of the sum of flavonoid compounds in extracts from inflorescences (expressed as mgL(-1) of apigenin) and leaves (expressed as mgL( 1) of linarin) of Cirsium oleraceum and Cirsium rivulare species by flow injection system with chemiluminescence detection (FI-CL) has been carried out. The method is based on the strong enhancement by polyphenols occurring in both plants of the CL signal generated by the reaction of cerium(IV) with rhodamine 6G in a sulfuric acid medium. Under the optimized conditions, the linear working ranges of 0.1-10 and 2.5-50MUmolL(-1) were obtained for apigenin and linarin, respectively. The developed method is simple, sensitive with the detection limits of 38nmolL(-1) (apigenin) and 840nmolL(-1) (linarin) and offers high sample throughput (up to 300 samples per hour). The relative standard deviation was 0.62% and 3.75% for 10 measurements of 5MUmolL(-1) apigenin and linarin, respectively. The proposed method has been successfully applied to determine the flavonoids/antioxidant levels in aqueous and methanolic extracts from inflorescences and leaves of C. oleraceum and C. rivulare. A possible mechanism of the enhancement of cerium(IV)-rhodamine 6G CL system by polyphenols was briefly discussed. For comparative studies, the antioxidant activity of C. oleraceum and C. rivulare extracts was also evaluated by spectrophotometric 1,1 diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging method. PMID- 22817954 TI - Determination of lipoic acid by flow-injection and high-performance liquid chromatography with chemiluminescence detection. AB - A new flow-injection (FI) and high performance liquid chromatography (HPLC) with chemiluminescence detection method has been proposed for the determination of alpha-lipoic acid (LA). The assay is based on the measurement of chemiluminescence (CL) produced during the reaction of alpha-lipoic acid with potassium permanganate in a sodium hexametaphosphate medium (pH 3). This reaction is accompanied by a weak CL, which is greatly increased in the presence of a formaldehyde solution. The proposed FI method allows the determination of LA over the range: 0.5-20MUgmL(-1) with LOD 4*10(-3)MUgmL(-1). An introduction of HPLC into the flow manifold improves selectivity of the method and allows the determination of LA in a complex sample. The chromatographic linear range is 2.5 30MUgmL(-1) with LOD 1.774MUgmL(-1). Chromatographic separation was achieved by isocratic elution (acetonitrile/potassium dihydrogen phosphate, pH 3, adjusted with phosphoric acid): 30/70 using a Cosmosil 5C(18)-MS-II (4.6mm*150mm I.D.) column at a flow rate of 1.0mLmin(-1). The presented methods were utilized to determine the alpha-lipoic acid content in "Alfa-lipoic acid" capsules and in food products. PMID- 22817955 TI - Highly sensitive sequential injection determination of p-aminophenol in paracetamol formulations with 18-molybdodiphosphate heteropoly anion based on elimination of Schlieren effect. AB - A highly sensitive, precise and automated method using sequential injection analysis to assay quantitatively low levels of the p-aminophenol (PAP) in paracetamol formulations has been developed. A solution containing PAP and paracetamol is injected into an acetate buffer carrier stream and merged on-line with 18-molybdodiphosphate heteropoly complex reagent to form a specific blue derivative that is subsequently detected spectrophotometrically at 820nm. The procedure has been optimized mainly with respect to measurement sensitivity. It is based on the leveling off of the refraction indices of the liquids mixed in the flow system by the careful matching of the refractive index of the reagent solution with that of the carrier and sample solutions. Amount as low as 0.5MUmolL(-1) of PAP, which corresponds to the 0.001% of PAP in paracetamol tablets, can be reliably determined using the proposed method, which is clearly below the specification limits recommended for PAP determination in paracetamol drug and tablet formulations (50ppm or 0.005% (w/w)). The developed method was successfully applied to the analysis of paracetamol formulations spiked with PAP and determination of PAP content in Rapidol tablets past their expiration date both by proposed SIA and reference HPLC methods. PMID- 22817956 TI - Examination of black inkjet printing inks by capillary electrophoresis. AB - Counterfeiting of documents is a common phenomenon in the modern world. A large proportion of forgeries relates to inkjet printed documents. Hence there is an evident need to develop an effective and reliable method for the differentiation and identification of inkjet inks on questioned documents. The aim of the presented study was to investigate the possibility of applying micellar electrokinetic capillary chromatography (MECC) to forensic analysis of inkjet inks extracted from black and white printouts. In order to achieve the above aim, a capillary electrophoresis system equipped with a diode array detector was used. The separation was performed using a fused silica capillary (60/50cm total/effective length, 75MUm i.d.) with a background electrolyte composed of 40mM sodium borate, 20mM SDS and 10% (v/v) acetonitrile (pH 9.5) at 25 degrees C and 30kV. Ink samples were extracted from black inkjet printouts with the use of dimethyl sulphoxide (DMSO). Differentiation of inks was based on the number of significant peaks at different wavelengths, the relative migration times and the characteristic UV-Vis spectra. The electropherograms of the inks extracted from paper showed patterns which in most cases were distinctly different from each other. The greatest diversity of electrophoretic profiles was revealed for documents printed by Hewlett-Packard inkjet technology. A database of electrophoretic separation results of inks has been constructed for further forensic use. PMID- 22817957 TI - Application of whole-body MRI to detect the recurrence of lung cancer. AB - Although some therapeutics provide an opportunity for cure, recurrence is a major obstacle to achieve a complete remission for lung cancers. Therefore, precise assessment of lung cancers has been a task with challenge. In recent years, integration of positron emission tomography and computed tomography (PET-CT) and whole-body magnetic resonance imaging (WB-MRI) have been introduced as an alternative to standard multimodality imaging strategies and are now increasingly applied to various malignancies. However, there is little information on the surveillance capability of WB-MRI in patients with lung cancers. We aimed to investigate the clinical potential of WB-MRI as a novel surveillance modality after curative treatments for lung cancers, comparing it with PET-CT. Sixty two consecutive patients with lung malignancy who underwent both WB-MRI and PET-CT were selected to assess the recurrent malignant lesions. The clinical data including radiologic and pathologic findings were collected and analyzed retrospectively. On each lymph node station, the ability of WB-MRI to detect malignant lesions significantly correlated with that of PET-CT (gamma=0.86; P<.01). The correlation coefficient ranged from 0.999 to 1 for assessing distant metastases from lung cancers by two modalities (P<.01). Based on the pathologic confirmation, both modalities showed an equivalent diagnostic accuracy (PET-CT: sensitivity 85.71%, specificity 47.27% versus WB-MRI: sensitivity 85.71%, specificity 56.25%). This study demonstrates the clinical potential of WB-MRI, together with PET-CT, as a novel surveillance modality for lung cancers after curative treatments. PMID- 22817958 TI - Point spread functions of the T2 decay in k-space trajectories with long echo train. AB - T(2) decay during long echo trains of magnetic resonance (MR) imaging pulse sequences is known to cause a blurring effect, due to the peak broadening of the point spread function (PSF). In contrast, the simultaneous amplitude-loss effect, led by the peak reduction of the PSF, has gained much less attention. In this report, we analyzed the PSFs of both the truncation and T(2) decay for Cartesian (linear profile ordering and low-high ordering) and spiral trajectories, respectively. Then, we derived simple formulas to characterize both the blurring and amplitude-loss effects, which are functions of the ratios of the echo train duration (T(k)) over T(2) (T(k)/T(2)). Signal-to-noise ratio (SNR) per unit time was thus analyzed considering both the amplitude-loss effect induced by the T(2) decay and the SNR gain from the long acquisition duration based on MR sampling theory. Optimum T(k)/T(2) ratios to achieve maximum SNR per unit time were 1.2 for the Cartesian trajectory and 0.8 for the spiral trajectory. PMID- 22817959 TI - Association of single nucleotide polymorphisms of beta2-adrenergic receptor gene with clinicopathological features of pancreatic carcinoma. AB - beta2-Adrenoceptor agonists induce pancreatic cancer occurrence and progression through beta2-AR. Polymorphisms in beta2-AR gene lead to modified sensitivity to agonists and variable tumorigenic potential. In this study, pancreatic carcinoma and non-neoplastic pancreatic tissues were genotyped at codons 16 and 27 by PCR restriction fragment length polymorphism and DNA sequencing. Expressions of beta2 AR, EGFR, VEGF and MMP-2 were detected by immunohistochemistry. The frequencies of genotypes and alleles at codon 16 between pancreatic carcinoma and non neoplastic pancreatic tissues showed no difference. The genotype frequencies were associated with TNM grade, lymph node metastasis, and one-year survival rate. The allele G at codon 16 frequently appeared in tumors with high TNM grade, lymph node metastasis, poor prognosis, high expression levels of beta2-AR, EGFR, VEGF and MMP-2. The genotype and allele frequencies of codon 27 were not associated with clinicopathological features and down-stream protein expressions. Collectively, SNPs of beta2-AR gene at codon 16 were associated with the biological behavior of pancreatic carcinoma. The allele G at codon 16 could facilitate the progression and metastasis of pancreatic carcinoma through elevating vascularization and activating the EGFR pathway. SNPs at codon 16 of beta2-AR are new useful biomarkers for predicting biological behavior and survival of pancreatic carcinoma and might be used as a new gene therapeutic target. PMID- 22817960 TI - The pre-election health environment in the USA. PMID- 22817961 TI - Chariots of fries. PMID- 22817962 TI - Sex workers and HIV-forgotten and ostracised. PMID- 22817963 TI - Shaping the renaissance of psychedelic research. PMID- 22817965 TI - Ken Powell: running the distance for physical activity. PMID- 22817966 TI - Prevalence of chronic kidney disease in China. PMID- 22817967 TI - Prevalence of chronic kidney disease in China. PMID- 22817968 TI - Prevalence of chronic kidney disease in China. PMID- 22817969 TI - Prevalence of chronic kidney disease in China. PMID- 22817971 TI - Prevalence of chronic kidney disease in China. PMID- 22817972 TI - Making haemophilia a global priority. PMID- 22817973 TI - Prevalence of chronic kidney disease in China. PMID- 22817975 TI - Mammography screening: truth, lies, and controversy. PMID- 22817974 TI - Rubella vaccination: must not be business as usual. PMID- 22817976 TI - A dual hyperthyroidism. PMID- 22817977 TI - Assessment of liver tumor response by high-field (3 T) MRI after radiofrequency ablation: short- and mid-term evolution of diffusion parameters within the ablation zone. AB - PURPOSE: To compare the apparent diffusion coefficient (ADC) values of malignant liver lesions on diffusion-weighted MRI (DWI) before and after successful radiofrequency ablation (RF ablation). MATERIALS AND METHODS: Thirty-two patients with 43 malignant liver lesions (23/20: metastases/hepatocellular carcinomas (HCC)) underwent liver MRI (3.0 T) before (<1 month) and after RF ablation (at 1, 3 and 6 months) using T2-, gadolinium-enhanced T1- and DWI-weighted MR sequences. Jointly, two radiologists prospectively measured ADCs for each lesion by means of two different regions of interest (ROIs), first including the whole lesion and secondly the area with the visibly most restricted diffusion (MRDA) on ADC map. Changes of ADCs were evaluated with ANOVA and Dunnett tests. RESULTS: Thirty-one patients were successfully treated, while one patient was excluded due to focal recurrence. In metastases (n=22), the ADC in the whole lesion and in MRDA showed an up-and-down evolution. In HCC (n=20), the evolution of ADC was more complex, but with significantly higher values (p=0.013) at 1 and 6 months after RF ablation. CONCLUSION: The ADC values of malignant liver lesions successfully treated by RF ablation show a predictable evolution and may help radiologists to monitor tumor response after treatment. PMID- 22817978 TI - A decade of civilian vascular trauma in Kosovo. AB - PURPOSE: We sought to analyze the results of arterial injury management in a busy metropolitan vascular unit and risk factors associated with mortality and morbidity. PATIENTS AND METHODS: We analyzed 120 patient with arterial injury treated between year 2000 and 2010 at the University Clinical Center of Kosovo. Seven of these years were prospective and three retrospective study. RESULTS: The mechanism of arterial injury was stabbing 46.66%, gunshot wounds in 31.66%, blunt in 13.33%, and landmine in 8.33%. The most frequently injured vessel was the superficial femoral artery (25%), followed by the brachial artery (20.9%), crural arteries (13.1%), forearm arteries (14.3%), iliac arteries (7.5%), abdominal aorta (3.3%), common femoral artery (3.3%) and popliteal artery (3.3%). Associated injuries including bone, nerve and remote injury (affecting the head, chest, or abdomen) were present in 24.2% of patients. The decision to operate was made based on the presence of "hard signs" of vascular trauma. Arterial reconstruction was performed in 90.8% of patients, 5.8% of patients underwent primary amputation and 3.2% died on the operation table. Overall survival rate was 95.8%. CONCLUSION: Injuries to the arteries are associated with significant mortality and morbidity. Mechanism of injury (blunt, gunshot, landmine or stub), hemodynamic stability at the admission, localization of injury, time from injury to flow restitution, associated injuries to the structures in the region and remote organs are critical factors influencing outcome. PMID- 22817979 TI - Creatine supplementation with specific view to exercise/sports performance: an update. AB - Creatine is one of the most popular and widely researched natural supplements. The majority of studies have focused on the effects of creatine monohydrate on performance and health; however, many other forms of creatine exist and are commercially available in the sports nutrition/supplement market. Regardless of the form, supplementation with creatine has regularly shown to increase strength, fat free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone. Creatine may be of benefit in other modes of exercise such as high-intensity sprints or endurance training. However, it appears that the effects of creatine diminish as the length of time spent exercising increases. Even though not all individuals respond similarly to creatine supplementation, it is generally accepted that its supplementation increases creatine storage and promotes a faster regeneration of adenosine triphosphate between high intensity exercises. These improved outcomes will increase performance and promote greater training adaptations. More recent research suggests that creatine supplementation in amounts of 0.1 g/kg of body weight combined with resistance training improves training adaptations at a cellular and sub-cellular level. Finally, although presently ingesting creatine as an oral supplement is considered safe and ethical, the perception of safety cannot be guaranteed, especially when administered for long period of time to different populations (athletes, sedentary, patient, active, young or elderly). PMID- 22817980 TI - [Low-affinity Fcgamma receptor IIa gene polymorphism and dengue bleeding disorder]. AB - INTRODUCTION: The pathophysiological changes that determine the severity of dengue are still not well known, therefore it is important to study the probable relationship with the host genetic. METHODS: We analyzed the possible association between the FcgammaRIIa polymorphism and clinical signs in individuals who suffered dengue infection in 2006, using contingency tables. RESULTS: We found that bleeding was significantly associated to FcgammaRIIa H/H131 genotype (80%). CONCLUSION: Our results suggest that in clinical dengue infection the bleeding could be associated to FcgammaRIIa H/H131 genotype. PMID- 22817981 TI - Calcium and repression in malaria sex: knowing when the time is right. AB - Translational repression is important for development of the malaria parasite when establishing infection in the mosquito. In this issue of Cell Host and Microbe, Sebastian et al. (2012) show that a calcium-dependent protein kinase is important for alleviating translational repression during developmental progression. PMID- 22817982 TI - Helicobacter pylori CagA tertiary structure reveals functional insights. AB - CagA is a major disease-associated factor injected by the gastric pathogen Helicobacter pylori. In this issue, Hayashi et al. (2012) report the crystallographic structure of the CagA N terminus (residues 24-876) at 3.19 A resolution. This study revealed three distinct domains, giving novel insights into intramolecular and intermolecular protein and phosphatidylserine interactions. PMID- 22817983 TI - NETs tangle with HIV. AB - Neutrophil extracellular traps (NETs) are comprised of extracellular DNA coated in cytotoxic proteins capable of ensnaring and killing bacteria. Saitoh et al. (2012) expand our understanding of NETs into antiviral immunity by demonstrating that HIV induces the formation of NETs, which can bind and neutralize viral particles. PMID- 22817984 TI - A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs. AB - Calcium-dependent protein kinases (CDPKs) play key regulatory roles in the life cycle of the malaria parasite, but in many cases their precise molecular functions are unknown. Using the rodent malaria parasite Plasmodium berghei, we show that CDPK1, which is known to be essential in the asexual blood stage of the parasite, is expressed in all life stages and is indispensable during the sexual mosquito life-cycle stages. Knockdown of CDPK1 in sexual stages resulted in developmentally arrested parasites and prevented mosquito transmission, and these effects were independent of the previously proposed function for CDPK1 in regulating parasite motility. In-depth translational and transcriptional profiling of arrested parasites revealed that CDPK1 translationally activates mRNA species in the developing zygote that in macrogametes remain repressed via their 3' and 5'UTRs. These findings indicate that CDPK1 is a multifunctional protein that translationally regulates mRNAs to ensure timely and stage-specific protein expression. PMID- 22817985 TI - Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA. AB - The Helicobacter pylori type IV secretion effector CagA is a major bacterial virulence determinant and critical for gastric carcinogenesis. Upon delivery into gastric epithelial cells, CagA localizes to the inner face of the plasma membrane, where it acts as a pathogenic scaffold/hub that promiscuously recruits host proteins to potentiate oncogenic signaling. We find that CagA comprises a structured N-terminal region and an intrinsically disordered C-terminal region that directs versatile protein interactions. X-ray crystallographic analysis of the N-terminal CagA fragment (residues 1-876) revealed that the region has a structure comprised of three discrete domains. Domain I constitutes a mobile CagA N terminus, while Domain II tethers CagA to the plasma membrane by interacting with membrane phosphatidylserine. Domain III interacts intramolecularly with the intrinsically disordered C-terminal region, and this interaction potentiates the pathogenic scaffold/hub function of CagA. The present work provides a tertiary structural basis for the pathophysiological/oncogenic action of H. pylori CagA. PMID- 22817986 TI - Chitinase 3-like-1 promotes Streptococcus pneumoniae killing and augments host tolerance to lung antibacterial responses. AB - Host antibacterial responses include mechanisms that kill bacteria, but also those that protect or tolerize the host to potentially damaging antibacterial effects. We determined that Chitinase 3-like-1 (Chi3l1), a conserved prototypic chitinase-like protein, is induced by Streptococcus pneumoniae and plays central roles in promoting bacterial clearance and mediating host tolerance. S. pneumoniae-infected Chi3l1 null mice exhibit exaggerated lung injury, inflammation and hemorrhage, more frequent bacterial dissemination, decreased bacterial clearance, and enhanced mortality compared to controls. Chi3l1 augments macrophage bacterial killing by inhibiting caspase-1-dependent macrophage pyroptosis and augments host tolerance by controlling inflammasome activation, ATP accumulation, expression of ATP receptor P2X7R, and production of thymic stromal lymphopoietin and type 1, type 2, and type 17 cytokines. These data demonstrate that Chi3l1 is induced during infection, where it promotes bacterial clearance while simultaneously augmenting host tolerance, and that these roles likely contributed to the retention of Chi3l1 over species and evolutionary time. PMID- 22817987 TI - Mucosal reactive oxygen species decrease virulence by disrupting Campylobacter jejuni phosphotyrosine signaling. AB - Reactive oxygen species (ROS) play key roles in mucosal defense, yet how they are induced and the consequences for pathogens are unclear. We report that ROS generated by epithelial NADPH oxidases (Nox1/Duox2) during Campylobacter jejuni infection impair bacterial capsule formation and virulence by altering bacterial signal transduction. Upon C. jejuni invasion, ROS released from the intestinal mucosa inhibit the bacterial phosphotyrosine network that is regulated by the outer-membrane tyrosine kinase Cjtk (Cj1170/OMP50). ROS-mediated Cjtk inactivation results in an overall decrease in the phosphorylation of C. jejuni outer-membrane/periplasmic proteins, including UDP-GlcNAc/Glc 4-epimerase (Gne), an enzyme required for N-glycosylation and capsule formation. Cjtk positively regulates Gne by phosphorylating an active site tyrosine, while loss of Cjtk or ROS treatment inhibits Gne activity, causing altered polysaccharide synthesis. Thus, epithelial NADPH oxidases are an early antibacterial defense system in the intestinal mucosa that modifies virulence by disrupting bacterial signaling. PMID- 22817988 TI - Infection-induced host translational blockage inhibits immune responses and epithelial renewal in the Drosophila gut. AB - Typically, immune responses control the pathogen, while repair and stress pathways limit damage caused by pathogenesis. The relative contribution of damage to the outcome of pathogenesis and the mechanistic links between the immune and repair pathways are poorly understood. Here, we analyze how the entomopathogenic bacterium Pseudomonas entomophila induces irreversible damage to the Drosophila gut. We find that P. entomophila ingestion induces a global translational blockage that impairs both immune and repair programs in the fly gut. P. entomophila-induced translational inhibition is dependent on bacterial pore forming toxins and reactive oxygen species produced by the host in response to infection. Translational arrest is mediated through activation of the GCN2 kinase and inhibition of the TOR pathway as a consequence of host damage. Together, our study draws a model of pathogenesis in which bacterial inhibition of translation by excessive activation of stress responsive pathways inhibits both immune and regenerative epithelial responses. PMID- 22817989 TI - Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. AB - Virus infection-induced global protein synthesis suppression is linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation preinitiation complexes. To study long-term stress responses, we developed an imaging approach for extended observation and analysis of SG dynamics during persistent hepatitis C virus (HCV) infection. In combination with type 1 interferon, HCV infection induces highly dynamic assembly/disassembly of cytoplasmic SGs, concomitant with phases of active and stalled translation, delayed cell division, and prolonged cell survival. Double-stranded RNA (dsRNA), independent of viral replication, is sufficient to trigger these oscillations. Translation initiation factor eIF2alpha phosphorylation by protein kinase R mediates SG formation and translation arrest. This is antagonized by the upregulation of GADD34, the regulatory subunit of protein phosphatase 1 dephosphorylating eIF2alpha. Stress response oscillation is a general mechanism to prevent long-lasting translation repression and a conserved host cell reaction to multiple RNA viruses, which HCV may exploit to establish persistence. PMID- 22817990 TI - Increased expression of LDL receptor-related protein 1 during human cytomegalovirus infection reduces virion cholesterol and infectivity. AB - In response to virus infection, cells can alter protein expression to modify cellular functions and limit viral replication. To examine host protein expression during infection with human cytomegalovirus (HCMV), an enveloped DNA virus, we performed a semiquantitative, temporal analysis of the cell surface proteome in infected fibroblasts. We determined that resident low density lipoprotein related receptor 1 (LRP1), a plasma membrane receptor that regulates lipid metabolism, is elevated early after HCMV infection, resulting in decreased intracellular cholesterol. siRNA knockdown or antibody-mediated inhibition of LRP1 increased intracellular cholesterol and concomitantly increased the infectious virus yield. Virions produced under these conditions contained elevated cholesterol, resulting in increased infectivity. Depleting cholesterol from virions reduced their infectivity by blocking fusion of the virion envelope with the cell membrane. Thus, LRP1 restricts HCMV infectivity by controlling the availability of cholesterol for the virion envelope, and increased LRP1 expression is likely a defense response to infection. PMID- 22817991 TI - An analog of the natural steroidal alkaloid cortistatin A potently suppresses Tat dependent HIV transcription. AB - The human immunodeficiency virus type 1 (HIV) Tat protein, a potent activator of HIV gene expression, is essential for integrated viral genome expression and represents a potential antiviral target. Tat binds the 5'-terminal region of HIV mRNA's stem-bulge-loop structure, the transactivation-responsive (TAR) element, to activate transcription. We find that didehydro-Cortistatin A (dCA), an analog of a natural steroidal alkaloid from a marine sponge, inhibits Tat-mediated transactivation of the integrated provirus by binding specifically to the TAR binding domain of Tat. Working at subnanomolar concentrations, dCA reduces Tat mediated transcriptional initiation/elongation from the viral promoter to inhibit HIV-1 and HIV-2 replication in acutely and chronically infected cells. Importantly, dCA abrogates spontaneous viral particle release from CD4(+)T cells from virally suppressed subjects on highly active antiretroviral therapy (HAART). Thus, dCA defines a unique class of anti-HIV drugs that may inhibit viral production from stable reservoirs and reduce residual viremia during HAART. PMID- 22817992 TI - Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1. AB - Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and alpha-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and alpha-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1. PMID- 22817994 TI - Post-operative mismatch negativity recovery in a temporal lobe epilepsy patient with cavernous angioma. PMID- 22817995 TI - Monogalactopyranosides of fluorescein and fluorescein methyl ester: synthesis, enzymatic hydrolysis by biotnylated beta-galactosidase, and determination of translational diffusion coefficient. AB - Fluorescein monoglycosides (D-galactopyranoside (FMG) and D-glucopyranoside) and their methyl ester (MFMG) have been prepared from acetobromoglucose/galactose and fluorescein methyl ester in good yields. Enzymatic hydrolysis experiments (using biotinylated beta-galactosidase) of the galacto derivatives have been performed and kinetic parameters were calculated. A 15-20 times increase of the fluorescence intensity has been observed during the hydrolysis. A linear increase of fluorescence has been noted at short time and low concentration of substrate, making these compounds useful and sensitive probes for galactosidases. The magnitude of the Michaelis-Menten constant (K(m)) value for MFMG is higher than that of FMG suggesting a possible conformational change of the fluorogenic substrate. K(m) value for biotinylated beta-Gal with FMG is lower than that for the native enzyme. This observation indicates higher substrate affinity of the biotinylated enzyme in comparison to the native enzyme. Translational diffusion coefficients have been measured, for both fluorogenic substrates and both the products, employing fluorescence correlation spectroscopy. Translational diffusion coefficients for fluorogenic substrates and the enzymatic hydrolysis products have been measured to be similar, in the range of 3.5-4.5*10(-10) m(2) s(-1). Thus an enhancement or retardation of the enzymatic kinetics due to difference in translational mobility of substrate and product is not that apparent. PMID- 22817996 TI - Structures and biosynthesis of the N- and O-glycans of recombinant human oviduct specific glycoprotein expressed in human embryonic kidney cells. AB - Oviduct-specific glycoprotein (OVGP1) is a major mucin-like glycoprotein synthesized and secreted exclusively by non-ciliated secretory cells of mammalian oviduct. In vitro functional studies showed that OVGP1 plays important roles during fertilization and early embryo development. We have recently produced recombinant human oviduct-specific glycoprotein (rhOVGP1) in human embryonic kidney 293 (HEK293) cells. The present study was undertaken to characterize the structures and determine the biosynthetic pathways of the N- and O-glycans of rhOVGP1. Treatment of the stable rhOVGP1-expressing HEK293 cells with either GalNAcalpha-Bn to block O-glycan extension, tunicamycin to block N-glycosylation, or neuraminidase increased the electrophoretic mobility of rhOVGP1. A detailed analysis of O- and N-linked glycans of rhOVGP1 by mass spectrometry showed a broad range of many simple and complex glycan structures. In order to identify the enzymes involved in the glycosylation of rhOVGP1, we assayed glycosyltransferase activities involved in the assembly of O- and N-glycans in HEK293 cells, and compared these to those from the immortalized human oviductal cells (OE-E6/E7). Our results demonstrate that HEK293 and OE-E6/E7 cells exhibit a similar spectrum of glycosyltransferase activities that can synthesize elongated and sialylated O-glycans with core 1 and 2 structures, as well as complex multiantennary N-glycans. It is anticipated that the knowledge gained from the present study will facilitate future studies of the role of the glycans of human OVGP1 in fertilization and early embryo development. PMID- 22817997 TI - Aquaporin-4 positron emission tomography imaging of the human brain: first report. AB - BACKGROUND AND PURPOSE: Aquaporin 4 (AQP-4) is the most abundant aquaporin isoform in the brain. Alterations in its expression and distribution have been correlated with the progression of several clinical disorders; however, the specific roles of AQP-4 in those disorders are not well understood. Visualizing AQP-4 in vivo is expected to provide fresh insights into its roles in disease pathology, as well as aiding the clinical assessment of those disorders. METHODS: We developed a 11C-labeled analogue of the AQP-4 ligand TGN-020 (2-nicotinamido 1,3,4-thiadiazole) suitable for in vivo positron emission tomography (PET) imaging. RESULTS: In the present study, we report the first PET images of AQP-4 in the human brain. The results unequivocally demonstrated a specific distribution pattern for AQP-4 within the brain, namely, the subpial and perivascular endfeet of astrocytes. The choroid plexus, where both AQP-4 and AQP 1 are expressed, also showed substantial uptake of the ligand. CONCLUSIONS: Based on these initial results, we believe [11C]TGN-020 PET will be valuable in determining the role of AQP-4 in disease progression, and for the clinical assessment of water homeostasis under various settings. PMID- 22817993 TI - Preserving immunogenicity of lethally irradiated viral and bacterial vaccine epitopes using a radio- protective Mn2+-Peptide complex from Deinococcus. AB - Although pathogen inactivation by gamma-radiation is an attractive approach for whole-organism vaccine development, radiation doses required to ensure sterility also destroy immunogenic protein epitopes needed to mount protective immune responses. We demonstrate the use of a reconstituted manganous peptide complex from the radiation-resistant bacterium Deinococcus radiodurans to protect protein epitopes from radiation-induced damage and uncouple it from genome damage and organism killing. The Mn(2+) complex preserved antigenic structures in aqueous preparations of bacteriophage lambda, Venezuelan equine encephalitis virus, and Staphylococcus aureus during supralethal irradiation (25-40 kGy). An irradiated vaccine elicited both antibody and Th17 responses, and induced B and T cell dependent protection against methicillin-resistant S. aureus (MRSA) in mice. Structural integrity of viruses and bacteria are shown to be preserved at radiation doses far above those which abolish infectivity. This approach could expedite vaccine production for emerging and established pathogens for which no protective vaccines exist. PMID- 22817998 TI - [Obstructive jaundice secondary to liver hilar lymph node tuberculosis]. PMID- 22817999 TI - Does age of onset of impairment impact on neuropsychological and personality features of adult ADHD? AB - The consideration of age of onset of impairment as part of the ADHD diagnosis is controversial and has been a revisited issue with the emergence of the new classifications in Psychiatry. The aim of this study is to compare patients with early and late onset of ADHD impairment in terms of neuropsychological and personality characteristics. Adult patients with ADHD (n = 415) were evaluated in the ADHD outpatient program at Hospital de Clinicas de Porto Alegre, Brazil. The diagnostic process for ADHD and comorbidities was based on DSM-IV criteria. The comparison between the two ages of onset groups (before 7; n = 209 or from 7 to 12 years; n = 206) was performed with ANOVA, followed by Stepwise forward regression analyses to restrict the number of comparisons and access the possible effect of multiple confounders. Patients with early onset ADHD present higher scores in novelty seeking in both analyses (respectively P = 0.016 and P = 0.002), but similar cognitive and attention features as compared with the late onset group. These data add to previous evidence that despite a more externalizing profile of early onset ADHD, the overall performance is similar reinforcing the need for awareness and inclusion of the late onset group in DSM-V diagnostic criteria. PMID- 22818000 TI - In vitro and in vivo anti-colon cancer effects of Garcinia mangostana xanthones extract. AB - BACKGROUND: Xanthones are a group of oxygen-containing heterocyclic compounds with remarkable pharmacological effects such as anti-cancer, antioxidant, anti inflammatory, and antimicrobial activities. METHODS: A xanthones extract (81% alpha-mangostin and 16% gamma-mangostin), was prepared by crystallization of a toluene extract of G. mangostana fruit rinds and was analyzed by LC-MS. Anti colon cancer effect was investigated on HCT 116 human colorectal carcinoma cells including cytotoxicity, apoptosis, anti-tumorigenicity, and effect on cell signalling pathways. The in vivo anti-colon cancer activity was also investigated on subcutaneous tumors established in nude mice. RESULTS: The extract showed potent cytotoxicity (median inhibitory concentration 6.5 +/- 1.0 MUg/ml), due to induction of the mitochondrial pathway of apoptosis. Three key steps in tumor metastasis including the cell migration, cell invasion and clonogenicity, were also inhibited. The extract and alpha-mangostin up-regulate the MAPK/ERK, c Myc/Max, and p53 cell signalling pathways. The xanthones extract, when fed to nude mice, caused significant growth inhibition of the subcutaneous tumor of HCT 116 colorectal carcinoma cells. CONCLUSIONS: Our data suggest new mechanisms of action of alpha-mangostin and the G. mangostana xanthones, and suggest the xanthones extract of as a potential anti-colon cancer candidate. PMID- 22818016 TI - Efficacy and safety of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: Whether mycophenolate mofetil is superior to cyclophosphamide as induction therapy for lupus nephritis (LN) remains controversial. OBJECTIVE: Our objective was to investigate the efficacy and safety of mycophenolate mofetil compared with cyclophosphamide as induction therapy for LN patients. METHODS: Randomized controlled trials (RCTs) on humans were identified in searches of PubMed/MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (all to 1 December 2011). Studies that compared the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients were selected. Methodological quality of the included trials was assessed according to Cochrane criteria and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The fixed effects model was applied for pooling where there was no significant heterogeneity, otherwise the random effects model (Dersimonian and Laird method) was performed. RESULTS: Seven trials were identified, including 725 patients. The Dersimonian and Laird method was applied for renal remission in the presence of significant heterogeneity, and no statistically significant differences were distinguished between mycophenolate mofetil and cyclophosphamide. To explore the possible source of heterogeneity, meta-regression was performed. It was suggested that no obvious study- or patient level factors could explain interstudy heterogeneity with statistical significance. Among all these factors, the mode of administration of cyclophosphamide could explain most of the heterogeneity, although the coefficient was insignificant. Therefore, we performed a sensitivity analysis by excluding the trial in which cyclophosphamide was administered orally instead of intravenously, which suggested that mycophenolate mofetil was more effective than intravenous cyclophosphamide for inducing complete remission (relative risk [RR] 1.72; 95% CI 1.17, 2.55; p = 0.006) and complete or partial remission (RR 1.18; 95% CI 1.04, 1.35; p = 0.01). In addition, mycophenolate mofetil was superior to cyclophosphamide for significantly reducing end-stage renal disease (ESRD) or death (RR 0.64; 95% CI 0.41, 0.98; p = 0.04). For the safety comparison, lower risks of leukopenia, amenorrhoea and alopecia, and a higher risk of diarrhoea were found with mycophenolate mofetil. No statistical differences in infection and gastrointestinal symptoms were distinguished between mycophenolate mofetil and cyclophosphamide. The relatively small number and the open-label fashion of eligible RCTs may limit the value of our meta-analysis. CONCLUSIONS: Mycophenolate mofetil is superior to intravenous cyclophosphamide for inducing renal remission, and has a significant advantage over cyclophosphamide for reducing ESRD or death. Furthermore, mycophenolate mofetil has lower risks of leukopenia, amenorrhoea and alopecia, but a higher risk of diarrhoea than cyclophosphamide. However, our conclusions need to be proved further in larger well designed trials. PMID- 22818015 TI - Ten years of experience with biphasic insulin aspart 30: from drug development to the latest clinical findings. AB - Biphasic insulin aspart 30 (BIAsp 30) includes 30% soluble rapid-acting insulin aspart (IAsp) along with an intermediate-acting 70% protaminated IAsp that provides coverage of prandial and basal insulin in a single injection. As BIAsp 30 has been available internationally for 10 years, this review provides a comprehensive overview of the discovery of BIAsp 30, its pharmacokinetic and pharmacodynamic profile, safety and efficacy outcomes from the clinical trial programme, 'real-life' clinical insights provided by observational study data, and cost effectiveness and quality-of-life information. These studies have demonstrated that BIAsp 30 once or twice daily is an appropriate option for insulin initiation. BIAsp 30 also provides a switch option in patients on biphasic human insulin (BHI). Switching from BHI to BIAsp 30 is associated with improved postprandial glucose (PPG) and reduced nocturnal and major hypoglycaemia, although daytime hypoglycaemia is higher with BIAsp 30. Intensification of BIAsp 30 can be achieved by increasing the number of daily doses up to three times daily with meals. Therefore, BIAsp 30 provides an intensification option for individuals who are not achieving control with basal insulin and would prefer the simplicity of a single biphasic insulin instead of progressing to a basal-bolus approach. BIAsp 30 has a simple dose-titration algorithm, which enables patients to effectively self-titrate their insulin dose. Cost-effectiveness analyses have demonstrated that BIAsp 30 is cost effective or dominant compared with BHI 30 or insulin glargine in a number of healthcare settings. In conclusion, BIAsp 30 offers a simple and flexible option for insulin initiation and intensification that provides coverage of both fasting and prandial glucose. PMID- 22818017 TI - Docetaxel: a review of its use for the first-line treatment of advanced castration-resistant prostate cancer. AB - Docetaxel (Taxotere(r)) is a well established anti-mitotic chemotherapy agent. Among other therapeutic indications, docetaxel plus prednisone is indicated for first-line chemotherapy in patients with castration-resistant prostate cancer (CRPC). Docetaxel every 3 weeks plus continuous prednisone has been standard first-line chemotherapy in CRPC since demonstrating improved survival compared with the previous standard regimen, mitoxantrone plus prednisone, in the phase III TAX 327 trial in 2004. Since that time, docetaxel has been combined with various agents that demonstrated additive or synergistic activity in preclinical studies in an effort to further improve outcomes, but to date, overall survival has not been extended compared with docetaxel plus prednisone. However, several promising agents are emerging with a potential role in docetaxel-based combinations based on efficacy and manageable toxicity, including bevacizumab, dasatinib and atrasentan. In the TAX 327 trial, neutropenia was relatively common in the group receiving 3-weekly docetaxel plus prednisone, but infection was rare. The tolerability of a weekly docetaxel regimen also administered in this trial was not significantly different to that of the 3-weekly regimen, except for a lower incidence of grade 3 or 4 neutropenia. However, weekly or 2-weekly docetaxel administration schedules may have a place in very elderly or frail patients in order to improve tolerability compared with the 3-weekly regimen. In conclusion, docetaxel every 3 weeks plus prednisone remains the optimum first line chemotherapy for most patients with advanced CRPC until such time that ongoing research with docetaxel and emerging therapeutic agents can demonstrate improved survival. PMID- 22818019 TI - The development and validation of an urbanicity scale in a multi-country study. AB - BACKGROUND: Although urban residence is consistently identified as one of the primary correlates of non-communicable disease in low- and middle-income countries, it is not clear why or how urban settings predispose individuals and populations to non-communicable disease (NCD), or how this relationship could be modified to slow the spread of NCD. The urban-rural dichotomy used in most population health research lacks the nuance and specificity necessary to understand the complex relationship between urbanicity and NCD risk. Previous studies have developed and validated quantitative tools to measure urbanicity continuously along several dimensions but all have been isolated to a single country. The purposes of this study were 1) To assess the feasibility and validity of a multi-country urbanicity scale; 2) To report some of the considerations that arise in applying such a scale in different countries; and, 3) To assess how this scale compares with previously validated scales of urbanicity. METHODS: Household and community-level data from the Young Lives longitudinal study of childhood poverty in 59 communities in Ethiopia, India and Peru collected in 2006/2007 were used. Household-level data include parents' occupations and education level, household possessions and access to resources. Community-level data include population size, availability of health facilities and types of roads. Variables were selected for inclusion in the urbanicity scale based on inspection of the data and a review of literature on urbanicity and health. Seven domains were constructed within the scale: Population Size, Economic Activity, Built Environment, Communication, Education, Diversity and Health Services. RESULTS: The scale ranged from 11 to 61 (mean 35) with significant between country differences in mean urbanicity; Ethiopia (30.7), India (33.2), Peru (39.4). Construct validity was supported by factor analysis and high corrected item-scale correlations suggest good internal consistency. High agreement was observed between this scale and a dichotomized version of the urbanicity scale (Kappa 0.76; Spearman's rank-correlation coefficient 0.84 (p < 0.0001). Linear regression of socioeconomic indicators on the urbanicity scale supported construct validity in all three countries (p < 0.05). CONCLUSIONS: This study demonstrates and validates a robust multidimensional, multi-country urbanicity scale. It is an important step on the path to creating a tool to assess complex processes like urbanization. This scale provides the means to understand which elements of urbanization have the greatest impact on health. PMID- 22818020 TI - Predicting on-going hemorrhage and transfusion requirement after severe trauma: a validation of six scoring systems and algorithms on the TraumaRegister DGU. AB - INTRODUCTION: The early aggressive management of the acute coagulopathy of trauma may improve survival in the trauma population. However, the timely identification of lethal exsanguination remains challenging. This study validated six scoring systems and algorithms to stratify patients for the risk of massive transfusion (MT) at a very early stage after trauma on one single dataset of severely injured patients derived from the TR-DGU (TraumaRegister DGU of the German Trauma Society (DGU)) database. METHODS: Retrospective internal and external validation of six scoring systems and algorithms (four civilian and two military systems) to predict the risk of massive transfusion at a very early stage after trauma on one single dataset of severely injured patients derived from the TraumaRegister DGU database (2002-2010). Scoring systems and algorithms assessed were: TASH (Trauma Associated Severe Hemorrhage) score, PWH (Prince of Wales Hospital/Rainer) score, Vandromme score, ABC (Assessment of Blood Consumption/Nunez) score, Schreiber score and Larsen score. Data from 56,573 patients were screened to extract one complete dataset matching all variables needed to calculate all systems assessed in this study. Scores were applied and area-under-the-receiver-operating characteristic curves (AUCs) were calculated. From the AUC curves the cut-off with the best relation of sensitivity-to-specificity was used to recalculate sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV). RESULTS: A total of 5,147 patients with blunt trauma (95%) was extracted from the TR-DGU. The mean age of patients was 45.7 +/- 19.3 years with a mean ISS of 24.3 +/- 13.2. The overall MT rate was 5.6% (n = 289). 95% (n = 4,889) patients had sustained a blunt trauma. The TASH score had the highest overall accuracy as reflected by an AUC of 0.889 followed by the PWH Score (0.860). At the defined cut-off values for each score the highest sensitivity was observed for the Schreiber score (85.8%) but also the lowest specificity (61.7%). The TASH score at a cut-off >= 8.5 showed a sensitivity of 84.4% and also a high specificity (78.4%). The PWH score had a lower sensitivity (80.6%) with comparable specificity. The Larson score showed the lowest sensitivity (70.9%) at a specificity of 80.4%. CONCLUSIONS: Weighted and more sophisticated systems such as TASH and PWH scores including higher numbers of variables perform superior over simple non-weighted models. Prospective validations are needed to improve the development process and use of scoring systems in the future. PMID- 22818021 TI - Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. AB - BACKGROUND: Apixaban is superior to aspirin for the prevention of stroke in patients with atrial fibrillation. Apixaban is partially renally excreted and may accumulate in patients with renal impairment. METHODS: We evaluated the efficacy and safety of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with aspirin 81 to 324 mg daily in 1697 patients with stage III chronic kidney disease (CKD) enrolled in the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial. Primary outcome was all stroke and non-central nervous system emboli. RESULTS: Compared with patients with estimated glomerular filtration rates (eGFRs) >=60 mL/min per 1.73 m2, stage III CKD patients (n = 1697; 30% of the cohort; mean eGFR 49 mL/min per 1.73 m2) were older (mean age 75 v 68 years) with more frequent hypertension, diabetes, heart failure, and previous stroke (all P < .01). Stage III CKD was an independent predictor of primary events (hazard ratio [HR] 1.6; P = .01) and major hemorrhage (HR 2.2; P = .02). Apixaban significantly reduced primary events by 68% (5.6% per year on aspirin v 1.8% per year on apixaban; HR 0.32; 95% confidence interval [CI] 0.18-0.55; P < .001) for stage III CKD participants and by 43% (2.8% per year on aspirin v 1.6% per year on apixaban; HR 0.57; 95% CI 0.37-0.87; P = .009) for patients with eGFRs >=60 mL/min per 1.73 m2 (P for interaction = .10). There was no significant difference in major hemorrhage in stage III CKD patients by treatment: 2.2% per year with aspirin versus 2.5% per year with apixaban (HR 1.2; 95% CI 0.65-2.1). CONCLUSIONS: Stage III CKD was an independent predictor of stroke in atrial fibrillation patients taking aspirin. Among stage III CKD patients, apixaban significantly reduced stroke relative to aspirin without a significant increase in major hemorrhage. PMID- 22818022 TI - Polymorphic variations in IL-1beta, IL-6 and IL-10 genes, their circulating serum levels and breast cancer risk in Indian women. AB - BACKGROUND: Cytokines are known as important regulators of the entire gamut of cancer from initiation, invasion and metastasis. This fact and plethora of gene polymorphism data prompted us to investigate cytokine gene polymorphisms in breast cancer (BC) patients. METHODS: Selected polymorphisms in the IL-1beta [ 511 T>C (rs16944) and +3954 C>T (rs1143634)]; IL-6 [-174 G>C (rs1800795)]; IL-10 [-1082 A>G (rs1800896), -819 T>C (rs1800871) and -592 A>C (rs1800872)] genes were genotyped in 200 BC patients and 200 healthy volunteers in a case-control study using PCR-RFLP and direct DNA sequencing techniques. Peripheral cytokine levels were measured using ELISA. Allele and genotype data were analyzed for significance of differences between cases and controls using Chi-Square [chi(2)] test. Two sided P-values of less than 0.05 were considered to be statistically significant. RESULTS: Peripheral level of all three cytokines did not show any significant difference between cases and controls. Allele and genotype frequency of IL-1beta [-511 T>C (rs16944)] did not show any difference between cases and controls. On the other hand mutant allele and genotype at IL-1beta [+3954 C>T (rs1143634)] associated with increased risk of BC. This was also true for pre menopausal cases and for mutant genotype in post-menopausal cases. Mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] appeared to be protective in nature such that controls had a higher frequency of both mutant alleles and genotypes. None of the three SNPs in IL-10 gene associated with risk of BC, except significant association of mutant allele and genotypes of -1082 A>G (rs1800896) polymorphism with postmenopausal BC. CONCLUSIONS: Mutant allele and genotype at IL-1beta [+3954 C>T (rs1143634)] site associated with increased BC risk, while mutant allele and genotypes at IL-6 [-174 G>C (rs1800795)] polymorphism appeared to be protective. Also, there was significant association of mutant allele and genotypes of IL-10 [-1082 A>G (rs1800896)] with postmenopausal BC. None of the other polymorphisms investigated appear to affect BC risk. PMID- 22818023 TI - Evaluation of submucosally injected polyethylene glycol-based hydrogel and bovine cross-linked collagen in the canine urethra using cystoscopy, magnetic resonance imaging and histopathology. AB - OBJECTIVE: To (1) investigate the tissue response to a novel urethral bulking agent, polyethylene glycol carboxymethyl cellulose hydrogel (PEG-CMC) injected submucosally in the canine urethra and (2) compare PEG-CMC with bovine collagen (BC), the current standard for urethral bulking. STUDY DESIGN: Experimental study. ANIMALS: Purpose-bred female hound dogs (n = 8). METHODS: Standardized submucosal urethral injections of BC and PEG-CMC were performed in 8 female dogs. Injection sites were evaluated by cystoscopy on days 0 (n = 8), 30 (n = 4), and 90 (n = 4), magnetic resonance imaging on days 0 (n = 8), 30 (n = 8), and 90 (n = 4) and by histopathology on days 30 (n = 4) and 90 (n = 4). RESULTS: Both PEG-CMC and BC were detectable on MRI as hyperintense foci on T2-weighted images. Grossly, PEG-CMC formed more prominent blebs than BC. On follow-up cystoscopic examination, 6/8 PEG-CMC injection needle tracts were visible, and 3 of these sites had mucosal erosions. Histopathologic scores for foreign body reaction and inflammation were significantly higher for PEG-CMC compared with BC (P < 0.005). BC elicited a lymphoplasmacytic reaction whereas PEG-CMC incited a granulomatous response. CONCLUSIONS: The overall physical characteristics and histologic response associated with PEG-CMC support its use as a urethral bulking agent; however, the current formulation needs to be adjusted for clinical use. PMID- 22818024 TI - A novel and green biomaterial based silver nanocomposite hydrogel: synthesis, characterization and antibacterial effect. AB - In the present study, we report a facile and eco-friendly method for the preparation of a novel silver nanocomposite hydrogel (SNH) based on poly(acrylic acid) (PAA) grafted onto salep as a water soluble polysaccharide backbone. The presence of inorganic silver nanoparticles (nano-Ag) in the hydrogel was confirmed by thermo-gravimetric (TG) analysis. The TEM images illustrated the presence of embedded nano-Ag throughout the hydrogel matrix. In addition, the transmission electron microscopy (TEM) images showed that the formed nano-Ag had an average particle size of 5-10 nm. The potential of obtained SNH was examined for Tetracycline hydrochloride (TH) release in simulated colon conditions. Lastly, the in vitro antibacterial properties of the obtained optimum sample were successfully evaluated against gram-negative and gram-positive bacteria. PMID- 22818025 TI - Simultaneous bioaccumulation of multiple metals from electroplating effluent using Aspergillus lentulus. AB - Toxic impacts of heavy metals in the environment have lead to intensive research on various methods of heavy metal remediation. However, in spite of abundant work on heavy metals removal from simple synthetic solutions, a very few studies demonstrate the potential of microbial strains for the treatment of industrial effluents containing mixtures of metals. In the present study, the efficiency of an environmental isolate (Aspergillus lentulusFJ172995), for simultaneous removal of chromium, copper and lead from a small-scale electroplating industry effluent was investigated. Initial studies with synthetic solutions infer that A. lentulus has a remarkable tolerance against Cr, Cu, Pb and Ni. During its growth, a significant bioaccumulation of individual metal was recorded. After 5 d of growth, the removal of metals from synthetic solutions followed the trend Pb(2+) (100%) > Cr(3+) (79%) > Cu(2+) (78%), > Ni(2+) (42%). When this strain was applied to the treatment of multiple metal containing electroplating effluent (after pH adjustment), the metal concentrations decreased by 71%, 56% and 100% for Cr, Cu and Pb, respectively within 11 d. Based on our results, we propose that the simultaneous removal of hazardous metals from industrial effluents can be accomplished using A. lentulus. PMID- 22818026 TI - Nuclear factor kappaB and cyclooxygenase-2 immunoexpression in oral dysplasia and oral squamous cell carcinoma. AB - Oral leukoplakia is the main potentially malignant oral lesion, and oral squamous cell carcinoma accounts for more than 95% of all malignant neoplasms in the oral cavity. Therefore, the aim of this study was to verify the immunoexpression of nuclear factor kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) proteins in dysplastic oral lesions and oral squamous cell carcinoma. Immunohistochemical reactions were performed on 6 inflammatory fibrous hyperplasia, 28 oral leukoplakia, and 15 oral squamous cell carcinoma paraffin-embedded samples. Immunoperoxidase reaction for NF-kappaB and COX-2 was applied on the specimens, and the positivity of the reactions was calculated for 1000 epithelial cells. Using the analysis of variance and the Tukey post hoc statistical analyses, a significantly increased immunoexpression for NF-kappaB was observed when oral squamous cell carcinoma samples were compared with the other groups studied. However, using the Kruskal-Wallis and the Dunn post hoc tests, a statistically significant result for COX-2 expression was obtained only when the moderate dysplasia group was compared with the inflammatory fibrous hyperplasia group. Nuclear factor kappaB may participate in the malignant phenotype acquisition process of the oral squamous cell carcinoma in its late stages, whereas COX-2 may be involved in the early stages of oral carcinogenesis process. PMID- 22818027 TI - Regulation of collateral blood vessel development by the innate and adaptive immune system. AB - The development of collateral circulation is an inherent compensatory mechanism to restore impaired blood perfusion following artery stenosis and/or occlusion. This process, termed arteriogenesis, is driven by inflammation and involves a complex remodeling of pre-existing conduit vessels running in parallel to the occluded artery. Recent studies have unveiled roles for different immune cell subsets as regulators of arteriogenesis, including natural killer (NK) cells, T helper 17 (Th17) cells, regulatory T lymphocytes (Tregs), and functional subsets of macrophages (e.g., M2 macrophages). This review summarizes recent findings and discusses future research needed to better define the time during which each cellular subset is active and reveal further critical regulatory switches. PMID- 22818028 TI - Determination of typhaneoside in rat plasma by liquid chromatography-tandem mass spectrometry. AB - A highly sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of typhaneoside in rat plasma using rutin as internal standard. The analyte and rutin (internal standard) were extracted with methanol followed by a rapid isocratic elution with 10 mM ammonium acetate buffer/methanol (v:v, 20:80) on an C(18) column (150 mm * 2.1 mm I.D.) and subsequent analysis by mass spectrometry in the multi-reaction-monitoring mode. The precursor to product ion transitions of m/z 769.3 -> 314.1 and m/z 609.2 -> 300.1 were used to measure the analyte and the internal standard. The assay was linear over the concentration range of 0.01-10 MUg/mL for typhaneoside in rat plasma. The lower limit of quantification was 0.01 MUg/mL and the extraction recovery was larger than 90.2% for typhaneoside. The inter- and intra day precision of the method at three concentrations was less than 6.8%. The method was firstly applied to pharmacokinetic study of typhaneoside in rats. PMID- 22818029 TI - A criterion for assessing homogeneity distribution in hyperspectral images. Part 1: homogeneity index bases and blending processes. AB - The Process Analytical Technologies (PAT) initiative of the US Food and Drug Administration (US FDA) has established a framework for the development of imaging techniques to determine the real-time distribution of mixture components during the production of solid dosage forms. This study, which is the first in a series of two parts, uses existing mixing indices and a new criterion called the "percentage of homogeneity" (H%) to assess image homogeneity. Image analysis techniques use feature extraction procedures to extract information from images subjected to treatments including colour segmentation and binarization. The surface distribution of components was determined by macropixel analysis, which splits an image into non-overlapping blocks of a preset size and calculates several statistical parameters for the resulting divisional structure. Such parameters were used to compute mixing indices. In this work, we explored the potential of image processing in combination with mixing indices and H% for assessing blending end-point and component distribution on images. As a simplified test, an arrangement of binary and ternary systems of coloured particles was mixed collecting at-line multispectral (MSI) and non-invasive RGB pictures at preset intervals. PMID- 22818031 TI - Women's experiences of participation in a pregnancy and postnatal group incorporating yoga and facilitated group discussion: a qualitative evaluation. AB - BACKGROUND: This paper reports on a small qualitative research study which explored women's experiences of participation in a pregnancy and postnatal group that incorporated yoga and facilitated discussion. The group is offered through a community based feminist non-government women's health Centre in Northern NSW Australia. QUESTION: The purpose of the research was to explore women's experiences of attending this pregnancy and postnatal group. METHODS: An exploratory qualitative approach was used to explore women's experiences of attending the group. Fifteen women participated in individual, in-depth face-to face interviews. Interviews were recorded and transcribed verbatim. Thematic analysis was undertaken to analyse the qualitative data. FINDINGS: Six themes were developed, one with 3 subthemes. One theme was labelled as: 'the pregnancy and motherhood journey' and included 3 sub-themes which were labelled: 'preparation for birth', 'connecting with the baby' and 'sharing birth stories.' The other five themes were: 'feminine nurturing safe space', 'watching and learning the mothering', 'building mental health, well-being and connections', the "group like a rock and a seed' and 'different from mainstream'. CONCLUSION: This research adds to the overall body of knowledge about the value of yoga in pre and postnatal care. It demonstrates the value of sharing birth stories and the strong capacity women have to support one another, bringing benefits of emotional and social well-being, information, resources and support derived from group based models of care. PMID- 22818032 TI - Multi-way metamodelling facilitates insight into the complex input-output maps of nonlinear dynamic models. AB - BACKGROUND: Statistical approaches to describing the behaviour, including the complex relationships between input parameters and model outputs, of nonlinear dynamic models (referred to as metamodelling) are gaining more and more acceptance as a means for sensitivity analysis and to reduce computational demand. Understanding such input-output maps is necessary for efficient model construction and validation. Multi-way metamodelling provides the opportunity to retain the block-wise structure of the temporal data typically generated by dynamic models throughout the analysis. Furthermore, a cluster-based approach to regional metamodelling allows description of highly nonlinear input-output relationships, revealing additional patterns of covariation. RESULTS: By presenting the N-way Hierarchical Cluster-based Partial Least Squares Regression (N-way HC-PLSR) method, we here combine multi-way analysis with regional cluster based metamodelling, together making a powerful methodology for extensive exploration of the input-output maps of complex dynamic models. We illustrate the potential of the N-way HC-PLSR by applying it both to predict model outputs as functions of the input parameters, and in the inverse direction (predicting input parameters from the model outputs), to analyse the behaviour of a dynamic model of the mammalian circadian clock. Our results display a more complete cartography of how variation in input parameters is reflected in the temporal behaviour of multiple model outputs than has been previously reported. CONCLUSIONS: Our results indicated that the N-way HC-PLSR metamodelling provides a gain in insight into which parameters that are related to a specific model output behaviour, as well as variations in the model sensitivity to certain input parameters across the model output space. Moreover, the N-way approach allows a more transparent and detailed exploration of the temporal dimension of complex dynamic models, compared to alternative 2-way methods. PMID- 22818033 TI - [Ergonomics in laparoscopic surgery: point of view of the woman surgeons]. PMID- 22818034 TI - [Migration of a sternum fixation bar to the abdominal cavity]. PMID- 22818035 TI - [Right hepatectomy combined with a nephrectomy and diaphragm resection as treatment of a recurrent malignant phaechromocytoma 12 years after resection]. PMID- 22818036 TI - [Bronchial-pancreatic fistula: diagnostic-therapeutic approach]. PMID- 22818037 TI - Using online roleplay in undergraduate midwifery education: a case-study. AB - Online roleplay i.e. role play which occurs using an online asynchronous discussion board, can be effectively utilised to teach a variety of skills to midwifery students. This paper will discuss the design and implementation of an online roleplay for a small (n = 19) class of final year undergraduate Midwifery students. It briefly describes the design of the online roleplay and outlines the expected learning outcomes of the activity. It then outlines evaluative survey results for student evaluation of the online role play. Results focus on student opinion of communication and collaboration skills developed through participation in the roleplay. Students considered that the online roleplay provided them with a means to allow communication skills to be developed and practiced. They also believed that the roleplay enable them to practice collaboration in an authentic real world setting. Finally implications for use of this method of teaching in nurse/midwife education are discussed. PMID- 22818038 TI - Synthesis, self-aggregation and bioactivity properties of a cationic aminoacyl surfactant, based on a new class of highly functionalized nucleolipids. AB - A highly functionalized aminoacyl nucleolipid based on uridine is here proposed as a novel cationic surfactant. To achieve this, a straightforward, high yielding and versatile protocol has been devised, in principle providing synthetic access to a variety of different, related analogs. Self-aggregation properties of this nucleolipid were determined by using a combined approach, including surface tension, conductivity and DLS measurements. Above the critical micellar concentration of 4 * 10(-5) mol kg(-1), large supramolecular assemblies with a counterion condensation degree of 0.25 were observed. The bioactivity profile of this new compound was investigated on cancer and non cancer cell lines. PMID- 22818039 TI - A series of 2-arylamino-5-(indolyl)-1,3,4-thiadiazoles as potent cytotoxic agents. AB - A series of 2-arylamino-5-(indolyl)-1,3,4-thiadiazoles 6a-v were prepared and studied for their anticancer activity against selected human cancer cell lines. The reaction of indolylhydrazides 3a-h with a variety of aryl isothiocyanates 4 afforded the key intermediate thiosemicarbazides 5a-v, which upon treatment with acetyl chloride produced the 2-arylamino-5-(indolyl)-1,3,4-thiadiazoles 6a-v in good yields. Most of the synthesized compounds showed selective cytotoxicity towards human breast cancer cell line (MDA-MB-231). Of the synthesized 2 arylamino-5-(indolyl)-1,3,4-thiadiazoles, compound 6f is the most potent towards tested cancer cell lines (IC(50) = 0.15-1.18 MUM). PMID- 22818040 TI - Synthesis and biological evaluation of novel C-indolylxylosides as sodium dependent glucose co-transporter 2 inhibitors. AB - Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure-activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats. PMID- 22818041 TI - New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines: synthesis, 2D-QSAR, anti inflammatory, analgesic and ulcerogenicity studies. AB - New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines were synthesized. A series of ylidene carbohydrazides 14a-i, and hydrazonate 15, were obtained from the prepared 3-carbohydrazide derivative 13. Pyrazole derivatives 12, 16a,b, 18, 19, 20, were also prepared through different reactions. The anti-inflammatory and analgesic activities of all new compounds were evaluated and most of them exerted comparable activity to indomethacin and celecoxib. Ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drugs. The most potent anti-inflammatory compound 12 showed an IC(50) of 6.00 MUmol/kg and low ulcer index. COX-1/COX-2 activity ratio of compounds 12 and 16b showed almost equal inhibitory effect on both isoenzymes. 2D QSAR studies revealed good predictive and statistically significant QSAR models. PMID- 22818042 TI - Azide-alkyne cycloaddition en route to novel 1H-1,2,3-triazole tethered isatin conjugates with in vitro cytotoxic evaluation. AB - 1H-1,2,3-triazole tethered isatin conjugates have been synthesized and evaluated for cytotoxicity on four human cancer cell lines. The results revealed 5a, 5c, 5e and 5n proved to be twice as potent as 5-fluorouracil on THP-1 cell line with 5a and 5c being most active exhibiting IC(50) values of <1 against all cell lines except Caco-2. Activity profiles showed dependence on the substituents on isatin rings with a preference for hydrogen while a strong electron withdrawing fluoro as well as nitro substituents on either ring decreased the anticancer activity. PMID- 22818044 TI - Bone sutures--prevention of vertical height gain in midface distraction during callus formation. PMID- 22818043 TI - Medical students' personal choice for mode of delivery in Santa Catarina, Brazil: a cross-sectional, quantitative study. AB - BACKGROUND: The increase in overall rates of cesarean sections (CS) in Brazil causes concern and it appears that multiple factors are involved in this fact. In 2009, undergraduate students in the first and final years of medical school at the University of Santa Catarina answered questionnaires regarding their choice of mode of delivery. The aim of the study was to evaluate whether the education process affects decision-making regarding the way of childbirth preferred by medical students. METHODS: A cross-sectional, quantitative study was conducted based on data obtained from questionnaires applied to medical students. The questions addressed four different scenarios in childbirth, as follows: under an uneventful pregnancy; the mode of delivery for a pregnant woman under their care; the best choice as a healthcare manager and lastly, choosing the birth of their own child. For each circumstance, there was an open question to explain their choice. RESULTS: A total of 189 students answered the questionnaires. For any uneventful pregnancy and for a pregnant woman under their care, 8.46% of the students would opt for CS. As a healthcare manager, only 2.64% of the students would recommend CS. For these three scenarios, the answers of the students in the first year did not differ from those given by students in the sixth year. In the case of the student's own or a partner's pregnancy, 41.4% of those in the sixth year and 16.8% of those in the first year would choose a CS. A positive association was found between being a sixth year student and a personal preference for CS according to logistic regression (OR = 2.91; 95%CI: 1.03-8.30). Pain associated with vaginal delivery was usually the reason for choosing a CS. CONCLUSIONS: A higher number of sixth year students preferred a CS for their own pregnancy (or their partner's) compared to first year students. Pain associated with vaginal delivery was the most common reason given for haven chosen a CS. The students' preference for childbirth changed over time during their graduation in favor of cesarean sections. This finding deserves considerable attention when structuring medical education in Obstetrics. PMID- 22818045 TI - Interim reconstruction and space maintenance of mandibular continuity defects preceding definitive osseous reconstruction. AB - The use of space maintenance in mandibular defects as an interim measure before definitive osseous reconstruction may prevent problems associated with delayed reconstruction including increased technical difficulty, contracture of soft tissues that limits the volume of the final reconstruction, and the potential for iatrogenic injury to adjacent anatomical structures. The use of a condyle/ramus spacer made of medical grade, ultrahigh-molecular-weight polyethylene, and a flexible body spacer made of high quality, inert, non-toxic medical and food grade silicone rubber, was tested in 38 patients with mandibular defects after the resection of benign but locally aggressive disease, advanced osteomyelitis, and injuries. The spacer was retained for a maximum of 8 weeks, and was then removed through an extraoral approach before definitive reconstruction with a particulate corticocancellous bone graft. One of the 38 patients failed to attend for follow up and returned 7 months later with severe, generalised sepsis that required removal of the spacer and exclusion from the study. Of the remaining 37 patients, 32 healed uneventfully, 1 required removal of the spacer 2 weeks after implantation for intraoral wound dehiscence, and 4 had mild to moderate disturbances of wound healing that required either minor revision or local wound care until removal at the time of reconstruction. The use of a spacer promotes wound healing and simplifies and expedites secondary reconstruction of mandibular defects. PMID- 22818046 TI - Country ownership and capacity building: the next buzzwords in health systems strengthening or a truly new approach to development? AB - BACKGROUND: During the last decade, donor governments and international agencies have increasingly emphasized the importance of building the capacity of indigenous health care organizations as part of strengthening health systems and ensuring sustainability. In 2009, the U.S. Global Health Initiative made country ownership and capacity building keystones of U.S. health development assistance, and yet there is still a lack of consensus on how to define either of these terms, or how to implement "country owned capacity building". DISCUSSION: Concepts around capacity building have been well developed in the for-profit business sector, but remain less well defined in the non-profit and social sectors in low and middle-income countries. Historically, capacity building in developing countries has been externally driven, related to project implementation, and often resulted in disempowerment of local organizations rather than local ownership. Despite the expenditure of millions of dollars, there is no consensus on how to conduct capacity building, nor have there been rigorous evaluations of capacity building efforts. To shift to a new paradigm of country owned capacity building, donor assistance needs to be inclusive in the planning process and create true partnerships to conduct organizational assessments, analyze challenges to organizational success, prioritize addressing challenges, and implement appropriate activities to build new capacity in overcoming challenges. Before further investments are made, a solid evidence base should be established concerning what works and what doesn't work to build capacity. SUMMARY: Country-owned capacity building is a relatively new concept that requires further theoretical exploration. Documents such as The Paris Declaration on Aid Effectiveness detail the principles of country ownership to which partner and donor countries should commit, but do not identify the specific mechanisms to carry out these principles. More evidence as to how country-owned capacity building plays out in practice is needed to guide future interventions. The Global Health Initiative funding that is currently underway is an opportunity to collect evaluative data and establish a centralized and comprehensive evidence base that could be made available to guide future country-owned capacity building efforts. PMID- 22818061 TI - Cerebral embolus following chiropractic manipulation in a patient with a calcified carotid artery. AB - BACKGROUND AND PURPOSE: Dissection of the cervicocranial vessels is the principal cause of ischemic brain injury following cervical spinal manipulation. Cervical spinal manipulation leading to cerebral embolus in the absence of dissection is not described in the literature. Current case documents cerebral embolism originating from extensively calcified internal carotid artery immediately following cervical spinal manipulation in the absence of dissection. METHODS: We describe a case and imaging findings of a 63-year-old male who underwent cervical spinal manipulation and developed sudden onset of left-arm numbness and weakness. RESULTS: Computed tomography angiography demonstrated extensively calcified right internal carotid artery at the site of redone carotid endarterectomy as well as calcified embolus in the right inferior middle cerebral artery. CONCLUSIONS: Calcified carotid artery may be at risk for embolization following cervical spinal manipulation. Our recommendation is that, patients with extensively calcified carotid arteries should refrain from aggressive neck maneuvers and cervical spine manipulation therapy to avoid liberation of cerebral embolus. PMID- 22818062 TI - Beta-blockade for mitral regurgitation: could the management of valvular heart disease actually be moving into the 21st century? PMID- 22818063 TI - Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52 week uncontrolled extension study. AB - OBJECTIVES: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension. BACKGROUND: Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening. METHODS: Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST 2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated. RESULTS: The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 +/- 67 m [n = 52] and 413 +/- 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 +/- 80 m [n = 51] and 410 +/- 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events. CONCLUSIONS: Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302). PMID- 22818065 TI - A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation. AB - OBJECTIVES: The purpose of the study was to evaluate the effect of long-term beta(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). BACKGROUND: Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. METHODS: Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or beta(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. RESULTS: Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the beta(1)-AR blockade group required mitral valve surgery (p = 0.23). CONCLUSIONS: beta(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428). PMID- 22818064 TI - S100A12 expression in thoracic aortic aneurysm is associated with increased risk of dissection and perioperative complications. AB - OBJECTIVES: The purpose of this study was to determine the relevance of S100A12 expression to human thoracic aortic aneurysms and type A thoracic aortic aneurysm dissection and to study mechanisms of S100A12-mediated dysfunction of aortic smooth muscle cells. BACKGROUND: Transgenic expression of proinflammatory S100A12 protein in murine aortic smooth muscle causes thoracic aneurysm in genetically modified mice. METHODS: Immunohistochemistry of aortic tissue (n = 50) for S100A12, myeloperoxidase, and caspase 3 was examined and S100A12-mediated pathways were studied in cultured primary aortic smooth muscle cells. RESULTS: We found S100A12 protein expressed in all cases of acute thoracic aortic aneurysm dissection and in approximately 25% of clinically stable thoracic aortic aneurysm cases. S100A12 tissue expression was associated with increased length of stay in patients undergoing elective surgical repair for thoracic aortic aneurysm, despite similar preoperative risk as determined by European System for Cardiac Operative Risk Evaluation. Reduction of S100A12 expression in human aortic smooth muscle cells using small hairpin RNA attenuates gene and protein expression of many inflammatory- and apoptosis-regulating factors. Moreover, genetic ablation of the receptor for S100A12, receptor for advanced glycation end products (RAGE), in murine aortic smooth muscle cells abolished cytokine-augmented activation of caspase 3 and smooth muscle cell apoptosis in S100A12-expressing cells. CONCLUSIONS: S100A12 is enriched in human thoracic aortic aneurysms and dissections. Reduction of S100A12 or genetic ablation of its cell surface receptor, the receptor for advanced glycation end products (RAGE), in aortic smooth muscle resulted in decreased activation of caspase 3 and in reduced apoptosis. By establishing a link between S100A12 expression and apoptosis of aortic smooth muscle cells, this study identifies novel S100A12 signaling pathways and indicates that S100A12 may be a useful molecular marker and possible target for treatment for human aortic diseases. PMID- 22818066 TI - The complex genetics of atrial fibrillation. PMID- 22818068 TI - Sex differences in mortality after transcatheter aortic valve replacement for severe aortic stenosis. AB - OBJECTIVES: The aim of this study was to examine sex differences in outcome after transcatheter aortic valve replacement (TAVR) with real-world data from 2 large centers in Canada. BACKGROUND: Transcatheter aortic valve replacement is an effective alternative to surgical valve replacement in symptomatic patients with severe aortic stenosis, but the impact of sex on outcomes remains unclear. The PARTNER (Placement of Aortic Transcatheter Valves) 1A trial demonstrated greater benefit of TAVR over surgery in women, but whether this was due to the poorer surgical outcome of women or better TAVR outcome, compared with men, is unknown. METHODS: Consecutive patients (n = 641) undergoing TAVR in Vancouver and Quebec City, Canada, were evaluated. Differences in all-cause mortality were examined with Kaplan-Meier estimates, adjusted logistic regression, and proportional hazards models. RESULTS: Women comprised 51.3% of the cohort. Balloon-expandable valves were used in 97% of cases, with transapical approach in 51.7 % women and 38.1% men. Women had more major vascular complications (12.4% vs. 5.4%, p = 0.003) and borderline significantly more major/life-threatening bleeds (21.6% vs. 15.8%, p = 0.08). At baseline, women had higher aortic gradients and worse renal function but better ejection fractions. Men had more comorbidities: prior myocardial infarction, prior revascularization, and chronic obstructive pulmonary disease. The adjusted odds ratio for 30-day all-cause mortality favored women, 0.39 (95% confidence interval: 0.19 to 0.80; p = 0.01), and this benefit persisted for 2 years, hazard ratio 0.60 (95% confidence interval: 0.41 to 0.88; p = 0.008). CONCLUSIONS: Female sex is associated with better short- and long term survival after TAVR. Added to the PARTNER 1A findings, these results suggest TAVR might be the preferred treatment option for elderly women with symptomatic severe aortic stenosis. PMID- 22818067 TI - Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation. AB - OBJECTIVES: The aim of this study was to test the hypothesis that 2 common polymorphisms in the chromosome 4q25 region that have been associated with atrial fibrillation (AF) contribute to the variable penetrance of familial AF. BACKGROUND: Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single nucleotide polymorphisms in the chromosome 4q25 region as independent AF susceptibility alleles. METHODS: Eleven families in which AF was present in >=2 members who also shared a candidate gene mutation were studied. These mutations were identified in all subjects with familial lone AF (n = 33) as well as apparently unaffected family members (age >50 years with no AF; n = 17). RESULTS: Mutations were identified in SCN5A (n = 6), NPPA (n = 2), KCNQ1 (n = 1), KCNA5 (n = 1), and NKX2.5 (n = 1). In genetic association analyses, unstratified and stratified according to age of onset of AF and unaffected age >50 years, there was a highly statistically significant association between the presence of both common (rs2200733 and rs10033464) and rare variants and AF (unstratified p = 1 * 10(-8), stratified [age of onset <50 years and unaffected age >50 years] p = 7.6 * 10(-5)) (unstratified p < 0.0001, stratified [age of onset <50 years and unaffected age >50 years] p < 0.0001). Genetic association analyses showed that the presence of common 4q25 risk alleles predicted whether carriers of rare mutations developed AF (p = 2.2 * 10(-4)). CONCLUSIONS: Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants. PMID- 22818069 TI - Will 3D at 3-T make myocardial stress perfusion magnetic resonance imaging even more competitive? PMID- 22818070 TI - Contemporary evidence about hospital strategies for reducing 30-day readmissions: a national study. AB - OBJECTIVES: This study sought to determine the range and prevalence of practices being implemented by hospitals to reduce 30-day readmissions of patients with heart failure or acute myocardial infarction (AMI). BACKGROUND: Readmissions of patients with heart failure or AMI are both common and costly; however, evidence on strategies adopted by hospitals to reduce readmission rates is limited. METHODS: We used a Web-based survey to conduct a cross-sectional study of hospitals' reported use of specific practices to reduce readmissions for patients with heart failure or AMI. We contacted all hospitals enrolled in the Hospital to Home (H2H) quality improvement initiative as of July 2010. Of 594 hospitals, 537 completed the survey (response rate of 90.4%). We used standard frequency analysis to describe the prevalence of key hospital practices in the areas of: 1) quality improvement resources and performance monitoring; 2) medication management efforts; and 3) discharge and follow-up processes. RESULTS: Nearly 90% of hospitals agreed or strongly agreed that they had a written objective of reducing preventable readmission for patients with heart failure or AMI. More hospitals reported having quality improvement teams to reduce preventable readmissions for patients with heart failure (87%) than for patients with AMI (54%). Less than one-half (49.3%) of hospitals had partnered with community physicians and only 23.5% had partnered with local hospitals to manage patients at high risk for readmissions. Inpatient and outpatient prescription records were electronically linked usually or always in 28.9% of hospitals, and the discharge summary was always sent directly to the patient's primary medical doctor in only 25.5% of hospitals. On average, hospitals used 4.8 of 10 key practices; <3% of hospitals utilized all 10 practices. CONCLUSIONS: Although most hospitals have a written objective of reducing preventable readmissions of patients with heart failure or AMI, the implementation of recommended practices varied widely. More evidence establishing the effectiveness of various practices is needed. PMID- 22818071 TI - 18 years of the Fontan operation at a single institution: results from 771 consecutive patients. AB - OBJECTIVES: The aim of this study was to evaluate Fontan peri-operative outcomes for 771 consecutive patients. BACKGROUND: Since the initial description by Fontan, mortality associated with the Fontan operation has declined substantially. However, postoperative effusions remain a significant challenge. Effusions are a key determinant of postoperative length-of-stay and have been shown to be associated with the development of protein-losing enteropathy and with decreased survival. METHODS: This study was a single-center, retrospective review of 771 patients who underwent Fontan palliation from 1992 to 2009. RESULTS: Patients were divided into 3 eras dictated by shift in clinical practice. Overall mortality was 3.5%, 1% since 1996. Importantly, age at Stage II palliation decreased from Era 1 to Era 3 (7.1 vs. 5.9 months; p = 0.0001), whereas age at Fontan increased (1.7 vs. 2.8 years; p = 0.0001). The proportion of patients with prolonged hospital stay (46.7% vs. 8.2% vs. 19.5%, p < 0.001) decreased substantially after Era 1. A diagnosis of hypoplastic left heart syndrome and longer operative support times were associated with prolonged pleural drainage (odds ratio [OR]: 2.17, p < 0.001; OR: 1.2, p = 0.001) and hospital stay (OR: 1.48, p = 0.05; OR: 1.34, p < 0.001). In patients who underwent invasive assessment, higher pulmonary artery pressure was associated with death (OR: 1.37, p < 0.001) and prolonged hospital stay (OR: 1.09, p = 0.019). Pulmonary arterial pressure >=15 mm Hg was 90% specific for discriminating unfavorable outcomes. CONCLUSIONS: Mortality in the modern era is rare, whereas postoperative pleural drainage remains the dominant morbidity. Elevated pulmonary artery pressure seems to be a marker of unfavorable outcome. Continued investigation is warranted to determine whether medical interventions or alterations to operative strategy can alter peri-operative results and improve long-term outcomes. PMID- 22818072 TI - Validation of dynamic 3-dimensional whole heart magnetic resonance myocardial perfusion imaging against fractional flow reserve for the detection of significant coronary artery disease. AB - OBJECTIVES: The goal of this study was to determine the diagnostic accuracy of dynamic 3-dimensional (3D) whole heart myocardial perfusion cardiovascular magnetic resonance (CMR) against invasively determined fractional flow reserve (FFR) and to establish the correlation between myocardium at risk defined by using the invasive Duke Jeopardy Score (DJS) and noninvasive 3D whole heart myocardial perfusion CMR. BACKGROUND: 3D whole heart myocardial perfusion CMR overcomes the limited spatial coverage of conventional two-dimensional perfusion CMR methods and allows estimation of the extent of ischemia. The method has shown good diagnostic accuracy for the detection of coronary artery disease (CAD) as defined by using quantitative coronary angiography. However, quantitative coronary angiography does not provide a functional assessment of CAD as available from pressure wire-derived FFR. In the catheter laboratory, the DJS can complement FFR to estimate the myocardium at risk. METHODS: Fifty-three patients referred for angiography underwent rest and adenosine stress 3D whole heart myocardial perfusion CMR at 3-T. Perfusion was scored visually on a patient and coronary territory basis, and ischemic burden was calculated by quantitative segmentation of the volume of hypoenhancement. FFR was measured in vessels with >=50% severity stenosis and an FFR <0.75 considered as hemodynamically significant. The DJS was calculated from the coronary angiograms to quantify the myocardium at risk. RESULTS: FFR was measured in 64 of 159 coronary vessels, and 39 had an FFR <0.75. Sensitivity, specificity, and diagnostic accuracy of CMR for the detection of significant CAD were 91%, 90%, and 91%, on a patient basis and 79%, 92%, and 88%, respectively, by coronary territory. There was a strong correlation between the DJS and ischemic burden on CMR (p < 0.0001; Pearson's r = 0.82). CONCLUSIONS: 3D whole heart myocardial perfusion CMR accurately detects functionally significant CAD as defined by using FFR and provides an assessment of ischemic burden in agreement with the invasive DJS. The accurate detection of significant CAD combined with an estimation of ischemic burden by using 3D myocardial perfusion CMR holds promise for noninvasive guidance of therapy and risk stratification of patients with CAD. PMID- 22818073 TI - Hospital strategies to reduce heart failure readmissions: where is the evidence? PMID- 22818074 TI - Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial (Cohort A). AB - OBJECTIVES: This study sought to compare health status and quality-of-life outcomes for patients with severe aortic stenosis (AS) and high surgical risk treated with either transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). BACKGROUND: For high-risk patients with severe AS, TAVR has been shown to result in similar 12-month survival but differing adverse events compared with AVR. METHODS: We evaluated the health status of 628 patients with severe, symptomatic AS at high risk of surgical complications who were randomized to either TAVR or AVR in the PARTNER Trial. Health status was assessed at baseline and 1, 6, and 12 months using the Kansas City Cardiomyopathy Questionnaire, the Short Form-12, and the EuroQol-5D. RESULTS: The primary outcome, the Kansas City Cardiomyopathy Questionnaire summary score, improved more rapidly with TAVR, but was similar for the 2 groups at 6 and 12 months. However, there was a significant interaction between the benefit of TAVR and access site (transapical vs. transfemoral). Patients eligible for transfemoral TAVR demonstrated significant health status benefits with TAVR versus AVR at 1 month (difference, 9.9 points; 95% confidence interval: 4.9 to 14.9; p < 0.001), whereas patients treated via the TA approach demonstrated no benefits with TAVR compared with AVR at any time point. Results for Kansas City Cardiomyopathy Questionnaire subscales and generic measures demonstrated similar patterns. CONCLUSIONS: In high-risk patients with severe AS, health status improved substantially between baseline and 1 year after either TAVR or AVR. TAVR via the transfemoral, but not the transapical route, was associated with a short-term advantage compared with surgery. (Placement of AoRTic TraNscathetER Valve [PARTNER] trial; NCT00530894). PMID- 22818075 TI - A FIRM grip on atrial fibrillation. PMID- 22818077 TI - Prenatal and paediatric imaging needs you! PMID- 22818076 TI - Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. AB - OBJECTIVES: We hypothesized that human atrial fibrillation (AF) may be sustained by localized sources (electrical rotors and focal impulses), whose elimination (focal impulse and rotor modulation [FIRM]) may improve outcome from AF ablation. BACKGROUND: Catheter ablation for AF is a promising therapy, whose success is limited in part by uncertainty in the mechanisms that sustain AF. We developed a computational approach to map whether AF is sustained by several meandering waves (the prevailing hypothesis) or localized sources, then prospectively tested whether targeting patient-specific mechanisms revealed by mapping would improve AF ablation outcome. METHODS: We recruited 92 subjects during 107 consecutive ablation procedures for paroxysmal or persistent (72%) AF. Cases were prospectively treated, in a 2-arm 1:2 design, by ablation at sources (FIRM guided) followed by conventional ablation (n = 36), or conventional ablation alone (n = 71; FIRM-blinded). RESULTS: Localized rotors or focal impulses were detected in 98 (97%) of 101 cases with sustained AF, each exhibiting 2.1 +/- 1.0 sources. The acute endpoint (AF termination or consistent slowing) was achieved in 86% of FIRM-guided cases versus 20% of FIRM-blinded cases (p < 0.001). FIRM ablation alone at the primary source terminated AF in a median 2.5 min (interquartile range: 1.0 to 3.1 min). Total ablation time did not differ between groups (57.8 +/- 22.8 min vs. 52.1 +/- 17.8 min, p = 0.16). During a median 273 days (interquartile range: 132 to 681 days) after a single procedure, FIRM-guided cases had higher freedom from AF (82.4% vs. 44.9%; p < 0.001) after a single procedure than FIRM-blinded cases with rigorous, often implanted, electrocardiography monitoring. Adverse events did not differ between groups. CONCLUSIONS: Localized electrical rotors and focal impulse sources are prevalent sustaining mechanisms for human AF. FIRM ablation at patient-specific sources acutely terminated or slowed AF, and improved outcome. These results offer a novel mechanistic framework and treatment paradigm for AF. (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation [CONFIRM]; NCT01008722). PMID- 22818078 TI - Struma ovarii, pseudo-Meigs' syndrome and raised CA125, a rare association. Answer to May e-quid. PMID- 22818079 TI - Distinct biological effects of golgicide a derivatives on larval and adult mosquitoes. AB - A collection of Golgicide A (GCA) analogs has been synthesized and evaluated in larval and adult mosquito assays. Commercially available GCA is a mixture of four compounds. One enantiomer (GCA-2) of the major diastereomer in this mixture was shown to be responsible for the unique activity of GCA. Structure-activity studies (SAR) of the GCA architecture suggested that the pyridine ring was most easily manipulated without loss or gain in new activity. Eighteen GCA analogs were synthesized of which five displayed distinct behavior between larval and adult mosquitos, resulting in complete mortality of both Aedes aegypti and Anopheles stephensi larvae. Two analogs from the collection were shown to be distinct from the rest in displaying high selectivity and efficiency in killing An. stephensi larvae. PMID- 22818080 TI - Investigation of 7-benzylidenenaltrexone derivatives as resistance reverser for chloroquine-resistant Plasmodium chabaudi. AB - Derivatives of 7-benzylidenenaltrexone (BNTX), which was recently reported to be an effective chloroquine (CQ)-resistance reverser, were synthesized and evaluated for their CQ-resistance reversing activities. The synthesized derivatives showed CQ-resistance reversing effects. They also reacted with glutathione (GSH) both enzymatically and chemically, and inhibited glutathione reductase activity. 7 Benzyl derivative, which was obtained by reduction of the olefin group in alpha,beta-unsaturated ketone structure of BNTX, also exhibited CQ-resistance reversing effect, but its potency was significantly lower than that of BNTX. These outcomes suggested that the decrease in GSH level could be one of the mechanisms of CQ-resistance reversing effects induced by BNTX derivatives. PMID- 22818081 TI - Eco-friendly synthesis and biological evaluation of substituted pyrano[2,3 c]pyrazoles. AB - An ecofriendly green approach for synthesis of substituted pyrano[2,3-c]pyrazoles has been developed via a multicomponent one pot approach in aqueous ethanol medium under totally non-catalytic conditions. The synthesized compounds were evaluated for their antibacterial, anti-inflammatory and cytotoxic activities. PMID- 22818082 TI - The optimization of pyridazinone series of glucan synthase inhibitors. AB - A detailed structure-activity relationship study of a novel series of pyridazine based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model. PMID- 22818083 TI - Is 45 the new 65: the rising role of geriatrics in traumatic injury. PMID- 22818084 TI - Commentary on: Age-related differences in hepatic ischemia/reperfusion: gene activation, liver injury, and protective effect of melatonin. PMID- 22818086 TI - Taste and mouthfeel assessment of porous and non-porous silicon microparticles. AB - Unlike the trace minerals iron, copper and zinc, the semiconductor silicon has not had its organoleptic properties assessed. Nanostructured silicon provides the nutrient orthosilicic acid through hydrolysis in the gastrointestinal tract and is a candidate for oral silicon supplements. Mesoporous silicon, a nanostructured material, is being assessed for both oral drug and nutrient delivery. Here we use taste panels to determine the taste threshold and taste descriptors of both solid and mesoporous silicon in water and chewing gum base.Comparisons are made with a metal salt (copper sulphate) and porous silica. We believe such data will provide useful benchmarks for likely consumer acceptability of silicon supplemented foodstuffs and beverages. PMID- 22818085 TI - Who teaches basic procedural skills: student experience versus faculty opinion. AB - INTRODUCTION: Learning procedural skills as a medical student has evolved, as task trainers and simulators are now ubiquitous. It is yet unclear whether they have supplanted bedside teaching or are adjuncts to it, and whether faculty or residents are responsible for student skills education in this era. In this study we sought to characterize the experience and opinions of both medical students and faculty on procedural skills training. METHODS: Surveys were sent to clinical medical students and faculty at UNC Chapel Hill. Opinions on the ideal learning environment for basic procedural skills, as well as who serves as primary teacher, were gathered using a 4-point Likert scale. Responses were compared via Fisher exact test. RESULTS: A total of 237 students and 279 faculty responded. Third-year students were more likely to report simulation as the primary method of education (64%), compared to either fourth-year students (35%; P < 0.0001) or faculty (43%; P = 0.0018). Third- and fourth-year students were also more likely to report interns as a primary teacher (15% and 10%, respectively) as opposed to faculty (2%), and less likely to suggest faculty were the primary teacher (30% and 21%, respectively, versus 35%), P < 0.0001. Residents were the primary teachers for all three groups (55%, 70%, and 63% respectively). CONCLUSIONS: Our data suggest that both medical students and faculty recognize the utility of simulation in procedural skills training, but vary in the degree to which they think simulation is or should be the primary instructional tool. Both groups suggest residents are the primary teacher of these skills. PMID- 22818087 TI - piRNAs and siRNAs collaborate in Caenorhabditis elegans genome defense. AB - Caenorhabditis elegans piRNAs promote genome surveillance by triggering siRNA mediated silencing of nonself DNA in competition with licensing programs that support endogenous gene expression. PMID- 22818088 TI - Spatial distribution and inter-year variation of hexabromocyclododecane (HBCD) and tris-(2,3-dibromopropyl) isocyanurate (TBC) in farm soils at a peri-urban region. AB - Hexabromocyclododecane (HBCD) is a high production volume brominated flame retardant (BFR) which has been of increasing environmental and public health concern due to its potential environmental persistency, bioaccumulation and toxicity. Tris-(2,3-dibromopropyl) isocyanurate (TBC) is another BFR which has recently been found in environmental matrices near a manufacturing plant, but its production volume and environmental distribution is currently not well known. This study was conducted to investigate the presence and distribution of these two BFRs in farm soils at a region in southeast Beijing. Total HBCD levels ranged from 0.17 to 34.5 ng g(-1) on a dry weight basis (dw) with a median level of 2.97 ng g(-1)dw. The composition profile of HBCD diastereoisomers was, on average, 28%, 13% and 59% for alpha-, beta- and gamma-HBCD, respectively. Detection frequency of TBC was only 25% in 2010 but was detected in all soil samples in 2011, and the median level was 0.19 ng g(-1)dw with the range between below detection limit to 1.62 ng g(-1) dw. There were no significant differences of HBCD and TBC levels among different irrigation sources in the region. The soil HBCD and TBC levels in samples collected in 2011 were significantly higher than in 2010. The increasing short-term temporal levels in farm soil might be due to the rapid urbanization in this region or could also reflect the increasing usage of HBCD and TBC after the phase out of other BFRs. PMID- 22818089 TI - Enhanced heavy metal immobilization in soil by grinding with addition of nanometallic Ca/CaO dispersion mixture. AB - This study investigated the use of a nanometallic Ca and CaO dispersion mixture for the immobilization of heavy metals (As, Cd, Cr and Pb) in contaminated soil. Simple grinding achieved 85-90% heavy metal immobilization, but it can be enhanced further to 98-100% by addition of a nanometallic Ca/CaO dispersion mixture produced by grinding. Observations using SEM-EDS elemental maps and semi quantitative analysis showed that the amounts of As, Cd, Cr, and Pb measurable on the soil particle surface decrease after nanometallic Ca/CaO treatment. The leachable heavy metal concentrations were reduced after nanometallic Ca/CaO treatment to concentrations lower than the Japan soil elution standard regulatory threshold: <0.01 mg L(-1) for As, Cd, and Pb; and 0.05 mg L(-1) for Cr. Effects of soil moisture and pH on heavy metal immobilization were not strongly influenced. The most probable mechanisms for the enhancement of heavy metal immobilization capacity with nanometallic Ca/CaO treatment might be due to adsorption and entrapment of heavy metals into newly formed aggregates, thereby prompting aggregation of soil particles and enclosure/binding with Ca/CaO associated immobile salts. Results suggest that the nanometallic Ca/CaO mixture is suitable for use in immobilization of heavy-metal-contaminated soil under normal moisture conditions. PMID- 22818090 TI - Impact of the lavender rhizosphere on the mercury uptake in field conditions. AB - Lavender plants as well as their rhizosphere and bulk soil were sampled on a wide range of soils with different land use within the Almaden mercury mining district. The aim of this work is to evaluate the role of the rhizosphere on mercury behavior in soil-lavender plant system including chemometric analysis. The edaphic parameters that significantly differed between lavender rhizosphere and bulk soil were: total Hg; easily available Hg; electrical conductivity; organic matter; cation exchange capacity; soluble ions (Cl(-); SO(4)(2-); PO(4)(3 ); NO(3)(-); Al(+); Mn(2+); Ca(2+) and Mg(2+)). The most important variable in the differentiation is electrical conductivity. Furthermore, both organic matter and Mn(2+) in rhizosphere soil seem to block Hg availability to plant. However, the presence of sulfates seems to favor it. Regarding other relationships, Hg seems to block Pb uptake by lavender plants and, on the other hand, the presence of Mn(2+) seems to favor it. Furthermore, Hg root uptake by lavender and its distribution throughout the plant have been studied. The more available Hg in rhizosphere soil, the more Hg is translocated to aerial part and less Hg is retained by root. In all cases, the Hg concentration in the root was higher than in the aerial part. PMID- 22818091 TI - Quality, oxidative markers and DNA damage (DNA) fragmentation of red deer thawed spermatozoa after incubation at 37 degrees C in presence of several antioxidants. AB - Antioxidants may be useful for supplementing sperm extenders. We have tested dehydroascorbic acid (DHA), TEMPOL, N-acetyl-cysteine (NAC) and rutin on epididymal spermatozoa from red deer, during incubation at 37 degrees C. Cryopreserved spermatozoa were thawed, washed and incubated with 1 mM or 0.1 mM of each antioxidant, including oxidative stress (Fe(2+)/ascorbate). Motility (CASA and clustering of subpopulations), viability, mitochondrial membrane potential, and acrosomal status were assessed at 2 and 4 h. Lipoperoxidation, intracellular reactive oxygen species (ROS) and DNA damage (DNA) status (TUNEL) were checked at 4 h. Oxidative stress increased ROS, lipoperoxidation and DNA damage. Overall, antioxidants negatively affected motility and physiological parameters. Only DHA 1 mm protected motility, increasing the fast and progressive subpopulation. However, it had a detrimental effect on acrosomal and DNA status, in absence of oxidative stress. Tempol and rutin efficiently reduced lipoperoxidation, ROS, and DNA damage in presence of oxidative stress. NAC was not as efficient as TEMPOL or rutin reducing lipoperoxidation or protecting DNA, and did not reduce ROS, but its negative effects were lower than the other antioxidants when used at 1 mm, increasing the subpopulation of hyperactivated like spermatozoa at 2 h. Our results show that these antioxidants have mixed effects when spermatozoa are incubated at physiological temperatures. DHA may not be suitable because of prooxidant effects, but TEMPOL, NAC and rutin may be considered for cryopreservation trials. In general, exposure of red deer spermatozoa to these antioxidants should be limited to low temperatures, when only protective effects may develop. PMID- 22818092 TI - Theoretic considerations regarding slow cooling and vitrification during cryopreservation. AB - This review presents the methodology of using theoretic models for development of cryopreservation protocols by designing specific cooling profiles and selecting appropriate external conditions to optimize cryopreservation survival. Biophysical events during the processes of cryopreservation were examined and corresponding theoretic equations were used to simulate cryopreservation procedures under various slow cooling conditions for rat zygotes in the presence of DMSO, using a 0.25-mL plastic straw as the container. Simulation revealed three regions with their own characteristics and cryopreservation relevance. In addition, this review discusses vitrification cryopreservation using two-step additions. The effects of exposure durations and exposure temperatures on cell survival and subsequent development rates were examined in a series of cryopreservation experiments. Values of accumulative osmotic damage were used to quantitatively examine the magnitude of the associated osmotic damage during cryoprotective agent (CPA) additions and dilutions. In these investigations, oocyte blastocyst rates were highly correlated with the values of accumulative osmotic damage in the processes of CPA additions/dilutions. This review emphasizes the most essential step of the selection of the cell container in the process of cryopreservation, and provides practical suggestions and guidelines for optimizing slow cooling protocols. The review stresses that conducting CPA addition steps at 25 degrees C would be preferable for vitrification. It also suggests that the final dilution process needs more systematic research to optimize vitrification procedures. PMID- 22818093 TI - Differences in blood and semen oxidative status in fertile and infertile men, and their relationship with sperm quality. AB - Oxidative stress plays a fundamental role in the aetiology of male infertility by negatively affecting sperm quality and function. Assessment of blood and seminal plasma oxidative profiles might be a valuable tool to improve evaluation of sperm reproductive capacity and functional competence. This study examined the lipid soluble antioxidant profile and levels of lipid peroxidation both in blood and seminal plasma samples of infertile and fertile males, in relation to semen parameters. Total antioxidant capacity (TAC) and vitamin E concentrations were significantly (P<0.05) lower in seminal plasma of infertile men compared with fertile subjects; concurrently, a significant accumulation of malondialdehyde was found in infertile patients (P=0.032 compared with controls), which was negatively correlated with sperm motility and morphology. In blood samples, infertile men presented lower concentrations of TAC, carotenoids and vitamin E than fertile subjects; TAC and carotenoids were positively correlated with sperm motility, morphology and concentration. Finally, blood TAC and vitamin E concentrations were positively correlated with the corresponding seminal values, confirming the close relationship between blood and semen antioxidants. All these results indicated the possibility of using not only seminal antioxidants but also blood antioxidants as biochemical markers to support sperm quality evaluation. Oxidative stress induced by reactive oxygen species (ROS) has been widely recognized as one of the major causes of male infertility; indeed, excessive ROS production can negatively impact sperm quality and function. The assessment of blood and seminal plasma oxidative profiles has been suggested as a valuable tool to improve the evaluation of sperm reproductive capacity and functional competence in infertile men. With this in mind, in the present study we examined the lipid soluble antioxidant profile (carotenoids and vitamins A and E) and the levels of lipid peroxidation (malondialdehyde; MDA) both in blood and seminal plasma samples of infertile and fertile males, in correlation with semen parameters namely motility, morphology and concentration. As a result, we obtained evidence that the total antioxidant capacity (TAC) and the concentrations of vitamin E of seminal plasma samples were significantly lower in infertile men than in fertile subjects; at the same time, a significant accumulation of MDA was found in infertile patients. MDA, in turn, negatively correlated with sperm motility and morphology, thus confirming that oxidative damage to lipids impairs sperm quality. In blood samples, infertile men presented lower TAC and lower concentrations of carotenoids and vitamin E than fertile subjects; interestingly, TAC and carotenoid concentrations were positively correlated with sperm motility, morphology, and concentration, confirming the close relationship between blood antioxidants and sperm quality. In conclusion, all these results suggested that the examination of blood and semen oxidative profiles might furnish useful information on sperm quality and function in infertile men. PMID- 22818094 TI - Office hysteroscopy improves pregnancy rates following IVF. AB - The aim of the study was to evaluate the effect of office hysteroscopy (OH) on pregnancy rate in patients undergoing IVF. A total of 1258 patients attending an IVF clinic with normal hysteroscopic findings were enrolled. The impact of timing of OH before embryo transfer on pregnancy rate was investigated. The women were evaluated in three groups: group 1, OH performed 50 days or less before embryo transfer (n=407), group 2, OH between 51 days to 6 months, (n=280) and group 3, OH more than 6 months before embryo transfer (n=571). The implantation rates were 22.1%, 16.1% and 11.1% in groups 1, 2 and 3, respectively. Overall pregnancy rates were 48.2%, 38.9% and 29.9% in groups 1, 2 and 3, respectively. The clinical pregnancy rates were 45.2%, 34.3% and 27.1% and the live birth rates were 36.9%, 27.9% and 22.6%, respectively. Implantation, pregnancy, clinical pregnancy and live birth rates were significantly higher in group 1 compared with groups 2 and 3 (all P<0.05). OH may improve pregnancy rates, but timing of the procedure is important. The endometrial effect is highest when hysteroscopy is performed 50 days or less before embryo transfer. Office hysteroscopy (OH), which helps the clinician for the evaluation of the uterine cavity before IVF treatment, may affect the pregnancy rates depending on when the procedure is performed. A total of 1258 patients attending an outpatient IVF clinic were enrolled in the study. The women were evaluated in three groups: group 1, OH performed 50 days or less before embryo transfer (n=407), group 2, OH between 51 days to 6 months, (n=280) and group 3, OH more than 6 months before embryo transfer (n=571). The implantation, pregnancy and clinical pregnancy rates were significantly higher in group 1 compared with groups 2 and 3. OH may improve pregnancy rates when performed 50 days or less before embryo transfer. PMID- 22818095 TI - Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure. AB - This prospective cohort study examined the effects of atosiban on uterine contraction, implantation rate (IR) and clinical pregnancy rate (CPR) in women undergoing IVF/embryo transfer. The study enrolled 71 women with repeated implantation failure (RIF; no pregnancies from an average of 4.8 previous embryo transfers with a mean of 12 top-quality embryos) undergoing IVF/embryo transfer using cryopreserved embryos. The total atosiban dose was 36.75 mg. The IR per transfer and CPR per cycle were 13.9% and 43.7%, respectively. Before atosiban, 14% of subjects had a high frequency of uterine contractions (>= 16 in 4 min). The frequency of uterine contractions was reduced after atosiban. This reduction of uterine contractions in all cycles was significant overall (from 6.0 to 2.6/4 min; P<0.01), in cycles with >= 16 uterine contractions/4 min at baseline (from 18.8 to 5.1; P<0.01) and in cycles with <16 uterine contractions/4 min (from 3.9 to 2.2; P<0.01). IR and CPR improved in all subjects, irrespective of baseline uterine contraction frequency. This is the first prospective study showing that atosiban may benefit subjects with RIF undergoing IVF/embryo transfer with cryopreserved embryos. One potential mechanism is the reduction in uterine contractility, but others may also contribute. Many women undergoing IVF/embryo transfer do not achieve the outcome that they wish for. In fact, IVF/embryo transfer repeatedly fails for a subgroup of patients. There are limited options available to help these patients with repeat implantation failure (RIF) to become pregnant. This study looks at one potential new treatment option for women who experience RIF. A drug called atosiban is already being used to delay premature labour by inhibiting contractions of the uterus. In this study, atosiban was given at the time of embryo transfer to women undergoing IVF/embryo transfer. Atosiban reduced the number of uterine contractions in these patients and also increased the implantation and pregnancy rates. The pregnancy rate went from zero to 43.7%. The beneficial effects of atosiban were observed not only in patients who had a high frequency of uterine contractions at baseline but also in those who had a low frequency. These findings suggest that atosiban may have other benefits in addition to its effect on contractions of the uterus. More studies are required to find out exactly how atosiban works and to increase the knowledge of its use in patients with RIF undergoing IVF/embryo transfer. PMID- 22818096 TI - Serum HCG measured in the peri-implantation period predicts IVF cycle outcomes. AB - The current study assessed the relationship between serum concentrations of human chorionic gonadotrophin (HCG) measured in the peri-implantation period and various outcome measures following blastocyst transfer in IVF cycles. The study group included 767 autologous IVF cycles, each with the transfer of two fresh blastocysts in a 6-year study period, ending 31 December 2009. Outcome measures were ectopic pregnancy, biochemical pregnancy loss, ongoing pregnancy, spontaneous abortion and multiple pregnancy. Peri-implantation serum HCG concentration measured 5 days after blastocyst transfer was highly predictive of these outcome measures. These findings suggest embryonic implantation and developmental fate are largely determined by 5 days after blastocyst transfer and that very early serum HCG measurements may be useful markers of IVF outcome. PMID- 22818097 TI - Surgically retrieved spermatozoa versus ejaculated spermatozoa in modified natural IVF-ICSI cycles. AB - A retrospective cohort study was performed to evaluate the outcome of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) cycles to compare 81 mnIVF-ICSI first cycles using ejaculated spermatozoa with 44 mnIVF-ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group (41.5 versus 36.5 years, P=0.001). There were no significant differences in fertilization rate or cleavage rate between the ejaculated and the surgically retrieved groups; however the prevalence of embryo transfer was higher in the surgically retrieved group (65.9% versus 45.7%, P=0.03). Only single-embryo transfer was performed. Biochemical (34.5% versus 37.8%) and clinical (31.0% versus 35.1%) pregnancy rates per embryo transfer were similar between the ejaculated and the surgically retrieved groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. The aim of the present study was to evaluate and compare the outcomes of modified natural IVF-intracytoplasmic sperm injection (mnIVF-ICSI) with surgically retrieved spermatozoa (in male partners with obstructive azoospermia) and ejaculated spermatozoa (in couples with mild-to-moderate male factor). Eighty-one mnIVF-ICSI first cycles using ejaculated spermatozoa were compared with forty-four mnIVF ICSI first cycles using surgically retrieved spermatozoa. There were no differences between the two groups in terms of number of oocytes retrieved, oocyte maturity or female age. However, male age was significantly higher in the surgically retrieved compared with the ejaculated group. There were no significant differences in fertilization rate, or cleavage rate between the two groups; however, there were more patients having embryo transfers in the surgically retrieved group. Only single-embryo transfer was performed. Biochemical and clinical pregnancy rates per embryo transfer were similar between both groups. The data suggest that mnIVF-ICSI is an alternative treatment option in couples with severe male factor infertility where surgical sperm retrieval is required. PMID- 22818098 TI - Bacterial pericarditis caused by Lactobacillus iners in an infant. AB - We report the case of a 6-month-old male infant with bacterial pericarditis due to Lactobacillus iners. Although the culture of pericardial fluid was negative, L. iners was identified by 16S rRNA gene amplification by polymerase chain reaction and a subsequent sequence analysis. This weakly pathogenic bacterium could develop a severe infection in infants. PMID- 22818099 TI - Curriculum for education and training of medical physicists in nuclear medicine: recommendations from the EANM Physics Committee, the EANM Dosimetry Committee and EFOMP. AB - PURPOSE: To provide a guideline curriculum covering theoretical and practical aspects of education and training for Medical Physicists in Nuclear Medicine within Europe. MATERIAL AND METHODS: National training programmes of Medical Physics, Radiation Physics and Nuclear Medicine physics from a range of European countries and from North America were reviewed and elements of best practice identified. An independent panel of experts was used to achieve consensus regarding the content of the curriculum. RESULTS: Guidelines have been developed for the specialist theoretical knowledge and practical experience required to practice as a Medical Physicist in Nuclear Medicine in Europe. It is assumed that the precondition for the beginning of the training is a good initial degree in Medical Physics at master level (or equivalent). The Learning Outcomes are categorised using the Knowledge, Skill and Competence approach along the lines recommended by the European Qualifications Framework. The minimum level expected in each topic in the theoretical knowledge and practical experience sections is intended to bring trainees up to the requirements expected of a Medical Physicist entering the field of Nuclear Medicine. CONCLUSIONS: This new joint EANM/EFOMP European guideline curriculum is a further step to harmonise specialist training of Medical Physicists in Nuclear Medicine within Europe. It provides a common framework for national Medical Physics societies to develop or benchmark their own curricula. The responsibility for the implementation and accreditation of these standards and guidelines resides within national training and regulatory bodies. PMID- 22818100 TI - No need to abandon unilateral parathyroid surgery. PMID- 22818102 TI - Unilateral vs bilateral parathyroidectomy: a healthy debate. PMID- 22818103 TI - Crisis checklists for the operating room, not with a simulator. PMID- 22818105 TI - Effect of conflict of interest on publication of collective review. PMID- 22818108 TI - Retroperitoneal dissection in patients with borderline resectable pancreatic cancer: operative principles and techniques. AB - Pancreatectomy with aggressive vascular resection is increasingly being recognized as an appropriate treatment strategy for patients with borderline resectable PDAC after administration of chemotherapy and/or chemoradiation. Because tumor downstaging is an uncommon event, both venous and hepatic arterial resection and reconstruction might be necessary to achieve negative surgical margins and the favorable short-term and long-term outcomes we have reported previously. The technical approaches we have described here can be used as a basic foundation for operative safety and efficiency during these challenging operations. PMID- 22818109 TI - Ethical and legal constraints to children's participation in research in Zimbabwe: experiences from the multicenter pediatric HIV ARROW trial. AB - BACKGROUND: Clinical trials involving children previously considered unethical are now considered essential because of the inherent physiological differences between children and adults. An integral part of research ethics is the informed consent, which for children is obtained by proxy from a consenting parent or guardian. The informed consent process is governed by international ethical codes that are interpreted in accordance with local laws and procedures raising the importance of contextualizing their implementation. FINDINGS: In Zimbabwe the parental informed consent document for children participating in clinical research is modeled after Western laws of ethics and requires that the parent or legally authorized representative provide consent on behalf of a minor. This article highlights the experiences and lessons learnt by Zimbabwean researchers in obtaining informed consent from guardians of orphaned children participating in a collaborative HIV clinical trial involving the Medical Research Council, United Kingdom and four centers, three of which are in Uganda. Researchers were faced with a situation where caregivers of orphaned children were not permitted to provide informed consent for trial participation. The situation contrasted with general clinical practice where consent for procedures on orphans is obtained from their caregivers who are not legal guardians. CONCLUSION: The challenges faced in obtaining informed consent for orphans in this clinical trial underscores the need for the Zimbabwe ethics committee to develop an ethical and legal framework for pediatric research that is based on international guidelines while taking into account the cultural context. The Medical Research Council of Zimbabwe has since started the process that is expected to involve critical stakeholders namely the community including children, ethicists, the legal fraternity and researchers. PMID- 22818111 TI - Growing prevalence of Providencia stuartii associated with the increased usage of colistin at a tertiary health care center. AB - From 2005 to 2009, at Detroit Medical Center, the prevalence of Providencia stuartii increased from 0.52 to 0.91/1000 patient-days (p<0.001). The use of colistin also increased (p<0.001) during the study period. The increase in the prevalence of P. stuartii was associated with an increased use of colistin (p<0.001). Facilities that frequently use colistin and tigecycline should closely monitor the prevalence of P. stuartii along with other Proteeae, since these organisms are intrinsically resistant to colistin and tigecycline. PMID- 22818110 TI - Prevalence of symptomatic intracranial atherosclerosis in Caucasians: a prospective, multicenter, transcranial Doppler study. AB - BACKGROUND: There are limited data available regarding symptomatic intracranial atherosclerosis (SIA) prevalence in Caucasians. We sought to investigate SIA prevalence among Caucasian patients hospitalized with acute cerebral ischemia (ACI) in a prospective, multicenter Transcranial Doppler sonography (TCD) study. METHODS: Consecutive patients with ACI were prospectively evaluated with TCD over a 24-month-period. The previously validated criteria of SONIA trial were used for detection of >50% intracranial stenosis with TCD. Brain angiography was performed to confirm the diagnosis in cases with abnormal TCD findings. SIA was diagnosed when there was evidence of a cerebral infarction in the territory of the stenotic artery (identified by TCD and confirmed by Magnetic resonance angiography [MRA]/Computed tomography angiography [CTA]). RESULTS: A total of 467 consecutive patients with ACI (60.4% men, mean age 58 +/- 14 years) were evaluated. SIA was documented in 43 patients (9.2%; 95%CI: 6.9%-12.2%). The most common SIA location was M1MCA (34.9%) followed by TICA (18.8%). Diabetes mellitus (OR: 4.25, 95%CI: 2.18-8.26; P < .001) and hypertension (OR: 2.41, 95%CI: 1.02-5.67; P = .045) were independently associated with SIA on multivariate models adjusting for potential confounders. CONCLUSIONS: SIA was identified in almost 10% of patients admitted with symptoms of ACI. These preliminary findings support further collaborative initiatives among stroke physicians to increase the yield of SIA detection in Caucasian patients with ACI. PMID- 22818112 TI - Asymmetric patterns in the cranial skeleton of zebrafish (Danio rerio) exposed to sodium pentachlorophenate at different embryonic developmental stages. AB - Bilaterally symmetric organisms display mirror copies of their structures on both sides of the body, and the development of both sides is regulated by the same set of genes. Environmental variations can directly affect phenotype, and exposure to chemical contaminants at certain stages may modify embryonic development. The pesticide sodium pentachlorophenate (NaPCP) was used at the no-observable-effect concentration (NOEC) to determine the degree of susceptibility of zebrafish (Danio rerio) embryos in different developmentally susceptible windows (zygote, blastula, gastrula, segmentation, pharyngula and larva). Shape variation in the zebrafish viscerocranium and fluctuating asymmetry (FA), which increases in direct proportion to environmental stress, induced by exposure to NaPCP were measured with geometric morphometrics. Procrustes ANOVA was performed to estimate the shape variation around a symmetric consensus that accounted for the following factors: shape variation in individuals (I), variation by sides (S), the Individuals*Sides interaction (I*S), and the stages of exposure to the toxicant (Stages). Factors I, S and IxS accounted for most of the morphological variation (p<0.0001). Extensive deformities throughout the viscerocranium occurred during the window of exposure from gastrula to larva. Embryonic mortality occurred and was dependent on the stage of exposure. The NOEC concentration of NaPCP affected embryonic development in D. rerio and also induced lethal effects in embryos. FA was determined in both unexposed and NaPCP-exposed embryos and was greater in the control than in some exposure windows; besides, no correlation was found between FA and developmental stages, so our results do not support FA as a bioindicator of chemical stress but confirm its value in the study of morphological effects of toxicants. PMID- 22818113 TI - Validation of the Stroke-specific Quality of Life for patients after aneurysmal subarachnoid hemorrhage and proposed summary subscores. AB - BACKGROUND: The identification of aneurysmal subarachnoid hemorrhage (aSAH) patients with a decrease in health-related quality of life (HRQOL) is challenging. Failure of clinical trials has been partially attributed to lack of sensitivity in outcome measures. Stroke-specific Quality of Life (SS-QOL) is a disease-specific HRQOL tool widely applied in ischemic stroke researches, but not in aSAH. AIM: This study aimed to validate a Chinese version of SSQOL (SS-QOL-CH) for aSAH patients and proposed summary scores for clinical application. METHODS: We carried out a prospective observational assessor-blinded multi-center study in Hong Kong. One hundred and four Chinese adults were recruited into the current study, and assessments of the outcome of aSAH patients were made 3months after ictus. RESULTS: Internal consistency was good and supported convergent validity for 12 domains of the SS-QOL-CH, with Cronbach's alpha coefficients ranging from 0.73 to 0.98. Principal component analyses suggested a two-component solution to explain a total of 65% variance. The two-component solution showed no significant floor or ceiling effects in our aSAH population. Validity of the criteria for the physical and psychosocial subtotal scores showed relevant and distinct correlations with other outcome measures. CONCLUSIONS: Dichotomization of physical and psychosocial subtotal scores is valid and can simplify applications of the scale. PMID- 22818114 TI - Opsoclonus: clinical and immunological features. AB - BACKGROUND: Opsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. METHODS: We recorded eye movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. RESULTS: In all patients but one the opsoclonus resolved within 2weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4-10Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. CONCLUSIONS: The clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus. PMID- 22818115 TI - 'Chasing the numbers': Australian Bachelor of Midwifery students' experiences of achieving midwifery practice requirements for registration. AB - OBJECTIVE: to explore one aspect of the findings from a qualitative study exploring Australian Bachelor of Midwifery students' experiences of achieving competency for beginning practice. DESIGN: a qualitative study using grounded theory, incorporating situational analysis. Data were collected by interviews, field observation and students' documents. SETTING: one university in Victoria, Australia, which was a member of a consortium of universities that first implemented Bachelor of Midwifery curricula. PARTICIPANTS: 19 women, aged 20-40 years, completing the Bachelor of Midwifery course between the years 2005 and 2008. FINDINGS: data analysis revealed an overarching social process of assimilation, and three related subprocesses namely realisation, adaptation and consolidation. This paper focuses on consolidation in terms of competency achievement in relation to set requirements. KEY CONCLUSIONS: while generally found competent for beginning practice, the Bachelor of Midwifery students in this study felt that their ability to achieve competency according to professional midwifery standards, was constrained by the restricted nature of midwifery practice and medical dominance in the hospitals where they were placed. Furthermore, they found it challenging to achieve the minimum midwifery experience requirements, as well as their own personal learning objectives, within the clinical practicum hours provided in the curriculum. IMPLICATIONS FOR PRACTICE: a review of the clinical hours provided by Bachelor of Midwifery curricula is required, with a view to ensure that clinical hours are consistent with recommended hours suggested by Australian Bachelor of Midwifery course accreditation standards. Universities implementing midwifery curricula in Australia need to be cognisant of the theory-practice gap and therefore the applicability of professional competency standards to the education of midwives. The concerns about the reliability of competency standards need to be addressed. Finally, further research is required to validate the current number of, minimum practice experience required for competency for beginning practice and registration as a midwife in Australia. PMID- 22818116 TI - Walking deterioration and gait analysis in adults with spastic bilateral cerebral palsy. AB - Walking deterioration occurs frequently in adults with spastic bilateral cerebral palsy (CP), but their gait characteristics are largely unknown. The study aims were (1) to compare selected gait analysis variables between those reporting and those not reporting walking deterioration, and (2) to characterise the overall gait deviations and classify the gait patterns. Participants (N=16) were recruited from a follow-up study, had spastic bilateral CP, <40 years in 2006, GMFCS levels I-III, and could walk at least 10 m without support. Eight reported walking deterioration (cases) and eight did not (controls). A theoretical framework linking work of walking, fatigue and deterioration in walking was developed. It was hypothesised that higher energy requirements during gait and larger gait deviations would be associated with deterioration in walking. Three dimensional gait analysis was used to obtain centre of mass work, mechanical joint work, lower limb kinematics, movement analysis profile (MAP), and gait profile scores (GPS). There were no differences between the cases and controls in centre of mass work, joint work, or in the GPS. The largest MAP deviations were seen in sagittal pelvis, hip, and knee angles and foot progression. Crouch and asymmetric gait were common patterns. Walking deterioration could not be explained by these work and kinematic variables. An individual's perception of deterioration in walking is subjective, and may be experienced and interpreted differently across people. Larger, longitudinal studies on the natural history of walking in spastic CP are needed. Qualitative studies on the subjective experiences of walking deterioration are also warranted. PMID- 22818117 TI - Single Event Multilevel Surgery in children with bilateral spastic cerebral palsy: a 5 year prospective cohort study. AB - BACKGROUND: Single Event Multilevel Surgery (SEMLS) is considered the standard of care to improve gait and function in children with bilateral spastic cerebral palsy (BSCP). We have demonstrated in a randomized controlled trial (RCT) of SEMLS, that gait was improved at 12 months after surgery and gross motor function at 24 months after surgery. The question addressed in this study, was to determine if improvements in gait and function, would be maintained at 5 year follow-up. METHODS: Nineteen children with BSCP, GMFCS levels II (14 children) and III (5 children), mean age 9.7 years (range 7.7-12.2 years) participated in a prospective cohort study following participation in a RCT, with follow-up to 5 years. Outcome measures were Gait Profile Score (GPS), Gillette Gait Index (GGI), Gait Deviation Index (GDI), Gross Motor Function Measure (GMFM66) and Functional Mobility Scale (FMS). RESULTS: Eighteen children have completed follow-up, with interval analysis at 1, 2 and 5 years post SEMLS. One child was excluded because of neurological deterioration and his diagnosis was revised to Hereditary Spastic Paraparesis (HSP). GPS improved by 5.29 degrees and GMFM66 by 3.3% at 5 years post SEMLS. Differences between outcome measures at 1 versus 5 years and 2 versus 5 years (except GMFM66) were not significant, indicating that improvements in gait and gross motor function were stable over time. CONCLUSIONS: SEMLS results in clinically and statistically significant improvements in gait and function, in children with BSCP, which were maintained at 5 years after surgery. PMID- 22818118 TI - Older adults are guided by their dynamic perceptions during aperture crossing. AB - Perceptions guide actions and these actions will affect perceptions (Gibson [1]). In return, these new perceptions will affect subsequent actions. The current study aimed to determine if the action differences previously observed in young and older adults are due to differences in perception and whether perceptual judgments guide action. Young (n=10) and older adults (n=9) completed two tasks; (1) judge the passability of various sized apertures during static and dynamic conditions and (2) physically pass through similar aperture sizes. The perceptual tasks required participants to give a yes/no response as to whether they could pass through an aperture (0.9-1.8 times SW (SW)) without rotating their shoulders from a distance of 5m from the aperture. During the passage through the aperture, the participants approached the aperture (1-1.8 times the SW) along a10m path at a self-selected pace and passed through the aperture using a suitable method. Results from the aperture crossing confirmed that older adults produce shoulder rotations at larger relative aperture widths than young adults and are more variable in their shoulder rotations at each aperture width. Perceptual results indicated that older adults had similar static but different dynamic perceptions than the young adults. The observed age-related differences in dynamic perceptions were most likely the result of differences in dynamic balance control. PMID- 22818119 TI - Fever of unknown origin (FUO) in an elderly adult due to Epstein-Barr virus (EBV) presenting as "typhoidal mononucleosis," mimicking a lymphoma. AB - We describe fever of unknown origin (FUO) in a 57-year-old woman with hepatosplenomegaly. The diagnostic workup was directed at diagnosing a lymphoma. Her history of travel and exposures to food and water did not make typhoid fever a likely diagnostic possibility. Because she presented with prolonged fevers, fatigue, anorexia, weight loss, and night sweats with hepatosplenomegaly, lymphoma was likely. Initially, Epstein-Barr virus (EBV) was not considered because of her age, the absence of pharyngitis and cervical adenopathy, and the higher likelihood of another diagnosis, ie, lymphoma. Eventually, her FUO was diagnosed as EBV presenting as "typhoidal mononucleosis." Typhoidal mononucleosis is an extremely rare presentation of EBV as a cause of FUO in an adult. All of her symptoms as well as her clinical and laboratory findings resolved spontaneously. PMID- 22818120 TI - Landmark success for diabetes at the World Health Assembly. PMID- 22818121 TI - The prognostic impact of microRNA sequence polymorphisms on the recurrence of patients with completely resected non-small cell lung cancer. AB - OBJECTIVES: MicroRNAs (miRNAs) are widely known for their function as regulators of gene expression via translational repression. Polymorphisms in miRNAs have been shown to affect the regulatory capacity of miRNAs by influencing miRNA processing and/or miRNA-mRNA interactions. The purpose of this study was to investigate the association between 7 single nucleotide polymorphisms (SNPs) commonly found in precursor miRNA (pre-miRNA) and primary miRNA (pri-miRNA) sequences and the recurrence of disease in patients who underwent a complete resection of non-small cell lung cancer (NSCLC). METHODS: Five SNPs found in pre miRNAs (rs11614913/miR-196a2, rs2910164/miR-146a, rs6505162/miR-423, rs2289030/miR-492, and rs895819/miR-27a) and 2 SNPs found in pri-miRNAs (rs7372209/miR-26a-1 and rs213210/miR-219-1) were genotyped in 388 patients with NSCLC. RESULTS: Among 388 patients, variants of the rs2910164 SNP were significantly associated with recurrence-free survival (RFS) (P = .016, log-rank test). When the results were subdivided by the tumor stage, variants of the rs2910164 and rs11614913 SNPs positively correlated with a better RFS (adjusted hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.28-0.80; adjusted HR, 0.60; 95% CI, 0.38-0.94, respectively) in patients with stage II and stage III disease. Moreover, RFS significantly improved in patients with higher numbers of variant alleles in the rs2910164 and rs11614913 SNPs. CONCLUSIONS: Our findings suggest that polymorphisms in the rs2910164 of miR-146a and the rs11614913 of miR 196a2 are associated with prognosis in patients with completely resected NSCLC. PMID- 22818122 TI - Development of a diagnosis- and procedure-based risk model for 30-day outcome after pediatric cardiac surgery. AB - OBJECTIVE: The study objective was to develop a risk model incorporating diagnostic information to adjust for case-mix severity during routine monitoring of outcomes for pediatric cardiac surgery. METHODS: Data from the Central Cardiac Audit Database for all pediatric cardiac surgery procedures performed in the United Kingdom between 2000 and 2010 were included: 70% for model development and 30% for validation. Units of analysis were 30-day episodes after the first surgical procedure. We used logistic regression for 30-day mortality. Risk factors considered included procedural information based on Central Cardiac Audit Database "specific procedures," diagnostic information defined by 24 "primary" cardiac diagnoses and "univentricular" status, and other patient characteristics. RESULTS: Of the 27,140 30-day episodes in the development set, 25,613 were survivals, 834 were deaths, and 693 were of unknown status (mortality, 3.2%). The risk model includes procedure, cardiac diagnosis, univentricular status, age band (neonate, infant, child), continuous age, continuous weight, presence of non-Down syndrome comorbidity, bypass, and year of operation 2007 or later (because of decreasing mortality). A risk score was calculated for 95% of cases in the validation set (weight missing in 5%). The model discriminated well; the C-index for validation set was 0.77 (0.81 for post-2007 data). Removal of all but procedural information gave a reduced C-index of 0.72. The model performed well across the spectrum of predicted risk, but there was evidence of underestimation of mortality risk in neonates undergoing operation from 2007. CONCLUSIONS: The risk model performs well. Diagnostic information added useful discriminatory power. A future application is risk adjustment during routine monitoring of outcomes in the United Kingdom to assist quality assurance. PMID- 22818123 TI - Percutaneous embolization of patent intercostal artery causing persistent type II endoleak and sac enlargement of thoracoabdominal aneurysm 2 years after hybrid repair. PMID- 22818124 TI - Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload. AB - OBJECTIVES: Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown. METHODS: Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB + AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment. RESULTS: Contractile performance was significantly improved in the PAB + AO group versus the PAB group for both ventricles. Relative to sham operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB + AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor beta genes. CONCLUSIONS: Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV. PMID- 22818125 TI - Single-center experience using the Freedom SOLO aortic bioprosthesis. AB - OBJECTIVE: This study reviews a single institution experience with the Freedom SOLO (Sorin Group, Saluggia, Italy) aortic bioprosthesis. METHODS: Between October 2006 and February 2010, 128 patients (64 men, 64 women; mean age, 75.8 +/ 5.1 years) underwent aortic valve replacement using the Freedom SOLO stentless aortic valve. The follow-up time was 36.7 +/- 1.2 months and 100% complete. RESULTS: Concomitant procedures were performed in 77 patients (60%). The mean standard European System for Cardiac Operative Risk Evaluation was 9 +/- 2.7. Grade 3 aortic stenosis was present in 73% of patients, mixed aortic stenosis and regurgitation were present in 40% of patients, and mitral regurgitation was present in 46% of patients. The mean crossclamp time was 53 +/- 12 minutes for isolated Freedom SOLO aortic valve implantation and 80 +/- 28 minutes for concomitant procedures, and the mean cardiopulmonary bypass time was 103 +/- 31 minutes. The mean implanted valve size was 22.6 +/- 1.4 mm. The mean intensive care unit and hospital stays were 2.4 +/- 1.1 days and 8.8 +/- 2.6 days, respectively. Three patients underwent reoperation for bleeding. The 15-day, 30 day, and perioperative mortality were all 4.6%. The 36-month survival was 95.4% +/- 1.6% for the cohort with a low European System for Cardiac Operative Risk Evaluation (<9) and 88.6% +/- 1.7% for the cohort with a high European System for Cardiac Operative Risk Evaluation (>9). Echocardiographic data preoperatively, immediately postoperatively, and at 3, 6, and 12 months postoperatively showed peak transvalvular gradients of 75 +/- 23, 17 +/- 6, 18 +/- 6.5, 16 +/- 6, and 16 +/- 9 mm Hg, respectively (P < .001), and a mean left ventricular end-diastolic diameter of 51 +/- 7, 50 +/- 6, 48 +/- 8, 47 +/- 6, and 46.5 +/- 7.5 mm, respectively (P < .05). There were only 3 cases of early mild aortic regurgitation (grade 1), which remained stable at 12 months. CONCLUSIONS: The Freedom SOLO stentless aortic valve has excellent early and intermediate-term results. PMID- 22818127 TI - Aortic constriction and the relevance of physiologic research. PMID- 22818126 TI - The impact of CHADS2 score on late stroke after the Cox maze procedure. AB - OBJECTIVE: The Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society jointly recommend indefinite warfarin anticoagulation in patients with CHADS2 (congestive heart failure, hypertension, age, diabetes, and stroke) score of at least 2 who have undergone ablation for atrial fibrillation. This study determined the impact of CHADS2 score on risk of late stroke or transient ischemic attack after the performance of a surgical Cox maze procedure. METHODS: A retrospective review of 433 patients who underwent a Cox maze procedure at our institution was conducted. Three months after surgery, warfarin was discontinued regardless of CHADS2 score if the patient showed no evidence of atrial fibrillation, was off antiarrhythmic medications, and had no other indication for anticoagulation. A follow-up questionnaire was used to determine whether any neurologic event had occurred since surgery. RESULTS: Follow-up was obtained for 90% of the study group (389/433) at a mean of 6.6 +/- 5.0 years. Among these patients, 32% (125/389) had a CHADS2 score of at least 2, of whom only 40% (51/125) remained on long-term warfarin after surgery. Six patients had late neurologic events (annualized risk of 0.2%). Neither CHADS2 score nor warfarin anticoagulation was significantly associated with the occurrence of late neurologic events. Among the individual CHADS2 criteria, both diabetes mellitus and previous stroke or transient ischemic attack were predictive of late neurologic events. CONCLUSIONS: The risk of stroke or transient ischemic attack in patients after a surgical Cox maze procedure was low and not associated with CHADS2 score or warfarin use. Given the known risks of warfarin, we recommend discontinuation of anticoagulation 3 months after the procedure if the patient has no evidence of atrial fibrillation, has discontinued antiarrhythmic medications, and is without any other indication for systemic anticoagulation. PMID- 22818128 TI - Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review. AB - OBJECTIVE: Invasive rhinocerebral fungal infections are a difficult and often fatal problem in children with hematologic malignancies, with increasing reports of rare pathogens. We describe a case of congenital acute lymphoblastic leukemia (ALL) and invasive fungal rhinosinusitis involving Acremonium and Phoma species, not previously reported in invasive pediatric fungal rhinosinusitis, and review all published cases of human Phoma infections. METHODS: A literature and institutional review for Phoma spp. was completed including patient demographics, infection site, immune status, treatment and outcome. RESULTS: A female neonate with acute lymphoblastic leukemia presented with hyperleukocytosis and advanced invasive Phoma and Acremonium spp. rhinosinusitis. Despite aggressive medical and surgical therapy, the disease progressed to a rhinocerebral infection with a fatal outcome. Twenty cases of Phoma spp. were found in a complete literature search, including 6 females and 14 males from 18 months to 77 years old. Infections were superficial in fifteen patients and involved deeper tissue in five patients, with sites including cutaneous, subcutaneous and deep tissue sites (eye, lung, extremity deep tissue compartments). CONCLUSIONS: This case highlights the risks and grave prognosis of fulminant invasive fungal rhinosinusitis in the context of congenital leukemia, and the potential for rare fungal species in neonates with immunosuppression. PMID- 22818129 TI - Y-SNP miniplexes for East Asian Y-chromosomal haplogroup determination in degraded DNA. AB - Four multiplex PCR systems followed by single base extension reactions were developed to score 22 single nucleotide polymorphisms (SNPs) and identify the most frequent East Asian Y chromosome haplogroups. Select Y chromosome SNPs allowed hierarchical testing for almost all of the major East Asian haplogroups along the revised Y chromosome tree. The first multiplex consists of six SNPs defining world-wide major haplogroups (M145, RPS4Y(711), M89, M9, M214, and M175). The second multiplex includes six SNPs of subhaplogroup O (M119, P31, M95, SRY(465), 47z, and M122). The third multiplex contains six SNPs that subdivide the subhaplogroup O3 (M324, P201, M159, M7, M134, and M133). The fourth multiplex comprises four SNPs of subhaplogroup C (M217, M48, M407, and P53.1). The sizes of the PCR amplicons ranged from 70 to 100bp to facilitate their application to degraded forensic and ancient samples. Validation experiments demonstrated that the multiplexes were optimized for analysis of low template DNA and highly degraded DNA. In a test using DNA samples from 300 Korean males, 16 different Y chromosome haplogroups were identified; haplogroup O2b* was the most frequently observed (29.3%), followed by haplogroups C3 (xC3c, C3d, C3e) (16.0%) and O3a3c1 (11.0%). These multiplex sets will be useful tools for Y-chromosomal haplogroup determination in anthropological and forensic studies of East Asian populations. PMID- 22818130 TI - Novel agents and approaches for advanced renal cell carcinoma. AB - PURPOSE: Targeted agents have changed the treatment paradigm for advanced renal cell carcinoma. Approved agents with demonstrated efficacy are sunitinib, sorafenib, pazopanib, bevacizumab, temsirolimus and everolimus. However, there is an unmet need for new agents to improve the clinical outcome in treatment naive patients and in those who are disease refractory or intolerant to traditional and targeted therapies. Many novel targeted agents, of which some have different mechanisms of action than approved agents, and immunomodulatory agents are currently in development for renal cell carcinoma. MATERIALS AND METHODS: We searched ClinicalTrials.gov to identify novel agents for advanced renal cell carcinoma in ongoing phase II/III clinical trials. Using the relevant agents as search terms we reviewed the medical literature for mechanisms of action and efficacy, and safety results to date, including data from recent major oncology meetings. RESULTS: A total of 11 novel targeted agents, including next generation tyrosine kinase inhibitors, and inhibitors of vascular endothelial growth factor ligand binding, Akt and endothelial cell proliferation, and 3 novel immunomodulatory agents, are under evaluation for renal cell carcinoma. In addition to ongoing phase II/III trials of emerging agents, head-to-head, crossover and combination trials of approved targeted agents are under way. CONCLUSIONS: Although many agents are approved or in development for renal cell carcinoma, comparative effectiveness data are lacking. Ongoing and future head-to head trials using appropriate comparators are essential to update renal cell carcinoma treatment guidelines. Future research should be aimed at identifying agents that improve patient outcomes and have decreased toxicity compared with currently approved agents with the goal of complete remission. PMID- 22818131 TI - Ethnicity and smoking status are associated with awareness of smoking related genitourinary diseases. AB - PURPOSE: Cigarette smoking is a recognized risk factor for kidney cancer, bladder cancer and erectile dysfunction. However, little is known regarding patient knowledge of these associations. We evaluated awareness of smoking as a risk factor for genitourinary disease and identified variables associated with awareness. MATERIALS AND METHODS: We performed a cross-sectional study in a convenience sample of 535 patients who presented to a urology clinic at a major public hospital between 2009 and 2011. Patient demographics and knowledge were captured in a self-reported questionnaire evaluating awareness of smoking as a risk factor for bladder, kidney and lung cancer, and erectile dysfunction. Factors associated with the awareness of smoking and genitourinary disease were identified by multivariable logistic regression. RESULTS: Urology patients generally had low overall awareness of smoking related genitourinary disease. Only 33.5%, 25.2% and 24.2% of patients identified smoking as a risk factor for kidney cancer, bladder cancer and erectile dysfunction, respectively, compared to 94.0% who identified it as a risk factor for lung cancer. Patients from ethnic minorities and current smokers consistently showed a more pronounced lack of awareness of the link between smoking and these diseases. Generally Hispanic and black patients were 2 to 3 times more likely than white patients to be unaware of the association of smoking with the diseases (p = 0.0019 to 0.059). Smokers were twice as likely as nonsmokers to be unaware of the link of smoking with kidney and bladder cancer (p = 0.025 and 0.0509, respectively). CONCLUSIONS: Our study highlights the need for increased awareness of smoking related genitourinary diseases, especially among minority patients and smokers. This study draws attention to an opportunity for urologists to provide smoking cessation assistance and education for this patient population. PMID- 22818132 TI - Adult care of children from pediatric urology: part 2. AB - PURPOSE: We describe the outcomes of undescended testes and sex development disorders in adolescence and young adulthood. We reviewed the requirements for the long-term care of children born with these and other major congenital anomalies of the genitourinary system. MATERIALS AND METHODS: The current English language literature was retrieved with a PubMed(r) search for articles on these subjects. Only articles covering outcomes at ages past puberty were included in analysis. The material was supplemented from the database of the clinic for adults with sex development disorders at University College London Hospitals. RESULTS: An undescended testis has impaired spermatogenesis. In men in whom a unilateral undescended testis was corrected before puberty the incidence of paternity is normal at around 90% of those who attempt it. The equivalent rate for those with bilateral undescended testes is about 65%. If surgery for bilateral undescended testes is delayed until after puberty, fertility is unlikely. The risk of testicular neoplasms is overestimated and the relative risk is between 2.5 and 8. Children born with a sex development disorder receive multidisciplinary treatment throughout childhood and require the same care as adults. Males who are under virilized likely have a micropenis (greater than 2 SD below the mean stretched length) but they may have normal sexual function. Fertility depends on the underlying condition. Virilized females, who most commonly have congenital adrenal hyperplasia, currently present to adult clinics with an inadequate vagina after infantile surgery. Reconstruction is required to allow intercourse. CONCLUSIONS: The care of adults born with abnormalities of the genitalia is complex. Early management may define upbringing in childhood but requirements for sexuality and fertility in adult life are different. Multidisciplinary care is essential and a case can be made to establish a subspecialty of urology to coordinate it. PMID- 22818133 TI - Detailed analysis of morbidity following nephrectomy for renal cell carcinoma in octogenarians. AB - PURPOSE: We evaluated the morbidity of nephrectomy in patients older than age 80 years. MATERIALS AND METHODS: Between June 2002 and March 2011, 2,530 patients underwent surgery for renal tumor at 5 French academic centers. Of these patients 180 (7.1%) were age 80 years or older, including 22 (12%) and 158 (88%) who underwent partial and radical nephrectomy, respectively, and 47 (26.1%) who were treated with a laparoscopic approach. RESULTS: Mean patient age was 82.3 years. Median Charlson score was 4. Mean preoperative glomerular filtration rate was 47 ml/minute. A total of 136 complications were recorded in 70 patients (38.8% of all patients). Of the patients 28 (15.5%), 25 (13.9%) and 17 (9.4%) experienced 1, 2 and 3 or more complications, respectively. According to the modified Clavien classification grade I, II, III, IV and V complications were observed in 7, 81, 19, 23 and 6 patients, respectively. The transfusion rate was 31.1% (56). On logistic regression analysis the parameters of Eastern Cooperative Oncology Group Performance Status 2 to 4 (p = 0.035) and preoperative glomerular filtration rate less than 30 ml/minute (p = 0.03) were independent predictive factors of morbidity. CONCLUSIONS: Morbidity and mortality are significant in the octogenarian population. The risk of complications should be considered in decision making for patients with renal cell carcinoma older than age 80 years. PMID- 22818134 TI - Factors associated with the adoption of minimally invasive radical prostatectomy in the United States. AB - PURPOSE: Minimally invasive radical prostatectomy has supplanted radical retropubic prostatectomy in popularity despite the absence of strong comparative effectiveness data demonstrating its superiority. We examined the influence of patient, surgeon and hospital characteristics on the use of minimally invasive radical prostatectomy vs radical retropubic prostatectomy. MATERIALS AND METHODS: Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data we identified 11,732 men who underwent radical prostatectomy from 2003 to 2007. We assessed the contribution of patient, surgeon and hospital characteristics to the likelihood of undergoing minimally invasive radical prostatectomy vs radical retropubic prostatectomy using multilevel logistic regression mixed models. RESULTS: Patient factors (36.7%) contributed most to the use of minimally invasive radical prostatectomy vs radical retropubic prostatectomy, followed by surgeon (19.1%) and hospital (11.8%) factors. Among patient specific factors Asian race (OR 1.86, 95% CI 1.27-2.72, p = 0.001), clinically organ confined tumors (OR 2.71, 95% CI 1.60-4.57, p <0.001) and obtaining a second opinion from a urologist (OR 3.41, 95% CI 2.67-4.37, p <0.001) were associated with the highest use of minimally invasive radical prostatectomy while lower income was associated with decreased use of minimally invasive radical prostatectomy. Among surgeon and hospital specific factors, higher surgeon volume (OR 1.022, 95% CI 1.015-1.028, p <0.001), surgeon age younger than 50 years (OR 2.68, 95% CI 1.69 4.24, p <0.001) and greater hospital bed size (OR 1.001, 95% CI 1.001-1.002, p <0.001) were associated with increased use of minimally invasive radical prostatectomy, while solo or 2 urologist practices were associated with decreased use of minimally invasive radical prostatectomy (OR 0.48, 95% CI 0.27-0.86, p = 0.013). CONCLUSIONS: The adoption of minimally invasive radical prostatectomy vs radical retropubic prostatectomy is multifactorial, and associated with specific patient, surgeon and hospital related factors. Obtaining a second opinion from another urologist was the strongest factor associated with opting for minimally invasive radical prostatectomy. PMID- 22818135 TI - Prostate biopsy in response to a change in nadir prostate specific antigen of 0.4 ng/ml after treatment with 5alpha-reductase inhibitors markedly enhances the detection rate of prostate cancer. AB - PURPOSE: We examined the effect of 5alpha-reductase inhibitor therapy on prostate cancer detection in men with persistently increased or fluctuating prostate specific antigen and prior negative prostate cancer biopsy. MATERIALS AND METHODS: A total of 276 men with prostate specific antigen greater than 4 ng/ml (208) or a prostate specific antigen velocity change of 0.75 ng/ml (68) and a normal digital rectal examination who had previously undergone biopsy a minimum of 2 times with prostate cancer not detected were given 5 mg finasteride (154) or dutasteride (122) daily. In phase 1, 97 patients had prostate specific antigen measured at 6 and 12 months with repeat transrectal ultrasonography and biopsy (12 cores) performed at 1 year. In phase 2, 179 patients underwent biopsy triggered by a change in nadir prostate specific antigen of more than 0.4 ng/ml. RESULTS: In phase 1 at 1 year prostate specific antigen had decreased by 2.4 ng/ml (-46.7%), and prostate volume had decreased 7.1 ml (-17.9%). Prostate cancer was detected in 27 of 97 (27.8%) patients and the mean minimum prostate specific antigen velocity from a nadir of 0.4 ng/ml was 0.6 ng/ml. In phase 2, 48 of 179 (26.8%) men underwent repeat biopsy at a mean of 14.6 months. Of these 48 men 26 (54.1%) were found to have prostate cancer. Of the 26 men in whom prostate cancer was detected 20 (76.9%) were found to have Gleason score 7 or greater disease. CONCLUSIONS: The magnitude of change in serum prostate specific antigen after 5alpha-reductase inhibitor therapy may be useful in diagnosing prostate cancer in patients with persistently increased or fluctuating prostate specific antigen and prior negative prostate biopsy. PMID- 22818136 TI - Preoperative statin therapy is not associated with biochemical recurrence after radical prostatectomy: our experience and meta-analysis. AB - PURPOSE: The effect of statins on prostate cancer recurrence has been investigated in several studies with inconsistent results. We investigated whether statins were associated with biochemical recurrence in a large cohort of men after radical prostatectomy. We also performed a meta-analysis of existing studies. MATERIALS AND METHODS: A total of 1,446 patients who underwent radical prostatectomy at New York University were followed a median of 57 months for biochemical recurrence events. Baseline demographic and clinical characteristics were compared between 437 statin users and 1,009 nonusers. Kaplan-Meier curves and Cox models were used to examine biochemical recurrence-free survival by statin use. A meta-analysis was performed with data from our cohort and 5 published studies using the random effects model. RESULTS: Statin users were slightly older and more likely to have diabetes (p <0.01). They were similar to nonusers in race and body mass index. Although preoperative prostate specific antigen and tumor stage were similar between the 2 groups, the proportion of patients with pathological Gleason score 7-10 tumors was slightly higher among statin users (p = 0.03). The biochemical recurrence-free survival rate was 87.4% and 89.0% for statin users and nonusers, respectively, at the end of followup (log rank p = 0.26). Overall biochemical recurrence was not associated with statin use (HR 1.15, 95% CI 0.82-1.61). Results were similar when patients were stratified by D'Amico low and intermediate or high risk groups. Meta-analysis revealed no overall association between statins and biochemical recurrence (pooled HR 1.00, 95% CI 0.80-1.19). CONCLUSIONS: Our findings are consistent with the results of the meta-analysis, which indicated that preoperative statin use does not impact the overall risk of biochemical recurrence. PMID- 22818137 TI - Conservative surgery for squamous cell carcinoma of the penis: resection margins and long-term oncological control. AB - PURPOSE: We assessed the oncological outcome of penile conserving surgery and identified parameters predicting local recurrence, including resection margins. MATERIALS AND METHODS: A total of 179 patients with invasive penile cancer treated with organ sparing surgery at a tertiary center between 2002 and 2010 fulfilled our study criteria. Demographic, histopathological, management and followup data were recorded in a prospective database. Local, regional and distant recurrence rates, time to recurrence and survival rates were calculated. Survival analysis was performed by the Kaplan-Meier method. Multivariate analysis was used to identify predictors of local recurrence. RESULTS: Mean followup was 42.8 months (range 4 to 107). Local, regional and distant metastatic recurrence developed in 16 (8.9%), 19 (10.6%) and 9 patients (5.0%) at a mean of 26.1, 26.8 and 11.7 months, respectively. The 5-year disease specific survival rate after recurrence was 54.7% (95% CI 46.1-63.3). For patients with isolated local recurrence the 5-year disease specific survival rate was 91.7% compared to 38.4% for those with regional recurrence. The overall 5-year local recurrence-free rate was 86.3% (95% CI 82.6-90.4). Tumor grade (p = 0.003), stage (p = 0.021) and lymphovascular invasion (p = 0.014) were identified as predictors of local recurrence on multivariate analysis. CONCLUSIONS: Penile conserving surgery is oncologically safe and a surgical excision margin of less than 5 mm is adequate. Higher local recurrence rates are associated with lymphovascular invasion, and higher tumor stage and grade. Local recurrence has no negative impact on long term survival. PMID- 22818138 TI - A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. AB - PURPOSE: We investigated whether the RNA assay uRNA(r) and its derivative Cxbladder(r) have greater sensitivity for the detection of bladder cancer than cytology, NMP22TM BladderChekTM and NMP22TM ELISA, and whether they are useful in risk stratification. MATERIALS AND METHODS: A total of 485 patients presenting with gross hematuria but without a history of urothelial cancer were recruited prospectively from 11 urology clinics in Australasia. Voided urine samples were obtained before cystoscopy. The sensitivity and specificity of the RNA tests were compared to cytology and the NMP22 assays using cystoscopy as the reference. The ability of Cxbladder to distinguish between low grade, stage Ta urothelial carcinoma and more advanced urothelial carcinoma was also determined. RESULTS: uRNA detected 41 of 66 urothelial carcinoma cases (62.1% sensitivity, 95% CI 49.3 73.8) compared with NMP22 ELISA (50.0%, 95% CI 37.4-62.6), BladderChek (37.9%, 95% CI 26.2-50.7) and cytology (56.1%, 95% CI 43.8-68.3). Cxbladder, which was developed on the study data, detected 82%, including 97% of the high grade tumors and 100% of tumors stage 1 or greater. The cutoffs for uRNA and Cxbladder were prespecified to give a specificity of 85%. The specificity of cytology was 94.5% (95% CI 91.9-96.5), NMP22 ELISA 88.0%, (95% CI 84.6-91.0) and BladderChek 96.4% (95% CI 94.2-98.0). Cxbladder distinguished between low grade Ta tumors and other detected urothelial carcinoma with a sensitivity of 91% and a specificity of 90%. CONCLUSIONS: uRNA and Cxbladder showed improved sensitivity for the detection of urothelial carcinoma compared to the NMP22 assays. Stratification with Cxbladder provides a potential method to prioritize patients for the management of waiting lists. PMID- 22818139 TI - Sex hormone-binding globulin is an independent predictor of biochemical recurrence after radical prostatectomy. AB - PURPOSE: We studied the association of serum sex hormone levels with clinicopathological variables and biochemical recurrence in men with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We prospectively studied preoperative serum sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and free and total testosterone in 372 patients undergoing radical prostatectomy. Biochemical recurrence was analyzed in 285 patients and defined as prostate specific antigen 0.2 ng/ml or higher at least 30 days after radical prostatectomy. Median followup was 43.6 months. RESULTS: Median sex hormone-binding globulin was 37.4 nmol/l, luteinizing hormone 4.1 mU/ml, follicle-stimulating hormone 5.9 mU/ml, and free and total testosterone 0.069 and 3.7 ng/ml, respectively. There was no significant association of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone or total testosterone with T and N stage, and margin status. Luteinizing hormone, follicle-stimulating hormone, and free and total testosterone were not associated with biochemical recurrence. In contrast, for each 10 U increase in sex hormone-binding globulin the risk of biochemical recurrence increased by 12% (p = 0.045). On multivariable analysis sex hormone binding globulin achieved independent predictor status after adjusting for standard clinicopathological variables. After stepwise regression a model containing T and N stage, Gleason score, margin status, prostate weight and sex hormone-binding globulin improved the accuracy of a base model by 1.3% (79.0% vs 77.7%). CONCLUSIONS: Preoperative serum sex hormone-binding globulin is independently associated with biochemical recurrence after radical prostatectomy and increases the predictive accuracy of a standard multivariable model. Routine assessment of sex hormone-binding globulin sex hormone-binding globulin may be a helpful adjunct to identify patients who need early adjuvant therapy. PMID- 22818140 TI - Assessment of the quality of medical care among patients with early stage prostate cancer undergoing expectant management in the United States. AB - PURPOSE: Given the increased attention to the quality and cost of medical care, the Institute of Medicine and Centers for Medicare and Medicaid Services have called for performance measurement and reporting. The clinical management of prostate cancer has been outlined, yet is not intended to describe quality prostate cancer care. Therefore, RAND researchers developed quality indicators for early stage prostate cancer. The ACoS (American College of Surgeons) used these indicators to perform the first national assessment to our knowledge of the quality of care among men with early stage prostate cancer undergoing expectant management. MATERIALS AND METHODS: Information from medical records was abstracted for evidence of compliance with the RAND indicators (structure and process). Weighted and stratified proportions were calculated to assess indicator compliance. Logistic regression models were fit and evaluated by hospital type and patient factors. RESULTS: A weighted and stratified total of 13,876 early stage prostate cancer cases on expectant management in 2000 to 2001 were investigated. Compliance with structural indicators was high (greater than 80%) and compliance with process indicators varied (19% to 87%). Differences in process indicators were observed from models by hospital type and comorbid conditions, but not for age, race or insurance status. CONCLUSIONS: Using the RAND quality indicators this study revealed several process areas for quality improvement among men with early stage prostate cancer on expectant management in the United States. Efforts to improve the quality of early stage prostate cancer care need to move beyond the paradigm of age, race and insurance status. PMID- 22818141 TI - Editorial comment. PMID- 22818143 TI - Identifying candidates for active surveillance: an evaluation of the repeat biopsy strategy for men with favorable risk prostate cancer. AB - PURPOSE: Active surveillance is increasingly recommended to reduce overtreatment in men with favorable risk prostate cancer. A repeat confirmatory biopsy has become the standard recommendation for these men to increase the precision of this risk attribution. We investigate the usefulness of this approach by comparing the current practice standard, repeat transrectal ultrasound biopsy, with template prostate mapping. MATERIALS AND METHODS: A total of 124 men who were attributed a favorable risk prostate cancer status based on transrectal ultrasound guided biopsy and who were considering a policy of active surveillance underwent combined transrectal ultrasound biopsy and template prostate mapping as a confirmatory strategy. Maximum Gleason grade and disease burden were compared between the 2 confirmatory tests. RESULTS: Depending on the definition used between 8% and 22% of men had prostate cancer reclassified as clinically important by repeat transrectal ultrasound biopsy whereas template guided prostate mapping reclassified the disease in 41% to 85% of the men. Repeat transrectal ultrasound biopsy failed to detect up to 80% of clinically important cancers detected by the reference standard. The sensitivity of repeat transrectal ultrasound biopsy to identify clinically important disease varied from 9% to 24% with the negative predictive value ranging from 23% to 60%. CONCLUSIONS: When applied to a population of men initially deemed to have favorable risk prostate cancer, transrectal ultrasound biopsy will miss a large proportion of clinically important cancers compared to template guided prostate mapping. The usefulness of repeat transrectal ultrasound biopsy in ruling out clinically important prostate cancer needs to be reconsidered. PMID- 22818144 TI - Investigation of a Ca2+ channel alpha2delta ligand for the treatment of interstitial cystitis: results of a randomized, double-blind, placebo controlled phase II trial. AB - PURPOSE: We investigated PD-0299685, a Ca(2+) channel alpha2delta ligand, for interstitial cystitis pain in a randomized, double-blind, placebo controlled phase IIa study. MATERIALS AND METHODS: Patients with interstitial cystitis/bladder pain syndrome received 30 or 60 mg PD-0299685 daily or placebo for 12 weeks. Primary end points were change in average daily worst pain severity score (on an 11-point numerical rating scale) and change in Interstitial Cystitis Symptom Index score from baseline to week 12. Secondary end points included global response assessment, micturition and urgency episode frequency per 24 hours and mean voided volume per micturition. Incidence of adverse events was also assessed. RESULTS: Of 161 patients 54 received 30 mg PD-0299685 daily, 55 received 60 mg PD-0299685 daily and 52 received placebo. At week 12 the 60 mg dose produced a clinically significant reduction in daily worst pain severity score from baseline compared to placebo (treatment difference [90% CI] -0.82 [ 1.72, 0.08]). A greater proportion of patients taking 60 mg PD-0299685 daily demonstrated improvement in global response assessment. PD-0299685 had no clinically significant effect on the Interstitial Cystitis Symptom Index score or urinary end points. More patients discontinued due to treatment related adverse events with 30 or 60 mg PD-0299685 daily than with the placebo. CONCLUSIONS: PD 0299685 failed to demonstrate positive proof of concept for the treatment of pain and other urinary end points associated with interstitial cystitis/bladder pain syndrome. PMID- 22818145 TI - [Greetings]. PMID- 22818146 TI - [Evaluation of medical products is possible. 5. Discussion forum of GFR abd IQWiG was devoted to studies of the therapeutic treatment with medical products]. PMID- 22818147 TI - [Barriers to clinical studies involving medical devices]. AB - Clinical trials with medical devices need to be considered in terms of the complexity of surgical procedures. Creating the proper environment for the conduct of trials includes improved academic career opportunities in the field of clinical research, methodological competence, and established structures. The challenges and pitfalls in the design of clinical trials involving medical devices are based on aspects such as blinding, placebo, learning curves and surgeons' expertise. Surgical procedures should be standardised, and a study hypothesis needs to be established which is answerable by a relevant and feasible sample size. Besides the above-mentioned challenges, efficient interactions between authorities, universities, hospitals, and medical device manufacturers are mandatory to allow for quality and relevance of clinical studies in this field. PMID- 22818149 TI - [Utility of medical devices: approaches to planning and conducting clinical trials]. AB - Medicines and medical devices do not only differ in the approval process, but also in the aim and conduct of clinical trials. We first discuss important differences between medicinal products and medical devices. Emphasis is put on the differences in the framework for clinical trials. We point out that a different analysis set should be used in clinical trials of medical devices when compared with medicinal products and medical devices in the USA. Specifically, regulators generally ask for the full analysis set based on the intention-to treat principle as proof of efficacy of medicines. A central aspect of clinical trials of medical devices is that they have to be tested under normal conditions of use according to the performance data. As a result, all data acquired while the medical device was not during normal conditions of use should be excluded from statistical analyses. We discuss statistical methodological particularities of medical devices, such as blinding and the control of placebo effects. Using the conservative treatment of anal incontinence as an example, we show that comprehensive technical and physical knowledge is required for assessing the utility of medical devices. Finally, we consider reporting of severe adverse events and of severe adverse device effects of medical devices. PMID- 22818151 TI - [Localised prostate cancer: the PREFERE trial]. AB - Prostate cancer is the most common carcinoma of the elderly man and holds the third place in the ranking of cancer-specific mortality. However, mortality rates of 3 % are low, and half of the patients will die from intercurrent disease. Due to the significantly improved diagnostic methods and the increasing use of PSA screening, there has been a stage migration towards early tumour stages that are prognostically heterogeneous and require differentiated treatment. Based on the discussions of the Joint Federal Committee (G-BA) and the conceptual work of the MDS, the Competence Centre Oncology of the MDK, the IQWIG and the National Association of Statutory Health Insurance Funds (GKV-Spitzenverband), a prospective randomised multicentre trial was developed comparing the four treatments actually recommended by the German and European guidelines for localised prostate cancer (radical prostatectomy, percutaneous radiotherapy and permanent seed implantation and active surveillance) allowing a rejection of one or two treatment options. The trial is expected to start at the beginning of next year. PMID- 22818153 TI - [Assessing the effectiveness of medical devices in patient-oriented surgical research]. AB - Surgery depends on the application of therapeutic procedures that are based on scientific evidence. It legitimises its claim in patient care through operations with proven benefit consisting of cure or improvement of symptoms. Moreover, clinical research and evaluation of surgical technique, strategy and innovation is closely entangled with medical devices. These surgical trials are regulated beyond the German drug and medical devices law, but scientific and ethical rules still follow the principles of clinical epidemiology and evidence-based medicine. Standardisation of surgical and perioperative care is the inevitable prerequisite in clinical trials to define and to evaluate effectiveness of surgical devices. The Study Centre of the German Surgical Society has established an efficient infrastructure for such trials in Germany and is working to refine the scientific methodology in order to improve the current basis of evidence. (As supplied by publisher). PMID- 22818155 TI - [Clinical trials investigating the therapeutic benefit of medical devices in orthopaedics and trauma surgery: practice examples plus commentary]. AB - Patients recognise relevant symptoms of the two leading diseases in orthopaedics and trauma surgery: osteoarthritis and fractures. Treatment effects can be demonstrated by patient reported outcomes. Total hip arthroplasty as an example for standard treatment regimen achieves large treatment effects. It is hard to demonstrate an additional benefit against standard treatment while observing ceiling effects. Alternative instruments are needed. Navigated total knee arthroplasty is done for better control of the postoperative axis as well as to reduce the revision burden. The time interval needed to demonstrate the decrease in revision has not yet passed. Additional benefits of total knee navigation have been observed for certain patient populations and for the training of physicians. These benefits have not been investigated so far. Using registries, expert opinions and case series the desired benefit from the use of medical devices can be shown. Safety is one major aspect of innovative medical devices as an additional benefit. The safety paradigm needs intense investigation in the future. The IDEAL Statement provides the clinical researcher with the methodological framework. The METEOR Statement focused on the medical problem and the possible benefit with using innovative medical devices. Within these recommendations a broad number of study types can be employed to demonstrate the benefits for patients. PMID- 22818157 TI - [Examples of practice: clinical trials for medical devices and their application: wound care]. AB - BACKGROUND: According to definition, chronic wounds do not show any tendency for healing over months. From the socio-economic perspective they are of great importance due to their frequency, patient burden and costs for the health system. In wound care, medical devices play a crucial, even more important role than drugs as nearly every wound needs at least a dressing. CLINICAL CARE AND RESEARCH: A wound passes through several phases of wound healing, which often demand different therapies and differentiated wound dressings in the sense of a "phase-adapted" wound therapy. "Modern wound care" reflects a cross-sectoral, interdisciplinary and interprofessional approach founded on evidence-based and quality-assured procedures according to the most recent medical knowledge. Clinical research on chronic wounds is characterised by a great variety of wound types and conditions, the strong impact of pathogenetic factors and complications, a multifaceted, frequently still manual therapy and long periods of healing. In many instances, several treatments are applied intermediately in the same patient, which serve different purposes and thus require different study endpoints. An analysis of the European Wound Management Association (EWMA) revealed that, on an international level, only few of the published clinical trials on chronic wounds meet the basic quality requirements. Accordingly, it is the objective to establish national and international consensus on standards of the methodology and interpretation of wound outcomes, such as the most recent EWMA activities and the German national consensus conference started in 2012. EXAMPLE OF A HIGH-QUALITY CLINICAL WOUND STUDY: As an example of a high quality randomised study on chronic wounds, hyperbaric oxygen treatment (HBOT) was evaluated as adjuvant treatment for diabetic foot ulcers compared to placebo (Londahl et al., 2010). This trial is characterised by a diligent study design, a substantiated study rationale and an independent steering committee. Precise and reliable definitions for the end points were selected, their evaluation performed in a double-blinded manner, and the ITT and PP analyses were described transparently. Outcomes included both clinical and patient-reported parameters. Reporting according to the consort criteria revealed a significantly higher healing rate in the HBOT group. CONCLUSION AND PERSPECTIVES: Chronic wound therapy is a complex intervention with highly variable clinical conditions. Parts of missing quality and validity in therapeutic studies on chronic wounds, however, might be improved without noteworthy efforts if existing guidance is followed. This includes the motto: "better fewer but better conducted studies". Clinical research should focus on key principles and products, and it should prioritise research questions. Research on central principles of action in wound products between companies could further increase global research efficiency. PMID- 22818159 TI - [The GRADE system: a prologue to the article series in the ZEFQ]. PMID- 22818160 TI - [GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables]. AB - This article is the first of a series providing guidance for the use of the GRADE system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments, and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence has been collected and summarised, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterised as strong or weak (alternative terms: conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarising evidence in succinct, transparent, and informative Summary of Findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations. PMID- 22818161 TI - [GRADE guidelines: 2. Framing the question and deciding on important outcomes]. AB - GRADE requires a clear specification of the relevant setting, population, intervention, and comparator. It also requires specification of all important outcomes - whether evidence from research studies is, or is not, available. For a particular management question, the population, intervention, and outcome should be sufficiently similar across studies so that a similar magnitude of effect is plausible. Guideline developers should specify the relative importance of the outcomes before gathering the evidence and again when evidence summaries are complete. In considering the importance of a surrogate outcome, authors should rate the importance of the patient-important outcome for which the surrogate is a substitute and subsequently rate down the quality of evidence for indirectness of outcome. PMID- 22818163 TI - Syndrome of inappropriate secretion of antidiuretic hormone due to desvenlafaxine. AB - OBJECTIVE: Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is not uncommon in patients receiving treatment of selective serotonin reuptake inhibitors or venlafaxine. METHOD: This is a case report of a 47-year-old man with depression, who developed hyponatremia after commencing treatment with desvenlafaxine. RESULTS: To our knowledge, this is the first case in which desvenlafaxine-associated SIADH was reported since the introduction of the drug. CONCLUSION: Physicians should be aware of the possibility of desvenlafaxine-associated hyponatremia in patients under age of 65. PMID- 22818164 TI - Anti-tumor necrosis factor-alpha induced systemic lupus erythematosus in a patient with metastatic Crohn's disease--what is the role of anti-TNF antibody? AB - Biological therapies are supposed to trigger the development of autoimmune diseases. We report a case of a 27-year old woman presenting with drug induced systemic lupus erythematosus (SLE) associated with infliximab therapy. The development of paradoxical inflammation in immune-mediated inflammatory diseases patients treated with anti TNF-alpha suggests that an unknown inflammatory pathway may be provoked by inhibiting TNF-alpha. We suppose that in our case a cross reactivity between anti-infliximab antibodies and autoantibodies may lead to the development of TNF-induced immune disease. PMID- 22818162 TI - Passing the baton: the HIF switch. AB - Hypoxia is an inadequate oxygen supply to tissues and cells, which can restrict their function. The hypoxic response is primarily mediated by the hypoxia inducible transcription factors, HIF-1 and HIF-2, which have both overlapping and unique target genes. HIF target gene activation is highly context specific and is not a reliable indicator of which HIF-alpha isoform is active. For example, in some cell lines, the individual HIFs have specific temporal and functional roles: HIF-1 drives the initial response to hypoxia (<24h) and HIF-2 drives the chronic response (>24h). Here, we review the significance of the HIF switch and the relation between HIF-1 and HIF-2 under both physiological and pathophysiological conditions. PMID- 22818165 TI - Central serous chorioretinopathy in patients who cannot discontinue steroids. PMID- 22818166 TI - The implementation of mentalization-based treatment for adolescents: a case study from an organizational, team and therapist perspective. AB - BACKGROUND: Reports on problems encountered in the implementation of complex interventions are scarce in psychotherapy literature. This is remarkable given the inherent difficulties of such enterprises and the associated safety risks for patients involved. CASE DESCRIPTION: A case study of the problematic implementation process of Mentalization- Based Treatment for Adolescents (MBT-A), a new therapy for 14 to 18 year old youngsters with severe personality disorders, is presented. The implementation process is described and analyzed at an organizational, team and therapist level. DISCUSSION AND EVALUATION: Our analysis shows that problems at all three levels contributed and interacted to make the implementation cumbersome and hazardous. CONCLUSION: The implementation of complex psychotherapeutic programs for difficult patients could benefit from a structured attention to processes at multiple levels. We therefore propose a new comprehensive heuristic model of treatment integrity. This new model includes organisational, team and therapist adherence to the treatment model as necessary components of treatment integrity in the implementation of complex interventions. The application of this new model of treatment integrity potentially increases the chance of successful implementations and reduces safety risks for first patients enrolling in a new program. PMID- 22818167 TI - BCL10 down-regulation in peripheral T-cell lymphomas. AB - The BCL10 gene encodes for a T-cell receptor signaling downstream protein involved in nuclear factor kappaB activation. It is expressed in normal lymphoid tissues and in several B-non Hodgkin lymphomas, its aberrant function being related to the pathogenesis of certain subtypes. Conversely, conflicting data are available concerning BCL10 expression in peripheral T cell lymphomas. We analyzed BCL10 expression in peripheral T cell lymphomas and correlated it with NFkappaB activation, proliferation, phenotypic aberration, and survival. First, gene expression analysis of 40 peripheral T cell lymphomas (28 peripheral T cell lymphomas/not otherwise specified, 6 anaplastic large cell lymphomas, and 6 angioimmunoblastic lymphomas), 4 reactive lymph nodes, and 20 samples of normal T lymphocytes, showed significantly lower BCL10 gene expression in all tumors in comparison to normal samples, the lowest values being detected in anaplastic large cell lymphoma. Secondly, we studied the immunohistochemical expression of BCL10 in 52 peripheral T cell lymphomas/not otherwise specified on tissue microarrays. BCL10 was expressed in 10/52 cases (19%), not showing any significant correlation with either expression of Ki-67 and the T-cell markers or NFkappaB activation. Furthermore, BCL10 expression was not associated with peculiar gene expression profiles. Finally, we did not find significant correlations with progression free survival and overall survival, although a favorable trend was recorded in BCL10(+) cases. In conclusion, BCL10 was commonly down-regulated in peripheral T cell lymphomas, suggest the T-cell receptor signaling cascade for future characterization. PMID- 22818168 TI - Spatial distribution of intertidal sandy beach polychaeta along an estuarine and morphodynamic gradient in an eutrophic tropical bay. AB - The spatial distribution of polychaeta along pollution gradients often reflects different degrees of disturbance. In order to evaluate polychaeta fauna of an organically polluted tropical bay, 20 sandy beaches distributed in five areas were sampled. The relationship between community structure, slope, beach index, exposure, sediment and water quality parameters were analysed. Multivariate analysis of variance (PERMANOVA) showed differences among areas and beaches. Scolelepis chilensis dominated at mouth of bay beaches whereas Streblospio gynobranchiata and Capitella capitata complex, at inner beaches. Highest polychaete density was recorded at areas 3 and 5 with the dominance of Saccocirrus sp. and the organic indicator species C. capitata complex and Polydora sp. The most important factors obtained from canonical analysis were sorting, slope, mud and organic matter percentage. Marine biotic index (AMBI) showed that areas 3 and 5 were highly affected by anthropogenic factors, given that a poor polychaeta fauna, dominated by opportunistic species, were found. Polychaete assemblages were affected by eutrophication along an estuarine gradient as well as by morphodynamic condition of the beaches. PMID- 22818169 TI - Raising the dead, etc. PMID- 22818170 TI - Treatment for paragangliomas: passing the test of time. PMID- 22818171 TI - Management strategy in paragangliomas. PMID- 22818173 TI - Use of a TLD-based multisphere spectrometry system to measure the neutron spectra around a not-self-shielded PET cyclotron: Preliminary results. AB - In the present work, we utilized the BSS system with TLD-600 and TLD-700 to measure the neutron spectra around the GE-PETtrace 8 cyclotron of the Development Centre of Nuclear Technology (CDTN/CNEN) in Belo Horizonte, Brazil. The cyclotron is capable of accelerating protons up to 16.5 MeV, to production of fluorine-18. Four points inside the bunker of the cyclotron were studied. Two points in front of the primary radiation beam and other two opposed to the primary radiation beam. The measurements were unfolded with the BUMS and the NSDUAZ computer codes. The dosimetric quantities obtained were in agreement with the other published data and were coherent with the expected from theoretical estimates obtained from source term informed by the manufacturer of the cyclotron. PMID- 22818172 TI - Stereotactic radiosurgery as the primary treatment for new and recurrent paragangliomas: is open surgical resection still the treatment of choice? AB - OBJECTIVE: Paragangliomas (PGs) or glomus tumors are rare, and publications comparing treatment alternatives are few. We sought to analyze our experience with stereotactic radiosurgery (SRS), review the literature, and develop treatment guidelines. METHODS: We retrospectively examined the outcomes of 41 PGs in 36 patients treated with SRS at Stanford. Our data from medical records, telephone interviews, and imaging studies were combined with previously reported SRS data and compared to results following other treatments. RESULTS: With a median clinical follow-up of 4.8 years (3.9 years radiographic), local control was 100%. Complications included increase in preexistent vertigo in one patient and transient cranial neuropathies in two patients. Published surgical series describe a lower local control rate as well as more frequent and severe complications. Published radiation therapy (RT) series document a slightly lower local control rate than SRS, but SRS can be delivered more quickly and conveniently. Open surgery and other combinations of treatments appear to be required for several subpopulations of PG patients. CONCLUSIONS: We feel that SRS should be the primary treatment for most new and recurrent PGs. Even some very large PGs are appropriate for SRS. RT remains an appropriate option in some centers, especially those where SRS is not available. PGs occurring in the youngest patients, catecholamine secreting PGs, and PGs causing rapidly progressing neurologic deficits may be more appropriate for open resection. Metastatic PGs may benefit from combinations of chemotherapy and SRS or RT. Treatment guidelines are proposed. PMID- 22818174 TI - Cognitive and clinical outcomes associated with cannabis use in patients with bipolar I disorder. AB - Studies investigating the impact of cannabis use on bipolar clinical characteristics and neurocognition are limited. The objective of the present study was to compare clinical and neurocognitive measures in individuals with bipolar disorder with a history of cannabis use disorder (CUD) versus those without a history of CUD. We conducted a retrospective analysis of a large cohort (N=200) of bipolar I subjects, either with (CUD+; N=50) or without (CUD-; N=150) a history of CUD. We compared the groups on clinical and demographic variables, as well as on performance on neurocognitive tests. Patient groups did not differ regarding age, age of onset or global assessment of functioning. Compared to the CUD- group, the CUD+ group had a higher proportion of men and a higher proportion of patients with a history of psychosis. CUD+ subjects demonstrated significantly better performance on measures of attention, processing speed, and working memory. The history of CUD is associated with history of psychosis, suggestive of poorer clinical prognosis. Interestingly, bipolar patients with history of CUD had better neurocognitive performance as compared to patients with no history of CUD. PMID- 22818175 TI - Novel kinetic model of the removal of divalent heavy metal ions from aqueous solutions by natural clinoptilolite. AB - Removal of heavy metal ions from aqueous solutions using zeolites is widely described by pseudo-second order kinetics although this model may not be valid under all conditions. In this work, we have extended approaches used for derivation of this model in order to develop a novel kinetic model that is related to the ion exchange mechanism underlying sorption of metal ions in zeolites. The novel model assumed two reversible steps, i.e. release of sodium ions from the zeolite lattice followed by bonding of the metal ion. The model was applied to experimental results of Cu(II) sorption by natural clinoptilolite-rich zeolitic tuff at different initial concentrations and temperatures and then validated by predictions of ion exchange kinetics of other divalent heavy metal ions (i.e. Mn(II), Zn(II) and Pb(II)). Model predictions were in excellent agreements with experimental data for all investigated systems. In regard to the proposed mechanism, modeling results implied that the sodium ion release rate was constant for all investigated metals while the overall rate was mainly determined by the rate of heavy metal ion bonding to the lattice. In addition, prediction capabilities of the novel model were demonstrated requiring one experimentally determined parameter, only. PMID- 22818176 TI - Overexpression of Elsholtzia haichowensis metallothionein 1 (EhMT1) in tobacco plants enhances copper tolerance and accumulation in root cytoplasm and decreases hydrogen peroxide production. AB - To evaluate the functional roles of metallothionein (MT) in copper tolerance, we generated transgenic tobacco plants overexpressing EhMT1 from the Cu-accumulator Elsholtzia haichowensis Sun. Overexpression of EhMT1 in tobacco plants imparted increased copper (Cu) tolerance based on seedling dry biomass when compared to wild-type plants. Plants expressing EhMT1 accumulated more Cu in roots, which was mainly attributable to an increase of the soluble fraction. Levels of lipid peroxidation and production of hydrogen peroxide were lower in roots of transgenic tobacco than in wild-type plants. EhMT1 was suggested to bind Cu in the cytoplasm, thereby decreasing activity of free Cu(2+) ions and blocking Cu(2+) from interacting with cytoplasmic components, which in turn decreases the production of reactive oxygen species. In addition, our results also indicate that EhMT1-overexpressing tobacco has a more efficient antioxidant system, with improved peroxidase activity to better cope with oxidative stress. PMID- 22818177 TI - One-pot solvothermal synthesis of three-dimensional (3D) BiOI/BiOCl composites with enhanced visible-light photocatalytic activities for the degradation of bisphenol-A. AB - Three-dimensional (3D) BiOI/BiOCl composite microspheres with enhanced visible light photodegradation activity of bisphenol-A (BPA) are synthesized by a simple, one-pot, template-free, solvothermal method using BiI(3) and BiCl(3) as precursors. These 3D hierarchical microspheres with heterojunction structures are composed of 2D nanosheets and have composition-dependent absorption properties in the ultraviolet and visible light regions. The photocatalytic oxidation of BPA over BiOI/BiOCl composites followed pseudo first-order kinetics according to the Langmuir-Hinshelwood model. The highest photodegradation efficiency of BPA, i.e., nearly 100%, was observed with the BiOI/BiOCl composite (containing 90% BiOI) using a catalyst dosage of 1 g L(-1) in the BPA solution (C(0)=20 mg L(-1), pH=7.0) under visible light irradiation for 60 min. Under these conditions, the reaction rate constant was more than 4 and 20 times greater than that of pure BiOI and the commercially available Degussa P25, respectively. The superior photocatalytic activity of this composite catalyst is attributed to the suitable band gap energies and the low recombination rate of the photogenerated electron hole pairs due to the presence of BiOI/BiOCl heterostructures. Only one intermediate at m/z 151 was observed in the photodegradation process of BPA by liquid chromatography combined with mass spectrometry (LC-MS) analysis, and a simple and hole-predominated photodegradation pathway of BPA was subsequently proposed. Furthermore, this photocatalyst exhibited a high mineralization ratio, high stability and easy separation for recycling use, suggesting that it is a promising photocatalyst for the removal of BPA pollutants. PMID- 22818178 TI - International conference for healthcare and medical students 2011 dublin, ireland. 4-5 november 2011. Abstracts. PMID- 22818179 TI - Morphological and nanostructural features of porous silicon prepared by electrochemical etching. AB - Porous layers were produced on a p-type (100) Si wafer by electrochemical anodic etching. The morphological, nanostructural and optical features of the porous Si were investigated as functions of the etching conditions. As the wafer resistivity was increased from 0.005 to 15 Omega.cm, the etched region exhibited 'sponge', 'mountain' and 'column'-type morphologies. Among them, the sponge-type structured sample showed the largest surface area per unit volume. Silicon nanocrystallites, 2.0 to 5.3 nm in size, were confirmed in the porous layers. The photoluminescence peaks varied in the wavelength range of 615 to 722 nm. These changes in the maximum peak position were related to the size distribution of the Si crystallites in the porous silicon. The doping levels of the wafers significantly affect the size distribution of the Si crystallites as well as the light-emitting behavior of the etched Si, which contains nanoscale Si crystallites. PMID- 22818180 TI - Subglottic stenosis in Shwachman-Diamond syndrome - is there a link? AB - Clinically relevant cartilaginous subglottic stenosis was found in 2 patients with Shwachman-Diamond syndrome (SDS) for which tracheotomy was required in one case. Considering the pathogenesis of SDS, including deficient chondrogenesis, we hypothesise that subglottic stenosis may be a rare symptom of SDS. Otorhinolaryngologist and paediatricians should be aware of the risk of airway pathology in patients with SDS. PMID- 22818181 TI - No additional value of fusion techniques on anterior discectomy for neck pain: a systematic review. AB - We aimed to assess the effects of additional fusion on surgical interventions to the cervical spine for patients with neck pain with or without radiculopathy or myelopathy by performing a systematic review. The search strategy outlined by the Cochrane Back Review Group (CBRG) was followed. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL and PEDro up to June 2011. Only randomised, controlled trials of adults with neck pain that evaluated at least one clinically relevant primary outcome measure (pain, functional status, recovery) were included. Two authors independently assessed the risk of bias by using the criteria recommended by the CBRG and extracted the data. Data were pooled using a random effects model. The quality of the evidence was rated using the GRADE method. In total, 10 randomised, controlled trials were identified comparing additional fusion upon anterior decompression techniques, including 2 studies with a low risk of bias. Results revealed no clinically relevant differences in recovery: the pooled risk difference in the short-term follow-up was -0.06 (95% confidence interval -0.22 to 0.10) and -0.07 (95% confidence interval -0.14 to 0.00) in the long-term follow-up. Pooled risk differences for pain and return to work all demonstrated no differences. There is no additional benefit of fusion techniques applied within an anterior discectomy procedure on pain, recovery and return to work. PMID- 22818182 TI - Osteopontin regulates interleukin-17 production in hepatitis. AB - The overexpression of osteopontin is associated with various inflammatory liver diseases. Interestingly, each of these diseases is also associated with IL-17 expression. Therefore, we sought to determine whether there is any mechanistic link between osteopontin and IL-17. Herein we show that IL-17 and osteopontin levels were significantly increased in patients with chronic hepatitis B. We found that IL-17 and osteopontin levels increased similarly in mice with concanavalin A-induced hepatitis. Both osteopontin- and IL-17-deficient mice were resistant to concanavalin A-induced hepatic injury. In addition, osteopontin markedly induced IL-17 expression by leukocytes (from humans and mice). This effect could be blocked by a specific antibody against osteopontin. beta3 integrin (one of the osteopontin receptors) was critically involved in the induction of IL-17 production by osteopontin. Osteopontin-induced IL-17 expression was mediated through the p38, JNK, and NF-kappaB pathways. These findings suggest that osteopontin regulates IL-17 production during the pathogenesis of hepatitis and provide new evidence for the critical roles of osteopontin and IL-17 in hepatitis. PMID- 22818183 TI - [Urinary incontinence 6 months after childbirth]. AB - BACKGROUND AND OBJECTIVE: Urinary incontinence initiated before and right after delivery and persisting 3 months after delivery tends to become chronic. We intended to estimate the persistence of urinary incontinence 6 months postpartum and to analyse the different factors associated with it. PATIENTS AND METHODS: Follow-up study 6 months after delivery of women presenting urinary incontinence symptoms in gestation or in the first 2 months of postpartum. The dependent variable was the persistence and the independent variables were grouped in obstetric and non-obstetric. Odds ratio (OR) were calculated with their confidence interval at 95% (IC 95%) in the bivariate analysis. The variables that showed an important risk of persistence of incontinence were used to perform a multivariate model of logistic regression. RESULTS: The persistence of incontinence 6 months after delivery was 21.4% (CI 95% 16-26.7). The risk of persistence increased with the Kristeller maneuver (OR 7.89, CI 95% 3.04-20.49), not weight recovery (OR 3.64, CI 95% 1.10-12.02), not practising pelvic floor muscle exercises in postpartum (OR 9.36, CI 95% 2.71-32.33), appearance of incontinence after delivery (OR 6.66, CI 95% 2.37-18.68) and the weight of the newborn>3.5 kg (OR 6.76, CI 95% 2.54-18.03), all of them explaining 58% of the variability of persistence. CONCLUSION: 21.4% of women with urinary incontinence caused by pregnancy/delivery will continue to have it 6 months postpartum. An important part of this persistence is associated with some factors easy to modify. PMID- 22818184 TI - [Sutureless aortic valve replacement for high surgical risk patients with aortic stenosis: systematic review]. AB - Sutureless aortic valve replacement is perceived to be an alternative treatment for high surgical risk patients with severe aortic stenosis. This work presents the results of a systematic review undertaken to assess the effectiveness and safety of this procedure. Eight low quality case series were identified. Six focused on prosthesis ATS 3f Enable((r)) and 2 on Perceval S. Results show good haemodynamic and clinical results for both prosthesis. Implantation of ATS 3f Enable((r)) valves was successful in more than 85% of the patients and the mean cardiopulmonary bypass (BCP) time ranged from 58 to 85 minutes. For Perceval S, implantation was successful in all patients and the mean BCP time was less than 30 minutes. Since there are no long term follow-up studies, the durability of the prosthesis and the appearance of late complications is uncertain. PMID- 22818185 TI - Resident work hour restrictions do not improve patient safety in surgery: a critical appraisal based on 7 years of experience in Switzerland. AB - In 2005 the Swiss government implemented new work-hour limitations for all residency programs in Switzerland, including a 50-hour weekly limit. The reduction in the working hours of doctors in training implicate an increase in their rest time and suggest an amelioration of doctors' clinical performance and consequently in patients' outcomes and safety - which was not detectable in a preliminary study at a large referral center in Switzerland. It remains elusive why work-hour restrictions did not improve patient safety. We are well advised to thoroughly examine and eliminate the known adverse effects of reduced work-hours to improve our patients' safety. PMID- 22818186 TI - Making it easier to do the right thing: a modern communication QI agenda. PMID- 22818187 TI - Saccharomyces cerevisiae Apn1 mutation affecting stable protein expression mimics catalytic activity impairment: implications for assessing DNA repair capacity in humans. AB - Apurinic/apyrimidinic (AP) endonucleases play a major role in the repair of AP sites, oxidative damage and alkylation damage in DNA. We employed Saccharomyces cerevisiae in an unbiased forward genetic screen to identify amino acid substitutions in the major yeast AP endonuclease, Apn1, that impair cellular DNA repair capacity by conferring sensitivity to the DNA alkylating agent methyl methanesulfonate. We report here the identification and characterization of the Apn1 V156E amino acid substitution mutant through biochemical and functional analysis. We found that steady state levels of Apn1 V156E were substantially decreased compared to wild type protein, and that this decrease was due to more rapid degradation of mutant protein compared to wild type. Based on homology to E. coli endonuclease IV and computational modeling, we predicted that V156E impairs catalytic ability. However, overexpression of mutant protein restored DNA repair activity in vitro and in vivo. Thus, the V156E substitution decreases DNA repair capacity by an unanticipated mechanism via increased degradation of mutant protein, leading to substantially reduced cellular levels. Our study provides evidence that the V156 residue plays a critical role in Apn1 structural integrity, but is not involved in catalytic activity. These results have important implications for elucidating structure-function relationships for the endonuclease IV family of proteins, and for employing simple eukaryotic model systems to understand how structural defects in the major human AP endonuclease APE1 may contribute to disease etiology. PMID- 22818189 TI - Can we see nursing? PMID- 22818190 TI - Nurse residency programs: an evidence-based review of theory, process, and outcomes. AB - Nursing shortages exist worldwide while job stress, dissatisfaction, lack of peer support and limited professional opportunities still contribute to attrition. The aim of this systematic review is to describe and evaluate the quality of the science, report recommendations and lessons learned about implementing and evaluating nurse residency programs (NRPs) designed to improve new graduate transitioning. Databases were searched between 1980 and 2010 using five search terms: nurse, intern, extern, transition and residency programs. Twenty studies reporting programs for new RNs fit the inclusion criteria. Three major discoveries include: 1. Wide variation in content, teaching and learning strategies make comparison across programs difficult; 2. Lack of theory in designing the educational intervention has limited the selection and development of new instruments to measure program effectiveness; and 3. Well designed quasi experimental studies are needed. As a major nursing education redesign, NRPs could be used to test the principles, concepts and strategies of organizational transformation and experiential-interactive learning theory. By focusing on fiscal outcomes, current administrators of NRPs are missing the opportunity to implement an organizational strategy that could improve workplace environments. Healthcare organizations need to envision NRPs as a demonstration of positive clinical learning environments that can enhance intra- and interprofessional education and practice. PMID- 22818188 TI - Recombinant origin, contamination, and de-discovery of XMRV. AB - The discovery and de-discovery of the xenotropic murine leukemia virus-related virus (XMRV) has been a tumultuous roller-coaster ride for scientists and patients. The initial associations of XMRV with chronic fatigue syndrome and prostate cancer, while providing much hope and optimism, have now been discredited and/or retracted following overwhelming evidence that (1) numerous patient cohorts from around the world are XMRV-negative, (2) the initial reports of XMRV-positive patients were due to contamination with mouse DNA, XMRV plasmid DNA, or virus from the 22Rv1 cell line and (3) XMRV is a laboratory-derived virus generated in the mid 1990s through recombination during passage of a prostate tumor xenograft in immuno-compromised mice. While these developments are disappointing to scientists and patients, they provide a valuable road map of potential pitfalls to the would-be microbe hunters. PMID- 22818191 TI - Global health competencies for nurses in the Americas. AB - This article reports the findings from an online survey of nursing faculty from the United States, Canada, Latin America, and Caribbean countries to identify their perceptions about global health competencies for undergraduate nursing students. A list of global health competencies for medical students developed by the Association of Faculties of Medicine of Canada Resource Group on Global Health and the Global Health Education Consortium was adapted for nurses and translated from English to Spanish and Portuguese. The competencies were divided into six subscales, and respondents rated each competency on a 4-point Likert scale, with high scores reflecting strong agreement that the competency was essential for undergraduate nursing students. E-mail invitations and links to the online survey were distributed using a nonprobability convenience sampling strategy. This article reports findings only from the respondents to the English and Spanish surveys. The final sample included 542 responses to the English survey and 51 responses to the Spanish survey. Cronbach's alpha reliability coefficients for the subscales ranged from .78 to .96. The mean values for all 6 subscales and for each of the 30 items were greater than 3.0 for the respondents to the Spanish survey, and the mean values for 27 of the items were greater than 3.0 for the respondents to the English survey. These findings suggest that respondents perceived the competencies as essential global health competencies for undergraduate nursing students in the Americas. Narrative comments written by respondents indicate additional competencies and specific concerns about adding additional content to an already full curricula. Results of this study can be used to guide faculty deliberations about global health competencies that should be incorporated in the nursing curricula. PMID- 22818192 TI - Evaluation outcomes of a dedicated education unit in a baccalaureate nursing program. AB - Quality clinical learning environments (CLE) are crucial to student education and clinical learning and are influenced by both academic and nursing service factors. The University at Buffalo School of Nursing implemented an innovative academic-service partnership model for clinical education of students called a Dedicated Education Unit (DEU). The aims of this study were to (a) investigate students' perceived outcomes of the DEU model on the CLE and (b) explore staff nurses' and faculty's perceived outcomes of the DEU. Qualitative and quantitative methodologies were used. Descriptive statistics and thematic analysis of focus groups are reported. Students and DEU nurses reported high scores for satisfaction. Focus group themes for students, faculty, and DEU nurse revealed appreciation for the benefits of the DEU model. The DEU is a worthwhile approach to clinical education that can enhance student's ability to receive diverse clinical experiences and access to clinical experts. Such programs can strengthen academic/service relationships. PMID- 22818193 TI - The relationship between emotional intelligence and clinical teaching effectiveness in nursing faculty. AB - Nursing faculty play an important role in facilitating nursing student learning and shaping student experience in the clinical setting. Emotional intelligence (EI) in clinical nursing faculty may be one avenue to develop teaching effectiveness. This study investigated the relationship between EI and clinical teaching effectiveness of nursing faculty in an undergraduate nursing program. Using a cross-sectional correlation design, data were collected from a convenience sample of nursing faculty (N = 47) using the BarOn Emotional Quotient Inventory: Short (EQ-i:S), the Nursing Clinical Teacher Effectiveness Inventory (NCTEI) and a demographic data page. The results indicated a statistically significant positive relationship between the EQ-i:S and the NCTEI total scores (rs = .599, P < .01) and between many subscales of these tools. These findings contribute new knowledge to nursing education, including the following: (a) a significant relationship between EI and clinical teaching effectiveness exists, (b) faculty exhibit effective overall EI functioning with room to enhance competencies, and (c) faculty members see themselves as effective in their clinical teaching. Implications for clinical teaching practice include the need for faculty development and strengthening the faculty-student relationship. Possibilities for future research are discussed. PMID- 22818194 TI - Returning enlisted veterans-upward (to) professional nursing: not all innovative ideas succeed. AB - Military licensed vocational nurses (LVNs) provide nursing care for the ill, injured, convalescent, or disabled persons. Those who have deployed both for humanitarian and wartime situations have a tremendous experiential base in stabilization of life-threatening frontline injuries and critical care intense facilities. An educational program was created called Returning Enlisted Veterans Upward (to) Professional Nursing for retired/discharged U.S. Army LVNs to acknowledge their special military education and experiences. This educational model represented one step in the right direction to increase men and minorities in the professional nursing workforce, yet the program had to be dissolved. "Lessons learned" are presented so others might consider a similar project. PMID- 22818195 TI - Speaking of workplace bullying. AB - Despite the increasing frequency of its reported incidence, especially in health care practice and education settings, workplace bullying seems to defy victims' clear understanding of its effects on them personally and to challenge their ability to provide cogent explanations about those effects to others. Especially, when it is subtle, as is the case in much of workplace bullying, the experience is emotionally confusing to its victims, and its inherent behaviors often seem absurd to those who have not lived through them firsthand. Moreover, the outwardly innocuous behaviors of subtle workplace bullying can yield long-term disorder for victims' coworkers and for employing organizations. Aptly capturing the mechanism of operation of workplace bullying, the concept of catastrophization may provide language to support understanding of victims' personal experiences of subtle workplace bullying and support administrators in recognizing bullying's paradoxical and long-term effects. PMID- 22818196 TI - From onsite to online: lessons learned from faculty pioneers. AB - As the demand for online courses grows, academic settings that do not offer this option risk losing potential students to universities that adopt more innovative approaches to education. Understanding strategies that will prepare faculty to meet the challenges associated with this transformation is essential to developing a quality online program. Most basic to this transition is the philosophic acceptance of online learning as an educational method equivalent to traditional didactic lecture. Because the knowledge and skills associated with navigating Web-based tools and resources are perceived as a barrier by many faculty, focused efforts must be undertaken to assess faculty learning needs and to provide formal and informal education related to recommended teaching strategies and available technology. Collaboration with course design experts and participation in faculty work groups will facilitate acceptance and promote a sense of involvement. Administrative support is also imperative to produce satisfactory student outcomes that meet the needs for accreditation agencies, certification, or higher education standards. PMID- 22818197 TI - The role of feedback control mechanisms on the establishment of oscillatory regimes in the Ras/cAMP/PKA pathway in S. cerevisiae. AB - : In the yeast Saccharomyces cerevisiae, the Ras/cAMP/PKA pathway is involved in the regulation of cell growth and proliferation in response to nutritional sensing and stress conditions. The pathway is tightly regulated by multiple feedback loops, exerted by the protein kinase A (PKA) on a few pivotal components of the pathway. In this article, we investigate the dynamics of the second messenger cAMP by performing stochastic simulations and parameter sweep analysis of a mechanistic model of the Ras/cAMP/PKA pathway, to determine the effects that the modulation of these feedback mechanisms has on the establishment of stable oscillatory regimes. In particular, we start by studying the role of phosphodiesterases, the enzymes that catalyze the degradation of cAMP, which represent the major negative feedback in this pathway. Then, we show the results on cAMP oscillations when perturbing the amount of protein Cdc25 coupled with the alteration of the intracellular ratio of the guanine nucleotides (GTP/GDP), which are known to regulate the switch of the GTPase Ras protein. This multi-level regulation of the amplitude and frequency of oscillations in the Ras/cAMP/PKA pathway might act as a fine tuning mechanism for the downstream targets of PKA, as also recently evidenced by some experimental investigations on the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast cells. PMID- 22818198 TI - The field evaluation of albendazole and triclabendazole efficacy against Fasciola hepatica by coproantigen ELISA in naturally infected sheep. AB - Albendazole (ABZ) has been used for control of ovine fasciolosis in Sweden for several decades. However, increasing prevalence of Fasciola hepatica in Sweden requires attention to diagnostic tools and current control strategies. The coproantigen reduction test (CRT) using commercial Bio-X K201 Fasciola coproantigen ELISA (Bio-X Diagnostics, Jemelle, Belgium) was recently suggested as a novel method for diagnosis of patent F. hepatica infection. The aim of this study was to compare the efficacy of albendazole and triclabendazole (TCBZ) treatment against F. hepatica in naturally infected sheep in south-western Sweden by CRT, and also to evaluate the usefulness of this test as a diagnostic marker for anthelmintic efficacy following treatment with ABZ. Three weeks after housing, 24 serologically positive ewes on a commercial farm in Sweden were randomly allocated into three groups, which were either dewormed with 5mg/kg ABZ, 10mg/ml TCBZ or left untreated. Twenty-six days after initial administration of these anthelmintics, all of the sheep in the ABZ group and untreated control groups were treated with 10mg/kg TCBZ. While TCBZ caused elimination of coproantigen and eggs in faeces 7 days after application, ABZ treatment failed completely. Neither anthelmintic resistance, underdosing, nor lack of efficacy due to the presence of immature flukes can be out ruled as possible causes. Despite some deviations in conformity between coproantigen levels and presence of fluke eggs, the CRT was a useful tool for measuring treatment efficacies. PMID- 22818199 TI - Mitochondrial DNA analysis of Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) in the Southern Cone of South America. AB - A genetic analysis of partial sequences of the mitochondrial 16S and 12S rDNA genes of Rhipicephalus sanguineus sensu lato collected in the Southern Cone of South America was carried out. Also, sequences of ticks belonging to this taxon from Europe, Africa and other South American localities were included. TCS networks constructed with 16S rDNA sequences showed two clusters of haplotypes, namely, Southern lineage (ST) and Northern lineage (NT). Haplotypes representing the specimens coming from localities of Argentina, Uruguay and Chile were included in the ST lineage, while haplotypes from Brazil, Paraguay, Colombia, South Africa, Mozambique and from two localities of Northern Argentina were grouped in the NT lineage. The phylogenetic trees obtained with both 16S and 12S sequences showed two distinct clades, one containing R. sanguineus s.l from Argentina, Uruguay, Chile (ST lineage) and Western Europe (Italy and France), and a second clade including R. sanguineus s.l from Argentina, Paraguay, Brazil, Colombia (NT lineage), South Africa and Mozambique. The results herein reported revealed that the taxon R. sanguineus s.l is represented by two lineages in the Southern Cone of South America. According with the genetic comparative analysis, NT lineage and the ticks from Mozambique and South Africa represent a species that is not R. sanguineus s.s, while R. sanguineus s.l ticks from Western Europe and Southern South America (ST lineage) probably represent true R. sanguineus, because the type locality of R. sanguineus s.s is located in France. The taxonomic issue described for R. sanguineus s.l in the South America has epidemiological implications. Difference in the vectorial competence for Ehrlichia canis between the two lineages of R. sanguineus s.l was found in previous works. Further investigations are needed in order to verify a possible different vectorial competence for the other pathogens transmitted by these ticks. PMID- 22818200 TI - Influence of outcome valence in the subjective experience of episodic past, future, and counterfactual thinking. AB - Recent findings suggest that our capacity to imagine the future depends on our capacity to remember the past. However, the extent to which episodic memory is involved in our capacity to think about what could have happened in our past, yet did not occur (i.e., episodic counterfactual thinking), remains largely unexplored. The current experiments investigate the phenomenological characteristics and the influence of outcome valence on the experience of past, future and counterfactual thoughts. Participants were asked to mentally simulate past, future, and counterfactual events with positive or negative outcomes. Features of their subjective experiences during each type of simulation were measured using questionnaires and autobiographical interviews. The results suggest that clarity and vividness were higher for past than future and counterfactual simulations. Additionally, emotional intensity was lower for counterfactual simulations than past and future simulations. Finally, outcome valence influenced participants' judgment of probability for future and counterfactual simulations. PMID- 22818201 TI - Obesity in young-adult Nigerians: variations in prevalence determined by anthropometry and bioelectrical impedance analysis, and the development of % body fat prediction equations. AB - BACKGROUND: Overweight/obesity is a growing global public health concern. The variations in the prevalence of overweight/obesity, defined by Body Mass Index (BMI), Waist Circumference (WC), Waist-to-Height Ratio (WHtR), Waist-to-Hip Ratio (WHpR) and Bioelectrical Impedance Analysis (BIA), were studied and a prediction equation for % body fat (%BF) developed. METHODS: A total of 1584 subjects (56.4% males) were recruited for the study. Data on age, gender, height, weight, hip circumference and WC were collected from the subjects using standard protocols. BMI, WHtR and WHpR were derived using standard equations. %BF was measured using a BIA device (Omron BF-400). Appropriate statistical tools were used for the data analysis. RESULTS: The prevalence of overweight/obesity in the population was 28.4% (36.3% for males; 22.6% for females) (BIA); 20.7% (17.5% for males; 24.8% for females) (BMI); 7.5% (1.3% for males; 16.1% for females) (WC); 2.9% (4.3% for males; 1.2% for females) (WHpR); and 15.4% (14.8% for males; 16.2% females) (WHtR). Taking BIA as the reference point, WC misclassified overweight/obesity the most for males (35%), while for the females, WHpR misclassified both disorders the most (21.4%). Correlation studies showed that only BMI correlated significantly, albeit weakly, with %BF among the males, whereas all the anthropometric measures, but WHpR correlated significantly with % body fat in females. Two prediction equations for %BF were generated, and %BF predicted with the two equations correlated significantly (P < 0.001) with that measured by BIA. CONCLUSION: The prevalence of overweight/obesity in this population vary widely depending on the definition used. The developed prediction equations could be useful in resource-poor settings, but require validation. PMID- 22818202 TI - Associations of dioxins, furans and dioxin-like PCBs with diabetes and pre diabetes: is the toxic equivalency approach useful? AB - Toxic equivalency factors for dioxins and dioxin-like compounds have been established by the World Health Organization. Toxic equivalency (TEQ) was derived using 6 chlorinated dibenzo-p-dioxins, 9 chlorinated dibenzofurans and 8 polychlorinated biphenyls, in blood, from the 1999-2004 National Health and Nutrition Examination Survey. Relationships of 8 individual chemicals, the number of compounds elevated, and TEQ with pre-diabetes and total diabetes (diagnosed and undiagnosed) were investigated using logistic regressions. For the 8 chemicals analyzed separately, values above the 75th percentile were considered elevated, whereas for the other 15 compounds, values above the maximum limit of detection were considered elevated. Pre-diabetes with glycohemoglobin (A1c) 5.9 6.4% was associated with PCB 126, PCB 118 and having one or more compounds elevated (odds ratio 2.47, 95% CI 1.51-4.06). Pre-diabetes with A1c 5.7-5.8% was not associated with any individual chemical or the number of compounds elevated. Total diabetes was associated with 6 of the 8 individual compounds tested, and was associated with having 4 or more compounds elevated. Toxic equivalency >=81.58 TEQ fg/g was associated with total diabetes (odds ratio 3.08, 95% CI 1.20 7.90), but was not associated with A1c 5.9-6.4%. Having multiple compounds elevated appeared to be important for total diabetes, whereas for pre-diabetes with A1c 5.9-6.4%, having a single compound elevated appeared most important. Diabetes plus A1c >=5.9% was associated with 34.16-81.57 TEQ fg/g (odds ratio 2.00, 95% CI 1.06-3.77) and with >=81.58 TEQ fg/g (odds ratio 2.48, 95% CI 1.21 5.11), indicating that half the population has elevated risk for this combination of conditions. PMID- 22818203 TI - Adsorption and thermal decomposition of 2-octylthieno[3,4-b]thiophene on Au(111). AB - The adsorption and thermal stability of 2-octylthieno[3,4-b]thiophene (OTTP) on the Au(111) surfaces have been studied using scanning tunneling microscopy (STM), temperature programmed desorption (TPD), and X-ray photoelectron spectroscopy (XPS). UHV-STM studies revealed that the vapor-deposited OTTP on Au(111) generated disordered adlayers with monolayer thickness even at saturation coverage. XPS and TPD studies indicated that OTTP molecules on Au(111) are stable up to 450 K and further heating of the sample resulted in thermal decomposition to produce H(2) and H(2)S via C-S bond scission in the thieno-thiophene rings. Dehydrogenation continues to occur above 600 K and the molecules were ultimately transformed to carbon clusters at 900 K. Highly resolved air-STM images showed that OTTP adlayers on Au(111) prepared from solution are composed of a well ordered and low-coverage phase where the molecules lie flat on the surface, which can be assigned as a (9*2?33)R5 degrees structure. Finally, based on analysis of STM, TPD, and XPS results, we propose a thermal decomposition mechanism of OTTP on Au(111) as a function of annealing temperature. PMID- 22818204 TI - Effects of chronic ethanol consumption on rat upper gastrointestinal system: functional and histologic findings. AB - The purpose of the present study was to determine the effect of chronic alcohol consumption on reactivity of esophageal tunica muscularis mucosae (TMM) and lower esophageal sphincter (LES) smooth muscle. Six male rats in alcohol-fed group received ethanol (7.2% v/v) in a modified liquid diet for 4 weeks. Two control groups were used; six rats in the standard diet-fed group received rat chow and water for 4 weeks. Six rats in sucrose-fed group were given sucrose and received a liquid diet. The smooth muscle reactivity of TMM and LES strips from ethanol fed and control animals was evaluated in organ chambers. Also histologic study was undertaken to show effects of chronic alcohol consumption. Maximum contractile responses of TMM to KCl and carbachol were decreased in the ethanol fed group compared to the control groups. Relaxant responses to serotonin were decreased in the ethanol-fed group compared to the control groups. In TMM, isoproterenol- and papaverine-induced relaxant responses were similar in the ethanol-fed and control groups. In LES smooth muscle, relaxant responses to papaverine or isoproterenol were similar in the control groups and the ethanol fed group. There was no change in agonist potency among the groups. The relaxation response elicited by nicotine and sodium nitroprusside (SNP) or contractile response elicited by carbachol and 80 mM KCl was decreased with maximum responses and pD(2) values, in the ethanol-fed group compared to that of the control groups in LES. Decreased nNOS immunoreactivity in myenteric plexus was found in alcohol-exposed group compared to control groups. Our findings suggest that chronic alcohol consumption impairs relaxant and contractile responses of both TMM and LES smooth muscle and it may contribute to gastroesophageal reflux commonly seen after alcohol binges. PMID- 22818205 TI - Preparation, characterization, and process performance of composite fibrous adsorbents as cation exchangers for high throughput and high capacity bioseparations. AB - Fibrous materials are proposed as novel chromatographic supports depicting high throughput and high product capacity. In this work, a composite fiber harboring strong cation-exchange moieties has been investigated. Such materials were characterized by a plethora of physical methods including degree of swelling (DS), scanning electron microscope (SEM), confocal laser scanning microscopy (CLSM), and Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR). The composite showed a high degree of grafting (~30%) and exhibited a high swelling ratio (~300%). Moreover, homogenous grafting and the development of an internal (functional) hydrogel were observed. The fibrous adsorbent was packed utilizing a designed "double roll" supported-structure and subsequently tested for packing efficiency and chromatography performance. The mentioned system showed similar packing efficiency of height equivalent to a theoretical plate (HETP) value and higher permeability coefficient (0.92 * 10-7 cm2) than commercial resins. Experimentally determined Peclet number (Pe) values were within the range 60-90, suggesting a close-to-plug-flow condition. Total ionic capacity of the fibrous adsorbent was determined by the transition pH method. A capacity of 6.5 mequiv./g was obtained. Moreover, a high dynamic binding capacity for lysozyme was found to be 283 mg/g. On the other hand, a bed of randomly packed fiber also demonstrated high-resolution ability when a mixture of model protein was utilized to that end. Resolution was maintained at high flow rates (up to 900 cm/h) and utilizing shorter gradient development routines. Direct sequestration of a model protein (lysozyme) was also possible from an artificial mixture containing 1.5% yeast homogenate. Summarizing, the composite fibrous adsorbents exhibited superior performance during early protein capture and intermediate-resolution applications. PMID- 22818206 TI - Simultaneous determination of blonanserin and its metabolite in human plasma and urine by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. AB - Blonanserin is a novel atypical antipsychotic with highly selective receptor antagonist activity to dopamine D2 and 5-HT(2A). N-desethyl blonanserin (blonanserin C) is its major active metabolite in human plasma. Herein we report a new highly sensitive, selective, and rapid liquid chromatography-tandem mass spectrometry method to determine blonanserin and blonanserin C simultaneously in human plasma and urine, with N-desethyl-chlor-blonanserin (blonanserin D) as internal standard (IS). Blonanserin and blonanserin C were extracted from aliquots of plasma and urine with ethyl acetate and dichloromethane (4:1) as the solvent and chromatographic separation was performed using an Agilent Eclipse Plus C18 column. The mobile phase was composed of: acetonitrile and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (87:13, v/v). To quantify blonanserin, blonanserin C, and blonanserin D, respectively, multiple reaction monitoring (MRM) transition of m/z 368.2->297.2, m/z 340.2->297.1, and m/z 356.2->313.3 was performed in positive mode. The analysis time was about 5.5 min. The calibration curve was linear in the concentration range of 0.01-2 ng/ml. The lower limit of quantification reached 0.01 ng/ml. The intra and inter-day precision and relative errors were less than 8.0% and 6.6% for three QC levels in plasma and urine. The current LC-MS/MS method was validated as simple, sensitive, and accurate and has been successfully applied to investigate the pharmacokinetics of blonanserin and blonanserin C in humans. PMID- 22818208 TI - Abecedarium: who am I? D'.... PMID- 22818209 TI - Positron emission tomography-computed tomography evaluation for recurrent differentiated thyroid carcinoma. AB - OBJECTIVES: Recurrence is observed in 15-20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography-computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC. METHOD: A comprehensive review and discussion of the medical literature was carried out. RESULTS: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck. CONCLUSION: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence. PMID- 22818207 TI - Acute injury in the peripheral nervous system triggers an alternative macrophage response. AB - BACKGROUND: The activation of the immune system in neurodegeneration has detrimental as well as beneficial effects. Which aspects of this immune response aggravate the neurodegenerative breakdown and which stimulate regeneration remains an open question. To unravel the neuroprotective aspects of the immune system we focused on a model of acute peripheral nerve injury, in which the immune system was shown to be protective. METHODS: To determine the type of immune response triggered after axotomy of the sciatic nerve, a model for Wallerian degeneration in the peripheral nervous system, we evaluated markers representing the two extremes of a type I and type II immune response (classical vs. alternative) using real-time quantitative polymerase chain reaction (RT qPCR), western blot, and immunohistochemistry. RESULTS: Our results showed that acute peripheral nerve injury triggers an anti-inflammatory and immunosuppressive response, rather than a pro-inflammatory response. This was reflected by the complete absence of classical macrophage markers (iNOS, IFN gamma, and IL12p40), and the strong up-regulation of tissue repair markers (arginase-1, Ym1, and Trem2). The signal favoring the alternative macrophage environment was induced immediately after nerve damage and appeared to be established within the nerve, well before the infiltration of macrophages. In addition, negative regulators of the innate immune response, as well as the anti-inflammatory cytokine IL-10 were induced. The strict regulation of the immune system dampens the potential tissue damaging effects of an over-activated response. CONCLUSIONS: We here demonstrate that acute peripheral nerve injury triggers an inherent protective environment by inducing the M2 phenotype of macrophages and the expression of arginase-1. We believe that the M2 phenotype, associated with a sterile inflammatory response and tissue repair, might explain their neuroprotective capacity. As such, shifting the neurodegeneration-induced immune responses towards an M2/Th2 response could be an important therapeutic strategy. PMID- 22818210 TI - A dermatologic affection that can be readily diagnosed by an ENT specialist. PMID- 22818211 TI - Temozolomide and unusual indications: review of literature. AB - Temozolomide (TMZ) was first known to be useful as a radiosensitiser in both primary brain tumours like glioblastoma multiforme and oligodendroglioma. Later, TMZ proved its efficacy in the treatment of melanoma. Multiple publications have demonstrated the benefit of TMZ in terms of efficacy and tolerance (used as mono therapy or as adjuvant chemotherapy) compared to the "gold standard" treatment of this kind of tumours. Furthermore, several recent clinical trials have shown the particular importance of TMZ in other types of cancer. This publication deals with the use of TMZ in cancers which are not formal indications for TMZ (excluding glioblastoma multiforme, oligodendroglioma and melanoma). It also includes a necessary review of recent literature about the role of TMZ in the treatment of brain metastases, lymphomas, refractory leukaemia, neuroendocrine tumours, pituitary tumours, Ewing's sarcoma, primitive neuroectodermal tumours, lung cancer and other tumours. PMID- 22818212 TI - Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. AB - The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC). Unfortunately, with the exclusion of SCLC, no large phase II and III trials for pulmonary neuroendocrine tumours have been published. Thus, several treatment approaches are available for their treatment but none of them has been validated in appropriately designed and adequately sized clinical trials. The main problem of the published studies is that they include neuroendocrine tumours from various sites of origin with different clinical behaviour. It is important that future studies consider these tumours separately. In this regard, increased awareness and referral of these patients to tertiary centres, in which a multidisciplinary management is available, may be of value. The aim of this review is to evaluate the state of the art and discuss future developments in the management of pulmonary neuroendocrine tumours excluding SCLC which we consider should be addressed in a different issue. PMID- 22818213 TI - Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review. AB - The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib are the standard of care for treating patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). Compared with interferon-based treatment, the previous standard of care, imatinib is associated with significantly higher cytogenetic response rates and prolonged overall survival. Nilotinib and dasatinib, both newer and more potent TKIs, significantly improve cytogenetic and molecular response rates compared with imatinib. Despite significant advances in CML treatment enabled by the TKIs, a fraction of patients who receive frontline treatment with a TKI demonstrate inadequate response. The reasons for this vary, but in many cases, inadequate response can be attributed to non-adherence to the treatment regimen, intolerance to the drug, intrinsic or acquired resistance to the drug, or a combination of reasons. More often than not, strategies to improve response necessitate a change in treatment plan, either a dose adjustment or a switch to an alternate drug, particularly in the case of drug intolerance or drug resistance. Improved physician-patient communication and patient education are effective strategies to address issues relating to adherence and intolerance. Because inadequate response to TKI treatment correlates with poor long-term outcomes, it is imperative that patients who experience intolerance or who fail to achieve appropriate responses are carefully evaluated so that appropriate treatment modifications can be made to maximize the likelihood of positive long term outcome. PMID- 22818214 TI - Adipose-derived stromal cells (ASCs). AB - Adipose-derived stromal cells (ASCs) are now emerging as a good alternative to bone marrow derived mesenchymal stromal cells (BM-MSC) for cellular therapy. Similarly to BM-MSC, ASCs can be easily isolated as adherent fibroblastoid cell population after processing lipoaspirate samples. Lipoaspiration provides a great number of cells, without extensive manipulation. ASCs express classical mesenchymal markers and only at early passages express CD34. ASCs can differentiate in cells of mesodermal lineages, such as adipocytes, osteocytes and condrocytes. ASCs share with BM-MSC the same ability to inhibit the proliferation of allogeneic, activated immune cells, thus affecting in vivo in animal models the onset and course of rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE), Crohn's disease (CD), ulcerous colitis (UC) and graft versus-host disease (GvHD). On the other hand, the main molecular pathway involved in this effect is still unclear. On the basis of this functional property, ASCs are used in different clinical trials to treat RA, CD, UC and GvHD. However, the most promising field of clinical application is represented by bone defect repair. Despite the ability to regenerate injured tissues and to block the progression of inflammatory disorders, some authors reported that ASCs can also induce, in in vivo animal models, the growth and vascularization of solid and hematological tumors. Conversely, ASCs have been shown to hamper tumor cell proliferation, reduce cell viability and induce necrosis. Thus, more accurate studies, collaborative protocols, high standardization of methods, and safety controls are required to exclude transformation of transplanted ASCs. PMID- 22818215 TI - Diagnosis and management of people with venous thromboembolism and advanced cancer: how do doctors decide? A qualitative study. AB - BACKGROUND: The treatment of cancer associated thrombosis (CAT) is well established, with level 1A evidence to support the recommendation of a low molecular weight heparin (LMWH) by daily injection for 3-6 months. However, registry data suggest compliance to clinical guidelines is poor. Clinicians face particular challenges in treating CAT in advanced cancer patients due to shorter life expectancy, increased bleeding risk and concerns that self injection may be too burdensome. For these reasons decision making around the diagnosis and management of CAT in people with advanced cancer, can be complex, and should focus on its likely net benefit for the patient. We explored factors that influence doctors' decision making in this situation and sought to gain an understanding of the barriers and facilitators to the application of best practice. METHODS: Think aloud exercises using standardised case scenarios, and individual in depth interviews were conducted. All were transcribed. The think aloud exercises were analysed using Protocol Analysis and the interviews using Framework Analysis. PARTICIPANTS: 46 participants took part in the think aloud exercises and 45 participants were interviewed in depth. Each group included oncologists, palliative physicians and general practitioners and included both senior doctors and those in training. SETTING: Two Strategic Health Authority regions, one in the north of England and one in Wales. RESULTS: The following key issues arose from the data synthesis: the importance of patient prognosis; the concept of "appropriateness"; "benefits and burdens" of diagnosis and treatment; LMWH or warfarin for treatment and sources of information which changed practice. Although interlinked, they do describe distinct aspects of the factors that influence doctors in their decisions in this area. CONCLUSIONS: The above factors are issues doctors take into account when deciding whether to send a patient to hospital for investigation or to anticoagulate a patient with confirmed or suspected VTE. Many factors interweave and are themselves influenced by and dependent on each other. It is only after all are taken into account that the doctor arrives at the point of referring the patient for investigation. Some factors including logistic and organisational issues appeared to influence whether a patient would be investigated or treated with LMWH for a confirmed VTE. It is important that services are optimised to ensure that these do not hinder the appropriate investigation and management of individual patients. PMID- 22818216 TI - Canine cutaneous peripheral nerve sheath tumours versus fibrosarcomas can be differentiated by neuroectodermal marker genes in their transcriptome. AB - The diagnostic differentiation between canine fibrosarcomas and peripheral nerve sheath tumours (PNSTs) is based on histopathological phenotype. Histological differentiation of these tumours can, however, be challenging and there is a lack of immunohistochemical markers to prove their histogenic origin. To identify possible PNST markers and to further characterize their histogenic origin we compared histologically well-defined canine fibrosarcomas and PNSTs by cDNA microarray analysis. Forty-five annotated gene products were significantly differentially expressed between both tumour types. Seven of these gene products, known to be specifically expressed in neuroectodermal tissues, had higher expression levels in PNSTs: FMN2, KIF1B, GLI1, ROBO1, NMUR2, DOK4 and HMG20B. Conversely, eight genes associated with carcinogenesis had higher expression in fibrosarcomas: FHL2, PLAGL1, FNBP1L, BAG2, HK1, CSK and Cox5A. Comparison of the fibrosarcoma and PNST transcriptome therefore identified PNST phenotype associated genes involved in neuroectodermal differentiation, which may be useful as diagnostic markers. Furthermore, the genes associated with the fibrosarcoma phenotype may serve as markers to differentiate fibrosarcomas from other tumour types. PMID- 22818219 TI - The extent of perfusion deficit does not relate to the visibility of acute ischemic lesions on fluid-attenuated inversion recovery imaging. AB - OBJECTIVES: Fluid-attenuated inversion recovery imaging (FLAIR) has been suggested as a surrogate marker of lesion age in acute ischemic stroke. In a subgroup analysis, we evaluated whether the extent of perfusion deficit influences FLAIR lesion visibility and thus plays a role as a confounding variable in the interpretation of FLAIR images. METHODS: A subgroup of patients from a previous study evaluating the use of FLAIR imaging as a surrogate marker of lesion age within the first 6 hours of ischemic stroke were examined to determine the influence of the amount of perfusion deficit on FLAIR lesion visibility. RESULTS: N = 48 patients were included into the analysis. In positive and negative FLAIR lesion cases the extent of perfusion deficits did not differ significantly (150 mL vs. 197 mL, P = .730) nor influenced FLAIR visibility independently. In contrast, diffusion weighted imaging (DWI) lesion volumes were larger (34 mL vs. 14 mL, P = .008) and time from symptom onset longer (180 vs. 120 minute, P = .071) in FLAIR-positive cases. CONCLUSION: Visibility of FLAIR lesions in acute stroke imaging is influenced by lesion size and time from symptom onset to MRI, but not by the amount of perfusion deficit calculated by time-to-peak (TTP) measurements. PMID- 22818218 TI - Patient-controlled encrypted genomic data: an approach to advance clinical genomics. AB - BACKGROUND: The revolution in DNA sequencing technologies over the past decade has made it feasible to sequence an individual's whole genome at a relatively low cost. The potential value of the information generated by genomic technologies for medicine and society is enormous. However, in order for exome sequencing, and eventually whole genome sequencing, to be implemented clinically, a number of major challenges need to be overcome. For instance, obtaining meaningful informed consent, managing incidental findings and the great volume of data generated (including multiple findings with uncertain clinical significance), re interpreting the genomic data and providing additional counselling to patients as genetic knowledge evolves are issues that need to be addressed. It appears that medical genetics is shifting from the present "phenotype-first" medical model to a "data-first" model which leads to multiple complexities. DISCUSSION: This manuscript discusses the different challenges associated with integrating genomic technologies into clinical practice and describes a "phenotype-first" approach, namely, "Individualized Mutation-weighed Phenotype Search", and its benefits. The proposed approach allows for a more efficient prioritization of the genes to be tested in a clinical lab based on both the patient's phenotype and his/her entire genomic data. It simplifies "informed-consent" for clinical use of genomic technologies and helps to protect the patient's autonomy and privacy. Overall, this approach could potentially render widespread use of genomic technologies, in the immediate future, practical, ethical and clinically useful. SUMMARY: The "Individualized Mutation-weighed Phenotype Search" approach allows for an incremental integration of genomic technologies into clinical practice. It ensures that we do not over-medicalize genomic data but, rather, continue our current medical model which is based on serving the patient's concerns. Service should not be solely driven by technology but rather by the medical needs and the extent to which a technology can be safely and effectively utilized. PMID- 22818220 TI - [Parvovirus B19 infection in healthy adults]. PMID- 22818221 TI - Premature diagnostic closure: an avoidable type of error. AB - A well-developed clinical interview makes it possible to adequately focus the diagnosis. However, cognitive psychology shows that mistakes are made when the persons face complex problems, such as those faced when making a diagnosis, especially if time or resources are limited. The main cause of failures in clinical reasoning is using "cognitive shortcuts". Among them, premature closure is a key factor triggering a diagnostic error. Cognitive errors are predictable and thus, it is possible to learn strategies to reduce or avoid them. Knowing the main features of cognitive shortcuts and identifying those automatically used is the first step towards preventing errors or minimizing their consequences. PMID- 22818222 TI - C/EBPbeta regulates multiple IL-1beta-induced human astrocyte inflammatory genes. AB - BACKGROUND: CCAAT enhancer-binding protein (C/EBP)beta regulates gene expression in multiple organ systems and cell types, including astrocytes in the central nervous system (CNS). Inflammatory stimuli, interleukin (IL)-1beta, tumor necrosis factor-alpha, human immunodeficiency virus (HIV)-1 and lipopolysaccharide induce astrocyte C/EBPbeta expression. C/EBPbeta is detectable in brains of Alzheimer's disease (AD), Parkinson's disease (PD) and HIV-1 associated dementia (HAD) patients, yet little is known about how C/EBPbeta contributes to astrocyte gene regulation during neuroinflammation. METHODS: The expression of 92 human inflammation genes was compared between IL-1beta-treated primary human astrocytes and astrocytes transfected with C/EBPbeta-specific small interfering (si)RNA prior to IL-1beta treatment for 12 h. Transcripts altered by>two-fold compared to control were subjected to one-way analysis of variance and Newman-Keuls post-test for multiple comparisons. Expression of two genes, cyclooxygenase-2 (COX-2) and bradykinin receptor B2 (BDKRB2) was further confirmed in additional human astrocyte donors. Astrocytes were treated with mitogen-activated protein kinase-selective inhibitors, then with IL-1beta for 12 or 24 h followed by COX-2 and BDKRB2, expression analyses. RESULTS: IL-1beta altered expression of 29 of 92 human inflammation genes by at least two-fold in primary human astrocytes in 12 h. C/EBPbeta knockdown affected expression of 17 out of 29 IL-1beta-regulated genes by>25%. Two genes relevant to neuroinflammation, COX-2 and BDKRB2, were robustly decreased and increased, respectively, in response to C/EBPbeta knockdown, and expression was confirmed in two additional donors. COX-2 and BDKRB2 mRNA remained altered in siRNA transfected astrocytes at 12, 24 or 72 h. Inhibiting p38 kinase (p38K) activation blocked IL-1beta-induced astrocyte COX-2 mRNA and protein expression, but not IL 1beta-induced astrocyte BDKRB2 expression. Inhibiting extracellular-regulated kinase (ERK)1/2 activation blocked IL-1beta-induced BDKRB2 mRNA expression while increasing COX-2 expression. CONCLUSION: These data support an essential role for IL-1beta in the CNS and identify new C/EBPbeta functions in astrocytes. Additionally, this work suggests p38K and ERK1/2 pathways may regulate gene expression in a complementary manner to fine tune the IL-1beta-mediated astrocyte inflammatory response. Delineating a role for C/EBPbeta and other involved transcription factors in human astrocyte inflammatory response may lead to effective therapies for AD, PD, HAD and other neurological disorders. PMID- 22818223 TI - [Invasive conservative care in cases of severe post-partum haemorrhage: future fertility and pregnancy outcome consequences]. AB - The development of conservative surgical approaches and interventionnal radiology for conservative treatment in cases of severe post-partum haemorrhage allows nowadays a preservation of the genital tract in most of the cases in developed countries. The consequences of these techniques for the future fertility and pregnancy outcome are not fully evaluated. Very few cases of infertility are reported and the majority of the patients seem to recover regular menstrual menses after application of any of the described conservative approach. Pregnancy outcomes appear unchanged without any consequence concerning foetal growth. However, complications might occur, impairing future fertility or pregnancy outcome: uterine synechia have been described after arterial embolization, ovarian failures occurred after stepwise surgical approach including lombo ovarian artery ligature, synechia and uterine infection impaired uterine compression sutures. Furthermore, recurrence of post-partum haemorrhage and abnormal placentation rates seem to be higher for future pregnancies. PMID- 22818225 TI - Interactive, technology-enhanced self-regulated learning tools in healthcare education: a literature review. AB - INTRODUCTION: Learning technology is increasingly being implemented for programmes of blended learning within nurse education. With a growing emphasis on self-directed study particularly in post-basic education, there is a need for learners to be guided in their learning away from practice and limited classroom time. Technology-enabled (TE) tools which engage learners actively can play a part in this. The effectiveness and value of interactive TE learning strategies within healthcare is the focus of this paper. OBJECTIVES: To identify literature that explores the effectiveness of interactive, TE tools on knowledge acquisition and learner satisfaction within healthcare with a view to evaluating their use for post-basic nurse education. DESIGN: A Literature Review was performed focusing on papers exploring the comparative value and perceived benefit of TE tools compared to traditional modes of learning within healthcare. DATA SOURCES: The Databases identified as most suitable due to their relevance to healthcare were accessed through EBSCOhost. REVIEW METHODS: Primary, Boolean and advanced searches on key terms were undertaken. Inclusion and exclusion criteria were applied which resulted in a final selection of 11 studies for critique. FINDINGS: Analysis of the literature found that knowledge acquisition in most cases was enhanced and measured learner satisfaction was generally positive for interactive, self-regulated TE tools. However, TE education may not suit all learners and this is critiqued in the light of the identified limitations. CONCLUSIONS: Interactive self regulation and/or testing can be a valuable learning strategy that can be incorporated into self-directed programmes of study for post-registration learners. Whilst acknowledging the learning styles not suited to such tools, the concurrent use of self-directed TE tools with those learning strategies necessitating a more social presence can work together to support enhancement of knowledge required to deliver rationale for nursing practice. PMID- 22818224 TI - [Hemodynamic effects of intravenous omeprazole in critically ill children]. AB - INTRODUCTION: Critical patients usually have hemodynamic disturbances which may become worse by the administration of some drugs. Omeprazole is a drug used in the prophylaxis of the gastrointestinal bleeding in these patients, but its cardiovascular effects are unknown. The objective was to study the hemodynamic changes produced by intravenous omeprazole in critically ill children and to find out if there are differences between two different doses of omeprazole. MATERIAL AND METHODS: A randomized prospective observational study was performed on 37 critically ill children aged from 1 month to 14 years of age who required prophylaxis for gastrointestinal bleeding. Of these, 19 received intravenous omeprazole 0.5mg/kg every 12 hours, and 18 received intravenous omeprazole 1mg/kg every 12 hours. Intravenous omeprazole was administered in 20 minutes by continuous infusion pump. Heart rate, systolic, diastolic and mean arterial blood pressure, central venous pressure and ECG were recorded at baseline, and at 15, 30, 60 and 120 minutes of the infusion. RESULTS: There were no significant changes in the electrocardiogram, heart rate, blood pressure and central venous pressure. No patients required inotropic therapy modification. There were no differences between the two doses of omeprazole. CONCLUSIONS: Intravenous omeprazole administration of 0.5mg/kg and 1mg/kg is a hemodynamically safe drug in critically ill children. PMID- 22818226 TI - A suicide education programme for nurses to educate the family caregivers of suicidal individuals: a longitudinal study. AB - Family members lack the ability to care for suicidal relatives. Nurses have a responsibility to improve family members' ability to care for their suicidal relatives. The aims of this study were to design a suicide education programme for nurses to educate family caregivers and to evaluate the longitudinal (12 months after the educational programme) effects of a suicide care education programme on the ability of families to care for suicidal relatives. A randomised controlled trial was conducted. The study population (n=61) was composed of the family caregivers of suicidal individuals. Several caregivers (n=26) were randomly allocated to an experimental group who attended a two-hour suicide care education programme, and the other caregivers (n=35) represented a control group who did not attend the education programme. All of the participants were given a questionnaire at baseline, 3 months, and 12 months during the period from 2009 to 2011. The results of the longitudinal effects of the suicide care education programme demonstrated that there were statistically significant differences after the educational programme as compared to before the programme with regard to "seeking assistance from resources" and the ability to care for those who were once suicidal. The longitudinal results of both groups showed that there was a significant difference in terms of "caring ability" at 12 months. The results of a multiple linear regression analysis indicated that evaluations performed at the three-month time point were able to effectively predict success in "seeking assistance from resources", "caring ability"; caring ability was also significantly improved among those who engaged in the educational programme at the 12-month time point. The suicide care education programme had long-term effects for family caregivers caring for their suicidal relatives. Nurses could employ this suicide care education programme to improve the ability of family caregivers to care for their suicidal relatives. PMID- 22818228 TI - A longitudinal study of cortisol responses, sleep problems, and psychological well-being as the predictors of changes in depressive symptoms among breast cancer survivors. AB - OBJECTIVE: This study examined whether the changes in sleep problems, attachment styles, meaning in life, and salivary cortisol over the course of 14 months were the predictors of changes in depressive symptoms in women with breast cancer at post-treatment stage. METHODS: The study included 76 participants who completed active breast cancer treatment with longitudinal data collected at five points, including baseline assessment (T0) and the four follow-ups after baseline: T1 (in the 2nd month), T2 (in the 5th month), T3 (in the 8th month), and T4 (in the 14th month). The self-reported questionnaires included the Medical Outcomes Study Sleep (MOS-Sleep) scale; the Beck Depression Inventory-II (BDI-II); the Experiences in Close Relationships-Revised (ECR-R) scale for measuring anxiety and avoidance dimensions of attachment style; and the Meaning in Life Questionnaire (MLQ), consisting of the MLQ-Presence scale and the MLQ-Search scale. The participants collected their salivary cortisol at home at six time points: upon waking, 30 and 45 min after waking, and at 1200 h, 1700 h, and 2100 h. RESULTS: Higher scores on for anxiety-related attachment style and the sleep problems index at baseline were associated with more severe initial depressive symptoms after the age, BMI, cancer, and treatment variables were controlled. The presence of meaning in life at baseline was negatively correlated with initial depressive symptoms. Moreover, the decreases in the presence of meaning in life over the course of 14 months predicted more severe depressive symptoms. In addition, the persistent increases of cortisol level at 2100 h across 14-month follow-ups predicted worsening depressive symptoms. CONCLUSIONS: Lacking presence of meaning in life as a predictor for severe depressive symptoms demonstrates that breast cancer survivors who lack psychological well-being are more likely to be depressed. The persistent elevation of cortisol levels at night also indicates breast cancer survivors to be at high risk of depression. PMID- 22818230 TI - Homeopathic treatment for peripheral nerve regeneration: an experimental study in a rat sciatic nerve transection model. AB - AIM: Effects of homeopathic treatment with Hypericum perforatum (Hypericum) on peripheral nerve regeneration was studied using a rat sciatic nerve transection model. METHODS: Fifty-four male healthy White Wistar rats were divided into three experimental groups (n = 18), randomly: Sham-operation (Sham), control: silicon tube (Sil) and treatment: silicon tube + Hypericum (Sil/Hypericum). In the Sham group after anesthesia left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis muscle was sutured. In the Sil group the left sciatic nerve was exposed the same way and transected proximal to tibio-peroneal bifurcation leaving a 10-mm gap. Proximal and distal stumps were each inserted into a silicone tube. In the Sil/Hypericum group a silicone tube was implanted the same way and each animal received three oral drops of Hypericum 30c twice daily for 1 week. Each group was subdivided into three subgroups of six animals each studied 4, 8, 12 weeks after surgery. RESULTS: Data were analyzed statistically by factorial analysis of variance (ANOVA) and, the Bonferroni test for pair-wise comparisons. Functional study showed faster and better recovery of regenerated axons in Sil/Hypericum than in Sil group (P < 0.05). Gastrocnemius muscle mass in Sil/Hypericum was significantly greater than in Sil group. Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in Sil/Hypericum were significantly higher than in control group. Immunohistochemistry, showed the location of reactions to S-100 in Sil/Hypericum was clearly more positive than in Sil group. CONCLUSION: Hypericum improves functional recovery of peripheral nerve regeneration in rats. PMID- 22818231 TI - Effects of microcurrent application alone or in combination with topical Hypericum perforatum L. and Arnica montana L. on surgically induced wound healing in Wistar rats. AB - OBJECTIVES: This study evaluated the wound healing activity of microcurrent application alone or in combination with topical Hypericum perforatum L. and Arnica montana L. on skin surgical incision surgically induced on the back of Wistar rats. DESIGN: The animals were randomly divided into six groups: (1) no intervention (control group); (2) microcurrent application (10 MUA/2 min); (3) topical application of gel containing H. perforatum; (4) topical application of H. perforatum gel and microcurrent (10 MUA/2 min); (5) topical application of gel containing A. montana; (6) topical application of A. montana gel and microcurrent (10 MUA/2 min). Tissue samples were obtained on the 2nd, 6th and 10th days after injury and submitted to structural and morphometric analysis. RESULTS AND CONCLUSION: Differences in wound healing were observed between treatments when compared to the control group. Microcurrent application alone or combined with H. perforatum gel or A. montana gel exerted significant effects on wound healing in this experimental model in all of the study parameters (P<0.05) when compared to the control group with positive effects seen regarding newly formed tissue, number of newly formed blood vessels and percentage of mature collagen fibers. The morphometric data confirmed the structural findings. In conclusion, application of H. perforatum or A. montana was effective on experimental wound healing when compared to control, but significant differences in the parameters studied were only observed when these treatments were combined with microcurrent application. PMID- 22818232 TI - Morphometry of white muscle fibers and performance of Nile tilapia (Oreochromis niloticus) fingerlings treated with methyltestosterone or a homeopathic complex. AB - BACKGROUND: Nile tilapia (Oreochromis niloticus), are widely used in fish farming, hormonal treatments are used to increase productivity. Studies of the characteristics of the fiber types are important in species that have well developed muscle mass, such as Nile tilapia. METHODS: A total of 4800 post-larval fish were randomly assigned by tank to receive one of three treatments: Control (30 degrees GL alcohol), Homeopathic complex (Homeopatila RS) or Hormone (17 alpha-methyltestosterone) supplemented in the feed for 28 days. Survival and morphological parameters were measured at day 45. RESULTS: At day 45, the survival rates were 54.1% (Control), 87.8% (Homeopathy), 50.3% (Hormone). The mean final weight for Homeopathy was statistically significantly lower (1.07 g) than the other two groups: Control (1.81 g) and Hormone (2.04 g). Mean total lengths were Control (4.75 cm), Hormone (4.49 cm), statistically significantly different from Homeopathy (3.83 cm). Average partial length, trunk length, height and body width were significantly lower for Homeopathy than Control or Hormone (p<0.05) Homeopathy treated fish had significantly greater muscle fiber diameter than the other two groups. CONCLUSIONS: Fish treated with the homeopathic complex had improved survival and muscle fiber hypertrophy, but were smaller (probably related to increased survival and overcrowding) compared to fingerlings treated with synthetic hormone or control. PMID- 22818233 TI - The therapeutic effect of Tarentula cubensis extract (Theranekron(r)) in foot-and mouth disease in cattle: a randomised trial in an endemic setting. AB - BACKGROUND: Foot-and-mouth disease (FMD) is a contagious viral disease of ruminant animals. Eradication of disease in western countries is by slaughter of infected and in contact animals but this is not possible in endemic countries. There is no standard treatment for FMD in endemic countries, but anti inflammatory drugs and mild disinfectant and protective dressing to inflamed areas to prevent secondary infection is recommended. METHOD: A randomised controlled clinical trial of a homeopathic preparation of Tarentula cubensis (Theranekron(r)) was conducted during an outbreak of FMD in cattle in Iran. A single subcutaneous injection of Theranekron(r) was used as sole treatment in 50 infected animals (treatment group). The control group comprised 15 infected animals treated with standard medication including: daily injection of flunixin meglumine and oxytetracycline and daily dressing of lesions with 4% sodium carbonate. Systemic and local signs were recorded over 14 days. RESULTS: Rectal temperature in treatment group subsided to normal range within 1 day of homeopathic treatment, and was significantly lower in test group than in control group on several successive days (P < 0.05). Healing of inflamed mucosal areas and appetite score of the treatment was significantly better than control during first 3 days of treatment (P < 0.05). CONCLUSION: It appears that Theranekron(r) is effective for treatment of systemic and local signs of FMD-infected cattle. Further research is justified. PMID- 22818234 TI - Toxicodendron pubescens retains its anti-arthritic efficacy at 1M, 10M and CM homeopathic dilutions. AB - BACKGROUND: Our previous studies of Toxicodendron pubescens (Rhus tox) in homeopathic dilutions have shown anti-inflammatory activity in line with the principle of similia. The present study aimed to evaluate its anti-inflammatory activity in 1M, 10M and CM dilutions in rats. METHOD: Arthritis was induced by subplantar injection of 0.1 ml of Complete Freund's Adjuvant (CFA) in the right hind paws of rats. The severity of inflammatory lesions was measured plethysmometrically on 21st day post CFA injection. The intensity of pain was measured using digital Von Frey apparatus. Other estimations included serum C reactive protein (CRP), hematological parameters, body weight changes, arthritic pain score and radiological analysis of the arthritic paws. RESULT: The 1M, 10M and CM homeopathic dilutions of Rhus tox reduced primary and secondary arthritic lesions, improved body weight gain and protected rats against CFA-induced hematological and radiological perturbations. A significant reduction in the serum levels of CRP and an improvement in pain threshold of injected paws was observed in the groups treated with the Rhus tox dilutions. CONCLUSION: The anti arthritic potential of Rhus tox is retained at 1M, 10M and CM dilutions. PMID- 22818235 TI - Anxiolytic effect of homeopathic preparation of Pulsatilla nigricans in Swiss albino mice. AB - BACKGROUND: The homeopathic preparation of Pulsatilla nigricans is used in the treatment of anxiety related disorders. Though in clinical use for many years, the anxiolytic activity of Pulsatilla nigricans (Puls) has not been evaluated experimentally. Hence the present study was conducted in Swiss albino mice to evaluate the anxiolytic activity of Puls and compare its activity with the standard anxiolytic drug, diazepam. METHODS: Twenty four mice were divided into 4 groups of 6 animals each, control, standard and two test groups. The control group was treated Ethyl alcohol 10 ml/kg. The standard group received Diazepam, 1 mg/kg. Puls 3x and 6x solutions were given at the dose of 10 ml/kg to the test groups. All animals were given the test and control treatments orally for 15 days. The anxiolytic effect was tested on days 1, 8 and 15 using the Elevated Plus Maze (EPM) and Open Field Test (OFT). RESULTS: Both diazepam and Puls showed significant anxiolytic activity in EPM and OFT test compared to control. The total number of entries and time spent in open arm in EPM was increased by both diazepam and Puls, the effect of 3x dilution of Puls was greater than diazepam. In the OFT the number of squares crossed, rearing and assisted rearings decreased with both diazepam and Puls compared to control and the anxiolytic effect of diazepam was greater than Puls. The anxiolytic effect is greater for the 3x dilution than 6x dilution of Puls. CONCLUSION: The study showed an anxiolytic effect of homeopathic preparation of Pulsatilla nigricans comparable to that found with a standard drug. PMID- 22818236 TI - Characteristics of visitors to practitioners of homeopathy in a large adult Norwegian population (the HUNT 3 study). AB - OBJECTIVES: The aim was to investigate characteristics of female and male visitors to practitioners of homeopathy in a large adult population in Norway. METHODS: A cross-sectional adult total population health survey from Central Norway (the Nord-Trondelag Health Study--HUNT 3) conducted in 2008. Variables included demographics, lifestyle, health status and health care use. Multivariate logistic regression models were employed to analyse the data. RESULTS: In total 50,827 participated (54% of the total population). The prevalence of visits to practitioners of homeopathy was 1.3%, a decline from 4.3% 10 years earlier. Both female and male visitors were 4-5 times more likely to experience recent somatic complaints. Further, female visitors were characterised by higher education, non smoking, more chronic complaints, and visiting a physician or a chiropractor the past year whereas male visitors were characterised by seeking help for psychiatric complaints and visiting a chiropractor. There were no associations of age, marital status, physical activity, perceived global health, respiratory, skin, or musculoskeletal diseases with visiting practitioners of homeopathy. CONCLUSIONS AND PROPOSALS: There has been a marked decline in visits to practitioners of homeopathy. The results indicate a change in reasons to consult from complaints that influences the visitors' global health to less chronic complaints. Further research should compare changes in visits complementary and alternative medicine (CAM) practitioners and the characteristics of visitors to practitioners of homeopathy to characteristics of other CAM visitors. PMID- 22818238 TI - Contemporary clinical spectrum of constrictive pericarditis: a 10-year experience. PMID- 22818237 TI - Nonlinear dynamical systems effects of homeopathic remedies on multiscale entropy and correlation dimension of slow wave sleep EEG in young adults with histories of coffee-induced insomnia. AB - BACKGROUND: Investigators of homeopathy have proposed that nonlinear dynamical systems (NDS) and complex systems science offer conceptual and analytic tools for evaluating homeopathic remedy effects. Previous animal studies demonstrate that homeopathic medicines alter delta electroencephalographic (EEG) slow wave sleep. The present study extended findings of remedy-related sleep stage alterations in human subjects by testing the feasibility of using two different NDS analytic approaches to assess remedy effects on human slow wave sleep EEG. METHODS: Subjects (N=54) were young adult male and female college students with a history of coffee-related insomnia who participated in a larger 4-week study of the polysomnographic effects of homeopathic medicines on home-based all-night sleep recordings. Subjects took one bedtime dose of a homeopathic remedy (Coffea cruda or Nux vomica 30c). We computed multiscale entropy (MSE) and the correlation dimension (Mekler-D2) for stages 3 and 4 slow wave sleep EEG sampled in artifact free 2-min segments during the first two rapid-eye-movement (REM) cycles for remedy and post-remedy nights, controlling for placebo and post-placebo night effects. RESULTS: MSE results indicate significant, remedy-specific directional effects, especially later in the night (REM cycle 2) (CC: remedy night increases and post-remedy night decreases in MSE at multiple sites for both stages 3 and 4 in both REM cycles; NV: remedy night decreases and post-remedy night increases, mainly in stage 3 REM cycle 2 MSE). D2 analyses yielded more sporadic and inconsistent findings. CONCLUSIONS: Homeopathic medicines Coffea cruda and Nux vomica in 30c potencies alter short-term nonlinear dynamic parameters of slow wave sleep EEG in healthy young adults. MSE may provide a more sensitive NDS analytic method than D2 for evaluating homeopathic remedy effects on human sleep EEG patterns. PMID- 22818239 TI - Endocrine associations with health-related quality of life in coronary artery disease patients. PMID- 22818240 TI - Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients. AB - Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6 12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease. PMID- 22818242 TI - A vaccine to prevent epidemic meningitis in Africa. PMID- 22818241 TI - Serogroup A meningococcal conjugate vaccination in Burkina Faso: analysis of national surveillance data. AB - BACKGROUND: An affordable, highly immunogenic Neisseria meningitidis serogroup A meningococcal conjugate vaccine (PsA-TT) was licensed for use in sub-Saharan Africa in 2009. In 2010, Burkina Faso became the first country to implement a national prevention campaign, vaccinating 11.4 million people aged 1-29 years. We analysed national surveillance data around PsA-TT introduction to investigate the early effect of the vaccine on meningitis incidence and epidemics. METHODS: We examined national population-based meningitis surveillance data from Burkina Faso using two sources, one with cases and deaths aggregated at the district level from 1997 to 2011, and the other enhanced with results of cerebrospinal fluid examination and laboratory testing from 2007 to 2011. We compared mortality rates and incidence of suspected meningitis, probable meningococcal meningitis by age, and serogroup-specific meningococcal disease before and during the first year after PsA-TT implementation. We assessed the risk of meningitis disease and death between years. FINDINGS: During the 14 year period before PsA-TT introduction, Burkina Faso had 148 603 cases of suspected meningitis with 17 965 deaths, and 174 district-level epidemics. After vaccine introduction, there was a 71% decline in risk of meningitis (hazard ratio 0.29, 95% CI 0.28-0.30, p<0.0001) and a 64% decline in risk of fatal meningitis (0.36, 0.33-0.40, p<0.0001). We identified a statistically significant decline in risk of probable meningococcal meningitis across the age group targeted for vaccination (62%, cumulative incidence ratio [CIR] 0.38, 95% CI 0.31-0.45, p<0.0001), and among children aged less than 1 year (54%, 0.46, 0.24-0.86, p=0.02) and people aged 30 years and older (55%, 0.45, 0.22-0.91, p=0.003) who were ineligible for vaccination. No cases of serogroup A meningococcal meningitis occurred among vaccinated individuals, and epidemics were eliminated. The incidence of laboratory-confirmed serogroup A N meningitidis dropped significantly to 0.01 per 100 000 individuals per year, representing a 99.8% reduction in the risk of meningococcal A meningitis (CIR 0.002, 95% CI 0.0004-0.02, p<0.0001). INTERPRETATION: Early evidence suggests the conjugate vaccine has substantially reduced the rate of meningitis in people in the target age group, and in the general population because of high coverage and herd immunity. These data suggest that fully implementing the PsA-TT vaccine could end epidemic meningitis of serogroup A in sub-Saharan Africa. FUNDING: None. PMID- 22818243 TI - [Muscles and connective tissue: histology]. AB - Here, we give some comments about the DVD movies "Muscle Attitudes" from Endovivo productions, the movies up lighting some loss in the attention given to studies on the connective tissue, and especially them into muscles. The main characteristics of the different components in the intra-muscular connective tissue (perimysium, endomysium, epimysium) are shown here with special references to their ordered architecture and special references to their spatial distributions. This connective tissue is abundant into the muscles and is in continuity with the muscles in vicinity, with their tendons and their sheath, sticking the whole on skin. This connective tissue has also very abundant connections on the muscles fibres. It is then assumed that the connective tissue sticks every organs or cells of the locomotion system. Considering the elastic properties of the collagen fibres which are the most abundant component of connective tissue, it is possible to up light a panel of connective tissue associated functions such as the transmission of muscle contractions or the regulation of protein and energetic muscles metabolism. PMID- 22818244 TI - Relationship between radiographic evidence of tracheobronchial lymph node enlargement and definitive or presumptive diagnosis. AB - Tracheobronchial lymphadenomegaly is commonly associated with lymphosarcoma and disseminated mycotic infection. Available data also suggest other pathologic causes of enlarged tracheobronchial lymph nodes. Our objective was to establish the distribution and prevalence of diseases that cause radiographically evident tracheobronchial lymphadenomegaly in a large population of dogs. Patients were divided into groups based on the methods of diagnoses with 25 having confirmed diagnoses and 85 with presumptive diagnoses. Of the 110 dogs in the study, 92 (84%) had neoplasia and 18 (16%) had infectious diseases. Infections were attributed to Coccidioides (12, 67%), Aspergillus (3, 17%), and 1 each (6%) to Nocardia, Penicillium, and Mycobacteriosis. Tumors were characterized as lymphoma (66, 60%) or nonlymphoid (26, 23.6%). Nonlymphomas in Group 1 included histiocytic sarcoma complex (16%), carcinoma (12%), adenocarcinoma (8%), osteosarcoma (8%), chemodectoma (4%), ganglioneuroblastoma (4%), and neuroendocrine (4%). The number of dogs with tracheobronchial lymphadenomegaly scores 1, 2, 3, 4, or 5 (with 5 being the greatest) was 8 (7%), 15 (14%), 30 (27%), 15 (14%), and 44 (38%), respectively. The results suggest that in addition to diagnoses of lymphoma and fungal infections, other neoplasms and in particular histiocytic sarcoma and metastatic adenocarcinoma, should be considered when tracheobronchial lymphadenomegaly is identified radiographically in dogs. When comparing the degree of tracheobronchial lymphadenopathy by disease category, there was no significant affiliation (P = 0.33). PMID- 22818245 TI - Beverage displacement between elementary and middle school, 2004-2007. AB - BACKGROUND: Sweetened beverages of low nutritional quality might be displacing more nutritious beverages, such as 100% fruit juice and milk, from children's diets. However, previous research has not examined changes in beverage intake over time using nationally representative longitudinal data. OBJECTIVE: Our objective was to examine changes in sweetened beverage, milk, and juice consumption between 5th and 8th grade. DESIGN: We used a longitudinal analysis of self-reported beverage consumption. PARTICIPANTS/SETTING: Data were from the Early Childhood Longitudinal Survey-Kindergarten Cohort 1998-1999 (ECLS-K), a nationally representative study of children followed from kindergarten through 8th grade. This analysis used data from Spring 2004 and 2007, when most children were in 5th and 8th grade, respectively (n=7,445). MAIN OUTCOME MEASURES: Main outcome measures were changes in consumption of sweetened beverages, milk, and 100% fruit juice last week. STATISTICAL ANALYSES PERFORMED: Survey-adjusted linear regression was used to estimate longitudinal relationships between servings of milk, sweetened beverages, and 100% fruit juice, controlling for child and family characteristics and food consumption. RESULTS: Children's milk consumption decreased between 5th and 8th grade, and these decreases were larger among children who drank sweetened beverages daily. However, after controlling for demographic characteristics, changes in children's milk consumption were not significantly related to changes in their consumption of sweetened beverages over time (beta=.005; P=0.81), while changes in milk consumption were positively related to changes in juice consumption (beta=.087; P<0.01). CONCLUSIONS: Observed decreases in average milk consumption from 5th to 8th grade were not related to changes in sweetened-beverage consumption. They were positively related to changes in fruit juice consumption, so not indicating displacement. Caloric beverages generally tended to increase or decrease in tandem, so focus must be placed on their role in children's entire diet and on balancing them with food and total beverage intake. PMID- 22818246 TI - Comparing Costs of Telephone vs Face-to-Face Extended-Care Programs for the Management of Obesity in Rural Settings. AB - BACKGROUND: A major challenge after successful weight loss is continuing the behaviors required for long-term weight maintenance. This challenge can be exacerbated in rural areas with limited local support resources. OBJECTIVE: This study describes and compares program costs and cost effectiveness for 12-month extended-care lifestyle maintenance programs after an initial 6-month weight-loss program. DESIGN: We conducted a 1-year prospective randomized controlled clinical trial. PARTICIPANTS/SETTING: The study included 215 female participants age 50 years or older from rural areas who completed an initial 6-month lifestyle program for weight loss. The study was conducted from June 1, 2003 to May 31, 2007. INTERVENTION: The intervention was delivered through local Cooperative Extension Service offices in rural Florida. Participants were randomly assigned to a 12-month extended-care program using either individual telephone counseling (n=67), group face-to-face counseling (n=74), or a mail/control group (n=74). MAIN OUTCOME MEASURES: Program delivery costs, weight loss, and self-reported health status were directly assessed through questionnaires and program activity logs. Costs were estimated across a range of enrollment sizes to allow inferences beyond the study sample. STATISTICAL ANALYSES PERFORMED: Nonparametric and parametric tests of differences across groups for program outcomes were combined with direct program cost estimates and expected value calculations to determine which scales of operation favored alternative formats for lifestyle maintenance. RESULTS: Median weight regain during the intervention year was 1.7 kg for participants in the face-to-face format, 2.1 kg for the telephone format, and 3.1 kg for the mail/control format. For a typical group size of 13 participants, the face-to-face format had higher fixed costs, which translated into higher overall program costs ($420 per participant) when compared with individual telephone counseling ($268 per participant) and control ($226 per participant) programs. Although the net weight lost after the 12-month maintenance program was higher for the face-to-face and telephone programs compared with the control group, the average cost per expected kilogram of weight lost was higher for the face-to-face program ($47/kg) compared with the other two programs (approximately $33/kg for telephone and control). CONCLUSIONS: Both the scale of operations and local demand for programs are important considerations in selecting a delivery format for lifestyle maintenance. In this study, the telephone format had a lower cost but similar outcomes compared with the face-to-face format. PMID- 22818247 TI - Why do older adult women fall short of the recommended follow-up care for coronary artery disease? AB - BACKGROUND: Many women with coronary artery disease (CAD), commonly referred to as coronary heart disease, do not receive an annual office visit to manage their disease. We set out to determine what barriers factor into women not receiving an office visit to manage their disease. METHODS: A purposive sample of 26 eligible women (>=65 years of age) diagnosed with CAD completed in-depth, qualitative interviews. Systematic analysis of the content of interviews was performed on transcripts from these interviews. Participants with an AARP Medicare Supplement Insurance Plan insured by UnitedHealthcare insurance company that did not receive an annual office visit were eligible. In addition, we surveyed 100 physicians to obtain their thoughts about why women may not schedule at least one annual visit to manage their CAD. RESULTS: The most common barriers identified were skepticism of heart problems, having to take the initiative to schedule the appointment, and dealing with seemingly more pressing health problems. Many of these barriers identified were substantiated in a survey of physicians that treat women with CAD, but the relative rankings of the importance of these problems differed somewhat. CONCLUSIONS: Many women were skeptical about their heart health and often lacked the initiative to schedule a follow-up appointment. Most agreed that they would make an appointment if contacted by their doctor's office. Many of these women were receptive to the idea of receiving educational information by mail. Active involvement by doctors' offices to schedule appointments may help improve care, as might mail-based reminders. PMID- 22818248 TI - Factors facilitating acceptable mammography services for women with disabilities. AB - BACKGROUND: Prior research has described general barriers to breast cancer screening for women with disabilities (WWD). We explored specific accommodations described as necessary by WWD who have accessed screening services, and the presence of such accommodations in community-based screening programs. METHODS: We surveyed WWD in the Carolina Mammography Registry to determine what accommodations were needed when accessing breast screening services, and whether or not these needs were met. The sample of 1,348 WWD was identified through a survey of limitations, with a response rate of 45.5% (4,498/9,885). Of the 1,348 WWD eligible for the second survey, 739 responded for a response rate of 54.8%. RESULTS: The most frequently needed accommodations were an accessible changing area with a bench (60.0%), oral description of the procedure by the technologist (60.5%), and handicapped/accessible parking (27.6%). Handicapped parking was the need most likely to go unmet (3.1%). CONCLUSION: Most needs are being met by radiology facilities and staff, and the few needs going unmet are related to the physical/built environment. Overall, for WWD who are in screening, the mammography system seems to be more accessible than generally perceived. PMID- 22818249 TI - Determinants of excessive gestational weight gain in urban, low-income women. AB - BACKGROUND: Factors influencing excessive weight gain in pregnancy have not been well-studied among urban, low-income women. METHODS: This prospective cohort study of 94 prenatal care patients at a large university hospital in Philadelphia examined associations of modifiable midpregnancy behaviors and nonmodifiable or early pregnancy factors with excessive gestational weight gain. Data were collected through questionnaires and medical record abstraction from 2009 to 2011. FINDINGS: The majority of women were African American (83%) and all (100%) received Medicaid. Nearly two thirds (60%) were overweight or obese in early pregnancy and 41% experienced excessive gain. In multivariable logistic regression analyses, significant predictors of excessive gestational weight gain included high early pregnancy body mass index (odds ratio [OR], 4.20; 95% confidence interval [CI], 1.43-12.34 for overweight/obese vs. normal weight), nulliparity (OR, 3.35; 95% CI, 1.17-9.62 for nulliparity vs. multiparity), and clinician advice discordant with Institute of Medicine guidelines (OR, 5.88; 95% CI, 1.04-33.32 for discordant vs. concordant advice). Watching under 2 hours of television daily (OR, 0.18; 95% CI, 0.03-1.03), and engaging in regular physical activity during pregnancy (OR, 0.35; 95% CI, 0.11-1.09) were suggestive of a reduced risk of excessive gain. CONCLUSIONS: In this sample of urban, low-income women, high early pregnancy body mass index, nulliparity, and discordant clinician advice were directly associated with excessive gestational weight gain, with a trend toward decreased risk for viewing fewer hours of television and engaging in regular physical activity. Intervening on these targets may optimize gestational weight gain and promote long-term maternal health. PMID- 22818255 TI - Ethnic differences in the use of intrapartum epidural analgesia. AB - BACKGROUND: Obstetric epidural analgesia (EA) is widely applied, but studies have reported that its use may be less extensive among immigrant women or those from minority ethnic groups. Our aim was to examine whether this was the case in our geographic area, which contains an important immigrant population, and if so, to describe the different components of this phenomenon. METHODS: Cross-sectional observational study. SETTING: general acute care hospital, located in Marbella, southern Spain. Analysis of computer records of deliveries performed from 2004 to 2010. Comparison of characteristics of deliveries according to the mothers' geographic origins and of vaginal deliveries noting whether EA was received, using univariate and bivariate statistical analysis and multiple logistic regression (MLR). RESULTS: A total of 21,034 deliveries were recorded, and 37.4% of these corresponded to immigrant women. EA was provided to 61.1% of the Spanish women and to 51.5% of the immigrants, with important variations according to geographic origin: over 52% of women from other European countries and South America received EA, compared with around 45% of the African women and 37% of the Asian women. These differences persisted in the MLR model after adjusting for the mother's age, type of labor initiation, the weight of the neonate and for single or multiple gestation. With the Spanish patients as the reference category, all the other countries of origin presented lower probabilities of EA use. This was particularly apparent for the patients from Asia (OR 0.38; 95%CI 0.31-0.46), Morocco (OR 0.49; 95%CI 0.43-0.54) and other Africa (OR 0.55; 95%CI 0.37-0.81). CONCLUSIONS: We observed a different use of EA in vaginal deliveries, according to the geographic origin of the women. The explanation for this involves a complex set of factors, depending both on the patient and on the healthcare staff. PMID- 22818256 TI - Clinical and laboratory characteristics of infectious mononucleosis by Epstein Barr virus in Mexican children. AB - BACKGROUND: Infectious mononucleosis (IM) or Mononucleosis syndrome is caused by an acute infection of Epstein-Barr virus. In Latin American countries, there are little information pertaining to the clinical manifestations and complications of this disease. For this reason, the purpose of this work was to describe the clinical and laboratory characteristics of infection by Epstein-Barr virus in Mexican children with infectious mononucleosis. METHODS: A descriptive study was carried out by reviewing the clinical files of patients less than 18 years old with clinical and serological diagnosis of IM by Epstein-Barr virus from November, 1970 to July, 2011 in a third level pediatric hospital in Mexico City. RESULTS: One hundred and sixty three cases of IM were found. The most frequent clinical signs were lymphadenopathy (89.5%), fever (79.7%), general body pain (69.3%), pharyngitis (55.2%), hepatomegaly (47.2%). The laboratory findings were lymphocytosis (41.7%), atypic lymphocytes (24.5%), and increased transaminases (30.9%), there were no rupture of the spleen and no deaths among the 163 cases. CONCLUSIONS: Our results revealed that IM appeared in earlier ages compared with that reported in industrialized countries, where adolescents are the most affected group. Also, the order and frequency of the clinical manifestations were different in our country than in industrialized ones. PMID- 22818258 TI - [For an evidence-based pharmacy]. PMID- 22818257 TI - Leucine content of dietary proteins is a determinant of postprandial skeletal muscle protein synthesis in adult rats. AB - BACKGROUND: Leucine (Leu) regulates muscle protein synthesis (MPS) producing dose dependent plasma Leu and MPS responses from free amino acid solutions. This study examined the role of Leu content from dietary proteins in regulation of MPS after complete meals. METHODS: Experiment 1 examined 4 protein sources (wheat, soy, egg, and whey) with different Leu concentrations (6.8, 8.0, 8.8, and 10.9% (w/w), respectively) on the potential to increase plasma Leu, activate translation factors, and stimulate MPS. Male rats (~250 g) were trained for 14 day to eat 3 meals/day consisting of 16/54/30% of energy from protein, carbohydrates and fats. Rats were killed on d14 either before or 90 min after consuming a 4 g breakfast meal. Experiment 2 compared feeding wheat, whey, and wheat + Leu to determine if supplementing the Leu content of the wheat meal would yield similar anabolic responses as whey. RESULTS: In Experiment 1, only whey and egg groups increased post-prandial plasma Leu and stimulated MPS above food-deprived controls. Likewise, greater phosphorylation of p70 S6 kinase 1 (S6K1) and 4E binding protein-1 (4E-BP1) occurred in whey and egg groups versus wheat and soy groups. Experiment 2 demonstrated that supplementing wheat with Leu to equalize the Leu content of the meal also equalized the rates of MPS. CONCLUSION: These findings demonstrate that Leu content is a critical factor for evaluating the quantity and quality of proteins necessary at a meal for stimulation of MPS. PMID- 22818259 TI - [Air pollution biomonitoring with plants and fungi: concepts and uses]. AB - Air pollution remains a major environmental concern of the French. Since about 30 years, due to evolution and diversification of sources, pollution became more and more complex, constituting a true "cocktail". Today, it is very important to know environmental and health effects of this cocktail. In this context air biomonitoring using plants and fungi can bring a lot of information. Biomonitoring includes four concepts: the use of biomarkers, bioindication biointegration and bioaccumulation. These four concepts are articulated according to the levels of biological organization, what links up biosurveillance on fundamental plan with ecotoxicology. It is a complementary approach of the physicochemical techniques of air pollution measurements. The main objectives of biomonitoring studies are the monitoring of the space and temporal distribution of pollutants effect; the monitoring of local sources; participation in the health risks assessment; the information of people and the help to decision in public policies. Biomonitoring of air quality is a method, which made its proof in numerous domains of application and brings fundamental information on the impacts of the quality of air. Recent evolution of low concerning biggest industries allows us to envisage the increase of air quality biomonitoring with plants and fungi applications in the field of the valuation of environmental and health risks. The recent normalization (French and European) of different methods will also allow the development of uses. PMID- 22818260 TI - [Hospital pharmacist has a rule for best practice use and French hospital activity tariffs. Example of a pharmaceutical quality control for drugs reimbursed in addition of DRGs]. AB - The best practice contract has given a new objective to the hospital pharmacists for the reimbursement in addition to Diagnosis Related Groups' (DRGs) tariffs. We built our pharmaceutical quality control for the administration traceability follow-up regarding the DRGs and the cost of care, for two reasons: the nominal drugs dispensation in link with the prescription made by pharmacist and the important expenditure of these drugs. Our organization depends on the development level of the informatized drugs circuit and minimizes the risk of financial shortfalls or wrong benefits, possible causes of economic penalties for our hospital. On the basis of this follow-up, we highlighted our activity and identified problems of management and drugs circuit organization. The quality of the administration traceability impacts directly on the quality of the medical records and the reimbursements of the expensive drugs. A better knowledge of prescription software is also required for a better quality and security of the medical data used in the medical informatic systems. The drugs management and the personal treatment in and between the care units need to be improved too. We have to continue and improve our organization with the future financial model for ATU drugs and the FIDES project. The health personnel awareness and the development of best informatic tools are also required. PMID- 22818261 TI - [Human biomonitoring, biomarkers, environmental biomonitoring]. AB - Human biomonitoring is a form of environmental public health surveillance. It is not to be confused with environmental biomonitoring (or ecomonitoring), which is the observation of living organisms implemented with the objective of monitoring quality of environments. Human biomonitoring enables us to monitor the presence of chemical pollutants in the body. Measurement of biomarkers has nevertheless some caveats: it does not directly tell us by which pathway a compound has penetrated the organism, and health risks associated with a certain level of impregnation are often unknown. A great number of biomonitoring studies have been conducted in France and in the world. The second national environment and health action plan (2009-2013) includes a national human biomonitoring program. It is composed of two parts: one perinatal-early childhood component which consists in the measurement of biomarkers in the ELFE cohort, recruited in 2011, and a national biomonitoring (environment, health nutrition) survey which will be implemented on a sample of 5000 persons (6-74), representative of the population living in metropolitan France. Regarding air quality, it is to be observed that human biomonitoring is ill-suited as an indicator of quality for a particular medium. Nevertheless, some studies make use of biomarkers which are relatively specific of air pollution exposure. They can be biomarkers of exposure, such as exhaled carbon monoxide, or biomarkers of effect, such as exhaled nitric oxide. PMID- 22818262 TI - [Schools, office buildings, leisure settings: diversity of indoor air quality issues. Global review on indoor air quality in these settings]. AB - This review provides a global overview of indoor air quality issues in schools, office buildings and recreational settings. It presents the most recent scientific publications and the on-going work conducted in France in the frame of the indoor air quality Observatory. Monitoring campaigns on indoor air quality in schools have been carried out in the recent years in Europe. However, few studies have specifically addressed the role of exposure in these buildings on children's health. Indoor air quality in office buildings has been little studied so far. However, some specificities, such as emissions from electronic devices, frequent cleaning, impossibility to open windows in high-rise buildings, for example, should be examined and their role on the health and comfort studied. Finally, even if the time spent in recreational settings is short, the quality of indoor air should also be considered because of specific pollution. This is the case of indoor swimming pools (exposure to chlorination byproducts) and ice-rinks (exposure to exhaust from machines used to smooth the ice). PMID- 22818263 TI - Overdosed prescription of paracetamol (acetaminophen) in a teaching hospital. AB - INTRODUCTION: Paracetamol is the most commonly used analgesic and antipyretic. Reviews of hospital use of paracetamol are scarce. Little is known about the appropriateness of the dose of paracetamol prescribed for hospitalized adults. The aim of this study was to report on the nature and the frequency of the overdosed prescription of paracetamol observed in adult patients over a 4.5-year period in a teaching hospital. METHODS: Prescription analysis by pharmacists was performed once a week in six medical and three surgical departments and daily in a post-emergency unit. In cases of prescription error, the pharmacist notified the physician through an electronic alert when a computerized prescription order entry system was available or otherwise by face-to-face discussion. For each drug related problem detected, the pharmacists recorded relevant details in a database. RESULTS: From October 2006 to April 2011, 44,404 prescriptions were reviewed and 480 alerts related to the overdosed prescription of paracetamol were made (1% of analyzed prescriptions). The extent of errors of dosage was within the intervals [90-120 mg/kg/d] and greater than 120 mg/kg/d for 87 and 11 patients respectively, who were prescribed a single non-combination paracetamol containing product. Sixty alerts concerned co-prescription of at least two paracetamol containing products with similar frequency for computerized (1.4/1000) or handwritten (1.2/1000) prescriptions. DISCUSSION: Prescriptions of paracetamol for hospitalized adults frequently exceed the recommended dosage. CONCLUSION: These results highlight the need for increased awareness of unintentional paracetamol overdose and support the initiation of an educational program aimed at physicians and nurses. PMID- 22818264 TI - [Interfacial behaviour of glycoconjugated tetraphenylporphyrins and their interaction with biomimetic models of the cell membrane]. AB - INTRODUCTION: Porphyrins are photosensitizers usable in photodynamic therapy. Although these molecules are clinically effective, their low water solubility and their lack of specificity are major drawbacks to their development. Our study was aimed at analysing the interfacial behaviour of glycoconjugated tetraphenylporphyrins newly synthesized at the Curie Institute, and their interaction with model membranes bearing a specific lectin mimicking a mannose membrane receptor in retinoblastoma. MATERIAL AND METHODS: The interfacial behaviour of the porphyrins was analysed by surface pressure measurements, and their specific interaction with the lectin, by dynamic light scattering (liposomes) and the quartz crystal microbalance technique (supported bilayers). RESULTS: All porphyrin derivatives were able to organize at the air/liquid interface. The dendrimeric compounds formed more stable monolayers than the others, and generally showed good mixing properties with the phospholipid used for liposome preparation. In the presence of concanavalin A, the porphyrin bearing-liposomes behaved differently depending on the nature (mannosylated or not) of the porphyrins. DISCUSSION: The interfacial behaviour of the tetraphenylporphyrins is directly related to the orientation of the tetrapyrrolic macrocycle controlled by the grafted groups. Incorporated into a liposome bilayer, glycodendrimeric porphyrins expose their sugar moieties at the vesicle surface. The spacer length plays a crucial role by increasing sugars freedom and enhancing glycosylated liposomes interaction with the lectin. CONCLUSION: Compared to the other studied compounds, the glycodendrimeric porphyrins seem very promising compounds and are now evaluated on cell cultures. PMID- 22818265 TI - Microwave freeze-thaw treatment of dose-banded cytotoxics injectable drugs: a review of the literature from 1980 to 2011. AB - INTRODUCTION: Microwave freeze-thaw treatment (MFTT) of injectable drugs can support the development of centralized intravenous admixtures services (CIVAS). The aim of this review is to collect information about the stability of cytotoxic and hazardous drugs after this treatment. METHODS: The scientific literature about drug stability studies was reviewed. The data describe the name of the drug, the manufacturer, the final concentration, the temperature and time of freezing storage, type of microwave oven, the thawing power, the measurement, the method and the results after treatment and final long-term storage at 5+/-3 degrees C. RESULTS: From 1980 to 2011, nine drugs (cyclophosphamide, cytarabine, daunorubicine, doxorubicine, epirubicine, fluorouracile, ganciclovir, methotrexate sodium, mitomycine C) were studied after MFTT and the results were presented in 10 publications. The storage freezing temperature ranged from -15 degrees C to -30 degrees C, the time storage from 14 to 364 days, the thaw from moderate to full power. High performance liquid chromatography is mainly used to measure drug concentrations. All drugs are stable during and after the treatment. However, mitomycine needs to be stored at -30 degrees C. The long-term stability after MFTT was evaluated only for the ganciclovir after 7 days, and for fluorouracile after 28 days. The concentration of the seven drugs was measured after one to 11 freezing-thawing cycles with a loss below 5%. CONCLUSIONS: This review can help the hospital pharmacist to take in charge the productions of nine dose-banded ready-to-use injectable cytotoxic and hazardous drugs. Freezing enhances their long-term stability without altering their chemical stability. Validated microwave thawing reduces the time of defrosting of these drugs at the studied concentrations. PMID- 22818266 TI - Methodological challenges in designing dementia prevention trials - the European Dementia Prevention Initiative (EDPI). AB - Recent epidemiological studies have indicated numerous associations between vascular and lifestyle related risk factors and incident dementia. However, evidence from randomised controlled trials (RCT) showing effectiveness of interventions aimed at these risk factors in preventing or postponing dementia onset is still lacking. Three large RCTs on multi-component interventions to prevent dementia (preDIVA, FINGER, MAPT) have been initiated in Europe to address these issues. Irrespective of some methodological differences, all three studies target cardiovascular and lifestyle related risk factors. Collaboration within the newly founded 'European Dementia Prevention Initiative' (EDPI) will allow for a comprehensive exploration of optimal target population, intervention and outcome measures, which are currently unknown. Combining data of the ongoing studies and running simulation analyses will facilitate determining the optimal design including accurate sample-size calculations for future multi-national clinical trials on dementia prevention. Interventions aiming at dementia prevention should be pragmatic and easy to implement on a large scale in different health care systems, without generating high additional costs or burden on participants or physicians. As the optimal age for intervention precedes the optimal age for outcome assessment, traditional trial designs might lead to suboptimal timing of either of the two. Separation of intervention and outcome assessment in time is a potential solution, but requires studies with very long follow-up. International collaboration of research groups with experience in dementia prevention studies and well-organised logistics for these major projects is pivotal to success for future large-scale dementia prevention studies. Founding of EDPI is an important first step in this direction. PMID- 22818267 TI - Rapid determination of disulfoton and its oxidative metabolites in human whole blood and urine using QuEChERS extraction and liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of disulfoton and five of its oxidative metabolites (disulfoton-sulfoxide, disulfoton-sulfone, demeton-S, demeton-S sulfoxide and demeton-S-sulfone) in human whole blood and urine. Extraction was undertaken using a QuEChERS method, which is commonly used in food analysis. D10 Disulfoton was used as the internal standard. Separation was carried out using a CAPCELL-PAK MG II column (35*2.0 mm i.d., 5 MUm, Shiseido) with a mobile phase of 10 m mol/L ammonium formate and methanol. This method was applied in an autopsy case, and disulfoton and its oxidative metabolites were successfully detected in both blood and urine. The concentrations of disulfoton in the blood and urine were 360 and 23.8 ng/mL, respectively. There was a relatively low concentration of demeton-S in both the blood (4.0 ng/mL) and urine (45.7 ng/mL). To date, there have been no reported cases of detection of demeton-S in human samples. PMID- 22818268 TI - [Profile and motivations of students performing a universitary degree in 2011]. AB - OBJECTIVE: Observational study relating to the inscriptions with universitary diplomas (DU) in relation with anesthesiology and intensive care during the year 2010-2011. We had in mind to know the profile and the motivations of the students concerned. METHOD: A questionnaire was put on line and the registered students with the various diplomas were contacted by e-mail. Different items investigated concerned: demography, type of exercise of the students, heading of diplomas, scientific level of the students, their motivations at the time of the inscription and finally practical organization. RESULTS: We collected 265 questionnaires, that is to say 42 % of answers. The demographic distribution of the registered voters was the followed: 71% of MD, 28% of residents. These doctors exerted for the majority with the public hospital (87%). The inscriptions concerned intensive care diplomas in 90% of the cases. The total scientific level of the students was high, since 46% of them had a diploma other than their medicine thesis. The students were registered for the majority of them "to widen their field of competence" (65%) or "in complement of their initial training" (46%). The other reasons were: "to make up a deficit of their initial training (26%)", "as continuous medical training" (16%) and finally "for the university validation of an asset" (10%). The rate of total satisfaction of the diplomas was very high (96%). Financial aid was assumed by the institution for 46% of students. Residents were less financially helped than senior practitioners. The overall costs of the DU/DIU, including the registration fee, transport and lodging, were important (>500 euros in 61% of the cases). CONCLUSION: DUs related to our specialty are much appreciated. They interest a majority of senior doctors, but also a considerable number of residents, which poses the problem of the place of these additional trainings within the framework of initial training. The principal motivations of the registered voters are to supplement their initial training or to widen their field of competence, much more than to make up a deficit of this initial training. Lastly, the total financial expenses associated with these diplomas remain important and appear inversely proportional to the incomes of the registered students. PMID- 22818269 TI - [Rescue ventilation of a status asthmaticus using sevoflurane and low-pressure helium with an anaesthesia ventilator]. PMID- 22818270 TI - [Ultrasound-guided TAP, rectus sheath, ilioinguinal and ilio-hypogastric blocks]. PMID- 22818271 TI - Testicular heterotopia of the lumbar spine. AB - We report an unusual case of testicular heterotopia in a child who underwent excision of a subcutaneous mass associated with a lipomyelomeningocele in the lumbosacral region. To the best of our knowledge testicular heterotopia has never been documented in humans, and this case report provides a possible embryological interpretation for such a presentation. PMID- 22818272 TI - Cerebroventricular clozapine would be a viable treatment modality for clozapine dependent schizophrenia patients with neutropenia. AB - The atypical antipsychotic clozapine is very effective for treatment of schizophrenia, but it causes agranulocytosis requiring drug cessation in up to 2% of cases. There has been some success rechallenging with clozapine at a later date or giving granulocyte colony stimulating factor or lithium while continuing clozapine. However, there are still some patients for whom these strategies do not work yet who cannot be controlled on other medications. This paper proposes that for such individuals, cerebroventricular administration of clozapine via Ommaya catheters could allow continued use of clozapine therapy. Direct infusion into cerebrospinal fluid means far smaller amounts of drug would be needed for efficacy, and clozapine concentrates in the central nervous system where it would not be exposed to bone marrow stem cells to cause agranulocytosis. This treatment paradigm would also provide a means for court-ordered clozapine therapy and a possible delivery system for future therapeutics based on trophic factors such as brain-derived neurotrophic factor. PMID- 22818274 TI - When should we operate on elderly patients with a hip fracture? It's about time! AB - Demographic predictions indicate the annual incidence of hip fractures will rise to 100,000 per annum in 2020. The annual costs to the NHS are approximately two billion pounds. Despite significant advances in the operating technique and management of these fractures, controversies still exist. One such matter for debate is the ideal timing for hip fracture surgery. There are arguments for and against early stabilization, yet all this evidence comes from observational studies. We present data from an often overlooked source, the largest patient safety reporting system in the world housed at the National Patient Safety Agency. Since 2003, 4325/4521 (96%) patients suffered some harm due to their operation being delayed. The issue of the ideal timing for hip surgery warrants an answer. This could be in the form of a controlled trial. A randomized trial comparing early surgery versus standard of care (site dependent) in hip fracture repair may provide some future guidance. In the meantime, current evidence suggests that we should stratify the elderly according to their medical morbidities; both new and old; optimize patient's who develop hypovolemia, accelerated hypertension, untreated infection, symptomatic arrhythmia or cardiopulmonary dysfunction; and attempt to bring patient's suffering from chronic diseases as close to their baseline level of functioning as normal. Hip fracture repair should then occur as soon as possible. PMID- 22818275 TI - Orbital exenteration in periorbital malignancies. AB - BACKGROUND: Orbital exenteration is a disfiguring procedure most commonly performed for locally advanced or recurrent periorbital malignancies. METHODS: We performed a retrospective review of 22 patients who underwent orbital exenteration for advanced periorbital malignancy at our institution, by the senior author over a seventeen-year period. Specifically, we have reviewed the tumour histology along with stage at presentation, patient age, history of previous surgical intervention and surgical outcomes. The review highlighted two main groups who required orbital exenteration - patients with recurrent or locally advanced periorbital skin cancers, and patients with malignancy of the sinus. CONCLUSION: We discuss the presentation and management of the two pathological processes and highlight the importance of aggressive early management of periorbital malignancy with a view to prevention of exenteration and improving survival. PMID- 22818276 TI - Laparoscopic vs. open liver resection for malignant liver disease. A systematic review. AB - INTRODUCTION: Since the introduction of minimally invasive techniques, there is little agreement about use of laparoscopic surgery for malignant liver lesions as compared to open resection. We aim to analyse all available data comparing both these groups. METHODS: All the studies that compared laparoscopic and open liver resections for malignant lesions were searched on various databases. Data were collected and analysed in Review Manager RevMan (version 5.0). RESULTS: There were total of 10 studies (n = 700) that compared laparoscopic (296/700) and open (404/700) hepatic resections for malignant lesions. Laparoscopic group was associated with reduced number of patients requiring blood transfusion [Odds ratio 0.35 CI 0.20, 0.60 P<0.001 HG 0.85], decreased number of positive resection margin [Odds ratio 0.34 CI 0.16, P0.006 HG 0.73] and decrease in overall complication rate [Odds ratio 0.43, CI 0.26, 0.73 P0.002 HG 0.22]. Laparoscopic group was associated with less operative blood loss [WMD 162.6 ml CI -261.79, 73.45 P<0.001] and reduced hospital stay [WMD 4.28 days CI -6.33, -2.23 P<0.001]; however, there was significant heterogeneity [HG <0.001] between the studies for these parameters. CONCLUSION: The laparoscopic group was associated with reduce overall complication rate, positive resection margins and number of patients requiring blood transfusion. There is still need for level I and II data to compare laparoscopic versus open hepatic resection in malignant lesions. PMID- 22818277 TI - Minimally invasive video-assisted parathyroidectomy is a safe procedure to treat primary hyperparathyroidism. AB - INTRODUCTION: Cervical exploration to identify the four parathyroid glands was considered to be the gold standard for management of primary hyperparathyroidism. In recent years, advances in preoperative localizing techniques have led to the use of more targeted, minimally invasive procedures to remove parathyroid glands. We present our series of patients who underwent Minimally Invasive Video-Assisted Parathyroidectomy (MIVAP) procedures and our results in treating primary hyperparathyroidism. METHODS: Patients who underwent video-assisted parathyroidectomy were identified from a prospectively maintained database. Clinico-pathological data including indications for surgery, complications, conversion to open procedure and success of surgery were obtained from clinical notes. RESULTS: A total of 56 patients underwent MIVAP between 2002 and 2010 at a district general hospital setup. The clinical indication was diagnosed primary hyperparathyroidism. Preoperative localization was attempted in all patients by sestamibi and high resolution ultrasound scans. The median age of patients was 65 years (32-82) and the median operating time was 78 min (20-168). Conversion to open procedure was done in 8/56 (14%) cases. The reason for conversion was failed exploration in 5 patients, inability to retrieve a very large friable adenoma in one patient, lipo-adenoma in one patient and very small parathyroid adenoma in one patient. Postoperative complications happened in one patient (2%) who developed postoperative sepsis resulting in temporary recurrent laryngeal nerve (RLN) palsy. All but 5 patients became normo-calcaemic following surgery. CONCLUSION: MIVAP is a safe and effective procedure for treating patients with primary hyperparathyroidism. It also allows classical 4 gland exploration, whenever necessary. PMID- 22818278 TI - Importance of strict patient selection criteria for combined carotid endarterectomy and coronary artery bypass grafting. AB - BACKGROUND: Management of patients with severe concomitant carotid and coronary disease remains controversial. We report our experience of combined carotid endarterectomy (CEA) and coronary artery bypass surgery (CABG) over a fifteen year period using strict patient selection criteria. METHODS: From 1st January 1995 to December 31st 2009 165 patients underwent combined CABG/CEA procedures at the Mater Hospital. Mean age was 68.2 years (range 43-88) and 127 (77%) were male. Fifty-three (32%) had symptomatic carotid disease. Indications for combined procedures were the presence of symptomatic >70% or asymptomatic >80% internal carotid artery stenosis in a patient requiring urgent CABG because of either unstable angina, recent MI, severe triple vessel disease or severe Left Anterior Descending or Left Main Stem stenosis. RESULTS: Thirty-day stroke and death rate was 3%. All neurological events were in the hemisphere contralateral to the carotid surgery and symptoms had completely resolved prior to discharge from hospital. One patient required evacuation of a cervical haematoma and there were two transient XII nerve palsies. CONCLUSION: Combined CEA/CABG can be performed safely with acceptable morbidity and mortality in patients selected in accordance with strict criteria in a centre with a large experience of both cardiac and carotid surgery. PMID- 22818279 TI - Painful swollen limb caused by pelvic granuloma in a patient with total hip replacement. PMID- 22818280 TI - The value of whole colonic imaging. PMID- 22818281 TI - Performing radical nephrectomy in octogenarians needs to be justified. PMID- 22818282 TI - The Robert Wood Johnson Foundation Nurse Faculty Scholars Program: an opportunity for junior nurse faculty. AB - The Robert Wood Johnson Foundation Nurse Faculty Scholars program provides promising junior faculty extramural funding, expert mentoring, and the training needed to be successful in the academic role. The Nurse Faculty Scholars program, which admitted its first cohort in 2008, is designed to address the nursing faculty shortage by enhancing leadership, educational, and research skills in junior nursing faculty. This article provides an overview of the program, its purpose, and its eligibility requirements. The authors give strategies for selecting mentors, developing the written application, and preparing for an oral interview. Finally, the authors provide an analysis of funded institutions, research design and methods from current and recently funded projects, and rank and positions held by nursing mentors. PMID- 22818283 TI - Nurses' disclosure of error scenarios in nursing homes. AB - BACKGROUND: Little work has explored the disclosure of errors in nursing homes (NHs). PURPOSE: This paper reports how nurses would disclose hypothetical errors that occur in NH settings. METHOD: A cross-sectional survey was given to a randomly selected sample of registered nurses (RNs) and registered practical nurses (RPNs) working in Ontario, Canada NHs. RESULTS: Of 1,180 respondents, only half might provide full details and the cause of the error and provide steps in how the error would be prevented if they were in situations described by the hypothetical scenarios. Scenarios that were less serious had an almost 3 times higher likelihood of an explicit apology (OR 2.97; 95% CI 1.36-6.51; P = 0.007). Nurses who were RNs, had more education, had a prior history of disclosing a serious error, and agreed with full disclosure were more likely to respond to disclosing more information about the error. Nurses also reported numerous barriers to effective disclosure in their workplace. CONCLUSION: Improvements in NH safety culture are necessary to enhance the error disclosure process. PMID- 22818284 TI - Characterization and compilation of polymorphic simple sequence repeat (SSR) markers of peanut from public database. AB - BACKGROUND: There are several reports describing thousands of SSR markers in the peanut (Arachis hypogaea L.) genome. There is a need to integrate various research reports of peanut DNA polymorphism into a single platform. Further, because of lack of uniformity in the labeling of these markers across the publications, there is some confusion on the identities of many markers. We describe below an effort to develop a central comprehensive database of polymorphic SSR markers in peanut. FINDINGS: We compiled 1,343 SSR markers as detecting polymorphism (14.5%) within a total of 9,274 markers. Amongst all polymorphic SSRs examined, we found that AG motif (36.5%) was the most abundant followed by AAG (12.1%), AAT (10.9%), and AT (10.3%).The mean length of SSR repeats in dinucleotide SSRs was significantly longer than that in trinucleotide SSRs. Dinucleotide SSRs showed higher polymorphism frequency for genomic SSRs when compared to trinucleotide SSRs, while for EST-SSRs, the frequency of polymorphic SSRs was higher in trinucleotide SSRs than in dinucleotide SSRs. The correlation of the length of SSR and the frequency of polymorphism revealed that the frequency of polymorphism was decreased as motif repeat number increased. CONCLUSIONS: The assembled polymorphic SSRs would enhance the density of the existing genetic maps of peanut, which could also be a useful source of DNA markers suitable for high-throughput QTL mapping and marker-assisted selection in peanut improvement and thus would be of value to breeders. PMID- 22818285 TI - Fertility after tubal ectopic pregnancy: results of a population-based study. AB - OBJECTIVE: To assess the reproductive outcome after an ectopic pregnancy (EP) based on the type of treatment used, and to identify predictive factors of spontaneous fertility. DESIGN: Observational population based-study. SETTING: Regional sistry. PATIENT(S): One thousand sixty-four women registered from 1992 to 2008. INTERVENTION(S): Laparoscopic (radical or conservative), or medical treatment. MAIN OUTCOME MEASURE(S): Epidemiologic characteristics, clinical presentation, treatments performed, reproductive outcome, recurrence. RESULT(S): The 24-month cumulative rate of intrauterine pregnancy (IUP) was 67% after salpingectomy, 76% after salpingostomy, and 76% after medical treatment. IUP rate was lower after radical treatment compared with conservative treatments in univariable analysis. In multivariate analysis, IUP rate was significantly lower for patients >35 years old or with history of infertility or tubal disease. For them, IUP rate was significantly higher after conservative treatment compared with salpingectomy. The 2-year cumulative rate of recurrences was 18.5% after salpingostomy or salpingectomy and 25.5% after medical treatment. History of infertility or of previous live birth would be protective, in contrast to history of voluntary termination of pregnancy. CONCLUSION(S): Conservative strategy seems to be preferred, whenever possible, to preserve patients' fertility without increasing the risk of recurrence. The choice between conservative treatments does not rely on subsequent fertility, but more likely on their own indications and therapeutic effectiveness. Risk factors of recurrence could be considered for secondary prevention. PMID- 22818286 TI - Supersensitive fluorescent semen analysis: validation on azoospermic and oligozoospermic samples. AB - OBJECTIVE: To compare the clinical utility of a supersensitive fluorescent semen analysis (SSSA) procedure published by Cooper et al. (2006) with a conventional World Health Organization (WHO)-based semen analysis technique in males with severe oligozoospermia or azoospermia who are undergoing fertility assessment. DESIGN: Prospective single-center study. SETTING: IVF clinic. PATIENT(S): Patients attending an infertility clinic for semen analysis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Presence of spermatozoa in the ejaculate. RESULT(S): Semen samples from 100 men were analyzed using conventional WHO 4th Edition semen analysis and determined to be either severely oligozoospermic or azoospermic (reported lower limit of detection of 0.1 million sperm/mL). An aliquot of the same unprocessed sample was also analyzed using the SSSA protocol (reported lower limit of detection of approximately 8000 sperm/mL). The SSSA method confirmed the results of conventional semen analysis in 77% of cases. In 22% of cases, sperm were identified only using SSSA. Overall, SSSA was capable of identifying the presence of sperm in significantly more samples than conventional semen analysis. CONCLUSION(S): The reliable differentiation of extreme oligospermia from azoospermia has profound implications in fertility management. This paper provides the first data comparing sperm detection rates using SSSA or conventional WHO-based approaches in extreme oligozoospermic and azoospermic men in an IVF setting. Results indicate that approximately one in four men classified as azoospermic by conventional semen analysis may actually have sperm present. The improved sensitivity of the SSSA technique may be of significant benefit to patients, particularly in fertility and assisted reproductive technique decision making. PMID- 22818287 TI - Dynamic changes of histone H3 trimethylated at positions K4 and K27 in human oocytes and preimplantation embryos. AB - OBJECTIVE: To investigate the distribution patterns of H3K4me3 and H3K27me3 in human oocytes and preimplantation embryos. DESIGN: Experimental study. SETTING: University reproductive medical center. PATIENT(S): Patients undergoing IVF cycles. INTERVENTION(S): Oocytes and embryos were collected from patients undergoing IVF cycles. MAIN OUTCOME MEASURE(S): The distribution patterns of H3K4me3 and H3K27me3 in oocytes and embryos were analyzed by indirect immunofluorescent staining and scanning confocal microscopy. RESULT(S): H3K4me3 and H3K27me3 signals were detectable at each stage of oocyte and embryonic development. However, only one of the pronuclei showed signal for H3K27me3 in each of the zygotes, whereas H3K4me3 staining was always uniform in all zygotes. The level of H3K4me3 decreased steadily from germinal vesicle to metaphase II stage, obviously increased from zygote stage to four-cell stage, and reached the lowest at eight-cell stage. A sharp increase was then observed at blastocyst stage. The level of H3K27me3 slightly changed from germinal vesicle stage to zygote stage, then decreased steadily and reached the lowest at eight-cell stage, followed by a significant increase at blastocyst stage. CONCLUSION(S): The levels of H3K4me3 and H3K27me3 show dynamic changes during human oocyte maturation and preimplantation embryonic development. Asymmetric distribution of H3K27me3 exists in human zygote pronuclei, whereas H3K4me3 is always uniform in all of the pronuclei. PMID- 22818288 TI - ETV5 mutations: revisiting Sertoli cell only syndrome. PMID- 22818289 TI - Emerging nonanticoagulant role of low molecular weight heparins on extravillous trophoblast functions and on heparin binding-epidermal growth factor and cystein rich angiogenic inducer 61 expression. AB - OBJECTIVE: To examine the effects of low molecular weight heparins (LMWHs) on extravillous trophoblast (EVTC) invasiveness and on EVTC expression/secretion of heparin binding-EGF (HB-EGF) and cystein-rich angiogenic inducer 61 (Cyr61), both of which are involved in the process of EVTC invasion. Furthermore, to investigate the intracellular DNA binding activity of activator protein (AP)-1. DESIGN: Experimental study. SETTING: Department of Obstetrics Gynecology, Universita Cattolica del Sacro Cuore, Rome, Italy. PATIENT(S): Cultures of primary EVTC cells isolated from patients with first trimester unexplained recurrent miscarriage. INTERVENTION(S): The effects of LMWHs on EVTC invasiveness were examined by an in vitro matrigel invasion assay. Matrix metalloprotease-2 activity (MMP-2) was examined by gelatin zimography. HB-EGF and Cyr61 expression and secretion were studied by Western blot analysis and ELISA assay. AP-1 activity was measured through a multiwell colorimetric assay. MAIN OUTCOME MEASURE(S): The EVTC invasiveness, the expression/secretion of HB-EGF and Cyr61 proteins, and the AP-1 DNA binding activity in the presence of increasing concentrations of LMWHs were investigated. RESULT(S): Both LMWHs, and primarily tinzaparin, increased EVTC invasiveness, by enhancing the MMP-2 proteolytic activity, and induced the expression/secretion of HB-EGF and Cyr61 in EVTC. This effect was mediated by an increased DNA binding activity of AP-1. CONCLUSION(S): Both LMWHs are able to promote EVTC development because they are able to stimulate the EVTC invasive properties. Our results may provide a possible biological rationale for the clinical use of LMWH for placental-mediated pregnancy complications unrelated to prothrombotic disorders. PMID- 22818290 TI - Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment. AB - OBJECTIVE: To determine whether altered follicular environment is associated with ovarian reserve or maternal age. DESIGN: Prospective study examining follicular fluid (FF) composition and follicular cell metabolism. SETTING: University research department and private IVF clinic. PATIENT(S): Women (n = 54) undergoing routine IVF treatment were allocated to one of three groups based on ovarian reserve and maternal age. INTERVENTION(S): Surplus FF, granulosa cells (GC), and cumulus cells (CC) were collected. MAIN OUTCOME MEASURE(S): Follicular fluid concentrations of carbohydrates, hormones, and selected ions. Metabolic analysis and gene expression of GCs and CCs. RESULT(S): Compared to women <35 years with normal ovarian reserve, FF glucose levels were significantly decreased and lactate and progesterone (P4) concentrations significantly increased in women with reduced ovarian reserve or advanced maternal age, whereas GC and CC glucose uptake, lactate production, and phosphofructokinase platelet gene expression were significantly increased. Granulosa cell P4 production from women with reduced ovarian reserve or advanced maternal age was decreased; however, in CCs the reverse was observed with increased gene expression in P4 receptor, prostaglandin E receptor-2, cytosolic phospholipase A2, and tumor protein 53. CONCLUSION(S): Women with either reduced ovarian reserve or advanced maternal age have altered follicular cell metabolism, FF metabolites, and P4 production. This perturbed environment may be responsible for impaired oocyte developmental competence and subsequent embryo development. PMID- 22818291 TI - Assessing the transmission risk of multidrug-resistant Mycobacterium tuberculosis epidemics in regions of Taiwan. AB - OBJECTIVE: The objective of this study was to link transmission dynamics with a probabilistic risk model to provide a mechanistically explicit assessment for estimating the multidrug-resistant tuberculosis (MDR TB) infection risk in regions of Taiwan. METHODS: A relative fitness (RF)-based MDR TB model was used to describe transmission, validated with disease data for the period 2006-2010. A dose-response model quantifying by basic reproduction number (R(0)) and total proportion of infected population was constructed to estimate the site-specific MDR TB infection risk. RESULTS: We found that the incidence rate of MDR TB was highest in Hwalien County (4.91 per 100,000 population) in eastern Taiwan, with drug-sensitive and multidrug-resistant R(0) estimates of 0.89 (95% CI 0.23-2.17) and 0.38 (95% CI 0.05-1.30), respectively. The predictions were in apparent agreement with observed data in the 95% credible intervals. Our simulation showed that the incidence of MDR TB will be falling by 2013-2016. Our results indicated that the selected regions of Taiwan had only ~1% probability of exceeding 50% of the population with infection attributed to MDR TB. CONCLUSIONS: Our study found that the ongoing control programs implemented in Taiwan may succeed in curing most patients with MDR TB and will reduce the TB incidence countrywide. PMID- 22818292 TI - Simple, obvious, forgotten. PMID- 22818294 TI - Alternative approach for the removal of problem miniscrews--a serendipitous finding. PMID- 22818293 TI - Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice. AB - The neurons in neocortex layer I (LI) provide inhibition to the cortical networks. Despite increasing use of mice for the study of brain functions, few studies were reported about mouse LI neurons. In the present study, we characterized intrinsic properties of LI neurons of the anterior cingulate cortex (ACC), a key cortical area for sensory and cognitive functions, by using whole cell patch clamp recording approach. Seventy one neurons in LI and 12 pyramidal neurons in LII/III were recorded. Although all of the LI neurons expressed continuous adapting firing characteristics, the unsupervised clustering results revealed five groups in the ACC, including: Spontaneous firing neurons; Delay sAHP neurons, Delay-fAHP neurons, and two groups of neurons with ADP, named ADP1 and ADP2, respectively. Using pharmacological approaches, we found that LI neurons received both excitatory (mediated by AMPA, kainate and NMDA receptors), and inhibitory inputs (which were mediated by GABA(A) receptors). Our studies provide the first report characterizing the electrophysiological properties of neurons in LI of the ACC from adult mice. PMID- 22818295 TI - Heart repair and regeneration: recent insights from zebrafish studies. AB - Cardiovascular disease is the leading cause of death in the U.S. and worldwide. Failure to properly repair or regenerate damaged cardiac tissues after myocardial infarction is a major cause of heart failure. In contrast to humans and other mammals, zebrafish hearts regenerate after substantial injury or tissue damage. Here, we review recent progress in studying zebrafish heart regeneration, addressing the molecular and cellular responses in the three tissue layers of the heart: myocardium, epicardium, and endocardium. We also compare different injury models utilized to study zebrafish heart regeneration and discuss the differences in responses to injury between mammalian and zebrafish hearts. By learning how zebrafish hearts regenerate naturally, we can better design therapeutic strategies for repairing human hearts after myocardial infarction. PMID- 22818296 TI - Awareness and management of chronic disease, insurance status, and health professional shortage areas in the REasons for Geographic And Racial Differences in Stroke (REGARDS): a cross-sectional study. AB - BACKGROUND: Limited financial and geographic access to primary care can adversely influence chronic disease outcomes. We examined variation in awareness, treatment, and control of hypertension, diabetes, and hyperlipidemia according to both geographic and financial access to care. METHODS: We analyzed data on 17,458 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study with either hypertension, hyperlipidemia, or diabetes and living in either complete Health Professional Shortage Area (HPSA) counties or non-HPSA counties in the U.S. All analyses were stratified by insurance status and adjusted for sociodemographics and health behaviors. RESULTS: 2,261 residents lived in HPSA counties and 15,197 in non-HPSA counties. Among the uninsured, HPSA residents had higher awareness of both hypertension (adjusted OR 2.30, 95% CI 1.08, 4.89) and hyperlipidemia (adjusted OR 1.50, 95% CI 1.01, 2.22) compared to non-HPSA residents. Also among the uninsured, HPSA residents with hypertension had lower blood pressure control (adjusted OR 0.45, 95% CI 0.29, 0.71) compared with non-HPSA residents. Similar differences in awareness and control according to HPSA residence were absent among the insured. CONCLUSIONS: Despite similar or higher awareness of some chronic diseases, uninsured HPSA residents may achieve control of hypertension at lower rates compared to uninsured non-HPSA residents. Federal allocations in HPSAs should target improved quality of care as well as increasing the number of available physicians. PMID- 22818299 TI - Invited commentary. PMID- 22818298 TI - Tracing sexual contacts of HIV-infected individuals in a rural prefecture, Eastern China. AB - BACKGROUND: Contact tracing is especially useful for identifying an infection with few cases in the population, such as HIV in China. Little such research is available in China. METHODS: Every newly diagnosed HIV case from 2008-2010 in Taizhou Prefecture, Zhejiang Province in China, was invited to participate as an "index case" in a contact tracing survey by providing contact information for up to eight sexual contacts who themselves were approached for voluntary HIV counseling and testing (VCT). Those who tested HIV-positive were then subjected to another contact tracing survey. This process was repeated until no more sexual contacts were reported or tested positive. RESULTS: A total of 463 HIV-infected individuals were newly identified during the study period, including 338 cases who were identified from routine surveillance programs and 125 cases who were identified from the present contact tracing survey. Among these 463 cases, 398 (86.0%) served as 'index cases' in the survey, including 290 (85.8%) out of the 338 cases identified from routine surveillance programs and 108 (86.4%) out of the 125 cases identified from the present survey. These 398 'index cases' reported a total of 1,403 contactable sexual contacts, of whom 320 (22.8%) received HIV testing and 125 (39.1%) tested positive for HIV. Willingness to receive HIV testing was high among spouses and long term heterosexual or homosexual partners but extremely low among casual and commercial sex partners of 'index cases'. Consistent condom use was rare for all participants. A total of 290 independent sexual network components were constructed, with high complexity. CONCLUSION: Contact tracing is useful for identifying new HIV infections from spouses or long term sexual partners of HIV-infected individuals. The complicated sexual networks existing between and beyond HIV-infected persons provide opportunities for rapid spread of HIV in such areas. PMID- 22818300 TI - Invited commentary. PMID- 22818301 TI - Invited commentary. PMID- 22818302 TI - Invited commentary. PMID- 22818303 TI - Invited commentary. PMID- 22818304 TI - Invited commentary. PMID- 22818305 TI - Invited commentary. PMID- 22818306 TI - Invited commentary. PMID- 22818307 TI - Invited commentary. PMID- 22818308 TI - Invited commentary. PMID- 22818309 TI - Near-infrared fluorescence imaging can help identify the contralateral phrenic nerve during robotic thymectomy. AB - PURPOSE: Unilateral robotic thymectomy is gaining popularity. Identifying the contralateral phrenic nerve is a key limitation to achieving maximal thymic tissue resection. We evaluated the feasibility and technique of fluorescence imaging on the daVinci-Si robot (Intuitive Surgical Inc, Sunnyvale, CA) to identify the contralateral periocardiophrenic neurovascular bundle (PNB). DESCRIPTION: A unilateral right robotic thymectomy was performed in 10 patients. The thymus and its poles were mobilized. Indocyanine green was injected and fluoresced to identify the left PNB in four different viewing angles to assess the view that consistently positively identified the PNB. EVALUATION: No complications from indocyanine green or injuries to the phrenic nerve occurred. The contralateral PNB was visualized in 80% of patients from a left pleural view, infrequently from a mediastinal view, and never distal to the aortopulmonary window. CONCLUSIONS: During right robotic thymectomy, fluorescence imaging facilitates identification of the contralateral phrenic nerve by fluorescing the pericardiophrenic vessels. It is best visualized from a left pleural view. This technology has the potential to maximize thymic tissue resection with a unilateral approach while reducing operative time and nerve injury. PMID- 22818310 TI - Recurrent laryngeal nerve paresis postpneumonectomy contralateral to site of surgery. AB - Recurrent laryngeal nerve (RLN) injury is a serious complication of thoracic surgery that increases morbidity and mortality. It is important to consider the long-term effects of mediastinal shift and the possibility of postpneumonectomy syndrome on RLN function. This report documents a unilateral vocal fold paresis contralateral to the side of pneumonectomy that presents for investigation 6 six years after surgery. PMID- 22818311 TI - Critically compromised airway secondary to expanding esophageal mucocele. AB - Expanding mucocele is a known but rare complication of bypass and surgical exclusion of the thoracic esophagus. When functional esophageal mucosa secretes mucin into the blind esophageal loop, tissue expansion can cause mass effect on nearby structures. We report the case of a critically compromised airway secondary to a dilated esophageal mucocele initially managed with right thoracotomy, partial esophagectomy and mucosectomy. This was complicated by mucocele recurrence, which was successfully managed with computed tomography guided drainage and absolute alcohol ablation of residual mucosa. PMID- 22818312 TI - Inverted valve after initially successful transfemoral aortic valve implantation. AB - A 73-year-old woman with severe aortic stenosis was accepted for transcatheter aortic valve implantation. There was minimal paravalvular leakage after the implantation, and the patient was stable. Twelve minutes after the implantation, the arterial pressure suddenly dropped. Transesophageal echocardiography showed severe left ventricular dysfunction. Cardiopulmonary resuscitation was started, and initially was successful with a systolic blood pressure of 90 mm Hg. However, despite initiation of extracorporeal circulation support, the patient deteriorated, pulmonary edema developed, and she died. Autopsy revealed an inverted aortic valve. The reasons why the patient had cardiac arrest and an inverted transfemoral aortic valve remain unclear. PMID- 22818313 TI - Management of multiple embolization arising from atrial myxoma. AB - This study reports detailed surgery procedures on a patient with cardiac myxoma and multiple embolization in the aortic artery, lower extremities, and the superior mesenteric and renal arteries, which is quite uncommon. As the first step in the surgery, conventional thrombectomy was used to remove emboli in abdominal aorta and bilateral lower extremities based on single-lumen Fogarty catheters accessed through bilateral femoral arteries. As the second step, double lumen Fogarty catheters and percutaneous aspiration thromboembolectomy accessed by bilateral femoral arteries again were used in combination to restore blood flow in the visceral artery and renal arteries without the need of laparotomy. Compared with traditional methods relying on laparotomy, the method by combining Fogarty catheters with percutaneous aspiration thromboembolectomy is less invasive and time consuming, and is a promising method in dealing with multiple embolization arising from cardiac myxoma. PMID- 22818314 TI - Partial anomalous connection of both superior pulmonary veins. AB - Several patterns of anomalous pulmonary venous drainage have been described in the literature, and bilateral partial pulmonary anomalous vein connection (PAPVC) has been described as a rare congenital cardiac anomaly. We report an unusual type of bilateral PAPVC, involving both the superior right and left pulmonary veins draining into the left brachiocephalic vein in a young adult who was symptomatic with dyspnea and a dry cough. PMID- 22818315 TI - Dysphagia aortica secondary to descending thoracic aortic pseudoaneurysm. PMID- 22818316 TI - Thrombosis of a bioprosthetic mitral valve under extracorporeal membrane oxygenation: thrombus formation in the left heart. PMID- 22818317 TI - Fenestrated rudimentary aortic valvular cusp: report of a case with dilatated cardiomyopathy. PMID- 22818318 TI - Closure of bronchopleural fistula with porcine dermal collagen and fibrin glue in an infant. AB - The management of an 11-month-old infant who developed a bronchopleural fistula (BPF) 3 weeks after video-assisted thoracic surgery for congenital cystic adenomatoid malformation of the right lower pulmonary lobe is presented. Being refractory to treatment with chest tubes, the BPF was managed using a bronchoscopic approach using porcine dermal collagen (PDC) combined with a fibrin glue plug. The single session was sufficient to manage the BPF and the postoperative course was uneventful. This case highlights the novelty in the successful management of BPF in infants after pulmonary surgery using PDC and fibrin glue using the minimal access bronchoscopic approach. PMID- 22818319 TI - Uniportal video-assisted thoracic resection of a solitary fibrous tumor of the pleura. AB - We describe the surgical removal of a pedunculated solitary fibrous tumor of the pleura through single-access (uniportal) video-assisted thoracoscopic surgery. At the end of the procedure, no chest drain was inserted and the patient discharged home after an 8-hour observation period. Uniportal video-assisted thoracoscopic surgery can represent a suitable surgical option for small solitary fibrous tumors of the pleura. PMID- 22818320 TI - Subclavian insertion of the bicaval dual lumen cannula for venovenous extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) has demonstrated utility in the management of adult respiratory failure refractory to mechanical ventilation. The recent introduction of a bicaval dual-lumen ECMO cannula has improved the efficiency of venovenous ECMO and has enabled the concept of full extracorporeal respiratory support in place of mechanical ventilation. Standard placement of this cannula through the right internal jugular vein is particularly troublesome in individuals of short stature, because of excess cannula length. We describe a method for cannula placement through the left subclavian vein that is well suited for smaller patients and convenient for patient mobility. PMID- 22818321 TI - An easy and useful exposure technique using a malleable ring for the distal anastomosis in total arch replacement. AB - Even if the thoracic endovascular aortic repair or open stent grafting technique becomes popular, surgical total arch replacement is still important and will continue to be necessary. Distal anastomosis of total arch replacement is critical in this procedure. This article describes an easy and useful method for using a malleable retractor ring in the distal anastomosis of the total arch replacement. PMID- 22818322 TI - Lung function and ECMO after lung transplantation. PMID- 22818323 TI - Metaanalysis on skeletonization of the internal thoracic artery. PMID- 22818326 TI - Safety of LeGoo Hemostatic Device for human use in coronary artery bypass grafting surgery. PMID- 22818327 TI - Sequential hybrid ablation for persistent atrial fibrillation. PMID- 22818329 TI - Impact of ventricular geometry on outcomes of surgical ventricular restoration. PMID- 22818332 TI - Banding of the patent ductus arteriosus during modified blalock-taussig shunt surgery in neonates with pulmonary atresia. PMID- 22818331 TI - Fundamental flaw in a fundamental measure: inaccuracies in death data reporting. PMID- 22818335 TI - Off-pump complete pericardiectomy for an unusual case of annular constrictive pericarditis. AB - We describe a case of a 64-year-old man with constrictive pericarditis of unusual anatomy. Preoperative investigations revealed the thickened and calcified pericardial ring encircling the right and left ventricular cavity at the level of the atrioventricular (AV) groove and crossing the left anterior descending coronary artery, leading to strangulation of the heart. Off-pump complete pericardiectomy was performed successfully. The patient's postoperative course was uneventful. PMID- 22818336 TI - Giant aortic aneurysm in an infant with arterial tortuosity syndrome. PMID- 22818337 TI - A rare case of diffuse mitral valve fibroelastoma. PMID- 22818338 TI - Supraannular aortic replacement for severe valve detachment attributable to Behcet's disease. AB - The occurrence of aortic regurgitation (AR) attributable to Behcet's disease is rare, but it brings extraordinary complexity to surgical intervention due to the high risk of postoperative morbidity as the result of valve dehiscence or pseudoaneurysms caused by fragile aortic structures and inflamed tissue. The high rate of prosthetic valve detachment after aortic valve replacement is one of the most serious consequences of aortic regurgitation in Behcet's disease, which results in severe aortic annular destruction, presenting a big challenge to cardiac surgeons. Under this condition, a conventional surgical technique is necessary to be modified for improving postoperative prognosis of patients. In this paper, we described the surgical treatment of 5 patients with Behcet's aortitis and report their long-term outcomes. PMID- 22818339 TI - How we compensate for memory loss in old age: adapting and validating the Memory Compensation Questionnaire (MCQ) for Spanish populations. AB - Compensating entails using external strategies and mechanisms that help overcome or alleviate the decreasing memory function that comes with age. This study aims to adapt and validate the MCQ in the elderly Spanish population. A total of 403 elderly people aged between 65 and 92 in the city of Valencia (Spain) completed the questionnaire for the validation process. The factorial validity of the scale was tested using confirmatory factor analysis. The result showed a first order five-factor model with 23 items that met the criteria for model fit according to multiple fit indices. As a general conclusion, the adaptation into Spanish provided a reliable and valid measure of compensation in the elderly population, and it could potentially be useful in both clinical practice and research in the elderly. PMID- 22818340 TI - No evidence of mumps transmission during air travel, United States, November 1, 2006-October 31, 2010. AB - Since November 2006, flight-related mumps contact investigations were conducted in the United States only for flights >=5 h long after an investigation showed minimal risk of mumps transmission on flights <5 h. Because the transmission risk on longer flights had not been evaluated, we investigated whether there was evidence to support the guidelines. We examined data from mumps contact investigations that were initiated by the US Centers for Disease Control and Prevention (CDC) from November 2006 to October 2010. We also cross-referenced passenger-contact data with data on mumps cases in the National Notifiable Diseases Surveillance System (NNDSS). Twenty-seven cases met inclusion criteria. Of 246 passengers identified as contacts, 166 (67%) were distributed to a US health department for contact tracing. Outcomes were reported for 21 (13%) of those 166 passengers. No secondary cases of mumps among passenger contacts were reported or identified by cross-referencing NNDSS data. The findings suggested that in-flight risk of mumps transmission is not high. Furthermore, these investigations have low yield, are resource intensive, there is no post-exposure prophylaxis, and mumps transmission has not been eliminated in the United States. Therefore, CDC discontinued conducting flight-related mumps contact investigations in May 2011. PMID- 22818341 TI - Transitioning patients with disorders of sex development to adult care: the role of the pediatric urologist. PMID- 22818342 TI - Is intralesional verapamil effective therapy for Peyronie's disease? PMID- 22818343 TI - The need for better decision tools in managing stone disease. PMID- 22818344 TI - Novel agents and approaches for advanced renal cell carcinoma. PMID- 22818345 TI - Management of panurethral stricture disease in India. AB - PURPOSE: Panurethral stricture involving the penile and bulbar urethra is a common urological problem on the South Asian subcontinent. It represents a particularly difficult challenge to manage and there is a relative paucity of literature on the subject. In India lichen sclerosus is the most common etiology of panurethral stricture, followed by iatrogenic causes. We present our experience with panurethral stricture repair using 1-stage, 1-side dissection dorsal onlay repair with oral mucosa grafts. MATERIALS AND METHODS: We retrospectively reviewed the records of 117 consecutive men who underwent treatment for panurethral stricture from June 1998 to December 2010. Median patient age was 47.8 years, mean stricture length was 14 cm and median followup was 59 months. The stricture was approached through a perineal incision, limiting dissection to only 1 side of the urethra. The penis was invaginated to provide access to the entire length of anterior urethra in 1 stage. Two oral mucosal grafts were placed dorsally. RESULTS: The outcome was considered a success if the patient required no further instrumentation, including dilation or urethrotomy. The overall success rate was 83.7% with a success rate of 86.5% for primary urethroplasty and 61.5% in patients in whom urethroplasty had previously failed. Most recurrent strictures developed at the proximal end of the graft. CONCLUSIONS: Repair of panurethral stricture in 1 stage with 1-side dissection and dorsal onlay of oral mucosa graft is a minimally invasive technique that is simple, fast, safe, effective and reproducible by any surgeon. PMID- 22818346 TI - Expectant management of localized prostate cancer--who, what, when, where and how? PMID- 22818347 TI - Clouds can lead to clear thinking. PMID- 22818348 TI - Trends in minimally invasive surgery for the kidney and prostate--when are you doing the patient a disservice by not referring? PMID- 22818349 TI - [Impact of the use of luer access devices on the quality of chronic hemodialysis]. AB - Luer access valves are medical devices used to reduce infectious risks by securing repetitive handling in chronic hemodialysis using central catheter. Their impact on the effectiveness of a hemodialysis session still remains poorly studied. This in vivo study aims to evaluate its effectiveness. Tego((r)) and Q Syte((r)) valves were used in alternation for each patient for four weeks (428 hemodialysis sessions). The two-luer access valves have led to a significant increase in the dysfunction of the hemodialysis sessions (51.8% compared to the usual care (39.3%) (P=0.012). The analysis by sub-category suggests a heterogeneous behavior of the two devices. The Q-Syte((r)) valve showed significantly more dysfunction than the Tego((r)) valve or the absence of valve. However, both valve systems tested can maintain the performance of the hemodialysis session as they don't change the dose of dialysis. This study highlights that an evaluation of each device must be performed prior to their use to assess the risk-benefit balance. PMID- 22818350 TI - Genetic and management factors affecting beef quality in grazing Hereford steers. AB - Attributes contributing to differences in beef quality of 206 Hereford steers finished on pasture were assessed. Beef quality traits evaluated were: Warner Bratzler meat tenderness and muscle and fat color at one and seven days after slaughter and trained sensory panel traits (tenderness, juiciness, flavor, and marbling) at seven days. Molecular markers were CAPN1 316 and an SNP in exon 2 on the leptin gene (E2FB). Average daily live weight gain, ultrasound monthly backfat thickness gain and rib-eye area gain were estimated. Molecular markers effects on meat quality traits were analyzed by mixed models. Association of meat quality with post weaning growth traits was analyzed by canonical correlations. Muscle color and marbling were affected by CAPN1 316 and E2FB and Warner-Bratzler meat tenderness by the former. The results confirm that marker assisted selection for tenderness is advisable only when beef aging is a common practice. The most important sources of variation in tenderness and color of meat remained unaccounted for. PMID- 22818353 TI - The effect of the new traffic law on drinking and driving in Sao Paulo, Brazil. AB - OBJECTIVE: To present data on drinking and driving in the city of Sao Paulo, Brazil, and the effects of the new traffic law (Law 11,705) introduced in 2008. METHODS: A cross-sectional study was performed using a questionnaire and passive breath test data to study the prevalence of drinking and driving and the association of drinking and driving with background characteristics and drinking patterns on two separate occasions. The data were gathered from 2007 to 2009 through roadside surveys conducted on busy public roads. Four thousand two hundred thirty-four (4234) drivers were approached, before and after prohibition, from the south, north, east, and west regions of the city of Sao Paulo, located in southeastern Brazil, including cars, motorcycles, and utility vehicles. A total of 3854 (91%) consented to participate in the survey and answered the questionnaire. Out of this group, 3229 (84%) agreed to take the passive breathalyzer test. RESULTS: Logistic regression analyses controlling for gender and age was used to predict a positive breath test (above 0.2g/l) and the impact of the new law. These analyses indicated that, after the passage of the new traffic law, there was a 45% decrease in driver behavior with positive breathalyzer results. Having a pattern of alcohol consumption of at least once a week and the habit of drinking and driving are risks for a positive breathalyzer. CONCLUSIONS: Despite the decline in the frequency of motorists driving under the influence of alcohol, traffic-related injuries and deaths, after the new law, other measures for a public policy related to alcohol should be considered based on scientific evidence, consistency of action, clear goals, community support, and greater reliability in the laws. PMID- 22818354 TI - Depressive symptoms and psychosocial stress at work among older employees in three continents. AB - BACKGROUND: To assess whether an association of psychosocial stress at work with depressive symptoms among older employees is evident in a set of comparable empirical studies from Europe, North America and Asia. METHODS: Cross-sectional and longitudinal multivariate regression analyses of data from 4 cohort studies with elder workers (2004 and 2006) testing associations of psychosocial stress at work ('effort-reward imbalance'; 'low control') with depressive symptoms. RESULTS: Cross-sectional analyses from 17 countries with 14.236 participants reveal elevated odds ratios of depressive symptoms among people experiencing high work stress compared to those with low or no work stress. Adjusted odds ratios vary from 1.64 (95% CI 1.02-2.63) in Japan to 1.97 (95% CI 1.75-2.23) in Europe and 2.28 (95% CI 1.59-3.28) in the USA. Odds ratios from additional longitudinal analyses (in 13 countries) controlling for baseline depression are smaller, but remain in part significant. CONCLUSION: Findings indicate that psychosocial stress at work might be a relevant risk factor for depressive symptoms among older employees across countries and continents. This observation may call for global policy efforts to improve quality of work in view of a rapidly aging workforce, in particular in times of economic globalization. PMID- 22818356 TI - The use of reflection in emergency medicine education. AB - Reflection is a cognitive process in which new information and experiences are integrated into existing knowledge structures and mental models, resulting in meaningful learning. Reflection often occurs after an experience is over, promoting professional development and lifelong learning. However, a reflective emergency physician (EP) is also able to apply reflection in real time: self monitoring, coping with the unexpected, and quickly thinking on his or her feet to solve complicated, unique, and challenging clinical problems. Reflection is a skill that can be taught and developed in medical education. Evidence demonstrating the value of teaching reflection is emerging that substantiates longstanding educational theories. While a few educators have started to explore the use of reflection for emergency medicine (EM) learners, the potential for broader application exists. This review summarizes the literature regarding reflection in medical education and provides a basic primer for teaching reflection. PMID- 22818355 TI - Pro-adrenomedullin usefulness in the management of children with community acquired pneumonia, a preliminar prospective observational study. AB - BACKGROUND: In adult population with community acquired pneumonia high levels of pro-adrenomedullin (pro-ADM) have been shown to be predictors of worse prognosis. The role of this biomarker in pediatric patients had not been analyzed to date. The objective of this study is to know the levels of pro-ADM in children with community acquired pneumonia (CAP) and analyze the relation between these levels and the patients' prognosis. FINDINGS: Prospective observational study including patients attended in the emergency service (January to October 2009) admitted to hospital with CAP and no complications at admission. The values for pro-ADM were analyzed in relation to: need for oxygen therapy, duration of oxygen therapy, fever and antibiotic therapy, complications, admission to the intensive care unit, and length of hospital stay. Fifty patients were included. Ten presented complications (7 pleural effusion). The median level of pro-ADM was 1.0065 nmol/L (range 0.3715 to 7.2840 nmol/L). The patients presenting complications had higher levels of pro-ADM (2.3190 vs. 1.1758 nmol/L, p = 0.013). Specifically, the presence of pleural effusion was associated with higher levels of pro-ADM (2.9440 vs. 1.1373 nmol/L, p < 0.001). CONCLUSIONS: In our sample of patients admitted to hospital with CAP, pro-ADM levels are related to the development of complications during hospitalization. PMID- 22818357 TI - Bioactive constituents of Clausena lansium and a method for discrimination of aldose enantiomers. AB - Glycosides, clausenosides A and B, and carbazole alkaloids, clausenaline A, claulamine A, and claulamine B, together with 50 known compounds, were isolated from the stems of Clausena lansium. Their structures were determined by means of spectroscopic methods, including that of CD and 1D/2D NMR analysis. Claulamine A has a 1-oxygenated carbazole skeleton with a rare 2,3-lactone ring, and claulamine B represents an hitherto unknown acetal carbazole alkaloid. Thirty-one of the isolated known compounds were evaluated in various assays for anti inflammatory activity. Among them, imperatorin, isoheraclenin, and osthol exhibited selective and potent inhibition of formyl-l-methionyl-l-leucyl-l phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation, and lansiumarin C also decreased nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production in lipopolysaccharide (LPS)-induced macrophages. In addition, a modified HPLC method of pre-column derivatization was developed that is more practical for simultaneous analysis of aldose enantiomers as compared to the literature method. The absolute configurations of the sugar moieties in clausenosides A and B were determined with this modified method. PMID- 22818358 TI - The potential of Cyathus africanus for transformation of terpene substrates. AB - The insecticidal sesquiterpenes cadina-4,10(15)-dien-3-one and aromadendr-1(10) en-9-one were administered to the fungus Cyathus africanus ATCC 35853. Biotransformation of the former produced (4R)-9alpha-hydroxycadin-10(15)-en-3 one, while the latter gave 2beta-hydroxyaromadendr-1(10)-en-9-one, 2alpha hydroxyaromadendr-1(10)-en-9-one and 10alpha-hydroxy-1beta,2beta epoxyaromadendran-9-one. The bioconversion of santonin led to the production of two analogues, 11,13-dihydroxysantonin and the hitherto unreported 8alpha,13 dihydroxysantonin, while cedrol yielded 3beta,8beta-dihydroxycedrane and 3alpha,8beta-dihydroxycedrane. Stemod-12-ene, a diterpene, was transformed to 2 oxostemar-13-ene, a hitherto unknown analogue with a rearranged carbon framework. When methyl betulonate, a triterpenoid belonging to the lupane family, was supplied to the fungus 18alpha-ursane and 18alpha-oleanane derivatives, namely 19beta-hydroxy-3-oxo-18alpha-oleanan-28-oic acid and 19alpha-hydroxy-3-oxo 18alpha-ursan-28-oic acids, were generated. There are no previous reports of fungal transformation of a triterpene in which a skeletal rearrangement occurred. All substrate administration experiments were done in the presence of the terpene cyclase inhibitor chlorocholine chloride (CCC), using the single phase - pulse feed method. PMID- 22818359 TI - Secondary metabolites from the stems of Engelhardia roxburghiana and their antitubercular activities. AB - Bioassay-guided fractionation of stems of Engelhardia roxburghiana led to isolation of: four diarylheptanoids, engelheptanoxides A-D (1-4); two cyclic diarylheptanoids, engelhardiols A (5) and B (6); one naphthoquinone dimer, engelharquinonol (7); and one 1-tetralone, (4S)-4,6-dihydroxy-1-tetralone (8), along with 24 known compounds (9-32). The structures of 1-8 were by spectroscopic analysis. Compounds 5, 6, 13, 22, and 23 showed antitubercular activity against Mycobacterium tuberculosis H(37)Rv with MIC values of 72.7, 62.1, 9.1, 15.3, and 70.1MUM, respectively. PMID- 22818360 TI - Relevance of alloimmunization in haemolytic transfusion reaction in sickle cell disease. AB - Transfusion remains a key treatment in sickle cell disease. The occurrence of a delayed haemolytic transfusion reaction is not rare and is a life-threatening event. The main cause of delayed haemolytic transfusion reaction is production of alloantibodies against red blood cell antigens. The high rate of alloimmunization in sickle cell disease patients is mainly due to the differences of red blood groups between patients of African descent, and the frequently Caucasian donors. From an immuno-haematological point of view, delayed haemolytic transfusion reaction in sickle cell disease patients has specific features: classical antibodies known to be haemolytic can be encountered, but otherwise non significant antibodies, autoantibodies and antibodies related to partial and rare blood groups are also frequently found in individuals of African descent. In some cases, there are no detectable antibodies. As alloimmunization remains the main cause of delayed haemolytic transfusion reaction, it is extremely important to promote blood donation by individuals of African ancestry to make appropriate blood available. PMID- 22818361 TI - [Letter on the article: "Kidney and HIV infection"]. PMID- 22818362 TI - Kinetic investigation on sono-degradation of Reactive Black 5 with core-shell nanocrystal. AB - The experimental data of sonocatalytic degradation of Reactive Black 5 (RB5) as an azo dye by core-shell nanocrystals (CdS-TiO(2)) were applied to the proper kinetic models. In this work, two kinetic models were proposed and fitted properly to the data. In the first one, the heterogeneous reaction was considered similar to the Langmuir-Hinshelwood (L-H) mechanism and the kinetic rate parameters were determined. In this model, short time of sonication with initial concentration changes has been applied and the contribution of the reaction intermediates has been neglected in degradation. Hence, this model may not be valid for longer reaction times where the reaction intermediates effects prevail. In the second one, two first-order reactions in series provided the most convincing rate form for the sonodegradation of dyes adsorbed on the synthesized nanocomposite. In these series reactions, the first step is the conversion of colored dye to colored intermediate, and the second step is the conversion to colorless product(s). The obtained results were in good agreement with the proposed kinetic models. The rate constants of degradation of catalyzed reaction were higher than that obtained without catalyst, solar and UV irradiation. PMID- 22818363 TI - Identifying paediatric nursing-sensitive outcomes in linked administrative health data. AB - BACKGROUND: There is increasing interest in the contribution of the quality of nursing care to patient outcomes. Due to different casemix and risk profiles, algorithms for administrative health data that identify nursing-sensitive outcomes in adult hospitalised patients may not be applicable to paediatric patients. The study purpose was to test adult algorithms in a paediatric hospital population and make amendments to increase the accuracy of identification of hospital acquired events. The study also aimed to determine whether the use of linked hospital records improved the likelihood of correctly identifying patient outcomes as nursing sensitive rather than being related to their pre-morbid conditions. METHODS: Using algorithms developed by Needleman et al. (2001), proportions and rates of records that identified nursing-sensitive outcomes for pressure ulcers, pneumonia and surgical wound infections were determined from administrative hospitalisation data for all paediatric patients discharged from a tertiary paediatric hospital in Western Australia between July 1999 and June 2009. The effects of changes to inclusion and exclusion criteria for each algorithm on the calculated proportion or rate in the paediatric population were explored. Linked records were used to identify comorbid conditions that increased nursing-sensitive outcome risk. Rates were calculated using algorithms revised for paediatric patients. RESULTS: Linked records of 129,719 hospital separations for 79,016 children were analysed. Identification of comorbid conditions was enhanced through access to prior and/or subsequent hospitalisation records (43% of children with pressure ulcers had a form of paralysis recorded only on a previous admission). Readmissions with a surgical wound infection were identified for 103 (4.8/1,000) surgical separations using linked data. After amendment of each algorithm for paediatric patients, rates of pressure ulcers and pneumonia reduced by 53% and 15% (from 1.3 to 0.6 and from 9.1 to 7.7 per 10,000 patient days) respectively, and an 84% increase in the proportion of surgical wound infection (from 5.7 to 10.4 per 1,000 separations). CONCLUSIONS: Algorithms for nursing-sensitive outcomes used in adult populations have to be amended before application to paediatric populations. Using unlinked individual hospitalisation records to estimate rates of nursing-sensitive outcomes is likely to result in inaccurate rates. PMID- 22818365 TI - Symptoms and course of intoxication with mesuximide--a case report. AB - We report on a 31-year-old, female patient who presented with somnolence due to an intoxication by the antiepileptic drug, mesuximide (MSM). The serum concentration of its metabolite n-desmethyl-mesuximide (85.7 mg/L) was above the so-called therapeutic range (10-40 mg/L) but below the concentration range that led to an impairment of consciousness in previous cases according to the German SPC (>150 mg/L). The symptoms remitted quickly under hemodialysis. In somnolent patients treated with MSM, the treating physicians should be aware of drug intoxication as a possible etiology. Therefore, the serum concentration should be measured early. Due to the, often, long latency until the results are available, treatment initiation may be necessary based on suspicion. PMID- 22818364 TI - Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation. AB - BACKGROUND: Elastin is an essential component of selected connective tissues that provides a unique physiological elasticity. Elastin may be considered a signature protein of lungs where matrix metalloprotease (MMP) -9-and -12, may be considered the signature proteases of the macrophages, which in part are responsible for tissue damage during disease progression. Thus, we hypothesized that a MMP-9/-12 generated fragment of elastin may be a relevant biochemical maker for lung diseases. METHODS: Elastin fragments were identified by mass-spectrometry and one sequence, generated by MMP-9 and -12 (ELN-441), was selected for monoclonal antibody generation and used in the development of an ELISA. Soluble and insoluble elastin from lung was cleaved in vitro and the time-dependent release of fragments was assessed in the ELN-441 assay. The release of ELN-441 in human serum from patients with chronic obstructive pulmonary disease (COPD) (n = 10) and idiopathic pulmonary fibrosis (IPF) (n = 29) were compared to healthy matched controls (n = 11). RESULTS: The sequence ELN-441 was exclusively generated by MMP 9 and -12 and was time-dependently released from soluble lung elastin. ELN-441 levels were 287% higher in patients diagnosed with COPD (p < 0.001) and 124% higher in IPF patients (p < 0.0001) compared with controls. ELN-441 had better diagnostic value in COPD patients (AUC 97%, p = 0.001) than in IPF patients (AUC 90%, p = 0.0001). The odds ratios for differentiating controls from COPD or IPF were 24 [2.06-280] for COPD and 50 [2.64-934] for IPF. CONCLUSIONS: MMP-9 and -12 time-dependently released the ELN-441 epitope from elastin. This fragment was elevated in serum from patients with the lung diseases IPF and COPD, however these data needs to be validated in larger clinical settings. PMID- 22818366 TI - Images in emergency medicine. A female with rash and fever: concomitant dermal and pulmonary varicella. PMID- 22818367 TI - Geriatric patients may not experience increased risk of oligoanalgesia in the emergency department. AB - STUDY OBJECTIVE: The aim of this study is to compare the pain management practices in geriatric patients in the emergency department (ED) with that in other adult ED patients to determine whether these patients face increased risk of oligoanalgesia. METHODS: This study was a prospective analysis of a convenience sample of patients presenting to an urban academic tertiary care hospital ED from 2000 through 2010. We compared patients aged 65 years and older (geriatric) with adults younger than 65 years and evaluated analgesic administration rates, opioid administration and dosing, and pain and satisfaction scores (0 to 10 scale). RESULTS: A total of 15,387 patients presented to the ED during the 10-year study period and agreed to participate in the study; 1,169 patients were geriatric (7.6%). Geriatric patients had a mean age of 75.0 years (SD 7.2 years), whereas mean age of the 14,218 nongeriatric patients was 35.5 years (SD 12.2 years). Geriatric patients reported less pain at presentation (6.2 versus 6.9). After adjusting for presentation pain scores, geriatric patients were not less likely to receive an analgesic during the ED visit (odds ratio 0.90; 95% confidence interval 0.78 to 1.05) or less likely to receive an opioid (odds ratio 1.01; 95% confidence interval 0.87 to 1.18). Geriatric patients, on average, received lower doses of morphine (3.3 versus 4.2 mg) and had longer waiting times for their initial dose of an analgesic medication (65 versus 75 minutes). CONCLUSION: Despite longer wait times for analgesia, geriatric and nongeriatric patients were similar in rates of analgesia and opioid administration for pain-related complaints. These findings contrast with previous studies reporting lower rates of analgesia administration among geriatric patients. PMID- 22818368 TI - There is oligo-evidence for oligoanalgesia. PMID- 22818369 TI - Low tidal volume ventilation should be the routine ventilation strategy of choice for all emergency department patients. PMID- 22818370 TI - Low tidal volume should not routinely be used for emergency department patients requiring mechanical ventilation. PMID- 22818371 TI - Commentary: preventable injury and a trauma system near you. PMID- 22818372 TI - Change of shift. My mistake. PMID- 22818373 TI - Annals of Emergency Medicine Journal Club. Biomarkers revisited: study design, validity, and STARD: Will S100-B affect computed tomography use in head injury patients?: Answers to the March 2012 Journal Club questions. PMID- 22818374 TI - Images in emergency medicine. Man with nausea and vomiting. Gastric emphysema complicating pancreatic cancer-related gastric outlet obstruction. PMID- 22818375 TI - Don't forget the 99%. PMID- 22818377 TI - Is routine pan computed tomography for patients with blunt trauma justified? PMID- 22818378 TI - Mutually undesired computed tomography for patients with blunt trauma: I don't want it. You don't want it. Who does want it? PMID- 22818381 TI - Stroke mimics and intravenous thrombolysis. PMID- 22818382 TI - Nondiscrimination and harassment. Policy statement. PMID- 22818383 TI - Subspecialty certification in critical care medicine. Policy statement. PMID- 22818384 TI - Trauma care systems development, evaluation, and funding. Policy statement. PMID- 22818385 TI - Images in emergency medicine. Young man with left thoracic pain. Recurrent pneumothorax after failed pleurodesis. PMID- 22818387 TI - Efficacy and limitations of multimodal endovascular revascularization other than clot retrieval for acute stroke caused by large-vessel occlusion. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of multimodal endovascular treatment (EVT) other than clot retrieval for acute large-vessel occlusion (LVO). METHODS: Fifty-six consecutive patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 15 were included this study. In all cases, intravenous administration of recombinant tissue plasminogen activator had failed (n = 23) or was contraindicated (n = 33). The modes of EVT performed included intra-arterial thrombolysis, mechanical clot disruption including balloon angioplasty, and stent placement. We retrospectively analyzed the treatment efficacy of these techniques and patient outcome. RESULTS: Successful reperfusion (Thrombolysis in Cerebral Infarction grade 2B or 3) was achieved in 40 of 56 patients (71.4%), and 26 of 56 patients (46.4%) had a favorable clinical outcome (modified Rankin Scale [mRS] score 0 to 2 at 90 days). Successful reperfusion (odds ratio [OR] 163; P = .003), age (OR 0.83; P = .007), and baseline NIHSS score (OR 0.71; P = .009) were independently associated with favorable clinical outcome by multivariate analysis. Successful reperfusion rates of internal carotid terminus or M1 proximal occlusions were significantly lower than those of other vessel occlusion (47.6% v 85.7%; P = .005). Clinically significant procedure-related complications occurred in 1.8% (1/56), and symptomatic intracerebral hemorrhage (sICH) within 48 hours after EVT was observed in 5.4% (3/56) of patients. CONCLUSIONS: Multimodal EVT for acute LVO yields a high reperfusion rate with a minimal risk of sICH and contributes to favorable patient outcomes. These techniques should be considered when clot retrieval is unsuitable or ineffective. PMID- 22818386 TI - Differential expression of vascular endothelial growth factor isoforms and receptor subtypes in the infarcted heart. AB - AIMS: The vascular endothelial growth factor (VEGF) family contains four major isoforms and three receptor subtypes. The expressions of each VEGF isoform and receptor subtype in cardiac repair/remodeling after myocardial infarction (MI) remain uncertain and are investigated in the current study. METHODS AND RESULTS: Temporal and spatial expressions of VEGF isoforms and VEGFR subtypes were examined in the infarcted rat heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all VEGF isoforms. Following MI, VEGF A was only increased in the border zone at day 1 and was significantly decreased in the infarcted heart during the 42 day observation period afterwards. VEGF-B was significantly suppressed in the infarcted heart. VEGF-C and VEGF-D were markedly increased in the infarcted heart in both early and late stages of MI. VEGFR-1 and 2 were significantly decreased in the infarcted heart, while VEGFR-3 was significantly increased, which was primarily expressed in blood vessels and myofibroblasts (myoFb). CONCLUSIONS: VEGF isoforms and VEGFR subtypes are differentially expressed in the infarcted heart. Increased VEGF-A in the very early stage of MI suggests the potential role in initiating the cardiac angiogenic response. Suppressed cardiac VEGF-B postMI suggests that it may not be critical to cardiac repair. The presence of enhanced VEGF-C and VEGF-D along with its receptor, VEGFR-3, in various cell types of the infarcted heart suggest that these isoforms may regulate multiple responses during cardiac repair/remodeling. PMID- 22818388 TI - Race and income disparity in ischemic stroke care: nationwide inpatient sample database, 2002 to 2008. AB - BACKGROUND: Health care disparities exist between demographic groups with stroke. We examined whether patients of particular ethnicity or income levels experienced reduced access to or delays in receiving stroke care. METHODS: We studied all admissions for ischemic stroke in the Nationwide Inpatient Sample (NIS) database between 2002 and 2008. We used statistical models to determine whether median income or race were associated with intravenous (i.v.) thrombolysis treatment, in hospital mortality, discharge disposition, hospital charges, and LOS in high- or low-volume hospitals. RESULTS: There were a total of 477,474 patients with ischemic stroke: 10,781 (2.3%) received i.v. thrombolysis, and 380,400 (79.7%) were treated in high-volume hospitals. Race (P < .0001) and median income (P < .001) were significant predictors of receiving i.v. thrombolysis, and minorities and low-income patients were less likely to receive i.v. thrombolysis. Median income was a predictor of access to high-volume hospitals (P < .0001), with wealthier patients more likely to be treated in high-volume hospitals, which had lower mortality rates (P = .0002). Patients in high-volume hospitals were 1.84 times more likely to receive i.v. thrombolysis (P < .0001). CONCLUSIONS: African Americans, Hispanics, and low median income patients are less likely to receive i.v. thrombolysis for ischemic stroke. Low median income patients are less likely to be treated at high-volume hospitals. High-volume hospitals have lower mortality rates and a higher likelihood of treating patients with i.v. thrombolysis. There is evidence for an influence of socioeconomic status and racial disparity in the treatment of ischemic stroke. PMID- 22818390 TI - The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway. AB - Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Literature concerning 5-HT3 antagonists on platelets is limited. In this report we examined the pharmacological effects of ondansetron on human washed platelets. Platelet aggregation induced by thrombin (0.1 U/mL), collagen (2 MUg/mL), arachidonic acid (0.5mM), ADP (10 MUM), or U46619 (2 MUM) was observed. The effects of ondansetron on platelet aggregation and ATP release were investigated at different concentrations. Cytosolic Ca(2+) influx concentration, TXB2, IP3, and the levels of cAMP and cGMP were monitored, and flow cytometric analysis and immunoblotting were performed to investigate downstream signaling components. Our results showed that ondansetron, in a concentration-dependent manner, inhibited agonist-induced platelet aggregation. At 75 MUM, ondansetron significantly attenuated intracellular Ca(2+) mobilization, thromboxane B2 formation, and ATP release by human washed platelets activated by thrombin, collagen, or U46619, whereas it only partially attenuated arachidonic acid-driven platelet activation. Administration of ondansetron resulted in attenuated IP3 production in the washed platelets stimulated by thrombin, as determined by reduced IP1 levels, as well as diminished p38 and ERK2 phosphorylation in response to thrombin. No effect of ondansetron on the levels of either cAMP or cGMP in washed platelets was observed. Furthermore, ondansetron mediated inhibition of platelet aggregation was not impacted by SR 57227A, the 5 HT3 agonist. Thus, rather than involving the 5-HT3-dependent pathway, the negative effect of ondansetron on platelet aggregation is instead manifested through the attenuation of agonist-induced IP3 production and MAPK (p38 and ERK2) phosphorylation that results in suppressed intracellular Ca(2+) mobilization, TXB2 formation, and ATP release. PMID- 22818389 TI - Acute kidney injury is associated with increased hospital mortality after stroke. AB - BACKGROUND: Acute kidney injury (AKI) is common and is associated with poor clinical outcomes. Information about the incidence of AKI and its effect on stroke outcomes is limited. METHODS: Data were analyzed from a registry of subjects with ischemic stroke and intracerebral hemorrhage (ICH) hospitalized at a single academic medical center. Admission creatinine was considered to be the baseline. AKI was defined as a creatinine increase during hospitalization of 0.3 mg/dL or a percentage increase of at least 50% from baseline. Multivariate logistic regression models were created for both stroke types, with hospital mortality as the outcome. Covariates included gender, race, age, admission creatinine, National Institutes of Health Stroke Scale score at admission, the performance of a contrast-enhanced computed tomographic scan of the head and neck, and medical comorbidities. RESULTS: There were 528 cases of ischemic stroke with 70 deaths (13%), and 829 cases of ICH with 268 deaths (32%). The mean age was 64 years; 56% of patients were men and 71% were white. AKI complicated 14% of ischemic stroke and 21% of ICH hospitalizations. In multivariate analysis stratified by stroke type, AKI was associated with increased hospital mortality from ischemic stroke (odds ratio [OR] 3.08; 95% confidence interval [CI] 1.49 6.35) but not ICH (OR 0.82; 95% CI 0.50-1.35), except for those surviving at least 2 days (OR 2.11; 95% CI 1.18-3.77). CONCLUSIONS: AKI occurs frequently after stroke and is associated with increased hospital mortality. Additional studies are needed to establish if the association is causal and if measures to prevent AKI would result in decreased mortality. PMID- 22818391 TI - The Affordable Care Act and academic medical centers. PMID- 22818392 TI - Midwifery scope of practice among staff nurses: a grounded theory study in Gujarat, India. AB - BACKGROUND: midwifery is a part of the nursing profession in India. This current study explores and describes the midwifery scope of practice among staff nurses. METHODS: a grounded theory approach was used to develop a model. Twenty-eight service providers from the maternity sections of public health facilities, selected through purposive and theoretical sampling were interviewed in-depth. Unstructured observations in the labour wards were also used for developing the model. FINDINGS: the midwifery practice of staff nurses was limited in scope compared to international standards of midwifery. Their practice was circumstance driven, ranging from extended to marginal depending on the context. Their right to practice was not legally defined, but they were not specifically prohibited from practice. As a consequence, the staff nurses faced loss of skills, and deskilling when their practice was restricted. Their practice was perceived as risky, when the scope of practice was extended because it was not rightfully endorsed, the nurses having no officially recognized right to practice midwifery at that level. The clinical midwifery education of nursing and midwifery students was marginalized because the education of medical students was given priority, and the students only got exposed to the restricted practice of staff nurses. CONCLUSIONS: unclear definitions of the right to practice and the scope of practice have led to the un-utilized potential of staff nurses practising midwifery. This is detrimental because India faces an acute shortage of qualified personnel to meet the need in providing human resources for maternal health. PMID- 22818393 TI - Cytomegalovirus associated transverse myelitis in an immunocompetent host with DNA detection in cerebrospinal fluid; a case report. AB - BACKGROUND: Cytomegalovirus associated transverse myelitis among immunocompetent adults has been rarely reported. We report a patient presenting with clinical myelitis followed by previously unreported finding of cytomegalovirus deoxyribonucleic acid in cerebrospinal fluid. CASE REPORT: A forty year old immunocompetent male presented with acute onset progressive bilateral lower limb weakness. His spinal magnetic resonance imaging findings, cerebrospinal fluid analysis and clinical picture were compatible with transverse myelitis. Polymerase chain reaction of the cerebrospinal fluid for cytomegalovirus was positive while other infectious agents were not detected by serology or polymerase chain reaction. He was treated with intravenous ganciclovir with partial clinical response. CONCLUSION: Viral genome detection in the cerebrospinal fluid was performed but negative in five out of ten reported cases of cytomegalovirus associated transverse myelitis in the immunocompetent host. In previous cases the inability to isolate the virus in cerebrospinal fluid was considered favouring an immunological mechanism leading to pathogenesis rather than direct viral toxicity but this case is against that theory. This case highlights the fact that Cytomegalovirus should be considered as an aetiological agent in patients with transverse myelitis and that the virus may cause serious infections in immunocompetent host. Therefore this report is of importance to neurologists and physicians in general. PMID- 22818394 TI - Stereoscopic 3D entertainment and its effect on viewing comfort: comparison of children and adults. AB - Children's and adults' viewing comfort during stereoscopic three-dimensional film viewing and computer game playing was studied. Certain mild changes in visual function, heterophoria and near point of accommodation values, as well as eyestrain and visually induced motion sickness levels were found when single setups were compared. The viewing system had an influence on viewing comfort, in particular for eyestrain levels, but no clear difference between two- and three dimensional systems was found. Additionally, certain mild changes in visual functions and visually induced motion sickness levels between adults and children were found. In general, all of the system-task combinations caused mild eyestrain and possible changes in visual functions, but these changes in magnitude were small. According to subjective opinions that further support these measurements, using a stereoscopic three-dimensional system for up to 2 h was acceptable for most of the users regardless of their age. PMID- 22818395 TI - Nail psoriasis: treatment with tazarotene 0.1% hydrophilic ointment. AB - INTRODUCTION: Nail involvement is common in psoriasis and has a considerable impact on patient quality of life. Its clinical presentation depends on which part of the nail is affected: the bed or the matrix. Fifty percent of patients report associated pain. In this study, we analyzed the safety and effectiveness of tazarotene 0.1% in a hydrophilic ointment in the treatment of nail psoriasis. MATERIAL AND METHODS: We performed an open observational study of 6 patients diagnosed with nail psoriasis. The patients applied a compounded preparation of tazarotene 0.1% ointment under occlusion every night for 6 months in their homes. They were not receiving any other topical or systemic treatments. Nail psoriasis severity (assessed using the Nail Psoriasis Severity Index [NAPSI]), subungual hyperkeratosis, onycholysis, splinter hemorrhages, oil stains, and nail pitting were evaluated at baseline and at 3 and 6 months. RESULTS: A statistically significant improvement between baseline and 6 months was observed in all patients: the mean (SD) NAPSI went from 14.3 (6.3; 95% CI, 11.74-16.92) to 2.3 (1.21; 95% CI, 1.84-2.3) while the median went from 15 to 2.5 (P = .007). The percentage improvement at the end of treatment was 87.9%. No adverse effects were observed. CONCLUSION: Our study shows the therapeutic potential of tazarotene ointment in nail psoriasis. PMID- 22818396 TI - Group antenatal intervention to reduce perinatal stress and depressive symptoms related to intergenerational conflicts: a randomized controlled trial. AB - BACKGROUND: Intergenerational conflicts are a major source of stress, which might lead to depression in new mothers. The conflict is heightened when grandparents are involved in childcare. OBJECTIVES: To examine the effectiveness of an interpersonal psychotherapy oriented group intervention to reduce stress and depressive symptoms in new mothers and enhance happiness and self-efficacy in managing intergenerational conflict in childcare. This study is one of the intervention projects of FAMILY: A Jockey Club Initiative for a Harmonious Society, funded by The Hong Kong Jockey Club Charities Trust. DESIGN: Multisite randomized controlled trial with two arms: an intervention group attended an additional 4-week program and a control group who received usual care only. SETTING: Six Maternal and Child Health Centres in Hong Kong PARTICIPANTS: From September 2009 to January 2010, 156 pregnant women who would have grandparents involved in childcare were recruited at their 14-32 weeks' gestation. METHODS: Participants were randomized to groups using computer generated random sequences by blinded recruitment staff. Primary outcomes were stress and depressive symptoms immediately after the intervention and 6-8 weeks after delivery. Secondary outcomes were happiness and self-efficacy in managing conflict. RESULTS: After screening 2870 pregnant women, 156 eligible participants were randomized. Intention-to-treat analysis showed that the intervention group (n=78) had significantly lower perceived stress (p=0.017; Cohen d=0.38) and greater happiness (p=0.004; Cohen d=0.41) than the control group (n=78) immediately after the intervention. However, the effects were not sustained at postnatal follow-up. Subgroup analysis showed that participants with depressive symptoms (EPDS>12) at baseline reported significantly lower stress, greater happiness (p=0.035 and 0.037, respectively; both Cohen d=0.61), greater self-efficacy in managing conflict (p=0.012; Cohen d=0.76) than the control group after the intervention. Also, after delivery, they had significantly greater self-efficacy in managing conflict (p=0.025; Cohen d=0.61) and more able to cooperate with grandparents in childcare (p=0.046; Cohen d=0.59) than the control group. CONCLUSION: The intervention was effective in reducing stress and enhancing happiness among new mothers, particularly those with higher EPDS scores. Postnatal follow-up contacts as booster interventions may be needed to achieve lasting effects of the intervention. PMID- 22818397 TI - Simplifying ART cohort monitoring: can pharmacy stocks provide accurate estimates of patients retained on antiretroviral therapy in Malawi? AB - BACKGROUND: Routine monitoring of patients on antiretroviral therapy (ART) is crucial for measuring program success and accurate drug forecasting. However, compiling data from patient registers to measure retention in ART is labour intensive. To address this challenge, we conducted a pilot study in Malawi to assess whether patient ART retention could be determined using pharmacy records as compared to estimates of retention based on standardized paper- or electronic based cohort reports. METHODS: Twelve ART facilities were included in the study: six used paper-based registers and six used electronic data systems. One ART facility implemented an electronic data system in quarter three and was included as a paper-based system facility in quarter two only. Routine patient retention cohort reports, paper or electronic, were collected from facilities for both quarter two [April-June] and quarter three [July-September], 2010. Pharmacy stock data were also collected from the 12 ART facilities over the same period. Numbers of ART continuation bottles recorded on pharmacy stock cards at the beginning and end of each quarter were documented. These pharmacy data were used to calculate the total bottles dispensed to patients in each quarter with intent to estimate the number of patients retained on ART. Information for time required to determine ART retention was gathered through interviews with clinicians tasked with compiling the data. RESULTS: Among ART clinics with paper-based systems, three of six facilities in quarter two and four of five facilities in quarter three had similar numbers of patients retained on ART comparing cohort reports to pharmacy stock records. In ART clinics with electronic systems, five of six facilities in quarter two and five of seven facilities in quarter three had similar numbers of patients retained on ART when comparing retention numbers from electronically generated cohort reports to pharmacy stock records. Among paper based facilities, an average of 13 4 hours was needed to calculate patient retention for cohort reporting using patient registers as compared to 2.25 hours using pharmacy stock cards. CONCLUSION: The numbers of patients retained on ART as estimated using pharmacy stock records were largely similar to estimates based on either paper registers or electronic data system. Furthermore, less time and staff effort was needed to estimate ART patient retention using pharmacy stock records versus paper-based registers. Reinforcing ARV stock management may improve the precision of estimates. PMID- 22818403 TI - Validity of the Optogait photoelectric system for the assessment of spatiotemporal gait parameters. AB - The purpose of this study was to evaluate the discriminant and concurrent (criterion-related) validity of a recently introduced floor-based photocell system (Optogait, Microgate, Bolzano, Italy) with a validated electronic walkway for the assessment of spatiotemporal gait parameters. Fifteen patients (mean age+/-standard deviation: 65+/-7 years) with total knee arthroplasty and 15 healthy matched control subjects were asked to walk at different velocities while gait variables were recorded simultaneously by the two instruments. The Optogait and the criterion instrument detected the same differences in walking parameters between patients and controls. Intraclass correlation coefficients ranged between 0.933 (swing time) and 0.999 (cycle time, cadence and walking speed). Cycle time and stance time were significantly longer, while swing time, step length, cadence and walking speed were significantly lower for Optogait (p<0.001) compared to the criterion instrument. The Optogait system demonstrated high discriminant and concurrent validity with an electronic walkway for the assessment of spatiotemporal gait parameters in orthopedic patients and healthy controls. However, the two measuring instruments cannot be used interchangeably for quantitative gait analysis, and further validation of floor-based photocell technology is warranted. PMID- 22818402 TI - Pitfalls associated with the therapeutic reference pricing practice of asthma medication. AB - BACKGROUND: Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is a method frequently employed for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in the real world with DDD and to evaluate whether TRP based on DDD could result in cost savings on maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. METHODS: Real-world data were derived from the Hungarian National Health Insurance Fund database. Average doses and costs were compared between the high dose and medium-dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. RESULTS: 27,779 patients with asthma were included in the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. CONCLUSIONS: Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits after exclusion of the effect of generic price erosion. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD does not result in reduced public healthcare spending in Hungary. Further analysis is required to show whether TRP generates additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalisability of our conclusions. PMID- 22818404 TI - Computing motor unit number index of the first dorsal interosseous muscle with two different contraction tasks. AB - Motor unit number index (MUNIX) is a recently developed novel neurophysiological technique providing an index proportional to the number of motor units in a muscle. The MUNIX is derived from maximum M wave and voluntary surface electromyogram (EMG) recordings. The objective of this study was to address a practical question for computing MUNIX in the first dorsal interosseous (FDI), a multifunctional muscle that generates torque about the second metacarpophalangeal joint, i.e., how will different lines of muscle activation influence its MUNIX estimates? To address this question, the MUNIX technique was applied in the FDI muscle of 15 neurologically intact subjects, using surface EMG signals from index finger abduction and flexion, respectively, while the maximum M wave remained the same. Across all subjects, the average MUNIX value of the FDI muscle was 228 +/- 45 for index finger abduction, slightly smaller than the MUNIX estimate of 251 +/ 56 for index finger flexion. Different FDI muscle activation patterns resulted in an approximately 10% difference in MUNIX estimates. The findings from this study suggest that appropriate definition of voluntary activation of the FDI muscle should be kept to ensure consistency in measurements and avoid source of error. The current study is limited by only assessing neurologically intact muscles. It is important to perform a similar analysis for patients with amyotrophic lateral sclerosis (ALS), given that ALS is the primary intention of the MUNIX method as a potential follow-up measurement for motor unit loss. PMID- 22818405 TI - Comparison of different methods of heart rate entropy analysis during acute anoxia superimposed on a chronic rat model of pulmonary hypertension. AB - Acute life-threatening situations are particularly critical when superimposed on chronic diseases. The objective of this study was the assessment of heart rate (HR) dynamics during episodes of acute anoxia superimposed on a rat model of chronic pulmonary hypertension. In 10 adult Wistar rats, five weeks after pulmonary hypertension induction with Monocrotaline, we analysed eight 1-min HR segments, during episodes of baseline, mechanical ventilation and acute anoxia, using linear indices, approximate entropy (ApEn), sample entropy (SampEn) and multiscale entropy (MSE). The transition from baseline or mechanical ventilation to early anoxia was identified through almost all indices, but SampEn(2,0.6) was the index that better identified all the transitions. MSE presented limited performance, possibly due to the non-stationary nature and short duration of the acute anoxia episodes. A systematic evaluation of all computed HR indices may help to identify which indices or combination of indices more adequately discriminates and monitors critical acute events superimposed on chronic clinical conditions. PMID- 22818408 TI - [Claudius Regaud (1870-1940): A pioneer of radiobiology and radiotherapy]. AB - Born in 1870, Claudius Regaud was a pioneer of radiobiology and radiotherapy. As histologist, he developed a new staining technique that allowed him to describe in detail all the reproduction system of a number of animal models. As radiobiologist, he contradicted the interpretations of Tribondeau and Bergonie about relationships between cell proliferation and radiosensitivity. In 1908, he suggested that chromatin was the main target of radiation. As physician, he defined the first bases of anti-cancer radiation treatments and treated patients suffering from incurable cancer from 1911. As military doctor, he organized war hospitals by creating multidisciplinary teams for the surgery of hurts. Organizer, he was one of the founders of the League against Cancer. As radiotherapist and brachytherapist, he contributed to make Institut Curie an international reference center for research and teaching, with nearly a thousand treated patients. As globe-trotter, he was at the origin of the creation of numerous worldwide radiotherapy and radiobiology centers. He died in December 1940 and let an impressive but still misknown scientific heritage. A re-reading of the familial archives and the Regaud Fund of Institut Curie is the occasion to remind the contribution of Regaud. PMID- 22818407 TI - Prostate-specific antigen spikes with 131Cs brachytherapy. Is there a difference with other radioisotopes? AB - PURPOSE: There is a suggestion that a dose-rate effect exists for the prostate specific antigen (PSA) spike after brachytherapy. 131Cs is a newer radioisotope with a half-life of 9.7 days that is being used for prostate brachytherapy. There is no published data on the PSA spike with this radioisotope and the goal of this study was to quantify PSA spikes with 131Cs and compare it with published data for other isotopes. METHODS AND MATERIALS: We have been maintaining a prospective database for all patients treated with 131Cs prostate brachytherapy at our institution. We selected patients for whom followup PSA was available for at least 24 months. The PSA spike was defined as an increase of 0.2 ng/mL, followed by a decline to prespike level. RESULTS: One hundred twenty-three patients had monotherapy, whereas 32 had external beam radiation therapy followed by a brachytherapy boost. Median followup was 36 months and mean numbers of PSAs obtained were 7. Forty-six (29.7%) patients had a PSA spike. The mean time and duration for the PSA spike were 12.5 and 8.8 months, respectively. The mean magnitude of increase and mean PSA value at increase were 0.63 and 1.56 ng/mL, respectively. CONCLUSIONS: The incidence of a PSA spike in our series is consistent with reported numbers for other radioisotopes. The occurrence of the spike at 12.5 months appears to be at the early end of the spectrum reported for (125)I, but the duration and magnitude are similar to other radioisotopes. PMID- 22818406 TI - More Active Mums in Stirling (MAMMiS): a physical activity intervention for postnatal women. Study protocol for a randomized controlled trial. AB - BACKGROUND: Many postnatal women are insufficiently physically active in the year after childbirth and could benefit from interventions to increase activity levels. However, there is limited information about the efficacy, feasibility and acceptability of motivational and behavioral interventions promoting postnatal physical activity in the UK. METHODS: The MAMMiS study is a randomized, controlled trial, conducted within a large National Health Service (NHS) region in Scotland. Up to 76 postnatal women will be recruited to test the impact of two physical activity consultations and a 10-week group pram-walking program on physical activity behavior change. The intervention uses evidence-based motivational and behavioral techniques and will be systematically evaluated using objective measures (accelerometers) at three months, with a maintenance measure taken at a six-month follow-up. Secondary health and well-being measures and psychological mediators of physical activity change are included. DISCUSSION: The (MAMMiS study will provide a test of a theoretical and evidence-based physical activity behavior change intervention for postnatal women and provide information to inform future intervention development and testing within this population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79011784. PMID- 22818409 TI - [Radiotherapy and chaos theory: the tit bird and the butterfly...]. AB - Although the same simple laws govern cancer outcome (cell division repeated again and again), each tumour has a different outcome before as well as after irradiation therapy. The linear-quadratic radiosensitivity model allows an assessment of tumor sensitivity to radiotherapy. This model presents some limitations in clinical practice because it does not take into account the interactions between tumour cells and non-tumoral bystander cells (such as endothelial cells, fibroblasts, immune cells...) that modulate radiosensitivity and tumor growth dynamics. These interactions can lead to non-linear and complex tumor growth which appears to be random but that is not since there is not so many tumors spontaneously regressing. In this paper we propose to develop a deterministic approach for tumour growth dynamics using chaos theory. Various characteristics of cancer dynamics and tumor radiosensitivity can be explained using mathematical models of competing cell species. PMID- 22818410 TI - [Evaluation and management of acute radiation dermatitis]. AB - Acute radiation dermatitis remains one of the most commonly observed side effect during radiation therapy leading to complication such as superinfection or treatment disruption. Its management is characterized by a great heterogeneity. Few strategies have demonstrated a benefit in preventing radiation dermatitis, which relies mostly on decreasing dose delivered to the skin and skin care practices. Simple emollients and use of topical steroids can be useful in early stages. The singularity of the skin toxicity seen with cetuximab and radiotherapy warrants a specific grading system and distinctive clinical treatment with use of antibiotics. PMID- 22818411 TI - Rapid health impact assessment of policies to reduce vehicle miles traveled in Oregon. AB - OBJECTIVE: Health impact assessments (HIAs) enable decisions-makers to assess proposed policies, projects and programmes with respect to their potential health impact. The purpose of this rapid HIA was to inform the debate within a state legislature about the value of state policy and provide information for local planning agencies to better incorporate health considerations into planning activities. STUDY DESIGN: Rapid HIA. METHODS: Literature review was used to evaluate three types of policies to reduce vehicle miles traveled: improving the built environment, increasing the costs of individual driving, and strengthening public transit. RESULTS: Select features of the built environment were found to be associated with increased physical activity, reduced collisions, and decreased air pollution. Increasing the cost of driving was not consistently found to reduce air pollution, increase physical activity, or reduce collisions. Strengthening public transit was associated with increased levels of physical activity. CONCLUSIONS: This rapid HIA provides a framework and focus for future HIAs in this topic area. PMID- 22818412 TI - Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. AB - PURPOSE: Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. METHODS AND MATERIALS: This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fisher's exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. RESULTS: Two hundred seventy individual lesions were treated, with the majority (97%) treated with >= 700 cGy; mean follow-up was 41.3 months (range, 3 180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sezary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. CONCLUSIONS: A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient. PMID- 22818413 TI - Cardiac-sparing whole lung IMRT in children with lung metastasis. AB - PURPOSE: To demonstrate the dosimetric advantages of cardiac-sparing (CS) intensity modulated radiation therapy (IMRT) in children undergoing whole lung irradiation (WLI). METHODS AND MATERIALS: Chest CT scans of 22 children who underwent simulation with 3-dimensional (n=10) or 4-dimensional (n=12) techniques were used for this study. Treatment planning was performed using standard anteroposterior-posteroanterior (S-RT) technique and CS-IMRT. Left and right flank fields were added to WLI fields to determine whether CS-IMRT offered any added protection to normal tissues at the junction between these fields. The radiation dose to the lung PTV, cardiac structures, liver, and thyroid were analyzed and compared. RESULTS: CS-IMRT had 4 significant advantages over S-RT: (1) superior cardiac protection (2) superior 4-dimensional lung planning target volume coverage, (3) superior dose uniformity in the lungs with fewer hot spots, and (4) significantly lower dose to the heart when flank RT is administered after WLI. CONCLUSIONS: The use of CS-IMRT and 4-dimensional treatment planning has the potential to improve tumor control rates and reduce cardiac toxicity in children receiving WLI. PMID- 22818414 TI - Comparison of the effects of high-energy photon beam irradiation (10 and 18 MV) on 2 types of implantable cardioverter-defibrillators. AB - PURPOSE: Radiation therapy for cancer may be required for patients with implantable cardiac devices. However, the influence of secondary neutrons or scattered irradiation from high-energy photons (>=10 MV) on implantable cardioverter-defibrillators (ICDs) is unclear. This study was performed to examine this issue in 2 ICD models. METHODS AND MATERIALS: ICDs were positioned around a water phantom under conditions simulating clinical radiation therapy. The ICDs were not irradiated directly. A control ICD was positioned 140 cm from the irradiation isocenter. Fractional irradiation was performed with 18-MV and 10 MV photon beams to give cumulative in-field doses of 600 Gy and 1600 Gy, respectively. Errors were checked after each fraction. Soft errors were defined as severe (change to safety back-up mode), moderate (memory interference, no changes in device parameters), and minor (slight memory change, undetectable by computer). RESULTS: Hard errors were not observed. For the older ICD model, the incidences of severe, moderate, and minor soft errors at 18 MV were 0.75, 0.5, and 0.83/50 Gy at the isocenter. The corresponding data for 10 MV were 0.094, 0.063, and 0 /50 Gy. For the newer ICD model at 18 MV, these data were 0.083, 2.3, and 5.8 /50 Gy. Moderate and minor errors occurred at 18 MV in control ICDs placed 140 cm from the isocenter. The error incidences were 0, 1, and 0 /600 Gy at the isocenter for the newer model, and 0, 1, and 6 /600Gy for the older model. At 10 MV, no errors occurred in control ICDs. CONCLUSIONS: ICD errors occurred more frequently at 18 MV irradiation, which suggests that the errors were mainly caused by secondary neutrons. Soft errors of ICDs were observed with high energy photon beams, but most were not critical in the newer model. These errors may occur even when the device is far from the irradiation field. PMID- 22818415 TI - Factors affecting the risk of brain metastasis in small cell lung cancer with surgery: is prophylactic cranial irradiation necessary for stage I-III disease? AB - PURPOSE: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. METHODS AND MATERIALS: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. RESULTS: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. CONCLUSIONS: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease. PMID- 22818416 TI - A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer. AB - PURPOSE: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). METHODS AND MATERIALS: We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. RESULTS: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. CONCLUSION: The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA. PMID- 22818417 TI - Is there an advantage in designing adapted, patient-specific PTV margins in intensity modulated proton beam therapy for prostate cancer? AB - PURPOSE: To investigate robust margin strategies in intensity modulated proton therapy to account for interfractional organ motion in prostate cancer. METHODS AND MATERIALS: For 9 patients, one planning computed tomography (CT) scan and daily and weekly cone beam CTs (CBCTs) were acquired and coregistered. The following planning target volume (PTV) approaches were investigated: a clinical target volume (CTV) delineated on the planning CT (CTV(ct)) plus 10-mm margin (PTV(10mm)); a reduced PTV (PTV(Red)): CTV(ct) plus 5 mm in the left-right (LR) and anterior-posterior (AP) directions and 8 mm in the inferior-superior (IS) directions; and a PTV(Hull) method: the sum of CTV(ct) and CTVs from 5 CBCTs from the first week plus 3 mm in the LR and IS directions and 5 mm in the AP direction. For each approach, separate plans were calculated using a spot scanning technique with 2 lateral fields. RESULTS: Each approach achieved excellent target coverage. Differences were observed in volume receiving 98% of the prescribed dose (V(98%)) where PTV(Hull) and PTV(Red) results were superior to the PTV(10mm) concept. The PTV(Hull) approach was more robust to organ motion. The V(98%) for CTVs was 99.7%, whereas for PTV(Red) and PTV(10mm) plans, V(98%) was 98% and 96.1%, respectively. Doses to organs at risk were higher for PTV(Hull) and PTV(10mm) plans than for PTV(Red), but only differences between PTV(10mm) and PTV(Red) were significant. CONCLUSIONS: In terms of organ sparing, the PTV(10mm) method was inferior but not significantly different from the PTV(Red) and PTV(Hull) approaches. PTV(Hull) was most insensitive to target motion. PMID- 22818418 TI - Metabolic response of lymph nodes immediately after RT is related with survival outcome of patients with pelvic node-positive cervical cancer using consecutive [18F]fluorodeoxyglucose-positron emission tomography/computed tomography. AB - PURPOSE: To evaluate the metabolic response of uterine cervix and pelvic lymph nodes (LNs) using consecutive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) immediately after RT and to correlate survival outcome with the metabolic response. METHODS AND MATERIALS: We retrospectively reviewed 48 patients with cervical cancer who had positive pelvic LNs by preradiation therapy (pre-RT) PET/CT. All patients underwent PET/CT scans immediately after RT (inter-RT PET/CT) after median 63 Gy to the gross LNs. The metabolic response of the LNs was assessed quantitatively and semiquantitatively by measurement of the maximal standardized uptake value (SUVmax). RESULTS: Classifying the metabolic response of all nodal lesions, 37 patients (77%) had LNs with complete metabolic response on the inter-RT PET/CT (LNCMRi), and 11 patients had a non-LNCMRi, including 4 patients with progressive metabolic disease. The overall 3-year survival rates were 83% for the patients with LNCMRi and 73% for the non-LNCMRi group (P=.038). The disease-free survival for patients with LNCMRi were significantly better than that for the non-LNCMRi group (71% vs 18%, respectively, P<.001). The 3-year distant metastasis-free survival rates were 79% for the patients with LNCMRi and 27% for the non-LNCMRi group (P<.001). There were no statistically significant differences in overall survival (76% vs 86%, respectively, P=.954) and disease-free survival rates (58% vs 61%, respectively, P=.818) between the CMR of primary cervical tumor and the non-CMR groups. CONCLUSIONS: The results showed a significant correlation between survival outcome and the interim metabolic response of pelvic LNs. CMR of nodal lesion on inter-RT PET/CT had excellent overall survival, disease-free survival and distant metastasis-free survival rates. This suggested that PET/CT immediately after RT can be a useful tool for the evaluation of the interim response of the LNs and identify a subset of patients with a high risk of recurrence and poor survival in patients with cervical cancer with initial positive LNs. PMID- 22818425 TI - Paralytic congenital talipes equinovarus of unknown origin: A new entity. Multicenter study of 42 cases. AB - BACKGROUND: Paralysis of the lateral and/or anterior leg muscles can lead to relapse of treated talipes equinovarus. HYPOTHESIS: The muscle function impairment is due to isolated permanent paralysis, and early palliative tendon transfer may prevent recurrence of the deformity. MATERIAL AND METHODS: Forty-two cases of congenital talipes equinovarus that recurred after conservative therapy were reviewed after a mean follow-up of 10 years. In 39 cases, second-line surgery was performed (posteromedial release, n=33; and muscle transfer, n=26). Outcomes were evaluated clinically. RESULTS: Separating the cases into two groups, based on whether muscle transfer was performed, showed a statistically significant difference: muscle transfer intended to restore eversion and/or dorsal flexion of the foot was associated with significantly better functional outcomes. DISCUSSION: In addition to providing etiological insights, the identification of paralysis in patients with talipes equinovarus can influence treatment decisions, depending on the nature of the muscle deficiencies, with the goal of preventing recurrences. Early muscle transfer to restore eversion and/or dorsal flexion of the foot may provide the best functional outcomes by minimizing the need for soft-tissue release. LEVEL OF EVIDENCE: IV, retrospective multicentre study. PMID- 22818424 TI - Epidemiology and clonality of carbapenem-resistant Acinetobacter baumannii from an intensive care unit in Palermo, Italy. AB - BACKGROUND: Multidrug-resistant Acinetobacter baumannii, initially considered as having a poor clinical relevance, is frequently isolated from infection cases in intensive care units. We describe the epidemiology of carbapenem resistant A. baumannii (CRAB) in a general ICU in Palermo, Italy, from October 2010 to March 2011. FINDINGS: 58 of 61 isolates exhibited MICs for meropenem or imipenem >=16 mg/L. Forty-nine carried blaOXA-23 and two blaOXA-58 genes.Five subtype clusters were detected by rep-PCR. Clusters D and E included 10 isolates that tested negative for the carbapenem resistance genes. MLST attributed all isolates, but two, with sequence type (ST)2, whereas the two remaining isolates with ST78.The respiratory tract was the most common site of infection (26 out of 36 cases. 72.2%). A high infection related mortality rate was observed (18 out of 35 patients, 51.4%). Nineteen patients tested positive for other multidrug resistant organisms in addition to CRAB. In eight cases isolates belonging to distinct subtype clusters and/or with distinct carbapenemase profiles were identified. CONCLUSIONS: Carbapenem resistance was prominently driven by the dissemination of CRAB isolates belonging to ST2, carrying the carbapenemase gene blaOXA-23. The colonization/infection of some patients by multiple strains is suggestive of an endemic circulation of CRAB. PMID- 22818426 TI - Trefoil factor family protein 3 (TFF3) is present in cartilage during endochondral ossification in the developing mouse fetus. AB - Trefoil factor family protein 3 (TFF3) is found in cartilage affected by osteoarthritis and septic arthritis, whereas no TFF3 presence is observed in healthy cartilage. During endochondral ossification, bone tissue replaces degenerating cartilage. There is no data about the role of TFF3 in this process. Our aim was to study the localization of TFF3 in cartilage during endochondral ossification in the mouse fetus. CD1 mouse fetuses, days 14-17, were isolated, fixed, and paraffin embedded. Fetuses were cut into 6MUm sections, and processed for immunohistochemical staining with affinity purified polyclonal rabbit anti TFF3 antibody. TFF3 was present in cartilage chondrocytes undergoing endochondral ossification, particularly in zone of proliferation, hypertrophy and calcification as well as in zone of cartilage degeneration during the monitored fetal period. Resting cartilage showed no presence of TFF3, while during endochondral ossification TFF3 localization showed an analogous pattern to that reported in cartilage affected by osteoarthritis and septic arthritis. Our data indicate that the role of TFF3 in these pathological conditions is similar to its role in the physiological process of endochondral ossification. PMID- 22818429 TI - PD plus error-dependent integral nonlinear controllers for robot manipulators with an uncertain Jacobian matrix. AB - In framework of traditional PID controllers, there are only three parameters available to tune, as a result, performance of the resulting system is always limited. As for Cartesian regulation of robot manipulators with uncertain Jacobian matrix, a scheme of PID controllers with error-dependent integral action is proposed. Compare with traditional PID controllers, the error-dependent integration is employed in the proposed PID controller, in which more parameters are available to be tuned. It provides additional flexibility for controller characteristics and tuning as well, and hence makes better transient performance. In addition, asymptotic stability of the resulting closed-loop system is guaranteed. All signals in the system are bounded when exogenous disturbances and measurement noises are bounded. Numerical example demonstrates the superior transient performance of the proposed controller over the traditional one via Cartesian space set-point manipulation of two-link robotic manipulator. PMID- 22818430 TI - Letter to the editor: Comments on Schwaiger et al. (2012). PMID- 22818432 TI - Granulomorphometry: a suitable tool for identifying hydrophobic and disulfide bonds in beta-lactoglobulin aggregates. Application to the study of beta lactoglobulin aggregation mechanism between 70 and 95 degrees C. AB - This work deals with the investigation of beta-lactoglobulin (beta-LG) aggregation by granulomorphometry. In the first part of this study, we showed that the binding interactions involved in aggregate structure could be identified by their appearance in granulomorphometric pictures. The reliability of this analytical approach was demonstrated by comparing the appearance of beta-LG aggregates in the presence and absence of a thiol-blocking agent (N ethylmaleimide). The translucency of the aggregates was associated with hydrophobic interactions and their opacity was associated with disulfide bonds. We state, based on the morphology of the aggregates, along with the color of protein aggregates and insoluble materials, that hydrophobic interactions had a better water-holding capacity than disulfide bonds. Additionally, our results suggest that disulfide and hydrophobic bonds compete for beta-LG aggregate shaping. In the second part of this work, interesting features of granulomorphometry useful for identifying aggregate binding interactions were highlighted to clarify the effect of temperature on the aggregation mechanisms occurring in a beta-LG concentrate with a moderate calcium content (6.6mmol.L( 1)). Heat treatment experiments were performed between 70 and 95 degrees C, and granulomorphometric measurements (aggregate size, aggregate number, and gray level of the picture) were conducted at different sampling times up to 4h. Results, which were interpreted in light of calculated beta-LG denaturation levels, revealed that the aggregation mechanism could be split into 2 steps. Initially, beta-LG denatured quickly, leading to fast beta-LG aggregation by disulfide bonds. The denaturation rate then declined, which drastically slowed the disulfide aggregation mechanism. From that point on, a second aggregation path became preponderant. It consisted of the agglomeration of small aggregates by hydrophobic interactions and resulted in the formation of large aggregates containing both interaction types. This second aggregation mechanism was clearly favored at high temperatures because it was not detected in our experiments at temperatures below 85 degrees C. PMID- 22818433 TI - Consumer acceptance and sensory evaluation of Monti Dauni Meridionali Caciocavallo cheese. AB - Twelve Caciocavallo cheeses were collected from 6 factories (A, B, C, D, E, F) located in the Monti Dauni Meridionali area (Southern Italy) that adopted different protocols for cheese production. A total of 160 consumers were involved in the sensory evaluation of Caciocavallo cheese after 180 d of ripening. Cheese attributes were used to describe the flavor, texture, and appearance of cheeses. The highest scores for the shiny attribute were assigned to cheeses B, C, and E, whereas color intensity was the highest in cheeses B, D, and F. Strength, salty, and piquant attributes were higher in cheeses F and A because of the use of raw milk (F), rennet paste (A), and percentage of salt in the brine (A, F). Consumers perceived a more granular structure during the second half of chewing of Caciocavallo cheese F, as evidenced by the highest value for the grainy attribute. A positive correlation was found between overall flavor and odor intensity and water-soluble nitrogen, low molecular weight peptides, and free fatty acids and between piquant and butyric and caproic acids. A principal components analysis applied to the sensory attributes accounted for 65% of the total variance. The score plot showed that cheeses F and A were located in a well defined zone of the plot, with cheeses in this zone displaying higher levels of strength, piquant, and salty attributes. The preference test assigned 40% of the preference to Caciocavallo cheese A, 38% to cheese F, 9% to cheese E, 8% to cheese D, and 7% to cheeses B and C. Sensory evaluation of Monti Dauni Meridionali Caciocavallo cheeses is a useful analysis to highlight the principal attributes able to influence consumers' liking that are related to biochemical features of the cheese. PMID- 22818434 TI - Incorporation of Lactobacillus casei in Iranian ultrafiltered Feta cheese made by partial replacement of NaCl with KCl. AB - Probiotic Iranian ultrafiltered Feta cheese was produced from ultrafiltration of milk with a volumetric concentration factor of 4.5:1. The heat-treated retentates were inoculated with 10(7) cfu of Lactobacillus casei LAFTI L26/mL. A mesophilic thermophilic mixed culture of Lactococcus lactis ssp. lactis, Lactococcus lactis ssp. cremoris, and Streptococcus thermophilus was also used. Three percent (wt/wt) salt with different ratios of NaCl:KCl (100% NaCl, 50% NaCl:50% KCl, 75% NaCl:25% KCl, and 25% NaCl:75% KCl) were used in cheese formulation. The viability of L. casei was determined in treatments during the ripening period (90d at 5 degrees C) within 15-d intervals. The pH, titratable acidity, and redox potential changes were monitored throughout the mentioned period. The mean pH drop rate, mean acidity increase rate, and mean redox potential increase rate were calculated at the end of the storage period. Also, total nitrogen, water soluble nitrogen, lactic acid, and acetic acid concentrations, and syneresis and sensory characteristics of the product were measured during the mentioned period every 30d. The maximum viability of L. casei was observed within d 15 to 30 of the ripening period in the treatment containing the lowest amount of sodium. Addition of KCl enhanced syneresis. Cheeses with NaCl alone and with only 25% replacement by KCl have the highest sensory acceptability. PMID- 22818435 TI - Effect of parity, days in milk, and milk yield on detailed milk protein composition in Mediterranean water buffalo. AB - The effects of some nongenetic factors on milk protein fraction contents and relative proportions were estimated in 606 individual milk samples of Mediterranean water buffalo. Content of alpha(S1)-casein (CN), alpha(S2)-CN, beta CN, gamma-CN, kappakappa-CN, glycosylated kappa-CN (glyco-kappa-CN), alpha lactalbumin, and beta-lactoglobulin was measured by reversed-phase HPLC. Relative contents of alpha(S1)-CN%, alpha(S2)-CN%, beta-CN%, and kappa-CN% were, respectively, 32.1, 17.1, 34.5, and 15.7%, whereas gamma-CN% accounted for 0.6% of total casein content. Increasing total casein content in milk would result in a greater proportion of beta-CN% at the expense of all of the other major casein fractions, especially of kappa-CN%. Values of alpha(S2)-CN%, beta-CN%, and gamma CN% tended to decrease with parity, although their variations were not significant, whereas alpha(S1)-CN% and glyco-kappa-CN% showed the opposite trend. Contents of most protein fractions showed the typical trends observed for milk components as lactation progressed, with high contents in early lactation, a minimum in midlactation, followed by a gradual increase toward the latter part of lactation. Values of alpha(S1)-CN% increased during lactation, whereas alpha(S2) CN% decreased. The proportion of beta-CN% had its maximum value between 60 and 160 d of lactation, followed by a decrease, whereas kappa-CN% had its minimum value in early lactation (<60 d) and remained relatively constant in the period of mid and late lactation. Glyco-kappa-CN% and beta-lactoglobulin% decreased in the first part of lactation, to reach their minimum values in midlactation, followed by an increase. Milk of top-producing buffaloes, compared with that of low-producing ones, had a significantly greater value of beta-CN% and glyco-kappa CN%, and lower proportion of alpha(S1)-CN%. The possible effect exerted by protein genetic variants in affecting variation of milk protein fraction contents and relative proportions should be further considered to better get insight into buffalo milk protein composition. PMID- 22818436 TI - Preparation and characterization of beta-lactoglobulin hydrolysate-iron complexes. AB - The purpose of this study was to determine the best preparation condition of beta lactoglobulin hydrolysate-iron complexes and characterize its structural transformation both before and after binding using the UV-visible absorption spectrum, Fluorescence spectrum, and Fourier transform infrared spectroscopy. Results showed that beta-lactoglobulin hydrolysates obtained with alcalase after hydrolysis for 6h possessed the highest iron-binding capacity. The highest yield of complexes was obtained when the mass ratio between beta-lactoglobulin hydrolysate and Fe(3+) reached 40:1, with the optimal pH value of 7.0. All of the spectra indicated that some sites such as amido bonds transformed during chelation, and nitrogen atoms could chelate with Fe(3+) to form coordinate bonds by offering electron pairs. Therefore, beta-lactoglobulin hydrolysate-iron complexes may be good carriers for iron and possess great potential to be used as iron supplements. PMID- 22818437 TI - Aggregation and conformational changes of bovine beta-lactoglobulin subjected to dynamic high-pressure microfluidization in relation to antigenicity. AB - Our previous research indicated that dynamic high-pressure microfluidization (DHPM) had a significant effect on the antigenicity of beta-lactoglobulin (beta LG). In this study, aggregation and conformational changes subjected to DHPM (0.1 160 MPa) were investigated in relation to antigenicity. When DHPM pressure increased from 0.1 to 80 MPa, disaggregation of beta-LG samples and partial unfolding of the molecule were accompanied by an increase in beta-LG antigenicity, which was reflected in the decrease of particle size, increase of free sulfhydryl (SH) contents and beta-strands contents, and slight exposure of aromatic amino acid residues. At pressures above 80 MPa, the reaggregation of beta-LG may contribute to the decrease in antigenicity, which was reflected by an increase in particle size, the formation of aggregates, a decrease of in SH and beta-strands contents, and slight changes in aromatic amino acid residues. Aggregation and conformational changes of beta-LG under DHPM was related to its antigenicity. PMID- 22818438 TI - Active compounds and distinctive sensory features provided by American ginseng (Panax quinquefolius L.) extract in a new functional milk beverage. AB - American ginseng (Panax quinquefolius L.) has recognized neurocognitive effects, and a ginsenoside-rich extract of the root of the plant has been shown to improve cognitive functions in young adults. This study aimed at assessing the chemical and sensory profiles of a UHT-treated, low-lactose functional milk containing American ginseng. Individual ginsenosides in the milk were analyzed by HPLC. Descriptive sensory analysis was performed by a trained panel to quantitatively document sensory changes resulting from the addition of ginseng and the UHT process on flavored and unflavored milks. Consumer acceptance of the product was also investigated. Total ginsenoside content in the UHT-treated milk enriched with the ginseng extract after UHT process treatment was 7.52 mg/100 g of milk, corresponding to a recovery of 67.6% compared with the content in the unprocessed extract. The intake of 150 to 300 mL of this ginseng-enriched milk provides the amount of total ginsenosides (11.5 to 23 mg) necessary to improve cognitive function after its consumption. Both the presence of ginsenosides and their thermal treatment affected some sensory properties of the milk, most notably an increase in bitterness and metallic taste, the appearance of a brownish color, and a decrease in milky flavor. Levels of brown color, bitterness, and metallic taste were highest in the industrially processed ginseng-enriched milk. The bitterness attributable to ginseng extract was reduced by addition of vanilla flavor and sucralose. A consumer exploratory study revealed that a niche of consumers exists who are willing to consume this type of product. PMID- 22818439 TI - Effect of addition of CO2 to raw milk on quality of UHT-treated milk. AB - The objective of this study was to evaluate the effect of addition of CO(2) to raw milk on UHT milk quality during storage. Control milk (without CO(2) addition) and treated milk (with CO(2) addition up to pH 6.2) were stored in bulk tanks at 4 degrees C for 6d. After storage, both samples were UHT processed using indirect heating (140 degrees C for 5s). Samples were aseptically packed in low density polyethylene pouches and stored in the dark at room temperature. Raw milk was evaluated upon receipt for physicochemical composition, proteolysis, lipolysis, standard plate count, psychrotrophic bacteria, and Pseudomonas spp. counts, and after 6d of storage for proteolysis, lipolysis, and microbial counts. After processing, UHT milk samples were evaluated for physicochemical composition, proteolysis, and lipolysis. Samples were evaluated for proteolysis and lipolysis twice a month until 120d. Peptides from pH 4.6-soluble N filtrates were performed by reversed-phase HPLC after 1 and 120d of storage. A split-plot design was used and the complete experiment was carried out in triplicate. The results were evaluated by ANOVA and Tukey's test. After 6d of storage, CO(2) treated raw milk kept its physicochemical and microbiological quality, whereas the untreated milk showed significant quality losses. A significant increase in proteolysis occurred during 120d of storage in both treatments, but the increase occurred 1.4 times faster in untreated UHT milk than in CO(2)-treated UHT milk. In both UHT milks, the proteolysis was a consequence of the action of plasmin and microbial proteases. However, the untreated UHT milk showed higher microbial protease activity than the treated UHT milk. The addition of CO(2) to the raw milk maintained the quality during storage, resulting in UHT milk with less proteolysis and possibly longer shelf life, which is usually limited by age gelation of UHT milk. PMID- 22818440 TI - Chemical, microbiological, textural, color, and sensory characteristics of pressed ewe milk cheeses with saffron (Crocus sativus L.) during ripening. AB - Adding saffron to dairy products represents an innovative practice to introduce them to niche markets. This paper represents a contribution to this field, as few studies have evaluated the influence of this spice on general aspects and ripening parameters of cheese. In this work, pasteurized ewe milk pressed cheeses with saffron were made to study compositional, microbiological, color, textural, and sensory characteristics in relation to saffron concentration and ripening time. The main changes were observed on sensory characteristics and color. In addition, compositional, textural, and microbiological changes could be observed; among them, saffron cheeses were firmer and more elastic but less prone to fracture. A remarkable result that could lead to further studies is that saffron addition slightly slowed down growth of total and lactic acid bacteria. This resulted in a slightly lower rate of pH decrease during pressing and, as a consequence, lower salt and water content. Compositional differences were not evident by the end of the ripening period. PMID- 22818441 TI - Short communication: Evaluation of bulk tank milk microbiological quality of nine dairy farms in Tennessee. AB - The purpose of this study was to evaluate the bulk tank milk (BTM) quality of 9 East Tennessee dairy farms and to determine its relationship with selected quality milk parameters. Bulk tank milk samples (n=1,141) were collected over a 42-mo period (June 2006 through November 2009) from farms, based on their preliminary incubation count (PIC) history. Parameters of BTM quality evaluated in this study included somatic cell count (SCC), standard plate count (SPC), PIC, laboratory pasteurization count (LPC), Staphylococcus spp. count, Streptococcus spp. count, and coliform count. Strong correlations between SPC and Streptococcus spp. counts (0.72) and between SPC and PIC (0.70) were found. However, moderate correlations were seen among other milk quality parameters. In addition, seasonal variations for some milk quality parameters were noted. For example, milk quality parameters such as SCC, SPC, LPC, and coliform count were significantly higher in summer, whereas Streptococcus spp. counts were significantly higher in winter. No seasonal variation in PIC or Staphylococcus spp. counts was observed. Summarizing, results from this investigation showed the importance of using several bacterial counts (SCC, SPC, PIC, LPC, Streptococcus spp. count, Staphylococcus spp. count, and coliform counts) as simultaneous indicators of milk quality. PMID- 22818442 TI - Short communication: Production of antihypertensive peptide HLPLP by enzymatic hydrolysis: optimization by response surface methodology. AB - This study evaluates the potential ability of proteolytic enzymes to release the antihypertensive peptide HLPLP, beta-casein f(134-138), from caseinate. Corolase PP (Rohm GmbH & Co. KG, Darmstadt, Germany) was found as the most appropriate enzyme to produce this peptide. The optimization of the main experimental variables involved in the process [concentration of Corolase PP, concentration of Peptidase 433P (Biocatalysts Ltd., Parc Nantgarw, UK), and the hydrolysis time on the HLPLP concentration, expressed as area of peak] were studied using a central composite face design. The optimum conditions to obtain the maximum concentration of HLPLP provided by the statistical program were a concentration of Corolase PP of 60 mg/g of protein and hydrolysis time of 24h. The use of the Peptidase 433P did not increase the amount of the active peptide. The obtained hydrolysate might be used as functional ingredient with antihypertensive properties. PMID- 22818443 TI - Conjugated linoleic acid synthesis-related protein proteasome subunit alpha 5 (PSMA5) is increased by vaccenic acid treatment in goat mammary tissue. AB - This study was conducted to identify proteins associated with the endogenous synthesis of conjugated linoleic acid (CLA) from trans-vaccenic acid (TVA; trans 11 C18:1, a precursor for CLA endogenous synthesis) in mammary tissues. Six lactating goats were divided into 2 groups. One group was given an intravenous bolus injection of TVA (150mg) twice daily over 4 d; the other group received saline injections. Treatment with TVA increased the concentration of cis-9,trans 11 CLA and TVA in goat milk. Additionally, TVA treatment increased the expression of stearoyl-CoA desaturase (SCD) in mammary tissue. Using 2-dimensional gel electrophoresis and electrospray ionization quadrupole time-of-flight mass spectrometry, 3 proteins affected by infusions of TVA were identified. Proteasome (prosome, macropain) subunit alpha type 5 (PSMA5) was upregulated, whereas peroxiredoxin-1 and translationally controlled tumor protein 1 were downregulated in TVA-treated animals compared with the vehicle-injected controls. Only the effect of TVA on PSMA5 could be confirmed by Western blot analysis. To further explore the regulation of PSMA5 in mammary epithelial cells when TVA is converted into CLA, we used a differentiated bovine mammary epithelial cell line treated with TVA for 6h. Changes in cis-9,trans-11 CLA concentrations and mRNA expression patterns of both SCD and PSMA5 were monitored. The concentration of cis-9,trans 11 CLA increased after TVA treatment. The mRNA expression level of PSMA5 was significantly elevated to 6h, but SCD mRNA expression only increased in 2h after TVA treatment. These results indicate that PSMA5 is highly expressed in goat mammary tissue and bovine mammary epithelial cells when TVA is converted into CLA. Our data suggest that PSMA5 protein is associated with CLA biosynthesis in mammary tissue. PMID- 22818444 TI - Short-term increases in stocking density affect the lying and social behavior, but not the productivity, of lactating Holstein dairy cows. AB - Reduced access to resources because of increased stocking density may have a detrimental effect on the behavior of the lactating dairy cow. The objective of this study was to determine the short-term responses in behavior, productivity, fecal cortisol metabolites, and udder and leg hygiene of lactating Holstein dairy cows housed at stocking densities of 100 (1 cow per freestall and headlock), 113, 131, and 142%. Multiparous cows (n=92) and primiparous cows (n=44) were assigned to 1 of 4 pens (34 cows per pen) in a 4-row freestall barn. Pens were balanced for parity, milk production, and days in milk. Stocking densities were imposed for 14 d using a 4 * 4 Latin square design. Time spent feeding and time spent ruminating were quantified by 24 h of direct observation of focal cows (n=12 per pen) beginning at 0800 h on d 11 of each period. Data loggers recorded lying behavior (time and bouts) from the same focal cows per pen at 1-min intervals during the final 5 d of each period. Fecal cortisol metabolites were quantified from samples collected on d 13 and 14 of each period from the same focal cows. Displacements from the feed barrier were recorded on a pen basis after 9 milkings over the last 4 d of each period. Productivity was assessed on a pen basis from milk yield (recorded from d 10 to 14 of each period) and milk components (quantified from composite samples collected on d 12 of each period). Milk composition was further analyzed for milk fatty acid profiles, which were determined from a subset (n=6 per pen) of the focal cows. Data were analyzed using the MIXED procedure of SAS, with the pen (n=4 per treatment, except displacements where n=3 per treatment) as the experimental unit. Feeding and ruminating (h/d) did not differ among treatments. Lying time was reduced at stocking densities of 131 and 142%, relative to 100 or 113%. Lying bouts were not affected by treatment. Stocking densities of 131 and 142% reduced the percentage of time cows spent ruminating within a freestall relative to 100%. Displacements from the feed bunk increased linearly across treatments. Fecal cortisol metabolites, udder hygiene score, milk yields, milk composition, and milk fatty acids did not differ among treatments. Decreased lying time and increased aggression at the feed bunk suggest that an alteration of the time budgets of lactating dairy cows may occur at higher stocking densities, but it is unclear at what point these changes might have further biological consequences. PMID- 22818445 TI - Validation of the Finnish national dairy disease register--data transfer from cow health cards to the disease register. AB - Information on diseases of dairy cows in Finland is entered into the national disease register. Before the data from such types of secondary database are used, the quality of the data needs to be validated. In this study, 7,324 veterinary records for culled cows were compared against records in the national disease register in the period 2002 to 2008. Evaluation of the national disease register data was done by calculating completeness and correctness values. Completeness is the proportion of events that were physically recorded in the secondary database, and correctness is the proportion of correctly recorded events of all recorded events. The use of both correctness and completeness is important when describing the accuracy of secondary data. The completeness and correctness values for the Finnish national dairy disease register were 83 and 92%, respectively. We found that 39% of all unmatched diagnostic events were unreported by the artificial insemination technician who transferred the data from cow cards to the register. Logistic regression models showed that diagnostic events for cows born into the herd had twice the odds of being transferred compared with events for purchased cows. Diagnostic events for reproductive diseases had higher odds of being transferred to the register compared with all other disease groups, and the odds for transfer of the diagnostic event decreased as the age increased. We also found that if the diagnostic event was the last diagnostic event on the cow card, then its odds of being transferred to the disease register were significantly lowered. Although the Finnish national dairy disease register has good completeness and excellent correctness values, different disease groups, age groups, origin of the cow, and timing of the diagnostic event affect how well diagnostic events are transferred to the Finnish national dairy register. PMID- 22818446 TI - Antimicrobial resistance profiles of common mastitis pathogens on Canadian dairy farms. AB - Monitoring of antimicrobial resistance (AMR) in bacteria has clinical and public health significance. The present study determined prevalence of AMR in common mastitis pathogens Staphylococcus aureus, including methicillin-resistant Staph. aureus (MRSA; n=1,810), Escherichia coli (n=394), and Klebsiella species (n=139), including extended-spectrum beta-lactamase (ESBL)-producing E. coli and Klebsiella species, isolated from milk samples on 89 dairy farms in 6 Canadian provinces. Minimum inhibitory concentrations (MIC) were determined using the Sensititer bovine mastitis plate (Trek Diagnostic Systems Inc., Cleveland, OH) and a National Antimicrobial Resistance Monitoring System gram-negative panel containing antimicrobials commonly used for mastitis treatment and control. Denim blue chromogenic agar and real-time PCR were used to screen and confirm MRSA, respectively. Resistance proportion estimates ranged from 0% for cephalothin and oxacillin to 8.8% for penicillin in Staph. aureus isolates, and 15% of the resistant Staph. aureus isolates were multidrug resistant. One MRSA isolate was confirmed (prevalence: 0.05%). Resistance proportion estimates ranged from 0% for ceftriaxone and ciprofloxacin to 14.8% for tetracycline in E. coli, and 0% for amikacin, ceftiofur, ciprofloxacin, and nalidixic acid to 18.6% for tetracycline in Klebsiella species isolates. Further, 62.8 and 55% of the resistant E. coli and Klebsiella species isolates were multidrug resistant, respectively. Resistance to >5 and >2 antimicrobials was most common in E. coli and Klebsiella species isolates, respectively, and no ESBL producers were found. Prevalence of AMR in bovine mastitis pathogens was low. Most gram-negative udder pathogens were multidrug resistant; MRSA was rarely found, and ESBL E. coli and Klebsiella species isolates were absent in Canadian milk samples. PMID- 22818447 TI - Overfeeding a moderate energy diet prepartum does not impair bovine subcutaneous adipose tissue insulin signal transduction and induces marked changes in peripartal gene network expression. AB - Mechanisms regulating subcutaneous adipose tissue (SAT) insulin sensitivity and gene network expression during the peripartal period were evaluated in cows fed to meet or exceed prepartal energy requirements. Holstein cows were dried off at 50 d relative to expected parturition and fed a controlled-energy diet [CON; net energy for lactation=1.24 Mcal/kg of dry matter (DM); 36% of DM as wheat straw] until -21 d. Cows were then randomly assigned (n=7/diet) to either the same CON diet or a moderate-energy close-up diet (OVE; net energy for lactation=1.47 Mcal/kg of DM) until parturition. Biopsies of SAT were harvested at -10, 7, and 21 d for mRNA expression of 48 genes associated with insulin signaling, adipogenesis, and lipolysis. In vitro basal and insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation (IRS1-PY) was assessed at -10 and 7 d. The OVE led to more positive energy balance and greater serum insulin concentration prepartum. Compared with CON, OVE led to a more drastic increase in serum NEFA and also greater overall serum BHBA postcalving, both of which were associated with greater hepatic total lipid and triacylglycerol concentration. Close-up OVE did not improve any aspect of performance. In prepartal SAT, insulin stimulated IRS1-PY was greater in OVE than in CON. However, IRS1-PY, serum insulin, and GLUT4 expression decreased postpartum regardless of prepartal treatment, suggesting a more severe state of insulin resistance. The expression of all genes encoding adipogenic regulators (PPARG and ZFP423), most lipogenic enzymes/inducers (FASN, SCD, DGAT2, and INSIG1), and basal-lipolysis regulators (ATGL and ABDH5) was greater at -10 d in OVE than in CON. Whereas adipogenic and basal lipolysis regulator expression remained greater in cows fed OVE by 7 d postpartum, expression of all lipogenic enzymes decreased regardless of diet. Despite those responses, the approximately 3-fold increase in expression of IRS1 and ZFP423 between 7 and 21 d suggested that insulin responsiveness and adipogenic capacity of SAT were partially restored. Expression of the preadipocyte marker DLK1, adiponutrin (PNPLA3), and fibroblast growth factor 21 (FGF21) was undetectable. Results suggested that close-up energy overfeeding did not exacerbate insulin resistance in SAT. Signs of restored insulin responsiveness (upregulation of IRS1, INSIG2, SREBF1, and ZFP423) were apparent as early as 3 wk postpartum. Thus, identifying specific nutrients capable of activating PPARgamma after calving in AT might help accelerate its replenishment. A regulatory network encompassing the genes and physiological measurements obtained is proposed. PMID- 22818448 TI - Herd-level risk factors associated with cow mortality in Swedish dairy herds. AB - An increase in on-farm mortality (euthanasia and death) in dairy herds has been reported in several countries in the last decade. This does not only imply possible problems with animal welfare, but it also causes economic losses to the farmer. The objective of this study was to evaluate time trends in on-farm dairy cow mortality in Sweden and identify potential herd-level risk factors. Data were retrieved on all Swedish dairy herds enrolled in the milk recording scheme between 2002 and 2010. Herds with a herd size of <20 cows or a mortality rate (MR) of >40 dead or euthanized cows per 100 cow-years were excluded. Two different models were used: 1 multiple-year analysis, which included 6,898 herds during the period 2002 to 2010 and 1 single-year analysis including 4,252 herds for the year 2010, where other variables that were not present during the entire multiple year study were analyzed. The outcome variable was the number of euthanized and dead cows per year and season. A negative binomial regression model, adjusted for clustering within herd, was applied to both models. Fixed effects in the multiple-year analysis were breed, calving interval, herd size, milk yield, region, season, pasture period, and year. The fixed effects in the single-year analysis were breed, calving interval, conventional versus organic farming, herd size, housing system, milk yield, region, and season. The results demonstrated that MR gradually increased from 5.1 to 6.6 events per 100 cow-years during the study period. Swedish MR are consequently on par with, or even greater than, MR among dairy herds in other comparable countries. Higher mortality was associated with larger herd size, longer calving intervals, and herds that had Swedish Holstein as the predominant breed. Lower mortality was observed in herds with a higher herd average milk yield, during the fall and winter, and in organically managed herds. There were regional differences in mortality. An interaction between herd size and season was found in both models. Also, an interaction between housing system and milk yield was found in the single-year analysis. This first assessment of on-farm mortality in Swedish dairy herds confirmed that the MR has increased over the last few years. The study also identified some herd-level risk factors. PMID- 22818449 TI - Evaluation of two doses of ceftiofur crystalline free acid sterile suspension for treatment of metritis in lactating dairy cows. AB - The objectives of this study were to evaluate efficacy of a 2-dose regimen of ceftiofur crystalline free acid sterile suspension (CCFA-SS) for treatment of acute metritis in lactating dairy cows under field conditions and to provide additional safety and injection site tolerance data for injections at the base of the ear. Cows at 15 dairies with rectal temperature >= 39.5 degrees C and fetid uterine discharge <= 10 d postcalving were randomly assigned by blocks of 2, based on order of entry and without regard to parity, to treatment with saline (1.5 mL/45.5 kg of body weight, n=509) or CCFA-SS (6.6 mg of ceftiofur equivalents/kg of body weight, n=514). Treatments were administered by subcutaneous injection in the posterior aspect of the ear where it attaches to the head; the first dose was administered on study d 0 and the second dose was administered in the contra lateral ear on study d 3. Rectal temperatures were recorded on study d 1 to 4 and 5 or 6 and cows were clinically evaluated daily from study d 1 to 13. Cows that exhibited increased adverse clinical signs of poor health or complications associated with metritis were categorized as a treatment failure and administered escape therapy. Each cow received a veterinary physical examination on study d 5 or 6 to determine if she should be removed from the study and on study d 14 to determine clinical cure or failure to cure. Clinical cure was defined as rectal temperature <39.5 degrees C and non-fetid and purulent or mucopurulent discharge on study d 14 and no escape therapy administered. The injection procedure was scored after each injection (study d 0 and 3) and injection sites and ear carriage were scored on study d 5 or 6, 14, and 57+/-3. Of the 1,023 cows enrolled, 7 were completely censored due to protocol deviations and 34 were removed for protocol deviations or medical conditions not related to metritis. Clinical cure rate was higher for CCFA-SS than for saline (74.3 vs. 55.3%) and rectal temperatures for each of study d 1 to 5 or 6 were lower for CCFA-SS than saline. Injection procedure indices showed that CCFA-SS could be practically and safely administered using commercial dairy facilities. Although injection site scores were higher for CCFA-SS than saline at study d 5 or 6 and 14, >=98.6% of ears were normal on d 57+/-3. Thus, a 2-dose treatment with CCFA-SS given 72h apart increased metritis clinical cure rate and was well tolerated in dairy cows. PMID- 22818450 TI - Combined use of Ovsynch and progesterone supplementation after artificial insemination in dairy cattle. AB - The objective of this study was to evaluate the effects of different Ovsynch protocols combined with progesterone (P4) supplementation after artificial insemination (AI) of Holstein-Friesian cows. Cows were randomly synchronized at 52 to 63 d after parturition with either the classical Ovsynch protocol (GnRH on d 0, PGF(2alpha) on d 7, GnRH 48 h after PGF(2alpha)) or with a modified Ovsynch protocol (second GnRH 60 h after PGF(2alpha)). On d 4 after timed AI (TAI), the cows were blocked by parity and randomly divided into 2 groups. Half of the cows were supplemented with P4 (P4+) by applying a P4-releasing intravaginal device intravaginally for 14 d, whereas the other half remained untreated (P4-). In 50% of randomly chosen cows, plasma P4 was measured on d 4, 5, and 18 after TAI. Sonographic pregnancy diagnosis was performed on d 33 after TAI in a total of 398 cows. Health status and body condition score (BCS) of all cows were examined at several stages of the study. Cows in the modified Ovsynch protocol tended to have higher P4 values on d 4 after TAI than cows in the classical Ovsynch protocol (2.1 +/- 0.2 vs. 1.6 +/- 0.2 ng/mL), but no difference in pregnancy per AI (P/AI) was observed between the 2 Ovsynch protocols (38.4% vs. 44.1%). Independent of the Ovsynch protocols, P4+ cows tended to have higher P/AI compared with P4- cows (44.4% vs. 38.1%). The retention of fetal membranes and BCS at the time of insemination affected P/AI. Moreover, an interaction between BCS at the time of insemination and P4 supplementation was apparent; that is, the difference in P/AI between P4+ and P4- cows was significant in cows with BCS >=3.25. Progesterone supplemented cows showed higher P4 values on d 5 (4.9 +/- 0.2 vs. 2.6 +/- 0.2) and d 18 (7.8 +/- 0.2 vs. 6.3 +/- 0.2) after TAI, respectively. In conclusion, the elongation of the time interval between the injections of PGF(2alpha) and the second GnRH from 48 to 60 h had no effect on P/AI. Progesterone supplementation after insemination improved the P/AI of the Ovsynch protocols, but this effect was more apparent in cows with BCS >=3.25. PMID- 22818451 TI - Prevalence, antimicrobial resistance, and molecular characterization of methicillin-resistant Staphylococcus aureus from bulk tank milk of dairy herds. AB - It was the objective of the study to estimate the prevalence of methicillin resistant Staphylococcus aureus (MRSA) in bulk tank milk from German dairy herds and to characterize isolates from bulk tank milk with respect to their Staph. aureus protein A (spa) and staphylococcal cassette chromosome mec (SCCmec) type, their phenotypic antimicrobial resistance and resistance- resp. virulence associated genes using broth microdilution and a microarray for Staph. aureus. Bulk tank milk samples (25 mL) were tested for MRSA using a 2-step selective enrichment protocol. Presumptive MRSA were confirmed by PCR. Thirty-six isolates collected from bulk tank milk of dairy herds in 2009 and 2010 were included in the characterization. All isolates displayed spa-types assigned to the clonal complex CC398. Based on the epidemiological cut-off values for the interpretation of minimum inhibitory concentrations isolates were resistant to tetracycline (100%), clindamycin (58%), erythromycin (52%), quinupristin/dalfopristin (36%), and kanamycin (27%). Isolates did not carry genes associated with typical virulence factors for Staph. aureus such as the Panton-Valentine leukocidin. However, they did carry hemolysin genes. Livestock-associated MRSA of CC398 does occur in German dairy herds and the strains have similar properties as described for strains from pigs. PMID- 22818452 TI - Effects of d-cloprostenol dose and corpus luteum age on ovulation, luteal function, and morphology in nonlactating dairy cows with early corpora lutea. AB - Luteolysis is a key event in cattle reproduction. A standard dose of exogenous PGF(2alpha) will induce full luteolysis in the majority of cows with a matured corpus luteum (CL). However, this will not occur in cows with a CL <5d old. To date, it is not known whether a larger dose will have a more potent luteolytic effect in cows during early diestrus. The objective of this study was to characterize the effect of 2 doses of d-cloprostenol (150 and 300 MUg) on the progesterone concentration, luteal diameter, and ovulation rate in nonlactating dairy cattle 96 to 132 h postovulation. Twenty nonlactating dairy cows were included in the study. Each cow received 2 treatments of d-cloprostenol in 2 consecutive cycles: a standard dose of 150 MUg and a double dose of 300 MUg. The cows were allocated randomly to 1 of 4 groups (5 cows in each group) according to the age of the CL at the time of treatment: 96, 108, 120, and 132 h. The exact time of ovulation was known within 12h, because of twice per day ultrasound examination. The CL diameter and progesterone concentration were measured before treatment (d 0) and 2 and 4d after treatment. Within each CL age group, the effect of d-cloprostenol dose on luteolysis was determined. More cows treated with double dose tended to have full luteolysis compared with the standard dose (8/10 vs. 4/10, respectively). This effect was only apparent in cows with CL of 120 and 132 h but not in earlier CL. The interval from treatment to ovulation was shorter (3.3 +/- 0.1d) in cows treated with a double dose than in cows treated with the standard dose (4.5 +/- 0.4d). PMID- 22818453 TI - Characteristics and retention of luteal structures, extended postinsemination cycle, progesterone, and pregnancy-specific protein B in serum after human chorionic gonadotropin treatment of dairy cows. AB - Our objectives were to determine characteristics (size, number, and stayability) of luteal structures formed in response to human chorionic gonadotropin (hCG) administered on d 7 after timed artificial insemination (AI) and the influence of hCG on returns to estrus and pregnancy outcome. Holstein cows (n=328), milked 3 times daily, previously inseminated at first service were assigned randomly to a completely randomized design consisting of 2 treatments when at least 1 corpus luteum (CL) was detected on d 7 after AI. Treatment consisted of 1,000 IU hCG or 1 mL of saline (control) administered i.m. Blood was collected and luteal structures were mapped and sized by transrectal ultrasonography on d 7, 14, 21, 28, and 32 after AI. Blood also was collected on d 60 in all pregnant cows. Treatment with hCG induced new luteal structures in 70% of cows, regardless of pregnancy status or number of pretreatment CL. Cows producing greater than the median 46 kg of energy-corrected milk per day were less likely to respond to hCG. The number of total luteal structures per cow, original CL volume, and total luteal volume (original CL + new luteal structures) were increased by hCG. Progesterone concentration was greater in pregnant than nonpregnant cows on d 14 unless cows responded to hCG by forming new luteal structures. Concentrations of progesterone were greatest in pregnant, hCG-treated cows. Pregnancy per AI at d 32 or 60 after first AI was less in hCG- than saline-treated cows because pregnancy outcome for hCG cows that had only 1 pretreatment CL and failed to respond to hCG was only 55 to 61% of that observed in controls. Proportions of cows returning to estrus from 18 to 25 d after AI were less in hCG than control cows but greater for cows returning >25 d. Regardless of treatment, 25% of cows in both treatments retained at least 1 original CL to d 28 after AI and were not pregnant on d 32. Progesterone concentrations in these nonpregnant cows with retained CL between d 14 and 28 after AI were intermediate between nonpregnant cows that returned to estrus by d 25 and all pregnant cows. Concentrations of pregnancy-specific protein B were elevated in some of these nonpregnant, CL retained cows, indicating early pregnancy loss. Retention of original luteal tissue in nonpregnant cows to d 28 after AI indicated that pregnancy had been initiated but failed, as verified by concentrations of progesterone and pregnancy specific protein B. PMID- 22818455 TI - The effects of overstocking Holstein dairy cattle during the dry period on cortisol secretion and energy metabolism. AB - The objective was to determine whether overstocking during the dry period could alter physiological parameters in dairy cattle associated with cortisol secretion and energy metabolism. Four groups of 10 late-gestation, nonlactating Holstein cows (6 multiparous cows and 4 heifers per group) were exposed to both a control [1 lying stall/cow and 0.67 m of linear feed bunk (FB) space/cow] and an overstocked (1 stall/2 cows and 0.34 m of FB space/cow) stocking density treatment in a replicated crossover design with 14-d treatment periods. On d 1, 3, 5, 7, 9, and 11 of each 14-d treatment period, blood and fecal samples were collected from each cow for the determination of plasma nonesterified fatty acids (NEFA), glucose, insulin, and fecal cortisol metabolite (11,17-dioxoandrostane; 11,17-DOA) concentrations. Glucose and ACTH challenges were conducted on d 13 and 14, respectively, of each treatment period. Dry matter intake per cow was greater during the overstocked period than during the control period (15.9 vs. 14.9 +/- 0.5 kg/d). Plasma NEFA and glucose concentrations were greater (0.11 vs. 0.09 +/- 0.006 mEq/L and 65.3 vs. 64.2 +/- 1.1mg/dL, respectively) and 11,17-DOA concentration tended to be greater (891 vs. 792 +/- 86 ng/g of fecal dry matter) during the overstocked period than during the control period. Insulin concentration was the same during the overstocked (29.0 +/- 2.1 MUIU/mL) and control (31.2 +/- 2.1 MUIU/mL) periods. Overstocking was associated with slightly slower glucose clearance from circulation as evidenced by a greater area under the curve estimate for the glucose response curves (2,882 vs. 2,657 +/- 165 mg/dL * 180 min) but a more attenuated insulin response (insulin area under the curve = 5,258 vs. 6,692 +/- 1,104 MUIU/mL * 180 min for the overstocked and control periods, respectively). Changes in tissue glucose uptake may be mediated by changes in pancreatic insulin secretion or peripheral tissue responses to insulin. The role of glucocorticoids in mediating these changes in energy metabolism is still unclear because stocking density treatment was not associated with changes in adrenal secretion of cortisol following ACTH stimulation. PMID- 22818454 TI - Microscopic differential cell counting to identify inflammatory reactions in dairy cow quarter milk samples. AB - The diagnosis of intramammary infections is mostly based on somatic cell count (SCC) and bacteriological analysis. As an alternative, differential cell counting (DCC) could be a useful method, because it identifies changes in the relative cell populations before the increase in total cell number occurs. The aim of the study was to identify cytological parameters that could be used in the field to classify mammary quarters as healthy or diseased, comparing cyto-bacteriological results with DCC. Overall, 48 cows were randomly selected from 3 herds in Lombardy region of Italy. Herd A was characterized by the absence of contagious microorganisms; in herds B and C, the prevalence of Staphylococcus aureus was 20 and 50%, respectively. Foremilk samples were aseptically collected from 188 quarters and submitted to bacteriological analysis, SCC, and DCC. For statistical analysis, the samples were clustered into 4 health groups, and DCC results were compared in each group. Ninety-six samples were classified as normal secretions (N), 30 as mastitis (M), 15 as latent mastitis (LM), and 47 as unspecific mastitis (UM) based on SCC and bacteriological results. Single percentages of lymphocytes, polymorphonuclear neutrophilic leukocytes (PMNL), or macrophages were first evaluated to established variables capable of identifying healthy and inflamed quarters. Then, combinations of cell populations were tested to increase the discrimination power of DCC: phagocytes, logarithmic PMNL:lymphocyte ratio, and logarithmic phagocyte:lymphocyte ratio. The mean percentage of lymphocytes was significantly higher in group N than in groups LM, UM, and M. The mean percentage of PMNL was significantly lower in group N than in groups UM and M, but not LM. Mean percentages of macrophages were not significantly influenced by the 4 groups. The mean value of phagocytes was significantly lower in group N than in the other groups. Both the logarithmic PMNL:lymphocyte and the logarithmic phagocyte:lymphocyte ratios were significantly lower in group N than in groups LM, UM, and M. Fisher (F-)values were calculated, and the highest F value was that of log PMNL:lymphocytes ratio (48.23). The explanation for this could be that log PMNL:Lym is the only variable that involved both cell populations statistically influenced by health groups but excluded macrophages. Microscopic DCC has potential as a tool to identify cows affected by any inflammatory process of the mammary gland, with the best results being achieved using log PMNL:lymphocyte as variable. PMID- 22818456 TI - Short communication: Relationship between competitive success during displacements at an overstocked feed bunk and measures of physiology and behavior in Holstein dairy cattle. AB - The objective of this study was to evaluate how behavioral and physiological parameters are affected based on a cow's level of success at displacing others at an overstocked feed bunk. Forty Holstein nonlactating, late-gestation dairy cattle were housed in an overstocked pen [5 stalls/10 cows and 0.34 m of linear feed bunk (FB) space/cow] in groups of 10 (4 heifers and 6 multiparous cows) for 14 d. Plasma nonesterified fatty acids, glucose, and fecal cortisol metabolites (11,17-dioxoandrostanes) were measured in blood and feces sampled every 2d. A glucose tolerance test and an ACTH challenge were conducted on all cows on d 13 and 14, respectively to further explore the effects of competitive success on energy metabolism and stress physiology. Feeding behavior and displacements at the FB were recorded between d 7 to 10 of the observation period. A competition index (CInd) was calculated for each cow by dividing the number of times the cow displaced another at the FB by the total number of displacements the cow was involved in, either as an actor or reactor. Cows were then divided into 3 subgroups based on their CInd: high success (HS: CInd >=0.6), medium success (0.4 <= CInd <0.6), and low success (LS: CInd <0.4). Heifers accounted for 7, 36, and 79% of the total number of animals in the HS (n=15), medium success (n=11), and LS (n=14) groups, respectively. No differences were observed in daily feeding time, total number of displacements, and time to approach the FB following fresh feed delivery between the 3 CInd groups; however, cows in the LS group had greater daily nonesterified fatty acid and 11,17-dioxoandrostane concentrations relative to cows in the HS group. No differences existed in cortisol response to an ACTH stimulation test between CInd categories. During the glucose tolerance test, glucose response curves were the same between all 3 CInd categories; however, the peak insulin response of LS cows was 130 MUIU/mL greater than the peak HS response, indicating that LS cows may have decreased tissue responses to insulin or increased pancreatic responses to glucose. In an overstocked environment, dairy cattle physiology is associated with a cow's level of success at displacing other individuals at the feed bunk. PMID- 22818457 TI - Short communication: Molecular typing of Prototheca zopfii from bovine mastitis in Japan. AB - Prototheca zopfii causes bovine mastitis, resulting in reduced milk production and the secretion of thin watery milk with white flakes. Prototheca zopfii has been biochemically and serologically divided into at least 2 genotypes, P. zopfii genotype 1 and P. zopfii genotype 2. The latter is known to be the main causative agent of bovine protothecal mastitis. Prototheca zopfii was later reclassified into 5 varieties: var. zopfii (genotypes 1 and 2), var. 1 (formerly Prototheca blaschkeae), var. 3 (formerly P. moriformis), and var. portoricensis. In this study, the 18S ribosomal DNA sequences of diverse clinical specimens from different areas in Japan were studied to clarify the pathogenicity of P. zopfii var. zopfii. The phylogenetic tree revealed that all genotype 2 isolates were grouped in a cluster of P. zopfii var. zopfii SAG 2021(T) (type strain genotype 2), and were independent from the cluster of the genotype 1 isolates. Thus, all isolates from bovine mastitis in Japan were identified as P. zopfii genotype 2. Therefore, P. zopfii var. zopfii genotype 2 is associated with bovine mastitis. PMID- 22818459 TI - Technical note: Data loggers are a valid method for assessing the feeding behavior of dairy cows using the Calan Broadbent Feeding System. AB - Assessing feeding behavior is important in understanding the effects of nutrition and management on the well-being of dairy cows. Historically, collection of these data from cows fed with a Calan Broadbent Feeding System (American Calan Inc., Northwood, NH) required the labor-intensive practices of direct observation or video review. The objective of this study was to evaluate the agreement between the output of a HOBO change-of-state data logger (Onset Computer Corp., Bourne, MA), mounted to the door shell and latch plate, and video data summarized with continuous sampling. Data (number of feed bin visits per day and feeding time in minutes per day) were recorded with both methods from 26 lactating cows and 10 nonlactating cows for 3 d per cow (n=108). The agreement of the data logger and video methods was evaluated using the REG procedure of SAS to compare the mean response of the methods against the difference between the methods. The maximum allowable difference (MAD) was set at +/-3 for bin visits and +/-20 min for feeding time. Ranges for feed bin visits (2 to 140 per d) and feeding time (28 to 267 min/d) were established from video data. Using the complete data set, agreement was partially established between the data logger and video methods for feed bin visits, but not established for feeding time. The complete data set generated by the data logger was screened to remove visits of a duration <=3 s, reflecting a cow unable to enter a feed bin (representing 7% of all data) and >=5,400 s, reflecting a failure of the data logger to align properly with its corresponding magnetic field (representing <1% of all data). Using the resulting screened data set, agreement was established for feed bin visits and feeding time. For bin visits, 4% of the data was beyond the MAD. For feeding time, 3% of the data was beyond the MAD and 74% of the data was +/-1 min. The insignificant P value, low coefficient of determination, and concentration of the data within the MAD indicate the agreement of the change-of-state data logger and video data. This suggests the usage of a change-of-state data logger to assess the feeding behavior of cows feeding from a Calan Broadbent Feeding System is appropriate. Use of the screening criteria for data analysis is recommended. PMID- 22818458 TI - Short communication: Evaluation of vaginal discharge following treatment with a progesterone insert. AB - Yellowish discharge after application of intravaginal progesterone releasing inserts is frequently observed in cows. The objective of this study was to compare the bacteriological contamination of the vagina and uterus before and after a treatment with a progesterone insert in heifers. Forty-two Holstein heifers received a progesterone releasing insert [Eazi-Breed controlled internal drug release (CIDR) insert; Pfizer Animal Health, Berlin, Germany] for 7d. The protruding tail had been removed from half of the inserts (no tail group: n=21; tail group: n=21). Nine heifers from the tail group lost the insert within the 7 d treatment interval and were excluded. Heifers identified in estrus were artificially inseminated on d 9 or 10. Vaginal discharge was scored on a 4-point scale [vaginal discharge score (VDS) 0 to 3] and vaginal swabs were taken for bacteriological examination on d 0 and 7 and the day of artificial insemination (AI). Furthermore, cytological and bacteriological samples were obtained from the uterus on d 7 and the day of AI. On d 0, coliforms and Streptococcus spp. were found in vaginal swabs of 21 heifers (64%). On d 7, all heifers showed purulent vaginal discharge (VDS 2 to 3). The VDS was higher in the tail group compared with the no tail group. Arcanobacterium pyogenes, coliforms, and Streptococcus spp. were isolated from the vaginal swabs in 32 of 33 (96%) heifers on d 7. On the day of AI, VDS had improved to 0 or 1 in 96% of the heifers. However, A. pyogenes, coliforms, and Streptococcus spp. were still isolated in 17 of 33 (53%) heifers from the vagina and in 32 of 33 (96%) heifers from the endometrium. Endometrial cytology revealed polymorphonuclear neutrophils (PMN) in 11 heifers (6 to 32% PMN). Five samples exceeded the threshold of 5% PMN, and 2 samples exceeded the 10% PMN threshold, indicative of subclinical endometritis. In conclusion, pyogenic bacteria were found in the vagina and uterus on d 7 and the day of AI after intravaginal progesterone treatment. The severity of the discharge was affected by the protruding tail of the insert. PMID- 22818460 TI - Milk production, nitrogen balance, and fiber digestibility prediction of corn, whole plant grain sorghum, and forage sorghum silages in the dairy cow. AB - Total mixed rations containing corn (CS), whole plant grain sorghum (WPGS), or forage sorghum (FS) silages were fed to 6 primiparous Italian Friesian cows to determine the effects on lactation performance, nutrient digestibility, and N balance. Furthermore, the relationship between in vivo total-tract neutral detergent fiber (NDF) digestibility (ttNDFD) and the ttNDFD derived by the Cornell Net Carbohydrate and Protein System (CNCPS) model was assessed. Cows were assigned to 1 of 3 diets in a replicated 3 * 3 Latin square with 28-d periods. The experimental treatment was silage type and 3 different silages were included in the diets. The diets were formulated to be iso-NDF. Accordingly, each diet was formulated to contain 41.5% CS silage, 36.7% WPGS silage, or 28.0% FS silage, on a DM basis. Starch content was balanced by adding the appropriate amount of corn meal. Separate collection of total urine and feces was performed. Dietary forages were analyzed for in vitro NDF digestibility (6 and 24h of incubation) to predict fiber digestion rate with 2 NDF pools (digestible and indigestible). Rumen digestibility of the potentially digestible NDF pool was predicted using CNCPS version 6.1, using the in vitro forage fiber digestion rate. The ttNDFD was predicted assuming that intestinal digestibility of the NDF amount escaping rumen digestion was 20%, according to the CNCPS model. Dry matter intake was decreased by approximately 1.8 kg/d in cows fed the FS diet compared with the other diets, probably for the greater particle size of FS diet. Hence, milk yield (kg/d) was lowest for FS (23.6), intermediate for WPGS (24.6), and highest for the CS diet (25.4). Milk urea N (mg/dL) was highest for FS (12.9), intermediate for WPGS (11.9), and lowest for CS (10.7) diet. In vivo ttNDFD (%) was 51.4 (CS), 48.6 (WPGS), and 54.1 (FS); this was probably due to a higher retention time of FS diet in the rumen rather than to a better quality of the FS silage, as confirmed by in situ and in vitro results. Urinary N excretion (% N intake) was highest for FS (31.8), intermediate for WPGS (29.3), and lowest for the CS (27.5) diet. The predicted ttNDFD (37.7, 36.3, and 39.5% for CS, WPGS, and FS, respectively) were lower than the in vivo results. Providing an adequate starch supplementation, whole plant grain sorghum silage can replace corn silage in dairy cows TMR. Forage sorghum silage had rumen NDF digestibility comparable to the other silages; however, it had a negative effect on dry matter intake and milk production, probably due to an inadequate effect of processing. PMID- 22818461 TI - Effect of supplementary concentrate type on nitrogen partitioning in early lactation dairy cows offered perennial ryegrass-based pasture. AB - Forty-four early lactation (64 +/- 20 d in milk) dairy cows of mixed parity were used to assess the effect of 4 supplementary concentrate types (n=11) on N partitioning. Animals were blocked on parity and calving date, and blocks were balanced for previous milk yield and milk protein yield. Cows received grazed pasture plus 5.17 kg of dry matter (DM)/d of one of the following isoenergetic concentrates: high crude protein (CP) with rolled barley (HP, 19% CP); low CP with rolled barley (LP, 15% CP); low CP with barley and supplementary 2-hydroxy-4 methylthio butanoic acid (HMBi; LP+HMBi, 15% CP); and low CP with ground corn (LP Corn, 15% CP). Nitrogen partitioning studies were conducted at wk 6 and 10 postpartum by using the n-alkane technique to determine pasture dry matter intake (DMI). Pasture DMI (13.3kg of DM/d) and dietary digestibility of DM were not affected by concentrate type. Milk yield was lower for LP compared with other concentrate types (25.4 vs. 28.3 kg/d). Yields of milk protein and milk casein were not affected by concentrate type. However, milk solid yield and milk fat yield were higher for LP+HMBi (1.97 and 0.92 kg/d) compared with LP (1.72 and 0.87 kg/d). Concentrations of fat, protein, lactose, and casein were not affected by concentrate type. Dietary N intake was higher for HP compared with other treatments (0.545 vs. 0.482 kg/d, HP vs. average of the 3 LP treatments). Dietary N intakes were not different among low CP concentrates. Fecal N excretion was not affected by concentrate type. However, urinary N excretion was related to N intake and was higher for HP compared with other treatments (0.261 vs. 0.195 kg/d, HP vs. average of the 3 LP treatments). Urinary N excretion was not different among low CP concentrates. Milk N output was higher for HP (0.139 kg/d) compared with LP (0.12 kg/d) but not LP+HMBi (0.137 kg/d) or LP Corn (0.138 kg/d). The portion of feed N excreted as feces N was lower for HP compared with other treatments (0.272 vs. 0.327, HP vs. average of the 3 LP treatmentsHowever, the portion of feed N excreted as urine N was higher for HP (0.466) compared with LP+HMBi (0.408) and LP Corn (0.366) but not compared with LP. The portion of feed N excreted as milk N was higher for LP Corn (0.282) compared with HP (0.257) but not LP+HMBi or LP. Dietary reformulation to reduce N excretion in pasture-based dairy production systems is possible. However, maintenance of milk yield and milk N when concentrate CP was reduced (19 vs. 15%) required the use of either protected AA (HMBi) or ground corn. PMID- 22818462 TI - Effects of starch content of calf starter on growth and rumen pH in Holstein calves during the weaning transition. AB - The objective of this study was to evaluate the effects of substituting high fiber byproducts for dry ground corn in calf starter on growth and rumen pH during the weaning transition. Holstein bull calves were raised on an intensified nursing program using milk replacer containing 26% CP and 18% fat. Calves were fed a texturized calf starter containing either dry ground corn at 18.8% of dry matter (DM; CRN), beet pulp replacing dry ground corn at 10.2% dietary DM (BP), or triticale dried distillers grains with solubles replacing dry ground corn and high-protein feedstuffs at 18.6% of dietary DM (DDGS) in the pellet; treatment calf starters differed only in the pellet portion. Starch concentrations of CRN, BP, and DDGS were 35.3, 33.4, and 31.4%, respectively. After a calf consumed 2.50 kg of starter for 3 consecutive days, a small ruminant rumen pH data logger was inserted orally and rumen pH was measured continuously for 4d. Calves were then killed and rumen fluid was sampled to determine volatile fatty acid profile. No difference was found in overall average daily gain or growth rates of hip height, withers height, and heart girth. During the weaning transition, rate of increase in calf starter intake was greater for calves fed DDGS compared with those fed CRN (87.7 vs. 77.5 g/d), but lower for calves fed BP compared with CRN (68.1 vs. 77.5 g/d). The area under pH 5.8 (470 vs. 295 min * pH/d) or pH 5.2 (72.7 vs. 16.4 min * pH/d) was greater for calves fed DDGS than those fed CRN. Rumen pH profile was not affected by BP treatment compared with CRN, but calves fed BP tended to have greater water intake than those fed CRN (6.6 vs. 5.8 L/d). Volatile fatty acid profile was not affected by treatment with the exception of molar proportion of butyrate, which tended to be lower for calves fed BP compared with those fed CRN (15.0 vs. 16.6%). Hay intake was positively correlated to mean rumen pH for calves used in this study (r=0.48). Decreasing dietary starch concentration did not mitigate rumen acidosis in calves during weaning transition, and low rumen pH did not adversely affect growth during the weaning transition. PMID- 22818463 TI - Protein fractionation byproduct from canola meal for dairy cattle. AB - Fiber-protein is a byproduct arising from a process for fractionating high quality protein from canola meal. The objective of this study was to evaluate the fiber-protein fraction by examining the chemical profiles, rumen degradation, and intestinal digestive characteristics and determining the nutritive value of the fiber-protein fraction as dietary components for dairy cattle in comparison with commercial canola meal and soybean meal. Available energy values were estimated based on National Research Council guidelines, whereas total true protein content potentially absorbable in the small intestine (DVE) were predicted using the predicted DVE/degraded protein balance (OEB) model. The results show that fiber protein was a highly fibrous material [neutral detergent fiber (NDF): 556; acid detergent fiber (ADF): 463; acid detergent lignin: 241 g/kg of dry matter (DM)] compared with canola meal (NDF: 254; ADF: 212; acid detergent lignin: 90 g/kg of DM) due to the presence of a higher level of seed hulls in fiber-protein. Compared with canola meal, fiber-protein contained 90 g/kg of DM less crude protein (CP), 25% of which consisted of undegradable acid detergent-insoluble CP. Most of the ruminally undegradable nutrient components present in canola meal appeared to be concentrated into fiber-protein during the manufacturing process and, as a result, fiber-protein showed a consistently lower effective degradability of DM, organic matter, CP, NDF, and ADF compared with both canola meal and soybean meal. Available energy content in fiber-protein contained two thirds of that of canola meal. The DVE was one-third that of soybean meal and one fifth that of canola meal [DVE value: 58 vs. 180 (soybean) and 291 g/kg of DM (canola meal)]. The OEB value of fiber protein was positive and about half of that of soybean and canola meal [OEB value: 74 vs. 162 (soybean) and 137 g/kg of DM (canola meal)]. Fiber-protein can be considered as a secondary source of protein in ruminant feed. PMID- 22818464 TI - Novel use of the wild species Cephalaria joppensis for silage preparation and its nutritive value for feeding lactating dairy cows. AB - This study presents a novel method for use of the wild plant species Cephalaria joppensis (CJ) as agricultural forage for ruminants. Domesticated CJ tends to have higher crop mass yield per hectare than a commercial wheat variety (W) but is similar in in vitro dry matter (DM) digestibility. This study was composed of 3 experiments. Experiment 1 aimed to measure effects of ensiling CJ versus W in packed polyethylene-wrapped bales. Three types of ensiled bales were produced for each plant: 1) direct-cut CJ versus W packed solely; 2) direct-cut CJ versus W mixed as sole roughage source together with dietary ingredient and packed in bales to create CJ total mixed ration (CJ-TMR) or W-TMR; 3) CJ silage versus W silage mixed as one-third of dietary roughage source together with two-thirds sorghum (S) silage and additional dietary ingredients and packed in bales to create CJ-S-TMR or W-S-TMR. Data showed that packing and wrapping created anaerobic conditions within the 4 types of TMR bales while reducing pH (4.12 to 4.37). Dry matter loss during ensilage was higher for the 2 types of TMR containing W compared with CJ. Ensilage decreased soluble nitrate content as well as yeast and mold contamination, and the 4 types of TMR bales were characterized by a long outdoor shelf life (3 mo) and high stability under aerobic exposure. Experiment 2 aimed to measure the intake and digestibility by sheep of the 4 types of packed TMR after 90 d of ensiling. Data demonstrated higher voluntary intake of the CJ-TMR compared with the other TMR types. The CJ-TMR was characterized by higher digestibility of DM, crude protein, and neutral detergent fiber components compared with the CJ-S-TMR. Experiment 3 examined intake, digestibility, and milk production by 21 pairs of lactating cows individually fed CJ-S-TMR versus W-S-TMR. Similar intake (21.6 to 22.0 kg/d) and digestibility of DM and crude protein were observed in cows fed the 2 TMR types (68 to 69% and 66 to 68%, respectively). However, neutral detergent fiber and cellulose digestibility were slightly higher in the cows fed W-S-TMR and this was reflected in a small increase in their milk and energy-corrected milk yield (36.5 and 31.4 kg/cow per day, respectively) compared with cows fed CJ-S-TMR (35.5 and 30.4 kg/cow per day, respectively). Results demonstrate that direct-cut CJ used as is, or CJ silage can be included and ensiled in TMR bales for feeding productive ruminants as a substitute for wheat silage. PMID- 22818465 TI - Effect of prepartum maternal energy density on the growth performance, immunity, and antioxidation capability of neonatal calves. AB - This study investigated the effect of prepartum diets differing in energy density on growth performance, immunity, and antioxidation capability of neonatal calves. Thirty Holstein dairy cows were allocated at random into 3 groups: low energy group [L; net energy of lactation (NE(L))=5.25 MJ/kg of dry matter (DM)]; medium energy group (M; NE(L)=5.88 MJ/kg of DM); and high energy group (H; NE(L)=6.48 MJ/kg of DM) at d 21 prepartum. Plasma was sampled for analysis of glucose, total protein, beta-hydroxybutyrate, and nonesterified fatty acids at 21, 14, and 7 d before parturition. After calving, birth weight and measurements of the calves in each group were recorded, and blood samples were collected for analysis of CD4, CD8, CD21, IL-2, IL-4, IL-6, total antioxidant capacity, superoxide dismutase, glutathione peroxidase, and maleic dialdehyde. The results indicated that although maternal weight did not differ among L, M, and H groups at 21, 14, and 7 d before parturition, the concentrations of glucose and beta-hydroxybutyrate at 14 and 7 d in the L group were decreased compared with that in the H group. In addition, nonesterified fatty acids concentrations increased significantly in the L group at 14 and 7 d before parturition compared with that in the M and H groups. Birth weight, body height, body length, abdominal circumference, thoracic girth, umbilical girth, and levels of CD4, CD4:CD8, IL-2, IL-4, total antioxidant capacity, and superoxide dismutase were decreased in calves of the L group compared with those of the H group. For the M group, CD4, CD4:CD8, and superoxide dismutase were decreased; and in the L group glutathione peroxidase and maleic dialdehyde levels were significantly increased compared with those of the H group. Reducing the maternal energy density during the last 21 d before parturition had a negative effect on growth and development, immunity, and antioxidation capability of neonatal calves. PMID- 22818466 TI - Development of colonic microflora as assessed by pyrosequencing in dairy calves fed waste milk. AB - The objective of the current study was to examine the effect of pasteurization of waste milk, used to feed dairy calves, on the bacterial diversity of their lower gut. Using 16S rDNA bacterial tag-encoded FLX amplicon pyrosequencing, fecal samples from dairy calves, ages 1 wk to 6 mo old and fed either pasteurized or nonpasteurized waste milk, were analyzed for bacterial diversity. Calves were maintained on 2 separate farms and, aside from how the waste milk was treated, were housed and cared for similarly. Fifteen calves were sampled from each age group (1, 2, and 4 wk, and 2, 4, and 6 mo of age; n=90 samples per milk treatment, 180 total samples) on each farm via rectal palpation and the samples shipped and frozen before analysis. In general, bacterial diversity, as represented by the total number of different species, was greater for the calves fed pasteurized waste milk at all ages (except 1 wk of age) and increased with increasing age in both treatments. Proteobacteria, Bacteroidetes, and Firmicutes were the predominant phyla. Differences in phyla and class were observed among treatments and age of calf but with no consistent trends. Salmonella were detected in 9 out of 14 (64%) of the 1-wk-old calves fed nonpasteurized milk. Treponema, an important beneficial bacterium in cattle rumen, was more prevalent in the pasteurized waste milk-fed animals and became higher in the older animals from this group. Escherichia-Shigella were detected among treatments at all ages, and highest at 1 wk of age, averaging approximately 21 and 20% of all bacteria for calves fed pasteurized and nonpasteurized waste milk, respectively, and decreasing as calves aged (2.6 and 1.3%). The consistent detection of Salmonella in the younger animals fed nonpasteurized milk and its absence in all other groups is an important finding related to this feeding practice. PMID- 22818467 TI - Effects of feeding dairy cows different legume-grass silages on milk phytoestrogen concentration. AB - Phytoestrogens are hormone-like substances in plants that can substantially influence human health (positively or negatively), and when fed to dairy cows are partly transferred to their milk. The aim of this study was to investigate the effects of varying the botanical composition and regrowth interval of legume grass silage on phytoestrogen intake and milk phytoestrogen concentrations. In one experiment, 15 Swedish Red dairy cows were fed 2- or 3-cut red clover-grass silage, or 2-cut birdsfoot trefoil-grass silage. In a second experiment, 16 Norwegian Red dairy cows were fed short-term ley silage with red clover or long term ley silage with white clover, and the effects of supplementation with alpha tocopherol were also tested. High concentrations of formononetin and biochanin A were found in all silage mixtures with red clover. The milk concentration of equol was highest for cows on the 2-cut red clover-grass silage diet (1,494 MUg/kg of milk). Because of the metabolism of biochanin A, genistein, and prunetin, their concentrations in milk and the apparent recovery were low. Coumestrol was detected in only short-term and long-term ley silage mixtures, and its milk concentration was low. Concentrations of secoisolariciresinol and matairesinol were higher in 2-cut birdsfoot trefoil-grass and long-term ley silage mixtures, those with legume species other than red clover, and the highest grass proportions. The 2-cut birdsfoot trefoil-grass silage diet also resulted in higher enterolactone concentration than the other diets (226 MUg/kg of milk). Lengthening the regrowth interval increased the intake of secoisolariciresinol and decreased the recovery of lignans. Feeding long-term ley silage resulted in higher milk lignan concentrations but lower milk isoflavone concentrations than feeding short-term ley silage. The apparent recovery of all phytoestrogens except prunetin was highest on the 2-cut birdsfoot trefoil-grass silage diet. No effect of alpha-tocopherol supplementation was observed on milk concentrations of any of the measured phytoestrogens. Variations were observed in milk concentrations of phytoestrogens, especially of equol, among cows, which could not be explained by variations in diet composition or phytoestrogen intake. The results show that milk phytoestrogen concentration is strongly influenced by silage botanical composition, but questions regarding phytoestrogen metabolism remain to be answered. PMID- 22818468 TI - Effect of supplemental concentrate type on milk production and metabolic status in early-lactation dairy cows grazing perennial ryegrass-based pasture. AB - Forty-four early-lactation dairy cows of mixed parity were used to examine the effect of 4 supplemental concentrate types (n=11) on milk production and metabolic status. Animals were blocked by parity and calving date, and blocks were balanced for previous milk yield and milk protein yield. Cows received grazed pasture plus 5.17 kg of DM/d of 1 of the following isoenergetic (1.1 units of energy for lactation) concentrates: 1) high crude protein (CP) with rolled barley (HP, 19% CP); b) low CP with rolled barley (LP, 15% CP); c) low CP with barley and a supplemental methionine hydroxy analog (HMBi; LP + HMBi, 15% CP); and d) low CP with ground corn (LP-corn, 15% CP). Milk yield was recorded from d 1 to 100 postpartum, with weekly milk sampling, body weight, and body condition score (BCS) measurements. Blood and rumen sampling were conducted weekly from wk 2 to 6 postpartum. Milk yield was lower for cows in the LP treatment compared with those offered other concentrate types (25.2 vs. 27.5 +/- 0.39 kg/d). Animals in the HP group had a higher milk yield than those in the LP + HMBi group (28.2 vs. 26.8 +/- 0.39 kg/d). Milk fat yield was lower from animals in the LP-corn group compared with those in the LP + HMBi group (0.94 vs. 1.03 +/- 0.03 kg/d). Milk protein yield was lower in the LP group compared with those in the HP group (0.88 vs. 0.97 +/- 0.02 kg/d). Animal body weight, BCS, and BCS loss were not affected by concentrate type. However, nonesterified fatty acids were higher from animals in the HP group than for those in the LP + HMBi group (0.41 vs. 0.33 +/- 0.03 mmol/L), and beta-hydroxy butyric acid was higher from animals in the HP group than for those in the other treatments (0.71 vs. 0.59 +/- 0.03 mmol/L). Glucose was higher from animals in the LP-corn group than for those in the HP and LP groups (3.3 vs. 3.2 +/- 0.05 mmol/L). Blood urea-N was higher from animals offered HP compared with those offered the other treatments (5.49.6 vs. 4.21 +/- 0.44 mmol/L). However, rumen NH(3)-N and volatile fatty acid concentration in the rumen were not affected by supplemental concentrate type. Reducing supplemental concentrate CP reduced milk yield. However, milk fat production and energy corrected milk were not different, reducing the likelihood of an improved energy balance or a more favorable blood metabolic profile in early-lactation dairy cows grazing perennial ryegrass. Offering HMBi with low-CP concentrates or replacing rolled barley with ground maize improves milk production relative to low-CP concentrates and metabolic status relative to high-CP concentrates. PMID- 22818469 TI - Production response to corn silage produced from normal, brown midrib, or waxy corn hybrids. AB - The objective was to evaluate the nutrient intake and digestibility and milk production response of lactating dairy cows fed diets based on corn silage produced from 3 different types of corn hybrids. Experimental diets contained 36.4% of the dietary dry matter (DM) from corn silage produced from normal (Agratech 1021, AgraTech Seeds Inc., Atlanta, GA), brown midrib (BMR; Mycogen F2F797, Mycogen Seeds, Indianapolis, IN), or waxy (Master's Choice 590, Master's Choice Hybrids, Ullin, IL) hybrids. Thirty-six multiparous and primiparous Holstein cows (66 +/- 22 d in milk, 41 +/- 8 kg/d of milk) were used in an 11-wk completely randomized design trial during the fall of 2009. All cows were fed a diet containing normal corn silage during the first 2wk of the trial before being assigned to 1 of 3 treatments for the following 9 wk. Data collected during the first 2 wk were used as a covariate in the statistical analysis. No difference was observed in dry matter intake (DMI) among treatments, which averaged 22.6 kg/d. Milk yield was higher for cows fed BMR (37.6 kg/d) compared with waxy (35.2 kg/d) but was similar to that of cows fed control (36.2 kg/d). Milk fat percentage tended to be lower for cows fed control (3.28%) compared with those fed BMR (3.60%) or waxy (3.55%) corn silage. Milk protein percentage tended to be lower for cows fed control (2.79%) compared with waxy (2.89%) but similar to that of those fed BMR (2.85%). No differences were observed in yield of milk components. Energy-corrected milk (ECM) yield and dairy efficiency (ECM:DMI) did not differ among treatments. Cows fed BMR tended to gain more body weight compared with those fed control and waxy. Results of this trial are consistent with previous reports in which cows fed diets based on corn silage produced from BMR hybrids have higher milk yield compared with those fed other hybrids. Corn silage produced from the waxy hybrid supported a similar yield of ECM because of higher milk components, but milk yield was not improved compared with the control. PMID- 22818470 TI - Factors associated with ruminal pH at herd level. AB - The objective of this study was to evaluate factors associated with ruminal pH at herd level. Four hundred and thirty-two cows of a Thuringian dairy herd were sampled before claw trimming using a rumen fluid scoop. Volume and pH of the rumen sample were measured, and lactation number, percentage of concentrates in the ration, days in milk (DIM), time of day, and daily milk yield were recorded. Rumen sampling was successful in 99.8% of the cows. The average sample volume was 25 mL. Rumen sample pH decreased with increasing percentage of concentrates in the ration. Ruminal pH decreased from calving to 77 DIM, and grew subsequently to 330 DIM. During the day, rumen pH followed a sinus curve, with maxima in the morning (0915 h) and afternoon (1533 h), and a minimum around noon (1227 h). Ruminal pH decreased with increasing daily milk yield. Lactation number interacted with daily milk yield on rumen pH. The percentage of concentrates in the ration, DIM, time of day, and daily milk yield were significant factors affecting ruminal pH at the herd level. PMID- 22818471 TI - Immune responses in lactating Holstein cows supplemented with Cu, Mn, and Zn as sulfates or methionine hydroxy analogue chelates. AB - The aim of this study was to compare effects of inorganic sulfate versus chelated forms of supplemental Cu, Mn, and Zn on milk production, plasma and milk mineral concentrations, neutrophil activity, and antibody titer response to a model vaccination. Holstein cows (n=25) were assigned in 2 cohorts based on calving date to a 12-wk randomized complete block design study. The first cohort consisted of 17 cows that had greater days in milk (DIM; mean of 77 DIM at the start of the trial) than the second cohort of 8 cows (32 DIM at the start of the trial). Diets were formulated to supplement 100% of National Research Council requirements of Cu, Mn, and Zn by either inorganic trace minerals (ITM) in sulfate forms or chelated trace minerals (CTM) supplied as metal methionine hydroxy analog chelates, without accounting for trace mineral contribution from other dietary ingredients. Intake and milk production were recorded daily. Milk composition was measured weekly, and milk Cu, Mn, and Zn were determined at wk 0 and 8. Plasma Cu and Zn concentrations and neutrophil activity were measured at wk 0, 4, 8, and 12. Neutrophil activity was measured by in vitro assays of chemotaxis, phagocytosis, and reactive oxygen species production. A rabies vaccination was administered at wk 8, and vaccine titer response at wk 12 was measured by both rapid fluorescent focus inhibition test and ELISA. Analyzed dietary Cu was 21 and 23mg/kg, Mn was 42 and 46mg/kg, and Zn was 73 and 94mg/kg for the ITM and CTM diets, respectively. No effect of treatment was observed on milk production, milk composition, or plasma minerals. Dry matter intake was reduced for CTM compared with ITM cows, but this was largely explained by differences in body weight between treatments. Milk Cu concentration was greater for CTM than ITM cows, but this effect was limited to the earlier DIM cohort of cows and was most pronounced for multiparous compared with primiparous cows. Measures of neutrophil function were unaffected by treatment except for an enhancement in neutrophil phagocytosis with the CTM treatment found for the later DIM cohort of cows only. Rabies antibody titer in CTM cows was 2.8 fold that of ITM cows as measured by ELISA, with a trend for the rapid fluorescent focus inhibition test. Supplementation of Cu, Mn, and Zn as chelated sources may enhance immune response of early lactation dairy cows compared with cows supplemented with inorganic sources. PMID- 22818472 TI - Supplementation of increasing amounts of linseed oil to dairy cows fed total mixed rations: effects on digestion, ruminal fermentation characteristics, protozoal populations, and milk fatty acid composition. AB - The effect of linseed oil (LO) supplementation on nutrient digestibility, forage (i.e., timothy hay) in sacco ruminal degradation, ruminal fermentation characteristics, protozoal populations, milk production, and milk fatty acid (FA) profile in dairy cows was investigated. Four ruminally cannulated, primiparous lactating cows were used in a 4 * 4 Latin square design (28-d periods). They were fed a total mixed ration (50:50 forage:concentrate (F:C) ratio [dry matter (DM) basis] without supplementation (control, CTL), or supplemented (wt/wt; DM basis) with LO at 2, 3, or 4%. Supplementation with LO had no effect on DM intake (19 kg/d) and apparent total-tract digestibility of nutrients (organic matter, neutral detergent fiber, acid detergent fiber, starch, and gross energy). Ruminal pH, ammonia, and total volatile FA concentrations were not changed by LO supplementation to diets. Extent of changes in volatile FA pattern and effective ruminal degradability of DM of timothy hay were minor. Neither the total numbers nor the genera distribution of protozoa was changed by the addition of increasing amounts of LO to the diet. Milk yield increased linearly (26.1, 27.3, 27.4, and 28.4 kg/d for CTL to LO4, respectively) as the amount of LO added to the diet increased. Milk fat content was not affected by LO supplementation, whereas milk protein content decreased linearly with increasing amounts of LO in the diet. Milk fat proportions of several intermediates of ruminal biohydrogenation of polyunsaturated FA (i.e., trans-10 18:1, trans-11 18:1, cis-9,trans-11 18:2, trans-11,cis-15 18:2, and cis-9,trans-11,cis-15 18:3) increased linearly with LO addition to the diet. The proportion of cis-9,cis-12 18:2 decreased linearly (2.06, 1.99, 1.91, and 1.83% for CTL to LO4, respectively) as the amount of LO in the diet increased. Milk fat content of cis-9,cis-12,cis-15 18:3 increased as the level of LO in the diet increased up to 3% but no further increase was observed when 4% of LO was fed (0.33, 0.79, 0.86, and 0.86% for CTL to LO4, respectively). A similar quadratic response to LO supplementation was also observed for cis 5,cis-8,cis-11,cis-14,cis-17 20:5 and cis-5,cis-7,cis-10,cis-13,cis-16 22:5. The results of the present study show that LO can be safely supplemented up to 4% in forage-based diets of dairy cows to enrich milk with potential health beneficial FA (i.e., n-3 FA) without causing any detrimental effects on rumen function, digestion, and milk production. PMID- 22818473 TI - Short communication: Characteristics of proteolytic activities of endo- and exopeptidases in alfalfa herbage and their implications for proteolysis in silage. AB - The pH optimum and thermostability of both exopeptidases and endopeptidases were investigated in this study to elucidate the possible role of plant proteases in proteolysis during ensiling of alfalfa herbage. Proteolytic activities of 4 classes of endopeptidases (i.e., serine, metallo, aspartic, and cysteine peptidase) and 5 classes of exopeptidases (i.e., aminopeptidase, carboxypeptidase, dipeptidase, dipeptidyl-peptidase, and tripeptidyl-peptidase) were examined within pH values of 3 to 9, and within temperatures from 20 to 90 degrees C. Serine and metalloproteases, the principal endopeptidases that hydrolyzed most of the protein to nonprotein nitrogen in alfalfa silage, had optimum activities at pH 4. Among the major exopeptidases contributing protein degradation in ensiled alfalfa, dipeptidase and tripeptidyl-peptidase had stable activities between pH 4 and 6, and carboxypeptidase activity was optimal at pH 5. The optimum temperature for most peptidase activities was 40 degrees C. Proteolytic activities of both endo- and exopeptidases increased with the elevation of incubating temperature from 20 to 40 degrees C. The pH value in well preserved alfalfa silage is often above 4.0, and the temperatures in the ensiled mass range from 25 to 40 degrees C. Therefore, high proteolytic activities between pH 4 and 6 and the temperature range of ensiled alfalfa suggest that plant peptidases play a role in hydrolyzing protein during prolonged storage. PMID- 22818474 TI - Short communication: Evaluation of serum immunoglobulin G concentrations using an automated turbidimetric immunoassay in dairy calves. AB - The absorption of maternal antibodies associated with colostrum feeding is critical to the health of calves. Multiple assays have been described to assess serum immunoglobulin G (IgG) concentrations in calves. However, none are ideal for routine use on farms. The purpose of this study was to evaluate the reliability of a new commercially available immunoassay and portable analyzer for measuring serum IgG concentrations in dairy calves. Serum from 100 Holstein calves that had received colostrum was collected for this study. Immunoglobulin G concentrations were run on each calf using both the rapid immunoassay method and radial immunodiffusion assay. Serum IgG concentrations in calves from this study ranged from 460 to 3,640 mg/dL (mean +/- SD: 1,515 +/- 71) as measured by radial immunodiffusion and 402 to 3,586 mg/dL (mean 1,473 +/- 70) as measured by the immunoassay. Based on regression analysis, the automated results closely paralleled those obtained by radial immunodiffusion with a coefficient of determination value of 0.98. Based on the results of this study, the immunoassay technique using the portable analyzer represents a reliable method that can be run within 15 min and provide an accurate serum IgG level. Although the cost is not insignificant, this assay could be easily implemented on a dairy farm to help monitor transfer of passive immunity. PMID- 22818475 TI - Hot topic: Effect of breeding strategies using genomic information on fitness and health. AB - A complex deterministic approach was used to model the breeding goal and breeding structure for the Austrian Fleckvieh (dual-purpose Simmental) breed. The reference breeding goal corresponded to the current total merit index (TMI-R), where dairy traits have a relative weight of 37.9% and fitness traits of 43.7% (beef traits 16.5%; milkability 2%). The breeding program was characterized by 280,000 cows under performance recording, 3,200 bull dams, 100 test bulls with a test capacity of 25%, and 15 proven bulls and 8 bull sires per year. The annual monetary genetic gain (AMGG) was generated mainly by increases in milk fat and milk protein yield (80.6%) and only to a small extent by fitness traits (6.6%). The inclusion of direct health traits (early reproductive disorders, cystic ovaries, and mastitis) with their economic weights increased the relative AMGG for fitness traits from 6.6 to 11.2%. The presently slightly negative AMGG for fertility index and udder health changed in a positive direction. Increasing the weight on the direct health traits by 50% resulted in a further shift toward fitness and health. The effect of strategies using genomic information in a total merit index (TMI) with varying weights on fitness and health traits was also analyzed. The conventional progeny-testing scheme was defined as the reference breeding program. A breeding program was considered to be genomically enhanced (GS50) when 50% of inseminations of herdbook cows and of bull dams were from young bulls with a genomic TMI, and a second program (GS100) did not rely on progeny-tested bulls at all. For GS50, a clear shift of the relative gain in AMGG toward fitness and health traits was observed for all 3 TMI scenarios, as a result of larger progeny groups and a shorter generation interval. For GS100, where no gene flow from progeny-tested bulls was assumed, the genetic gain per generation was lower for the fertility and udder health index but higher per year. The results based on natural genetic gain per year showed that no positive genetic response for fertility and udder health index were achieved for TMI-R (without the inclusion of direct health traits) in GS50 and GS100. The direction of the genetic trend was determined by the weights given to fertility and udder health indices within the TMI. When appropriate weights generated a clear positive trend, GS50 and GS100 reinforced this trend. PMID- 22818476 TI - Association of DGAT1 genotype, fatty acid composition, and concentration of copper in milk with spontaneous oxidized flavor. AB - In 136 cows with altogether 969 milk samples, we investigated the effect of the acyl-coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) K232A polymorphism on milk fatty acid (FA) composition and how, in combination with copper concentration in milk, this influences the occurrence of spontaneous oxidized flavor. All milk samples were analyzed for concentrations of copper and individual FA and subjected to sensory analysis by trained judges. We found an effect of DGAT1 genotype on FA composition where mainly the long-chain FA were affected. The 232A allele was associated with larger proportions of the C18:2 cis 9,trans-11 conjugated linoleic acid and lower proportions of C16:0 FA. Milk concentrations of unsaturated FA and copper showed strong and unfavorable associations with spontaneous oxidized flavor (SOF) development. The interaction between FA and copper indicates that SOF will not develop as easily in milk with high copper content unless the substrate is available (i.e., in addition to the previously shown effect of copper in milk, unsaturated FA are required for the process of oxidation to progress). We observed a marked effect of the DGAT1 genotype on SOF development where the A allele was associated with a higher risk of SOF. Moreover, our results suggest that the effects of the FA C18:3 n-3 and of the polyunsaturated index on SOF development are beyond the effect of the DGAT1 genotype. Breed had an effect on FA composition but not on SOF development. Our results imply that copper, FA composition, and DGAT1 genotype are risk factors for SOF and considerations to these factors might be necessary in future breeding decisions. PMID- 22818477 TI - Joint estimation of genetic parameters for test-day somatic cell count and mastitis in the United Kingdom. AB - Genetic parameters were estimated in a joint analysis of log(e)-transformed somatic cell count (TSCC) with either mastitis as a binary trait (MAS) or the number of mastitis cases (NMAS) in Holstein-Friesian cows for the first 3 lactations using a random regression model. In addition, a multi-trait analysis of MAS and NMAS was also implemented. There were 67,175, 30,617, and 16,366 cows with records for TSCC, MAS, and NMAS in lactations 1, 2, and 3, respectively. The frequency of MAS was 14, 20, and 25% in lactations 1, 2, and 3 respectively. The model for TSCC included herd-test-day, age at calving and month of calving, fixed lactation curves nested with calving year groups, and random regressions with Legendre polynomials of order 2 for animal and permanent environmental effects. The model for MAS and NMAS included fixed herd-year-season, age at calving and month of calving, and random animal and permanent environmental effects. All analyses were carried out using Gibbs sampling. Estimates of mean daily heritability averaged over a 305-d lactation were 0.11, 0.14, and 0.15 for TSCC for lactations 1, 2, and 3, respectively. Corresponding heritability estimates for MAS were 0.05, 0.07, and 0.09. The heritabilities for NMAS were similar at 0.06, 0.07, and 0.12, respectively, for lactations 1, 2, and 3. The genetic correlations between lactations 1 and 2, 1 and 3, and 2 and 3 were 0.75, 0.64, and 0.92 for computed 305-d lactation TSCC; 0.55, 0.48, and 0.89 for MAS; and 0.62, 0.42, and 0.85 for NMAS, respectively. The genetic correlations between MAS and TSCC were positive and generally moderate to high. The genetic correlations between computed 305-d lactation TSCC and MAS were 0.53, 0.61, and 0.68 in lactations 1, 2, and 3, respectively. Similar corresponding genetic correlations were obtained between computed 305-d lactation TSCC and NMAS in the respective parities. Mastitis as a binary trait and NMAS in the same lactation were very highly correlated and were genetically the same trait. It is intended that the new parameters will be used in setting up a national evaluation system for the joint analysis of TSCC and MAS. PMID- 22818478 TI - Computational strategies for national integration of phenotypic, genomic, and pedigree data in a single-step best linear unbiased prediction. AB - The single-step genomic BLUP (SSGBLUP) is a method that can integrate pedigree and genotypes at molecular markers in an optimal way. However, its present form (regular SSGBLUP) has a high computational cost (cubic in the number of genotyped animals) and may need extensive rewriting of genetic evaluation software. In this work, we propose several strategies to implement the single step in a simpler manner. The first one expands the single-step mixed-model equations to obtain equivalent equations from which the regular (including pedigree and records only) mixed-model equations are a subset. These new equations (unsymmetric extended SSGBLUP) have low computational cost, but require a nonsymmetric solver such as the biconjugate gradient stabilized method or successive underrelaxation, which is a variant of successive overrelaxation, with a relaxation factor lower than 1. In addition, we show a new derivation of the single-step method, which includes, as an extra effect, deviations from strictly polygenic breeding values. As a result, the same set of equations as above is obtained. We show that, whereas the new derivation shows apparent problems of nonpositive definiteness for certain covariance matrices, a proper equivalent model including imaginary effects always exists, leading always to the regular SSGBLUP mixed model equations. The system of equations can be solved (iterative SSGBLUP) by iterating between a pedigree and records evaluation and a genomic evaluation (each one solved by any iterative or direct method), whereas global iteration can use a block version of successive underrelaxation, which ensures convergence. The genomic evaluation can explicitly include marker or haplotype effects and possibly involve nonlinear (e.g., Bayesian by Markov chain Monte Carlo) methods. In a simulated example with 28,800 individuals and 1,800 genotyped individuals, all methods converged quickly to the same solutions. Using existing efficient methods with limited memory requirements to compute the products Gt and A(22)t for any t (where G and A(22) are genomic and pedigree relationships for genotyped animals, and t is a vector), all strategies can be converted to iteration on data procedures for which the total number of operations is linear in the number of animals + number of genotyped animals * number of markers. PMID- 22818479 TI - Long-term selection strategies for complex traits using high-density genetic markers. AB - Selection of animals for breeding ranked on estimated breeding value maximizes genetic gain in the next generation but does not necessarily maximize long-term response. An alternative method, as practiced by plant breeders, is to build a desired genotype by selection on specific loci. Maximal long-term response in animal breeding requires selection on estimated breeding values with constraints on coancestry. In this paper, we compared long-term genetic response using either a genotype building or a genomic estimated breeding value (GEBV) strategy for the Australian Selection Index (ASI), a measure of profit. First, we used real marker effects from the Australian Dairy Herd Improvement Scheme to estimate breeding values for chromosome segments (approximately 25 cM long) for 2,650 Holstein bulls. Second, we selected 16 animals to be founders for a simulated breeding program where, between them, founders contain the best possible combination of 2 segments from 2 animals at each position in the genome. Third, we mated founder animals and their descendants over 30 generations with 2 breeding objectives: (1) to create a population with the "ideal genotype," where the best 2 segments from the founders segregate at each position, or (2) obtain the highest possible response in ASI with coancestry lower than that achieved under breeding objective 1. Results show that genotype building achieved the ideal genotype for breeding objective 1 and obtained a large gain in ASI over the current population (+A$864.99). However, selection on overall GEBV had greater short-term response and almost as much long-term gain (+A$820.42). When coancestry was lowered under breeding objective 2, selection on overall GEBV achieved a higher response in ASI than the genotype building strategy. Selection on overall GEBV seems more flexible in its selection decisions and was therefore better able to precisely control coancestry while maximizing ASI. We conclude that selection on overall GEBV while minimizing average coancestry is the more practical strategy for dairy cattle where selection is for highly polygenic traits, the reproductive rate is relatively low, and there is low tolerance of coancestry. The outcome may be different for traits controlled by few loci of relatively large effects or for different species. In contrast to other simulations, our results indicate that response to selection on overall GEBV may continue for several generations. This is because long-term genetic change in complex traits requires favorable changes to allele frequencies for many loci located throughout the genome. PMID- 22818480 TI - Comparison of genomic predictions using medium-density (~54,000) and high-density (~777,000) single nucleotide polymorphism marker panels in Nordic Holstein and Red Dairy Cattle populations. AB - This study investigated genomic prediction using medium-density (~54,000; 54K) and high-density marker panels (~777,000; 777K), based on data from Nordic Holstein and Red Dairy Cattle (RDC). The Holstein data comprised 4,539 progeny tested bulls, and the RDC data 4,403 progeny-tested bulls. The data were divided into reference data and test data using October 1, 2001, as a cut-off date (birth date of the bulls). This resulted in about 25% genotyped bulls in the Holstein test data and 20% in the RDC test data. For each breed, 3 data sets of markers were used to predict breeding values: (1) 54K data set with missing genotypes, (2) 54K data set where missing genotypes were imputed, and (3) imputed high density (HD) marker data set created by imputing the 54K data to the HD data based on 557 bulls genotyped using a 777K single nucleotide polymorphism chip in Holstein, and 706 bulls in RDC. Based on the 3 marker data sets, direct genomic breeding values (DGV) for protein, fertility, and udder health were predicted using a genomic BLUP model (GBLUP) and a Bayesian mixture model with 2 normal distributions. Reliability of DGV was measured as squared correlations between deregressed proofs (DRP) and DGV corrected for reliability of DRP. Unbiasedness was assessed by regression of DRP on DGV, based on the bulls in the test data sets. Averaged over the 3 traits, reliability of DGV based on the HD markers was 0.5% higher than that based on the 54K data in Holstein, and 1.0% higher than that in RDC. In addition, the HD markers led to an improvement of unbiasedness of DGV. The Bayesian mixture model led to 0.5% higher reliability than the GBLUP model in Holstein, but not in RDC. Imputing missing genotypes in the 54K marker data did not improve genomic predictions for most of the traits. PMID- 22818481 TI - Temperature and relative humidity influence the microbial and physicochemical characteristics of Camembert-type cheese ripening. AB - To evaluate the effects of temperature and relative humidity (RH) on microbial and biochemical ripening kinetics, Camembert-type cheeses were prepared from pasteurized milk seeded with Kluyveromyces marxianus, Geotrichum candidum, Penicillium camemberti, and Brevibacterium aurantiacum. Microorganism growth and biochemical changes were studied under different ripening temperatures (8, 12, and 16 degrees C) and RH (88, 92, and 98%). The central point runs (12 degrees C, 92% RH) were both reproducible and repeatable, and for each microbial and biochemical parameter, 2 kinetic descriptors were defined. Temperature had significant effects on the growth of both K. marxianus and G. candidum, whereas RH did not affect it. Regardless of the temperature, at 98% RH the specific growth rate of P. camemberti spores was significantly higher [between 2 (8 degrees C) and 106 times (16 degrees C) higher]. However, at 16 degrees C, the appearance of the rind was no longer suitable because mycelia were damaged. Brevibacterium aurantiacum growth depended on both temperature and RH. At 8 degrees C under 88% RH, its growth was restricted (1.3 * 10(7) cfu/g), whereas at 16 degrees C and 98% RH, its growth was favored, reaching 7.9 * 10(9) cfu/g, but the rind had a dark brown color after d 20. Temperature had a significant effect on carbon substrate consumption rates in the core as well as in the rind. In the rind, when temperature was 16 degrees C rather than 8 degrees C, the lactate consumption rate was approximately 2.9 times higher under 88% RH. Whatever the RH, temperature significantly affected the increase in rind pH (from 4.6 to 7.7 +/- 0.2). At 8 degrees C, an increase in rind pH was observed between d 6 and 9, whereas at 16 degrees C, it was between d 2 and 3. Temperature and RH affected the increasing rate of the underrind thickness: at 16 degrees C, half of the cheese thickness appeared ripened on d 14 (wrapping day). However, at 98% RH, the underrind was runny. In conclusion, some descriptors, such as yeast growth and the pH in the rind, depended solely on temperature. However, our findings highlight the fact that the interactions between temperature and RH played a role in P. camemberti sporulation, B. aurantiacum growth, carbon substrate consumption rates, and the thickening of the cheese underrind. Moreover, the best ripening conditions to achieve an optimum between microorganism growth and biochemical kinetics were 13 degrees C and 94% RH. PMID- 22818482 TI - A simple formulation and solution to the replacement problem: a practical tool to assess the economic cow value, the value of a new pregnancy, and the cost of a pregnancy loss. AB - This study contributes to the research literature by providing a new formulation for the cow replacement problem, and it also contributes to the Extension deliverables by providing a user-friendly decision support system tool that would more likely be adopted and applied for practical decision making. The cow value, its related values of a new pregnancy and a pregnancy loss, and their associated replacement policies determine profitability in dairy farming. One objective of this study was to present a simple, interactive, dynamic, and robust formulation of the cow value and the replacement problem, including expectancy of the future production of the cow and the genetic gain of the replacement. The proven hypothesis of this study was that all the above requirements could be achieved by using a Markov chain algorithm. The Markov chain model allowed (1) calculation of a forward expected value of a studied cow and its replacement; (2) use of a single model (the Markov chain) to calculate both the replacement policies and the herd statistics; (3) use of a predefined, preestablished farm reproductive replacement policy; (4) inclusion of a farmer's assessment of the expected future performance of a cow; (5) inclusion of a farmer's assessment of genetic gain with a replacement; and (6) use of a simple spreadsheet or an online system to implement the decision support system. Results clearly demonstrated that the decision policies found with the Markov chain model were consistent with more complex dynamic programming models. The final user-friendly decision support tool is available at http://dairymgt.info/ -> Tools -> The Economic Value of a Dairy Cow. This tool calculates the cow value instantaneously and is highly interactive, dynamic, and robust. When a Wisconsin dairy farm was studied using the model, the solution policy called for replacing nonpregnant cows 11 mo after calving or months in milk (MIM) if in the first lactation and 9 MIM if in later lactations. The cow value for an average second-lactation cow was as follows: (1) when nonpregnant, (a) $897 in MIM = 1 and (b) $68 in MIM = 8; (2) when the cow just became pregnant,(a) $889 for a pregnancy in MIM = 3 and (b) $298 for a pregnancy in MIM = 8; and (3) the value of a pregnancy loss when a cow became pregnant in MIM = 5 was (a) $221 when the loss was in the first month of pregnancy and (b) $897 when the loss was in the ninth month of pregnancy. The cow value indicated pregnant cows should be kept. The expected future production of a cow with respect to a similar average cow was an important determinant in the cow replacement decision. The expected production in the rest of the lactation was more important for nonpregnant cows, and the expected production in successive lactations was more important for pregnant cows. A 120% expected milk production for a cow with MIM = 16 and 6 mo pregnant in the present lactation or in successive lactations determined between 1.52 and 6.48 times the cow value, respectively, of an average production cow. The cow value decreased by $211 for every 1 percentage point of expected genetic gain of the replacement. A break even analysis of the cow value with respect to expected milk production of an average second-parity cow indicated that (1) nonpregnant cows in MIM = 1 and 8 could still remain in the herd if they produced at least 84 and 98% in the present lactation or if they produced at least 78 and 97% in future lactations, respectively; and (2) cows becoming pregnant in MIM = 5 would require at least 64% of milk production in the rest of the lactation or 93% in successive lactations to remain in the herd. PMID- 22818483 TI - Retrospective evaluation of health event data recording on 50 dairies using Dairy Comp 305. AB - The purpose of this study was to characterize health data recording in herds using Dairy Comp 305 (Valley Agricultural Software, Tulare, CA), focused on the most common diseases of dairy cattle: mastitis, uterine infection (metritis), and diseases causing lameness. Herds using Dairy Comp 305 were chosen for the study because it was the most commonly used program in the United States (35% of operations using computer records/60% of cows on operations using computer records), the authors were familiar with the program, and there was convenient access to herds using the program. Specific objectives were to (1) determine the percentage of herds recording mastitis, metritis, and diseases causing lameness and the number of user-defined events used to record those diseases, (2) identify the information recorded in the remarks about the event used for each disease, and (3) evaluate the consistency of health event remarks recorded. A convenience sample of 50 Dairy Comp 305 compressed cow files was obtained directly from dairies that the authors had contact with or files obtained from industry consultants. The 50 herds included in the study were from 9 different states: California (n=3), Colorado (n=2), Iowa (n=2), Idaho (n=8), Minnesota (n=2), New Mexico (n=9), Oregon (n=2), Texas (n=2), Utah (n=1), and Washington (n=19). The average number of milking cows of the herds was 3,053 (median=2,217), ranging from 310 to 12,490 cows. The majority of dairies in this study were recording health events associated with mastitis, metritis, and diseases causing lameness. However, as reported previously, most health records observed in the current study lacked the accuracy and consistency needed to be useful for evaluating and informing herd-level health management decisions. This situation likely reflects the intended use of those records by farm personnel and the user-defined nature of health records in the absence of accepted industry standards or recommendations for health data-recording practices. PMID- 22818484 TI - How do dairy cows chew?--particle size analysis of selected feeds with different particle length distributions and of respective ingested bolus particles. AB - Not only feed but also respective bolus particle size could alter diet efficiency and cow performance. The objective of this project was to characterize particle size of selected feeds and respective swallowed boli. Feed samples included 6 different particle length rye grass hay samples, 1 grass silage, 1 corn silage, and 1 total mixed ration (TMR). Rye grass hay samples consisted of long hay and chopped hay particles retained on the 19- (19_PSPS hay), 8- (8_PSPS hay), and 1.18-mm (1.18_PSPS hay) Penn State Particle Separator (PSPS) screens and those collected on the pan (PSPS_pan hay). A sixth hay treatment was rye grass forage cut at 50-mm lengths and dried to hay (50-mm hay). Treatments were offered to 4 nonlactating and 4 lactating cows following rumen evacuation. Swallowed boli were collected and the number of chews per gram of ingested feed dry matter was determined. Feed and bolus particles of lengths >=5mm were collected on a 1.6-mm screen using a horizontal wet sieving technique. This cut point was chosen, as the literature suggests that most fecal particles are shorter than 5mm. Dry matter proportions on this screen (PROP_1.6) were determined and particle lengths of retained particles were measured by image analysis. Mean particle lengths (ML) were calculated considering particles >=5mm in length. Boli of long hay, of 19_PSPS hay, of 8_PSPS hay, and of 50-mm hay had similar ML of 10 to 11mm. Bolus PROP_1.6 were also similar between these treatments, ranging from 0.54 to 0.69. Bolus particle lengths and distributions of these treatments were not related to respective hay particles. Bolus of 1.18_PSPS hay had PROP_1.6 of 0.51 and a smaller ML of 8mm. The PSPS_pan hay had PROP_1.6 of only 0.33, but was still chewed intensely. Apparently, little particle size reduction occurred when cows ate the TMR or the silages. Feed and respective bolus PROP_1.6 were as follows: 0.66 and 0.59 in grass silage, 0.52 and 0.55 in corn silage, and 0.44 and 0.38 in the TMR. Feed and respective bolus ML were as follows: 13.8 and 11.6mm in grass silage, 12.0 and 11.2mm in corn silage, and 13.1 and 12.5mm in the TMR. Rye grass hay particles retained on PSPS screens >=8mm, with ML of at least 25mm were longer compared with TMR particles, but respective bolus particles were shorter. Bolus particle size is not associated with the size of large feed particles chewed to a constant size that is appropriate for deglutition. This size may be related to feed chemical composition. PMID- 22818485 TI - International genetic evaluation of Holstein bulls for overall type traits and body condition score. AB - The study documents the procedures used to estimate genetic correlations among countries for overall conformation (OCS), overall udder (OUS), overall feet and legs (OFL), and body condition score (BCS) of Holstein sires. Major differences in traits definition are discussed, in addition to the use of international breeding values (IBV) among countries involved in international genetic evaluations, and similarities among countries through hierarchical clustering. Data were available for populations from 20 countries for OCS and OUS, 18 populations for OFL, and 11 populations for BCS. The IBV for overall traits and BCS were calculated using a multi-trait across-country evaluation model. Distance measures, obtained from genetic correlations, were used as input values in the cluster analysis. Results from surveys sent to countries participating in international genetic evaluation for conformation traits showed that different ways of defining traits are used: the overall traits were either computed from linear or composite traits or defined as general characteristics. For BCS, populations were divided into 2 groups: one scored and evaluated BCS, and one used a best predictor. In general, populations were well connected except for Estonia and French Red Holstein. The average number of common bulls for the overall traits ranged from 19 (OCS and OUS of French Red Holstein) to 514 (OFL of United States), and for BCS from 17 (French Red Holstein) to 413 (the Netherlands). The average genetic correlation (range) across countries was 0.75 (0.35 to 0.95), 0.80 (0.41 to 0.95), and 0.68 (0.12 to 0.89) for OCS, OUS, and OFL, respectively. Genetic correlations among countries that used angularity as best predictor for BCS and countries that scored BCS were negative. The cluster analysis provided a clear picture of the countries distances; differences were due to trait definition, trait composition, and weights in overall traits, genetic ties, and genotype by environment interactions. Harmonization of trait definition and increasing genetic ties could improve genetic correlations across countries and reduce the distances. In each national selection index, all countries, except Estonia and New Zealand, included at least one overall trait, whereas none included BCS. Out of 18 countries, 9 have started genomic evaluation of conformation traits. The first were Canada, France, New Zealand, and United States in 2009, followed by Switzerland, Germany, and the Netherlands in 2010, and Australia and Denmark-Finland-Sweden (joint evaluation) in 2011. Six countries are planning to start soon. PMID- 22818486 TI - Associations among social capital, parenting for active lifestyles, and youth physical activity in rural families living in upstate New York. AB - While emerging research supports a positive relationship between social capital and youth physical activity (PA), few studies have examined possible mechanisms explaining this relationship and no studies have focused on rural youth. In this study, we examined parents' support of children's PA as an intermediary factor linking social capital and youth PA in a largely rural cross sectional sample of American children aged 6- to 19-years and their parents/guardians (N=767 families) living in upstate New York. Parents completed a self-administered survey assessing demographic factors, perceived social capital, support for children's PA, and children's PA including time spent outdoors and days per week of sufficient PA. Structural equation modeling was used to test the hypothesis that higher social capital is linked with higher parental support for PA and, in turn, higher PA in children. Analyses were conducted separately for younger (6-12 years) and older (13-19 years) children and controlled for demographic factors (child age, household education, participation in a food assistance program) and perceived neighborhood safety. Anticipated relationships among social capital, parents' activity-related support, and children's PA were identified for older, but not younger children. Findings suggest that parent support for children's PA is one possible mechanism linking social capital and youth PA and the parents of adolescents may rely more heavily on cues from their social environment to shape their approaches to supporting their children's PA than parents of younger children. PMID- 22818487 TI - Nighttime parenting strategies and sleep-related risks to infants. AB - A large social science and public health literature addresses infant sleep safety, with implications for infant mortality in the context of accidental deaths and Sudden Infant Death Syndrome (SIDS). As part of risk reduction campaigns in the USA, parents are encouraged to place infants supine and to alter infant bedding and elements of the sleep environment, and are discouraged from allowing infants to sleep unsupervised, from bed-sharing either at all or under specific circumstances, or from sofa-sharing. These recommendations are based on findings from large-scale epidemiological studies that generate odds ratios or relative risk statistics for various practices; however, detailed behavioural data on nighttime parenting and infant sleep environments are limited. To address this issue, this paper presents and discusses the implications of four case studies based on overnight observations conducted with first-time mothers and their four-month old infants. These case studies were collected at the Mother Baby Behavioral Sleep Lab at the University of Notre Dame USA between September 2002 and June 2004. Each case study provides a detailed description based on video analysis of sleep-related risks observed while mother-infant dyads spent the night in a sleep lab. The case studies provide examples of mothers engaged in the strategic management of nighttime parenting for whom sleep-related risks to infants arose as a result of these strategies. Although risk reduction guidelines focus on eliminating potentially risky infant sleep practices as if the probability of death from each were equal, the majority of instances in which these occur are unlikely to result in infant mortality. Therefore, we hypothesise that mothers assess potential costs and benefits within margins of risk which are not acknowledged by risk-reduction campaigns. Exploring why mothers might choose to manage sleep and nighttime parenting in ways that appear to increase potential risks to infants may help illuminate how risks occur for individual infants. PMID- 22818488 TI - Women's health in urban Mali: social predictors and health itineraries. AB - Social and marital factors may influence women's health outcomes. This is of particular relevance in sub-Saharan Africa, where women's health indicators lag behind the rest of the world. Our study examines the impact of social mediators of women's health during key events (pregnancy and illness) in urban Mali. In this cross-sectional study, we interviewed 324 women aged 15-80, living in Bamako, the capital city, in 1999. We used mixed quantitative and qualitative methods to obtain detailed histories of pregnancy and illness during specific time periods preceding the survey. We examined the role of marital factors (polygyny, widowhood), social factors (sources of support and scales derived for social network and social power), and household wealth on women's therapeutic itineraries. We compared the sociodemographic characteristics of our sample with those of the 2001 Mali Demographic and Health Survey and used their data on contraception to enrich analyses. We found that most pregnant women delivered in a health center and most women sought medical care during an illness event. Household wealth influenced illness reporting, and financial concerns were obstacles to medical care. Polygyny was associated with lower prevalence of contraceptive use, lower social power, as well as with less support received during pregnancy from women's husbands and in-laws. Widowhood appeared to increase susceptibility to illness, while decreasing resort to biomedical care. Our social composite scores highlighted differences in healthcare utilization in an urban setting with near-uniform access to biomedical care. We validate the utility of locally-derived composite scores, which may provide a deeper understanding into the social mediation of health outcomes for women. PMID- 22818489 TI - Early childhood economic disadvantage and the health of Hispanic children. AB - This research provides a longitudinal view of early childhood economic deprivation and its associations with health among young Hispanic children born in the United States. Of additional interest is whether economic deprivation is associated with child health similarly across all Hispanic children or whether associations differ by maternal nativity or country of origin. Fragile Families and Child Wellbeing data and multinomial logistic regression are used to estimate the effects of total years in poverty, material hardship, and lack of health insurance on Hispanic children's health status at age 5 and change in health status between ages 1 and 5. Results show that multiple measures of early childhood economic deprivation have additive negative associations with Hispanic child health, and that living more years in poverty is associated with declining health status among young Hispanic children. Interaction effects indicate that early childhood poverty has stronger associations with lower age 5 health status and declining health between ages 1 and 5 for children with foreign-born Hispanic mothers than for those with native-born Hispanic mothers. No differences were found in the associations between economic deprivation and child health by maternal country of origin. These results suggest an important role of economic resources for protecting Hispanic child health, and that poor Hispanic children with immigrant mothers may be at particularly high risk of developing health problems as they move out of infancy and into early childhood. PMID- 22818490 TI - Does socio-economic status explain use of modern and traditional health care services? AB - Although socioeconomic status is acknowledged to be an important determinant of modern health care utilisation, most analyses to date have failed to include traditional systems as alternative, or joint, providers of care. In developing countries, where pluralistic care systems are common, individuals are likely to be using multiple sources of health care, and the order in which systems are chosen is likely to vary according to income. This paper uses self-collected data from households in Ghana and econometric techniques (biprobit modelling and ordered logit) to show that rising income is associated with modern care use whilst decreasing income is associated with traditional care use. When utilisation is analysed in order, results show rising income to have a positive effect on choice of modern care as a first provider, whilst choosing it second, third or never is associated with decreasing income. The effects of income on utilisation patterns of traditional care are stronger: as income rises, utilisation of traditional care as a first choice decreases. Policy should incorporate traditional care into the general utilisation framework and recognise that strategies which increase income may encourage wider utilisation of modern over traditional care, whilst high levels of poverty will see continued use of traditional care. PMID- 22818492 TI - Inorganic materials using 'unusual' microorganisms. AB - A promising avenue of research in materials science is to follow the strategies used by Mother Nature to fabricate ornate hierarchical structures as exemplified by organisms such as diatoms, sponges and magnetotactic bacteria. Some of the strategies used in the biological world to create functional inorganic materials may well have practical implications in the world of nanomaterials. Therefore, the strive towards exploring nature's ingenious work for designing strategies to create inorganic nanomaterials in our laboratories has led to development of biological and biomimetic synthesis routes over the past decade or so. A large proportion of these relentless efforts have explored the use of those microorganisms, which are typically not known to encounter these inorganic materials in their natural environment. Therefore, one can consider these microorganisms as 'unusual' for the purpose for which they have been utilized - it is in this context that this review has been penned down. In this extensive review, we discuss the use of these 'unusual' microorganisms for deliberate biosynthesis of various nanomaterials including biominerals, metals, sulfides and oxides nanoparticles. In addition to biosynthesis approach, we have also discussed a bioleaching approach, which can provide a noble platform for room temperature synthesis of inorganic nanomaterials using naturally available raw materials. Moreover, the unique properties and functionalities displayed by these biogenic inorganic materials have been discussed, wherever such properties have been investigated previously. Finally, towards the end of this review, we have made efforts to summarize the common outcomes of the biosynthesis process and draw conclusions, which provide a perspective on the current status of the biosynthesis research field and highlights areas where future research in this field should be directed to realize the full potential of biological routes towards nanomaterials synthesis. Furthermore, the review clearly demonstrates that the biological route to inorganic materials synthesis is not merely an addition to the existing list of synthesis routes; biological routes using 'unusual' microorganisms might in fact provide an edge over other nanomaterials synthesis routes in terms of their eco-friendliness, low energy intensiveness, and economically-viable synthesis. This review has significant importance for colloids and interface science since it underpins the synthesis of colloidal materials using 'unusual' microorganism, wherein the role of biological interfaces for controlled synthesis of technologically important nanomaterials is clearly evident. PMID- 22818491 TI - Geographic variation in participation for physically disabled adults: the contribution of area economic factors to employment after spinal cord injury. AB - This study investigates the role of area economic characteristics in predicting employment-a key aspect of social participation for adults with physical disabilities-using data from a national registry of persons with spinal cord injury (SCI). SCI results in chronic impairment and most commonly occurs during young adulthood when working is a key aspect of the adult social role. Geocoded data were collected from two of the 14 SCI Model Systems (SCIMS) centers involved in the National SCIMS database and used to link individual-level data with area level measures extracted from the 2000 US Census. The analysis included participants of working-age (18-64 years) and living in the community (N=1013). Hierarchical generalized linear modeling was used to estimate area-level variation in participation and the relative contribution of area-level economic indicators, adjusted for individual-level health, functioning, and background characteristics. The likelihood of employment for adults with SCI varied by area and was associated with area SES and urbanicity, but not area unemployment. These findings suggest that variation in area economic conditions may affect the feasibility of employment for persons who experience chronic physical disability during adulthood, thus limiting full participation in society. PMID- 22818493 TI - The cessation in pregnancy incentives trial (CPIT): study protocol for a randomized controlled trial. AB - BACKGROUND: Seventy percent of women in Scotland have at least one baby, making pregnancy an opportunity to help most young women quit smoking before their own health is irreparably compromised. By quitting during pregnancy their infants will be protected from miscarriage and still birth as well as low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. In the UK, the NICE guidelines: 'How to stop smoking in pregnancy and following childbirth' (June 2010) highlighted that little evidence exists in the literature to confirm the efficacy of financial incentives to help pregnant smokers to quit. Its first research recommendation was to determine: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? DESIGN AND METHODS: This study is a phase II exploratory individually randomized controlled trial comparing standard care for pregnant smokers with standard care plus the additional offer of financial voucher incentives to engage with specialist cessation services and/or to quit smoking during pregnancy.Participants (n = 600) will be pregnant smokers identified at maternity booking who, when contacted by specialist cessation services, agree to having their details passed to the NHS Smokefree Pregnancy Study Helpline to discuss the trial. The NHS Smokefree Pregnancy Study Helpline will be responsible for telephone consent and follow-up in late pregnancy. The primary outcome will be self reported smoking in late pregnancy verified by cotinine measurement. An economic evaluation will refine cost data collection and assess potential cost effectiveness while qualitative research interviews with clients and health professionals will assess the level of acceptance of this form of incentive payment. The research questions are: What is the likely therapeutic efficacy? Are incentives potentially cost-effective? Is individual randomization an efficient trial design without introducing outcome bias? Can incentives be introduced in a way that is feasible and acceptable? DISCUSSION: This phase II trial will establish a workable design to reduce the risks associated with a future definitive phase III multicenter randomized controlled trial and establish a framework to assess the costs and benefits of financial incentives to help pregnant smokers to quit. TRIAL REGISTRATION: Current Controlled Trials ISRCTN87508788. PMID- 22818494 TI - More than just a cut: a qualitative study of penile practices and their relationship to masculinity, sexuality and contagion and their implications for HIV prevention in Papua New Guinea. AB - BACKGROUND: Male circumcision (MC) has been shown to reduce vaginal transmission of HIV to men. While community acceptability is important in a countries preparedness to introduce MC, it is equally important to map contemporary MC and other penile cutting practices, and the socio-cultural dimensions underpinning these practices. METHODS: A total of 482 men and women (n = 276 and n = 210, respectively) participated in 82 semi-structured and 45 focus group discussions from four different provinces of Papua New Guinea (PNG), each representing one of the four socially and geographically diverse regions of the country. RESULTS: Of the men interviewed 131 self-reported that they had undergone a penile alteration with some reporting multiple types. Practices were diverse and could be grouped into five broad categories: traditional (customary) penile cutting; contemporary penile cutting; medical circumcision; penile inserts; and penile bloodletting practices in which sharp objects are used to incise the glans and or inserted and withdrawn from the male urethra or in order to induce bleeding. Socio-cultural traditions, enhanced sexual pleasure and improved genital hygiene were key motivators for all forms of penile practices. CONCLUSIONS: The findings from this study highlight the complex and diverse nature of penile practices in PNG and their association with notions of masculinity, sexuality and contagion. Contemporary penile practices are critical to a community's acceptance of MC and of a country's ability to successfully implement MC in the context of a rich and dynamic culture of penile practices. If a MC program were to be successfully rolled out in PNG to prevent HIV it would need to work within and build upon these diverse cultural meanings and motivators for penile practices already commonly performed in PNG by men. PMID- 22818495 TI - Changes in transfusion practice over time in adult patients undergoing liver transplantation. AB - OBJECTIVE: The aim of this study was to investigate changes in transfusion practice over time in liver transplantation surgery and to evaluate potential causes for changes in practice and report associated perioperative morbidity and mortality. DESIGN: A retrospective cohort study. SETTING: A single tertiary referral academic hospital. PARTICIPANTS: Two cohorts of 100 sequential adult primary liver transplant recipients: Early practice (1990-1991) and recent practice (2005-2006). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Perioperative transfusion and hemoglobin data were recorded. Mortality and postoperative complications were identified up to 30 days postoperatively. Appropriate intergroup statistical comparisons were made; p <= 0.05 was considered statistically significant. Compared with the early group, the recent group had significantly fewer perioperative allogeneic red blood cell transfusions, intraoperative autotransfusions, and transfusions of other blood products. No change in perioperative transfusion triggers was identified. There were no significant alterations in perioperative morbidity or mortality. CONCLUSIONS: When compared with patients in the early group, recent cohort patients received significantly fewer blood transfusions. The authors attribute this observation to changes in surgical technique rather than a significant alteration in transfusion triggers over the studied time period. PMID- 22818496 TI - Fibrinogen concentrate therapy in complex cardiac surgery. AB - OBJECTIVES: Fibrinogen concentrate increasingly is used to treat coagulopathic bleeding in cardiac surgery although its effectiveness and safety have not been shown. The authors conducted a cohort study to quantify the effects of fibrinogen concentrate on postoperative blood loss and transfusion and the occurrence of adverse clinical events in complex cardiac surgery patients. DESIGN: A cohort analysis using prospectively collected data. SETTING: A teaching hospital. PARTICIPANTS: One thousand seventy-five patients who underwent complex cardiac surgery in the years 2007 to 2010. INTERVENTION: A nonrandomized intervention with fibrinogen concentrate during complex cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Of the 1,075 patients, 264 (25%) received fibrinogen concentrate during surgery (median dose = 2 g). In the adjusted analysis, the effect of fibrinogen concentrate on blood loss and transfusion in the intensive care unit showed a ratio of geometric means of 1.02 (0.91-1.14) and an odds ratio of 1.14 (0.83 1.56), respectively. For the risk of 30-day mortality, myocardial infarction, cerebrovascular accident/transient ischemic attack, renal insufficiency/failure, total infections, and prolonged mechanical ventilation the adjusted odds ratios were 0.96 (0.48-1.92), 1.10 (0.53-2.27), 1.16 (0.50-2.72), 0.62 (0.29-1.32), 1.18 (0.72-1.95), and 1.44 (0.83-2.49), respectively. CONCLUSIONS: Fibrinogen concentrate infusion during surgery did not reduce postoperative blood loss and transfusion, and no increased risk for clinical adverse events was measured. The lower doses and the relatively late intervention with fibrinogen concentrate might have attenuated its hemostatic effect. This study reports the initial clinical use of fibrinogen concentrate in complex cardiac surgery. A randomized clinical trial has been initiated to investigate the hemostatic role of fibrinogen concentrate in cardiac surgery. PMID- 22818497 TI - Cerebral oxygenation impairment and S-100beta protein release during off-pump coronary artery revascularization. AB - OBJECTIVE: To elucidate the magnitude of global cerebral oxygenation impairment, using cerebral oxygenation indices and S-100beta protein as potential markers, during off-pump coronary artery bypass grafting (OPCAB). DESIGN: Prospective cohort study. SETTING: Tertiary cardiac center. PARTICIPANTS: Thirty-five patients undergoing OPCAB. INTERVENTIONS: Jugular bulb and arterial blood samples for cerebral oxygenation indices (arterial oxygen and carbon dioxide partial pressures, jugular bulb oxygen saturation, arterial-jugular bulb oxygen content, arterial-jugular carbon dioxide partial pressure, brain oxygen extraction ratio, and estimated respiratory quotient) and S-100beta protein determination were collected at anesthesia induction; anterior, inferior, and posterior wall anastomoses; after sternal closure; and 6 hours postoperatively. Concomitant hemodynamic data were obtained. The S-100beta determination was extended to 12 and 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Heart positioning for the target vessel exposure induced significant hemodynamic deterioration (p < 0.001). Although cerebral oxygenation indices were influenced adversely by a low cardiac-output state mainly during vertical heart dislocation (p < 0.001), they remained within normal limits. Hemodynamic and cerebral oxygenation statuses reverted to baseline within 6 hours postoperatively. Similarly, S-100beta jugular bulb and arterial protein levels presented a gradual increase, which peaked by the end of surgery (means, 0.54 and 0.62 MUg/L, respectively; p < 0.001) and then decreased by the first postoperative day. Jugular bulb-arterial S-100beta levels were maximized during posterior wall anastomosis (0.098 MUg/L; p < 0.01). CONCLUSION: Although exposure of the 3 main coronary arteries during OPCAB promotes derangement of the cerebral oxygen indices and S-100beta release, this seems to be transient, remains within the near-normal range, and is reversible almost completely 6 hours postoperatively. PMID- 22818498 TI - Percutaneous dilatation tracheostomy in the critically ill: use of ultrasound to detect an aberrant course of the brachiocephalic trunk. PMID- 22818512 TI - Gender, violence and brief interventions for alcohol in the emergency department. AB - BACKGROUND: The impact of gender and violence on brief interventions (BIs) for alcohol use in the emergency department (ED) has not been studied. Our objective was to examine the effectiveness of alcohol BIs in an ED population stratified by gender and violence. METHODS: This was a secondary analysis of datasets pooled from three ED-based randomized controlled studies of alcohol BIs. AUDIT-C was the primary outcome measure; secondary outcomes were binge drinking and achievement of NIAAA safe drinking levels. We conducted univariate comparisons and developed generalized linear models (GLM) for the primary outcome and generalized estimating equation (GEE) models for secondary outcomes to examine the intervention effect on the whole study group, gender-stratified subgroups, and gender- and violence-stratified subgroups. RESULTS: Of 1219 participants enrolled, 30% were female; 31% of women and 42% of men reported violence involvement at baseline. In univariate analysis, no differences in outcomes were found between intervention and control groups for any subgroup. However, in multivariable models, men demonstrated an intervention effect for likelihood of safe drinking limits. Stratifying further by violence, only men without violence involvement demonstrated a positive intervention effect for safe drinking limits. There was no evidence of an intervention effect on women. CONCLUSIONS: Analyzing the overall effect of ED-based BI may mask its ability to improve alcohol-related outcomes in a subset of the population. Alternatively, interventions may need to be significantly improved in subsets of the ED population, e.g., in women and in men with involvement in violence. PMID- 22818514 TI - Utilizing a multimodal assessment strategy to examine variations of impulsivity among young adults engaged in co-occurring smoking and binge drinking behaviors. AB - BACKGROUND: Smoking among young adults predicts a greater severity of alcohol use and contributes to an increased difficulty in maturing out of heavy drinking behaviors that are established during college. Moreover, research has implicated impulsivity in the initiation and maintenance of both behaviors. Much less is known, however, about potential variations of impulsivity among young adults and whether a relationship exists between this construct and abstinence from smoking. As a result, this study examined differences and changes in trait and behavioral indices of impulsivity as a function of binge drinking among a sample of cigarette smokers using a multimodal assessment strategy. METHODS: Participants (N=40) were regular cigarette smokers who reported engagement in binge drinking or no binge drinking during the past year. All participants completed self-report and behavioral assessments of impulsivity prior to and following a period of smoking abstinence. RESULTS: Compared to their non-binge drinking peers, binge drinking smokers reported significantly higher scores on the UPPS (lack of) Premeditation factor (p<.05), while also exhibiting a greater deficit in inhibitory control while in a nicotine satiated state (p<.05). However, no significant differences of inhibitory control were observed between groups following the 24-h deprivation period. CONCLUSIONS: Findings suggest that baseline differences in lack of planning and inhibitory control exist among young adults who concurrently smoke and binge drink. These results provide preliminary data for the need of tailored interventions for this population. PMID- 22818513 TI - Risk for prescription opioid misuse among patients with a history of substance use disorder. AB - BACKGROUND: History of substance use disorder (SUD) is associated with risk for prescription opioid misuse in chronic pain patients; however, little data are available regarding risk for prescription opioid misuse within the subgroup of patients with SUD histories. METHODS: Participants with chronic pain, histories of SUD, and current opioid prescriptions were recruited from a single VA Medical Center. Participants (n=80) completed measures of risk for prescription opioid misuse, pain severity, pain-related interference, pain catastrophizing, attitudes about managing pain, emotional functioning, and substance abuse. RESULTS: Participants were divided into three groups based on risk for prescription opioid misuse, as assessed by the Pain Medication Questionnaire (PMQ). Participants in the High-PMQ group reported more pain severity, interference, catastrophizing, depressive symptoms, and lowest self-efficacy for managing pain, relative to the Low-PMQ group; the High-PMQ group and Moderate-PMQ group differed on measures of pain severity, catastrophizing, and psychiatric symptoms (all p-values <0.05). The High-PMQ group had the highest rates of current SUD (32% versus 20% and 0, p=0.009). A regression analysis evaluated factors associated with PMQ scores: pain catastrophizing was the only variable significantly associated with risk for prescription opioid misuse. CONCLUSIONS: Among patients with SUD histories, those with higher risk for prescription opioid misuse reported more pain and impairment, symptoms of depression, and were more likely to have current SUD, relative to patients with lower risk for prescription opioid misuse. In adjusted analyses, pain catastrophizing was significantly associated with risk for prescription opioid misuse, but current SUD status was not a significant predictor. PMID- 22818515 TI - RNA virus genetic robustness: possible causes and some consequences. AB - In general terms, robustness is the capacity of biological systems to function in spite of genetic or environmental perturbations. The small and compacted genomes and high mutation rates of RNA viruses, as well as the ever-changing environments wherein they replicate, create the conditions for robustness to be advantageous. In this review, I will enumerate possible mechanisms by which viral populations may acquire robustness, distinguishing between mechanisms that are inherent to virus replication and population dynamics and those that result from the interaction with host factors. Then, I will move to review some evidences that RNA virus populations are robust indeed. Finally, I will comment on the implications of robustness for virus evolvability, the emergence of new viruses and the efficiency of lethal mutagenesis as an antiviral strategy. PMID- 22818517 TI - Right superior longitudinal fasciculus: implications for visuospatial neglect mimicking Gerstmann's syndrome. PMID- 22818518 TI - Symptomatic epidural cerebrospinal fluid collection following lumbar puncture and aneurysm clipping. PMID- 22818516 TI - Prevalence of multisite musculoskeletal symptoms: a French cross-sectional working population-based study. AB - BACKGROUND: The musculoskeletal disorders in working population represent one of the most worrying work-related health issues at the present time and although the very great majority of available data on the subject focus on musculoskeletal disorders defined by anatomical site, a growing number of studies indicate the low prevalence of disorders strictly confined to a specific anatomical site. The objective of this study was to describe the prevalence and characteristics of multisite musculoskeletal symptoms (multisite MS) in a large French working population. METHODS: This study was performed on surveillance data of the cross sectional survey (2002-2005) conducted by a network of occupational physicians in the working population of the Loire Valley region (from 20 to 59 years old). Data concerning MS were collected in the waiting room of the occupational physicians by means of the self-administrated standardized NORDIC questionnaire. RESULTS: The study population comprised 3,710 workers (2,162 men (58%) and 1,548 women (42%)) with a mean age of 38.4 years (standard deviation: 10.4 years). The prevalence of MS during the past 12 months was 83.8% with 95% confidence interval of [82.8-85.3] for men and 83.9% [82.0-85.7] for women. The prevalence of subacute MS (lasting at least 30 days) over the past 12 months was 32.8% [30.9 34.8] for men and 37.3% [34.9-39.7] for women. Two-thirds of workers reported MS in more than one anatomical site and about 20% reported MS lasting at least 30 days in more than one anatomical site. The anatomical sites most frequently associated with other MS were the upper back, hip, elbow and neck. The majority of these multisite MS were widespread, involving at least two of the three anatomical regions (upper limb, axial region and lower limb). CONCLUSIONS: The frequency and extent of multisite MS reported by workers are considerable. Further research must be conducted in this field in order to provide a better understanding of the characteristics and determinants of these multisite MS. PMID- 22818519 TI - Nurse migration and health workforce planning: Ireland as illustrative of international challenges. AB - Ireland began actively recruiting nurses internationally in 2000. Between 2000 and 2010, 35% of new recruits into the health system were non-EU migrant nurses. Ireland is more heavily reliant upon international nurse recruitment than the UK, New Zealand or Australia. This paper draws on in-depth interviews (N=21) conducted in 2007 with non-EU migrant nurses working in Ireland, a quantitative survey of non-EU migrant nurses (N=337) conducted in 2009 and in-depth interviews conducted with key stakeholders (N=12) in late 2009/early 2010. Available primary and secondary data indicate a fresh challenge for health workforce planning in Ireland as immigration slows and nurses (both non-EU and Irish trained) consider emigration. Successful international nurse recruitment campaigns obviated the need for health workforce planning in the short-term, however the assumption that international nurse recruitment had 'solved' the nursing shortage was short-lived and the current presumption that nurse migration (both emigration and immigration) will always 'work' for Ireland over-plays the reliability of migration as a health workforce planning tool. This article analyses Ireland's experience of international nurse recruitment 2000-2010, providing a case study which is illustrative of health workforce planning challenges faced internationally. PMID- 22818520 TI - [Diagnosis and management of uterine perforations after intrauterine device insertion: a report of 11 cases]. AB - OBJECTIVE: Intrauterine device insertion is common. It is however not harmless and uterine perforation can be serious. PATIENTS AND METHODS: Eleven cases of uterine perforation after intrauterine device insertion were listed at Tourcoing hospital between 2005 and 2009. They were analyzed to identify risk factors of uterine perforation and specify management. RESULTS: The main symptom was pelvic pain (4 cases), pregnancy occurrence (3 cases) or inability to remove the IUD (2 cases). The intrauterine device was set during the first 9 months of post-partum in 7 cases, 2 patients were still breastfeeding. Seven patients underwent laparoscopy, 2 needed switch for laparotomy, one was treated by laparotomy only and one was lost of follow-up. DISCUSSION AND CONCLUSION: Incidence of uterine perforation after IUD insertion ranges from 0,1 to 3/1000. Pelvic pain is the most revealing symptom. Fifteen percent of perforations complicate with adjacent organ lesion. Perforation incidence seems greater if the intrauterine device is set during the 6 first weeks of post-partum and breastfeeding, but non influenced by operator practical experience. Ultrasound follow-up of patients carrying intrauterine device is controversial. Facing a suspicion of ectopic intrauterine device, pelvic ultrasound examination is the first step imaging modality and using 3D could be useful. If it fails to localize the intrauterine device, an abdominal X-ray must be performed. Ectopic intrauterine device removal is recommended. PMID- 22818521 TI - [Preterm birth: evolution 1994 to 2006]. AB - OBJECTIVE: Evaluate the incidence of births before 33 weeks of amenorrhea over a 12-year period and the place of prematurity induced among them. Determine the evolution of various causes of birth prior to that and draw up a detailed inventory. PATIENTS AND METHODS: This is a retrospective study from 1994 to 2006, concerning mothers who gave birth in the Network Users Association of computerized records in Pediatrics, Obstetrics and Gynecology (AUDIPOG) between 22 and 32+6 days of maternity. A total of 3781 deliveries were included. The statistical significance of links between the degree of prematurity (high prematurity/extreme prematurity) and the type of prematurity (induced/spontaneous) or mode of early work in the event of induced prematurity (trigger/prior cesarean work) was determined. The evolution of different etiologies was also studied with a complete inventory in 2006. RESULTS: We observed a significant increase in the rate of births before 33 SA: it was multiplied by 3 in 12 years and stood at 1.7% of births in 2006. No increase in prematurity induced was observed, but in case of preterm labor induced the number of births by caesarean section increased significantly. Concerning the evolution of etiologies, vaginal and urinary infections decreased the most, followed by fetal malformations. Only multiple pregnancies increased significantly. The principle cause of preterm birth was hypertension. Prior to 28 SA, premature births were caused by metrorrhagia and infections at greater levels than 28-32 SA. DISCUSSION AND CONCLUSION: The growing number of births before 33 SA is a serious phenomenon that must be monitored as they are increasingly common in France. PMID- 22818523 TI - Alkaloids from Melodinus yunnanensis. AB - Ten monoterpenoid indole alkaloids, namely meloyine, 19S-methoxytubotaiwine N4 oxide, 16,19-epoxy-Delta14-vincanol, 14beta-hydroxymeloyunine, meloyunine, Delta14-vincamenine N4-oxide, 16beta,21beta-epoxy-vincadine, 14beta,15beta-20S quebrachamine, 3-oxo-voaphylline, 2alpha,7alpha-dihydroxy-dihydrovoaphylline, and 32 known alkaloids were isolated from leaves and twigs of Melodinus yunnanensis. Their structures were elucidated based on 1- and 2-D NMR, FTIR, UV, and MS spectroscopic data. Meloyine I showed weak cytotoxic activity against four human cancer cell lines: MCF-7 breast cancer, SMMC-7721 hepatocellular carcinoma, HL-60 myeloid leukemia, and A-549 lung cancer. PMID- 22818522 TI - The influence of DNA sequence on epigenome-induced pathologies. AB - Clear cause-and-effect relationships are commonly established between genotype and the inherited risk of acquiring human and plant diseases and aberrant phenotypes. By contrast, few such cause-and-effect relationships are established linking a chromatin structure (that is, the epitype) with the transgenerational risk of acquiring a disease or abnormal phenotype. It is not entirely clear how epitypes are inherited from parent to offspring as populations evolve, even though epigenetics is proposed to be fundamental to evolution and the likelihood of acquiring many diseases. This article explores the hypothesis that, for transgenerationally inherited chromatin structures, "genotype predisposes epitype", and that epitype functions as a modifier of gene expression within the classical central dogma of molecular biology. Evidence for the causal contribution of genotype to inherited epitypes and epigenetic risk comes primarily from two different kinds of studies discussed herein. The first and direct method of research proceeds by the examination of the transgenerational inheritance of epitype and the penetrance of phenotype among genetically related individuals. The second approach identifies epitypes that are duplicated (as DNA sequences are duplicated) and evolutionarily conserved among repeated patterns in the DNA sequence. The body of this article summarizes particularly robust examples of these studies from humans, mice, Arabidopsis, and other organisms. The bulk of the data from both areas of research support the hypothesis that genotypes predispose the likelihood of displaying various epitypes, but for only a few classes of epitype. This analysis suggests that renewed efforts are needed in identifying polymorphic DNA sequences that determine variable nucleosome positioning and DNA methylation as the primary cause of inherited epigenome induced pathologies. By contrast, there is very little evidence that DNA sequence directly determines the inherited positioning of numerous and diverse post translational modifications of histone side chains within nucleosomes. We discuss the medical and scientific implications of these observations on future research and on the development of solutions to epigenetically induced disorders. PMID- 22818524 TI - Anti-hepatitis B virus constituents from the stem bark of Streblus asper. AB - Seven compounds, (7'S,8'S)-trans-streblusol A, (7'R,8'S)-erythro-streblusol B, (7'S,8'S)-threo-streblusol B, 8'R-streblusol C, streblusquinone, (8R,8'R) streblusol D, and streblusol E, along with 15 known compounds (8-22) were isolated from the n-butanol-soluble part of the MeOH extract of stem bark of Streblus asper. Their structures were elucidated through application of extensive spectroscopic methods, including ESI-MS and 2D NMR spectroscopy (HMQC and HMBC). The stereochemistry at the chiral centers was determined using CD spectra, as well as analyses of coupling constants and optical rotation data. The isolated lignans and allylbenzene derivatives were evaluated for their anti-HBV activities in vitro using the HBV transfected Hep G2.2.15 cell line. The most active compounds, magnolol and 9-beta-xylopyranosyl-isolariciresinol, exhibited significant anti-HBV activities with IC(50) values of 2.03 and 6.58MUM for secretion of HBsAg, with no cytotoxicity, and of 3.76 and 24.86MUM for secretion of HBeAg, with no cytotoxicity. PMID- 22818525 TI - Polyphenol metabolism provides a screening tool for beneficial effects of Onobrychis viciifolia (sainfoin). AB - Onobrychis viciifolia (sainfoin) is a traditional fodder legume showing multiple benefits for the environment, animal health and productivity but weaker agronomic performance in comparison to other legumes. Benefits can be mainly ascribed to the presence of polyphenols. The polyphenol metabolism in O. viciifolia was studied at the level of gene expression, enzyme activity, polyphenol accumulation and antioxidant activity. A screening of 37 accessions regarding each of these characters showed a huge variability between individual samples. Principal component analysis revealed that flavonols and flavan 3-ols are the most relevant variables for discrimination of the accessions. The determination of the activities of dihydroflavonol 4-reductase and flavonol synthase provides a suitable screening tool for the estimation of the ratio of flavonols to flavan 3 ols and can be used for the selection of samples from those varieties that have a specific optimal ratio of these compounds for further breeding. PMID- 22818526 TI - The arogenate dehydratase gene family: towards understanding differential regulation of carbon flux through phenylalanine into primary versus secondary metabolic pathways. AB - Phe is formed from arogenate in planta through the action of arogenate dehydratase (ADT), and there are six ADT isoenzymes in the "model" vascular plant species Arabidopsis thaliana. This raised the possibility that specific ADTs may be differentially regulated so as to control Phe biosynthesis for protein synthesis vs its much more massive deployment for phenylpropanoid metabolism. In our previous reverse genetics study using 25 single/multiple ADT knockout (KO) lines, a subset of these knockouts was differentially reduced in their lignin contents. In the current investigation, it was hypothesized that Phe pool sizes might correlate well with reduction in lignin contents in the affected KO lines. The free amino acid contents of these KO lines were thus comprehensively analyzed in stem, leaf and root tissues, over a growth/developmental time course from 3 to 8 weeks until senescence. The data obtained were then compared to, and contrasted with, the differential extent of lignin deposition occurring in the various lines. Relative changes in pool sizes were also analyzed by performing a pairwise confirmatory factor analysis for Phe:Tyr, Phe:Trp and Tyr:Trp, following determination of the deviation from the mean for Phe, Tyr and Trp in each plant line. It was found that the Phe pool sizes measured were differentially reduced only in lignin-deficient lines, and in tissues and at time points where lignin biosynthesis was constitutively highly active (in wild type lines) under the growth conditions employed. In contrast, this trend was not evident across all ADT KO lines, possibly due to maintenance of Phe pools by non-targeted isoenzymes, or by feedback mechanisms known to be in place. PMID- 22818527 TI - Impaired pain processing in Parkinson's disease and its relative association with the sense of smell. AB - BACKGROUND AND PURPOSE: Many non-motor symptoms are associated with Parkinson's disease (PD). Of these, pain and olfactory disturbance tend to be common premotor symptoms. PD has been shown to exhibit abnormal central pain processing, although underlying mechanisms are not yet fully understood. In order to investigate this further, we assessed PD patients by specific Adelta stimulation with intra epidermal needle electrode and determined olfactory function. METHODS: Forty-two patients (18 males and 24 females) with PD and 17 healthy control subjects (8 males and 9 females) were studied. A thin needle electrode was used to stimulate epidermal Adelta fibers, and somatosensory evoked potentials (SEPs) recorded at the vertex. Olfactory function was evaluated using the Odor Stick Identification Test for Japanese (OSIT-J) and its relationship with pain-related SEPs was investigated. RESULTS: There were no significant differences in N1 latencies or P1 latencies although N1/P1 peak-to-peak amplitudes were significantly lower (p < 0.01) in PD patients than in control subjects. In PD patients, there were significant correlations between N1/P1 amplitudes and disease duration (r = 0.35, p < 0.05), Hoehn-Yahr stage (r = -0.38, p < 0.05) and UPDRS part III (r = 0.42, p < 0.01). Furthermore, the OSIT-J scores correlated with SEP amplitude (r = 0.41, p < 0.01). CONCLUSION: Pain processing in PD patients was impaired under specific nociceptive stimulation of Adelta fibers and significant correlation with smell dysfunction was detected. We suggest that this mechanism may involve the limbic system during PD pathology. PMID- 22818528 TI - Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. AB - BACKGROUND: Mutations in the microtubule associated protein tau (MAPT) and progranulin (PGRN) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT, PGRN, or C9orf72 mutations. METHODS: MAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. RESULTS: We found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72. Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. DISCUSSION: MAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS. PMID- 22818529 TI - Neuroferritinopathy. AB - Neuroferritinopathy is an autosomal dominantly inherited disorder caused by mutations in the gene encoding the ferritin light chain polypeptide. It leads to iron deposition particularly in the cerebellum, basal ganglia and motor cortex. The disease becomes clinically apparent in adulthood mainly with extrapyramidal signs and progresses slowly over decades. Patients usually have intact cognition until the very late stages of this disorder. Neuroimaging is the most helpful investigation and shows a very distinctive picture. So far no medication has been shown to have a disease-modifying effect. We present five new cases of this condition and review the current understanding of the pathogenesis and its clinical findings. PMID- 22818530 TI - Back to atheroablation: renaissance or deja vu? PMID- 22818531 TI - Transcatheter aortic valve replacement under monitored anesthesia care versus general anesthesia with intubation. AB - AIMS: Most transcatheter aortic valve replacement (T-AVR) using the Edwards SAPIEN transcatheter heart valve (Edwards Lifesciences, Irvine, CA) is done under general anesthesia. The present study aimed to examine the feasibility and safety of T-AVR under monitored anesthesia care and aimed to compare the clinical outcome to the outcome of patients who underwent general anesthesia. METHODS: The analysis included 92 consecutive patients undergoing T-AVR via the transfemoral approach guided by transesophageal echocardiography using the Edwards SAPIEN valve. The cohort was divided into two groups: I, monitored anesthesia care (n=70; 76.1%) and II, intubation (n=22; 23.9%). Monitored anesthesia care was given by anesthesiologists in one of two protocol regimens: Ketamine & Propofol or Dexmedetomidine. The crossover rate to general anesthesia and the clinical outcome of these two groups were compared. RESULTS: Baseline clinical characteristics of the two groups were similar, except for higher logistic EuroSCORE and prior stroke in the monitored anesthesia care group. Surgical access of the femoral artery was performed in 15 (68.1%) from the general anesthesia group and in 24 (34.2%) from the monitored anesthesia care group, p=0.05. The median procedure duration was significantly lower in the monitored anesthesia care group (91 vs. 155 min, p=0.008) and there was a trend to lower median intensive care unit stay and hospital stay (27 vs. 72 h, p=0.07 and 5 vs. 7.5 days, p=0.06, respectively). Of the patients with monitored anesthesia care, 8 (11.4%) converted to general anesthesia. CONCLUSION: T-AVR using the Edwards SAPIEN valve can be performed in the majority of cases with controlled monitored anesthesia care, thereby avoiding the necessity of general anesthesia and resulting in shorter procedure time and in-hospital length of stay. PMID- 22818532 TI - Endovascular recanalization of central venous access to allow for pacemaker implantation or upgrade. AB - BACKGROUND: Several patients undergoing permanent pacemaker (PPM) implantation/upgrade present with difficult access due to sub- or total central vein occlusion. Our institution has used the endovascular approach to recanalize central veins to allow for subsequent PPM implantation. Here we aim to describe the feasibility and safety of using this approach to allow for PPM implantation/upgrade. METHODS: From October 2006 to November 2010, 50 consecutive patients who underwent central vein recanalization prior to PPM implantation were included in this analysis. RESULTS: The population's mean age was 70 years, with a high rate of comorbidities including chronic renal failure (52.0%), congestive heart failure (64.0%), diabetes (33.3%) and peripheral vascular disease (36.0%). The endovascular recanalization procedure was performed via femoral access in all patients; however adjuvant brachial access was required in 13 cases and subclavian vein in one. Subclavian vein (74.5%) followed by innominate vein (21.6%) were the most common locations/target for recanalization. Successful vein recanalization followed by successful PPM implantation/upgrade was achieved in 48 patients (96.0%) without peri-procedural complications. Two patients died during the hospitalization, one due to severe respiratory failure and a second due to complicated end-stage renal disease, although neither was related to the endovascular procedure. No other event, including myocardial infarction, cerebral vascular accident, bleeding/transfusion, or renal failure was identified. CONCLUSIONS: This study proved the feasibility and safety of the endovascular approach to recanalize central veins in patients with poor vascular access to allow for further PPM implantation/upgrade. PMID- 22818533 TI - Determination of vitamin D in relation to body mass index and race in a defined population of black and white women. AB - OBJECTIVE: To examine the contributions of obesity and race to levels of 25 hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) in a defined cohort of black and white women. METHODS: An interventional study was conducted from October 2004 to March 2008, among 219 healthy female volunteers. Serum 25(OH)D and PTH levels were determined in 117 African American women and 102 white women and the results were compared with body mass index (BMI), percentage body fat, serum lipids, and PTH levels. RESULTS: Black women had lower median levels of 25(OH)D compared with white women (27.3 nmol/L vs 52.4 nmol/L; P<0.001). Serum levels of 25(OH)D below 50 nmol/L were found in 98% of black women and 45% of white women (P<0.001). The differences between the racial groups in the levels of 25(OH)D persisted despite adjustments for body weight, percentage body fat, and BMI. Black women had higher median serum levels of PTH than white women (31.9 pg/mL vs 22.3 pg/mL; P<0.01). CONCLUSION: African American women are at significant risk for low vitamin D levels. Studies are needed to determine if low vitamin D status in young African American women is associated with a greater risk for vitamin D-related chronic diseases that can be reduced with vitamin D supplementation. PMID- 22818534 TI - Stereophotogrammetry of the perineum during vaginal delivery. AB - OBJECTIVE: To analyze deformation of the perineum during normal vaginal delivery in order to identify clinical steps that might be beneficial when executing manual perineal protection. METHODS: The present prospective study at Charles University Hospital, Pilsen, Czech Republic, enrolled 10 primiparous women at term undergoing non-instrumental vaginal delivery assisted by the same obstetrician between September 2009 and September 2010. A modified hands-poised technique performed concurrently with stereophotogrammetry was used to analyze and quantify perineal deformation and strain at the final stage of delivery. RESULTS: The highest tissue strain (mean, 177%; 95% confidence interval [CI], 106.3-248.5) was in a transverse direction and occurred at the level of the fourchette (i.e. 1cm was transversely stretched and deformed to 2.77 cm during the final stage of vaginal delivery). This strain was more than 4 times higher than the maximum anteroposterior strain (mean, 43%; 95% CI, 28.6-57.4). CONCLUSION: On the basis of these stereophotogrammetry data, a technique of perineal protection executed by fingers of the posterior (right) hand can be proposed. Further experimental and clinical studies are needed to evaluate whether this technique might assist in reducing obstetric perineal trauma. PMID- 22818535 TI - Prevalence and risk factors for HIV, hepatitis B virus, and syphilis among pregnant women in Mayotte, Indian Ocean, 2008-2009. AB - OBJECTIVE: To assess the prevalence and risk factors for HIV, hepatitis B virus (HBV), and syphilis among pregnant women living on the Indian Ocean island of Mayotte. METHODS: A cross-sectional survey was conducted among 671 pregnant women at 11 prenatal clinics on Mayotte between September 15, 2008, and September 27, 2009. Sociodemographic and behavioral characteristics were collected by interviewer-administered questionnaire. Blood samples were obtained for HIV, HBV, and syphilis testing. Risk factors were analyzed by exact logistic regression. RESULTS: No prevalent case of HIV infection was detected among the study population. The prevalence of HBV surface antigen and active syphilis (defined as a positive test result by both rapid plasma reagin and Treponema pallidum hemagglutination assays) was 3.4% and 2.1%, respectively. A positive HBV surface antigen test was associated with being born in Comoros and having sex with a casual partner during the previous year. Lack of education and a history of sexually transmitted infections in the past 5 years were associated with active syphilis. CONCLUSION: The continuing low prevalence of HIV and high prevalence of sexually transmitted infections among pregnant women on Mayotte confirmed the so called "Indian Ocean paradox." PMID- 22818536 TI - Spontaneous fetal reduction and early pregnancy complications in multiple pregnancies following in vitro fertilization. AB - OBJECTIVE: To determine the incidence of spontaneous pregnancy reduction and early pregnancy complications among multiple pregnancies conceived via in vitro fertilization (IVF). METHODS: Spontaneous pregnancy reduction was assessed among multiple pregnancies conceived after IVF treatment in a private assisted reproduction center in Lagos, Nigeria, between January 2008, and June 2011. The pregnancies were diagnosed at 6-8 weeks of gestation by ultrasound scan, which was repeated at 11-14 weeks to determine the incidence of spontaneous reduction. RESULTS: The incidence of multiple pregnancies was 35.2%. There were 11 (20.0%) twin, 6 triplet (10.5%), and 2 quintuplet (3.6%) pregnancies. Spontaneous reduction occurred in 9 (47.7%) of these pregnancies, including 15.8% of twins, 21% of triplets, and 10.5% of quintuplets. Spontaneous reduction was significant among triplets and quintuplets (P<0.05). Six women (31.5%) older than 36 years had spontaneous reduction (P<0.05). Vaginal bleeding occurred in 3 (15.5%) women, 2 (66.7%) of whom had spontaneous abortion. In all instances of monochorionic placentation, spontaneous reduction resulted in spontaneous abortion. CONCLUSION: The incidence of spontaneous reduction among multiple pregnancies conceived after IVF was high. Vaginal bleeding was a warning sign of eventual abortion. Early pregnancy complications were fewer among pregnancies with dichorionic and trichorionic placentation. PMID- 22818537 TI - Assessment of endometrial volume and vascularization using transvaginal 3D power Doppler angiography in women with postmenopausal bleeding. AB - OBJECTIVE: To compare the usefulness of 3D power Doppler angiography (3D-PDA) and endometrial thickness measurement by 2D Doppler ultrasound in the distinction of benign from malignant disease in postmenopausal women with abnormal uterine bleeding (AUB) and an endometrial thickness greater than 4.5mm. METHODS: Forty eight women with AUB and an endometrial thickness greater than 4.5mm on 2D ultrasound underwent 3D-PDA. The endometrium and a 5-mm subendometrial "shell" were evaluated at rotation angles of 9 degrees and 30 degrees . Endometrial volume, vascularity index, flow index, and vascularization flow index were obtained. RESULTS: The histologic findings were normal or benign for 38 women (79%) and malignant for 10 (21%). All vascular indices were significantly higher in the group with malignancies except for the vascularization flow index. There were no differences in the values obtained using the 9 degrees or the 30 degrees angle. Receiver-operating characteristics curves were traced for all indices. The vascularity index had the best area under the curve (0.78), 77.8% sensitivity, and 82.6% specificity. The areas under the curve were smaller for the shell than for the endometrium. CONCLUSION: 3D-PDA was not found better than 2D ultrasound at distinguishing benign from malignant disease in women with AUB and an endometrial thickness greater than 4.5mm. PMID- 22818538 TI - Activation of central alpha2-adrenoceptors mediates salivary gland vasoconstriction. AB - OBJECTIVE: Peripheral treatment with the cholinergic agonist pilocarpine increases salivary gland blood flow and induces intense salivation that is reduced by the central injection of moxonidine (alpha2-adrenoceptors/imidazoline agonist). In the present study, we investigated the effects of the intracerebroventricular (i.c.v.) injection of pilocarpine alone or combined with moxonidine also injected i.c.v. On submandibular/sublingual gland (SSG) vascular resistance. In addition, the effects of these treatments on arterial pressure, heart rate and on mesenteric and hindlimb vascular resistance were also tested. DESIGN: Male Holtzman rats with stainless steel cannula implanted into lateral ventricle and anaesthetized with urethane+alpha-chloralose were used. RESULTS: Pilocarpine (500nmol/1MUl) injected i.c.v. Reduced SSG vascular resistance and increased arterial pressure, heart rate and mesenteric vascular resistance. Contrary to pilocarpine alone, the combination of moxonidine (20nmol/1MUl) and pilocarpine injected i.c.v. Increased SSG vascular resistance, an effect abolished by the pre-treatment with the alpha2-adrenoceptor antagonist yohimbine (320nmol/2MUl). The increase in arterial pressure, heart rate and mesenteric resistance was not modified by the combination of moxonidine and pilocarpine i.c.v. CONCLUSION: These results suggest that the activation of central alpha2 adrenoceptors may oppose to the effects of central cholinergic receptor activation in the SSG vascular resistance. PMID- 22818539 TI - A randomized, single-blinded pilot study evaluating use of a laparoscope or a cystoscope for cystoscopy during gynecologic surgery. AB - STUDY OBJECTIVE: To prospectively evaluate time required to perform cystoscopy with a laparoscope or a cystoscope after laparoscopic hysterectomy. Urinary tract symptoms, infection, adverse events, and expense were also evaluated. DESIGN: Randomized, single-blind pilot study (Canadian Task Force classification I). SETTING: Suburban private gynecology group practice and local community hospital. SUBJECTS: Sixty-six subjects scheduled to undergo laparoscopic hysterectomy between January and July 2009. INTERVENTION: Either cystoscopy with a laparoscope or a cystoscope. MEASUREMENTS AND MAIN RESULTS: Subjects were randomized to undergo either form of cystoscopy, and events were reported. Each subject completed self-reported urinary tract symptom questionnaires before surgery and at 2 weeks after surgery. Clean-catch urine samples were obtained before surgery and postoperatively at day 1 and 2 weeks. In the group who underwent laparoscope cystoscopy, a suction-irrigator device, a 5-mm needle-nose suction irrigator tip, and a 5-mm 0-degree video laparoscope were required. In the group who underwent traditional cystoscopy, a 70-degree video telescope with a 17F sleeve, irrigation fluid, and a light source were required. Subjects were followed up for 6 weeks postoperatively. Adverse events were minimal, with 1 in the laparoscope group and 6 in the traditional cystoscope group. Two postoperative urinary tract infections occurred in the traditional cystoscopy group. The mean total procedural time for laparoscope cystoscopy of 137 seconds was statistically less (p < .001) compared with the 296 seconds in the traditional cystoscopy group. Improvements in urinary tract symptom scores improved from baseline, but were not statistically significantly different between the groups. Traditional cystoscopy equipment cost approximately $60 more per subject. CONCLUSION: The study results suggest that laparoscope cystoscopy is more time-efficient and cost-effective than traditional cystoscopy and that the incidence of urinary tract symptoms, infection, and injury did not increase. PMID- 22818540 TI - Laparoscopy as the most effective tool for management of postmenopausal complex adnexal masses when expectancy is not advisable. AB - Postmenopausal women with adnexal masses suspicious for malignancy must undergo surgery for histopathologic confirmation. The low positive predictive value for malignancy of the currently available preoperative examinations results in 5 to 220 surgeries performed for each case of pelvic malignancy detected, depending on the evaluation method and patient selection. Although extensively reviewed as an effective tool for the investigation and treatment of adnexal masses, laparoscopy is still underused for this purpose in postmenopausal women. Some reasons are uncertainty about the incidental diagnosis of a malignant lesion during laparoscopy, concern about the effect of laparoscopy over the course of a pelvic malignant lesion, and inadequate referral of patients at high risk to specialized centers with oncologic gynecologists. Identification of patients at low risk might also be inadequate, causing them to undergo unnecessary laparotomy. Herein we demonstrate through a comprehensive literature review that laparoscopy is a highly effective tool for investigation and treatment of suspected adnexal masses in postmenopausal women, both in general medical settings without oncologic backup and in specialized centers. The indications for laparoscopy in this context can be further expanded without oncologic harm if patients at low and high risk are appropriately selected for surgery at general and specialized settings, respectively. PMID- 22818541 TI - Introduction to transfusion practices in neonates: risks, benefits, and alternatives. PMID- 22818542 TI - Red blood cell transfusion: decision making in pediatric intensive care units. AB - The results of the Transfusion Requirements in Pediatric Intensive Care Unit study suggest that a red blood cell transfusion is not required in stable or stabilized pediatric intensive care unit children as long as their hemoglobin level is >7 g/dL. Subgroup analyses suggest that this recommendation is also adequate for stable critically ill children with a high severity of illness, respiratory dysfunction, acute lung injury, sepsis, neurological dysfunction, severe head trauma, or severe trauma, and during the postoperative period, for noncyanotic patients older than 28 days. A small randomized clinical trial suggests that a hemoglobin level of 9 g/dL is safe in the postoperative care of children with single-ventricle physiology undergoing cavopulmonary connection. Although there is consensus that blood is clearly indicated for the treatment of hemorrhagic shock, the clinical determinants that should prompt pediatric intensivists to prescribe a red blood cell transfusion to unstable PICU children are not well characterized. PMID- 22818544 TI - International survey of transfusion practices for extremely premature infants. AB - Our objective was to survey neonatologists regarding international practice of red cell transfusion thresholds for premature infants with <1000-g birth weight and/or <28-week gestation. An invitation to fill out an 11-question web-based survey was distributed to neonatologists through their professional societies in 22 countries. Physicians were asked about which specific factors, in addition to hemoglobin levels, influenced their decisions about transfusing premature infants. These factors included gestational age, postnatal age, oxygen need, respiratory support, reticulocyte count, and inotropic support. Physicians were presented with 5 scenarios and asked to identify hemoglobin cutoff values for transfusing infants with <1000-g birth weight and/or <28-week gestation. One thousand eighteen neonatologists responded: the majority were from the United States (67.5%), followed by Germany (10.7%), Japan (8.0%), the United Kingdom (4.9%), Spain (3.9%), Italy (2.6%), Colombia (0.6%), Argentina (0.4%), Canada (0.4%), Belgium (0.1%), and the Netherlands (0.1%). Half of the respondents (51.1%) reported having a written policy with specific red cell transfusion guidelines in their unit. Factors considered "very important" regarding the need to administer blood transfusions included degree of oxygen requirement (44.7%) and need for respiratory support (44.1%). Erythropoietin was routinely used to treat anemia by 26.0% of respondents. Delayed cord clamping or cord milking was practiced by 29.1% of respondents. The main finding was of a wide variation in the hemoglobin values used to transfuse infants, regardless of postnatal age. Step-wise increments in the median hemoglobin cutoffs directly paralleled an increase in the need for levels of respiratory support. In the first week of life, there was a wider range in the distribution of hemoglobin transfusion thresholds for infants requiring no respiratory support and full mechanical ventilation compared with the thresholds used in the second, third, and fourth weeks of life. An international survey using hypothetical scenarios shows that red blood cell transfusion practices vary widely among practicing neonatologists in participating countries. PMID- 22818543 TI - Nonpharmacological, blood conservation techniques for preventing neonatal anemia- effective and promising strategies for reducing transfusion. AB - The development of anemia after birth in very premature, critically ill newborn infants is a universal well-described phenomenon. Although preventing anemia in this population, along with efforts to establish optimal red blood cell (RBC) transfusion and pharmacologic therapy continue to be actively investigated, the present review focuses exclusively on nonpharmacological approaches to the prevention and treatment of neonatal anemia. We begin with an overview of topics relevant to nonpharmacological techniques. These topics include neonatal and fetoplacental hemoglobin levels and blood volumes, clinical and laboratory practices applied in critically ill neonates, and current RBC transfusion practice guidelines. This is followed by a discussion of the most effective and promising nonpharmacological blood conservation strategies and techniques. Fortunately, many of these techniques are feasible in most neonatal intensive care units. When applied together, these techniques are more effective than existing pharmacotherapies in significantly decreasing neonatal RBC transfusions. They include increasing hemoglobin endowment and circulating blood volume at birth; removing less blood for laboratory testing; and optimizing nutrition. PMID- 22818546 TI - Intestinal hemodynamics and oxygenation in the perinatal period. AB - The neonatal gastrointestinal tract is a site of intense anabolic and metabolic activity, as it is responsible for the assimilation of nutritional intake and exhibits accelerated growth shortly after birth. The hypermetabolic state of the gastrointestinal tract requires sufficient blood flow and oxygen delivery to sustain adequate oxygen consumption to meet these metabolic needs. Therefore, an understanding of the mechanisms regulating intestinal vascular perfusion in the normal state and during pathophysiological conditions in the perinatal period is important to elucidate potential contributions to the development of intestinal pathologies in the neonate. The goal of this review is to summarize the available literature on the regulation of intestinal blood flow and oxygenation in the fetus and newborn in normal states and during pathological stress. PMID- 22818547 TI - Do transfusions cause necrotizing enterocolitis? The complementary role of randomized trials and observational studies. AB - A systematic review and a meta-analysis of the published literature on the association between transfusions in newborns and the occurrence of transfusion associated necrotizing enterocolitis were performed. We discuss the differences between findings in randomized trials, and the results of observational studies that first explored this putative link. We suggest the following framework: where observational studies play a hypothesis generating- role for therapies and harm, and randomized studies allow an acid test of that hypothesis. It is acknowledged that not all questions can be subject to a randomized evaluation, but argued that this particular association is amenable to such a test. PMID- 22818545 TI - Effect of processing and storage on red blood cell function in vivo. AB - Red blood cell (RBC) transfusion is indicated to improve oxygen delivery to tissue, and for no other purpose. We have come to appreciate that donor RBCs are fundamentally altered during processing and storage in a manner that both impairs oxygen transport efficacy and introduces additional risk by perturbing both immune and coagulation systems. The protean biophysical and physiological changes in RBC function arising from storage are termed the "storage lesion;" many have been understood for some time; for example, we know that the oxygen affinity of stored blood rises during the storage period and that intracellular allosteric regulators, notably 2,3-bisphosphoglyceric acid and ATP, are depleted during storage. Our appreciation of other storage lesion features has emerged with improved understanding of coagulation, immune, and vascular signaling systems. Here, we review key features of the "storage lesion." Additionally, we call particular attention to the newly appreciated role of RBCs in regulating linkage between regional blood flow and regional O(2) consumption by regulating the bioavailability of key vasoactive mediators in plasma, and discuss how processing and storage disturb this key signaling function and impair transfusion efficacy. PMID- 22818548 TI - Necrotizing enterocolitis and the role of anemia of prematurity. AB - Necrotizing enterocolitis (NEC) is one of the most common surgical diseases of preterm infants, with significant short- and long-term morbidity and mortality. Although the etiology of NEC remains elusive, multiple factors adversely affecting the intestinal mucosal integrity of preterm infants are known to be associated with NEC. Anemia and red blood cell (RBC) transfusion-related gut injury have been shown to have strong correlation with NEC. Anemia potentially compromises mucosal integrity with subsequent poor healing, and this injury may be augmented by yet unknown factors associated with RBC transfusions. Although convincing evidence is lacking, there is a need for guidelines to keep the hematocrit within clinically and physiologically relevant limits by appropriate interventions. Further investigations need to focus on assessing the interplay between anemia, chronically hypoxemic/hypoperfused intestines, and early iron therapy or other pharmacologic approaches for prevention/treatment of anemia and RBC transfusions. PMID- 22818549 TI - Associations between "early" red blood cell transfusion and severe intraventricular hemorrhage, and between "late" red blood cell transfusion and necrotizing enterocolitis. AB - Transfusion of banked donor erythrocytes can be life saving for small and ill neonates with severe anemia or active hemorrhage. However, risks of transfusions exist and must be weighed against potential benefits each time a transfusion is considered. The present review seeks to bring together the published data supporting 2 newly postulated risks of transfusions among very low-birth-weight neonates. The first is an association between "early" red blood cell transfusions, those administered in the first few days after birth, and the subsequent occurrence of a grade 3 or 4 intraventricular hemorrhage. The second is an association between "late" RBC transfusions and the subsequent occurrence of necrotizing enterocolitis. Much remains to be discovered about the pathogenetic links between transfusion and these adverse outcomes. Moreover, work is needed to clearly establish whether transfusions are causatively associated with these adverse outcomes or are covariables. The purpose of this chapter is to review the associations between transfusion and intraventricular hemorrhage and between transfusions and necrotizing enterocolitis and to use these associations to hypothesize that evidence-based improvements in transfusion practice have the potential to improve neonatal intensive care unit outcomes. PMID- 22818550 TI - Neurodevelopmental outcome of extremely low-birth-weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion. AB - Surviving extremely low-birth-weight infants are at risk of severe neurodevelopmental disability. Transfusion with packed red cells is almost universal in the care of these infants, but the hemoglobin threshold at which these transfusions should be given is unclear. Different clinical trials of restrictive (low hemoglobin) versus liberal (high hemoglobin) thresholds have addressed either neurodevelopmental outcomes at 18-21 months of corrected gestational age or psychological tests and brain imaging at 8-15 years of age. Early follow-up shows differences in cognitive outcome favoring the liberal strategy, but as a post hoc secondary outcome. The childhood studies favor the restrictive strategy, but include major methodological problems of secondary recruitment. No firm conclusion can be reached, other than to report that serious adverse effects may be attributable to one or other of these strategies, that prudent practice is to remain within trial protocols, and that further redesigned clinical trials are required. PMID- 22818551 TI - Transfusion-related acute gut injury: feeding, flora, flow, and barrier defense. AB - TRAGI (transfusion-related acute gut injury) is an acronym we proposed to characterize a severe neonatal gastrointestinal reaction temporally related to a transfusion of packed blood red cells (PRBCs) for anemia in very low birth weights. The following are in support of a causative relationship: (1) the timing of necrotizing enterocolitis after a PRBC transfusion not being random, (2) traditional risk factors for necrotizing enterocolitis are often absent, (3) significant anemia appears to be a universal finding, (4) the age of donor blood is often slightly older than controls, (5) TRAGI is not postnatal age dependent, and (6) TRAGI does not show a centering at 31 weeks' postconceptual age as does nontransfusion-related NEC. Although TRAGI is linked to the timing of PRBC transfusions, we propose a novel hypothesis that the convergence at 31 weeks' postconceptual age for classic NEC approximates the age of presentation of other oxygen delivery and neovascularization syndromes (eg, retinopathy of prematurity), suggesting its etiologic link to a generalized systemic maturational mechanism or another common developmental theme. This report will begin by reviewing the history of the clinical presentation and discovery of TRAGI and will then analyze various pathophysiologic mechanisms that may account for the phenomenon when clinicians render therapies. We will end by a call to action for randomized clinical trials to test various etiologic theories. PMID- 22818552 TI - Therapeutic efficacy and safety of dihydroartemisinin-piperaquine versus artesunate-mefloquine in uncomplicated Plasmodium falciparum malaria in India. AB - BACKGROUND: Resistance in Plasmodium falciparum to commonly used anti-malarial drugs, especially chloroquine, is being increasingly documented in India. By 2007, the first-line treatment for uncomplicated malaria has been revised to recommend artemisinin-based combination therapy (ACT) for all confirmed P. falciparum cases. OBJECTIVE: The objective of this study was to compare the efficacy, safety and tolerability between dihydroartemisinin-piperaquine (DP) and artesunate plus mefloquine (A + M) drug combinations in the treatment of uncomplicated P. falciparum malaria in India. METHODS: Between 2006 and 2007, 150 patients with acute uncomplicated P. falciparum malaria were enrolled, randomized to DP (101) or A + M (49) and followed up for 63 days as part of an open-label, non-inferiority, randomized, phase III multicenter trial in Asia. RESULTS: The heterogeneity analysis showed no statistically significant difference between India and the other countries involved in the phase III study, for both the PCR corrected and uncorrected cure rates. As shown at the whole study level, both forms of ACT were highly efficacious in India. In fact, in the per protocol population, the 63-day cure rates were 100% for A + M and 98.8% for DP. The DP combination exerted a significant post-treatment prophylactic effect, and compared with A + M a significant reduction in the incidence of new infections for DP was observed (respectively 17.1% versus 7.5% of patients experienced new infection within follow up). Parasite and fever clearance was rapid in both treatment arms (median time to parasite clearance of one day for both groups). Both DP and A + M were well tolerated, with the majority of adverse events of mild or moderate severity. The frequencies of individual adverse events were generally similar between treatments, although the incidence of post treatment adverse events was slightly higher in patients who received A + M with respect to those treated with DP. CONCLUSION: DP is a new ACT displaying high efficacy and safety in the treatment of uncomplicated P. falciparum malaria and could potentially be considered for the first-line treatment of uncomplicated falciparum malaria in India. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 81306618. PMID- 22818554 TI - Foreword. PMID- 22818553 TI - Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: a promising tool for early detection of COPD and lung cancer in smokers. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disorder associated to cigarette smoke and lung cancer (LC). Since epigenetic changes in oncogenes and tumor suppressor genes (TSGs) are clearly important in the development of LC. In this study, we hypothesize that tobacco smokers are susceptible for methylation in the promoter region of TSGs in airway epithelial cells when compared with non-smoker subjects. The purpose of this study was to investigate the usefulness of detection of genes promoter methylation in sputum specimens, as a complementary tool to identify LC biomarkers among smokers with early COPD. METHODS: We determined the amount of DNA in induced sputum from patients with COPD (n = 23), LC (n = 26), as well as in healthy subjects (CTR) (n = 33), using a commercial kit for DNA purification, followed by absorbance measurement at 260 nm. The frequency of CDKN2A, CDH1 and MGMT promoter methylation in the same groups was determined by methylation-specific polymerase chain reaction (MSP). The Fisher's exact test was employed to compare frequency of results between different groups. RESULTS: DNA concentration was 7.4 and 5.8 times higher in LC and COPD compared to the (CTR) (p < 0.0001), respectively. Methylation status of CDKN2A and MGMT was significantly higher in COPD and LC patients compared with CTR group (p < 0.0001). Frequency of CDH1 methylation only showed a statistically significant difference between LC patients and CTR group (p < 0.05). CONCLUSIONS: We provide evidence that aberrant methylation of TSGs in samples of induced sputum is a useful tool for early diagnostic of lung diseases (LC and COPD) in smoker subjects. VIRTUAL SLIDES: The abstract MUST finish with the following text: Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1127865005664160. PMID- 22818555 TI - Brief overview of the coagulation cascade. PMID- 22818556 TI - Pharmacology of anticoagulants. PMID- 22818557 TI - An algorithmic approach to coagulation testing. PMID- 22818558 TI - Complications of anticoagulation. PMID- 22818559 TI - Practice guidelines for reversal of new and old anticoagulants. PMID- 22818560 TI - Assessment of advantages and disadvantages of agents used for therapeutic anticoagulation. PMID- 22818561 TI - Icariin enhances the healing of rapid palatal expansion induced root resorption in rats. AB - Icariin has been reported to enhance bone healing and treat osteoporosis. In this study, we examined the effect of Icariin on rapid palatal expansion induced root resorption in rats. Our hypothesis is that Icariin can enhance the healing of rapid palatal expansion induced root resorption. Forty-eight male Wistar rats were divided randomly and equally into three groups (n=16 rats each). The rats were untreated (negative control) or treated with rapid palatal expansion without (positive control) or with Icariin at 2.5 mg/kg day (Icariin-treated groups). An initial force of 50*g was applied to the areas between the right and left upper first molars of the rats for 21 days. Eight rats were randomly chosen from each group, and the root resorption index (RRI) was determined with scanning electron microscopy (SEM). Upper first molar-centered buccal- lingual tissue slices were generated from the upper first molars and peridentium of the remaining eight rats from each group. Specimen slices were analyzed with HE and tararate-resistant acid phosphatase staining, osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) immunohistochemistry, and optical microscopy. Analyses of cell number, densitometry, and one-way analysis of variance were performed. The Icariin-treated groups displayed decreased RRI values, decreased osteoclast numbers and activity levels, and increased OPG/RANKL expression ratios. High-power SEM revealed reparative cementum in the Icariin treated samples. Icariin regulates osteoclast differentiation via the OPG/RANKL ratio, evoking a reparative effect on rapid palatal expansion induced root resorption in rats. PMID- 22818562 TI - Analysis of current situation of Chinese health care reform by studying emergency overcrowding in a typical Shanghai hospital. PMID- 22818563 TI - Prognostic markers in young patients with premature coronary heart disease. AB - OBJECTIVES: To evaluate the survival and prognostic implications of cardiovascular, inflammatory and prothrombotic risk factors in young patients with premature coronary heart disease (CHD). METHODS: Follow-up data were obtained from 353 young patients with a first cardiac event (men <=45 years and women <=55 years). Baseline characteristics on traditional risk factors were collected at the time of the first event, and plasma levels of C-reactive protein (CRP), von Willebrand Factor (VWF), and fibrinogen were measured one to three months after the first event to exclude an acute phase response. We performed age and sex adjusted Cox regression analyses to assess the relationship between these factors and recurrent events with three different endpoints: all cause mortality, recurrent cardiac event (myocardial infarction or revascularisation procedure), and any recurrent event (cardiac event, cerebrovascular event or all cause mortality). RESULTS: During a total follow-up time of 1483 person years (mean 4.2 years), 11 patients died (3%), 42 patients had a recurrent cardiac event (12%), and 53 patients had any recurrent event (15%). CRP was associated with an increased risk of any recurrent event (HR 1.28[95% CI = 1.02-1.59] per unit increase in lnCRP). Also, both CRP (5.00[1.04-24.04]) and fibrinogen (5.04[1.05 24.23]) were associated with all cause mortality when levels were above the 50th percentile. CONCLUSIONS: Fifteen percent of young patients with a first cardiac event have a recurrent event or die within a median follow-up of 4.2 years. In these young patients we have shown that, independently of cardiovascular risk factors, high CRP levels contribute to the risk of recurrent events, including all cause mortality, and high fibrinogen levels are associated with all cause mortality. PMID- 22818564 TI - A comparison of non-HDL and LDL cholesterol goal attainment in a large, multinational patient population: the Lipid Treatment Assessment Project 2. AB - OBJECTIVE: This study evaluated the success in attaining non-HDL-cholesterol (non HDL-C) goals in the multinational L-TAP 2 study. METHODS: 9955 patients >=20 years of age with dyslipidemia on stable lipid-lowering therapy were enrolled from nine countries. RESULTS: Success rates for non-HDL-C goals were 86% in low, 70% in moderate, and 52% in high-risk patients (63% overall). In patients with triglycerides of >200 mg/dL success rates for non-HDL-C goals were 35% vs. 69% in those with <=200 mg/dL (p < 0.0001). Among patients attaining their LDL-C goal, 18% did not attain their non-HDL-C goal. In those with coronary disease and at least two risk factors, only 34% and 30% attained respectively their non-HDL-C and LDL-C goals. Rates of failure in attaining both LDL-C and non-HDL-C goals were highest in Latin America. CONCLUSIONS: Non-HDL-C goal attainment lagged behind LDL-C goal attainment; this gap was greatest in higher-risk patients. PMID- 22818565 TI - Editorial comment. PMID- 22818566 TI - Live robotic surgery: are outcomes compromised? AB - OBJECTIVE: To determine the outcomes of patients undergoing robotic partial nephrectomy as a live broadcast surgery compared to a cohort treated without observers. METHODS: From 2007 to 2011, 39 robotic partial nephrectomies were performed as live broadcast surgery by 1 of 5 high volume surgeons. Live broadcast cases were defined as surgeries viewed by multiple visiting physicians via live teleconference in which the visitors were able to interact with the operating surgeon. Live cases were compared with 847 cases performed under standard operating procedure during the same period. Cases performed under standard operating procedure were not broadcasted. Demographic, clinicopathologic, and perioperative outcomes were compared between groups. Logistic regression analysis was performed to the test the association between live broadcast surgery and adverse perioperative outcomes. RESULTS: Demographic and clinicopathologic data were similar between both groups. The live broadcast surgery group experienced equivalent operative times (196.3 vs 183.8 minutes; P = .22), estimated blood loss (EBL; 187.8 vs 190.7; P = .93), warm ischemia time (WIT; 20.8 vs 18.8; P = .17), hospital length of stay (LOS; 2.8 vs 2.8 days; P = .99), positive surgical margin rate (2.6% vs 2.3%; P = .83), and rates of postoperative complications (5.1% vs 12.8%; P = .16). There were no Clavien III to V complications in the live broadcast group. Logistic regression analyses demonstrated that live broadcast surgery was not associated with any unfavorable perioperative parameter. CONCLUSION: Live robotic surgery is associated with excellent patient outcomes which compare favorably to cases done under normal operating procedures. Live robotic surgery represents a powerful educational tool which may be used without increasing patient morbidity. PMID- 22818580 TI - Genotype-phenotype mapping in a post-GWAS world. AB - Understanding how metabolic reactions, cell signaling, and developmental pathways translate the genome of an organism into its phenotype is a grand challenge in biology. Genome-wide association studies (GWAS) statistically connect genotypes to phenotypes, without any recourse to known molecular interactions, whereas a molecular biology approach directly ties gene function to phenotype through gene regulatory networks (GRNs). Using natural variation in allele-specific expression, GWAS and GRN approaches can be merged into a single framework via structural equation modeling (SEM). This approach leverages the myriad of polymorphisms in natural populations to elucidate and quantitate the molecular pathways that underlie phenotypic variation. The SEM framework can be used to quantitate a GRN, evaluate its consistency across environments or sexes, identify the differences in GRNs between species, and annotate GRNs de novo in non-model organisms. PMID- 22818581 TI - Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. AB - The localization of atherosclerotic lesion formation to regions of disturbed blood flow associated with certain arterial geometries, in humans and experimental animals, suggests an important role for hemodynamic forces in the pathobiology of atherosclerosis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these different biomechanical stimuli and transduce them into genetic regulatory programs that modulate endothelial function. In this brief review, we discuss how biomechanical stimuli generated by blood flow can influence endothelial functional phenotypes, and explore the working hypothesis of "atheroprone" hemodynamic environments as "local risk factors" in atherogenesis. In addition, we consider the therapeutic implications of the activation of "atheroprotective genes" and their role as "critical regulatory nodes" in vascular homeostasis. PMID- 22818583 TI - [Lung disease associated with connective tissue disease]. AB - Connective tissue diseases are often associated with lung diseases that lead to high morbidity and mortality, including interstitial disease, airway disease, pleural lesions, and vascular disease. High resolution CT has high sensitivity for detecting parenchymal disease and potentially reversible lesions, helping to guide treatment. This article emphasizes interstitial pneumonia in association with connective tissue disease and the characteristics that differentiate this entity from idiopathic types. Likewise, we review the most common pulmonary manifestations of each connective tissue disease with the aim of providing the radiologist with a practical approach to the diagnosis and management of these diseases in daily clinical practice. PMID- 22818582 TI - Diabetes mellitus accelerates cartilaginous metaplasia and calcification in atherosclerotic vessels of LDLr mutant mice. AB - BACKGROUND: Vascular calcification is highly prevalent in patients with type II diabetes mellitus (T2DM). Little is known about whether T2DM is causative. METHODS: Low-density lipoprotein receptor mutant (LDLr(-/-)) mice were fed with customized diabetogenic and/or procalcific diets to induce atherosclerosis, cartilaginous metaplasia and calcification, along with obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia at various levels, and euthanized for study after 18-24 weeks on diet. RESULTS: We found that T2DM accelerated cartilaginous and calcific lesion development by ~3- and 13-fold as determined by incidence of vascular cartilaginous metaplasia and calcification in LDLr(-/-) mice. Lowering dietary fat from ~60% to ~40% kcal reduced body weight and serum glucose and insulin levels, leading to a 2-fold decrease in aortic calcium content. Correlation analysis of calcium content with a calculated insulin resistance index, homeostasis model assessment of insulin resistance, showed a positive correlation of insulin resistance with vascular calcification. Finally, we used genetic fate mapping strategy to trace cells of SM origin in these animals. Vascular smooth muscle cells (SMCs) were found to be a major cell source contributing to osteochondrogenic differentiation and calcification. Receptor for advanced glycation end-products (RAGE) was up-regulated, co-localizing with osteochondrogenic SMCs. CONCLUSIONS: Through quantitative measure of aortic calcium content, we provided experimental findings that LDLr(-/-) mice, like T2DM patients, are predisposed to vascular calcification. Our study is also the first to establish a distinct role of hyperglycemia and hypercholesterolemia in osteochondrogenic differentiation of SMCs and determined these cells as a major source contributing to cartilaginous and calcifying lesions of T2DM blood vessels, possibly mediated by RAGE. PMID- 22818584 TI - Accurate detection of blood vessels improves the detection of exudates in color fundus images. AB - Exudates are one of the earliest and most prevalent symptoms of diseases leading to blindness such as diabetic retinopathy and macular degeneration. Certain areas of the retina with such conditions are to be photocoagulated by laser to stop the disease progress and prevent blindness. Outlining these areas is dependent on outlining the lesions and the anatomic structures of the retina. In this paper, we provide a new method for the detection of blood vessels that improves the detection of exudates in fundus photographs. The method starts with an edge detection algorithm which results in a over segmented image. Then the new feature based algorithm can be used to accurately detect the blood vessels. This algorithm considers the characteristics of a retinal blood vessel such as its width range, intensities and orientations for the purpose of selective segmentation. Because of its bulb shape and its color similarity with exudates, the optic disc can be detected using the common Hough transform technique. The extracted blood vessel tree and optic disc could be subtracted from the over segmented image to get an initial estimate of exudates. The final estimation of exudates can then be obtained by morphological reconstruction based on the appearance of exudates. This method is shown to be promising since it increases the sensitivity and specificity of exudates detection to 80% and 100% respectively. PMID- 22818585 TI - Intramedullary screw fixation with bone autografting to treat proximal fifth metatarsal metaphyseal-diaphyseal fracture in athletes: a case series. AB - BACKGROUND: Delayed unions or refractures are not rare following surgical treatment for proximal fifth metatarsal metaphyseal-diaphyseal fractures. Intramedullary screw fixation with bone autografting has the potential to resolve the issue. The purpose of this study was to evaluate the result of the procedure. METHODS: The authors retrospectively reviewed 15 athletes who underwent surgical treatment for proximal fifth metatarsal metaphyseal-diaphyseal fracture. Surgery involved intramedullary cannulated cancellous screw fixation after curettage of the fracture site, followed by bone autografting. Postoperatively, patients remain non weight-bearing in a splint or cast for two weeks and without immobilization for an additional two weeks. Full weight-bearing was allowed six weeks postoperatively. Running was permitted after radiographic bone union, and return-to-play was approved after gradually increasing the intensity. RESULTS: All patients returned to their previous level of athletic competition. Mean times to bone union, initiation of running, and return-to-play were 8.4, 8.8, and 12.1 weeks, respectively. Although no delayed unions or refractures was observed, distal diaphyseal stress fractures at the distal tip of the screw occurred in two patients and a thermal necrosis of skin occurred in one patient. CONCLUSIONS: There were no delayed unions or refractures among patients after carrying out a procedure in which bone grafts were routinely performed, combined with adequate periods of immobilization and non weight-bearing. These findings suggest that this procedure may be useful option for athletes to assuring return to competition level. PMID- 22818586 TI - [Effect of sub-anaesthetic doses of ketamine in the postoperative period in a patient with uncontrolled depression]. AB - Recent studies indicate that the intravenous infusion of ketamine hydrochloride (an N-methyl-D-aspartate receptor antagonist) leads to a rapid reduction in depressive symptoms. A 42 year-old woman with breast cancer and major depression resistant to medical treatment received a 90 minute intravenous infusion of 0.3 mg/kg ketamine for 5 consecutive days. A significant reduction from 22 to 13 ( 41%) was observed in the symptoms assessed using the Hamilton scale, with the effect maintained for 14 days. The possible therapeutic mechanism is discussed. PMID- 22818587 TI - Influence of low ultrasound intensity on the degradation of dextran catalyzed by dextranase. AB - In our current research work, the effect of ultrasound irradiation on the enzymatic activity and enzymatic hydrolysis kinetic parameters of dextran catalysis by dextranase were investigated. Furthermore, the effects of ultrasound irradiation on the structure of dextranase were investigated with the aid of fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The maximum activity of dextranase was observed when the sample was treated with ultrasound at 25 kHz, 40 W for 15 min, under which the enzyme activity increased by 13.43% compared the routine thermal incubation at 50 degrees C. Experimental Kinetics results, demonstrated that, both the V(max) and K(M) values of dextranase increased with ultrasound-treated compared with the incubation at 50 degrees C. Likewise, both the catalytic and specificity constants were higher under the effects of an ultrasonic field, indicating that, the substrate is converted into the product at an increased rate when compared with the incubation at 50 degrees C. On the other hand, fluorescence and CD spectra reflected that the ultrasound irradiation had increased the number of tryptophan on dextranase surface with increased alpha-helix by 15.74% and reduced random coil by 5.41% upon ultrasound treated dextranase protein compared to the control, which were helpful for the improvement of its activity. PMID- 22818588 TI - Verification of retail food outlet location data from a local health department using ground-truthing and remote-sensing technology: assessing differences by neighborhood characteristics. AB - Obtaining valid and accurate data on community food environments is critical for research evaluating associations between the food environment and health outcomes. This study utilized ground-truthing and remote-sensing technology to validate a food outlet retail list obtained from an urban local health department in Baltimore, Maryland in 2009. Ten percent of outlets (n=169) were assessed, and differences in accuracy were explored by neighborhood characteristics (96 census tracts) to determine if discrepancies were differential or non-differential. Inaccuracies were largely unrelated to a variety of neighborhood-level variables, with the exception of number of vacant housing units. Although remote-sensing technologies are a promising low-cost alternative to direct observation, this study demonstrated only moderate levels of agreement with ground-truthing. PMID- 22818590 TI - Investigation of the possibility of using waste cooking oil as a rejuvenating agent for aged bitumen. AB - The ageing of the bitumen during storage, mixing, transport and laying on the road, as well as in service life, are the most important problems presented by the use of bitumen in pavements. This paper investigates the possibility of using waste cooking oil (WCO), which is a waste material that pollutes landfills and rivers, as an alternative natural rejuvenating agent for aged bitumen to a condition that resembles the original bitumen. With this target, the physical and chemical properties of the original bitumen, aged bitumen and rejuvenated bitumen were measured and compared by the bitumen binder tests - softening point, penetration, Brookfield viscosity, dynamic shear rheometer and Fourier transform infrared spectroscopy. In addition, the behaviour of the WCO rejuvenated bitumen is investigated and compared with virgin bitumen after using the rolling thin film oven ageing process. In general, the results showed that using 3-4% of WCO the aged bitumen group 40/50 was rejuvenated to a condition that closely resembled the physical, rheological properties of the original bitumen (80/100), however, there was a difference in the tendency to ageing between the WCO rejuvenated bitumen and the virgin bitumen during mixing, transport and laying on the road. PMID- 22818589 TI - Adolescent girls' most common source of junk food away from home. AB - Contextual factors associated with adolescent girls' dietary behaviors could inform future interventions to improve diet. High school girls completed a 7-day diary, recording all trips made. In places other than home or school they recorded the food eaten. Girls made an average of 11.4 trips per week other than to home or school. Snacks high in solid oils, fats and added sugars (SOFAS) were frequently consumed. Girls reported eating an average of 3.5 servings per week of snacks high in SOFAS at someone else's house compared to 3.0 servings per week at retail food outlets. Findings demonstrate that low nutrient foods are ubiquitous and efforts should be made to reduce their availability in multiple settings. PMID- 22818591 TI - Arsenic contamination in the food chain and its risk assessment of populations residing in the Mekong River basin of Cambodia. AB - In the present study, we investigated the potential arsenic exposure of Cambodian residents from their daily food consumption. Environmental and ecological samples such as paddy soils, paddy rice (unhusked), staple rice (uncooked and cooked), fish and vegetables were collected from Kandal, Kratie and Kampong Cham provinces in the Mekong River basin of Cambodia. After acid-digestion, digestates were chemically analyzed by inductively coupled plasma mass spectrometry. Results revealed that the means of total arsenic concentration ([As]tot) in paddy soils and paddy rice from Kandal were significantly higher than those from Kampong Cham province (t-test, p<0.05). Moreover, a significant positive correlation between the [As]tot in paddy soils and paddy rice was found (r(14) = 0.826, p<0.01). Calculations of arsenic intake from food consumption indicated that the upper end of the range of the daily dose of inorganic arsenic for Kandal residents (0.089 8.386 MUg d(-1) kg(-1) body wt.) was greater than the lower limits on the benchmark dose for a 0.5% increased incidence of lung cancer (BMDL0.5 is equal to 3.0 MUg d(-1) kg(-1) body wt.). The present study suggests that the residents in Kandal are at risk of arsenic intake from their daily food consumption. However, the residents in Kratie and Kampong Cham provinces are less likely to be exposed to arsenic through their daily dietary intake. To the best of our knowledge, this is the first report estimating the daily intake and daily dose of inorganic arsenic from food consumption in the Mekong River basin of Cambodia. PMID- 22818592 TI - Decalcification resistance of alkali-activated slag. AB - This paper analyses the effects of decalcification in concentrated 6M NH(4)NO(3) solution on mechanical and microstructural properties of alkali-activated slag (AAS). Portland-slag cement (CEM II/A-S 42.5 N) was used as a benchmark material. Decalcification process led to a decrease in strength, both in AAS and in CEM II, and this effect was more pronounced in CEM II. The decrease in strength was explicitly related to the decrease in Ca/Si atomic ratio of C-S-H gel. A very low ratio of Ca/Si ~0.3 in AAS was the consequence of coexistence of C-S-H(I) gel and silica gel. During decalcification of AAS almost complete leaching of sodium and tetrahedral aluminum from C-S-H(I) gel also took place. AAS showed significantly higher resistance to decalcification in relation to the benchmark CEM II due to the absence of portlandite, high level of polymerization of silicate chains, low level of aluminum for silicon substitution in the structure of C-S-H(I), and the formation of protective layer of polymerized silica gel during decalcification process. In stabilization/solidification processes alkali-activated slag represents a more promising solution than Portland-slag cement due to significantly higher resistance to decalcification. PMID- 22818593 TI - Emerging genetic influences in benign epilepsy with centro-temporal spikes - BECTS. AB - BECTS is considered to be the most common childhood epileptic syndrome. Multifactorial inheritance is the most important model accounting for the genetic behavior of the common epilepsies. In recent years, different mutations in genes that control the excitability of neurons have been described. Recent reports on the involvement of the BDNF and ELP4 genes with possible roles in cell motility, migration, and adhesion have provided first insights into the complex molecular bases of childhood focal epilepsies. However, in the most common idiopathic benign childhood epilepsies (BECTS and occipital epilepsies), major breakthroughs are still awaited. PMID- 22818623 TI - Plasma levels of antibodies against oxidized LDL are inherited but not associated with HDL-cholesterol level in families with early coronary heart disease. AB - OBJECTIVE: Oxidized low-density lipoproteins (oxLDL) and antibodies against them (anti-oxLDLs) are thought to play a central role in atherosclerosis. One proposed antiatherosclerotic mechanism for HDL is to prevent oxidation of LDL. This study examined whether plasma HDL-cholesterol (HDL-C) is related to plasma anti-oxLDL levels. METHODS: We collected families based on probands with low HDL-C and premature coronary heart disease (CHD). Antibody levels were determined in samples from 405 subjects. Immunoglobulin G, M and A levels against two in vitro models of oxLDL, malondialdehyde-acetaldehyde-modified LDL (MAA-LDL) and copper oxidized LDL (CuOx-LDL), were measured by ELISA. We carried out heritability estimation of antibody traits and bivariate analyses between HDL-C, LDL-C and antibody traits. RESULTS: All the antibody levels were significantly inherited (p < 0.001), heritability estimates ranging from 0.28 to 0.65. HDL-C exhibited no environmental or genetic cross-correlations with antibody levels. Significant environmental correlations were detected between LDL-C and both IgG levels (rho(E) = 0.40, p = 0.046 and rho(E) = 0.39, p < 0.001). There were no differences in antibody levels between subjects with normal and low HDL-C, or between CHD-affected and non-affected subjects. CONCLUSION: In this study, low HDL-C level displayed no significant associations with the anti-oxLDL levels measured. The heritability of the anti-oxLDL levels was a novel and interesting finding. PMID- 22818624 TI - Increased popliteal circumferential wall tension induced by orthostatic body posture is associated with local atherosclerotic plaques. AB - OBJECTIVE: Lower limb arteries are exposed to higher hemodynamic burden in erectile posture. This study evaluated the effects of body posture on popliteal, carotid and brachial circumferential wall tension (CWT) and investigated the relationship between local CWT and atherosclerotic plaques in subjects with cardiovascular risk factors. METHODS: Two hundred and three subjects (118 women and 85 men) with cardiovascular risk factors (smoking, hypertension or diabetes mellitus) underwent clinical and laboratory analysis and had their blood pressure measured in the arm and calf in supine and orthostatic positions. Arteries were evaluated by ultrasound analysis, while CWT was calculated according to Laplace's law. RESULTS: Among the enrolled participants, 47%, 29% and none presented popliteal, carotid and brachial plaques, respectively. Carotid CWT measurements were not associated with local plaques after adjustment for potential confounders. Conversely, general linear model and logistic regression analyses adjusted for potential confounders demonstrated that peak orthostatic CWT was the only local hemodynamic parameter showing significant relationship with popliteal plaques in the whole sample. In gender-specific analyses, although positively correlated with popliteal plaques in both genders, local peak orthostatic CWT exhibited an independent association with popliteal plaques after adjustment for potential confounders only in women. CONCLUSION: Popliteal CWT measured in orthostatic posture, rather than in supine position, is associated with popliteal atherosclerotic plaques, particularly in women. These findings suggest that erectile posture might play a role in the atherogenesis of leg arteries by modifying local hemodynamic forces and that there may be gender differences in this regard. PMID- 22818625 TI - Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. AB - OBJECTIVE: To investigate, in male Wistar rats, the effects of long-term moderate red wine (RW) consumption (equivalent to ~0.15 mg% resveratrol RS), or RS in low (L, 0.15 mg%) or high (H, 400 mg%) doses in chow. BACKGROUND: Both RW and RS exhibit cardioprotection. RS extends lifespan in obese rats. It is unclear whether RW consumption or low-dose RS delay vascular aging and prolong life span in the absence of overt risk factors. METHODS: Endpoints were aerobic performance, exercise capacity, aging biomarkers (p53,p16,p21, telomere length and telomerase activity in aortic homogenates), vascular reactivity. Data were compared with controls (C) given regular chow. RESULTS: Expressions of p53 decreased ~50% ~with RW and LRS (p < 0.05 vs. C), p16 by ~29% with RW (p < 0.05 vs. C) and p21 was unaltered. RW and LRS increased telomere length >6.5-fold vs. C, and telomerase activity increased with LRS and HRS. All treatments increased aerobic capacity (C 32.5 +/- 1.2, RW 38.7 +/- 1.7, LRS 38.5 +/- 1.6, HRS 38.3 +/- 1.8 mlO(2) min(-1) kg(-1)), and RW or LRS also improved time of exercise tolerance vs. C (p < 0.05). Endothelium-dependent relaxation improved with all treatments vs. C. Life span, however, was unaltered with each treatment vs. C = 673 +/- 30 days, p = NS. CONCLUSIONS: RW and LRS can preserve vascular function indexes in normal rats, although not extending life span. These effects were translated into better aerobic performance and exercise capacity. PMID- 22818626 TI - Recent epidemiological trends in tuberculous pleural effusion in Galicia, Spain. AB - OBJECTIVE: Knowledge on the distribution and determinants of tuberculous pleural effusions (TBPE) is incomplete. We aimed to describe the epidemiological trends and individual characteristics of TBPE in Galicia, Spain, over a 10-year period (2000-2009). DESIGN: A retrospective, observational study based on epidemiological data obtained from the Galician Tuberculosis Register. RESULTS: There were 1835 cases of TBPE (16.3% of the total 11,241 TB cases reported). The number and incidence of TBPE decreased significantly during the study period, from (262 and 9.6/100,000 inhabitants in 2000, to 133 and 4.8 in 2009, respectively; P<.001 for both). The mean annual decrease in TBPE incidence was 6.9%, and 50% overall. TBPE mainly affected males (63.5%), precisely 61.2% young males between 15 and 44 years. Twenty-five percent had lung involvement (chest X ray), and 41.7% had a positive sputum culture. A significant increase (P<.001) was observed during the study in the percentage of patients who had more TB risk factors. CONCLUSIONS: The incidence of TBPE decreased significantly during the study period, with no changes in epidemiological characteristics, and with trends similar to the total number of TB cases. The introduction of the Galician Prevention and Control Plan (GPCP) for tuberculosis appears to be effective for better control of TB. PMID- 22818627 TI - Causes and correlates of anemia in 200 patients with acute cardiogenic pulmonary edema. AB - BACKGROUND: Acute heart failure has a poor prognosis and the presence of anemia may increase the risk of adverse outcomes. However, the clinical and laboratory characteristics of anemia in acute heart failure are poorly known. We aimed to assess the causes and the clinical and laboratory correlates of anemia in patients with acute cardiogenic pulmonary edema (ACPE). METHODS: This observational study, performed in an Emergency Unit, enrolled 200 patients treated with medical therapy and continuous positive airway pressure. RESULTS: Anemia was found in 36% of patients (38.5% of females and 32.5% of males) and was severe (hemoglobin <9 g/dL) in 6.9% of cases. The most frequent causes of anemia were chronic renal failure (27.8%), chronic inflammatory states (27.8%) and the clustering of multiple factors (18.1%). A wider spectrum of etiological factors was found in females than in males. Microcytic anemia was observed only in females (20% of those anemic), mainly due to iron deficiency/chronic blood loss. Glomerular filtration rate, serum iron, serum albumin, total cholesterol and diastolic blood pressure were independently associated with hemoglobin levels. CONCLUSIONS: The etiology of anemia in ACPE is heterogeneous, with several causal factors besides impaired renal function. The pattern of anemia is different between genders, suggesting that sex-specific diagnostic and therapeutic targets should be implemented. PMID- 22818628 TI - Bacillus anthracis lethal toxin induces complex changes in sympathetic nerve discharge regulation. AB - Bacillus anthracis lethal toxin (LeTx) alters blood pressure and visceral sympathetic nerve discharge (SND) regulation (Garcia et al., 2012). The present results indicate that LeTx infusions produce similar response profiles in peripheral (lumbar) and visceral (renal) SND; an initial widespread activation of sympathetic nerve outflow, followed by a generalized reduction in lumbar and renal SND from peak levels, although the sympathoinhibition tended to be attenuated in lumbar SND. Combined hypoxia+hypercapnia during the hypotensive phase of LeTx infusions increased lumbar and renal SND, indicating that sympathetic neural circuits can be activated during the circulatory shock phase of B. anthracis septicemia. PMID- 22818629 TI - [Physical activity and physical and rehabilitation medicine]. PMID- 22818644 TI - Tissue plasminogen activator and stroke: review of the literature for the clinician. AB - BACKGROUND: Alteplase (tPA) is a United States (US) Food and Drug Administration approved treatment for acute ischemic stroke, though there are significant barriers to thrombolytic use, including Emergency Physicians' (EPs') concern for level of supporting evidence. STUDY OBJECTIVES: To review the medical literature on the topic of acute cerebrovascular accident (CVA) management and to offer EPs evidence-based recommendations for patients who present to the Emergency Department with an acute CVA. METHODS: A MEDLINE literature search from 1990 to 2011 and limited to human studies written in English for articles with keywords of: CVA AND (thromboly* OR alteplase). Guideline statements and non-systematic reviews were excluded. Studies targeting differences between specific populations (males vs. females) were excluded. Studies identified then underwent a structured review from which results could be evaluated. RESULTS: There were 407 papers on thrombolytic use screened, and 15 appropriate articles were rigorously reviewed and recommendations given. CONCLUSIONS: tPA is an effective treatment for stroke when given in prepared stroke centers; EPs and hospitals treating stroke patients with tPA need to have the necessary resources in place and a specific plan for timely care of patients with acute stroke. PMID- 22818643 TI - Comparison of CareStartTM HRP2/pLDH COMBO rapid malaria test with light microscopy in north-west Ethiopia. AB - BACKGROUND: In Ethiopia, light microscopy is the gold standard for malaria diagnosis although it is not available in most peripheral health facilities. It is time consuming, requires trained personnel and needs careful preparation and application of reagents to ensure quality results. This study was aimed at testing the diagnostic performance of CareStartTM malaria rapid diagnostic test (RDT) with reference to light microscopy for the diagnosis of falciparum and vivax malaria in Ethiopia. METHODS: Blood samples were collected from 254 patients suspected to have malaria at Kola Diba Health Center in the late malaria transmission peak season from November 2011 to December 2011. The samples were examined immediately by light microscopy and the RDT (CareStartTM Malaria HRP2/pLDH COMBO Test kit). Statistical analysis was performed using SPSS version 16 and the JavaStat two-way contingency table analysis. RESULTS: The overall sensitivity and specificity of CareStartTM RDT was found to be 95% (90-97.9%, 95% CI) and 94.2% (90.9-96%, 95% CI), respectively. The sensitivity of the CareStartTM RDT for Plasmodium falciparum or mixed infection was calculated to be 92.9% (82.5-98%, 95%CI) while a sensitivity of 90.9% (74.1-98.4%, 95%CI) was found for non-falciparum species. The specificity for P. falciparum or mixed infections was found to be 95.4% (92.5-96.8%, 95%CI) while it was 97.3% (94.8 98.4%, 95%CI) for non-falciparum species. There was an excellent agreement between the two tests with a kappa value of 0.918. CONCLUSION: The CareStartTM RDT test showed good sensitivity and specificity with an excellent agreement to the reference light microscopy. The RDT could therefore be used in place of light microscopy, which in poor set-ups cannot be used routinely. PMID- 22818645 TI - Physicians' assessment of pediatric returns to the Emergency Department. AB - BACKGROUND: Return visits to the Emergency Department (ED) requiring admission are frequently reviewed for the purpose of quality improvement. Treating physicians typically perform this review, but it is unclear if they accurately identify the reasons for the returns. OBJECTIVES: To assess the characteristics of pediatric return visits to the ED, and the ability of treating physicians to identify the root causes for these return visits. METHODS: This retrospective cohort study reviewed all returns within 96 h of an initial visit over a 2-year period at a tertiary care pediatric ED. Baseline characteristics were determined from review of patients' charts. The treating physicians, the primary author, and independent reviewers identified the root cause for the returns. RESULTS: There were 97,374 patients that presented to the ED during the study, and 1091 (1.1%) of these children returned to the ED and were admitted. Returns were most common among children aged<5 years, arriving between 3:00 p.m. and 11:00 p .m. via private transportation, with infectious diseases. The physician involved in the care of the patient attributed 3.1% of returns to potential deficiencies in medical management, whereas the independent reviewers attributed 13% to potential deficiencies. CONCLUSIONS: Both returns and the subset of returns due to potential deficiencies in management are more common than previously estimated, rendering review of returns a valuable quality improvement tool. However, EDs should not rely exclusively on the treating physicians to identify the reason for returns, as they seem to underestimate the frequency of returns due to potential deficiencies in medical management. PMID- 22818646 TI - Racial disparity in emergency department triage. AB - BACKGROUND: Previous reports of lower triage acuity scores and longer Emergency Department (ED) wait times for African Americans compared to Caucasians had insufficient information to determine if this was due to bias or appropriately based on medical history and clinical presentation. OBJECTIVE: (1) Determine if African Americans are assigned lower triage acuity scores (TAS) after adjusting for a number of demographic and clinical variables likely to affect triage scores. (2) Determine if lower TAS translate into clinically significant longer wait times to assignment to a treatment area. METHODS: This was a retrospective matched cohort design analysis of de-identified data extracted from the ED electronic medical record system, which included demographic and clinical information, as well as TAS, and ED process times. Triage scores were assigned using a 5-point scale (ESI), with 1 being most urgent and 5 being least urgent. Mean TAS and wait times to a treatment area for specific chief complaints were compared by race; after adjusting for age, gender, insurance status, time of day, day of week, presence of co-morbidities, and abnormal vital signs using a 1:1 matched case analysis. RESULTS: The overall mean TAS for African Americans was 2.97 vs. 2.81 for Caucasians (difference of 0.18; p<0.001), translating to a lower acuity rating. African Americans had a significantly longer wait time to a treatment area compared to case-matched Caucasians (10.9min; p<0.001), with much larger differences in wait times noted within certain specific chief complaint categories. CONCLUSION: Our current study supports the hypothesis that racial bias may influence the triage process. PMID- 22818647 TI - Point-of-care ultrasound diagnosis of a ruptured live ectopic pregnancy with massive hemoperitoneum. PMID- 22818648 TI - Rickets in an infant. PMID- 22818649 TI - Shear stress-dependent cell detachment from temperature-responsive cell culture surfaces in a microfluidic device. AB - A new approach to quantitatively estimate the interaction between cells and material has been proposed by using a microfluidic system, which was made of poly(dimethylsiloxane) (PDMS) chip bonding on a temperature-responsive cell culture surface consisted of poly(N-isopropylacrylamide) (PIPAAm) grafted tissue culture polystyrene (TCPS) (PIPAAm-TCPS) having five parallel test channels for cell culture. This construction allows concurrently generating five different shear forces to apply to cells in individual microchannels having various resistance of each channel and simultaneously gives an identical cell incubation condition to all test channels. NIH/3T3 mouse fibroblast cells (MFCs) and bovine aortic endothelial cells (BAECs) were well adhered and spread on all channels of PIPAAm-TCPS at 37 degrees C. In our previous study, reducing culture temperature below the lower critical solution temperature (LCST) of PIPAAm (32 degrees C), cells detach themselves from hydrated PIPAAm grafted surfaces spontaneously. In this study, cell detachment process from hydrated PIPAAm-TCPS was promoted by shear forces applied to cells in microchannels. Shear stress-dependent cell detachment process from PIPAAm-TCPS was evaluated at various shear stresses. Either MFCs or BAECs in the microchannel with the strongest shear stress were found to be detached from the substrate more quickly than those in other microchannels. A cell transformation rate constant C(t) and an intrinsic cell detachment rate constant k(0) were obtained through studying the effect of shear stress on cell detachment with a peeling model. The proposed device and quantitative analysis could be used to assess the possible interaction between cells and PIPAAm layer with a potential application to design a cell sheet culture surface for tissue engineering. PMID- 22818650 TI - The influence of matrix integrity on stress-fiber remodeling in 3D. AB - Matrix anisotropy is important for long term in vivo functionality. However, it is not fully understood how to guide matrix anisotropy in vitro. Experiments suggest actin-mediated cell traction contributes. Although F-actin in 2D displays a stretch-avoidance response, 3D data are lacking. We questioned how cyclic stretch influences F-actin and collagen orientation in 3D. Small-scale cell populated fibrous tissues were statically constrained and/or cyclically stretched with or without biochemical agents. A rectangular array of silicone posts attached to flexible membranes constrained a mixture of cells, collagen I and matrigel. F-actin orientation was quantified using fiber-tracking software, fitted using a bi-model distribution function. F-actin was biaxially distributed with static constraint. Surprisingly, uniaxial cyclic stretch, only induced a strong stretch-avoidance response (alignment perpendicular to stretching) at tissue surfaces and not in the core. Surface alignment was absent when a ROCK inhibitor was added, but also when tissues were only statically constrained. Stretch-avoidance was also observed in the tissue core upon MMP1-induced matrix perturbation. Further, a strong stretch-avoidance response was obtained for F actin and collagen, for immediate cyclic stretching, i.e. stretching before polymerization of the collagen. Results suggest that F-actin stress-fibers avoid cyclic stretch in 3D, unless collagen contact guidance dictates otherwise. PMID- 22818651 TI - Self-assembled complex of probe peptide--E. Coli RNA I conjugate and nano graphene oxide for apoptosis diagnosis. AB - Caspase-3 plays an important role in the initiation and propagation of apoptosis which is involved in various kinds of diseases including neurodegenerative diseases and inflammatory diseases. The capase-3 cleavable site of Asp-Glu-Val Asp (DEVD) connected to a partial sequence of Escherichia coli RNAI was labeled with tetramethyl-6-carboxyrhodamine (TAMRA) as an optical probe. Graphene oxide (GO) was synthesized by a modified Hummer's method and exploited for the preparation of nano-sized GO (NGO) conjugated with polyethylene glycol (PEG). After binding the NGO-PEG by pi-pi stacking, the quenched fluorescence of TAMRA DEVD-single stranded DNA (ssDNA) conjugate was recovered via the enzymatic cleavage by caspase-3 in live A549 cells. The comparative study with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay clearly confirmed the specific detection of apoptosis by the non-covalent TAMRA-DEVD ssDNA/NGO-PEG complex. Furthermore, the self-assembled NGO complex was successfully exploited for in vivo diagnosis of apoptosis-related diseases like hypoxic-ischemic encephalopathy (HIE) and liver cirrhosis. PMID- 22818652 TI - Enhanced cartilage formation by inhibiting cathepsin K expression in chondrocytes expanded in vitro. AB - Although engineered cartilage has great potential in cartilage regeneration and reconstruction, dedifferentiation of chondrocytes during in vitro expansion remains a technical bottleneck in the clinical application. To overcome the problem, a gene modification approach was developed to knock-down the key gene involving dedifferentiation of human chondrocytes. A microarray assay revealed 84 up-regulated genes and 56 down-regulated genes in passage 4 (dedifferentiated) human chondrocytes compared to passage 1 cells. Among them, cathepsin K (CTSK) was the key gene (with 28 folds of increased gene expression), which was further confirmed by RT-PCR and Western-Blot. Furthermore, over-expression of CTSK led to reduced matrix production in cultured human chondrocytes in vitro and poor formation of engineered cartilage in vivo. In contrast, CTSK knock-down could better maintain the chondrogenic phenotype of in vitro expanded cells with increased gene and protein expression of collagen II and aggrecan when compared to control cells. More importantly, after 6 passages, the knock-down cells formed much better engineered cartilage than the control cells after in vivo implantation with 30% Pluronic F127 for 8 weeks as the experimental group formed much bigger sized cartilages with significantly increased weight and glycosaminoglycan content (p < 0.05) than the control group. Histologically, the knock-down cells formed a more homogenous cartilage structure with enhanced production of collagen II and proteoglycans. Overall, these results suggest that CTSK knock-down may provide a feasible way to expand functional human chondrocytes in vitro for engineering good quality human cartilage and thus may have its great potential in the clinical translation of engineered cartilage in the future, given the fact that biosafe RNA interference techniques are already available. PMID- 22818653 TI - The alignment of MC3T3-E1 osteoblasts on steps of slip traces introduced by dislocation motion. AB - Bone tissue shows a highly anisotropic microstructure comprising biological apatite and collagen fibrils produced by the mutual activities of bone cells, which dominates its mechanical function. Accordingly, directional control of osteoblasts is crucial for forming anisotropic bone tissue. A new approach was proposed for controlling cell directionality by using crystallographic slip traces caused by dislocation glide. Dislocations were introduced into alpha titanium single crystals by plastic deformation of (011-0)[21-1-0] slip system, inducing a step-like structure with acute angles between the surface normal and the slip plane. Topographical properties of step patterning, including step interval and step height, could be controlled by varying the compressive plastic strain. The step geometry introduced by plastic deformation strongly influenced osteoblast elongation, and it aligned preferentially along slip traces. Ti substrates under 10% plastic strain with step height of approximately 300 nm and step interval of 10 MUm induced osteoblast alignment most successfully. Actin stress fibers elongated parallel to slip traces, with polarized vinculin accumulation between steps. PMID- 22818654 TI - Impact of the nature, size and chain topologies of carbohydrate-phosphorylcholine polymeric gene delivery systems. AB - With the recent significant advances in the field polymer chemistry, it is now possible to produce well-defined and non-toxic cationic polymers with advanced molecular structures of desired molecular weights and compositions. Carefully engineered polymer architectures are found to impact significantly their DNA condensation and gene delivery efficacies. In a previous study, the statistical carbohydrates based copolymers were found to show high gene expression and low toxicity, however there aggregation in the presence of serum proteins was a major drawback. In this study, carbohydrate and phosphorylcholine based cationic polymers having a different architecture, compositions and varying molecular weights are produced and are termed as cationic 'block-statistical' copolymers. These cationic copolymers are evaluated for their gene delivery efficacies, interactions with serum protein, cellular uptake and nuclear localization ability. As compared to the statistical analogue, 'block-statistical' copolymers showed high gene expression, low interactions with serum proteins, as well as low toxicity in hepatocytes and human dermal fibroblasts. In addition, 2- methacryloyloxyethyl phosphorylcholine (MPC) based 'block-statistical' copolymers and their sugar incorporated analogues were prepared and were found to serve as improved gene delivery vectors than their statistical analogues. PMID- 22818655 TI - [Contribution of platelet concentrates to oral and maxillo-facial surgery]. AB - INTRODUCTION: We evaluated the clinical contribution of platelet concentrates to oral and maxillo-facial surgery. MATERIAL AND METHOD: This bibliographic research was made using the PubMed MeSH database with the following keywords: "platelet rich fibrin" (PRF), "platelet rich plasma" (PRP), "bone", "facial bone", "dental implant", and "blood platelet". The research was made without any date or language limitation since English summaries were available. All summaries were read to evaluate the relevance of the article. Only original articles and case reports were considered. The articles were classified as "in vitro studies", "animal experiments", or "clinical studies". The research was stopped on March 22, 2012. RESULTS: One hundred and sixty-nine articles were validated after excluding irrelevant articles, reviews, technical notes, and articles without English or French summaries. Seventeen were in vitro studies, 61 animal experiments, and 91 clinical studies. One hundred and ten complete articles were read to complete summary data. The data of in vitro studies univocally supports of using platelet concentrates. The data from animal experiment studies was less consensual and the validity of animal models was contested. The disparity of clinical study designs and the lack of rigorous methodology did not allow clearly determining platelet concentrate benefits for oral and maxillo-facial surgery. DISCUSSION: PRF or PRP clinical benefit has not been clearly demonstrated yet. French regulations relative to their use should be clarified. PMID- 22818656 TI - Exercise for diabetic neuropathy: a toe in the therapeutic door. PMID- 22818657 TI - Atypical SREDA in sleep. PMID- 22818658 TI - The effect of cervical traction combined with neural mobilization on pain and disability in cervical radiculopathy. A case report. AB - Cervical radiculopathy is the result of cervical nerve root pathology that may lead to chronic pain and disability. Although manual therapy interventions including cervical traction and neural mobilization have been advocated to decrease pain and disability caused by cervical radiculopathy, their analgesic effect has been questioned due to the low quality of research evidence. The purpose of this paper is to present the effect of cervical traction combined with neural mobilization on pain and disability in a patient experiencing cervical radiculopathy. A 52-year-old woman presented with a 2 month history of neurological cervico-brachial pain and whose presentation was consistent with cervical radiculopathy. Cervical traction and a slider neural mobilization of the medial nerve were applied simultaneously to reduce the patient's pain and disability measured at baseline and at 2 and 4 weeks using the Numeric Pain Rating Scale, the Neck Disability Index and the Patient-Specific Functional Scale. Improvements in all outcome measures were noted over a period of four weeks. Scores in all outcome measures revealed that the patient's pain had almost disappeared and that she was able to perform her household chores and job tasks without difficulties and limitations. In conclusion, the findings of this study support that the application of cervical traction combined with neural mobilization can produce significant improvements in terms of pain and disability in cervical radiculopathy. PMID- 22818659 TI - Antiviral activity of zinc salts against transmissible gastroenteritis virus in vitro. AB - Zinc has been shown to mediate antiviral effects against certain viruses. However, the underlying mechanisms are still largely unknown. We investigated the effects of the two zinc salts, zinc chloride (ZnCl(2)) and zinc sulfate (ZnSO(4)), on infection of swine testicle (ST) cells with transmissible gastroenteritis virus (TGEV) and compared it to the effects of a control salt, magnesium sulfate (MgSO(4)). Virus yield reduction experiments showed that ZnCl(2) and ZnSO(4) did not exhibit direct virucidal effects and did not affect adsorption of TGEV to ST cells. However, ZnCl(2) and ZnSO(4) markedly reduced viral titers as well as TGEV RNA and viral protein synthesis when applied during virus penetration and at different time points after viral cell entry. The results of the study suggest that zinc salts do not interfere with TGEV-cell binding but that they mediate antiviral effects through inhibition of viral penetration or egress or the intracellular phase of the viral life-cycle. PMID- 22818660 TI - Mycobacterium bovis infection in a collared peccary (Tayassu tajacu): insights on tuberculosis wild reservoirs. PMID- 22818661 TI - Implementation of a community-based mature driver screening and referral program: A feasibility study. AB - We tested the feasibility of implementing a community mature driver screening and referral program utilizing the Roadwise Review screening instrument. We recruited a convenience sample of 151 mature drivers (age 65 and over) at six community senior centers in suburban Connecticut. A 30 item survey collected demographic information, driving history, and self-reported vision, physical fitness, and attention problems. Participants completed a 30min computer screening program that assessed 8 areas associated with driving ability. Referrals were provided to participants with identified impairments. A post survey measured program satisfaction; a two week follow-up determined intent to address impairments. Among the problems/issues reported: reading highway/street signs or seeing other vehicles at night (25%), trouble looking over shoulder when changing lanes (18%), avoidance of night driving (22%) or in unfamiliar places (31%). Screening found mild impairments in 86% of participants and 52% with serious impairments. Referrals were given to 75%; at follow-up, 74% reported intent to complete referrals. Most participants (94%) would recommend the program to family/friends. In conclusion, this study was feasible to implement and identified driving impairments among mature drivers. Most participants intended follow-up with driving recommendations and program satisfaction was high. PMID- 22818662 TI - Computer modeling of deployment and mechanical expansion of neurovascular flow diverter in patient-specific intracranial aneurysms. AB - Flow diverter (FD) is an emerging neurovascular device based on self-expandable braided stent for treating intracranial aneurysms. Variability in FD outcome has underscored a need for investigating the hemodynamic effect of fully deployed FD in patient-specific aneurysms. Image-based computational fluid dynamics, which can provide important hemodynamic insight, requires accurate representation of FD in deployed states. We developed a finite element analysis (FEA) based workflow for simulating mechanical deployment of FD in patient-specific aneurysms. We constructed FD models of interlaced wires emulating the Pipeline Embolization Device, using 3D finite beam elements to account for interactions between stent strands, and between the stent and other components. The FEA analysis encompasses all steps that affect the final deployed configuration including stent crimping, delivery and expansion. Besides the stent, modeling also includes key components of the FD delivery system such as microcatheter, pusher, and distal coil. Coordinated maneuver of these components allowed the workflow to mimic clinical operation of FD deployment and to explore clinical strategies. The workflow was applied to two patient-specific aneurysms. Parametric study indicated consistency of the deployment result against different friction conditions, but excessive intra-stent friction should be avoided. This study demonstrates for the first time mechanical modeling of braided FD stent deployment in cerebral vasculature to produce realistic deployed configuration, thus paving the way for accurate CFD analysis of flow diverters for reliable prediction and optimization of treatment outcome. PMID- 22818663 TI - An integrated model of active glenohumeral stability. AB - We present the first model of the glenohumeral joint implementing active muscle driven humeral positioning and stabilization without a priori constraints on glenohumeral kinematics. Previously established methods were used to predetermine the path, activation timing and resultant force contribution of 27 individual muscle segments at any given joint position. Artificial boundary conditions were applied in a three-dimensional finite element model of the joint and progressively released until the humeral head was completely free to rotate and translate within the fixed glenoid according to the compressive component of the predetermined resultant force. The shear component was then added such that no boundary conditions other than muscular force were applied. The framework was exploited to simulate elevation as a composite of instantaneous positions and theoretically demonstrate that joint stability can be achieved exclusively through muscular activity. Predicted muscle moment arms, muscle activation timing, humeral head translations, joint contact forces and stability ratio were comparable with existing experimental and in vivo data. This framework could be valuable for subject specific modeling and may be used to address clinical hypotheses related to shoulder joint stability that cannot be pursued using simplified modeling approaches. PMID- 22818664 TI - Growth under elevated atmospheric CO(2) concentration accelerates leaf senescence in sunflower (Helianthus annuus L.) plants. AB - Some morphogenetic and metabolic processes were sensitive to a high atmospheric CO(2) concentration during sunflower primary leaf ontogeny. Young leaves of sunflower plants growing under elevated CO(2) concentration exhibited increased growth, as reflected by the high specific leaf mass referred to as dry weight in young leaves (16 days). The content of photosynthetic pigments decreased with leaf development, especially in plants grown under elevated CO(2) concentrations, suggesting that high CO(2) accelerates chlorophyll degradation, and also possibly leaf senescence. Elevated CO(2) concentration increased the oxidative stress in sunflower plants by increasing H(2)O(2) levels and decreasing activity of antioxidant enzymes such as catalase and ascorbate peroxidase. The loss of plant defenses probably increases the concentration of reactive oxygen species in the chloroplast, decreasing the photosynthetic pigment content as a result. Elevated CO(2) concentration was found to boost photosynthetic CO(2) fixation, especially in young leaves. High CO(2) also increased the starch and soluble sugar contents (glucose and fructose) and the C/N ratio during sunflower primary leaf development. At the beginning of senescence, we observed a strong increase in the hexoses to sucrose ratio that was especially marked at high CO(2) concentration. These results indicate that elevated CO(2) concentration could promote leaf senescence in sunflower plants by affecting the soluble sugar levels, the C/N ratio and the oxidative status during leaf ontogeny. It is likely that systemic signals produced in plants grown with elevated CO(2), lead to early senescence and a higher oxidation state of the cells of these plant leaves. PMID- 22818665 TI - [Pediatric mucoceles: clinical aspects and therapeutic approaches]. AB - INTRODUCTION: Paranasal sinuses mucoceles are extremely rare in children and adolescents. The objective of this study was to assess their clinical presentations and the contribution of endoscopic surgery in their management. MATERIAL AND METHODS: we retrospectively reviewed 11 children with paranasal sinus mucoceles who were managed during a period of 15 years (1995-2009). RESULTS: The mean age was 11.8 years with a sex ratio of 2.66. One patient had a history of nasal polyposis surgery. The symptomatology was dominated by ophthalmological complains. The ethmoid sinus was the main localization. Orbital extension was found in eight cases, pyomucocele in one case. The surgical management was endoscopic (nine cases), and by an external approach (two cases). Two cases of recurrence were assessed. The mean follow-up was 22.3 months. DISCUSSION: Paranasal sinuses mucocele is exceptional in children. Cystic fibrosis is the main etiologic factor. The symptoms depend on the location and size of the mucocele. The treatment is surgical and most authors prefer the endoscopic approach. PMID- 22818666 TI - HLA class I protective alleles in an HIV-1-infected subject homozygous for CCR5 Delta32/Delta32. AB - Homozygosity for a 32 bp deletion in CCR5 (CCR5-Delta32/Delta32) is associated with strong resistance against HIV-1 infection. Several HLA types have been associated to improved viral control and/or delayed progression to AIDS. We report a unique HIV-1 infected individual homozygous for CCR5-Delta32/Delta32 and carrier of HLA-A*2402 and HLA-B*5701. In comparison with earlier data and although a replication competent virus has been isolated, the patient presents better immune status, response to treatment and disease evolution, which may be related to the control exerted by HLA class I restricted T cell immunity. Importantly, the accumulation of protective factors does not warrant a complete protection to HIV infection and the subsequent life-long treatment. PMID- 22818710 TI - Extending and encoding existing biological terminologies and datasets for use in the reasoned semantic web. AB - BACKGROUND: Clinical phenotypes and disease-risk stratification are most often determined through the direct observations of clinicians in conjunction with published standards and guidelines, where the clinical expert is the final arbiter of the patient's classification. While this "human" approach is highly desirable in the context of personalized and optimal patient care, it is problematic in a healthcare research setting because the basis for the patient's classification is not transparent, and likely not reproducible from one clinical expert to another. This sits in opposition to the rigor required to execute, for example, Genome-wide association analyses and other high-throughput studies where a large number of variables are being compared to a complex disease phenotype. Most clinical classification systems and are not structured for automated classification, and similarly, clinical data is generally not represented in a form that lends itself to automated integration and interpretation. Here we apply Semantic Web technologies to the problem of automated, transparent interpretation of clinical data for use in high-throughput research environments, and explore migration-paths for existing data and legacy semantic standards. RESULTS: Using a dataset from a cardiovascular cohort collected two decades ago, we present a migration path - both for the terminologies/classification systems and the data - that enables rich automated clinical classification using well-established standards. This is achieved by establishing a simple and flexible core data model, which is combined with a layered ontological framework utilizing both logical reasoning and analytical algorithms to iteratively "lift" clinical data through increasingly complex layers of interpretation and classification. We compare our automated analysis to that of the clinical expert, and discrepancies are used to refine the ontological models, finally arriving at ontologies that mirror the expert opinion of the individual clinical researcher. Other discrepancies, however, could not be as easily modeled, and we evaluate what information we are lacking that would allow these discrepancies to be resolved in an automated manner. CONCLUSIONS: We demonstrate that the combination of semantically-explicit data, logically rigorous models of clinical guidelines, and publicly-accessible Semantic Web Services, can be used to execute automated, rigorous and reproducible clinical classifications with an accuracy approaching that of an expert. Discrepancies between the manual and automatic approaches reveal, as expected, that clinicians do not always rigorously follow established guidelines for classification; however, we demonstrate that "personalized" ontologies may represent a re-usable and transparent approach to modeling individual clinical expertise, leading to more reproducible science. PMID- 22818711 TI - Supportive evidence for the association between the Gln2Pro polymorphism in the SIGMAR1 gene and schizophrenia in the Japanese population: a case-control study and an updated meta-analysis. PMID- 22818712 TI - (+)-Episesamin inhibits adipogenesis and exerts anti-inflammatory effects in 3T3 L1 (pre)adipocytes by sustained Wnt signaling, down-regulation of PPARgamma and induction of iNOS. AB - Obesity and its associated health risks still demand for effective therapeutic strategies. Drugs and compositions derived from Oriental medicine such as green tea polyphenols attract growing attention. Previously, an extract from the Japanese spice bush Lindera obtusiloba (L. obtusiloba) traditionally used for treatment of inflammation and prevention of liver damage was shown to inhibit adipogenesis. Aiming for the active principle of this extract (+)-episesamin was identified, isolated and applied in adipogenic research using 3T3-L1 (pre)adipocytes, an established cell line for studying adipogenesis. With an IC50 of 10MUM (+)-episesamin effectively reduced the growth of 3T3-L1 preadipocytes and decreased hormone-induced 3T3-L1 differentiation as shown by reduced accumulation of intracellular lipid droplets and diminished protein expression of GLUT-4 and vascular endothelial growth factor. Mechanistically, the presence of (+)-episesamin during hormone-induced differentiation provoked a reduced phosphorylation of ERK1/2 and beta-catenin along with a reduced protein expression of peroxisome proliferator-activated receptor gamma and a strongly increased protein expression of iNOS. Treatment of mature adipocytes with (+) episesamin resulted in a reduction of intracellular stored lipid droplets and induced the proapoptotic enzymes caspases-3/-7. Besides interfering with adipogenesis, (+)-episesamin showed anti-inflammatory activity by counteracting the lipopolysaccharide- and tumor necrosis factor alpha-induced secretion of interleukin 6 by 3T3-L1 preadipocytes. In conclusion, (+)-episesamin seems to be the active drug in the L. obtusiloba extract being responsible for the inhibition of adipogenesis and, thus, should be evaluated as a novel potential complementary treatment for obesity. PMID- 22818713 TI - Silibinin protects H9c2 cardiac cells from oxidative stress and inhibits phenylephrine-induced hypertrophy: potential mechanisms. AB - Cardiac hypertrophy is the main response of the heart to various extrinsic and intrinsic stimuli, and it is characterized by specific molecular and phenotypic changes. Recent in vitro and in vivo studies indicate the involvement of reactive oxygen species in the hypertrophic response. In this study, silibinin, a plant flavonolignan extracted from milk thistle with potent antioxidant activity, was evaluated for its effects in (a) preventing hydrogen peroxide (H2O2)-induced cellular damage and (b) blocking the phenylephrine-induced hypertrophic response. Using the in vitro model of embryonic rat heart-derived H9c2 cells, we showed that silibinin has a rather safe profile as concentrations up to 200MUM did not affect cell viability. Pretreatment of H9c2 cells with silibinin resulted in better protection of H9c2 cells under conditions of H2O2-induced cellular stress compared to untreated cells as indicated by cell viability and DNA fragmentation assays. Furthermore, silibinin attenuated the phenylephrine-induced hypertrophic response as evidenced by the measurement of cell surface, up-regulation of atrial natriuretic peptide and increase of cellular protein levels. Moreover, silibinin repressed the phenylephrine-induced phosphorylation of ERK1/2 kinases, while it appeared to inhibit the weakly activated by phenylephrine phosphorylation of Akt. Based on our results, silibinin may attenuate the phenylephrine-induced hypertrophic response of H9c2 cells via antioxidant mechanisms involving mainly the inhibition of the intracellular signaling pathways mediated by ERK1/2 MAPKs and Akt. PMID- 22818714 TI - Role of curcuminoids in ameliorating oxidative modification in beta thalassemia/Hb E plasma proteome. AB - Thalassemic patients often exhibit high levels of oxidative stress and iron overload, which can lead to hazardous complications. Curcuminoids, extracted from the spice turmeric, are known to have antioxidant and iron-chelating properties and have been proposed as a potential upstream therapy of thalassemia. Here we have applied proteomic techniques to study the protein profile and oxidative damage in the plasma of beta-thalassemia/Hb E patients before and after treatment with curcuminoids. In this study, 10 beta-thalassemia/Hb E patients were treated with 500 mg curcuminoids daily for 12 months. The plasma protein profile and protein carbonyl content were determined at baseline, 6 and 12 months using two dimensional fluorescence difference gel electrophoresis and carbonyl immunoblotting, respectively. Other hematological, clinical, and biochemical parameters were also analyzed. Twenty-six spots, identified as coagulation factors and proteins involved in iron homeostasis, showed significantly decreased intensity in thalassemic plasma, compared to those of normal subjects. Treatment with curcuminoids up-regulated the plasma levels of these proteins and reduced their oxidative damage. Serum non-transferrin bound iron, platelet factor-3 like activity, oxidative stress parameters and antioxidant enzymes were also improved after curcuminoids treatment. This study is the first proteomic study of plasma in the thalassemic state and also shows the ameliorating role of curcuminoids towards oxidative stress and iron overload in the plasma proteome. PMID- 22818715 TI - Exposure to a maternal n-3 fatty acid-deficient diet during brain development provokes excessive hypothalamic-pituitary-adrenal axis responses to stress and behavioral indices of depression and anxiety in male rat offspring later in life. AB - Brain docosahexaenoic acid (DHA, 22:6n-3) accumulates rapidly during brain development and is essential for normal neurological function. The aim of this study was to evaluate whether brain development was the critical period in which DHA deficiency leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress later in life. Rats were exposed to an n-3 fatty acid deficient diet or the same diet supplemented with fish oil as an n-3 fatty acid adequate diet either throughout the preweaning period from embryo to weaning at 3 weeks old or during the postweaning period from 3 to 10 weeks old. Exposure to the n-3 fatty acid-deficient diet during the preweaning period resulted, at weaning, in a significant decrease in hypothalamic DHA levels and a reduced male offspring body weight. DHA deficiency during the preweaning period significantly increased and prolonged restraint stress-induced changes in colonic temperature and serum corticosterone levels, caused a significant increase in GABA(A) antagonist-induced heart rate changes and enhanced depressive-like behavior in the forced swimming test and anxiety-like behavior in the plus-maze test in later life. These effects were not seen in male rats fed the n-3 fatty acid-deficient diet during the postweaning period. These results suggest that brain development is the critical period in which DHA deficiency leads to excessive HPA responses to stress and elevated behavioral indices of depression and anxiety in adulthood. We propose that these effects of hypothalamic DHA deficiency during brain development may involve a GABA(A) receptor-mediated mechanism. PMID- 22818716 TI - Soluble plantain fibre blocks adhesion and M-cell translocation of intestinal pathogens. AB - Dietary fibres may have prebiotic effects mediated by promotion of beneficial bacteria. This study explores the possibility that soluble plant fibre may also improve health by inhibiting epithelial adhesion and translocation by pathogenic bacteria. We have focussed on soluble non-starch polysaccharide (NSP) from plantain bananas (Musa spp.) which previous studies showed to be particularly effective at blocking Escherichia coli epithelial adherence. In vitro and ex vivo studies assessed the ability of plantain NSP to inhibit epithelial cell adhesion and invasion of various bacterial pathogens, and to inhibit their translocation through microfold (M)-cells and human Peyer's patches mounted in Ussing chambers. Plantain NSP showed dose-related inhibition of epithelial adhesion and M-cell translocation by a range of pathogens. At 5mg/ml, a concentration readily achievable in the gut lumen, plantain NSP inhibited adhesion to Caco2 cells by Salmonella Typhimurium (85.0 +/- 8.2%, P<.01), Shigella sonnei (46.6 +/- 29.3%, P<.01), enterotoxigenic E.coli (56.1 +/- 23.7%, P<.05) and Clostridium difficile (67.6 +/- 12.3%, P<.001), but did not inhibit adhesion by enteropathogenic E.coli. Plantain NSP also inhibited invasion of Caco2 cells by S. Typhimurium (80.2 +/- 9.7%) and Sh. sonnei (46.7 +/- 13.4%); P<.01. Plantain NSP, 5mg/ml, also inhibited translocation of S. Typhimurium and Sh. sonnei across M-cells by 73.3 +/- 5.2% and 46.4 +/- 7.7% respectively (P<.05). Similarly, S. Typhimurium translocation across Peyer's patches was reduced 65.9 +/- 8.1% by plantain NSP (P<.01). Soluble plantain fibre can block epithelial adhesion and M-cell translocation of intestinal pathogens. This represents an important novel mechanism by which soluble dietary fibres can promote intestinal health and prevent infective diarrhoea. PMID- 22818717 TI - Lead exposure in Nunavik: from research to action. AB - BACKGROUND: In 1999, the Government of Canada regulated the use of lead shot for hunting. Concurrently, the Nunavik Regional Board of Health and Social Services (NRBHSS) was informed of the results of an isotope study that pointed to lead ammunition as a likely source of lead exposure in Nunavik. Rapidly thereafter, a coalition for the banning of lead shot was implemented by the NRBHSS as well as by regional/local partners and by Inuit hunters in order to disseminate this information to the public. OBJECTIVES: The purpose of this article is to describe the intervention conducted in the winter of 1999 by the NRBHSS and to assess the combined impact of national legislation and an awareness campaign on blood lead levels in Nunavik. STUDY DESIGN: Impact assessment of the intervention for the banning of lead shot conducted in 1999 in Nunavik using blood lead levels data before and after the intervention. METHODS: Data on blood lead levels in Nunavik describing foetal exposure as well as during childhood and in adults published between 1992 and 2009 were compiled. Blood lead levels in Nunavik prior to and after the interventions were compared. To assess the current situation, the most recent blood lead levels were compared with those from surveys conducted during the same period in North America. RESULTS: Analysis of blood samples collected from umbilical cord and from adults show that blood lead levels in Nunavik significantly declined between 1992 and 2004. Nevertheless, lead exposure in Nunavik still remains higher in comparison to that observed in other North American surveys. CONCLUSIONS: The current situation regarding lead exposure in Nunavik has significantly improved as a result of the implemented intervention. However, according to recent data, a gap still subsists relative to other North American populations. PMID- 22818718 TI - Traditional food consumption is associated with higher nutrient intakes in Inuit children attending childcare centres in Nunavik. AB - OBJECTIVES: To describe traditional food (TF) consumption and to evaluate its impact on nutrient intakes of preschool Inuit children from Nunavik. DESIGN: A cross-sectional study. METHODS: Dietary intakes of children were assessed with a single 24-hour recall (n=217). TF consumption at home and at the childcare centres was compared. Differences in children's nutrient intakes when consuming or not consuming at least 1 TF item were examined using ANCOVA. RESULTS: A total of 245 children attending childcare centres in 10 communities of Nunavik were recruited between 2006 and 2010. The children's mean age was 25.0+/-9.6 months (11-54 months). Thirty-six percent of children had consumed at least 1 TF item on the day of the recall. TF contributed to 2.6% of total energy intake. Caribou and Arctic char were the most reported TF species. Land animals and fish/shellfish were the main contributors to energy intake from TF (38 and 33%, respectively). In spite of a low TF intake, children who consumed TF had significantly (p<0.05) higher intakes of protein, omega-3 fatty acids, iron, phosphorus, zinc, copper, selenium, niacin, pantothenic acid, riboflavin, and vitamin B12, and lower intakes of energy and carbohydrate compared with non-consumers. There was no significant difference in any of the socio-economic variables between children who consumed TF and those who did not. CONCLUSION: Although TF was not eaten much, it contributed significantly to the nutrient intakes of children. Consumption of TF should be encouraged as it provides many nutritional, economic, and sociocultural benefits. PMID- 22818719 TI - Translational research to reduce trans-fat intakes in Northern Quebec (Nunavik) Inuit communities: a success story? AB - Following our results, based on population studies conducted in Greenland and Northern Canada, that Nunavik Inuit were thrice as highly exposed to dietary trans-fat as were Greenlandic Inuit, and that the biological levels found in Nunavik were already associated with deleterious blood lipid profiles, we decided to engage in translational activities. Our goal was to support Inuit communities in the practical implementation of a reduction of the trans-fat content of food sold in Nunavik. We carried out a preliminary feasibility study in Kuujjuaq and participated in several meetings. This translational phase involved an Inuk leader, an Inuk student, a southern student, a southern nutritionist and a southern researcher in the framework of a public health project. In the present article, we recount the different phases of the process, from research implementation to results dissemination and institutional commitment to implement a primary prevention program of reduction in trans-fat exposure in Nunavik. This is the occasion to draw broader conclusions on the factors that could either act in favour of or, on the contrary, would likely compromise the implementation of primary prevention interventions dealing with food and nutrition in the Arctic. Finally, we share some reflections on future translational activities dealing with trans-fat as well as other junk food issues. The analytical framework we propose integrates a range of factors, from geo-climatic to socio-economic, ethno cultural, and even political, that we think should be examined while identifying and building preventive recommendations and strategies related to the Northern diet. PMID- 22818720 TI - Mandatory menu labeling, medical foods, enhancing adherence in type 2 diabetes, and other timely topics. PMID- 22818721 TI - The Olympic torch: symbolizing excellence. PMID- 22818722 TI - What is sedentarism? PMID- 22818723 TI - Describing career satisfaction of registered dietitians with management responsibilities. PMID- 22818724 TI - Biophysiologic outcomes of the Enhancing Adherence in Type 2 Diabetes (ENHANCE) trial. AB - BACKGROUND: Behavioral research to improve lifestyle in broadly defined populations of patients with type 2 diabetes is limited. OBJECTIVE: We evaluated a behavioral intervention featuring technology-based self-monitoring on biophysiologic outcomes of glycemic control and markers of cardiovascular risk. DESIGN: In this single-site, randomized clinical trial, participants were stratified by good and poor glycemic control (glycated hemoglobin <8% or >=8%) and absence or presence of kidney disease, (estimated glomerular filtration rate >=60 or <60 mL/min) and randomized within strata. Measurements were obtained at 0, 3, and 6 months. PARTICIPANTS/SETTING: Self-referred, community-dwelling adults with type 2 diabetes mellitus. INTERVENTION: The intervention group received Social Cognitive Theory-based counseling paired with technology-based self-monitoring, and results were compared with an attention control group. MAIN OUTCOME MEASURES: Glycated hemoglobin, fasting serum glucose, lipid levels, blood pressure, weight, body mass index, and waist circumference were evaluated. STATISTICAL ANALYSES PERFORMED: Mean differences within and between randomization groups were compared over time. Intervention effects over time were estimated using random intercept models. RESULTS: Two hundred ninety-six subjects were randomized, 256 (86.5%) completed 3-month and 246 (83.1%) completed 6-month assessments. Glycated hemoglobin was reduced in the intervention group by 0.5% at 3 months and 0.6% at 6 months (P<0.001 for each), and the control group by 0.3% (P<0.001) at 3 months and 0.2% (P<0.05) at 6 months; but between-group differences were not significant. In those with baseline glycated hemoglobin >=8% and estimated glomerular filtration rate >=60 mL/min, glycated hemoglobin was reduced in the intervention group by 1.5% at 3 months and 1.8% at 6 months (P<0.001 for each), and the control group by 0.9% (P<0.001) at 3 months and 0.8% (P<0.05) at 6 months; but between-group differences were not significant. In random intercept models, the estimated reduction in glycated hemoglobin of 0.29% was not significant. CONCLUSIONS: Two behavioral approaches to improving general lifestyle management in individuals with type 2 diabetes mellitus were effective in improving glycemic control, but no significant between-group differences were observed. PMID- 22818725 TI - Daily apple versus dried plum: impact on cardiovascular disease risk factors in postmenopausal women. AB - BACKGROUND: Evidence suggests that consumption of apple or its bioactive components modulate lipid metabolism and reduce the production of proinflammatory molecules. However, there is a paucity of such research in human beings. OBJECTIVE: Women experience a lower rate of cardiovascular disease before menopause compared with men. However, after the onset of menopause, the risk of cardiovascular disease increases drastically due to ovarian hormone deficiency. Hence, we conducted a 1-year clinical trial to evaluate the effect of dried apple vs dried plum consumption in reducing cardiovascular disease risk factors in postmenopausal women. DESIGN: One-hundred sixty qualified postmenopausal women were recruited from the greater Tallahassee, FL, area during 2007-2009 and were randomly assigned to one of two groups: dried apple (75 g/day) or dried plum (comparative control). Fasting blood samples were collected at baseline, 3, 6, and 12 months to measure various parameters. Physical activity recall and 7-day dietary recall were also obtained. RESULTS: Neither of the dried fruit regimens significantly affected the participants' reported total energy intake throughout the study period. On the contrary, women who consumed dried apple lost 1.5 kg body weight by the end of the study, albeit not significantly different from the dried plum group. In terms of cholesterol, serum total cholesterol levels were significantly lower in the dried apple group compared with the dried plum group only at 6 months. Although dried plum consumption did not significantly reduce serum total cholesterol and low-density lipoprotein cholesterol levels, it lowered their levels numerically by 3.5% and 8%, respectively, at 12 months compared with baseline. This may explain the lack of significance observed between the groups. However, within the group, women who consumed dried apple had significantly lower serum levels of total cholesterol and low-density lipoprotein cholesterol by 9% and 16%, respectively, at 3 months compared with baseline. These serum values were further decreased to 13% and 24%, respectively, after 6 months but stayed constant thereafter. The within-group analysis also reported that daily apple consumption profoundly improved atherogenic risk ratios, whereas there were no significant changes in lipid profile or atherogenic risk ratios as a result of dried plum consumption. Both dried fruits were able to lower serum levels of lipid hydroperoxide and C-reactive protein. However, serum C-reactive protein levels were significantly lower in the dried plum group compared with the dried apple group at 3 months. CONCLUSIONS: There were no significant differences between the dried apple and dried plum groups in altering serum levels of atherogenic cholesterols except total cholesterol at 6 months. However, when within treatment group comparisons are made, consumption of 75 g dried apple (about two medium-sized apples) can significantly lower atherogenic cholesterol levels as early as 3 months. Furthermore, consumption of dried apple and dried plum are beneficial to human health in terms of anti-inflammatory and antioxidative properties. PMID- 22818726 TI - The relative validity and reproducibility of an iron food frequency questionnaire for identifying iron-related dietary patterns in young women. AB - BACKGROUND: Using food frequency data to identify dietary patterns is a newly emerging approach to assessing the relationship between dietary intake and iron status. Food frequency questionnaires should be assessed for validity and reproducibility before use. OBJECTIVE: We aimed to investigate the relative validity and reproducibility of an iron food frequency questionnaire (FeFFQ) specifically designed to identify iron-related dietary patterns. DESIGN: Participants completed the FeFFQ at baseline (FeFFQ1) and 1 month later (FeFFQ2) to assess reproducibility. A 4-day weighed diet record (4DDR) was completed between these assessments to determine validity. Foods appearing in the 4DDR were classified into the same 144 food groupings as the FeFFQ. Factor analysis was used to determine dietary patterns from FeFFQ1, FeFFQ2, and the 4DDR. PARTICIPANTS/SETTING: A convenience sample of women (n=115) aged 18 to 44 years living in Auckland, New Zealand, during 2009. STATISTICAL ANALYSES PERFORMED: Agreement between diet pattern scores was compared using correlation coefficients, Bland-Altman analysis, cross-classification, and the weighted kappa statistic. RESULTS: A "healthy" and a "sandwich and drinks" dietary pattern were identified from all three dietary assessments. Correlation coefficients between FeFFQ1 and the 4DDR diet pattern scores (validity) were 0.34 for the healthy, and 0.62 for the sandwich and drinks pattern (both Ps<0.001). Correlation coefficients between the two FeFFQs (reproducibility) were 0.76 for both the healthy and sandwich and drinks pattern (P<0.001). The FeFFQ1 correctly classified >50% of participants into the correct tertile and <10% into the opposite tertile for both the healthy and sandwich and drinks diet pattern scores when compared with the 4DDR and FeFFQ2. CONCLUSIONS: The FeFFQ appears to be a reproducible and relatively valid method for identifying dietary patterns, and could be used to investigate the relationship between dietary patterns and iron status. PMID- 22818727 TI - Intra-family role expectations and reluctance to change identified as key barriers to expanding vegetable consumption patterns during interactive family based program for Appalachian low-income food preparers. AB - Few Americans eat sufficient vegetables, especially the protective deep orange and dark green vegetables. To address this, a community-based wellness program to broaden vegetables served at evening meals targeting Appalachian food preparers and their families was tested in a randomized, controlled intervention. Food preparers (n=50) were predominately married (88%), white (98%), and female (94%), with several children living at home. Experimental food preparers (n=25) attended the program sessions and controls (n=25) were mailed relevant handouts and recipes. At program sessions, participants received nutrition information, hands on cooking instruction, and prepared recipes to take home for family evaluation. As qualitative assessment, 10 couples from each treatment group (n=20 couples) were randomly selected for baseline and immediate post-intervention interviews to explore impact on the food preparer's family. These in-depth interviews with the food preparer and their adult partner were tape-recorded and transcribed verbatim. Two researchers conducted thematic analysis using constant comparison. Family flexibility about food choices was assessed using roles, rules, and power concepts from Family Systems Theory. Interviews at baseline revealed dinner vegetable variety was very limited because food preparers served only what everyone liked (a role expectation) and deferred to male partner and children's narrow vegetable preferences (power). Control couples reported no change in vegetable dinner variety post-intervention. Most experimental couples reported in home tasting and evaluation was worthwhile and somewhat broadened vegetables served at dinners. But the role expectation of serving only what everyone liked and the practice of honoring powerful family members' vegetable preferences remained major barriers to change. PMID- 22818729 TI - Vegetable variety: an effective strategy to increase vegetable intake in adults. AB - Effective strategies are needed to increase vegetable intake in accordance with health recommendations. Previous research has shown that increasing the variety of foods leads to increased consumption, yet this strategy has not been investigated for promoting vegetable intake. This crossover study, conducted in 2008 and 2009, tested whether filling half the plate with a variety of vegetables influences vegetable consumption and meal energy intake. Once a week for 4 weeks, a meal of pasta and cooked vegetables was consumed ad libitum by 66 adults (34 women, 32 men). The meals were varied in the type of vegetables offered: at three meals 600 g of a single vegetable was served (broccoli, carrots, or snap peas) and at one meal 200 g of each of the three vegetables was served side by side. Data were analyzed using a mixed linear model with repeated measures. In this study, serving a variety of vegetables increased vegetable intake at the meal (P<0.0001). Subjects ate more vegetables when served the variety than when served any single type; the mean increase was 48+/-6 g, or more than one-half serving. This increase remained significant when intake of the variety of vegetables was compared with the preferred vegetable of each participant (mean 25+/-8 g; P=0.002). Vegetable intake was not significantly related to energy intake at the meal. The results of this study demonstrate that increasing the variety of low energy-dense vegetables served at a meal can be used as a strategy to increase vegetable intake. PMID- 22818728 TI - Food products made with glycomacropeptide, a low-phenylalanine whey protein, provide a new alternative to amino Acid-based medical foods for nutrition management of phenylketonuria. AB - Phenylketonuria (PKU), an inborn error in phenylalanine metabolism, requires lifelong nutrition management with a low-phenylalanine diet, which includes a phenylalanine-free amino acid-based medical formula to provide the majority of an individual's protein needs. Compliance with this diet is often difficult for older children, adolescents, and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet because it is naturally low in phenylalanine. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein use and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phenylalanine dietary protein for people with PKU. PMID- 22818730 TI - Differences by race/ethnicity in older adults' beliefs about the relative importance of dietary supplements vs prescription medications: results from the SURE Study. AB - Dietary supplement use is widespread among adults across races/ethnicities, yet reasons for use can vary across these groups. The Supplement Reporting (SURE) study quantified dietary supplement use and reasons for taking supplements in a multiethnic sample of adults who took at least one supplement. This study explored sociodemographic differences, including by race/ethnicity, associated with specific reasons/motivations for taking dietary supplements, including perceived importance of taking supplements relative to prescription medications. The study time period was March 2005 to August 2006. Participants (n=397) were older adults (ages 52 to 88 years) recruited from the Multiethnic Cohort Study in Hawaii and Los Angeles, CA, with equal representation of males and females from six ethnic groups (ie, white, Japanese American, Native Hawaiian, African American, US-born Latino, and foreign-born Latino). Subgroups of participants were compared by chi(2) tests and logistic regression. The most common reasons for taking supplements were to maintain a healthy life, because they were recommended by a health professional, and to prevent a disease/medical problem. A majority (76%) of participants reported that their dietary supplements were as important as prescription medications, with foreign-born Latinos and Japanese Americans being most likely to state this belief. The relative importance of supplements was not associated with excessive use, but 27% of participants exceeded the upper limit for a nutrient. It is crucial for health professionals to better understand why individuals take supplements and the importance that they attach to their use. This information could lead to better monitoring and education efforts to prevent overuse of supplements and possible interactions with medications. PMID- 22818731 TI - Assessment of food, nutrition, and physical activity practices in Oklahoma child care centers. AB - The purpose of the current study was to determine the obesogenic practices in all day child-care centers caring for preschool-aged children. This study used a cross-sectional, self-reported survey mailed to centers across Oklahoma (n=314). Frequency of responses and chi(2) were calculated comparing region and star rating. Items where the majority of centers frequently report best practices include: daily fruits served (76%), daily nonfried vegetables served (71%), rarely/never served sugary drinks (92%), rarely/never used food to encourage good behaviors (88%), staff join children at table most of the time (81%), staff rarely eat different foods in view of children (69%), visible self-serve or request availability of water (93%), regular informal communication about healthy eating (86%), opportunities for outdoor play (95%), not withholding activity for punishment (91%), accessible play equipment (59% to 80% for different types of equipment), and minimization of extended sitting time (78%). Practices where centers can improve include increasing variety of vegetables (18%), reducing frequency of high-fat meats served (74% serve more than once per week), increasing high-fiber and whole-grain foods (35% offer daily), serving style of "seconds" (28% help kids determine whether they are still hungry), nonfood holiday celebrations (44% use nonfood treats), having toys and books that encourage healthy eating (27%) and physical activity (25%) in all rooms in the center, a standard nutrition (21%) and physical education (50%) curriculum, and following a written physical activity policy (43%). Practitioners can use these data to develop benchmarks and interventions, as this was the first study to assess statewide obesogenic practices in child care. PMID- 22818732 TI - The inter-relationships between vegetarianism and eating disorders among females. AB - When individuals with a suspected or diagnosed eating disorder adopt a vegetarian diet, health care professionals might worry that this choice could function as a socially acceptable way to legitimize food avoidance. Yet only limited research has examined vegetarianism in relation to eating disorders. Our study objectives were to compare individuals with and without an eating disorder history and individuals at different stages of eating disorder recovery on past and current vegetarianism and motivations for and age at becoming vegetarian. Participants were females seen at some point for an eating disorder (n=93) and controls who never had an eating disorder (n=67). Recruitment and data collection for this cross-sectional study occurred in 2007-2008. chi(2) analyses and analyses of variance and covariance were used to examine the research questions. Compared with controls, individuals with an eating disorder history were considerably more likely to ever have been vegetarian (52% vs 12%; P<0.001), to be currently vegetarian (24% vs 6%; P<0.01), and to be primarily motivated by weight-related reasons (42% vs 0%; P<0.05). The three recovery status groups (fully recovered, partially recovered, and active eating disorder) did not differ significantly in percentiles endorsing a history of vegetarianism or weight-related reasons as primary, but they differed significantly in current vegetarianism (33% of active cases, 13% of partially recovered, 5% of fully recovered; P<0.05). Most perceived that their vegetarianism was related to their eating disorder (68%) and emerged after its onset. Results shed light on the vegetarianism-eating disorders relation and suggest intervention considerations for clinicians (eg, investigating motives for vegetarianism). PMID- 22818733 TI - Ethical issues for students. PMID- 22818734 TI - Position of the Academy of Nutrition and Dietetics: food and nutrition for older adults: promoting health and wellness. AB - It is the position of the Academy of Nutrition and Dietetics that all Americans aged 60 years and older receive appropriate nutrition care; have access to coordinated, comprehensive food and nutrition services; and receive the benefits of ongoing research to identify the most effective food and nutrition programs, interventions, and therapies. Health, physiologic, and functional changes associated with the aging process can influence nutrition needs and nutrient intake. The practice of nutrition for older adults is no longer limited to those who are frail, malnourished, and ill. The population of adults older than age 60 years includes many individuals who are living healthy, vital lives with a variety of nutrition-related circumstances and environments. Access and availability of wholesome, nutritious food is essential to ensure successful aging and well-being for the rapidly growing, heterogeneous, multiracial, and ethnic population of older adults. To ensure successful aging and minimize the effects of disease and disability, a wide range of flexible dietary recommendations, culturally sensitive food and nutrition services, physical activities, and supportive care tailored to older adults are necessary. National, state, and local strategies that promote access to coordinated food and nutrition services are essential to maintain independence, functional ability, disease management, and quality of life. Those working with older adults must be proactive in demonstrating the value of comprehensive food and nutrition services. To meet the needs of all older adults, registered dietitians and dietetic technicians, registered, must widen their scope of practice to include prevention, treatment, and maintenance of health and quality of life into old age. PMID- 22818735 TI - Are diets from paleolithic times relevant today? PMID- 22818736 TI - Theoretical comparison of the performance of gradient elution chromatography at constant pressure and constant flow rate. AB - The theory of gradient elution usually assumes a constant flow rate. This works extends it to gradients performed under constant pressure drop and variable flow rates. The peak capacity is derived under both constant flow rate and constant pressure gradient chromatography by integrating the rate of increase of the peak capacity from the hold-up time to the end of the gradient time. Assuming that the eluent mixture is incompressible, the chromatographic system isothermal, the pressure has no effect on the retention pattern, and neglecting the contributions of the instrument to the total pressure drop and the total peak width, it is found that both modes of gradient elution chromatography are strictly equivalent, provided that the elution time of the last eluted compound and the volume gradient are kept the same in both cases. PMID- 22818737 TI - Separations of petroleum products involving supercritical fluid chromatography. AB - This paper gives a survey of the most attractive trends and applications of supercritical fluid chromatography in the petroleum industry: simulated distillation, group-type analysis and related applications including the implementation of multidetection in a so-called "hypernated" system, as well as the hyphenation to GC*GC for improved group-type separation, SFC*GC and first promising SFC*SFC results. Some specific technical information related to the use of capillary columns or conventional packed columns in combination with FID (or detectors that require decompression and in some instances splitting of the mobile phase prior detection) is also provided. PMID- 22818738 TI - Analyzing freely dissolved concentrations of cationic surfactant utilizing ion exchange capability of polyacrylate coated solid-phase microextraction fibers. AB - A 7-MUm polyacrylate (PA) coated fiber was successfully employed to determine freely dissolved concentrations of cationic surfactants by solid-phase microextraction (SPME) and utilizing the capability of the PA-coating to sorb organic cations via ion-exchange at carboxylic groups. Measured fiber-water partitioning coefficients (K(fw)) were constant below a fiber loading of 2mmol per liter polyacrylate, allowing for simple and accurate analysis in a concentration range that is relevant from a risk assessment point of view. Ion exchange was confirmed to be the main sorption mechanism because of a decreasing K(fw) with either higher CaCl(2) concentrations or lower pH, and maximum fiber uptake at the polyacrylate cation-exchange capacity (CEC, at 30mmol/L PA). Fiber water sorption isotherms were established in various aqueous media in toxicological relevant concentrations. The developed SPME method has a high potential for application in ecotoxicological studies, as demonstrated in sorption studies with humic acid in different electrolyte solutions at aqueous concentrations down to the sub nM range. Cationic surfactant sorption affinities for humic acid also depend on medium composition but are orders of magnitude higher than to the PA fiber on a sorbent weight basis. PMID- 22818739 TI - Central nervous system lesions in Malawian children: identifying the treatable. AB - In Malawi, children with central nervous system (CNS) tumours are seldom able to be treated with curative intent. A study was undertaken of 29 children who underwent CNS MRI during a two year period. A combination of neoplastic and non neoplastic diagnoses were noted, seven of which were revised on review. As a result an effective system has been set up for remote urgent review to guide prognosis and treatment. The opinion of a paediatric neuro-radiologist greatly assists in differentiating infectious and non infectious causes of CNS lesions and can enable the local team to effectively triage patients. PMID- 22818740 TI - Acute-phase proteins in pregnant Sudanese women with severe Plasmodium falciparum malaria. AB - A case-control study was carried out in Kassala and Medani Maternity Hospitals in Sudan to investigate acute-phase proteins [haptoglobin, C-reactive protein (CRP), ferritin and albumin] in three groups of pregnant women (32 in each arm) comprising those with severe Plasmodium falciparum malaria or uncomplicated P. falciparum malaria and healthy controls. Whilst there was no significant difference in the levels of albumin and haptoglobin, ferritin and CRP levels were significantly higher in pregnant women with severe P. falciparum malaria. There were significant positive correlations between parasite count and haptoglobin, and medium positive correlations between parasite count and CRP. PMID- 22818741 TI - Evaluation of PCR for cutaneous leishmaniasis diagnosis and species identification using filter paper samples in Panama, Central America. AB - Cutaneous leishmaniasis (CL) is a major vectorborne disease in Panama. In this study, the diagnostic performance and usefulness of two DNA extraction procedures from skin scraping samples collected on FTA filter paper for subsequent PCR diagnosis of CL was evaluated. A positive CL laboratory diagnosis was based on a positive parasitological test (Giemsa-stained smears or in vitro culture) and/or positive PCR test performed from skin scrapings collected in TE buffer (PCR-TE). Of 100 patients with skin lesions suggestive of CL, 82 (82%) were confirmed as CL positive. The sensitivity was calculated for each of the PCR approaches from samples collected on filter paper. The highest sensitivity was achieved by PCR FTA processed by Chelex 100 (PCR-Chelex) (0.94). PCR-FTA extracted using the FTA purification reagent presented a lower sensitivity (0.60). Good concordance between routine PCR-TE and PCR-Chelex was observed (percent agreement=0.88, kappa index=0.65). In conclusion, use of FTA filter paper for skin scraping collection combined with PCR is a reliable and convenient method for CL diagnosis in Panama, with comparable performance to the routine PCR method and with improved sensitivity compared with those of conventional parasitological methods. PMID- 22818742 TI - Blood group phenotypes A and B are risk factors for cerebral malaria in Odisha, India. AB - There is increasing evidence that the ABO blood group phenotypes modulates Plasmodium falciparum rosetting and may influence the clinical manifestation of severe malaria. Whether blood group phenotypes are associated with risk of severe falciparum malaria in Odisha, we analyzed 343 adult malaria patients. The results showed high prevalence of blood group B in both mild (n=110) and severe malaria (cerebral malaria [CM]; n=130 and non-cerebral severe malaria [NCSM]; n=103) categories among the non-O group and while type O is significantly associated with protection against CM, patients with type A and B group had increased risk for developing CM. Further, the strength of association for B group (p=< 0.0001) was high and has double the risk of (OR=5.0) of developing CM compared to blood group A (OR=2.5). Such findings may probably be due to strain specific blood group preferences of P. falciparum and high prevalence of B group. However, the ABO blood group distribution of mild malaria was comparable with that of the NCSM group of patients. The lack of association of ABO phenotypes with NCSM is evidence for the hypothesis that the underlying pathogenesis cascades are different in CM and NCSM clinical presentations. PMID- 22818743 TI - Geographic, symptomatic and laboratory predictors of parasitic and bacterial causes of diarrhoea in travellers. AB - An observational study of patients presenting with diarrhoea to a walk-in service for returning travellers was conducted with the aim of identifying features that would help predict whether pathogens were bacterial or parasitic. In total, 509 cases were included, of which a bacterial aetiology was found in 55/440 (12.5%) and a parasitic cause in 51/428 (11.9%). Patients with symptoms of <=14 days were significantly more likely to have a bacterial diagnosis than those with longer symptoms (p<0.001), whereas parasitic causes of diarrhoea were not associated with length of symptoms and became proportionately more likely with time. Raised CRP, faecal white cells and fever were all predictive of positive bacterial culture (p<0.001, p=0.001 and p=0.001, respectively) but did not predict parasitic infection. Travellers to South and Southeast Asia were more likely to have parasites detected in their stool than travellers to other tropical areas (OR=1.96; p=0.041). Gender, ethnicity, reason for travel and length of stay abroad were not significantly associated with the faecal pathogen identified. These findings should help guide appropriate antimicrobials when empirical therapy is indicated. PMID- 22818744 TI - Comparison of placental blood microscopy and the ICT HRP2 rapid diagnostic test to detect placental malaria. AB - Monitoring interventions to prevent malaria in pregnancy requires sensitive detection of placental infection. Rapid diagnostic tests (RDTs) are good candidates, but little information is available on their sensitivity on placental blood. We have evaluated the agreement (kappa coefficient) between microscopy and a Plasmodium falciparum histidine-rich protein 2 (HRP2)-based immuno chromatographic test (ICT) on placental blood from 1151 women at delivery. Prevalences of placental infection by microscopy and RDT were 5.1% and 5.0%, respectively, showing 82.9% agreement (p<0.0001). Discordances were found at low parasitemias (<500 parasites/MUL) or negative microscopy. The results suggest that the HRP2-RDTs from ICT diagnostics is a good alternative to microscopy for diagnosing placental malaria at delivery. PMID- 22818745 TI - The expression and potential functions of placental myostatin. AB - Myostatin (growth differentiation factor-8; GDF-8) is a potent negative regulator of muscle development affecting both proliferation and differentiation. Myostatin has been reported to enhance the release of cytokines, including TNF-alpha (a pro inflammatory cytokine involved in implantation). In the human placenta, myostatin production is negatively correlated with gestational age and has been implicated in the control of glucose uptake. Preliminary data indicate its expression is primarily localized to cytotrophoblast and syncytiotrophoblast. The role of myostatin in the placenta, however, remains to be fully elucidated. We speculate that myostatin is key regulator that contributes to placentation and the regulation of placental function throughout pregnancy. PMID- 22818754 TI - Flow cytometric readout based on Mitotracker Red CMXRos staining of live asexual blood stage malarial parasites reliably assesses antibody dependent cellular inhibition. AB - BACKGROUND: Functional in vitro assays could provide insights into the efficacy of malaria vaccine candidates. For estimating the anti-parasite effect induced by a vaccine candidate, an accurate determination of live parasite count is an essential component of most in vitro bioassays. Although traditionally parasites are counted microscopically, a faster, more accurate and less subjective method for counting parasites is desirable. In this study mitochondrial dye (Mitotracker Red CMXRos) was used for obtaining reliable live parasite counts through flow cytometry. METHODS: Both asynchronous and tightly synchronized asexual blood stage cultures of Plasmodium falciparum were stained with CMXRos and subjected to detection by flow cytometry and fluorescence microscopy. The parasite counts obtained by flow cytometry were compared to standard microscopic counts obtained through examination of Giemsa-stained thin smears. A comparison of the ability of CMXRos to stain live and compromised parasites (induced by either medium starvation or by anti-malarial drug treatment) was carried out. Finally, parasite counts obtained by CMXRos staining through flow cytometry were used to determine specific growth inhibition index (SGI) in an antibody-dependent cellular inhibition (ADCI) assay. RESULTS: Mitotracker Red CMXRos can reliably detect live intra-erythrocytic stages of P. falciparum. Comparison between staining of live with compromised parasites shows that CMXRos predominantly stains live parasites with functional mitochondria. Parasite counts obtained by CMXRos staining and flow cytometry were highly reproducible and can reliably determine the ability of IgG from hyper-immune individuals to inhibit parasite growth in presence of monocytes in ADCI assay. Further, a dose-dependent parasite growth inhibitory effect could be detected for both total IgG purified from hyper-immune sera and affinity purified IgGs against the N-terminal non-repeat region of GLURP in ADCI assays coupled with determination of parasite counts through CMXRos staining and flow cytometry. CONCLUSIONS: A flow cytometry method based on CMXRos staining for detection of live parasite populations has been optimized. This is a rapid and sensitive method with high inter-assay reproducibility which can reliably determine the anti-parasite effect mediated by antibodies in functional in vitro assays such as ADCI assay. PMID- 22818755 TI - Exposure to residential radon and lung cancer in never-smokers: the preliminary results of the LCRINS study. AB - INTRODUCTION AND OBJECTIVE: Residential radon is the second most important risk factor for lung cancer and the first among never-smokers. The objective of this study is to report the concentrations of residential radon in a series of never smoker cases recruited in a multicenter study of cases and controls in northwestern Spain. In this study, all the hospitals in the Spanish province of Galicia and one from Asturias participated. PATIENTS AND METHODS: The present article includes a series of cases with residential radon measurements. All the subjects were personally interviewed, 3 ml of blood were taken from each, and they were each given instructions about how to place a residential radon detector in their homes. RESULTS: Sixty-nine case subjects were recruited, 84% of whom were women with a mean age of 71, and 81% of whom had adenocarcinoma. The average concentration of residential radon in the cases was 237 Bq/m(3), while the average concentration in the Galician population is 79 Bq/m(3). No relationship was observed between the concentration of residential radon and either sex or age at the time of diagnosis of the cases, but there was a tendency towards having a greater concentration in those diagnosed with small-cell and large-cell carcinoma. CONCLUSIONS: The concentrations of residential radon in the cases included are very high at about three times the average concentration of residential radon to which the general population of Galicia is exposed. PMID- 22818756 TI - Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. AB - BACKGROUND: Effective nonsurgical modalities are limited in the treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). OBJECTIVE: We sought to evaluate the efficacy and viability of superficial x-ray therapy in the treatment of BCC and SCC in an outpatient setting. METHODS: A retrospective analysis was performed on 1715 histologically confirmed primary cutaneous BCC and SCC treated with superficial x-ray therapy at Dermatology Associates of Tallahassee in Florida between 2000 and 2010. RESULTS: Of the 1715 tumors reviewed during this period, 712 were histologically proven BCC (631 nodular and 81 superficial), 994 were SCC (861 SCC in situ and 133 invasive SCC), and 9 displayed distinct features of both BCC and SCC in the same biopsy specimen. Kaplan-Meier estimates (with 95% confidence intervals) of cumulative recurrence rates of all tumors at 2 and 5 years were 1.9% (1%-2.7%) and 5.0% (3.2%-6.7%), respectively; of BCC at 2 and 5 years were 2% (0.8%-3.3%) and 4.2% (1.9%-6.4%), respectively; and of all SCC at 2 and 5 years were 1.8% (0.8%-2.8%) and 5.8% (2.9%-8.7%), respectively. Tumors on male patients and those with a diameter greater than 2 cm were associated with a statistically significant increase in recurrence likelihood. LIMITATIONS: This study represents only patients treated in 1 dermatology office in North Florida and may not be representative of the general patient population. CONCLUSIONS: Superficial x-ray therapy remains a viable nonsurgical option for the treatment of primary BCC and SCC in patients where surgical intervention is declined, unadvisable, or potentially associated with significant cosmetic or functional limitations. PMID- 22818757 TI - Evaluation of the Standard Diagnostics Leptospira IgM ELISA for diagnosis of acute leptospirosis in Lao PDR. AB - The diagnostic utility of the Standard Diagnostics Leptospira IgM ELISA for detection of acute leptospirosis was assessed in febrile adults admitted in Vientiane, Laos. Using the cut-off suggested by the manufacturer [optical density (OD) >=0.75], the assay demonstrated limited diagnostic capacity with a sensitivity of 95% and a specificity of 41% compared with the Leptospira microscopic agglutination test, which is the serological gold standard. However, re-evaluation of the diagnostic cut-off to an OD of 1.7 demonstrated improved diagnostic accuracy overall (sensitivity 70%; specificity 78%). PMID- 22818758 TI - Cardiac involvement in leptospirosis. AB - Leptospirosis is a neglected global disease with significant morbidity and mortality. Cardiac complications such as chest pain, arrhythmias, pulmonary oedema and refractory shock have been reported in patients with severe disease. However, the frequency and extent of cardiac involvement in leptospirosis, are under-reported and poorly understood. Multiple factors may contribute to clinical manifestations that suggest cardiac involvement, causing diagnostic confusion. A variety of electrocardiographic changes occur in leptospirosis, with atrial fibrillation, atrioventricular conduction blocks and non-specific ventricular repolarization abnormalities being the most common. Electrolyte abnormalities are likely to contribute to electrocardiographic changes; direct effects on Na(+) K(+)-Cl(-) transporters in the renal tubules have been postulated. Echocardiographic evidence of myocardial dysfunction has not been adequately demonstrated. The diagnostic value of cardiac biomarkers is unknown. Histopathological changes in the myocardium have been clearly shown, with myocardial inflammation and vasculitis present in postmortem studies. Nonetheless, the pathophysiology of cardiac involvement in leptospirosis is poorly understood. Cardiac involvement, demonstrated electrocardiographically or clinically, tends to predict poor outcome. No specific therapies are available to prevent or treat cardiac involvement in leptospirosis; current management is based on correction of deranged homeostasis and supportive therapy. Evidence suggests that direct myocardial damage occurs in patients with severe leptospirosis, and further studies are recommended to elucidate its pathophysiology, clinical features and contribution to overall prognosis, and to identify appropriate diagnostic investigations and specific therapies. PMID- 22818764 TI - Disseminated Mycobacterium genavense infection after immunosuppressive therapy shows underlying new composite heterozygous mutations of beta1 subunit of IL-12 receptor gene. PMID- 22818765 TI - Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions. AB - BACKGROUND: One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear. OBJECTIVE: We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies. METHODS: Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T cell phenotype and function. RESULTS: Australian cord naive T cells (CD4(+)CD25( )CD127(+) cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro. CONCLUSIONS: This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life. PMID- 22818766 TI - When asides become central: small talk and big talk in interpreted health interactions. AB - OBJECTIVE: In health interactions which require an interpreter, there are occasions when there are uninterpreted asides between participants. These are often construed to be features which hinder the interpreting process. However they have potential to yield critical information in certain health care contexts. METHODS: This paper examines 17 instances of asides in interpreted interactions which took place in 3 intercultural health care contexts in South Africa. The asides were transcribed, translated and analysed based on conversation analysis principles. RESULTS: The topics of the asides as well as who initiates them appear highly dependent on contextual features. There is evidence for the emergence of 'small talk' which serves the purpose of framing comfort levels, aligning the interpreter and patient or offering guidance for example, and the emergence of 'big talk' or engagement on topics which for cultural and historical reasons and power imbalances between the health practitioner and patient may be too difficult to raise directly. Such information also yields critical diagnostic and therapeutic information. CONCLUSION: Our findings suggest evidence for the presence of multiple patterns and roles that the interpreter may assume in such interactions. PRACTICE IMPLICATIONS: Implications for team training and practice are provided. PMID- 22818768 TI - Towards multiscale plant models: integrating cellular networks. AB - One of the ambitions of 'crop systems biology' is to combine information from molecular biology with a broader view of plant development and growth. In the context of modeling, this calls for a multiscale perspective that focuses on the interplay between cellular and macroscopic studies. With this in mind, in this review we aim to draw attention to a panel of approaches that were developed in the context of systems biology and are used for analyzing and describing the behavior of cellular networks. Ultimately, insights obtained from these methods can be exploited to refine the description of plant processes, leading to integrated plant-cellular models. PMID- 22818767 TI - Providing support to patients in emotional encounters: a new perspective on missed empathic opportunities. AB - OBJECTIVE: Studies have repeatedly found that providers miss 70-90% of opportunities to express empathy. Our study sought to characterize provider responses to patients' emotions, with the overall goal of better understanding reasons for lack of empathic response. METHODS: We analyzed 47 visits between patients and their providers. We defined empathic opportunities as instances where patients expressed a strong negative emotion. We then developed thematic categories to describe provider response. RESULTS: We found a total of 29 empathic opportunities within 21 visits. Provider responses were categorized as ignore, dismiss, elicit information, problem-solve, or empathize. An empathic statement occurred at some point in the response sequence in 13/29 opportunities (45%). When problem-solving was the initial response, empathic statements rarely occurred in subsequent dialogue. Among the 16 instances with no empathic statements, providers engaged in problem-solving in 8 (50%). CONCLUSION: Similar to other studies, we found providers missed most opportunities to respond empathically to patient emotion. Yet contrary to common understanding, providers often addressed the problem underlying the emotion, especially when the problem involved logistical or biomedical issues, as opposed to grief. PRACTICE IMPLICATIONS: With enhanced awareness, providers may better recognize situations where they can offer empathy in addition to problem-solving. PMID- 22818769 TI - Fungal superhighways: do common mycorrhizal networks enhance below ground communication? AB - In many natural communities communication between plants and other organisms below ground drives community dynamics. This communication is primarily through the release and detection of infochemicals, which must traverse the soil matrix to be effective. In this opinion article, we propose the Network Enhanced Bioactive Zone (NEBaZ) model, which posits that common mycorrhizal networks (CMNs) increase the bioactive zones of infochemicals by serving as superhighways directly connecting plants below ground. Here we argue that infochemical transport via CMNs allows for systemic defense signaling across plant populations and directed allelochemical delivery to target plants. Plant-animal interactions may also be facilitated by CMNs, suggesting that these fungal networks may be crucial components of many natural ecosystems. PMID- 22818770 TI - Simplified dosing regimens of teicoplanin for patient groups stratified by renal function and weight using Monte Carlo simulation. AB - The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30 MUg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400 mg twice on Day 1, followed by 400 mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72 h after the initial loading dose (C(min)(72 h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72 h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72 h) was <10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72 h) and C(ss)(min) of 15 MUg/mL and 20-25 MUg/mL, respectively. The percentage of C(min)(72 h) and C(ss)(min) in the range 15-30 MUg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30 MUg/mL. PMID- 22818771 TI - Hydrodynamic radius determination with asymmetrical flow field-flow fractionation using decaying cross-flows. Part II. Experimental evaluation. AB - In this study we investigate the effect of programmed cross-flows on the error in the hydrodynamic radii (r(h)) determination with asymmetrical flow field-flow fractionation (AsFlFFF). Three different standard polystyrene particles (nominal radii of 30 and 40 and 50 nm) are fractionated with exponentially and linearly decaying cross-flows with different decay rates. Hydrodynamic radii are calculated according to retention theory including steric effects. Rapid decay is expected to give rise to systematic deviations in r(h) determination. The error in r(h) was found to be small when decay rates with half-lives longer than 6 min were used, whereas steeper decays could give rise to errors as high as 16% of the particle size. The error is often explained in terms of secondary relaxation. However, comparisons show that experimental errors are significantly larger than what would be expected due to secondary relaxation, suggesting that other factors also have to be considered in order to fully understand deviations for rapidly decaying cross-flow. PMID- 22818772 TI - Trace adsorption of positively charged proteins onto Sepharose FF and Sepharose FF-based anion exchangers. AB - Agarose-based matrices have been widely used in ion exchange chromatography (IEC). We have herein observed that positively charged proteins (lysozyme and cytochrome c) are adsorbed on the agarose-based anion-exchangers (Q and DEAE Sepharose FF gels) in a capacity of 10-40 MUg/mL. In contrast, negatively charged protein (bovine serum albumin) is not adsorbed to Sepharose FF and SP Sepharose FF gels. Elemental analysis of the gel indicated that the residual anionic sulfate groups in agarose would have worked as the cation exchange groups for the positively charged proteins. The trace adsorption behavior of lysozyme onto Sepharose FF and Sepharose FF-based anion exchangers was studied and the effects of NaCl concentration and cation group density on the adsorption were examined for better understanding of the trace adsorption in chromatographic processes. At NaCl concentrations less than 0.05 mol/L, which is the normal adsorption condition in IEC, the trace adsorption kept at a high level, so this trace adsorption cannot be avoided in the ionic strength range of routine IEC operations. Grafting poly(ethylenimine) (PEI) chain of 60 kDa to a cation group density of 700 mmol/L could reduce the adsorption capacity to about 20 MUg/mL, but further reduction was not possible by increasing the cation group density to 1200 mmol/L. Therefore, attentions need to be paid to the phenomenon in protein purification practice using agarose-based matrices. The research is expected to call attentions to the trace adsorption on agarose-based matrices and to the importance in the selection of the suitable solid matrices in the production of high-purity protein products in large-scale bioprocesses. PMID- 22818773 TI - Analytical method for the identification and assay of 12 phthalates in cosmetic products: application of the ISO 12787 international standard "Cosmetics Analytical methods-Validation criteria for analytical results using chromatographic techniques". AB - Esters of phthalic acid, more commonly named phthalates, may be present in cosmetic products as ingredients or contaminants. Their presence as contaminant can be due to the manufacturing process, to raw materials used or to the migration of phthalates from packaging when plastic (polyvinyl chloride--PVC) is used. 8 phthalates (DBP, DEHP, BBP, DMEP, DnPP, DiPP, DPP, and DiBP), classified H360 or H361, are forbidden in cosmetics according to the European regulation on cosmetics 1223/2009. A GC/MS method was developed for the assay of 12 phthalates in cosmetics, including the 8 phthalates regulated. Analyses are carried out on a GC/MS system with electron impact ionization mode (EI). The separation of phthalates is obtained on a cross-linked 5%-phenyl/95%-dimethylpolysiloxane capillary column 30 m * 0.25 mm (i.d.) * 0.25 mm film thickness using a temperature gradient. Phthalate quantification is performed by external calibration using an internal standard. Validation elements obtained on standard solutions, highlight a satisfactory system conformity (resolution>1.5), a common quantification limit at 0.25 ng injected, an acceptable linearity between 0.5 MUg mL-1 and 5.0 MUg mL-1 as well as a precision and an accuracy in agreement with in house specifications. Cosmetic samples ready for analytical injection are analyzed after a dilution in ethanol whereas more complex cosmetic matrices, like milks and creams, are assayed after a liquid/liquid extraction using ter-butyl methyl ether (TBME). Depending on the type of cosmetics analyzed, the common limits of quantification for the 12 phthalates were set at 0.5 or 2.5 MUg g-1. All samples were assayed using the analytical approach described in the ISO 12787 international standard "Cosmetics-Analytical methods-Validation criteria for analytical results using chromatographic techniques". This analytical protocol is particularly adapted when it is not possible to make reconstituted sample matrices. PMID- 22818774 TI - Dispersive liquid-liquid microextraction coupled with programmed temperature vaporization-large volume injection-gas chromatography-tandem mass spectrometry for multiclass pesticides in water. AB - A simple solvent-less procedure for the determination of seventeen pesticides and related compounds in environmental water and wastewater using dispersive liquid liquid microextraction (DLLME) coupled with gas chromatography-mass spectrometry in tandem (GC-MS/MS) with large-volume injection, having a programmed temperature vaporizer (PTV-LVI), is described. The parameters affecting the extraction efficiency of the target analytes from water samples were systematically investigated. A response surface Doehlert design was used. The best extraction conditions involved a rapid injection of a mixture of 1.9 mL of acetonitrile (as a dispersant) and 178 MUL of trichloroethane (as an extractant) into 10 mL of water placed in a conical bottom glass tube. After manually shaken for 3.0 min and centrifugation at 3600 rpm (5 min), 50 MUL of the sedimented phase was directly injected into the PTV-LVI-GC-MS/MS system. The limits of quantitation (LOQs) ranged from 0.5 to 18 ng L-1 for all pesticides, except empentrin (132 ng L-1). The relative standard deviations (RSDs) for the analytes ranged between 0.8 and 14.6% for both intraday and interday precision. Accuracy, expressed as the mean extraction recovery, was between 70 and 130%. Using the internal standard method and surrogate deuterated standards, the total concentration of pesticides was in the range from 2.7 to 440 ng L-1 in seawater, river water and sewage water. PMID- 22818775 TI - A one-step method for priority compounds of concern in tar from former industrial sites: trimethylsilyl derivatisation with comprehensive two-dimensional gas chromatography. AB - A dense non-aqueous phase liquid sample formed by release of coal tar into the environment was derivatised by trimethylsilylation using the reagent N,O bis(trimethylsilyl)trifluoroacetamide (BSTFA) and extracted in hexane using accelerated solvent extraction. This procedure enables comprehensive extraction of an extensive suite of organic compounds from tar, which has not previously been described. Comprehensive two dimensional gas chromatography coupled to time of flight mass spectrometry (GC*GC-TOFMS) was used for the analysis of the sample for concurrent evaluation of -OH functional group-containing compounds along with aliphatics, polycyclic aromatic hydrocarbons and other typical tar compounds normally determined via classic gas chromatography. Using statistically designed experiments, a range of conditions were tested for complete recovery of four different surrogates. The robustness and repeatability of the optimised derivatisation/extraction method was demonstrated. Finally, more than a hundred and fifty derivatised compounds were identified using mass spectra elucidation and GC*GC logical order of elution. PMID- 22818776 TI - A nonlinear electrophoretic model for PeakMaster: part III. Electromigration dispersion in systems that contain a neutral complex-forming agent and a fully charged analyte. Theory. AB - We introduce a new nonlinear electrophoretic model for complex-forming systems with a fully charged analyte and a neutral ligand. The background electrolyte is supposed to be composed of two constituents, which do not interact with the ligand. In order to characterize the electromigration dispersion (EMD) of the analyte zone we define a new parameter, the nonlinear electromigration mobility slope, S(EMD,A). The parameter can be easily utilized for quantitative prediction of the EMD and for comparisons of the model with the simulated and experimental profiles. We implemented the model to the new version of PeakMaster 5.3 Complex that can calculate some characteristic parameters of the electrophoretic system and can plot the dependence of S(EMD,A) on the concentration of the ligand. Besides S(EMD,A), also the relative velocity slope, S(X), can be calculated. It is commonly used as a measure of EMD in electrophoretic systems. PeakMaster 5.3 Complex software can be advantageously used for optimization of the separation conditions to avoid high EMD in complexing systems. Based on the theoretical model we analyze the S(EMD,A) and reveal that this parameter is composed of six terms. We show that the major factor responsible for the electromigration dispersion in complex-forming electrophoretic systems is the complexation equilibrium and particularly its impact on the effective mobility of the analyte. To prove the appropriateness of the model we showed that there is a very good agreement between peak shapes calculated by PeakMaster 5.3 Complex (plotted using the HVLR function) and the profiles simulated by means of Simul 5 Complex. The detailed experimental verification of the new mode of PeakMaster 5.3 Complex is in the next part IV of the series. PMID- 22818777 TI - Successes and failures in modular genetic engineering. AB - Synthetic biology relies on engineering concepts such as abstraction, standardization, and decoupling to develop systems that address environmental, clinical, and industrial needs. Recent advances in applying modular design to system development have enabled creation of increasingly complex systems. However, several challenges to module and system development remain, including syntactic errors, semantic errors, parameter mismatches, contextual sensitivity, noise and evolution, and load and stress. To combat these challenges, researchers should develop a framework for describing and reasoning about biological information, design systems with modularity in mind, and investigate how to predictively describe the diverse sources and consequences of metabolic load and stress. PMID- 22818778 TI - An analysis of driving and working hour on commercial motor vehicle driver safety using naturalistic data collection. AB - Current hours-of-service (HOS) regulations prescribe limits to commercial motor vehicle (CMV) drivers' operating hours. By using naturalistic-data-collection, researchers were able to assess activities performed in the 14-h workday and the relationship between safety-critical events (SCEs) and driving hours, work hours, and breaks. The data used in the analyses were collected in the Naturalistic Truck Driving Study and included 97 drivers and about 735,000 miles of continuous driving data. An assessment of the drivers' workday determined that, on average, drivers spent 66% of their shift driving, 23% in non-driving work, and 11% resting. Analyses evaluating the relationship between driving hours (i.e., driving only) and SCE risk found a time-on-task effect across hours, with no significant difference in safety outcomes between 11th driving hour and driving hours 8, 9 or 10. Analyses on work hours (i.e., driving in addition to non driving work) found that risk of being involved in an SCE generally increased as work hours increased. This suggests that time-on-task effects may not be related to driving hours alone, but implies an interaction between driving hours and work hours: if a driver begins the day with several hours of non-driving work, followed by driving that goes deep into the 14-h workday, SCE risk was found to increase. Breaks from driving were found to be beneficial in reducing SCEs (during 1-h window after a break) and were effective in counteracting the negative effects of time-on-task. PMID- 22818779 TI - An examination of the environmental, driver and vehicle factors associated with the serious and fatal crashes of older rural drivers. AB - Motor vehicle crashes involving rural drivers aged 75 years and over are more than twice as likely to result in a serious or fatal injury as those involving their urban counterparts. The current study examined some of the reasons for this using a database of police-reported crashes (2004-2008) to identify the environmental (lighting, road and weather conditions, road layout, road surface, speed limit), driver (driver error, crash type), and vehicle (vehicle age) factors that are associated with the crashes of older rural drivers. It also determined whether these same factors are associated with an increased likelihood of serious or fatal injury in younger drivers for whom frailty does not contribute to the resulting injury severity. A number of environmental (i.e., undivided, unsealed, curved and inclined roads, and areas with a speed limit of 100km/h or greater) and driver (i.e., collision with a fixed object and rolling over) factors were more frequent in the crashes of older rural drivers and additionally associated with increased injury severity in younger drivers. Moreover, when these environmental factors were entered into a logistic regression model to predict whether older drivers who were involved in crashes did or did not sustain a serious or fatal injury, it was found that each factor independently increased the likelihood of a serious or fatal injury. Changes, such as the provision of divided and sealed roads, greater protection from fixed roadside objects, and reduced speed limits, appear to be indicated in order to improve the safety of the rural driving environment for drivers of all ages. Additionally, older rural drivers should be encouraged to reduce their exposure to these risky circumstances. PMID- 22818780 TI - Structural elements of primary CCR5-using HIV-1 gp120 proteins influencing sensitivity and resistance to the broadly neutralizing monoclonal antibody b12. AB - Structure-guided approaches to HIV-1 vaccine design depend on knowledge of the presentation of neutralizing epitopes on gp120, such as the epitope for the broadly neutralizing mAb b12. Here, we characterized predicted three-dimensional structures of functionally diverse gp120 proteins in their b12-bound conformation, to better understand the gp120 determinants that expose or occlude the b12 epitope. Mapping the gp120-b12 binding interface identified amino acid polymorphisms within the C2, C3, C4 and V5 regions of gp120 associated with augmented b12 binding, and importantly, identified residues in the b12-exclusive binding domain of gp120 that are important for b12 neutralization resistance. Structural studies suggest that these b12 resistance variants promote reduced conformational flexibility in the b12 recognition site, which we show involves structural alterations within the gp120 CD4 binding loop and the V4 loop. Together, our studies provide new mechanistic insights into the gp120 determinants influencing sensitivity and resistance to HIV-1 neutralization by b12. PMID- 22818782 TI - Effects of diet type on establishment of pregnancy and embryo development in beef heifers. AB - The objectives were to determine the effects of elevated blood urea concentrations on: (i) the response to superovulation, fertilisation rate, and early embryonic development in beef heifers, and (ii) embryo survival from days 7 to 35 of gestation. In Experiment 1, heifers (18-24 months) were allocated at random (n=20 per treatment) to one of the following diets: (i) ad libitum grass silage plus 5 kg commercial beef concentrates per day (controls); (ii) ad libitum grass silage plus 5 kg concentrates and 250 g feed grade urea per day (HE/HU); or (iii) ad libitum wheaten straw plus 250 g feed grade urea and 50 g vitamin/mineral mix per day (LE/HU). Serum urea concentrations were monitored throughout the experiment. Oestrus in heifers was synchronised using an intravaginal releasing device (CIDR((r)), InterAg, New Zealand). Oestrus was detected and in vitro produced blastocysts (day 7, morphological grades 1 and 2) were transferred to the heifers 7 days later (19 days after start of treatment diets). The heifers were maintained on the dietary treatments for a further 28 days, when pregnancy status was determined by transrectal ultrasonography. Detected pregnancies were terminated using 15 mg luprostiol and recycled for Experiment 2. In Experiment 2, following a 14-day dietary rest period, the heifers were re-allocated at random to the three dietary treatments above. Heifers were treated with a CIDR for 8 days and 15 mg luprostiol was given 12h before pessary withdrawal. They received 144 mg pFSH (Folltropin((r))-V, Vetrepharm, Canada) given as 8 injections over 4 days commencing on day 6 of CIDR/dietary treatment. Heifers were artificially inseminated 48 h after progesterone pessary withdrawal using commercial semen of proven fertility by a competent inseminator. The heifers were maintained on their diets until slaughter, 3 days post insemination when corpora lutea numbers were determined and embryos were recovered and cell numbers determined visually. Serum urea concentrations were greater in heifers on LE/HU than in those on HE/HU diets, which in turn were greater than controls (7.1 +/- 0.5, 4.9 +/- 0.3 and 3.2 +/- 0.1 mmol/L, respectively; P<0.05). There was no effect of diet type on pregnancy rate at day 35 (42%, 47% and 46%) and on the number of corpora lutea following superovulation (5.2 +/- 0.8, 5.8 +/- 1.5 and 6.8 +/- 1.1) for heifers on control, HE/HU and LE/HU diets, respectively. The total number of embryos recovered per heifer was not different between the three groups (2.7 +/- 0.6, 3.4 +/- 1.1 and 4.8 +/- 0.8 for heifers on control, HE/HU and LE/HU diets, respectively; P>0.05), but the number of embryos with 8 or more cells at recovery was greater in heifers on LE/HU than on control diets (3.4 +/- 0.8 compared with 1.0 +/- 0.3; P<0.05). However the percentage of embryos recovered with 8 or more cells was not different between groups (70.0 +/- 13.3, 86.9 +/- 7.2 and 76.5 +/- 7.9%, for heifers on control, HE/HU and LE/HU diets respectively). Fertilisation rate, expressed as the proportion of embryos with more than one cell at recovery relative to the total number of embryos recovered, was less in the heifers on the control diet than in the other two dietary treatments (61.3 +/- 11.8, 92.0 +/- 3.5 and 86.8 +/- 5.4% for heifers on control, HE/HU and LE/HU diets, respectively; P<0.05). Deleterious effects of urea on reproduction were not found, suggesting that adverse effects of urea are likely to take place at the early oocyte development stage prior to ovulation or fertilisation following an increase in protein intake. PMID- 22818781 TI - Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus. AB - BACKGROUND: To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS: This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS: Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS: Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations. PMID- 22818783 TI - [Zuckerkandl's tubercle. Location, shape and dimensions]. AB - INTRODUCTION AND OBJECTIVE: Although Zuckerkandl's tubercle is not known by many head and neck surgeons, it is a fundamental surgical anatomical detail, already described in the nineteenth century. Its detection is of great importance as the reference in the search for the recurrent nerve and superior parathyroid gland. MATERIAL AND METHOD: We designed a prospective study to analyse the posterolateral border of thyroid lobes, looking for this tubercle. We included 107 thyroidectomies performed by the same surgeon; 88 were total thyroidectomies (82.24%) and 19 hemithyroidectomies (17.75%), with dissection of a total of 195 thyroid lobes. Zuckerkandl's tubercle should be sought by displacing the posterolateral margin of the thyroid lobes. RESULTS: It was reliably detected in 155 thyroid lobes (79.48%). The mean tubercle dimensions were 11 mm transverse axis and 9 mm longitudinal axis. The shape of the Zuckerkandl's tubercle was sessile (70.96%) or pedunculated (29.03%). In the 5.80% of cases, the Zuckerkandl's tubercle distal end was bifid. We did not find a Zuckerkandl's tubercle individualised as an ectopic thyroid (0.00%). Zuckerkandl's tubercle was more frequent in the right thyroid lobe (P=.06). CONCLUSION: Zuckerkandl's tubercle is recognised by its location, shape and dimensions. PMID- 22818785 TI - Prognostic information of glycogen phosphorylase isoenzyme BB in patients with suspected acute coronary syndrome. AB - Early and adequate risk stratification is essential in patients with suspected acute coronary syndrome (ACS). The aim of the present study was to investigate whether glycogen phosphorylase BB (GPBB) could add prognostic information in the context of contemporary sensitive troponin I determination and B-type natriuretic peptide (BNP). Patients with suspected ACS were consecutively enrolled at 3 German study centers from January 2007 through December 2008. Troponin I, GPBB, and BNP were determined at admission. Follow-up information on the combined end point of death, myocardial infarction, revascularization, and hospitalization owing to a cardiovascular cause was obtained 6 months after enrollment. In total 1,818 patients (66% men) were enrolled of whom 413 (23%) were diagnosed as having acute myocardial infarction and 240 (13%) as having unstable angina pectoris, whereas in 1,165 patients (64%) an ACS could be excluded. Follow-up information was available in 98% of patients; 203 events were registered. GPBB measured on admission predicted an unfavorable outcome with a hazard ratio of 1.24 (p <0.05) in an unadjusted Cox regression model and showed a tendency with a hazard ratio of 1.13 (p = 0.07) in a fully adjusted model. Kaplan-Meier analysis revealed a poorer outcome in patients with increased GPBB levels amendatory to the information provided by troponin I or BNP. In conclusion, GPBB measurement provides predictive information on midterm prognosis in patients with chest pain in addition to BNP and troponin I. PMID- 22818784 TI - Functional and hemodynamic cardiac determinants of exercise capacity in patients with systolic heart failure. AB - Decreased exercise capacity is the main symptom in patients with heart failure (HF). We assessed the association among noninvasively determined maximal cardiac output at exercise, systolic and diastolic cardiac functions at rest, and peak oxygen uptake (pVo(2)) exercise capacity in patients with congestive HF. We studied 102 patients 62 +/- 11 years of age with New York Heart Association class II to IV stable HF and left ventricular (LV) ejection fraction <45%. All patients underwent echocardiography and a treadmill cardiopulmonary exercise test for evaluation of pVo(2) corrected for fat-free mass. During the cardiopulmonary exercise test, cardiac output was estimated noninvasively and continuously using Nexfin HD. Fat-free mass-corrected pVo(2) was associated in an univariate linear regression analysis with peak exercise cardiac index (CI) (beta 0.511, p <0.001), LV end-diastolic pressure estimates (peak early diastolic filling velocity/early diastolic tissue velocity [E/e'], beta -0.363, p = 0.001), and right ventricular function (tricuspid annular plane systolic excursion, beta 0.393, p <0.001). In multivariate analysis peak exercise CI (beta 0.380, p = 0.001), but not cardiac output or LV ejection fraction at rest, was an independent predictor of pVo(2). Other independent predictors of pVo(2) were E/e' (beta -0.276, p = 0.009) and tricuspid annular plane systolic excursion (beta 0.392, p <0.001), also when adjusted for age and gender. In conclusion, peak CI is an independent predictor of fat-free mass-corrected pVo(2) in patients with systolic HF. Of all echocardiographic parameters at rest, right ventricular function and E/e' were independently and significantly associated with pVo(2), whereas LV ejection fraction at rest was not. PMID- 22818786 TI - Cloning and characterization of histone deacetylase from Babesia bovis. AB - The effect of inhibitors of histone deacetylase (HDAC) on Apicomplexa has been previously reported with the discovery of apicidin, a cyclic tetrapeptide having broad-spectrum antiparasitic activity. In the current study, we expressed Babesia bovis (B. bovis) recombinant-HDAC 3 (rBbHDAC3) as a GST-fusion protein in Escherichia coli (E. coli) and found that it was antigenic. An antiserum against the recombinant protein was generated in mice. The mice serum demonstrated the presence of HDAC in B. bovis by a Western blot assay. The murine anti-rBbHDAC3 reacted with B. bovis, Babesia bigemina (B. bigemina), Theileria equi (T. equi), and Babeisa caballi (B. caballi) merozoites in the indirect fluorescent antibody test (IFAT). Furthermore, the HDAC-enzymatic activity of the rBbHDAC3 protein was evaluated by a colorimetric assay. The enzymatic activity of rBbHDAC3 was inhibited by 100 ng/ml of apicidin, and the inhibitory effect of apicidin was dose-dependent. The inhibition of BbHDAC3 by apicidin was confirmed by Western blot, IFAT, and reverse transcription-polymerase chain reaction (RT-PCR). Finally, apicidin potentially inhibited the in vitro growth of Babesia parasites. The lower IC(50) values of apicidin against apicomplexan parasites than those of mammalian cells point to HDAC as an excellent drug target. The findings of the present study indicate that BbHDAC3 is a potential target for apicidin and might be a promising target for the development of novel anti-babesial drugs. PMID- 22818787 TI - Experimental infection with Cryptosporidium parvum IIaA21G1R1 subtype in immunosuppressed mice. AB - Cryptosporidium parvum subtype IIaA21G1R1 oocysts were used to infect dexamethasone immunosuppressed N: NIH Swiss mice. This is the first Cryptosporidium mouse model in which the relationship between infection and apoptosis has been histologically studied at each portion of the gut in order to observe this dynamic in chronic cryptosporidiosis. Histology showed developmental stages in the duodenum, proximal and distal jejunum, ileum, cecum and colon, with the small intestine remaining infected until day 35 post infection. At proximal jejunum an inverse correlation between infection and apoptosis was observed at days 28 and 35 p.i. Data suggests that jejunum could be an interesting place to carry out further studies on the dynamics of Cryptosporidium infection and apoptosis. Based on these findings, this mouse model was useful to evaluate clinical, parasitological and histological aspects of C. parvum subtype IIaA21G1R1 infection, and it will be an appropriate tool to investigate different aspects of Cryptosporidium infection. PMID- 22818788 TI - Histogram analysis of apparent diffusion coefficient map of standard and high B value diffusion MR imaging in head and neck squamous cell carcinoma: a correlation study with histological grade. AB - RATIONALE AND OBJECTIVES: A histologic grade in head and neck squamous cell carcinoma (HNSCC) is clinically important because of its association with prognosis. The purpose of this study was to investigate the efficacy of histographic analysis of apparent diffusion coefficient (ADC) maps on the basis of the entire tumor volume in differentiating histologic grades in HNSCC at standard (b = 1000 s/mm(2)) and high (b = 2000 s/mm(2)) b values. MATERIALS AND METHODS: Fifty-four patients with HNSCC, including well-differentiated (WD; n = 35), moderately differentiated (MD; n = 13) and poorly differentiated (PD; n = 6) carcinomas, were retrospectively evaluated. ADC maps were obtained at two different b values (1000 and 2000 s/mm(2)) in each patient. Tumors were delineated on each slice of ADC maps, and data were collected to obtain a histogram for the entire tumor volume. Histographic parameters were calculated, including mean, standard deviation, kurtosis, skewness, and the ratio of the kurtosis measured at b values of 1000 and 2000 s/mm(2). These parameters were correlated with histologic grades. RESULTS: There was no significant correlation between tumor grades and histographic parameters obtained from ADC maps at b = 1000 s/mm(2). However, mean ADC at b = 2000 s/mm(2) was significantly higher in WD HNSCC (881 +/- 131 * 10(-6) mm(2)/s) than in MD and PD HNSCC (770 +/- 163 and 780 +/- 158 * 10(-6) mm(2)/s, respectively) (P < .05). Kurtosis ratio was significantly higher in PD HNSCC (115 +/- 10%) compared to WD and MD HNSCC (91 +/ 21% and 86 +/- 26%, respectively) (P < .05). Diagnostic accuracy was 100%, 76.9%, and 65.8% for PD, MD, and WD HNSCC, respectively. CONCLUSIONS: Histographic analysis of ADC maps on the basis of the entire tumor volume can be useful in differentiating histologic grades of HNSCC using mean ADC at b = 2000 s/mm(2) and kurtosis ratio. PMID- 22818789 TI - Dual-energy computed tomography (DECT) in renal masses: nonlinear versus linear blending. AB - RATIONAL AND OBJECTIVES: To investigate whether a nonlinear-blending algorithm improves tumor conspicuity and image quality in the evaluation of renal masses at dual-energy computed tomography (DECT) during nephrographic phase of enhancement. MATERIALS AND METHODS: The Institutional Review Board approved this retrospective study from archival material from patients consenting to the use of medical records for research purposes. A retrospective review of contrast-enhanced abdominal DECT scans in 45 patients (mean age, 59.5 years; range, 24-84 years) was performed. DECT data were reconstructed using nonlinear and linear blending. A region of interest was located within tumors and adjacent normal parenchyma; attenuation differences and contrast-to-noise ratios (CNRs) were calculated for renal masses on nonlinear- and linear-blended images. The two datasets were subjectively compared in terms of tumor detection and image quality. An exact Wilcoxon's matched pairs signed rank and marginal homogeneity tests were used to test whether differences in attenuation, CNR, and subjective assessment were greater using nonlinear blending. RESULTS: The mean difference in attenuation for renal masses and adjacent portion of renal parenchyma was 138.4 Hounsfield units +/- 28.9 SD using nonlinear blending, and 121.6 HU +/- 18.0 SD using linear blending (P < .001). Mean CNR was 12.6 +/- 2.5 SD using nonlinear blending, and 9.6 +/- 2.2 SD using 0.3 linear-blended (P < .001). No significant difference in tumor detection was observed between the two algorithms. Image quality was significantly better (P < .001) using nonlinear blending. CONCLUSION: Compared with standard linear blending, nonlinear-blending algorithm improves tumor conspicuity and image quality in renal masses at DECT evaluation during nephrographic phase of enhancement. PMID- 22818790 TI - Intraluminal air within an obstructed appendix: a CT sign of perforated or necrotic appendicitis. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the predictive value of intraluminal air for appendiceal necrosis and/or perforation when not apparent on imaging. Additional factors of intraluminal appendicoliths, age, and gender were also assessed. MATERIALS AND METHODS: Patients with pathologically proven appendicitis who underwent multidetector computed tomographic imaging over a 3-year period (n = 487) were retrospectively reviewed. Those with imaging evidence for perforation were excluded to create a study population of apparent uncomplicated acute appendicitis (n = 374). Each scan was assessed for intraluminal appendiceal air and appendicoliths on multidetector computed tomography and compared against surgical and pathologic results for appendiceal necrosis and/or perforation. RESULTS: Image-occult necrosis or perforation was present in 17.4% (65 or 374) of the study cohort. Intraluminal air and appendicoliths were predictive variables by univariate logistic regression (P = .001 and P <= .001, respectively), with odds ratios of 2.64 (95% confidence interval, 1.48-4.73) for intraluminal air and 2.67 (95% confidence interval, 1.55 4.61) for appendicoliths. Both remained independent variables on multivariate modeling despite multicollinearity. Increasing age was also predictive (odds ratio, 1.25; 95% confidence interval, 1.09-1.44; P = .002), whereas gender was not (P = .472). CONCLUSIONS: Intraluminal appendiceal air in the setting of acute appendicitis is a marker of perforated or necrotic appendicitis. Recognition of this finding in otherwise uncomplicated appendicitis at imaging should raise suspicion for image-occult perforation or necrosis. PMID- 22818791 TI - Pitfalls of 3D FLAIR brain imaging: a prospective comparison with 2D FLAIR. AB - RATIONALE AND OBJECTIVES: To prospectively compare the image contrast of various brain lesions on two-dimensional (2D) and three-dimensional (3D) fluid-attenuated inversion-recovery (FLAIR) images and to highlight the pitfalls of 3D FLAIR. MATERIALS AND METHODS: Institutional review board approval was obtained. We examined 94 brain lesions with 2D and 3D FLAIR at 3T. First, we optimized the repetition time and echo time of 3D FLAIR with a volunteer study. Then, we assessed the conspicuity and detection of the various lesions qualitatively, and the contrast ratio between the gray or white matter and lesions was calculated as a quantitative assessment. We also performed a phantom study to investigate the effects of different flow velocities on 2D and 3D FLAIR. RESULTS: With regard to the conspicuity and detection of most lesions (multiple sclerosis, ischemic lesions or infarction, brain tumors, or chronic trauma), 3D FLAIR was equal or superior to 2D FLAIR. For these lesions, the mean contrast ratios were higher on 3D FLAIR than on 2D FLAIR images. In terms of lesion conspicuity in the patients with hippocampal sclerosis and leptomeningeal metastasis, however, 3D FLAIR was equal or inferior to 2D FLAIR. The ivy sign in patients with moyamoya disease was frequently obscured on 3D FLAIR. The phantom study demonstrated that the signal intensity ratio on 3D FLAIR decreased more rapidly with increasing velocity than that on 2D FLAIR. CONCLUSION: Although 3D FLAIR may replace 2D FLAIR images for most patients, radiologists should keep in mind that 3D has some pitfalls. PMID- 22818792 TI - Power of crowdsourcing: novel methods of data collection in psoriasis and psoriatic arthritis. AB - BACKGROUND: Crowdsourcing is a novel method of collecting research data from diverse patient populations. The quality of research data obtained through crowdsourcing is unknown. OBJECTIVE: The primary aim of this pilot study was to examine how data collected from an online crowdsourcing World Wide Web site compare with those from published literature in psoriasis and psoriatic arthritis (PsA). METHODS: Crowdsourced data were collected from a health crowdsourcing site from August 23, 2008, to June 27, 2011. The crowdsourced data were compared with findings from systematic reviews, meta-analyses, and clinical trials. RESULTS: A total of 160 online patients with psoriasis or PsA were included in the analysis. Among them, 127 patients with psoriasis provided 313 complete responses on psoriasis symptoms and 276 complete responses to psoriasis treatments; 33 patients with PsA provided 91 complete responses on PsA symptoms and 79 responses to PsA treatments. We compared topical treatments, phototherapy, and systemic treatments for psoriasis and PsA from crowdsourced data with the published literature. For the treatment with the largest response rates, equivalency testing was performed comparing crowdsourced data and the published literature. Overall, crowdsourced data were not equivalent to those published in the medical literature. LIMITATIONS: Crowdsourcing sites used different outcomes measures from those reported in clinical trials. CONCLUSION: Differences existed in assessment of treatment effectiveness between crowdsourced data and those published in the literature. With improvements in the collection of crowdsourced data, crowdsourcing can be a valuable tool for collecting patient data in real world settings for psoriasis and PsA. PMID- 22818793 TI - A facile two-step etching method to fabricate porous hollow silica particles. AB - We report here the fabrication of hollow silica particles with mesopores larger than 10nm on their wall via a facile two-step etching method. Different from the conventional template method, the new method uses the silica particles as starting materials, which were synthesized using the well-known Stober method. In the hollow silica preparation, first, we gently etch the silica particles with a NaOH solution without using template molecules to make them porous. Then, we coat the porous silica particles with poly-dimethyldiallylammonium chloride (PDDA) and treat the PDDA-coated porous silica with an ammonia solution to form the hollow silica nanospheres. In this study, we found that the NaOH dosage and ammonia concentration have significant impact on the morphology of the final products. Adsorption was also studied and results show that the hollow nanospheres can effectively uptake protein-based biomolecules (hemoglobin). PMID- 22818794 TI - Solubilization of saikosaponin a by ginsenoside Ro biosurfactant in aqueous solution: mesoscopic simulation. AB - Ginsenoside Ro (Ro), a natural anionic biosurfactant derived from ginseng, has been found to markedly increase the solubility of saikosaponin a (SSa), which is the active ingredient of Radix Bupleuri. SSa is minimally soluble in water. To determine the mechanism by which Ro solubilizes SSa, the self-assembly behavior of Ro and the phase behavior of blended Ro and SSa systems were studied by mesoscopic dynamics (MesoDyn) and dissipative particle dynamics (DPD) simulations. The simulation results show that Ro can form vesicles via the closure of oblate membranes. At low concentrations, SSa molecules are solubilized in the palisade layer of the Ro vesicles. At high concentrations, they interact with Ro molecules to form mixed vesicles with Ro adsorbing on the surfaces of the vesicles. The evaluation of the SSa solubilization process reveals that, at low concentrations, Ro aggregates preferentially to form vesicles, which then absorb SSa into themselves. However, at high concentrations, SSa first self-aggregates and then dissolves. This is because the solubilization behavior of Ro shifts the precipitation-dissolution equilibrium in the direction of dissolution. These results of the simulations are consistent with those of transmission electron microscopy (TEM) and dynamic light scattering (DLS). PMID- 22818795 TI - Amorphous iron-(hydr) oxide networks at liquid/vapor interfaces: in situ X-ray scattering and spectroscopy studies. AB - Surface sensitive X-ray reflectivity (XR), fluorescence (XF), and grazing incidence X-ray diffraction (GIXD) experiments were conducted to determine the accumulation of ferric iron Fe (III) or ferrous iron Fe (II) under dihexadecyl phosphate (DHDP) or arachidic acid (AA) Langmuir monolayers at liquid/vapor interfaces. Analysis of the X-ray reflectivity and fluorescence data of monolayers on the aqueous subphases containing FeCl(3) indicates remarkably high levels of surface-bound Fe (III) in number of Fe(3+) ions per molecule (DHDP or AA) that exceed the amount necessary to neutralize a hypothetically completely deprotonated monolayer (DHDP or AA). These results suggest that nano-scale iron (hydr) oxide complexes (oxides, hydroxides or oxyhydroxides) bind to the headgroups and effectively overcompensate the maximum possible charges at the interface. The lack of evidence of in-plane ordering in GIXD measurements and strong effects on the surface-pressure versus molecular area isotherms indicate that an amorphous network of iron (hydr) oxide complexes contiguous to the headgroups is formed. Similar experiments with FeCl(2) generally resulted with the oxidation of Fe (II)-Fe (III) which consequently leads to ferric Fe (III) complexes binding albeit with less iron at the interface. Controlling the oxidation of Fe (II) changes the nature and amount of binding significantly. The implications to biomineralization of iron (hydr) oxides are briefly discussed. PMID- 22818796 TI - Wear-resistant rose petal-effect surfaces with superhydrophobicity and high droplet adhesion using hydrophobic and hydrophilic nanoparticles. AB - Surfaces exhibiting the so-called "petal effect" (superhydrophobicity with high droplet adhesion) have potential for applications such as the transport of small volumes of liquid. It is known that the microstructure pitch value and nanostructure density are important in achieving this effect, both in rose petals themselves and in synthetic petal-effect surfaces. However, the effect of the surface energy of materials on these values has not been systematically studied. In addition, wear resistance, which is critical for industrial applications, has rarely been examined for petal-effect surfaces. In this study, surfaces of varying microstructure pitch and nanostructure density were fabricated by depositing ZnO nanoparticles onto micropatterned substrates. The prepared surfaces were then modified with octadecylphosphonic acid (ODP) in order to hydrophobize the ZnO nanoparticles. The wettability of the surfaces was characterized both before and after ODP modification. The effect of hydrophobizing the nanostructure was examined with regards to the values of microstructure pitch and nanostructure density necessary to achieve the petal effect. In addition, to study wear resistance for industrial applications, a wear experiment was performed using an atomic force microscope (AFM). PMID- 22818797 TI - Carbonated ferric green rust as a new material for efficient phosphate removal. AB - Phosphate uptake from aqueous solutions by a recently discovered ferric oxyhydroxide is investigated. Carbonated ferric green rust {GR(CO(3)(2-))*} is prepared by varying two synthesis parameters, which are (1) the aging period after the ferrous-ferric green rust {GR(CO(3)(2-))} synthesis step and (2) the rate of the hydrogen peroxide addition to oxidize GR(CO(3)(2-)) into GR(CO(3)(2 ))*. These two parameters permit the control of the size, morphology and cristallinity of the synthesized particles. As prepared GR* samples are then evaluated, in batch experiments, as possible low-cost efficient phosphate removal materials. Firstly, kinetic experiments reveal that a fast sorption step initially occurs and equilibrium is reached at ~500 min. The adsorption kinetics data at pH=7 can be adequately fitted to a pseudo-second order model. Secondly, the Freundlich model provides the best correlation and effectively describes phosphate sorption isotherms for all GR(CO(3)(2-))* samples synthesized. Finally, the phosphate adsorption capacity decreases when pH increases. The highest adsorption capacity is 64.8 mg g(-1) at pH=4 and corresponds to the GR(CO(3)(2 ))* sample displaying the smallest and least crystallized particles thus reflecting the importance of the synthesis conditions. Overall, all sorption capacities are higher than the main iron oxide minerals, making GR(CO(3)(2-))* a potentially attractive phosphate adsorbent. PMID- 22818798 TI - Preparation of controlled gold nanoparticle aggregates using a dendronization strategy. AB - In this work, a dendronization strategy was used to control interparticle spacing and the optical properties of gold nanoparticle (NP) aggregates in aqueous media. To achieve this goal, two dendritic disulfides bearing different functionalities on their periphery were synthesized and used as ligands to dendronize gold NPs. The dendronized NPs then undergo aggregation; this process was followed by UV-vis spectroscopy, dynamic light scattering (DLS), and transmission electronic microscopy (TEM) measurements and correlated with Generalized Mie Theory electrodynamics calculations. For comparison, NP functionalization was also studied using a nondendritic ligand. It was found that the use of dendritic disulfides allows for the preparation of controlled NP aggregates. This study demonstrates how different dendronization parameters, such as disulfide concentration, temperature, time and nature of the ligand (dendritic vs nondendritic), determine the control exerted over the size and stability of the NP aggregates. PMID- 22818799 TI - Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192. AB - Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia. PMID- 22818800 TI - Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. AB - PURPOSE: To investigate intraocular concentrations and pharmacokinetics of ranibizumab after a single intravitreal injection in humans. DESIGN: Prospective, noncomparative, interventional case series. METHODS: We included 18 nonvitrectomized eyes of 18 patients (age range, 61-85 years) that were diagnosed with both clinically significant cataract and macular edema secondary to either exudative age-related macular degeneration, diabetic maculopathy, or retinal vein occlusion. Each eye received a single intravitreal injection of 0.5 mg ranibizumab. An aqueous humor sample was obtained during cataract surgery between 1 and 37 days after injection. Concentrations of unbound ranibizumab in these samples were quantified by enzyme-linked immunosorbent assay. RESULTS: Ranibizumab concentration in aqueous humor peaked the first day after injection (range, 36.9-66.1 MUg/mL) and subsequently declined in a mono-exponential fashion. Nonlinear regression analysis determined an initial peak concentration (c(max)) of 56.1 MUg/mL and an elimination half-life (t(1/2)) of 7.19 days with a coefficient of determination (R(2)) of 0.90. Correction of ranibizumab concentrations for ocular volume as calculated from axial length measurements did not alter regression analysis results significantly (t(1/2), 7.15 days; R(2), 0.89). CONCLUSIONS: In human nonvitrectomized eyes, the aqueous half-life of 0.5 mg intravitreally injected ranibizumab is 7.19 days, slightly shorter than the half-life of 9.82 days previously determined for bevacizumab by comparable methods. PMID- 22818801 TI - Positional independence of optic nerve head and retinal nerve fiber layer thickness measurements with spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate repeatability and positional independence of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) thickness measurements in sitting and supine body positions using portable spectral-domain optical coherence tomography (iVue SD-OCT; Optovue Inc). DESIGN: Evaluation of diagnostic technology. METHODS: Sixty eyes of 30 subjects (10 healthy younger adults aged 20 27 years, 10 healthy older adults aged 50-66 years, and 10 glaucoma patients aged 38-82 years) were included prospectively. For each participant, all measurements were taken in a single session. After 5 minutes in the supine position, 5 scans were obtained from both eyes. Following a 5-minute sitting adaptation, 5 scans were then obtained in the sitting position. The same instrument was used for all measurements. Repeatability and correlation between supine and sitting measurements of 4 ONH and 3 RNFL parameters were assessed using intraclass correlation coefficients (ICC), concordance correlation coefficients (rho), and Bland-Altman plots. RESULTS: Measurements were highly repeatable within individual eyes, both for ONH (ICC range, 73%-99%) and RNFL (ICC range, 72%-99%) parameters. The correlation between supine and sitting ONH measurements was strong and ranged from rho = 97%-99% (younger healthy) to rho = 98%-99% (older healthy) and rho = 84%-99% (glaucoma). Bland-Altman plots indicated good agreement between sitting and supine readings of ONH and RNFL parameters. CONCLUSIONS: Repeatability of measurements of ONH and RNFL is high and measurements between sitting and supine are highly correlated. The ability of the iVue SD-OCT to evaluate ONH and RNFL parameters is good to excellent in both body positions. PMID- 22818802 TI - Outcome after VAC(r) therapy for infected bypass grafts in the lower limb. AB - OBJECTIVE: To assess the outcome of vacuum-assisted wound closure (VAC((r))) therapy for infected bypass grafts. METHODS: A retrospective 7-year review of patient records from 2004 to 2011 of all patients receiving VAC((r)) therapy for infected bypass grafts. RESULTS: Thirty-seven patients with 42 wounds and 45 infected bypass (28 synthetic) grafts received VAC((r)) treatment. Two serious bleeding episodes from the suture lines occurred. The median VAC((r)) therapy time was 20 days. The proportion of patent bypass grafts was 91% (41/45) at a median time of 3.5 months from the start of VAC((r)) therapy. Five patients with seven bypasses had persistent infection or re-infection, and the total graft preservation rate was 76% (34/45). The median follow-up time was 15 months. The presence of two infected bypass grafts in one groin wound was associated with an increased major amputation rate (hazard ratio (HR) 7.4 [95% confidence interval (CI) 2.0-27.5]), and synthetic graft infection (HR 5.0 [95% CI 1.5-17.4]) and non healed wound (HR 3.6 [95% CI 1.5-8.7]) were associated with mortality. CONCLUSION: VAC((r)) therapy of infected bypass grafts was able to induce effective wound healing without compromising the early bypass function. Two infected synthetic bypasses in the wound were associated with the highest risk of adverse outcome. PMID- 22818803 TI - Acute abdominal aortic aneurysm: significant regional differences across Norway. PMID- 22818804 TI - Effect of oral hygiene interventions on opportunistic pathogens in patients after stroke. AB - BACKGROUND: Despite the role of the oral cavity as a reservoir of opportunistic pathogens for infection in patients following stroke, the evaluation of the effects of oral hygiene interventions has been largely neglected. METHODS: This randomized clinical trial included 102 patients undergoing hospital-based rehabilitation for stroke. Patients were randomized to one of 3 groups: oral hygiene instruction (OHI) only; OHI and 0.2% chlorhexidine mouth rinse twice daily; or OHI, 0.2% chlorhexidine mouth rinse twice daily, and assisted brushing twice weekly. Oral samples were obtained at baseline and after 3 weeks for detection of Staphylococcus aureus, aerobic and facultatively anaerobic gram negative bacilli, and yeasts. RESULTS: Almost three-quarters (72.8%) of the patients harbored oral anaerobic gram-negative bacilli at baseline, and more than half had detectable S aureus (56.8%) and yeasts (59.3%). Percentage frequencies and viable counts of pathogens remained relatively stable during the course of the clinical trial, and no significant differences were observed among the 3 patient groups. CONCLUSIONS: In our study cohort, there was no significant difference in the effectiveness of the 3 different oral hygiene interventions on the prevalence or viable counts of oral opportunistic pathogens. PMID- 22818816 TI - Cardiogenic shock secondary to metamizole-induced type II Kounis syndrome. PMID- 22818805 TI - Feasibility of delivering influenza vaccine to household contacts of pediatric patients in a residents' continuity clinic. AB - BACKGROUND: Since 2004, influenza vaccine has been recommended for household contacts (HCs) of healthy infants and young children, who are at high risk for complications from influenza disease. We examined the feasibility of providing influenza vaccine to HCs of pediatric patients during the children's outpatient clinic visits. METHODS: During influenza season 2006-07, influenza vaccine was offered at no cost to HCs of all patients aged <60 months who received primary care at a pediatric residents' continuity clinic at Children's Medical Center Dallas. The percentage of individuals receiving their first dose of influenza vaccine was calculated for all vaccinated adult HCs and also for a subset of vaccinated adult HCs for whom vaccine was recommended in a previous year, based on the pediatric patient's age. RESULTS: Influenza vaccine was administered to 1,042 HCs of 611 pediatric patients. Fifty percent of all vaccinated adult HCs had no previous history of influenza vaccination. Eighty-five of the 218 (39%) vaccinated adult HCs for whom influenza vaccine was also recommended in a previous year received their first dose through our program. CONCLUSIONS: Delivery of influenza vaccine to HCs of pediatric patients can be integrated into the children's clinic visits and may increase vaccine uptake. PMID- 22818817 TI - [Family medicine in the university sphere: musings of a 4th year medical student]. PMID- 22818819 TI - Centenaire du journal de chirurgie: the journal at its 100th anniversary. PMID- 22818820 TI - [Not Available]. AB - C. Khosrovaninejad, Ph. Marchal, S. Daligaux, M. Blaustein, G. Martane, Ch. Bodiou Hemorrhoidectomy is the treatment of choice for Stage 3 and 4 hemorrhoids; the most popular technique is that described by Milligan et al. Longo has recently introduced stapled anopexy as an alternative to the Milligan hemorrhoidectomy, however long-term results do not yet demonstrate a convincing superiority. The Parks technique of hemorrhoidectomy is another alternative to Milligan's procedure; it is an established and widely known procedure. The present prospective trial reports the immediate and medium-term results of Parks hemorrhoidectomy performed on 327 consecutive patients between 1997 and 2001. All patients were interviewed using a standard questionnaire before surgery and at 1 and 3 weeks after surgery. An anal incontinence score was recorded before and after surgery in the first 198 patients. No serious operative complications were seen. The daily mean postoperative pain score was less than 3. Mean hospital stay was 2.2 days and work incapacity was 11 days. The anal incontinence score was unchanged or improved in 179 patients (90.4%) and was worsened in 19 patients (9.6%). This trial confirms that Parks hemorrhoidectomy is safe and leads to satisfactory outcome. Postoperative pain is reduced and anal functional sequelae are few. PMID- 22818818 TI - Statins are diabetogenic--myth or reality? AB - Multiple clinical trials have demonstrated the beneficial effects of statins in lowering levels of low-density lipoprotein and in the prevention of cardiovascular disease. However, although statins have a good safety profile, a debate has been ongoing as to whether use of statins increases risk of new-onset diabetes. Recent large scale meta-analyses of statin trials support the concept of a diabetogenic effect of statins, as do some other small trials assessing changes in glycaemia parameters and insulin levels. However, a definitive mechanism of action has not yet been elucidated. Nevertheless, the level of evidence has been sufficient to lead the FDA to make a change to the labelling of statins. This review assesses the current available evidence and offers a clinical perspective. PMID- 22818821 TI - Experimental assessment of eye protection efficiency against high speed projectiles. AB - INTRODUCTION: Work in hazardous zones with the risk of mechanical injuries requires protection with safety spectacles. Mechanical eye injuries with metal foreign bodies are often caused by rotational material machining or production processes with high pressure or high velocity moving parts. Normative regulations restrict to tests with small and fast flying objects (e.g. 6mm ball). The literature does not provide any information about protection capabilities against larger objects with high mass and arbitrary shape. The purpose of this study was to test the protection efficiency of safety spectacles against flying objects. The scope of this paper is to present a new test setup for mechanical impact resistance testing of personal protective eyewear against objects with arbitrary shape and mass. MATERIAL AND METHODS: The setup is based on a catapult platform, accelerating a sliding carriage on a rail. A pull rope system allows velocities up to 62+/-2 m.s(-1). A photo sensor was used for velocity measurement. The carriage can be loaded with projectiles of up to 30mm*30mm*40mm in size with arbitrary orientation, depending on the carriage insert. Testing and validation was done with projectiles such as 7g metal chips and fragments with approximate dimensions of 10mm*15mm. Samples were standard occupational safety spectacles mounted on a test head. The projectile impact was captured with a monochrome high speed camera. RESULTS: The aiming accuracy test showed deviations of approximately 1mm of two impacts on the same spectacle surface with a free flight distance of 150mm. All tests with slow, medium and high speed projectiles showed no contact with the eye medium. Objects with velocities from 10 m.s(-1) to 62 m.s(-1) fired the spectacle off from the test head. The medium speed test cut off one side of the spectacle frame. The high speed test with 62+/-2 m.s(-1) cracked the polycarbonate shield. DISCUSSION: We describe a method for accelerating arbitrary objects up to 62 m.s(-1) and for aiming these objects on safety eyewear, mounted on a test head. The setup allows a variety of projectile shapes, orientations and velocities. The accuracy of velocity measurement is +/- 2 m.s( 1) for high velocity (< +/- 5%). Further studies will address optimization of this setup due to signs of wear and gliding properties of the carriage, wireless ignition and higher velocities. PMID- 22818822 TI - Fear of recurrence significantly influences quality of life in oral cancer patients. AB - OBJECTIVES: Besides survival time quality of life (QoL) is the most important criterion for measuring the success of the therapy and rehabilitation of patients with carcinoma of the oral cavity. Interestingly, assessments by doctors sometimes differ from those of patients concerning QoL and level of information. Particularly the probability of cancer recurrence is unclear for many patients. MATERIAL AND METHODS: Fear of recurrence (FOR) data were gathered from a total collective of 1761 patients from 38 hospitals within the German-language area of Germany, Austria and Switzerland (DOSAK-REHAB-STUDIE) yielding 1652 patient questionnaires containing 147 items which were evaluated. They refer to periods at least 6 months after therapy. QoL was determined by the patient and ranges from 0% to 100% and FOR was measured using a Likert scale. Statistical analysis was performed using SPSS 19.0. RESULTS: FOR affected 80% of the patients to a varying degree and influenced QoL very significantly. Patients with a high level of FOR were also more mentally instable. Their functional impairment in particular contributed to a reduced QoL. They felt less informed by their doctors about their illness and rehabilitation. The medical parameters had a smaller influence on FOR and QoL. CONCLUSION: The patients' knowledge of their medical situation must be improved to make patient assessment of QoL more realistic, particularly when patients with good prospects indicate low QoL. The patients' subjective evaluations have to be more strongly integrated into the concept of the multi-disciplinary team in establishing a comprehensive therapy and rehabilitation plan. PMID- 22818823 TI - Association of VEGF-A genetic polymorphisms with cancer risk and survival in advanced-stage oral squamous cell carcinoma patients. AB - BACKGROUND: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, is overexpressed in a wide variety of human cancers, including oral squamous cell carcinoma (OSCC). In this study, we examined whether individual polymorphisms within VEGF-A gene, rs699947 (-2578C/A), rs1570360 (-1154G/A), rs2010963 (-634G/C), rs3025039 (+936C/T) or their haplotypes are associated with an oral cancer risk and survival. METHODS: A case-control study was conducted on 114 OSCC patients and control group of 126 individuals without a previous cancer history, all the Caucasian race and the same ethnicity, matched by age and gender. VEGF-A genotypes were analyzed using TaqMan SNP Genotyping Assays, Applied Biosystems. RESULTS: The -1154 GG genotype was significantly associated with the decreased overall survival in OSCC patients (p = 0.010, log rank test). Stratified analysis revealed that in patients with nodal metastases and stage III, -1154 GG genotype was related to worse survival, p = 0.009, p = 0.013, respectively. The multivariate analysis revealed that -1154 GG genotype is an independent adverse factor for survival in the OSCC (HR = 1.899, [1.138-3.168], p = 0.014). The +936 CC genotype was associated with advanced staged OSCC (p = 0.050). The three polymorphisms, -2578, -1154 and -634 were in linkage disequilibrium (LD). The CAG haplotype could be associated with an increased oral cancer risk, OR = 7.967, [1.730-36.689], p = 0.008, while CGG haplotype could be associated with a decreased oral cancer risk, OR = 0.561, [0.326-0.964], p = 0.036. CONCLUSIONS: VEGF-A -1154 GG genotype could be considered as a prognostic marker of poor survival in advanced-stage OSCC patients. Haplotypes of VEGF-A gene may be associated with susceptibility to OSCC. PMID- 22818825 TI - Whatever happened to the EENT specialists? AB - As specialization in surgery grew in the late 19th and early 20th centuries, practices that combined ophthalmology with otolaryngology were common in the United States. When the knowledge base and technical skills for each of these fields grew and diverged, these practices became rarer. Their end was signaled by the formal separation in 1979 of the American Academy of Ophthalmology and Otolaryngology into two separate associations. PMID- 22818824 TI - The Dutch Healthy Diet index (DHD-index): an instrument to measure adherence to the Dutch Guidelines for a Healthy Diet. AB - BACKGROUND: The objective was to develop an index based on the Dutch Guidelines for a healthy Diet of 2006 that reflects dietary quality and to apply it to the Dutch National Food Consumption Survey (DNFCS) to examine the associations with micronutrient intakes. METHODS: A total of 749 men and women, aged 19-30 years, contributed two 24-hour recalls and additional questionnaires in the DNFCS of 2003. The Dutch Healthy Diet index (DHD-index) includes ten components representing the ten Dutch Guidelines for a Healthy Diet. Per component the score ranges between zero and ten, resulting in a total score between zero (no adherence) and 100 (complete adherence). RESULTS: The mean +/- SD of the DHD index was 60.4 +/- 11.5 for women and 57.8 +/- 10.8 for men (P for difference = 0.002). Each component score increased across the sex-specific quintiles of the DHD-index. An inverse association was observed between the sex-specific quintiles of the DHD-index and total energy intake. Calcium, riboflavin, and vitamin E intake decreased with increasing DHD-index, an inverse association which disappeared after energy adjustment. Vitamin C showed a positive association across quintiles, also when adjusted for energy. For folate, iron, magnesium, potassium, thiamin, and vitamin B6 a positive association emerged after adjustment for energy. CONCLUSIONS: The DHD-index is capable of ranking participants according to their adherence to the Dutch Guidelines for a Healthy Diet by reflecting variation in nine out of ten components that constitute the index when based on two 24-hour recalls. Furthermore, the index showed to be a good measure of nutrient density of diets. PMID- 22818826 TI - A weed by any other name. AB - A 39-year-old white man presented with intractable headaches and papilledema. The initial workup, with normal MRI and MRV but elevated cerebrospinal fluid protein raised concerns about the putative diagnosis of idiopathic intracranial hypertension, and his condition remained refractory to maximum medical treatment. Angiography revealed cerebral venous sinus stenosis, thought to represent chronic thrombosis. The diagnosis and treatment of cerebral venous sinus stenosis and thrombosis are discussed. PMID- 22818828 TI - Cicer alpha-galactosidase immobilization onto chitosan and Amberlite MB-150: optimization, characterization, and its applications. AB - Cicer alpha-galactosidase was immobilized onto chitosan and Amberlite with immobilization efficiency of 62% and 51%, respectively. Compared to soluble enzyme, immobilized enzyme had a broader operational pH range and thermal stability. Temperature optimum for chitosan immobilized enzyme and Amberlite immobilized enzyme was 70 degrees C, whereas it was 50 degrees C for soluble enzyme. After 120days storage at 4 degrees C chitosan immobilized enzyme retained 54% activity and Amberlite immobilized enzyme showed 32% activity. After using the immobilized enzymes 12 times, chitosan immobilized enzyme showed 52% activity, while Amberlite immobilized enzyme retained 22% activity with pNPGal. The immobilized enzyme exhibited higher K(m) compared to the soluble enzyme. Raffinose family oligosaccharides (RFOs) are mainly responsible for flatulence on taking of soybean derived food products. Immobilized enzyme can be used effectively for the hydrolysis of RFOs. After five runs, chitosan and Amberlite immobilized enzyme retained 53% and 34% activity, respectively with soybean RFOs. The easy availability of enzyme source, ease of its immobilization on matrices, non-toxicity and low cost of matrices, increased stability of immobilized enzyme, and effective hydrolysis of RFOs makes it a suitable product with potential applications at industries. PMID- 22818829 TI - Factors determining family planning in Catalonia. Sources of inequity. AB - INTRODUCTION: In recent decades, the foreign population in Spain has increased significantly, particularly for Catalonia, an autonomous region of Spain (2.90% in 2000 and 15.95% in 2010) and in particular Girona province (6.18% in 2000 and 21.55% in 2010). Several studies have shown a lower use of family planning methods by immigrants. This same trend is observed in Spain. The objective of this paper is to determine the existence of differences and possible sources of inequity in the use of family planning methods among health service users in Catalonia (Spain) by sex, health status, place of birth and socioeconomic conditions. METHODS: Data were taken from an ad-hoc questionnaire which was compiled following a qualitative stage of individual interviews. Said questionnaire was administered to 1094 Catalan public health service users during 2007. A complete descriptive analysis was carried out for variables related to public health service users' sociodemographic characteristics and variables indicating knowledge and use of family planning methods, and bivariate relationships were analysed by means of chi-square contrasts. Considering the use (or non-use) of family planning methods as a dependent variable and a set of demographic, socioeconomic and health status variables as explanatory factors, the relationship was modelled using mixed models. RESULTS: The analysed sample is comprised of 54.3% women and 45.7% men, with 74.3% natives (or from the EU) and 25.7% economic immigrants. 54.8% use some method of family planning, the condom (46.7%) and the pill (28.0%) being the two most frequently used methods. Statistical modelling indicates that those factors which most influence the use of family planning methods are level of education (30.59% and 39.29% more likelihood) and having children over 14 (35.35% more likelihood). With regard to the origin of the user, we observe that patients from North Africa,sub. Saharan Africa and Asia are less likely to use family planning methods (36.68%, 38.59% and 70.51%, respectively). CONCLUSIONS: The use of family planning methods is positively related to a higher level of education and having children over 14. Factors such as sex, age, income and self-perceived health do not appear to influence their use. Furthermore, being a native of this country, the European Union or Central/South America represents a greater likelihood of use than being African or Asian. Although no general differences in use were found between sexes, the difference found in the case of Asian women stands out, with a higher likelihood of use. PMID- 22818830 TI - Compounding as a current therapeutic option in dermatology. AB - Compounding continues to play a key role in the treatment of skin conditions, despite the abundance of products made by the pharmaceutical industry. Right from the earliest days of dermatology, compounding proved very useful in the treatment of diseases for which no specific drugs were available. However, as new products came onto the market, this usefulness was called into question, and doubts over safety, stability, and effectiveness were raised. Today, compounding is regaining the place it once held in routine dermatological practice. We review the advantages and disadvantages of compounding, the most common indications, current legislation in our setting, and the latest developments in active ingredients and vehicles. PMID- 22818832 TI - Intra-arterial injection of acrylic cement as a complication of percutaneous vertebroplasty. AB - Percutaneous vertebroplasty (PVP) with polymethylmethacrylate (PMMA) is a minimally invasive procedure that provides significant pain relief in a high percentage of patients with osteoporotic fractures. The complication rate of PVP is reported to be below 6%. This case illustrates, for the first time, an arterial PMMA embolus to the aorta and its branches as a complication of PVP. PMID- 22818833 TI - [Acute anuria and a giant inguinoscrotal hernia of sudden growth]. PMID- 22818834 TI - Mild depressive symptoms do not influence cognitive functioning in patients with type 2 diabetes. AB - Type 2 diabetes (T2DM) is associated both with cognitive decrements and depressive symptoms. Since depression in itself has been associated with cognitive decrements we aimed to investigate the influence of depressive symptoms on the relation between T2DM and cognitive functioning. Data were derived from three independent studies on cognitive functioning in patients with T2DM (n=366) and controls without diabetes (n=204), two with longitudinal and one with only cross-sectional assessments. Depressive symptoms were measured with self-report inventories (CES-D or BDI-II). The composite z-score of the domains memory, information-processing speed, and attention and executive function was the primary cognitive outcome measure. Mixed linear regression analyses were used in a stepped approach to compare cognitive functioning between (1) patients with T2DM and controls (cross-sectionally and longitudinally), (2) participants with and without depressive symptoms, separately for patients and controls, and (3) patients and controls after adjustment for depressive symptoms. In addition the mediating effect of depressive symptoms was assessed with a bootstrapping technique. Depressive symptoms were present in 11% of the patients with T2DM and in 7% of controls (p=0.15). Cognitive performance in patients with T2DM was worse than in controls (overall difference composite z-score -0.13). However, T2DM was not associated with accelerated cognitive decline over three years of follow-up relative to controls. Controls with depressive symptoms performed worse than those without depressive symptoms, although not statistically significant. Performance in patients with T2DM with and without depressive symptoms was similar. Adjustment for depressive symptoms and estimation of the mediating effect showed that the difference between patients and controls was not mediated by depressive symptoms. In conclusion, the modest cognitive decrements that are associated with T2DM are not due to the presence of mild depressive symptoms. PMID- 22818835 TI - Imaging axillary lymph nodes in patients with newly diagnosed breast cancer. AB - The presence of axillary lymph node metastasis in patients newly diagnosed with breast cancer carries significant prognostic and management implications. As a result, there is increasing interest to stage accurately the axilla with preoperative imaging to facilitate treatment planning. Currently, the most widespread imaging techniques for the evaluation of the axilla include ultrasound and magnetic resonance imaging. In many settings, the ability to detect axillary lymph nodes containing metastases with imaging and image-guided biopsy can allow surgeons to bypass sentinel lymph node dissection and proceed with full axillary lymph node dissection. However, no imaging modality currently has sufficient negative-predictive value to obviate surgical staging of the axilla if no abnormal lymph nodes are detected. Promising advanced imaging technologies, such as diffusion-weighted imaging and magnetic resonance lymphangiography, hold the potential to improve the accuracy of axillary staging and thereby transform management of the axilla in patients newly diagnosed with breast cancer. PMID- 22818836 TI - Metastatic melanoma to the heart. AB - Melanoma is a common neoplasm with a propensity to metastasize to the heart. Although cardiac metastasis is rarely diagnosed ante mortem, using a multimodality approach, several imaging findings may be seen. Echocardiography is often the initial imaging method used to detect cardiac metastases and their complications. On computed tomography, intraluminal filling defects and myocardial/pericardial nodules may be seen. On magnetic resonance imaging, metastatic melanoma is classically hyperintense on T1 images and hypointense on T2 images, a result of the T1 shortening of melanin; however, this is seen in a minority of cases. As melanoma metastases are fluorine-18-fluorodeoxyglucose avid, fluorine-18-fluorodeoxyglucose positron emission tomography may also be used to detect cardiac metastases. PMID- 22818837 TI - Imaging of congenital and acquired disorders of the pulmonary artery. AB - The pulmonary artery is affected by a multitude of conditions that can be congenital or acquired. These disorders may be detected incidentally, or the clinical features of the different conditions may overlap. This pictorial review illustrates the imaging findings of some of the main conditions that affect the pulmonary artery by considering them in 3 main categories: congenital disorders; enlargement of the pulmonary arteries, most commonly seen in pulmonary hypertension; obstruction or occlusion of the pulmonary arteries, as seen in thromboembolic disease or large vessel vasculitis. It is important for the radiologist to understand the radiological manifestations of these disorders, as early recognition would be of significant benefit in their diagnosis and treatment. PMID- 22818838 TI - Uncommon causes of acute abdominal pain: multidetector computed tomography pearls and pitfalls for the radiologist on call. AB - We review uncommon causes of acute abdominal pain in which inconclusive multidetector computed tomography (MDCT) studies were followed by emergency surgery and unexpected diagnoses. Despite dedicated protocols and technical advances, MDCT of uncommon causes of acute abdominal pain still represents a significant challenge for the radiologist on call. We emphasize diagnostic pearls and pitfalls that may help the radiologist on call identify or suspect these uncommon causes of acute abdominal pain on MDCT. PMID- 22818839 TI - Spectrum of multidetector computed tomography/magnetic resonance imaging findings in intrahepatic vascular shunts: classification, characterization, and management. AB - With the increasing use of multidetector computed tomography and dynamic magnetic resonance imaging in evaluation of liver pathologies, a variety of vascular shunts are detected in the liver. These shunts can be related to tumors or they can be nonneoplastic. Identification of these shunts can help in diagnosing an underlying condition. We classify and describe a wide spectrum of intrahepatic vascular shunts with their key imaging features. After reviewing this article, the reader should have improved ability to detect and characterize intrahepatic vascular shunts, which will help in diagnosing an underlying condition and facilitate optimal patient care. PMID- 22818840 TI - Usefulness of beta-trace protein and cystatin C for the prediction of mortality in non ST segment elevation acute coronary syndromes. AB - Beta-trace protein (BTP) is a low-molecular mass protein belonging to the lipocalin protein family, which is more sensitive than serum creatinine for detecting impaired renal function. The aims of the present study were to evaluate whether plasma BTP improves the risk stratification of patients with non-ST segment elevation acute coronary syndromes and to compare it to cystatin C (CysC), serum creatinine, and estimated glomerular filtration rate. Two hundred twenty-six consecutive patients with non-ST-segment elevation acute coronary syndromes were prospectively included. Blood samples were obtained within 24 hours of hospital admission to measure BTP, CysC, and creatinine. The study end point was all-cause death. Over a median follow-up period of 859 days (interquartile range [IQR] 524 to 1,164), 24 patients (10.6%) died. Decedents had higher concentrations of BTP (1.03 mg/L [IQR 0.89 to 1.43] vs 0.74 mg/L [IQR 0.61 to 0.92], p <0.001), CysC (1.16 mg/L [IQR 0.91 to 1.59] vs 0.90 mg/L [IQR 0.76 to 1.08], p = 0.001), and serum creatinine (1.10 mg/L [IQR 0.87 to 1.46] vs 0.94 mg/L [IQR 0.80 to 1.10], p = 0.004) and a lower mean estimated glomerular filtration rate (60 +/- 20 vs 80 +/- 24 ml/min/1.73 m(2), p <0.001). After multivariate adjustment, BTP and CysC were predictors of all-cause death, while estimated glomerular filtration rate and serum creatinine concentrations did not achieve statistical significance. In stratified analyses according to kidney function, elevated BTP and CysC were associated with a higher risk for all-cause death. Reclassification analyses showed that BTP and CysC added complementary information to Global Registry for Acute Coronary Events (GRACE) risk score. In conclusion, BTP and CysC levels were associated with all-cause death risk and modestly improved prognostic discrimination beyond the GRACE risk score in patients with non-ST segment elevation acute coronary syndromes. PMID- 22818841 TI - The editor's roundtable: advances in stem cell therapy for treatment of cardiovascular disease. PMID- 22818842 TI - Prognostic factors in pelvic exenteration for gynecological malignancies. AB - OBJECTIVES: Analyze morbidity, mortality and prognostic factors after pelvic exenteration (PE) for gynecological malignancies. METHODS: We reviewed a series of 107 individuals who underwent PE at A.C. Camargo Cancer Hospital from August 1982 to September 2010. RESULTS: Median age was 56.4 years. Primary tumor sites were uterine cervix in 73 cases (68.2%); vaginal, 10 (9.3%); endometrial, 14 (13.1%); vulvar, 7 (6.5%); and uterine sarcomas, 3 (2.8%). Median tumor size was 5.5 cm. Total PE was performed in 56 cases (52.3%), anterior in 31 (29.9%), posterior in 10 (9.3%) and lateral extended in 10. Median operation time, blood transfusion and hospital stay length were 420 min (range: 180-780), 900 ml (range: 300-4500) and 13 days (range: 4-79), respectively. There was no intra operative death. Fifty-seven (53.3%) and 48 (44.8%) patients had early and late complications, respectively. Five-year progression free survival (PFS), overall survival (OS) and cancer specific survival (CSS) were 35.8%, 27.4% and 41.1%, respectively. Endometrial cancer had better 5-year OS (64.3%) than cervical cancer (23.1%). Lymph node metastasis negatively impacted PFS, CSS and OS. Presence of perineural invasion negatively impacted PFS and CSS. No variable retained the risk of recurrence or death in the multivariate analysis. CONCLUSIONS: PE has acceptable morbidity and mortality and may be the only method that can offer long-term survival in highly selected patients. PMID- 22818843 TI - Diaphragmatic rupture, a new complication of Bevacizumab. AB - INTRODUCTION: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor has demonstrated a significant benefit on overall survival (OS) and progression free survival (PFS) in patients with metastatic colorectal carcinoma. Many adverse effects of Bevacizumab are well-known. We report here the first case of diaphragmatic perforation after Bevacizumab treatment. PATIENTS AND METHODS: A case of Bevacizumab induced diaphragmatic perforation was reported and a search of PubMed and Cochrane databases was performed in order to review relevant literature on the adverse effects of Bevacizumab. DISCUSSION: Serious late surgical complications may occur even if the delay between surgery and Bevacizumab treatment is respected. These complications may be life threatening for patients, and demonstrate the importance of careful monitoring after postoperative administration of Bevacizumab. PMID- 22818844 TI - Comments on cytoreductive surgery and intraperitoneal chemotherapy. PMID- 22818845 TI - Occurrence and accumulation of mercury in two species of wild grown Pleurotus mushrooms from Southeastern Nigeria. AB - The aim of this study was to evaluate the degree of contamination and intake rates, as well as the risk of Hg contained in two wild species of Pleurotus mushrooms--Oyster Mushroom (P. ostreatus) and King Tuber Mushroom (P. tuber regium)--which are widely consumed in southeastern Nigeria; and to also assess their potential to accumulate Hg. The mean Hg concentrations in caps of P. ostreatus from distant sites of Ekeoba, Ntigha, and Ubakala in Abia State, were 31+/-11, 28+/-8, and 29+/-5 ng g(-1) dry weight, respectively; while the mean concentrations for stipes were 37+/-5, 36+/-17, and 28+/-6 ng g(-1) dw, in the respective communities. The caps and stipes were characterized by a mean bioconcentration factor value of ~2, indicating that P. ostreatus is a very weak Hg accumulator and probably takes in Hg solely from the wooden substratum. Sclerotia of P. tuber-regium, purchased from five different regional markets: Ukwunwangwu (Uturu), Ekeama (Umuobiala), and Ahonta (Eluama) of Abia State; and from Abakpa market and Eke-Okigwe of Imo State; contained Hg in total range of 3.3 to 180 ng g(-1) dw. A meal consisting of 300 g of caps and stipes of P. ostreatus, or of fresh sclerotia of P. tuber-regium, would expose a consumer to <1.2, and between 0.39 and 1.2 MUg Hg, respectively; and, if eaten daily for a week, would contribute less than 0.03%, and between 0.76% and 2.3% of the provisionally tolerable weekly intake (PTWI). The consumption of P. ostreatus and sclerotia of P. tuber-regium harvested from the areas investigated, therefore, poses no toxicological or health risks to the inhabitants. PMID- 22818846 TI - Metabolomic investigation of Mytilus galloprovincialis (Lamarck 1819) caged in aquatic environments. AB - Environmental metabolomics was applied to assess the metabolic responses in transplanted mussels to environmental pollution. Specimens of Mytilus galloprovincialis, sedentary filter-feeders, were caged in anthropogenic-impacted and reference sites along the Augusta coastline (Sicily, Italy). Chemical analysis revealed increased levels of PAHs in the digestive gland of mussels from the industrial area compared with control, and marked morphological changes were also observed. Digestive gland metabolic profiles, obtained by 1H NMR spectroscopy and analyzed by multivariate statistics, showed changes in metabolites involved in energy metabolism. Specifically, changes in lactate and acetoacetate could indicate increased anaerobic fermentation and alteration in lipid metabolism, respectively, suggesting that the mussels transplanted to the contaminated field site were suffering from adverse environmental condition. The NMR-based environmental metabolomics applied in this study results thus in it being a useful and effective tool for assessing environmental influences on the health status of aquatic organisms. PMID- 22818847 TI - Toxic effects of two brominated flame retardants BDE-47 and BDE-183 on the survival and protein expression of the tubificid Monopylephorus limosus. AB - The toxic effects of two brominated diphenyl ethers (BDE), BDE-47, and BDE-183, on a benthic oligochaete tubificid, Monopylephorus limosus were studied under laboratory conditions. Investigated responses included survival, growth, and protein expression profiles, at BDE concentrations of 1, 10, 100, and 700 ng/g on a dry soil weight basis, with isooctane as the carrier solvent. Body weight losses among treatments were insignificant after 8 weeks of exposure. The 8-wk LC(50) of BDE-47 and -183 were 2311 and 169 ng/g, respectively. By applying multivariate analysis techniques, protein expression patterns were compared and correlated with stressful sources of long-term culture, carrier solvent, BDE-47 and -183. The treatment of 8-wk 100 ng/g BDE-47 was most closely clustered to the 10 ng/g BDE-183 treatment, based on the 40 examined protein spots. This indicated that BDE-183 was more potent to M. limosus, than was BDE-47. The 2-wk and 8-wk controls clustered into different groups indicating the occurrence of physiological changes due to long-term laboratory culture. Additionally, solvent effect was shown by grouping the isooctane carrier to different clusters. With further characterization by principle component analysis, it was found that the separation was mainly contributed by the 2nd principal-component. And, the primarily inhibitory variation was at spots 2 (UMP-CMP kinase) and 40 (plasma retinol-binding protein precursor) in the 8-wk groups. On the contrary, protein spots 16 (cell division control protein 2 homolog) and 24 (mitochondrial DNA mismatch repair protein) showed stimulatory variation. In all, the observed proteomic responses suggest that BDEs disrupted metabolic function in M. limosus and multivariate analysis tool offers significant potential for the assessment of various stress sources at biochemical level. PMID- 22818848 TI - Novel oxazolo[4,5-g]quinazolin-2(1H)-ones: dual inhibitors of EGFR and Src protein tyrosine kinases. AB - Quinazoline-containing derivatives are an important class of synthetic products and represent an attractive scaffold for EGFR inhibitors. A series of oxazolo[4,5 g]quinazolin-2(1H)-one derivatives were synthesized and the EGFR and Src inhibition activities were evaluated using Gefitinib as lead compound. The three most potent compounds 5y, 5l and 5a each inhibited EGFR at the IC(50) value of 61 nM, 67 nM and 78 nM. Among them, 5c also demonstrated excellent inhibition activity against Src with the IC(50) value of 3.1 MUM. Several of these derivatives also showed good anti-proliferation effects against KB and A498 cells. PMID- 22818849 TI - Synthesis, design and biological evaluation of novel highly potent tacrine congeners for the treatment of Alzheimer's disease. AB - New tacrine derivatives 5a-d, 6a-d with piperazino-ethyl spacer linked with corresponding secondary amines and tacrine homodimer 8 were synthesized and tested as cholinesterase inhibitors on human acetylcholinesterase (hAChE) and human plasmatic butyrylcholinesterase (hBChE). In most cases the majority of synthesized derivatives exhibit a high AChE and BChE inhibitory activity with IC(50) values in the low-nanomolar range, being clearly more potent than the reference standard tacrine (9-amino-1,2,3,4-tetrahydroacridine, 1) and 7-MEOTA (7 methoxy-9-amino-1,2,3,4-tetrahydroacridine). Among them, inhibitors 8 and 5c, showed a strong inhibitory activity against hAChE, with an IC(50) value of 4.49 nM and 4.97, nM resp., and a high selectivity to hAChE. The compound 5d acted as the most potent inhibitor against hBChE with an IC(50) value of 33.7 nM and exhibited also a good selectivity towards hBChE. The dissociation constants K(i) of the selected inhibitors were compared with their IC(50) values. Molecular modeling studies were performed to predict the binding modes between individual derivatives and hAChE/hBChE. PMID- 22818850 TI - Students perceived stress in academic programs: consequences for its management. AB - BACKGROUND: Academic stress contributes to the deterioration of the students' quality of life. Psychological determinants involved in the stress process, trait anxiety and coping, have been neglected when assessing the role of academic programs in stress. This study aimed at determining whether academic programs are associated with a high level of perceived stress above and beyond potential personal and environmental risk factors, as well as coping strategies. METHODS: A cross-sectional survey was conducted in 2009 among third-year medical (total n=170, participants 88%), dental (n=63, 94%), psychology (n=331, 61%) and sports sciences (n=312, 55%) students in Montpellier (France). The stress level experienced during the last 2months, trait anxiety and coping strategies were appraised. Substance use, psychological care, and stress triggers were also collected using a self-administered questionnaire. RESULTS: Compared with medicine and after adjusting for gender and age, only the sports program was associated with a lower perceived stress risk: adjusted odds ratio: 0.54 [95% Confidence interval: 0.30; 0.99]. Substantial reductions in perceived stress risks were observed in science students after additional adjustments for non academic stress triggers, substance use, psychological care (adjusted odds ratio: 0.20 [95% Confidence interval: 0.09; 0.41]), and also for trait anxiety and coping strategies (adjusted odds ratio: 0.23 [95% Confidence interval: 0.10; 0.54]). Compared with medicine and after these additional adjustments, psychology had a significantly lower perceived stress risk (0.34 [0.18; 0.64]; 0.40 [0.19; 0.86], respectively), dentistry had a similar risk (0.82 [0.35; 1.91]; 0.53 [0.20; 1.43], respectively). CONCLUSION: Sports and psychology programs had a lower perceived stress risk compared with medicine. Personal and environmental risk factors and coping strategies modified the association between academic program and perceived stress. Developing efficient coping strategies in students and improving academic environment could contribute to prevent the potential deleterious consequences of stress. PMID- 22818852 TI - Relationship between duration of crying/fussy behavior and actigraphic sleep measures in early infancy. AB - OBJECTIVE: The objective of the study is to understand the relationship between sleep development and crying episodes during early infancy more accurately by longitudinal and objective sleep evaluations. DESIGN: The study is designed as a prospective longitudinal study of infants in the first 4 months of life. METHODS: This study included 31 healthy term infants. At approximately 4- to 6-week intervals, when the infants were aged 4-6 weeks, 8-10 weeks, and 14-16 weeks, their mothers recorded the duration of crying/fussy behavior of infants in a timetable and attached an actigraph to the infants for 3 days. The relationship between 24-h crying/fussy behavior duration and actigraphic sleep measures was examined from both a cross-sectional (age group) and longitudinal (within infants) perspective. Interactions with diverse covariates were studied by multiple regression analysis. RESULTS: A significant correlation was found between 24-h crying/fussy behavior duration and proportion of active sleep in infants at 14-16 weeks and in within-infant relationships. Among potential covariates, gestational age and co-sleeping had a significant impact on proportion of active sleep. Results of multiple regression analysis showed that gestational age and co-sleeping were positively associated with proportion of active sleep, whereas 24-h crying/behavior duration was not associated with proportion of active sleep. CONCLUSIONS: Subsiding of early crying and decreasing of proportion of active sleep are parallel phenomena in some infants. However, this association was thought to be attributable to the influence of covariates, including co-sleeping or gestational age. The underlying mechanisms regulating these developmental processes might overlap with one another, as covariates that affect one process could affect the other. PMID- 22818853 TI - Selective killing of cancer stem cells by a novel dual-targeting strategy. AB - Chemo- and radio-resistance of cancer stem cells (CSCs) in solid tumors are the root causes of some cancer treatment failures in clinics. To eradicate tumors, in the present study we proposed a novel strategy against CSCs with a core-shell dual-targeting system, which consists of outer layers and inner parts. Anti-tumor therapeutic agents are loaded in the outer layer targeting cancer cells whereas antibody-drug conjugates (ADCs) with CSC targeting are encapsulated in the inner parts. The novel system we proposed can be concentrated in tumor tissue by the enhanced permeability and retention (EPR) effect. The drugs dispersed in the outer layer are supposed to kill the cancer cells, and then ADCs will be released gradually from the inner part at the tumor site which can target CSCs and help to eliminate cancer cells. In this regard, we may be able to kill the CSCs with these therapeutic drug combinations and improve the therapeutic effect of chemotherapy in cancer treatments. PMID- 22818854 TI - Discovery of serum biomarkers implicated in the onset and progression of serous ovarian cancer in a rat model using iTRAQ technique. AB - OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and early tumor detection is the most promising approach for improving the EOC survival rate. The goal of this study was to identify the biomarkers underlying ovarian carcinogenesis. STUDY DESIGN: To mimic the onset and progression of human ovarian cancer, we established a rat model of ovarian neoplasm by implanting 7,12-dimethylbenz(a)anthracene (DMBA)-coated silk cloth strips onto the ovaries. Sera collected from rats bearing serous ovarian carcinoma (SOC) at baseline, 12 and 24 weeks after DMBA treatment and from controls were analyzed using iTRAQ combined with two-dimensional liquid chromatography and tandem mass spectrometry. The data were analyzed with ProteinPilot software for peptide matching, protein identification, and protein quantitation. Ingenuity pathway analysis software was used to identify the canonical pathways and biological interaction networks of differentially expressed proteins. RESULTS: The cumulative ovarian tumor incidence rate reached 75% at 32 weeks after DMBA treatment. Out of all tumors, 94% were EOC, and 51% of the EOC cases were SOC. A total of 225 unique, non-redundant proteins were identified with 95% confidence. Twenty-seven differentially expressed proteins were significantly up- or down-regulated during the early or advanced carcinogenesis of SOC. Fifteen proteins were previously reported to be involved in ovarian cancer, and 12 proteins, including MMRN1, SERPINC1, TLN1, AHSG, PLG, APOA2, HPX, APOC1, APOC2, FERMT3, FETUB and HBB, were identified for the first time in our study. CONCLUSION: The discovery of these differentially expressed proteins provides valuable clues for understanding the molecular mechanism underlying the dynamic carcinogenic process of ovarian cancer. These proteins could be used as diagnostic biomarkers for early detection, disease monitoring and therapeutic targets. PMID- 22818855 TI - A permutation procedure to correct for confounders in case-control studies, including tests of rare variation. AB - Many case-control tests of rare variation are implemented in statistical frameworks that make correction for confounders like population stratification difficult. Simple permutation of disease status is unacceptable for resolving this issue because the replicate data sets do not have the same confounding as the original data set. These limitations make it difficult to apply rare-variant tests to samples in which confounding most likely exists, e.g., samples collected from admixed populations. To enable the use of such rare-variant methods in structured samples, as well as to facilitate permutation tests for any situation in which case-control tests require adjustment for confounding covariates, we propose to establish the significance of a rare-variant test via a modified permutation procedure. Our procedure uses Fisher's noncentral hypergeometric distribution to generate permuted data sets with the same structure present in the actual data set such that inference is valid in the presence of confounding factors. We use simulated sequence data based on coalescent models to show that our permutation strategy corrects for confounding due to population stratification that, if ignored, would otherwise inflate the size of a rare variant test. We further illustrate the approach by using sequence data from the Dallas Heart Study of energy metabolism traits. Researchers can implement our permutation approach by using the R package BiasedUrn. PMID- 22818856 TI - Dominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical cores. AB - Congenital myopathies are clinically and genetically heterogeneous diseases that typically present in childhood with hypotonia and weakness and are most commonly defined by changes observed in muscle biopsy. Approximately 40% of congenital myopathies are currently genetically unresolved. We identified a family with dominantly inherited congenital myopathy characterized by distal weakness and biopsy changes that included core-like areas and increased internalized nuclei. To identify the causative genetic abnormality in this family, we performed linkage analysis followed by whole-exome capture and next-generation sequencing. A splice-acceptor variant in previously uncharacterized CCDC78 was detected in affected individuals and absent in unaffected family members and > 10,000 controls. This variant alters RNA-transcript processing and results in a 222 bp in-frame insertion. CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and the triad, and found in intracellular aggregates in patient muscle. Modeling of the CCDC78 mutation in zebrafish resulted in changes mirroring the human disease that included altered motor function and abnormal muscle ultrastructure. Using a combination of linkage analysis, next-generation sequencing, and modeling in the zebrafish, we have identified a CCDC78 mutation associated with a unique myopathy with prominent internal nuclei and atypical cores. PMID- 22818857 TI - Acute maternal cytomegalovirus infection is associated with significantly decreased numbers of CD34+ cells in umbilical cord blood. AB - OBJECTIVE AND BACKGROUND: There is little information regarding the serologic status of umbilical cord blood (UCB) donors. Cytomegalovirus (CMV) is the most frequent agent transmitted by blood products and studies have reported that CMV can inhibit myelopoiesis, however, its effects on the cellular content of UCB have not been documented. STUDY DESIGN AND METHODS: We investigated, retrospectively, the prevalence of serological evidence of infection in 857 women donating their UCB at a public university hospital and studied the influence of acute CMV exposure on UCB content of CD34+ cells. The biological characteristics of UCB from serology positive-donors were compared with those of women with negative tests. RESULTS: We found that 51 of 857 (6%) UCB units were positive for infectious disease markers; anti-CMV IgM was the most prevalent marker, 43 of 51 (86%) of cases with infectious markers. UCB collected from anti-CMV IgM-positive donors more frequently met rejection criteria for use as a transplanation product. The CD34+ cell count was the most often affected, 2.48*10(6) in anti-CMV IgM-positive donors compared to 1.48*10(6) in unaffecetd donors( p=0.006). The probability of a UCB meeting a CD34+ cell content>=2*10(6) was significantly lower in units from IgM anti-CMV+ women compared to unaffecetd donors [Odds ratio (OR)=0.428 (95% CI 0.182-0.632; p=0.015]; the total nucleated cell count (TNC) was lower but not statistically significant [p=0.068]. CONCLUSION: UCB donated by anti-CMV IgM-positive women has a high probability of not meeting the criteria required for cryopreservation for future use as a transplantation product, because of the low number of CD34+ cells. PMID- 22818859 TI - A study on mutual interaction between cytokine induced killer cells and umbilical cord-derived mesenchymal cells: Implication for their in-vivo use. AB - Recently a number of cellular therapy based-clinical trials have been carried out using mesenchymal stromal cells (MSC) or cytokine-induced-killer (CIK) cells aiming to improve outcome of allogeneic hematopoietic stem cell transplantation. We have isolated MSC from umbilical cord (UC) exploring the interaction between CIK cells and UC-MSC. We found that UC-MSC could suppress CIK cells activity, when co-cultured in a cell-to-cell system. In addition, CIK cells could potentially lyse UC-MSC in a time and ratio dependent manner that could have implications for their in vivo use. Here we provide experimental data on the mutual interaction of CIK cells and UC-MSC, suggesting a negative interference when the two cell types are used in combination. In the light of our observations, when CIK and UC-MSC will be used in clinical trials, timing and sequencing of their infusion should be considered. PMID- 22818860 TI - Traditional nurse triage: an outdated model? PMID- 22818858 TI - Long term follow up of 93 families with myeloproliferative neoplasms: life expectancy and implications of JAK2V617F in the occurrence of complications. AB - The long-term evolution of familial myeloproliferative neoplasms was studied in 93 families with 227 subjects including 97 with polycythemia vera (PV), 105 essential thrombocythemia (ET), 14 primary myelofibrosis (PMF) and 11 chronic myeloid leukemia (CML). In PV patients, with 12years of median follow-up, overall survival was 83% at 10years and 37% at 20years. A high JAK2(V617F) allele burden was correlated with the transformation to myelofibrosis (p<0.0001), but not with the transformation to acute leukemia. Among the 105 ET, with 8years of median follow-up, overall survival was 83% at 10years and 57% at 20years. Progression to acute leukemia and progression to myelofibrosis were 10% and 13%. There was a trend toward a more frequent evolution to myelofibrosis when the JAK2(V617F) mutated allele burden was >50% (p=0.09), but not to AML. Hematologic transformation of the MPN was responsible for 69% of the deaths, cerebral stroke for 7% and 4% died of myocardial infarction. Eleven JAK2(V617F) mutated patients developed 13 deep splanchnic thromboses in PV and ET. Finally whereas patients with familial PV and ET have a comparable prognosis to non-familial MPN, the JAK2(V617F) mutation was associated with a more frequent occurrence of thrombosis in the entire population. PMID- 22818861 TI - Visual and aberrometric outcomes in eyes with an angle-supported phakic intraocular lens. AB - PURPOSE: To evaluate the postoperative changes in spherical aberration and the point-spread function (PSF) induced by the implantation of a new angle-supported phakic intraocular lens (pIOL). SETTING: Department of Ophthalmology, St. Bassiano Hospital, Bassano del Grappa, Italy. DESIGN: Prospective nonrandomized cohort study. METHODS: Eyes with high myopia had implantation of an Acrysof Cachet angle-supported pIOL. Preoperative and postoperative total spherical aberration and PSF were measured using a Luneau 80 Wave+ wavefront aberrometer (high-resolution Hartmann-Shack technology) at a fixed entrance pupil scan size of 5.0 mm under pharmacologic mydriasis. Preoperative and postoperative data were analyzed and compared using the Student t test. RESULTS: Thirty-five eyes of 18 patients were included in the statistical analysis. The Student t test for paired data (95% confidence interval) showed a statistically significant difference between preoperative data and postoperative data. The mean preoperative total spherical aberration Z(4,0) was -0.001 MUm +/- 0.076 (SD) preoperatively and 0.13 +/- 0.11 MUm postoperatively (P<=.05). The mean PSF was 0.28 +/- 0.15 preoperatively and 0.34 +/- 0.16 postoperatively (P<.05). CONCLUSION: Implantation of the angle-supported pIOL in eyes with high myopia improved the quality of vision, inducing negative spherical aberration and increasing the PSF under mesopic conditions. PMID- 22818862 TI - Assessing Counter-Terrorism field training with multiple behavioral measures. AB - Development of behavioral pattern recognition and analysis skills is an essential element of Counter-Terrorism training, particularly in the field. Three classes of behavioral measures were collected in an assessment of skill acquisition during a US Joint Forces Command-sponsored course consisting of Combat Tracking and Combat Profiling segments. Measures included situational judgment tests, structured behavioral observation checklists, and qualitative assessments of the emergence of specific knowledge-skills-attitudes over the course of the training. The paper describes statistical evidence across the three types of measures that indicate that behavioral pattern recognition and analysis skills were successfully acquired by most students (a mix of Army and civilian law enforcement personnel) during the field training exercises. Implications for broader training of these critical skills are also discussed. PMID- 22818863 TI - [Superficial hysteroscopic resection for polypoid endometrium: preliminary results of an innovative approach for women of childbearing age]. AB - OBJECTIVE: To evaluate the reproductive safety and long-term efficacy of hysteroscopic superficial endometrial resection for polypoid endometrium in symptomatic patients (menorrhagia, dysmenorrhea and unexplained infertility). PATIENTS AND METHODS: The present retrospective descriptive case series study included 44 patients of reproductive age who underwent superficial hysteroscopic endometrial resection between January 1st, 2004 and December 31, 2009. Reproductive outcome, and the patients' perceptions of menstrual symptoms after the surgical intervention were collected from the clinical notes and a semi structured telephone interview. RESULTS: Of the patients presenting abnormal uterine bleeding, 59% reported long-term improvement of this symptom; of those with dysmenorrhea, 52% reported long-term relief. Among 26 infertile women who wanted to become pregnant immediately after the procedure, 58% succeeded (n=15), with a live-born rate of 38%. The pregnancy rate in primary and secondary infertility cases was respectively 53% (n=8/15) and 64% (n=7/11). CONCLUSION: Superficial endometrial resection is an alternative for treating polypoid endometrium when it is associated with menorrhagia, dysmenorrhea and infertility. It treats menstrual symptoms successfully, with no adverse impact on fertility. PMID- 22818864 TI - The growth of interventional radiology in Canada. PMID- 22818865 TI - Percutaneous gastrostomy feeding tubes in end stage dementia: don't "just do it". PMID- 22818866 TI - Comparison of heterogeneity quantification algorithms for brain SPECT perfusion images. AB - BACKGROUND: Several algorithms from the literature were compared with the original random walk (RW) algorithm for brain perfusion heterogeneity quantification purposes. Algorithms are compared on a set of 210 brain single photon emission computed tomography (SPECT) simulations and 40 patient exams. METHODS: Five algorithms were tested on numerical phantoms. The numerical anthropomorphic Zubal head phantom was used to generate 42 (6 * 7) different brain SPECT simulations. Seven diffuse cortical heterogeneity levels were simulated with an adjustable Gaussian noise function and six focal perfusion defect levels with temporoparietal (TP) defects. The phantoms were successively projected and smoothed with Gaussian kernel with full width at half maximum (FWHM = 5 mm), and Poisson noise was added to the 64 projections. For each simulation, 5 Poisson noise realizations were performed yielding a total of 210 datasets. The SPECT images were reconstructed using filtered black projection (Hamming filter: alpha = 0.5).The five algorithms or measures tested were the following: the coefficient of variation, the entropy and local entropy, fractal dimension (FD) (box counting and Fourier power spectrum methods), the gray-level co-occurrence matrix (GLCM), and the new RW.The heterogeneity discrimination power was obtained with a linear regression for each algorithm. This regression line is a mean function of the measure of heterogeneity compared to the different diffuse heterogeneity and focal defect levels generated in the phantoms. A greater slope denotes a larger separation between the levels of diffuse heterogeneity.The five algorithms were computed using 40 99mTc-ethyl-cysteinate-dimer (ECD) SPECT images of patients referred for memory impairment. Scans were blindly ranked by two physicians according to the level of heterogeneity, and a consensus was obtained. The rankings obtained by the algorithms were compared with the physicians' consensus ranking. RESULTS: The GLCM method (slope = 58.5), the fractal dimension (35.9), and the RW method (31.6) can differentiate the different levels of diffuse heterogeneity. The GLCM contrast parameter method is not influenced by a focal defect contrary to the FD and RW methods. A significant correlation was found between the RW method and the physicians' classification (r = 0.86; F = 137; p < 0.0001). CONCLUSIONS: The GLCM method can quantify the different levels of diffuse heterogeneity in brain-simulated SPECT images without an influence from the focal cortical defects. However, GLCM classification was not correlated with the physicians' classification (Rho = -0.099). The RW method was significantly correlated with the physicians' heterogeneity perception but is influenced by the existence of a focal defect. PMID- 22818867 TI - The restrictive cardiomyopathies. PMID- 22818868 TI - Radiology in the undergraduate medical curriculum -- who, how, what, when, and where? PMID- 22818869 TI - Effect of lysine, vitamin B(6), and carnitine supplementation on the lipid profile of male patients with hypertriglyceridemia: a 12-week, open-label, randomized, placebo-controlled trial. AB - BACKGROUND: Fat metabolism is known to be altered in hypertriglyceridemia. Fat oxidation requires carnitine, which can be obtained either from the diet (animal or dairy products) or through synthesis in the body using both lysine and vitamin B(6). OBJECTIVE: The goal of this study was to investigate the effect of lysine, vitamin B(6), and carnitine supplementation on both glycemia and the lipid profiles, specifically triglyceride (TG) levels, in men with hypertriglyceridemia. METHODS: This 12-week, randomized, placebo-controlled clinical trial was conducted at a Lebanese medical center. A total of 85 hypertriglyceridemic (TG> 150 mg/dL) male patients were randomized to 1 of 5 groups and given supplements of lysine (1 g/d), vitamin B(6) (50 mg/d), lysine (1 g/d) + vitamin B(6) (50 mg/d), carnitine (1 g/d), or placebo for 12 weeks. The lipid profile (TG, total cholesterol, LDL-C, and HDL-C) and fasting plasma glucose levels were assessed at baseline and at 6 and 12 weeks. RESULTS: Adults (~50 years) Lebanese males from a low socioeconomic status in Beirut were given the appropriate supplements. Vitamin B(6) supplementation was associated with a significant reduction in total cholesterol and HDL-C of ~10%. In addition, plasma TG was reduced by 36.6 mg/dL at 6 weeks, whereas levels in the placebo group increased by 18 mg/dL; this difference failed to reach statistical significance. No major changes in the lipid profile were observed in the lysine and carnitine groups or when lysine was added to vitamin B(6). CONCLUSION: Vitamin B(6) supplementation in these male patients with hypertriglyceridemia reduced plasma total cholesterol and HDL-C concentrations. PMID- 22818870 TI - Cost-effectiveness of varenicline versus bupropion, nicotine-replacement therapy, and unaided cessation in Greece. AB - BACKGROUND: Varenicline was designed to relieve symptoms of nicotine withdrawal, including cigarette craving, and to block the reinforcing effects of continued nicotine use. The cost-effectiveness of varenicline in some countries has not been studied. OBJECTIVE: The aim of this study was to compare the cost effectiveness of varenicline to that of bupropion, nicotine-replacement therapy (NRT), and unaided cessation in the Greek health care setting. The analysis takes into account a societal security (third-party payer) perspective. METHODS: To perform the analyses of the benefits of smoking cessation in terms of smoking related morbidity, mortality, and associated medical costs, a Markov model was used that simulated the progress of a hypothetical cohort of current smokers making a single attempt to quit smoking at the beginning of the timeframe of the analysis. The robustness of the results was assessed using a series of 1-way sensitivity analyses. RESULTS: Varenicline was associated with the potential prevention of 14.1, 14.2, and 35.1 additional cases of the 4 smoking-related diseases incorporated into the model, per 1000 smokers willing to quit, versus bupropion, NRT, and unaided cessation, respectively. Potentially avoided smoking related deaths with varenicline were estimated at 3.24, 3.26, and 7.5 per 1000 quitters versus the 3 comparators. Varenicline led to a potential gain of 33.78, 33.91, and 83.97 QALYs per 1000 persons willing to make a quit attempt versus the 3 comparators. Varenicline was associated with cost-savings against both active comparators for the lifetime horizon. Overall, the cost per additional quitter with varenicline, considering only the costs of the smoking-cessation strategy, was ?2659 (?1015) for a lifetime horizon compared with bupropion (NRT); however, when all direct costs were incorporated into the analysis, varenicline was cost saving. CONCLUSION: The findings from the present study suggest that, compared with the widely used treatment options bupropion and NRT, as well as unaided cessation, varenicline may enhance smoking-cessation treatment outcomes while substantially reducing the overall costs of smoking to the health care system. PMID- 22818871 TI - Evolution of highly pathogenic avian influenza (H5N1) virus populations in Vietnam between 2007 and 2010. AB - We report on the genetic analysis of 213 highly pathogenic avian influenza (HPAI) H5N1 viruses isolated from poultry in Vietnam between 2007 and 2010. Phylogenetic analyses of the viral genomes revealed 38 distinct viral genotypes, 29 were novel and 9 were reported in Vietnam or neighboring countries in recent years. Viruses from only six genotypes persisted beyond one season or year. Thus, most reassortant viruses were transient, suggesting that such genotypes lacked significant fitness advantages. Viruses with clade 2.3.2.1 HA were re-introduced into Vietnam in 2009 and their prevalence rose steeply towards the end of 2010. Clade 2.3.4-like viruses (genotype V) were predominant in northern Vietnam and caused the majority of zoonotic infections, whereas clade 1.1 (genotype Z) viruses were only detected in the Mekong delta region, in southern Vietnam. Antigenic analysis of representative viruses from the four clades indicated substantial drift. PMID- 22818872 TI - Cell models for McArdle disease and aminoglycoside-induced read-through of a premature termination codon. AB - McArdle disease results from mutations in the gene encoding muscle glycogen phosphorylase (PYGM) protein and the two most common mutations are a premature termination codon (R50X) and a missense mutation (G205S). Myoblasts from patients cannot be used to create a cell model of McArdle disease because even normal myoblasts produce little or no PYGM protein in cell culture. We therefore created cell models by expressing wild-type or mutant (R50X or G205S) PYGM from cDNA integrated into the genome of Chinese hamster ovary cells. These cell lines enable the study of McArdle mutations in the absence of nonsense-mediated decay of mRNA transcripts. Although all cell lines produced stable mRNA, only wild-type produced detectable PYGM protein. Our data suggest that the G205S mutation affects PYGM by causing misfolding and accelerated protein turnover. Using the N terminal region of PYGM containing the R50X mutation fused to green fluorescent protein, we were able to demonstrate both small amounts of truncated protein production and read-through of the R50X premature termination codon induced by the aminoglycoside, G418. PMID- 22818874 TI - Sex determination using free fetal DNA at early gestational ages: a comparison between a modified mini-STR genotyping method and real-time PCR. AB - OBJECTIVE: Recently the use of free fetal deoxyribonucleic acid (DNA) in maternal plasma and serum has been applicable for noninvasive prenatal genetic diagnosis. In this study, we applied a new algorithmic base conventional polymerase chain reaction (PCR) genotyping method and also real-time PCR for detecting fetal X and Y-chromosome sequences in maternal plasma to determine fetal sex in pregnant women in their early gestational ages (5-13 weeks). Finally, we compared the efficiency of each method in sex determination. STUDY DESIGN: DNA was extracted from 106 pregnant women and their husbands' blood samples. Fetus mini-short tandem repeat (STR) genotyping was accomplished through amplification of 19 mini STRs and 3 non-STR markers using conventional PCR followed by polyacrylamide gel electrophoresis analysis. Simultaneously, TaqMan real-time PCR was done with the use of DYS14-specific primers and probe. RESULTS: In conventional PCR method, 47 cases were diagnosed to be male and 49 to be female. In comparison, real-time PCR amplified DYS14 (Y-marker) sequences in 45 pregnant women plasma samples. Sensitivity and specificity were calculated to be 95.9% and 98% for conventional PCR and 91.8% and 100% for real-time PCR method, respectively. CONCLUSION: According to our study, the conventional PCR method was more sensitive than real time PCR and it could be employed in future clinical diagnostics singly or in combination with real-time PCR. PMID- 22818876 TI - Abnormal second-trimester serum analytes are more predictive of preterm preeclampsia. AB - OBJECTIVE: We sought to determine the association of abnormal second-trimester serum analytes with early preterm preeclampsia. STUDY DESIGN: We conducted a retrospective study of 7767 subjects undergoing second-trimester serum aneuploidy screening. Values of maternal serum alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (hCG), and inhibin (INH) were calculated as multiples of the median (MoM) and evaluated by gestational age at delivery and occurrence of preeclampsia. RESULTS: Of 459 (6.5%) cases of preeclampsia, 65 (14%) delivered <34 weeks and 394 (86%) delivered >34 weeks. Elevated AFP, hCG, and INH >2 MoM were associated with preeclampsia, and the odds ratio was higher for the development of preeclampsia <34 weeks than >34 weeks (odds ratio, 8.04 vs 2.91 for AFP, 3.6 vs 2 for hCG, and 4.17 vs 3.08 for INH, P < .001 for all). The higher the MoM for each analyte the greater the likelihood of preeclampsia. CONCLUSION: Elevated AFP, hCG, and INH levels >2 MoM are associated with developing early preeclampsia, and the more elevated they are, the higher the likelihood. PMID- 22818875 TI - The effect of race/ethnicity on adverse perinatal outcomes among patients with gestational diabetes mellitus. AB - OBJECTIVE: The purpose of this study was to determine racial/ethnic differences in perinatal outcomes among women with gestational diabetes mellitus. STUDY DESIGN: We conducted a retrospective cohort study of 32,193 singleton births among women with gestational diabetes mellitus in California from 2006, using Vital Statistics Birth and Death Certificate and Patient Discharge Data. Data were divided by race/ethnicity: white, black, Hispanic, or Asian. Multivariable logistic regression was used to analyze associations between race/ethnicity and adverse outcomes that were controlled for potential confounders. Outcomes included primary cesarean delivery, preeclampsia, neonatal hypoglycemia, preterm delivery, macrosomia, fetal anomaly, and respiratory distress syndrome. RESULTS: Compared with women in other races, black women had higher odds of preeclampsia (adjusted odds ratio [aOR], 1.57; 95% confidence interval [CI], 1.47-1.95), neonatal hypoglycemia (aOR, 1.79; 95% CI, 1.07-3.00), and preterm delivery <37 weeks' gestation (aOR, 1.56; 95% CI, 1.33-1.83). Asian women had the lowest odds of primary cesarean delivery (aOR, 0.75; 95% CI, 0.69-0.82), large-for gestational-age infants (aOR, 0.40; 95% CI, 0.33-0.48), and neonatal respiratory distress syndrome (aOR, 0.54; 95% CI, 0.40-0.73). CONCLUSION: Perinatal outcomes among women with gestational diabetes mellitus differ by race/ethnicity and may be attributed to inherent sociocultural differences that may impact glycemic control, the development of chronic comorbidities, genetic variability, and variation in access to prenatal care, and quantity and quality of prenatal care. PMID- 22818877 TI - Recognition of finger flexion motion from ultrasound image: a feasibility study. AB - Muscle contraction results in structural and morphologic changes of the related muscle. Therefore, finger flexion can be monitored from measurements of these morphologic changes. We used ultrasound imaging to record muscle activities during finger flexion and extracted features to discriminate different fingers' flexions using a support vector machine (SVM). Registration of ultrasound images before and after finger flexion was performed to generate a deformation field, from which angle features and wavelet-based features were extracted. The SVM was then used to classify the motions of different fingers. The experimental results showed that the overall mean recognition accuracy was 94.05% +/- 4.10%, with the highest for the thumb (97%) and the lowest for the ring finger (92%) and the mean F value was 0.94 +/- 0.02, indicating high accuracy and reliability of this method. The results suggest that the proposed method has the potential to be used as an alternative method of surface electromyography in differentiating the motions of different fingers. PMID- 22818879 TI - Direct mean strain estimation for elastography using nearest-neighbor weighted least-squares approach in the frequency domain. AB - Ultrasound elastography is emerging with enormous potential as a medical imaging modality for effective discrimination of pathological changes in soft tissue. It maps the tissue elasticity or strain due to a mechanical deformation applied to it. The strain image most often calculated from the derivative of the local displacement field is highly noisy because of the de-correlation effect mainly due to unstable free-hand scanning and/or irregular tissue motion; consequently, improving the SNR of the strain image is still a challenging problem in this area. In this paper, a novel approach using the nearest-neighbor weighted least squares is presented for direct estimation of the 'mean' axial strain for high quality strain imaging. Like other time/frequency domain reported schemes, the proposed method exploits the fact that the post-compression rf echo signal is a time-scaled and shifted replica of the pre-compression rf echo signal. However, the elegance of our technique is that it directly computes the mean strain without explicitly using any post filter and/or previous local displacement/strain estimates as is usually done in the conventional approaches. It is implemented in the short-time Fourier transform domain through a nearest neighbor weighted least-squares-based Fourier spectrum equalization technique. As the local tissue strain is expected to maintain continuity with its neighbors, we show here that the mean strain at the interrogative window can be directly computed from the common stretching factor that minimizes a cost function derived from the exponentially weighted windowed pre- and post-compression rf echo segments in both the lateral and axial directions. The performance of our algorithm is verified for up to 8% applied strain using simulation and experimental phantom data and the results reveal that the SNR of the strain image can be significantly improved compared to other reported algorithms in the literature. The efficacy of the algorithm is also tested with in vivo breast data known to have malignant or benign masses from histology. PMID- 22818880 TI - [Brain lesion]. PMID- 22818878 TI - Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. AB - The blood-brain barrier (BBB) inhibits the entry of the majority of chemotherapeutic agents into the brain. Previous studies have illustrated the feasibility of drug delivery across the BBB using focused ultrasound (FUS) and microbubbles. Here, we investigated the effect of FUS-enhanced delivery of doxorubicin on survival in rats with and 9L gliosarcoma cells inoculated in the brain. Each rat received either: (1) no treatment (control; N = 11), (2) FUS only (N = 9), (3) IV liposomal doxorubicin (DOX only; N = 17), or (4) FUS with concurrent IV injections of liposomal doxorubicin (FUS+DOX; N = 20). Post treatment by magnetic resonance imaging (MRI) showed that FUS+DOX reduced tumor growth compared with DOX only. Further, we observed a modest but significant increase in median survival time after a single treatment FUS+DOX treatment (p = 0.0007), whereas neither DOX nor FUS had any significant impact on survival on its own. These results suggest that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain. PMID- 22818883 TI - Defence response of tomato seedlings to oxidative stress induced by phenolic compounds from dry olive mill residue. AB - ADOR is an aqueous extract obtained from the dry olive mill residue (DOR) which contains the majority of its soluble phenolic compounds, which are responsible for its phytotoxic properties. Some studies have shown that ADOR negatively affects seed germination. However, to date, few studies have been carried out on the effect of ADOR on the oxidative stress of the plant. It is well known that saprobe fungi can detoxify these phenolic compounds and reduce the potential negative effects of ADOR on plants. To gain a better understanding of the phytotoxic effects and oxidative stress caused by this residue, tomato seeds were germinated in the presence of ADOR, treated and untreated with Coriolopsis rigida, Trametes versicolor, Pycnoporus cinnabarinus and Penicillium chrysogenum 10 saprobe fungi. ADOR sharply reduced tomato seed germination and also generated high levels of malondialdehyde (MDA), O(2)(-) and H(2)O(2). However, bioremediated ADOR did not negatively affect germination and reduced MDA, O(2)(-) and H(2)O(2) content in different ways depending on the fungus used. In addition, the induced defense response was studied by analyzing the activity of both antioxidant enzymes (superoxide dismutase (SOD), catalase, ascorbate peroxidasa, glutathione reductase (GR), peroxidases and coniferil alcohol peroxidasa) and detoxification enzymes (glutathione-S-transferase (GST)). Our findings suggest that, because ADOR is capable of inducing oxidative stress, tomato seedlings trigger a defense response through SOD, GR, and GST activity and through antioxidant and lignification processes. On the other hand, the bioremediation of ADOR plays an important role in counteracting the oxidative stress induced by the untreated residue. PMID- 22818881 TI - [Myelopathy due to Schistosoma mansoni]. AB - INTRODUCTION: Neurological complications of schistosomiasis remain exceptional even in hyperendemic area. CASE REPORT: We report a 26-year-old Senegalese man, without past medical history, who was admitted for spastic paraplegia, acute retention of urine, and pain in low back and lower limbs. The final diagnosis was spinal cord schistosomiasis. Diagnosis was based on the endemic context, MRI medullar conus imaging, schistosoma serology in cerebrospinal fluid and blood, and the absence of other cause of myelopathy. Treatment was based on praziquantel, corticosteroids and physiotherapy. The outcome was favorable after a 2-year follow-up. CONCLUSION: Schistosomiasis should be included in the differential diagnosis of myelopathy in patients living actually, or even traveled in the past, in endemic tropical areas. PMID- 22818884 TI - Alterations observed in the endothelial HUVEC cell line exposed to pure Cylindrospermopsin. AB - The cyanobacterial toxin Cylindrospermopsin (CYN) is receiving great interest due to its increasing presence in waterbodies, which has lead to recognize it as a potential threat to drinking water safety. CYN is a potent inhibitor of protein and glutathione synthesis. The present work studies for the first time the effects of CYN in endothelial cells. The basal cytotoxicity endpoints studied at 24 and 48 h were total protein content (PC), neutral red (NR) uptake and the tretazolium salt, MTS, reduction. Moreover, the effect of subcytotoxic concentrations of CYN on the generation of intracellular reactive oxygen species (ROS), the activity of gamma-glutamylcysteine synthetase (GCS) and glutathione (GSH) content have been investigated. In addition, morphological alterations of HUVEC cells subsequent to CYN exposure were recorded. The cytotoxicity endpoints revealed a decrease in the cellular viability in a time and concentration dependent way. The most sensitive cytotoxicity endpoint was NR uptake assay, with reductions in cell viability of 95% at 48 h of exposure to 40 MUg mL(-1) CYN. Intracellular ROS production was increased only at the lowest concentration assayed, while GCS activity and GSH content underwent concentration-dependent enhancements. The most remarkable morphological alterations observed were: nucleolar segregation with altered nuclei, degenerated Golgi apparatus, increases in the presence of granules and apoptosis. PMID- 22818885 TI - Influence of temperature and macromolecular mobility on sorption of TCE on humic acid coated mineral surfaces. AB - This study demonstrates differences in sorptive capacity of volatile organic compound (VOC) trichloroethylene (TCE) onto natural organic matter (NOM) coated and uncoated mineral surfaces above and below the NOM glass transition temperature. TCE sorption isotherms for dry NOM-mineral systems below the NOM glass transition temperature (T(g)) demonstrated sorption behavior characteristic of micropore filling, with sorption capacities reduced relative to uncoated mineral matrices. Such differences were not entirely associated with differences in surface areas of the coated and uncoated mineral matrices, but were likely associated with either a blockage of pore space available to the VOC or a kinetic limitation that does not allow the VOC access to the internal porosity of the model soil within the time periods of the experiment. TCE sorption in dry NOM mineral matrices above the T(g), however, was described in terms of sorption within a more fluid, macromolecular dissolution medium that does not hinder access to mineral surfaces. Such observations have potential important implications for modeling the fate and transport of VOCs in soils and sediment systems. PMID- 22818886 TI - EMAS clinical guide: low-dose vaginal estrogens for postmenopausal vaginal atrophy. AB - Vaginal atrophy is common in postmenopausal women. This clinical guide provides the evidence for the clinical use of vaginal estrogens for this condition focussing on publications since the 2006 Cochrane systematic review. Use after breast cancer, before assessment of cervical cytology and prolapse surgery is also discussed. PMID- 22818887 TI - The effect of coping/veneer thickness on the fracture toughness and residual stress of implant supported, cement retained zirconia and metal-ceramic crowns. AB - OBJECTIVES: The aim of the work was to assess the influence of coping and veneer thickness on the fracture resistance of porcelain-metal and porcelain-zirconia crowns in a clinically representative model. METHODS: A total of 30 zirconia and 30 precious metal copings were fabricated. There were 10 copings in each group of 0.5mm, 1mm and 1.5mm thickness. Each group of 10 was further divided into two groups with a total thickness of three and four millimeters inclusive of veneering ceramic. The specimens were cemented to a titanium abutment with zinc oxide cement and tested using a microindenter. Crack length, hardness and spalling (chipping) were recorded using an optical microscope from which fracture toughness was calculated. RESULTS: Kruskal-Wallis tests and simple linear regression analysis were used to analyze the results, revealing a significant difference between zirconia (ZrCC) and metal (MCC) specimens for crack length. 0.5mm coping thicknesses and MCC specimens showed the highest fracture toughness values. Simple linear regression analysis showed a limited effect of the overall thickness or veneer thickness on crack length and hardness; however coping thickness showed a positive correlation with both. Spalling was higher in zirconia specimens. Residual stresses were higher for ZrCC specimens and showed a positive correlation with crack length. The ratio of veneer to coping thickness was negatively correlated with residual stress. SIGNIFICANCE: Residual stresses due to thermal mismatch between the coping and the veneering ceramic should be kept to a minimum. The ZrCC specimens were found to have lower apparent fracture toughness than MCC specimens. Thermal mismatch caused a larger drop in apparent fracture toughness than the inherent differences in the materials used. PMID- 22818888 TI - Functional characterization of SlscADH1, a fruit-ripening-associated short-chain alcohol dehydrogenase of tomato. AB - A tomato short-chain dehydrogenase-reductase (SlscADH1) is preferentially expressed in fruit with a maximum expression at the breaker stage while expression in roots, stems, leaves and flowers is very weak. It represents a potential candidate for the formation of aroma volatiles by interconverting alcohols and aldehydes. The SlscADH1 recombinant protein produced in Escherichia coli exhibited dehydrogenase-reductase activity towards several volatile compounds present in tomato flavour with a strong preference for the NAD/NADH co factors. The strongest activity was observed for the reduction of hexanal (K(m)=0.175mM) and phenylacetaldehyde (K(m)=0.375mM) in the presence of NADH. The oxidation process of hexanol and 1-phenylethanol was much less efficient (K(m)s of 2.9 and 23.0mM, respectively), indicating that the enzyme preferentially acts as a reductase. However activity was observed only for hexanal, phenylacetaldehyde, (E)-2-hexenal and acetaldehyde and the corresponding alcohols. No activity could be detected for other aroma volatiles important for tomato flavour, such as methyl-butanol/methyl-butanal, 5-methyl-6-hepten-2-one/5 methyl-6-hepten-2-ol, citronellal/citronellol, neral/nerol, geraniol. In order to assess the function of the SlscADH1 gene, transgenic plants have been generated using the technique of RNA interference (RNAi). Constitutive down-regulation using the 35S promoter resulted in the generation of dwarf plants, indicating that the SlscADH1 gene, although weakly expressed in vegetative tissues, had a function in regulating plant development. Fruit-specific down-regulation using the 2A11 promoter had no morphogenetic effect and did not alter the aldehyde/alcohol balance of the volatiles compounds produced by the fruit. Nevertheless, SlscADH1-inhibited fruit unexpectedly accumulated higher concentrations of C5 and C6 volatile compounds of the lipoxygenase pathway, possibly as an indirect effect of the suppression of SlscADH1 on the catabolism of phospholipids and/or integrity of membranes. PMID- 22818889 TI - Absorption of momilactone A and B by Arabidopsis thaliana L. and the growth inhibitory effects. AB - Although most allelochemicals can potentially cause growth inhibition in receiver plants, there is little information available about the absorption of these allelochemicals by the receiver plants. The present research describes the absorption of momilactone A and B by Arabidopsis thaliana (L.) and effects of the absorption on Arabidopsis growth. Exogenously applied momilactone A and B inhibited the growth of Arabidopsis hypocotyls and roots at concentrations greater than 10 and 1MUmol/L, respectively. The levels of momilactone A and B in Arabidopsis hypocotyls were approximately 3.2 and 2.4% of momilactone A and B, respectively, in the medium and those in Arabidopsis roots were about 3.9-3.4%, respectively. The absorption rates of momilactone A and B by Arabidopsis were not significantly different. The present research suggests that momilactone A and B may be absorbed in proportion to their applied levels, and the growth inhibitory effects of momilactone A and B may also correlated with their endogenous levels. However, the effectiveness of momilactone B on growth inhibition was much greater than that of momilactone A, and the sensitivities of hypocotyls to momilactone A and B were greater than those of roots. This is the first report describing the absorption of potent rice allelochemicals, momilactone A and B by receiver plants. PMID- 22818890 TI - Science versus politics: the need for supervised injection facilities in Montreal, Canada. PMID- 22818891 TI - Supply-side harm reduction strategies: Bolivia's experiment with social control. AB - Harm reduction approaches to drug control have almost exclusively focussed on consumers in northern countries. This article supports recent analysis that indicates that such policies also hold relevance for producer countries by drawing on recent policy innovations in Bolivia. When Evo Morales, the president of the national coca grower confederation, was elected the country's first indigenous president in 2005, he promised to fundamentally change 25 years of the U.S.-funded "drug war" that had generated repeated human rights violations. The new policy, which implicitly incorporates harm reduction principles combined with respect for human rights, recognizes coca leaf's traditional use and cultural importance and relies on vigorous local organizations to implement a community based programme called social control. Results to date indicate that Bolivia's social control experience has reduced violence in coca growing communities, ensured small farmers a subsistence income from coca and increased sovereignty, while making a modest contribution to containing expansion of coca cultivation. The programme has registered 50,000 farmers who are allowed to cultivate limited quantities of coca to supply traditional users and helped them gain secure title to their land. This registration is combined with satellite surveillance to guarantee that farmers do not exceed limits established by law. To date, the programme's reach is incomplete and coca is still diverted to the drug trade. Nonetheless, the approach may offer lessons for other drug producer countries, particularly where strong socio-political organizations are found in combination with closeknit communities holding shared cultural values. PMID- 22818892 TI - Bispecific targeting of EGFR and uPAR in a mouse model of head and neck squamous cell carcinoma. AB - OBJECTIVES: To investigate the efficacy of the bispecific targeted toxin, dEGFATFKDEL, on head and neck carcinoma cell lines in vitro and in vivo. MATERIALS AND METHODS: A deimmunized bispecific anti-cancer agent was constructed to simultaneously target both the overexpressed EGF receptor on carcinomas and the urokinase receptor (uPAR), that is found on the endothelial cells of the neovasculature within tumors. Flow cytometry assays were performed to determine the level of EGFR expressed on a variety of carcinoma lines. These lines were then tested in tritiated leucine incorporation assays to determine the efficacy of dEGFATFKDEL. Human vein endothelial primary cells were also tested to determine the effectiveness of the ATF portion of the molecule that binds uPAR. Furthermore, mouse studies were performed to determine whether dEGFATFKDEL was effective at inhibiting tumor growth in vivo. RESULTS: UMSCC-11B and NA, two head and neck squamous cell carcinomas, highly expressed EGFR. Both the carcinoma lines and the human vein endothelial cells were inhibited at sub-nanomolar concentrations by dEGFATFKDEL. The tumor studies showed that the tumors treated with dEGFATFKDEL were significantly inhibited whereas the negative control and untreated tumors progressed. In a separate in vivo study involving another carcinoma line, MDA-MB-231, the effectiveness of dEGFATFKDEL was confirmed. No toxicity was seen at the doses used in either of these mouse studies. CONCLUSIONS: This bispecific agent is effective in a mouse model of head and neck squamous cell carcinoma. Further study of this reagent for use in the treatment of carcinomas is warranted. PMID- 22818893 TI - Current strategies for the treatment of proximal humeral fractures: an analysis of a survey carried out at 348 hospitals in Germany, Austria, and Switzerland. AB - BACKGROUND: The therapeutic spectrum for the treatment of displaced proximal humeral fractures ranges from conservative therapy to head-preserving surgical interventions and joint replacement. This study initiated a survey on the current treatment options with regard to diagnostics, choice of therapy, and complications that are encountered at trauma surgeries and orthopedic hospitals in Germany, Austria, and Switzerland. MATERIALS AND METHODS: The survey included 743 hospitals. The questionnaire covered information on demographics, diagnostics, classification, therapy, and complications of proximal humeral fractures. RESULTS: The questionnaire was completed by 348 hospitals. Five of 6 hospitals treat more than 40% of the fractures surgically. The percentage distribution of the available implants is at 63.4% for angular stable plates, 30.9% for intramedullary nails, and 10.1% for fracture prostheses. The 5 complications reported most frequently were nonanatomic reduction (83%), implant perforation (73%), secondary displacement of the fracture (71%), avascular necrosis (67%), and implant-related impingement (59%). CONCLUSIONS: A preference for surgical treatment of proximal humeral fractures was found, with stabilization predominantly being attempted by the use of angle-stable implants. The 2 most common complications were "nonanatomic reduction of fractures" and the more specific problem of "implant perforation" when fixed-angle implants were used for treatment. PMID- 22818894 TI - Rotator cuff healing after continuous subacromial bupivacaine infusion: an in vivo rabbit study. AB - BACKGROUND: The objective of this study was to evaluate the effects of continuous subacromial bupivacaine infusion on supraspinatus muscle and rotator cuff tendon healing using gross, biomechanical, and histologic analyses. MATERIALS AND METHODS: Thirty-three New Zealand White rabbits underwent unilateral supraspinatus transection and rotator cuff repair (RCR). Rabbits were assigned to 1 of 3 groups: (1) RCR only, (2) RCR with continuous saline infusion for 48 hours, or (3) RCR with continuous 0.25% bupivacaine with epinephrine (1:200,000) infusion for 48 hours. Rabbits were euthanized postoperatively at 2 weeks (for histologic assessment) or 8 weeks (for biomechanical and histologic assessment). RESULTS: Tensile testing showed a significantly higher load to failure in intact tendons compared with repaired tendons (P < .01); however, no statistical differences were detected among RCR only, RCR saline, and RCR bupivacaine groups. Histologically, the enthesis of repaired tendons showed increased cellularity and disorganized collagen fibers compared with intact tendons, with no differences between treatment groups. Muscle histology demonstrated scattered degenerative muscle fibers at 2 weeks in RCR saline and RCR bupivacaine groups, but no degeneration was noted at 8 weeks. CONCLUSIONS: The healing supraspinatus tendons exposed to bupivacaine infusion showed similar histologic and biomechanical characteristics compared with untreated and saline-infused RCR groups. Muscle histology showed fiber damage at 2 weeks for the saline and bupivacaine-treated groups, with no apparent disruption at 8 weeks, suggesting a recovery process. Therefore, subacromial bupivacaine infusion in this rabbit rotator cuff model does not appear to impair muscle or tendon after acute injury and repair. PMID- 22818895 TI - Canonical Wnt signaling is required for Panax notoginseng saponin-mediated attenuation of the RANKL/OPG ratio in bone marrow stromal cells during osteogenic differentiation. AB - Panax notoginseng saponins (PNS) are known to regulate the osteogenic differentiation of bone marrow stromal cells (BMSCs). In the present study, we investigated whether PNS could promote the osteogenic differentiation of BMSCs through modulating the Wnt/beta-catenin signaling pathways, which are implicated in BMSCs osteogenesis. We found that PNS enhanced the mRNA expression of OPG, beta-catenin, and cyclin D1 while decreased the mRNA expression of RANKL and PPARgamma2. The actions of PNS on BMSCs were reversed (or partially) by DKK-1, a classical inhibitor of Wnt/beta-catenin signaling. These results suggest that PNS stimulating bone formation by promoting the proliferation and osteogenic differentiation of BMSCs, and could also protect the skeletal system by decreasing bone resorption through reduction of RANKL/OPG expression via Wnt/beta catenin signaling pathways. PMID- 22818896 TI - Bevacizumab for neovascular age-related macular degeneration in China. AB - OBJECTIVE: To evaluate 2 different dosing regimens of intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration (AMD) patients in China. DESIGN: Multicenter, randomized, prospective, open-label clinical trial. PARTICIPANTS: One hundred eighty-five patients with active neovascular AMD, exclusion of a macular scar, choroidal neovascularization not resulting from AMD, and polypoidal choroidal vasculopathy. INTERVENTION: Patients were assigned randomly to receive intravitreal injections of bevacizumab every 6 weeks for the first 3 injections followed by injections every 6 weeks (regimen A, n = 91) or every 12 weeks (regimen B, n = 94). MAIN OUTCOME MEASURES: The primary outcome measure was a comparison of the mean change in visual acuity from baseline. The secondary outcome measure was a comparison of the proportion of patients with a change in visual acuity of 15 letters or more. Adverse events were monitored. RESULTS: One-hundred eighty five patients were enrolled. At 48 weeks, the increase in the mean visual acuity measurements from baseline were 12.58 letters in regimen A and 10.06 letters in regimen B (P = 0.288). At 48 weeks, the percentage of eyes losing fewer than 15 letters was 96.2% in regimen A and 93.9% in regimen B (P = 0.720). At 48 weeks, the median decrease in central retinal thickness measurements from baseline was 119 MUm in regimen A and 60 MUm in regimen B (P = 0.221). Adverse events during the 48 weeks included anterior chamber inflammation in 17 patients (18.7%) from regimen A and 9 patients (9.6%) from regimen B (P = 0.075). There were no other notable ocular adverse events in either group. CONCLUSIONS: Intravitreal bevacizumab improved visual acuity and decreased macular thickness in patients with neovascular AMD when dosed either every 6 weeks or every 12 weeks after 3 doses given at 6-week intervals. Although there were no statistically significant differences between the 2 regimens, the results tended to favor the group dosed every 6 weeks (regimen A). PMID- 22818897 TI - [Mediastinal hibernoma: singular appearance on computed tomography]. AB - Hibernomas are very uncommon benign tumors of brown fat; they are rarely located within the thorax and are even rarer in the mediastinum. We present the case of a 14-year-old girl with a hibernoma seen on CT as a homogeneous fat density mass located in the anterior mediastinum. Histological study revealed the typical microscopic characteristics of these tumors. To our knowledge, this is the first report of these CT imaging characteristics in association with a hibernoma. PMID- 22818898 TI - [Whole-body magnetic resonance imaging in a patient with an occult abdominal neuroblastoma and opsoclonus-myoclonus syndrome]. AB - Opsoclonus-myoclonus syndrome is a rare neurological disorder. In children, the etiology varies, although it is a paraneoplastic manifestation (mainly of neuroblastoma) in 40% to 80% of cases. Whole-body MRI promises to be a powerful tool in the search for a possible primary tumor in this condition for which the diagnostic algorithm is yet to be established. We present the case of a two-year old boy with signs of opsoclonus-myoclonus syndrome in whom a retroperitoneal neuroblastoma was detected by whole-body MRI. PMID- 22818899 TI - [Natural history of lumbar disc hernias: does gadolinium enhancement have any prognostic value?]. AB - OBJECTIVES: To evaluate the percentage of disc hernias that have disappeared after one year of follow-up and the time to disappearance. To determine whether gadolinium enhancement is useful for predicting whether the hernia will disappear. To analyze whether the pattern of enhancement can help predict whether the fragment will disappear. MATERIAL AND METHODS: This prospective study included 118 patients with acute symptoms of lumbosciatica and a herniated disc diagnosed by CT. In 72 patients, we performed gadolinium-enhanced MRI every 6 months for one year or until the herniation disappeared; we related the findings of protrusion, extrusion, and the enhancement pattern with the disappearance or persistence of herniated disc material. We analyzed the results with univariate and multivariate statistics. RESULTS: The 59% of the hernias disappeared within 1 year of follow-up and 66% disappeared within the first 8 months of follow-up. The 83% of the extruded hernias disappeared, and this was significant in the multivariate analysis (P<.005). The absence of enhancement was significantly associated with the persistence of the hernia in the univariate analysis. The enhancement pattern was not useful for predicting whether the hernia would disappear. Five hernias disappeared within the first two months. CONCLUSIONS: A high percentage of disc hernias disappear. We found a significant association between extrusion and disappearance but no correlation between the pattern of gadolinium uptake and the disappearance of the hernia. PMID- 22818900 TI - The brachial plexus outcome measure: development, internal consistency, and construct validity. AB - PURPOSE: The purpose of this article was to report the development of a new assessment tool, the Brachial Plexus Outcome Measure (BPOM) and the evaluation of its internal consistency and construct validity. METHODS: A retrospective case series of children aged 4-19 years with obstetrical brachial plexus palsy (OBPP) was conducted. Intraclass coefficients were calculated for the BPOM Activity Scale items. Correlation between the Active Movement Scale (AMS) and BPOM Activity Scale scores were conducted to determine the convergent validity. RESULTS: The BPOM Activity Scale items (N=306) had good internal consistency (Cronbach's alpha=0.87). A strong correlation between the BPOM Activity Scale and AMS (n=284) was found (r=0.71, p=0.001, alpha=0.05). CONCLUSIONS: The BPOM Activity Scale demonstrates good internal consistency and construct validity as a discriminative functional outcome measure in children with OBPP. LEVEL OF EVIDENCE: IV. PMID- 22818901 TI - Unravelling fungal immunity through primary immune deficiencies. AB - Fungal infections affect individuals with an impaired immune system and are on the increase, often with serious consequences. Recent studies in patients with primary immune deficiencies (PIDs) have led to important breakthroughs in our understanding of the different, mutually exclusive pathways underlying immunity to mucocutaneous as opposed to invasive fungal infections. Patients with defects affecting segments of innate (dectin-1, CARD9, IL12RB1) or adaptive immunity (interleukin (IL)17-F, IL-17 receptor, STAT1, STAT3, antibodies to Th-17 cytokines) that disrupt the Th-17 pathway, are unable to clear superficial Candida or Dermatophyte infections and suffer with chronic mucocutaneous candidiasis (CMC). Patients with defects affecting phagocyte function (oxidative killing, neutropenia) or a severely impaired immune system are at risk of developing invasive, often fatal fungal disease with Aspergillus, Candida, Cryptococcai and other fungi. PIDs are hugely beneficial in promoting our knowledge of fungal immunity and provide important contributions toward evidence based diagnosis and improved patient care. PMID- 22818902 TI - Reduced multisensory facilitation in persons with autism. AB - Although the literature concerning auditory and visual perceptual capabilities in the autism spectrum is growing, our understanding of multisensory integration (MSI) is rather limited. In the present study, we assessed MSI in autism by measuring whether participants benefited from an auditory cue presented in synchrony with the color change of a target during a complex visual search task. The synchronous auditory pip typically increases search efficacy (pip and pop effect), indicative of the beneficial use of sensory input from both modalities. We found that for conditions without auditory information, autistic participants were better at visual search compared to neurotypical participants. Importantly, search efficiency was increased by the presence of auditory pip for neurotypical participants only. The simultaneous occurrence of superior unimodal performance with altered audio-visual integration in autism suggests autonomous sensory processing in this population. PMID- 22818903 TI - Lateralized processing of false memories and pseudoneglect in aging. AB - Aging is associated with higher propensity to false memories and decreased retrieval of previously studied items. When young adults (YA) perform on a lateralized version of the Deese-Roediger-McDermott (DRM) paradigm, the right cerebral hemisphere (RH) is more sensitive than the left (LH) to false memories, suggesting hemispheric imbalance in the cerebral mechanisms supporting semantic and episodic memory processes. Since cerebral asymmetries tend to be reduced with age, we surmised that behavioral asymmetries in the generation of false memories would be diminished with aging. To probe this hypothesis, a lateralized version of the DRM paradigm was administered to healthy older adults (OA) and YA. During the encoding phase, lists of semantically associated words were memorized. During the retrieval session, targets (previously seen words), lures (LU) (never seen strongly semantically related words) and distracters (never seen, unrelated words) were briefly displayed either in the left or right visual fields, thus primarily stimulating the RH or LH, respectively. Participants had to decide whether the word was previously studied (Old/New), but also whether they had a strong episodic recollection (Remember) or a mere feeling of familiarity (Know) about Old words. In line with our predictions, false memories were globally higher in OA than YA, and vivid false recollections (i.e., Remember responses) were higher when LU were presented in the RH in YA, but not in OA. Additionally, we found significant correlations between YA participants' Familiarity scores and leftward attentional bias as previously evidenced using a visuospatial landmark task (Schmitz and Peigneux, 2011), an effect not present in OA. This result is in line with the hypothesis of an interplay between attentional resources allocated to visuospatial and memory processes, suggesting a memory pseudoneglect phenomenon that would be altered with aging. PMID- 22818904 TI - Correlation of integrity of cone outer segment tips line with retinal sensitivity after half-dose photodynamic therapy for chronic central serous chorioretinopathy. AB - PURPOSE: To investigate the relationship between the integrity of the photoreceptor microstructures and retinal sensitivity after half-dose photodynamic therapy (PDT) in eyes with chronic central serous chorioretinopathy (CSC). DESIGN: Prospective, noncomparative, interventional case series. METHODS: Thirteen eyes of 13 patients with chronic CSC who had received half-dose verteporfin PDT were studied. The best-corrected visual acuity (BCVA), macular retinal sensitivity in the central 12 degrees, and optical coherence tomographic (OCT) findings were evaluated at baseline and at 1, 3, 6, and 12 months after the half-dose PDT. The integrities of the external limiting membrane (ELM), the inner segment/outer segment junction (IS/OS) line, and the cone outer segment tips (COST) line were determined. The retinal sensitivity was determined by MP-1 microperimetry. RESULTS: The serous retinal detachment (SRD) was completely resolved in 11 eyes at 1 month and in 1 eye at 3 months. The remaining eye had a persistent SRD throughout the follow-up period. The mean retinal sensitivity was significantly better at 1, 3, 6, and 12 months after the half-dose PDT than at baseline. Before the PDT, 12 eyes had a continuous ELM and 1 eye had a fragmented ELM. The number of eyes with an intact IS/OS line and COST line increased with increasing post-PDT time. At 12 months after PDT, the IS/OS line was detected in 11 eyes and the COST line in 6 eyes. At 6 and 12 months, the retinal sensitivity was significantly higher in eyes with an intact COST line and IS/OS lines than in eyes with an intact IS/OS line only. However, no difference was found in the visual acuity of these 2 groups. The 1 eye with a persistent SRD and another eye with fragmented ELM and absent IS/OS and COST lines through the follow-up periods were associated with poor retinal sensitivity of 8.5 dB and 10.9 dB respectively. CONCLUSIONS: Our findings show that there is a significant improvement in the macular sensitivity after half-dose PDT in eyes with chronic CSC. The improvement was correlated with the recovery of the IS/OS and COST lines at 6 and 12 months. PMID- 22818905 TI - Intraindividual comparison of visual performance after posterior chamber phakic intraocular lens with and without a central hole implantation for moderate to high myopia. AB - PURPOSE: To compare postoperative visual performance after implantable Collamer lenses with and without a central hole (Hole ICL and conventional ICL) are implanted to correct moderate to high myopia. DESIGN: Prospective intraindividual comparative study. PATIENTS AND METHODS: This study evaluated 58 eyes of 29 patients with spherical equivalents of -7.55 +/- 2.09 diopters (D) [mean +/- standard deviation] who underwent Hole ICL implantation in one eye and conventional ICL implantation in the other eye by randomization assignment. Ocular higher-order aberrations (HOAs) and contrast sensitivity (CS) function were measured by Hartmann-Shack aberrometry and a contrast sensitivity unit before and 3 months after surgery, respectively. From the contrast sensitivity, the area under the log CS function was calculated. RESULTS: For 4-mm and 6-mm pupils, the changes after Hole ICL implantation in coma-like aberrations, spherical-like aberrations, and total HOAs are similar to those after conventional ICL implantation (P > .05, Wilcoxon signed rank test). The postoperative area under the log CS function was significantly increased after Hole ICL implantation (P < .05), and was equivalent to that after conventional ICL implantation under photopic, mesopic, or mesopic with glare conditions. Subjective symptoms such as glare or halo were also essentially equivalent after Hole ICL and conventional ICL implantation. CONCLUSIONS: A newly developed Hole ICL implantation appears to be equivalent in the induction of HOAs and CS function to conventional ICL implantation for the correction of moderate to high myopia, suggesting its viability as a surgical option for the treatment of such eyes, because it does not require additional peripheral iridotomies and may also reduce the risk of cataract formation. PMID- 22818907 TI - The relation between visual performance and clinical ocular manifestations in Stevens-Johnson syndrome. AB - PURPOSE: To investigate the relation between visual function, clinical findings, and visual symptoms in Stevens-Johnson syndrome (SJS) and to compare the results with Sjogren syndrome (SS) patients and normal subjects. DESIGN: Cross-sectional comparative study. METHODS: One hundred fifteen eyes of 59 consecutive patients with SJS and toxic epidermal necrolysis (TEN), 208 eyes of 104 healthy normal subjects, and 132 eyes of 66 SS patients were investigated in this multicenter study. All study subjects underwent tear function and ocular surface examinations, Landolt and functional visual acuity examinations, and the Japanese version of the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire). RESULTS: The mean ocular surface grading scores were significantly higher and the mean score of all 12 NEI VFQ subscales was significantly lower in the SJS patients compared to the SS patients and the normal subjects (P < .05). The conventional and functional logarithm of minimal angle of resolution (logMAR) visual acuities in SJS patients with minimal corneal complications were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. The conventional and functional logMAR visual acuities and the mean ocular surface grading scores in SJS with aqueous deficiency were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. Strong correlations between best-corrected logMAR functional visual acuities and either ocular surface grading scores or the composite NEI VFQ-25 scores were observed. CONCLUSIONS: The functional visual acuity examination reflects the severity of clinical ocular surface findings and vision-related quality of life more than the standard conventional visual acuity in SJS. PMID- 22818906 TI - The association of consumption of fruits/vegetables with decreased risk of glaucoma among older African-American women in the study of osteoporotic fractures. AB - PURPOSE: To explore the association between consumption of fruits and vegetables and the presence of glaucoma in older African-American women. DESIGN: Cross sectional study. METHODS: Disc photographs and suprathreshold visual fields were obtained from the 662 African-American participants in the Study of Osteoporotic Fractures. Masked, trained readers graded all discs, and 2 glaucoma specialists reviewed photographs and visual fields. The Block Food Frequency Questionnaire assessed food consumption. Relationships between selected fruit/vegetable/nutrient consumption and glaucoma were evaluated using logistic regression models after adjusting for potential confounders. RESULTS: After excluding women missing Food Frequency Questionnaire and disc data, 584 African American women (88.2% of total African-American cohort) were included. Glaucoma was diagnosed in at least 1 eye in 77 subjects (13%). Women who ate 3 or more servings/day of fruits/fruit juices were 79% (odds ratio [OR] = 0.21; 95% confidence interval [CI]: 0.08-0.60) less likely to have glaucoma than women who ate less than 1 serving/day. Women who consumed more than 2 servings/week of fresh oranges (OR = 0.18; 95% CI: 0.06-0.51) and peaches (OR = 0.30; 95% CI: 0.13 0.67) had a decreased odds of glaucoma compared to those consuming less than 1 serving/week. For vegetables, >1 serving/week compared to <=1 serving/month of collard greens/kale decreased the odds of glaucoma by 57% (OR = 0.43; 95% CI: 0.21-0.85). There was a protective trend against glaucoma in those consuming more fruit/fruit juices (P = .023), fresh oranges (P = .002), fresh peaches (P = .002), and collard greens/kale (P = .014). Higher consumption of carrots (P = .061) and spinach (P = .094) also showed some associations. Individual nutrient intake from food sources found protective trends with higher intakes of vitamin A (P = .011), vitamin C (P = .018), and alpha-carotene (P = .021), and close to statistically significant trends with beta-carotene (P = .052), folate (P = .056), and lutein/zeaxanthin (P = .077). CONCLUSION: Higher intake of certain fruits and vegetables high in vitamins A and C and carotenoids may be associated with a decreased likelihood of glaucoma in older African-American women. Randomized controlled trials are needed to determine whether the intake of specific nutrients changes the risk of glaucoma. PMID- 22818908 TI - The epidermal growth factor receptor as a therapeutic target in epithelial ovarian cancer. AB - A majority of patients with ovarian carcinoma who receive conventional treatment of surgical staging and platinum-based chemotherapy recur and ultimately succumb to their diseases. Novel therapies that target specific pathways involved in ovarian tumorigenesis are rapidly emerging. The epidermal growth factor receptor (EGFR) is overexpressed in 30-98% of epithelial ovarian carcinoma (EOC), and the signaling cascades activated are related with cell proliferation, migration and invasion, and angiogenesis, as well as resistance to cell apoptosis. Various trials are ongoing focusing on EGFR as an attractive target in treatment of EOC. Anti-EGFR monoclonal antibodies (MAbs), cetuximab and panitumumab, and tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, are the most advanced in clinical development. The available data suggests that MAbs and TKIs only show marginal activity when they are used alone, but combination with platinum-based chemotherapy can induce elevated overall response rate in recurrent EOC patients. Consequently, mechanisms for intrinsic and extrinsic resistance have been explored due to the poor clinical response to EGFR-targeted therapy. Careful consideration of these clinical studies and the possible mechanisms involved in resistance can provide evidence for improvements in subsequent research. Identification of responder profiles and development of rational regimen of combination therapy of EGFR-targeted therapy with other effective treatment modalities may eventually bring about substantial progress in the treatment of epithelial ovarian cancers. PMID- 22818909 TI - Angiographic and clinical outcomes of stent postdilatation in ST-elevation myocardial infarction. AB - INTRODUCTION: Stent postdilatation is commonly performed to optimise stent deployment during percutaneous coronary intervention (PCI). However, it is controversial in the setting of acute myocardial infarction (AMI) due to the theoretically increased risk of thrombus embolization causing no-reflow. This study aimed to evaluate the immediate angiographic effects and long-term clinical outcomes of stent postdilatation in the setting of ST-elevation myocardial infarction (STEMI). METHODS: This was a single-centre retrospective observational study involving patients who presented with STEMI and received primary PCI, from July 2009 till June 2010. The angiographic endpoints were final TIMI coronary flow (TMF) and TIMI myocardial perfusion (TMP) score. The clinical endpoint was a composite endpoint of major adverse cardiac events (MACEs) i.e. AMI, target vessel revascularisation or cardiac death at one, six and twelve months after PCI. RESULTS: One hundred and sixty patients with a mean age of 62 years were included in this study. Seventy-one patients (44.4%) had stent postdilatation and 89 patients (55.6%) did not. Patient demographics, risk factors, clinical presentation and baseline angiographic and procedural characteristics, were similar among these two subgroups. There was also no significant difference in the proportions of patients achieving grade III in final TMF (60/71 vs. 74/89, respectively, p>0.05) and final TMP (52/71 vs. 64/89, respectively, p>0.05), as well as the MACE-free survival probability by Kaplan-Meier estimate (85.1% vs. 86.9%, p=0.95), between the two subgroups. CONCLUSION: Stent postdilatation does not seem to have any detrimental effects on patients' final angiographic results and long-term clinical outcomes, in the setting of STEMI. PMID- 22818910 TI - Examining the concept of convenient collection: an application to extended producer responsibility and product stewardship frameworks. AB - Increasingly, Extended Producer Responsibility (EPR) and Product Stewardship (PS) frameworks are being adopted as a preferred policy approach to promote cost effective diversion and recovery of post-consumer solid waste. Because the application of EPR/PS generally requires the creation of a separate and often parallel collection and/or management system, key to increasing the amount of waste recovered is to maximize the convenience of the collection system to maximize consumer participation. Convenient collection is often mandated in EPR/PS laws, however it is not defined. Convenience is a subjective construct rendering it extremely difficult to define. However, based on a dissection of post-consumer collection efforts under a generic EPR/PS system, this paper identifies and examines five categories of convenience - knowledge requirements, proximity to a collection site, opportunity to drop-off materials, the draw of the collection site, and the ease of the process-and the various factors of convenience within each of these categories. By using a simplified multiple criteria decision analysis, this paper proposes a performance matrix of criteria of convenience. Stakeholders can use this matrix to assist in the design, assessment, and/or implementation of a convenient post-consumer collection system under an EPR/PS framework. PMID- 22818911 TI - Assessment of toxicity of polycyclic aromatic hydrocarbons in sediments of Kaohsiung Harbor, Taiwan. AB - Polycyclic aromatic hydrocarbon (PAH) contamination and toxicity levels in the surface sediments of Kaohsiung Harbor, Taiwan were evaluated using sediment quality guidelines (SQGs) and toxic equivalent factors. Eighty surface sediment samples were collected from twenty locations in Kaohsiung Harbor for PAH analysis using gas chromatography/mass spectrometry (GC/MS). Concentrations of total PAHs varies from 34.0 to 16,700 ng/g with a mean concentration of 1490+/-2689 ng/g. The spatial distribution of PAHs reveals that PAH concentration is relatively higher in the river mouth regions, especially in the Salt River mouth where it gradually diminishes toward the harbor region. Distributions of PAHs, during both the wet and dry seasons, show that PAHs are more easily disbursed in the receiving sea water thereby leading to a wider range of chemical distribution. Hence, most of the chemicals accumulate in the harbor water channel. Diagnostic ratios show that the possible source of PAHs in the southern industrial area of the harbor could be coal combustion while in the other zones it could be petroleum combustion and/or a mixed sources. The toxic equivalent concentrations (TEQ(carc)) of PAHs varied from 3.9 to 1970 ng TEQ/g. The higher total TEQ(carc) values were found in the southern industrial area of the harbor. As compared with US sediment quality guidelines, the observed levels of PAHs in the industrial zone exceeded the effects range low (ERL), which will eventually cause acute biological damage. Based on the analyses using the SQGs, surface sediments from Kaohsiung Harbor were moderately contaminated and most samples have a low probability of toxicity pollution, except for the Salt River mouth situated in the south Kaohsiung Harbor area. This area has a medium to high probability of toxicity pollution. PMID- 22818912 TI - Thiamine deficiency: a viable hypothesis for paralytic syndrome in Baltic birds. Commentary on Sonne et al., 2012. A review of the factors causing paralysis in wild birds: implications for the paralytic syndrome observed in the Baltic Sea. Science of the Total Environment 416:32-39. PMID- 22818913 TI - Genetic consequences of programmed genome rearrangement. AB - The lamprey (Petromyzon marinus) undergoes developmentally programmed genome rearrangements that mediate deletion of~20% of germline DNA from somatic cells during early embryogenesis. This genomic differentiation of germline and soma is intriguing, because the germline plays a unique biological role wherein it must possess the ability to undergo meiotic recombination and the capacity to differentiate into every cell type. These evolutionarily indispensable functions set the germline at odds with somatic tissues, because factors that promote recombination and pluripotency can potentially disrupt genome integrity or specification of cell fate when misexpressed in somatic cell lineages (e.g., in oncogenesis). Here, we describe the development of new genomic and transcriptomic resources for lamprey and use these to identify hundreds of genes that are targeted for programmed deletion from somatic cell lineages. Transcriptome sequencing and targeted validation studies further confirm that somatically deleted genes function both in adult (meiotic) germline and in the development of primordial germ cells during embryogenesis. Inferred functional information from deleted regions indicates that developmentally programmed rearrangement serves as a (perhaps ancient) biological strategy to ensure segregation of pluripotency functions to the germline, effectively eliminating the potential for somatic misexpression. PMID- 22818914 TI - Nek9 phosphorylation of NEDD1/GCP-WD contributes to Plk1 control of gamma-tubulin recruitment to the mitotic centrosome. AB - The accumulation of gamma-tubulin at the centrosomes during maturation is a key mechanism that ensures the formation of two dense microtubule (MT) asters in cells entering mitosis, defining spindle pole positioning and ensuring the faithful outcome of cell division. Centrosomal gamma-tubulin recruitment depends on the adaptor protein NEDD1/GCP-WD and is controlled by the kinase Plk1. Surprisingly, and although Plk1 binds and phosphorylates NEDD1 at multiple sites, the mechanism by which this kinase promotes the centrosomal recruitment of gamma tubulin has remained elusive. Using Xenopus egg extracts and mammalian cells, we now show that it involves Nek9, a NIMA-family kinase required for normal mitotic progression and spindle organization. Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of gamma-tubulin to the centrosome in mitotic cells. This role of Nek9 requires its activation by Plk1-dependent phosphorylation but is independent from the downstream related kinases Nek6 and Nek7. Our data contribute to understand the mechanism by which Plk1 promotes the recruitment of gamma-tubulin to the centrosome in dividing cells and position Nek9 as a key regulator of centrosome maturation. PMID- 22818916 TI - Mechanical regulation of auxin-mediated growth. AB - BACKGROUND: The phytohormone auxin is a primary regulator of growth and developmental pattern formation in plants. Auxin accumulates at specific sites (e.g., organ primordia) and induces localized growth within a tissue. Auxin also mediates developmental responses to intrinsic and external physical stimuli; however, exactly how mechanics influences auxin distribution is unknown. RESULTS: Here we show that mechanical strain can regulate auxin transport and accumulation in the tomato shoot apex, where new leaves emerge and rapidly grow. Modification of turgor pressure, application of external force, and artificial growth induction collectively show that the amount and intracellular localization of the auxin efflux carrier PIN1 are sensitive to mechanical alterations. In general, the more strained the tissue was, the more PIN1 was present per cell and the higher the proportion localized to the plasma membrane. Modulation of the membrane properties alone was sufficient to explain most of the mechanical effects. CONCLUSIONS: Our experiments support the hypothesis that the plasma membrane acts as a sensor of tissue mechanics that translates the cell wall strain into cellular responses, such as the intracellular localization of membrane-embedded proteins. One implication of this fundamental mechanism is the mechanical enhancement of auxin-mediated growth in young organ primordia. We propose that growth-induced mechanical strain upregulates PIN1 function and auxin accumulation, thereby promoting further growth, in a robust positive feedback loop. PMID- 22818915 TI - A molecular framework of light-controlled phytohormone action in Arabidopsis. AB - Environmental changes strongly affect plant growth and development. Phytohormones, endogenous plant-made small molecules such as ethylene, regulate a wide range of processes throughout the lifetime of plants. The ability of plants to integrate external signals with endogenous regulatory pathways is vital for their survival. Ethylene has been found to suppress hypocotyl elongation in darkness while promoting it in light. How ethylene regulates hypocotyl elongation in such opposite ways is largely unknown. In particular, how light modulates and even reverses the function of ethylene has yet to be characterized. Here we show that the basic-helix-loop-helix transcription factor phytochrome-interacting factor 3 (PIF3) is directly activated by ETHYLENE-INSENSITIVE 3 (EIN3) and is indispensible for ethylene-induced hypocotyl elongation in light. Ethylene via EIN3 concomitantly activates two contrasting pathways: the PIF3-dependent growth promoting pathway and an ethylene response factor 1 (ERF1)-mediated growth inhibiting pathway. In the light, growth-promoting PIFs are limiting due to light dependent destabilization, and thus ethylene stimulates growth under these conditions. In contrast, ERF1 is destabilized, and thus limiting, under dark conditions, explaining why ethylene inhibits growth in the dark. Our findings provide a mechanistic insight into how light modulates internal hormone-regulated plant growth. PMID- 22818931 TI - Rethinking our approach to physical activity. PMID- 22818932 TI - Physical activity: more of the same is not enough. PMID- 22818933 TI - Stressing harms of physical inactivity to promote exercise. PMID- 22818934 TI - Physical activity for people with disabilities. PMID- 22818935 TI - Policies to promote physical activity in Brazil. PMID- 22818936 TI - Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. AB - BACKGROUND: Strong evidence shows that physical inactivity increases the risk of many adverse health conditions, including major non-communicable diseases such as coronary heart disease, type 2 diabetes, and breast and colon cancers, and shortens life expectancy. Because much of the world's population is inactive, this link presents a major public health issue. We aimed to quantify the eff ect of physical inactivity on these major non-communicable diseases by estimating how much disease could be averted if inactive people were to become active and to estimate gain in life expectancy at the population level. METHODS: For our analysis of burden of disease, we calculated population attributable fractions (PAFs) associated with physical inactivity using conservative assumptions for each of the major non-communicable diseases, by country, to estimate how much disease could be averted if physical inactivity were eliminated. We used life table analysis to estimate gains in life expectancy of the population. FINDINGS: Worldwide, we estimate that physical inactivity causes 6% (ranging from 3.2% in southeast Asia to 7.8% in the eastern Mediterranean region) of the burden of disease from coronary heart disease, 7% (3.9-9.6) of type 2 diabetes, 10% (5.6 14.1) of breast cancer, and 10% (5.7-13.8) of colon cancer. Inactivity causes 9% (range 5.1-12.5) of premature mortality, or more than 5.3 million of the 57 million deaths that occurred worldwide in 2008. If inactivity were not eliminated, but decreased instead by 10% or 25%, more than 533 000 and more than 1.3 million deaths, respectively, could be averted every year. We estimated that elimination of physical inactivity would increase the life expectancy of the world's population by 0.68 (range 0.41-0.95) years. INTERPRETATION: Physical inactivity has a major health eff ect worldwide. Decrease in or removal of this unhealthy behaviour could improve health substantially. FUNDING: None. PMID- 22818937 TI - Global physical activity levels: surveillance progress, pitfalls, and prospects. AB - To implement effective non-communicable disease prevention programmes, policy makers need data for physical activity levels and trends. In this report, we describe physical activity levels worldwide with data for adults (15 years or older) from 122 countries and for adolescents (13-15-years-old) from 105 countries. Worldwide, 31.1% (95% CI 30.9-31.2) of adults are physically inactive, with proportions ranging from 17.0% (16.8-17.2) in southeast Asia to about 43% in the Americas and the eastern Mediterranean. Inactivity rises with age, is higher in women than in men, and is increased in high-income countries. The proportion of 13-15-year-olds doing fewer than 60 min of physical activity of moderate to vigorous intensity per day is 80.3% (80.1-80.5); boys are more active than are girls. Continued improvement in monitoring of physical activity would help to guide development of policies and programmes to increase activity levels and to reduce the burden of non-communicable diseases. PMID- 22818938 TI - Correlates of physical activity: why are some people physically active and others not? AB - Physical inactivity is an important contributor to non-communicable diseases in countries of high income, and increasingly so in those of low and middle income. Understanding why people are physically active or inactive contributes to evidence-based planning of public health interventions, because effective programmes will target factors known to cause inactivity. Research into correlates (factors associated with activity) or determinants (those with a causal relationship) has burgeoned in the past two decades, but has mostly focused on individual-level factors in high-income countries. It has shown that age, sex, health status, self-efficacy, and motivation are associated with physical activity. Ecological models take a broad view of health behaviour causation, with the social and physical environment included as contributors to physical inactivity, particularly those outside the health sector, such as urban planning, transportation systems, and parks and trails. New areas of determinants research have identified genetic factors contributing to the propensity to be physically active, and evolutionary factors and obesity that might predispose to inactivity, and have explored the longitudinal tracking of physical activity throughout life. An understanding of correlates and determinants, especially in countries of low and middle income, could reduce the eff ect of future epidemics of inactivity and contribute to effective global prevention of non-communicable diseases. PMID- 22818939 TI - Evidence-based intervention in physical activity: lessons from around the world. AB - Promotion of physical activity is a priority for health agencies. We searched for reviews of physical activity interventions, published between 2000 and 2011, and identified effective, promising, or emerging interventions from around the world. The informational approaches of community-wide and mass media campaigns, and short physical activity messages targeting key community sites are recommended. Behavioural and social approaches are effective, introducing social support for physical activity within communities and worksites, and school-based strategies that encompass physical education, classroom activities, after-school sports, and active transport. Recommended environmental and policy approaches include creation and improvement of access to places for physical activity with informational outreach activities, community-scale and street-scale urban design and land use, active transport policy and practices, and community-wide policies and planning. Thus, many approaches lead to acceptable increases in physical activity among people of various ages, and from different social groups, countries, and communities. PMID- 22818941 TI - The pandemic of physical inactivity: global action for public health. AB - Physical inactivity is the fourth leading cause of death worldwide. We summarise present global efforts to counteract this problem and point the way forward to address the pandemic of physical inactivity. Although evidence for the benefits of physical activity for health has been available since the 1950s, promotion to improve the health of populations has lagged in relation to the available evidence and has only recently developed an identifiable infrastructure, including efforts in planning, policy, leadership and advocacy, workforce training and development, and monitoring and surveillance. The reasons for this late start are myriad, multifactorial, and complex. This infrastructure should continue to be formed, intersectoral approaches are essential to advance, and advocacy remains a key pillar. Although there is a need to build global capacity based on the present foundations, a systems approach that focuses on populations and the complex interactions among the correlates of physical inactivity, rather than solely a behavioural science approach focusing on individuals, is the way forward to increase physical activity worldwide. PMID- 22818940 TI - The implications of megatrends in information and communication technology and transportation for changes in global physical activity. AB - Physical inactivity accounts for more than 3 million deaths per year, most from non-communicable diseases in low-income and middle-income countries. We used reviews of physical activity interventions and a simulation model to examine how megatrends in information and communication technology and transportation directly and indirectly affect levels of physical activity across countries of low, middle, and high income. The model suggested that the direct and potentiating eff ects of information and communication technology, especially mobile phones, are nearly equal in magnitude to the mean eff ects of planned physical activity interventions. The greatest potential to increase population physical activity might thus be in creation of synergistic policies in sectors outside health including communication and transportation. However, there remains a glaring mismatch between where studies on physical activity interventions are undertaken and where the potential lies in low-income and middle-income countries for population-level effects that will truly affect global health. PMID- 22818943 TI - Cutaneous reactions induced by oxcarbazepine in Southern Han Chinese: incidence, features, risk factors and relation to HLA-B alleles. AB - PURPOSE: Oxcarbazepine (OXC) is a promising alternative for patients who cannot tolerate carbamazepine. Recently, however, it has been reported that OXC-induced cutaneous adverse drug reactions (cADRs) are prevalent and may lead to drug discontinuation. Additionally, these reactions are thought to be associated with HLA-B*1502. This study aims to investigate the incidence, features and risk factors of OXC-cADRs, and to explore their relation to HLA-B alleles in Southern Han Chinese. METHODS: A prospective study was performed to investigate the incidence, features and risk factors of OXC-cADRs, in which 252 new users were recruited. To examine the association between OXC-cADRs and HLA-B alleles, 14 maculopapular eruption (MPE) cases, including 9 additional cases beyond this prospective observation, were genotyped by PCR-SSP and sequencing. Thirty-five OXC-tolerant patients served as controls. RESULTS: Five patients (2.0%) developed an OXC-cADR, and all were mild MPE. History of other AED allergy (p=0.005, OR=121.23) and non-AED allergy (p=0.006, OR=59.92) were significant risk factors for OXC-cADRs in multivariate logistic regression analysis. Only one patient with OXC-MPE was positive for HLA-B*1502; and the frequency of HLA-B*1502 in OXC-MPE did not differ significantly from that in OXC-tolerant controls. Four HLA-B*1302 alleles were detected in OXC-MPE cases, which was significantly different from that in general population of southern Han Chinese (p=0.001, OR=7.83). CONCLUSIONS: The incidence of OXC-induced cADRs was low, and no severe reactions occurred. Patients with a history of allergy are more susceptible to OXC-cADRs. No significant association between HLA-B*1502 and OXC-MPE was found. The associations between OXC-MPE and HLA alleles warrant further studies. PMID- 22818942 TI - Engineered T cells for anti-cancer therapy. AB - Recent advances enabling efficient delivery of transgenes to human T cells have created opportunities to address obstacles that previously hindered the application of T cell therapy to cancer. Modification of T cells with transgenes encoding TCRs or chimeric antigen receptors allows tumor specificity to be conferred on functionally distinct T cell subsets, and incorporation of costimulatory molecules or cytokines can enable engineered T cells to bypass local and systemic tolerance mechanisms. Clinical studies of genetically modified T cell therapy for cancer have shown notable success; however, these trials demonstrate that tumor therapy with engineered high avidity tumor-reactive T cells may be accompanied by significant on-target toxicity, necessitating careful selection of target antigens and development of strategies to eliminate transferred cells. PMID- 22818944 TI - Challenges in the simultaneous quantitation of sumatriptan and naproxen in human plasma: application to a bioequivalence study. AB - An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of sumatriptan and naproxen in human plasma using naratriptan and indomethacin as the internal standards (ISs). The plasma samples were prepared by solid phase extraction on Phenomenex Strata-X cartridges using 100 MUL human plasma sample. Chromatography was carried out on Waters Acquity UPLC BEH C18 (50 mm * 2.1 mm, 1.7 MUm) analytical column under isocratic conditions using a mobile phase consisting of methanol-acetonitrile-4.0mM ammonium acetate (70:10:20, v/v/v). The precursor >product ion transition for both the analytes and ISs was monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and positive ionization mode. The method was validated over a wide dynamic concentration range of 0.050-100 ng/mL for sumatriptan and 0.050-100 MUg/mL for naproxen. Matrix effect was assessed by post-column analyte infusion and the extraction recovery was >95.0% across four quality control levels for both the analytes. Stability was evaluated under different conditions including bench top, processed sample, freeze and thaw and long term. The method was applied to support a bioequivalence study of 85 mg sumatriptan+500 mg naproxen sodium fixed dose formulation in 28 healthy Indian subjects. Assay reproducibility was demonstrated by reanalysis of 123 incurred samples. PMID- 22818945 TI - Validation of a sequential extraction and liquid chromatography-tandem mass spectrometric method for determination of dihydrotestosterone, androstanediol and androstanediol-glucuronide in prostate tissues. AB - Androgens are key mediators of prostate development and function, a role that extends to the development of prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In prostate, DHT is the major androgen and reduction and glucuronidation are the major metabolic pathways for DHT elimination. A streamlined method for quantitation of dihydrotestosterone (DHT), 5alpha-androstan-3alpha,17beta-diol (3alpha-diol), and 3alpha-diol glucuronide (diol-gluc) was established and validated for use with archived prostate tissue specimens to facilitate examination of the roles of the underlying metabolism. This involved a sequential 70/30 hexane/ethyl acetate (hex/EtOAc) extraction of steroids, followed by an ethyl acetate extraction for diol-gluc. Derivatization of the hex/EtOAc fraction with2-fluoro-1-methylpyridinium p-toluene-4-sulfonate (FMP) was used to enhance sensitivity for hydroxyl steroids and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was utilized for analysis of both fractions. The method was validated with calibration standards followed by recovery assessment from spiked samples of BPH and normal prostate. Lower limits of quantitation (LLOQ) were 50 pg/g, 20 pg/g and 100 pg/g for DHT, 3alpha-diol and diol-gluc, respectively for extracts from 50mg equivalents of tissue. Prepared samples were stable for up to three weeks at 4 degrees C and 37 degrees C. The method provides excellent sensitivity and selectivity for determination of tissue levels of DHT, 3alpha-diol, and diol-gluc. Furthermore, this protocol can easily be extended to other hydroxyl steroids, is relatively straightforward to perform and is an effective tool for assessing steroid levels in archived clinical prostate samples. PMID- 22818946 TI - Classifying developmental trajectories over time should be done with great caution: a comparison between methods. AB - OBJECTIVE: In the analysis of data from longitudinal cohort studies, there is a growing interest in the analysis of developmental trajectories in subpopulations of the cohort under study. There are different advanced statistical methods available to analyze these trajectories, but in the epidemiologic literature, most of those are never used. The purpose of the present study is to compare five statistical methods to detect developmental trajectories in a longitudinal epidemiological data set. STUDY DESIGN AND SETTING: All five statistical methods (K-means clustering, a "two-step" approach with mixed modeling and K-means clustering, latent class analysis [LCA], latent class growth analysis [LCGA], and latent class growth mixture modeling [LCGMM]) were performed on a real-life data set and two manipulated data sets. The first manipulated data set contained four different linear developments over time, whereas the second contained two linear and two quadratic developments. RESULTS: For the real-life data set, all five classification methods revealed comparable trajectories. Regarding the manipulated data sets, LCGA performed best in detecting linear trajectories, whereas none of the methods performed well in detecting a combination of linear and quadratic trajectories. Furthermore, the optimal solution for LCA and LCGA contained more classes compared with LCGMM. CONCLUSION: Although LCGA and LCGMM seem to be preferable above the more simple methods, all classification methods should be applied with great caution. PMID- 22818948 TI - Halophyte filter beds for treatment of saline wastewater from aquaculture. AB - The expansion of aquaculture and the recent development of more intensive land based marine farms require efficient and cost-effective systems for treatment of highly nutrient-rich saline wastewater. Constructed wetlands with halophytic plants offer the potential for waste-stream treatment combined with production of valuable secondary plant crops. Pilot wetland filter beds, constructed in triplicate and planted with the saltmarsh plant Salicornia europaea, were evaluated over 88 days under commercial operating conditions on a marine fish and shrimp farm. Nitrogen waste was primarily in the form of dissolved inorganic nitrogen (TDIN) and was removed by 98.2 +/- 2.2% under ambient loadings of 109 383 MUmol l(-1). There was a linear relationship between TDIN uptake and loading over the range of inputs tested. At peak loadings of up to 8185 +/- 590 MUmol l( 1) (equivalent to 600 mmol N m(-2) d(-1)), the filter beds removed between 30 and 58% (250 mmol N m(-2) d(-1)) of influent TDIN. Influent dissolved inorganic phosphorus levels ranged from 34 to 90 MUmol l(-1), with 36-89% reduction under routine operations. Dissolved organic nitrogen (DON) loadings were lower (11-144 MUmol l(-1)), and between 23 and 69% of influent DON was removed during routine operation, with no significant removal of DON under high TDIN loading. Over the 88-day study, cumulative nitrogen removal was 1.28 mol m(-2), of which 1.09 mol m(-2) was retained in plant tissue, with plant uptake ranging from 2.4 to 27.0 mmol N g(-1) dry weight d(-1). The results demonstrate the effectiveness of N and P removal from wastewater from land-based intensive marine aquaculture farms by constructed wetlands planted with S. europaea. PMID- 22818947 TI - The eight-item modified Medical Outcomes Study Social Support Survey: psychometric evaluation showed excellent performance. AB - OBJECTIVE: Evaluation and validation of the psychometric properties of the eight item modified Medical Outcomes Study Social Support Survey (mMOS-SS). STUDY DESIGN AND SETTING: Secondary analyses of data from three populations: Boston breast cancer study (N=660), Los Angeles breast cancer study (N=864), and Medical Outcomes Study (N=1,717). The psychometric evaluation of the eight-item mMOS-SS compared performance across populations and with the original 19-item Medical Outcomes Study Social Support Survey (MOS-SS). Internal reliability, factor structure, construct validity, and discriminant validity were evaluated using Cronbach's alpha, principal factor analysis (PFA), and confirmatory factor analysis (CFA), Spearman and Pearson correlation, t-test and Wilcoxon rank sum tests. RESULTS: mMOS-SS internal reliability was excellent in all three populations. PFA factor loadings were similar across populations; one factor >0.6, well-discriminated two factor (instrumental/emotional social support four items each) >0.5. CFA with a priori two-factor structure yielded consistently adequate model fit (root mean squared errors of approximation 0.054-0.074). mMOS SS construct and discriminant validity were similar across populations and comparable to MOS-SS. Psychometric properties held when restricted to women aged >= 65 years. CONCLUSION: The psychometric properties of the eight-item mMOS-SS were excellent and similar to those of the original 19-item instrument. Results support the use of briefer mMOS-SS instrument; better suited to multidimensional geriatric assessments and specifically in older women with breast cancer. PMID- 22818949 TI - Effects of hypochlorous acid exposure on the rejection of salt, polyethylene glycols, boron and arsenic(V) by nanofiltration and reverse osmosis membranes. AB - The separation layer of polyamide-based (PA) thin film composite (TFC) membranes can be modified by active chlorine species. The PA-TFC membranes, NF90, BW30 and NF270, were exposed to different concentrations of sodium hypochlorite (NaOCl) at pH 5 for 24 h. Elemental composition obtained from X-ray Photoelectron Spectroscopy (XPS) showed that the chlorine content in the PA layer increased with the chlorine concentrations. Treatment of membranes with 10 ppm Cl increased the membrane hydrophilicity. By contrast, when treated with 1000 ppm Cl or more, the membranes became less hydrophilic. Water permeability values for all 3 membrane types declined with increased chlorine concentrations. Filtration of polyethylene glycols (PEGs) with molecular weights of 200, 400 and 600 Daltons (Da) was performed to investigate the influence of chlorine treatment on membrane molecular weight cut off (MWCO) and rejection by size exclusion. Treatment with 10 and 100 ppm Cl lowered the MWCO while treatment with higher concentrations increased the MWCO. All chlorinated membranes experienced higher NaCl rejection compared to virgin ones. The performance of NF90 was tested with respect to the rejection of inorganic contaminants including boron (H(3)BO(3)) and arsenic (H(2)AsO(4)(-)). The boron rejection results paralleled PEG rejection whereas those for arsenic followed NaCl rejection patterns. The changes in membrane performance due to chlorine treatment were explained in terms of competing mechanisms: membrane tightening, bond cleavage by N-chlorination and chlorination promoted polyamide hydrolysis. PMID- 22818950 TI - Disinfection by-products in ballast water treatment: an evaluation of regulatory data. AB - To reduce the global spread of invasive aquatic species, international regulations will soon require reductions of the number of organisms in ballast water discharged by ships. For this purpose, ballast water treatment systems were developed and approved by an international procedure. These systems rely on established water treatment principles which, to different degrees, have been proven to generate disinfection by-products with hazardous properties but have only scarcely been investigated in marine environments. Our study evaluates the publicly available documentation about approved ballast water treatment systems with regard to by-product formation. The most commonly employed methods are chlorination, ozonation, and ultraviolet (UV) irradiation. Chlorination systems generate trihalomethanes, halogenated acetic acids, and bromate in substantially larger quantities than reported for other areas of application. Levels are highest in brackish water, and brominated species predominate, in particular bromoform and dibromoacetic acid. Ozonation, which is less frequently utilized, produces bromoform in lower concentrations but forms higher levels of bromate, both of which were effectively reduced by active carbon treatment. In systems based on UV radiation, medium pressure lamps are employed as well as UV-induced advanced oxidation. For all UV systems, by-product formation is reported only occasionally. The most notable observations were small increases in nitrite, hydrogen peroxide, halogenated methanes and acetic acids. The assessment of by product formation during ballast water treatment is limited by the lacking completeness and quality of available information. This concerns the extent and statistical characterisation of chemical analysis as well as the documentation of the test water parameters. PMID- 22818951 TI - Earthy odor compounds production and loss in three cyanobacterial cultures. AB - Geosmin and 2-methylisoborneol (MIB) related odor events caused by cyanobacteria have been a very common problem to water supply. This paper investigated the effects of temperature (18 and 25 degrees C) and light intensity (10 and 100 MUmol photons m(-2) s(-1)) on the production behaviors of earthy odor compounds by three odorous cyanobacteria, i.e., the geosmin-producing planktonic Anabaena circinalis (Ana 318), geosmin-producing benthic Phormidium amoenum (Pho 012) and MIB-producing benthic Phormidium sp. (Pho 689). At the same time, the effects of biodegradation and volatilization on the fates of the released odor compounds in water were also evaluated. The combination of high temperature (25 degrees C) and light intensity (100 MUmol photons m(-2) s(-1)) favored the growth of the three cyanobacteria and the production of chl-a and odor compounds. However, higher chl-a and odor yields (average odor compounds per cell) were achieved for the two benthic cyanobacteria at the temperature of 18 degrees C. Most of geosmin was included within the cells for Ana 318 (95-99%) and Pho 012 (85-60%), while only 20-40% MIB was bound to the cells for Pho 689. The half-life times of MIB and geosmin due to volatilization varied between 18.8 and 35.4 days, while 8 out of 10 samples exhibited a half-life time (t(1/2)) for geosmin biodegradation shorter than 1 day (0.38-15.0 h), showing that biodegradation could affect the fate of geosmin significantly in aquatic environments. In comparison, biodegradation of MIB was much slower (t(1/2): 122-2166 h). Denaturing gradient gel electrophoresis (DGGE) analysis showed that Pseudomonas- and Sphingomonas like bacteria coexisted with cyanobacteria in the cultures, and may have played an important role in geosmin/MIB biodegradation. The result of this study will be helpful for better understanding and managing the earthy odor problems caused by cyanobacteria in water supply. PMID- 22818952 TI - Removal of charged micropollutants from water by ion-exchange polymers -- effects of competing electrolytes. AB - A wide variety of environmental compounds of concern, e.g. pharmaceuticals or illicit drugs, are acids or bases that may predominantly be present as charged species in drinking water sources. These charged micropollutants may prove difficult to remove by currently used water treatment steps (e.g. UV/H(2)O(2), activated carbon (AC) or membranes). We studied the sorption affinity of some ionic organic compounds to both AC and different charged polymeric materials. Ion exchange polymers may be effective as additional extraction phases in water treatment, because sorption of all charged compounds to oppositely charged polymers was stronger than to AC, especially for the double-charged cation metformin. Tested below 1% of the polymer ion-exchange capacity, the sorption affinity of charged micropollutants is nonlinear and depends on the composition of the aqueous medium. Whereas oppositely charged electrolytes do not impact sorption of organic ions, equally charged electrolytes do influence sorption indicating ion-exchange (IE) to be the main sorption mechanism. For the tested polymers, a tenfold increased salt concentration lowered the IE-sorption affinity by a factor two. Different electrolytes affect IE with organic ions in a similar way as inorganic ions on IE-resins, and no clear differences in this trend were observed between the sulphonated and the carboxylated cation-exchanger. Sorption of organic cations is five fold less in Ca(2+) solutions compared to similar concentrations of Na(+), while that of anionic compounds is three fold weaker in SO(4)(2-) solutions compared to equal concentrations of Cl(-). PMID- 22818953 TI - Every move counts in learning: filipino clinical instructors' scaffolding behaviors in teaching medication administration. AB - The role of clinical instructors in preparing student nurses for the realities and dynamics of clinical practice cannot be underestimated. Previous literature has identified scaffolding as a diagnostic tool that enables both supervisor and learner to recognize knowledge-in-waiting and knowledge-in-use (Spouse, 1998). The pivotal role of scaffolding in the teaching-learning process cannot be underestimated. However, literature pertaining to its use in nursing is hard to locate (Dickieson, Carter and Walsh, 2008; Spouse, 1998). Hence, this qualitative study was conducted to capture nursing students' views and experiences of the scaffolding moves of their clinical instructors as they learn medication administration. From the thickness and richness of the descriptions of a select group of nursing students (n=31) in a comprehensive university in the Philippines, three interesting and yet intersecting themes surfaced relative to the scaffolding moves employed by clinical instructors, which include: (1) thought-provoking; (2) focus-steering; and (3) action-enabling. The said moves are carried out in a timely fashion to facilitate students' acquisition of knowledge, skills and attitudes pertaining to medication administration. Through the understanding of clinical instructors' scaffolding behaviors, this study provides a platform for more effective clinical instruction aimed at supporting future nurses' role in medication safety. PMID- 22818954 TI - A cross-sectional study of paramedics' readiness for interprofessional learning and cooperation: results from five universities. AB - INTRODUCTION: Healthcare systems are evolving to feature the promotion of interprofessional practice more prominently. The development of successful and functional interprofessional practice is best achieved through interprofessional learning. Given that most paramedic programmes take an isolative uni-professional educational approach to their healthcare undergraduate courses, serious questions must be raised as to whether students are being adequately prepared for the interprofessional healthcare workplace. The objective of this study was to assess the attitudes of paramedic students towards interprofessional learning across five Australian universities. METHODS: Using a convenience sample of paramedic student attitudes towards interprofessional learning and cooperation were measured using two standardised self-reporting instruments: Readiness for Interprofessional Learning Scale (RIPLS) and Interdisciplinary Education Perception Scale (IEPS). RESULTS: Students' readiness for interprofessional learning did not appear to be significantly influenced by their gender nor the type of paramedic degree they were undertaking. As students progressed through their degrees their appreciation for collaborative teamwork and their understanding of paramedic identity grew, however this appeared to negatively affect their willingness to engage in interprofessional learning with other healthcare students. The tertiary institute attended also appeared to influence students' preparedness and attitudes to shared learning. CONCLUSIONS: This study has found no compelling evidence that students' readiness for interprofessional learning is significantly affected by either their gender or the type of degree undertaken. By contrast it was seen that the tertiary institutions involved in this study produced students at different levels of preparedness for IPL and cooperation. PMID- 22818955 TI - [Incidence of prolonged grief disorder in relatives of patients who die during or after admission in Intensive Care Unit]. AB - OBJECTIVES: To determine the incidence of "Prolonged Grief Disorder" from one year after the death of a relative admitted to the Intensive Care Unit. MATERIAL AND METHODS: A cross-sectional, longitudinal follow-up study was conducted in a general ICU of a reference hospital. The relatives were evaluated approximately one year after the death using the "Consensus Criteria for Prolonged Grief Disorder" as a tool. The prevalence between the first and second years was determined. RESULTS: A total of 151 relatives of patients who died in ICU were included. The follow-up was carried out 22.1+/-5.3 months after the death. Eleven relatives (10.3%) fulfilled the "Consensus Criteria for Prolonged Grief Disorder". Of all the grieving relatives, those identified with prolonged grief disorder are the ones who most often require psychological/psychiatric support. CONCLUSIONS: In a sample of close relatives of patients who died in ICU, a significant minority fulfilled the criteria for "Prolonged Grief Disorder" 1-2 years after the death. This condition, which is often overlooked, and could require some kind of psychological treatment, should be taken into consideration. PMID- 22818957 TI - Modeling contact angle hysteresis of a liquid droplet sitting on a cosine wave like pattern surface. AB - A liquid droplet sitting on a hydrophobic surface with a cosine wave-like square array pattern in the Wenzel state is simulated by using the Surface Evolver to determine the contact angle. For a fixed drop volume, multiple metastable states are obtained at two different surface roughnesses. Unusual and non-circular shape of the three-phase contact line of a liquid droplet sitting on the model surface is observed due to corrugation and distortion of the contact line by structure of the roughness. The contact angle varies along the contact line for each metastable state. The maximum and minimum contact angles among the multiple metastable states at a fixed viewing angle correspond to the advancing and the receding contact angles, respectively. It is interesting to observe that the advancing/receding contact angles (and contact angle hysteresis) are a function of viewing angle. In addition, the receding (or advancing) contact angles at different viewing angles are determined at different metastable states. The contact angle of minimum energy among the multiple metastable states is defined as the most stable (equilibrium) contact angle. The Wenzel model is not able to describe the contact angle along the three-phase contact line. The contact angle hysteresis at different drop volumes is determined. The number of the metastable states increases with increasing drop volume. Drop volume effect on the contact angles is also discussed. PMID- 22818958 TI - Surface dilational moduli of poly (ethylene oxide), poly (methyl methacrylate), and their blend films. AB - Surface dilational moduli of poly (ethylene oxide) (PEO), poly (methyl methacrylate) (PMMA), and compatible PEO/PMMA blend films spread at the air-water interface were investigated as a function of surface concentration. The surface dilational modulus of an expanded PEO film increased as the surface concentration increased to 0.4 mg/m(2), which corresponds to the limiting surface area of PEO. After peaking at this value, the surface dilational modulus decreased with an increase in the PEO concentration. Lissajous orbits of PEO films exhibited positive hysteresis loops for all surface concentration ranges. On the other hand, the surface dilational modulus of a condensed PMMA film steeply increased as the surface concentration increased. Lissajous orbits of PMMA films changed from positive hysteresis loops to negative loops at the surface concentration at which the surface pressure reached in the plateau region. The magnitude of the surface dilational modulus of PMMA was larger than that of PEO at a fixed surface concentration. The surface dilational moduli of the PEO/PMMA blend films increased with the total surface concentration and their magnitudes were less than those of the individual PMMA films and larger than those of the individual PEO films at fixed surface concentrations. Lissajous orbits of the PEO/PMMA blend films also changed from positive hysteresis loops to negative loops beyond the surface concentration at which the plateau surface pressure of PEO was attained. PMID- 22818956 TI - Endocytosis and control of Notch signaling. AB - The Notch signaling pathway controls patterning and cell fate decisions during development in metazoans, and is associated with human diseases such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and certain cancers. Studies over the last several years have revealed sophisticated regulation of both the membrane-bound Notch receptor and its ligands by vesicle trafficking. This is perhaps most evident in neural progenitor cells in Drosophila, which divide asymmetrically to segregate Numb, an endocytic adaptor protein that acts as a Notch pathway inhibitor, to one daughter cell. Here, we discuss recent findings addressing how receptor and ligand trafficking to specific membrane compartments control activation of the Notch pathway in asymmetrically dividing cells and other tissues. PMID- 22818959 TI - Tailoring CuO nanostructures for enhanced photocatalytic property. AB - We report on one-pot synthesis of various morphologies of CuO nanostructures. PEG200 as a structure directing reagent under the synergism of alkalinity by hydrothermal method has been employed to tailor the morphology of CuO nanostructures. The CuO products have been characterized by XRD, SEM, and TEM. The morphologies of the CuO nanostructures can be tuned from 1D (nanoseeds, nanoribbons) to 2D (nanoleaves) and to 3D (shuttle-like, shrimp-like, and nanoflowers) by changing the volume of PEG200 and the alkalinity in the reaction system. At neutral and relatively low alkalinity (OH(-)/Cu(2+)<=3), the addition of PEG200 can strongly influence the morphologies of the CuO nanostructures. At high alkalinity (OH(-)/Cu(2+)>=4), PEG200 has no influence on the morphology of the CuO nanostructure. The different morphologies of the CuO nanostructures have been used for the photodecomposition of the pollutant rhodamine B (RhB) in water. The photocatalytic activity has been correlated with the different nanostructures of CuO. The 1D CuO nanoribbons exhibit the best performance on the RhB photodecomposition because of the exposed high surface energy {-121} crystal plane. The photocatalytic results show that the high energy surface planes of the CuO nanostructures mostly affect the photocatalytic activity rather than the morphology of the CuO nanostructures. Our synthesis method also shows it is possible to control the morphologies of nanostructures in a simple way. PMID- 22818960 TI - New insight into mesoporous silica for nano metal-organic framework. AB - A micropore- and mesopore-integrated material was synthesized by using a mesoporous silica and a metal-organic framework (MOF). The composite was composed of nano MOF crystals and mesoporous silica showing high porosity based on the intrinsic micropores of MOF and mesopores of mesoporous silica and additional pore spaces that should be from the void between nano MOF crystals. The composite shows higher adsorption rate of ethanol at 303 K than that of the bulk MOF. PMID- 22818961 TI - Driveline infections in left ventricular assist devices: implications for destination therapy. AB - BACKGROUND: Infection is one of the major limitations to successful long-term support after ventricular assist device implantation. There are limited data specifically examining the incidence and predictors of driveline infections (DLI), with a changing treatment paradigm toward destination therapy (DT) and longer duration of support. METHODS: Between January 2007 and 2011, 143 patients underwent HeartMate II (Thoratec, Pleasanton, CA) implantation, with 87 (61%) as DT. Driveline maintenance strategy included sterile dressing changes with chlorhexidine and saline application, without prophylactic oral antibiotics. RESULTS: DLI developed in 18 patients (12%) at a median of 182 days (range, 26 to 1,138 days) after implantation, among which 12 (66%) were from the DT cohort. Infections were superficial in 15 (82%) and deep in 3 (18%). Trauma was documented in 6 patients (33%). Seven patients (38%) needed readmission for DLI. Surgical debridement was needed in 3 (17%). All patients were managed successfully, without the need for device explantation or urgent cardiac transplantation. No patient required continuous antibiotic prophylaxis after the infection subsided. Risk factor analysis identified duration of support as the only independent predictor of infection (mean. 600 vs 390 days; p = 0.03). The odds of having a DLI rose by 4% for every month of support. CONCLUSIONS: Longer duration of support significantly increased the risk of DLI and hence increased the risk of DLI in patients with DT. DLI may be successfully managed with antibiotics and local wound care. Most of the infections were superficial, and progression to deep pocket or pump infection is rare in our experience. PMID- 22818963 TI - Predicting in-hospital mortality after redo cardiac operations: development of a preoperative scorecard. AB - BACKGROUND: The present study generated a risk model and an easy-to-use scorecard for the preoperative prediction of in-hospital mortality for patients undergoing redo cardiac operations. METHODS: All patients who underwent redo cardiac operations in which the initial and subsequent procedures were performed through a median sternotomy were included. A logistic regression model was created to identify independent preoperative predictors of in-hospital mortality. The results were then used to create a scorecard predicting operative risk. RESULTS: A total of 1,521 patients underwent redo procedures between 1995 and 2010 at a single institution. Coronary bypass procedures were the most common previous (58%) or planned operations (54%). The unadjusted in-hospital mortality for all redo cases was higher than for first-time procedures (9.7% vs. 3.4%; p<0.001). Independent predictors of in-hospital mortality were a composite urgency variable (odds ratio [OR], 3.47), older age (70-79 years, OR, 2.74; >=80 years, OR, 3.32), more than 2 previous sternotomies (OR, 2.69), current procedure other than isolated coronary or valve operation (OR, 2.64), preoperative renal failure (OR, 1.89), and peripheral vascular disease (PVD) (OR, 1.55); all p<0.05. A scorecard was generated using these independent predictors, stratifying patients undergoing redo cardiac operations into 6 risk categories of in-hospital mortality ranging from <5% risk to >40%. CONCLUSIONS: Reoperation represents a significant proportion of modern cardiac surgical procedures and is often associated with significantly higher mortality than first-time operations. We created an easy-to use scorecard to assist clinicians in estimating operative mortality to ensure optimal decision making in the care of patients facing redo cardiac operations. PMID- 22818962 TI - Late clinical features of patients with pulmonary atresia or critical pulmonary stenosis with intact ventricular septum after biventricular repair. AB - BACKGROUND: We aimed to reveal late clinical features of patients with pulmonary atresia with intact ventricular septum (PA/IVS) or critical pulmonary stenosis (cPS) after biventricular repair (BVR) based on preoperative right ventricular (RV) end-diastolic volume (RVEDV) findings. METHODS: Since 1985, 23 of 73 patients with PA/IVS (n=22) or cPS (n=1) with a tripartite RV and without major sinusoidal communication underwent BVR with a hybrid approach. The mean age and weight at BVR were 1.4+/-2.1 years and 6.9+/-5.9 kg, respectively. Mean follow-up was 10.1+/-6.4 years (range, 1.1 to 24.6 years). RESULTS: Overall survival, reintervention-free, and arrhythmia-free rates at 20 years were 90.6%, 75.4%, and 50.4%, respectively. In 19 patients with preoperative RVEDV of 60% to 120% of normal, echocardiography at 10 years after BVR showed well-maintained RV systolic function. However, RV volume was quantitatively dilated in 16 (88.9%) due to moderate or greater tricuspid regurgitation in 8 (44.4%), pulmonary regurgitation in 12 (66.7%), or both, which caused arrhythmia in 3 patients more than 10 years after BVR. Two patients with preoperative RVEDV of greater than 120% of normal required tricuspid valve replacement after BVR, after which refractory atrial tachyarrhythmia developed in both patients. Furthermore, 2 patients with preoperative RVEDV of less than 60% of normal showed a cardiac index value within 2.5 L/min/m2 at 1 year after BVR, which did not improve. CONCLUSIONS: Patients with PA/IVS or cPS and adequately sized RV showed good late clinical features after BVR. However, long-term follow-up examinations are necessary for RV dilatation and late-onset arrhythmia. PMID- 22818964 TI - Mitroflow aortic bioprosthesis 5-year follow-up: north american prospective multicenter study. AB - BACKGROUND: The Mitroflow valve (Sorin Group, Milan, Italy) has been in use since 1982 and has shown long-term durability in large studies from European centers but has not been studied for long-term hemodynamics in large standardized multicenter trials. This study sought to assess the hemodynamics of the Mitroflow valve by extending the duration of follow-up in an ongoing prospective multicenter trial conducted in North America. METHODS: Six sites participated in this midterm study requiring annual follow-up and echocardiographic evaluation using a standardized transthoracic echocardiography acquisition protocol. RESULTS: There were 276 patients enrolled (age 74+/-8 years) and 54% were in New York Heart Association (NYHA) functional class III-IV. Follow-up from the time of valve implantation had a mean of 4.0+/-1.7 years with a cumulative follow-up of 1,102 patient-years. At 5 years of follow-up, 99% of patients were free of moderate or severe aortic regurgitation and 94% were in NYHA functional class I or II. Between baseline and 5 years, mean gradients increased an average of 0.4 to 4.3 mm Hg. The change in effective orifice area was appreciably small (-0.1 to -0.3 cm2) after 5 years. There were 57 deaths (4 early and 53 late) and 9 valve explants. CONCLUSIONS: The Mitroflow valve implanted in the aortic position has shown to be hemodynamically stable over a 5-year follow-up in an elderly population with a high prevalence of comorbid conditions. PMID- 22818965 TI - A randomized multiinstitution comparison of the laparoscopic Nissen and Hill repairs. AB - BACKGROUND: Laparoscopic Hill repair (LHR) and laparoscopic Nissen fundoplication (LNF) are established surgical antireflux procedures but have never been compared in a prospective trial. This trial was designed to compare the effectiveness of LHR against the gold-standard LNF. METHODS: Patients with uncomplicated gastroesophageal reflux from two esophageal centers were randomly assigned and blinded from 2003 to 2007. Preoperative and postoperative evaluation included two quality of life metrics--Quality of Life in Reflux and Dyspepsia, and Dysphagia- as well as endoscopy, video esophogram, manometry, and pH testing. RESULTS: Of 121 patients who consented to the trial, 102 underwent surgery; 46 LNF and 56 LHR were performed, with a mean follow-up of 12 months. Postoperatively, the DeMeester score normalized for both repairs, with no difference between them (LNF 6.8, LHR 11.1, p=0.26). Postoperative medication use was 4%, and the groups were equivalent. Lower esophageal sphincter pressure increased significantly for LNF (14.93 to 24.10, p=0.001) but not for LHR (19.91 to 20.25, p=0.87). Quality of life scores improved significantly for both repairs (LNF 3.77 to 6.65; LHR 3.84 to 6.54, p<0.001), and postoperative results were equivalent (p=0.99). Dysphagia scores preoperative/postoperative were LNF 33.88 to 38.33 and LHR 35.44 to 38.72, and were equivalent postoperatively (p=0.94). Two LNF and two LHR required reoperation for failed repair. CONCLUSIONS: The LHR and the LNF both yield excellent and equivalent results for uncomplicated gastroesophageal reflux at 12 months. Their mechanisms of action may be different. PMID- 22818966 TI - Conventional aortic valve replacement in transcatheter aortic valve implantation candidates: a 5-year experience. AB - BACKGROUND: Patient selection for transcatheter aortic valve implantation (TAVI) remains highly controversial. Some screened patients subsequently undergo conventional aortic valve replacement (AVR) because they are unsuitable TAVI candidates. This study examined the indications and outcomes for these patients, thereby determining the efficacy of the screening process. METHODS: Between January 2006 and December 2010, 79 consecutive patients (49% men), aged older than 75 years with high surgical risk, were screened for TAVI, but subsequently underwent conventional AVR through a partial or complete sternotomy. The indications, demographics, and outcomes of this cohort were studied. RESULTS: Mean age was 80.4+/-3.6 years. Mean left ventricular ejection fraction was 0.55+/ 0.16, and the mean logistic European System for Cardiac Operative Risk Evaluation was 13%+/-7%. Of the 79 patients, 6 (7.6%) had prior cardiac surgical procedures. Indications for TAVI denial after patient evaluations were a large annulus in 31 (39%), acceptable risk profile for AVR in 24 (30%), need for urgent operation in 11 (14%), and concomitant cardiovascular pathology in 5 (6%). Mean cross-clamp time was 55+/-14 minutes, and cardiopulmonary bypass time was 81+/-21 minutes. Concomitant procedures included a Maze in 12 patients (15%). Postoperative morbidity included permanent stroke in 2 (2.5%), respiratory failure in 9 (11%), and pacemaker implantation in 2 (2.5%). Hospital mortality was 1.3% (1 of 79). Cumulative survival at 6, 12, and 36 months was 88.5%, 87.1% and 72.7%, respectively. CONCLUSIONS: Our existing patient evaluation process accurately defines an acceptable risk cohort for conventional AVR. The late mortality rate reflects the advanced age and comorbidities of this cohort. The data suggest that overzealous widening of TAVI inclusion criteria may be inappropriate. PMID- 22818967 TI - Early and late results of graft replacement for dissecting aneurysm of thoracoabdominal aorta in patients with Marfan syndrome. AB - BACKGROUND: When treating dissecting aneurysm of the thoracoabdominal aorta surgically in patients with Marfan syndrome, we have usually performed graft replacement- including the entire thoracoabdominal aorta and reconstruction of all visceral branches, even if dilatation is mild in some segments-to avoid further aortic operations in the follow-up period. METHODS: From October 1999 through July 2011, 20 consecutive patients with Marfan syndrome underwent repair of dissecting aneurysm of the thoracoabdominal aorta (median age, 45 years; range, 19-65 years). All patients underwent surgical intervention with cerebrospinal fluid (CSF) drainage and distal aortic and selective organ perfusion. Deep hypothermia was used in 13 patients for spinal cord protection. RESULTS: No in-hospital mortality was observed. One patient had temporary spinal cord ischemia but was fully recovered by discharge. Other complications included exploration for bleeding (n=1), prolonged ventilation (n=1), and graft infection (n=1). At a mean follow-up of 54 months (range, 9-129 months), 1 patient had died of interstitial pneumonia at 38 months postoperatively. Survival at 8% years was 91.2+/-9.0%. Two patients required additional aortic procedures (total arch replacement and aortic valve-sparing surgery). Actuarial rate of freedom from aortic operations at 8 years was 83.9%+/-10.5%, but no patient needed required repeated thoracotomy for an aortic procedure. Neither false nor patch aneurysms were observed using computed tomography (CT) during follow-up surveillance. CONCLUSIONS: Graft replacement for dissecting aneurysm of the thoracoabdominal aorta in Marfan syndrome offers good early and long-term results. We believe total aortic replacement including the entire thoracoabdominal aorta and reconstruction of all visceral arteries should be recommended for selected patients with Marfan syndrome. PMID- 22818968 TI - The reciprocal interaction between obesity and obstructive sleep apnoea. AB - Obesity is a significant risk factor in the pathogenesis of obstructive sleep apnoea (OSA) altering airway anatomy and collapsibility, and respiratory control. The association between obesity and OSA has led to an increasing focus on the role of weight loss as a potential treatment for OSA. To date, most discussion of obesity and OSA assumes a one-way cause and effect relationship, with obesity contributing to the pathogenesis of OSA. However, OSA itself may contribute to the development of obesity. OSA has a potential role in the development and reinforcement of obesity via changes to energy expenditure during sleep and wake periods, dietary habits, the neurohormonal mechanisms that control satiety and hunger, and sleep duration arising from fragmented sleep. Thus, there is emerging evidence that OSA itself feeds back into a complex mechanism that leads either to the development or reinforcement of the obese state. Whilst current evidence does not confirm that treatment of OSA directly influences weight loss, it does suggest that the potential role OSA plays in obesity and weight loss deserves further research. PMID- 22818969 TI - Minority variants associated with resistance to HIV-1 nonnucleoside reverse transcriptase inhibitors during primary infection. AB - BACKGROUND: Recent data suggest that subjects harbouring low-frequency variants of HIV that are resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTI) could suffer virological failure when treated with NNRTI-based therapy. Rilpivirine, a second-generation NNRTI, will be used in first-line regimen therapy, but the prevalence of minority variants that are resistant to rilpivirine is unknown. OBJECTIVES: We evaluated the presence of low-frequency NNRTI resistance associated mutations (RAMs) in 27 patients with a primary HIV-1 infection. STUDY DESIGN: We performed genotypic resistance test at baseline and used ultradeep pyrosequencing (UDPS) to detect minority RAMs. RESULTS: Bulk genotyping identified NNRTI-resistant RAMs in 3/27 (11%) patients while UDPS identified NNRTI-resistant RAMs in 10/27 (37%) patients. The 11 RAMs not detected by bulk sequencing were A98G (n=2), L100I (n=3), K101E (n=2), V106I (n=3) and E138G (n=1). The prevalence of these minority variants was 0.34-18.26%. The absolute copy numbers of minority resistant variants were 3.21-5.53 log copies/mL. CRF02 harboured more minority resistant variants than subtypes B (P<0.05). Four samples (15%) had a major rilpivirine resistant mutation (E138G, K101E and E138A), 3 of which were detected by UDPS. CONCLUSION: In these primary HIV infected patients, as regards to the detection of RAMs at the cut-off level>15-25% of the virus population, the concordance between bulk genotypic and UDPS was perfect. UDPS detected additional major NNRTI-resistant mutations, including rilpivirine resistant variants. Further studies are needed to assess the impact of these minority variants on treatment efficacy. PMID- 22818970 TI - Current management of severe pelvic and perineal trauma. AB - Mortality associated with pelvic and perineal trauma (PPT) has fallen from 25% to 10% in the last decade thanks to progress accomplished in medical, surgical and interventional radiology domains (Dyer and Vrahas, 2006) [1]. The management strategy depends on the hemodynamic status of the patient (stable, unstable or extremely unstable). Open trauma requires specific treatment in addition to control of bleeding. All surgical centers can be confronted some day with patients with hemorrhagic PPT and for this reason, all surgeons should be familiar with the initial management. In expert centers, management of patients with severe PPT is complex, multidisciplinary and often requires several re interventions. Obstetrical and sexual trauma, also requiring specific management, will not be dealt with herein. PMID- 22818971 TI - (+)-Pinoresinol is a putative hypoglycemic agent in defatted sesame (Sesamum indicum) seeds though inhibiting alpha-glucosidase. AB - Defatted sesame seeds have been reported for hypoglycemic effect in mice and T2DM women. An attempted to identify active components responsible for this effect was conducted using alpha-glucosidase-guided fractionation, resulting in the isolation of various lignans. Of compounds isolated, only (+)-pinoresinol showed inhibitory activity against rat intestinal maltase with an IC(50) value of 34.3 MUM. The kinetic study indicated that enzymatic hydrolysis of maltose is inhibited by (+)-pinoresinol through competitive and noncompetitive manners. However, a lower dissociation constant (k(i) 288 M) of EI complex suggested that competitive inhibition is predominant over noncompetitive mode (k'(i) 1342 M). PMID- 22818972 TI - Optimization of acetonitrile co-solvent and copper stoichiometry for pseudo ligandless click chemistry with nucleic acids. AB - The copper(I) catalyzed azide-alkyne cycloaddition 'click' reaction yields a specific product under mild conditions and in some of the most chemically complex environments. This reaction has been used extensively to tag DNA, proteins, glycans and only recently RNA. Click reactions in aqueous buffer typically include a ligand for Cu(I), however we find that acetonitrile as a minor co solvent can serve this role. Here we investigate the click labeling of RNA and DNA in aqueous buffer to determine the relationship between the stoichoimetry of Cu(I) and the acetonitrile co-solvent that affects nucleic acid stability. We find that very low concentrations of acetonitrile perform equally well and obviate the need for any additional Cu(I) stabilizing ligand. These pseudo ligandless reaction conditions are optimal for nucleic acids click conjugations. PMID- 22818973 TI - Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants. AB - Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10 fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D. PMID- 22818974 TI - Growing sphere of influence: Cdc48/p97 orchestrates ubiquitin-dependent extraction from chromatin. AB - The AAA (ATPases associated with various cellular activities) family member Cdc48/p97 is best known for its role in ubiquitin-dependent proteasomal degradation of aberrant endoplasmic reticulum (ER) proteins, a process known as ER-associated degradation (ERAD). However, recent studies have also defined Cdc48/p97 as a central player in various chromatin-associated processes linked to cell cycle progression, DNA replication, transcription, and the DNA damage response. Notwithstanding the apparent differences in location and function, the role of Cdc48/p97 in ubiquitin-dependent extraction from chromatin (UDEC) bears striking similarities with its action in ERAD. Here, we discuss recent data that expand our current model of the role of Cdc48/p97 as a ubiquitin-selective segregase in the nuclear chromatin environment. PMID- 22818975 TI - Theory connections. PMID- 22818976 TI - Neurosensory and functional evaluation in distraction osteogenesis of the anterior mandibular alveolar process. AB - Neurosensory status and craniomandibular function of 19 patients (mean age 35.2 years, range 17.8-58.8 years) treated by combined surgical orthodontic treatment with distraction osteogenesis of the mandibular anterior alveolar process (DO group) was compared with that in 41 orthodontically treated patients (mean age 22.9 years, range 15.1-49.0 years; control group). Clinical examination took place on average 5.9 years (DO group) and 5.4 years (control group) after treatment ended. Neurosensory status was determined by two-point discrimination (2-pd) and the pointed and blunt test. Lateral cephalograms evaluated advancement of the mandibular alveolar process and possible relapse. There was no significant difference in craniomandibular function and neurosensory status between the groups. Age was significantly correlated with 2-pd at the lips (DO: p=0.01, R=0.575; control group: p=0.039, R=0.324) and chin (DO: p=0.029, R=0.501; control group: p=0.008, R=0.410). Younger patients had smaller 2-pd values. Gender, age, the amount of advancement, and relapse at point B or incision inferior show no correlation with craniomandibular function and neurosensory impairment. DO of the mandibular anterior alveolar process is a valuable and safe method with minor side effects regarding neurosensory impairment. PMID- 22818977 TI - Evaluation of UV/TiO(2) and UV/ZnO photocatalytic systems coupled to a biological process for the treatment of bleaching pulp mill effluent. AB - This paper presents an exploratory study of pulp mill bleaching effluent treatment by a biological-photocatalytic coupled system. A fungus, Trametes pubescens, immobilized on polyurethane foam was used to inoculate the biological pre-treatment system. The pretreated effluent was then exposed to a photocatalytic treatment in which two catalysts (TiO(2) and ZnO) and two supports (aluminum foil and Luffa cylindrica) were tested. Catalyst characterization was carried out by means of X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). Information about crystalline structure, chemical composition, morphology, homogeneity and distribution on the support surface area was obtained. The overall biological-photocatalytic coupled system achieved degradation of 96% of initial total organic carbon (TOC), 97% of 2-chlorophenol (2-CP), 90% of 2,4 dichlorophenol (2,4-CP) and 99% of 2,4,6-trichlorophenol (2,4,6-TCP). This approach of synergistic coupling of T. pubescens and a semiconductor photocatalyst appears to be a viable alternative for the treatment of these non biodegradable effluents. PMID- 22818978 TI - Are primary health care centres that target injecting drug users attracting and serving the clients they are designed for? A case study from Sydney, Australia. AB - BACKGROUND: Low-threshold primary healthcare (PHC) centres targeting injecting drug users (IDUs) are increasingly being created to offer preventative and opportunistic services. However, no data are available on the characteristics of clients who utilise such services, or the effectiveness of these services in facilitating prevention or treatment. METHOD: A retrospective clinical record audit examined the characteristics, service utilisation patterns and referral uptake of 384 clients presenting to a low-threshold PHC service in Sydney, Australia. RESULTS: Of the 384 clients, 85% were IDUs. Sixty-two percent reported also having access to a general medical practitioner (GP), with this group more likely to report taking benzodiazepines or other psychoactive medication. Despite this relatively high level of GP access, only 50% were fully vaccinated against hepatitis B virus (HBV). Testing for blood-borne viral and sexually transmitted infections were the most common reasons for presentation to the PHC. Most (82%) clients made at least one return visit, with an average of 3.5 presentations per client. All clients were offered HBV vaccination where indicated (n = 145); and more than half (55%) of referrals to external services were attended. Clients accessing this PHC were younger, more likely to be male and born outside Australia than IDUs attending needle syringe programs (NSPs) in Australia's most populous state, New South Wales. CONCLUSION: Results suggest that this low threshold PHC service was underutilised and its role as a low-threshold healthcare outlet remains limited. Further research is needed to more clearly delineate the health and economic benefits of this model. PMID- 22818979 TI - Induction of therapeutic neoangiogenesis using in vitro-generated endothelial colony-forming cells: an autologous transplantation model in rat. AB - BACKGROUND: Accumulating evidence shows the potential of bone marrow-derived endothelial colony-forming cells (bmECFCs) as promising tools for vascular repair. However, knowledge about their in vitro expansion, characterization, and functional behavior is still controversial. We demonstrate the in vitro generation of rat bmECFCs and analyze their ability to promote tissue reperfusion in a chronic hind-limb ischemia model. METHODS: Either in vitro-generated and characterized autologous bmECFCs or placebo was injected into ischemic hind limbs of Sprague-Dawley rats. Tissue perfusion was quantified by laser Doppler, in perfusion units (PU), at days 0, 15, and 30. RESULTS: Rat bmECFCs acquire a typical phenotype (CD34(+)VEGFR2(+)CD133(+)CXCR4(+)CD45(-)), culture, and functional behavior (Dil-ac-LDL+) in vitro. Injection of autologous bmECFCs improves tissue perfusion in ischemic hind limbs (183.5 +/- 3.29 PU(bmECFCs/day 30)versus 131 +/- 3.9 PU(controls/day 30), P < 0.001). CONCLUSIONS: We conclude that rat bmECFCs promote ischemic tissue reperfusion and their proangiogenic properties are a potential mechanism for this effect. PMID- 22818980 TI - Neo-vascularization of the stroke cavity by implantation of human neural stem cells on VEGF-releasing PLGA microparticles. AB - Replacing the tissue lost after a stroke potentially provides a new neural substrate to promote recovery. However, significant neurobiological and biotechnological challenges need to be overcome to make this possibility into a reality. Human neural stem cells (hNSCs) can differentiate into mature brain cells, but require a structural support that retains them within the cavity and affords the formation of a de novo tissue. Nevertheless, in our previous work, even after a week, this primitive tissue is void of a vasculature that could sustain its long-term viability. Therefore, tissue engineering strategies are required to develop a vasculature. Vascular endothelial growth factor (VEGF) is known to promote the proliferation and migration of endothelial cells during angio- and arteriogenesis. VEGF by itself here did not affect viability or differentiation of hNSCs, whereas growing cells on poly(D,L-lactic acid-co glycolic acid) (PLGA) microparticles, with or without VEGF, doubled astrocytic and neuronal differentiation. Secretion of a burst and a sustained delivery of VEGF from the microparticles in vivo attracted endothelial cells from the host into this primitive tissue and in parts established a neovasculature, whereas in other parts endothelial cells were merely interspersed with hNSCs. There was also evidence of a hypervascularization indicating that further work will be required to establish an adequate level of vascularization. It is therefore possible to develop a putative neovasculature within de novo tissue that is forming inside a tissue cavity caused by a stroke. PMID- 22818982 TI - The therapeutic efficacy of CdTe and CdSe quantum dots for photothermal cancer therapy. AB - Fluorescent quantum dots (QDs) used for biomedical imaging and diagnostics have attracted considerable attention over the past decade. Here, we report our finding regarding the therapeutic efficacy of the popularly used red/brown, brown or close to black CdTe and CdSe QDs. Upon 671-nm laser irradiation, these QDs can rapidly convert light energy into heat, both in vitro and in vivo. In the present study, the growth of mouse melanoma tumors injected with CdTe(710) QDs coated with a silica shell (SiO(2)) was significantly inhibited after laser irradiation, with eventual disappearance of the tumor. In contrast, tumors injected with the silica-coated QDs without subsequent irradiation continued to grow over time. They had a growth rate close to that of tumors injected with SiO(2) or phosphate buffered saline, with or without laser irradiation. In conclusion, our data suggest that the popularly used CdTe and CdSe QDs have great potential in the treatment of cancer using photothermal therapy. PMID- 22818981 TI - Self-assembling nanoparticles for intra-articular delivery of anti-inflammatory proteins. AB - Intra-articular delivery of therapeutics to modulate osteoarthritis (OA) is challenging. Delivery of interleukin-1 receptor antagonist (IL-1Ra), the natural protein inhibitor of IL-1, to modulate IL-1-based inflammation through gene therapy or bolus protein injections has emerged as a promising therapy for OA. However, these approaches suffer from rapid clearance and reduced potency over time. Nano/microparticles represent a promising strategy for overcoming the shortcomings of intra-articular drug delivery. However, these delivery vehicles are limited for delivery of protein therapeutics due to their hydrophobic character, low drug loading efficiency, and harsh chemical conditions during particle processing. We designed a new block copolymer that assembles into submicron-scale particles and provides for covalently tethering proteins to the particle surface for controlled intra-articular protein delivery. This block copolymer self-assembles into 300 nm-diameter particles with a protein tethering moiety for surface covalent conjugation of IL-1Ra protein. This copolymer particle system efficiently bound IL-1Ra and maintained protein bioactivity in vitro. Furthermore, particle-tethered IL-1Ra bound specifically to target synoviocyte cells via surface IL-1 receptors. Importantly, IL-1Ra nanoparticles inhibited IL-1-mediated signaling to equivalent levels as soluble IL-1Ra. Finally, the ability of nanoparticles to retain IL-1Ra in the rat stifle joint was evaluated by in vivo imaging over 14 days. IL-1Ra-tethered nanoparticles significantly increased the retention time of IL-1Ra in the rat stifle joint over 14 days with enhanced IL-1Ra half-life (3.01 days) compared to that of soluble IL 1Ra (0.96 days) and without inducing degenerative changes in cartilage structure or composition. PMID- 22818983 TI - In vivo fluorescence imaging of apoptosis during foreign body response. AB - Quantification of apoptotic tissues during inflammatory processes induced by biomaterials is challenging in vivo. Here we present a non-invasive method using a fluorescence imaging system which facilitates intermittent snap shots of the current state of local apoptotic tissue. For this purpose, apoptotic cells around two different subcutaneously implanted materials (titanium discs and copper coated titanium discs) in hairless but immunocompetent mice were quantified after 4, 8 and 23 days of implantation. For validation, the results of fluorescence signals were compared to the histology of the inflammatory tissue using apoptotic specific TUNEL-, macrophage-specific F4/80-, neutrophile-specific NIMP-R14- and chloroacetate esterase-staining. We could demonstrate that the fluorescence signals were well suited to quantify the extent of apoptosis in vivo and this is a good indication for the biocompatibility of biomaterials. This study shows that non-invasive monitoring of tissue processes following the implantation of biomaterials is possible in vivo and may help to reduce the number of animals in studies addressing biocompatibility. PMID- 22818984 TI - Selective stimulation of caveolae-mediated endocytosis by an osmotic polymannitol based gene transporter. AB - Controlling the cellular uptake mechanism and consequent intracellular route of polyplexes is important to improve the transfection efficiency of the non-viral gene delivery. Here, we report a new non-viral vector, polymannitol-based gene transporter (PMT), generated by crosslinking low molecular weight polyethylenimine with mannitol diacrylate, which has low cytotoxicity and good transfection efficiency. Interestingly, the uptake pathway of PMT/DNA complexes was shifted into caveolae-mediated endocytosis, avoiding lysosomal degradation. The mechanism of increased caveolae-mediated endocytosis of PMT/DNA complexes was found to be correlated with mechanosensing signal transduction by the hyperosmotic polymannitol part. Our results suggested that PMT, polymannitol based gene transporter, is a safe and efficient gene delivery system with a well modulated uptake pathway and intracellular route for gene therapy. PMID- 22818985 TI - Comparative evaluation of MSCs from bone marrow and adipose tissue seeded in PRP derived scaffold for cartilage regeneration. AB - The aims of this study were to (1) determine whether platelet-rich plasma (PRP) could be prepared as a bioactive scaffold capable of endogenous growth factor release for cartilage repair; (2) compare the chondrogenic differentiation ability of mesenchymal stem cells (MSCs) from bone marrow (BMSC) and from adipose (ADSC) seeded within the PRP scaffold; and (3) test the efficacy of ADSC-PRP construct in cartilage regeneration in vivo. In vitro evaluation showed that a 3 dimensional scaffold with a mesh-like microstructure was formed from PRP, with the capability of endogenous growth factor release and ready cell incorporation. Upon seeding in the PRP scaffold, BMSC showed higher proliferation rate, and higher expression of cartilage-specific genes and proteins than ADSC. In an osteochondral defect model in rabbits, implanted BMSC seeded within PRP scaffold also exhibited better gross appearance and histological and immunohistochemical characteristics, higher cartilage-specific gene and protein expression as well as subchondral bone regeneration. ADSC seeded constructs developed into functional chondrocytes secreting cartilaginous matrix in rabbits at 9 weeks post implantation. Our findings suggest that PRP is a candidate bioactive scaffold capable of releasing endogenous growth factors and that BMSC and ADSC seeded within the PRP scaffold differentiate into chondrocytes and may be suitable for cell-based cartilage repair. PMID- 22818987 TI - Biomedical applications of amino acid-modified chitosans: a review. AB - The presence of reactive primary amines in the backbone structure of chitosan, enables the derivatisation with different functional groups and thereby improving and expanding its properties, such as solubility and mucoadhesiveness, for biomedical applications. Such derivatives can be exploited with good results in a number of biomedical areas, including enhancement of nucleic acid transfection in gene therapy, as well as many other applications aiming to maximize drug delivery and aiding tissue engineering. The aim of this review is to provide an up to date overview of the methods used for derivatizing the chitosan with amino acids and to discuss the characteristics and potential biomedical application of the different amino acid derivatized chitosans described in the literature. PMID- 22818986 TI - The attenuation of restenosis following arterial gene transfer using carbon nanotube coated stent incorporating TAT/DNA(Ang1+Vegf) nanoparticles. AB - This study report the development of a nanobiohybrid hydrogel based endovascular stent device capable of preventing postangioplasty in-stent restenosis (ISR) by promoting significant vascular endothelial recovery in a site-specific manner. The hydrogel is comprised of fibrin matrices, assembled layer-by-layer (LbL) on stent surface with alternate layers carrying endosomolytic Tat peptide/DNA nanoparticles (NPs) or NPs hybridized to polyacrylic acid (PAA) wrapped single walled carbon nanotubes (NP-CNT). Here, the hydrogel works as a reservoir to carry, protect, and simultaneously deliver pro-angiogenic, vascular endothelial growth factor (Vegf) and Angiopoietin-1(Ang1), gene carrying NPs to the target site. In vitro results demonstrated that CNTs incorporated in the hydrogel layers play a major role in tuning the bioactivity of the stent. In addition, the developed stent formulation can significantly reduce the loss of therapeutics while traversing through the vessel and during deployment. In vivo experiments in balloon-injured canine femoral artery demonstrated that the NCS (+) group, carrying NP(vegf+Ang1), can significantly enhance re-endothelialization of injured artery compared to control NCS (-), carrying NP(Null), and bare metal stent (BMS) groups, attenuate stenosis (18.5+/-9.03% vs 39.56+/-13.8 vs 45.34+/ 8.3%; n=8, p<0.05) and prevent neointima formation (1.53+/-0.36 mm(2) vs 2.51+/ 0.27 mm(2) vs 2.66+/-0.14 mm(2); n=8, p<0.05) as analyzed angiography and histomorphometric analysis. These data collectively implicate that this new technology can be useful for stent and other biomedical devices through controlled delivery of multiple biotherapeutics. PMID- 22818988 TI - Functional replication of the tendon tissue microenvironment by a bioimprinted substrate and the support of tenocytic differentiation of mesenchymal stem cells. AB - Although many studies have demonstrated that cell phenotype is affected by the surface properties of biomaterials, these materials often fail to mimic the complexity of the native tissue microenvironment (TME). In this study, we have developed a new experimental model that allows the characterisation and functional reconstruction of natural TME. We discovered that mesenchymal stem cells (MSC) cultured on cryostat sections of bovine Achilles tendon adopted an elongated and aligned morphology, and expressed tenocyte marker tenomodulin (TNMD). This suggests that tendon sections contain the signalling cues that guide MSCs to commit to the tenogenic lineage. To reconstruct this instructive niche, we prepared PDMS replica by using tendon sections as template. The resulting bioimprint faithfully copied the physical topography and elasticity of the section. This replica, when coated with collagen 1, supported tenogenesis of MSC without requiring exogenous growth factors. This study illustrates how extracellular biophysical and biochemical features intertwines to form a niche that influences the cell fate and demonstrated that such complex information could be conveniently reconstructed with synthetic materials and purified extracellular matrix proteins. PMID- 22818989 TI - Hyperbranched polydiselenide as a self assembling broad spectrum anticancer agent. AB - This work presents a highly efficient, broad spectrum and self-delivery anticancer agent, which is the hyperbranched polydiselenide (HPSe) consisting of alternative hydrophobic diselenide groups and hydrophilic phosphate segments in the backbone framework. The data of systematic evaluations demonstrate that HPSe is very potent to inhibit the proliferation of many forms of cancer cell. The dose of HPSe required for growth inhibition of 50% (IC(50)) in all of the tested cancer cell lines is within the concentration range between 1 and 2.5 MUg mL(-1) with the incubation time of 72 h. Furthermore, the amphiphilic HPSe can self assembly into nanomicelles with an average diameter of 50 nm and spontaneously enter into tumor cells by the enhanced permeability and retention (EPR) effect. Besides, other hydrophobic anticancer drugs such as doxorubicin (DOX) can be encapsulated into HPSe micelles for combining therapy. PMID- 22818990 TI - Alexander disease with mild dorsal brainstem atrophy and infantile spasms. AB - We present the case of a Japanese male infant with Alexander disease who developed infantile spasms at 8 months of age. The patient had a cluster of partial seizures at 4 months of age. He presented with mild general hypotonia and developmental delay. Macrocephaly was not observed. Brain magnetic resonance imaging (MRI) findings fulfilled all MRI-based criteria for the diagnosis of Alexander disease and revealed mild atrophy of the dorsal pons and medulla oblongata with abnormal intensities. DNA analysis disclosed a novel heterozygous missense mutation (c.1154 C>T, p.S385F) in the glial fibrillary acidic protein gene. At 8 months of age, tonic spasms occurred, and electroencephalography (EEG) revealed hypsarrhythmia. Lamotrigine effectively controlled the infantile spasms and improved the abnormal EEG findings. Although most patients with infantile Alexander disease have epilepsy, infantile spasms are rare. This comorbid condition may be associated with the distribution of the brain lesions and the age at onset of Alexander disease. PMID- 22818991 TI - Gallbladder adenomyomatosis: a malignant masquerader. PMID- 22819001 TI - Biomechanical comparison of internal fixation techniques for the Akin osteotomy of the proximal phalanx. AB - The Akin osteotomy is performed at the proximal phalanx for correction of an abducted great toe in a hallux abducto valgus deformity. Several internal fixation techniques have been widely advocated; however, their respective stabilities have not been compared. A biomechanical analysis was performed comparing 5 commonly used fixation techniques for the Akin osteotomy to determine the strongest method in simulated weightbearing in sawbone models. An Akin osteotomy was uniformly performed on 25 sawbones and fixated with 5 different internal fixation types, including a 2-hole locking plate and locking screws, a heat-sensitive memory staple (8 mm * 8 mm), a 28-gauge monofilament wire, 2.7-mm bicortical screws, and crossed 0.062-in. Kirschner wires. The results of simulated weightbearing load to failure rates with an Instron compression device demonstrated the following mean load to failures: crossed Kirschner wire, 57.05 N; 2-hole locking plate, 36.49 N; monofilament wire, 35.69 N; heat-sensitive memory staple, 34.32 N; and 2.7-mm bicortical screw, 13.66 N. Statistical analysis demonstrated the crossed Kirschner wire technique performed significantly better than the other fixation techniques (p < .007); the 4 other techniques were found not to be significantly different statistically (p = .041) from each another. Our study results suggest a crossing Kirschner wire construct significantly increases the stability of the Akin osteotomy in a sawbone model. This might be clinically extrapolated in an effort to improve patient outcomes because these osteotomies can undergo nonunion and malunion, resulting in postoperative pain and swelling. PMID- 22819002 TI - Early protected weightbearing after open reduction internal fixation of ankle fractures. AB - The present retrospective study assessed the complications and loss of reduction in 126 patients aged 16 years or older who bore weight in a short leg cast within 15 days after surgical repair of acute unilateral closed ankle fractures from January 1997 to December 2003. Fracture reduction was assessed on immediate postoperative and weightbearing digital radiographs at least 6 weeks after surgery. The medical records were reviewed for postoperative complications. Complete radiographs were available for 81 patients. The mean follow-up period was 171 (range 42 to 1275) days. The mean patient age was 50 years. Patients began walking an average of 8 days after surgery. From the medical record review, no cases of malunion or nonunion occurred. A total of 14 complications developed in 12 (9.5%) of 126 patients, including a delay in wound healing in 6, nerve paresthesia in 5, and hardware migration in 1. The patients aged 60 years or older had a slightly greater overall complication rate (6 of 38, p = .18). Patients who walked on postoperative day 1 had slightly more wound problems (2 of 19, p = .36). Of the 81 ankle fracture radiographs, 80 (98.8%) showed no displacement in fracture reduction on the final follow-up examination. One patient had a 2-mm loss of fracture reduction and was allowed to walk on postoperative day 1 (p = .09). These results support early protected weightbearing after operative treatment of closed isolated lateral malleolar and bimalleolar ankle fractures without syndesmotic involvement in patients of all ages. PMID- 22819003 TI - Symptomatic first metatarsocuneiform nonunion revised by arthroscopic lapidus arthrodesis. AB - Lapidus arthrodesis is indicated for painful, advanced hallux valgus and symptomatic first ray hypermobility with or without arthrosis of the joint. Nonunion of the first metatarsocuneiform joint fusion is the most frequent complication of attempted lapidus arthrodesis. We present a case of painful first metatarsocuneiform nonunion that was successfully treated using arthroscopic revision lapidus arthrodesis to describe this unusual approach to a known postoperative complication. PMID- 22819004 TI - Bronchoscopy during non-invasive mechanical ventilation: a review of techniques and procedures. AB - Non-invasive mechanical ventilation (NIMV) is used to treat acute respiratory failure by improving gas exchange abnormalities and reducing the signs of respiratory effort, dyspnea and the activity of accessory respiratory muscles. Bronchoscopy is a key technique in the study of respiratory diseases that is necessary to perform in acute and critical patients, often times only after orotracheal intubation (OTI) due to possible complications of the technique. In this review, we evaluate the evidence of NIMV use during bronchoscopy, concluding that its use should be considered in severe patients as an alternative that is capable of preventing the complications related with OTI and mechanical ventilation, especially in patients with chronic obstructive pulmonary disease and with a tendency towards developing hypercapnia. PMID- 22819005 TI - Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: a meta analysis of epidemiological studies: pesticide exposure as a risk factor for ALS. AB - BACKGROUND: Exposure to pesticides and agricultural chemicals has been linked to amyotrophic lateral sclerosis (ALS) although findings have been inconsistent. A meta-analysis of studies published through May, 2011 was conducted to investigate the association of pesticide exposure and risk of ALS. METHODS: Six peer-reviewed studies that met criteria were included in a meta-analysis of men involving 1,517 ALS deaths from one retrospective cohort study and 589 ALS or motor neuron disease cases from five case-control studies. A random effects model was used to calculate sex-specific pooled odds ratios (ORs). RESULTS: Evidence was found for an association of exposure to pesticides and risk of ALS in male cases compared to controls (OR=1.88, 95% CI: 1.36-2.61), although the chemical or class of pesticide was not specified by the majority of studies. CONCLUSION: This meta analysis supports the relationship of exposure to pesticides and development of ALS among male cases compared to controls. The weight of evidence links pesticide exposure to ALS; however, additional prospective studies with a target exposure group are necessary to better elucidate the relationship. Future research should focus on more accurate exposure assessment and the use of job exposure matrices. PMID- 22819006 TI - Subclinical porcine circovirus infection: what lies beneath. PMID- 22819007 TI - A new system to classify submucous myomas: a Brazilian multicenter study. AB - OBJECTIVE: To evaluate 2 different predicting scores of submucous myoma removal, fluid balance, and operative time in woman undergoing hysteroscopic myomectomy. DESIGN: A multicenter and prospective study (Canadian Task Force classification II-2). SETTING: Six hysteroscopy centers in Brazil. PATIENTS: A total of 191 women who underwent hysteroscopic resection of 205 submucous myomas. INTERVENTION: Resection of submucous myomas (hysteroscopic myomectomy). Myomas were scored according to the European Society for Gynaecological Endoscopy (ESGE) and STEPW (size, topography, extension, penetration, and wall) classifications. The validation of the 2 classifications was assessed with sensitivity and specificity of each classification, with their best cutoff point. MAIN OUTCOME MEASURES: To correlate ESGE and STEPW classifications with complete or incomplete removal of submucous myoma, length of surgery, surgical complications, and fluid balance. RESULTS: Removal of the myoma was complete in 190 (92.7%) of 205 myomectomies, and incomplete in 15 (7.3%). All 140 (100%) of 140 myomas with a score <= 4 in the STEPW classification were completely removed, and 50 (76.9%) of 65 myomas with a score >4 were removed. All 15 (100%) cases of incomplete hysteroscopic myomectomy had a STEPW score >4. With the ESGE classification, 156/164 (95.1%) cases of type 0 and type 1 myomas, and 34/41 (82.9%) of type 2 were completely resected. STEPW scores >4 were statistically associated with longer duration of surgery, surgical complications, higher levels of fluid balance, and use of gonadotropin releasing hormone analogue if compared with lower scores. The ESGE scores were not associated with any of these variables. CONCLUSION: Classifying submucous myomas with the STEPW classification allows better prediction of myoma removal, fluid balance, length of surgery and surgical complications in hysteroscopic myomectomy than ESGE classification. PMID- 22819008 TI - The "Ruston Stretch": a simple way to get a large specimen out through a small hole. AB - The balance between port-site size and ease of specimen removal is often a challenge in laparoscopic surgery. Herein we describe a simple technique that circumvents this dilemma by means of port-site dilation using Hegar dilators. PMID- 22819009 TI - Analysis of gait and balance through a single triaxial accelerometer in presymptomatic and symptomatic Huntington's disease. AB - PURPOSE: To investigate the capacity of a single triaxial accelerometer sensor in detecting gait and balance impairments in pre-manifest and manifest Huntington's disease (HD) subjects. METHODS: Fourteen manifest HD (MHD) (age: 51.83+/-14.8), ten pre-manifest HD (PHD) (age: 44.8+/-11.7) and ten healthy subjects (HLY) (age: 56.4+/-10.9) were recruited. The sensor was attached to the upper sternum as subjects completed gait and Romberg balance tests. An inverted pendulum model of the body's centre of mass and an unbiased autocorrelation procedure were employed to derive gait parameters from the triaxial accelerometer signal. The accuracy of the gait measurements was compared to those recorded by a computerized walkway. RESULTS: Strong agreement was seen between the sensor and the walkway; cadence (ICC=0.95, CI=[0.75, 0.97]), velocity (ICC=0.94, CI=[0.75, 0.97]) and step length (ICC=0.89, CI=[0.77, 0.95]). Sensor derived velocity was significantly higher in HLY (p<0.001) and PHD (p<0.005) when compared to MHD. Step and stride length was significantly longer in HLY (p<0.05) and PHD (p<0.001) when compared to MHD. Significant differences between subject groups across all four balance tasks (p<0.001) were found. CONCLUSION: An accelerometer based sensor may be an effective means of differentiating between pre-manifest and manifest Huntington's disease subjects. PMID- 22819010 TI - Stance width influences frontal plane balance responses to centripetal accelerations. AB - Whenever the body is moving in a curvilinear path, inertial torques resulting from centripetal accelerations act on the body and must be counteracted to maintain stability. We tested the hypothesis that healthy subjects orient their center of mass in the position where gravitational torques offset the inertial torques due to centripetal accelerations. Ten healthy subjects stood on a platform that rotated in a circle at either a slow or fast speed, eyes open or closed, and in narrow or wide stance. Upper body, lower body, and center of mass (CoM) tilt with respect to vertical were measured and averaged across a 40 second time period of constant velocity. Body tilt was compared to the gravito-inertial acceleration (GIA) angle with respect to vertical. In all moving conditions, the upper body, lower body, and CoM tilted inward. However, this inward tilt did not reach the predicted GIA angle (CoM tilt was ~78% and 39% toward the predicted GIA angle in narrow and wide stance, respectively). Ratios of body tilt to GIA angle were minimally influenced by visual availability and magnitude of centripetal acceleration; but were largely influenced by stance width whereby narrow stance inward tilt was greater than wide stance. These results further highlight the important influence of the base of support on balance control strategies and enhance our understanding of how the balance control system compensates for inertial torques generated from centripetal accelerations. PMID- 22819011 TI - Pre-mRNA splicing in disease and therapeutics. AB - In metazoans, alternative splicing of genes is essential for regulating gene expression and contributing to functional complexity. Computational predictions, comparative genomics, and transcriptome profiling of normal and diseased tissues indicate that an unexpectedly high fraction of diseases are caused by mutations that alter splicing. Mutations in cis elements cause missplicing of genes that alter gene function and contribute to disease pathology. Mutations of core spliceosomal factors are associated with hematolymphoid neoplasias, retinitis pigmentosa, and microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). Mutations in the trans regulatory factors that control alternative splicing are associated with autism spectrum disorder, amyotrophic lateral sclerosis (ALS), and various cancers. In addition to discussing the disorders caused by these mutations, this review summarizes therapeutic approaches that have emerged to correct splicing of individual genes or target the splicing machinery. PMID- 22819013 TI - In-vitro validation of cytokine neutralizing antibodies by testing with ovine mononuclear splenocytes. AB - Cytokines have gained increasing attention as therapeutic targets in inflammation related disorders and inflammatory conditions have been investigated in sheep. Monoclonal antibodies (mAbs) specific for the ovine pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 could be used to study the effects of blocking pro-inflammatory cytokines in sheep. Ovine-specific IL-1beta and IL-6 proteins and mAbs specific for these molecules were produced and the ability of the mAbs to neutralize the proteins was tested in cultures of ovine splenic mononuclear cells. Expression of nuclear factor (NF)-kappabeta and signal transducer and activator of transcription (STAT)-3 was evaluated by western blotting and densitometric quantification. Treatment with purified IL-1beta and IL-6 proteins increased NF-kappabeta (P < 0.001) and STAT-3 (P < 0.01) expression, respectively, in cell culture. Treatment with these proteins that were pre incubated with IL-1beta and IL-6 mAbs attenuated (P < 0.01) these effects. These results confirm the bioactivity of ovine IL-1beta and IL-6 proteins and the neutralizing capacity of anti-ovine-IL-1beta and -IL-6 mAbs in vitro. These mAbs could be used to investigate anti-inflammatory strategies for attenuation of the effects of these pro-inflammatory cytokines in sheep. PMID- 22819012 TI - Malignant dysembryoplastic neuroepithelial tumour in a zebrafish (Danio rerio). AB - Neuroectodermal tumours in man, including medulloblastoma, medulloepithelioma, neuroblastoma, esthesioneuroblastoma, primitive neuroectodermal tumour and dysembryoplastic neuroepithelial tumour, typically occur in children and young adults. These tumour types are occasionally observed in juvenile and adult zebrafish (Danio rerio) either as induced tumours in carcinogen-exposed zebrafish or as an incidental finding in zebrafish>=2years of age. An adult zebrafish submitted for routine histological examination was sent for a second opinion consultation after an uncharacteristic brain mass was identified. Microscopically, the expansile and infiltrative extracortical mass arising from the cerebellum had a diffuse microcystic pattern with solid hypercellular regions occupying 80% of the extrameningeal space and effacing the endomeninx and significantly displacing the metencephalon. The mass was composed of dense sheets of oligodendrocyte-like cells, random neurons and pseudocysts containing 'floating neurons' within a scant mucinous matrix. Neoplastic cells demonstrated positive perinuclear and intracytoplasmic expression of S-100. Malignant dysembryoplastic neuroepithelial tumour was diagnosed based on the histological features of the brain mass, which were indistinguishable from the human tumour. To our knowledge, this is the first report of a dysembryoplastic neuroepithelial tumour in a zebrafish. PMID- 22819014 TI - Expression of leucocyte function-associated antigen-1 and intercellular adhesion molecule-1 in the lungs of pigs infected with Actinobacillus pleuropneumoniae. AB - The aim of this study was to determine the expression of leucocyte function associated antigen (LFA)-1 (CD11a/CD18) by neutrophils and intercellular adhesion molecule (ICAM)-1 (CD54) by endothelial cells in the lungs of pigs that had been infected experimentally with Actinobacillus pleuropneumoniae. Sixty-four 7-week old conventional pigs were allocated randomly into infected (n = 40) or control (n = 24) groups. Five infected and three uninfected pigs were killed at 3, 6, 9, 12, 24, 36, 48 and 60 h post inoculation (hpi). Strong immunohistochemical expression of LFA-1 and ICAM-1 was detected frequently in neutrophils in the alveolar space and in endothelial cells in the capillaries of the alveolar septa, respectively. LFA-1 and ICAM-1 expression appeared to correlate with the onset of neutrophil infiltration into the alveolar space. The interaction between ICAM-1 and LFA-1 may be associated with the adherence of neutrophils to vascular endothelium, thereby permitting transmigration of these cells into inflamed lung. PMID- 22819015 TI - Acute and chronic disease associated with naturally occurring T-2 mycotoxicosis in sheep. AB - A flock of approximately 1,000 sheep were exposed intermittently to food contaminated with T-2 toxin (T-2), a potent type-A trichothecene mycotoxin produced primarily by Fusarium sporotrichioides and Fusarium poae. In the acute stage of the intoxication, affected sheep developed anorexia, decreased water consumption, ruminal atony, soft faeces and apathy. One hundred and ninety of the exposed sheep died. The main gross lesions observed in animals dying during the acute disease were rumenitis and ulcerative abomasitis, depletion of lymphocytes in lymphoid organs, necrosis of the exocrine pancreas, myocarditis and intense oedema of the skin and brain. Sheep developing the chronic stage of disease showed weight loss and reproductive inefficiency and the main pathological features observed in animals dying during this stage were gastrointestinal inflammation, myocardial fibrosis and necrotic and suppurative lesions in the oral cavity. Opportunistic infections (e.g. mycotic mastitis or parasitic pneumonia) were also identified in these animals. Increased serum concentrations of lactate dehydrogenase and creatine kinase were observed, most likely related to heart lesions. T-2 toxins were detected in all samples of the diet of these animals that were analyzed. The changes in the sheep reported here are similar to those described previously in experimental studies. Lesions observed in the present animals suggest an additional cardiotoxic effect of T-2 in sheep. PMID- 22819016 TI - Histopathological and immunohistochemical features of vitreoretinopathy in Shih Tzu dogs. AB - Fifty cases of Shih Tzu ocular vitreoretinopathy were selected from the database of the Comparative Ocular Pathology Laboratory of Wisconsin. Cases with severe coexisting conditions (e.g. corneal disease, uveitis or endophthalmitis) were excluded. Microscopical changes were evaluated and immunohistochemistry was used to define spindle cells, gliosis and the presence of basement membranes in the vitreous. Expression of glial fibrillary acidic protein, vimentin and smooth muscle actin was also performed. The mean age of the 50 cases was 10.1 years (range 2.5-15 years). The most characteristic microscopical abnormalities (50/50 cases) were retinal detachment and extensive retinal tear. Additionally, extracellular, eosinophilic matrix material admixed with few spindle cells, and pre-iridal fibrovascular membrane, goniodysgenesis, secondary glaucoma, hypermature and subcapsular cataract were detected. The spindle cells within the collagen matrix were strongly labelled for expression of vimentin, with weaker expression of smooth muscle actin. PMID- 22819017 TI - Well-differentiated hepatocellular carcinoma in a ring-tailed lemur (Lemur catta). AB - A 16-year-old male ring-tailed lemur (Lemur catta) was presented with severe cachexia and an abdominal mass. The encapsulated, multilobular mass replaced the right medial lobe of the liver and compressed the adjacent gall bladder. Multiple haemorrhages and necrotic foci were found within the mass. Microscopically, neoplastic cells formed cords of moderately pleomorphic, polygonal cells with mild to moderate anaplasia. Immunohistochemical markers used for diagnosis of hepatocellular carcinomas in man were used to characterize the neoplastic cells, which expressed hepatocyte-specific antigen, but not glypican-3 or polyclonal carcinoembryonic antigen. Gross, microscopical and immunohistochemical features of the tumour were most consistent with a well-differentiated hepatocellular carcinoma. Although this tumour is common among prosimians, to the authors' knowledge this is the first documented case in a ring-tailed lemur. Hepatocellular carcinomas have been associated with hepatitis virus infections and excessive hepatic iron in man; however, no association was established between this tumour and viral infection or hepatic iron storage disease in the present case. PMID- 22819018 TI - Molecular phenotype in mammary tumours of queens: correlation between primary tumour and lymph node metastasis. AB - The molecular characterization of mammary tumours represents a new stage in the development of effective predictive models and targeted therapies. The aim of this study was to evaluate the relationship between the molecular phenotype of a primary feline mammary tumour and that of a related lymph node metastasis. Twenty one mammary tumour samples and their lymph node metastases were selected and evaluated immunohistochemically for expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (c-erbB-2), cytokeratin 5/6, cytokeratin 14, cytokeratin 19 and protein 63. Mammary tumours were classified into five subtypes: luminal A, luminal B, c-erbB-2 overexpressing, basal-like and normal-like, based on an algorithm applied in both human and veterinary medicine. Concordance between the primary tumour and its lymph node metastasis was detected in 12 of 21 cases (57.1%). In the remaining nine cases (42.9%) there was discordance in the molecular profile at the two sites. Therefore, the tumour molecular profile must be evaluated in both sites in order to obtain definitive identification of the tumour profile (or profiles) and to plan an appropriate therapy. PMID- 22819019 TI - Congenital ascites due to hepatoblastoma with extensive peritoneal implantation metastases in a premature equine fetus. AB - A premature dead equine fetus with excessive fluctuating distension of the abdomen was delivered by extraction. Post-mortem examination revealed ascites and a solitary, irregular, bulging, multinodular, firm, yellow mass of 25 cm in diameter in the right liver lobe. Extensive peritoneal implantation metastases were present. The masses were composed of polygonal embryonal cells arranged in sheets and nests. Based on the immunohistochemical expression of Ki67, low molecular weight cytokeratin and alpha-1 fetoprotein, a diagnosis of hepatoblastoma with peritoneal implantation metastases was made. PMID- 22819020 TI - Do persistent RNA viruses fit the trade-off hypothesis of virulence evolution? AB - The evolution of virulence has been studied from a number of theoretical perspectives, and a few experimental systems. Although there is no consensus on an overarching framework that covers all situations, the 'trade-off' hypothesis is a useful framework for examining the nature of symbiotic relationships between viruses and their hosts. Here we use this framework to look at persistent RNA viruses of unicellular eukaryotes and fungi that are themselves parasites of more complex eukaryotes. In these tripartite symbioses we look at the cost to the microbial host as well as the macrobial host. In some cases benefits conferred by the virus to the microbial host result in greater costs to the macrobial host, in other cases the microbial host suffers a greater cost but the macrobial host wins, and in some cases everyone wins. In all cases the trade-off hypothesis can be invoked. PMID- 22819021 TI - Mechanisms of human T-lymphotropic virus type 1 transmission and disease. AB - Human T-lymphotrophic virus type-1 (HTLV-1) infects approximately 15-20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3-5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma, or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as p30, p12, p13 and the antisense-encoded HTLV-1 basic leucine zipper factor (HBZ). While progress has been made in knowledge of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full-length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1. PMID- 22819022 TI - The diversity of human cancer viruses. PMID- 22819036 TI - Prognostic impact of diabetes mellitus and hypertension for mid-term outcome of patients with acute myocardial infarction who underwent percutaneous coronary intervention. AB - BACKGROUND: The synergistic effect of diabetes mellitus (DM) and hypertension on mid-term outcome among acute myocardial infarction (MI) patients undergoing percutaneous coronary intervention (PCI) is still controversial. METHODS: A total of 2438 patients with acute MI who underwent PCI from January 2007 to November 2010 were studied. Patients were stratified to four groups according to the presence of DM or hypertension and followed up during 12 months. We analyzed the influence of hypertension and DM on major adverse cardiac events (MACE: death, recurrent MI, repeated coronary artery revascularization). RESULTS: No history of hypertension or DM was found in 35.0%, a history of hypertension in 27.2%, a history of DM in 15.0%, and a history of both disease entities in 22.8%. The rate of MACE was significantly higher in hypertensive DM group (15.9% vs. 22.9% vs. 28.8% vs. 37.0%, log-rank p<0.001). In multivariate analysis, hypertension and DM were meaningful predictors of mid-term mortality, and the combination of the two was a stronger predictor (hazard ratio=1.790; 95% confidence interval=1.313 2.442; p<0.001). CONCLUSIONS: After PCI, acute MI patients with a history of DM or hypertension had a higher mid-term mortality than acute MI patients without such a history. The combination of DM and hypertension appeared to be more strongly associated with mortality than DM or hypertension alone. PMID- 22819037 TI - Role of apoptosis in left ventricular remodeling after acute myocardial infarction. PMID- 22819038 TI - Predictive factors for successful weaning from percutaneous cardiopulmonary support in patients with cardiogenic shock complicating acute myocardial infarction. AB - BACKGROUND AND PURPOSE: Percutaneous cardiopulmonary support (PCPS) is useful in the rescue of patients who have experienced severe cardiogenic shock. We investigated the predictive factors of survival among patients with cardiogenic shock requiring PCPS. METHODS AND SUBJECTS: We enrolled 29 patients (21 men and 8 women, 73 +/- 10 years old) with circulatory collapse complicating acute myocardial infarction (AMI) requiring PCPS. Fifteen patients could be weaned from PCPS and survived for more than 1 month (group A), while the other 14 patients could not (group B). We investigated the initial PCPS settings, and performed the appropriate laboratory tests. Hemodynamic data and arterial base excess (BE) values were recorded throughout the PCPS treatment. RESULTS: There was no difference in the laboratory test results or the left ventricular ejection fraction between the groups at the start of PCPS. PCPS flow (l/min) was significantly lower in group A than in group B at the 24th hour of PCPS (2.26 +/- 0.36 and 2.54 +/- 0.41, respectively). There were no differences in blood pressure between the groups. During the 24-h period prior to the end of PCPS, BE remained almost normal in group A. In group B, BE decreased continuously throughout the same period. BE values were significantly lower compared to those obtained in group A 12h prior to the end of PCPS. CONCLUSIONS: A reduction in PCPS flow without hemodynamic collapse may allow for successful weaning from PCPS. BE may be a potent factor in determining when to terminate PCPS. PMID- 22819039 TI - Clinical significance of acid-base balance in an emergency setting in patients with acute heart failure. AB - BACKGROUND AND PURPOSE: The role of an arterial blood gas analysis in acute heart failure (AHF) remains unclear. The acid-base balance could help to treat AHF, and it might help to distinguish different types of AHF, while it might be associated with the AHF prognosis. The present study was conducted to determine the relationship between the arterial blood gas sample at the time of hospital admission and clinical findings on admission, outcomes. METHODS AND RESULTS: Six hundred twenty-one patients with AHF admitted to the intensive care unit were analyzed. Patients were assigned to an alkalosis group (n=99, pH>7.45), normal group (n=178, 7.35<= pH<= 7.45), and acidosis group (n=344, pH<7.35). The clinical findings on admission and outcomes (in-hospital mortality and any-cause death within 2 years) were compared between the three groups. The white blood cell counts (WBC), serum levels of total protein, albumin, and glucose were significantly lower, and the serum levels of C-reactive protein (CRP) and total bilirubin were significantly higher in the alkalosis group. Patients with orthopnea were significantly fewer, and the systolic blood pressure (SBP) and heart rate (HR) were significantly lower in the alkalosis group. The results of a multivariate logistic regression model for in-hospital mortality found that alkalosis was an independent risk factor (p=0.017, odds ratio: 2.589; 95% confidence interval: 1.186-5.648). The Kaplan-Meier curves showed the prognosis for any-cause death to be significantly poorer in the alkalosis group than in the normal group (p=0.026). CONCLUSIONS: The factors associated with alkalosis AHF were high CRP, bilirubin, and low WBC, glucose, total protein, and albumin. The patients with alkalosis AHF were less likely to have orthopnea with low SBP and HR. They suggested that the patients with alkalosis AHF might have experienced AHF for a few days and were associated with high mortality. PMID- 22819040 TI - Ongoing myocardial damage in patients with heart failure and preserved ejection fraction. AB - BACKGROUND: The relationship between ongoing myocardial damage and heart failure with preserved left ventricular systolic function (HF-PEF) is still unclear. To investigate this relationship, we measured the cardiac-specific cytosolic marker, heart-type fatty acid binding protein (H-FABP), and a myofibrillar component (troponin T), and analyzed clinical outcomes. METHODS AND RESULTS: Consecutive heart failure patients (n=151) with echocardiographic left ventricular ejection fraction >50% were prospectively enrolled. The cut-off values for myocardial membrane injury (H-FABP >4.3 ng/mL) and myofibrillar injury (troponin T >0.01 ng/mL) were defined using receiver operating characteristic curves. Myocardial membrane injury was observed more frequently than myofibrillar injury (41% vs. 26% of patients, p<0.05). Patients were followed up for a median of 694 days, with the end-points being cardiovascular death or re-hospitalization. By multivariate analysis, the serum H-FABP level was an independent predictor of cardiovascular events (hazard ratio 1.165 per 1 ng/mL increase, 95% confidence interval 1.034-1.314, p=0.012). CONCLUSIONS: Latent myocardial injury was frequently observed in patients with HF-PEF. The circulating H-FABP level was an independent predictor of subsequent cardiovascular events. PMID- 22819043 TI - Building waste management core indicators through Spatial Material Flow Analysis: net recovery and transport intensity indexes. AB - In this paper, the material and spatial characterization of the flows within a municipal solid waste (MSW) management system are combined through a Network Based Spatial Material Flow Analysis. Using this information, two core indicators are developed for the bio-waste fraction, the Net Recovery Index (NRI) and the Transport Intensity Index (TII), which are aimed at assessing progress towards policy-related sustainable MSW management strategies and objectives. The NRI approaches the capacity of a MSW management system for converting waste into resources through a systematic metabolic approach, whereas the TII addresses efficiency in terms of the transport requirements to manage a specific waste flow throughout the entire MSW management life cycle. Therefore, both indicators could be useful in assessing key MSW management policy strategies, such as the consecution of higher recycling levels (sustainability principle) or the minimization of transport by locating treatment facilities closer to generation sources (proximity principle). To apply this methodological approach, the bio waste management system of the region of Catalonia (Spain) has been chosen as a case study. Results show the adequacy of both indicators for identifying those points within the system with higher capacity to compromise its environmental, economic and social performance and therefore establishing clear targets for policy prioritization. Moreover, this methodological approach permits scenario building, which could be useful in assessing the outcomes of hypothetical scenarios, thus proving its adequacy for strategic planning. PMID- 22819041 TI - Distal-less 3 haploinsufficiency results in elevated placental oxidative stress and altered fetal growth kinetics in the mouse. AB - Distal-less 3 (Dlx3)(-/-) mice die at E9.5 presumably due to an abnormal placental phenotype including reduced placental vasculature and secretion of placental growth factor. To examine the role of Dlx3 specifically within the epiblast, Dlx3 conditional knockout mice were generated using an epiblast specific Meox2(CreSor) allele. Dlx3(-/fl), Meox2(CreSor) animals were born at expected frequencies and survived to weaning providing indirect evidence that loss of Dlx3 within the trophoectoderm plays a critical role in fetal survival in the Dlx3(-/-) mouse. We next examined the hypothesis that loss of a single Dlx3 allele would have a negative impact on placental and fetal fitness. Dlx3(+/-) mice displayed reduced fetal growth beginning at E12.5 compared with Dlx3(+/+) controls. Altered fetal growth trajectory occurred coincident with elevated oxidative stress and apoptosis within Dlx3(+/-) placentas. Oral supplementation with the superoxide dismutase mimetic, Tempol, rescued the fetal growth and placental cell death phenotypes in Dlx3(+/-) mice. To determine the potential mechanisms associated with elevated oxidative stress on the Dlx3(+/-) placentas, we next examined vascular characteristics within the feto-placental unit. Studies revealed reduced maternal spiral artery luminal area in the Dlx3(+/-) mice receiving water; Dlx3(+/-) mice receiving Tempol displayed maternal spiral artery luminal area similar to control Dlx3(+/+) mice. We conclude that reduced Dlx3 gene dose results in diminished fetal fitness associated with elevated placental cell oxidative stress and apoptosis coincident with altered vascular remodeling. Administration of antioxidant therapy ameliorated this feto-placental phenotype, suggesting that Dlx3 may be required for adaptation to oxidative stresses within the intrauterine environment. PMID- 22819042 TI - Critical role for mast cells in interleukin-1beta-driven skin inflammation associated with an activating mutation in the nlrp3 protein. AB - Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin 1beta (IL-1beta) production induced by mutations in the NLRP3 protein in humans, but the mechanisms involved remain poorly understood. Using a mouse model, we show a role for the indigenous microbiota and mast cells (MCs) in skin disease associated with mutant Nlrp3 protein. Unlike normal cells, MCs expressing mutant Nlrp3 produced IL-1beta in response to lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha). In neonatal mice, the microbiota induced TNF-alpha and IL-1beta and promoted skin disease. MC deficiency greatly reduced disease in Nlrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1beta in MCs. Surprisingly, neutralization of TNF-alpha abrogated IL-1beta production and skin disease in neonatal Nlrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1beta production and skin inflammation in neonatal mice with the CAPS-associated Nlrp3 mutation. PMID- 22819044 TI - Review on recent applications of the liquid waveguide capillary cell in flow based analysis techniques to enhance the sensitivity of spectroscopic detection methods. AB - Incorporation of long path length liquid waveguide capillary cell (LWCC or LCW) into spectrometric detection systems can increase the sensitivity of these by orders of magnitude (up to 500 times), and consequently can reduce the detection limits. The combination of the long path length spectrophotometry with flow methodologies can provide analytical solutions for various challenges in the field of environmental, biochemical and food chemistry. In this present work, the analytical applications of the long capillary cells are summarised and critically discussed. A historical overview of the cell development is given; applications in different areas are presented and grouped by analyte type. Major improvements achieved based on the use of the LWCC in the analytical characteristics (like sensitivity and detection limit) are emphasised while some of the limitations are also discussed. PMID- 22819045 TI - Single-drop microextraction as a powerful pretreatment tool for capillary electrophoresis: A review. AB - Single drop microextraction (SDME) is a convenient and powerful preconcentration and sample cleanup method for capillary electrophoresis (CE). In SDME, analytes are typically extracted from a sample donor solution into an acceptor drop hanging at the inlet tip of a capillary. The enriched drop is then introduced to the capillary for CE analysis. Since the volume of the acceptor drop can be as small as a few nanoliters, the consumption of solvents can be minimized and the preconcentration effect is enhanced. In addition, by covering the acceptor phase with an organic layer or by using an organic acceptor phase, inorganic ions such as salts in the sample solution can be blocked from entering the acceptor phase, providing desalting effects. Here, we describe the basic principles and instrumentation for SDME and its coupling with CE. We also review recent developments and applications of SDME-CE. PMID- 22819046 TI - Zeolite A functionalized with copper nanoparticles and graphene oxide for simultaneous electrochemical determination of dopamine and ascorbic acid. AB - A novel Cu-zeolite A/graphene modified glassy carbon electrode for the simultaneous electrochemical determination of dopamine (DA) and ascorbic acid (AA) has been described. The Cu-zeolite A/graphene composites were prepared using Cu(2+) functionalized zeolite A and graphene oxide as the precursor, and subsequently reduced by chemical agents. The composites were characterized by X ray diffraction, Fourier transform infrared spectra and scanning electron microscopy. Based on the Cu-zeolite A/graphene-modified electrode, the potential difference between the oxidation peaks of DA and AA was over 200mV, which was adequate for the simultaneous electrochemical determination of DA and AA. Also the proposed Cu-zeolite/graphene-modified electrode showed higher electrocatalytic performance than zeolite/graphene electrode or graphene-modified electrode. The electrocatalytic oxidation currents of DA and AA were linearly related to the corresponding concentration in the range of 1.0*10(-7)-1.9*10(-5)M for DA and 2.0*10(-5)-2.0*10(-4)M for AA. Detection limits (S/N=3) were estimated to be 4.1*10(-8)M for DA and 1.1*10(-5)M for AA, respectively. PMID- 22819047 TI - Electro membrane extraction of biological anions with ion chromatographic analysis. AB - A simple and sensitive single step electro membrane extraction (EME) procedure was demonstrated for biological organic anions with determination by ion chromatography (IC). Nitrite, adipate, oxalate, iodide, fumarate, thiocyanate and perchlorate were extracted from aqueous donor solutions, across a supported liquid membrane (SLM) consisting of methanol impregnated in the walls of a porous polypropylene membrane bag and into an alkaline aqueous acceptor solution in the lumen of the propylene envelope by the application of potential of 12V applied across the SLM. The acceptor solution was analyzed by IC. Parameters affecting the extraction performance such as type of SLM, extraction time, pH of the donor and acceptor solution, and extraction voltage were studied. The most favorable EME conditions were methanol as the SLM, extraction time of 5min, pH of acceptor and sample solutions of 12 and 4, respectively, and a voltage of 12V. Portable 12V batteries were used in the study. Under these optimized conditions, all anions had enrichment factors ranging from 3.6 to 36.2 with relative standard deviations (n=3) of between 6.6 and 17.5%. Good linearity ranging from 0.1 to 10MUgmL(-1) with coefficients of correlation (r) of between 0.9981 and 0.9996 were obtained. The limits of detection of the EME-IC method were from 0.01 to 0.14MUgmL(-1). The developed methodology was applied to amniotic fluid samples to evaluate the feasibility of the method for real applications. PMID- 22819048 TI - Evaluation of DGT techniques for measuring inorganic uranium species in natural waters: Interferences, deployment time and speciation. AB - Three adsorbents (Chelex-100, manganese dioxide [MnO(2)] and Metsorb), used as binding layers with the diffusive gradient in thin film (DGT) technique, were evaluated for the measurement of inorganic uranium species in synthetic and natural waters. Uranium (U) was found to be quantitatively accumulated in solution (10-100MUgL(-1)) by all three adsorbents (uptake efficiencies of 80-99%) with elution efficiencies of 80% (Chelex-100), 84% (MnO(2)) and 83% (Metsorb). Consistent uptake occurred over pH (5-9), with only MnO(2) affected by pH<5, and ionic strength (0.001-1molL(-1) NaNO(3)) ranges typical of natural waters, including seawater. DGT validation experiments (5 days) gave linear mass uptake over time (R(2)>=0.97) for all three adsorbents in low ionic strength solution (0.01M NaNO(3)). Validation experiments in artificial sea water gave linear mass uptake for Metsorb (R(2)>=0.9954) up to 12h and MnO(2) (R(2)>=0.9259) up to 24h. Chelex-100 demonstrated no linear mass uptake in artificial sea water after 8h. Possible interferences were investigated with SO(4)(2-) (0.02-200mgL(-1)) having little affect on any of the three DGT binding layers. PO(4)(3-) additions (5MUgL( 1)-5mgL(-1)) interfered by forming anionic uranyl phosphate complexes that Chelex 100 was unable to accumulate, or by directly competing with the uranyl species for binding sites, as with MnO(2) and the Metsorb. HCO(3)(-) (0.1-500mgL(-1)) additions formed anionic species which interfered with the performance of the Chelex-100 and the MnO(2), and the Ca(2+) (0.1-500mgL(-1)) had the affect of forming labile calcium uranyl species which aided uptake of U by all three resins. DGT field deployments in sea water (Southampton Water, UK) gave a linear mass uptake of U over time with Metsorb and MnO(2) (4 days). Field deployments in fresh water (River Lambourn, UK) gave linear uptake for up to 7 and 4 days for Metsorb and MnO(2) respectively. Field deployment of the Metsorb-DGT samplers with various diffusive layer thicknesses (0.015-0.175cm) allowed accurate measurements of the diffusive boundary layer (DBL) and allowed DBL corrected concentrations to be determined. This DBL-corrected U concentration was half that determined when the effect of the DBL was not considered. The ability of the DGT devices to measure U isotopic ratios with no isotopic fractionation was shown by all three resins, thereby proving the usefulness of the technique for environmental monitoring purposes. PMID- 22819050 TI - A strategy for efficient discovery of new natural compounds by integrating orthogonal column chromatography and liquid chromatography/mass spectrometry analysis: Its application in Panax ginseng, Panax quinquefolium and Panax notoginseng to characterize 437 potential new ginsenosides. AB - To discover new natural compounds from herbal medicines tends to be more and more difficult. In this paper, a strategy integrating orthogonal column chromatography and liquid chromatography/mass spectrometry (LC/MS) analysis was proposed, and was applied for rapid discovery of new ginsenosides from Panax ginseng (PG), Panax quinquefolium (PQ), and Panax notoginseng (PN). The ginsenosides extracts were fractionated by MCI gel*silica gel orthogonal column chromatography. The fractions were then separated on a C(18) HPLC column, eluted with a three component mobile phase (CH(3)CN/CH(3)OH/3mM CH(3)COONH(4)H(2)O), and detected by electrospray ionization tandem mass spectrometry. The structures of unknown ginsenosides were elucidated by analyzing negative and positive ion mass spectra, which provided complementary information on the sapogenins and oligosaccharide chains, respectively. A total of 623 comprising 437 potential new ginsenosides were characterized from the ethanol extracts of PG, PQ and PN. New acylations, diversified saccharide chains and C-17 side chains constituted novelty of the newly identified ginsenosides. An interpretation guideline was proposed for structural characterization of unknown ginsenosides by LC/MS. To confirm reliability of this strategy, two targeted unknown trace ginsenosides were obtained in pure form by LC/MS-guided isolation. Based on extensive NMR spectroscopic analysis and other techniques, they were identified as 3-O-[6-O-(E) butenoyl-beta-D-glucopyranosyl(1,2)-beta-D-glucopyranosyl]-20(S)-protopanaxadiol 20-O-beta-D-glucopyranosyl(1,6)-beta-D-glucopyranoside (named ginsenoside IV) and 3-O-beta-D-glucopyranosyl(1,2)-beta-D-glucopyranosyl-3beta,12beta,20(S),24(R) tetra hydroxy-dammar-25-ene-20-O-beta-D-glucopyranosyl(1,6)-beta-D glucopyranoside (ginsenoside V), respectively. The fully established structures were consistent with the MS-oriented structural elucidation. This study expanded our understanding on ginsenosides of Panax species, and the proposed strategy was proved efficient and reliable in the discovery of new minor compounds from herbal extracts. PMID- 22819049 TI - A quantitative liquid chromatography tandem mass spectrometry method for metabolomic analysis of Plasmodium falciparum lipid related metabolites. AB - Plasmodium falciparum is the causative agent of malaria, a deadly infectious disease for which treatments are scarce and drug-resistant parasites are now increasingly found. A comprehensive method of identifying and quantifying metabolites of this intracellular parasite could expand the arsenal of tools to understand its biology, and be used to develop new treatments against the disease. Here, we present two methods based on liquid chromatography tandem mass spectrometry for reliable measurement of water-soluble metabolites involved in phospholipid biosynthesis, as well as several other metabolites that reflect the metabolic status of the parasite including amino acids, carboxylic acids, energy related carbohydrates, and nucleotides. A total of 35 compounds was quantified. In the first method, polar compounds were retained by hydrophilic interaction chromatography (amino column) and detected in negative mode using succinic acid (13)C(4) and fluorovaline as internal standards. In the second method, separations were carried out using reverse phase (C18) ion-pair liquid chromatography, with heptafluorobutyric acid as a volatile ion pairing reagent in positive detection mode, using d(9)-choline and 4-aminobutanol as internal standards. Standard curves were performed in P. falciparum-infected and uninfected red blood cells using standard addition method (r(2)>0.99). The intra- and inter-day accuracy and precision as well as the extraction recovery of each compound were determined. The lower limit of quantitation varied from 50pmol to 100fmol/3*10(7)cells. These methods were validated and successfully applied to determine intracellular concentrations of metabolites from uninfected host RBCs and isolated Plasmodium parasites. PMID- 22819051 TI - De novo analysis of electron impact mass spectra using fragmentation trees. AB - The automated fragmentation analysis of high resolution EI mass spectra based on a fragmentation tree algorithm is introduced. Fragmentation trees are constructed from EI spectra by automated signal extraction and evaluation. These trees explain relevant fragmentation reactions and assign molecular formulas to fragments. The method enables the identification of the molecular ion and the molecular formula of a metabolite if the molecular ion is present in the spectrum. These identifications are independent of existing library knowledge and, thus, support assignment and structural elucidation of unknown compounds. The method works even if the molecular ion is of very low abundance or hidden under contaminants with higher masses. We apply the algorithm to a selection of 50 derivatized and underivatized metabolites and demonstrate that in 78% of cases the molecular ion can be correctly assigned. The automatically constructed fragmentation trees correspond very well to published mechanisms and allow the assignment of specific relevant fragments and fragmentation pathways even in the most complex EI-spectra in our dataset. This method will be very helpful in the automated analysis of metabolites that are not included in common libraries and it thus has the potential to support the explorative character of metabolomics studies. PMID- 22819052 TI - Development of an automatic multi-channel ink-jet ejection chemiluminescence system and its application to the determination of horseradish peroxidase. AB - In this work, an automatic multi-channel ink-jet for chemiluminescence (CL) analysis was developed. The four-channel ink-jet device was controlled by a home made circuit. Differing from the classic flow injection CL, the whole procedure for CL analysis was automatically completed on a hydrophobic glass side. CL reaction of luminal and hydrogen peroxide for the determination of horseradish peroxidase (HRP) was selected as an application to automatic CL analysis platform. All solutions delivered by different channels were precisely ejected to the same position of the glass slide for the CL analysis. The consumption of reaction solution was reduced to nanoliter level. The whole CL analysis could be completed in less than 4min, which was benefited from the prompt solution mixing in small size of droplet. The CL intensity increased linearly with HRP concentration in the range from 0.01 to 0.5MUgmL(-1). The limit of detection (LOD) (S/N=3) was 0.005MUgmL(-1). Finally, the automatic CL system could also be used for the detection of HRP in HRP-protein conjugates, which showed its practical application in immunoassay. PMID- 22819053 TI - Detecting solution pH changes using poly (N-isopropylacrylamide)-co-acrylic acid microgel-based etalon modified quartz crystal microbalances. AB - Poly (N-isopropylacrylamide)-co-acrylic acid (pNIPAm-co-AAc) microgel-based etalons have been shown to have visible color and unique spectral properties, which both depend on solution temperature and pH. In this investigation, pNIPAm co-AAc microgel-based etalons were fabricated on the Au electrode of a quartz crystal microbalance (QCM), and the resonant frequency of the QCM monitored as a function of temperature, at pH 3.0. Furthermore, the resonant frequency at either pH 3.0 or 7.0 was monitored while keeping the solution temperature constant at various temperatures. In all cases, when the solution temperature was below the collapse transition for the microgels (~32 degrees C), the resonant frequency at pH 3.0 was lower than at pH 7.0, which we attribute to the film transitioning from a deswollen to swollen state, respectively. It was observed that the magnitude of the resonant frequency change increased as the solution temperature approached the collapse temperature for the microgels. The overall sensitivity to pH was determined to be 1.3*10(-8)M [H(+)]Hz(-1) and a theoretical detection limit of 390nM was obtained. This sensitivity will be exploited further for future biosensing applications. PMID- 22819054 TI - A sensitive microextraction by packed sorbent-based methodology combined with ultra-high pressure liquid chromatography as a powerful technique for analysis of biologically active flavonols in wines. AB - A new approach based on microextraction by packed sorbent (MEPS) and reversed phase high-throughput ultra high pressure liquid chromatography (UHPLC) method that uses a gradient elution and diode array detection to quantitate three biologically active flavonols in wines, myricetin, quercetin, and kaempferol, is described. In addition to performing routine experiments to establish the validity of the assay to internationally accepted criteria (selectivity, linearity, sensitivity, precision, accuracy), experiments are included to assess the effect of the important experimental parameters such as the type of sorbent material (C2, C8, C18, SIL, and C8/SCX), number of extraction cycles (extract discard), elution volume, sample volume, and ethanol content, on the MEPS performance. The optimal conditions of MEPS extraction were obtained using C8 sorbent and small sample volumes (250MUL) in five extraction cycle and in a short time period (about 5min for the entire sample preparation step). Under optimized conditions, excellent linearity (R(values)(2)>0.9963), limits of detection of 0.006MUgmL(-1) (quercetin) to 0.013MUgmL(-1) (myricetin) and precision within 0.5 3.1% were observed for the target flavonols. The average recoveries of myricetin, quercetin and kaempferol for real samples were 83.0-97.7% with relative standard deviation (RSD, %) lower than 1.6%. The results obtained showed that the most abundant flavonol in the analyzed samples was myricetin (5.8+/-3.7MUgmL(-1)). Quercetin (0.97+/-0.41MUgmL(-1)) and kaempferol (0.66+/-0.24MUgmL(-1)) were found in a lower concentration. The optimized MEPS(C8) method was compared with a reverse-phase solid-phase extraction (SPE) procedure using as sorbent a macroporous copolymer made from a balanced ratio of two monomers, the lipophilic divinylbenzene and the hydrophilic N-vinylpyrrolidone (Oasis HLB) were used as reference. MEPS(C8) approach offers an attractive alternative for analysis of flavonols in wines, providing a number of advantages including highest extraction efficiency (from 85.9+/-0.9% to 92.1+/-0.5%) in the shortest extraction time with low solvent consumption, fast sample throughput, more environmentally friendly and easy to perform. PMID- 22819055 TI - A data treatment method for detecting fluorescence anisotropy peaks in capillary electropherograms. AB - A data treatment method is presented to detect fluorescence anisotropy (FA) peaks in capillary electrophoresis electropherograms. The data treatment method converts plots of fluorescence anisotropy vs. time that contain no peaks that are distinguishable from the noise of the anisotropy background into plots that show distinct fluorescence anisotropy peaks. The method was demonstrated using laser induced fluorescence anisotropy data from individual Abeta (1-42) aggregates separated using capillary electrophoresis. Applying this data treatment method enabled the detection of anisotropy peaks for individual Abeta aggregate fluorescence peaks that were not observed prior to the data treatment method. The data treatment method is not specifically designed for Abeta aggregate analysis or capillary electrophoresis, and it should be applicable to other applications and other separation methods with FA detection. PMID- 22819057 TI - Dopa responsive burning mouth syndrome: restless mouth syndrome or oral variant of restless legs syndrome? AB - Burning mouth syndrome (BMS) is an oral dysesthesia presenting as a burning sensation of the tongue and other oral and perioral mucosae. A painful symptomatology in different bodily regions (extraoral) may also be a common feature in patient with BMS. The management of BMS is challenging and there is no clear guideline for the management of idiopathic BMS. Herein, we describe a group of patients (5 patients) in whom symptoms of BMS responded to levodopa. In parallel, four patients fulfilled the criteria for restless legs syndrome (RLS). Family history of RLS was positive in two patients. We reviewed the literature and noted a marked overlap between BMS and RLS. Overlaps were noted in epidemiological profiles, pattern of clinical features and even in neurophysiological observations (alterations in the striatal dopaminergic system). We suggest that a subset of patients with BMS may be a phenotypic variant of RLS and a trial of dopaminergic drugs should be given in patients with BMS who has a history suggestive of RLS or in a patient who do not show a response to usual therapies for BMS. PMID- 22819056 TI - Phosphodiesterase inhibitor modulation of brain microvascular endothelial cell barrier properties. AB - BACKGROUND AND PURPOSE: Brain microvascular disorders, including cerebral microscopic hemorrhage, have high prevalence but few treatment options. To develop new strategies for these disorders, we analyzed the effects of several phosphodiesterase (PDE) inhibitors on human brain microvascular endothelial cells (HBECs). METHODS: We modified barrier properties and response to histamine of HBECs using cilostazol (PDE3 inhibitor), rolipram (PDE4 inhibitor), and dipyridamole (non-specific PDE inhibitor). RESULTS: Cilostazol and dipyridamole altered the distribution of endothelial F-actin. Cilostazol increased expression of tight junction protein claudin-5 by 118% compared to control (p<.001). Permeability to albumin was decreased by cilostazol (21% vs control, p<.05), and permeability to dextran (70Kd) was decreased by both cilostazol (37% vs control, p<.001) and dipyridamole (44% vs control, p<.0001). Cilostazol increased trans endothelial electrical resistance (TEER) after 12h by 111% compared to control (p<.0001). Protein kinase A (PKA) inhibitors H89 and KT5720 attenuated the TEER increase by cilostazol. Transient increased permeability in response to histamine was significantly mitigated by cilostazol, but not by other PDE inhibitors. CONCLUSIONS: These findings demonstrate distinctive effects of cilostazol and other PDE inhibitors on HBECs, including enhanced barrier characteristics and mitigation of response to histamine. PKA-mediated effects of cilostazol were prominent in this model. These in vitro findings are consistent with therapeutic potential of PDE inhibitors in human brain microvascular disorders. PMID- 22819058 TI - Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III. AB - We describe a 33-year-old male patient with mental retardation and cerebellar ataxia whose brain magnetic resonance imaging (MRI) showed diffuse central hypomyelination. The associated hypogonadotropic hypogonadism and hypodontia were consistent with the clinical diagnosis of 4H syndrome. Two compound heterozygous mutations in POLR3A were found: p.Met852Val and p.Asn1249His. MRI of the brain showed cerebellar atrophy, atrophy of the corpus callosum, and diffuse hypomyelination extending as far as the U-fibers, with preservation of the basal ganglia. T2 hyperintensity was observed in the bilateral middle cerebellar peduncles. The patient showed almost normal development until 4-5years of age. After 25years of age, the patient showed a gradual but consistent motor and cognitive deterioration. We demonstrated the involvement of the corticospinal tract electrophysiologically, but peripheral nerve conduction was normal. Although this disease may start very early in life, the clinical course in the present case suggests that brains that initially appear to have developed normally may show dysfunction later in life, although the pathophysiological bases for this dysfunction may not be evident on MRIs. PMID- 22819060 TI - Disc swelling and mild initial visual acuity loss predict a better short-term visual acuity outcome in bilateral acute optic neuritis. AB - Bilateral acute optic neuritis (AON) is rare in adults in Western countries, but is relatively common in Asian populations. We aimed to document clinical features in Chinese patients with bilateral AON, and to identify factors that are predictive of visual acuity outcome. We reviewed 41 patients (23 males, 18 females; age 18-74 years) diagnosed with bilateral AON from three centers between 2003 and 2009. Demographic and clinical data were compared to a group of patients with unilateral AON. Univariate analysis and multivariate linear regression were used to identify prognostic factors. We found that the median visual acuity (expressed as the logarithm of the minimal angle of resolution [LogMAR] scores) in our patients was 1.55 at presentation and 0.72 at discharge (p<0.001). There was a higher proportion of males (56% compared to 34%, p=0.015), a higher percentage with disc swelling (71% compared to 48%, p=0.014), and poorer visual acuity at presentation (median LogMAR scores: 1.55 compared to 1.70, p=0.001) in patients with bilateral AON than in those with unilateral AON. Both disc swelling (p=0.036) and visual acuity at presentation (p=0.023) were significantly associated with visual acuity at discharge. Our study suggests that bilateral AON has some clinical differences to unilateral AON, and that disc swelling and initial visual acuity may predict a short-term visual acuity outcome in bilateral AON. PMID- 22819061 TI - A prospective, randomized, single-blinded trial on the effect of early rehabilitation on daily activities and motor function of patients with hemorrhagic stroke. AB - To investigate whether early rehabilitation has a positive impact on the recovery of the activities of daily living and motor function after intracerebral hemorrhagic stroke, 364 patients with hemorrhagic stroke were selected and randomly divided into a rehabilitation group and a control group. The rehabilitation group underwent a standardized, three-stage rehabilitation program. The control group was treated with standard hospital ward, internal medical intervention. The simplified Fugl-Myere assessment scale (FMA) and Modified Barthel Index (MBI) were administered at various time points. The magnitude of improvement was significantly higher in the rehabilitation group than in the control group for both the FMA (p<0.05) and MBI scores (p<0.05). The greatest improvement was observed in the first month post-stroke. Thus, our study shows that early rehabilitation can significantly improve the daily activities and motor functions of patients with stroke. PMID- 22819059 TI - Autophagy in Apicomplexa: a life sustaining death mechanism? AB - Programmed cell death (PCD) pathways remain understudied in parasitic protozoa in spite of the fact that they provide potential targets for the development of new therapy. The best understood PCD pathway in higher eukaryotes is apoptosis although emerging evidence also points to autophagy as a mediator of death in certain physiological contexts. Bioinformatic analyses coupled with biochemical and cell biological studies suggest that parasitic protozoa possess the capacity for PCD including a primordial form of apoptosis. Recent work in Toxoplasma and emerging data from Plasmodium suggest that autophagy-related processes may serve as an additional death promoting pathway in Apicomplexa. Detailed mechanistic studies into the molecular basis for PCD in parasitic protozoa represent a fertile area for investigation and drug development. PMID- 22819062 TI - [Behind the scenes of scientific articles: defining categories of fraud and regulating cases]. PMID- 22819069 TI - Test-retest reliability of dynamic plantar loading and foot geometry measures in diabetics with peripheral neuropathy. AB - Pedobarography is commonly employed in patients with diabetic peripheral neuropathy (DPN). However there is no evidence regarding test-retest reliability of this technique in this population, and therefore it was the purpose of the current study to address this clear gap. Dynamic plantar loading and foot geometry data were collected during barefoot gait with the EMED platform (Novel GmbH, Germany) from 10 patients with DPN over two sessions, separated by 28 days. Intra-class Correlation Coefficients (ICCs) and Coefficients of Variation (CoVs) were calculated to determine test-retest reliability. For dynamic plantar loading, reliability differed by outcome measure and foot region, with ICCs of >0.8 and CoVs of <15% observed in most cases. For dynamic foot geometry, ICCs of >0.88 and CoVs of <3% were observed for hallux angle, arch index and coefficient of spreading, while sub-arch angle was less reliable (ICC 0.76, CoV 23%). Overall, the current study observed high levels of test-retest reliability which were generally commensurate with that previously reported in healthy populations. PMID- 22819070 TI - Altered extrafocal iomazenil activity in mesial temporal lobe epilepsy. AB - To investigate involvement of extrafocal regions in mesial temporal lobe epilepsy (MTLE), we retrospectively explored abnormalities in distribution of iomazenil (IMZ) activity by identifying interhemispheric asymmetry on IMZ-SPECT images of patients with MTLE. Fourteen MTLE patients in whom a good surgical outcome was achieved were included in the study. Voxel-based (VB) analysis and volume-of interest (VOI) analysis with predefined VOIs were applied to compare IMZ binding between the hemispheres ipsilateral and contralateral to the epileptic focus. VB analysis showed significant decreases in iomazenil binding not only in the ipsilateral anterior temporal lobe including the mesial temporal structures but also in the ipsilateral extratemporal region including the insula, putamen, and medial occipital lobe. VOI analysis showed similar significant decreases in the ipsilateral parahippocampal gyrus, amygdala, putamen, lateral temporal lobe, and lateral occipital lobe. Results of the SPECT analyses suggest that decreased or dysfunctional IMZ activity extends from the mesial temporal lobe to the ipsilateral extrafocal region in patients with MTLE. PMID- 22819071 TI - Reorganization of posterior language area in temporal lobe epilepsy: a cortico cortical evoked potential study. AB - OBJECTIVE: To investigate the connectivity associated with the reorganized language network in patients with temporal lobe epilepsy (TLE) using cortico cortical evoked potential (CCEP), which reveals the brain networks. METHODS: Six patients with intractable TLE who underwent chronic intracranial electrode placement and revealed an atypical distribution of posterior language areas (Wernicke's areas) were studied. Alternating 1 Hz electrical stimuli were delivered to the anterior language areas (Broca's areas). CCEPs were recorded by averaging electrocorticograms time-locked to stimuli from the subdural electrodes. Thereafter, the posterior language areas identified by the electrical cortical mapping and CCEP distributions were compared by calculating the root mean square of CCEP responses. RESULTS: CCEP responses were observed in various areas within the temporal, temporo-parietal or temporo-occipital area. The correlation between CCEP distributions and posterior language areas revealed two patterns. In two patients, the posterior language areas were located within CCEP distribution, but out of the maximum responses in the temporal lobe. On the other hand, parts of the language areas were outside CCEP-positive areas in four patients. CONCLUSION: Our results suggest that language reorganization might be associated with a functional shift from the termination of anterior-posterior language connection to the surrounding cortices. It should be noted that language areas can be identified outside the anterior-posterior language connection. PMID- 22819072 TI - Reflex myoclonic epilepsy in infancy: a multicenter clinical study. AB - PURPOSE: To describe the clinical and electroencephalographic (EEG) features of reflex myoclonic epilepsy in infancy (RMEI) and long-term cognitive outcome. METHODS: We enrolled 31 children from 16 neuropediatric centres in Italy, who underwent clinical and video-EEG evaluation. Cognitive assessment was performed in all patients using standardized psychometric tests. RESULTS: The age at onset ranged from 3 to 24 months of age. Seizures were characterised in all patients by symmetric myoclonic seizures (MS), triggered by sudden unexpected acoustic (38.7%) or tactile stimuli (29%) or both (29%). Spontaneous attacks were reported in 32.2% of the cases. Ictal EEG showed generalized high-amplitude 3 Hz polyspike and wave discharges, synchronous with brief rhythmic bursts of electromyographic activity. Patients were re-evaluated after a period of 7.2 +/- 5.6 years. The prognosis for seizure control was excellent in all cases and reflex MS disappeared spontaneously or after valproate treatment. The cognitive outcome was excellent in 90.3% of children. CONCLUSIONS: RMEI appears to be a variety of idiopathic generalized epilepsy with specific features that occurs in developmentally normal children. PMID- 22819073 TI - Improving the prognostic assessment of myelodysplastic syndromes by understanding the biology of the disease. PMID- 22819074 TI - Overexpression of MDR1 and survivin, and decreased Bim expression mediate multidrug-resistance in multiple myeloma cells. AB - Multidrug resistance represents a major obstacle for the chemotherapy of a wide variety of human tumors. To investigate the underlying mechanisms associated with resistance to anti-cancer drugs, we established anti-cancer drug-resistant multiple myeloma (MM) cell lines RPMI8226/ADM, RPMI8226/VCR, RPMI8226/DEX, and RPMI8226/L-PAM, the 50% inhibitory concentration values of which were 77-, 58-, 79-, and 30-fold higher than their parental cell lines, respectively. The resistant cell lines overexpressed MDR1 and survivin, or showed decreased Bim expression. These results indicated that regulating these factors with inhibitors might be a viable approach to increasing the susceptibility of quiescent MM cells to chemotherapy. PMID- 22819075 TI - Sagittal plane kinematics during the transition run in triathletes. AB - OBJECTIVES: Epidemiological evidence indicates more than 70% of all injuries that occur while training for or competing in triathlon happen during running. Maintaining an aerodynamic position on a bicycle during a triathlon places triathletes in a prolonged trunk flexed position which may affect lower extremity running biomechanics following cycling and influence both injury risk and performance in these athletes. The aim of this study was to compare sagittal plane running kinematics after a 30-min cycling protocol to a baseline run without prior exercise. DESIGN: Descriptive laboratory study. METHODS: Healthy participants with prior triathlon experience (n=28; height=1.73+/-0.09m; mass=63.0+/-7.7kg; age=24.6+/-5.8years) ran at a self-selected speed on a custom built treadmill surrounded by a 12-camera motion analysis system before and after a 30-min cycling protocol (RPE 12-14). Three-dimensional kinematics were measured before, and at 2-min, 6-min, 10-min, and 14-min post-cycling. A 1*5 series of repeated measures univariate ANOVAs were used to determine changes in kinematic parameters resulting from the cycling protocol. Statistical significance was set a priori at (p<0.05). RESULTS: Peak angles for anterior pelvic tilt (p<0.001), hip flexion (p<0.001), and spine extension (p<0.001) increased and hip extension decreased (p<0.001) at all time points while running following cycling compared to baseline. CONCLUSIONS: Cycling in an aerodynamic position for 30min induces changes in sagittal plane running kinematics of the spine, pelvis, and hip for at least 14min following cycling. Alterations in kinematics may increase the risk for lower extremity injuries and affect running performance in triathletes. PMID- 22819076 TI - Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 dihydroxyphenylalanine positron emission tomography: a meta-analysis. AB - RATIONALE AND OBJECTIVES: The aim of this study was to perform a meta-analysis of published data about the diagnostic performance of (18)F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) or PET/computed tomography (CT) in detecting recurrent medullary thyroid carcinoma (MTC). MATERIALS AND METHODS: A comprehensive literature search of studies indexed in the PubMed/MEDLINE, Scopus, and Embase databases through January 2012 and regarding (18)F-DOPA PET or PET/CT in patients with suspected recurrent MTC was carried out. Pooled detection rates (DR) in per patient and per lesion analyses were calculated. A subanalysis considering serum levels of calcitonin and carcinoembryonic antigen, device used, and carbidopa pretreatment was also performed. RESULTS: Eight studies including 146 patients with suspected recurrent MTC were included. The DRs of (18)F-DOPA PET and PET/CT in per patient and per lesion analyses were 66% and 71%, respectively. DRs significantly increased in patients with serum calcitonin >=1000 ng/L (86%) and calcitonin doubling times <24 months (86%). CONCLUSIONS: Fluorine-18-DOPA PET and PET/CT may be useful functional imaging methods in detecting recurrent MTC. The DR of recurrent MTC using these imaging methods increases in patients with higher calcitonin levels and lower calcitonin doubling times. PMID- 22819077 TI - Functional characterization of the Caenorhabditis elegans DNA repair enzyme APN 1. AB - Caenorhabditis elegans possesses two distinct DNA repair enzymes EXO-3 and APN-1 that have been identified by cross-specie complementation analysis of the Saccharomyces cerevisiae apn1Deltaapn2Deltatpp1Delta triple mutant deficient in the ability to repair apurinic/apyrimidinc (AP) sites and DNA strand breaks with blocked 3'-ends. While purified EXO-3 directly incises AP sites and removes 3' blocking groups, such characterization has not been previously reported for APN 1. We recently documented that C. elegans knockdown for apn-1 is unable to maintain integrity of the genome. Despite the presence of EXO-3, the apn-1 knockdown animals are also defective in the division of the P1 blastomere, an observation consistent with the accumulation of unrepaired DNA lesions suggesting a unique role for APN-1 DNA repair functions. Herein, we show that C. elegans APN 1 is stably expressed as GST-fusion protein in S. cerevisiae only when it carries a nuclear localization signal, and with this requirement rescued the DNA repair defects of the S. cerevisiae apn1Deltaapn2Deltatpp1Delta triple mutant. We purified the APN-1 from the yeast expression system and established that it displays AP endonuclease and 3'-diesterase activities. In addition, we showed that APN-1 also possesses a 3'- to 5'-exonuclease and the nucleotide incision repair activity. This latter activity is capable of directly incising DNA at the 5'-side of various oxidatively damaged bases, as previously observed for Escherichia coli endonuclease IV and S. cerevisiae Apn1, underscoring the importance of this family of enzymes in removing these types of lesions. Glycine substitution of the conserved amino acid residue Glu261 of APN-1, corresponding to Glu145 involved in coordinating Zn(2+) ions in the active site pocket of E. coli endonuclease IV, resulted in an inactive variant that lose the ability to rescue the DNA repair defects of S. cerevisiae apn1Deltaapn2Deltatpp1Delta mutant. Interestingly, the Glu261Gly variant did not sustain purification and yielded a truncated polypeptide. These data suggest that the Glu261 residue of APN-1 may have a broader role in maintaining the structure of the protein. PMID- 22819078 TI - A single mutation in Securin induces chromosomal instability and enhances cell invasion. AB - Pituitary tumour transforming gene (pttg1) encodes Securin, a protein involved in the inhibition of sister chromatid separation binding to Separase until the onset of anaphase. Separase is a cysteine-protease that degrades cohesin to segregate the sister chromatids to opposite poles of the cell. The amount of Securin is strongly regulated because it should allow Separase activation when it is degraded by the anaphase promoting complex/cyclosome, should arrest the cell cycle after DNA damage, when it is degraded through SKP1-CUL1-betaTrCP ubiquitin ligase, and its overexpression induces tumour formation and correlates with metastasis in multiple tumours. Securin is a phosphoprotein that contains 32 potentially phosphorylatable residues. We mutated and analysed most of them, and found a single mutant, hSecT60A, that showed enhanced oncogenic properties. Our fluorescence activated cell sorting analysis, fluorescence in situ hybridisation assays, tumour cell migration and invasion experiments and gene expression by microarrays analysis clearly involved hSecT60A in chromosomal instability and cell invasion. These results show, for the first time, that a single mutation in pttg1 is sufficient to trigger the oncogenic properties of Securin. The finding of this point mutation in patients might be used as an effective strategy for early detection of cancer. PMID- 22819079 TI - Poor health in the Korean older population: age effect or adverse socioeconomic position. AB - The objective of this study was to examine the impact of socioeconomic status and age on poor health among elderly people. Data were taken from the 2006 baseline survey of the Korean Longitudinal Study of Aging (KLoSA). We compared self-rated poor health, depressive symptoms, chronic disease, and disability in middle-aged (age 45-64), old (age 65-74), and very old (age 75-105) individuals. Logistic regression models were used to assess the effect of a poor social environment on health. Elderly Koreans generally had poor socioeconomic status and reported a high prevalence of poor health compared with middle-aged people. Respondents aged 65-74 years old and those aged 75+ were approximately three and four times more likely, respectively, to report self-rated poor health than middle-aged people. These differences were reduced by 41-71% after controlling for education, employment, and income. Elderly persons were also more likely to report depression, chronic disease, or disability, and the differences between age groups were reduced after adjustment for socioeconomic status, but to a lesser extent than was self-rated poor health. Our results indicate that a substantial portion of the gap in health status between middle-aged and older Koreans may be accounted for by the typically low socioeconomic status of elderly people. Income security and health-related interventions are required to improve the health of the elderly cohort who are confronted with the synergistic effects of aging and low socioeconomic status on health. PMID- 22819081 TI - Measuring effective radium concentration with large numbers of samples. Part I- experimental method and uncertainties. AB - Effective radium concentration EC(Ra), product of radium concentration and radon emanation, is the source term for radon release into the pore space of rocks and the environment. To measure EC(Ra), we have conducted, over a period of three years, more than 5500 radon-222 accumulation experiments in the laboratory with scintillation flasks, and about 700 with integrating solid state nuclear track detectors, leading to experimental values of EC(Ra) for more than 1570 rock and soil samples. Through detailed systematic checks and intercomparison between various repeated experiments, the experimental uncertainty has been assessed, and ranges from 30% (1 sigma) for EC(Ra) values smaller than 0.2 Bq kg(-1) to about 8 10% for EC(Ra) values larger than 50 Bq kg(-1). The detection limit, defined as the 90% probability for obtaining a non-zero experimental EC(Ra) value at 68% confidence level, depends on the mass of the sample with respect to the volume of the accumulation volume, and typically varies between 0.04 and 0.09 Bq kg(-1). To measure EC(Ra) from large numbers of samples with sufficient accuracy and uncertainty for our purpose, i.e. for the most natural objects encountered in the environment, the accumulation method with scintillation flask emerged as particularly useful and robust. Properties of EC(Ra) and interpretations inferred from this large data set are presented in the companion paper. PMID- 22819080 TI - Association between physical activity (PA) guidelines and body composition variables in middle-aged and older women. AB - The aim of this study was to investigate the association between volume and frequency of moderate-intensity PA and step-based recommendations and individual body composition variables. Our cohort included 167 healthy ambulatory women (mean age 62.8 +/- 4.8 years; body mass index [BMI] 27.3 +/- 4.2 kg/m(2)) who carried out daily activities while wearing the ActiGraph GT1M accelerometer over a seven day period. Measurements of BMI, body fat mass index (BFMI), fat-free mass index (FFMI), waist-hip ratio (WHR) and visceral fat area (VFA) were obtained by the InBody 720 multifrequency bioelectrical impedance analysis (MFBIA) device. The significant relationship (r(s)=0.66; p<0.05) was found between moderate PA and steps per day. Moderate PA (r(2)=0.03-0.06) and steps per day (r(2)=0.05-0.20) were significantly associated with observed body composition parameters. Women spending > 300 min/week in moderate PA showed significantly lower values of BFMI (p=0.02) than those who spent 150-300 min/week. Carrying out moderate PA for 30 min 5 days a week was significantly associated with lower BMI (p=0.04; eta(2)=0.02), BFMI (p=0.02; eta(2)=0.03) and VFA (p=0.03; eta(2)=0.03). In addition, higher amounts of daily steps were significantly associated with lower BMI (p=0.00; eta(2)=0.16), BFMI (p=0.00; eta(2)=0.21), VFA (p=0.00; eta(2)=0.20) and WHR (p=0.00; eta(2)=0.13). A clear association was found between the generally recommended PA guidelines and body composition variables for the women examined in this study. However, the concept of 10,000 steps/day appears to be the strongest predictor of health-related body composition values. PMID- 22819082 TI - Genetics of rheumatoid arthritis: an impressionist perspective. AB - Rheumatoid arthritis (RA) is the most common rheumatic disease. The genetic basis of RA is supported through the identification of more than 30 susceptibility genetic variants. Each of these genes individually makes only a slight contribution to the risk of disease. Moreover, there is significant disparity in the genetic variants associated with different RA subgroups and patient ethnicities, which emphasizes the intricate nature of the disease's pathogenesis, and the complexities involved in large-scale genetic studies. This review evaluates critically the recent literature on the genetic contribution to RA and assesses the methodology used to identify these risk alleles. PMID- 22819083 TI - Ultrasonography applications in diagnosis and management of early rheumatoid arthritis. AB - Ultrasonography is an elegant tool for the detection of tenosynovitis, synovitis, and erosions very early in rheumatoid arthritis, and the presence of a power Doppler signal is one of the best predictors of joint damage. Although clinical scores remain the mainstay of disease activity assessment, ultrasonography has proved to be a remarkably robust tool for reliable assessment of changes in rheumatoid arthritis. There is no evidence to suggest that problems with operator dependence would be greater than with other imaging modalities or physical examination, if performed by trained providers. PMID- 22819084 TI - Magnetic resonance imaging applications in early rheumatoid arthritis diagnosis and management. AB - Early diagnosis and treatment have been recognized as essential for improving clinical outcomes in patients with rheumatoid arthritis (RA). Magnetic resonance imaging (MRI) is a sensitive modality that can assess both inflammatory and structural lesions. MRI can assist in following the disease course in patients treated with traditional disease-modifying antirheumatic drugs and biological therapies both in the clinic and in research trials. Therefore, it is anticipated that MRI becomes the diagnostic imaging modality of choice in RA clinical trials while remaining a useful tool for clinicians evaluating patients with RA. PMID- 22819085 TI - Disease activity assessment and patient-reported outcomes in patients with early rheumatoid arthritis. AB - Quantitative assessment of disease activity and patient-reported outcomes are recognized as valuable in the management of rheumatoid arthritis (RA). Complexities of assessment of RA include challenges concerning measures themselves, as a gold standard measure for disease status does not exist. This article discusses the hurdles in the implementation of quantitative assessment of RA in usual clinical care and also provides an example to monitor patients with early RA. PMID- 22819086 TI - Initial management of rheumatoid arthritis. AB - The prognosis for the patient with newly diagnosed rheumatoid arthritis (RA) has dramatically changed over the last two decades. If a patient is diagnosed and treated early by a rheumatologist with the goal of remission or low disease activity, half of patients can expect to achieve remission while taking their disease-modifying antirheumatic drugs. This article discusses the initial therapy in early RA and reviews the studies and trials available in the literature. PMID- 22819087 TI - Tight disease control in early RA. AB - The past decade has brought increasing evidence to support aggressive therapeutic intervention in early rheumatoid arthritis (RA). Treat-to-target strategies that focus on frequent monitoring and treatment adjustments to achieve states of low disease activity or clinical remission have shown superior long-term results. Both oral disease-modifying antirheumatic drugs and biologic agents are effective in treating early RA. It remains unclear if initial combination therapy or biologic use is more effective in early active disease as compared with the traditional approach. The authors review various studies on the treatment of early RA with a focus on studies with a treat-to-target approach. PMID- 22819088 TI - Evolution of classification criteria for rheumatoid arthritis: how do the 2010 criteria perform? AB - Classification criteria are created in an attempt to produce a homogenous group of subjects with rheumatoid arthritis (RA) who can be used for clinical and basic research. The 1987 revised criteria lead to improved performance and more confidence in correct classification compared with the 1958 criteria. As therapies were introduced and early, aggressive approaches to RA management became common, there was a growing need for clinical trials focusing on early RA. The 2010 criteria were created to facilitate study of subjects at earlier stages in the disease. This article reviews the diagnostic performance of the 2010 criteria. PMID- 22819089 TI - Early juvenile idiopathic arthritis. AB - Early juvenile idiopathic arthritis (JIA) is important to recognize as timely diagnosis and treatment improves prognosis. It is a misconception that complications of JIA arise only from long-standing disease and that children will outgrow it. Early aggressive treatment is the paradigm as early disease activity has long-term consequences. There are predictors of persistent disease and joint erosions that may identify patients at higher risk. Control of disease activity within the first 6 months of onset confers improved clinical course and outcomes. The treatment perspective is thus one of early aggressive treatment for induction of disease control and ultimately remission. PMID- 22819090 TI - Early psoriatic arthritis. AB - Psoriatic arthritis is an inflammatory musculoskeletal disease associated with psoriasis that is usually seronegative for rheumatoid factor. Psoriatic arthritis affects men and women equally, usually during the fourth decade, although it may affect children and octogenarians. Psoriatic arthritis may lead to deformities, joint damage, reduced quality of life and function. Early detection and treatment may prevent untoward outcomes. PMID- 22819091 TI - Early spondyloarthritis. AB - Spondyloarthritis (SpA) is a large family of chronic inflammatory diseases characterized by inflammation of the axial skeleton, a typically asymmetric peripheral arthritis of the lower limbs, enthesitis, typical extra-articular manifestations, and shared genetic background. The prevalence in the general population is up to 2% for the entire group. SpA, particularly ankylosing spondylitis, has been associated with a diagnostic delay of up to 10 years. Important efforts toward shortening this delay have been made, including the development of new classification criteria. This article discusses the current concept of the disease, typical manifestations, advances in diagnosis, and current treatment recommendations. PMID- 22819093 TI - Epilogue: how will we care for patients with early arthritis? AB - This article draws conclusions about pinpointing the actual onset of disease and when interventions should start to occur. The identification of necessary biomarkers will be discussed. We will also examine the incremental consequences of delaying therapy, particularly for 'preclinical' disease. Medical economic analyses can help us balance benefits and avoid some adverse outcomes for patients. To conclude, we will discuss the new roles that need developing for primary care physicians and non-physican providers. PMID- 22819094 TI - Early arthritis: a race to the starting line. PMID- 22819095 TI - A 40 year-old female with an acute onset left lateral neck and supraclavicular swelling. PMID- 22819092 TI - Environmental and gene-environment interactions and risk of rheumatoid arthritis. AB - Multiple environmental factors including hormones, dietary factors, infections, and exposure to tobacco smoke, as well as gene-environment interactions, have been associated with increased risk for rheumatoid arthritis (RA). The growing understanding of the prolonged period before the first onset of symptoms of RA suggests that these environmental and genetic factors are likely acting to drive the development of RA-related autoimmunity long before the appearance of the first joint symptoms and clinical findings that are characteristic of RA. This article reviews these factors and interactions, especially those that have been investigated in a prospective fashion before the symptomatic onset of RA. PMID- 22819096 TI - Smoking or alcohol dependence among Indigenous Australians: treatment may be needed, not just education. AB - BACKGROUND: In trying to help Aboriginal and Torres Strait Islander (Indigenous) individuals or communities to stop smoking or reduce the harms from alcohol, it is important to be aware of the strong biological basis of the drive to return to nicotine or alcohol. METHODS: In this paper we briefly describe the social and neurobiological factors that drive a dependent smoker or drinker to keep using. We set out the current range of pharmacological treatments for dependence, their role in assisting a person to either stop using or avoid relapse, and we discuss issues relating to their use in Aboriginal Australians. CONCLUDING COMMENTS: There is a firm evidence base for the use of pharmacological treatments for nicotine or alcohol dependence, particularly in severe dependence or when counselling or non-pharmacological approaches have failed. Indigenous Australians should be able to access the full range of approaches to managing these conditions. Working in partnership with Indigenous health staff and agencies can help ensure that appropriate access to treatment and quality treatment delivery occurs. PMID- 22819097 TI - Changes in exercise capacity and cardiac performance in a series of patients with Eisenmenger's syndrome transitioned from selective to dual endothelin receptor antagonist. AB - BACKGROUND: Differences in clinical effects between selective and dual endothelin (ET) receptor antagonists (ERA) in patients with pulmonary arterial hypertension (PAH) are currently unknown. We aimed to assess prospectively how transition from selective (sitaxsentan) to dual (bosentan) ERA affected exercise capacity and cardiocirculatory performance in patients with Eisenmenger's syndrome. METHODS: A series of seven stable patients with Eisenmenger's syndrome aged 40.0 (30.0-56.0) years old treated with sitaxsentan were assessed before and three months after transition to bosentan. Six minute walk test and magnetic resonance to assess LV and RV mass, volume and ejection fraction, and pulmonary flow, and laboratory tests were performed. RESULTS: We observed an increase in LV mass [96.5 (66.0 116.0) vs. 123.0 (93.0-146.0)g; p=0.03], LV ejection fraction [55.0 (44.0-63.0) vs. 65.0 (58.0-70.0)%; p=0.02)], and pulmonary flow [64 (53.0-71.0) vs. 69.0 (55.0-84.0)ml/beat; p=0.046]. This was accompanied by an increase of oxygen saturation, elongation of 6MWD [435.0 (378.0-482.3) vs. 474 (405.0-534.7); p=0.02], decrease of NTproBNP level and increase of ET-1 level. CONCLUSIONS: Three month follow-up of stable patients with Eisenmenger's syndrome transitioned from sitaxsentan to bosentan revealed improvement of exercise capacity despite significant elevation of ET-1 level. Concurrent increase of LV ejection fraction and pulmonary flow might have contributed to these favourable effects. PMID- 22819098 TI - In-vitro identification of distinctive metabolic signatures of intact varicose vein tissue via magic angle spinning nuclear magnetic resonance spectroscopy. AB - OBJECTIVES: Nuclear magnetic resonance (NMR) spectroscopy is an established tool for metabolic profiling of tissues or biofluids with utility in identifying disease biomarkers and changes in enzymatic or gene expression. This pilot study aims to compare the metabolic profiles of intact varicose and non-varicose vein tissue via magic angle spinning (MAS) NMR spectroscopy with a view to promoting the understanding of the pathogenesis of varicose vein formation. METHODS: Varicose vein tissue (n = 8) was collected from patients undergoing varicose veins surgery. Control non-varicose great saphenous vein samples were collected from patients undergoing lower limb amputation (n = 3) and peripheral arterial bypass surgery (n = 5). Intact tissue samples (average weight 10.33 +/- 0.8 mg) from each vein segment were analysed using 1D MAS (1)H NMR (600 MHz) spectroscopy. For selected vein samples, two-dimensional (2D) NMR experiments were performed. Differences between spectra from varicose and non-varicose tissues were elucidated using a variety of multivariate statistical analyses. RESULTS: The metabolic profiles of varicose veins samples were clearly differentiated from non-varicose veins samples. Lipid metabolites were present at a higher concentration in the non-varicose veins group whilst creatine, lactate and myo-inositol metabolites were more characteristic of the varicose veins group. CONCLUSION: We demonstrate differential metabolic profiles between varicose veins and non-varicose veins. Elucidating the metabolic signature underlying varicose veins can further improve our understanding of the biological mechanisms of disease initiation, progression, and aid in identifying putative therapeutic targets. PMID- 22819099 TI - Polyhistidine triad proteins of pathogenic streptococci. AB - The polyhistidine triad (Pht) proteins are an intriguing family of proteins found on the surface of members of the genus Streptococcus. Their defining feature is the presence of multiple copies of the eponymous His triad motif HxxHxH. This review focuses on the Pht proteins of Streptococcus pneumoniae, which contribute to virulence and are leading candidates for inclusion in protein-based pneumococcal vaccines. They appear to have multiple functions, including metal ion homeostasis, evasion of complement deposition and adherence of bacteria to host cells. Across the streptococci, there are many Pht homologs, which can be grouped according to structural features. Critically, there is considerable potential to use members of the Pht protein family as components of vaccines targeted at other streptococci. PMID- 22819100 TI - Measuring change in health care equity using small-area administrative data - evidence from the English NHS 2001-2008. AB - This study developed a method for measuring change in socio-economic equity in health care utilisation using small-area level administrative data. Our method provides more detailed information on utilisation than survey data but only examines socio-economic differences between neighbourhoods rather than individuals. The context was the English NHS from 2001 to 2008, a period of accelerated expenditure growth and pro-competition reform. Hospital records for all adults receiving non-emergency hospital care in the English NHS from 2001 to 2008 were aggregated to 32,482 English small areas with mean population about 1500 and combined with other small-area administrative data. Regression models of utilisation were used to examine year-on-year change in the small-area association between deprivation and utilisation, allowing for population size, age-sex composition and disease prevalence including (from 2003 to 2008) cancer, chronic kidney disease, coronary heart disease, diabetes, epilepsy, hypertension, hypothyroidism, stroke, transient ischaemic attack and (from 2006 to 2008) atrial fibrillation, chronic obstructive pulmonary disease, obesity and heart failure. There was no substantial change in small-area associations between deprivation and utilisation for outpatient visits, hip replacement, senile cataract, gastroscopy or coronary revascularisation, though overall non-emergency inpatient admissions rose slightly faster in more deprived areas than elsewhere. Associations between deprivation and disease prevalence changed little during the period, indicating that observed need did not grow faster in more deprived areas than elsewhere. We conclude that there was no substantial deterioration in socio economic equity in health care utilisation in the English NHS from 2001 to 2008, and if anything, there may have been a slight improvement. PMID- 22819101 TI - Gene expression changes induced by unilateral ureteral obstruction in mice. AB - PURPOSE: Loss of renal function is often the impetus for operative intervention in renal obstruction cases. Obstructive nephropathy is characterized by discrete morphological and physiological changes, including tubular dilatation, apoptosis and atrophy as well as interstitial cellular infiltration and progressive interstitial fibrosis. We hypothesized that gene expression alterations correlate with obstructive nephropathy and could serve as biomarkers for early intervention. MATERIALS AND METHODS: C57BL/6 mice were subjected to unilateral ureteral obstruction or sham surgery at postnatal day 21. Kidneys were harvested 1, 2, 5 and 9 days postoperatively. RNA was extracted from kidneys and comprehensive gene expression profiling was performed with microarrays. IPA(r) pathway analysis software was used to analyze the biological function and gene networks of gene expression data. RESULTS: Microarray analysis revealed more than 1,800 transcripts that were up-regulated or down-regulated during days 1 through 9 after obstruction, including many previously reported transcripts (FOS, CD44, CLU, SPP1 and EGF). Pathway analysis showed significant enrichment of transcripts in cell activation/differentiation, immune/inflammatory responses, cell cycle, metabolic process and transport. Network analysis using IPA showed that transcriptional regulatory pathways involving CEBPB and HNF4A are involved in obstructive nephropathy. CONCLUSIONS: This data set provides a foundation for development of biomarkers for obstructive nephropathy. PMID- 22819102 TI - Re: Functional recovery after partial nephrectomy: effects of volume loss and ischemic injury: M. N. Simmons, S. P. Hillyer, B. H. Lee, A. F. Fergany, J. Kaouk and S. C. Campbell. J Urol 2012; 187: 1667-1673. PMID- 22819103 TI - BCG prostatitis. PMID- 22819104 TI - Usefulness of concomitant autologous blood and dextranomer/hyaluronic acid copolymer injection to correct vesicoureteral reflux. AB - PURPOSE: We present the long-term results of a new modification of endoscopic treatment of vesicoureteral reflux involving concomitant injection of autologous blood following the standard hydrodistention injection technique to prevent bulking agent leakage immediately after the procedure. MATERIALS AND METHODS: A total of 341 children underwent endoscopic implantation of dextranomer/hyaluronic acid for vesicoureteral reflux. A subset of 171 patients underwent hydrodistention autologous blood injection, while 170 underwent classic hydrodistention injection. Frequency of symptomatic urinary tract infection after endoscopic treatment was recorded. Success was defined as absence of vesicoureteral reflux on postoperative voiding cystourethrography. RESULTS: A total of 523 ureters in 214 girls and 127 boys were treated. In patients undergoing hydrodistention autologous blood injection mean age was 39.48 months, mean maximal reflux grade was 3.02 and success rate was 93.6% after the first injection (98.0% in patients with grade II, 92.1% with grade III, 93.3% with grade IV and 85.7% with grade V reflux). In patients who underwent classic hydrodistention injection mean age was 36.12 months, mean maximal reflux grade 3.05 and success rate was 81.8% after the first injection (91.5% in patients with grade II, 89.4% with grade III, 74.4% with grade IV and 44.4% with grade V reflux). The success rate was significantly higher (p = 0.001) in patients undergoing hydrodistention autologous blood injection vs classic hydrodistention injection. Of the patients 1.7% in the hydrodistention autologous blood injection group and 2.9% in the classic hydrodistention injection group reported symptomatic urinary tract infection during followup. CONCLUSIONS: Immediate injection of autologous blood following dextranomer/hyaluronic acid injection to create a blood clot and barricade against bulking agent leakage is more effective than pure dextranomer/hyaluronic acid implantation. This novel modification stabilizes the subureteral implant mount and may affect the antireflux outcome. PMID- 22819105 TI - Preoperative assessment of neurovesical function in children with anorectal malformation: association with vertebral and spinal malformations. AB - PURPOSE: We preoperatively assessed neurovesical function and spinal cord function in children with anorectal malformations. In cases of neurovesical dysfunction we looked for an association with vertebral malformation or myelodysplasia. MATERIALS AND METHODS: We prospectively evaluated 80 children with anorectal malformations via preoperative urodynamics and magnetic resonance imaging of the spine. Bladder compliance and volume, detrusor activity and vesicosphincteric synergy during voiding allowed urodynamic evaluation. Results were reported according to Wingspread and Krickenbeck classifications of anorectal malformations. RESULTS: Urodynamic findings were pathological in 14 children (18%). Pathological evaluations did not seem related to type of fistula or level of anorectal malformation. Vertebral anomalies were seen in 34 patients (43%) and myelodysplasia in 16 (20%). Neither vertebral anomaly nor myelodysplasia seemed associated with type of fistula or severity of anorectal malformation. Of 14 children with pathological urodynamics no vertebral anomaly or myelodysplasia was found in 7. Of 66 children with normal urodynamics 40 presented with vertebral or spinal malformation. CONCLUSIONS: Lower urinary tract dysfunction is common in patients with anorectal malformations. Normal spine or spinal cord does not exclude neurovesical dysfunction. Myelodysplasia or vertebral anomaly does not determine lower urinary tract dysfunction. Thus, we recommend preoperative urodynamic assessment of the bladder and magnetic resonance imaging of the spine in children with anorectal malformations. PMID- 22819106 TI - Fragility of brushite stones in shock wave lithotripsy: absence of correlation with computerized tomography visible structure. AB - PURPOSE: Brushite stones were imaged in vitro and then broken with shock wave lithotripsy to assess whether stone fragility correlates with internal stone structure visible on helical computerized tomography. MATERIALS AND METHODS: A total of 52 brushite calculi were scanned by micro computerized tomography, weighed, hydrated and placed in a radiological phantom. Stones were scanned using a Philips(r) Brilliance iCT 256 system and images were evaluated for the visibility of internal structural features. The calculi were then treated with shock wave lithotripsy in vitro. The number of shock waves needed to break each stone to completion was recorded. RESULTS: The number of shock waves needed to break each stone normalized to stone weight did not differ by HU value (p = 0.84) or by computerized tomography visible structures that could be identified consistently by all observers (p = 0.053). Stone fragility correlated highly with stone density and brushite content (each p <0.001). Calculi of almost pure brushite required the most shock waves to break. When all observations of computerized tomography visible structures were used for analysis by logistic fit, computerized tomography visible structure predicted increased stone fragility with an overall area under the ROC curve of 0.64. CONCLUSIONS: The shock wave lithotripsy fragility of brushite stones did not correlate with internal structure discernible on helical computerized tomography. However, fragility did correlate with stone density and increasing brushite mineral content, consistent with clinical experience with patients with brushite calculi. Thus, current diagnostic computerized tomography technology does not provide a means to predict when brushite stones will break well using shock wave lithotripsy. PMID- 22819107 TI - Kidney stone volume estimation from computerized tomography images using a model based method of correcting for the point spread function. AB - PURPOSE: We propose a method to improve the accuracy of volume estimation of kidney stones from computerized tomography images. MATERIALS AND METHODS: The proposed method consisted of 2 steps. A threshold equal to the average of the computerized tomography number of the object and the background was first applied to determine full width at half maximum volume. Correction factors were then applied, which were precalculated based on a model of a sphere and a 3 dimensional gaussian point spread function. The point spread function was measured in a computerized tomography scanner to represent the response of the scanner to a point-like object. Method accuracy was validated using 6 small cylindrical phantoms with 2 volumes of 21.87 and 99.9 mm(3), and 3 attenuations, respectively, and 76 kidney stones with a volume range of 6.3 to 317.4 mm(3). Volumes estimated by the proposed method were compared with full width at half maximum volumes. RESULTS: The proposed method was significantly more accurate than full width at half maximum volume (p <0.0001). The magnitude of improvement depended on stone volume with smaller stones benefiting more from the method. For kidney stones 10 to 20 mm(3) in volume the average improvement in accuracy was the greatest at 19.6%. CONCLUSIONS: The proposed method achieved significantly improved accuracy compared with threshold methods. This may lead to more accurate stone management. PMID- 22819108 TI - Inducible nitric oxide synthase and PPARgamma are involved in bladder cancer progression. AB - PURPOSE: We evaluated the role of inducible nitric oxide synthase and PPARgamma as prognostic factors for bladder cancer. MATERIALS AND METHODS: Inducible nitric oxide synthase and PPARgamma were evaluated by Western blot and immunohistochemistry in a mouse bladder cancer model of nonmuscle invasive and invasive MB49-I tumor cells, and in human bladder cancer samples. RESULTS: Inducible nitric oxide synthase expression was negative in mouse normal urothelium and higher in invasive than in noninvasive MB49 tumors. In vitro inducible nitric oxide synthase activity, determined as nitrite, was higher in MB49-I than in MB49 cells (p <0.001). In human samples expression was also associated with tumor invasion. Nuclear PPARgamma expression was negative in normal mouse urothelium but higher in nonmuscle invasive MB49 than in MB49-I tumors. Similarly in human tumors low PPARgamma was associated with poor prognosis factors, such as high histological grade (p = 0.0160) and invasion status (p = 0.0352). A positive correlation was noted between inducible nitric oxide synthase and PPARgamma in low histological grade and nonmuscle invasive tumors (Pearson correlation index 0.6368, p = 0.0351, 0.4438 and 0.0168, respectively). As determined by gene reporter assay, PPARgamma activity was induced by nitric oxide only in nonmuscle invasive MB49 cells (p <0.001). CONCLUSIONS: Results suggest that increased PPARgamma controls inducible nitric oxide synthase expression at early tumor stages. However, regulation is lost at advanced tumor stages, when the increase in inducible nitric oxide synthase and the decrease in PPARgamma seem to be associated with bladder cancer progression. PMID- 22819109 TI - Altered caveolar mediated purinergic signaling in spontaneously hypertensive rats with detrusor overactivity. AB - PURPOSE: Loss of bladder smooth muscle caveolae, which are membrane invaginations involved in signaling regulation, is associated with detrusor dysfunction. We investigated whether caveolar loss in bladder smooth muscle from SHR rats contributes to detrusor overactivity by dysregulating caveolar mediated signaling. MATERIALS AND METHODS: Caveolar density and caveolin-1 protein expression were compared between SHR and WKY rats by ultrastructural and molecular analysis. The functional effects of caveolar depletion achieved by methyl-beta-cyclodextrin on neurogenic and agonist induced contractions, and spontaneous activity in isolated bladder tissue were also compared between the strains. P2X1 receptor and caveolin-1 interaction was investigated by confocal microscopy, co-immunoprecipitation and proximity ligation assay. RESULTS: Bladder smooth muscle caveolar density and caveolin-1 expression were decreased in SHR vs WKY rats. Responses to alpha-beta-methylene adenosine triphosphate at baseline were lower in SHR than in WKY rats. Methyl-beta-cyclodextrin significantly decreased alpha-beta-methylene adenosine triphosphate responses in WKY rats but had less effect in SHR rats. Methyl-beta-cyclodextrin decreased the amplitude of the purinergic component of neurally mediated contractions in each strain but had no effect on the cholinergic component. Bladder spontaneous activity was significantly higher in SHR than in WKY rats. Exposure to methyl-beta cyclodextrin or P2X1 receptor antagonist significantly increased spontaneous activity in WKY rats but had no effect in SHR rats. P2X1 receptor and caveolin-1 were co-localized and co-precipitated in bladder smooth muscle tissue. CONCLUSIONS: Caveolar depletion in WKY bladders results in a functional phenotype analogous to that of overactive SHR bladder. The intrinsically decreased caveolae in SHR rats causes loss of the caveolar mediated regulation of purinergic signaling and augmented spontaneous activity, conditions that may lead to detrusor overactivity. PMID- 22819110 TI - Cause of residual urine in bladder outlet obstruction: an experimental study in the rat. AB - PURPOSE: We explored the role of bladder mechanoreceptors in post-void residual urine in rats with bladder outlet obstruction. MATERIALS AND METHODS: Partial bladder outlet obstruction was induced by a urethral ligature in 11 adult female Sprague-Dawley(r) rats. Nine sham operated rats served as controls. The outcome was evaluated in acute experiments using alpha-chloralose anesthesia 6 weeks later. Bladders were catheterized for infusion, pressure recording and intravesical electrical stimulation. Bladder efferent activity was recorded from a thin pelvic nerve branch close to the bladder. Micturition contractions were triggered at different bladder volumes by a brief train of electrical stimulation of bladder afferents while monitoring post-stimulus efferent activity and reflex bladder contractions. The degree of obstruction was assessed by bladder wet weight at the end of the experiment. RESULTS: Bladder weight, micturition threshold volume, anatomical bladder capacity and peak contraction force were significantly increased in obstructed rats. In sham operated controls a triggered micturition reflex was sustained by afferent feedback from the bladder until the bladder was empty. In contrast, reflex discharges failed with substantial volume remaining in the bladder in obstructed rats. The minimal micturition reflex volume correlated positively with bladder weight, micturition threshold volume and maximal bladder capacity (r >=0.74). CONCLUSIONS: In rats with partial bladder outlet obstruction the micturition reflex failed before the bladder was empty due to a decreased afferent drive from bladder mechanoreceptors. Similar changes may contribute to post-void residual urine in humans with bladder outlet obstruction. PMID- 22819111 TI - Long-term bladder function followup in boys with posterior urethral valves: comparison of noninvasive vs invasive urodynamic studies. AB - PURPOSE: We studied whether noninvasive urodynamic evaluation can be as effective and safe as invasive urodynamics in detecting lower urinary tract dysfunction and in preventing late onset renal failure during long-term management of boys with posterior urethral valves. MATERIALS AND METHODS: We evaluated 47 boys with posterior urethral valves using repeat urodynamics. A total of 28 patients with followup of at least 3 years and repeat evaluation of serum creatinine were included in the study. The first 14 boys in the series underwent cystometry and pressure-flow study at least every 3 years (group A), and the remaining 14 patients were monitored annually from age 5 with bladder diary, uroflowmetry, post-void residual urine on ultrasound and serum creatinine (group B). Lower urinary tract dysfunction and serum creatinine were compared (Fisher exact test and Mann-Whitney test) between groups A and B, and by stratifying patients into subgroups by age (5 to 6, 7 to 13 and older than 13 years). In all patients urodynamic diagnosis of lower urinary tract dysfunction was matched and confirmed with lower urinary tract symptoms. RESULTS: During followup the prevalence of lower urinary tract dysfunction did not differ significantly between group A (71% in boys 5 to 6, 43% in boys 7 to 13 and 85% in boys older than 13 years) and group B (36%, 43% and 60%, respectively). Late onset renal failure was observed in 2 boys in group A and 2 in group B. CONCLUSIONS: Noninvasive urodynamic evaluation seems to be as safe and effective as invasive urodynamic study in the long-term management of boys with posterior urethral valves. Based on these findings, invasive urodynamics may be reserved for cases of progressive deterioration of lower urinary tract dysfunction or renal function. PMID- 22819112 TI - Pioglitazone, a peroxisome proliferator activated receptor gamma agonist, decreases renal crystal deposition, oxidative stress and inflammation in hyperoxaluric rats. AB - PURPOSE: Kidney stone disease has characteristics similar to those of metabolic syndrome, including inflammation and oxidative stress. The peroxisome proliferator activated receptor gamma agonist pioglitazone (AK Scientific, Union, California) is used to treat type 2 diabetes mellitus with an adjunctive effect that improves glycemic control and has anti-inflammatory and antioxidative effects. We investigated the preventive effects of pioglitazone for stone formation in a hyperoxaluric rat model. MATERIALS AND METHODS: We divided Sprague Dawley(r) rats into a control group, a 1% ethylene glycol group and a 1% ethylene glycol plus 10 mg/kg pioglitazone group. Blood and 24-hour urine samples, and kidney sections were collected on days 7, 14 and 28. We examined crystal formation using Pizzolato staining and polarized light optical microscopy. We also evaluated cell injury, apoptosis and oxidative stress with N-acetyl-beta glucosaminidase, 8-hydroxydeoxyguanosine and TUNEL assay. Expression of crystal and inflammation related genes was examined by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Kidney crystal formation was significantly less in the ethylene glycol plus pioglitazone group than in the ethylene glycol group. Cell injury, apoptosis and oxidative stress markedly decreased after pioglitazone administration. Expression of osteopontin and ED1 for proinflammatory macrophages was lower in the ethylene glycol plus pioglitazone group than in the ethylene glycol group while that of ED2 for anti-inflammatory macrophages was the same in the 2 groups. Linear regression analysis showed a significant change in the correlation coefficient with pioglitazone treatment between Spp1 and Sod1 expression, and the amount of crystals. CONCLUSIONS: Pioglitazone suppressed kidney crystal formation through renal tubular cell protection, and antioxidative and anti-inflammatory effects in hyperoxaluric rats. PMID- 22819117 TI - Symptomatic mullerian duct cyst. PMID- 22819113 TI - Mifepristone inhibits GRbeta coupled prostate cancer cell proliferation. AB - PURPOSE: The GR gene produces GRalpha and GRbeta isoforms by alternative splicing of a C-terminal exon. GRalpha binds glucocorticoids, modulates transcription in a glucocorticoid dependent manner and has a growth inhibitory role in prostate cells. Due to this role glucocorticoids are often used to treat androgen independent prostate cancer. In contrast, GRbeta has intrinsic transcriptional activity and binds mifepristone (RU486) but not glucocorticoids to control gene expression. To our knowledge the role of GRbeta in prostate cell proliferation is unknown. MATERIALS AND METHODS: We determined GRbeta levels in various prostate cancer cell lines by reverse transcriptase-polymerase chain reaction and Western blot. The effect of GRbeta on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined after siRNA mediated knockdown and over expression of GRbeta. RESULTS: GRbeta mRNA and protein were up-regulated in LNCaP cells that over expressed the androgen receptor co-factor ARA70beta. Treatment of LNCaP-ARA70beta with mifepristone or siRNA targeting GRbeta inhibited proliferation compared to that of parental LNCaP cells. The immortal but nontumorigenic RC165 prostate cell line and the tumorigenic DU145 prostate cell line with endogenous GRbeta also showed partial growth reduction upon GRbeta depletion but to a lesser extent than LNCaP ARA70beta cells. The growth stimulatory effect of ARA70beta on LNCaP cells was partly GRbeta dependent, as was the proliferation of RC165 cells and to a lesser extent of DU145 cells. CONCLUSIONS: Results suggest that patients with a primary tumor that expresses GRbeta and ARA70beta may benefit from mifepristone. PMID- 22819118 TI - The accuracy of different biopsy strategies for the detection of clinically important prostate cancer: a computer simulation. AB - PURPOSE: The true accuracy of different biopsy strategies for detecting clinically significant prostate cancer is unknown, given the positive evaluation bias required for verification by radical prostatectomy. To evaluate how well different biopsy strategies perform at detecting clinically significant prostate cancer we used computer simulation in cystoprostatectomy cases with cancer. MATERIALS AND METHODS: A computer simulation study was performed on prostates acquired at radical cystoprostatectomy. A total of 346 prostates were processed and examined for prostate cancer using 3 mm whole mount slices. The 96 prostates that contained cancer were digitally reconstructed. Biopsy simulations incorporating various degrees of random localization error were performed using the reconstructed 3-dimensional prostate computer model. Each biopsy strategy was simulated 500 times. Two definitions of clinically significant prostate cancer were used to define the reference standard, including definition 1--Gleason score 7 or greater, and/or lesion volume 0.5 ml or greater and definition 2--Gleason score 7 or greater, and/or lesion volume 0.2 ml or greater. RESULTS: A total of 215 prostate cancer foci were present. The ROC AUC to detect and rule out definition 1 prostate cancer was 0.69, 0.75, 0.82 and 0.91 for 12-core transrectal ultrasound biopsy with a random localization error of 15 and 10 mm, 14-core transrectal ultrasound biopsy and template prostate mapping using a 5 mm sampling frame, respectively. CONCLUSIONS: To our knowledge our biopsy simulation study is the first to evaluate the performance of different sampling strategies to detect clinically important prostate cancer in a population that better reflects the demographics of a screened cohort. Compared to other strategies standard transrectal ultrasound biopsy performs poorly for detecting clinically important cancer. Marginal improvement can be achieved using additional cores placed anterior but the performance attained by template prostate mapping is optimal. PMID- 22819119 TI - Involvement of opioid receptors in inhibition of bladder overactivity induced by foot stimulation in cats. AB - PURPOSE: We examined the role of opioid receptors in the inhibition of bladder overactivity induced by electrical stimulation of the foot. MATERIALS AND METHODS: Experiments were done in 6 cats under alpha-chloralose anesthesia when the bladder was infused with saline or 0.25% acetic acid. Naloxone (1 mg/kg intravenously) was administered to block opioid receptors. To modulate reflex bladder activity electrical stimulation (5 Hz, 0.2 millisecond pulse width) was applied to the foot via skin surface electrodes at intensities of multiple times the threshold needed to induce observable toe movement. RESULTS: Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to a mean +/- SE 25.3% +/- 5.9% that of saline control capacity (p = 0.0001). Foot stimulation at 4T suppressed acetic acid induced bladder overactivity and significantly increased bladder capacity to 47.1% +/- 5.9% of control (p = 0.0007). Naloxone did not significantly change bladder capacity during acetic acid irritation but it completely eliminated the inhibition of bladder overactivity induced by foot stimulation. CONCLUSIONS: Results indicate that opioid receptors have an important role in foot afferent inhibition of bladder overactivity. This raises the possibility that opioid receptors might be used as a pharmacological target to enhance the efficacy of foot stimulation for inhibiting bladder overactivity. PMID- 22819120 TI - Dutch adolescent private drinking places: prevalence, alcohol consumption, and other risk behaviors. AB - The aim of this research was to explore the increasingly popular Dutch health phenomenon of 'gathering in private peer group settings (barracks)', with a focus on the prevalence and characteristics of barracks, alcohol consumption, and other (risk) behaviors of their visitors. Three studies were conducted. The first consisted of field research in which 51 barracks were visited and group interviews were held. The second was an Internet study in which 442 barracks' websites were analyzed using content analysis. The third consisted of a questionnaire completed by 1457 adolescents, aged 15-17, in order to explore differences in behavior between barracks visitors and non-visitors. There was wide variation in barracks' characteristics and culture. Barracks' members and visitors also organize diverse activities that are publicly shown on the websites. Barracks are associated with various legal issues, such as alcohol sales to minors, lack of parental supervision, and illicit drug use. Barracks' visitors drink alcohol more frequently, drink more alcohol per occasion (up to fifteen bottles of beer a night), and have been drunk more frequently than non visitors. Policymakers must be aware of the barracks phenomenon and use their powers in adjacent political and legal areas (such as in binge drinking, illicit drug use, and public safety) to intervene and create solid, responsible, and tailor-made policies. PMID- 22819121 TI - Alcohol intoxication in road traffic accidents leads to higher impact speed difference, higher ISS and MAIS, and higher preclinical mortality. AB - Alcohol is one of the most important personal risk factors for serious and fatal injuries, contributing to approximately one third of all deaths from accidents. It is also described that alcohol intoxication leads to a higher mortality in the clinical course. In this study, we hypothesized that alcohol intoxication leads to different accident kinematics, a higher ISS (Injury Severity Score), and higher preclinical mortality compared to sober patients. A technical and medical investigation of alcohol intoxicated road users was performed on the scene of the crash and at the primary admitting hospital. Alcohol testing was performed with either breath alcohol tests or measurement of blood alcohol concentration (BAC) in a standard laboratory test. Between 1999 and 2010, 37,635 road traffic accidents were evaluated by the Accident Research Unit. Overall 20,741 patients were injured, 2.3% of the patients were killed. Among the injured patients, 2.2% with negative BAC were killed, compared to 4.6% fatal injuries in patients with a positive BAC (p < 0.0001). Of the patients with a positive BAC, 8.0% were severely injured, compared to 3.6% in the BAC negative group (p < 0.0001). Regarding the relative speed at impact (Deltav for motorized drivers, vehicle collision speed for pedestrians and bikers), there was a significant higher difference for BAC positive patients (30 +/- 20) compared to the BAC negative patients (25 +/- 19, p < 0.0001). Alcohol intoxication in trauma patients leads to higher preclinical mortality, higher impact speed difference, and higher injury severity. The subgroup analysis for different alcohol concentrations shows no difference in ISS, MAIS, and relative speed, but a correlation of increasing age of patients with higher alcohol concentrations. PMID- 22819122 TI - The cardioprotection of simvastatin in reperfused swine hearts relates to the inhibition of myocardial edema by modulating aquaporins via the PKA pathway. AB - BACKGROUND AND OBJECTIVE: Myocardial edema plays a role in myocardial no-reflow and infarction during ischemia and reperfusion. The effects of statins against no reflow and infarction may relate to the inhibition of myocardial edema. The current study investigated the role of protein kinase A (PKA) in statin-reduced myocardial edema in reperfused swine hearts. METHODS AND RESULTS: Minipigs were treated with simvastatin (SIM, 2mg/kg), SIM+H-89 (a PKA inhibitor, 1.0 MUg/kg/min), or H-89 alone 1h before 90-min ischemia and 3-h reperfusion or sham operation. Ischemia or ischemia-reperfusion induced severe myocardial edema, PKA activation, and up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no reflow myocardium. SIM pretreatment reduced the sizes of no-reflow and infarct areas by 18.5% and 11.1% (P<0.01), decreased water content in the left ventricle, reflow and no-reflow myocardium by 1.4%, 5.3%, and 4.3% (P<0.05), inhibited cardiomyocytes swelling in the reflow and no-reflow areas by 19.8% and 13.1% (P<0.01), suppressed mitochondrial water accumulation in the reflow and no-reflow areas by 49.0% and 35.9% (P<0.01), increased PKA activity (P<0.01), and blocked the up-regulation of aquaporin-1, -4, -8, and -9 in the reflow and no-reflow myocardium. However, these beneficial effects of SIM were partially abolished by inhibiting PKA with H-89. CONCLUSIONS: The cardioprotective effects of acute SIM therapy against myocardial no-reflow and infarction relate to the reduction of myocardial edema by suppressing the expression of aquaporin-1, -4, -8, and -9 in a partially PKA-dependent manner. PMID- 22819123 TI - Criminal offending before and after the onset of psychosis: examination of an offender typology. AB - OBJECTIVE: Clinicians often consider whether or not offenders with psychosis have a history of offending pre-dating the onset of their illness. The typology of offenders based on age at first offence, developed in the field of criminology, has been recently extended to mentally disordered groups, but this ignores the potential role of illness onset. METHOD: Using a large UK cohort of individuals with both psychosis and offending histories (n=331), we compared those with a history of offending pre-dating their illness (pre-morbid offenders) to those who commenced offending after becoming unwell (post-morbid offenders). We compared the demographic, clinical and offending pattern characteristics of the two groups. RESULTS: 198 (60%) had offended before the onset of psychosis. These pre morbid offenders were more likely to be male, have a lower pre-morbid IQ and have had a history of neurological abnormality. Pre-morbid offenders also committed more crime overall, but this was due to an excess of acquisitive, drug and minor offending, rather than violent offending, which was comparable to the post-morbid offending group. CONCLUSION: Currently, standardised clinical risk assessment tools view offenders with mental illness as a homogenous group with respect to life-course patterns of offending in relation to illness. Taking account of an individual's pathway to offending may improve risk assessment and management. PMID- 22819124 TI - Never resting region--mPFC in schizophrenia. AB - Reduced functional connectivity (FC) in schizophrenia has been demonstrated either in task related or 'default network' areas, but not between these networks, which interact meaningfully. We examined the role of FC between the inferior frontal gyrus (IFG) and medial prefrontal cortex (mPFC) in determining language-lateralization during a language task, and its association with structural integrity of the corpus-callosum. Only schizophrenia patients presented increased mPFC-IFG FC during task, which additionally corresponded to decreased white-matter organization of the corpus-callosum. These findings suggest that inability to suppress irrelevant internally-generated information while processing external stimuli might be the basis of functional psychopathology in schizophrenia. PMID- 22819125 TI - Subacute thyroiditis (de Quervain's) due to influenza A: presenting as fever of unknown origin (FUO). AB - Subacute (de Quervain's) thyroiditis is a rare but important cause of fever of unknown origin. Most cases of subacute thyroiditis are caused by a variety of viruses, for example, Coxsackie, cytomegalovirus, Epstein-Barr virus, and adenovirus. Influenza immunization or infection may cause subacute thyroiditis. We present the first reported case of a fever of unknown origin due to seasonal influenza A in a 67-year-old woman. PMID- 22819126 TI - Computer-assisted surgery: a teacher of TKAs. AB - INTRODUCTION: The hypothesis of this study is that computer-aided navigation experience could improve the ability to better place components in the coronal plane and to improve visual/spatial awareness based on the ability of navigation to provide instant feedback. The purpose of this study is to demonstrate the educational role of the navigation system to obtain a better alignment of the prosthetic components with standard instrumentation after a computer-aided navigation experience. MATERIALS AND METHODS: One hundred fifty patients were operated by the same surgeon, with more than 5 years experience with TKA. They were equally divided in three groups: group A (operated with non-navigated technique by surgeon without computer-assisted experience); group B (operated with computer-assisted surgery by the same surgeon); group C (operated with non navigated technique by the same surgeon after the computer-navigated experience). We evaluated by full-length weight-bearing radiographs the overall alignment of the lower limb in the coronal plane. The optimum placement of the components was considered when the angle was within the limits of +/-3 degrees varus/valgus on the coronal x-rays. Comparison between groups was done using one-way ANOVA followed by post hoc Bonferroni test and Pearson chi-square statistics for proportions of optimum placement (P<0.05). RESULTS: In the group A 34 patients (68%) had the optimum placement on the coronal x-rays; in the group B they were 46 (92%) and in the group 41 (82%). The difference is statistically significant in comparing group A and Group B (<0.001), group A and group C (P=0.04), but not for group B and C (P=0.2). CONCLUSION: We believe that the navigation system has an educational role to improve the ability of surgeon of positioning prosthetic components precisely in the coronal plane. PMID- 22819127 TI - Intraspecific differentiation of Paramecium novaurelia strains (Ciliophora, Protozoa) inferred from phylogenetic analysis of ribosomal and mitochondrial DNA variation. AB - Paramecium novaurelia Beale and Schneller, 1954, was first found in Scotland and is known to occur mainly in Europe, where it is the most common species of the P. aurelia complex. In recent years, two non-European localities have been described: Turkey and the United States of America. This article presents the analysis of intraspecific variability among 25 strains of P. novaurelia with the application of ribosomal and mitochondrial loci (ITS1-5.8S-ITS2, 5' large subunit rDNA (5'LSU rDNA) and cytochrome c oxidase subunit 1 (COI) mtDNA). The mean distance observed for all of the studied P. novaurelia sequence pairs was p=0.008/0.016/0.092 (ITS1-5.8S-ITS2/5'LSU rDNA/COI). Phylogenetic trees (NJ/MP/BI) based on a comparison of all of the analysed sequences show that the studied strains of P. novaurelia form a distinct clade, separate from the P. caudatum outgroup, and are divided into two clusters (A and B) and two branches (C and D). The occurrence of substantial genetic differentiation within P. novaurelia, confirmed by the analysed DNA fragments, indicates a rapid evolution of particular species within the Paramecium genus. PMID- 22819128 TI - Objective anthropometric analysis of eyelid reconstruction procedures. AB - Before undergoing facial tumour resection and reconstruction, especially of the eyelids, patients are worried about their postoperative appearance. "Eye-balling" of postoperative results may not be sufficient to adequately judge surgical results. Reference anthropometric measurements for the eyelids are available. We present an evaluation of a series of tumour resection and reconstructive procedures of the eyelids on standardized photographs based on reference anthropometric data. 51 patients underwent eyelid reconstruction with different established techniques after resection of local eyelid tumours. Analysis included intercanthal width, biocular width, eye fissure width, eye fissure height, lid sulcus height, upper lid height, upper iris coverage, lower iris coverage, position of cornea to palpebra inferior, scleral show, ectropion, and canthal tilt. We clearly differentiated between resections including eyelid margin or not. Time (p = 0.04) and surgery (p = 0.03) showed a significant association with decreased values of lower eyelid coverage. Resection of the eyelid margin showed no significant influence on the values investigated. In all the patients analysed the indices were reproducible and reliable. Not surprisingly an association between surgery and lower eyelid retraction was found. Resection of the eyelid margin does not seem to cause a greater risk of eyelid deformity. The standard measurements described are accurate and objective to evaluate postoperative results. PMID- 22819129 TI - Methoxetamine: from drug of abuse to rapid-acting antidepressant. AB - Methoxetamine is a dissociative anaesthetic showing pharmacodynamic similarities with its analogue ketamine, a medication with demonstrated rapid-acting antidepressant effects. Like ketamine and other arylcyclohexylamine compounds, methoxetamine is thought to be both a noncompetitive NMDA receptor antagonist and a dopamine reuptake inhibitor. Furthermore, it acts as an agonist at dopamine D2, serotonin 5HT2, muscarinic cholinergic, sigma-1, opioid mu and k receptors. The hypothesis is that methoxetamine can produce rapid antidepressant effects in patients with resistant and non-resistant unipolar and bipolar depression. PMID- 22819131 TI - Dyscalculia and vestibular function. AB - BACKGROUND: A few studies in humans suggest that changes in stimulation of the balance organs of the inner ear (the 'vestibular system') can disrupt numerical cognition, resulting in 'dyscalculia', the inability to manipulate numbers. Many studies have also demonstrated that patients with vestibular dysfunction exhibit deficits in spatial memory. OBJECTIVES: It is suggested that there may be a connection between spatial memory deficits resulting from vestibular dysfunction and the occurrence of dyscalculia, given the evidence that numerosity is coupled to the processing of spatial information (e.g., the 'spatial numerical association of response codes ('SNARC') effect'). RESULTS AND CONCLUSION: The evidence supporting this hypothesis is summarised and potential experiments to test it are proposed. PMID- 22819130 TI - Protective effects of adenosine on the diabetic myocardium against ischemia reperfusion injury: role of calpain. AB - Myocardial ischemia/reperfusion injury (I/RI) is the principal cause of mortality and morbidity in diabetic patients undergoing cardiac surgery. However, there is no specific measure available to protect diabetic hearts in this clinical setting. Our clinical studies showed that adenosine pre-treatment or post treatment and adding adenosine to cardioplegia solution had significant myocardial protective effects in patients undergoing cardiac surgery. However, the specific protective effects and mechanisms of adenosine in diabetic myocardial I/RI are not clear. Calpain is an important proteolytic enzyme in the myocardium. Studies show that the activation of calpain is an injury factor in not only the diabetic myocardium but also myocardial I/RI progression. We therefore hypothesize that adenosine play a protective role in diabetic myocardial I/RI through the inhibition of calpain. PMID- 22819132 TI - Benefit of combining quantitative cardiac CT parameters with troponin I for predicting right ventricular dysfunction and adverse clinical events in patients with acute pulmonary embolism. AB - OBJECTIVE: To prospectively evaluate the diagnostic accuracy of quantitative cardiac CT parameters alone and in combination with troponin I for the assessment of right ventricular dysfunction (RVD) and adverse clinical events in patients with acute pulmonary embolism (PE). MATERIALS AND RESULTS: This prospective study had institutional review board approval and was HIPAA compliant. In total 83 patients with confirmed PE underwent echocardiography and troponin I serum level measurements within 24 h. Three established cardiac CT measurements for the assessment of RVD were obtained (RV/LVaxial, RV/LV4-CH, and RV/LVvolume). CT measurements and troponin I serum levels were correlated with RVD found on echocardiography and adverse clinical events according to Management Strategies and Prognosis in Pulmonary Embolism Trial-3 (MAPPET-3 criteria. 31 of 83 patients with PE had RVD on echocardiography and 39 of 83 patients had adverse clinical events. A RV/LVvolume ratio>1.43 showed the highest area under the curve (AUC) (0.65) for the prediction of adverse clinical events when compared to RV/LVaxial, RV/LV4Ch and troponin I. The AUC for the detection of RVD of RV/LVaxial, RV/LV4Ch, RV/LVvolume, and troponin I were 0.86, 0.86, 0.92, and 0.69, respectively. Combination of RV/LVaxial, RV/LV4Ch, RV/LVvolume with troponin I increased the AUC to 0.87, 0.87 and 0.93, respectively. CONCLUSION: A combination of cardiac CT parameters and troponin I measurements improves the diagnostic accuracy for detecting RVD and predicting adverse clinical events if compared to either test alone. PMID- 22819133 TI - Can pretreatment ADC values predict recurrence of bladder cancer after transurethral resection? AB - OBJECTIVE: The aim of this retrospective study was to investigate the association between the pretreatment apparent diffusion coefficient (ADC) value and recurrence of bladder cancer after transurethral resection. METHODS: Patients with superficial bladder cancer were identified. Mean ADC values of the tumors were compared between patients with and without recurrence following trans urethral resection. A receiver-operator characteristic curve was used for determining the optimal cutoff ADC value. Univariate and multivariate analyses were used to determine the effect of ADC values and other factors. RESULTS: With a mean follow-up period of 25 months, bladder cancer recurred in 14 of 44 patients (32%). The mean ADC value of tumors in patients with recurrence was lower than in those without recurrence (1.08 mm2/s vs. 1.28*10(-3) mm2/s; p=0.003). The optimal cutoff ADC value for predicting recurrence was determined to be 1.12*10(-3) mm2/s. A modest and significant negative correlation was observed between the ADC values and tumor size (r=-0.436, p=0.008). After adjustment for size and risk groups, an ADC value equal to or less than the optimal cutoff remained a significant predictor of recurrence (odds ratio 6.3, 95% CI 1.23-32.2, p=0.027). CONCLUSION: Pretreatment ADC values may be an independent predictor of bladder cancer recurrence. PMID- 22819135 TI - Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice. AB - Understanding the contribution of cerebrovascular factors in the progression of cognitive decline in Alzheimer's disease (AD) is a key step for the development of preventive therapies. Among these factors, chronic cerebral hypoperfusion is an early component of AD pathogenesis that can predict the progression from mild cognitive impairment to AD. Here, we investigated the effects of a protocol of mild chronic cerebral hypoperfusion in the APPswe/PS1 transgenic mouse model of AD. We observed that the permanent occlusion of the right common carotid artery induced spatial learning impairments in young APPswe/PS1 mice, but not in their wild type littermates. Furthermore, the extent of learning deficits strongly correlated with the number of cortical beta-amyloid plaques, with the mobilization of monocytes into the blood and with the number of bone marrow derived microglia in the brain. These results indicate that a mild reduction of cerebral blood flow can selectively induce cognitive deficits at an early stage of amyloid pathology, eliciting a cellular innate immune response, even without causing neuronal death. PMID- 22819136 TI - Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice. AB - The retinal degeneration Pde6b(rd1) (rd) mutation can be a major pitfall in behavioral studies using tg2576 mice bred on a B6:SJL genetic background, 1 of the most widely used models of Alzheimer's disease. After a pilot study in wild type mice, performance of 8- and 16-month-old tg2576 mice were assessed in several behavioral tasks with the challenge of selecting 1 or more task(s) showing robust memory deficits on this genetic background. Water maze acquisition was impossible in rd homozygotes, whereas Y-maze alternation, object recognition, and olfactory discrimination were unaffected by both the transgene and the rd mutation. Spatial memory retention of 8- and 16-month-old tg2576 mice, however, was dramatically affected independently of the rd mutation when mice had to recognize a spatial configuration of objects or to perform the Barnes maze. Thus, the latter tasks appear extremely useful to evaluate spatial memory deficits and to test cognitive therapies in tg2576 mice and other mouse models bred on a background susceptible to visual impairment. PMID- 22819134 TI - Epidemiology and genetics of frontotemporal dementia: a door-to-door survey in southern Italy. AB - The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a southern Italian population. The study population consisted of subjects >= 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations. PMID- 22819138 TI - Can dual-energy x-ray absorptiometry-based hip structural analysis be used in patients treated with strontium ranelate? PMID- 22819139 TI - Prevalence of low bone mineral density in men and women infected with human immunodeficiency virus 1 and a proposal for screening strategy. AB - We analyzed data collected during screening for eligibility in the ANRS-120 FOSIVIR clinical trial to estimate the prevalence of osteoporosis in patients infected with human immunodeficiency virus 1 (HIV-1), to study its risk factors, and to develop a screening strategy. McNemar test was used to compare the estimated prevalence of osteoporosis, using 3 different definitions. We then derived a screening strategy for HIV-infected men. We analyzed data for 700 men and 192 women. The prevalence of osteoporosis differed markedly according to the definition used. Based on the "T-score <= -2.5" definition, 14.9% of men and 1.0% of women had osteoporosis. Factors associated with low bone mineral density comprised not only classical risk factors for osteoporosis such as low body mass index (BMI) or older age but also factors associated with HIV infection such as lower CD4 T-cell nadir in men and AIDS in women, and with antiretroviral treatment such as recent tenofovir therapy. In addition to postmenopausal women, we recommend osteoporosis screening for HIV-infected men older than 60 yr, men younger than 60 yr with BMI < 20 kg/m(2), and men younger than 60 yr with both BMI 20-23 kg/m(2) and a CD4 T-cell nadir <= 200/mm(3). PMID- 22819137 TI - A2E accumulation influences retinal microglial activation and complement regulation. AB - Age-related macular degeneration is an outer retinal disease that involves aging and immune dysfunction. In the aging retina, microglia aggregate in the outer retina and acquire intracellular autofluorescent lipofuscin deposits. In this study, we investigated whether accumulation of A2E, a key bisretinoid constituent of ocular lipofuscin, alters the physiology of retinal microglia in pathologically relevant ways. Our findings show that sublethal accumulations of intracellular A2E in cultured retinal microglia increased microglial activation and decreased microglial neuroprotection of photoreceptors. Increased A2E accumulation also lowered microglial expression of chemokine receptors and suppressed microglial chemotaxis, suggesting that lipofuscin accumulation may potentiate subretinal microglial accumulation. Significantly, A2E accumulation altered microglial complement regulation by increasing complement factor B and decreasing complement factor H expression, favoring increased complement activation and deposition in the outer retina. Taken together, our findings highlight the role of microglia in the local control of complement activation in the retina and present the age-related accumulation of ocular lipofuscin in subretinal microglia as a cellular mechanism capable of driving outer retinal immune dysregulation in age-related macular degeneration pathogenesis. PMID- 22819140 TI - Estimation of bone strength parameters and response to treatment in McCune Albright syndrome using peripheral quantitative computed tomography of the tibia. PMID- 22819141 TI - Secretory IgA as a diagnostic tool for Pseudomonas aeruginosa respiratory colonization. AB - BACKGROUND: Pseudomonas aeruginosa sinusitis may be the focus for intermittent lung colonization in patients with cystic fibrosis (CF). The sinusitis may induce elevated IgA levels in nasal secretion and saliva against P. aeruginosa. METHODS: 120 CF patients chronically infected, intermittently colonized or without P. aeruginosa in the lungs participated in this cross-sectional study. IgA and IgG against P. aeruginosa sonicate and alginate were measured in nasal secretions, saliva, and in serum by ELISA. RESULTS: The intermittently colonized patients had significantly higher IgA levels in nasal secretions and saliva than those without P. aeruginosa in the lungs, indicating that P. aeruginosa sinusitis may precede intermittent colonization and chronic infection of the lungs. CONCLUSIONS: Specific IgA against P. aeruginosa in nasal secretions and saliva can contribute to differentiation between patients chronically infected, intermittently colonized, and without P. aeruginosa in the lungs. The diagnostic value of the IgA ELISA awaits a prospective study. PMID- 22819142 TI - Crossed aphasia after right anterior temporal lobectomy. A case report. AB - The occurrence of crossed aphasia as a complication after temporal lobe epilepsy surgery is extremely rare. We report the case of a 47-year-old right-handed patient with drug-resistant mesial temporal lobe epilepsy (MTLE) who developed a transitory aphasic syndrome after a right temporal anterior lobectomy. This syndrome was characterized by anomia, poor verbal fluency, verbal perseveration, and verbal comprehension difficulties. He also showed writing difficulties, reading substitutions, and calculation task errors. The patient was regularly assessed with language tasks, and showed a spontaneous and progressive recovery of his symptoms, with remaining naming difficulties. We discuss the role that epileptogenic zone could play in cortical reorganization of the language systems. PMID- 22819143 TI - A systematic review to determine the reliability of knee joint position sense assessment measures. AB - BACKGROUND: The assessment of joint position sense (JPS) is the most widely used measurement of knee proprioceptive capability within the literature. However, it remains unclear what the most reliable method is to assess this. The purpose of this study was to determine the intra- and inter-rater reliability of the various methods used to assess knee JPS. METHODS: A systematic review of published and unpublished literature sources was conducted up to June 2012. All studies principally assessing the reliability (intra- or inter-rater) or reproducibility of a JPS of the knee were included. The methodological quality of each study was reviewed using the Critical Appraisal Skills Programme tool. RESULTS: A total of 18 studies were eligible, assessing the reliability of JPS with 456 knees. The reliability of four methods of JPS has been recorded: position replication using a model, image recorded angulation, electrogoniometry and dynamometry/angular motion chair. Intra-rater reliability was good for the assessment of JPS using photographs and digital images, and replicating knee position using a paper model, this was good but variable when electrogoniometry was used, and moderate but variable when assessed using dynamometry/angle motion chairs. The assessment of JPS by image recorded angulation, electrogoniometry and dynamometry/angular motion chair has demonstrated good inter-rater reliability. CONCLUSIONS: Whilst JPS methods appear to have variable reliability, the four assessment methods should be further assessed with pathological populations such as those following patellar dislocation or anterior cruciate ligament rupture. This will better facilitate the generalisability of JPS assessment methods to inform clinical practice. PMID- 22819146 TI - Sperm or no sperm, that is the question! Finding the elusive spermatozoa. PMID- 22819145 TI - Thrombin enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts; possible involvement in the pathogenesis of preeclampsia. AB - OBJECTIVE: To investigate the possible impact of thrombin on soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in trophoblasts. DESIGN: Experimental. SETTING: University hospital laboratory. INTERVENTIONS(S): A trophoblast cell line (HRT-8/SVneo) was treated with thrombin, protease-activated receptor 1 (PAR 1)-specific agonist SFLLERN, and thrombin antagonist PPACK. MAIN OUTCOME MEASURE(S): mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in trophoblasts, with the use of real-time polymerase chain reaction; and the secretion of sFlt-1, VEGF, and PlGF protein from trophoblasts, with the use of ELISA. RESULT(S): Administration of thrombin (10 U/mL) and PAR-1-specific agonist SFLLRN (300 MUmol/L) increased sFlt-1 mRNA expression (4.24 +/- 0.74- and 4.21 +/- 0.79-fold, respectively) and protein secretion (5.08 +/- 0.42- and 1.89 +/- 0.16-fold, respectively) in HRT-8/SVneo. The induction of sFlt-1 protein secretion by thrombin was dose dependent. The effect of thrombin was completely reduced by thrombin inhibitor PPACK. Thrombin increased mRNA expression of VEGF but did not change VEGF secretion and PlGF mRNA expression and secretion. CONCLUSION(S): During placental development, thrombin, generated in the local hemorrhage of the uteroplacenta increases trophoblast expression of sFlt-1. Consequently, thrombin may contribute to the pathogenesis of preeclampsia. PMID- 22819144 TI - Pathogenesis and pathophysiology of endometriosis. AB - Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition. PMID- 22819147 TI - Surgery and intraoperative electron radiotherapy in recurrent or metastatic oligotopic extrapelvic cancer: long-term outcome. AB - PURPOSE: To evaluate the feasibility and long-term outcome of surgery combined with intraoperative electron radiotherapy (IOERT) as rescue treatment in patients with recurrent and/or metastatic oligotopic extrapelvic cancer. METHODS AND MATERIALS: From April 1996 to April 2010, we treated 28 patients using 34 IOERT procedures. The main histopathology findings were adenocarcinoma (39%) and squamous cell carcinoma (29%). The original cancer sites were gynecologic (67%), urologic (14%) and colorectal (14%). The location of recurrence was the para aortic region in 53.5% of patients. RESULTS: Median follow-up was 39 months (1-84 months), during which time 14% of patients experienced local recurrence and 53.5% developed distant metastasis. Overall survival at 2 and 5 years was 57% and 35% respectively. At the time of the analysis, 13 patients were alive, 6 for more than 55 months of follow-up. Local control was not significantly affected by the following histopathologic characteristics of the resected surgical specimen: number of fragments submitted for pathology study (1 to >6), maximal tumor dimension (<= 2 to >= 6 cm), rate of involved nodes (0-100%) and involved resection margin (local recurrence 23% vs 7%; p = 0.21). Local recurrence was significantly affected by microscopic cancer in more than 50% of specimen fragments (38% vs 9%, p = 0.02). CONCLUSIONS: IOERT for recurrence of oligotopic extrapelvic cancer increased long-term survival in patients with controlled cancer and appears to compensate for some adverse prognostic features in local control. Individualized treatment strategies for this heterogeneous category of patients with recurrent cancer will make it possible to optimize results. PMID- 22819148 TI - Comparative in vitro activity of common antibiotics and relationship with changes in Streptococcus pneumoniae serotypes causing otitis in children prior to and 10 years after introduction of conjugate vaccines in Spain. PMID- 22819149 TI - Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence. AB - There has been growing interest in disrupting bacterial virulence mechanisms as a form of infectious disease control through the use of 'anti-infective' drugs. Pseudomonas aeruginosa is an opportunistic pathogen noted for its intrinsic antibiotic resistance that causes serious infections requiring new therapeutic options. In this study, an analysis of the P. aeruginosa PAO1 deduced proteome was performed to identify pathogen-associated proteins. A computational screening approach was then used to discover drug repurposing opportunities, i.e. identifying approved drugs that bind and potentially disrupt the pathogen associated protein targets. The selective oestrogen receptor modulator raloxifene, a drug currently used in the prevention of osteoporosis and/or invasive breast cancer in post-menopausal women, was predicted from this screen to bind P. aeruginosa PhzB2. PhzB2 is involved in production of the blue pigment pyocyanin produced via the phenazine biosynthesis pathway. Pyocyanin is toxic to eukaryotic cells and has been shown to play a role in infection in a mouse model, making it an attractive target for anti-infective drug discovery. Raloxifene was found to strongly attenuate P. aeruginosa virulence in a Caenorhabditis elegans model of infection. Treatment of P. aeruginosa wild-type strains PAO1 and PA14 with raloxifene resulted in a dose-dependent reduction in pyocyanin production in vitro; pyocyanin production and virulence were also reduced for a phzB2 insertion mutant. These results suggest that raloxifene may be suitable for further development as a therapeutic for P. aeruginosa infection and that such already approved drugs may be computationally screened and potentially repurposed as novel anti-infective/anti-virulence agents. PMID- 22819150 TI - In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds. AB - Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7 MUM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide. PMID- 22819151 TI - Impact of recent antibiotics on nasopharyngeal carriage and lower airway infection in Indigenous Australian children with non-cystic fibrosis bronchiectasis. AB - Indigenous Australian children have increased rates of bronchiectasis. Despite a lack of high-level evidence on effectiveness and antibiotic resistance, these children often receive long-term antibiotics. In this study, we determined the impact of recent macrolide (primarily azithromycin) and beta-lactam antibiotic use on nasopharyngeal colonisation, lower airway infection (>10(4) CFU/mL of bronchoalveolar lavage fluid culture) and antibiotic resistance in non-typeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae and Moraxella catarrhalis isolates from 104 Indigenous children with radiographically confirmed bronchiectasis. Recent antibiotic use was associated with significantly reduced nasopharyngeal carriage, especially of S. pneumoniae in 39 children who received macrolides [odds ratio (OR)=0.22, 95% confidence interval (CI) 0.08-0.63] and 26 children who received beta-lactams (OR=0.07, 95% CI 0.01-0.32), but had no significant effect on lower airway infection involving any of the three pathogens. Children given macrolides were significantly more likely to carry (OR=4.58, 95% CI 1.14-21.7) and be infected by (OR=8.13, 95% CI 1.47-81.3) azithromycin-resistant S. pneumoniae. Children who received beta-lactam antibiotics may be more likely to have lower airway infection with beta-lactamase positive ampicillin-resistant NTHi (OR=4.40, 95% CI 0.85-23.9). The risk of lower airway infection by antibiotic-resistant pathogens in children receiving antibiotics is of concern. Clinical trials to determine the overall benefit of long-term antibiotic therapy are underway. PMID- 22819152 TI - Selectivity for and destruction of Salmonella typhimurium via a membrane damage mechanism of a cell-penetrating peptide ppTG20 analogue. AB - P7, an analogue of the cell-penetrating peptide (CPP) ppTG20, was derived by replacing Phe and Trp with Arg based on the structure-activity relationships of CPPs and antimicrobial peptides (AMPs). P7 showed antimicrobial activity against Salmonella typhimurium at 4 MUM and possessed broad antimicrobial activity greater than its parent peptide. P7 displayed good selectivity, with low haemolysis below its minimum inhibitory concentration range, but displayed cytotoxic activity against the HT29 and MDA-MB231 mammalian cell lines. Studies of calcein leakage from egg yolk L-alpha-phosphatidylcholine/egg yolk L-alpha phosphatidyl-DL-glycerol (EYPC/EYPG) (bacterial membrane mimic) and EYPC/cholesterol (eukaryotic membrane mimic) vesicles also demonstrated that P7 exhibited high selectivity and caused pore formation in the bacterial membrane. Circular dichroism experiments suggested that the conformation of P7 underwent transitions from a random coil in sodium phosphate buffer to an alpha-helical conformation in bacterial model membranes. P7 induced influx of the membrane fluorescent probe 1-N-phenylnaphthylamine (NPN) and the nucleic acid fluorescent probe SYTOX((r)) Green by increasing live S. typhimurium cell outer membrane and plasma membrane permeability, respectively. P7 also induced ion channel formation in the cell plasma membrane causing leakage of potassium ions. Flow cytometric analysis demonstrated that S. typhimurium cell membrane integrity was destroyed following incubation with P7. These results indicated that P7 exhibited good bacterial selectivity and exerted its antibacterial activity by a membrane damage mechanism. Furthermore, these results suggested that CPPs may represent a source of templates for AMP design. PMID- 22819153 TI - Identification of new structural elements within 'porosomes' of the exocrine pancreas: a detailed study using high-resolution electron microscopy. AB - In the past two decades, great progress has been made in our knowledge of how cells secrete. This progress has been possible primarily due to discovery of the 'porosome', the universal secretory portals at the plasma membrane in cells. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where membrane-bounded secretory vesicles temporarily dock and fuse to expel all or part of their contents during cellular secretion. Porosomes have been found in neurons, in neuroendocrine cells, as well as in the exocrine pancreas. Furthermore, porosomes have been isolated, functionally reconstituted, and their composition determined. Although, the neuronal porosome has been exhaustively investigated, the detailed morphology of porosomes in the exocrine pancreas in situ remains to be further explored. The current study was carried out to determine the detailed morphology of the porosome in rat exocrine pancreas using high-resolution electron microscopy. Results from our study, demonstrate for the first time the presence of tethers or cables (which could be t-SNAREs) associated at the base of porosomes. Furthermore, for the first time our studies demonstrate the docking of a single secretory vesicle at the base of more than one porosome complex. Detailed spoke-like elements lining the porosome cup are also demonstrated for the first time in our study, providing a better understanding of the molecular architecture and physiology of this important cellular organelle. PMID- 22819154 TI - Incidence, prevalence, risk factor and outcome of delirium in intensive care unit: a study from India. AB - OBJECTIVE: To evaluate the incidence, prevalence, risk factors and outcome of delirium in the respiratory intensive care unit of a tertiary care hospital. METHODS: Consecutive patients admitted to an eight-bed respiratory intensive care unit were screened for presence of delirium by a psychiatrist. Patients found to have delirium were evaluated using univariate techniques for their clinical profiles, risk factors for delirium, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, duration of stay (in days) and outcome at discharge from intensive care unit besides evaluation on Delirium Rating Scale Revised 98 version (DRS-R-98). RESULTS: Incidence and prevalence rate of delirium were 24.4% and 53.6% respectively. Univariate analyses revealed that the prevalence of delirium was higher (64%) in mechanically ventilated patients. The predisposing risk factors identified for delirium in univariate analysis were higher age; higher Glasgow Coma Scale score; increased APACHE II score; hyperuricemia; hypoalbuminemia; presence of acidosis; abnormal alkaline transferase levels; use of mechanical ventilation; higher number of total medication received and use of sedative, steroids and insulin. Univariate analysis showed that patients who were diagnosed with delirium had significantly longer duration of intensive care unit (ICU) stay and higher mortality rates. Age, multiple organ failure, hypoactive delirium and higher DRS-R-98 scores were significant risk factors for mortality in patients with delirium. CONCLUSIONS: Delirium is highly prevalent in the ICU setting and delirium is associated with longer ICU stay and higher mortality. PMID- 22819155 TI - Dental health - a challenging problem for a patient with autism spectrum disorder. AB - Patients with autism spectrum disorders (ASDs) are at an increased risk for many diseases. However, little has been published about the dental health of patients with ASDs. Here, we describe the clinical presentations in a 28-year-old woman with autistic disorder. The most striking finding was the severe dental problems which had been neglected for several years. Our patient exhibited a combination of several factors that may have increased the risk of development of severe dental problem. The early recognition is still challenging to managing this unusual condition in patients with ASDs. From the experience of caring for this patient, a team of parents or caregivers, psychiatrist and dentist should be involved in maintaining oral health care of such patients with early intervention and long-term follow-up. Evidence-based behavioral management approaches for patients with ASD need to be developed to improve compliance with oral care procedures. PMID- 22819156 TI - Prevention of hip dysplasia in children and adults. AB - Klisic and Pajic summarized the history of early diagnosis and treatment of hip dysplasia when they wrote, Devising the preventive approach to developmental dysplasia of the hip (DDH) required much time.... Despite the 2400-year-old suggestion made by Hippocrates that children's hip dislocations are curable if treatment is started very early, the preventive approach was proposed by Roser only in 1879 [who] described early diagnosis in newborns and performed reduction by abduction... He also advocated early treatment by fixing babies' hips in abduction. However, surgeons did not readily accept these proposals, despite the good results shown by Froelich in 1906 and Le Damany in 1911. In 1927, Putti succeeded in interesting some orthopedic surgeons in the procedure by showing the results of early treatment. But the practical problem remained: ie, how to detect the DDH in patients at an early age. The turning point came in 1935 when pediatrician Ortolani introduced early detection of DDH by "early clinical search" shortly after a child's birth, instructing obstetricians, pediatricians, and midwives to perform the search. Rediscovering the diagnostic "segno della scatto," ie, reducible displacement, he popularized the prophylactic approach to DDH by early detection and treatment. Fifteen years later, another pediatrician, Palmen, organized systematic screening in nurseries by pediatricians. Since Klisic and Pajic wrote this in 1993, the use of ultrasound, albeit still controversial in some ways, has influenced the treatment and prevention of DDH. Klisic's attempts to universally prevent the disease may still be able to be incorporated into further efforts at disease prevention through education and the systematic trials of hip abduction pillows or braces similar to his wide-diaper diapering technique. The goal of prevention is to eradicate a disease so that it does not present to the physician. For DDH, this goal may be tenable. PMID- 22819157 TI - Strategies to improve nonoperative childhood management. AB - Early diagnosis is of paramount importance to favorably alter the natural history of DDH. Most cases of dysplasia can be diagnosed by careful history taking and physical examination. Imaging modalities, such as ultrasonography, have increased our ability to detect subtleties not appreciated by means of physical examination or plain radiography. Although the evaluation of children with risk factors for DDH is important, most dysplasia occurs in girls who have no other risk factors. For all infants, a competent newborn physical examination using the Ortolani maneuver is the most useful procedure to detect hip instability. Early treatment of an unstable hip with a Pavlik harness or similarly effective orthosis is effective, safe, and strongly advised. PMID- 22819158 TI - Strategies to improve outcomes from operative childhood management of DDH. AB - The operative management of DDH is technically challenging. To achieve excellent results, surgeons need to select the most appropriate operative treatment, minimize the risk of complications, and be aggressive in the management of serious complications, such as redislocation and AVN, when they occur. We have described specific steps and strategies to assist in each of these key steps. PMID- 22819159 TI - Surgical treatment of hip dysplasia in children and adolescents. AB - Residual hip dysplasia (a relatively common condition in young children and adolescents) left undetected or partially treated, almost certainly leads to further progression of deformity, eventually ending in a nonfunctional, painful hip joint. Therefore, every effort should be made to identify and treat hip dysplasia early.The use of 3D imaging, including CT and MRI assessment, has enhanced the diagnosis and treatment of patients with dysplasia because they facilitate proper identification of important pathomorphologic anatomy and cartilage degeneration. Future studies should take these novel imaging modalities into consideration with the attempt to (re-) evaluate optimal selection criteria for surgery, risk factors for clinical failure and optimal deformity correction. Treatment of residual hip dysplasia requires corrective surgery. The goal of surgical treatment is to normalize joint loading by increasing the contact area and improving the level arm of the hip to forestall the development of OA. Proper selection and performance of a correction osteotomy and adjunctive procedures are prerequisites for a good clinical outcome and high survivorship of the reconstructed hip. Augmentation procedures, such as the Chiari osteotomy or the shelf procedure described by Staheli, remain as a salvage option in cases when irreversible cartilage damage is present or when reorientation is not feasible. PMID- 22819160 TI - Surgery for residual femoral deformity in adolescents. AB - Abnormalities of the femur frequently accompany acetabular dysplasia as primary or secondary deformities. Femoral surgery is often a component of surgical treatment of acetabular dysplasia either at the onset or to treat a secondary or residual deformity. Proper analysis of the abnormal geometry of the bony femur, as well as the abnormal lever arms around the hip related to the lesser and greater trochanteric positions, is an essential part of a successful surgical plan. An a la carte approach makes the most sense in the treatment of the wide variety of disorders of the upper femur. Over 100 years of hip surgery has proven that normalizing the anatomy and muscle forces around the hip to as close to normal as possible, extends the future life of the hip while also treating current pain and disability. PMID- 22819161 TI - Imaging hip dysplasia in the skeletally mature. AB - Hip disorders in the young adult manifest along a continuum that ranges from an excessively constrained, impinging joint, to an overly shallow, unstable hip. Knowledge of simple measures on plain radiographs can aid in efficient and accurate identification of mechanically compromised hips that may be at risk for premature OA. Improvements in joint-preserving surgery have shown promise in delaying or preventing progression of articular degeneration; thus, timely diagnosis is important. Once a diagnosis is established, specialized imaging can be individualized to supplement surgical planning, assess the degree of cartilage damage, and facilitate discussion regarding the prognosis of hip-preserving procedures. PMID- 22819162 TI - Periacetabular osteotomy for hip preservation. AB - The Bernese PAO has now been performed for nearly 30 years. In that time, it has proved itself a technically complex procedure with the potential to considerably improve the natural history of the dysplastic hip. Significant refinements in the surgical technique combined with the recognition of FAI, improvements in the understanding of hip biomechanics and acetabular orientation, and more discerning patient selection have improved the outcomes related to this procedure. Although the recovery can be demanding and the potential for complications exists, the results are reproducible and the technique has become the gold standard for acetabular reorientation. PMID- 22819163 TI - Total hip arthroplasty and hip resurfacing arthroplasty in the very young patient. AB - Severe hip arthritis in an adolescent or very young adult can be a devastating disability that affects all aspects of a patient's life. Newer treatment strategies in pediatric orthopedic surgery and hip preservation potentially could lessen the impact of this severe disorder in the future. Careful patient selection can lead to excellent outcomes for both THA and/or HRA in young patients. Further study will likely shed more light on whether HRA truly has more improved functional results than THA, and studies with longer follow-up that show definitive revision rates also should affect the future of HRA. PMID- 22819164 TI - Acetabular considerations during total hip arthroplasty for hip dysplasia. AB - The wide spectrum of anatomic abnormalities that characterize hip dysplasia dictate the need for different reconstructive techniques when hip replacement is required. Multiple factors such as young age and high activity level of this patient population, coupled with the increased complexity of surgery, explain the somewhat elevated historical failure rate of hip arthroplasty in DDH and emphasize the need for careful analysis of each case and selection of the most appropriate reconstruction options. One particular problem specific to acetabular reconstruction is the deficient bone stock that may limit the ability to place the component fully on native bone at the true acetabular region. When standard techniques of reconstruction leave a significant portion of the component uncovered, the alternatives include acetabular augmentation with bone autograft, intentional high placement of the component, or medialization of the component with or without medial wall osteotomy. Uncemented sockets have provided promising midterm results with supplemental bone augmentation and are the authors' preferred method of treatment for hips with moderate dysplasia and anterolateral acetabular bone deficiency. PMID- 22819165 TI - Femoral considerations for total hip replacement in hip dysplasia. AB - THAin the dysplastic hip is a technically demanding procedure that requires careful preoperative planning. The common deformities associated with the dysplastic femur include hypoplasia, excessive neck anteversion, a valgus neck shaft angle, metaphyseal-diaphyseal mismatch, and a posteriorly displaced greater trochanter. In selected cases, osteotomy of the femur may be performed to correct anteversion and/or avoid excessive leg lengthening and stretch of the sciatic nerve. All of these issues mandate careful preoperative planning. With the advent of modern surgical techniques and implants, the bone deformities in hip dysplasia can be successfully addressed and THA has proved to be a successful and durable operation. PMID- 22819166 TI - Technical considerations in total hip arthroplasty after femoral and periacetabular osteotomies. AB - The purpose of this article is to outline key technical considerations in the performance of total hip arthroplasty after common osteotomies of both the proximal femur and acetabulum. Attention is called to anatomic variation, both innate and incurred. After a femoral osteotomy, specific focus should be placed on incision selection, residual hardware management, abductor handling, and proper version establishment. After a periacetabular osteotomy, similar concern should be granted to cup position and fixation. Results of total hip arthroplasty after common osteotomies are also reviewed and importance of these issues highlighted. PMID- 22819167 TI - Bearing surface considerations for total hip arthroplasty in young patients. AB - Bearing selection for total hip arthroplasty in young patients is important because of the likely long service life of the implant. Careful consideration of the next operation is recommended when choosing components. No prospective, randomized studies exist that document the clear superiority of any bearing couple in young, active patients. Modern metals, ceramics, and polyethylenes all hold promise. Further long-term data on modern bearings are needed to determine the clinical performance of these bearings. This article summarizes the available data on various bearing couples in patients aged younger than 50 years. PMID- 22819168 TI - Contribution of UVB radiation to bacterial inactivation by natural sunlight. AB - The contribution of different components of sunlight to the lethal action exerted by this radiation on bacteria was studied using Pseudomonas aeruginosa ATCC27853 as a model organism. When solar UVB was excluded from the incident radiation by filtering it through a naphthalene solution (cut off 327 nm), significant modifications were observed in the cell-death kinetics. These modifications were comparable to those expected for a reduction of 27-32% in the dose rate, according to the model used in the analysis of the survival curves, and were also observed when the effects of sunlight filtered through polyethylene terephthalate (cut off 331 nm) or polystyrene (cut off 298 nm) were compared. Viability of P. aeruginosa remained almost unchanged when the incident radiation was filtered through a sodium nitrite solution (cut off 406 nm) in order to exclude the UVA and UVB components of sunlight. Nevertheless, a delay in colony formation was detected in bacteria treated in this way, suggesting that a non-lethal effect was exerted by visible light. The results are not consistent with a generally accepted notion which attributes the lethal action of sunlight to the radiation with wavelengths above 320 nm. The characterization of UVB contribution to the lethal effect of sunlight on bacteria is relevant for understanding of the mechanism of cell death, and for improvement of dosimetry techniques and irradiation procedures. PMID- 22819169 TI - Protective immune responses in ducklings induced by a suicidal DNA vaccine of the VP1 gene of duck hepatitis virus type 1. AB - A suicidal DNA vaccine based on a Semliki Forest virus (SFV) replicon was evaluated for the development of a vaccine against duck hepatitis virus type 1 (DHV-1). The VP1 gene of DHV-1 was cloned and inserted into pSCA1, an SFV DNA based replicon vector. The resultant plasmid, pSCA/VP1, was transfected into BHK 21 cells and the antigenicity of the expressed protein was confirmed using an indirect immunofluorescence and western blot assay. Immunogenicity was studied in ducklings. Ducklings were injected intramuscularly two times with pSCA/VP1 at 14 days intervals. Anti-DHV-1 antibodies were detected by ELISA, the lymphocyte proliferation response was also tested by the 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide method and neutralizing antibodies were measured by microneutralization tests. Our results showed that DHV-1-specific antibodies, neutralizing antibodies and lymphocyte proliferation were well induced in ducklings. Furthermore, all the ducklings were protected against challenge with wild DHV-1. In conclusion, we demonstrate that the suicidal DNA vaccine is a promising vaccine candidate facilitating the prevention of duck hepatitis caused by DHV-1. PMID- 22819170 TI - PRKAG3 and CAST genetic polymorphisms and quality traits of dry-cured hams--II. Associations in French dry-cured ham Jambon de Bayonne and their dependence on salt reduction. AB - This study aimed to evaluate the effects of PRKAG3 Ile199Val and CAST Arg249Lys and CAST Ser638Arg polymorphisms on the quality traits of the French dry-cured ham Jambon de Bayonne and their interaction with salt reduction. Significant (p<0.05) and suggestive associations (p<0.10) between the polymorphisms and several quality traits of dry-cured ham, mainly related to processing and textural properties, were found. PRKAG3 Ile/Val and CAST 249Lys/638Arg presented the highest scores for sensory and processing properties, whatever the salt content. PMID- 22819171 TI - Antiangiogenic treatment in metastatic urothelial cancer. PMID- 22819172 TI - Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. AB - BACKGROUND: The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. METHODS: In an open-label, single-group, phase 2 study, patients (aged >=18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. FINDINGS: The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17.1%, 95% CI 7.2-32.1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. INTERPRETATION: Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. FUNDING: Fondazione IRCCS Istituto Nazionale dei Tumori provided the grant. GlaxoSmithKline provided the study drug and provided funding for the independent radiological review. PMID- 22819173 TI - Decrease in clinically relevant pancreatic fistula by coverage of the pancreatic remnant after distal pancreatectomy. AB - BACKGROUND: Pancreatic fistulas after distal pancreatectomy occur in up to 60% of patients with distal pancreatectomy. Several techniques for closure of the pancreatic stump have been advocated, but the best management of stump closure remains controversial. Our aim was to evaluate the clinical benefits of coverage of the pancreatic resection margin by autologous tissue. METHODS: One hundred seventeen consecutive patients underwent distal pancreatectomy at the university hospital in Heidelberg between May 2009 and September 2010. A coverage procedure was performed in 73 of these patients. All patients were recorded prospectively, and the clinical course was evaluated focusing on the occurrence of pancreatic fistula as defined by the International Study Group on Pancreatic Fistula. A treatment cost analysis was performed. RESULTS: The rate of clinically relevant pancreatic fistulas (types B and C) was decreased in patients with coverage compared to the standard controls (type B, 7% vs 9%; type C, 7% vs 25%; P < .002). Patients with a coverage procedure had a shorter duration of stay in the hospital (P < .02), and treatment costs were lower (P < .001) compared to patients without coverage. CONCLUSION: Coverage of the pancreatic remnant after distal pancreatectomy decreases the rate of clinically relevant pancreatic fistulas, duration of stay, and treatment costs. A randomized trial is needed to verify these results. PMID- 22819174 TI - Comparing anisotropic diffusion filters for the enhancement of sodium magnetic resonance images. AB - The anisotropic diffusion (AND) filter, an image processing technique derived from physics, was applied to low-resolution sodium magnetic resonance imaging (MRI) to examine the possibilities of image enhancement by postprocessing. We compared six different variants of AND filters. Besides the qualitative good results on phantom measurements, quantitative analyses on MRI of human kidney yielded major improvements in noise reduction and other quality measures: the noise (i.e., the standard deviation in the image background) could be reduced to 1%-2% of its original value, while linear filters (Gaussian, Fermi, Hamming) achieved a reduction to 42%-64%. Besides that, less than 5% of structures and intensities are lost when using AND filters. Comparing the different variants, the two-dimensional and the three-dimensional AND filter outperformed the histogram-of-gradient and tensor-based AND filter. We envision that by using these AND filters, quantitative analysis of sodium MRI of kidney could be improved. PMID- 22819175 TI - Assessment of hepatocellular carcinoma using apparent diffusion coefficient and diffusion kurtosis indices: preliminary experience in fresh liver explants. AB - OBJECTIVES: The objective was to perform ex vivo evaluation of non-Gaussian diffusion kurtosis imaging (DKI) for assessment of hepatocellular carcinoma (HCC), including presence of treatment-related necrosis, using fresh liver explants. METHODS: Twelve liver explants underwent 1.5-T magnetic resonance imaging using a DKI sequence with maximal b-value of 2000 s/mm(2). A standard monoexponential fit was used to calculate apparent diffusion coefficient (ADC), and a non-Gaussian kurtosis fit was used to calculate K, a measure of excess kurtosis of diffusion, and D, a corrected diffusion coefficient accounting for this non-Gaussian behavior. The mean value of these parameters was measured for 16 HCCs based upon histologic findings. For each metric, HCC-to-liver contrast was calculated, and coefficient of variation (CV) was computed for voxels within the lesion as an indicator of heterogeneity. A single hepatopathologist determined HCC necrosis and cellularity. RESULTS: The 16 HCCs demonstrated intermediate-to-substantial excess diffusional kurtosis, and mean corrected diffusion coefficient D was 23% greater than mean ADC (P=.002). HCC-to-liver contrast and CV of HCC were greater for K than ADC or D, although these differences were significant only for CV of HCCs (P<=.046). ADC, D and K all showed significant differences between non-, partially and completely necrotic HCCs (P<=.004). Among seven nonnecrotic HCCs, cellularity showed a strong inverse correlation with ADC (r=-0.80), a weaker inverse correlation with D (-0.24) and a direct correlation with K (r=0.48). CONCLUSIONS: We observed non-Gaussian diffusion behavior for HCCs ex vivo; this DKI model may have added value in HCC characterization in comparison with a standard monoexponential model of diffusion weighted imaging. PMID- 22819176 TI - Use of hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate to probe the effects of the anticancer agent dichloroacetate on mitochondrial metabolism in vivo in the normal rat. AB - Development of hyperpolarized technology utilizing dynamic nuclear polarization has enabled the measurement of (13)C metabolism in vivo at very high signal-to noise ratio (SNR). In vivo mitochondrial metabolism can, in principle, be monitored with pyruvate, which is catalyzed to acetyl-CoA via pyruvate dehydrogenase (PDH). The purpose of this work was to determine whether the compound sodium dichloroacetate (DCA) could aid the study of mitochondrial metabolism with hyperpolarized pyruvate. DCA stimulates PDH by inhibiting its inhibitor, pyruvate dehydrogenase kinase. In this work, hyperpolarized [1 (13)C]pyruvate and [2-(13)C]pyruvate were used to probe mitochondrial metabolism in normal rats. Increased conversion to bicarbonate (+181+/-69%, P=.025) was measured when [1-(13)C]pyruvate was injected after DCA administration, and increased glutamate (+74+/-23%, P=.004), acetoacetate (+504+/-281%, P=.009) and acetylcarnitine (+377+/-157%, P=.003) were detected when [2-(13)C]pyruvate was used. PMID- 22819177 TI - Input permutation method to detect active voxels in fMRI study. AB - Correctly identifying voxels or regions of interest (ROI) that actively respond to a given stimulus is often an important objective/step in many functional magnetic resonance imaging (fMRI) studies. In this article, we study a nonparametric method to detect active voxels, which makes minimal assumption about the distribution of blood oxygen level-dependent (BOLD) signals. Our proposal has several interesting features. It uses time lagged correlation to take into account the delay in response to the stimulus, due to hemodynamic variations. We introduce an input permutation method (IPM), a type of block permutation method, to approximate the null distribution of the test statistic. Also, we propose to pool the permutation-derived statistics of preselected voxels for a better approximation to the null distribution. Finally, we control multiple testing error rate using the local false discovery rate (FDR) by Efron [Correlation and large-scale simultaneous hypothesis testing. J Am Stat Assoc 102 (2007) 93-103] and Park et al. [Estimation of empirical null using a mixture of normals and its use in local false discovery rate. Comput Stat Data Anal 55 (2011) 2421-2432] to select the active voxels. PMID- 22819178 TI - Comparison of different mathematical models of diffusion-weighted prostate MR imaging. AB - PURPOSE: To evaluate which mathematical model (monoexponential, biexponential, statistical, kurtosis) fits best to the diffusion-weighted signal in prostate magnetic resonance imaging (MRI). MATERIALS AND METHODS: 24 prostate 3-T MRI examinations of young volunteers (YV, n=8), patients with biopsy proven prostate cancer (PC, n=8) and an aged matched control group (AC, n=8) were included. Diffusion-weighted imaging was performed using 11 b-values ranging from 0 to 800 s/mm(2). RESULTS: Monoexponential apparent diffusion coefficient (ADC) values were significantly (P<.001) lower in the peripheral (PZ) zone (1.18+/-0.16 mm(2)/s) and the central (CZ) zone (0.73+/-0.13 mm(2)/s) of YV compared to AC (PZ 1.92+/-0.17 mm(2)/s; CZ 1.35+/-0.21 mm(2)/s). In PC ADC(mono) values (0.61+/-0.06 mm(2)/s) were significantly (P<.001) lower than in the peripheral of central zone of AC. Using the statistical analysis (Akaike information criteria) in YV most pixels were best described by the biexponential model (82%), the statistical model, respectively kurtosis (93%) each compared to the monoexponential model. In PC the majority of pixels was best described by the monoexponential model (57%) compared to the biexponential model. CONCLUSION: Although a more complex model might provide a better fitting when multiple b-values are used, the monoexponential analyses for ADC calculation in prostate MRI is sufficient to discriminate prostate cancer from normal tissue using b-values ranging from 0 to 800 s/mm(2). PMID- 22819179 TI - Minimum SNR and acquisition for bias-free estimation of fractional anisotropy in diffusion tensor imaging - a comparison of two analytical techniques and field strengths. AB - Although it is known that low signal-to-noise ratio (SNR) can affect tensor metrics, few studies reporting disease or treatment effects on fractional anisotropy (FA) report SNR; the implicit assumption is that SNR is adequate. However, the level at which low SNR causes bias in FA may vary with tissue FA, field strength and analytical methodology. We determined the SNR thresholds at 1.5 T vs. 3 T in regions of white matter (WM) with different FA and compared FA derived using manual region-of-interest (ROI) analysis to tract-based spatial statistics (TBSS), an operator-independent whole-brain analysis tool. Using ROI analysis, SNR thresholds on our hardware-software magnetic resonance platforms were 25 at 1.5 T and 20 at 3 T in the callosal genu (CG), 40 at 1.5 and 3 T in the anterior corona radiata (ACR), and 50 at 1.5 T and 70 at 3 T in the putamen (PUT). Using TBSS, SNR thresholds were 20 at 1.5 T and 3 T in the CG, and 35 at 1.5 T and 40 at 3 T in the ACR. Below these thresholds, the mean FA increased logarithmically, and the standard deviations widened. Achieving bias-free SNR in the PUT required at least nine acquisitions at 1.5 T and six acquisitions at 3 T. In the CG and ACR, bias-free SNR was achieved with at least three acquisitions at 1.5 T and one acquisition at 3 T. Using diffusion tensor imaging (DTI) to study regions of low FA, e.g., basal ganglia, cerebral cortex, and WM in the abnormal brain, SNR should be documented. SNR thresholds below which FA is biased varied with the analytical technique, inherent tissue FA and field strength. Studies using DTI to study WM injury should document that bias-free SNR has been achieved in the region of the brain being studied as part of quality control. PMID- 22819180 TI - High-field magnetic resonance imaging using solenoid radiofrequency coils. AB - High-resolution magnetic resonance imaging using dedicated high-field radiofrequency micro-coils at 16.4 T (700 MHz) was investigated. Specific solenoid coils primarily using silver and copper as conductors with enamel and polyurethane coatings were built to establish which coil configuration produces the best image. Image quality was quantified using signal-to-noise ratio and signal variation over regions of interest. Benchmarking was conducted using 5-mm diameter coils, as this size is comparable to an established coil of the same size. Our 1.4-mm-diameter coils were compared directly to each other, from which we deduce performance as a function of conductor material and coating. A variety of materials and conductor coatings allowed us to choose an optimal design, which we used to image a kidney section at 10-micron resolution. We applied zero-fill extrapolation to achieve 5-micron resolution. PMID- 22819181 TI - Assessing the impact of breeding strategies on inherited disorders and genetic diversity in dogs. AB - In the context of management of genetic diversity and control of genetic disorders within dog breeds, a method is proposed for assessing the impact of different breeding strategies that takes into account the genealogical information specific to a given breed. Two types of strategies were investigated: (1) eradication of an identified monogenic recessive disorder, taking into account three different mating limitations and various initial allele frequencies; and (2) control of the population sire effect by limiting the number of offspring per reproducer. The method was tested on four dog breeds: Braque Saint Germain, Berger des Pyrenees, Coton de Tulear and Epagneul Breton. Breeding policies, such as the removal of all carriers from the reproduction pool, may have a range of effects on genetic diversity, depending on the breed and the frequency of deleterious alleles. Limiting the number of offspring per reproducer may also have a positive impact on genetic diversity. PMID- 22819182 TI - Use of CD10 as a marker of canine mammary myoepithelial cells. AB - CD10 is an important cell marker in the diagnosis of acute lymphoblastic leukaemia and of breast myoepithelial (ME) cells in humans. The objective of this study was to assess the value of CD10 as a marker of canine ME cells using immunohistochemistry on routinely processed normal, dysplastic and neoplastic mammary tissue. Five different CD10 positive cell types were identified on the basis of cell morphology, pattern of immunoreactivity, and on the co-expression of additional cell lineage-specific markers. Type 1 cells were typical fusiform cells with a ME cell phenotype (calponin- and cytokeratin [CK] 14-positive, CK8/18-negative). Type 2 cells were typical or atypical polyhedral cells with a luminal epithelial (LE) cell phenotype (calponin- and CK14-negative, CK8/18 positive). Type 3 cells had a type 1 phenotype with variable morphology, and type 4 were atypical neoplastic cells with a mixed ME/LE phenotype. Type 5 cells were typical fusiform cells with a stromal phenotype. Type 1 cells were considered normal ME cells and were found in all sample types; type 2 cells were considered normal or neoplastic LE cells and were also found in all sample types; types 3 and 4 cells were restricted to tumour samples and to malignant tumours, respectively, and type 5 cells were found in all sample types, although predominantly in neoplastic tissue. The findings indicate that the CD10 antigen is a sensitive (although not specific) marker of canine ME cells in normal, dysplastic and neoplastic mammary tissue. Differences in the distribution and staining intensity of CD10-positive cells suggest a number of potential roles for this protein in the pathogenesis of canine mammary neoplasia. PMID- 22819183 TI - Influence of diluent and sample processing methods on the recovery of the biocontrol agent Pantoea agglomerans CPA-2 from different fruit surfaces. AB - Determining the populations of biocontrol agents applied as a postharvest treatment on fruit surfaces is fundamental to the assessment of the microorganisms' ability to colonise and persist on fruit. To obtain maximum recovery, we must develop a methodology that involves both diluent and processing methods and that does not affect the viability of the microorganisms. The effect of diluent composition was evaluated using three diluents: phosphate buffer, peptone saline and buffered peptone saline. An additional study was performed to compare three processing methods (shaking plus sonication, stomaching and shaking plus centrifugation) on the recovery efficiency of Pantoea agglomerans strain CPA 2 from apples, oranges, nectarines and peaches treated with this biocontrol agent. Overall, slight differences occurred among diluents, although the phosphate buffer maintained the most ideal pH for CPA-2 growth (between 5.2 and 6.2). Stomaching, using the phosphate buffer as diluent, was the best procedure for recovering and enumerating the biocontrol agent; this fact suggested that no lethal effects from naturally occurring antimicrobial compounds present on the fruit skins and/or produced when the tissues were disrupted affected the recovery of the CPA-2 cells, regardless of fruit type. The growth pattern of CPA-2 on fruits maintained at 20 degrees C and under cold conditions was similar to that obtained in previous studies, which confirms the excellent adaptation of this strain to conditions commonly used for fruit storage. PMID- 22819184 TI - [Orthostatic hypotension: implications for the treatment of cardiovascular diseases]. AB - Several cardiovascular drugs may induce or worsen orthostatic hypotension especially in patients treated for hypertension, coronary artery disease and heart failure. Orthostatic hypotension is more frequent in polymedicated elderly patients with co-morbidities (prevalence 23%). In hypertensive elderly patients, the combination of three antihypertensive agents including a beta-blocker induces more frequently orthostatic hypotension. Supplementation in water and especially salt is generally not recommended in case of hypertension and heart failure. Education of patient to preventive counter-pressure maneuvers and muscle training of the lower limbs must be part of treatment. Midodrine causes supine hypertension in almost 25% of patients precluding to take this medication at the end of the afternoon. In severe heart failure, midodrine seems to be helpful to optimize drug treatment in patients suffering from hypotension. PMID- 22819185 TI - What is endosalpingiosis? AB - OBJECTIVE: To describe the demographics and clinical presentation of endosalpingiosis. To compare endosalpingiosis with endometriosis, particularly in regards to infertility and chronic pelvic pain. DESIGN: Retrospective analysis. SETTING: Hospital. PATIENT(S): We included women with a histologic diagnosis of endosalpingiosis, a second group with a histologic diagnosis of endometriosis, and a final group who had neither endosalpingiosis nor endometriosis, with histology reports after undergoing gynecologic surgery. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Infertility and chronic pelvic pain. RESULT(S): We found that 34.5% of endosalpingiosis cases had concurrent endometriosis; 40% of the endosalpingiosis group were postmenopausal. Endometriosis was significantly associated with infertility (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.4-8.5) and chronic pelvic pain (OR 3.0, 95% CI 1.7-5.5). In contrast, there was no significant link between endosalpingiosis and infertility (OR 1.6, 95% CI 0.7 3.7) nor chronic pelvic pain (OR 0.8, 95% CI 0.5-1.5). Gynecologic malignancy occurred significantly more in premenopausal women with endosalpingiosis than in those without (OR 10.3, 95% CI 3.6-29.8). CONCLUSION(S): Endosalpingiosis appears to affect postmenopausal women at a rate much higher than previously reported. Endosalpingiosis and endometriosis occur concurrently in 34% of endosalpingiosis cases; however, the two diseases have different clinical presentations. This demonstrates that endosalpingiosis is not a variant of endometriosis. PMID- 22819186 TI - The clinical relevance of luteal phase deficiency: a committee opinion. AB - Luteal phase deficiency (LPD) has been described in healthy normally menstruating women and in association with other medical conditions. While progesterone is important for the process of implantation and early embryonic development, LPD, as an independent entity causing infertility, has not been proven. PMID- 22819187 TI - Synchronization of ovarian stimulation with follicle wave emergence in patients undergoing in vitro fertilization with a prior suboptimal response: a randomized, controlled trial. AB - OBJECTIVE: To test the hypothesis that synchronizing initiation of ovarian stimulation with follicle wave emergence would optimize IVF/intracytoplasmic sperm injection (ICSI) outcomes in patients with a prior suboptimal response. DESIGN: Prospective, randomized, controlled trial. SETTING: Academic and private reproductive endocrinology and infertility centers. PATIENT(S): Eighty women <= 43 years of age with a history of a suboptimal response. INTERVENTION(S): Initiation of recombinant FSH/GnRH antagonist/recombinant LH/hCG on day 1 (n = 39) or day 4 (n = 41). MAIN OUTCOME MEASURE(S): Numbers of clinical and biochemical pregnancies, follicles >= 10 and >= 15 mm, oocytes collected, fertilized oocytes, cleavage stage embryos, and blastocysts; serum E(2) concentrations. Outcomes were compared between treatment groups. RESULT(S): The numbers of follicles that developed to >= 10 and >= 15 mm and serum E(2) were greater when recombinant FSH was initiated on day 1 (5.4, 4.3, 5,827.2 pmol/L) versus day 4 (3.6, 2.5, 4,230.1 pmol/L). The numbers of collected, metaphase II, and fertilized oocytes; cleavage stage embryos; and blastocysts were not different between groups. When we evaluated only those cycles that proceeded to oocyte pick-up, a lower implantation rate (16.1%, 56.0%), biochemical pregnancy rate (PR) (16.1%, 48.0%), and clinical PR (12.9% vs. 36.0%) were detected in the day 1 group versus day 4 group. CONCLUSION(S): Synchronizing initiation of ovarian stimulation with follicle wave emergence in patients with a prior suboptimal response resulted in an increase in the number of dominant follicles and serum E(2) concentrations; however, improvements in oocyte, embryo, or pregnancy outcomes did not occur. CLINICAL TRIAL REGISTRATION NUMBER: NCT00439829. PMID- 22819188 TI - The pathophysiology of uterine adenomyosis: an update. AB - The diagnosis of adenomyosis using noninvasive techniques such as vaginal ultrasounds and magnetic resonance has clear clinical applications and has renewed the interest in the pathogenesis of uterine adenomyosis. However, the research remains hampered by the lack of consensus on the classification of lesions. Magnetic resonance imaging and transvaginal ultrasound have comparable diagnostic accuracy. Minimal interventional biopsy techniques have recently been introduced. This article reviews human and animal studies and provides an update on the pathophysiology of adenomyosis. Recent views on the pathogenesis and links with endometriosis are discussed. PMID- 22819189 TI - Triamcinolone decreases bupivacaine toxicity to intervertebral disc cell in vitro. AB - BACKGROUND CONTEXT: Local anesthetics combined with corticosteroids are commonly used for management of back pain in interventional spinal procedures. Several recent studies suggest cytotoxicity of bupivacaine, whereas others report protective and cytotoxic effects of corticosteroids on chondrocytes and intervertebral disc cells. Considering the frequent use of these agents in spinal interventions, it is meaningful to know how they affect intervertebral disc cells. PURPOSE: This study was conducted to assess the effects of bupivacaine and triamcinolone, both alone and in combination, on viability of intervertebral disc cells in vitro. STUDY DESIGN: Controlled laboratory study. METHODS: Nucleus pulposus cells were isolated from human disc specimens from patients undergoing surgery because of disc herniation or degenerative disc disease. They were grown in three-dimensional alginate beads for 1 week to maintain their differentiated phenotypes and to allow for matrix formation before analysis. After 1 week of culture, the cells were exposed to bupivacaine (0.1%, 0.25%, 0.5%, and 1%) or bupivacaine (0.1%, 0.25%, 0.5%, and 1%) with 1 mg of triamcinolone for 1, 3, or 6 hours. Cell viability was measured using trypan blue exclusion assay and flow cytometry. Live cell/dead cell fluorescent imaging was assessed using confocal microscopy. RESULTS: Trypan blue exclusion assays demonstrated dose- and time dependent cytotoxic effects of bupivacaine on human nucleus pulposus cells. Similar but reduced cytotoxicity was observed after exposure to the combination of bupivacaine and 1 mg of triamcinolone. Flow cytometry showed a dose-dependent cytotoxic effect of bupivacaine on nucleus pulposus cells after 3 hours of exposure. The reduced cytotoxicity of bupivacaine combined with 1 mg of triamcinolone was also confirmed in flow cytometry. Confocal images showed that the increase in dead cells correlated with the concentration of bupivacaine. Nevertheless, fewer cells died after exposure to several different concentrations of bupivacaine combined with 1 mg of triamcinolone than did after exposure to bupivacaine alone. CONCLUSIONS: The combination of bupivacaine and triamcinolone induced dose- and time-dependent cytotoxicity on human intervertebral disc cells in vitro, but the cytotoxicity was much weaker than that of bupivacaine alone. This study shows a potential protective influence of triamcinolone on intervertebral disc cells. PMID- 22819190 TI - Design and synthesis of marine fungal phthalide derivatives as PPAR-gamma agonists. AB - On the basis of a marine fungal phthalide (paecilocin A) skeleton, we synthesized 20 analogs and evaluated them for peroxisome proliferator-activated receptor gamma (PPAR-gamma) binding and activation. Among these analogs, 6 and 7 had significant PPAR-gamma binding activity, and 7 showed further PPAR-gamma activation in rat liver Ac2F cells. In docking simulation, 7 formed H bonds with key amino acid residues of the PPAR-gamma binding domain, and the overall positioning was similar to rosiglitazone. This new phthalide derivative is considered an interesting new molecular class of PPAR-gamma ligands. PMID- 22819191 TI - Synthesis, biological evaluation, and molecular docking studies of N-((1,3 diphenyl-1H-pyrazol-4-yl)methyl)aniline derivatives as novel anticancer agents. AB - A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)aniline derivatives (5a-8d) have been designed and synthesized, and their biological activities were also evaluated as potential antitumor and cyclin dependent kinase 2 (CDK2) inhibitors. Among all the compounds, compound 5a displayed the most potent CDK2/cyclin E inhibitory activity in vitro, with an IC(50) of 0.98 +/- 0.06 MUM. Antitumor assays indicated that compound 5a owned high antiproliferative activity against MCF-7 and B16-F10 cancer cell lines with IC(50) values of 1.88 +/- 0.11 and 2.12 +/- 0.15 MUM, respectively. Docking simulation was performed to insert compound 5a into the crystal structure of CDK2 at active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity in tumor growth may be a potential anticancer agent. PMID- 22819192 TI - Genetic control of functional brain network efficiency in children. AB - The human brain is a complex network of interconnected brain regions. In adulthood, the brain's network was recently found to be under genetic influence. However, the extent to which genes influence the functional brain network early in development is not yet known. We report on the heritability of functional brain efficiency during early brain development. Using a twin design, young children underwent resting-state functional magnetic resonance imaging brain scans (N=86 from 21MZ and 22DZ twin-pairs, age=12 years). Functional connectivity, defined as the temporal dependency of neuronal activation patterns of anatomically separated brain regions, was explored using graph theory and its heritability was examined using structural equation modeling. Our findings suggest that 'global efficiency of communication' among brain regions is under genetic control (h2 lambda=42%), irrespectively of the total number of brain connections (connectivity density). In addition, no influence of genes or common environment to local clustering (gamma) was found, suggesting a less pronounced effect of genes on local information segregation. Thus our findings suggest that a set of genes is shaping the underlying architecture of functional brain communication during development. PMID- 22819193 TI - A transition pilot program for adolescents with sickle cell disease. AB - INTRODUCTION: Transition from pediatric to adult care is challenging for adolescents with chronic illnesses, including those with sickle cell disease (SCD). We describe a pilot program created to facilitate transition from pediatric to adult care by helping adolescents with SCD identify an adult medical home. METHODS: We investigated the feasibility of this program by evaluation of overall participation, satisfaction, and acceptance. A secondary objective was to compare the proportion of adolescents who fulfilled a first appointment with an adult hematologist among participants and nonparticipants. RESULTS: During the first 18 months of the program, 83 adolescents were invited and 34 (41%) agreed to participate; 25 (74%) completed their first visit within 3 months after leaving the pediatric program, compared with 16 of 49 (33%) of nonparticipants (p = .0002). Overall, 41 of 83 adolescents (49%) completed an appointment with an adult SCD program, regardless of program participation, in contrast with 11 of 75 adolescents (15%) who did so during the 18 months before the program was created (p < .0001). DISCUSSION: This transition pilot program was feasible, and most adolescent participants with SCD established an adult medical home. PMID- 22819194 TI - FDG-PET/CT in pulmonary and cardiac Langerhans' cell histiocytosis and metastatic non-small cell lung cancer. PMID- 22819195 TI - An improved strategy for the synthesis of [18F]-labeled arabinofuranosyl nucleosides. AB - The expression of the herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene can be imaged efficaciously using a variety of 2'-[(18)F]fluoro-2'-deoxy-1-b-D arabinofuranosyl-uracil derivatives [[(18)F]-FXAU, X=I(iodo), E(ethyl), and M(methyl)]. However, the application of these derivatives in clinical and translational studies has been impeded by their complicated and long syntheses (3 5h). To remedy these issues, in the study at hand we have investigated whether microwave or combined catalysts could facilitate the coupling reaction between sugar and nucleobase and, further, have probed the feasibility of establishing a novel approach for [(18)F]-FXAU synthesis. We have demonstrated that the rate of the trimethylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed coupling reaction between the 2-deoxy-sugar and uracil derivatives at 90 degrees C can be significantly accelerated by microwave-driven heating or by the addition of Lewis acid catalyst (SnCl(4)). Further, we have observed that the stability of the alpha- and beta-anomers of [(18)F]-FXAU derivatives differs during the hydrolysis step. Using the microwave-driven heating approach, overall decay-corrected radiochemical yields of 19%-27% were achieved for [(18)F]-FXAU in 120min at a specific activity of >22MBq/nmol (595Ci/mmol). Ultimately, we believe that these high yielding syntheses of [(18)F]-FIAU, [(18)F]-FMAU and [(18)F]-FEAU will facilitate routine production for clinical applications. PMID- 22819196 TI - Amplification of DNA damage by a gammaH2AX-targeted radiopharmaceutical. AB - (111)In-DTPA-anti-gammaH2AX-Tat, which combines an anti-gammaH2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, (111)In, targets the DNA damage signalling protein, gammaH2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to investigate whether (111)In-DTPA-anti-gammaH2AX-Tat labelled to high specific activity (6MBq/MUg) can amplify treatment-related DNA damage for therapeutic gain. METHODS: MDA-MB-468 and MDA-MB-231/H2N (231-H2N) breast cancer cells were incubated with (111)In-DTPA-anti-gammaH2AX-Tat (3MBq, 6MBq/MUg) or a control radioimmunoconjugate, (111)In-DTPA-mIgG-Tat, and exposed to IR or bleomycin. DNA damage was studied by counting gammaH2AX foci and by neutral comet assay. Cytotoxicity was evaluated using clonogenic assays. (111)In-DTPA-anti-gammaH2AX Tat was administered intravenously to 231-H2N-xenograft-bearing Balb/c nu/nu mice in tumor growth inhibition studies. RESULTS: The number of gammaH2AX foci was greater after exposure of cells to IR (10Gy) plus (111)In-DTPA-anti-gammaH2AX-Tat compared to IR alone (20.6+/-2.5 versus 10.4+/-2.3 foci/cell; P<.001).(111)In DTPA-anti-gammaH2AX-Tat resulted in a reduced surviving fraction in cells co treated with IR (4Gy) versus IR alone (5.2%+/-0.9% versus 47.8%+/-2.8%; P<.001). Similarly, bleomycin (25-200MUg/mL) plus (111)In-DTPA-anti-gammaH2AX-Tat resulted in a lower SF compared to bleomycin alone. The combination of a single exposure to IR (10Gy) plus (111)In-DTPA-anti-gammaH2AX-Tat significantly decreased the growth rate of 231-H2N xenografts in vivo compared to either (111)In-DTPA-anti gammaH2AX-Tat or IR alone (-0.002+/-0.004 versus 0.036+/-0.011 and 0.031+/ 0.014mm(3)/day, respectively, P<.001). CONCLUSION: (111)In-DTPA-anti-gammaH2AX Tat amplifies anticancer treatment-related DNA damage in vitro and has a potent anti-tumor effect when combined with IR in vivo. PMID- 22819197 TI - Oxysterol receptors, AKT and prostate cancer. AB - Oxysterols derive from cholesterol oxidation. They display various biological activities such as regulating cholesterol, fatty acid and glucose homeostasis as well as cell survival/apoptosis balance. Oxysterols display these metabolic and transcriptional activities mainly through their nuclear receptors known as Liver X Receptors (LXRs) alpha and beta. There is accumulating evidence that LXRs are key modulators of prostate cancer cell survival. Hence, LXR activation increases cholesterol efflux and induces a disruption of lipid rafts. The decrease of membrane cholesterol causes a down regulation of AKT survival pathway and consequently apoptosis. Moreover cholesterol is associated with an increased risk of developing aggressive forms of prostate cancer. These data highlight the interest of targeting the LXR-AKT axis in prostate carcinogenesis. PMID- 22819198 TI - Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. AB - Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents. PMID- 22819199 TI - Use of order sets in inpatient computerized provider order entry systems: a comparative analysis of usage patterns at seven sites. AB - BACKGROUND: Many computerized provider order entry (CPOE) systems include the ability to create electronic order sets: collections of clinically related orders grouped by purpose. Order sets promise to make CPOE systems more efficient, improve care quality and increase adherence to evidence-based guidelines. However, the development and implementation of order sets can be expensive and time-consuming and limited literature exists about their utilization. METHODS: Based on analysis of order set usage logs from a diverse purposive sample of seven sites with commercially and internally developed inpatient CPOE systems, we developed an original order set classification system. Order sets were categorized across seven non-mutually exclusive axes: admission/discharge/transfer (ADT), perioperative, condition-specific, task specific, service-specific, convenience, and personal. In addition, 731 unique subtypes were identified within five axes: four in ADT (S=4), three in perioperative, 144 in condition-specific, 513 in task-specific, and 67 in service specific. RESULTS: Order sets (n=1914) were used a total of 676,142 times at the participating sites during a one-year period. ADT and perioperative order sets accounted for 27.6% and 24.2% of usage respectively. Peripartum/labor, chest pain/acute coronary syndrome/myocardial infarction and diabetes order sets accounted for 51.6% of condition-specific usage. Insulin, angiography/angioplasty and arthroplasty order sets accounted for 19.4% of task-specific usage. Emergency/trauma, obstetrics/gynecology/labor delivery and anesthesia accounted for 32.4% of service-specific usage. Overall, the top 20% of order sets accounted for 90.1% of all usage. Additional salient patterns are identified and described. CONCLUSION: We observed recurrent patterns in order set usage across multiple sites as well as meaningful variations between sites. Vendors and institutional developers should identify high-value order set types through concrete data analysis in order to optimize the resources devoted to development and implementation. PMID- 22819200 TI - Parent-reported quality of preventive care for children at-risk for developmental delay. AB - OBJECTIVE: To compare preventive care quality for children at risk and not at risk for developmental, behavioral, or social delays. METHODS: Using the 2007 National Survey of Children's Health (n = 22,269), we used the Parents' Evaluation of Developmental Status (PEDS) questionnaire to identify children ages 10 months to 5 years who were at risk for delays. We examined parent-reported quality measures to evaluate whether care was comprehensive, coordinated, family centered, effective in providing developmental surveillance and screening, and provided within a medical home. Bivariate and multivariate analyses were used. RESULTS: Twenty-eight percent of children were at-risk for delay, with 17% at moderate risk and 11% at high risk. Greater proportions of children at high, moderate, and no/low risk had a usual source of care (89%-96%) and a personal doctor/nurse (91%-94%); smaller proportions of children underwent a standardized developmental screening (16%-23%) and had parental developmental concerns elicited from their doctor (47%-48%). In adjusted analyses, moderate-risk and high-risk children were less likely than no/low-risk children to receive needed care coordination (adjusted odds ratio [AOR] for high risk 0.33, 95% confidence interval [95% CI] 0.24-0.46) and referrals (high risk AOR 0.40, 95% CI 0.25 0.65), family-centered care (high-risk AOR 0.47, 95% CI 0.36-0.62), and to have a medical home (high-risk AOR 0.41, 95% CI 0.32-0.54). CONCLUSIONS: Our findings may reflect either poorer quality of care provided to at-risk children, or higher level of parental need that routine visits are not currently meeting. For at-risk children, enhanced screening and detection followed by targeted increases in communication and follow-up may help clinicians better anticipate families' needs. PMID- 22819201 TI - Hospital electronic medical record use and cost of inpatient pediatric care. AB - OBJECTIVE: Electronic medical record (EMR) systems are costly for hospitals to implement and maintain, and the effects of EMR on the cost of care for inpatient pediatrics remain unknown. Our objective was to determine whether delivering care with advanced-stage EMR was associated with a decreased cost per case in a national sample of hospitalized children. METHODS: The Healthcare Cost and Utilization Project Kids Inpatient Dataset 2009 identified pediatric discharges. The Healthcare Information and Management Systems Society 2009 database identified hospitals' EMR use. EMR was classified into 3 stages, with advanced stage 3 EMR including automation of ancillary services, automation of nursing workflow, computerized provider order entry, and clinical decision support. Multivariable linear regression was used to determine the independent effect of advanced-stage EMR on cost per case. Propensity score adjustment was included to control for nonrandom assignment of EMR use. RESULTS: This analysis included 4,605,454 weighted discharges. EMR use by hospitals that care for children was common: 24% for stage 1, 23% stage 2, and 32% advanced stage 3. The multivariable model demonstrated that advanced stage EMR was associated with an average 7% greater cost per case ($146 per discharge). CONCLUSIONS: The care of children across the United States with EMRs may create a safer health care system but is not associated with inpatient cost savings. In fact our primary analysis shows a 7% additional cost per case. This finding is contrary to predicted savings and may represent an added barrier in the adoption of EMR for inpatient pediatrics. PMID- 22819202 TI - Miniaturised free flow isotachophoresis of bacteria using an injection moulded separation device. AB - A new design of miniaturised free flow electrophoresis device has been produced. The design contains a separation chamber that is 45 mm long by 31.7 mm wide with a depth of 50 MUm and has nine inlet and nine outlet holes to allow for fraction collection. The devices were formed of polystyrene with carbon fibre loaded polystyrene drive electrodes and produced using injection moulding. This means that the devices are low cost and can potentially be mass produced. The devices were used for free flow isotachophoresis (FFITP), a technique that can be used for focussing and concentrating analytes contained within complex sample matrices. The operation of the devices was demonstrated by performing separations of dyes and bacterial samples. Analysis of the output from FFITP separations of samples containing the bacterium Erwinia herbicola, a biological pathogen, by cell culturing and counting showed that fractionation of the output was achieved. PMID- 22819203 TI - Trends in data processing of comprehensive two-dimensional chromatography: state of the art. AB - The operation of advanced chromatographic systems, namely comprehensive two dimensional (2D) chromatography coupled to multidimensional detectors, allows achieving a great deal of data that need special care to be processed in order to characterize and quantify as much as possible the analytes under study. The aim of this review is to identify the main trends, research needs and gaps on the techniques for data processing of multidimensional data sets obtained from comprehensive 2D chromatography. The following topics have been identified as the most promising for new developments in the near future: data acquisition and handling, peak detection and quantification, measurement of overlapping of 2D peaks, and data analysis software for 2D chromatography. The rational supporting most of the data processing techniques is based on the generalization of one dimensional (1D) chromatography although algorithms, such as the inverted watershed algorithm, use the 2D chromatographic data as such. However, for processing more complex N-way data there is a need for using more sophisticated techniques. Apart from using other concepts from 1D chromatography, which have not been tested for 2D chromatography, there is still room for new improvements and developments in algorithms and software for dealing with 2D comprehensive chromatographic data. PMID- 22819204 TI - Simultaneous determination of three sesquiterpene lactones from Herba Inula extract in rat plasma by LC/MS/MS and its application to pharmacokinetic study. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of 1-acetoxy-6alpha hydroxyeriolanolide, 1beta-hydroxyalantolactone and ivangustin from Herba Inula extract in rat plasma. Plasma samples were pretreated by protein precipitation with methanol. Chromatographic separation was accomplished on a TOSOH TSKgel ODS column with mobile phase consisting of methanol and 0.3% formic acid (80:20, v/v). The detection was carried out by multiple-reaction monitoring mode under positive electrospray ionization. The quantification was performed using the transitions of m/z 309.1/185.0 for 1-acetoxy-6alpha-hydroxyeriolanolide, m/z 249.0/231.1 for 1beta-hydroxyalantolactone and ivangustin and m/z 285.0/193.0 for diazepam, respectively. Calibration curves were linear over the concentration range of 4-800 ng/mL for 1-acetoxy-6alpha-hydroxyeriolanolide, 8-500 ng/mL for 1beta-hydroxyalantolactone and ivangustin. The limit of detection (LOD) was 1 ng/mL for 1-acetoxy-6alpha-hydroxyeriolanolide, 1.6 ng/mL for 1beta hydroxyalantolactone and ivangustin (S/N=3). The intra-day and inter-day precisions (RSD%) for the three compounds were less than 7.8% and 8.6%, and the accuracy (RE%) ranged from -4.6 to 6.8%. The method was successfully applied to pharmacokinetic studies of the three sesquiterpene lactones after oral administration of 300 mg/kg Herba Inula extract to rats, the t(1/2) of 1-acetoxy 6alpha-hydroxyeriolanolide, 1beta-hydroxyalantolactone and ivangustin was 9.65+/ 1.43, 14.88+/-0.82 and 13.93+/-2.74 (h). The AUC((0-t)) of 1-acetoxy-6alpha hydroxyeriolanolide, 1beta-hydroxyalantolactone and ivangustin was 1102.46+/ 247.04, 808.92+/-117.53 and 990.35+/-275.49 (ng h/mL), respectively. PMID- 22819205 TI - 'Watchful waiting' or 'active monitoring' in depression management in primary care: exploring the recalled content of general practitioner consultations. AB - BACKGROUND: Current NICE depression guidelines recommend a period of 'active monitoring' prior to commencing treatment with antidepressants. The content of consultations during active monitoring or supportive care has not been previously prescribed. METHODS: As part of a randomised trial of supportive care versus supportive care plus SSRI consultation content was measured through patient recall for the purpose of testing equity in content between trial arms. An exploratory analysis of the consultation content measure is presented together with a measure of consultation satisfaction (MISS) and depression severity (HMRD). A score for 'psychoactive consultation content' (PSAC) was generated to enable comparison between groups. RESULTS: 220 patients were randomised in the study. The majority of participants recalled a discussion of practical problems they faced and many reported some element of problem solving; a significant minority reported discussions about changing the way they thought, addressing relationships or talking to trusted friends or family. Consultation content was unrelated to depression outcome although in multivariate analysis it was strongly related to consultation satisfaction. LIMITATIONS: This is a secondary analysis based on patient recall of consultation content. CONCLUSIONS: Supportive care is not a passive process as patients report several potentially therapeutic discussions within the consultation and these occur regardless of whether antidepressants are prescribed. It is not known whether these discussions do have any therapeutic value in this context. Consultation content was unrelated to outcome in this study but did predict satisfaction with the consultation. Further work is required to validate the patient report of consultation content and to identify what if any consultation strategies have therapeutic effect. PMID- 22819206 TI - Determination of essential amino acids in human serum by a targeting method based on automated SPE-LC-MS/MS: discrimination between artherosclerotic patients. AB - An automated method based on a hyphenated SPE-LC-MS/MS configuration has been optimized for the determination of essential amino acids (threonine, valine, methionine, leucine, isoleucine, lysine, tryptophan, and phenylalanine) in human serum, with the aim of discriminating between different states of coronary artery disease. Validation in terms of sensitivity (detection limits below 28.0 ng on column) and precision (repeatability expressed as relative standard deviation below 6.0%) supports the suitability of the method for application to a cohort of 122 atherosclerosis patients confirmed by a catheterization test. The cohort was composed by 80 individuals diagnosed with stable angina and 42 patients who suffered from acute myocardial infarction (AMI). Both groups of individuals are differentiated by the occurrence of ischemia in AMI patients due to the formation of thrombi. The chemometric treatment of the data obtained by multivariate analysis of variance (MANOVA) allowed comparison between both groups of diagnosed patients. Therefore, amino acids whose serum levels were affected by ischemia have been identified. The contribution of risk factors such as obesity and hypercholesterolemia as well as the individuals' gender to the concentration of essential amino acids has also been studied. PMID- 22819207 TI - Characterization of the metabolism of sibiricaxanthone F and its aglycone in vitro by high performance liquid chromatography coupled with Q-trap mass spectrometry. AB - To explain the low bioavailability of sibiricaxanthone F (SF) following oral administration and to predict its possible metabolites in vivo, the in vitro biotransformation of SF and its metabolic stability in intestinal bacteria (BI) were studied. The metabolism of SF and its aglycone (1,3,6-trihydroxy-2,7 dimethoxyxanthone, Xan) was characterized after incubation with human and rat liver microsomes (HLMs and RLMs). The chemical structures of the metabolites were tentatively identified on the basis of their mass profiles using high performance liquid chromatography coupled with an enhanced mass spectrometry-information dependent acquisition-enhanced product ion (EMS-IDA-EPI) scan mode on a hybrid triple quadrupole-linear ion trap mass spectrometer. The metabolic stability of SF in BI was determined using the multiple reaction monitoring (MRM) mode. As a result, five hydrolyzed metabolites (M1-M4 and Xan) were generated stepwise for SF when it was incubated with BI, whereas two demethylated products (M1 and M5) were detected for Xan in BI. The metabolic stability study of SF in BI revealed that the parent compound could be rapidly hydrolyzed by BI and that Xan, the main corresponding metabolite, increased rapidly. In RLMs and HLMs, two hydrolyzed metabolites (M2 and M3) mediated by CYP450 isoenzymes appeared for SF in the presence of an NADPH-regenerating system, whereas no metabolite was detected for Xan under the same conditions. One (M6) and three glucuronidated metabolites (M7 M9) were generated from SF and Xan, respectively, by phase II isoenzymes in liver microsomal proteins in the presence of uridine 5'-diphosphoglucuronic acid (UDPGA). Overall, the present study revealed that extensive first-pass elimination occurred for SF in intestinal bacteria and hepatic subcellular proteins in vitro, which could be one of the main reasons for the low bioavailability of SF; furthermore, the possible SF-related metabolites in rats and humans were elucidated to be mono-glucuronidated derivatives of Xan following oral administration of SF. PMID- 22819208 TI - Determination of soluble vascular endothelial growth factor receptor 3 (sVEGFR-3) in plasma as pharmacodynamic biomarker. AB - Soluble VEGFR-3 (sVEGFR-3) is a potential biomarker for the anti-angiogenic activity of tyrosine kinase inhibitors. The aim of this investigation was the validation of an enzyme-linked immunosorbent assay (ELISA) to measure sVEGFR-3 in human plasma and the investigation of its applicability in clinical trials as first step of the biomarker validation process. General validation criteria were assessed based on current guidelines and recommendations for immunoassays. The ELISA was applied in two clinical trials including healthy volunteers and metastatic colorectal cancer (mCRC) patients receiving 50 or 37.5mg sunitinib per day, respectively. SVEGFR-3 was measured at predefined time points. Undiluted, inactivated fetal calf serum was identified as surrogate matrix to substitute for human plasma. Dilutional linearity and parallelism could be successfully confirmed. The analyte was measured in the study matrix with intra- and inter-run precision and accuracy <=20%. Stability was proven over a period of at least 15 months as well as upon three freeze-thaw cycles. SVEGFR-3 concentrations decreased in response to sunitinib to 57% (IQR 50-88%) and 58% (IQR 47-80%) of the respective baseline concentrations in healthy volunteers and mCRC patients, respectively, with subsequent increase after stop of treatment. The ELISA for the quantification of sVEGFR-3 in human plasma was successfully validated. The applicability of the assay was demonstrated in two clinical trials. PMID- 22819209 TI - Impurity profiling of etimicin sulfate by liquid chromatography ion-trap mass spectrometry. AB - A reversed phase (RP)-LC method using a C(18) column resistant to basic pH and an alkaline (pH 10) aqueous mobile phase was developed and coupled to MS with an electrospray ionization (ESI) source in the positive ion mode which provides MS(n) capability. In total, 26 impurities were detected in a commercial sample. The structures of the impurities were proposed based on comparison of their fragmentation patterns with those of the available reference substances, the synthetic route and literature data. Starting material and its residual impurities, intermediates, synthetic by-products and degradation products were the main sources of those impurities. 14 impurities described in this work were newly identified. PMID- 22819210 TI - The clinical development of molecularly targeted agents in combination with radiation therapy: a pharmaceutical perspective. AB - This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the clinicaltrials.gov Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with clinicaltrials.gov protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such trials are not given priority by pharmaceutical companies. The potential reasons for this and some challenges and possible solutions are discussed. PMID- 22819211 TI - Clinical features of Sturge-Weber syndrome without facial nevus: five novel cases. AB - Classic Sturge-Weber syndrome (SWS) is characterized by presence of flammeus nevus involving the first sensory branch of trigeminal nerve, ipsilateral leptomeningeal angiomatosis, and choroidal angioma. Sporadic cases of SWS without facial nevus (SWS type III) have been rarely reported. Here we report the clinical and neuroradiological findings of five patients with SWS type III and compare their findings with those described in the literature. This study confirmed that SWS type III should be considered in any child or young adult presenting with seizures or complicated migraine and intracranial unilateral calcification. The diagnosis must be confirmed with contrast-enhanced MRI images of the brain. Surgical therapy should be considered in patients with drug resistant and persistent epileptic seizures. PMID- 22819212 TI - Regulation of lipid metabolism by p53 - fighting two villains with one sword. AB - Both cellular and systemic metabolism of lipids are paramount for homeostasis, and their malfunction leads to devastating pathologies. Recently, exciting findings have linked the p53 tumor suppressor to the regulation of lipid metabolism. Here, we summarize these findings showing a clear role for p53 in enhancing lipid catabolism while inhibiting its anabolism. We also describe the multitude of genes regulated by p53 that participate in or regulate systemic lipid transport. From the compilation of available data a scenario is emerging in which p53 regulates genes involved in lipid metabolism - both in a cancer preventive effort and, intriguingly, as a means to prevent atherosclerosis. Thus, by regulating lipid metabolism, p53 fights the two major causes of death worldwide - atherosclerosis and cancer. PMID- 22819214 TI - Slower postnatal motor development in infants of mothers with latent toxoplasmosis during the first 18 months of life. AB - Toxoplasmosis, a zoonosis caused by a protozoan, Toxoplasma gondii, is probably the most widespread human parasitosis in developed countries. Pregnant women with latent toxoplasmosis have seemingly younger fetuses especially in the 16th week of gestation, which suggests that fetuses of Toxoplasma-infected mothers have slower rates of development in the first trimester of pregnancy. In the present retrospective cohort study, we analyzed data on postnatal motor development of infants from 331 questionnaire respondents including 53 Toxoplasma-infected mothers to search for signs of early postnatal development disorders. During the first year of life, a slower postnatal motor development was observed in infants of mothers with latent toxoplasmosis. These infants significantly later developed the ability to control the head position (p=0.039), to roll from supine to prone position (p=0.022) and were slightly later to begin crawling (p=0.059). Our results are compatible with the hypothesis that the difference in the rates of prenatal and early postnatal development between children of Toxoplasma-negative and Toxoplasma-positive mothers might be caused by a decreased stringency of embryo quality control in partly immunosuppressed Toxoplasma-positive mothers resulting in a higher proportion of infants with genetic or developmental disorders in offspring. However, because of relatively low return rate of questionnaires and an associated risk of a sieve effect, our results should be considered as preliminary and performing a large scale prospective study in the future is critically needed. PMID- 22819213 TI - The dynamic regulation of NAD metabolism in mitochondria. AB - Mitochondria are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. Although the maintenance of an optimal NAD/NADH ratio is essential for mitochondrial function, it has recently become apparent that the maintenance of the mitochondrial NAD pool is also of crucial importance. The biosynthesis, transport, and catabolism of NAD and its key intermediates play an important role in the regulation of NAD-consuming mediators, such as sirtuins, poly-ADP-ribose polymerases, and CD38/157 ectoenzymes, in intra- and extracellular compartments. Mitochondrial NAD biosynthesis is also modulated in response to nutritional and environmental stimuli. In this article, we discuss this dynamic regulation of NAD metabolism in mitochondria to shed light on the intimate connection between NAD and mitochondrial function. PMID- 22819215 TI - [Invasive meningitis due to serogroup 29E meningococci]. PMID- 22819216 TI - Structures of lysenin reveal a shared evolutionary origin for pore-forming proteins and its mode of sphingomyelin recognition. AB - Pore-forming proteins insert from solution into membranes to create lesions, undergoing a structural rearrangement often accompanied by oligomerization. Lysenin, a pore-forming toxin from the earthworm Eisenia fetida, specifically interacts with sphingomyelin (SM) and may confer innate immunity against parasites by attacking their membranes to form pores. SM has important roles in cell membranes and lysenin is a popular SM-labeling reagent. The structure of lysenin suggests common ancestry with other pore-forming proteins from a diverse set of eukaryotes and prokaryotes. The complex with SM shows the mode of its recognition by a protein in which both the phosphocholine headgroup and one acyl tail are specifically bound. Lipid interaction studies and assays using viable target cells confirm the functional reliance of lysenin on this form of SM recognition. PMID- 22819217 TI - Structure and 3D arrangement of endoplasmic reticulum membrane-associated ribosomes. AB - In eukaryotic cells, cotranslational protein translocation across the endoplasmic reticulum (ER) membrane requires an elaborate macromolecular machinery. While structural details of ribosomes bound to purified and solubilized constituents of the translocon have been elucidated in recent years, little structural knowledge of ribosomes bound to the complete ER protein translocation machinery in a native membrane environment exists. Here, we used cryoelectron tomography to provide a three-dimensional reconstruction of 80S ribosomes attached to functional canine pancreatic ER microsomes in situ. In the resulting subtomogram average at 31 A resolution, we observe direct contact of ribosomal expansion segment ES27L and the membrane and distinguish several membrane-embedded and lumenal complexes, including Sec61, the TRAP complex and another large complex protruding 90 A into the lumen. Membrane-associated ribosomes adopt a preferred three-dimensional arrangement that is likely specific for ER-associated polyribosomes and may explain the high translation efficiency of ER-associated ribosomes compared to their cytosolic counterparts. PMID- 22819218 TI - Motif D of viral RNA-dependent RNA polymerases determines efficiency and fidelity of nucleotide addition. AB - Fast, accurate nucleotide incorporation by polymerases facilitates expression and maintenance of genomes. Many polymerases use conformational dynamics of a conserved alpha helix to permit efficient nucleotide addition only when the correct nucleotide substrate is bound. This alpha helix is missing in structures of RNA-dependent RNA polymerases (RdRps) and RTs. Here, we use solution-state nuclear magnetic resonance to demonstrate that the conformation of conserved structural motif D of an RdRp is linked to the nature (correct versus incorrect) of the bound nucleotide and the protonation state of a conserved, motif-D lysine. Structural data also reveal the inability of motif D to achieve its optimal conformation after incorporation of an incorrect nucleotide. Functional data are consistent with the conformational change of motif D becoming rate limiting during and after nucleotide misincorporation. We conclude that motif D of RdRps and, by inference, RTs is the functional equivalent to the fidelity helix of other polymerases. PMID- 22819220 TI - Tako-tsubo syndrome and heart failure: long-term follow-up. AB - INTRODUCTION AND OBJECTIVES: Tako-tsubo syndrome produces a variable degree of transient left ventricular dysfunction. Our objective was to determine the short- and long-term prognosis of this syndrome, the incidence of and risk factors for the development of heart failure, and the influence on heart failure on the long term outcome in our patient population. METHODS: We prospectively recorded the clinical features and events during the hospital stay and follow-up of 100 patients with tako-tsubo syndrome. The risk factors for heart failure during hospital stay, considered as Killip class>=II, were assessed. RESULTS: Most of the patients were women (89%), with a mean age of 68 years. The distribution according to Killip class was: Killip I, 70 patients; Killip II, 15; Killip III, 5; and Killip IV, 10. Cardiovascular risk factors, including diabetes, were common in the overall group, but were more so in the heart failure cohort. The left ventricular ejection fraction was lower in the heart failure group (51% vs 42%; P<.01). There were no differences in preadmission medications or biomarkers of necrosis. Over a median follow-up of 1380 days, the incidence of events reported during the hospital stay and long-term follow-up, both for death and the combined endpoints, was higher in the heart failure cohort. CONCLUSIONS: Although the prognosis in tako-tsubo syndrome is usually good, heart failure occurs quite frequently, mainly in patients with a greater number of comorbidities and poorer previous functional class. Moreover, heart failure is associated with a higher number of early and late adverse events. The overall long-term prognosis is good. Full English text available from:www.revespcardiol.org. PMID- 22819219 TI - An autoinhibited noncanonical mechanism of GTP hydrolysis by Rheb maintains mTORC1 homeostasis. AB - Rheb, an activator of mammalian target of rapamycin (mTOR), displays low intrinsic GTPase activity favoring the biologically activated, GTP-bound state. We identified a Rheb mutation (Y35A) that increases its intrinsic nucleotide hydrolysis activity ~10-fold, and solved structures of both its active and inactive forms, revealing an unexpected mechanism of GTP hydrolysis involving Asp65 in switch II and Thr38 in switch I. In the wild-type protein this noncanonical mechanism is markedly inhibited by Tyr35, which constrains the active site conformation, restricting the access of the catalytic Asp65 to the nucleotide-binding pocket. Rheb Y35A mimics the enthalpic and entropic changes associated with GTP hydrolysis elicited by the GTPase-activating protein (GAP) TSC2, and is insensitive to further TSC2 stimulation. Overexpression of Rheb Y35A impaired the regulation of mTORC1 signaling by growth factor availability. We demonstrate that the opposing functions of Tyr35 in the intrinsic and GAP stimulated GTP catalysis are critical for optimal mTORC1 regulation. PMID- 22819221 TI - LRP1 gene polymorphisms are associated with premature risk of cardiovascular disease in patients with familial hypercholesterolemia. AB - INTRODUCTION AND OBJECTIVES: LRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis. METHODS: Ten polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study. RESULTS: The c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]). CONCLUSIONS: The c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism. PMID- 22819222 TI - Interpretation pearls for MR imaging of parotid gland tumor. PMID- 22819223 TI - Synovial sarcoma of the lateral pharyngeal wall. AB - OBJECTIVE: The present study describes the clinical, radiological and histological features of pharyngeal synovial sarcoma, on the basis of one clinical case, and discusses management. CASE STUDY: A male patient, aged 27 years, presented with synovial sarcoma of the lateral pharyngeal wall, revealed by pharyngeal discomfort and bloody sputum. CT and MRI showed a partially necrotic tumoral process centered on the upper half of the piriform sinus. Pathologic analysis found a malignant biphasic tumor, suggestive of synovial sarcoma. Partial pharyngolaryngectomy was performed on a lateral approach, with associated radiotherapy. DISCUSSION: Synovial sarcoma raises diagnostic and therapeutic issues. Prognostic factors are not clearly established. CONCLUSION: Pharyngeal synovial sarcoma is a rare tumor. Treatment is essentially surgical, requiring wide margins; radiotherapy is usually associated. The value of chemotherapy has yet to be assessed. PMID- 22819224 TI - Ossiculoplasty positioned via posterior tympanotomy. AB - Tympanoplasty now frequently uses cartilage to repair bone lysis in the external auditory canal (EAC) and to reinforce the tympanic membrane. Once in place, however, the cartilage may complicate ossiculoplasty by obstructing visualization of the stapedial region. Posterior tympanotomy, when included in the tympanoplasty procedure, may provide an interesting means of positioning the ossiculoplasty. PMID- 22819225 TI - Dietary intake of PBDEs of residents at two major electronic waste recycling sites in China. AB - The dietary intake of polybrominated diphenyl ether (PBDE) of local residents from 2 major electronic waste (e-waste) processing sites (Guiyu, Guangdong Province and Taizhou, Zhejiang Province) in China was investigated. Seventy-four food items were collected from these sites, divided into 9 food groups (freshwater fish, marine fish, shellfish, pork, poultry, chicken offal, egg, vegetables and cereals), and examined for residual PBDE concentrations. Out of all food items examined, the freshwater bighead carp (Aristichthys nobilis) contained extremely high (11,400+/-254 ng/g wet wt.) concentrations of PBDE, the highest concentrations amongst published data concerning PBDE detected in freshwater fish. Food consumption data obtained through semi-quantitative food intake questionnaires showed that Guiyu residents had a PBDE dietary intake of 931+/-772 ng/kg bw/day, of which BDE-47 (584 ng/kg bw/day) exceeded the US EPA's reference dose (100 ng/kg/day). Taizhou (44.7+/-26.3 ng/kg bw/day) and Lin'an (1.94+/-0.86 ng/kg bw/day) residents exhibited lower readings. The main dietary source of PBDEs in Guiyu and Taizhou residents was seafood (88-98%) and pork (41%) in Lin'an. The present results indicated that health risks arising from PBDE dietary exposure are of significance in terms of public health and food safety to local residents of e-waste processing sites. PMID- 22819226 TI - The nasal and paranasal architecture of the Middle Miocene ape Pierolapithecus catalaunicus (primates: Hominidae): phylogenetic implications. AB - The internal (nasal and paranasal) cranial anatomy of the Middle Miocene (11.9 Ma [millions of years ago]) great ape Pierolapithecus catalaunicus (Hominidae: Dryopithecini) is described on the basis of computed-tomography scans of the holotype specimen (IPS21350), with particular emphasis on its phylogenetic implications. Pierolapithecus displays the following characters: an anteriorly restricted maxillary sinus that posteriorly spreads towards the ethmoidal area (thus resembling the pongine condition), although being situated well above the molar roots (as in kenyapithecins, other dryopithecins and pongines); lack of frontal sinus (a synapomorphy of derived pongines, independently acquired by both cercopithecoids and hylobatids); posteriorly-situated turbinals (as in Pongo); anteriorly-projecting nasolacrimal canal (as in Pongo); and probably stepped nasal floor with non-overlapping premaxillary-maxillary contact (as in dryopithecines and stem hominoids, although it cannot be conclusively shown due to bone damage). Overall, Pierolapithecus displays a mosaic of primitive hominid and derived pongine features that are inconsistent with this taxon being a hominine (as previously suggested). Two alternative phylogenetic interpretations are possible: Pierolapithecus may be a stem member of the Hominidae as previously suggested in its original description, or alternatively this taxon may be a stem member of the Ponginae s.l. (with the European dryopithecines being the sister taxon to the Asian pongines). PMID- 22819227 TI - New endemic platyrrhine femur from Haiti: description and locomotor analysis. PMID- 22819228 TI - Reduced white matter fractional anisotropy and clinical symptoms in schizophrenia: a voxel-based diffusion tensor imaging study. AB - Although not consistently replicated, diffusion tensor imaging (DTI) studies in schizophrenia have revealed lower fractional anisotropy (FA) in various white matter regions, a finding consistent with the disruption of white matter integrity. In this study, we used voxel-based DTI to investigate possible whole brain differences in the white matter FA values between 58 schizophrenia patients and 58 healthy controls. We also explored the association between FA values and clinical symptoms in schizophrenia. Compared with the controls, the schizophrenia patients showed significant FA reductions in bilateral superior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus, and genu of right internal capsule. Furthermore, in the patient group, the FA value of the anterior part of the corpus callosum was negatively correlated with the avolition score on the Scale for the Assessment of Negative Symptoms. These findings suggest widespread disruption of white matter integrity in schizophrenia, which could partly explain the severity of negative symptomatology. PMID- 22819231 TI - The hematological and clinical effects of X-ray contrast medium contaminating autologous blood for transfusion purposes. AB - Little information is available regarding the influence of non-ionic low-osmolar iodinated contrast medium (CM) in stored blood on the quality of blood components. We sought to evaluate the quality of such CM-contaminated blood in terms of the degree of hemolysis, production of microaggregates, level of iodine concentration, and RBC shape, and to identify the pros and cons of autologous blood donation immediately after X-ray examination using CM. In conclusion, contamination by such CM in blood collected around 2h after the completion of X ray examination appears unlikely to induce deleterious effects on blood components. PMID- 22819229 TI - Early regression of left ventricular mass associated with diastolic improvement after transcatheter aortic valve implantation. AB - BACKGROUND: The aim of this study was to investigate the effects of transcatheter aortic valve implantation (TAVI) on left ventricular (LV) hypertrophy and diastolic function in patients with severe aortic valve stenosis (AVS). There are few and conflicting data on LV mass remodeling and LV diastolic function after TAVI. METHODS: Echocardiography and clinical assessment were performed at baseline and at 6 months in high-risk patients affected by severe AVS who underwent TAVI. RESULTS: One hundred thirty-five patients successfully underwent TAVI. Peak transvalvular aortic pressure gradient and mean transvalvular aortic pressure gradient were reduced from 87 +/- 25 to 18 +/- 7 mm Hg and from 54 +/- 14 to 9 +/- 4 mm Hg, respectively (P < .001), accompanied by significant clinical improvement. The mean LV ejection fraction improved from 50 +/- 13% to 54 +/- 11% during follow-up (P = .009). At 6-month follow-up, interventricular septal wall thickness regressed from 14 +/- 2 to 12 +/- 1 mm and posterior wall thickness from 13 +/- 3 to 11 +/- 2 mm (P < .001). LV mass and LV mass index decreased from 332 +/- 106 to 228 +/- 58 g (P < .001) and from 191 +/- 58 to 132 +/- 30 g/m(2) (P < .001), respectively. Ninety-seven patients (72%) showed improvements in LV diastolic filling pattern. The mean e' value increased from 4.1 +/- 1.7 to 5.6 +/ 2.2 cm/sec, and the mean E/e' ratio decreased from 24 +/- 7 to 17 +/- 6 (P < .001) after TAVI. CONCLUSIONS: Significant LV mass reverse remodeling associated with improvement in LV systolic and diastolic function was found in patients with severe AVS 6 months after TAVI. These changes may have relevant clinical prognostic value. PMID- 22819232 TI - Height, socioeconomic status and marriage in Italy around 1900. AB - This study examines the role of height in the process of mate selection in two Italian populations at the turn of the twentieth century, Alghero, in the province of Sassari, and Treppo Carnico, in the province of Udine. Based on a linkage between military registers and marriage certificates, this study reveals a negative selection of short men on marriage and a differential effect of tallness by population in the process of mate choice. These findings emerge once SES is taken into account in the risk models of marriage. PMID- 22819233 TI - Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders. AB - Mitochondrial diseases arise as a result of dysfunction of the respiratory chain, leading to inadequate ATP production required to meet the energy needs of various organs. On the other hand, nitric oxide (NO) deficiency can occur in mitochondrial diseases and potentially play major roles in the pathogenesis of several complications including stroke-like episodes, myopathy, diabetes, and lactic acidosis. NO deficiency in mitochondrial disorders can result from multiple factors including decreased NO production due to endothelial dysfunction, NO sequestration by cytochrome c oxidase, NO shunting into reactive nitrogen species formation, and decreased availability of the NO precursors arginine and citrulline. Arginine and citrulline supplementation can result in increased NO production and hence potentially have therapeutic effects on NO deficiency-related manifestations of mitochondrial diseases. Citrulline is a more efficient NO donor than arginine as it results in a greater increase in de novo arginine synthesis, which plays a major role in driving NO production. This concept is supported by the observation that the three enzymes responsible for recycling citrulline to NO (argininosuccinate synthase and lyase, and nitric oxide synthase) function as a complex that can result in compartmentalizing NO synthesis and channeling citrulline efficiently to NO synthesis. Clinical research evaluating the effect of arginine and citrulline in mitochondrial diseases is limited to uncontrolled open label studies demonstrating that arginine administration to subjects with MELAS syndrome results in improvement in the clinical symptoms associated with stroke-like episodes and a decrease in the frequency and severity of these episodes. Therefore, controlled clinical studies of the effects of arginine or citrulline supplementation on different aspects of mitochondrial diseases are needed to explore the potential therapeutic effects of these NO donors. PMID- 22819234 TI - Is the "impact factor" a valid measure of the impact of research published in Clinical Neurophysiology and Muscle & Nerve? PMID- 22819235 TI - Reply to "Atypical SREDA in sleep". PMID- 22819236 TI - Cure by age and stage at diagnosis for colorectal cancer patients in North West England, 1997-2004: a population-based study. AB - BACKGROUND: Stage and age at diagnosis are important prognostic factors for patients with colorectal cancer. However, the proportion cured by stage and age is unknown in England. MATERIALS AND METHODS: This population-based study includes 29,563 adult patients who were diagnosed and registered with colorectal cancer during 1997-2004 and followed till 2007 in North West England. Multiple imputation was used to provide more reliable estimates of stage at diagnosis, when these data were missing. Cure mixture models were used to estimate the proportion 'cured' and the median survival of the uncured by age and stage. RESULTS: For both colon and rectal cancer the proportion of patients cured and median survival time of the uncured decreased with advancing stage and increasing age. Patients aged under 65 years had the highest proportion cured and longest median survival of the uncured. CONCLUSION: Cure of colorectal cancer patients is dependent on stage and age at diagnosis with younger patients or those with less advanced disease having a better prognosis. Further efforts are required, in order to reduce the proportion of patients presenting with stage III and IV disease and ultimately increase the chance of cure. PMID- 22819237 TI - Piecewise controller design for affine fuzzy systems via dilated linear matrix inequality characterizations. AB - This paper studies the problem of state feedback controller design for a class of nonlinear systems, which are described by continuous-time affine fuzzy models. A convex piecewise affine controller design method is proposed based on a new dilated linear matrix inequality (LMI) characterization, where the system matrix is separated from Lyapunov matrix such that the controller parametrization is independent of the Lyapunov matrix. In contrast to the existing work, the derived stabilizability condition leads to less conservative LMI characterizations and much wider scope of the applicability. Furthermore, the results are extended to H(infinity) state feedback synthesis. Finally, two numerical examples illustrate the superiority and effectiveness of the new results. PMID- 22819238 TI - Bilateral central retinal artery occlusions in an infant with hyperhomocysteinemia. AB - A previously healthy 7-week-old boy developed bilateral central retinal artery occlusions in the presence of hyperhomocysteinemia and elevated serum methylmalonic acid and was found to have a transcobalamin receptor mutation. Retinal arterial occlusion is uncommon in young patients and typically prompts a systemic workup. In cases of atypical retinal arterial occlusion, hyperhomocysteinemia should be investigated. PMID- 22819239 TI - Rapid detection and simultaneous molecular profile characterization of Acanthamoeba infections. AB - Diagnosis of Acanthamoeba by microscopic examination, culture, and polymerase chain reactions (PCRs) has several limitations (sensitivity, specificity, lack of detection of several strains, cost of testing for discrimination among strains). We developed a new high-resolution melting real-time PCR (HRM) to detect and characterize Acanthamoeba infections. HRM performances were evaluated with strains from the American Type Culture Collection (ATCC) and with 20 corneal scrapings. The DNA extracted from specimens were amplified, detected, and characterized in 1 run using 2 original primers diluted in a solution containing an intercalating dye. Detection and molecular characterization of Acanthamoeba infections could be achieved in less than 2.5 h with a dramatic reduction in cost of reactants (postamplification procedures and radioactive or fluorescent-labeled molecular probes were unnecessary). HRM detection limits were 0.1 cyst/MUL or less (including genotypes T5 and T11), and its sensitivity and specificity were higher than other molecular tests. For the tested strains from the ATCC, the HRM drafted 4 different profiles: Type I (genotypes T2 and T4), Type II (T5 and T7), Type III (T8), and Type IV (T1, T3, T6, T9, T11, T12, and T13). PMID- 22819240 TI - An evaluation of the Xpert MTB/RIF assay and detection of false-positive rifampicin resistance in Mycobacterium tuberculosis. AB - Recent reports suggest that false-positive rifampicin resistance may be assigned by the Xpert MTB/RIF assay. We analysed 169 specimens using the MTB/RIF assay. Using culture as the gold standard, we found that the assay had 100% sensitivity and specificity for detecting M. tuberculosis. However, we found that the assay incorrectly assigned rifampicin resistance in 4/13 (31%) of cases. PMID- 22819241 TI - Macrolide and tetracycline resistance among Moraxella catarrhalis isolates from 2009 to 2011. AB - The activity of macrolides and other antimicrobials was evaluated by Clinical and Laboratory Standards Institute reference broth microdilution methods for Moraxella catarrhalis isolates collected during 2009-2011. In Europe, the United States, and Latin America, M. catarrhalis resistance to macrolides and tetracycline was <1%. However, in the Asia-Pacific region, clarithromycin and tetracycline resistance was 7.6% and 3.2%, respectively. The higher resistance rate in the Asia-Pacific region to clarithromycin and tetracycline was primarily due to isolates from multiple locations in China. PMID- 22819242 TI - Activity of JNJ-Q2 against Staphylococcus aureus isolated from patients with acute bacterial skin and skin-structure infection obtained during a Phase 2 clinical trial. AB - JNJ-Q2, a fluorinated 4-quinolone, was very active against both methicillin susceptible Staphylococcus aureus (n = 42; MIC(50/90), 0.008/0.12 MUg/mL) and methicillin-resistant S. aureus (n = 69; MIC(50/90), 0.12/0.12 MUg/mL) obtained from patients with acute bacterial skin and skin-structure infection (ABSSSI). Overall moxifloxacin and levofloxacin resistance rates were 31.5% and 46.9%, respectively. These favorable results support the continued clinical development of JNJ-Q2 to treat ABSSSI. PMID- 22819243 TI - TWEAK promotes the production of Interleukin-17 in rheumatoid arthritis. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is an inflammatory cytokine that modulates several biological responses by inducing chemokines and proinflammatory cytokines. We hypothesized that TWEAK could promote secretion of IL-17, an amplifier of inflammatory arthritis. To test this, we investigated the capacity of TWEAK to induce IL-17 production in T cells via the fibroblast growth factor-inducible gene 14 (Fn14, also known as TWEAK receptor) signal pathway in rheumatoid arthritis (RA). Fn14 and IL-17 were highly expressed in arthritic tissues of collagen-induced arthritis (CIA) mice. TWEAK induced production of IL-17 alone and synergistically with lipopolysaccharide. In naive murine T cells, TWEAK promoted Th17 differentiation. The expression of Fn14 was predominant in Th17 cells. TWEAK and IL-17 concentrations were significantly higher in synovial fluid and serum in RA patients than OA patients. In addition, we identified CD4(+)IL-17(+)Fn14(+) cells in synovium from RA patients. TWEAK promoted IL-17 production synergistically with IL-23 or IL-21 and blockade of Fn14 with Fn14-Fc suppressed Th17 differentiation. Conversely, this treatment enhanced Treg differentiation. These results suggest that TWEAK induces IL-17 production and may be a therapeutic target in the treatment of RA. PMID- 22819244 TI - G-CSF-treated donor CD4+ T cells attenuate acute GVHD through a reduction in Th17 cell differentiation. AB - The immunoregulatory effects of granulocyte colony-stimulating factor (G-CSF) on allogeneic peripheral blood cell transplantation (PBCT) have been demonstrated to reduce acute graft-versus-host disease (GVHD). However, the underlying mechanism is still not clear. In this study, we focused on the direct effects of G-CSF on donor CD4(+) T cell responses after transplantation. We observed that lethally irradiated B6D2F1 recipient mice that are transplanted with CD4(+) T cells from G CSF-treated B6 donors showed mild attenuations in severity and mortality compared with recipients transplanted with PBS-treated CD4(+) T cells. Notably, skin GVHD was significantly reduced, but no such reduction was observed in other organs. Although there was no difference with respect to alloreactive expansion or Foxp3(+) Treg induction, the use of G-CSF-treated CD4(+) T cells significantly reduced the numbers of IL-17-producing and RORgammat-expressing cells in the secondary lymphoid organs of allogeneic recipients after transplantation compared with the use of the control cells. Finally, we found that the suppressor of cytokine signaling-3 (SOCS3) expression in G-CSF-treated donor CD4(+) T cells was much higher than that in control CD4(+) T cells. Our results demonstrate that the inhibition of Th17 cell differentiation by SOCS3 induction is associated with the immunoregulatory role of G-CSF in CD4(+) T cell-mediated acute GVHD. PMID- 22819245 TI - Association of matrix metalloproteinase (MMP)-1, 3, 9, interleukin (IL)-2, 8 and cyclooxygenase (COX)-2 gene polymorphisms with chronic periodontitis in a Chinese population. AB - Chronic periodontitis (CPs) could result in damage of periodontal tissues, loss of teeth and impose troublesome hindrance to restore teeth satisfyingly as well. Functional gene polymorphisms of matrix metalloproteinases, cytokines and cyclooxygenase-2 have been found to play important roles in periodontitis. This study was to investigate the association between MMP-1-1067, MMP-3-1171, MMP-9 1562, IL-2-330, IL-8-251, COX-2-765 polymorphisms, and the susceptibility to CP in a Chinese population. A total of 122 patients with CP were evaluated for MMP 1, MMP-3, MMP-9, IL-2, IL-8 and COX-2 genetic polymorphisms and were compared with 532 healthy control subjects using PCR-RFLP analysis. Clinical periodontal parameters were recorded. Serum levels of MMP-1, MMP-3, MMP-9, IL-2, IL-8 and COX 2 were measured by ELISA. The data were analyzed by chi-square, logistic regression and Mann-Whitney-U-tests and t test. There were significant differences between CP patients and healthy subjects in the genotype distribution and allele frequency of MMP-3-1171, MMP-9-1562, IL-2-330, IL-8-251 and COX-2-765 genetic polymorphisms. Significant difference between patients and controls were also observed for MMP-1-1067 genotype frequency, but not for allele frequency. Differences between rare allele carriage rates of CP and healthy groups regarding all the genetic polymorphisms in our study were significant (p<0.05). Serum levels of all the cytokines were higher in the CP patients compared to healthy subjects. These data show that MMP-1-1067, MMP-3-1171, MMP-9-1562 and IL-8-251 polymorphisms are associated with susceptibility to CP. MMP-1-1067 2G, MMP-3-1171 6A, MMP-9-1562 T and IL-8-251 A allele are associated with decreased susceptibility to CP in Chinese population. PMID- 22819246 TI - Bronchial hyperresponsiveness in seasonal allergic rhinitis patients is associated with increased IL-18 during natural pollen exposure. AB - BACKGROUND: The mechanism of bronchial hyperresponsiveness (BHR) is not certain in seasonal allergic rhinitis (SAR) patients. OBJECTIVE: We aimed to investigate the effects of natural pollen exposure on IL-18 and its relationship with BHR. METHODS: Thirty-two SAR patients with grass pollen sensitivity, 14 nonallergic rhinitis (NAR) patients and 17 normal-controls were included. Sixteen SAR patients had BHR during pollen season and off-season. Serum IL-18 levels were measured in SAR patients during pollen season between May-August and off-season between November-February. IL-18 levels were measured in NAR patients and normal controls once. RESULTS: During pollen season, SAR patients with BHR had significantly increased levels of IL-18 than those without BHR (279.2 +/- 161.1 versus 145.3 +/- 101.0 pg/ml, p=0.012). Serum IL-18 levels were not different between SAR patients with and without BHR during off-season (233.8 +/- 139.7 versus 183.2 +/- 162.9 pg/ml, p=0.16). Serum IL-18 levels in SAR patients during pollen season (212.3 +/- 148.8 pg/ml) and off-season (208.5 +/- 151.5 pg/ml) were not different than those NAR patients (224.8 +/- 180.1 pg/ml, p=0.98 and p=1.0, respectively) and normal controls (174.8 +/- 76.0 pg/ml, p=0.60 and p=0.76, respectively). CONCLUSION: The results suggested us that BHR in SAR patients is associated with increased IL-18 during natural pollen exposure. PMID- 22819248 TI - Ovarian endometrioma but not deep infiltrating endometriosis is associated with increased serum levels of interleukin-8 and interleukin-6. AB - Cytokines, and specifically interleukin 6 (IL-6) and interleukin 8 (IL-8), have been associated with the pathogenesis of endometriosis. We studied serum concentrations of IL-6 and IL-8 in patients with deep infiltrating endometriosis (DIE) or ovarian endometriomas (OE), but no other forms of associated endometriosis disease type. We carried out a case-control study including 19 patients with OE alone (OE group), 14 patients with DIE alone (DIE group) and 24 healthy patients without endometriosis (C group). Serum concentrations of IL-6 and IL-8 were measured in the three groups of patients. Serum levels of both IL-6 and IL-8 were significantly higher in the OE group. A high positive correlation was found between serum IL-6 and IL-8 levels in the OE group but not in the DIE and C groups. Serum IL-8 alone achieved the highest predictive value of the presence of OE (adjusted OR: 1.44; sensitivity: 78.2%; specificity: 76.2%). The combination of IL-6 and IL-8 levels did not significantly improve the discrimination between subjects with OE and those with DIE over that of IL-8. OE but not DIE are associated with increased serum levels of IL-6 and IL-8, and thus these may become useful tools for discriminating OE alone from DIE. PMID- 22819247 TI - The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a neuropsychiatric condition that affects about one-sixth of the US population. Chronic epidural stimulation (EpCS) of the left dorsolateral prefrontal cortex (DLPFC) was recently evaluated as a treatment option for refractory MDD and was found to be effective during the open label phase. However, two potential sources of variability in the study were differences in electrode position and the range of stimulation modes that were used in each patient. The objective of this study was to examine these factors in an effort to characterize successful EpCS therapy. METHODS: Data were analyzed from eleven patients who received EpCS via a chronically implanted system. Estimates were generated of response probability as a function of duration of stimulation. The relative effectiveness of different stimulation modes was also evaluated. Lastly, a computational analysis of the pre- and post-operative imaging was performed to assess the effects of electrode location. The primary outcome measure was the change in Hamilton Depression Rating Scale (HDRS-28). RESULTS: Significant improvement was observed in mixed mode stimulation (alternating cathodic and anodic) and continuous anodic stimulation (full power). The changes observed in HDRS-28 over time suggest that 20 weeks of stimulation are necessary to approach a 50% response probability. Lastly, stimulation in the lateral and anterior regions of DLPFC was correlated with greatest degree of improvement. CONCLUSIONS: A persistent problem in neuromodulation studies has been the selection of stimulation parameters and electrode location to provide optimal therapeutic response. The approach used in this paper suggests that insights can be gained by performing a detailed analysis of response while controlling for important details such as electrode location and stimulation settings. PMID- 22819249 TI - Effective stakeholder participation in setting research priorities using a Global Evidence Mapping approach. AB - OBJECTIVE: We present a multistep process for identifying priority research areas in rehabilitation and long-term care of traumatic brain-injured (TBI) patients. In particular, we aimed to (1) identify which stakeholders should be involved; (2) identify what methods are appropriate; (3) examine different criteria for the generation of research priority areas; and (4) test the feasibility of linkage and exchange among researchers, decision makers, and other potential users of the research. STUDY DESIGN AND SETTING: Potential research questions were identified and developed using an initial scoping meeting and preliminary literature search, followed by a facilitated mapping workshop and an online survey. Identified research questions were then prioritized against specific criteria (clinical importance, novelty, and controversy). Existing evidence was then mapped to the high-priority questions using usual processes for search, screening, and selection. A broad range of stakeholders were then brought together at a forum to identify priority research themes for future research investment. Using clinical and research leaders, smaller targeted planning workshops prioritized specific research projects for each of the identified themes. RESULTS: Twenty-six specific questions about TBI rehabilitation were generated, 14 of which were high priority. No one method identified all high-priority questions. Methods that relied solely on the views of clinicians and researchers identified fewer high priority questions compared with methods that used broader stakeholder engagement. Evidence maps of these high-priority questions yielded a number of evidence gaps. Priority questions and evidence maps were then used to inform a research forum, which identified 12 priority themes for future research. CONCLUSION: Our research demonstrates the value of a multistep and multimethod process involving many different types of stakeholders for prioritizing research to improve the rehabilitation outcomes of people who have suffered TBI. Enhancing stakeholder representation can be augmented using a combination of methods and a process of linkage and exchange. This process can inform decisions about prioritization of research areas. PMID- 22819250 TI - Outcomes for four-part proximal humerus fractures treated with a locking compression plate and an autologous iliac bone impaction graft. AB - OBJECTIVES: The study aims to evaluate outcomes of autologous iliac bone impaction grafts (AIBIGs) with locking-compression plates (LCPs) in four-part proximal humeral fracture. METHODS: Between October 2004 and October 2008, 21 AIBIG with LCP osteosyntheses were done for four-part proximal humeral fractures. Patients included seven males and 14 females. Their mean age at the time of the operation was 66.3+/-16.9 years (range: 24-87 years). Five patients had high energy fractures other than fall from standing height. There were two fracture dislocation cases, and three valgus-impacted fractures. The length of the calcar segment attached to the articular segment was 7.04+/-6.10mm; 13 of the 21 cases had lengths less than 8mm. Medial-hinge displacement was 16.77+/-15.84mm; 19 of the 21 cases had displacements more than 2mm. RESULTS: There was no avascular necrosis of the humeral head and union was achieved in all cases. Varus collapse and hardware-related complications were not observed. Postoperative neck-shaft angles were found to be 129+/-9 degrees (range: 109-146 degrees ). Neer scores were 92.0+/-6.3 (range: 81-100). CONCLUSION: The results of using AIBIG with LCP for four-part proximal humeral fractures are excellent. There are significant bone defects in osteoporotic or comminuted fractures and LCP alone does not always provide reliable fixation. Therefore, meticulous technique and use of AIBIG in this complicated type of fracture can ensure a favourable outcome. PMID- 22819251 TI - EGF receptor targeted tumor imaging with biotin-PEG-EGF linked to (99m)Tc-HYNIC labeled avidin and streptavidin. AB - INTRODUCTION: As direct radiolabeled peptides suffer limitations for in vivo imaging, we investigated the usefulness of radioloabeled avidin and streptavidin as cores to link peptide ligands for targeted tumor imaging. METHODS: Human epidermal growth factor (EGF) was site specifically conjugated with a single PEG biotin molecule and linked to (99m)Tc-HYNIC labeled avidin-FITC (Av) or streptavidin-Cy5.5 (Sav). Receptor targeting was verified in vitro, and in vivo pharmacokinetic and biodistribution profiles were studied in normal mice. Scintigraphic imaging was performed in MDA-MB-468 breast tumor xenografted nude mice. RESULTS: Whereas both (99m)Tc-Av-EGF and (99m)Tc-Sav-EGF retained receptor specific binding in vitro, the two probes substantially diverged in pharmacokinetic and biodistribution behavior in vivo. (99m)Tc-Av-EGF was rapidly eliminated from the circulation with a T1/2 of 4.3 min, and showed intense hepatic accumulation but poor tumor uptake (0.6%ID/gm at 4 h). (99m)Tc-Sav-EGF displayed favorable in vivo profiles of longer circulation (T1/2beta, 51.5 min) and lower nonspecific uptake that resulted in higher tumor uptake (3.8 %ID/gm) and clear tumor visualization at 15 h. CONCLUSION: (99m)Tc-HYNIC labeled streptavidin linked with growth factor peptides may be useful as a protein-ligand complex for targeted imaging of tumor receptors. PMID- 22819252 TI - Comparison of IVF outcomes using conventional insemination and ICSI in ovarian cycles in which only one or two oocytes are obtained. AB - OBJECTIVE: Compare outcomes of patients in whom only one or two oocytes were retrieved who underwent conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: Patients who received IVF and only one to two oocytes were obtained on the day of oocyte retrieval. Fertilization rate, good-quality embryo rate, pregnancy Demographic data and clinical characteristics were recorded and analyzed. RESULTS: Of 194 patients, 118 received conventional IVF and 76 ICSI. There were no significant differences in age (mean age, 36 years in both groups), infertility parameters, and number of oocytes retrieved between the groups. ICSI patients had a higher fertilization rate (82.7% vs. 67.0%) and 2PN fertilization rate (78.8% vs. 59.7%); however, no difference in good-quality embryo rate or PR was noted. For women less than 35 years of age, there was no significant difference in these outcome parameters between the groups. For patients greater or equal to 35 years of age ICSI was associated with a higher fertilization rate (83.1% vs. 62.4%) and 2PN fertilization rate (80.3% vs. 55.0%); however, there was no difference in PR. CONCLUSIONS: ICSI did not improve the good-quality embryo rate or clinical PR rate compared to conventional IVF using semen with normal parameters in women with poor ovarian reserve. PMID- 22819253 TI - [Facial coloboma: report of an exceptional prenatal case and interest of three dimensional ultrasonography]. AB - We report a rare case of Tessier no. 4 craniofacial cleft diagnosed by ultrasound imaging at 10 weeks' gestation. Tessier no. 4 craniofacial cleft is a very rare and complex congenital abnormality, characterized by an oblique orbitomaxillary facial cleft. Prenatal diagnosis of orofacial clefting is usually done at midtrimester of pregnancy, based on careful sonographic examination of the fetal face. However conventional 2D ultrasound is limited in screening isolated cleft palate and defects of the secondary palate. Thus, 3D ultrasound shows a greater sensitivity in a referred population and antenatal evaluation of facial clefs. PMID- 22819254 TI - The volume of goal shooting during training can predict shoulder soreness in elite female water polo players. AB - OBJECTIVES: Examine the association between measures shoulder soreness and the goal shooting volume in high performance women's water polo. DESIGN: Seven national level female water polo players were monitored across two training camps (squad selection and team game-based). METHODS: Performance analysis coded all shots for each athlete during the training camps and the shoulder soreness information was gathered through an athlete self-rating survey. Residual maximal likelihood analysis was used to predict shoulder soreness. RESULTS: It was shown that 74% (p=0.013) of shoulder soreness was explained by the volume of goal shooting during training (R(2) 0.743) with greater soreness associated with less rest time between shots (p=0.032). Greater levels of shoulder soreness were reported in the squad selection training camp compared to team game-based camp (p=0.002) with 29% of this shoulder soreness prediction based on individual athlete differences. CONCLUSIONS: Shoulder soreness increased with a greater number of shots in conjunction with less rest. Monitoring athletes on an individual basis seemed the most appropriate method of identifying increased shoulder soreness. PMID- 22819255 TI - Divergent muscle fatigue during unilateral isometric contractions of dominant and non-dominant quadriceps. AB - OBJECTIVES: We examined mechanical and electromyographic responses of unilateral dominant and non-dominant m. quadriceps femoris during fatiguing submaximal isometric contractions and early recovery. DESIGN: Within subjects randomized. METHODS: Healthy males (n=18, age: 20+/-2yr, height: 181+/-7cm, and body mass: 79.4+/-10.5kg) attended two sessions. Leg dominance was based on the preferred kicking leg. Maximal voluntary isometric force, endurance time and force fluctuations during a 20%MVIF until exhaustion were measured simultaneously with surface electromyography (EMG) of m.vastus lateralis and m.vastus medialis at a knee angle of 90 degrees as well as the MVIF 20s after exhaustion (early recovery). RESULTS: The maximal voluntary isometric force of dominant m. quadriceps femoris was 4.6% higher (D: 749+/-178N, ND: 716+/-184N, and P=0.01). The m. quadriceps femoris of both legs had similar endurance times during the 20%MVIF (D: 367+/-157s, ND: 381+/-153s, and P=0.40). Force fluctuations during the 20%MVIF increased over time (two-way ANOVA, P<0.05) with no differences between legs at comparable time points. Changes in median frequency and root mean square of m.vastus lateralis and m.vastus medialis during the 20%MVIF were similar for both legs. However, after the 20%MVIF, early recovery, quantified by the fatigue index, showed larger force loss for dominant m. quadriceps femoris (D: 39.9+/-15.7%, ND: 34.8+/-16.0%, and P<0.05). CONCLUSIONS: Muscle fatigue that develops during submaximal sustained isometric contractions may not be accurately quantified by force loss soon after exhaustion. The present study has implications for unilateral studies to examine mechanisms of muscle fatigue. PMID- 22819256 TI - [Measures to ensure data confidentiality in Clinical Units in order to achieve quality accreditation in Andalusia]. AB - OBJECTIVE: To analyse the measures introduced by Health Care Units to ensure the confidentiality of health information on patients that been validated as adequate by an assessment team of the Agency for Healthcare Quality in Andalusia (Spain). MATERIAL AND METHODS: A retrospective study was conducted on Health Care Units accredited by the Agency for Healthcare Quality in Andalusia. A total of 272 Health Care Units were evaluated between January 2003 and December 2010. We analysed the measures that were assessed as adequate to ensure the confidentiality of data by this team, establishing categories after analysing records of the application that supports the certification process (ME_joraC). RESULTS: Using on- site surveys, areas of improvement were found in the safeguarding of medical records (64.1%) and the internal control of implementing the information security measure (19.6%). The measures introduced into the Health Care Services were mainly technological actions (28.5%), which were related to the increasing presence of electronic history. It also frequently provided solutions related to implementation (17.9%) and dissemination (22.3%) protocols for use of medical records. CONCLUSIONS: Accreditation processes help to identify areas for improvement and the introduction of procedures for ensure confidentiality of data in the healthcare system. Technological solutions that respond to the needs created by the computerisation of medical records, and the effective implementation of protocols and monitoring the adherence to these protocols using self-assessment, strengthen the efforts to ensure confidentiality. Furthermore, it promotes the involvement and responsibility of the professionals on this topic. PMID- 22819257 TI - Damage control to control a severe obstetrical haemorrhage. PMID- 22819258 TI - Deaths on board ships assisted by the Centro Internazionale Radio Medico in the last 25 years. AB - Data on occupational diseases of seafarers and of causes of death during their career are sparse. The causes of deaths on board ships assisted by Centro Internazionale Radio Medico (CIRM), the Italian Telemedical Maritime Assistance Service (TMAS) were reviewed by examining 29,146 files of patients treated from 1986 to 2010. In the 25 years, 383 deaths occurred (1.31%). Diseases of the circulation were the most frequent, followed by external causes such as accidents and violence, infectious and parasitic diseases, alcohol and drug addiction, respiratory system diseases. Cardiovascular and external causes were the principal causes of deaths among seafarers. This investigation is the first study on the causes of death on board ships obtained from data of a maritime telemedical centre, that has assisted seafarers when they were alive or immediately after their death. The fact that diseases of the circulatory system are the first cause of death of sailing seafarers deserves specific initiatives. They should include campaigns for adequate lifestyles and the availability on ships of medical devices useful for diagnostic purposes, resuscitation as well as for verification of death. PMID- 22819260 TI - Effectiveness of heliotherapy for psoriasis clearance in low and mid-latitudinal regions: a theoretical approach. AB - The action spectrum for psoriasis clearance is reconstructed taking into account the results obtained in the early 1980s. The antipsoriatic action spectrum is used for weighting the medical cabinet UV spectra, and the solar spectra measured in San Diego (USA) and Belsk (Poland). The mean cumulative antipsoriatic effective dose of 450 mJ cm(-2), due to TL-01 (UVB narrowband) tubes, is taken by a patient with skin phototype II during routine 20 phototherapy sessions carried out in a phototherapy cabinet in the Medical University of Lodz. Thus, the daily mean dose of value 22.5 mJ cm(-2) is proposed as the threshold for daily solar dose for numbers of out-door exposures to clear psoriasis. We assume that the heliotherapy will last a whole month with every day 2h exposition to the direct sunlight around local noon. The heliotherapy will be successful if weather conditions permit at least 20 days with the daily exposure over the threshold. The minimum cumulative ambient erythemal dose, necessary for psoriasis clearance, is estimated as 144 standard erythema dose (SED) for the whole heliotherapy period. We find that heliotherapy could be effectively used in March through October (San Diego) and in June through August (Belsk). Thus, the heliotherapy against psoriasis is possible not only at southern resorts but even at the mid latitude sites. PMID- 22819259 TI - Blockade of NFkappaB activity by Sunitinib increases cell death in Bortezomib treated endometrial carcinoma cells. AB - Endometrial carcinoma is one of the most common malignancies in the female genital tract, usually treated by surgery and radiotherapy. Chemotherapy is used when endometrial carcinoma is associated with widespread metastasis or when the tumor recurs after radiation therapy. In the present study, we demonstrate that the tyrosine kinase receptor inhibitor Sunitinib reduces cell viability, proliferation, clonogenicity and induces apoptotic cell death in endometrial carcinoma cell lines, which is not due to its action through the most known targets like VEGFR, nor through EGFR as demonstrated in this work. Interestingly, Sunitinib reduces NFkappaB transcriptional activity either at basal level or activation by EGF or TNF-alpha. We observed that Sunitinib was able to inhibit the Bortezomib-induced NFkappaB transcriptional activity which correlates with a decrease of the phosphorylated levels of IKKalpha and beta, p65 and IkappaBalpha. We evaluated the nature of the interaction between Sunitinib and Bortezomib by the dose effect method and identified a synergistic effect (combination index < 1). Analogously, silencing of p65 expression by lentiviral-mediated short-hairpin RNA delivery in Bortezomib treated cells leads to a strongly increased sensitivity to Bortezomib apoptotic cell death. Altogether our results suggest that the combination of Sunitinib and Bortezomib could be considered a promising treatment for endometrial carcinoma after failure of surgery and radiation. PMID- 22819261 TI - Salinity induced synthesis of UV-screening compound scytonemin in the cyanobacterium Lyngbya aestuarii. AB - Lyngbya aestuarii is the dominant cyanobacterium in Chilika lagoon occurring in all the seasons irrespective of variation in the salinity regime ranging from 3 to 28 ppt. The organism possess the UV screening scytonemin pigment, which was maximum when grown at 56 ppt salinity. Three different forms of scytonemin were detected in L. aestuarii with retention time (RT) 1.76, 2.42 and 2.94 min, however, occurrence of these forms was influenced by the salinity. Scytonemin with RT 2.42 was sensitive to higher salinity and its maximum concentration was obtained at 28 ppt salinity correlated with the highest salinity level of Chilika. Formation of multilayer colored sheath around the trichome was prominently observed at the salinity of the culture from 28 to 56 ppt. But at salinity below 7 ppt and also at more than 56 ppt salinity degradation of sheath with corresponding decrease in scytonemin was observed. PMID- 22819262 TI - The search for genetic mouse models of prodromal Parkinson's disease. AB - Parkinson's disease is characterized and diagnosed by bradykinetic motor symptoms caused by the loss of dopamine neurons in the substantia nigra. The pathological and non-motor behavioral changes that occur prior to degeneration are less well characterized, although changes in gait, olfaction and cognition have been recognized in familial Parkinson's disease subjects. Gene mutations associated familial Parkinson's disease give rise to mitochondrial changes, altered energy homeostasis and intracellular trafficking deficits, and these can be modeled in transgenic mice. Here we discuss the recent finding of prodromal behavioral disturbances in a PINK1 deficient mouse that manifest prior to dopaminergic cell death and correlate to 5-HT fiber losses and mitochondrial morphological changes. We discuss the representation of the PINK1 deficient mouse and other genetic models to accurately recapitulate early Parkinson's disease. Prodromal symptoms and underlying pathology modeled in mice and cell lines from human subjects may have wide implications for earlier diagnosis. Current and emerging therapies need to be tailored to target both early cognitive and late stage motor symptoms. PMID- 22819263 TI - Heparin and platelet activation. PMID- 22819264 TI - Carbon monoxide (CO)-releasing molecule-derived CO regulates tissue factor and plasminogen activator inhibitor type 1 in human endothelial cells. AB - INTRODUCTION: Heme oxygenase-1 (HO-1) is the rate limiting enzyme that catalyzes the conversion of heme into biliverdin, free iron, and carbon monoxide (CO). The first human case of HO-1 deficiency showed abnormalities in blood coagulation and the fibrinolytic system. Thus, HO-1 or HO-1 products, such as CO, might regulate coagulation and the fibrinolytic system. This study examined whether tricarbonyldichlororuthenium (II) dimer (CORM-2), which liberates CO, modulates the expression of tissue factor (TF) and plasminogen activator inhibitor type 1 (PAI-1) in human umbilical vein endothelial cells (HUVECs), and TF expression in peripheral blood mononuclear cells (PBMCs). Additionally, we examined the mechanism by which CO exerts its effects. MATERIALS AND METHODS: HUVECs were pretreated with 50 MUM CORM-2 for 3 hours, and stimulated with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) for an additional 0-5 hours. PBMCs were pretreated with 50-100 MUM CORM-2 for 1 hour followed by stimulating with lipopolysaccharid (LPS, 10 ng/ml) for additional 0-9 hours. The mRNA and protein levels were determined by RT-PCR and western blotting, respectively. RESULTS: Pretreatment with CORM-2 significantly inhibited TNF-alpha-induced TF and PAI-1 up-regulation in HUVECs, and LPS-induced TF expression in PBMCs. CORM-2 inhibited TNF-alpha-induced activation of p38 MAPK, ERK1/2, JNK, and NF-kappaB signaling pathways in HUVECs. CONCLUSIONS: CORM-2 suppresses TNF-alpha-induced TF and PAI-1 up-regulation, and MAPKs and NF-kappaB signaling pathways activation by TNF-alpha in HUVECs. CORM-2 suppresses LPS-induced TF up-regulation in PBMCs. Therefore, we envision that the antithrombotic activity of CORM-2 might be used as a pharmaceutical agent for the treatment of various inflammatory conditions. PMID- 22819265 TI - The impact of CYP3A5*1/*3, PIA1/A2 and T744C polymorphisms on clopidogrel and acetylsalicylic acid response variability in Mexican population. AB - INTRODUCTION: Clopidogrel is recommended in addition to aspirin to prevent atherothrombotic events in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, an interindividual variability in platelet inhibition response to clopidogrel has been demonstrated, and is associated with recurrent cardiovascular events. Multiple mechanisms have been associated with no response including genetics factors. MATERIALS AND METHODS: The present study enrolled 60 patients with ACS undergoing emergent PCI. Platelet aggregation to adenosine diphosphate and arachidonic acid was assessed by turbidimetric method at 24 hours after dual administration of 300 mg of clopidogrel and 300 mg of acetylsalicylic acid loading dose. Clopidogrel or acetylsalicylic acid resistance was defined by persistence of Platelet Reactivity (PR=ADP-Ag >70% or PR=Arachidonic Acid-Ag>20%) respectively. The CYP3A51*/5*, PIA1/A2, and T744C polymorphisms were determined in all participants by PCR-RFLP. RESULTS: The allelic frequencies were: CYP3A5*3 (71.65%), PIA2 (10.8%), and 744 C (15.0%). We founded high percent of clopidogrel resistance (60.0%), compared with 8.3% of acetylsalicylic acid in those patients. The genotype frequencies of those polymorphisms were similar between responders and non responders defined by PR. There was a high percent of coronary adverse events. CONCLUSIONS: We identified a high percent of clopidogrel resistance in Mexican patients with ACS undergoing PCI. However, a normal platelet response to acetylsalicylic acid was observed in most of them. There was no association between CYP3A5*1/*3, PIA1/A2, and T744C polymorphisms and clopidogrel resistance. More studies are needed to determine the possible interaction between genetics factors, platelet response to clopidogrel and cardiovascular adverse events. PMID- 22819266 TI - A new definition of wrist sprain necessary after findings in a prospective MRI study. AB - INTRODUCTION: Wrist injuries with negative X-rays are diagnosed as acute wrist sprains. The prognosis is usually good, but some patients suffer from long lasting pain and reduced wrist function, probably due to missed diagnosis followed by inappropriate treatment. The aim of this study was to investigate acute wrist sprains with MRI to detect the pathoanatomy of the injury. PATIENTS AND METHODS: This prospective magnetic resonance imaging (MRI) study included patients between 18 and 49 years, who attended the Accident and Emergency Department (A&E) Bergen, Norway, after sustaining an acute wrist trauma within the previous week. Initial X-rays of the wrist were normal. MRI was done within a median of 1 day (range 0-31 days) after the trauma, 80% within 4 days. The study period lasted from 5 November 2009 to 4 November 2010. RESULTS: A total of 155 acute MRIs were done, out of which 30 were completely normal. Patients with positive MRI had a median of two (range 0-8) pathological findings. We found 54 fractures and 56 bone bruises, mostly located to the radius followed by the scaphoid, the triquetrum, the capitate and the lunate. There were 73 soft-tissue injuries, which included 15 injuries to the triangular fibrocartilage complex (TFCC) and five scapho-lunate (SL) ligament lesions. CONCLUSIONS: Wrist sprain is an inaccurate diagnosis. In four out of five patients with normal X-rays, MRI identified pathological findings and a large variety of injuries in different structures. We suggest that wrist sprain should be defined as "occult partial or complete soft tissue (ligament, tendon, muscle) or bony injury in relation to a trauma with negative X-ray". The MRI findings led to a more differentiated treatment in more than a third of the patients. We recommend that MRI should be considered as a part of an early investigation, especially when the wrist pain does not settle within the first couple of weeks. PMID- 22819267 TI - Immunology of chronic BVDV infections. AB - Bovine viral diarrhea virus can maintain prolonged infections within immunoprivileged sites after an otherwise transient infection of a cow, calf, or bull. Various sites provide unique niches for viral replication which are not susceptible to the complete surveillance commonly provided by the bovine immune system. Evidence indicates that pestiviral infections may be significantly prolonged within ovarian tissue, testicular tissue, central nervous system tissue, and circulating white blood cells. Within avascular portions of the ovarian follicle, granulosa cells and oocytes may maintain BVDV infections which cannot be attacked by cell-mediated immunity. When infections occur within seminiferous tubules in testicular tissue, similar protection from the immune system is provided for BVDV by the blood-testes barrier. Likewise, the blood brain barrier has been hypothesized to provide protection for BVDV in a case involving neuropathology associated with immunohistochemical detection of BVDV. Furthermore, infections of circulating white blood cells may perturb their stimulation of an adaptive immune response and facilitate chronic infection of these cells. Thus, BVDV has demonstrated an ability to maintain prolonged viral infections in immunoprivileged sites within its natural host. The role of chronic infections in maintaining and disseminating BVDV within the cattle population and heterologous host species remains to be fully understood. PMID- 22819268 TI - Burned-out tumour: a case report. PMID- 22819269 TI - Innovating information-delivery for potential clinical trials participants. What do patients want from multi-media resources? AB - OBJECTIVE: To discover whether the provision of clinical trials information via a multi-media platform could better meet the needs, preferences and practices of potential cancer trial participants. METHODS: A mixed qualitative and quantitative questionnaire was delivered to 72 participants from cancer support groups to elicit views on the provision and design features of multimedia resources in delivering clinical trials information. RESULTS: Perceived lack of information is an expressed barrier to clinical trials participation. Multimedia resources were viewed positively as a way to address this barrier by most potential clinical trials participants; in particular by helping to align information to individual needs, promote active engagement with information, and by allowing more control of the learning experience. Whilst text remained the most valued attribute of any resource, other highly rated attributes included the resource being simple to use, easily accessible, having a clear focus, incorporating examples and visual aids, and being interactive. Provision of support for the learning resource was also rated highly. CONCLUSION: As in other areas, such as education, multimedia resources may enhance the delivery and acceptance of information regarding clinical trials. PRACTICE IMPLICATIONS: Better alignment of information may have a positive impact on recruitment and retention into clinical trials. PMID- 22819270 TI - "I am worried, Doctor!" Emotions in the doctor-patient relationship. AB - OBJECTIVE: To review research on emotional communication in medical interviews regarding predictors, physiological correlates and effects of clinicians' responses to patients' cues and concerns and individual differences among patients. METHODS: A selective review of research literature on emotional communication in medical interviews was conducted. RESULTS: Four questions regarding emotional communication were explored: What factors predict how clinicians respond to emotional cues and concerns? What happens in the brain and the body of both patients and clinicians during emotional talk? Are there individual differences in patients' responses to emotional talk in medical interviews? Do clinicians' responses to emotion affect health outcome? CONCLUSION: Building on evidence reviewed, research on predictors of clinician responses, physiological correlates of behavior, individual differences and effects on outcome should be further pursued. PRACTICE IMPLICATIONS: In communication skills training programs, better understanding of the phenomena described could have implications for training clinicians to handle emotions in clinical interviews. PMID- 22819271 TI - Combined use of preoperative transvaginal ultrasonography and intraoperative gross examination in the assessment of myometrial invasion in endometrial carcinoma. AB - OBJECTIVE: To evaluate the diagnostic performance of gross examination and transvaginal ultrasonography in the assessment of the depth of myometrial infiltration when they are used alone or together as a combined test. STUDY DESIGN: The data of 219 consecutive patients with a diagnosis of endometrial cancer were evaluated retrospectively. Transvaginal ultrasound was carried out as a part of the routine preoperative work-up within three days of surgical intervention in all cases. All patients underwent hysterectomy with bilateral salpingo-oophorectomy and routine surgical staging and all uterine specimens were examined immediately after hysterectomy. The depth of myometrial invasion was classified into two groups: no or <50% invasion and >=50% invasion. The findings of ultrasound and intraoperative gross examination were compared with the final histopathological results. The data of these two methods were integrated to evaluate the diagnostic performance of the combined test. If the results of myometrial invasion evaluation were different for the same patient, the deeper one (the depth of invasion >=50%) was accepted. RESULTS: Sensitivity, specificity, PPV, NPV and accuracy of preoperative ultrasonography in predicting myometrial infiltration >=50% were 62%, 81%, 60%, 82%, and 75% respectively. The corresponding rates for intraoperative gross examination were 61%, 88%, 70%, 83% and 79%, respectively. For the combined test they were 78%, 76%, 60%, 88% and 70% respectively. There was no statistically significant difference in sensitivity and specificity between ultrasound and gross examination. The sensitivity of the combined test was significantly higher than that of ultrasound and gross examination (p=0.001 and p<0.0001, respectively). The specificity of the combined test was significantly lower than that of TVS and gross examination (p=0.008 and p<0.0001, respectively). CONCLUSION: Combining ultrasonography and intraoperative gross examination may be a good option to assess the depth of myometrial invasion, as it has a higher sensitivity and negative predictive value in comparison to using these methods alone. PMID- 22819272 TI - The clinical features and treatment of endodermal sinus tumor of vagina. PMID- 22819273 TI - Decelerated early growth in infants of overweight and obese mothers. AB - OBJECTIVE: To investigate the relationship between maternal prepregnancy body mass index and early infant growth and body composition. STUDY DESIGN: Prospective cohort study performed at a university hospital/surrounding community. Ninety-seven nondiabetic mothers with singleton, term, healthy infants completed study visits at 2 weeks and 3 months of age. Before pregnancy, 59 mothers were normal weight, 18 were overweight, and 20 were obese. Infant anthropometrics and body composition via air-displacement plethysmography were measured. Infant feeding information and maternal prepregnancy weight were self reported. Additional data were obtained via self-report and the medical record. Main outcome measures were change in weight, length, fat-free mass, and fat mass from 2 weeks to 3 months of age. Analysis was done via multivariate linear regression. RESULTS: At 2 weeks, anthropometrics and body composition did not differ across maternal body mass index groups. At 3 months, infants of overweight or obese mothers had gained less weight (P = .02), grew less in length (P = .01), and gained less fat mass (P = .01). Adjustment for breastfeeding status and regression to the mean via conditional change variables did not alter the results. The results were not altered after adjusting for maternal glucose values from a 50-g glucose challenge and for maternal smoking in a subset including 80% of the women. CONCLUSIONS: Maternal overweight/obesity is associated with early deceleration in linear growth and adipose tissue accrual; replication of these findings is needed. PMID- 22819274 TI - Point-of-care differentiation of Kawasaki disease from other febrile illnesses. AB - OBJECTIVE: To test whether statistical learning on clinical and laboratory test patterns would lead to an algorithm for Kawasaki disease (KD) diagnosis that could aid clinicians. STUDY DESIGN: Demographic, clinical, and laboratory data were prospectively collected for subjects with KD and febrile controls (FCs) using a standardized data collection form. RESULTS: Our multivariate models were trained with a cohort of 276 patients with KD and 243 FCs (who shared some features of KD) and validated with a cohort of 136 patients with KD and 121 FCs using either clinical data, laboratory test results, or their combination. Our KD scoring method stratified the subjects into subgroups with low (FC diagnosis, negative predictive value >95%), intermediate, and high (KD diagnosis, positive predictive value >95%) scores. Combining both clinical and laboratory test results, the algorithm diagnosed 81.2% of all training and 74.3% of all testing of patients with KD in the high score group and 67.5% of all training and 62.8% of all testing FCs in the low score group. CONCLUSIONS: Our KD scoring metric and the associated data system with online (http://translationalmedicine.stanford.edu/cgi-bin/KD/kd.pl) and smartphone applications are easily accessible, inexpensive tools to improve the differentiation of most children with KD from FCs with other pediatric illnesses. PMID- 22819275 TI - Lipoprotein subfractions by ion mobility in lean and obese children. AB - OBJECTIVE: To establish normative data for lipoprotein subfractions using a novel ion mobility assay in healthy lean children and to compare their data with those of obese children preselected with normal glucose, blood pressure, and relatively normal lipids. STUDY DESIGN: Fasting blood samples in 162 children aged 7.0-18.9 years (75 lean [body mass index: 18.6 +/- 6.6 kg/m(2)] and 87 obese [body mass index: 31.7 +/- 5.4 kg/m(2)]) were analyzed. Correlation of lipoprotein subfractions with anthropometric and laboratory markers was performed. Principal component analysis was used to avoid using correlated variables. RESULTS: Normative data for lipid subfractions were obtained in healthy children. Lean children had higher high-density lipoprotein (HDL)-large (76%), HDL-small (13%), and HDL-total (27%) compared with obese (P < .01), and lower low-density lipoprotein (LDL)-medium (-30%, P < .01) and medium + small (-21%, P = .02) as well as LDL-total (-13%, P = .035). In both groups, the LDL component was higher in males and pubertal children (P < .01). Prepubertal children had a higher HDL component than pubertal ones (P < .004). Adjusting for sex and pubertal status LDL component was positively, and HDL component negatively, correlated with obesity (P < .004). CONCLUSIONS: Despite relatively normal triglycerides and cholesterol measured with standard assays at screening, ion mobility analysis showed significant differences in lipid and apolipoprotein subfractions between lean and obese children, even those prepubertal. Long-term, prospective follow-up may better characterize the predictability of lipid subfractions for future cardiovascular disease risk in children. PMID- 22819276 TI - Stigma of Suicide Attempt (STOSA) scale and Stigma of Suicide and Suicide Survivor (STOSASS) scale: two new assessment tools. AB - This study aimed at validating two new assessment tools, the Stigma of Suicide Attempt (STOSA) scale and the Stigma of Suicide and Suicide Survivor (STOSASS) scale. The Devaluation-Discrimination scale of Link et al. was translated into Italian and adapted to measure stigma towards suicidal behavior. Both scales were administered to a mixed sample including members of the general population (n=282), patients with a mental disorder (n=113), suicide attempters (n=57) and people who had lost a significant other to suicide (n=75). Reliability of the scales was good in terms of both internal coherence and test-retest stability. Factor analysis produced an acceptable solution for the STOSA-scale. Items were distributed into two factors, one grouping items to measure supportive, respectful and caring attitudes, the other factor grouping items oriented towards stigmatizing attitudes and beliefs. The clinical populations were more inclined towards stigmatization of suicide than were people from the general population, who might be less aware of the stigma attached to suicide. The two scales may be helpful to quantify stigma at individual level in order to provide targeted supportive interventions, and at population level to measure changes in the beliefs and attitudes of the general population. PMID- 22819277 TI - Psychopaths lack the automatic avoidance of social threat: relation to instrumental aggression. AB - Psychopathy (PP) is associated with marked abnormalities in social emotional behaviour, such as high instrumental aggression (IA). A crucial but largely ignored question is whether automatic social approach-avoidance tendencies may underlie this condition. We tested whether offenders with PP show lack of automatic avoidance tendencies, usually activated when (healthy) individuals are confronted with social threat stimuli (angry faces). We applied a computerized approach-avoidance task (AAT), where participants pushed or pulled pictures of emotional faces using a joystick, upon which the faces decreased or increased in size, respectively. Furthermore, participants completed an emotion recognition task which was used to control for differences in recognition of facial emotions. In contrast to healthy controls (HC), PP patients showed total absence of avoidance tendencies towards angry faces. Interestingly, those responses were related to levels of instrumental aggression and the (in)ability to experience personal distress (PD). These findings suggest that social performance in psychopaths is disturbed on a basic level of automatic action tendencies. The lack of implicit threat avoidance tendencies may underlie their aggressive behaviour. PMID- 22819278 TI - Prolonged excretion of 7-aminoclonazepam in urine after repeated ingestion of clonazepam: a case report. AB - Urinary analyses of the metabolite 7-aminoclonazepam (7-AC) can be helpful in monitoring drug abuse and in the context of suspected drug-facilitated sexual assaults (DFSA). Only two studies have reported detection times of 7-AC in urine after a single dose of clonazepam, and no previous studies have reported detection times after repeated ingestions of clonazepam. This report describes along detection time of 7-AC in urine in the case of a 28-year-old woman with a two year history of daily drug abuse of heroin and clonazepam, who was admitted to a detoxification unit. Urinary samples were delivered every morning for 9 days. Screening analysis in urine was performed by immunoassay, and confirmation analysis by LC-MS/MS. 7-AC was detected for 9 days, and the concentration at day 9 was still high (97 ng/ml), compared to previously reported data. These results indicate that after repeated ingestions of clonazepam, 7-AC can possibly be detected for about 2-3 weeks after cessation, applying cut-off levels commonly used in drug testing programs and DFSA cases. PMID- 22819279 TI - Allogeneic stem cell transplantation for advanced primary cutaneous T-cell lymphoma: a systematic review. AB - Primary cutaneous T-cell lymphomas (CTCL) are non-Hodgkin lymphomas usually running an indolent course. However, some patients progress to tumor stages or leukemic phase for which no curative treatment is available. Although initial response rates are high, remissions are often short-lived. Recent reports suggest a potential curative role for allogeneic stem cell transplantation (alloSCT). We searched databases for genetically randomized controlled trials (RCT) comparing alloSCT with conventional therapy. Data extraction and quality assessment were performed following the guidelines of the Cochrane Collaboration. Primary outcome measures were overall survival, secondary criteria included time-to-progression and response rate. A total number of 2077 primary citations were screened for relevant studies. Detailed analysis revealed that no RCTs on this subject have been performed and no systematic meta-analysis could be carried out. Nevertheless, several retrospective analyses and case series addressed the question of alloSCT for patients with advanced CTCL or Sezary syndrome. In this review, we will discuss the currently available data. PMID- 22819280 TI - Squamous-cell carcinoma of the lungs: is it really so different? AB - BACKGROUND: Squamous cell carcinoma (SCC) is the predominant histological type in men, and adenocarcinoma is the most common subtype in women in the world. The incidence of SCC is decreasing in men, while the incidence of adenocarcinoma (AC) is stable or slightly increasing in western countries. There is active research on the AC subtype but SCC remains poorly studied. CONCLUSIONS: In this review, we have studied different aspects of the SCC subtype, including epidemiology, clinical features, pathology, molecular biology markers, and new therapeutic targets, treatments and prognosis implications. PMID- 22819281 TI - Ovarian and PGF2alpha responses to stimulation of endogenous PRL pulses during the estrous cycle in mares. AB - The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2alpha secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 +/- 1.9 ng/mL; mean +/- SEM) than in the controls (11.5 +/- 1.8 ng/mL). Concentrations of a metabolite of PGF2alpha (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported. PMID- 22819282 TI - Effects of oral treatment with N-acetylcysteine on the viscosity of intrauterine mucus and endometrial function in estrous mares. AB - Persistent breeding-induced endometritis is ranked as the third most common medical problem in the adult mare and leads to enormous economic loss in horse breeding. In mares suffering from persistent breeding-induced endometritis, increased amounts of intrauterine (i.u.) fluid or viscous mucus in estrus or after breeding may act as a barrier for sperm and can contribute to low fertility. Current therapies of these mares aim to eliminate i.u. fluid and mucus by uterine lavage and/or administration of ecbolic drugs. Recently, i.u. administration of N-acetylcysteine (NAC) has been shown to support therapy in mares with endometritis. It was the objective of the present study to investigate effects of an oral administration of NAC on the viscosity of i.u. fluid in estrous mares. It was hypothesized that oral treatment with NAC reduces the viscosity of i.u. fluid and has a positive effect on the inflammatory response of the endometrium. Mares (n = 12) were included in the study as soon as estrus was detected (ovarian follicle >3.0 cm and endometrial edema), which was defined as Day 1. They were randomly assigned to a treatment (10 mg/kg NAC on Days 1-4) or a control group (no treatment). On days 1 and 5 i.u. mucus was collected and its rheologic properties were accessed. On Day 5, endometrial biopsies were obtained and evaluated for integrity of the luminal epithelium, number of polymorphonuclear neutrophils (PMN), staining for cyclooxygenase 2 (COX2), staining with Kiel 67 antigen (Ki-67), lectins and periodic acid Schiff (PAS). In the treatment group, viscosity of i.u. mucus increased significantly between Days 1 and 5 (P < 0.05), while no differences were found in control mares (n.s.). At no time were significant differences between treated and control mares seen. Integrity of epithelium was not affected. After NAC treatment the mean number of PMN in endometrial biopsies was significantly lower compared to mares of the control group (1.9 +/- 0.3 vs. 4.8 +/- 0.4; P < 0.05). Nuclear immunostaining for COX2 was significantly lower after NAC treatment compared to control mares (P < 0.05). Score for PAS and Alcain staining of mucus in deep uterine glands differed significantly between groups (both P < 0.05). We conclude that oral NAC treatment does not reduce viscosity of uterine mucus but has an antiinflammatory effect on the equine endometrium. PMID- 22819283 TI - Osmotic tolerance and intracellular ion concentrations of bovine sperm are affected by cryopreservation. AB - In this study, the effects of cryopreservation on osmoregulation and ion homeostasis in bovine sperm were studied. We determined: (1) the osmotic tolerance limits and cell volume response upon exposure to anisotonic conditions, (2) the intracellular pH and potassium concentration, and (3) expression and localization of proteins encoding for potassium and chloride ion channels. A flow cytometric approach was used for simultaneous assessment of cell volume and viability of propidium iodide stained sperm in anisotonic media. Osmotic tolerance was found to be decreased after cryopreservation, especially in the 120 to 60 mOsm/kg osmotic range. The critical osmolality at which half of the sperm population survived increased from 55 to 89 mOsm/kg. The osmotic cell volume response for viable sperm was similar before and after cryopreservation, with an osmotic inactive volume of about 70%. The intracellular pH, determined by recording changes in carboxyfluorescein fluorescence of sperm in media with different pH before and after addition of digitonin, decreased from 6.28 in diluted sperm to 6.16 after cryopreservation. The intracellular potassium concentration, determined using the potassium ionophore nigericin and incubation in media with various potassium concentrations, increased from 154 mM to 183 mM before and after cryopreservation, respectively. The levels of the chloride and potassium ion channel proteins chloride channel 3 protein (CLC-3) and two pore domain potassium channel 2 protein (TASK-2), as detected using Western blot analysis, were not affected by cryopreservation. Immunolocalization studies showed that CLC-3 is present in the acrosome and midpiece as well as in the upper and lower tail. In conclusion, cryopreserved sperm exhibit reduced tolerance to hypotonic stress, a decreased intracellular pH, and increased intracellular potassium level. PMID- 22819284 TI - Effect of immunomodulatory therapy on the endometrial inflammatory response to induced infectious endometritis in susceptible mares. AB - The objective of the present study was to evaluate the effect of immunomodulatory therapy (glucocorticoids (GC) and mycobacterium cell wall extract (MCWE)) on the endometrial gene expression of inflammatory cytokines in susceptible mares with induced infectious endometritis. Endometrial gene expression of pro- and anti inflammatory cytokines; interleukin (IL)-1beta, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, IL-1 receptor antagonist (ra), acute phase protein (APP) serum amyloid A (SAA) and clinical parameters were evaluated. Five mares were classified as susceptible to persistent endometritis based on their endometrial histopathology and ability to clear an induced uterine inflammation. To investigate the effect of immunomodulatory therapy, the mares were inoculated with 10(5) colony forming units (CFU) Escherichia coli in three consecutive estrus cycles in a modified cross-over study design. Thus, each mare served as its own control and the treatment type was performed in randomized order. The effect of treatment with MCWE (1.5 mg Settle IV), dexamethasone (0.1 mg per kg IV) or no treatment was investigated. All mares were free from uterine inflammation before each E. coli inoculation. Endometrial biopsies were recovered 3, 24 and 72 h post inoculation. Relative gene-expression analyses were performed by quantitative reverse transcriptase PCR (qRT-PCR). Endometrial gene expression of inflammatory cytokines was modulated by administration of GC. Expression of proinflammatory cytokines (IL-1beta, IL-6, IL-8) and SAA was significantly lower in the GC treated group late in the study period (72 h) compared to "no treatment" and MCWE treatment. Increased expression of the anti-inflammatory cytokine IL-10 was observed 3 and 24 h after E. coli infusion and GC treatment. A significant decrease of SAA expression was observed after MCWE treatment compared to "no treatment". MCWE and GC treatment had a significant effect on the clearance of uterine pathogens and number of mares retaining fluid after E. coli infusion. The results of the current investigation suggest that GC is capable of effectively modulating the innate immune response to induced infectious endometritis in susceptible mares. PMID- 22819285 TI - Production and manipulation of bovine embryos: techniques and terminology. AB - There are numerous publications regarding bovine embryos, ranging from descriptions of their appearance and development to emerging techniques in the field of assisted reproductive technology. Concurrently, several specialized terms have been developed to describe the bovine embryo. The purpose of the current review is two-fold; it is primarily to describe techniques involved in the in vivo and in vitro production of bovine embryos and their manipulation, and secondarily to summarize specialized terms used in these processes. The intention is not to review these techniques in detail, but instead to provide salient points and current knowledge regarding these techniques, with a focus on terminology. The first review dealt with classical and contemporary terminology used to describe morphologic aspects of ovarian dynamics in cattle. Subsequently, the terms and current understanding of processes involved in preattachment bovine embryos were described in the second review. As the third article in a series, this mini-review is focused on defining the production, manipulation, and transfer of bovine preattachment embryos. PMID- 22819286 TI - The effect of timing of the induction of ovulation on embryo production in superstimulated lactating Holstein cows undergoing fixed-time artificial insemination. AB - Two experiments evaluated the effects of timing of the induction of ovulation in superstimulated lactating Holstein donor cows that were fixed-time artificially inseminated. Secondary objectives were to evaluate the effects of the timing of progesterone (P4) device removal (Experiment 1) or the addition of a second norgestomet implant (Experiment 2) during superstimulation. In Experiment 1, 12 cows were allocated to one of four treatment groups with the timing of P4 device removal (24 or 36 h) and pLH treatment (48 or 60 h), after the first PGF as main factors, in a Latin Square (cross-over) design. There was an interaction (P = 0.03) between time of P4 device removal and time of pLH treatment. Mean (+/- SEM) numbers of transferable embryos were higher when the P4 device was removed at 36 h and pLH was administered at 60 h after the first PGF (P36LH60 =6.3 +/- 1.4) compared to other treatments (P24LH60 =3.7 +/- 1.1; P24LH48 =2.4 +/- 0.8; or P36LH48 =2.2 +/- 0.7). In Experiment 2, 40 cows were randomly allocated into one of four treatments with the number of norgestomet implants (one or two) and the time of induction of ovulation with GnRH relative to the first PGF (48 vs. 60 h) as main effects. The mean number of transferable embryos was higher (P = 0.02) when GnRH was administered at 60 h (4.2 +/- 1.3) compared to at 48 h (2.7 +/- 0.8), and the number of freezable embryos was increased (P = 0.01) in cows receiving two (3.0 +/- 1.0) rather than one norgestomet implant (1.5 +/- 0.5). In summary, embryo production in lactating Holstein cows was increased when the ovulatory stimulus (pLH or GnRH) was given 60 h after the first PGF, particularly when the P4 device was removed 36 h after the first PGF and when two norgestomet ear implants were used during the superstimulation protocol. PMID- 22819287 TI - Characterization of ovarian follicular dynamics in dromedary camels (Camelus dromedarius). AB - Ovarian follicular dynamics was monitored by transrectal ultrasonography, for a period of 60 to 90 days, and its correlation with plasma estradiol-17beta (E2) and progesterone (P4) were studied in seventeen, multiparous, non-lactating, 12 to 20-year-old dromedary camels. The average number of follicles recruited (12.77 +/- 0.93) in each wave between animals varied (P < 0.001). The number of follicles recruited during different follicular waves was highly repeatable (0.95) within individual animals. The growth and mature phase periods of the dominant follicle (DF) were 6.10 +/- 0.15 and 10.20 +/- 0.47 days, respectively with a linear growth rate of 1.17 +/- 0.02 mm/day between Day 0 and 10 of the follicular wave. There was an inverse relationship between the diameter of the largest DF and number of follicles (r = -0.95, P < 0.001). The DF development did not regularly alternate between the ovaries and the incidence of codominance was 45%. The mean maximum diameter of DF during its mature phase was 27.30 +/- 0.78 mm and oversized follicle was 38.43 +/- 1.41 mm. In 73.3% waves, the DF continued its growth for a period of 10.64 +/- 1.53 days even after losing its dominance and developed into oversized follicle. The duration of the regression phase of DF and oversized follicle were 24.71 +/- 3.79 and 18.50 +/- 2.23 days. The mean duration of a complete follicular wave was 47.11 +/- 2.94 days with an interwave interval (IWI) of 16.36 +/- 0.37 days. The IWI within an individual was repeatable (0.88) and between the animals was variable (P < 0.001). Plasma E2 concentration profiles showed a wave like pattern. The peak plasma E2 concentrations were attained approximately 12 days after beginning of the growth phase, when the largest DF grew to a diameter of 18.7 mm. Plasma concentration of P4 was below 1.0 ng/mL in 85% of waves and above 1.0 ng/mL in 15% of the waves for a period of 3 to 6 days in the absence of spontaneous ovulation. It is concluded that ovarian follicular development and plasma E2 concentrations occurs in a wave like pattern in dromedary camels and the IWI and follicle numbers recruited per wave are variable between the animals and repeatable within an individual animal. PMID- 22819288 TI - Echocardiographic and Doppler assessment of maternal cardiovascular function in normal and abnormal canine pregnancies. AB - The objective was to verify maternal hemodynamic differences between normal and abnormal pregnancies in dogs. Brucella-negative pregnant bitches (n = 31) were retrospectively classified into abnormal (which had either their pregnancy interrupted between Days 52 and 60 or perinatal death of more than 50% of the litter; n = 14) and normal (which had delivered healthy puppies at term; n = 17). These dogs were evaluated with echocardiography every 10 days from Days 0 to 60 of gestation (Day 0 = estimated day of LH peak). Systolic blood pressure was also assessed. At Day 50 of gestation, left ventricular free wall in systole increased in the normal but not in the abnormal group (P < 0.01). In contrast, end systolic stress (P < 0.01) and systolic blood pressure (P < 0.01) diminished only in normal animals. We concluded that signs of altered maternal cardiovascular adaptation to pregnancy may be predictors of obstetrical complications in dogs. PMID- 22819289 TI - Simple tools for complex syndromes: a three-level difficulty test for hepatic encephalopathy. AB - BACKGROUND: Despite the impact of hepatic encephalopathy on quality of life and prognosis, easily administered tests for its diagnosis are still lacking. AIM: To assess the usefulness of the Scan package, a three-level-difficulty computerised reaction time test, to diagnose varying degrees of hepatic encephalopathy. METHODS: Sixty-one cirrhotic patients underwent clinical evaluation, paper-and pencil psychometry and the Scan package; 32 healthy controls served as reference. RESULTS: Twenty-nine patients were classified as unimpaired, 15 as having minimal and 17 as having overt hepatic encephalopathy. All healthy controls were able to complete the Scan package; in contrast, the number of patients who were able to complete three/two/one part decreased in parallel with the degree of encephalopathy (chi(2)=17, p=0.01). Reaction times in all three parts increased significantly with the severity of encephalopathy. However, the profile of increase was different [group: F(3,77)=26, p<0.0001; test: F(2,154)=277, p<0.0001; group*test: F(6,154)=7, p<0.0001], with different parts being more/less sensitive to varying degrees of encephalopathy. CONCLUSIONS: The Scan package seems useful for the diagnosis of hepatic encephalopathy and covers a considerable portion of its spectrum of severity. PMID- 22819290 TI - The case for intrauterine gene therapy. AB - Single-gene disorders can cause perinatal mortality or severe permanent morbidity. Intrauterine gene therapy seeks to correct the genetic defect in the early stages of pathogenesis through delivery of a vector system expressing the therapeutic transgene to the fetus. Advantages of intrauterine gene therapy include prevention of irreversible organ damage, potentially inducing central tolerance and wider bio-distribution, including the brain after delivery of vector. Already, proof-of-cure has been demonstrated in knockout animal models for several diseases. Long-term outcomes pertaining to efficacy and durability of transgene expression and safety are under investigation in clinically relevant non-human primate models. Bystander effects in the mother from transplacental vector trafficking require further assessment. In this chapter, we discuss the candidate diseases amenable to intrauterine gene therapy, current state-of-the art evidence, and potential clinical applications. PMID- 22819291 TI - Cytochemistry of sialoglycoconjugates and lysozyme in canine anal glands as studied by electron microscopic methods. AB - The distribution of sialoglycoconjugates and lysozyme in the secretory cells of canine anal glands was studied by means of electron microscopic cytochemical methods, particularly lectin cytochemistry and immunocytochemistry. Sialic acids were predominantly present in the secretory granules, Golgi bodies, surface coat of the plasma membrane and luminal secretions. In addition, within these structures, the secretory granules, Golgi bodies and luminal secretions exhibited high levels of sialoglycoconjugates that terminated in Siaalpha2-6Gal/GalNAc or Siaalpha2-3Galbeta1-4GlcNAc. In the secretory cells, reactive gold particles representing lysozyme were mainly detectable in the secretory granules and Golgi bodies. Sialic acids possess diverging functional properties, whereas lysozyme contributes to the non-specific defense against microorganisms. Therefore, their presence and secretion are suggestive of protective effects of both secretory products at the anal mucosa. PMID- 22819292 TI - Immunolocalization of NOS, VIP, galanin and SP in the small intestine of suckling pigs treated with red kidney bean (Phaseolus vulgaris) lectin. AB - Lectins belong to a family of glycoproteins that can act both beneficially and detrimentally on the morphology of the small intestine. The aim of the study was to determine whether experimental treatment with red kidney bean (Phaseolus vulgaris) lectin influences the chemical code of the small intestine nervous system of suckling pigs. The immunolocalization sites of vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), substance P (SP) and galanin were determined in control and lectin-treated animals. In all segments of the small intestine (duodenum, jejunum, ileum), the subpopulations of VIP-, NOS-, SP- and galanin-immunoreactive (IR) myenteric neurons were unchanged. After lectin stimulation, increased proportions of NOS-IR and decreased numbers of VIP-IR submucous neurons/mucosa innervating nerve fibers were observed in the duodenum, jejunum and ileum. In lectin-treated animals down-regulation of submucous neurons expressing SP and up-regulation of galanin-IR submucous neurons were seen in the duodenum and jejunum (but not in the ileum). The distribution patterns of NOS-IR, galanin-IR and SP-IR nerve fibers supplying the duodenum, jejunum and ileum of the lectin-treated animals showed no substantial differences in relation to control piglets. We conclude that exposure to red kidney bean (P. vulgaris) lectin substantially changes the chemical content of VIP, NOS, SP and galanin in submucous neurons of the small intestine. These results are in line with previous findings outlining the key role(s) of these substances in enteric neuroplasticity processes and may constitute the basis for further functional studies on maturation of the gut. PMID- 22819293 TI - Prevalence and correlates for nonmedical use of prescription opioids among urban and rural residents. AB - BACKGROUND: In the United States, rural areas have reported an increase in overdose deaths secondary to nonmedical use of prescription opioids. Little is known about the differences in nonmedical use of prescription opioids among urban and rural adults. METHODS: Using the 2008-2009 National Survey on Drug Use and Health, we examined the prevalence of nonmedical use of prescription opioids in urban and rural counties and determined bivariate and multivariate associations, stratified by county. We also compared type of opioids, stratified by county. RESULTS: Among 75,964 respondents, the prevalence of nonmedical use of prescriptions opioids was similar among residents in urban and rural counties (4.7% vs. 4.3%, p=0.15). Urban and rural residents with severe psychological distress and nonmedical use of other prescription medications were more likely to report nonmedical use of opioids. Urban residents whose first use of illicit drugs was between the age of 18 and 25 and who reported alcohol use were more likely to report nonmedical use. Black and Hispanic urban residents were less likely to use prescription opioids nonmedically compared to white urban residents. Rural residents were more likely than urban residents to use acetaminophen with propoxyphene (61.1% vs. 55.8%, p=0.02), methadone (14.8% vs. 9.1%, p=0.003) and acetaminophen with codeine (3.5% vs. 1.9%, p=0.05). CONCLUSIONS: Prevalence and risk factors related to nonmedical use of opioids are similar between urban and rural residents; however rural residents report propoxyphene, codeine, and methadone use more than their urban counterparts. Prevention and treatment interventions may need to be tailored for specific communities. PMID- 22819294 TI - Dermoscopic diagnosis of melanoma in a 4D space constructed by active contour extracted features. AB - Dermoscopy, also known as epiluminescence microscopy, is a major imaging technique used in the assessment of melanoma and other diseases of skin. In this study we propose a computer aided method and tools for fast and automated diagnosis of malignant skin lesions using non-linear classifiers. The method consists of three main stages: (1) skin lesion features extraction from images; (2) features measurement and digitization; and (3) skin lesion binary diagnosis (classification), using the extracted features. A shrinking active contour (S ACES) extracts color regions boundaries, the number of colors, and lesion's boundary, which is used to calculate the abrupt boundary. Quantification methods for measurements of asymmetry and abrupt endings in skin lesions are elaborated to approach the second stage of the method. The total dermoscopy score (TDS) formula of the ABCD rule is modeled as linear support vector machines (SVM). Further a polynomial SVM classifier is developed. To validate the proposed framework a dataset of 64 lesion images were selected from a collection with a ground truth. The lesions were classified as benign or malignant by the TDS based model and the SVM polynomial classifier. Comparing the results, we showed that the latter model has a better f-measure then the TDS-based model (linear classifier) in the classification of skin lesions into two groups, malignant and benign. PMID- 22819295 TI - Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene. AB - Mutations in mitochondrial DNA (mtDNA) encoded nucleotide 8993 can cause NARP syndrome (neuropathy, ataxia, and retinitis pigmentosa) or MILS (maternally inherited Leigh syndrome). The rare T8993C mutation in the MT-ATP6 gene is generally considered to be clinically milder, but there is marked clinical heterogeneity ranging from asymptomatic carriers to fatal infantile Leigh syndrome. Clinical heterogeneity has mostly been attributed to mtDNA heteroplasmy, but environmental, autosomal, tissue-specific factors, nuclear modifier genes, and mtDNA variations may also modulate disease expression. Here, we report the results of whole mitochondrial genome analysis of a family with m.8993T>C mutation in the MT-ATP6 gene and associated with NARP/MILS, and discuss the familial inheritance, effects of variation in combinations and heteroplasmy levels on the clinical findings. The whole mitochondrial genome was sequenced with ~182* average depth of coverage per sample with next-generation sequencing technology. Thus, all heteroplasmic (>%10) and homoplasmic variations were determined (except for 727C insertion) and classified according to the associations with mitochondrial diseases. PMID- 22819296 TI - Variants in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population. AB - Loss-of-function mutations of flavin-containing monooxygenase 3 (FMO3), the enzyme responsible for trimethylamine N-oxygenation, cause the inherited disorder trimethylaminuria, or fish odor syndrome. The aim of this study was to further investigate the inter-individual variations of FMO3 activity in a Japanese cohort that we had studied previously. The subjects were 640 Japanese volunteers with self-reported trimethylaminuria; genomic DNA was sequenced in those that had 10 70% FMO3 metabolic capacity in urine tests. A heterozygote for the novel single nucleotide substitution p.Ile441Thr (proband 1) and a heterozygote for the novel single nucleotide substitution p.Ser195Leu (proband 2) were identified. The biological parents of probands 1 and 2 were heterozygous and had >90% trimethylamine N-oxygenation metabolic capacity. In addition, single nucleotide substitutions p.Val58Ile, p.Pro70Leu, and p.Gly421Val in FMO3 were found in probands 3-7. In the course of DNA sequencing, another FMO3 variant, p.Thr488Ala, was found in two unrelated heterozygous subjects. Variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased activity toward typical FMO3 substrates. Although the allele frequencies of these six novel variants were low (<1%), the present results suggest that individuals homozygous or heterozygous for any of the six novel missense FMO3 variants or known nonsense mutations such as p.Cys197stop or p.Arg500stop may possess abnormal trimethylamine N-oxygenation. PMID- 22819297 TI - Benign paroxysmal positional vertigo as a complication of orthognathic surgery. AB - Benign paroxysmal positional vertigo (BPPV) is a clinical disorder that may develop following surgical trauma to the maxilla, for example as a result of closed sinus lifting with the use of mallet and osteotome during implant surgery. We proposed that BPPV may also occur following maxillary Le Fort osteotomy during orthognathic surgery. In a prospective study of 50 consecutive cases of orthognathic surgery, we observed that one patient developed BPPV in the postoperative period following bimaxillary orthognathic surgery. The patient was a 23-year-old woman who met the strict criteria for a diagnosis of BPPV, including a positive Dix-Hallpike test. We have described BPPV in more detail and have discussed the necessity of increasing awareness and knowledge of surgeons about BPPV as a possible complication of craniomaxillofacial surgery. PMID- 22819298 TI - Evaluation of post-surgical relapse after mandibular setback surgery with minimal orthodontic preparation. AB - BACKGROUND: The aim of this study was to evaluate of the patterns of post surgical relapse after mandibular setback surgery with minimal orthodontic preparation (MS-MO). MATERIALS AND METHODS: The subjects consisted of 15 patients with minimal pre-surgical orthodontic preparation (1.37 +/- 1.69 months). Lateral cephalograms were taken in pre-surgical (T0), post-surgical 1 month (T1) and immediately after debonding (T2) stages. To evaluate the surgical changes (T1-T0) and the relapse (T2-T1), the linear and angular measurements were analyzed using paired t-test. Pearson's correlation coefficients of the horizontal and vertical relapses of Pog and Me to other measurements were calculated. Pog or Me in T1 were displaced rotationally on Ar-Pog or Ar-Me lines in T2 to evaluate the remaining surgical relapse except the rotational relapse from total relapse. RESULTS: The mandible relapsed anteriorly 3.53 mm (Pog) and 4.00 mm (Me) and superiorly 2.72 mm (Pog) and 2.44 mm (Me). FH to Ar-Pog and FH to Ar-Me decreased by about 2 degrees . Pure surgical relapses at Pog and Me, except rotational relapses, were about 0.5 mm anteriorly and inferiorly 0.8 mm. CONCLUSION: The vertical relapse might induce mandibular rotation with the horizontal relapse. For an accurate prediction after MS-MO, the rotational relapse might be considered. PMID- 22819299 TI - Assessment of bone healing and hypoesthesia in the upper lip after Le Fort I osteotomy with self-setting alpha-tricalcium phosphate and absorbable plates. AB - PURPOSE: The purpose of this study was to evaluate hypoesthesia of the upper lip and bone formation using self-setting alpha-tricalcium phosphate (Biopex((r))) between the segments following Le Fort I osteotomy with bent absorbable plate fixation. SUBJECTS AND METHODS: The subjects were 47 patients (94 sides) who underwent Le Fort I osteotomy with and without mandibular osteotomy. They were divided into a Biopex((r)) group (48 sides) and a control group (46 sides). The Biopex((r)) was inserted into the anterior part of the gap between the segments in the Biopex((r)) group. Trigeminal nerve hypoesthesia at the region of the upper lip was assessed bilaterally by the trigeminal somatosensory-evoked potential (TSEP) method. The area of the Biopex((r)) at the anterior part in the maxilla was assessed immediately after surgery and 1 year postoperatively by computed tomography (CT). RESULTS: The mean measurable period and standard deviation were 13.2 +/- 18.5 weeks in the control group, 14.5 +/- 17.9 weeks in the Biopex((r)) group, and there was no significant difference in TSEP. The area of the Biopex((r)) after 1 year was significantly smaller than that immediately after surgery (right side: P = 0.0024, left side: P = 0.0001) and bone defects between the segments could not be found in the Biopex((r)) group. In the control group, although the areas of bone defect after 1 year were significantly smaller than that immediately after surgery on the right side (P = 0.0133) and left side (P = 0.0469) in the frontal view, complete healing of the bone defects could be seen in 12 of 46 sides after 1 year. CONCLUSION: This study suggested that inserting Biopex((r)) in the gap between the maxillary segments was useful for new bone formation and it did not prevent the recovery of upper lip hypoesthesia after Le Fort I osteotomy with absorbable plate fixation. PMID- 22819300 TI - Choreito, a formula from Japanese traditional medicine (Kampo medicine), for massive hemorrhagic cystitis and clot retention in a pediatric patient with refractory acute lymphoblastic leukemia. AB - Hemorrhagic cystitis is critical in patients with hemato-oncological disorders. Unlike adult patients, there are limited modalities and invasive procedures are often not well tolerated in children with poor general conditions. We report a pediatric patient with refractory acute lymphoblastic leukemia who developed life threatening massive gross hematuria. Along with platelet infusion every other day due to suppressed hematopoiesis, his gross hematuria and clot retention in the bladder were successfully treated with choreito, a formula from Japanese traditional medicine (Kampo medicine). He survived free from hematuria for more than four months. Choreito was well tolerated, and no adverse effects were observed throughout the course. PMID- 22819301 TI - Enzyme kinetic and molecular docking studies on the metabolic interactions of 1 hydroxy-2,3,5-trimethoxy-xanthone, isolated from Halenia elliptica D. Don, with model probe substrates of human cytochrome P450 enzymes. AB - Halenia elliptica D. Don is a Tibetan herb and medicinal preparations containing Halenia elliptica have been commonly used for the treatment of hepatitis B virus infection in China. The metabolism of 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1) to its metabolites is mediated through cytochrome P450 enzymes. This study aimed to investigate the herb-drug interaction potential of HM-1 by studying its effects on the metabolism of model probe substrates of five major CYP450 isoforms in human liver microsomes. HM-1 showed moderate inhibitory effects on CYP1A2 (IC50 = 1.06 MUM) and CYP2C9 (IC50 = 3.89 MUM), minimal inhibition on CYP3A4 (IC20 = 11.94 MUM), but no inhibition on model CYP2D6 (dextromethorphan) and CYP2E1 (chlorzoxazone) probe substrates. Inhibition kinetic studies showed that the K(i) values of HM-1 on CYP1A2, CYP2C9 and CYP3A4 were 5.12 MUM, 2.00 MUM and 95.03 MUM, respectively. HM-1 competitively inhibited testosterone 6beta hydroxylation (CYP3A4) but displayed mixed type inhibitions for phenacetin O deethylation (CYP1A2) and tolbutamide 4-hydroxylation (CYP2C9). Molecular docking study confirmed the inhibition modes of HM-1 on these human CYP isoforms. PMID- 22819302 TI - Preventive and protective effects of silymarin on doxorubicin-induced testicular damages correlate with changes in c-myc gene expression. AB - This study aimed to investigate the preventive and protective effects of silymarin (SMN) on doxorubicin (DOX)-induced damages in the testis. Wistar rats were divided into six groups (n=8), including: control (C), DOX-treated (DOX, 15 mg/kg, i.p.), DOX- and SMN-treated and SMN-treated animals (SMN, 50 mg/kg, orally). Those groups, which received either compounds, were sub-grouped based on the preventive (PVT), protective (PTT) and/or therapeutic regimens (TPT) of SMN administration. The antioxidant status analyses, hormonal assay, and histopathological examinations in the testis were conducted. The expression of c myc at mRNA level also was analyzed. SMN in preventive and protective forms significantly (p<0.05) improved the DOX-induced weight loss and lowered the alkaline phosphatase level. Pretreatment and co-treatment with SMN attenuated the DOX-induced carbonyl stress. The DOX-induced histopathological damages including negative TDI and IR were significantly (p<0.05) improved with SMN pretreatment and co-administration. SMN in preventive and protective forms prevented from DOX induced DNA fragmentation in the testis. SMN ameliorated the DOX-reduced serum level of sexual hormones including testosterone, inhibin B, LH and FSH in PVT and PTT groups. The c-myc expression at mRNA level was completely and relatively down regulated in the testis of animals that received SMN as pretreatment and concurrent administration, respectively. Our data suggests that the DOX-induced biochemical and histopathological alterations could be prevented and/or protected by SMN. Moreover, the SMN protective and preventive effects attribute to its capacity in the reduction of DOX-induced carbonyl stress and DNA damage, which may be mediated by c-myc expression. PMID- 22819304 TI - A multilayer stent in the aorta may not seal the aneurysm, thereby leading to rupture. AB - The multilayer stents are occasionally used for the treatment of complicated aortic aneurysms, including thoracoabdominal aneurysms. No aneurysm-related mortality among patients treated with this technique has been described in the literature to date. We describe a case of rupture of an aortic aneurysm previously treated with a multilayer stent. PMID- 22819303 TI - Molecular-biological analysis of acute lung injury (ALI) induced by heat exposure and/or intravenous administration of oleic acid. AB - The aim of this study was to molecular-biologically investigate the interaction between heat exposure and pulmonary fat embolization in regards to the development of acute lung injury (ALI). Ten-week-old Wistar male rats were divided into four groups: (1) oleic acid injected into caudal vein after heat exposure, (2) oleic acid injected without heat exposure, (3) soybean oil injected after heat exposure, and (4) soybean oil injected without heat exposure, and then mRNA expression of eight inflammatory mediators related to ALI/acute respiratory distress syndrome (ARDS) and heat shock protein 70 (Hsp70) in lung was determined 1h after the injection. mRNA expression of interleukin 1 beta (Il1b), tumor necrosis factor alpha (Tnfa), vascular endothelial growth factor A (Vegfa), transforming growth factor beta 1 (Tgfb1) and Hsp70 was significantly increased by heat exposure, while that of Il1b, interleukin 6 (Il6), Tnfa, macrophage inflammatory protein 2 (Mip2) and granulocyte macrophage-colony stimulating factor (Gm-csf) was significantly elevated by the injection of oleic acid. Moreover, the expressions of inflammatory cytokines and chemokines in lung almost paralleled their mRNA expressions. In particular, IL-1beta expression was synergistically elevated by heat exposure followed by injection of oleic acid. Additionally, IL-6 expression tended to increase under the same conditions as well. It is likely that heat exposure itself injures lung tissue within a short time, and that more than two conditions which induce ALI/ARDS interact with each other synergistically, exacerbating the development of ALI/ARDS. PMID- 22819305 TI - A 10-year incidence of acute whiplash injuries after road traffic crashes in a defined population in northern Sweden. AB - OBJECTIVE: To examine the annual incidence of acute whiplash injuries after road traffic crashes in a geographic catchment area in Northern Sweden during the period 2000-2009. DESIGN: Descriptive epidemiology determined by prospectively collected data from a defined population. SETTING: The study was conducted at a public hospital in Sweden. PARTICIPANTS: The population of the hospital's catchment area (136,600 inhabitants in 1999 and 144,500 in 2009). METHODS: At the emergency department, all injured persons (approximately 11,000 per year) were asked to answer a questionnaire about the injury incident. Data from the medical records also were analyzed. From 2000-2009, 15,506 persons were injured in vehicle crashes. Persons who were subject to an acute neck injury within whiplash associated disorder grades 1-3 were included. The overall and annual incidences were calculated as incidence. Age, gender, type of injury event, and direction of impact were described. The incidences were compared with national statistics on insurance claims from 2003, 2007, and 2008 to detect changes in the proportions of claims. MAIN OUTCOME MEASURES: The annual incidence of acute whiplash injuries. Secondary outcome measures were types of injury events, age and gender distribution, changes in the proportion of rear-end crashes during 2000-2009, and changes in the proportion of insurance claims during 2003-2008. RESULTS: During 2000-2009, 3297 cases of acute whiplash injury were encountered. The overall incidence was 235/100,000/year. The average yearly increase in incidence was 1.0%. Women comprised 51.9% and men 48.1% of the injured. Car occupants (86.4%) and bicycle riders (6.1%) were most frequently injured. The proportion of rear end crashes decreased from 55% to 45% from 2000-2009. The proportion of insurance claims significantly decreased between 2003 and 2008 (P < .0001, chi(2) test). CONCLUSION: The incidence of emergency department visits attributable to acute whiplash injuries after road traffic crashes have been relatively stable during the past decade in our area, except in 2007 and 2008, when a peak occurred. PMID- 22819306 TI - Experimental evolution. AB - Experimental evolution is the study of evolutionary processes occurring in experimental populations in response to conditions imposed by the experimenter. This research approach is increasingly used to study adaptation, estimate evolutionary parameters, and test diverse evolutionary hypotheses. Long applied in vaccine development, experimental evolution also finds new applications in biotechnology. Recent technological developments provide a path towards detailed understanding of the genomic and molecular basis of experimental evolutionary change, while new findings raise new questions that can be addressed with this approach. However, experimental evolution has important limitations, and the interpretation of results is subject to caveats resulting from small population sizes, limited timescales, the simplified nature of laboratory environments, and, in some cases, the potential to misinterpret the selective forces and other processes at work. PMID- 22819307 TI - The importance of defining 'uncomplicated bone metastases'. PMID- 22819308 TI - Not all ambiguous words are created equal: an EEG investigation of homonymy and polysemy. AB - Event-related potentials (ERPs) were used to investigate the time-course of meaning activation of different types of ambiguous words. Unbalanced homonymous ("pen"), balanced homonymous ("panel"), metaphorically polysemous ("lip"), and metonymically polysemous words ("rabbit") were used in a visual single-word priming delayed lexical decision task. The theoretical distinction between homonymy and polysemy was reflected in the N400 component. Homonymous words (balanced and unbalanced) showed effects of dominance/frequency with reduced N400 effects predominantly observed for dominant meanings. Polysemous words (metaphors and metonymies) showed effects of core meaning representation with both dominant and subordinate meanings showing reduced N400 effects. Furthermore, the division within polysemy, into metaphor and metonymy, was supported. Differences emerged in meaning activation patterns with the subordinate meanings of metaphor inducing differentially reduced N400 effects moving from left hemisphere electrode sites to right hemisphere electrode sites, potentially suggesting increased involvement of the right hemisphere in the processing of figurative meaning. PMID- 22819309 TI - Where the brain appreciates the final state of an event: the neural correlates of telicity. AB - In this study we investigated whether the human brain distinguishes between telic events that necessarily entail a specified endpoint (e.g., reaching), and atelic events with no delimitation or final state (e.g., chasing). We used functional magnetic resonance imaging to explore the patterns of neural response associated with verbs denoting telic and atelic events, and found that the left posterior middle temporal gyrus (pMTG), an area consistently engaged by verb processing tasks, showed a significantly higher activation for telic compared with atelic verbs. These results provide the first evidence that the human brain appreciates whether events lead to an end or a change of state. Moreover, they provide an explanation for the long-debated question of which verb properties modulate neural activity in the left pMTG, as they indicate that, independently of any other semantic property, verb processing and event knowledge in this area are specifically related to the representation of telicity. PMID- 22819310 TI - Optimization of chondrocyte isolation and characterization for large-scale cartilage tissue engineering. AB - BACKGROUND: Advancements in cartilage tissue engineering have the potential to ameliorate facial and joint reconstructive surgery as we know it. The translation of in vitro models of cartilage regeneration into clinical scenarios is the next phase of cartilage tissue engineering research. To engineer larger, more robust, and clinical relevant constructs, a great number of viable chondrocytic cells are needed. However, there is a paucity of literature concerning the most favorable method of chondrocyte isolation. Isolation methods are inconsistent, resulting in small yields and poor cell quality, and thus unreliable neocartilage formation. This study aimed to optimize the chondrocyte isolation protocol to give a maximum yield with optimal cell viability for the engineering of large cartilaginous constructs such as the human nose and ear. METHODS: We employed several enzymes (pronase, dispase, hyaluronidase, and collagenase), enzyme concentrations, and digest lengths to digest freshly harvested ovine nasoseptal cartilage. We used automated trypan blue live/dead staining, immunofluorescent labeling of CD44, collagenase II, collagenase I, and Aggrecan, and alamarBlue to assess cell yield and viability. RESULTS: Incubation length in enzymatic solutions had the greatest effect on cell viability, whereas concentrations of enzymes had a lesser effect. Isolated cells maintained their expression of chondrocyte-specific cell surface markers. CONCLUSIONS: The optimum incubation period was 10 h using collagenase at a 0.2% (w/v) solution. An average of 1-1.5 * 10(6) cells could be harvested per gram of cartilage using this method. PMID- 22819311 TI - Correlation between augmenter of liver regeneration and IFN-gamma expression in graft after rat orthotopic liver transplantation. AB - BACKGROUND: Previous data suggested that augmenter of liver regeneration (ALR) has immunomodulation function by suppressing liver-resident NK cell activity and reducing IFN-gamma expression in human liver diseases. The correlation between ALR and IFN-gamma expression in graft after rat orthotopic liver transplantation remains uncertain. METHODS: A Lewis-to-BN (allograft group) and BN-to-BN (isograft group) rat liver transplantation model was used to investigate the ALR and IFN-gamma expression in liver graft. Graft recipients were sacrificed at days 1, 3, 5, and 7 posttransplantation. The histopathologic changes of grafts were observed under light microscope and the intragraft expression of ALR and IFN gamma mRNA and protein was determined by real-time PCR and immunohistochemistry staining, respectively. Correlation between ALR and IFN-gamma expression in graft was evaluated by Spearman rank correlation analysis. RESULTS: The light microscope inspection revealed severe acute rejection in the allograft group but not in the isograft group at day 7 after liver transplantation. The intragraft ALR showed slight protein expression at day 1 after liver transplantation in both groups and it was significantly increased at days 3, 5, and 7 (P < 0.05). There was no significant difference in ALR mRNA expression between the allograft group and isograft group at day 1 (1.09 +/- 0.12 and 1.13 +/- 0.10, respectively; P > 0.05, n = 3). The ALR mRNA level was slightly reduced at day 3 in both groups compared with that at day 1 (0.81 +/- 0.11 and 0.59 +/- 0.10, respectively, P > 0.05). However, it was markedly increased at day 5 (2.86 +/- 0.37) and day 7 (3.19 +/- 0.33) in the isograft group and was 1.57 +/- 0.27 and 1.98 +/- 0.13 in the allograft group at days 5 and 7, respectively. IFN-gamma protein and mRNA expression in the allograft group was increased at day 1 posttransplantation and reached a peak at day 3, and then it had a slight tendency of decline at day 5 and day 7. And they in the isograft group were at a low level at all times. The levels of ALR mRNA showed a negative correlation with levels of IFN-gamma mRNA in the allograft group (r = -0.86, P < 0.05, y = -0.241x + 0.586), whereas there is no correlation between ALR and IFN-gamma mRNA expression in the isograft group. CONCLUSION: These data revealed an obviously negative correlation between ALR and IFN-gamma levels intragraft, which indicated that ALR may participate in immunoregulation of acute rejection. PMID- 22819312 TI - Osteoporosis self-assessment tool for Asians as a simple risk index of identifying a poor prognosis in women surgically treated for colorectal cancer. AB - BACKGROUND: Osteoporosis and colorectal cancer (CRC) in older women are considered enormous public health burdens. The effects of osteoporosis on the oncologic outcome of CRC surgery are poorly understood. We evaluated the use of the Osteoporosis Self-assessment Tool for Asians (OSTA) for predicting postoperative outcome in older women after receiving surgical treatment of CRC. MATERIALS AND METHODS: The present single-institution retrospective study analyzed patients who had undergone surgery for CRC in 2002-2008. To characterize the major population of women with osteoporosis, which consists of postmenopausal women, only patients aged 50 years and older were analyzed. Their OSTA scores were evaluated for correlations with cancer-specific survival after surgery for CRC by performing univariate, multivariate, and survival analyses. RESULTS: During a 7-year period, 440 women were studied. The cancer-specific mortality and overall mortality rate was 28.4% and 33.4%, respectively. The univariate analyses revealed that significant predictors of cancer-specific mortality after CRC surgery were the International Union Against Cancer (UICC) stage, OSTA category, histologic grading, lymph node metastases, and tumor invasion depth. After risk adjustment, the UICC stage and OSTA risk index were independent predictors of mortality. A comparison of OSTA risk index among patients with different UICC stages showed that the accuracy of the index in predicting cancer-specific survival after CRC surgery was greatest for patients with stage II and III disease. CONCLUSIONS: The UICC stage and OSTA risk status showed independent positive associations with postoperative mortality in aged female patients with CRC. Moreover, the OSTA index had a particularly strong association with cancer specific mortality in patients with UICC stage II and III. PMID- 22819313 TI - Is the impact of the extent of lymphadenectomy in radical prostatectomy related to the disease risk? A single center prospective study. AB - BACKGROUND: Controversy exists regarding the extent of pelvic lymph node dissection (PLND) in radical prostatectomy (RP) for prostate cancer. Impact of the extent of PLND may be determined by the disease risk. The aim of our study was to find the association between the extent of PLND on biochemical progression and disease risk. METHODS: The study included 360 consecutive patients treated with RP for clinically localized prostate cancer at our department between 2000 and 2003. Patients were randomized to receive extended PLND (n = 180) and standard PLND (n = 180) at RP. Clinical and pathological data were prospectively collected. The patients did not receive any neoadjuvant or adjuvant therapy. The relation of disease risk and the extent of PLND to biochemical progression-free survival (BPFS) were examined. RESULTS: There were no significant differences in age, prostate-specific antigen, and other preoperative features in patients who underwent standard and extended PLND. Mean patient age was 68 y old and median follow-up was 74 mo. BPFS for the standard PLND group and the extended PLND group was 90.1% and 91.3% in low risk disease (log rank P = 0.807), 73.1% and 85.7% in intermediate risk disease (log rank P = 0.042), and 51.1% and 71.4% in high risk disease (log rank P = 0.036), respectively. In multivariate Cox proportional hazard analysis, extended PLND was an independent prognostic factor of biochemical progression-free survival when adjusting for other clinical and pathologic features. CONCLUSIONS: In intermediate and high risk patients, extended PLND positively affects BPFS. In low risk patients, extended PLND may be omitted to reduce operation time and complications. PMID- 22819314 TI - Combined treatment with regulatory T cells and vascularized bone marrow transplantation creates mixed chimerism and induces donor-specific tolerance to vascularized composite allografts without cytoreductive conditioning. AB - BACKGROUND: Cotreatment with regulatory T cells (T(reg)) and conventional allogeneic bone marrow transplantation (BMT) successfully induced durable chimerism and tolerance to nonvascularized skin allografts without cytoreductive conditioning in mice. We sought to determine whether T(reg) treatment combined with vascularized BMT (VBMT) could create mixed chimerism and induce tolerance to vascularized composite allografts (VCAs) without cytoreductive conditioning in rats. METHODS: Recipient Lewis rats treated (day 0) with or without naturally sorted T(reg) (3 * 10(6)) from Lewis rat spleen and lymph nodes received costimulation blockade (anti-CD154 monoclonal antibody, days 0 and 1 and CTLA-4 immunoglobin, days 2, 4, and 6), rapamycin (days -1, 0, and 2), and concurrent transplantation of fully mismatched allogeneic donor VCAs (day 0) from the Brown Norway rat hindlimb containing VBMT. The mixed chimerism level was assessed monthly using flow cytometry. Survival of VCAs and occurrence of graft-versus host disease were assessed clinically and histologically. RESULTS: The combination of T(reg) and VBMT treatment led to long-term multilineage hematopoietic mixed chimerism (12-18%) and long-term donor-specific tolerance to VCAs (89% acceptance rate). Neither stable mixed chimerism nor VCA acceptance was observed in recipients without T(reg) treatment. Graft-versus-host disease did not occur in the VBMT recipients. CONCLUSIONS: Cotreatment with T(reg) and VBMT created stable mixed chimerism and induced long-term donor-specific tolerance to VCAs without requiring cytoreductive conditioning. This noncytoreductive T(reg) VBMT protocol has potential for clinical application in VCAs. PMID- 22819315 TI - Severe maternal morbidity due to abortion prospectively identified in a surveillance network in Brazil. AB - OBJECTIVE: To evaluate the occurrence of severe maternal complications associated with abortion in Brazil. METHODS: In a cross-sectional multicenter study, prospective surveillance was done for cases of potentially life-threatening conditions (PLTC), maternal near miss (MNM), and maternal death (MD) among 9555 women with obstetric complications between June 2009 and May 2010. Abortion was evaluated as a cause, and sociodemographic and obstetric characteristics, safety conditions where the abortion was performed, and the medical procedures used were also assessed. Prevalence ratios adjusted for the cluster effect of the design were calculated with 95% confidence intervals. Multiple logistic regression analysis was performed to identify factors independently associated with greater severity. RESULTS: For 237 women (2.5%), abortion resulted in severe complications including PLTC (81.9%), MNM (15.2%), and MD (3%). When abortion was unsafe, infectious causes were more common for PLTC, whereas management criteria were more important for MNM and MD. In multivariate analysis, the presence of previous maternal conditions (sickle cell disease, low weight, neoplasm), being transferred or referred, previous uterine scar, and delays were associated with greater severity. CONCLUSION: Abortion was responsible for only a small percentage of the complications associated with pregnancy; however, the risk of abortion-related complications progressing unfavorably was higher. PMID- 22819317 TI - Knowledge of infective endocarditis and prophylaxis among Spanish dentists. PMID- 22819316 TI - Missed opportunities for prevention of mother-to-child transmission of HIV-1 in the NISDI Perinatal and LILAC cohorts. AB - OBJECTIVE: To evaluate cases of mother-to-child transmission of HIV-1 at multiple sites in Latin America and the Caribbean in terms of missed opportunities for prevention. METHODS: Pregnant women infected with HIV-1 were eligible for inclusion if they were enrolled in either the NISDI Perinatal or LILAC protocols by October 20, 2009, and had delivered a live infant with known HIV-1 infection status after March 1, 2006. RESULTS: Of 711 eligible mothers, 10 delivered infants infected with HIV-1. The transmission rate was 1.4% (95% CI, 0.7-2.6). Timing of transmission was in utero or intrapartum (n=5), intrapartum (n=2), intrapartum or early postnatal (n=1), and unknown (n=2). Possible missed opportunities for prevention included poor control of maternal viral load during pregnancy; late initiation of antiretrovirals during pregnancy; lack of cesarean delivery before labor and before rupture of membranes; late diagnosis of HIV-1 infection; lack of intrapartum antiretrovirals; and incomplete avoidance of breastfeeding. CONCLUSION: Early knowledge of HIV-1 infection status (ideally before or in early pregnancy) would aid timely initiation of antiretroviral treatment and strategies designed to prevent mother-to-child transmission. Use of antiretrovirals must be appropriately monitored in terms of adherence and drug resistance. If feasible, breastfeeding should be completely avoided. Presented in part at the XIX International AIDS Conference (Washington, DC; July 22-27, 2012); abstract WEPE163. PMID- 22819318 TI - The prognostic value of catastrophizing for predicting the clinical evolution of low back pain patients: a study in routine clinical practice within the Spanish National Health Service. AB - BACKGROUND CONTEXT: Experimental studies suggest that catastrophizing may worsen the prognosis of low back pain (LBP) and LBP-related disability and increase the risk of chronicity. PURPOSE: To assess the prognostic value of baseline catastrophizing for predicting the clinical evolution of LBP patients in routine clinical practice and the association between the evolution of pain and catastrophizing. STUDY DESIGN/SETTING: Prospective study in routine clinical practice of the Spanish National Health Service. PATIENT SAMPLE: One thousand four hundred twenty-two acute and chronic adult LBP patients treated in primary and hospital care. OUTCOME MEASURES: Pain, disability, and catastrophizing measured through validated instruments. METHODS: Patients were managed according to routine clinical practice. Outcome measures were assessed at baseline and 3 months later. Logistic regression models were developed to estimate the association between baseline catastrophizing score and the improvement of LBP and disability, adjusting for baseline LBP and leg pain (LP) severity, disability, duration of the pain episode, workers' compensation coverage, radiological findings, failed back surgery, and diagnostic procedures and treatments undertaken throughout the study. Another model was developed to estimate the association between the evolution of LBP and the change in catastrophizing, adjusting for the same possible confounders plus the evolution of LP and disability. Models were repeated excluding the treatments undergone after the baseline assessment. RESULTS: Regression models showed that the degree of baseline catastrophizing does not predict the evolution of LBP and disability. Conversely, as the degree of pain improvement increases, so does the odds ratio for improvement in catastrophizing, ranging from three (95% confidence interval [95% CI], 2.00-4.50; p<.001) for improvements in pain between 1.1 and 4 visual analog scale (VAS) points, to 7.3 (95% CI, 3.49-15.36; p<.001) for improvements in pain more than 6.1 VAS points. Similar results were obtained when treatments were excluded from the models. CONCLUSIONS: In routine practice, assessing the baseline score for catastrophizing does not help clinicians to predict the evolution of LBP and disability at 3 months. PMID- 22819319 TI - Interleukin-33 acts as a pro-inflammatory cytokine and modulates its receptor gene expression in highly metastatic human pancreatic carcinoma cells. AB - Human pancreatic cancer is one of the most fatal of all solid tissue malignancies. Pancreatic inflammation plays a key role in the development of pancreatic malignancy mediated by pro-inflammatory signalling cascades. Despite advances in surgery and radiation oncology, no significant improvements in overall survival have yet been achieved. Recent investigations suggest a crucial role of interleukin-33 (IL-33), a novel IL-1 family cytokine, in the pathogenesis of chronic pancreatitis and possibly pancreatic cancer. However, the precise role of IL-33 in pancreatic carcinogenesis is poorly understood. As IL-33 mediates its effects via the heterodimeric ST2L/IL-1 receptor accessory protein (IL-1RAcP) receptor complex, we investigated the influence of IL-33 alone, IL-33 combined with IL-1 and other inflammatory cytokines on IL-33 receptor/ligand mRNA expression and production of tumorigenic factors in the highly metastatic human pancreatic adenocarcinoma cell line Colo357. Our results demonstrated that IL-1 and IL-3 up-regulated IL-33 mRNA while IL-12 showed the opposite effect. We also detected a counter-regulatory effect of IL-33 and IL-1 on the mRNA expression of soluble IL-33 receptor ST2 and membrane-bound receptor ST2L. Furthermore, IL-33 and IL-1 acted synergistically in up-regulating secretion of pro-inflammatory IL 6. IL-33 alone stimulated spontaneous release of pro-angiogenic IL-8, but it did not affect IL-1-induced IL-8 secretion. IL-33/IL-1 effects on cytokine production appear to be mediated via NF-kappaB activation. These data argue for the pro inflammatory role of IL-33 in Colo357 cells implying that IL-33 might act as a crucial mediator in inflammation-associated pancreatic carcinogenesis. PMID- 22819320 TI - Fasciola hepatica products induce apoptosis of peritoneal macrophages. AB - Immunomodulatory properties have been described for Fasciola hepatica excretory secretory products (FhESP), with their interaction with the innate immune cells being crucial during the early stages of infection. Previously, we demonstrated that FhESP induce eosinophil apoptosis. In this work, the ability of FhESP to induce apoptosis of peritoneal macrophages was evaluated. These parasite products were observed to induce apoptosis in peritoneal macrophages stimulated in vitro with FhESP, as well as in cells recovered from infected mice. The ability of FhESP to modify the viability of macrophages by apoptosis induction may constitute a crucial event for extending its survival in the host. PMID- 22819321 TI - Internet-based tools to assess diet and provide feedback in chronic kidney disease stage IV: a pilot study. AB - BACKGROUND: Successfully changing patients' dietary behavior is a challenging problem in the management of chronic kidney disease (CKD). We conducted a pilot study to test the feasibility and acceptability of an Internet-based, self administered, dietary assessment tool equipped with instructional feedback, aimed at facilitating dietary adherence to disease-specific nutritional guidelines among CKD stage IV patients while reducing resource burdens on providers. METHODS: Focus groups were used to develop a user-friendly dietary reporting format. The report was then calibrated to the dietary guidelines outlined by Kidney Disease Outcomes Quality Initiative (K/DOQI) and incorporated into the assessment tool. Elements of the report were developed based on the "transtheoretical model of behavior change" theory, aimed at facilitating patients to enter the action stage of change. The tool was later deployed in a nephrology care site at an academic medical center, where 12 patients diagnosed with stage IV CKD (late-stage, predialysis) completed a dietary assessment before their provider encounter as well as questionnaires gauging their computer literacy, nutritional education history, nutritional knowledge and awareness, and acceptability of the tool. The report was made available to the provider during the clinical encounter, and both patient and physician perception of the report's utility was assessed after the encounter. RESULTS: Approximately 25% to 30% of the patients were severely noncompliant to the K/DOQI guidelines for each nutrient. Awareness about the role of diet in CKD management was widely variable, ranging from 0% to 58% of the patients over different nutrients. All of the patients successfully completed the Web-based dietary assessment. Eighty-four percent of the patients positively rated the tool on its ability to record the patients' dietary data, 58% noted the tool was always able to satisfactorily estimate portion sizes, and 50% thought the navigation was easy or very easy. Eleven of the 12 patients were satisfied with the time taken (range: 10 to 40 minutes, median time: 20 minutes) to complete the dietary assessment. Patients and physicians differed considerably in their perception of the use of the report during the clinical encounter. CONCLUSION: Dietary knowledge and adherence to K/DOQI guidelines among CKD patients is suboptimal. However, interest and motivation is high. Web-based tools are well accepted among CKD patients as an aid to assessing dietary adherence to K/DOQI guidelines and may pose a cost effective approach to bridging the adherence gap. PMID- 22819322 TI - Promoters recognized by forkhead proteins exist for individual 21U-RNAs. AB - C. elegans 21U-RNAs are equivalent to the piRNAs discovered in other metazoans and have important roles in gametogenesis and transposon control. The biogenesis and molecular function of 21U-RNAs and piRNAs are poorly understood. Here, we demonstrate that transcription of each 21U-RNA is regulated separately through a conserved upstream DNA motif. We use genomic analysis to show that this motif is associated with low nucleosome occupancy, a characteristic of many promoters that drive expression of protein-coding genes, and that RNA polymerase II is localized to this nucleosome-depleted region. We establish that the most conserved 8-mer sequence in the upstream region of 21U-RNAs, CTGTTTCA, is absolutely required for their individual expression. Furthermore, we demonstrate that the 8-mer is specifically recognized by Forkhead family (FKH) transcription factors and that 21U-RNA expression is diminished in several FKH mutants. Our results suggest that thousands of small noncoding transcription units are regulated by FKH proteins. PMID- 22819323 TI - Quantitative in vivo redox sensors uncover oxidative stress as an early event in life. AB - Obstacles in elucidating the role of oxidative stress in aging include difficulties in (1) tracking in vivo oxidants, in (2) identifying affected proteins, and in (3) correlating changes in oxidant levels with life span. Here, we used quantitative redox proteomics to determine the onset and the cellular targets of oxidative stress during Caenorhabditis elegans' life span. In parallel, we used genetically encoded sensor proteins to determine peroxide levels in live animals in real time. We discovered that C. elegans encounters significant levels of oxidants as early as during larval development. Oxidant levels drop rapidly as animals mature, and reducing conditions prevail throughout the reproductive age, after which age-accompanied protein oxidation sets in. Long lived daf-2 mutants transition faster to reducing conditions, whereas short-lived daf-16 mutants retain higher oxidant levels throughout their mature life. These results suggest that animals with improved capacity to recover from early oxidative stress have significant advantages later in life. PMID- 22819324 TI - Structural and mechanistic basis for the inhibition of Escherichia coli RNA polymerase by T7 Gp2. AB - The T7 phage-encoded small protein Gp2 is a non-DNA-binding transcription factor that interacts with the jaw domain of the Escherichia coli (Ec) RNA polymerase (RNAp) beta' subunit and inhibits transcriptionally proficient promoter-complex (RPo) formation. Here, we describe the high-resolution solution structure of the Gp2-Ec beta' jaw domain complex and show that Gp2 and DNA compete for binding to the beta' jaw domain. We reveal that efficient inhibition of RPo formation by Gp2 requires the amino-terminal sigma(70) domain region 1.1 (R1.1), and that Gp2 antagonizes the obligatory movement of R1.1 during RPo formation. We demonstrate that Gp2 inhibits RPo formation not just by steric occlusion of the RNAp-DNA interaction but also through long-range antagonistic effects on RNAp-promoter interactions around the RNAp active center that likely occur due to repositioning of R1.1 by Gp2. The inhibition of Ec RNAp by Gp2 thus defines a previously uncharacterized mechanism by which bacterial transcription is regulated by a viral factor. PMID- 22819325 TI - Monitoring spatiotemporal biogenesis of macromolecular assemblies by pulse-chase epitope labeling. AB - Many cellular proteins perform their roles within macromolecular assemblies. Hence, an understanding of how these multiprotein complexes form is a fundamental question in cell biology. We developed a translation-controlled pulse-chase system that allows time-resolved isolation of newly forming multiprotein complexes in chemical quantities suitable for biochemical and cell biological analysis. The "pulse" is triggered by an unnatural amino acid, which induces immediate translation of an amber stop codon repressed mRNA encoding the protein of interest with a built-in tag for detection and purification. The "chase" is elicited by stopping translation of this bait via a riboswitch in the respective mRNA. Over the course of validating our method, we discovered a distinct time resolved assembly step during NPC biogenesis and could directly monitor the spatiotemporal maturation of preribosomes via immunofluorescence detection and purification of a pulse-labeled ribosomal protein. Thus, we provide an innovative strategy to study dynamic protein assembly within cellular networks. PMID- 22819326 TI - Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. AB - Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance. PMID- 22819328 TI - Clearance of the retropancreatic margin in pancreatic carcinomas: total mesopancreas excision or extended lymphadenectomy? PMID- 22819327 TI - Fluorescence-based sensors to monitor localization and functions of linear and K63-linked ubiquitin chains in cells. AB - Ubiquitin chains modify a major subset of the proteome, but detection of ubiquitin signaling dynamics and localization is limited due to a lack of appropriate tools. Here, we employ ubiquitin-binding domain (UBD)-based fluorescent sensors to monitor linear and K63-linked chains in vitro and in vivo. We utilize the UBD in NEMO and ABIN (UBAN) for detection of linear chains, and RAP80 ubiquitin-interacting motif (UIM) and TAB2 Npl4 zinc finger (NZF) domains to detect K63 chains. Linear and K63 sensors decorated the ubiquitin coat surrounding cytosolic Salmonella during bacterial autophagy, whereas K63 sensors selectively monitored Parkin-induced mitophagy and DNA damage responses in fixed and living cells. In addition, linear and K63 sensors could be used to monitor endogenous signaling pathways, as demonstrated by their ability to differentially interfere with TNF- and IL-1-induced NF-kappaB pathway. We propose that UBD-based biosensors could serve as prototypes to track and trace other chain types and ubiquitin-like signals in vivo. PMID- 22819329 TI - Genetic variations in interleukin-12 related genes in immune-mediated diseases. AB - The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease. PMID- 22819330 TI - Sonochemiluminescence observation of lipid- and polymer-shelled ultrasound contrast agents in 1.2 MHz focused ultrasound field. AB - Ultrasound contrast agents (UCAs) are frequently added into the focused ultrasound field as cavitation nuclei to enhance the therapeutic efficiency. Since their presence will distort the pressure field and make the process unpredictable, comprehension of their behaviors especially the active zone spatial distribution is an important part of better monitoring and using of UCAs. As shell materials can strongly alter the acoustic behavior of UCAs, two different shells coated UCAs, lipid-shelled and polymer-shelled UCAs, in a 1.2 MHz focused ultrasound field were studied by the Sonochemiluminescence (SCL) method and compared. The SCL spatial distribution of lipid-shelled group differed from that of polymer-shelled group. The shell material and the character of focused ultrasound field work together to the SCL distribution, causing the lipid shelled group to have a maximum SCL intensity in pre-focal region at lower input power than that of polymer-shelled group, and a brighter SCL intensity in post focal region at high input power. The SCL inactive area of these two groups both increased with the input power. The general behavior of the UCAs can be studied by both the average SCL intensity and the backscatter signals. As polymer-shelled UCAs are more resistant to acoustic pressure, they had a higher destruction power and showed less reactivation than lipid-shelled ones. PMID- 22819331 TI - Oromandibular and limb hypogenesis syndrome: treatment report. AB - The oromandibular and limb hypogenesis syndrome is characterized by aglossia or hypoglossia presenting with limb anomalies. In this case report, we describe congenital hypoglossia associated with glossopalatine ankylosis and middle finger hypomelia, a type III-D malformation in the Hall Classification. The orthodontic and surgical treatment consisted of 3 maxillary expansions, mandibular surgery, and dental alignment. This extensive treatment resulted in acceptable function and esthetic appearance; however, because of lingual hypoglossia, it did not effect perfect occlusion. PMID- 22819333 TI - A hypothesis on the desired postoperative position of the condyle in orthognathic surgery: a review. AB - It is very important to clarify the relationship between a dentofacial structure and a temporomandibular joint (TMJ) structure in orthognathic surgery. Recently, it was reported that the skeletal and occlusal patterns were associated with the TMJ morphology, including the disk position. In orthognathic surgery, some surgeons state that alterations in the condylar position from surgery can lead to malocclusion associated with the risk of early relapse, and also favor the development of temporomandibular disorders. For these reasons, several positioning devices have been proposed and applied, but now there is no scientific evidence to support the use of condylar positioning devices. There are some reasons why scientific evidence cannot be obtained; however, it also includes the question of whether the preoperative position of the condyle is the desired postoperative position. The purpose of this study was to verify the desired condylar position in orthognathic surgery, based on literature on the postoperative condylar position in orthognathic surgery. From the studies reviewed, it was suggested that the preoperative position of the condyle was not the desired postoperative position in orthognathic surgery. PMID- 22819332 TI - Flapless implant surgery: a 2-year follow-up study of 40 implants. AB - OBJECTIVES: Flapless implant surgery is fast gaining popularity because of several advantages, such as reduced surgical time, postoperative bleeding, and swelling. Studies have shown that flap elevation results in some amount of bone loss. The aim of the current study was to compare the amount of bone loss in procedures using the flapless technique and those where flap elevation was done. Papillary fill was also compared in both techniques, which is unique to this study. STUDY DESIGN: Forty patients, selected according to certain inclusion and exclusion criteria, were randomly assigned to 1 of 2 groups: Flap (F), or Flapless (FL). The amount of crestal bone loss was measured from standardized radiographs at baseline, 6 months, 1 year, and 2 years after implant placement. Papillary fill was evaluated using the Papillary presence index, which was measured 6 months after loading. RESULTS: The bone loss was greater for the F group during all time periods and the mean papillary fill was greater for the FL group. CONCLUSIONS: In conclusion, the results of the current study show that flapless implant surgery results in less crestal bone loss both during the healing period and after loading. In addition, it can produce better papillary fill. The cases selected for this study were ideal cases in terms of bone volume and the operator was well experienced, however. Care should be taken during case selection for flapless implant surgery. PMID- 22819334 TI - Enhancement of bone formation by genetically engineered human umbilical cord derived mesenchymal stem cells expressing osterix. AB - OBJECTIVES: The aim of this study was to investigate if overexpression of osterix (Osx) in human umbilical cord-derived mesenchymal stem cells (UC-MSCs) would facilitate osteogenic differentiation in bone regeneration. STUDY DESIGN: UC-MSCs were isolated from UCs. A pEGFP-Osx plasmid was constructed and applied to transfect UC-MSCs. Cell proliferation, alkaline phosphatase (ALP) activity, and expression of bone-related genes were examined to evaluate the osteogenic potential of UC-MSCs. Bone regeneration in vivo was evaluated in nude mice using PLGA as a carrier. RESULTS: Reverse-transcription polymerase chain reaction showed that pEGFP-Osx transfection enhanced expression of bone matrix proteins. Overexpression of Osx in UC-MSCs enhanced ALP activity, while not inhibited their proliferation rate. The Osx-transduced group formed significantly more bone at 4 weeks. CONCLUSIONS: Concerning their simple isolation and proliferation, it is believed that genetically engineered UC-MSCs could play important roles in the study and application of bone tissue engineering. PMID- 22819335 TI - Late skip lymph node metastasis of oral squamous cell carcinoma or metastasis of unknown second primary tumor? Answer by mitochondrial DNA analysis. AB - Patients with head and neck squamous cell carcinoma (SCC) are at risk of developing additional tumors in the head and neck. The detection of a late lymph node metastasis poses a problem to the clinician: it could be a delayed regional metastasis or a new metastasis from a yet unknown second primary tumor. Differentiation between metastasis and recurrence of primary tumors versus second primary tumor may be difficult because all lesions have the histologic appearance of SCC. Differentiation between these possibilities, however, carries important differences in therapeutic and prognostic consequences. In the following case report we present an unusually late regional lymph node metastasis in a patient who was treated 4 years earlier for an SCC in the inferior alveolar ridge. The purpose of the present study was to apply mitochondrial DNA D-loop analysis to assess the clonal relationship between oral tumor and node metastasis. PMID- 22819336 TI - [Acute bacterial meningitis caused by Streptococcus pyogenes]. PMID- 22819337 TI - A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) cleaves Reelin in an isoform-dependent manner. AB - Reelin is a glycoprotein essential for brain development and functions. Reelin is subject to specific proteolysis at two distinct (N-t and C-t) sites, and these cleavages significantly diminish Reelin activity. The decrease of Reelin activity is detrimental for brain function, but the protease that catalyzes specific cleavage of Reelin remains elusive. Here we found that a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) cleaves Reelin in an isoform-specific manner. Among ADAMTS-4 isoforms, p50 cleaves the N-t site only, while p75 cleaves both sites. This is the first report identifying a protease that can specifically cleave Reelin. PMID- 22819338 TI - A Rho GTPase signal treadmill backs a contractile array. AB - VIDEO ABSTRACT: Contractile arrays of actin filaments (F-actin) and myosin-2 power diverse biological processes. Contractile array formation is stimulated by the Rho GTPases Rho and Cdc42; after assembly, array movement is thought to result from contraction itself. Contractile array movement and GTPase activity were analyzed during cellular wound repair, in which arrays close in association with zones of Rho and Cdc42 activity. Remarkably, contraction suppression prevents translocation of F-actin and myosin-2 without preventing array or zone closure. Closure is driven by an underlying "signal treadmill" in which the GTPases are preferentially activated at the leading edges and preferentially lost from the trailing edges of their zones. Treadmill organization requires myosin-2 powered contraction and F-actin turnover. Thus, directional gradients in Rho GTPase turnover impart directional information to contractile arrays, and proper functioning of these gradients is dependent on both contraction and F-actin turnover. PMID- 22819340 TI - [Management of motility disorders secondary to iatrogenic orbital fracture during endoscopic sinus surgery]. AB - PURPOSE: Orbital wall fracture may occur during endoscopic sinus surgery, resulting in oculomotor disorders. We report the management of four cases presenting with this surgical complication. METHODS: A non-comparative observational retrospective study was carried out on four patients presenting with diplopia after endoscopic ethmoidal sinus surgery. All patients underwent full ophthalmologic and orthoptic examination as well as orbital imaging. RESULTS: All four patients presented with diplopia secondary to a medial rectus lesion confirmed by orbital imaging. A large horizontal deviation as well as limitation of adduction was present in all cases. Surgical management consisted of conventional recession-resection procedures in three cases and muscle transposition in one patient. A useful field of binocular single vision was restored in two of the four patients. CONCLUSION: Orbital injury may occur during endoscopic sinus surgery and cause diplopia, usually secondary to medial rectus involvement due to the proximity of this muscle to the lamina papyracea of the ethmoid bone. Surgical management is based on orbital imaging, duration of the lesion, evaluation of anterior segment vasculature, results of forced duction testing and intraoperative findings. In most cases, treatment is aimed at the symptoms rather than the cause, and the functional prognosis remains guarded. PMID- 22819339 TI - Sox2+ stem cells contribute to all epithelial lineages of the tooth via Sfrp5+ progenitors. AB - The continuously growing mouse incisor serves as a valuable model to study stem cell regulation during organ renewal. Epithelial stem cells are localized in the proximal end of the incisor in the labial cervical loop. Here, we show that the transcription factor Sox2 is a specific marker for these stem cells. Sox2+ cells became restricted to the labial cervical loop during tooth morphogenesis, and they contributed to the renewal of enamel-producing ameloblasts as well as all other epithelial cell lineages of the tooth. The early progeny of Sox2-positive stem cells transiently expressed the Wnt inhibitor Sfrp5. Sox2 expression was regulated by the tooth initiation marker FGF8 and specific miRNAs, suggesting a fine-tuning to maintain homeostasis of the dental epithelium. The identification of Sox2 as a marker for the dental epithelial stem cells will facilitate further studies on their lineage segregation and differentiation during tooth renewal. PMID- 22819341 TI - [Spectral domain OCT in eyes with retinal artery occlusion]. AB - INTRODUCTION: Retinal artery occlusions are a straightforward, essentially clinical diagnosis. The role of spectral domain ocular coherence tomography (SD OCT) in this condition is not well described. PURPOSE: Anoxic retinal edema develops in the acute phase of retinal artery occlusion (RAO) followed by a regressive phase giving way to retinal atrophy. The purpose of the study was to determine dynamics of theses retinal changes in central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO) using spectral domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: A prospective study of patients hospitalized at Hopital Edouard-Herriot de Lyon between June and September 2009 was performed after patient education and informed consent. Retinal thickness of patients with central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO) or cilio-retinal artery occlusion was measured centered on the macula or on the site of occlusion with spectral domain optical coherence tomography (SD-OCT) using Cirrus((r)) (Carl Zeiss Meditec, Germany) upon admission, throughout hospitalization, at 1 month and at 3 months. Thickness and reflectivity of the various retinal layers were compared with the fellow eye. RESULTS: Fourteen patients were included (seven CRAO, six BRAO and one cilio-retinal artery occlusion). SD-OCT in the acute phase showed retinal thickening and increased reflectivity confined to the inner retinal layers supplied by the retinal circulation with decreased reflectivity from the photoreceptor and retinal pigment epithelial layers secondary to a shadowing effect in the affected area. These changes subsequently resolved at 1 month and gave way to a marked thinning of the inner retinal layers by 3 months. In one case of CRAO associated with an ophthalmic artery occlusion and consequent occlusion of the ciliary circulation as well, initial OCT revealed complete retinal thickening involving both the inner and outer layers. DISCUSSION: This study demonstrates that the anoxic intracellular edema resulting from retinal artery occlusions (RAO) observed histologically appears on OCT as a thickening of the inner retinal layers in the acute stage of the condition, giving way to atrophic areas starting at approximately 1 month ("pseudonormalization") and becoming clearly atrophic at 3 months. CONCLUSION: SD-OCT is useful in the diagnosis of RAO, especially if the patient is seen later in the disease process, when the ischemic retinal whitening is no longer present on fundus exam. PMID- 22819343 TI - A multi-country perspective on nurses' tasks below their skill level: reports from domestically trained nurses and foreign trained nurses from developing countries. AB - BACKGROUND: Several studies have concluded that the use of nurses' time and energy is often not optimized. Given widespread migration of nurses from developing to developed countries, it is important for human resource planning to know whether nursing education in developing countries is associated with more exaggerated patterns of inefficiency. OBJECTIVES: First, to describe nurses' reports on tasks below their skill level. Second, to examine the association between nurses' migratory status (domestically trained nurse or foreign trained nurse from a developing country) and reports on these tasks. DESIGN: The Registered Nurse Forecasting Study used a cross-sectional quantitative research design to gather data from 33,731 nurses (62% response rate) in 486 hospitals in Belgium, England, Finland, Germany, Greece, Ireland, the Netherlands, Norway, Poland, Spain, Sweden and Switzerland. METHODS: For this analysis, nurse-reported information on migratory status and tasks below their skill level performed during their last shift was used. Random effects models estimated the effect of nurses' migratory status on reports of these tasks. RESULTS: 832 nurses were trained in a developing country (2.5% of total sample). Across countries, a high proportion of both domestically trained and foreign trained nurses from developing countries reported having performed tasks below their skill level during their last shift. After adjusting for nurses' type of last shift worked, years of experience, and level of education, there remained a pronounced overall effect of being a foreign trained nurse from a developing country and an increase in reports of tasks below skill level performed during the last shift. CONCLUSION: The findings suggest that there remains much room for improvement to optimize the use of nurses' time and energy. Special attention should be given to raising the professional level of practice of foreign trained nurses from developing countries. Further research is needed to understand the influence of professional practice standards, skill levels of foreign trained nurses from developing countries and values attached to these tasks resulting from previous work experiences in their home countries. This will allow us to better understand the conditions under which foreign trained nurses from developing countries can optimally contribute to professional nursing practice in developed country contexts. PMID- 22819342 TI - Genetic prediction of common diseases. Still no help for the clinical diabetologist! AB - Genome-wide association studies (GWAS) have identified several loci associated with many common, multifactorial diseases which have been recently used to market genetic testing directly to the consumers. We here addressed the clinical utility of such GWAS-derived genetic information in predicting type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in diabetic patients. In addition, the development of new statistical approaches, novel technologies of genome sequencing and ethical, legal and social aspects related to genetic testing have been also addressed. Available data clearly show that, similarly to what reported for most common diseases, genetic testing offered today by commercial companies cannot be used as predicting tools for T2DM and CAD. Further studies taking into account the complex interaction between genes as well as between genetic and non genetic factors, including age, obesity and glycemic control which seem to modify genetic effects on the risk of T2DM and CAD, might mitigate such negative conclusions. Also, addressing the role of relatively rare variants by next generation sequencing may help identify novel and strong genetic markers with an important role in genetic prediction. Finally, statistical tools concentrated on reclassifying patients might be a useful application of genetic information for predicting many common diseases. By now, prediction of such diseases, including those of interest for the clinical diabetologist, have to be pursued by using traditional clinical markers which perform well and are not costly. PMID- 22819344 TI - Finite element analysis of the deformation of deep veins in the lower limb under external compression. AB - Compression devices applied to the lower limb can help improve venous flow by deforming the muscles and veins. In this study, a two-dimensional finite element model using displacement boundary conditions was employed to simulate the deformations of deep veins in the calf under external compression. Magnetic resonance (MR) scans were performed on four healthy volunteers with and without compression stockings. The displacement boundary condition was extracted from the corresponding deformed (with stocking) and undeformed (without stocking) MR images by using a non-rigid image registration procedure. In the finite element model, soft tissues of the calf were simplified as a homogenous material with hyperelastic properties. The effective bulk modulus of the material was evaluated at a chosen transverse section for each subject, which was also applied to three other locations at 2mm, 6mm and 10mm below the original section. Comparison between the simulation and measurement showed good agreement in area reduction of deep veins (discrepancy=8.7+/-6.4%), especially for sections close to the chosen location where the effective bulk modulus was evaluated. Beyond a certain distance, the discrepancies increased and became quite variable. The reason for this is that the architecture and stiffness of the calf tissues vary along the leg. The results also showed considerable variation in effective bulk modulus among the four subjects examined. PMID- 22819345 TI - [The efficacy and toxicity of gemcitabine and cisplatin chemotherapy in advanced/metastatic bladder urothelial carcinoma]. AB - OBJECTIVE: Many new agents have been introduced as an alternative to standard MVAC therapy with improved efficacy and lower toxicity profile in advanced bladder carcinoma. The aim of this study is to evaluate the response rate and toxic side effects of gemcitabine-cisplatin (GC) in patients with advanced/metastatic bladder carcinoma. METHODS: Between January 2001 and April 2006, 58 patients with histologically confirmed advanced/metastatic transitional cell carcinoma (TCC) were enrolled in the study. All patients received 1,000 mg/m(2) gemcitabine administered via intravenous infusion of 30-60 minutes on days 1, 8 and 15, and 70 mg/m(2) cisplatin as an infusion of 60-min on day 2. All toxicities were graded using the WHO scale and the National Cancer Institute scale. RESULTS: The average number of cycles was 4.1. Neutropenia and thrombocytopenia were clinically significant treatment-related side-effects. Hematologic toxicity included mainly grade 3-4 neutropenia in 56%, grade 3-4 thrombocytopenia in 59%, and grade 3- 4 anemia in 33% of patients. There was only one death from neutropenic sepsis. Complete response and partial response were obtained in 13 (22.4%) and 17 (29.3%) of patients, respectively, 17 (29.3%) of patients were found to have stable disease, and progression was observed in 11 patients (18.9%). Median survival for the whole group was 14.7 months (2-67). CONCLUSIONS: GC therapy is an effective regimen owing to its high tumor response and long survival with a low incidence of toxicity in advanced or metastatic patients. PMID- 22819346 TI - [Evaluating the role of computerized tomography triphasic urography in patients with painless haematuria: a practical view]. PMID- 22819347 TI - [Solitary fibrous tumor of the renal hilum: a rare a diagnosis for a not so rare clinical picture]. PMID- 22819348 TI - [Prevalence of co-morbidities in patients with erectile dysfunction]. AB - INTRODUCTION: Erectile dysfunction (ED) is a multifactorial process which requires an integral approach. It is also a sentinel symptom of endothelial dysfunction that opens a door to the overall health of a man. OBJECTIVES: To analyze the prevalence of cardiovascular risk factors and other disorders in patients with ED. The relationship between the severity of ED and the total serum testosterone level and the therapeutic approach of doctors were also analyzed. MATERIAL AND METHODS: An observational, multicenter, national study in patients > 18 years who came to uroandrology or primary care consultations. Sociodemographic, anthropometric, lifestyle habits and medical history data of patients and the physician's therapeutic approach, were all collected. ED was diagnosed and total testosterone was assessed when necessary. RESULTS: 1340 patients aged from 22-81 years took part in the study. Age was the most prevalent factor to develop the condition. Abdominal obesity, diabetes, and smoking had a high prevalence. Half of the patients presented psychological and/or sexual problems. 33% and 13.5% of patients had suboptimal levels of total testosterone (cut-off point of 12 nmol/l and 8 nmol/l, respectively), with a direct relationship with disease severity. CONCLUSION: Our study supports the need to examine cardiovascular risk factors in patients with ED and to identify patients who might benefit from testosterone replacement therapy. Psychological disorders should receive specialized care. PMID- 22819350 TI - [Agreed on medical reports in prostate cancer. APInfo-Cap project]. PMID- 22819349 TI - [Simplified renorrhaphy using self-retaining barbed suture during laparoscopic partial nephrectomy]. AB - INTRODUCTION AND OBJECTIVES: Laparoscopic partial nephrectomy (LPN) is a challenging procedure that requires quick and effective intracorporeal suturing, that could limit widespread adoption. Refinements of surgery have improved warm ischemia times and facilitated renal reconstruction. We present a technique that makes renorrhaphy easier using Self-Retaining Barbed Suture (SRBS) weaving two threads. PATIENTS AND METHODS: Two patients with carcinoma of the kidney, 3.4 and 1.5 cm respectively, were subjected to the LPN. The SRBS is an absorbable polygluconate with small projections along its axis which are anchored in the tissue, distributing the tension of the suture line and eliminating the need for knots. Renorrhaphy was performed using the SRBS by two continuous suture lines without knots, setting the sutures with clips of Hem-o-lok((r)) and adjusting it with the technique of "sliding clip", without placing "bolsters" inside the renal parenchymal defect. RESULTS: Operative time was 156 minutes and 163 minutes, intraoperative bleeding was 50 ml and 850 ml, the warm ischemia time was 14.3 minutes and 23 minutes and follow-up time was 7 months and 3 months in the first and second cases respectively. The hospital stay was 5 days and there were no postoperative complications. CONCLUSIONS: Simplified renorrhaphy using SRBS is effective, hemostatic, facilitates the renal reconstruction, and can help reduce the warn ischemia time. PMID- 22819351 TI - [Intrarenal smooth muscle: histology of a complex urodymamic machine]. AB - OBJECTIVE: To know better the microscopic arrangement of the bundles of smooth muscle in the human renal parenchyma, their distribution and anatomical relationships, trying to make a reconstruction of this muscular system. METHODS: Five adult human kidneys and one fetal kidney were processed "in toto" with cross sections every 300MUm. In the histological sections we identify the smooth muscle fibers trying to determine its insertion, course and anatomical relationship with other structures of the kidney tissue. RESULTS: There are bundles of smooth muscle fibers of variable thickness parallel to the edges of the medullary pyramids, bundles that surrounding the medulla in a spiral course, and bundles that accompany arcuate vessels, the latter being the most abundant and easy to identify. These groups of muscle fibers do not have a precise or constant insertion site, their periodicity is not homogeneous and they are not a direct extension of the muscle of the renal pelvis, although some bundles are in contact with it. There are also unusual and inconstant small muscle fibers no associated to vessels in the interstitium of the cortex and, exceptionally, in the medulla. CONCLUSION: There is a complex microscopic system of smooth muscle fibers that partially surround the renal medulla and are related to renal pelvic muscles without a direct continuity with them. Although this small muscular system is under-recognized, could be very important in urodynamics. PMID- 22819353 TI - Cutting a long story short: reaction times in acute stroke are associated with longer term cognitive outcomes. AB - BACKGROUND: The viability and usefulness of cognitive assessment in acute stroke have been questioned, with practical challenges arising from the focal nature of neurological deficits as well as heterogeneity in arousal state. We aimed to test whether acute measures of attention correlate with attentional function at 3 months post-stroke. METHODS: Patients with confirmed stroke completed 2 computerised cognitive tasks (CogState) within 2 weeks of stroke. The tasks were a simple reaction time task (Detection) and a choice reaction time task (Identification) that required a button press to visual stimuli (playing cards). Each task took approximately 4 min. The Montreal Cognitive Assessment (MoCA) and an extended neuropsychological battery were administered at 3 months post-stroke. RESULTS: Thirty-three patients (mean age 75.5 years, SD 11.9) participated in this preliminary study. Correlations indicated that both Detection speed (r= 0.73, p<0.001) and Identification speed (r=-0.61, p=0.007) at baseline were associated with attentional function at 3 months, as measured by established neuropsychological tests (Trails-A, Digit span, Digit symbol). In addition, Detection speed at baseline was correlated with total 3-month MoCA score (r= 0.54, p=0.012). CONCLUSION: Simple and brief computerised assessment of attentional function in acute stroke is possible and is related to longer term attentional and cognitive performance. PMID- 22819352 TI - Chronic vascular risk factors (cholesterol, homocysteine, ethanol) impair spatial memory, decline cholinergic neurons and induce blood-brain barrier leakage in rats in vivo. AB - Epidemiological studies show that vascular risk factors (e.g. atherosclerosis, diabetes, homocysteine, hypertension or cholesterol) may play a role in the development of Alzheimer's disease. Animal models may help to discover the role of vascular risk factors on cognition. In the present project we treated male Sprague Dawley rats with a diet containing homocysteine (hyperhomocysteinemia) or cholesterol (hypercholesterolemia) for 5 months or exposed the rats to ethanol (20% in drinking water) or a combination of cholesterol+ethanol (mix) for 12 months. Our experiments show that all 3 treatments (homocysteine, cholesterol, ethanol) declined spatial memory in the 8-arm radial maze, reduced the number of cholinergic neurons and induced blood-brain barrier leakage in the cortex. Rats treated with cholesterol also displayed markedly enhanced inflammation in the cortex. Levels of amyloid precursor protein, beta-amyloid((1-42)), as well as tau and phospho-tau 181 were significantly enhanced in the cortex of cholesterol-fed rats. A combination of ethanol and cholesterol did not further potentiate the effects on spatial memory, cholinergic neurons and blood-brain barrier leakage. The data suggest that chronic mild vascular risk factors over months induce small lesions of the brain capillaries in the cortex, which may contribute to the development of vascular dementia or also Alzheimer's disease. PMID- 22819354 TI - Balancing between autonomy and support: coping strategies by patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) makes a strong psychological impact, and the study of efforts by patients to cope with the course of the disease could be an important first step in the optimisation of care treatment. With this aim, in our study we assessed the coping strategies by a population of ALS patients, according to some clinical parameters and the worsening of the disease. We have administered the MND coping scale to 62 patients, firstly at the admission to our neurorehabilitation unit and secondly after 1year. Each factor score has been related to age and progression of the disease, and comparisons between males and females have also been made. The increasing relevance of seeking support from families and technological devices is probably the most interesting finding: such a result stimulates remarkable considerations about the proper balance between such support and patients' autonomy. As a whole, data confirm the importance of a proper and well-timed psychological intervention for patients and their families. In detail, improving adaptive coping strategies, together with sustaining those which tend to weaken along the progression of the disease, could be an important goal in psychological counselling for both patients and family members. PMID- 22819355 TI - Soluble CD40 as a modulator of CD40 pathway. PMID- 22819356 TI - Eosinophilic pustular folliculitis of infancy: a series of 15 cases and review of the literature. AB - BACKGROUND: Eosinophilic pustular folliculitis (EPF) of infancy is characterized by the presence of pustular lesions containing eosinophils. It is the least well characterized of the EPF diseases. OBJECTIVES: We sought to define the clinical and histopathologic features of the condition. METHODS: We conducted a retrospective review of the clinical data and histologic findings of 15 patients given the diagnosis of EPF of infancy at the Hospital Nino Jesus, Madrid, Spain, from 1995 to 2011, and of patient data published in MEDLINE with such a diagnosis from the disease description (1984-2011). RESULTS: A total of 61 cases were collected. The disease was more common in males than females (ratio 4:1), and presented before 14 months of life in 95% of cases (mean 6.1 months; median 5 months). All patients had recurrent outbreaks and scalp involvement, and 65% had lesions on areas of the body other than the scalp. Tissue eosinophilia was present in all cases; however, true follicular involvement was observed only in 62% of cases in which histologic study was available. More than 80% of the patients were cured by 3 years of age (mean 25.3 months; median 18 months). Topical steroids were effective in 90% of cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: EPF of infancy presents most often in the first 14 months of life and usually resolves by 3 years of age. All patients showed scalp involvement, tissue eosinophilia, and recurrent outbreaks. The condition does not require aggressive treatment, as it is benign and self-limiting. PMID- 22819357 TI - Increased iris-lens contact following spontaneous blinking: mathematical modeling. AB - The purpose of this work was to study in silico how iris root rotation due to spontaneous blinking alters the iris contour. An axisymmetric finite-element model of the anterior segment was developed that included changes in the iris contour and the aqueous humor flow. The model geometry was based on average values of ocular dimensions. Blinking was modeled by rotating the iris root posteriorly and returning it back to the anterior. Simulations with maximum rotations of 2 degrees , 4 degrees , 6 degrees , and 8 degrees were performed. The iris-lens contact distance and the pressure difference between the posterior and anterior chambers were calculated. When the peak iris root rotation was 2 degrees , the maximum iris-lens contact increased gradually from 0.28 to 0.34mm within eight blinks. When the iris root was rotated by 6 degrees and 8 degrees , the pressure difference between the posterior and anterior chambers dropped from a positive value (1.23Pa) to negative values (-0.86 and -1.93Pa) indicating the presence of reverse pupillary block. Apparent iris-lens contact increased with steady blinking, and the increase became more pronounced as posterior rotation increased. We conclude that repeated iris root rotation caused by blinking could maintain the iris in a posterior position under normal circumstances, which would then lead to the clinically observed anterior drift of the iris when blinking is prevented. PMID- 22819358 TI - The important role of inflammatory biomarkers pre and post bare-metal and drug eluting stent implantation. AB - In-stent restenosis and stent thrombosis are major complications after percutaneous coronary intervention and coronary stent placement. The inflammatory status of an individual, as reflected by biomarkers and genetic polymorphisms, is a strong predictor of the risk of in-stent restenosis and stent thrombosis. Identifying biomarkers and studying their values are crucial for a more efficient personalized intervention. General inflammatory biomarkers, evidence of inflammation, and the difference between inflammatory biomarkers after bare-metal stent and drug-eluting stent placement are discussed. Clinical implications and the use of antiplatelet and anti-inflammatory medications, as well as future directions in coronary intervention, in reducing the occurrence of these complications, are also discussed. PMID- 22819359 TI - Neurocirculatory responses to carbohydrates in patients with heart failure and healthy controls: more similar than different. PMID- 22819360 TI - Hemodynamic stability after transitioning between endothelin receptor antagonists in patients with pulmonary arterial hypertension. AB - BACKGROUND: Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients. METHODS: We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data. RESULTS: Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of >=5 mm Hg, and 4 had pulmonary artery wedge pressure increase of >=5 mm Hg. CONCLUSIONS: Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures. PMID- 22819361 TI - Correlations between digit ratio and infertility in Chinese men. AB - BACKGROUND: Digit ratio, especially second to fourth digit ratio (2D:4D) is lower in men than in women. The ratios of digit may be established in utero and is negatively correlated with sperm counts and testosterone in men and positively correlated with estrogen in men and women. AIM: To study whether the digit ratio (especially 2D:4D) are associated with the a+b ratio of sperm number in Chinese populations. METHODS: Photocopies of the two hands of 268 men (controls: 72; patients: 196) and seminal parameters of masturbatory semen samples were collected. RESULTS: The mean values of digit ratio of the controls and the patients all presented a trend as 2D:3D<2D:4D<3D:4D<2D:5D<4D:5D<3D:5D; the patients have higher mean values than controls; significant variances of 2D:3D, 3D:4D (left: P<0.05; right: P <= 0.05) and 2D:4D (left: P<0.001; right: P<0.01) were found between two groups; there was a higher percentage of 2D>4D in the patients; the relationship between 2D:4D and a+b ratio of sperm number in the patients was significant (P<0.001). CONCLUSION: Digit ratio, especially 2D:4D in the left hand maybe one of the important markers of infertility in men for early diagnosis. PMID- 22819363 TI - Contact dermatitis due to methylchloroisothiazolinone/methylisothiazolinone (Kathon CG) as a contaminant in the manufacturing process of a cream. PMID- 22819362 TI - Molecular methods for the detection of Mycoplasma and ureaplasma infections in humans: a paper from the 2011 William Beaumont Hospital Symposium on molecular pathology. AB - Mycoplasma and Ureaplasma species are well-known human pathogens responsible for a broad array of inflammatory conditions involving the respiratory and urogenital tracts of neonates, children, and adults. Greater attention is being given to these organisms in diagnostic microbiology, largely as a result of improved methods for their laboratory detection, made possible by powerful molecular-based techniques that can be used for primary detection in clinical specimens. For slow growing species, such as Mycoplasma pneumoniae and Mycoplasma genitalium, molecular-based detection is the only practical means for rapid microbiological diagnosis. Most molecular-based methods used for detection and characterization of conventional bacteria have been applied to these organisms. A complete genome sequence is available for one or more strains of all of the important human pathogens in the Mycoplasma and Ureaplasma genera. Information gained from genome analyses and improvements in efficiency of DNA sequencing are expected to significantly advance the field of molecular detection and genotyping during the next few years. This review provides a summary and critical review of methods suitable for detection and characterization of mycoplasmas and ureaplasmas of humans, with emphasis on molecular genotypic techniques. PMID- 22819364 TI - A prediction model for N2 disease in T1 non-small cell lung cancer. AB - OBJECTIVE: Controversy remains over the routine use of mediastinoscopy or positron emission tomography in T1 non-small cell lung cancer without lymph node enlargement on computed tomography because the risk of N2 involvement is comparatively low. We aimed to develop a prediction model for N2 disease in cT1N0 non-small cell lung cancer to aid in the decision-making process. METHODS: We reviewed the records of 530 patients with computed tomography-defined T1N0 non small cell lung cancer who underwent surgical resection with systematic lymph node dissection. Correlations between N2 involvement and clinicopathologic parameters were assessed using univariate analysis and binary logistic regression analysis. A prediction model was built on the basis of logistic regression analysis and was internally validated using bootstrapping. RESULTS: The incidence of N2 disease was 16.8%. Four independent predictors were identified in multivariate logistic regression analysis and included in the prediction model: younger age at diagnosis (odds ratio, 0.974; 95% confidence interval, 0.952 0.997), larger tumor size (odds ratio, 2.769; 95% confidence interval, 1.818 4.217), central tumor location (odds ratio, 3.204; 95% confidence interval, 1.512 6.790), and invasive adenocarcinoma histology (odds ratio, 3.537; 95% confidence interval, 1.740-7.191). This model shows good calibration (Hosmer-Lemeshow test: P = .784), reasonable discrimination (area under the receiver operating characteristic curve, 0.726; 95% confidence interval, 0.669-0.784), and minimal overfitting demonstrated by bootstrapping. CONCLUSIONS: We developed a 4 predictor model that can estimate the probability of N2 disease in computed tomography-defined T1N0 non-small cell lung cancer. This prediction model can help to determine the cost-effective use of mediastinal staging procedures. PMID- 22819365 TI - Early and midterm outcomes of quick proximal arch replacement with mild hypothermia and rapid rewarming for type A acute aortic dissection. AB - OBJECTIVE: We assessed the efficacy of our unique procedure with mild hypothermic circulatory arrest and rapid rewarming during emergency surgery for type A acute aortic dissection. METHODS: During the last 6 years, 91 patients with acute aortic dissection and an average age of 66.2 +/- 14.1 years underwent our newly modified quick hemiarch replacement. Eighteen patients (19.8%) had independent predictors for surgical mortality, such as preoperative cardiopulmonary arrest or malperfusion of vital organs. During open distal anastomosis with a rectal temperature of 28 degrees C without any cerebral perfusion, circulating blood in the cardiopulmonary bypass circuit was warmed to 40 degrees C, accompanied by warming of the patient's body using a heating mat. As soon as distal anastomosis was completed, rapid rewarming was initiated by 40 degrees C blood perfusion. RESULTS: Circulatory arrest, cardiopulmonary bypass, and overall operation times were 19.1 +/- 5.1, 86.2 +/- 17.8, and 150.1 +/- 25.2 minutes, respectively. Five patients (5.5%) required reexploration for bleeding, and 4 patients (4.4%) had strokes, but none had acute renal failure. The hospital mortality rate was 3.3% (3 patients), and the postoperative hospital stay was 10.6 +/- 4.7 days. Five patients required replacement of the distal arch or descending aorta at a later stage. Eight patients died during follow-up. A postoperative midterm computed tomography scan revealed a closed distal arch in more than 80% of patients and partial abdominal open false lumen in 45% of patients. Echocardiograms showed mild aortic valve regurgitation in 8 patients. The freedom from reoperation rate at 5 years was 90.0%. Actuarial survival including operative death was 82.7% at 5 years. CONCLUSIONS: Our original technique is a safe and less-invasive procedure that enables a quicker surgery. The midterm outcome also was favorable. PMID- 22819366 TI - Gentamicin collagen sponges for the prevention of sternal wound infection: a meta analysis of randomized controlled trials. AB - OBJECTIVE: The study objective was to determine whether the application of gentamicin collagen sponges reduces sternal wound infections in patients undergoing cardiac surgery. METHODS: A meta-analysis of randomized controlled trials was performed. RESULTS: Four randomized controlled trials were eligible for inclusion. By pooling data from 4 randomized controlled trials (4672 per protocol patients), gentamicin collagen sponges reduced deep sternal wound infections (risk ratio, 0.62; 95% confidence interval, 0.39-0.97) and any sternal wound infections (risk ratio, 0.61; confidence interval, 0.39-0.98). In contrast, no benefit was demonstrated regarding superficial sternal wound infections (4 randomized controlled trials [4672 patients]; risk ratio, 0.65; 95% confidence interval, 0.34-1.25) and all-cause mortality (3 randomized controlled trials [3994 patients]; risk ratio, 0.90; 95% confidence interval, 0.57-1.42). On the basis of data from 2 randomized controlled trials (3410 patients), gentamicin collagen sponges also seemed to reduce surgically treated sternal wound infections (risk ratio, 0.59; 95% confidence interval, 0.41-0.86). The most commonly isolated pathogens were coagulase-negative Staphylococcus spp (43%) and Staphylococcus aureus (28%). CONCLUSIONS: Gentamicin collagen sponges seem to reduce the sternal wound infection rate in patients undergoing cardiac surgery. The statistical heterogeneity among the existing trials underlines the need for additional large, high-quality randomized controlled trials. PMID- 22819367 TI - Pneumatic nebulization gas-solid extraction of some pesticides in liquor. AB - In general, solid phase extraction (SPE) was applied to the separation and concentration of analytes from liquid samples. However, the SPE generally cannot be applied directly to the separation and concentration of analytes from liquor in which the concentration of ethanol is high, because the ethanol can elute the analytes from the SPE column and the analytes can hardly been adsorbed onto the column. In the work, the pneumatic nebulization coupled with gas-solid extraction (PN-GSE) was applied to the extraction of several pesticides, including fenuron, chlortoluron, karmex, linuron and prebane, from liquor samples. The high concentration of ethanol in the liquor samples cannot elute the analytes from the SPE column. The high performance liquid chromatography was applied to the separation and determination of the analytes. Experimental parameters affecting the performances of PN-GSE, such as types and amount of packed material of the column, temperature of the spray chamber, flow rate of carrier gas, pumping rate of gas and volume of elution solvent were examined and optimized. The limits of detection for the analytes were in the range of 0.19-0.26 MUg L-1. Liquor samples were analyzed and the recoveries of the analytes in spiked samples were from 91.0 to 106.3%. The relative standard deviations were lower than 6.5%. PMID- 22819368 TI - Determination of 20 coccidiostats in egg and avian muscle tissue using ultra high performance liquid chromatography-tandem mass spectrometry. AB - A quantitative, comprehensive multiresidue method which includes 20 coccidiostat residues has been developed. The method described uses a simple one-step liquid extraction with acetonitrile to isolate analytes from both the polyether ionophore and chemical classes of coccidiostats. Subsequent to a further concentration step, samples were analysed via UHPLC-MS/MS. The method was validated according to the Commission Decision 2002/657/EEC in egg and avian muscle. The method permitted quantitative confirmation for 13 compounds below target concentrations, and screening for a further 7 compounds. Within-laboratory repeatability gave accuracy values in the range of 68-129%, while reproducibility ranged between 75 and 123%. Calibration ranges were typically 1-50 MUg kg-1, although higher ranges were used for dinitrocarbanilide, imidocarb and toltrazuril residues. A regression coefficient (R2) value of greater than 0.98 was obtained for all analytes. Precision results ranged from 2.3 to 19.7% CV for egg and from 2.6 to 23.6% CV in muscle. CCalpha was in the range from 1.13 MUg kg 1 (clopidol) to 179 MUg kg-1 (lasalocid) in egg. In muscle, CCalpha ranged from 2.25 MUg kg-1 (aprinocid) to 4579 MUg kg-1 (dinitrocarbanilide). CCbeta was from 1.29 MUg kg-1 (clopidol) to 209 MUg kg-1 (lasalocid) in egg, and 2.58 MUg kg-1 (arprinocid) to 6060 MUg kg-1 (dinitrocarbanilide) in muscle. Limits of quantification were 1 MUg kg-1 for all compounds, except imidocarb and dinitrocarbanilide (10 MUg kg-1), and toltrazuril and metabolites (50 MUg kg-1). PMID- 22819369 TI - Study of the interaction polybutadiene/fillers using inverse gas chromatography. AB - In this study, the coupling of IGC-ID analysis and carbon blacks impregnation with increasing ratios of polymer allow us to highlight the affinity of the polymer to the solid surface. The variations of the dispersive component of the surface energy and of the nanomorphology index are monitored versus the degree of carbon black impregnation. A clear correlation between the decrease in the dispersive component of the surface energy and the increase in the nanomorphological index is observed. The PBu macromolecules shield progressively the slot shaped sites on the carbon blacks surface. IGC reveals clear differences in surface properties between CB of different grades. PMID- 22819370 TI - Do obesity-promoting food environments cluster around socially disadvantaged schools in Glasgow, Scotland? AB - Increase in the consumption of food and drinks outside the home by adolescents and young people and associations with rising levels of obesity is a significant concern worldwide and it has been suggested that the food environment around schools may be a contributory factor. As few studies have explored this issue in a UK setting, we examined whether different types of food outlets are clustered around public secondary schools in Glasgow, and whether this pattern differed by social disadvantage. We found evidence of clustering of food outlets around schools but a more complex picture in relation to deprivation was observed. Across all schools there were numerous opportunities for pupils to purchase energy dense foods locally and the implications for policy are discussed. PMID- 22819371 TI - [Using treatment compliance to determine the under-notification of tuberculosis in a health region for the years 2007-2009]. AB - INTRODUCTION: To determine the annual incidence of tuberculosis (TB) in the health region of Lleida (RS) through the reported cases, and/or dispensing of the treatment drugs, as well as the level of compliance, based on the prescription drugs dispensed. METHODS: Descriptive study of incidence based on reported cases of TB and TB drug dispensing (ATB) in the RS of Lleida, Catalonia in the period 2007-2009. RESULTS: The incidence in the Health Region between 2007 and 2009 ranged between 38 to 29 cases per 100,000 population. The majority (72.6%) of cases were notified, while the rest were detected by identifying the treatment drugs dispensed in pharmacies. There was a higher incidence of TB among the immigrant population. Spanish-born patients had a higher percentage of compliance (75.8% versus 61.2%). Among the immigrant groups, those from North Africa had the lowest compliance (43.7%), and those from Latin America had the highest compliance (82.4%). CONCLUSIONS: The incidence of TB in our health region has declined between 2007 and 2009, with the highest incidence among the immigrant population. There is a high amount of non-notified cases of tuberculosis. The Spanish-born population has a greater adherence to treatment. There is a lot of work to be done on disease notification, particularly among primary care doctors, as well as information on treatment adherence for the immigrant population. It would be interesting to study the socioeconomic factors that could determine the incidence and the poor adherence to treatment by immigrant populations. PMID- 22819372 TI - Organophosphate poisoning: prediction of severity and outcome by Glasgow Coma Scale, poisoning severity score, Acute Physiology and Chronic Health Evaluation II score, and Simplified Acute Physiology Score II. PMID- 22819373 TI - Disaster planning considerations involving the geriatric patient: part I. PMID- 22819374 TI - The patient who "broke the mold": an autistic child in irreversible shock. PMID- 22819375 TI - Nurses becoming political advocates. PMID- 22819376 TI - Drug shortages in the emergency department: managing a threat to patient safety. PMID- 22819377 TI - Intra-prostatic injection of botulinum toxin type A in treatment of dogs with spontaneous benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a common, naturally developing, age-related condition in dogs. The pathogenesis of BPH is not completely known; however, DHT is a hormone involved in enlargement of the prostate. Recently, the effect of botulinum toxin A (BT-A) was investigated in the rat and human prostate and has shown to induce atrophy of the gland on the canine prostate. This study investigated the effect of BT-A in the canine prostate and on the semen. Eight sexually intact male dogs with BPH (detected radiographically and ultrasonographically), and with clinical signs of BPH (e.g. hematuria or tenesmus) were used. Each lobe of the prostate received an injection of 125 U of BT-A with one-needle pass under transabdominal ultrasound guidance. The clinical results were evaluated at baseline and after treatment. No local complications or systemic adverse effects were reported. At 4 weeks, the mean prostate volume (PV) was not significantly changed after BT-A (from 17.70 +/- 6.34 to 16.48 +/- 5.98 cm(3)). At 8 weeks the PV had further decreased to 16.04 +/- 5.80 cm(3), reaching its maximum effect, but that change was not significant. The results were maintained at 16 weeks. All dogs had normal libido, erection, and ejaculation during semen collection. No significant difference was observed in all seminal parameters. Results suggest that the administration of 250 U of BT-A do not contribute to PV reduction and do not adversely affect the semen quality of dogs with BPH. PMID- 22819378 TI - A review of mobile bearing unicompartmental knee in patients aged 80 years or older and comparison with younger groups. AB - The Knee Society scores and other outcome measures in patients aged 80 years or older (n = 51) who had mobile bearing unicompartmental knee arthroplasty performed in Tayside, Scotland, were reviewed retrospectively. The results were compared with those in younger age groups: "younger than 60 years" (n = 110), "60 to 69 years" (n = 164), and "70 to 79" years (n = 145). In the study group, the mean Knee Society knee score (objective) at 1-year follow-up was 85.21, compared with a mean of 77.82 for younger-than-60-years age group, 81.28 for 60-to-69 years age group, and 87.33 for 70-to-79-years age group. The differences between the knee scores in the study group and the other groups were not statistically significant. Revision rate and survival of implant were not different between the groups. We conclude that patients aged 80 or older should be considered for mobile bearing unicompartmental knee arthroplasty if they fulfill the described criteria. PMID- 22819379 TI - Femoral neck fracture after Birmingham Hip Resurfacing Arthroplasty: prevalence, time to fracture, and outcome after revision. AB - A consecutive cohort of 3076 Birmingham Hip Resurfacings from a single institution was analyzed. The prevalence of femoral neck fracture, the time to fracture, and the outcome after revision were investigated. Fractures occurred in 34 hips (prevalence, 1.1%). Median time to fracture was 0.27 year (range, 0.014 11.2 years). Mean operation time for revision was 59 minutes, and 71% underwent isolated femoral component revision. At a mean follow-up of 5.5 years since revision, 3 patients required re-revision (2 aseptic loosening, 1 for sepsis) giving a survival of 95.7% (confidence interval, 86.9%-100%) at 5 years for the revision. Median Oxford Hip Score was 12.5% (interquartile range, 3.2%-32.3%). There were no cases of radiologic failure during follow-up. Most fractures occur early after hip resurfacing and were straightforward to revise. PMID- 22819380 TI - Heterogeneity of chromatin modifications in testicular spermatocytic seminoma point toward an epigenetically unstable phenotype. AB - Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche. PMID- 22819381 TI - Comprehensive cytogenetic study of primary cutaneous gamma-delta T-cell lymphoma by means of spectral karyotyping and genome-wide single nucleotide polymorphism array. AB - Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL), which originates from activated mature gamma-delta T cells with a cytotoxic phenotype is a rare T-cell lymphoproliferative disease. The prognosis of PCGD-TCL has been rather unfavorable due to poor response to conventional chemotherapy, and its molecular features and pathophysiology underlying disease development remain unknown. We report here a case with primarily treatment-resistant PCGD-TCL featuring highly complex cytogenetic and genetic aberrations detected by spectral karyotyping and genome-wide single nucleotide polymorphism (SNP) array. Chromosomal aberrations included several chromosomal translocations involving breakpoints at 9p21, 14q11.2, 14q32.1, or 16q23.1, suggesting the involvement of WWOX, TCL gene cluster, and BCL11B, which are crucial for tumorigenesis in T-cell lymphomas. SNP analysis also identified genome copy number gains and losses in various regions, which can potently deregulate expression of various pro- and anti-oncogenic genes involved in RAS-related protein pathways, PI3K/AKT/MTOR-related pathways, MYC related signaling, or TP53-related signaling. Thus, this case report may shed some light on the complex molecular abnormalities involved in the development of PCGD-TCL and on information that can aid the search for druggable target molecules in this disease. PMID- 22819382 TI - Neonatal outcome of congenital ventriculomegaly. AB - Enlargement of the cerebral ventricles (ventriculomegaly) occurs in 1-2 per 1000 live births. Ventriculomegaly is frequently diagnosed antenatally and hence the perinatologist is faced with counselling the prospective parents. This review considers the diagnosis, management and prognosis of this condition. A particular emphasis is placed on the outcome of isolated ventriculomegaly as these are commonly the most difficult to counsel antenatally. PMID- 22819383 TI - Synthesis, characterization and antifungal activity of quaternary derivatives of chitosan on Aspergillus flavus. AB - Two series of new chitosan derivatives were synthesized by reaction of deacetylated chitosan (CH) with propyl (CH-Propyl) and pentyl (CH-Pentyl) trimethylammonium bromides to obtain derivatives with increasing degrees of substitution (DS). The derivatives were characterized by (1)H NMR and potentiometric titration techniques and their antifungal activities on the mycelial growth of Aspergillus flavus were investigated in vitro. The antifungal activities increase with DS and the more substituted derivatives of both series, CH-Propyl and CH-Pentyl, exhibited antifungal activities respectively three and six times higher than those obtained with commercial and deacetylated chitosan. The minimum inhibitory concentrations (MIC) were evaluated at 24, 48 and 72 h by varying the polymer concentration from 0.5 to 16 g/L and the results showed that the quaternary derivatives inhibited the fungus growth at polymer concentrations four times lower than that obtained with deacetylated chitosan (CH). The chitosans modified with pentyltrimethylammonium bromide exhibited higher activity and results are discussed taking into account the degree of substitution (DS). PMID- 22819384 TI - On typing amyloidosis using immunohistochemistry. Detailled illustrations, review and a note on mass spectrometry. AB - Every amyloid disease needs to be assessed for chemical composition of its amyloid because amyloid is pathogenetically diverse and each of the chemical amyloid types requires a different therapy. Basically four different approaches are being applied for typing of amyloid using immunohistochemistry, immunochemistry, mass spectrometry and chemistry. It is shown here how an easy immunohistochemical procedure has been developed over the years that can be used to classify specifically amyloid proteins for clinico-pathologic routine use. A larger number of tissues with chemically or immunochemically typed amyloids served as prototypes for developing a set of validated amyloid antibodies. These were examined for their performance to classify a larger number of tissues of patients submitted to us and other institutions allowing independent evaluation. The data reveal that out of 663 patients, including 15 different amyloid types, all 119 prototype Amyloids (100%) have been classified correctly and 97.9% of consecutive 581 unknown amyloid tissues submitted for typing to our laboratory of whom 37 became later prototypes. Twelve samples (2.1%) could not be classified. By using appropriate amyloid antibodies in a comparative manner, this procedure is accurate. It identifies the respective amyloid type and excludes simultaneously other amyloids. Its improved performance leads to an accurate amyloid diagnosis in most cases and provides a diagnostic marker which is independend of any other information for therapeutic considerations. These results can be obtained within a day in institutes competent in performing immunohistochemistry. This is the first report on immunhistochemical typing of amyloid providing detailed illustrations of the original results for training purposes. When the immunohistochemical method presented here was compared with mass spectrometry, a more recent method for amyloid typing, the advantages and failures of both methods became apparent in an international blinded comparison. PMID- 22819385 TI - Wetting of solid surfaces: fundamentals and charge effects. AB - Wetting is important when solids are brought in contact with a liquid and for movement of micro-drops on solids. The Young equation that describes the wetting of a solid and the relations between adhesion and wetting and vapor adsorption and wetting are discussed first. The characterization of low-energy surfaces is discussed as these surfaces are important for electrowetting on a dielectric (EWOD) and the characterization methods reveal that both dispersion and acid-base interactions are important for wetting. Surfactant solutions are very suitable for modifying the wetting behavior; the distinct differences between low- and high-energy surfaces in relation to surfactant adsorption are discussed. The effects of surface charges on the wetting behavior are considered for both adsorbed charges and charges due to an applied electric potential (electrowetting). The physical interpretation of Young-Lippmann equation, which describes EWOD, is critically examined and contact angle saturation is briefly discussed. PMID- 22819386 TI - Pharmacist- versus physician-initiated admission medication reconciliation: impact on adverse drug events. AB - BACKGROUND: Medication reconciliation (MR) has proven to be a problematic task for many hospitals to accomplish. It is important to know the clinical impact of physician- versus pharmacist-initiated MR in the resource-limited hospital environment. METHODS: This quasi-experimental study took place from December 2005 to February 2006 at an urban US Veterans Affairs hospital. MR was implemented on 2 similar general medical units: one received physician-initiated MR and the other received pharmacist-initiated MR. Adverse drug events (ADEs) and a 72-hour medication-prescribing risk score were ascertained by research pharmacists for all admitted patients by structured record review. Multivariable models were tested for intervention effect, accounting for quasi-experimental design and clustered observations, and were adjusted for patient and encounter covariates. RESULTS: Pharmacists completed the MR process in 102 admissions and physicians completed the process in 116 admissions. In completing the MR process, pharmacists documented statistically more admission medication changes than physicians (3.6 vs 0.8; P < 0.001). The adjusted odds of an ADE caused by an admission prescribing change with pharmacist-initiated MR compared with a physician-initiated MR were 1.04 with a 95% CI of 0.53 to 2.0. The adjusted odds of an ADE caused by an admission prescribing change that was a prescribing error with pharmacist-initiated MR compared with a physician-initiated MR were 0.38 with a confidence interval of 0.14 to 1.05. No difference was observed in 72-hour prescribing risk score (coefficient = 0.10; 95% CI, -0.54 to 0.75). CONCLUSION: MR performed by pharmacists versus physicians was more comprehensive and was followed by lower odds of ADEs from admission prescribing errors but with similar odds of all types of ADEs. Further research is warranted to examine how MR tasks may be optimally divided among clinicians and the mechanisms by which MR affects the likelihood of subsequent ADEs. PMID- 22819387 TI - Validation of the European Society of Urogenital Radiology scoring system for prostate cancer diagnosis on multiparametric magnetic resonance imaging in a cohort of repeat biopsy patients. AB - BACKGROUND: Wide variations in acquisition protocols and the lack of robust diagnostic criteria make magnetic resonance imaging (MRI) detection of prostate cancer (PCa) one of the most challenging fields in radiology and urology. OBJECTIVE: To validate the recently proposed European Society of Urogenital Radiology (ESUR) scoring system for multiparametric MRI (mpMRI) of the prostate. DESIGN, SETTING, AND PARTICIPANTS: An institutional review board-approved multicentric prospective study; 129 consecutive patients (1514 cores) referred for mpMRI after at least one set of negative biopsies. INTERVENTION: Transfer of mpMRI-suspicious areas on three-dimensional (3D) transrectal ultrasound images by 3D elastic surface registration; random systematic and targeted cores followed by core-by-core analysis of pathology and mpMRI characteristics of the core locations. The ESUR scores were assigned after the procedure on annotated Digital Imaging and Communications in Medicine archives. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships between ESUR scores and biopsy results were assessed by the Mann-Whitney U test. The Yates correction and Pearson chi(2) tests evaluated the association between categorical variables. A teaching set was randomly drawn to construct the receiver operating characteristic curve of the ESUR score sum (ESUR-S). The threshold to recommend biopsy was obtained from the Youden J statistics and tested in the remaining validation set in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS AND LIMITATIONS: Higher T2-weighted, dynamic weighted imaging and dynamic contrast-enhanced ESUR scores were observed in areas yielding cancer-positive cores. The proportion of positive cores increased with the ESUR-S aggregated in five increments (ESUR-S 3-5: 2.9%; ESUR-S 6-8: 11.1%; ESUR-S 9-10: 38.2%; ESUR-S 11-12: 63.4%; and ESUR-S 13-15: 83.3%; p<0.0001). A threshold of ESUR-S >= 9 exhibited the following characteristics: sensitivity: 73.5%; specificity: 81.5%; positive predictive value: 38.2%; negative predictive value: 95.2%; and accuracy: 80.4%. Although the study was not designed to compare repeat biopsy strategies, more targeted cores than random systematic cores were found to be positive for cancer (36.3% compared with 4.9%, p<0.00001). CONCLUSIONS: In the challenging situation of repeat biopsies, the ESUR scoring system was shown to provide clinically relevant stratification of the risk of showing PCa in a given location. PMID- 22819388 TI - Results from the Quality Research in Radiation Oncology (QRRO) survey: Evaluation of dosimetric outcomes for low-dose-rate prostate brachytherapy. AB - PURPOSE: We report on quality of dose delivery to target and normal tissues from low-dose-rate prostate brachytherapy using postimplantation dosimetric evaluations from a random sample of U.S. patients. METHODS AND MATERIALS: Nonmetastatic prostate cancer patients treated with external beam radiotherapy or brachytherapy in 2007 were randomly sampled from radiation oncology facilities nationwide. Of 414 prostate cancer cases from 45 institutions, 86 received low dose-rate brachytherapy. We collected the 30-day postimplantation CT images of these patients and 10 test cases from two other institutions. Scans were downloaded into a treatment planning system and prostate/rectal contours were redrawn. Dosimetric outcomes were reanalyzed and compared with calculated outcomes from treating institutions. RESULTS: Median prostate volume was 33.4cm(3). Reevaluated median V(100), D(90), and V(150) were 91.1% (range, 45.5 99.8%), 101.7% (range, 59.6-145.9%), and 53.9% (range, 15.7-88.4%), respectively. Low gland coverage included 27 patients (39%) with a D(90) lower than 100% of the prescription dose (PD), 12 of whom (17% of the entire group) had a D(90) lower than 80% of PD. There was no correlation between D(90) coverage and prostate volume, number of seeds, or implanted activity. The median V(100) for the rectum was 0.3cm(3) (range, 0-4.3cm(3)). No outcome differences were observed according to the institutional strata. Concordance between reported and reevaluated D(90) values (defined as within +/-10%) was observed in 44 of 69 cases. CONCLUSIONS: Central review of postimplantation CT scans to assess the quality of prostate brachytherapy is feasible. Most patients achieved excellent dosimetric outcomes, yet 17% had less than optimal target coverage by the PD. There was concordance between submitted target-coverage parameters and central dosimetric review in 64% of implants. These findings will require further validation in a larger cohort of patients. PMID- 22819389 TI - Knowledge and perceptions of junior and senior Spanish resident doctors about antibiotic use and resistance: results of a multicenter survey. AB - BACKGROUND: Antibiotic resistance has been recognized as a worldwide problem. Our aim was to assess the perceptions of Spanish residents about antibiotic use and resistance. METHODS: An online cross-sectional survey was conducted on all resident doctors in five teaching hospitals (September to November 2010). A link to the questionnaire was e-mailed to 844 doctors. The questionnaire collected demographical characteristics, residents' knowledge about microorganisms of known clinical relevance, their habits in the antibiotic prescription process, and their perceptions on the activities aimed to improve antibiotic use. RESULTS: We received 279 responses corresponding to 33.05% of all targeted residents. The response rate was higher among junior than among senior residents (39.95% vs. 26.12%; p<0.05). Residents of all hospitals, specialties and seniority mostly considered that antimicrobial resistance was a significant problem at national level (94.3%), at their institution (91.3%), and for their daily practice (83.8%). Residents considered their training regarding antibiotics insufficient, although up to 86.5% had prescribed antibiotics in the last month. They preferred the availability of local antibiotic guidelines (65%), specific teaching sessions, specific antimicrobial management teams or readily accessible advice from a group or an infectious diseases specialist, to improve antibiotic prescribing, rather than other restrictive interventions. CONCLUSIONS: Most residents at the hospitals surveyed believed that antibiotic resistance was a serious problem. The results of this survey provided very important information to optimize adherence to Antimicrobial Stewardship Programs (ASPs). Educational strategies and non-restrictive aids are the most valuable interventions, which ASPs should capitalize on to improve antimicrobial prescription. PMID- 22819390 TI - Genetic association of CR1 with Alzheimer's disease: a tentative disease mechanism. AB - CR1 is a novel Alzheimer's disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms. PMID- 22819391 TI - MAPT H1 haplotype is associated with enhanced alpha-synuclein deposition in dementia with Lewy bodies. AB - The microtubule-associated protein tau (MAPT) H1 haplotype has been identified as a genetic risk factor for synucleinopathies. However, whether it modulates tau or alpha-synuclein pathology remains unknown. Our aim was to investigate the relationship between MAPT haplotypes and pathologic aggregates of tau and alpha synuclein in pathologically confirmed cases of dementia with Lewy bodies (DLB). Twenty-two cases fulfilling clinical and neuropathological criteria for DLB were included. Clinical and neuropathological data were collected, and APOE and MAPT genotypes were determined. Tau and alpha-synuclein pathology was assessed semiquantitatively in 17 brain areas and total scores were calculated. DLB H1/H1 (n = 12) and H2 carriers (n = 10) did not differ in demographics, clinical variables, concomitant Alzheimer's pathology, or APOE genotype. Total alpha synuclein scores were significantly increased in the H1/H1 group (p = 0.011), largely due to an increase in brainstem regions. This difference was driven by an increase in Lewy bodies and diffuse and punctuate cytoplasmatic alpha-synuclein aggregates (p = 0.007 and p = 0.025 respectively). These findings provide a mechanistic link for the genetic association between MAPT haplotypes and synucleinopathies. PMID- 22819392 TI - How and when does fabrication damage adversely affect the clinical performance of ceramic restorations? AB - OBJECTIVES: As compared to factory-processed ceramic parts, one unique trait of all-ceramic dental restorations is that they are custom-fabricated, which implies a greater susceptibility to fabrication defects. A variety of processing techniques is now available for the custom fabrication of all-ceramic single and multi-unit restorations, these include sintering, heat-pressing, slip-casting, hard machining and soft machining, all in combination with a final staining or veneering step. All these fabrication techniques, from shaping to firing, are associated with the production of flaws of various shapes and sizes, in conjunction with thermal residual stresses, all of which are capable of inducing failure. METHODS: This review will examine the various types of fabrication damage inherent to each technique and attempt to establish a relationship between fabrication defects and clinical performance of all-ceramic dental restorations with particular attention to their longevity in vivo. RESULTS: Failure mechanisms in dental ceramics can be very complex and often involve the combination of physical factors, to which are added patient and clinician-related variables such as restoration design and in vivo conditions. SIGNIFICANCE: Tremendous progress has been made in understanding the failure mechanisms of all-ceramic dental restorations over the past thirty years. It remains that there is still a need for laboratory tests that usefully simulate clinical conditions. PMID- 22819393 TI - Attachment of nickel oxide nanoparticles on the surface of palygorskite nanofibers. AB - NiO nanoparticles were assembled on the surface of palygorskite (PAL) nanofibers to produce NiO/palygorskite (NiO/PAL) composites via electrostatic attraction. The samples were characterized by thermogravimetric-differential scanning calorimetry (TG-DSC), X-ray diffraction (XRD), Brunauer-Emmet-Teller (BET), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR). The interfacial characteristics between NiO nanoparticles and PAL nanofibers were in detail investigated. The PAL nanofibers were uniformly decorated with well-dispersed crystalline NiO nanoparticles with an average size of 8 nm. The results further indicated that the interfacial binding of NiO and PAL fiber ensured the stable composite structure of NiO/PAL. The NiO/PAL composites exhibited higher photocatalytic activity than pure NiO for methyl orange photodegradation under UV light. The as-synthesized nanocomposites showed an interesting potential application in the environmental fields. PMID- 22819394 TI - Solvation effects with a photoresponsive two-component 12-hydroxystearic acid azobenzene additive organogel. AB - A "light-triggerable" azobenzene amine derivative (additive 1) was synthesized and then introduced into organogels of 12-hydroxystearic acid (HSA) in the molar ratio of 1:3. The organogels (HSA/1) consisting of additive 1 and HSA were analyzed by (1)H nuclear magnetic resonance (NMR), Fourier transform-infrared (FT IR), and X-ray diffraction (XRD). The homogeneity of the gel networks was observed using field emission scanning electron microscopy (FE-SEM). Additive 1 formed a complex with HSA in HSA organogels due to salification between the terminal amine group of additive 1 and the carboxylic acid group of HSA. Additive 1 in the gels of HSA/1 showed the potential for photo-isomerization, and we achieved a reversible control of HSA/1 sol-gel transition in toluene by the alternating irradiation with UV and visible light. Interestingly, the opposite phenomenon was observed in CHCl(3) system, namely, the orange solution of HSA/1 in CHCl(3) was turned to a red-transparent gel by exposure to UV light. PMID- 22819395 TI - Time-dependent ion selectivity in capacitive charging of porous electrodes. AB - In a combined experimental and theoretical study, we show that capacitive charging of porous electrodes in multicomponent electrolytes may lead to the phenomenon of time-dependent ion selectivity of the electrical double layers (EDLs) in the electrodes. This effect is found in experiments on capacitive deionization of water containing NaCl/CaCl(2) mixtures, when the concentration of Na(+) ions in the water is five times the Ca(2+)-ion concentration. In this experiment, after applying a voltage difference between two porous carbon electrodes, first the majority monovalent Na(+) cations are preferentially adsorbed in the EDLs, and later, they are gradually replaced by the minority, divalent Ca(2+) cations. In a process where this ion adsorption step is followed by washing the electrode with freshwater under open-circuit conditions, and subsequent release of the ions while the cell is short-circuited, a product stream is obtained which is significantly enriched in divalent ions. Repeating this process three times by taking the product concentrations of one run as the feed concentrations for the next, a final increase in the Ca(2+)/Na(+)-ratio of a factor of 300 is achieved. The phenomenon of time-dependent ion selectivity of EDLs cannot be explained by linear response theory. Therefore, a nonlinear time dependent analysis of capacitive charging is performed for both porous and flat electrodes. Both models attribute time-dependent ion selectivity to the interplay between the transport resistance for the ions in the aqueous solution outside the EDL, and the voltage-dependent ion adsorption capacity of the EDLs. Exact analytical expressions are presented for the excess ion adsorption in planar EDLs (Gouy-Chapman theory) for mixtures containing both monovalent and divalent cations. PMID- 22819396 TI - Dendritic PtCo alloy nanoparticles as high performance oxygen reduction catalysts. AB - We proposed a facile route to one-step synthesis of well-dispersed PtCo alloy nanoparticles with dendritic morphology. Platinum acetylacetonate [Pt(acac)(2)] and cobalt acetylacetone [Co(acac)(2)] were chosen as the precursors to prepare PtCo alloy nanoparticles under a relatively mild condition with anhydrous ethylenediamine and poly(vinyl pyrrolidone) (PVP) as solvent and surfactant, respectively, in the presence of NaBH(4). Structural characterizations with transmission electron microscopy (TEM) and X-ray powder diffraction (XRD) revealed that PtCo nanoparticles possess an interesting dendritic morphology with excellent structural continuity and integrity. As an alternative cathodic electrocatalyst, PtCo nanodendrites (NDs) showed very high activity for oxygen reduction reaction (ORR) with half-wave potential at ~0.877 V (versus RHE), which is nearly 50 mV more positive as compared with that of the commercial Pt/C catalyst (0.828 V). The Pt mass activity and specific activity were 0.11A/mg(Pt) and 0.68 mA/cm(2), respectively (~1.5 and ~4.5 times higher than the corresponding values for the commercial Pt catalysts), at 0.9 V. PMID- 22819397 TI - Endomyocardial fibrosis in the context of hypereosinophilic syndrome: the contribution of cardiac MRI. PMID- 22819398 TI - Postoperative infection rates in low risk patients undergoing percutaneous nephrolithotomy with and without antibiotic prophylaxis: a matched case control study. AB - PURPOSE: Current guidelines recommend prophylactic antibiotic therapy for all patients undergoing percutaneous nephrolithotomy. We examined the effects of antibiotic prophylaxis in patients undergoing percutaneous nephrolithotomy with negative preoperative urine cultures. MATERIALS AND METHODS: Of the 5,803 patients in the CROES (Clinical Research Office of the Endourological Society) Percutaneous Nephrolithotomy Global Study database, a group of 162 patients undergoing percutaneous nephrolithotomy with a negative baseline urine culture who did not receive antibiotic prophylaxis were matched on preoperative nephrostomy, the presence of staghorn calculi and diabetes status with an equal number of patients who received antibiotic prophylaxis. Comparisons were made between the 2 groups in terms of operative and postoperative outcomes, including the incidence of fever and other complications. RESULTS: Patients who received antibiotic prophylaxis had a lower mean (SD) age at 44.9 (14.2) vs 50.1 (14.4) years (p = 0.001). They were also more likely to be in the prone position during the procedure (71.6% vs 39.5%, p <0.001) but less likely to receive postoperative stenting (17.3% vs 32.7%, p = 0.002) than those who did not receive prophylaxis. The 2 groups were comparable in terms of all other baseline characteristics and operative factors. Patients who received antibiotic prophylaxis were less likely to experience fever (2.5% vs 7.4%, p = 0.040) and other postoperative complications (1.9% vs 22.0%, p <0.0001), and had a higher stone-free rate after percutaneous nephrolithotomy (86.3% vs 74.4%, p = 0.006). CONCLUSIONS: Antibiotic prophylaxis of patients undergoing percutaneous nephrolithotomy with a negative baseline urine culture is associated with a significant reduction in the rate of postoperative fever and other complications. PMID- 22819399 TI - Application of small intestinal submucosa graft for repair of complicated vesicovaginal fistula: a pilot study. AB - PURPOSE: Vesicovaginal fistula is a socially debilitating problem with important psychological and medicolegal implications. Complicated fistulas include large fistulas or those with failed prior repair attempts. The key to successful closure of such fistulas is the use of adjuncts such as a Martius, peritoneal or omental flap. Small intestinal submucosa is an acellular collagen matrix graft that is nonimmunogenic, biodegradable and ready to use off the shelf. We evaluated small intestinal submucosa as an interposition patch during complicated vesicovaginal fistula repair. MATERIALS AND METHODS: A total of 23 women with a mean age of 33.5 years who had a complicated vesicovaginal fistula were enrolled in this clinical trial. Complicating factors were failed primary repair in 9 cases, excessive perifistulous scarring in 4 patients and a fistula 1.5 cm or greater in the remainder. Transvaginal repair was done in 7 low fistula cases and transabdominal repair was done in the remainder with a high fistula. A small intestinal submucosa patch was interposed in all cases at classic abdominal or vaginal repair. All patients were evaluated 1, 3 and 6 months postoperatively. RESULTS: All patients who underwent vaginal repair were dry during followup. Of the 16 women who underwent transabdominal repair 14 were dry. The overall success rate was 91.3%. No reported allergic or inflammatory reactions were documented. CONCLUSIONS: Using small intestinal submucosa as an interposition layer at anatomical vaginal and/or transabdominal repair of complicated vesicovaginal fistulas seems to be a simple, feasible solution. PMID- 22819400 TI - Editorial comment. PMID- 22819401 TI - "Snodgraft" technique for the treatment of primary distal hypospadias: pushing the envelope. AB - PURPOSE: "Snodgraft" modification has been proposed to reduce the risk of meatal/neourethral stenosis in distal hypospadias. We applied the Snodgraft technique by using inner preputial graft in primary distal hypospadias repair. MATERIALS AND METHODS: A total of 102 consecutive patients undergoing the Snodgraft procedure were prospectively studied between 2006 and 2011. Mean patient age was 7.2 years. Localization of the meatus was glanular in 5 patients, coronal in 49, subcoronal in 45 and mid penile in 3. In all patients the posterior urethral plate was incised, and the graft harvested from the inner prepuce was sutured from the old meatus to the tip of the glans. A neourethra was created over a urethral catheter using 6-zero polyglactin suture. An interpositional flap was laid over the urethra as a second barrier. All patients were followed at 3 to 6-month intervals for cosmetic and functional results. RESULTS: At a mean of 2.4 years of followup no patient had meatal stenosis or diverticulum at the inlay graft site. However, urethrocutaneous fistula was observed in 10 patients (9.8%). A slit-like appearance of neomeatus was achieved in all patients. During followup no obstructive urinary flow pattern was detected, and early and long-term maximum urine flow rates were comparable. CONCLUSIONS: No meatal/neourethral stenosis was observed in any patient undergoing a Snodgraft procedure. A randomized trial will be needed to prove that the incidence of meatal/neourethral stenosis is lower after Snodgraft repair compared to routine tubularized incised plate repair. PMID- 22819402 TI - Long-term infection outcomes of 3-piece antibiotic impregnated penile prostheses used in replacement implant surgery. AB - PURPOSE: Patients who undergo device revision surgery are at higher risk for infection than virgin implant recipients. The revision rate due to virgin implant infection is statistically significantly lower for minocycline/rifampin impregnated than for nonimpregnated inflatable penile prostheses. We determined whether the frequency of infection revision events after device replacement surgery would also be lower for minocycline/rifampin impregnated inflatable penile prostheses. MATERIALS AND METHODS: Patient information forms voluntarily submitted to AMS(r) after replacement inflatable penile prosthesis implantation between 2001 and 2007 were retrospectively reviewed to compare secondary infection related revision events for antibiotic impregnated vs nonimpregnated implants. Only men who received an inflatable penile prosthesis at a first recorded operation to replace a previously implanted penile prosthesis were included in the study. Life table survival analysis was done between the groups to compare infection related events resulting in a second surgical revision after replacement implantation. Survival function extrapolation was based on parametric analysis using the Weibull distribution model. RESULTS: On life table survival analysis secondary revision due to infection was significantly less common in the minocycline/rifampin impregnated group than in the nonimpregnated group (log rank p = 0.0252). At up to 6.6 years of followup 2.5% of 9,300 men with vs 3.7% of 1,764 without an impregnated device underwent secondary revision due to infection. CONCLUSIONS: This long-term device survival analysis provides clinical evidence of a significant decrease in infection related secondary revisions using minocycline/rifampin impregnated prostheses vs nonimpregnated inflatable penile prostheses at replacement implant surgery. PMID- 22819403 TI - Content and construct validation of a robotic surgery curriculum using an electromagnetic instrument tracker. AB - PURPOSE: Rapid adoption of robot-assisted surgery has outpaced our ability to train novice roboticists. Objective metrics are required to adequately assess robotic surgical skills and yet surrogates for proficiency, such as economy of motion and tool path metrics, are not readily accessible directly from the da Vinci(r) robot system. The trakSTARTM Tool Tip Tracker is a widely available, cost-effective electromagnetic position sensing mechanism by which objective proficiency metrics can be quantified. We validated a robotic surgery curriculum using the trakSTAR device to objectively capture robotic task proficiency metrics. MATERIALS AND METHODS: Through an institutional review board approved study 10 subjects were recruited from 2 surgical experience groups (novice and experienced). All subjects completed 3 technical skills modules, including block transfer, intracorporeal suturing/knot tying (fundamentals of laparoscopic surgery) and ring tower transfer, using the da Vinci robot with the trakSTAR device affixed to the robotic instruments. Recorded objective metrics included task time and path length, which were used to calculate economy of motion. Student t test statistics were performed using STATA(r). RESULTS: The novice and experienced groups consisted of 5 subjects each. The experienced group outperformed the novice group in all 3 tasks. Experienced surgeons described the simulator platform as useful for training and agreed with incorporating it into a residency curriculum. CONCLUSIONS: Robotic surgery curricula can be validated by an off-the-shelf instrument tracking system. This platform allows surgical educators to objectively assess trainees and may provide credentialing offices with a means of objectively assessing any surgical staff member seeking robotic surgery privileges at an institution. PMID- 22819404 TI - National trends and disparities in the use of minimally invasive adult pyeloplasty. AB - PURPOSE: Minimally invasive pyeloplasty might have several advantages compared to open pyeloplasty in the management of ureteropelvic junction obstruction. Nonetheless, minimally invasive pyeloplasty appears to be underused in North America. We examined specific patient and hospital characteristics that may be associated with these disparities. MATERIALS AND METHODS: The Nationwide Inpatient Sample was used to identify a national estimate of 29,456 patients with ureteropelvic junction obstruction treated with minimally invasive pyeloplasty (laparoscopic or robotic) and open pyeloplasty between 1998 and 2009. The rates of use of minimally invasive and open pyeloplasty were assessed according to year of surgery, and patient and hospital characteristics. The determinants of minimally invasive pyeloplasty were evaluated using logistic regression models adjusted for clustering. RESULTS: Overall 15.3% of patients underwent minimally invasive pyeloplasty between 1998 and 2009. The use of minimally invasive pyeloplasty increased remarkably during the study period from 2.4% to 55.3%, a 23 fold increase. On multivariable logistic regression analysis African-American race (OR 0.584, p = 0.015) and other insurance status (including uninsured patients, OR 0.613, p = 0.013) were associated with a lower rate of minimally invasive pyeloplasty. Patients treated at teaching (OR 1.788, p = 0.003) and/or urban (OR 4.819, p <0.001) institutions were significantly more likely to undergo minimally invasive pyeloplasty. CONCLUSIONS: In the last decade there has been a dramatic increase in the use of minimally invasive pyeloplasty in the United States and in 2009 a slight majority underwent minimally invasive pyeloplasty. Nonetheless, treatment disparities exist. African-American patients with other insurance status (including those uninsured) treated at nonteaching, rural hospitals were less likely to undergo minimally invasive pyeloplasty. Efforts should be made to understand these treatment disparities and broaden the availability of minimally invasive pyeloplasty. PMID- 22819405 TI - Effect of extracorporeal shock wave lithotripsy on kidney growth in children. AB - PURPOSE: We investigated whether shock wave lithotripsy affects kidney growth in children. MATERIALS AND METHODS: This prospective controlled study included 150 children with renal stones who presented for shock wave lithotripsy between March 2005 and February 2010 (group A). The control arm included 100 children without any urological problems who were enrolled in the study after obtaining written maternal consent (group B). All children in both groups underwent abdominal ultrasound to assess renal size (bipolar renal length), which was repeated after 6 months for group A and after 1 year for both groups. RESULTS: Bipolar renal size in group A increased significantly at 6 months and 1 year after shock wave lithotripsy. Renal growth did not differ based on patient age at shock wave lithotripsy (p = 0.472), number of shock wave lithotripsy sessions (p = 0.65) or number of stones (p = 0.405). There was no significant difference between the rate of kidney growth in children who underwent shock wave lithotripsy during the year of the study and normal controls. CONCLUSIONS: Shock wave lithotripsy has no deleterious effect on the normal rate of renal growth in children. This outcome is not affected by either the number of stones or the age of the child at shock wave lithotripsy. PMID- 22819406 TI - A prospective, randomized study of the clinical effects of shock wave delivery for unilateral kidney stones: 60 versus 120 shocks per minute. AB - PURPOSE: We assessed the effects of different shock wave delivery rates in patients treated with shock wave lithotripsy for renal stones, particularly treatment success, degree of renal injury and pain experienced, and analgesic demand. MATERIALS AND METHODS: A total of 206 patients with renal stones were prospectively randomized to receive shock waves delivered at 60 (group 1) or 120 (group 2) shocks per minute using a Sonolith(r) Vision at a single institution in October 2008 and August 2010. The primary outcome was successful treatment 12 weeks after 1 lithotripsy session. Secondary outcome measures included the degree of renal injury, as reflected by changes in urinary markers of renal injury, as well as patient pain scores and analgesia consumed during treatment. RESULTS: Mean stone size in groups 1 and 2 was 8.95 and 9.28 mm, respectively (p = 0.525). The overall treatment success rate was 43.2%. It was significantly better in group 1 than in group 2 (50.5% vs 35.9%, p = 0.035). There was no between group difference in the success rate for stones 10 mm or less but the success rate was statistically better for group 1 patients with stones greater than 10 mm (p = 0.002). Immediately after shock wave lithotripsy there was a statistically significant greater increase in urinary NAG (p = 0.003) and interleukin-18 (p = 0.022) in group 1. There was no between group difference in pain scores, analgesic consumption during shock wave lithotripsy or unplanned hospital visits. CONCLUSIONS: Slower shock wave delivery yielded better treatment outcomes, particularly for stones greater than 10 mm, without increasing patient pain or analgesic demand. However, slower shock wave delivery also appeared to cause a statistically significant increase in acute renal injury markers, although the clinical implication was uncertain. PMID- 22819407 TI - Removal of endoprosthesis with urethral preservation and simultaneous urethral reconstruction. AB - PURPOSE: We describe our experience with, and technique and outcomes of complex UroLume(r) stent extraction with simultaneous urethral preservation and reconstruction. MATERIALS AND METHODS: A retrospective review of our institutional review board approved database identified 12 patients who underwent successful UroLume stent extraction with urethral preservation using a standard atraumatic approach between 2000 and 2011. Patient demographics, indication for stent removal, number of stents removed, and stricture length, location and etiology are described. Urethral reconstruction type and outcomes were analyzed. RESULTS: Urethral preservation was possible in all cases. No patient required en bloc urethral resection. A total of 16 stents (12 anterior and 4 posterior urethra) were successfully removed by standard vertical urethrotomy with wire extraction. Average patient age was 52.8 years and mean stricture length was 6.7 cm. Obstruction or recurrent stricture in 83% of cases, pain in 42% and urinary tract infection in 33% were the main indications for extraction. Eight patients underwent dorsal onlay urethroplasty, 3 ventral onlay urethroplasty (with a gracilis muscle flap in 2) and 1 perineal urethrostomy. Ten of the 12 patients (83%) were stricture-free at a median followup of 4 years. One patient treated with 12 cm ventral fasciocutaneous flap reconstruction required repeat urethroplasty. Treatment failed in a morbidly obese patient with a history of external beam and brachytherapy radiation for prostate cancer, requiring suprapubic tube diversion. CONCLUSIONS: Removal of the dysfunctional UroLume stent using an atraumatic technique allows for urethral preservation and simultaneous urethral reconstruction. En bloc urethral resection and tissue loss are not necessary for stent extraction and successful urethral reconstruction. PMID- 22819408 TI - Biomechanical properties and associated collagen composition in vaginal tissue of women with pelvic organ prolapse. AB - PURPOSE: The pelvic tissue of women with pelvic organ prolapse is stiffer than that of controls but there are scant data on the collagen composition that corresponds to these mechanical properties. We evaluated human vaginal wall stiffness using the novel scanning haptic microscope and correlated these measurements to collagen expression in women with and without pelvic organ prolapse. In this simultaneous biomechanical and biochemical assessment we evaluated the usefulness of this measurement technology for pelvic floor disorder research and confirmed an association between mechanical properties and composition. MATERIALS AND METHODS: The elastic constant (a measure of stiffness) of vaginal wall tissue was measured with the scanning haptic microscope. Protein expression of collagen types I and III of the same tissues were determined by Western blot. The Student t test was used for comparisons between groups. RESULTS: The anterior and posterior vaginal walls of premenopausal and postmenopausal women with pelvic organ prolapse were significantly stiffer than those of controls (p <0.05). Collagen III protein expression in the anterior vaginal wall in the control group was higher than in menopausal women. Collagen I expression was not significantly different between controls and cases. CONCLUSIONS: The scanning haptic microscope produced reliable mechanical measurements in small tissue samples without tissue destruction. Vaginal wall tissues are stiffer in women with pelvic organ prolapse than in controls. This vaginal wall stiffness was associated with lower protein expression of collagen III in the vaginal wall compared to that in asymptomatic controls. PMID- 22819409 TI - Robot-assisted laparoscopic reoperative repair for failed pyeloplasty in children: a safe and highly effective treatment option. AB - PURPOSE: Failed pyeloplasty represents a management dilemma, with treatment options including balloon dilation, endopyelotomy and reoperative pyeloplasty. We review our experience with robot-assisted laparoscopic reoperative repair of recurrent/persistent ureteropelvic junction obstruction in children and compare this method to other approaches. MATERIALS AND METHODS: We reviewed in detail all cases of failed prior ureteropelvic junction procedures, either open or laparoscopic, managed by robot-assisted laparoscopic reoperative repair between 2006 and July 2011. RESULTS: Robot-assisted laparoscopic repair was performed in 16 cases for persistent or recurrent ureteropelvic junction obstruction following a prior procedure involving the ureteropelvic junction (12 open pyeloplasties, 4 robot-assisted laparoscopic repairs). Additional interventions had been performed in 12 patients. Reoperative robot-assisted laparoscopic pyeloplasty was performed in 13 patients and reoperative robot-assisted laparoscopic ureterocalycostomy in 3. Patient age ranged from 12 months to 15.3 years (mean 6.1 years). Mean operative time and length of stay were 303 minutes and 1.6 days, respectively. Mean followup was 14.9 months. All symptomatic patients had resolution of symptoms postoperatively. A total of 14 patients (88%) had improved radiological findings. One patient underwent transfusion and conversion to an open procedure due to bleeding. CONCLUSIONS: Robot-assisted laparoscopic reoperative repair of persistent/recurrent ureteropelvic junction obstruction is a safe, highly effective procedure even in the setting of multiple prior procedures. In our series all patients improved symptomatically, 88% improved radiographically and none have required further surgical intervention. Success is greater than with endopyelotomy and comparable to open reoperative repair for this challenging condition during short-term and intermediate followup. PMID- 22819410 TI - Outcomes of metallic stents for malignant ureteral obstruction. AB - PURPOSE: Malignant ureteral obstruction often necessitates chronic urinary diversion and is associated with high rates of failure with traditional ureteral stents. We evaluated the outcomes of a metallic stent placed for malignant ureteral obstruction and determined the impact of risk factors previously associated with increased failure rates of traditional stents. MATERIALS AND METHODS: Patients undergoing placement of the metallic Resonance(r) stent for malignant ureteral obstruction at an academic referral center were identified retrospectively. Stent failure was defined as unplanned stent exchange or nephrostomy tube placement for signs or symptoms of recurrent ureteral obstruction (recurrent hydroureteronephrosis or increasing creatinine). Predictors of time to stent failure were assessed using Cox regression. RESULTS: A total of 37 stents were placed in 25 patients with malignant ureteral obstruction. Of these stents 12 (35%) were identified to fail. Progressive hydroureteronephrosis and increasing creatinine were the most common signs of stent failure. Three failed stents had migrated distally and no stents required removal for recurrent infection. Patients with evidence of prostate cancer invading the bladder at stent placement were found to have a significantly increased risk of failure (HR 6.50, 95% CI 1.45-29.20, p = 0.015). Notably symptomatic subcapsular hematomas were identified in 3 patients after metallic stent placement. CONCLUSIONS: Failure rates with a metallic stent are similar to those historically observed with traditional polyurethane based stents in malignant ureteral obstruction. The invasion of prostate cancer in the bladder significantly increases the risk of failure. Patients should be counseled and observed for subcapsular hematoma formation with this device. PMID- 22819411 TI - Resistive index of prostate capsular arteries: a newly identified parameter to diagnose and assess bladder outlet obstruction in patients with benign prostatic hyperplasia. AB - PURPOSE: We evaluated the association of the resistive index of the prostate capsular arteries and bladder outlet obstruction severity in men with benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 74 patients histologically diagnosed with benign prostatic hyperplasia were ultimately enrolled in this prospective study. Urodynamics were performed by a urologist to determine bladder outlet obstruction. Baseline parameters measured in patients with benign prostatic hyperplasia were the prostate capsular artery resistive index, International Prostate Symptom Score, quality of life score, total prostate and transition zone volume, and the transition zone index. ROC curves were produced to calculate the ROC AUC and evaluate the diagnostic performance of the prostate capsular artery resistive index, International Prostate Symptom Score, obstructive symptoms, total prostate and transition zone volume, and the transition zone index for bladder outlet obstruction. RESULTS: Significant difference between patients with and without bladder outlet obstruction was observed in the resistive index, which showed the highest coefficient with the degree of obstruction (r = 0.712, p <0.0001). At a cutoff of 0.69 the resistive index distinguished patients with and without bladder outlet obstruction with 78% sensitivity and 86.4% specificity. The prostate capsular artery resistive index had the maximum AUC of 0.823. CONCLUSIONS: The prostate capsular artery resistive index is significantly higher in patients with benign prostatic hyperplasia related bladder outlet obstruction than in those without such obstruction. The resistive index might serve as a novel indicator to diagnose and assess bladder outlet obstruction in patients with benign prostatic hyperplasia. PMID- 22819412 TI - Editorial comment. PMID- 22819414 TI - A cutoff value based on analysis of a reference population decreases overestimation of the prevalence of nocturnal polyuria. AB - PURPOSE: We sought criteria for nocturnal polyuria in asymptomatic, nonurological adults of all ages by reporting reference values of the ratio of daytime and nighttime urine volumes, and finding nocturia predictors. MATERIALS AND METHODS: Data from a database of frequency-volume charts from a reference population of 894 nonurological, asymptomatic volunteers of all age groups were analyzed. The nocturnal polyuria index and the nocturia index were calculated and factors influencing these values were determined by multivariate analysis. RESULTS: The nocturnal polyuria index had wide variation but a normal distribution with a mean +/- SD of 30% +/- 12%. The 95th percentile of the values was 53%. Above this cutoff a patient had nocturnal polyuria. This value contrasts with the International Continence Society definition of 33% but agrees with several other reports. On multivariate regression analysis with the nocturnal polyuria index as the dependent variable sleeping time, maximum voided volume and age were the covariates. However, the increase in the nocturnal polyuria index by age was small. Excluding polyuria and nocturia from analysis did not alter the results in a relevant way. The nocturnal voiding frequency depended on sleeping time and maximum voided volume but most of all on the nocturia index. CONCLUSIONS: The prevalence of nocturnal polyuria is overestimated. We suggest a new cutoff value for the nocturnal polyuria index, that is nocturnal polyuria exists when the nocturnal polyuria index exceeds 53%. The nocturia index is the best predictor of nocturia. PMID- 22819415 TI - Editorial comment. PMID- 22819416 TI - Causes of death after radical prostatectomy at a large tertiary center. AB - PURPOSE: Most men treated with radical prostatectomy do not die of prostate cancer. We evaluated the cause of death in a large series of patients who underwent radical prostatectomy and compared the rate of death to that of the general American population. MATERIALS AND METHODS: The study population consisted of 18,209 men who underwent radical prostatectomy at our institution between 1975 and 2009. Close patient followup and a national database were used to identify which patients died and classify the cause of death. These data were compared with general American population data from the National Vital Statistics System. RESULTS: Median age at radical prostatectomy was 59 years (IQR 54.0 63.0). At a median followup of 7.4 years (IQR 3.7-11.9) 1,419 patients had died (7.8%), including 379 of prostate cancer. Actuarial 10 and 20-year overall survival rates after radical prostatectomy were 92.6% and 69.2%, respectively. The overall death rate was lower in men treated with radical prostatectomy than in the general American population (standardized mortality ratio 0.47, 95% CI 0.44-0.49). Differences were particularly pronounced for heart disease, chronic respiratory conditions, diabetes and infection. Of men who died of a nonprostate cancer cause 44.0% died of a secondary malignancy. CONCLUSIONS: Overall survival after radical prostatectomy is excellent. Men who undergo radical prostatectomy usually die of a nonprostate cancer cause. Almost half of patients who survive prostate cancer die of a secondary malignancy, likely due to the selection of surgical candidates at low cardiopulmonary risk. PMID- 22819417 TI - Editorial comment. PMID- 22819418 TI - Is the R.E.N.A.L. nephrometry scoring system predictive of the functional efficacy of nephron sparing surgery in the solitary kidney? AB - PURPOSE: We evaluated the ability of renal tumor complexity, as assessed by the R.E.N.A.L. (radius, exophytic, nearness to collecting system, anterior/posterior and location) nephrometry scoring system, to predict the functional efficacy of nephron sparing surgery. MATERIALS AND METHODS: We evaluated 42 patients who presented with an anatomically (32) or a functionally (10) solitary kidney and underwent partial nephrectomy. Each renal unit was assigned a R.E.N.A.L. nephrometry score using preoperative imaging. The CKD-EPI equation was applied to calculate the estimated glomerular filtration rate. The difference between the estimated glomerular filtration rate at baseline and at postoperative time points served as a measurement of the renal functional loss attributable to partial nephrectomy. RESULTS: In the 42 patients who underwent partial nephrectomy the mean preoperative estimated glomerular filtration rate was 61.5 ml/minute/1.73 m(2). The median total nephrometry score was 8 (range 4 to 10). In the immediate postoperative period the cohort mean estimated glomerular filtration rate of 48.6 ml/minute/1.73 m(2) was significantly less than the preoperative value (p <0.0001). At 6-month followup the mean estimated glomerular filtration rate had recovered at 54.1 ml/minute/1.73 m(2) but it remained significantly less than the preoperative value (p = 0.0002). We noted no relationship between the postoperative decrease in the estimated glomerular filtration rate and the assigned total nephrometry score or in any individual component of the R.E.N.A.L. scoring system related to the targeted lesion. CONCLUSIONS: Neither the individual components of the R.E.N.A.L. nephrometry scoring system nor the total nephrometry score predicted the realized functional loss, as assessed by the estimated glomerular filtration rate in patients with a solitary kidney treated with nephron sparing surgery. However, nephron sparing surgery was quite efficacious for preserving renal function since only a durable 11.6% decrease was noted in the estimated glomerular filtration rate. PMID- 22819419 TI - Location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. AB - PURPOSE: Anterior tumors are estimated to constitute 20% of prostate cancers. Current data indicate that transperineal biopsy is more reliable than transrectal biopsy in identifying these tumors. If correct, this superior reliability should result in an increased proportion of anterior tumors identified by transperineal biopsy. We investigated this hypothesis with reference to prostatectomy specimens. MATERIALS AND METHODS: Radical prostatectomy histopathology records were retrospectively examined. Patients were grouped based on primary transperineal or transrectal biopsy as the modality used to identify the initial cancer. After grouping, tumor location and size were recorded and, thus, the proportion of anterior tumors was determined. RESULTS: A total of 1,132 (414 transperineal and 718 transrectal) prostatectomy specimens were examined. Overall mean tumor size (1.8 and 2.0 cm(3)), stage (pT2 63.3% and 61%) and significance (5.1% and 5.1%) for the transperineal and transrectal methods were similar. However, the transperineal method was associated with proportionally more anterior tumors (16.2% vs 12%, p = 0.046), and identified them at a smaller size (1.4 vs 2.1 cm(3), p = 0.03) and lower stage (extracapsular extension 13% vs 28%, p = 0.03) compared to the transrectal method. The pT3 positive surgical margin rate for anterior vs other tumors was 69% vs 34.9%, respectively. CONCLUSIONS: Overall transrectal and transperineal biopsy identify cancers that are similar in size, stage and significance. However, transperineal biopsy detected proportionally more anterior tumors (16.2% vs 12%), and identified them at a smaller size (1.4 vs 2.1 cm(3)) and stage (extracapsular extension 13% vs 28%) compared to transrectal biopsy. Identifying anterior tumors early is important because the positive surgical margin rate for anterior pT3 lesions is significantly higher. PMID- 22819420 TI - Editorial comment. PMID- 22819421 TI - Editorial comment. PMID- 22819422 TI - The value of transurethral bladder biopsy after intravesical bacillus Calmette Guerin instillation therapy for nonmuscle invasive bladder cancer: a retrospective, single center study and cumulative analysis of the literature. AB - PURPOSE: We evaluated the need of routine transurethral biopsies after an induction course of intravesical bacillus Calmette-Guerin for high grade nonmuscle invasive bladder cancer. MATERIALS AND METHODS: This retrospective study included 180 patients with high grade nonmuscle invasive bladder cancer who underwent a 6-week induction course of bacillus Calmette-Guerin. Cystoscopic findings, urinary cytology and pathological results of transurethral biopsy were evaluated. For cumulative meta-analysis we systematically reviewed studies indexed in MEDLINE(r), EMBASE(r) and Web of Science(r). The records of 740 patients from a total of 7 studies were finally analyzed. RESULTS: Biopsy was positive in 58 patients (32%). Cystoscopy appeared normal in 75 patients (42%) and showed only erythema in 51 (28%) and tumor in 54 (30%), of whom 6 (8%), 11 (22%) and 41 (76%), respectively, showed positive findings at biopsy. The positive predictive value of erythema was 15% with negative cytology and 56% with positive cytology. The positive predictive value of a tumor with negative and positive cytology was 63% and 89%, respectively. A combination of negative cytology and normal cystoscopy was associated with a negative biopsy in 94% of cases. A total of 970 bladder biopsies were taken, of which 137 (14%) were positive, including 20 of 125 erythematous lesions (16%), 73 of 107 tumors (68%) and 44 of 738 normal-appearing areas (6%). Cumulative analysis findings were comparable. CONCLUSIONS: Routine transurethral bladder biopsies after a bacillus Calmette-Guerin induction course are not necessary. An individually approach is recommended, tailored from cystoscopic findings and cytology. PMID- 22819424 TI - Demographic and co-morbid predictors of stress (takotsubo) cardiomyopathy. AB - Little is known about the epidemiology of stress (takotsubo) cardiomyopathy (SC). We used a 3-arm case-control study to assess differences in demographic and co morbid predictors of SC compared to orthopedic controls and myocardial infarction (MI) controls to characterize (1) population-level predictors of SC generally and (2) differences and similarities in determinants of SC compared to MI. We included data on all discharges of patients diagnosed with SC from the 2008 to 2009 National Inpatient Samples and randomly selected 1-to-1 age-matched controls from patients hospitalized with MI and patients hospitalized with joint injuries after trauma. We used McNemar tests to assess differences in demographic characteristics and co-morbidities between patients with SC and controls. There were 24,701 patients with SC in our study. Of patients with SC, 89.0% were women compared to 38.9% of patients with MI and 55.7% of orthopedic controls. Patients with SC were more likely to be white and to reside in wealthier ZIP codes compared to MI and orthopedic controls. Patients with SC were less likely to have cardiovascular risk factors compared to MI and orthopedic controls but were more likely to have had histories of cerebrovascular accidents, drug abuse, anxiety disorders, mood disorders, malignancy, chronic liver disease, and sepsis. In conclusion, demographic and co-morbid predictors of SC differ substantially from those of MI and may be of interest to providers when diagnosing SC. Several co morbid risk factors predictive of SC may operate by increased catecholamines. PMID- 22819423 TI - Benefit of percutaneous coronary intervention in early latecomers with acute ST segment elevation myocardial infarction. AB - The clinical benefit of percutaneous coronary intervention (PCI) is controversial in stable early latecomers with ST-segment elevation myocardial infarction (STEMI). We evaluated the efficacy of PCI in 2,344 stable patients with STEMI presenting 12 to 72 hours after symptom onset. Patients who had impaired hemodynamics or who had undergone fibrinolysis or immediate or urgent PCI were excluded. The patients were divided into the PCI group (n = 1,889) and medical treatment group (n = 455). The 12-month clinical outcome was compared between the 2 groups. After adjustment using propensity score stratification, the PCI group had lower mortality (3.1% vs 10.1%; hazard ratio 0.31; 95% confidence interval 0.20 to 0.47; p <0.001) and a lower incidence of composite death/myocardial infarction (3.8% vs 11.2%; hazard ratio 0.36; 95% confidence interval 0.25 to 0.53; p <0.001) at 12 months. The benefit of PCI was consistent across all subgroups, including patients presenting without chest pain. In conclusion, in stable patients with STEMI presenting 12 to 72 hours after symptom onset, PCI was associated with significant improvement in the 12-month clinical outcome. PMID- 22819425 TI - Comparison of lipid control in patients with coronary versus peripheral artery disease following the first vascular intervention. AB - Peripheral arterial disease (PAD) is a strong risk factor for cardiovascular morbidity and mortality. Therefore, target low-density lipoprotein (LDL) cholesterol level in patients with PAD is <=70 mg/dl, similar to patients with coronary artery disease (CAD). However, despite their high cardiovascular risk, patients with PAD less frequently achieve LDL cholesterol goals compared to patients with CAD. We aimed to compare LDL cholesterol control in patients after first coronary or peripheral vascular intervention. Included were patients >=18 years of age without a history of cardiovascular disease who underwent first coronary or peripheral vascular intervention from 2004 through 2010. Primary end points were percentage of patients who achieved the LDL cholesterol goal of <100 and <70 mg/dl. Of 9,138 patients available for analysis, 7,512 (82.2%) underwent first coronary revascularization and 1,626 (17.8%) underwent first peripheral revascularization. Patients after first coronary revascularization were treated more frequently with any statin and with highly potent statins. Furthermore, they more frequently achieved the LDL cholesterol goals compared to patients after first peripheral intervention. This was true for the LDL cholesterol goal of <100 mg/dl (65% and 46.7%, p <0.0001) and for the lower LDL cholesterol goal of <70 mg/dl (23.3% and 13.3%, p <0.0001). Differences in LDL cholesterol control between the 2 groups remained statistically significant after multivariate adjustment. In conclusion, lipid control in patients with PAD is poor and significantly inferior to that of patients with CAD even after the first vascular intervention. PMID- 22819426 TI - Stress imaging use and repeat revascularization among medicare patients with high risk coronary artery disease. AB - The optimal use of stress testing after coronary revascularization remains unclear, and overuse of stress testing might increase the rates of repeat revascularization. We analyzed the association at both the patient and regional level between the use of stress testing and repeat revascularization for a cohort of Medicare beneficiaries receiving revascularization within 30 days of an admission for symptomatic coronary artery disease. The sample consisted of 219,748 Medicare beneficiaries aged >65 years who received percutaneous coronary intervention or cardiac bypass artery grafting after hospital admission for symptomatic coronary artery disease in 2003 to 2004. Medicare claims data through 2008 identified the use of stress testing and repeat revascularization. The associations between the cumulative incidence of stress testing and repeat revascularization were analyzed using linear regression analysis. Within 6 years of the initial revascularization, the cumulative incidence of events was 0.61 for stress testing and 0.23 for repeat revascularization. Most (53.1%) repeat revascularizations were preceded by a stress test. Only 10.3% of repeat revascularization procedures were preceded by myocardial infarction. The 4-year cumulative incidence of repeat revascularization and stress testing varied between the Hospital Referral Regions represented by the sample, and the positive correlation between the rates by the health referral region accounted for only a small portion of the total health referral region variation in revascularization rates. In conclusion, stress testing is commonly performed among Medicare patients after the initial revascularization, and most repeat procedures are performed for stable coronary artery disease. The variation in stress testing patterns only explained a modest fraction of the regional variation in the repeat revascularization rates. PMID- 22819428 TI - Incidence, predictors, and implications of access site complications with transfemoral transcatheter aortic valve implantation. AB - Our study objective was to assess the incidence, predictors, and implications of access site complications related to transfemoral transcatheter aortic valve implantation (TAVI). We pooled the prospective TAVI databases of 5 experienced centers in Europe enrolling only transfemoral cases for this analysis. Access site complications were defined according to the Valve Academic Research Consortium end-point definitions. The global transfemoral TAVI database contained 986 patients. Percutaneous access and closure was performed in 803 patients (81%) and a surgical strategy in 183 (19%). Incidences of major vascular complications, life-threatening/disabling bleeding, and major bleeding were 14.2%, 11%, and 17.8% respectively. In the patient cohort with a completely percutaneous access strategy, major vascular complications and life-threatening/disabling bleedings were related to closure device failure in 64% and 29%, respectively. Female gender (odds ratio 1.63, 95% confidence interval 1.12 to 2.36) and use of >19Fr system (2.87, 1.68 to 4.91) were independent predictors for major vascular complications. Female gender (odds ratio 2.04, 95% confidence interval 1.31 to 3.17), use of >19Fr system (1.86, 1.02 to 3.38), peripheral arterial disease (2.14, 1.27 to 3.61), learning effect (0.45, 0.27 to 0.73), and percutaneous access strategy (2.39, 1.16 to 4.89) were independently associated with life threatening/disabling bleedings. In conclusion, transfemoral TAVI is associated with a >10% incidence of major vascular-related complications. A considerable number of these events is related to arteriotomy closure failure. Arterial sheath size and female gender are important determinants of major vascular complications and life-threatening/disabling bleeding. PMID- 22819427 TI - Usefulness of the six-minute walk test after continuous axial flow left ventricular device implantation to predict survival. AB - The goal of this study was to describe the predictors and significance of poor exercise tolerance after left ventricular assist device (LVAD) implantation. Despite LVAD therapy, some patients continue to exhibit exercise intolerance. The predictors and outcomes of these patients are unknown. A retrospective review of 65 LVAD recipients who performed 6-minute walk tests was conducted. Patients walking <300 m were considered to have poor exercise tolerance. Twenty patients exhibited poor exercise tolerance (221 +/- 45 m), compared to 45 patients with better exercise tolerance (406 +/- 76 m). Postoperatively, poor performers were not easily identified by functional symptoms alone, because 42% of these patients reported New York Heart Association functional class I or II symptoms. Preoperative New York Heart Association class, inotrope therapy, and intra-aortic balloon pump use were similar between the 2 groups. Multivariate analysis using all adequately powered (n >50) univariate predictors identified diabetes mellitus (odds ratio 10.493, p = 0.003) and elevated 1-month right atrial pressure (odds ratio 2.985 for every 5 mm Hg, p = 0.003) as significant predictors of poor performance (<300 m; area under the curve 0.85). The poorly performing group had increased mortality (p = 0.011), with 21% increased risk for overall mortality for every 10 m short of 300 m (fitted Cox model: hazard ratio 1.211, p = 0.0001). The distance walked in meters in a postoperative 6-minute walk test was the strongest predictor of late post-LVAD mortality (p = 0.0002). In conclusion, despite similar severity of heart failure preoperatively, some LVAD recipients may have persistent exercise intolerance postoperatively as assessed by the 6 minute walk test that is independently associated with subsequent reduced survival. PMID- 22819429 TI - Predicting risk of hospitalization or death among patients with heart failure in the veterans health administration. AB - Patients with heart failure (HF) are at high risk of hospitalization or death. The objective of this study was to develop prediction models to identify patients with HF at highest risk for hospitalization or death. Using clinical and administrative databases, we identified 198,460 patients who received care from the Veterans Health Administration and had >=1 primary or secondary diagnosis of HF that occurred within 1 year before June 1, 2009. We then tracked their outcomes of hospitalization and death during the subsequent 30 days and 1 year. Predictor variables chosen from 6 clinically relevant categories of sociodemographics, medical conditions, vital signs, use of health services, laboratory tests, and medications were used in multinomial regression models to predict outcomes of hospitalization and death. In patients who were in the >=95th predicted risk percentile, observed event rates of hospitalization or death within 30 days and 1 year were 27% and 80% respectively, compared to population averages of 5% and 31%, respectively. The c-statistics for the 30-day outcomes were 0.82, 0.80, and 0.80 for hospitalization, death, and hospitalization or death, respectively, and 0.82, 0.76, and 0.77, respectively, for 1-year outcomes. In conclusion, prediction models using electronic health records can accurately identify patients who are at highest risk for hospitalization or death. This information can be used to assist care managers in selecting patients for interventions to decrease their risk of hospitalization or death. PMID- 22819430 TI - Morphology of the bicuspid aortic valve and elasticity of the adjacent aorta in children. AB - Bicuspid aortic valve (BAV) is a common congenital malformation with the known sequela of ascending aortic dilation. The morphology of the BAV and the elasticity of the adjacent ascending aorta appear to influence the outcome. We prospectively examined 48 pediatric patients with an isolated, native BAV for the morphology and size of the aortic valve, aortic root, sinotubular junction, and ascending aorta and their elasticity indexes. A cohort of 48 matching subjects with tricuspid aortic valves was investigated as controls. A comparison of the aortic valve subtypes showed normal-size aortic dimensions in the tricuspid aortic valves. In contrast, in the BAVs, the ascending aorta and aortic valve itself tended to dilate with age and aortic elasticity deteriorated. In the BAVs, the stiffness was significantly greater (4.43 +/- 1.82 vs 3.43 +/- 0.81 in the tricuspid aortic valves; p = 0.001). The distensibility indexes decreased inversely in the BAVs (6.57 +/- 2.83 vs 7.84 +/- 2.04 cm(2) * dynes(-1) * 10(-6), p = 0.013; and 53.5 +/- 26.0 versus 64.3 +/- 17.9 kPa(-1) * 10(-3), p = 0.020). The anteroposterior-oriented phenotype of BAVs showed significantly stiffer and less distensible elasticity even after correction for congenital valve dysfunction, which was more frequent in the left-right-oriented phenotype. In conclusion, the morphology of the BAV seems to play a major role in the outcome of BAV disease, although the left-right phenotype is more prone to congenital valve dysfunction, the anteroposterior phenotype showed worse elasticity quality. PMID- 22819431 TI - Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. AB - Early repolarization pattern (ERP) has recently been associated with idiopathic ventricular fibrillation and with cardiovascular mortality in the general population. We aimed to identify electrocardiographic tools to differentiate the "malignant" form of ERP from benign ERP in a population-based study. We retrospectively assessed the prevalence of ERP by recording electrocardiograms in 1,161 southwestern French subjects 35 to 64 years old. ERP was defined by an elevation of the J point >=1 mm in 2 consecutive leads excluding leads V(1) through V(3). We categorized ERP as notching or slurring pattern as located in inferior and/or lateral leads and measured the J-point elevation amplitude. ST segment after ERP was categorized as ascendant or horizontal/nonascendant and T waves as negative or positive. Association of ERP with all-cause and cardiovascular mortalities was assessed by adjusted Cox proportional hazard models. ERP was found in 157 subjects (13.3%). During a mean follow-up of 14.2 +/ 2 years, 77 subjects died (6.6%), of whom 24 (2.1%) died from cardiovascular causes. Subjects with ERP had an increased hazard ratios for all-cause mortality (2.45, 95% confidence interval [CI] 1.44 to 4.15, p = 0.001) and cardiovascular mortality (5.60, 95% CI 2.27 to 11.8, p = 0.001). The highest risk was found for notching ERP and ERP with a nonascendant/horizontal ST segment, yielding when associated increased hazard ratios of 3.84 (95% CI 2.14 to 6.92, p = 0.001) and 8.75 (95% CI 3.48 to 22.0, p = 0.001) for all-cause and cardiovascular mortalities, respectively. Conversely, a slurring ERP or ascendant ST segment was not associated with increased mortality. ERP localization, J-point elevation amplitude, or T-wave morphology did not distinguish benign from malignant forms of ERP. In conclusion, ERP with notching pattern and horizontal/descendant ST segments was associated with the highest risk of all-cause and cardiovascular deaths. These electrocardiographic patterns may be used for risk stratification in subjects with ERP. PMID- 22819432 TI - Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). AB - AMR101 is an omega-3 fatty acid agent containing >=96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (>=200 and <500 mg/dl) despite low density lipoprotein (LDL) cholesterol control (>=40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A(2) (19.0%), and high-sensitivity C reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A(2), and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations. PMID- 22819433 TI - Detection of previously undiagnosed atrial fibrillation in patients with stroke risk factors and usefulness of continuous monitoring in primary stroke prevention. AB - The detection of undiagnosed atrial tachycardia/atrial fibrillation (AT/AF) among patients with stroke risk factors could be useful for primary stroke prevention. We analyzed newly detected AT/AF (NDAF) using continuous monitoring in patients with stroke risk factors but without previous stroke or evidence of AT/AF. NDAF (AT/AF >5 minutes on any day) was determined in patients with implantable cardiac rhythm devices and >=1 stroke risk factors (congestive heart failure, hypertension, age >=75 years, or diabetes). All devices were capable of continuously monitoring the daily cumulative time in AT/AF. Of 1,368 eligible patients, NDAF was identified in 416 (30%) during a follow-up of 1.1 +/- 0.7 years and was unrelated to the CHADS(2) score (congestive heart failure, hypertension [blood pressure consistently >140/90 mm Hg or hypertension treated with medication], age >=75 years, diabetes mellitus, previous stroke or transient ischemic attack). The presence of AT/AF >6 hours on >=1 day increased significantly with increased CHADS(2) scores and was present in 158 (54%) of 294 patients with NDAF and a CHADS(2) score of >=2. NDAF was sporadic, and 78% of patients with a CHADS(2) score of >=2 with NDAF experienced AT/AF on <10% of the follow-up days. The median interval to NDAF detection in these higher risk patients was 72 days (interquartile range 13 to 177). In conclusion, continuous monitoring identified NDAF in 30% of patients with stroke risk factors. In patients with NDAF, AT/AF occurred sporadically, highlighting the difficulty in detecting paroxysmal AT/AF using traditional monitoring methods. However, AT/AF also persisted for >6 hours on >=1 days in most patients with NDAF and multiple stroke risk factors. Whether patients with CHADS(2) risk factors but without a history of AF might benefit from implantable monitors for the selection and administration of anticoagulation for primary stroke prevention merits additional investigation. PMID- 22819434 TI - Evidence-based editing: factors influencing the number of citations in a national journal. AB - PURPOSE: Citations received by papers published within a journal serve to increase its bibliometric impact. The objective of this paper was to assess the influence of publication language, article type, number of authors, and year of publication on the citations received by papers published in Gaceta Sanitaria, a Spanish-language journal of public health. METHODS: The information sources were the journal website and the Web of Knowledge, of the Institute of Scientific Information. The period analyzed was from 2007 to 2010. We included original articles, brief original articles, and reviews published within that period. We extracted manually information regarding the variables analyzed and we also differentiated among total citations and self-citations. We constructed logistic regression models to analyze the probability of a Gaceta Sanitaria paper to be cited or not, taking into account the aforementioned independent variables. We also analyzed the probability of receiving citations from non-Spanish authors. RESULTS: Two hundred forty papers fulfilled the inclusion criteria. The included papers received a total of 287 citations, which became 202 when excluding self citations. The only variable influencing the probability of being cited was the publication year. After excluding never cited papers, time since publication and review papers had the highest probabilities of being cited. Papers in English and review articles had a higher probability of citation from non-Spanish authors. CONCLUSIONS: Publication language has no influence on the citations received by a national, non-English journal. Reviews in English have the highest probability of citation from abroad. Editors should decide how to manage this information when deciding policies to raise the bibliometric impact factor of their journals. PMID- 22819435 TI - The influence of socioeconomic status on the predictive power of self-rated health for 6-year mortality in English and Brazilian older adults: the ELSA and Bambui cohort studies. AB - PURPOSE: There is mixed evidence that socioeconomic status (SES) affects the predictive power of self-rated health (SRH) for mortality. We sought to compare the predictive value of SRH for 6-year mortality in English and Brazilian older adults, and to assess whether this association varies by SES in these populations. METHODS: Data came from the English and the Bambui (Brazil) cohort studies of aging. Potential confounding variables included sociodemographic characteristics, lifestyle, self-reported diseases, physical functioning, mental symptoms, and selected biomarker measures. RESULTS: Participants were 5183 English and 1499 Brazilians aged 60 years and over. Low health ratings were independently associated with subsequent mortality in both populations. However, the predictive power of poor SRH for death was much higher for English (a population with higher SES level) than for Brazilians (adjusted hazard ratios 4.45 [95% confidence interval, 3.04-6.51] and 1.88 [1.25-2.81], respectively). In both populations, the predictive value of SRH for mortality was higher among those in the highest income tertile. CONCLUSIONS: Our results suggest that the association between SRH and mortality is underestimated in populations and in subgroups of population with low SES level. Further international research is needed to examine the generalizability of this pattern. PMID- 22819437 TI - Switching from methadone to tapentadol for cancer pain. PMID- 22819436 TI - Use of pregabalin in the management of chronic uremic pruritus. AB - CONTEXT: Uremic pruritus (UP) affects many patients suffering from chronic kidney disease (CKD) and has a negative impact on quality of life and survival. It has become increasingly evident that central transmission and sensitization processes similar to those observed in chronic pain are important mechanisms of pruritus. OBJECTIVES: To test the potential role of pregabalin in reducing the intensity of UP in CKD patients. METHODS: We prospectively collected data on CKD patients who suffered from severe intractable pruritus. Patients were asked to record the intensity of pruritus on a visual analogue scale. RESULTS: Twelve patients were studied. The average pretreatment pruritus score was 9.7 +/- 0.9 and decreased to 3.7 +/- 2.35, 3.2 +/- 1.75, and 3 +/- 1.5 after one, four, and 24 weeks of treatment, respectively (P < 0.05). The positive effect of pregabalin was demonstrated during the first week of therapy in six patients. Most patients required 25mg a day. Pregabalin was well tolerated, with somnolence and dizziness developing in two patients. CONCLUSION: We demonstrated dramatic improvement of long-standing UP after the initiation of pregabalin. We suggest that pregabalin can be used safely in CKD but careful titration of the dose is required to obtain an optimal response and minimize the possible adverse effects. PMID- 22819438 TI - Enhancing patient-professional communication about end-of-life issues in life limiting conditions: a critical review of the literature. AB - CONTEXT: The End of Life Care Strategy for England highlights effective communication between patients and professionals as key to facilitating patient involvement in advance care planning. The strategy emphasizes that, currently, communication in patients with noncancer life-limiting conditions is likely to be inadequate, and research has identified that patients with chronic obstructive pulmonary disease and heart failure have a poor understanding of their condition. OBJECTIVES: To identify existing interventions of patient-professional communication developed for life-limiting conditions and explore the applicability of interventions developed within a cancer framework to other diagnostic groups. METHODS: A comprehensive literature review of studies describing communication interventions for patients receiving end-of-life care was undertaken. Ten electronic databases were searched. Inclusion criteria were all English language studies relating to patient-professional communication interventions for patients with life-limiting conditions receiving end-of-life care. RESULTS: Of the 755 articles initially identified, 16 met the inclusion criteria. Three core themes emerged from the synthesis of the literature: using education to enhance professional communication skills, using communication to improve patient understanding, and using communication skills to facilitate advance care planning. CONCLUSION: Although limited, evidence relating to the development and evaluation of communication interventions for patients with life limiting illnesses would suggest that a successful intervention should include combined components of training, patient discussion, and education. In a context of limited resources and an increasing number of patients living and dying with chronic life-limiting conditions, the need for appropriate and effective communication strategies should be seen as a priority for both research and policy. PMID- 22819439 TI - Analyzing phase III studies in hospice/palliative care. a solution that sits between intention-to-treat and per protocol analyses: the palliative-modified ITT analysis. AB - Intention-to-treat (ITT) analyses are the standard way to evaluate randomized controlled trials (RCTs) to minimize Type I errors related to differential rates of noncompletion from one study arm. People in palliative care often die sooner than predicted as a direct result of disease progression, some of whom will be participating in RCTs and who will, therefore, withdraw or die after randomization for reasons unrelated to the intervention. This proportion of withdrawals is statistically negligible in other clinical disciplines, but commonplace in hospice/palliative care, creating a systematic bias away from the true effect. ITT analyses in hospice/palliative care that deem all withdrawals to be treatment failures or that impute data from deteriorating participants systematically underestimate the benefits of interventions, reducing the power of these studies. Equally unacceptable would be a per protocol analysis that excludes all withdrawals after randomization as this will underestimate toxicity. A modified analytic approach is needed on a continuum between ITT and per protocol analyses. To address data after randomization where there is a high rate of withdrawals because of death or deterioration, criteria need to include being: 1) prespecified in the original protocol; 2) clinically absolutely the result of disease progression; 3) identified by the blinded Independent Data Monitoring Committee as being unrelated to the intervention(s); and 4) accounted for in the study's CONSORT diagram. Such data should not be included in the analysis of the primary outcome. This article aims to define a better way of balancing Type I and Type II errors in hospice/palliative care RCT analyses using the palliative modified ITT analysis. Arguably, the palliative-modified ITT analysis should be the primary evaluation of hospice/palliative care Phase III studies but, as a minimum, should routinely be the key sensitivity analysis. PMID- 22819440 TI - Palliative sedation: reliability and validity of sedation scales. AB - CONTEXT: Observer-based sedation scales have been used to provide a measurable estimate of the comfort of nonalert patients in palliative sedation. However, their usefulness and appropriateness in this setting has not been demonstrated. OBJECTIVES: To study the reliability and validity of observer-based sedation scales in palliative sedation. METHODS: A prospective evaluation of 54 patients under intermittent or continuous sedation with four sedation scales was performed by 52 nurses. Included scales were the Minnesota Sedation Assessment Tool (MSAT), Richmond Agitation-Sedation Scale (RASS), Vancouver Interaction and Calmness Scale (VICS), and a sedation score proposed in the Guideline for Palliative Sedation of the Royal Dutch Medical Association (KNMG). Inter-rater reliability was tested with the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient. Correlations between the scales using Spearman's rho tested concurrent validity. We also examined construct, discriminative, and evaluative validity. In addition, nurses completed a user-friendliness survey. RESULTS: Overall moderate to high inter-rater reliability was found for the VICS interaction subscale (ICC = 0.85), RASS (ICC = 0.73), and KNMG (ICC = 0.71). The largest correlation between scales was found for the RASS and KNMG (rho = 0.836). All scales showed discriminative and evaluative validity, except for the MSAT motor subscale and VICS calmness subscale. Finally, the RASS was less time consuming, clearer, and easier to use than the MSAT and VICS. CONCLUSION: The RASS and KNMG scales stand as the most reliable and valid among the evaluated scales. In addition, the RASS was less time consuming, clearer, and easier to use than the MSAT and VICS. Further research is needed to evaluate the impact of the scales on better symptom control and patient comfort. PMID- 22819442 TI - Vanishing glioblastoma after corticosteroid therapy: does this occurrence modify our surgical strategy? PMID- 22819441 TI - Platelet serotonin in primary Sjogren's syndrome: level and relation with disease activity. AB - Primary Sjogren's syndrome (pSS) is chronic autoimmune disorder of unknown ethiopathogenesis. In line with the concept of neuroimmunohormonal dysregulation in inflammatory rheumatic diseases, the aim of this study was to investigate platelet serotonin level (PSL) in patients with pSS and its relation with the activity and duration of the disease. Significantly lower PSL in pSS patients (N=61) was shown as compared to healthy controls (N=103). No correlation was found between PSL and the actual disease activity assessed by the recently developed EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI). Results suggest involvement of the serotonin system in the pathogenesis of pSS. PMID- 22819443 TI - External tissue expanders as adjunct therapy in closing difficult wounds. PMID- 22819444 TI - Bidirectional ventricular tachycardia secondary to subacute myocarditis. AB - We report a case of subacute myocarditis with severe heart failure referred for urgent cardiac transplantation. The patient had an episode of bidirectional ventricular tachycardia during the acute admission. Subacute myocarditis should be added to the limited differential diagnosis of bidirectional ventricular tachycardia. PMID- 22819445 TI - Periprocedural antithrombotic management of patients undergoing ablation for atrial fibrillation: what we currently do...and what should we do? PMID- 22819446 TI - Integrating palliative care in the intensive care unit. AB - The admission of cancer patients into intensive care units (ICUs) is on the rise. These patients are at high risk for physical and psychosocial suffering. Patients and their families often face difficult end-of-life decisions that highlight the importance of effective and empathetic communication. Palliative care teams are uniquely equipped to help care for cancer patients who are admitted to ICUs. When utilized in the ICU, palliative care has the potential to improve a patient's symptoms, enhance the communication between care teams and families, and improve family-centered decision making. Within the context of this article, we will discuss how palliative care can be integrated into the care of ICU patients and how to enhance family-centered communication; we will also highlight the care of ICU patients at the end of life. PMID- 22819447 TI - The sterols isolated from Evening Primrose oil modulate the release of proinflammatory mediators. AB - Evening Primrose oil is a natural product extracted by cold-pressed from Oenothera biennis L. seeds. The unsaponifiable matter of this oil is an important source of interesting minor compounds, like long-chain fatty alcohols, sterols and tocopherols. In the present study, sterols were isolated from the unsaponifiable matter of Evening Primrose oil, and the composition was identified and quantified by GC and GC-MS. The major components of sterols fraction were beta-Sitosterol and campesterol. We investigated the ability of sterols from Evening Primrose oil to inhibit the release of different proinflammatory mediators in vitro by murine peritoneal macrophages stimulated with lipopolysaccharide. Sterols significantly and dose-dependently decreased nitric oxide production. Western blot analysis showed that nitric oxide reduction was a consequence of the inhibition of inducible nitric oxide synthetase expression. Sterols also reduced tumor necrosis factor-alpha, interleukine 1beta and tromboxane B2. However, sterols did not reduce prostaglandin E2. The reduction of eicosanoid release was related to the inhibition of cyclooxygenase-2 expression. These results showed that sterols may have a protective effect on some mediators involved in inflammatory damage development, suggesting its potential value as a putative functional component of Evening Primrose oil. PMID- 22819448 TI - The novel phloroglucinol derivative BFP induces apoptosis of glioma cancer through reactive oxygen species and endoplasmic reticulum stress pathways. AB - Prenyl-phloroglucinol derivatives from hop plants have been shown to have anticancer activities. This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (2,4-bis(4 fluorophenylacetyl)phloroglucinol; BFP). BFP induced cell death and anti proliferation in three glioma, U251, U87 and C6 cells, but not in primary human astrocytes. BFP-induced concentration-dependently cell death in glioma cells was determined by MTT and SRB assay. Moreover, BFP-induced apoptotic cell death in glioma cells was measured by Hochest 33258 staining and fluorescence-activated cell sorter (FACS) of propidine iodine (PI) analysis. Treatment of U251 human glioma cells with BFP was also found to induce reactive oxygen species (ROS) generation, which was detected by a fluorescence dye used FACS analysis. Treatment of BFP also increased a number of signature endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP)-78, GRP-94, IRE1, phosphorylation of eukaryotic initiation factor-2alpha (eIF-2alpha) and up-regulation of CAAT/enhancer-binding protein homologous protein (CHOP). Moreover, treatment of BFP also increased the down-stream caspase activation, such as pro-caspase-7 and pro-caspase-12 degradation, suggesting the induction of ER stress. Furthermore, BFP also induced caspase-9 and caspase-3 activation as well as up-regulation of cleaved PARP expression. Treatment of antioxidants, or pre-transfection of cells with GRP78 or CHOP siRNA reduced BFP-mediated apoptotic-related protein expression. Taken together, the present study provides evidences to support that ROS generation, GRP78 and CHOP activation are mediating the BFP-induced human glioma cell apoptosis. PMID- 22819449 TI - Quercetin 3,7,3',4'-tetrasulphated isolated from Flaveria bidentis inhibits tissue factor expression in human monocyte. AB - Sulphated esters of the flavonoids sulphated quercetin 3,7,3',4'-tetrasulphated (QTS) and quercetin 3-acetyl-7,3,4'-trisulphate (ATS), isolated from Flaveria bidentis, have demonstrated anticoagulant and antiplatelet properties. In this study, we examined if both compounds affected the expression of the procoagulant tissue factor (TF) induced by lipopolysaccharide (LPS) on human monocyte. Monocytes were pretreated with different concentrations of each flavonoid (0.1 500 MUM), followed by a 4h incubation with LPS in order to induce TF expression. Results of the TF expression showed different behaviors for the two flavonoids studied. A slight inhibitory effect on the TF expression was detected at a QTS concentration of 0.1 MUM, but from 1 MUM onwards a significant inhibitory effect that remained up to 500 MUM could be observed. In contrast, ATS induced a poor inhibitory effect on TF expression at all concentrations tested. These results suggest that QTS has another antithrombotic property, to be added to its already renowned ability as an anticoagulant and antiplatelet compound. PMID- 22819450 TI - Carbonyl reductase mRNA abundance and enzymatic activity as potential biomarkers of oxidative stress in marine fish. AB - Carbonyl reductase (CBR) is an enzyme involved in protection from oxidative stress. In rainbow trout (Oncorhynchus mykiss), the hepatic mRNA abundance of the two isoforms (A and B) is increased after exposure to treated sewage effluents, as well as after exposure with beta-naphthoflavone (beta-NF) and the pro-oxidant paraquat. In this study, we show that the same chemicals similarly increase the single known hepatic CBR mRNA level and CBR catalytic activity in the coastal living eelpout (Zoarces viviparus). Hepatic CBR mRNA abundance and catalytic activity were also compared between eelpout collected at contaminated and reference sites on the Swedish west coast, but no differences were observed. In conclusion, CBR is a potential biomarker candidate for monitoring the exposure and effects of AhR agonists and/or pro-oxidants in the marine environment, but more research is needed to investigate temporal regulation as well as dose dependency for different chemicals. The mRNA and enzymatic assays presented in this study provide two additional tools for researchers interested in expanding their biomarker battery. PMID- 22819451 TI - Detecting human mitigation intervention: effects of sewage treatment upgrade on rocky macrofaunal assemblages. AB - The effectiveness of secondary vs primary treatments of wastewaters in mitigating the effects of sewage discharge on the multivariate structure and diversity of rocky invertebrate assemblages was assessed over a nine-year period through a beyond-BACI experimental design. Assemblages from different tidal levels (i.e. mid-shore, low-shore, 3 m and 8 m subtidal) were sampled at the impact location (I) and three control locations (Cs) at a hierarchy of spatial scales. The improvement in water treatment significantly changed the structure, diversity and cover of low intertidal assemblages. Faunal cover at 8 m subtidal increased significantly after the treatment upgrade at I. The secondary treatment also affected patterns of spatial heterogeneity between I and Cs for mid-shore and 3 m subtidal assemblages. This study demonstrates that powerful experimental designs combined with univariate and multivariate analytical approaches are fundamental in distinguishing the subtle effects of human impact from those of natural processes. PMID- 22819452 TI - Myositis ossificans in medial, lateral pterygoid, and contralateral temporalis muscles: a rare case report. AB - Myositis ossificans is ossification and bone formation within muscle. It is a rare and unusual pathologic entity that has defied most efforts to establish definite etiology, pathogenesis, and satisfactory treatment. Myositis ossificans is mainly of 2 types: myositis ossificans progressiva (MOP) and myositis ossificans traumatica (MOT). Myositis ossificans idiopathic is also reported in the literature. When it affects the muscles of mastication, it causes severe trismus. Computed tomography scans and magnetic resonance imaging can effectively delineate the calcified mass. In this article, we present a case of MOT of the medial, lateral pterygoid, and contralateral temporalis muscles. PMID- 22819453 TI - Characteristics and cost impact of severe odontogenic infections. AB - OBJECTIVE: The objective of this study was to retrospectively analyze the clinical presentation, surgical management, and cost implications of inpatients treated for odontogenic infections at a public tertiary care hospital. STUDY DESIGN: Specific analysis from 3 years of chart review included length of stay, cost of hospitalization, site of infection, number of infected spaces, microbiology profile, antibiotics administered, intensive care unit (ICU) stay, number of days intubated, comorbidities, number of operating room visits, imaging studies, and whether the patients received preadmission treatment. RESULTS: Multiple fascial spaces were involved in most of the infections. The average length of stay was 4.57 days and average time in the ICU was 3.1 days. Ninety percent of the patients had a coexisting medical comorbidity. The overall hospital costs totaled $749,382 averaging $17,842 per person. CONCLUSIONS: This study reveals a staggering cost burden on a public health care facility as a result of odontogenic infections. PMID- 22819454 TI - Comparison of lidocaine metabolism for different anesthesia techniques in rabbits with liver disease. AB - OBJECTIVE: This study was designed to investigate the serum lidocaine concentrations (SLC) after local infiltration anesthesia (IA) and mandibular anesthesias (MA) in rabbits with carbon tetrachloride (CCl4)-induced chronic liver damage (CLD). STUDY DESIGN: Fourteen rabbits were administered CCl4 in group 1, MA (CLD-MA; n = 7); in group 2, IA (CLD-IA; n = 7); in group 3, MA (H MA; n = 7); and in group 4, IA (H-IA; n = 6) was performed. SLC were measured. RESULTS: SLC showed difference over time. At the 10th minute, mean SLC in IA groups were higher than in MA groups. At the 120th minute, the highest mean concentration was found in the CLD-IA group. CONCLUSIONS: SLC increases in CLD, and serum lidocaine concentration after IA in the mandibular anterior region is higher than it is after MA. PMID- 22819455 TI - Effect of 2 flap designs on postoperative pain and swelling after impacted third molar surgery. AB - OBJECTIVE: The aim of this study was to evaluate 2 flap designs (envelope and modified triangular flap) for postoperative pain and swelling after mandibular impacted third molar surgery. STUDY DESIGN: Thirty patients who had symmetric bilateral fully impacted mandibular third molars were selected. Left teeth were approached with an envelope flap, and right teeth were removed using a modified triangular flap. Postoperative pain and swelling were evaluated until the seventh day by using 2 verbal rating scales. RESULTS: Statistical analyses showed that there were no significant differences between the 2 incision techniques regarding postoperative pain and swelling (P > .05). CONCLUSIONS: There is no significant difference between the envelope and modified triangular flap regarding postoperative pain and swelling after impacted third molar surgery. PMID- 22819456 TI - Pattern of mandibular third molar impaction in the Indian population: a retrospective clinico-radiographic survey. AB - OBJECTIVE: The objective of this study was to study incidence of type of impaction of mandibular third molars in the Indian population. STUDY DESIGN: Data of 1200 patients examined during a 5-year period were reviewed, which included status of mandibular third molar for inclination, emergence in oral cavity, and prevalence of caries. Radiographically, angulation of tooth, level of occlusal surface of third molar with respect to second molar, relationship between ascending ramus of mandible and distal surface of third molar, and proximity to inferior alveolar nerve were studied. RESULTS: Of 1200 patient data reviewed, 620 (51.77%) were of men and 580 (48.3%) were women in the age group of 20 to 40 years (26.3 years). Mesioangular impaction was most prevalent followed by distoangular. A strong statistical significance was found between gender and ramus relationship. Fifty percent of cases showed proximity to the inferior alveolar nerve, which was more frequent in males (58.3%). CONCLUSION: Our study highlights mesioangular impaction as the most frequently encountered angulation in impacted teeth. PMID- 22819457 TI - Effective medical treatment in patients with SAPHO syndrome involving the mandible. PMID- 22819458 TI - Transketolase-like protein 1 expression in recurrent oral squamous cell carcinoma after curative resection: a case report. AB - BACKGROUND: Squamous cell carcinoma of the oral cavity (OSCC) is one of the common malignant tumors of the head and neck worldwide. Transketolase-like protein 1 (TKTL1), which has an important role in controlling the nonoxidative pentose-phosphate pathway, is significantly overexpressed in several different tumor entities. TKTL1 overexpression confers an advantage on malignant cells, allowing them to grow faster and to metastasize. However, to date, there is no link between TKTL1 expression and (metastatic) OSCC. CASE REPORT: We report the first case of simultaneous penile, lung, bone, and suprarenal gland metastases from a primary bifocal moderately differentiated keratinized OSCC in a 53-year old man that occurred 7 months after primary diagnosis. The tumor stained positive for TKTL1, epithelial growth factor receptor, and cyclooxygenase-2 (COX 2). To the best of our knowledge, no case has been reported to date on the manifestation of synchronous distant metastases of OSCC in the penile and the suprarenal gland. CONCLUSIONS: Secondary malignancy of the penis is an uncommon clinical entity. Because of the possibility of penile metastatic spread, this case report suggests that particular attention should be paid to physical examination of patients who undergo surgical procedures from OSCC, including those seemingly without metastatic disease. For the first time, our case provides evidence that TKTL1 expression in recurrent OSCC might be associated with tumor formation and metastasis. Antibodies, small molecules, COX-2 inhibitors, or a ketogenic diet might be promising for therapy of metastatic OSCC. PMID- 22819459 TI - Management of aggressive and extensive benign mandibular lesions by resection, curettage, freezing, and reimplantation of involved segment. AB - OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of treatment of aggressive and extensive benign mandibular lesions by resection, curettage, freezing, and reimplantation of involved segments. STUDY DESIGN: In 9 patients with extensive, recurrent, and aggressive mandibular lesions, reimplantation of resected segment after immersing in liquid nitrogen was done. RESULTS: After >=18 months' follow-up, out of the 9 patients, one developed wound dehiscence that healed with conservative management and another local abscess and subsequent pathologic fracture that was treated by open reduction and internal fixation. No recurrence was found within the follow-up period. CONCLUSIONS: Our study showed that management of aggressive lesions of the mandible by this method decreases the recurrence rate and eliminates the requirement of another operation for harvesting bone graft and reconstruction. PMID- 22819460 TI - Evaluation of collagen-based membranes for guided bone regeneration, by three dimensional computerized microtomography. AB - OBJECTIVE: The aim of this study was to evaluate the use of a collagen-based membrane compared with no treatment on guided bone regeneration by 3-dimensional computerized microtomography (MUCT). STUDY DESIGN: Defects were created between the mesial and distal premolar roots of the second and third premolars (beagle dogs; n = 8). A collagen-based membrane (Vitala; Osteogenics Biomedical Inc., TX, USA) was placed in one of the defects (membrane group; n = 16), and the other was left untreated (no-membrane group; n = 16). Left and right sides provided healing samples for 2 and 16 weeks. Three-dimensional bone architecture was acquired by MUCT and categorized as fully regenerated (F, bone height and width) or nonregenerated (N). RESULTS: Chi-square tests (95% level of significance) showed that tooth did not have an effect on outcome (P = .5). Significantly higher F outcomes were observed at 16 weeks than 2 weeks (P = .008) and in membrane group than in no-membrane group (P = .008). CONCLUSIONS: The collagen-based membrane influenced bone regeneration at the furcation. PMID- 22819461 TI - Tuberculous osteomyelitis of zygoma: an unusual location. AB - Tubercular osteomyelitis of midfacial bones is extremely rare, although tuberculosis of long bones and the vertebral column is not uncommon. Because of the rare incidence, myriad presentation, and lack of specific symptoms, this condition presents a challenge in diagnosis and calls for acute clinical awareness. This article presents a case report of a 12-year-old girl with complaints of gradually increasing swelling lateral to and below her right eye for 4 months with pus discharge. She was treated with surgical curettage and 4 drug antitubercular therapy and responded with complete remission of the sinus. PMID- 22819462 TI - Medicinal leech therapy on head and neck patients: a review of literature and proposed protocol. AB - OBJECTIVES: To this day, a standardized protocol for medicinal leech therapy does not exist. The purpose of this article was to review literature in the hope of proposing a unified, coherent, feasible, and safe protocol for using medicinal leeches when warranted. STUDY DESIGN: A literature search was conducted in the following databases: PubMed, MDConsult, The Cochrane Library, OMIM, and Google. This was supplemented by a search for selected authors. Keywords used were medicinal leech therapy, leech therapy, leeching, replantation, thromboembolism, venous congestion, Hirudo medicinalis, Hirudotherapy, leech protocol, and Hirudo protocol. RESULTS: Based on titles and abstracts, 26 articles and 1 Web site were identified. CONCLUSIONS: Leech therapy can be an excellent alternative for the treatment of venous congestion in free flaps, pedicled flaps, and replanted tissues. Psychological precounseling, antibiotic therapy, number of leeches to be used, length of therapy, and laboratory checks should be taken into consideration before initiating therapy. PMID- 22819463 TI - Evaluation of the nutritional state of the elderly. PMID- 22819464 TI - The plasma leptin/adiponectin ratio predicts first cardiovascular event in men: a prospective nested case-control study. AB - OBJECTIVE: The plasma leptin/adiponectin (L/A) ratio has been proposed as a preferential marker of atherosclerosis susceptibility compared to leptin and adiponectin alone. We determined the extent to which the L/A ratio predicts incident cardiovascular disease (CVD) taking account of clinical risk factors, microalbuminuria, the total cholesterol/HDL cholesterol (TC/HDL-C ratio), triglycerides, high sensitive C-reactive protein (hs-CRP) and insulin sensitivity (homeostasis model assessment (HOMA(ir))). METHODS: A community-based prospective nested case-control study was carried out in 103 non-diabetic men who developed a first cardiovascular event (cases) and 106 male control subjects (no clinically manifest CVD and no lipid lowering drug use at baseline; median follow-up of 3.0 and 10.5 years, respectively). Plasma leptin, adiponectin, the leptin/adipnectin (L/A) ratio, as well as hs-CRP, HOMA(ir) and the TC/HDL-C ratio were determined at baseline. RESULTS: Plasma leptin levels and the L/A ratio were higher in cases vs. controls (p=0.002 for both), but the difference in adiponectin was not significant (p=0.10). Age-adjusted incident CVD was associated with plasma leptin, adiponectin and the L/A ratio (p=0.045 to p=0.001). The relationships of incident CVD with plasma leptin (p=0.19) and adiponectin (p=0.073) lost statistical significance after additional adjustment for smoking, waist circumference, hypertension, microalbuminuria, the TC/HDL-C ratio, hs-CRP and HOMA(ir). In this fully adjusted analysis, the L/A ratio remained predictive of incident CVD (hazard ratio: 1.40 (95% CI 1.05-1.87), p=0.024). CONCLUSION: This study suggests that the L/A ratio may be a preferential marker of a first cardiovascular event in men compared to plasma leptin and adiponectin levels alone. PMID- 22819465 TI - Proton channels in algae: reasons to be excited. AB - A fundamental requirement of all eukaryotes is the ability to translocate protons across membranes. This is critical in bioenergetics, for compartmentalized metabolism, and to regulate intracellular pH (pH(i)) within a range that is compatible with cellular metabolism. Plants, animals, and algae utilize specialized transport machinery for membrane energization and pH homeostasis that reflects the prevailing ionic conditions in which they evolved. The recent characterization of H(+)-permeable channels in marine and freshwater algae has led to the discovery of novel functions for these transport proteins in both cellular pH homeostasis and sensory biology. Here we review the potential implications for understanding the origins and evolution of membrane excitability and the phytoplankton-based marine ecosystem responses to ocean acidification. PMID- 22819466 TI - Mix-and-match: ligand-receptor pairs in stomatal development and beyond. AB - Stomata are small valves on the plant epidermis balancing gas exchange and water loss. Stomata are formed according to positional cues. In Arabidopsis, two EPIDERMAL PATTERNING FACTOR (EPF) peptides, EPF1 and EPF2, are secreted from stomatal precursors enforcing proper stomatal patterning. Here, I review recent studies revealing the ligand-receptor pairs and revising the previously predicted relations between receptors specifying stomatal patterning: ERECTA-family and TOO MANY MOUTHS (TMM). Furthermore, EPF-LIKE9 (EPFL9/Stomagen) promotes stomatal differentiation from internal tissues. Two EPFL peptides specify inflorescence architecture, a process beyond stomatal development, as ligands for ERECTA. Thus, broadly expressed receptor kinases may regulate multiple developmental processes through perceiving different peptide ligands, each with a specialized expression pattern. TMM in the epidermis may fine-tune multiple EPF/EPFL signals to prevent signal interference. PMID- 22819467 TI - Order by disorder in plant signaling. AB - Protein intrinsic disorder (ID), referring to the lack of a fixed tertiary structure, is an emerging topic in plant science. Proteins with ID challenge our perception of protein interactions because of their malleable behavior. They are abundant in highly regulated processes such as cellular signaling and transcription, where they exploit the flexibility of ID. In this opinion article we highlight trends in the field of protein ID and discuss its implications for interactions between plant transcription factors (TFs) and the cellular signaling hub protein RADICAL-INDUCED CELL DEATH 1 (RCD1). We envision RCD1-TF interactions as models for translating knowledge of ID-based interactions in vitro to the organismal level in vivo, and urge increased focus on ID in basic plant research and agricultural sciences. PMID- 22819468 TI - Ischemic mitral regurgitation: an intraoperative echocardiographic perspective. PMID- 22819469 TI - The effect of isoflurane on survival and myocardial infarction: a meta-analysis of randomized controlled studies. AB - OBJECTIVE: The aim of this meta-analysis was to investigate the cardioprotective properties of isoflurane versus any comparator in terms of the rate of myocardial infarction and all-cause mortality. DESIGN: Pertinent studies were searched independently in Biomed, Central, PubMed, Embase, and the Cochrane Central Register of clinical trials. The primary endpoint was mortality at the longest follow-up available. SETTING: A hospital. PARTICIPANTS: Randomized controlled trials. INTERVENTION: A meta-analysis of 37 trials. MEASUREMENTS AND MAIN RESULTS: The 37 included trials randomized 3,539 patients in cardiac (16 studies) and in noncardiac surgery (21 studies) with noninhalation comparators in 55% of trials. The overall analysis showed no difference in mortality between the isoflurane and control groups (16/1,602 [1.0%] v 23/1,937 [1.2%], odds ratios (OR) = 0.76 [0.39-1.47], p = 0.4 with 37 studies included) and no difference in the rate of myocardial infarction (3/1,312 [0.2%] v 1/1,532 [0.07%], OR = 2.03 [0.27-15.49], p = 0.5 with 30 studies included). Mortality was reduced in the isoflurane group when only studies with a low risk of bias were included in the analyses (0/540 [0%] v 5/703 [0.7%] in the control arm, OR = 0.13 [0.02-0.76], p = 0.02) with 4 cardiac and 6 noncardiac trials included and 5 noninhalation and 5 inhalation agents as the comparator. A trend was noted when a subanalysis was performed with propofol as a comparator (1/544 [0.2%] v 6/546 [1.1%], p = 0.05, with 16 studies included). CONCLUSIONS: Isoflurane reduced mortality in high quality studies and showed a trend toward a reduction in mortality when it was compared with propofol. No differences in the rates of overall mortality and myocardial infarction were noted. PMID- 22819470 TI - [SMART syndrome: case report of a rare complication after cerebral radiation therapy]. AB - The authors report a 71-year-old woman case who developed, 7 years after a cerebral radiation therapy for a parietooccipital glioblastoma, a stroke-like migraine attacks after radiotherapy syndrome (SMART syndrome), a rare complication characterized by reversible neurologic deficits with migraine described after cerebral irradiation. Transient gyriform reversible enhancement is found on MRI during crises. This case report allows discussing the clinical, iconographic presentation and the clinical outcome of this syndrome at the light of the literature publication. PMID- 22819471 TI - Tranexamic acid therapy in pediatric cardiac surgery: a single-center study. AB - BACKGROUND: We conducted a retrospective study of cyanotic and acyanotic patients undergoing cardiopulmonary bypass to determine the effect of tranexamic acid on blood loss and blood products administered during the operation in pediatric cardiac surgery. METHODS: From January 2008 to December 2011, during 2 different periods, a total of 231 pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (123 cyanotic, 108 acyanotic) were included in this study. A total of 104 patients were in the antifibrinolytic group and exclusively treated with tranexamic acid that was given as a bolus of 20 mg/kg(-1) after anesthetic induction and 20 mg/kg(-1) after protamine. The other 127 patients were in the control group. We analyzed intraoperative and postoperative outcomes of tranexamic acid administration. RESULTS: There were no differences in mortality or operative time, but blood loss in 48 hours was greater in the control group (p=0.0012). A significant difference was found in the amount of intraoperative erythrocyte concentrate transfused (140+/-55 vs 170+/-78 mL, p=0.0011) but not in number. The number and amount of erythrocyte concentrate transfused in the first 48 postoperative hours were also greater in the control group (45 vs 77 patients, p=0.012; 100+/-40 vs 120+/-55 mL, p=0.0022). There were not many differences in the effect of tranexamic acid between the cyanotic and acyanotic subgroup. CONCLUSIONS: This retrospective study provides evidence that tranexamic acid may be used in the field of congenital cardiac surgery effectively. PMID- 22819472 TI - The role of consolidation therapy for stage III non-small cell lung cancer with persistent N2 disease after induction chemotherapy. AB - BACKGROUND: Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III N2 non-small cell lung cancer patients. This population has high rates of local regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients. METHODS: In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local regional failure, distant failure, and overall survival. RESULTS: All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p=0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p=0.003). However, additional postoperative chemotherapy had no affect on local-regional failure. CONCLUSIONS: Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery. PMID- 22819474 TI - A promising inert support for laccase production and decolouration of textile wastewater by the white-rot fungus Trametes pubescesns. AB - Cubes of nylon sponge, cubes of polyurethane foam (PUF), cuttings of stainless steel sponges and the commercial carriers KaldnesTM K1 were tested as inert supports for laccase production by the white-rot fungus Trametes pubescens under semi-solid-state fermentation conditions. The cultures operating with KaldnesTM K1 led to the highest laccase activity (3667 U/l). In addition this support could be re-utilised, making the whole process more economical. Subsequently, the decolouration of simulated textile wastewater (STW) by T. pubescens grown on the different tested supports under semi-solid-state fermentation conditions was studied. Decolouration percentages around 66-80% were obtained in 96 h. It was found that STW decolouration was due to two mechanisms: laccase action (biodegradation) and adsorption onto fungal mycelium, save for the PUF cultures in which decolouration was mainly due to adsorption onto the support. Further, the decolouration of STW by KaldnesTM K1 cultures in three successive batches of 96 h each was studied. Decolouration percentages of 51.3, 70.0 and 69.8%, were attained for each batch, respectively. PMID- 22819475 TI - Apology letter. PMID- 22819476 TI - Separation of low concentration of cesium ion from wastewater by electrochemically switched ion exchange method: experimental adsorption kinetics analysis. AB - A series of experiments were performed to evaluate the continuous separation of cesium based on an electrochemically switched ion exchange (ESIX) process using a diaphragm-isolated reactor with two identical nickel hexacyanoferrate/porous three-dimensional carbon felt (NiHCF/PTCF) electrodes as working electrodes. The effects of applied potential, initial concentrations and pH values of the simulation solutions on the adsorption of cesium ion were investigated. The adsorption rate of cesium ion in the ESIX process was fitted by a pseudo-first order reaction model. The experiments revealed that the introduction of applied potential on the electrodes greatly enhanced the adsorption/desorption rate of Cs(+) and increased the separation efficiency. H(3)O(+) was found to play a dual role of electrolyte and competitor, and the adsorption rate constant showed a curve diversification with an increase in pH value. Also, it was found that the electrochemically switched adsorption process of Cs(+) by NiHCF/PTCF electrodes proceeded in two main steps, i.e., an ESIX step with a fast adsorption rate and an ion diffusion step with a slow diffusion rate. Meanwhile, the NiHCF/PTCF film electrode showed adsorption selectivity for Cs(+) in preference to Na(+). PMID- 22819478 TI - Virus inactivation in the presence of quartz sand under static and dynamic batch conditions at different temperatures. AB - Virus inactivation is one of the most important factors that controls virus fate and transport in the subsurface. In this study the inactivation of viruses in the presence of quartz sand was examined. The bacteriophages MS2 and PhiX174 were used as model viruses. Experiments were performed at 4 degrees C and 20 degrees C, under constant controlled conditions, to investigate the effect of virus type, temperature, sand size, and initial virus concentration on virus inactivation. The experimental virus inactivation data were satisfactorily represented by a pseudo-first order expression with time-dependent rate coefficients. Furthermore, the results indicated that virus inactivation was substantially affected by the ambient temperature and initial virus concentration. The inactivation rate of MS2 was shown to be greater than that of PhiX174. However, the greatest inactivation was observed for MS2 without the presence of sand, at 20 degrees C. Sand surfaces offered protection against inactivation especially under static conditions. However, no obvious relationship between sand particle size and virus inactivation could be established from the experimental data. Moreover, the inactivation rates were shown to increase with decreasing virus concentration. PMID- 22819477 TI - Influence of the different oxidation treatment on the performance of multi-walled carbon nanotubes in the catalytic wet air oxidation of phenol. AB - Multi-walled carbon nanotubes (MWCNTs) functionalized by different oxidants (HNO(3)/H(2)SO(4), H(2)O(2), O(3) and air) have been used as catalysts for the wet air oxidation of phenol. To investigate the effect of the oxidation conditions on the structure of the functionalized MWCNTs, various characterization techniques, e.g., scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy, Fourier-transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS) have been used. The MWCNTs treated with O(3) and H(2)O(2) show higher amounts of oxygen-containing functional groups and carboxylic acid groups, and a weaker acidic nature, in comparison with those treated with other oxidizing agents. All the functionalized MWCNTs exhibit good activity in the catalytic wet air oxidation (CWAO) of phenol. However, the MWCNTs treated with O(3) show the highest activity with desirable stability in comparison with other functionalized MWCNTs, indicating that the functionalization of carbon nanotubes with O(3) is a very promising strategy in synthesizing efficient catalysts for CWAO. PMID- 22819479 TI - Bhopal atmospheric dispersion revisited. AB - There is a vital need to understand details of the methylisocyanate (MIC) release that occurred at the 1984 Union Carbide Ltd. pesticide plant in Bhopal, India in order to avoid or respond to such releases in the future. However, we believe there are serious deficiencies in currently available dispersion predictions of the impact of toxic materials on humans and animals downwind of the plant. Specifically, cloud densities have been underestimated due to failure to account for the presence of a liquid/solid aerosol that would have been produced by the chemical reactions that caused the problem. Using data reported in Union Carbide's own investigation of the accident, which included chemical reaction data, we estimated aerosol compositions and cloud densities, then modeled the Bhopal release, simulating potential exposure levels at various locations under a number of wind-condition scenarios. For the worst-case (low wind speed and high aerosol densities), our predicted MIC concentrations at ground level are at least one order of magnitude greater than any previously published estimates. The centerline elevation of the jetting plume released at 33 m elevation is predicted to rise to about 41 m before falling, resulting in a 40 ppm (Immediately Dangerous to Life or Health, IDLH) concentration contour that reaches the ground at about 410 m downwind of the release location. This is consistent with observations that the plant environs were not hard-hit while the public immediately downwind of the plant perimeter was severely exposed. Concentrations on the order of 1000 ppm are predicted at some ground-level locations, which are more consistent than previous estimates with the reported large numbers of deaths and injuries of humans and animals. PMID- 22819480 TI - Seasonal alterations of landfill leachate composition and toxic potency in semi arid regions. AB - The present study investigates seasonal variations of leachate composition and its toxic potency on different species, such as the brine shrimp Artemia franciscana (formerly Artemia salina), the fairy shrimp Thamnocephalus platyurus, the estuarine rotifer Brachionus plicatilis and the microalgal flagellate Dunaliella tertiolecta. In specific, leachate regularly collected from the municipal landfill site of Aigeira (Peloponissos, Greece) during the year 2011, showed significant alterations of almost all its physicochemical parameters with time. Further analysis showed that seasonal alterations of leachate composition are related with the amount of rainfall obtained throughout the year. In fact, rainfall-related parameters, such as conductivity (Cond), nitrates (NO(3)(-)), total nitrogen (TN), ammonium (NH(4)-N), total dissolved solids (TDS) and the BOD(5)/NH(4)-N ratio could merely reflect the leachate strength and toxicity, as verified by the significant correlations occurred among each of them with the toxic endpoints, 24 h LC(50) and/or 72 h IC(50), obtained in all species tested. According to the result of the present study, it could be suggested that the aforementioned leachate parameters could be used independently, or in combination as a low-cost effective tools for estimating leachate strength and toxic potency, at least in the case of semi-arid areas such as the most of the Mediterranean countries. PMID- 22819481 TI - Pilot scale ex-situ bioremediation of heavily PAHs-contaminated soil by indigenous microorganisms and bioaugmentation by a PAHs-degrading and bioemulsifier-producing strain. AB - This study aims at the remediation of heavily PAH-contaminated soil containing 375 mg of total PAHs per kilogram dry soil. Pilot scale bioremediation experiments were carried out by three approaches with contaminated soil from abandoned sites of Beijing Coking Plant using outdoor pot trials. The first approach was bioaugmentation with a bacterial strain which degrades PAH and produces bioemulsifier, the second approach comprised of biostimulation of indigenous microorganisms with supplementing nutrients and the last approach involved the combination of both biostimulation and bioaugmentation. An on-site land farming group was set as a control in which the total PAHs and 4-6 ring-PAHs were reduced by 23.4% and 10.1%, respectively after 175 days. Meanwhile, in the first approach group, the total PAHs and 4-6 ring-PAHs were reduced by 26.82% and 35.36%, respectively; in the second approach group both percentages were 33.9% and 11.0%, respectively; while in the third approach group, these pollutants were reduced by 43.9% and 55.0%, respectively. The results obtained suggested that biostimulation and bioaugmentation combined could significantly enhance the removal of PAHs in the contaminated soil. PMID- 22819482 TI - The use of chitosan as a coagulant in the pre-treatment of turbid sea water. AB - One of the problems that encounters desalination industry is the fouling that takes place due to the poor quality of the sea water received, especially when it rains. In such a situation, the sea water reaches the desalination plant having high turbidity. Chitosan was tested as a coagulant in the removal of the turbidity of sea water to replace inorganic coagulants having hazardous effects. Jar test was performed to test some factors that may affect the coagulation process. The factors tested were dose of coagulant (0-370 mg/L), initial pH (2 11), type of coagulant (chitosan versus metal coagulants), and the chitosan solvent. Chitosan's turbidity removal efficiency was found to be greater than ferrous sulfate and comparable to that of alum. While most researches emphasize the use of chitosan in acidic or neutral media, it worked well in the alkaline pH. The highest turbidity removal efficiency of 97.5% was obtained at initial pH of 8.1. The optimum dose was found to be 18 mg/L. Chitosan dissolved in HCl was found to perform better than that dissolved in acetic acid. Comparable turbidity removal efficiencies were obtained using alum and chitosan. However, much higher doses were used when using alum which implies higher cost and increase of residual aluminum concentration in treated water. PMID- 22819484 TI - Coblation technique as an alternative treatment modality for oral lymphangioma. AB - Lymphangiomas of the tongue are relatively uncommon, and traditional treatment modalities carry a high failure rate. We present here a case report of effective treatment of lymphangioma circumscriptum of the oral tongue using radiofrequency coblation, while including a review of the current literature. PMID- 22819483 TI - T-wave inversion and diastolic dysfunction in patients with electrocardiographic left ventricular hypertrophy. AB - OBJECTIVES: The aim of this study was to investigate if T-wave inversion (TWI) in the settings of electrocardiogram (ECG)-left ventricular hypertrophy (LVH) is associated with advanced diastolic dysfunction (DD) in subjects with preserved ejection fraction (EF). BACKGROUND: Animal studies suggested that an abnormal transmural repolarization sequence from endocardium to epicardium may contribute to DD. However, little is known about abnormal repolarization sequence and DD in humans. METHODS: We studied 231 patients with ECG-diagnosed LVH and with an EF of 50% or greater (measured within 6 months of the index ECG). T-wave inversion was assessed on leads I, aVL, V(4), V(5), or V(6). Diastolic dysfunction was defined based on echocardiographic estimation of the left atrial pressure. We used multiple logistic regression to estimate the odds ratio of DD comparing patients with TWI with those without TWI. RESULTS: The average age was 65.0 +/- 14.2 years, and 61% were women. The mean EF was 61.8% +/- 6.6%. Patients with TWIs were more likely to have coronary artery disease (P = .013) and diabetes (P = .007). There was a 5.6-fold increased odds of DD in patients with TWI compared with those without TWI in a model adjusting for sex, age, relative wall thickness, body mass index, hypertension, coronary artery disease, diabetes, hyperlipidemia, and smoking. When comparing different echocardiographic estimates of the left atrial pressure, patients with TWI displayed higher values for septal and lateral E/e', left atrial volume index, and right ventricular/right atrial peak systolic gradient (P < .01 for each parameter). CONCLUSIONS: T-wave inversion is associated with increased odds of DD in patients with ECG-LVH with preserved systolic function. The reversal of the normal sequence of repolarization manifested on the 12-lead ECG as TWI may be a factor to DD. PMID- 22819485 TI - Bacterial involvement in otitis media with effusion. AB - OBJECTIVE: Otitis media with effusion (OME), a common chronic childhood condition affecting hearing, is thought to be a result of bacterial infection, with biofilms recently implicated. Although bacterial DNA can be detected by polymerase chain reaction in 80% of patients, typically fewer than half of effusions are positive using standard culture techniques. We adopted an alternative approach to demonstrating bacteria in OME, using a bacterial viability stain and confocal laser scanning microscopy (CLSM): staining allows detection of live bacteria without requiring growth on culture, while CLSM allows demonstration of the three-dimensional structure typical of biofilms. METHODS: Effusion samples were collected at the time of ventilation tube insertion, analysed with CLSM and bacterial viability stain, and extended culture techniques performed with the intention of capturing all possible organisms. RESULTS: Sixty two effusions (42 patients) were analysed: 28 (45.2%) were culture-positive, but 51 (82.3%) were CLSM-positive. Combining the two techniques demonstrated live bacteria in 57 (91.8%) samples. Using CLSM, bacteria exhibited biofilm morphology in 25 effusions and were planktonic in 26; the proportion of samples exhibiting biofilm morphology was similar in the culture-positive and culture-negative groups (50.0% and 48.3%, respectively). Biofilm samples contained an average of 1.7 different bacterial isolates and planktonic samples 2.0, with the commonest bacteria identified being coagulase-negative staphylococci. CONCLUSION: Live bacteria are present in most effusions, strongly suggesting that bacteria and biofilms are important in the aetiopathogenesis of OME. PMID- 22819487 TI - Idiopathic pulmonary fibrosis--clinical presentation, outcome and baseline prognostic factors in a Portuguese cohort. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is the most common disease in the subgroup of idiopathic interstitial pneumonias. It is inevitably associated to a bad prognosis, although assuming a highly variable clinical course. METHODS: Patients with IPF, observed at Interstitial Lung Diseases outpatient clinic of Centro Hospitalar de Sao Joao - Porto, Portugal, were identified and clinical, functional, radiological and bronchoalveolar lavage (BAL) parameters were reviewed. Their clinical course and survival were analyzed in order to identify prognostic factors. RESULTS: Eighty-one patients were included, with a mean age at diagnosis of 63.8 years old. At diagnosis, the main functional abnormalities were restrictive physiology, reduced lung diffusion and exercise capacity impairment. Clinical course was mainly slowly progressive (72.3%). Ten patients (13.2%) had a rapid progression and 11 (14.5%) patients had an acute exacerbation during the course of the disease. IPF's rapid progression was associated to a higher functional impairment at diagnosis, namely in what is related with Forced Vital Capacity (FVC) and Total Lung Capacity (TLC). Median survival was 36 months. A significant difference in survival was observed among different types of clinical course - 41 months for slow progressors and 9 months for rapid progressors. Lower levels of FVC, TLC, 6th minute walk test distance and rest PaO2, and higher BAL neutrophil count were associated with poorer survival in univariate analysis. CONCLUSION: The analysis of this group of IPF patients confirms two clearly different phenotypes, slow and rapid progressors. Those phenotypes seem to have different presentations and a remarkably different natural history. These results could mean different physiopathologic pathways, which could implicate different therapeutic approaches. PMID- 22819486 TI - Human herpesviruses 6, 7, and 8 from a dermatologic perspective. AB - Human herpesviruses (HHVs) have frequently been suspected as etiologic agents or cofactors in cutaneous disease. However, clearly established associations are rare. Investigations into an etiologic association between HHVs and cutaneous disease are complicated by the ubiquity and nearly universal prevalence of some herpesviruses. This article summarizes the associations between cutaneous disease and HHV-6, HHV-7, and HHV-8. In addition to a personal library of references, the PubMed database of biomedical literature was searched using the following Medical Subject Heading terms: HHV-6, HHV-7, and HHV-8, each in conjunction with cutaneous manifestations, virology, epidemiology, dermatopathology, and therapeutics, between 1998 and March 2011. Free-text searches with known or suspected disease associations were added for broader coverage. The results have been summarized to provide a practical review for the physician likely to encounter cutaneous diseases. PMID- 22819488 TI - Evaluation of shock waveform configuration on the defibrillation capacity of implantable cardioverter defibrillators in dogs. AB - BACKGROUND: Implantable cardioverter defibrillators (ICD) are programmed to detect ventricular arrhythmias and terminate them by delivering an electrical shock. A defibrillation threshold (DFT) at least 10 J below the maximum device output is recommended for successful therapy. Shock waveform configuration is a programmable parameter used to achieve a low DFT. It is hypothesized that a fixed pulse configuration results in lower defibrillation energy requirements than a fixed-tilt configuration. ANIMALS: 10 mongrel dogs. MATERIALS AND METHODS: ICD generator and transvenous lead were surgically implanted. Defibrillation threshold was determined using a protocol guided by the upper limit of vulnerability. Fixed-pulse and fixed-tilt (50%/50%) waveform configurations were tested in a random order. Plasma cardiac troponin I (cTnI) was measured for signs of myocardial injury. RESULTS: The experiment was completed in 9 dogs. Overall mean DFT value was 424 +/- 88 V (9.2 +/- 3.9 J). Mean differences among voltage, energy and impedance at the DFT for fixed-pulse (422 +/- 97 V, 9.1 +/- 4.2 J, 62.6 +/- 13.8 Omega) and fixed-tilt (426 +/- 83 V, 9.3 +/- 3.8 J, 62.8 +/- 18.5 Omega) configurations were not statistically significant (All P > 0.21). Cardiac TnI concentration changed from 0.03 ng/mL (95% CI: 0.02-0.04) at baseline to 0.11 ng/mL (95 CI: 0.08-0.16) after DFT was obtained with the first waveform configuration and 0.19 ng/mL (95% CI: 0.13-0.28) at the end of the study period. There were no significant changes in heart rate, end-tidal CO2 and blood pressure over time (all P > 0.09). CONCLUSION: The tested ICD device and lead placement reliably produced acceptable DFT values, based on a 10-J safety margin below the maximum device output. A benefit of fixed-pulse configuration could not be demonstrated over the standard fixed-tilt waveform. Signs of acute myocardial damage from repeated high-voltage shocks and episodes of ventricular fibrillation seemed of limited clinical significance. PMID- 22819489 TI - [Prostate specific antigen decrease and prostate cancer diagnosis: recognizing the fundamental previous progresses and moving forward]. PMID- 22819490 TI - [Utility of seriated sections in prostate biopsies]. AB - INTRODUCTION: With the routine use of prostate specific antigen, focal carcinomas and atypical small acini proliferation (ASAP) are currently detected more frequently. The number of sections per cylinder needed to detect most of them is still unknown. METHODS: We reviewed 250 sextant prostate biopsies in the 2008 2011 period. The average number of cylinders per biopsy was 14. In each case, in addition to the original sections with three histological levels, three more sections were performed with three levels (total: 12 levels). Biopsies with focal lesion were analyzed immunohistochemically. The frequency of focal lesions was compared to a previous study of 1000 biopsies in which a single section was made with three histological levels. The main clinical and laboratory data were recorded. RESULTS: There were 16 focal lesions (6.4%). Seven (2.8%) corresponded to focal carcinomas and nine (3.6%) to atypical proliferation. In the previous study, thirteen (1.3%) focal carcinomas and 29 (2.9%) cases with atypical proliferation were found. CONCLUSIONS: There was an increase of 4.2% to 6.4% of focal lesions carcinomas increased from 1.3% to 2.8%. Making additional sections in all biopsies may have practical drawbacks. However, they could be performed in patients with high clinical suspicion of carcinoma (especially in young patients), or when there is a history of atypical glandular proliferations consistent with carcinoma in previous biopsies. PMID- 22819491 TI - [Haemostasis control during laparoscopic partial nephrectomy without parenchymal renorrhaphy: the VIVOSTAT((r)) experience]. AB - OBJECTIVE: To present our experience using an autologous fibrin sealant prepared with the Vivostat system((r)) to control haemostasis without any renal parenchymal reconstruction. MATERIAL AND METHODS: We performed 45 laparoscopic partial nephrectomies using this haemostatic agent. The surgical steps were: colon mobilization, identification of ureter, renal vessels and renal tumor, renal artery control with Rummel tourniquet, tumor excision with harmonic scalpel, application of fibrin glue to the resection bed twice (before and after kidney reperfusion). Patients were evaluated for acute or delayed bleeding. RESULTS: Mean age was 63.9 years (33-80); mean tumor size was 2.5cm (1.5-4); mean operative time was 136.1min (90-180). Mean warm ischemia time was 19.2min (10 30). Mean blood loss was 97ml (50-300). Individual haemostatic stitches were performed before application of the sealant if acute bleeding was observed (14 cases). We did not achieve any case of postoperative bleeding from resection bed or renal failure. 1 patient required transfusion due to an abdominal wall haematoma. 65% were clear cell carcinoma, 10% were papillary carcinoma, 20% were oncocitoma. Free margin rate was 100%. Mean hospital stay was 4 days (2-6). Mean follow-up was 14 months (5-45). CONCLUSIONS: Excluding renorrhaphy during laparoscopic partial nephrectomy is feasible and safe. Our initial experience with the vivostat system in laparoscopic partial nephrectomy has been encouraging, but longer follow-up is needed to determine the real benefit of this surgical technique in laparoscopic partial nephrectomy. PMID- 22819492 TI - Effect of antithrombin III on glycoprotein Ib/IX/V activation in human platelets: suppression of thromboxane A2 generation. AB - We have previously shown that ristocetin, an activator of glycoprotein Ib/IX/V, induces release of soluble CD40 (sCD40) ligand via thromboxane (TX) A(2) production from human platelets. In the present study, we investigated the effect of antithrombin-III (AT-III), an anticoagulant, on the ristocetin-induced glycoprotein Ib/IX/V activation in human platelets. AT-III inhibited ristocetin stimulated platelet aggregation. The ristocetin-induced production of 11-dehydro TXB(2), a stable metabolite of TXA(2), and the release of sCD40 ligand were suppressed by AT-III. AT-III also reduced the ristocetin-stimulated secretion of platelet-derived growth factor (PDGF)-AB. AT-III failed to affect U46619-, a TXA(2) receptor agonist, induced levels of p38 mitogen-activated protein kinase phosphorylation or sCD40 ligand release. AT-III reduced the binding of SZ2, a monoclonal antibody to the sulfated sequence in the alpha-chain of glycoprotein Ib, to the ristocetin-stimulated platelets. These results strongly suggest that AT-III reduced ristocetin-stimulated release of sCD40 ligand due to inhibiting TXA(2) production in human platelets. PMID- 22819493 TI - Can people strategically control the encoding and retrieval of some morphologic and typographic details of words? AB - This study investigated whether the encoding and retrieval of plurality information and letter-case information of words in recognition memory can be inhibited. Response-deadline experiments (Hintzman & Curran, 1994) using single words have indicted a controlled processing mode, whereas studies using meaningful sentences (e.g., Jou & Harris, 1991) have indicated an automatic mode of processing plurality information. Two similar opposing views have existed on the processing of letter-case information. The abstractionist view contends that we retain the abstract lexical information and discard the superficial perceptual case information. The proceduralist view holds that perceptual details cannot be separated from the lexical information. Using an intentional and an attention diverted learning procedure and instructions to ignore plurality and case, we found that subjects experienced a consistent interference effect of changed plurality from study to test but slightly less interference from changed case, suggesting strong automaticity for plurality, and comparatively less automaticity, for case processing. PMID- 22819494 TI - Synthetic biology advancing clinical applications. AB - The 'omics' era, with its identification of genetic and protein components, has combined with systems biology, which provided insights into network structures, to set the stage for synthetic biology, an emerging interdisciplinary life science that uses engineering principles. By capitalizing on an iterative design cycle that involves molecular and computational biology tools to assemble functional designer devices from a comprehensive catalogue of standardized biological components with predictable functions, synthetic biology has significantly advanced our understanding of complex control dynamics that program living systems. Such insights, collected over the past decade, are priming a variety of synthetic biology-inspired biomedical applications that have the potential to revolutionize drug discovery and production technologies, as well as treatment strategies for infectious diseases and metabolic disorders. PMID- 22819495 TI - Silk sericin/polyacrylamide in situ forming hydrogels for dermal reconstruction. AB - In situ forming tissue sealants are advantageous due to ease in application, complete coverage of defect site and assured comfort levels to patients. The interconnected three-dimensional hydrophilic networks perfectly manage typical dermal wounds by suitably scaffolding skin fibroblast, diffusing the nutrients, therapeutics and exudates while still maintaining an adequately moist environment. We evaluate the cell homing ability of semi-interpenetrating non mulberry tropical tasar silk sericin/polyacrylamide hydrophilic network with a keen understanding of its network characteristics and correlation of protein concentration with the performance as cell scaffold. Interconnectivity of porous networks observed through scanning electron micrograph revealed pore sizes ranging from 23 to 52 MUm. The enhanced beta-sheet content with the increasing sericin concentration in far red spectroscopy study supported their corresponding improved compressive strength. These semi-interpenetrating networks were found to possess a maximum fluid uptake of 112% of its weight, hence preventing the accumulation of exudates at the wound area. The present systems appear to possess characteristics like rapid gelation (~5min) at 37 degrees C, 98% porosity enabling the migration of fibroblasts during healing (observed through confocal and scanning electron micrographs), cell adhesion together with the absence of any cyto-toxic effect suggesting its potential as in situ tissue sealants. The compressive strength up to 61 kPa ensured ease in handling even when wet. The results prove the suitability to use non-mulberry tasar cocoon silk sericin/polyacrylamide semi-interpenetrating network as a reconstructive dermal sealant. PMID- 22819496 TI - A tissue factor targeted nanomedical system for thrombi-specific drug delivery. AB - Tissue factor (TF) is a 47 kDa membrane-bound glycoprotein, which is present at high concentrations on damaged endothelium, atherosclerotic plaques or tumor vasculature, and is an important trigger of coagulation cascade. In this study, we have expressed and purified the TF targeting protein-EGFP-EGF1, which was thiolated and conjugated to the malemide of the PEG-PLGA nanoparticle to form a TF targeting nanomedical system: EGF1-EGFP-NP. The system was carefully characterized and the targeting efficiency was systematically evaluated. The EGF1 EGFP-NP could significantly facilitate specific uptake by TF overexpressed BCEC via EGF1/TF mediated endocytosis pathway. In addition, the pharmacokinetic study demonstrated that EGF1-EGFP-NP has the same blood circulation time as NP. Enhanced accumulation of EGF1-EGFP-NP in the cortex infarction region was also observed by real-time fluorescence image. Confocal microscopy and TEM further showed that EGF1-EGFP-NP combined with TF and further transfected through the damaged endothelium. Moreover, in vitro cell viability experiment and in vivo coagulation ability confirmed that the EGF1-EGFP-NP was safe. PMID- 22819497 TI - Ultrabright and ultrastable near-infrared dye nanoparticles for in vitro and in vivo bioimaging. AB - We report a new strategy of using carrier-free pure near-infrared (NIR) dye nanoparticles (NPs) to achieve highly luminescent NIR fluorescent probes for in vitro and in vivo imaging. Bis(4-(N-(2-naphthyl)phenylamino) phenyl) fumaronitrile (NPAPF) NPs are shown to exhibit favorable biocompatibility, wide range pH stability (pH 4-10) and much more superior photostability than conventional dyes. Importantly, the combined merits of high dye loading content and aggregation-induced emission enhancement properties, endow the NIR probes with high brightness and a high quantum yield up to 14.9%. The NPAPF NPs can be readily conjugated with folic acid for targeted in vitro cell imaging. Applications of the NPs probes in high efficiency in vivo and ex vivo imaging were successfully demonstrated. Intense fluorescent signals of NPAPF NPs can be distinctly, selectively and spatially resolved in tumor sites with ultrahigh sensitivity, even with 5 ms exposure time, due to the preferentially accumulation of NPs in tumor sites through passive enhanced permeability and retention effect. The totality of results clearly demonstrate the exciting potential of the functionalized NPAPF NPs as a NIR fluorescent probe for in vitro and in vivo imaging and diagnostics. PMID- 22819498 TI - Effect of bone marrow-derived extracellular matrix on cardiac function after ischemic injury. AB - Ischemic heart disease is a leading cause of death, with few options to retain ventricular function following myocardial infarction. Hematopoietic-derived progenitor cells contribute to angiogenesis and tissue repair following ischemia reperfusion injury. Motivated by the role of bone marrow extracellular matrix (BM ECM) in supporting the proliferation and regulation of these cell populations, we investigated BM-ECM injection in myocardial repair. In BM-ECM isolated from porcine sternum, we identified several factors important for myocardial healing, including vascular endothelial growth factor, basic fibroblast growth factor-2, and platelet-derived growth factor-BB. We further determined that BM-ECM serves as an adhesive substrate for endothelial cell proliferation. Bone marrow ECM was injected in a rat model of myocardial infarction, with and without a methylcellulose carrier gel. After one day, reduced infarct area was noted in rats receiving BM-ECM injection. After seven days we observed improved fractional shortening, decreased apoptosis, and significantly lower macrophage counts in the infarct border. Improvements in fractional shortening, sustained through 21 days, as well as decreased fibrotic area, enhanced angiogenesis, and greater c-kit positive cell presence were associated with BM-ECM injection. Notably, the concentrations of BM-ECM growth factors were 10(3)-10(8) fold lower than typically required to achieve a beneficial effect, as reported in pre-clinical studies that have administered single growth factors alone. PMID- 22819499 TI - The microclimate pH in poly(D,L-lactide-co-hydroxymethyl glycolide) microspheres during biodegradation. AB - The microclimate pH (MUpH) in biodegradable polymers, such as poly(D,L-lactic-co glycolic acid) (PLGA) 50/50, commonly falls to deleterious acidic levels during biodegradation, resulting in instability of encapsulated acid-labile molecules. The MUpH distribution in microspheres of a more hydrophilic polyester, poly(D,L lactide-co-hydroxymethyl glycolide) (PLHMGA), was measured and compared to that in PLGA 50/50 of similar molecular weight and degradation time scales. pH mapping in the polymers was performed after incubation under physiological conditions by using a previously validated ratiometric method employing confocal laser scanning microscopy (CLSM). Confocal MUpH maps revealed that PLHMGA microspheres, regardless of copolymer composition, developed a far less acidic MUpH during 4 weeks of incubation compared with microspheres from PLGA. A pH-independent fluorescent probe marker of polymer matrix diffusion of MUpH-controlling water soluble acid degradation products, bodipy, was observed by CLSM to diffuse ~3-7 fold more rapidly in PLHMGA compared to PLGA microspheres, consistent with much more rapid release of acids observed from the hydrophilic polymer during bioerosion. Hence, PLHMGA microspheres are less susceptible to acidification during degradation as compared to similar PLGA formulations, and therefore, PLHMGA may be more suitable to deliver acid labile molecules such as proteins. PMID- 22819500 TI - [Objective severity markers in women with severe postpartum haemorrhage: a 310 case series]. AB - OBJECTIVES: Postpartum haemorrhage (PPH) is a major contributor to maternal morbidity and mortality in France. The objective of our study was to reveal predictive factors of severity or cure, allowing an adapted management as less invasive as possible, in case of severe PPH. PATIENTS AND METHODS: This retrospective study included 310 patients, who had been treated for a severe PPH in Lariboisiere university hospital from April 2007 to April 2009. RESULTS: The predictive factors found for an invasive management (surgery or embolization) are: at clinical examination, heart rate (88 versus 100 pulses per minute), importance of bleeding and the tonicity of the uterine globe. At biological examination, they are haemoglobin level (9 versus 8.2g/dL) and clotting factors, especially fibrinogen (3 versus 2g/L) and prothrombin time (PT) (76 versus 63%). The identified cure factors are the same ones as severity factors. With multivariate analysis, initial independent predictive factors about an invasive management were: the tonicity of the uterine globe (OR=0.14), heart frequency (OR=1.3) and PT (OR=0.76). DISCUSSION AND CONCLUSION: In case of severe haemorrhage, there may be the question of transfer of the patient. The difficulty is to avoid unnecessary transport, without delay for the future care. Very few studies searched predictive factors of severity or cure. Our study found, as predictive factors of invasive treatment, elements of physical examination (heart rate and the tonicity of the uterine globe) and biological factors (hemoglobin level and clotting factors). PMID- 22819501 TI - An unusual cause of melena and abdominal pain. PMID- 22819502 TI - An unusual cause of recurrent massive upper gastrointestinal bleeding. PMID- 22819503 TI - A woman with ascites, nodular liver contour, and splenomegaly. PMID- 22819504 TI - Synthesis, spectral characterization and biological evaluation of a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan-2-yl]-7H [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. AB - On account of the reported anticancer activity of triazolothiadiazines, we have synthesized a novel series of 6-arylsubstituted-3-[2-(4-substitutedphenyl)propan 2-yl]-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and tested for in-vitro cytotoxicity by trypan blue exclusion and MTT assay. These compounds were also evaluated for their in-vivo anthelmintic activity, as well as in-vitro antimicrobial studies. Amongst the tested compounds, the compound 7j was the most promising cytotoxic agent with IC(50) value of 10.54MUM in MCF-7 cells. The compounds 7l and 7q exhibited excellent anthelmintic activity. The compounds 7d, 7f, 7j, 7l, 7o, 7p and 7r showed good antibacterial activity, whereas compounds 7e and 7k exhibited excellent antifungal activity. The structures of newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR and LCMS analysis. PMID- 22819505 TI - Discovery and characterization of novel allosteric FAK inhibitors. AB - Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5 dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases. PMID- 22819506 TI - Laurene-type sesquiterpenes from the Red Sea red alga Laurencia obtusa as potential antitumor-antimicrobial agents. AB - Three new laurene-type sesquiterpenes, 12-hydroxy isolaurene (1), 8,11-dihydro-12 hydroxy isolaurene (2) and isolauraldehyde (3) were isolated from the organic extract of the red alga Laurencia obtusa. The chemical structures of isolates were determined by interpretation of their spectral data 1D and 2D NMR, UV, IR and MS. The newly isolated compounds were tested for their antimicrobial and antitumor activities. Compounds (1-3) exhibited potent activity against the gram positive Bacillus subtilis and Staphylococcus aureus, where 3 proved to be the most active (MIC 35 and 27 MUg/mL, respectively). Moreover, compound 3 exhibited a significant activity against Candida albicans (MIC of 70 MUg/mL) and revealed to have very promising activity in an in vitro model of Ehrlich ascites Carcinoma. PMID- 22819507 TI - Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents. AB - Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets. PMID- 22819508 TI - [Parsonage-Turner syndrome revealing a primary HIV infection]. PMID- 22819509 TI - [Lethal meningitis due to Pasteurella multocida]. PMID- 22819510 TI - Epidemiology of Streptococcus pneumoniae. AB - The epidemiology of S. pneumoniae invasive infections in France, over the last few years, was modified by two public health measures. A nationwide campaign for the rationalization of antibiotic prescription was implemented in 2001 and vaccination of young children with the pneumococcal 7-valent conjugate vaccine in 2003. These measures led to a decrease in antibiotic resistance in S. pneumoniae strains, a lower incidence of invasive infections due to vaccine serotypes, but a higher incidence of infections due to non-vaccine serotypes, especially 7F and 19A. Despite the replacement, the incidence of invasive pneumococcal infections in children less than 2 years of age remains lower than it was before introducing the 7-valent conjugate vaccine. PMID- 22819511 TI - Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. PMID- 22819512 TI - Basophil reactivity, wheal size, and immunoglobulin levels distinguish degrees of cow's milk tolerance. AB - BACKGROUND: In our previous study about 75% of children with cow's milk allergy tolerated baked milk products, which improved their prognosis and quality of life. OBJECTIVE: We sought to identify biomarkers of varying degrees of clinical tolerance among a cohort of children with cow's milk allergy. METHODS: One hundred thirty-two subjects were initially classified as baked milk-reactive, baked milk-tolerant, or having "outgrown milk allergy" based on the results of oral food challenges. The baked milk-tolerant group was then divided into 3 groups based on the amount and degree of heat-denatured milk protein that they could tolerate. Serum was analyzed for allergen-specific IgE and IgG(4) levels, basophil reactivity was assessed in whole blood stimulated with serial 10-fold dilutions of milk protein, and skin prick tests (SPTs) were performed to commercial milk extract. Activated basophils were defined by using flow cytometry as CD63(bright)CD203c(+)CD123(+)HLA-DR(dim/-)CD41a(-)lineage(-). Data were analyzed by using the Jonckheere-Terpstra test. RESULTS: Significant differences across the 5 clinical groups were seen for median casein- and milk-specific IgE levels, casein-specific IgG(4) levels, and casein IgE/IgG(4) ratios; milk specific to nonspecific basophil activation ratio, median basophil reactivity, and spontaneous basophil activation (CD203c expression after stimulation with RPMI); and milk SPT wheal diameters. Casein- and milk-specific IgE level, milk specific basophil reactivity, and milk SPT wheal diameter are all significantly greater among patients with milk allergy who react to baked milk than among those who tolerate it. CONCLUSIONS: The majority of patients with milk allergy are able to tolerate some forms of baked milk in their diets. Different phenotypes of children with cow's milk allergy can be distinguished by casein- and milk specific IgE levels, milk-specific basophil reactivity, and milk SPT mean wheal diameters. Spontaneous basophil activation is greater among patients with more severe clinical milk reactivity. PMID- 22819514 TI - Assembly and disassembly of cell matrix adhesions. AB - The formation of tissues and organs requires cells to adhere to each other and/or to migrate and polarize in contact with components of the extracellular matrix. The connection between the cytoskeleton and the extracellular environment is provided by heterodimeric transmembrane receptors of the integrin family. In response to extracellular ligand binding, integrins undergo a conformational switch that permits the recruitment of cytoplasmic adapter proteins, eventually linking the integrin receptors to the actin cytoskeleton, progressively forming highly complex cell-matrix adhesions. A major challenge in the field consists in identifying the regulatory mechanisms, which drive the assembly of cell-matrix adhesions as they are based on posttranslational modifications as well as allosteric conformational changes caused by protein-protein as well as protein lipid interactions. In response to mechanical tension, generated either by intra cellular acto-myosin contraction, shear stress or mechanical strain on the extracellular scaffold, the composition and signaling of cell-matrix adhesion changes, leading either to increased anchorage or controlled disassembly of cell matrix adhesions, both processes critically involved in cell migration. The aim of this review is to provide insight into the mechanisms leading to the progressive assembly of focal adhesions, how they are modulated in response to mechanical challenges and which mechanisms are used for their disassembly. PMID- 22819516 TI - [Introduction and management of an eye disease screening unit for diabetic patients in primary care]. PMID- 22819513 TI - The extracellular matrix and ciliary signaling. AB - The primary cilium protrudes like an antenna from the cell surface, sensing mechanical and chemical cues provided in the cellular environment. In some tissue types, ciliary orientation to lumens allows response to fluid flow; in others, such as bone, ciliary protrusion into the extracellular matrix allows response to compression forces. The ciliary membrane contains receptors for Hedgehog, Wnt, Notch, and other potent growth factors, and in some instances also harbors integrin and cadherin family members, allowing receipt of a robust range of signals. A growing list of ciliopathies, arising from deficient formation or function of cilia, includes both developmental defects and chronic, progressive disorders such as polycystic kidney disease (PKD); changes in ciliary function have been proposed to support cancer progression. Recent findings have revealed extensive signaling dialog between cilia and extracellular matrix (ECM), with defects in cilia associated with fibrosis in multiple contexts. Further, a growing number of proteins have been determined to possess multiple roles in control of cilia and focal adhesion interactions with the ECM, further coordinating functionality. We summarize and discuss these recent findings. PMID- 22819517 TI - Geochemistry of the northern Cyprus (NE Mediterranean) shelf sediments: Implications for anthropogenic and lithogenic impact. AB - The concentrations of heavy metals and organic carbon in sediment were determined to evaluate spatial distributions from the three different regions of Cilician basin (Eastern Mediterranean) in 2011. The ranges of Cu, Pb, Zn, Ni, Co, Mn, Cr, As, Fe and organic carbon contents of sediments from the study area were 1.6-74, 1.6-9.2, 5.0-78, 6.6-114, 1.6-17, 141-1241, 9.0-46, 3.3-55.4, 1800-84400mg kg(-1) and 0.99-1.66%, respectively. The concentrations of Pb, Zn, Co, Cr, Al were lower than those average crustal values, which indicated that there were no major sources of pollution for these elements. The results showed that the sediments of northern, eastern and western shelf were polluted with As, Ni and Mn, As and Cu, Fe, respectively. The contamination factor of Cu in the western and As were found to be of moderate contamination in the eastern and northern parts of the study area. Metal levels were evaluated in sediments in accordance with the numerical SQG of the USEPA. PMID- 22819515 TI - Cadherin complexity: recent insights into cadherin superfamily function in C. elegans. AB - Cadherin superfamily proteins mediate cell-cell adhesion during development. The C. elegans embryo is a powerful system for analyzing how cadherins function in highly stereotyped morphogenetic events. In the embryo, the classical cadherin HMR-1 acts along with the Rac pathway and SAX-7/L1CAM during gastrulation. As adherens junctions mature, PAR complex proteins differentially regulate cadherin complex localization, and SRGP-1/Slit/Robo GAP aids adhesion by promoting membrane bending. Once adherens junctions form, actin is linked to the cell surface via HMP-1/alpha-catenin, whose actin binding activity is regulated in novel ways. FMI-1/Flamingo and CDH-4/Fat-like regulate axonal morphology of both pioneer and follower neurons. C. elegans thus continues to be useful for uncovering precise functions for cadherin superfamily proteins and their associates in a simple metazoan. PMID- 22819518 TI - Does valence matter? Effects of negativity on children's early understanding of the truth and lies. AB - Early deceptive behavior often involves acts of wrongdoings on the part of children. As a result, it has often been assumed, although not tested directly, that children are better at identifying lies about wrongdoing than lies about other activities. We tested this assumption in two studies. In Study 1, 67 3- to 5-year-olds viewed vignettes in which a character truthfully or falsely claimed to have committed a good or bad act. Children were biased to label claims that the character had committed a good act as the truth and claims that the character had committed a bad act as lies. In Study 2, 51 4- to 6-year-olds viewed vignettes in which characters either admitted or denied committing a good or bad act. Children were better at identifying truth-tellers and liars when the acts were good. Results suggest that young children initially overgeneralize the concept of lie to include all negative acts and the concept of the truth to include all good acts and only gradually make a distinction between act valence and honesty. As a result, including wrongdoing in scenarios to test children's early understanding of the meaning of lying is likely to underestimate children's abilities. PMID- 22819519 TI - Identification of isometric contractions based on High Density EMG maps. AB - Identification of motion intention and muscle activation strategy is necessary to control human-machine interfaces like prostheses or orthoses, as well as other rehabilitation devices, games and computer-based training programs. Pattern recognition from sEMG signals has been extensively investigated in the last decades, however, most of the studies did not take into account different strengths and EMG distributions associated to the intended task. The identification of such quantities could be beneficial for the training of the subject or the control of assistive devices. Recent studies have shown the need to improve pattern-recognition classification by reducing sensitivity to changes in the exerted strength, muscle-electrode shifts and bad contacts. Surface High Density EMG (HD-EMG) obtained from 2-dimensional arrays can provide much more information than electrode pairs for inferring not only motion intention but also the strategy adopted to distribute the load between muscles as well as changes in the spatial distribution of motor unit action potentials within a single muscle because of it. The objectives of this study were: (a) the automatic identification of four isometric motor tasks associated with the degrees of freedom of the forearm: flexion-extension and supination-pronation and (b) the differentiation among levels of voluntary contraction at low-medium efforts. For this purpose, monopolar HD-EMG maps were obtained from five muscles of the upper limb in healthy subjects. An original classifier is proposed, based on: (1) Two steps linear discriminant analysis of the EMG information for each type of contraction, and (2) features extracted from HD-EMG maps and related to its intensity and distribution in the 2D space. The classifier was trained and tested with different effort levels. Spatial distribution-based features by themselves are not sufficient to classify the type of task or the effort level with an acceptable accuracy; however, when calculated with the "isolated masses" method proposed in this study and combined with intensity-base features, the performance of the classifier is improved. The classifier is capable of identifying the tasks even at 10% of Maximum Voluntary Contraction, in the range of effort level developed by patients with neuromuscular disorders, showing that intention end effort of motion can be estimated from HD-EMG maps and applied in rehabilitation. PMID- 22819520 TI - Exercise oxygen flow titration methods in COPD patients with respiratory failure. AB - We compare the adequacy of several titration procedures of oxygen flow in maintaining SpO(2) > 90% during the activities of daily life in patients with very severe COPD. Thirty-one very severe COPD patients undergoing oxygen-therapy were recruited. Three titration methods were randomly performed: (1) 6-min walking tests; (2) cycle-ergometer constant work-rate tests at a load equivalent to 12 ml/min/kg of oxygen uptake; (3) one single constant work-rate test at 40 W 12-h pulse-oximeter monitoring was performed on four consecutive days with the following oxygen flow during exercise: 1 l.min(-1) above the resting prescription (NOTT guidelines) and those established by the titration procedures. The time spent SpO(2) < 90% was higher for the titration based on NOTT and walking tests than for the oxygen flow established by the constant work-rate tests at 12 ml O(2)/min/kg (22.1 +/- 18.7, 20.8 +/- 19.5 and 6.7 +/- 12.7%, respectively). As for the oxygen uptake-based titration, the simplified procedure (a single exercise test at 40 w) generates longer times spent SpO(2) < 90% and SpO(2) < 85%, although it maintains a SpO(2) > 90% for more 90% of the time. In COPD patients, exercise oxygen flow titrations by NOTT guidelines or walking tests do not allow a suitable oxygenation during the activities of daily life. Two more adequate alternative methods, based on constant work-rate tests, are proposed. PMID- 22819521 TI - Add-on montelukast vs double-dose budesonide in nonasthmatic eosinophilic bronchitis: a pilot study. AB - BACKGROUND: Budesonide at 800 MUg/d is generally suggested for treatment of nonasthmatic eosinophilic bronchitis (NAEB). In asthma, adjunctive therapy with montelukast has been shown to confer addictive anti-inflammatory effects to inhaled corticosteroid (ICS). However, whether such effects could be extrapolated to NAEB is not known. OBJECTIVES: To study the efficacy and tolerability of add on therapy with montelukast as compared to double-dose ICS in suppressing airway eosinophilia and decreasing cough severity in NAEB. METHODS: In a randomized controlled trial, 26 nonsmoking, steroid-naive NAEB patients presenting with chronic cough were treated with 800 MUg/d budesonide or 400 MUg/d budesonide plus montelukast 10 mg/d for 4 weeks. Cough visual analogue scale (CVAS) and eosinophil differential ratio in induced sputum (Eos) were monitored at baseline, Week 1, 2 and 4. Adverse events during treatment were recorded. RESULTS: The two groups were comparable in age, gender distribution, cough duration, FEV(1)% predicted, FEV(1)/FEV ratio, baseline CVAS and geometric mean of Eos. Both regimens significantly reduced Eos and CVAS throughout the treatment course, with abrogation of sputum eosinophilia at end of therapy. There was no significant difference between the two groups in reduction of Eos and CVAS at all time points. Both regimens were well tolerated. CONCLUSIONS: This preliminary study demonstrated that add-on montelukast might be an effective and well tolerated alternative to the generally suggested dose of ICS in treating steroid-naive NAEB, with suppression of eosinophilic inflammation, reduction of cough severity and sparing of ICS doses. (NCT01121016). PMID- 22819522 TI - Effect of interface reflection in pseudophakic eyes with an additional refractive intraocular lens. AB - PURPOSE: To compare the surface reflections in a pseudophakic model eye with and without a monofocal additional refractive intraocular lens (add-on IOL). SETTING: Department of Ophthalmology, Rudolf-Virchow-Klinikum Glauchau, Glauchau, and Experimental Ophthalmology, Saarland University, Homburg, Germany. DESIGN: Experimental study. METHODS: The Liou and Brennan model eye was used to determine the retinal surface reflections in a pseudophakic model eye with and without an add-on IOL. The crystalline lens of the model eye was replaced by (1) a standard posterior chamber IOL (PC IOL) with a refractive power of 22.0 diopters (D) and (2) a PC IOL and an add-on IOL with refractive powers of 19.0 D and 2.5 D, respectively. To theoretically estimate the impact of the reflected images to visual impression, the signal-to-noise ratio (SNR) was calculated under 2 conditions: without and with straylight and double reflection effects. RESULTS: Compared with the pseudophakic model eye without an add-on IOL, the pseudophakic model eye with an add-on IOL showed no relevant differences in the SNR under both conditions. CONCLUSION: Findings indicate that implantation of monofocal add-on IOLs will not induce relevant additional disturbing glare compared with conventional pseudophakia. PMID- 22819523 TI - In vitro optical performance of nonrotational symmetric and refractive diffractive aspheric multifocal intraocular lenses: impact of tilt and decentration. AB - PURPOSE: To evaluate the optical quality of Acrysof Restor SN6AD1 refractive diffractive +3.00 D and Lentis Mplus LS-312 nonrotational symmetric +3.00 D aspheric multifocal intraocular lenses (IOLs) and analyze the effect of tilt and decentration. SETTING: University of Valencia, Valencia, and University of Murcia, Murcia, Spain. DESIGN: Experimental study. METHODS: An artificial model eye was used to measure wavefront aberrations of both IOL models. The modulation transfer function (MTF) and point-spread function (PSF) were calculated for a 5.0 mm pupil and under 5 situations: centered, 0.2 mm and 0.4 mm decentered, and 2 degrees and 4 degrees tilted. RESULTS: The refractive-diffractive IOL had the highest MTF values at all spatial frequencies. Similarly, the PSF was worse for the refractive-diffractive IOL. The MTFs for the refractive-diffractive IOL decreased when the IOL was decentered or tilted, being more robust for tilting than decentration. The MTFs for the nonrotational symmetric IOL were similar under all testing conditions. Cutoff frequencies for the refractive-diffractive IOL were stable over the range of tilting studied and comparable with the cutoff when the IOL was centered (approximately 50 cycles per degree [cpd]). When the IOL was decentered, the cutoff frequency decreased by approximately 40 cpd. The nonrotational symmetric IOL cutoff frequencies for misalignment and tilt were low (approximately 30 cpd) and similar under all conditions. CONCLUSIONS: The refractive-diffractive IOL provided better optical quality than the nonrotational symmetric IOL. Tilt and decentration had a significant impact on optical quality with both IOLs, being more severe with the nonrotational symmetric IOL. PMID- 22819524 TI - CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane. AB - Although substantial progress has been made in understanding the mechanisms underlying the expression of mtDNA-encoded polypeptides, the regulatory factors involved in mitoribosome-mediated synthesis and simultaneous insertion of mitochondrial oxidative phosphorylation (OXPHOS) polypeptides into the inner membrane of mitochondria are still unclear. In the present study, disruption of the mouse Crif1 gene, which encodes a mitochondrial protein, resulted in a profound deficiency in OXPHOS caused by the disappearance of OXPHOS subunits and complexes in vivo. CRIF1 was associated with large mitoribosomal subunits that were located close to the polypeptide exit tunnel, and the elimination of CRIF1 led to both aberrant synthesis and defective insertion of mtDNA-encoded nascent OXPHOS polypeptides into the inner membrane. CRIF1 interacted with nascent OXPHOS polypeptides and molecular chaperones, e.g., Tid1. Taken together, these results suggest that CRIF1 plays a critical role in the integration of OXPHOS polypeptides into the mitochondrial membrane in mammals. PMID- 22819525 TI - Dramatic decrease of aortic longitudinal elastic strength in a rat model of aortic dissection. AB - BACKGROUND: This study aimed to evaluate thoracic aortic longitudinal elastic strength in a rat model of aortic dissection (AD). METHODS: Young Sprague Dawley rats were fed 0.25% beta-aminopropionitrile (BAPN). Biomechanical and biochemistry properties of the aorta were analyzed. Elasticity modulus, maximum stretching length, draw ratio, maximum load, maximum strength, and maximum extensibility were measured. RESULTS: More than one-half of BAPN-treated rats (52.9%) died of aortic rupture secondary to AD during the experiment. The diameter of the aneurysms was 6.33 +/- 1.17 mm and the length was 9.33 +/- 4.95 mm. The maximum diameter was significantly increased in BAPN-treated rats with AD (group B2) compared with rats without AD (group B1) and control group (group A) (P = 0.001 and P < 0.001, respectively), but was not different between group B1 and group A (P = 0.108). Thickness of media and initial area in aorta of BAPN treated rats were significantly increased compared with control group (P = 0.001 and P < 0.001, respectively), but no difference in initial area was observed between group B1 and group B2 (P = 0.54). Maximum stretching length, draw ratio, maximum load, maximum strength, maximum extensibility, and elasticity modulus were dramatically decreased in group B2 compared with group B1 and group A (group B2 vs. group B1: P < 0.001; group B1 vs. group A: P < 0.001). CONCLUSIONS: We successfully established a rat model of AD with a high incidence of rupture and mortality. Examinations of strain and stress parameters as well as elasticity modulus of the dissected and the nondissected aorta help understand pathogenesis of AD. PMID- 22819526 TI - Vascular surgeons in France: an endangered species? AB - BACKGROUND: In France, in the next 10 years, a large number of vascular surgeons will retire, and the risk of them not being replaced has raised the question of our capability to predict future activity in this discipline. Otherwise, the French population is expanding and aging. It will increase by 2.7% in 2020, and the number of individuals aged >65 years is expected to increase by 3.3 million, which represents a 33% rise between 2005 and 2020. As the number of vascular surgery procedures is closely associated with aging population, we can expect a significant increase in vascular surgery workload. We present a model to predict changes in vascular surgery activity according to population aging, including other parameters that could affect workload evolution. METHODS: To meet vascular surgeons' needs in the coming years, we initially performed an overview of the demographics of practitioners and estimated the retirements. The second part of our work consisted in studying three groups of arterial surgical and endovascular procedures used in the treatment of infrarenal abdominal aortic aneurysm, peripheral arterial occlusive disease (PAOD), and carotid artery occlusive disease. Data were selected and extracted from the national Medical Information System Program database. Our predictive model is based on the OMPHALE method developed by the National Institute for Statistics and Economic Studies, and we applied it from the year 2000 to 2030. To integrate other parameters affecting workload, we established, from year 2000 data, a prediction based on aging population for the year 2008. Based on this model, we defined a weighted index for each group by comparing expected and observed workloads. This index has been applied to validate our weighted predictive model for year 2009. RESULTS: Among the 611 vascular surgeons in activity in 2011, nearly two-thirds will retire in the next 15 years. Compared with the number of surgeons in formation, there will be a lack of four surgeons per year in the same period. Our predictive model reported an increase by 61% for the three groups for the period 2000 to 2030. Between 2009 and 2030, nearly 22,700 additional acts are expected, representing a 38% increase. According to the model, between 2000 and 2008 only, vascular procedures increased in total by 52.2%, with an increase of 89% in the PAOD group. Between 2000 and 2009, the global increase was 58.0%, with 3.9% for abdominal aortic aneurysm, 101.7% for PAOD, and +13.2% for carotid artery occlusive disease. Our weighted model based on aging population and corrected by a weighted factor predicted this increase. If the activity for each surgeon remained constant, 183 additional surgeons would be needed according to our refined model. CONCLUSION: In addition to the replacement of numerous retired surgeons, aging population and other factors could result in a significant increase in the demand for vascular surgical services. PMID- 22819527 TI - Carotid artery rupture and cervicofacial actinomycosis. AB - Cervicofacial actinomycosis is an uncommon, progressive infection caused by bacilli of the Actinomyces genus. Actinomyces are common commensal saprophytes in the oral cavity which may have medical importance as facultative pathogens. Subsequent to local injuries to the oral mucosa, they may penetrate the deep tissues and be responsible for suppurative or granulomatous infections. We herein report a case of a 65-year-old man who underwent surgery followed by chemotherapy and radiotherapy for a tonsillar carcinoma. An ulcerous lesion in the base of the tongue developed and spread to the carotid artery wall. The man died of a massive hemorrhage due to left carotid artery rupture. Postmortem computed tomography angiography performed prior to autopsy allowed the precise localization of the source of bleeding to be detected. Postmortem biochemical investigations confirmed the presence of inflammation associated with local bacterial infection. Histological investigations revealed the rupture of the left carotid artery surrounded by numerous colonies of Actinomyces. Acute and chronic inflammation with tissue necrosis as well as post-actinic, fibrotic changes were also found in the tissues surrounding the ruptured artery wall. PMID- 22819529 TI - Binding of adiponectin and C1q in human serum, and clinical significance of the measurement of C1q-adiponectin / total adiponectin ratio. AB - OBJECTIVE: Adiponectin and C1q have similar sequences, exist abundantly in blood, and are produced by adipose tissues. The aim of this study was to examine whether adiponectin and C1q form protein-complex in blood and to know the clinical significance of the C1q-adiponectin (C1q-APN) complex in serum. METHODS: The direct interaction between adiponectin and C1q was investigated by far western blotting and co-immunoprecipitation. The relationship between serum C1q-APN and various clinical features was analyzed in 329 Japanese men who underwent health check-up, including measurements of visceral (VFA) and subcutaneous fat area (SFA) by computed tomography (Victor-J study). RESULTS: Adiponectin bound to C1q in vitro and C1q-APN complex existed in human blood. C1q-APN complexes were identified in high- and middle-molecular weight forms of adiponectin in human serum by gel-filtration chromatography. Stepwise multiple regression analysis identified body mass index, VFA and SFA as significant determinants of serum C1q APN level. Serum C1q-APN/Total-APN ratio correlated positively with cardiovascular risk factor accumulation in subjects with VFA >=100 cm(2). CONCLUSIONS: These results indicate that high- and middle-molecular forms of adiponectin partly consist of adiponectin-complex with other proteins including C1q and that the blood C1q-APN/Total-APN ratio may serve as a biomarker of the metabolic syndrome in general male subjects. PMID- 22819528 TI - Estimated plasma stearoyl co-A desaturase-1 activity and risk of incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study. AB - OBJECTIVE: Evidence from pre-clinical studies suggests inhibition of stearoyl co A desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study. METHODS: In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD 1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes. RESULTS: During follow-up (mean 8.0+/-SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition - only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05). CONCLUSIONS: In a large community based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended. PMID- 22819530 TI - Daidzein-metabolizing phenotypes in relation to bone density and body composition among premenopausal women in the United States. AB - BACKGROUND: Bone density has been suggested as a marker of cumulative hormone exposure. Small studies also suggest that patterns of daidzein metabolism may be related to hormone concentrations. To our knowledge, no studies in premenopausal women have compared bone density by daidzein-metabolizing phenotypes in the absence of a soy intervention. OBJECTIVE: The objective was to evaluate the relationship between daidzein-metabolizing phenotypes [equol and O desmethylangolensin (ODMA) production] and bone density and body composition in premenopausal women in the United States. MATERIALS/METHODS: Two hundred and three women attended a clinic visit during which their bone density and body composition were measured by DXA, and 200 (99 %) provided a urine sample following a 3-day soy challenge. Samples were analyzed for isoflavones to determine daidzein-metabolizing phenotypes. RESULTS: In adjusted analyses, there were no differences in hip, spine, femoral neck, or head bone mineral density (BMD) or body composition between producers and non-producers of either equol or ODMA (P > .05). CONCLUSIONS: In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and hip, spine, femoral neck, or head BMD or body composition, suggesting that these phenotypes per se do not influence premenopausal bone density or body composition. PMID- 22819531 TI - Pathological features in the LmnaDhe/+ mutant mouse provide a novel model of human otitis media and laminopathies. AB - Genetic predisposition is recognized as an important pathogenetic factor in otitis media (OM) and associated diseases. Mutant Lmna mice heterozygous for the disheveled hair and ears allele (Lmna(Dhe/+)) exhibit early-onset, profound hearing deficits and other pathological features mimicking human laminopathy associated with the LMNA mutation. We assessed the effects of the Lmna(Dhe/+) mutation on development of OM and pathological abnormalities characteristic of laminopathy. Malformation and abnormal positioning of the eustachian tube, accompanied by OM, were observed in all of the Lmna(Dhe/+) mice (100% penetrance) as early as postnatal day P12. Scanning electronic microscopy revealed ultrastructural damage to the cilia in middle ears that exhibited OM. Hearing assessment revealed significant hearing loss, paralleling that in human OM. Expression of NF-kappaB, TNF-alpha, and TGF-beta, which correlated with inflammation and/or bony development, was up-regulated in the ears or in the peritoneal macrophages of Lmna(Dhe/+) mice. Rugous, disintegrative, and enlarged nuclear morphology of peritoneal macrophages and hyperphosphatemia were found in Lmna(Dhe/+) mutant mice. Taken together, these features resemble the pathology of human laminopathies, possibly revealing some profound pathology, beyond OM, associated with the mutation. The Lmna(Dhe/+) mutant mouse provides a novel model of human OM and laminopathy. PMID- 22819533 TI - Fibrinogen excretion in the urine and immunoreactivity in the kidney serves as a translational biomarker for acute kidney injury. AB - Fibrinogen (Fg) is significantly up-regulated in the kidney after acute kidney injury (AKI). We evaluated the performance of Fg as a biomarker for early detection of AKI. In rats and mice with kidney tubular damage induced by ischemia/reperfusion (I/R) or cisplatin administration, respectively; kidney tissue and urinary Fg increased significantly and correlated with histopathological injury, urinary kidney injury molecule-1 (KIM-1) and N-acetyl glucosaminidase (NAG) corresponding to the progression and regression of injury temporally. In a longitudinal follow-up of 31 patients who underwent surgical repair of abdominal aortic aneurysm, urinary Fg increased earlier than SCr in patients who developed postoperative AKI (AUC-ROC = 0.72). Furthermore, in a cohort of patients with biopsy-proven AKI (n = 53), Fg immunoreactivity in the tubules and interstitium increased remarkably and was able to distinguish patients with AKI from those without AKI (n = 59). These results suggest that immunoreactivity of Fg in the kidney, as well as urinary excretion of Fg, serves as a sensitive and early diagnostic translational biomarker for detection of AKI. PMID- 22819534 TI - KLF6 loss of function in human prostate cancer progression is implicated in resistance to androgen deprivation. AB - Inactivation of the transcription factor/tumor suppressor Kruppel-like factor 6 (KLF6) has been described in prostate cancer (PC). This study investigated the prevalence and significance of KLF6 exon 2 mutations and splice variants (SVs) in different stages of human PC progression. By using laser-capture microdissection and recombinant clone isolation of DNA sequences to enhance sensitivity, base changes were found in 20 (24.7%) of 81 PC tissues versus 1 (4%) of 25 normal prostate tissues (P = 0.02). Of 26 base changes, 54% produced nonsynonymous mutations. Only three mutations had driver characteristics (PCs, 4%; NPs, 0%). By using microdissection of fresh-frozen tissues and recombinant isolation of RNA sequences, SVs were found in 39 (75%) of 52 PCs and in 10 (45%) of 22 NPs (P = 0.01). Sixteen different SVs, including 13 unique SVs, were identified that used cryptic splicing sites and encoded nonfunctional KLF6 proteins. PCs that had survived hormone (androgen)-deprivation therapy (n = 21) had a significantly higher (P < 0.05) incidence, number, and expression level of nonfunctional SVs than either NPs (n = 22) or hormone-naive PCs (n = 25). Forced expression of nonfunctional SVs conferred a survival advantage of androgen-dependent LNCaP cells under castration-simulated culture conditions. Together, these data suggest that decreased availability of functional KLF6 contributes to clinical PC progression. This decrease arises infrequently by somatic mutation and more commonly by the acquisition of SVs that provide a survival advantage under castrate conditions, enabling resistance to hormone therapy. PMID- 22819535 TI - Sex differences in spinal processing of transient and inflammatory colorectal stimuli in the rat. AB - Sex differences in the spinal processing of somatic and visceral stimuli contribute to greater female sensitivity in many pain disorders. The present study examined spinal mechanisms that contribute to sex differences in visceral sensitivity. The visceromotor response to colorectal distention (CRD) was more robust in normal female rats and after intracolonic mustard oil compared with that in male rats. No sex difference was observed in the CRD-evoked response of lumbosacral (LS) and thoracolumbar (TL) colonic afferents in normal and mustard oil-treated rats, but there was a sex difference in spontaneous activity that was exacerbated by intracolonic mustard oil. The response of visceroceptive dorsal horn neurons to CRD was greater in normal female rats in the LS and TL spinal segments. The effect of intracolonic mustard oil on the CRD-evoked response of different phenotypes of visceroceptive dorsal horn neurons was dependent on sex and segment. The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) dose-dependently attenuated the visceromotor response in normal rats with greater effect in male rats. Correspondingly, there was greater cell membrane expression of the GluN1 subunit in dorsal horn extracts in female rats. After intracolonic mustard oil, there was no longer a sex difference in the effect of APV nor GluN1 expression in LS segments, but greater female expression in TL segments. These data document a sex difference in spinal processing of nociceptive visceral stimuli from the normal and inflamed colon. Differences in dorsal horn neuronal activity and NMDA receptor expression contribute to the sex differences in the visceral sensitivity observed in awake rats. PMID- 22819536 TI - Sex differences in serotonin enhancement of capsaicin-evoked calcitonin gene related peptide release from human dental pulp. AB - Serotonin (5HT) is a pronociceptive mediator in the periphery, and evidence implicates involvement in trigeminal pain processing. However, the mechanism(s) by which 5HT modulates trigeminal nociceptors remains unclear. Trigeminal pain can be evoked by the transient receptor potential V1 channel (TRPV1), which is expressed by nociceptive trigeminal neurons and induces release of proinflammatory calcitonin gene-related peptide (CGRP). In our preclinical models, 5HT evoked thermal hyperalgesia and enhanced calcium influx and CGRP release from the TRPV1 population of trigeminal nociceptors. Whether this occurs in humans is unknown. As dental pulp is densely innervated by trigeminal nociceptors, routine tooth extractions offer a unique opportunity to examine whether 5HT enhances CGRP release from human nociceptors. Pulpal tissue was collected from 140 extracted molar teeth from men and women, and basal release samples were collected before treatment with saline or 5HT 100MUmol/L. CGRP release was then stimulated with the TRPV1 agonist capsaicin 1MUmol/L and quantitated by enzyme immunoassay. Additional samples were collected for Western blots to examine 5HT receptor expression. We report that 5HT induced a significant increase in capsaicin-evoked CGRP release, and that this enhancement was observed only in female dental pulp, with no effect of 5HT on male dental pulp. The greatest amount of CGRP release occurred in dental pulp from women in the luteal phase of the menstrual cycle. These results indicate that 5HT enhances capsaicin-evoked CGRP release from human trigeminal nociceptors in a sexually dimorphic manner providing a mechanistic basis for prevalence of trigeminal pain disorders in women. PMID- 22819537 TI - Awareness and knowledge of congenital cytomegalovirus infection among health care providers in France. AB - BACKGROUND: Cytomegalovirus (CMV) is the most frequent cause of congenital virus infection. CMV infects approximately 1% of newborns at birth with severe consequences among 10% of them and antenatal and postnatal treatments, although promising, are still under evaluation in randomised control trials. Efficacy of hygienic counselling to prevent CMV infection is nowadays established and should be spread. OBJECTIVE: To evaluate health care providers' awareness of CMV infection during pregnancy in France. STUDY DESIGN: A questionnaire on CMV infection was sent by e-mail to obstetricians, paediatricians, midwives and laboratory physicians, members of medical or midwives association. We evaluated their knowledge concerning CMV epidemiology, transmission, symptoms in adults, newborns and children. RESULTS: The questionnaire was completed by 800 respondents (half midwives and one third obstetricians). Most of them were unaware of the precise transmission route of CMV. Laboratory physicians had the highest score concerning maternal symptoms and post natal long term effects. 20% of respondents were wrongly convinced that in utero treatment options for congenital CMV infection were already available in France at the time of the study. The mean knowledge scores regarding transmission and neonatal symptoms increased with a more advanced career stage (i.e. older age) among obstetrician. CONCLUSIONS: This study tends to confirm that there is a large gap between knowledge of CMV during pregnancy and the burden of this disease. To bridge this gap, health care providers should improve their knowledge about congenital CMV by various means: medical reviews, continuing medical education, meetings, conferences, the Internet. PMID- 22819538 TI - A case of a male presenting with fever, myalgia, leucopenia, thrombocytopenia and acute kidney injury. PMID- 22819541 TI - [Cost and cost-effectiveness analysis of the preferred treatment for initial antiretroviral therapy in HIV infected adults according to 2012 GESIDA/National AIDS Plan guidelines]. PMID- 22819539 TI - TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. AB - Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the "sepsis syndrome," a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection. PMID- 22819540 TI - [Septic arthritis with negative cultures, usefulness of molecular techniques]. PMID- 22819542 TI - Overcoming challenges to sustain a telestroke network. AB - Our objectives are to identify and help overcome obstacles to telestroke practice, to present tips for sustaining a telestroke network, to suggest strategies for obtaining buy-in from clinicians and administrative leadership and providers, and to identify and engage champions and stakeholders of telestroke. PMID- 22819543 TI - Rate of antithrombotic drug use and clinical outcomes according to CHADS2 scores in patients with an initial cardioembolic stroke who had nonvalvular atrial fibrillation. AB - BACKGROUND: This study investigated the relationship between CHADS2 scores and the rate of antithrombotic drug use and clinical outcomes in patients with an initial cardioembolic stroke who had nonvalvular atrial fibrillation (NVAF). METHODS: In 234 patients (135 men and 99 women; mean age [+/- SD] 76 +/- 11 years) with initial cardiogenic cerebral embolism with NVAF who were admitted to our hospital between April 2007 and March 2011, the CHADS2 score, use of warfarin, and clinical outcomes were retrospectively investigated. RESULTS: CHADS2 scores were as follows: 0 points, n = 21 (9%); 1 point, n = 72 (31%); 2 points, n = 92 (39%); 3 points, n = 47 (20%); and 4 points, n = 2 (1%). The overall warfarin use rate was low (14.1%; n = 33), and it was significantly (P = .023) lower for paroxysmal atrial fibrillation (8%) than for chronic atrial fibrillation (18.5%). The clinical outcomes evaluated by the modified Rankin Scale (mRS) score after 3 months were: CHADS2 score 0 points, mRS 0 to 2 (81%) and 3 to 6 (19%); 1 point, mRS 0 to 2 (46%) and 3 to 6 (54%); 2 points, mRS 0 to 2 (46%) and 3 to 6 (54%); and >= 3 points, mRS 0 to 2 (29%) and 3 to 6 (71%). The clinical outcome worsened as the CHADS2 score increased (P = .002). Logistic regression analysis revealed that being >= 75 years of age and having a high National Institutes of Health Stroke Scale (NIHSS) score on admission were related to a poor outcome (P < .001). CONCLUSIONS: The overall warfarin use rate was low in initial cardioembolic stroke patients with NVAF. Clinical outcomes deteriorated with increases in the CHADS2 score, age >= 75 years, and NIHSS score on admission were related to a poor clinical outcome. PMID- 22819544 TI - Telestroke network business model strategies. AB - Our objective is to summarize the evidence that supports the reliability of telemedicine for diagnosis and efficacy in acute stroke treatment, identify strategies for funding the development of a telestroke network, and to present issues with respect to economic sustainability, cost effectiveness, and the status of reimbursement for telestroke. PMID- 22819545 TI - Exploring the impact of clinical placement models on undergraduate midwifery students. AB - BACKGROUND: Learning undertaken through clinical placements provides up to 50% of the educational experience for students in pre-registration midwifery courses. However little is known about of the impact various models of clinical placement have on the learning experiences of undergraduate midwifery students. Two clinical placement models have been employed for undergraduate midwifery students at Monash University, including the block placement model and the continuous two days per week model. OBJECTIVE: This project sought to explore the learning experiences of students in these two models of placement. METHOD: Focus groups were held on two campuses with a total of 17 students from different cohorts and programs. DISCUSSION: No one type of placement was favoured over another both had benefits and disadvantages. Further, this study found that regardless of program and clinical placement model the major learning impact for students was related to the midwife they worked with each day on placement rather than to the model. CONCLUSION: No one type of placement was favoured over another both had benefits and disadvantages. Further, this study found that regardless of program and clinical placement model the major learning impact for students was related to the midwife they worked with each day on placement rather than to the model. PMID- 22819546 TI - Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic beta-cell survival and function via CREB. AB - Chronic hyperlipidemia causes beta-cell apoptosis and dysfunction, thereby contributing to the pathogenesis of type 2 diabetes (T2D). Thus, searching for agents to promote pancreatic beta-cell survival and improve its function could be a promising strategy to prevent and treat T2D. We investigated the effects of kaempferol, a small molecule isolated from ginkgo biloba, on apoptosis and function of beta-cells and further determined the mechanism underlying its actions. Kaempferol treatment promoted viability, inhibited apoptosis and reduced caspase-3 activity in INS-1E cells and human islets chronically exposed to palmitate. In addition, kaempferol prevented the lipotoxicity-induced down regulation of antiapoptotic proteins Akt and Bcl-2. The cytoprotective effects of kaempferol were associated with improved insulin secretion, synthesis, and pancreatic and duodenal homeobox-1 (PDX-1) expression. Chronic hyperlipidemia significantly diminished cyclic adenosine monophosphate (cAMP) production, protein kinase A (PKA) activation, cAMP-responsive element binding protein (CREB) phosphorylation and its regulated transcriptional activity in beta-cells, all of which were restored by kaempferol treatment. Disruption of CREB expression by transfection of CREB siRNA in INS-1E cells or adenoviral transfer of dominant negative forms of CREB in human islets ablated kaempferol protection of beta-cell apoptosis and dysfunction caused by palmitate. Incubation of INS-1E cells or human islets with kaempferol for 48h induced PDX-1 expression. This effect of kaempferol on PDX-1 expression was not shared by a host of structurally related flavonoid compounds. PDX-1 gene knockdown reduced kaempferol-stimulated cAMP generation and CREB activation in INS-1E cells. These findings demonstrate that kaempferol is a novel survivor factor for pancreatic beta-cells via up-regulating the PDX-1/cAMP/PKA/CREB signaling cascade. PMID- 22819547 TI - Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart. AB - There is increasing evidence indicating that inflammatory processes are involved in the development and progression of diabetic complications. However, effective anti-inflammatory treatments for patients who have diabetic complications have yet been practically identified. Curcumin is a main component of Curcuma longa with numerous pharmacological activities. Previously, we synthesized a novel curcumin analogue (B06) that exhibited an improved pharmacokinetic and enhanced anti-inflammatory activity compared to curcumin. The present study aimed to test the hypothesis that B06 may reduce high-glucose-induced inflammation and inflammation-mediated diabetic complications. In vitro, pretreatment with B06 at a concentration of 5 MUM significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages. This anti-inflammatory activity of B06 is associated with its inhibition of c-Jun N-terminal kinase/nuclear factor kappaB activation. In vivo, despite that B06 administration at 0.2 mg . kg(-1) . d(-1) for 6 weeks did not affect the blood glucose profile of diabetic rats, the B06-treated animals displayed significant decreases in inflammatory mediators in the serum, kidney, and heart and renal macrophage infiltration. This was accompanied with an attenuation of diabetes-induced structural and functional abnormalities in the kidney and heart. Taken together, these data suggest that the novel derivative B06 might be a potential therapeutic agent for diabetic complications via an anti-inflammatory mechanism and support the potential application in diabetic complication therapy via anti-inflammatory strategy. PMID- 22819548 TI - The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism. AB - The nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that responds to oxidative stress by binding to the antioxidant response element (ARE) in the promoter of genes coding for antioxidant enzymes like NAD(P)H:quinone oxidoreductase 1 and proteins for glutathione synthesis. The Nrf2/ARE pathway has nutritional interest owing to its activation by phytochemicals such as sulforaphane. Recently, the Nrf2 pathway was identified as having regulatory functions in mitochondrial biogenesis, adipocyte differentiation and liver energy metabolism. Activation of Nrf2 increases energy metabolism and conversely suppresses lipid synthesis. Lard-based, but not soybean oil-based, high-fat diets reduce mRNA expression of Nrf2 and its downstream targets, suggesting a macronutrient influence on the activation of the Nrf2 pathway and susceptibility to oxidative stress. This review examines data revealing the Nrf2 pathway's regulatory role in energy metabolism at the molecular, cellular and whole animal levels. Understanding the relationship of Nrf2 and energy metabolism in cells, tissues and physiologic systems will provide novel insights for nutritional interventions for obesity and its comorbidities such as diabetes. PMID- 22819549 TI - Glucose acts as a regulator of serum iron by increasing serum hepcidin concentrations. AB - Mutual clinical and molecular interactions between iron and glucose metabolism have been reported. We aimed to investigate a potential effect of glucose on iron homeostasis. We found that serum iron concentrations gradually decreased over 180 min after the administration of 75 g of glucose from 109.8 +/- 45.4 mg/L to 94.4 +/- 40.4 mg/L (P<.001; N=40) but remained unchanged in control subjects receiving tap water (N=21). Serum hepcidin, the key iron regulatory hormone which is mainly derived from hepatocytes but also expressed in pancreatic beta-cells, increased within 120 min after glucose ingestion from 19.7 +/- 9.9 nmol/L to 31.4 +/- 21.0 nmol/L (P<.001). In cell culture, glucose induced the secretion of hepcidin and insulin into the supernatant of INS-1E cultures, but did not change the amount of hepcidin detectable in the hepatocyte cell culture HepG2. We additionally confirmed the expression of hepcidin in a human islet cell preparation. These results suggest that glucose acts as a regulator of serum iron concentrations, most likely by triggering the release of hepcidin from beta-cells. PMID- 22819550 TI - Quercetin intake during lactation modulates the AMP-activated protein kinase pathway in the livers of adult male rat offspring programmed by maternal protein restriction. AB - Quercetin, a naturally occurring flavonoid, has been reported to possess numerous biological activities including activation of adenosine-5'-monophosphate activated protein kinase (AMPK). We investigated the effects of quercetin intake during lactation on the AMPK activation in the livers of adult offspring programmed by maternal protein restriction during gestation. Pregnant Wistar rats were fed control and low-protein diets during gestation. Following delivery, each dam received a control or 0.2% quercetin-containing control diet during lactation as follows: control on control (CC), control on restricted (LPC) and 0.2% quercetin-containing control on restricted (LPQ). At weaning (week 3), some of the pups from each dam were killed, and the remaining pups (CC, n=8; LPC, n=10; LPQ, n=13) continued to receive a standard laboratory diet and were killed at week 23. Blood chemistry and phosphorylation levels of AMPKalpha, acetyl-CoA carboxylase (ACC), endothelial nitric oxide synthase (eNOS) and mammalian target of rapamycin (mTOR) in the livers of male offspring were examined. At week 3, the level of phosphorylated AMPK protein in LPQ increased about 1.5- and 2.1-fold compared with LPC and CC, respectively, and the level in LPQ at week 23 increased about 1.9- and 2.9-fold, respectively. A significant increase in phosphorylated ACC and eNOS levels was found in LPQ. There was no significant difference among the three groups in the level of phosphorylated mTOR protein. In conclusion, quercetin intake during lactation up-regulates AMPK activation in the adult offspring of protein-restricted dams and modulates the AMPK pathway in the liver. PMID- 22819551 TI - Protective effects of (-)-epigallocatechin-3-gallate against TNF-alpha-induced lung inflammation via ROS-dependent ICAM-1 inhibition. AB - Oxidative stresses are considered to play an important role in the induction of cell adhesion molecules and proinflammatory cytokines implicated in inflammatory processes. Heme oxygenase (HO)-1 and suppressors of cytokine signaling (SOCS)-3 exert several biological functions, including antiapoptotic and anti-inflammatory effects. Here, we report that HO-1 and SOCS-3 were induced in A549 cells and human pulmonary alveolar epithelial cells (HPAEpiCs) treated with (-) epigallocatechin-3-gallate (EGCG). EGCG protected against tumor necrosis factor (TNF)-alpha-mediated lung inflammation by down-regulation of oxidative stress and intercellular adhesion molecule (ICAM)-1 expression in A549 cells or HPAEpiCs and the lungs of mice. EGCG inhibited TNF-alpha-induced ICAM-1 expression, THP-1 cells adherence, pulmonary hematoma and leukocyte (eosinophils and neutrophils) count in bronchoalveolar lavage fluid in mice. In addition, EGCG also attenuated TNF-alpha-induced oxidative stress, p47(phox) translocation, MAPKs activation, and STAT-3 and activating transcription factor (ATF)2 phosphorylation. EGCG also reduced the formation of a TNFR1/TRAF2/Rac1/p47(phox) complex. Moreover, in this study, the observed suppression of TNF-alpha-stimulated ICAM-1 expression and reactive oxygen species (ROS) generation by EGCG was abrogated by transfection with siRNA of SOCS-3 or HO-1. These results suggested that HO-1 or SOCS-3 functions as a suppressor of TNF-alpha signaling, not only by inhibiting adhesion molecules expression but also by diminishing intracellular ROS production and STAT-3 and ATF2 activation in A549 cells or HPAEpiCs and the lungs of mice. PMID- 22819552 TI - Resveratrol promotes cellular glucose utilization in primary cultured cortical neurons via calcium-dependent signaling pathway. AB - BACKGROUND AND PURPOSE: Impairment of glucose utilization contributes to neuronal degeneration of Alzheimer's disease patients. Cellular glucose utilization can be regulated by calcium-dependent signaling pathways. Resveratrol (RSV) is a plant derived polyphenol with multiple beneficial effects, including neuroprotection and metabolic improvement. Here, we investigated the effect of RSV on neuronal calcium signal and glucose utilization. EXPERIMENTAL METHODS: Primary culture of cortical neurons, calcium imaging, 2-NBDG assay and western blotting were employed to investigate RSV-mediated effects on neuronal calcium signal and glucose utilization. RESULTS: RSV elevated intracellular calcium in cortical neurons via modulation of secondary messenger system including nitrous oxide, cGMP and cAMP. Secondarily, a calcium-dependent enhancement of neuronal glucose utilization after RSV treatment was observed. The effects on neuronal glucose utilization are largely dependent on RSV-induced calcium-dependent AMP-activated protein kinase activation. CONCLUSION: Our findings show that activation of calcium-dependent signaling pathways by RSV may convey improvements of neuronal glucose utilization. PMID- 22819553 TI - L-theanine promotes nitric oxide production in endothelial cells through eNOS phosphorylation. AB - Consumption of tea (Camellia sinensis) improves vascular function and is linked to lowering the risk of cardiovascular disease. Endothelial nitric oxide is the key regulator of vascular functions in endothelium. In this study, we establish that l-theanine, a non-protein amino-acid found in tea, promotes nitric oxide (NO) production in endothelial cells. l-theanine potentiated NO production in endothelial cells was evaluated using Griess reaction, NO sensitive electrode and a NO specific fluorescent probe (4-amino-5-methylamino-2',7'-difluororescein diacetate). l-Theanine induced NO production was partially attenuated in presence of l-NAME or l-NIO and completely abolished using eNOS siRNA. eNOS activation was Ca(2+) and Akt independent, as assessed by fluo-4AM and immunoblotting experiments, respectively and was associated with phosphorylation of eNOS Ser 1177. eNOS phosphorylation was inhibited in the presence of ERK1/2 inhibitor, PD 98059 and partially inhibited by PI3K inhibitor, LY-294002 and Wortmanin suggesting PI3K-ERK1/2 dependent pathway. Increased NO production was associated with vasodilation in ex ovo (chorioallantoic membrane) model. These results demonstrated that l-theanine administration in vitro activated ERK/eNOS resulting in enhanced NO production and thereby vasodilation in the artery. The results of our experiments are suggestive of l-theanine mediated vascular health benefits of tea. PMID- 22819554 TI - Methylation of histone H3 at lysine 4 and expression of the maltase-glucoamylase gene are reduced by dietary resistant starch. AB - Methylated histone H3 at lysine 4 (K4) is associated with euchromatin and is involved in the transactivation of genes. However, it is unknown whether histone methylation is involved with changes in gene expression induced by nutrients. In this study, we examined whether methylations of histone H3 at K4 on maltase glucoamylase (Mgam), which is responsible for the digestion of starch in the small intestine, as well as Mgam expression were altered by feeding rats an indigestible starch (resistant starch, RS). The mRNA and protein levels and the activities of MGAM were reduced in rats fed an RS diet compared with those fed a regular starch diet. Furthermore, we found that decreases in di- and tri methylation of histone H3 at K4, as well as reduced acetylation of histones H3 and H4 on the Mgam gene were associated with a reduction of Mgam gene expression. These results suggest that the reductions of jejunal MGAM levels and activities caused by the RS diet are regulated at the mRNA level through a decrease in methylation of histone H3 at K4 and reduced acetylation of histones H3 and H4 on the Mgam gene. PMID- 22819555 TI - Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals. AB - The management of overweight subjects by interventions aimed at reducing inflammation is highly desirable. To date, observational studies have identified a link between increased dietary antioxidant intake and reduced cardiovascular morbidity. However, direct trial evidence regarding the ability of antioxidants to influence inflammation is lacking. Therefore, this study examined lycopene's ability to lower systemic and high-density lipoprotein (HDL)-associated inflammation in moderately overweight middle-aged subjects. Serum was collected before and after a 12-week intervention from 54 moderately overweight, middle aged individuals. Subjects were randomised to one of three groups: control diet (<10 mg lycopene/week), lycopene-rich diet (224-350 mg lycopene/week) and lycopene supplement (70 mg lycopene/week). HDL was subfractionated into HDL(2&3) by rapid ultracentrifugation. Compliance was monitored by assessing lycopene concentration in serum and HDL(2&3). Systemic and HDL-associated inflammation was assessed by measuring serum amyloid A (SAA) levels. HDL functionality was determined by monitoring the activities of paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT). Lycopene increased in serum and HDL(2&3) following both lycopene interventions (P<.001, for all), while SAA decreased in serum following the lycopene supplement and in HDL(3) following both lycopene interventions (P<.05 for all). PON-1 activity increased in serum and HDL(2&3) in both lycopene groups (P<.05, for all). Furthermore, the activity of CETP decreased in serum following the lycopene supplement, while the activity of LCAT increased in serum and HDL(3) following both lycopene interventions (P<.05 for all). These results demonstrate that in moderately overweight, middle-aged subjects, increasing lycopene intake leads to changes to HDL(2&3), which we suggest enhanced their antiatherogenic properties. Overall, these results show the heart-protective properties of increased lycopene intake. PMID- 22819556 TI - 3,3'-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells. AB - 3,3'-Diindolylmethane (DIM) is a major in vivo condensation product of indole-3 carbinol, which is present in cruciferous vegetables. Although these compounds have been widely implicated in antitumorigenic and proapoptotic properties in animal as well as in vitro models of cancer, the underlying cellular mechanisms regulated by DIM are only partially understood. Activating transcription factor 3 (ATF3) is a member of the ATF/c-AMP response element-binding (CREB) subfamily of the basic-region leucine zipper family and has been known to induce apoptosis in human colorectal cancer (CRC) cells. The present study was performed to elucidate the molecular mechanism of ATF3 induction by DIM in human CRC cells. The DIM treatment induced apoptosis and induced ATF3 gene expression at protein and messenger RNA levels. DIM increased ATF3 promoter activity, and the region of -84 to +34 within ATF3 promoter was responsible for promoter activation by DIM. This region contained an ATF binding site. Deletion and point mutation of the ATF binding site (-23 to -16) abolished ATF3 promoter activation by DIM, and overexpression of ATF4 enhanced ATF3 transactivation. Chromatin immunoprecipitation assay confirmed the binding of ATF4 in the ATF3 promoter. Inhibition of ATF4 expression by small interference RNA results in repression of DIM-induced ATF3 expression. The current study demonstrates that DIM stimulates ATF3 expression through ATF4-mediated pathway and subsequently induces apoptosis in human CRC cells. PMID- 22819557 TI - Pigs fed saturated fat/cholesterol have a blunted hypothalamic-pituitary-adrenal function, are insulin resistant and have decreased expression of IRS-1, PGC1alpha and PPARalpha. AB - The increasing incidence of insulin resistance has been linked to both increased intake of saturated fatty acids and disruption of the hypothalamic-pituitary adrenal (HPA) axis. We tested the hypothesis that adding saturated fat/cholesterol to the diet of growing pigs would both disrupt HPA function and cause insulin resistance. Three-month-old pigs were fed either a control (13% energy from fat) or a high saturated fatty acid cholesterol (HSFC) diet (44% energy from fat; 2% cholesterol). After 10 weeks on the diets, intravenous ACTH, insulin and glucose challenges were performed, and after 12 weeks, tissue samples were taken for measurement of mRNA and for lipid-rich aortic lesions. Plasma total, HDL- and LDL-cholesterol were significantly increased in pigs fed the HSFC diet. Cortisol release during the ACTH challenge was suppressed in HSFC-fed pigs which were also more insulin resistant and glucose intolerant than controls. The HSFC diet decreased the expression of insulin receptor (IR) and insulin receptor substrate-1 in muscle and adipose tissue as well as adiponectin and adiponectin receptor 2 expression in fat. The HSFC diet decreased PGC-1alpha and PPARalpha expression in muscle but increased PPARalpha expression in liver. There was a trend for an increase in lipid-stained lesion frequency around the abdominal branches of the aorta in HSFC-fed pigs. We conclude that feeding increased saturated fat to pigs causes disruption in the HPA axis, insulin resistance and decreased muscle and adipose expression of genes controlling insulin signalling and mitochondrial oxidative capacity. PMID- 22819558 TI - Sexual dimorphism in development of kidney damage in aging Fischer-344 rats. AB - BACKGROUND: Aging kidneys exhibit slowly developing injury and women are usually protected compared with men, in association with maintained renal nitric oxide. OBJECTIVES: Our purpose was to test 2 hypotheses: (1) that aging intact Fischer 344 (F344) female rats exhibit less glomerular damage than similarly aged males, and (2) that loss of female ovarian hormones would lead to greater structural injury and dysregulation of the nitric oxide synthase (NOS) system in aging F344 rat kidneys. METHODS: We compared renal injury in F344 rats in intact, ovariectomized, and ovariectomized with estrogen replaced young (6 month) and old (24 month) female rats with young and old intact male rats and measured renal protein abundance of NOS isoforms and oxidative stress. RESULTS: There was no difference in age-dependent glomerular damage between young or old intact male and female F344 rats, and neither ovariectomy nor estrogen replacement affected renal injury; however, tubulointerstitial injury was greater in old males than in old females. These data suggest that ovarian hormones do not influence these aspects of kidney aging in F344 rats and that the greater tubulointerstitial injury is caused by male sex. Old males had greater kidney cortex NOS3 abundance than females, and NOS1 abundance (alpha and beta isoforms) was increased in old males compared with both young males and old females. NOS abundance was preserved with age in intact females, ovariectomy did not reduce NOS1 or NOS3 protein abundance, and estrogen replacement did not uniformly elevate NOS proteins, suggesting that estrogens are not primary regulators of renal NOS abundance in this strain. Nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide production and nitrotyrosine immunoreactivity were increased in aging male rat kidneys compared with females, which could compromise renal nitric oxide production and/or bioavailability. CONCLUSIONS: The kidney damage expressed in aging F344 rats is fairly mild and is not related to loss of renal cortex NOS3 or NOS1 alpha. PMID- 22819559 TI - Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. AB - Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification. Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). In high-risk populations, high total uncarboxylated MGP (t-ucMGP) was associated with decreased CAC, while high non-phosphorylated uncarboxylated MGP (dp-ucMGP) was associated with a poor vitamin K status. This cross-sectional study investigated the association of MGP species with CAC, vitamin K status among 200 healthy women. Circulating dp-ucMGP, t-ucMGP and, non-phosphorylated carboxylated MGP (dp-cMGP) levels were measured by ELISA techniques and Agatston score by multi-detector computed tomography. The ratio of uncarboxylated to carboxylated osteocalcin was used as proxy of vitamin K status. A borderline significant (P=.06) association between higher circulating dp-ucMGP levels and high CAC was observed (beta=0.091, 95% CI-0.01; 0.19). In the entire study population, high t-ucMGP levels tended to be associated (P=.09) with lower CAC (beta=-0.36, 95% CI:-0.78; 0.06). This association strengthened amongst women with CAC to a significant relation between high t-ucMGP levels and lower CAC (beta=-0.55, 95% CI-1.01;-0.10). Dp-cMGP was not associated with CAC. Low vitamin K-status was associated with high dp-ucMGP concentrations (beta=0.138, 95% CI 0.09; 0.19) but not with other MGP species. These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed. PMID- 22819560 TI - Protective effects of dietary EPA and DHA on ischemia-reperfusion-induced intestinal stress. AB - The immunoregulatory effects of dietary omega-3 fatty acids are still not fully characterized. The aim of this study was to determine whether dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake limits intestinal ischemia-reperfusion (IR) injury. To test this, rats were fed either control or EPA/DHA supplemented diet for 3 weeks following which they underwent either a sham or an IR surgical protocol. A significant reduction in mucosal damage was observed after EPA/DHA supplemented diet as reflected by maintenance of total protein content. To address the underlying mechanisms of protection, we measured parameters of oxidative stress, intestinal and serological cytokines and intestinal eicosanoids. Interestingly, EPA/DHA fed animals displayed a higher activity of oxidative stress enzyme machinery, i.e., superoxide dismutase and catalase in addition to a reduction in total nitrate/nitrite content. While no changes in cytokines were observed, eicosanoid analyses of intestinal tissue revealed an increase in metabolites of the 12-lipoxygenase pathway following IR. Further, IR in EPA/DHA fed animals was accompanied by a significant increase of 17,18-epoxyeicosatetraenoic acid, 8-Iso prostaglandin F(3alpha) and thromboxane B(3), by more than 12-, 6-, 3-fold, respectively. Thus, the data indicate that EPA/DHA supplementation may be able to reduce early intestinal IR injury by anti oxidative and anti-inflammatory mechanisms. PMID- 22819561 TI - Anti-apoptotic and anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's rat model. AB - In the present study, we examined the molecular mechanism by which Piperine (bioactive compound of Piper nigrum) inhibits neuronal cell apoptosis. We further investigated the anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's disease. Consistent with its antioxidant properties, Piperine (10 mg/kg bwt) reduced 6-OHDA-induced lipid peroxidation and stimulated glutathione levels in striatum of rats. Furthermore, Piperine treatment diminished cytochrome c release from mitochondria and reduced caspase-3 and caspase-9 activation induced by 6-OHDA. Treatment with Piperine markedly inhibited poly(ADP-ribose) polymerase activation, pro-apoptotic Bax levels and elevation of Bcl-2 levels. Piperine reduces contralateral rotations induced by apomorphine. Further narrow beam test and rotarod also showed improvement in motor coordination and balance behavior in rats treated with Piperine. In addition Piperine depletes inflammatory markers, TNF-alpha and IL-1beta in 6-OHDA-induced Parkinson's rats. We propose that, in addition to its antioxidant properties Piperine exerts a protective effect via anti-apoptotic and anti-inflammatory mechanism on 6-OHDA induced Parkinson's disease. PMID- 22819562 TI - Oxidative stress programming in a rat model of postnatal early overnutrition- role of insulin resistance. AB - Postnatal early overfeeding (EO) is related to later development of overweight and other metabolic disorders. As oxidative stress is implicated in most human diseases, as obesity and diabetes, we decided to study some parameters related to oxidative stress and insulin signaling in liver from EO animals in adult life. To induce EO, litter size was reduced to three pups per litter (SL: small litter) and groups with normal litter size (NL:10 pups per litter) were used as control. After weaning, rats had free access to standard diet and water. Body weight and food intake were monitored daily and offspring were killed at 180 days-old. Significant differences had P<.05 or less. As expected, SL rats had hyperphagia, higher body weight and higher visceral fat mass at weaning and adulthood. In liver, postnatal EO programmed for lower catalase (-42%), superoxide dismutase ( 45%) and glutathione peroxidase (-65%) activities. The evaluation of liver injury in adult SL group showed lower nitrite content (-10%), higher liver and plasma malondialdehyde content (+25% and 1.1-fold increase, respectively). No changes of total protein bound carbonyl or Cu/Zn superoxide dismutase protein expression in liver were detected between the groups. Regarding insulin signaling pathway in liver, SL offspring showed lower IRbeta (-66%), IRS1 (-50%), phospho-IRS1 (-73%), PI3-K (-30%) and Akt1 (-58%). Indeed, morphological analysis showed that SL rats presented focal areas of inflammatory cell infiltrate and lipid drops in their cytoplasm characterizing a microsteatosis. Thus, we evidenced that postnatal EO can program the oxidative stress in liver, maybe contributing for impairment of the insulin signaling. PMID- 22819563 TI - Dietary conjugated nonadecadienoic acid prevents adult-onset obesity in nescient basic helix-loop-helix 2 knockout mice. AB - Conjugated linoleic acid (CLA) has been extensively studied during the last two decades with regard to its effects on controlling body composition. As a cognate to CLA, conjugated nonadecadienoic acid (CNA) has been previously reported to reduce body fat more effectively than CLA. However, it is not known whether CNA supplementation can influence adult-onset obesity. Thus, the purpose of this study was to evaluate the effects of dietary CNA on the prevention of adult-onset inactivity-induced obesity using nescient basic helix-loop-helix 2 knockout (N2KO) mice. CNA supplementation at 0.1 w/w% level starting in the preobese state significantly prevented the reduction of voluntary movement and the increase in weight gain in N2KO mice during the experimental period compared to wild-type animals. In both wild-type and N2KO mice, respiratory exchange ratio was significantly reduced by CNA treatment during light and dark cycles, and dietary CNA significantly increased energy expenditure in N2KO mice. Selected gene expression profiles in white adipose tissue, muscle or liver showed a beneficial action of CNA on lipid metabolism and energy expenditure. These findings suggest that CNA could prevent adult-onset obesity by enhancing voluntary activity and energy expenditure in N2KO mice. PMID- 22819564 TI - Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes. AB - Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of the soy isoflavone genistein on diabetic wound healing and investigate underlying mechanisms. Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds received 0.2, 1 or 5mg/kg/day of genistein via subcutaneous injection. Genistein dose dependently rescued the delay of wound closure in diabetic mice. A dose of 5 mg/kg/day of genistein treatment significantly increased the mean perfusion rate, and in vitro treatment with genistein protected against high glucose-induced impairment of capillary tube formation in cultured endothelial cells. Diabetic conditions significantly increased superoxide anion (O(2).(-)) production and nitrotyrosine formation, and decreased nitrite levels in wound tissues. Genistein treatment at all doses normalized the elevated O(2).(-) production and nitrotyrosine formation, and reversed the attenuated nitrite level. In diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was activated, and genistein administration prevented increased iNOS activity. Moreover, genistein attenuated diabetic cutaneous silent information regulator 1 and forkhead box O transcription factor 1 (FoxO1) levels and potentiated ac-FoxO1 in a dose dependent manner. Genistein rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetes in mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress. PMID- 22819565 TI - Lecithin/cholesterol acyltransferase modulates diet-induced hepatic deposition of triglycerides in mice. AB - Lecithin/cholesterol acyltransferase (LCAT) is responsible for the esterification of the free cholesterol of plasma lipoproteins. Here, we investigated the involvement of LCAT in mechanisms associated with diet-induced hepatic triglyceride accumulation in mice. LCAT-deficient (LCAT(-/-)) and control C57BL/6 mice were placed on a Western-type diet (17.3% protein, 48.5% carbohydrate, 21.2% fat, 0.2% cholesterol, 4.5kcal/g) for 24weeks, then histopathological and biochemical analyses were performed. We report that, in our experimental setup, male LCAT(-/-) mice are characterized by increased diet-induced hepatic triglyceride deposition and impaired hepatic histology and architecture. Mechanistic analyses indicated that LCAT deficiency was associated with enhanced intestinal absorption of dietary triglycerides (3.6+/-0.5mg/dl per minute for LCAT(-/-) vs. 2.0+/-0.7mg/dl per minute for C57BL/6 mice; P<.05), accelerated clearance of postprandial triglycerides and a reduced rate of hepatic very low density lipoprotein triglyceride secretion (9.8+/-1.1mg/dl per minute for LCAT(-/ ) vs. 12.5+/-1.3mg/dl per minute for C57BL/6 mice, P<.05). No statistical difference in the average daily food consumption between mouse strains was observed. Adenovirus-mediated gene transfer of LCAT in LCAT(-/-) mice that were fed a Western-type diet for 12weeks resulted in a significant reduction in hepatic triglyceride content (121.2+/-5.9mg/g for control infected mice vs. 95.1+/-5.8mg/g for mice infected with Ad-LCAT, P<.05) and a great improvement of hepatic histology and architecture. Our data extend the current knowledge on the functions of LCAT, indicating that LCAT activity is an important modulator of processes associated with diet-induced hepatic lipid deposition. PMID- 22819566 TI - Distribution patterns and major sources of dioxins in soils of the Changsha Zhuzhou-Xiangtan urban agglomeration, China. AB - Surface soils from an industrial base, the Changsha-Zhuzhou-Xiangtan urban agglomeration in central China were analyzed for 2378-substituted polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). The PCDD/F concentrations ranged from 268 to 7510 pg g(-1) dry weight (dw), 72% of which were above the U.S. guideline value (1000 pg g(-1)). It was found that octachlorodibenzo-p-dioxin (OCDD) was the most dominant congener accounting for 78.4-99.3% of the total PCDD/Fs, which was consistent with the PCDD/F profiles reported in other Asian countries. It is recommended that the four major sources of PCDD/Fs in the region can be diesel-fuel vehicles, open straw burning, mass burn-water wall (MB-WW), pentachlorophenate (PCP)/PCP-Na and boilers-hazardous waste incineration. This study is one of the few studies with a focus on the PCDD/F pollution in central China, providing evidences for establishing priorities in reduction of ecological risks posed by PCDD/Fs in central China and elsewhere. PMID- 22819567 TI - A temporal study on fate of Al2O3 nanoparticles in a fresh water microcosm at environmentally relevant low concentrations. AB - This study on a microcosm, brings out the temporal changes in physico-chemical behavior of aluminum oxide nanoparticles (for a period of 210 days), at environmentally relevant concentrations (1000 MUg/L and below). The dynamics of particle behavior in terms of mean hydrodynamic diameter, specific surface area and dissolution of soluble aluminum and, their possible ecological implications have been presented in this study. A thorough statistical analysis brings out nanoparticle behavior, where a rapid aggregation of particles (79+/-13 nm at 0 h to 1464+/-80 nm at 48 h), with a decrease in specific surface area (32 m2/g at 0 h to 1.7 m2/g at 48 h) was observed. Ion release profile indicated a significant increase in soluble aluminum concentration only after 36 h (277+/-15 MUg/L at 0 h to 462+/-3 MUg/L at 36 h) which reduced over a period of 60 days (279+/-20 MUg/L). A differential response at 1000 MUg/L concentration was observed, short term exposure (5 days) showed an immediate effect on the resident algal population (~25% decreased viability) and the long term (7 months/210 days) exposure showed a gradual recovery. Thus, nanomaterials may not have the stipulated toxic response, at low concentration and longer standing period, presumably owing to the complexity of the natural systems. PMID- 22819569 TI - A novel MRI compatible soft tissue indentor and fibre Bragg grating force sensor. AB - MRI is an ideal method for non-invasive soft tissue mechanical properties investigation. This requires mechanical excitation of the body's tissues and measurement of the corresponding boundary conditions such as soft tissue deformation inside the MRI environment. However, this is technically difficult since load application and measurement of boundary conditions requires MRI compatible actuators and sensors. This paper describes a novel MRI compatible computer controlled soft tissue indentor and optical Fibre Bragg Grating (FBG) force sensor. The high acquisition rate (100Hz) force sensor was calibrated for forces up to 15N and demonstrated a maximum error of 0.043N. Performance and MRI compatibility of the devices was verified using indentation tests on a silicone gel phantom and the upper arm of a volunteer. The computer controlled indentor provided a highly repeatable tissue deformation. Since the indentor and force sensor are composed of non-ferromagnetic materials, they are MRI compatible and no artefacts or temporal SNR reductions were observed. In a phantom study the mean and standard deviation of the temporal SNR levels without the indentor present were 500.18 and 207.08, respectively. With the indentor present the mean and standard deviation were 501.95 and 200.45, respectively. This computer controlled MRI compatible soft tissue indentation system with an integrated force sensor has a broad range of applications and will be used in the future for the non-invasive analysis of the mechanical properties of skeletal muscle tissue. PMID- 22819570 TI - Decreased expression of pigment epithelium-derived factor and increased microvascular density in ovarian endometriotic lesions in women with endometriosis. AB - OBJECTIVES: To determine whether women with endometriosis have altered expression of pigment epithelium-derived factor (PEDF) in ovarian endometriotic lesions as compared to women without endometriosis. STUDY DESIGN: Ectopic and eutopic and normal endometrial tissues were sampled from 40 women with ovarian endometriosis and 20 control women, respectively. Endometrial PEDF expression and microvascular density (MVD) using an antibody to von Willebrand factor (vWF) and alpha-smooth muscle actin (alpha-SMA) were evaluated by using immunohistochemical staining. RESULTS: We detected decreased PEDF expression and increased MVD using anti-vWF and -alpha-SMA in ovarian endometriotic lesions in women with endometriosis compared with the control group. In women with endometriosis, the MVD using anti vWF and -alpha-SMA but not PEDF expression in ovarian endometriotic lesions correlated with the size of ovarian endometriotic cysts and the severity of the disease. Moreover, the MVD using anti-vWF was negatively correlated with PEDF expression in control endometrium but not in ovarian endometriotic lesions. CONCLUSIONS: Our results suggest that decreased PEDF expression and increased MVD in ovarian endometriotic lesions might play an important role in the pathogenesis of ovarian endometriosis. PMID- 22819571 TI - PCOS patients can benefit from in vitro maturation (IVM) of oocytes. AB - OBJECTIVE: Our aim was to compare treatment outcome following in vitro maturation (IVM) compared with IVF in patients with polycystic ovarian syndrome (PCOS). STUDY DESIGN: Retrospective evaluation of treatment in women with PCOS who underwent IVM (108) and IVF (108). RESULTS: We found a significant difference in outcome between IVM and IVF, with an increase in the number of mature oocytes derived (10.5 +/- 6.5 vs. 15.3 +/- 8.8, p<0.0001) and the cleavage rate (92.4 +/- 13.0 vs. 95.2 +/- 11.7, p=0.03) in IVM cycles. Due to the lower implantation rate (16.1% vs. 21.6%, p=0.07) we tend to transfer more embryos in the IVM group (3.4 +/- 0.8 vs. 2.8 +/- 1.0, p<0.0001), but the multiple pregnancy rate in that group was not higher. Importantly, the delivery rate was similar in both groups (26.8% vs. 25%). We also report a yearly change in the success rate of IVM during this period. CONCLUSIONS: IVM treatment for PCOS patients may be a valid alternative treatment to IVF with the advantage of eliminating the risk of OHSS and reducing the cost of medication, whilst maintaining high clinical pregnancy rate. PMID- 22819572 TI - A preliminary study of the relationship between the long arm of the Y chromosome (Yqh+) and reproductive outcomes in IVF/ICSI-ET. AB - OBJECTIVE: To compare the reproductive outcomes of Yqh+-carrying and control couples undergoing IVF/ICSI treatments. STUDY DESIGN: Retrospective analysis of 72 Yqh+ carriers and 986 Yqh+ non-carriers undergoing their first cycle of ART in a single centre between August 2005 and May 2011. RESULTS: Yqh+ carrying couples had significantly worse reproductive outcomes compared with control couples undergoing IVF treatment. There were a significantly higher cancellation rate (20.69% vs 7.9%; P<0.05; OR, 3.03; CI, 1.18-7.79) and a significant lower fertilisation rate (50.05% vs 66.01%; P<0.05; OR, 0.61; CI, 0.49-0.57), implantation rate (8.33% vs 20.87%; P<0.05; OR, 0.35; CI, 0.14-0.87), good quality embryo ratio (44.70% vs 57.89%; P<0.05; OR, 0.59; CI, 0.43-0.80) and clinical pregnancy rate (17.39% vs 39.59%; P<0.05; OR, 0.32; CI, 0.11-0.96) in Yqh+ group compared with control group undergoing IVF treatment. Yqh+ carrying couples had similar reproductive outcomes compared with control couples undergoing ICSI treatment. CONCLUSIONS: The Y chromosome polymorphic variant Yqh+ most likely plays a role in infertility. Yqh+ couples with poor reproductive outcomes in IVF treatment can be advised to undergo ICSI to improve their reproductive results in the next cycle. PMID- 22819573 TI - Comparison of perioperative outcomes and cost of robotic-assisted laparoscopy, laparoscopy and laparotomy for endometrial cancer. AB - OBJECTIVE: To analyze the perioperative outcomes and cost of three surgical approaches in the treatment of endometrial cancer: robotic, laparoscopy and laparotomy. STUDY DESIGN: We studied 347 patients with endometrial cancer treated in a single institution: 71 patients were operated by robotics, 84 by conventional laparoscopy and 192 by laparotomy. All patients underwent total hysterectomy, bilateral salpingoophorectomy and pelvic and para-aortic lymphadenectomy depending on the pathological features. RESULTS: Operative time was longer in the laparoscopy group as compared to robotics and laparotomy (218.2 min, 189.2 min, and 157.4 min respectively, p=0.000). The estimated blood loss was lower in the robotic group relative to the other groups (99.4 ml in robotic, 190.0 ml in laparoscopy and 231.5 ml in laparotomy, p=0.000). Similar findings were observed for the pre- and post-operative mean hemoglobin levels (-1.3g/dl, 2.3g/dl and -2.5 g/dl respectively, p=0.000), and transfusion rate (4.2%, 7.1% and 14.1% respectively, p=0.036). The length of hospital stay was higher in the laparotomy group compared to robotics and laparoscopy (8.1, 3.5 and 4.6 days respectively; p=0.000). The conversion rate to laparotomy was lower for robotics (2.4% for robotics and 8.1% for laparoscopy, p=0.181). Overall complications were similar for robotics and laparoscopy (21.1%, 28.5%) (p=0.079). Robotic complications were significantly lower as compared to laparotomy (21.2 vs 34.9% (p=0.036). No differences were found relative to disease-free or overall survival among the three groups. The global costs were similar for the three approaches (p=0.566). CONCLUSION: Robotics is a safe alternative to laparoscopy and laparotomy for endometrial cancer patients, offering improved perioperative outcomes and similar cost as compared to the other two surgical approaches. PMID- 22819574 TI - Garrulitas vulvae: a case refractory to repeated attempts at surgical correction, solved by a novel treatment. PMID- 22819575 TI - Pain relief in laparoscopic tubal ligation using intraperitoneal lignocaine: a double masked randomized controlled trial. AB - OBJECTIVE: The intraperitoneal route of analgesia has been studied over the years for effective perioperative pain relief during minimally invasive surgery, but there were conflicting reports of the use of intraperitoneal analgesic administration and moreover there was no consensus regarding the dose and type of drugs used. We report a randomized trial to assess the safety and effectiveness of intraperitoneal lignocaine as an intraoperative and postoperative analgesic in laparoscopic tubal ligation. STUDY DESIGN: This is a double masked, randomized parallel group placebo-controlled trial of women seeking laparoscopic sterilization under local anaesthesia at a university hospital. The intervention group and placebo group received 20 ml of 0.5% lignocaine and 20 ml of isotonic saline intraperitoneally respectively. Allocation concealment was done by fixed block randomization. The participating women, the surgeon, anaesthetist, technician and the doctor who assessed the pain score were masked to the type of intervention. Intraoperative and postoperative pain was assessed by visual analogue pain scale and the scores are expressed as mean difference (95% confidence interval) between groups. Our trial is registered with the Clinical Trials Registry, India (http://www.ctri.nic.in/, CTRI/2009/091/000072). RESULTS: Out of 200 women recruited, 196 were available for final analysis with 98 women in each arm. The mean difference in the intraoperative pain score at the time of tubal ligation was 3.5 cm (95% CI 2.91-4.09). The mean difference in the postoperative pain scores at half an hour was 2.9 (95% CI 2.50-3.44), 1h was 2.5 (95% CI 2.08-3.00) and 3h was 1.2 (95% CI 0.75-1.76). There was no case of adverse reaction to lignocaine. CONCLUSION: Our findings show that intraperitoneal instillation of lignocaine is a safe and effective method for perioperative pain relief during laparoscopic tubal occlusion performed under conscious sedation. PMID- 22819576 TI - Suprascapular nerve anatomy during shoulder motion: a cadaveric proof of concept study with implications for neurogenic shoulder pain. AB - BACKGROUND: The suprascapular nerve (SSN) carries sensory fibers which may contribute to shoulder pain. Prior anatomic study demonstrated that alteration in SSN course with simulated rotator cuff tendon (RCT) tears cause tethering and potential traction injury to the nerve at the suprascapular notch. Because the SSN has been implicated as a major source of pain with RCT tearing, it is critical to understand nerve anatomy during shoulder motion. We hypothesized that we could evaluate the SSN course with a novel technique to evaluate effects of simulated RCT tears, repair, and/or release of the nerve. METHODS: The course of the SSN was tracked with a dual fluoroscopic imaging system in a cadaveric model with simulated rotator cuff muscle forces during dynamic shoulder motion. RESULTS: After a simulated full-thickness supraspinatus/infraspinatus tendon tear, the SSN translated medially 3.5 mm at the spinoglenoid notch compared to the anatomic SSN course. Anatomic footprint repair of these tendons restored the SSN course to normal. Open release of the transverse scapular ligament caused the SSN to move 2.5 mm superior-posterior out of the suprascapular notch. CONCLUSION: This pilot study demonstrated that the dynamic SSN course can be evaluated and may be altered by a RCT tear. Preliminary results suggest release of the transverse scapular ligament allowed the SSN to move upward out of the notch. This provides a biomechanical proof of concept that SSN traction neuropathy may occur with RCT tears and that release of the transverse scapular ligament may alleviate this by altering the course of the nerve. PMID- 22819577 TI - Closed reduction techniques in acute anterior shoulder dislocation: modified Milch technique compared with traction-countertraction technique. AB - BACKGROUND: To perform closed manual reduction of acute anterior shoulder dislocation using the traction-countertraction technique requires sedation (TCTS) and the participation of 2 people. We studied the modified Milch (MM) technique, a positional reductive maneuver that requires 1 operator, without patient sedation or analgesia. MATERIALS AND METHODS: The study comprised 56 prospective nonrandomized consecutive patients, of whom 31 were in group A (MM, nonsedated) and 25 in group B (TCTS). RESULTS: The success rate of MM technique was 83.9% (26 of 31), which increased to 96.3% (26 of 27) when 4 patients with associated greater tuberosity fractures were excluded. The success rate was 100% in the TCTS group, with 5 patients with associated greater tuberosity fractures. The reduction in pain from the preprocedural to intraprocedural phases in MM group was significant (P < .001), at a reduction rate of 2.07 (29%) on the numeric rating scale pain score. There was a greater pain reduction rate of 2.43 (34%) on the numeric rating scale when patients with greater tuberosity fractures were excluded. The MM group had a significantly shorter hospital stay (mean, 35 minutes) than the TCTS group (mean, 4 hours). No postreduction neurovascular or fracture complications occurred in either group. CONCLUSIONS: The results showed that the Milch technique was effective, safe, shortened hospital stay, and was well tolerated. We recommend the modified Milch technique as a first-line maneuver for acute anterior shoulder dislocations without associated fractures. PMID- 22819578 TI - Impact of prosthetic design on clinical and radiologic outcomes of total shoulder arthroplasty: a prospective study. AB - BACKGROUND: This prospective longitudinal study compared clinical and radiologic outcomes of total shoulder arthroplasty (TSA) using 3 different prosthetic designs, the Neer II system, the Bigliani-Flatow (BF), and a stemless prosthesis, the Total Evolutive Shoulder System (TESS). MATERIALS AND METHODS: Patients with advanced osteoarthritis of the glenohumeral joint who underwent TSA were followed up for 2 years. Four patient-oriented disability outcomes were used. The clinical data collected before surgery and at follow-up assessments during a 2-year period included active range of motion (ROM) in 6 directions and strength. Radiographic signs of glenoid and humeral component loosening were recorded. The incidence of humeral head subluxation was documented. RESULTS: Seventy-four patients completed the study. There was a significant improvement in the 4 disability measures, ROM, and strength at 2 years in all 3 groups (P < .0001). Active external rotation at 90 degrees abduction was statistically significantly lower in the Neer II group (P = .001). The incidence of lucent lines around the glenoid component was higher in the Neer II group (P = .0002). No statistically significant relationship was seen between type of prosthesis and patient satisfaction (P > 0.05). CONCLUSIONS: The 3 types of TSA prostheses used in this study all provided significant improvement in pain and function and were associated with high patient satisfaction. The Neer II was associated with less active external rotation and more lucent lines. PMID- 22819579 TI - Quantitative assessment of dynamic PET imaging data in cancer imaging. AB - Clinical imaging in positron emission tomography (PET) is often performed using single-time-point estimates of tracer uptake or static imaging that provides a spatial map of regional tracer concentration. However, dynamic tracer imaging can provide considerably more information about in vivo biology by delineating both the temporal and spatial pattern of tracer uptake. In addition, several potential sources of error that occur in static imaging can be mitigated. This review focuses on the application of dynamic PET imaging to measuring regional cancer biologic features and especially in using dynamic PET imaging for quantitative therapeutic response monitoring for cancer clinical trials. Dynamic PET imaging output parameters, particularly transport (flow) and overall metabolic rate, have provided imaging end points for clinical trials at single-center institutions for years. However, dynamic imaging poses many challenges for multicenter clinical trial implementations from cross-center calibration to the inadequacy of a common informatics infrastructure. Underlying principles and methodology of PET dynamic imaging are first reviewed, followed by an examination of current approaches to dynamic PET image analysis with a specific case example of dynamic fluorothymidine imaging to illustrate the approach. PMID- 22819580 TI - Cardiac magnetic resonance imaging in arrhythmogenic right ventricular cardiomyopathy: correlation to the QRS dispersion. AB - The aim of the study was to evaluate the relationship between the presence of right ventricular abnormalities detected by cardiac magnetic resonance (CMR) and QRS dispersion, the strongest independent predictor of sudden death in ARVC. A consecutive series of 40 patients from a single institution were recruited with a clinical diagnosis of ARVC based on the diagnostic criteria. All patients underwent systematic clinical evaluation, including history and examination, electrocardiography, 24-h Holter monitor, chest radiography, echocardiography and CMR examination and were divided into two groups according to the QRS dispersion: group I, QRS dispersion >=40 ms; group II, QRS dispersion <40 ms. The relationship between the characteristic parameters of CMR image and QRS dispersion were analyzed in two groups. There were significant differences in QRS dispersion (57+/-14 ms vs. 26+/-11 ms), right ventricular end-diastolic diameter (57+/-10 mm vs. 48+/-11 mm, P=.012), right ventricular end-systolic diameter (52+/-10 mm vs. 44+/-11 mm, P=.010), right ventricular end-diastolic volume (260+/-105 ml vs. 180+/-66 ml, P=.006), right ventricular end-systolic volume (222+/-98 ml vs. 148+/-61 ml, P=.006) and myocardial fibrosis detection rate (74% vs. 38%, P=.024) between two groups. For all patients with ARVC, QRS dispersion and right ventricular end-diastolic volume (r=0.66, P<.001), right ventricular end-systolic volume (r=0.67, P<.001), right ventricular outflow tract area (r=0.68, P<.001) showed a moderate positive correlation. Right ventricular outflow tract area, right ventricular end-diastolic volume and end-systolic volume detected by CMR in patients with ARVC were positively correlated to the extent of QRS dispersion (>=40 ms), the strongest independent predictor of sudden cardiac death. PMID- 22819581 TI - Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: correlating sodium MRI and F-18 FLT PET on a voxel-wise basis. AB - We evaluate novel magnetic resonance imaging (MRI) and positron emission tomography (PET) quantitative imaging biomarkers and associated multimodality, serial-time-point analysis methodologies, with the ultimate aim of providing clinically feasible, predictive measures for early assessment of response to cancer therapy. A focus of this work is method development and an investigation of the relationship between the information content of the two modalities. Imaging studies were conducted on subjects who were enrolled in glioblastoma multiforme (GBM) therapeutic clinical trials. Data were acquired, analyzed and displayed using methods that could be adapted for clinical use. Subjects underwent dynamic [(18)F]fluorothymidine (F-18 FLT) PET, sodium ((23)Na) MRI and 3-T structural MRI scans at baseline (before initiation of therapy), at an early time point after beginning therapy and at a late follow-up time point after therapy. Sodium MRI and F-18 FLT PET images were registered to the structural MRI. F-18 FLT PET tracer distribution volumes and sodium MRI concentrations were calculated on a voxel-wise basis to address the heterogeneity of tumor physiology. Changes in, and differences between, these quantities as a function of scan timing were tracked. While both modalities independently show a change in tissue status as a function of scan time point, results illustrate that the two modalities may provide complementary information regarding tumor progression and response. Additionally, tumor status changes were found to vary in different regions of tumor. The degree to which these methods are useful for GBM therapy response assessment and particularly for differentiating true progression from pseudoprogression requires additional patient data and correlation of these imaging biomarker changes with clinical outcome. PMID- 22819582 TI - Phase-difference and spectroscopic imaging for monitoring of human brain temperature during cooling. AB - Decrease of the human brain temperature was induced by intranasal cooling. The main purpose of this study was to compare the two magnetic resonance methods for monitoring brain temperature changes during cooling: phase-difference and magnetic resonance spectroscopic imaging (MRSI) with high spatial resolution. Ten healthy volunteers were measured. Selective brain cooling was performed through nasal cavities using saline-cooled balloon catheters. MRSI was based on a radiofrequency spoiled gradient echo sequence. The spectral information was encoded by incrementing the echo time of the subsequent eight image records. Reconstructed voxel size was 1*1*5 mm(3). Relative brain temperature was computed from the positions of water spectral lines. Phase maps were obtained from the first image record of the MRSI sequence. Mild hypothermia was achieved in 15-20 min. Mean brain temperature reduction varied in the interval <-3.0; -0.6> degrees C and <-2.7; -0.7> degrees C as measured by the MRSI and phase-difference methods, respectively. Very good correlation was found in all locations between the temperatures measured by both techniques except in the frontal lobe. Measurements in the transversal slices were more robust to the movement artifacts than those in the sagittal planes. Good agreement was found between the MRSI and phase-difference techniques. PMID- 22819583 TI - Nonlocal maximum likelihood estimation method for denoising multiple-coil magnetic resonance images. AB - Effective denoising is vital for proper analysis and accurate quantitative measurements from magnetic resonance (MR) images. Even though many methods were proposed to denoise MR images, only few deal with the estimation of true signal from MR images acquired with phased-array coils. If the magnitude data from phased array coils are reconstructed as the root sum of squares, in the absence of noise correlations and subsampling, the data is assumed to follow a non central-chi distribution. However, when the k-space is subsampled to increase the acquisition speed (as in GRAPPA like methods), noise becomes spatially varying. In this note, we propose a method to denoise multiple-coil acquired MR images. Both the non central-chi distribution and the spatially varying nature of the noise is taken into account in the proposed method. Experiments were conducted on both simulated and real data sets to validate and to demonstrate the effectiveness of the proposed method. PMID- 22819584 TI - Diffusion-weighted imaging of local recurrent prostate cancer after radiation therapy: comparison with 22-core three-dimensional prostate mapping biopsy. AB - Accurate localization of local recurrence within the prostate gland is important to perform focal salvage therapy effectively with minimal complications. The purpose of this study was to evaluate the usefulness of diffusion-weighted imaging (DWI) in the detection and localization of prostate cancer recurrence in patients with biochemical failure after definitive radiation therapy using 22 core three-dimensional prostate mapping biopsy (3D-PMB) as a standard reference. Ten patients who underwent magnetic resonance imaging and 22-core 3D-PMB were retrospectively analyzed. For visual assessment of DWI, the prostate was divided into 22 regions corresponding to 3D-PMB. Two diagnostic radiologists determined the presence of abnormal high signal intensity in each region on DWI, and the results of DWI were compared with those of 3D-PMB. Of the 220 regions, 16 regions in six patients were positive for cancer on 3D-PMB, and 30 regions in six patients were judged as positive on DWI. On a patient-by-patient basis, sensitivity and specificity were 100% (6/6) and 100% (4/4), respectively. On a region-by-region basis, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 69% (11/16), 91% (185/204), 37% (11/30), 97% (185/190) and 89% (196/220), respectively. For discrepant localization between DWI and pathology, DWI-positive and pathology-positive regions tended to be adjacent to each other. In conclusion, DWI is a useful tool for the detection and localization of recurrent prostate cancer in patients with biochemical failure after radiation therapy and may be helpful in the planning of focal salvage therapy. PMID- 22819585 TI - [Learning curve for lumbar disc surgery]. AB - BACKGROUND AND PURPOSE: Various techniques are available for lumbar disc surgery. But failure and severe adverse events still occur during such procedures. Recent work concluded that the use of microscope was not mandatory for such procedures. METHODS: The first 70 spinal procedures for lower limb radicular syndrome by a surgeon at the beginning of this activity where studied. Particular interest was paid on adverse events, especially complications and failures. RESULT: Average duration of surgery (50min) and rate of reoperation (six reoperations needed out of 65 patients, five of them by the same surgeon) where, as expected, a bit higher than published in experienced hands. But no battered-root syndrome, injury to neighboring structures or other severe complication was observed. Noteworthy is that no patient was neurologically worsened by surgery. CONCLUSIONS: If the use of microscope may not be needed for lumbar disc open surgery in experienced hands, we strongly advice surgeons at the beginning of their practice to use it. At least, to avoid unforgiving mistakes such as picking out the root instead of the herniation. PMID- 22819586 TI - Expression and immunological characterization of the heat shock protein-70 homologue from Babesia bigemina. AB - The Babesia bigemina heat shock protein-70 gene (BbigHSP-70) was cloned from cDNA by polymerase chain reaction (PCR) and sequenced. The length of the gene is 1947 bp and the predicted polypeptide is 649 amino acids long with a calculated molecular weight of 70.85 kDa. BbigHSP-70 has a signal peptide of 15 amino acids. Phylogenetic analysis of the amino acid sequence of BbigHSP-70 showed that B. bigemina was most closely related to B. caballi and B. bovis and lies within a phylogenetic cluster with Theileria. rBbigHSP-70 was expressed in E. coli as a soluble GST-fusion protein with a molecular mass of 96.8-kDa. The serum raised in mice against rBbigHSP-70 detected the native protein in B. bigemina, B. bovis, B. caballi, B. gibsoni, and B. microti lysates and also reacted with B. bigemina, B. bovis, and B. caballi merozoites in the IFAT. Mice vaccinated with rBbigHSP-70 showed lower parasitemia against the challenge infection with B. microti than GST vaccinated and non-vaccinated controls. These results added a new member of Babesia heat shock proteins70 that is well conserved among intraerythrocytic protozoa and demonstrated its protective effects in an experimental model of rodent babesiosis. PMID- 22819587 TI - Additional novel Cryptosporidium genotypes in ornamental fishes. AB - Current knowledge on the prevalence and genotypes of Cryptosporidium in fishes is still limited. This study investigated the prevalence of Cryptosporidium species in 171 ornamental fishes, belonging to 33 species, collected from 8 commercial aquariums around Perth, Western Australia. All samples were screened by nested PCR targeting the 18S rRNA locus. A total of 6 positives were identified by PCR at the 18S locus from 4 different species of fishes (red eye tetra, Moenkhausia sanctaefilomenae; gold gourami, Trichogaster trichopterus; neon tetra, Paracheirodon innesi; goldfish, Carassius auratus auratus), giving an overall prevalence of 3.5% (6/171). Four different genotypes were identified, only one of which has been previously reported in fish; piscine genotype 4 in a neon tetra isolate, a rat genotype III-like isolate in a goldfish, a novel genotype in three isolates from red eye (piscine genotype 7) which exhibited a 3.5% genetic distance from piscine genotype 1 and a piscine genotype 6-like from a gold gourami (1% genetic distance). Further biological and genetic characterisation is required to determine the relationship of these genotypes to established species and strains of Cryptosporidium. PMID- 22819588 TI - Exploring the host transcriptome for mechanisms underlying protective immunity and resistance to nematode infections in ruminants. AB - Nematode infections in ruminants are a major impediment to the profitable production of meat and dairy products, especially for small farms. Gastrointestinal parasitism not only negatively impacts weight gain and milk yield, but is also a major cause of mortality in small ruminants. The current parasite control strategy involves heavy use of anthelmintics that has resulted in the emergence of drug-resistant parasite strains. This, in addition to increasing consumer demand for animal products that are free of drug residues has stimulated development of alternative strategies, including selective breeding of parasite resistant ruminants. The development of protective immunity and manifestations of resistance to nematode infections relies upon the precise expression of the host genome that is often confounded by mechanisms simultaneously required to control multiple nematode species as well as ecto- and protozoan parasites, and microbial and viral pathogens. Understanding the molecular mechanisms underlying these processes represents a key step toward development of effective new parasite control strategies. Recent progress in characterizing the transcriptome of both hosts and parasites, utilizing high throughput microarrays and RNA-seq technology, has led to the recognition of unique interactions and the identification of genes and biological pathways involved in the response to parasitism. Innovative use of the knowledge gained by these technologies should provide a basis for enhancing innate immunity while limiting the polarization of acquired immunity can negatively affect optimal responses to co-infection. Strategies for parasite control that use diet and vaccine/adjuvant combination could be evaluated by monitoring the host transcriptome for induction of appropriate mechanisms for imparting parasite resistance. Knowledge of different mechanisms of host immunity and the critical regulation of parasite development, physiology, and virulence can also selectively identify targets for parasite control. Comparative transcriptome analysis, in concert with genome-wide association (GWS) studies to identify quantitative trait loci (QTLs) affecting host resistance, represents a promising molecular technology to evaluate integrated control strategies that involve breed and environmental factors that contribute to parasite resistance and improved performance. Tailoring these factors to control parasitism without severely affecting production qualities, management efficiencies, and responses to pathogenic co-infection will remain a challenge. This review summarizes recent progress and limitations of understanding regulatory genetic networks and biological pathways that affect host resistance and susceptibility to nematode infection in ruminants. PMID- 22819589 TI - Sevoflurane requirement to maintain bispectral index-guided steady-state level of anesthesia during the rewarming phase of cardiopulmonary bypass with moderate hypothermia. AB - OBJECTIVES: The authors aimed to quantify any increase and the extent of the increase in sevoflurane requirements for maintaining hypnosis during hypothermic cardiopulmonary bypass (CPB) with the bispectral index (BIS) maintained between 40 and 50. DESIGN: An observational prospective study. SETTING: A single-center tertiary referral center at a university hospital. PARTICIPANTS: Fifty patients undergoing elective coronary artery bypass graft surgery with CPB. INTERVENTIONS: End-tidal oxygenator expiratory gas concentrations were used to quantify sevoflurane requirements while maintaining a BIS level between 40 and 50 during the rewarming phase. RESULTS: Sevoflurane requirements progressively increased as temperature increased. The difference in sevoflurane requirement at 35 degrees C and 29 degrees C was compared using analysis of variance for repeated measures, which was statistically significant. When relating temperature and sevoflurane requirement, the Pearson correlation coefficient was 0.67. Linear regression analysis using temperature as the independent variable and expiratory sevoflurane as the dependent variable showed a temperature beta-coefficient of 0.11 and a constant of -2.34. Other parameters like fresh gas flows and pump flows were correlated to find out if they affected end-tidal sevoflurane levels on CPB. They were not significant in multivariate analysis. CONCLUSIONS: The sevoflurane requirement increases during the rewarming phase of hypothermic CPB. The percent increase in the requirement for sevoflurane is uniform and follows a particular pattern, which may be predicted. PMID- 22819590 TI - The complexity of adverse side-effects to biological agents. AB - Whereas adverse effects induced by xenobiotics are mainly linked to the pharmacological effect, the adverse side-effects induced by biological agents (BA) are often target-related and linked to the biological consequences of their action. Based on these differences, an original classification of the adverse effects has been proposed. Five types of adverse effects induced by BA are described (alpha, beta, gamma, delta, and epsilon). This classification provides a very useful scheme for a better understanding of these adverse effects. This approach should help to better characterize the pathogenic mechanisms involved and to optimize their management. Healthcare professionals should be aware of the specific risks related to this relatively new class of drugs. Close monitoring of these BA is therefore recommended. PMID- 22819593 TI - Dioxin emissions from municipal solid waste incinerators (MSWIs) in France. AB - The objective of this study was to determine whether the fear of dioxin/furan emissions from waste-to-energy plants was justified by the 2007 status of emissions of French municipal solid waste incinerators (MSWIs). All emissions were examined, plant by plant, but this paper focuses on the incinerator emission that is most frequently mentioned in the French media, toxic dioxins and furans. The study showed that there are 85 large MSWI that generate electricity or heat, i.e., waste-to-energy (WTE) plants, and 39 smaller MSW incinerators. The results showed that all French MSWI are operated well below the EU and French standard of 0.1 ng TEQ Nm(-3) (toxic equivalent nanograms per standard cubic meter) and that their total dioxin/furan emissions decreased from 435 g TEQ in 1997 to only 1.2g in 2008. All other industrial emissions of dioxins have also decreased and the major source is residential combustion of wood (320 g TEQ). It was extremely difficult to obtain MSWI emission data. This unwarranted lack of transparency has resulted in the public perception that MSWI plants are major contributors to dioxin emissions while in fact they have ceased to be so. PMID- 22819592 TI - Incidence and characteristics of the 2009 influenza (H1N1) infections in inflammatory bowel disease patients. AB - BACKGROUND: In 2009, influenza A (H1N1) infections spread worldwide. Because the use of immunomodulators is associated with an increased risk of infection, inflammatory bowel disease (IBD) patients who are on immunomodulators might be concerned about H1N1 influenza infections. The aim of this study was to investigate the age distribution and risk factors associated with H1N1 influenza of IBD patients in 2009-2010. METHODS: A multicenter, prospective study was conducted, and 570 IBD patients were enrolled. Patients were followed up for 10 months to identify any new infections. The incidence and age distribution of the H1N1 influenza infections were analyzed. IBD patients with H1N1 influenza infections and 2 matched, noninfected IBD patients were selected to assess the effect of specifying the medication on the incidence of infections. RESULTS: A total of 38 patients (6.7%) developed H1N1 influenza infections. The incidence of H1N1 influenza infections in patients aged less than 20 years was significantly higher than that among patients in other age groups (p<0.01). The age distribution for H1N1 influenza infections in IBD patients was comparable to those in the general population. No patients needed hospitalization due to influenza infection. A total of 29 patients (76%) recovered from the H1N1 influenza symptoms within 7 days and 20 patients (53%) received antiviral treatment. The percentage of patients who used steroids or thiopurine was comparable between the cases of H1N1 influenza infection and the control group. CONCLUSION: Our prospective study showed that younger IBD patients were frequently infected with the influenza A (H1N1) virus as well as general population. Admission and fatal cases due to H1N1 influenza infections were not observed. PMID- 22819594 TI - Synthesis of new chiral xanthone derivatives acting as nerve conduction blockers in the rat sciatic nerve. AB - The synthesis and structure elucidation of three new chiral xanthone (9H-xanthon 9-one) derivatives (2-4) are fully reported. The coupling reactions of the synthesized building block 6-methoxy-9-oxo-9H-xanthene-2-carboxylic acid (1) with two enantiomerically pure amino alcohols ((S)-(+)-valinol and (S)-(+)-leucinol) and one amine ((S)-(-)-alpha-4-dimethylbenzylamine), were carried out using the coupling reagent O-(benzotriazol-1-yl-)-N,N,N',N'-tetramethylluronium tetrafluoroborate (TBTU). The coupling reactions were performed with yields higher than 97% and enantiomeric excess higher than 99%. The structures of the compounds were established by IR, MS, and NMR ((1)H, (13)C, HSQC, and HMBC) techniques. Taking into account that these new chiral xanthone derivatives have molecular moieties structurally very similar to local anaesthetics, the ability to block compound action potentials (CAP) at the isolated rat sciatic nerve was also investigated. Nerve conduction blockade might result from a selective interference with Na(+) ionic currents or from a non-selective modification of membrane stabilizing properties. Thus, the mechanism, by which the three chiral xanthone derivatives cause conduction blockade in the rat sciatic nerve and their ability to prevent hypotonic haemolysis, given that erythrocytes are non excitable cells devoid of voltage-gated Na(+) channels, are also described. Data suggest that nerve conduction blockade caused by newly-synthesized xanthone derivatives might result predominantly from an action on Na(+) ionic currents. This effect can be dissociated from their ability to stabilize cell membranes, which became apparent only upon increasing the concentration of compounds 2-4 to the higher micromolar range. PMID- 22819595 TI - Proteins associated with reproductive disorders in testes of human erythropoietin gene-harboring transgenic boars. AB - To investigate reproductive disorder in human erythropoietin (EPO)-expressing pig, we performed comparative proteomic analyses of testicular tissues from human erythropoietin (hEPO) gene-harboring transgenic pigs and wild type pigs born from natural conception. In hEPO TG pigs, we found relatively low sperm motility and higher death rate indicating impaired sperm development. Consistently, plasma concentration of testosterone was significantly lower in the transgenic post pubertal boars compared with wild type boars. Normalized protein spots showing higher than 2-fold differential expression intensity in two-dimensional polyacrylamide gel electrophoresis were selected for matrix associated laser desorption/ionization time-to-flight mass spectrometry analysis. Specific proteins were identified by searching the NCBI protein sequence databases. Among 55 proteins selected, 12 proteins were identified as those differentially expressed between transgenic and wild type pigs. Three downregulated proteins (beta-globin, carbonyl reductase 1, and peroxiredoxin 6) and nine upregulated proteins (cytoskeletal beta-actin, alpha 2,3-sialyltransferase, apolipoprotein A I, tubulin alpha-1A chain, tropomodulin 3, thioredoxin, heat shock Protein 70.2, ch4/domains of swine IgM, and albumin), all of which are closely related to apoptosis and cytoskeletal development, were found in the transgenic boar testes. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay confirmed the increased occurrence of apoptosis in the transgenic boar testes compared with the wild type boar testes. Reproductive defects of the hEPO expressing transgenic pigs may be caused by the abnormal expression of the genes identified in this study. PMID- 22819596 TI - Ipsilateral cortical activation in fibromyalgia patients during brushing correlates with symptom severity. AB - OBJECTIVE: To evaluate cortical activation patterns during mechanical-tactile stimulation in fibromyalgia syndrome (FMS) patients and to correlate cortical activation changes with clinical symptoms. METHODS: Nineteen female FMS patients and 18 matched, healthy control subjects underwent EEG examination during brushing stimulation of the right forearm. Participants rated any pain experienced and underwent a manual tender point scale (MTPS) examination. Amplitude changes of cortical rhythms during brushing were analysed in alpha (8 13 Hz) and beta (16-24 Hz) frequency bands. RESULTS: Thirteen patients reported pain during brushing. Independent t-test comparison of event related desynchronisation (ERD) during brushing revealed a cluster of electrodes over ipsilateral (right) central-parietal region which demonstrated ERD in patients only. Clinical MTPS scores correlated with beta-band ERD in this cluster of electrodes. Beamformer analysis revealed a widespread array of source activations in patients, including bilateral insula and primary and secondary somatosensory cortices. Control subject source activations were limited to contralateral (left) hemisphere. CONCLUSIONS: Results indicate ipsilateral cortical activations in FMS patients, but not in healthy controls, during brushing. Ipsilateral ERD during brushing is associated with MTPS score suggesting abnormal processing of somatosensory input which may contribute to clinical pain. SIGNIFICANCE: Altered functioning in FMS may reflect physiological changes in response to afferent somatosensory information manifesting in chronic pain. PMID- 22819597 TI - Need for improvements in physical pretreatment of source-separated household food waste. AB - The aim of the present study was to investigate the efficiency in physical pretreatment processes of source-separated solid organic household waste. The investigation of seventeen Swedish full-scale pretreatment facilities, currently receiving separately collected food waste from household for subsequent anaerobic digestion, shows that problems with the quality of produced biomass and high maintenance costs are common. Four full-scale physical pretreatment plants, three using screwpress technology and one using dispergation technology, were compared in relation to resource efficiency, losses of nitrogen and potential methane production from biodegradable matter as well as the ratio of unwanted materials in produced biomass intended for wet anaerobic digestion. Refuse generated in the processes represent 13-39% of TS in incoming wet waste. The methane yield from these fractions corresponds to 14-36Nm(3)/ton separately collected solid organic household waste. Also, 13-32% of N-tot in incoming food waste is found in refuse. Losses of both biodegradable material and nutrients were larger in the three facilities using screwpress technology compared to the facility using dispersion technology.(1) Thus, there are large potentials for increase of both the methane yield and nutrient recovery from separately collected solid organic household waste through increased efficiency in facilities for physical pretreatment. Improved pretreatment processes could thereby increase the overall environmental benefits from anaerobic digestion as a treatment alternative for solid organic household waste. PMID- 22819598 TI - VFA and ammonia from residential food waste as indicators of odor potential. AB - Research was conducted to determine suitable chemical parameters as indicators of odor from decomposing food wastes. Prepared food scraps were stored in 18 l plastic buckets (2 kg wet weight each) at 20 degrees C and 8 degrees C to reproduce high and low temperature conditions. After 1, 3, 7, 10 and 14 days of storage, the odor from the buckets were marked to an intensity scale of 0 (no odor) to 5 (intense) and the corresponding leachate analyzed for volatile fatty acids, ammonia and total organic carbon. A linear relationship between odor intensity and the measured parameter indicates a suitable odor indicator. Odor intensified with longer storage period and warmer surroundings. The study found ammonia and isovaleric acid to be promising odor indicators. For this food waste mixture, offensive odors were emitted if the ammonia and isovaleric acid contents exceeded 360 mg/l and 940 mg/l, respectively. PMID- 22819599 TI - Relationship between fatigue and gait abnormality in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. AB - Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterised by joint hypermobility, skin hyperextensibility and tissue fragility. It has recently been shown that muscle weakness occurs frequently in EDS, and that fatigue is a common and clinically important symptom. The aim of this study was to investigate the relationship between fatigue severity and the gait pattern using 3D Gait Analysis (GA). Eleven individuals with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility type (JHS/EDS-HT) were investigated using muscle strength measured with standardised questionnaire measuring fatigue (Fatigue Severity Scale, FSS) and quantitative 3D GA. Our data showed that FSS value well correlated with the peak of vertical component of ground reaction force (r=-0.66, p<0.05). The negative correlation gives evidence that the higher the fatigue is the more reduced force is during gait. Our results showed that the ground reaction force has been applied as a functional evaluation score for detecting pathology in gait of JHS/EDS-HT participants and the found correlation between vertical force and fatigue demonstrated that muscle fatigue may be associated with a loss of proprioceptive acuity in lower limb muscles. PMID- 22819600 TI - Protected areas and freshwater conservation: a survey of protected area managers in the Tennessee and Cumberland River Basins, USA. AB - As the scientific community has highlighted the plight of freshwater species, there have been increasing calls for protected area (PA) designation and management specific to the conservation of aquatic species and ecosystems. In this study we examined PA management in one relatively well-resourced (high levels of financial and technical resources) part of the world: the Tennessee and Cumberland River Basins, USA. We asked managers their perceptions about the current status of freshwater ecosystems within PAs, the sources of stress that are degrading freshwater ecosystem integrity, the degree to which PAs address these stressors, and the availability of technical, human, and financial resources for management activities that benefit freshwater ecosystems and the species they support. Managers generally perceive that freshwater ecosystems within PAs are under low levels of stress, with less than half reporting any alteration to ecosystem integrity, and very few reporting alterations at medium or high levels. Most PAs have fewer resources dedicated to freshwater conservation and management than to other activities, and some PAs completely lack resources for freshwater management. We recommend a review of every PA's goals and objectives and any needed updates to include the conservation of freshwater ecosystems. We also recommend an analysis to determine the most pressing stressors to aquatic life within each PA, stemming from sources both from within and outside of a PA's boundaries, and that this information be used to guide future management. Finally, we suggest that management resources be prioritized for PAs that include large portions of the catchments of their freshwater systems; that can address the dominant sources of stress within the PA; or that contain representative ecosystems, species assemblages or populations of rare, endemic, and threatened species. PMID- 22819602 TI - Reply to "Filling hard gelatin capsules by the dosator nozzle system--is it possible to predict where the powder goes?". PMID- 22819601 TI - Backrest position in prevention of pressure ulcers and ventilator-associated pneumonia: conflicting recommendations. AB - Pressure ulcers and ventilator-associated pneumonia (VAP) are both common in acute and critical care settings and are considerable sources of morbidity, mortality, and health care costs. To prevent pressure ulcers, guidelines limit bed backrest elevation to less than 30 degrees, whereas recommendations to reduce VAP include use of backrest elevations of 30 degrees or more. Although a variety of risk factors beyond patient position have been identified for both pressure ulcers and VAP, this article will focus on summarizing the major evidence for each of these apparently conflicting positioning strategies and discuss implications for practice in managing mechanically ventilated patients with risk factors for both pressure ulcers and VAP. PMID- 22819603 TI - The Elephant Vanishes: impact of human-elephant conflict on people's wellbeing. AB - Human-wildlife conflicts impact upon the wellbeing of marginalised people, worldwide. Although tangible losses from such conflicts are well documented, hidden health consequences remain under-researched. Based on preliminary clinical ethnographic inquiries and sustained fieldwork in Assam, India, this paper documents mental health antecedents and consequences including severe untreated psychiatric morbidity and substance abuse. The case studies presented make visible the hidden mental health dimensions of human-elephant conflict. The paper illustrates how health impacts of conflicts penetrate far deeper than immediate physical threat from elephants, worsens pre-existing mental illness of marginalised people, and leads to newer psychiatric and social pathologies. These conflicts are enacted and perpetuated in institutional spaces of inequality. The authors argue that both wildlife conservation and community mental health disciplines would be enhanced by coordinated intervention. The paper concludes by generating questions that are fundamental for a new interdisciplinary paradigm that bridges ecology and the clinic. PMID- 22819604 TI - Activity of JNJ-Q2, a novel fluoroquinolone, tested against Neisseria gonorrhoeae, including ciprofloxacin-resistant strains. AB - JNJ-Q2 is a broad-spectrum fluoroquinolone with activity against Gram-positive and -negative pathogens. The in vitro activity of JNJ-Q2 was evaluated when tested against Neisseria gonorrhoeae isolates, including 31 ciprofloxacin resistant strains with documented mutations in the quinolone resistance determining region. MIC values were determined using reference agar dilution methods using ciprofloxacin, penicillin, ceftriaxone, tetracycline, and azithromycin as comparators. All isolates were inhibited by <=0.25 MUg/mL of JNJ Q2 (range, 0.004-0.25 MUg/mL; MIC(50/90), 0.03/0.25 MUg/mL) which was 8-fold (MIC(50)) and 32-fold more potent (MIC(90)) compared to ciprofloxacin. Few strains were susceptible to penicillin (3.0%) and tetracycline (6.1%), and with the use of the European Committee on Antimicrobial Susceptibility Testing interpretive criteria, 13.6% were resistant to azithromycin. All strains were susceptible to ceftriaxone, the most potent agent (MIC(90), 0.06 MUg/mL) followed by JNJ-Q2 (MIC(90), 0.25 MUg/mL). JNJ-Q2 appears to be a potent fluoroquinolone when tested against contemporary multidrug-resistant N. gonorrhoeae. PMID- 22819605 TI - Accurate and rapid species typing from cutaneous and mucocutaneous leishmaniasis lesions of the New World. AB - The heat-shock protein 70 gene (hsp70) has been exploited for Leishmania species identification in the Old and New World, using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis. Three new Leishmania-specific hsp70 PCRs were recently described, and we applied 2 of these on 89 clinical samples from a total of 73 Peruvian patients with either cutaneous or mucocutaneous leishmaniasis. The new PCRs on average showed a 2- to 3-fold improved sensitivity in the tested sample types (lesion biopsies, aspirates, and scrapings), for both genus detection and species typing, and were most successful in biopsies. Leishmania braziliensis, L. peruviana, and L. guyanensis were encountered. About one third of the L. braziliensis parasites contained 2 hsp70 alleles. This study is a paradigm for the implementation of a globally applicable upgraded tool for the identification of Leishmania directly on human specimens from cutaneous and mucocutaneous lesions in the New World. PMID- 22819606 TI - Discrepancy of calcium detection between gray scale intravascular ultrasound and spectral analysis of radiofrequency data. AB - BACKGROUND: We evaluated discrepancy of calcium detection between gray scale intravascular ultrasound (IVUS) and virtual histology (VH)-IVUS and the association between coronary calcium and plaque composition. METHODS: Study population consisted of 162 consecutive patients who underwent percutaneous coronary intervention with VH-IVUS study. Subjects were divided into 3 groups based on gray scale IVUS findings; No calcification group (n=50), spotty group (n=56) who had a lesion containing only small calcium deposits within an arc <90 degrees and diffuse group (n=56) who had a diffuse calcified lesion with an arc >= 90 degrees in >= 1 cross-sectional image of the lesion. RESULTS: No calcification group was younger than spotty and diffuse groups (54.4 +/- 13.0 years vs. 61.1 +/- 10.7 years and 64.2 +/- 9.9 years, p=0.011 and p<0.001, respectively). No calcification group had some degree of dense calcium (5. 7 +/- 6.9 mm(3)) by VH-IVUS analysis. Furthermore, calcified volume by VH-IVUS in no calcification group was similar to those in spotty group (5.7 +/- 6.9 mm(3) vs. 5.4 +/- 4.4mm(3)). Dense calcium volume was correlated directly with plaque volume (r=0.65, p<0.001), fibrous volume (r=0.54, p<0.001), fibro-fatty volume (r=0.29, p<0.001) and lipid core volume (r=0.77, p<0.001). In multiple regression analysis, lipid core volume (beta=0.287, 95% confidence interval (CI) 0.187 0.388, p<0.001) was an independent predictor of dense calcium volume. CONCLUSIONS: This study showed that coronary calcium can be present even if invisible in gray scale IVUS and associated with lipid core volume, which is a characteristic of plaque vulnerability. PMID- 22819607 TI - Transient increase in blood pressure after the Great East Japan Earthquake in patients with hypertension living around Tokyo. PMID- 22819608 TI - Purification of recombinant hepatitis B core antigen from unclarified Escherichia coli feedstock using phage-immobilized expanded bed adsorption chromatography. AB - Fusion M13 phage with disulfide constrained heptapeptide, C-WSFFSNI-C, inserted into the minor coat protein (gpIII), has been selected in the current study as ligand in direct purification of hepatitis B core antigen (HBcAg) from unclarified Escherichia coli (E. coli) feedstock. The selected fusion phage showed strong association with the surface of the core particle. In the present study, this fusion M13 phage was immobilized onto Streamline base matrix via epoxy activation and used as adsorbent to capture HBcAg from crude E. coli homogenate. The maximum binding capacity for the adsorbent was 3.76 mg/mL with equilibrium coefficient of 1.83 mg/mL. Due to the slow uptake rate of HBcAg by M13 phage-immobilized adsorbents, a modified EBAC operation with recirculation of feedstock into the expanded bed has been investigated in this study. The introduction of feedstock recirculation has led to an 18% increase in yield; however, the purity of the eluted product was reduced by 15% compared with typical EBAC operation. The level of antigenicity exhibited by the core particles purified by both EBAC operations employed in the present study was comparable to that purified using sucrose ultracentrifugation. PMID- 22819609 TI - Simultaneous determination of three flavonoid C-glycosides in mice biosamples by HPLC-ESI-MS method after oral administration of Abrus mollis extract and its application to biodistribution studies. AB - A simple HPLC-ESI-MS method was developed for the determination of vicenin-2 (1), isoschaftoside (2), and schaftoside (3) of Abrus mollis extract in mice plasma and tissues (heart, liver, spleen, lungs, and kidneys). The separation was achieved by HPLC on a Shim-Pack CLC-ODS column with a mobile phase composed of 0.1% formic acid (mobile phase A, 72%) and methanol-isopropanol (9:1) (mobile phase B, 28%). The electrospray source of the MS was operated in the selective ion monitoring (SIM) mode at m/z 593 ([M-H]-) for 1, and 563 ([M-H]-) for 2 and 3, respectively. The limit of detection (LOD) of 1-3 was in the range of 8.5-12.6 ng/mL for plasma, and 32.5-49.4 ng/g for tissue tested. The limit of quantification (LOQ) was found to be 25 ng/mL for plasma, and 100 ng/g for tissue. The calibration curves were linear in all matrices (r2 > 0.994) in the concentration range of 25-500 ng/mL in plasma or 100-1250 ng/g in tissue, respectively. Intra-day and inter-day precision studies demonstrate that the method is precise with coefficients of variation intra-day and inter-day below 5.9 and 7.4% for all the samples, respectively. The recoveries of three flavonoid C-glycosides ranged from 95.3 to 106.4% for plasma, and 92.6 to 107.3% for tissues. Following oral administration of A. mollis extract to mice at a dose of 72 mg/kg, the concentrations of 1-3 in plasma and tissues were quantifiable in bio-samples collected up to 180 min. The method described is suitable for studies on the distribution of three flavonoid C-glycosides of A. mollis extract in plasma and different tissues of mice. PMID- 22819610 TI - Comments on "Recovery of active anti TNF-alpha ScFv through matrix-assisted refolding of bacterial inclusion bodies using CIM monolithic support". PMID- 22819611 TI - Ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) for the rapid, simultaneous analysis of thiamin, riboflavin, flavin adenine dinucleotide, nicotinamide and pyridoxal in human milk. AB - A novel, rapid and sensitive ultra-performance liquid-chromatography tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of several B vitamins in human milk was developed. Resolution by retention time or multiple reaction monitoring (MRM) for thiamin, riboflavin, flavin adenine dinucleotide (FAD), nicotinamide and pyridoxal (PL) has been optimized within 2 min using a gradient of 10 mM ammonium formate (aq) and acetonitrile. Thiamin-(4-methyl-13C thiazol-5-yl-13C3) hydrochloride, riboflavin-dioxo-pyrimidine-13C4,15N2, and pyridoxal-methyl-d3 hydrochloride were used as internal standards. A sample-like matrix was found to be mandatory for the external standard curve preparation. 13C3-caffeine was added for direct assessment of analyte recovery. Intra- and inter-assay variability for all analytes ranged from 0.4 to 7.9% and from 2.2 to 5.2%, respectively. Samples were subjected to protein precipitation and removal of non-polar constituents by diethyl ether prior to analysis. Quantification was done by ratio response to the stable isotope labeled internal standards. The standard addition method determined recovery rates for each vitamin (73.0 100.2%). The limit of quantitation for all vitamins was between 0.05 and 5 ppb depending on the vitamin. Alternative approaches for sample preparation such as protein removal by centrifugal filter units, acetonitrile or trichloroacetic acid revealed low recovery and a greater coefficient of variation. Matrix effect studies indicated a significant influence by matrix constituents, showing the importance of stable isotope labeled internal standards for analyte quantitation in complex matrices. PMID- 22819612 TI - Intraarterial infusion therapy for cerebral vasospasm: promising but preliminary. PMID- 22819614 TI - Endoscopic resection of the peroneal tubercle. AB - Hypertrophy of the peroneal tubercle can be a source of discomfort when wearing shoes. Occasionally, it can cause tenosynovitis or a tear of the peroneal tendons. The symptoms can be successfully treated by complete resection of the tubercle, tenosynovectomy, and early range of motion exercises of the hindfoot joints. Traditionally, this is an open procedure. We report the technique of endoscopic resection of the peroneal tubercle. PMID- 22819613 TI - Is calcaneal inclination higher in patients with insertional Achilles tendinosis? A case-controlled, cross-sectional study. AB - Insertional Achilles tendinosis is a condition where a patient complains of isolated pain at the Achilles tendon insertion site due to intratendinous degeneration. It has been suggested that this condition is associated with cavus foot deformity. However, to our knowledge, there is no study that has confirmed this observation. We carried out a cross-sectional, case-controlled study to explore the association of increased calcaneal inclination-a surgically important characteristic of cavus foot deformity-with insertional Achilles tendinosis. Patients with Achilles tendinosis and matched controls without the pathology were compared. Although a statistically significant difference was detected in calcaneal inclination angle between these 2 groups (p = .038), we felt that the difference was not clinically significant (calcaneal inclination angle = 20.9 vs. 18.9, respectively). Within the limitations of the study, we conclude that there is no clinically significant difference in calcaneal inclination between those with or without insertional Achilles tendinosis. PMID- 22819615 TI - Autologous split peroneus longus lateral ankle stabilization. AB - Lateral ankle instability is a common clinical entity, and a variety of surgical procedures are available for stabilization after conservative management fails. Herein the authors reviewed outcomes after performing autologous split peroneus longus lateral ankle stabilization, using a previously described surgical technique to anatomically recreate the anterior talofibular and calcaneofibular ligaments. Twenty-five consecutive patients from 2 surgeons' practices underwent reconstruction between March 2007 and January 2011 with a minimum follow-up of 12 (range 12 to 51) months (mean 29.5 months). Follow-up interviews demonstrated 92.0% good or excellent outcomes with only 8.0% rating the outcome as fair and none as poor; 92.0% had no recurrent sprains or difficulty going up or down hills; 88.0% related no difficulty with uneven ground. The authors conclude that the autologous split peroneus longus lateral ankle stabilization results in a stable ankle with a low rate of complications and high patient satisfaction. PMID- 22819616 TI - Incidence of talar dome lesions with concomitant peroneal tendon pathologic features: a magnetic resonance imaging evaluation. AB - Few studies have evaluated the incidence of talar dome lesions and injuries to the peroneal tendons occurring concomitantly. The purpose of our research was to evaluate the incidence of osteochondral lesions of the talus (OLT) with peroneal tendon pathologic features according to the magnetic resonance imaging (MRI) findings. A database search was conducted in the Department of Radiology at the Western Pennsylvania Hospital and Forbes Regional Campus for all MRI examinations ordered by attending physicians of the Department of Foot and Ankle Surgery from 2008 to 2010. A total of 810 MRI reports were reviewed, of which 198 contained a diagnosis of peroneal tendon pathologic features (e.g., tenosynovitis, split tears) or OLT (i.e., chondral, osteochondral, subchondral edema, cystic changes), or both. MRI scans were then reviewed to confirm the report findings and findings not identified in the report. A total of 76 patients were identified as having an OLT. Of these 76 patients, 49 had associated peroneal tendon pathologic features. MRI evaluation revealed that 49 (65.3%) of the 76 patients with a talar dome lesion had concomitant peroneal pathologic features. Talar dome lesions with concomitant tears/tendinopathy of the peroneus brevis were associated in 14.6%. The incidence of an OLT with tears/tenosynovitis of the peroneus longus was 10.6%, because tears/tendinopathy of both peroneal tendons was present in 18.6%. Tenosynovitis of the brevis and longus were seen in 21.3% of those with an OLT. Our findings suggest the need for an increased level of suspicion for injuries to the lateral ankle ligaments, peroneal tendon complex, and ankle joint when evaluating a patient with ankle instability and chronic pain. PMID- 22819617 TI - Treatment of dysplasia epiphysealis hemimelica: a systematic review of published reports and a report of seven patients. AB - Dysplasia epiphysealis hemimelica is a rare entity. It is characterized by cartilage overgrowth in the epiphyses and is considered to be an epiphyseal osteochondroma. It usually presents during childhood and can cause pain and functional limitations. The aim of the present study was to describe the entity through our cases and published data and to present the results of our suggested treatment. A systematic search was performed to retrieve and describe all studies on dysplasia epiphysealis hemimelica. Studies were included if sufficient information on the patient characteristics, lesion location, treatment, and outcomes were described. In addition, we report on 7 of our patients. In our review, 48 studies were found, of which 42 could be included. Owing to the large heterogeneity in the studies, no pooling of data was performed. The studies included 138 patients with 255 lesions. Approximately 27% were female patients. The age at presentation ranged from 3 months to 66 years; however, in most, the entity was discovered before 8 years of age. No apparent guidelines were presented concerning the treatment strategy; however, most investigators performed resection because of pain or limitations in the range of motion. Most lesions were located in the ankle or foot (139 of 255). In our own cases, 5 of 7 patients experienced pain, limited range of motion, or activity restriction. The mean follow-up period was 4 years. Dysplasia epiphysealis hemimelica is a rare entity, occurring predominantly in the lower extremity of in young male patients. Its aggressive growth warrants aggressive treatment in the case of pain or functional or range of motion limitations. PMID- 22819618 TI - Rate of residual osteomyelitis after partial foot amputation in diabetic patients: a standardized method for evaluating bone margins with intraoperative culture. AB - The purpose of this study was to determine the rate of residual osteomyelitis after different foot amputations in diabetic patients with a standardized method of determining a clean bone margin. This retrospective observational pilot study evaluated 27 diabetic patients who had a forefoot amputation (toe, partial ray, or transmetatarsal) for osteomyelitis at our institution from January 1, 2010, to August 1, 2011. A standardized method was used intraoperatively to determine if bone margins were negative for residual osteomyelitis. Short-term outcomes were assessed. Negative outcomes included wound dehiscence, re-ulceration, re amputation, or death. The overall rate of residual osteomyelitis was 40.7% (11/27 patients). Patients who underwent toe amputation with joint disarticulation had a positive margin culture rate of 23.1% (3/13). Patients who underwent partial metatarsal or transmetatarsal amputation had a positive margin culture rate of 57.1% (8/14). Although twice as frequent, this was not considered to be statistically significant (p = .1201). Overall, 48.1% (13/27) of patients were considered to have poor outcomes, and 9/11 (81.8%) patients with a positive bone margin had poor outcomes, whereas only 4/16 (25%) patients with a negative bone margin had poor outcomes. This difference was considered statistically significant (p = .0063). Although this is a pilot study, our results do confirm the high incidence of residual osteomyelitis with associated poor outcomes. Based on our data, we recommend routine standardized bone margin culture after thorough debridement and irrigation. PMID- 22819619 TI - Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. AB - Neuroendocrine tumors (NET) are classified according to the Ki67 in low intermediate grade (Ki67<20%) and high grade (Ki67>20%). The NET of the latter group are also known as neuroendocrine carcinoma (NEC), and their prognosis is dismail. While in the former group biotherapy and radionuclide therapy can be proposed, chemotherapy represents the only treatment usually proposed for NEC. Cisplatin/etoposide combination is usually chosen based on the rationale that NEC are clinically similar to small cell lung cancer. However, evidence for cisplatin/etoposide in NEC is poor and controversial, and different schedules and response rate have been published so far. These aspects, combined with the heterogeneous characteristics of NEC, prompt us to have some doubt in considering cisplatin/etoposide as the gold standard. Some evidence exists that carboplatin can be used instead of cisplatin and irinotecan instead of etoposide without reducing efficacy. Furthermore other drugs, as gemcitabine, oxaliplatin or temozolomide can be evaluated in NEC with non-neuroendocrine component or in mixed adenoneuroendocrine carcinomas. NEC are a category of NET that should be deeply studied to verify if the response to cisplatin/etoposide is homogeneous related to the different Ki67, different morphology and/or different primary site. PMID- 22819620 TI - Reduced N400 semantic priming effects in adult survivors of paediatric and adolescent traumatic brain injury. AB - The immediate and long-term neural correlates of linguistic processing deficits reported following paediatric and adolescent traumatic brain injury (TBI) are poorly understood. Therefore, the current research investigated event-related potentials (ERPs) elicited during a semantic picture-word priming experiment in two groups of highly functioning individuals matched for various demographic variables and behavioural language performance. Participants in the TBI group had a recorded history of paediatric or adolescent TBI involving injury mechanisms associated with diffuse white matter pathology, while participants in the control group never sustained any insult to the brain. A comparison of N400 Mean Amplitudes elicited during three experimental conditions with varying semantic relatedness between the prime and target stimuli (congruent, semantically related, unrelated) revealed a significantly smaller N400 response in the unrelated condition in the TBI group, indicating residual linguistic processing deviations when processing demands required the quick detection of a between category (unrelated) violation of semantic expectancy. PMID- 22819621 TI - Candidatus Mycoplasma haematoparvum and Mycoplasma haemocanis infections in dogs from the United States. AB - Mycoplasma haemocanis (Mhc) and Candidatus Mycoplasma haematoparvum (CMhp) have been described in dogs. Historically, microscopic visualization of hemotropic Mycoplasma spp. has occurred most often in immunocompromised or splenectomized dogs. The aim of this study was to determine the Mhc and CMhp prevalences among dogs from the United States. Novel 16S rRNA and RNAseP gene PCR assays were used to amplify hemotropic Mycoplasma species DNA for GenBank sequence alignment. Among the study population, hemoplasma prevalence was 1.3% (7 out of 506), with Mhc and CMhp prevalences of 0.6% and 0.8%, respectively. Two of six CMhp-infected dogs were co-infected with a Bartonella sp., and a third dog was seroreactive to Bartonella henselae antigens. The prevalence of Mhc and CMhp in this study was low; potential blood donors should be screened; and dogs and people can be co infected with hemoplasma and Bartonella spp. PMID- 22819624 TI - Enhancing a declarative memory in humans: the effect of clonazepam on reconsolidation. AB - A consolidated memory recalled by a specific reminder can become unstable (labile) and susceptible to facilitation or impairment for a discrete period of time. This labilization phase is followed by a process of stabilization called reconsolidation. The phenomenon has been shown in diverse types of memory, and different pharmacological agents have been used to disclose its presence. Several studies have revealed the relevance of the GABAergic system to this process. Consequently, our hypothesis is that the system is involved in the reconsolidation of declarative memory in humans. Thus, using our verbal learning task, we analyzed the effect of benzodiazepines on the re-stabilization of the declarative memory. On Day 1, volunteers learned an association between five cue- response-syllables. On Day 2, the verbal memory was labilized by a reminder presentation, and then a placebo capsule or 0.25 mg or 0.03 mg of clonazepam was administered to the subjects. The verbal memory was evaluated on Day 3. The volunteers who had received the 0.25 mg clonazepam along with the specific reminder on Day 2, exhibited memory improvement. In contrast, there was no effect when the drug was given without retrieval, when the memory was simply retrieved instead of being reactivated or when short-term memory testing was performed 4 h after reactivation. We discuss the GABAergic role in reconsolidation, which shows a collateral effect on other memories when the treatment is aimed at treating anxiety disorders. Further studies might elucidate the role of GABA in the reconsolidation process associated with dissimilar scenarios. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22819625 TI - Rational design of modular allosteric aptamer sensor for label-free protein detection. AB - An aptamer can be redesigned to new functional molecules by conjugating with other oligonucleotides. However, it requires experimental trials to optimize the conjugating module with the sensitivity and selectivity toward a target. To reduce these efforts, we report rationally-designed modular allosteric aptamer sensor (MAAS), which is composed of coupled two aptamers and the regulator. For label-free protein detection, the protein-aptamer was conjugated with the malachite green (MG) aptamer for signaling. The MAAS additionally has the regulator domain which is designed to hybridize to a protein binding domain. The regulator makes MAAS to be inactive by destructing the original structure of the two aptamers. However, its conformation becomes active by dissociating the hybridization from the protein recognition signal, thereby inducing the binding of MG emitting the enhanced fluorescence. The design of regulator is based on the thermodynamic energy difference by the RNA conformational change and protein aptamer affinity. Here we first demonstrated the MAAS for hepatitis C helicase and replicase. The target proteins were detected up to 250nM with minimized blank signals and displayed high specificities 10-fold greater than in non-specific proteins. The MAAS provides valuable tools that can be adapted to a wide range of configurations in bioanalytical applications. PMID- 22819626 TI - Structure of the O-polysaccharide of Azorhizobium caulinodans HAMBI 216; identification of 3-C-methyl-D-rhamnose as a component of bacterial polysaccharides. AB - The O-polysaccharide was obtained from the lipopolysaccharide of the stem nodulating nitrogen-fixing bacterium Azorhizobium caulinodans HAMBI 216 and studied by sugar and methylation analyses along with (1)H and (13)C NMR spectroscopy. The polysaccharide was found to have a linear pentasaccharide repeating unit containing D-rhamnose and its rarely occurring 2-O-methyl (Rha2OMe) and 3-C-methyl (Rha3CMe) derivatives and having the following structure: ->3)-alpha-D-Rhap2OMe-(1->2)-beta-D-Rhap3CMe-(1->3)-alpha-D-Rhap-(1 >2)-beta-D-Rhap3CMe-(1->3)-alpha-D-Rhap-(1-> . PMID- 22819627 TI - Women's health research agenda for the next decade. A report by the Women's Health Expert Panel of the American Academy of Nursing. AB - Research in women's health has regained momentum with the recent release of several reports from various institutes and organizations. The Office of Research on Women's Health (ORWH) of the National Institutes of Health and the Institute of Medicine (IOM) both reported on women's health research. Within a year, Congress enacted the Affordable Care Act, stipulating support for clinical preventive services for women, prompting further reports focused on clinical care for women. These two research-dominant reports (NIH ORWH and the IOM) are the subject of this manuscript. The purpose is to outline and critically analyze the reports from a grounded nursing perspective and to propose a complementary and expanded agenda for furthering research in women's health. A separate manuscript analyzes and makes recommendations based on additional reports about clinical services and policies that will benefit the health status of women. PMID- 22819628 TI - Influence of staff education on the function of hospitalized elders. AB - Functional loss during hospitalization can prevent older adults from returning home. This study was designed to examine the effects of an intervention on discharge destination, function, length of stay (LOS), pressure ulcers, and fall rate in older adults >= 75 years old. The intervention included staff education on geriatric care and infrastructural change to promote function. Data on discharge destination and the change in function measured by Katz's activities of daily living (ADL) were collected. The LOS, pressure ulcer, and fall rate were compared with previous year's data using t-tests, and Chi-square analyses. There was a 14% increase in discharges to home (n = 404), minimal ADL loss (4.60 baseline ADL vs. 4.20 discharge ADL), and a significant decrease in nosocomial pressure ulcer. There was no decrease in LOS or fall rate. This preliminary study suggests that staff education with infrastructural change to promote independence may be helpful in patients' return to home, functional status, and hospital complications. PMID- 22819629 TI - The impact of simulation-based learning on students' English for Nursing Purposes (ENP) reading proficiency: a quasi-experimental study. AB - AIM: This is a report of a study which evaluated simulation-based learning as a teaching strategy for improving participants' ENP reading proficiency in the senior college program of students whose first language is Chinese, not English. BACKGROUND: Simulation-based learning is known to be one of most effective teaching strategies in the healthcare professional curricula, which brings a clinical setting into the classroom. However, developing English reading skills for English written nursing journals through simulation-based learning in the nursing curricula, is largely unknown. METHOD: We used a quasi-experimental approach with nonequivalent control group design to collect the causal connections between intervention and outcomes. 101 students were enrolled in this study (response rate 92.6%) of these 48 students volunteered for the intervention group, and 53 students for the control group. RESULTS: The findings indicated that the intervention group had significantly higher mean scores in ENP reading proficiency with unknown words in the article (p=.004), vocabulary (p<.001), and comprehension (p<.001) compared to the control group. Also, the intervention students showed more improvement in their English reading, both from quantitative and qualitative findings. CONCLUSION: Simulation-based learning may have some advantages in improving the English reading ability on English written nursing journals among nursing students. However, the benefits to the students of this study is still to be determined, and further exploration is needed with well designed research and a universal method of outcome measurement. PMID- 22819630 TI - Measuring effective radium concentration with large numbers of samples. Part II- general properties and representativity. AB - Effective radium concentration EC(Ra), product of radium concentration and radon emanation, is the source term for radon release into the pore space of rocks and the environment. Over a period of three years, we performed more than 6000 radon 222 accumulation experiments in the laboratory with scintillation flasks and SSNTDs and we obtained experimental EC(Ra) values from more than 1570 rock and soil samples. With this method, which allowed the measurement of EC(Ra) from large numbers of samples with sufficient accuracy and uncertainty, as detailed in the companion paper, the dependence of the emanation factor on temperature and moisture content is revisited. In addition, with such a large EC(Ra) dataset, dispersion of EC(Ra) can be studied at sample-scale (cm to dm) and at scarp-scale (m to tens of m). Furthermore, we are able to discuss the representativity of obtained EC(Ra) values at field-scale, and to investigate the spatial variations of EC(Ra) over kilometric scales, within geological formations and across formations and faults. This experimental study opens new perspectives in the understanding of radium geochemistry and illustrates the importance of studying the radon source term with large numbers of samples for the modelling of geological and environmental processes, and also for the assessment of the radon health hazard. PMID- 22819631 TI - Suture compression induced bone resorption with intensified MMP-1 and 13 expressions. AB - Suture compression is a widely used approach to inhibit maxillary growth; however, biological responses in sutures to compressive force are still unclear. The objective of this pilot study was to investigate the matrix metalloproteinase (MMP) expression and osteoclast activities during the midpalatal suture compression. METHODS: 56 six-week old male C57BL/6 mice were randomly assigned to the control and compression groups. The mice in the compression and control groups received helix springs bonded to the maxillary molars delivering initial compressive forces of 0.20 and 0N (no activation), respectively. On Days 1, 4, 7 and 14, animals were sacrificed and scanned using micro-computed tomography to quantify suture width and bone mineral density. Serial histological sections were stained with HE, TRAP, and immunohistochemistry to observe changes in bone resorption, osteoclast activities, and MMP-1, 8, and 13 expressions. Bone volume/total volume (Bv/Tv) ratio, osteoclast count, osteoclast covering area, and MMP expression intensity were measured. The Mann-Whitney and the Kruskal Wallis tests with Bonferroni post-hoc corrections were performed to compare differences between groups and between time points in the same group at significant level of P<0.05. RESULTS: Compared to the control, suture width in the compression group was significantly reduced on Day 1, but continuously widened with reduced bone mineral density afterwards. With MMP-1 and -13 evidently intensified expressions, osteoclast number and activities significantly increased, leading to reduced Bv/Tv ratio and progressive bone resorption from Days 4 to 14. CONCLUSIONS: Suture compression elevated the MMP-1 and 13 expressions, activated osteoclasts, reduced bone density, and induced bone resorption adjacent to the suture. It suggests that suture compression can be used for bone volume reduction. PMID- 22819632 TI - Reactive oxygen species (ROS) generated by cyanobacteria act as an electron acceptor in the biocathode of a bio-electrochemical system. AB - The enhanced electricity generation in a biocathode bio-electrochemical system (BES) with Microcystis aeruginosa IPP as the cathodic microorganism under illumination is investigated. The results show that this cyanobacterium is able to act as a potential cathodic microorganism under illumination. In addition, M. aeruginosa IPP is found to produce reactive oxygen species (ROS) in its growth in the BES. ROS, as more competitive electron acceptors than oxygen, are utilized prior to oxygen. The BES current is substantially reduced when the ROS production is inhibited by mannitol, indicating that the ROS secreted by the cyanobacterium play an important role in the electricity generation of such a biocathode BES. This work demonstrates that the ROS released by cyanobacteria benefit for an enhanced electricity generation of BES. PMID- 22819633 TI - Electrochemical immunosensor for label free epidermal growth factor receptor (EGFR) detection. AB - This paper presents an electrochemical immune sensor for label free detection of epidermal growth factor receptor (EGFR) by immobilizing anti-EGFR antibody (Anti EGFRab) on dithiobissuccinimidyl propionate (DTSP) self-assembled monolayer (SAM) on gold (Au) electrode. Electrochemical studies show that increased surface concentration of redox moieties onto Anti-EGFRab/DTSP immuno-electrode leads to high electron transport and improved sensing performance. The antigen-antibody complex demonstrates a high association constant (5*10(12)L/mol) that results in high affinity of Anti-EGFRab to EGFR, confirming that the DTSP-SAM provides a conducive environment for anti-EGFR immobilization. The electrochemical response of EA/Anti-EGFRab/DTSP/Au electrode as a function of EGFR concentrations exhibits a linear range from 1pg/mL to 100ng/mL, a detection limit of 1pg/mL at a sensitivity of 2.02MUA M(-1)at a regression coefficient of 0.99. PMID- 22819634 TI - California pertussis epidemic, 2010. AB - OBJECTIVE: In 2010, California experienced the highest number of pertussis cases in >60 years, with >9000 cases, 809 hospitalizations, and 10 deaths. This report provides a descriptive epidemiologic analysis of this epidemic and describes public health mitigation strategies that were used, including expanded pertussis vaccine recommendations. STUDY DESIGN: Clinical and demographic information were evaluated for all pertussis cases with onset from January 1, 2010, through December 31, 2010, and reported to the California Department of Public Health. RESULTS: Hispanic infants younger than 6 months had the highest disease rates; all deaths and most hospitalizations occurred in infants younger than 3 months. Most pediatric cases were vaccinated according to national recommendations, although 9% of those aged 6 months to 18 years were completely unvaccinated against pertussis. High disease rates also were observed in fully vaccinated preadolescents, especially 10-year-olds. Mitigation strategies included expanded tetanus, diphtheria, and acellular pertussis vaccine recommendations, public and provider education, distribution of free vaccine for postpartum women and contacts of infants, and clinical guidance on diagnosis and treatment of pertussis in young infants. CONCLUSIONS: Infants too young to be fully vaccinated against pertussis remain at highest risk of severe disease and death. Data are needed to evaluate strategies offering direct protection of this vulnerable population, such as immunization of pregnant women and of newborns. The high rate of disease among preadolescents suggests waning of immunity from the diphtheria, tetanus, and acellular pertussis series; additional studies are warranted to evaluate the efficacy and duration of protection of the diphtheria, tetanus, and acellular pertussis series and the tetanus, diphtheria, and acellular pertussis series. PMID- 22819635 TI - Making a difference: nursing scholarship and leadership in tobacco control. AB - This report from members of the Health Behavior Expert Panel of the American Academy of Nursing (AAN) provides an overview of nurse-led scholarship in tobacco control. We reviewed published reviews of nurse-led studies in the field. The synthesis includes theory development, methodological approaches, studies focused on prevention of tobacco use, nursing interventions for tobacco dependence including studies with selected populations, investigations to reduce secondhand smoke, and studies of health care systems and policy. Gaps in the literature provided direction for stimulating nursing science, accelerating adoption of evidence-based recommendations in practice, expanding nursing education, and increasing nursing visibility and influence in health care policy efforts. The AAN is positioned to maximize nursing leadership in this effort. PMID- 22819636 TI - Validation of Nordic dairy cattle disease recording databases--completeness for locomotor disorders. AB - The Nordic countries Denmark (DK), Finland (FIN), Norway (NO) and Sweden (SE) all have unique national databases holding the disease records of dairy cows. The objective of this study was to estimate and compare completeness for locomotor disorders in the four Nordic national databases. Completeness figures for farmer recorded disease events were calculated on two different levels: the first refers to disease events that were observed on the farm regardless of whether a veterinarian had been involved (FARMER); the second refers to farmer records of cases attended by a veterinarian, i.e. to veterinarian-treated disease events (VET). A sample of herds with 15 or more cows was obtained from a simple random sample of dairy farms in FIN, NO and SE, and from a systematic random sample in DK. There were 105, 167, 179 and 129 participating farmers in DK, FIN, NO and SE, respectively, and during two 2-month periods in 2008 these farmers recorded the disease events they observed on the farm. Data from the four national databases were extracted in May 2009. The two data sources, farmer recordings and national databases, were managed in a comparable way in all four countries, and common diagnostic codes were created and added to match recordings appearing in both datasets. In all 555 farmers completed data records in the first data-recording period, and 515 farmers did so in the second period. In DK, FIN, NO and SE, 55%, 77%, 82% and 75%, participating farmers completed the recordings during the first recording period, respectively; the corresponding figures for the second recording period were 71%, 82%, 83% and 91%. To calculate completeness, disease cases recorded in the national databases were compared with the farmer recordings using an exact match for the locomotor complex defined as same country, herd identification number (id), cow id, and event date at the levels of FARMER and VET. Completeness at FARMER level were 0.22, 0.21, 0.23 and 0.12 in DK, FIN, NO and SE, respectively. At VET level they were 0.37, 0.27, 0.34 and 0.17. To compare differences in completeness between countries exact 95% confidence intervals were calculated. There were significant differences in completeness between DK and SE at both FARMER and VET level. The completeness indicate that the ability to estimate true disease occurrences in the four national databases varies and is in general poor. Completeness should be taken into account when disease occurrences in different countries are compared. PMID- 22819637 TI - Using egg production data to quantify within-flock transmission of low pathogenic avian influenza virus in commercial layer chickens. AB - Even though low pathogenic avian influenza viruses (LPAIv) affect the poultry industry of several countries in the world, information about their transmission characteristics in poultry is sparse. Outbreak reports of LPAIv in layer chickens have described drops in egg production that appear to be correlated with the virus transmission dynamics. The objective of this study was to use egg production data from LPAIv infected layer flocks to quantify the within-flock transmission parameters of the virus. Egg production data from two commercial layer chicken flocks which were infected with an H7N3 LPAIv were used for this study. In addition, an isolate of the H7N3 LPAIv causing these outbreaks was used in a transmission experiment. The field and experimental estimates showed that this is a virus with high transmission characteristics. Furthermore, with the field method, the day of introduction of the virus into the flock was estimated. The method here presented uses compartmental models that assume homogeneous mixing. This method is, therefore, best suited to study transmission in commercial flocks with a litter (floor-reared) housing system. It would also perform better, when used to study transmission retrospectively, after the outbreak has finished and there is egg production data from recovered chickens. This method cannot be used when a flock was affected with a LPAIv with low transmission characteristics (R(0)<2), since the drop in egg production would be low and likely to be confounded with the expected decrease in production due to aging of the flock. Because only two flocks were used for this analysis, this study is a preliminary basis for a proof of principle that transmission parameters of LPAIv infections in layer chicken flocks could be quantified using the egg production data from affected flocks. PMID- 22819638 TI - Do surgical trials meet the scientific standards for clinical trials? PMID- 22819640 TI - Successful localization of recurrent thyroid cancer in reoperative neck surgery using ultrasound-guided methylene blue dye injection. AB - BACKGROUND: Reoperation in the neck can be challenging and is associated with increased complication rates and operative times. Here we analyze our methylene blue dye injection method to localize reoperative neck pathology in patients with thyroid cancer and lymph node metastases. STUDY DESIGN: We retrospectively reviewed the records of all patients at a single university tertiary care center who had reoperative neck surgery for recurrent thyroid cancer between 2004 and 2009, and who also underwent intraoperative methylene blue dye injection. Outcomes measured were efficacy and safety of the injection technique as well as complication rates. RESULTS: Fifty-three operations were performed in 44 patients (average age, 51.2 years [range 16 to 83 years]). Ninety-one percent (48 of 53) of the operations resulted in successful resection of recurrent disease. Of these, 96% (46 of 48) were guided successfully by blue dye injection. Thyroglobulin became undetectable in 42% (11 of 26) of patients. Neck pathology included the following thyroid cancers: papillary (48 of 53), follicular (2 of 53), medullary (2 of 53), and tall cell variant (1 of 53). Among these patients, there were a total of 26 central and 38 lateral neck dissections. The average number of previous neck dissections was 2 (range 1 to 5). The mean intraoperative ultrasound/injection time was 21.3 min (n = 13). Median operative time was 90 minutes (range 40 to 300 minutes). Complications included 2 permanent vocal cord paralyses, 1 instance of permanent hypocalcemia, and 3 instances of temporary hypocalcemia. There were no complications related to the dye injection. CONCLUSIONS: Intraoperative, ultrasound-guided, methylene blue dye injection is a safe and effective technique. It facilitates tumor localization and removal especially in patients requiring reoperative neck surgery. PMID- 22819639 TI - Heparin-binding epidermal growth factor-like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. AB - BACKGROUND: We have shown that administration of heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) protects the intestines from experimental necrotizing enterocolitis (NEC). We have also demonstrated that systemically administered mesenchymal stem cells (MSC) can engraft into injured intestines. This study investigated the effects of HB-EGF on MSC in vitro, and whether MSC and HB-EGF can act synergistically to prevent NEC in vivo. STUDY DESIGN: In vitro, the effect of HB-EGF on MSC proliferation, migration, and apoptosis was determined. In vivo, rat pups received MSC either intraperitoneally (IP) or intravenously (IV). Pups were assigned to 1 of 7 groups: Group 1, breast fed; Group 2, experimental NEC; Group 3, NEC+HB-EGF; Group 4, NEC+MSC IP; Group 5, NEC+HB-EGF+MSC IP; Group 6, NEC+MSC IV; or Group 7, NEC+HB-EGF+MSC IV. Mesechymal stem cell engraftment, histologic injury, intestinal permeability, and mortality were determined. RESULTS: Heparin-binding EGF-like growth factor promoted MSC proliferation and migration, and decreased MSC apoptosis in vitro. In vivo, MSC administered IV had increased engraftment into NEC-injured intestine compared with MSC administered IP (p < 0.05). Heparin binding EGF-like growth factor increased engraftment of IP-administered MSC (p < 0.01) and IV administered MSC (p < 0.05). Pups in Groups 3 to 7 had a decreased incidence of NEC compared with nontreated pups (Group 2), with the lowest incidence in pups treated with HB-EGF+MSC IV (p < 0.01). Pups in Group 7 had a significantly decreased incidence of intestinal dilation and perforation, and had the lowest intestinal permeability, compared with other treatment groups (p < 0.01). Pups in all experimental groups had significantly improved survival compared with pups exposed to NEC, with the best survival in Group 7 (p < 0.05). CONCLUSIONS: Heparin-binding EGF-like growth factor and MSC act synergistically to reduce injury and improve survival in experimental NEC. PMID- 22819641 TI - Shorter duration of femoral-popliteal bypass is associated with decreased surgical site infection and shorter hospital length of stay. AB - BACKGROUND: Duration of femoral-popliteal bypass is based on multiple patient specific, system-specific, and surgeon-specific factors, and is subject to considerable variability. We hypothesized that shorter operative duration is associated with improved outcomes and might represent a potential quality improvement measure. STUDY DESIGN: Patients who underwent primary femoral popliteal bypass with autogenous vein between 2005 and 2009 were identified from the American College of Surgeons NSQIP dataset using ICD-9 codes. Operative duration quartiles (Q) were determined (Q1: <=149 minutes, Q2: 150 to 192 minutes, Q3: 193 to 248 minutes; and Q4: >=249 minutes). Perioperative outcomes included mortality, surgical site infection, cardiopulmonary complications, and length of hospital stay. Relevant patient-specific and system-specific confounders, including age, body mass index, smoking, diabetes, end-stage renal disease, indication, American Society of Anesthesiologists' class, type of anesthesia, intraoperative transfusion, nonoperative time in the operating room, and participation of a trainee during the procedure, were adjusted for using multivariable regression. RESULTS: There were 2,644 femoral-popliteal bypass procedures in our study. Mean age was 65.9 years and 62% of patients were male. Longer duration of surgery was associated with increased perioperative surgical site infection (Q1: 6.3%; Q2: 9.0%; Q3: 10.1%; and Q4: 13.9%; p < 0.001) and longer length of stay (5.4 +/- 6.8 days; 6.1 +/- 6.7 days; 7.0 +/- 11.3 days; 8.1 +/- 8.0 days, respectively; p < 0.001). In multivariable analysis, longer operative duration was independently associated with higher surgical site infection and longer hospital length of stay. Operative duration of >=260 minutes increased the risk of surgical site infection by 50% compared with operative time of 150 minutes. CONCLUSIONS: Longer duration of femoral-popliteal bypass with autogenous vein was associated with a significantly higher risk of perioperative surgical site infection and longer hospital length of stay. Surgeon-specific parameters that lead to faster operative time might lead to improved clinical outcomes and more efficient hospital resource use. PMID- 22819642 TI - Single-incision surgery has higher cost with equivalent pain and quality-of-life scores compared with multiple-incision laparoscopic cholecystectomy: a prospective randomized blinded comparison. AB - BACKGROUND: Since the development of single-incision surgery, several retrospective studies have demonstrated its feasibility; however, randomized prospective trials are still lacking. We report a prospective randomized single blinded trial with a cost analysis of single-incision (SI) to multi-incision (MI) laparoscopic cholecystectomy. STUDY DESIGN: After obtaining IRB approval, patients with chronic cholecystitis, acute cholecystitis, or biliary dyskinesia were offered participation in this multihospital, multisurgeon trial. Consenting patients were computer randomized into either a transumbilical SI or standard MI group; patient data were then entered into a prospective database. RESULTS: We report 79 patients that were prospectively enrolled and analyzed. Total hospital charges were found to be significantly different between SI and MI groups (MI $15,717 +/- $14,231 vs SI $17,817 +/- $5,358; p < 0.0001). Broken down further, the following subcharges were found to also be significant: operating room charges (MI $4,445 +/- $1,078 vs SI $5,358 +/- 893; p < 0.0001); medical/surgical supplies (MI $3,312 +/- $6,526 vs SI $5,102 +/- $1,529; p < 0.0001); and anesthesia costs (MI $579 +/- $7,616 vs SI $820 +/- $23,957; p < 0.0001). A validated survey (ie, Surgical Outcomes Measurement System) was used to evaluate various patient quality-of-life parameters at set visits after surgery; scores were statistically equivalent for fatigue, physical function, and satisfaction with results. No difference was found between visual analogue scale scores or inpatient and outpatient pain-medication use. CONCLUSIONS: We show SI surgery to have higher costs than MI surgery with equivalent quality-of-life scores, pain analogue scores, and pain-medication use. PMID- 22819645 TI - Atomic Force Microscopy of the fungi-mineral interface: applications in mineral dissolution, weathering and biogeochemistry. AB - The interaction between mycorrhizal fungi and minerals is of fundamental importance in affecting the geochemical carbon cycle and CO(2) concentration in the atmosphere, alongside roles in soil creation and the release of nutrients. The symbiosis between the fungi and the plant, supported by photosynthesis in the host plant, has as one of its key features the interfacial zone where mineral and fungi come into contact. At this interface, the organism exudes a complex mixture of organic acids, chelating molecules, protons, and extracellular polysaccharide. In this review, examples will be given of recent Atomic Force Microscopy experiments to monitor the colonization of phyllosilicate minerals in sterile controlled microcosm environments containing only tree seedlings, mineral chips and mycorrhizal fungi. The surface activity of the colonizing fungal hyphae is extensive and complex. In complementary experiments involving exposure of minerals surfaces to single organic acids, it has been possible to monitor dissolution at the unit cell level and to extract activation energies for specific dissolution processes, for example 49 kJ mol(-1) for 100 mM oxalic acid acting upon a biotite sample. The link between these simpler model experiments and the whole microcosm studies is illustrated partly by observations of fungal colonized mineral surfaces from microcosms after careful removal of the organism and biolayer. These mineral surfaces give clear indications of basal plane modification and fungal weathering. PMID- 22819644 TI - Advances in targeted genome editing. AB - New technologies have recently emerged that enable targeted editing of genomes in diverse systems. This includes precise manipulation of gene sequences in their natural chromosomal context and addition of transgenes to specific genomic loci. This progress has been facilitated by advances in engineering targeted nucleases with programmable, site-specific DNA-binding domains, including zinc finger proteins and transcription activator-like effectors (TALEs). Recent improvements have enhanced nuclease performance, accelerated nuclease assembly, and lowered the cost of genome editing. These advances are driving new approaches to many areas of biotechnology, including biopharmaceutical production, agriculture, creation of transgenic organisms and cell lines, and studies of genome structure, regulation, and function. Genome editing is also being investigated in preclinical and clinical gene therapies for many diseases. PMID- 22819646 TI - Validity of chronic drug exposure presumed from repeated patient interviews varied according to drug class. AB - OBJECTIVE: To evaluate the validity of chronic drug exposure presumed from cross sectional interviews taking reimbursement data as reference. STUDY DESIGN AND SETTING: The study concerned 2,985 elderly persons of the French Three-City cohort (1) who were interviewed on current drug use 2 and 4 years after inclusion and (2) whose reimbursement data were obtained from the main health care insurance system. Validity (sensitivity, Se; specificity, Sp; positive predictive value, PPV; negative predictive value, NPV) of chronic exposure presumed from follow-up interviews was investigated taking two exposure definitions from reimbursements as reference for the period between interviews: at least 80% coverage with and without a maximal time between reimbursements of 60 days. RESULTS: Using 80% coverage as reference, validity of interview data was substantial for cardiovascular and antithrombotic drugs (Se, 85.3-95.4%; Sp, 67.1 97.6%; PPV, 65.9-86.6%; NPV, 93.3-99.3%). For benzodiazepines, nonsteroidal anti inflammatory drugs, or analgesics, validity was low especially owing to PPVs (15.8-51.4%). CONCLUSION: Using reported use at cross-sectional interviews as a proxy for chronic exposure between interviews was valid for drugs used regularly but not so for drugs used more irregularly. PMID- 22819647 TI - A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-beta) species, stops associated ROS production and prevents Cu(II)-induced Abeta aggregation. AB - The synthesis of the H(2)L(2-) ligand (N,N'-Bis[(5-sulfonato-2-hydroxy)benzyl] N,N'-dimethyl-ethane-1,2-diamine) and characterizations of the corresponding Cu(II) complex [Cu(L)(H(2)O)](2-) (1) by X-ray diffraction, EPR, UV-Visible and potentiometry are described. At pH 7.4, the affinity of Cu(II) for this ligand is approximately 4 * 10(14)M(-1). Coordination of redox active metal ions such as copper or iron to the amyloid-beta (Abeta) peptide has been linked to deleterious processes encountered in the etiology of Alzheimer disease (AD), such as Abeta aggregation and reactive oxygen species (ROS) production. In this context, the ability of the H(2)L(2-) to extract Cu(II) from Cu(Abeta) species where Abeta is the peptide involved in AD, is reported as well as its capacity to redox silence the Cu(Abeta) induced ROS formation and to prevent Cu(II)-induced Abeta aggregation. Such water soluble sulfonato-derivatives of Cu(II) chelators are very interesting counterparts for in vitro study of chelators' properties required to attend further biological applications as therapeutic tools against AD. PMID- 22819648 TI - Metal ions affect insulin-degrading enzyme activity. AB - Insulin degradation is a finely tuned process that plays a major role in controlling insulin action and most evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, the biomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure, rendering the specific enzyme activity quite difficult to target. On the other hand, biometals, such as copper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer's disease or diabetes mellitus. The metabolic disorders connected with the latter lead to some metallostasis alterations in the human body and many studies point at a high level of interdependence between diabetes and several cations. We have previously reported (Grasso et al., Chem. Eur. J. 17 (2011) 2752-2762) that IDE activity toward Abeta peptides can be modulated by metal ions. Here, we have investigated the effects of different metal ions on the IDE proteolytic activity toward insulin as well as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very low affinity for metal ions. The results obtained by different experimental techniques clearly show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II). PMID- 22819649 TI - Understanding trans platinum complexes as potential antitumor drugs beyond targeting DNA. AB - This focused review is devoted to our advances in developing trans platinum complexes as antitumoral complexes, in particular those bearing aliphatic amines. It includes some fundamental aspects of the understanding of non conventional metallodrug mechanism. The perspective is arranged by those fundamental aspects and within each section only the most successful examples have been included and also those in which clearly SAR's (structure activity relationships) have been observed. PMID- 22819651 TI - Laws against sodomy and the HIV epidemic in African prisons. PMID- 22819650 TI - Engineering Macaca fascicularis cytochrome P450 2C20 to reduce animal testing for new drugs. AB - In order to develop in vitro methods as an alternative to P450 animal testing in the drug discovery process, two main requisites are necessary: 1) gathering of data on animal homologues of the human P450 enzymes, currently very limited, and 2) bypassing the requirement for both the P450 reductase and the expensive cofactor NADPH. In this work, P450 2C20 from Macaca fascicularis, homologue of the human P450 2C8 has been taken as a model system to develop such an alternative in vitro method by two different approaches. In the first approach called "molecular Lego", a soluble self-sufficient chimera was generated by fusing the P450 2C20 domain with the reductase domain of cytochrome P450 BM3 from Bacillus megaterium (P450 2C20/BMR). In the second approach, the need for the redox partner and also NADPH were both obviated by the direct immobilization of the P450 2C20 on glassy carbon and gold electrodes. Both systems were then compared to those obtained from the reconstituted P450 2C20 monooxygenase in presence of the human P450 reductase and NADPH using paclitaxel and amodiaquine, two typical drug substrates of the human P450 2C8. The K(M) values calculated for the 2C20 and 2C20/BMR in solution and for 2C20 immobilized on electrodes modified with gold nanoparticles were 1.9 +/- 0.2, 5.9 +/- 2.3, 3.0 +/- 0.5 MUM for paclitaxel and 1.2 +/- 0.2, 1.6+/-0.2 and 1.4 +/- 0.2 MUM for amodiaquine, respectively. The data obtained not only show that the engineering of M. fascicularis did not affect its catalytic properties but also are consistent with K(M) values measured for the microsomal human P450 2C8 and therefore show the feasibility of developing alternative in vitro animal tests. PMID- 22819652 TI - Men who have sex with men: stigma and discrimination. PMID- 22819654 TI - Common roots: a contextual review of HIV epidemics in black men who have sex with men across the African diaspora. AB - Pooled estimates from across the African diaspora show that black men who have sex with men (MSM) are 15 times more likely to be HIV positive compared with general populations and 8.5 times more likely compared with black populations. Disparities in the prevalence of HIV infection are greater in African and Caribbean countries that criminalise homosexual activity than in those that do not criminalise such behaviour. With the exception of US and African epidemiological studies, most studies of black MSM mainly focus on outcomes associated with HIV behavioural risk rather than on prevalence, incidence, or undiagnosed infection. Nevertheless, black MSM across the African diaspora share common experiences such as discrimination, cultural norms valuing masculinity, concerns about confidentiality during HIV testing or treatment, low access to HIV drugs, threats of violence or incarceration, and few targeted HIV prevention resources. PMID- 22819653 TI - Comprehensive clinical care for men who have sex with men: an integrated approach. AB - Men who have sex with men (MSM) have unique health-care needs, not only because of biological factors such as an increased susceptibility to infection with HIV and sexually transmitted infections associated with their sexual behaviour, but also because of internalisation of societal stigma related to homosexuality and gender non-conformity, resulting in depression, anxiety, substance use, and other adverse outcomes. Successful responses to the global HIV/AIDS epidemic will require the development of culturally sensitive clinical care programmes for MSM that address these health disparities and root causes of maladaptive behaviour (eg, societal homophobia). Health-care providers need to become familiar with local outreach agencies, hotlines, and media that can connect MSM with positive role models and social opportunities. Research is needed to understand how many MSM lead resilient and productive lives in the face of discrimination to develop assets-based interventions that build on community support. Optimum clinical care for sexual and gender minorities is a fundamental human right. MSM deserve to be treated with respect, and health-care providers need to interact with them in ways that promote disclosure of actionable health information. PMID- 22819655 TI - MSM, AIDS research activism, and HAART. PMID- 22819656 TI - Comparisons of disparities and risks of HIV infection in black and other men who have sex with men in Canada, UK, and USA: a meta-analysis. AB - BACKGROUND: We did a meta-analysis to assess factors associated with disparities in HIV infection in black men who have sex with men (MSM) in Canada, the UK, and the USA. METHODS: We searched Embase, Medline, Google Scholar, and online conference proceedings from Jan 1, 1981, to Dec 31, 2011, for racial comparative studies with quantitative outcomes associated with HIV risk or HIV infection. Key words and Medical Subject Headings (US National Library of Medicine) relevant to race were cross-referenced with citations pertinent to homosexuality in Canada, the UK, and the USA. Data were aggregated across studies for every outcome of interest to estimate overall effect sizes, which were converted into summary ORs for 106,148 black MSM relative to 581,577 other MSM. FINDINGS: We analysed seven studies from Canada, 13 from the UK, and 174 from the USA. In every country, black MSM were as likely to engage similarly in serodiscordant unprotected sex as other MSM. Black MSM in Canada and the USA were less likely than other MSM to have a history of substance use (odds ratio, OR, 0.53, 95% CI 0.38-0.75, for Canada and 0.67, 0.50-0.92, for the USA). Black MSM in the UK (1.86, 1.58-2.18) and the USA (3.00, 2.06-4.40) were more likely to be HIV positive than were other MSM, but HIV-positive black MSM in each country were less likely (22% in the UK and 60% in the USA) to initiate combination antiretroviral therapy (cART) than other HIV-positive MSM. US HIV-positive black MSM were also less likely to have health insurance, have a high CD4 count, adhere to cART, or be virally suppressed than were other US HIV-positive MSM. Notably, despite a two-fold greater odds of having any structural barrier that increases HIV risk (eg, unemployment, low income, previous incarceration, or less education) compared with other US MSM, US black MSM were more likely to report any preventive behaviour against HIV infection (1.39, 1.23-1.57). For outcomes associated with HIV infection, disparities were greatest for US black MSM versus other MSM for structural barriers, sex partner demographics (eg, age, race), and HIV care outcomes, whereas disparities were least for sexual risk outcomes. INTERPRETATION: Similar racial disparities in HIV and sexually transmitted infections and cART initiation are seen in MSM in the UK and the USA. Elimination of disparities in HIV infection in black MSM cannot be accomplished without addressing structural barriers or differences in HIV clinical care access and outcomes. FUNDING: None. PMID- 22819657 TI - Disparities in HIV/AIDS in black men who have sex with men. PMID- 22819658 TI - The cultural challenge of HIV/AIDS. PMID- 22819659 TI - Successes and challenges of HIV prevention in men who have sex with men. AB - Men who have sex with men (MSM) have been substantially affected by HIV epidemics worldwide. Epidemics in MSM are re-emerging in many high-income countries and gaining greater recognition in many low-income and middle-income countries. Better HIV prevention strategies are urgently needed. Our review of HIV prevention strategies for MSM identified several important themes. At the beginning of the epidemic, stand-alone behavioural interventions mostly aimed to reduce unprotected anal intercourse, which, although somewhat efficacious, did not reduce HIV transmission. Biomedical prevention strategies reduce the incidence of HIV infection. Delivery of barrier and biomedical interventions with coordinated behavioural and structural strategies could optimise the effectiveness of prevention. Modelling suggests that, with sufficient coverage, available interventions are sufficient to avert at least a quarter of new HIV infections in MSM in diverse countries. Scale-up of HIV prevention programmes for MSM is difficult because of homophobia and bias, suboptimum access to HIV testing and care, and financial constraints. PMID- 22819661 TI - The irony of homophobia in Africa. PMID- 22819660 TI - Global epidemiology of HIV infection in men who have sex with men. AB - Epidemics of HIV in men who have sex with men (MSM) continue to expand in most countries. We sought to understand the epidemiological drivers of the global epidemic in MSM and why it continues unabated. We did a comprehensive review of available data for HIV prevalence, incidence, risk factors, and the molecular epidemiology of HIV in MSM from 2007 to 2011, and modelled the dynamics of HIV transmission with an agent-based simulation. Our findings show that the high probability of transmission per act through receptive anal intercourse has a central role in explaining the disproportionate disease burden in MSM. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiological data show substantial clustering of HIV infections in MSM networks, and higher rates of dual-variant and multiple-variant HIV infection in MSM than in heterosexual people in the same populations. Prevention strategies that lower biological transmission and acquisition risks, such as approaches based on antiretrovirals, offer promise for controlling the expanding epidemic in MSM, but their potential effectiveness is limited by structural factors that contribute to low health-seeking behaviours in populations of MSM in many parts of the world. PMID- 22819662 TI - From personal survival to public health: community leadership by men who have sex with men in the response to HIV. AB - Community leadership and participation by gay men and men who have sex with men (MSM) have been central to the response to HIV since the beginning of the epidemic. Through a wide array of actions, engagement of MSM has been important in the protection of communities. The connection between personal and community health as drivers of health advocacy continue to be a powerful element. The passion and urgency brought by MSM communities have led to the targeting and expansion of HIV and AIDS research and programming, and have improved the synergy of health and human rights, sustainability, accountability, and health outcomes for all people affected by HIV. MSM are, however, frequently excluded from the evidence-based services that they helped to develop, despite them generally being the most effective actors in challenging environments. Without MSM community involvement, government-run health programmes might have little chance of effectively reaching communities or scaling up interventions to lessen, and ultimately end, the HIV pandemic. PMID- 22819664 TI - Gregorio Millett: an improbable journey. PMID- 22819663 TI - A call to action for comprehensive HIV services for men who have sex with men. AB - Where surveillance has been done, it has shown that men (MSM) who have sex with men bear a disproportionate burden of HIV. Yet they continue to be excluded, sometimes systematically, from HIV services because of stigma, discrimination, and criminalisation. This situation must change if global control of the HIV epidemic is to be achieved. On both public health and human rights grounds, expansion of HIV prevention, treatment, and care to MSM is an urgent imperative. Effective combination prevention and treatment approaches are feasible, and culturally competent care can be developed, even in rights-challenged environments. Condom and lubricant access for MSM globally is highly cost effective. Antiretroviral-based prevention, and antiretroviral access for MSM globally, would also be cost effective, but would probably require substantial reductions in drug costs in high-income countries to be feasible. To address HIV in MSM will take continued research, political will, structural reform, community engagement, and strategic planning and programming, but it can and must be done. PMID- 22819665 TI - Recent structures, evolution and mechanisms of glycosyltransferases. AB - Cellular glycome assembly requires the coordinated action of a large number of glycosyltransferases that catalyse the transfer of a sugar residue from a donor to specific acceptor molecules. This enzyme family is very ancient, encompassing all three domains of life. There has been considerable recent progress in structural glycobiology with the determination of crystal structures of several important glycosyltransferase members, showing novel folds and variations around a common alpha/beta scaffold. Structural, kinetic and inhibitor data have led to the emergence of various scenarios with respect to their evolutionary history and reaction mechanisms thus highlighting the different solutions that nature has selected to catalyse glycosyl transfer. PMID- 22819666 TI - Glycan recognition by the Bacteroidetes Sus-like systems. AB - The human gut Bacteroidetes employ multiple cell-envelope associated protein complexes, termed Sus-like systems, to capture and degrade glycans. Recently the structures of key glycan-binding Sus proteins, the surface located SusD proteins and the periplasmic sensor domains of the membrane spanning hybrid two-component systems (HTCS) controlling Sus expression, have been solved, providing insight into glycan acquisition and sensing in these symbionts. The alpha-helical SusD proteins bind glycans at the cell surface, and likely facilitate the shuttling of oligosaccharides to an associated TonB-dependent porin. The HTCS sensor domains adopt two distinct folds and the structures of these sensors with glycan suggest that signal transduction across the cytoplasmic membrane is different from classical two component systems. PMID- 22819667 TI - Recent progress in membrane protein structures and investigation methods. PMID- 22819668 TI - Keeping the night going: the role of hookah bars in evening drinking behaviours. PMID- 22819669 TI - Influence of time in-situ and implant type on fixation strength of cemented tibial trays - a post mortem retrieval analysis. AB - BACKGROUND: Loosening of the tibial tray is cited as the most common cause of failure in total knee arthroplasty but the mechanism remains unclear. Post mortem specimens provide a unique opportunity to investigate the clinical condition. METHODS: Twenty two cemented components were serially retrieved in situ at autopsy from a university clinic. They were investigated for mechanical stability by pull-out, which was related to cement morphology and bone quality from CT scans, and to polyethylene wear by score analysis. Implants were grouped into three types: a particular fixed bearing design (n=8), a particular rotating platform design (n=5) and other mixed designs (n=9). FINDINGS: Trends were observed for pull-out force to decrease with time in situ and increase with cement penetration but was unrelated to bone density or polyethylene wear. For the fixed bearing implants decreasing pull-out strength was related to an increasing proportion of failure at the bone-cement interface. For the mixed designs the opposite was observed. The rotating platform implants failed at the implant-cement interface. INTERPRETATION: The analysis demonstrated that interface failure is dependent on the implant design, but that both the stem and the bone interfaces weaken with time in situ. Published findings for laboratory implantations have demonstrated that greater cement penetration improves fixation and this was reflected for clinical samples in this study. PMID- 22819670 TI - The effect of isolated gastrocnemius contracture and gastrocnemius recession on lower extremity kinematics and kinetics during stance. AB - BACKGROUND: Isolated gastrocnemius contracture limits ankle dorsiflexion with full knee extension and is potentially problematic during mid-stance of gait when 10 degrees of dorsiflexion and full knee extension are needed. It is during this time that patients with isolated gastrocnemius contracture may demonstrate altered kinematics and/or kinetics. When conservative management fails to resolve painful foot pathologies associated with non-spastic isolated gastrocnemius contracture, gastrocnemius recession surgery has been suggested to resolve contracture and improve function and strength. However, there are no published reports on lower extremity kinematics/kinetics in the non-spastic isolated gastrocnemius contracture population. Assessment of alterations in gait mechanics is necessary to examine the effects of this potential surgical intervention. METHODS: Lower extremity kinematics and kinetics were assessed in 6 patients clinically diagnosed with isolated gastrocnemius contracture pre- and post surgical recession compared with 33 healthy control participants. FINDINGS: Pre operatively, patients with isolated gastrocnemius contracture demonstrated significantly increased peak knee flexion angles and knee flexion moments during mid-stance. There were no differences in peak ankle dorsiflexion angle or peak plantar flexion moment. Gastrocnemius recession did not alter gait kinematics/kinetics following surgery. Joint kinematic strategies utilized to compensate for isolated gastrocnemius contracture varied minimally between participants with IGC; most employed a flexed knee strategy, while one participant utilized a reduced ankle dorsiflexion strategy. INTERPRETATION: Select post-surgical gait mechanics were unaltered; however, gait mechanics were not similar between non-spastic isolated gastrocnemius contracture patients and healthy control participants. Surgical intervention for patients with isolated gastrocnemius contracture does not appear to create any negative gait adaptations; however, patients may benefit from gait retraining post-recession as maladaptive gait patterns persist post operatively. PMID- 22819671 TI - Presentation and management of school bullying and the impact of anti-bullying strategies for pupils: a self-report survey in London schools. AB - OBJECTIVES: To investigate differences in the presentation and management of bullying in two London boroughs, one with high levels of deprivation and the other with low levels of deprivation; and to explore pupils' views on successful approaches to tackle bullying. STUDY DESIGN: Problems associated with bullying in childhood can manifest with mental disorders, depression and poorer perceived health in adulthood. However, despite the recent development of anti-bullying policies within schools, bullying remains a significant issue for many pupils. An original self-report survey was undertaken to investigate this important area. METHOD: A web-based questionnaire was undertaken with pupils from year 8 (aged 12 13 years) at four secondary schools in London. The study was approved by King's College London Research Ethics Committee. RESULTS: In total, 304 pupils completed the questionnaire, 55% of whom were affected by bullying at their school. Deprivation had no impact on the prevalence of pupils involved in a bullying culture. School membership is the most important independent factor for determining bullying. CONCLUSIONS: Policy could be aimed at changing pupils' views on dealing with bullying, and it is vital that policies and practices around bullying are active and alive and do not become 'file fodder'. PMID- 22819672 TI - Abnormal vasculature interferes with optic fissure closure in lmo2 mutant zebrafish embryos. AB - Ocular coloboma is a potentially blinding congenital eye malformation caused by failure of optic fissure closure during early embryogenesis. The optic fissure is a ventral groove that forms during optic cup morphogenesis, and through which hyaloid artery and vein enter and leave the developing eye, respectively. After hyaloid artery and vein formation, the optic fissure closes around them. The mechanisms underlying optic fissure closure are poorly understood, and whether and how this process is influenced by hyaloid vessel development is unknown. Here we show that a loss-of-function mutation in lmo2, a gene specifically required for hematopoiesis and vascular development, results in failure of optic fissure closure in zebrafish. Analysis of ocular blood vessels in lmo2 mutants reveals that some vessels are severely dilated, including the hyaloid vein. Remarkably, reducing vessel size leads to rescue of optic fissure phenotype. Our results reveal a new mechanism leading to coloboma, whereby malformed blood vessels interfere with eye morphogenesis. PMID- 22819673 TI - EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. AB - Tight junctions (TJs) connect epithelial cells and form a semipermeable barrier that only allows selective passage of ions and solutes across epithelia. Here we show that mice lacking EpCAM, a putative cell adhesion protein frequently overexpressed in human cancers, manifest intestinal barrier defects and die shortly after birth as a result of intestinal erosion. EpCAM was found to be highly expressed in the developing intestinal epithelium of wild-type mice and to localize to cell-cell junctions including TJs. Claudin-7 colocalized with EpCAM at cell-cell junctions, and the two proteins were found to associate with each other. Claudins 2, 3, 7, and 15 were down-regulated in the intestine of EpCAM mutant mice, with claudin-7 being reduced to undetectable levels. TJs in the mutant intestinal epithelium were morphologically abnormal with the network of TJ strands scattered and dispersed. Finally, the barrier function of the intestinal epithelium was impaired in the mutant animals. These results suggest that EpCAM contributes to formation of intestinal barrier by recruiting claudins to cell cell junctions. PMID- 22819675 TI - Desmosomal adhesiveness is developmentally regulated in the mouse embryo and modulated during trophectoderm migration. AB - During embryonic development tissues remain malleable to participate in morphogenetic movements but on completion of morphogenesis they must acquire the toughness essential for independent adult life. Desmosomes are cell-cell junctions that maintain tissue integrity especially where resistance to mechanical stress is required. Desmosomes in adult tissues are termed hyper adhesive because they adhere strongly and are experimentally resistant to extracellular calcium chelation. Wounding results in weakening of desmosomal adhesion to a calcium-dependent state, presumably to facilitate cell migration and wound closure. Since desmosomes appear early in mouse tissue development we hypothesised that initial weak adhesion would be followed by acquisition of hyper adhesion, the opposite of what happens on wounding. We show that epidermal desmosomes are calcium-dependent until embryonic day 12 (E12) and become hyper adhesive by E14. Similarly, trophectodermal desmosomes change from calcium dependence to hyper-adhesiveness as blastocyst development proceeds from E3 to E4.5. In both, development of hyper-adhesion is accompanied by the appearance of a midline between the plasma membranes supporting previous evidence that hyper adhesiveness depends on the organised arrangement of desmosomal cadherins. By contrast, adherens junctions remain calcium-dependent throughout but tight junctions become calcium-independent as desmosomes mature. Using protein kinase C (PKC) activation and PKCalpha-/- mice, we provide evidence suggesting that conventional PKC isoforms are involved in developmental progression to hyper adhesiveness. We demonstrate that modulation of desmosomal adhesion by PKC can regulate migration of trophectoderm. It appears that tissue stabilisation is one of several roles played by desmosomes in animal development. PMID- 22819674 TI - The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development. AB - Agr2 is a putative protein disulfide isomerase (PDI) initially identified as an estrogen-responsive gene in breast cancer cell lines. While Agr2 expression in breast cancer is positively correlated with estrogen receptor (ER) expression, it is upregulated in both hormone dependent and independent carcinomas. Several in vitro and xenograft studies have implicated Agr2 in different oncogenic features of breast cancer; however, the physiological role of Agr2 in normal mammary gland development remains to be defined. Agr2 expression is developmentally regulated in the mammary gland, with maximum expression during late pregnancy and lactation. Using a mammary gland specific knockout mouse model, we show that Agr2 facilitates normal lobuloalveolar development by regulating mammary epithelial cell proliferation; we found no effects on apoptosis in Agr2(-/-) mammary epithelial cells. Consequently, mammary glands of Agr2(-/-) females exhibit reduced expression of milk proteins, and by two weeks post-partum their pups are smaller in size. Utilizing a conditional mouse model, we show that Agr2 constitutive expression drives precocious lobuloalveolar development and increased milk protein expression in the virgin mammary gland. In vitro studies using knock down and overexpression strategies in estrogen receptor positive and negative mammary epithelial cell lines demonstrate a role for Agr2 in estradiol induced cell proliferation. In conclusion, the estrogen-responsive Agr2, a candidate breast cancer oncogene, regulates epithelial cell proliferation and lobuloalveolar development in the mammary gland. The pro-proliferative effects of Agr2 may explain its actions in early tumorigenesis. PMID- 22819676 TI - Ndrg2 regulates vertebral specification in differentiating somites. AB - It is generally thought that vertebral patterning and identity are globally determined prior to somite formation. Relatively little is known about the regulators of vertebral specification after somite segmentation. Here, we demonstrated that Ndrg2, a tumor suppressor gene, was dynamically expressed in the presomitic mesoderm (PSM) and at early stage of differentiating somites. Loss of Ndrg2 in mice resulted in vertebral homeotic transformations in thoracic/lumbar and lumbar/sacral transitional regions in a dose-dependent manner. Interestingly, the inactivation of Ndrg2 in osteoblasts or chondrocytes caused defects resembling those observed in Ndrg2(-/-) mice, with a lower penetrance. In addition, forced overexpression of Ndrg2 in osteoblasts or chondrocytes also conferred vertebral defects, which were distinct from those in Ndrg2(-/-) mice. These genetic analyses revealed that Ndrg2 modulates vertebral identity in segmented somites rather than in the PSM. At the molecular level, combinatory alterations of the amount of Hoxc8-11 gene transcripts were detected in the differentiating somites of Ndrg2(-/-) embryos, which may partially account for the vertebral defects in Ndrg2 mutants. Nevertheless, Bmp/Smad signaling activity was elevated in the differentiating somites of Ndrg2(-/-) embryos. Collectively, our findings unveiled Ndrg2 as a novel regulator of vertebral specification in differentiating somites. PMID- 22819677 TI - FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. AB - Fibroblast growth factor (FGF) signaling to the epithelium and mesenchyme mediated by FGF10 and FGF9, respectively, controls cecal formation during embryonic development. In particular, mesenchymal FGF10 signals to the epithelium via FGFR2b to induce epithelial cecal progenitor cell proliferation. Yet the precise upstream mechanisms controlling mesenchymal FGF10 signaling are unknown. Complete deletion of Fgf9 as well as of Pitx2, a gene encoding a homeobox transcription factor, both lead to cecal agenesis. Herein, we used mouse genetic approaches to determine the precise contribution of the epithelium and/or mesenchyme tissue compartments in this process. Using tissue compartment specific Fgf9 versus Pitx2 loss of function approaches in the gut epithelium and/or mesenchyme, we determined that FGF9 signals to the mesenchyme via Pitx2 to induce mesenchymal Fgf10 expression, which in turn leads to epithelial cecal bud formation. PMID- 22819679 TI - Host-parasite interactions: a litmus test for ocean acidification? AB - The effects of ocean acidification (OA) on marine species and ecosystems have received significant scientific attention in the past 10 years. However, to date, the effects of OA on host-parasite interactions have been largely ignored. As parasites play a multidimensional role in the regulation of marine population, community, and ecosystem dynamics, this knowledge gap may result in an incomplete understanding of the consequences of OA. In addition, the impact of stressors associated with OA on host-parasite interactions may serve as an indicator of future changes to the biodiversity of marine systems. This opinion article discusses the potential effects of OA on host and parasite species and proposes the use of parasites as bioindicators of OA disturbance. PMID- 22819678 TI - A comparison of insight in body dysmorphic disorder and obsessive-compulsive disorder. AB - Insight/delusionality of beliefs is an important dimension of psychopathology across psychiatric disorders. This construct is of increasing interest in obsessive-compulsive and related disorders, including obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD). Even though OCD and BDD are considered closely related, no prior study has compared these disorders across a range of categories of global insight (excellent, good, fair, poor, absent/delusional), and only one study has compared these disorders on individual components of insight. Using the reliable and valid Brown Assessment of Beliefs Scale (BABS), this study examined insight/delusionality of OCD- or BDD-related beliefs in 211 individuals with primary OCD versus 68 individuals with primary BDD. In both disorders, levels of insight spanned the full range, from excellent to absent (i.e., delusional beliefs). However, the distribution of BABS scores across insight categories differed significantly by disorder, with the majority of OCD subjects showing excellent or good insight, and the majority of BDD subjects showing poor or absent insight. Compared to OCD subjects, BDD subjects had significantly poorer insight both overall (total BABS score) and on all individual BABS items. BABS score was significantly correlated with BDD and OCD severity, but in regressions it accounted for only 21% of the variance in OCD and 28% in BDD. In summary, both global insight and its individual components are poorer in BDD than in OCD, which has implications for research and clinical care, as well as understanding of the relationship between these disorders. Disorder severity is associated with but not equivalent to insight/delusionality. PMID- 22819680 TI - Is there space for the quantum domain in consciousness research?: Comment on 'Consciousness, biology, and quantum hypotheses' by Baars and Edelman. PMID- 22819681 TI - Hoarseness due to subcutaneous emphysema and pneumomediastinum. PMID- 22819682 TI - Use of the relationship between absolute lymphocyte count and CD4 count to improve earlier consideration of pneumocystis pneumonia in HIV-positive emergency department patients with pneumonia. AB - BACKGROUND: The ability to accurately assess the level of immunosuppression in HIV+ patients in the emergency department (ED) is often limited and can affect management of these patients. OBJECTIVE: To evaluate the relationship between the absolute lymphocyte count (ALC) and CD4 count in HIV patients admitted through the ED with pneumonia and how utilization of this relationship may affect early consideration and evaluation of Pneumocystis jiroveci pneumonia (PCP). METHODS: Retrospective multicenter 5-year study of HIV+ patients with an ICD-9 diagnosis of pneumonia. Included patients had an ALC measured on ED presentation and a CD4 count measured in < 24 h. A receiver operator curve (ROC), decision plot analysis, and McNemar test of proportions were used to characterize the relationship between study variables. RESULTS: Six hundred eighty six patients were enrolled, 23.2% (95% confidence interval [CI] 20.2-26.1) were diagnosed with PCP. The geometric mean CD4 count and ALC were 81 and 1089, respectively. The correlation between ALC and CD4 was r = 0.60 (95% CI 0.55-65, p < 0.01). The ROC was 0.78 (0.75-0.82). An ALC < 1700 cells/mm(3) had a sensitivity of 84% (95% CI 80-87) and specificity of 55% (95% CI 48-70) for a CD4 < 200 cells/mm(3). An ALC threshold of 1700 cells/mm(3) would have identified 86% of patients with PCP but falsely identified 2.5 patients without PCP for every one accurately identified. CONCLUSION: The ALC threshold of 1700 cells/mm(3) retains significant discriminatory value and would moderately improve identification of patients with a CD4 < 200 cells/mm(3) but is not likely to be reliable as the sole method of early recognition and evaluation of PCP. PMID- 22819683 TI - Disentangling sources of individual differences in diurnal salivary alpha amylase: reliability, stability and sensitivity to context. AB - In the present study, we employ a longitudinal design and a generalizability framework to examine the sources of variance in the diurnal rhythm of salivary alpha-amylase (sAA). The sample consisted of 122 first-year law students (55% male, mean age=23.9 years), who collected five saliva samples on each of three consecutive days at each of five data collection waves. In total, over 6900 saliva samples were collected, which allowed us to examine the properties of diurnal variation in sAA in great detail. Systematic individual differences accounted for 15-29% of the variability in the awakening response and diurnal slope, and for 61-65% of the variation in overall daily levels (i.e., diurnal mean, area under the curve with respect to ground [AUCg]). Although less than 1% of the variation was due to differences between waves and between days, the generalizability analyses revealed that between 16% and 17% of the variance in the diurnal mean, slope and AUCg is due to person by wave interactions, indicating that individuals vary in their biological sensitivity to environmental influences. In sum, this study documents sufficient stability and variation in diurnal sAA to warrant future studies on the origins and consequences of alterations in the diurnal rhythm of sAA worthwhile, and proposes guidelines on obtaining reliable measures. PMID- 22819684 TI - Shining light on materials--a self-sterilising revolution. AB - This review focuses on the development of light activated antimicrobial surfaces. These surfaces kill microbes by the action of light and have potential applications in domestic and healthcare settings. The inspiration for the new self-cleaning surfaces originates from photodynamic therapy where light is used to locate and destroy tumours. The first generation photosensitiser molecules, based on a porphyrin ring structure, could be considered as bioinspired and chemically related to chlorophyll. The review looks at developments of both soft polymeric surfaces with either surface bound or impregnated photosensitiser molecules; and hard inorganic surfaces such as modified titanium dioxide. The bacterial kill mechanisms are looked into with both surface types showing primary microbial kill through a radical induced pathway. The hard inorganic surfaces also show low bacterial adherence by means of a light activated photo-wetting of the surfaces meaning that they are "Easy Clean" and wash off microbes uniformly. PMID- 22819685 TI - Dosimetry estimation on variations of patient size in prostate volumetric modulated arc therapy. AB - This study investigated the dosimetric variations of the target and critical organs of patients who had weight loss associated with prostate volumetric modulated arc therapy (VMAT). Five patients with prostate volumes ranging from 32 86.5 cm3 were selected from a group of 30 patients. Prostate VMAT plans were carried out on each patient using the 6-MV photon beam with a single 360 degrees arc. Decrease of patient size as a result of weight loss was mimicked by contracting the patient's external contour in the anterior, left, and right directions with depths from 0.5-2 cm. Soft tissue excluded by the contracted external contour was replaced by air and the dose distribution was recalculated using the same beam geometry and dose prescription. Dose-volume histograms and dose-volume points such as D99% and D5% for the planning target volume (PTV), clinical target volume (CTV), rectum, bladder, and femoral heads were calculated with variations of reduced depth. In addition, the minimum, maximum, and mean doses for the target and critical organs were determined. PTV and CTV D99% were found to have increased 2.86 +/- 0.30% per cm and 2.75 +/- 0.38% per cm of reduced depth ranging from 0.5-2 cm. Moreover, the rectal and bladder D30% increased 2.20 +/- 0.20% per cm and 2.31 +/- 0.83% per cm, and the femoral head D5% increased 3.30 +/- 0.11% per cm of reduced depth. Results from variations of the minimum, maximum, and mean doses of the PTV, CTV, rectum, bladder, and femoral heads showed that there was a >5% increase of dose when the reduced depth reached 2 cm. This study provided dosimetry estimation for radiation oncology staff to justify dose variations of the target and critical organs when patients' weight loss occurred in prostate VMAT. Dose variations >5% were seen when the patients' reduced depth was equal to 2 cm. PMID- 22819686 TI - Evolution of venom antigenaemia and antivenom concentration in patients bitten by snakes in Uruguay. AB - In this work we describe the first study carried out in Uruguay of venom antigenaemia and antivenom concentration in patients bitten by snakes. Between 50 and 70 snake bite accidents per year are caused in Uruguay by 2 species: Rhinocerophis alternatus and Bothropoides pubescens. The patients are treated with a specific polyvalent antivenom. Gaining insight on the evolution of venom antigenaemia and antivenom concentration in patients is important to improve treatment protocols. Blood samples of 29 patients were analysed to determine venom and antivenom concentrations at different times. Venom was detected in 18 of 19 samples before antivenom administration, with a mean concentration of 57 ng/mL. Most of the patients received 4 or 8 vials to neutralize the venom effects. Only one patient needed a total of 16 vials. He showed a severe envenomation and needed supplementary amounts of antivenom after the fifth day of the snake bite accident to reach normal clotting parameters. Antivenom concentrations were determined at 12 h, 24 h and 15 days after antivenom administration. It was found a faster antivenom decrease between 12 and 24 h than to 24 h to 15 days. This was explained by a different clearance mechanism in each period. In the first phase, the cause would be the neutralization of venom present in the blood whereas in the second phase it would be due to unbound antivenom elimination. PMID- 22819687 TI - Orally administered aqueous extract of Inonotus obliquus ameliorates acute inflammation in dextran sulfate sodium (DSS)-induced colitis in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat several disorders through its various biological functions. I. obliquus is claimed to produce general immune-potentiating and strengthening, antiinflammatory, and antitumor properties, but its effects on intestinal inflammation (ulcerative colitis) are clearly not understood. AIM OF THE STUDY: To determine the effects and mode of action of an aqueous extract of I. obliquus (IOAE) on experimental colitis in mice induced by dextran sulfate sodium (DSS). MATERIALS AND METHODS: Female 5-week-C57BL/6 mice were randomized into groups differing in treatment conditions (prevention and treatment) and doses of IOAE (50 and 100mg/kg body weight). Mice were exposed to DSS (2%) in their drinking water over 7 day to induce acute intestinal inflammation. In colon tissues, we evaluated histological changes by hematoxylin and eosin staining, levels of iNOS by immuno-histochemical staining, and neutrophil influx by myeloperoxidase assay. mRNA expression of pro-inflammatory mediators TNF-alpha, IL-1beta, IL-6, and IFN-gamma was determined by RT-PCR. RESULTS: Histological examinations indicated that IOAE suppressed edema, mucosal damage, and the loss of crypts induced by DSS. IOAE markedly attenuated DSS-induced iNOS levels and myeloperoxidase accumulation in colon tissues, demonstrating its suppressive effect on infiltration of immune cells. In addition, IOAE significantly inhibited mRNA expression of pro-inflammatory cytokines induced by DSS in colon tissues. CONCLUSION: Our results suggest anti-inflammatory effect of IOAE at colorectal sites due to down-regulation of the expression of inflammatory mediators. Suppression of TNF-alpha and iNOS together with IL-1beta by IOAE denotes that it might be a useful supplement in the setting of inflammatory bowel disease. PMID- 22819689 TI - Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer's disease and other forms of senile dementia. AIMS OF THE STUDY: In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. MATERIALS AND METHODS: We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. RESULTS: In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. CONCLUSION: These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety. PMID- 22819688 TI - Antidiabetic effects of Justicia spicigera Schltdl (Acanthaceae). AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Justicia spicigera is a plant species used for the Teenak (Huesteca Potosina) and Mayan (Yucatan peninsula) indigenous for the empirical treatment of diabetes, infections and as stimulant. AIM OF THE STUDY: To evaluate the cytotoxicity, antioxidant and antidiabetic properties of J. spicigera. MATERIALS AND METHODS: The effects of ethanolic extracts of J. spicigera (JSE) on the glucose uptake in insulin-sensitive and insulin-resistant murine 3T3-F442A and human subcutaneous adipocytes was evaluated. The antioxidant activities of the extract of JSE was determined by ABTS and DPPH methods. Additionally, it was evaluated the antidiabetic properties of JSE on T2DM model. RESULTS: JSE stimulated 2-NBDG uptake by insulin-sensitive and insulin-resistant human and murine adipocytes in a concentration-dependent manner with higher potency than rosiglitazone 1mM. JSE showed antioxidant effects in vitro and induced glucose lowering effects in normoglycemic and STZ-induced diabetic rats. CONCLUSION: The antidiabetic effects of administration of J. spicigera are related to the stimulation of glucose uptake in both insulin-sensitive and insulin-resistant murine and human adipocytes and this evidence justify its empirical use in Traditional Medicine. In addition, J. spicigera exerts glucose lowering effects in normoglycemic and STZ-induced diabetic rats. PMID- 22819690 TI - [Chest ultrasonography in pleurapulmonary disease]. AB - Although the initial diagnosis and follow-up of pleuropulmonary disease are normally done with plain chest films and the gold standard for chest disease is computed tomography, diverse studies have established the usefulness of chest ultrasonography in the diagnosis of different pleuropulmonary diseases like pleural effusion and lung consolidation, among others. In this article, we show the different ultrasonographic patterns for pleuropulmonary disease. The availability of ultrasonography in different areas (ICU, recovery areas) makes this technique especially important for critical patients because it obviates the need to transfer the patient. Moreover, ultrasonography is noninvasive and easy to repeat. On the other hand, it enables the direct visualization of pleuropulmonary disease that is necessary for interventional procedures. PMID- 22819691 TI - [Chronic bronchial obstruction caused by an endobronchial lipoma]. PMID- 22819692 TI - Novel approach to the study of jaw kinematics in an alloplastic TMJ reconstruction. AB - Total alloplastic temporomandibular joint (TMJ) reconstruction is a reliable treatment modality in patients with severely diseased TMJ with good clinical behaviour. TMJ mandibular function after alloplastic reconstruction has scarcely been analysed as a biomechanical parameter and investigation has generally been limited to interincisal measurements without deeper insight into joint kinematics. Dynamic stereometry to assess condylar movements relative to the fossa was performed at the 5 year follow-up of a patient who underwent condylar resection of the right TMJ followed by total alloplastic joint reconstruction to treat pigmented villonodular synovitis. The patient could achieve wide mouth opening, but overall mandibular kinematics showed a strong deviation towards the prosthetic side due to the lack of mandibular translation caused by the absence of the lateral pterygoid attachment. Possible overloading of the joint contralateral to the TMJ prosthesis might be prevented by optimizing replacement joint design. PMID- 22819693 TI - Medial pterygoid muscle and stylomandibular ligament: the effects on postoperative stability. AB - The postoperative skeletal stability following surgical advancement of the mandible can be influenced by several factors. The effect of the medial pterygoid muscle and the stylomandibular ligament on the stability of results following surgical advancement has possibly been underestimated. In this retrospective study, the long-term postoperative skeletal stability following surgical advancement of the mandible in two groups of patients was studied and compared. In one group the medial pterygoid muscle and the stylomandibular ligament were stripped from the medial side of the angle of the mandible during the bilateral sagittal split osteotomy (BSSO) procedure while for the other group of patients these muscles and ligaments were left attached. The long term skeletal stability of the two groups was compared and the group that had the muscles and the ligaments stripped proved to be more stable than the other group. PMID- 22819694 TI - Assessment of the systemic effects of low-level laser therapy (LLLT) on thyroid hormone function in a rabbit model. AB - The aim of this study was to assess the effects of low-level laser therapy (LLLT) applied to a dental extraction socket on thyroid gland function in a rabbit model, based on serum triiodothyronine and thyroxine levels. Sixteen male New Zealand rabbits were randomly distributed into two groups: a control group (non irradiated animals) and an experimental group (irradiated animals: one irradiation point in the extraction socket of the lower incisor). Animals in the experimental group were irradiated with an aluminium gallium arsenide diode laser (AlGaAs; wavelength 830 nm, 40 mW, CW laser), for 13 days, every 48 h, at a dose of 6 J/cm(2) per session, resulting in a total dose of 42 J/cm(2). Serum triiodothyronine and thyroxine levels were measured in both groups before extraction and on the last day of observation (day 15). There were no statistically significant differences between the groups in pre- and post irradiation triiodothyronine and thyroxine values. With the irradiation protocol used in this study, LLLT did not affect thyroid function in rabbits as assessed by circulating serum triiodothyronine and thyroxine levels. PMID- 22819695 TI - New protocol to prevent TMJ reankylosis and potentially life threatening complications in triad patients. AB - The management of patients with the triad of temporomandibular joint (TMJ) ankylosis, micrognathia and obstructive sleep apnea syndrome is challenging for the oral and maxillofacial surgeon because it involves achieving the desired oral opening, correction of micrognathia, and correction of the obstructed airway. Seven of the authors' triad patients, in whom only the release of ankylosis was performed, developed bradycardia and respiratory distress during postoperative jaw physiotherapy, leading to their non-compliance for active jaw physiotherapy and subsequent reankylosis. This paper suggests a new surgical protocol for the management of patients with the triad, to achieve correction of the obstructed airway, relief of the respiratory distress symptoms, correction of micrognathia and restricted mouth opening. It also provides a logical reason for the occurrence of bradycardia following ankylosis release and its potential role in TMJ reankylosis. It emphasizes that the occurrence of bradycardia in triad patients during jaw exercises is dictated by the severity of their apnea-hypopnea index and the degree of narrowing of their posterior airway space. The recognition and prevention of this by the new protocol is discussed in 7 patients. PMID- 22819696 TI - Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma. AB - OBJECTIVES: Urothelial carcinomas (UC) from the upper urinary tract represent 7% 10% of all kidney malignancies. With current ureteroscopic (URS) techniques, small tissue samples are usually the only available histopathologic material for evaluation, representing a diagnostic challenge. Precision in diagnosis is essential for treatment decision making. There has been much debate as to whether tumor grade and stage found on biopsy agree with final pathology. The purpose of this study is to evaluate whether URS biopsy volume affects tumor grading and staging agreement between biopsy and nephroureterectomy (NU) specimens. MATERIALS AND METHODS: We reviewed 137 URS biopsies in 81 patients with suspected upper urinary tract UC performed from April 2002 to April 2011. Of those, 54 patients had both the URS biopsy and NU performed at our institution and were available for review. Biopsy dimensions were recorded to calculate estimated ellipsoid volume, and 2 urological pathologists independently evaluated histologic grade (ISUP/WHO 2004), (based on pleomorphism and mitosis) and depth of invasion. Statistical analysis was performed to evaluate URS biopsy and NU specimen grade and stage concordance. In addition, univariable and multivariable analyses was performed to assess the effect of biopsy volume on agreement. RESULTS: Of the 54 patients studied, low grade and high grade UC biopsy were found in 8 (15%) and 46 (85%), URS biopsies, respectively. Regarding biopsy stage, 51 (94%), 1 (2%), and 2 (4%) were stage Ta, T1, T2, respectively. Grade concordance was 92.6%, (95% CI: 82.4%-98.0%). Stage concordance was 43% (95% CI: 28.7%-55.9%). Multivariable analysis showed biopsy volume did not affect tumor assessment of grade (P = 0.81) or stage (P = 0.44). CONCLUSIONS: Histologic grade assigned on the URS biopsy sample accurately predicts histologic grade in the resected specimen (92.6%), even when the biopsy volume is small. Grading in URS biopsies provides sufficient information for clinical decision making that is independent of sample volume. PMID- 22819697 TI - The Patient Protection and Affordable Care Act: the impact on urologic cancer care. AB - In March 2010, the Patient Protection and Affordable Care Act as well as its amendments were signed into law. This sweeping legislation was aimed at controlling spiraling healthcare costs and redressing significant disparities in healthcare access and quality. Cancer diagnoses and their treatments constitute a large component of rising healthcare expenditures and, not surprisingly, the legislation will have a significant influence on cancer care in the USA. Because genitourinary malignancies represent an impressive 25% of all cancer diagnoses per year, this legislation could have a profound impact on urologic oncology. To this end, we will present key components of this landmark legislation, including the proposed expansion to Medicaid coverage, the projected role of Accountable Care Organizations, the expected creation of quality reporting systems, the formation of an independent Patient-Centered Outcomes Research Institute, and enhanced regulation on physician-owned practices. We will specifically address the anticipated effect of these changes on urologic cancer care. Briefly, the legal ramifications and current barriers to the statutes will be examined. PMID- 22819699 TI - Localization and expression of inducible nitric oxide synthase in patients after BCG treatment for bladder cancer. AB - Treatment with Bacillus Calmette Guerin (BCG) bladder instillations is an established treatment modality for superficial urinary bladder cancer and carcinoma in situ (CIS), but the anti-tumor mechanisms following BCG instillations remain largely unknown. Previous data show increased nitric oxide (NO) concentrations in the urinary bladder from patients treated with BCG suggesting that NO-formation may be involved in the BCG mediated effect. In the present study we evaluated 11 patients with urinary bladder cancer who had received BCG treatment and 11 tumor free control subjects. We performed immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) on bladder biopsies to establish inducible nitric oxide synthase (iNOS) protein levels and localization as well as iNOS mRNA expression. Endogenous NO formation in the bladder was also measured. In patients with bladder cancer who had received BCG treatment iNOS-like immunoreactivity was found in the urothelial cells but also in macrophages in the submucosa. Furthermore, endogenously formed NO was significantly increased (p<0.001) in the BCG treated patients and they had a ten-fold increase in mRNA expression for iNOS compared to healthy controls (p=0.003). In conclusion iNOS was found to be localized to the urothelium and macrophages underlying it. Our study also confirms elevated levels of endogenously formed NO and increased mRNA expression and protein levels for iNOS in patients with BCG treated bladder cancer. These data further support the notion that NO may be involved in the anti-tumor mechanism that BCG exerts on bladder cancer cells. PMID- 22819698 TI - Copper modulates the phenotypic response of activated BV2 microglia through the release of nitric oxide. AB - Microglia are resident immune cells of the central nervous system. Their persistent activation in neurodegenerative diseases, traditionally attributed to neuronal dysfunction, may be due to a microglial failure to modulate the release of cytotoxic mediators such as nitric oxide (NO). The persistent activation of microglia with the subsequent release of NO vis-a-vis the accumulation of redox transition metals such as copper (Cu) in neurodegenerative diseases, prompted the hypothesis that copper would alter NO signaling by changing the redox environment of the cell and that, by altering the fate of NO, microglia would adopt a different phenotype. We have used the microglial cell model, BV2, to examine the effects of Cu(I) on NO production and activation as they have been shown to be phenotypically plastic. Our results show that cell viability is not affected by Cu(I) in BV2 microglia and that it has no effect on iNOS mRNA, protein expression and nitrite release. However, when LPS is added to Cu(I)-treated medium, nitrite release is abrogated while iNOS expression is not significantly altered. This effect is Cu(I)-specific and it is not observed with other non-redox metals, suggesting that Cu(I) modulates NO reactivity. Immunofluorescence analysis shows that the M1 (inflammatory) phenotype of BV2 microglia observed in response to LPS, is shifted to an M2 (adaptive) phenotype when Cu(I) is administered in combination with LPS. This same shift is not observed when iNOS function is inhibited by 1400W. In the present study we show that Cu(I) modulates the release of NO to the media, without altering iNOS expression, and produces phenotypic changes in BV2 microglia. PMID- 22819701 TI - Intracellular signaling pathways involved in the relaxin-induced proliferation of rat Sertoli cells. AB - Regulation of Sertoli cell number is a key event to determine normal spermatogenesis. We have previously shown that relaxin and its G-protein coupled receptor RXFP1 are expressed in rat Sertoli cells, and that relaxin stimulates Sertoli cell proliferation. This study examined the mechanisms underlying the mitogenic effect of relaxin in a primary culture of Sertoli cells removed from testes of immature rats. Stimulation with exogenous relaxin increased Sertoli cell number and the expression of the proliferating cell nuclear antigen (PCNA), but did not affect the mRNA level of the differentiation markers cadherins 1 and 2. Relaxin-induced Sertoli cell proliferation was blocked by inhibition of MEK/ERK1/2 or PI3K/AKT pathways, but not by inhibition of PKC or EGFR activity. Relaxin induced a rapid and transient activation of ERK1/2 phosphorylation, which was MEK and SRC-dependent, and involved upstream activation of G(i). AKT activation could be detected 5 min after relaxin stimulation, and was still detected after 24h of stimulation with relaxin. Relaxin-induced AKT phosphorylation was G(i)- but not PKA-dependent, and it was blocked by both PI3K and MEK inhibitors. In conclusion, the mitogenic effect of relaxin in Sertoli cell involves coupling to G(i) and activation of both MEK/ERK1/2 and PI3K/AKT pathways. PMID- 22819700 TI - A multicenter application and evaluation of the oxford classification of IgA nephropathy in adult chinese patients. AB - BACKGROUND: The Oxford classification of immunoglobulin A (IgA) nephropathy (IgAN) provides a histopathologic grading system that is associated with kidney disease outcomes independent of clinical features. We evaluated the Oxford IgAN classification in a large cohort of patients from China. STUDY DESIGN: Retrospective study. SETTING & PARTICIPANTS: 1,026 adults with IgAN from 18 referral centers in China. Inclusion criteria and statistical analysis were similar to the Oxford study. PREDICTORS: Histologic findings of mesangial hypercellularity score, endocapillary proliferation, segmental sclerosis or adhesion, crescents, necrosis, and tubular atrophy/interstitial fibrosis. Clinical features, blood pressure, estimated glomerular filtration rate (eGFR), proteinuria, and treatment modalities. OUTCOMES: Time to a 50% reduction in eGFR or end-stage renal disease (the combined event); the rate of eGFR decline (slope of eGFR); proteinuria during follow-up. RESULTS: Compared with the Oxford cohort, the Chinese cohort had a lower proportion of patients with mesangial hypercellularity (43%) and endocapillary proliferation (11%), higher proportion with segmental sclerosis or adhesion (83%) and necrosis (15%), and similar proportion with crescents (48%) and tubular atrophy/interstitial fibrosis (moderate, 24%; severe, 3.3%). During a median follow-up of 53 (25th-75th percentile, 36-67) months, 159 (15.5%) patients reached the combined event. Our study showed that patients with a mesangial hypercellularity score higher than 0.5 were associated with a 2.0-fold (95% CI, 1.5-2.8; P<0.001) higher risk of the combined event than patients with a score of 0.5 or lower. Patients with tubular atrophy/interstitial fibrosis of 25%-50% and >50% versus <25% were associated with a 3.7-fold (95% CI, 2.6-5.1; P<0.001) and 15.1-fold (95% CI, 9.5-24.2; P<0.001) higher risk of the combined event, respectively. Endocapillary proliferation, glomerular crescents, and necrosis were not significant. LIMITATIONS: Retrospective study; the therapeutic interventions were miscellaneous. CONCLUSIONS: We confirmed the associations of mesangial hypercellularity and tubular atrophy/interstitial fibrosis with kidney disease outcomes. PMID- 22819702 TI - Activation of AMPK-Sirt1 pathway by telmisartan in white adipose tissue: A possible link to anti-metabolic effects. AB - Telmisartan exerts anti-metabolic effects beyond its angiotensin receptor blockade activities, but the mechanisms have hitherto remained elusive. We sought to elucidate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) dependent and PPAR-gamma-independent mechanisms underlying the anti-metabolic effects of telmisartan in white adipose tissue. Nine-week-old male C57BL/6 mice were fed with a 60% high-fat diet for 6 weeks, with 1mg/kg telmisartan or vehicle administrated orally during the last 3 weeks. 3T3-L1 adipocytes were cultured with telmisartan either with 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective irreversible antagonist of PPAR-gamma, or compound C, an ATP competitive inhibitor of AMPK. Western blotting and semiquantitative RT-PCR analysis were used to assess adiponectin, Sirt1, and AMPK levels. Lipid accumulation was assessed by Oil red O staining. The activation of transcription factor PPAR-gamma2 was evaluated by using a luciferase reporter assay for mPPAR gamma2 expression plasmid vector. Treatment with telmisartan increased serum adiponectin levels in high-fat diet-fed mice concomitantly with an upregulation of adiponectin mRNA in visceral adipose tissue. In vitro telmisartan treatment dose-dependently increased adiponectin mRNA in 3T3-L1 cells; the increase was inhibited by compound C, but not by GW9662. Telmisartan increased expression of Sirt1 mRNA and Sirt1 protein as well as the phosphorylation of AMPK in 3T3-L1 cells. Telmisartan can increase adiponectin production in white adipose tissue partly via a PPAR-gamma2-independent mechanism. Precise understanding of this molecular mechanism will require further investigation. PMID- 22819703 TI - Phospholipase A2 activities in skin physiology and pathology. AB - Skin inflammatory diseases are most commonly treated with corticosteroids, especially topical preparations, benefitting from high potency and unparalleled formulation flexibility. However, these benefits are limited due to side effects, especially under long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) which block the COX pathways have been used as safer alternatives to corticosteroids, and much effort and resources have been invested in developing COX inhibitors. However, synthetic NSAIDs are less potent than steroids, have limited formulation flexibility and have their own safety issues, thereby yielding unsatisfactory results, with some high-profile drugs (e.g., the COX-2 inhibitors Vioxx, Celebrex) being withdrawn from the market due to safety concerns. The potency and safety challenges of NSAIDs are related to inter eicosanoid dynamics, pertaining to their pro-versus anti-inflammatory action, homeostatic functions and tissue-specific activities. Instead, the upstream control of phospholipase A2 (PLA2) enzymatic activity, which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production, has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions. Yet, PLA(2) inhibitors have hardly been tested for treating skin inflammatory/allergic conditions. In this article we review the involvement of PLA(2)s in skin physiology and pathology, and discuss the prospect of PLA(2) inhibition for the treatment of dermatological diseases. PMID- 22819704 TI - Effect of exendin (exenatide)--GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model. AB - Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 +/- 8.7 vs. 10.5 +/- 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency. PMID- 22819705 TI - Cardio-respiratory effects of systemic neurotensin injection are mediated through activation of neurotensin NTS1 receptors. AB - The purpose of our study was to determine the cardio-respiratory pattern exerted by the systemic injection of neurotensin, contribution of neurotensin NTS(1) receptors and the neural pathways mediating the responses. The effects of an intravenous injection (i.v.) of neurotensin were investigated in anaesthetized, spontaneously breathing rats in following experimental schemes: (i) control animals before and after midcervical vagotomy; (ii) in three separate subgroups of rats: neurally intact, vagotomized at supranodosal level and initially midcervically vagotomized exposed to section of the carotid sinus nerves (CSNs); (iii) in the intact rats 2 minutes after blockade of neurotensin NTS(1) receptors with SR 142948. Intravenous injection of 10 MUg/kg of neurotensin in the intact rats evoked prompt increase in the respiratory rate followed by a prolonged slowing down coupled with augmented tidal volume. Midcervical vagotomy precluded the effects of neurotensin on the frequency of breathing, while CSNs section reduced the increase in tidal volume. In all the neural states neurotensin caused significant fall in mean arterial blood pressure preceded by prompt hypertensive response. The cardio-respiratory effects of neurotensin were blocked by pre treatment with NTS(1) receptor antagonist. The results of this study showed that neurotensin acting through NTS(1) receptors augments the tidal component of the breathing pattern in a large portion via carotid body afferentation whereas the respiratory timing response to neurotensin depends entirely on the intact midcervical vagi. Blood pressure effects evoked by an intravenous neurotensin occur outside vagal and CSNs pathways and might result from activation of the peripheral vascular NTS(1) receptors. PMID- 22819706 TI - Changes of cytosolic calcium and contractility of young rat vas deferens by acute treatment with amphetamine, fluoxetine or sibutramine. AB - Previous studies conducted in our laboratory indicated that administration of amphetamine, fluoxetine or sibutramine affects the sympathetic nervous system of the rat vas deferens. Therefore, our goal was to verify the role of calcium in vasa deferentia from young rats pretreated with a single dose of these drugs. Young 40-day-old male Wistar rats were pretreated with amphetamine 3 mg/kg, fluoxetine 10 mg/kg or sibutramine 6 mg/kg for 4 h before the experiments. CaCl(2) (10 mM) was used to induce contraction through time-effect curves in calcium-free solution to measure phasic and tonic components. We also evaluated the calcium-induced fluorescence of vas deferens cut into thin slices. In rats pretreated with amphetamine, we found an increase of the tonic contraction component which was reduced by verapamil. The phasic and tonic responses were increased in the group treated with fluoxetine, but only the tonic response was more sensitive to the antagonism by verapamil. The group treated with sibutramine showed an increase of phasic response whereas the tonic component was decreased. In this group an increase of the affinity for verapamil antagonism was found. In the calcium fluorescence study it was observed that the group treated with amphetamine, fluoxetine or sibutramine showed higher basal Ca(2+) fluorescence after stimulus with KCl (70 mM), noradrenaline (10(-4)M) or acetylcholine (10( 4)M). In all pretreated groups the calcium fluorescence was diminished by nifedipine 10(-7)M. Therefore, the pretreatment with amphetamine, fluoxetine or sibutramine seems to affect the calcium contractility and homeostasis in young rat vas deferens. PMID- 22819707 TI - Novel diallyldisulfide analogs ameliorate cardiovascular remodeling in rats with L-NAME-induced hypertension. AB - Diallyldisulfide (DADS), an active principle of garlic (Allium sativum) is known for its antihypertensive properties. The present study was designed to evaluate the effect of novel DADS analogs, against L-NAME induced hypertension in Wistar rats. The daily administration of L-NAME (50mg/kg) for six weeks along with DADS analogs (20 mg/kg) significantly decreased the elevated systolic blood pressure (SBP) and the activity of angiotensin converting enzyme (ACE) and also inhibited the decline in nitrite/nitrate (NO(x)) concentrations and cyclic guanosine monophosphate (cGMP) levels. Adverse changes such as lipid peroxidation, protein damage and a decrease in the levels of antioxidant enzymes, were rectified after the administration of DADS analogs. Oral administration of DADS analogs preserved the expression of endothelial nitric oxide synthase (eNOS). The ability of the DADS analogs to inhibit L-NAME induced hypertension was compared with Enalapril (15 mg/kg), which was taken as a standard. The DADS analogs prevented L-NAME induced cardio toxicity, which was also reflected at the microscopic level indicative of its cardio protective effects. DADS analogs induced vasorelaxation was completely abolished by the removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. DADS analogs inhibited the calcium influx induced by phenylephrine (0.3 MUM) and high K(+) (60mM) and this effect was completely abolished by pretreatment of L-NAME. Taken together, our results show that the DADS analogs induce vasorelaxation and have antihypertensive properties, which may be mediated through activation of eNOS. PMID- 22819708 TI - Alpha-lipoic acid induces adipose triglyceride lipase expression and decreases intracellular lipid accumulation in HepG2 cells. AB - Non-alcoholic fatty liver disease can be attributed to the imbalance between lipogenesis and lipolysis in the liver. Alpha-lipoic acid has been shown to activate the 5'-AMP-activated protein kinase (AMPK) signalling pathway and to effectively inhibit the lipogenesis pathway in liver. However, whether alpha lipoic acid stimulates lipolysis remains unclear. Recently, adipose triglyceride lipase (ATGL) was shown to be responsible for triacylglycerol hydrolase activity in cells. In the present study, we established a fatty liver cell model by incubating HepG2 cells in a high glucose (30mM glucose) and high fat (0.1mM palmitate) medium. We found that the activation of the AMPK signalling pathway induced ATGL protein expression and enhanced lipid hydrolysis. Similarly, treatment of the fatty liver cell model with alpha-lipoic acid reduced intracellular lipid accumulation in HepG2 cells, increased AMPK phosphorylation, and induced ATGL expression. We showed that insulin phosphorylates the transcription factor forkhead box O1 (FOXO1), which regulates ATGL expression and inhibits FOXO1 translocation into the nucleus. In contrast, alpha-lipoic acid dephosphorylated FOXO1 and reversed the nuclear exclusion of FOXO1. These data suggest that alpha-lipoic acid can effectively ameliorate intracellular lipid accumulation and induce ATGL expression through the FOXO1/ATGL pathway in liver cells. Thus, alpha-lipoic acid may be a potential therapeutic agent for treating fatty liver disease. PMID- 22819709 TI - Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats. AB - We investigated the effects of fasudil, a Rho kinase inhibitor, in the endothelial dysfunction of aortas from spontaneously hypertensive rats (SHRs). SHRs were divided in three groups; intraperitoneally (i.p.) vehicle-treated SHRs (SHR), SHRs treated with fasudil 3 mg/kg i.p. (Fas3), and SHRs treated with fasudil 10 mg/kg i.p. (Fas10). Vehicle-treated Wistar rats were used as normo tensive control group. After a six-week-treatment, blood pressure and heart rate were measured by the tail cuff method. Afterwards animals were sacrificed and aortas were examined in vitro by organ bath studies to evaluate the contraction and relaxation ability. Rho kinase activity, myosin light chain (MLC), phosphorylated MLC (phospho-MLC), eNOS, phospho-eNOS protein expression and eNOS mRNA levels were evaluated. SHR demonstrated a significant hypercontractility and impaired relaxation compared to the control. Fasudil 10mg/kg significantly corrected the hypercontractility, restored the relaxation, and significantly decreased the mean arterial blood pressure, while no change observed in the systolic blood pressure. Rho kinase activity was significantly higher in the SHR, and was significantly inhibited by the high dose of fasudil. There was a slight up-regulation in the MLC, and phospho-MLC protein levels in the SHR. eNOS and phospho-eNOS protein levels were significantly lower in the SHR, and this abnormality was significantly normalized by fasudil treatment. No significant difference was observed in the eNOS gene expression. This study suggests that fasudil by inhibiting the Rho kinase activity normalizes the eNOS expression and phosphorylation and ameliorates the endothelial dysfunction induced by hypertension in the SHR model. PMID- 22819710 TI - Primary care providers' communication with patients during weight counseling: a focus group study. AB - OBJECTIVE: Primary care providers (PCPs) are encouraged to counsel their obese patients about weight loss. We used focus groups to explore how PCPs communicate with patients about weight management. METHODS: During the summer of 2010, we conducted five focus groups of community-based PCPs who had patients enrolled in a practice-based, randomized controlled weight loss trial in Maryland. Focus groups were audio-recorded and transcribed verbatim. Two investigators independently coded transcripts for thematic content using editing style analysis. RESULTS: Twenty-six PCPs from six different practices participated. Mean years in practice were 16.4 (SD 11.7) and 77% practiced internal medicine. We identified three communication-based themes about weight loss counseling: (1) motivating patients to lose weight, (2) partnering with the patient to achieve weight loss, and (3) handling challenges that arise during weight counseling. CONCLUSION: PCPs use a variety of strategies to communicate with their patients about weight loss. Some PCPs already use patient-centered approaches to communicate with their patients about weight loss, suggesting that future weight counseling interventions should be tailored to build upon this strength. PRACTICE IMPLICATIONS: PCPs' weight loss counseling may be improved by using techniques with demonstrated behavior change effectiveness such as the 5A's or motivational interviewing. PMID- 22819711 TI - Physician's gender, communication style, patient preferences and patient satisfaction in gynecology and obstetrics: a systematic review. AB - OBJECTIVE: Review of studies published in the last 10 years about women seeking gynecological- or obstetrical care and physician's gender in relation to patient preferences, differences in communication style and patient satisfaction. METHODS: Studies were identified by searching the online databases PubMed, PsycINFO, Embase and the Cochrane Library. The search strategies 'gender'; 'obstetrics' and 'gynecology' were combined with 'communication'; 'physician patient relations'; 'patient preference' and 'patient satisfaction'. RESULTS: After screening title and abstract, evaluating full text and quality assessment, 9 articles were included in this review. Most patients preferred a female rather than a male gynecologist-obstetrician. This was partly explained by a more patient-centered communication style used by female gynecologists-obstetricians. Also experience and clinical competence were important factors in choosing a gynecologist-obstetrician. It was not clear whether patient's age or ethnicity influenced patients gender preference. Patient satisfaction increased when gynecologists-obstetricians used a patient-centered communication style. CONCLUSION: Preference for a female gynecologist-obstetrician might be explained by a more patient-centered communication style used by female gynecologists obstetricians. Using a patient-centered communication style increases patient satisfaction. PRACTICE IMPLICATIONS: To increase patient satisfaction, gynecologists-obstetricians should learn to integrate patient-centered communication style into the consultation. PMID- 22819712 TI - Posttranscriptional regulation of expression of plasminogen activator inhibitor type-1 by sphingosine 1-phosphate in HepG2 liver cells. AB - Altered expression of plasminogen activator inhibitor type-1 (PAI-1), a major physiologic inhibitor of fibrinolysis, is implicated in the progression of atherosclerosis. Sphingosine 1-phosphate (S1P) regulates expression of diverse genes and alters expression of PAI-1 in several types of cells. However, the nature of posttranscriptional regulation of expression of PAI-1 by S1P has not yet been thoroughly elucidated. The present study was undertaken to determine whether S1P has important effects on the posttranscriptional regulation of PAI-1 expression. To evaluate this possibility, we determined promoter activity, mRNA levels, 3'-untranslated region (UTR) activity, and protein levels of PAI-1 in HepG2 cells. S1P increased PAI-1 promoter activity and the expression of PAI-1 mRNA within 4h of exposure. It decreased the expression of PAI-1 mRNA and the accumulation of PAI-1 protein into the media in 24h. Human PAI-1 mRNA exists in two subspecies (3.2 and 2.2kb). S1P decreased the baseline luciferase activity of the 1kb fragment of the 3' terminus (+2177 to 3176nt) of the 3'-UTR of the 3.2kb PAI-1 mRNA [3'-UTR (+2177-3176)]. S1P decreased expression of PAI-1 protein, presumably by regulating PAI-1 expression at the posttranscriptional level thereby affecting mRNA stability. SERPINE1 mRNA binding protein (SERBP1) and ARE3 in the 3'-UTR were involved in the posttranscriptional regulation by S1P. Our data suggest that S1P can destabilize 3.2kb PAI-1 mRNA through specific effects on the 3'-UTR. These effects appear to involve SERBP1 leading to decreased expression of PAI-1 protein. PMID- 22819713 TI - Pseudo three-dimensional vision-based nail-fold morphological and hemodynamic analysis. AB - In this study, a Pseudo three-dimensional Vision-based Nail-fold Morphological and Hemodynamic Analysis (PTVNMHA) is proposed to automatically extract morphological/hemodynamic features from a microscopic nail-fold image sequence, reconstruct the corresponding pseudo three-dimensional microvascular models, and visualize the dynamic blood flow in the model constructed. The morphological features extracted include the number, width/height, density, arteriolar limb caliber, curved segment caliber, venular limb caliber, blood color, tortuosity, and width of the curved segment of capillaries. The hemodynamic features identified are blood flow velocity and blood flow rate. All are significant pathological indicators with a spatial precision up to 1.6 MUm. The diameters of cross-sections along the centerlines of capillaries are identified and employed to reconstruct the pseudo three-dimensional microvascular surface meshes. The microscopic image sequence acquired is mapped to the corresponding microvascular model constructed to perform dynamic blood flow visualization. Compared with laser Doppler velocimetry, PTVNMHA can derive blood flow velocities for each capillary across the microscopic range separately in much higher precision and obtain diversified morphological and hemodynamic features of capillaries with a low-cost equipment setup. In addition to the blood flow velocity, blood flow rate, which keeps almost constant no matter where the measuring position is in a capillary, has also been measured and proposed as a useful feature to discriminate patients with hypertension from the normal with great significance (p<0.001). In the future, large scale experiments will be conducted to diagnose patients with anemia as well as patients with essential and secondary hypertension to verify effectiveness of the PTVNMHA system. PMID- 22819714 TI - Longitudinal study on the sources of Listeria monocytogenes contamination in cold smoked salmon and its processing environment in Italy. AB - The aim of the present study was to investigate the sources of Listeria monocytogenes contamination in a cold smoked salmon processing environment over a period of six years (2003-2008). A total of 170 samples of raw material, semi processed, final product and processing surfaces at different production stages were tested for the presence of L. monocytogenes. The L. monocytogenes isolates were characterized by multiplex PCR for the analysis of virulence factors and for serogrouping. The routes of contamination over the six year period were traced by PFGE. L. monocytogenes was isolated from 24% of the raw salmon samples, 14% of the semi-processed products and 12% of the final products. Among the environmental samples, 16% were positive for L. monocytogenes. Serotyping yielded three serovars: 1/2a, 1/2b, 4b, with the majority belonging to serovars 1/2a (46%) and 1/2b (39%). PFGE yielded 14 profiles: two of them were repeatedly isolated in 2005-2006 and in 2007-2008 mainly from the processing environment and final products but also from raw materials. The results of this longitudinal study highlighted that contamination of smoked salmon occurs mainly during processing rather than originating from raw materials, even if raw fish can be a contamination source of the working environment. Molecular subtyping is critical for the identification of the contamination routes of L. monocytogenes and its niches into the production plant when control strategies must be implemented with the aim to reduce its prevalence during manufacturing. PMID- 22819715 TI - Survival rate of wine-related yeasts during alcoholic fermentation assessed by direct live/dead staining combined with fluorescence in situ hybridization. AB - Real-time detection of microorganisms involved in complex microbial process, such as wine fermentations, and evaluation of their physiological state is crucial to predict whether or not those microbial species will be able to impact the final product. In the present work we used a direct live/dead staining (LDS) procedure combined with fluorescence in situ hybridization (FISH) to simultaneously assess the identity and viability of Saccharomyces cerevisiae (Sc) and Hanseniaspora guilliermondii (Hg) during fermentations performed with single and mixed cultures. The population evolution of both yeasts was determined by plating and by LDS combined with species-specific FISH-probes labeled with Fluorescein. Since the FISH method involves the permeabilization of the cell membrane prior to hybridization and that it may influence the free diffusion of PI in and out of the cells, we optimized the concentration of this dye (0.5 MUg of PI per 10(6) cells) for minimal diffusion (less than 2%). Fluorescent cells were enumerated by hemocytometry and flow cytometry. Results showed that the survival rate of Sc during mixed cultures was high throughout the entire process (60% of viable cells at the 9th day), while Hg began to die off at the 2nd day, exhibited 98% of dead cells at the 3rd day (45 g/l of ethanol) and became completely unculturable at the 4th day. However, under single culture fermentation the survival rate and culturability of Hg decreased at a much slower pace, exhibiting at the 7th day (67 g/l of ethanol) 8.7*10(4) CFU/ml and 85% of dead cells. Thus, our work demonstrated that the LDS-FISH method is able to simultaneously assess the viability and identity of these wine-related yeast species during alcoholic fermentation in a fast and reliable way. In order to validate PI-staining as a viability marker during alcoholic fermentation, we evaluated the effect of ethanol on the membrane permeability of Sc and Hg cells, as well as their capacity to recover membrane integrity after being exposed to different levels of ethanol (1%, 6%, 10%, 12% v/v). Results showed that while Sc cells were able to recover membrane integrity after ethanol exposure, Hg cells were not. However, under alcoholic fermentation Sc cells didn't recover membrane integrity after the mid-term (4-5 days) of alcoholic fermentation. PMID- 22819716 TI - Detection and treatment of subclinical tuberculosis. AB - Reduction of active disease by preventive therapy has the potential to make an important contribution towards the goal of tuberculosis (TB) elimination. This report summarises discussions amongst a Working Group convened to consider areas of research that will be important in optimising the design and delivery of preventative therapies. The Working Group met in Cape Town on 26th February 2012, following presentation of results from the GC11 Grand Challenges in Global Health project to discover drugs for latent TB. PMID- 22819717 TI - Activation of androgen receptor induces ID1 and promotes hepatocellular carcinoma cell migration and invasion. AB - Androgen receptor (AR) activity is associated with cancer development and progression. In hepatocellular carcinoma (HCC), AR contributes to HCC incidence, but the role of AR in HCC cell migration and invasion remains largely unknown. In this study, we found that AR was expressed at high levels in a subgroup of HCC cell lines with high metastatic potential. Experiments using lentiviral overexpression or small hairpin RNA knockdown of AR as well as activation of AR by its ligand indicated that AR activation promoted HCC cell migration and invasion. We also found that AR activation enhanced the expression of a metastasis-promoting gene, ID1, which led to increased HCC cell migration and invasion. An AR antagonist was able to block this process, suggesting that AR activation in AR-positive HCC may be therapeutically inhibited as a potential intervention strategy. PMID- 22819718 TI - Current treatment of low grade astrocytoma: a review. AB - Through a comprehensive review of the current literature, the present article investigates several aspects of low grade astrocytomas (LGA), including prognostic factors, treatment strategies and follow-up regimes. LGA are in general relatively slow-growing primary brain tumours, but they have a very heterogeneous clinical behaviour. Several factors affect prognosis, and these include age, histological subtype, and Karnofsky Performance Score (KPS) prior to surgery. Furthermore, a number of different molecular genetic alterations have been shown to affect both the prognosis as well as the course of disease. The current literature seems to support the idea that treatment with radical tumour resection, where possible, yields better long term outcome for patients with LGA. However, adjuvant therapy is often necessary. Administering early postoperative radiotherapy to patients with partially resected LGA yields a longer period of progression-free survival, whereas patients with radically resected tumours should receive radiotherapy at the time of progression. Regarding chemotherapy, we found evidence to suggest that patients respond to both temozolomide (TMZ) and the combination of procarbazine, lomustine and vincristine (PCV). However, the response rates in patients receiving PCV seem superior to those of patients receiving TMZ. In follow-up PET scans, the tracers (18)F-FDG and MET provide high sensitivities for detection of new suspicious lesions and these tracers are furthermore effective in discriminating between tumour progression and radiation necrosis. The research into biomarkers is currently limited with regards to their applications in LGA diagnostics, and therefore further studies including larger patient populations are needed. PMID- 22819719 TI - Salmonella typhi Ty21a bacterial ghost vector augments HIV-1 gp140 DNA vaccine induced peripheral and mucosal antibody responses via TLR4 pathway. AB - Because of their stability and ease of manipulation, DNA vaccines have considerable potential for eliciting immune responses. However, they are limited by their weak immunogenicity, especially in humans. To address this challenge, we explored a new strategy of HIV vaccine delivery using Salmonella typhi Ty21a bacterial ghosts (BGs). We found that Ty21a BGs loaded with an HIV gp140 DNA vaccine (Ty21a BG-DNA) were readily taken up by murine macrophage RAW264.7 cells, and gp140 was efficiently expressed in these cells. Peripheral and intestinal mucosal anti-gp120 antibody responses in mice vaccinated with BGs-DNA vaccine were significantly higher than those in mice immunized with naked DNA vaccine. The enhancement of antibody responses was associated with BG-induced production of IL-10 through TLR4 pathway. These results demonstrate that Ty21a BGs is a novel and effective delivery vehicle for DNA vaccines, which could therefore be used as a new strategy for development of HIV vaccines. PMID- 22819720 TI - Effectiveness of the 2010-2011 seasonal influenza vaccine in preventing confirmed influenza hospitalizations in adults: a case-case comparison, case-control study. AB - INTRODUCTION: We estimated influenza vaccine effectiveness (IVE) to prevent laboratory-confirmed influenza-related hospitalizations in patients 18 years old or older during the 2010-2011 influenza season. METHODS: We conducted a prospective case-control study in five hospitals, in Valencia, Spain. Study subjects were consecutive emergency hospitalizations for predefined conditions associated with an influenza-like illness episode <8 days before admission. Patients were considered immunized if vaccinated >=14 days before influenza-like illness onset. Cases were those with a real time reverse transcriptase polymerase chain reaction (RT-PCR) positive for influenza and controls were RT-PCR positive for other respiratory viruses. Adjusted IVE was estimated as 100*(1-adjusted odds ratio). To account for indication bias we computed adjusted IVE for respiratory syncytial virus related hospitalizations. RESULTS: Of 826 eligible hospitalized patients, 102 (12%) were influenza positive and considered cases, and 116 (14%) were positive for other respiratory viruses and considered controls. Adjusted IVE was 54% (95% confidence interval, 11-76%). By subgroup, adjusted IVE was 53% (4 77%) for those with high-risk conditions, 59% (16-79%) for those >=60 years of age, and, 54% (4-79%) for those >=60 years of age with high-risk conditions. No influenza vaccine effect was observed against respiratory syncytial virus related hospitalization. CONCLUSION: Influenza vaccination was associated with a significant reduction on the risk of confirmed influenza hospitalization, irrespective of age and high-risk conditions. PMID- 22819721 TI - Against all odds: a preliminary study comparing hospital personnel and rescue personnel reactions to Haiti's earthquake. PMID- 22819722 TI - Safety and efficacy of combined clozapine-azathioprine treatment in a case of resistant schizophrenia associated with Behcet's disease: a 2-year follow-up. AB - Behcet's disease (BD) is a recurrent inflammatory disorder involving multisystems of the body. Neuropsychiatric symptoms, like psychosis and depression, often occur in BD, but the safety and efficacy of combined clozapine-azathioprine treatment have never been assessed. We here report on a 37-year-old man with BD and treatment-resistant schizophrenia who obtained an improvement following the introduction of clozapine in addition to azathioprine, without developing agranulocytosis or other severe adverse side effects during a 2-year follow-up. PMID- 22819725 TI - HRMAS-NMR spectroscopy and multivariate analysis meat characterisation. AB - 1H-High resolution magic angle spinning-nuclear magnetic resonance spectroscopy was employed to gain the metabolic profile of longissimus dorsi and semitendinosus muscles of four different breeds: Chianina, Holstein Friesian, Maremmana and Buffalo. Principal component analysis, partial least squares projection to latent structure - discriminant analysis and orthogonal partial least squares projection to latent structure - discriminant analysis were used to build models capable of discriminating the muscle type according to the breed. Data analysis led to an excellent classification for Buffalo and Chianina, while for Holstein Friesian the separation was lower. In the case of Maremmana the use of intelligent bucketing was necessary due to some resonances shifting allowed improvement of the discrimination ability. Finally, by using the Variable Importance in Projection values the metabolites relevant for the classification were identified. PMID- 22819724 TI - Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes. AB - Evidence suggests a proinflammatory role of lysophosphatidic acid (LPA) in various pathologic abnormalities, including in the central nervous system. Herein, we describe LPA as an important mediator of inflammation after spinal cord injury (SCI) in zebrafish and mice. Furthermore, we describe a novel monoclonal blocking antibody raised against LPA that potently inhibits LPA's effect in vitro and in vivo. This antibody, B3, specifically binds LPA, prevents it from interacting with its complement of receptors, and blocks LPA's effects on the neuronal differentiation of human neural stem/progenitor cells, demonstrating its specificity toward LPA signaling. When administered systemically to mice subjected to SCI, B3 substantially reduced glial inflammation and neuronal death. B3-treated animals demonstrated significantly more neuronal survival upstream of the lesion site, with some functional improvement. This study describes the use of anti-LPA monoclonal antibody as a novel therapeutic approach for the treatment of SCI. PMID- 22819723 TI - Evaluating brief screeners to discriminate between drug use disorders in a sample of treatment-seeking adults. AB - OBJECTIVE: The objective was to identify a potential core set of brief screeners for the detection of individuals with a substance use disorder (SUD) in medical settings. METHOD: Data were from two multisite studies that evaluated stimulant use outcomes of an abstinence-based contingency management intervention as an addition to usual care (National Drug Abuse Treatment Clinical Trials Network trials 006-007). The sample comprised 847 substance-using adults who were recruited from 12 outpatient substance abuse treatment settings across the United States. Alcohol and drug use disorders were assessed by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Checklist. Data were analyzed by factor analysis, item response theory (IRT), sensitivity and specificity procedures. RESULTS: Comparatively prevalent symptoms of dependence, especially inability to cut down for all substances, showed high sensitivity for detecting an SUD (low rate of false negative). IRT-defined severe (infrequent) and low discriminative items, especially withdrawal for alcohol, cannabis and cocaine, had low sensitivity in identifying cases of an SUD. IRT-defined less severe (frequent) and high discriminative items, including inability to cut down or taking larger amounts than intended for all substances and withdrawal for amphetamines and opioids, showed good-to-high values of area under the receiver operating characteristic curve in classifying cases and noncases of an SUD. CONCLUSION: Findings suggest the feasibility of identifying psychometrically reliable substance dependence symptoms to develop a two-item screen for alcohol and drug disorders. PMID- 22819726 TI - Development of QuEChERS-based extraction and liquid chromatography-tandem mass spectrometry method for quantifying flumethasone residues in beef muscle. AB - A rapid, specific, and sensitive method based on liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the positive ion mode using multiple reaction monitoring (MRM) was developed and validated to quantify flumethasone residues in beef muscle. Methods were compared between the original as well as the EN quick, easy, cheap, effective, rugged, and safe (QuEChERS)-based extraction. Good linearity was achieved at concentration levels of 5-30 MUg/kg. Estimated recovery rates at spiking levels of 5 and 10 MUg/kg ranged from 72.1 to 84.6%, with relative standard deviations (RSDs)<7%. The results of the inter-day study, which was performed by fortifying beef muscle samples (n=18) on 3 separate days, showed an accuracy of 93.4-94.4%. The precision (expressed as relative standard deviation values) for the inter-day variation at two levels of fortification (10 and 20 MUg/kg) was 1.9-5.2%. The limit of detection (LOD) and limit of quantitation (LOQ) were 1.7 and 5 MUg/kg, at signal-to-noise ratios (S/Ns) of 3 and 10, respectively. The method was successfully applied to analyze real samples obtained from large markets throughout the Korean Peninsula. The method proved to be sensitive and reliable and, thus, rendered an appropriate means for residue analysis studies. PMID- 22819727 TI - Structure and spectral sensitivity of photoreceptors of two anchovy species: Engraulis japonicus and Engraulis encrasicolus. AB - The morphology, fine structure and spectral sensitivity of retinal photoreceptors of two anchovy species were investigated using light and electron microscopy and microspectrophotometry. Distinct regional specialisation of cones was observed. Long and short (bilobed) cones were observed in the horizontal retinal belt, including the nasal and temporal retinal zones. Only triple cones with two long lateral components, one small central component were observed in the dorsal and ventro-nasal retinal regions. The long cones presented various lamellar organisation patterns: (1) in parallel along the cell axis in the central retina, (2) oriented transversely at the base of the outer segment, and (3) tilted longitudinally while extending to the tip of the cone in the retinal periphery. In the short cones, the lamellae were always oriented along the cell axis, and their planes were perpendicular to the lamellae in the long cones, providing a structural basis for the detection of polarisation of incident light. The lamellae in all the outer segments of the triple cones are arranged perpendicular to the long cell axis. In both species, the long and short cones from the ventro temporal retina were slender and more densely packed, and the outer segments of the long cones lay far more sclerad compared with the outer segments of the bifid cones. Microspectrophotometry revealed that in both species the lateral components of the triple cones displayed a maximum absorbance wavelength (lambda(max)) of approximately 502nm, while the short central components were more shortwave sensitive (lambda(max)=475nm). The lambda(max) of all long and short cones in the ventro-temporal zone was 492nm, compared to 502nm in other retinal regions. Anchovies are unique among vertebrates in that they contain clear structural basis for both colour and polarisation vision in the same retina. PMID- 22819728 TI - Spatial summation properties of the human ocular following response (OFR): dependence upon the spatial frequency of the stimulus. AB - Ocular following responses (OFRs) are the initial tracking eye movements that can be elicited at ultra-short latency by sudden motion of a textured pattern. The OFR magnitude depends upon stimulus size, and also upon the spatial frequency (SF) of sine-wave gratings. Here we investigate the interaction of size and SF. We recorded initial OFRs in human subjects when 1D vertical sine-wave gratings were subject to horizontal motion. Gratings were restricted to elongated horizontal apertures-"strips"-aligned with the axis of motion. In Experiment 1 the SF and the height of a single strip was manipulated. The magnitude of the OFR increased with strip height up to some optimum value, while strip heights greater than this optimum produced smaller responses. This effect was strongly dependent on SF: the optimum strip height was smaller for higher SFs. In order to explore the underlying mechanism, Experiment 2 measured OFRs to stimuli composed of two thin horizontal strips-one in the upper visual field, the other in the lower visual field-whose vertical separation varied 32-fold. Stimuli of different sizes can be reconstructed from the sum of such horizontal strips. We found that the OFRs in Experiment 1 were smaller than the sum of the responses to the component stimuli, but greater than the average of those responses. We defined an averaging coefficient that described whether a given response was closer to the sum or to the average. For any one SF, the averaging coefficients were similar over a wide range of stimulus sizes, while they varied considerably (7-fold) for stimuli of different SFs. PMID- 22819729 TI - The transfer of object learning across exemplars and their orientation is related to perceptual similarity. AB - Recognition of objects improves after training. The exact characteristics of this visual learning process remain unclear. We examined to which extent object learning depends on the exact exemplar and orientation used during training. Participants were trained to name object pictures at as short a picture presentation time as possible. The required presentation time diminished over training. After training participants were tested with a completely new set of objects as well as with two variants of the trained object set, namely an orientation change and a change of the exact exemplar shown. Both manipulations led to a decrease in performance compared to the original picture set. Nevertheless, performance with the manipulated versions of the trained stimuli was better than performance with the completely new set, at least when only one manipulation was performed. Amount of transfer to new images of an object was related to perceptual similarity, but not to pixel overlap or to measurements of similarity in the different layers of a popular hierarchical object recognition model (HMAX). Thus, object learning generalizes only partially over changes in exemplars and orientation, which is consistent with the tuning properties of neurons in object-selective cortical regions and the role of perceptual similarity in these representations. PMID- 22819730 TI - Interaction of first- and second-order signals in the extraction of global-motion and optic-flow. AB - The intention of this series of experiments was to determine the extent to which the pathways sensitive to first-order and second-order motion are independent of one another at, and above, the level of global motion integration. We used translational, radial and rotational motion stimuli containing luminance modulated dots, contrast-modulated dots, or a mixture of both. Our results show that the two classes of motion stimuli interact perceptually in a global motion coherence task, and the extent of this interaction is governed by whether the two varieties of local motion signal produce an equivalent response in the pathways that encode each type of motion. This provides strong psychophysical evidence that global motion and optic flow processing are cue-invariant. The fidelity of the first-order motion signal was moderated by either reducing the luminance of the dots or by increasing the displacement of the dots on each positional update. The experiments were carried out with two different types of second-order elements (contrast-modulated dots and flicker-modulated dots) and the results were comparable, suggesting that these findings are generalisable to a variety of second-order stimuli. In addition, the interaction between the two different types of second-order stimuli was investigated and we found that the relative modulation depth was also crucial to whether the two populations interacted. We conclude that the relative output of local motion sensors sensitive to either first-order or second-order motion dictates their weight in subsequent cue invariant global motion computations. PMID- 22819731 TI - Sex ratios of Dirofilaria immitis in naturally infected dogs show female bias at low worm intensities. AB - Sex ratios in invertebrates commonly deviate from parity (1:1). Various genetic and epigenetic factors distort sex ratios to favor males or females. We examined sex ratios in Dirofilaria immitis (heartworms) obtained from naturally-infected dogs. Dirofilaria from 84 naturally-infected pound-source dogs were extracted at necropsy, counted and sexed. Dogs had a median worm intensity of 15 filariae. Overall, sex ratios equaled 1. However, at low worm intensities, dogs were more likely to have female than male worms. Of eight unisex infections, seven were all female (range 1-11 worms), while only one dog had a single male worm. Similarly, in mixed-sex infection at worm intensities<20 worms, dogs were more likely to have more female worms than male worms. Our results suggest that sex disequilibrium exists in D. immitis at lower worm intensities, but disappears with higher worm intensities. Reasons for this disequilibrium are unknown, but presumably confer a species survival advantage. PMID- 22819732 TI - Bacterial isolates from the urine of cattle affected by urothelial tumors of the urinary bladder. AB - Microbiological investigations were performed on urine samples from 108 cows affected by urothelial tumors of the urinary bladder. Bacteria, frequently of mixed population, were isolated from 100 animals. Gram-positive bacteria prevailed, with Staphylococcus spp. and Bacillus spp. being the most common. Escherichia coli and Acinetobacter spp. were the most frequently recovered Gram negative bacteria. E5 oncoprotein was detected in 86 of the 108 urothelial tumors under study. In the majority of cases, bacterial agents and BPV-2 E5 were simultaneously detected. A marked down-regulation of Tamm-Horsfall protein was also observed in the examined cases. In addition, the p65 subunit of the nuclear factor-kappaB (NF-kappaB) transcription factor appeared to be overexpressed. In all cases, a mild to severe chronic inflammation was evident in the stroma of urinary bladder tumors. Bacterial components may play a role in the activation of the NF-kappaB and might cause chronic inflammation resulting in an impaired ability to clear BPV-2 infection, thus cooperating with the virus in cancer development. As in man, therefore, bacteria could play both a direct and an indirect role in bovine bladder carcinogenesis. PMID- 22819733 TI - Recruitment of dental pulp cells by dentine and pulp extracellular matrix components. AB - The present study aimed to determine whether dentine tissue and preparations of extracellular matrix (ECM) from pulp (pECM) and dentine (dECM), and breakdown products, influenced pulp cell migration. Chemotaxis transwell and agarose spot assays demonstrated that both dentine and pulp ECM molecules acted as chemoattractants for primary pulp cells. Chemoattractant activities of dECM and pECM were enhanced when subjected to acid and enzymatic breakdown, respectively. This enhanced activity following physiologically relevant breakdown may be pertinent to the disease environment. Pulp cell migration in response to dental ECMs was dependent on an active rho pathway. Recruited cells exhibited increased stem cell marker expression indicating that dental ECMs and their breakdown products selectively attract progenitor cells that contribute to repair processes. In conclusion, combined these results indicate that ECM molecules contribute to cell recruitment necessary for regeneration of the dentine-pulp complex after injury. PMID- 22819734 TI - A selection platform for carbon chain elongation using the CoA-dependent pathway to produce linear higher alcohols. AB - Production of green chemicals and fuels using metabolically engineered organisms has been a promising alternative to petroleum-based production. Higher chain alcohols (C4-C8) are of interest because they can be used as chemical feedstock as well as fuels. Recently, the feasibility of n-hexanol synthesis using Escherichia coli has been demonstrated by extending the modified Clostridium CoA dependent n-butanol synthesis pathway, thereby elongating carbon chain length via reactions in reversed beta-oxidation, (or beta-reduction). Here, we developed an anaerobic growth selection platform that allows selection or enrichment of enzymes for increased synthesis of C6 and C8 linear alcohols. Using this selection, we were able to improve the carbon flux towards the synthesis of C6 and C8 acyl-CoA intermediates. Replacement of the original enzyme Clostridium acetobutylicum Hbd with Ralstonia eutropha homologue PaaH1 increased production of n-hexanol by 10-fold. Further directed evolution by random mutagenesis of PaaH1 improved n-hexanol and n-octanol production. This anaerobic growth selection platform may be useful for selecting enzymes for production of long chain alcohols and acids using this CoA-dependent pathway. PMID- 22819736 TI - "Not all my fault": genetics, stigma, and personal responsibility for women with eating disorders. AB - Medical researchers and clinicians increasingly understand and present eating disorders (anorexia and bulimia nervosa) as biologically-based psychiatric disorders, with genetic risk factors established by high heritability estimates in twin studies. But there has been no research on interpretation of genetic involvement by people with eating disorders, who may hold other views. Their interpretations are particularly important given the frequent presumption that biogenetic framing will reduce stigma, and recent findings that it exacerbates stigma for other mental illnesses. To identify implications of genetic framing in eating disorders, I conducted semi-structured interviews with 50 US women with a history of eating disorders (half recovered, half in treatment; interviewed 2008 9 in the USA). Interviews introduced the topic of genetics, but not stigma per se. Analysis followed the general principles of grounded theory to identify perceived implications of genetic involvement; those relevant to stigma are reported here. Most anticipated that genetic reframing would help reduce stigma from personal responsibility (i.e., blame and guilt for eating disorder as ongoing choice). A third articulated ways it could add stigma, including novel forms of stigma related to genetic-essentialist effacing of social factors. Despite welcoming reductions in blame and guilt, half also worried genetic framing could hamper recovery, by encouraging fatalistic self-fulfilling prophecies and genetic excuses. This study is the first to elicit perceptions of genetic involvement by those with eating disorders, and contributes to an emerging literature on perceptions of psychiatric genetics by people with mental illness. PMID- 22819735 TI - Delay discounting and intake of ready-to-eat and away-from-home foods in overweight and obese women. AB - A shift from home-prepared to away-from-home and ready-to-eat foods has occurred in recent decades, which has implications for obesity and health. This study tested whether delay discounting, a facet of impulsivity reflecting sensitivity to immediate reward, is associated with the frequency of consumption and typical amount consumed of home-prepared, away-from-home, and ready-to-eat foods among overweight and obese women. Seventy-eight participants completed a binary choice task assessing discounting of delayed monetary rewards. Nutrient analysis of weighed food records characterized dietary intake over seven consecutive days. Foods were categorized as home-prepared, away-from-home, or ready-to-eat by a registered dietitian from information provided by participants. Delay discounting was not associated with the frequency of consuming home-prepared, away-from-home, and ready-to-eat foods as reflected in the percentages of recorded foods or total energy intake from each category. However, once consuming away-from-home and ready-to-eat foods (but not home-prepared foods), impulsive women consumed more energy than less impulsive women. Exploratory analyses indicated that more impulsive women chose away-from-home foods with a higher energy density (kcal/g). Impulsivity was associated with the quantity of away-from-home and ready-to-eat foods consumed, but not the frequency of their consumption. Home food preparation may be critical to weight control for impulsive individuals. PMID- 22819737 TI - How complexity science can inform scale-up and spread in health care: understanding the role of self-organization in variation across local contexts. AB - Health care systems struggle to scale-up and spread effective practices across diverse settings. Failures in scale-up and spread (SUS) are often attributed to a lack of consideration for variation in local contexts among different health care delivery settings. We argue that SUS occurs within complex systems and that self organization plays an important role in the success, or failure, of SUS. Self organization is a process whereby local interactions give rise to patterns of organizing. These patterns may be stable or unstable, and they evolve over time. Self-organization is a major contributor to local variations across health care delivery settings. Thus, better understanding of self-organization in the context of SUS is needed. We re-examine two cases of successful SUS: 1) the application of a mobile phone short message service intervention to improve adherence to medications during HIV treatment scale up in resource-limited settings, and 2) MRSA prevention in hospital inpatient settings in the United States. Based on insights from these cases, we discuss the role of interdependencies and sensemaking in leveraging self-organization in SUS initiatives. We argue that self-organization, while not completely controllable, can be influenced, and that improving interdependencies and sensemaking among SUS stakeholders is a strategy for facilitating self-organization processes that increase the probability of spreading effective practices across diverse settings. PMID- 22819738 TI - The impact of gender on in-hospital outcomes after carotid endarterectomy or stenting. AB - AIM: We sought to better define the impact of sex on 'in-hospital outcomes' after carotid endarterectomy (CEA) or stenting (CAS). METHODS: Hospital discharge databases for all carotid interventions obtained from the New York State (NYS) Department of Health, Statewide Planning and Research Cooperative System between 2000 and 2009 (29,917 women, 39,771 men) were analysed. Mortality, stroke and composite event (stroke/death) were compared between procedures after matching of patients by propensity score. Acute myocardial infarction (AMI) was our secondary 'end' point. RESULTS: More than 90% of patients in both sexes were asymptomatic (27,439 women and 36,295 men). Compared to men, asymptomatic women experienced more strokes after CEA (women: 1.38%, men: 1.16%, P = 0.03) and higher AMI rates after both procedures (CEA; women: 0.75%, men: 0.51%, P = 0.0009, CAS; women: 0.96%, men: 0.28%, P = 0.01). Between procedures, symptomatic women undergoing CAS showed higher rates of mortality (CAS: 4.19%, CEA: 0.47%, P = 0.01) and combined (stroke/mortality) events (CAS: 12.09%, CEA: 6.05%, P = 0.02). In all other cohorts, no statistically significant difference was found between the procedures. CONCLUSIONS: Compared to CEA, CAS led to inferior in-hospital outcomes only in symptomatic women in the last decade in NYS. Men and asymptomatic women showed comparable outcomes after both procedures, whereas asymptomatic females were more prone to AMI after both interventions. These sex associated differences should be taken into account for the treatment of carotid artery disease. PMID- 22819739 TI - No benefit from carotid intervention in fatal stroke prevention for >80-year-old patients. AB - BACKGROUND: Invasive management of patients >=80 years of age with carotid stenosis may be questionable. The higher likelihood of stroke needs to be balanced with the increased perioperative risk and the reduced life expectancy of this ageing population. The purpose of this study was to evaluate the clinical relevance of carotid stenosis revascularisation in octogenarians. METHODS: All patients >=80 years of age who received carotid revascularisation in 2001-2010 were reviewed for perioperative and 5-year outcomes. The experience was comprehensive of carotid endarterectomy (CEA) and carotid stenting (CAS) performed during the training frame when age was not a contraindication for this procedure. Mortality rates were compared to those of octogenarians of the same geographical territory according to all-cause and stroke-related mortality national statistics datasets. RESULTS: A total of 348 procedures performed in >=80-year-old patients (272 males) were reviewed: 162 (46.6%) were by CAS and 169 (48.6%) were for symptomatic disease. Perioperative stroke/death rate was 5.5% and was non-significantly higher for symptomatic disease (7.1% vs. 3.9% asymptomatic; p = 0.24), after CAS (6.2% vs. 4.8% CEA; p = 0.64) and in females (6.6% vs. 5.1% males; p = 0.57). At median follow-up of 36.18 months, 95 deaths and 21 new ischaemic strokes (12 fatal) occurred with 5-year Kaplan-Meier freedom from stroke of 84.8% (78.7%, symptomatic vs. 90.3% asymptomatic; p = 0.003). According to national datasets, in 80-85-year-old resident population 5-year mortality was 29.9% (23.4% females, 40.6% males) and ischaemic stroke-related mortality was 14.9% (16.8% females, 13.0% males). Corresponding figures from treated population showed a 5-year mortality of 49.4%, higher in males (39.5% females, 52.5% males) and ischaemic stroke-related mortality of 20.2%, higher in females (40.0% females, 15.6% males). Comparing data from the study population with residents' figures, ischaemic stroke-related mortality hazard was significantly higher in the study females: odds ratio (OR) 3.2, 95% confidence interval (CI) 1.16-9.17; p = 0.029 (for males: OR 0.97, 95%CI 0.89-1.10; p = 0.99). CONCLUSIONS: Despite perioperative stroke/death risks being lower compared with CAS, the benefit of surgical carotid revascularisation in old patients remains controversial due to limited life expectancy and high fatality of stroke in this ageing population. Invasive treatment of carotid stenosis may not be warranted in most patients >=80 years of age with carotid stenosis, especially when female and asymptomatic. PMID- 22819740 TI - Anchoring barbs and balloon expandable stents: what is the risk of perforation and failed stent deployment? AB - PURPOSE: Balloon expandable stents may on occasion be deployed in close proximity to the anchoring barbs of endovascular grafts. The aim of this study was to determine the risk and effect of balloon perforation by anchoring barbs and to assess whether these risks are different if the balloon is protected by a covered stent mounted upon it. METHODS: A bench-top model was developed to mimic the penetration of anchoring barbs into the lumen of medium sized blood vessels. The model allowed variation of angle and depth of vessel penetration. Both bare balloons and those with covered stents mounted upon them were tested in the model to determine whether there was a risk of perforation and which factors increased or decreased this risk. RESULTS: All combinations of barb angle and depth caused balloon perforation but this was most marked when the barb was placed perpendicular to the long axis of the balloon. When the deployment of covered stents was attempted balloon perforation occurred in some cases but full stent deployment was achieved in all cases where the perforation was in the portion of the balloon covered by the stent. The only situation in which stent deployment failed was where the barb was intentionally placed in the uncovered portion of the balloon. This resulted in only partial deployment of the stent. CONCLUSIONS: Balloon rupture is a distinct possibility when deploying balloon-expandable stents in close proximity to anchoring barbs. Care should be taken in this circumstance to ensure that the barb is well away from the uncovered portion of the balloon. PMID- 22819741 TI - High compression pressure over the calf is more effective than graduated compression in enhancing venous pump function. AB - BACKGROUND: Graduated compression is routinely employed as standard therapy for chronic venous insufficiency. AIM: The study aims to compare the haemodynamic efficiency of a multi-component graduated compression bandage (GCB) versus a negative graduated compression bandage (NGCB) applied with higher pressure over the calf. METHODS: In 20 patients, all affected by greater saphenous vein (GSV) incompetence and candidates for surgery (Clinical, etiologic, anatomic and pathophysiologic data, CEAP C2-C5), the ejection fraction of the venous calf pump was measured using a plethysmographic method during a standardised walking test without compression, with GCB and NGCB, all composed of the same short-stretch material. Sub-bandage pressures were measured simultaneously over the distal leg and over the calf. RESULTS: NGCBs with median pressures higher at the calf (62 mmHg) than at the distal leg (50 mmHg) achieved a significantly higher increase of ejection fraction (median +157%) compared with GCB, (+115%) with a distal pressure of 54 mmHg and a calf pressure of 28 mmHg (P < 0.001). CONCLUSIONS: Patients with severe venous incompetence have a greater haemodynamic benefit from NGCB, especially during standing and walking, than from GCB. PMID- 22819742 TI - Serial change and its determinants of residual plaque characteristics under sirolimus-eluting stent: a coronary angioscopic study. AB - OBJECTIVES: To examine serial change in the residual plaque behind the sirolimus eluting stent (SES) using coronary angioscopy in patients with SES implantation and to identify its baseline determinants. BACKGROUND: Previous coronary angioscopic studies have demonstrated that SES enhances the yellow grade of residual plaque during follow-up period. METHODS: A total of 42 patients with stable angina pectoris or silent ischemic heart disease, who had a successful SES implantation were examined by coronary angioscopy both at the baseline (SES implantation) and the follow-up period (9-14 month follow-up). The patients were divided into three groups as: worsened group (WS: yellow color grade of coronary plaque at the follow-up period was worsened compared to the baseline period, n=15), no change group (NP: no change compared to the baseline, n=16), and improved group (IP: improved compared to the baseline, n=11). Then, the determinants of the nominal change of yellow color grade were examined by multiple regression analysis. RESULTS: The low-density lipoprotein cholesterol (LDL-C) level in IP group at the follow-up was significantly decreased compared to baseline (from 120.0+/-29.8mg/dl to 74.3+/-16.7mg/dl, p=0.0005), and was the lowest among three groups (WS: 103.5+/-16.4mg/dl, NC: 105.7+/-18.7mg/dl, and IP: 74.3+/-16.7mg/dl). Multiple regression analysis revealed that family history, statin administration, baseline serum creatinine, baseline 'in-stent' thrombus, and follow-up LDL-C were significant determinants to the nominal change of yellow color grade after the SES implantation (p<0.0001). CONCLUSIONS: Serial change in tissue characteristics within residual plaque under SES is determined by several factors, especially LDL-C level as well as statin administration. Adequate management of LDL-C by statins might be crucial for stabilizing residual plaque after SES implantation. PMID- 22819743 TI - Structure, mechanism and inhibition of Golgi alpha-mannosidase II. AB - The mature N-glycan on human glycoproteins is built up by the activity and regulation of enzymes in the endoplasmic reticulum and Golgi apparatus. A key enzyme in the maturation of N-glycans is the first glycoside hydrolase in the Golgi pathway, alpha-mannosidase II (GMII). This enzyme has the unusual ability to cleave two different glycosidic linkages in it catalytic center. As such, it removes two terminal mannoses following the activity of N-acetyl-glucosaminyl transferase I, and is a critical step in the formation of mature glycans. Structural analyses of the Drosophila homologue of GMII have led to insights into its unusual mechanism and substrate specificity. In addition, the results build the foundation for the development of specific clinically relevant inhibitors. PMID- 22819744 TI - Advances in communication technology: implications for new nursing skills. PMID- 22819745 TI - Benzocaine-induced methemoglobinemia in the pediatric population. PMID- 22819746 TI - Centering autism within the family: a qualitative approach to autism and the family. AB - The lived experience of parents of children with autism living in a rural area was explored through a phenomenological approach. Twenty-eight parents from multiple rural communities participated in semi-structured interviews. Van Manen's (1990) selective highlighting approach was used to isolate thematic statements of the experience. Findings revealed that autism became centered within the family thereby affecting how parents parented. Parenting now included: (a) multiple roles; (b) an intense focus on their child's needs; and (c) finding a balance. Although parents acquired multiple roles and faced many unmet needs, parents were determined to strive for balance within the family. PMID- 22819748 TI - Improving the lives of children and their families-integrating clinical research into everyday pediatric nursing practice. PMID- 22819747 TI - Active and passive distraction in children undergoing wound dressings. AB - The aim of this study was to test how distraction influences pain, distress and anxiety in children during wound care. Sixty participants aged 5-12 years were randomized to three groups: serious gaming, the use of lollipops and a control group. Self-reported pain, distress, anxiety and observed pain behaviour were recorded in conjunction with wound care. Serious gaming, an active distraction, reduced the observed pain behaviour and self-reported distress compared with the other groups. A sense of control and engagement in the distraction, together, may be the explanation for the different pain behaviours when children use serious gaming. PMID- 22819749 TI - Periprocedural outcomes after surgical revascularization and stenting for postradiotherapy carotid stenosis. AB - BACKGROUND: Treatment of head and neck malignancy commonly involves radiotherapy, which is associated with the development of carotid artery stenosis. There is little evidence to guide clinicians on how to intervene in significant postradiotherapy carotid stenosis. This systematic review collated data pertaining to perioperative outcomes of carotid artery surgery and carotid stenting in postradiotherapy carotid stenosis to aid the clinical decision-making process. METHODS: A systematic review of the literature, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines, was performed. We screened 575 articles related to carotid artery surgery or stenting in postradiotherapy carotid stenosis, from which 21 studies were included for quantitative analysis. The primary outcome was stroke or death <= 30 days of the procedure. Secondary outcomes included cranial nerve injury, restenosis, stroke, and death at >30 days. RESULTS: Nine publications recorded 211 surgical procedures in 179 patients. In symptomatic patients, the 30-day mortality rate was 2.6% and the stroke or death rate was 2.7%. In asymptomatic patients, the 30-day mortality rate was 0% and the stroke or death rate was 1.1%. Permanent cranial nerve palsy was experienced by 0.6% of patients. Twelve publications recorded 510 carotid artery stenting procedures in 482 patients. In symptomatic patients, the 30-day mortality rate was 5.1%, and the stroke or death rate was 5.1%. In asymptomatic patients, the 30-day mortality rate was 1.4%, and the stroke or death rate was 2.1%. There was no statistically significant difference in 30-day stroke or death rate between surgical revascularization and carotid artery stenting in all (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.17-1.70; P = .43), symptomatic (OR, 0.52; 95% CI, 0.14-1.98; P = .38), or asymptomatic patients (OR, 0.55; 95% CI, 0.06-5.42; P = .99). CONCLUSIONS: The published outcomes from high-volume centers demonstrate that surgical revascularization and stenting are both technically feasible in postradiotherapy carotid stenosis and have similar safety profiles to nonirradiated necks. Radiation should therefore not be considered a contraindication to surgical intervention. PMID- 22819750 TI - Late expulsion of a Dacron patch after carotid endarterectomy. AB - Patch angioplasty using synthetic materials such as Dacron and polytetrafluoroethylene has become the standard of care after carotid endarterectomy. This method has been shown to reduce recurrent stenosis and stroke as compared to primary closure. Complications, including infection and pseudoaneurysm, are very rare. Another complication that has been described in two case reports to date is the late rejection of a polytetrafluoroethylene patch. We present the first reported case of a late Dacron patch expulsion 4 years after carotid endarterectomy. The patient was managed conservatively after a selective carotid arteriogram demonstrated no evidence of stenosis or pseudoaneurysm formation. PMID- 22819751 TI - Extracranial-intracranial bypass: resurrection of a nearly extinct operation. AB - BACKGROUND: Giant intracranial artery aneurysms (GIAAs) are often not amenable to neurosurgical clipping or endovascular coiling. Extracranial-intracranial (EC-IC) bypass, a procedure that has been essentially abandoned for the treatment of intracranial ischemic disease, followed by parent vessel occlusion, is often successful in treating these aneurysms. Vascular surgeons should be familiar with this operation, especially in centers with neurosurgical capability. METHODS: A retrospective review of patients treated from 1990 to 2010 at New York University Medical Center was performed. Office and hospital records of all patients identified were reviewed with attention to the age and sex of the patient, presenting symptoms, preoperative testing, procedure performed, type of bypass conduit, graft patency, intraoperative and postoperative complications, length of follow-up, and overall outcome. EC-IC bypass was performed using a graft of great saphenous vein (GSV) or radial artery (RA). The vascular surgeon harvested the vascular conduit, tunneled the graft, and performed the extracranial anastomosis, and the intracranial anastomosis was performed by the neurosurgeon. RESULTS: A total of 36 patients (14 men, 22 women) underwent 37 EC-IC bypasses with 34 GSV and three RA grafts. The median age was 57 years (interquartile range, 49-66 years), and the median follow-up was 53 months (interquartile range, 29-77 months). Aneurysm location was the internal carotid artery in 30 patients, the basilar artery in three, and the middle cerebral artery in four. All 37 aneurysms were excluded from the cerebral circulation, with 33 grafts remaining patent at follow-up, as determined by serial cerebral or magnetic resonance angiogram. At follow-up, 33 of 34 of the GSV grafts (88%) and three of three (100%) of the RA grafts were patent. There were two deaths (5.6%), despite patent grafts. Postoperative graft occlusion led to homonymous hemianopsia in one patient and temporary hemiparesis in another (5.6%). Graft occlusions were asymptomatic in two patients. CONCLUSIONS: EC-IC bypass is a safe and effective treatment for GIAAs, with acceptable rates of morbidity (5.6%), mortality (5.6%), and graft patency (89.2%). We suggest that the technique described in this report should be routinely used for treatment of GIAAs in centers where neurosurgery and vascular surgery services are available and should be considered a standard procedure in the armamentarium of the vascular surgeon. PMID- 22819752 TI - Nutcracker syndrome due to left-sided inferior vena cava compression and treated with superior mesenteric artery transposition. AB - Left renal vein hypertension secondary to left renal vein compression has been described as a cause of persistent hematuria in nutcracker syndrome. Malformation of the inferior vena cava (IVC), although rare and frequently asymptomatic, may also result in left renal vein hypertension, with resultant hematuria when it is severely compressed. We report a 20-year-old man with persistent hematuria due to compression of left-sided IVC. The patient was successfully treated by means of superior mesenteric artery (SMA) transposition and division of the fibrous bundle at the origin of the SMA. His postoperative course was uneventful. Compression of the left IVC is a unique form of nutcracker syndrome. SMA transposition, together with division of a fibrous bundle at the origin of the SMA if present, is a safe and effective surgical procedure for this special entity. PMID- 22819753 TI - Hybrid repair of a Kommerell diverticulum associated with a right aortic arch and a left descending aorta. AB - This report describes the first successful case of a hybrid endovascular approach for management of aneurysmal Kommerell diverticulum arising from the left descending aorta in a right aortic arch. This patient also had dilatation of the ascending aorta and a small aortic arch aneurysm. This three-step procedure consisted of (1) ascending aorta replacement with total debranching using a handmade quarto-branched composite graft; (2) endovascular exclusion of Kommerell diverticulum and the aortic arch aneurysm by covering the whole aortic arch; and (3) coil embolization against the root of the left subclavian artery. The patient had no complications at 16 months after completion. PMID- 22819754 TI - The impact of diabetes on postoperative outcomes following lower-extremity bypass surgery. AB - OBJECTIVE: The effect of diabetes type (noninsulin dependent vs insulin dependent) on outcomes after lower-extremity bypass (LEB) has not been clearly defined. Therefore, we analyzed associations between diabetes type and outcomes after LEB in patients with critical limb ischemia. METHODS: We performed a retrospective analysis of 1977 infrainguinal LEB operations done for critical limb ischemia between 2003 and 2010 within the Vascular Study Group of New England. Patients were categorized as nondiabetic (ND), noninsulin-dependent diabetic (NIDD), or insulin-dependent diabetic (IDD) based on their preoperative medication regimen. Our main outcome measures were in-hospital mortality and major adverse events (MAEs)--a composite outcome, including myocardial infarction, dysrhythmia, congestive heart failure, wound infection, renal insufficiency, and major amputation. We compared crude and adjusted rates of mortality and MAEs using logistic regression across diabetes categories. RESULTS: Overall, 41% of patients were ND, 28% were NIDD, and 31% were IDD. Crude rates of in-hospital mortality were similar across these groups (1.7% vs 3.1% vs 2.1%; P = .211). Adjusted analyses accounting for differences in patient characteristics showed that diabetes is not associated with increased risk of in-hospital mortality. However, type of diabetes was associated with a higher risk of MAEs in both crude (15.1% for ND; 21.1% for NIDD; and 25.2% for IDD; P < .001) and adjusted analyses (odds ratio for NIDD, 1.41; 95% confidence interval, 1.2-1.7; odds ratio for IDD, 1.53; 95% confidence interval, 1.3-1.8). CONCLUSIONS: Diabetes is a significant contributor to the risk of postoperative complications after LEB surgery, and insulin dependence is associated with higher risk. Quality measures aimed at limiting complications after LEB may have the most impact if these initiatives are focused on patients who are IDD. PMID- 22819755 TI - Intervention for intracranial atherosclerosis after SAMMPRIS. PMID- 22819756 TI - Developmental programs are kept alive during adulthood by stem cells: the aging aspect. AB - Stem cells are fundamental for life-long preservation of cellular somatic maintenance. Tissue-borne stem cells replenish worn-out critical elements. Provided they remain fit over lifetime, enduring stem cell activities avert the emergence of age-associated chronic degenerative diseases and pathologies. Although experimentally still unclear, it is assumed that stem cells reside in protected niches. Freshly isolated mesenchymal stem cells exhibit donor-specific aberrations, which cannot solely be ascribed to differences in genetic background. Besides inevitably accumulating intrinsic modifications, the systemic environment also impacts on basic properties of mesenchymal stem cells such as their inherent multi-lineage differentiation potential. Chronic systemic aberrations over time comprise unwholesome influences, in particular in terms of regeneration and repair when stem cells recapitulate distinct developmental programs. During or thereafter, stem cells can diversify either because of insufficiently silencing activated building cycles, or by acquiring epigenetic deviations. PMID- 22819757 TI - Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents. AB - Restriction of dietary methionine by 80% slows the progression of aged-related diseases and prolongs lifespan in rodents. A salient feature of the methionine restriction phenotype is the significant reduction of adipose tissue mass, which is associated with improvement of insulin sensitivity. These beneficial effects of MR involve a host of metabolic adaptations leading to increased mitochondrial biogenesis and function, elevated energy expenditure, changes of lipid and carbohydrate homeostasis, and decreased oxidative damage and inflammation. This review summarizes observations from MR studies and provides insight about potential mediators of tissue-specific responses associated with MR's favorable metabolic effects that contribute to health and lifespan extension. PMID- 22819758 TI - Low-grade fibromyxoid sarcoma with prominent giant rosettes and heterotopic ossification. AB - Low-grade fibromyxoid sarcoma is a rare soft tissue sarcoma of fibroblastic differentiation characterized by a deceptively benign morphologic appearance with almost consistent MUC4 expression and recurrent chromosomal translocations, t(7;16)(q34;p11) and t(11;16)(p11;p11), resulting in the FUS-CREB3L2 and FUS CREB3L1 fusion genes, respectively. A subset of the tumors show peculiar histologic features, designated as giant rosettes, and were formerly referred to as hyalinizing spindle cell tumor with giant rosettes. We herein report a case of low-grade fibromyxoid sarcoma showing the presence of numerous giant rosettes, with and without collagenous centers, distributed throughout the lesion and unusual rim-like heterotopic ossification. Such a case might present a diagnostic challenge. The diagnosis of the tumor was confirmed by positive immunoreactivity to MUC4 and the FUS-CREB3L2 fusion detected by molecular testing using formalin fixed, paraffin-embedded tissue. This case, which has such unusual clinicopathologic features, would help to further expand our knowledge regarding the morphologic diversities of low-grade fibromyxoid sarcoma. PMID- 22819759 TI - Interleukin-6 in pregnancy and gestational disorders. AB - IL6 is a multifunctional cytokine with pivotal roles in the inflammatory response and in directing T cell differentiation in adaptive immunity. IL6 is widely expressed in the female reproductive tract and gestational tissues, and exerts regulatory functions in embryo implantation and placental development, as well as the immune adaptations required to tolerate pregnancy. Here, we summarise the current understanding of how membrane-bound and soluble receptors mediate IL6 signalling to regulate leukocytes and non-haemopoietic cells. We review the published literature regarding the expression and actions of IL6 in the uterus, decidua and placenta, and studies implicating this cytokine in pregnancy disorders. Elevated IL6 is frequently evident in the altered cytokine profiles characteristic of unexplained infertility, recurrent miscarriage, preeclampsia and preterm delivery. Notably, there is compelling evidence indicating altered systemic IL6 trans-signalling in women prone to recurrent miscarriage, with excessive IL6 bioavailability potentially inhibiting generation of CD4+ T regulatory cells required for pregnancy tolerance. Insufficient local IL6 may also contribute to fetal loss, since IL6 expression is reduced in the endometrium of women with recurrent miscarriage, and in the fetal-placental tissue of CBA*DBA/2 mice. Consistent with the role of IL6 in key reproductive events, Il6 null mutant mice exhibit elevated fetal resorption and delayed parturition. Investigation of the association between IL6 signalling components and T cell responses in pregnant women, as well as detailed analysis of the maternal immune response in IL6-deficient mice, is now required to define the mechanisms by which this cytokine exerts influence on reproductive success. PMID- 22819761 TI - Complete androgen insensitivity syndrome associated with bilateral Sertoli cell adenomas and paratesticular leiomyomas: case report and review of the literature. AB - BACKGROUND: Complete androgen insensitivity syndrome (CAIS) is a rare and usually unexpected cause of primary amenorrhoea that results from receptor resistance to androgens, producing a female phenotype in genetically male patients. CASE: A 16 year-old girl was diagnosed with CAIS after investigations for primary amenorrhoea. Her left inguinal gonad and the right intra-abdominal gonad were resected and histopathology revealed the presence of dysgenetic multinodular testes with absence of germ cells, significant hyperplasia of Sertoli cells (Sertoli cell adenoma) and presence of paratesticular leiomyomas. CONCLUSION: Although the risk of gonadal tumour development is considered to be low, a variety of tumours have been described in association with CAIS, but this is the first report of development of bilateral paratesticular leiomyomas developing concurrently with Sertoli cell adenomas. PMID- 22819760 TI - Duplex system ureterocele in infants: should we reconsider the indications for secondary surgery after endoscopic puncture or partial nephrectomy? AB - OBJECTIVE: We assessed outcomes and need for secondary surgery after primary trans-urethral puncture (TUP) or upper pole partial nephrectomy (UPPN) in duplex system ureterocele (DSU) patients undergoing management that disregards vesicoureteral reflux and upper pole function. SUBJECTS AND METHODS: Between 2003 and 2010, 41 DSU <1 year underwent TUP (n = 32) or UPPN (n = 9). Postoperatively, additional investigations and surgery were limited to cases showing persistent hydroureteronephrosis or developing recurrent febrile urinary tract infections (UTI). Outcome parameters included upper tract decompression, UTI after decompression, continence status, and secondary surgery rate. Preoperative variables were compared between patients who required secondary surgery and those who did not. RESULTS: Additional surgery was required for persistent hydroureteronephrosis in 20% of cases after TUP vs none after UPPN. After decompression, 4 female patients developed recurrent febrile UTI and 2 required additional surgeries. No case suffered from urinary incontinence. After a median (range) follow-up of 46 (17-102) months, TUP or UPPN was the only surgery required in 32 (78%) cases irrespective of preoperative variables. CONCLUSION: UPPN seems more effective than TUP in decompressing severely dilated urinary tracts. After decompression, disregarding VUR status and upper pole function, TUP or UPPN is the only procedure required in 80% of DSU cases, regardless of preoperative variables. PMID- 22819762 TI - Development of 'DFG-out' inhibitors of gatekeeper mutant kinases. AB - HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors. PMID- 22819763 TI - A substituted 3,4-dihydropyrimidinone derivative (compound D22) prevents inflammation mediated neurotoxicity; role in microglial activation in BV-2 cells. AB - A novel synthetic 3,4-dihydropyrimidinone derivative, compound D22 (ethyl 6 methyl-4-(3-phenoxyphenyl)-2-thioxo-3,4-dihydropyrimidine-5-carboxylate), was found to exert anti-inflammatory properties in lipopolysaccharide-stimulated microglial BV-2 cells. Compound D22 reduced the pro-inflammatory factors such as nitric oxide, prostaglandin E(2), tumor necrosis factor-alpha and interleukin 1beta. Moreover, it suppressed the expressions of inducible NO synthase and cyclooxygenase-2. Compound D22 inhibited the activation of mitogen-activated protein kinases. When compound D22-conditioned media from BV-2 cells were applied to N2a cells, neuronal cell death was inhibited via suppression of caspase-3 activation and regulation of Bcl-2 and Bax proteins expression. These results suggest that compound D22 may be useful for treating neurodegenerative diseases related with neuroinflammation. PMID- 22819764 TI - Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR. AB - Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474). PMID- 22819765 TI - Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-pyrano-[2,3-b]naphthoquinones with anticancer activity. AB - 4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses. PMID- 22819766 TI - SAR studies around a series of triazolopyridines as potent and selective PI3Kgamma inhibitors. AB - Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kgamma inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kgamma activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kgamma inhibitor with high oral bioavailability and selectivity over PI3Kalpha and PI3Kdelta. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kbeta. PMID- 22819767 TI - Long-term antiviral treatment for recurrent hepatitis C after liver transplantation. AB - BACKGROUND AND AIMS: The management of patients treated for hepatitis C recurrence after liver transplantation and not achieving virological response following treatment with interferon plus ribavirin is controversial. METHODS: A retrospective analysis of the outcomes of 70 patients non-responders to antiviral treatment after liver transplantation was performed. Twenty-one patients (30.0%; Group A) were treated for <= 12 months and 49 (70.0%; Group B) for more than 12 months. RESULTS: The 2 groups were comparable for main demographic, clinical and pathological variables. Median duration of antiviral treatment was 8.2 months in Group A and 33.4 months in Group B. No patient achieved a complete virological response. The 5-year patient hepatitis C-related survival rate was 49.2% in Group A and 88.3% in Group B (P=0.002), while the 5-year graft survival rate was 49.2% in Group A and 85.9% in Group B (P=0.007). The median yearly fibrosis progression rate was 1.21 per year in Group A and 0.40 per year in Group B (P=0.001). CONCLUSIONS: Prolonged antiviral treatment showed an overall beneficial effect in transplanted patients with a recurrent hepatitis C infection and not responding to conventional therapy. The treatment should be continued as long as it is permitted, in order to improve clinical and histological outcomes. PMID- 22819769 TI - Chagasic cardiomyopathy, from acute to chronic: is this mediated by host susceptibility factors? AB - Chronic chagasic cardiomyopathy (CCC) is the main contributor to morbidity and mortality among individuals chronically infected with the protozoan parasite Trypanosoma cruzi. However, cardiomyopathy develops in fewer than one-third of these patients. Among the different mechanisms to explain this variability are environmental factors, T. cruzi genetic diversity, and host susceptibility. CCC is the culmination of a pathologic process with an onset during the acute infection phase. Previous studies of host genetic factors have been limited to a few candidate genes. This review describes the pathologic features of acute and chronic myocarditis and the host susceptibility factors that may contribute to the development of chagasic cardiomyopathy. PMID- 22819768 TI - Human ocular biometry. AB - The aim of this study was to examine growth of the human eye globe and cornea from early in gestation to late in adult life. Globe antero-posterior length, horizontal and vertical diameters, corneal horizontal and vertical (white to white) diameters and posterior pole to limbus distances were measured using digital calipers (+/-0.01 mm) in 541 postmortem eyes. Additional pre- and postnatal data for some of the dimensions were obtained from the literature. All dimensions examined increase rapidly during prenatal development but postnatal growth differs. Growth of globe antero-posterior length, vertical and horizontal diameters as well as corneal vertical and horizontal diameters stops within 1 year after birth. Logistic analysis is consistent with an asymptotic prenatal growth mode and no further growth after its completion around 1 year after birth. Horizontal and vertical globe diameters are the same at all ages but the corneal horizontal diameter is always larger than the vertical diameter. No differences could be detected between males and females in any of the ocular dimensions. Globe and corneal growth take place primarily during the prenatal growth mode and dimensions reach their maxima, shortly after birth. It is suggested that cessation of a growth stimulating signal at birth marks the end of the prenatal growth mode and that the small increases over the next year are due to cells already stimulated. Male and female eyes of the same age have the same globe and cornea dimensions. PMID- 22819770 TI - Pyomyositis in the upper Negro river basin, Brazilian Amazonia. AB - Pyomyositis remains poorly documented in tropical Latin America. We therefore performed a retrospective review of cases admitted to a hospital in the upper Negro river basin during 2002-2006. Seasonality was assessed by the cosinor model and independent predictors of outcome were identified by logistic regression. Determinants of time-to-fever resolution were analysed using Cox regression. No seasonal trend was observed (p=0.284) among 82 hospitalised patients. The disease predominated in young males and the most commonly affected part of the body was the lower limb (68 [63.5%] out of 107 lesions). Staphylococcus aureus was the only identified infecting organism (18 of 20 culture results, 90%). Complications occurred in 17 patients (20.7%) and the case fatality rate was 2.4%. Children were more likely to present with eosinophilia than adults (OR= 4.20, 95% CI 1.08 16.32, p=0.048), but no other significant differences regarding clinical presentation and outcomes were observed. The time-to-fever resolution was the only independent determinant of poor outcome (OR=1.52, 95% CI 1.22-1.92, p<0.001) and was significantly longer in patients treated with combined antibiotic therapy than in those treated with single antibiotics (HR=0.523, 95% CI 0.296-0.926, p=0.026). Further studies to determine the best antibiotic therapy modality for the treatment of pyomyositis are required. PMID- 22819771 TI - Estrogen blocks the protective action of melatonin in a behavioral model of ethanol-induced hangover in mice. AB - Melatonin has antioxidant and neuroprotective properties in human beings and experimental models, as well as 'anti-estrogenic' effects. Ethanol (EtOH) affects various behavioral parameters during a period known as ethanol-induced hangover. Our study evaluated the neuroprotective effect of melatonin on motor performance during ethanol hangover in male and female Swiss mice. The females were subjected to specific hormonal states: ovariectomized (OVX) and OVX estrogenized (OVX E(2)). Mice received melatonin (25 MUg/ml) or vehicle in their drinking water for seven days and were given intraperitoneal (i.p.) injections of EtOH (3.8 g/kg) or saline on the morning of the eighth day. Motor performance was evaluated by the tightrope test 6h after EtOH exposure (hangover onset). During ethanol hangover, males exhibited lower motor performance than controls (p<0.01) but pretreatment with melatonin significantly improved performance during hangover (p<0.05). In females, melatonin treatment before ethanol-induced hangover led to a better motor performance in OVX compared with intact females (p<0.01) and a lower performance in OVX-E(2) compared with not-estrogenized OVX (p<0.05). Consequently, estrogen reversed the motor performance enhancement afforded by melatonin. We conclude that estrogen interferes with the protective action of melatonin on motor performance during ethanol hangover. PMID- 22819772 TI - Purification and cDNA cloning of a novel neurotoxic peptide (Acra3) from the scorpion Androctonus crassicauda. AB - Androctonus crassicauda is one of the Southeastern Anatolian scorpions of Turkey with ethno-medical and toxicological importance. Two toxic peptides (Acra1 and Acra2) were isolated and characterized from the venom of this scorpion. In this communication, the isolation of an additional toxin (Acra3) by chromatographic separations (HPLC and TSK-gel sulfopropyl) and its chemical and functional characterization is reported. Acra3 is a 7620Da molecular weight peptide, with 66 amino acid residues crosslinked by four disulfide bridges. The gene coding for this peptide was cloned and sequenced. Acra3 is anticipated to undergo post translational modifications at the C-terminal region, having an amidated serine as last residue. Injection of Acra3 induces severe neurotoxic events in mice, such as: excitability and convulsions, leading to the death of the animals within a few minutes after injection. Electrophysiological assays conducted with pure Acra3, using cells that specifically expressed sodium channels (Nav1.1-Nav1.6) showed no clear effect. The exact molecular target of Acra3 remained undiscovered, similar to three other scorpion peptides that clustered very closely in the phylogenetic tree included here. The exact target of these four peptides is not very clear. PMID- 22819773 TI - Dipeptidyl-peptidase-IV by cleaving neuropeptide Y induces lipid accumulation and PPAR-gamma expression. AB - We evaluated the effects of dipeptidyl peptidase-IV (DPPIV), and its inhibitor, vildagliptin, on adipogenesis and lipolysis in a pre-adipocyte murine cell line (3T3-L1). The exogenous rDPPIV increased lipid accumulation and PPAR-gamma expression, whereas an inhibitor of DPPIV, the anti-diabetic drug vildagliptin, suppresses the stimulatory role of DPPIV on adipogenesis and lipid accumulation, but had no effect on lipolysis. NPY immunoneutralization or NPY Y(2) receptor blockage inhibited DPPIV stimulatory effects on lipid accumulation, collectively, indicating that DPPIV has an adipogenic effect through NPY cleavage and subsequent NPY Y(2) activation. Vildagliptin inhibits PPAR-gamma expression and lipid accumulation without changing lipolysis, suggesting that this does not impair the ability of adipose tissue to store triglycerides inside lipid droplets. These data indicate that DPPIV and NPY interact on lipid metabolism to promote adipose tissue depot. PMID- 22819774 TI - GHRH antagonist inhibits focal adhesion kinase (FAK) and decreases expression of vascular endothelial growth factor (VEGF) in human lung cancer cells in vitro. AB - Lung cancers which show increased vascularization and high microvessel density are considered highly metastatic and with poor prognosis. Growth hormone releasing hormone (GHRH) antagonists are anticancer agents without adverse events in lung cancer tumor models. In the present study we investigated the in vitro effect of GHRH antagonist, MZ-5-156, on focal adhesion kinase (FAK) activity, on the expression of MMP-2 and MMP-9 metalloproteinases, as well as on vascular endothelial growth factor (VEGF) levels in A549 non-small cell lung (NSCLC) cancer cells and H727 bronchial carcinoid cells. We demonstrate for the first time that GHRH antagonist, MZ-5-156, inhibits FAK signaling in lung cancer cells and decreases the expression of additional factors involved in angiogenesis and invasion. In contrast, GHRH itself counteracted these effects. Our study contributes to the further understanding of the processes which govern the mechanism of action of GHRH and its antagonists in cancers. PMID- 22819775 TI - Behavior and brain enzymatic changes after long-term intoxication with cadmium salt or contaminated potatoes. AB - This study investigated the cadmium (Cd) intoxication on cognitive, motor and anxiety performance of rats subjected to long-term exposure to diet with Cd salt or with Cd from contaminated potato tubers. Potato plantlets were micropropagated in MS medium and transplanted to plastic trays containing sand. Tubers were collected, planted in sand boxes and cultivated with 0 or 10 MUM Cd and, after were oven-dried, powder processed and used for diet. Rats were divided into six groups and fed different diets for 5 months: control, potato, potato+Cd, 1, 5 or 25 mg/kg CdCl2. Cd exposure increased Cd concentration in brain regions. There was a significant decrease in the step-down latency in Cd-intoxicated rats and, elevated plus maze task revealed an anxiolytic effect in rats fed potato diet per se, and an anxiogenic effect in rats fed 25 mg/kg Cd. The brain structures of rats exposed to Cd salt or Cd from tubers showed an increased AChE activity, but Na+,K+-ATPase decreased in cortex, hypothalamus, and cerebellum. Therefore, we suggest an association between the long-term diet of potato tuber and a clear anxiolytic effect. Moreover, we observed an impaired cognition and enhanced anxiety-like behavior displayed by Cd-intoxicated rats coupled with a marked increase of brain Cd concentration, and increase and decrease of AChE and Na+,K+ ATPase activities, respectively. PMID- 22819777 TI - Maternal antibodies to infectious agents and risk for non-affective psychoses in the offspring--a matched case-control study. AB - BACKGROUND: An increasing number of studies suggest that certain maternal infections are associated with non-affective psychoses in the offspring. Here we investigated if maternal exposure to Toxoplasma gondii, cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) prior to delivery was associated with future diagnosis of schizophrenia or other non-affective psychoses in the offspring. METHODS: This case-control study included 198 individuals born in Sweden 1975-85, diagnosed with schizophrenia (ICD-10, F20) and other non-affective psychoses (ICD-10, F21-29) as in- or outpatients, and 524 matched controls. Specific immunoglobulin G (IgG) levels in archived neonatal dried blood samples from these individuals were determined by immunoassays. Reference levels were determined by prevalences among pregnant women in Sweden 1975-85. Odds ratios (OR) for schizophrenia and other non-affective psychoses were calculated, considering maternal and gestational factors as covariates. RESULTS: Levels of IgG directed at T. gondii corresponding to maternal exposure was associated with subsequent schizophrenia (OR=2.1, 95% CI 1.0-4.5) as were levels of IgG directed at CMV (OR=2.2, 95% CI 1.0-5.1) but not at HSV-1 or -2. There were even stronger associations with higher levels of T. gondii or CMV antibodies. There were no associations between any of the infectious agents and other non-affective psychoses. CONCLUSIONS: This study supports findings of maternal exposure to T. gondii and schizophrenia risk in offspring, and extends the risk to also include maternal exposure to CMV. Future studies should confirm the association with CMV exposure and identify mechanisms underlying these associations. PMID- 22819776 TI - Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1alpha. AB - Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial dynamics contribute to neurodegeneration, including ALS, previous reports remain conflicted. Here, we report an improved technique to isolate, transfect, and culture rat spinal cord motor neurons. Using this improved system, we demonstrate that mutant SOD1(G93A) triggers a significant decrease in mitochondrial length and an accumulation of round fragmented mitochondria. The increase of fragmented mitochondria coincides with an arrest in both anterograde and retrograde axonal transport and increased cell death. In addition, mutant SOD1(G93A) induces a reduction in neurite length and branching that is accompanied with an abnormal accumulation of round mitochondria in growth cones. Furthermore, restoration of the mitochondrial fission and fusion balance by dominant-negative dynamin-related protein 1 (DRP1) expression rescues the mutant SOD1(G93A)-induced defects in mitochondrial morphology, dynamics, and cell viability. Interestingly, both SIRT3 and PGC-1alpha protect against mitochondrial fragmentation and neuronal cell death by mutant SOD1(G93A). This data suggests that impairment in mitochondrial dynamics participates in ALS and restoring this defect might provide protection against mutant SOD1(G93A)-induced neuronal injury. PMID- 22819778 TI - Effect of cigarette smoke exposure in the behavioral changes induced by ketamine. PMID- 22819779 TI - Frequency of normative word associations in the speech of individuals at familial high-risk for schizophrenia. AB - The intrusion of associations into speech in schizophrenia disrupts coherence and comprehensibility, a feature of formal thought disorder referred to as loosened associations. We have previously proposed that loosened associations may result from hyperactivity in semantic association networks, leading to an increased frequency of associated words appearing in speech. Using Computed Associations in Sequential Text (CAST) software to quantify the frequency of such associations in speech, we have reported more frequent normative associations in language samples from patients with schizophrenia and in individuals with schizotypal characteristics. The present study further examined this deviance in schizophrenia by studying normative associations in those who share genes with an individual with schizophrenia, (i.e. first-degree relatives of probands with schizophrenia; HR) but who do not have an illness. Familial high-risk participants (n=22), and controls (n=24) provided verbal responses to cards from the Thematic Apperception Test. CAST analysis revealed that HR used more associated words in their speech compared to controls. Furthermore, the frequency of normative word associations was positively correlated with dimensional and total scores of schizotypy derived from ratings of the structured interview for schizotypy, which confirms past research showing a relationship between schizotypy and hyperassociations. Our results suggest that some language disturbances in schizophrenia likely arise from an underlying psychopathological mechanism, hyperactivity of semantic associations. PMID- 22819780 TI - Is optimal timing of sentinel lymph node biopsy before neoadjuvant chemotherapy in patients with breast cancer? A literature review. AB - BACKGROUND: Twenty five percent of women with breast cancer who undergo preoperative chemotherapy do not have axillary metastases. These patients need to withstand sentinel lymph node biopsy (SLNB). The optimal timing of SLNB in patients with neoadjuvant chemotherapy has not yet been defined. METHODS: We systematically reviewed the literature for studies concerning the efficacy of sentinel lymph node biopsy before neoadjeuvant chemotherapy. A literature search was performed for the years 1993 through 2011 using the databases MEDLINE and EMBASE. Data that assessed the reliability of sentinel lymph node biopsy before chemotherapy were collected. RESULTS: We identified 10 high-quality studies from 387 papers, which are analyzed further in this review. The identification rates reported ranged from 97% to 100%. The sensitivities of sentinel lymph node biopsy were 100%, and the false negative rates were 0%. Use an isotope combined with blue dye was associated with a higher probability of identification than that of using an isotope or blue dye alone (99.5% vs 98.5%). Only two studies compared data based on different timing for the sentinel lymph node biopsy. They achieved a lower false negative rate (0% vs 15.8%) and higher success rate (100% vs 81%) in patients with sentinel lymph node biopsy prior to neoadjuvant chemotherapy. CONCLUSION: Sentinel lymph node biopsy prior to chemotherapy potentially gives a more accurate evaluation of axillary status, because it is unaffected by any previous therapeutic intervention. PMID- 22819781 TI - [Electronic fetal monitoring and management of adverse outcomes: how to perform and improve a training program for clinicians?]. AB - Electronic fetal monitoring during labor is the most commonly used method to evaluate the fetal status, but it remains exposed to some criticism. By comparison with intermittent auscultation and in the light of the results of the great studies in the last 30 years, it may be accused its failure to improve the neonatal outcome and its responsibility in the increase on operative deliveries. Actually, the electronic fetal monitoring is a tool whose effectiveness is linked to the accuracy of the analysis developed by the clinician. Studies on assessment of the tracing interpretation indicate that there is always a lack of quality, which may be improved through training programs. It also reveals the benefit of the fetal blood sampling to reduce operative deliveries and the generalization of this method, in addition to electronic fetal monitoring, is recommended by referral agencies. More generally, the continuous monitoring is only a part of the patient safety strategy in the labour ward and we are currently observing, in some European countries and in the United States, the development of training programs concerning the management of the adverse outcomes in obstetrics. The good performances related to the quality of care are demonstrated by the findings of the studies performed in the centers that have implemented an active training policy. In France, the professionals directly involved in the field of the perinatology should benefit from such educational programs that could be organized within the care networks under the authority of referral agencies. PMID- 22819782 TI - Comparison of direct microscopy, culture and calcofluor white for the diagnosis of onychomycosis. AB - BACKGROUND: Mycological diagnosis of onychomycosis can be performed by direct microcopy (KOH), cultures and calcofluor white. AIMS: To compare the percentage of positivity and the degree of correlation of KOH, cultures and calcofluor white for the diagnosis of onychomycosis. METHODS: Descriptive, transversal and comparative study. Samples of toenails with onychomycosis were used for KOH, cultures and calcofluor white under fluorescence. The percentage of positivity of the different techniques was calculated and the degree of correlation between them was determined (Epi Info v 3.4.3((c))). RESULTS: KOH was positive in 66.67% of the cases, cultures in 33.33% and calcofluor white in 57.58%. KOH and calcofluor white had a higher percentage of positivity than culture (p<0.01 and p<0.05 respectively). The degree of correlation between KOH and calcofluor white was excellent (kappa=0.8085; p<0.0001); however, the degree of correlation between KOH and culture and between calcofluor white and culture was poor. CONCLUSIONS: The use of calcofluor white is not recommended in routine laboratories because it does not seem to bring any additional benefits when comparing with KOH. This is especially important when funding is a great problem. PMID- 22819783 TI - Effects of suppression and acceptance of sadness on the urge for non-suicidal self-injury and self-punishment. AB - The present study wanted to test the course of the urge for non-suicidal self injury (UNSSI) and the urge for self-punishment (USP) when suppressing or accepting upcoming emotions in response to a sadness-inducing film clip in female participants with borderline personality disorder (BPD). Thirty-six women with BPD were allocated either to a condition in which they were asked to engage in expressive suppression or acceptance while watching a sadness-inducing film clip. Ratings of UNSSI, USP, and positive and negative emotions were assessed prior to the clip (baseline), immediately after it (t1) and after a 5min waiting period (t2), during which participants viewed landscape pictures. Additionally, physiological measures were obtained. Main results revealed a significant increase in UNSSI from baseline to t2 in the acceptance, but not in the suppression group. Furthermore, USP scores significantly increased from baseline to t2 in the acceptance, but not in the suppression condition. However, there was no differential impact on the sympathetic and parasympathetic branch depending on strategy. The results are in line with recent literature showing that expressive suppression in BPD may also have an adaptive function. PMID- 22819784 TI - Maternal low-dose estradiol-17beta exposure during pregnancy impairs postnatal progeny weight development and body composition. AB - Endocrine disrupting chemicals with estrogenic activity play an important role as obesogens. However, studies investigating the most potent natural estrogen, estradiol-17beta (E2), at low dose are lacking. We examined endocrine and physiological parameters in gilts receiving distinct concentrations of E2 during pregnancy. We then investigated whether adverse effects prevail in progeny due to a potential endocrine disruption. E2 was orally applied to gilts during the entire period of pregnancy. The concentrations represented a daily consumption at the recommended ADI level (0.05 MUg/kg body weight/day), at the NOEL (10 MUg/kg body weight/day) and at a high dosage (1000 MUg/kg body weight/day). Plasma hormone concentrations were determined using enzyme immuno assays. Offspring body fat was assessed by dual-energy X-ray absorptiometry scanning. In treated gilts receiving 1000MUg E2/kg body weight/day we found significantly elevated plasma E2 levels during pregnancy, paralleled by an increased weight gain. While offspring showed similar weight at birth, piglets exhibited a significant reduction in weight at weaning even though their mothers had only received 0.05 MUg E2/kg body weight/day. At 8 weeks of age, specifically males showed a significant increase in overall body fat percentage. In conclusion, prenatal exposure to low doses of E2 affected pig offspring development in terms of body weight and composition. In line with findings from other obesogens, our data suggest a programming effect during pregnancy for E2 causative for the depicted phenotypes. Therefore, E2 exposure may imply a possible contribution to childhood obesity. PMID- 22819787 TI - Effect of autoimmune diseases on risk and survival in female cancers. AB - OBJECTIVES: Patients with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited. METHODS: We analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIRs) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008. RESULTS: For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma. CONCLUSIONS: Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks. PMID- 22819786 TI - Impact of beta blockers on epithelial ovarian cancer survival. AB - OBJECTIVE: Stress may promote ovarian cancer progression through mechanisms including autonomic nervous system mediators such as norepinephrine and epinephrine. Beta blockers, used to treat hypertension, block production of these adrenergic hormones, and have been associated with prolonged survival in several malignancies. We sought to determine the association between beta blocker use and epithelial ovarian cancer (EOC) disease progression and survival. METHODS: We performed an institutional retrospective review of patients with EOC treated between 1996 and 2006. Patients underwent cytoreductive surgery followed by platinum-based chemotherapy. Women were considered beta blocker users if these medications were documented on at least two records more than 6 months apart. Statistical tests included Fisher's exact, Kaplan-Meier, and Cox regression analyses. RESULTS: 248 met inclusion criteria. 68 patients used antihypertensives, and 23 used beta blockers. Median progression-free survival for beta blocker users was 27 months, compared with 17 months for non-users (p=0.05). Similarly, overall disease-specific survival was longer for beta blocker users (56 months) compared with non-users (48 months, p=0.02, hazard ratio=0.56). Multivariate analysis identified beta blocker use as an independent positive prognostic factor, after controlling for age, stage, grade, and cytoreduction status (p=0.03). Overall survival remained longer for beta blocker users (56 months) when compared with hypertensive patients on other medications (34 months) and patients without hypertension (51 months) (p=0.007). CONCLUSIONS: In this cohort of patients with EOC, beta blocker use was associated with a 54% reduced chance of death compared with that of non-users. PMID- 22819785 TI - Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal. AB - 4-Hydroxy-2-nonenal (4HNE) and acrolein (ACR) are highly reactive neurotoxic products of lipid peroxidation that are implicated in the pathogenesis and progression of Alzheimer's and Parkinson's diseases. Conjugation with glutathione (GSH) initiates the 4HNE and ACR detoxification pathway, which generates the mercapturates of 4HNE and ACR that can be excreted. Prior work has shown that the efficiency of the GSH-dependent renal detoxification of haloalkene derived mercapturates is significantly decreased upon their deacetylation because of rapid transformation of the deacetylated products into toxic compounds mediated by beta-lyase. The enzymes of the GSH-conjugation pathway and beta-lyases are expressed in the brain, and we hypothesized that a similar toxicity mechanism may be initiated in the brain by the deacetylation of 4HNE- and ACR-mercapturate. The present study was performed to identify an enzyme(s) involved in 4HNE- and ACR mercapturate deacetylation, characterize the brain expression of this enzyme and determine whether its inhibition decreases 4HNE and 4HNE-mercapturate neurotoxicity. We demonstrated that of two candidate deacetylases, aminoacylases 1 (AA1) and 3 (AA3), only AA3 efficiently deacetylates both 4HNE- and ACR mercapturate. AA3 was further localized to neurons and blood vessels. Using a small molecule screen we generated high-affinity AA3 inhibitors. Two of them completely protected rat brain cortex neurons expressing AA3 from the toxicity of 4HNE-mercapturate. 4HNE-cysteine (4HNE-Cys) was also neurotoxic and its toxicity was mostly prevented by a beta-lyase inhibitor, aminooxyacetate. The results suggest that the AA3 mediated deacetylation of 4HNE-mercapturate may be involved in the neurotoxicity of 4HNE. PMID- 22819788 TI - Preoperative identification of a suspicious adnexal mass. PMID- 22819789 TI - Suitable restriction enzyme for standardization of pulsed-field gel electrophoresis protocol and interlaboratory comparison of Acinetobacter baumannii. AB - BACKGROUND/PURPOSE: Interlaboratory comparison of pulsed-field gel electrophoresis (PFGE) patterns is difficult. A key reference of standardized PFGE protocol for Acinetobacter baumannii may address this issue. This study aimed to determine restriction enzymes with rare cutting sites on A baumannii genomes and evaluate their cost-effectiveness, discriminatory power, and interlaboratory consistence of band assignments. METHODS: There were 42 A baumannii isolates collected, including nine from three hospital outbreaks and 33 sporadic isolates. The numbers of cutting sites for the restriction enzymes were explored using the "Restriction Digest and PFGE" program. The cost-effectiveness for PFGE analysis was evaluated for the tested restriction enzymes, while its discriminatory ability was expressed through a discriminatory index and 95% confidence interval. The interlaboratory consistence of band assignments was evaluated for the 42 A baumannii isolates. RESULTS: ApaI was the most cost effective restriction enzyme for a PFGE protocol for A baumannii. Both AscI and AsiSI were reasonable in terms of costs. ApaI, AscI, and AsiSI exhibited similar discriminatory indices. ApaI generated more than 40 fragments that were close and not easy to resolve, resulting in less consistence of band assignments. AscI and AsiSI generated 10-20 fragments that were clearly resolved, resulting in higher consistence of band assignments. AscI exhibited a close discriminatory power to that of AsiSI and at half of the cost of AsiSI for PFGE analysis. CONCLUSION: We recommend AscI as the primary enzyme and AsiSI as the secondary enzyme for standardizing the PFGE protocol and interlaboratory comparisons of A baumannii. PMID- 22819790 TI - Increased expression of tryptophan-5-hydroxylase 1, but not 2, in brainstem as a result of intrauterine malnutrition. AB - The aim of this study was to determine whether intrauterine malnutrition (IUM) produces a change in the expression of tryptophan-5-hydroxylase (TPH) 1 and/or 2 as the primary mechanism to explain the observed chronic cerebral acceleration of the synthesis of 5-hydroxytryptamine (5-HT). We used an IUM model and controls with ages of 1, 15 and 21 days. The brainstem was obtained to determine L tryptophan, 5-HT and TPH activity. Expression of TPH1 and TPH2 via specific antibodies for each was also evaluated by immunocytochemistry and Western blot. Malnourished offspring had a significant elevation of L-Trp, TPH activity and 5 HT in the brainstem. Both isoforms (1 and 2) of TPH were expressed from birth in both groups; however, TPH1 expression was significantly higher in offspring with IUM in relation to the controls. Importantly, these malnourished offspring showed reduced expression of TPH2 compared to controls. It was confirmed that IUM produces an increase in 5-HT in the brainstem and also showed increased expression of TPH1 at birth, with decreased expression of TPH2. These findings together allow us to propose that chronic elevation of synthesis of 5-HT observed in the brain of the offspring with IUM is probably due to a change in the expression and activity of TPH1 induced from fetal life. PMID- 22819791 TI - The role of liposome-protamine-DNA nanoparticles containing CpG oligodeoxynucleotides in the course of infection induced by Leishmania major in BALB/c mice. AB - An inoculation of virulent Leishmania major is known as leishmanization (LZ) which is proven to be the most effective control measure against cutaneous leishmaniasis (CL) and mimic natural infection. However, use of LZ is restricted due to various reasons such as development of uncontrolled lesion. In the present study, the efficacy of coadminstration of live L. major with liposome-protamine DNA nanoparticles (LPD) containing immunostimulatory CpG oligodeoxynucleotides (CpG ODN) which is an improved adjuvant delivery system is examined to check Leishmania pathology and immune response generated. BALB/c mice were inoculated subcutaneously (SC) with L. major plus LPD (CpG), CpG ODN or PBS buffer. The results showed that group of mice received LPD nanoparticles developed a significantly smaller lesion and the mice in this group showed minimum number of L. major in the spleen and lymph nodes. In addition, using LPD (CpG) resulted in a Th1 type of immune response with a preponderance of IgG2a isotype which is concurrent with the production of LPD induced IFN-gamma in the spleen of the mice. Taken together, the results suggested that immune modulation using LPD nanoparticles might be a practical approach to improve the safety of LZ. PMID- 22819792 TI - SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition. AB - Abnormal protein aggregates have been suggested as a common pathogenesis of many neurodegenerative diseases. Two well-known protein degradation pathways are responsible for protein homeostasis by balancing protein biosynthesis and degradative processes: the ubiquitin-proteasome system (UPS) and autophagy lysosomal system. UPS serves as the primary route for degradation of short-lived proteins, but large-size protein aggregates cannot be degraded by UPS. Autophagy is a unique cellular process that facilitates degradation of bulky protein aggregates by lysosome. Recent studies have demonstrated that autophagy plays a crucial role in the pathogenesis of neurodegenerative diseases characterized by abnormal protein accumulation, suggesting that regulation of autophagy may be a valuable therapeutic strategy for the treatment of various neurodegenerative diseases. Sirtuin-2 (SIRT2) is a class III histone deacetylase that is expressed abundantly in aging brain tissue. Here, we report that SIRT2 increases protein accumulation in murine cholinergic SN56 cells and human neuroblastoma SH-SY5Y cells under proteasome inhibition. Overexpression of SIRT2 inhibits lysosome mediated autophagic turnover by interfering with aggresome formation and also makes cells more vulnerable to accumulated protein-mediated cytotoxicity by MG132 and amyloid beta. Moreover, MG132-induced accumulation of ubiquitinated proteins and p62 as well as cytotoxicity are attenuated in siRNA-mediated SIRT2-silencing cells. Taken together, these results suggest that regulation of SIRT2 could be a good therapeutic target for a range of neurodegenerative diseases by regulating autophagic flux. PMID- 22819793 TI - Synthesis and characterization of a cyclooctapeptide analogue of omega-agatoxin IVB enhancing the activity of Cav2.1 calcium channels activity in cultured hippocampal neurons. AB - The structure of the toxin omega-agatoxin IVB, extracted from the venom of funnel web spider Agelenopsis aperta, is an important lead structure when considering the design of modulators of synaptic transmission which largely involves P/Q-type (CaV2.1) voltage gated calcium channels (VGCC) at central synapses. Focusing on the loop 2 of the omega-agatoxin IVB that seems to be the most preeminent interacting domain of the toxin with the CaV2.1 VGCC, cyclooctapeptides mimicking this loop were synthesized. While (14)Trp is essential for the binding of the neurotoxin to the CaV2.1 VGCC, the substitution of the (12)Cys for a glycidyl residue led to a cyclooctapeptide named EP14 able to enhance CaV2.1 VGCC associated currents measured with patch-clamp recordings and to evoke omega agatoxin IVA-sensitive intracellular Ca(2+) increase as measured by fura-2 spectrofluoroimaging. Furthermore, this cyclooctapeptide was able to potentiate spontaneous excitatory synaptic transmission in a network of cultured hippocampal neurons, consistent with the activation of presynaptic VGCC by EP14. In addition, this peptide did not affect cell survival measured with the MTT assay. Therefore, such new cyclopeptidic structures are potential good candidates for synthesis of new agents aimed at the restoration deficient excitatory synaptic transmission. PMID- 22819795 TI - WITHDRAWN: VEGF evokes reactive astroglia to convert into neuronal cells by affecting the biological function of MeCP2 in adult rat brain after cerebral ischemia. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22819794 TI - Conserved dorsal-ventral gradient of dopamine release and uptake rate in mice, rats and rhesus macaques. AB - Although the vast majority of research on the dopamine system has been performed in rodents, and it is assumed that this work will inform us about the human condition, there have been very few direct comparisons of presynaptic dopamine terminal function across multiple species. Because it is difficult to query rapid sub-second dopamine signaling in humans using voltammetric methods, we chose to compare dopamine signals across multiple striatal subregions in slices from C57BL/6J mice, Sprague-Dawley rats and rhesus macaques. We found a dorsal to ventral gradient of dopamine uptake rates with highest levels in the dorsal striatum and lowest levels in the nucleus accumbens shell, which is conserved across species. In addition to uptake rates, there was also a dorsal to ventral, high to low, gradient in the magnitude of stimulated DA release observed in monkeys, mice, and rats. These data demonstrate that there is considerable functional homology across striatal regions in non-human primates and rodents, lending support to the use of rodents as model systems to study dopamine-related circuitry and disorders that are clinically relevant to the human population. PMID- 22819796 TI - Association between incidence of candidaemia and consumption of antifungal agents at a medical centre in Taiwan. AB - This study investigated the correlations between consumption of antifungal agents and species distribution in candidaemia. The incidence of patients with community acquired candidaemia (CAC) (per 1000 admissions) and healthcare-associated candidaemia (HCAC) (per 1000 admissions) as well as data on annual consumption [defined daily doses (DDD)/1000 patient-days] of various antifungal agents at a medical centre in Taiwan from 2000 to 2010 were evaluated. A total of 2682 episodes of candidaemia were identified, including 2468 HCAC (92.0%) and 214 CAC (8.0%). The most prevalent species was Candida albicans (53.3%), followed by Candida tropicalis (20.5%), Candida glabrata (15.4%), Candida parapsilosis (14.1%), Candida guilliermondii (1.7%) and Candida krusei (1.5%). The overall incidence of candidaemia remained stable, whereas that of candidaemia due to C. parapsilosis and C. guilliermondii decreased significantly with time. Significant negative correlations were found between the use of echinocandins and voriconazole and the incidence of C. parapsilosis candidaemia and between the use of caspofungin and the incidence of C. guilliermondii candidaemia. In contrast, there were significant positive correlations between the use of echinocandins and the incidence of C. tropicalis candidaemia, the use of azoles and the incidence of C. glabrata and non-albicans Candida candidaemia, and the use of itraconazole and the incidence of C. parapsilosis and C. guilliermondii candidaemia. Increased use of fluconazole was associated with an increased incidence of HCAC due to non albicans Candida spp. In conclusion, the impact of consumption of antifungal agents on the incidence of candidaemia caused by different Candida spp. varies and warrants further studies to confirm these findings. PMID- 22819797 TI - Escherichia coli K1-induced cytopathogenicity of human brain microvascular endothelial cells. AB - Pathophysiology of Escherichia coli sepsis is complex involving circulating bacterial products, cytokine release, and sustained bacteremia resulting in the damage of vascular endothelium. Here, it is shown that E. coli K1 produced cytopathogenicity of human brain microvascular endothelial cells (HBMEC), that constitute the blood-brain barrier. Whole bacteria or their conditioned medium produced severe HBMEC damage suggesting E. coli K1-cytopathogenicity is a contact independent process. Using lipopolysaccharide (LPS) inhibitor, polymyxin B, purified LPS extracted from E. coli K1 as well as LPS mutant derived from E. coli K1, we showed that LPS is not the sole determinant of E. coli K1-mediated HBMEC death. Bacterial product(s) for HBMEC cytopathogenicity was heat-labile suggesting LPS-associated proteins. Several isogenic gene-deletion mutants (DeltaompA, DeltaibeA, DeltaibeB, Deltacnf1) exhibited HBMEC cytopathogenicity similar to that produced by wild type E. coli K1. E. coli K1-mediated HBMEC death was independent of phosphatidylinositol 3-kinase (PI3K) but dependent partially on focal adhesion kinase (FAK) using HBMEC expressing dominant negative FAK and PI3K. PMID- 22819798 TI - Weak binder for MHC molecule is a potent Mycobacterium tuberculosis-specific CTL epitope in the context of HLA-A24 allele. AB - Tuberculosis causes serious health problem for the world population. Antigenic peptides selected by pathogen-specific cytotoxic T lymphocytes (CTLs) are presented by major histocompatibility complex (MHC; or human leukocyte antigen [HLA] in humans) molecules, and HLA-A restricted responses may be of interest for vaccine development and the understanding of cellular immunity. A series of peptides derived from the 10-KDa culture filtrate protein (CFP10) and the 6 kDa early secretory antigenic target (ESAT-6) in the Mycobacterium tuberculosis (Mtb) have been screened and a CTL epitope restricted by the human leukocyte antigen HLA-A24, a common HLA allele in Asian people, has been identified. In this study, we studied a panel of CFP10 and ESAT-6-derived peptides to identify those with binding motifs for HLA-A24 molecules. The antigenicity of candidate peptides was assessed with in vitro refolding tests and an enzyme-linked immunospot (ELISPOT) assay, and by tetramer staining to determine the capacity to stimulate CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A24-positive TB Patients. We report that one novel candidate peptide at positions 5-14 of ESAT-6 of Mtb could induce peptide-specific CTLs from PBMCs of HLA-A24-positive patients, but not from HLA-A24-negative patients and HLA-A24-positive healthy controls. Identified epitope is a weak binder for HLA-A24 molecule in a mini MHC refolding assay. Since the peptide is presented by a common HLA class I molecule, it may be useful for immunotherapy against Mtb infection and vaccine development in the large population of Mtb-infected patients. PMID- 22819799 TI - Barking up the wrong tree: what's the deal with obesity, adiponectin and inflammation in dogs? PMID- 22819800 TI - A veterinary review of endurance riding as an international competitive sport. AB - The popularity of competitive endurance riding is growing worldwide and this has led to considerable changes in the discipline (e.g., fitter and faster horses and different types of injuries), which create challenges to all involved in the sport, including veterinarians. During endurance competitions, horses are closely monitored by veterinarians throughout the ride, with the aim of removing from the competition animals whose welfare appears to be endangered. This close monitoring provides veterinarians with an insight into problems during competitions. However, there is a relatively small amount of clinically relevant, evidence based data published on endurance horses, and this article reviews the evolution of the discipline, the published information on epidemiological data on endurance rides, the problems veterinarians face at competitions, and highlights those areas where research is warranted. PMID- 22819801 TI - A dialogue with Dr. Craig B. Thompson about metabolism and its relevance for tumor growth, progression and metastasis. PMID- 22819802 TI - High expression of human monocyte iNOS mRNA induced by Paracoccidioides brasiliensis is not associated with increase in NO production. AB - In this study we investigated the role of nitric oxide (NO) in monocyte fungicidal activity against Paracoccidioides brasiliensis. We found that cells primed with IFN-gamma, TNF-alpha or GM-CSF and challenged with a high-(Pb18) or low-virulence (Pb265) strain of the fungus increase their fungicidal activity. Expression of iNOS mRNA was increased after priming cells with each cytokine, and tended to be inhibited by Pb18. Despite up-regulation of iNOS mRNA expression by Pb265, an equivalent increase in NO production was not detected, as metabolite levels were similar in all cultures. The results indicated that high expression of human monocyte iNOS mRNA induced by P. brasiliensis is not correlated with NO concentrations produced. PMID- 22819803 TI - Differential cognitive effects of energy drink ingredients: caffeine, taurine, and glucose. AB - Energy drinks containing caffeine, taurine, and glucose may improve mood and cognitive performance. However, there are no studies assessing the individual and interactive effects of these ingredients. We evaluated the effects of caffeine, taurine, and glucose alone and in combination on cognitive performance and mood in 24-hour caffeine-abstained habitual caffeine consumers. Using a randomized, double-blind, mixed design, 48 habitual caffeine consumers (18 male, 30 female) who were 24-hour caffeine deprived received one of four treatments (200 mg caffeine/0 mg taurine, 0 mg caffeine/2000 mg taurine, 200 mg caffeine/2000 mg taurine, 0 mg caffeine/0 mg taurine), on each of four separate days, separated by a 3-day wash-out period. Between-participants treatment was a glucose drink (50 g glucose, placebo). Salivary cortisol, mood and heart rate were measured. An attention task was administered 30-minutes post-treatment, followed by a working memory and reaction time task 60-minutes post-treatment. Caffeine enhanced executive control and working memory, and reduced simple and choice reaction time. Taurine increased choice reaction time but reduced reaction time in the working memory tasks. Glucose alone slowed choice reaction time. Glucose in combination with caffeine, enhanced object working memory and in combination with taurine, enhanced orienting attention. Limited glucose effects may reflect low task difficulty relative to subjects' cognitive ability. Caffeine reduced feelings of fatigue and increased tension and vigor. Taurine reversed the effects of caffeine on vigor and caffeine-withdrawal symptoms. No effects were found for salivary cortisol or heart rate. Caffeine, not taurine or glucose, is likely responsible for reported changes in cognitive performance following consumption of energy drinks, especially in caffeine-withdrawn habitual caffeine consumers. PMID- 22819804 TI - Abcb and Abcc transporter homologs are expressed and active in larvae and adults of zebra mussel and induced by chemical stress. AB - Multixenobiotic resistance (MXR) of aquatic invertebrates has so far been associated with cellular efflux activity mediated by P-glycoprotein (ABCB1) and MRP (multidrug resistance protein; ABCC) type ABC (ATP binding cassette) transporters. Expression and activity of an abcb1/Abcb1 homolog has been shown in eggs and larvae of the zebra mussel Dreissena polymorpha. Here we report identification of a partial cDNA sequence of an abcc/Abcc homolog from zebra mussel that is transcribed and active as a cellular efflux transporter in embryos and gill tissue of adult mussels. Transcript expression levels were comparatively low in eggs and sharply increased after fertilization, then maintaining high expression levels in 1 and 2 dpf (days post fertilization) larvae. MK571, a known inhibitor of mammalian ABCC transporters, blocks efflux of calcein-am in larvae and gill tissue as indicated by elevated calcein fluorescence; this indicates the presence of active Abcc protein in cells of the larvae and gills. Dacthal and mercury used as chemical stressors both induced expression of abcb1 and abcc mRNAs in larvae; accordingly, assays with calcein-am and ABCB1 inhibitor reversin 205 and ABCC inhibitor MK571 indicated enhanced Abcb1 and Abcc efflux activities. Responses to chemicals were different in gills, where abcb1 transcript abundances were enhanced in dacthal and mercury treatments, whereas abcc mRNA was only increased with mercury. Abcb1 and Abcc activities did not in all cases show increases that were according to respective mRNA levels; thus, Abcc activity was significantly higher with dacthal, whereas Abcb1 activity was unchanged with mercury. Our data indicate that abcb1/Abcb1 and abcc/Abcc transporters are expressed and active in larvae and adult stages of zebra mussel. Expression of both genes is induced as cellular stress response, but regulation appears to differ in larvae and tissue of adult stages. PMID- 22819805 TI - Absorption, distribution, and elimination of graded oral doses of methylmercury in juvenile white sturgeon. AB - Mercury (Hg) is toxic and is released into the environment from a wide variety of anthropogenic sources. Methylmercury (MeHg), a product of microbial methylation, enables rapid Hg bioaccumulation and biomagnification in the biota. Methylmercury is sequestered and made available to the rest of the biota through the benthic detrital component leading to the high risk of exposure to benthic fish species, such as white sturgeon (Acipenser transmontanus). In the present study, a combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized to characterize the absorption, distribution, and elimination of Hg in white sturgeon over a 48h exposure. Mercury, as methylmercury chloride, at either 0, 250, 500, or 1000 MUg Hg/kg body weight, was orally intubated into white sturgeon, in groups of five. The blood was repeatedly sampled and urine collected from the fish over the 48h post intubation period, and at 48h, the fish were sacrificed for Hg tissue concentration and distribution determinations. The fractional rate of absorption (K), blood Hg concentration (MUg/ml), tissue concentration (MUg/g dry weight) and distribution (%), and urinary Hg elimination flux (MUg/kg/h) are significantly different (p<0.05) among the MeHg doses. Complete blood uptake of Hg was observed in all MeHg treated fish by 12h. The maximal observed blood Hg concentration peaks are 0.56+/-0.02, 0.70+/ 0.02, and 2.19+/-0.07 MUg/ml (mean+/-SEM) for the 250, 500, and 1000 MUgHg/kg body weight dose groups, respectively. Changes in blood Hg profiles can be described by a monomolecular function in all of the MeHg treated fish. The Hg concentration asymptote (A) and K are dose dependent. The relationship between A and the intubation dose, however, is nonlinear. Mercury levels in certain tissues are comparable to field data and longer-term study, indicating that the lower doses used in the current study are ecologically relevant for the species. Tissue Hg concentrations are in the following decreasing order: gastro-intestinal tract>kidney>spleen>gill>heart>liver>brain>white muscle and remaining whole body. At 48h, Hg was found to be preferentially distributed to metabolically active tissues. Digestibility is highest at the lowest MeHg dose. Measurable urinary Hg was observed in the fish treated with the highest MeHg dose, and a significant increase in the elimination flux was observed between 3 and 12h post intubation. PMID- 22819806 TI - Waterborne copper exposure inhibits ammonia excretion and branchial carbonic anhydrase activity in euryhaline guppies acclimated to both fresh water and sea water. AB - Inhibition of ammonia excretion (J(amm)) is a common response to Cu exposure in freshwater (FW) and seawater (SW) organisms. To determine the mechanism of this response, a euryhaline species of guppy (Poecilia vivipara) was exposed to 20 MUg Cu/l in FW (0 ppt) and SW (25 ppt) for 96 h. In both salinities, Cu transiently inhibited ammonia excretion (J(amm)) followed by a full recovery by the end of the 96 h exposure. The activities of Na(+)/K(+)-ATPase, H(+)-ATPase, and carbonic anhydrase (CA) were examined in the gills at 12 and 96 h of Cu exposure. In both salinity acclimations, CA activity was significantly inhibited following 12h of Cu exposure in P. vivipara, marking the first in vivo evidence of Cu-induced inhibition of CA in fish. Moreover, the inhibition and recovery of this enzyme were correlated with the inhibition and recovery of J(amm) in both salinity acclimations. The blockade of CA potentially acts as a common mechanism of J(amm) inhibition in FW and SW. There were no significant effects on Na(+)/K(+)-ATPase or H(+)-ATPase activity at either time point or salinity. However, H(+)-ATPase activity was upregulated at 96 h relative to the 12h time point, potentially involving this enzyme in re-establishing J(amm). PMID- 22819807 TI - Anti-androgen vinclozolin impairs sperm quality and steroidogenesis in goldfish. AB - In mammals, vinclozolin (VZ) is known as anti-androgen, which causes male infertility via androgen receptor (AR) antagonism. In aquatic animals, the VZ effects on reproductive functions are largely unknown and results are somewhat contradictory. To understand VZ adverse effects on male reproduction, mature goldfish (Carassius auratus) were exposed to three nominal VZ concentrations (100, 400, and 800 MUg/L) and alternations in gonadosomatic (GSI) and hepatosomatic indices (HSI), 17beta-estradiol (E(2)), 11-ketotestosterone (11-KT) and sperm quality were investigated compared to the solvent control. One group was exposed to E(2) (nominal concentration of 5 MUg/L), an estrogenic compound, as a negative control. Following one month exposure, GSI and HSI were unchanged in all VZ treated groups compared to solvent control. Sperm volume, motility and velocity were reduced in fish exposed to 800 MUg/L VZ. This was associated with the decrease in 11-KT level, suggesting direct VZ effects on testicular androgenesis and sperm functions. In goldfish exposed to 100 MUg/L VZ, 11-KT was increased but E(2) remained unchanged. This is, probably, the main reason for unchanged sperm quality at 100 MUg/L VZ. In goldfish exposed to E(2), GSI and 11 KT were decreased, E(2) was increased and no sperm was produced. The present study shows different dose-dependent VZ effects, which lead to impairment in sperm quality via disruption in steroidogenesis. In addition to VZ effects through competitive binding to AR, our data suggests potential effects of VZ by direct inhibition of 11-KT biosynthesis in fish as well as abnormalities in sperm morphology. PMID- 22819808 TI - Expression profiling in vivo demonstrates rapid changes in liver microRNA levels of whitefish (Coregonus lavaretus) following microcystin-LR exposure. AB - At present, little is known about the role of miRNAs in liver response of fish to the cyanobacterial hepatotoxin microcystin-LR (MC-LR) treatment, despite the fact that the exposure is thought to underlie multiple acute and chronic effects. To address this question, we used the Real-Time PCR method to examine the differential expression of 6 miRNAs putatively playing roles in signal transduction (let-7c, miR-9b), apoptosis and cell cycle (miR-16a, miR-21a, miR 34a) and fatty acid metabolism (miR-122) in whitefish (Coregonus lavaretus) liver, during the first 48h after intraperitoneal injection of MC-LR (100 MUg/kg body weight). In addition, we analyzed expression levels of 8 mRNAs and p53 protein, known to be involved in the cell response on the exposure to environmental stressors. Following the challenge we observed a rapid and transient increase in the mean (n=5) levels of individual miRNA expression (from 2.7-fold for miR-122 to 6.8-fold for let-7c), compared to the respective levels in control fish, which mostly peaked at 24h of the experiment. This increase was correlated with a reduction in the expression of mRNAs of genes coding for ferritin H (frih) and HNK Ras -like protein (p-ras) and an overexpression of mRNAs of genes coding for bcl2-associated X protein (bax), cyclin dependent kinase inhibitor 1a (cdkn1a), dicer (dcr), histone 2A (h2a) and p53. Expression of the remaining caspase 6 (cas6) mRNA did not change over 48 h of the treatment. Moreover, exposure to MC-LR did not alter whitefish p53 protein levels. Bearing in mind a variety of likely silencing targets for, and the onset of, the aberrant miRNA expression it may be concluded that they are involved in molecular pathways, such as liver cell metabolism, cell cycle regulation and apoptosis, and may contribute to the early phase of MC-LR induced hepatotoxicity. PMID- 22819809 TI - [Renal function and blood pressure in type 1 diabetes mellitus]. AB - INTRODUCTION: Persistent microalbuminuria is the accepted marker for early detection of a high risk of developing diabetic nephropathy in patients diagnosed with Type I Diabetes mellitus. The Ambulatory Blood Pressure Monitoring (ABPM) evaluates the circadian variations of blood pressure while awake and asleep. OBJECTIVE: To show the renal function characteristics and the data provided by ABPM in a cohort of insulin dependent diabetic children referred to our hospital. MATERIAL AND METHODS: A total of 61 patients with an age range between 6 and 17 years were studied. In each child blood pressure monitoring was arranged, the glomerular filtration rate in 24 hour urine was estimated, and glycosylated haemoglobin (HbA1c), total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, was measured. RESULTS: None of the cases showed persistent microalbuminuria. The renal function showed an increase in the glomerular filtration rate (146.6 +/-22 ml/minute/1.73 m(2)). In 39% of the cases there was no drop in systolic blood pressure during the night, whereas 11% of the patients in our series had a decrease in diastolic pressure. The cases were analysed depending on whether or not there had been a physiological arterial or diastolic pressure drop during the night: there were no significant differences in anthropometric data, glycosylated haemoglobin (HbA1c) levels, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, glomerular filtration rate (GFR), proteinuria and microalbuminuria between both groups. CONCLUSION: In Type I Diabetes Mellitus a decrease in the physiological blood pressure during the night is a frequent finding. There is also an increase in the glomerular filtration rate. PMID- 22819810 TI - Efficacy of 7 days per week inpatient admissions and rehabilitation therapy. AB - OBJECTIVE: To evaluate the efficacy of 7 d/wk of inpatient admissions and rehabilitation therapy (7DART) in a rehabilitation hospital. DESIGN: Cross sectional, retrospective electronic data review. SETTING: Rehabilitation hospital. PARTICIPANTS: Adult patients who participated in the 7DART program and were admitted and discharged between February 2009 and January 2010 (n=1808), and adult patients who received 5 d/wk of inpatient admissions and rehabilitation therapy (5DART), and were admitted and discharged between February 2008 and January 2009 (n=1692). INTERVENTIONS: Occupational therapy and physiotherapy during the weekends (7DART only). MAIN OUTCOME MEASURES: FIM rating change from admission to discharge, length of hospital stay, rehabilitation workload per patient, and discharge destination. RESULTS: There were 3500 patients admitted with a mean age +/- SD of 72.1+/-13.3 years and a male-to-female ratio of 1:1.9. Under 7DART conditions, there was a 6.9% increase in admissions (7DART=1808 vs 5DART=1692, P=.006), an 86% increase in weekend admissions (255 vs 137, P<.001), a 13.2% increase in rehabilitation workload per patient (40.7 h vs 36 h, P<.001), and a 5.4% decrease in rehabilitation hospital stay (19.3 d vs 20.3 d, P=.043). Similar FIM rating changes were obtained from admission to discharge under both conditions (18.2 for 7DART vs 18.7 for 5DART, P=.099). Both groups resulted in 94% of patients achieving their rehabilitation goals (7DART=94.1%, 5DART=94.5%; P=.967), and 88.6% of patients returning to their homes (7DART=88.1%, 5DART=89.2%; P=.334). CONCLUSIONS: Despite the fact that patients in both groups had similar functional outcomes and discharge destination, the 7DART rehabilitation model reduced length of hospital stay and increased rehabilitation workload, demonstrating increased efficiency and access to care by admitting more patients from acute care, rehabilitating them, and discharging them to the community in less time than the 5DART model. PMID- 22819811 TI - An in vitro comparison of four intra-oral ceramic repair systems. AB - OBJECTIVES: This study evaluated the effect of different surface conditioning methods on the tensile bond strength (TBS) and integrity of the leucite reinforced glass ceramic (Cerana((r)) inserts)-resin composite interface, using four commercially available ceramic repair systems. METHODS: Two hundred extra large Cerana((r)) inserts were mechanically treated and stored in artificial saliva for 3 weeks and subsequently randomly assigned to one of the following ceramic repair systems (n=40/group): Group 1, Ceramic Repair((r)) (Ivoclar Vivadent, Liechtenstein); Group 2, Cimara((r)) (Voco, Germany); Group 3, Clearfil Repair((r)) (Kuraray, Japan); Group 4, CoJet system((r)) (3M ESPE, Germany); and Group 5, no surface conditioning and no adhesive system applied: the control group. Subsequently, resin composite material was added to the substrate surfaces and the ceramic-resin composite specimens were subjected to TBS testing. Representative samples from the test groups were subjected to scanning electron microscopy (SEM) to determine the mode of failure. The data were analysed statistically using a one-way multivariate analysis of variance and Kruskal Wallis test at a 95% confidence interval level. RESULTS: Surface conditioning with the CoJet((r)) system resulted in significantly higher bond strength values (5.2 +/- 1.1 MPa) than surface conditioning with the other repair systems (p=0.03). The SEM examination of the failed interfaces revealed that all the specimens examined failed adhesively. SIGNIFICANCE: Whilst highest bond strength values were observed with the CoJet((r)) system all tested repair systems resulted in relatively weak TBS values and, as a consequence, these repair systems may be indicated only as interim measures. PMID- 22819812 TI - One-bottle self-etching adhesives applied to dentine air-abraded using bioactive glasses containing polyacrylic acid: an in vitro microtensile bond strength and confocal microscopy study. AB - OBJECTIVES: The aim of this study was to test the microtensile bond strength (MUTBS) of two "simplified" self-etching adhesives bonded to air-abraded dentine using experimental bioactive glass powders containing polyacrylic acid. METHODS: Sound dentine specimens were air-abraded using a pure Bioglass 45S5 (Bioglass) powder or two Bioglass powders containing different concentration of polyacrylic acid (PAA: 15 wt% or 40 wt%). The bonding procedures were accomplished by the application of two self-etching adhesives (CS3: Clearfil S3 Bond; Kuraray, Osaka, Japan or GB: G Bond; GC Ltd. Tokyo, Japan). The resin-bonded specimens were cut in beams (0.9 mm(2)) and the MUTBS testing was performed after 24h or 6months of phosphate buffer solution (PBS) storage. The results were statistically analysed by three-way ANOVA and Student-Newman-Keuls test used (alpha=0.05). Further bonded-dentine specimens were used for the confocal microscopy interfacial characterisation and micropermeability analysis. RESULTS: The CS3 adhesive system achieved higher MUTBS than those attained in the specimens bonded with GB both after 24h and 6 months of PBS storage. The CLSM analysis performed after 6months of PBS storage indicated severe micropermeability within the bonded-dentine interfaces created using GB applied onto dentine air-abraded with Bioglass/PAA-15 and Bioglass/PAA-40. Conversely, CS3 exhibited no dye penetration (micropermeability) at the resin-dentine interface. CONCLUSION: It is possible to affirm that air-abrasion procedures performed using pure Bioglass or Bioglass containing 15 wt% PAA do not interfere with the immediate bonding performance of self-etching adhesives. However, the durability of the bonded-dentine interfaces created subsequent air-abrasion procedures using bioactive glasses will depend also upon the chemical composition of the self-etch adhesive systems. PMID- 22819813 TI - Subcellular localization of adenylate kinases in Plasmodium falciparum. AB - Adenylate kinases (AK) play a key role in nucleotide signaling processes and energy metabolism by catalyzing the reversible conversion of ATP and AMP to 2 ADP. In the malaria parasite Plasmodium falciparum this reaction is mediated by AK1, AK2, and a GTP:AMP phosphotransferase (GAK). Here, we describe two additional adenylate kinase-like proteins: PfAKLP1, which is homologous to human AK6, and PfAKLP2. Using GFP-fusion proteins and life cell imaging, we demonstrate a cytosolic localization for PfAK1, PfAKLP1, and PfAKLP2, whereas PfGAK is located in the mitochondrion. PfAK2 is located at the parasitophorous vacuole membrane, and this localization is driven by N-myristoylation. PMID- 22819814 TI - One step back before moving forward: regulation of transcription elongation by arrest and backtracking. AB - RNA polymerase II backtracking is a well-known phenomenon, but its involvement in gene regulation is yet to be addressed. Structural studies into the backtracked complex, new reactivation mechanisms and genome-wide approaches are shedding some light on this interesting aspect of gene transcription. In this review, we briefly summarise these new findings, comment about some results recently obtained in our laboratory, and propose a new model for the influence of the chromatin context on RNA polymerase II backtracking. PMID- 22819815 TI - The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis. AB - Guanylyl cyclase C (GC-C) is predominantly expressed in intestinal epithelial cells and serves as the receptor for the gastrointestinal hormones guanylin and uroguanylin, and the heat-stable enterotoxin, the causative agent for Travellers' Diarrhea. Activation of GC-C results in an increase in intracellular levels of cGMP, which can regulate fluid and ion secretion, colon cell proliferation, and the gut immune system. This review highlights recent findings arising from studies in the GC-C knock-out mouse, along with enigmatic results obtained from the first descriptions of human disease caused by mutations in the GC-C gene. We provide some insight into these new findings and comment on areas of future study, which may enhance our knowledge of this evolutionarily conserved receptor and signaling system. PMID- 22819816 TI - The glucose-6-phosphate transport is not mediated by a glucose-6 phosphate/phosphate exchange in liver microsomes. AB - A phosphate-linked antiporter activity of the glucose-6-phosphate transporter (G6PT) has been recently described in liposomes including the reconstituded transporter protein. We directly investigated the mechanism of glucose-6 phosphate (G6P) transport in rat liver microsomal vesicles. Pre-loading with inorganic phosphate (Pi) did not stimulate G6P or Pi microsomal inward transport. Pi efflux from pre-loaded microsomes could not be enhanced by G6P or Pi addition. Rapid G6P or Pi influx was registered by light-scattering in microsomes not containing G6P or Pi. The G6PT inhibitor, S3483, blocked G6P transport irrespectively of experimental conditions. We conclude that hepatic G6PT functions as an uniporter. PMID- 22819817 TI - In silico identification of catalytic residues and domain fold of the family GH119 sharing the catalytic machinery with the alpha-amylase family GH57. AB - The glycoside hydrolase family 119 (GH119) contains the alpha-amylase from Bacillus circulans and five other hypothetical proteins. Until now, nothing has been reported on the catalytic residues and catalytic-domain fold of GH119. Based on a detailed in silico analysis involving sequence comparison in combination with BLAST searches and structural modelling, an unambiguous relationship was revealed between the families GH119 and GH57. This includes sharing the catalytic residues, i.e. Glu231 and Asp373 as catalytic nucleophile and proton donor, respectively, in the predicted catalytic (beta/alpha)(7)-barrel domain of GH119 B. circulans alpha-amylase. The GH57 and GH119 families may thus define a new CAZy clan. PMID- 22819818 TI - PC-PLC is involved in osteoclastogenesis induced by TNF-alpha through upregulating IP3R1 expression. AB - The precise mechanism of how TNF-alpha promotes osteoclast formation is not clear. Previous reports show TNF-alpha targets molecules that regulate calcium signaling. Inositol-1,4,5-trisphosphate receptors (IP3Rs) are important calcium channel responsible for evoking intracellular calcium oscillation. We found that TNF-alpha increased the expression of IP3R1 and promoted osteoclastogenesis in RANKL-induced mouse BMMs. Phosphatidylcholine-specific phospholipase C (PC-PLC) specific inhibitor D609 eliminated the upregulation of IP3R1 by TNF-alpha, and decreased the autoamplification of nuclear factor of activated T-cells 1 (NFATc1), thus resulted in less osteoclasts formation. However, D609 did not inhibit RANKL-induced osteoclastogenesis. Our data suggest TNF-alpha promotes RANKL-induced osteoclastogenesis, at least partially, through PC-PLC/IP3R1/NFATc1 pathway. PMID- 22819819 TI - Clearance of extracellular misfolded proteins in systemic amyloidosis: experience with transthyretin. AB - Increasing evidence indicates that accumulation of misfolded proteins in the form of oligomers, protofibrils or amyloid fibrils, and their consequences in triggering intracellular signaling cascades with toxic consequences represent unifying events in many of slowly progressive neurodegenerative disorders. Studies with small compounds or molecules, known to recognize and disrupt amyloidogenic structures, have proven efficient in promoting clearance of protein aggregates in experimental models of systemic and localized forms of amyloidoses. Doxycycline and EGCG were efficient in removing aggregates in pre-clinical studies in a transgenic mouse model for transthyretin (TTR) systemic amyloidosis and represent an opportunity to address mechanisms and key players in deposit removal. Extracellular chaperones, such as clusterin and metalloproteinases play an important role in this process. PMID- 22819820 TI - Epigenetic regulation of miR-124 by hepatitis C virus core protein promotes migration and invasion of intrahepatic cholangiocarcinoma cells by targeting SMYD3. AB - Hepatitis C Virus core protein (HCVc) plays important roles in the development of intrahepatic cholangiocarcinoma (ICC). MicroRNAs (miRNAs) contribute to tumor progression by interacting with downstream target genes. However, the regulation and role of miRNAs in HCV-related intrahepatic cholangiocarcinoma (HCV-ICC) is poorly understood. In this study, we found that miR-124 was down-regulated in HCV ICC and the induction of DNMT1 by HCVc mediated the suppression of miR-124. Over expression of miR-124 suppressed cell migration and invasion in vitro, and reduced the protein levels of SMYD3 and downstream target genes (c-Myc and MMP9). Knockdown of SMYD3 inhibited cell migration and invasion resembling that of miR 124 over-expression. In conclusion, our studies indicate that low miR-124 levels mediated by HCVc via DNMT1 promote ICC cell migration and invasion by targeting SMYD3. PMID- 22819821 TI - Generating pluripotent stem cells: differential epigenetic changes during cellular reprogramming. AB - Pluripotent stem cells hold enomous potential for therapuetic applications in tissue replacement therapy. Reprogramming somatic cells from a patient donor to generate pluripotent stem cells involves both ethical concerns inherent in the use of embryonic and oocyte-derived stem cells, as well as issues of histocompatibility. Among the various pluripotent stem cells, induced pluripotent stem cells (iPSC)--derived by ectopic expression of four reprogramming factors in donor somatic cells--are superior in terms of ethical use, histocompatibility, and derivation method. However, iPSC also show genetic and epigenetic differences that limit their differentiation potential, functionality, safety, and potential clinical utility. Here, we discuss the unique characteristics of iPSC and approaches that are being taken to overcome these limitations. PMID- 22819822 TI - Cold-inducible RNA-binding protein (CIRP) regulates target mRNA stabilization in the mouse testis. AB - Cold-inducible RNA-binding protein (CIRP) is an RNA-binding protein that is expressed in normal testis and down-regulated after heat stress. Recent studies suggest that CIRP contributes to male fertility problems but the mechanisms are unclear. The purpose of this study was to identify the likely mechanism of CIRP in reproduction. Based on the RNA-Binding Protein Immunoprecipitation-Microarray (Chip) Profiling (RIP-Chip) and biotin pull-down assays, we found that the mRNAs binding with CIRP in testis were mostly associated with translation regulator activity, antioxidant activity, envelope and reproduction, including important mRNAs related to male infertility. We also discovered that (Un)(n >=2) was the possible core recognition sequence, and the binding mRNAs increased their stabilization. Our results improve our understanding of the mechanism by which heat stress causes male infertility. PMID- 22819823 TI - Analysis of solvent tolerance in Pseudomonas putida DOT-T1E based on its genome sequence and a collection of mutants. AB - Pseudomonas putida strains are prevalent in a variety of pristine and polluted environments. The genome of the solvent-tolerant P. putida strain DOT-T1E which thrives in the presence of high concentrations of monoaromatic hydrocarbons, contains a circular 6.3 Mbp chromosome and a 133 kbp plasmid. Omics information has been used to identify the genes and proteins involved in solvent tolerance in this bacterium. This strain uses a multifactorial response that involves fine tuning of lipid fluidity, activation of a general stress-response system, enhanced energy generation, and induction of specific efflux pumps that extrude solvents to the medium. Local and global transcriptional regulators participate in a complex network of metabolic functions, acting as the decision makers in the response to solvents. PMID- 22819824 TI - miR-615-5p is restrictedly expressed in cirrhotic and cancerous liver tissues and its overexpression alleviates the tumorigenic effects in hepatocellular carcinoma. AB - microRNAs aberrant behavior in heptocellular carcinoma (HCC) plays a major role in HCC pathogenesis. miR-615-5p expression has never been evaluated in HCC. We showed that miR-615-5p was preferentially expressed in HCC, cirrhotic liver tissues and HCC cell lines, but undetected in normal livers. Forced miR-615-5p expression in HCC cell lines led to significant decrease in cell growth and migration. In-silico predication revealed insulin-like growth factor-II (IGF-II) as a potential downstream target for miR-615-5p. Forcing the expression of miR 615-5p showed downregulation of IGF-II mRNA, as well as inhibition of the luciferase activity in a luciferase reporter vector harboring the IGF-II-3'UTR target sequence. miR-615-5p acts as tumor-suppressor in HCC through targeting IGF II. PMID- 22819825 TI - TRIAD1 inhibits MDM2-mediated p53 ubiquitination and degradation. AB - Murine double minute (MDM2) is an E3 ligase that promotes ubiquitination and degradation of tumor suppressor protein 53 (p53). MDM2-mediated regulation of p53 has been investigated as a classical tumorigenesis pathway. Here, we describe TRIAD1 as a novel modulator of the p53-MDM2 axis that induces p53 activation by inhibiting its regulation by MDM2. Ablation of TRIAD1 attenuates p53 levels activity upon DNA damage, whereas ectopic expression of TRIAD1 promotes p53 stability by inhibiting MDM2-mediated ubiquitination/degradation. Moreover, TRIAD1 binds to the C-terminus of p53 to promote its dissociation from MDM2. These results implicate TRIAD1 as a novel regulatory factor of p53-MDM2. PMID- 22819826 TI - Life at the dry edge: microorganisms of the Atacama Desert. AB - The Atacama Desert, located in northern Chile, is the driest and oldest desert on Earth. Research aimed at the understanding of this unique habitat and its diverse microbial ecosystems begun only a few decades ago, mainly driven by NASA's astrobiology program. A milestone in these efforts was a paper published in 2003, when the Atacama was shown to be a proper model of Mars. From then on, studies have been focused to examine every possible niche suitable for microbial life in this extreme environment. Habitats as different as the underside of quartz rocks, fumaroles at the Andes Mountains, the inside of halite evaporates and caves of the Coastal Range, among others, have shown that life has found ingenious ways to adapt to extreme conditions such as low water availability, high salt concentration and intense UV radiation. PMID- 22819827 TI - SARA is dispensable for functional TGF-beta signaling. AB - Smad anchor for receptor activation (SARA or ZFYVE9) has been proposed to mediate transforming growth factor beta (TGF-beta) signaling by direct interaction with the non-activated Smad proteins and the TGF-beta receptors; however, these findings are controversial. We demonstrate no correlation between SARA expression and the levels of TGF-beta-induced phosphorylation of Smads in various B-cell lymphomas. Moreover, knockdown of SARA in HeLa cells did not interfere with TGF beta-induced Smad activation, Smad nuclear translocation, or induction of TGF beta target genes. Various R-Smads and TGF-beta receptors did not co immunoprecipitate with SARA. Collectively, our results demonstrate that SARA is dispensable for functional TGF-beta-mediated signaling. PMID- 22819828 TI - Immunoregulatory molecules are master regulators of inflammation during the immune response. AB - The balance between pro- and anti-inflammatory signalling is critical to maintain the immune homeostasis under physiological conditions as well as for the control of inflammation in different pathological settings. Recent progress in the signalling pathways that control this balance has led to the development of novel therapeutic agents for diseases characterized by alterations in the activation/suppression of the immune response. Different molecules have a key role in the regulation of the immune system, including the receptors PD-1 (Programmed cell Death 1), CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) and galectins; or the intracellular enzyme IDO (indoleamine 2,3-dioxygenase). In addition, other molecules as CD69, AhR (Aryl hydrocarbon Receptor), and GADD45 (Growth Arrest and DNA Damage-inducible 45) family members, have emerged as potential targets for the regulation of the activation/suppression balance of immune cells. This review offers a perspective on well-characterized as well as emergent negative immune regulatory molecules in the context of autoimmune inflammatory diseases. PMID- 22819829 TI - N-terminal tyrosine phosphorylation of caveolin-2 negates anti-proliferative effect of transforming growth factor beta in endothelial cells. AB - Here we show that tyrosine phosphorylation of caveolin-2 (Cav-2) negatively regulates the anti-proliferative function of transforming growth factor beta (TGF beta) in endothelial cells. In contrast to wild-type-Cav-2, retroviral re expression of Y19/27F-Cav-2 in Cav-2 knockout endothelial cells did not affect anti-proliferative effect of TGF-beta compared to empty vector. Conversely, although less effective than wild-type, re-expression of S23/36A-Cav-2 reduced the effect of TGF-beta compared to empty vector. This differential effect of tyrosine and serine phosphorylation mutants of Cav-2 correlated with TGF-beta induced Smad3 phosphorylation and transcriptional activation of plasminogen activator inhibitor-1. Thus tyrosine-phosphorylated Cav-2 counteracts anti proliferative effect of TGF-beta in endothelial cells. PMID- 22819830 TI - tRNA concentration fine tunes protein solubility. AB - Clusters of codons pairing to low-abundance tRNAs synchronize the translation with co-translational folding of single domains in multidomain proteins. Although proven with some examples, the impact of the ribosomal speed on the folding and solubility on a global, cell-wide level remains elusive. Here we show that upregulation of three low-abundance tRNAs in Escherichia coli increased the aggregation propensity of several cellular proteins as a result of an accelerated elongation rate. Intriguingly, alterations in the concentration of the natural tRNA pool compromised the solubility of various chaperones consequently rendering the solubility of some chaperone-dependent proteins. PMID- 22819831 TI - The importance of flavodoxin for environmental stress tolerance in photosynthetic microorganisms and transgenic plants. Mechanism, evolution and biotechnological potential. AB - Ferredoxins are electron shuttles harboring iron-sulfur clusters which participate in oxido-reductive pathways in organisms displaying very different lifestyles. Ferredoxin levels decline in plants and cyanobacteria exposed to environmental stress and iron starvation. Flavodoxin is an isofunctional flavoprotein present in cyanobacteria and algae (not plants) which is induced and replaces ferredoxin under stress. Expression of a chloroplast-targeted flavodoxin in plants confers tolerance to multiple stresses and iron deficit. We discuss herein the bases for functional equivalence between the two proteins, the reasons for ferredoxin conservation despite its susceptibility to aerobic stress and for the loss of flavodoxin as an adaptive trait in higher eukaryotes. We also propose a mechanism to explain the tolerance conferred by flavodoxin when expressed in plants. PMID- 22819832 TI - Effect of ion-bombarded silicone tympanostomy tube on ciprofloxacin-resistant Pseudomonas aeruginosa biofilm formation. AB - OBJECTIVES: Many materials and surface preparations have been developed to resist the formation of biofilm. Ion-bombarded silicone tympanostomy tube was introduced to resist both staphylococcal and pseudomonal biofilm formation. To date, there are no reports that have evaluated the use of ion-bombarded tympanostomy tubes against the ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilm formation. The purpose of this study is to evaluate the ion-bombarded tympanostomy tube for CRPA biofilm resistance. METHODS: Commercial ion-bombarded tympanostomy tubes and simple silicone tympanostomy tubes were processed for an evaluation of the CRPA biofilm formation in vitro. RESULTS: The ion-bombarded tubes showed no resistance to CRPA adhesion and biofilm formation. Thick and dense conglomeration was less formed in the ion-bombarded tympanostomy tubes, compared to that of the simple silicone tube. CONCLUSION: The preventive effect against the CRPA biofilm formation of the ion-bombarded silicone tympanostomy tube was not observed. Our result suggests that only the surface modification by an ion bombardment is not enough to resist CRPA biofilm formation. PMID- 22819834 TI - The effect of enterovirus 71 immunization on neuropathogenesis and protein expression profiles in the thalamus of infected rhesus neonates. AB - Enterovirus 71 (EV71) is a major pathogen that causes hand-foot-mouth disease (HFMD). Our previous studies have demonstrated that the complete process of pathogenesis, which may include tissue damage induced by host inflammatory responses and direct tissue damage caused by viral infection, can be observed in the central nervous system (CNS) of animals infected in the laboratory with EV71. Based on these observations, the neuropathogenesis and protein expression profiles in the thalamic tissues of EV71-infected animals were further analyzed in the present study. Changes in protein expression profiles following immunization with the inactivated EV71 vaccine followed by virus challenge were observed and evaluated, and their physiological roles in viral pathogenesis are discussed. Taken together, the results of these experiments provide evidence regarding the neuropathogenesis and molecular mechanisms associated with EV71 infection and identify several protein indicators of pathogenic changes during viral infection. PMID- 22819833 TI - Senior-Loken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. AB - Senior-Loken syndrome (SLS) is an autosomal recessive disease characterized by development of a retinitis pigmentosa (RP)- or Leber congenital amaurosis (LCA) like retinal dystrophy and a medullary cystic kidney disease, nephronophthisis. Mutations in several genes (called nephrocystins) have been shown to cause SLS. The proteins encoded by these genes are localized in the connecting cilium of photoreceptor cells and in the primary cilium of kidney cells. Nephrocystins are thought to have a role in regulating transport of proteins bound to the outer segment/primary cilium; however, the precise molecular mechanisms are largely undetermined. This review will survey the biochemistry, cell biology and existing animal models for each of the nephrocystins as it relates to photoreceptor biology and pathogenesis of retinal degeneration. PMID- 22819835 TI - Phylogenetically diverse TT virus viremia among pregnant women. AB - Infections during pregnancy have been suggested to be involved in childhood leukemias. We used high-throughput sequencing to describe the viruses most readily detectable in serum samples of pregnant women. Serum DNA of 112 mothers to leukemic children was amplified using whole genome amplification. Sequencing identified one TT virus (TTV) isolate belonging to a known type and two putatively new TTVs. For 22 mothers, we also performed TTV amplification by general primer PCR before sequencing. This detected 39 TTVs, two of which were identical to the TTVs found after whole genome amplification. Altogether, we found 40 TTV isolates, 29 of which were putatively new types (similarities ranging from 89% to 69%). In conclusion, high throughput sequencing is useful to describe the known or unknown viruses that are present in serum samples of pregnant women. PMID- 22819837 TI - The enigmatic reaction of flavins with oxygen. AB - The reaction of flavoenzymes with oxygen remains a fascinating area of research because of its relevance for reactive oxygen species (ROS) generation. Several exciting recent studies provide consistent mechanistic clues about the specific functional and structural properties of the oxidase and monooxygenase flavoenzymatic systems. Specifically, the spatial arrangement of the reacting oxygen that is in direct contact with the flavin group is emerging as a crucial factor that differentiates between oxidase and monooxygenase enzymes. A challenge for the future will be to use these emerging concepts to rationally engineer flavoenzymes, paving the way to new research avenues with far-reaching implications for oxidative biocatalysis and metabolic engineering. PMID- 22819836 TI - Susceptibility of Xenopus laevis tadpoles to infection by the ranavirus Frog Virus 3 correlates with a reduced and delayed innate immune response in comparison with adult frogs. AB - Xenopus laevis adults mount effective immune responses to ranavirus Frog Virus 3 (FV3) infections and clear the pathogen within 2-3 weeks. In contrast, most tadpoles cannot clear FV3 and succumb to infections within a month. While larval susceptibility has been attributed to ineffective adaptive immunity, the contribution of innate immune components has not been addressed. Accordingly, we performed a comprehensive gene expression analysis on FV3-infected tadpoles and adults. In comparison to adults, leukocytes and tissues of infected tadpoles exhibited modest (10-100 time lower than adult) and delayed (3 day later than adult) increase in expression of inflammation-associated (TNF-alpha, IL-1beta and IFN-gamma) and antiviral (Mx1) genes. In contrast, these genes were readily and robustly upregulated in tadpoles upon bacterial stimulation. Furthermore, greater proportions of larval than adult PLs were infected by FV3. Our study suggests that tadpole susceptibility to FV3 infection is partially due to poor virus elicited innate immune responses. PMID- 22819838 TI - Non-HLA-antibodies targeting Angiotensin type 1 receptor and antibody mediated rejection. AB - Antibody-mediated mechanisms directed against non-HLA related targets may exert negative impact on allograft function and survival. Angiotensin type 1 receptor (AT(1)R) emerges as a functional target for non-HLA allo- and autoantibodies (AT(1)R-Abs) comprising of IgG1 and IgG3 subclasses. Proof of concept for pathophysiologic relevance of AT(1)R-Abs in antibody mediated rejection (AMR) in renal transplants was provided by passive transfer studies in animal model and therapeutic rescue of patients. Although AT(1)R-Abs may belong to complement fixing IgG subclasses, C4d positivity in renal transplant biopsies was not frequently detected implicating complement independent mechanisms of injury. AT(1)R-Abs exert direct effects on endothelial and vascular smooth muscle cells by induction of Erk1/2 signaling and increased DNA binding of transcription factors associated with pro-inflammatory and pro-coagulatory responses. Establishment of enzyme-linked immunosorbent assay employing extracts of cells overexpressing AT(1)R in its native conformation was instrumental for recent studies in independent cohorts. Assessing the AT(1)R-Ab-status along with the HLA antibodies may help to identify patients at particular risk for irreversible acute or chronic allograft injuries and improve overall outcomes. This review summarizes the current state of research in AT(1)R biology, development in diagnostic strategies, discusses recent clinical studies, and provides perspectives on further refinements in understanding AT(1)R-Ab-actions. PMID- 22819839 TI - Glucagon-like peptide 1 receptor plays an essential role in geniposide attenuating lipotoxicity-induced beta-cell apoptosis. AB - beta-Cell apoptosis is considered to be a major cause of loss of beta cells in diabetes. Geniposide could prevent oxidative stress-induced neuron apoptosis, and improved glucose stimulated insulin secretion by activating glucagon-like peptide 1 receptor (GLP-1R) in INS-1 cells. Here we have investigated whether geniposide can exert a direct effect against pancreatic beta-cell lipoapoptosis. The results indicated that pretreatment pancreatic INS-1 cells with geniposide for 7h attenuated palmitate-induced beta-cell apoptosis and active caspase-3 expression, but this effect was disappeared at 18 h. Long-term incubation with palmitate decreased GLP-1R expression in INS-1 cells, and exendin (9-39), an antagonist for GLP-1R, inhibited the effect of geniposide on palmitate-induced apoptosis in INS 1 cells. Moreover, geniposide also improved the impairment of GLP-1R signaling through enhancing the phosphorylation of Akt and Foxo1, and increased the expression of PDX-1 in palmitate-treated INS-1 cells. These results suggest that geniposide inhibits early stage of lipotoxicity-induced beta-cell apoptosis, and GLP-1R plays a critical role in geniposide counteracting the action of lipotoxicity in INS-1 pancreatic beta cells. PMID- 22819840 TI - Synergistic killing effect of chloroquine and androgen deprivation in LNCaP cells. AB - Modulation of autophagy is a new paradigm in cancer therapeutics. Recently a novel function of chloroquine (CLQ) in inhibiting degradation of autophagic vesicles has been revealed, which raises the question whether CLQ can be used as an adjuvant in targeting autophagic pro-survival mechanism in prostate cancer (PCa). We previously showed that autophagy played a protective role during hormone ablation therapy, in part, by consuming lipid droplets in PCa cells. In addition, blocking autophagy by genetic and pharmacological means in the presence of androgen deprivation caused cell death in PCa cells. To further investigate the importance of autophagy in PCa survival and dissect the role of CLQ in PCa death, we treated hormone responsive LNCaP cells with CLQ in combination with androgen deprivation. We observed that CLQ synergistically killed LNCaP cells during androgen deprivation in a dose- and time-dependent manner. We further confirmed that CLQ inhibited the maturation of autophagic vesicles and decreased the cytosolic ATP. Moreover, CLQ induced nuclear condensation and DNA fragmentation, a hallmark of apoptosis, in androgen deprived LNCaP cells. Taken together, our finding suggests that CLQ may be an useful adjuvant in hormone ablation therapy to improve the therapeutic efficacy. PMID- 22819841 TI - CDK2 differentially controls normal cell senescence and cancer cell proliferation upon exposure to reactive oxygen species. AB - Reactive oxygen species modulate cell fate in a context-dependent manner. Sublethal doses of H(2)O(2) decreased the level of proliferating cell nuclear antigen (PCNA) in normal cells (including primary human dermal fibroblasts and IMR-90 cells) without affecting cyclin-dependent kinase 2 (CDK2) activity, leading to cell cycle arrest and subsequent senescence. In contrast, exposure of cancer cells (such as HeLa and MCF7 cells) to H(2)O(2) increased CDK2 activity with no accompanying change in the PCNA level, leading to cell proliferation. A CDK2 inhibitor, CVT-313, prevented H(2)O(2)-induced cancer cell proliferation. These results support the notion that the cyclin/CDK2/p21(Cip1)/PCNA complex plays an important role as a regulator of cell fate decisions. PMID- 22819842 TI - Identification of proteins susceptible to thiol oxidation in endothelial cells exposed to hypochlorous acid and N-chloramines. AB - Hypochlorous acid (HOCl) is a potent oxidant produced by the enzyme myeloperoxidase, which is released by neutrophils under inflammatory conditions. Although important in the immune system, HOCl can also damage host tissue, which contributes to the development of disease. HOCl reacts readily with free amino groups to form N-chloramines, which also cause damage in vivo, owing to the extracellular release of myeloperoxidase and production of HOCl. HOCl and N chloramines react readily with cellular thiols, which causes dysfunction via enzyme inactivation and modulation of redox signaling processes. In this study, the ability of HOCl and model N-chloramines produced on histamine and ammonia at inflammatory sites, to oxidize specific thiol-containing proteins in human coronary artery endothelial cells was investigated. Using a proteomics approach with the thiol-specific probe, 5-iodoacetamidofluorescein, we show that several proteins including peptidylprolyl isomerase A (cyclophilin A), protein disulfide isomerase, glyceraldehyde-3-phosphate dehydrogenase and galectin-1 are particularly sensitive to oxidation by HOCl and N-chloramines formed at inflammatory sites. This will contribute to cellular dysfunction and may play a role in inflammatory disease pathogenesis. PMID- 22819843 TI - Type-I IFN signaling is required for the induction of antigen-specific CD8(+) T cell responses by adenovirus vector vaccine in the gut-mucosa. AB - Adenovirus vector (Adv) vaccination at a systemic site, such as intramuscular (i.m.) immunization, can induce antigen-specific CD8(+) T cell responses in both systemic and mucosal compartments. It remains unclear, however, how antigen specific CD8(+) T cell response is induced in the mucosa. In this study, we found that type-I IFN signaling is required for the induction of mRNA expression of retinal dehydrogenase in the draining lymph nodes following the i.m. Adv vaccination. We show that type-I IFN signaling is required for the induction of antigen-specific CD8(+) T cell response in the gut-mucosal compartment following the i.m. Adv vaccination. PMID- 22819844 TI - Investigating the prevalence of queuine in Escherichia coli RNA via incorporation of the tritium-labeled precursor, preQ(1). AB - There are over 100 modified bases that occur in RNA with the majority found in transfer RNA. It has been widely believed that the queuine modification is limited to four transfer RNA species in vivo. However, given the vast amount of the human genome (60-70%) that is transcribed into non-coding RNA (Mattick [10]), probing the presence of modified bases in these RNAs is of fundamental importance. The mechanism of incorporation of queuine, via transglycosylation, makes this uniquely poised to probe base modification in RNA. Results of incubations of Escherichia coli cell cultures with [(3)H] preQ(1) (a queuine precursor in eubacteria) clearly demonstrate preQ(1) incorporation into a number of RNA species of various sizes larger than transfer RNA. Specifically, significant levels of preQ(1) incorporation into ribosomal RNA are observed. The modification of other large RNAs was also observed. These results confirm that non-coding RNAs contain modified bases and lead to the supposition that these modifications are necessary to control non-coding RNA structure and function as has been shown for transfer RNA. PMID- 22819845 TI - Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. AB - OBJECTIVE: Recent investigations have suggested that the inflammasome plays a role in the development of vascular inflammation and atherosclerosis; however, its precise role remains controversial. We produced double-deficient mice for apolipoprotien E (Apoe) and caspase-1 (Casp1), a key component molecule of the inflammasome, and investigated the effect of caspase-1 deficiency on vascular inflammation and atherosclerosis. METHODS AND RESULTS: Atherosclerotic plaque areas in whole aortas and aortic root of Western diet (WD)-fed Apoe(-/-)Casp1(-/ ) mice were significantly reduced compared to those in Apoe(-/-) mice. The amount of macrophages and vascular smooth muscle cells in the plaques was also reduced in Apoe(-/-)Casp1(-/-) mice. No significant differences in plasma lipid profiles and body weight change were observed between these mice. Expression of interleukin (IL)-1beta in the plaques as well as plasma levels of IL-1beta, IL 1alpha, IL-6, CCL2, and TNF-alpha, in Apoe(-/-)Casp1(-/-) mice were lower than those in Apoe(-/-) mice. In vitro experiments showed that calcium phosphate crystals induced caspase-1 activation and secretion of IL-1beta and IL-1alpha in macrophages. CONCLUSION: Our findings suggest that caspase-1 plays a critical role in vascular inflammation and atherosclerosis, and that modulation of caspase 1 could be a potential target for prevention and treatment of atherosclerosis. PMID- 22819846 TI - Hepatoma-derived growth factor stimulates podosome rosettes formation in NIH/3T3 cells through the activation of phosphatidylinositol 3-kinase/Akt pathway. AB - Hepatoma-derived growth factor (HDGF) stimulates the migration, invasion and metastasis in several types of cancer cells. However, the mechanism underlying HDGF-stimulated migration remains unclear. In this study, we investigated the influence of HDGF on cytoskeleton remodeling and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in non-transformed NIH/3T3 cells. Exogenous HDGF promoted the migration and the formation of dorsal ruffles and podosome rosettes. Besides, HDGF supply increased the PI3K expression and Akt phosphorylation in dose- and time-dependent manners. Application of LY294002, a PI3K inhibitor, attenuated the HDGF-induced migration, dorsal ruffles and podosome rosettes formation. Consistently, the HDGF-overexpressing NIH/3T3 transfectants exhibited significantly increased motility and elevated PI3K/Akt activities, which were repressed by LY294002 or adenovirus-mediated overexpression of endogenous PI3K antagonist, PTEN. In summary, HDGF elicits the activation of PI3K/Akt signaling cascade, thereby promoting cytoskeleton remodeling to stimulate cellular migration. PMID- 22819847 TI - Walk more (frequently, farther, faster): the perfect preventive medicine. PMID- 22819848 TI - Cognition and communication dysfunctions in early-onset schizophrenia: effect of risperidone. AB - BACKGROUND: Cognitive impairment and formal thought disorder, also referred to as communication disturbances, are considered the core symptoms of schizophrenia, strongly affecting social functioning and long-term outcome. Several studies in adult patients suggest improvement of both functions after the treatment with atypical antipsychotic drugs. Such medications are also used as first line treatment in early-onset schizophrenia, however their efficacy in cognitive and communication domains in this population have not been systematically assessed. AIM OF THE STUDY: Evaluation of risperidone efficacy at psychopathological symptoms, cognitive impairment and formal thought disorder in adolescents with schizophrenia spectrum diagnosis. MATERIAL AND METHOD: Psychopathological symptoms, cognitive functioning and formal thought disorder were evaluated in 32 hospitalized adolescent patients with schizophrenia spectrum diagnosis at the beginning of risperidone treatment and after clinical improvement and compared to the results of matched healthy control group. RESULTS: Risperidone treatment was associated with reduction of symptom severity and moderate improvement of formal thought disorder and some aspects of executive functions. Working memory and verbal fluency were not improved. There were few correlations between psychopathological symptoms and results of cognitive tests, mainly between negative symptoms and executive functions. DISCUSSION: In early-onset schizophrenia spectrum disorders atypical antipsychotic treatment is associated with alleviation of symptoms and only selective and moderate cognitive and communication improvement. PMID- 22819849 TI - Proteasome deubiquitinases as novel targets for cancer therapy. AB - The ubiquitin-proteasome system (UPS) is a conserved pathway regulating numerous biological processes including protein turnover, DNA repair, and intracellular trafficking. Tumor cells are dependent on a functioning UPS, making it an ideal target for the development of novel anti-cancer therapies. The development of bortezomib (Velcade((r))) as a treatment for multiple myeloma and mantle cell lymphoma has verified this and suggests that targeting other components of the UPS may be a viable strategy for the treatment for cancer. We recently described a novel class of proteasome inhibitors that function by an alternative mechanism of action (D'Arcy et al., 2011). The small molecule b-AP15 blocks the deubiquitinase (DUB) activity of the 19S regulatory particle (19S RP) without inhibiting the proteolytic activities of the 20S core particle (20S CP). b-AP15 inhibits two proteasome-associated DUBs, USP14 and UCHL5, resulting in a rapid accumulation of high molecular weight ubiquitin conjugates and a functional proteasome shutdown. Interestingly, b-AP15 displays several differences to bortezomib including insensitivity to over-expression of the anti-apoptotic mediator Bcl-2 and anti-tumor activity in solid tumor models. In this review we will discuss the potential of proteasome deubiquitinase inhibitors as additions to the therapeutic arsenal against cancer. PMID- 22819850 TI - Signals from noncoding RNAs: unconventional roles for conventional pol III transcripts. AB - A range of noncoding RNAs are transcribed by pol III. A lot of them such as tRNA, 7SL RNA, 7SK RNA, 5S RNA, MRP RNA, Y RNAs, H1 RNA, and vault RNAs are considered as "house keeping" RNAs essential for eukaryotic cells. In recent years, researchers started to recognize the existence of unconventional functions of many pol III transcripts other than classical "house keeping" roles. Therefore, these ncRNAs could now be viewed as molecules with functional regulatory signals as well as cellular building blocks. These noncoding RNAs, all transcribed by pol III, may assemble regulatory networks with analogy to signaling pathways in eukaryotic cells. In this review we discuss these unconventional roles of pol III transcripts. PMID- 22819852 TI - Use of micro-emulsion technology for the directed evolution of antibodies. AB - Affinity reagents, such as antibodies, are needed to study protein expression patterns, sub-cellular localization, and post-translational modifications in complex mixtures and tissues. Phage Emulsion, Secretion, and Capture (ESCape) is a novel micro-emulsion technology that utilizes water-in-oil (W/O) emulsions for the identification and isolation of cells secreting phage particles that display desirable antibodies. Using this method, a large library of antibody-displaying phage will bind to beads in individual compartments. Rather than using biopanning on a large mixed population, phage micro-emulsion technology allows us to individually query clonal populations of amplified phage against the antigen. The use of emulsions to generate microdroplets has the promise of accelerating phage selection experiments by permitting fine discrimination of kinetic parameters for binding to targets. In this study, we demonstrate the ability of phage micro emulsion technology to distinguish two scFvs with a 300-fold difference in binding affinities (100nM and 300pM, respectively). In addition, we describe the application of phage micro-emulsion technology for the selection of scFvs that are resistant to elevated temperatures. PMID- 22819853 TI - Uniform amplification of phage display libraries in monodisperse emulsions. AB - In this paper, we describe a complete experimental setup for the uniform amplification of libraries of phage. Uniform amplification, which multiplies every phage clone by the same amount irrespective of the growth rate of the clone is essential for phage-display screening. Amplification of phage libraries in a common solution is often non-uniform: it favors fast-growing clones and eliminates those that grow slower. This competition leads to elimination of many useful binding clones, and it is a major barrier to identification of ligands for targets with multiple binding sites such as cells, tissues, or mixtures of proteins. Uniform amplification is achieved by encapsulating individual phage clones into isolated compartments (droplets) of identical volume. Each droplet contains culture medium and an excess of host (Escherichia coli). Here, we describe microfluidics devices that generate mono-disperse droplet-based compartments, and optimal conditions for amplification of libraries of different size. We also describe the detailed synthesis of a perfluoro surfactant, which gives droplets exceptional stability. Droplets stabilized by this compound do not coalesce after many hours in shaking culture. We identified a commercially available compound (Krytox), which destabilizes these droplets to recover the amplified libraries. Overall, uniform amplification is a sequence of three simple steps: (1) encapsulation of mixture of phage and bacteria in droplets using microfluidics; (2) incubation of droplets in a shaking culture; (3) destabilization of droplets to harvest the amplified phage. We anticipate that this procedure can be easily adapted in any academic or industrial laboratory that uses phage display. PMID- 22819851 TI - A potential role for integrin signaling in mechanoelectrical feedback. AB - Certain forms of heart disease involve gross morphological changes to the myocardium that alter its hemodynamic loading conditions. These changes can ultimately lead to the increased deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin, which together work to pathologically alter the myocardium's bulk tissue mechanics. In addition to changing the mechanical properties of the heart, this maladaptive remodeling gives rise to changes in myocardium electrical conductivity and synchrony since the tissue's mechanical properties are intimately tied to its electrical characteristics. This phenomenon, called mechanoelectrical coupling (MEC), can render individuals affected by heart disease arrhythmogenic and susceptible to Sudden Cardiac Death (SCD). The underlying mechanisms of MEC have been attributed to various processes, including the action of stretch activated channels and changes in troponin C-Ca(2+) binding affinity. However, changes in the heart post infarction or due to congenital myopathies are also accompanied by shifts in the expression of various molecular components of cardiomyocytes, including the mechanosensitive family of integrin proteins. As transmembrane proteins, integrins mechanically couple the ECM with the intracellular cytoskeleton and have been implicated in mediating ion homeostasis in various cell types, including neurons and smooth muscle. Given evidence of altered integrin expression in the setting of heart disease coupled with the associated increased risk for arrhythmia, we argue in this review that integrin signaling contributes to MEC. In light of the significant mortality associated with arrhythmia and SCD, close examination of all culpable mechanisms, including integrin-mediated MEC, is necessary. PMID- 22819854 TI - Methods for studying quadruplexes: sequence, structure, recognition and biological behaviour. PMID- 22819855 TI - Deep sequencing analysis of phage libraries using Illumina platform. AB - This paper presents an analysis of phage-displayed libraries of peptides using Illumina. We describe steps for the preparation of short DNA fragments for deep sequencing and MatLab software for the analysis of the results. Screening of peptide libraries displayed on the surface of bacteriophage (phage display) can be used to discover peptides that bind to any target. The key step in this discovery is the analysis of peptide sequences present in the library. This analysis is usually performed by Sanger sequencing, which is labor intensive and limited to examination of a few hundred phage clones. On the other hand, Illumina deep-sequencing technology can characterize over 10(7) reads in a single run. We applied Illumina sequencing to analyze phage libraries. Using PCR, we isolated the variable regions from M13KE phage vectors from a phage display library. The PCR primers contained (i) sequences flanking the variable region, (ii) barcodes, and (iii) variable 5'-terminal region. We used this approach to examine how diversity of peptides in phage display libraries changes as a result of amplification of libraries in bacteria. Using HiSeq single-end Illumina sequencing of these fragments, we acquired over 2*10(7) reads, 57 base pairs (bp) in length. Each read contained information about the barcode (6bp), one complimentary region (12bp) and a variable region (36bp). We applied this sequencing to a model library of 10(6) unique clones and observed that amplification enriches ~150 clones, which dominate ~20% of the library. Deep sequencing, for the first time, characterized the collapse of diversity in phage libraries. The results suggest that screens based on repeated amplification and small-scale sequencing identify a few binding clones and miss thousands of useful clones. The deep sequencing approach described here could identify under represented clones in phage screens. It could also be instrumental in developing new screening strategies, which can preserve diversity of phage clones and identify ligands previously lost in phage display screens. PMID- 22819856 TI - Anti-idiotypic monobodies for immune response profiling. AB - A major goal in the study of autoimmune disease is the identification of biomarkers of disease to allow early diagnosis and initiation of treatment. The production of autoantibodies is the key feature of most autoimmune disease, so much effort has focused on characterizing the antigens reactive with these antibodies. However, even for the most well understood autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, identification of antigens that detect autoantibodies in all patients have yet to be discovered. We describe a novel strategy for deriving mimotopes to disease-specific serum antibodies by selecting anti-idiotypic monobodies from a large molecular diversity library. Monobodies are derived by partial randomization of two surface exposed loops of a fibronectin domain scaffold in a phage display vector. The phage library is selected for binding to serum antibodies using a subtractive panning strategy. We evaluated this strategy by selecting the monobody library on a pool of serum immunoglobulin derived from a group of rheumatoid arthritis patients and evaluated selected clones for multi-patient reactivity and specificity for rheumatoid arthritis. The use of the fibronectin scaffold to derive stable, easy to produce molecular probes for diagnosis of autoimmune disease could be of significant value in improving diagnostic assays for virtually any disease that exhibits a characteristic immune response. PMID- 22819857 TI - Phage display as a method for discovering cellular targets of small molecules. AB - Phage display can be used for the discovery of cellular targets of small molecules in order to unravel their mechanism of action, which is important in the drug discovery field to assess biological effects of drugs at the molecular level and to investigate pharmacokinetic characteristics of drugs in clinical use. The potential of phage display in the drug discovery field is shown by a lot of successful cellular target identifications of drug-like small molecules in the last decade. More recently, phage display was also introduced in environmental science to predict risks of small molecules, like nickel, 17beta estradiol and bisphenol A on both environmental and human health, wherefore knowledge about the mechanism of action and cellular targets is essential. This paper discusses some important aspects of the phage display approach for the discovery of cellular targets of small molecules. The different phage display libraries and immobilization strategies used for the discovery of cellular target of small molecules are described. In general, the phage display approach is very useful in drug discovery and environmental science as a fast and cost-effective in vitro tool to determine cellular targets of small molecules, which increases our understanding of the mechanisms of action of small molecules. PMID- 22819858 TI - Next generation phage display by use of pVII and pIX as display scaffolds. AB - Phage display technology has evolved to become an extremely versatile and powerful platform for protein engineering. The robustness of the phage particle, its ease of handling and its ability to tolerate a range of different capsid fusions are key features that explain the dominance of phage display in combinatorial engineering. Implementation of new technology is likely to ensure the continuation of its success, but has also revealed important short comings inherent to current phage display systems. This is in particular related to the biology of the two most popular display capsids, namely pIII and pVIII. Recent findings using two alternative capsids, pVII and pIX, located to the phage tip opposite that of pIII, suggest how they may be exploited to alleviate or circumvent many of these short comings. This review addresses important aspects of the current phage display standard and then discusses the use of pVII and pIX. These may both complement current systems and be used as alternative scaffolds for display and selection to further improve phage display as the ultimate combinatorial engineering platform. PMID- 22819859 TI - Nitric oxide implication in cadmium-induced programmed cell death in roots and signaling response of yellow lupine plants. AB - The sequence of events leading to the programmed cell death (PCD) induced by heavy metals in plants is still the object of extensive investigation. In this study we showed that roots of 3-day old yellow lupine (Lupinus luteus L.) seedlings exposed to cadmium (Cd, 89MUM CdCl(2)) resulted in PCD starting from 24h of stress duration, which was evidenced by TUNEL-positive reaction. Cd induced PCD was preceded by a relatively early burst of nitric oxide (NO) localized mainly in the root tips. Above changes were accompanied by the NADPH oxidase-dependent superoxide anion (O(2)(.-)) production. However, the concomitant high level of both NO and O(2)(.-) at the 24th h of Cd exposure did not provoke an enhanced peroxynitrite formation. The treatment with the NADPH oxidase inhibitor and NO-scavenger significantly reduced O(2)(.-) and NO production, respectively, as well as diminished the pool of cells undergoing PCD. The obtained data indicate that boosted NO and O(2)(.-) production is required for Cd-induced PCD in lupine roots. Moreover, we found that in roots of 14-day old lupine plants the NO-dependent Cd-induced PCD was correlated with the enhanced level of the post-stress signals in leaves, including distal NO cross talk with hydrogen peroxide. PMID- 22819860 TI - Effect of season, needle age and elevated CO2 concentration on photosynthesis and Rubisco acclimation in Picea abies. AB - While downward photosynthetic acclimation in response to elevated CO(2) (EC) is frequently accompanied by reduction in Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase), the exact mechanism behind this decrease and its dynamics are not well understood. We comprehensively studied Rubisco adjustment to EC in coniferous Picea abies using an electrophoretic (protein content), spectrophotometric (initial (RA(initial)) and total (RA(total)) in vitro Rubisco activities), and gas-exchange (maximum carboxylation activity in vivo (V(Cmax))) techniques. With respect to differing carbon sink strength and nitrogen remobilization, we hypothesized greater acclimation of photosynthesis in one-year old as compared to current-year needles and at the end than at the beginning of the vegetation season. EC treatment led to a decrease in V(Cmax) values in current-year needles, but the ribulose-1,5-bisphosphate (RuBP)-limited rate of photosynthesis (J(max)) remained unaffected. Indeed, both V(Cmax) and J(max) were reduced by the EC treatment in one-year-old needles. The extent of photosynthetic acclimation in EC plants did not increase, however, during the vegetation season. EC decreased the activation state of Rubisco (RA(initial)/RA(total)) by 16% and 5% in current-year and one-year-old needles, respectively (averaged over the growing season). While during spring (short-term effect) EC treatment did not influence the Rubisco content per unit leaf area and decreased its specific activity (activity per unit Rubisco mass) in both needle age classes studied, exposure to EC during the entire vegetation season tended to reduce the Rubisco content while increasing its specific activity. Irrespective of CO(2) treatment and needle age, a hyperbolic-decay relationship was observed between Rubisco specific activity and its content. PMID- 22819861 TI - Differential expression of ion transporters and aquaporins in leaves may contribute to different salt tolerance in Malus species. AB - Maintaining ion and water homeostasis in plants is an important defense strategy against salinity stress. Divergence in ion homeostasis between the salt-tolerant Malus hupehensis Rehd. and salt-sensitive Malus prunifolia 'yingyehaitang' was studied to understand their mechanisms for tolerance. Compared with the control on Day 15, plants of those two genotypes under high-salinity treatment had less K(+) in the leaves, stems, and roots. Contents were higher in the roots but lower in the leaves of M. hupehensis while levels in the stems were similar to those from M. prunifolia. For both genotypes, the sodium content increased after salinity treatment in all tissue types. However, the leaves from M. hupehensis had less Na(+) and maintained a lower Na(+)/K(+) ratio. To understand the basis for these differences, we studied the ion transporters and regulation of aquaporin transcripts in the leaves. Transcript levels for both MdHKT1 and MdSOS1 were higher in M. hupehensis, implying that this species had better capacity to exclude sodium so that less Na(+) occurred in the leaves but more in the stems. M. hupehensis also had a greater amount of MdNHX1 transcripts, which could have assisted in sequestering excess Na(+) into the vacuoles and sustaining a better cellular environment. A relatively higher level of aquaporin transcript was also found in M. hupehensis, suggesting that those plants were more capable of maintaining a better leaf water status and diluting excess ions effectively under high-salinity conditions. Therefore, these tested transporters may play important roles in determining how salinity tolerance is conferred in Malus species. PMID- 22819862 TI - Increased de novo riboflavin synthesis and hydrolysis of FMN are involved in riboflavin secretion from Hyoscyamus albus hairy roots under iron deficiency. AB - Riboflavin secretion by Hyoscyamus albus hairy roots under Fe deficiency was examined to determine where riboflavin is produced and whether production occurs via an enhancement of riboflavin biosynthesis or a stimulation of flavin mononucleotide (FMN) hydrolysis. Confocal fluorescent microscopy showed that riboflavin was mainly localized in the epidermis and cortex of the root tip and, at the cellular level, in the apoplast. The expressions of three genes involved in the de novo biosynthesis of riboflavin (GTP cyclohydrolase II/3,4-dihydroxy-2 butanone 4-phosphate synthase; 6,7-dimethyl-8-ribityllumazine synthase; riboflavin synthase) were compared between Fe-starved and Fe-replete roots over a time-course of 7 days, using RT-PCR. All three genes were found to be highly expressed over the period 1-7 days in the roots cultured under Fe deficiency. Since riboflavin secretion began to be detected only from 3 days, there was a lag phase observed between the increased transcript accumulations and riboflavin secretion. To determine whether FMN hydrolysis might contribute to the riboflavin secretion in Fe-deficient root cultures, FMN hydrolase activity was determined and was found to be substantially increased after 3 days, when riboflavin secretion became detectable. These results suggested that not only de novo riboflavin synthesis but also the hydrolysis of FMN contributes to riboflavin secretion under conditions of Fe deficiency. Respiration activity was assayed during the time-course, and was also found to be enhanced after 3 days under Fe deficiency, suggesting a possible link with riboflavin secretion. On the other hand, several respiratory inhibitors were found not to affect riboflavin synthase transcript accumulation. PMID- 22819863 TI - An oral CD3-specific antibody suppresses T-cell-induced colitis and alters cytokine responses to T-cell activation in mice. AB - BACKGROUND & AIMS: New therapeutic approaches are needed for inflammatory bowel diseases. A monoclonal antibody against CD3 (anti-CD3) suppresses T-cell-mediated autoimmune diseases such as experimental allergic encephalomyelitis. We explored the effects of anti-CD3 in mice with colitis. METHODS: Severe combined immunodeficient mice were given injections of CD4(+)CD45RB(high) T cells to induce colitis. Four weeks later, the mice were given 2 or 5 MUg/day of anti-CD3 or hamster immunoglobulin (Ig)G (control), via gavage, for 5 or 10 days. The effect of oral anti-CD3 on cytokine responses was studied by activating T cells using intraperitoneal injections of anti-CD3 monoclonal antibody 2 days after oral administration of the antibody. We collected intestine samples for histology analysis and cells were analyzed by flow cytometry. Cytokines in sera were analyzed by cytometric bead array. RESULTS: Oral administration of anti-CD3 protected the mice from wasting disease and intestinal inflammation. Analyses of spleen and mesenteric lymph node cells showed no differences in total cell counts, or percentages of CD4(+) and forkhead box P3(+) regulatory T cells, between mice given anti-CD3 or the control immunoglobulin. Colitis therefore was not suppressed by induction of forkhead box P3(+) regulatory T cells, or depletion or limited expansion of T cells. Oral administration of anti-CD3 ameliorated the enteropathy induced by intraperitoneal injection of the antibody. In mice with enteropathy, oral anti-CD3 reduced levels of inflammatory cytokines such as interferon-gamma, tumor necrosis factor-alpha, and interleukin (IL)-6; it also increased levels of the anti-inflammatory cytokines IL-10 and transforming growth factor-beta. The effects of oral anti-CD3 required IL-10. CONCLUSIONS: Oral administration of anti-CD3 to mice induces changes in the mucosal immune response that prevent colitis, independent of specific antigen, and reduce T-cell activation in an IL-10-dependent manner. Oral anti-CD3 therefore might be developed for the treatment of patients with inflammatory bowel disease. PMID- 22819864 TI - Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. AB - BACKGROUND & AIMS: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. METHODS: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. RESULTS: At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported. CONCLUSIONS: In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival. PMID- 22819865 TI - Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice. AB - BACKGROUND & AIMS: Pancreatic adenocarcinoma (PAC) is often diagnosed at an advanced and inoperable stage, and standard systemic treatments are generally ineffective. We investigated the effects of adoptive transfer of tumor-specific T cells that express chimeric antibody-based receptors (CAR) to mice with primary and metastatic PAC xenografts. METHODS: Human effector T cells were genetically modified to express CAR against Her2/neu or CD24, a putative PAC stem cell antigen. The antitumor reactivity of the engineered T cells (T-bodies) was evaluated in SCID mice with different PAC xenografts. A total of 1 * 10(7) T bodies were injected via the tail vein or directly administered to the subcutaneous tumor on 3 or 4 alternating days. Mice were then given twice-daily intraperitoneal injections of interleukin-2 for 10 days. RESULTS: Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. Intravenous injection of T-bodies reduced tumor size and prolonged survival of mice with orthotopically transplanted tumors; more than 50% of animals appeared to be disease-free more than 2 months later. Additional systemic administration of T-bodies 8 weeks after the initial injection eliminated primary tumors, along with liver and draining lymph node metastases. A single administration of the Her2/neu-specific T-bodies prolonged the survival of mice with tumors in which most of the cells expressed the target antigen. In contrast, the CD24-specific T-bodies prolonged survival of mice in which only a subpopulation of the tumor cells expressed the antigen. CONCLUSIONS: CAR redirected T cells stop growth and metastasis of PAC xenografts in mice. T-bodies specific to CD24, a putative cancer stem cell antigen, were effective against PAC xenografts that had only a subset of antigen-expressing cells. PMID- 22819866 TI - Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine. AB - BACKGROUND & AIMS: Tissue inhibitor of metalloproteinases (TIMP)-3 is an inhibitor of matrix metalloproteinases, which regulates tissue inflammation, damage, and repair. We investigated the role of TIMP-3 in intestinal inflammation in human beings and mice. METHODS: We used real-time polymerase chain reaction and flow cytometry to measure levels of TIMP-3 in intestine samples from patients with Crohn's disease (CD) and those without (controls). We also analyzed TIMP-3 levels in lamina propria mononuclear cells (LPMCs) collected from biopsy samples of individuals with or without CD (controls) and then stimulated with transforming growth factor (TGF)-beta1, as well as in biopsy samples collected from patients with CD and then incubated with a Smad7 anti-sense oligonucleotide (knock down). LPMCs and biopsy samples from patients with CD were cultured with exogenous TIMP-3 and levels of inflammatory cytokines were measured. We evaluated the susceptibility of wild-type, TIMP-3-knockout (TIMP-3-KO), and transgenic (TIMP-3-Tg) mice to induction of colitis with 2, 4, 6-trinitrobenzene-sulfonic acid (TNBS), and the course of colitis in recombinase-activating gene-1-null mice after transfer of wild-type or TIMP-3-KO T cells. RESULTS: Levels of TIMP-3 were reduced in intestine samples from patients with CD compared with controls. Incubation of control LPMCs with TGF-beta1 up-regulated TIMP-3; knockdown of Smad7, an inhibitor of TGF-beta1, in biopsy samples from patients with CD increased levels of TIMP-3. Exogenous TIMP-3 reduced levels of inflammatory cytokines in CD LPMCs and biopsy samples. TIMP-3-KO mice developed severe colitis after administration of TNBS, whereas TIMP-3-Tg mice were resistant to TNBS induced colitis. Reconstitution of recombinase-activating gene-1-null mice with T cells from TIMP-3-KO mice increased the severity of colitis, compared with reconstitution with wild-type T cells. CONCLUSIONS: TIMP-3 is down-regulated in inflamed intestine of patients with CD. Its expression is regulated by TGF-beta1, and knock-down of Smad7 in intestinal tissues from patient with CD up-regulates TIMP-3. Loss or reduction of TIMP-3 in mice promotes development of colitis. PMID- 22819867 TI - Studying psychoactive substance use in injured patients: does exclusion of late arriving patients bias the results? AB - BACKGROUND: Most studies of the prevalence of psychoactive substances in injured emergency department patients have excluded those who arrive more than 6h after injury. This may cause a selection bias. The aim of this study was: (1) to describe the characteristics of patients who arrive more than 6h after injury, compared to patients who arrive sooner (2) to examine whether self-report can add to the assessment of alcohol use when the patient is assessed more than 6h after injury. METHODS: Blood sample analysis and self-report data were used to assess the prevalence of psychoactive substances in injured patients admitted to an emergency department within 48 h of injury (n=1611). Discriminant function analysis was used to assess group differences. RESULTS: The patients who arrived more than 6h after injury differed significantly from those who arrived earlier in several respects. They more often screened positive for hypnotics; they were older, they were more likely to have had a fall and they were more often injured at home and at night. Self reported use of alcohol showed good consistency with blood sample screening within 6h of injury and could therefore be used to assess alcohol use more than 6h after injury. CONCLUSIONS: Patients who arrive more than 6h after injury differ significantly from those who arrive earlier. Future studies on the prevalence of psychoactive substances in emergency departments could expand the inclusion window. PMID- 22819868 TI - Hazardous alcohol consumption among young adult IDU and its association with high risk behaviors. AB - BACKGROUND: Heavy alcohol consumption has been associated with risk-taking behaviors in intravenous drug users (IDU). However, limited information exists on the relationship between alcohol use and injecting and sexual risk in young adult IDU (<30 years) who are at risk for hepatitis C virus (HCV) and HIV infection. METHODS: We conducted a cross-sectional study of young adult IDU in San Francisco (2006-2012) who had not previously tested positive for HCV. Participants completed a structured interview and HCV testing. We examined whether hazardous drinking (Alcohol Use Disorders Test-Consumption [AUDIT-C] 3-9 for women and 4-9 for men) and probable dependent drinking (AUDIT-C 10-12) levels were associated with injecting and sexual risk behaviors and HCV status, indicated by adjusted odds ratios (AOR) in separate models controlling for potential confounders. RESULTS: Of the 326 participants, 139 (42.6%) were hazardous drinkers and 82 (25.2%) were probable dependent drinkers; thus over two-thirds evidenced problem drinking. Being a hazardous drinker was significantly associated with injecting drug residue from another's drug preparation equipment (AOR 1.93). Probable dependent drinking was significantly associated with sharing non-sterile drug preparation equipment (AOR 2.59), and inversely, with daily/near daily injecting (AOR 0.42). Both heavy drinking levels were associated with having >=2 sexual partners (AOR 2.43 and 2.14). Drinking category was not associated with HCV test results. CONCLUSION: The young adult IDU reported consuming alcohol at very high levels, which was associated with some unsafe sexual and injecting behaviors. Our study demonstrates the urgent need to intervene to reduce alcohol consumption in this population. PMID- 22819869 TI - The impact of the prohibition of benzylpiperazine (BZP) 'legal highs' on the prevalence of BZP, new legal highs and other drug use in New Zealand. AB - BACKGROUND: Benzylpiperazine (BZP) is the psychoactive ingredient in a range of 'legal highs' sold worldwide. BZP was prohibited in New Zealand in 2008. AIM: To investigate the impact of the prohibition of BZP legal highs on the prevalence of BZP, replacement legal highs and other drugs. METHODS: A population survey of BZP and other drugs was conducted in 2006 (while BZP was legal) and repeated in 2009 (+12 months after BZP was prohibited). Respondents were asked to provide the reason(s) why they had stopped using BZP. Annual surveys of frequent drug users were conducted from 2006 to 2010. RESULTS: Last year prevalence of BZP among the general population fell from 15.3% in 2006 to 3.2% in 2009. The most common reasons for stopping BZP use in 2008 were 'it's illegal now' (43%), 'just experimenting' (26%), 'don't know where to get it now it's illegal' (24%) and 'bad hangover effect' (18%). Three per cent of the general population had used any new legal high in 2009. Use of BZP declined among frequent methamphetamine users from 32% in 2006 to 7% in 2010; among frequent ecstasy users from 65% in 2006 to 11% in 2010; and among frequent injecting drug users from 30% in 2007 to 20% in 2010. The use of new legal highs in 2010 was lower than the former use of BZP in 2006. CONCLUSIONS: Unpleasant side-effects and the prohibition contributed to a decline in BZP use. The overall level of legal high use was lower following the prohibition of BZP. PMID- 22819870 TI - Compression and swelling of activated sludge cakes during dewatering. AB - A drainage/filtration apparatus was developed for automatically determining sedimentation velocity and dewatering rate. Pressure-step testing was used to study filter cake compressibility, resistance, and swelling. Activated sludge was analysed, and the data indicate that the sludge is highly compressible even at low pressures (10 kPa). Furthermore, compressed sludge cakes swell if the pressure is released. Hence, the average specific cake resistance decreases if the pressure is released, though the resistance is higher after the compression cycle than before. Sludge must be dewatered under low pressure, because higher pressure only compresses the cake and does not improve the dewatering rate. PMID- 22819871 TI - Toxic effect of the combined antibiotics ciprofloxacin, lincomycin, and tylosin on two species of marine diatoms. AB - The role that antibiotics and other "emerging contaminants" play in shaping environmental microbial communities is of growing interest. The use of the prokaryotic metabolic inhibitors tylosin (T), lincomycin (L), and ciprofloxacin (C) in livestock and humans is both global and extensive. Each of these antibiotic compounds exhibits an affinity for sediment particles, increasing the likelihood of their deposition in the benthos of aquatic systems and each are often present in environmental samples. The purpose of this study was to determine if T, L, and C and their mixtures exhibit significant toxicity to two species of marine diatoms, an algal class comprised of ubiquitous eukaryotic primary producers. Subpopulations from laboratory cultures of Cylindrotheca closterium and Navicula ramosissima were reared in 24-well microtiter plates in the presence of single or combined antibiotics in dilution series. Population growth rates were assessed via epifluorescent microscopic cell counts, from which the half-max inhibitory concentrations (IC(50)) were calculated and used as part of a toxic unit (TU) method for assessing mixture interactions. The single compound IC(50)'s were, for C. closterium: T = 0.27 mg L(-1), L = 14.16 mg L(-1), C = 55.43 mg L(-1), and for N. ramosissima: T = 0.99 mg L(-1), L = 11.08 mg L( 1), C = 72.12 mg L(-1). These values were generally higher than similar metrics for freshwater species. Mixture IC(50)'s were generally synergistic against C. closterium and additive for N. ramosissima. Both single and combined treatments reduced or eliminated diatom motility. Monochemical responses were similar between species and were not useful for predicting mixture interactions. Mixtures had compound-specific and species-specific effects, favoring N. ramosissima. These results suggest that anthropogenic antibiotics may play a significant role in the ecology of environmental benthic microbial communities. They also suggest single-compound/species studies do not yield useful predictions of the ecological impact of anthropogenic pharmaceuticals. PMID- 22819872 TI - Physical characterisation of the sludge produced in a sequencing batch biofilter granular reactor. AB - Sequencing batch biofilter granular reactor (SBBGR) is a recently developed biological wastewater treatment technology characterised by a very low sludge production, among other numerous advantages. Even if costs for sludge treatment and disposal are mainly dependent on the amount of sludge produced, sludge properties, especially those linked to solid-liquid separation, play a key role as well. In fact, such properties deeply influence the type of treatments sludge has to undergo before disposal and the final achievable solids concentration, strongly affecting treatment and disposal costs. As sludge from SBBGR is a special mixture of biofilm and aerobic granules, no information is available so far on its treatability. This study addresses the characterisation of the sludge produced from SBBGR in terms of some physical properties (settling properties, dewaterability, rheology). The results show that such sludge is characterised by good settling and dewatering properties, adding a new advantage for the full scale application of SBBGR technology. PMID- 22819873 TI - Temporal flux and spatial dynamics of nutrients, fecal indicators, and zoonotic pathogens in anaerobic swine manure lagoon water. AB - Confined animal feeding operations (CAFOs) often use anaerobic lagoons for manure treatment. In the USA, swine CAFO lagoon water is used for crop irrigation that is regulated by farm-specific nutrient management plans (NMPs). Implementation of stricter US environmental regulations in 2013 will set soil P limits; impacting land applications of manure and requiring revision of NMPs. Precise knowledge of lagoon water quality is needed for formulating NMPs, for understanding losses of N and C in ammonia and greenhouse gas emissions, and for understanding risks of environmental contamination by fecal bacteria, including zoonotic pathogens. In this study we determined year-round levels of nutrients and bacteria from swine CAFO lagoon water. Statistical analysis of data for pH, electrical conductivity (EC), inorganic and organic C, total N, water-soluble and total minerals (Ca, Cu, Fe, K, Mg, Mn, P, and Zn) and bacteria (Escherichia coli, enterococci, Clostridium perfringens, Campylobacter spp., Listeria spp., Salmonella spp., and staphylococci) showed that all differed significantly by dates of collection. During the irrigation season, levels of total N decreased by half and the N:P ratio changed from 9.7 to 2.8. Some seasonal differences were correlated with temperature. Total N and inorganic C increased below 19 degrees C, and decreased above 19 degrees C, consistent with summer increases in ammonia and greenhouse gas emissions. Water-soluble Cu, Fe, and Zn increased with higher summer temperatures while enterococci and zoonotic pathogens (Campylobacter, Listeria, and Salmonella) decreased. Although their populations changed seasonally, the zoonotic pathogens were present year-round. Increasing levels of E. coli were statistically correlated with increasing pH. Differences between depths were also found. Organic C, total nutrients (C, Ca, Cu, Fe, Mg, Mn, N, P, and Zn) and C. perfringens were higher in deeper samples, indicating stratification of these parameters. No statistical interactions were found between collection dates and depths. PMID- 22819874 TI - Enteric pathogens in stool samples of Chicago-area water recreators with new onset gastrointestinal symptoms. AB - BACKGROUND: Characterizing pathogens responsible for recreational waterborne gastrointestinal illness is important in estimating risk and developing management strategies to prevent infection. Although water recreation is associated with sporadic cases of gastrointestinal illness, pathogens responsible for such illness are not well characterized. METHODS: A prospective cohort study was conducted enrolling non-water recreators (such as cyclists and joggers) and two groups of limited-contact waters recreators (such as boaters and kayakers): those on an effluent-dominated urban waterway and those on general use waters. Stool samples were collected from participants who developed gastrointestinal symptoms during a three-week follow-up period. Samples were analyzed for bacterial, viral, and protozoan pathogens. Logistic regression models were used to identify associations between water recreation and the presence of pathogens in stool samples. RESULTS: Among 10,998 participants without gastrointestinal symptoms at baseline, 2,429 (22.1%) developed at least one symptom during 21 days of follow-up. Of those, 740 (30.5%) provided at least one stool sample, of which 76 (10.3%) were positive for a pathogen. Rotavirus, found primarily among adults, accounted for 53 of the 76 (70%) infections. Among participants with symptoms, pathogen presence was not associated with water recreation or the extent of water exposure. The range of pathogens that could be identified and sample size limitations may have contributed to this lack of association. CONCLUSIONS: We did not find specific pathogens or groups of pathogens associated with recreational waterborne gastrointestinal illness. Although pathogens responsible for outbreaks of waterborne gastrointestinal illness have been described, microbes that cause sporadic cases remain poorly defined. PMID- 22819875 TI - The role of effluent nitrate in trace organic chemical oxidation during UV disinfection. AB - Most conventional biological treatment wastewater treatment plants (WWTPs) contain nitrate in the effluent. Nitrate undergoes photolysis when irradiated with ultraviolet (UV) light in the 200-240 and 300-325 nm wavelength range. In the process of nitrate photolysis, nitrite and hydroxyl radicals are produced. Medium pressure mercury lamps emitting a polychromatic UV spectrum including irradiation below 240 nm are becoming more common for wastewater disinfection. Therefore, nitrified effluent irradiated with polychromatic UV could effectively become a de facto advanced oxidation (hydroxyl radical) treatment process. UV based advanced oxidation processes commonly rely on addition of hydrogen peroxide in the presence of UV irradiation for production of hydroxyl radicals. This study compares the steady-state concentration of hydroxyl radicals produced by nitrate contained in a conventional WWTP effluent to that produced by typical concentrations of hydrogen peroxide used for advanced oxidation treatment of water. The quantum yield of hydroxyl radical production from nitrate by all pathways was calculated to be 0.24 +/- 0.03, and the quantum yield of hydroxyl radicals from nitrite was calculated to be 0.65 +/- 0.06. A model was developed that would estimate production of hydroxyl radicals directly from nitrate and water quality parameters. In effluents with >5 mg-N/L of nitrate, the concentration of hydroxyl radicals is comparable to that produced by addition of 10 mg/L of H(2)O(2). Nitrifying wastewater treatment plants utilizing polychromatic UV systems at disinfection dose levels can be expected to achieve up to 30% degradation of some micropollutants by hydroxyl radical oxidation. Increasing UV fluence to levels used during advanced oxidation could achieve over 95% degradation of some compounds. PMID- 22819877 TI - Transitioning the adolescent with type 1 diabetes mellitus. PMID- 22819876 TI - Redox regulation of protein tyrosine phosphatase activity by hydroxyl radical. AB - Substantial evidence suggests that transient production of reactive oxygen species (ROS) such as hydrogen peroxide (H(2)O(2)) is an important signaling event triggered by the activation of various cell surface receptors. Major targets of H(2)O(2) include protein tyrosine phosphatases (PTPs). Oxidation of the active site Cys by H(2)O(2) abrogates PTP catalytic activity, thereby potentially furnishing a mechanism to ensure optimal tyrosine phosphorylation in response to a variety of physiological stimuli. Unfortunately, H(2)O(2) is poorly reactive in chemical terms and the second order rate constants for the H(2)O(2) mediated PTP inactivation are ~10M(-1)s(-1), which is too slow to be compatible with the transient signaling events occurring at the physiological concentrations of H(2)O(2). We find that hydroxyl radical is produced from H(2)O(2) solutions in the absence of metal chelating agent by the Fenton reaction. We show that the hydroxyl radical is capable of inactivating the PTPs and the inactivation is active site directed, through oxidation of the catalytic Cys to sulfenic acid, which can be reduced by low molecular weight thiols. We also show that hydroxyl radical is a kinetically more efficient oxidant than H(2)O(2) for inactivating the PTPs. The second-order rate constants for the hydroxyl radical-mediated PTP inactivation are at least 2-3 orders of magnitude higher than those mediated by H(2)O(2) under the same conditions. Thus, hydroxyl radical generated in vivo may serve as a more physiologically relevant oxidizing agent for PTP inactivation. This article is part of a Special Issue entitled: Chemistry and mechanism of phosphatases, diesterases and triesterases. PMID- 22819879 TI - Health datapalooza 2012. PMID- 22819880 TI - A 5-year experience with cardiopulmonary resuscitation using extracorporeal life support in non-postcardiotomy patients with cardiac arrest. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) using extracorporeal life support (ECLS) system has been successfully used to support patients with in- and out-of hospital cardiac arrest (IHCA, OHCA) when conventional measures have failed. The purpose of the current study is to report on our experience with extracorporeal CPR in non-postcardiotomy patients. METHODS: We retrospectively analysed a total of 85 consecutive adult patients, who have been treated with ECLS between January 2007 and January 2012. RESULTS: The mean CPR duration was 40 min (20-70 min). The mean ECLS support duration was 49 h (12-92 h). Twenty-eight patients (33%) had ECLS related complications. Forty patients (47%) were successfully weaned and 29 patients (34%) survived to hospital discharge. Among survivors, 93% were without severe neurologic deficit. Duration of CPR was shorter for survivors than for non survivors [(25: 20-50 min) vs. (50: 25-86 min); p=0.003]. Immediately after ECLS start, the mean blood lactate level was lower (p=0.003), and the mean pH value was higher in the survivors' group (p<0.0001) compared to the non-survivors' group. The CPR duration for the IHCA group (25: 20-50 min) was shorter compared to the OHCA group (70: 55-110min; p<0.0001). The survival rate in this group was higher compared to the OHCA group (42% vs. 15%; p<0.02). CONCLUSIONS: CPR using modern miniaturized ECLS systems should be established in the treatment of prolonged cardiac arrest and unsuccessful conventional CPR in selected patients. CPR with ECLS for OHCA has worse outcomes compared to IHCA. Duration of CPR was independent risk factor for mortality after extracorporeal CPR. PMID- 22819881 TI - Chest injury following cardiopulmonary resuscitation: a prospective computed tomography evaluation. AB - INTRODUCTION: Traumatic chest injuries may occur following cardiopulmonary resuscitation (CPR). The aim of this study was to address the frequency of injuries, especially rib and sternal fractures, and also to identify factors that contribute to post-CPR trauma. METHODS: This study was a prospective cross sectional study conducted in the emergency departments (ED) of eight academic tertiary care centers. To evaluate injuries secondary to CPR, we performed chest computed tomography (CT) in patients who were successfully resuscitated from cardiac arrest. Contributing factors that might be related to injuries were also investigated. RESULTS: We enrolled 71 patients between 1 January 2011 and 30 June 2011. Rib and sternal fractures were diagnosed in 22 and 3 patients, respectively. Females were more susceptible to rib fracture (p=0.036). When non physicians participated as chest compressors in the ED, more ribs were fractured (p=0.048). The duration of CPR and number of compressors were not contributing factors to trauma secondary to CPR. There was a wide variation in the frequency of rib fractures from hospital to hospital (0-83.3%). In high-risk hospitals (in which more than 50% of patients had rib fractures), the average age of the patients was higher, and non-physicians took part in ED CPR more often than they did at low-risk hospitals. CONCLUSION: The incidence of rib fracture following CPR was different in various hospitals. The presence of non-physician chest compressors in the ED was one of the contributing factors to rib fracture. Further studies on the influence of resuscitators and relation between quality of chest compression and CPR-induced injuries are warranted to reduce complications following CPR. PMID- 22819882 TI - From highly polluted Zn-rich acid mine drainage to non-metallic waters: implementation of a multi-step alkaline passive treatment system to remediate metal pollution. AB - Complete metal removal from highly-polluted acid mine drainage was attained by the use of a pilot multi-step passive remediation system. The remediation strategy employed can conceptually be subdivided into a first section where the complete trivalent metal removal was achieved by the employment of a previously tested limestone-based passive remediation technology followed by the use of a novel reactive substrate (caustic magnesia powder dispersed in a wood shavings matrix) obtaining a total divalent metal precipitation. This MgO-step was capable to abate high concentrations of Zn together with Mn, Cd, Co and Ni below the recommended limits for drinking waters. A reactive transport model anticipates that 1 m(3) of MgO-DAS (1 m thick * 1 m(2) section) would be able to treat a flow of 0.5 L/min of a highly acidic water (total acidity of 788 mg/L CaCO(3)) for more than 3 years. PMID- 22819883 TI - Polybrominated diphenyl ethers exposure in breast milk in Shanghai, China: levels, influencing factors and potential health risk for infants. AB - The use of polybrominated diphenyl ethers (PBDEs) is increasing annually in China. Although several studies have reported significant contamination by these compounds in biological samples in China, little is known about the factors that may influence the levels of exposure and the potential health risk for infants. We investigated PBDE exposure levels in breast milk, its influencing factors and the potential health risk for infants in Shanghai, China by enrolling 48 healthy women between September 2006 and April 2007. PBDE exposure was assessed by analyses of seven PBDE congeners in breast milk. The estimated daily intake of PBDEs by infants via breastfeeding was determined for evaluating the potential health risk for infants. The median (range) of total PBDE content in breast milk was 8.81 (1.92-41.55) ng/g lipid. 34 (71%) of the 48 samples tested positive for all seven congeners. Maternal education level and household monthly salary were positively associated with PBDE concentration in breast milk (r=0.337, p=0.019 and r=0.436, p=0.004, respectively). The median of estimated daily intake of BDE 99 (6.67 ng/kg/day) by infants via breastfeeding was below the human no adverse effect level (NAEL) set for BDE-99 for neurodevelopmental toxicity (18.8 ng/kg/day). However, 3 (6%) of the samples exceeded the human NAEL. Taking the high detection rate of PBDEs in breast milk together with 6% of their EDI higher than NAEL in Shanghai, more studies on the effects of maternal PBDE exposure on fetal growth and child neurodevelopment are warranted. PMID- 22819884 TI - The altered ecology of Lake Christina: a record of regime shifts, land-use change, and management from a temperate shallow lake. AB - We collected two sediment cores and modern submerged aquatic plants and phytoplankton from two sub-basins of Lake Christina, a large shallow lake in west central Minnesota, and used stable isotopic and elemental proxies from sedimentary organic matter to explore questions about the pre- and post settlement ecology of the lake. The two morphologically distinct sub-basins vary in their sensitivities to internal and external perturbations offering different paleoecological information. The record from the shallower and much larger western sub-basin reflects its strong response to internal processes, while the smaller and deeper eastern sub-basin record primarily reflects external processes including important post-settlement land-use changes in the area. A significant increase in organic carbon accumulation (3-4 times pre-settlement rates) and long term trends in delta(13)C, organic carbon to nitrogen ratios (C/N), and biogenic silica concentrations shows that primary production has increased and the lake has become increasingly phytoplankton-dominated in the post-settlement period. Significant shifts in delta(15)N values reflect land-clearing and agricultural practices in the region and support the idea that nutrient inputs have played an important role in triggering changes in the trophic status of the lake. Our examination of hydroclimatic data for the region over the last century suggests that natural forcings on lake ecology have diminished in their importance as human management of the lake increased in the mid-1900s. In the last 50 years, three chemical biomanipulations have temporarily shifted the lake from the turbid, algal-dominated condition into a desired clear water regime. Two of our proxies (delta(13)C and BSi) measured from the higher resolution eastern basin record responded significantly to these known regime shifts. PMID- 22819885 TI - Dust storms and the risk of asthma admissions to hospitals in Kuwait. AB - OBJECTIVE: Arid areas in the Arabian Peninsula are one of the largest sources of global dust, yet there is no data on the impact of this on human health. This study aimed to investigate the impact of dust storms on hospital admissions due to asthma and all respiratory diseases over a period of 5 years in Kuwait. METHODS: A population-based retrospective time series study of daily emergency asthma admissions and admissions due to respiratory causes in public hospitals in Kuwait was analyzed in relation to dust storm events. Dust storm days were defined as the mean daily PM(10)>200 MUg/m(3) based on measurements obtained from all six monitoring sites in the country. FINDINGS: During the five-year study period, 569 (33.6%) days had dust storm events and they were significantly associated with an increased risk of same-day asthma and respiratory admission, adjusted relative risk of 1.07 (95% CI: 1.02-1.12) and 1.06 (95% CI: 1.04-1.08), respectively. This was particularly evident among children. CONCLUSION: Dust storms have a significant impact on respiratory and asthma admissions. Evidence is more convincing and robust compared to that from other geographical settings which highlights the importance of public health measures to protect people's health during dust storms and reduce the burden on health services due to dust events. PMID- 22819886 TI - Tracing pharmaceuticals in a municipal plant for integrated wastewater and organic solid waste treatment. AB - The occurrence and removal of 42 pharmaceuticals, belonging to different therapeutic groups (analgesics and anti-inflammatory drugs, anti-ulcer agent, psychiatric drugs, antiepileptic drug, antibiotics, beta-blockers, diuretics, lipid regulator and cholesterol lowering statin drugs and anti-histamines), were studied in the wastewater and sewage sludge trains of a full scale integrated treatment plant. The plant employs a biological nutrient removal (BNR) process for the treatment of municipal wastewater, and a single-stage mesophilic anaerobic co-digestion for the treatment of wasted activated sludge mixed with the organic fraction of municipal solid waste (OFMSW), followed by a short-cut nitrification-denitrification of the anaerobic supernatant in a sequential batch reactor. Influent and effluent wastewater, as well as thickened, digested and treated sludge were sampled and analyzed for the selected pharmaceuticals in order to study their presence and fate during the treatment. Twenty three compounds were detected in influent and effluent wastewater and eleven in sludge. Infiltration of groundwater in the sewer system led to a dilution of raw sewage, resulting in lower concentrations in wastewater (up to 0.7 MUg/L in influent) and sludge (70 ng/g d.w.). Due to the dilution, overall risk quotient for the mixture of pharmaceuticals detected in effluent wastewater was less than one, indicating no direct risk for the aquatic environment. A wide range of removal efficiencies during the treatment was observed, i.e. <20% to 90%. The influent concentrations of the target pharmaceuticals, as polar compounds, were undoubtedly mostly affected by BNR process in the wastewater train, and less by anaerobic-co digestion. Mass balance calculations showed that less than 2% of the total mass load of the studied pharmaceuticals was removed by sorption. Experimentally estimated distribution coefficients (<500 L/kg) also indicated that the selected pharmaceuticals preferably remain in the aqueous phase, and that biodegradation/transformation is the primary removal mechanism for these compounds during wastewater treatment. PMID- 22819888 TI - Arsenic speciation and trace element analysis of the volcanic rio Agrio and the geothermal waters of Copahue, Argentina. AB - Surface water originating from the Copahue volcano crater-lake was analysed for total arsenic and four arsenic species: arsenite (iAs(III)), arsenate (iAs(V)), monomethylarsonic acid (MA(V)) and dimethylarsinic acid (DMA(V)) and other trace elements (Fe, Mn, V, Cr, Ni, Zn). A novel in-field technique for the preconcentration and separation of four arsenic species was, for the first time, used for the analysis of geothermal and volcanic waters. Total arsenic levels along the rio Agrio ranged from <0.2-3783 MUg/l As(T). The highest arsenic levels were recorded in the el Vertedero spring (3783 MUg/l As(T)) on the flank of the Copahue volcano, which feeds the acidic rio Agrio. Arsenite (H(3)AsO(3)) predominated along the upper rio Agrio (78.9-81.2% iAs(III)) but the species distribution changed at lago Caviahue and arsenate (H(2)AsO(4)(-)) became the main species (51.4-61.4% iAs(V)) up until Salto del Agrio. The change in arsenic species is potentially a result of an increase in redox potential and the formation of iron-based precipitates. Arsenic speciation showed a statistically significant correlation with redox potential (r=0.9697, P=0.01). Both total arsenic and arsenic speciation displayed a statistically significant correlation with vanadium levels along the river (r=0.9961, P=0.01 and r=0.8488, P=0.05, respectively). This study highlights that chemical speciation analysis of volcanic waters is important in providing ideas on potential chemical toxicity. Furthermore there is a need for further work evaluating how arsenic (and other trace elements), released in volcanic and geothermal streams/vents, impacts on both biota and humans (via exposure in thermal pools or consuming commercial drinking water). PMID- 22819887 TI - The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders. AB - Arsenic is a toxic metal with harmful effects on human health, particularly on cognitive function. Autism Spectrum Disorders (ASDs) are lifelong neurodevelopmental and behavioral disorders manifesting in infancy or early childhood. We used data from 130 children between 2 and 8 years (65 pairs of ASD cases with age- and sex-matched control), to compare the mean total blood arsenic concentrations in children with and without ASDs in Kingston, Jamaica. Based on univariable analysis, we observed a significant difference between ASD cases and controls (4.03 MUg/L for cases vs. 4.48 MUg/L for controls, P<0.01). In the final multivariable General Linear Model (GLM), after controlling for car ownership, maternal age, parental education levels, source of drinking water, consumption of "yam, sweet potato, or dasheen", "carrot or pumpkin", "callaloo, broccoli, or pak choi", cabbage, avocado, and the frequency of seafood consumption per week, we did not find a significant association between blood arsenic concentrations and ASD status (4.36 MUg/L for cases vs. 4.65 MUg/L for controls, P=0.23). Likewise, in a separate final multivariable GLM, we found that source of drinking water, eating avocado, and eating "callaloo, broccoli, or pak choi" was significantly associated with higher blood arsenic concentrations (all three P<0.05). Based on our findings, we recommend assessment of arsenic levels in water, fruits, and vegetables, as well as increased awareness among the Jamaican population regarding potential risks for various exposures to arsenic. PMID- 22819889 TI - Has Alberta oil sands development increased far-field delivery of airborne contaminants to the Peace-Athabasca Delta? AB - Identifying potential regional contamination by Alberta oil sands industrial emissions on sensitive ecosystems like the Peace-Athabasca Delta, ~200 km to the north, requires knowledge of historical contaminant levels and trends. Here we provide some of these critically-needed data, based on analysis of metals in a sediment core from an upland precipitation-fed lake in the delta. The lake is well-situated to record the anthropogenic history of airborne contaminant deposition for this region. Sediment records of metals of concern (Pb, Sb, As, Hg) reflect early to mid-20th century increases in North American industrial emissions, followed by reduced emissions due to improved industrial practices after 1950-70. Notably, Pb, Sb, As and Hg have declined since the onset of Alberta oil sands production, belying concerns that this activity has enhanced far-field atmospheric delivery of these contaminants to the delta. PMID- 22819890 TI - Diversity of microbial communities in an attached-growth system using BauxsolTM pellets for wastewater treatment. AB - Columns of BauxsolTM pellets were used in a field experiment as biomass support particle for wastewater microbial communities. The attached microbial community structure was analysed using denaturing gradient gel electrophoresis (DGGE), targeting the 16S rDNA gene's V3 region. DGGE profiles showed that the type and composition of support particles used (i.e. BauxsolTM pellets or gravel) had a significant impact on the attached bacterial communities (64% dissimilarity). In addition, ecological indices revealed a more heterogeneous bacterial community structure on the BauxsolTM pellets. TOC/TN ratios post-experiment (6.5-9.3) suggested a good level of biological activity (i.e. active biofilm) in the BauxsolTM columns. Moreover, BauxsolTM pellets were mostly made of inorganic carbon, suggesting insoluble carbonate biomineralisation. Polymerase chain reaction (PCR) amplification of specific marker genes (i.e. bacterial and archaeal amoA genes, nosZ gene, and hzo gene) were used to identify the presence of attached bacterial communities associated with nitrogen transformation. The results along with geochemical data (i.e. up to 50% nitrogen removal) revealed co existence of ammonia-oxidising bacteria, denitrifiers, and anammox organisms. This study conclusively demonstrates that microbial communities are well-adapted to BauxsolTM pellets and bacterial communities involved in the nitrogen cycle are present. PMID- 22819891 TI - Bioaccessibility of trace elements in soils in Northern Ireland. AB - Assessment of elevated concentrations of potentially toxic elements (PTE) in soils and the association with specific soil parent material have been the focus of research for a number of years. Risk-based assessment of potential exposure scenarios to identified elevated PTE concentrations has led to the derivation of site- and contaminant-specific soil guideline values (SGVs), which represent generic assessment criteria (GACs) to identify exceeded levels that may reflect an unacceptable risk to human health. A better understanding of the 'bioavailable' or 'bioaccessible' contaminant concentrations offers an opportunity to better refine contaminant exposure assessments. Utilizing a comprehensive soil geochemical dataset for Northern Ireland provided by the Tellus Survey (GSNI) in conjunction with supplementary bioaccessibility testing of selected soil samples following the Unified BARGE Method, this paper uses exploratory data analysis and geostatistical analysis to investigate the spatial variability of pseudo-total and bioaccessible concentrations of As, Cd, Co, Cr. Cu, Ni, Pb, U, V and Zn. The paper investigates variations in individual element concentrations as well as cross-element correlations and observed lithological/pedological associations. The analysis of PTE concentrations highlighted exceeded levels of GAC values for V and Cr and exceeded SGV/GAC values for Cd, Cu, Ni, Pb, and Zn. UBM testing showed that for some soil parent materials associated with elevated PTE concentrations e.g. the Antrim Lava Group with high Ni concentrations, the measured oral bioaccessible fraction was relatively low. For other soil parent materials with relatively moderate PTE concentrations, measured oral bioaccessible fraction was relatively high (e.g. the Gala Sandstone Group of the Southern Uplands-Down Longford Terrain). These findings have implications for regional human health risk assessments for specific PTEs. PMID- 22819892 TI - Comparison of particulate number concentrations in three Central European capital cities. AB - Number size distributions of atmospheric aerosol particles in the mobility diameter range from 10 to 1000 nm were determined in Budapest, Prague and Vienna for a one-year-long period. Particle number concentrations in various size fractions, their diurnal and seasonal variations, mean size distributions and some properties of new particle formation events were derived and compared. Yearly median particle number concentrations for Budapest, Prague and Vienna were 10.6*10(3), 7.3*10(3) and 8.0*10(3) cm(-3). Differences were linked to the different pollution levels of the cities, and to diverse measurement environments and local conditions. Mean contributions of ultrafine particles (particles with a mobility diameter <100 nm) to the total number concentration were 80%, 84% and 74% for Budapest, Prague and Vienna, thus these particles represent an overwhelming share of all particles in each city. Seasonal variation of particle number concentrations was not obvious. Diurnal variations of particles with a diameter between 100 and 1000 nm (N(100-1000)) exhibited similar shape for the cities, which was related to the time-activity pattern of inhabitants and regional influences. The structure of the diurnal variation for ultrafine particles was also similar. It contained a huge morning peak in each city which was explained by emissions from vehicular traffic. The second peak was shifted from afternoon rush hours to late evenings as a result of the daily cycling in meteorological parameters. The character of the measurement site also influenced the diurnal variation. Diurnal variation of the mean ratio of ultrafine particles to N(100-1000) clearly revealed the presence and importance of new particle formation and subsequent growth in urban environments. Nucleation frequencies in Budapest and Prague were 27% and 23%, respectively on a yearly time scale. They showed a minimum in winter for both places, while the largest nucleation activity was observed in spring for Budapest, and in summer for Prague. PMID- 22819893 TI - Estimation of submarine groundwater discharge and associated nutrient fluxes in Tolo Harbour, Hong Kong. AB - Tolo Harbour, located in the northeastern part of Hong Kong's New Territories, China, has a high frequency of algal blooms and red tides. An attempt was made to first quantify the submarine groundwater discharge (SGD) into Tolo Harbour using (226)Ra, and then to estimate the nutrient fluxes into the Harbour by this pathway. The total SGD was estimated to be 8.28*10(6) m(3) d(-1), while the fresh submarine groundwater discharge (FSGD) was estimated to be 2.31*10(5) m(3) d(-1). This showed that a large amount of SGD was contributed by recirculated seawater rather than fresh groundwater in the Harbour. Using the SGD and groundwater nutrient information around Tolo Harbour, the nutrient loading through SGD was estimated to be 1.1*10(6) mold(-1) for DIN, 1.4*10(4) mold(-1) for PO(4)(3-)-P and 1.4*10(6) mold(-1) for SiO(2)-Si, which was much more significant than its counterpart through the river discharge. Despite uncertainties in the estimation, the nutrient loading to Tolo Harbour by SGD is clearly significant. Thus, the current efforts for management of red tides in Tolo Harbour have to be reviewed and control of groundwater contamination is obviously required. PMID- 22819894 TI - A Monte Carlo approach to the inverse problem of diffuse pollution risk in agricultural catchments. AB - The hydrological and biogeochemical processes that operate in catchments influence the ecological quality of freshwater systems through delivery of fine sediment, nutrients and organic matter. Most models that seek to characterise the delivery of diffuse pollutants from land to water are reductionist. The multitude of processes that are parameterised in such models to ensure generic applicability make them complex and difficult to test on available data. Here, we outline an alternative--data-driven--inverse approach. We apply SCIMAP, a parsimonious risk based model that has an explicit treatment of hydrological connectivity. We take a bayesian approach to the inverse problem of determining the risk that must be assigned to different land uses in a catchment in order to explain the spatial patterns of measured in-stream nutrient concentrations. We apply the model to identify the key sources of nitrogen (N) and phosphorus (P) diffuse pollution risk in eleven UK catchments covering a range of landscapes. The model results show that: 1) some land use generates a consistently high or low risk of diffuse nutrient pollution; but 2) the risks associated with different land uses vary both between catchments and between nutrients; and 3) that the dominant sources of P and N risk in the catchment are often a function of the spatial configuration of land uses. Taken on a case-by-case basis, this type of inverse approach may be used to help prioritise the focus of interventions to reduce diffuse pollution risk for freshwater ecosystems. PMID- 22819895 TI - Adsorption behavior of arsenic relating to different natural solids: soils, stream sediments and peats. AB - The sorption of anthropogenically derived arsenic to natural solids plays an important role in the mobility and fate of this toxic metalloid in the environment. The adsorption affinity of dissolved As(V) and As(III) to contrasting natural solids was investigated using model solutions of As(V)/As(III) and homogenized samples of soils, stream sediments and peat cores. The adsorption of As(III) and As(V) on investigated sorbents ran mostly according to the Langmuir model, with high correlation factors (>0.7). Sorption capacities varied from 3.5*10(-3) to 2.0*10(-1) mmol/g of As, whereas As(III) achieved a higher adsorption affinity due to the presence of Fe ions in the model solution. The lower horizons of soils and the intact peat, characterized by high enrichment factors of As content (R>1), represented a more stable system with decreased adsorption/desorption dynamics of As transport. A higher surface activity of solids associated with R<1, and an increased As mobility in the solid-water interface, prevailed in upper horizons of the soil and intact peat, where the contact with atmospheric deposition was expected. Stream sediments proved to be a well-balanced system with R~1. A strong As-Fe correlation in the natural solids confirmed As affinity to Fe particles. PMID- 22819896 TI - Using ultrasound to measure the fibre angle of vastus medialis oblique: a cadaveric validation study. AB - BACKGROUND: The assumption that the vastus medialis oblique (VMO) is involved in medial patellar stabilisation has led to speculation that patellofemoral pain (PF) may be a result of abnormal patellar tracking, due to weakness or difference in fibre orientation of the VMO. Recent studies have reported that the VMO fibre angle, measured in vivo with ultrasound (US), is reduced in patellofemoral pain (PF) patients. However, the validity of US in measuring this parameter was not investigated and this would inevitably cast doubt on whether the US results are comparable to direct measurement. The aim of this study was to validate the use of ultrasound (US) in measuring VMO fibre angle by comparing results obtained both from US and direct measurement. METHODS: The VMO fibre angle was determined in relation to the femoral axis in nine lower limbs from five soft-fixed cadavers, first using US and then by direct measurement. RESULTS: The Pearson correlation coefficient between the two methods was 0.92 (p<0.01) indicating a very strong relationship. The average difference in measurements between the two methods was 0.20. Bland/Altman analysis showed 95% limit of agreement to be between -2.550 and 30, showing minimal discrepancies between results obtained by the two methods. CONCLUSION: In conclusion, the VMO fibre angle values obtained by the US method were proved to be valid and comparable to those obtained from direct measurement. We show, therefore, that US can be used with confidence to measure VMO fibre angles in the cadaver, and, by implication, in clinical practice. PMID- 22819897 TI - The breath test system involving a novel tracer, 13C-uracil and Wagner-Nelson analysis: comparison with the gastric emptying scintigraphy. AB - BACKGROUND/AIMS: In this pilot study, a new breath test system for gastric emptying study has been proposed. METHODOLOGY: The system involves 13C-uracil as a novel tracer and the Wagner-Nelson method for analyzing breath data. RESULTS: In three healthy volunteers, the new breath system allowed quantification of gastric emptying profiles as accurately as the scintigraphic technique. CONCLUSIONS: Further validation studies with a lager sample size are needed. PMID- 22819898 TI - Evaluation of surgical resection for gallbladder carcinoma at a Japanese cancer institute. AB - BACKGROUND/AIMS: Surgical resection is a radical treatment option for gallbladder carcinoma (GBC); however, it is still difficult to cure and patient prognosis is poor. An assessment of the surgical results and chemotherapy options may elucidate effective treatments. METHODOLOGY: We retrospectively examined the demographics, surgical records and outcome in 33 patients with GBC undergoing surgical resection. RESULTS: Postoperative cancer recurrence was observed in 36% of patients. Mean cancer-free survival time was 84 months and 3-year cancer-free survival rate was 70% Mean overall survival time was 96 months and 5-year overall survival rate was 52%. The 3-year cancer-free survival and the 5-year overall survival were significantly different between the final tumor stages (p<0.001). Higher CEA and CA19- 9 level were significantly related to poor overall survival (p<0.05). Macroscopically, papillary type tumor showed significantly better overall survival compared to nodular or flat types (p<0.05). Degree of invasion, node metastasis, moderate or poor differentiation, vascular or perineural invasion and invasion of the liver or hepatoduodenal ligament were significantly associated with poor overall survival (p<0.05). A cancerfree margin at the hepatic cut end and dissected periductal structures showed a significantly poor prognosis (p<0.05). The overall survival in final curability A was significantly associated with better curability than B or C (p<0.05). CONCLUSIONS: Radically extended surgical resection for GBC is necessary to obtain improved patient survival and new adjuvant chemotherapy would be expected to improve results after surgery. PMID- 22819899 TI - Adiponectin and its receptors in chronic hepatitis B patients with metabolic syndrome in China. AB - BACKGROUND/AIMS: Adiponectin can initiate a broad range of metabolic and immunological effects. Little is known about the role of adiponectin in hepatitis B related liver disease and metabolic syndrome (MS). METHODOLOGY: We studied 138 patients with untreated chronic hepatitis B (CHB), who were from Beijing Ditan hospital in 2005 to 2009. According to MS, two groups (65 with MS vs. 73 without MS) were established. They were compared with characteristics and stained immunohistochemically for adiponectin and adiponectin receptor2 (adipoR2). RESULTS: In the group of CHB patients with MS, the levels of LDH, gamma-GT, FPG, FINS, HOMA-IR, HOMA-beta, TG and HBeAg positive were significantly higher than those in the group without MS (p<0.05). Liver steatosis in the group with MS is significantly more severe than that in the group without MS (p<0.001). With binary logistic regression analyses, BMI and HOMA-IR showed independent predictors to MS in patients with CHB. In patients with chronic HBV, the insulin sensitizing adipokine adiponectin and its receptor AdipoR2 was associated with diabetes in patients with CHB and MS. CONCLUSIONS: Our findings showed the CHB patients with MS may be presence of more severe steatosis. MS in CHB patients may be closely correlated with insulin resistance and less effect of viruses. Reduced hepatic expression of adiponectin and adipoR2 might be of pathophysiological relevance in CHB patients with MS. PMID- 22819900 TI - Parenteral glutamine supplement has synergic effects in minimally invasive surgery of subtotal gastrectomy patients. AB - BACKGROUND/AIMS: Exogenous glutamine supplement is known to improve morbidity and mortality of critically-ill patients. This study was conducted to elucidate the role of glutamine in minimally invasive surgery. METHODOLOGY: We retrospectively reviewed subtotal gastrectomy patients in National Taiwan University Hospital from Dec 2005 to Dec 2008. The patients were divided into three groups. Group 1 underwent subtotal gastrectomy by laparotomy without glutamine supplement, group 2 underwent subtotal gastrectomy by laparotomy with glutamine supplement and group 3 underwent gasless laparoscopy-assisted subtotal gastrectomy with parenteral glutamine supplement. RESULTS: There were 155 patients in total; 85 patients in group 1, 17 in group 2 and 53 in group 3. The mean flatus days after operation are 3.6, 3.1 and 2.8 for groups 1, 2 and 3, respectively (p=0.001). Oral intake after operation was commenced after 6.7, 5.0 and 4.7 days (p=0.006). The body temperature had borderline differences between groups 3 and 1. There were significant differences in postoperative systemic responses including heart rates (p<0.001) and tenderness (p=0.011) 5 days after operation for group 3 vs. group 1. Minimally invasive surgery was a negative factor for postoperative body temperature change. Glutamine was a significant factor for postoperative heart rate change and reduction of tenderness. CONCLUSIONS: Glutamine supplement may have synergic effects of rapid recovery in minimal invasive surgery for subtotal gastrectomy patients by minimizing the postoperative systemic response and accelerating recovery. PMID- 22819901 TI - Extramedullary hemopoiesis and littoral cell angioma of the spleen: our experience and review. AB - Littoral cell angioma (LCA) is a rare primary vascular neoplasm of the spleen. A 54-year-old man was referred to our emergency department for abdominal pain. A CT scan showed multiple round hypodense lesions of various sizes throughout the spleen. The spleen was increased in volume. An MRI confirmed the lesion with a suspect of multiple angiomas vs. amartomas. The haematologists excluded any haematological disease. After a collegial discussion, we decided to perform laparotomic splenectomy. Histologically, the multiple lesions consisted in anastomosing vascular channels lined by plump cells. There was an increased number of dysmorphic megakaryocites inside the splenic parenchyma and along the tumour's border, known signs of extramedullary hemopoiesis, whose etiology in our patient was unexplained. To the best of our knowledge this is the third description of the association between littoral cell angioma and extramedullary hemopoiesis. LCA is a rare primary splenic vascular tumour that originates from the splenic littoral cells. The diagnosis of littoral cell angioma is confirmed histologically and on immunohistochemistry. This case report underlines the rarity of this type of benign splenic neoplams, but since the malignant potential of LCA, we recommend close clinical follow- up of patients with LCA of the spleen. PMID- 22819902 TI - Anterior vs. posterior mediastinal routes in colon interposition after esophagectomy. AB - BACKGROUND/AIMS: Colon interposition is the most commonly used method of esophageal reconstruction when the stomach cannot be used; however, this method may cause surgical complications such as anastomotic leakage and sepsis due to colon necrosis. Therefore, many surgeons use a retrosternal or subcutaneous route because it is easier to manage the subcutaneous drainage when anastomotic leakage occurs. However, some researchers have reported that the posterior mediastinal route provides better long-term functional outcomes after surgery than the anterior mediastinal route. Thus, in this study, we compared these reconstruction routes used for colon interposition, with or without the supercharge technique, in patients with a history of distal gastrectomy, who have undergone colon interposition after esophagectomy. METHODOLOGY: We retrospectively studied 30 patients who underwent esophagectomy with colon interposition. These patients were divided into 2 groups based on the reconstruction route: the anterior mediastinal or subcutaneous route (A group), or the posterior mediastinal route (R group). RESULTS: Anastomotic leakages were observed in 4 patients (26.7%) in the A group and in 1 patient (6.7%) in the R group. CONCLUSIONS: Ischemia is not always the result of arterial failure, but may also originate from venous blood flow impairment due to injury or distortion of veins. PMID- 22819903 TI - Double balloon enteroscopy: a 3-year experience at a tertiary care center. AB - BACKGROUND/AIMS: To evaluate the indications, diagnostic yield, therapeutic interventions, complications and safety of double balloon enteroscopy (DBE) in clinical practice. METHODOLOGY: The medical records of the patients who underwent DBE at the Turkiye Yuksek Ihtisas Hospital between October 2007 and January 2010 were examined to note the demographic data, indications for the examination, results of previous non-invasive small bowel imaging and endoscopic procedures and the results of DBE including findings, endoscopic interventions, complications and pathological reports. RESULTS: A total of 139 procedures were performed in 118 patients. DBE was performed 81 times through mouth and 26 times through anus and additionally both approaches were used 16 times in the same patients. Panenteroscopy was successfully performed in 13 of 16 patients (87.5%) in whom it was attempted. The most common indication was obscure gastrointestinal bleeding (28.8%). DBE had an overall diagnostic and/or therapeutic contribution in 63 (53.4%) patients. The main pathologies detected on DBE were polyps (12.7%), infammation (10.7%) and vascular lesions (3.4%). Complications were recognized in four cases (3.4%) but no major complication occured. CONCLUSIONS: Our retrospective analysis showed that DBE is a useful, safe and well-tolerated method with a diagnostic and therapeutic impact for the management of small bowel diseases. PMID- 22819904 TI - The risk of lymph node metastasis in mucosal gastric carcinoma: especially for a mixture of differentiated and undifferentiated adenocarcinoma. AB - BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) is gaining wider acceptance for the treatment of early gastric carcinoma (EGC) and its indication has been extended to mucosal gastric carcinoma with undifferentiated component in some institutes. Our aims were to confirm the frequency of lymph node metastasis in such cases and clarify the demarcation in indications for ESD. METHODOLOGY: We evaluated medical data of 287 patients with mucosal gastric carcinoma who underwent surgical resection between 1996 and 2008. The tumours were histologically classified into purely differentiated (PD), differentiated predominant mixed (DPM), undifferentiated-predominant mixed (UPM) and purely undifferentiated (PU) types. RESULTS: Lymph node metastasis was identified in seven (2.4%) of the 287 patients and was detected more frequently in UPM (10%, two of 20) and PU (4%, four of 98), compared with PD (none of 148) (p=0.01 and 0.02, respectively). In mixed-type carcinoma, size was a significant risk factor for lymph node metastasis (p=0.04). CONCLUSIONS: It might be better to select gastrectomy rather than ESD for the treatment of mucosal gastric carcinoma with an undifferentiated component. PMID- 22819905 TI - Thymidylate synthase and cyclin D1 protein expression in lymph node negative colorectal cancer: role as prognostic factors? AB - BACKGROUND/AIMS: Thymidylate synthase (TS) is an enzyme for DNA-synthesis and the target for 5-fluorouracil whereas cyclin-D1 plays a critical role in the progression of cells through the G1 phase of the cell-cycle. There is evidence that expression of these markers may predict the outcome of patients with colorectal cancers. The aim of this study was to examine the prognostic value of TS and cyclin D1 protein expression in patients with node negative colorectal cancers. METHODOLOGY: TS and cyclin D1 protein expression from 140 patients with UICC stage I and II colorectal cancer was analyzed by immunhistochemistry in paraffin-embedded primary tumour specimens. RESULTS: The 1-, 5- and 10-year overall-survival rates were 96%, 86% and 71%, respectively. Tumour stage and recurrence were associated with overall-survival. Low- and high TS immunoreactivity was present in 68 (48%) and 72 (52%) of cancers, respectively. Low- and high cyclin D1 immunoreactivity was present in 98 (70%) and 42 (30%) of the cancers, respectively. Patients (n=72) with high TS expressing tumours had a worse overall-survival than patients (n=68) with low TS expressing colorectal cancers (p=0.011). No difference in overall-survival was seen between patients with high and low cyclin D1 expressing cancers. CONCLUSIONS: TS may be helpful as a prognostic marker in lymph node negative colorectal cancer. PMID- 22819906 TI - Correlations between serum levels of vascular endothelial growth factor and endostatin with clinical pathological characteristics of patients with gastrointestinal cancers. AB - BACKGROUND/AIMS: To study the relationship between serum levels of vascular endothelial growth factor (VEGF), endostatin and pathological characteristics of patients with gastrointestinal cancers. METHODOLOGY: Serum VEGF and endostatin levels were measured by enzyme-linked immunoassay in 60 patients with gastric carcinoma, 55 with hepatocellular carcinoma and 58 with colorectal carcinoma before and after surgical resection. RESULTS: The preoperative levels of VEGF and endostatin in patients with gastrointestinal cancers were significantly higher than those in control groups respectively. They were closely related to the grades of cell differentiation, size of primary tumors, depth of invasion, metastasis and pathological stage, but not to tumor site and gender. The postoperative VEGF levels were significantly lower than those of preoperation, while postoperative endostatin levels were significantly higher than those of preoperation. CONCLUSIONS: Preoperative serum VEGF and endostatin levels may be used for evaluating the biological behavior, invasion and metastasis of gastric, hepatocellular and colorectal carcinoma. Elevated serum endostatin levels were found in the patients with gastric cancer, HCC and colorectal cancer after surgery. Gastrointestinal tumor itself may be not the main source of endostatin. PMID- 22819907 TI - Diagnostic utility of computer tomographic enterography for patients presenting with unexplained gastrointestinal symptoms. AB - BACKGROUND/AIMS: Computer tomographic enterography (CTE) is gaining approval for evaluation of small bowel diseases. However, the diagnostic yields of CTE for diseases other than Crohn's disease have not yet been well elucidated. The aim of the present study was to determine the diagnostic utility of CTE and to ascertain the clinical factors predictive of the positive diagnostic rate in patients with unexplained gastrointestinal symptoms or signs. METHODOLOGY: The clinical and radiological data of 193 patients with unexplained gastrointestinal symptoms that had a CTE examination at Severance Hospital between May 2007 and April 2010 were retrospectively analyzed. RESULTS: CTE revealed positive findings that explained the symptoms in 51 of the 193 patients (diagnostic yield 26.4%). Positive findings of diagnosis included cancer (12 patients), Crohn's disease (10), intestinal stricture/obstruction (9), small bowel bleeding (7), colitis (6), intestinal Behcet's disease (4), intestinal tuberculosis (2) and intestinal fistula (1). According to univariate analysis, the positive findings of CTE were significantly associated with higher segmentated neutrophil count (p<0.001), higher erythrocyte sedimentation rate (ESR) (p=0.003), higher C-reactive protein (CRP) level (p=0.008) and lower serum albumin level (p=0.037). Multivariate analysis indicated that elevated CRP level was a significant risk factor for the positive findings of CTE (odds ratio 1.950; 95% CI (1.165-3.265), p=0.011). CONCLUSIONS: The results of this study suggest that CTE could be helpful in patients suffering from unexplained gastrointestinal symptoms that cannot be explained by established examinations, especially those with elevated C-reactive protein levels. PMID- 22819908 TI - Somatostatinoma of the first jejunal loop in a patient with neurofibromatosis von Recklinghausen and bilateral pheochromocytoma. AB - Somatostatinoma is a rare neuroendocrine tumor which especially develops in the pancreas. There are few communicated cases about extra-pancreatic localization, having as a particularity the absence of somatostatin hypersecretion syndrome and frequent association with von Recklinghausen neurofibromatosis. We present the case of a 42-year old patient with Von Recklinghausen neurofibromatosis admitted in our clinic with a chronic upper digestive obstruction syndrome. The presence of a first jejunal loop somatostatinoma was an intraoperative surprising diagnosis that imposed jejunal resection and association of complementary specific treatment. Despite the therapeutic correct management, the status of the patient deteriorated very fast, confirming the aggressiveness of this neoplasia. PMID- 22819909 TI - Primary Budd-Chiari syndrome - a single center experience. AB - BACKGROUND/AIMS: Budd-Chiari syndrome (BCS) is recognized as a clinical manifestation of various prothrombotic conditions which may be lethal within 3 years of the onset of symptoms if untreated. This study is a retrospective analysis of patients with BCS managed between 2004 and 2011. METHODOLOGY: The diagnosis was confirmed with contrast CT-angiography and/or Doppler ultrasound. RESULTS: BCS was diagnosed in 20 patients (11 females and 9 males), median age 38 years (ranging from 18 to 56). Twelve patients were referred as acute BCS for the liver transplant (LTx) assessment. Thrombosis of the hepatic veins was caused by myeloproliferative disorders (n=8), end-stage liver disease (n=4), protein C deficiency (n=3), paroxysmal nocturnal hemoglobinuria (PNH) (n=1), antiphospholipid syndrome (n=1) and secondary poliglobulia (n=1). In two patients the origin of BCS could not be established despite appropriate screening. Median follow-up was 29 months. Low molecular heparin with subsequent conversion to vitamin K antagonists was routinely applied in all patients. Two patients underwent TIPS procedure with good long term outcome and 10 subjects received LTx; 1 patient was lost to follow-up and 1 died of chest infection 9 years since the diagnosis of BCS was made; 14 patients, including those who received LTx, were alive and well at least one year after BCS diagnosis. All survivors remain stable and are followed-up on a regular basis. CONCLUSIONS: Strict adherence to the diagnostic and therapeutic guidelines plays a crucial role in the management of BCS patients. Our results confirm the efficacy of anticoagulation as well as TIPS and/or OLT in treatment of this rare condition. PMID- 22819910 TI - Features and outcome after liver resection for non-B non-C hepatocellular carcinoma. AB - BACKGROUND/AIMS: We investigated the clinicopathological findings and outcome after surgery for hepatocellular carcinoma in patients without hepatitis B or C virus infection. METHODOLOGY: Among 562 patients who underwent curative resection for hepatocellular carcinoma, the sera from 97 patients (B group) were positive for hepatitis B surface antigen alone, sera from 355 patients (C group) were positive for anti-hepatitis C virus antibody alone and sera from 104 patients (NBNC group) were negative for both hepatitis B surface antigen and anti hepatitis C virus antibody. We compared the clinicopathological findings and postoperative outcomes in the 3 groups. RESULTS: The prevalence of diabetes mellitus, hypertension, hyperlipidemia and alcohol abuse were higher in the NBNC group than in the other groups. The prevalence of obesity was higher in the NBNC group than in the B group. Non-alcoholic steatohepatitis was detected in 16 NBNC patients. The tumor- free survival rate was higher in the NBNC group than in the C group. CONCLUSIONS: Obesity, diabetes mellitus, hypertension, hyperlipidemia, alcohol abuse and non-alcoholic steatohepatitis were the possible risk factors for hepatocellular carcinoma in the NBNC group. The patients in the NBNC group are expected to show a better outcome as compared to patients in the C group. PMID- 22819911 TI - An improved technique for liver transection using a new device for soft coagulation in living donor hepatectomy. AB - BACKGROUND/AIMS: In LDLT, parechymal resection is the most invasive process in the donor procedure. The control of bleeding is crucial for donor safety without the occlusion of hepatic inflow. Therefore, a reliable coagulation device is necessary for the transection of the hepatic parenchyma. This study evaluated a newly developed monopolar applicator, SOFT COAG (ERBE Elektromedizin, Tubingen) for rapid soft coagulation with regulated power output. Our objective was to assess an improved hepatic resection technique using a the SOFT COAG device for LDLT. METHODOLOGY: Between July 1999 and May 2008, 195 consecutive donors underwent a hepatic resection for LDLT. For graft extraction, 50 patients had a left lateral sectionectomy (LLS), 65 had a left hemihepatectomy (LHH), and 80 had a right hemihepatectomy (RHH). RESULTS: In 125 donors, the control of parenchymal bleeding was performed by coagulation with bipolar forceps and in 70 donors it was controlled by soft coagulation with a monopolar electrode. The intraoperative blood loss was 763.9+/-494.4 mL and 435.2+/-424.7mL in RHH with bipolar and soft coagulation, respectively, with a statistically significant difference. Regarding postoperative liver function, most of the laboratory data showed no significant difference according to coagulation device. There was no significant difference in the incidence of postoperative complications. CONCLUSIONS: It is evident that the new soft coagulation device represents a safe and feasible technique for donor hepatic parenchymal transection without inflow occlusion. PMID- 22819912 TI - Amantadine in non-responder patients with chronic hepatitis C: a randomized prospective study. AB - BACKGROUND/AIMS: The management of non-responders (NR) represents the most challenging of all aspects in the care of patients with chronic hepatitis C (CHC). The purpose of the study was to evaluate the efficacy of amantadine. METHODOLOGY: Fourty- three patients with CHC who did not respond to prior combination therapy [IFNalpha-2a plus ribavirin for 48 weeks] were enrolled into the study. The first group (n=21) was administered pegylated IFN-alpha2a (180 mcg/week) plus ribavirin (1000-1200 mg/day) and amantadine (200mg/day) for 48 weeks. After discontinuation of therapy, patients were followed-up for an additional 24 weeks. The second group (n=22) received only amantadine (200mg/day) daily for at least 24 weeks (mean 96 weeks) and starting from the 24th week, HCV RNA was assessed every 12 weeks without discontinuation of therapy. RESULTS: Mean ALT levels before treatment were 115.30 units in the first and 107.73 units in the second group whereas they were 48.38 and 54.76 units, respectively, after the treatment (p<0.001 for both). Sustained viral response rate for the first group at the 72nd week was 52.3% (11/21) (p<0.025). Among patients receiving amantadine, 1 patient became HCV-RNA negative at the 24th and 3 patients at the 48th week (response rate at week 48 was 18.2%), 1 patient at the second year and 1 patient at the fourth year of the treatment (p=0.031). CONCLUSIONS: Amantadine has a potential anti-inflammatory activity that can be a safe alternative for NR CHC subjects to combination therapy. PMID- 22819913 TI - Roles of hepatic progenitor cells activation, ductular reaction proliferation and Notch signaling in morbid obesity. AB - BACKGROUND/AIMS: Hepatic progenitor cells (HPCs) activation, proliferative ductular reaction (DR), replicative arrest and Notch signaling have been demonstrated in a variety of human liver diseases. The relationships are poorly understood in morbid obesity. We investigated factors responsible for the HPCs/DR, replicative arrest and Notch signaling in non-NASH and NASH groups. METHODOLOGY: Cytokeratin 7 (and 19), p21, CD34, Ki67 and different Notch receptors and ligands immunohistochemical stained biopsies from morbid obese patients with non-NASH (n=10) and NASH (n=25) were studied. These results were correlated with clinicopathological variables. RESULTS: NASH patients presented with abnormal liver function tests and had higher HbA1c percentage. Strong association between HPCs and DR was seen (r=0.785, p<0.000). BMI, interface activity and replicative arrest were associated with HPCs expansion and DR in NASH patients. A strong association between CD34 with HPCs and DR was found in non-NASH patients. In NASH group, Notch 3 was important in bile ductular proliferation; whereas Notch 4 was associated with sinusoidal neovessels proliferation and Kupffer cell activation. CONCLUSIONS: HPCs and DR played an important role in hepatic regeneration in fatty liver disease of morbid obesity. An altered replication pathway in NASH promotes HPCs activation and DR. Notch-3 and Notch-4 were significantly different between non-NASH and NASH groups. PMID- 22819914 TI - Donor hepatectomy using hanging maneuvers: Tokyo University experiences in 300 donors. AB - BACKGROUND/AIMS: The liver hanging maneuver (LHM) is a widely used novel suspending technique for facilitating liver transection. However, little evidence is available to reveal its safety and true advantages in donor operations for living donor liver transplantation (LDLT). METHODOLOGY: The medical records of 422 consecutive living donors at a single institute were reviewed. The feasibility and outcomes of the use of LHM in donor operation for LDLT were investigated. RESULTS: Two types of hanging maneuvers, namely, Belghiti's conventional method and a modified approach where the sling is placed after full mobilization of the liver, have been routinely adopted selectively since 2000, and to date, 304 LHM have been carried out. Marked reduction in the liver transection time needed for harvesting a hemiliver graft has been obtained after the introduction of LHM (p<0.0001). No major complications associated with the LHM have been recorded. Comparison of the conventional and modified LHM revealed similar outcomes for the two, except that the modified approach required a longer liver dissection time (81 vs. 98 min; p=0.0004). CONCLUSIONS: Considering its high feasibility and several advantages in facilitating liver transection, LHM might be worth attempting in donor operations where a major hepatectomy is required. PMID- 22819915 TI - Precise hepatectomy guided by minimally invasive surgery: a novel strategy for liver resection. AB - Liver resection has been established currently as an effective and standard treatment for patients suffering from both benign and malignant hepatobiliary diseases. Although substantial improvement in perioperative mortality rate and morbidity resulting from appropriate candidates selection, advanced surgical techniques and enhanced perioperative care, hepatectomy is still burdened by about 5% mortality rate and some lethal postoperative complications, especially postoperative liver insufficiency and failure. Various approaches have been advocated to minimize stress and insult on patients due to operative procedures. It becomes important to preserve remnant hepatic function as much as possible to improve the outcome of hepatectomy. Minimally invasive concept and fast track surgery are crucial breakthrough in the natural history of surgery and have been employed in liver resection. To safely and accurately perform hepatic resection, owing to our experiences with recent advances in surgical techniques and perioperative administration for liver resection, a novel strategy, "precise hepatectomy" originating from minimally invasive surgery has been developed, which includes precise preoperative planning, sophisticated intraoperative techniques and careful postoperative management. This strategy is characteristic by involvement of minimally invasive concept in overall therapy, from preoperative assessment to postoperative care, optimization of a series of advanced techniques and proper employment of surgical instruments in light of actual individual information. However, further prospective studies, especially randomized controlled trials in high volume centers, remain essential to compare the safety and therapeutic efficacies between precise hepatectomy and conventional surgical procedures. PMID- 22819916 TI - Relationship between microvessel count and clinicopathological characteristics and postoperative survival in patients with pancreatic carcinoma. AB - BACKGROUND/AIMS: The present study aimed to elucidate the relationship between microvessel count (MVC) according to CD34 expression and clinicopathological characteristics or prognosis in pancreatic carcinoma (PC) patients who underwent hepatectomy. METHODOLOGY: CD34 expression was analyzed using immunohistochemical methods. Mean MVC in 5 areas per specimen and clinicopathological factors were consecutively examined in 42 PC patients. RESULTS: Median MVC for PC patients was 123/mm2, which was applied as a cut-off value. Higher MVC was significantly associated with the advanced Japanese tumor-node-metastasis stage IVa and IVb (p=0.034). Univariate survival analysis identified higher carcinoembryonic antigen (CEA) and CA19-9 level, infiltrative type on macroscopic examination, invasive ductal carcinoma, node metastasis and higher tumor-node-metastasis classification were significantly associated with poor survival. The 5-year overall survival rate in the higher MVC group tended to be lower than that in the higher MVC group (37 vs. 55%), but not statistically significant (p=0.15). CONCLUSIONS: Tumor MVC might be a candidate prognostic marker of PC patient survival after pancreatectomy and further investigation in a larger series is warranted to clarify the significance of this marker. PMID- 22819917 TI - Reappraisal of pancreatic adenocarcinoma undergoing pancreaticoduodenectomy. AB - BACKGROUND/AIMS: This study is to reappraise the clinical presentations, surgical and survival outcomes of pancreatic head adenocarcinoma. METHODOLOGY: Data of pancreatic head adenocarcinomas undergoing pancreaticoduodenectomy were reappraised and compared between period 1 (1984-1996) and period 2 (1997-2009). RESULTS: Surgical mortality was 3.6% in period 2 and 5.0% in period 2. The surgical morbidity was 35.7% in period 1, 35.3% in period 2. Pancreatic leakage was significantly lower (3.4%) in pancreaticogastrostomy group, as compared to 11.7% in pancreaticojejunostomy. There was 57.5% positive lymph node involvement and 77.4% perineural invasion. More patients underwent adjuvant or palliative chemotherapy in period 2 (42.2%) than in period 1 (14.8%). The 5-year survival for resected pancreatic head adenocarcinoma was 3.7% in period 1 and 11.1% in period 2. The 5-year survival after curative resection in period 1 was significantly lower than that in period 2 (4.2% vs. 14.7%). CONCLUSIONS: Although surgical mortality has significantly decreased recently, pancreaticoduodenectomy continues to be a complex and technically-demanding procedure with high and unchanged surgical morbidity. The poor survival outcome of pancreatic head adenocarcinoma might be a combined reflection of difficulty in early detection, aggressive biological behavior of tumor itself and complex surgical anatomy for resection. PMID- 22819918 TI - Manometric evidence of earlier recovery of fasting gastric motility after antecolic duodenojejunostomy than after retrocolic duodenojejunostomy following PPPD. AB - BACKGROUNDS/AIMS: Gastric stasis is a unique complication of pylorus-preserving pancreatoduodenectomy (PPPD). Although some studies reported less prevalence of gastric stasis after antecolic duodenojejunostomy, there have been no reports on detailed comparison of gastric motility after antecolic vs. retrocolic duodenojejunostomy after PPPD. METHODOLOGY: Thirty-six patients underwent PPPD with the modified Child reconstruction. Retrocolic duodenojejunostomy was utilized in initial 13 patients (retrocolic group). For comparison, antecolic duodenojejunostomy was employed in subsequent 23 patients (antecolic group). A manometric tube assembly was inserted into the gastric antrum and jejunum during PPPD. Gastrointestinal motility was recorded for 3 hours a day, starting on 6 to 14 days after surgery and repeated at a weekly interval until the first appearance of phase 3 gastric motility. Various clinical parameters were also assessed. RESULTS: Recovery of gastric phase 3 was identified in 19 of 36 patients. Recovery of phase 3 was faster in antecolic group than in retrocolic group (p<0.01). The amount of the gastric juice output during 14 postoperative days was larger in retrocolic group than in antecolic group (p<0.01). Resumption of water intake and food intake was earlier and the length of intravenous hyperalimentation and hospital stay was shorter in antecolic group than in retrocolic group (p<0.05). CONCLUSIONS: Antecolic duodenojejunostomy contributes to early recovery of gastric phase 3 motility in patients after PPPD, leading to prevention of early gastric stasis. PMID- 22819919 TI - Spleen enlargement after distal gastrectomy in patients without hepatitis. AB - BACKGROUND/AIMS: Platelet count-to-spleen diameter ratio is reported to be the best non-invasive predictor of esophageal varices in cirrhotic patients. However, spleen enlargement is frequently detected during follow-up of patients after gastrectomy. Thus, we studied the relationship of the platelet count-to-spleen diameter ratio with the development of esophageal varices after distal gastrectomy in patients without liver cirrhosis or hepatitis. METHODOLOGY: We retrospectively studied 64 patients who underwent distal gastrectomy. Their platelet counts, spleen diameters and platelet count-to-spleen diameter ratios were correlated with the occurrence rate of esophageal varices after the surgery. RESULTS: Esophageal varices were not detected during the first 6 months after surgery; however, esophageal varices were detected in 2 patients (3%) at 12 months after surgery and their mean platelet count-to-spleen diameter ratio was 2,628 +/- 409. CONCLUSIONS: The platelet count-to-spleen diameter ratio is a useful parameter for non-invasive prediction of esophageal varices after distal gastrectomy. In addition, we suggest that the occurrence rate of esophageal varices increases beyond 6 months after distal gastrectomy and when the platelet count-to-spleen diameter ratio is less than approximately 2600 and thus, endoscopy should be performed to determine the presence of esophageal varices. PMID- 22819920 TI - CpG island structure and trithorax/polycomb chromatin domains in human cells. AB - TrxG and PcG complexes play key roles in the epigenetic regulation of development through H3K4me3 and H3K27me3 modification at specific sites throughout the human genome, but how these sites are selected is poorly understood. We find that in pluripotent cells, clustered CpG-islands at genes predict occupancy of H3K4me3 and H3K27me3, and these "bivalent" chromatin domains precisely span the boundaries of CpG-island clusters. These relationships are specific to pluripotent stem cells and are not retained at H3K4me3 and H3K27me3 sites unique to differentiated cells. We show that putative transcripts from clustered CpG islands predict stem-loop structures characteristic of those bound by PcG complexes, consistent with the possibility that RNA facilitates PcG recruitment or maintenance at these sites. These studies suggest that CpG-island structure plays a fundamental role in establishing developmentally important chromatin structures in the pluripotent genome, and a subordinate role in establishing TrxG/PcG chromatin structure at sites unique to differentiated cells. PMID- 22819921 TI - Towards the elucidation of the regulatory network guiding the insulin producing cells' differentiation. AB - This study pertains to the regulatory network of neurogenin3 (NGN3, approved symbol: NEUROG3), the main regulator of insulin producing cells' formation. In silico regulatory region analyses of known and novel targets of NGN3 revealed the presence of two variants of a regulatory module that appeared conserved at the most phylogenetically distant species with pancreas. Both variants of this module contained binding sites of six transcription factors implicated in pancreas development. Nevertheless, an additional factor was found only into the module of the down-regulated by NGN3 genes. Whole genome analyses confirmed the statistical significance of these regulatory modules. Investigation of protein-protein interactions among the factors bound into these sequences indicated the formation of alternative protein complexes resulting into the up- or down-regulation of the respective genes. Subsequently, an NGN3-guided regulatory network, was modeled, describing the interactions among the analyzed genes with their transcriptional regulators, leading into the differentiation of cells capable of producing insulin. PMID- 22819922 TI - Water channels and their roles in some ocular tissues. AB - Water is a major component of the eye, and water channels (aquaporins) are ubiquitous in ocular tissues, and quite abundant at their different locations. AQP1 is expressed in corneal endothelium, lens epithelium, ciliary epithelium, and retinal pigment epithelium. AQP3 is expressed in corneal epithelium, and in conjunctival epithelium. AQP4 is expressed in ciliary epithelium and retinal Muller cells. AQP5 is expressed in corneal epithelium, and conjunctival epithelium. AQP0 is expressed in lens fiber cells. It is known that five ocular tissues transport fluid, namely: (1) Corneal endothelium; (2) Conjunctival epithelium; (3) Lens epithelium; (4) Ciliary epithelium; (5) Retinal pigment epithelium. For the corneal endothelium, aquaporins are not the main route for trans-tissue water movement, which is paracellular. Instead, we propose that aquaporins allow fast osmotic equilibration of the cell, which is necessary to maintain optimal rates of fluid movement since the cyclic paracellular water transfer mechanism operates separately and tends to create periodic osmotic imbalances (tau~5 s). PMID- 22819923 TI - The good, the bad, and the ugly of alcohol consumption and taxes. AB - The new contribution in these pages by Lhachimi et al. (2012) tallies up the net effects on mortality from internal and external causes that are likely to derive from changes in alcohol taxes in 11 countries within the European Union. Health economists prefer the efficiency of taxes to quotas or outright prohibition, but there are costs as well as benefits associated with any tax, because it drives a wedge between demanders and suppliers and thus reduces welfare. To guide public policy in this area, researchers should measure costs and benefits broadly defined, and Lhachimi et al. provide a useful first step. PMID- 22819924 TI - Structural mass spectrometry in biologics discovery: advances and future trends. AB - Mass spectrometry (MS) is one of the key techniques in protein characterization. In this article, the workflow for MS-based structural characterization of biologics in biopharmaceutical drug discovery is presented, including characterization of primary and higher order structures. Advances in MS techniques in protein characterization are illustrated, including electron transfer dissociation MS (ETD-MS) for primary structure analysis and hydrogen/deuterium exchange MS (HDX-MS) for probing protein higher order structures and mapping epitopes. Future trends in applications of MS to evaluate and optimize candidate molecules in biologics stability studies is also described. PMID- 22819925 TI - Decision theory and the evaluation of risks and benefits of clinical trials. AB - Research ethics committees (RECs) are tasked to assess the risks and the benefits of a clinical trial. In previous studies, it was shown that RECs find this task difficult, if not impossible, to do. The current approaches to benefit-risk assessment (i.e. Component Analysis and the Net Risk Test) confound the various risk-benefit tasks, and as such, make balancing impossible. In this article, we show that decision theory, specifically through the expected utility theory and multiattribute utility theory, enable for an explicit and ethically weighted risk benefit evaluation. This makes a balanced ethical justification possible, and thus a more rationally defensible decision making. PMID- 22819926 TI - Nucleic acid sample preparation for in vitro molecular diagnosis: from conventional techniques to biotechnology. AB - Nucleic acid (DNA and RNA)-based molecular diagnosis is a promising laboratory technique because of its ability to identify disease accurately. However, one of its disadvantages is the inevitable purification and detection of nucleic acids from other contaminated entities. Different nano- and microparticles have been developed for use in an advanced, efficient high-throughput autosystem for the purification and detection of nucleic acid samples for use in molecular diagnoses. In this review, we discuss recent advances in the development of particle-based nucleic acid purification and detection. PMID- 22819927 TI - Platforms for high-throughput screening of Wnt/Frizzled antagonists. AB - Signaling cascades initiated by Wnt lipoglycoproteins and their receptors of the Frizzled family regulate many aspects of animal development and physiology. Improper activation of this signaling promotes carcinogenic transformation and metastasis. Development of agents blocking the Wnt-Frizzled signaling is of prime interest for drug discovery. Despite certain progress no such agents are as yet brought to the market or even to clinical trials. One reason for these delays might be the use of suboptimal readout assays. In this article we overview existing and developing assay platforms to screen for Wnt-Frizzled antagonists. Among those, G protein-activating assays built on the emerging GPCR properties of Frizzleds are highlighted. PMID- 22819928 TI - Inhibition of cytosolic phospholipase A(2) alpha protects against focal ischemic brain damage in mice. AB - It is postulated that inhibition of cytosolic phospholipase A(2) alpha (cPLA(2)alpha) can reduce severity of stroke injury. This is supported by the finding that cPLA(2)alpha-deficient mice are partially protected from transient, focal cerebral ischemia. The object of this study was to determine the effect of cPLA(2)alpha inhibition with arachidonyl trifluoromethyl ketone (ATK) on stroke injury in mice. Male C57BL/6 mice were subjected to 1h of focal cerebral ischemia followed by 24 or 72 h of reperfusion. Mice were treated with ATK or vehicle by intermittent intraperitoneal injection or continuous infusion via an implanted infusion pump. ATK injections 1h before and then 1 and 6h after the start of reperfusion significantly reduced infarction volumes in striatum and hemisphere after 24h of reperfusion. ATK did not reduce injury if it was not administered before onset of ischemia or was not administered after 6h of reperfusion. Intermittent doses of ATK failed to reduce infarct volume after 72 h of reperfusion. Continuous infusion with ATK throughout 72h of reperfusion significantly reduced cortical and whole hemispheric infarct volume compared to vehicle treatment. Following ischemia and reperfusion, ATK treatment significantly reduced brain PLA(2) activity. These results are the first to demonstrate a therapeutic effect of cPLA(2)alpha inhibition on ischemia and reperfusion injury and define a therapeutic time window. cPLA(2)alpha activity augments injury in the acute and delayed phases of cerebral ischemia and reperfusion injury. We conclude that cPLA(2)alpha inhibition may be clinically useful if started before initiation of cerebral ischemia. PMID- 22819929 TI - Low frequency and intensity ultrasound induces apoptosis of brain glioma in rats mediated by caspase-3, Bcl-2, and survivin. AB - Low frequency and intensity ultrasound (LFU) sonication can selectively induce brain tumor cell apoptosis without damaging neural cells, while also enhancing drug delivery to brain tumors. To explore the underlying mechanisms of related pathways in LFU-induced apoptosis, we investigated the expression of proteins associated with LFU-induced apoptosis. C6 cells were used for in vitro experiments and C6 tumor-bearing rats were used during in vivo experiments. 3 [4.5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazolyl blue (MTT) assay was used to detect C6 cell viability in vitro. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to check the apoptotic cells, and they were counted and analyzed both in vitro and in vivo. Transmission electron microscopy (TEM) was used to illustrate the ultrastructure of apoptotic nuclei of cancer cells in vivo. The expressions of caspase-3, Bcl-2, and survivin proteins were assessed by immunofluorescence, immunohistochemistry and Western blot analysis in vivo. C6 cell viability decrease was statistically significant; the numbers of apoptotic C6 cells in the LFU sonication groups were higher than those in the control group both in vitro and in vivo. The expression of caspase-3 increased, yet the expressions of Bcl-2 and survivin decreased significantly 6h after LFU sonication, compared with the control group in vivo. This study suggests that LFU can induce apoptosis in vitro and in vivo, and that three signaling proteins, caspase-3, Bcl-2, and survivin, might be involved in LFU-induced apoptosis. PMID- 22819930 TI - In vitro and in vivo interactions between glioma and marrow-isolated adult multilineage inducible (MIAMI) cells. AB - The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvements in radio- and chemo-therapies. We recently showed that marrow-isolated adult mutilineage inducible (MIAMI) cells, a subpopulation of human mesenchymal stromal cells (MSCs), can serve as cellular carriers of drug loaded nanoparticles to brain tumors. However, the safety of MIAMI cells as cellular treatment vectors in glioma therapy must be evaluated, in particular their effect on glioma growth and their fate in a tumor environment. In this study, we showed that MIAMI cells were able to specifically migrate toward the orthotopic U87MG tumor model and did not influence its growth. In this model, MIAMI cells did not give rise to cells resembling endothelial cells, pericytes, cancer-associated fibroblasts (CAFs), or astrocytes. Despite these encouraging results, the effects of MIAMI cells may be glioma-dependent. MIAMI cells did not migrate toward the orthotopic Lab1 GB and they can induce the proliferation of other glioma cell lines in vitro. Furthermore, a fraction of MIAMI cells was found to be in a state of proliferation in the U87MG tumor environment. These findings indicate that the use of MIAMI cells as cellular treatment vectors for malignant tumors must be controlled. These cells may be used as "suicide vectors": vectors for killing not only tumor cells but themselves. PMID- 22819931 TI - Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder. AB - Anhedonic symptoms, which include loss of pleasure, appetite and motivation, are key symptoms of major depressive disorder (MDD) and are thought to depend on a neural circuit of the mesolimbic system. The neuropeptide ghrelin plays a crucial role in appetite and reward. Little is known, however, about the role of ghrelin in MDD. We examined the association between morphometric change and plasma ghrelin levels in patients with MDD. Twenty-four patients with MDD and 24 healthy control subjects were studied. Plasma concentration of acylated ghrelin was measured after a period of fasting. Using voxel-based morphometry, we found a main effect of ghrelin on the volume of several brain regions. We then compared these regional volumes in patients with MDD versus healthy subjects. We also compared brain volumes between the two groups, controlling for ghrelin level. There was no significant difference in plasma acylated ghrelin level between patients with MDD and healthy subjects. In the MDD group, ghrelin levels positively correlated with the severity of reduced appetite. Ghrelin levels negatively correlated with gray matter volume of the ventral tegmental area (VTA) in the total sample. The patients with MDD showed significantly smaller VTA gray matter volume compared to healthy subjects. Controlling for the plasma acylated ghrelin level, patients with MDD showed significantly smaller gray matter volume of right substantia nigra compared to healthy subjects. Our findings suggest that plasma acylated ghrelin is associated with neural abnormalities of the pleasure/reward system and may be involved in the pathophysiology of MDD. PMID- 22819932 TI - Oleic acid decreases BCRP mediated efflux of mitoxantrone in Caco-2 cell monolayers. AB - Breast cancer resistance protein (BCRP) efflux restricts intestinal absorption of substances like heterocyclic amines, mycotoxins and certain human and veterinary drugs. Fat rich meals seem to increase absorption of drugs which are BCRP substrates or inhibitors. We therefore hypothesize that absorption of toxicants normally effluxed by BCRP are increased by fatty acids in food. Transport across and accumulation of 3H-Mitoxantrone (MXR) in Caco-2 cell monolayers were measured after 60 min exposure to emulsions of 3H-MXR (1MUM) and oleic acid (0.5-5 mM). In addition, BCRP gene expression (RT-PCR) and the amount of BCRP protein (Western blot) were measured in oleic acid exposed Caco-2 cells. Oleic acid increased transport of MXR in a concentration dependent manner and 2 mM oleic acid or higher increased accumulation of MXR in cells, without any signs of cytotoxicity. Gene expression of BCRP was increased after exposure to oleic acid for 6 h, but the amount of BCRP protein was not increased. In conclusion, oleic acid clearly induced BCRP gene expression and reduced BCRP mediated efflux, although the amount of BCRP in cells was not affected. Consequently, effects of fatty acids on BCRP mediated efflux are important to consider in risk assessment of toxicants in food. PMID- 22819933 TI - Lignan constituents of Tilia amurensis and their biological evaluation on antitumor and anti-inflammatory activities. AB - In the recent decade, numerous lignan derivatives isolated from plants have been proven to have the potential as an anti-cancer substance. On the search for anti cancer compounds from Korean medicinal plants, the methanolic extract from the trunk of Tilia amurensis Rupr. (Tiliaceae) was found to have significant cytotoxicity against A549 (lung carcinoma), SK-OV-3 (ovary malignant ascites), SK MEL-2 (skin melanoma), and HCT-15 (colon adenocarcinoma) in our screening test. Hence, a bioassay-guided fractionation and chemical investigation of the methanolic extract resulted in the isolation and identification of 10 lignan derivatives (1-10) including two new lignan glycosides named tiliamurosides A (1) and B (2). The structures of these new compounds were determined by spectroscopic methods, namely 1D and 2D nuclear magnetic resonance (NMR) techniques, high resolution mass spectrometry (HRMS), circular dichroism (CD) data, and chemical methods. Tiliamuroside B (2) and schizandriside (3) showed significant cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with inhibitory concentration (IC50) values of 3.26-8.89 MUM. Moreover, (-) syringaresinol (8) and (-)-pinoresinol 4-O-beta-D-glucopyranoside (10) significantly inhibited nitric oxide (NO) production in murine microglia BV-2 with IC50 values of 15.05 and 34.35 MUM, respectively. PMID- 22819934 TI - Toxicity of a novel anti-tumor agent 20(S)-ginsenoside Rg3: a 26-week intramuscular repeated administration study in rats. AB - The purpose of this study is to investigate the potential subchronic toxicity of 20(S)-Ginsenoside Rg3(Rg3), by a 26-week repeated intramuscular administration in rats. Rg3 was administrated to rats at dose levels of 0, 4.2, 10.0 or 20.0 mg/kg/day. There was no treatment-related mortality and, at the scheduled autopsy, dose-dependent increases in the absolute and relative spleen weights, of both the 10.0 mg/kg and 20.0 mg/kg dose groups were observed. Absolute and relative kidney weights were significantly elevated in the female 10.0 mg/kg dose group and in the male 20.0 mg/kg dose group. Hematological investigations revealed a dose-dependent increase in the total white blood cell (WBC) count and in the percentage of neutrophils, but a decrease in the percentage of lymphocytes, in rats treated with doses of 10.0/20.0 mg/kg. These effects were completely reversible during the recovery period, and no other adverse effects were observed. It was concluded that the 26-week repeated intramuscular dose of Rg3 caused increases in the spleen and kidney weights, WBC counts and in the percentage of neutrophils, but a decrease in the percentage of lymphocytes, with doses of 10.0 or 20.0 mg/kg/day. The no-observed-adverse-effect level for rats was considered to be 4.2 mg/kg/day. PMID- 22819935 TI - Development of non-competitive enzyme-linked immunosorbent assays for mummichog Fundulus heteroclitus gonadotropins - examining seasonal variations in plasma FSH and LH levels in both sexes. AB - The mummichog Fundulus heteroclitus is an excellent experimental fish for reproductive physiology because of its adequate size, easiness for rearing, and controllable reproduction under laboratory conditions. Furthermore, it is the only species that the native GtHs and their subunits have been purified among small experimental fishes. In this study, homologous non-competitive enzyme linked immunosorbent assays (ELISAs) for the mummichog FSH and LH were developed by raising monoclonal and polyclonal antibodies against the purified GtHs or their subunits, and the plasma hormone levels in various seasons were examined. The cross-reactivity of LH in the FSH ELISA and the cross-reactivity of FSH in the LH ELISA were low, 2.3% and 0.2% respectively, indicating high specificities of both GtH assays. The practical detection limits were 10 pg/well (0.125 ng/ml plasma) for the FSH ELISA and 8 pg/well (0.1 ng/ml plasma) for the LH ELISA. Plasma FSH levels in females indicated distinct correlations with ovarian stages: they were almost undetectable (<0.125 ng/ml) during the post-spawning immature phase (September), low values (0.3 ng/ml) during the cortical alveoli accumulation phase (December), considerably high (1.8 ng/ml) in the vitellogenic phase (February), and very high values (12 ng/ml) during the spawning season (June). The male FSH levels showed similar pattern of changes to that of females, also indicating distinct correlations with testicular activities. Plasma LH levels were considerably high during the spawning period in both sexes (3.3 ng/ml in females and 4.5 ng/ml in males). They were low or undetectable values in non spawning seasons, and clear correlation with the gonadal stages was not observed. These results indicate the importance of FSH for various reproductive events in multiple spawning fishes, and are consistent with the general understanding that the LH is responsible for final gametes maturation in both sexes. Nonetheless, they further suggest that the role of LH for various reproductive events other than the final maturation may be limited. PMID- 22819936 TI - Expression and purification of coronavirus envelope proteins using a modified beta-barrel construct. AB - Coronavirus envelope (E) proteins are short (~100 residues) polypeptides that contain at least one transmembrane (TM) domain and a cluster of 2-3 juxtamembrane cysteines. These proteins are involved in viral morphogenesis and tropism, and their absence leads in some cases to aberrant virions, or to viral attenuation. In common to other viroporins, coronavirus envelope proteins increase membrane permeability to ions. Although an NMR-based model for the TM domain of the E protein in the severe acute respiratory syndrome virus (SARS-CoV E) has been reported, structural data and biophysical studies of full length E proteins are not available because efficient expression and purification methods for these proteins are lacking. Herein we have used a novel fusion protein consisting of a modified beta-barrel to purify both wild type and cysteine-less mutants of two representatives of coronavirus E proteins: the shortest (76 residues), from SARS CoV E, and one of the longest (109 residues), from the infectious bronchitis virus (IBV E). The fusion construct was subsequently cleaved with cyanogen bromide and all polypeptides were obtained with high purity. This is an approach that can be used in other difficult hydrophobic peptides. PMID- 22819937 TI - Neighborhood deprivation and risk of cervical cancer morbidity and mortality: a multilevel analysis from Sweden. AB - OBJECTIVES: To analyze whether there is an association between neighborhood deprivation and cervical cancer morbidity and mortality, beyond individual level characteristics. DESIGN: The entire Swedish population aged 25 to 74, a total of 1.9 million women, were followed from January 1, 1990, until hospital admission due to cervical cancer during the study period, or the end of the study on December 31, 2008. Multilevel logistic regression was used in the analysis with individual level characteristics (age, marital status, family income, education, immigration status, urban/rural status, mobility, comorbidities, parities, and number of partners) at the first level and level of neighborhood deprivation at the second level. Neighborhood deprivation was measured at small area market statistics level by the use of an index. RESULTS: There was a strong association between level of neighborhood deprivation and cervical cancer morbidity and mortality. In the full model, which took account of the individual level characteristics, the risks of cervical cancer morbidity and mortality were 1.25 and 1.36, respectively, in the most deprived neighborhoods. The between neighborhood variance was over twice the standard error, indicating significant differences in cervical cancer morbidity and mortality between neighborhoods. CONCLUSIONS: This study is the largest to date of the influences of neighborhood deprivation on cervical cancer morbidity and mortality. The results suggest that neighborhood characteristics affect cervical cancer morbidity and mortality independently of individual level sociodemographic characteristics. Both individual and neighborhood level approaches are important in health care policies. PMID- 22819938 TI - Neoadjuvant chemotherapy plus radical surgery followed by chemotherapy in locally advanced cervical cancer. AB - OBJECTIVES: To evaluate the efficacy, in terms of safety, overall survival and progression free survival of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemotherapy in patients affected by locally advanced cervical cancer (stage IB2-IIB) with or without node metastases. METHODS: Between June 2000 and February 2007, all patients with diagnosis of locally advanced cervical cancer referred to the Division of Gynecologic Oncology of the University Campus Bio-Medico of Rome were eligible for this protocol. All enrolled patients received 3 cycles of platinum-based chemotherapy every 3 weeks according to the scheme Cisplatin 100mg/mq and Paclitaxel 175 mg/mq. After neoadjuvant chemotherapy all patients with stable or progressive disease were excluded from the protocol, the others were submitted to classical radical hysterectomy, bilateral salpingo-oophorectomy and bilateral systematic pelvic lymphadenectomy and 4 cycles of adjuvant treatment with platinum based chemotherapy were executed. RESULTS: Concerning intention to treat basis analysis, 5 year overall survival (OS) and disease-free survival (DFS) are 77% and 61%, respectively. The 5-year OS of patients with positive pelvic nodes and those with negative nodes metastases was respectively 60% and 87%. Concerning the according to protocol analysis, the 5-year OS and DFS are 81% and 70% respectively. The 5-year OS in patient with positive and negative lymph nodes is 75% and 88% respectively. CONCLUSIONS: The adjuvant chemotherapy regimen after neoadjuvant chemotherapy and radical surgery represents a valid treatment for patients with locally advanced cervical cancer. PMID- 22819940 TI - Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia. AB - Mitochondrial membranes are essential for the good functioning of the organelle. For instance, the inner mitochondrial membrane contains the oxidative phosphorylation system that permits ATP synthesis. Phospholipids environment and especially cardiolipin are crucial for the mitochondrial energy metabolism. Indeed, cardiolipin is known to provide essential structural and functional support to several proteins involved in oxidative phosphorylation. Alterations in cardiolipin structure, content and fatty acids composition have been associated with mitochondrial dysfunction in several physiopathological conditions and diseases. Cancer cachexia is a complex and dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism which leads to a drastic loss in body weight that aggravate prognosis of cancer patients. The underlying mechanisms of hypermetabolism are not fully understood. Whether the mitochondrial energy metabolism is altered during this disease and may participate to hypermetabolism is not clear. This mini-review focuses on cardiolipin especially its biosynthesis and remodeling pathways, its relation with mitochondrial energy metabolism and its possible implication in the cancer cachexia syndrome. PMID- 22819939 TI - Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits. AB - Youths with conduct disorder or oppositional defiant disorder and psychopathic traits (CD/ODD+PT) are at high risk of adult antisocial behavior and psychopathy. Neuroimaging studies demonstrate functional abnormalities in orbitofrontal cortex and the amygdala in both youths and adults with psychopathic traits. Diffusion tensor imaging in psychopathic adults demonstrates disrupted structural connectivity between these regions (uncinate fasiculus). The current study examined whether functional neural abnormalities present in youths with CD/ODD+PT are associated with similar white matter abnormalities. Youths with CD/ODD+PT and comparison participants completed 3.0 T diffusion tensor scans and functional magnetic resonance imaging scans. Diffusion tensor imaging did not reveal disruption in structural connections within the uncinate fasiculus or other white matter tracts in youths with CD/ODD+PT, despite the demonstration of disrupted amygdala-prefrontal functional connectivity in these youths. These results suggest that disrupted amygdala-frontal white matter connectivity as measured by fractional anisotropy is less sensitive than imaging measurements of functional perturbations in youths with psychopathic traits. If white matter tracts are intact in youths with this disorder, childhood may provide a critical window for intervention and treatment, before significant structural brain abnormalities solidify. PMID- 22819941 TI - HPV infection in Brazilian patients with esophageal squamous cell carcinoma: interpopulational differences, lack of correlation with surrogate markers and clinicopathological parameters. AB - The role of HPV in esophageal squamous cell carcinoma (ESCCs) is controversial. Therefore, we determined, through different methodologies, the prevalence of HPV in 264 ESCC samples from Brazil, and correlated it with the presence of surrogate markers and clinicopathological characteristics. HPV is present in 13% of ESCC, and with a 3-fold variation between high and medium incidence areas. Most HPV positive tumors were infected with HPV16, but this was not associated with p16 expression, TP53 mutation status, patient age, amount of tobacco or alcohol consumption, or overall survival. We conclude that HPV infection may not have a role in ESCC. PMID- 22819942 TI - Synthesis of benzo-annulated tryptanthrins and their biological properties. AB - A series of benzo-annulated derivatives of tryptanthrin were prepared and their optical and redox properties were studied. Tryptanthrin and its benzo-annulated derivatives showed selective inhibitory activity on topo I with an increase of activity on topo II by benzo-annulation on quinazolin-4(3H)-one moiety. Although the benzo-annulation on quinazolin-4(3H)-one ring did not affect significantly on the inhibitory activities against topo I and II, the benzoannulation on indolin-3 one ring affected the inhibitory activity very much especially by linear annulation. Cytotoxicities were not significantly changed upon benzoannulation, which were not directly related either to the inhibitory activities against topo I and II or to the reduction potentials. PMID- 22819943 TI - The impact of production type and region on polychlorinated biphenyl (PCB), polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) concentrations in Canadian chicken egg yolks. AB - Chicken eggs from five different production types (conventional, omega-3 enriched, free range, organic and free run) were collected, when available, from three regions (west, central and east) of Canada to determine persistent organic pollutant (POP) concentrations. Total polychlorinated biphenyl (PCB) concentrations (?37 congeners) in yolks from the eggs ranged from 0.162 ng g(-1) lipid to 24.8 ng g(-1) lipid (median 1.25 ng g(-1) lipid) while the concentration of the sum of the 6 indicator PCBs ranged from 0.100 ng g(-1) lipid to 9.33 ng g( 1) lipid (median 0.495 ng g(-1) lipid). Total polychlorinated dibenzo-p dioxin/dibenzofuran (PCDD/F) concentrations ranged from 2.37 pg g(-1) lipid to 382 pg g(-1) lipid (median 9.53 pg g(-1) lipid). The 2005 WHO toxic equivalency (TEQ) ranged from 0.089 pg TEQ(PCDD/F+dioxin-like[DL]-PCB) g(-1) lipid to 12.8 pg TEQ(PCDD/F+DL-PCB) g(-1) lipid (median 0.342 pg TEQ(PCDD/F+DL-PCB) g(-1) lipid). PCB and PCDD/F concentrations were significantly different (p<0.001) in egg yolks from different regions of collection. In contrast to observations in Europe, PCB and PCDD/F concentrations in Canadian egg yolks were not impacted solely by the production type (e.g., conventional, free range, organic, etc.) used to maintain the laying chickens. Additionally, only one Canadian free range yolk from western Canada (12.8 pg TEQ(PCDD/F+DL-PCB) g(-1) lipid) exceeded the European toxic equivalent concentration limits for eggs (5 pg TEQ(PCDD/F+DL-PCB) g(-1) lipid). This differs from observations in Europe where free range/home produced eggs frequently have higher POP concentrations than eggs from other production types. Median PCB dietary intake estimates based on consumption of eggs were less than 10 ng d(-1) while median PCDD/F intakes were less than 45 pg d(-1). PMID- 22819944 TI - Bottom-up approach for the reaction of xenobiotics and their metabolites with model substances for natural organic matter by electrochemistry-mass spectrometry (EC-MS). AB - Risk assessment of xenobiotics requires a comprehensive understanding of their transformation in the environment. As most of the transformation processes usually involve a redox reaction or a hydrolysis as the first steps of the transformation, we applied an approach that uses an electrochemical cell to investigate model "redox" reactions in aqueous solutions for environmental processes. We investigated the degradation of a variety of xenobiotics from polar to nonpolar and analyzed their degradation products by on-line coupling of electrochemistry with mass spectrometry (EC-MS). Furthermore, we evaluated possible binding reactions with regard to the generation of non-extractable residues with some model substances (catechol, phthalic acid, gamma-L-Glutamyl-L cysteinyl-glycine (GSH) and L-histidine) deduced from a natural organic matter (NOM) structure model and identified possible binding-sites. Whereas typically investigations in soil/water-systems have been applied, we used to our knowledge for the first time a bottom-up approach, starting from the chemicals of interest and different model substances for natural organic matter to evaluate chemical binding mechanisms (or processes) in the EC-MS under redox conditions. Under oxidative conditions, bindings of the xenobiotics with catechol, GSH and histidine were found, but no reactions with the model compound phthalic acid were observed. In general, no chemical binding has yet been found under reductive conditions. In some cases (i.e. benzo[a]anthracene) the oxidation product only underwent a binding reaction, whereas the xenobiotic itself did not undergo any reactions. EC-MS is a promising fast and simple screening method to investigate the environmental behavior of xenobiotics and to evaluate the potential risks of newly synthesized substances. PMID- 22819945 TI - The natural rehabilitation of an anthropogenically acidified tropical Lake: two decades of monitoring. AB - The rehabilitation of a pond after approximately 20 years of strong acidified conditions due to industrial and domestic waste deposition in its catchment basin is reviewed. We describe in this study the acidification process that occurred in a tropical pond in Northeast Brazil (Dunas Lake), the rehabilitation plan for the pond and the subsequent monitoring conducted over two decades. After the contamination assessment by the late 80s, a rehabilitation plan was carried out in the early 90s, in which the contaminated soil and water have been removed and reduced, respectively. No further attempt to neutralize the water or any remediation has been carried out. A toxicity monitoring plan based on toxicity assays with the fish Poecilia reticulata was employed to verify the natural rehabilitation of the pond. The data on toxicity, pH, conductivity, sulphate and dissolved iron recorded from 1994 to 2010 were also compiled and discussed. The collected data in 2003 and 2004 indicated changes in water quality and from them complementary management actions, namely improvement in the containment plant, were conducted in 2005. Results for toxicity assays and pH results indicated interannual changes in the water quality similar to rainy-dry periods. Moving average approach using pH data clearly showed the recovery process of Dunas Lake as well as the importance of the containment plan to reduce the contamination. Finally, a summary of the recent situation after two decades of rehabilitation is provided. PMID- 22819946 TI - Comparison of real-time PCR and MassTag PCR for the multiplex detection of highly pathogenic agents. AB - Multiplex PCR assays are a cost- as well as labour-effective way to analyse one sample for several pathogens simultaneously. Besides the mutual competition of the individual PCR reactions included in a multiplex PCR assay, their specific read-out displays a limiting factor for the total number of PCR reactions that can be multiplexed. In this study, two PCR systems with different read-out approaches are compared, using a pentaplex PCR assay for the detection of highly pathogenic agents. A pentaplex assay was used since five represents the current limit of real-time PCR multiplexing capacity due to the low resolution of fluorescence emission peaks of the current equipment. In contrast, MassTag PCR as a quite new technique offers the possibility to detect up to 20-30 target sequences from one reaction. After extensive and separate optimisation of the PCR protocol for both platforms, a comparative probit analysis showed good sensitivities for MassTag and real-time PCR detection. Nevertheless, the detection limits of MassTag PCR have been undercut by the real-time PCR for each target. We therefore conclude that MassTag PCR is a useful diagnostic technique for the sensitive screening for pathogens by highly multiplexed PCR assays, but cannot reach the sensitivity of real-time PCR for lower multiplexed PCR assays. PMID- 22819948 TI - Site-directed mutagenesis and over expression of aroG gene of Escherichia coli K 12. AB - 3-Deoxy-D-arabino-heptulonate-7-phosphate (DAHP) synthetase is one of the key enzymes, which catalyzes the first step in the aromatic amino acid biosynthetic pathway and yields the three amino acids tyrosine, tryptophan, and phenylalanine. In Escherichia coli (E. coli), three differently regulated DAHP synthases carry out the first regulated step in the aromatic amino acid biosynthetic pathway. The three DAHP synthases encoded by the genes aroG, aroF and aroH are inhibited by phenylalanine, tyrosine and tryptophan, respectively. In this work, the aroG gene was cloned and mutated by site-directed mutagenesis using splicing overlap extension PCR (SOE-PCR) technique. The feedback-resistant DAHP synthase encoded by aroG was achieved by replacing the residue Leu175 of aroG with Asp as to increase net carbon flow down the common pathway. SDS-PAGE which was used to access the protein expression level of aroGM showed the strain harbored mutated aroGM gene achieve over-expression compared to strain contain empty plasmid pET 28b (+). PMID- 22819949 TI - Do women who choose to become surrogate mothers have different psychological profiles compared to a normative female sample? AB - BACKGROUND: Surrogate mothers are routinely assessed for their suitability to function in the role of surrogacy. Such assessments often include psychological testing including the Minnesota multiphasic personality inventory-revised (MMPI 2). There has been a paucity of research detailing the personality structures of these women, especially with the MMPI-2. RESEARCH OBJECTIVE: The current study examined the validity and clinical profiles of surrogate mothers (N=43) compared to a non-patient, normative reference sample of women (N=40) using their MMPI-2 results. METHOD: This study examined between group differences among the 68 scales of the MMPI-2. Independent-sample t-tests were conducted for each of the scales, with those violating homogeneity of variance assessed with a non parametric, Mann-Whitney U test. FINDINGS: The findings demonstrated that surrogate mothers produce profiles with lower values than normative samples across several MMPI-2 scales. For this unique group, elevations were observed on scales that assess profile validity, views on traditional gender roles, repression, ego strength, social obligation and duties, and contained hostility, relative to the normative group. CONCLUSION: The findings provide an initial examination of the profiles of surrogate mothers on the MMPI-2. The findings revealed that the psychological suitability of surrogate mother candidates appear to be a composite of being both tough-minded and sensitive, sufficiently resilient to manage the role of surrogacy, and aware of the importance of emotional boundary-setting related to pre-natal attachment. PMID- 22819947 TI - Microcystin-LR, a protein phosphatase inhibitor, induces alterations in mitotic chromatin and microtubule organization leading to the formation of micronuclei in Vicia faba. AB - BACKGROUND AND AIMS: Microcystin-LR (MCY-LR) is a cyanobacterial toxin, a specific inhibitor of type 1 and 2A protein phosphatases (PP1 and PP2A) with significant impact on aquatic ecosystems. It has the potential to alter regulation of the plant cell cycle. The aim of this study was improved understanding of the mitotic alterations induced by cyanotoxin in Vicia faba, a model organism for plant cell biology studies. METHODS: Vicia faba seedlings were treated over the long and short term with MCY-LR purified in our laboratory. Short-term treatments were performed on root meristems synchronized with hydroxylurea. Sections of lateral root tips were labelled for chromatin, phosphorylated histone H3 and beta-tubulin via histochemical and immunohistochemical methods. Mitotic activity and the occurrence of mitotic alterations were detected and analysed by fluorescence microscopy. The phosphorylation state of histone H3 was studied by Western blotting. KEY RESULTS: Long-term MCY-LR exposure of lateral root tip meristems increased the percentage of either early or late mitosis in a concentration-dependent manner. We observed hypercondensed chromosomes and altered sister chromatid segregation (lagging chromosomes) leading to the formation of micronuclei, accompanied by the formation of disrupted, multipolar and monopolar spindles, disrupted phragmoplasts and the hyperphosphorylation of histone H3 at Ser10. Short-term MCY LR treatment of synchronized cells showed that PP1 and PP2A inhibition delayed the onset of anaphase at 1 ug mL(-1) MCY-LR, accelerated cell cycle at 10 ug mL( 1) MCY-LR and induced the formation of lagging chromosomes. In this case mitotic microtubule alterations were not detected, but histone H3 was hyperphosphorylated. CONCLUSIONS: MCY-LR delayed metaphase-anaphase transition. Consequently, it induced aberrant chromatid segregation and micronucleus formation that could be associated with both H3 hyperphosphorylation and altered microtubule organization. However, these two phenomena seemed to be independent. The toxin may be a useful tool in the study of plant cell cycle regulation. PMID- 22819950 TI - Direct recordings in human cortex reveal the dynamics of gamma-band [50-150 Hz] activity during pursuit eye movement control. AB - The time course of neural activity in human brain regions involved in mediating pursuit eye movements is unclear. To address this question, we recorded intracerebral electroencephalography activity in eight epileptic patients while they performed a pursuit task that dissociates reactive, predictive and inhibited pursuits. A sustained gamma band (50-150 Hz) activity corresponding to pursuit maintenance was observed in the pursuit (and not saccade) area of the frontal eye field (FEF), in the ventral intraparietal sulcus (VIPS) and in occipital areas. The latency of gamma increase was found to precede target onset in FEF and VIPS, suggesting that those areas could also be involved during pursuit preparation/initiation. During pursuit inhibition, a sustained gamma band response was observed within prefrontal areas (pre-supplementary-motor-area, dorso-lateral prefrontal and frontopolar cortex). This study describes for the first time the dynamics of the neural activity in four areas of the pursuit system, not previously available in humans. These findings provide novel timing constraints to current models of the human pursuit system and establish the relevance of direct recordings to precisely relate eye movement behavior with neural activity in humans. PMID- 22819951 TI - Mechanisms for consideration for intervention in the development of organophosphorus-induced delayed neuropathy. AB - Organophosphorus-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterised by ataxia progressing to paralysis with concomitant central and peripheral distal axonopathy. Symptoms of OPIDN in people include tingling of the hands and feet. This tingling is followed by sensory loss, progressive muscle weakness and flaccidity of the distal skeletal muscles of the lower and upper extremities and ataxia, which appear about 8-14 days after exposure. Some organophosphorus compounds (OPs) that are still used in worldwide agriculture have potential to induce OPIDN, including methamidophos, trichlorfon, dichlorvos and chorpyrifos. This review summarizes experimental attempts to prevent and/or treat OPIDN and the different mechanisms involved in each approach. The initial mechanism associated with development of OPIDN is phosphorylation and inhibition of neuropathy target esterase (NTE). The phosphorylated enzyme undergoes a second reaction known as "aging" that results in the loss of one of the "R" groups bound to the phosphorus of the OP. A second mechanism involved in OPIDN is an imbalance in calcium homeostasis. This can lead to the activation of calcium-activated neutral protease and increases in calcium/calmodulin-dependent protein kinases. These events contribute to aberrant phosphorylation of cytoskeletal proteins and protein digestion in the terminal axon that can proceed similarly to Wallerian-type degeneration. Several experimental studies demonstrated alleviation of the signs and symptoms of OPIDN by restoring calcium balance. Other studies have used preadministration of NTE inhibitors, such as carbamates, thiocarbamates, sulfonyl fluorides and phosphinate to prevent OPIDN. Progress is being made, but there is yet no single specific treatment available for use in clinical practice to prevent or alleviate the severe effects of OPIDN. PMID- 22819952 TI - Hispidin produced from Phellinus linteus protects against peroxynitrite-mediated DNA damage and hydroxyl radical generation. AB - Oxidative stress plays an important role in the progression of many chronic diseases including cardiovascular diseases, diabetes, cancer and neurodegenerative disorders. One such mediator of oxidative stress is peroxynitrite, which is highly toxic to cultured neurons and astrocytes, and has been reported to be involved in the pathogenesis of various types of neuronal diseases. Therefore, searching for natural compounds with peroxynitrite scavenging activity might be an effective therapy for peroxynitrite-mediated cytotoxicity. Hispidin, a phenolic compound from Phellinus linteus (a medicinal mushroom), has been shown to possess strong antioxidant, anticancer, and antidiabetic properties. However, the astrocyte protective efficacy of hispidin has been not examined. This study was undertaken to investigate whether the astrocyte protective effect of hispidin is associated with inhibition of peroxynitrite-induced DNA damage, a critical event leading to peroxynitrite mediated cytotoxicity. Our results showed that peroxynitrite can cause DNA damage in phiX-174 plasmid DNA and rat primary astrocytes. The presence of hispidin (10 20 MUg/ml) was found to significantly inhibit peroxynitrite-induced DNA damage and cytotoxicity. EPR spectroscopy demonstrated that the formation of DMPO hydroxyl radical adduct (DMPO-OH) from peroxynitrite, and that hispidin potently diminished the adduct signal in a concentration-dependent manner. Taken together, these results demonstrate for the first time that hispidin can protect against peroxynitrite-mediated cytotoxicity, DNA damage and hydroxyl radical formation. PMID- 22819953 TI - Ecological relationship analysis of the urban metabolic system of Beijing, China. AB - Cities can be modelled as giant organisms, with their own metabolic processes, and can therefore be studied using the same tools used for biological metabolic systems. The complicated distribution of compartments within these systems and the functional relationships among them define the system's network structure. Taking Beijing as an example, we divided the city's internal system into metabolic compartments, then used ecological network analysis to calculate a comprehensive utility matrix for the flows between compartments within Beijing's metabolic system from 1998 to 2007 and to identify the corresponding functional relationships among the system's compartments. Our results show how ecological network analysis, utility analysis, and relationship analysis can be used to discover the implied ecological relationships within a metabolic system, thereby providing insights into the system's internal metabolic processes. Such analyses provide scientific support for urban ecological management. PMID- 22819954 TI - Influence of internal-gap width and cement type on the retentive force of zirconia copings in pullout testing. AB - OBJECTIVES: The purpose of this study was to evaluate the influence of internal gap width and cement type on the retentive force of zirconia copings. METHODS: A CAD/CAM system was used to mill 48 identical abutments on extracted human molars and fabricate 48 zirconia copings. The internal-gap width for cement was set to 40 MUm or 160 MUm (n=24 each). Three cement types (Panavia F, RelyX Unicem, and RelyX Luting) were used with each internal-gap width (n=8/cement type). The intaglio surfaces of the copings were airborne-particle abraded, and each coping was cemented onto the corresponding abutment using the indicated luting agent. After 10,000 cycles of thermocycling, the retentive force was evaluated by pullout tests. Kruskal-Wallis and Wilcoxon Rank Sum tests were used for data analysis (alpha=0.05). RESULTS: In the 40-MUm gap groups, Panavia F had the highest mean retentive force compared to RelyX Unicem and RelyX Luting (P<0.000). In 160-MUm gap groups, RelyX Unicem had the highest mean retentive force compared to Panavia F and RelyX Luting (P<0.000). CONCLUSIONS: With the increase in internal gap width, a resin cement with self-etching agents as a co-initiator for autopolymerization resulted in significantly decreased retentive force, whereas a resin-modified glass ionomer cement or a self-adhesive resin cement did not. Use of resin cements rather than resin-modified glass ionomer cements improved the retentive force of zirconia copings regardless of the amount of internal gap width. PMID- 22819955 TI - The effects of finishing and polishing techniques on surface roughness and color stability of nanocomposites. AB - OBJECTIVES: The aim of this in vitro study was to evaluate the effects of different finishing and polishing techniques on the surface roughness and color stability of nanocomposites. METHODS: Two nanohybrid (Grandio, Aelite Aesthetic Enamel), two nanofill (Filtek Supreme XT Dentin and Translucent), and a microhybrid (Filtek Z250) composites were used. Two hundred and eighty disc shaped specimens were cured under a mylar strip. Seven specimens of each resin composite were randomly assigned to one of the seven polishing systems. A profilometer was used for assessing surface roughness. DeltaE was calculated with a colorimeter at baseline and 48 h after storage in a coffee solution. The results were analysed by two-way ANOVA and Tukey's HSD test (alpha=0.05). Regression analysis was used to examine the correlation between surface roughness and color stability (alpha=0.01). RESULTS: There was no significant difference in R(a) values between mylar strips and Sof-Lex polishing discs (p>0.05). The highest DeltaE and R(a) values were obtained from Grandio (p<0.05), and Aelite Aesthetic Enamel had the lowest DeltaE values (p<0.05). The Enhance system showed the lowest color differences among all the finishing systems. The highest DeltaE values were found in the composite resin groups under mylar strips and finished with diamond burs (p<0.05). CONCLUSIONS: While the Sof-Lex discs provided the lowest surface roughness, the Enhance Polishing system provided the most stain resistant groups. Grandio presented the highest surface roughness and staining susceptibility after storage in coffee solution. Aelite Aesthetic Enamel, which did not include TEGDMA in its composition, showed the least discoloration. CLINICAL SIGNIFICANCE: The composites with smaller filler size did not necessarily show low surface roughness and discoloration. Staining of composite resins was dependent on monomer structure, as well as surface irregularities. PMID- 22819956 TI - Differences in impact of patient and prosthetic characteristics on oral health related quality of life among implant-retained overdenture wearers. AB - OBJECTIVES: To evaluate the oral health-related quality of life (OHRQoL) of implant-retained overdenture users. METHODS: 63 patients aged 50-90 years treated with at least one implant overdenture at the Complutense University (Madrid) in 2000-2010 were included. Of those, 42 answered the Oral Health Impact Profile (OHIP-14 sp) questionnaire. The additive method was used in the OHIP analysis. Data regarding sociodemographic background, overdenture features, and clinical factors were recorded. Sociodemographic and overdenture-related variables for the lost patients (n=21) were also gathered from their history files. Descriptive probes, Mann-Whitney and Kruskal-Wallis tests, and the Spearman correlation coefficient were applied (p <= 0.05). RESULTS: The predominant participants' profile was that of a 71-80-year-old woman wearing a mandibular overdenture with a bar retention system and a complete denture in the opposite jaw. 71.4% of the respondents suffered from some kind of impact on OHRQoL, showing an average score of 2.7 +/- 3.0 (range: 0-13). 100% of respondents reported no impact for the "social disability" and "handicap" dimensions. The most prevalently affected domain was "physical pain", followed by "functional limitation" and "psychological discomfort". Variables such as the overdenture location or the retention system affected specific OHIP subscales (p <= 0.05). The greatest total score was achieved when the antagonist was a complete denture (p<0.01). CONCLUSIONS: Implant-retained overdentures provide a seemingly acceptable quality of life in the elderly population studied, irrespective of the influence of the location, retention system, and antagonist. CLINICAL SIGNIFICANCE: Although further research is necessary, mandibular implant overdentures are more comfortable than maxillary ones. Ball-retained prostheses facilitate eating the most, whereas the presence of oral ulcers and/or candidiasis was only detected in the case of bars, thus impairing OHRQoL. A complete denture as antagonist decreases the patient overall satisfaction. PMID- 22819957 TI - Prevalence of avian haemosporidian parasites and their host fidelity in the central Philippine islands. AB - We examined the prevalence and host fidelity of avian haemosporidian parasites belonging to the genera Haemoproteus, Leucocytozoon and Plasmodium in the central Philippine islands by sampling 23 bird families (42 species). Using species specific PCR assays of the mitochondrial cytochrome b gene (471 base pairs, bp), we detected infections in 91 of the 215 screened individuals (42%). We also discriminated between single and multiple infections. Thirty-one infected individuals harbored a single Haemoproteus lineage (14%), 18 a single Leucocytozoon lineage (8%) and 12 a single Plasmodium lineage (6%). Of the 215 screened birds, 30 (14%) presented different types of multiple infections. Intrageneric mixed infections were generally more common (18 Haemoproteus/Haemoproteus, 3 Leucocytozoon/Leucocytozoon, and 1 Plasmodium/Plasmodium) than intergeneric mixed infections (7 Haemoproteus/Leucocytozoon and 1 Haemoproteus/Leucocytozoon/Plasmodium). We recovered 81 unique haemosporidian mitochondrial haplotypes. These clustered in three strongly supported monophyletic clades that correspond to the three haemosporidian genera. Related lineages of Haemoproteus and Leucocytozoon were more likely to derive from the same host family than predicted by chance; however, this was not the case for Plasmodium. These results indicate that switches between host families are more likely to occur in Plasmodium. We conclude that Haemoproteus has undergone a recent diversification across well supported host-family specific clades, while Leucocytozoon shows a longer association with its host(s). This study supports previous evidence of a higher prevalence and stronger host-family specificity of Haemoproteus and Leucocytozoon compared to Plasmodium. PMID- 22819958 TI - Treatment of mining acidic leachates with indigenous limestone, Zimapan Mexico. AB - An experimental study to evaluate the potential of using indigenous limestones in a passive system to treat acid mine drainage, at a mining zone of Mexico was carried out. Chemical and mineralogical characteristics of four types of native rocks (KIT1, KIT2, KSS, QZ) showed distinct CaCO3 contents. Synthetic aqueous leachates from an old tailings impoundment had a pH of 2.18, 34 mg/L As, 705 mg/L Fetotal, and 3975 mg/L SO4(2-). To evaluate dissolution behavior of rocks, kinetic batch experiments with an acid Fe-rich solution were performed. Decaying kinetic constants adjusting H(+) concentration to a first order exponential process were: KIT1 (k = 2.89), KIT2 (k = 0.89) and KSS (k = 0.47). Infrared spectrum and XRD of precipitates showed schwertmannite formation. To determine As and heavy metals (Fe, Cd, Zn, Al) removal from the synthetic leachates, batch experiments using KIT1 were developed. Arsenic decreased from 34.00 mg/L to 0.04 mg/L, Fe and Al were totally removed, and concentrations of Zn and Cd decreased 88% and 91% respectively. Analyses by IR and SEM-EDS indicate that co precipitation with Fe-Hydroxides formed upon leachate interaction with limestone is the main As removal process. Chamosite, identified by XRD may participate in the removal of Al, SiO2 and a fraction of Fe. PMID- 22819959 TI - Adsorption of ofloxacin and norfloxacin on carbon nanotubes: hydrophobicity- and structure-controlled process. AB - Adsorption of antibiotics on solid particles is a key process controlling their fate in the subsurface. This study compared the adsorption of ofloxacin and norfloxacin (NOR) on carbon nanotubes (CNTs) to evaluate the role of structural and hydrophobic properties in regulating their adsorption. A significant relationship was observed between single-point adsorption coefficients (K(d)) and specific surface area (highly hydrophobic), but not between K(d)s and oxygen content. This result suggested that site-specific adsorption was not important but hydrophobic effect may have an important contribution to OFL and NOR adsorption on CNTs. However, normalizing the adsorption coefficients by OFL and NOR solubilities enlarged their adsorption difference indicating that hydrophobicity was not the only factor controlling the difference between OFL and NOR adsorption on CNTs. Their chemical structures show that both chemicals could interact with CNTs through an electron-donor-acceptor mechanism. This mechanism was correlated with the different adsorption of OFL and NOR on functionalized CNTs (namely hydroxylized, carboxylized, and graphitized CNTs). This study revealed that OFL and NOR adsorption was controlled by their both structural- and hydrophobic-properties. PMID- 22819960 TI - Origin, mobility, and temporal evolution of arsenic from a low-contamination catchment in Alpine crystalline rocks. AB - The reduction to 10 MUg/l of the limit for arsenic in drinking water led many resource managers to deal with expensive treatments. In the very common case of arsenic levels close to the recommended maximum concentration, knowing the origin and temporal evolution of As has become of great importance. Here we present a case study from an alpine basin. Arsenic speciation, isotopic compositions of pyrite, sulfate and water, and concentrations of major and trace elements demonstrate a geogenic source for arsenic linked to the dissolution of pyrite. We provide new tools to further study As at low concentrations where many processes may be masked. The observed negative correlation between delta(34)SSO4 and [As] is interpreted as a Rayleigh-type sulfur-isotope fractionation during increasing pyrite dissolution. The observed positive correlation between delta(18)OSO4 and As(V)/As(III) could help to retrieve initial redox conditions. A 3-year long monitoring at high-resolution demonstrated that drought conditions enhance pyrite dissolution whose degradation products are scavenged by recharge water. An increase in As in groundwater may result from droughts due to enhanced oxygen entry in the unsaturated zone. The 2003 European heatwave had a major effect. PMID- 22819961 TI - Quantification of trace arsenic in soils by field-portable X-ray fluorescence spectrometry: considerations for sample preparation and measurement conditions. AB - Recent technological improvements have led to the widespread adoption of field portable energy dispersive X-ray fluorescence (FP-XRF) by governmental agencies, environmental consultancies and research institutions. FP-XRF units often include analysis modes specifically designed for the quantification of trace elements in soils. Using these modes, X-ray tube based FP-XRF units can offer almost "point and shoot" ease of use and results comparable to those of laboratory based instruments. Nevertheless, FP-XRF analysis is sensitive to spectral interferences as well as physical and chemical matrix effects which can result in decreased precision and accuracy. In this study, an X-ray tube-based FP-XRF analyser was used to determine trace (low ppm) concentrations of As in a floodplain soil. The effect of different sample preparation and analysis conditions on precision and accuracy were systematically evaluated. We propose strategies to minimise sources of error and maximise data precision and accuracy, achieving in situ limits of detection and precision of 6.8 ppm and 14.4%RSD, respectively for arsenic. We demonstrate that soil moisture, even in relatively dry soils, dramatically affects analytical performance with a signal loss of 37% recorded for arsenic at 20 wt% soil moisture relative to dry soil. We also highlight the importance of the use of certified reference materials and independent measurement methods to ensure accurate correction of field values. PMID- 22819963 TI - A plasma membrane Ca(2+)-ATPase (PMCA) from the liver fluke, Fasciola hepatica. AB - Fasciolosis is a parasitic infection by the liver fluke Fasciola hepatica, which costs the global agricultural community over US $2 billion per year. Its prevalence is rising due to factors such as climate change and drug resistance. ATP-dependent membrane transporters are considered good potential drug targets as they are essential for cellular processes and are in an exposed, accessible position in the cell. Immunolocalisation studies demonstrated that a plasma membrane calcium ATPase (PMCA) was localised to the parenchymal tissue in F. hepatica. The coding sequence for a F. hepatica PMCA (FhPMCA) has been obtained. This sequence encodes a 1,163 amino acid protein which contains motifs which are commonly conserved in PMCAs. Molecular modelling predicted that the protein has 10 transmembrane segments which include a potential calcium ion binding site and phosphorylation motif. FhPMCA interacts with the calmodulin-like protein FhCaM1, but not the related proteins FhCaM2 or FhCaM3, in a calcium-ion dependent manner. This interaction occurs through a region in the C-terminal region of FhPMCA which most likely adopts an alpha-helical conformation. When FhPMCA was heterologously expressed in a budding yeast strain deleted for its PMCA (Pmc1p), it restored viability. Microsomes prepared from these yeast cells had calcium ion stimulated ATPase activity which was inhibited by the known PMCA inhibitors, bisphenol and eosin. The potential of FhPMCA as a new drug target is discussed. PMID- 22819962 TI - Multiplex proteomics analysis of gender-associated proteins in Brugia malayi. AB - Gender-associated (GA) genes are important for the development and reproduction of filarial nematodes. Identification and characterization of GA genes may provide insight into major pathways and processes involved in development and reproduction. The recent completion of the Brugia malayi genome has provided a good foundation for proteomics studies. Multiplex protein labelling and two dimensional difference in-gel electrophoresis (2D-DIGE) combined with MALDI TOF/TOF tandem MS were used to identify GA proteins. Thirty male and 32 female associated proteins were identified in this study. Many of these GA genes have homologues in Caenorhabditis elegans (83% male and 69% female), and most of the homologues have severe RNA interference (RNAi) phenotypes (72% male and 55% female) in C. elegans. Functional analysis showed that the male-associated genes are enriched for energy production, metabolic processes and cytoskeleton, while the female-associated genes are enriched for RNA modification and transcription. GA genes encode many excreted/secreted proteins. In situ localization studies showed that GA genes are mainly expressed in reproductive organs, and this is further evidence for their involvement in reproduction. Improved understanding of the basic biology of filarial nematodes may lead to improved tools for prevention and treatment of filarial infections. This study combined proteomics, in situ hybridization (ISH) and bioinformatics in a systems biology approach to improve understanding of gender differences and key proteins involved in reproduction in filarial worms. Advanced proteomics methods and bioinformatics led to the identification of 62 GA proteins for B. malayi. ISH revealed that most of those GA genes are expressed during embryogenesis or spermatogenesis. ISH results were consistent with RNAi data for C. elegans that linked the homologues of the B. malayi proteins to gamete production and embryogenesis. PMID- 22819964 TI - HOMOR: higher order model outlier rejection for high b-value MR diffusion data. AB - Diffusion MR images are prone to artefacts caused by head movement and cardiac pulsation. Previous techniques for the automated voxel-wise detection of signal intensity outliers have relied on the fit of the diffusion tensor to the data (RESTORE). However, the diffusion tensor cannot appropriately model more than a single fibre population, which may lead to inaccuracies when identifying outlier voxels in crossing fibre regions, particularly when high b-values are used to obtain increased angular contrast. HOMOR (higher order model outlier rejection) was developed to overcome this limitation and is introduced in this study. HOMOR is closely related to RESTORE, but employs a higher order model capable of resolving multiple fibre populations within a voxel. Using high b-value (b=3000 s/mm2) diffusion data from a population of 90 healthy participants, as well as simulations, HOMOR was found to identify a decreased number of outlier voxels compared to RESTORE primarily within areas of crossing, bending and fanning fibres. At lower b-values, however, RESTORE and HOMOR give similar results, which is demonstrated using diffusion data acquired at b=1000 s/mm2 in a mixed cohort. This study demonstrates that, although RESTORE is suitable for low b-value data, HOMOR is better suited for high b-value data. PMID- 22819966 TI - A novel gene encoding goose immunoglobulin lambda light chain. PMID- 22819965 TI - Involvement of V-Ets erythroblastosis virus E26 oncogene homolog 2 in regulation of transcription activity of MDR1 gene. AB - Over-expression of MDR1 confers multidrug resistance (MDR) in cancers and remains a major cause for the failure of chemotherapy. In the present study, we found that V-Ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) could activate MDR1 transcription and P-glycoprotein (P-gp) expression in SGC7901 cells. Knockdown of ETS2 attenuated MDR1 transcription and P-gp expression, and increased the sensitivity of MDR cancer cells to cytotoxic drugs that were transported by P-gp in SGC7901/VCR cells. ETS2 could bind to the ETS2 sites on the MDR1 promoter and activate its transcription. The regulation of MDR1 expression by ETS2 may provide potential ways to overcome MDR in cancer treatment. PMID- 22819967 TI - Anatomical and functional enhancements of the insula after loss of large primary somatosensory fibers. AB - Brain changes associated with the loss of a sensory modality such as vision and audition have previously been reported. Here, we examined the effect of loss of discriminative touch and proprioception on cortical thickness and functional connectivity. We performed structural magnetic resonance imaging and resting state functional magnetic resonance imaging scans on a 60-year-old female who at age 31 suffered a selective loss of large-diameter myelinated primary afferents and, therefore, relies mainly on her intact thin-fiber senses (temperature, pain, itch, and C-fiber touch) and vision to negotiate her environment. The patient showed widespread cortical thinning compared with 12 age-matched female controls. In contrast, her right anterior insula was significantly thick. Seed-based resting-state analysis revealed that her right anterior insula had increased connectivity to bilateral posterior insula. A separate independent component analysis revealed the increased connectivity between the insula and visual cortex in the patient. As the insula is an important processing area for temperature and C-fiber tactile information, the increased intrainsular and insular-visual functional connectivity could be related to the patient's use of C-fiber (gentle) touch and temperature information in conjunction with visual information to navigate her environment. We, thus, demonstrated plasticity in networks involving the insular cortex following denervation of large-diameter somatosensory afferents. PMID- 22819968 TI - Resting-state synchrony during early alcohol abstinence can predict subsequent relapse. AB - Short-term abstinent alcoholics have shown increased engagement of reward regions and reduced engagement of executive control regions. There is no report yet on whether these differences can predict relapse. This is the first study that investigates whether differences in resting-state networks can predict later relapse. Resting-state functional magnetic resonance imaging data were collected from 69 short-term abstinent alcoholics. Participants performed the affective go/no-go task outside of the scanner. At 6-month follow-up, participants were grouped as abstainers (N = 40; age: M = 46.70, standard deviation [SD] = 6.83) and relapsers (N = 29; age: M = 46.91, SD = 7.25). We examined baseline resting state synchrony (RSS) using seed-based measures. Compared with abstainers, relapsers showed significantly decreased RSS within both the reward and executive control networks as well as within the visual network (P < 0.05). Lower RSS in relapsers could predict relapse (P < 0.05) and was significantly correlated with poor inhibitory control of emotional-laden stimuli (P < 0.017) and with alcohol use (P < 0.05). Results suggest that lower RSS during short-term abstinence may predict subsequent relapse. The association of lower RSS with poorer inhibitory control suggests that low RSS may constitute a faulty foundation for future responses to external cues, which can be manifested as the inability to inhibit behavior. PMID- 22819969 TI - Neonatal fibroblast growth factor treatment enhances cocaine sensitization. AB - Growth factors are critical in neurodevelopment and neuroplasticity, and recent studies point to their involvement in addiction. We previously reported increased levels of basic fibroblast growth factor (FGF2) in high novelty/drug-seeking rats (bred high responders, bHR) compared to low novelty/drug-seeking rats(bred low responders, bLRs). The present study asked whether an early life manipulation of the FGF system(a single FGF2 injection on postnatal day 2) can impact cocaine sensitization and associated neurobiological markers in adult bHR/bLR animals. Neonatal FGF2- and vehicle-treated bHR/bLR rats were sensitized to cocaine(7 daily injections, 15 mg/kg/day, i.p.) in adulthood. Neonatal FGF2 markedly increased bLRs' typically low psychomotor sensitization to cocaine (day 7 locomotor response to cocaine), but had little effect on bHRs' cocaine sensitization. Gene expression studies examined dopaminergic molecules as well as FGF2 and the FGFR1 receptor in cocaine naive animals, to investigate possible neurobiological alterations induced by neonatal FGF2 exposure that may influence behavioral response to cocaine. bLRs showed decreased tyrosine hydroxylase in the ventral tegmental area (VTA), decreased D1 and increased D2 receptor expression in the nucleus accumbens core, as well as decreased FGF2 in the VTA, substantia nigra, accumbens core, and caudate putamen compared to bHRs. Neonatal FGF2 selectively increased D1 receptor and FGF2 mRNA in the accumbens core of bLRs, which may contribute to their heightened cocaine sensitization. Our results suggest increased FGF2 in the mesodopaminergic circuit (as in baseline bHRs and neonatal FGF2-exposed bLRs vs. baseline bLRs) enhances an individual's susceptibility to cocaine sensitization and may increase vulnerability to drug seeking and addiction. PMID- 22819970 TI - mGluR5 knockout mice display increased dendritic spine densities. AB - Alterations in dendritic spine densities and morphologies have been correlated with the abnormal functioning of the synapse. Specifically the metabotropic glutamate receptor 5 (mGluR5) has been implicated in dendrogenesis and spineogenesis, since its activation triggers various signaling cascades that have been demonstrated to play roles in synaptic maturation and plasticity. Here we used the Golgi impregnation technique to analyze the dendritic spines of mGluR5( /-) knockout mice in comparison to their heterozygote mGluR5(+/-) littermates. mGluR5(-/-) mice had elevated spine densities irrespective of spine type or location along their dendritic trees in comparison to mGluR5(+/-) animals. Such anatomical changes may underlie the hyperexcitability observed in mGluR5 total knockout mice. PMID- 22819971 TI - Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is the leading genetic cause of infantile death and caused by the loss of functional Survival Motor Neuron 1 (SMN1). The remaining copy gene, SMN2, is unable to rescue from disease because the primary gene product lacks the final coding exon, exon 7, due to an alternative splicing event. While SMNDelta7 is a rapidly degraded protein, exon 7 is not specifically required in a sequence-specific manner to confer increased functionality to this truncated protein. Based upon this molecular observation, aminoglycosides have been examined to artificially elongate the C-terminus of SMNDelta7 by "read through" of the stop codon. An SMNDelta7 read-through event benefits intermediate mouse models of SMA. Here we demonstrate that delivery of a read-through inducing compound directly to the CNS can partially lessen the severity of a severe model of SMA (Smn(-/-); SMN2(+/+)), albeit not to the extent seen in the less severe model. This further demonstrates the utility of read-through inducing compounds in SMA. PMID- 22819972 TI - Preliminary genetic imaging study of the association between estrogen receptor alpha gene polymorphisms and harsh human maternal parenting. AB - A failure of neural changes initiated by the estrogen surge in late pregnancy to reverse the valence of infant stimuli from aversive to rewarding is associated with dysfunctional maternal behavior in nonhuman mammals. Estrogen receptor-alpha plays the crucial role in mediating these neural effects of estrogen priming. This preliminary study examines associations between estrogen receptor-alpha gene polymorphisms and human maternal behavior. Two polymorphisms were associated with human negative maternal parenting. Furthermore, hemodynamic responses in functional magnetic resonance imaging to child stimuli in neural regions associated with social cognition fully mediated the association between genetic variation and negative parenting. This suggests testable hypotheses regarding a biological pathway between genetic variants and dysfunctional human maternal parenting. PMID- 22819973 TI - Effects of peripheral kappa opioid receptor activation on inflammatory mechanical hyperalgesia in male and female rats. AB - Activation of peripheral kappa opioid receptors (KOR) effectively relieves pain and hyperalgesia in preclinical and clinical models of pain. Although centrally located KOR activation results in sexually dimorphic effects, it is unclear whether peripheral KOR also produces sex dependent effects in persistent inflammatory pain conditions. In this study, we investigated whether local administration of a specific KOR agonist, U50, 488 relieve mechanical hyperalgesia induced by the injection of complete Freund's adjuvant (CFA) in the rat hindpaw, and whether there are sex differences. The effects of U50, 488 were assessed three days after the induction of CFA-induced inflammation, a time point at which mechanical hyperalgesia was most prominent. There were no sex differences in baseline and CFA-induced changes in mechanical thresholds between male and female rats. Local treatment of U50, 488 produced moderate, but significant, anti-hyperalgesia in both male and female rats. However, U50, 488 was significantly more effective in male rats at the highest dose of U50, 488. We confirmed that the highest dose of U50, 488 used in this study did not produce systemic effects, and that the drug effect is receptor specific. On the basis of these results, we suggest that local KOR agonists are effective in mitigating mechanical hyperalgesia under a persistent inflammatory pain condition and that sex differences in anti-hyperalgesic effects become more evident at high doses. PMID- 22819974 TI - Repeated treatment with nicotine induces phosphorylation of NMDA receptor NR2B subunit in the brain regions involved in behavioral sensitization. AB - Protein phosphorylation is an important mechanism for the post-translational modulation of N-methyl-d-aspartate (NMDA) receptor functions. In the present study, we investigated the levels of NR2B phosphorylation at Tyr1472 and Ser1303 in the nucleus accumbens, striatum, frontal cortex, and hippocampus of rats that exhibit behavioral sensitization to nicotine. Repeated treatment of rats with nicotine (0.6mg/kg, s.c., for 7 days) produced locomotor sensitization accompanied by increased NR2B phosphorylation at Tyr1472 in the nucleus accumbens and striatum, brain regions involved in behavioral sensitization. In contrast, no changes in NR2B phosphorylation were observed after a single treatment with nicotine in these brain regions. In addition, no changes in NR2B phosphorylation at Ser1303 were observed after repeated treatment with nicotine in any examined brain regions. These results suggest that repeated treatment with nicotine induces NR2B phosphorylation at Tyr1472 in the nucleus accumbens and striatum, which might contribute to the development of synaptic and behavioral plasticity in response to nicotine. PMID- 22819975 TI - Different in vitro toxicity of ribosome-inactivating proteins (RIPs) on sensory neurons and Schwann cells. AB - OBJECTIVE: To study the neurotoxicity induced by Ricinus communis agglutinin (RCA), ricin A chain (RTA), and trichosanthin (TCS) in vitro. METHODS: Rat neurons and Schwann cells were cultured and real-time up-take of RIPs was traced. TUNEL, Annexin V and DAPI were employed to study the mechanism. RESULTS: The purity of both primary neuronal and Schwann cell cultures attained 80-90%. In neuritis, transport of FITC-RCA was demonstrated, but RTA and TCS were not detected. RCA elicited the strongest TUNEL and annexin V signals in both cultures. RTA evoked a stronger apoptotic signal than TCS in neurons. In contrast, compared with TCS, RTA elicited an attenuated apoptotic reaction in Schwann cells. All internalized RIPs were concentrated in the cytoplasm of the cells and their nuclei were not stained by DAPI. CONCLUSION: The toxicity of these RIPs on neurons is different from that on Schwann cells. Although they enter cells by different mechanisms they all induce apoptosis. These results may find application in in vivo neural lesioning studies and clinical therapy. PMID- 22819976 TI - Use of dynamic weight bearing as a novel end-point for the assessment of Freund's Complete Adjuvant induced hypersensitivity in mice. AB - Animal models are an integral part of pain research. However, current models tend to rely on evoked responses and there is a belief that non-evoked responses may be a more relevant behavioural readout as the animal responds in a more natural manner. Here, dynamic weight bearing (DWB), a novel method for assessing mechanical hypersensitivity, was evaluated using the Freund's Complete Adjuvant (FCA) model of inflammatory pain in mice. DWB enables the measurement of weight placed through all four paws of a freely moving animal. The data obtained from DWB was compared with data acquired using the standard static weight bearing (incapacitance) test. In both tests reversal of FCA induced mechanical hypersensitivity was investigated using the selective COX2 inhibitor celecoxib. Mice treated with FCA placed less weight through the ipsilateral hindpaw compared to vehicle controls. This reduction was reversed by celecoxib (30mg/kg p.o.) in the dynamic and static weight bearing tests. The data presented here suggests that dynamic weight bearing may provide a novel end point for the development of new analgesics. PMID- 22819977 TI - The androgen receptor facilitates inhibition of human dopamine transporter (DAT1) reporter gene expression by HESR1 and HESR2 via the variable number of tandem repeats. AB - A functional genetic polymorphism in the 3'-untranslated region (UTR) within exon 15 of the human DAT gene (DAT1) has been described. This 3'-UTR contains a variable number of tandem repeats (VNTR) 40 bp in length; many association studies of psychiatric or developmental disorders with this VNTR have been conducted. We previously demonstrated that HESR1 (the Hairy/enhancer of split related transcriptional factor 1 with YRPW motif) and HESR2 reduced DAT reporter gene expression via this 3'-UTR. VNTR allele-dependent altered reporter gene expression was also observed. In the present study, we wanted to clarify the molecular characterization of HESR1 and HESR2, focusing on its cis-element and co factor. Deletion of the VNTR domain increased reporter gene expression both with and without transfection of HESRs, suggesting that the VNTR inhibits DAT expression, and is responsive to HESRs. In the presence of transfected androgen receptor (AR), activity of the luciferase reporter with the nine-repeat allele (9r) decreased, while that with the ten-repeat allele (10r), the most frequent in the population, increased significantly. Furthermore, co-expression of HESR1 or HESR2 with AR increased the inhibitory effect of the HESRs. Our data indicate that a functional modification occurs when the HESRs are coupled with AR. This HESR-AR interaction could be the molecular basis of sexual dimorphisms in DAT expression, or other dopamine-related behavioral traits. PMID- 22819978 TI - Translational and rotational mobility of methanol-d4 molecules in NaX and NaY zeolite cages: a deuteron NMR investigation. AB - Nuclear magnetic resonance (NMR) provides means to investigate molecular dynamics at every state of matter. Features characteristic for the gas phase, liquid-like layers and immobilized methanol-d(4) molecules in NaX and NaY zeolites were observed in the temperature range from 300 K down to 20K. The NMR spectra at low temperature are consistent with the model in which molecules are bonded at two positions: horizontal (methanol oxygen bonded to sodium cation) and vertical (hydrogen bonding of hydroxyl deuteron to zeolite framework oxygen). Narrow lines were observed at high temperature indicating an isotropic reorientation of a fraction of molecules. Deuteron spin-lattice relaxation gives evidence for the formation of trimers, based on observation of different relaxation rates for methyl and hydroxyl deuterons undergoing isotropic reorientation. Internal rotation of methyl groups and fixed positions of hydrogen bonded hydroxyl deuterons in methyl trimers provide relaxation rates observed experimentally. A change in the slope of the temperature dependence of both relaxation rates indicates a transition from the relaxation dominated by translational motion to prevailing contribution of reorientation. Trimers undergoing isotropic reorientation disintegrate and separate molecules become localized on adsorption centers at 166.7 K and 153.8K for NaX and NaY, respectively, as indicated by extreme broadening of deuteron NMR spectra. Molecules at vertical position remain localized up to high temperatures. That indicates the dominating role of the hydrogen bonding. Mobility of single molecules was observed for lower loading (86 molecules/uc) in NaX. A direct transition from translation to localization was observed at 190 K. PMID- 22819979 TI - Zinc supplementation prevents cardiomyocyte apoptosis and congenital heart defects in embryos of diabetic mice. AB - Oxidative stress induced by maternal diabetes plays an important role in the development of cardiac malformations. Zinc (Zn) supplementation of animals and humans has been shown to ameliorate oxidative stress induced by diabetic cardiomyopathy. However, the role of Zn in the prevention of oxidative stress induced by diabetic cardiac embryopathy remains unknown. We analyzed the preventive role of Zn in diabetic cardiac embryopathy by both in vivo and in vitro studies. In vivo study revealed a significant decrease in lipid peroxidation, superoxide ions, and oxidized glutathione and an increase in reduced glutathione, nitric oxide, and superoxide dismutase in the developing heart at embryonic days (E) 13.5 and 15.5 in the Zn-supplemented diabetic group when compared to the diabetic group. In addition, significantly down-regulated protein and mRNA expression of metallothionein (MT) in the developing heart of embryos from diabetic group was rescued by Zn supplement. Further, the nuclear microscopy results showed that trace elements such as phosphorus, calcium, and Zn levels were significantly increased (P<0.001), whereas the iron level was significantly decreased (P<0.05) in the developing heart of embryos from the Zn supplemented diabetic group. In vitro study showed a significant increase in cellular apoptosis and the generation of reactive oxygen species (ROS) in H9c2 (rat embryonic cardiomyoblast) cells exposed to high glucose concentrations. Supplementation with Zn significantly decreased apoptosis and reduced the levels of ROS. In summary, oxidative stress induced by maternal diabetes could play a role in the development and progression of cardiac embryopathy, and Zn supplementation could be a potential therapy for diabetic cardiac embryopathy. PMID- 22819981 TI - Oxidative and nitrosative stress in the maintenance of myocardial function. AB - Reactive oxygen species (ROS) are generated by several different cellular sources, and their accumulation within the myocardium is widely considered to cause harmful oxidative stress. On the other hand, their role as second messengers has gradually emerged. The equilibrium of the nitroso/redox balance between reactive nitrogen species and ROS is crucial for the health of cardiomyocytes. This review provides a comprehensive overview of sources of oxidative stress in cardiac myocytes and describes the role of the nitroso/redox balance in cardiac pathophysiology. Although the exact mechanism of ROS production by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox's) is not completely understood, Nox2 and Nox4 have particularly important roles within the myocardium. Increasing evidence suggests that Nox2 produces superoxide and Nox4 generates only hydrogen peroxide. We also discuss the key role of nitric oxide synthases (NOSs) in the maintenance of the nitroso/redox balance: uncoupled endothelial NOS has been suggested to shift from nitric oxide to ROS production, contributing to increased oxidative stress within the myocardium. Furthermore, we highlight the importance of sequentially targeting and/or regulating the specific sources of oxidative and nitrosative stress to prevent and/or reverse myocardial dysfunction. Inhibition of NADPH oxidase dependent ROS is considered to be a potential strategy for treatment of cardiomyopathy. Neither in vivo nor clinical data are available for NADPH oxidase inhibitors. Specifically targeting the mitochondria with the antioxidant MitoQ would be a very promising translation approach, because it could prevent mitochondrial permeability transition pore opening when ROS are produced during heart reperfusion. Enhancing NO signaling could also be a promising therapeutic approach against myocardial dysfunction. PMID- 22819980 TI - Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. AB - The goal of the current study was to evaluate whether CYP2E1 plays a role in binge-ethanol induced steatosis and if autophagy impacts CYP2E1-mediated hepatotoxicity, oxidative stress and fatty liver formation produced by ethanol. Wild type (WT), CYP2E1 knockin (KI) and CYP2E1 knockout (KO) mice were gavaged with 3g/kg body wt ethanol twice a day for four days. This treatment caused fatty liver, elevation of CYP2E1 and oxidative stress in WT and KI mice but not KO mice. Autophagy was impaired in ethanol-treated KI mice compared to KO mice as reflected by a decline in the LC3-II/LC3-I ratio and lower total LC-3 and Beclin 1 levels coupled to increases in P62, pAKT/AKT and mTOR. Inhibition of macroautophagy by administration of 3-methyladenine enhanced the binge ethanol hepatotoxicity, steatosis and oxidant stress in CYP2E1 KI, but not CYP2E1 KO mice. Stimulation of autophagy by rapamycin blunted the elevated steatosis produced by binge ethanol. Treatment of HepG2 E47 cells which express CYP2E1 with 100mM ethanol for 8 days increased fat accumulation and oxidant stress but decreased autophagy. Ethanol had no effect on these reactions in HepG2 C34 cells which do not express CYP2E1. Inhibition of autophagy elevated ethanol toxicity, lipid accumulation and oxidant stress in the E47, but not C34 cells. The antioxidant N-acetylcysteine, and CYP2E1 inhibitor chlormethiazole blunted these effects of ethanol. These results indicate that CYP2E1 plays an important role in binge ethanol-induced fatty liver. We propose that CYP2E1-derived reactive oxygen species inhibit autophagy, which subsequently causes accumulation of lipid droplets. Inhibition of autophagy promotes binge ethanol induced hepatotoxicity, steatosis and oxidant stress via CYP2E1. PMID- 22819982 TI - Bilirubin augments radiation injury and leads to increased infection and mortality in mice: molecular mechanisms. AB - Our earlier results demonstrated that clinically relevant concentrations of unconjugated bilirubin (UCB) possessed immunotoxic effects. Whole-body irradiation (WBI) with 1 to 6 Gy leads to acute radiation syndrome, immunosuppression, and makes the host susceptible to infection. Since hyperbilirubinemia has been shown to be associated with several types of cancer, the present studies were undertaken to evaluate the radiomodifying effects of UCB in radiation-exposed mice having elevated levels of UCB. Pretreatment of splenic lymphocytes with UCB (1-50 MUM at UCB/BSA ratio <1) augmented radiation-induced DNA strand breaks, MMP loss, calcium release, and apoptosis. Combination treatment of mice with UCB (50mg/kg bw) followed by WBI (2 Gy) 0.5h later, resulted in significantly increased splenic atrophy, bone marrow aplasia, decreased counts of peritoneal exudate cells, and different splenocyte subsets such as CD3+ T, CD4+ T, CD8+ T, CD19+ B, and CD14+ macrophages as compared to either UCB or WBI treatment. Hematological studies showed that WBI-induced lymphopenia, thrombocytopenia, and neutropenia were further aggravated in the combination treatment group. UCB pretreatment of mice potentiated WBI-induced apoptosis and decreased WBI-induced loss of functional response of various immune cells leading to augmentation of immunosuppression and infection susceptibility caused by WBI. In an acute bacterial peritonitis model, UCB pretreatment of mice significantly increased WBI-induced proinflammatory cytokines, nitric oxide, and peritoneal bacterial load resulting in increased infection and death. Studies using the pharmacological inhibitor of p38MAPK demonstrated the involvement of p38MAPK activation in the inflammatory cascade of peritonitis. These findings should prove useful in understanding the potential risk to hyperbilirubinemic patients during radiotherapy and victims of acute radiation exposure in the course of radiation accidents. PMID- 22819983 TI - Detection of Ras GTPase protein radicals through immuno-spin trapping. AB - Over the past decade immuno-spin trapping (IST) has been used to detect and identify protein radical sites in numerous heme and metalloproteins. To date, however, the technique has had little application toward nonmetalloproteins. In this study, we demonstrate the successful application of IST in a system free of transition metals and present the first conclusive evidence of (*)NO-mediated protein radical formation in the HRas GTPase. HRas is a nonmetalloprotein that plays a critical role in regulating cell-growth control. Protein radical formation in Ras GTPases has long been suspected of initiating premature release of bound guanine nucleotide. This action results in altered Ras activity both in vitro and in vivo. As described herein, successful application of IST may provide a means for detecting and identifying radical-mediated Ras activation in many different cancers and disease states in which Ras GTPases play an important role. PMID- 22819984 TI - Polybrominated diphenyl ethers in maternal serum, umbilical cord serum, colostrum and mature breast milk. Insights from a pilot study and the literature. AB - Human serum and mother's milk are frequently used to assess exposure to polybrominated diphenyl ethers (PBDEs), including transplacental transfer to the foetus. However, little is known about the kinetics of PBDEs, especially the highly brominated BDE congeners. In this pilot study, maternal serum samples were collected from 10 women at delivery and five to six weeks post partum. Umbilical serum was also obtained. Milk was donated two to five days, and five to six weeks after delivery. The amount of PBDEs in these samples was determined using liquid liquid extraction and GC/MS. Low, moderately and highly brominated diphenyl ethers were present in umbilical cord serum, indicating placental transfer. The lipid-adjusted levels of BDE-47, BDE-207 and BDE-209 were similar in maternal and umbilical cord serum, whereas the cord serum levels for the penta- to octa-BDEs quantified were lower than in maternal serum. Marked changes were seen in the congener pattern in breast milk during the first month of lactation, whereas maternal serum levels did not change significantly. The general pattern was an enrichment of low to moderately brominated congeners (i.e. from BDE-17 to BDE 154, with the exception of BDE-28) in colostrum compared with maternal serum. In contrast, more highly brominated congeners were found at similar, or lower levels in colostrum than in maternal serum. After the transition from colostrum to mature milk, the levels of BDE-153 and BDE-209 were substantially reduced, and BDE-209 was below the limit of detection in 6 out of 9 samples. A literature review on the design and reporting of studies on the transfer of PBDEs from mother to infant revealed a lack of transparency in many cases. The use of the recently published STROBE-ME guidelines is therefore recommended. PMID- 22819986 TI - Cognitive and affective Theory of Mind in neurodegenerative diseases: neuropsychological, neuroanatomical and neurochemical levels. AB - The paper reviews of all of the current evidence on Theory of Mind (ToM) abilities in patients with neurodegenerative diseases. ToM refers to the abilities to attribute mental states to others. Two neural systems are involved in processing other people's beliefs and intentions (cognitive component) and others' emotions and feelings (affective component). We hypothesize that patients with different neurodegenerative diseases may present different patterns of ToM deficits on the basis of how different neuropathological processes affect the neural bases of ToM components during the progression of a disease. The studies we reviewed provided evidence of a deficit of the cognitive ToM component in cortical (Alzheimer's disease and frontotemporal dementia) and frontal subcortical (amyotrophic lateral sclerosis and basal ganglia disorders) neurodegenerative diseases. As regards the affective ToM component, it resulted markedly impaired in frontotemporal dementia; it also resulted that performances in tasks assessing this process are heterogeneous in Parkinson's disease and amyotrophic lateral sclerosis. The findings presented support the opportunity to introduce validated ToM tasks in the neuropsychological assessment of neurodegenerative diseases. PMID- 22819987 TI - Effectiveness of the monovalent AS03-adjuvanted influenza A(H1N1)pdm09 vaccine against hospitalization in children because of influenza. AB - We studied the effectiveness of the AS03-adjuvanted monovalent vaccine (Pandemrix((r))) for the prevention of severe pandemic influenza A(H1N1)pdm09 in children, in 2009. All children hospitalized for influenza-like illness in Stockholm County during the peak of the pandemic were included. We compared the frequency of vaccinated children between influenza A(H1N1)pdm09 PCR positive cases and PCR negative controls in a retrospective case-control study. 95 cases and 177 controls were identified. About half of the children in both groups were between 6 months and 2 years of age. Only 1/95 (1%) cases had been vaccinated more than 14 days prior to admission, compared to 23/177 controls (13%), corresponding to a vaccine effectiveness, adjusted for co-morbid conditions, of 91% (95% confidence interval [CI] 30-99). In contrast, the risk for being a case was significantly higher among children vaccinated between 1 and 14 days prior to hospitalization, than among those who were non-vaccinated 13/95 vs. 7/177 (OR 3.6, 95% CI 1.4-9.5). We conclude that a single dose of adjuvanted vaccine was highly protective against hospitalization for influenza A(H1N1)pdm09 in children 6 month to 17 years. The reason for the increased rate of hospitalizations with confirmed influenza in children just following immunization is unclear and should be studied further. PMID- 22819988 TI - Gaps in the 2010 measles SIA coverage among migrant children in Beijing: evidence from a parental survey. AB - China suffers from high incidence of measles partly due to high population mobility and low vaccination rates among migrants. In this study, we assessed the vaccination coverage of the nationwide measles supplementary immunization activity (SIA) of 2010 and its determinants among migrant children in Beijing. Information was collected through face-to-face interviews with the caregivers of 589 migrant children at train and long-distance bus stations in January 2011, when migrants were traveling home for the Chinese New Year holiday. We estimated that 83.4% of migrant children aged 8 months to 14 years received the measles vaccine during the SIA. This estimated coverage is lower than the official report of 96% among all eligible children in Beijing. Factors associated with being unvaccinated through the SIA included children being at home or in the kindergarten, living in a single-child family, and having a parent who was unaware of the SIA or who had a low level of trust in the government-administered measles campaign. We recommend more focused targeting on migrant children in future measles vaccination campaigns, improved immunization service delivery in unregulated migrant-run kindergartens and at the community level, as well as development of more effective communication methods to reach disadvantaged migrants. PMID- 22819989 TI - Tools for cellular immunology and vaccine research the in the guinea pig: monoclonal antibodies to cell surface antigens and cell lines. AB - The use of monoclonal antibodies directed against membrane proteins of leukocytes has greatly contributed to our understanding of the function and development of the immune system. Meanwhile these reagents provide valuable tools in many fields of research, stretching far beyond immunology and hematology. For guinea pigs only a limited number of such reagents have been described, and the information about availability and specificity is scattered over many years and journals. We provide an overview on the monoclonal antibodies produced since the technique was applied first in this species, with a focus on those reagents which have been characterized in more detail, and which should still be available either commercially or directly from the labs that created them. PMID- 22819990 TI - Chimeric flagellin as the self-adjuvanting antigen for the activation of immune response against Helicobacter pylori. AB - Helicobacter pylori infection can cause gastritis, peptic ulcer and can lead to gastric cancer. Lengthy antibiotic therapy does not protect the host against reinfection. H. pylori evolved to evade the recognition of the immune response by modifying several of its components whose orthologous proteins from other bacteria activate the innate immune response. Flagella are essential for the H. pylori effective colonization of human duodenum and stomach. TLR5, a member of the Toll-like receptor family, recognizes flagellin of most bacteria, such as Escherichia coli, but does not recognize the flagellin FlaA of H. pylori. We restored the ability of FlaA for the recognition by TLR5 by engineering a chimeric flagellin, in which both terminal segments of H. pylori flagellin were replaced by the corresponding segments from TLR5-activating E. coli flagellin. Recombinant chimeric flagellin folded correctly and was able to activate TLR5. Significantly increased serum IgG and IgA antibody responses were determined in mice vaccinated with chimeric flagellin in comparison to mice vaccinated with a control protein (FlaA) or negative control. Antibody titers remained high even 8 months after the last immunization. Antibodies were able to bind native flagellin from H. pylori lysate. Vaccination with chimeric flagellin provided mice with significant protection against H. pylori. The approach of chimeric flagellin can therefore generate effective immunogens that enable activation of innate and adaptive immune response and can be used to construct efficient vaccines against H. pylori or other flagellated bacteria that evade TLR5 recognition. PMID- 22819985 TI - Early life manipulations alter learning and memory in rats. AB - Much research shows that early life manipulations have enduring behavioral, neural, and hormonal effects. However, findings of learning and memory performance vary widely across studies. We reviewed studies in which pre-weaning rat pups were exposed to stressors and tested on learning and memory tasks in adulthood. Tasks were classified as aversive conditioning, inhibitory learning, or spatial/relational memory. Variables of duration, type, and timing of neonatal manipulation and sex and strain of animals were examined to determine if any predict enhanced or impaired performance. Brief separations enhanced and prolonged separations impaired performance on spatial/relational tasks. Performance was impaired in aversive conditioning and enhanced in inhibitory learning tasks regardless of manipulation duration. Opposing effects on performance for spatial/relational memory also depended upon timing of manipulation. Enhanced performance was likely if the manipulation occurred during postnatal week 3 but performance was impaired if it was confined to the first two postnatal weeks. Thus, the relationship between early life experiences and adulthood learning and memory performance is multifaceted and decidedly task dependent. PMID- 22819992 TI - Ultrastructural studies of cilia formation during thyroid gland differentiation in grass snake embryos. AB - The process of ciliogenesis that accompanies the differentiation of the thyroid gland in grass snake Natrix natrix L. embryos was studied ultrastructurally. Based on this study, it can be concluded that the ciliogenesis occurred in two waves and that new centrioles duplicated via centriolar pathways. The first wave of ciliogenesis started in the post-mitotic thyrocytes before their polarisation. It ended approximately halfway through the developmental period. The second wave of ciliogenesis took place after the polarization of thyrocytes and before the resting phase of the embryonic thyroid. This wave of ciliogenesis stopped shortly before hatching when fully differentiated thyrocytes restarted their activity. During the first half of thyroid differentiation, the cilia were formed "intracellularly" but during the second half, they differentiated "extracellularly" In the differentiating thyrocytes one cilium per cell was found; however, it could not be excluded that more than one cilium per cell may be formed. These cilia lacked central fibres and therefore they had a 9+0 formula that suggested that they were immotile. PMID- 22819991 TI - Dietary fat types differently modulate the activity and expression of mitochondrial carnitine/acylcarnitine translocase in rat liver. AB - The carnitine/acylcarnitine translocase (CACT), an integral protein of the mitochondrial inner membrane, belongs to the carnitine-dependent system of fatty acid transport into mitochondria, where beta-oxidation occurs. CACT exchanges cytosolic acylcarnitine or free carnitine for carnitine in the mitochondrial matrix. The object of this study was to investigate in rat liver the effect, if any, of diets enriched with saturated fatty acids (beef tallow, BT, the control), n-3 polyunsaturated fatty acids (PUFA) (fish oil, FO), n-6 PUFA (safflower oil, SO), and mono-unsaturated fatty acids (MUFA) (olive oil, OO) on the activity and expression of CACT. Translocase exchange rates increased, in parallel with CACT mRNA abundance, upon FO-feeding, whereas OO-dietary treatment induced a decrease in both CACT activity and expression. No changes were observed upon SO-feeding. Nuclear run-on assay revealed that FO-treatment increased the transcriptional rate of CACT mRNA. On the other hand, only in the nuclei of hepatocytes from OO fed rats splicing of the last intron of CACT pre-mRNA and the rate of formation of the 3'-end were affected. Overall, these findings suggest that compared to the BT-enriched diet, the SO-enriched diet did not influence CACT activity and expression, whereas FO- and OO-feeding alters CACT activity in an opposite fashion, i.e. modulating its expression at transcriptional and post transcriptional levels, respectively. PMID- 22819993 TI - Biochemical characterization and comparative analysis of two distinct serine proteases from Bothrops pirajai snake venom. AB - This study reports the isolation and biochemical characterization of two different serine proteases from Bothrops pirajai snake venom, thus providing a comparative analysis of the enzymes. The isolation process consisted of three consecutive chromatographic steps (Sephacryl S-200, Benzamidine Sepharose and C2/C18), resulting in two serine proteases, named BpirSP27 and BpirSP41 after their molecular masses by mass spectrometry (27,121 and 40,639 Da, respectively). Estimation by SDS-PAGE under denaturing conditions showed that, when deglycosylated with PNGase F, BpirSP27 and BpirSP41 had their molecular masses reduced by approximately 15 and 42%, respectively. Both are acidic enzymes, with pI of approximately 4.7 for BpirSP27 and 3.7 for BpirSP41, and their N-terminal amino acid sequences showed 57% identity to each other, with high similarity to the sequences of other snake venom serine proteases (SVSPs). The enzymes showed different actions on bovine fibrinogen, with BpirSP27 acting preferentially on the Bbeta chain and BpirSP41 on both Aalpha and Bbeta chains. The two serine proteases were also able to degrade fibrin and blood clots in vitro depending on the doses and incubation periods, with higher results for BpirSP41. Both enzymes coagulated the human plasma in a dose-dependent manner, and BpirSP41 showed a higher coagulant potential, with minimum coagulant dose (MCD) of ~3.5 MUg versus 20 MUg for BpirSP27. The enzymes were capable of hydrolyzing different chromogenic substrates, including S-2238 for thrombin-like enzymes, but only BpirSP27 acted on the substrate S-2251 for plasmin. They also showed high stability against variations of temperature and pH, but their activities were significantly reduced after preincubation with Cu(2+) ion and specific serine protease inhibitors. In addition, BpirSP27 induced aggregation of washed platelets to a greater extent than BpirSP41. The results showed significant structural and functional differences between B. pirajai serine proteases, providing interesting insights into the structure-function relationship of SVSPs. PMID- 22819994 TI - Mycobacterial lipolytic enzymes: a gold mine for tuberculosis research. AB - Tuberculosis (TB) is one of the deadliest infectious diseases worldwide with a strong impact in developing countries. Mycobacterium tuberculosis, the etiological agent of TB, has a high capacity to evade the host immune system and establish a chronic, asymptomatic and latent infection. In a latent TB infection, persistent bacilli are present in a non-replicating dormant state within host granulomas. During reactivation, bacilli start replicating again leading to an active TB infection that can be highly contagious. Mycobacterial lipids and lipolytic enzymes are thought to play important physiological roles during dormancy and reactivation. The role of lipolytic enzymes in the physiology of M. tuberculosis and physiopathology of the disease will be discussed in this review, with an emphasis on the secreted or cell wall-associated, surface exposed lipolytic enzymes characterized to date. Studies on the localization, enzymatic activity and immunological properties of these enzymes highlighted their possible usefulness as new diagnostic markers in the fight against TB. PMID- 22819995 TI - Bioactive aldehyde-modified phosphatidylethanolamines. AB - Lipid peroxidation generates a variety of lipid aldehydes, which have been recognized to modify protein and DNA, causing inflammation and cancer. However, recent studies demonstrate that phosphatidylethanolamine (PE) is a major target for these aldehydes, forming aldehyde-modified PEs (al-PEs) as a novel family of mediators for inflammation. This review summarizes our current understanding of these al-PEs, including formation, detection, structural characterization, physiological relevance and mechanism of action. PMID- 22819996 TI - Searching the scientific literature: implications for quantitative and qualitative reviews. AB - Literature reviews are an essential step in the research process and are included in all empirical and review articles. Electronic databases are commonly used to gather this literature. However, several factors can affect the extent to which relevant articles are retrieved, influencing future research and conclusions drawn. The current project examined articles obtained by comparable search strategies in two electronic archives using an exemplar search to illustrate factors that authors should consider when designing their own search strategies. Specifically, literature searches were conducted in PsycINFO and PubMed targeting review articles on two exemplar disorders (bipolar disorder and attention deficit/hyperactivity disorder) and issues of classification and/or differential diagnosis. Articles were coded for relevance and characteristics of article content. The two search engines yielded significantly different proportions of relevant articles overall and by disorder. Keywords differed across search engines for the relevant articles identified. Based on these results, it is recommended that when gathering literature for review papers, multiple search engines should be used, and search syntax and strategies be tailored to the unique capabilities of particular engines. For meta-analyses and systematic reviews, authors may consider reporting the extent to which different archives or sources yielded relevant articles for their particular review. PMID- 22819997 TI - Is the transtheoretical model and motivational interviewing approach applicable to the treatment of eating disorders? A review. AB - Research in eating disorders is reviewed examining the (1) utility of the Transtheoretical Model in predicting outcome, and (2) efficacy of Motivational Interviewing (MI). There were promising results showing significant relationships between initial stage of change and treatment outcome related to eating pathology (not including purging), body mass index, and some aspects of psychopathology. Of those treatment studies utilising a control group, there was little indication that using MI conferred significant treatment benefit, with the exception of improving motivation and binge eating for people with binge eating disorder and bulimia nervosa. Overall the content of the studies varied greatly with relation to: stage of change and outcome measures, format of MI, diagnostic groupings, age of participants, utilisation of other adjunctive treatments, sample size, presence of follow-up assessments, and study design. Few of the 9 studies examining the efficacy of MI could be considered to have robust methodology. It is recommended that future research using the Transtheoretical Model to predict outcome adopt more uniform methodology so that we can more specifically determine its applicability, and that well-designed treatment studies in eating disorder populations be conducted so that we develop a stronger evidence base from which to decide whether MI confers benefit. PMID- 22819998 TI - A meta-analysis of imagery rehearsal for post-trauma nightmares: effects on nightmare frequency, sleep quality, and posttraumatic stress. AB - This meta-analysis evaluates the efficacy of imagery rehearsal as a treatment for nightmares, general sleep disturbance, and symptoms of post-traumatic stress. Bibliographic databases and cited references were searched to identify clinical trials of imagery rehearsal in individuals with post-trauma nightmares. Thirteen studies met inclusion criteria and reported sleep and post-traumatic stress outcomes in sufficient detail to calculate effect sizes. Results indicate that imagery rehearsal had large effects on nightmare frequency, sleep quality, and PTSD symptoms from the initial to post-treatment assessments. These effects were sustained through 6 to 12 months follow-up. Furthermore, interventions that included both imagery rehearsal and cognitive behavioral therapy for insomnia resulted in greater treatment-related improvement in sleep quality than imagery rehearsal alone. Combined treatment did not improve outcomes for PTSD or nightmares. Notably, effect sizes were small in the single study that included an active-treatment control condition. Future research should identify necessary and sufficient components of interventions for trauma-related sleep disturbance and post-traumatic stress (e.g., exposure, cognitive reappraisal, sleep and circadian regulation). PMID- 22819999 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin G3kappa deposits in association with parvovirus B19 infection. AB - Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is a recently described disease entity, characterized by nonorganized electron-dense deposits in glomeruli and immunofluorescence findings indicating monoclonal immunoglobulin G deposits. The pathogenesis of many cases of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits remains unknown. We herein report 2 patients with parvovirus B19 infection who developed acute nephritic syndrome with hypocomplementemia (patient 1) or persistent proteinuria and congestive heart failure (patient 2); however, neither patient had detectable levels of serum monoclonal immunoglobulin G. Renal biopsy in both patients showed diffuse endocapillary proliferative glomerulonephritis with monoclonal immunoglobulin G3kappa deposits, and electron microscopy showed nonorganized electron-dense deposits mainly in the subendothelial and mesangial areas. Clinical symptoms, abnormal laboratory findings, and urinary abnormalities recovered spontaneously in both cases within 4 weeks. Our 2 cases may be the first reported patients with proliferative glomerulonephritis with monoclonal immunoglobulin G deposits possibly associated with parvovirus B19 infection. Virus infection-associated immune disorders could be implicated in the pathogenesis of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits. PMID- 22820000 TI - E-cadherin expression in the epithelial components of mammary phyllodes tumors. AB - Phyllodes tumors are rare but clinically important fibroepithelial tumors of the breast. Both epithelial and stromal components actively interact with each other to participate in phyllodes tumor development. Accumulated evidence suggests that the Wnt signaling pathway is important in this stromal-epithelial interaction. Given that Wnt signaling also affects E-cadherin-dependent cellular adhesion and alteration of E-cadherin is common in epithelial cancers, it is possible that alteration of E-cadherin occurs also in the epithelial components of phyllodes tumor. We assessed epithelial E-cadherin expression in 155 phyllodes tumor cases, including 92 benign (59%), 42 borderline (27%), and 21 malignant phyllodes tumor (14%), by immunohistochemistry. Its expression was correlated with clinicopathologic features and phyllodes tumor recurrence. Significant correlations of both membranous and cytoplasmic E-cadherin expression were found with stromal cellularity (P = .009 and .013, respectively), overgrowth (P = .005 and .009, respectively), and mitotic counts (P = .023 and .029, respectively) but not tumor grade, margin, and nuclear atypia. Interestingly, a significantly higher level of cytoplasmic epithelial E-cadherin expression was found in those tumors with recurrence (score, 278.79+/-40.91 versus 250.00+/-63.46) and shorter specific disease-free survival (172.24+/-12.63 versus 207.24+/-19.71 months). Further multivariate analysis showed epithelial E-cadherin expression as an independent prognostic factor for phyllodes tumor-specific survival (P<.001 for cytoplasmic staining and .001 for membranous staining). In conclusion, we have demonstrated an association of epithelial E-cadherin expression with stromal histologic features and disease recurrence in phyllodes tumor. These findings provide further evidence of the importance of stromal-epithelial interactions in phyllodes tumors and highlight the potential value of epithelial components in prognostication. PMID- 22820001 TI - HECA-452 is a non-function blocking antibody for isolated sialyl Lewis x adhesion to endothelial expressed E-selectin under flow conditions. AB - E-selectin, expressed on inflamed endothelium, and sialyl Lewis x (sLe(x)), present on the surface of leukocytes, play a key role in leukocyte-endothelial interactions during leukocyte recruitment to sites of inflammation. HECA-452 is a monoclonal antibody (mAb) that recognizes sLe(x) and is routinely used by investigators from diverse fields who seek to unravel the mechanisms of leukocyte adhesion. The data regarding the ability of HECA-452 to inhibit carbohydrate mediated leukocyte adhesion to E-selectin remains conflicted, in part due to the presence of a variety of potential E-selectin reactive moieties on leukocytes. Recognizing this, we utilized a complementary approach to gain insight into HECA 452 adhesion assays. Specifically, we used sLe(x) microspheres to investigate the hypothesis that HECA-452 is a non-function blocking mAb for isolated sLe(x) mediated adhesion to endothelial expressed E-selectin. Flow cytometric analysis revealed that HECA-452 recognizes and binds to the sLe(x) microspheres. Perfusion of the sLe(x) microspheres over human umbilical vein endothelial cells (HUVEC) at 1.5 dyn/cm2 revealed that the microspheres attach to 4h interleukin (IL)-1beta activated HUVEC specifically via E-selectin. Pretreatment of the sLe(x) microspheres with HECA-452 did not influence sLe(x) microsphere initial tethering and accumulation on IL-1beta activated HUVEC. Neuraminidase and fucosidase treatments of sLe(x) microspheres revealed that sialic acid and fucose are required for E-selectin binding, whereas HECA-452 recognition of sLe(x) does not depend on the fucose moiety to the extent required for E-selectin recognition. This latter finding suggests there are potential subtle differences between the sLe(x) antigens for E-selectin and HECA-452. Combined, the data indicate that HECA-452 is a non-inhibitor of sLe(x)-mediated adhesion to endothelial expressed E-selectin. PMID- 22820002 TI - High mobility group B proteins regulate mesoderm formation and dorsoventral patterning during zebrafish and Xenopus early development. AB - The high mobility group (HMG) proteins constitute a superfamily of nuclear proteins that regulate the expression of a wide range of genes through architectural remodeling of the chromatin structure, and the formation of multiple protein complexes on promoter/enhancer regions, but their function in germ layer specification during early development is not clear. Here we show that hmgb genes regulate mesoderm formation and dorsoventral patterning both in zebrafish and Xenopus early embryos. Overexpression of hmgb3 blocks the expression of the pan-mesoderm gene no tail/Xbra and other ventrolateral mesoderm genes, and results in embryos with shortened anteroposterior axis, while overexpression of hmgb3EnR, which contains the engrailed repressor domain, most potently repressed no tail expression and mesoderm formation. However, hmgb3VP16, which contains the transcriptional activation domain of VP16, had an opposite effect, indicating that hmgb3 may function as a repressor during mesoderm induction and patterning. In addition, we show that hmgb3 inhibits target gene expression downstream of mesoderm-inducing factors. Furthermore, using reporter gene assays in Xenopus whole embryos, we show that hmgb3 differentially regulates the activation of various mesendoderm reporter genes. In particular, it up regulates the goosecoid, but inhibits the Xbra reporter gene activation. Therefore, our results suggest that hmgb genes may function to fine-tune the specification and/or dorsoventral patterning of mesoderm during zebrafish and Xenopus development. PMID- 22820003 TI - The impact of emerging standards adoption on automated quality reporting. AB - Current quality measurement processes are labor-intensive, involving manual chart reviews and use of paper-based quality measures that vary in format and definitions from measure to measure. Automated quality reporting is considered by many to be an important tool that will help close the gaps in the quality of US health by increasing the timeliness, effectiveness, and use of quality assessment. In 2007, the US Department of Health and Human Services Office of the National Coordinator for Health Information Technology (ONC) funded three Nationwide Health Information Network (NHIN) health information exchanges (HIE) to demonstrate the feasibility of automated quality reporting by using existing or emerging standards to aggregate information from multiple providers, transmit patient-level quality data in standardized formats, perform an automated quality assessment, and generate a quality report document for electronic transmission. Long Beach Network for Health (LBNH), a NHIN Cooperative HIE, developed a web based, real-time quality assessment service that calculates quality of care measure using clinical data aggregated through a HIE. LBNH used a set of draft standards to demonstrate automated quality reporting, but noted three important recommendations for future work. First, greater coordination is needed around initiatives that address the gaps in electronic quality measurement standards and processes, including strong Federal involvement and guidance. Second, a harmonized, evergreen quality use case is needed to provide stakeholders with a common understanding on the constantly evolving approaches towards automated quality measurement and reporting. Finally, there needs to be substantial investment in building on existing work and developing a comprehensive set of data and messaging standards to preserve semantic interoperability of quality measure data. PMID- 22820004 TI - Quantifying conformational dynamics using solid-state R1rho experiments. AB - We demonstrate the determination of quantitative rates of molecular reorientation in the solid state with rotating frame (R(1rho)) relaxation measurements. Reorientation of the carbon chemical shift anisotropy (CSA) tensor was used to probe site-specific conformational exchange in a model system, d(6)-dimethyl sulfone (d(6)-DMS). The CSA as a probe of exchange has the advantage that it can still be utilized when there is no dipolar mechanism (i.e. no protons attached to the site of interest). Other works have presented R(1rho) measurements as a general indicator of dynamics, but this study extracts quantitative rates of molecular reorientation from the R(1rho) values. Some challenges of this technique include precise knowledge of sample temperature and determining the R(2)(0) contribution to the observed relaxation rate from interactions other than molecular reorientation, such as residual dipolar couplings or fast timescale dynamics; determination of this term is necessary in order to quantify the exchange rate due to covariance between the 2 terms. Low-temperature experiments measured an R(2)(0) value of 1.8+/-0.2s(-1) Allowing for an additional relaxation term (R(2)(0)), which was modeled as both temperature-dependent and temperature independent, rates of molecular reorientation were extracted from field strength dependent R(1rho) measurements at four different temperatures and the activation energy was determined from these exchange rates. The activation energies determined were 74.7+/-4.3kJ/mol and 71.7+/-2.9kJ/mol for the temperature independent and temperature-dependent R(2)(0) models respectively, in excellent agreement with literature values. The results of this study suggest important methodological considerations for the application of the method to more complicated systems such as proteins, such as the importance of deuterating samples and the need to make assumptions regarding the R(2)(0) contribution to relaxation. PMID- 22820005 TI - Simulation and analysis of the interactions between split gradient coils and a split magnet cryostat in an MRI-PET system. AB - Splitting a magnetic resonance imaging (MRI) magnet into two halves can provide a central region to accommodate other modalities, such as positron emission tomography (PET). This approach, however, produces challenges in the design of the gradient coils in terms of gradient performance and fabrication. In this paper, the impact of a central gap in a split MRI system was theoretically studied by analysing the performance of split, actively-shielded transverse gradient coils. In addition, the effects of the eddy currents induced in the cryostat on power loss, mechanical vibration and magnetic field harmonics were also investigated. It was found, as expected, that the gradient performance tended to decrease as the central gap increased. Furthermore, the effects of the eddy currents were heightened as a consequence of splitting the gradient assembly into two halves. An optimal central gap size was found, such that the split gradient coils designed with this central gap size could produce an engineering solution with an acceptable trade-off between gradient performance and eddy current effects. These investigations provide useful information on the inherent trade-offs in hybrid MRI imaging systems. PMID- 22820006 TI - Deconvolution of the EPR spectra of vanadium oxide nanotubes. AB - In this work we report results of continuous wave (CW) electron paramagnetic resonance (EPR) spectroscopy of vanadium oxide nanotubes. The observed EPR spectra are composed of a weak well-resolved spectrum of isolated V(4+) ions on top of an intense and broad structure-less line shape, attributed to spin-spin exchanged V(4+) clusters. With the purpose to deconvolute the structured weak spectrum from the composed broad line, a new approach based on the Krylov basis diagonalization method (KBDM) is introduced. It is based on the discrimination between broad and sharp components with respect to a selectable threshold and can be executed with few adjustable parameters, without the need of a priori information on the shape and structure of the lines. This makes the method advantageous with respect to other procedures and suitable for fast and routine spectral analysis, which, in conjunction with simulation techniques based on the spin Hamiltonian parameters, can provide a full characterization of the EPR spectrum. Results demonstrate and characterize the coexistence of two V(4+) species in the nanotubes and show good progress toward the goal of obtaining high fidelity deconvoluted spectra from complex signals with overlapping broader line shapes. PMID- 22820007 TI - Liquid state DNP for water accessibility measurements on spin-labeled membrane proteins at physiological temperatures. AB - We demonstrate the application of continuous wave dynamic nuclear polarization (DNP) at 0.35 T for site-specific water accessibility studies on spin-labeled membrane proteins at concentrations in the 10-100 MUM range. The DNP effects at such low concentrations are weak and the experimentally achievable dynamic nuclear polarizations can be below the equilibrium polarization. This sensitivity problem is solved with an optimized home-built DNP probe head consisting of a dielectric microwave resonator and a saddle coil as close as possible to the sample. The performance of the probe head is demonstrated with both a modified pulsed EPR spectrometer and a dedicated CW EPR spectrometer equipped with a commercial NMR console. In comparison to a commercial pulsed ENDOR resonator, the home-built resonator has an FID detection sensitivity improvement of 2.15 and an electron spin excitation field improvement of 1.2. The reproducibility of the DNP results is tested on the water soluble maltose binding protein MalE of the ABC maltose importer, where we determine a net standard deviation of 9% in the primary DNP data in the concentration range between 10 and 100 MUM. DNP parameters are measured in a spin-labeled membrane protein, namely the vitamin B(12) importer BtuCD in both detergent-solubilized and reconstituted states. The data obtained in different nucleotide states in the presence and absence of binding protein BtuF reveal the applicability of this technique to qualitatively extract water accessibility changes between different conformations by the ratio of primary DNP parameters epsilon. The epsilon-ratio unveils the physiologically relevant transmembrane communication in the transporter in terms of changes in water accessibility at the cytoplasmic gate of the protein induced by both BtuF binding at the periplasmic region of the transporter and ATP binding at the cytoplasmic nucleotide binding domains. PMID- 22820008 TI - Extending the use of Earth's Field NMR using Bayesian methodology: application to particle sizing. AB - There is currently much interest in extending the use of low-field magnetic resonance measurements and in particular, to obtain spatial information from these data. Here, we demonstrate the application of a Bayesian magnetic resonance approach for the sizing of objects using low magnetic field measurement technology, where there is insufficient signal-to-noise to allow a conventional imaging approach for structural characterisation. The method is illustrated in application to the sizing of spheres, in this case of radius 9.5mm, using an Earth's Field Nuclear Magnetic Resonance (EFNMR) spectrometer with pre polarisation. Numerical simulations of the measurement at different signal-to noise ratios and implementation of different k-space sampling schemes are considered to identify the optimal experimental protocol. In this example, the determination of sphere radius is found to be accurate to +/-1mm. We confirm that the posterior distribution provides an accurate estimate of the uncertainty in the measurement. PMID- 22820009 TI - Dual-scan acquisition for accelerated continuous-wave EPR oximetry. AB - Statistical analysis reveals that, given a fixed acquisition time, linewidth (and thus pO(2)) can be more precisely determined from multiple scans with different modulation amplitudes and sweep widths than from a single-scan. For a Lorentzian lineshape and an unknown but spatially uniform modulation amplitude, the analysis suggests the use of two scans, each occupying half of the total acquisition time. We term this mode of scanning as dual-scan acquisition. For unknown linewidths in a range [Gamma(min), Gamma(max)], practical guidelines are provided for selecting the modulation amplitude and sweep width for each dual-scan component. Following these guidelines can allow for a 3-4 times reduction in spectroscopic acquisition time versus an optimized single-scan, without requiring hardware modifications. Findings are experimentally verified using L-band spectroscopy with an oxygen sensitive particulate probe. PMID- 22820010 TI - Elimination of mutual inductance in NMR phased arrays: the paddle design revisited. AB - This study proposes a method to empirically minimize mutual inductance, using passive end-ring circular paddles, with neighboring coil loops placed in a non overlapped configuration. The proposed concepts are validated through B(1)-field simulations for resonant coils at f(o)=300.5 MHz, having various sizes (3-10 cm), and for paddles with sizes ranging from 16 to 30 mm, and bench tests on constructed 4*4cm(2) two- (1*2) and four-coil loop (2*2) planar arrays. Simulation results yield total mean percentage B(1)-field differences of only 7.03% between the two non-overlapping coil array configurations (paddles vs. no paddles). Pair-wise comparisons of elicited mean B(1)-field differences from the use of different circular and rectangular paddle sizes, yield values <5.3%. Theoretical calculation of the normalized mutual coupling coefficient in the non overlapped coil configuration reduces to almost zero with optimally sized-paddles having a radius of approximately 28% the coil's largest dimension. In the absence of paddles, differences in the split of resonance peaks of 9.9 MHz were observed for the two coils in the 1*2 array, which vanished with paddle placement. Single coil responses (unloaded/loaded) without paddles, and responses from array coils with use of optimally-sized paddles yielded quality factor ratios that ranged between 1.1-1.86 and 1.0-1.5, respectively. Phantom and mouse loaded reflection coefficients S(11)/S(22) were -16.7/-16.2dB and -28.2/-16.1 dB, for the two array loops, respectively. Under unloaded conditions and in the absence of paddles, split resonances were observed for the 1*2 array, yielding transmission coefficients of -5.5 to -8.1 dB, reversing to single resonance responses upon paddle placements, with transmission coefficients of -14.4 to -15.6 dB. PMID- 22820011 TI - Nanoparticles based on albumin: preparation, characterization and the use for 5 flurouracil delivery. AB - The aim of the study was to formulate and evaluate nanoparticles based on albumin to deliver 5-fluorouracil. The nanoparticles were prepared by coacervation method. The nanoparticles were characterized for particle size, surface charge, size distribution and drug loading capacity. The drug loading capacity varied from 4.22% to 19.8% (w/w). The mean particle size was 141.9 nm and surface charge was -30.3 mV. The drug loaded particles exerted a bi-phasic release pattern with an initial burst effect followed by a sustained release in pH 7.4 phosphate buffer. The drug release was first order diffusion controlled and the mechanism was Fickian. The drug loaded nanoparticles showed superior cytotoxicity when compared to the free drug. PMID- 22820013 TI - Pharmaceutical therapies to recode nonsense mutations in inherited diseases. AB - Nonsense codons, generated from nonsense mutations or frameshifts, contribute significantly to the spectrum of inherited human diseases such as cystic fibrosis, Duchenne muscular dystrophy, hemophilia, spinal muscular atrophy, and many forms of cancer. The presence of a mutant nonsense codon results in premature termination to preclude the synthesis of a full-length protein and leads to aberrations in gene expression. Suppression therapy to recode a premature termination codon with an amino acid allowing readthrough to rescue the production of a full-length protein presents a promising strategy for treatment of patients suffering from debilitating nonsense-mediated disorders. Suppression therapy using aminoglycosides to promote readthrough in vitro have been known since the sixties. Recent progress in the field of recoding via pharmaceuticals has led to the continuous discovery and development of several pharmacological agents with nonsense suppression activities. Here, we review the mechanisms that are involved in discriminating normal versus premature termination codons, the factors involved in readthrough efficiency, the epidemiology of several well known nonsense-mediated diseases, and the various pharmacological agents (aminoglycoside and non-aminoglycoside compounds) that are currently being employed in nonsense suppression therapy studies. We also discuss how these therapeutic agents can be used to regulate gene expression for gene therapy applications. PMID- 22820014 TI - Lung injuries secondary to mechanical chest compressions. PMID- 22820012 TI - Insulin in the brain: there and back again. AB - Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain. PMID- 22820015 TI - Association between maternal exposure to perfluorooctanoic acid (PFOA) from electronic waste recycling and neonatal health outcomes. AB - OBJECTIVE: Perfluorooctanoic acid (PFOA) has applications in numerous industrial and consumer products. The widespread prevalence of PFOA in humans demonstrated in recent studies has drawn considerable interest from the public. We aimed to evaluate the exposure of mothers to PFOA and the potential hazards to neonates in a primitive electronic waste recycling area, Guiyu, China, and a control area, Chaonan, China. METHODS: Our investigation included analyses of maternal serum samples, health effect examinations, and other relevant factors. Questionnaires were administered and maternal serum samples were collected for 167 pregnant women. Solid phase extraction method was used for all analytical sample preparation, and analyses were completed using high performance liquid chromatography tandem mass spectrometry method. RESULTS: The PFOA concentration was higher in maternal serum samples from Guiyu than in samples from Chaonan (median 16.95, range 5.5-58.5 ng mL(-1); vs. 8.7, range 4.4-30.0 ng mL(-1); P<0.001). Residence in Guiyu, involvement in e-waste recycling, husband's involvement in e-waste and use of the family residence as workshop were significant factors contributing to PFOA exposure. Maternal PFOA concentrations were significantly different between normal births and adverse birth outcomes including premature delivery, term low birth weight, and stillbirths. After adjusting for potential confounders, PFOA was negatively associated with gestational age [per lg-unit: beta=-15.99 days, 95% confidence interval (CI), 27.72 to -4.25], birth weight (per lg-unit: beta=-267.3g, 95% CI, -573.27 to 37.18), birth length (per lg-unit: beta=-1.91 cm, 95% CI, -3.31 to -0.52), and Apgar scores (per lg-unit: beta=-1.37, 95% CI, -2.42 to -0.32), but not associated with ponderal index. CONCLUSIONS: Mothers from Guiyu were exposed to higher levels of PFOA than those from control areas. Prenatal exposure to PFOA was associated with decreased neonatal physical development and adverse birth outcomes. PMID- 22820017 TI - In vivo role of aldehyde reductase. AB - BACKGROUND: Aldehyde reductase (AKR1A; EC 1.1.1.2) catalyzes the reduction of various types of aldehydes. To ascertain the physiological role of AKR1A, we examined AKR1A knockout mice. METHODS: Ascorbic acid concentrations in AKR1A knockout mice tissues were examined, and the effects of human AKR1A transgene were analyzed. We purified AKR1A and studied the activities of glucuronate reductase and glucuronolactone reductase, which are involved in ascorbic acid biosynthesis. Metabolomic analysis and DNA microarray analysis were performed for a comprehensive study of AKR1A knockout mice. RESULTS: The levels of ascorbic acid in tissues of AKR1A knockout mice were significantly decreased which were completely restored by human AKR1A transgene. The activities of glucuronate reductase and glucuronolactone reductase, which are involved in ascorbic acid biosynthesis, were suppressed in AKR1A knockout mice. The accumulation of d glucuronic acid and saccharate in knockout mice tissue and the expression of acute-phase proteins such as serum amyloid A2 are significantly increased in knockout mice liver. CONCLUSIONS: AKR1A plays a predominant role in the reduction of both d-glucuronic acid and d-glucurono-gamma-lactone in vivo. The knockout of AKR1A in mice results in accumulation of d-glucuronic acid and saccharate as well as a deficiency of ascorbic acid, and also leads to upregulation of acute phase proteins. GENERAL SIGNIFICANCE: AKR1A is a major enzyme that catalyzes the reduction of d-glucuronic acid and d-glucurono-gamma-lactone in vivo, besides acting as an aldehyde-detoxification enzyme. Suppression of AKR1A by inhibitors, which are used to prevent diabetic complications, may lead to the accumulation of d-glucuronic acid and saccharate. PMID- 22820018 TI - Role of key regulators of the cell cycle in maintenance of hematopoietic stem cells. AB - BACKGROUND: Hematopoietic stem cells (HSCs) are characterized by pluripotentiality and self-renewal ability. To maintain a supply of mature blood cells and to avoid HSC exhaustion during the life span of an organism, most HSCs remain quiescent, with only a limited number entering the cell cycle. SCOPE OF REVIEW: The molecular mechanisms by which quiescence is maintained in HSCs are addressed, with recent genetic studies having provided important insight into the relation between the cell cycle activity and stemness of HSCs. MAJOR CONCLUSIONS: The cell cycle is tightly regulated in HSCs by complex factors. Key regulators of the cell cycle in other cell types-including cyclins, cyclin-dependent kinases (CDKs), the retinoblastoma protein family, the transcription factor E2F, and CDK inhibitors-also contribute to such regulation in HSCs. Most, but not all, of these regulators are necessary for maintenance of HSCs, with abnormal activation or suppression of the cell cycle resulting in HSC exhaustion. The cell cycle in HSCs is also regulated by external factors such as cytokines produced by niche cells as well as by the ubiquitin-proteasome pathway. GENERAL SIGNIFICANCE: Studies of the cell cycle in HSCs may shed light on the pathogenesis of hematopoietic disorders, serve as a basis for the development of new therapeutic strategies for such disorders, prove useful for the expansion of HSCs in vitro as a possible replacement for blood transfusion, and provide insight into stem cell biology in general. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22820020 TI - Alignment-free distance measure based on return time distribution for sequence analysis: applications to clustering, molecular phylogeny and subtyping. AB - The data deluge in post-genomic era demands development of novel data mining tools. Existing molecular phylogeny analyses (MPAs) developed for individual gene/protein sequences are alignment-based. However, the size of genomic data and uncertainties associated with alignments, necessitate development of alignment free methods for MPA. Derivation of distances between sequences is an important step in both, alignment-dependant and alignment-free methods. Various alignment free distance measures based on oligo-nucleotide frequencies, information content, compression techniques, etc. have been proposed. However, these distance measures do not account for relative order of components viz. nucleotides or amino acids. A new distance measure, based on the concept of 'return time distribution' (RTD) of k-mers is proposed, which accounts for the sequence composition and their relative orders. Statistical parameters of RTDs are used to derive a distance function. The resultant distance matrix is used for clustering and phylogeny using Neighbor-joining. Its performance for MPA and subtyping was evaluated using simulated data generated by block-bootstrap, receiver operating characteristics and leave-one-out cross validation methods. The proposed method was successfully applied for MPA of family Flaviviridae and subtyping of Dengue viruses. It is observed that method retains resolution for classification and subtyping of viruses at varying levels of sequence similarity and taxonomic hierarchy. PMID- 22820021 TI - Genetic divergence and population demography of the Hainan endemic Black-throated Laughingthrush (Aves: Timaliidae, Garrulax chinensis monachus) and adjacent mainland subspecies. AB - Geographic variation in the Black-throated Laughingthrush (Garrulax chinensis) is examined to infer the influence of Pleistocene glacial oscillations on the genetic diversity of its subspecies. Mitochondrial evidence suggests that the endemic Hainan Island taxon, G. c. monachus, is monophyletic, whereas its closest continental relatives, G. c. chinensis and G. c. lochmius, are not. Multilocus coalescent analysis based on two mitochondrial and two nuclear intron loci indicates inter-subspecific genetic differentiation during the Pleistocene and substantial post-divergence genetic introgression from G. c. chinensis into G. c. lochmius. In contrast, G. c. monachus experienced no post-divergence gene flow despite occasional land-bridge contact with its continental relatives, suggesting its isolation may have been imposed by ecology as well as geography. It is probably reproductively isolated and should be treated as a distinct species. PMID- 22820022 TI - Associations between perceived parental physical activity and aerobic fitness in schoolchildren. AB - BACKGROUND: Parental behavior is an important correlate of child health. The aim of this study was to investigate the association between perceived parental physical activity (PA) and schoolchildren's aerobic fitness. METHODS: English schoolchildren's (n = 4029, 54% boys, 10.0-15.9 yrs) fitness was assessed by 20 m shuttle run test and categorized using criterion-referenced standards. Parental PA was reported by the child. RESULTS: Boys and girls were more likely to be fit (OR 1.4, 95% CI 1.1-1.8; OR 1.5, 95% CI 1.1-2.0; respectively) if at least 1 parent was perceived as active compared with when neither parents were. Girls were even more likely to be fit (OR 1.8, 95% CI 1.2-2.8) if both parents were active. Associations between parental PA and child fitness were generally stronger when parent and child were of the same gender, although girls with active fathers were more likely (OR 2.5, 95% CI 1.7-3.7) to be fit compared with inactive fathers. CONCLUSION: Schoolchildren perceiving at least 1 parent as active are more likely to meet health-related fitness standards. Underlying mechanisms remain elusive, but same-gender associations suggest that social rather than genetic factors are of greater importance. Targeting parental PA or at least perceptions of parental PA should be given consideration in interventions aiming to improve child health. PMID- 22820019 TI - Biochemistry of epidermal stem cells. AB - BACKGROUND: The epidermis is an important protective barrier that is essential for maintenance of life. Maintaining this barrier requires continuous cell proliferation and differentiation. Moreover, these processes must be balanced to produce a normal epidermis. The stem cells of the epidermis reside in specific locations in the basal epidermis, hair follicle and sebaceous glands and these cells are responsible for replenishment of this tissue. SCOPE OF REVIEW: A great deal of effort has gone into identifying protein epitopes that mark stem cells, in identifying stem cell niche locations, and in understanding how stem cell populations are related. We discuss these studies as they apply to understanding normal epidermal homeostasis and skin cancer. MAJOR CONCLUSIONS: An assortment of stem cell markers have been identified that permit assignment of stem cells to specific regions of the epidermis, and progress has been made in understanding the role of these cells in normal epidermal homeostasis and in conditions of tissue stress. A key finding is the multiple stem cell populations exist in epidermis that give rise to different structures, and that multiple stem cell types may contribute to repair in damaged epidermis. GENERAL SIGNIFICANCE: Understanding epidermal stem cell biology is likely to lead to important therapies for treating skin diseases and cancer, and will also contribute to our understanding of stem cells in other systems. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22820023 TI - Microneurography: towards a biomarker of spontaneous pain. PMID- 22820024 TI - Implications for operational control of adult mosquito production in cisterns and wells in St. Augustine, FL using attractive sugar baits. AB - The aim of this study was to further investigate the use of attractive sugar baits as an effective, inexpensive, and environmentally friendly tool for integrated mosquito management programs. Mosquitoes were offered dyed sugar bait in wells and cisterns in an urban tourist area in St. Augustine, FL. Exit traps were constructed to cover the well and cistern openings so the number of resting and emerging mosquitoes stained by feeding on the sugar bait could be monitored. Four mosquito species were collected from these structures: Aedes albopictus (Skuse), Anopheles crucians (Wiedemann), Culex quinquefasciatus Say, and Toxorhynchites rutilus rutilus (Coquillett). Overall, 90% (1482/1644) of the mosquitoes trapped were stained. In general, the number of mosquitoes stained was significantly greater in wells (P<0.0001) and cisterns (P<0.0001) than the numbers that were not stained by the colored bait. Based on the number of mosquitoes stained, we would have expected considerable mosquito mortality had the sugar bait contained an oral toxin. The results of this study support the concept of using attractive toxic sugar baits as an effective tool for integrated mosquito management. PMID- 22820026 TI - Assessing the genetic diversity of the vir genes in Indian Plasmodium vivax population. AB - Variant surface antigens (VSAs) present on the surface of parasitized erythrocytes facilitate many Plasmodium spp. to escape the host immune system during infection. Multigene families coding for VSAs exist in several Plasmodium spp. and are located on telomeric and subtelomeric regions of the chromosomes. P. vivax genome also contains a multigene superfamily vir (variant interspersed repeats), present in the subtelomeric region with a possible role in immune evasion like the var gene in P. falciparum. Blood samples from 148 symptomatic malaria cases were collected from five different regions of India, viz. Mangalore, Rourkela, Goa, Delhi and Jabalpur. P. vivax isolates (74 single infections) were sequenced for four vir genes (viz. vir 27, vir 4, vir 12 and vir 21) and analyzed for the genetic variability existing in different populations of India. The results indicate that vir genes in different P. vivax populations in India are highly divergent both within and between the isolates. High levels of single nucleotide polymorphisms (SNPs) were observed attributing to the existing polymorphism for all the four vir genes studied across the population. Detailed knowledge of the genetic variation among the vir genes will help in understanding the evolutionary aspects of vir genes and may also provide basis for understanding the disease chronicity. PMID- 22820025 TI - High level of Schistosoma mansoni infection in pre-school children in Sierra Leone highlights the need in targeting this age group for praziquantel treatment. AB - BACKGROUND: Schistosomiasis and soil-transmitted helminth (STH) infections are endemic in Sierra Leone. The consequences of these diseases to pre-school children are well understood. The national control program currently does not target this group of children for schistosomiasis, while mass drug administration (MDA) has been performed six monthly for STHs in children 12-59 months of age since 2006. METHODS: To assist the national decision on MDA strategy to control schistosomiasis and STH, three cross-sectional surveys were conducted in pre school children in 2009-2011 as part of routine surveillance performed in different areas and in different phases of MDA, including known 'Hard to Reach' villages where consistently poor coverage results were seen in recent MDA. Thirty 4-5 year-old children were randomly selected per site and a stool sample from each child was examined by Kato-Katz thick smear. Pooled data were analyzed for schistosomiasis and separate sets of data were presented for STHs. In total 61 sites were surveyed and a total of 1803 children were examined. RESULTS: The overall prevalence and intensity of Schistosoma mansoni was 11.2% (95% CI 9.7 12.8) and 33.5 epg (95% CI 19.7-47.3). Relatively high level of infection was found in Kono (35.4% and 102.9 epg), Tonkolili (30.4% and 142.3 epg) and Koinadugu (20.8% and 47.0 epg). There were 8.1% of children 4-5 years old moderately or heavily infected with S. mansoni. Overall level of STH infections were generally low, with hookworm 8.4-22.8%, Ascaris lumbricoides 0.2-17.2%, and Trichuris trichiura 0.9-2.6% in three surveys. However, prevalence of hookworm and A. lumbricoides was relatively high in those hard-to-reach villages even two months after MDA. CONCLUSIONS: Relatively high levels of S. mansoni infections were found in children aged 4-5 years old in Sierra Leone, in line with geographical distribution of the disease observed in older children in the country. The results suggest that this group of children should not be neglected further in the schistosomiasis MDA and a global guideline is needed. Overall prevalence of STH infection was relatively low. Although there was no baseline data for direct comparison, it did show a marked reduction in STH infections, compared with historical data. However, relatively higher prevalence in hard-to reach villages suggests the difficulty and quality of implementing MDA in such difficult locations, and more efforts and perhaps different delivery strategies are needed in these locations to increase the quality of MDA. PMID- 22820027 TI - Use of exclusive enteral nutrition in paediatric Crohn's disease in The Netherlands. AB - BACKGROUND AND AIMS: A six-week course of exclusive enteral nutrition (EEN) is recommended as first treatment in active paediatric Crohn's disease (CD). We aimed to assess short-term and long-term outcome of EEN, and to identify predictive factors of treatment success. METHODS: The medical records of newly diagnosed paediatric CD patients initiating EEN as remission induction therapy between January 2008 and October 2011 were retrospectively studied. Treatment outcome was assessed using a previously described pattern recognition model. RESULTS: 77 CD patients (median age 13.9 years, 57% male) initiated a six-week course of EEN, combined with azathioprine maintenance treatment in 92%. Patients received EEN as either hyperosmolar sip feeds or polymeric formula by nasogastric tube. In patients completing a six-week course of EEN (n=58), complete remission was achieved in 71%, partial remission in 26%, and no response in 3%. Complete remission rates were higher in children presenting with isolated ileal/ileocaecal disease and malnutrition. Nineteen patients discontinued EEN before the intended treatment period due to worsening of symptoms (n=9) or adherence issues (n=10). Non-adherence occurred more often in older children, females, children from non Dutch parents, and patients taking hyperosmolar sip feeds compared with polymeric formula by nasogastric tube. The likelihood of relapsing disease within the first year after EEN treatment was 59%. CONCLUSION: A six-week course of EEN is effective in newly diagnosed paediatric CD, with response rates that seem to be influenced by disease location and nutritional status, but not by type of formula. Non-adherence occurs frequently and limits the success of this treatment in everyday clinical practice. PMID- 22820029 TI - Hepatic interaction between quinidine and digoxin: role of inhibition of sinusoidal Na+/K+ ATPase digoxin binding. AB - The mechanism by which quinidine affects hepatic digoxin pharmacokinetics remains controversial. Here, we study the role of displacement of digoxin from hepatic sinusoidal binding sites by quinidine. We used the impulse-response technique in the single-pass perfused rat liver to describe the digoxin hepatic disposition by a physiologically-based pharmacokinetic liver model. The impulse-response study involved analysis of outflow curves following two consecutive doses of digoxin (42 and 125 MUg) without and with quinidine (10 MUM) in perfusate. In addition, the effect of quinidine on digoxin binding in liver subcellular fractions was quantified. Quinidine increased the peak outflow concentration for digoxin at the low digoxin dose but not at the high dose. This increase could be adequately described when digoxin displacement from sinusoidal and intrahepatic binding sites was included in the model. Inhibition of digoxin binding by quinidine was also observed in vitro. The decrease of biliary excretion of digoxin by quinidine was accompanied by a linear increase in sinusoidal efflux of digoxin's primary metabolite, digoxigenin bisdigitoxoside (Dg2). In contrast to biliary excretion, inhibition of sinusoidal uptake may become dominant only for high concentrations of quinidine. PMID- 22820028 TI - Gallic acid-grafted chitooligosaccharides suppress antigen-induced allergic reactions in RBL-2H3 mast cells. AB - In this study, a bioactive derivative of chitooligosaccharides (3-5 kDa) was synthesized via grafting of gallic acid onto chitooligosaccharides (G-COS) to enhance anti-allergic activity. Hence, G-COS was evaluated for its capabilities against allergic reactions in RBL-2H3 mast cells sensitized with dinitrophenyl specific immunoglobulin E antibody and stimulated by antigen dinitrophenyl-bovine serum albumin. It was revealed that G-COS exhibited significant inhibition on histamine release and production as well as intracellular Ca(2+) elevation at the concentration of 200MUg/ml. Likewise, the suppressive effects of G-COS on expression and production of interleukin (IL)-4 and tumor necrosis factor (TNF) alpha were evidenced. Moreover, G-COS treatment caused a remarkable blockade on degradation of inhibitory kappaB-alpha (IkappaB-alpha) protein, translocation of nuclear factor (NF)-kappaB, and phosphorylation of mitogen-activated protein kinases (MAPKs). Notably, the inhibitory activities of G-COS on allergic reactions were found as a consequence of suppression of FcepsilonRI expression in antigen-stimulated cells. Accordingly, G-COS was suggested to be a promising candidate of novel inhibitors against allergic reactions. PMID- 22820030 TI - Topical effects of nebivolol on wounds in diabetic rats. AB - OBJECTIVE: Recently, it has reported that nebivolol might be useful in the treatment of diabetes mellitus foot ulcers. The aim of this study was to examine treatment of the wounds in streptozotocin-induced diabetic rats with topical nebivolol. METHODS: Two 15 * 15 mm-sized wounds were created in 56 streptozotocin induced rats. A total of 56 diabetic wounds were studied in eight groups (n=7). No treatment was administered to the first and second groups. The third and fourth groups consisted of diabetic rats that were administered 1:1 mixture of lanolin and vaseline for 7 and 14 days, respectively. Five percent nebivolol plus 1:1 mixture of lanolin and vaseline was administered to rats in the fifth and sixth groups for 7 and 14 days, respectively, and 10% nebivolol plus 1:1 mixture of lanolin and vaseline was administered to rats in the seventh and eighth groups for 7 and 14 days, respectively. On days 7 and 14, wound healing was observed, and the percent of wound healing was determined by measuring its size and histopathologic examination. The ratio was calculated by the formula, healing ratio (%)=100 *(1-wound area/initial wound area). Statistical analysis was performed by ANOVA with Tukey's HSD test and Mann-Whitney U test, using SPSS 15.0 software. RESULTS: On days 7 and 14, rates of wound healing in the fifth, sixth, seventh, and eighth groups were 57.42%, 89.16%, 60.80%, and 91.80%, respectively. Multiple comparison showed that rates of wound healing were significantly higher in rats administered 5% and 10% nebivolol than those in rats administered a mixture of lanolin and vaseline and in the untreated group (P<0.05). CONCLUSION: Topical nebivolol therapy may be useful for wound healing in diabetic rats. Further studies are needed to support these data. PMID- 22820031 TI - Evaluation of layers of the rat airway epithelial cell line RL-65 for permeability screening of inhaled drug candidates. AB - A rat respiratory epithelial cell culture system for in vitro prediction of drug pulmonary absorption is currently lacking. Such a model may however enhance the understanding of interspecies differences in inhaled drug pharmacokinetics by filling the gap between human in vitro and rat in/ex vivo drug permeability screens. The rat airway epithelial cell line RL-65 was cultured on Transwell inserts for up to 21 days at an air-liquid (AL) interface and cell layers were evaluated for their suitability as a drug permeability measurement tool. These layers were found to be morphologically representative of the bronchial/bronchiolar epithelium when cultured for 8 days in a defined serum-free medium. In addition, RL-65 layers developed epithelial barrier properties with a transepithelial electrical resistance (TEER) >300 Omega cm(2) and apparent (14)C mannitol permeability (P(app)) values between 0.5-3.0 * 10(-6)cm/s; i.e., in the same range as established in vitro human bronchial epithelial absorption models. Expression of P-glycoprotein was confirmed by gene analysis and immunohistochemistry. Nevertheless, no vectorial transport of the established substrates (3)H-digoxin and Rhodamine123 was observed across the layers. Although preliminary, this study shows RL-65 cell layers have the potential to become a useful in vitro screening tool in the pre-clinical development of inhaled drug candidates. PMID- 22820032 TI - Viability of freeze dried microencapsulated human retinal pigment epithelial cells. AB - Encapsulated human retinal pigment epithelial cell line ARPE-19 has been successfully used in experimental cell therapy of retinal degenerations and Parkinson's disease, but the long-term storage of encapsulated cells is still an unresolved question. Reconstitution of viable encapsulated cells from dry form would benefit the development of cell therapy products. We freeze dried and reconstituted microencapsulated ARPE19 and ARPE19-SEAP cells. Cross-linked alginate matrix with polycation (poly-l-lysine, cationic starch) coating was used for microencapsulation. Cell viability was assessed with fluorescence microscopy and oxygen consumption of the cells. Freeze dried and reconstituted cell microcapsules were imaged using scanning electron microscopy (SEM) and environmental scanning electron microscopy (ESEM). We show partial viability of microencapsulated cells after freeze-drying. Unlike poly-l-lysine (PLL) coating, cationic starch supported microcapsule shape and cell viability during freeze drying. Trehalose pre-treatment augmented cell viability. Likewise, some lyoprotectants (trehalose, glycerol) enabled preservation of cell viability. Upon reconstitution the freeze dried cell microcapsules rapidly regained their original spherical shape. This proof-of-concept study demonstrates that microencapsulated cells can retain their viability during freeze-drying. Therefore, this approach can be further optimized for the benefit of cell therapy product development. PMID- 22820033 TI - Development and optimization of baicalin-loaded solid lipid nanoparticles prepared by coacervation method using central composite design. AB - The objective of this study was to design and optimize a novel baicalin-loaded solid lipid nanoparticles (SLNs) carrier system composed of a stearic acid alkaline salt as lipid matrix and prepared as per the coacervation method in which fatty acids precipitated from their sodium salt micelles in the presence of polymeric nonionic surfactants. A two-factor five-level central composite design (CCD) was introduced to perform the experiments. A quadratic polynomial model was generated to predict and evaluate the independent variables with respect to the dependent variables. The composition of optimal formulation was determined as 0.69% (w/v) lipid and 26.64% (w/w) drug/lipid ratio. The results showed that the optimal formulation of baicalin-loaded SLN had entrapment efficiency (EE) of 88.29%, particle size of 347.3 nm and polydispersity index (PDI) of 0.169. The morphology of nanoparticles was found to be nearly spherical in shape by scanning electron microscopy (SEM) observation. The differential scanning calorimetry (DSC) analysis indicated that the drug incorporated into SLN was not in an amorphous form but in a crystalline state. The C(max), MRT, AUMC(0->infinity) and AUC(0->infinity) values of SLN were approximately 1.6-fold, 1.9-fold, 5.0-fold and 2.6-fold greater than that of reference preparation, respectively. PMID- 22820034 TI - Unexpected severity of cases of influenza B infection in patients that required hospitalization during the first postpandemic wave. AB - OBJECTIVES: After the last pandemic the knowledge regarding influenza A infection has improved however, the outcomes of influenza B infection remain poorly studied. The aim of this study was to compare the features of influenza B versus influenza A(H1N1)pdm09 infections during the 2010-2011 epidemic-season. METHODS: A prospective, observational-cohort of adults with laboratory-confirmed influenza infection during the 2010-2011 epidemic-season was studied RESULTS: Fifty cases of influenza B and 80 of influenza A(H1N1)pdm09 infection were enrolled. Among patients with influenza B, the median age was 34 years-old (23-64), 30% pregnant, 24% obese, 34% transplant recipients and 14% with bacterial co-infection. Twenty eight percent of patients had pneumonia with alveolar localized pattern and five (10%) died. Pneumonia was associated with delayed antiviral therapy, older age, higher Charlson score, invasive mechanical ventilation and bacterial co infection. Obesity and pregnancy were not associated with complicated influenza B infection. The proportion of pneumonia, admission to the ICU and mortality did not differ between cases of influenza A(H1N1)pdm09 and influenza B infection. CONCLUSIONS: Influenza B infection causes severe infection and it is associated with pneumonia or death, similar to influenza A(H1N1)pdm09 infection. Rapid diagnosis and early antiviral therapy are necessary for managing influenza pneumonia during epidemic periods. PMID- 22820035 TI - AedesCAPA-PVK-1 displays diuretic and dose dependent antidiuretic potential in the larval mosquito Aedes aegypti (Liverpool). AB - This study reveals that AedesCAPA-PVK-1 (GPTVGLFAFPRV-NH(2)) inhibits basal and serotonin stimulated fluid secretion in the Malpighian tubules of larval Aedes aegypti at femtomolar concentrations. Conversely 10(-4)moll(-1) of the peptide stimulated fluid secretion rates. The diuretic effects of 10(-4)moll(-1)AedesCAPA PVK-1 and antidiuretic effects of 10(-15)moll(-1)AedesCAPA-PVK-1 were abolished by protein kinase A (PKA) and protein kinase G (PKG) inhibition, respectively. Similar to the peptide, 10(-3)moll(-1) cGMP stimulated fluid secretion but doses in the micromolar to nanomolar range inhibited fluid secretion of the Malpighian tubules. Stimulatory effects of cGMP were abolished by PKA inhibition and inhibitory effects of cGMP were abolished by PKG inhibition. Furthermore, the nitric oxide synthase inhibitor l-NAME attenuated the inhibitory effects of AedesCAPA-PVK-1 but did not affect inhibition by cGMP. Based on the results we propose that AedesCAPA-PVK-1 inhibits fluid secretion rates of larval Malpighian tubules via the NOS/cGMP/PKG pathway and that high doses of the peptide lead to diuresis through the cGMP mediated activation of PKA. PMID- 22820036 TI - Autotaxin in liver fibrosis. AB - Autotaxin (ATX) hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), a multi-functional bioactive lipid mediator. ATX is a major determinant of LPA levels in the blood, and the pathophysiological functions of ATX are thought to be largely attributed to its ability to produce LPA. Liver fibrosis is one of the rare disorders exhibiting the increased ATX and LPA levels in the blood. This review summarizes the recent findings on the relation between ATX or LPA and liver fibrosis, the usefulness of serum ATX levels to predict the stages of liver fibrosis, and speculated roles of increased serum ATX and plasma LPA levels in liver fibrosis. PMID- 22820038 TI - The interaction between expected values and risk levels in a modified Iowa gambling task. AB - Performance on the Iowa gambling task (IGT) supports somatic marker hypothesis (SMH), which proposes that the process of decision making depends on emotion (Damasio, 1994). However, the bad decks in the IGT are also more risky and that confounds the results. To resolve this issue, the IGT-Yen, a variant of the IGT, was created to independently examine the effects of expected value and risk. After 20 trials, participants selected more high-risk bad decks than low-risk bad decks and more low-risk good decks than high-risk good decks. Greater anticipatory skin conductance levels (SCLs) were associated with choosing high risk bad decks compared to choosing low-risk bad decks in trials 21-80, and greater anticipatory SCLs were associated with choosing low-risk good decks compared to choosing high-risk good decks in trials 81-100. Therefore, the anticipatory SCLs were associated with expected values of the decks and with their levels of risk. PMID- 22820037 TI - Plasma vasopressin and interpersonal functioning. AB - The neuropeptide vasopressin has traditionally been associated with vasoconstriction and water reabsorption by the kidneys. However, data from experimental animal studies also implicate vasopressin in social bonding processes. Preliminary work suggests that vasopressin also plays a role in social behaviors in humans. The goal of this cross-sectional study was to evaluate associations among plasma vasopressin and self-reported interpersonal functioning in a sample of married couples. During a 24-h admission to a hospital-based research unit, 37 couples completed measures of interpersonal functioning and provided blood samples for neuropeptide analyses. Results showed that vasopressin was associated with markers of interpersonal functioning, but not with general psychological distress. Specifically, greater plasma vasopressin levels were related to a larger social network, fewer negative marital interactions, less attachment avoidance, more attachment security, and marginally greater spousal social support. These results indicate that vasopressin is likely implicated in different relationship maintenance processes in humans. PMID- 22820039 TI - You don't like me, do you? Enhanced ERP responses to averted eye gaze in social anxiety. AB - Social anxiety is associated with an attentional bias toward angry and fearful faces, along with an enhanced processing of faces per se. However, little is known about the processing of gaze direction, a subtle but important social cue. Participants with high or low social anxiety (HSA/LSA) observed eye pairs with direct or averted gaze while subjective ratings and event-related potentials (ERPs) were measured. Behaviorally, all participants rated averted gaze as more unpleasant than direct gaze. Neurally, only HSA participants showed a trend for higher P100 amplitudes to averted gaze and significantly enhanced processing at late latencies (Late positive potential [LPP]), indicative of a specific processing bias for averted gaze. Furthermore, HSA individuals showed enhanced processing of both direct and averted gaze relative to the LSA group at intermediate latencies (Early posterior negativity [EPN]). Both general and specific attentional biases play a role in social anxiety. Averted gaze- potential sign of disinterest--deserves more attention in the attentional bias literature. PMID- 22820040 TI - A new account of the effect of probability on task switching: ERP evidence following the manipulation of switch probability, cue informativeness and predictability. AB - This task-switching ERP study of 16 young participants investigated whether increased RT slowing on stay trials and faster RTs on switch trials for frequent than infrequent switching are explained by an activation or preparation account. The activation account proposes that task sets are maintained at a higher baseline activation level for frequent switching, necessitating increased task set updating, as reflected by a larger and/or longer lasting early parietal positivity. The preparation account assumes advance (pre-cue) switch preparation (i.e., task-set reconfiguration), preceding stay and switch trials for frequent switching, as reflected by pre-cue and post-cue late parietal positivities. By and large, the data support the activation account. However, we also found increased, pre-cue task-set updating on frequent stay trials and pre-cue, task set reconfiguration prior to predictable, frequent switches. These results lead us to propose an extended activation account to explain the effects of switch probability on the executive processes underlying task-switching behavior. PMID- 22820041 TI - Establishment of monoclonal antibodies against a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10. AB - Eosinophilic inflammation is the prominent feature of bronchial asthma, though the importance of eosinophils in the pathogenesis of this disease is controversial. We here established monoclonal antibodies against a newly identified cell surface molecule specifically expressed on mouse eosinophils. Eosinophils were highly purified from small intestine lamina propria and thymus as CD11c(+)Gr1(low)F4/80(+)B220(-) cells. Upon comparative microarray analysis for mRNA expressed in eosinophils and other leukocytes, major facilitator super family domain containing 10 (Mfsd10) was identified as a novel eosinophil specific cell surface molecule. Hybridomas were established from spleen cells of rats immunized with Mfsd10-introduced Ba/F3 cells. One of three monoclonal antibodies against Mfsd10 displayed selective binding activity against eosinophils recovered in bronchoalveolar lavage fluid of ovalbumin-immunized and challenged mice. Administration of this antibody in vivo induced a significant reduction of eosinophils recruited in the allergic lungs. Anti-Mfsd10 antibody is useful for investigating the pathophysiological roles of eosinophils with its selective binding and neutralizing activity for mouse eosinophils. PMID- 22820042 TI - The associations between cardiovascular risk factors, physical activity, and arterial stiffness in youth. AB - BACKGROUND: The primary aim of this population-based study was to determine if arterial stiffness is associated with cardiovascular disease (CVD) risk factor clustering and physical activity in youth 12-14 years old. We hypothesized that arterial stiffness would be positively associated with CVD risk factor clustering and negatively associated with physical activity in a dose-response manner in this cohort of youth. METHODS: This was a cross sectional study of 485 youth recruited from the 1995 Manitoba birth cohort. The primary outcome, arterial stiffness, was assessed noninvasively using conventional pulse wave analysis and velocity. The primary exposure variables included 1) a measure of cardiometabolic risk, defined as a composite of novel and traditional risk factors for cardiovascular disease and type 2 diabetes and 2) self-reported physical activity. RESULTS: Neither cardiometabolic risk factor clustering, nor physical activity were associated with either measure of arterial stiffness in this cohort of youth 12-14 years. Cardiometabolic risk decreased with increasing levels of vigorous physical activity, (P < .05) and increased with increasing body mass index. CONCLUSIONS: Cardiometabolic risk factor clustering and physical activity are not associated with arterial stiffness in youth 12-14 years of age. Increased vigorous physical activity is associated with reduced cardiometabolic risk in youth independent of body mass index. PMID- 22820043 TI - Binding studies of the antidiabetic drug, metformin to calf thymus DNA using multispectroscopic methods. AB - Interaction between antidiabetic drug, Metformin and calf thymus DNA (CT-DNA) in (50mM Tris-HCl) buffer were studied by UV-Visible absorption, fluorescence, CD spectroscopy and viscosity measurements. In fluorimetric studies, the enthalpy and entropy of the reaction between the drug and CT-DNA showed that the reaction is exothermic (DeltaH=-35.4522 kJ mol(-1); DeltaS=-49.9523 J mol(-1)K(-1)). The competitive binding studies showed that the drug could release Hoechst 33258 completely. The complex showed absorption hyperchromism in its UV-Vis spectrum with DNA. The calculated binding constant, K(b), obtained from UV-Vis absorption studies was 8.3*10(4)M(-1). Moreover, the changes in the CD spectra in the presence of the drug show stabilization of the right-handed B form of CT-DNA. Finally, viscosity measurements revealed that the binding of the complex with CT DNA could be surface binding, mainly due to groove binding. PMID- 22820044 TI - FT-IR and FT-Raman spectra, thermo dynamical behavior, HOMO and LUMO, UV, NLO properties, computed frequency estimation analysis and electronic structure calculations on alpha-bromotoluene. AB - In this work, the vibrational spectral analysis was carried out by using Raman and infrared spectroscopy in the range 100-4,000 cm(-1) and 50-4,000 cm(-1), respectively, for the title molecules. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on Hartee Fock (HF) and density functional theory (DFT) method and different basis sets combination. The complete vibrational assignments of wavenumbers were made on the basis of potential energy distribution (PED). The scaled B3LYP/6-311++G(d,p) results show the best agreement with the experimental values over the other methods. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The influences of bromine atom and methyl group on the geometry of benzene and its normal modes of vibrations have also been discussed. The results of the calculations were applied to simulated spectra of the title compounds, which show excellent agreement with observed spectra. PMID- 22820045 TI - (E)-3-chloro-N-((5-nitrothiophen-2-yl)methylene)aniline: a combined crystallographic, theoretical and antimicrobial activity investigation. AB - The title molecule, (E)-3-chloro-N-((5-nitrothiophen-2-yl)methylene)aniline, (C(11)H(7)ClN(2)O(2)S), was synthesized and characterized by IR and single crystal X-ray structure determination. The compound crystallizes in the monoclinic space group P2(1)/c. In addition, the molecular geometry, vibrational frequencies and frontier molecular orbitals analysis of the title compound in the ground state have been calculated by using the PM3 semi-empirical, HF/6-31G(d) and B3LYP/6-31G(d) ab initio methods. The results of the optimized molecular structure are exhibited and compared with the experimental X-ray diffraction and the calculated results are show that the optimized geometry can well reproduce the crystal structure. The Schiff base compounds are very important in medicinal and pharmaceutical fields because of their wide spectrum of biological activities. Most of them show biological activities such as antimicrobial, antifungal as well as antitumor activity. Therefore, (C(11)H(7)ClN(2)O(2)S) was investigated for their antimicrobial activities, Gram-positive and Gram-negative bacteria. PMID- 22820046 TI - Spectrophotometric and spectrofluorimetric studies on the selective sensing of fluoride ions by Co(II) and Ni(II) complexes of naphthoquinone derivative possessing enhanced H-bonding property. AB - A novel colorimetric chemosensor based on aminonaphthoquinone (L) bearing an N-H receptor unit directly attached to quinone signaling unit has been designed, synthesized and demonstrated. The ligand showed a highly selective colorimetric response to fluoride ions based on H-bond formation with the receptor unit. The binding constants of the L and its square planar [Co(L)Cl(2)].3H(2)O and [Ni(L)Cl(2)].4H(2)O complexes, computed using fluorescent enhancement data, were found to be 0.6, 1.5 and 0.9*10(8)M(-1), respectively, indicating enhancement of H-bond donor ability of the receptor unit, as a result of complexation with metal ions, towards fluoride ion sensing. Also, these sensors had high selectivity for fluoride ion detection over other common anions, such as Cl(-), Br(-), I(-), AcO( ), NO(3)(-), H(2)PO(4)(-) and CN(-) in acetonitrile. PMID- 22820047 TI - Synthesis, spectroscopic characterization and quantum chemical computational studies of (S)-N-benzyl-1-phenyl-5-(pyridin-2-yl)-pent-4-yn-2-amine. AB - The synthesis and characterization of a novel compound (S)-N-benzyl-1-phenyl-5 (pyridin-2-yl)-pent-4-yn-2-amine (abbreviated as BPPPYA) was presented in this study. The spectroscopic properties of the compound were investigated by FT-IR, NMR and UV spectroscopy experimentally and theoretically. The molecular geometry and vibrational frequencies of the BPPPYA in the ground state were calculated by using density functional theory (DFT) B3LYP method invoking 6-311++G(d,p) basis set. The geometry of the BPPPYA was fully optimized, vibrational spectra were calculated and fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. The results of the energy and oscillator strength calculated by time-dependent density functional theory (TD DFT) and CIS approach complement with the experimental findings. Total and partial density of state (TDOS and PDOS) and also overlap population density of state (COOP or OPDOS) diagrams analysis were presented. The theoretical NMR chemical shifts ((1)H and (13)C) complement with experimentally measured ones. The dipole moment, linear polarizability and first hyperpolarizability values were also computed. The linear polarizabilities and first hyper polarizabilities of the studied molecule indicate that the compound is a good candidate of nonlinear optical materials. The calculated vibrational wavenumbers, absorption wavelengths and chemical shifts showed the best agreement with the experimental results. PMID- 22820048 TI - Exploring the binding mechanism of Guaijaverin to human serum albumin: fluorescence spectroscopy and computational approach. AB - The Guaijaverin (Gua) is a polyphenolic substance which exhibits some pharmacological activities such as antibacterial and antioxidant activities. Here we have investigated the binding of Gua with human serum albumin (HSA) at physiological pH 7.0. In this study, the fluorescence spectroscopy, ab initio and molecular modeling calculations were applied. The Stern-Volmer quenching constant (K(SV)) and its modified form (K(a)) were calculated at 298, 303 and 308 K, with the corresponding thermodynamic parameters DeltaH, DeltaG and DeltaS as well. The fluorescence quenching method was used to determine the number of binding sites (n) and binding constants (K(b)) values at 298, 303 and 308 K. The distance between donor (HSA) and acceptor (Gua) was estimated according to fluorescence resonance energy transfer. The geometry optimization of Gua was performed in its ground state by using ab initio DFT/B3LYP functional with a 6-31G(d,p) basis set used in calculations. Molecular modeling calculation indicated that the Gua is located within the hydrophobic pocket of the subdomain IIA of HSA. The theoretical results obtained by molecular modeling were corroborated by fluorescence spectroscopy data. PMID- 22820049 TI - Why do patients derogate physicians who use a computer-based diagnostic support system? AB - OBJECTIVE: To better understand 1) why patients have a negative perception of the use of computerized clinical decision support systems (CDSSs) and 2) what contributes to the documented heterogeneity in the evaluations of physicians who use a CDSS. METHODS: Three vignette-based studies examined whether negative perceptions stemmed directly from the use of a computerized decision aid or the need to seek external advice more broadly (experiment 1) and investigated the contributing role of 2 individual difference measures, attitudes toward statistics (ATS; experiment 2) and the Multidimensional Health Locus of Control Scale (MHLC; experiment 3), to these findings. RESULTS: A physician described as making an unaided diagnosis was rated significantly more positively on a number of attributes than a physician using a computerized decision aid but not a physician who sought the advice of an expert colleague (experiment 1). ATS were unrelated to perceptions of decision aid use (experiment 2); however, greater internal locus of control was associated with more positive feelings about unaided care and more negative feelings about care when a decision aid was used (experiment 3). CONCLUSION: Negative perceptions of computerized decision aid use may not be a product of the need to seek external advice more generally but may instead be specific to the use of a nonhuman tool and may be associated with individual differences in locus of control. Together, these 3 studies may be used to guide education efforts for patients. PMID- 22820050 TI - Endogeneity in prison risk classification. AB - Security designation tools are a key feature of all prisons in the United States, intended as objective measures of risk that funnel inmates into security levels to prison environments varying in degree of intrusiveness, restriction, dangerousness, and cost. These tools are mostly (if not all) validated by measuring inmates on a set of characteristics, using scores from summations of that information to assign inmates to prisons of varying security level, and then observing whether inmates assumed more risky did in fact offend more. That approach leaves open the possibility of endogeneity--that the harsher prisons are themselves bringing about higher misconduct and thus biasing coefficients assessing individual risk. The current study assesses this potential bias by following an entry cohort of inmates to more than 100 facilities in the Federal Bureau of Prisons (BOP) and exploiting the substantial variation in classification scores within a given prison that derive from systematic overrides of security-level designations for reasons not associated with risk of misconduct. By estimating pooled models of misconduct along with prison-fixed effects specifications, the data show that a portion of the predictive accuracy thought associated with the risk-designation tool used in BOP was a function of facility-level contamination (endogeneity). PMID- 22820052 TI - Chronic hyperdopaminergic activity of schizophrenia is associated with increased DeltaFosB levels and cdk-5 signaling in the nucleus accumbens. AB - Chronic subcortical hyperdopaminergic activity is associated with the positive symptoms of schizophrenia and is a hallmark feature of a number of animal models of the disorder. However, the molecular changes induced by increased dopaminergic activity associated with schizophrenia are not clear. Increased levels of DeltaFosB have been found in association with chronic subcortical hyperdopaminergic activity following repeated cocaine or amphetamine administration. Therefore, we investigated DeltaFosB signaling in a putative neurodevelopmental animal model of schizophrenia showing chronic subcortical hyperdopaminergic activity. Increased protein levels of the transcription factor DeltaFosB as well as cyclin-dependent kinase-5 (cdk-5), p35, p25 and the GluR2 subunit of the AMPA glutamate receptor were observed in the nucleus accumbens (NA). Cdk-5, p35 and GlurR2 are all proteins regulated by DeltaFosB, while p25 is a degradation product of p35. Increased total protein levels of cdk-5, p35 and p25 resulted in increased cdk-5 kinase activity as determined by increased phosphorylation of dopamine and adenosine regulated phosphoprotein-32 (DARPP32) at Thr(75) in the NA. DARPP32 Thr(75) is selectively phosphorylated by cdk-5 and phosphorylation of DARPP32 at Thr(75) suppresses DARPP32 activity, a critical step in the regulation of both glutamatergic and dopaminergic activity in neurons. We also found that apomorphine-induced locomotor activity was further increased following intra-accumbens infusions of roscovitine, a cdk-5 blocker, in a dose-dependent manner. Our results indicate that chronic hyperdopaminergic activity, as seen in schizophrenia, may affect glutamate and dopamine function in the NA via DeltaFosB-mediated transcriptional modulation. PMID- 22820053 TI - The onion skin-like organization of the septum arises from multiple embryonic origins to form multiple adult neuronal fates. AB - In the past several decades, tremendous progress has been achieved through developmental studies of the central nervous system structures such as the cerebral cortex. The septum, which receives reciprocal connections from a variety of brain structures, contains diverse projection neurons but few interneurons. However, the mechanisms underlying its development remain poorly understood. Here we show that the septum is organized into an onion skin-like structure composed of five groups of neurons. These neurons are parvalbumin, choline acetyltransferase, neuronal nitric oxide synthase, calretinin and calbindin immunoreactive. Using the BrdU birth-dating method, we found that these five groups of neurons in the septum are grossly generated following an outside-in pattern. Interestingly, the distinct molecular identities of these neuronal subtypes correspond to their heterogeneous subpallial origins. Using three specific transgenic mouse lines and focal in utero electroporation of Cre reporter plasmid, we showed that septal neurons originate from not only local progenitor regions but also neighboring progenitor regions including the medial ganglionic eminence and preoptic area. Thus, the neuronal diversity of the septum is achieved through both temporal and spatial control. Our results also suggest that multiple neuronal subtypes arrive to the septum through both radial and tangential migration. Based on these findings, we proposed a novel developmental model involving multiple spatial-temporal origins of septal neurons. This study presents new perspectives for comprehensively exploring septal functions in brain circuits. PMID- 22820051 TI - Optogenetic induction of aversive taste memory. AB - The Drosophila melanogaster gustatory system consists of several neuronal pathways representing diverse taste modalities. The two predominant modalities are a sweet-sensing pathway that mediates attraction, and a bitter-sensing pathway that mediates avoidance. A central question is how flies integrate stimuli from these pathways and generate the appropriate behavioral response. We have developed a novel assay for induction of taste memories. We demonstrate that the gustatory response to fructose is suppressed when followed by the presence of bitter quinine. We employ optogenetic neural activation using infrared laser in combination with heat-sensitive channel - TRPA1 to precisely activate gustatory neurons. This optogenetic system allows for spatially and temporally controlled activation of distinct neural classes in the gustatory circuit. We directly activated bitter-sensing neurons together with presentation of fructose for remote induction of aversive taste memories. Here we report that activation of bitter-sensing neurons in the proboscis suffices as a conditioning stimulus. Spatially restricted stimulation indicates that the conditioning stimulus is indeed a signal from the bitter neurons in the proboscis and it is independent of postingestive feedback. The coincidence of temporally specific activation of bitter-sensing neurons with fructose presentation is crucial for memory formation, establishing aversive taste learning in Drosophila as associative learning. Taken together, this optogenetic system provides a powerful new tool for interrogation of the central brain circuits that mediate memory formation. PMID- 22820054 TI - Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing. AB - BACKGROUND: Left ventricular pacing (LVP) in canine heart alters ventricular activation, leading to reduced transient outward potassium current (I(to)), loss of the epicardial action potential notch, and T-wave vector displacement. These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to I(to), are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in I(to) as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex. OBJECTIVE: To test the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R, and I(to) are prevented by blocking subunit trafficking. METHODS: We used standard electrophysiological, biophysical, and biochemical methods to study 4 groups of dogs: (1) Sham, (2) 2h LVP, (3) LVP + colchicine (microtubule disrupting agent), and (4) LVP + losartan (AT1R blocker). RESULTS: The T-wave vector displacement was significantly greater in LVP than in Sham and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in KChIP2 and AT1R proteins in the membrane fraction after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes, AngII-induced I(to) reduction and loss of action potential notch were blocked by colchicine. CONCLUSIONS: LVP induced reduction of KChIP2 in plasma light membranes depends on an AngII mediated pathway and intact microtubular status. Loss of I(to) and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits. PMID- 22820055 TI - Phantom crosstalk. PMID- 22820056 TI - The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. AB - BACKGROUND: The clinical efficacy of catheter ablation of paroxysmal atrial fibrillation (AF) remains limited by difficulty in achieving durable pulmonary vein isolation (PVI). Suboptimal catheter tip-to-tissue contact force (CF) during lesion delivery is believed to reduce clinical efficacy. OBJECTIVE: To determine the relationship between catheter CF during irrigated catheter ablation for AF and clinical recurrences during follow-up. METHODS: Thirty-two patients with paroxysmal AF underwent PVI by using a radiofrequency ablation catheter with a CF sensor integrated at its tip, and they were followed for 12 months. The relationship between the CF and clinical outcomes was determined. RESULTS: Acute PVI was achieved in 100% of the veins. Thirty-five percent (351 of 1017) of the applications were placed with an average CF of <10 g (low CF). All patients treated with an average CF of <10 g (5 of 5 patients) experienced recurrences, whereas 80% of the patients treated with an average CF of >20 g (8 of 10 patients) were free from AF recurrence at 12 months. The analysis of the average force-time integral showed that 75% of the patients treated with <500 gs were recurrent whereas only 31% of the patients treated with >1000 gs had recurrences at 12 months. CONCLUSIONS: The CF during catheter ablation for AF correlates with clinical outcome. Arrhythmia control is best achieved when ablation lesions are placed with an average CF of >20 g, and clinical failure is universally noted with an average CF of <10 g. PMID- 22820057 TI - A method for rapid dose-response screening of environmental chemicals using human embryonic stem cells. AB - INTRODUCTION: Human embryonic stem cells (hESC) provide an invaluable model for assessing the effects of environmental chemicals and drugs on human prenatal development. However, hESC are difficult to adapt to 96-well plate screening assays, because they survive best when plated as colonies, which are difficult to count and plate accurately. The purpose of this study is to present an experimental method and analysis procedure to accomplish reliable screening of toxicants using hESC. METHODS: We present a method developed to rapidly and easily determine the number of cells in small colonies of hESC spectrophotometerically and then accurately dispense equivalent numbers of cells in 96-well plates. The MTT assay was used to evaluate plating accuracy, and the method was tested using known toxicants. RESULTS: The quality of the plate set-up and analysis procedure was evaluated with NIH plate validation and assessment software. All statistical parameters measured by the software were acceptable, and no drift or edge effects were observed. The 96-well plate MTT assay with hESC was tested by performing a dose-response screen of commercial products, which contain a variety of chemicals. The screen was done using single wells/dose, and the reliability of this method was demonstrated in a subsequent screen of the same products repeated three times. The single and triple screens were in good agreement, and NOAELs and IC(50)s could be determined from the single screen. The effects of vapor from volatile chemicals were studied, and methods to monitor and avoid vapor effects were incorporated into the assay. DISCUSSION: Our method overcomes the difficulty of using hESC for reliable quantitative 96-well plate assays. It enables rapid dose-response screening using equipment that is commonly available in laboratories that culture hESC. This method could have a broad application in studies of environmental chemicals and drugs using hESC as models of prenatal development. PMID- 22820058 TI - Babesia bovis biological clones and the inter-strain allelic diversity of the Bv80 gene support subpopulation selection as a mechanism involved in the attenuation of two virulent isolates. AB - The virulence phenotype of Babesia bovis subpopulations was evaluated using biological clones derived from the high-virulence BboS2P and the low-virulence BboR1A strain and two original virulent isolates, BboL15 and BboL17, multiplied extensively in vitro or attenuated by successive passages in splenectomized calves. The virulence phenotype was assessed both by inoculation of normal Holstein adult steers and by analyses of polymorphic fragments of the single-copy Bv80 gene as a subpopulation marker. BboS2P and its nine derived clones contained a single 750 bp fragment with identical nucleotide sequences and numbers of repeats. A single fragment of approximately 850 bp was observed in BboR1A and its derived clones (Ca3B1, Ca2B1). Ca3B1 and Ca2B1 were differentiated by a stable deletion of 15 contiguous nucleotides in the Bv80 allele of Ca3B1. Both alleles were identified in the parental strain. Original isolates BboL15 and BboL17 contained two Bv80 fragments of different sizes. Interestingly, the heavy and light fragments persisted in the in vivo-attenuated strains and the virulent in vitro-multiplied strains, respectively. Despite the inter-strain allelic diversity of the Bv80 gene, the fragments had identical nucleotide sequences and numbers of repeats compared to their respective parental Bv80 genes. The high virulence and low-virulence phenotypes remained unchanged after they were multiplied in vitro. In conclusion, the polymorphic B. bovis Bv80 gene, was a useful marker for differentiating subpopulations with different phenotypes. The brevity of the procedure to isolate one parasite from the original isolate or strain before in vitro cloning and the fact that the continuous in vitro multiplication did not modify the virulence phenotype of B. bovis clones strongly suggest that the in vivo-attenuated subpopulations existed in the original isolates before they were selected by passages in splenectomized calves. PMID- 22820060 TI - In erosive hand osteoarthritis more inflammatory signs on ultrasound are found than in the rest of hand osteoarthritis. AB - OBJECTIVE: To compare inflammation as assessed by ultrasound between patients with the subset erosive hand osteoarthritis (EOA) versus non-EOA. METHODS: Consecutive hand osteoarthritis (HOA) patients (fulfilling ACR criteria) were included. Eighteen interphalangeal joints were scored on radiographs using the Verbruggen-Veys anatomical phase score; E and R phases were defined as erosive. Patients were assigned to EOA when at least one joint was erosive. Effusion, synovial thickening and power Doppler signal (PDS) were scored with ultrasound on a 4-point scale. Generalised estimated equation analyses were used to compare ultrasound features between EOA and HOA, and to associate ultrasound features with.anatomical phases; OR with 95% CI were calculated with adjustments for patient effects and confounders. RESULTS: Of 55 HOA patients (mean age 61 years, 86% women) 51% had EOA. In 94 erosive joints, synovial thickening, effusion and PDS were found in 13%, 50% and 15%, respectively; in 896 non-erosive joints in 10%, 26% and 8%, respectively. In summated scores of PDS, effusion was higher in EOA than in non-EOA. Effusion and synovial thickening were more frequent in S, J, E and R phases compared to N phase. PDS was only associated with E phase (OR 5.3, 95% CI 1.3 to 20.5) not with other phases. Non-erosive joints in EOA demonstrated more PDS (OR 3.2, 95% CI 1.6 to 6.4) and effusion (OR 2.2, 95% CI 1.2 to 3.8) in comparison to joints in non-EOA. CONCLUSIONS: Inflammatory signs are more frequent in EOA than in non-EOA, not only in erosive joints but also in non erosive joints, suggesting an underlying systemic cause for erosive evolution. PMID- 22820061 TI - Positive parenting of children with developmental disabilities: a meta-analysis. AB - Although a large body of literature exists supporting the relationship between positive parenting and child outcomes for typically developing children, there are reasons to analyze separately the relevant literature specific to children with developmental disabilities. However, that literature has not been synthesized in any systematic review. This study examined the association between positive parenting attributes and outcomes of young children with developmental disabilities through meta-analytic aggregation of effect sizes across 14 studies including 576 participants. The random effects weighted average effect size was r=.22 (SE=.06, p<.001), indicative of a moderate association between positive parenting attributes and child outcomes. Publication bias did not appear to be a substantial threat to the results. There was a trend for studies with more mature parents to have effect sizes of higher magnitude than studies with young parents. The results provide support for efforts to evaluate and promote effective parenting skills when providing services for young children with disabilities. PMID- 22820062 TI - Assisting patients with disabilities to actively perform occupational activities using battery-free wireless mice to control environmental stimulation. AB - The latest studies have adopted software technology to turn the battery-free wireless mouse into a high performance object location detector using a newly developed object location detection program (OLDP). This study extended OLDP functionality to assess whether two patients recovering from cerebral vascular accidents would be able to actively perform occupational activities by controlling their favorite environmental stimulation using battery-free wireless mice and OLDP software. Using an ABAB design we found substantial increases in both participants' target responses (i.e. the performance of occupational activities) to activate the control system to produce environmental stimulation during intervention phrases. The practical and developmental implications of the findings are discussed. PMID- 22820063 TI - What do we know about the atypical development of exploratory actions during infancy? AB - Recent theoretical approaches to infant development have highlighted the importance of exploratory actions to motor, perceptual and cognitive development in infancy. However, the performance of infants exposed to risk factors when exploring objects has been frequently overlooked as a variable of interest. The aim of this study was to review scientific publications investigating the role of developmental risk factors on the development of exploratory actions over objects. Electronic databases (Medline and Science Direct) were searched for papers by using for the following key-words in combination: "exploration", "exploratory", "infants". Eighteen papers were included in the review. The performance of infants exposed to various risk conditions such as prematurity, blindness, Down syndrome, autism and low socioeconomic level have been addressed in the literature. Each risk condition has influenced infants' behaviors in particular ways. Considerations for further research were made based on issues raised by the review that still need to be further understood. PMID- 22820064 TI - Strength and agility training in adolescents with Down syndrome: a randomized controlled trial. AB - The purpose of this study was to investigate the effects of a proposed strength and agility training program of adolescents with Down syndrome. Ninety-two adolescents were recruited and evenly randomized to two intervention groups (exercise group vs. control group). The mean age for the exercise and the control group was 10.6+/-3.2 and 11.2+/-3.5 respectively. The exercise training program consisted of a 5-min treadmill exercise and one 20-min virtual-reality based activity administered three times a week for 6 weeks. Pre- and post-test measures were taken for muscle strength and agility performance. The measured muscle included hip extensor, hip flexor, knee extensor, knee flexors, hip abductors, and ankle plantarflexor. A handheld dynamometer was used to measure the lower extremities muscle strength, and agility performance was assessed by the strength and agility subtests of the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition. The exercise group had significant improvements in agility (p=0.02, d=0.80) and muscle strength of all muscle group (all p's<0.05, d=0.51-0.89) assessed in comparison to the control group after the 6-week intervention. Knee muscle groups including both flexors and extensors had the greatest gains among all the muscles measured. A short-term exercise training program used in this study is capable of improving muscle strength and agility performance of adolescents with DS. PMID- 22820065 TI - The toolbox of vesicle sidedness determination. AB - Vesicles prepared from cellular plasma membranes are widely used in science for different purposes. The outer membrane leaflet differs from the inner membrane leaflet of the vesicle, and during vesicle preparation procedures two types of vesicles will be generated: right-side-out vesicles, of which the outer leaflet is topologically equivalent to the outer monolayer of the cellular plasma membrane, and inside-out vesicles. Because two populations of vesicles exist, sidedness information of the vesicle preparation is indispensable. This note focuses on the ins and outs of sidedness determination of vesicles and compares various methodologies used to establish this ratio. PMID- 22820066 TI - Asymptomatic presence of Nosema spp. in Spanish commercial apiaries. AB - Nosemosis is caused by intracellular parasites (Nosema apis and Nosema ceranae) that infect the midgut epithelial cells in adult honey bees. Recent studies relate N. ceranae to Colony Collapse Disorder and there is some suggestion that Nosema spp., especially N. ceranae, induces high mortality in honey bees, a fact that is considered as a serious threat for colony survival. 604 samples of adult honey bees for Nosema spp. analysis were collected from beekeeping colonies across Spain and were analysed using PCR with capillary electrophoresis. We also monitored 77 Andalusian apiaries for 2 years; the sampled hives were standard healthy colonies, without any special disease symptoms. We found 100% presence of Nosema spp. in some locations, indicating that this parasite was widespread throughout the country. The two year monitoring indicated that 87% of the hives with Nosema spp. remained viable, with normal honey production and biological development during this period of time. The results of these trials indicated that both N. ceranae and N. apis could be present in these beehives without causing disease symptom and that there is no evidence for the replacement of N. apis by N. ceranae, supporting the hypothesis that nosemosis is not the main reason of the collapse and death of beehives. PMID- 22820067 TI - Impact of Nosema (Microsporidia) infection and fumagillin treatment on Lygus lineolaris (Hemiptera: Miridae). AB - A consistent supply of healthy tarnished plant bug, Lygus lineolaris (Palisot de Beauvois) (Hemiptera: Miridae), is necessary for the development of novel management strategies targeting this pest. After being in culture for several years, a substantial portion of a tarnished plant bug colony was found to be infected with a Nosema (Microsporidia) species. Studies were subsequently undertaken to evaluate the impact of Nosema infection on tarnished plant bug productivity and to test the efficacy of fumagillin to treat this infection. Using buffalo black stain, infections could not be reliably detected in adult tarnished plant bugs until adults were 6-8 days post eclosion. Nosema infections reduced adult longevity and fecundity. Maximum fecundity was restored using a concentration of 16.8 ppm fumagillin while maximum longevity for females was at a concentration of 33.6 ppm fumagillin incorporated into the tarnished plant bug diet. Minimum infection scores were obtained at 67.2 ppm, the highest concentration tested. A field survey of tarnished plant bugs in Mississippi found Nosema infections in 3% of wild tarnished plant bugs. PMID- 22820069 TI - The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development. AB - The glycocalyx, and the thicker endothelial surface layer (ESL), are necessary both for endothelial barrier function and for sensing mechanical forces in the adult. The goal of this study is to use a combination of imaging techniques to establish when the glycocalyx and endothelial surface layer form during embryonic development and to determine the biological significance of the glycocalyx layer during vascular development in quail embryos. Using transmission electron microscopy, we show that the glycocalyx layer is present as soon as blood flow starts (14 somites). The early endothelial glycocalyx (14 somites) lacks the distinct hair-like morphology that is present later in development (17 and 25 somites). The average thickness does not change significantly (14 somites, 182 nm +/- 33 nm; 17 somites, 218 +/- 30 nm; 25 somites, 212 +/- 32 nm). The trapping of circulating fluorescent albumin was used to evaluate the development of the ESL. Trapped fluorescent albumin was first observed at 25 somites. In order to assess a functional role for the glycocalyx during development, we selectively degraded luminal glycosaminoglycans. Degradation of hyaluronan compromised endothelial barrier function and prevented vascular remodeling. Degradation of heparan sulfate down regulated the expression of shear-sensitive genes but does not inhibit vascular remodeling. Our findings show that the glycocalyx layer is present as soon as blood flow starts (14 somites). Selective degradations of major glycocalyx components were shown to inhibit normal vascular development, examined through morphology, vascular barrier function, and gene expression. PMID- 22820068 TI - Non-muscle myosin IIB is essential for cytokinesis during male meiotic cell divisions. AB - Cytokinesis, the final stage of cell division, bisects the cytoplasm into two daughter cells. In mitotic cells, this process depends on the activity of non muscle myosin II (NMII), a family of actin-binding motor-proteins that participate in the formation of the cleavage furrow. The relevance of NMII for meiotic cell division, however, is poorly understood. The NMII family consists of three members, NMIIA, NMIIB, and NMIIC, containing different myosin heavy chains (MYH9, MYH10, and MYH14, respectively). We find that a single non-muscle myosin II, NMIIB, is required for meiotic cytokinesis in male but not female mice. Specifically, NMIIB-deficient spermatocytes exhibit cytokinetic failure in meiosis I, resulting in bi-nucleated secondary spermatocytes. Additionally, cytokinetic failure at meiosis II gives rise to bi-nucleated or even tetra nucleated spermatids. These multi-nucleated spermatids fail to undergo normal differentiation, leading to male infertility. In spite of the presence of multiple non-muscle myosin II isoforms, we demonstrate that a single member, NMIIB, plays an essential and non-redundant role in cytokinesis during meiotic cell divisions of the male germline. PMID- 22820070 TI - Chromatin associated Sin3A is essential for male germ cell lineage in the mouse. AB - Spermatogenesis is a complex process that requires coordinated proliferation and differentiation of male germ cells. The molecular events that dictate this process are largely unknown, but are likely to involve highly regulated transcriptional control. In this study, we investigate the contribution of chromatin associated Sin3A in mouse germ cell lineage development. Genetic inactivation of Sin3A in the male germline leads to sterility that results from the early and penetrant apoptotic death observed in Sin3A-deleted germ cells, coincident with the reentry in mitosis. Sin3A-deleted testes exhibit a Sertoli cell only phenotype, consistent with the absolute requirement for Sin3A in germ cells' development and/or viability. Interestingly, transcripts analysis revealed that the expression program of Sertoli cells is altered upon inactivation of Sin3A in germ cells. These studies identified a central role for the mammalian Sin3-HDAC complex in the germ cell lineage, and point to an exquisite transcriptional crosstalk between germ cells and their niche to support fertility in mammals. PMID- 22820071 TI - Purification and concentration of mycobacteriophage D29 using monolithic chromatographic columns. AB - Bacteriophages are used widely in many fields, and phages with high purity and infectivity are required. Convective interaction media (CIM) methacrylate monoliths were used for the purification of mycobacteriophage D29. The lytic phages D29 from bacterial lysate were purified primarily by polyethylene glycol 8000 or ammonium sulphate, and then the resulting phages were passed through the CIM monolithic columns for further purification. After the whole purification process, more than 99% of the total proteins were removed irrespective which primary purification method was used. The total recovery rates of viable phages were around 10-30%. Comparable results were obtained when the purification method was scaled-up from a 0.34 mL CIM DEAE (diethylamine) monolithic disk to an 8 mL CIM DEAE monolithic column. PMID- 22820072 TI - Development of a high throughput, semi-automated, infectious center cell-based ELISA for equine infectious anemia virus. AB - A faster semi-automated 96-well microtiter plate assay to determine viral infectivity titers, or viral focal units (vfu), of equine infectious anemia virus (EIAV) stocks is described. Optimization of the existing method modernizes a classic virological technique for viral titer determination by quantitating EIAV in experimentally infected cells via a cell-based ELISA. To allow for automation, multiple parameters of the current assay procedures were modified resulting in an assay that required only one quarter the original amount of virus and/or serum for infectivity or neutralization assays, respectively. Equivalent reductions in the required volumes of tissue culture, cell processing, and protein detection reagents were also achieved. Additionally, the new assay decreased the time required from start to finish from 10 days to 6 days (viral titer) or 7 days (viral neutralization), while increasing the number of samples that can be processed concurrently by transition to a 96-well microtiter plate format and by automated counting. PMID- 22820073 TI - Detection of avian group D rotavirus using the polymerase chain reaction for the VP6 gene. AB - Group D rotaviruses (RVs-D) have been documented in birds and, while they may be common in these animals, few molecular studies are available for this specific group. In this study, specific primers for the gene that encodes for the RVs-D VP6 protein were designed and used in a reverse transcription polymerase chain reaction (RT-PCR). Thirty pools of samples were tested by polyacrylamide gel electrophoresis (PAGE) yielding a 30% (9/30) positivity. These pools were subjected subsequently to RT-PCR, with a 53% (16/30) positivity rate. The sensitivity of the PCR assay was demonstrated up to a dilution of 5 * 10( 4)ng/MUL (0.5 pg/MUL) of the cloned VP6 gene. The four samples were sequenced and showed 90.8-91.1% similarity with regards to the RVs-D VP6 gene. To assess for specificity our RT-PCR was applied to nine samples known to contain enteric viral agents other than group D rotaviruses including picobirnavirus, rotavirus group A, and reovirus with negative results. Overall, the data confirm the specificity of the primers used for detecting the RVs-D by RT-PCR, suggesting that this assay can be used for diagnostic purposes. PMID- 22820074 TI - Comparison of ELISA attachment and infectivity assays for murine norovirus. AB - Human noroviruses cause approximately 58% of foodborne illnesses in the USA. Recent studies have shown norovirus attachment to the carbohydrates moieties of host cellular receptors. Using murine norovirus (MNV) as a surrogate, an ELISA method was utilized to assess attachment through binding to host cell receptors; MNV attachment was correlated to infectivity determined by plaque assay. ELISA plates were coated with porcine gastric mucin and untreated, heat-, high pressure , ozone- and UV-treated MNV was added followed by monoclonal anti-MNV IgG antibody. The average OD(405) of MNV-containing wells were divided by negative control wells and expressed as the 'P/N ratio'; values >=2 were considered positive. Infectivity of MNV following heat and HPP treatments was determined using the plaque assay. Heat-treated MNV attachment decreased significantly with decreasing viral infectivity whereby the P/N ratio was <2 after treatment at 80 and 100 degrees C for 5 min which correlated with a non-intact capsid as shown by RNase treatment. No significant difference in attachment was observed for pressure-, ozone- and UV-treated MNV. These findings suggest potentially different effects on the viral capsid due to different food processing methods. PMID- 22820075 TI - Analytical performance of RNA isolated from BD SurePathTM cervical cytology specimens by the PreTectTM HPV-Proofer assay. AB - Several commercial HPV ancillary tests are available for detection of E6/E7 RNA. It is not clear how storage of a cervical Pap affects the analytical and clinical performance of the PreTectTM HPV-Proofer assay. To investigate the qualitative performance of RNA extracted from BD SurePathTM liquid-based cytology (LBC) specimens for the detection of human papillomavirus (HPV) E6/E7 mRNA using the PreTectTM HPV-Proofer assay, studies including stability, reproducibility, residual specimen analysis, and storage medium comparison assays were performed. Cervical cytology specimens were collected and stored in BD SurePathTM LBC preservative fluid and/or PreTectTM Transport Media. RNA was isolated using the RecoverAllTM Total Nucleic Acid Isolation kit and RNA integrity was evaluated in the PreTectTM HPV-Proofer assay. The performance of RNA isolated from cervical cells collected and stored in BD SurePathTM LBC preservative fluid or PreTectTM Transport Media was also evaluated through a storage medium comparison study. The RNA was found to be stable for a minimum of 21 days when stored at ambient temperature and displayed high reproducibility with the mean percentage reproducibility ranging from 90.5% to 100% for the HPV types detected by the PreTectTM HPV-Proofer assay. The prevalence rate of HPV types in this study cohort was consistent with published reports. A 93.7% first pass acceptance rate was demonstrated across all cytology grades. The positive human U1 snRNP specific A protein (U1A) and HPV rate for BD SurePathTM LBC and PreTectTM Transport Media specimens was statistically equivalent for both normal and abnormal specimens. This data support the use of RNA isolated from BD SurePathTM LBC for ancillary HPV testing and demonstrates the feasibility of using BD SurePathTM preservative fluid as a specimen type with the PreTectTM HPV-Proofer assay. PMID- 22820076 TI - Loop-mediated isothermal amplification for rapid detection of the causal agents of cassava brown streak disease. AB - The causal agents of cassava brown streak disease have recently been identified as Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Primers have been developed for rapid detection of these viruses by reverse transcription loop-mediated isothermal amplification (RT-LAMP). Performance of the RT-LAMP assays compared favourably with published RT-PCR and real-time RT-PCR methods. Furthermore, amplification by RT-LAMP is completed in 40 min and does not require thermal cycling equipment. Modification of the RT LAMP reactions to use labelled primers allowed rapid detection of amplification products using lateral flow devices containing antibodies specific to the incorporated labels, avoiding the need for fluorescence detection or gel electrophoresis. PMID- 22820077 TI - Longitudinal change in active and sedentary behavior during the after-school hour. AB - BACKGROUND: Relatively little is known regarding after-school behavior. This study examined after-school active and sedentary behaviors among youth participating in the Study of Early Child Care and Youth Development. METHODS: An interview guided time-use approach was used to obtain detailed longitudinal information about after-school (3-6 PM) behavior of a mixed gender cohort (n = 886) at ages 9 and 11 yrs. Responses obtained in 15-min intervals were coded into 29 exclusive behaviors and separated into 3 main categories [moderate and vigorous-intensity physical activity (MVPA), light-intensity physical activity, and sedentary]. Sedentary category was further divided into screen and nonscreen categories. A mixed ANOVA design was used to examine gender and age-related differences in MVPA, light-intensity physical activity, sedentary, screen, and nonscreen. RESULTS: MVPA was higher among boys compared with girls (P < .001) and decreased from 9 to 11 yrs (P < .001). Overall, total sedentary time was comparable between boys and girls despite a difference in reported screen time (boys > girls; P < .001) and nonscreen time (boys < girls; P < .001). Total sedentary time increased from 9 to 11 yrs (P < .001). CONCLUSION: Engagement in after-school behavior appears to change during preadolescence. Additional research is needed to understand factors associated with the selection of active and sedentary behavior over time. PMID- 22820078 TI - Prenatal diagnosis of an atypical 1q21.1 microdeletion and duplication associated with foetal urogenital abnormalities. PMID- 22820079 TI - Novel mutations in the MNX1 gene in two families with Currarino syndrome and variable phenotype. AB - The Currarino syndrome (CS) consists of a sacral defect, an anorectal malformation and a pre-sacral mass. It manifests as an autosomal dominant congenital malformation in familial settings, with varying penetrance. The disease-causing gene, Motor neuron and pancreas homeobox-1 (MNX1), is known to be mutated in almost all familial cases, but due to the lack of genotype-phenotype correlation, there is a need for better clinical and molecular genetic characterization of the CS. Here, we report two novel mutations in the MNX1 gene in two cases. Each case was found to be familial upon further investigation of the other members of each family. The first affected case (a one year old boy) exhibited a missense mutation, p.Phe289Ser, in exon 3 in the highly conserved third helix of the homeodomain, which is considered to affect the DNA binding property and transcription regulation of the protein. The mutation seemed to display full penetrance of the disease in this family, but with different time of on-set. The second affected case (a 5 months old boy) displayed a 13 basepair insertion in exon 1, creating a complex frameshift mutation which results in a premature truncation of the protein that lacks the third helix homeodomain. Other members of the boy's family, who harbored the same mutation, were found to be completely asymptomatic. In conclusion, we detected two novel mutations in the MNX1 gene in cases with CS, which supports mutational analysis in the diagnosis of CS, even though the variability in the genotype and phenotype correlation maintains. PMID- 22820080 TI - Association of prion protein expression with pancreatic adenocarcinoma survival in the SEER residual tissue repository. AB - Pancreatic ductal adenocarcinoma (PDAC) is an important cause of cancer death with no clear prognostic biomarker. Expression of prion (PrP) has been reported to be a marker of poor prognosis in a series of Caucasian PDAC cases. We determined the prognostic value of PrP in a racially and geographically diverse population-based series of PDAC cases. PrP expression was examined in 142 PDAC cases from three cancer registries. Cases included 71 Caucasian, 54 Asian/Pacific Islanders and 17 Blacks diagnosed from 1983-2000, and followed through 2008. Hazard ratios (HR) and 95% confidence intervals (CIs) for the association of PrP expression with survival were computed after adjustment for case attributes. The risk of death was about four times higher (HR=3.8; 95% PDAC cases with PrP(+) tumors (median survival 5 months) compared to the 34 cases with PrP(-) tumors (median survival 20 months). Of 51 cases with resected, localized PDAC median survival was 74 months for 17 cases with PrP(-) tumors versus 14 months for 34 cases with PrP(+) tumors (HR=6.7; 95% CI: 2.6, 17.4). All 6 surviving cases had PrP(-) negative tumors (median survival, > 10 years). PrP may have potential as a prognostic biomarker in PDAC patient management. PMID- 22820081 TI - The mutational spectrum of HRAS, KRAS, NRAS and FGFR3 genes in bladder cancer. AB - Bladder cancer is one of the most common cancers worldwide. A number of genetic and epigenetic alterations have been identified in bladder tumorigenesis, including activating mutations in fibroblast growth factor receptor 3 (FGFR3) and RAS family genes. In this study, we have analysed the mutational spectrum of FGFR3 and RAS genes (HRAS, NRAS and KRAS). We have also studied the relationship between mutations. A total of 234 patients with different stages and grades were included in the present study (58 superficial low-grade, 53 superficial high grade and 123 muscle-invasive tumours). Mutations in exons 1 and 2 of HRAS, KRAS and NRAS genes were screened by PCR and direct sequencing. The hot spot mutations in exons 7, 10 and 15 of the FGFR3 oncogene were studied by multiplex PCR and the SNaP-shot protocol. Overall, 8.97% (21/234) of samples were mutant for one of the RAS genes. Among these mutations 47.61% were detected in KRAS, 33.33% in HRAS and only 19.04% most frequent RAS mutations were KRAS p.G12C and p.G12D. The correlation between RAS mutations and tumour subgroups does not report a statistical significant association (p=0.876). The FGFR3 mutations were detected in 31.19% (73/234) of bladder tumours and were associated with low stages and grades. The study of relationship between RAS and FGFR3 genes revealed that FGFR3 mutations were mutually exclusive with RAS ones (p=10(-4)). In conclusion we retain that activated RAS and FGFR3 do not appear to be drivers in bladder cancer but the mutually exclusive relationship between RAS and FGFR3 mutations indicates a possible clonal advantage of modified signaling via a common pathway. PMID- 22820082 TI - Myeloperoxidase and free iron levels: potential biomarkers for early detection and prognosis of ovarian cancer. AB - OBJECTIVE: The study sought to identify whether a relationship exists between serum myeloperoxidase (MPO) and free iron with stages of ovarian cancer. METHODS: Serum and tissue samples were collected from women with stages I through IV ovarian cancer, benign gynecologic conditions, inflammation, and healthy controls. Myeloperoxidase ELISA and VITROS Fe Slide assays were used to measure serum and tissue MPO and free iron levels, respectively. Data were analyzed with a one-way ANOVA with post-hoc comparisons (p < 0.05 considered significant). RESULTS: There was a significant increase in the level of free iron in serum and tissues obtained from stages II-IV as compared to early-stage (stage I) ovarian cancer. There was an overlap between early-stage and inflammation serum MPO levels, however serum free iron levels were significantly higher in early-stage. There was no significant change in serum free iron levels between non-cancer groups. In contrast, there was a significant increase in serum free iron levels in early-stage as compared to non-cancer groups. CONCLUSIONS: Collectively, these findings clearly indicate a role for the combination of serum MPO and free iron as biomarkers for early detection and prognosis of ovarian cancer. PMID- 22820083 TI - Concurrent alteration of p16 and PTEN tumor suppressor genes could be considered as potential molecular marker for specific subgroups of NSCLC patients. AB - p16 and PTEN are tumor suppressors that are commonly inactivated in human cancers. Loss of each of these molecules is widely studied in lung cancer, including non-small cell lung carcinoma (NSCLC), its most common clinical form. However, the importance of their mutual alterations for NSCLC pathogenesis has been barely examined so far. In this study we tested hypothesis that aberrant p16 might cooperate with inactive PTEN during pathogenesis of NSCLC, particularly in promoting tumor aggressiveness and invasiveness. Initially, we screened NSCLC tumor samples from patients for the presence of the most common genetic and epigenetic alterations of p16 and further correlated them with previously detected aberrations in PTEN gene. Statistical analyses showed that aberrant p16 directly correlated with altered PTEN. Such significant correlation was also observed in groups of patients with high genomic instability, with squamocellular histological subtype, with disease grade 2 and with lymph node invasion. Finally, survival analyses revealed dramatic decrease in survival rate of patients with mutual alterations of p16 and PTEN, but without prognostic significance. Overall results implicate cooperation between aberrant p16 and PTEN in pathogenesis of NSCLC and suggest that their combination might be considered as potential molecular marker for specific subgroups of NSCLC patients. PMID- 22820084 TI - Plasma biomarkers correlating with clinical outcome in a phase II study of sorafenib in advanced NSCLC. AB - We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed/refractory advanced non-small cell lung cancer (NSCLC) treated with 400~mg bid sorafenib in a phase II trial. Blood samples were collected at baseline, on day 15 of cycle 1 (C1D15), and on day 1 of cycle 3 (C3D1), and plasma concentrations of total VEGF, VEGF-165, soluble (s) VEGFR-2, PDGF-BB, sPDGFR-beta, sEGFR, sHER-2, uPA, PAI-1, uPAR, TIMP 1, and circulating Ras p21 were assayed by ELISA. Elevated baseline VEGF, VEGF 165, PDGF-BB, Ras p21, and TIMP-1 concentrations were associated with poorer patient outcomes (shorter overall survival [OS] and/or progression-free survival [PFS]). During treatment, the mean concentrations of sVEGFR-2, PDGF-BB, sPDGFR beta, TIMP-1, uPAR, and PAI-1 decreased, while the mean sEGFR concentration increased. Increases in VEGF, VEGF-165, PDGF-BB, and TIMP-1 during treatment were associated with better outcomes (longer OS and/or PFS), whereas increases in plasma Ras p21 during treatment were associated with shorter PFS. The associations between baseline concentrations and/or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and/or predict the efficacy of sorafenib in patients with NSCLC. PMID- 22820086 TI - Hypoxic and normoxic in vitro cultures maintain similar numbers of long-term reconstituting hematopoietic stem cells from mouse bone marrow. PMID- 22820087 TI - Built environment associations with health behaviors among hispanics. AB - BACKGROUND: Few studies of the built environment and physical activity or other health behaviors have examined minority populations specifically. The purpose of this study was to examine associations between the built environment and multiple health behaviors and outcomes among Hispanic adults. METHODS: Community partners distributed surveys (n = 189) in 3 communities in southwest Kansas. Logistic regression was used to examine relationships between neighborhood perceptions and 4 outcomes. RESULTS: Meeting physical activity recommendations was associated with the presence of sidewalks and a safe park, and inversely related to higher crime. Residential density and shops nearby were related to active commuting. Sedentary behavior was inversely related to having a bus stop, bike facilities, safe park, interesting things to look at, and seeing people active. Finally, seeing people active was positively associated with being overweight. CONCLUSIONS: This study suggests that among Hispanics, many built environment variables are related to health behaviors and should be targets for future neighborhood change efforts and research. PMID- 22820088 TI - Subgenotype D5, BCP and MHR mutations in hepatic complications among hepatitis B virus infected patients from Orissa, India. AB - The study was undertaken to investigate the clinical implications of hepatitis B virus (HBV) genotypes, basal core promoter (BCP), precore (PC) and surface gene mutations in HBV infected patients from Orissa, southeastern India. HBV infections were identified by serology testing and HBV DNA amplification by polymerase chain reaction among the 152 patients. After sequencing, surface gene mutation were studied by sequence analysis as well as by using BLOSUM scores and BCP mutations were studied only by sequence analysis. A high proportion of HBV/D5 (66.0%) was found among the study samples having significant relation with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients (p<0.05). The BCP mutation, TA (81.4%) and C1753/TA (75.0%) was found in significant proportion (p<0.05) among HCC cases and in fact a gradual increase in these mutations were noted between inactive carriers (IC) to HCC group and also showed higher viral load. An increasing trend of major hydrophilic region (MHR) mutations in S gene was also observed from IC (56.0%) to chronic liver disease (CLD) (60.4%) to LC (72.4%) to HCC (95.0%) patients. In conclusion, our study suggests that the predominant HBV subgenotype HBV/D5 with high viral load and BCP mutations (double and triple) and high mutations in MHR region was significantly associated with advanced liver disease (LC and HCC) and might act as predictor of severe hepatic complications. PMID- 22820089 TI - Sparse regularized discriminant analysis with application to microarrays. AB - For cancer prediction using large-scale gene expression data, it often helps to incorporate gene interactions in the model. However it is not straightforward to simultaneously select important genes while modeling gene interactions. Some heuristic approaches have been proposed in the literature. In this paper, we study a unified modeling approach based on the l(1) penalized likelihood estimation that can simultaneously select important genes and model gene interactions. We will illustrate its competitive performance through simulation studies and applications to public microarray data. PMID- 22820090 TI - Development and characterization of colloidal soft nano-carriers for transdermal delivery and bioavailability enhancement of an angiotensin II receptor blocker. AB - The purpose of this study was to develop and characterize a successful colloidal soft nano-carrier viz. microemulsion system, for the transdermal delivery of an angiotensin II receptor blocker: olmesartan medoxomil. Different microemulsion formulations were prepared. The microemulsions were characterized visually, with the polarizing microscope, and by photon correlation spectroscopy. In addition, the pH and conductivity (sigma) of the formulations were measured. The type and structure of microemulsions formed were determined using conductivity measurements analysis, Freezing Differential Scanning Calorimetry (FDSC) and Diffusion-Ordered Spectroscopy (DOSY). Alterations in the molecular conformations of porcine skin were determined using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) biophysical assessment. Olmesartan medoxomil delivery from the investigated formulations was assessed across porcine skin ex vivo using Franz diffusion cells; the drug was analyzed by liquid chromatography mass spectroscopy (LC/MS/MS). A comparative pharmacokinetic study was done on healthy human subjects between the selected microemulsion and the commercial oral tablets. The physico-chemical and spectroscopic methods revealed the presence of water-in-oil and bicontinuous structures. Biophysical assessment demonstrated various stratum corneum (SC) changes. Olmesartan medoxomil was delivered successfully across the skin with flux achieving 3.65MUgcm(-2)h(-1). Higher bioavailability compared to commercial oral tablets with a more sustainment behavior was achieved. PMID- 22820091 TI - Identification of neurons specifically activated after recall of context fear conditioning. AB - The learning of new information and recall of that information presumably involves modification of and access to shared circuitry in the brain. However, learning and recall may involve the activation of distinct parts of that circuitry, according to the quite distinct functional differences between these two processes. Previously we examined neuronal activation following learning of context fear conditioning. Using the Fos-Tau-LacZ (FTL) transgenic mouse to label activated neurons, we identified a number of distinct populations of neurons in amygdala and hypothalamus which showed learning specific activation. These populations of neurons showed much less activation following recall. Here we ask what populations of neurons might be specifically activated following recall. We trained mice in context fear conditioning, and then looked at FTL activation following recall of context fear. We identified a number of populations of neurons which showed recall specific activation in nucleus accumbens shell, the anterio-medial bed nucleus of stria terminalis, the anterior commissural nucleus and the periventricular hypothalamic nucleus. These were all different populations of neurons compared with those activated following context fear learning. These different functional activation patterns occurring between learning and recall may reflect the different brain functions occurring between these two memory related processes. PMID- 22820093 TI - Peptide linkage to the alpha-subunit of MHCII creates a stably inverted antigen presentation complex. AB - Class II proteins of the major histocompatibility complex (MHCII) typically present exogenous antigenic peptides to cognate T cell receptors of CD4-T lymphocytes. The exact conformation of peptide-MHCII complexes (pMHCII) can vary depending on the length, register and orientation of the bound peptide. We have recently found the self-peptide CLIP (class-II-associated invariant chain-derived peptide) to adopt a dynamic bidirectional binding mode with regard to the human MHCII HLA-DR1 (HLA, human leukocyte antigen). We suggested that inversely bound peptides could activate specific T cell clones in the context of autoimmunity. As a first step to prove this hypothesis, pMHC complexes restricted to either the canonical or the inverted peptide orientation have to be constructed. Here, we show that genetically encoded linkage of CLIP and two other antigenic peptides to the HLA-DR1 alpha-chain results in stable complexes with inversely bound ligands. Two-dimensional NMR and biophysical analyses indicate that the CLIP-bound pMHC(inv) complex (pMHC(inv), inverted MHCII-peptide complex) displays high thermodynamic stability but still allows for the exchange against higher-affinity viral antigen. Complemented by comparable data on a corresponding beta-chain fused canonical HLA-DR1/CLIP complex, we further show that linkage of CLIP leads to a binding mode exactly the same as that of the corresponding unlinked constructs. We suggest that our approach constitutes a general strategy to create pMHC(inv) complexes. Such engineering is needed to create orientation-specific antibodies and raise T cells to study phenomena of autoimmunity caused by isomeric pMHCs. PMID- 22820092 TI - The primary and secondary translocase activities within E. coli RecBC helicase are tightly coupled to ATP hydrolysis by the RecB motor. AB - Escherichia coli RecBC, a rapid and processive DNA helicase with only a single ATPase motor (RecB), possesses two distinct single-stranded DNA (ssDNA) translocase activities that can operate on each strand of an unwound duplex DNA. Using a transient kinetic assay to detect phosphate release, we show that RecBC hydrolyzes the same amount of ATP when translocating along ssDNA using only its primary translocase (0.81+/-0.05ATP/nt), only its secondary translocase (1.12+/ 0.06ATP/nt), or both translocases simultaneously (1.07+/-0.09ATP/nt). A mutation within RecB (Y803H) that slows the primary translocation rate of RecBC also slows the secondary translocation rate to the same extent. These results indicate that the ATPase activity of the single RecB motor drives both the primary and secondary RecBC translocases in a tightly coupled reaction. We further show that RecBC also hydrolyzes the same amount of ATP (0.95+/-0.08ATP/bp) while processively unwinding duplex DNA, suggesting that the large majority, possibly all, of the ATP hydrolyzed by RecBC during DNA unwinding is used to fuel ssDNA translocation rather than to facilitate base pair melting. A model for DNA unwinding is proposed based on these observations. PMID- 22820094 TI - Strontium signaling: molecular mechanisms and therapeutic implications in osteoporosis. AB - Osteoporosis is an important age-related bone disease characterized by increased bone turnover with insufficient bone formation relative to bone resorption. According to the current understanding of this disorder, anti-resorptive and anabolic drugs have been developed for therapeutic intervention. Another therapeutic approach consists of dissociating bone resorption and formation. Preclinical and clinical studies provided evidence that strontium (in the form of ranelate) induces beneficial effects on bone mass and resistance in animal models of bone loss and in osteoporotic patients. These effects are mediated in part by the pharmacological actions of strontium on bone metabolism, by reducing bone resorption and maintaining or increasing bone formation. Current pharmacological studies showed that strontium activates multiple signaling pathways in bone cells to achieve its pharmacological actions. Notably, activation of the calcium sensing receptor by strontium in osteoclasts or osteoblasts leads to activation of phospholipase Cbeta, inositol 1,4,5-triphosphate, release of intracellular Ca2+, and activation of MAPK ERK1/2 and Wnt/NFATc signaling. Strontium-mediated activation of these pathways results in the modulation of key molecules such as RANKL and OPG that control bone resorption, and to the regulation of genes promoting osteoblastic cell replication, differentiation and survival. This review focuses on the more recent knowledge of strontium signaling in bone cells and describes how the resulting pharmacological actions on bone metabolism have important therapeutic implications in the treatment of age-related bone loss and possibly other disorders. PMID- 22820096 TI - Virological evidence supporting the use of raltegravir in HIV post-exposure prophylaxis regimens. AB - BACKGROUND: The goal of post-exposure prophylaxis (PEP) for HIV is to prevent the establishment of a persistent infection following exposure to the virus. Integrase inhibitors have several potential advantages in PEP regimens, including the capacity to inhibit integration of HIV genomes that have already proceeded through reverse transcription, thereby becoming refractory to reverse transcriptase inhibitors. We sought to determine if integrase inhibitors extend the window of time during which PEP intervention might be successful. METHODS: Primary costimulated CD4(+) T-cells or macrophages were infected with a luciferase-bearing HIV reporter virus, permitting sensitive detection of viral gene expression under different drug treatment conditions. Relevant antiretroviral agents were added at various pre- or post-infection time points. RESULTS: We showed that raltegravir effectively blocks HIV infection, even when cells are challenged with a large amount of virus. We also demonstrated that during infection of both primary costimulated CD4(+) T-cells and primary macrophages, raltegravir can inhibit infection when added at later post-infection time points than the reverse transcriptase inhibitor efavirenz. CONCLUSIONS: This longer post-infection efficacy window, coupled with favourable pharmacokinetic properties and low toxicity, suggest that raltegravir may prove useful in HIV PEP. PMID- 22820097 TI - Recombinant antibody mixtures: production strategies and cost considerations. AB - Recombinant monoclonal antibodies have during the last two decades emerged as a very successful class of biological drugs for the treatment of a variety of different diseases used either as biological mono therapy or in combination with small molecule based drugs. Recombinant antibody mixtures offering targeting of more than one antigen is one of the new promising antibody technologies resulting in higher therapeutic effectiveness and/or broader reactivity. Such recombinant antibody mixtures can in principle be manufactured by different approaches but two main strategies is often applied, either individual manufacturing of the constituent antibodies or single batch manufacturing of the recombinant antibody mixture. Symphogen has developed an expression platform, SympressTM, allowing single batch manufacturing of recombinant antibody mixtures, while other companies are currently using a manufacturing strategy based on production of the individual constituent monoclonal antibodies. An overview and comparison of the different approaches with focus on the challenges in terms of cell banking strategy, manufacturing approach, and strategies for release and characterization will be reviewed in the present manuscript. Furthermore, the two manufacturing approaches are compared based on different parameters such as development timelines, preclinical developmental costs, and manufacturing cost of goods sold (COGS). We conclude that the single batch manufacturing approach expressing a mixture of full length IgG provides a robust and reproducible platform that can be used for cost effective manufacturing of recombinant antibody mixtures. PMID- 22820098 TI - Influence of main channel structure on H(2)O(2) access to the heme cavity of catalase KatE of Escherichia coli. AB - The main channel for H(2)O(2) access to the heme cavity in large subunit catalases is twice as long as in small subunit catalases and is divided into two distinct parts. Like small subunit catalases, the 15A of the channel adjacent to the heme has a predominantly hydrophobic surface with only weak water occupancy, but the next 15A extending to the protein surface is hydrophilic and contains a complex water matrix in multiple passages. At the approximate junction of these two sections are a conserved serine and glutamate that are hydrogen bonded and associated with H(2)O(2) in inactive variants. Mutation of these residues changed the dimensions of the channel, both enlarging and constricting it, and also changed the solvent occupancy in the hydrophobic, inner section of the main channel. Despite these structural changes and the prominent location of the residues in the channel, the variants exhibited less than a 2-fold change in the k(cat) and apparent K(M) kinetic constants. These results reflect the importance of the complex multi-passage structure of the main channel. Surprisingly, mutation of either the serine or glutamate to an aliphatic side chain interfered with heme oxidation to heme d. PMID- 22820099 TI - Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling. AB - Osteosarcoma is a common malignant bone tumor. Cisplatin (CDDP) achieves a high response rate in osteosarcoma. However, osteosarcoma usually exhibits cisplatin resistance. Many members of receptor tyrosine kinases (RTKs)(1) have been demonstrated to be overexpressed and constitutively activated in various tumors including osteosarcoma, resulting in malignant progression and insensitivity to chemotherapy. Hepatocyte growth factor receptor (HGFR/c-Met) also appears overexpressed and activated in osteosarcoma cells. Nevertheless, which role of c Met activation in cisplatin efficacy against osteosarcoma cells remains still elusive. This study found that inhibition of c-Met activity by PHA-665752 or blockade of the interaction of autocrined HGF with c-Met with neutralizing anti HGF antibody promoted cisplatin efficacy in osteosarcoma cells, while addition of recombinant human HGF (rh-HGF) counteracts cisplatin cytotoxicity. Specifically, we demonstrated that inhibition of c-Met activity led to suppression of the PI3K Akt pathway, thus enhancing cisplatin chemosensitivity. Our study clearly suggests that inhibition of c-Met activity can effectively sensitize osteosarcoma cells to cisplatin via suppression of the PI3K-Akt signaling. PMID- 22820100 TI - Mechanism of resistance to cetuximab therapy in colorectal cancer: Possible role of antibodies to immunoglobulin allotypes. PMID- 22820101 TI - Mullerian adenosarcoma arising in a subserosal adenomyoma. AB - Mullerian adenosarcomas most commonly arise in the uterine corpus from the eutopic endometrium. Occasionally, they arise in the cervix, vagina, broad and round ligaments, and ovaries and rarely in extragenital sites, usually in association with endometriosis. The authors report a rare case of extraendometrial, intramural adenosarcoma of low grade arising from a subserosal adenomyoma in a 46-year-old woman who presented with vaginal bleeding. No evidence of eutopic endometrial origin was identified; the adenosarcoma showed only limited myometrial invasion and no serosal involvement. Because of its subserosal location, the tumor would be overstaged as IC (deeply myoinvasive) in the new FIGO staging system. Stage IC tumors would normally be considered for adjuvant treatment, which would be inappropriate in this case. To avoid overstaging and inappropriate treatment, it is important to recognize that adenosarcoma can, rarely, arise in adenomyomas (or adenomyosis). PMID- 22820095 TI - Low-density lipoprotein receptor-related protein 1: a physiological Abeta homeostatic mechanism with multiple therapeutic opportunities. AB - Low-density lipoprotein receptor-related protein-1 (LRP1) is the main cell surface receptor involved in brain and systemic clearance of the Alzheimer's disease (AD) toxin amyloid-beta (Abeta). In plasma, a soluble form of LRP1 (sLRP1) is the major transport protein for peripheral Abeta. LRP1 in brain endothelium and mural cells mediates Abeta efflux from brain by providing a transport mechanism for Abeta across the blood-brain barrier (BBB). sLRP1 maintains a plasma 'sink' activity for Abeta through binding of peripheral Abeta which in turn inhibits re-entry of free plasma Abeta into the brain. LRP1 in the liver mediates systemic clearance of Abeta. In AD, LRP1 expression at the BBB is reduced and Abeta binding to circulating sLRP1 is compromised by oxidation. Cell surface LRP1 and circulating sLRP1 represent druggable targets which can be therapeutically modified to restore the physiological mechanisms of brain Abeta homeostasis. In this review, we discuss how increasing LRP1 expression at the BBB and liver with lifestyle changes, statins, plant-based active principles and/or gene therapy on one hand, and how replacing dysfunctional plasma sLRP1 on the other regulate Abeta clearance from brain ultimately controlling the onset and/or progression of AD. PMID- 22820102 TI - Contemporary imaging of normal mitral valve anatomy and function. AB - PURPOSE OF REVIEW: Mitral valve disease is highly prevalent. Accurate characterization of normal anatomy and function of the mitral valve is crucial to understand the pathophysiology of mitral valve disease. This review summarizes recent advances in noninvasive cardiac imaging to assess normal mitral valve anatomy and function and provides an overview of the clinical applications of these novel imaging techniques in the evaluation of patients with mitral valve disease. RECENT FINDINGS: Echocardiography remains the first imaging technique for evaluation of the anatomy and function of the mitral valve. However, advances in minimally invasive and transcatheter valve repair/replacement procedures demand high spatial resolution images to accurately assess the anatomy of the mitral valve and its surrounding structures. Three-dimensional echocardiography improves two-dimensional echocardiography morphological and functional mitral valve evaluation. Furthermore, computed tomography provides high spatial resolution three-dimensional data and may constitute the modality of choice for additional morphological or geometrical study of the mitral valve and surrounding structures. In addition, cardiac magnetic resonance permits accurate assessment of anatomy and function of the mitral valve and is considered the method of reference to quantify mitral flow. SUMMARY: Any abnormality in any of the components of the mitral valve (annulus, leaflets, subvalvular apparatus, left ventricle and left atrium) may lead to mitral valve dysfunction. Current noninvasive cardiac imaging modalities permit accurate assessment of mitral valve anatomy and function. These imaging techniques refine our diagnostic performance, provide additional (patho)physiological insights and help to design new strategies for interventional or surgical treatment of the diseased mitral valve. PMID- 22820103 TI - Starting and staying on preventive medication for cardiovascular disease. AB - PURPOSE OF REVIEW: To synthesize the qualitative research literature regarding medication use to prevent cardiovascular disease in order to explain the variation in healthcare professional (HCP) and patient behaviours, and to evaluate the implications for practice. RECENT FINDINGS: The decision to start preventive medication is affected by the patient-HCP relationship and by the design of the service. Both HCPs and patients are influenced by their understanding of the evidence regarding the value of preventive interventions; their values and preferences; and their sociopolitical context and the organizational structure of their practice environment. The design of their service affects uptake as a consequence of its impact on clinical communication and the extent to which the service is tailored to the needs of the local community. Continuing to take prescribed medication is affected by both contextual and practical factors. Recommendations for practice can be split into those with a clinical focus and those with a patient or community focus. More sophisticated analyses have moved beyond recommendations for patient and HCP education, and address constraints in the organization of clinical services and the social context of evidence translation. SUMMARY: Qualitative health research provides important insights into the experience of and context for decision making about medication prescription and adherence that can help efforts to prevent cardiovascular disease. PMID- 22820104 TI - Treatment of tobacco addiction and the cardiovascular specialist. AB - PURPOSE OF REVIEW: Tobacco smoking is the leading cause of avoidable deaths worldwide, and half of these deaths are due to cardiovascular disease (CVD). Physicians specialized in the management of CVD play a key role in ensuring that all smokers with cardiovascular disorders are offered best evidence support to help them quit smoking. This review summarizes recent findings on smoking as a risk factor for CVD, effects of smoking cessation on the prognosis of CVD patients, interactions between drug treatment for CVD and smoking, effective interventions to promote quitting in CVD patients and policy issues regarding tobacco control. RECENT FINDINGS: Smoking cessation following an acute cardiovascular event yields a substantial reduction in morbidity and mortality. Recent declines in CVD mortality were mainly a result of risk factor modification rather than improvement of medical treatments for CVD. The latter are also less effective in smokers than in nonsmokers, and smokers are at high risk of medication nonadherence. Effective interventions to support quit attempts in smokers with CVD are available. Cardiovascular specialists should encourage policy-makers to take appropriate tobacco control action. SUMMARY: Cardiovascular specialists are in a unique position to promote cardiovascular health at the individual as well as at a population level. PMID- 22820105 TI - Preventing cardiovascular disease in women: how can we do better? AB - PURPOSE OF REVIEW: This review highlights advances in the primary and secondary prevention of cardiovascular disease (CVD) in women in the preceding 12 months. RECENT FINDINGS: The American Heart Association (AHA) has recently published guidelines on the prevention of CVD in women, which brought new attention to this important topic. Limited progress has been made regarding an awareness of CVD among women, and modest progress has been made on the creation of health behavior change programs that effectively reduce smoking, increase physical activity and improve nutrition. Preventive therapies have been demonstrated to improve outcomes in women with diagnosed disease, but more research that includes women is required to further assess the benefits of primary preventive strategies and therapies. SUMMARY: A review of the literature from the past year confirms the recommendations and direction set in the AHA's updated prevention guidelines. This review illuminates promising new directions for practice and the need for future research focused on strategies to advance early and lasting lifestyle changes to promote cardiovascular health and the prevention of CVD. Adoption of and adherence to the guidelines, continued evaluation and publication of effective practice strategies, and ongoing research are critical to improve efforts to prevent CVD in women. PMID- 22820106 TI - Factors associated with adolescents' perspectives on health needs and preference for health information sources in Taiwan. AB - OBJECTIVE: To identify health needs, preferred sources of health information and associated factors in Taiwanese adolescents. DESIGN: Cross-sectional questionnaire-based survey conducted in Taiwanese adolescents aged 12-18 years in 2010. OUTCOME MEASURES: Adolescents were queried about their health needs, healthcare service utilisation and preferred sources of health information. We compared differences in reported health needs and available sources among gender groups and grade levels. Demographic correlates of adolescent health needs were further examined using multiple ordinal logistic regression analysis. RESULTS: Participants (n=5018) needed weight and height information most, followed by dietary health advice. Academic stress was emphasised more than behavioural issues. Perceived needs for health information varied by age and gender. General high school programme, suburban location and chronic illness were associated with higher need. Only a small proportion (4.3%) of adolescents used healthcare services for mental and emotional concerns. Parents were the primary sources of health information, although students also turned to teachers, particularly for sensitive issues. Moreover, the mass media and internet were increasingly popular sources of information. CONCLUSIONS: To achieve continuous care from childhood through adolescence to adulthood, paediatricians should understand adolescents' diverse views of health needs and preferred sources of health information. Several demographic variables were shown to influence their health needs, reflecting the East Asian cultural context. Anticipatory guidance on body image, dietary health and academic stress should be emphasised while caring for these adolescents. We therefore advocate the development and effective delivery of culturally relevant adolescent-friendly health services. PMID- 22820107 TI - Effects of long-term treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet endocrine cells in non-obese type 2 diabetic Goto-Kakizaki rats. AB - Reduced beta cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence beta and alpha cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, beta and alpha cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. beta cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced beta and alpha cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet beta cell mass in GK rats by facilitating the proliferation of islet endocrine cells. PMID- 22820109 TI - Performance of double-layer biofilter packed with coal fly ash ceramic granules in treating highly polluted river water. AB - To improve trickling filters' denitrification efficiency, a biofilter with a trickling upper layer and a submerged lower layer was developed and applied in treating highly polluted river water. It was packed with porous coal fly ash ceramic granules. Its start-up characteristics, influence of hydraulic loading rates (HLR), carbon/nitrogen (C/N) ratio and filter depth on pollutants removal were investigated. The results indicated this biofilter was started quickly in 16 days with river sediment as inoculum. Alternating nitrification and denitrification were achieved when water flowed downwards. COD and nitrogen were mainly removed in the upper layer and the lower layer, respectively. With HLR of 4.0-5.0m(3)/(m(2)d), chemical oxygen demand (COD), ammonium (NH(4)(+)-N) and total nitrogen (TN) in the effluent were below 50, 5 and 15 mg/L, respectively. This biofilter removed more than 80% of COD, 85% of NH(4)(+)-N and 60% of TN with C/N ratios ranging from 6 to 10. PMID- 22820108 TI - Sigma receptor antagonists attenuate acute methamphetamine-induced hyperthermia by a mechanism independent of IL-1beta mRNA expression in the hypothalamus. AB - Methamphetamine is currently one of the most widely abused drugs worldwide, with hyperthermia being a leading cause of death in methamphetamine overdose situations. Methamphetamine-induced hyperthermia involves a variety of cellular mechanisms, including increases in hypothalamic interleukin-1 beta (IL-1beta) expression. Methamphetamine also interacts with sigma receptors and previous studies have shown that sigma receptor antagonists mitigate many of the behavioral and physiological effects of methamphetamine, including hyperthermia. The purpose of the current study was to determine if the attenuation of methamphetamine-induced hyperthermia by the sigma receptor antagonists, AZ66 and SN79, is associated with a concomitant attenuation of IL-1beta mRNA expression, particularly in the hypothalamus. Methamphetamine produced dose- and time dependent increases in core body temperature and IL-1beta mRNA expression in the hypothalamus, striatum, and cortex in male, Swiss Webster mice. Pretreatment with the sigma receptor antagonists, AZ66 and SN79, significantly attenuated methamphetamine-induced hyperthermia, but further potentiated IL-1beta mRNA in the mouse hypothalamus when compared to animals treated with methamphetamine alone. These findings suggest sigma receptor antagonists attenuate methamphetamine-induced hyperthermia through a different mechanism from that involved in the modulation of hypothalamic IL-1beta mRNA expression. PMID- 22820110 TI - Utilization of bivalve shell-treated Zea mays L. (maize) husk leaf as a low-cost biosorbent for enhanced adsorption of malachite green. AB - In this work, two low-cost wastes, bivalve shell (BS) and Zea mays L. husk leaf (ZHL), were investigated to adsorb malachite green (MG) from aqueous solutions. The ZHL was treated with calcined BS to give the BS-ZHL, and its ability to adsorb MG was compared with untreated ZHL, calcined BS and Ca(OH)(2)-treated ZHL under several different conditions: pH (2-8), adsorbent dosage (0.25-2.5 g L( 1)), contact time (10-30 min), initial MG concentration (10-200 mg L(-1)) and temperature (303-323 K). The equilibrium studies indicated that the experimental data were in agreement with the Langmuir isotherm model. The use of 2.5 g L(-1) BS-ZHL resulted in the nearly complete removal of 200 mg L(-1) of MG with a maximum adsorption capacity of 81.5 mg g(-1) after 30 min of contact time at pH 6 and 323 K. The results indicated that the BS-ZHL can be used to effectively remove MG from aqueous media. PMID- 22820111 TI - Effects of low-density static magnetic fields on the growth and activities of wastewater bacteria Escherichia coli and Pseudomonas putida. AB - The aim of this study was to explore the influence of a moderate static magnetic field (SMF) of different densities on Escherichia coli and Pseudomonas putida that are commonly found in wastewater treatment plants. In line with literature reports that SMF increases the efficiency of wastewater treatment the findings of this study indicated that SMF negatively influenced the growth but positively influenced the enzymatic activities and ATP levels of the two model bacteria. The inhibitory effect of SMF on growth of E. coli and P. putida was most pronounced at their optimal growth temperature (37 degrees C and 28 degrees C respectively) and was reversible shortly after the SMF had been terminated. Finally, the results suggested that the induced energy metabolism reflected in higher dehydrogenase activities and ATP levels may be more important for survival, and adaptation to SMF induced stress than the increase in the expression of the rpoS gene. PMID- 22820112 TI - Design of new strategy for green algal photo-hydrogen production: spectral selective photosystem I activation and photosystem II deactivation. AB - A new strategy in photosynthetic hydrogen (photo-H(2)) production from green algae was developed based on theory and successfully demonstrated. The new strategy applied a spectral-selective photosystem I (PSI) activating/photosystem II (PSII) deactivating radiation (or PSI light) that would drive a steady flow of electrons in the electron transport chain for delivery to hydrogenase for photo H(2) production, but would reduce oxygen production through water photolysis below the respiratory oxygen consumption so that an anoxic condition would be maintained as required by hydrogenase. Implementing the strategy by using a PSI light (692 nm peak, 680-700 nm) on Chlamydomonas reinhardtii cells resulted in relatively sustained photo-H(2) production (total of 0.108 mL H(2)mg(-1)Chl, exceeding 0.066 mL H(2)mg(-1)Chl under white light). The strategy also proved successful and convenient in allowing cells to alternately switch between photo H(2) production and a recovery period by simply turning on or off the PSI light. PMID- 22820113 TI - Comparison of seven types of thermo-chemical pretreatments on the structural features and anaerobic digestion of sunflower stalks. AB - Sunflower stalks can be used for the production of methane, but their recalcitrant structure requires the use of thermo-chemical pretreatments. Two thermal (55 and 170 degrees C) and five thermo-chemical pretreatments (NaOH, H(2)O(2), Ca(OH)(2), HCl and FeCl(3)) were carried out, followed by anaerobic digestion. The highest methane production (259 +/- 6 mL CH(4)g(-1) VS) was achieved after pretreatment at 55 degrees C with 4% NaOH for 24h. Acidic pretreatments at 170 degrees C removed more than 90% of hemicelluloses and uronic acids whereas alkaline and oxidative pretreatments were more effective in dissolving lignin. However, no pretreatment was effective in reducing the crystallinity of cellulose. Methane production rate was positively correlated with the amount of solubilized matter whereas methane potential was negatively correlated with the amount of lignin. Considering that the major challenge is obtaining increased methane potential, alkaline pretreatments can be recommended in order to optimize the anaerobic digestion of lignocellulosic substrates. PMID- 22820114 TI - Optimizing anaerobic digestion by selection of the immobilizing surface for enhanced methane production. AB - Maximizing methane production while maintaining an appreciable level of process stability is a crucial challenge in the anaerobic digestion industry. In this study, the role of six parameters: the type of immobilizing supports, loading rate, inoculum levels, C:N ratio, trace nutrients concentrations and mixing rate, on methane production were investigated under thermophilic conditions (55 +/- 1 degrees C) with synthetic substrate medium. The immobilizing supports were Silica gel, Sand, Molecular Sieve and Dowex Marathon beads. A Taguchi Design of Experiment (DOE) methodology was employed to determine the effects of different parameters using an L(16) orthogonal array. Overall, immobilizing supports influenced methane production substantially (contributing 61.3% of the observed variation in methane yield) followed by loading rate and inoculum which had comparable influence (17.9% and 17.7% respectively). Optimization improved methane production by 153% (from 183 to 463 ml CH(4)l(-1)d(-1)). PMID- 22820115 TI - Application of power plant flue gas in a photobioreactor to grow Spirulina algae, and a bioactivity analysis of the algal water-soluble polysaccharides. AB - A novel photobioreactor was developed with a total volume of 30 m(3) which required merely 100 m(3) of land footprint. The bioreactor was capable of utilizing CO(2) in the flue gas of a power plant as the carbon source for the growth of a freshwater alga, Spirulina platensis, mitigating the greenhouse effect caused by the same amount of CO(2) discharge. Results of the study indicated that the photobioreactor was capable of fixing 2,234 kg of CO(2) per annum. Upon deducting the energy consumption of operating the bioreactor unit, the estimated amount of CO(2) to be fixed by a scaled-up reactor would be 74 tons ha(-1)year(-1). In addition, the study prove that protein-free polysaccharides of S. platensis could induce the production of pro-IL-1 and IL-1 proteins through the mediation of ERK, JNK, and p38 MAPKs pathways. As a consequence, immunogenic activities of the macrophage cells were enhanced. PMID- 22820116 TI - Inhibition of canine parvovirus replication in cultured cells by small interfering RNAs expressed from plasmid vectors. AB - Small interfering RNAs (siRNAs) target complementary mRNA for specific degradation, a mechanism many viruses are susceptible too. Thus, siRNA degradation of target RNAs can be exploited as novel therapeutics. In this report, we show that the vector-based siRNAs (psiSTRIKEs) expressed by a human U6 promoter could efficiently inhibit CPV replication in cell culture. A series of PsiSTRIKE vectors expressing siRNA were constructed that target structural protein genes or nonstructural protein genes of CPV genome. These plasmids were transfected into FK81 cells via lipofectin and the stable transfection clones were selected. The immunostaining, plaque assay, and cell proliferation assay of the cells infected by CPV were performed. The results show that siRNAs against nonstructural protein genes effectively inhibited CPV replication. The inhibition efficiencies detected by immunostaining assay of psiSTRIKE/vp1510, psiSTRIKE/NS160, and psiSTRIKE/NS1939 were 66%, 76% and 78%, respectively at 48h, and 69%, 46% and 67%, respectively at 96h. Plaque assay showed that, comprising to the control, the psiSTRIKE/NS160 reduced the virion production by 100-fold, and psiSTRIKE/NS1939 or psiSTRIKE/VP1510 reduced the virion production 13-fold. When compared to control, the viability of cells transfected psiSTRIKE/NS160 increased 78% and 124%, respectively at 72 and 120h. Our study may provide a potential therapy against CPV infection. PMID- 22820118 TI - Mitogenomic analysis of the genus Pseudois: evidence of adaptive evolution of morphological variation in the ATP synthase genes. AB - The genus Pseudois includes two variable taxa, blue sheep (Pseudois nayaur) and dwarf blue sheep (Pseudois schaeferi), that exhibit notable geographic variation in morphology and ecological niche, suggesting the potential for significant adaptive differentiation between these two goats. Blue sheep are broadly distributed in the Tibetan Plateau and peripheral mountains through Central Asia, while dwarf blue sheep are only found in the gorges of the upper Yangtze River (Jinsha River) near Batang county, Sichuan province and adjacent mountains. Although they are all adapted to high altitude environments, endangered dwarf blue sheep show unique morphological variation and niche shifts compared to blue sheep. Mitochondria play important roles in oxygen usage and energy metabolism. The energetically demanding lifestyles of these high altitude species may have altered the selective regimes on mitochondrial genes encoding proteins related to cellular respiration. Here, we compared the sequences of 13 protein-coding genes in the mitochondrial genome of dwarf blue sheep with those of blue sheep to understand the genetic basis of morphological variation. Using neighbor-joining, maximum-likelihood and Bayesian approaches, we estimated rates of synonymous (d(S)) and nonsynonymous (d(N)) substitutions. Independent analyses showed that no omega ratio was larger than 1, suggesting that all mitochondrial 13 genes were under the purifying selection. Surprisingly, we found that the omega ratio (d(N)/d(S)) of the ATP synthase complex (ATP6 and ATP8) in blue sheep is sixteen times that of dwarf blue sheep (0.340 compared to 0.021). This result was confirmed by a separate analysis of ATP synthase genes from two additional P. schaeferi individuals and two P. nayaur individuals. We hypothesize that the large body size and diverse feeding styles are factors influencing the nonsynonymous substitutions in the ATP synthase complex of blue sheep. PMID- 22820119 TI - Molecular base of biochemical complex I deficiency. AB - The oxidative phosphorylation (OXPHOS) system, consisting of five enzyme complexes (I-V) together with 2 electron carriers, has an important role in the energy metabolism of the cell. With 45 subunits, complex I is the first and largest complex of the respiratory chain. It is under bigenomic control and a proper interaction between the mitochondrial and the nuclear genome is important for a good biogenesis and functioning of the complex. Isolated complex I deficiency is the most frequently diagnosed form of mitochondrial disorders caused by the disturbance of the OXPHOS system. It has a wide clinical variety and, at present, in many patients the underlying genetic cause of the complex I deficiency is still not known. In this review, the role of complex I in the oxidative phosphorylation and the localization and function of the different complex I subunits will be described. Furthermore, a brief overview of the assembly process and biochemical studies, performed when a patient is suspected of a mitochondrial disorder is given. Finally, the present knowledge for molecular base of complex I deficiency is described and the findings in a research cohort of patients with complex I deficiency are reported. Identifying new genes encoding proteins involved in complex I biogenesis is challenging and in the near future new powerful techniques will make high throughput screening possible. Progress in elucidating the genetic defect causing complex I deficiencies is important for a better genetic counseling, prenatal diagnostic possibilities and further development of new treatment strategies to cure the complex I deficiencies in the future. PMID- 22820120 TI - Repeated regions in mitochondrial genomes: distribution, origin and evolutionary significance. AB - All complete or nearly complete mitochondrial genomes of Metazoa (2819) have been subject to bioinformatic analysis to investigate the distribution and features of repeated and palindromic sequences. Repeats are ubiquitous, with 29.9% of genomes containing at least one and 1.95% of total genome length being repeated. Repeat boundaries were tested for the presence of secondary structure motifs, consensus sequences or small repeats, features generally reported as associated with duplications. No significant relationship was detected, suggesting the non ubiquitousness of such features. A mechanism related to gene conversion is proposed to explain the origin of small interspersed repeats. PMID- 22820121 TI - Cow's milk elimination: a novel dietary approach to treat eosinophilic esophagitis. AB - OBJECTIVES: Cow's-milk protein is one of the food antigens responsible for causing eosinophilic esophageal inflammation in a majority of children. We describe our experience with treating eosinophilic esophagitis (EoE) in children by eliminating only cow's milk from their diets. METHODS: This retrospective study assessed the short-term clinical and histological response to eliminating cow's-milk protein from the diet of children with EoE. Only patients undergoing a subsequent upper endoscopy to assess their histological response were included in this analysis. RESULTS: We identified 17 (12 boys and 5 girls) children with EoE who excluded only cow's milk from their diet. Remission was induced in 11 of 17 (65%) patients; within the remission group, 7 (41%) achieved complete histological remission and 4 patients (24%) were in significant histological remission. The mean peak pre- and posttreatment counts for those in remission were 76 +/- 40 and 2 +/- 4 (P < 0.01), respectively. CONCLUSIONS: Elimination of cow's milk-induced clinical and histological remission in 65% (95% confidence interval 42%-88%) of children with EoE in whom it was attempted. This approach offers distinct advantages over other dietary treatment approaches for the initial management of children with EoE. The role of eliminating cow's milk alone for the treatment of EoE warrants further prospective study. PMID- 22820122 TI - Time- and segment-related changes of postresected intestine: a 4-dimensional model of intestinal adaptation. AB - OBJECTIVES: The aim of the present study was to investigate the segment- and time related changes in rat short bowel syndrome and construct a 4-dimensional (4D) geometrical model of intestinal adaptation. METHODS: Sprague-Dawley rats were divided into 3 groups: 2-day, 7-day, and 15-day postresection groups in which 75% of the jejunoileum was removed. Histological and morphometrical parameters in the remaining proximal to distal intestinal segments, from the jejunum to the distal colon, were comparatively evaluated in the groups. The data were used to construct a 4D geometric model in which villi were considered as cylinders, and their surface area was expressed as cylinder lateral area. RESULTS: Major adaptive changes were observed in the ileum consisting of an increase in both the diameter of base and the height of villi. A parallel reduction in their number/mm was observed. The resulting ileal architecture was characterized by a limited number of large villi. An opposite pattern was observed in the jejunum whose postresection structure consisted of an increased number of villi. No changes were observed in the colon. Postresection restructuring was early and faster in the ileum than in the jejunum resulting in an increase in absorptive area of 81.5% and 22.5% in the ileum and jejunum, respectively. CONCLUSIONS: Postresection adaptation is intestinal segment-specific because all of the major changes occur in the ileum rather than in the jejunum. Sparing ileal segments during resection may improve the outcome of patients undergoing extensive intestinal resection. Our 4D model can be used to test interventions aimed at optimizing postresection intestinal adaptation. PMID- 22820123 TI - Intestinal failure in children: the European view. AB - Intestinal failure (IF) is a condition in which severe intestinal malabsorption mandates artificial nutrition through a parenteral route. Causes of severe protracted IF include short bowel syndrome, congenital diseases of enterocyte development, and severe motility disorders (total or subtotal aganglionosis or chronic intestinal pseudo-obstruction syndrome). IF can result in nutritional failure, defined as the long-term failure to nourish a child by natural or artificial means. Today, IF-associated liver disease is the most common cause of parenteral nutrition (PN) failure, but catheter-related sepsis and extensive vascular thrombosis may also jeopardize the health of those receiving PN. For a child with nutritional failure, intestinal transplantation, often in the form of a composite visceral graft, offers the only chance for long-term survival. The management of IF requires a multidisciplinary approach. There have been a number of recent advances in both medical and surgical treatments of IF. In particular, new intestinal lengthening techniques and the use of PN formulas rich in fish oil both have resulted in decreased rates of severe complications of IF and its treatments. In addition, better awareness of the risks and benefits of intestinal transplantation have resulted in better patient selection, and ultimately in improved patient survival, hence restricting the indication to transplantation only to patients with nutritional failure and no other chance to survive. PMID- 22820117 TI - Curbing cancer's sweet tooth: is there a role for MnSOD in regulation of the Warburg effect? AB - Reactive oxygen species (ROS), while vital for normal cellular function, can have harmful effects on cells, leading to the development of diseases such as cancer. The Warburg effect, the shift from oxidative phosphorylation to glycolysis, even in the presence of adequate oxygen, is an important metabolic change that confers many growth and survival advantages to cancer cells. Reactive oxygen species are important regulators of the Warburg effect. The mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD) is vital to survival in our oxygen-rich atmosphere because it scavenges mitochondrial ROS. MnSOD is important in cancer development and progression. However, the significance of MnSOD in the regulation of the Warburg effect is just now being revealed, and it may significantly impact the treatment of cancer in the future. PMID- 22820124 TI - The perceived importance of physical activity: associations with psychosocial and health-related outcomes. AB - BACKGROUND: The purpose of this study was to assess the extent to which participation in a 12-month exercise program changed the degree of importance that older adults attached to physical activity. In addition, associations among changes in physical activity importance and health-related and psychosocial outcomes were examined. METHODS: Community-dwelling older adults (N = 179) were recruited to participate in a 12-month exercise trial examining the association between changes in physical activity and fitness with changes in brain structure and psychological health. Participants were randomly assigned to a walking condition or a flexibility, toning, and balance condition. Physical, psychological, and cognitive assessments were taken at months 0, 6, and 12. RESULTS: Involvement in a 12-month exercise program increased the importance that participants placed on physical activity; this positive change was similar across exercise condition and sex. Changes in importance, however, were only associated with changes in physical health status and outcome expectations for exercise midway through the intervention. There were no significant associations at the end of the program. CONCLUSIONS: Regular participation in physical activity can positively influence the perceived importance of the behavior itself. Yet, the implications of such changes on physical activity-related outcomes remain equivocal and warrant further investigation. PMID- 22820126 TI - Elman RNN based classification of proteins sequences on account of their mutual information. AB - In the present work we have employed the method of estimating residue correlation within the protein sequences, by using the mutual information (MI) of adjacent residues, based on structural and solvent accessibility properties of amino acids. The long range correlation between nonadjacent residues is improved by constructing a mutual information vector (MIV) for a single protein sequence, like this each protein sequence is associated with its corresponding MIVs. These MIVs are given to Elman RNN to obtain the classification of protein sequences. The modeling power of MIV was shown to be significantly better, giving a new approach towards alignment free classification of protein sequences. We also conclude that sequence structural and solvent accessible property based MIVs are better predictor. PMID- 22820125 TI - Sedentary behavior, health-related quality of life, and fatigue among breast cancer survivors. AB - BACKGROUND: Many cancer survivors experience declines in health-related quality of life (HRQOL) and increases in fatigue as a result of cancer and its treatment. Exercise is linked to improvements in these outcomes, but little is known about the role of sedentary behavior. In a large, ethnically-diverse cohort of breast cancer survivors, we examined the relationship between sedentary time, HRQOL, and fatigue, and examined if that relationship differed by recreational moderate vigorous physical activity (MVPA) level. METHODS: Participants were 710 women diagnosed with stage 0-IIIA breast cancer in the Health, Eating, Activity, and Lifestyle Study. Women completed questionnaires at approximately 30-months postdiagnosis (sedentary time; recreational MVPA) and 41-months postdiagnosis (HRQOL; fatigue). In multivariate models, we regressed these outcomes linearly on quartiles of daily sedentary time, and a variable jointly reflecting sedentary time quartiles and MVPA categories (0; >0 to <9; >=9 MET-hrs/wk). RESULTS: Sedentary time was not independently related to subscales or summary scores of HRQOL or fatigue. In addition, comparisons of women with high vs. low (Q4:Q1) sedentary time by MVPA level did not result in significant differences in HRQOL or fatigue. CONCLUSION: In this breast cancer survivor cohort, self-reported sedentary time was not associated with HRQOL or fatigue, 3.5 years postdiagnosis. PMID- 22820127 TI - Simplification of reversible Markov chains by removal of states with low equilibrium occupancy. AB - We present a practical method for simplifying Markov chains on a potentially large state space when detailed balance holds. A simple and transparent technique is introduced to remove states with low equilibrium occupancy. The resulting system has fewer parameters. The resulting effective rates between the remaining nodes give dynamics identical to the original system's except on very fast timescales. This procedure amounts to using separation of timescales to neglect small capacitance nodes in a network of resistors and capacitors. We illustrate the technique by simplifying various reaction networks, including transforming an acyclic four-node network to a three-node cyclic network. For a reaction step in which a ligand binds, the law of mass action implies a forward rate proportional to ligand concentration. The effective rates in the simplified network are found to be rational functions of ligand concentration. PMID- 22820128 TI - Pioglitazone prevents hyperglycemia induced decrease of AdipoR1 and AdipoR2 in coronary arteries and coronary VSMCs. AB - BACKGROUND: Adiponectin receptors play an important role in inflammatory diseases like diabetes and atherosclerosis. Former studies revealed that the regulation of adiponectin receptors expression differs in the receptor responses to pioglitazone. However, expression of AdipoRs has not been investigated in the coronary arteries or the coronary vascular smooth muscle cells (VSMCs). In the present study we investigated the effect of pioglitazone on the adiponectin receptors both in vitro and in vivo. METHODS: Male Sprague-Dawley rats were randomly divided in three groups. One of them fed with regular chow (the Control group) and two of them fed with high-fat diet and then received low-dose Streptozotocin once by intraperitoneal injection (the DM groups). Rats in one of the DM groups were further treated with pioglitazone (the PIO group). Blood pressure, serum adiponectin, fasting blood glucose, fasting serum insulin, cholesterol, triglyceride, AdipoR1 and AdipoR2 expression, and TNF-alpha expression in coronary arteries of these groups were investigated. For the in vitro study, the rat coronary VSMCs maintained under defined in vitro conditions were treated with either PIO or the PIO+ GW9662 (PPAR-gamma antagonist), and then stimulated with high glucose. AdipoR1 and AdipoR2 expression, TNF-alpha expression and PPAR-gamma expression were investigated. RESULTS: Compared to the DM group, treatment with PIO in vivo significantly attenuated cholesterol level, triglyceride level, fasting serum insulin and TNF-alpha overexpression (p<0.05). PIO also increased AdipoR1 and AdipoR2 expression in coronary arteries, which were reduced notably in the DM group (p<0.05). Consistently, in the study with rat coronary VSMCs, PIO prominently downregulated TNF-alpha expression and induced PPAR-gamma expression, as well as prevented hyperglycemia induced decrease of AdipoR1 and AdipoR2 expression (p<0.05). And pretreatment of PIO+GW9662 did not manifest the prevention effect. CONCLUSION: In this study, we showed that treatment with PIO could ameliorate coronary insulin resistant and upregulate the expression of AdipoR1/R2. PIO showed an anti-atherogenic property via the activation of PPAR-gamma, suppression of TNF-alpha overexpression in coronary and coronary VSMCs. PMID- 22820129 TI - Identification, spatial expression analysis and functional characterization of a pyrokinin-1 receptor in the Chagas' disease vector, Rhodnius prolixus. AB - The capability or capa gene, encodes a pyrokinin-related peptide (known as pyrokinin-1, PK1) that contains the consensus carboxy-terminal sequence of WFGPRL NH(2). Although the CAPA precursor polypeptide in Rhodnius prolixus yields the anti-diuretic hormone, RhoprCAPA-alpha2, no function has yet been elucidated for the pyrokinin-1 peptide, RhoprCAPA-alphaPK1. In order to elucidate the possible physiological roles of the PK1-related peptides in R. prolixus, we have isolated and functionally characterized the PK1 receptor, RhoprPK1-R. Additionally, we have determined a set of three optimal reference genes to utilize for normalization of data obtained when carrying out spatial expression analyses via quantitative reverse transcriptase PCR (RT-qPCR) in various tissues of fifth instar R. prolixus. The RhoprPK1-R expression profile differs strikingly from the receptor for the anti-diuretic hormone RhoprCAPA-alpha2, which is localized mainly to gut epithelial tissues. Instead, RhoprPK1-R expression in fifth instar stage insects was identified in tissues that are not involved in osmotic and ionic balance, including the prothoracic glands, male reproductive tissues and a pooled sample composed of fat body, dorsal vessel, abdominal nerves and female reproductive tissues. Thus, this research establishes novel possibilities for the physiological roles of the pyrokinin-related peptides in this medically relevant disease vector. PMID- 22820130 TI - Repression of sterol regulatory element-binding protein 1-c is involved in the protective effects of exendin-4 in pancreatic beta-cell line. AB - Exendin-4 (Ex-4), a long-acting agonist of glucagon-like peptide-1 receptor, is a novel anti-diabetic drug that prevents beta-cells against various toxicities. However, the mechanism and molecules mediating the protection procession of Ex-4 are not fully understood. We investigated the protective effect of Ex-4 against lipotoxicity, mediated by a repression of sterol regulatory element-binding protein (SREBP)-1c, a regulator of genes expression involved in fat and cholesterol synthesis. To observe the effect of Ex-4, we evaluated glucose stimulated insulin secretion (GSIS) and apoptosis in the MIN6 pancreatic beta cell line, which were cultured in DMEM medium containing 500 MUM palmitate, with or without 10 nM Ex-4. We also examined the roles of SREBP-1c in lipotoxicity model by knockdown with si-RNA. Treatment with Ex-4 improved insulin secretion and survival as well as reduced SREBP-1c expression and activity in palmitate treated MIN6 cells. This improvement was accompanied with an upregulation of PI3K/Akt signaling pathway, and LY294.002, a specific inhibitor of PI3 kinase, abrogated effects of Ex-4 on insulin secretion. Moreover, SREBP-1c in nuclei was increased by the inhibition of PI3 kinase. Lipotoxic effects of palmitate in the insulin secretion and apoptosis were significantly prevented by SREBP-1 knockdown. In conclusion, Ex-4 protects beta-cell against palmitate-induced beta cell dysfunction and apoptosis, by inhibiting SREBP-1c expression and activity through the PI3K/Akt signaling pathway. PMID- 22820131 TI - First analysis of human herpesvirus 6T-cell responses: specific boosting after HHV6 reactivation in stem cell transplantation recipients. AB - Early human herpesvirus 6 (HHV6) reactivation after hematopoietic stem cell transplantation (HSCT) is associated with poor survival. We characterized HHV6 immuneresponses in HSCT patients during lymphopenia. Prospectively, HHV6 DNA-load was measured weekly by realtime-PCR. Numbers of IFNgamma-producing HHV6-T-cells were retrospectively determined by enzyme-linked immunospot assay 2 months after HSCT. HHV6-specific T-cell proliferative capacity was analyzed with a newly developed assay using antigen-presenting autologous HHV6-infected PBMC. Fifty-six patients were included (median age 4.6 years; range 0.2-21.2 years). HHV6 reactivation occurred in 29/56 (52%) patients with a median time of 14 (range 1 41) days after HSCT. The median number of IFN-gamma producing HHV6-specific T cells at 2 months and the HHV6-specific CD8+ T-cell proliferative capacity at 6 months after HSCT was increased after HHV6-reactivation compared to non reactivating patients (P=0.006 and p=0.019). In conclusion, HHV6-specific immuneresponses can be initiated during lymphopenia early after HSCT, which implicates a potential window for development of HHV6-specific (immuno)therapy. PMID- 22820132 TI - Poly(acrylic acid) microspheres loaded with lidocaine: preparation and characterization for arterial embolization. AB - A new embolic agent, poly(acrylic acid) microspheres (PMs), was synthesized and the cytocompatibility was proved by mouse L929 fibroblast cells. An analgesic drug, lidocaine, was loaded on the PMs to relief pain caused by embolization. PMs and lidocaine loaded microspheres (LMs) were characterized by investigating infrared spectrum, morphology, particle size, and equilibrium water contents (EWC). A series of tests were employed to evaluate the elasticity of PMs, LMs and EmbosphereTM, including once compression, twice compression, and stress relaxation test. The pressures of PMs and LMs passing through a catheter were measured on line by our new designed device. Drug release was studied with T-cell apparatus. The properties of PMs and LMs were proved to be suitable for embolization. Both PMs and LMs in this study might be potential embolic agents in the future. PMID- 22820134 TI - Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations. AB - Spray drying is an efficient technology for solid dispersion manufacturing since it allows extreme rapid solvent evaporation leading to fast transformation of an API-carrier solution to solid API-carrier particles. Solvent evaporation kinetics certainly contribute to formation of amorphous solid dispersions, but also other factors like the interplay between the API, carrier and solvent, the solution state of the API, formulation parameters (e.g. feed concentration or solvent type) and process parameters (e.g. drying gas flow rate or solution spray rate) will influence the final physical structure of the obtained solid dispersion particles. This review presents an overview of the interplay between manufacturing process, formulation parameters, physical structure, and performance of the solid dispersions with respect to stability and drug release characteristics. PMID- 22820133 TI - Fluxgate magnetorelaxometry: a new approach to study the release properties of hydrogel cylinders and microspheres. AB - Hydrogels are under investigation as long term delivery systems for biomacromolecules as active pharmaceutical ingredients. The release behavior of hydrogels can be tailored during the fabrication process. This study investigates the applicability of fluxgate magnetorelaxometry (MRX) as a tool to characterize the release properties of such long term drug delivery depots. MRX is based on the use of superparamagnetic core-shell nanoparticles as model substances. The feasibility of using superparamagnetic nanoparticles to study the degradation of and the associated release from hydrogel cylinders and hydrogel microspheres was a major point of interest. Gels prepared from two types of photo crosslinkable polymers based on modified hydroxyethylstarch, specifically hydroxyethyl starch hydroxyethyl methacrylate (HES-HEMA) and hydroxyethyl starch-polyethylene glycol methacrylate (HES-P(EG)(6)MA), were analyzed. MRX analysis of the incorporated nanoparticles allowed to evaluate the influence of different crosslinking conditions during hydrogel production as well as to follow the increase in nanoparticle mobility as a result of hydrogel degradation during release studies. Conventional release studies with fluorescent markers (half-change method) were performed for comparison. MRX with superparamagnetic nanoparticles as model substances is a promising method to analyze pharmaceutically relevant processes such as the degradation of hydrogel drug carrier systems. In contrast to conventional release experiments MRX allows measurements in closed vials (reducing loss of sample and sampling errors), in opaque media and at low magnetic nanoparticle concentrations. Magnetic markers possess a better long-term stability than fluorescent ones and are thus also promising for the use in in vivo studies. PMID- 22820135 TI - Thermoresponsive hydrogels with low toxicity from mixtures of ethyl(hydroxyethyl) cellulose and arginine-based surfactants. AB - Ethyl(hydroxyethyl) cellulose (EHEC) is known to form hydrogels in water at elevated temperatures in the presence of an ionic surfactant. In this paper, the potential use of arginine-based surfactants is explored considering the production of a low toxicity thermoresponsive hydrogel for pharmaceutical and biomedical applications. The interactions between EHEC and the monomeric surfactant N(alpha)-lauroyl-L-arginine methyl ester (LAM) and two gemini surfactants N(alpha),N(omega)-bis(N(alpha)-acylarginine) alpha,omega-dialkyl amides were evaluated by Rheo-Small Angle Light Scattering measurements. The complex viscosity of the systems was dependent on surfactant concentration and temperature. Under specific conditions, soft gels of homogeneous structure were produced. The cloud point (CP) of the EHEC-LAM system varied significantly with surfactant concentration, while only moderate CP changes were found in the presence of the gemini surfactants. Finally, the effect of the surfactants on the viability of a human cell line was evaluated. Despite the lower toxicity of LAM, the superior gel forming efficiency of the gemini surfactants at lower concentrations revealed their advantageous suitability as components of a biocompatible thermoresponsive gel system. PMID- 22820136 TI - Differential gene expression analysis of peripheral blood mononuclear cells reveals novel test for early detection of pancreatic cancer. AB - BACKGROUND: We sought to validate global microarray results indicating the differential expression of 383 genes in Peripheral Blood Mononuclear Cells (PBMCs) from patients with pancreatic cancer (PC) and to further evaluate their PC diagnostic potential. METHODS AND MATERIALS: In total, 177 patients were recruited (47 healthy controls (HC), 35 chronic pancreatitis (CP) patients, and 95 PC patients). PBMC expressions of six genes from our previous study (ANXA3, ARG1, CA5B, F5, SSBP2, and TBC1D8) along with four new genes (MIC1, NGAL, MUC1, and MUC16) were analyzed using multiplex Q-RT PCR. RESULTS: Differential expressions of 5 of the 6 genes previously identified by PBMC microarray were validated in this study. Multivariate models for PBMC gene expression were attempted to determine if any combination was diagnostically superior to CA19-9 alone. We found that addition of PBMC CA5B, F5, SSBP2, and MIC1 expression levels to CA19-9 significantly improved CA19-9's diagnostic abilities when comparing resectable PC to CP patients (p=0.023). CONCLUSIONS: Results of our previous study were validated, indicating reproducibility of PC-associated PBMC expression profiling. We identified a score-based model that can differentiate resectable PC from CP better than CA19-9, potentiating that PBMC differential expression analysis may offer a novel tool for early PC diagnosis. PMID- 22820137 TI - Gene expression profiling identifies ARSD as a new marker of disease progression and the sphingolipid metabolism as a potential novel metabolism in chronic lymphocytic leukemia. AB - BACKGROUND: Several studies demonstrated IGVH mutational status and ZAP70 expression as the most relevant prognostic markers in Chronic Lymphocytic Leukemia (CLL), suggesting the separation of two patient subgroups: with good mutated ZAP70 negative (MTZAP70(-) and poor unmutated ZAP70 positive (UMZAP70(+)) prognosis. DESIGN AND METHODS: We determined the gene expression of B cells in 112 CLL patients divided into three classes: class 1 with MTZAP70(-), class 2 with UMZAP70(+), and class 3 included both UMZAP70(-) and MTZAP70(+). RESULTS: We found LPL, AGPAT2, MBOAT1, CHPT1, AGPAT4, PLD1 genes encoding enzymes involved in lipid metabolism overexpressed in UMZAP70(+). In addition, this study identified ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP70(+) compared to MTZAP70(-). Western blots confirmed that ARSD protein levels were significantly different between the 3 classes of patients and normal controls. Statistical analysis identified a significant correlation between ARSD and IGVH; however, both ARSD protein level and IGVH were independently associated with the need for therapy of CLL patients. CONCLUSIONS: ARSD is a novel prognostic factor as the time to start therapy is shorter in patients with high levels of ARSD protein and sphingolipid metabolism could represent a new biological mechanism in CLL. PMID- 22820138 TI - Application of HBx-induced anti-URGs as early warning biomarker of cirrhosis and HCC. AB - BACKGROUND: Hepatitis B virus (HBV) carriers are at high risk for the development of hepatocellular carcinoma (HCC), but there are no reliable markers that will identify such high-risk patients. HBV up-regulates the expression of selected genes (URGs) in the liver during chronic infection. These aberrantly expressed proteins trigger corresponding antibodies (anti-URGs) that appear prior to the detection of HCC. This study was undertaken to see if the anti-URGs could be used as early warning biomarker of HBV-induced liver cirrhosis and HCC. METHODS: A cross sectional study using a total of 625 serum samples from HBV infected and uninfected controls were tested for the anti-URGs using specific ELISAs. RESULTS: The number and specificity of anti-URGs correlated with the severity of liver disease Anti-URGs were predominantly present among patients with HBV-associated HCC (55.2%) and cirrhosis (60.7%), and at a lower frequency among patients with chronic hepatitis (35.8%), and at still lower frequencies in most asymptomatic carriers (12.3%) with normal ALT, among patients with chronic hepatitis C (38.5%) and blood donors (0.9%). These anti-URGs were rarely detected in sera from those with tumors other than HCC, except among HBV infected patients with cholangioicarcinoma and in some patients with drug induced hepatitis. 3 or more anti-URGs could precede the diagnosis of cirrhosis or HCC 11.8 months on average, and HBV hepatitis patients with 3 or more anti-URGs have much higher risk (5/20 vs 0/30) to develop cirrhosis and HCC than those patients with less anti-URGs. As the early warning biomarker, 3 or more anti-URGs were served as the threshold to separate the cirrhosis and HCC from others with a moderate sensitivity (58.3%) and specificity (80.0%), which was better than other biomarkers (AFP, AFP-L3, GPC3 and GP73) and would improve up to 70.3% when combined with another biomarker. CONCLUSIONS: The results of this clinical validation study suggest that the anti-URGs might have diagnostic/prognostic utility among patients at high risk for the development of cirrhosis and HCC. PMID- 22820139 TI - Clinical significance of suppressor of cytokines signalling-3 mRNA expression from patients with non-Hodgkin lymphoma under chemotherapy. AB - INTRODUCTION: To date, little is known about blood immune marker changes that may be related to the development of Non Hodgkin Lymphoma (NHL) and treatment response with few serum biomarkers that could be useful in follow- up of the patients. OBJECTIVE: To quantify the expression of suppressor of cytokine signalling-3-(SOCS-3) gene at the mRNA level in the peripheral blood of patients with NHL and correlate with clinical pathological features and response to treatment. METHODS: Thirty patients with NHL and 20 healthy controls were enrolled in the study. The SOCS-3 mRNA level in peripheral blood (PB) was detected by semi-quantitative real-time polymerase chain reaction. Quantification of cytokines such as interleukin 6 and tumour necrosis factor alpha (IL-6 & TNF alpha) were performed using sandwich enzyme-linked immunosorbent assays (ELISA). RESULTS: Increased expression of SOCS-3 mRNA in peripheral blood plus increased serum levels of IL-6 and TNF alpha from NHL cases with no complete remission after therapy. Higher levels of expression of SOCS-3 are associated with advanced disease, bone marrow involvement, extranodal involvement, poor performance status, B cell symptoms (fever, night sweats and weight loss) and high serum lactate dehydrogenase level which are evaluated by international prognostic index (IPI). Complete responses occur in 60% of patients with normal expression of SOCS 3 gene. Increased expression of SOCS-3 is common in diffuse large B cell lymphoma, CLL/small lymphocytic B cell lymphoma and follicular lymphoma. CONCLUSIONS: Over-expression of SOCS-3 mRNA from peripheral blood of NHL patients correlates with advanced disease and poor response to treatment. SOCS-3 mRNA expression in peripheral blood from NHL patients might be used to monitor response during treatment. PMID- 22820140 TI - Expression of matrix metalloproteinase-2 and its tissue inhibitor-2 in fetal and neoplastic thyroid tissue and their significance as diagnostic and prognostic markers in papillary carcinoma. AB - Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have roles in physiological and pathological processes. We evaluated immunohistochemical expression of MMP-2 and TIMP-2 in paraffin sections of 12 human fetal thyroids at mid-term gestation and 79 thyroid tumors of follicular origin. Besides evaluating expression of these proteins during fetal development and neoplastic transformation, we determined whether expression of MMP-2 and TIMP-2 may help to differentiate papillary thyroid carcinoma (PTC) from follicular thyroid adenoma (FTA) and/or peritumoral tissue (PT). We also investigated their relationship with prognostically important clinicopathological parameters of PTC. Immunoreactive MMP-2 and TIMP-2 were found in all fetal thyroid tissues examined. Tumor tissues contained variable amounts of MMP-2 and TIMP-2, with overexpression of these proteins in PTC compared to FTA and PT tissue. According to the statistical analysis, MMP-2 distinguished follicular variant of PTC from FTA and overall PTC from total nonmalignant lesions. In PTC, high MMP-2 expression correlated with lymph node metastasis (P=0.022), while high TIMP-2 expression was positively correlated with tumor size (P=0.049) and extrathyroid invasion (P=0.017). Overall, these results indicate a role for MMP-2 and TIMP-2 in both thyroid development and malignant transformation and suggest that positive immunohistochemistry for MMP-2 and TIMP-2 might support diagnosis of PTC and predict unfavorable biological behavior. PMID- 22820141 TI - Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A. AB - Botulinum neurotoxin type-A (BoNT-A) is clinically used for patients with pain disorders and dystonia. The precise mechanism whereby BoNT-A controls pain remains elusive. Here, we studied how BoNT-A affects the expression of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a cation channel critically implicated in nociception, in the trigeminal system. Histological studies revealed that subcutaneous BoNT-A injection (0.25, 0.5, or 5 ng/kg) into the face targeted the ophthalmic division of trigeminal ganglion (TG) neurons and decreased TRPV1-immunoreactive neurons in the TG and TRPV1 immunoreactive fibers in rat trigeminal terminals. Of note, TG neurons that received projections from the dura mater, a principal site of headache generation, had reduced TRPV1 expression. BoNT-A-induced cleavage of SNAP25 (synaptosomal-associated protein of 25-kDa) in the TG became obvious 2 days after BoNT-A administration and persisted for at least 14 days. Quantitative real-time RT-PCR (reverse transcription-polymerase chain reaction) data indicated that the TRPV1-decreasing effects of BoNT-A were not mediated by transcriptional downregulation. By employing a surface protein biotin-labeling assay, we demonstrated that BoNT-A inhibited TRPV1 trafficking to the plasma membrane in primary TG neurons. Moreover, Y200F-mutated TRPV1, which is incapable of trafficking to the plasma membrane, was expressed in PC12 cells by transfection, and pharmacological studies revealed that TRPV1 in the cytoplasm was more predisposed to proteasome-mediated proteolysis than plasma membrane-located TRPV1. We conclude that the mechanism by which BoNT-A reduces TRPV1 expression involves the inhibition of TRPV1 plasma membrane trafficking and proteasome mediated degradation in the cytoplasm. This paradigm seems to explain how BoNT-A alleviates TRPV1-mediated pain. Our data reveal a likely molecular mechanism whereby BoNT-A treatment reduces TRPV1 expression in the trigeminal system and provide important clues to novel therapeutic measures for ameliorating craniofacial pain. PMID- 22820142 TI - Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. AB - Activated microglia and infiltrating lymphocytes are neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motoneuron disease. Although both cell types play pivotal roles in the ALS pathogenic process, the interactions between microglia and lymphocytes, specifically regulatory CD4+CD25High T lymphocytes (Tregs) and cytotoxic CD4+CD25- T lymphocytes (Teffs), have not been addressed. When co-cultured with mSOD1 adult microglia, mSOD1 Tregs suppressed the cytotoxic microglial factors NOX2 and iNOS through an IL-4-mediated mechanism, whereas Teffs were only minimally effective; IL-4 inhibitory antibodies blocked the suppressive function of mSOD1 Tregs, and conditioned media from mSOD1 Tregs or the addition of IL-4 reduced microglial NOX2 expression. During the stable disease phase, the total number of Tregs, specifically the numbers of CD4+CD25HighIL-4+, CD4+CD25HighIL-10+ and CD4+CD25HighTGF-beta+ Tregs, were increased in ALS mice compared with WT mice; Tregs isolated during this phase reduced Teff proliferation. In contrast, during the rapidly progressing phase, the number of mSOD1 Tregs decreased while the proliferation of mSOD1 Teffs increased. The combination of IL-4, IL-10, and TGF-beta was required to inhibit the proliferation of mSOD1 Teffs by mSOD1 Tregs that were isolated during the slow phase, while inhibition of mSOD1 Teffs by mSOD1 Tregs during the rapid phase, as well as WT Teffs, was not dependent on these factors. Thus, mSOD1 Tregs at the slow phase suppressed microglial toxicity and SOD1 Teff proliferation through different mechanisms; microglial activation was suppressed through IL-4 whereas mSOD1 Teffs were suppressed by IL-4, IL-10 and TGF-beta. These data suggest that mSOD1 Tregs contribute to the slowly progressing phase in ALS mice and may offer a novel therapeutic option for ALS patients. PMID- 22820144 TI - L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: insights into regulation and function. AB - Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons have been found in the striatum after dopamine depletion; however, little is known about the mechanism underlying their appearance or their functional significance. We previously showed an increase in striatal TH-ir neurons after L-DOPA treatment in mice with unilateral 6-OHDA lesions in the striatum. In the present study, we further examined the time-course and persistence of the effects of chronic L-DOPA treatment on the appearance and regulation of TH-ir neurons as well as their possible function. We found that the L-DOPA-induced increase in striatal TH-ir neurons is dose-dependent and persists for days after L-DOPA withdrawal, decreasing significantly 10 days after L-DOPA treatment ends. Using hemiparkinsonian D1 receptor knock-out (D1R-/-) and D2 receptor knock-out (D2R-/ ) mice, we found that the D1R, but not the D2R, is required for the L-DOPA induced appearance of TH-ir neurons in the dopamine-depleted striatum. Interestingly, our experiments in aphakia mice, which lack Pitx3 expression in the brain, indicate that the L-DOPA-dependent increase in the number of TH-ir neurons is independent of Pitx3, a transcription factor necessary for the development of mesencephalic dopaminergic neurons. To explore the possible function of L-DOPA-induced TH-ir neurons in the striatum, we examined dopamine overflow and forelimb use in L-DOPA-treated parkinsonian mice. These studies revealed a tight spatio-temporal correlation between the presence of striatal TH ir neurons, the recovery of electrically stimulated dopamine overflow in the lesioned striatum, and the recovery of contralateral forelimb use with chronic L DOPA treatment. Our results suggest that the presence of TH-ir neurons in the striatum may underlie the long-duration response to L-DOPA following withdrawal. Promotion of these neurons in the early stages of Parkinson's disease, when dopamine denervation is incomplete, may be beneficial for maintaining motor function. PMID- 22820143 TI - Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. AB - Many women with breast cancer, especially those treated with chemotherapy, experience cognitive decline due in part to neurotoxic brain injury. Recent neuroimaging studies suggest widespread brain structural abnormalities pointing to disruption of large-scale brain networks. We applied resting state functional magnetic resonance imaging and graph theoretical analysis to examine the connectome in breast cancer survivors treated with chemotherapy relative to healthy comparison women. Compared to healthy females, the breast cancer group displayed altered global brain network organization characterized by significantly decreased global clustering as well as disrupted regional network characteristics in frontal, striatal and temporal areas. Breast cancer survivors also showed significantly increased self-report of executive function and memory difficulties compared to healthy females. These results suggest that topological organization of both global and regional brain network properties may be disrupted following breast cancer and chemotherapy. This pattern of altered network organization is believed to result in reduced efficiency of parallel information transfer. This is the first report of alterations in large-scale functional brain networks in this population and contributes novel information regarding the neurobiologic mechanisms underlying breast cancer-related cognitive impairment. PMID- 22820145 TI - Bio-inspired particle separator design based on the food retention mechanism by suspension-feeding fish. AB - A new particle separator is designed using a crossflow filtration mechanism inspired by suspension-feeding fish in this study. To construct the model of the bio-inspired particle separator, computational fluid dynamics techniques are used, and parameters related to separator shape, fluid flow and particle properties that might affect the performance in removing particles from the flow, are varied and tested. The goal is to induce a flow rotation which enhances the separation of particles from the flow, reduce the particle-laden flow that exits via a collection zone at the lower/posterior end of the separator, while at the same time increase the concentration of particles in that flow. Based on preliminary particle removal efficiency tests, an exiting flow through the collection zone of about 8% of the influent flow rate is selected for all the performance tests of the separator including trials with particles carried by air flow instead of water. Under this condition, the simulation results yield similar particle removal efficiencies in water and air but with different particle properties. Particle removal efficiencies (percentage of influent particles that exit through the collection zone) were determined for particles ranging in size from 1 to 1500 um with a density between 1000 and 1150 kg m(-3) in water and 2 and 19 mm and 68 and 2150 kg m(-3) in air. As an example, removal efficiencies are 66% and 64% for 707 um diameter particles with a density of 1040 kg m(-3) in water and for 2 mm particles with a density of 68 kg m(-3) in air, respectively. No significant performance difference is found by geometrically scaling the inlet diameter of the separator up or down in the range from 2.5 to 10 cm. PMID- 22820146 TI - Effect of western and high fat diets on memory and cholinergic measures in the rat. AB - Recent evidence shows an association between obesity and cognitive decline. The present study aimed to determine whether a very high fat (60%) or western diet can affect working or spatial memory in rats and whether the diet-induced cognitive impairment is linked to the level of acetylcholine in the brain. Three groups of male Long Evans rats were fed either chow, western diet (21% fat, 0.15% cholesterol) or a high fat diet (60% fat) for 12 weeks (n=12 per group). Body weight, food intake and blood pressure were measured weekly. Behavioural testing, novel object recognition and Y-maze were carried out at 12 weeks. At the end of the study brain choline acetyltransferase and acetylcholinesterase levels were estimated. Results showed that consumption of a western diet for twelve weeks impaired a rat's spatial memory (p<0.05), and increased body weight, calorie intake, blood pressure and triglyceride levels. Conversely our high fat diet also impaired spatial memory (p<0.05) but this effect was independent of the rat's body weight or blood pressure. No significant changes in brain acetylcholine markers were observed. In conclusion, diets with higher fat content impaired hippocampal-dependant memory, even when hypertension and obesity are absent; however the mechanism is still unclear. PMID- 22820147 TI - The evolving story of macrophages in acute liver failure. AB - Acute liver failure (ALF) remains a worldwide problem. The innate immune system acts as an important regulator of ALF. Kupffer cells (KCs), the resident macrophages in liver, play a key role in liver innate immune response. Recent researches have shown that macrophages display a remarkable plasticity and can differentiate into functionally diverse subsets. However, the dynamic polarized phenotypes and functional status of macrophages at different stage of ALF are not clear. In this paper, we present a review of evidence that KCs play a significant role in the pathogenesis of ALF, including the phenotype and functions of macrophages, signaling pathways involved in macrophage functional status and cell crosstalks of KCs with other immune cells. More information on macrophages will promote a better understanding of the cellular molecular mechanisms of ALF and provide new insights for the development of therapeutic targets for ALF. PMID- 22820148 TI - Structure of solid-supported lipid membrane probed by noble metal nanoparticle deposition. AB - Direct deposition of a noble metal layer onto a solid-supported membrane was proposed as an indirect microscopy tool to visually observe different lipid phases that may develop in the lipid membrane. The method relied on the different permeability of the lipid membrane towards the incident atoms during deposition. Liquid state or structural defects such as phase boundaries, step ledges in a multi-lamellar stack, and pores permitted the metal atoms to penetrate and nucleate inside the membrane whereas rigid gel state was relatively impermeable to the incident atoms, thus enabling visualization of liquid phase or structural defects inside the gel state. Based on the proposed method, we demonstrated the phase states resulting from thermotropic transitions of 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC), dioleoylphosphatidylethanolamine (DOPE)/DPPC mixture, and 1,2-dioleoyl-3-trimethylammonium propane (DOTAP). Although the proposed method does not allow in-situ observation of equilibrium states, the method should be an excellent complementary tool for visualizing the lipid phases as the method can resolve fine structural details (up to tens of nanometer scale) as seen in the DPPC membrane while providing macroscopic images (up to several micrometers). PMID- 22820149 TI - Anticancer mechanisms of action of two small amphipathic beta(2,2)-amino acid derivatives derived from antimicrobial peptides. AB - We have recently discovered that small antimicrobial beta(2,2)-amino acid derivatives (Mw<500) also display activity against cancer cells. To explore their drug potential, we have presently investigated the mechanisms of action of two derivatives BAA-1 (IC(50) 8.1MUg/ml) and BAA-2 (IC(50) 3.8MUg/ml) on Ramos human Burkitt's lymphoma cells. Studies using annexin-V-FITC/propidium iodide staining and flow cytometry revealed essential mechanistic differences, which was confirmed by screening for active caspases, investigation of mitochondrial membrane potential, and electron microscopy studies. Our results indicated that BAA-1 killed Ramos cells by destabilizing the cell membrane, whereas BAA-2 caused apoptosis by the mitochondrial-mediated pathway. PMID- 22820150 TI - Alpha-synuclein pore forming activity upon membrane association. AB - Alpha-synuclein is a natively unfolded protein widely expressed in neurons at the presynaptic level. It is linked to Parkinson's disease by two lines of evidence: amyloid fibrils of the protein accumulate in patients' brains and three genetic mutants cause autosomal dominant forms of the disease. The biological role of the protein and the mechanisms involved in the etiopathogenesis of Parkinson's disease are still unknown. Membrane binding causes the formation of an amphipathic alpha-helix, which lies on the surface without crossing the bilayer. Recent observations however reported that the application of a voltage induces a pore-like activity of alpha-synuclein. This study aims to characterize the pore forming activity of the protein starting from its monomeric form. In particular, experiments with planar lipid membranes allowed recording of conductance activity bursts with a defined and reproducible fingerprint. Additional experiments with deletion mutants and covalently bound alpha-synuclein dimers were performed to understand both pore assembly and stoichiometry. The information acquired allowed formulation of a model for pore formation at different conductance levels. PMID- 22820151 TI - A systematic review of staff training interventions to reduce the behavioural and psychological symptoms of dementia. AB - Behavioural and psychological symptoms of dementia (BPSD) are highly prevalent and problematic in care settings. Given the limited effectiveness of medical treatments, training care staff to understand and manage these symptoms is essential for the safety and quality of life of people with dementia. This review evaluated the effectiveness of staff training interventions for reducing BPSD. A systematic literature search identified 273 studies. Twenty studies, published between 1998 and 2010, were found to meet the inclusion criteria. Overall, there was some evidence that staff training interventions can impact on BPSD: twelve studies resulted in significant symptom reductions, four studies found positive trends and four studies found no impact on symptoms. No links were found between the theoretical orientation of training programmes and their effectiveness. Training was also found to impact on the way staff behaved towards residents. A quality screening, using pre-specified criteria, revealed numerous methodological weaknesses and many studies did not adhere to the recommended guidelines for the conduct of cluster randomised controlled trials. There is an urgent need for more high quality research and evidence-based practice in BPSD. PMID- 22820152 TI - Overexpression of a multiple stress-responsive gene, ZmMPK4, enhances tolerance to low temperature in transgenic tobacco. AB - Mitogen-activated protein kinase (MAPK) cascades play important roles in mediating biotic and abiotic stress responses. In this study, we found that ZmMPK4 protein was predominantly localized in the nucleus. Semi-quantitative RT PCR analysis revealed that the ZmMPK4 transcription in maize leaves was up regulated by low temperature, high temperature and exogenous signaling molecules such as hydrogen peroxide, methyl jasmonate and ethephon. Hydrogen peroxide acted as second messenger to mediate 4 degrees C-induced up-regulation of ZmMPK4 mRNA. Transgenic tobacco of overexpressing ZmMPK4 accumulated less reactive oxygen species (ROS), more peroxidase and catalase activities, more proline and soluble sugar contents, and more stress-responsive genes expression, leading to enhancing low temperature stress tolerance compared to the control plants. Taken together, these results strongly suggest that ZmMPK4 positively regulates low temperature stress tolerance in plants. PMID- 22820153 TI - Agent-based modeling of physical activity behavior and environmental correlations: an introduction and illustration. AB - PURPOSE: To introduce Agent-Based Model (ABM) to physical activity (PA) research and, using data from a study of neighborhood walkability and walking behavior, to illustrate parameters for an ABM of walking behavior. METHOD: The concept, brief history, mechanism, major components, key steps, advantages, and limitations of ABM were first introduced. For illustration, 10 participants (age in years: mean = 68, SD = 8) were recruited from a walkable and a nonwalkable neighborhood. They wore AMP 331 triaxial accelerometers and GeoLogger GPA tracking devices for 21 days. Data were analyzed using conventional statistics and highresolution geographic image analysis, which focused on a) path length, b) path duration, c) number of GPS reporting points, and d) interaction between distances and time. RESULTS: Average steps by subjects ranged from 1810-10,453 steps per day (mean = 6899, SD = 3823). No statistical difference in walking behavior was found between neighborhoods (Walkable = 6710 +/- 2781, Nonwalkable = 7096 +/- 4674). Three environment parameters (ie, sidewalk, crosswalk, and path) were identified for future ABM simulation. CONCLUSION: ABM should provide a better understanding of PA behavior's interaction with the environment, as illustrated using a real-life example. PA field should take advantage of ABM in future research. PMID- 22820154 TI - Severe acute respiratory infections in the postpandemic era of H1N1. AB - PURPOSE OF REVIEW: Shortly after the advent of severe acute respiratory syndrome and the avian influenza, the emergence of the influenza A(H1N1)2009 pandemic caused significant vibrations to the public health authorities and stressed the health systems worldwide. We sought to investigate whether this experience has altered our knowledge and our current and future practice on the management of severe acute respiratory infections (SARI) and community-acquired pneumonia. RECENT FINDINGS: A changing epidemiology was demonstrated, with obesity and pregnancy beyond established risk groups for influenza A, other clinical syndromes beyond primary viral pneumonia, possible coinfections by other viral beyond bacterial pathogens and a disappointing performance of all available severity assessment tools. On the treatment topic, accumulating evidence suggesting worse outcomes argues against the use of corticosteroids, but some noninvasive ventilating modalities require further assessment. SUMMARY: The recent influenza A(H1N1)2009 pandemic has highlighted our weaknesses relating to the diagnosis and assessment of severity of SARI, compromising early treatment and ultimate outcomes; further research based on this experience will help to improve prognosis and boost our future preparedness. An important message is the necessity of international collaboration for the rapid dissemination of locally acquired knowledge. PMID- 22820155 TI - Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation. AB - PURPOSE OF REVIEW: Antibiotic dosing for critically ill patients that is derived from other patient groups is likely to be suboptimal because of significant antibiotic pharmacokinetic changes, particularly in terms of drug volume of distribution and clearance. Organ support techniques including renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) increase the pharmacokinetic variability. This article reviews the recently published antibiotic pharmacokinetic data associated with burns patients, those receiving continuous RRT (CRRT), sustained low-efficiency dialysis (SLED) and ECMO. RECENT FINDINGS: These groups develop increases in volume of distribution that necessitate the use of higher initial doses to rapidly achieve therapeutic antibiotic concentrations. Burns patients have supranormal drug clearances requiring more frequent administration of antibiotics. Patients receiving CRRT or SLED have variable drug clearances related to different equipment and RRT settings at different institutions. ECMO presents a different challenge because there is such a dearth of data with higher than standard doses potentially required, even in the presence of end-organ failure. SUMMARY: In the context of such variable pharmacokinetics, a guideline approach to dosing remains elusive because of insufficient available data and, therefore, use of therapeutic drug monitoring should be considered advantageous where possible. PMID- 22820156 TI - Update on bloodstream infections in ICUs. AB - PURPOSE OF REVIEW: To describe new developments in the epidemiology and outcomes associated with bloodstream infections (BSIs) in ICUs. RECENT FINDINGS: The incidence and outcomes associated with BSI among patients admitted to ICUs have been changing as a result of increasing numbers of older patients with comorbid medical illnesses suffering critical illness. Community-onset healthcare associated BSIs are recognized as important causes of BSIs in ICUs and are distinct from community-acquired and nosocomial BSIs. Electronic surveillance systems are evolving that provide efficient information about the occurrence of BSIs and for tracking the emergence of resistance. SUMMARY: The incidence of healthcare-associated BSIs increases and is associated with bacteria resistant to antimicrobials used in community-acquired infections. The recent years have witnessed the emergence of extensively resistant bacteria in many regions worldwide, and this is associated with major implications for failure of antimicrobial therapies. Enhanced preventive efforts and optimization of therapy are needed in order to reduce the major burden of BSIs in critically ill patients and to minimize the further emergence of resistance. PMID- 22820157 TI - The lung transplant patient in the ICU. AB - PURPOSE OF REVIEW: Lung transplantation (LTx) has become established as a standard intervention for patients suffering from end-stage lung disease. Transplant recipients are, however, predisposed to numerous unique complications arising from the surgery, transplant immunology and the lifelong medication. Clinicians working in intensive care are increasingly likely to be exposed to these patients and it is therefore important to have a working knowledge of the common complications. RECENT FINDINGS: Common complications encountered following LTx include primary graft dysfunction (PGD), airway complications, acute rejection, chronic lung allograft dysfunction (CLAD), thrombotic microangiopathy (TMA) and infection, all of which impact significantly on long-term survival. PGD arises in the first weeks following transplantation. Acute rejection, airway complications and TMA represent the main complications in the first posttransplantation year. CLAD usually occurs later, but continues to represent the main obstacle to long-term survival. Infection poses significant risk at all stages following transplantation and a full spectrum of bacterial, fungal and viral pathogens has been implicated. SUMMARY: This review highlights the most important complications after LTx and gives an update on diagnostic algorithms and treatment challenges for patients following LTx. PMID- 22820158 TI - The acute effects of yoga on executive function. AB - BACKGROUND: Despite an increase in the prevalence of yoga exercise, research focusing on the relationship between yoga exercise and cognition is limited. The purpose of this study was to examine the effects of an acute yoga exercise session, relative to aerobic exercise, on cognitive performance. METHODS: A repeated measures design was employed where 30 female college-aged participants (Mean age = 20.07, SD = 1.95) completed 3 counterbalanced testing sessions: a yoga exercise session, an aerobic exercise session, and a baseline assessment. The flanker and n-back tasks were used to measure cognitive performance. RESULTS: Results showed that cognitive performance after the yoga exercise bout was significantly superior (ie, shorter reaction times, increased accuracy) as compared with the aerobic and baseline conditions for both inhibition and working memory tasks. The aerobic and baseline performance was not significantly different, contradicting some of the previous findings in the acute aerobic exercise and cognition literature. CONCLUSION: These findings are discussed relative to the need to explore the effects of other nontraditional modes of exercise such as yoga on cognition and the importance of time elapsed between the cessation of the exercise bout and the initiation of cognitive assessments in improving task performance. PMID- 22820159 TI - Identifying leukemia stem cells--is it feasible and does it matter? AB - Present evidence indicates that acute myeloid leukemia (AML) is a stem cell disease. Leukemia stem cells (LSC) might originate from malignant transformation of normal hematopoietic stem cells (HSC), or alternatively, from progenitors in which the acquired mutations have re-installed a dysregulated self-renewal program. Since LSC, similar to their normal counterparts, divide extreme slowly, this might account for the ineffectiveness of conventional chemotherapy in inducing long-term cure. The present review will focus on the detection of LSC, their cellular and molecular biology, their genetic heterogeneity and on correlative studies that have demonstrated the clinical significance of estimating LSC burden. For long-term cure of AML, it is of importance to define LSC candidates and to understand their biology compared to normal HSC. Finally, we will discuss the perspectives of developing treatment strategies for eradication of LSC. PMID- 22820160 TI - Inhibition of Ca(2+)-activated Cl(-) channel ANO1/TMEM16A expression suppresses tumor growth and invasiveness in human prostate carcinoma. AB - The etiology of prostatic adenocarcinoma remains unclear. Prostate cancer cells of varying metastatic potential and apoptotic resistance show altered expression of plasma membrane ion channels and unbalanced Ca2+ homeostasis. Ca(2+)-activated Cl(-) channels (CaCCs) are robustly expressed in epithelial cells and function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis in proliferation, differentiation and apoptosis. ANO1/TMEM16A was recently identified as a CaCC, and it is of interest to determine whether ANO1 plays a role in development and metastasis of prostate carcinoma. Here we show that ANO1 mRNA and protein are highly expressed in human metastatic prostate cancer LNCaP and PC-3 cells by quantitative analysis of real-time PCR and Western blot. These findings were confirmed by whole-cell patch clamp recording of LNCaP and PC-3 cells with increased current density of ANO1 channels. Immunohistochemistry staining further revealed overexpression of ANO1 in human prostate cancer tissues, which correlated with the clinical TNM stage and Gleason score. Experiments with small hairpin RNAs (shRNAs) targeting human ANO1 resulted in a significant reduction of proliferation, metastasis and invasion of PC-3 cells using WST-8, colony formation, wound-healing and transwell assays. Moreover, intratumoral injection of ANO1 shRNA completely inhibited established tumor growth and survival in orthotopic nude mice implanted with PC-3 cells. Our findings provide compelling evidence that upregulation of CaCC ANO1 is involved in the proliferation, progression and pathogenesis of metastatic prostate cancer. Membrane ANO1 protein may therefore serve as a biomarker, and inhibition of overexpressed ANO1 has potential for use in prostate cancer therapy. PMID- 22820161 TI - Multi-layer polymeric implants for sustained release of chemopreventives. AB - Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. To overcome this limitation, we report an improvised implant formulation ("coated" implants) using curcumin, individual curcuminoids, withaferin A and oltipraz. This method involves the coating of blank polycaprolactone implants with 20-30 layers of 10-20% polycaprolactone solution in dichloromethane containing 0.5-2% of the test agent. The in vitro release showed that while oltipraz was released with almost zero-order kinetics over 8 weeks, curcumin, individual curcuminoids and withaferin A were released with some initial burst. The in vivo release was determined by grafting implants subcutaneously in A/J mice. When delivered by coated implants, oltipraz significantly diminished lung DNA adducts in mice treated with dibenzo[a,l]pyrene compared with sham treatment (28 +/- 7 versus 54 +/- 17 adducts/10(9) nucleotides). Withaferin A also diminished DNA adducts, but it was insignificant. Curcumin and individual curcuminoids were ineffective. Analysis of lung, liver and brain by UPLC-fluorescence showed the presence of the three test curcuminoids indicating effectiveness of the implant delivery system. Further, based on its known antitumor activity in vivo, withaferin A given via the implants significantly inhibited human lung cancer A549 xenograft in athymic nude mice, while it was ineffective when the same total dose was administered i.p. and required over 2-fold higher dose to elicit effectiveness. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, can furnish sustained release for long duration, and elicit DNA damage-inhibiting and anti-tumor activities. PMID- 22820163 TI - Phosphorylation of Tara by Plk1 is essential for faithful chromosome segregation in mitosis. AB - Trio-associated repeat on actin (Tara) is an F-actin binding protein and regulates actin cytoskeletal organization. In our previous study, we have found that Tara associates with telomeric repeat binding factor 1 (TRF1) and mediates the function of TRF1 in mitotic regulation. We also found that overexpression HECTD3, a member of HECT E3 ubiquitin ligases, enhances the ubiquitination of Tara in vivo and promotes the degradation of Tara, and such degradation of Tara facilitates cell cycle progression. However, less is known about the post translational modification of Tara in mitosis. Here we show that Tara is a novel Polo-like kinase 1 (Plk1) target protein. Plk1 interacts with and phosphorylates Tara in vivo and in vitro. Actually, the Thr-457 in Tara was a bona fide in vivo phosphorylation site for Plk1. Interestingly, we found that the centrosomal localization of Tara depended on the Thr-457 phosphorylation and the kinase activity of Plk1. Furthermore, overexpression of non-phosphorylatable mutant of Tara caused aberrant mitosis delay in HeLa cells. Our study demonstrated that Plk1-mediated phospho-dependent centrosomal localization of Tara is important for faithful chromosome segregation, and provided novel insights into understanding on the role of Plk1 in cooperation with Tara in mitotic progression. PMID- 22820162 TI - Retinoic acid and tumor necrosis factor-alpha induced monocytic cell gene expression is regulated in part by induction of transcription factor MafB. AB - All-trans-retinoic acid (RA), the major active metabolite of vitamin A, is a regulator of gene expression with many roles in cell differentiation. In the present study, we investigated RA in the regulation of MafB, a basic leucine zipper transcription factor with broad roles in embryonic development, hematopoiesis and monocyte-macrophage differentiation. In RA-treated THP-1 human monocytic cells, MafB mRNA and protein levels were up-regulated by RA dose and time-dependently, while, additionally, RA and tumor necrosis factor (TNF)alpha, also known to induce monocyte to macrophage differentiation, increased MafB expression synergistically. Screening of potential targets containing Maf recognition elements (MARE motifs) in their promoter regions identified SPOCK1, Blimp1 and CCL2 as potential targets; these genes are related to cell communication, recruitment and differentiation, respectively. Across cell treatments, SPOCK1, Blimp1 and CCL2 mRNA levels were highly correlated (P<0.001) with MafB. ChIP assays demonstrated increased MafB protein binding to MARE elements in the promoter regions of SPOCK1, Blimp1 and CCL2 in RA and TNFalpha treated cells, as well as acetylation of histone-H4 in MARE-containing regions, indicative of chromatin activation. Conversely, reducing MafB protein by microRNA silencing significantly decreased the expression of SPOCK1, Blimp1 and CCL2 (P<0.01). Moreover, the reduction in MafB expression and these downstream targets correlated with decreased cell differentiation as determined by cell-surface CD11b expression and phagocytic activity. We conclude that MafB may be a key factor in mediating the ability of RA and TNFalpha to regulate monocytic cell communication, recruitment and differentiation through regulation of MafB target genes including SPOCK1, CCL2 and Blimp1. PMID- 22820164 TI - Mechanisms underlying the augmentation of phenylbiguanide and capsaicin induced cardiorespiratory reflexes by Mesobuthus tamulus venom. AB - Phenylbiguanide (PBG) and capsaicin evoke cardiorespiratory reflexes utilizing two separate pathways. It is known that Indian Red Scorpion (Mesobuthus tumulus; MBT) venom augments PBG (5-HT(3)) responses but, the effect of MBT venom on capsaicin (TRPV1)-induced response is not known. Therefore, the present study was undertaken to ascertain whether MBT venom also augments the capsaicin-induced reflex responses involving mechanisms similar to PBG. Experiments were performed on anaesthetized adult rats. Blood pressure, respiratory excursions and ECG were recorded. At the end of each experiment pulmonary water content was determined. PBG (10 MUg/kg) produced hypotension, bradycardia and apnoea-bradypnoea. Capsaicin (10 MUg/kg) also produced hypotension, bradycardia and apnoea bradypnoea. MBT venom (100 MUg/kg) augmented PBG as well as capsaicin-induced responses and produced pulmonary oedema (increased pulmonary water content). Prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) blocked the venom induced augmentation of PBG and capsaicin reflexes. Kinin synthase inhibitor (aprotinin; 6000 KIU) and guanylate cyclase (GC) inhibitor (methylene blue; 5 mg/kg) blocked the venom-induced augmentation of PBG response but not the capsaicin response. However, pulmonary oedema was blocked by these antagonists. Phosphodiesterase V inhibitor (sildenafil; 100 MUg/kg) augmented the PBG response but not the capsaicin response, though pulmonary oedema was seen in both the groups. The present results indicate that MBT venom also augments the capsaicin induced responses. The augmentation of capsaicin response involves PGs and pulmonary oedema-independent mechanisms whereas, the augmentation of PBG response involves kinin mediated GC-cGMP pathway and pulmonary oedema-dependent mechanisms. PMID- 22820165 TI - Expression of NADPH oxidase in human pancreatic islets. AB - AIMS: NADPH oxidase (NOX) is a known source of superoxide anions in phagocytic and non-phagocytic cells. In this study, the presence of this enzyme in human pancreatic islets and the importance of NADPH oxidase in human beta-cell function were investigated. MAIN METHODS AND KEY FINDINGS: In isolated human pancreatic islets, the expression of NADPH oxidase components was evidenced by real-time PCR (p22(PHOX), p47(PHOX) and p67(PHOX)), Western blotting (p47(PHOX) and p67(PHOX)) and immunohistochemistry (p47(PHOX), p67(PHOX) and gp91(PHOX)). Immunohistochemistry experiments showed co-localization of p47(PHOX), p67(PHOX) and gp91(PHOX) (isoform 2 of NADPH oxidase-NOX2) with insulin secreting cells. Inhibition of NADPH oxidase activity impaired glucose metabolism and glucose stimulated insulin secretion. SIGNIFICANCE: These findings demonstrate the presence of the main intrinsic components of NADPH oxidase comprising the NOX2 isoform in human pancreatic islets, whose activity also contributes to human beta cell function. PMID- 22820166 TI - Ultra-low dose naloxone restores the antinocicepitve effect of morphine in PTX treated rats: association of IL-10 upregulation in the spinal cord. AB - AIMS: Ultra-low dose naloxone has been shown to restore the antinociceptive effect of morphine in pertussis toxin (PTX)-treated rats by suppressing spinal microglia activation and inhibiting inflammatory cytokine expression. This study was further investigated the mechanism by which ultra-low dose naloxone promotes analgesia in pertussis toxin-treated rats. MAIN METHODS: Male Wistar rats were implanted with an intrathecal (i.t.) catheter and injected either saline or PTX (1 MUg). Four days later, rats randomly received either saline, or ultra-low dose naloxone, or recombinant rat interleukin-10 (rrIL-10) (1 MUg) injection followed by saline or morphine (10 MUg) 30 min later. In some experiments, mouse anti-rat IL-10 antibody (10 MUg) was injected intrathecally into PTX injected rats daily on days 4, 5, 6, and 7. On day 7, ultra-low dose naloxone was given 1h after antibody injection with or without subsequent morphine injection. KEY FINDINGS: PTX injection induced notable thermal hyperalgesia and mechanical allodynia. Injection of ultra-low dose naloxone preserved the antinociceptive effect of morphine in PTX-treated rats and associated an increasing of IL-10 protein expression. Intrathecal injection rrIL-10 alone or in combination with morphine, not only reversed mechanical allodynia but also partially restored the antinociceptive effect of morphine; injection of anti-rat IL-10 antibody attenuated the effect of morphine plus ultra-low dose naloxone on mechanical allodynia and completely inhibited the antinociceptive effect of morphine. SIGNIFICANCE: These results indicate that intrathecal ultra-low dose naloxone induces IL-10 expression in spinal neuron and microglia, which suppresses PTX induced neuroinflammation and restores the antinociceptive effect of morphine. PMID- 22820167 TI - GPR55 and GPR35 and their relationship to cannabinoid and lysophospholipid receptors. AB - This review presents a summary of what is known about the G-protein coupled receptors GPR35 and GPR55 and their potential characterization as lysophospholipid or cannabinoid receptors, respectively. Both GPR35 and GPR55 have been implicated as important targets in pain and cancer, and additional diseases as well. While kynurenic acid was suggested to be an endogenous ligand for GPR35, so was 2-arachidonoyl lysophosphatidic acid (LPA). Similarly, GPR55 has been suggested to be a cannabinoid receptor, but is quite clearly also a receptor for lysophosphatidylinositol. Interestingly, 2-arachidonyl glycerol (2 AG), an endogenous ligand for cannabinoid receptors, can be metabolized to 2 arachidonoyl LPA through the action of a monoacylglycerol kinase; the reverse reaction has also been demonstrated. Thus, it appears that mutual interconversion is possible between 2-arachidonoyl LPA and 2-AG within a cell, though the direction of the reaction may be site-dependent. The GPR55 natural ligand, 2 arachidonoyl LPI, can be degraded either to 2-AG by phospholipase C or to 2 arachidonoyl LPA by phospholipase D. Thus, GPR35, GPR55 and CB receptors are linked together through their natural ligand conversions. Additional agonists and antagonists have been identified for both GPR35 and GPR55, which will facilitate the future study of these receptors with respect to their physiological function. Potential therapeutic targets include pain, cancer, metabolic diseases and drug addiction. PMID- 22820168 TI - Over-expression of endothelin-1 in astrocytes, but not endothelial cells, ameliorates inflammatory pain response after formalin injection. AB - AIMS: Endothelin-1 (ET-1) has been suggested to be involved in different types of pain due to its neuromodulatory nature. However, its role in inflammatory pain processing, specifically the origin-specific effect, has not yet been clearly defined. Therefore, the aim of this study is to determine the role of cell-type specific ET-1 induction in the modulation of inflammatory pain processing. MAIN METHODS: The current study assesses the effects of ET-1 over-expression specifically targeted to astrocytes (GET-1) or endothelial cells (TET-1) on the expression of pain-like behaviors induced by a model of inflammatory pain, consisting of a formalin injection into the hind paw. KEY FINDINGS: The baseline sensitivity thresholds of GET-1 and TET-1 mice to the response elicited by tactile and radiant heat stimulation were similar to those observed in age matched non-transgenic (NTg) controls. Relative to the NTg controls, GET-1 mice displayed a marked decrease in pain-like behavioral responses during the second phase of formalin-induced pain (i.e., 15-20 min after injection), whereas the responses elicited in TET-1 mice were unaltered. The levels of mRNA encoding adrenomedullin, calcitonin gene-related peptide and calcitonin-like receptor were elevated in the spinal cord of saline-injected GET-1 mice compared to those of NTg mice. SIGNIFICANCE: The current results support a suppressor role for astrocyte-derived ET-1 in inflammatory pain and suggest that the study of GET-1 mice might provide mechanistic insights for improving the treatment of inflammatory pain. PMID- 22820169 TI - Favorable and unfavorable lactation modulates the effects of electrical stimulation on brain excitability: a spreading depression study in adult rats. AB - AIMS: We investigated how different nutritional states resulting from distinct lactation conditions modulate the effects of cortical electrical stimulation (CES) on the excitability-related phenomenon known as cortical spreading depression (CSD). MAIN METHODS: Wistar rats were reared in different litter sizes with 12, 6 or 3 pups, designated as malnourished (M), well-nourished (W) and overnourished (Ov), respectively. CSD was recorded for 4h on 2 cortical points of each cerebral hemisphere at baseline and after CES. CES was applied for 20 min on the left cortex using a bipolar electrode placed between the CSD recording electrodes. Paired Student t test and ANOVA followed by Tukey test were used for statistical analysis (p<0.05). KEY FINDINGS: The lactation conditions significantly influenced body weight (the M and Ov groups presented the lowest and largest average weight, respectively) and modified the CSD velocities of propagation in adulthood (Ov 0.05). Eccentric training with overspeed stimuli was more effective than traditional resistance training in increasing peak power in the countermovement jump (94 +/- 55 W; ES: 0.95). Eccentric training induced no beneficial training response in maximal running speed (p > 0.05); however, the addition of overspeed exercises salvaged this relatively negative effect when compared with eccentric training alone (0.03 +/- 0.01 seconds; ES: 1.33). These training results achieved in 3-week training blocks suggest that it is important to target-specific aspects of both force and movement velocity to enhance functional measures of power expression. PMID- 22820208 TI - Physical outcome in a successful Italian Serie A soccer team over three consecutive seasons. AB - The aim of this study was to examine the physical performance of a successful Italian Serie A team of more than 3 consecutive seasons. Twenty-five players participated in the study and were classified into 3 playing positions: defenders (n = 9), midfielders (n = 11), and forwards (n = 5). Activities match were studied by an analysis of multiple match camera SICS throughout the competition Italian Serie A matches played at home (n = 90) for 3 consecutive seasons (first: 2004/2005; second: 2005/2006; and third: 2006/2007). Total team ball possession and time-motion characteristics were examined. Results showed that total ball possession (52.1-54.9%) and the number of points accumulated at home (40/48) improved in the past 3 seasons, whereas the final rankings at home were stable. The total distances covered by minutes of play were significantly different between the 3 seasons (118.32 +/- 6.69 m.min to 111.96 +/- 8.05 m.min). Distance running and high-intensity activities were similar in the 3 seasons, whereas the distance covered in moderate-intensity running decreased in the third (p < 0.05). Variations between playing positions were found during the 3 consecutive seasons, with midfielders covering greater distances than defenders (p < 0.05) and forwards (p < 0.01). This study showed how for 3 consecutive seasons a Serie A team of successful players reduced their distances performed at submaximal speeds, and increased ball possession, while maintaining the high-intensity activities and the number of points at home. It is suggested that this is because of a better understanding of roles and tactics team organization and to act collectively and individually on these parameters to reduce energy expenditure during the game to maintain a high-level performance throughout the season. PMID- 22820209 TI - Building without a plan: the career experiences of Australian strength and conditioning coaches. AB - The purpose of this investigation was to explore the career experiences of Australian strength and conditioning coaches. Six Australian strength and conditioning coaches (mean age = 33.7 years, SD = 6.0 years) with a mean of 10.4 (SD = 4.9) years experience working with elite Olympic and professional athletes were interviewed about their experiences of career development. Each interview was transcribed verbatim and analyzed to produce key themes and subthemes relating to (a) work environments, (b) sport management practice, (c) career development processes, and (d) career building strategies. The work environments of Australian strength and conditioning coaches were found to be poor because of long working hours and irregular human resource policy and management practices of sport organizations. Because of the volatile and unpredictable nature of their working conditions, the coaches interviewed have only a short-term view of their career creating considerable stress in their lives. The coaches interviewed found it difficult to develop their careers because their only options were self supported and self-funded professional development activities. The coaches in this study believed that more needed to be done at a policy and management level by sport organizations and their professional body to enhance the career development of strength and conditioning coaches because they play a key role in both athlete and sport organization performance. These results may help sport organizations develop policies and management practices that enhance the careers of strength and conditioning coaches and will have important practical implications for the education and development of sport professionals. PMID- 22820210 TI - Topical cooling (icing) delays recovery from eccentric exercise-induced muscle damage. AB - It is generally thought that topical cooling can interfere with blood perfusion and may have positive effects on recovery from a traumatic challenge. This study examined the influence of topical cooling on muscle damage markers and hemodynamic changes during recovery from eccentric exercise. Eleven male subjects (age 20.2 +/- 0.3 years) performed 6 sets of elbow extension at 85% maximum voluntary load and randomly assigned to topical cooling or sham groups during recovery in a randomized crossover fashion. Cold packs were applied to exercised muscle for 15 minutes at 0, 3, 24, 48, and 72 hours after exercise. The exercise significantly elevated circulating creatine kinase-MB isoform (CK-MB) and myoglobin levels. Unexpectedly, greater elevations in circulating CK-MB and myoglobin above the control level were noted in the cooling trial during 48-72 hours of the post-exercise recovery period. Subjective fatigue feeling was greater at 72 hours after topical cooling compared with controls. Removal of the cold pack also led to a protracted rebound in muscle hemoglobin concentration compared with controls. Measures of interleukin (IL)-8, IL-10, IL-1beta, and muscle strength during recovery were not influenced by cooling. A peak shift in IL-12p70 was noted during recovery with topical cooling. These data suggest that topical cooling, a commonly used clinical intervention, seems to not improve but rather delay recovery from eccentric exercise-induced muscle damage. PMID- 22820211 TI - Physiological responses and activity profiles of football small-sided games. AB - The aim of this study was to identify the acute physiological responses and activity profiles of football small-sided games (SSG) formats. Ten professional football players participated in 4 variations of SSG (2-, 3-, 4-, and 5-a-side) with an intermittent regime involving 3 * 6-minute bouts with 1 minute of passive planned rest in which the heart rate (HR), rating of perceived exertion (RPE), activity profile, and body load were recorded. The higher percentage of maximum HR values were found in 2- and 3-a-side formats (p <= 0.05). The lowest RPE value was found at the 5-a-side, and the highest was found at the 2-a-side (13.48 +/- 2.67 and 17.01 +/- 1.80, respectively, p <= 0.05). The distance covered in the 2 a-side format (598.97 +/- 78.91 m) was smaller than in all other formats. The 2-a side format presented the lowest number of sprints (0.71 +/- 0.86) and the 3-a side the highest (2.50 +/- 1.65). Statistically significant differences were found across SSG in the total body load. The 4-a-side presented the highest and the 5-a-side the lowest values (95.18 +/- 17.54 and 86.43 +/- 14.47, respectively). The body load per minute declined each 2 minutes of play. Maintaining a constant area:player ratio, coaches can use lower number of players (2- and 3-a-side) to increase cardiovascular effects but use higher number of players (4- and 5-a-side) to increase variability and specificity according to the competition demands. PMID- 22820212 TI - Expression of transient receptor potential (TRP) channel mRNAs in the mouse olfactory bulb. AB - Transient receptor potential (TRP) channels are a large family of cation channels. The 28 TRP channel subtypes in rodent are divided into 6 subfamilies: TRPC1-7, TRPV1-6, TRPM1-8, TRPP2/3/5, TRPML1-3 and TRPA1. TRP channels are involved in peripheral olfactory transduction. Several TRPC channels are expressed in unidentified neurons in the main olfactory bulb (OB), but the expression of most TRP channels in the OB has not been investigated. The present study employed RT-PCR as an initial survey of the expression of TRP channel mRNAs in the mouse OB and in 3 cell types: external tufted, mitral and granule cells. All TRP channel mRNAs except TRPV5 were detected in OB tissue. Single cell RT-PCR revealed that external tufted, mitral and granule cell populations expressed in aggregate 14 TRP channel mRNAs encompassing members of all 6 subfamilies. These different OB neuron populations expressed 7-12 channel mRNAs. Common channel expression was more similar among external tufted and mitral cells than among these cells and granule cells. These results indicate that a large number of TRP channel subtypes are expressed in OB neurons, providing the molecular bases for these channels to regulate OB neuron activity and central olfactory processing. PMID- 22820213 TI - The propylthiouracil dilemma. AB - PURPOSE OF REVIEW: To bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982 2008) for acute liver failure in PTU-treated hyperthyroid patients, and propose recommendations for the clinical use of PTU. Thirteen files of PTU-related severe liver adverse effects were analyzed for the pediatric population, seventeen for nonpregnant adults and two for pregnant women. RECENT FINDINGS: The recent findings showed that the daily PTU dose administered was high in the children, with a mean of 300 mg/day for an average 10-year-old individual. With regard to treatment duration, PTU administration lasted for at least 4 months in 75% of pediatric cases. Similarly, in a majority of adult cases (64%), PTU-induced liver injury occurred after a relatively long treatment period (4 months to >1 year). SUMMARY: PTU should not be used in children, in whom methimazole (MMI) represents the logical alternative. In adults, PTU should be restricted to those rare patients with Graves' disease for whom no better alternative can be offered and in patients with thyroid storm. For the special circumstance of pregnancy, PTU is the preferred choice during early gestation; switching back to MMI during later gestational stages remains a matter of clinical judgment. It is unknown whether liver function tests monitoring is worthwhile to prevent life-threatening, PTU related hepatotoxicity. PMID- 22820215 TI - Are Older Adults Who Volunteer to Participate in an Exercise Study Fitter and Healthier than Non-Volunteers? The participation bias of the study population. AB - BACKGROUND: Participation bias in exercise studies is poorly understood among older adults. This study was aimed at looking into whether older persons who volunteer to participate in an exercise study differ from non-volunteers. METHODS: A self-reported questionnaire on physical activity and general health was mailed out to 1000 persons, aged 60 or over, who were covered by the medical insurance of the French National Education System. Among them, 535 answered it and sent it back. Two hundred and thirty-three persons (age 69.7 +/-7.6, 65.7% women) said they would volunteer to participate in an exercise study and 270 (age 71.7 +/-8.8, 62.2% women) did not. RESULTS: Volunteers were younger and more educated than non-volunteers, but they did not differ in sex. They had less physical function decline and higher volumes of physical activity than non volunteers. Compared to volunteers, non-volunteers had a worse self-reported health and suffered more frequently from chronic pain. Multiple logistic regressions showed that good self-reported health, absence of chronic pain, and lower levels of physical function decline were associated with volunteering to participate in an exercise study. CONCLUSIONS: Volunteers were fitter and healthier than non-volunteers. Therefore, caution must be taken when generalizing the results of exercise intervention studies. PMID- 22820214 TI - Iodine-induced thyroid dysfunction. AB - PURPOSE OF REVIEW: To summarize the mechanisms of iodine-induced hypothyroidism and hyperthyroidism, identify the risk factors for thyroid dysfunction following an iodine load, and summarize the major sources of excess iodine exposure. RECENT FINDINGS: Excess iodine is generally well tolerated, but individuals with underlying thyroid disease or other risk factors may be susceptible to iodine induced thyroid dysfunction following acute or chronic exposure. Sources of increased iodine exposure include the global public health efforts of iodine supplementation, the escalating use of iodinated contrast radiologic studies, amiodarone administration in vulnerable patients, excess seaweed consumption, and various miscellaneous sources. SUMMARY: Iodine-induced thyroid dysfunction may be subclinical or overt. Recognition of the association between iodine excess and iodine-induced hypothyroidism or hyperthyroidism is important in the differential diagnosis of patients who present without a known cause of thyroid dysfunction. PMID- 22820216 TI - Hybrid PIV-PTV technique for measuring blood flow in rat mesenteric vessels. AB - The micro-particle tracking velocimetry (MU-PTV) technique is used to obtain the velocity fields of blood flow in the microvasculature under in vivo conditions because it can provide the blood velocity distribution in microvessels with high spatial resolution. The in vivo MU-PTV technique usually requires a few to tens of seconds to obtain a whole velocity profile across the vessel diameter because of the limited number density of tracer particles under in vivo conditions. Thus, the MU-PTV technique alone is limited in measuring unsteady blood flows that fluctuate irregularly due to the heart beating and muscle movement in surrounding tissues. In this study, a new hybrid PIV-PTV technique was established by combining PTV and particle image velocimetry (PIV) techniques to resolve the drawbacks of the MU-PTV method in measuring blood flow in microvessels under in vivo conditions. Images of red blood cells (RBCs) and fluorescent particles in rat mesenteric vessels were obtained simultaneously. Temporal variations of the centerline blood velocity were monitored using a fast Fourier transform-based cross-correlation PIV method. The fluorescence particle images were analyzed using the MU-PTV technique to extract the spatial distribution of the velocity vectors. Data from the MU-PTV and PIV methods were combined to obtain a better estimate of the velocity profile in actual blood flow. This technique will be useful in investigating hemodynamics in microcirculation by measuring unsteady irregular blood flows more accurately. PMID- 22820223 TI - Views of biobanking research among Alaska native people: the role of community context. AB - BACKGROUND: Research using stored clinical data and samples held in biobanks has potential to address health disparities in minority communities. However, ethical and cultural considerations about use of these samples for research warrant attention. Literature about how Alaska Native people (ANs) view biobanking research consists largely of theoretical papers and position statements with limited systematic information gathered from a broad range of ANs. OBJECTIVES: To explore the views of biobanking research among AN community members and leaders across Alaska using a community-based participatory research approach with tribal and federal partners. METHODS: We approached tribal health organizations (THOs) to partner and guide the study in their regions. Community liaisons were hired to lead study recruitment. Twenty-nine focus groups were conducted in 14 locations with participation from 82 community members and 81 tribal leaders. Data were analyzed using a grounded theory approach. RESULTS: We identified five themes that contributed to participants' views on biobanking: (1) Prior experiences with research and medical care, (2) stigmatizations, relevance, and applicability, (3) effects of governmental and cultural change, (4) concerns about unknown capability of future technologies, and (5) benefit for future generations. Respondents raised AN-specific cultural concerns along with global ethical concerns alongside the potential promise of research in improving AN health. CONCLUSIONS: This study offers considerations for researchers partnering with AN communities when planning research and public health surveillance projects. Findings also have implications for other minority communities harmed by past research and other societal changes. PMID- 22820222 TI - Community-based HIV clinical trials: an integrated approach in underserved, rural, minority communities. AB - BACKGROUND: Although racial and ethnic minorities have disproportionately high rates of HIV infection, these groups are underrepresented in HIV-related clinical trials. This illustrates the need for more innovation in attempts to engage underrepresented populations in calls for interdisciplinary and translational research. OBJECTIVES: Eleven focus groups and 35 interviews were conducted with people living with HIV/AIDS (PLWHA) to explore the perspectives of rural community leaders, service providers, and PLWHA about bringing HIV-related research, including clinical trials, into rural communities. METHODS: Over a period of 3 months in spring 2007, we collected qualitative data from three sources: Community leaders, service providers, and PLWHA. Text data were analyzed using the constant comparative method and content analysis techniques of theme identification. RESULTS: Respondents want an integrated approach to HIV research that builds trust, meets community needs, and respects their values. They conceptualize HIV research as part of a broader spectrum of HIV testing, prevention, and care, and suggest integrating HIV trials with existing community services, organizations, and structures, engaging various segments of the community, and conducting research using a personal approach. CONCLUSIONS: These findings support calls for more relevant, translational, and engaged research. An integrated approach may be an important innovation to transform the research enterprise to meet these goals and more directly improve the health of individuals. PMID- 22820224 TI - Location and organizational features: what type of veteran communities participate in health programs? AB - BACKGROUND: Research shows that community-based membership organizations are effective partners in health promotion activities; however, most community organizations do not participate in such partnerships. There is little research regarding the geographical and organizational characteristics associated with participation. OBJECTIVE: We examined the factors associated with community-based veterans service organization (VSO) units' decision to participate in a health promotion project. METHODS: We collected location and organizational characteristics regarding 218 VSO units asked to participate in POWER, a partnership to improve hypertension self-management skills between the Medical College of Wisconsin, the Milwaukee Veterans Affairs Medical Center (VAMC) and Wisconsin branches of the American Legion, Veterans of Foreign Wars (VFW), Vietnam Veterans of America, and National Association of Black Veterans. We tested the association of these characteristics with participation using chi square and Fisher's exact tests for categorical variables, and analysis of variance and the Kruskal-Wallis test for continuous variables. We used multivariable logistic regression to identify factors independently associated with participation. RESULTS: In bivariable analyses, likelihood of participation was positively associated with increasing membership (p < .001), meeting attendance (p < .001), publication of an organizational newsletter (p < .001), presence of a women's auxiliary (p = .02), and location within 44 miles of the VAMC (p = .047). On multivariable analysis, only meeting attendance and census tract-level educational attainment predicted participation. CONCLUSIONS: Greater membership sizes, meeting attendance, and more group resources might be important factors for researchers to consider when initiating community-based health and wellness programs. PMID- 22820225 TI - Exploring community gardens in a health disparate population: findings from a mixed methods pilot study. AB - BACKGROUND: Despite recommendations, there have been few efforts to apply the community-based participatory research (CBPR) approach in the development, implementation, and evaluation of community gardens. OBJECTIVES: As guided by the CBPR approach and grounded in a social-ecological model and behavioral theory, the purpose of this mixed methods study was to understand opinions and interests in developing and implementing a community garden and to understand factors impacting fruit, vegetable, and gardening behaviors. METHODS: Community and academic members collaborated to develop and execute this study. The qualitative phase- targeting regional key informants-was designed to elicit perceived benefits and challenges of community gardens at the environmental, community, and individual levels. The quantitative phase targeted low resourced youth and parents and included a variety of validated theory-based questionnaires to understand factors impacting fruit, vegetable, and gardening behaviors. RESULTS: Major benefits of community gardens that emerged from the 10 qualitative interviews included increasing community cohesion and improving nutrition and physical activity factors. The quantitative phase included 87 youth and 67 parents. Across 16 items for fruits and vegetables, the average willingness to try was 1.32 (standard deviation [SD] = 0.40) on a 2-point scale. The majority of youth indicated they would work in a garden (n = 59; 68%) and eat food grown in their garden (n = 71; 82%). Among parents, gardening attitude, belief, and self efficacy scores were all above average; however, gardening intentions were neutral. CONCLUSION: This research illustrates the successful partnering a community-academic team and has provided the partnership with a clearer lens to conceptualize and launch future regional community garden efforts. PMID- 22820226 TI - Training of community health workers to deliver cancer patient navigation to rural African American seniors. AB - BACKGROUND: Rural African American (AA) seniors may experience significant challenges during cancer treatment. Previous research suggests community health workers (CHWs) can provide effective cancer patient navigation (CPN) support. OBJECTIVES: To develop a Train the Trainers (TTT) program for CHWs in rural Central Virginia who would navigate local AA seniors with cancer and train their support persons to provide similar types of assistance. METHODS: We conducted focus groups with rural AA seniors, consulted with experienced CHW trainers, recruited and trained CHWs through a combination of online learning and distance education, evaluated the TTT via surveys and focus groups, and hired CHWs to the study team. RESULTS/LESSONS LEARNED: Lessons learned from our TTT experience include the value of incorporating CHW trainers and trainees as full members of the research team. CONCLUSIONS: Training should be accessible and flexible, providing trainees community-level resources and enriched educational experiences. Findings have informed a culturally tailored support CHW intervention to address cancer diagnosis and treatment needs for older rural AAs. PMID- 22820228 TI - Youth-led tobacco prevention: lessons learned for engaging Southeast Asian American youth. AB - BACKGROUND: Southeast Asian Americans are highly at risk for tobacco use. Youth led, environmentally focused tobacco prevention programs have been identified as highly effective in engaging youth in tobacco research and prevention, but may be challenging for the most at-risk youths. OBJECTIVES: We report on lessons learned in a pilot tobacco prevention program with Southeast Asian youth in Northern California. METHODS: We reviewed meeting notes, participatory research products, and a transcribed focus group with tobacco prevention project participants. LESSONS LEARNED: Challenges to the youths' participation related to structural issues (limited time, scheduling conflicts, financial difficulties, aging out of programs) and personal issues (school and work pressure, family stressors). Coordinating with ongoing program activities and the county coalition enabled some supports as well as challenges. CONCLUSIONS: Key supports for youth were youth leaders, social and financial rewards, and the ability to interpret tobacco prevention information in culturally and age-relevant media. PMID- 22820229 TI - Development of the live well curriculum for recent immigrants: a community-based participatory approach. AB - BACKGROUND: There are few weight gain prevention interventions aimed at new immigrants. Live Well, a community-based participatory research (CBPR) study, was designed to address this gap. OBJECTIVE: The goal of this paper is to describe the development of the Live Well nutrition and physical activity curriculum. METHODS: The curriculum draws on behavioral theory and popular education and was co-created, implemented, and will be evaluated by community partners and academic researchers. RESULTS: The time it took to develop the curriculum exceeded initial estimates. However, the extra time taken was spent engaging in needed dialogue to create a better product, fully co-created by academic and community partners. Additionally, working with an outside expert created the opportunity for all partners to train together, build capacity, and increase cohesion. Our approach developed relationships and trust, and resulted in a unique curriculum. CONCLUSIONS: The commitment to partnership resulted in a curriculum to empower immigrant women to improve health decisions and behaviors. This will inform future research and programming targeting other at-risk and new immigrant communities. PMID- 22820231 TI - Team-building activities as strategies for improving community-university partnerships: lessons learned from Nuestro Futuro Saludable. AB - BACKGROUND: Collaboration characterized by mutual capacity building, asset sharing, and tangible outcomes that work to further health equity are central tenets of community-based participatory (CBPR) approaches to research. Such efforts require the establishment, development, and maintenance of trusting relationships between community and institutional stakeholders. OBJECTIVES: The objective of the strategies discussed here was to strengthen a community-academic partnership by facilitating communication and empowering project partners. METHODS: Team-building activities and experiential exercises were intentionally utilized with project stakeholders to clarify roles and responsibilities, provide alternative avenues for authentic communication, and share power. LESSONS LEARNED: Team-building activities can be effective in promoting CBPR partnerships when utilized appropriately. Through the course of the partnership building process, best practices emerged for utilizing experiential learning exercises to enhance partnership dynamics. CONCLUSIONS: Team-building activities provide a useful tool for developing supportive environments that encourage open dialogue. PMID- 22820230 TI - Mobilizing for policy: using community-based participatory research to impose minimum packaging requirements on small cigars. AB - THE PROBLEM: Cigarette sales have declined in the United States over the past decade; however, small cigar sales have been rapidly increasing. In most urban areas, small cigars are inexpensive and are sold as singles without health warnings. PURPOSE OF ARTICLE: This paper describes a community- academic-practice partnership's (CAPP) efforts to decrease small cigar use in young adults living in Baltimore, Maryland, through legislative strategies. KEY POINTS: Survey data among young adults not in school indicated that 20% of individuals reported current small cigar use, often in combination with cigarettes. The community- academic partnership engaged the community in discussion about small cigar use in the fall of 2007. In collaboration with partners, bills were submitted to the legislative bodies for the city and state to impose minimum packaging requirements on small cigars. CONCLUSION: Collaborative partnerships between community-based organizations, public health agencies, and academic institutions can lead to policy initiatives with the potential to improve public health. PMID- 22820232 TI - Dimensions of community and organizational readiness for change. AB - BACKGROUND: Readiness can influence whether health interventions are implemented in, and ultimately integrated into, communities. Although there is significant research interest in readiness and capacity for change, the measurement of these constructs is still in its infancy. OBJECTIVE: The purpose of this review was to integrate existing assessment models of community and organizational readiness. DATA SOURCES: The database PubMed was searched for articles; articles, book chapters, and practitioner guides identified as references cited in the list of core articles. REVIEW METHODS: Studies were included if they met the following criteria: (1) Empirical research, (2) identified community or organizational readiness for innovative health programming in the study's title, purpose, research questions, or hypotheses, and (3) identified methods to measure these constructs. Duplicate articles were deleted and measures published before 1995 were excluded. The search yielded 150 studies; 13 met all criteria. RESULTS: This article presents the results of a critical review of 13 community and organizational readiness assessment models, stemming from articles, chapters, and practitioner's guides focusing on assessing, developing, and sustaining community and organizational readiness for innovative public health programs. CONCLUSIONS: Readiness is multidimensional and different models place emphasis on different components of readiness, such as (1) community and organizational climate that facilitates change, (2) attitudes and current efforts toward prevention, (3) commitment to change, and (4) capacity to implement change. When initiating the program planning process, it is essential to assess these four domains of readiness to determine how they apply to the nuances across different communities. Thus, community-based participatory research (CBPR) partnerships, in efforts to focus on public health problems, may consider using readiness assessments as a tool for tailoring intervention efforts to the needs of the community. PMID- 22820235 TI - Brain networks subserving fixed versus performance-adjusted delay stop trials in a stop signal task. AB - The stop signal task is a widely used tool for assessing inhibitory motor control. Two main task variants exist: (1) a fixed delay version, where all volunteers complete the same trials, resulting in performance differences due to individual variation in inhibitory capacity, and (2) a performance-adjusted version that uses a tracking algorithm to equate performance and task difficulty across subjects, leading to ~50% successful inhibition for every participant. Our aim was to investigate commonalities, mean differences and between-subject variability in brain activation for successful response inhibition between the performance-adjusted and fixed delay version. We conducted a functional magnetic resonance imaging (fMRI) study in 18 healthy individuals, using a within-subject, within-task design where both adjusting and fixed delay trials were analysed separately. Conjunction analyses identified a network of areas involved in successful response inhibition in both task versions. In comparing the fixed and performance-adjusted versions, we found no significant differences between delay conditions during successful inhibition. While activation measures in the inhibitory networks of both delay variants were highly comparable, the neural responses to fixed delay trials were more variable across participants. This suggests that performance-adjusted stop signal tasks may be more suitable for studies in which the performance differences need to be controlled for, such as for developmental or clinical studies. Fixed delay stop signal tasks may be more appropriate in studies assessing the neural basis of individual differences in performance, such as studies of personality traits or genetic associations. PMID- 22820234 TI - Curcumin produces antidepressant effects via activating MAPK/ERK-dependent brain derived neurotrophic factor expression in the amygdala of mice. AB - The potential antidepressant effects of curcumin have been demonstrated in various animal models of depression, however, there is little information regarding the site and mechanisms of curcumin in promoting antidepressant effects. The present study attempts to explore the mechanisms underlying the antidepressant-like action of curcumin by measuring the contents of brain derived neurotrophic factor (BDNF) in the amygdala of animal model of depression. The results showed that treatment with curcumin (40 mg/kg, i.p.) significantly reduced depressive-like behaviors of mice in the forced swim test. Chronic administration of curcumin (40 mg/kg, i.p., 21 days) increased BDNF protein levels in the amygdala and this enhancement was suppressed by pretreatment with the extracellular signal-regulated kinase (ERK) inhibitor SL327. Additionally, the increased levels of ERK phosphoryation in the amygdala by curcumin were blocked by the ERK inhibitor, and inhibition of this kinase prevented the antidepressant effects of curcumin. All of these effects of curcumin, were essentially identical to that observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of curcumin in the forced swim test are mediated, at least in part, by an ERK regulated increase of BDNF expression in the amygdala of mice. PMID- 22820236 TI - 3alpha5beta-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia. AB - Neuroactive steroids modulate receptors for neurotransmitters in the brain and thus might be efficacious in the treatment of various diseases of the central nervous system such as schizophrenia. We have designed and synthetized a novel use-dependent NMDA receptor antagonist 3alpha5beta-pregnanolone glutamate (3alpha5beta-P-Glu). In this study, we evaluate procognitive properties of 3alpha5beta-P-Glu in an animal model of schizophrenia induced by systemic application of MK-801. The procognitive properties were evaluated using active place avoidance on a rotating arena (Carousel maze). We evaluated effects of 3alpha5beta-P-Glu on the avoidance, on locomotor activity, and anxiety. 3alpha5beta-P-Glu alone altered neither spatial learning nor locomotor activity in control animals. In the model animals, 3alpha5beta-P-Glu reversed the MK-801 induced cognitive deficit without reducing hyperlocomotion. The highest dose of 3alpha5beta-P-Glu also showed anxiolytic properties. Taken together, 3alpha5beta P-Glu may participate in the restoration of normal brain functioning and these results may facilitate the development of new promising drugs improving cognitive functioning in schizophrenia. PMID- 22820233 TI - Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. AB - Mutations in neurexin and neuroligin genes have been associated with neurodevelopmental disabilities including autism. Autism spectrum disorder is diagnosed by aberrant reciprocal social interactions, deficits in social communication, and repetitive, stereotyped patterns of behaviors, along with narrow restricted interests. Mouse models have been successfully used to study physiological and behavioral outcomes of mutations in the trans-synaptic neurexin neuroligin complex. To further understand the behavioral consequences of Neuroligin2 (NLGN2) mutations, we assessed several behavioral phenotypes relevant to autism in neuroligin2 null (Nlgn2(-/-)), heterozygote (Nlgn2(+/-)), and wildtype (Nlgn2(+/+)) littermate control mice. Reduced breeding efficiency and high reactivity to handling was observed in Nlgn2(-/-) mice, resulting in low numbers of adult mice available for behavioral assessment. Consistent with previous findings, Nlgn2(-/-) mice displayed normal social behaviors, concomitant with reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones. No spontaneous stereotypies or repetitive behaviors were detected. Acoustic, tactile, and olfactory sensory information processing as well as sensorimotor gating were not affected. Nlgn2(-/-) pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2(+/+) littermate controls. The present findings add to the growing literature on the role of neurexins and neuroligins in physiology and behavior relevant to neurodevelopmental disorders. PMID- 22820237 TI - Corticosterone attenuates conditioned fear responses and potentiates the expression of GABA-A receptor alpha-2 subunits in the brain structures of rats selected for high anxiety. AB - The aim of the experiment was to assess the effects of an acutely administered corticosterone on the expression of GABA-A receptor alpha-2 subunits in the brain structures of high (HR) and low (LR) anxiety rats (divided according to their conditioned fear-induced freezing response) subjected to a second conditioned fear session (1 week after fear conditioning). We found that corticosterone (20 mg/kg, sc) given to rats prior to the second conditioned fear session significantly enhanced a decrease in fear expression in the HR group. The behavioural effect of fear was accompanied by the increased expression of alpha-2 subunits in the basolateral amygdala (BLA) and the dentate gyrus of the hippocampus (DG) of the HR group. Corticosterone potentiated the effect of fear on alpha-2 subunit expression in the BLA, DG, the cingulate cortex area 1 and the secondary motor cortex (areas Cg1 and M2). The current study provides insight into the mechanisms that may be responsible for the beneficial effects of glucocorticoids in the therapy of some anxiety disorders. PMID- 22820238 TI - Discrimination of type 2 diabetes mellitus corresponding to different traditional Chinese medicine syndromes based on plasma fatty acid profiles and chemometric methods. AB - AIMS OF THE STUDY: Traditional Chinese medicine (TCM) has a long history and particular advantages in the diagnosis and treatment of type 2 diabetes mellitus (T2DM). Syndrome differentiation is the foundation and essence of TCM theories. The aims of the study are to discriminate T2DM corresponding to different syndromes (Qi-deficiency, Qi and Yin-deficiency and Damp heat) and discover syndrome-related biomarkers using metabolomics technology. MATERIALS AND METHODS: Plasma fatty acid profiles of 85 clinical samples were established by high performance liquid chromatography (HPLC). Moreover, some of the lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), were obtained through clinical testing methods. Orthogonal signal correction-partial least squares (OSC-PLS) and uncorrelated linear discriminant analysis (ULDA) were employed to establish two class models for three different syndromes. RESULTS: Compared with the plasma fatty acid profiles of healthy controls, the characteristic fatty acids of three TCM syndromes were discovered (p<0.01). Totally, the plasma fatty acids of T2DM were up-regulated, while significant differences existed in different syndromes. Results of ULDA indicate that the three TCM syndromes could be effectively separated by the plasma fatty acid profiles and the syndrome-related biomarkers were also screened. CONCLUSIONS: The fact that three TCM syndromes can be separated indicates certain metabolic differences in different TCM syndromes of T2DM really exist and such differences can be manifested by fatty acids and lipid parameters. The results benefit modern biological interpretation of the three TCM syndromes and in a sense the diagnosis and treatment of diabetes. PMID- 22820239 TI - Pomegranate peel and fruit extracts: a review of potential anti-inflammatory and anti-infective effects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Punica granatum L. (Punicaceae) has been used for centuries in many cultures for the prevention and treatment of a wide number of health disorders such as inflammation, diabetes, diarrhea, dysentery, dental plaque and to combat intestinal infections and malarial parasites. AIM OF THE REVIEW: This review aims at providing an up-to-date overview of the chemical constituents, traditional uses, phytochemistry, pharmacology and toxicology of Punica granatum L. Moreover, the focus of this review is the possible exploitation of this species to treat different diseases and to suggest future investigations. MATERIALS AND METHODS: An extensive and systematic review of the extant literature was carried out, and the data under various sections were identified by using a computerized bibliographic search via PubMed, Web of Science and Google Scholar. All abstracts and full-text articles were examined. The most relevant articles were selected for screening and inclusion in this review. KEY FINDINGS: A variety of pomegranate ethnomedical uses have been recorded. Additionally, over the last decade, there has been a dramatic increase of interest in pomegranate as a medicinal and nutritional product due to its n1ewly identified potential health effects, which include treatment and prevention of cancer and cardiovascular diseases. From the toxicological perspective, pomegranate fruit juice, extracts and preparations have been proven to be safe. CONCLUSIONS: The ethnopharmacological relevance of pomegranate is fully justified by the most recent findings indicating the fruit is a medicinal and nutritional agent useful for treating a wide range of human disorders and maladies. Further investigations are needed to fully understand the mode of action of the active constituents and to fully exploit pomegranate's preventive and therapeutic potential. PMID- 22820241 TI - Life or death: neuroprotective and anticancer effects of quercetin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Quercetin is a ubiquitous flavonoid that is present in numerous plants that are utilized in many different cultures for their nervous system and anticancer effects. To better understand the neuroprotective and antiproliferative activities of quercetin, we present a comprehensive review of the divergent actions that contribute to the ethnopharmacological profile of these plants. RESULTS: The pharmacological activities of quercetin that modulate antioxidation/oxidation/kinase-signaling pathways might be differentially elicited in neurons compared with malignant cells, ultimately promoting cell survival or death in a cell type- and metabolism-specific manner. Whereas the broad antioxidation and anti-inflammatory activities of quercetin are important for neuronal survival, the oxidative, kinase- and cell cycle-inhibitory, apoptosis-inducing effects of quercetin are essential for its anticancer effects. The diverse mechanistic interactions and activities of quercetin that modulate the phosphorylation state of molecules as well as gene expression would alter the interconnected and concerted intracellular signaling equilibrium, either inhibiting or strengthening survival signals. These mechanisms, which have been mainly observed in in vitro studies, cannot be easily translated into an explanation of the divergent simultaneous neuroprotective and anticancer effects observed in vivo. This is in part due to low bioavailability in plasma and in the brain, as well as the nature of the actual active molecules. CONCLUSIONS: Numerous studies have demonstrated the beneficial effects of chronic quercetin intake, which is ethnopharmacologically meaningful, as many plants that are chronically ingested by people contain quercetin. Although quercetin and quercetin-containing plants exhibit potential as therapeutic modalities in neuropathology and in cancer, the data collectively highlight the need to elucidate issues such as bioavailability as well as its correlation with effectiveness at biomarkers in vivo. There would be an increased potentential of these plants for chemoprevention and neuropathology prevention. PMID- 22820240 TI - Effect of the flavonoid fraction of Lithocarpus polystachyus Rehd. on spontaneously hypertensive and normotensive rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lilhocarpus polystachys Rehd. (Sweet Tea, ST) is a folk herbal medicine that has been traditionally used as a natural remedy for hypertension in China, whose mechanism remains unveiled. Flavonoid fraction is considered as the major active components in ST. This study aimed to provide experimental evidence for the anti-hypertension activity of flavonoid fraction of ST (ST-F) and investigate the underlying mechanism. The effect of ST-F on the blood pressure of normotensive rats was also to be determined. MATERIALS AND METHODS: Spontaneously hypertensive rats (SHRs) were treated with ST-F daily for 10 weeks. Blood pressure of SHRs was measured before and biweekly during ST-F treatment. Subsequently, animals were sacrificed either immediately at the end of treatment or 2 weeks after ST-F treatment discontinuance. The activities of plasma rennin (PRA), angiotensin II (Ang-I), endothelin (ET), nitric oxide (NO), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured as well as skin microcirculatory flux. In normotensive rats, blood pressure was determined after six months' treatment of ST-F. RESULTS: ST-F treatment significantly reduced the blood pressure of SHRs along with decreasing plasma levels of PRA and Ang II. ST-F did not show obvious effects on plasma levels of ET, NO or SOD, but it significantly decreased the plasma level of MDA and improved skin microcirculatory flux. Compared to the anti-hypertensive drug enalapril, ST-F showed a modest effect on lowering blood pressure of SHRs without obvious withdrawal reactions. But long-term intake of ST-F did not change the blood pressure in normotensive rats. CONCLUSION: ST-F had an antihypertensive effect on SHRs. The underlying mechanism could be related to modulation on the rennin angiotensin-aldosterone system (RAAS) and antioxidation system, as well as regulation of skin microcirculation. Compared to its anti-hypertensive effect on SHRs, ST-F did not cause hypotension in normotensive rats. The results indicated that ST-F could potentially be used as natural drugs or functional foods for preventing hypertension. PMID- 22820242 TI - Anti-cancer properties of terpenoids isolated from Rhizoma Curcumae--a review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Curcumae is a popular type of traditional Chinese medicine whose essential oils are widely used in the treatment of cancer in China. This review aims to systematically summarize and analyze the anti cancer properties of terpenoids, the main components of essential oils in Rhizoma Curcumae, and thus enable the development of new anti-cancer drugs. MATERIALS AND METHODS: Information on the recent progress of anti-cancer studies on terpenoids isolated from Rhizoma Curcumae, including beta-elemene, delta-elemene, furanodiene, furanodienone, curcumol, and germacrone, was gathered and analyzed. RESULTS: Among these terpenoids, beta-elemene is the most widely studied, whereas delta-elemene, furanodiene, furanodienone, curcumol, and germacrone have just recently attracted the attention of researchers. The anti-cancer effects of these terpenoids are related to the retardation of cell cycle arrest, the induction of apoptosis, and the inhibition of metastasis or tissue invasion, among others. CONCLUSIONS: Most studies have focused on the in vitro data, and in vivo data is urgently needed. Further insight into the anti-cancer activity and the molecular basis of these compounds, combined with efforts in pharmaceutical chemistry and/or pharmaceutics, will potentially enable the development of new anti-cancer agents. PMID- 22820243 TI - Ethnomedicinal practices in different communities of Uttara Kannada district of Karnataka for treatment of wounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Uttara Kannada district is located in the heart of the Western Ghats, one of the biodiversity hotspots, in Karnataka state of India. The thick evergreen forests are home to several ethnic communities. The study was under taken for documentation and analysis of ethnomedicinal plants in the treatment of wounds. MATERIALS AND METHODS: Field trips were made in Uttara Kannada district to identify the key informants. The collection of information was through semi-structured open ended interviews with a questionnaire. The questionnaire was designed to obtain the information about their experience in the field of treatment, number of patients treated per week, knowledge about the medicinal plants, vernacular names, parts of the plants used and other ingredients added during the drug formulations. Plants mentioned for treatment were photographed in the field, cuttings of the samples were taken and voucher specimens are deposited in the herbarium of P.G. Department of Botany, Karnatak University, Dharwad. The information such as botanical name, status, family, vernacular name habit and habitat, statistical analysis like percentage of parts used, Use value (UV) and Informants Consensus Factor (ICF) are provided. RESULTS: Present study resulted in recording 106 medicinal plant species of 55 families and 86 formulations to treat different types of wounds by 44 key informants. Among the 106 plants recorded four species are endemic to India and 22 species have the nativity outside India. Rest of the species have nativity both in India and elsewhere. The highest number of species belonged to Apocynaceae and Rubiaceae (6 species each). Trees are used more often (35.84%), followed by herbs (28.30%), shrubs (23.58%), climbers (11.32) and parasites (0.80%). Leaves are the major part of the plants used in the formulations (28.57%). The highest Use value is for Calycopteris floribunda (1.80), followed by Rauvolfia serpentina and Achyranthes aspera (1.67). The different types of wounds treated by traditional healers are classified into 15 categories and the highest ICF scored is for the burns (0.66). CONCLUSIONS: Ethnomedicinal survey in Uttara Kannada district of Karnataka revealed uses of 106 plants in traditional practices for curing various types of wounds. The statistical analysis confirmed high degree of sharing the knowledge amongst 44 key informants. Information about the largest number of remedies was obtained from the Havyaka Brahmin ethnic community which has strong Sanskrit background. PMID- 22820244 TI - Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis. AB - The rapid rise in bacterial drug resistance coupled with the low number of novel antimicrobial compounds in the discovery pipeline has led to a critical situation requiring the expedient discovery and characterization of new antimicrobial drug targets. Enzymes in the bacterial fatty acid synthesis pathway, FAS-II, are distinct from their mammalian counterparts, FAS-I, in terms of both structure and mechanism. As such, they represent attractive targets for the design of novel antimicrobial compounds. Enoyl-acyl carrier protein reductase II, FabK, is a key, rate-limiting enzyme in the FAS-II pathway for several bacterial pathogens. The organism, Porphyromonas gingivalis, is a causative agent of chronic periodontitis that affects up to 25% of the US population and incurs a high national burden in terms of cost of treatment. P. gingivalis expresses FabK as the sole enoyl reductase enzyme in its FAS-II cycle, which makes this a particularly appealing target with potential for selective antimicrobial therapy. Herein we report the molecular cloning, expression, purification and characterization of the FabK enzyme from P. gingivalis, only the second organism from which this enzyme has been isolated. Characterization studies have shown that the enzyme is a flavoprotein, the reaction dependent upon FMN and NADPH and proceeding via a Ping Pong Bi-Bi mechanism to reduce the enoyl substrate. A sensitive assay measuring the fluorescence decrease of NADPH as it is converted to NADP(+) during the reaction has been optimized for high-throughput screening. Finally, protein crystallization conditions have been identified which led to protein crystals that diffract x-rays to high resolution. PMID- 22820245 TI - Screening for the efficacy on lipid accumulation in 3T3-L1 cells is an effective tool for the identification of new anti-diabetic compounds. AB - Reducing lipid accumulation in insulin target tissues is critical for the treatment of type 2 diabetes. This study aimed to develop a biochemical assay in cells for high throughput (HTP) screening of anti-diabetic drugs by reducing lipid accumulation via different mechanisms. We designed a new method to extract triglyceride (TG) with KOH to allow biochemical quantification of TGs for HTP screening in 3T3-L1 cells. This new method was validated for its biochemical properties with identical results of TG obtained with or without KOH (r(2) = 0.9978, p < 0.001) and a fourfold improvement in TG extraction recovery rate (88 95%, p < 0.001) as compared to the conventional chloroform/methanol extraction (12-18%). The ability of this phenotype screening to capture potential anti diabetic drugs was verified by pharmacological agents well known to alter lipid accumulation by different mechanisms including AMPK activators, fatty acid synthesis inhibitors, PPARgamma activator and several lipogenic substrates. To further demonstrate the application of this screening tool for discovery of new anti-diabetic drugs, we screened >200 new candidates selected from Chinese medicine and identified 49 compounds from different classes which reduced TG content by >50% at 1 MUM or >75% at 10 MUM. Finally, we tested two selected leads (albiflorin and oxymatrine) in vivo and confirmed their efficacy in reducing visceral adiposity, glucose intolerance and hepatic steatosis in high fat-fed or high fructose-fed mice. Our results indicate that screening for the efficacy on lipid accumulation in cells by biochemical quantification of TGs with KOH extraction is an effective tool for the identification of new anti-diabetic compounds. PMID- 22820246 TI - Human UDP-glucuronosyltransferases: feedback loops between substrates and ligands of their transcription factors. AB - Expression profiles of human adult and fetal hepatic and intestinal UDP glucuronosyltransferases (UGTs), information about their endo- and xenobiotic substrates, and their transcriptional regulation suggests regulatory circuits between some UGT substrates and ligands of their transcription factors. For examples: (i) bilirubin is solely conjugated by UGT1A1 and activates its transcription factors Ah receptor, PXR and CAR. (ii) Hepatotoxic lithocholic acid (LCA) is oxidized to hyodeoxycholic acid, the latter conjugated by UGT2B4 and UGT2B7. LCA is also an agonist of FXR and PPARalpha, which are controlling these UGTs. (iii) Similar feedback loops possibly exist between some eicosanoids, PPARalpha and UGTs. (iv) Regulatory circuits may also have evolved between dietary polyphenols, which are efficient substrates of UGTs and activators of the Ah receptor. Although many newly developed drugs are conjugated by promiscuous UGTs, the discussed regulatory circuits may provide hints to evolutionary important UGT substrates. PMID- 22820247 TI - Allosteric inhibition of the DNA-dependent ATPase activity of Escherichia coli DNA gyrase by a representative of a novel class of inhibitors. AB - A novel class of bacterial DNA gyrase inhibitors has been shown previously to form a ternary complex with DNA and gyrase in a site distinct from the fluoroquinolone and ATP binding sites and does not cause double-strand-cleaved complex stabilization like fluoroquinolones. We show that, unlike fluoroquinolones, a representative compound inhibits DNA-dependent ATP hydrolysis by Escherichia coli gyrase and also blocks cleaved complex stabilization by ciprofloxacin. Conversely, ciprofloxacin blocks ATPase inhibition by the novel compound. We conclude that the compound acts allosterically to inhibit ATP binding or hydrolysis and interferes with the gyrase catalytic cycle at a different point than ciprofloxacin. PMID- 22820248 TI - Ursodeoxycholic acid stimulates the formation of the bile canalicular network. AB - Ursodeoxycholic acid (UDCA) is a hepatoprotective bile acid used in the treatment of chronic liver diseases. Although several pharmacological effects, including choleresis and inhibition of apoptosis, have been proposed, the impact of UDCA on hepatic structure is not well understood. Here, the influence of UDCA on bile canalicular (BC) morphology was evaluated in vitro in immortalized rat hepatocytes (McA-RH 7777 cells) and primary rat hepatocytes. Cells cultured for 3 days in the presence of UDCA, the BC lumen was enlarged and the bile canaliculi were surrounded by multiple cells (>=5) with a continuous canal-like structure, reminiscent of the in vivo BC network. The effects were dependent on p38MAPK and conventional PKC in McA-RH cells, and partially dependent on p38MAPK, MAPK/ERK kinase, and conventional PKC in primary rat hepatocytes. These findings were then studied in vivo in a rat model of dimethylnitrosamine-induced hepatic injury, in which the BC network is significantly disrupted. In accordance with the in vitro observations, administration of UDCA (40 mg/kg/day) to the injured rats for 18 days improved the BC network compared with the vehicle control. Serum hepatic markers were not altered by UDCA treatment, suggesting that the morphological effects were due to the direct actions of UDCA on network formation. Our data provide new evidence of the pharmacological potential of UDCA in accelerating or regenerating BC network formation in vitro, in hepatic cell culture models, and in vivo in a rat model of hepatic injury, and provide a basis for understanding its hepatoprotective effects. PMID- 22820249 TI - Profound conformational changes of PED/PEA-15 in ERK2 complex revealed by NMR backbone dynamics. AB - PED/PEA-15 is a small, non-catalytic, DED containing protein that is widely expressed in different tissues and highly conserved among mammals. PED/PEA-15 has been found to interact with several protein targets in various pathways, including FADD and procaspase-8 (apoptosis), ERK1/2 (cell cycle entry), and PLD1/2 (diabetes). In this research, we have studied the PED/PEA-15 in a complex with ERK2, a MAP kinase, using NMR spectroscopic techniques. MAP Kinase signaling pathways are involved in the regulation of many cellular functions, including cell proliferation, differentiation, apoptosis and survival. ERK1/2 are activated by a variety of external stimuli, including growth factors, hormones and neurotransmitters. Inactivated ERK2 is primarily found in the cytosol. Once the ERK/MAPK cascade is initiated, ERK2 is phosphorylated and stimulated, allowing it to redistribute in the cell nucleus and act as a transcription factor. Previous studies have shown that PED/PEA-15 complexes with ERK2 in the cytoplasm and prevents redistribution into the nucleus. Although the NMR structure and dynamics of PED/PEA-15 in the free form have been documented recently, no detailed structural and dynamic information for the ERK2-bound form is available. Here we report NMR chemical shift perturbation and backbone dynamic studies at the fast ps-ns timescale of PED/PEA-15, in its free form and in the complex with ERK2. These analyses characterize motions and conformational changes involved in ERK2 recognition and binding that orchestrate the reorganization of the DED and immobilization of the C-terminal tail. A new induced fit binding model for PED/PEA-15 is proposed. PMID- 22820250 TI - Post-genomic insight into thylakoid membrane lateral heterogeneity and redox balance. AB - Photosynthetic machinery requires balanced distribution of excitation energy from the light-harvesting complexes to photosystems. The efficiency of light harvesting is regulated by thermal dissipation of excess energy, while the distribution of energy between photosystems is dependent on STN7 kinase and phosphorylation of thylakoid proteins. The regulation of excitation energy transfer has been linked to the lateral segregation of photosynthetic complexes along the thylakoid membrane. The study of photosynthetic regulation mechanisms using Arabidopsis mutants, which have been available for the last ten years, has challenged traditional views on regulation of excitation energy distribution. Here, we discuss an urgent need to create a holistic view of the dynamics of the thylakoid membrane using systematic research of the mutants available today. PMID- 22820251 TI - The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses. AB - In response to environmental stresses, cells need to activate an adaptive program to maximize cell progression and survival. Stress-activated protein kinases (SAPK) are key signal transduction kinases required to respond to stress. Prototypical members of SAPKs are the yeast Hog1 and mammalian p38. Upon stress, those enzymes play a critical role in mounting the adaptive responses to stress such as the regulation of metabolism and the control of gene expression. In addition, a major function of SAPKs in response to stress is to modulate cell cycle progression. In this review, we focus on the role of Hog1 and p38 in the control of cell cycle progression in response to environmental stresses. PMID- 22820252 TI - Chromatin organization is a major influence on regional mutation rates in human cancer cells. AB - Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature-levels of the heterochromatin-associated histone modification H3K9me3-can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells. PMID- 22820253 TI - A biophysical signature of network affiliation and sensory processing in mitral cells. AB - One defining characteristic of the mammalian brain is its neuronal diversity. For a given region, substructure, layer or even cell type, variability in neuronal morphology and connectivity persists. Although it is well known that such cellular properties vary considerably according to neuronal type, the substantial biophysical diversity of neurons of the same morphological class is typically averaged out and ignored. Here we show that the amplitude of hyperpolarization evoked sag of membrane potential recorded in olfactory bulb mitral cells is an emergent, homotypic property of local networks and sensory information processing. Simultaneous whole-cell recordings from pairs of cells show that the amount of hyperpolarization-evoked sag potential and current (Ih) is stereotypic for mitral cells belonging to the same glomerular circuit. This is corroborated by a mosaic, glomerulus-based pattern of expression of the HCN2 (hyperpolarization-activated cyclic nucleotide-gated channel 2) subunit of the Ih channel. Furthermore, inter-glomerular differences in both membrane potential sag and HCN2 protein are diminished when sensory input to glomeruli is genetically and globally altered so that only one type of odorant receptor is universally expressed. Population diversity in this intrinsic property therefore reflects differential expression between local mitral cell networks processing distinct odour-related information. PMID- 22820254 TI - Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. AB - The identification of somatic activating mutations in JAK2 (refs 1-4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors. PMID- 22820255 TI - Bacterial virulence proteins as tools to rewire kinase pathways in yeast and immune cells. AB - Bacterial pathogens have evolved specific effector proteins that, by interfacing with host kinase signalling pathways, provide a mechanism to evade immune responses during infection. Although these effectors contribute to pathogen virulence, we realized that they might also serve as valuable synthetic biology reagents for engineering cellular behaviour. Here we exploit two effector proteins, the Shigella flexneri OspF protein and Yersinia pestis YopH protein, to rewire kinase-mediated responses systematically both in yeast and mammalian immune cells. Bacterial effector proteins can be directed to inhibit specific mitogen-activated protein kinase pathways selectively in yeast by artificially targeting them to pathway-specific complexes. Moreover, we show that unique properties of the effectors generate new pathway behaviours: OspF, which irreversibly inactivates mitogen-activated protein kinases, was used to construct a synthetic feedback circuit that shows novel frequency-dependent input filtering. Finally, we show that effectors can be used in T cells, either as feedback modulators to tune the T-cell response amplitude precisely, or as an inducible pause switch that can temporarily disable T-cell activation. These studies demonstrate how pathogens could provide a rich toolkit of parts to engineer cells for therapeutic or biotechnological applications. PMID- 22820257 TI - Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies. AB - The existence of multiple variants with differences in either charge, molecular weight or other properties is a common feature of monoclonal antibodies. These charge variants are generally referred to as acidic or basic compared with the main species. The chemical nature of the main species is usually well-understood, but understanding the chemical nature of acidic and basic species, and the differences between all three species, is critical for process development and formulation design. Complete understanding of acidic and basic species, however, is challenging because both species are known to contain multiple modifications, and it is likely that more modifications may be discovered. This review focuses on the current understanding of the modifications that can result in the generation of acidic and basic species and their affect on antibody structure, stability and biological functions. Chromatography elution profiles and several critical aspects regarding fraction collection and sample preparations necessary for detailed characterization are also discussed. PMID- 22820256 TI - Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. AB - Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild type, beta-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signalling in medulloblastoma. PMID- 22820259 TI - Ultrathin layers of graphene, h-BN and other honeycomb structures. PMID- 22820258 TI - The vasorelaxing effect of resveratrol on abdominal aorta from rats and its underlying mechanisms. AB - Evidence has indicated that resveratrol (Res) produces vasorelaxation and may decrease the coronary heart disease mortality. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed, therefore, to test the probable ion channels or receptors involved in the mechanism. The abdominal aortic rings from the male Sprague-Dawley rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. Treatment with L-NAME (a nitric oxide synthase inhibitor), glibenclamide and tetraethylammonium (TEA) significantly attenuated the vasorelaxing effect of Res. In lower concentration Res relaxed the ring in an endothelium-dependent manner, while in higher concentration the endothelium independent manner could be observed. In calcium-free Kreb's solution, Res inhibited vasoconstriction induced by NE. With intracellular calcium depleted by thapsigargin, Res also inhibited vasoconstriction induced by Kreb's solution with high potassium via L-Ca(2+) channel. In a word, Res decreased both extracellular calcium influx and intracellular calcium release. These results suggest that: (1) Res may exert its relaxing effect on abdominal aorta by opening K(+) channel to hyperpolarize vascular smooth muscle.(2) Res relaxes the abdominal aorta in both endothelium-dependent and endothelium-independent manners. (3) Finally, Res attenuates both extracellular calcium influx and intracellular calcium release, which results in vasorelaxation. PMID- 22820260 TI - A system for endoscopic mechanically scanned localized proton MR and light induced fluorescence emission spectroscopies. AB - Molecular and near-cellular modalities offer new opportunities in assessing living tissue in situ, and multimodality approaches, which offer complementary information, may lead to improved characterization of tissue pathophysiology benefiting diagnosis and focal therapy. However, many such modalities are limited by their low penetration through tissue, which has led to minimally invasive trans-cannula approaches to place the corresponding sensors locally at the area of interest. This work presents a system for performing localized fluorescence emission and proton magnetic resonance (MR) spectroscopies via endoscopic access. The in-house developed side-firing 1.9-mm wide dual-sensor integrates a three fiber optical sensor for fluorescence emission optical spectroscopy and a 1-mm circular radiofrequency (RF) coil for localized MR proton spectroscopy. An MR compatible manipulator was developed for carrying and mechanically translating the dual-sensor along a linear access channel. The hardware and software control of the system allows reconfigurable synchronization of the manipulator-assisted translation of the sensor, and MR and optical data collection. The manipulator serves as the mechanical link for the three modalities and MR images, MR spectra and optical spectra are inherently co-registered to the MR scanner coordinate system. These spectra were then used to generate spatio-spectral maps of the fluorophores and proton MR-signal sources in three-compartment phantoms with optically- and MR-visible, and distinguishable, materials. These data demonstrate a good spatial match between MR images, MR spectra and optical spectra along the scanned path. In addition to basic research, such a system may have clinical applications for assessing and characterizing cancer in situ, as well as guiding focal therapies. PMID- 22820261 TI - Simultaneous estimation of T1 and the flip angle in hyperpolarized NMR experiments using acquisition at non-regular time intervals. AB - In NMR spectroscopy of the liquid state T(1) is typically measured using an inversion recovery pulse sequence; but with hyperpolarized spins use is made of a sequence of multiple small radiofrequency (RF) induced nutations, alpha. Depending on the values of alpha and tau, the time interval between the pulses, the estimate of T(1) can be artifactually smaller than the real value; so without knowing the value of alpha the estimate of T(1) can be incorrect. Thus, we propose a method that involves a series of pulses with timing governed by a geometric sequence (or in general, any mathematically specified non-uniformly spaced sequence). This approach enables the simultaneous estimation of both the intrinsic T(1) value and alpha. The method was successfully applied to obtain T(1)=(44.9 +/- 0.3)s and alpha=(4.0 +/- 0.2) degrees (n=3) for a sample of hyperpolarized (13)C-urea in solution, matching with the inversion recovery pulse sequence estimate of T(1)=44 +/- 2s using non-hyperpolarized (13)C-urea in solution. PMID- 22820262 TI - Neuroprotection of neurotrophin-3 against focal cerebral ischemia/reperfusion injury is regulated by hypoxia-responsive element in rats. AB - Exogenous delivery of the neurotrophin-3 (NT-3) gene may provide a potential therapeutic strategy for ischemic stroke. To investigate the neuroprotective effects of NT-3 expression controlled by 5HRE after focal cerebral ischemia, we constructed a recombinant retrovirus vector (RV) with five copies of hypoxia responsive elements (5HRE or 5H) and NT-3 and delivered it to the rat brain. Three groups of rats received RV-5H-NT3, RV-5H-EGFP or saline injection. Three days after gene transfer, the rats underwent 90min of transient middle cerebral artery occlusion (tMCAO), followed by 1-28days of reperfusion. Three days after tMCAO, brain NT-3 expression was significantly increased in the RV-5H-NT3 transduced animals compared with the RV-5H-EGFP or saline group, and brain infarct volume was smaller in the RV-5H-NT3-transduced group than the RV-5H-EGFP or saline group. The percentage of TUNEL-positive cells was reduced in RV-5H-NT3 transduced brains compared with the RV-5H-EGFP or saline group 3 and 7days after tMCAO. Furthermore, the neurological status of RV-5H-NT3-transduced rats was better than that of RV-5H-EGFP- or saline-transduced animals from 1day to 4weeks after tMCAO. Our results demonstrated that 5HRE could modulate NT-3 expression in the ischemic brain environment and that the up-regulated NT-3 could effectively improve neurological status following tMCAO due to decreased initial damage. To avoid unexpected side effects, 5HRE-controlled gene expression might be a useful tool for gene therapy of ischemic disorders in the central nervous system. PMID- 22820264 TI - alpha7 Nicotinic acetylcholine receptor agonist attenuates neuropathological changes associated with intracerebral hemorrhage in mice. AB - We have demonstrated previously that nicotine affords neuroprotective and anti inflammatory effects against intracerebral hemorrhage (ICH)-associated neuropathological changes. The present study was undertaken to clarify whether subtype-specific agonists of nicotinic acetylcholine receptors (nAChRs) could preserve tissue integrity in mouse ICH model in vivo. ICH was induced by unilateral injection of collagenase into the striatum of male C57BL/6 mice. Daily intraperitoneal injection of alpha7 nAChR agonist PNU-282987 (3-10mg/kg) for 3 days, starting from 3h after induction of ICH, significantly increased the number of surviving neurons in the central and the peripheral regions of hematoma at 3 days after ICH. In contrast, alpha4beta2 nAChR agonist RJR-2403 (2-10 mg/kg) given in the same regimen showed no significant effect. PNU-282987 and RJR-2403 did not affect either the size of hemorrhage or the extent of brain edema associated with ICH. PNU-282987 decreased the number of activated microglia/macrophages accumulating in the perihematoma region at 3 days after ICH, in a dose-dependent manner. On the other hand, the number of microglia/macrophages in the central region of hematoma at early phase of pathology (6 h after ICH) was increased by 10mg/kg PNU-282987. These results suggest that alpha7 nAChR agonist can provide neuroprotective effect on ICH induced injury, independently of its anti-inflammatory actions. PMID- 22820263 TI - Tissue plasminogen activator treatment of stroke in type-1 diabetes rats. AB - BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is a major stroke risk factor and is associated with poor recovery compared with nondiabetic stroke patients. In the present study, we investigated the effects of tissue plasminogen activator (tPA) treatment of stroke in diabetic and non-diabetic rats. METHODS: Type-1 diabetes (T1DM) was induced by injection of streptozotocin. Non-T1DM and T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with or without tPA 2h after MCAo. Functional outcomes and immunostaining for advanced glycation endproducts receptor (RAGE), matrix metalloproteinase-9 (MMP-9) and toll-like receptor 4 (TLR4) and Western blotting were performed. RESULTS: tPA treatment of WT-MCAo rats significantly improved the functional outcome and reduced the lesion volume compared with non-treatment WT-MCAo rats (p<0.05). There was no significant difference between treatment with or without tPA in the WT-MCAo group in brain hemorrhage, BBB leakage and expression of inflammatory mediators, RAGE, MMP-9 and TLR4. However, tPA treatment in T1DM-MCAo rats (T1DM-MCAo+tPA) significantly enlarged brain hemorrhage, augmented BBB leakage, and failed to decrease lesion volume and improve functional outcome after stroke compared to T1DM-MCAo control. tPA treatment also significantly increased the expression of RAGE, MMP-9 and TLR4 in the ischemic brain in T1DM MCAo rats compared with T1DM-MCAo control rats (p<0.05). Brain hemorrhage was significantly correlated with functional deficit and RAGE and TLR4 expression, respectively. CONCLUSIONS: Treatment of stroke with tPA increased brain hemorrhage, BBB leakage and failed to improve functional outcome in T1DM rats. The increased inflammatory response may contribute to the failed neuroprotective effects of tPA treatment in T1DM rats. PMID- 22820265 TI - Involvement of the glutamatergic system in the nociception induced intrathecally for a TRPA1 agonist in rats. AB - The transient receptor potential ankyrin 1 (TRPA1) is expressed in peripheral and spinal terminals of sensory neurons, jointly to the vanilloid receptor (TRPV1). A relevant peripheral role of TRPA1 receptor has been implicated in a variety of processes, including the detection of noxious cold, and diverse painful stimulus, but the functional role of TRPA1 receptor in nociceptive transmission at spinal cord in vivo is poorly known. Therefore, the aim of this study was to evaluate whether the glutamatergic system is involved in the transmission of nociceptive stimulus induced for a TRPA1 agonist in the rat spinal cord. We observed that cinnamaldehyde, a TRPA1 agonist, on spinal cord synaptosomes leads to an increase in [Ca(2+)](i) and a rapid release of glutamate, but was not able to change the specific [(3)H]-glutamate binding. In addition, spinally administered cinnamaldehyde produced heat hyperalgesia and mechanical allodynia in rats. This behavior was reduced by the co-injection (i.t.) of camphor (TRPA1 antagonist) or MK-801 (N-methyl-D-aspartate (NMDA) receptor antagonist) to cinnamaldehyde. Besides, the pretreatment with resiniferatoxin (RTX), a potent TRPV1 agonist, abolished the cinnamaldehyde-induced heat hyperalgesia. Here, we showed that intrathecal RTX results in a decrease in TRPA1 and TRPV1 immunoreactivity in dorsal root ganglion. Collectively, our results demonstrate the pertinent participation of spinal TRPA1 in the possible enhancement of glutamatergic transmission of nociceptive signals leading to increase of the hypersensitivity, here observed as heat hyperalgesia. Then the modulation of spinal TRPA1 might be a valuable target in painful conditions associated with central pain hypersensitivity. PMID- 22820266 TI - Modulation of parvalbumin interneuron number by developmentally transient neocortical vasopressin receptor 1a (V1aR). AB - Arginine-vasopressin (AVP) and the vasopressin 1a receptor (V1aR) modulate social behavior and learning and memory in adult animals. Both functions depend upon the normal emergence of the balance of excitation and inhibition (E/I balance) in the neocortex. Here, we tested the hypothesis that V1aR signaling and E/I balance converge through the influence of the neuropeptide on interneuron number achieved in the neocortex. Postnatal mapping of forebrain V1aR binding in male and female mice revealed a transient expression of high levels of receptor in the neocortex and hippocampus in the second and third post-natal weeks. Receptor binding levels in these cortical structures fell dramatically in the adult, maintaining high levels of expression subcortically. Surprisingly, we observed sex differences in the number of calbindin interneurons, and a contribution of V1aR to the number of parvalbumin-immunoreactive neurons in the adult mouse neocortex. These data suggest that individual differences in developmentally transient V1aR signaling and even sex may alter the development of E/I balance in the neocortex, with long lasting influence on information processing. PMID- 22820267 TI - A review of alpha activity in integrative brain function: fundamental physiology, sensory coding, cognition and pathology. AB - AIM OF THE REVIEW: Questions related to the genesis and functional correlates of the brain's alpha oscillations around 10Hz (Alpha) are one of the fundamental research areas in neuroscience. In recent decades, analysis of this activity has been not only the focus of interest for description of sensory-cognitive processes, but has also led to trials for establishing new hypotheses. The present review and the companion review aim to constitute an ensemble of "reasonings and suggestions" to understand alpha oscillations based on a wide range of accumulated findings rather than a trial to launch a new "alpha theory". SURVEYED DESCRIPTIONS RELATED TO PHYSIOLOGY AND BRAIN FUNCTION: The review starts with descriptions of earlier extracellular recordings, field potentials and also considers earlier alpha hypotheses. Analytical descriptions of evoked and event related responses, event-related desynchronization, the relationship between spontaneous activity and evoked potentials, aging brain, pathology and alpha response in cognitive impairment are in the content of this review. In essence, the gamut of the survey includes a multiplicity of evidence on functional correlates in sensory processing, cognition, memory and vegetative system, including the spinal cord and heart. PMID- 22820269 TI - Weight status, physical activity, and vascular health in 9- to 12-year-old children. AB - BACKGROUND: The purpose of this study was to determine the independent and joint association of weight status and physical activity on resting blood pressure and C-reactive protein in children. METHODS: Participants were 174 (71 males, 103 females) children (mean age = 10.5 +/- 0.4 yrs). Physical activity was self reported, body mass index was calculated from measured height and body mass, and blood pressure was measured according to standard procedures. A subset of 91 children had C-reactive protein measured by fingerstick blood sample. Four weight/physical activity groups were created by cross tabulation of weight status classification and physical activity level. RESULTS: The prevalence of low physical activity (< 5 days/wk moderate-vigorous activity) did not differ between overweight and normal weight children (50%). Physical activity was not correlated with C-reactive protein (r = 0.01; P = 0.91) and C-reactive protein was not significantly different between physical activity groups (P = 0.87). Physical activity did not modify the difference in blood pressure or C-reactive protein within weight categories. CONCLUSIONS: Fatness (specifically overweight and obesity), but not physical activity, was shown to be associated with blood pressure and C-reactive protein levels in children. Physical activity did not attenuate blood pressure or C-reactive protein in overweight and obese children. PMID- 22820268 TI - Measurement fidelity of heart rate variability signal processing: the devil is in the details. AB - Heart rate variability (HRV) is a particularly valuable quantitative marker of the flexibility and balance of the autonomic nervous system. Significant advances in software programs to automatically derive HRV have led to its extensive use in psychophysiological research. However, there is a lack of systematic comparisons across software programs used to derive HRV indices. Further, researchers report meager details on important signal processing decisions making synthesis across studies challenging. The aim of the present study was to evaluate the measurement fidelity of time- and frequency-domain HRV indices derived from three predominant signal processing software programs commonly used in clinical and research settings. Triplicate ECG recordings were derived from 20 participants using identical data acquisition hardware. Among the time-domain indices, there was strong to excellent correspondence (ICC(avg)=0.93) for SDNN, SDANN, SDNNi, rMSSD, and pNN50. The frequency-domain indices yielded excellent correspondence (ICC(avg)=0.91) for LF, HF, and LF/HF ratio, except for VLF which exhibited poor correspondence (ICC(avg)=0.19). Stringent user-decisions and technical specifications for nuanced HRV processing details are essential to ensure measurement fidelity across signal processing software programs. PMID- 22820270 TI - Linking microalgae and cyanobacteria culture conditions and key-enzymes for carbohydrate accumulation. AB - Microalgae are regarded as a potential biomass source for biofuel purposes. With regard to bioethanol production, microalgae seem to overcome traditional substrate drawbacks. Enzymatic activities are responsible for carbon allocation and hence for carbohydrate profiles. Enzyme activities may be manipulated by metabolic engineering; however, this goal may also be achieved by controlling environmental conditions of the culture system. We outline the key-enzymes as well as the main operational conditions applied to microalgae growth (inorganic nutrient supplementation, irradiance and temperature) that affect carbohydrate synthesis on microalgae and cyanobacteria. Normally, harsh conditions are needed for such a goal and thus, arrested microalgae growth may occur. Potential strategies to avoid arrested growth, while enhancing carbohydrate accumulation, were also pointed out in this review. PMID- 22820271 TI - Ifenprodil, a NR2B-selective antagonist of NMDA receptor, inhibits reverse Na+/Ca2+ exchanger in neurons. AB - Glutamate-induced delayed calcium dysregulation (DCD) is causally linked to excitotoxic neuronal death. The mechanisms of DCD are not completely understood, but it has been proposed that the excessive influx of external Ca(2+) is essential for DCD. The NMDA-subtype of glutamate receptor (NMDAR) and the plasmalemmal Na(+)/Ca(2+) exchanger operating in the reverse mode (NCX(rev)) have been implicated in DCD. In experiments with "younger" neurons, 6-8 days in vitro (6-8 DIV), in which the NR2A-containing NMDAR expression is low, ifenprodil, an inhibitor of NR2B-containing NMDAR, completely prevented DCD whereas PEAQX, another NMDAR antagonist that preferentially interacts with NR2A-NMDAR, was without effect. With "older" neurons (13-16 DIV), in which NR2A- and NR2B-NMDARs are expressed to a greater extent, both ifenprodil and PEAQX applied separately failed to prevent DCD. However, combined application of ifenprodil and PEAQX completely averted DCD. Ifenprodil and ifenprodil-like NR2B-NMDAR antagonists Ro 25-6981 and Co 101244 but not PEAQX or AP-5 inhibited gramicidin- and Na(+)/NMDG replacement-induced increases in cytosolic Ca(2+) mediated predominantly by NCX(rev). This suggests that ifenprodil, Ro 25-6981, and Co 101244 inhibit NCX(rev). The ability of ifenprodil to inhibit NCX(rev) correlates with its efficacy in preventing DCD and emphasizes an important role of NCX(rev) in DCD. Overall our data suggest that both NR2A- and NR2B-NMDARs are involved in DCD in "older" neurons, and it is necessary to inhibit both NMDARs and NCX(rev) to prevent glutamate-induced DCD. PMID- 22820272 TI - Diurnal variation in nicotine sensitivity in mice: role of genetic background and melatonin. AB - Despite the evidence that there is a daily rhythm in smoking behavior and that the effects of drugs of abuse exhibit diurnal variations, very few studies have explored the extent to which sensitivity to the effects of nicotine vary over the course of the day. In the studies described in this report, the melatonin proficient mouse strain C3H/Ibg and the melatonin deficient mouse strains C57BL/6J and DBA/2J were assessed for diurnal variations in sensitivity to the effects of nicotine. Results indicated that there is significant variation in sensitivity to both activity and body temperature depressant effects of nicotine in the melatonin proficient C3H/Ibg strain with maximal sensitivity occurring during the latter third of the light period of the light cycle and minimal sensitivity taking place during the last third of the dark phase of the light cycle. The melatonin deficient strains did not exhibit diurnal differences in sensitivity to the effects of nicotine suggesting a potential role for melatonin in modulating the effects of nicotine. Experiments with knockout mice lacking both the Mtnr1a and Mtnr1b melatonin receptors confirmed that the reduced sensitivity observed during the dark phase is melatonin dependent. Diurnal variation in nicotinic receptor expression also was measured in cortex, hippocampus, hypothalamus and striatum using [(125)I]-alpha-bungarotoxin and [(125)I]-epibatidine. [(125)I]-alpha-bungarotoxin binding in hypothalamus of C3H mice exhibited a diurnal pattern with maximal binding observed in the latter third of the light portion of the light cycle. No other significant differences in binding were detected. PMID- 22820274 TI - Lipid rafts, synaptic transmission and plasticity: impact in age-related neurodegenerative diseases. AB - The synapse is a crowded area. In the last years, the concept that proteins can be organized in different membrane domains according to their structure has emerged. Cholesterol-rich membrane domains, or lipid rafts, form an organized portion of the membrane that is thought to concentrate signaling molecules. Accumulating evidence has shown that both the pre-synaptic and post-synaptic sites are highly enriched in lipid rafts, which are likely to organize and maintain synaptic proteins in their precise localization. Here we review recent studies highlighting the importance of lipid rafts for synaptic function and plasticity, as well as their relevance for age or disease-related cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22820273 TI - Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by alpha3beta4alpha5 nicotinic acetylcholine receptors. AB - The human CHRNA5 D398N polymorphism (rs16969968) causes an aspartic acid to asparagine change in the nicotinic acetylcholine receptor (nAChR) alpha5 subunit gene. The N398 variant of CHRNA5 is linked to increased risk for nicotine dependence. In this study, we explored the effect of the CHRNA5 D398N polymorphism on the properties of human alpha3beta4* nicotinic acetylcholine receptors in human embryonic kidney (HEK) cells. Addition of either D398 or N398 variant of alpha5 subunit in the alpha3beta4* receptor did not affect total [(125)I]-epibatidine binding or surface expression of the receptor. However, addition of alpha5(D398) into alpha3beta4* receptor decreased the maximal response to agonist without significantly affecting EC(50) in aequorin intracellular calcium assay. alpha3beta4alpha5(N398) nAChRs showed further decreased maximal response. The differences in agonist efficacy between the receptor subtypes were found to be dependent upon the concentration of external calcium but independent of external sodium. Moreover, activation of alpha3beta4alpha5 nAChRs led to significantly greater intracellular calcium release from IP(3) stores relative to alpha3beta4 nAChRs although no effect of the alpha5 polymorphism was observed. Finally, inclusion of the alpha5 variant caused a small shift to the left in IC(50) for some of the antagonists tested, depending upon alpha5 variant but did not affect sensitivity of alpha3beta4* receptors to desensitization in response to incubation with nicotine. In conclusion, addition of either variant of alpha5 into an alpha3beta4alpha5 receptor similarly effects receptor pharmacology and function. However, the N398 variant exhibits a reduced response to agonists when extracellular calcium is high and it may lead to distinct downstream cellular signaling. PMID- 22820277 TI - Suicidal behaviors in adolescents with ADHD: associations with depressive and other comorbidity, parent-child conflict, trauma exposure, and impairment. AB - OBJECTIVE: To examine potential predictors of lifetime suicidal behaviors (SBs) in adolescents with ADHD. METHOD: Participants were 101 adolescents with ADHD aged 11 to 18 years, evaluated for lifetime SB and psychopathology with semistructured interviews, and for lifetime trauma exposure, parent-child conflict, ADHD symptoms, and functional impairment with child, parent, and teacher ratings. RESULTS: Controlling for the effects of age, female sex, and comorbid depressive and other disorders, lifetime SB (n = 28) remained significantly associated (p = .001) with parent-child conflict, and to a lesser extent (p < .05) with impairment in nonacademic domains of function and breadth of exposure to victimization events. Measures related to past and current ADHD symptoms and signs were not associated with lifetime SB. CONCLUSION: Apart from depression, clinicians should pay particular attention to parent-child conflict, victimization trauma, and social impairment rather than levels of ADHD symptoms when weighing the likelihood of SB in youth with ADHD. PMID- 22820278 TI - Cost effectiveness analysis of graft options in spinal fusion surgery using a Markov model. AB - STUDY DESIGN: Statistical decision model. OBJECTIVE: To determine the most cost effective graft option in spinal fusion. SUMMARY OF BACKGROUND DATA: Spinal fusion has been shown to be an effective technique to treat lumbar degenerative spondylolisthesis. There have been significant advances in bone graft options to improve outcomes related to spinal fusion. RhBMP-2 (RhBMP), iliac crest bone graft (ICBG), local bone alone (LBG), demineralized bone matrix with local bone (DBM), local bone with corticocancellous allograft chips (CCA) have all been used as graft options. There has not been significant research in which graft option is most cost effective. METHODS: A Markov decision model has been created to identify the most cost-effective graft option for use in spinal fusion to treat 1 level (L4-L5) degenerative spondylolisthesis in a cohort of 60-year-old patients. Costs and effectiveness of successful spinal fusion surgery and revision surgery associated with each graft option was estimated through published data. The quality adjusted life years (QALYs) from these surgeries were compared with the amount of QALYs associated with living with chronic back pain. RESULTS: : In the base case, the incremental cost-effective ratio for each graft option when compared with living with chronic back pain was $21,308/QALY for ICBG, $16,595/QALY for RhBMP, $21,204/QALY for LBG, $21,287/QALY for DBM, and $28,153/QALY for CCA. Therefore, the most cost-effective graft option in the base case was RhBMP. Sensitivity analysis shows that RhBMP is not the most cost effective option if the revision rate is significantly raised. If the cost of treatment with RhBMP rises >$42,250 then LBG becomes the likely cost-effective treatment. CONCLUSIONS: RhBMP is the most cost-effective graft option for L4-L5 fusion for degenerative spondylolisthesis largely due to the reduced rate of revision spine surgery. The increased upfront cost and list of complications associated with RhBMP is offset by the reduced rate of revision surgery. PMID- 22820276 TI - Differences between synaptic plasticity thresholds result in new timing rules for maximizing long-term potentiation. AB - The fundamental observation that the temporal spacing of learning episodes plays a critical role in the efficiency of memory encoding has had little effect on either research on long-term potentiation (LTP) or efforts to develop cognitive enhancers. Here we review recent findings describing a spaced trials phenomenon for LTP that appears to be related to recent evidence that plasticity thresholds differ between synapses in the adult hippocampus. Results of tests with one memory enhancing drug suggest that the compound potently facilitates LTP via effects on 'high threshold' synapses and thus alters the temporally extended timing rules. Possible implications of these results for our understanding of LTP substrates, neurobiological contributors to the distributed practice effect, and the consequences of memory enhancement are discussed. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22820275 TI - Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons. AB - Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on the measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM's effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1-1 mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg) significantly decreased early positive and negative components of the sensory evoked LFP response. Higher doses (0.3-1 mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike field coherence was enhanced by 1 mg/kg ATM across frequency bands. Finally, coherence between LC fields and EEG signals was generally increased by 1 mg/kg ATM, whereas 0.1 and 0.3 mg/kg respectively decreased and increased coherence values in specific frequency bands. Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may play a role in the cognitive effects of ATM. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22820279 TI - Does the fusion of a lumbar disk herniation improve the clinical outcome? an investigation with a minimum 10-year follow-up. AB - STUDY DESIGN: A retrospective long-term (minimum 10 y) follow-up and comparative study. OBJECTIVE: To compare the clinical outcome of surgically treated primary lumbar disk herniation (LDH) by conventional discectomy alone and discectomy with posterolateral fusion without instrumentation. SUMMARY OF BACKGROUND DATA: Primary LDH is usually treated by discectomy alone. The long-term outcome of discectomy alone is generally satisfactory. However, the superiority of a discectomy alone in comparison with a discectomy with fusion for primary LDH has yet to be determined. METHODS: Conventional discectomy without fusion was performed in 39 patients in hospital A (without-fusion group) and conventional discectomy with posterolateral fusion without instrumentation was performed in 109 patients in hospital B (with-fusion group). The subjective symptoms (analgesic use, continuing gait time, 4-grade modified outcome criteria, numerical rating scale of pain and satisfaction with the operation, and the Japanese version of the Roland-Morris Disability Questionnaire) and objective symptoms (straight leg raising test, manual muscle test, and sensory disturbance) were assessed. RESULTS: There were no differences detected in the subjective and objective symptoms between the without-fusion and with-fusion group. CONCLUSIONS: Routine fusion surgery for a primary LDH was therefore found to have no apparent benefit even in the long-term outcome. PMID- 22820280 TI - Anterior or posterior surgery for right thoracic adolescent idiopathic scoliosis (AIS)? A prospective cohorts' comparison using radiologic and functional outcomes. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: Prospectively compare patient reported as well as clinical and radiologic outcomes after anterior or posterior surgery for right thoracic adolescent idiopathic scoliosis (AIS) in a single center by the same surgeons. SUMMARY OF BACKGROUND DATA: Anterior and posterior spinal instrumentation and arthrodesis are both well-established treatments of thoracic AIS. The majority of studies comparing the 2 approaches have focused on radiographic outcomes. There remains a paucity of prospectively gathered patient reported outcomes comparing surgical approaches. METHODS: Forty-two consecutive patients with right thoracic AIS were treated in a single center by one of 2 surgeons with either anterior (n=18) or posterior (n=24) approaches and followed up for over 2 years. Radiographic, clinical, and patient-reported outcomes of the Modified Scoliosis Research Society Outcome Instrument were gathered and analyzed by an independent surgeon. RESULTS: Patients reported significant improvements in all areas of the Modified Scoliosis Research Society Outcome Instrument, especially pain and self-image domains. There were no significant differences in the degree of improvement in any domains between the groups. Posterior and anterior surgery corrected rib hump by 53% and 61%, respectively (P=0.4). The Main thoracic curve Cobb angle was corrected from 69 to 26 degrees (62%) by posterior surgery and 61 to 23 degrees (64%) by anterior surgery (P=0.6). Posterior surgery significantly reduced kyphosis and lumbosacral lordosis. Anterior surgery had no overall affect of sagittal alignment but seemed able to correct those hypokyphotic preoperatively. Complications differed and were largely approach-related--intrathoracic in anterior and wound-related in posterior surgery. CONCLUSIONS: Patients with right thoracic AIS of differing curve types but otherwise similar preoperatively demonstrated that anterior and posterior surgery are largely equivalent. Patient-reported outcomes are improved similarly by either approach. Both offer excellent radiographic and trunk deformity correction. Differences in the effect of sagittal alignment, operative time, and complications should be considered when selecting approach. PMID- 22820281 TI - Effect of Spinal Fixation in Rabbits With Metastatic Tumor Using a Novel Spinal Fusion Model. AB - STUDY DESIGN: An experimental assessment of the impact of spinal stabilization on metastasis growth using a rabbit model. OBJECTIVE: To investigate the influence of spinal stabilization on the growth of metastatic spinal tumors in rabbits using a novel method of spinal fusion. SUMMARY OF BACKGROUND DATA: For spinal metastasis patients, gait disturbances caused by back pain or paraplegia correlates with their prognosis. Palliative surgeries are good options for some patients; however, the appropriate timing and method of spinal surgery remains controversial. METHODS: The biomechanical properties of a novel spinal fixation model with a locking plating system were first examined on the L2-L4 fixed vertebrae of 18 Japanese white rabbits. Biomechanical and radiographic examinations were performed at 0, 4, and 8 weeks as compared with controls. After this, another 31 rabbits were then inoculated with VX2 carcinoma cells into the L3 vertebral body and divided into fixation (N=16) and sham (N=15) groups to assess the impact of spinal stabilization on tumor growth. The time to paraplegia, and tumor cell growth and proliferation were evaluated by rabbit behavior, computed tomography, myelogram, and cell proliferation marker (MIB-1 index). RESULTS: In the biomechanical loading test, fixed segments showed one eighth of the range of motion and 15 times bending stiffness as compared with controls at each timepoint. No pathologic fractures were observed in the rabbits inoculated with VX2 carcinoma cells before paraplegia, and there was no difference in the time to paraplegia between the fixation and sham groups (26.7 and 28 d, respectively). Similarly, no differences were observed in osteolytic area expansion or tumor cell proliferation (MIB-1 index; 38.1% and 38.0%, respectively). CONCLUSIONS: Our locking plate fixation of rabbit spines exhibited sufficient biomechanical properties. Spinal fixation had little influence on the growth of the aggressive carcinoma and the time to paraplegia. However, further investigation is needed to determine the influence of spinal stabilization on slow-growing tumors. PMID- 22820282 TI - Is congenital bony stenosis of the cervical spine associated with congenital bony stenosis of the thoracic spine? An anatomic study of 1072 human cadaveric specimens. AB - SUMMARY OF BACKGROUND DATA: Tandem stenosis of the cervical and lumbar spine is known to occur in 5% of individuals with symptomatic neural compression in one region. However, the prevalence of concurrent cervical and thoracic stenosis is not known. Whether this relationship is due to an increased risk of degenerative disease in these individuals, or whether this finding is due to the tandem presence of a congenitally small cervical and thoracic canal is unknown. OBJECTIVES: To determine the prevalence of concurrent thoracic and cervical stenosis and whether the presence of stenosis in the cervical spine is associated with stenosis in the thoracic spine. STUDY DESIGN: A morphoanatomic study of the cervical and thoracic cadaveric spines. METHODS: A total of 1072 adult skeletal specimens from the Hamann-Todd Collection in the Cleveland Museum of Natural History were selected. Canal area at each level was also calculated using a geometric formula. A standard distribution for each level was created, and values that were 2 SD below mean were considered as being congenitally stenotic. Linear regression analysis was used to determine the association between the additive canal areas at all levels in the cervical and thoracic spine and to determine the association between the number of stenotic levels in the cervical and thoracic spine. Logistic regression was used to calculate odds ratios for concurrent cervical and thoracic stenosis. RESULTS: The prevalence of concurrent cervical and thoracic stenosis is 1%. A positive association was found between the additive areas of all cervical and thoracic levels (P<0.01). No association, however, was found between the number of stenotic thoracic and cervical levels (P=0.689). Log regression demonstrated no significant association (odds ratio <1) between stenosis in the thoracic and cervical spine. CONCLUSIONS: The area changes in the cervical spine correlate with area variations in the thoracic spine and the severity of stenosis in the thoracic spine increases as the levels of stenosis increase in the cervical spine. The presence of tandem cervical and thoracic stenosis does seem to be, in part, related to the tandem presence of a congenitally small cervical and thoracic canal. PMID- 22820283 TI - Proximal instrumented vertebral body chance fracture after pedicle screw instrumentation in a thoracic kyphosis patient with osteoporosis. AB - STUDY DESIGN: We present a case of proximal vertebral body chance fracture after pedicle screw instrumentation and fusion in a 67-year-old woman with osteoporosis and thoracic kyphosis. OBJECTIVE: To report the rare and unique complication of proximal vertebral body chance fracture after pedicle screw instrumentation and fusion in a kyphosis patient. SUMMARY OF BACKGROUND DATA: Pedicle screw instrumentation has been associated with complications not limited to neurological or vascular injury, loss of curve correction, intraoperative pedicle fracture or loosening, dural laceration, deep infection, and pseudarthrosis. To the best of our knowledge, there are no previous reports describing a chance-type fracture generated by a pedicle screw fixation at the proximal end of a construct. METHODS: A 67-year-old woman suffered from progressive thoracic kyphosis and mid thoracic pain presented 2 weeks after pedicle screw instrumentation and correction. She developed a vertebral body fracture at the proximal end of the instrumentation construct. Surgical intervention, including removal of the screws in the fractured vertebrae and extension of the instrumented fusion across the cervicothoracic junction, effectively restored the physiological sagittal alignment. RESULTS: Postoperatively, at 12-month follow up, the patient is doing exceptionally well with near-complete relief of back pain and an excellent maintenance of correction. CONCLUSIONS: Chance fracture in osteoporotic bone at the proximal end of a construct due to a pedicle screw is a rare complication but it may result in catastrophic consequences. Early recognition of this complication, reduction of the fraction-dislocation, and an extension of the instrumentation can be utilized for realignment and long-term stabilization. PMID- 22820284 TI - miR-122 regulates hepatic lipid metabolism and tumor suppression. AB - In this issue of JCI, two independent groups describe the effects of germline and liver-specific deletion of Mir122a, the predominant liver miRNA. Their findings reveal a critical role for miR-122 in fat and cholesterol metabolism but suggest that other metabolic actions of the liver are independent of miR-122. Knockout mice also displayed hepatic inflammation, fibrosis, and a high incidence of hepatocellular carcinoma, suggesting that miR-122 has a tumor suppressor role in hepatocytes. PMID- 22820285 TI - Memory CD4+ T cells: beyond "helper" functions. AB - In influenza virus infection, antibodies, memory CD8+ T cells, and CD4+ T cells have all been shown to mediate immune protection, but how they operate and interact with one another to mediate efficient immune responses against virus infection is not well understood. In this issue of the JCI, McKinstry et al. have identified unique functions of memory CD4+ T cells beyond providing "help" for B cell and CD8+ T cell responses during influenza virus infection. PMID- 22820286 TI - How many neutrophils are enough (redux, redux)? AB - Many chemotherapeutic regimens produce neutropenia, which predisposes to microbial infection. However, not all neutropenic individuals develop infections, so the ability to predict this outcome would be a powerful clinical tool. In this issue of the JCI, Malka et al. describe a dynamic system model of neutrophil bactericidal activity that confirms and extends the concept of critical neutrophil concentration. The authors demonstrate that when the neutrophil concentration approaches the critical concentration, bacterial populations in contact with them exhibit bistability. Their experimental findings raise the intriguing possibility of greater variability in bactericidal activity of neutrophils from healthy adults than heretofore recognized; their model predicts that this could have life-and-death consequences. PMID- 22820287 TI - Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. AB - Memory CD4+ T cells combat viral infection and contribute to protective immune responses through multiple mechanisms, but how these pathways interact is unclear. We found that several pathways involving memory CD4+ T cells act together to effectively clear influenza A virus (IAV) in otherwise unprimed mice. Memory CD4+ T cell protection was enhanced through synergy with naive B cells or CD8+ T cells and maximized when both were present. However, memory CD4+ T cells protected against lower viral doses independently of other lymphocytes through production of IFN-gamma. Moreover, memory CD4+ T cells selected for epitope specific viral escape mutants via a perforin-dependent pathway. By deconstructing protective immunity mediated by memory CD4+ T cells, we demonstrated that this population simultaneously acts through multiple pathways to provide a high level of protection that ensures eradication of rapidly mutating pathogens such as IAV. This redundancy indicates the need for reductionist approaches for delineating the individual mechanisms of protection mediated by memory CD4+ T cells responding to pathogens. PMID- 22820288 TI - Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. AB - miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR 122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV. PMID- 22820289 TI - PES1 promotes breast cancer by differentially regulating ERalpha and ERbeta. AB - The initiation of breast cancer is associated with increased expression of tumor promoting estrogen receptor alpha (ERalpha) protein and decreased expression of tumor-suppressive ERbeta protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen inducible protein that is overexpressed in breast cancer, can regulate the balance between ERalpha and ERbeta. We found that PES1 modulated many estrogen responsive genes by enhancing the transcriptional activity of ERalpha while inhibiting transcriptional activity of ERbeta. Consistent with this regulation of ERalpha and ERbeta transcriptional activity, PES1 increased the stability of the ERalpha protein and decreased that of ERbeta through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERalpha expression and negatively with ERbeta expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERalpha and ERbeta and may be a better target for the development of drugs that selectively regulate ERalpha and ERbeta activities. PMID- 22820290 TI - MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. AB - MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR 122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a(-/-) livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a(-/-) mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC. PMID- 22820292 TI - Evidence for bistable bacteria-neutrophil interaction and its clinical implications. AB - Neutropenia, which may develop as a consequence of chemotherapy, increases the risk of bacterial infection. Similarly, increased risk of bacterial infection appears in disorders of phagocytic functions, such as the genetic disorder chronic granulomatous disease. To elucidate the organizing principles behind these distinct immunodeficiency conditions, we investigated the interaction between in vitro bacteria and human neutrophils by experiments and mathematical modeling. The model and the experiments showed that the in vitro bacterial dynamics exhibit bistability for a certain range of neutrophil concentration and function. Thus, there is a critical bacterial concentration above which infection develops, and below which neutrophils defeat the bacteria. Whereas with normal neutrophil concentration and function, an infection may develop when the initial bacterial concentration is very high, under neutropenic conditions or when there is neutrophil dysfunction, the critical bacterial concentration can be lower, within the clinically relevant range. We conclude that critical bacterial concentration has clinically relevant implications. The individual maximum bearable bacterial concentration depended on neutrophil concentration, phagocytic activity, and patient barrier integrity; thus, the resulting maximal bearable bacterial concentration may vary by orders of magnitude between patients. Understanding the interplay between neutrophils and bacteria may enhance the development of new therapeutic approaches to bacterial infections. PMID- 22820291 TI - Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis. AB - Several lines of evidence suggest a link between age-related macular degeneration and retinal cholesterol maintenance. Cytochrome P450 27A1 (CYP27A1) is a ubiquitously expressed mitochondrial sterol 27-hydroxylase that plays an important role in the metabolism of cholesterol and cholesterol-related compounds. We conducted a comprehensive ophthalmic evaluation of mice lacking CYP27A1. We found that the loss of CYP27A1 led to dysregulation of retinal cholesterol homeostasis, including unexpected upregulation of retinal cholesterol biosynthesis. Cyp27a1-/- mice developed retinal lesions characterized by cholesterol deposition beneath the retinal pigment epithelium. Further, Cyp27a1 null mice showed pathological neovascularization, which likely arose from both the retina and the choroid, that led to the formation of retinal-choroidal anastomosis. Blood flow alterations and blood vessel leakage were noted in the areas of pathology. The Cyp27a1-/- retina was hypoxic and had activated Muller cells. We suggest a mechanism whereby abolished sterol 27-hydroxylase activity leads to vascular changes and identify Cyp27a1-/- mice as a model for one of the variants of type 3 retinal neovascularization occurring in some patients with age related macular degeneration. PMID- 22820293 TI - Targeting PES1 for restoring the ERalpha/ERbeta ratio in breast cancer. AB - Alteration of the ERalpha/ERbeta balance is a critical step in breast cancer development and progression, and selective restoration of the activity of estrogen receptors has been proposed as one of the major therapeutic approaches for breast cancer. In this issue of JCI, Cheng et al. show that, by differentially modulating the stability of ERalpha and ERbeta, PES1 increases the ERalpha/ERbeta ratio and triggers breast tumor growth. These findings highlight PES1 as a potential target for the treatment of breast cancer. PMID- 22820294 TI - Development and characterization of multiplex panels of microsatellite markers for Syphacia obvelata, a parasite of the house mouse (Mus musculus), using a high throughput DNA sequencing approach. AB - Syphacia obvelata is a common gastro-intestinal parasitic nematode of the house mouse (Mus musculus), a prime model rodent species. Investigations of the genetic structure, variability of parasite populations and other biological aspects of this host-parasite system are limited due to the lack of genetic resources for S. obvelata. To fill this gap, we developed a set of microsatellite markers for S. obvelata, using a 454 pyrosequencing approach. We designed three multiplex panels allowing genotyping of 10 polymorphic loci and scrutinized them on 42 samples from two different regions inhabited by two different house mouse subspecies (Mus musculus musculus and M. m. domesticus). The numbers of alleles ranged from 2 to 6 with mean observed heterozygosities 0.1476 and 0.2095 for domesticus and musculus worms, respectively. The described markers will facilitate further studies on population biology and co-evolution of this host-parasite system. PMID- 22820295 TI - The effect of multisensory cues on attention in aging. AB - The attention network test (ANT) assesses the effect of alerting and orienting cues on a visual flanker task measuring executive attention. Previous findings revealed that older adults demonstrate greater reaction times (RT) benefits when provided with visual orienting cues that offer both spatial and temporal information of an ensuing target. Given the overlap of neural substrates and networks involved in multisensory processing and cueing (i.e., alerting and orienting), an investigation of multisensory cueing effects on RT was warranted. The current study was designed to determine whether participants, both old and young, benefited from receiving multisensory alerting and orienting cues. Eighteen young (M=19.17 years; 45% female) and eighteen old (M=76.44 years; 61% female) individuals that were determined to be non-demented and without any medical or psychiatric conditions that would affect their performance were included. Results revealed main effects for the executive attention and orienting networks, but not for the alerting network. In terms of orienting, both old and young adults demonstrated significant orienting effects for auditory somatosensory (AS), auditory-visual (AV), and visual-somatosensory (VS) cues. RT benefits of multisensory compared to unisensory orienting effects differed by cue type and age group; younger adults demonstrated greater RT benefits for AS orienting cues whereas older adults demonstrated greater RT benefits for AV orienting cues. Both groups, however, demonstrated significant RT benefits for multisensory VS orienting cues. These findings provide evidence for the facilitative effect of multisensory orienting cues, and not multisensory alerting cues, in old and young adults. PMID- 22820296 TI - Decreased VEGF expression and microvascular density, but increased HIF-1 and 2alpha accumulation and EPO expression in chronic moderate hyperoxia in the mouse brain. AB - Normal brain function is dependent on continuous and controlled oxygen delivery. Chronic moderate hypoxia leads to angiogenesis, suggesting a modulatory role for oxygen in determining capillary density. The objective of this study was to determine physiologic and brain angiogenic adaptational changes during chronic moderate normobaric hyperoxia in mice. Four-month old C56BL/6J mice were kept in a normobaric chamber at 50% O(2) for up to 3 weeks. Normoxic littermates were kept in the same room outside the chamber. Freshly collected or fixed brain specimens were analyzed by RT-PCR, Western blot analysis and immunohistochemistry. Results show accumulation of hypoxia inducible factors 1 and 2alpha (HIF-1 and 2alpha), and increased expression of erythropoietin (EPO), cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2). Conversely, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (KDR/Flk-1), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) and prolylhydroxylase-2 (PHD-2) expressions were decreased. VEGF mRNA level was diminished but there was no change in HIF-1alpha mRNA and von Hippel Lindau E3 ubiquitin ligase (VHL) protein expression. Microvascular density was significantly diminished by the end of the 3rd week of hyperoxia. Overall, our results are: (1) increased expression of the potent neuroprotective molecule, EPO; (2) diminished expression of the potent angiogenic factor, VEGF; and (3) decreased microvascular density. We can, therefore, conclude that brain microvascular density can be controlled by HIF-independent mechanisms, and that brain capillary density is a continuously adjusted variable with tissue oxygen availability as one of the controlling modulators. PMID- 22820297 TI - The atypical antidepressant mirtazapine attenuates expression of morphine-induced place preference and motor sensitization. AB - Opioid abuse and dependence remains prevalent despite having multiple FDA approved medications to help maintain abstinence. Mirtazapine is an atypical antidepressant receiving attention for substance abuse pharmacotherapy, and its action includes alterations in monoaminergic transmission. As monoamines are indirectly altered by opioids, the current investigation assessed the ability of mirtazapine to ameliorate morphine-induced behaviors. Conditioned place preference (CPP) is a behavioral assay wherein a rewarding drug is paired with a distinct environmental context resulting in reward-related salience of cues through learning-related neuronal plasticity. A second behavioral assay involved motor sensitization (MSn), wherein repeated administration results in an enhanced motoric response to an acute challenge, also reflecting neuronal plasticity. Attenuation of CPP and/or MSn provides two behavioral measures to suggest therapeutic potential for addiction therapy, and the present study evaluated the effectiveness of mirtazapine to reduce both behaviors. To do so, morphine-induced CPP was established using an eight day conditioning paradigm, and expression of CPP was tested on day 10 following a 24h or 30min mirtazapine pretreatment. To determine if mirtazapine altered the expression of MSn, on day 11, rats received a pretreatment of mirtazapine, followed 30min later by a challenge injection of morphine. Pretreatment with mirtazapine 24h prior to the CPP test had no effect on CPP expression. In contrast, a 30min pretreatment of mirtazapine attenuated the expression of both CPP and MSn. Collectively, these results indicate that mirtazapine may help to maintain abstinence in opioid dependent patients. PMID- 22820298 TI - Spatial patterns of intrinsic neural activity in depressed patients with vascular risk factors as revealed by the amplitude of low-frequency fluctuation. AB - To investigate spatial patterns of intrinsic neural activity of depressed patients with vascular risk factors using resting-state functional magnetic resonance imaging (fMRI) and to examine the relationship between regional activity abnormalities and symptom severity factor, we analyzed spatial patterns of spontaneous brain activity in 19 depressed patients with vascular risk factors and 18 healthy subjects. Intrinsic brain activity was measured by the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level dependent signal. Depressed patients with vascular risk factors showed decrease in ALFF in the limbic-cortical-striatal-pallidal-thalamic circuit. Specifically, the altered ALFF values (i.e., left insula and right superior frontal gyrus) were significantly correlated with depression severity in the depressed group. In addition, higher ALFF values in the right middle temporal gyrus and right superior temporal gyrus were observed in depressed patients with vascular risk factors. Our findings reveal distinct functional patterns of abnormal brain activity in depressed patients with vascular risk factors and have implications for the understanding of the pathophysiology of this understudied population. PMID- 22820299 TI - The interaction of arousal and valence in affective priming: behavioral and electrophysiological evidence. AB - The affective priming paradigm has been studied extensively and applied in many fields during the past two decades. Most research thus far has focused on the valence dimension. Whether emotional arousal influences affective priming remains poorly understood. The present study demonstrates how arousal impacts evaluation of affective words using reaction time and event-related potential (ERP) measures. Eighteen younger subjects evaluated pleasantness of target words after seeing affective pictures as primes. The participants' responses were faster and/or more accurate for valence-congruent trials than for incongruent trials, particularly with high-arousal stimuli. An ERP affective priming effect (N400) also occurred mainly in high-arousing stimulus pairs. In addition, whereas valence congruency influenced both the N400 and the LPP, arousal congruency influenced only the LPP, suggesting that arousal congruency mainly modulates post semantic processes, but valence congruency effects begin with semantic processes. Overall, our current findings indicate that the arousal level of visual images impacts both behavioral and ERP effects of affective priming. PMID- 22820300 TI - BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice. AB - We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15-20% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists. PMID- 22820301 TI - Opioid growth factor arrests the progression of clinical disease and spinal cord pathology in established experimental autoimmune encephalomyelitis. AB - An endogenous neuropeptide, opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, arrested the progression of established disease in a mouse model of multiple sclerosis (MS) called experimental autoimmune encephalomyelitis (EAE). This study treated mice who demonstrated 2 consecutive days of behavioral decline following injections of myelin oligodendrocyte glycoprotein (MOG) with daily injections of OGF (10mg/kg) or saline (0.1ml) for 40 days. Within 6 days of OGF treatment, mice initially demonstrating clinical signs of EAE had significant reductions (45% reduction) in their behavioral scores relative to EAE mice receiving saline. Behavior was attenuated for the entire 40-day period with mice receiving OGF showing only limp tails and wobbly gait in comparison to saline treated EAE mice who displayed paralysis of one or more limbs. Neuropathological studies revealed that OGF treatment initiated after the appearance of disease reduced the number of activated astrocytes and damaged neurons, decreased demyelination, and inhibited T cell proliferation. These results demonstrate that OGF can halt the progression of established EAE, return aberrant pain sensitivity to normal levels, inhibit proliferation of T cells and astrocytes, and prevent further spinal cord pathology. The data extend our observations that OGF given at the time of disease induction prevented disease onset, reduced the severity of clinical signs of disease, and reversed neurological deficits in a non-toxic manner. Our data substantiate the role of the OGF-OGFr axis in EAE and support the use of OGF as a biotherapy for MS. PMID- 22820302 TI - Effects of ethylenediamine in rodent models of seizure, motor coordination and anxiety. AB - Ethylenediamine (EDA) activates GABA(A) receptors via both direct and indirect mechanisms. EDA has been shown to reduce seizures caused by systemic injection of proconvulsants in an animal model of generalized tonic-clonic seizures. However, there does not appear to have been any report on the effects of EDA in other seizure models. Hence, we used male Sprague-Dawley rats to test the effects of EDA on topically applied bicuculline (a model of simple partial seizures) and on maximal electroshock (MES, a model of generalized tonic-clonic seizures). We also examined the effects of EDA on motor coordination using a rotarod treadmill, and its potential anxiolytic properties using an elevated plus maze (EPM). EDA at concentrations of 50 MUM and above reduced the frequency of epileptiform spikes on an electrocorticogram in a concentration-dependent manner. EDA at 100 and 1000 mg/kg i.p. increased the threshold for inducing limb extension on the MES. EDA did not affect the time spent by rats on the rotarod at 10 or 100mg/kg, but significantly reduced the time spent at doses of 1000 mg/kg. In the EPM, EDA at 10 or 100mg/kg significantly increased the frequency of entries and time spent in the open arms. We conclude that EDA has antiepileptic and anxiolytic activity at doses that do not affect motor coordination. PMID- 22820304 TI - Impact of lower- vs. upper-hemifield presentation on automatic colour-deviance detection: a visual mismatch negativity study. AB - The automatic processing of deviances from the temporal context of the visual environment has become an important topic in visual cognitive sciences, which is often investigated using the visual mismatch negativity (vMMN). This event related potential (ERP) component is elicited by an irregular stimulus (e.g., a red disc) presented in a series of stimuli (e.g., green discs) comprising a temporal regularity (e.g., colour repetition). We determined the influence of lower- vs. upper-hemifield presentation of the irregular stimulus on the vMMN while using whole-field stimulus displays controlling for sustained shifts in spatial attention. Deviances presented in the lower hemifield elicited a larger vMMN than the ones presented in the upper hemifield at a latency of 200-280ms. However, this asymmetry was preceded by deviance-related hemifield effects already emerging at an earlier latency (110-150ms), where upper-hemifield deviances elicited a positive potential but lower-hemifield deviances did not. With variable resolution electromagnetic tomography (VARETA) early deviance related activity was localised to retinotopically organised regions of the visual cortex (BA 17/18) and vMMN-sources were localised to the middle/superior occipital gyrus, to higher areas along the temporal visual stream, but also to BA 17/18. We argue that the upper/lower-hemifield vMMN asymmetry relies at least partially on the hemifield-dependent differential sensitivity of early deviance related activity generated in retinotopically organised regions of the visual cortex. However, a superior automatic processing of deviances presented in the lower visual hemifield may also contribute to the effect. PMID- 22820305 TI - Differences in parvalbumin and calbindin chemospecificity in the centers of the turtle ascending auditory pathway revealed by double immunofluorescence labeling. AB - Using double immunofluorescence labeling, quantitative ratio between parvalbumin- and calbindin-containing neurons, neurons that co-localize both peptides, as well as the intensity of their immunoreactivities were studied in the brainstem, midbrain and forebrain auditory centers of two chelonian species, Testudo horsfieldi and Emys orbicularis. In the spiral ganglion and first-order cochlear nuclei, highly immunoreactive parvalbumin-containing neurons predominated, and almost all neurons in these nuclei also exhibited weak immunoreactivity to calbindin. The number of strongly calbindin-immunoreactive (-ir) cells increased in the second-order brainstem auditory centers (the laminar cochlear nucleus, superior olivary complex, lateral lemniscal nucleus), and co-localization with parvalbumin in some of them was observed. In the midbrain, a complementary distribution of parvalbumin and calbindin immunoreactivity was found: the central (core) region of the torus semicircularis showed strong parvalbumin immunoreactivity, while the laminar (belt) nucleus was strongly calbindin-ir. In the thalamic nucleus reuniens, almost complete topographic overlapping of the parvalbumin-ir and calbindin-ir neurons was shown in its dorsomedial region (core), with the intensity of immunoreactivity to calbindin being much higher than that to parvalbumin. The predominance of calbindin immunoreactivity in neurons of the dorsomedial region of the nucleus reuniens is correlated with the existence of the dense calbindin-ir terminal field in its projection area in the telencephalon. We conclude that the turtle auditory pathway is chemically heterogeneous with respect to calcium-binding proteins, the predominance of parvalbumin in the brainstem and midbrain centers giving way to that of calbindin in the forebrain centers; the portion of neurons co-localizing both peptides nonlinearly decreases from lower to higher order centers. PMID- 22820303 TI - Targeted gene transfer of different genes to presynaptic and postsynaptic neocortical neurons connected by a glutamatergic synapse. AB - Genetic approaches to analyzing neuronal circuits and learning would benefit from a technology to first deliver a specific gene into presynaptic neurons, and then deliver a different gene into an identified subset of their postsynaptic neurons, connected by a specific synapse type. Here, we describe targeted gene transfer across a neocortical glutamatergic synapse, using as the model the projection from rat postrhinal to perirhinal cortex. The first gene transfer, into the presynaptic neurons in postrhinal cortex, used a virus vector and standard gene transfer procedures. The vector expresses an artificial peptide neurotransmitter containing a dense core vesicle targeting domain, a NMDA NR1 subunit binding domain (from a monoclonal antibody), and the His tag. Upon release, this peptide neurotransmitter binds to NMDA receptors on the postsynaptic neurons. Antibody mediated targeted gene transfer to these postsynaptic neurons in perirhinal cortex used a His tag antibody, as the peptide neurotransmitter contains the His tag. Confocal microscopy showed that with untargeted gene transfer, ~3% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. In contrast, with targeted gene transfer, >= 20% of the presynaptic axons were proximal to a transduced postsynaptic dendrite. Targeting across other types of synapses might be obtained by modifying the artificial peptide neurotransmitter to contain a binding domain for a different neurotransmitter receptor. This technology may benefit elucidating how specific neurons and subcircuits contribute to circuit physiology, behavior, and learning. PMID- 22820306 TI - Solution structure of an atypical PHD finger in BRPF2 and its interaction with DNA. AB - Plant homeodomain (PHD) finger is found to be a versatile reader that functions in recruiting transcription factors and chromatin modification complexes. Bromodomain- and PHD finger-containing (BRPF) proteins are identified as scaffold component in a couple of histone acetyltransferase (HATs) complexes but the biological function of PHD fingers, composing the motif called PZPM (PHD/Zn knuckle/PHD Motif), in BRPF proteins is far from being well understood. Here we report the three-dimensional solution structure of the second PHD finger of PZPM in human BRPF2. According to the structure, BRPF2 PHD2 possesses a two-strand beta sheet which is different from any other PHD fingers. Functionally, this PHD finger can potentially bind DNA non-specifically with an evolutionarily conserved and positively charged surface. We provide the structural and interaction information of this atypical PHD finger and categorize this BRPF2 PHD2 into a new subset of PHD finger. Moreover our work also shed light on the functional aspect of the PZPM. PMID- 22820307 TI - The role of fibrinogen spacing and patch size on platelet adhesion under flow. AB - Platelet adhesion to the vessel wall during vascular injury is mediated by platelet glycoproteins binding to their respective ligands on the vascular wall. In this study we investigated the roles that ligand patch spacing and size play in regulating platelet interactions with fibrinogen under hemodynamic flow conditions. To regulate the size and distance between patches of fibrinogen we developed a photolithography-based technique to fabricate patterns of proteins surrounded by a protein-repellant layer of poly(ethylene glycol). We demonstrate that when mepacrine labeled whole blood is perfused at a shear rate of 100 s -1 over substrates patterned with micron-sized wide lines of fibrinogen, platelets selectively adhere to the areas of patterned fibrinogen. Using fluorescent and scanning electron microscopy we demonstrate that the degree of platelet coverage (3-35%) and the ability of platelet aggregates to grow laterally are dependent upon the distance (6-30 MUm) between parallel lines of fibrinogen. We also report on the effects of fibrinogen patch size on platelet adhesion by varying the size of the protein patch (2-20 MUm) available for adhesion, demonstrating that the downstream length of the ligand patch is a critical parameter in platelet adhesion under flow. We expect that these results and protein patterning surfaces will be useful in understanding the spatial and temporal dynamics of platelet adhesion under physiologic flow, and in the development of novel platelet adhesion assays. PMID- 22820308 TI - Specific effects of PEGylation on gene delivery efficacy of polyethylenimine: interplay between PEG substitution and N/P ratio. AB - While an effective non-viral gene carrier, 25 kDa branched polyethylenimine (PEI) is cytotoxic, and decreasing its toxicity while maintaining its functionality is vital. Conjugation of carriers with polyethylene glycol (PEG) is a common approach to decreasing toxicity and improving biodistribution; however, the effect of PEGylation on PEI transfection efficacy is contradictory at present. The aim of this work was to reveal the details of this dependence. Polymers were synthesized by grafting 2 kDa PEG to 25 kDa PEI at multiple ratios. Unlike typical investigations, parallel studies based on either total polymer weight or PEI-backbone weight were employed at the same time for accurate investigation into the specific effects of PEGylation. Polymers were assessed for toxicity and plasmid DNA (pDNA) binding, while polyplexes were formed at various polymer/pDNA weight ratios and monitored by dynamic light scattering (DLS) in the presence of serum. The efficacy of the polyplexes for pDNA delivery and transgene expression in HEK293 cells was assessed by flow cytometry. This approach unexpectedly revealed that increased PEG substitution caused lower toxicity and pDNA-binding on a per total polymer weight basis, but not on a per PEI-backbone weight basis. DLS indicated that high PEGylation prevents an increase in polyplex size in the presence of serum. Plasmid uptake and transgene expression were found to have a complex relationship with PEG substitution, dependent on the polymer/plasmid-DNA weight ratio. PEGylation generally decreased the transfection efficacy of PEI, but under ideal conditions of PEG substitution and polymer/pDNA ratio, PEGylation provided more effective carrier formulations than the native PEI itself. PMID- 22820309 TI - Design and characterization of microporous hyaluronic acid hydrogels for in vitro gene transfer to mMSCs. AB - The effective and sustained delivery of DNA locally could increase the applicability of gene therapy in tissue regeneration and therapeutic angiogenesis. One promising approach is to use porous hydrogel scaffolds to encapsulate and deliver nucleotides in the form of nanoparticles to the affected sites. We have designed and characterized microporous (MU-pore) hyaluronic acid hydrogels which allow for effective cell seeding in vitro post-scaffold fabrication and allow for cell spreading and proliferation without requiring high levels of degradation. These factors, coupled with high loading efficiency of DNA polyplexes using a previously developed caged nanoparticle encapsulation (CnE) technique, then allowed for long-term sustained transfection and transgene expression of incorporated mMSCs. In this study, we examined the effect of pore size on gene transfer efficiency and the kinetics of transgene expression. For all investigated pore sizes (30, 60, and 100 MUm), encapsulated DNA polyplexes were released steadily, starting by day 4 for up to 10 days. Likewise, transgene expression was sustained over this period, although significant differences between different pore sizes were not observed. Cell viability was also shown to remain high over time, even in the presence of high concentrations of DNA polyplexes. The knowledge acquired through this in vitro model can be utilized to design and better predict scaffold-mediated gene delivery for local gene therapy in an in vivo model where host cells infiltrate the scaffold over time. PMID- 22820311 TI - Direct molecular tissue analysis by MALDI imaging mass spectrometry in the field of gastrointestinal disease. PMID- 22820310 TI - Optical measurement of biomechanical properties of individual erythrocytes from a sickle cell patient. AB - Sickle cell disease (SCD) is characterized by the abnormal deformation of red blood cells (RBCs) in the deoxygenated condition, as their elongated shape leads to compromised circulation. The pathophysiology of SCD is influenced by both the biomechanical properties of RBCs and their hemodynamic properties in the microvasculature. A major challenge in the study of SCD involves accurate characterization of the biomechanical properties of individual RBCs with minimum sample perturbation. Here we report the biomechanical properties of individual RBCs from a SCD patient using a non-invasive laser interferometric technique. We optically measure the dynamic membrane fluctuations of RBCs. The measurements are analyzed with a previously validated membrane model to retrieve key mechanical properties of the cells: bending modulus; shear modulus; area expansion modulus; and cytoplasmic viscosity. We find that high cytoplasmic viscosity at ambient oxygen concentration is principally responsible for the significantly decreased dynamic membrane fluctuations in RBCs with SCD, and that the mechanical properties of the membrane cortex of irreversibly sickled cells (ISCs) are different from those of the other types of RBCs in SCD. PMID- 22820312 TI - Transcription network analysis by a sparse binary factor analysis algorithm. AB - Transcription factor activities (TFAs), rather than expression levels, control gene expression and provide valuable information for investigating TF-gene regulations. The underlying bimodal or switch-like patterns of TFAs may play important roles in gene regulation. Network Component Analysis (NCA) is a popular method to deduce TFAs and TF-gene control strengths from microarray data. However, it does not directly examine the bimodality of TFAs and it needs TF-gene connection topology a priori known. In this paper, we modify NCA to model gene expression regulation by Binary Factor Analysis (BFA), which directly captures switch-like patterns of TFAs. Moreover, sparse technique is employed on the mixing matrix of BFA, and thus the proposed sparse BYY-BFA algorithm, developed under Bayesian Ying-Yang (BYY) learning framework, can not only uncover the latent TFA profile’s switch-like patterns, but also be capable of automatically shutting off the unnecessary connections. Simulation study demonstrates the effectiveness of BYY-BFA, and a preliminary application to Saccharomyces cerevisiae cell cycle data and Escherichia coli carbon source transition data shows that the reconstructed binary patterns of TFAs by BYY-BFA are consistent with the ups and downs of TFAs by NCA, and that BYY-BFA also works well when the network topology is unknown. PMID- 22820313 TI - Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. AB - AIMS: To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03). CONCLUSIONS: The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'. PMID- 22820314 TI - Dysnatraemia in heart failure. AB - AIMS: To investigate in detail the correlates of dysnatremia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF. Background Hyponatraemia has been shown to carry important prognostic information in patients with heart failure with reduced left ventricular ejection fraction (LVEF). However, exact serum sodium cut-off levels are not defined and the implications for heart failure with preserved ejection fraction (HF-pEF) are unclear. The prognostic value of hypernatraemia has not been investigated systematically. Therefore, the aim of this study was to investigate in detail the correlates of dysnatraemia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF. METHODS AND RESULTS: One thousand consecutive patients with heart failure of any cause and severity from the Wurzburg Interdisciplinary Network for Heart Failure registry were included. Non-linear models for the association between serum sodium and mortality risk were calculated using restricted cubic splines and Cox proportional hazard regression. Median follow-up time for survivors was 5.1 years. Results Independent correlates of dysnatraemia included guideline-recommended medication for chronic heart failure, indicators of renal function, and reverse associations with established cardiac risk factors. Overall mortality was 56%. Both hyponatraemia (n = 72) and hypernatraemia (n = 98) were associated with a significantly increased mortality risk: hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.60-2.77; and HR 1.91, 95% CI 1.49-2.45, respectively. A U-shaped association of serum sodium with mortality risk was found. Prognosis was best for patients with high normal sodium levels, i.e. 140 145 mmol/L. CONCLUSIONS: Both hypo- and hypernatraemia indicate a markedly compromised prognosis in heart failure regardless of LVEF. Sodium levels within the reference range carry differential information on survival, with serum levels of 135-139 mmol/L indicating an increased mortality risk. PMID- 22820315 TI - Why do drugs for acute heart failure fail? PMID- 22820316 TI - A tissue-engineered jellyfish with biomimetic propulsion. AB - Reverse engineering of biological form and function requires hierarchical design over several orders of space and time. Recent advances in the mechanistic understanding of biosynthetic compound materials, computer-aided design approaches in molecular synthetic biology 4,5 and traditional soft robotics, and increasing aptitude in generating structural and chemical micro environments that promote cellular self-organization have enhanced the ability to recapitulate such hierarchical architecture in engineered biological systems. Here we combined these capabilities in a systematic design strategy to reverse engineer a muscular pump. We report the construction of a freely swimming jellyfish from chemically dissociated rat tissue and silicone polymer as a proof of concept. The constructs, termed 'medusoids', were designed with computer simulations and experiments to match key determinants of jellyfish propulsion and feeding performance by quantitatively mimicking structural design, stroke kinematics and animal-fluid interactions. The combination of the engineering design algorithm with quantitative benchmarks of physiological performance suggests that our strategy is broadly applicable to reverse engineering of muscular organs or simple life forms that pump to survive. PMID- 22820317 TI - Associative transcriptomics of traits in the polyploid crop species Brassica napus. PMID- 22820318 TI - Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. AB - Genome-wide transcriptome analyses are routinely used to monitor tissue-, disease and cell type-specific gene expression, but it has been technically challenging to generate expression profiles from single cells. Here we describe a robust mRNA Seq protocol (Smart-Seq) that is applicable down to single cell levels. Compared with existing methods, Smart-Seq has improved read coverage across transcripts, which enhances detailed analyses of alternative transcript isoforms and identification of single-nucleotide polymorphisms. We determined the sensitivity and quantitative accuracy of Smart-Seq for single-cell transcriptomics by evaluating it on total RNA dilution series. We found that although gene expression estimates from single cells have increased noise, hundreds of differentially expressed genes could be identified using few cells per cell type. Applying Smart-Seq to circulating tumor cells from melanomas, we identified distinct gene expression patterns, including candidate biomarkers for melanoma circulating tumor cells. Our protocol will be useful for addressing fundamental biological problems requiring genome-wide transcriptome profiling in rare cells. PMID- 22820320 TI - Comparative study on the pregnancy outcomes of in vitro fertilization-embryo transfer between long-acting gonadotropin-releasing hormone agonist combined with transvaginal ultrasound-guided cyst aspiration and long-acting gonadotropin releasing hormone agonist alone. AB - OBJECTIVE: To retrospectively analyze the effects of long-acting gonadotropin releasing hormone agonist (GnRH-a) combined with transvaginal ultrasound-guided cyst aspiration on the pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET) in the infertile patients with ovarian endometriosis. METHODS: The 134 patients with ovarian endometriosis who underwent GnRH-a combined with transvaginal ultrasound-guided cyst aspiration and IVF-ET were served as experimental group. The 102 patients with ovarian endometriosis who underwent GnRH-a and IVF-ET were served as control group. After treatment, the cyst size, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), number of ovum pick-up, fertility rate, cleavage rate, high-quality embryo rate, implantation rate, clinical pregnancy rate and abortion rate were compared between the two groups. RESULTS: In the 134 patients of experimental group, 138 cysts disappeared after GnRH-a combined with three times of transvaginal ultrasound-guided cyst aspiration. In the 102 patients of control group, of the 114 cysts, 34 disappeared after GnRH-a, 67 were decreased and 13 were unchanged. The abortion rate was significantly lower in experimental group than in control group. The level of serum E2 on HCG day, the number of ovarian follicles with 14 mm or more, the number of retrieved oocytes, high-quality embryo rate, implantation rate and clinical pregnancy rate were higher in experimental group than in control group (all P<0.05). CONCLUSION: GnRH-a combined with transvaginal ultrasound-guided cyst aspiration can obtain better therapeutic effects and pregnancy outcomes in infertile patients with ovarian endometriosis who underwent IVF-ET. PMID- 22820319 TI - Ethical considerations and rationale of the MAKI trial: a multicenter double blind randomized placebo-controlled trial into the preventive effect of palivizumab on recurrent wheezing associated with respiratory syncytial virus infection in children with a gestational age of 33-35 weeks. AB - BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the most frequent cause of bronchiolitis during infancy. Long-term airway morbidity with recurrent post bronchiolitis wheezing (PBW) episodes, which are probably associated with respiratory infections, occurs in 30 to 70% of infants that were hospitalised with RSV LRTI. METHODS: We set up a multicenter, placebo-controlled double-blind randomized clinical trial in healthy preterm infants born between 33 and 35 weeks gestational age (WGA). The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections. RESULTS: The primary objective was to determine the preventive effect of RSV immunoprophylaxis (palivizumab) on the development of recurrent wheezing during the first year of life. The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs. As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms. We will also examine wheezing at age 1, 3 and 6 years both reported by the parents and the general practitioner and quality of life as secondary outcomes. This trial is possible because RSV immunoprophylaxis, although effective in this population, is not completely used in the Netherlands due to its high costs. CONCLUSION: The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo. PMID- 22820321 TI - Is pulmonary vascular resistance index predictive of exercise tolerance in adult patients with idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Clinical trials for adults with pulmonary arterial hypertension use exercise capacity, as measured by walking distance, as the primary endpoint to measure symptomatic improvement. In this article, we look at the relationship between walking distance and a hemodynamic variable, pulmonary vascular resistance index (PVRI), from the available trials. METHODS: Patient-level data from 16 randomized controlled clinical trials were obtained. All idiopathic subjects with a baseline and study endpoint measurement of both hemodynamic and exercise endpoints were included. Changes from baseline in both endpoints and the relationship between the endpoints were summarized. Receiver operating characteristic curves were used to investigate the predictive ability. Measures of surrogacy were also calculated. RESULTS: There is a weak correlation between changes in PVRI and exercise capacity. Receiver operating characteristic analysis shows a high false positive rate of using one variable to predict the other. Measures of surrogacy show the proportion of variability in exercise capacity explained by PVRI is approximately 5%. CONCLUSIONS: PVRI should not be used as a surrogate marker to predict changes in exercise capacity. PMID- 22820322 TI - Evaluation of a policy to integrate physical activity into the school day. AB - BACKGROUND: Implementing physical activity (PA) within academic curricula increases energy expenditure and enhances academic achievement in elementary students. The purposes of the study were to determine the extent teachers met the 20-minute PA policy, identify how teachers met the policy, and measure the level of intensity of PA provided. METHODS: Four elementary schools (grades K-5; 68 classroom teachers) implemented a district-mandated 20-minute PA policy. Teachers recorded PA for 1 week in September 2010 and February 2011. A sample of 142 students (grades K-5) wore accelerometers to measure school day PA. RESULTS: While 40% and 4% of teachers in September and February respectively met the policy all 5 days, 72.5% and 45.7% of teachers in September and February respectively implemented PA at least 3 days/week. Accelerometry results indicated curriculum-based lessons (CBL; 59.92 +/- 20.38 min) or walk/run periods (51.56 +/ 18.67 min) significantly increased school day MVPA (P < .05) above no additional activity (30.96 +/- 22.57 min). CONCLUSIONS: Although the teachers did not meet the 20-minute policy every day, the increased amount of PA achieved each week through the teachers' efforts is a significant contributor to total daily PA levels of children. PMID- 22820323 TI - Vocal rate as an assessment process during fallow deer contests. AB - Two types of model propose that strategic decisions during contests are determined either by (i) a mutual-assessment process or (ii) a self-assessment process. Vocal signals are thought to convey information about the competitive abilities of individuals, the ultimate function of which is a reduction in costs associated with fighting consistent with the principle of mutual assessment. Nevertheless, the limited evidence that male ungulates engage in mutual assessment of vocal rates during dyadic contests has been questioned. Therefore, we examined the vocal rates of winners and losers during escalated dyadic contests between male fallow deer in order to further inform on this issue. Our results showed that winners and losers did not differ in vocal rate. The best model fit that accounted for individual vocal rates included a preponderance of factors related to the opponent indicating that contestants were attending to their opponent during fights. Vocal rate was, therefore, dependent on estimates of opponent quality without reference to self, supporting an 'opponent-only' rather than a mutual assessment process. PMID- 22820324 TI - Intact polar and core glycerol dibiphytanyl glycerol tetraether lipids of group I.1a and I.1b thaumarchaeota in soil. AB - Ecological studies of thaumarchaeota often apply glycerol dibiphytanyl glycerol tetraether (GDGT)-based intact membrane lipids. However, these components have only been characterized for thaumarchaeota from aquatic environments. Thaumarchaeota have been shown to play an important role in the nitrogen cycle in soil as ammonium oxidizers, and GDGTs are common lipids encountered in soil. We report the core and intact polar lipid (IPL) GDGTs produced by three newly available thaumarchaeota isolated from grassland soil in Austria ("Nitrososphaera viennensis," group I.1b) and enriched from agricultural soils in South Korea ("Candidatus Nitrosoarchaeum koreensis" MY1, group I.1a; and "Candidatus Nitrososphaera" strain JG1, group I.1b). The soil thaumarchaeota all synthesize crenarchaeol as their major core GDGT, in agreement with the fact that crenarchaeol has also been detected in thaumarchaeota from aquatic environments. The crenarchaeol regioisomer apparently is produced in significant quantities only by soil thaumarchaeota of the I.1b subgroup. In addition, GDGTs with 0 to 4 cyclopentane moieties and GDGTs containing an additional hydroxyl group were detected. The IPL head groups of their membrane lipids comprised mainly monohexose, dihexose, trihexose, phosphohexose, and hexose-phosphohexose moieties. The hexose-phosphohexose head group bound to crenarchaeol occurred in all soil thaumarchaeota, and this IPL is at present the only lipid that is detected in all thaumarchaeota analyzed so far. This specificity and its lability indicate that it is the most suitable biomarker lipid to trace living thaumarchaeota. This study, in combination with previous studies, also suggests that hydroxylated GDGTs occur in the I.1a, but not in the I.1b, subgroup of the thaumarchaeota. PMID- 22820325 TI - Requirement of signal peptidase ComC and thiol-disulfide oxidoreductase DsbA for optimal cell surface display of pseudopilin ComGC in Staphylococcus aureus. AB - Staphylococcus aureus is an important Gram-positive bacterial pathogen producing many secreted and cell surface-localized virulence factors. Here we report that the staphylococcal thiol-disulfide oxidoreductase DsbA is essential for stable biogenesis of the ComGC pseudopilin. The signal peptidase ComC is indispensable for ComGC maturation and optimal cell surface exposure. PMID- 22820326 TI - Effects of disinfection on Legionella spp., eukarya, and biofilms in a hot water system. AB - Legionella species are frequently detected in hot water systems, attached to the surface as a biofilm. In this work, the dynamics of Legionella spp. and diverse bacteria and eukarya associated together in the biofilm, coming from a pilot scale 1 system simulating a real hot water system, were investigated throughout 6 months after two successive heat shock treatments followed by three successive chemical treatments. Community structure was assessed by a fingerprint technique, single-strand conformation polymorphism (SSCP). In addition, the diversity and dynamics of Legionella and eukarya were investigated by small-subunit (SSU) ribosomal cloning and sequencing. Our results showed that pathogenic Legionella species remained after the heat shock and chemical treatments (Legionella pneumophila and Legionella anisa, respectively). The biofilm was not removed, and the bacterial community structure was transitorily affected by the treatments. Moreover, several amoebae had been detected in the biofilm before treatments (Thecamoebae sp., Vannella sp., and Hartmanella vermiformis) and after the first heat shock treatment, but only H. vermiformis remained. However, another protozoan affiliated with Alveolata, which is known as a host cell for Legionella, dominated the eukaryal species after the second heat shock and chemical treatment tests. Therefore, effective Legionella disinfection may be dependent on the elimination of these important microbial components. We suggest that eradicating Legionella in hot water networks requires better study of bacterial and eukaryal species associated with Legionella in biofilms. PMID- 22820327 TI - Biological role of pigment production for the bacterial phytopathogen Pantoea stewartii subsp. stewartii. AB - Pantoea stewartii subsp. stewartii, the causal agent of Stewart's wilt of sweet corn, produces a yellow carotenoid pigment. A nonpigmented mutant was selected from a bank of mutants generated by random transposon mutagenesis. The transposon insertion site was mapped to the crtB gene, encoding a putative phytoene synthase, an enzyme involved in the early steps of carotenoid biosynthesis. We demonstrate here that the carotenoid pigment imparts protection against UV radiation and also contributes to the complete antioxidant pathway of P. stewartii. Moreover, production of this pigment is regulated by the EsaI/EsaR quorum-sensing system and significantly contributes to the virulence of the pathogen in planta. PMID- 22820328 TI - Roles of four putative DEAD-box RNA helicase genes in growth of Listeria monocytogenes EGD-e under heat, pH, osmotic, ethanol, and oxidative stress conditions. AB - To examine the role of the four putative DEAD-box RNA helicase genes of Listeria monocytogenes EGD-e in stress tolerance, the growth of the Deltalmo0866, Deltalmo1246, Deltalmo1450, and Deltalmo1722 deletion mutant strains at 42.5 degrees C, at pH 5.6 or pH 9.4, in 6% NaCl, in 3.5% ethanol, and in 5 mM H(2)O(2) was studied. Restricted growth of the Deltalmo0866 deletion mutant strain in 3.5% ethanol suggests that Lmo0866 contributes to ethanol stress tolerance of L. monocytogenes EGD-e. The Deltalmo1450 mutant strain showed negligible growth at 42.5 degrees C, at pH 9.4, and in 5 mM H(2)O(2) and a lower maximum growth temperature than the wild-type EGD-e, suggesting that Lmo1450 is involved in the tolerance of L. monocytogenes EGD-e to heat, alkali, and oxidative stresses. The altered stress tolerance of the Deltalmo0866 and Deltalmo1450 deletion mutant strains did not correlate with changes in relative expression levels of lmo0866 and lmo1450 genes under corresponding stresses, suggesting that Lmo0866- and Lmo1450-dependent tolerance to heat, alkali, ethanol, or oxidative stress is not regulated at the transcriptional level. Growth of the Deltalmo1246 and Deltalmo1722 deletion mutant strains did not differ from that of the wild-type EGD-e under any of the conditions tested, suggesting that Lmo1246 and Lmo1722 have no roles in the growth of L. monocytogenes EGD-e under heat, pH, osmotic, ethanol, or oxidative stress. This study shows that the putative DEAD-box RNA helicase genes lmo0866 and lmo1450 play important roles in tolerance of L. monocytogenes EGD-e to ethanol, heat, alkali, and oxidative stresses. PMID- 22820329 TI - Mycobacterial shuttle vectors designed for high-level protein expression in infected macrophages. AB - Mycobacterial shuttle vectors contain dual origins of replication for growth in both Escherichia coli and mycobacteria. One such vector, pSUM36, was re engineered for high-level protein expression in diverse bacterial species. The modified vector (pSUM-kan-MCS2) enabled green fluorescent protein expression in E. coli, Mycobacterium smegmatis, and M. avium at levels up to 50-fold higher than that detected with the parental vector, which was originally developed with a lacZalpha promoter. This high-level fluorescent protein expression allowed easy visualization of M. smegmatis and M. avium in infected macrophages. The M. tuberculosis gene esat-6 was cloned in place of the green fluorescence protein gene (gfp) to determine the impact of ESAT-6 on the innate inflammatory response. The modified vector (pSUM-kan-MCS2) yielded high levels of ESAT-6 expression in M. smegmatis. The ability of ESAT-6 to suppress innate inflammatory pathways was assayed with a novel macrophage reporter cell line, designed with an interleukin 6 (IL-6) promoter-driven GFP cassette. This stable cell line fluoresces in response to diverse mycobacterial strains and stimuli, such as lipopolysaccharide. M. smegmatis clones expressing high levels of ESAT-6 failed to attenuate IL-6-driven GFP expression. Pure ESAT-6, produced in E. coli, was insufficient to suppress a strong inflammatory response elicited by M. smegmatis or lipopolysaccharide, with ESAT-6 itself directly activating the IL-6 pathway. In summary, a pSUM-protein expression vector and a mammalian IL-6 reporter cell line provide new tools for understanding the pathogenic mechanisms deployed by various mycobacterial species. PMID- 22820331 TI - High-salt stress conditions increase the pAW63 transfer frequency in Bacillus thuringiensis. AB - Conjugation experiments with Bacillus thuringiensis and transfer kinetics demonstrated that salt stress has a positive impact on plasmid transfer efficiency. Compared to standard osmotic conditions (0.5% NaCl), plasmid transfer occurred more rapidly, and at higher frequencies (>100-fold), when bacteria were exposed to a high-salt stress (5% NaCl) in liquid brain heart infusion (BHI). Under milder salt conditions (2.5% NaCl), only a 10-fold effect was observed in Luria-Bertani broth and no difference was detected in BHI. These observations are particularly relevant in the scope of potential gene exchanges among members of the Bacillus cereus group, which includes food-borne contaminants and pathogens. PMID- 22820330 TI - TetR-based gene regulation systems for Francisella tularensis. AB - There are a number of genetic tools available for studying Francisella tularensis, the etiological agent of tularemia; however, there is no effective inducible or repressible gene expression system. Here, we describe inducible and repressible gene expression systems for F. tularensis based on the Tet repressor, TetR. For the inducible system, a tet operator sequence was cloned into a modified F. tularensis groESL promoter sequence and carried in a plasmid that constitutively expressed TetR. To monitor regulation the luminescence operon, luxCDABE, was cloned under the hybrid Francisella tetracycline-regulated promoter (FTRp), and transcription was initiated with addition of anhydrotetracycline (ATc), which binds TetR and alleviates TetR association with tetO. Expression levels measured by luminescence correlated with ATc inducer concentrations ranging from 20 to 250 ng ml(-1). In the absence of ATc, luminescence was below the level of detection. The inducible system was also functional during the infection of J774A.1 macrophages, as determined by both luminescence and rescue of a mutant strain with an intracellular growth defect. The repressible system consists of FTRp regulated by a reverse TetR mutant (revTetR), TetR r1.7. Using this system with the lux reporter, the addition of ATc resulted in decreased luminescence, while in the absence of ATc the level of luminescence was not significantly different from that of a construct lacking TetR r1.7. Utilizing both systems, the essentiality of SecA, the protein translocase ATPase, was confirmed, establishing that they can effectively regulate gene expression. These two systems will be invaluable in exploring F. tularensis protein function. PMID- 22820332 TI - Identification and partial characterization of extracellular aspartic protease genes from Metschnikowia pulcherrima IWBT Y1123 and Candida apicola IWBT Y1384. AB - The extracellular acid proteases of non-Saccharomyces wine yeasts may fulfill a number of roles in winemaking, which include increasing the available nitrogen sources for the growth of fermentative microbes, affecting the aroma profile of the wine, and potentially reducing protein haze formation. These proteases, however, remain poorly characterized, especially at genetic level. In this study, two extracellular aspartic protease-encoding genes were identified and sequenced, from two yeast species of enological origin: one gene from Metschnikowia pulcherrima IWBT Y1123, named MpAPr1, and the other gene from Candida apicola IWBT Y1384, named CaAPr1. In silico analysis of these two genes revealed a number of features peculiar to aspartic protease genes, and both the MpAPr1 and CaAPr1 putative proteins showed homology to proteases of yeast genera. Heterologous expression of MpAPr1 in Saccharomyces cerevisiae YHUM272 confirmed that it encodes an aspartic protease. MpAPr1 production, which was shown to be constitutive, and secretion were confirmed in the presence of bovine serum albumin (BSA), casein, and grape juice proteins. The MpAPr1 gene was found to be present in 12 other M. pulcherrima strains; however, plate assays revealed that the intensity of protease activity was strain dependent and unrelated to the gene sequence. PMID- 22820333 TI - Chemotaxis of Marinobacter adhaerens and its impact on attachment to the diatom Thalassiosira weissflogii. AB - Alga-bacterium interactions are crucial for aggregate formation and carbon cycling in aquatic systems. To understand the initiation of these interactions, we investigated bacterial chemotaxis within a bilateral model system. Marinobacter adhaerens HP15 has been demonstrated to attach to the diatom Thalassiosira weissflogii and induce transparent exopolymeric particle and aggregate formation. M. adhaerens possesses one polar flagellum and is highly motile. Bacterial cells were attracted to diatom cells, as demonstrated by addition of diatom cell homogenate or diatom culture supernatant to soft agar, suggesting that chemotaxis might be important for the interaction of M. adhaerens with diatoms. Three distinct chemotaxis-associated gene clusters were identified in the genome sequence of M. adhaerens, with the clusters showing significant sequence similarities to those of Pseudomonas aeruginosa PAO1. Mutations in the genes cheA, cheB, chpA, and chpB, which encode histidine kinases and methylesterases and which are putatively involved in either flagellum-associated chemotaxis or pilus-mediated twitching motility, were generated and mutants with the mutations were phenotypically analyzed. DeltacheA and DeltacheB mutants were found to be swimming deficient, and all four mutants were impaired in biofilm formation on abiotic surfaces. Comparison of the HP15 wild type and its chemotaxis mutants in cocultures with the diatom revealed that the fraction of bacteria attaching to the diatom decreased significantly for mutants in comparison to that for the wild type. Our results highlight the importance of M. adhaerens chemotaxis in initiation of its interaction with the diatom. In-depth knowledge of these basic processes in interspecies interactions is pivotal to obtain a systematic understanding of organic matter flux and nutrient cycling in marine ecosystems. PMID- 22820335 TI - Isolated microbial single cells and resulting micropopulations grow faster in controlled environments. AB - Singularized cells of Pichia pastoris, Hansenula polymorpha, and Corynebacterium glutamicum displayed specific growth rates under chemically and physically constant conditions that were consistently higher than those obtained in populations. This highlights the importance of single-cell analyses by uncoupling physiology and the extracellular environment, which is now possible using the Envirostat 2.0 concept. PMID- 22820334 TI - Involvement of the major capsid protein and two early-expressed phage genes in the activity of the lactococcal abortive infection mechanism AbiT. AB - The dairy industry uses the mesophilic, Gram-positive, lactic acid bacterium (LAB) Lactococcus lactis to produce an array of fermented milk products. Milk fermentation processes are susceptible to contamination by virulent phages, but a plethora of phage control strategies are available. One of the most efficient is to use LAB strains carrying phage resistance systems such as abortive infection (Abi) mechanisms. Yet, the mode of action of most Abi systems remains poorly documented. Here, we shed further light on the antiviral activity of the lactococcal AbiT system. Twenty-eight AbiT-resistant phage mutants derived from the wild-type AbiT-sensitive lactococcal phages p2, bIL170, and P008 were isolated and characterized. Comparative genomic analyses identified three different genes that were mutated in these virulent AbiT-insensitive phage derivatives: e14 (bIL170 [e14(bIL170)]), orf41 (P008 [orf41(P008)]), and orf6 (p2 [orf6(p2)] and P008 [orf6(P008)]). The genes e14(bIL170) and orf41(P008) are part of the early-expressed genomic region, but bioinformatic analyses did not identify their putative function. orf6 is found in the phage morphogenesis module. Antibodies were raised against purified recombinant ORF6, and immunoelectron microscopy revealed that it is the major capsid protein (MCP). Coexpression in L. lactis of ORF6(p2) and ORF5(p2), a protease, led to the formation of procapsids. To our knowledge, AbiT is the first Abi system involving distinct phage genes. PMID- 22820336 TI - Regulatable vectors for environmental gene expression in Alphaproteobacteria. AB - Two expression vectors utilizing the inducible taurine promoter (tauAp) were developed. Plasmid pLMB51 is a stable low-copy vector enabling expression in the environment and in planta. The higher copy number pLMB509 enables BD restriction independent cloning, expression, and purification of polyhistidine-tagged proteins. PMID- 22820338 TI - Engineering fungal secondary metabolism: a roadmap to novel compounds. AB - Natural products play important roles not only in the environment but also as useful compounds in various applications like in medicine or plant protection. An enormous number of such compounds have derived from microorganisms colonizing various habitats. Traditionally, new isolates of bacteria or fungi have been screened for their potential to produce biologically active compounds. In the post genomic era, however, there is a growing number of novel methods based on genetic engineering to obtain new metabolites. In this review, we summarize the recent progress made in the development of novel promising approaches for natural product discovery in fungi using genome mining, activation of silent gene clusters, heterologous expression of biosynthesis genes, exchange of enzyme modules as well as redesign of metabolic flux. PMID- 22820337 TI - Mechanisms by which ambient humidity may affect viruses in aerosols. AB - Many airborne viruses have been shown to be sensitive to ambient humidity, yet the mechanisms responsible for this phenomenon remain elusive. We review multiple hypotheses, including water activity, surface inactivation, and salt toxicity, that may account for the association between humidity and viability of viruses in aerosols. We assess the evidence and limitations for each hypothesis based on findings from virology, aerosol science, chemistry, and physics. In addition, we hypothesize that changes in pH within the aerosol that are induced by evaporation may trigger conformational changes of the surface glycoproteins of enveloped viruses and subsequently compromise their infectivity. This hypothesis may explain the differing responses of enveloped viruses to humidity. The precise mechanisms underlying the relationship remain largely unverified, and attaining a complete understanding of them will require an interdisciplinary approach. PMID- 22820339 TI - Immobilization of enterokinase on magnetic supports for the cleavage of fusion proteins. AB - Magnetic nanobiocatalysts for tag cleavage on fusion proteins have been prepared by immobilizing enterokinase (EK) onto iron oxide magnetic nanoparticles coated with biopolymers. Two different chemistries have been explored for the covalent coupling of EK, namely carbodiimide (EDC coupling) and maleimide activation (Sulfo coupling). Upon immobilization, EK initial activity lowered but EDC coupling lead to higher activity retention. Regarding the stability of the nanobiocatalysts, these were recycled up to ten times with the greater activity losses observed in the first two cycles. The immobilized EK also proved to cleave a control fusion protein and to greatly simplify the separation of the enzyme from the reaction mixture. PMID- 22820340 TI - Effect of hypothermic temperatures on production of rabies virus glycoprotein by recombinant Drosophila melanogaster S2 cells cultured in suspension. AB - Aiming at maximizing the production of transmembrane rabies virus glycoprotein (rRVGP), the influence of hypothermic temperature on a recombinant Drosophila melanogaster S2 cell culture in Sf-900II medium was investigated. Cell growth and rRVGP production were assessed at 4 culture temperatures in Schott flasks: 16, 20, 24 and 28 degrees C. The maximum specific growth rates MU(max) were, respectively: 0.009, 0.019, 0.038 and 0.035 h(-1), while the maximum rRVGP levels C(max)(rRVGP) were: 0.075, 2.973, 0.480 and 1.404 mg L(-1). The best production temperature (20 degrees C) was then tested in a bioreactor with control of pH and dissolved oxygen in batch and fed-batch modes. In the batch culture, MU(max) and C(max)(rRVGP) were 0.060 h(-1) and 0.149 mg L(-1) at 28 degrees C and 0.026 h(-1) and 0.354 mg L(-1) at 20 degrees C, respectively. One batch-culture experiment was carried out with adaptation of the cells by the temperature falling in steps from 20 degrees C to 16 degrees C, so that MU(max) fell from 0.023 to 0.013 h(-1), while C(max)(rRVGP) was improved to 0.567 mg L(-1). In the fed-batch mode at 20 degrees C, MU(max) was 0.025 h(-1) and C(max)(rRVGP) was 1.155 mg L(-1). Taken together, these results indicate that the best strategy for optimized rRVGP production is the culture at hypothermic temperature of 20 degrees C, when MU(max) is kept low and with feeding of limitant aminoacids. PMID- 22820341 TI - Testing the activation-orientation account of spatial attentional asymmetries using transcranial direct current stimulation. AB - The general population shows an attentional bias to the left, known as pseudoneglect. This bias is thought to be driven by higher levels of activation in right parietal areas. Using transcranial direct current stimulation (tDCS) to manipulate activation, this study examined whether tDCS over the left and right posterior parietal cortices (PPC) affects pseudoneglect. Normal participants received tDCS over the left or right PPCs (15 in each group). Pseudoneglect was measured using the greyscales task, which requires a forced-choice discrimination of luminance between two opposing luminance gradients. The greyscales task was administered both before and after; (a) anodal (b) cathodal and (c) sham tDCS. Participants who received tDCS over the left PPC demonstrated pseudoneglect for the greyscales task, which was significantly reduced by anodal tDCS, but was unaffected by sham or cathodal tDCS. In contrast, for those participants who received right PPC tDCS, pseudoneglect for the greyscales task was unaffected by tDCS. Anodal tDCS, which is known to elevate neural excitation, may have overcome lower levels of activation in the left PPC, resulting in decreased pseudoneglect. These findings provide convincing evidence in support of an activation orientation model of pseudoneglect and have implications for models of left neglect. PMID- 22820342 TI - Threat, domain-specificity and the human amygdala. AB - It is well documented that the human amygdala responds strongly to human faces, especially when depicting negative emotions. The extent to which the amygdala also responds to other animate entities - as well as to inanimate objects - and how that response is modulated by the object's perceived affective valence and arousal value remains unclear. To address these issues, subjects performed a repetition detection task to photographs of negative, neutral, and positive faces, animals, and manipulable objects equated for emotional valence and arousal level. Both the left and right amygdala responded more to animate entities than manipulable objects, especially for negative objects (fearful faces, threatening animals, versus weapons) and to neutral stimuli (faces with neutral expressions, neutral animals, versus tools). Thus, in the absence of contextual cues, the human amygdala responds to threat associated with some object categories (animate things) but not others (weapons). Although failing to activate the amygdala, relative to viewing other manipulable objects, viewing weapons did elicit an enhanced response in dorsal stream regions linked to object action. Thus, our findings suggest two circuits underpinning an automatic response to threatening stimuli; an amygdala-based circuit for animate entities, and a cortex-based circuit for responding to manmade, manipulable objects. PMID- 22820343 TI - Extrastriate cortex and medial temporal lobe regions respond differentially to visual feature overlap within preferred stimulus category. AB - It has been proposed that domain-specific regions in extrastriate cortex, parahippocampal cortex and the medial temporal lobe (MTL, particularly the hippocampus, HC, and perirhinal cortex, PrC) may respond differently to the degree of feature complexity present in sets of visual stimuli, with the latter two regions tuned to represent the differences among stimuli with a high degree of visual overlap or featural ambiguity (Graham, Barense, & Lee, 2010; Cowell, Bussey, & Saksida, 2010a). To test this prediction, healthy participants viewed blocks containing visually similar or visually different exemplars from four stimulus categories (scenes, faces, inanimate objects and animate objects). Independent functional regions of interest were identified in extrastriate and MTL regions that were preferentially responsive to one or more of these visual categories, and the main experimental data interrogated for any evidence of an interaction between visual category and degree of feature overlap. In PrC and posterior HC (PostHC) viewing sets of stimuli with a large number of overlapping features resulted in greater activity than blocks containing items that were more visually distinct. The opposite pattern was found in fusiform face area (FFA), parahippocampal place area (PPA) and lateral occipital complex (LOC). The increased response in the HC and PrC to high visual similarity was seen only for visual categories that effectively activate these regions (PrC-faces and objects; PostHC-scenes). This study confirms that regions throughout the visual ventral stream, parahippocampal cortex and MTL are engaged differentially by visual complexity, consistent with recent lesion experiments in which MTL damage affects discrimination and learning of, as well as recognition memory for, exemplars with a high degree of visual feature overlap. PMID- 22820345 TI - Spectroscopic investigation, nucleation, growth, optical, thermal and second harmonic studies of novel semi-organic nonlinear optical crystal - thiourea urea zinc sulfate. AB - A new nonlinear optical crystal thiourea urea zinc sulfate (TUZS) has been grown by slow evaporation technique in equimolar ratio. Solubility and metastable zone width measurements have been determined for the grown crystal. Single crystal XRD revealed that the crystal system belongs to orthorhombic with cell parameters a=7.78A, b=11.15A and c=15.47A. The sharp and well defined Bragg peaks observed in the powder XRD pattern confirm the crystalline nature of the TUZS compound. The grown mechanism and surface features were investigated by optical microscopic techniques such as scanning electron microscopy (SEM). The presence of zinc in the grown crystal was detected by atomic absorption spectroscopy and EDAX analysis. The compound has been confirmed by (1)H NMR, mass and FTIR spectral studies. The transmittance spectrum of TUZS has been used to calculate the extinction coefficient K, reflectance R, as functions of photon energy. The optical band gap of TUZS is 4.046 eV. The SHG efficiency has been tested by the Kurtz powder technique using Nd: YAG laser and KDP sample has been used as a standard reference material. PMID- 22820344 TI - Decoding information in the human hippocampus: a user's guide. AB - Multi-voxel pattern analysis (MVPA), or 'decoding', of fMRI activity has gained popularity in the neuroimaging community in recent years. MVPA differs from standard fMRI analyses by focusing on whether information relating to specific stimuli is encoded in patterns of activity across multiple voxels. If a stimulus can be predicted, or decoded, solely from the pattern of fMRI activity, it must mean there is information about that stimulus represented in the brain region where the pattern across voxels was identified. This ability to examine the representation of information relating to specific stimuli (e.g., memories) in particular brain areas makes MVPA an especially suitable method for investigating memory representations in brain structures such as the hippocampus. This approach could open up new opportunities to examine hippocampal representations in terms of their content, and how they might change over time, with aging, and pathology. Here we consider published MVPA studies that specifically focused on the hippocampus, and use them to illustrate the kinds of novel questions that can be addressed using MVPA. We then discuss some of the conceptual and methodological challenges that can arise when implementing MVPA in this context. Overall, we hope to highlight the potential utility of MVPA, when appropriately deployed, and provide some initial guidance to those considering MVPA as a means to investigate the hippocampus. PMID- 22820346 TI - Oxidative stress in Niemann-Pick type C patients: a protective role of N-butyl deoxynojirimycin therapy. AB - Niemann-Pick type C (NPC) is a rare neurodegenerative disorder biochemically characterized by the accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes of the affected patients. N-butyl-deoxynojirimycin is the only approved drug for patients with NPC disease. It inhibits glycosphingolipid synthesis, therefore reducing intracellular lipid storage. Although the mechanisms underlying the neurologic damage in the NPC disease are not yet well established, in vitro and in vivo studies suggest an involvement of reactive species in the pathophysiology of this disease. In this work we aimed to evaluate parameters of lipid and protein oxidation, measured by thiobarbituric acid reactive species (TBA-RS) and protein carbonyl formation, respectively, as well as the enzymatic and non-enzymatic antioxidant defenses in plasma, erythrocytes and fibroblasts from NPC1 patients, at diagnosis and during treatment with N butyl-deoxynojirimycin. We found a significant increase of TBA-RS in plasma and fibroblasts, as well as increased protein carbonyl formation and decreased total antioxidant status (TAS) in plasma of untreated NPC1 patients as compared to the control group. In addition, erythrocyte glutathione peroxidase (GSH-Px) activity was increased, whereas CAT and SOD activities were normal in these patients. We also observed that patients treated with N-butyl-deoxynojirimycin normalized plasma TBA-RS and TAS, as well as erythrocyte GSH-Px activity. Taken together, the present data indicate that oxidative stress is increased in patients with NPC1 disease and that treatment with N-butyl-deoxynojirimycin is able to confer protection against this pathological process. PMID- 22820347 TI - Phosphatidylinositol-4,5-bisphosphate ionization and domain formation in the presence of lipids with hydrogen bond donor capabilities. AB - Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) is an important lipidic signaling molecule that is involved in a broad range of cellular processes. Its interaction with proteins and its lateral distribution are governed by the ionization state of the phosphomonoester groups and its ability to form intra- and intermolecular hydrogen bonds. In this study we have investigated the ionization state of PI(4,5)P(2) in ternary lipid vesicle systems that contain in addition to PI(4,5)P(2) and phosphatidylcholine (PC) either phosphatidylethanolamine (PE), phosphatidylserine (PS) or phosphatidylinositol (PI). In the presence of PE we find an increased ionization of PI(4,5)P(2), which can be attributed to increased deprotonation due to hydrogen bond formation between PE and the PI(4,5)P(2) phosphomonoester groups. However, the effect of PE on PI(4,5)P(2) ionization is significantly smaller than it had been found previously for phosphatidic acid in the presence of PE (Kooijman et al., 2005). The reduced impact of PE on PI(4,5)P(2) ionization can be attributed to competing intramolecular hydrogen bond formation between the phosphomonoester groups and neighboring hydroxyl groups. It is noteworthy that the presence of PE affects more strongly the ionization of the 5-phosphate group than that of the 4 phosphate, suggesting that the interaction of PE with the 5-phosphate is stronger. In PI(4,5)P(2)/PS/PC lipid vesicles, the presence of PS was expected to yield an increased protonation of the PI(4,5)P(2) phosphomonoester groups due to a decreased interfacial pH as a result of the increased negative interfacial charge. However, the effect of PS on PI(4,5)P(2) ionization is only minor, potentially suggesting that PS and PI(4,5)P(2) are demixed. The PI(4,5)P(2)/PI/PC vesicle system was characterized by a surprising mixing behavior that has potentially far reaching consequences: fluorescence microscopy measurements of giant unilammellar vesicles composed of PI(4,5)P(2)/PI/PC at physiological concentrations show that PI and PI(4,5)P(2) form macroscopic, fluid phase domains in contact with a fluid PC rich phase (fluid/fluid demixing). Despite the fact that PI and PI(4,5)P(2) co-localize, the effect of PI on PI(4,5)P(2) ionization behavior is only noticeable above pH 7. Apparently two opposing effects lead to the observed behavior: Due to the presence of the anionic PI, the interfacial pH drops, which is expected to lead to an enhanced protonation of the PI(4,5)P(2) phosphomonoester groups. In turn, hydrogen bond formation between PI and PI(4,5)P(2) would lead to the opposite, i.e. increased deprotonation of the phosphomonoester group. Apparently these two effects compensate each other for pH values smaller than about 7, while for higher pH values the increased interfacial pH in the presence of PI has a stronger impact than PI/PI(4,5)P(2) hydrogen bond formation. The cooperative formation of PI/PI(4,5)P(2) mixed domains has potentially important ramifications for the spatial organization of phosphoinositide mediated signaling events. PMID- 22820348 TI - Species-specificity of DNA trimer densities in chromosomes and their use in the classification of closely related organisms. AB - 16S rDNA sequences are conventionally used for classification of organisms. However, the use of these sequences is sometimes not successful, especially for closely related species. For better classification of these organisms, several methods that are genome sequence-based have been developed. Sequence alignment based methods are tedious and time-consuming, as they need conserved coding sequences to be identified and deduced prior to sequence alignment. Likewise, method that relies on gene function needs genes to be assessed for function similarity. Other alignment-free methods, which are based on particular genome sequence properties, so far have been complex and not species-specific enough for classification of organisms below genus level. The present study found that the ratios of DNA trimer frequencies to chromosomal length were species-specific. Density of a trimer in a chromosomal sequence was defined as the average frequency of the trimer per 1 kbp. The species-specificity of trimer densities in chromosomes of many closely related bacteria was compared in parallel with 16S rDNA sequences in these same bacteria. The results of these comparisons indicate that trimer densities in chromosomes can be used to simply and efficiently classify the organisms below genus level. PMID- 22820349 TI - Templating of arrays of Ru nanoclusters by monolayer graphene/Ru Moires with different periodicities. AB - We have studied the formation of Ru nanocluster arrays on several monolayer graphene/Ru Moire structures with different relative orientations of the graphene and Ru lattices. Experiments and ab initio calculations clearly show that the presence of a graphene/Ru Moire does not guarantee the ordered adsorption of Ru nanoclusters. The simultaneous deposition of Ru onto coexisting Moires demonstrates that a structure with aligned graphene and Ru lattices templates the formation of arrays of small Ru clusters with narrow size spread and adsorption exclusively in a single site (the 'low fcc' site). The other Moires considered here gave rise to substantially larger clusters with broader size distribution and without detectable site selectivity. Calculations explain these findings via the density of states (DOS) at different sites of the graphene/Ru Moire. The ordered nucleation of many small clusters instead of incorporation of metal atoms into larger ones requires one Moire site with a large DOS at the Fermi level, so that the binding of metal adatoms to this site is stronger than to competing sites in the Moire and to existing metal clusters. PMID- 22820350 TI - Regulation of growth hormone (GH) receptor (GHR1 and GHR2) mRNA level by GH and metabolic hormones in primary cultured tilapia hepatocytes. AB - Growth hormone (GH) regulates essential physiological functions in teleost fishes, including growth, metabolism, and osmoregulation. Recent studies have identified two clades of putative receptors for GH (GHR1 clade and GHR2 clade) in fishes, both of which are highly expressed in the liver. Moreover, the liver is an important target for the anabolic effects of GH via endocrine IGFs, and liver sensitivity to GH is modulated by metabolic hormones. We investigated the effects of GH, insulin, glucagon, cortisol and triiodothyronine on GHR1 and GHR2 mRNA levels in primary cultured tilapia hepatocytes. Physiological concentrations of GH strongly stimulated GHR2 mRNA level (0.5-50*10(-9) M), but did not affect GHR1 mRNA level. Insulin suppressed stimulation of GHR2 mRNA level by GH (10(-8)-10( 6) M). Insulin increased basal GHR1 mRNA level (10(-8)-10(-6) M). Cortisol increased basal GHR2 mRNA level (10(-7)-10(-6) M), but did not consistently affect GH-stimulated GHR2 mRNA level. Cortisol increased basal GHR1 mRNA level (10(-9)-10(-6) M). Glucagon suppressed GH-stimulated GHR2 mRNA level and increased basal GHR1 mRNA level at a supraphysiological concentration (10(-6) M). A single injection of GH (5 MUg/g) increased liver GHR2 mRNA level, and insulin injection (5 MUg/g) decreased both basal and GH-stimulated GHR2 mRNA levels after 6 h. In contrast, insulin and GH injection had little effect on liver GHR1 mRNA level. This study shows that GHR1 and GHR2 gene expression are differentially regulated by physiological levels of GH and insulin in tilapia primary hepatocytes. PMID- 22820351 TI - Women bound to be active: differences in long-term physical activity between completers and noncompleters of a book club intervention. AB - BACKGROUND: Ideal approaches to increasing long-term physical activity (PA) adherence in women remain unclear. This study used a longitudinal mixed-methods approach to 1) determine the effectiveness of an 8-month book club intervention for increasing PA participation and self-worth, and reducing barriers at 1-year followup; and 2) identify reasons why completers and noncompleters did or did not maintain PA. METHODS: One year after the cessation of Women Bound to be Active (WBA), completers (participated in posttesting; n = 30) and noncompleters (did not participate in posttesting; n = 22) responded to questionnaires and interviews assessing their body mass index (BMI), current PA participation, barriers, and global self-worth. RESULTS: Compared with noncompleters, completers reported decreases in BMI, higher motivation for PA, higher ratio of benefits to barriers, and more consistent PA. Both groups still reported barriers to PA, especially time; however, completers more often reported strategies for overcoming these barriers. Completers more directly discussed the impact of their improved self-worth on their PA participation. CONCLUSIONS: In the future, a greater focus on time management and self-regulation strategies should be emphasized in PA interventions, specifically those that focus on women. This may help to prevent program and long-term PA attrition. PMID- 22820352 TI - CD19 as an attractive target for antibody-based therapy. AB - Despite progress in the treatment of B cell disorders, novel treatment approaches are still highly needed. CD19 is a pan-B cell marker that is recognized as a potential immunotherapy target for B cell disorders, including blood-borne malignancies and autoimmune diseases. Although initial attempts to target CD19 were unsuccessful, a new wave of investigational agents is currently in development. These agents are based on novel antibody-based technologies and formats that appear to better exploit CD19's therapeutic potential, and some promising clinical study data has already been reported. This review provides an overview and the rationale for the most advanced CD19-targeting programs in development. PMID- 22820353 TI - [Immunohistochemical comparison between GCDFP-15 and estrogen and progesterone receptors in the diagnosis of metastatic carcinoma of the breast]. AB - BACKGROUND: In the workup of tumors of unknown primary origin in women, a frequent consideration is breast carcinoma, because it is common and may initially present as metastasis. OBJECTIVE: Describe and compare the immunohistochemical profile of hormonal receptors (estrogen receptor and progesterone receptor) and GCDFP-15 in lymph node metastatic breast carcinoma according the histological grade. METHODS: Retrospective study analyzing 30 patients with identified primary breast cancer and lymph node metastasis. The cases were divided in three groups: grade I (well differentiated), grade II (moderately differentiated) and grade III (poorly differentiated). We used three antibodies (estrogen receptor, progesterone receptor and GCDFP-15) in the lymph node and compare the expression according the histological grade. RESULTS: In metastatic lymph node from grade I breast carcinomas the hormone receptors were 100% positive and GCDFP-15 was 80% positive. In grade II, estrogen receptor and progesterone receptor were positive in 90 and 40% respectively, and GCDFP-15 was positive in 80%. In grade III, estrogen receptor and progesterone receptor were positive in 30 and 50% respectively, and GCDFP-15 in 60%. CONCLUSIONS: The immunohistochemical expression of hormonal receptors and GCDFP-15 in metastatic breast carcinoma is related to histological grade in the breast. PMID- 22820354 TI - [Influence of predisposing, enabling, and health care need variables on the use of dental health services among Mexican adolescents from a semi-rural location]. AB - OBJECTIVE: The purpose of this study was to quantify the influence of some of the predisposing, enabling, and healthcare need variables on dental health services utilization (DHSU) among Mexican adolescents. MATERIAL AND METHODS: This is a cross-sectional analytical study including 1,538 Mexican teenagers 12 and 15 years of age. The dependent variable was DHSU in the previous 12 months. Data were collected through a questionnaire and included demographic, socioeconomic, and behavioral factors. The study included an oral examination. The analysis included nonparametric statistics and a logistic regression model. RESULTS: Of the 1,538 adolescents, 688 were 12 years old and 850 were 15 years old. Girls accounted for 49.9%. The prevalence of DHSU was 15%. In the final model we found that having moved at least once from the community in which the child was born was associated with DHSU (OR: 1.24; 95% CI: 1.10-1.40; p > 0.05), just as it was observed for purchasing purified water for home consumption instead of relying on piped water supplies (OR: 1.52; 95% CI: 1.03-2.25), higher educational attainment of the mother (OR: 1.39; 95% CI: 1.02-1.91) and of the father (OR: 1.87; 95% CI: 1.09-3.19). Having more sound teeth (OR: 0.96; 95% CI: 0.94-0.98), and having at least one tooth with caries (OR: 1.10; 95% CI: 1.01-1.18) were also associated with DHSU (p > 0.05). CONCLUSION: The percentage of subjects with DHSU in the prior 12 months was low compared with other studies. Our identification of the variables associated with DHSU (often surrogates of socioeconomic position) indicated the existence of oral health inequalities and the need to develop strategies to reduce the gaps identified. PMID- 22820355 TI - [Survey about responsiveness of third-level hospitals to a medical disaster: after the pandemic influenza in Mexico]. AB - BACKGROUND: The recent pandemic influenza AH1N1 virus made it clear that planning for medical disaster response is critical. OBJECTIVE: To know the responsiveness of a sample of highly specialized hospitals in Mexico to a medical disaster, with the previous pandemic influenza AH1N1 as reference. METHODS: A survey was conducted among the Medical Directors of a sample of highly specialized hospitals, covering: previous experience with the pandemic influenza, space considerations, material resources, staff, logistics, and current general perspectives. Descriptive statistics were used for analysis. RESULTS: A 95% response was obtained from the institutions (19 hospitals). Of these, 47.4% considered that the medical institution was not ready to respond to pandemic influenza. The median surge capacity for the Intensive Care Unit beds was 30% (range 0 to 32 beds). The least reserve in medication was found in the antivirals (26.3%). Only 47.4% considered having enough intensive care nurses and 57.9% enough respiratory technicians; 42.1% would not have an easy access to resources in an emergency. CONCLUSIONS: Prevention is key in responsiveness to medical disasters, and therefore the basic steps for planning strategies must be considered. PMID- 22820356 TI - [High cholesterol diet modifies the repairing effect of the hepatocyte growth factor]. AB - Currently, fatty liver represents a serious public health problem in the Western world. In our country, a large amount of food rich in cholesterol is consumed. Cholesterol is an important component in lipid rafts, where many receptors for growth factors are localized, so its functionality could be altered in the presence of high cholesterol concentration. Hepatocyte growth factor (HGF) and its receptor c-Met are known to promote repair after an injury. The aim in the present work was to study the effect of a high cholesterol diet in the molecular repair process mediated by HGF in hepatocytes and liver tissue. Data show a delay in the activation of the HGF-mediated signaling cascade which results in a deficient repair process, that in the case of a continuous aggression could favor the progression of liver damage. PMID- 22820358 TI - [An update on the secondary prevention of cerebral infarction due to atrial fibrillation]. AB - Stroke is the second most common cause of death in the world and produces a high number of cases with neurological dysfunction. Atrial fibrillation (AF) is the main risk factor in patients with cardioembolic stroke. In Mexico, there are approximately 850,000 patients with AF. In three stroke and TIA Mexican series including 3,194 patients, the frequency of AF in cases of stroke and TIA were 12.5 and 8.1%, respectively. AF increase stroke risk in six times. Different approaches to AF detection in stroke patients have been postulated. Besides electrocardiogram, non-invasive cardiac monitoring is useful for AF detection. Is very important to detect particular subgroups with high risk of paroxysmal AF, including those with cryptogenic stroke. Is important to stratify the risk of stroke in patients with AF. More than a dozen of scales have been proposed. CHADS2 is one of the most commonly used, and recently another one has been proposed (CHA2DS2-VASc). Warfarin has been successfully used in stroke prevention in AF. However need of coagulation monitoring as well diet and drugs restriction limit their use. New oral anticoagulants without these restrictions as well low rates of hemorrhagic complications are now available. PMID- 22820357 TI - [Solar exposure time for sunburn in Mexican population]. AB - INTRODUCTION: THe minimal erythemal dose (MED) quantifies an individual's sensitivity to UV radiation (UVR). To estimate it in our population and establish the time of exposure inducing it during daily activities would allow us to calculate risk intervals. METHODS: From 2005-2012, the UV solar radiation was measured with terrestrial radiometry and compared to public UV index (UVI). We determined the MED in 90 individuals with the prevalent phototypes in Mexico (III, IV, V), and estimated the time needed for the development of sunburn. RESULTS: The average MED for phototype III was 39 (IC 95%: 35-42) mJ/cm2, for IV 48 (IC 95%:42-53) mJ/cm2, and for V was 84 (IC 95%:75-92) mJ/cm2 (ANOVA, p <= 0.001). Approximately, 80% of the daily UVR was accumulated between 10:00-16:00 h, and 77% of the annual UV dose is received between March-October. The public UVI had a high correlation with the one quantified at terrestrial level (r = 0.89; p <= 0.001). CONCLUSIONS: Mexico receives continuously high levels of UVR. Phototype III will present sunburn after 22-33 min in a summer day, while phototype V will require over one hour of exposure. This last group is at risk of chronic exposure without considering consequences. PMID- 22820359 TI - [New anticoagulants: dabigatran, rivaroxaban and apixaban]. AB - To date, the most widely used drugs in our anticoagulation clinics are acenocoumarin and warfarin, which belong to the category of vitamin K antagonists (VKA). They have about 70 years of use in the clinic, with proven efficacy for various thrombotic diseases, but also with known problems of variability and dietary and drug interactions. In hospital thromboprophylaxis, the most widely used anticoagulant is enoxaparin, a low molecular weight heparin (LMWH). A new generation of anticoagulants are available, the direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban), with obvious advantages over conventional anticoagulants. This paper summarizes what has been published to date for these new antithrombotics. PMID- 22820360 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis in children]. AB - The Stevens-Johnson syndrome (SJS) and the toxic epidermal necrolysis (TEN) are clinical conditions manifesting as adverse cutaneous reaction to drugs in majority of cases, constituting the same clinical spectrum, differing only in the severity of epidermolysis; both conditions are distinguished by their severity and extensiveness of skin lesions; it can also involve mucous membranes of eyes, respiratory, digestive and urogenital tracts. Two per 1,000,000 are affected annually, among them approximately 20% are children and both of them are considered as potentially fatal medical emergency conditions. Even though the condition was described 89 years ago, until now the exact pathophysiology has not been completely explained. An immune-mediated mechanism has been implicated in its origin, which involves cytotoxic lymphocytes, cytokines, Fas-ligand in keratinocyte apoptosis; genetic makers also has been identified in some racial groups (HLA-B*1520, HLA-B*5801) in relationship with specific susceptibility to certain drugs such as carbamazepine, allopurinol. In children there are no uniform criteria for classification of the skin lesions, neither for the treatment, however recently the authors describe better response of the patients with use intravenous immunoglobulin (IGIV). PMID- 22820361 TI - [The Social Service in medicine after 75 years of its establishment]. PMID- 22820362 TI - [Social conditions in which medical students from the faculty of medicine of the National University of Mexico (UNAM) perform their Social Service in rural areas]. AB - The aim of this work is to describe the conditions in which medical students perform their Social Service, highlighting their experiences in areas such as: information before they move and the motivation to leave home; the perception of personal and environmental lack of safety; the institutional support that they receive during their work in the community and the financial support provided. The methodological design of the study included an exploratory phase, in which collective interviews were performed, using the focal group technique, with students who had been in rural areas. Three hundred sixty cases were considered, 72.8% corresponded to rural areas, and 27.7% to Mexico City. According to the findings, the following actions are proposed: give better information and improve the process of vacancy selection; increase the scholarship received by students in Social Service; establish legal, police, and community support mechanisms to guarantee the student's personal safety; pay attention to aspects such as the student's emotional and social situation, and design programs with gender perspective to enhance certainty and safety. PMID- 22820363 TI - [The historical environment from which Social Service emerged]. AB - The historic background in which Social Service appeared dates back to the time when L. Cardenas (1934-1940) was president of Mexico. In 1935, the reaction of the University to the reformation of article 3 was considered as an antirevolutionary behavior and was seen as opposite to the State's education project. Our history begins in this scenario. During L. Chico Goerne's term, the University signs a new agreement with the Government in which, among other things, the Social Service as a mandatory requirement to obtain a university degree is established. Thus, the mandatory Social Service organized by G. Baz, director of the Facultad de Medicina, who reinforced it as the University rector. Since the establishment of the Social Service, the University did not have to fight for financial support and also restored its prestige and social usefulness before the government that used to exclude the University from its project. PMID- 22820364 TI - [Law framework of the Social Service]. AB - November 22, 1910. During the celebrations of the first one-hundred anniversary of Mexico's Independence War, the solemn reopening of the Universidad Nacional de Mexico takes place. July 22, 1937. Mexico's president general L. Cardenas and the rector of the Universidad Nacional Autonoma de Mexico, L. Chico Goerne, established an agreement by which the University would extend its function and complete its field of activity through teaching, research, and cultural services. Seventy-five years after the start of the Social Service, its regulations must be reformed to have a better law framework for his important activity. Hence, it is necessary to create a new National System of Social Service or a National Commission of Social Service which, based on general, uniform, equal and fair principles, coordinates, supervises, promotes, and structures students' Social Service for the benefit of the society and the State. PMID- 22820365 TI - [Benefits for the nation: population health care]. AB - The best way to assess the Social Service is by measuring its impact on the population, on the health care institutions and on the very students in Social Service. Yet, we have to face the difficulty to obtain reliable data to measure those benefits beyond any doubt. How much the health system is really benefited from these students in relation to the benefits for the population and to the students themselves is also a matter of speculation. Thus, the Social Service could be evaluated as a public policy, a medical act, and a teaching process, if it is really so. The number of consultations provided is not enough, since also preventive actions and health promotion activities are also performed which are even harder to be measured. PMID- 22820366 TI - [Perspectives for the near future]. AB - A rapid balance of these 75 years in which Medicine has contributed with medical students in Social Service to the National Health System, with positive results is presented here as a basis to discuss and reflect on the conditions and characteristics that should be present in the Social Service performed by medical students. Some changes to the conditions under which the Social Service is performed are necessary, as well as improving the medical services to enhance medical continuing education. The main problems to deal with are: redefining sites characteristics, the gradual creation of different alternatives, regionalization, and the creation of double-vacancies in marginal rural zones, among others. In the intermediate term, it is necessary: adjust the legal situation, implementing continuous supervision and tutorship, and in the long term that general practitioners are in charge of all primary care in marginal and urban areas, and become tutors to the students in Social Service. These measures would allow us to strengthen continuing education and a more efficient collaboration to train human resources for the health care of our population. PMID- 22820368 TI - [Difficulties of the negotiation process of the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of biology and medicine (and a call for its adhesion)]. AB - Making an attempt to frame the controversial topic of bioethics within international law and with the aim of watching over the society, the Council of Europe elaborated the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of biology and medicine. The instrument, which came into force 12 years ago, is opened to all countries but only 29 states have ratified it. This legal document represents the base of a universal legislation on the subject. The present article examines the origin of the Convention, its process and evolution. It analyses the intense debates with regard to the human dignity, the freedom of science, the beginning of life, among others; equally it explores the interests at stake within the convention, whether political, moral, scientific, and economic, at the moment of its draft and in the present. Finally, the article analyses the possibility of the adoption of the Convention by the Mexican government. It concludes on the effectiveness of the international law of bioethics, and calls for the need that the Convention be used as a base for universal legislation. PMID- 22820367 TI - [Late recurrence of the granulosa cell tumor: a case report]. AB - Granulosa cell tumor of the ovary is an uncommon neoplasm characterized by a long natural history, late recurrence capacity and good prognosis. We report the case of a woman with adult-type granulosa cell tumor of the ovary, which developed late recurrence with contralateral ovarian disease, intra-abdominal spread and liver metastases. PMID- 22820369 TI - [Charcot and his legacy to medicine]. AB - Jean-Martin Charcot (1825-1893) was a French physician whose professional life is divided into two phases: the first dedicated to neurology, and the second dedicated to the psychiatry area. Charcot is considered the father of modern neurology. In the Hospice de la Salpetriere he began his research on neurological diseases, founded a laboratory of pathology (including microscopy and photography), and gave hospital classes based on pathological anatomy related to clinical manifestations based in the field of neurology. His research led to the description and study of different neurological diseases, such as multiple sclerosis, lateral amyotrophic sclerosis, hereditary motor and sensory neuropathy, motor ataxia, Parkinson's disease, Gilles de la Tourette syndrome, epilepsy, visual aphasia and agnosia, to name a few. Some signs and diseases took their name as an eponym, and some are still mentioned in the current medicine, while others are left in oblivion. PMID- 22820370 TI - Mechanisms of sodium-chloride cotransporter modulation by angiotensin II. AB - PURPOSE OF REVIEW: The renin-angiotensin-aldosterone system is an important modulator of renal salt excretion and arterial pressure. An important body of evidence now supports that angiotensin II (AngII) modulates the function of the renal sodium-chloride cotransporter (NCC), independently of aldosterone. Here we summarize these data, as well as recent knowledge regarding the intracellular mechanisms underlying this effect. RECENT FINDINGS: AngII has the ability to modulate NCC total expression, apical localization, and phosphorylation by aldosterone-independent mechanisms. Recent evidence suggests that these effects are achieved through modulation of the With No Lysine kinase 4 (WNK4) and Ste20 related, proline-alanine-rich kinase (SPAK) pathway. Missense mutations in the acidic domain of WNK4, which are the cause of one of the subtypes of pseudohypoaldosteronism type II (PHAII), could be mimicking the effect produced by AngII on NCC through the WNK4-SPAK pathway. WNK4 activity has been shown to vary in response to changes in calcium concentration and PHAII-WNK4 mutants apparently lose this ability. Thus, AngII may regulate WNK4 activity through the modulation of intracellular calcium concentration. SUMMARY: Modulation of WNK4 activity by AngII underlies the effects of AngII on NCC activity and this is probably important for the stimulation of renal sodium retention, as well as for the prevention of potassium loss, during hypovolemia. PMID- 22820371 TI - Vitamin D and hypertension: an update and review. AB - PURPOSE OF REVIEW: Vitamin D deficiency and hypertension are highly prevalent. This review will discuss the association between vitamin D deficiency and blood pressure. RECENT FINDINGS: During the past several years multiple prospective cohorts and randomized studies have been published. Recent studies have focused mostly on 25-hydroxy vitamin D, but a small number of trials used active vitamin D analog compounds. SUMMARY: Data from cross-sectional studies report that low 25 hydroxy vitamin D is associated with higher systolic blood pressure and higher incidence of hypertension. Large observational studies show a weaker, yet similar association, but they have not largely accounted for the change in vitamin D levels over time. Randomized control trials conflict with observational data probably due to differences in populations studied, doses of vitamin D used, and unmeasured confounders. Further research is needed before clinical practice recommends vitamin D prescription as treatment for hypertension in the general population. PMID- 22820372 TI - Renin and prorenin as biomarkers in hypertension. AB - PURPOSE OF REVIEW: This review examines the evidence that plasma renin and/or prorenin level may be used to guide therapy in hypertension and as an independent risk factor for future cardiovascular events. RECENT FINDINGS: A large number of retrospective analyses of patient populations in clinical trials, in whom 'baseline' renin measurements were available, supports that high renin, but not high prorenin levels, are indicative of future cardiovascular disease and death, particularly in patients with kidney dysfunction and/or hypertension. The relationship is not affected by the use of renin-angiotensin system (RAS) blockers. High renin levels also tend to support the use of RAS inhibitors as first-choice antihypertensive agents. However, the added value of a renin measurement on top of traditional risk factors is modest, and the pressure response to RAS blockade, even in high-renin patients, varies widely. SUMMARY: Measuring 'baseline' renin as a marker of future cardiovascular events or to determine the choice of drug is of limited value in an individual patient. PMID- 22820373 TI - Approaches for targeting blood pressure control in sleep disorders. AB - PURPOSE OF REVIEW: One of the underappreciated causes of hypertension is disordered sleep. There have been a number of studies evaluating sleep in the context of blood pressure control, and these will be reviewed. RECENT FINDINGS: Original novel articles document that disruption of deep sleep stage, regardless of cause, if chronic, contributes to an increased risk for development of hypertension. Studies have evaluated disrupted sleep especially in older people requiring use of the bathroom at night and demonstrate higher risk of hypertension in such people. Correction of sleep apnea with continuous positive airway pressure (CPAP) reduces blood pressure in those who are adherent; however, as the reduction is only from 2 to 5 mmHg systolic, adjunctive medications are almost always needed. Use of angiotensin receptor blockers and some beta-blockers has shown some improvement in blood pressure. Renal denervation has also been shown in a pilot study to offer benefit on blood pressure reduction. SUMMARY: Innovations of combined use of devices with certain classes of antihypertensive medications help reduce blood pressure in people with sleep disorders. CPAP alone provides only modest reduction in blood pressure; however, restoration of deep sleep reduces blood pressure and reduces variability. PMID- 22820374 TI - Cell signaling pathways that regulate transcellular solute transport in the renal tubule. PMID- 22820375 TI - Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. AB - The PI(3)K-PKB-FOXO signalling network provides a major intracellular hub for the regulation of cell proliferation, survival and stress resistance. Here we report an unexpected role for FOXO transcription factors in regulating autophagy by modulating intracellular glutamine levels. To identify transcriptional targets of this network, we performed global transcriptional analyses after conditional activation of the key components PI(3)K, PKB/Akt, FOXO3 and FOXO4. Using this pathway approach, we identified glutamine synthetase as being transcriptionally regulated by PI(3)K-PKB-FOXO signalling. Conditional activation of FOXO also led to an increased level of glutamine production. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes in a glutamine-synthetase-dependent manner. This resulted in an increased level of autophagy as measured by LC3 lipidation, p62 degradation and fluorescent imaging of multiple autophagosomal markers. Inhibition of FOXO3-mediated autophagy increased the level of apoptosis, suggesting that the induction of autophagy by FOXO3-mediated glutamine synthetase expression is important for cellular survival. These findings reveal a growth-factor-responsive network that can directly modulate autophagy through the regulation of glutamine metabolism. PMID- 22820376 TI - Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells. AB - The formation of epithelial tissues requires both the generation of apical-basal polarity and the coordination of this polarity between neighbouring cells to form a central lumen. During de novo lumen formation, vectorial membrane transport contributes to the formation of a singular apical membrane, resulting in the contribution of each cell to only a single lumen. Here, from a functional screen for genes required for three-dimensional epithelial architecture, we identify key roles for synaptotagmin-like proteins 2-a and 4-a (Slp2-a/4-a) in the generation of a single apical surface per cell. Slp2-a localizes to the luminal membrane in a PtdIns(4,5)P(2)-dependent manner, where it targets Rab27-loaded vesicles to initiate a single lumen. Vesicle tethering and fusion is controlled by Slp4-a, in conjunction with Rab27/Rab3/Rab8 and the SNARE syntaxin-3. Together, Slp2-a/4-a coordinate the spatiotemporal organization of vectorial apical transport to ensure that only a single apical surface, and thus the formation of a single lumen, occurs per cell. PMID- 22820377 TI - Brassinosteroid, gibberellin and phytochrome impinge on a common transcription module in Arabidopsis. AB - Brassinosteroid and gibberellin promote many similar developmental responses in plants; however, their relationship remains unclear. Here we show that BR and GA act interdependently through a direct interaction between the BR-activated BZR1 and GA-inactivated DELLA transcription regulators. GA promotion of cell elongation required BR signalling, whereas BR or active BZR1 suppressed the GA deficient dwarf phenotype. DELLAs directly interacted with BZR1 and inhibited BZR1-DNA binding both in vitro and in vivo. Genome-wide analysis defined a BZR1 dependent GA-regulated transcriptome, which is enriched with light-regulated genes and genes involved in cell wall synthesis and photosynthesis/chloroplast function. GA promotion of hypocotyl elongation requires both BZR1 and the phytochrome-interacting factors (PIFs), as well as their common downstream targets encoding the PRE-family helix-loop-helix factors. The results demonstrate that GA releases DELLA-mediated inhibition of BZR1, and that the DELLA-BZR1-PIF4 interaction defines a core transcription module that mediates coordinated growth regulation by GA, BR and light signals. PMID- 22820379 TI - Galectins in the abdominal cavity of the conger eel Conger myriaster participate in the cellular encapsulation of parasitic nematodes by host cells. AB - Congerin is a proto-type galectin distributed on the skin and mucosal epithelia of the upper digestive tract of the Japanese conger eel Conger myriaster. It has at least 2 isotypes, namely, congerin I and II, and plays a role in bio-defense at the body surface. In the current study, we identified both isotypes in the peritoneal fluid and peritoneal cells of C. myriaster by western blot and mass spectrometry (MS)/MS analysis. Cucullanus nematodes parasitize the abdominal cavity of C. myriaster, and immunohistochemical analyses demonstrated that congerins can bind to both the body surface of the encapsulated nematodes and the encapsulating cells. Furthermore, adhesion of the peritoneal cells to Sepharose particles was greatly accelerated when the microspheres were coated with congerin. Indeed, this effect was significantly hampered by the addition of lactose. These results indicate that congerin participates in the cellular encapsulation of the Cucullanus nematode via the induction of cellular adhesion to the parasites depending on lectin-glycoside recognition. PMID- 22820378 TI - Interaction between BZR1 and PIF4 integrates brassinosteroid and environmental responses. AB - Plant growth is coordinately regulated by environmental and hormonal signals. Brassinosteroid (BR) plays essential roles in growth regulation by light and temperature, but the interactions between BR and these environmental signals remain poorly understood at the molecular level. Here, we show that direct interaction between the dark- and heat-activated transcription factor phytochrome interacting factor 4 (PIF4) and the BR-activated transcription factor BZR1 integrates the hormonal and environmental signals. BZR1 and PIF4 interact with each other in vitro and in vivo, bind to nearly 2,000 common target genes, and synergistically regulate many of these target genes, including the PRE family helix-loop-helix factors required for promoting cell elongation. Genetic analysis indicates that BZR1 and PIFs are interdependent in promoting cell elongation in response to BR, darkness or heat. These results show that the BZR1-PIF4 interaction controls a core transcription network, enabling plant growth co regulation by the steroid and environmental signals. PMID- 22820380 TI - The smooth and stable operation of centromeres. AB - The centromere functions as a unique chromosomal attachment site for microtubules. Appropriate microtubule attachment is fundamental for organized chromosome behavior during mitosis and meiosis. Hence, centromeres must function both smoothly and stably. However, centromeric DNA sequences are poorly conserved between species despite common functions and similar centromeric protein composition, which leads us to the question: how are centromeres established and maintained? In this review, we summarize the recent progress in deciphering the mechanisms of centromere function. Specifically, we focus our attention on mechanisms closely-related to centromeric DNA and chromatin. By gathering such information, we hope to reveal a new dimension to the true nature of centromeres. PMID- 22820381 TI - Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response. AB - The SOS response is readily triggered by replication fork stalling caused by DNA damage or a dysfunctional replicative apparatus in Escherichia coli cells. E. coli dinB encodes DinB DNA polymerase and its expression is upregulated during the SOS response. DinB catalyzes translesion DNA synthesis in place of a replicative DNA polymerase III that is stalled at a DNA lesion. We showed previously that DNA replication was suppressed without exogenous DNA damage in cells overproducing DinB. In this report, we confirm that this was due to a dose dependent inhibition of ongoing replication forks by DinB. Interestingly, the DinB-overproducing cells did not significantly induce the SOS response even though DNA replication was perturbed. RecA protein is activated by forming a nucleoprotein filament with single-stranded DNA, which leads to the onset of the SOS response. In the DinB-overproducing cells, RecA was not activated to induce the SOS response. However, the SOS response was observed after heat-inducible activation in strain recA441 (encoding a temperature-sensitive RecA) and after replication blockage in strain dnaE486 (encoding a temperature-sensitive catalytic subunit of the replicative DNA polymerase III) at a non-permissive temperature when DinB was overproduced in these cells. Furthermore, since catalytically inactive DinB could avoid the SOS response to a DinB-promoted fork block, it is unlikely that overproduced DinB takes control of primer extension and thus limits single-stranded DNA. These observations suggest that DinB possesses a feature that suppresses DNA replication but does not abolish the cell's capacity to induce the SOS response. We conclude that DinB impedes replication fork progression in a way that does not activate RecA, in contrast to obstructive DNA lesions and dysfunctional replication machinery. PMID- 22820382 TI - Genome-scale identification of MLO domain-containing genes in soybean (Glycine max L. Merr.). AB - In plants, powdery-mildew-resistance locus o (Mlo) genes encode proteins that are calmodulin-binding proteins involved in a variety of cellular processes. However, systematic characterization of this gene family in soybean (Glycine max L. Merr.) has not been yet reported. In this study, we identified MLO domain-contained members in soybean and examined their expression under phytohormone treatment and abiotic stress conditions. A total of 20 soybean Mlo genes were identified (GmMlo1-20), which are distributed on 13 chromosomes, and display diverse exon intron structures. Phylogenetic analysis indicated that the Mlo family can be classified into four subfamilies. Sequence comparison was used to reveal the conserved calmodulin-binding domain (CaMBD) in GmMLO proteins. The expression of GmMlo genes was influenced by various phytohormone treatments and abiotic stresses, suggesting that these Mlo genes have various roles in the response of soybean to environmental stimuli. Promoter sequence analysis revealed an overabundance of stress and/or phytohormone-related cis-elements in GmMlo genes. These data provide important clues for elucidating the functions of genes of the Mlo gene family. PMID- 22820383 TI - Genetic dissection of Nucleoporin 160 (Nup160), a gene involved in multiple phenotypes of reproductive isolation in Drosophila. AB - Previous reports have suggested that the Nucleoporin 160 (Nup160) gene of Drosophila simulans (Nup160(sim)) causes the hybrid inviability, female sterility, and morphological anomalies that are observed in crosses with D. melanogaster. Here we have confirmed this observation by transposon excision from the P{EP}Nup160(EP372) insertion mutation of D. melanogaster. Null mutations of the Nup160 gene resulted in the three phenotypes caused by Nup160(sim), but revertants of the gene did not. Interestingly, several mutations produced by excision partially complemented hybrid inviability, female sterility, or morphological anomalies. In the future, these mutations will be useful to further our understanding of the developmental mechanisms of reproductive isolation. Based on our analyses with the Nup160(sim) introgression line, the lethal phase of hybrid inviability was determined to be during the early pupal stage. Our analysis also suggested that homozygous Nup160(sim) in D. melanogaster leads to slow development. Thus, Nup160(sim) is involved in multiple aspects of reproductive isolation between these two species. PMID- 22820384 TI - Analysis of candidate genes of spontaneous arthritis in mice deficient for interleukin-1 receptor antagonist. AB - Previously, we identified a major quantitative trait locus (QTL) on mouse chromosome 1 that regulates the susceptibility to arthritis in an F2 population generated from arthritis-prone BALB/c and arthritis-resistant DBA/1 mice deficient for interleukin-1 receptor antagonist. To further select candidate genes for the QTL, we analyzed the expression patterns of arthritis in 38 F2 individuals and compared the expression levels of key candidate genes to the parental strains. Two distinct subpopulations of arthritic mice were identified in the 38 F2 mice. One subgroup of diseased mice was characterized by myeloid cell dominant inflammation, whereas the other was mainly associated with increased anti-apoptotic activities of inflammatory cells. Several differentially expressed important candidate genes in parental strains in the QTL region are relevant to myeloid cell, apoptotic activities, or to both. About one-quarter of those genes have been previously linked to arthritis in literature. The present study reveals two distinct subpopulations of arthritic mice with spontaneous arthritis due to deficiency for interleukin-1 receptor antagonist, suggesting that genes with function relevant to myeloid cell and/or apoptotic activities are most likely the key candidate genes for the QTL. PMID- 22820385 TI - Structural and functional properties of CiNTH, an endonuclease III homologue of the ascidian Ciona intestinalis: critical role of N-terminal region. AB - Oxidatively damaged bases in DNA can cause cell death, mutation and/or cancer induction. To overcome such deleterious effects of DNA base oxidation, cells are equipped with base excision repair (BER) initiated by DNA glycosylases. Endonuclease III (Nth), a major DNA glycosylase, mainly excises oxidatively damaged pyrimidines from DNA. The aims of this study were to obtain an overview of the repair mechanism of oxidatively damaged bases and to elucidate the function of BER in maintaining genome stability during embryogenesis and development. In this study, we used the ascidian Ciona intestinalis because at every developmental stage it is possible to observe the phenotype of individuals with DNA damage or mutations. Sequence alignment analysis revealed that the amino acid sequence of Ciona intestinalis Nth homologue (CiNTH) had high homology with those of Escherichia coli, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and human Nth homologues. It was evident that two domains, the Helix-hairpin-Helix and 4Fe-4S cluster domains that are critical regions for the Nth activity, are well conserved in CiNTH. CiNTH efficiently complemented the sensitivity of E. coli nth nei mutant to H(2)O(2). CiNTH was bifunctional, with DNA glycosylase and AP lyase activities. It removed thymine glycol, 5 formyluracil and 8-oxoguanine paired with G from DNA via a beta-elimination reaction. Interestingly, the N-terminal 44 amino acids were essential for the DNA glycosylase activity of CiNTH. PMID- 22820386 TI - Linkage disequilibrium in a population undergoing periodic fragmentation and admixture. AB - Glacial and interglacial cycles are considered to have caused the fragmentation and admixture of populations in many organisms. A simple model incorporating such periodic changes of the population structure is analysed in order to investigate the behaviour of neutral genetic variation at one and two loci. The equilibrium is reached very quickly in terms of cycles if the length of a cycle is long, as would be expected of the glaciation cycles. Heterozygosity and linkage disequilibrium are shown to depend on the length of time of the fragmented and admixed phases, population sizes, and number (n) of subpopulations in the fragmented phase. If the population size is small in the fragmented phase and its duration is long, the squared correlation coefficient of two loci (a measure of linkage disequilibrium) just after the admixture is approximated by 1/(n-1) for n > 1. After admixture, the correlation decays at a rate of approximately twice the recombination rate. Therefore, if post-glaciation admixture created linkage disequilibrium, we expect to observe linkage disequilibrium even between moderately linked loci, and its decay pattern along the chromosome is very different from that in a random mating population at equilibrium. This is especially true in organisms with long generation times such as trees. PMID- 22820387 TI - Application of real-time PCR-based SNP detection for mapping of Net2, a causal D genome gene for hybrid necrosis in interspecific crosses between tetraploid wheat and Aegilops tauschii. AB - Available information on genetically assigned molecular markers is not sufficient for efficient construction of a high-density linkage map in wheat. Here, we report on application of high resolution melting (HRM) analysis using a real-time PCR apparatus to develop single nucleotide polymorphism (SNP) markers linked to a hybrid necrosis gene, Net2, located on wheat chromosome 2D. Based on genomic information on barley chromosome 2H and wheat expressed sequence tag libraries, we selected wheat cDNA sequences presumed to be located near the Net2 chromosomal region, and then found SNPs between the parental Ae. tauschii accessions of the synthetic wheat mapping population. HRM analysis of the PCR products from F(2) individuals' DNA enabled us to assign 44.4% of the SNP-representing cDNAs to chromosome 2D despite the presence of the A and B genomes. In addition, the designed SNP markers were assigned to chromosome 2D of Ae. tauschii. The order of the assigned SNP markers in synthetic hexaploid wheat was confirmed by comparison with the markers in barley and Ae. tauschii. Thus, the SNP-genotyping method based on HRM analysis is a useful tool for development of molecular markers at target loci in wheat. PMID- 22820388 TI - Oral ethanol self-administration in inbred Roman high- and low-avoidance rats: gradual versus abrupt ethanol presentation. AB - Outbred Roman high-avoidance rats are known to consume more ethanol than inbred Roman low-avoidance rats. To determine whether ethanol consumption in inbred strains could be modulated by experiential factors, preference for a target 10% ethanol concentration was tested after either the gradual introduction of ethanol in increasing concentrations or the abrupt introduction of the target concentration. Whereas high-avoidance rats consumed more ethanol at lower concentrations, consumption and preference for ethanol over water were not differential across strains and administration procedure (gradual vs. abrupt). At the 4% concentration, ethanol was preferred over water by Roman high-avoidance rats, but water was preferred over ethanol by Roman low-avoidance rats. Ethanol consumption and preference for a 10% concentration appear to be immune to modification by either the gradual or abrupt ethanol presentation. PMID- 22820389 TI - Copy number variations (CNVs) in human pluripotent cell-derived neuroprogenitors. AB - Results from the analysis of copy number variations (CNVs) in human pluripotent cell-derived neuroprogenitor cell lines (hiPSC and hESC-derived NPC) are presented. Two different types of CNVs were detected: a) CNVs inherited from the original source of pluripotent cells (hESC and hiPSC) and b) CNVs detected either in the original source of pluripotent cells or in the derived NPC cell lines but not in both at the same time. Our data suggest that submicroscopic chromosomal changes happened during culture and manipulation of cells and those differentiation procedures could result in gains and losses of genomic regions in pluripotent cell-derived neuroprogenitors. Overall, the results indicate that even chromosomally stable stem cell lines would need to be analyzed in detail by high resolution methodologies before their clinical use. PMID- 22820390 TI - Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. AB - The liver performs a vital role in metabolic process, which makes it an attractive target organ for gene therapy. To improve the effects of gene therapy in disorders caused by metabolic disturbance, we quantitatively evaluated six promoters, CMV, EF1alpha, PGK, apoE, thyroxine binding globulin (TBG), and cytochrome P450 2E1 (CYP2E1) by measuring the expression of alpha1-antitrypsin, which is controlled by these promoters and introduced via a lentivirus-mediated delivery system in the liver. The results showed that the TBG promoter presents as highly active though in general it is slightly lower than the ubiquitous CMV and EF1alpha. The expression of exogenous genes driven by the TBG promoter demonstrates to be much higher than by PGK, apoE, and CYP2E1 promoters, and the fragment of -435bp to -26bp from transcription start site (TSS) in the TBG promoter region is identified as the optimum region to direct transgene expression at a higher level. In addition, we further confirmed that the TBG promoter confers transgene persistent and specific expression within the liver up to several months after integration. The data suggests that the TBG promoter is a valuable tool and will greatly facilitate the optimization of vector design in hepatic gene therapy. PMID- 22820391 TI - A new mutational mechanism for hypertrophic cardiomyopathy. AB - We describe a male patient affected by hypertrophic cardiomyopathy (HCM) with no point mutations in the eight sarcomeric genes most commonly involved in the disease. By multiple ligation-dependent probe amplification (MLPA) we have identified a multi-exons C-terminus deletion in the cardiac myosin binding protein C (MYBPC3) gene. The rearrangement has been confirmed by long PCR and breakpoints have been defined by sequencing. The 3.5 kb terminal deletion is mediated by Alu-repeat elements and is predicted to result in haploinsufficiency of MYBPC3. To exclude the presence of other rare pathogenic variants in additional HCM genes, we performed targeted next-generation sequencing (NGS) of 88 cardiomyopathy-associated genes but we did not identify any further mutation. Interestingly, the MYBPC3 multi-exons deletion was detectable by NGS. This finding broadens the range of mutational spectrum observed in HCM, contributing to understanding the genetic basis of the most common inherited cardiovascular disease. Moreover, our data suggest that NGS may represent a new tool to achieve a deeper insight into molecular basis of complex diseases, allowing to detect in a single experiment both point mutations and gene rearrangements. PMID- 22820392 TI - Mutation screening of EXT genes in Chinese patients with multiple osteochondromas. AB - Multiple osteochondromas (MO), a dominantly inherited genetic disorder, is characterized by the presence of multiple osteochondromas in the long bones. EXT1 and EXT2 are the causative genes in most MO patients. We have characterized 9 MO families and 1 sporadic case involving a total of 25 patients. The coding exons of EXT1 and EXT2 were screened in 10 probands affected with MO. In five of the 10 probands novel pathogenic mutations have been identified: two in EXT1 and three in EXT2. Four probands carried recurrent mutations and one proband had no detectable mutation. Our study extends the mutational spectrum in EXT1 and EXT2 and will facilitate the deep understanding of the pathophysiology of the disease. PMID- 22820393 TI - Alternate splicing and expression of the glutamate transporter EAAT5 in the rat retina. AB - Excitatory amino acid transporter 5 (EAAT5) is an unusual glutamate transporter that is expressed in the retina, where it is localised to two populations of glutamatergic neurons, namely the bipolar neurons and photoreceptors. EAAT5 exhibits two distinct properties, acting both as a slow glutamate transporter and as a glutamate-gated inhibitory receptor. The latter property is attributable to a co-associated chloride conductance. EAAT5 has previously been thought to exist only as a full-length form. We now demonstrate by PCR cloning and sequencing, the presence of five novel splice variant forms of EAAT5 which skip either partial or complete exons in the rat retina. Furthermore, we demonstrate that each of these variants is expressed at the protein level as assessed by Western blotting using splice-specific antibodies that we have generated. We conclude that EAAT5 exists in multiple spliced forms, and propose, based upon retention or absence of key structural features, that these variant forms may potentially exhibit distinct properties relative to the originally described form of EAAT5. PMID- 22820394 TI - Identification of a selective small-molecule inhibitor series targeting the eyes absent 2 (Eya2) phosphatase activity. AB - Eya proteins are essential coactivators of the Six family of homeobox transcription factors and also contain a unique protein tyrosine phosphatase activity, belonging to the haloacid dehalogenase family of phosphatases. The phosphatase activity of Eya is important for a subset of Six1-mediated transcription, making this a unique type of transcriptional control. It is also responsible for directing cells to the repair instead of apoptosis pathway upon DNA damage. Furthermore, the phosphatase activity of Eya is critical for transformation, migration, invasion, and metastasis of breast cancer cells. Thus, inhibitors of the Eya phosphatase activity may be antitumorigenic and antimetastatic, as well as sensitize cancer cells to DNA damage-inducing therapies. In this article, we identified a previously unknown chemical series using high-throughput screening that inhibits the Eya2 phosphatase activity with IC(50)s ranging from 1.8 to 79 uM. Compound activity was confirmed using an alternative malachite green assay and H2AX, a known Eya substrate. Importantly, these Eya2 phosphatase inhibitors show specificity and do not significantly inhibit several other cellular phosphatases. Our studies identify the first selective Eya2 phosphatase inhibitors that can potentially be developed into chemical probes for functional studies of Eya phosphatase or into anticancer drugs in the future. PMID- 22820395 TI - Distribution of Th17 cells and Foxp3-expressing T cells in tumor-infiltrating lymphocytes in patients with uterine cervical cancer. AB - BACKGROUND: Recent studies suggest a potential impact of Th17 cells on tumor. In the present study, we investigated the distribution of Th17 cells in relation to Foxp3-expressing T cells in the tumor-infiltrating lymphocytes (TILs) from patients with uterine cervical cancer (UCC), cervical tissues from patients with cervical intraepithelial neoplasia (CIN) and healthy cervical tissues. METHODS: Th17 cells and Foxp3-expressing T cells were evaluated by immunohistochemical staining. IL-6, TGF-beta, IL-17 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining for microvessel density (MVD) was performed in order to assess the association of IL-17 expression with angiogenesis. RESULTS: Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells and Foxp3-expressing T cells, when the ratio of Th17/Foxp3-expressing T cells in TILs was decreased in individual cases, it was more markedly decreased in TILs than normal cervical tissues. Meanwhile, the cytokine(IL-6, TGF-beta and IL-10) concentrations were significantly higher in UCC patients than those in healthy controls. Interestingly, the levels of intratumoral Th17 cells were positively correlated with MVD in tumors. CONCLUSIONS: The imbalance of Th17/Foxp3-expressing T cells may play critical roles in the development and progression of UCC and Th17 cells may promote tumor progression by fostering angiogenesis. PMID- 22820396 TI - First pilot newborn screening for four lysosomal storage diseases in an Italian region: identification and analysis of a putative causative mutation in the GBA gene. AB - We report the first newborn screening pilot study in an Italian region for four lysosomal disorders including Pompe disease, Gaucher disease, Fabry disease and mucopolysaccharidosis type 1. The screening has been performed using enzymatic assay on Dry Blood Spot on filter paper. A total of 3403 newborns were screened. One newborn showed a reduction of beta-glucosidase activity in leucocytes. Molecular analysis revealed a status of compound heterozygous for the panethnic mutation N370S and for the sequence variation E388K, not yet correlated to Gaucher disease onset. The functional consequences of the E388K replacement on beta-glucosidase activity were evaluated by in vitro expression, showing that the mutant protein retained 48% of wild type activity. Structural modeling predicted that the E388K replacement, localized to a surface of the enzyme, would change the local charges distribution which, in the native protein, displays an overwhelming presence of negative charges. However, the newborn, and a 4 year old sister showing the same genomic alterations, are currently asymptomatic. This pilot newborn screening for lysosomal diseases appears to be feasible and affordable to be extended to large populations. Moreover other lysosomal diseases for which a therapy is available or will be available, could be included in the screening. PMID- 22820397 TI - Natriuretic peptides and NGAL in heart failure: does a link exist? AB - In recent years there has been growing interest in the development of new diagnostic tools and particularly in laboratory tests for the identification of heart failure (HF) patients. Because of the rise in HF occurrence, it is necessary to use simple and reliable method to recognize those patients at risk before the onset of the clinical symptoms. To date HF diagnosis remains difficult: its symptoms and signs are often non specific as well as being poor sensitive indicators for HF severity. Throughout the last 10 years published literature has highlighted a boom in the use of biomarkers for HF. Both B-type and N-terminal pro-B-type natriuretic peptides have demonstrated specific role in heart failure diagnosis, as well as risk assessment. A single determination of BNP at any time during the development of chronic heart failure (CHF) provides a clinically useful tool to establish the outcome. Renal dysfunction is often associated with heart failure and predicts adverse clinical outcomes. Many studies have recently suggested the clinical use of serum neutrophil gelatinase associated lipocalin (NGAL) levels in patients admitted to the hospital for acute HF can be used to estimate the risk of early worsening renal function. This could be potentially applied in clinical practice for early identification of renal dysfunction development in patients with HF. NGAL levels appear also to predict renal dysfunction in patients with chronic HF and preserved renal function. For all these reasons, BNP and NGAL are two emerging tools useful for diagnosis and prognosis in HF. The combination of two laboratory biomarkers could potentially identify patients with more elevated risks of both cardiac hemodynamic impairment and kidney dysfunction. PMID- 22820398 TI - Dynamic hydraulic flow stimulation on mitigation of trabecular bone loss in a rat functional disuse model. AB - Bone fluid flow (BFF) has been demonstrated as a critical regulator in mechanotransductive signaling and bone adaptation. Intramedullary pressure (ImP) and matrix strain have been identified as potential generators to regulate BFF. To elevate in vivo oscillatory BFF using ImP, a dynamic hydraulic stimulation (DHS) approach was developed. The objective of this study was to evaluate the effects of DHS on mitigation of bone loss and structural alteration in a rat hindlimb suspension (HLS) functional disuse model. Sixty-one 5-month old female Sprague-Dawley rats were divided into five groups: 1) baseline control, 2) age matched control, 3) HLS, 4) HLS+static loading, and 5) HLS+DHS. Hydraulic flow stimulation was carried out daily on a "10 min on-5 min off-10 min on" loading regime, 5 days/week, for a total of 4 weeks in the tibial region. The metaphyseal trabecular regions of the proximal tibiae were analyzed using MUCT and histomorphometry. Four weeks of HLS resulted in a significant loss of trabecular bone, leading to structural deterioration. HLS with static loading alone was not sufficient to attenuate the bone loss. Bone quantity and microarchitecture were significantly improved by applying DHS loading, resulting increase of 83% in bone volume fraction, 25% in trabecular number and mitigation of 26% in trabecular separation compared to HLS control. Histomorphometry analysis on trabecular mineralization coincided with the MUCT analysis, in which DHS loading yielded increases of 34% in histomorphometric BV/TV, 121% in MS/BS, 190% in BFR/BS and 146% in BFR/BV, compared to the HLS control. Overall, the data demonstrated that dynamic hydraulic flow loading has potentials to provide regulatory signals for mitigating bone loss induced by functional disuse. This approach may provide a new alternative mechanical intervention for future clinical treatment for osteoporosis. PMID- 22820399 TI - Srgap3-/- mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes. AB - Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders. PMID- 22820400 TI - Population structure of Blackberry yellow vein associated virus, an emerging crinivirus. AB - Blackberry yellow vein disease (BYVD), a disorder caused by virus complexes, has become a major threat to fresh market blackberry production in the United States. Blackberry yellow vein associated virus (BYVaV) is the most prevalent virus in the BYVD complexes; detected in about 50% of samples exhibiting typical disease symptoms. Thirty-four virus isolates infecting wild and cultivated blackberries were collected from several areas with high BYVD incidence. Sequence variability and virus evolution predictions were calculated for four genomic regions coding for six proteins and accounting for about 30% of the virus genome. Nucleotide diversity ranged between 7 and 12%, and all proteins studied were under negative selection. Several isolates were identified as potential recombinants suggesting that recombination might be a driving force behind BYVaV evolution. PMID- 22820401 TI - HIV RNA dimerisation interference by antisense oligonucleotides targeted to the 5' UTR structural elements. AB - The HIV-1 genome consists of two identical RNA molecules non-covalently linked by their 5' unstranslatable regions (5' UTR). The high level of sequence and structural conservation of this region correlates with its important functional involvement in the viral cycle, making it an attractive target for antiviral treatments based on antisense technology. Ten unmodified DNA antisense oligonucleotides (ODNs) targeted against different conserved structural elements within the 5' UTR were assayed for their capacity to interfere with HIV-1 RNA dimerisation, inhibit gene expression, and prevent virus production in cell cultures. The results show that, in addition to the well-characterised dimerisation initiation site (DIS), targeting of the AUG-containing structural element may reflect its direct role in HIV-1 genomic RNA dimerisation in vitro. Similarly, blocking the 3' end sequences of the stem-loop domain containing the primer biding site interferes with RNA dimerisation. Targeting the apical portion of the TAR element, however, appears to promote dimerisation. ODNs targeted against the conserved polyadenylation signal [Poly(A)], the primer binding site (PBS), the major splicing donor (SD) or the major packaging signal (Psi), and AUG containing structural elements led to a highly efficient inhibition of HIV-1 gene expression and virus production in cell culture. Together, these results support the idea that ODNs possess great potential as molecular tools for the functional characterisation of viral RNA structural domains. Moreover, the targeting of these domains leads to the potent inhibition of viral replication, underscoring the potential of conserved structural RNA elements as antiviral targets. PMID- 22820402 TI - Controllable p-doping of graphene on Ir(111) by chlorination with FeCl3. AB - The in situ chlorination of graphene on Ir(111) has been achieved by depositing FeCl(3) followed by its thermal decomposition on the surface into FeCl(2) and Cl. This process is accompanied by an intercalation of Cl under graphene and formation of an epitaxial FeCl(2) film on top, which can be removed upon further annealing. A pronounced hole doping of graphene has been observed as a consequence of the annealing-assisted intercalation of Cl. This effect has been studied by a combination of core-level and angle-resolved photoelectron spectroscopies (CL PES and ARPES, respectively), near-edge x-ray absorption fine structure (NEXAFS) spectroscopy and low-energy electron diffraction (LEED). The ease of preparation, the remarkable reproducibility of the doping level and the reversibility of the doping upon annealing are the key factors making chlorination with FeCl(3) a promising route for tuning the electronic properties in graphene. PMID- 22820403 TI - Disruption of the p53-p21 pathway inhibits efficiency of the lytic-replication cycle of herpes simplex virus type 2 (HSV-2). AB - Cellular p53 and its downstream mediator p21, the major cellular growth suppression and DNA repair markers, have recently been implicated in viral amplification. Here, we show that herpes simplex virus type 2 (HSV-2) infection of both HCT116 p53(+/+)and NIH3T3 cells resulted in sustained increases of p21. HSV-2 infection did not increase cellular p53 expression, but led to phosphorylation of this protein at Ser20. This phosphorylation was accompanied by the increase of p21 protein levels. Furthermore, specific knockdown of endogenous p21 by siRNAs severely impaired virus production represented by HSV envelope glycoprotein B (gB) expression and progeny virus titers. Disruption of the p53 p21 pathway by either knocking down p53 in HCT116 p53(+/+) and NIH3T3 cells or using p53-deficient HCT116 p53(-/-) cells, led to a significant reduction of HSV 2 production. Together, these results suggest that the p53-p21 pathway is required for efficient HSV-2 lytic replication cycle. Because HSV infection induces the G0/G1 phase arrest at the early step of lytic-replication cycle, we propose that HSV-2 might hijack the cellular p53-p21 pathway to arrest the host cell cycle at G0/G1 phase, blocking cellular DNA synthesis, for its own benefit, i.e., to favor its own viral replication by avoiding competition in generating viral nucleotide pools. PMID- 22820404 TI - Severe acute respiratory syndrome coronavirus accessory proteins 6 and 9b interact in vivo. AB - The 3'proximal one-third of the severe acute respiratory syndrome coronavirus (SARS-CoV) genome encodes the structural proteins and eight accessory proteins, including 3a, 3b, 6, 7a, 7b, 8a, 8b and 9b, varying in length from 39 to 274aa which do not share significant homology with viral proteins of known coronaviruses. The SARS-CoV protein 6 is 63 amino acids in length and has been previously involved in virus pathogenicity and replication. To further analyze this functions, the interaction of SARS-CoV protein 6 with other viral and/or cellular factors has been analyzed during SARS-CoV infective cycle. Protein 6 immunoprecipitation from extracts of SARS-CoV infected cells and mass spectrometry analysis revealed an interaction of viral proteins 6 and 9b in biologically relevant conditions. This interaction has been reinforced by co localization of both proteins in the cytoplasm of SARS-CoV infected cells. PMID- 22820406 TI - Does laparoscopic mobilisation of the stomach as part of a trans-thoracic oesophageal resection result in improved peri-operative outcomes as compared with an open approach? AB - A best evidence topic in surgery was written according to a structured protocol. The question addressed was whether laparoscopic mobilisation of the stomach as part of a trans-thoracic oesophageal resection results in improved peri-operative outcomes as compared with an open approach. 319 papers were found using the reported search; the 5 representing the best evidence to answer the question are discussed. The evidence on this subject is poor, none of the studies were randomised and only one was prospective. We conclude that laparoscopically assisted gastric mobilisation during trans-thoracic oesophageal resection may have advantages over open surgery in terms of short-term peri-operative outcomes including reduced blood loss, reduced dependence on ventilatory support and shortened intensive care and overall hospital stay. However there was no difference between laparoscopic and open surgery in terms of overall morbidity or mortality rates. PMID- 22820405 TI - Construction of an infectious cDNA clone and gene expression vector of Tobacco vein banding mosaic virus (genus Potyvirus). AB - Tobacco vein banding mosaic virus (TVBMV, genus Potyvirus) mainly infects solanaceous plants and is of increasing economic importance in China. Here, we report sequence determination of the full-length 5'-untranslated region of TVBMV isolate HN39 and construction of an infectious clone. The resultant clone, pTVBMV, which was stabilized by introducing three introns in the P3 and CI encoding regions, induced similar disease symptoms and accumulated similar titers of virus in plants of Nicotiana benthamiana, Nicotiana tabacum and N. rustica as the wild type HN39 isolate. Mutation of arginine to isoleucine (R182I) or aspartic acid to lysine (D198K) in HC-Pro alleviated the symptoms of pTVBMV significantly, indicating a role of the two amino acids in regulating virulence of TVBMV. The Aequoria victoriae gene for green fluorescent protein was inserted between the NIb and CP encoding regions of pTVBMV and expressed stably in the systemically infected N. benthamiana leaves, indicating suitability of pTVBMV for expression of foreign proteins in plants. PMID- 22820407 TI - Norepinephrine depresses the nitric oxide production in the ascidian hemocytes. AB - Norepinephrine (NE) is a neuro-hormone released by vertebrates and invertebrates during acute stress, and can influence their immune function. We found that NE depressed the production of nitric oxide (NO) by the hemocytes of ascidians. Our results with a fluorescent indicator for NO in assays using both NE and either alpha or beta-antagonist revealed that NE down-regulated NO production by the ascidian hemocytes. Our data suggest that NE may be acting via specific hemocyte receptors to induce a decrease in immune function. PMID- 22820408 TI - Biobehavioral influences on recovery following hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is a rigorous therapy that carries significant risk of morbidity and mortality to individuals with hematologic malignancies undergoing this treatment. While relationships between psychosocial factors, immune function, and clinical outcomes have been documented in other cancer populations, similar studies of cancer patients undergoing HSCT have not yet been conducted. The clinical significance of these relationships may be particularly salient in this population given the critical role of a timely immune recovery and optimal immune regulation in preventing infections, mitigating risk for graft-versus-host disease, and eliminating malignant cells, thereby reducing morbidity and mortality. Evidence for the potential role of biobehavioral processes following HSCT is reviewed, mechanisms by which psychosocial factors may influence immune processes relevant to post-transplant outcomes are discussed, and a framework to ground future psychoneuroimmunology (PNI) research in this area is provided. The review suggests that the recovery period following HSCT may provide a "window of opportunity" during which interventions targeting stress-related behavioral factors can influence the survival, health, and well-being of HSCT recipients. PMID- 22820409 TI - Mindfulness-Based Stress Reduction training reduces loneliness and pro inflammatory gene expression in older adults: a small randomized controlled trial. AB - Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition * time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF kappaB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-kappaB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition * time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. PMID- 22820410 TI - The management of small-cell carcinomas of the gynecologic tract. AB - PURPOSE OF REVIEW: Small-cell carcinomas of the gynecologic tract are aggressive malignancies that can be misdiagnosed or inappropriately managed. This review provides a summary of current literature that will help the clinician to correctly diagnose and treat patients with small-cell carcinomas of the cervix, ovary, uterus, vagina, and vulva. RECENT FINDINGS: Small-cell carcinomas of gynecologic sites are rare and carry a poor prognosis. Stage is an important prognostic factor in small-cell carcinoma of the cervix, uterus, and ovary. Early stage disease has varied treatment approaches based on the site of malignancy, but systemic chemotherapy with or without radiation plays a role in the adjuvant setting to mitigate the risk of recurrence. Advanced stage patients require treatment with chemotherapy and possibly radiation, usually in a manner analogous to small-cell lung cancer. The preferred chemotherapy regimen contains a platinum agent and etoposide. For small-cell ovarian carcinomas, it is important to differentiate those of the hypercalcemic type from those of the pulmonary type. The small-cell carcinomas of the vagina and vulva need to be distinguished from Merkel cell cancers. SUMMARY: The majority of small-cell tumors of the gynecologic tract will require systemic chemotherapy with a platinum agent and etoposide, both in the setting of early and advanced stage disease. Prospective trials with new chemotherapy or targeted agents are needed to improve the treatment of this aggressive cancer. PMID- 22820411 TI - Early stage follicular lymphoma, current management and controversies. AB - PURPOSE OF REVIEW: In this article, we focus on the epidemiology, outcomes, and treatment options of early stage follicular lymphoma. RECENT FINDINGS: Radiation therapy has been the predominant treatment for patients with early stage follicular lymphoma for decades. It is associated with a 10-year progression-free survival of 45-60%, thought to represent cures in this otherwise incurable disease with conventional modalities. Limiting the radiation field and dose does not diminish outcomes. On the contrary, the addition of chemotherapy does not benefit this patient population as a whole. The use of polymerase chain reaction for Bcl-2 gene rearrangements to detect molecular disease, however, may identify patients with early occult disseminated disease, who are at risk for relapse and would benefit from the addition of systemic therapy. For patients in whom radiation would be too toxic or prefer to not have radiation, observation is a reasonable alternative and a proportion of patients observed do not require therapy for a number of years. Despite the potential cures achieved by radiation therapy, a minority of patients in the United States receive such therapy; the majority are instead observed or treated with chemoimmunotherapy. SUMMARY: Patients with early stage follicular lymphoma enjoy excellent outcomes following definitive radiation therapy, many of whom may even be cured. The addition of other therapies has not enhanced cure rates but identifying patients at greatest risk for disease relapse may change this paradigm. Despite the proven success of radiation, the majority of early stage follicular lymphoma patients in the United States do not receive radiation. PMID- 22820412 TI - New insights into meningioma: from genetics to trials. AB - PURPOSE OF REVIEW: In view of growing interest and need for nonsurgical therapies of meningiomas, we reviewed relevant articles published in the period from December 2010 to April 2012. RECENT FINDINGS: Large population-based, case control studies have resulted in identification of new etiology factors, such as smoking or allergy, as well as new genes shown to play a role in meningioma susceptibility. Although aggressive surgery is still the treatment of choice for meningioma patients, even in the elderly population, postoperative radiotherapy remains debated and limited to Grade II residual cases as well as Grade III tumors. Although preclinical studies have pinpointed new candidate drugs to stop meningioma growth, such as trabectedin and histone deacetylase inhibitors, there are currently no effective therapies for meningiomas. Several clinical trials are under way, mostly on heavily pretreated patients, to determine the efficacy of some of the most promising candidate drugs, platelet-derived growth factor receptor-targeted therapies, and antiangiogenetic drugs being on the top list. Robust genetically engineered mouse models should be used as 'filters' to select agents for human clinical trials. SUMMARY: Surgical approach combined with radiotherapy in selected cases remains the most appropriate for meningioma patients. New therapies are under investigation and should modify treatment paradigms in the future. PMID- 22820413 TI - Targeted therapy in brain metastasis. AB - PURPOSE OF REVIEW: To review the state of the art and new developments in the field of targeted agents for brain metastases. RECENT FINDINGS: The huge amount of information on new molecular compounds and the advances in understanding the molecular pathways that mediate brain colonization have led to an increase of interest in preclinical and clinical investigations in the field of brain metastases. Targeted therapies can be employed either on established brain metastases or in a prevention setting. Targeting angiogenesis is an attractive approach. Up to date, large clinical trial datasets have shown that antiangiogenic agents do not increase the risk of bleeding into the brain. Bevacizumab (an anti-VEGF agent) is undergoing investigation in clinical trials on brain metastases from non-small cell lung cancer (NSCLC), breast cancer and melanoma. Sunitinib, a multitarget small molecule tyrosine kinase inhibitor (TKI), is a promising agent in brain metastases from renal cell cancer. The EGFR inhibitors gefitinib and erlotinib have a definite activity in brain metastases from NSCLC with activating EGFR mutations. Regarding HER2-positive breast cancer patients with established brain metastases, lapatinib (small molecule TKI) seems particularly active in association with capecitabine. Lapatinib alone is attractive in the prevention setting. Brain metastases from melanoma with BRAF V600E mutations respond to a specific inhibitor, such as vemurafenib. The immunomodulator ipilimumab is also active on brain metastases from melanoma. SUMMARY: The use of targeted agents in brain metastases from solid tumors is promising. The setting of prevention will be probably expanded in the next years. Well designed clinical trials with proper endpoints are needed. PMID- 22820414 TI - Spectroscopic verification of zinc absorption and distribution in the desert plant Prosopis juliflora-velutina (velvet mesquite) treated with ZnO nanoparticles. AB - The impact of metal nanoparticles (NPs) on biological systems, especially plants, is still not well understood. The aim of this research was to determine the effects of zinc oxide (ZnO) NPs in velvet mesquite (Prosopis juliflora-velutina). Mesquite seedlings were grown for 15 days in hydroponics with ZnO NPs (10 nm) at concentrations varying from 500 to 4000 mg L(-1). Zinc concentrations in roots, stems and leaves were determined by inductively coupled plasma optical emission spectroscopy (ICP-OES). Plant stress was examined by the specific activity of catalase (CAT) and ascorbate peroxidase (APOX); while the biotransformation of ZnO NPs and Zn distribution in tissues was determined by X-ray absorption spectroscopy (XAS) and micro X-ray fluorescence (MUXRF), respectively. ICP-OES results showed that Zn concentrations in tissues (2102 +/- 87, 1135 +/- 56, and 628 +/- 130 mg kg(-1) d wt in roots, stems, and leaves, respectively) were found at 2000 mg ZnO NPs L(-1). Stress tests showed that ZnO NPs increased CAT in roots, stems, and leaves, while APOX increased only in stems and leaves. XANES spectra demonstrated that ZnO NPs were not present in mesquite tissues, while Zn was found as Zn(II), resembling the spectra of Zn(NO(3))(2). The MUXRF analysis confirmed the presence of Zn in the vascular system of roots and leaves in ZnO NP treated plants. PMID- 22820415 TI - Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. AB - The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. FXR plays an important role in positively regulating genes (transactivation) involved in bile acid homeostasis, fat and glucose metabolism. Recently, it has become clear that an additional important role for FXR consists of downregulating genes involved in inflammation. Because of this broad spectrum of regulated genes, therapeutically targeting FXR with full agonists will likely result in adverse side effects, in line with what is described for other NRs. It may therefore be necessary to develop selective FXR modulators. However, the molecular mechanisms that distinguish between FXR-mediated transactivation and transrepression are currently unknown. For other NRs, post-translational modifications such as SUMOylation and phosphorylation have been reported to be unique to either transactivation or transrepression. Here, we review current knowledge on post translational regulation of FXR with respect to transactivation and transrepression. Ultimately, increased understanding of the different mechanisms of transactivation and transrepression of nuclear receptors will aid in the development of NR drugs with fewer side effects. PMID- 22820417 TI - Association of staff behaviors and afterschool program features to physical activity: findings from Movin' After School. AB - BACKGROUND: Children's achievement of recommendations for moderate-to-vigorous physical activity (MVPA) in afterschool programs (ASP) is complex. It is unclear what elements of the ASP environment influence children's physical activity (PA). The purpose of this study was to determine the relationship of staff behaviors and ASP features (eg, organized activity, recreational equipment) to MVPA participation in youth attending ASPs. METHODS: Data were collected in 12 ASPs in the Midwest. Staff behavior and child PA was measured using the System for Observing Play and Leisure Activity in Youth. The percentage of children's MVPA was examined in relation to staff behaviors and ASP features. RESULTS: Increases in MVPA were observed when staff were directly engaged in PA, verbally promoted MVPA, and when PA was organized and equipment was present. When 3 or more of these characteristics were present, the proportion of children engaged in MVPA increased by 25%-30%. Conversely, MVPA levels decreased when these characteristics were absent and when staff were attending to other ASP duties or were supervising. CONCLUSION: This study provides evidence about the specific staff behaviors that may influence higher proportions of youth being active during ASP and implies specific skills that need to be incorporated into ASP staff training. PMID- 22820416 TI - Phase-amplitude investigation of spontaneous low-frequency oscillations of cerebral hemodynamics with near-infrared spectroscopy: a sleep study in human subjects. AB - We have investigated the amplitude and phase of spontaneous low-frequency oscillations (LFOs) of the cerebral deoxy- and oxy-hemoglobin concentrations ([Hb] and [HbO]) in a human sleep study using near-infrared spectroscopy (NIRS). Amplitude and phase analysis was based on the analytic signal method, and phasor algebra was used to decompose measured [Hb] and [HbO] oscillations into cerebral blood volume (CBV) and flow velocity (CBFV) oscillations. We have found a greater phase lead of [Hb] vs. [HbO] LFOs during non-REM sleep with respect to the awake and REM sleep states (maximum increase in [Hb] phase lead: ~pi/2). Furthermore, during non-REM sleep, the amplitudes of [Hb] and [HbO] LFOs are suppressed with respect to the awake and REM sleep states (maximum amplitude decrease: 87%). The associated cerebral blood volume and flow velocity oscillations are found to maintain their relative phase difference during sleep, whereas their amplitudes are attenuated during non-REM sleep. These results show the potential of phase amplitude analysis of [Hb] and [HbO] oscillations measured by NIRS in the investigation of hemodynamics associated with cerebral physiology, activation, and pathological conditions. PMID- 22820418 TI - Discovery of glycosyltransferases using carbohydrate arrays and mass spectrometry. AB - Glycosyltransferases catalyze the reaction between an activated sugar donor and an acceptor to form a new glycosidic linkage. Glycosyltransferases are responsible for the assembly of oligosaccharides in vivo and are also important for the in vitro synthesis of these biomolecules. However, the functional identification and characterization of new glycosyltransferases is difficult and tedious. This paper describes an approach that combines arrays of reactions on an immobilized array of acceptors with an analysis by mass spectrometry to screen putative glycosyltransferases. A total of 14,280 combinations of a glycosyltransferase, an acceptor and a donor in four buffer conditions were screened, leading to the identification and characterization of four new glycosyltransferases. This work is notable because it provides a label-free method for the rapid functional annotation of putative enzymes. PMID- 22820419 TI - Transient GPI-anchored protein homodimers are units for raft organization and function. AB - Advanced single-molecule fluorescent imaging was applied to study the dynamic organization of raft-associated glycosylphosphatidylinositol-anchored proteins (GPI-APs) in the plasma membrane and their stimulation-induced changes. In resting cells, virtually all of the GPI-APs are mobile and continually form transient (~200 ms) homodimers (termed homodimer rafts) through ectodomain protein interactions, stabilized by the presence of the GPI-anchoring chain and cholesterol. Heterodimers do not form, suggesting a fundamental role for the specific ectodomain protein interaction. Under higher physiological expression conditions , homodimers coalesce to form hetero- and homo-GPI-AP oligomer rafts through raft-based lipid interactions. When CD59 was ligated, it formed stable oligomer rafts containing up to four CD59 molecules, which triggered intracellular Ca(2+) responses that were dependent on GPI anchorage and cholesterol, suggesting a key part played by transient homodimer rafts. Transient homodimer rafts are most likely one of the basic units for the organization and function of raft domains containing GPI-APs. PMID- 22820421 TI - Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity. AB - This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague-Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. PMID- 22820420 TI - A stand-alone adenylation domain forms amide bonds in streptothricin biosynthesis. AB - The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L beta-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containing thiolation (T) and condensation (C) domains) and ORF 19 (a stand-alone A domain). We demonstrate that ST biosynthesis begins with adenylation of L-beta-lysine by ORF 5, followed by transfer to the T domain of ORF 18. In contrast, L-beta-lysine molecules adenylated by ORF 19 are used to elongate an L-beta-lysine peptide chain on ORF 18, a reaction unexpectedly catalyzed by ORF 19 itself. Finally, the C domain of ORF 18 catalyzes the condensation of L-beta-lysine oligopeptides covalently bound to ORF 18 with a freely diffusible intermediate to release the ST products. These results highlight an unusual activity for an A domain and unique mechanisms of crosstalk within NRPS machinery. PMID- 22820422 TI - Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats. AB - Lipocalins tailored with high affinity for prescribed ligands, so-called anticalins, constitute promising candidates as antidotes. Here, we present an animal study to investigate both pharmacokinetic and clinical effects of an anticalin specific for the digitalis compound digoxin. Intravenous digoxin (2.5 50 MUg/kg/min) was administered to rats until first changes in the ECG occurred (dose finding study) or a priori for 30 min (kinetic study). The anticalin DigA16(H86N), dubbed DigiCal, was administered intravenously at absolute doses of 1, 5, 10 and 20 mg, while the control group received isotonic saline. Hemodynamic changes, several ECG parameters and digoxin concentration in plasma were monitored at given time intervals. After DigiCal administration free digoxin concentration in plasma ultrafiltrate declined dramatically within 1 min to the presumably non-toxic range. There was also a significant and DigiCal dose dependent effect on longer survival, less ECG alterations, arrhythmia, and improved hemodynamics. Infusion of a lower digoxin dose (2.5 MUg/kg/min) resulted in a more sustained reduction of free digoxin in plasma after DigiCal administration compared to a higher digoxin dose (25 MUg/kg/min), whereas ECG and hemodynamic parameters did not markedly differ, reflecting the known relative insensitivity of rats towards digoxin toxicity. Notably, we observed a re increase of free digoxin in plasma some time after bolus administration of DigiCal, which was presumably due to toxin redistribution from tissue in combination with the relatively fast renal clearance of the rather small protein antidote. We conclude that anticalins with appropriately engineered drug-binding activities and, possibly, prolonged plasma half-life offer prospects for next generation antidotal therapy. PMID- 22820423 TI - Left ventricular diastolic function in workers occupationally exposed to mercury vapour without clinical presentation of cardiac involvement. AB - The aim of the study was to evaluate left ventricular diastolic function in workers occupationally exposed to mercury vapour without clinical presentation of cardiac involvement. The studies included 115 workers (92 men and 23 women) occupationally exposed to mercury vapour without clinical presentation of cardiac involvement (mean age: 47.83+/-8.29). Blood samples were taken to determine blood lipid profile, urine was collected to estimate mercury concentration (HgU) and echocardiographic examination was performed to evaluate diastolic function of the left ventricle. In the entire group of workers occupationally exposed to mercury vapour without clinical presentation of cardiac involvement, Spearman correlations analysis demonstrated the following significant linear relationships: between body mass index (BMI) and ratio of maximal early diastolic mitral flow velocity/early diastolic mitral annular velocity (E/E') (r=0.32, p<0.05), between serum HDL concentration and E/E' (r=-0.22, p<0.05), between HgU and E/E' (r=0.35, p<0.05), between HgU and isovolumetric relaxation time (IVRT') (r=0.41, p<0.05), between HgU and ratio of maximal early diastolic mitral flow velocity/maximal late diastolic mitral flow velocity (E/A) (r=-0.31, p<0.05) and between serum HDL concentration and E/A (r=0.43, p<0,05). In logistic regression analysis it as shown that independent factors of left ventricular diastolic dysfunction risk in the study group included a higher urine mercury concentration, a higher value of BMI and a lower serum HDL concentration (OR(Hg U)=1.071, OR(BMI)=1.200, OR(HDL)=0.896, p<0.05). Summing up, occupational exposure to mercury vapour may be linked to impaired left ventricular diastolic function in workers without clinical presentation of cardiac involvement. PMID- 22820424 TI - Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation. AB - Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3beta, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation. PMID- 22820425 TI - Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. AB - Several studies have reported the adverse effects of nano-CuO on hippocampal CA1 neuron, whereas little has been known about nano-CuO neurotoxicity in vivo. In the present study, we investigated the effects of nano-CuO on spatial cognition and electrophysiological alterations in rats. In addition, histological and biochemical changes in rat's hippocampus were measured as well. Morris water maze (MWM) test showed that learning and memory abilities in nano-CuO-treated group were weakened significantly. The long-term potentiation (LTP) test exhibited that field excitatory postsynaptic potentials (fEPSPs) slopes were significantly lower in nano-CuO-treated group compared to that in control group. Furthermore, the levels of ROS and malonaldehyde (MDA) in hippocampal homogenate of nano-CuO treated group were considerably enhanced while the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were statistically reduced. Moreover, the enhanced 4-hydroxynonenal (HNE) and caspase-3 implied the progression of apoptosis in the hippocampus. The results suggested that the neuronal damage, induced by impairing oxidation-antioxidation homeostasis, led to the impairment of hippocampal LTP, which was associated with the poor performance of animals in behavior tests. PMID- 22820426 TI - Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles. AB - Silver nanoparticles (Ag NPs) are used in consumer products and wound dressings due to their antimicrobial properties. However, in addition to toxic effects on microbes, Ag NPs can also induce stress responses as well as cytotoxicity in mammalian cells. We observed that Ag NPs are efficiently internalized via scavenger receptor-mediated phagocytosis in murine macrophages. Confocal and electron microscopy analysis revealed that internalized Ag NPs localize in the cytoplasm. Ag NPs cause mitochondrial damage, induce apoptosis and cell death. These effects were abrogated in presence of Ag ion-reactive, thiol-containing compounds suggesting the central of Ag ions in Ag NP toxicity. Quantitative image analysis revealed that intracellular dissolution of Ag NPs occurs about 50 times faster than in water. In conclusion, we demonstrate for the first time that Ag NPs are internalized by scavenger receptors, trafficked to cytoplasm and induce toxicity by releasing Ag ions. PMID- 22820427 TI - Role of Nrf2 in protection against triptolide-induced toxicity in rat kidney cells. AB - Triptolide is a major active ingredient of the Chinese herb Tripterygium wilfordii Hook f. (TWHF) and has been shown to possess multiple biological activities, such as anti-inflammatory, anti-fertility, anti-neoplastic and immunosuppressive activities. However, severe adverse effects, especially nephrotoxicity, limit its clinical use. Oxidative stress has been reported to be involved in triptolide-induced renal injury, but the existence of other mechanisms remains unclear. This study aimed to investigate whether NF-E2-related factor 2 (Nrf2), which is an antioxidant nuclear transcription factor, plays a protective role in defense against triptolide-induced toxicity in a normal rat kidney cell line (NRK-52E). Triptolide induced oxidative stress in NRK-52E cells by induction of reactive oxygen species (ROS) and depletion of glutathione (GSH), which resulted in a rapid increase in Nrf2 nuclear accumulation, as well as an induction of antioxidant response element (ARE)-driven genes. In addition, overexpression of Nrf2 protected against triptolide-induced cell death, whereas knockdown of Nrf2 by its specific small interfering RNA resulted in increased cytotoxicity. We also found that Nrf2 knockdown enhanced both the production of ROS and the depletion of GSH. Taken together, these results indicate that activation of Nrf2 plays a protective role against triptolide-induced cytotoxicity in NRK-52E cells through the counteraction of oxidative stress. PMID- 22820428 TI - Relative embryotoxic potency of p-substituted phenols in the embryonic stem cell test (EST) and comparison to their toxic potency in vivo and in the whole embryo culture (WEC) assay. AB - The applicability of the embryonic stem cell test (EST) as an alternative for in vivo embryotoxicity testing was evaluated for a series of five p-substituted phenols. To this purpose, the potency ranking for this class of compounds derived from the inhibition of cardiomyocyte differentiation in the EST was compared to in vivo embryotoxic potency data obtained from literature and to the potency ranking defined in the in vitro whole embryo culture (WEC) assay. From the results obtained it appears that the EST was able to identify the embryotoxic potential for p-substituted phenols, providing an identical potency ranking compared to the WEC assay. However, the EST was not able to predict an accurate ranking for the phenols compared to their potency observed in vivo. Only phenol, the least potent compound within this series, was correctly ranked. Furthermore, p-mercaptophenol was correctly identified as a relative potent congener of the phenols tested, but its ranking was distorted by p-heptyloxyphenol, of which the toxicity was overestimated in the EST. It is concluded that when attempting to explain the observed disparity in potency rankings between in vitro and in vivo embryotoxicity, the in vitro models should be combined with a kinetic model describing in vivo absorption, distribution, metabolism and excretion processes of the compounds. PMID- 22820429 TI - In vivo formation of N7-guanine DNA adduct by safrole 2',3'-oxide in mice. AB - Safrole, a naturally occurring product derived from spices and herbs, has been shown to be associated with the development of hepatocellular carcinoma in rodents. Safrole 2',3'-oxide (SFO), an electrophilic metabolite of safrole, was shown to react with DNA bases to form detectable DNA adducts in vitro, but not detected in vivo. Therefore, the objective of this study was to investigate the formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine (N7gamma-SFO Gua) resulting from the reaction of SFO with the most nucleophilic site of guanine in vitro and in vivo with a newly developed isotope-dilution high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method. N7gamma-SFO-Gua and [(15)N(5)]-N7-(3 benzo[1,3]dioxol-5-yl-2-hydroxypropyl)guanine ([(15)N(5)]-N7gamma-SFO-Gua) were first synthesized, purified, and characterized. The HPLC-ESI-MS/MS method was developed to measure N7gamma-SFO-Gua in calf thymus DNA treated with 60 MUmol of SFO for 72 h and in urine samples of mice treated with a single dose of SFO (30 mg/kg body weight, intraperitoneally). In calf thymus DNA, the level of N7gamma SFO-Gua was 2670 adducts per 10(6)nucleotides. In urine of SFO-treated mice, the levels of N7gamma-SFO-Gua were 1.02+/-0.14 ng/mg creatinine (n=4) on day 1, 0.73+/-0.68 ng/mg creatinine (n=4) on day 2, and below the limit of quantitation on day 3. These results suggest that SFO can cause in vivo formation of N7gamma SFO-Gua, which may then be rapidly depurinated from the DNA backbone and excreted through urine. PMID- 22820430 TI - Pediatric reference values for serum zinc concentration in Iranian subjects and an assessment of their dietary zinc intakes. AB - OBJECTIVES: To determine pediatric reference values for serum zinc concentration in Iranian subjects. DESIGN AND METHODS: Serum zinc concentration was measured by flame atomic absorption spectrometry in 699 children and adolescents. Reference values for serum zinc were determined according to the Clinical and Laboratory Standards Institute/International Federation of Clinical Chemistry guidelines. Dietary zinc intake was assessed using a validated semiquantitative food frequency questionnaire. RESULTS: Overall 95% reference values for serum zinc concentrations were 9.7-31.5, 9.2-30.9, and 9.3-31.1 MUmol/L in boys, girls, and total population respectively. Serum zinc concentrations were comparable in boys and girls (17.5 +/- 5.3 MUmol/L vs. 17.2 +/- 5.6 MUmol/L, p=0.242). The dietary zinc intake of 7.6% (4.9% boys and 10.2% girls, p<0.01) was lower than the estimated average requirement. CONCLUSIONS: This study presents pediatric reference values for serum zinc concentrations, values that could help diagnose and manage zinc deficiency in pediatrics. PMID- 22820431 TI - Stabilization of cell-free RNA in blood samples using a new collection device. AB - OBJECTIVE: To investigate whether a new blood collection device stabilizes cell free RNA (cfRNA) in blood post-phlebotomy when compared to collection using K(3)EDTA tubes. DESIGN AND METHODS: Blood samples were drawn from healthy donors into K(3)EDTA tubes and Cell-Free RNA BCTs (BCTs) and stored at room temperature (20-25 degrees C). At specified time points (days 0-3), plasma was separated and cfRNA was extracted. Reverse transcription real-time PCR was used to quantify mRNA for c-fos, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and for 18S rRNA. RESULTS: Blood drawn into K(3)EDTA tubes showed a steady increase in RNA concentration over 3 days of ex vivo incubation. Blood drawn into BCTs showed no statistically significant change in RNA copy number except for GAPDH on day 3. CONCLUSIONS: The novel chemical cocktail contained in the new device allows for the stabilization of cfRNA in blood samples at room temperature, which potentially enhances the clinical utility of cfRNA. PMID- 22820432 TI - The involvement of nitric oxide in the physiopathology of hepatoportal sclerosis. AB - BACKGROUND AND AIM: Hepatoportal sclerosis (HPS) is a clinical syndrome of unspecified etiology depicted by enlarged spleen and portal hypertension in the lack of other chronic liver disease findings, hematological disorders or any infectious disease in the liver. Nitric oxide (NO) molecule has many important functions in human body including phagocytosis in macrophages, neural transmission and endothelial relaxation. Although there is no data in literature that depicts the role of NO in HPS pathogenesis, this study was conducted in order to evaluate the potential role of NO in patients with HPS. PATIENTS AND METHODS: The study participants included 24 HPS patients and 20 healthy controls. The median age of HPS and control patients was 41.2 +/- 13.9 and 46.5 +/- 12.4 years, respectively. NO was predicted as nitric oxide metabolites (NOx) by Griess reaction after transformation of nitrate to nitrite by nitrate reductase using the commercially obtainable Nitric Oxide Assay Kit. RESULTS: Serum NOx levels were 2.69 +/- 2.98 MUmol/L and 0.85 +/- 1.05 MUmol/L for the HPS patients and controls, respectively. Serum NO levels were significantly higher in patients with HPS compared to the control group (p<0.001). ROC curve analysis suggested that the optimum NOx cut-off point for HPS was 1.305 with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 83.3%, 90 %, 90.9 %, and 81.8% respectively. CONCLUSION: Circulating NO concentration was notably higher in patients with HPS in comparison to the control group. Our study verified that an elevated level of NO might have a role in the pathogenesis of HPS. PMID- 22820434 TI - Novel alpha-galactosidase A mutation in a female with recurrent strokes. AB - Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human alpha-galactosidase A gene have been determined and to date, several disease-causing alpha-galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution. PMID- 22820433 TI - Short-term prognostic value of serum neuron specific enolase and S100B in acute stroke patients. AB - OBJECTIVE: To explore the value of blood markers for brain injury as outcome predictors in acute stroke. DESIGN AND METHODS: The study included 61 patients with acute stroke (44 ischemic and 17 hemorrhagic) and a high risk control group (79 individuals with no known history of neurological disease). Serum neuron specific enolase (NSE) and S100B were determined by immunoassay (CanAg Diagnostics, Sweden). Outcome at 60 days was evaluated with clinical scales. RESULTS: Higher concentrations of NSE and S100B were measured in patients compared to high risk controls, but they were not related to stroke severity on admission. NSE was associated with functional neurological outcome at 60 days and to the degree of recovery, whereas S100B exhibited a strong correlation with depression symptoms at 60 days. CONCLUSIONS: The measurements of serum concentrations of NSE and S100B after acute stroke may be clinically relevant for predicting functional neurological outcome and post-stroke depression, respectively. PMID- 22820435 TI - Variation of serum C-reactive protein (CRP) over time in pediatric cancer patients with febrile illness and its relevance to identified pathogen. AB - OBJECTIVE: To evaluate the correlation of serum CRP with clinical and laboratory parameters proven to be related to the cause of infection in pediatric cancer patients. METHODS: We studied prospectively for a 12-month period, 37 pediatric cancer patients, who presented with 70 episodes of febrile illness (38 bacterial and 13 viral infections). At fever's onset and 48 h later, infection indices, such as CRP, WBC, ANC were measured in the peripheral blood. Moreover we calculated the change rate of CRP over 48 h [CRP/t=(CRP48h-initial CRP)/t (t=2 days)]. Cultures of biological fluids, PCR and antibody detection of infectious agents were also obtained. RESULTS: When comparing patients with viral vs. bacterial infections, mean CRP levels on admission (11.0 vs. 33.1mg/L, p=0.005) and at 48 h (13.4 vs. 71.9 mg/L, p=0.0007), and CRP/t (0.9 vs. 18.8 mg/L/day, p=0.030) were significantly lower in the group with viral infection. At 48 h - follow-up, patients with positive culture had higher CRP levels (57.3 vs. 43.3mg/L, p=0.048) and higher CRP/t (15.9 vs. 7.7 mg/L/day, p=0.025), compared to those without proven infection. CRP/t at 48 h was correlated with both the fever duration (r=0.27, p=0.027) and maximum temperature (Tmax) during the febrile episode (r=0.30, p=0.013). CONCLUSIONS: Single CRP values on fever initiation can differentiate between viral and bacterial infections in febrile pediatric cancer patients. Moreover the change rate of CRP over time (CRP/t) is offered as a prognostic index of bacterial infection and a marker of the total duration of fever and Tmax. PMID- 22820436 TI - Evaluation of a method for the simultaneous detection of multiple tumor markers using a multiplex suspension bead array. AB - OBJECTIVE: To achieve higher tumor detection efficiency, we evaluated a multiplex assay for TM analysis based on the Luminex-100 multiplex suspension bead array. DESIGN: The assay simultaneously determined the concentrations of nine TMs in 1114 human serum specimens (546 patients with tumors, 158 patients with non-tumor inflammatory diseases, and 410 normal controls). The nine TMs were AFP, CEA, CA125, CYFRA 21-1, CA242, f-PSA, t-PSA, NSE and free beta-hCG. The multiplex suspension bead assays were compared with conventional methods used in clinical laboratories. RESULTS: The Luminex assay has the same levels of sensitivity, specificity and accuracy in the prediction of positive tumor specimens as conventional methods. CONCLUSION: Multiplex suspension bead arrays have promising applications in clinical laboratories. PMID- 22820437 TI - Development of an enzymatic assay for sphingomyelin with rapid and automatable performances: Analysis in healthy subjects and coronary heart disease patients. AB - BACKGROUND: Sphingomyelin (SM) is an important choline group-containing phospholipid and is considered to be an independent risk factor for coronary heart disease. METHODS: We have developed a specific enzymatic assay for SM measurement with rapid and automatable performances by using two-reagent system involving sphingomyelinase. We performed within-run and between-run precision, linearity test, detection limit, recovery test and interference to validate this assay. Then, we measured the serum SM concentration in 194 healthy subjects and 141 consecutive patients undergoing coronary angiography. RESULTS: The within-run and between-run coefficients of variation for SM concentrations were 1.1-1.3% and 1.0-1.2%, respectively. Quantitative measurements to a lower limit of 30 MUmol/L were shown to be possible. The recoveries of the exogenously added SM to the control samples were 98.7%-101.5%. No effect was observed after the addition of some interference materials. The mean +/- SD of the serum SM concentration in the 194 healthy subjects was 553.3 +/- 100.1 MUmol/L. We found that the SM concentration was significantly higher among an acute coronary syndrome subjects than among the healthy subjects (P<0.01) and that the serum SM concentrations were significantly correlated with the serum magnesium concentration. CONCLUSIONS: We have developed a rapid and automatable enzymatic assay for SM that enables the automatic measurement of choline-containing phospholipids. This assay may be useful for various types of biochemical and clinical research. PMID- 22820438 TI - Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and contributes to endothelial dysfunction. The aim of the present longitudinal study was to investigate the effects of tumour necrosis factor alpha (TNFalpha) antagonists on serum concentrations of ADMA in RA patients. DESIGN AND METHODS: Thirty-five patients (age (mean +/- SD) 55 +/- 15 years, 21 women) who qualified for anti-TNFalpha therapy were included in the study. ADMA was measured by ELISA in all patients prior to starting anti-tumour necrosis factor alpha treatment, and 2 weeks and 3 months after initiation of treatment. Generalised estimating equations were used to analyse the change in a range of factors after the treatment commenced, and to test the relationship between ADMA and various inflammatory parameters. RESULTS: Anti-tumour necrosis factor alpha therapy significantly reduced ESR, CRP, fibrinogen and disease activity score 28 (all p<0.001). ADMA levels did not change significantly following 2 weeks or 3 months treatment using three different tumour necrosis factor alpha inhibitors, despite the fact that CRP (p=0.016), and DAS28 (p=0.025) were found to be significantly associated with ADMA levels after treatment with TNFalpha antagonists. CONCLUSION: ADMA levels do not change significantly during anti-TNF therapy, despite the fact that they associate with CRP and DAS28, which are significantly reduced during such treatment in patients with rheumatoid arthritis. Levels of inflammation after treatment with TNFalpha antagonists are significantly associated with ADMA levels in patients with rheumatoid arthritis. PMID- 22820440 TI - Second-line 90Yttrium-ibritumomab tiuxetan (Zevalin) in a patient with conjunctival mucosa-associated lymphoid tissue lymphoma refractory to rituximab. AB - Lymphoma of mucosa-associated lymphoid tissue (MALT) is the most common variety of lymphoma seen in the ocular adnexae. The authors present the case of a patient with MALT lymphoma refractory to treatment with rituximab. Subsequent treatment with 90Yttrium-Ibritumomab tiuxetan yielded a complete response. PMID- 22820439 TI - Influence of fasting and sample collection time on 38 biochemical markers in healthy children: a CALIPER substudy. AB - OBJECTIVES: Fasting samples can be difficult to obtain in the pediatric setting, particularly in neonates. As part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), we aimed to determine if there are differences in serum concentrations of pediatric biochemical markers measured at fasting, postprandial, and random time points throughout the day. DESIGN AND METHODS: Blood was drawn from 27 healthy children and adolescents (aged 4-18) with informed consent at 4 time points: after overnight fast, mid-morning after breakfast, within 2h after lunch, and late afternoon. The effect of fasting on 38 chemistries was evaluated by paired, two-tailed student'st-tests. Analysis of the effect of time of day was done using paired, repeated-measures ANOVA. RESULTS: Fasting significantly affected 22 analytes, with HDL cholesterol being the most highly affected. Values tended to decrease postprandially, except for five analytes, including triglycerides, which increased. By ANOVA, 28 chemistries significantly differed across times of day tested. CONCLUSIONS: Fasting is necessary for analysis of certain chemistries in pediatric subjects. Pediatricians should consider diurnal factors when ordering non-fasting tests and interpreting test results. PMID- 22820441 TI - Percutaneous embolization of an orbital hemangiopericytoma with Onyx facilitates its surgical excision. AB - This is a case report on the surgical treatment of orbital hemangiopericytoma. The patient initially underwent an attempted excision of the tumor with significant hemorrhage elsewhere, which precluded its complete excision. Due to continued growth and pain, the patient underwent percutaneous embolization with Onyx-18 under fluoroscopic radiographic guidance. The patient continued to have pain, progressive enlargement of the tumor, and underwent surgical excision. The excision was noted to have minimal bleeding and was relatively easy to dissect and excise compared with the typical hemangiopericytoma. Embolization with Onyx 18 may be a useful preoperative treatment option for hemangiopericytomas and other vascular lesions of the orbit, and elsewhere. PMID- 22820442 TI - Hidradenoma papilliferum presenting as an eyelid mass. AB - Hidradenoma papilliferum is a benign adnexal tumor originating from apocrine glands of skin. It is commonly seen in the anogenital region of middle-aged women and presents as an asymptomatic, slow-growing, solitary nodule. Rarely this tumor occurs at extragenital sites and is called ectopic hidradenoma papilliferum. Although head and neck is a common site for this group, only 3 cases in the upper eyelid have been described. We present the first case of ectopic hidradenoma papilleferum presenting as a cystic swelling in the lower eyelid. A brief review of literature is included. PMID- 22820443 TI - The psychosocial benefits of secondary hydroxyapatite orbital implant insertion and prosthesis wearing for patients with anophthalmia. AB - PURPOSE: Anophthalmia is associated with a range of psychosocial difficulties and hydroxyapatite orbital implant insertion and prosthesis wearing is the predominant rehabilitation therapy for anophthalmia. However, few articles have compared preoperative and postoperative psychosocial outcomes using standardized questionnaires. This study aimed to investigate the psychosocial benefits of hydroxyapatite orbital implant insertion and prosthesis wearing in this patient population. METHODS: In all, 36 participants were tested preoperatively and 6 months postoperatively using standardized measures of anxiety and depression (Hospital Anxiety and Depression Scale), social anxiety and social avoidance (Derriford Appearance Scale-Short Form), and quality of life (World Health Organization Quality of Life Scale-Short Form). RESULTS: Before treatment, levels of depression were comparable with population norms; however, levels of general anxiety were slightly raised, levels of social anxiety, social avoidance, and quality of life were significantly poorer than population norms. Treatment resulted in significant improvement in psychosocial adjustment with improvements in all study variables for the participant group as a whole. CONCLUSION: Hydroxyapatite orbital implant insertion and prosthesis wearing offers significant improvements in psychological and physical functioning for patients with anophthalmia. PMID- 22820444 TI - Tear film osmolarity in epiphora. AB - PURPOSE: To examine whether patients complaining of epiphora have tears of a lower osmolarity. METHODS: Sixty-three eyes of 39 patients attending an oculoplastic clinic with a primary complaint of epiphora, had their tear osmolarity recorded. Subjects were excluded if they had current or recent topical eye therapy, active ocular infection or allergy, ocular surface scarring, evidence of dry eye, previous laser eye surgery, or a contact lens worn within the previous 12 hours. Patients were divided into 2 groups. The first included those whose primary complaint was of epiphora due to either punctal stenosis, nasolacrimal duct obstruction (partial or complete), or eyelid laxity (without evidence of frank ectropion or entropion). The second group formed the controls, and consisted of the second eye of some of the above patients, or those attending the clinic for other oculoplastic procedures not related to epiphora. Testing of tear osmolarity was performed in the clinic using the TearLab osmometer. RESULTS: Sixty-three readings were obtained, of which 32 were from patients with a primary complaint of epiphora and 31 were allocated to the control group. Patients with epiphora had a mean tear osmolarity of 291.8 mOsms/l (range, 269-324, standard deviation 16.6), compared with the control group mean of 303.7 mOsms/l (range, 269-354, standard deviation 24.1). This difference was found to be statistically significant (p = 0.025). CONCLUSION: Patients complaining of epiphora in the absence of other ocular surface pathology have a significantly lower tear osmolarity. PMID- 22820445 TI - Subciliary incision for external dacryocystorhinostomy. AB - PURPOSE: To report the cosmetic and functional outcomes of subciliary incision for external dacryocystorhinostomy (DCR). METHODS: Prospective interventional study reporting subciliary incision to perform external DCR for primary acquired nasolacrimal duct obstruction. Successful functional outcome was defined as relief from epiphora, and patent lacrimal irrigation. Final cosmetic outcome of the scar was evaluated by subjective grading of the scar by the patient, and objective grading by the physician using high-resolution digital photographs. RESULTS: Seventeen eyes of 16 patients (4 males) with a mean age of 41.75 years (range, 26-71) underwent subciliary approach external DCR over a period of 22 months (March 2010 to December 2011). Pre-operative diagnosis was primary acquired nasolacrimal duct obstruction in all cases. Anatomic and functional success was noted in all 17 (100%) eyes. At the final follow up, objective grading of the scar by the physician reported 47% scars to be invisible (grade 0), and 88.2% scars to be invisible or minimally visible (grade 0-1). At the final follow up, subjective scar grading by the patient reported 88% scars to be invisible (grade 0), and 100% scars to be invisible or minimally visible (grade 0 1). In 2 (11.7%) cases, the physician reported the final scar as moderately visible (grade 2). Average follow up after surgery was 29 weeks (range, 6-72 weeks). In 2 eyes (first 2 cases), the incision extended medially by 2 mm. No other surgery related complications were noted. CONCLUSIONS: Subciliary DCR provides an excellent functional cosmetic scar outcome while retaining the access and advantages of external DCR procedure. PMID- 22820446 TI - Indications for orbital decompression for patients undergoing keratoprosthesis surgery. AB - INTRODUCTION: Optimizing the ocular surface and achieving acceptable cosmesis are important considerations in the rehabilitation of patients with keratoprosthesis (KPro). In osteo-odonto-KPro and type 1 Boston KPro surgery, it is important to ensure a healthy ocular surface to increase the chance of functional success. MATERIALS AND METHODS: The authors present 2 patients with KPros undergoing orbital decompression surgery. This series highlights a novel indication for orbital decompression surgery for patients, who are usually 1-eyed, undergoing KPro surgery. It illustrates the importance of globe position to either optimize the ocular surface or allow a cosmetic shell to be worn. To the authors' knowledge, such indications for orbital decompression have not been reported to date. RESULTS: Two-wall and intraconal fat orbital decompression surgery achieved globe retroplacement of 6 mm and 7 mm, allowing fitting of a cosmetic shell over the osteo-odonto-KPro and reducing lagophthalmos and corneal exposure in patients 1 and 2, respectively. CONCLUSION: Indications for orbital decompression exist in patients undergoing osteo-odonto-KPro or KPro to reduce pseudoproptosis or exposure. PMID- 22820447 TI - Body composition and mortality risk in later life. AB - BACKGROUND: body mass index is used widely to define overweight and obesity. Both high and low body mass indices are associated with increased mortality risk during middle age, but the relationship is less clear in later life. Thus, studies on the relationships between other aspects of body composition and mortality among older subjects are needed. OBJECTIVE: to investigate associations between different aspects of body composition and mortality in older people. METHODS: the study population comprised 921 participants aged >=65 years who underwent dual-energy X-ray (DXA) absorptiometric examination at the Sports Medicine Unit, Umea University. The main reason for admission was clinical suspicion of osteoporosis. Total, abdominal and gynoid fat masses and lean body mass were measured by DXA absorptiometry at baseline, and the cohort was followed (mean duration, 9.2 years) for mortality events. RESULTS: during follow-up, 397 participants died. Lean mass was associated negatively with mortality in men and women (P < 0.001). Total fat mass showed a U-shaped association with mortality in men (P < 0.01) and a negative association in women (P < 0.01). A higher ratio of abdominal to gynoid fat mass increased mortality risk in women (P = 0.04), but not in men (P = 0.91). CONCLUSIONS: lean mass is associated strongly with survival in older subjects. Greater fat mass is protective in older women, whereas very low or very high fat mass increases the risk of death in men. Further research is needed to better understand the mechanisms underlying these associations. PMID- 22820448 TI - A library of strictly linear poly(ethylene glycol)-poly(ethylene imine) diblock copolymers to perform structure-function relationship of non-viral gene carriers. AB - A library of 39 strictly linear poly(ethylene glycol)-poly(ethylene imine) (PEG PEI) diblock copolymers was synthesized for the delivery of plasmid DNA using PEG of 2, 5, or 10 kDa in combination with linear PEI with a molecular weight (MW) ranging from 1.5 to 10.8 kDa. In contrast to other approaches, the copolymers demonstrated a clear separation between the hydrophilic PEG and the nucleic acid condensing PEI moieties. Hence, the hypothesis was that PEG may not sterically counteract the interaction between the nucleic acid and PEI and that consequently, the copolymers are perfectly suited to build small and stable polyplexes. Analysis of the polyplexes revealed structure-function relationships and the general guideline was that the PEG domain had a greater influence on the physicochemical properties of the polyplexes than PEI. A PEG content higher than 50% led to small (<150 nm), nearly neutral polyplexes with favorable stability. The transfection efficacy of these polyplexes was significantly reduced compared to the PEI homopolymer, but was restored by the application of the corresponding degradable copolymer, which involved a redox triggerable PEG domain. In conclusion, valuable design criteria for the optimization of gene delivery carriers, which is only possible through the screening of such a large library, were gained. PMID- 22820449 TI - In situ application of hydrogel-type fibrin-islet composite optimized for rapid glycemic control by subcutaneous xenogeneic porcine islet transplantation. AB - Maximum engraftment of transplanted islets is essential for the clinical application of a subcutaneous site. Significant barriers to the current approaches are associated with their low effectiveness, complexity and unproven biosafety. Here, we evaluated and optimized a fibrin-islet composite for effective glycemic control in a subcutaneous site whose environment is highly hypoxic due to low vascularization potential. In the setting of xenogeneic porcine islet transplantation into the subcutaneous space of a diabetic mouse, the in vivo islet functions were greatly affected by the concentrations of fibrinogen and thrombin. The optimized hydrogel-type fibrin remarkably reduced the marginal islet mass to approximately one tenth that of islets without fibrin. This marginal islet mass was comparable to that in the setting of the subcapsular space of the kidney, which is a highly vascularized organ. Highly vascularized structures were generated inside and on the outer surface of the grafts. A hydrogel-type fibrin-islet composite established early diabetic control within an average of 3.4days after the transplantation. In the mechanistic studies, fibrin promoted local angiogenesis, enhanced islet viability and prevented fragmentation of islets into single cells. In conclusion, in situ application of hydrogel-type fibrin-islet composite may be a promising modality in the clinical success of subcutaneous islet transplantation. PMID- 22820450 TI - Optimizing long-range order, band gap, and group velocities for graphene on close packed metal surfaces. AB - We compare different growth methods with the aim of optimizing the long-range order of a graphene layer grown on Ru(0001). Combining chemical vapor deposition with carbon loading and segregation of the surface layer leads to autocorrelation lengths of 240 A. We present several routes to band gap and charge carrier mobility engineering for the example of graphene on Ir(111). Ir cluster superlattices self-assembled onto the graphene moire pattern produce a strong renormalization of the electron group velocity close to the Dirac point, leading to highly anisotropic Dirac cones and the enlargement of the gap from 140 to 340 meV. This gap can further be enhanced to 740 meV by Na co-adsorption onto the Ir cluster superlattice at room temperature. This value is close to that of Ge, and the high group velocity of the charge carriers is fully preserved. We also present data for Na adsorbed without the Ir clusters. In both cases we find that the Na is on top of the graphene layer. PMID- 22820451 TI - Hyaluronic acid-bearing lipoplexes: physico-chemical characterization and in vitro targeting of the CD44 receptor. AB - The mechanism by which hyaluronic acid (HA)-bearing lipoplexes target the A549 lung cancer cell line was evaluated. For this purpose, cationic liposomes targeting the CD44 receptor were designed thanks to the incorporation in their composition of a conjugate between high molecular weight HA and the lipid DOPE (HA-DOPE). Liposomes containing HA-DOPE were complexed at different lipids:DNA ratios with a reporter plasmid encoding the green fluorescent protein (GFP). Diameter, zeta potential, lipoplex stability and DNA protection from nucleases have been determined. Lipids:DNA ratios of 2, 4 and 6 provided a diameter around 250 nm with a zeta potential of -30 mV. The strength of lipids:DNA interaction and the fraction of DNA protected from enzymatic degradation increased with the lipids:DNA ratio. 2D-immunoelectrophoresis demonstrated the low capacity to activate the C3 fraction of the complement system of any of these three ratios, with and without HA-DOPE. Transfection efficiency in the presence of 0, 10 and 15% of HA-DOPE or unconjugated HA, was determined on the CD44-expressing A549 cells by flow cytometry. Lipoplexes at a lipids:DNA ratio of 2 containing 10% (w/w) of HA-DOPE were the most efficient for transfection. The maximal level of GFP expression was obtained after 6h of incubation demonstrating a slow transfection kinetics of lipoplexes. Finally, lipoplex cellular uptake, measured indirectly by the level of transfection using flow cytometry and validated by fluorescence microscopy, was shown to be mediated by the CD44 receptor and caveolae. These results demonstrate the strong specificity of DNA targeting through the CD44 receptor using HA of high molecular weight as a ligand. PMID- 22820452 TI - Release pathways of interferon alpha2a molecules from lipid twin screw extrudates revealed by single molecule fluorescence microscopy. AB - The pathways of interferon alpha2a release from a triglyceride based implant system were studied by single molecule fluorescence microscopy. The protein was labeled with a stable fluorescent dye ATTO647N, freeze-dried and embedded into the lipid matrix via twin-screw extrusion. The implant system consisted of a pore forming agent (water soluble PEG 6000) and two types of triglycerides with different melting ranges which allowed the production of the implants at moderate temperatures and without the use of organic solvents. Single molecule microscopy and single particle tracking of labeled proteins contained in these implants revealed that two populations of diffusing proteins were present. Moreover, proteins were not only released via water-filled pores (created by dissolution of the pore-former), but surprisingly also through diffusion in a phase of molten lipid. Diffusion coefficients of IFNalpha 2a derived by tracking of individual protein molecules within the implant system were similar to diffusion coefficients obtained from control measurements in pure molten lipid and highly concentrated solutions of PEG 6000. In conclusion, tracking of individual protein molecules was successfully used to elucidate the release pathways of proteins from a relevant lipid based implant system. PMID- 22820453 TI - How obstructing is an obstacle? The influence of starting posture on obstacle avoidance. AB - The introduction of non-target objects into a workspace leads to temporal and spatial adjustments of reaching trajectories towards a target. Currently, there are two different explanations for this phenomenon: the non-target objects are considered as either physical obstacles to which we maintain a preferred distance (see Tresilian, 1998) or as distractors that interfere with movement planning (see Tipper, Howard, & Jackson, 1997). These components are difficult to disentangle, however. Our aim was to determine the unique contribution of the avoidance of a physical obstacle to the adjustments of reaching trajectories. In this study, we manipulate the degree of physical obstruction by non-target objects while keeping the a priori visual layout of the workspace more or less constant. This is achieved by placing participants in different starting postures with respect to the orientation of their limb segments. Participants reach towards and grasp target objects with non-targets present in the workspace in a frontal and a lateral starting posture. In the frontal conditions participants showed larger movements away from the non-target on the ipsilateral side of the workspace than in the lateral conditions. The results provide evidence for the interpretation that non-targets influence the movement trajectory partly because they are 'obstructing'. PMID- 22820454 TI - A matter of time: antecedents of one-reason decision making based on recognition. AB - The notion of adaptive decision making implies that strategy selection in both inferences and preferences is driven by a trade-off between accuracy and effort. A strategy for probabilistic inferences which is particularly attractive from this point of view is the recognition heuristic (RH). It proposes that judgments rely on recognition in isolation-ignoring any further information that might be available-and thereby allows for substantial effort-reduction. Consequently, it is herein hypothesized that and tested whether increased necessity of effort reduction-as implemented via time pressure-fosters reliance on the RH. Two experiments corroborated that this was the case, even with relatively mild time pressure. In addition, this result held even when non-compliance with the response deadline did not yield negative monetary consequences. The current investigations are among the first to tackle the largely open question of whether effort-related factors influence the reliance on heuristics in memory-based decisions. PMID- 22820455 TI - Parafoveal semantic information extraction in traditional Chinese reading. AB - Semantic information extraction from the parafovea has been reported only in simplified Chinese for a special subset of characters and its generalizability has been questioned. This study uses traditional Chinese, which differs from simplified Chinese in visual complexity and in mapping semantic forms, to demonstrate access to parafoveal semantic information during reading of this script. Preview duration modulates various types (identical, phonological, and unrelated) of parafoveal information extraction. Parafoveal semantic extraction is more elusive in English; therefore, we conclude that such effects in Chinese are presumably caused by substantial cross-language differences from alphabetic scripts. The property of Chinese characters carrying rich lexical information in a small region provides the possibility of semantic extraction in the parafovea. PMID- 22820456 TI - The perception and representation of orientations: a study in the haptic modality. AB - This research examines the haptic perception of orientations in the frontal plane in order to identify the nature of their representation. Blindfolded participants inserted the tip of the index finger into a thimble mounted on the extremity of a haptic interface and manually explored the orientation of a "virtual rod". After a short delay, participants had to reproduce the scanned orientation with the same hand without the guidance of the virtual rod. The analysis of the systematic errors showed that the recalled orientations were markedly biased toward the nearest diagonal in each quadrant with the exception of the orientations nearest to the vertical, which were biased toward the vertical. The variable error was greater for the oblique orientations than for the horizontal or vertical orientation. These results are interpreted with the Category-Adjustment model, which posits that orientations are categorically represented. We show that it is necessary to assume the existence of vertical and horizontal categories in addition to the previously postulated oblique categories to predict the error patterns observed in the present and former studies. The similarity of the error patterns in the visual and haptic modalities suggests that a common mechanism is at play in perceiving and reproducing orientations in both sensory modalities. PMID- 22820457 TI - A familial case with interstitial 2q36 deletion: variable phenotypic expression in full and mosaic state. AB - Submicroscopic chromosomal anomalies play an important role in the etiology of craniofacial malformations, including midline facial defects with hypertelorism (MFDH). MFDH is a common feature combination in several conditions, of which Frontonasal Dysplasia is the most frequently encountered manifestation; in most cases the etiology remains unknown. We identified a parent to child transmission of a 6.2 Mb interstitial deletion of chromosome region 2q36.1q36.3 by array-CGH and confirmed by FISH and microsatellite analysis. The patient and her mother both presented an MFDH phenotype although the phenotype in the mother was much milder than her daughter. Inspection of haplotype segregation within the family of 2q36.1 region suggests that the deletion arose on a chromosome derived from the maternal grandfather. Evidences based on FISH, microsatellite and array-CGH analysis point to a high frequency mosaicism for presence of a deleted region 2q36 occurring in blood of the mother. The frequency of mosaicism in other tissues could not be determined. We here suggest that the milder phenotype observed in the proband's mother can be explained by the mosaic state of the deletion. This most likely arose by an early embryonic deletion in the maternal embryo resulting in both gonadal and somatic mosaicism of two cell lines, with and without the deleted chromosome. The occurrence of gonadal mosaicism increases the recurrence risk significantly and is often either underestimated or not even taken into account in genetic counseling where new mutation is suspected. PMID- 22820459 TI - Matrix production and remodeling capacity of cardiomyocyte progenitor cells during in vitro differentiation. AB - Cell-based therapy has emerged as a treatment modality for myocardial repair. Especially cardiac resident stem cells are considered a potential cell source since they are able to differentiate into cardiomyocytes and have improved heart function after injury in a preclinical model for myocardial infarction. To avoid or repair myocardial damage it is important not only to replace the lost cardiomyocytes, but also to remodel and replace the scar tissue by "healthy" extracellular matrix (ECM). Interestingly, the role of cardiac stem cells in this facet of cardiac repair is largely unknown. Therefore, we investigated the expression and production of ECM proteins, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in human cardiomyocyte progenitor cells (CMPCs) undergoing differentiation towards the cardiomyogenic lineage. Our data suggest that CMPCs have the capacity to synthesize and modulate their own matrix environment, especially during differentiation towards the cardiomyogenic lineage. While undifferentiated CMPCs expressed collagen I, III, IV and fibronectin, but no elastin, during the process of differentiation the expression of collagen I, III, IV and fibronectin increased and interestingly also elastin expression was induced. Furthermore, undifferentiated CMPCs express MMP-1 -2 and 9 and upon differentiation the expression of MMP-1 decreased, while the expression of MMP-2 and MMP-9, although the latter only in the early stage of differentiation, increased. Additionally, the expression of TIMP-1, -2 and -4 was induced during differentiation. This study provides new insights into the matrix production and remodeling capacity of human CMPCs, with potential beneficial effects for the treatment of cardiac injury. PMID- 22820460 TI - The effects of sampling on delimiting species from multi-locus sequence data. AB - As a fundamental unit in biology, species are used in a wide variety of studies, and their delimitation impacts every subfield of the life sciences. Thus, it is of utmost importance that species are delimited in an accurate and biologically meaningful way. However, due to morphologically similar, cryptic species, and processes such as incomplete lineage sorting, this is far from a trivial task. Here, we examine the accuracy and sensitivity to sampling strategy of three recently developed methods that aim to delimit species from multi-locus DNA sequence data without a priori assignments of samples to putative species. Specifically, we simulate data at two species tree depths and a variety of sampling strategies ranging from five alleles per species and five loci to 20 alleles per species and 100 loci to test (1) Structurama, (2) Gaussian clustering, and (3) nonparametric delimitation. We find that Structurama accurately delimits even relatively recently diverged (greater than 1.5 N generations) species when sampling 10 or more loci. We also find that Gaussian clustering delimits more deeply divergent species (greater than 2.5 N generations) relatively well, but is not sufficiently sensitive to delimit more recently diverged species. Finally, we find that nonparametric delimitation performs well with 25 or more loci if gene trees are known without error, but performs poorly with estimated gene genealogies, frequently over-splitting species and mis-assigning samples. We thus suggest that Structurama represents a powerful tool for use in species delimitation. It should be noted, however, that intraspecific population structure may be delimited using this or any of the methods tested herein. We argue that other methods, such as other species delimitation methods requiring a priori putative species assignments (e.g. SpeDeSTEM, Bayesian species delimitation), and other types of data (e.g. morphological, ecological, behavioral) be incorporated in conjunction with these methods in studies attempting to delimit species. PMID- 22820461 TI - Reactive oxygen species regulation of autophagy in cancer: implications for cancer treatment. AB - Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases including cancers. Autophagy is one of the first lines of defense against oxidative stress damage. The autophagy pathway can be induced and upregulated in response to intracellular ROS or extracellular oxidative stress. This leads to selective lysosomal self-digestion of intracellular components to maintain cellular homeostasis. Hence, autophagy is the survival pathway, conferring stress adaptation and promoting viability under oxidative stress. However, increasing evidence has demonstrated that autophagy can also lead to cell death under oxidative stress conditions. In addition, altered autophagic signaling pathways that lead to decreased autophagy are frequently found in many human cancers. This review discusses the advances in understanding of the mechanisms of ROS-induced autophagy and how this process relates to tumorigenesis and cancer therapy. PMID- 22820462 TI - Learning from the experts: exploring playground experience and activities using a write and draw technique. AB - BACKGROUND: Qualitative research into the effect of school recess on children's physical activity is currently limited. This study used a write and draw technique to explore children's perceptions of physical activity opportunities during recess. METHODS: 299 children age 7-11 years from 3 primary schools were enlisted. Children were grouped into Years 3 & 4 and Years 5 & 6 and completed a write and draw task focusing on likes and dislikes. Pen profiles were used to analyze the data. RESULTS: Results indicated 'likes' focused on play, positive social interaction, and games across both age groups but showed an increasing dominance of games with an appreciation for being outdoors with age. 'Dislikes' focused on dysfunctional interactions linked with bullying, membership, equipment, and conflict for playground space. Football was a dominant feature across both age groups and 'likes/dislikes' that caused conflict and dominated the physically active games undertaken. CONCLUSION: Recess was important for the development of conflict management and social skills and contributed to physical activity engagement. The findings contradict suggestions that time spent in recess should be reduced because of behavioral issues. PMID- 22820463 TI - The assay design used for measurement of therapeutic antibody concentrations can affect pharmacokinetic parameters: Case studies. AB - To interpret pharmacokinetic (PK) data of biotherapeutics, it is critical to understand which drug species is being measured by the PK assay. For therapeutic antibodies, it is generally accepted that "free" circulating antibodies are the pharmacologically active form needed to determine the PK/pharmacodynamic (PD) relationship, safety margin calculations, and dose projections from animals to humans and the eventual characterization of the exposure in the clinic. However, "total" drug may be important in evaluating the dynamic interaction between the drug and the target, as well as the total drug exposure. In the absence of or with low amounts of soluble ligand/shed receptor, total and free drug species are often equivalent and their detection is less sensitive to assay formats or reagent choices. In contrast, in the presence of a significant amount of ligand, assay design and characterization of assay reagents are critical to understanding the PK profiles. Here, we present case studies where different assay formats affected measured PK profiles and data interpretation. The results from reagent characterizations provide a potential explanation for the observed discrepancies and highlight the importance of reagent characterization in understanding which drug species are being measured to accurately interpret PK parameters. PMID- 22820464 TI - Design and validation of a passive deposition sampler. AB - A new, passive particle deposition air sampler, called the Einstein-Lioy Deposition Sampler (ELDS), has been developed to fill a gap in passive sampling for near-field particle emissions. The sampler can be configured in several ways: with a protective hood for outdoor sampling, without a protective hood, and as a dust plate. In addition, there is an XRF-ready option that allows for direct sampling onto a filter-mounted XRF cartridge which can be used in conjunction with all configurations. A wind tunnel was designed and constructed to test the performance of different sampler configurations using a test dust with a known particle size distribution. The sampler configurations were also tested versus each other to evaluate whether or not the protective hood would affect the collected particle size distribution. A field study was conducted to test the sampler under actual environmental conditions and to evaluate its ability to collect samples for chemical analysis. Individual experiments for each configuration demonstrated precision of the sampler. The field experiment demonstrated the ability of the sampler to both collect mass and allow for the measurement of an environmental contaminant i.e. Cr(6+). The ELDS was demonstrated to be statistically not different for Hooded and Non-Hooded models, compared to each other and the test dust; thus, it can be used indoors and outdoors in a variety of configurations to suit the user's needs. PMID- 22820465 TI - Early involvement of prefrontal cortex in visual bottom-up attention. AB - Visual attention is guided to stimuli either on the basis of their intrinsic saliency against their background (bottom-up factors) or through willful search of known targets (top-down factors). Posterior parietal cortex (PPC) is thought to be important for the guidance of visual bottom-up attention, whereas dorsolateral prefrontal cortex is thought to represent top-down factors. Contrary to this established view, we found that, when monkeys were tested in a task requiring detection of a salient stimulus defined purely by bottom-up factors and whose identity was unknown before the presentation of a visual display, prefrontal neurons represented the salient stimulus no later than those in the PPC. This was true even though visual response latency was shorter in parietal than in prefrontal cortex. These results suggest an early involvement of the prefrontal cortex in the bottom-up guidance of visual attention. PMID- 22820467 TI - Epitaxial growth of graphene on transition metal surfaces: chemical vapor deposition versus liquid phase deposition. AB - The epitaxial growth of graphene on transition metal surfaces by ex situ deposition of liquid precursors (LPD, liquid phase deposition) is compared to the standard method of chemical vapor deposition (CVD). The performance of LPD strongly depends on the particular transition metal surface. For Pt(111), Ir(111) and Rh(111), the formation of a graphene monolayer is hardly affected by the way the precursor is provided. In the case of Ni(111), the growth of graphene strongly depends on the applied synthesis method. For CVD of propene on Ni(111), a 1 * 1 structure as expected from the vanishing lattice mismatch is observed. However, in spite of the nearly perfect lattice match, a multi-domain structure with 1 * 1 and two additional rotated domains is obtained when an oxygen containing precursor (acetone) is provided ex situ. PMID- 22820468 TI - In silico design, synthesis and evaluation of 3'-O-benzylated analogs of salacinol, a potent alpha-glucosidase inhibitor isolated from an Ayurvedic traditional medicine "Salacia". AB - With the aid of an in silico method, alpha-glucosidase inhibitors with far more potent activities than salacinol (1), a potent natural alpha-glucosidase inhibitor isolated from an Ayurvedic traditional medicine Salacia reticulata, have been developed. PMID- 22820466 TI - Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. AB - Amyloid-beta (Abeta) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Abeta and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Abeta-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Abeta-PrP(C) interaction leads to Fyn kinase activation. Soluble Abeta assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Abeta engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Abeta-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Abeta oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease. PMID- 22820469 TI - Bacterial adhesion to unworn and worn silicone hydrogel lenses. AB - PURPOSE: The objective of this study was to determine the bacterial adhesion to various silicone hydrogel lens materials and to determine whether lens wear modulated adhesion. METHODS: Bacterial adhesion (total and viable cells) of Staphylococcus aureus (31, 38, and ATCC 6538) and Pseudomonas aeruginosa (6294, 6206, and GSU-3) to 10 commercially available different unworn and worn silicone hydrogel lenses was measured. Results of adhesion were correlated to polymer and surface properties of contact lenses. RESULTS: S. aureus adhesion to unworn lenses ranged from 2.8 * 10 to 4.4 * 10 colony forming units per lens. The highest adhesion was to lotrafilcon A lenses, and the lowest adhesion was to asmofilcon A lenses. P. aeruginosa adhesion to unworn lenses ranged from 8.9 * 10 to 3.2 * 10 colony forming units per lens. The highest adhesion was to comfilcon A lenses, and the lowest adhesion was to asmofilcon A and balafilcon A lenses. Lens wear altered bacterial adhesion, but the effect was specific to lens and strain type. Adhesion of bacteria, regardless of genera/species or lens wear, was generally correlated with the hydrophobicity of the lens; the less hydrophobic the lens surface, the greater the adhesion. CONCLUSIONS: P. aeruginosa adhered in higher numbers to lenses in comparison with S. aureus strains, regardless of the lens type or lens wear. The effect of lens wear was specific to strain and lens. Hydrophobicity of the silicone hydrogel lens surface influenced the adhesion of bacterial cells. PMID- 22820470 TI - Optical performance of multifocal soft contact lenses via a single-pass method. AB - PURPOSE: A physical model eye capable of carrying soft contact lenses (CLs) was used as a platform to evaluate optical performance of several commercial multifocals (MFCLs) with high- and low-add powers and a single-vision control. METHODS: Optical performance was evaluated at three pupil sizes, six target vergences, and five CL-correcting positions using a spatially filtered monochromatic (632.8 nm) light source. The various target vergences were achieved by using negative trial lenses. A photosensor in the retinal plane recorded the image point-spread that enabled the computation of visual Strehl ratios. The centration of CLs was monitored by an additional integrated en face camera. Hydration of the correcting lens was maintained using a humidity chamber and repeated instillations of rewetting saline drops. RESULTS: All the MFCLs reduced performance for distance but considerably improved performance along the range of distance to near target vergences, relative to the single-vision CL. Performance was dependent on add power, design, pupil, and centration of the correcting CLs. Proclear (D) design produced good performance for intermediate vision, whereas Proclear (N) design performed well at near vision (p < 0.05). AirOptix design exhibited good performance for distance and intermediate vision. PureVision design showed improved performance across the test vergences, but only for pupils >=4 mm in diameter. Performance of Acuvue bifocal was comparable with other MFCLs, but only for pupils >4 mm in diameter. Acuvue Oasys bifocal produced performance comparable with single-vision CL for most vergences. CONCLUSIONS: Direct measurement of single-pass images at the retinal plane of a physical model eye used in conjunction with various MFCLs is demonstrated. This method may have utility in evaluating the relative effectiveness of commercial and prototype designs. PMID- 22820471 TI - Objective measures of the effects of the "Read Without Glasses Method". AB - PURPOSE: The Read Without Glasses Method is a home-based vision training program designed to "avoid, eliminate, or reduce the need for bifocals" in presbyopic patients with 6 minutes of daily vision exercises. The purpose of this study was to objectively measure changes in accommodation and near unaided visual acuity (VA) in emmetropic presbyopes using this program. METHODS: Eight emmetropic presbyopes between 50 and 65 years of age participated in 2 pretreatment and 2 post-treatment visits. Primary outcome measures included near unaided VA (MNREAD acuity chart) and accommodative accuracy at near (Grand Seiko). Pupil size was measured at each visit during accommodative measures to assess the possibility that pupil size may have had an impact on near VA. Subjects were also queried about compliance and use of reading glasses after treatment. RESULTS: Repeated measures analysis of variance showed no significant change in unaided near VA pre or post-treatment (p = 0.956). A statistically significant change in accommodation (0.176 D) was found at visit 3 (p = 0.0098) that did not persist at visit 4; however, this change was not clinically significant. Pupil size did not show significant change across all study visits. Survey results indicated that 87.5% of subjects reported that their near vision was slightly to significantly improved after the use of the program. CONCLUSIONS: The Read Without Glasses Method does not produce clinically or statistically significant changes in unaided near VA and fails to show clinically significant changes in accommodation at near in presbyopic emmetropes despite favorable subjective responses of participants. PMID- 22820472 TI - Have we misinterpreted the study of Hoogerheide et al. (1971)? AB - In 1971, Rempt et al. reported peripheral refraction patterns (skiagrams) along the horizontal visual field in 442 people. Later in the same year, Hoogerheide et al. used skiagrams in combination with medical records to relate skiagrams in emmetropes and hyperopes to progression of myopia in young adults. The two articles have spurred interest in peripheral refraction in the past decade. We challenge the understanding that their articles provide evidence that the peripheral refraction pattern along the horizontal visual field is predictive of whether or not a person develops myopia. First, although it has been generally assumed that the skiagrams were measured before the changes in refraction were monitored, Hoogerheide et al. did not state that this was the case. Second, if the skiagrams were obtained at an initial examination and given the likely rates of recruitment and successful completion of training, the study must have taken place during a period of 10 to 15 years; it is much more likely that Hoogerheide et al. measured the skiagrams in a shorter period. Third, despite there being many more emmetropes and hyperopes in the Rempt et al. article than there are in the Hoogerheide et al. article, the number of people in two types of "at risk" skiagrams is greater in the latter; this is consistent with the central refraction status being reported from an earlier time by Hoogerheide et al. than by Rempt et al. In summary, we believe that the skiagrams reported by Hoogerheide et al. were taken at a later examination, after myopia did or did not occur, and that the refraction data from the initial examination were retrieved from the medical archives. Thus, this work does not provide evidence that peripheral refraction pattern is indicative of the likely development of myopia. PMID- 22820473 TI - Estimating tear film spread and stability through tear hydrodynamics. AB - PURPOSE: The stability and ease of spread of the tear-film over the contact lens surface may be an indicator of contact lens surface dewetting. The present in vivo methods of determining lens dewetting are complex. This study introduces a novel and objective way of determining the upward spread and stability of the tear-film through measurement of tear-film particle dynamics. METHODS: Ten adapted contact lens wearers wore the same type of contact lens. Using a video camera mounted to a slit-lamp, the tear-film spread over the lens surface was recorded after a blink, at 8* magnification and capture rate of 30 frames per second, at morning after lens insertion, and after 8 h of lens wear. Images from 20 videos, without blinks and without an observable change in fixation were analyzed without any further postprocessing of the images. Using a customized calibrated ImageJ macro for particle tracking, the velocity of naturally occurring reflective particles was determined. The results were analyzed using the R program and ProFit. RESULTS: The results established that the upward particle velocity was highest immediately after a blink and declined with time. The spread of the tear film measured through upward particle velocity was different on lens insertion than after 8 h of lens wear (p = 0.001). The exponential time constants +/- SE were 346.02 +/- 29.0 for lens insertion at morning and 1413.13 +/- 419.6 after 8 h of lens wear. CONCLUSIONS: A novel and non-invasive way to measure in vivo spread and stability of the prelens tear-film has been developed. Additional studies are needed to understand whether this simple measure is able to differentiate the performance of different soft contact lenses and how this method may help in the understanding other aspects of lens performance such as non-invasive tear breakup time, surface deposition, and lens comfort. PMID- 22820474 TI - The physics and psychophysics of microperimetry. AB - PURPOSE: To assess the influences of stimulus parameters (physics) on measures of visual field sensitivity (psychophysics). METHODS: Subjects' thresholds were measured on three different clinically available perimeters: the Humphrey Field Analyzer (HFA), the Nidek MP1 (MP1), and the Opko OCT/SLO (OSLO). On all machines, visual field testing was done with a 10-2 spatial distribution of test points, using Goldmann Size III and Size I stimuli, with a presentation time of 200 ms, and using a 4-2 threshold algorithm. RESULTS: All the MP1 and OSLO data fell below the values for the corresponding points on the HFA. For the Goldmann Size III target, the HFA median threshold was 33 dB, whereas the MP1 median threshold was 19 dB and the OLSO, 18 dB. Using the increment intensity values at each dB level for each microperimeter, the data were converted to equivalent HFA dB. Using this conversion, the smallest increment displayed in the MP1 (1.27 cd/m) was equivalent to 34 HFA dB, and the brightest increment displayed by the MP1 was 14 HFA dB (127 cd/m). The smallest increment displayed in the OSLO (1.56 cd/m) was equivalent to 33.1 HFA dB, and the brightest increment displayed by the OSLO was 13.6 HFA dB (137 cd/m). There was good correspondence among these results when compared using equivalent increment threshold units. However, discrepancies in our findings made us acutely aware of the importance of evaluating the consequences of design choices made by the manufacturers. CONCLUSIONS: The findings underscore the need for users to check their assumptions about what the equipment is doing and to always evaluate the psychophysical consequences of the stimuli that are used by a particular instrument. PMID- 22820475 TI - Soft contact lens-related dryness with and without clinical signs. AB - PURPOSE: To report demographics, wearing patterns, and symptoms from soft contact lens (SCL) wearers with significant SCL-related dryness symptoms with and without significant ocular signs of dryness. METHODS: In a multicenter, prospective observational clinical trial, symptomatic SCL wearers reported significant SCL related dryness via self-administered questionnaire of frequency and intensity of dryness after a dry eye (DE) examination. DE etiology was assigned post hoc by an expert panel, and those with and without significant DE-related signs were analyzed by univariate logistic regression. Possible DE etiologies were aqueous tear deficiency, SCL-induced tear instability, meibomian gland dysfunction, or "other." Wearers without signs that qualified for any DE etiology were designated as No DE Signs (NDES). RESULTS: Of the 226 SCL symptomatic wearers examined, 23% were without signs, 30% had aqueous tear deficiency, 25% had SCL-induced tear instability, 14% had meibomian gland dysfunction, and 8% had "other" diagnoses. The NDES wearers had significantly longer pre-lens break-up time (9.8 vs. 6.6 s, p < 0.0001), better lens wetting (3.4 vs. 2.4 0 to 4 scale, p < 0.0001), lower levels of film deposits on lenses (0.45 vs. 0.92, 0 to 4 scale, p < 0.0001), and of most slit lamp signs. The NDES wearers were significantly more likely to be male (36% vs.19%, p = 0.013), were less likely to have deteriorating comfort during the day (81% vs. 97%, p = 0.001), reported longer average hours of comfortable wear (11 +/- 3 vs. 9 +/- 4 h, p = 0.014), had older contact lenses (18 +/- 14 vs. 13 +/- 12 days, p = 0.029), and greater intensity of photophobia early and late in the day (p = 0.043 and 0.021). CONCLUSIONS: Symptoms of dryness in SCL wearers stem from a variety of underlying causes. However, nearly one quarter of these symptomatic SCL wearers appear to be free of signs of dryness. The effective management of CL-related dryness requires a comprehensive range of clinical assessments and the use of a diverse range of management strategies. PMID- 22820477 TI - Familial screening in Wilson's disease: think at the previous generation! PMID- 22820476 TI - Intraocular pressure and central corneal thickness in the COMET cohort. AB - PURPOSE: To describe intraocular pressure (IOP) and central corneal thickness (CCT) in ethnically diverse, myopic young adults enrolled in COMET (the Correction of Myopia Evaluation Trial) and their association with ocular and demographic factors. METHODS: IOP (Goldmann tonometry), CCT (handheld pachymetry), refractive error (cycloplegic autorefraction), and ocular components (A-scan ultrasonography) were measured in 385 of the original 469 subjects (mean age = 20.3 +/- 1.3 years). Summary statistics for descriptive analysis, Pearson correlation coefficients, and linear regression models to formally test the association of IOP and CCT with other covariates were used. RESULTS: Mean IOP was 15.1 +/- 0.1 mm Hg and differed by ethnicity and CCT but did not vary by gender, magnitude of myopia, or vitreous chamber depth (VCD). Adjusting for CCT, IOP in black participants was 1.8 mm Hg higher than in Hispanics (p = 0.0001) and 0.8 mm Hg higher than in whites (p = 0.03). Mean CCT was 562.4 +/- 1.8 MUm and differed by ethnicity, VCD, and IOP after adjusting for covariates. Blacks had thinner corneas than Asians, whites, and Hispanics, with adjusted differences of 15.4, 11.8, and 15.3 MUm (p = 0.03, < 0.01 and < 0.01), respectively. Eyes with shorter VCD (<17.8 mm) had 8.0-MUm thinner CCT (p = 0.03). CCT did not vary by gender or magnitude of myopia. Overall, a modest positive correlation (r = 0.25, P < 0.0001) was found between IOP and CCT, which varied by ethnicity in Asians (r = 0.47; p = 0.008), blacks (r = 0.29; p = 0.002), and whites (r = 0.24; p = 0.002). CONCLUSIONS: Myopic, black young adults had higher IOP and thinner corneas relative to other ethnic groups, suggesting that evaluation of these parameters during routine examination of these individuals should begin at a young age. Their thinner CCT should also be considered in evaluations for refractive surgery. PMID- 22820478 TI - Regular coffee but not espresso drinking is protective against fibrosis in a cohort mainly composed of morbidly obese European women with NAFLD undergoing bariatric surgery. AB - BACKGROUND & AIMS: The aim of this study was to determine the influence of coffee and other caffeinated drinks on liver fibrosis of severely obese European patients. METHODS: A specific questionnaire exploring various types of coffee (regular filtrated coffee and espresso), caffeinated drinks, and chocolate was filled in by 195 severely obese patients. All patients had liver biopsies that were analyzed according to the NASH Clinical Research Network Scoring System. Univariate and multivariate analyses of significant fibrosis were performed. RESULTS: Caffeine came mainly from coffee-containing beverages (77.5%). Regular coffee and espresso were consumed in 30.8% and 50.2% of the patients, respectively. Regular coffee, espresso, and total caffeine consumption was similar between patients with and without NASH. While consumption of espresso, caffeinated soft drinks, and chocolate was similar among patients, with respect to the level of fibrosis, regular coffee consumption was lower in patients with significant fibrosis (F >=2). According to logistic regression analysis, consumption of regular coffee was an independent protective factor for fibrosis (OR: 0.752 [0.578-0.980], p=0.035) in a model including level of AST (OR: 1.04 [1.004-1.076], p=0.029), presence of NASH (OR: 2.41 [1.007-5.782], p=0.048), presence of the metabolic syndrome (NS), and level of HOMA-IR (NS). Espresso, but not regular coffee consumption was higher in patients with lower HDL cholesterol level, higher triglyceride level, and the metabolic syndrome. CONCLUSIONS: Consumption of regular coffee but not espresso is an independent protective factor for liver fibrosis in severely obese European patients. PMID- 22820479 TI - Adenoviral dominant-negative soluble PDGFRbeta improves hepatic collagen, systemic hemodynamics, and portal pressure in fibrotic rats. AB - BACKGROUND & AIMS: Platelet-derived growth factor (PDGF) is the most potent stimulus for proliferation and migration of stellate cells. PDGF receptor beta (PDGFRbeta) expression is an important phenotypic change in myofibroblastic cells that mediates proliferation and chemotaxis. Here we analyzed the relationship between PDGFRbeta expression, hemodynamic deterioration, and fibrosis in CCl(4) treated rats. Thereafter, we investigated the effects produced by an adenovirus encoding a dominant-negative soluble PDGFRbeta (sPDGFRbeta) on hemodynamic parameters, PDGFRbeta signaling pathway, and fibrosis. METHODS: Mean arterial pressure, portal pressure, PDGFRbeta mRNA expression, and hepatic collagen were assessed in 6 controls and 21 rats induced to hepatic fibrosis/cirrhosis. Next, 30 fibrotic rats were randomized into three groups receiving iv saline and an adenovirus encoding for sPDGFRbeta or beta-galactosidase. After 7days, mean arterial pressure, portal pressure, serum sPDGFRbeta, and hepatic collagen were measured. RESULTS: CCl(4)-treated animals for 18weeks showed a significantly higher increase in PDGFRbeta mRNA compared to those treated for 13weeks and control rats. In CCl(4)-treated rats, the fibrous tissue area ranged from moderate to severe fibrosis. A direct relationship between the degree of fibrosis, hemodynamic changes, and PDGFRbeta expression was observed. Fibrotic rats transduced with the adenovirus encoding sPDGFRbeta showed increased mean arterial pressure, decreased portal pressure, lower activation of the PDGFRbeta signaling pathway, and reduced hepatic collagen than fibrotic rats receiving beta galactosidase or saline. CONCLUSIONS: PDGFRbeta activation closely correlates with hemodynamic disorders and increased fibrosis in CCl(4)-treated rats. Adenoviral dominant negative soluble PDGFRbeta improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated. PMID- 22820480 TI - Multipotent stem/progenitor cells in the human foetal biliary tree. AB - BACKGROUND & AIMS: Biliary tree, liver, and pancreas share a common embryological origin. We previously demonstrated the presence of stem/progenitor cells of endodermal origin in the adult human extrahepatic biliary tree. This study evaluated the human foetal biliary trees as sources of stem/progenitor cells of multiple endodermal-derived mature fates. METHODS: Human foetal intrahepatic and extrahepatic biliary tree tissues and isolated cells were tested for cytoplasmic and surface markers of stem cells and committed progenitors, as well as endodermal transcription factors requisite for a liver versus pancreatic fate. In vitro and in vivo experiments were conducted to evaluate the potential mature fates of differentiation. RESULTS: Foetal biliary tree cells proliferated clonogenically for more than 1 month on plastic in a serum-free Kubota medium. After culture expansion, cells exhibited multipotency and could be restricted to certain lineages under defined microenvironments, including hepatocytes, cholangiocytes, and pancreatic islet cells. Transplantation of foetal biliary tree cells into the livers of immunodeficient mice resulted in effective engraftment and differentiation into mature hepatocytes and cholangiocytes. CONCLUSIONS: Foetal biliary trees contain multipotent stem/progenitor cells comparable with those in adults. These cells can be easily expanded and induced in vitro to differentiate into liver and pancreatic mature fates, and engrafted and differentiated into mature cells when transplanted in vivo. These findings further characterise the development of these stem/progenitor cell populations from foetuses to adults, which are thought to contribute to liver and pancreas organogenesis throughout life. PMID- 22820481 TI - New polymer-halloysite hybrid materials--potential controlled drug release system. AB - New hybrid materials based on a natural host (halloysite), biodegradable polymer (poly(vinyl alcohol)) and diphenhydramine hydrochloride as drug were synthesized and tested as a potential controlled drug delivery system. The formation of these hybrid materials was proved using different characterization methods like Spectroscopic techniques (FTIR, XPS and UV-vis), thermogravimetrical analysis and scanning electron microscopy (SEM). The hybrid materials exhibit different features regarding the drug release. In vitro drug release tests showed that there are several factors which exhibit a strong influence on the drug release rate. Thus the initial drug concentration used at the hybrid materials synthesis, the presence of a polymer in the hybrid composition and the pH value of the release medium are the most important factors. PMID- 22820482 TI - Drug delivery to inflamed colon by nanoparticles: comparison of different strategies. AB - For inflammatory bowel disease (IBD) treatment, local delivery of molecules loaded in nanoparticles to the inflamed colon could be a promising strategy. The aim of this study was to investigate how drug-loaded polymeric nanoparticles target the site of inflammation and to analyse the influence of different colon specific delivery strategies. Three different polymeric nanoparticles were formulated using ovalbumin (OVA) as a model drug. pH-sensitive nanoparticles were made with Eudragit((r)) S100. Mucoadhesive nanoparticles were created with trimethylchitosan (TMC). A mix of polymers, PLGA, PEG-PLGA and PEG-PCL, were used to obtain a sustained drug delivery. Furthermore, ligands targeting immune cells (i.e. mannose) or the inflamed colon (i.e. a specific peptide) were grafted on the PEG chain of PCL. Interaction of nanoparticles with the intestinal epithelium was explored using Caco-2 monolayers designed to mimic an inflamed epithelium and then visualized using confocal laser microscopy. TMC nanoparticles had the highest apparent permeability for OVA in the untreated model. However, in the inflamed model, there were no difference between TMC, PLGA-based and Eudragit((r)) nanoparticles. The uptake of nanoparticles in the inflamed mouse colon was assessed in a horizontal diffusion chamber. Mannose-grafted PLGA nanoparticles showed the highest accumulation of OVA in inflamed colon. Based on these results, active targeting of macrophages and dendritic cells may be a promising approach for targeting the colon in IBD. PMID- 22820483 TI - How individual genetic test disclosure may affect population health. PMID- 22820484 TI - Parents trust other parents: lay vaccination narratives on the Web may create doubt about vaccination safety. PMID- 22820485 TI - Truvada PrEP: why I voted "yes". PMID- 22820486 TI - Effect of therapeutic touch on brain activation of preterm infants in response to sensory punctate stimulus: a near-infrared spectroscopy-based study. AB - OBJECTIVE: The purpose of this study was to determine whether therapeutic touch in preterm infants can ameliorate their sensory punctate stimulus response in terms of brain activation measured by near-infrared spectroscopy. METHODS: The study included 10 preterm infants at 34-40 weeks' corrected age. Oxyhaemoglobin (Oxy-Hb) concentration, heart rate (HR), arterial oxygen saturation (SaO2) and body movements were recorded during low-intensity sensory punctate stimulation for 1 s with and without therapeutic touch by a neonatal development specialist nurse. Each stimulation was followed by a resting phase of 30 s. All measurements were performed with the infants asleep in the prone position. RESULTS: sensory punctate stimulus exposure significantly increased the oxy-Hb concentration but did not affect HR, SaO2 and body movements. The infants receiving therapeutic touch had significantly decreased oxy-Hb concentrations over time. CONCLUSIONS: Therapeutic touch in preterm infants can ameliorate their sensory punctate stimulus response in terms of brain activation, indicated by increased cerebral oxygenation. Therefore, therapeutic touch may have a protective effect on the autoregulation of cerebral blood flow during sensory punctate stimulus in neonates. PMID- 22820487 TI - To cool or not to cool? Hypothermia treatment outside trial criteria. AB - Most infants undergoing therapeutic hypothermia for hypoxic-ischaemic encephalopathy fit the clinical criteria used in the main randomised controlled trials. Many infants who would not strictly have qualified for trial entry may nevertheless benefit from hypothermia. These may include infants presenting with postnatal collapse, infants with neonatal stroke and moderately preterm infants. Given the relative safety and potential lifelong benefits of hypothermia treatment, all patients who may benefit from cooling should receive it in a timely and consistent manner. This article reviews several clinical scenarios where cooling may be considered for neuroprotection and provides practical management guidance based on available evidence. The authors emphasise the importance of clear communication with parents and of maintaining national registers to record practices. PMID- 22820488 TI - Causes and implications of colloid and microorganism retention hysteresis. AB - Experiments were designed to better understand the causes and implications of colloid and microorganism retention hysteresis with transients in solution ionic strength (IS). Saturated packed column experiments were conducted using two sizes of carboxyl modified latex (CML) microspheres (0.1 and 1.1 MUm) and microorganisms (coliphage phiX174 and E. coli D21g) under various transient solution chemistry conditions, and 360 MUm Ottawa sand that was subject to different levels of cleaning, namely, a salt cleaning procedure that removed clay particles, and a salt+acid cleaning procedure that removed clay and reduced microscopic heterogeneities due to metal oxides and surface roughness. Comparison of results from the salt and salt+acid treated sand indicated that microscopic heterogeneity was a major contributor to colloid retention hysteresis. The influence of this heterogeneity increased with IS and decreasing colloid/microbe size on salt treated sand. These trends were not consistent with calculated mean interaction energies (the secondary minima), but could be explained by the size of the electrostatic zone of influence (ZOI) near microscopic heterogeneities. In particular, the depth of local minima in the interaction energy has been predicted to increase with a decrease in the ZOI when the colloid size and/or the Debye length decreased (IS increased). The adhesive interaction was therefore largely irreversible for smaller sized 0.1 MUm CML colloids, whereas it was reversible for larger 1.1 MUm CML colloids. Similarly, the larger E. coli D21g exhibited greater reversibility in retention than phiX174. However, direct comparison of CML colloids and microbes was not possible due to differences in size, shape, and surface properties. Retention and release behavior of CML colloids on salt+acid treated sand was much more consistent with mean interaction energies due to reduction in microscopic heterogeneities. PMID- 22820489 TI - Gene silencing by chemically modified siRNAs. AB - RNA interference (RNAi) has not only already risen as a gold standard for validating gene function in basic science studies, but also holds great promise as a new therapeutic paradigm. Advantages of RNAi-based therapeutics include relatively fast initial screening and the ability to target proteins not yet addressable by traditional drug design strategies. In this review we describe the development of chemically modified small inhibiting siRNAs and their application as potential therapeutics during the past decade. Focus is on proper siRNA design, choice of chemical modification and how to circumvent immunogenicity as well as off-target effects. PMID- 22820490 TI - Living donor vs. deceased donor liver transplantation for patients with hepatitis C virus-related diseases. AB - BACKGROUND & AIMS: Living donor liver transplantation (LDLT) provides a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatitis C virus-related (HCV-related) diseases in the circumstances of severe organ dearth. However, the patient and graft outcomes, and recurrence of HCV after LDLT remain controversial. Here we sought to compare the post-transplant outcomes after LDLT and DDLT. METHODS: A systematic review and meta-analysis were performed. PubMed/MEDLINE, EMBASE, and the Cochrane database were searched for eligible literatures. The major end points were patient survival, graft survival, recurrence rate, and acute rejection. The pooled odds ratio (OR) was calculated using random-effects model to synthesize the results. Heterogeneity and publication bias were quantitatively evaluated. RESULTS: Fourteen studies with a total of 2024 participants were included in this analysis. We found comparable patient survival between groups (1-year: OR, 0.78, 95% CI, 0.48-1.26, p=0.31; 2 year: OR, 0.71, 95% CI, 0.41-1.23, p=0.23; 3-year: OR, 0.79, 95% CI, 0.5-1.12, p=0.18; 4-year: OR, 0.92, 95% CI, 0.43-1.95, p=0.83; 5-year: OR, 1.06, 95% CI, 0.53-2.14, p=0.86, respectively). Although 1- and 3-year graft survivals were inferior in LDLT, 2-, 4- and 5-year graft survivals were similar. HCV recurrence rates and acute rejection rates were equivalent. CONCLUSIONS: LDLT was equivalent to DDLT in terms of patient survival, long-term graft survival, HCV recurrence, and acute rejection rates, with potentially lower short-term patient and graft survival. PMID- 22820491 TI - Modeling evolutionary growth of a microRNA-mediated regulation system. AB - Gene duplication plays a crucial role in the development of complex biosystems, but the evolutionary forces behind the growth of biosystems are poorly understood. In this work, we introduce a model for such a growth through gene duplication. Plant microRNAs (miRNAs) are considered as a model. miRNAs are one of the non-coding small RNAs (19-25 nucleotides), which are involved in the post transcriptional gene regulation. A single kind of miRNAs can be encoded by multiple genomic regions called miRNA genes, and can regulate multiple kinds of functional gene families. It is assumed that a single miRNA system involves all these genes, miRNA genes and their target gene families. We are interested in how duplication of miRNA genes affects the evolution of the miRNA system by focusing on the numbers of miRNA genes and their target gene families, denoted by x and y, respectively. We here theoretically explore the evolutionary growth of (x,y); the former increases by duplication of the miRNA gene while the latter increases when an independent gene family acquires a novel binding site of the miRNA by mutations. We first investigate the evolutionary patterns of (x,y) under three commonly assumed scenarios for the evolution of duplicated genes, that is, the positive and negative dosage and neofunctionalization scenarios. The results indicate that under the three scenarios, the transient process of (x,y) is unidirectional, although the direction is different depending on the model. This pattern is not consistent with the observation in the Arabidopsis thaliana genome, suggesting that a model that incorporates at least two directional evolutionary forces is needed to explain the observation. Then, such a model called the "complexity growth model" is introduced, in which we assume that duplication of miRNA genes is evolutionary advantageous in that the system can encode a complex and sophisticated pattern of regulation because multiple miRNA genes can have different expression patterns. This is helpful to optimize the regulation of a few particular functional gene families, but there is a cost; once the system is optimized for one purpose, it could be difficult for other purposes to use it. That is, duplication of miRNA genes would narrow down the potential gene families that can join the system. Our theoretical analysis revealed that this model can explain the observation of Arabidopsis miRNAs. Although we consider plant miRNAs as an example in this work, the model can be readily applied to other regulation systems with some modifications. Further development of such models would provide insights into the evolutionary growth of the complexity of biosystems. PMID- 22820492 TI - Punishment can promote defection in group-structured populations. AB - Pro-social punishment, whereby cooperators punish defectors, is often suggested as a mechanism that maintains cooperation in large human groups. Importantly, models that support this idea have to date only allowed defectors to be the target of punishment. However, recent empirical work has demonstrated the existence of anti-social punishment in public goods games. That is, individuals that defect have been found to also punish cooperators. Some recent theoretical studies have found that such anti-social punishment can prevent the evolution of pro-social punishment and cooperation. However, the evolution of anti-social punishment in group-structured populations has not been formally addressed. Previous work has informally argued that group-structure must favour pro-social punishment. Here we formally investigate how two demographic factors, group size and dispersal frequency, affect selection pressures on pro- and anti-social punishment. Contrary to the suggestions of previous work, we find that anti social punishment can prevent the evolution of pro-social punishment and cooperation under a range of group structures. Given that anti-social punishment has now been found in all studied extant human cultures, the claims of previous models showing the co-evolution of pro-social punishment and cooperation in group structured populations should be re-evaluated. PMID- 22820493 TI - Mechanical growth and morphogenesis of seashells. AB - Seashells grow through the local deposition of mass along the aperture. Many mathematical descriptions of the shapes of shells have been provided over the years, and the basic logarithmic coiling seen in mollusks can be simulated with few parameters. However, the developmental mechanisms underlying shell coiling are largely not understood and the ubiquitous presence of ornamentation such as ribs, tubercles, or spines presents yet another level of difficulty. Here we develop a general model for shell growth based entirely on the local geometry and mechanics of the aperture and mantle. This local description enables us to efficiently describe both arbitrary growth velocities and the evolution of the shell aperture itself. We demonstrate how most shells can be simulated within this framework. We then turn to the mechanics underlying the shell morphogenesis, and develop models for the evolution of the aperture. We demonstrate that the elastic response of the mantle during shell deposition provides a natural mechanism for the formation of three-dimensional ornamentation in shells. PMID- 22820494 TI - Tumor growth modeling based on cell and tumor lifespans. AB - This paper deals with the lifespan modeling of heterogenous tumors treated by radiotherapy. A bi-scale model describing the cell and tumor lifespans by random variables is proposed. First- and second-order moments as well as the cumulative distribution functions and confidence intervals are expressed for the two lifespans with respect to the model parameters. One interesting result is that the mean value of the tumor lifespan can be approached by a logarithmic function of the initial cancer cell number. Moreover, we show that TCP and NTCP, used in radiotherapy to evaluate, optimize and compare treatment plans, can be derived from the tumor lifespan and the surrounding healthy tissue, respectively. Finally, we propose a ROC curve, entitled ECT (Efficiency-Complication Trade off), suited to the selection by clinicians of the appropriate treatment planning. PMID- 22820495 TI - Abstracts of the British Geriatrics Society Spring Meeting. May 16-18, 2012. Llandudno, United Kingdom. PMID- 22820496 TI - Prevalence and correlates of physical activity within on-reserve first nations youth. AB - BACKGROUND: Youth in Canada age 5-17 years require a minimum of 60 minutes of moderate to vigorous physical activity (PA) everyday. Regrettably, there are no published studies on levels of PA within on-reserve First Nations youth in Canada that use validated surveys. The objective was to determine what percentage of Saskatoon Tribal Council (STC) First Nations on-reserve youth met the Canadian Society for Exercise and Physiology's (CSEP) definition for being physically active, and what influences are associated with meeting this standard. METHODS: Students in grades 5-8 within the STC were asked to complete a youth health survey. RESULTS: Only 7.4% of STC youth met CSEP's PA standard. Male youth (13.9%) were more likely to meet the PA standard than female youth (4.1%). Having parents who watch youth participate and who provide transportation to classes, having enough equipment at home, having friends bike or walk to school, participating in physical activity headed by a coach or instructor, and participating in structured classes are associated with meeting the standard. CONCLUSIONS: The prevalence of meeting the PA standard among on-reserve First Nations youth is very low. More research is needed to identify independent risk indicators of being physically inactive. PMID- 22820497 TI - Evidence for the dysregulated expression of TWIST1, TGFbeta1 and SMAD3 in differentiating osteoblasts from primary hip osteoarthritis patients. AB - OBJECTIVE: This study compared human primary osteoblasts derived from hip osteoarthritis (OA) cases against controls (CTLs) to investigate candidate OA disease genes, twist homologue 1 (TWIST1), wingless MMTV integration site family member 5B (WNT5B), transforming growth factor-beta (TGFbeta1) and SMAD family member 3 (SMAD3), during osteoblast differentiation, relative to calcium apposition and elemental mineral composition. MATERIALS & METHODS: Primary osteoblast cultures were generated from intertrochanteric trabecular bone samples from five female primary hip OA cases and five age-matched female CTLs. During a 42-day differentiation time-course, alizarin red stains, energy-dispersive X-ray spectroscopy and real-time RT-polymerase chain reaction (PCR) were used to quantify calcium, elemental composition and gene expression, respectively. Data were analysed using linear mixed effects models and Pearson correlation matrices. RESULTS: Significant differences, correlations and associations were found in OA and CTL osteoblasts between gene and mineral measures. The calcium: phosphorous (Ca:P) ratio was significantly more varied in OA compared to CTL. Calcium apposition, mineral composition as well as TWIST1 and TGFbeta1 mRNA expression changed significantly over time. TWIST1 mRNA expression was elevated and correlated with SMAD3 mRNA levels in the OA cohort during the time-course. Associations were observed between tissue non-specific alkaline phosphatase (TNAP), osteocalcin (OCN), TWIST1, TGFbeta1, SMAD3 mRNA levels and mineral measures in OA against CTL. Temporal differences between SMAD3 mRNA expression and mineral composition were also found in OA. CONCLUSIONS: Dysregulated expression of TWIST1, TGFbeta1 and SMAD3 mRNA observed in OA bone is reflected in the functionality of the osteoblast when these cells are cultured ex vivo. The results presented here are consistent with at least part of the aetiology of primary hip OA deriving from altered intrinsic properties of the osteoblast. PMID- 22820498 TI - Non-destructive evaluation of articular cartilage defects using near-infrared (NIR) spectroscopy in osteoarthritic rat models and its direct relation to Mankin score. AB - OBJECTIVE: The aim of this study was to demonstrate the potential of near infrared (NIR) spectroscopy for categorizing cartilage degeneration induced in animal models. METHOD: Three models of osteoarthritic degeneration were induced in laboratory rats via one of the following methods: (1) menisectomy (MSX); (2) anterior cruciate ligament transection (ACLT); and (3) intra-articular injection of mono-ido-acetate (1 mg) (MIA), in the right knee joint, with 12 rats per model group. After 8 weeks, the animals were sacrificed and tibial knee joints were collected. A custom-made near-infrared (NIR) probe of diameter 5 mm was placed on the cartilage surface and spectral data were acquired from each specimen in the wave number range 4,000-12,500 cm(-1). Following spectral data acquisition, the specimens were fixed and Safranin-O staining was performed to assess disease severity based on the Mankin scoring system. Using multivariate statistical analysis based on principal component analysis and partial least squares regression, the spectral data were then related to the Mankin scores of the samples tested. RESULTS: Mild to severe degenerative cartilage changes were observed in the subject animals. The ACLT models showed mild cartilage degeneration, MSX models moderate, and MIA severe cartilage degenerative changes both morphologically and histologically. Our result demonstrates that NIR spectroscopic information is capable of separating the cartilage samples into different groups relative to the severity of degeneration, with NIR correlating significantly with their Mankin score (R(2) = 88.85%). CONCLUSION: We conclude that NIR is a viable tool for evaluating articular cartilage health and physical properties such as change in thickness with degeneration. PMID- 22820499 TI - Silibinin inhibits Wnt/beta-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. AB - Silibinin is a natural compound isolated from milk thistle seed extracts, and has traditionally been used as a hepatoprotectant. A number of studies have also established the cancer therapeutic and chemopreventive role of silibinin in both in vitro and in vivo models. The low density lipoprotein receptor-related protein 6 (LRP6) is an essential Wnt co-receptor for the Wnt/beta-catenin pathway and represents a promising target for cancer prevention and therapy. In the present study, we found that silibinin was able to repress endogenous LRP6 expression and block Wnt3A-induced LRP6 phosphorylation and Wnt/beta-catenin signaling activation in HEK293 cells. Importantly, silibinin was also able to suppress endogenous LRP6 expression and phosphorylation and block Wnt/beta-catenin signaling in prostate cancer PC-3 and DU-145 cells and breast cancer MDA-MB-231 and T-47D cells. Mechanistically, silibinin inhibited LRP6 promoter activity and decreased LRP6 mRNA levels in prostate and breast cancer cells. Finally, we demonstrated that silibinin displayed anticancer activity with IC(50) values comparable to those shown to suppress LRP6 expression and Wnt/beta-catenin signaling activities in prostate and breast cancer cells. Our data indicate that silibinin is a novel small molecule Wnt/beta-catenin signaling inhibitor by suppressing Wnt co-receptor LRP6 expression at the transcription level, and that the anti-cancer activity of silibinin is associated with its inhibitory effect on Wnt/LRP6 signaling. PMID- 22820501 TI - Small GTPase Rho regulates R-cadherin through Dia1/profilin-1. AB - R-cadherin is a member of the classical cadherins. Though much is known about E cadherin in adherens junction formation in epithelial cells, the role of R cadherin in epithelial cells remains elusive. This study examines regulation of R cadherin adherens junctions by the small GTPase Rho and its downstream effectors in MDA-MB-231 breast cancer cells, MDA-MB-231 cells stably expressing the N terminus of c-Cbl, and MCF10A normal breast epithelial cells. We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells. Importantly, R-cadherin adherens junction formation facilitates a mesenchymal to epithelial-like transition in MDA-MB-231 cells. Additionally, our data suggest an inverse relationship between EGFR signaling and R-cadherin adherens junction formation. Taken together, results from this study indicate that R-cadherin is a critical regulator of epithelial phenotype. PMID- 22820500 TI - Monocyte chemotactic protein-induced protein (MCPIP) promotes inflammatory angiogenesis via sequential induction of oxidative stress, endoplasmic reticulum stress and autophagy. AB - Major diseases such as cardiovascular diseases, rheumatoid arthritis, diabetes, obesity and tumor growth are known to involve inflammation. Inflammatory molecules such as MCP-1, TNF-alpha, IL-1beta and IL-8 are known to promote angiogenesis. MCP-induced protein (MCPIP), originally discovered as a novel zinc finger protein induced by MCP-1, is also induced by other inflammatory agents. MCPIP was shown to mediate MCP-1-induced angiogenesis. Whether angiogenesis induced by other inflammatory agents is mediated via MCPIP is unknown and the molecular mechanisms involved in angiogenesis induced by MCPIP have not been elucidated. The aim of this study was to bridge this gap and delineate the sequential processes involved in angiogenesis mediated via MCPIP. siRNA knockdown of MCPIP was used to determine whether different inflammatory agents, MCP-1, TNF alpha, IL-1beta and IL-8, mediate angiogenesis via MCPIP in human umbilical vein endothelial cells (HUVECs). Chemical inhibitors and specific gene knockdown approach were used to inhibit each process postulated. Oxidative stress was inhibited by apocynin or cerium oxide nanoparticles or knockdown of NADPH oxidase subunit, phox47. Endoplasmic reticulum (ER) stress was blocked by tauroursodeoxycholate or knockdown of ER stress signaling protein IRE-1 and autophagy was inhibited by the use of 3'methyl adenine, or LY 294002 or by specific knockdown of beclin1. Matrigel assay was used as a tool to study angiogenic differentiation induced by inflammatory agents or MCPIP overexpression in HUVECs. Tube formation induced by inflammatory agents, TNF-alpha, IL-1beta, IL 8 and MCP-1 was inhibited by knockdown of MCPIP. Forced MCPIP-expression induced oxidative stress, ER stress, autophagy and angiogenic differentiation in HUVECs. Inhibition of each step caused inhibition of each subsequent step postulated. The results reveal that angiogenesis induced by inflammatory agents is mediated via induction of MCPIP that causes oxidative and nitrosative stress resulting in ER stress leading to autophagy required for angiogenesis. The sequence of events suggested to be involved in inflammatory angiogenesis by MCPIP could serve as possible targets for therapeutic intervention of angiogenesis-related disorders. PMID- 22820502 TI - Leukemia-associated mutations in SHIP1 inhibit its enzymatic activity, interaction with the GM-CSF receptor and Grb2, and its ability to inactivate PI3K/AKT signaling. AB - The inositol 5-phosphatase SHIP1 is a negative regulator of the PI3K/AKT pathway, which is constitutively activated in 50-70% of acute myeloid leukemias (AML). Ten different missense mutations in SHIP1 have been described in 3% of AML patients suggesting a functional role of SHIP1 in AML. Here, we report the identification of two new SHIP1 mutations T162P and R225W that were detected in 2 and 1 out of 96 AML patients, respectively. The functional analysis of all 12 AML-associated SHIP1 mutations, one ALL-associated SHIP1 mutation (Q1076X) and a missense SNP (H1168Y) revealed that two mutations i.e. Y643H and P1039S abrogated the ability of SHIP1 to reduce constitutive PI3K/AKT signaling in Jurkat cells. The loss of function of SHIP1 mutant Y643H which is localized in the inositol phosphatase domain was due to a reduction of the specific activity by 84%. Because all other SHIP1 mutants had a normal enzymatic activity, we assumed that these SHIP1 mutants may be functionally impaired due to a loss of interaction with plasma membrane receptors or adapter proteins. In agreement with this model, we found that the SHIP1 mutant F28L located in the FLVR motif of the SH2 domain was incapable of binding tyrosine-phosphorylated proteins including the GM-CSF receptor and that the SHIP1 mutant Q1076X lost its ability to bind to the C terminal SH3 domain of the adapter protein Grb2. In addition, SHIP1 mutant P1039S which does not reduce PI3K/AKT signaling anymore is located in a PXXP SH3 domain consensus binding motif suggesting that mutation of the conserved proline residue interferes with binding of SHIP1 to a so far unidentified SH3 domain containing protein. In summary, our data indicate that SHIP1 mutations detected in human leukemia patients impair the negative regulatory function of SHIP1 on PI3K/AKT signaling in leukemia cells either directly by reduced enzymatic activity or indirectly by disturbed protein interaction with tyrosine-phosphorylated membrane receptors or adapter proteins. These results further support a functional role of SHIP1 as tumor suppressor protein in the pathogenesis of AML. PMID- 22820503 TI - Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells. AB - The small GTPase RalA has been implicated in glucose uptake in insulin-stimulated adipocytes, although it remains unclear whether RalA has a similar role in insulin signaling in other types of cells. Recently, we have demonstrated that the Rho family GTPase Rac1 has a critical role in insulin-dependent glucose uptake in myoblast culture and mouse skeletal muscle. However, the mechanisms underlying Rac1-dependent glucose uptake, mostly mediated by the plasma membrane translocation of the glucose transporter GLUT4, remain largely unknown. The purpose of this study is to examine the involvement of RalA in Rac1 regulation of the translocation of GLUT4 to the plasma membrane in muscle cells. Ectopic expression of a constitutively activated RalA mutant indeed stimulated GLUT4 translocation, suggesting an important role of RalA also in muscle cells. GLUT4 translocation induced by constitutively activated mutation of Rac1 or more physiologically by upstream Rac1 regulators, such as phosphoinositide 3 kinase and the guanine nucleotide exchange factor FLJ00068, was abrogated when the expression of RalA was downregulated by RNA interference. The expression of constitutively activated Rac1, on the other hand, caused GTP loading and subcellular redistribution of RalA. Collectively, we propose a novel mechanism involving RalA for Rac1-mediated GLUT4 translocation in skeletal muscle cells. PMID- 22820504 TI - Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. AB - Previous studies have indicated that bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired proliferation, differentiation, and immune modulation capacities. Thus, MSCs may be associated with the pathogenesis of SLE. The aim of this study was to determine whether MSCs from SLE patients were senescent and to determine the mechanism underlying this phenomenon. MSCs from both untreated and treated SLE patients showed characteristics of senescence. The expression of p16(INK4A) was significantly increased, whereas levels of CDK4, CDK6 and p-Rb expression were decreased in the MSCs from both untreated and treated SLE patients. Knockdown of p16(INK4A) expression reversed the senescent features of MSCs and upregulated TGF beta expression. In vitro, when purified CD4+ T cells were incubated with p16(INK4A)-silenced SLE MSCs, the percentage of regulatory T cells was significantly increased. Further, we have found that p16(INK4A) promotes MSC senescence via the suppression of the extracellular signal regulated kinase (ERK) pathway. p16(INK4A) knockdown up-regulated ERK1/2 activation. Our results demonstrated that MSCs from SLE patients were senescent and that p16 (INK4A) plays an essential role in the process by inhibiting ERK1/2 activation. PMID- 22820505 TI - Clenbuterol upregulates histone demethylase JHDM2a via the beta2 adrenoceptor/cAMP/PKA/p-CREB signaling pathway. AB - BACKGROUND: beta(2)-Adrenergic receptor (beta(2)-AR) signaling activated by the agonist clenbuterol is important in the metabolism of muscle and adipose cells. Additionally, the significant role of histone demethylase JHDM2a in regulating metabolic gene expression was also recently demonstrated in Jhdm2a(-/-) mice. To elucidate the molecular mechanism involved in clenbuterol-induced adipocyte reduction from an epigenetic perspective, this study focused on cAMP-responsive element binding protein (CREB) to determine whether JHDM2a is regulated by the beta(2)-AR/cAMP/protein kinase A (PKA) signaling pathway. RESULTS: In porcine tissues treated with clenbuterol, JHDM2a expression was upregulated, and in porcine cells, expression of exogenous CREB led to increased JHDM2a expression. In addition, changes in JHDM2a expression were coincident with variations in the phosphorylation of CREB and p-CREB/CBP interaction in porcine and human cells treated with drugs known to modify the beta(2)-AR/cAMP/PKA pathway. Finally, binding assays demonstrated that CREB regulated JHDM2a by binding directly to the CRE site nearest to the transcription start site. CONCLUSION: Our results reveal that clenbuterol activates the beta(2)-AR signaling pathway upstream of JHDM2a and that CREB acts as an intermediate link regulated by cAMP-PKA to induce activity of the JHDM2a promoter. These findings suggest that clenbuterol decreases adipose cell size and increases muscle fiber size in porcine tissues by virtue of JHDM2a-mediated demethylation, which regulates downstream metabolic and related genes. PMID- 22820506 TI - Down-regulation of estrogen receptor alpha (ERalpha) transcriptional activity by p27 is mediated by inhibition of ERalpha nuclear localization and modulation of the ERalpha transcriptional complex. AB - To investigate the role of p27 on estrogen receptor (ER)alpha-mediated transcription, we generated MCF-7 cells with knocked down p27 via retroviral delivery of p27 shRNA. Suppression of p27 expression in MCF-7 cells resulted in up-regulation of ERalpha-mediated transcription by estradiol compared to the levels in control MCF-7 cells. Accordingly, transient transfection studies in 293T cells revealed that overexpression of p27 reduced ERalpha-mediated transcription. The effect of p27 on ERalpha transcriptional activity was independent of cell cycle arrest by p27, as cell cycle arrest induced by serum starvation did not significantly affect ERalpha-mediated transcription. Further, we observed that p27 inhibited nuclear localization of ERalpha, and that p27 was associated with ERalpha in the cytoplasm. We also investigated the role of p27 in the modulation of ERalpha transcriptional activity in the nucleus. We found that p27 negatively modulated ERalpha transcriptional activity by inhibiting association of cyclin D1 with ERalpha and recruiting BRCA1 to ERalpha transcriptional complex. Taken together, these data suggest that p27 inhibits ERalpha transcriptional activity by two independent mechanisms, namely, physical nuclear exclusion of ERalpha, and modulation of the ERalpha transcriptional complex. PMID- 22820507 TI - Role of Ca2+ in proteolysis-inducing factor (PIF)-induced atrophy of skeletal muscle. AB - Proteolysis-inducing factor (PIF) induces muscle loss in cancer cachexia through a high affinity membrane bound receptor. This study investigates the mechanism by which the PIF receptor communicates to intracellular signalling pathways. C(2)C(12) murine myoblasts were used as a model using PIF purified from MAC16 tumours. Calcium imaging was determined using fura-4-acetoxymethyl ester (Fura-4 AM). PIF induced a rapid rise in Ca(2+)(i), which was completely attenuated by a anti-receptor antibody, or peptides representing 20 mers of the N-terminus of the PIF receptor. Other agents catabolic for skeletal muscle including angiotensin II (AngII) tumour necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS) also induced a rise in Ca(2+)(i), but this was not attenuated by anti-PIF receptor antibody. The rise in Ca(2+)(i) induced by PIF and AngII was completely attenuated by the Zn(2+) chelator D-myo-inositol-1,2,6-triphosphate, and this was reversed by administration of exogenous Zn(2+). The Ca(2+)(i) rise induced by PIF was independent of the presence of extracellular Ca(2+), and attenuated by the Ca(2+) pump inhibitor thapsigargin, suggesting that the Ca(2+)(i) rise was due to release from intracellular stores. This rise in Ca(2+)(i) induced by PIF was attenuated by both the phospholipase C inhibitor U73122 and 2-APB, an inhibitor of the inositol 1,4,5-triphosphate receptor, suggesting the involvement of a G protein. Binding of the PIF to its receptor in skeletal muscle triggers a rise in Ca(2+)(i), which initiates a signalling cascade leading to a depression in protein synthesis, and an increase in protein degradation. PMID- 22820508 TI - High-yield boron nitride nanosheets from 'chemical blowing': towards practical applications in polymer composites. AB - An improved 'chemical blowing' route presuming atmospheric-pressure pre-treatment and moderate heating rate of designated precursors was developed to synthesize ultra-thin boron nitride (BN) nanosheets with high yield and large lateral dimensions. The yield reached as high as 40 wt% with respect to raw materials (ammonia borane). The strong oxygen-related ultraviolet luminescence together with a blue emission of these BN nanosheets was then documented and analyzed. This implies potential applications in solid-state lighting, ultraviolet lasing and full-color luminescence. Mechanical strength of different polymeric composites with a small fraction of BN nanosheet fillers was dramatically increased by tens of per cent, while high transparency of composite materials was still maintained in the visible optical range. The increased yield and reduced cost of BN nanosheets should promote their wide practical applications in various composites. PMID- 22820509 TI - Trifunctional antibody ertumaxomab: Non-immunological effects on Her2 receptor activity and downstream signaling. AB - BACKGROUND: The trifunctional antibody ertumaxomab bivalently targets the human epidermal growth factor receptor 2 (Her2) on epithelial (tumor) cells and the T cell specific CD3 antigen, and its Fc region is selectively recognized by Fcgamma type I/III receptor-positive immune cells. As a trifunctional immunoglobulin, ertumaxomab therefore not only targets Her2 on cancer cells, but also triggers immunological effector mechanisms mediated by T and accessory cells (e.g., macrophages, dendritic cells, natural killer cells). Whether molecular effects, however, might contribute to the cellular antitumor efficiency of ertumaxomab are largely unknown. METHODS: Potential molecular effects of ertumaxomab on Her2 overexpressing BT474 and SK-BR-3 breast cancer cells were evaluated. The dissociation constant Kd of ertumaxomab was calculated from titration curves that were recorded by flow cytometry. Treatment-induced changes in Her2 homodimerization were determined by flow cytometric fluorescence resonance energy transfer measurements on a cell-by-cell basis. Potential activation / deactivation of Her2, ERK1/2, AKT and STAT3 were analyzed by western blotting, Immunochemistry and immunofluorescent cell staining. RESULTS: The Kd of ertumaxomab for Her2-binding was determined at 265 nM and the ertumaxomab binding epitope was found to not overlap with that of the therapeutic anti-Her2 monoclonal antibodies trastuzumab and pertuzumab. Ertumaxomab caused an increase in Her2 phosphorylation at higher antibody concentrations, but changed neither the rate of Her2-homodimerization /-phosphorylation nor the activation state of key downstream signaling proteins analyzed. CONCLUSIONS: The unique mode of action of ertumaxomab, which relies more on activation of immune-mediated mechanisms against tumor cells compared with currently available therapeutic antibodies for breast cancer treatment, suggests that modular or sequential treatment with the trifunctional bivalent antibody might complement the therapeutic activity of other anti-Her2/anti-ErbB receptor reagents. PMID- 22820510 TI - G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. AB - AIMS/HYPOTHESIS: Activation of the G protein-coupled receptor (GPR)40 by long chain fatty acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to the G protein subunit Galpha(q/11) but the signalling cascade activated downstream is unknown. This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS by fatty acids. METHODS: Insulin secretion in response to glucose, oleate or diacylglycerol (DAG) was assessed in dynamic perifusions and static incubations in islets from wild-type (WT) and Gpr40 (-/-) mice. Depolymerisation of filamentous actin (F-actin) was visualised by phalloidin staining and epifluorescence. Pharmacological and molecular approaches were used to ascertain the roles of protein kinase D (PKD) and protein kinase C delta in GPR40-mediated potentiation of GSIS. RESULTS: Oleate potentiates the second phase of GSIS, and this effect is largely dependent upon GPR40. Accordingly, oleate induces rapid F-actin remodelling in WT but not in Gpr40 (-/-) islets. Exogenous DAG potentiates GSIS in both WT and Gpr40 (-/-) islets. Oleate induces PKD phosphorylation at residues Ser-744/748 and Ser-916 in WT but not Gpr40 (-/-) islets. Importantly, oleate-induced F-actin depolymerisation and potentiation of GSIS are lost upon pharmacological inhibition of PKD1 or deletion of Prkd1. CONCLUSIONS/INTERPRETATION: We conclude that the signalling cascade downstream of GPR40 activation by fatty acids involves activation of PKD1, F-actin depolymerisation and potentiation of second phase insulin secretion. These results provide important information on the mechanisms of action of GPR40, a novel drug target for type 2 diabetes. PMID- 22820511 TI - Including known covariates can reduce power to detect genetic effects in case control studies. AB - Genome-wide association studies (GWAS) search for associations between genetic variants and disease status, typically via logistic regression. Often there are covariates, such as sex or well-established major genetic factors, that are known to affect disease susceptibility and are independent of tested genotypes at the population level. We show theoretically and with data from recent GWAS on multiple sclerosis, psoriasis and ankylosing spondylitis that inclusion of known covariates can substantially reduce power for the identification of associated variants when the disease prevalence is lower than a few percent. Whether the inclusion of such covariates reduces or increases power to detect genetic effects depends on various factors, including the prevalence of the disease studied. When the disease is common (prevalence of >20%), the inclusion of covariates typically increases power, whereas, for rarer diseases, it can often decrease power to detect new genetic associations. PMID- 22820512 TI - Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. AB - The 1000 Genomes Project and disease-specific sequencing efforts are producing large collections of haplotypes that can be used as reference panels for genotype imputation in genome-wide association studies (GWAS). However, imputing from large reference panels with existing methods imposes a high computational burden. We introduce a strategy called 'pre-phasing' that maintains the accuracy of leading methods while reducing computational costs. We first statistically estimate the haplotypes for each individual within the GWAS sample (pre-phasing) and then impute missing genotypes into these estimated haplotypes. This reduces the computational cost because (i) the GWAS samples must be phased only once, whereas standard methods would implicitly repeat phasing with each reference panel update, and (ii) it is much faster to match a phased GWAS haplotype to one reference haplotype than to match two unphased GWAS genotypes to a pair of reference haplotypes. We implemented our approach in the MaCH and IMPUTE2 frameworks, and we tested it on data sets from the Wellcome Trust Case Control Consortium 2 (WTCCC2), the Genetic Association Information Network (GAIN), the Women's Health Initiative (WHI) and the 1000 Genomes Project. This strategy will be particularly valuable for repeated imputation as reference panels evolve. PMID- 22820513 TI - Immune deficiency and autoimmunity. AB - PURPOSE OF REVIEW: To provide an overview of the mechanisms of autoimmunity associated with primary immunodeficiencies. RECENT FINDINGS: Over the past several years, new concepts of the relationship between primary immunodeficiencies and autoimmunity have developed that promise to illuminate the mechanisms by which alterations in the same gene may alternately, or sometimes concomitantly, lead to increased susceptibility to infection and loss of self tolerance. A common pathway in the process leading to autoimmunity involves gene defects that permit effector T-cell development in the absence of sufficient regulatory T-cell function. Conversely, gene defects that primarily lead to autoimmunity may impair host defense by neutralizing key elements of immunity. The production of neutralizing antibodies against cytokines comprises a newly recognized mechanism in which autoimmunity may lead to immunodeficiency. SUMMARY: Autoimmunity has long been known to be a part of the presenting symptoms and clinical course of many primary immunodeficiencies. This review will provide an overview of the new concepts regarding the complex relationship between the genetic immune deficiencies and autoimmunity. The mechanisms by which immunodeficiency may lead to autoimmunity or, in some instances, by which autoimmunity produces immunodeficiency can provide important insights into the underlying pathogenic processes and ultimately better diagnosis and treatment for the patient. PMID- 22820514 TI - Diffuse and interstitial lung disease and childhood rheumatologic disorders. AB - PURPOSE OF REVIEW: Advances in genetics and clinical diagnostics, along with recently described clinical entities and refined classification schemes, have improved our understanding of diffuse and interstitial lung diseases in children. This review presents recent updates in these disorders in the context of systemic inflammatory conditions. RECENT FINDINGS: Classification of childhood diffuse lung disease (DLD) using adult paradigms is not useful. Distinct clinical pathologic entities exist in children. Infants are more likely to present with genetic and developmental disorders, and older children with inflammatory and immune-mediated conditions. A combination of clinical evaluation, high-resolution computed tomography scanning, pulmonary function testing and serology, with bronchoscopy and surgical lung biopsy in selected cases, is most useful in the evaluation of DLD in the context of rheumatologic conditions. Common causes of DLD, such as infection, especially in the setting of immunodeficiency, must be ruled out. Optimal therapy for specific disorders will require careful analysis of data from national registries. Emerging use of biomarkers and high-throughput molecular analysis will yield novel insight into these disorders. SUMMARY: In the setting of known or suspected rheumatologic disorders, diagnosis and management of DLD are challenging, and require close collaboration among rheumatologists, pulmonologists, and other specialists. PMID- 22820516 TI - FRAX updates 2012. AB - PURPOSE OF REVIEW: There is an increasing recognition that the management of osteoporosis requires the characterization of fracture risk to be based on absolute risk rather than single measures such as bone mineral density (BMD). FRAX, the most widely used tool that incorporates clinical risk factors with or without BMD, was launched in 2008. This brief review addresses the development of FRAX since then and describes some of the issues that continue to be discussed as FRAX plays an increasing role in clinical practice. RECENT FINDINGS: FRAX is a platform technology that will continue to develop. High-quality updated epidemiology of fracture and mortality can lead to recalibration of models. The addition of new risk factors is complex as the process requires validation in an international setting as well as a comprehensive assessment of how such new factors interact with the existing FRAX variables. Nonetheless, clinical interpretation can be enhanced by taking into account the potential adjustments of FRAX probabilities and several of these are described. SUMMARY: FRAX is being incorporated in an increasing number of clinical guidelines, and assessment and intervention thresholds have been provided to instruct clinical decision-making. There is an increasing body of evidence that patients deemed at highest risk of fracture by FRAX, with or without the use of BMD, will overlap significantly with those identified by previous guidelines and will respond to appropriate osteoporosis therapy. PMID- 22820518 TI - A microfluidic flow-stretch chip for investigating blood vessel biomechanics. AB - This microfluidic flow-stretch chip integrates fluid shear stress (FSS) and cyclic stretch (CS), two major mechanical stimulations in cardiovascular systems, for cultured cells. The model chip can deliver FSS and CS simultaneously or independently to vascular cells to mimic the haemodynamic microenvironment of blood vessels in vivo. By imposing FSS-only, CS-only, and FSS+CS stimulation on rat mesenchymal stem cells and human umbilical vein endothelial cells, we found the alignment of the cellular stress fibers varied with cell type and the type of stimulation. The flow-stretch chip is a reliable tool for simulating the haemodynamic microenvironment. PMID- 22820515 TI - HIV and its effects on bone: a primer for rheumatologists. AB - PURPOSE OF REVIEW: As patients with HIV are living longer because of effective treatments, rates of comorbid chronic diseases such as bone complications are increasing. There is a growing body of literature showing increased rates of osteopenia and osteporosis in the HIV population. Less is known about the risk of fracture, as well as other bone complications, such as avascular necrosis (AVN). RECENT FINDINGS: Increased rates of osteopenia and osteoporosis are seen in the HIV population, likely secondary to an interaction of traditional osteoporotic and HIV-specific risk factors, and possibly the effect of antiretroviral therapy (ART). There are conflicting recent data as to whether the decrease in bone mineral density seen in the HIV population, specifically with particular ART regimens, translates into an increased risk of fracture. Conflicting evidence emerges from recent studies exploring whether supplementation of vitamin D and calcium can prevent the bone loss seen with specific ART regimens. SUMMARY: Bone disease is common in the HIV population, and will likely be a medical problem increasingly seen by rheumatologists. The role of ART regimens on bone complications such as fracture and AVN is unclear, and further research in this area as well as possible prevention strategies are needed. PMID- 22820519 TI - Isolation and molecular characterization of methicillin-resistant staphylococci from horses, personnel and environmental sites at an equine hospital in Turkey. AB - The present study was carried out to assess the frequency of methicillin resistant staphylococci (MRS) among racehorses (n=209) and veterinary personnel (n=13) as well as environmental surfaces (n=14) at an equine hospital in Adana, Turkey. In addition, species distribution, antimicrobial susceptibility, resistance genes, staphylococcal chromosomal cassette mec (SCCmec) type and clonality of these isolates were also investigated. MRS were identified by 16S rRNA sequencing, and typed by pulsed-field gel electrophoresis (PFGE). As a result, MRS was isolated in horses (48.3%), clinic staff (92.3%) and environmental samples (71.4%). Of the 123 MRS isolates, 118 isolates were identified as Staphylococcus lentus, and the remaining ones were found to be S. sciuri (n=3), S. intermedius (n=1) and S. fleuretti (n=1). All isolates were found to be susceptible against vancomycin, quinupristin-dalfopristin and rifampicin. Additionally, single or various combinations of resistance genes were detected among MRS isolates. SCCmec type II was identified in all isolates. Similar PFGE patterns were observed among MRS isolated from horses, humans, and environmental samples. Since MRS were concurrently isolated from horses and humans it is suggested that cross-transmission of MRS between horses and humans might occur. However, it cannot be ruled out that transmission is human to animal or animal to human. PMID- 22820520 TI - Uranium-mediated reductive conversion of CO2 to CO and carbonate in a single vessel, closed synthetic cycle. AB - The new neopentyl (Neop)-substituted tris(aryloxide) U(III) complex [(((Neop,Me)ArO)(3)tacn)U(III)] reacts with CO(2) to form CO and the bridging carbonate complex [{(((Neop,Me)ArO)(3)tacn)U(IV)}(2)(MU-CO(3))]. The uranium(IV) bridging oxo [{(((Neop,Me)ArO)(3)tacn)U(IV)}(2)(MU-O)] has been determined to be the intermediate in this reaction. For the first time, both U(iv) complexes can be reduced back to the U(III) starting material. Thus, with KC(8) as reductant, [(((Neop,Me)ArO)(3)tacn)U(III)] engages in a synthetic cycle, in which CO(2) is converted to CO and CO(3)(2-). PMID- 22820521 TI - Improving the affinity and activity of CYP101D2 for hydrophobic substrates. AB - CYP101D2 is a cytochrome P450 monooxygenase from Novosphingobium aromaticivorans which is closely related to CYP101A1 (P450cam) from Pseudomonas putida. Both enzymes selectively hydroxylate camphor to 5-exo-hydroxycamphor, and the residues that line the active sites of both enzymes are similar including the pre-eminent Tyr96 residue. However, Met98 and Leu253 in CYP101D2 replace Phe98 and Val247 in CYP101A1, and camphor binding only results in a maximal change in the spin state to 40 % high-spin. Substitutions at Tyr96, Met98 and Leu253 in CYP101D2 reduced both the spin state shift on camphor binding and the camphor oxidation activity. The Tyr96Ala mutant increased the affinity of CYP101D2 for hydrocarbon substrates including adamantane, cyclooctane, hexane and 2-methylpentane. The monooxygenase activity of the Tyr96Ala variant towards alkane substrates was also enhanced compared with the wild-type enzyme. The crystal structure of the substrate-free form of this variant shows the enzyme in an open conformation (PDB: 4DXY), similar to that observed with the wild-type enzyme (PDB: 3NV5), with the side chain of Ala96 pointing away from the heme. Despite this, the binding and activity data suggest that this residue plays an important role in substrate binding, evidencing that the enzyme probably undergoes catalysis in a more closed conformation, similar to those observed in the crystal structures of CYP101A1 (PDB: 2CPP) and CYP101D1 (PDB: 3LXI). PMID- 22820522 TI - Production of polysaccharide from Agaricus subrufescens Peck on solid-state fermentation. AB - The interest upon products obtained from fungi has increased during the recent years. Among the most noticeable, nutraceuticals, enzymes, and natural drugs occupy a privileged position. Fungal biomass for the obtainment of those products can be produced either by solid-state fermentation (SSF) or submersed fermentation. SSF has been employed for the production of spawn on pretreated wheat grains with the objective of increasing the fungal polysaccharide (glucomannans) contents. Among the important factors for the production of spawn, time of cooking, time of resting after grain cooking, consequently grain moisture, substrate pH, temperature of incubation, and initial inoculum amount are among the most significant. For wheat grains, cooking time of 21 min followed by a 24-min resting time has been shown as optimal for the production of glucomannans by the fungus Agaricus subrufescens (=Agaricus brasiliensis). Amendments of CaSO(4) (up to 3 %) and CaCO(3) (up to 1 %) had an important influence on the substrate pH. In general, better results for glucomannan production were obtained when no supplement was added or when up to 0.25 % CaCO(3) (pH 6.6) has been added to the mix. Our results demonstrate that the inoculum amount necessary for the best polysaccharide levels is around 10.3 %, while the best temperature is around 27.2 degrees C. Besides using the spawn for its main purpose, it could potentially and alternatively be used as nutraceutical due to the high levels of glucomannan observed (6.89 %), a compound technically proven to be a potent immunostimulatory and antitumoral agent. PMID- 22820523 TI - Current state and perspectives on erythropoietin production. AB - Erythropoietin is a major regulator of erythropoiesis which maintains the body's red blood cell mass and tissue oxygenation at an optimum level. Recombinant human erythropoietin (rhEPO), which is a widely used therapeutic agent for the treatment of anemia and which represents one of the largest biopharmaceuticals markets, is produced from recombinant Chinese hamster ovary cells. rhEPO is a glycoprotein with complex glycan structure, which is responsible for its therapeutic efficacy, including the in vivo activity and half-life. In order to obtain an optimal and consistent glycoform profile of rhEPO and concurrently maintain a high production yield, various approaches in drug development and cell culture technology have been attempted. Recent advances in rhEPO production are classified into three types: the development of improved rhEPO molecules by protein engineering; improvement of production host cells by genetic engineering; and culture condition optimization by fine control of the production mode/system, process parameters, and culture media. In this review, we focus on rhEPO production strategies as they have progressed thus far. Furthermore, the current status of the market and outlook on rhEPO and its derivatives are discussed. PMID- 22820524 TI - Transcriptional changes associated with lack of lipid synthesis in parasitoids. AB - Phenotypic regression of morphological, behavioral, or physiological traits can evolve when reduced trait expression has neutral or beneficial effects on overall performance. Studies on the evolution of phenotypic degradation in animals have concentrated mostly on the evaluation of resulting phenotypes, whereas much less research has been dedicated to uncovering the molecular mechanisms that underlie phenotypic regression. The majority of parasitoids (i.e., insects that develop on or inside other arthropods), do not accumulate lipid reserves during their free living adult life-stage and represent an excellent system to study phenotypic regression in animals. Here, we study transcriptional patterns associated with lack of lipogenesis in the parasitic wasp Nasonia vitripennis. We first confirmed that N. vitripennis does not synthesize lipids by showing a reduction in lipid reserves despite ingestion of dietary sugar, and a lack of incorporation of isotopic labels into lipid reserves when fed deuterated sugar solution. Second, we investigated transcriptional responses of 28 genes involved in lipid and sugar metabolism in short- and long-term sugar-fed females relative to starved females of N. vitripennis. Sugar feeding did not induce transcription of fatty acid synthase (fas) or other key genes involved in the lipid biosynthesis pathway. Furthermore, several genes involved in carbohydrate metabolism had a lower transcription in fed than in starved females. Our results reveal that N. vitripennis gene transcription in response to dietary sugar deviates markedly from patterns typically observed in other organisms. This study is the first to identify differential gene transcription associated with lack of lipogenesis in parasitoids and provides new insights into the molecular mechanism that underlies phenotypic regression of this trait. PMID- 22820525 TI - Virus-modified exosomes for targeted RNA delivery; a new approach in nanomedicine. AB - A major goal in biomedical research is to clinically reverse the cause of disease rather than treating the symptoms. Gene therapy has the potential to meet this goal and the discovery of RNA interference (RNAi) has lead to a new class of highly selective therapeutics. However, initial enthusiasm is reduced due to safety concerns associated with virus-based delivery vectors that are used for in vivo delivery. Viral vectors for siRNA delivery into target cells are used because of their high target specificity and delivery efficacy (endosomal escape). Recent discoveries suggest that a specialized form of nano-sized lipid vesicles called exosomes can incorporate and transport functional RNAs into target cells and may serve as an attractive alternative. Evidence is accumulating that most pluricellular organisms sustain exosome-based communications via inter cellular exchange of mRNA and miRNAs between cells. We discovered that viruses have found ways to exploit this communication pathway and we argue here that adaptations of exosomes imposed by viruses maybe exploited for superior delivery of RNA in vivo. We discuss recent discoveries in exosome biogenesis their physical properties, targeting and delivery strategies and how the knowledge of exosome production in virus infected cells could propel their entry into clinical settings. PMID- 22820526 TI - Nanoproteomics enabling personalized nanomedicine. AB - Nucleic Acid Programmable Protein Arrays utilize a complex mammalian cell free expression system to produce proteins in situ. In alternative to fluorescent labeled approaches a new label free method, emerging from the combined utilization of three independent and complementary nanotechnological approaches, appears capable to analyze protein function and protein-protein interaction in studies promising for personalized medicine. Quartz Micro Circuit nanogravimetry, based on frequency and dissipation factor, mass spectrometry and anodic porous alumina overcomes indeed the limits of correlated fluorescence detection plagued by the background still present after extensive washes. This could be further optimized by a homogeneous and well defined bacterial cell free expression system capable to realize the ambitious objective to quantify the regulatory protein networks in humans. Implications for personalized medicine of the above label free protein array using different test genes proteins are reported. PMID- 22820527 TI - How smart do biomaterials need to be? A translational science and clinical point of view. AB - Over the last 4 decades innovations in biomaterials and medical technology have had a sustainable impact on the development of biopolymers, titanium/stainless steel and ceramics utilized in medical devices and implants. This progress was primarily driven by issues of biocompatibility and demands for enhanced mechanical performance of permanent and non-permanent implants as well as medical devices and artificial organs. In the 21st century, the biomaterials community aims to develop advanced medical devices and implants, to establish techniques to meet these requirements, and to facilitate the treatment of older as well as younger patient cohorts. The major advances in the last 10 years from a cellular and molecular knowledge point of view provided the scientific foundation for the development of third-generation biomaterials. With the introduction of new concepts in molecular biology in the 2000s and specifically advances in genomics and proteomics, a differentiated understanding of biocompatibility slowly evolved. These cell biological discoveries significantly affected the way of biomaterials design and use. At the same time both clinical demands and patient expectations continued to grow. Therefore, the development of cutting-edge treatment strategies that alleviate or at least delay the need of implants could open up new vistas. This represents the main challenge for the biomaterials community in the 21st century. As a result, the present decade has seen the emergence of the fourth generation of biomaterials, the so-called smart or biomimetic materials. A key challenge in designing smart biomaterials is to capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue. We are still a long way from recreating the molecular architecture of the ECM one to one and the dynamic mechanisms by which information is revealed in the ECM proteins in response to challenges within the host environment. This special issue on smart biomaterials lists a large number of excellent review articles which core is to present and discuss the basic sciences on the topic of smart biomaterials. On the other hand, the purpose of our review is to assess state of the art and future perspectives of the so called "smart biomaterials" from a translational science and specifically clinical point of view. Our aim is to filter out and discuss which biomedical advances and innovations help us to achieve the objective to translate smart biomaterials from bench to bedside. The authors predict that analyzing the field of smart biomaterials from a clinical point of view, looking back 50 years from now, it will show that this is our heritage in the 21st century. PMID- 22820529 TI - Remote and local control of stimuli responsive materials for therapeutic applications. AB - Materials offering the ability to change their characteristics in response to presented stimuli have demonstrated application in the biomedical arena, allowing control over drug delivery, protein adsorption and cell attachment to materials. Many of these smart systems are reversible, giving rise to finer control over material properties and biological interaction, useful for various therapeutic treatment strategies. Many smart materials intended for biological interaction are based around pH or thermo-responsive materials, although the use of magnetic materials, particularly in neural regeneration, has increased over the past decade. This review draws together a background of literature describing the design principles and mechanisms of smart materials. Discussion centres on recent literature regarding pH-, thermo-, magnetic and dual responsive materials, and their current applications for the treatment of neural tissue. PMID- 22820530 TI - A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. AB - Intravenous administration of low (milligram) doses of nanoparticulate materials in pigs can lead to acute cardiopulmonary, hemodynamic, hematological, biochemical and dermatological changes within minutes, mimicking the human infusion (or anaphylactoid) reactions to many state-of-the-art (nano)medicines and biologicals. Because of the causal role of complement (C) activation, the phenomenon was called C activation-related pseudoallergy (CARPA). This review summarizes the available information on porcine CARPA caused by different liposomes and polymers. It provides methodical details of the model and addresses the quantitation, sensitivity, specificity, reproducibility and variability of symptoms caused by different reactogenic drugs. We describe a unique feature of the model: the rise of tachyphylaxis (self-induced tolerance) as a function of structural properties of reactogenic agents. For drugs that cause tachyphylactic CARPA, such as liposomal doxorubicin (Doxil), the review recapitulates a recently reported method of desensitization, which may prevent this, as well as many similar hypersensitivity reactions. In explaining the underlying mechanism of tachyphylactic CARPA, a new theory on "double hit" is outlined, wherein the pulmonary intravascular macrophages (PIM cells) of pigs give aggravated response to simultaneous stimulation of their anaphylatoxin and other surface receptors (e.g., toll-like, PAMP, DAMP or mannose) that recognize vesicle surface molecular patterns. The porcine CARPA model might provide unique advantages in studying the mechanism of severe hypersensitivity reactions in man to i.v. drugs, as well as in identifying drugs and drug carriers that may cause such reactions. PMID- 22820531 TI - Immunotoxicity derived from manipulating leukocytes with lipid-based nanoparticles. AB - Lipid-based nanoparticles (LNPs) such as liposomes, micelles, and hybrid systems (e.g. lipid-polymer) are prominent delivery vehicles that already made an impact on the lives of millions around the globe. A common denominator of all these LNP based platforms is to deliver drugs into specific tissues or cells in a pathological setting with minimal adverse effects on bystander cells. All these platforms must be compatible to the physiological environment and prevent undesirable interactions with the immune system. Avoiding immune stimulation or suppression is an important consideration when developing new strategies in drug and gene delivery, whereas in adjuvants for vaccine therapies, immune activation is desired. Therefore, profound understanding of how LNPs elicit immune responses is essential for the optimization of these systems for various biomedical applications. Herein, I describe general concepts of the immune system and the interaction of subsets of leukocytes with LNPs. Finally, I detail the different immune toxicities reported and propose ways to manipulate leukocytes' functions using LNPs. PMID- 22820532 TI - Exosomes as nano-theranostic delivery platforms for gene therapy. AB - Exosomes are biological membrane vesicles measuring 30 to 100 nm. They contain an abundance of small molecules like tetraspanins, receptors for targeting and adhesion, lipids, and RNA. They are secreted by most biological cells, and are involved in a plethora of physiological functions including, but not limited to, transport of genetic material, modulation of the immune system, and cell-to-cell communication. It has been further reported that exosomes utilize a mechanism similar to that of viruses for gaining entry into cells. Due to their viral-like transfection efficiency and inherent biological function, compelling evidence indicates that exosomes can be used as novel delivery platforms for gene therapy. Furthermore, RNA-containing exosomes derived from cells can serve as functional genetic biomarkers for diseases. This twin modality of therapeutic and diagnostic is termed theranostics in the emerging field of nanomedicine. Hence in this review, we seek to expound on the various facets of exosomes, highlighting their significance in and relevance to nano-theranostic platforms for gene therapy. PMID- 22820533 TI - The role of exosomes and microRNAs in senescence and aging. AB - Senescence is viewed as a cellular counterpart to aging of tissues and organisms, characterized by an irreversible growth arrest and a combination of changes in cell morphology, function and behavior. microRNAs (miRNAs), the most studied small non-coding RNAs, play an important role in many biological processes by the regulation of gene expression. Recent evidence has shown that miRNAs are contained in exosomes that are tiny vesicles of endocytic origin and released by a variety of different cells as a means for cell-to-cell contact and information transfer. Exosomes and miRNAs have been found to participate in the complex networks of cellular senescence and contribute to aging. Here, we will give an overview on the involvement of secretory factors including exosomes and miRNA in the regulation of cellular senescence, demonstrating the potential role of exosomes and miRNAs in biological processes and signaling pathways of senescence and aging. PMID- 22820528 TI - Personalized nanomedicine advancements for stem cell tracking. AB - Recent technological developments in biomedicine have facilitated the generation of data on the anatomical, physiological and molecular level for individual patients and thus introduces opportunity for therapy to be personalized in an unprecedented fashion. Generation of patient-specific stem cells exemplifies the efforts toward this new approach. Cell-based therapy is a highly promising treatment paradigm; however, due to the lack of consistent and unbiased data about the fate of stem cells in vivo, interpretation of therapeutic effects remains challenging hampering the progress in this field. The advent of nanotechnology with a wide palette of inorganic and organic nanostructures has expanded the arsenal of methods for tracking transplanted stem cells. The diversity of nanomaterials has revolutionized personalized nanomedicine and enables individualized tailoring of stem cell labeling materials for the specific needs of each patient. The successful implementation of stem cell tracking will likely be a significant driving force that will contribute to the further development of nanotheranostics. The purpose of this review is to emphasize the role of cell tracking using currently available nanoparticles. PMID- 22820534 TI - Role of the NO/sGC/PKG signaling pathway of hippocampal CA1 in morphine-induced reward memory. AB - Evidence suggests that the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP dependent protein kinase (PKG) signaling pathway plays a key role in memory processing, but the actual participation of this signaling cascade in the hippocampal CA1 during morphine-induced reward memory remains unknown. In this study, we investigated the role of the NO/sGC/PKG signaling pathway in the CA1 on morphine-induced reward memory using a conditioned place preference (CPP) paradigm. We found that rats receiving an intraperitoneal (i.p.) injection of 4mg/kg morphine exhibited CPP, whereas rats treated with only 0.2mg/kg morphine failed to produce CPP. Intra-CA1 injection of the neuronal NO synthase (nNOS) inhibitor 7-NI, the sGC inhibitor ODQ or the PKG inhibitor Rp-8-Br-PET-cGMPS had no effect on the acquisition of CPP by 4mg/kg morphine. Intra-CA1 injection of 7 NI blocked the consolidation of CPP induced by 4mg/kg morphine, and this amnesic effect of 7-NI was mimicked by ODQ and Rp-8-Br-PET-cGMPS. Intra-CA1 injection of the NOS substrate L-arg or the sGC activator YC-1 with an ineffective dose of morphine (0.2mg/kg, i.p.) elicited CPP. This response induced by L-arg or YC-1 was reversed by pre-microinjection of Rp-8-Br-PET-cGMPS in the CA1. These results indicated that the activation of the NO/sGC/PKG signaling pathway in the CA1 is necessary for the consolidation of morphine-related reward memory. PMID- 22820535 TI - Identification of differentially expressed proteins between bull X and Y spermatozoa. AB - Differential expression of genes leads to variation in phenotypes of X and Y sperm, even though some differential gene products are shared through an intercellular bridge. Differentially expressed proteins between X and Y sperm sorted from semen of nine bulls were compared using two-dimensional electrophoresis (2-DE) coupled with mass spectrometry (MS) analysis. Overall, 663+/-12 and 647+/-22 protein spots were detected in X sperm and Y sperm, respectively, and 42 significant protein spots were differentially expressed between them (P<0.05). Sixteen of these protein spots were successfully identified by MS and tandem MS and were found to be closely relevant to energy metabolism, stress resistance, cytoskeletal structure and the activity of serine proteases. Expression levels of two of these proteins, CAPZB and UQCRC1, were verified by Western blot. We propose that these differentially expressed proteins may affect the phenotype of X and Y sperm, binding and fusion of sperm/oocyte and development of the zygotic embryo. Our preliminary results provide an overview of differential expression in total protein levels between X and Y spermatozoa. Identification of these altered proteins may provide a theoretical basis for understanding the biological differences between the two types of sperm. PMID- 22820536 TI - Proteomic identification of endothelial cell surface proteins isolated from the hepatic portal vein of mice infected with Schistosoma bovis. AB - Schistosomes are blood parasites adapted to their intravascular habitat that have evolved mechanisms to evade the immune and hemostatic responses of their hosts. It has been observed that the schistosome can regulate the endothelium function along the infection, which contributes to modulation of host defensive responses and parasite survival. The purpose of this work was the analysis of the changes induced by Schistosoma bovis adult worms in the proteome expressed by infected mice on the endothelial surface of their portal vein. With this aim, we have utilized a methodology that allows the purification, identification and relative quantification of endothelial cell surface proteins after their selective in vivo labeling with biotin. Trypsin digestion of the biotinylated proteins and subsequent liquid chromatography and tandem mass spectrometry analysis (LC-MS/MS) resulted in the identification of a total 127 non-redundant proteins. All these proteins have been classified according to their function and cellular location, and the differences between S. bovis-infected and non-infected mice in their endothelial surface proteomes have been analyzed. The present work provides the first data on the proteome of the endothelial surface of the portal vein, and identifies some of the changes induced in it after an infection by S. bovis. PMID- 22820537 TI - Instrumentation and software for mass spectrometry imaging--making the most of what you've got. AB - Whilst it might be desirable to be able to purchase an up to date mass spectrometry platform and dedicate it to mass spectrometry imaging, this is not the situation initially for many laboratories. There are a variety of methods by which existing mass spectrometers can be upgraded/adapted to perform mass spectrometry imaging using MALDI, DESI or LAESI as the means of generating ions. The focus of this article is on relatively low cost adaptations of existing instrumentation with suggestions made for performance enhancements where appropriate. A brief description of attempts to perform SIMS imaging on quadrupole time of flight mass spectrometers is also given. The required software is described with particular emphasis on freeware packages which can be used to display/enhance data. Requirements for data pre-processing prior or statistical analysis are discussed along with the use of MATLAB(r) for the analysis itself. PMID- 22820540 TI - Complicated atazanavir-associated cholelithiasis: a report of 14 cases. AB - Fourteen human immunodeficiency virus (HIV)-infected patients receiving an atazanavir (ATV)-based antiretroviral regimen developed complicated cholelithiasis. ATV was found in biliary calculi in 8 of 11 cases: infrared spectrometry analysis of calculi revealed that ATV made up a median of 89% (range, 10%-100%) of the total calculus composition. Development and management of ATV-associated cholelithiasis are discussed. PMID- 22820538 TI - Developmental fluoride neurotoxicity: a systematic review and meta-analysis. AB - BACKGROUND: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children's neurodevelopment. OBJECTIVE: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development. METHODS: We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, because many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using random-effects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg's funnel plot, and Egger test to assess publication bias, and conducted meta-regressions to explore sources of variation in mean differences among the studies. RESULTS: The standardized weighted mean difference in IQ score between exposed and reference populations was -0.45 (95% confidence interval: -0.56, -0.35) using a random effects model. Thus, children in high-fluoride areas had significantly lower IQ scores than those who lived in low-fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease. CONCLUSIONS: The results support the possibility of an adverse effect of high fluoride exposure on children's neurodevelopment. Future research should include detailed individual-level information on prenatal exposure, neurobehavioral performance, and covariates for adjustment. PMID- 22820541 TI - An updated systematic review and meta-analysis on the treatment of active tuberculosis in patients with HIV infection. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection increases the risk of poor outcomes in active tuberculosis. We updated a systematic review and meta analysis assessing the effects of duration of rifamycins, schedule of dosing, and antiretroviral therapy (ART) on failure, relapse, death during treatment, and acquired drug resistance (ADR) in patients with HIV and active tuberculosis. METHODS: We searched for randomized control trials (RCTs) and observational studies published between January 2008 and November 2011. We pooled risk differences (RD) from RCTs comparing rifampin for >=9 months and 6 months. Within strata of the 3 treatment covariates, we calculated pooled risks and adjusted odds ratios (aORs) using outcomes from RCTs and observational studies. RESULTS: After screening 2293 citations, 7 studies were added in the update. Risk of relapse was lowered with rifampin treatment for >=9 months compared with 6 months (pooled RD = -9.1%; 95% CI, -16.5, -1.8). Odds of relapse were higher with shorter durations of rifamycins (aOR 2 vs >=8 months = 5.0 [1.9, 13.2]; 6 vs >=8 months = 2.4 [1.2, 5.0]) and in the absence of ART (aOR = 14.3, [2.1, 97.8]). Post hoc meta-regression restricted to arms with ART demonstrated no associations between rifamycin duration, dosing schedule, and outcomes. CONCLUSIONS: In patients with HIV and active tuberculosis, ART reduces the risk of TB relapse. Use of rifamycins for >=8 months and daily dosing in the intensive phase also improve TB treatment outcomes; however, a paucity of evidence makes their importance less clear for patients on ART. There is an urgent need to increase the number of coinfected patients receiving ART. PMID- 22820543 TI - Akhawayni and the first fever curve. AB - By the time of Hippocrates the typical paroxysmal fever patterns of tertian (every 48 hours) and quartan (every 72 hours) fevers caused by malaria were known. Through the ensuing centuries, ancient Greek, Roman, and Persian physicians made additional contributions to the understanding of fevers. By the end of that era, there was a working definition of what constitutes a fever, the distinction between fever as a symptom and fever as a disease, an elaborate classification scheme for multiple types of fever, hypotheses as to the causes of fever, and methods for diagnosing and treating fevers. Based on the definition of fever at that time, the 10th century ce Persian physician Akhawayni created fever curves hundreds of years before they were routinely used in the clinical setting. In Hidayat al-Muta'allimin fi al-Tibb, Akhawayni describes a system for fever curves and draws fever curves for tertian and quartan Fevers, as well as the double tertian, double quartan, and triple quartan fevers. In this work we examine the history of fevers in the ancient world and the first description of the fever curve. PMID- 22820542 TI - High incidence of renal stones among HIV-infected patients on ritonavir-boosted atazanavir than in those receiving other protease inhibitor-containing antiretroviral therapy. AB - BACKGROUND: Little information is available on the incidence of renal stones with ritonavir-boosted atazanavir (ATV/r) use. METHODS: In a single-center study, the incidence of renal stones was compared between human immunodeficiency virus (HIV) infected patients who commenced ritonavir-boosted atazanavir (ATV/r)-containing antiretroviral (ARV) therapy (the ATV/r group) and those who were receiving other protease inhibitors (the other PIs group). The effects of ATV/r were estimated by univariate and multivariate Cox proportional hazards regression models. Other possible risk factors were evaluated by univariate analysis, and those found to be significant were entered into multivariate analysis. RESULTS: Renal stones were diagnosed in 31 patients (23.7 cases per 1000 person-years) in the ATV/r group (n = 465) and 4 in patients (2.2 cases per 1000 person-years) in the other PIs group (n = 775). ATV/r use was significantly associated with renal stones, by univariate and multivariate analyses (adjusted hazard ratio, 10.44; 95% confidence interval [CI], 3.685-29.59; P < .001). ATV/r remained a significant risk factor for renal stones in all subgroups stratified by the median values of baseline variables. In the 31 patients receiving ATV/r who developed renal stones, the median time from commencement of ATV/r to diagnosis was 24.5 months (interquartile range, 14.7-34.6 months). Of the 18 patients who continued ATV/r despite the diagnosis of renal stones, 6 (33.3%) experienced recurrence. No patient who discontinued ATV/r experienced recurrence during the observation period (250.6 person-months). CONCLUSIONS: The incidence of renal stones was substantially higher among patients in the ATV/r group, compared with patients in the other PIs group. Continuation of ATV/r after diagnosis of renal stones was associated with a high rate of recurrence. Switching ATV/r to other ARVs is warranted in patients who develop renal stones. PMID- 22820544 TI - Testosterone effect on the expression of genes that mediate testosterone metabolism and genes that mediate the effect of those metabolites on the prostate. AB - AIMS: The aim of this study was to investigate the effect of testosterone treatment on the proliferation index and the mRNA expression levels of 5alpha reductase, CYP7B1, androgen receptor (AR), and estrogen receptor beta (EpsilonRbeta) in the canine prostate. MAIN METHODS: Immature dogs were treated with testosterone for one month, after which prostate gland growth was assessed by comparing the proliferation index in prostates from testosterone-treated dogs with that of untreated control dogs. The relative mRNA expression levels of the aforementioned genes in the prostate glands of testosterone-treated and untreated dogs were determined by real time PCR. KEY FINDINGS: Testosterone treatment induced a highly significant reduction in proliferation index in prostate gland. This inhibition of prostate gland growth was associated with differential mRNA expression of 5alpha-reductase, CYP7B1, AR, and EpsilonRbeta by the prostate gland of testosterone-treated dogs, as compared to that of untreated dogs. While the expression levels of 5alpha-reductase and CYP7B1 mRNA were significantly down regulated by testosterone treatment, the expression level of ER-beta mRNA was highly up-regulated. In contrast, AR mRNA expression was not significantly altered. SIGNIFICANCE: Prostate gland proliferation appeared to be associated with the expression levels of genes that encode proteins that control intra prostatic levels of testosterone metabolites and their respective receptors. Testosterone treatment may regulate gene expression in the prostate to generate a phenotype that suppresses growth-promoting signaling through AR and enhances anti proliferative signaling through ERbeta. Therefore, targeting disturbances of this genetic machinery in benign prostate hyperplasia and prostate cancer is of a therapeutic potential. PMID- 22820545 TI - Induction of mitochondrial dysfunction and oxidative stress in human fibroblast cultures exposed to serum from septic patients. AB - AIMS: Sepsis which is the leading cause of death in intensive care units is usually related to the number and the severity of organ failure, but the mechanisms remain to be fully established. Findings of microvascular flow abnormalities, decreased oxygen consumption and elevated tissue oxygen tensions suggest that problems may lay in cellular oxygen utilization rather than in oxygen delivery per se. Several serum factors, released during sepsis syndrome, might be involved in induction of cytopathic hypoxia and increase of cellular oxidative stress. MAIN METHODS: Human fibroblast cultures were incubated 12h with 10% v/v severe septic patients' sera and measurements were carried out on cellular oxygen consumption, mitochondrial respiratory enzymes activity, H(2)O(2) generation and serum levels of cytokines/chemokines by multiplex assay. KEY FINDINGS: In fibroblast cultures a significant depression of cellular respiration and activity of mitochondrial complexes and increased H(2)O(2) production was observed after incubation with septic sera showing increased levels of TNFalpha, IL-1beta and IL-6. SIGNIFICANCE: During sepsis syndrome some increased cytokines might target specific mitochondrial enzymes inducing an impairment of cellular energy metabolism leading to multiple organ failure. PMID- 22820547 TI - Femtosecond laser processing for optofluidic fabrication. AB - Femtosecond laser direct writing is a promising technique for fabricating optofluidic devices since it can modify the interior of glass in a spatially selective manner through multiphoton absorption. The chemical properties of laser irradiated regions in glass are modified allowing them to be selectively etched by subsequent wet etching using aqueous solutions of etchants such as hydrofluoric (HF) acid. This technique can be used to directly form three dimensional microfluidic systems. The two-step process can also be used to fabricate free-space optical components such as micromirrors and microlenses inside glass. In addition, femtosecond laser direct writing can alter the optical properties of a substrate to create a wide range of micro-optical components inside glass, including optical waveguides, Mach-Zehnder interferometers, and optical attenuators. The unique ability of femtosecond laser direct writing to simultaneously alter the chemical and optical properties of glass opens up a new avenue for fabricating a variety of optofluidic microchips for biological analysis. Optofluidic microchips fabricated using femtosecond lasers have been used to determine the functions of living microorganisms, determine the concentrations of liquid samples, detect and manipulate single cells, and rapidly screen algae populations. This paper presents a comprehensive review of optofluidic devices for biological analysis fabricated by femtosecond laser processing. PMID- 22820546 TI - Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity. AB - AIMS: To design and synthesize novel N-(1-phenyl-2,3 dihydroxypropyl)arachidonylamides and evaluate their analgesic and anti inflammatory potential. MAIN METHODS: The murine macrophage cell line RAW 264.7 has been widely used as a model for inflammatory responses in vitro. Our model consists of cultured monolayers of RAW 264.7 cells in which media concentrations of 15-deoxy-Delta(13,14)-PGJ2 (PGJ) are measured by ELISA following LPS (10ng/ml) stimulation and treatment with 0.1, 0.3, 1.0, 3.0 and 10MUM concentrations of the compounds. KEY FINDINGS: Our data indicate that several of our compounds have the capacity to increase production of PGJ and may also increase the occurrence of programmed cell death (apoptosis). SIGNIFICANCE: Thus these agents are potential candidates for the therapy of conditions characterized by ongoing (chronic) inflammation and its associated pain. PMID- 22820550 TI - Nanoscale mapping of plasmon resonances of functional multibranched gold nanoparticles. AB - The optical response of multibranched gold nanoparticles is studied by means of electron energy-loss spectroscopy (EELS) in aberration corrected STEM mode. In every case the plasmon response is constant and variations in the maxima positions were found to be dependent on the branches aspect ratio. The good spatial resolution combined with the high energy resolution (0.18 eV) of the monochromated electron beam allows mapping the different plasmonic modes along the entire nanoparticles ranging from 0.7 eV up to 2.25 eV. PMID- 22820549 TI - Na+ and K+ ion imbalances in Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with impaired glutamate clearance and depressed Na(+)/K(+) ATPase levels in AD brain that might lead to a cellular ion imbalance. To test this hypothesis, [Na(+)] and [K(+)] were analyzed in postmortem brain samples of 12 normal and 16 AD individuals, and in cerebrospinal fluid (CSF) from AD patients and matched controls. Statistically significant increases in [Na(+)] in frontal (25%) and parietal cortex (20%) and in cerebellar [K(+)] (15%) were observed in AD samples compared to controls. CSF from AD patients and matched controls exhibited no differences, suggesting that tissue ion imbalances reflected changes in the intracellular compartment. Differences in cation concentrations between normal and AD brain samples were modeled by a 2 fold increase in intracellular [Na(+)] and an 8-15% increase in intracellular [K(+)]. Since amyloid beta peptide (Abeta) is an important contributor to AD brain pathology, we assessed how Abeta affects ion homeostasis in primary murine astrocytes, the most abundant cells in brain tissue. We demonstrate that treatment of astrocytes with the Abeta 25-35 peptide increases intracellular levels of Na(+) (~2-3-fold) and K(+) (~1.5-fold), which were associated with reduced levels of Na(+)/K(+) ATPase and the Na(+)-dependent glutamate transporters, GLAST and GLT-1. Similar increases in astrocytic Na(+) and K(+) levels were also caused by Abeta 1-40, but not by Abeta 1-42 treatment. Our study suggests a previously unrecognized impairment in AD brain cell ion homeostasis that might be triggered by Abeta and could significantly affect electrophysiological activity of brain cells, contributing to the pathophysiology of AD. PMID- 22820548 TI - GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation. AB - GCK-MODY, dominantly inherited mild fasting hyperglycemia, has been associated with >600 different mutations in the glucokinase (GK)-encoding gene (GCK). When expressed as recombinant pancreatic proteins, some mutations result in enzymes with normal/near-normal catalytic properties. The molecular mechanism(s) of GCK MODY due to these mutations has remained elusive. Here, we aimed to explore the molecular mechanisms for two such catalytically 'normal' GCK mutations (S263P and G264S) in the F260-L270 loop of GK. When stably overexpressed in HEK293 cells and MIN6 beta-cells, the S263P- and G264S-encoded mutations generated misfolded proteins with an increased rate of degradation (S263P>G264S) by the protein quality control machinery, and a propensity to self-associate (G264S>S263P) and form dimers (SDS resistant) and aggregates (partly Triton X-100 insoluble), as determined by pulse-chase experiments and subcellular fractionation. Thus, the GCK-MODY mutations S263P and G264S lead to protein misfolding causing destabilization, cellular dimerization/aggregation and enhanced rate of degradation. In silico predicted conformational changes of the F260-L270 loop structure are considered to mediate the dimerization of both mutant proteins by a domain swapping mechanism. Thus, similar properties may represent the molecular mechanisms for additional unexplained GCK-MODY mutations, and may also contribute to the disease mechanism in other previously characterized GCK-MODY inactivating mutations. PMID- 22820552 TI - BCx layers with honeycomb lattices on an NbB2(0001) surface. AB - At elevated temperatures of 1000-1500 K, carbon (C) atoms that segregated to a surface and mixed with the boron (B) honeycomb lattice resulted in the formation of three different BC(x) layers as the topmost layers of NbB(2)(0001). Two of the layers were commensurate lattices: ?7 * ?7 and ?3 * ?3 structures; the third was incommensurate. The characteristic features of the ?3 * ?3 lattice with a honeycomb structure are discussed on the basis of the experimental data. PMID- 22820551 TI - High-affinity monoclonal antibodies to cell surface tumor antigen glypican-3 generated through a combination of peptide immunization and flow cytometry screening. AB - Isolating high-affinity antibodies against native tumor antigens on the cell surface is not straightforward using standard hybridoma procedures. Here, we describe a combination method of synthetic peptide immunization and high throughput flow cytometry screening to efficiently isolate hybridomas for cell binding. Using this method, we identified high-affinity monoclonal antibodies specific for the native form of glypcian-3 (GPC3), a target heterogeneously expressed in hepatocellular carcinoma (HCC) and other cancers. We isolated a panel of monoclonal antibodies (YP6, YP7, YP8, YP9 and YP9.1) for cell surface binding. The antibodies were used to characterize GPC3 protein expression in human liver cancer cell lines and tissues by flow cytometry, immunoblotting and immunohistochemistry. The best antibody (YP7) bound cell surface-associated GPC3 with equilibrium dissociation constant, KD = 0.3 nmol/L and was highly specific for HCC, not normal tissues or other forms of primary liver cancers (such as cholangiocarcinoma). Interestingly, the new antibody was highly sensitive in that it detected GPC3 in low expression ovarian clear cell carcinoma and melanoma cells. The YP7 antibody exhibited significant HCC xenograft tumor growth inhibition in nude mice. These results describe an improved method for producing high-affinity monoclonal antibodies to cell surface tumor antigens and represent a general approach to isolate therapeutic antibodies against cancer. The new high affinity antibodies described here have significant potential for GPC3-expressing cancer diagnostics and therapy. PMID- 22820553 TI - GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT7 receptor activation in rats suffering from neuropathic pain. AB - Among receptors mediating serotonin actions in pain control, the 5-HT(7)R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT(7)R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT(7)R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT(7)R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1beta mRNA overexpression in ipsilateral L4-L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 MUg i.t.), but neither phaclofen (5 MUg i.t.) nor naloxone (10 MUg i.t.), significantly reduced the anti hyperalgesic effects of 5-HT(7)R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT(7)R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT(7)R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved. PMID- 22820554 TI - Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. AB - BACKGROUND: Modafinil, a putative cognitive enhancing drug, has previously been shown to improve performance of healthy volunteers as well as patients with attention deficit disorder and schizophrenia, mainly in tests of executive functions. The aim of this study was to investigate the effects of modafinil on non-verbal cognitive functions in healthy volunteers, with a particular focus on variations of cognitive load, measures of motivational factors and the effects on creative problem-solving. METHODS: A double-blind placebo-controlled parallel design study evaluated the effect of 200 mg of modafinil (N = 32) or placebo (N = 32) in non-sleep deprived healthy volunteers. Non-verbal tests of divergent and convergent thinking were used to measure creativity. A new measure of task motivation was used, together with more levels of difficulty on neuropsychological tests from the CANTAB battery. RESULTS: Improvements under modafinil were seen on spatial working memory, planning and decision making at the most difficult levels, as well as visual pattern recognition memory following delay. Subjective ratings of enjoyment of task performance were significantly greater under modafinil compared with placebo, but mood ratings overall were not affected. The effects of modafinil on creativity were inconsistent and did not reach statistical significance. CONCLUSIONS: Modafinil reliably enhanced task enjoyment and performance on several cognitive tests of planning and working memory, but did not improve paired associates learning. The findings confirm that modafinil can enhance aspects of highly demanding cognitive performance in non sleep deprived individuals. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22820555 TI - Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. AB - Modafinil is a central nervous system wake promoting agent used for the treatment of excessive daytime sleeping. Its vigilance promoting properties and low abuse potential has intrigued the scientific community and has led to use it as a cognitive enhancer, before its neural functions were understood. Here, we review the effects of modafinil in human cognition and emotion and its specific actions on symptoms in patients with schizophrenia and whether these are consistently effective throughout the literature. We also performed a systematic review on the effects of modafinil on neurotransmitter signalling in different areas of the brain in order to better understand the neuromechanisms of its cognitive and emotional enhancing properties. A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions, with pro-mnemonic effects and problem solving improvements. Emotional processing also appears to be enhanced by the drug, although to date there are only a limited number of studies. The systematic review on the neurochemical modulation of the modafinil suggests that its mnemonic enhancing properties might be the result of glutamatergic and dopaminergic increased neuronal activation in the hippocampus and in the prefrontal cortex respectively. Other neurotransmitters were also activated by modafinil in various limbic brain areas, suggesting that the drug acts on these brain regions to influence emotional responses. These reviews seek to delineate the neuronal mechanisms by which modafinil affects cognitive and emotional function. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22820556 TI - Neuroprotection of apelin and its signaling pathway. AB - Apelin was initially isolated from bovine stomach and is an endogenous neuropeptide. It is a native ligand of the apelin receptor (APJ). Some research has found that apelin peptides alter blood pressure, feeding behavior, and pituitary hormone release. However, a new neuroprotective effect of apelin peptides was only recently discovered. This review summarizes the evidence of apelin-neuroprotection, which has the potential to cure acute and chronic neurological diseases. PMID- 22820557 TI - Abstraction Augmented Markov Models. AB - High accuracy sequence classification often requires the use of higher order Markov models (MMs). However, the number of MM parameters increases exponentially with the range of direct dependencies between sequence elements, thereby increasing the risk of overfitting when the data set is limited in size. We present abstraction augmented Markov models (AAMMs) that effectively reduce the number of numeric parameters of k(th) order MMs by successively grouping strings of length k (i.e., k-grams) into abstraction hierarchies. We evaluate AAMMs on three protein subcellular localization prediction tasks. The results of our experiments show that abstraction makes it possible to construct predictive models that use significantly smaller number of features (by one to three orders of magnitude) as compared to MMs. AAMMs are competitive with and, in some cases, significantly outperform MMs. Moreover, the results show that AAMMs often perform significantly better than variable order Markov models, such as decomposed context tree weighting, prediction by partial match, and probabilistic suffix trees. PMID- 22820558 TI - HIV infection among persons born outside the United States. PMID- 22820559 TI - Role of extracorporeal life support in bridging patients to pulmonary transplantation. PMID- 22820560 TI - Intraoperative superselective embolization of a biopsy-related arteriocalyceal fistula during a kidney transplantation. PMID- 22820561 TI - Heart transplantation in a 36-year-old experiencing terminal heart failure caused by systemic sclerosis. PMID- 22820562 TI - Elevated troponin I and NT-proBNP at the time of transplantation may predict a major adverse cardiac event in the early postoperative period after renal transplantation. PMID- 22820563 TI - Use of an internal jugular vein graft for middle hepatic vein tributary reconstruction in right-lobe living-donor liver transplantation. PMID- 22820564 TI - Inhibitors of interleukin-2 inducible T-cell kinase as potential therapeutic candidates for the treatment of various inflammatory disease conditions. AB - Interleukin-2 inducible T-cell kinase (ITK), a member of Tec family of non receptor protein tyrosine kinases plays a domineering role in the T-cell development, differentiation and production of pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10, IL-13 and IL-17. This kinase is also an important contributor in Th 2 cells mediated autoimmune and allergic disease conditions, e.g. psoriasis, atopic dermatitis and allergic asthma. ITK modulates T-cell signaling by activating PLCgamma1 and regulating the extent of Ca2+ flux. It contributes in prolific T-cell responses by maintaining cellular adhesion and cytoskeleton reorganization via actin polymerization and integrin binding. This review article describes the structure of ITK and its role in T-cell signaling. In addition to this, data regarding small molecule inhibitors of ITK has also been reviewed from different papers and patents published. PMID- 22820565 TI - 16,17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and beta-cell proliferation in diabetic rat. AB - Reduces levels of intact GLP-1 and inhibition of DPPIV augments levels of intact GLP-1 improves glycemic control in type 2 diabetes patients and diabetic animal model. Although, GLP-1 is known to stimulate insulin secretion, insulin biosynthesis and dose insulin gene transcription, augmented supplies of insulin for secretion. DHIM is an indole alkaloid, isolated from Mitragyna parvifolia. In the present in vitro study, we investigated the inhibitor activity of novel alkaloid on DPP IV. DHIM produced marked inhibition of DPP IV. Accordingly, we used 5, 10 and 20 MUg DHIM alkaloids in DPPIV assay, and then found 18%, 56%, and 68% inhibition activity. In the present in vivo study, we examined the 16,17 dihydro-17b-hydroxy (DHIM) effect on neonatal Wistar albino rats treated with streptozotocin, an established model of type 2 diabetes. Diabetic rats, 8 weeks chronic administered with DHIM (100mg/kg) markedly reduced plasma glucose concentration, increased glucose tolerance in response to glucose loading. Consequently, GLP-1 and IL-10 levels were also significantly increased in treated diabetic rats. Despite, body weight was not found changed significantly; the insulin content and beta-cell mass at 2 months were significantly increased by DHIM. Immunostaining and Confocal image of TUNEL assay showed that DHIM stimulates beta-cell proliferation and reduced pancreatic cell apoptosis in diabetic treated rats. These results suggest that DHIM induces proliferation of pancreatic cells and increases the formation of beta-cells. PMID- 22820566 TI - Robotic-assisted endoscopic atrial septal defect closure: analysis of 115 cases in a single center. AB - OBJECTIVE: To summarize the experience with the application of robotic technique in totally endoscopic atrial septal defect closure in a single center. METHODS: Between January 2007 and September 2011, 115 patients with the diagnosis of secundum type atrial septal defects underwent robotic atrial septal defect repair with the assistance of da Vinci surgical system. The patients had a median age of 35 years and a median defect diameter of 28 mm. Cardiopulmonary bypass was established via peripheral cannulation. Via three 8-mm ports and one 15-mm port in the right chest, the surgeon manipulated the microinstruments to complete the defect closure with or without tricuspid valve plasty. Echocardiography was performed intraoperatively, before discharge and at 30 days after the operation. RESULTS: Atrial septal defect closure was completed on arrested heart in 44 patients and on beating heart in 61 patients. No deaths or conversions to alternate techniques occurred in these cases. No residual shunt was detected by intraoperative or postoperative echocardiography. The mean operating time and cardiopulmonary bypass time on bearing heart group were significantly shorter than those on arrested heart group. The median ventilation time, intensive care unit stay, drainage volume, or length of hospital stay showed no significant differences between the two groups. CONCLUSION: Secundum type atrial septal defect closure can be successfully performed with the assistance of the robotic system with good surgical results. PMID- 22820567 TI - [An anti-human ovarian carcinoma and CD3 bispecific single-chain antibody mediates CDR3 spectratype drift of T cell receptor alpha and beta chains]. AB - OBJECTIVE: To analyze the drift of T cell receptor (TCR) Valpha and Vbeta gene family CDR3 spectratype in response to ovarian carcinoma cells mediated by an anti-human ovarian carcinoma/CD3 bispecific single-chain antibody (BHL-1), and explore the mechanism of the bispecific single-chain antibody-mediated T cell immune response. METHODS: Immunoscopic spectratyping technique was used to analyze the TCR repertoire diversity (CDR3 spectratype distribution) of the T cells from 6 healthy donors before and after stimulation of the cells with human ovarian carcinoma in the presence of BHL-1. The predominant usage of TCR alpha and Vbeta chain CDR3 was analyzed after the stimulation, and sequence analysis was performed for the CDR3 region of the monoclonal T cells. RESULTS: The spectratypes of Valpha and Vbeta gene family TCR CDR3 region showed a Gaussian distribution before stimulation of the T cells from the 6 donors. After stimulation of the T cells, CDR3 spectratype drift occurred in the T cells, and some TCR Valpha and Vbeta families showed an anomalous and oligoclonal expansion. Different CDR3 sequences of the Valpha and Vbeta gene family TCR were found in the monoclonal T cells stimulated with BHL-1. CONCLUSION: CDR3 spectratype drift occurs in TCR alpha and Vbeta chains of T cells after stimulation with human ovarian carcinoma cells and BHL-1, indicating that the predominant usage of TCR Valpha and Vbeta families is associated with the specific T cell immune response mediated by BHL-1. PMID- 22820568 TI - [Protective effects of pomegranate polyphenols on cardiac function in rats with myocardial ischemia/reperfusion injury]. AB - OBJECTIVE: To determine the protective effect of pomegranate polyphenols on cardiac function in rats with myocardial ischemia/reperfusion (I/R) injury and explore the possible mechanism. METHODS: Fifty SD rats were randomized into 5 equal groups, including a sham-operated group, an I/R model group, and 3 pomegranate polyphenol dose groups (150, 300, and 600 mg/kg). The rats were subject to a 45-min left main coronary artery occlusion followed by a 180-min reperfusion to induce myocardial I/R injury except for the rats those in the sham operated group. The cardiac functions were monitored continuously during the experiment. At the end of the reperfusion, arterial blood samples were obtained to measure plasma contents of lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA) and the activities of superoxide dismutase (SOD). Triphenyltetrazolium chloride (TTC) staining was used to evaluate the infarct size. RESULTS: Compared with the sham-operated group, all the rats with I/R showed significantly decreased left ventricular systolic pressure (LVSP), maximal rates of increase/decrease of the left ventricular pressure (+/-dp/dtmax) (P<0.01) and significantly increased left ventricular end-diastolic pressure (LVEDP) (P<0.01). Compared with the I/R model group, all the 3 pomegranate polyphenol groups had significantly improved cardiac function (P<0.05), decreased plasma contents of CK, LDH and MDA (P<0.01), increased SOD activities (P<0.01), and obviously reduced infarct size (P<0.01). CONCLUSION: Pomegranate polyphenols can protect the cardiac function of rats with I/R injury probably in association with their actions in enhancing oxygen free radical scavenging activity and decreasing lipid peroxidative damage of the myocardial tissues. PMID- 22820569 TI - [Blocking p38 signal pathway lowers MMP-9 expression and reduces brain edema in rats with traumatic brain injury]. AB - OBJECTIVE: To explore the role of p38 signal pathway in regulating matrix metalloproteinase-9 (MMP-9) expression and brain edema formation in a rat model of traumatic brain injury (TBI). METHODS: A total of 130 adult male Sprague Dawley rats were randomly divided into 4 groups, namely the normal group (n=10), sham-operated group (n=40), TBI (induced by Feeney free falling methods) group (n=40), and SB group with intraperitoneal SB203580 treatment (10 umol/L) 15 min before TBI (n=40). The rats were sacrificed 2 h and 2 days after TBI. The expressions of p38, p-p38, and MMP-9 mRNA and protein were detected by RT-PCR and Western blotting. The blood brain barrier permeability was detected by Evans Blue (EB) test, and the brain water content (BWC) was determined using a gravimetric technique. RESULTS: The expression of p-p38 protein increased markedly 2 h after TBI (P<0.05), and was suppressed by SB203580 treatment (P<0.05). MMP-9 mRNA and protein showed no obvious increase at 2 h after TBI, but significantly increased at 2 days as compared with those in the sham-operated group (P<0.05). MMP-9 mRNA and protein were much lower in SB group than in TBI group 2 days after TBI (P<0.05). The blood brain barrier permeability significantly increased 2 h after TBI (P<0.05) and kept increasing until 2 days (P<0.05), but was reduced significantly by SB203580 (P<0.05). BWC increased obviously 2 days after TBI (P<0.05) and was lessened by SB203580 (P<0.05). CONCLUSION: Blocking p38 signal pathway can attenuate MMP-9 upregulation and brain edema after TBI, suggesting the important role of p38 in regulating MMP-9 expression to affect traumatic brain edema. PMID- 22820570 TI - [Protective effect of lentivirus-mediated Bcl-2 gene transfection against phosphoramide mustard-induced apoptosis of human ovarian granulosa cells]. AB - OBJECTIVE: To investigate the effect of lentivirus-mediated Bcl-2 gene transfection in protecting human primary ovarian granulosa cells against phosphoramide mustard (PM)-induced apoptosis. METHODS: Granulosa cells were isolated from the follicle fluid of women undergoing in vitro fertilization and embryo transfer. The lentiviral vectors carrying Bcl-2 gene (pGC-FU-Bcl-2) and enhanced green fluorescence protein (pGC-FU-EGFP) were constructed and packaged into high-titer lentiviruses. The resulting recombinant lentivirus carrying Bcl-2 and EGFP genes or the empty vector were used to infect the primary human ovarian granulosa cells, followed by addition of PM in the cell culture, with untreated granulosa cells as the control. The cell apoptosis was detected by Annexin V and Hochst 33258 staining, and the expression of Bcl-2 protein was assessed using Western blotting. RESULTS: The control granulosa cells showed an apoptotic rate of (1.93+/-0.28)%. The cells infected with pGC-FU-Bcl-2 prior to PM exposure had a apoptotic rate of (6.99+/-10.55)%, significantly higher than that of the control cells, but significantly lower than that of the cells with PM exposure only and those infected with the empty vector before PM exposure (P<0.05). The expression of Bcl-2 was the highest in the cells infected with pGC-FU-Bcl-2 prior to PM exposure (P<0.05). CONCLUSION: Lentivirus-mediated Bcl-2 gene transfection can protect human ovarian granulosa cells against PM-induced apoptosis by upregulating Bcl-2 protein expression. PMID- 22820571 TI - [Effect of ultrasound stimulation at the acupoint Guanyuan on follicular development in menopausal rats]. AB - OBJECTIVE: To observe the effect of ultrasound stimulation at the acupoint Guanyuan (CV 4) on follicular development in menopausal rats. METHODS: Menopausal female SD rats were selected by vaginal smear examinations. The rats were subjected to ultrasound stimulation at the acupoint Guanyuan with the output power of 0.1 W, working frequency of 9 MHz, and focal length of 4.5-5 mm. Electrochemiluminescence immunoassay was used to detect the serum estrogen levels of the menopausal rats. The changes in the ovarian tissue histology and the follicle number were observed. RESULTS: Compared with the control group, a 10-day ultrasound stimulation for 10 and 5 min daily at Guanyuan significantly increased the serum estrogen levels and the numbers of primary and secondary follicles (P<0.05) and reduced the number of atretic follicles in the menopausal rats (P<0.05). CONCLUSION: Ultrasound stimulation at the acupoint Guanyuan can increase the estrogen secretion function and promote the development of follicles in menopausal rats. PMID- 22820572 TI - [Protective effect of epalrestat against high glucose-induced endothelial cell injuries]. AB - OBJECTIVE: To study the protective effect of epalrestat against endothelial cell injuries induced by high glucose. METHODS: Human umbilical vein endothelial cells were pretreated with epalrestat (0.1 umol/L) for 30 min followed by exposure to high glucose for 8 h. NO concentration in the cell culture supernatant was assayed using chemiluminescence method following the exposure. Real-time PCR and Western blotting were used to detect eNOS mRNA and protein expression levels and the protein expressions of AR gene (the target gene of epalrestat) and NOX4 (the upstream gene of NO). RESULTS: Compared with mannitol treatment, an 8-h exposure to high glucose caused significantly decreased NO levels and eNOS mRNA and protein expression in the vascular endothelial cells (P<0.05). Pretreatment with epalrestat prior to high glucose exposure resulted in elevated eNOS mRNA and protein expression levels and NO up-regulation in the cell culture as compared with the glucose exposure alone group (P<0.05), causing also decreased expression of AR and NOX4 in the cells. CONCLUSIONS: High glucose can induce endothelial cell damage characterized by a lowered level of NO secretion. Epalrestat can protect the endothelial cells against high glucose-induced injury by inhibiting the expression of AR and NOX4. PMID- 22820573 TI - [Prolonged angiotensin-(1-7) infusion inhibits hepatic fibrosis in rats with bile duct ligation]. AB - OBJECTIVE: To observe the inhibitory effect of angiotensin-(1-7) on liver fibrosis induced by bile duct ligation in rats. METHODS: Eighteen Wistar rats were randomized into 3 groups and subject to sham operation, bile duct ligation (BDL), or BDL with angiotensin-(1-7) treatment. An osmotic minipump was implanted intraperitoneally for administration of saline in the sham-operated and BDL groups and angiotensin-(1-7) (25 ug.kg(-1).h(-1)) in angiotensin-(1-7) treatment group. After a 4-week treatments, the fibrosis score, Masson staining, and hydroxyproline assay were used to evaluate the level of liver fibrosis in the rats, and immunohistochemistry was used to detect expression of alpha-smooth muscle actin (alpha-SMA) in the liver tissue. RESULTS: Compared with BDL group, a 4-week treatment with angiotensin-(1-7) following BDL significantly reduced the fibrosis score (2.33+/-0.52 vs 5.17+/-0.75), hydroxyproline content (0.36+/-0.03 vs 0.52+/-0.04) and alpha-SMA expression (54.11+/-17.55 vs 191.84+/-31.72) in the liver tissue of the rats (P<0.01). CONCLUSION: Prolonged infusion of angiotensin (1-7) inhibit the formation of hepatic fibrosis in rats following bile duct ligation. PMID- 22820574 TI - [Design and realization of an algorithm for capsule endoscope image recognition system]. AB - Discrimination of abnormal images from the numerous wireless capsule endoscope (WCE) video sequence images is laborious and time-consuming, so that a computer based automatic image recognition system is desired for this task. We propose an algorithm to allow feature extraction from each image channel and decision fusion using multiple BP neural networks. The algorithm was tested and the results demonstrated its high efficiency and accuracy in identification of abnormalities in the WCE images. PMID- 22820575 TI - [Preparation and antibacterial properties of nano-TiO(2-x)N(x) film]. AB - OBJECTIVE: To prepare a nano-TiO2 film and characterize its antibacterial properties for dental application. METHODS: The TiO(2-x)N(x) antibacterial film was prepared by radio frequency (RF) magnetron sputtering. The crystal structure and surface morphology of the film were characterized by X-ray diffraction, scanning electron microscopy, and EDS, and the antibacterial properties of the film against common dental pathogenic bacteria were evaluated. RESULTS: The TiO(2 x)N(x) antibacterial film presented with an anatase phase with a mass ratio of nitrogen of 0.13% and compact and smooth surface. Antibacterial assay of the film showed a resistance rate of 97.79% against Streptococcus mutans, 49.42% against Actinomyces viscosus, and 96.84% against Candida albicans. CONCLUSION: The nano TiO(2-x)N(x) film shows strong antibacterial effects against common dental pathogenic bacteria and can be used as a novel antibacterial dental material. PMID- 22820576 TI - [Construction and functional studies of uropathogenic E. coli strains with ompT gene knockout]. AB - OBJECTIVE: To explore the role of ompT gene in uropathogenic E. coli (UPEC) CFT073 strain in urinary tract infection (UTI). METHODS: An ompT deletion mutant (COTD) was generated by lambda Red recombineering in the UPEC CFT073 strain, which was characterized by PCR and sequencing. C57B/L6 mouse models of acute UTI with the mutant and wild-type strains were established to compare the colonization abilities of the two strains in the bladder. The adhesion of CFT073 mutant to human unthelial 5637 cells was also investigated in vitro. RESULTS: PCR and DNA sequencing confirmed the loss of ompT gene in the mutant COTD. The in vitro adhesion rate of the mutant strain COTD to 5637 cells was (6.7+/-2.2)%, significantly lower than that of (8.3+/-1.9)% of the wild-type strain (P<0.05). In the murine models of acute UTI, the mutant strain showed a mean colonization number of about (17+/-8)*104 cfu, which was significantly lower than that of (7?2)*105 cfu of the wide-type CFT073 strain (P<0.05). CONCLUSION: OmpT gene can be involved in the colonization of UPEC in the bladder tissue and plays an important role in the pathogenesis of UPEC-induced UTI. PMID- 22820577 TI - [Relationship between traditional Chinese medicine syndrome types and serum HBV DNA level in chronic HBV carriers positive for HBeAg]. AB - OBJECTIVE: To explore the relationship between the syndrome types in traditional Chinese medicine (TCM) and serum HBV DNA load in chronic HBV carriers positive for HBeAg. METHODS: According to the TCM syndrome types, 185 chronic HBV carriers with HBeAg positivity were classified into single syndrome group (liver Qi depression, kidney Qi deficiency, spleen Qi deficiency, and kidney Yang deficiency), compound syndrome group, and unidentifiable syndrome group; based on the nature of the condition in TCM terms, the patients were classified into excess syndrome group, deficiency syndrome group and comorbidity syndrome group. The serum HBV DNA levels in these cases were analyzed in relation to the TCM syndrome types and disease nature. RESULTS: HBV DNA levels showed no significant difference among the patients with single syndrome, compound syndromes and unidentifiable syndrome (F=0.910, P=0.404), nor among the patients with the 5 different single TCM syndromes (chi2=4.672, P=0.323) or those with different disease nature (F=0.631, P=0.596). CONCLUSION: Serum HBV DNA level can not be considered as the evidence for syndrome differentiation in chronic HBV carriers with positive HBeAg. PMID- 22820578 TI - [Reduced expression of CASP8 in nasopharyngeal carcinoma and its clinical significance]. AB - OBJECTIVE: To explore the expression of CASP8 and its clinical significance in nasopharyngeal carcinoma (NPC). METHODS: The differentially expressed genes between pooled NPC tissues and non-cancerous nasopharyngeal (NP) tissues were screened using 8 microarrays. Real-time PCR and immunohistochemistry were used to validate the detection results of CASP8 expression in NPC, and the correlation of CASP8 expression to the clinical characteristics was analyzed in the NPC cases. RESULTS: Real-time PCR confirmed a reduced expression of CASP8 mRNA level in NPC tissues (P<0.0001), which was consistent with the microarray data. Immunohistochemistry indicated that CASP8 protein expression was also significantly down-regulated in NPC tissue compared to that in the non-cancerous nasopharyngeal tissues (P=0.02). The reduction of CASP8 expression was inversely correlated to lymph node metastasis (P=0.002) and the clinical stages (P=0.026) of NPC. CONCLUSION: Decreased CASP8 expression is an unfavorable factor that promotes the development and progression of NPC. PMID- 22820579 TI - [Effect of total flavonoids of Scutellaria baicalensis Georgi on expression of influenza A virus nucleoprotein in HeLa cells]. AB - OBJECTIVE: To investigate the effect of total flavonoids of Scutellaria baicalensis Georgi (TFSB) on exogenous expression of influenza A virus nucleoprotein (NP) in HeLa cells. METHODS: HeLa cells were transiently transfected with the empty vector pcDNA3.1(+) or pcDNA3.1(+)/NP vector harboring influenza A virus NP. The pcDNA3.1(+)/NP-transfected cells were treated with TSFB and the expression of influenza A virus NP in the cell supernatant was measured using colloidal gold immunochromatography 48 h after the transfection; fluorescent quantitative RT-PCR was performed to measure the starting copy number of NP gene. RESULTS: The cells transfected with pcDNA3.1 (+)/NP with and without TFSB treatment were positive for NP expression. Fluorescent quantitative RT-PCR showed that the starting copy number of NP gene in pcDNA3.1(+)/NP-transfected cells was (8.90+/-2.53)*106 copies/ul, showing no significant difference from that of (6.15+/-1.49)*106 copies/ul in pcDNA3.1(+)/NP-transfected cells with subsequent TFSB treatment (P>0.05). CONCLUSION: TFSB treatment does not obviously affect exogenous influenza A virus NP gene expression or its protein synthesis in HeLa cells. PMID- 22820580 TI - [Deferoxamine suppresses microglia activation and protects against secondary neural injury after intracerebral hemorrhage in rats]. AB - OBJECTIVE: To investigate the effect of the iron chelator deferoxamine (DFA) in suppressing microglia activation and protecting against secondary neural injury in a rat model of intracerebral hemorrhage (ICH). METHODS: SD rats were randomly divided into sham-operated group, ICH group and DFA treatment group. ICH model was established by infusion of type IV collagenase into the right basal ganglia, and starting from 1 h after the operation, the rats received intraperitoneal DFA injections every 12 h for 7 days. The iron content in the perihematoma brain tissue was determined at different time points after DFA administration, and OX42 immunohistochemistry was used to observe the changes in the microglia. The contents of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) in the brain tissue were detected by ELISA. The neural death and neurological deficiency were measured using Nissl staining and neurological scores, respectively. RESULTS: The iron content in the brain tissues around the hematoma was significantly increased 3 days after ICH and maintained a high level till 28 days, accompanied by a marked increase of microglial cells as compared to the sham-operated group. DFA injection caused significantly decreased iron content in the brain tissue, reduced number of microglial cells, and lowered levels of IL-1beta and TNF-alpha. Neuronal loss around the hematoma was obviously reversed after DFA injections, which resulted in improved neurological deficiency. CONCLUSION: DFA can suppress microglia activation by removing iron overload from the perihematoma brain tissue, thus reducing secondary neuronal death and neurological deficiency in rats with ICH. PMID- 22820581 TI - [Role of K(Ca)3.1 channel in proliferation and migration of rat vascular smooth muscle cells of the proliferative phenotype]. AB - OBJECTIVE: To investigate the role of K(Ca)3.1 channel in the proliferation and migration of rat vascular smooth muscle cells of the proliferative phenotype. METHODS: Rat vascular smooth muscle cells (VSMCs) were cultured with tissue adhesion method. The morphological characteristics of the fist and ninth passages of VSMCs were observed with light and electron microscopy and immunocytochemistry. The expressions of K(Ca)3.1 channel mRNA and protein in the cells were detected using RT-PCR and immunocytochemistry, respectively. MTT and transwell assay were employed to assess the effect of the K(Ca)3.1 channel blocker TRAM-34 on the proliferation and migration of VSMCs. RESULTS: The first and ninth passages of VSMCs showed morphological characteristics of contractile and proliferative phenotypes, respectively. Compared with the first- passage cells, the ninth-passage VSMCs exhibited significantly increased K(Ca)3.1 channel mRNA and protein expressions with enhanced cell proliferation and migration (P<0.01), which was inhibited by the application of TRAM-34 (P<0.01). TRAM-34 produced no obvious effect on the first-passage VSMCs. CONCLUSION: Upregulated expression of K(Ca)3.1 channel can promote the proliferation and migration of rat VSMCs of the proliferative phenotype. PMID- 22820582 TI - [Evaluation of carotid artery plaque stability with 18F-FDG PET/CT and contrast enhanced ultrasonography]. AB - OBJECTIVE: To assess the value of contrast-enhanced ultrasonography (CEUS) and fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in evaluating the stability of carotid atherosclerosis. METHODS: Seventeen patients with 21 carotid artery plaques received examinations with CEUS. According to the nature of the plaques, the patients were divided into soft and mixed plaque group and hard and calcified plaque group. The maximal enhancement intensity of the plaques (I(MAX)) and maximal plaque density (D(MAX)) were measured to quantify the neovasculature. The patients also underwent concurrent 18F-FDG PET/CT, and 18F-FDG uptake was quantified by the mean standard uptake values (SUV(mean)), an index reflecting the inflammatory activity in the plaque. The findings in CEUS and PET/CT were comparatively analyzed for these cases. RESULTS: The D(MAX) of the plaque in soft and mixed plaque group was significantly greater than that in hard and calcified plaque group (4.26+/-3.65 vs 1.41+/-1.47, P<0.05); the I(MAX) was also greater in the former group, but this difference was not statistically significant (26.83+/-19.61 vs 24.73+/ 29.85, P=0.869). The soft and mixed plaques tended to have higher SUVmean than the hard and calcified plaques (1.70+/-0.45 vs 1.47+/-0.12, P=0.099). The values of I(MAX) and D(MAX) were not found to correlate to SUV(mean) in these patients. CONCLUSION: CEUS can sensitively show the status of neovascularization within the carotid atherosclerosis plaques, and PET/CT reflects the inflammatory activity in the plaques. The combination of these two imaging modalities allows the evaluation of plaque stability in terms of neoangiogenesis and inflammatory activity. PMID- 22820583 TI - [Expression of SATB1 in hepatocellular carcinoma cell lines with different invasive capacities]. AB - OBJECTIVE: To study the expression of special AT-rich sequence binding protein 1 (SATB1) in hepatocellular carcinoma (HCC) cell lines with different invasive capacities. METHODS: SATB1 expression was detected using real-time fluorescence quantitative PCR, RT-PCR, Western blotting and immunofluorescence in immortalized liver cell line HL-7702, noninvasive HCC cell lines HepG2 and SMMC-7721, MHCC97L cells with low invasiveness, and highly invasive cell lines MHCC97H and HCCLM3. RESULTS: In comparison with HL-7702 cells, all the 5 HCC cell lines showed overexpression of SATB1 mRNA, which was the highest in the highly invasive HCCLM3 and MHCC97H cells, followed by MHCC97L cell line, and then by SMMC-7721 and HepG2 cell lines (P<0.001). The relative expression quantity of SATB1 protein in HepG2, SMMC-7721, MHCC97L, MHCC97H, and HCCLM3 cell lines was 0.271+/-0.002, 0.351+/ 0.023, 0.621+/-0.026, 0.878+/-0.026, and 1.236+/-0.006, respectively. SATB1 expression level in HCCLM3 cell line was 4.6-fold higher than that in HepG2 cell line (P<0.001). SATB1 was found to localize in the cytoplasm and cell nuclei of the 5 HCC cell lines, and the highly invasive HCCLM3 and MHCC97H cell lines showed a strong positive staining for SATB1 in immunofluorescence assay. CONCLUSION: SATB1 expression levels differ distinctly between the HCC cell lines with different invasive capacities and are possibly associated with the metastatic potentials of the cells. PMID- 22820584 TI - [Comparison of temporomandibular joint injuries after three-dimensional conformal and intensity-modulated radiotherapies for nasopharyngeal carcinoma]. AB - OBJECTIVE: To compare the radiation injuries of the temporomandibular joint (TMJ) following three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Thirty-nine NPC patients without previous radiotherapy underwent 3D-CRT and another 32 received IMRT in our institute. The distance between the 2 dens incisivus medialis (DDIM) and LENT SOMA criteria were employed to evaluate TMJ injuries, clinical outcomes, and the performance-to-price ratios. RESULTS: The short-term local response rates were similar between the two groups (P=0.878). The mean radiation doses of the TMJ were significantly higher in 3D-CRT group than in IMRT group (57.06 vs 40.90 Gy, P<0.001). The DDIM showed significant changes in 3D-CRT groups after the radiotherapy (P<0.05). No significant difference was found in the TMJ injuries between the two groups according to the SOMA criteria (P>0.05). CONCLUSION: Radiation injuries of the TMJ are tolerable in both 3D-CRT and IMRT groups, and 3D-CRT is a more economic choice for patients who can not afford IMRT. PMID- 22820585 TI - [Effect of lentiviral vector-mediated short hairpin RNA targeting survivin against endometriosis-like lesions in chick embryo chorioallantoic membrane]. AB - OBJECTIVE: To investigate the inhibitory effect of lentiviral vector-mediated short hairpin RNA targeting survivin (LV-survivin shRNA) on angiogenesis and growth of endometriosis-like lesions in chick en embryo chorioallantoic membrane. METHODS: Eutopic endometrium from women with endometriosis was transplanted onto the non-vascular region of (CAM), where LV-survivin shRNA was delivered subsequently. The angiogenesis and the growth of endometriosis-like lesions in the CAM model were evaluated. RESULTS: The angiogenesis and formation of endometriosis-like lesions were significantly suppressed in the CAM model by treatment with LV-survivin shRNA in comparison with those in the untreated CAM models and models treated with empty LV or DMEM (P<0.001). LV-survivin shRNA also caused a significantly higher cell apoptotic rate in the endometriosis-like lesions than the other treatments (P<0.001) and induced necrosis in the lesions. CONCLUSION: LV-survivin shRNA can effectively inhibit angiogenesis induced by the eutopic endometrium and markedly suppress the formation of endometriosis-like lesions in the CAM model. PMID- 22820586 TI - [Long-term outcomes of nilotinib treatment for chronic myelogenous leukemia patients with imatinib resistance or intolerance]. AB - OBJECTIVE: To evaluate the long-term clinical efficacy and safety of nilotinib in the treatment of chronic myelogenous leukemia (CML) patients with imatinib resistance or intolerance. METHODS: Twenty-six CML patients with imatinib resistance or intolerance received nilotinib treatment at the dose of 400 mg once or twice daily. The patients were followed up for nearly 5 years with regular monitoring of the hematologic, cytogenetic and molecular biological markers and recording of the clinical manifestations and biochemical indicators to evaluate the therapeutic effect and adverse events. RESULTS: The median duration of nilotinib therapy was 17 (1-56) months, and the patients were follow up for a median of 51 months. At the last follow-up, 16 (61.5%) patients achieved a complete hematologic response, 13 (50.0%) achieved a major cytogenetic response, 9 (34.6%) achieved a complete cytogenetic response, and 7 (26.9%) achieved a major molecular response accumulatively. Nonhematologic adverse events were mostly of grade l or 2. The most common adverse effects possibly related to nilotinib were increased bilirubin (69.2%) and rash (57.7%). Grade 3 or 4 hematologic adverse events included thrombocytopenia (53.8%), neutropenia (26.9%) and anemia (19.2%). The patients in chronic and remission phase had better efficacy and fewer hematological side effects than those in advanced phase. CONCLUSION: Nilotinib is an effective and safe treatment option for imatinib resistant or -intolerant CML patients, especially for those in chronic and remission phase. PMID- 22820587 TI - [Fractional anisotropy and somatosensory evoked potentials in the postcentral gyrus subcortex after acute infarction of the posterior limb of the internal capsule]. AB - OBJECTIVE: To investigate the relationship between fractional anisotropy (FA) and somatosensory evoked potentials (SEP) in the postcentral gyrus subcortex in patients with acute infarction of the posterior limb of the internal capsule. METHODS: Thirty-one patients with acute infarction of the posterior limb of the internal capsule underwent diffusion tensor imaging to obtain the FA values of the subcortical region of the postcentral gyrus with manual placement of the regions of interest (ROI). SEP and the sensory functions of the patients were examined and graded. RESULTS: In each SEP grade group, the FA values of the subcortical region of the postcentral gyrus were significantly decreased on the diseased side compared to those of the normal side (P<0.05). The FA values of the diseased side differed significantly between patients with different SEP grades (P<0.05), and increased SEP abnormalities were associated with lowered FA values. The sensory function of the patients was positively correlated to the grade of SEP (r=0.520, P<0.05). CONCLUSION: For patients with acute infarction of the posterior limb of the internal capsule, the changes of FA in the postcentral gyrus subcortex on the diseased side are correlated and complementary to SEP in evaluating the prognosis. PMID- 22820588 TI - [Impact of cytomegalovirus infections on T lymphocyte subsets in children with beta-thalassemia major early after allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the effect of human cytomegalovirus (HCMV) infection on T lymphocyte subsets in children with beta-thalassemia major (TM) during the initial 6 months after allogeneic hematopoietic stem cell transplantation (Allo HSCT). METHODS: From January, 2010 to January, 2011, 35 children with TM underwent Allo-HSCT. Peripheral blood samples were obtained from the children 6 month after the transplantation to examine the changes of T lymphocytes subsets in relation to HCMV seropositivity. RESULTS: Thirteen children were found seropositive and 22 were seronegative for HCMV. The HCMV-seropositive children had a higher CD8+ cell percentage but a lower CD4+ cell percentage than those without HCMV infection. Compared with those seronegative for HCMV, the children with HCMV seropositivity showed increased percentages of CD8+ cells and CD8+CD28- cells with a decreased percentage of CD8+CD28+ cells. A positive linear correlation was found between the percentages of CD8+CD28- cells and CD8+ cells. CONCLUSION: HCMV infection can lead to the accumulation of CD8+CD28 cells to cause increased CD8+ T cells in the peripheral blood in TM children after Allo HSCT. The percentages of CD8+CD28- cells has a positive linear correlation to that of CD8+ cells. PMID- 22820589 TI - [Laparoscopic radical cystectomy with extended pelvic lymph node dissection for bladder urothelial carcinoma: complications and oncologic outcomes in 210 cases]. AB - OBJECTIVE: To investigate the complications and oncologic outcomes of 210 cases of bladder urothelial carcinoma (BUC) treated with laparoscopic radical cystectomy (LRC) with extended pelvic lymph node dissection (EPLND) and assess the feasibility and safety of this surgical technique. METHODS: From January, 2003 to March 2010, 210 patients with BUC underwent LRC with EPLND. The cases with positive lymph nodes or T3a disease received adjuvant chemotherapy after the operation. The complications and oncologic results were recorded and analyzed. RESULTS: The mean operative time was 105 min in these cases with a mean blood loss of 220 ml and a rate of perioperative blood transfusion of 20.5%. The mean number of harvested lymph nodes was 17.6, and 42 (20%) cases were found to have positive lymph nodes. Minor and major perioperative complications occurred in 19% and 5.3% of the cases, respectively. The 5-year estimated overall survival, cancer-specific survival, recurrence-free survival and metastasis-free survival rates were 73.8%, 83.3%, 81.8% and 90.5%, respectively. CONCLUSIONS: LRC with EPLND is a safe and feasible technique for management of BUC and can produce satisfactory oncologic results. PMID- 22820590 TI - [Differential diagnosis of malignant and benign peripheral pulmonary lesions based on two characteristic echo features of endobronchial ultrasonography]. AB - OBJECTIVE: To assess the feasibility of endobronchial ultrasonography (EBUS) in the differential diagnosis of malignant and benign lesions based on the two characteristic echo features of malignancy. METHODS: EBUS images from 102 patients undergoing bronchoscopy for peripheral lung lesions were analyzed. The sensitivity and specificity were determined for each echo feature, namely the halo sign and low-level echoes that indicated malignancy, or their combination in diagnosing malignant and benign lesions. RESULTS: Low-level echoes showed a sensitivity of 89.46% and a specificity of 83% in the diagnosis of malignancy, both higher than those of the halo sign (69.51% and 65%, respectively). The presence of either of the two echo features had a diagnostic sensitivity of 94.6% for malignant lesions, and the coexistence of the two features had a specificity of 93% for a diagnosis of malignant lesions. CONCLUSION: EBUS is a useful adjunctive modality for lung cancer diagnosis, especially in cases where peripheral lung lesions are invisible in conventional bronchoscopy. PMID- 22820591 TI - [Association of cellular inhibitor of apoptosis protein-2 expression with clinical outcomes of hepatocellular carcinoma]. AB - OBJECTIVE: To study the expression of cellular inhibitor of apoptosis protein-2 (C-IAP2) mRNA and protein in hepatocellular carcinoma (HCC) and its relationship with the clinical outcomes. METHODS: Quantitative PCR and immunohistochemical staining were used to detect the expression of C-IAP2 mRNA and protein in the tumor tissues and corresponding adjacent non-cancerous tissues from HCC patients. RESULTS: The expression of C-IAP2 mRNA in HCC tissues was 2.70 folds higher than that in the non-cancerous tissues (P<0.001). The expression rate of C-IAP2 protein in HCC tissues was 70.8%, significantly higher than that in the non cancerous tissues (27.8%, P=0.001). The expression of C-IAP2 mRNA and protein was associated with the tumor emboli, lymph node metastasis, AFP level, histological differentiation, TNM stage, postoperative recurrence and metastasis (P<0.05), but not with the patients' gender, age, HbsAg positivity, number of tumors, cirrhosis or the presence of tumor encapsulation (P>0.05). CONCLUSION: The expression of C IAP2 in HCC is associated with tumor recurrence and metastasis, and can be a biological marker for prognostic evaluation of HCC. PMID- 22820592 TI - [Loop-mediated isothermal amplification for detecting enterohemorrhagic Escherichia coli O157:H7: a comparison with PCR]. AB - OBJECTIVE: To establish a rapid method of loop-mediated isothermal amplification (LAMP) for detecting enterohemorrhagic Escherichia coli (EHEC) O157:H7. METHODS: Six primers that specifically recognized the rfbE gene of EHEC O157:H7 were designed. Under the optimized reaction conditions, LAMP and PCR were evaluated for the sensitivity and specificity in the detection of 39 laboratory samples of EHEC O157:H7 strains, and their detection results of contaminated fresh pork samples were compared. RESULTS: LAMP assay correctly identified all the 7 EHEC O157:H7 strains and showed negative results for all the 32 non-EHEC O157:H7 strains. The detection limit of LAMP was much lower than that of rfbE-PCR (10 vs 100 cfu/ml). In the detection of the contaminated pork samples, both LAMP and PCR yielded results consistent with those by the conventional detection method. CONCLUSION: The rfbE-based LAMP assay can serve as a rapid, sensitive, specific and low-cost means for detecting EHEC O157:H7 strain. PMID- 22820593 TI - [Chronic exposure to trace chromium induces oxidative stress in mouse liver cells]. AB - OBJECTIVE: To explore the effects of chronic exposure to trace chromium (VI) as a result of metal-on-metal hip arthroplasty on oxidative stress in mouse liver cells. METHODS: Eighty NIH mice were randomly divided into 4 groups and subject to intraperitoneal injection of CrO(3) at the dose of 0, 5, 10 or 20 mg/kg every other day for 16 weeks. Five mice from each group were selected every 4 weeks for determining the content of chromium (VI) in the whole blood and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione reductase (GR) activity, and glutamate cysteine ligase (GCL) expression in the liver cells. The ultrastructural changes of the liver cells were also observed using transmission electron microscopy. RESULTS: Exposure to 5 and 10 mg/kg CrO(3) caused significantly increased blood chromium concentration and ROS level, which reached the peak level at 8 weeks and became stabilized, whereas at the dose of 20 mg/kg, CrO(3) exposure resulted in progressive, time dependent increase of blood chromium concentration and ROS level. MDA showed no significant changes in the 4 groups. With the prolongation of the exposure time, GSH content and GR activity were decreased in these groups. In 5 and 10 mg/kg CrO(3) groups, GCL expression increased at each time point of measurement, but in 20 mg/kg group, GCL expression decreased gradually with a prolonged exposure. Transmission electron microscopy revealed apoptotic changes of the liver cells in 20 mg/kg group. CONCLUSION: The slow accumulation of trace chromium (VI) after metal-on-metal hip arthroplasty may cause oxidative stress and changes in the oxidative stress system in the liver cells. PMID- 22820594 TI - [Application of micro-computed tomography-based 3D visualization in diagnosis and treatment of cervical cancer]. AB - OBJECTIVE: To define the optimal development time of micro-computed tomography (micro-CT) venography in cervical cancer patients and establish 3D CT-based digital pelvic model of the patients. METHODS: Thirty patients with cervical cancer stratified by FIGO surgical staging underwent micro-CT scanning of the arterial phase and the venous phase with a delay time of 70, 90 and 120 s. The images were interpreted independently by two experienced radiologists to define the optimal development time in venous phase and establish the imaging diagnosis. Based on the pelvic CT scan data, we segmented the images using the abdominal medical image-3D visualization system followed by 3D image reconstruction to establish the 3D digital pelvic model using FreeForm Modeling System to modify the reconstructed images. RESULTS: The optimal images were obtained by scanning with a 90-sec delay time. Micro-CT was not sensitive to IB1 phase or earlier phases (1/5), but efficient in advanced stages (>=IB2 phase). In our cases, 25 were diagnosed by micro-CT with a diagnostic accuracy of 64%. Based on these CT data, the pelvic 3D model covering the main organs, vessels, cervical neoplasm, and supplying vessels of the tumor in the pelvic cavity were successfully reconstructed to allow spatial observations of the uterus and the neighboring organs. CONCLUSION: The 3D digital pelvic model reconstructed provides a means for staging cervical cancer and facilitates further surgical simulation studies. PMID- 22820595 TI - [Chaiqiyigan granula enhances Taxol-induced growth inhibition of hepatocellular carcinoma xenografts in nude mice: an in vivo fluorescence imaging study]. AB - OBJECTIVE: To study the effects of Chaiqiyigan Granula (CG) and Taxol on the growth of hepatocellular carcinoma (HCC) xenografts and expression of Bax, p53 and VEGF in nude mice. METHODS: Whole-body fluorescence imaging was used to visualize the growth of HCC in nude mice bearing hepG2/EGFP cell xenograft. Immunohistochemistry was used to determine the content of Bax, p53 and vascular endothelial growth factor (VEGF) in the tumor tissues. RESULTS: Compared with normal saline, Taxol alone and in combination with CG significantly inhibited the growth of HCC xenografts in the nude mice. The combined treatment with CG and Taxol produced a stronger inhibitory effect on the tumor growth than Taxol alone in the third and fourth weeks. The volume and weight of the xenografts were decreased in the combined treatment group compared with those in saline treatment group. CG combined with Taxol increased the expression of Bax and reduced the expression of p53 and VEGF in the tumor xenografts. CONCLUSION: CG can enhance the inhibitory effects of Taxol on the growth of HCC xenografts, and this effect is related to the up-regulation of Bax and down-regulation of p53 and VEGF expression in the tumor. PMID- 22820596 TI - [Effect of painless urethral catheterization combined with lidocaine on urethral irritation]. AB - OBJECTIVE: To evaluate the effect of placement of urethral catheter combined with lidocaine on urethral irritation caused by postoperative indwelling catheters. METHODS: A total of 120 male surgical patients requiring postoperative indwelling catheters between June 2011 and January 2012 were divided into two equal groups for placement of painless urethral catheter combined with bladder washing with lidocaine on the first postoperative day, or for routine catheter placement only. The symptoms of urethral irritation such as urethral pain, urinary urgency, and perineal discomforts were observed and compared between the two groups. RESULTS: In patients with painless urethral catheter placement combined with bladder washing with lidocaine, 11 developed urethral irritation symptoms, as compared to 24 in the patients with routine catheter placement only, showing a significant difference between the two groups (P<0.05). CONCLUSION: Placement of painless urethral catheter combined with bladder washing with lidocaine can significantly reduce the incidence of urethral irritation due to postoperative indwelling catheters. PMID- 22820597 TI - [Value of magnetic resonance imaging in preoperative staging of endometrial carcinoma according to International Federation of Gynecology and Obstetrics (2009) staging criteria]. AB - OBJECTIVE: To analyze the magnetic resonance imaging (MRI) features of endometrial carcinoma and their value in endometrial carcinoma staging according to the International Federation of Gynecology and Obstetrics (FIGO 2009) staging criteria. METHODS: Fifty-four patients with pathologically confirmed endometrial carcinoma and complete clinical data underwent preoperative MRI examination. According to FIGO 2009 staging criteria of endometrial carcinoma, the MRI features of the tumor lesions were evaluated for assessment of myometrial invasion and cervical involvement and preoperative staging. RESULTS: The 54 cases included 27 stage Ia cases, 9 stage Ib cases, 10 stage II cases, 5 stage III cases, and 3 stage IV cases. The total lesion display rate by MRI was 94% (51/54). With an isointensity or hypo-intensity on T1WI, the tumor lesions showed a moderate hyper-intensity on T2WI. In enhanced MRI scanning, the lesions showed a moderate heterogeneous enhancement, which had a lower intensity than the marked enhancement of the myometrium. Combination of T2WI and T1WI in fat suppression sequence enhanced scan had a diagnostic accuracy of 91% (49/54) for myometrial invasion, and the sensitivity, specificity and accuracy of MRI for detecting cervical involvement were 77%, 89%, and 83%, respectively. The accuracy of preoperative MRI-based staging of endometrial carcinoma was 89% (48/54), showing no significant difference from the results of postoperative FIGO 2009 staging and pathological examination (P>0.05). CONCLUSION: MRI has a high accuracy in the diagnosis, evaluation of myometrial and cervical invasion depth, and preoperative staging of endometrial carcinoma, and serves as an important modality in assisting clinical decisions on the optimal therapeutic protocols and in prognostic estimation. PMID- 22820598 TI - [Effect of necrotic wound tissue decomposition products on serum inflammation factors in rabbits]. AB - OBJECTIVE: To observe the effect of the decomposition products of necrotic tissues from wounds on the serum levels of inflammation factors in comparison with endotoxin. METHODS: Thirty adult New Zealand rabbits were randomly divided into 3 groups and received injections of saline, necrotic tissue homogenate or endotoxin. From each rabbit, blood samples (2 ml) were collected from the central artery of the ears at 0, 2, 6, 12, 24, 30, 36, 48, and 60 h after the injection for measurement of serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6. RESULTS: The serum level of TNF-alpha, IL-1 and IL 6 in the rabbits increased 2-4 h after injection of the necrotic tissue homogenate and reached the peak level at 12 h, followed by a gradual reduction since 36 h. No obvious changes in the levels of the inflammatory factors were found in saline group (P<0.01). Compared with endotoxin, necrotic tissue homogenate resulted in an early increment (2-4 h vs 5-6 h) and significantly higher peak levels (at 30 h) of the inflammation factors (P<0.05). Curve fitting showed a distinct difference between necrotic tissue homogenate and endotoxin in their effect on the inflammatory factors. CONCLUSION: The necrotic tissue decomposition products contain toxic substances that possess a different toxicity profile from endotoxin, and their toxicity can be even stronger. PMID- 22820599 TI - [Endoscope-assisted goniosynechialysis with phacoemulsification and intraocular lens implantation for treatment of primary angle-closure glaucoma]. AB - OBJECTIVE: To evaluate the early therapeutic effect of endoscope-assisted goniosynechialysis combined with phacoemulsification and intraocular lens implantation for management of primary angle-closure glaucoma. METHODS: Endoscope assisted goniosynechialysis combined with phacoemulsification and intraocular lens implantation was performed in 31 patients (31 eyes) with primary angle closure glaucoma, including 17 eyes with acute angle closure glaucoma and 14 eyes with chronic angle closure glaucoma. The patients were regularly followed up to observe the postoperative complications and changes in the intraocular pressure, visual acuity, anterior chamber depth and anterior chamber angle. RESULTS: Hyphema occurred in 3 eyes after the operation and was absorbed gradually. The intraocular pressure decreased significantly in all the patients after the operation (P<0.05) but showed no significant differences between the acute and chronic cases (P>0.05). The intraocular pressure was over 21 mmHg in only one eye in the chronic group, and could be controlled by ocular hypotensive agents. Visual acuity improved and the anterior chamber depth increased in all the patients, showing no significant differences between the two groups (P>0.05). The anterior chamber angle all opened after the operation in 16 eyes (94.1%) in acute group, a rate significantly higher than that in the chronic group (9 eyes, 64.3%) (P<0.05). Anterior chamber angle was adhesive in 1 eye in the acute group and in 5 eyes in the chronic group. No further extension of goniosynechiae was found in these cases during the follow-up period. CONCLUSIONS: Endoscope-assisted goniosynechialysis has such advantages as optimized visualization, accuracy and safety in the management of primary angle-closure glaucoma. PMID- 22820600 TI - [Granzyme B-VEGF receptor-binding peptide fusion protein expressed in B. longum induces apoptosis of KDR-positive cells]. AB - OBJECTIVE: To express granzyme B-vascular endothelial growth factor (VEGF) receptor-binding peptide (GrB-VRB) fusion protein in Bifidobacteria longum (B. longum) and investigate the effects of this fusion protein on the proliferation and apoptosis of cells expressing VEGF receptor II, the kinase domain receptor (KDR). METHODS: The recombinant expression vectors pBBADx-VRB, pBBADx-GrB and pBBADx-GrB-VRB were separately transformed into B. longum cells by electroporation. The expressed products were identified by enzyme-linked immunosorbent assay and Western blotting, and their effects on KDR-positive cells were analyzed using proliferation assay and TUNEL assay. RESULTS: The expressed products were detected in both the supernatant and cellular fractions of B. longum cells. The recombinant GrB-VRB fusion protein reacted with such KDR positive cells as human umbilical vein endothelial cells (HUVEC) and mouse colon cancer cell line CT-26, and caused obvious cell proliferation inhibition, cytotoxicity and cell apoptosis in these cells. CONCLUSION: The recombinant GrB VRB fusion protein secreted by the engineered B. longum cells can induce KDR positive cell death as the result of GrB-induced cell apoptosis following the cell recognition by VRB. PMID- 22820601 TI - [Prophylactic recombinant human thrombopoietin treatment alleviates chemotherapy- induced thrombocytopenia in tumor patients]. AB - OBJECTIVE: To assess the efficacy of prophylactic treatment with recombinant human thrombopoietin (rhTPO) on chemotherapy-induced thrombocytopenia in tumor patients. METHODS: In this randomized cross-over self-controlled clinical trial, 24 patients with malignant neoplasms were randomized group A (12 cases) and group B (12 cases). All the patients underwent two identical cycles of chemotherapy. In group A, RhTPO (1.0 ug/kg) was administered subcutaneously on a daily basis 3 days before the second chemotherapy cycle for 7 consecutive days, and in group B, RhTPO was administered daily 6-24 h after the second chemotherapy cycle for 7 days. In both groups, RhTPO was not administered in the first chemotherapy cycle, which served as the control cycle. RESULTS: In both the groups, platelet count was significantly higher in the second cycle than in the control cycle, and the duration of thrombocytopenia was significantly shortened in the second cycle. Compared with group B, the patients in group A showed a significantly higher platelet count in the second cycle and a significantly shorter duration of thrombocytopenia in the second cycle. CONCLUSION: Prophylactic administration of rhTPO can significantly reduce the severity and duration of thrombocytopenia and promote platelet recovery in patients undergoing chemotherapy for malignant tumors. PMID- 22820602 TI - Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. AB - Glycolipids presented by the major histocompatibility complex (MHC) class I homolog CD1d are recognized by natural killer T cells (NKT cells) characterized by either a semi-invariant T cell antigen receptor (TCR) repertoire (type I NKT cells or iNKT cells) or a relatively variable TCR repertoire (type II NKT cells). Here we describe the structure of a type II NKT cell TCR in complex with CD1d lysosulfatide. Both TCR alpha-chains and TCR beta-chains made contact with the CD1d molecule with a diagonal footprint, typical of MHC-TCR interactions, whereas the antigen was recognized exclusively with a single TCR chain, similar to the iNKT cell TCR. Type II NKT cell TCRs, therefore, recognize CD1d-sulfatide complexes by a distinct recognition mechanism characterized by the TCR-binding features of both iNKT cells and conventional peptide-reactive T cells. PMID- 22820604 TI - Effects of 17beta-estradiol on human corneal wound healing in vitro. AB - PURPOSE: To investigate the effect of 17beta-estradiol on corneal wound healing, particularly on epithelial mitosis and migration. METHODS: Immortalized human corneal epithelial cells (HCECs) were cultured in media with different concentrations of 17beta-estradiol (10, 50, 100, and 200 pg/mL), Dulbecco modified Eagle medium: Nutrient Mixture F-12 (negative control), and serum containing Dulbecco modified Eagle medium: Nutrient Mixture F-12 (positive control). After 6 or 24 hours of hormone treatment, to evaluate the migratory potential of 17beta-estradiol, wound healing assays were conducted via the manual scraping of HCECs and western blot analysis of fibronectin and matrix metalloproteinase 9 (MMP9). The proliferative potential of 17beta-estradiol was evaluated via a proliferation assay using western blot analysis for proliferating cell nuclear antigen. In addition, epidermal growth factor (EGF) was measured by reverse transcription-polymerase chain reaction, and for the inhibition of epidermal growth factor receptor (EGFR)-mediated signal transduction, a wound healing assay was conducted after HCECs cultured with EGFR small interfering RNA were stimulated with 100 pg/mL 17beta-estradiol. RESULTS: Wound healing assay rates were enhanced as 17beta-estradiol increased, with statistically significant changes seen in 50, 100, and 200 pg/mL 17beta-estradiol-treated and positive control cells, compared with negative control cells (P < 0.05, in each group). Western blot analysis revealed that the expression of the MMP9 gene was upregulated by 17beta-estradiol, and the expression of the fibronectin gene was downregulated by 17beta-estradiol. The mitosis assay via western blot analysis showed that the expression cell cycle-associated protein, proliferating cell nuclear antigen, increased gradually as a result of 17beta-estradiol treatment. Reverse transcription-polymerase chain reaction showed that EGF was upregulated by 17beta-estradiol, and the EGFR small interfering RNA did not totally block the wound healing of the 17beta-estradiol-treated cells but statistically significantly reduced the wound healing rate (P = 0.031). CONCLUSIONS: 17beta Estradiol facilitated the maintenance of the beneficial effect on corneal epithelial migration and proliferation, and the promoting effect of 17beta estradiol is partially related to increased EGF in vitro. PMID- 22820603 TI - Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. AB - Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRalpha and TCRbeta chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells. PMID- 22820605 TI - Novel maneuver facilitating Descemet membrane unfolding in the anterior chamber. AB - PURPOSE: To describe a new technique for unfolding of the Descemet membrane (DM) during Descemet membrane endothelial keratoplasty. METHODS: DM and endothelium were stripped from donor corneas submerged in corneal storage solution. Donor DM diameters were 8.5 mm. The central 8 mm of DM was stripped from the recipient cornea. After staining with trypan blue to improve visualization, donor DM was inserted through a 2.75-mm incision. Unfolding was achieved with simultaneous digital pressure in the equatorial region and tapping of the corneal surface. This technique was performed in Descemet membrane endothelial keratoplasty patients with Fuchs endothelial dystrophy (n = 6) and bullous keratopathy (n = 4). RESULTS: In all cases, a fast attachment of the DM was achieved. The recurling was successfully hindered because of the simultaneous equatorial pressurization and induced fluid currents inside the anterior chamber by appropriate corneal tapping. In all cases, a rapid corneal clearance was achieved with significantly increased visual acuity (logarithm of the minimal angle of resolution visual acuity preoperative = 0.90, logarithm of the minimal angle of resolution visual acuity final assessment = 0.19, P < 0.001; follow-up 14 +/- 5 weeks). CONCLUSION: Simultaneous digital pressure with corneal tapping is a helpful maneuver to unfold the DM inside the anterior chamber. This technique may reduce the need for unnecessary instrumental and noninstrumental manipulation of the graft. PMID- 22820606 TI - Histological findings in a failed corneal riboflavin-UVA collagen cross-linking performed for progressive keratoconus. AB - PURPOSE: To report the histological and immunohistochemical findings in a cornea removed from a patient who had undergone collagen cross-linking (CXL) with riboflavin and ultraviolet-A for progressive keratoconus. CXL was performed following the Siena protocol. Two years post-CXL, a visual acuity impairment in the treated eye secondary to corneal stromal opacity had occurred, together with corneal thinning and flattening. METHODS: The excised cornea was formalin-fixed, paraffin-embedded, and examined microscopically. Deparaffinized 4-MUm sections were stained with hematoxylin-eosin and Masson trichrome. Further tissue sections were subjected to immunohistochemical evaluation of CD34 and Ki-67 antigens. RESULTS: Histologically, there was no scar tissue in the failed cornea. The biomicroscopic stromal opacity corresponded microscopically to an acellular area, devoid of keratocytes, and to compaction of the lamellar collagen. Amorphous, weakly eosinophilic interlamellar deposits, extending from the anterior to the posterior two thirds of the stroma, were noted. CONCLUSIONS: CXL is a promising procedure for the treatment of progressive keratoconus with minimal reported side effects. In the present case, we speculate that the short corneal soaking time (15 minutes according to the Siena protocol) may have resulted in inefficient ultraviolet-A blocking, thermal injury, and deeper keratocyte death. Inadequate keratocyte stem cells reservoir could also play a role in individual cases. PMID- 22820607 TI - Eye bank tissue utilization between endothelial keratoplasty and penetrating keratoplasty. AB - PURPOSE: To determine rates of tissue use for corneal transplants via endothelial keratoplasty (EK) relative to penetrating keratoplasty (PK). METHODS: Retrospective chart review of all cornea tissues (n = 3669) distributed from the Lions Eye Bank of Wisconsin for EK or PK from August 1, 2004 through July 31, 2009 (60 months). Rates of tissue use for EK relative to PK were determined both on a yearly basis and for the overall study period. Replacement frequency and time to subsequent surgery were established for each group. Donor tissue and recipient characteristics were compared between groups. RESULTS: Donor characteristics did not differ between the 2 groups; 11.9% of EK tissues failed and were replaced during the study period compared with 5.1% of PK tissues (P < 0.0001). Additional tissue for the same eye came at a mean of 174 days after an EK surgery compared with 558 days after a PK (P < 0.0001). Surgeons requesting tissue for EK increased each year, whereas the number of repeat tissue requests decreased over time. CONCLUSIONS: Additional tissues were required for recipients of EK more than twice as often as for recipients of PK, and replacement of EK grafts occurred at a mean of more than 1 year before replacement of PK grafts. This pattern of tissue utilization during the first 5 years of distribution for EK did not negatively affect the Lions Eye Bank of Wisconsin from meeting the surgeon demand for tissue in its service area. Eye banks may wish to monitor tissue utilization as part of their quality assurance program. PMID- 22820608 TI - Assessing natural groupings of common leisure-time physical activities and its correlates among US adolescents. AB - OBJECTIVES: We examined the natural groupings of leisure-time physical activities (LTPA) among US adolescents and their correlates. METHODS: Data came from the 1999-2006 NHANES, restricted to 3865 boys and 3641 girls 12-19 years old. Respondents were asked to report > 40 types of moderate-to-vigorous LTPA in the past month. Latent class analyses were used to identify natural groupings of the top 10 LTPA using the proportion of each activity's metabolic equivalents (METs) to total energy expenditure from all physical activities. RESULTS: For each gender, 5 natural groupings of LTPA were identified. Among boys, they were basketball players and runners (72.8%), football players (9.0%), bicycle riders (7.5%), soccer players (5.8%), and walkers (4.7%). For girls, the 5 natural groupings in descending order were dancers/walkers/joggers (79.0%), aerobic exercisers (6.1%), swimmers (5.6%), volleyball players (4.9%), and soccer players (4.2%). The natural groupings of physical activities were also impacted by age, race, weight status, region, and season of interview. CONCLUSIONS: The natural groupings of LTPA reflect adolescent's preference and these activity patterns are likely shaped by their social and physical environments. Better understanding of common LTPAs and their natural groupings is useful in the design of effective PA interventions. PMID- 22820609 TI - Diffusion driven optofluidic dye lasers encapsulated into polymer chips. AB - Lab-on-a-chip systems made of polymers are promising for the integration of active optical elements, enabling e.g. on-chip excitation of fluorescent markers or spectroscopy. In this work we present diffusion operation of tunable optofluidic dye lasers in a polymer foil. We demonstrate that these first order distributed feedback lasers can be operated for more than 90 min at a pulse repetition rate of 2 Hz without fluidic pumping. Ultra-high output pulse energies of more than 10 MUJ and laser thresholds of 2 MUJ are achieved for resonator lengths of 3 mm. By introducing comparatively large on-chip dye solution reservoirs, the required exchange of dye molecules is accomplished solely by diffusion. Polymer chips the size of a microscope cover slip (18 * 18 mm(2)) were fabricated in batches on a wafer using a commercially available polymer (TOPAS((r)) Cyclic Olefin Copolymer). Thermal imprinting of micro- and nanoscale structures into 100 MUm foils simultaneously defines photonic resonators, liquid core waveguides, and fluidic reservoirs. Subsequently, the fluidic structures are sealed with another 220 MUm foil by thermal bonding. Tunability of laser output wavelengths over a spectral range of 24 nm on a single chip is accomplished by varying the laser grating period in steps of 2 nm. Low-cost manufacturing suitable for mass production, wide laser tunability, ultra-high output pulse energies, and long operation times without external fluidic pumping make these on chip lasers suitable for a wide range of lab-on-a-chip applications, e.g. on-chip spectroscopy, biosensing, excitation of fluorescent markers, or surface enhanced Raman spectroscopy (SERS). PMID- 22820610 TI - Live cell imaging of lysosomal pH changes with pH responsive ratiometric lanthanide probes. AB - Europium and terbium complexes of two structurally related ligands have been evaluated as optical probes to monitor changes in lysosomal pH; calibration using ionophores and fluorescent probes allows monitoring of the time dependence of lysosomal pH change, examining the green/red intensity ratio from internalised Tb Eu complexes. PMID- 22820611 TI - Neuropathic truncal pain--a case series. PMID- 22820612 TI - Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus non-nucleoside reverse transcriptase inhibitor-based regimens. AB - OBJECTIVES: To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens. DESIGN: Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine. METHODS: Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation. RESULTS: Sixteen HIV positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4 T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4 T-cell percentage was due largely to declines in CD8 T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8 T-cell numbers in the duodenal tissue lamina propria. CONCLUSIONS: This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4 T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8 T lymphocytes in GALT. Factors other than viral induced CD8 expansion may be contributing to this local immunologic response. PMID- 22820613 TI - The care processes for acute cholecystitis according to clinical practice guidelines based on the Japanese administrative database. AB - Acute cholecystitis is one of the most frequently encountered conditions in daily practice in Japan. However, there is a shortage of detailed data about treatments that have been performed according to the clinical practice guidelines (CPGs) for acute cholecystitis. We therefore examined the management of acute cholecystitis for adherence to the appropriate CPGs using the Japanese administrative database associated with the Diagnosis Procedure Combination (DPC) system. We collected data from 6,070 patients with acute cholecystitis, examining for the application of four recommended treatments (administration of antimicrobial drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) and performance of early and laparoscopic cholecystectomy). The patients were classified according to the procedures documented for each case: no gallbladder drainage (n = 4,333), gallbladder drainage without supportive care (ventilation or hemodiafiltration or the use of vasopressor) (n = 1,591) and gallbladder drainage and supportive care (n = 146). Multiple logistic regression models revealed that patients with gallbladder drainage without supportive care and those with gallbladder drainage and supportive care significantly higher received administration of antimicrobial drugs and NSAIDs, while these patients underwent less early or laparoscopic cholecystectomy than did patients without gallbladder drainage, after adjusting for potential confounding effects of the clinical variables. This study demonstrated that there were various differences with regard to the performance of recommended treatments between the levels of procedures required for acute cholecystitis. In addition, this administrative database was a feasible tool for the evaluation of care processes and will provide useful information contributing to improved quality of medical care. PMID- 22820614 TI - Accumulation of arsenic by aquatic plants in large-scale field conditions: opportunities for phytoremediation and bioindication. AB - This work focuses on the potential of aquatic plants for bioindication and/or phytofiltration of arsenic from contaminated water. More than 71 species of aquatic plants were collected at 200 sampling points in running waters. The results for the 18 most representative plant species are presented here. The species Ranunculus trichophyllus, Ranunculus peltatus subsp. saniculifolius, Lemna minor, Azolla caroliniana and the leaves of Juncus effusus showed a very highly significant (P<0.001) positive correlation with the presence of arsenic in the water. These species may serve as arsenic indicators. The highest concentration of arsenic was found in Callitriche lusitanica (2346 mg/kg DW), Callitriche brutia (523 mg/kg DW), L. minor (430 mg/kg DW), A. caroliniana (397 mg/kg DW), R. trichophyllus (354 mg/kg DW), Callitriche stagnalis (354 mg/kg DW) and Fontinalis antipyretica (346 mg/kg DW). These results indicate the potential application of these species for phytofiltration of arsenic through constructed treatment wetlands or introduction of these plant species into natural water bodies. PMID- 22820615 TI - Impact of sampling frequency on mean concentrations and estimated loads of suspended sediment in a Norwegian river: implications for water management. AB - Reliable estimates of mean concentrations and loads of pollutants in rivers have become increasingly important for management purposes, particularly with the implementation of the European Union Water Framework Directive (WFD). Here, the Numedalslagen River (5500 km(2)) in southern Norway was used as a case study to evaluate the effects of sampling frequency on mean concentrations and estimated loads of suspended particulate matter (SPM). Daily monitoring data from five seasons (April/June-October/November 2001-2005) were analyzed, and three different load estimation techniques were tested: rating curves, linear interpolation, and the ratio method. The reliability of mean SPM concentrations improved with increasing sampling frequency, but even weekly sampling gave error rates as high as 70% in seasons with elevated sediment loads. Load estimates varied considerably depending on both the sampling frequency and the calculation method used. None of the methods provided consistently good results, but the lowest error rate was achieved when using the rating curve on data from fortnightly sampling and additional sampling during floods. Sampling at monthly intervals gave the highest error rates and cannot be recommended for any of the calculation methods applied here. SPM concentrations were correlated (r(2)>0.5) with arsenic, lead, nickel, orthophosphate, and total phosphorus in the Numedalslagen River. Therefore, the current findings may also have implications for substances other than SPM. The discussion considers examples from actual use of infrequently collected data, and it is advised that managers account for uncertainties in both concentration means and load estimates when assessing the state of a water body or planning mitigation measures. PMID- 22820616 TI - Metals in residential soils and cumulative risk assessment in Yaqui and Mayo agricultural valleys, northern Mexico. AB - This investigation examines the extent of soil metal pollution associated with the Green Revolution, relative to agricultural activities and associated risks to health in the most important agricultural region of Mexico. Metal contents in bulk soil samples are commonly used to assess contamination, and metal accumulations in soils are usually assumed to increase with decreasing particle size. This study profiled the spatial distribution of metals (Ni, Cr, Pb, Cu, Fe, Cd, V, Hg, Co, P, Se, and Mn) in bulk soil and fine-grained fractions (soil derived dust) from 22 towns and cities. The contamination of soil was assessed through the use of a geoaccumulation index (Igeo) and pollution index (PI). The results of this study indicated that a number of towns and cities are moderately to highly polluted by soil containing Be, Co, Hg, P, S, V, Zn, Se, Cr, and Pb in both size fractions (coarse and fine). Hazard index in fine fraction (HI(children)=2.1) shows that risk assessment based on Co, Mn, V, and Ni spatially related to power plants, have the potential to pose health risks to local residents, especially children. This study shows that risk assessment based on metal content in bulk soil could be overestimated when compared to fine grained fraction. Our results provide important information that could be valuable in establishing risk assessment associated with residential soils within agricultural areas, where children can ingest and inhale dust. PMID- 22820617 TI - Problems with the reconciliation of good ecological status and public participation in the Water Framework Directive. AB - The Water Framework Directive (WFD) is an ambitious piece of legislation focused on achieving good ecological status as defined by deviations from reference conditions. Achieving good ecological status depends on collaboration between stakeholders, scientists and the public. However, public participation is restricted to consultations about implementing measures to achieve good ecological status, not in the goal setting. There are multiple, competing interpretations of good ecological status. This study addresses two of the pillars of the WFD, good ecological status and public participation. We argue that these two pillars are currently at odds when defining reference conditions for surface waters, and it is unclear how they can work together in practice. We also contend that there is an intention in the WFD to integrate these two pillars, but there is no legal support for their connection. In a case study of a small boreal lake in Sweden, we show that local people possess a great deal of historical knowledge, which they use to conceptualize reference conditions. Their conceptualizations are compared with fish and water chemistry monitoring by the regulatory authority as well as paleolimnological reconstructions of water quality dating back to the beginning of the 20th century. The knowledge that the local people have corresponds to the historical data available for the lake, particularly with water clarity. We highlight the subjective nature of the concept of 'undisturbed state' to show that it varies depending on values, knowledge and perceptions of lay-people, scientists and relevant authorities. The subjectivity of the concept of undisturbed state promises to be a way of linking the two pillars of the WFD. PMID- 22820618 TI - Ultrasound scanning for recalcitrant plantar fasciopathy. Basis of a new classification. AB - OBJECTIVE: The treatment of recalcitrant plantar fasciopathy is often empirical. Imaging is usually in the form of radiographs, if undertaken at all. The aim of this study is to characterise the disease pattern in recalcitrant cases of plantar fasciopathy. This allows classification of the pathology, which in turn allows meaningful evaluation of current and future treatments. MATERIALS AND METHODS: One hundred and twenty-five consecutive feet with symptoms of 'plantar fasciitis' lasting longer than 6 months (all of which had failed to improve with a stepwise conservative management protocol) had confirmed plantar fasciopathy on ultrasound scanning. The disease characteristics were evaluated based on the scan findings. RESULTS: Of the patients evaluated, 66 % had typical insertional disease. The remaining 34 % had atypical distal fascia disease; 22 % had mixed insertional and distal disease, and 12 % had pure distal disease. Patients with pure distal disease were found to have either distal thickening or discrete fibromata. CONCLUSION: In this cohort of recalcitrant cases, ultrasound scans detected a high proportion of atypical non-insertional plantar fascia disease. This would not be detected without imaging studies, and therefore we recommend the use of ultrasound scanning in cases of recalcitrant plantar heel pain that have failed proper first-line management, in order to confirm the clinical diagnosis and to classify the disease as either insertional or non-insertional plantar fasciopathy (or mixed disease). Only in this way can treatments for this group of patients be systematically evaluated against different disease patterns to determine their effectiveness. PMID- 22820620 TI - Association between family history of prostate cancer and positive biopsies in a Brazilian screening program. AB - PURPOSE: To test the association between family history of prostate cancer (FH) and prostate cancer (PCa) risk in a large screening program in Brazil, as no conclusive study has yet investigated this. METHODS: Between 2004 and 2007, 17,569 men were screened in 231 small municipalities using mobile screening units. Positive FH was defined as any relative having PCa among screened men. Men were biopsied if they had digital rectal examination suggestive of PCa or PSA >4.0 ng/mL or PSA of 2.5-4 ng/mL with percent free PSA <= 15 %. We analyzed the association between FH and PCa using multivariable logistic regression in the first screening round of the program. RESULTS: Positive FH was present in 735 men (4.2 % of total), and they were younger, better educated and more likely to have had previous PCa screening (41.5 vs. 28.5 %; P < 0.001) compared to men with negative FH. FH status did not affect compliance rates in men recommended to undergo biopsy (P = 0.94). In first round, PCa was detected in 3.1 % of screened men (n = 552). In multivariable analysis, positive FH was associated with increased PCa risk (OR = 1.79; 95 % CI, 1.21-2.65; P = 0.003). However, Gleason scores (P = 0.78) or percent of positive cores (P = 0.32) among men with positive biopsies were similar, regardless of FH status. CONCLUSIONS: In Brazil, men with positive FH were at increased PCa risk, which could not be explained by differential biopsy rates. This finding suggests that FH is also a true PCa risk factor in Brazil, a country with highly diverse population in terms of race, ethnicity, culture and socioeconomic status. PMID- 22820619 TI - Exposure to violence in relation to depressive symptoms among male and female adolescent students in Cambodia. AB - PURPOSE: In spite of the apparent increases in family and community violence, research into its effects on adolescent mental health has received limited attention in Cambodia. This study examines the association between exposure to violence and depressive symptoms among adolescents controlling for the effects of several factors in family and school domains. METHODS: We randomly selected 993 male and 950 female students proportionally from 11 junior high schools and high schools in Battembang provincial city. Students were questioned about the violence to which they were subjected and which they witnessed in their family and community. The Asian adolescent depression scale was used to measure depressive symptoms. RESULTS: In this study, 27.9% of male students and 21.5% of female students had been victimized in at least one case of family violence, while 18.0% of male and 5.8% of female students had been victimized in at least one case of community violence. After adjustment, increased levels of depressive symptoms were significantly associated with being the victim of or witnessing family or community violence among both male and female students. However, the positive association between the levels of depressive symptoms and being a witness to community violence was found only in female students. CONCLUSIONS: Efforts to prevent depression in adolescent students should focus on reducing family and community violence; such efforts should also consider gender differences. PMID- 22820621 TI - Laparoscopic radical cystectomy: initial experience using the single-incision triangulated umbilical surgery (SITUS) technique. AB - INTRODUCTION: As could be demonstrated for simple and radical nephrectomy, single incision triangulated umbilical surgery (SITUS) is an interesting alternative to laparoscopic single-site surgery. We present our initial experience with the SITUS technique in radical cystectomy. MATERIALS AND METHODS: Between September 2010 and September 2011, eight patients underwent SITUS radical cystectomy (SITUS Cx), pelvic lymph node dissection and extracorporeal urinary diversion. A cutaneous ureterostomy was performed in three, an ileum conduit in one and an ileal neobladder in four patients. Data were collected prospectively, including patients' characteristics, intraoperative parameters, pathological stage and postoperative outcome. RESULTS: Mean age of the patients was 67 years and the mean body mass index 24 kg/m(2). SITUS Cx was successfully completed in all patients without conversion to conventional laparoscopic or open surgery. Mean surgical time was 434 min and mean estimated blood loss 643 ml. No major intra- or postoperative surgical complications occurred. All patients recovered quickly reporting low postoperative pain levels. Mean hospital stay was 16 (7-24 days). Histopathological evaluation revealed a mean of 16 (6-33) retrieved lymph nodes and no positive margins. CONCLUSION: In the present experience, SITUS Cx proved to be feasible with surgical outcome comparable to conventional techniques. Because SITUS Cx combines the advantages of traditional laparoscopy (straight instruments and triangulation) with those of single-port surgery (superior cosmesis and minimal invasiveness), it presents an attractive alternative to other minimally invasive techniques. PMID- 22820622 TI - Epitaxial growth of boron-doped graphene by thermal decomposition of B4C. AB - We grew graphene by thermal decomposition of B(4)C and investigated its features by high-resolution transmission electron microscope observations. At temperatures higher than 1600 degrees C in a vacuum, B(4)C decomposes and graphene forms epitaxially on its surface. The number and the morphology of the graphene layers depend on the surface orientation. An electron diffraction technique revealed the presence of a superstructure with a two-times larger unit cell, which is consistent with the structure of BC(3). We have directly confirmed boron in the graphene layers by electron energy loss spectroscopy measurements and boron mapping experiments. PMID- 22820623 TI - Association of MIF-173G/C and MBL2 codon 54 gene polymorphisms with rheumatoid arthritis: a meta-analysis. AB - The aim of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173G/C (rs755622), mannose-binding lectin (MBL2) exon 1 codon 54 (rs1800450) gene polymorphisms and rheumatoid arthritis (RA) susceptibility in ethnically different populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on the MIF-173G/C polymorphism across five studies (four European and one Asian studies), and the MBL2 codon 54 polymorphism with five studies (four Asian and one European studies), respectively. Meta-analysis indicated an association between the MIF-173G/C in all study subjects in allelic contrast (OR=1.19, 95%CI: 1.05-1.35, P=0.001), the additive model (OR=1.68, 95CI: 1.13-2.49, P=0.001), the dominant model (OR=1.17, 95CI: 1.01-1.35, P=0.003), the recessive model (OR=1.63, 95CI: 1.10-2.42, P=0.001). While stratified by ethnicity with European populations, an association was found in allelic contrast (OR=1.20, 95CI: 1.04-1.38, P=0.002), the additive model (OR=1.85, 95CI: 1.19 2.88, P=0.001), the dominant model (OR=1.20, 95CI: 1.02-1.41, P=0.003). With respect to MBL2 codon 54 polymorphism and RA, no association was found in all study subjects in all comparisons, but there was an association while stratified by ethnicity with Asian populations in the dominant model (OR=1.50, 95CI: 1.01 2.23, P=0.007). In conclusion, the present study suggests that the MIF-173G/C polymorphism is associated with RA susceptibility, but the MBL2 codon 54 polymorphism is not associated with RA. PMID- 22820624 TI - Associations between TNFSF4 and TRAF1-C5 gene polymorphisms and systemic lupus erythematosus: a meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether tumor necrosis factor superfamily 4 (TNFSF4) and TNF receptor-associated factor 1-complement 5 (TRAF1 C5) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE). METHODS: The authors conducted meta-analyses on associations between polymorphisms of the TNFSF4 (rs2205960, rs1234315, rs10489265) and TRAF1-C5 (rs10818488, rs3761847) genes and SLE susceptibility, using fixed and random effects models. RESULTS: A total of 21 comparative studies were included in this meta-analysis; meta-analysis showed an association between the minor allele of rs2205960 of TNFSF4 and SLE in all study subjects (odds ratio [OR]=1.356, 95% confidence interval [CI]=1.275-1.442, p<1.0*10(-9)). Meta-analysis revealed an association between the minor alleles of rs1234315 and rs10489265 of TNFSF4 and SLE in Asians (OR=1.366, 95% CI=1.295-1.440, p<1.0*10(-9); OR=1.463, 95% CI=1.208 1.771, p=9.7*10(-5)). The minor allele of rs10818488 of TRAF1-C5 was found to be significantly associated with SLE in Europeans (OR=1.210, 95% CI=1.115-1.313, p=5.0*10(-6)). The association p-values remained significant after multiple corrections. CONCLUSIONS: This meta-analysis confirms that TNFSF4 polymorphisms are associated with susceptibility to SLE in Asians and Europeans. An association was found between the rs10818488 polymorphism of TRAF1-C5 and susceptibility to SLE in Europeans. PMID- 22820625 TI - Comparison of localized versus systemic levels of Matrix metalloproteinases (MMPs), its tissue inhibitors (TIMPs) and cytokines in tuberculous and non tuberculous pleuritis patients. AB - The interaction of Matrix metalloproteinases (MMPs), its tissue inhibitors (TIMPs) and pro-inflammatory cytokines in response to Mycobacterium tuberculosis (MTB) infection is important to understand the immune response at the site of infection. We compared the levels of MMPs, TIMPs and cytokines in plasma (BL) and pleural fluid (PF) of tuberculosis (TB) and non tuberculosis (NTB) patients. Comparison between BL and PF showed significantly higher levels of MMP-1, TIMP-1 and -3 in TB PF; of MMP-7, -8, -9 in BL of both groups. Also, levels of MMP-1,-8, 9 and TIMP-3 were significantly higher in TB PF compared to NTB. Cytokines INF gamma, TNF-alpha, and IL-6 significantly increased in PF of both groups. A positive correlation of MMPs with TIMPs in TB, MMP-1 and -9 with IL-6 in TB PF and MMP-9 with IFN-gamma in NTB PF was observed. This study implicates the possible usage of MMPs as bio-markers aiding diagnosis in TB pleuritis. PMID- 22820626 TI - Cellular and humoral immunity elicited by influenza vaccines in pediatric hematopoietic-stem cell transplantation. AB - Immunity induced by influenza vaccines following hematopoietic stem-cell transplantation (HSCT) is poorly understood. Here, 14 pediatric recipients (mean age: 6 years) received H1N1 (n=9) or H1N1/H3N2 (n=5) vaccines at a median of 5.7 months post-HSCT (HLA-identical related bone-marrow graft: 10/14). Fourteen clinically-matched non-vaccinated recipients were included as controls. Cellular response to vaccination was assessed by a T-cell proliferation assay. Humoral response was assessed by H1N1-specific antibody titration. IL2 and IFNgamma responses to influenza were also evaluated by an intracellular cytokine accumulation method for some of the recipients. Higher proliferative responses to H1N1 (p=0.0001) and higher H1N1-specific antibody titers (p<0.02) were observed in vaccines opposed to non-vaccinated recipients. In some cases, proliferative responses to H1N1 developed while at the same time antibody titers did not reach protective (>=1:40) levels. Most recipients vaccinated with only the H1N1 strain had proliferative responses to both H1N1 and H3N2 (median stimulation index H1N1: 96, H3N2: 126 in responders). Finally, IL2 responses predominated over IFNgamma responses (p<0.02) to influenza viruses in responders. In conclusion, H1N1 vaccination induced substantial cell-mediated immunity, and to a lesser extent, humoral immunity at early times post-HSCT. H1N1/H3N2 T-cell cross-reactivity and protective (IL2) rather than effector (IFNgamma) cytokinic profiles were elicited. PMID- 22820627 TI - Human leukocyte antigen-G (HLA-G) expression in cervical cancer lesions is associated with disease progression. AB - The immunotolerant human leukocyte antigen (HLA)-G has direct inhibitory effects on natural killer cells, dendritic cells, T cells and can indirectly induce tolerant regulatory cells. The significance of the aberrant HLA-G expression in malignant contexts has been intensively investigated. In the current study, HLA-G expression in 22 normal cervical tissues, 14 cervical intraepithelial neoplasia (CIN) patients and 129 patients with squamous cell cervical cancer were examined using immunohistochemistry. The association of HLA-G expression with disease progression was calculated with the Pearson Chi-square test. It was found that HLA-G expression was absent in normal cervical tissues, and that HLA-G expression was increased from patients with CIN III (35.7%, 4/14) to patients with cervical cancer (62.8%, 81/129). Among the cervical cancer patients, HLA-G expression in FIGO stage I, II, and stage III+IV was 53.6% (45/84), 76.3% (29/38), and 100.0% (7/7), respectively. Taken together, our findings indicated that HLA-G expression was associated with the disease progression in patients with cervical cancer. PMID- 22820628 TI - Association of TIMP-1 +372 SNP with digital ulcer manifestation in female systemic sclerosis patients. AB - A candidate gene for TIMP-1 gene located on the X-chromosome (rs4898) was selected for a control case study to investigate a possible association of this SNP with the susceptibility to systemic sclerosis and its digit ulcer manifestation. A total of 461 individuals of Italian Caucasian origin (228 SSc patients and 233 healthy control subjects) were genotyped for TIMP-1 +372 T/C single nucleotide polymorphism rs4898. Subgroups were analyzed according to the presence or absence of digital ulcers. The CC genotype and C allele frequencies were significantly lower in female SSc patients than in controls (OR 0.53, CI 0.29-0.96, p=0.03 and OR 0.72, CI 0.53-0.98 p=0.04, respectively). CC genotypes frequency was lower also in female patients with ulcers than those without ulcers (OR 0.37, CI 0.14-1.00, p=0.03). Furthermore, CC genotype and C allele frequencies were lower also in female patients with ulcers in comparison to female healthy control subjects (OR 0.27, CI 0.10-0.70, p=0.004; OR 0.60, CI 0.40 0.89, p=0.01, respectively). The TIMP-1 rs4898 polymorphism may play a protective role in the susceptibility to SSC in females, and in particular to digital ulcer formation. PMID- 22820629 TI - Testing the effectiveness of exercise videogame bikes among families in the home setting: a pilot study. AB - BACKGROUND: Interactive stationary bikes provide positive affective experiences and physiological benefits; however, research is limited. METHODS: This study compared usage of GameBikes to traditional stationary bikes among families in the home following a 6-week randomized, controlled trial design. Parents completed questionnaires featuring constructs of the theory of planned behavior (TPB). Usage was tracked by all family members and belief elicitation with GameBike families followed the trial. RESULTS: Usage across the trial was significantly different for children in favor of the GameBike group (t36 = 2.61, P = .01, d = .85). No differences were identified for parents. Significant time effects for parents' (F5,48 = 5.07, P < .01; eta2 = .35) and children's (F5,32 = 8.24, P < .01; eta2 = .56) usage were found with declines across 6 weeks. Affective attitude was the only significant TPB variable between groups at both time one (t57 = 2.53, P = .01; d = .65) and follow-up (t52 = 2.70, P = .01; d = .74) in favor of the GameBike group. Elicited beliefs were primarily affective-and control-based. CONCLUSIONS: The results provide support for use of interactive video games to augment current PA initiatives. Larger-scale trials with longer durations are warranted. PMID- 22820630 TI - HIV in persons born outside the United States, 2007-2010. AB - CONTEXT: Persons born outside the United States comprise about 13% of the US population, and the challenges these persons face in accessing health care may lead to poorer human immunodeficiency virus (HIV) disease outcomes. OBJECTIVE: To describe the epidemiology of HIV among persons born outside the United States and among US-born persons diagnosed in the United States. DESIGN, SETTING, AND PARTICIPANTS: Analysis of the estimated number of US-born persons and persons born outside the United States diagnosed with HIV from 2007 through 2010 in 46 states and 5 US territories, the demographic characteristics, and the HIV transmission risk factors reported to the National HIV Surveillance System. Foreign-born persons were defined as persons born outside the United States and its territories, inclusive of naturalized citizens. MAIN OUTCOME MEASURE: Diagnosis of HIV infection. RESULTS: From 2007 through 2010, HIV was diagnosed in 191,697 persons in the US population; of these, 16.2% (95% CI, 16.0%-16.3%) (n = 30,995) were born outside the United States. Of the 25,255 persons with a specified country or region of birth outside the United States, 14.5% (n = 3656) were from Africa, 41.0% (n = 10,343) were from Central America (including Mexico), and 21.5% (n = 5418) were from the Caribbean. The 4 states (California, Florida, New York, and Texas) reporting the highest numbers of persons born outside the United States and diagnosed with HIV were also the top 4 reporters of HIV cases overall. Among persons born outside the United States with HIV, 73.5% (n = 22,773) were male. Among whites, 1841 of 55,574 (3.3%) of HIV diagnoses were in persons born outside the United States; in blacks, 8614 of 86,547 diagnoses (10.0%); in Hispanics, 17,913 of 42,431 diagnoses (42.2%); and in Asians, 1987 of 3088 diagnoses (64.3%). The percentage infected through heterosexual contact was 39.4% among persons born outside the United States vs 27.2% for US-born persons. CONCLUSIONS: Among persons in 46 US states and 5 US territories who received a diagnosis of HIV from 2007 through 2010, 16.2% were born outside the United States. Compared with US-born persons diagnosed with HIV, persons born outside the United States had different epidemiologic characteristics. PMID- 22820631 TI - The role of polarity in antonym and synonym conceptual knowledge: evidence from stroke aphasia and multidimensional ratings of abstract words. AB - This study describes an investigation of different types of semantic relationship among abstract words: antonyms (e.g. good-bad), synonyms (e.g. good-great), non antonymous, non-synonymous associates (NANSAs; e.g. good-fun) and unrelated words (e.g. good-late). The comprehension and semantic properties of these words were examined using two distinct methodologies. Experiment 1 tested the comprehension of pairs of abstract words in three patients with global aphasia using a spoken word to written word matching paradigm. Contrary to expectations, all three patients showed superior antonym comprehension compared with synonyms or NANSAs, discriminating antonyms with a similar level of accuracy as unrelated words. Experiment 2 aimed to explore the content or semantic attributes of the abstract words used in Experiment 1 through the generation of control ratings across nine cognitive dimensions (sensation, action, thought, emotion, social interaction, space, time, quantity and polarity). Discrepancy analyses revealed that antonyms were as or more similar to one another than synonyms on all but one measure: polarity. The results of Experiment 2 provide a possible explanation for the novel pattern of neuropsychological data observed in Experiment 1, namely that polarity information is more important than other semantic attributes when discriminating the meaning of abstract words. It is argued that polarity is a critical semantic attribute of abstract words, and that simple 'dissimilarity' metrics mask fundamental consistencies in the semantic representation of antonyms. It is also suggested that mapping abstract semantic space requires the identification and quantification of the contribution made to abstract concepts by not only sensorimotor and emotional information but also a host of other cognitive dimensions. PMID- 22820632 TI - Neural correlates of abstract rule learning: an event-related potential study. AB - Abstract rule learning is a fundamental aspect of human cognition, and is essential for language acquisition. However, despite its importance, the neural mechanisms underlying abstract rule learning are still largely unclear. In this study, we investigated the neural correlates of abstract rule learning by recording auditory event-related potentials (ERPs). Participants were first presented with artificial three-syllable sequences containing ABA or ABB abstract rules for learning. They were then tested on sequences of novel syllables following the ABA or ABB abstract rules, half of which were inconsistent with the rule previously learned. Grand-averaged ERPs revealed significant decreases in positivity at 200-260ms in response to consistent sequences during the earlier session of the test phase, and increased negativity at around 400ms in response to inconsistent sequences in the later session. The potentials exhibited a left anterior-dominant distribution. The appearance of the N400-like negativity in the later session suggests that temporal ERP changes occurred with the abstract rule learning process, and that the N400-like negativity is associated with the acquisition of abstract rules. PMID- 22820633 TI - The role of the striatum in sentence processing: disentangling syntax from working memory in Huntington's disease. AB - The role of sub-cortical structures in language processing remains controversial. In particular, it is unclear whether the striatum subserves language-specific processes such as syntax or whether it solely affects language performance via its significant role in executive functioning and/or working memory. Here, in order to address this issue, we attempted to equalize working memory constraints while varying syntactic complexity, to study sentence comprehension in 15 patients with striatal damage, namely Huntington's disease at early stage, and in 15 healthy controls. More particularly, we manipulated the syntactic relation between a name and a pronoun while holding the distance between them constant. We exploited a formal principle of syntactic theory called Principle C. This principle states that whereas in a sentence such as "Paul smiled when he entered" Paul and he can be a single person, this interpretation is blocked in sentences such as "He smiled when Paul entered". In a second experiment we varied working memory load using noun-adjective gender agreement in center-embedded and right branching relatives (e.g., "the girl who watches the dog is green" vs. "the girl watches the dog which is green"). The results show that HD patients correctly establish name-pronoun co-reference but they fail to block it when Principle C should apply. Furthermore, they have good performance with both center-embedded and right-branching relatives, suggesting that their difficulties in sentence comprehension do not arise from memory load impairment during sentence processing. Taken together, our findings indicate that the striatum holds a genuine role in syntactic processing, which cannot be reduced to its involvement in working memory. However, it only impacts on particular aspects of syntax that may relate to complex computations whereas other operations appear to be preserved. Hypotheses about the role of the striatum in syntactic processing are discussed. PMID- 22820634 TI - Neural strategies for reading Japanese and Chinese sentences: a cross-linguistic fMRI study of character-decoding and morphosyntax. AB - Japanese and Chinese share virtually identical morphographic characters invented in ancient China. Whereas modern Chinese retained the original morphographic functionality of these characters (hanzi), modern Japanese utilizes these characters (kanji) as complex syllabograms. This divergence provides a unique opportunity to systematically investigate brain strategies for sentence reading in Japanese-Chinese bi-literates. Accordingly, we investigated brain activation associated with Japanese and Chinese reading in 14 native Japanese speakers literate in Mandarin and 14 native Mandarin speakers literate in Japanese using functional magnetic resonance imaging performed on a 3T system. The activation pattern exhibited clearly distinct features specific for each language. Regardless of the subject's native language literacy, Chinese reading activated an area significantly larger than Japanese reading, suggesting that brain processes involved in Chinese reading were much more complex than Japanese reading. Significant recruitment of corresponding cortical areas in the right hemisphere with Chinese reading was also apparent. The activation patterns associated with Japanese reading by native Japanese literates was highly consistent with previous reports, and included the left inferior frontal gyrus (IFG), left posterior temporal lobe (PTL), and left ventral premotor cortex (PMv). The activation pattern associated with Chinese reading by native Chinese literates was also highly consistent with previous reports, namely the left IFG, left PTL, left PMv, left anterior temporal lobe (ATL), and bilateral parieto occipital lobes (LPOL). The activation pattern associated with Chinese reading by native Japanese literates was virtually identical to that by native Chinese literates, whereas the activation pattern associated with Japanese reading by native Chinese literates was signified by additional activation of LPOL compared to that by native Japanese literate. The study indicated that IFG and PTL are universal language areas, while PMv is the area for decoding complex syllabograms. LPOL is the "Chinese language area," while ATL is essential for languages with analytic morphosyntax. PMID- 22820636 TI - Mechanisms supporting superior source memory for familiar items: a multi-voxel pattern analysis study. AB - Recent cognitive research has revealed better source memory performance for familiar relative to novel stimuli. Here we consider two possible explanations for this finding. The source memory advantage for familiar stimuli could arise because stimulus novelty induces attention to stimulus features at the expense of contextual processing, resulting in diminished overall levels of contextual processing at study for novel (vs. familiar) stimuli. Another possibility is that stimulus information retrieved from long-term memory (LTM) provides scaffolding that facilitates the formation of item-context associations. If contextual features are indeed more effectively bound to familiar (vs. novel) items, the relationship between contextual processing at study and subsequent source memory should be stronger for familiar items. We tested these possibilities by applying multi-voxel pattern analysis (MVPA) to a recently collected functional magnetic resonance imaging (fMRI) dataset, with the goal of measuring contextual processing at study and relating it to subsequent source memory performance. Participants were scanned with fMRI while viewing novel proverbs, repeated proverbs (previously novel proverbs that were shown in a pre-study phase), and previously known proverbs in the context of one of two experimental tasks. After scanning was complete, we evaluated participants' source memory for the task associated with each proverb. Drawing upon fMRI data from the study phase, we trained a classifier to detect on-task processing (i.e., how strongly was the correct task set activated). On-task processing was greater for previously known than novel proverbs and similar for repeated and novel proverbs. However, both within and across participants, the relationship between on-task processing and subsequent source memory was stronger for repeated than novel proverbs and similar for previously known and novel proverbs. Finally, focusing on the repeated condition, we found that higher levels of hippocampal activity during the pre-study phase, which we used as an index of episodic encoding, led to a stronger relationship between on-task processing at study and subsequent memory. Together, these findings suggest different mechanisms may be primarily responsible for superior source memory for repeated and previously known stimuli. Specifically, they suggest that prior stimulus knowledge enhances memory by boosting the overall level of contextual processing, whereas stimulus repetition enhances the probability that contextual features will be successfully bound to item features. Several possible theoretical explanations for this pattern are discussed. PMID- 22820635 TI - Attention to language: novel MEG paradigm for registering involuntary language processing in the brain. AB - Previous research indicates that, under explicit instructions to listen to spoken stimuli or in speech-oriented behavioural tasks, the brain's responses to senseless pseudowords are larger than those to meaningful words; the reverse is true in non-attended conditions. These differential responses could be used as a tool to trace linguistic processes in the brain and their interaction with attention. However, as previous studies relied on explicit instructions to attend or ignore the stimuli, a technique for automatic attention modulation (i.e., not dependent on explicit instruction) would be more advantageous, especially when cooperation with instructions may not be guaranteed (e.g., neurological patients, children etc). Here we present a novel paradigm in which the stimulus context automatically draws attention to speech. In a non-attend passive auditory oddball sequence, rare words and pseudowords were presented among frequent non-speech tones of variable frequency and length. The low percentage of spoken stimuli guarantees an involuntary attention switch to them. The speech stimuli, in turn, could be disambiguated as words or pseudowords only in their end, at the last phoneme, after the attention switch would have already occurred. Our results confirmed that this paradigm can indeed be used to induce automatic shifts of attention to spoken input. At ~250ms after the stimulus onset, a P3a-like neuromagnetic deflection was registered to spoken (but not tone) stimuli indicating an involuntary attention shift. Later, after the word-pseudoword divergence point, we found a larger oddball response to pseudowords than words, best explained by neural processes of lexical search facilitated through increased attention. Furthermore, we demonstrate a breakdown of this orderly pattern of neurocognitive processes as a result of sleep deprivation. The new paradigm may thus be an efficient way to assess language comprehension processes and their dynamic interaction with those of attention allocation. It does it in an automatic and task-free fashion, indicating its potential benefit for assessing uncooperative clinical populations. PMID- 22820637 TI - When 'slime' becomes 'smile': developmental letter position dyslexia in English. AB - We report the first three cases of selective developmental letter position dyslexia in English. Although the parents and teachers of the children were concerned about these children's reading, standard tests did not reveal their deficit. It was only when the appropriate target words were presented, in this case, migratable words, that their letter position dyslexia was detected. Whereas previous research has described cases with acquired and developmental forms of letter position dyslexia in Hebrew and Arabic readers, this is the first report of this type of reading disorder in English. The cardinal symptom of letter position dyslexia is the migration of letters within the word (reading slime as 'smile'; pirates as 'parties'). These migration errors occur in reading aloud as well as in tasks of silent reading. This study provides further evidence that migration errors emerge at the level of early visual-orthographic analysis, in the letter position encoding function. Alternative explanations for the occurrence of migration errors such as poor phonological processing or a deficit in the orthographic input lexicon are ruled out. PMID- 22820638 TI - High frequency rTMS over the left parietal lobule increases non-word reading accuracy. AB - Increasing evidence in the literature supports the usefulness of Transcranial Magnetic Stimulation (TMS) in studying reading processes. Two brain regions are primarily involved in phonological decoding: the left superior temporal gyrus (STG), which is associated with the auditory representation of spoken words, and the left inferior parietal lobe (IPL), which operates in phonological computation. This study aimed to clarify the specific contribution of IPL and STG to reading aloud and to evaluate the possibility of modulating healthy participants' task performance using high frequency repetitive TMS (hf-rTMS). The main finding is that hf-rTMS over the left IPL improves non-word reading accuracy (fewer errors), whereas hf-rTMS over the right STG selectively decreases text reading accuracy (more errors). These results confirm the prevalent role of the left IPL in grapheme-to-phoneme conversion. The non-word reading improvement after Left-IPL stimulation provide a direct link between left IPL activation and advantages in sublexical procedures, mainly involved in non-word reading. Results indicate also the specific involvement of STG in reading morphologically complex words and in processing the representation of the text. The text reading impairment after stimulation of the right STG can be interpreted in light of an inhibitory influence on the homologous area. In sum, data document that hf-rTMS is effective in modulating the reading accuracy of expert readers and that the modulation is task related and site specific. These findings suggest new perspectives for the treatment of reading disorders. PMID- 22820639 TI - Hemispheric inference priming during comprehension of conversations and narratives. AB - In this study we examined asymmetric semantic activation patterns as people listened to conversations and narratives that promoted causal inferences. Based on the hypothesis that understanding the unique features of conversational input may benefit from or require a modified pattern of conceptual activation during conversation, we compared semantic priming in both hemispheres for inferences embedded in conversations and in narratives. Participants named inference-related target words or unrelated words presented to the left visual field-right hemisphere (lvf-RH) or to the right visual field-left hemisphere (rvf-LH) at critical coherence points that required an inference in order to correctly understand an utterance in the context of the conversation or narrative. Fifty seven undergraduates listened to 36 conversations or narratives and were tested at 100 target inference points. During narrative comprehension, inference-related priming was reliable and equally strong in both hemispheres. In contrast, during conversation comprehension, inference-related priming was only reliable for target words presented to lvf-RH. This work demonstrates that priming for inference-related concepts can be measured with input in conversational form and suggests the language processing style of the RH is advantageous for comprehending conversation. PMID- 22820640 TI - Media guidelines in the internet age. PMID- 22820642 TI - Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. AB - Breast cancer metastasis is a key determinant of long-term patient survival. By comparing the transcriptomes of primary and metastatic tumor cells in a mouse model of spontaneous bone metastasis, we found that a substantial number of genes suppressed in bone metastases are targets of the interferon regulatory factor Irf7. Restoration of Irf7 in tumor cells or administration of interferon led to reduced bone metastases and prolonged survival time. In mice deficient in the interferon (IFN) receptor or in natural killer (NK) and CD8(+) T cell responses, metastasis was accelerated, indicating that Irf7-driven suppression of metastasis was reliant on IFN signaling to host immune cells. We confirmed the clinical relevance of these findings in over 800 patients in which high expression of Irf7 regulated genes in primary tumors was associated with prolonged bone metastasis free survival. This gene signature may identify patients that could benefit from IFN-based therapies. Thus, we have identified an innate immune pathway intrinsic to breast cancer cells, the suppression of which restricts immunosurveillance to enable metastasis. PMID- 22820643 TI - MDM4 is a key therapeutic target in cutaneous melanoma. AB - The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (~65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy. PMID- 22820644 TI - The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. AB - Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-alpha (TNF-alpha)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-alpha-responsive, heparan sulfate-specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue. PMID- 22820646 TI - Impact of lyoprotectants for the stabilization of biodegradable nanoparticles on the performance of air-jet, ultrasonic, and vibrating-mesh nebulizers. AB - Strategies for further advancements in pulmonary drug delivery include the application of colloidal carriers. Freeze-drying in the presence of lyoprotectants is a valuable approach to improve long-term stability of biodegradable nanoparticles, but possibly constrains aerosol generation after powder rehydration, when employing traditional nebulizers. Here, we investigated the impact of lyoprotectants on both output and aerodynamic performance of air jet, ultrasonic, and vibrating-mesh nebulization. Additionally, changes in formulation temperature and concentration were monitored, to estimate physicochemical alterations of formulations during nebulization. The stability of poly(d,l-lactide-co-glycolide) nanoparticles was maintained for lyoprotectant/nanoparticle ratios above 5/1. All nebulized formulations displayed suitable output and aerodynamic characteristics for peripheral lung deposition. Air-jet- and ultrasonic nebulization was associated with considerable temperature (~10 degrees C) and concentration changes (up to 156%) of the reservoir fluid, which consequently, caused significant shifting of surface tension and viscosity. By contrast, vibrating-mesh nebulization caused marginal temperature increase (~5 degrees C) with no apparent signs of concentration. Thus, the changing surface tension and viscosity were fitted employing Eotvos' rule and the Andrade equation (R(2)>0.98), allowing to predict the physicochemical properties of each formulation for prolonged nebulization periods. In particular, vibrating-mesh nebulization seems to be promising for aerosol application of rehydrated freeze dried biodegradable nanoparticles to the respiratory tract. PMID- 22820647 TI - Active pharmaceutical ingredient (API) production involving continuous processes- a process system engineering (PSE)-assisted design framework. AB - A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and fermentation-based products. The method exploits the synergic combination of continuous flow technologies (e.g., microfluidic techniques) and process systems engineering (PSE) methods and tools for faster process design and increased process understanding throughout the whole drug product and process development cycle. The design framework structures the many different and challenging design problems (e.g., solvent selection, reactor design, and design of separation and purification operations), driving the user from the initial drug discovery steps--where process knowledge is very limited--toward the detailed design and analysis. Examples from the literature of PSE methods and tools applied to pharmaceutical process design and novel pharmaceutical production technologies are provided along the text, assisting in the accumulation and interpretation of process knowledge. Different criteria are suggested for the selection of batch and continuous processes so that the whole design results in low capital and operational costs as well as low environmental footprint. The design framework has been applied to the retrofit of an existing batch-wise process used by H. Lundbeck A/S to produce an API: zuclopenthixol. Some of its batch operations were successfully converted into continuous mode, obtaining higher yields that allowed a significant simplification of the whole process. The material and environmental footprint of the process--evaluated through the process mass intensity index, that is, kg of material used per kg of product--was reduced to half of its initial value, with potential for further reduction. The case-study includes reaction steps typically used by the pharmaceutical industry featuring different characteristic reaction times, as well as L-L separation and distillation-based solvent exchange steps, and thus constitutes a good example of how the design framework can be useful to efficiently design novel or already existing API manufacturing processes taking advantage of continuous processes. PMID- 22820645 TI - Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. AB - Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics. PMID- 22820648 TI - Study of drug release and tablet characteristics of silicone adhesive matrix tablets. AB - Matrix tablets of a model drug acetaminophen (APAP) were prepared using a highly compressible low glass transition temperature (T(g)) polymer silicone pressure sensitive adhesive (PSA) at various binary mixtures of silicone PSA/APAP ratios. Matrix tablets of a rigid high T(g) matrix forming polymer ethyl cellulose (EC) were the reference for comparison. Drug release study was carried out using USP Apparatus 1 (basket), and the relationship between the release kinetic parameters of APAP and polymer/APAP ratio was determined to estimate the excipient percolation threshold. The critical points attributed to both silicone PSA and EC tablet percolation thresholds were found to be between 2.5% and 5% w/w. For silicone PSA tablets, satisfactory mechanical properties were obtained above the polymer percolation threshold; no cracking or chipping of the tablet was observed above this threshold. Rigid EC APAP tablets showed low tensile strength and high friability. These results suggest that silicone PSA could eliminate issues related to drug compressibility in the formulation of directly compressed oral controlled release tablets of poorly compressible drug powder such as APAP. No routinely used excipients such as binders, granulating agents, glidants, or lubricants were required for making an acceptable tablet matrix of APAP using silicone PSA. PMID- 22820649 TI - FDG PET/CT is useful for the interim evaluation of response to therapy in patients affected by haematogenous spondylodiscitis. AB - PURPOSE: Antibiotic therapy in patients affected by discitis is often empirical. Therefore, early evaluation of response to therapy is important. In many patients inflammatory indexes are low during all the phases of the diseases or are altered by concomitant diseases. The aim of the study was to assess the possible role of FDG PET/CT for the early evaluation of response to therapy in patients affected by infective discitis, in comparison to C-reactive protein (CRP) serum levels. METHODS: Enrolled in the study were 38 patients diagnosed with haematogenous infective discitis. Of the 38 patients, 7 had tubercular infection, 1 fungal infection and 30 pyogenic discitis. Four patients were excluded because the second PET/CT scan was not performed. Thus 34 patients (18 women, mean age 64 years) were analysed. All the patients included underwent a FDG PET/CT scan and determination of CRP level at baseline and again 2 to 4 weeks after the start of therapy. The PET results in terms of SUV of the first and second scans (SUV1 and SUV2) and delta-SUVmax were compared to the inflammatory indexes and clinical status during therapy. RESULTS: The mean SUVmax at diagnosis was 8.6 +/- 3.7. The mean CRP level at diagnosis was 3.8 +/- 3.8 mg/dl. A progressive clinical response was seen in 26 patients and 8 patients showed no response. SUV1 was not correlated with the baseline CRP level (CRP1, p = 0.7) and SUV2 was not correlated with the CRP level at the time of the second scan (CRP2, p = 0.4). In responders, SUV2 and CRP2 were significantly lower than SUV1 and CRP1 (p < 0.0001 and p = 0.001, respectively). ROC curves for delta-SUVmax showed a sensitivity of 82 % and a specificity of 82 % with a cut-off of 34 %. ROC curves for SUV2 showed a sensitivity of 83 % and a specificity of 46 % with a cut-off of 6.4. ROC curves for delta-CRP showed a sensitivity of 67 % and a specificity of 89 % with a cut off of 74 %. ROC curves for CRP2 showed a sensitivity of 65 % and a specificity of 70 % with a cut-off of 0.7 mg/dl. No statistically significant difference was found between delta-SUVmax AUC and delta-CRP AUC (p = 0.5). CONCLUSION: Delta SUVmax provided a higher sensitivity and specificity for identifying responders. SUV2 provided comparable sensitivity, but significantly lower specificity. CRP level performed less well for identifying responders. There was no significant difference in the global performance of the two tests (delta-SUVmax AUC and delta CRP AUC). However, the higher sensitivity of delta-SUVmax for the early identification of responders may have an important clinical impact in guiding antibiotic therapy especially in patients with a noninformative CRP test at diagnosis. PMID- 22820650 TI - Automated analysis of small animal PET studies through deformable registration to an atlas. AB - PURPOSE: This work aims to develop a methodology for automated atlas-guided analysis of small animal positron emission tomography (PET) data through deformable registration to an anatomical mouse model. METHODS: A non-rigid registration technique is used to put into correspondence relevant anatomical regions of rodent CT images from combined PET/CT studies to corresponding CT images of the Digimouse anatomical mouse model. The latter provides a pre segmented atlas consisting of 21 anatomical regions suitable for automated quantitative analysis. Image registration is performed using a package based on the Insight Toolkit allowing the implementation of various image registration algorithms. The optimal parameters obtained for deformable registration were applied to simulated and experimental mouse PET/CT studies. The accuracy of the image registration procedure was assessed by segmenting mouse CT images into seven regions: brain, lungs, heart, kidneys, bladder, skeleton and the rest of the body. This was accomplished prior to image registration using a semi automated algorithm. Each mouse segmentation was transformed using the parameters obtained during CT to CT image registration. The resulting segmentation was compared with the original Digimouse atlas to quantify image registration accuracy using established metrics such as the Dice coefficient and Hausdorff distance. PET images were then transformed using the same technique and automated quantitative analysis of tracer uptake performed. RESULTS: The Dice coefficient and Hausdorff distance show fair to excellent agreement and a mean registration mismatch distance of about 6 mm. The results demonstrate good quantification accuracy in most of the regions, especially the brain, but not in the bladder, as expected. Normalized mean activity estimates were preserved between the reference and automated quantification techniques with relative errors below 10 % in most of the organs considered. CONCLUSION: The proposed automated quantification technique is reliable, robust and suitable for fast quantification of preclinical PET data in large serial studies. PMID- 22820651 TI - Shaping our future. PMID- 22820652 TI - Clinical and forensic examinations of glycaemic marker methylglyoxal by means of high performance liquid chromatography-tandem mass spectrometry. AB - The postmortem determination of hyperglycaemic coma is quite difficult because of the lack of morphological findings and the difficult interpretation of biochemical parameters. Methylglyoxal (MG) is a reactive oxoaldehyde, which is mainly derived from glycolysis. An electrospray ionisation liquid chromatography tandem mass spectrometric procedure for the determination of methylglyoxal in human serum and postmortem blood was developed. It involves protein precipitation with perchloric acid and a derivatisation step with 2,3-diaminonaphthalene. The assay was validated according to international guidelines. Serum samples from diabetics obtained at a diabetes clinic and from non-diabetics were used to assess data about reference concentrations in human serum. The assay showed linearity within the physiological concentrations in serum (5-500 ng/ml). Intraday imprecision at three concentrations was 10.3, 9.2 and 8.3 %, and interday imprecision was 15.3, 14.2 and 9.4 %; the limit of detection was 1.3 ng/ml, and limit of quantification, 3.2 ng/ml. One hundred and eighteen clinical (100 diabetics, 18 non-diabetics) and 98 forensic samples (84 non-diabetics, 14 in a status of hyperglycaemic coma) were measured. During life, diabetics showed significantly (p < 0.001) higher serum concentrations of MG than non-diabetics. After death, concentrations of MG increased significantly (p < 0.001). However, there was no correlation between the sum formula of Traub in vitreous humour and MG femoral blood concentrations (R = 0.237). This indicates that MG concentrations in the deceased cannot distinguish deaths due to a hyperglycaemic coma from other causes of death. PMID- 22820653 TI - Validation of the PLEX-IDTM mass spectrometry mitochondrial DNA assay. AB - For very challenged biological samples, mitochondrial DNA (mtDNA) analysis can often provide results when the more traditional nuclear DNA markers fail. While reliable, the current method of mtDNA analysis by Sanger sequencing is expensive, labor-intensive, and time-consuming and is limited by its inability to quantify mixed samples. The Abbott PLEX-IDTM instrument, which enables analysis of mtDNA amplicons via electrospray ionization mass spectrometry (ESI-MS), produces comparable accuracy and sensitivity while offering a faster and less expensive alternative to Sanger sequencing. Unlike Sanger sequencing, this system is capable of quantifying DNA species and thus may be exploited for evaluating heteroplasmy and, possibly, mixture deconvolution. Validation studies of the PLEX IDTM mtDNA assay confirmed that the instrument is highly sensitive and capable of yielding reproducible results. Samples commonly encountered in a forensic setting, as well as population samples, were typed correctly. The PLEX-IDTM mtDNA assay yields reliable results for single-source samples, which are the same sample types currently examined in forensic laboratories via Sanger sequencing, at a level that meets or exceeds that of the current method. While the instrument has the demonstrated capability to quantify mixed samples, the specific assay design for mtDNA analysis can be used only in a limited fashion to analyze mixtures due to the formation of chimeric mtDNA products. PMID- 22820654 TI - Population genetic analyses of the STR loci of the AmpFlSTR NGM SElectTM kit for Han population in Fujian Province, China. AB - Allele frequencies and forensically relevant population statistics of the STR loci in the AmpFlSTR(r) NGM SElectTM PCR Amplification Kit were estimated for the Han population from Fujian province in China (n = 454). All loci were highly polymorphic and the cumulative match probability was 5.4 * 10(-21). No significant departure from Hardy-Weinberg equilibrium and linkage equilibrium was detected after correction for sampling. The population substructure of Fujian Han population is minor. PMID- 22820655 TI - Perfluorinated compounds in surface water and organisms from Baiyangdian Lake in North China: source profiles, bioaccumulation and potential risk. AB - The concentrations of 16 perfluorinated compounds (PFCs) were measured in surface water and organisms from Baiyangdian Lake. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid, and perfluorobutanoic acid (PFBA) were the major PFC species in the water at 6.8-56.8, 0.1-17.5 and 3.0-14.6 ng/L, respectively. The PFC contamination in Baiyangdian Lake was significantly impacted by the inflow from Pinghe River and Fuhe River. There was no significant correlation between the concentrations of PFCs and the trophic levels in aquatic organisms. There were no significant PFC risks in Baiyangdian Lake according to the risk assessment of PFCs in water. PMID- 22820656 TI - Residues and dynamics of kasugamycin in chilli and soil. AB - A simple and efficient method for determination of kasugamycin in chilli and soil was developed, and the fate of kasugamycin in chilli field ecosystem was also studied. Kasugamycin residues were extracted from sample, cleaned up by solid phase extraction and chromatographic column and then determined by ultra performance liquid chromatography with tandem mass spectrometry detection. The method got recoveries ranged from 77.82% to 83.35% with relative standard deviations of 2.20%-6.54%. As far as the accuracy and precision was concerned, the method met certain standard. The LODs of kasugamycin calculated as a sample concentration (S/N ratio of 3) was 2.50 MUg kg(-1). The degradation of kasugamycin in chilli and soil was determined. The results showed that kasugamycin degradation in chilli plant and soil followed the first-order kinetics. The half-lives of kasugamycin in chilli and soil was 2.76-3.77 and 3.07 3.91 days, respectively. The final kasugamycin residues in chilli and soil were undetectable at levels of recommended and 1.5 times recommended dosage with an interval of 21 days. PMID- 22820657 TI - Tissue pattern recognition error rates and tumor heterogeneity in gastric cancer. AB - The anatomic pathology discipline is slowly moving toward a digital workflow, where pathologists will evaluate whole-slide images on a computer monitor rather than glass slides through a microscope. One of the driving factors in this workflow is computer-assisted scoring, which depends on appropriate selection of regions of interest. With advances in tissue pattern recognition techniques, a more precise region of the tissue can be evaluated, no longer bound by the pathologist's patience in manually outlining target tissue areas. Pathologists use entire tissues from which to determine a score in a region of interest when making manual immunohistochemistry assessments. Tissue pattern recognition theoretically offers this same advantage; however, error rates exist in any tissue pattern recognition program, and these error rates contribute to errors in the overall score. To provide a real-world example of tissue pattern recognition, 11 HER2-stained upper gastrointestinal malignancies with high heterogeneity were evaluated. HER2 scoring of gastric cancer was chosen due to its increasing importance in gastrointestinal disease. A method is introduced for quantifying the error rates of tissue pattern recognition. The trade-off between fully sampling tumor with a given tissue pattern recognition error rate versus randomly sampling a limited number of fields of view with higher target accuracy was modeled with a Monte-Carlo simulation. Under most scenarios, stereological methods of sampling-limited fields of view outperformed whole-slide tissue pattern recognition approaches for accurate immunohistochemistry analysis. The importance of educating pathologists in the use of statistical sampling is discussed, along with the emerging role of hybrid whole-tissue imaging and stereological approaches. PMID- 22820659 TI - Quantitative analysis of estrogen receptor expression shows SP1 antibody is more sensitive than 1D5. AB - Studies comparing rabbit monoclonal SP1 antibody with 1D5 for estrogen receptor (ER) immunohistochemical testing show conflicting results. Here we use a standardized quantitative immunofluorescent (QIF) ER assay to determine the level and significance of discordance between the antibodies. Both antibodies were assessed by QIF on our Index TMA of cell lines and case controls, followed by QIF and immunohistochemical analysis on 2 retrospective cohorts from Yale. On the Index TMA, SP1 displayed stronger signal-to-noise ratio compared with 1D5. On the patient cohorts, the range of discrepancy between the 2 antibodies was 8% to 16.9%, with the majority of discrepant cases being SP1 positive/1D5 negative. Kaplan-Meier analysis of the discrepant cases showed outcomes comparable to those of double-positive cases, suggesting that SP1 is more sensitive than 1D5. A series of cases with high levels of ER-beta shows that neither antibody cross reacts, suggesting equivalent specificity. Future efforts are needed to determine whether response to endocrine therapies show superiority of either antibody as a companion diagnostic test. PMID- 22820658 TI - Selective immunophenotyping for diagnosis of B-cell neoplasms: immunohistochemistry and flow cytometry strategies and results. AB - Determining the immunophenotype of hematologic malignancies is now an indispensable part of diagnostic classification, and can help to guide therapy, or to predict clinical outcome. Diagnostic workup should be guided by morphologic findings and evaluate clinically important markers, but ideally should avoid the use of overly broad panels of immunostains that can reveal incidental findings of uncertain significance and give rise to increased costs. Here, we outline our approach to diagnosis of B-cell neoplasms, combining histologic and clinical data with tailored panels of immunophenotyping reagents, in the context of the 2008 World Health Organization classification. We present data from cases seen at our institution from 2004 through 2008 using this approach, to provide a practical reference for findings seen in daily diagnostic practice. PMID- 22820660 TI - Expression of BRAF V600E mutant protein in epithelial ovarian tumors. AB - BACKGROUND: Genetic analyses have identified BRAF V600E mutations in a subset of ovarian carcinomas. The aim of this study was to investigate the expression of BRAF V600E aberrant protein using a novel mutation-specific antibody in epithelial ovarian tumors. METHODS: We immunohistochemically analyzed expression of V600E-mutant BRAF protein in archival formalin-fixed, paraffin-embedded tissue specimens of 142 epithelial ovarian tumors [98 invasive carcinomas and 44 tumors of low malignant potential (LMP)] using monoclonal antibody VE1. BRAF mutation status was validated in all immunopositive cases and in 6 immunonegative control cases by gene sequencing. RESULTS: We found anti-BRAF V600E immunolabeling in 4 serous carcinomas and 5 serous LMP. Presence of a BRAF V600E mutation was confirmed by sequencing analysis in 6 of the 9 cases (3 LMP tumors, 3 low-grade carcinomas). In 2 partially VE1-positive tumors deriving from 1 patient (1 LMP and 1 contralateral invasive high-grade serous carcinoma), genetic analysis repeatedly resulted in BRAF wild-type, arguing for false-positive immunostaining results. One immunopositive case was repeatedly inconclusive in genetic analysis. In all 6 genetically confirmed cases, BRAF V600E mutant protein expression was homogenous throughout the tumor tissue. CONCLUSIONS: We found BRAF V600E mutations in 13% (4/31) of serous LMP and 5% (3/62) of invasive serous carcinomas. No BRAF V600E mutations were detected in nonserous epithelial ovarian tumors. For reliable assessment of the BRAF V600E status in ovarian epithelial tumor samples, an integrated approach using immunohistochemistry and genetic analysis seems advisable, as both methods lead to incorrect results in some cases. PMID- 22820661 TI - Melan A (A103) is not a marker of mesothelioma. AB - Although a large number of immunohistochemical markers have been proven to be valuable in the differential diagnosis between epithelioid mesotheliomas and metastatic carcinomas involving the serosal membrane, no single antibody has been found that is absolutely sensitive and/or specific in making this distinction. A recent study reported melan A positivity in all 12 of the epithelioid mesotheliomas stained with a melan A antibody (clone A103). To fully determine the practical value of this antibody for assisting in the differential diagnosis of mesotheliomas, we investigated the expression of melan A (A103) in 40 mesotheliomas (27 epithelioid, 6 sarcomatoid, and 7 biphasic), 10 lung adenocarcinomas, and 10 serous carcinomas of the ovary. None of the mesotheliomas, lung adenocarcinomas, or serous carcinomas of the ovary were melan A (A103) positive. Similar staining results were observed in the 20 mesotheliomas immunostained in another institution using the same antibody clone from a different commercial source. On the basis of these results, it is concluded that in contrast to the initial report, melan A (A103) is not expressed in mesotheliomas and therefore, immunostaining with this antibody has no utility in the diagnosis of mesothelioma. The possible cause of the discrepancies between the results obtained in the present investigation and those of the initial study is discussed. PMID- 22820662 TI - Low frequency of HIF-1alpha overexpression in germ cell tumors of the testis. AB - Cellular hypoxia is a hallmark of cancer. Hypoxia-inducible factor-1alpha (HIF 1alpha) and von Hippel-Lindau protein (pVHL) are the key mediators of cellular response to hypoxia. Little is known about their role in germ cell tumors of the testis. We therefore examined their status in a cohort of germ cell tumors of the testis. Thirty-six primary germ cell tumors of the testis (11 seminomas, 24 mixed germ cell tumors, and 1 case of pure intratubular germ cell neoplasia) were included in the study. HIF-1alpha and pVHL expression were studied using immunohistochemical (IHC) methods in the tumor and adjacent benign tissue. Selected cases with a low pVHL expression were further tested for genetic alterations using polymerase chain reaction. HIF-1alpha protein expression was not detectable in adjacent atrophic seminiferous tubules. In contrast, HIF-1alpha was expressed in one third of the malignancies, but in a low percentage of cells (mean, 3%; range, 0% to 20%). No difference in HIF-1alpha expression was observed between seminomas and nonseminomas (P=0.71). pVHL was expressed in atrophic tubular epithelium and in the Leydig cells, whereas a substantial loss of pVHL expression was observed in germ cell tumors regardless of the histologic type (mean, 45.6%; range, 0% to 100%). No genetic alterations of the VHL gene were observed in the cases with low pVHL expression. No significant correlation between HIF-1alpha and pVHL expression was observed (P=0.16). Germ cell tumors of the testis, regardless of the histologic type, are characterized by consistently low HIF-1alpha protein overexpression and a partial loss of pVHL without underlying VHL gene alterations. Further studies are necessary to clarify the functional importance of such alterations in testicular germ cell tumors. PMID- 22820663 TI - A proposed score for assessing progression in pT1 high-grade urothelial carcinoma of the bladder. AB - We tested a selected series of patients with single urothelial high-grade pT1 stage (pT1 HG) or urothelial carcinoma in situ (CIS) with a set of immunohistochemical markers to elaborate a risk score for progression. We retrospectively reviewed all first diagnoses of single, <3 cm, urothelial papillary carcinoma pT1 HG or isolated CIS between 2006 and 2009. Galectin-3, CD44, E-cadherin, CD138, p16, survivin, HYAL-1, and topoisomerase-II alpha were used. A grading score 0 or 1 for each immunohistochemical staining was assigned to obtain a total score for assessing the progression. The median "progression score" was selected as cutoff value for statistical analysis. Overall, 23 patients (19 pT1 HG and 4 CIS) were included in the study. After a median follow up of 21 months (range, 12 to 34 mo), 9 patients (39.1%) showed disease recurrence whereas 4 patients (17.4%) showed tumor progression. Topoisomerase-II alpha, p16, survivin, galectin-3, and CD138 were significantly associated with progression. Progression score ranged from 0 (best prognosis) to 7 (worst prognosis). Using a score >=5 as a threshold, specificity was 78.9%, sensitivity 100%, positive predictive value 50%, and negative predictive value 100%. ROC area (a 95% confidence interval, 0.807-1.000; P<0.001). This immunohistochemistry based progression score using a threshold >=5, might help the clinician to focus on patients with HG pT1 or extended CIS at high risk for disease progression. These patients might benefit from a more intensive follow-up program or early cystectomy. PMID- 22820664 TI - Atypical intradermal smooth muscle neoplasms (formerly cutaneous leiomyosarcomas): case series, immunohistochemical profile and review of the literature. AB - Atypical intradermal smooth muscle neoplasms (AISMN, formerly known as cutaneous leiomyosarcomas) are uncommon neoplasms, which seem to be remarkable for their excellent prognosis in contrast to their deeper counterparts. The rarity of AISMN has posed a challenge for characterizing the morphologic spectrum, immunohistochemical staining pattern, and behavior. In this study we evaluated the histologic and immunohistochemical features of 20 cases of AISMN. Clinical follow-up was available on 19 out of 20 patients and ranged from 1 to 124 months with an average of 35 months and a median of 20 months with a male predominance (male to female ratio was 2.3:1). Our data show a wide variation in differentiation and atypical features. Among these, the presence of mitotic figures is diagnostically valuable in rendering the final diagnosis. A broad panel of immunohistochemical stains revealed that smooth muscle actin and muscle specific actin, when used in combination, identified smooth muscle differentiation in 100% of the cases. With some caveats, CD34, S100, and CK 5/6 were helpful in ruling out other important cutaneous spindle cell neoplasms. Significantly, loss of phosphatase and tensin homolog (PTEN) staining was seen in the majority of our cases (80%), supporting a role for PTEN loss in the etiology of these lesions. Logistic regression analysis revealed that positive margin status was helpful for predicting recurrence (100% sensitivity and 94% specificity). We conclude that AISMN can have significant morphologic variation and overlap with other spindle cell neoplasms of the skin and that a limited panel of key immunohistochemical stains should be used to distinguish this lesion. The different surgical measures such as wide excision versus Mohs procedure showed a similar clinical outcome. Although the significance of frequent PTEN loss supports a molecular mechanism of tumor genesis, the diagnostic utility of the stain remains to be determined. PMID- 22820665 TI - Immunoprofile of mucinous non-neoplastic cyst of the pancreas. AB - BACKGROUND: A recently described mucinous non-neoplastic cyst (MNNC) of the pancreas is a benign cyst and should be distinguished from mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN) due to different management and prognosis. The immunoprofile of MNNC has not been well studied. DESIGN: Twenty-three MNNCs diagnosed on surgical resection were retrieved. Immunohistochemical (IHC) staining was performed on surgically resected specimen. Sixteen IPMN and 15 MCN cases were also retrieved for comparison. Cyst fluid carcinoembryonic antigen and amylase concentrations were retrieved. RESULT: MNNCs were randomly located in the pancreas and were either unilocular or multilocular cysts that were lined by a single layer of bland columnar or cuboidal mucinous cells and supported by paucicellular stroma. The glandular epithelial cells were diffusely positive for CK7 (100%) and PDX-1 (65%); focally positive for CD10 (superficial, 65%), CD99 (basally, 100%), CDX-2 (17%), and CK20 (4%); and negative for MUC2. Only rare stromal cells in the cyst wall were weakly positive for estrogen receptor or progesterone receptor in only 6% of cases and negative for inhibin. These results were also compared with the immunoprofile of IPMN and MCN. CONCLUSIONS: Although MNNC shares some IHC markers with IPMN or MCN, an IHC panel can help distinguish MNNC from IPMN or MCN. The results suggest that MNNC is different from IPMN and MCN. PMID- 22820666 TI - Comparison of the PharmDx immunohistochemical system with standard methods for assessing estrogen and progesterone receptors in invasive carcinoma of the breast. AB - AIM: Accurate assessment of estrogen receptor (ER) and progesterone receptor (PR) status of breast cancers is essential for selecting patients for endocrine treatment. This study aimed to compare immunohistochemistry for these markers using the pharmDx system and standard methods. METHODS: Sections of 203 core biopsies of invasive carcinoma of the breast were stained for ER and PR using the pharmDx system and standard methods. RESULTS: Using a cutoff of H score of 10, there was agreement between the 2 methods in 201 tumors (99%) for both ER and PR. Using a cutoff of 1% staining there was agreement of 99.5% for ER and 96% for PR. CONCLUSIONS: The pharmDx system shows good agreement with standard methods for assessing ER and PR in breast cancer. PMID- 22820667 TI - Mechanical exfoliation of epitaxial graphene on Ir(111) enabled by Br2 intercalation. AB - We show here that Br(2) intercalation is an efficient method to enable exfoliation of epitaxial graphene on metals by adhesive tape. We exemplify this method for high-quality graphene of macroscopic extension on Ir(111). The sample quality and the transfer process are monitored using low-energy electron diffraction (LEED), scanning tunneling microscopy (STM), scanning electron microscopy (SEM) and Raman spectroscopy. The developed process provides an opportunity for preparing graphene of strictly monatomic thickness and well defined orientation including the transfer to poly(ethylene terephthalate) (PET) foil. PMID- 22820668 TI - Charge-order driven proton arrangement in a hydrogen-bonded charge-transfer complex based on a pyridyl-substituted TTF derivative. AB - A unique N(+)-H...N hydrogen-bonded (H-bonded) dimer motif based on partially oxidized pyridyl-substituted TTF was constructed in the charge-transfer complex. The charge ordering in the TTF column by the charge disproportionation in the dimer regulates the arrangement of the H-bonded proton, evidencing the proton electron coupled state. PMID- 22820669 TI - Denaturation mapping of Saccharomyces cerevisiae. AB - Optical mapping of DNA provides large-scale genomic information that can be used to assemble contigs from next-generation sequencing, and to detect rearrangements between single cells. A recent optical mapping technique called denaturation mapping has the advantage of using physical principles rather than the action of enzymes to probe genomic structure. Denaturation mapping uses fluorescence microscopy to image the pattern of partial melting along a DNA molecule extended in a channel of cross-section 120 nm at the heart of a nanofluidic device. We used denaturation mapping to locate single DNA molecules on the yeast genome (12.1 Mbp) by comparing images to a computationally predicted map for the entire genome sequence. By locating 84 molecules we assembled an optical map of the yeast genome with > 50% coverage. PMID- 22820670 TI - Calorie restriction from a young age preserves the functions of pancreatic beta cells in aging rats. AB - Calorie restriction (CR) is a simple method for delaying aging process, extending lifespan, and preventing the onset of aging-related diseases, such as diabetes. However, the mechanism, by which CR influences beta-cell functions during the aging process, still remains unclear. In this study, sixteen 8-week-old male Sprague-Dawley rats were randomized to control group with food intake ad libitum and CR group fed with 70% of food intake of the control group. Twenty-four weeks later, the body weights of the rats with CR were significantly lower with the smaller amounts of perirenal and epididymal fats, compared to those of control rats. The beta-cell activity, as judged by the early insulin secretion in the intraperitoneal glucose tolerance test, was significantly higher in the CR group than that in control animals. Moreover, CR animals showed the increased beta cell mass and proliferation of beta-cells in pancreas. The plasma level of malondialdehyde was lower in CR rats than that in control rats, while the activities of superoxide dismutase, catalase and glutathione peroxidase in plasma were higher in CR rats than control rats. These results indicate that aging is associated with the increases in oxidative stress, which was, however, alleviated by CR. In conclusion, CR from a young age preserves the principal beta-cell function of early insulin secretion in rats probably by stimulating the beta-cell proliferation. Our observations provide the evidence for clinical significance of CR in preventing beta-cell dysfunction during the aging process, which may delay the onset of aging-related disease, including diabetes in humans. PMID- 22820671 TI - An antithrombin-heparin complex increases the anticoagulant activity of fibrin clots. AB - Clotting blood contains fibrin-bound thrombin, which is a major source of procoagulant activity leading to clot extension and further activation of coagulation. When bound to fibrin, thrombin is protected from inhibition by antithrombin (AT) + heparin but is neutralized when AT and heparin are covalently linked (ATH). Here, we report the surprising observation that, rather than yielding an inert complex, thrombin-ATH formation converts clots into anticoagulant surfaces that effectively catalyze inhibition of thrombin in the surrounding environment. PMID- 22820672 TI - Liver X Receptor Agonists Inhibit the Phospholipid Regulatory Gene CTP: Phosphoethanolamine Cytidylyltransferase-Pcyt2. AB - Metabolic pulse-chase experiments demonstrated that 25-hydroxycholesterol (25 OH), the endogenous activator of the liver X receptor (LXR), significantly reduced the biosynthesis of phosphatidylethanolamine via CDP-ethanolamine (Kennedy) pathway at the step catalyzed by CTP: phosphoethanolamine cytidylyltransferase (Pcyt2). In the mouse embryonic fibroblasts C3H10T1/2, the LXR synthetic agonist TO901317 lowered Pcyt2 promoter-luciferase activity in a concentration-dependent manner. Furthermore, 25-OH and TO901317 reduced mouse Pcyt2 mRNA and protein levels by 35-60%. The inhibitory effects of oxysterols and TO901317 on the Pcyt2 promoter function, mRNA and protein expression were conserved in the human breast cancer cells MCF-7. These studies identify the Pcyt2 gene as a novel target whereby LXR agonists may indirectly modulate inflammatory responses and atherosclerosis. PMID- 22820673 TI - Competitive sports participation in athletes with congenital long QT syndrome. PMID- 22820674 TI - Cognitive testing of the STAR-Q: insights in activity and sedentary time reporting. AB - PURPOSE: The qualitative attributes and quantitative measurement properties of physical activity questionnaires are equally important considerations in questionnaire appraisal, yet fundamental aspects such as question comprehension are not often described in the literature. Here we describe the use of cognitive interviewing to evaluate the Sedentary Time and Activity Reporting Questionnaire (STAR-Q), a self-administered questionnaire designed to assess overall activity energy expenditure and sedentary behavior. METHODS: Several rounds of one-on-one interviews were conducted by an interviewer trained in qualitative research methods. Interviewees included a convenience sample of volunteers and participants in the Tomorrow Project, a large cohort study in Alberta, Canada. Following each round of interviews the STAR-Q was revised and cognitively tested until saturation was achieved. RESULTS: Six rounds of cognitive interviewing in 22 adults (5 males, 17 females) age 23-74 years, led to revisions involving 1) use of recall aids; 2) ambiguous terms; and 3) specific tasks, such as averaging across multiple routines, reporting time asleep and self-care, and reporting by activity domain. CONCLUSIONS: Cognitive interviewing is a critical step in questionnaire development. Knowledge gained in this study led to revisions that improved respondent acceptability and comprehension of the STAR-Q and will complement ongoing validity testing. PMID- 22820675 TI - N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats. AB - The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N acetylcysteine (NAC) - a putative precursor of the most important tissue antioxidant glutathione - in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50-100mg/kg, ip) or IMI (10mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity - TAC and the superoxide dismutase activity - SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity. PMID- 22820676 TI - Gender differences in cognitive function of patients with chronic schizophrenia. AB - Schizophrenic patients have cognitive impairments, but gender differences in these cognitive deficits have had limited study. This study assessed cognitive functioning in 471 subjects including 122 male and 78 female schizophrenic patients and 141 male and 130 female healthy controls. We found that immediate memory, language, delayed memory and total RBANS scores were significantly decreased in schizophrenia compared with healthy controls for both genders. Male patients had significant lower immediate memory, delayed memory and total RBANS scores than female patients, and healthy controls showed a similar gender difference. The RBANS showed modest correlations with PANSS scores, duration of illness and antipsychotic dose (chlorpromazine equivalents). Almost all RBANS scores in the schizophrenics and healthy controls showed significant positive correlations with education. Thus, patients of both sexes with schizophrenia experienced more deteriorated performance than healthy controls on cognitive domains of immediate memory, language and delayed memory. Furthermore, male schizophrenic patients had more serious cognitive deficits than female patients in immediate and delayed memory, but not in language, visuospatial and attention indices. PMID- 22820677 TI - Flux module decomposition for parameter estimation in a multiple-feedback loop model of biochemical networks. AB - Computer simulation is an important technique to capture the dynamics of biochemical networks. Since few quantitative values are measured in vivo, the values for unmeasured parameters should be estimated so that the simulation agrees with the experimental data. Considering the sparsity and error rates of experimentally measured data, the first thing is not to find a numerically exact and global solution but to explore a variety of the plausible parameter solutions. To find many plausible parameter solutions without any biases, we developed the two-phase search (TPS) method. However, calculation complexity makes it hard for TPS to optimize a large-scale dynamic model. In this study divide-and-conquer methods are used to solve this problem. The flux module decomposition (FMD) is first proposed that separates a complex, large-scale dynamic model into multiple flux modules without deteriorating its basic control architectures. FMD is combined with TPS, named FMD-TPS, to find many plausible parameter solutions for a dynamic model. To demonstrate the feasibility of FMD TPS, it is applied to the E. coli ammonia assimilation system that consists of multiple-feedback loops. The variability of the solutions is verified by measuring the space distribution of the parameter solution vectors and by defining the binary vectors checking the consistency with biological behaviors. Compared with non-decomposition methods, FMD-TPS efficiently explored a variety of plausible parameter solutions that reproduce the dynamic behaviors in vivo. PMID- 22820678 TI - Different intravenous contrast media concentrations do not affect clinical assessment of 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans in an intraindividual comparison. AB - OBJECTIVE: The purpose of this study was to perform an intraindividual comparison of the influences of different iodine contrast media on tracer uptake, contrast enhancement, and image quality in combined positron emission tomography (PET)/computed tomography (CT). MATERIALS AND METHODS: Fifty-one patients underwent baseline and follow-up combined PET/CT consisting of low-dose unenhanced and venous contrast-enhanced CT with contrast media containing a high concentration of iodine (iopromide, 370 mg/mL) and a standard iodine concentration (iopromide, 300 mg/mL). The total iodine load (44.4 g) and the iodine delivery rate (1.29 g/s) were identical for the 2 protocols. The mean and maximum standard uptake values, as measures of tracer uptake and contrast enhancement for unenhanced and contrast-enhanced PET/CT, were quantified at 10 different anatomical sites, and images were analyzed for clinically relevant differences. RESULTS: The mean and maximum standard uptake values were significantly increased in contrast-enhanced PET/CT compared with unenhanced PET/CT at each anatomical site (P < 0.05). Comparison of tracer uptake between the 300- and 370-mg iodine contrast media showed no significant differences (all P > 0.05). Comparison of contrast enhancement between the 300- and 370-mg iodine contrast media showed no significant difference at any anatomical site (all P > 0.05). Analysis of image quality revealed no clinically relevant differences between the 2 different iodine contrast media (P = 0.739). CONCLUSION: The use of contrast-enhanced CT scans for attenuation correction in PET/CT does not cause clinically relevant artifacts in PET scan reconstruction, regardless of the iodine concentration used. Standard- and high-iodine contrast media can be used equivalently. PMID- 22820680 TI - Long-term exposure to traffic-related PM(10) and decreased heart rate variability: is the association restricted to subjects taking ACE inhibitors? AB - BACKGROUND: Alterations in heart rate variability (HRV) are a potential link between exposure to traffic-related air pollution and cardiovascular mortality. OBJECTIVES: We investigated whether long-term exposure to traffic-related PM(10) (TPM(10)) is associated with HRV in older subjects and/or in participants taking specific cardiovascular treatment or with self-reported heart disease. METHODS: We included 1607 subjects from the general population aged 50 to 72 years. These participants from the SAPALDIA cohort underwent ambulatory 24-hr electrocardiogram monitoring. Associations of average annual exposure to TPM(10) over 10 years with HRV parameters from time and frequency domains were estimated using multivariable mixed linear models. Effect estimates are expressed as percent changes in geometric means. RESULTS: HRV was only associated with TPM(10) in participants under ACE inhibitor therapy (N=94). A 1 MUg/m(3) increment, approximately equivalent to an interquartile range, in 10 year average TPM(10) was associated with decrements of 14.5% (95% confidence interval (CI), -25.9 to 1.3) in high frequency (HF) power, of 4.5% (-8.2 to -0.5) in the standard deviation of all normal-to-normal RR intervals (SDNN), of 10.6% (-18.5 to -1.9) in total power (TP) and an increase of 9.2% (0.8 to 20.2) in the LF/HF power ratio. CONCLUSIONS: In the absence of an overall effect our results suggest that alterations in HRV, a measure of autonomic control of the cardiac rhythm, may not be a central mechanism by which long-term exposure to TPM(10) increases cardiovascular mortality. Novel evidence on an effect in persons under ACE inhibitor treatment needs to be confirmed in future studies. PMID- 22820679 TI - Multiple enhancers associated with ACAN suggest highly redundant transcriptional regulation in cartilage. AB - The chondroitin sulfate proteoglycan core protein aggrecan is the major protein constituent of cartilage aside from collagen, and is largely responsible for its distinctive mechanical properties. Aggrecan is required both for proper cartilage formation in development and maintenance of mature cartilage. Prominent ACAN transcription is a conserved feature of vertebrate cartilage, although little is known about its specific transcriptional regulation. We examined the genomic interval containing human ACAN for transcriptional enhancers directing expression to cartilage, using a functional assay in transgenic zebrafish. We tested 24 conserved non-coding sequences, representing ~6% of the total sequence in the interval, and identified eleven independently capable of regulating reporter gene expression in cartilage. These enhancers were widely spaced, from >100kb upstream of the gene to within the first intron. While the majority displayed broad cartilage expression in zebrafish larvae, several were restricted to a subset of cartilage cells in the craniofacial skeleton. In older fish, the enhancers displayed differential activity; some maintained expression, either in all cartilage or preferentially in articular cartilage at the joints, while others were not active. This remarkable degree of overlapping regulatory control has been highly conserved; we identified clear orthologues of six enhancers at the chicken ACAN locus, arranged in the same order relative to the gene. These were also functional in directing expression to cartilage in transgenic zebrafish. Several enhancers contain potential binding sites for Sox9, consistent with its described role as an upstream regulator of ACAN expression. However, others lacked Sox9 consensus binding sites, implicating additional pathways and transcription factors as regulators of ACAN expression in cartilage, either in development or adult tissue. Our identification of these enhancer sequences is the necessary first step in detailed examination of the upstream regulators of ACAN expression. PMID- 22820681 TI - Evaluation of environmental impacts of two common restoration methodologies for pipes that convey stormwater runoff. AB - This study investigated the environmental impact of two commercial stormwater pipe-repair technologies (Ultraliner and Troliner). These technologies use liners believed to contain three plasticizers of potential environmental concern: bisphenol A (BPA), di-(2-ethylhexyl) phthalate (DEHP), and benzyl butyl phthalate (BBP). The release of these two products was investigated both experimentally and mathematically. Kinetic batch experiments were conducted to determine if contaminants were leaching from Ultraliner, Troliner, and the grout (used with Troliner) into water. In all cases for all incubation times up to 48 h, none of the three plasticizers were detected in water in contact with any of the pipe repair materials. A generic GC-FID scan did not detect any unidentified compounds relative to control samples. In addition, a mathematical model of plasticizer leaching from the pipe-liner material was developed. Under various pipe geometries, simulated aqueous concentrations of the plasticizers were less than regulatory limits. PMID- 22820682 TI - Effects of cilostazol against the progression of carotid IMT in symptomatic ischemic stroke patients. AB - Carotid intima-media thickness (IMT) is a surrogate marker for evaluating atherosclerotic vascular diseases. The phosphodiesterase inhibitor cilostazol attenuates the increase in carotid IMT in diabetes patients. We studied whether cilostazol can reduce the progression of carotid IMT in symptomatic ischemic stroke patients. From our prospective registry of acute ischemic stroke patients who were admitted during a 4.5-year period, follow-up carotid ultrasound was performed in a random sample of survivors. Patients were divided into two groups: the cilostazol group, who continued cilostazol treatment during the follow-up period; and the control group, who were prescribed antiplatelets other than cilostazol. Analysis of covariance and propensity score-matched analysis were used to evaluate the difference between groups. Among a total of 1,049 cases in our registry, 208 patients were utilized to construct two comparable sets by propensity score analysis, including 101 who received cilostazol and 107 who took antiplatelet medication without cilostazol. Both maximum and mean carotid IMT values were significantly reduced in the cilostazol group but increased in the control group (maximum left -0.048 +/- 0.186 vs. 0.022 +/- 0.163 mm, p = 0.001; maximum right -0.037 +/- 0.173 vs. 0.050 +/- 0.200 mm, p = 0.001; mean left 0.052 +/- 0.102 vs. 0.023 +/- 0.112 mm, p < 0.001; and mean right -0.038 +/- 0.106 vs. 0.042 +/- 0.139 mm, p < 0.001). After matching by propensity score, the improvements in both maximum and mean carotid IMT values in the cilostazol group remained significant. This study shows that cilostazol causes a significant regression in carotid IMT in symptomatic stroke patients. PMID- 22820683 TI - Clinical neurogenetics: recent advances. AB - In this review, progress in clinical neurogenetics research published in the Journal of Neurology during the past year is summarized. PMID- 22820684 TI - Long-term neuromuscular sequelae of critical illness. AB - In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18-75 years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24 months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47-60) and the median ODSS score was 0 (range 0-8). CIP was diagnosed in 21 patients (41 %). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0-8) versus 0 (range 0-5); p < 0.001 and lower median MRC sum scores 56 (range 47-60) versus 60 (range 58-60); p < 0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r = -0.33; p = 0.02) and the ODSS score (r = 0.31; p = 0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6-33) versus 16.5 (range 6-28); p = 0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11 days (range 2-74) versus 4 days (range 1 61); p = 0.015, and had more days of ventilator support 8 days (range 1-59) versus 2 days (range 1-46); p = 0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient's case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant diseases. PMID- 22820686 TI - Solid-phase PCR in a picowell array for immobilizing and arraying 100,000 PCR products to a microscope slide. AB - We present a method for performing highly parallel PCR reactions in a picowell array (PWA) simultaneously immobilizing generated PCR products in a covalent and spatially-resolved manner onto a microscope slide via solid-phase PCR (SP-PCR). This so called PWA-SP-PCR was performed in picowell arrays featuring 100,000 wells cm(-2) of 19 pL reaction volumes with a surface-to-volume ratio of 0.2 MUm( 1). Positive signals were obtained in 97.2% of the 110,000 wells in an area of 110 mm(2). Immobilized DNA was either indirectly detected using streptavidin-Cy5 or directly by molecular hybridisation of Cy3- and/or Cy5-labelled probes. Amplification and immobilization was demonstrated for template DNA ranging from 100 bp up to 1513 bp lengths. Even single DNA molecules were successfully amplified and immobilized demonstrating digital solid-phase PCR. Compared to widely established emulsion based PCR (emPCR) approaches, leading to PCR products immobilized onto bead surfaces in a highly parallel manner, the novel technique results in direct spatial registration of immobilized PCR products in a microarray format. This enables the subsequent use for massively parallel analysis similar to standard microarrays. PMID- 22820685 TI - Statin use and risk of Parkinson's disease: a meta-analysis of observational studies. AB - Inconsistent results regarding the association between statin use and risk of Parkinson's disease (PD) have been reported. We therefore examined the association between statin use and risk of PD by conducting a detailed meta analysis of all observational studies published regarding this subject. A literature search in the PubMed database was undertaken through April 2012, looking for observational studies evaluating the association between statin use and risk of PD. Combined relative risk (RR) estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. Subgroup and sensitivity analyses were also performed. A total of eight (five case-control and three cohort) studies contributed to the analysis. There was heterogeneity and publication bias among the studies. Statin use significantly reduced the risk of PD by 23 % (RR 0.77, 95 % CI 0.64-0.92, p = 0.005). However, long-term statin use did not significantly affect the risk of PD (RR 0.72, 95 % CI 0.45-1.13, p = 0.15). Stratification of studies by age and smoking status significantly affected the final estimate (age-adjusted RR 0.61, 95 % CI 0.42-0.86, p = 0.005; age-not adjusted RR 0.93, 95 % CI 0.83-1.05, p = 0.23 and smoking-adjusted RR 0.60, 95 % CI 0.42-0.87, p = 0.007; smoking-not-adjusted RR 0.92, 95 % CI 0.82-1.02, p = 0.10). Furthermore, sensitivity analysis confirmed the stability of results. Our meta-analysis supports the hypothesis that statin use reduced the risk of PD. Nevertheless, more randomized clinical trials and observational studies are required to confirm this association with underlying biological mechanisms in the future. PMID- 22820688 TI - Klebsiella pneumoniae necrotizing fasciitis in a Latin American male. AB - Necrotizing fasciitis, caused by Klebsiella pneumoniae, is a rare and life threatening bacterial infection. Most documented cases have been reported from Asia, particularly associated with diabetes mellitus. The prevalence of this infection in the USA is rare, especially among persons of non-Asian descent and those without travel to Asia. We report a case of disseminated necrotizing fasciitis, caused by K. pneumoniae, in a Latin American male with diabetes mellitus. Given our review of the literature, this is the only case report, to our knowledge, of a Latin American patient with Klebsiella necrotizing fasciitis in the USA. This case may reflect the geographical spread and emergence of K. pneumoniae infection in the USA. Clinicians need to be aware of the possible relationship between this organism and necrotizing fasciitis in persons of Latin American descent with diabetes mellitus. PMID- 22820687 TI - Single-crystal organic charge-transfer interfaces probed using Schottky-gated heterostructures. AB - Organic semiconductors based on small conjugated molecules generally behave as insulators when undoped, but the heterointerfaces of two such materials can show electrical conductivity as large as in a metal. Although charge transfer is commonly invoked to explain the phenomenon, the details of the process and the nature of the interfacial charge carriers remain largely unexplored. Here we use Schottky-gated heterostructures to probe the conducting layer at the interface between rubrene and PDIF-CN(2) single crystals. Gate-modulated conductivity measurements demonstrate that interfacial transport is due to electrons, whose mobility exhibits band-like behaviour from room temperature to ~150 K, and remains as high as ~1 cm(2) V(-1) s(-1) at 30 K for the best devices. The electron density decreases linearly with decreasing temperature, an observation that can be explained quantitatively on the basis of the heterostructure band diagram. These results elucidate the electronic structure of rubrene/PDIF-CN(2) interfaces and show the potential of Schottky-gated organic heterostructures for the investigation of transport in molecular semiconductors. PMID- 22820689 TI - Misidentification of Burkholderia pseudomallei as Burkholderia cepacia by the VITEK 2 system. AB - A previously healthy Chinese male returned from working in the Malaysian jungle with a fever. A blood culture grew Gram-negative bacilli that were initially identified as Burkholderia cepacia by the VITEK 2 system but were subsequently found to be Burkholderia pseudomallei by partial sequencing of the 16S rRNA gene. The identification of B. pseudomallei using commercially available automated systems is problematic and clinicians in non-endemic areas should be aware of the possibility of melioidosis in patients with a relevant travel history and blood cultures growing Burkholderia spp. PMID- 22820690 TI - Raoultella planticola bacteraemia. PMID- 22820691 TI - Diagnosis of pulmonary mucormycosis aiding the diagnosis of small cell lung cancer. AB - Mucormycosis is a rare complication in immunocompromised patients. Antemortem diagnosis of mucormycosis is difficult and often incorrect. We report a case of pulmonary mucormycosis caused by Cunninghamella bertholletiae in an elderly man with interstitial pneumonia. The diagnosis of mucormycosis was established by bronchoalveolar lavage. A coexisting immune deficiency condition was considered. Lung cancer was suspected because of an elevated progastrin-releasing peptide level and bilateral hilar and mediastinal lymphadenopathy; it was diagnosed after performing endoscopic ultrasound-guided fine-needle aspiration. Treatment by intravenous liposomal amphotericin B was effective, but relapse occurred because of bone marrow suppression caused by chemotherapy for lung cancer. Treatment for mucormycosis was resumed, but the patient died of carcinomatous lymphangiosis. Autopsy confirmed the diagnosis of pulmonary mucormycosis and revealed refractory anaemia with small cell lung cancer. Mucormycosis often occurs in immunocompromised patients, but this case is rare because the mucormycosis was diagnosed before the diagnosis of malignancy. Because prognosis is often poor, the possibility of coexisting malignancies should always be investigated in patients with mucormycosis infections. PMID- 22820692 TI - Autolytic activity and molecular characteristics of Staphylococcus haemolyticus strains with induced vancomycin resistance. AB - The aim of this study was to investigate the molecular characteristics of induced vancomycin resistance in Staphylococcus haemolyticus. Autolytic properties and phenotypic characteristics of passage-selected vancomycin-resistant S. haemolyticus strains were examined. In addition, expression of autolysis-related genes (atl, lrgAB, sarA and lytS) was investigated using the RNase protection assay (RPA). The RPA results indicated that only the expression of the atl gene was significantly upregulated (2.5- to 6-fold increase) in vancomycin intermediate and vancomycin-resistant strains. The vancomycin-resistant strains exhibited lower expression of murein hydrolase proteins and reduced autolytic activity compared with the parent strain. In addition, a reduced growth rate, cell wall thickening and higher survival rate in the presence of lysostaphin were observed in vancomycin-intermediate and vancomycin-resistant induced strains compared with the parent strain. In conclusion, altered autolytic properties, in particular upregulation of the atl gene, may contribute to vancomycin resistance in S. haemolyticus. PMID- 22820693 TI - An unusual dual infection with Salmonella bredeney, including bacteraemia, and enterohaemorrhagic Escherichia coli O157 that posed a therapeutic dilemma. AB - In this case report, we describe an unusual case of a patient who had a dual infection with Salmonella bredeney including bacteraemia and enterohaemorrhagic Escherichia coli O157 following travel to Cyprus. This posed a therapeutic dilemma. We delayed treatment of the Salmonella infection until signs of colitis had resolved. PMID- 22820694 TI - In vivo characteristics of Korean Beijing Mycobacterium tuberculosis strain K1 in an aerosol challenge model and in the Cornell latent tuberculosis model. AB - The Beijing Mycobacterium tuberculosis family is widely distributed and is the most common M. tuberculosis strain in East Asia. The highly transmissible and predominant Beijing M. tuberculosis strain in Korea, M. tuberculosis K1, was characterized using an aerobic challenge mouse model and a latent tuberculosis model with M. tuberculosis H37Rv as a reference. M. tuberculosis K1 multiplied over ten times more rapidly than M. tuberculosis H37Rv during the early stage of infection and induced high levels of histopathology in the lung. Low levels of T helper cell (Th) Th1 [interferon (IFN)-gamma, interleukin (IL)-12p40] and Th2 cytokines (IL-4, IL-10) were induced in the lungs of M. tuberculosis K1-infected mice. In the latent model, mice infected with M. tuberculosis K1 exhibited more frequent relapse from the latent state than did mice infected with M. tuberculosis H37Rv. In conclusion, M. tuberculosis K1, a prevalent Beijing strain in Korea, is expected to spread due to its rapid growth during the early stages of infection, low-level induction of the immune response and high relapse rates from a latent state. PMID- 22820695 TI - A real-time multiplex PCR assay for the rapid detection of CTX-M-type extended spectrum beta-lactamases directly from blood cultures. PMID- 22820696 TI - Molecular mechanism of macrolide-lincosamide resistance in Moraxella catarrhalis. AB - We identified a Moraxella catarrhalis strain with high-level resistance to azithromycin (MIC>256 mg l(-1)), NSH1, isolated from nasopharyngeal swab samples from an inpatient with acute bronchitis in a Japanese hospital in 2011 and determined its mechanism of macrolide-lincosamide resistance. Antimicrobial susceptibility of M. catarrhalis strains was determined using the Etest and agar dilution methods. Mutations in the four 23S rRNA alleles, the ribosomal proteins L4 and L22, and methylase genes erm(B) and erm(F) were tested by PCR and/or sequencing. The efflux system was examined using appropriate inhibitors. Transformation experiments were performed using DNA amplicons of the 23S rRNA gene of M. catarrhalis strain NSH1. This strain showed high-level resistance to erythromycin, clarithromycin, azithromycin, clindamycin (MICs>256 mg l(-1)) and josamycin (MIC = 128 mg l(-1)), and contained the A2058T mutation (Escherichia coli numbering) in four of the 23S rRNA alleles. Mutation of the ribosomal proteins and overproduction of the efflux system were not observed, and methylase genes were not detected. When amplified DNA containing the single A2058T mutation was transformed into M. catarrhalis strains, transformants with three A2058T mutated 23S rRNA alleles showed high-level resistance to macrolide-lincosamide, similar to strain NSH1. In contrast, transformants with two A2058T-mutated 23S rRNA alleles showed low-level MICs (azithromycin: 0.38-0.5 mg l(-1)). Thus, a single A2058T mutation occurring in at least three 23S rRNA alleles confers high level resistance to 14-, 15- and 16-membered macrolides and lincosamides in M. catarrhalis possessing four 23S rRNA alleles. This study represents the first evidence, to our knowledge, of this effect in M. catarrhalis. PMID- 22820697 TI - Vertebral histomorphometry in a child with glucocorticoid-induced osteoporosis. AB - Vertebral fractures are an under-recognized problem in children with glucocorticoid-induced osteoporosis (GIO). They cause severe back pain and spinal column deformity with a decrease of quality of life. For evaluating the bone mass, bone mineral density measurements have been widely carried out using dual energy X-ray absorptiometry. However, bone histomorphometric analyses of GIO in children are scarce. Bone histomorphometric analyses of vertebral bodies have not been reported. Our aim is to report the first bone histomorphometric data for vertebrae from an autopsied child with GIO. A 15-year-old girl with systemic lupus erythematosus was started on a daily oral dose of 10 mg of prednisolone at 6 years of age. She presented with back pain from 12 years of age. Magnetic resonance imaging at 14 years of age showed a compression fracture of the first lumbar (L1) vertebral body. At 15 years of age, she died of heart failure owing to pulmonary hypertension. Collapsed (L1) and non-collapsed (seventh thoracic vertebrae; T7) vertebral bodies were autopsied for bone histomorphometry and compared. T7 showed severe osteoporosis (bone volume, 4.99%; trabecular thickness, 59 um; trabecular separation, 1,134 um). Compared with T7, L1 showed increased bone volume (33.9%) and trabecular thickness (77 um), and decreased trabecular separation (156 um) owing to the impact of the vertebral fracture. The bone formation and bone resorption parameters were comparable between the two vertebrae. These histological findings suggest that severe osteoporosis developed after long-term glucocorticoid administration, and that the remodeling activities were similar in the fractured and non-fractured vertebrae. PMID- 22820698 TI - Cardiovascular consequences of new-onset hyperglycemia after kidney transplantation. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is associated with high cardiovascular (CV) risk and reduced patient survival. It is unclear whether this risk is newly acquired or represents preexisting CV disease in patients with this complication. METHODS: Included are 1146 adults, recipients of first kidney transplants from 1984 to 2008 treated with modern immunosuppressants. RESULTS: One year after transplantation, 29.8% of patients experienced impaired fasting glycemia and 13.4% NODAT. The risk of NODAT related to recipient variables include the following: older age, male gender, higher body mass index, higher pretransplantation glucose and triglyceride levels, and lower high-density lipoprotein level. Increasing fasting glucose levels at 1, 4, or 12 months after transplantation, independent of other factors, related to reduced patient survival (12 months hazard ratio [HR]=1.146 [1.132-1.161], P<0.0001 for 10mg/dL increase in glucose), and this was primarily because of an increase in CV deaths. Hyperglycemia related to all major CV events (MCVE), cardiac (HR=1.113 [1.094 1.132], P<0.0001), vascular (HR=1.168 [1.140-1.197], P<0.0001), and strokes (HR=1.156 [1.123-1.191], P=0.003). These relations were statistically independent of other risk factors. The increased risk of MCVE was noted particularly in patients without MCVE before transplantation (HR=1.145 [1.126-1.165], P<0.0001). Furthermore, among patients with after transplantation MCVE (n=123, 11%), hyperglycemia increases the risk of death (NODAT: HR=2.410 [1.125-5.162], P=0.024). CONCLUSIONS: After transplantation hyperglycemia is a strong independent risk factor for MCVE and death, mainly from CV causes. This risk is independent of the presence of CV disease identified before transplantation. PMID- 22820699 TI - Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients. AB - BACKGROUND: We conducted a prospective cohort study in highly sensitized kidney transplant candidates with a calculated panel reactive antibody (cPRA) greater than 50% and on the deceased-donor waiting list for more than 5 years to investigate the effects of intravenous immunoglobulin (IVIG) and rituximab treatment. METHODS: Desensitization protocol included two doses of IVIG (2 g/kg, max 120 g each dose) and a single dose of rituximab (375 mg/m(2)). Patients were followed up monthly by Luminex single antigen beads. Whole blood gene expression profiles were studied by Affymetrix Human 1.0 ST GeneChips before and after treatment. RESULTS: Forty patients were eligible for desensitization treatment. Thirteen of these patients agreed to participate, and 11 completed the treatment. After a mean follow-up of 334 +/- 82 days, two desensitized patients (18%) received a kidney transplant compared with 14 patients (52%) in the nondesensitized group. Comparing with 14 patients who received transplants without any desensitization treatment, desensitized patients showed higher class I (99% vs. 80%) and class II (98% vs. 69%) cPRA levels and more unacceptable antigens (32 vs. 8). Desensitization treatment did not lead to any significant reduction in patients' class I and II cPRA levels and any change in the mean number of unacceptable antigens or their mean fluorescence intensity values. Whole blood gene expression analysis by microarrays demonstrated down-regulation of immunoglobulin and B-cell-associated transcripts after treatment. CONCLUSION: These results suggested that pretransplant desensitization with IVIG and rituximab was not successful in highly sensitized kidney transplant candidates with cPRA levels higher than 90%. PMID- 22820700 TI - Distribution of ABO blood group antibody titers in pediatric patients awaiting renal transplantation: implications for organ allocation policy. AB - BACKGROUND: Blood group-incompatible transplantation is one strategy used when a potential recipient does not have a compatible living donor. Current practice includes desensitization strategies to reduce antibody titers. However, when antibodies are low, in cardiac transplantation in neonates for example, no desensitization is required. This study is the first to examine the distribution of ABO blood group antibody titers in a population of pediatric patients on the deceased-donor renal transplantation waiting list. METHODS: All patients from two pediatric nephrology centers active on the national deceased-donor waiting list had antibody titers (total immunoglobulin load) measured. A simulation modeling the effect of allocating blood group-incompatible deceased-donor kidneys to those patients with titers of 16 or lower was developed. RESULTS: Twenty-four children were screened; eight (33.3%) had titers of either anti-A or anti-B antibodies of 8 or lower. A further three (12.5%) had either an anti-A or anti-B antibody titer of 16. Blood group A or B patients had lower antibody levels than blood group O patients. In blood group O patients, levels of anti-A antibodies were higher than anti-B antibodies (Wilcoxon signed rank test, P=0.028). The simulation model showed that a change in organ allocation policy would increase pediatric transplant activity by 2.2% and reduce the median waiting time for a transplant. CONCLUSION: This allocation strategy may be of particular benefit to those pediatric patients who have been on the deceased-donor waiting list for a long time or those with a high calculated reaction frequency. PMID- 22820701 TI - Surgical management of gastrointestinal posttransplant lymphoproliferative disorders in liver transplant recipients. AB - BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a well established complication of immunosuppression. The involvement of the gastrointestinal (GI) tract occurs in 25% of all cases of PTLD. Fortunately, surgical intervention is seldom required. We report our experience of surgical treatment of complicated GI-PTLD after liver transplantation (LTx). METHODS: A retrospective analysis of 5677 adult patients who underwent LTx between 1983 and 2009 was conducted. RESULTS: Thirty-six patients presented with GI-PTLD. Sixteen patients presented with complications associated with GI-PTLD requiring emergency surgery. The average (SD) time from LTx to GI surgery was 7.9 (5.8) years (range, 4 months to 17 years). Indications for surgical intervention were small bowel obstruction (seven cases), perforation (six cases), and GI bleeding (three cases). Most GI-PTLD occurred in the small bowel or right colon (81%). In addition to the surgery, treatment of PTLD consisted of reduction of immunosuppression, use of rituximab (n=10), and systemic chemotherapy (n=7). Overall mortality was 69%, with most of the deaths occurring within 8 months after emergency laparotomy. GI bleeding and perforation were associated with higher mortality (>66%). Despite higher early mortality in the surgical group, no differences on long-term outcome were observed between patients with GI-PTLD who required surgery and those who did not (P=0.371). CONCLUSIONS: In summary, GI PTLD requiring surgical intervention is an extremely rare condition with high early mortality. Most of the cases are monoclonal, present a late onset, and involve the lower GI tract. Intestinal obstruction is the main indication for surgical intervention and is associated with better prognosis. PMID- 22820702 TI - Low energy electron microscopy and photoemission electron microscopy investigation of graphene. AB - Low energy electron microscopy (LEEM) and photoemission electron microscopy (PEEM) are two powerful techniques for the investigation of surfaces, thin films and surface supported nanostructures. In this review, we examine the contributions of these microscopy techniques to our understanding of graphene in recent years. These contributions have been made in studies of graphene on various metal and SiC surfaces and free-standing graphene. We discuss how the real-time imaging capability of LEEM facilitates a deeper understanding of the mechanisms of dynamic processes, such as growth and intercalation. Numerous examples also demonstrate how imaging and the various available complementary measurement capabilities, such as selected area or micro low energy electron diffraction (MULEED) and micro angle resolved photoelectron spectroscopy (MUARPES), allow the investigation of local properties in spatially inhomogeneous graphene samples. PMID- 22820703 TI - Importance of polypeptide chain length for the correct local folding of a beta sheet protein. AB - Equine beta-lactoglobulin is a 162-residue beta-sheet protein. A partially folded form of equine beta-lactoglobulin contains a beta-hairpin and an alpha-helix. The beta-hairpin converts into non-native alpha-helices at temperatures <0 degrees C. CHIBL, a truncated equine beta-lactoglobulin (residues 88-142), contains the low temperature alpha-helical structure even at room temperature, indicating that the interactions responsible for the stability of the beta-hairpin reside in non CHIBL residues. For the study reported herein, we characterized two truncated mutants and their leucine103 -> proline103 variants to identify residues that stabilize the beta-hairpin. The dependence of their circular dichroism spectra on chloride ion concentration and temperature revealed that the ability to transition from the non-native alpha-helices to the beta-hairpin depends on the polypeptide chain length and improves as the chain length increases despite the apparent absence of any ordered structure in the extended sequences. PMID- 22820704 TI - Outcome of laparoscopic colectomy for cancer in elderly patients. AB - BACKGROUND: Resection for colon cancer in the elderly is a major undertaking. However, data on the outcome and survival of elderly patients who underwent laparoscopic resection for colon cancer are limited. This study of patients older than 75 years compared outcome and survival between those who underwent laparoscopic resection and those who had open resection for colorectal cancer. METHODS: From 2000 to 2009, 434 patients ages 75 years and older who underwent elective resection for colon cancer were included in the study. Patients who had rectal cancer or had undergone emergency operations were excluded. Preoperative diagnosis was determined by colonoscopy, and computed tomography scan was performed for preoperative staging. Data on the patients' demographics, operative details, pathology results, postoperative results, and survival were collected prospectively. The patients who underwent laparoscopic surgery were compared with those who had open surgery. RESULTS: The study included 434 patients (210 men) with a median age of 80 years (range 75-95 years). Of these 434 patients, 189 underwent laparoscopic resection. Nine patients (4.8%) required conversion to open operation. The patients did not differ in terms of age, gender, incidence of medical comorbidities, or stage of disease. The median operating time was longer in the laparoscopic group, but the blood loss was significantly less. Laparoscopic resection was associated with a lower mortality rate and a shorter hospital stay (p < 0.05). The open resection group had significantly more cardiac complications (p < 0.05). The overall 5-year survival rates were similar between the patients who had laparoscopic resections and those who had open surgery. CONCLUSIONS: For patients older than 75 years, laparoscopic resection of colon is associated with less intraoperative blood loss, a shorter hospital stay, fewer cardiac complication, and a lower mortality rate than open resection. Therefore, the authors recommend laparoscopic resection of colon cancer as the treatment of choice for elderly patients. PMID- 22820705 TI - One Health approach in the South East Asia region: opportunities and challenges. AB - The outbreaks of SARS, avian influenza, and Nipah virus in Asian countries clearly demonstrated that new highly infectious agents periodically emerge at the human-animal interface. The experiences of regional countries with prevention and control of avian influenza, SARS have reinforced the need for sustained, well coordinated, multi-sector, multi-disciplinary, community-based actions to address emerging disease threats. 'One Health' is a cost-effective, sustainable, and practical approach to find solutions for problems which need holistic, multidisciplinary approaches, particularly in resource-constrained countries. While there is a growing recognition of One Health, it has to be translated from concept into actions through country level activities that are relevant for specific situations. PMID- 22820706 TI - Development of a One Health National Capacity in Africa : the Southern African Centre for Infectious Disease Surveillance (SACIDS) One Health Virtual Centre Model. AB - Among the many challenges to health, infectious diseases stand out for their ability to have a profound impact on humans and animals. The recent years have witnessed an increasing number of novel infectious diseases. The numerous examples of infections which originated from animals suggest that the zoonotic pool is an important and potentially rich source of emerging diseases. Since emergence and re-emergence of pathogens, and particularly zoonotic agents, occur at unpredictable rates in animal and human populations, infectious diseases will constitute a significant challenge for the public health and animal health communities in the twenty-first century. The African continent suffers from one of the highest burdens of infectious diseases of humans and animals in the world but has the least capacity for their detection, identification and monitoring. Lessons learnt from recent zoonotic epidemics in Africa and elsewhere clearly indicate the need for coordinated research, interdisciplinary centres, response systems and infrastructures, integrated surveillance systems and workforce development strategies. More and stronger partnerships across national and international sectors (human health, animal health, environment) and disciplines (natural and social sciences) involving public, academic and private organisations and institutions will be required to meet the present and future challenges of infectious diseases. In order to strengthen the efficiency of early warning systems, monitoring trends and disease prediction and timely outbreak interventions for the benefit of the national and international community, it is essential that each nation improves its own capacity in disease recognition and laboratory competence. The SACIDS, a One Health African initiative linking southern African academic and research institutions in smart partnership with centres of science excellence in industrialised countries as well as international research centres, strives to strengthen Africa's capacity to detect, identify and monitor infectious diseases of humans and animals, to better manage health and socio-economic risks posed by them, and to improve research capacity in investigating the biologic, socio-economic, ecologic and anthropogenic factors responsible for emergence and re-emergence of infectious diseases. PMID- 22820707 TI - An autoregulatory loop reverts the mechanosensitive Sirt1 induction by EGR1 in skeletal muscle cells. AB - Muscle contraction is associated with the production of reactive oxygen species (ROS). Mechanisms of ROS scavenging are fundamental to avoid muscle damage. We had previously discovered a stretch-induced genetic program in myotubes that triggers an antioxidant defense. At the core of this mechanism, transcriptional activation of SIRT1 by the early growth response protein EGR1 results in increased MnSOD activity through the activation of Sod2 by SIRT1/FOXO pathway. In this report, we show experimental evidence that; a) EGR1 and SIRT1 proteins physically interact at the time of maximal Sirt1 induction, b) SIRT1 has a negative effect on the activation of the Sirt1 promoter by EGR1. Thus, the interaction between EGR1 and SIRT1 describes an autoregulatory loop that shuts down the stretch-induced Sirt1 expression. PMID- 22820708 TI - Total synthesis of (+/-)-pallambins C and D. AB - The first total synthesis of (+/-)-pallambins C and D has been accomplished in a linear 38 step reaction from (+/-)-Wieland-Miescher ketone. The key conversions are featured as follows: a Grob fragmentation-intramolecular aldol cyclization and a thiourea/palladium-catalyzed carbonylative annulation. PMID- 22820709 TI - Physical activity in preschool children with the transition to outdoors. AB - BACKGROUND: It is known that children are more physically active outdoors than indoors. However, few previous studies have observed the time course for physical activity as young children transition from indoor to outdoor activities. METHODS: Participants were 3- to 5-year-old children enrolled in the Children's Activity and Movement in Preschool Study (CHAMPS). Trained observers used the Observational System for Recording Physical Activity in Children-Preschool Version (OSRAC-P) to record children's physical activity levels over 20 minutes in outdoor settings. The 20-minute outdoor observational period began immediately following the transition from indoors to outdoors. RESULTS: Children's activity levels were moderately high at the time of transition and declined over the 20 minute observation period. Different patterns, however, were observed for boys and girls. Overall, boys were more active than girls. Boys' activity levels declined in a linear fashion over the 20-minute period, while girls' activity levels increased slightly, decreased, and then increased slightly again. CONCLUSIONS: These data indicate that physical activity levels decline with increased duration of outdoor play. The frequency and duration of outdoor play should be investigated for the purpose of optimizing physical activity levels. PMID- 22820710 TI - Cloning, expression and characterization of lepidopteran isopentenyl diphosphate isomerase. AB - Isopentenyl diphosphate isomerase (IPPI) of the spruce budworm, Choristoneura fumiferana, and of the tobacco hornworm, Manduca sexta, was cloned and its catalytic properties assessed. In the presence of Mg(2+) or Mn(2+), the recombinant protein from C. fumiferana (CfIPPI) efficiently isomerized IPP to dimethylallyl diphosphate (DMAPP). While C. fumiferana IPPI transcript levels were evenly distributed in a wide variety of tissues, they were highly abundant in the corpora allata. Because IPPI plays an alternate role in lepidopteran juvenile hormone (JH) biosynthesis by catalyzing the isomerization of the homologous substrate, homoisopentenyl diphosphate (HIPP), the ability of CfIPPI to convert HIPP to homodimethylallyl diphosphate (HDMAPP) was also studied. As expected, HIPP isomerization was efficient and the formation of HDMAPP occurred, but the regiospecificity of the reaction was lower than previously found in M. sexta corpora allata homogenates and with purified Bombyx mori IPPI. Differences in inhibitory potency for several alkylated ammonium diphosphates and higher homologs of DMAPP were noted between CfIPPI and a vertebrate IPPI, suggesting that the lepidopteran enzyme has a larger active site cavity. To determine the structural factors responsible for homologous substrate coupling, site directed mutagenesis of several residues identified through sequence alignment and homology modeling analysis was performed. The results suggest that unlike other IPPIs, W216 (C. fumiferana numbering) works in concert with a tyrosine residue (Y105) to allow binding of larger substrates and to stabilize the high-energy intermediate formed during substrate isomerization. PMID- 22820711 TI - Calcitonin-like diuretic hormones in insects. AB - Insect neuropeptides control various biological processes including growth, development, homeostasis and reproduction. The calcitonin-like diuretic hormone (CT/DH) is one such neuropeptide that has been shown to affect salt and water transport by Malpighian tubules of several insects. With an increase in the number of sequenced insect genomes, CT/DHs have been predicted in several insect species, making it easier to characterize the gene encoding this hormone and determine its function in the species in question. This mini review summarizes the current knowledge on insect CT/DHs, focusing on mRNA and peptide structures, distribution patterns, physiological roles, and receptors in insects. PMID- 22820712 TI - Preexposure prophylaxis for HIV infection. PMID- 22820713 TI - Management of simple (types A and B) closed tibial shaft fractures using percutaneous lag-screw fixation and Ilizarov external fixation in adults. AB - PURPOSE: Although intramedullary fixation of closed simple (type A or B) diaphyseal tibial fractures in adults is well tolerated by patients, providing lower morbidity rates and better mobility, it is associated with some complications. This study evaluated the results of managing these fractures using percutaneous minimal internal fixation using one or more lag screws, and Ilizarov external fixation. METHODS: This method was tested to evaluate its efficacy in immediate weight bearing, fracture healing and prevention of any post immobilisation stiffness of the ankle and knee joints. This randomised blinded study was performed at a referral, academically supervised, level III trauma centre. Three hundred and twenty-four of the initial 351 patients completed this study and were followed up for a minimum of 12 (12-88) months. Patient ages ranged from 20 to 51 years, with a mean of 39 years. Ankle and knee movements and full weight bearing were encouraged immediately postoperatively. Solid union was assessed clinically and radiographically. Active and passive ankle and knee ranges of motion were measured and compared with the normal side using the Wilcoxon signed rank test for matched pairs. Subjective Olerud and Molander Ankle Score was used to detect any ankle joint symptoms at the final follow-up. RESULTS: No patient showed delayed or nonunion. All fractures healed within 95 129 days. CONCLUSIONS: Based on final clinical and radiographic outcomes, this technique proves to be adequate for managing simple diaphyseal tibial fractures. On the other hand, it is relatively expensive, technically demanding, necessitates exposure to radiation and patients are expected to be frame friendly. PMID- 22820714 TI - Risk factors for hemodialysis and mortality in patients with contrast-induced nephropathy. AB - The purpose of this study was to identify risk factors for renal failure requiring hemodialysis and mortality in patients who developed contrast-induced nephropathy (CIN) after cardiac catheterization. Out of 13,742 patients who received cardiac catheterization at Westchester Medical Center/New York Medical College from 2005 to 2008, 268 patients (2%) with a discharge diagnosis of renal failure were screened for CIN. CIN was defined as either a >25% increase of the serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL within the first 48 hours of the procedure. Chart reviews were performed on 80 patients (1%) who met the criteria for CIN. The 80 patients in the study included 46 men and 34 women, mean age 69 +/- 14 years. Of the 80 patients, 18 patients (23%) died, and 22 patients (28%) developed renal failure requiring hemodialysis. Stepwise logistic regression analysis showed that independent risk factors for mortality were the use of calcium channel blockers [odds ratio = 0.0025, 95% confidence interval (CI), 0.0001-0.1210, P < 0.01], catecholamine use (odds ratio = 71.2177, 95% CI, 4.2153-1203, P < 0.01), circulatory failure with lactic acidosis (odds ratio = 32.1405, 95% CI, 2.6331-392, P < 0.01), and renal failure requiring hemodialysis (odds ratio = 17.0376, 95% CI, 1.2344-235, P < 0.05). Significant independent risk factors for renal failure requiring hemodialysis were smoking (odds ratio = 0.06, 95% CI, 0.0045-0.8080, P < 0.05), N acetylcysteine use (odds ratio = 0.08, 95% CI, 0.0148-0.4179, P < 0.01), anemia (odds ratio = 11.32, 95% CI, 2.57-50, P < 0.01), and circulatory failure with lactic acidosis (odds ratio = 9.76, 95% CI, 2.37-40, P < 0.01). Our data showed that risk factors for mortality in patients with CIN were catecholamine use, circulatory failure with lactic acidosis, and renal failure requiring hemodialysis. Risk factor for reducing mortality in patients with CIN was calcium channel blocker use. Significant risk factors for renal failure requiring hemodialysis were anemia, and circulatory failure with lactic acidosis. Risk factors for reducing renal failure requiring hemodialysis were N-acetylcysteine use and smoking. PMID- 22820715 TI - Effect of cardiovascular drugs on cardiovascular events in 1599 patients followed in an academic outpatient cardiology practice. AB - This study investigated the effects of medical therapy on incidences of myocardial infarction (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABG) in an academic outpatient cardiology practice. Chart reviews were performed in 1599 treated patients (1138 men and 461 women), mean age 72 years. Medications investigated included the use of statins, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aspirin. The mean follow-up was 63 months during 1977-2009. Of 1599 patients, MI occurred in 100 patients (6%), PCI occurred in 296 patients (19%), and CABG occurred in 235 patients (15%). Stepwise logistic regression analysis showed that significant independent risk factors for MI were statins [odds ratio = 0.07; 95% confidence interval (CI), 0.05-0.11, P < 0.001], beta blockers (odds ratio = 0.15, 95% CI, 0.10-0.23, P < 0.001), ACE inhibitors (odds ratio = 0.27, 95% CI, 0.16-0.45, P < 0.001), ARBs (odds ratio = 0.09, 95% CI, 0.04-0.20, P < 0.001), and aspirin (odds ratio = 0.18, 95% CI, 0.12-0.29, P < 0.001). Significant independent risk factors for PCI were statins (odds ratio = 0.15, 95% CI, 0.11-0.20, P < 0.001), beta blockers (odds ratio = 0.26, 95% CI, 0.20-0.35, P < 0.001), ACE inhibitors (odds ratio = 0.25, 95% CI, 0.18-0.34, P < 0.001), and ARBs (odds ratio = 0.18, 95% CI, 0.11-0.28, P < 0.001). Significant independent risk factors for CABG were statins (odds ratio = 0.16, 95% CI, 0.12 0.22, P < 0.001), beta blockers (odds ratio = 0.43, 95% CI, 0.32-0.58, P < 0.001), ACE inhibitors (odds ratio = 0.38, 95% CI, 0.27-0.53, P < 0.001), ARBs (odds ratio = 0.19, 95% CI, 0.11-0.31, P < 0.001), and aspirin (odds ratio = 0.45, 95% CI, 0.33-0.61, P < 0.001). PMID- 22820716 TI - Warfarin use and prevalence of coronary artery calcification assessed by multislice computed tomography. AB - Warfarin inhibits the synthesis and function of matrix Gla protein, a vitamin K dependent protein, which is a potent inhibitor of tissue calcification. We had earlier reported the association of warfarin use with valvular calcification in patients with nonvalvular atrial fibrillation. The aim of our present study was to investigate the association of warfarin use with the presence and severity of coronary artery calcification. A total of 233 patients underwent computed tomography scan (CT) at our institution for the assessment of coronary artery calcium score (CACS). Of 233 patients, the mean age was 63 years, 28 patients (12%) were treated with warfarin, and 205 patients (88%) were not on warfarin. Based on their total CACS, the patients were subsequently stratified into 59 with no coronary calcium (CACS = 0), 63 with low CACS (1-100), 49 with moderate CACS (101-400), 33 with severe CACS (410-1000), and 29 with very severe CACS (>1000). The chi test and Student t-test were used for the comparison of categorical and continuous variables, respectively, between warfarin users and nonusers. Using the variables age, gender, race, smoking, hypertension, diabetes, dyslipidemia, glomerular filtration rate, calcium-phosphorus product, alkaline phosphatase, use of aspirin, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins, stepwise logistic regression analysis did not show any association of coronary calcification with use of warfarin. In our study, warfarin use was not associated with a higher prevalence or severity of CACS assessed by coronary computed tomography. PMID- 22820717 TI - Hormonal secretion and quality of life in Nelson syndrome and Cushing disease after long acting repeatable octreotide: a short series and update. AB - Clinical management of persistent adrenocorticotropin hormone (ACTH) excess in Nelson syndrome (NS) and Cushing disease (CD) remains a challenge. Somatostatin and its analogs as octreotide decrease ACTH secretion through somatostatin receptors of pituitary cells. To our knowledge, there are no reports on the effect of long-acting repeatable octreotide (oct-lar) on hormonal secretion and quality of life in patients with NS and CD who failed conventional therapy. Herein, we describe the effects of treatment with oct-lar (20 mg/month intramurally) in 1 woman with NS and 2 women with persistent CD. Oct-lar therapy reduced ACTH secretion and improved the quality of life in NS patient. By contrast, in CD patients, it failed to control ACTH and cortisol secretion, and the quality of life remained unchanged. PMID- 22820718 TI - A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations. AB - Fospropofol is a sedative hypnotic with a slower onset and longer duration of action. Fospropofol has demonstrated successful dose-dependent sedation at 6.5 mg/kg. This study evaluated the efficacy and safety of a lower weight-adjusted dose compared with the approved dose (4.875 or 6.5 mg/kg depending on patient subgroup) in high-risk elderly patients undergoing colonoscopy. In this study, 153 subjects were classified into 3 subgroups based on the following: age, weight, and American Society of Anesthesiologist (ASA) physical status criteria. The patients were randomized to the approved dose or weight-adjusted dose of fospropofol in a 1:1 ratio. Subgroup 1 (n = 50) consisted of patients weighing <60 kg, age 18-65 years, and ASA I or II; subgroup 2 (n = 50) consisted of patients weighing <60 kg; age 65 years and above, and ASA I-IV; and subgroup 3 (n = 53) consisted of patients weighing >=60 kg, age 65 years and above, and ASA I IV. Sedation, modified sedation and treatment success, and safety parameters were assessed. The approved dose had a significantly higher sedation success compared with the weight-adjusted dose: 96% versus 72% for subgroup 1; 84% versus 72% for subgroup 2; and 96% versus 67.9% for subgroup 3. There was a decreased need for alternative sedatives in subgroups 1 and 3 and fewer sedation- and treatment emergent adverse events in all the subgroups for the approved dose. Additionally, sedation success data pooled across subgroups and examined based on age, weight, and ASA categories showed a significantly higher rate of sedation success in the approved dose arm across all the subgroups. The rate of sedation, modified sedation, and treatment success were higher in patients administered the approved dose for all the subgroups. No clinically significant advantage was demonstrated using a lower modified dose in this study population. The approved dose is recommended in the elderly, more obese, and high-risk patients when used for moderate sedation. PMID- 22820720 TI - Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease. AB - Non-motor symptoms (NMS) of Parkinson's disease (PD) have only recently been increasingly recognized for their impact on a patient's quality of life. In this study, we applied the validated, comprehensive self-completed NMS questionnaire for PD (NMS Quest) to 101 patients with young-onset PD (onset between 21 and 45 years, YOPD) and 107 patients with late-onset PD (onset of PD >= 55 years, LOPD). The mean total NMS (NMSQ-T) was 11.9 +/- 6.0 (range: 0 to of a maximum of 26) in LOPD and 7.7 +/- 5.8 (range: 0 to of a maximum of 26) in YOPD (p < 0.05). Compared to YOPD, dribbling of saliva, loss of taste/smell, nocturia, forgetfulness, loss of interest, hallucinations, lack of concentration, anxiety, change in libido and difficulty in sexual activities, were significantly more prevalent in LOPD. The only NMS more prevalent in YOPD were restless legs and sweating, although such findings might be associated with drug effects. Among the nine NMS Quest domains, in both LOPD and YOPD patients the three most prevalent domains were depression/anxiety, urinary and sexual. Also, in both groups, hallucinations/delusions had the lowest frequency. In the multivariate linear regression model, the Hoehn and Yahr (HY) stage of the disease and activities of daily living scores in YOPD patients, while only the HY stage in LOPD patients appeared to be statistically significant predictors of increasing number of NMS. In contrast to a previous suggestion that YOPD patients might have an increased risk for NMS, we found a higher prevalence of NMS in LOPD patients than in those with YOPD. PMID- 22820721 TI - Recovery of aphasia after stroke: a 1-year follow-up study. AB - Semantics, phonology, and syntax are essential elements of aphasia diagnosis and treatment. Until now, these linguistic components have not been specifically addressed in follow-up studies of aphasia recovery after stroke. The aim of this observational prospective follow-up study was to investigate semantic, phonological, and syntactic recovery in aphasic stroke patients. In addition, we investigated the recovery of verbal communication and of aphasia severity. We assessed 147 aphasic patients at 1, 2, and 6 weeks, 3 and 6 months, and 1 year after stroke with the ScreeLing, a screening test for detecting deficits on the three main linguistic components, the aphasia severity rating scale (ASRS), a measure of verbal communication, and the Token test, a measure of aphasia severity. We investigated the differences in scores between the six time points with mixed models. Semantics and syntax improved up to 6 weeks (p < 0.001) after stroke, and phonology up to 3 months (p <= 0.001). ASRS improved up to 6 months (p < 0.05) and the Token test up to 3 months (p < 0.001). We conclude that in aphasia after stroke, various linguistic components have a different recovery pattern, with phonology showing the longest period of recovery that paralleled aphasia severity, as measured with the Token test. The improvement of verbal communication continues after the stabilization of the recovery of the linguistic components. PMID- 22820723 TI - Superficial siderosis is a warning sign for future intracranial hemorrhage. AB - Supratentorial superficial siderosis (SS) is a frequent imaging marker of cerebral amyloid angiopathy (CAA). It is most probably caused by focal subarachnoid hemorrhages (fSAHs). Based on single-case observations, it has been proposed that such fSAHs might be a predisposing factor for future intracranial hemorrhage. Here we tested the hypothesis if a SS as a residue of fSAHs must be regarded as a warning sign for future intracranial hemorrhage. Fifty-one consecutive patients with SS and no apparent cause other than possible or probable CAA were identified through a database search and followed-up for a median interval of 35.3 months (range 6-120 months). Main outcome measures were rate and location of new intracranial hemorrhages. Twenty-four patients (47.1 %) had experienced any new intracranial hemorrhage, 18 patients (35.3 %) had an intracerebral hemorrhage (ICH), and in 13 of them (25.5 %), the hemorrhage was located at the site of pre-existing siderosis. Six patients (11.7 %) had developed a new subarachnoid hemorrhage (SAH), four of them at the site of siderosis. Patients with SS are at substantial risk for subsequent intracranial hemorrhage. SS can be considered a warning sign of future ICH or SAH, which frequently occur adjacent to pre-existing SS. Prospective studies are needed to confirm these findings. PMID- 22820725 TI - No evidence for an early excess incidence of progressive multifocal leukencephalopathy in HIV-infected patients treated with rituximab. PMID- 22820726 TI - The Core Diseasome. AB - Large amounts of protein-protein interaction (PPI) data are available. The human PPI network currently contains over 56 000 interactions between 11 100 proteins. It has been demonstrated that the structure of this network is not random and that the same wiring patterns in it underlie the same biological processes and diseases. In this paper, we ask if there exists a subnetwork of the human PPI network such that its topology is the key to disease formation and hence should be the primary object of therapeutic intervention. We demonstrate that such a subnetwork exists and can be obtained purely computationally. In particular, by successively pruning the entire human PPI network, we are left with a "core" subnetwork that is not only topologically and functionally homogeneous, but is also enriched in disease genes, drug targets, and it contains genes that are known to drive disease formation. We call this subnetwork the Core Diseasome. Furthermore, we show that the topology of the Core Diseasome is unique in the human PPI network suggesting that it may be the wiring of this network that governs the mutagenesis that leads to disease. Explaining the mechanisms behind this phenomenon and exploiting them remains a challenge. PMID- 22820728 TI - Response of Cassava canopy to mid-day pseudo sunrise induced by solar eclipse. AB - Variations in CO(2) concentration over a cassava canopy were measured during a solar eclipse at Thiruvananthapuram, India. The analysis presented attempts to differentiate between the eclipse effect and the possible effect of thick clouds, taking CO(2) as a proxy for photosynthesis. CO(2) and water vapor were measured at a rate of 10 Hz, and radiation at 1 Hz, together with other meteorological parameters. A rapid reduction in CO(2) observed post-peak eclipse, due apparently to intense photosynthesis, appears similar to what happens at daybreak/post sunrise. The increase in CO(2) (4 ppm) during peak eclipse, with radiation levels falling below the photosynthesis cut-off for cassava, indicates domination of respiration due to the light-limiting conditions. PMID- 22820727 TI - Effects of living at two ambient temperatures on 24-h blood pressure and neuroendocrine function among obese and non-obese humans: a pilot study. AB - The effects of environmental temperature on blood pressure and hormones in obese subjects in Japan were compared in two seasons: summer vs winter. Five obese (BMI, 32 +/- 5 kg/m(2)) and five non-obese (BMI, 23 +/-3 kg/m(2)) men participated in this experiment at latitude 35 degrees 10' N and longitude 136 degrees 57.9' E. The average environmental temperature was 29 +/- 1 degrees C in summer and 3 +/- 1 degrees C in winter. Blood samples were analyzed for leptin, ghrelin, catecholamines, thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), total cholesterol, triglycerides, insulin and glucose. Blood pressure was measured over the course of 24 h in summer and winter. A Japanese version of the Profile of Mood States (POMS) questionnaire was also administered each season. Systolic and diastolic blood pressures in obese men were significantly higher in winter (lower environmental temperatures) than in summer (higher environmental temperatures). Noradrenaline and dopamine concentrations were also significantly higher at lower environmental temperatures in obese subjects, but ghrelin, TSH, fT3, fT4, insulin and glucose were not significantly different in summer and winter between obese and non-obese subjects. Leptin, total cholesterol and triglyceride concentrations were significantly higher in winter in obese than non-obese men. Results from the POMS questionnaire showed a significant rise in Confusion at lower environmental temperatures (winter) in obese subjects. In this pilot study, increased blood pressure may have been due to increased secretion of noradrenaline in obese men in winter, and the results suggest that blood pressure control in obese men is particularly important in winter. PMID- 22820729 TI - Characterization of the structures and dynamics of phosphoric acid doped benzimidazole mixtures: a molecular dynamics study. AB - Benzimidazole-based polymer membranes like poly(2,5-benzimidazole) (ABPBI) doped with phosphoric acid (PA) are electrolytes that exhibit high proton conductivity in fuel cells at elevated temperatures. The benzimidazole (BI) moiety is an important constituent of these membranes, so the present work was performed in order to achieve a molecular understanding of the BI-PA interactions in the presence of varying levels of the PA dopant, using classical molecular dynamics (MD) simulations. The various hydrogen-bonding interactions, as characterized based on structural properties and hydrogen-bond lifetime calculations, show that both BI and PA molecules exhibit dual proton-acceptor/donor functionality. An examination of diffusion coefficients showed that the diffusion of BI decreases with increasing PA uptake, whereas the diffusion of PA slightly increases. The hydrogen-bond lifetime calculations pointed to the existence of competitive hydrogen bonding between various sites in BI and PA. PMID- 22820730 TI - Structure-based design of nitrogen-linked macrocyclic kinase inhibitors leading to the clinical candidate SB1317/TG02, a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3). AB - A high-throughput screen against Aurora A kinase revealed several promising submicromolar pyrimidine-aniline leads. The bioactive conformation found by docking these leads into the Aurora A ATP-binding site had a semicircular shape. Macrocycle formation was proposed to achieve novelty and selectivity via ring closing metathesis of a diene precursor. The nature of the optimal linker and its size was directed by docking. In a kinase panel screen, selected macrocycles were active on other kinase targets, mainly FLT3, JAK2, and CDKs. These compounds then became leads in a CDK/FLT3/JAK2 inhibitor project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. Interaction with this residue explains the observed selectivity. The Asp86 residue is conserved in most CDKs, resulting in potent pan-CDK inhibition by these compounds. Optimized macrocycles generally have good DMPK properties, and are efficacious in mouse models of cancer. Compound 5 (SB1317/TG02), a pan CDK/FLT3/JAK2 inhibitor, was selected for preclinical development, and is now in phase 1 clinical trials. PMID- 22820731 TI - Intravenous ferumoxytol allows noninvasive MR imaging monitoring of macrophage migration into stem cell transplants. AB - PURPOSE: To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints. MATERIALS AND METHODS: With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixed effects model. MR imaging data were correlated with histopathologic findings. RESULTS: All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of iron-loaded macrophages into MASIs. CONCLUSION: Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model. PMID- 22820732 TI - Incremental prognostic value of different components of coronary atherosclerotic plaque at cardiac CT angiography beyond coronary calcification in patients with acute chest pain. AB - PURPOSE: To systematically evaluate the incremental predictive value of cardiac computed tomographic (CT) angiography beyond the assessment of coronary artery calcium (CAC) in patients who present with acute chest pain but without evidence of acute coronary syndrome (ACS). MATERIALS AND METHODS: The human research committee approved this study and waived the need for individual written informed consent. The study was HIPAA compliant. A total of 458 patients (36% male; mean age, 55 years +/- 11) with acute chest pain at low to intermediate risk for coronary artery disease underwent coronary calcification assessment with cardiac CT angiography. All patients who did not experience ACS at index hospitalization were followed for instances of a major adverse cardiac event (MACE), such as a myocardial infarct, revascularization, cardiac death, or angina requiring hospitalization. CAC score and cardiac CT angiography were used to derive the presence and extent of atherosclerotic plaque (calcified, noncalcified, or mixed), and obstructive lesions (>50% luminal narrowing) were related to outcomes by using univariate and adjusted Cox proportional hazards models. RESULTS: Of the 458 patients, 70 (15%) experienced MACE (median follow-up, 13 months). Patients with no plaque at cardiac CT angiography remained free of events during the follow-up period, while 11 (5%) of 215 patients with no CAC had MACE. The extent of plaque was the strongest predictor of MACE independent of traditional risk factors (hazard ratio [HR], 151.77 for four or more segments containing plaque as compared with those containing no plaque; P < .001). Patients with mixed plaque were more likely to experience MACE (HR, 86.96; P = .002) than those with exclusively noncalcified plaque (HR, 58.06; P = .005) or exclusively calcified plaque (HR, 32.94; P = .02). CONCLUSION: The strong prognostic value of cardiac CT angiography is incremental to its known diagnostic value in patients with acute chest pain without ACS and is independent of traditional risk factors and CAC. PMID- 22820733 TI - Assessment of median nerve with MR neurography by using diffusion-tensor imaging: normative and pathologic diffusion values. AB - PURPOSE: To determine normative diffusion values of the median nerve at several anatomic locations in healthy men and women of variable age and to compare these normative values with those in patients with carpal tunnel syndrome. MATERIALS AND METHODS: After ethics board approval and written informed consent were obtained, 45 healthy volunteers (30 women, 15 men) and 15 patients (10 women, five men) were studied. Volunteers were divided into three age groups. Magnetic resonance (MR) neurography with diffusion-tensor imaging (DTI) was performed in all study participants at 3.0 T by using a single-shot echo-planar imaging sequence (repetition time msec/echo time msec, 10 123/40; b=1200 sec/mm2). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the median nerve were determined by two readers at three locations: the levels of the distal radioulnar joint, pisiform bone, and hamate bone. RESULTS: Normative FA and ADC values were calculated for men and women, different age groups, and different anatomic locations. FA and ADC did not differ between men and women (P=.28 and P=.38, respectively). FA decreased and ADC increased when moving from proximal to distal locations (P<.001). FA decreased and ADC increased significantly with age (P<.001). There was a significant difference between healthy volunteers and patients with carpal tunnel syndrome (P<.001 for both FA and ADC). An FA threshold of 0.47 and an ADC threshold of 1.054*10(-3) mm2/sec might be used in the diagnosis of carpal tunnel syndrome. CONCLUSION: Normative diffusion values for MR neurography of the median nerve with DTI depend on the anatomic location and age but not on sex. Age-specific FA and ADC threshold values might be used to diagnose carpal tunnel syndrome. PMID- 22820734 TI - Accelerated late gadolinium enhancement cardiac MR imaging with isotropic spatial resolution using compressed sensing: initial experience. AB - PURPOSE: To evaluate the use of low-dimensional-structure self-learning and thresholding (LOST) compressed sensing acquisition and reconstruction in the assessment of left atrial (LA) and left ventricular (LV) scar by using late gadolinium enhancement (LGE) magnetic resonance (MR) imaging with isotropic spatial resolution. MATERIALS AND METHODS: The study was approved by the local institutional review board and was compliant with HIPAA. All subjects provided written informed consent. Twenty-eight patients (eight women; mean age, 58.0 years +/- 10.1) with a history of atrial fibrillation were recruited for the LA LGE study, and 14 patients (five women; mean age, 54.2 years +/- 18.6) were recruited for assessment of LV myocardial infarction. With use of a pseudorandom k-space undersampling pattern, threefold accelerated three-dimensional (3D) LGE data were acquired with isotropic spatial resolution and reconstructed off-line by using LOST. For comparison, subjects were also imaged by using standard 3D LGE protocols with nonisotropic spatial resolution. Images were compared qualitatively by three cardiologists with regard to diagnostic value, presence of enhancement, and image quality. The signed rank test and Wilcoxon unpaired two sample test were used to test the hypothesis that there would be no significant difference in image quality ratings with different resolutions. RESULTS: Interpretable images were obtained in 26 of the 28 patients (93%) in the LA LGE study. LGE was seen in 17 of 30 cases (57%) with nonisotropic resolution and in 18 cases (60%) with isotropic resolution. Diagnostic quality scores of isotropic images were significantly higher than those of nonisotropic images with coronal views (median, 3 vs 2, respectively [25th and 75th percentiles: 3, 3 vs 2, 3]; P < .001) and sagittal views (median, 3 vs 2 [25th and 75th percentiles: 3, 4 vs 2, 3]; P < .001) but lower with axial views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 3, 3]; P < .001). For the LV LGE study, all patients had interpretable images. LGE was seen in six of 14 patients (43%), with 100% agreement between both data sets. Diagnostic quality scores of high-isotropic resolution LV images were higher than those of nonisotropic images with short axis views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 2, 3]; P = .014) and two-chamber views (median, 4 vs 3 [25th and 75th percentiles: 3, 4 vs 2, 3]; P = .001). CONCLUSION: An accelerated LGE acquisition with LOST enables imaging with high isotropic spatial resolution for improved assessment of LV, LA, and pulmonary vein scar. PMID- 22820735 TI - Feasibility and acceptability of using pedometers as an intervention tool for Latinas. AB - BACKGROUND: Due to high rates of inactivity and related chronic illnesses among Latinas, the current study examined the feasibility and acceptability of using pedometers as an intervention tool in this underserved population. METHODS: Data were taken from a larger randomized, controlled trial2 and focused on the subsample of participants (N = 43) who were randomly assigned to receive a physical activity intervention with pedometers and instructions to log pedometer use daily and mail completed logs back to the research center each month for 6 months. RESULTS: Retention (90.7% at 6 months) and adherence to the pedometer protocol (68.89% returned >= 5 of the 6 monthly pedometer logs) were high. Overall, participants reported increased physical activity at 6 months and credited pedometer use for helping them achieve these gains (75.7%). Participants who completed a high proportion (>= 5/6) of pedometer logs reported significantly greater increases in physical activity and related process variables (stages of change, self-efficacy, behavioral processes of change, social support from friends) than those who were less adherent (completed < 5 pedometer logs). CONCLUSIONS: Pedometers constitute a low-cost, useful tool for encouraging self monitoring of physical activity behavior in this at-risk group. PMID- 22820737 TI - Hemodynamic determinants of aortic dissection propagation by 2D computational modeling: implications for endovascular stent-grafting. AB - AIM: Aortic dissection is a life-threatening aortic catastrophe where layers of the aortic wall are separated allowing blood flow within the layers. Propagation of aortic dissection is strongly linked to the rate of rise of pressure (dp/dt) experienced by the aortic wall but the hemodynamics is poorly understood. The purpose of this study was to perform computational fluid dynamics (CFD) simulations to determine the relationship between dissection propagation in the distal longitudinal direction (the tearing force) and dp/dt. METHODS: Five computational models of aortic dissection in a 2D pipe were constructed. Initiation of dissection and propagation were represented in 4 single entry tear models, 3 of which investigated the role of length of dissection and antegrade propagation, 1 of which investigated retrograde propagation. The 5th model included a distal re-entry tear. Impact of pressure field distribution on tearing force was determined. RESULTS: Tearing force in the longitudinal direction for dissections with a single entry tear was approximately proportional to dp/dt and L2 where L is the length of dissection. Tearing force was much lower under steady flow than pulsatile flow conditions. Introduction of a second tear distally along the dissection away from the primary entry tear significantly reduced tearing force. CONCLUSION: The hemodynamic mechanism for dissection propagation demonstrated in these models support the use of beta-blockers in medical management. Endovascular stent-graft treatment of dissection should ideally cover both entry and re-entry tears to reduce risk of retrograde propagation of aortic dissection. PMID- 22820738 TI - Acute type A aortic dissection intimal tears by 64-slice computed tomography: a role for endovascular stent-grafting? AB - AIM: The goal of this study was to identify physical characteristics of primary intimal tears in patients arriving to the hospital alive with acute type A aortic dissection using 64-multislice computerized tomography (MSCT) in order to determine anatomic feasibility of endovascular stent-grafting (ESG) for future treatment. METHODS: Radiology database was screened for acute type A aortic dissection since the time of acquisition of the 64-slice CT scanner and cross referenced with surgical database. Seventeen patients met inclusion criteria. Images were reviewed for number, location, and size of intimal tears and aortic dimensions. Potential obstacles for ESG were determined. RESULTS: Ascending aorta (29%) and sinotubular junction (29%) were the most frequent regions where intimal tears originated. Location of intimal tears in nearly 75% of patients was inappropriate for ESG, and 94% of patients did not have sufficient proximal or distal landing zone required for secure fixation. Only 71% of patients underwent surgical aortic dissection repair after imaging and 86% of entry tears detected on MSCT were confirmed on intraoperative documentation. Only one patient would have met all technical criteria for ESG using currently available devices. CONCLUSION: Location of intimal tear, aortic valve insufficiency, aortic diameter>38 mm are major factors limiting use of ESG for acute type A dissection. Available stents used to treat type B aortic dissection do not address anatomic constraints present in type A aortic dissection in the majority of cases, such that development of new devices would be required. PMID- 22820739 TI - Anterior cruciate ligament tears: what we already know. PMID- 22820736 TI - Methylation by Set9 modulates FoxO3 stability and transcriptional activity. AB - The FoxO family of transcription factors plays an important role in longevity and tumor suppression by regulating the expression of a wide range of target genes. FoxO3 has recently been found to be associated with extreme longevity in humans and to regulate the homeostasis of adult stem cell pools in mammals, which may contribute to longevity. The activity of FoxO3 is controlled by a variety of post translational modifications that have been proposed to form a 'code' affecting FoxO3 subcellular localization, DNA binding ability, protein-protein interactions and protein stability. Lysine methylation is a crucial post-translational modification on histones that regulates chromatin accessibility and is a key part of the 'histone code'. However, whether lysine methylation plays a role in modulating FoxO3 activity has never been examined. Here we show that the methyltransferase Set9 directly methylates FoxO3 in vitro and in cells. Using a combination of tandem mass spectrometry and methyl-specific antibodies, we find that Set9 methylates FoxO3 at a single residue, lysine 271, a site previously known to be deacetylated by Sirt1. Methylation of FoxO3 by Set9 decreases FoxO3 protein stability, while moderately increasing FoxO3 transcriptional activity. The modulation of FoxO3 stability and activity by methylation may be critical for fine-tuning cellular responses to stress stimuli, which may in turn affect FoxO3's ability to promote tumor suppression and longevity. PMID- 22820740 TI - The preclinical sheep model of high tibial osteotomy relating basic science to the clinics: standards, techniques and pitfalls. AB - PURPOSE: To develop a preclinical large animal model of high tibial osteotomy to study the effect of axial alignment on the lower extremity on specific issues of the knee joint, such as in articular cartilage repair, development of osteoarthritis and meniscal lesions. Preoperative planning, surgical procedure and postoperative care known from humans were adapted to develop a HTO model in the adult sheep. METHODS: Thirty-five healthy, skeletally mature, female Merino sheep between 2 and 4 years of age underwent a HTO of their right tibia in a medial open-wedge technique inducing a normal (group 1) and an excessive valgus alignment (group 2) and a closed-wedge technique (group 3) inducing a varus alignment with the aim of elucidating the effect of limb alignment on cartilage repair in vivo. Animals were followed up for 6 months. RESULTS: Solid bone healing and maintenance of correction are most likely if the following surgical principles are respected: (1) medial and longitudinal approach to the proximal tibia; (2) biplanar osteotomy to increase initial rotatory stability regardless of the direction of correction; (3) small, narrow but long implant with locking screws; (4) posterior plate placement to avoid slope changes; (5) use of bicortical screws to account for the brittle bone of the tibial head and to avoid tibial head displacement. CONCLUSION: Although successful high tibial osteotomy in sheep is complex, the sheep may--because of its similarities with humans- serve as an elegant model to induce axial malalignment in a clinically relevant environment, and osteotomy healing under challenging mechanical conditions. PMID- 22820741 TI - Nanoscale patterning of complex magnetic nanostructures by reduction with low energy protons. AB - Techniques that can produce patterns with nanoscale details on surfaces have a central role in the development of new electronic, optical and magnetic devices and systems. High-energy ion irradiation can produce nanoscale patterns on ferromagnetic films by destroying the structure of layers or interfaces, but this approach can damage the film and introduce unwanted defects. Moreover, ferromagnetic nanostructures that have been patterned by ion irradiation often interfere with unpatterned regions through exchange interactions, which results in a loss of control over magnetization switching. Here, we demonstrate that low energy proton irradiation can pattern an array of 100-nm-wide single ferromagnetic domains by reducing [Co(3)O(4)/Pd](10) (a paramagnetic oxide) to produce [Co/Pd](10) (a ferromagnetic metal). Moreover, there are no exchange interactions in the final superlattice, and the ions have a minimal impact on the overall structure, so the interfaces between alternate layers of cobalt (which are 0.6 nm thick) and palladium (1.0 nm) remain intact. This allows the reduced [Co/Pd](10) superlattice to produce a perpendicular magnetic anisotropy that is stronger than that observed in the metallic [Co/Pd](10) superlattices we prepared for reference. We also demonstrate that our non-destructive approach can reduce CoFe(2)O(4) to metallic CoFe. PMID- 22820742 TI - A monolithic array of three-dimensional ion traps fabricated with conventional semiconductor technology. AB - The coherent control of quantum-entangled states of trapped ions has led to significant advances in quantum information, quantum simulation, quantum metrology and laboratory tests of quantum mechanics and relativity. All of the basic requirements for processing quantum information with arrays of ion-based quantum bits (qubits) have been proven in principle. However, so far, no more than 14 ion-based qubits have been entangled with the ion-trap approach, so there is a clear need for arrays of ion traps that can handle a much larger number of qubits. Traps consisting of a two-dimensional electrode array have undergone significant development, but three-dimensional trap geometries can create a superior confining potential. However, existing three-dimensional approaches, as used in the most advanced experiments with trap arrays, cannot be scaled up to handle greatly increased numbers of ions. Here, we report a monolithic three dimensional ion microtrap array etched from a silica-on-silicon wafer using conventional semiconductor fabrication technology. We have confined individual (88)Sr(+) ions and strings of up to 14 ions in a single segment of the array. We have measured motional frequencies, ion heating rates and storage times. Our results demonstrate that it should be possible to handle several tens of ion based qubits with this approach. PMID- 22820743 TI - Graphene coating makes carbon nanotube aerogels superelastic and resistant to fatigue. AB - Lightweight materials that are both highly compressible and resilient under large cyclic strains can be used in a variety of applications. Carbon nanotubes offer a combination of elasticity, mechanical resilience and low density, and these properties have been exploited in nanotube-based foams and aerogels. However, all nanotube-based foams and aerogels developed so far undergo structural collapse or significant plastic deformation with a reduction in compressive strength when they are subjected to cyclic strain. Here, we show that an inelastic aerogel made of single-walled carbon nanotubes can be transformed into a superelastic material by coating it with between one and five layers of graphene nanoplates. The graphene-coated aerogel exhibits no change in mechanical properties after more than 1 * 10(6) compressive cycles, and its original shape can be recovered quickly after compression release. Moreover, the coating does not affect the structural integrity of the nanotubes or the compressibility and porosity of the nanotube network. The coating also increases Young's modulus and energy storage modulus by a factor of ~6, and the loss modulus by a factor of ~3. We attribute the superelasticity and complete fatigue resistance to the graphene coating strengthening the existing crosslinking points or 'nodes' in the aerogel. PMID- 22820744 TI - Surfactant-directed assembly of mesoporous metal-organic framework nanoplates in ionic liquids. AB - Mesoporous MOF nanoplates were formed in surfactant-IL solutions. This method is simple, requires less energy, and is environmental friendly, and can be easily applied to the synthesis of other MOFs with different morphologies and porosities. PMID- 22820745 TI - Remote identification of a shipwreck site from MBES backscatter. AB - The method described attempts to remotely identify the shape of an anthropogenic object, such as a wreck of a modern vessel, using reflectivity data from Multi Beam Echosounder (MBES) systems. In the beam domain, the backscatter strength values - geometrically and radiometrically corrected - are used to extract a large number of Gray Level Co-occurrence Matrix (GLCM) features with different input parameters. Principal Component Analysis (PCA) is applied in order to achieve dimensionality reduction whilst a K-means algorithm clusters as "shipwreck site" a large number of beams for each line. After the geo-referencing process, a K-nearest-neighbors (K-NN) technique is applied as a filter for possible misclassifications. Finally, the shape of the shipwreck site is defined from the georeferenced beams using the alpha-shape method, constructing an output compatible with Geographic Information Systems (GIS). PMID- 22820746 TI - Recovery of iron oxides from acid mine drainage and their application as adsorbent or catalyst. AB - Iron oxide particles recovered from acid mine drainage represent a potential low cost feedstock to replace reagent-grade chemicals in the production of goethite, ferrihydrite or magnetite with relatively high purity. Also, the properties of iron oxides recovered from acid mine drainage mean that they can be exploited as catalysts and/or adsorbents to remove azo dyes from aqueous solutions. The main aim of this study was to recover iron oxides with relatively high purity from acid mine drainage to act as a catalyst in the oxidation of dye through a Fenton like mechanism or as an adsorbent to remove dyes from an aqueous solution. Iron oxides (goethite) were recovered from acid mine drainage through a sequential precipitation method. Thermal treatment at temperatures higher than 300 degrees C produces hematite through a decrease in the BET area and an increase in the point of zero charge. In the absence of hydrogen peroxide, the solids adsorbed the textile dye Procion Red H-E7B according to the Langmuir model, and the maximum amount adsorbed decreased as the temperature of the thermal treatment increased. The decomposition kinetics of hydrogen peroxide is dependent on the H(2)O(2) concentration and iron oxides dosage, but the second-order rate constant normalized to the BET surface area is similar to that for different iron oxides tested in this and others studies. These results indicate that acid mine drainage could be used as a source material for the production of iron oxide catalysts/adsorbents, with comparable quality to those produced using analytical grade reagents. PMID- 22820747 TI - Assessment of salinity intrusion in the James and Chickahominy Rivers as a result of simulated sea-level rise in Chesapeake Bay, East Coast, USA. AB - Global sea level is rising, and the relative rate in the Chesapeake Bay region of the East Coast of the United States is greater than the worldwide rate. Sea-level rise can cause saline water to migrate upstream in estuaries and rivers, threatening freshwater habitat and drinking-water supplies. The effects of future sea-level rise on two tributaries of Chesapeake Bay, the James and Chickahominy (CHK) Rivers, were evaluated in order to quantify the salinity change with respect to the magnitude of sea-level rise. Such changes are critical to: 1) local floral and faunal habitats that have limited tolerance ranges to salinity; and 2) a drinking-water supply for the City of Newport News, Virginia. By using the three-dimensional Hydrodynamic-Eutrophication Model (HEM-3D), sea-level rise scenarios of 30, 50, and 100 cm, based on the U.S. Climate Change Science Program for the mid-Atlantic region for the 21st century, were evaluated. The model results indicate that salinity increases in the entire river as sea level rises and that the salinity increase in a dry year is greater than that in a typical year. In the James River, the salinity increase in the middle-to-upper river (from 25 to 50 km upstream of the mouth) is larger than that in the lower and upper parts of the river. The maximum mean salinity increase would be 2 and 4 ppt for a sea-level rise of 50 and 100 cm, respectively. The upstream movement of the 10 ppt isohaline is much larger than the 5 and 20 ppt isohalines. The volume of water with salinity between 10 and 20 ppt would increase greatly if sea level rises 100 cm. In the CHK River, with a sea-level rise of 100 cm, the mean salinity at the drinking-water intake 34 km upstream of the mouth would be about 3 ppt in a typical year and greater than 5 ppt in a dry year, both far in excess of the U.S. Environmental Protection Agency's secondary standard for total dissolved solids for drinking water. At the drinking-water intake, the number of days of salinity greater than 0.1 ppt increases with increasing sea-level rise; during a dry year, 0.1 ppt would be exceeded for more than 100 days with as small a rise as 30 cm. PMID- 22820748 TI - Inhibition of Candida albicans by Fluvastatin Is Dependent on pH. AB - The cholesterol-lowering drug fluvastatin (FS) has an inhibitory effect on the growth of the pathogenic yeast Candida albicans that is dependent on the pH of the medium. At the low pH value of the vagina, FS is growth inhibitory at low and at high concentrations, while at intermediate concentrations (1-10 mM), it has no inhibitory effect. Examination of the effect of the common antifungal drug fluconazole in combination with FS demonstrates drug interactions in the low concentration range. Determination of intracellular stress and the activity of the FS target enzyme HMG-CoA reductase confirm our hypothesis that in the intermediate dose range adjustments to the sterol biosynthesis pathway can compensate for the action of FS. We conclude that the pH dependent uptake of FS across yeast membranes might make FS combination therapy an attractive possibility for treatment of vaginal C. albicans infections. PMID- 22820749 TI - Metabolism of a Glycosaminoglycan during Metamorphosis in the Japanese Conger eel, Conger myriaster. AB - Hyaluronan (HA) is a linear polysaccharide of high molecular weight that exists as a component of the extracellular matrix. The larvae (leptocephali) of the Japanese conger eel (Anguilliformes: Conger myriaster) have high levels of hyaluronan (HA) which is thought to help control body water content. We isolated glycosaminoglycans (GAGs) from Japanese conger eel leptocephali and measured the changes in tissue HA content during metamorphosis. HA content decreased during metamorphosis. In contrast, neutral sugar content increased during metamorphosis. We hypothesize that the leptocephali utilize a metabolic pathway that converts HA to glucose during metamorphosis. Glucose may then be metabolized to glycogen and stored in the juvenile life-history stage. PMID- 22820750 TI - Two Distantly Spaced Basic Patches in the Flexible Domain of Huntingtin Interacting Protein 1 (HIP1) Are Essential for the Binding of Clathrin Light Chain. AB - The interaction between HIP family proteins (HIP1 and HIP12/1R) and clathrin is fundamental to endocytosis. We used circular dichroism (CD) to study the stability of an HIP1 subfragment (aa468-530) that is splayed open. CD thermal melts show HIP1 468-530 is only stable at low temperatures, but this HIP1 fragment contains a structural unit that does not melt out even at 83 degrees C. We then created HIP1 mutants to probe our hypothesis that a short hydrophobic path in the opened region is the binding site for clathrin light chain. We found that the binding of hub/LCb was sensitive to mutating two distantly separated basic residues (K474 and K494). The basic patches marked by K474 and K494 are conserved in HIP12/1R. The lack of conservation in sla2p (S. cerevisiae), HIP1 from D. melanogaster, and HIP1 homolog ZK370.3 from C. elegans implies the binding of HIP1 and HIP1 homologs to clathrin light chain may be different in these organisms. PMID- 22820751 TI - Dephosphorylation of Centrins by Protein Phosphatase 2C alpha and beta. AB - In the present study, we identified protein phosphatases dephosphorylating centrins previously phosphorylated by protein kinase CK2. The following phosphatases known to be present in the retina were tested: PP1, PP2A, PP2B, PP2C, PP5, and alkaline phosphatase. PP2C alpha and beta were capable of dephosphorylating P-Thr(138)-centrin1 most efficiently. PP2Cdelta was inactive and the other retinal phosphatases also had much less or no effect. Similar results were observed for centrins 2 and 4. Centrin3 was not a substrate for CK2. The results suggest PP2C alpha and beta to play a significant role in regulating the phosphorylation status of centrins in vivo. PMID- 22820752 TI - What differs on the enzymatic acetylation mechanisms for arylamines and arylhydrazines substrates? A theoretical study. AB - The acetylation mechanisms of several selected typical substrates from experiments, including arylamines and arylhydrazines, are investigated with the density functional theory in this paper. The results indicate that all the transition states are characterized by a four-membered ring structure, and hydralazine (HDZ) is the most potent substrate. The bioactivity for all the compounds is increased in a sequence of PABA ~ 4-AS < 4-MA < 5-AS ~ INH < HDZ. The conjunction effect and the delocalization of the lone pairs of N atom play a key role in the reaction. All the results are consistent with the experimental data. PMID- 22820753 TI - Multiplex detection and genotyping of point mutations involved in charcot-marie tooth disease using a hairpin microarray-based assay. AB - We previously developed a highly specific method for detecting SNPs with a microarray-based system using stem-loop probes. In this paper we demonstrate that coupling a multiplexing procedure with our microarray method is possible for the simultaneous detection and genotyping of four point mutations, in three different genes, involved in Charcot-Marie-Tooth disease. DNA from healthy individuals and patients was amplified, labeled with Cy3 by multiplex PCR; and hybridized to microarrays. Spot signal intensities were 18 to 74 times greater for perfect matches than for mismatched target sequences differing by a single nucleotide (discrimination ratio) for "homozygous" DNA from healthy individuals. "Heterozygous" mutant DNA samples gave signal intensity ratios close to 1 at the positions of the mutations as expected. Genotyping by this method was therefore reliable. This system now combines the principle of highly specific genotyping based on stem-loop structure probes with the advantages of multiplex analysis. PMID- 22820754 TI - The C-681G polymorphism of the PPAR-gamma gene is associated with susceptibility to non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is defined as excessive accumulation of fatty acid in the liver, a common disease in the world. The research of single nucleotide polymorphisms (SNPs) provides a new approach for managing NAFLD. SNPs may increase or decrease the functions of the target genes and their encoding proteins. Peroxisome proliferator-activated receptor (PPAR) plays a key role in modulating metabolism of hepatic triglycerides and consequently magnitude of NAFLD. In this study, we investigated the effect of three SNPs in the PPAR-gamma gene i.e. rs10865710 (C-681G), rs7649970 (C-689T) and rs1801282 (C34G, also termed Pro12Ala) on susceptibility to NAFLD. The participants were selected from our epidemiological survey. Totally 169 participants were enrolled in NAFLD group, and 699 healthy subjects were included as controls. PCR-RFLP was applied to detect the SNPs. The G allele frequency of rs10865710 in NAFLD group (41.1%) was significantly higher than that (34.8%) in controls (p = 0.03). Differences in other two loci (rs7649970 and rs1801282) were not statistically significant between the two groups (p > 0.05). This result was confirmed by haplotype analysis. The GCC haplotype (a set of 3 adjacent SNPs in linkage disequilibrium, corresponding to the three alleles of above polymorphisms in order) was a risk factor for the susceptibility to NAFLD (p = 0.03). This study has revealed that the G allele of rs10865710 in the PPAR-gamma gene is associated with the increased susceptibility to NAFLD. Our findings may provide novel diagnostic biomarkers and therapeutic targets for NAFLD. PMID- 22820755 TI - Cerebellar hemangioblastoma associated with diffuse neonatal hemangiomatosis in an infant. AB - INTRODUCTION: Hemangioblastomas (HBLs) comprise approximately 2% of all primary central nervous system (CNS) tumors. Although histological features of this rare tumor are generally benign, its outcome is often unfavorable due to high risk of recurrence and multifocal localization. HBLs can be detected as sporadic or associated with Von Hippel-Lindau disease. Diffuse neonatal hemangiomatosis (DNH) presents with multiple, progressive, rapidly growing cutaneous hemangiomas associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges. DNH with predominant CNS involvement is rarely reported. Herein, we present a neonatal case of cerebellar HBL associated with DNH. CASE REPORT: A 5-day-old male baby was referred with complaints of multiple cutaneous lesions. Purple papules were noted on the trunk, extremities, and the head. Thoracic magnetic resonance imaging demonstrated multiple hyperintense lesions on the chest wall and apex of the right lung. On MRI, a 3*2-cm mass lesion in the right cerebellar hemisphere was detected. Total resection of the mass and ventriculoperitoneal shunting was performed. Histopathologic examination confirmed the diagnosis of HBL. Steroid therapy was administered for disseminated hemangiomatosis, and the lesions showed regression; the patient showed good clinical recovery. The parents refused further treatment, and he was out of our control when he was 9 months old. CONCLUSION: According to our knowledge, the presented newborn is the second case of cerebellar HBL associated with diffuse skin and visceral hemangiomas in the English medical literature. Clinicians must be vigilant about the predictive value of visceral and/or cutaneous hemangioma for an associated intracranial HBL. PMID- 22820756 TI - Examining the impact of 45 minutes of daily physical education on cognitive ability, fitness performance, and body composition of African American youth. AB - OBJECT: Increased importance on academic achievement has resulted in many school districts focusing on improved academic performance leading to reductions in physical education time. The purpose was to examine the effects of 45 minutes of daily physical education on the cognitive ability, fitness performance and body composition of African American elementary and middle school youth. METHODS: Participants completing the informed consent in grades 2nd to 8th were included in the study. A pre/posttest design was used with repeated measures analysis of variance. Experimental and control school participants were pretested on the cognitive measures (ie, Fluid Intelligence and Perceptual Speed) and Fitnessgram(r) physical fitness test items (eg, aerobic capacity, muscular strength and muscular endurance, body composition) in September 2009 and posttested in May 2010. RESULTS: Experimental elementary and middle school participants observed significantly greater improvements compared with control elementary and middle school participants on 7 of 16 fitness and body composition measures and on 8 of 26 cognitive measures. These fitness, body composition, and cognitive improvement differences were more noticeable among elementary and middle school females. CONCLUSIONS: Providing 45 minutes of daily physical education can perhaps increase cognitive ability while increasing fitness and decreasing the prevalence of overweight and obese youth. PMID- 22820757 TI - Reduced CD19 expression and decreased memory B cell numbers in transient hypogammaglobulinemia of infancy. AB - We aimed to evaluate the role of the CD19 complex in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and to better characterize the subsets of memory B cells. The study population consisted of 22 male and 14 female patients with a mean age at presentation of 20 +/- 9.9 months. The CD19 complex and B cell subsets were evaluated by flow cytometry. While the CD19 median fluorescence index (MFI) in patients with THI was significantly lower than controls (122.9 +/- 66.7 in patients; 184.2 +/- 39 in controls, p < 0.01), expression of CD21 and CD81 was increased (94.4 +/- 3, 96.8 +/- 2.5 % in patients; 91 +/- 3.9; 94.7 +/- 3.5 % in controls, p < 0.01 vs. p < 0.05, respectively). The expressions of switched memory B cells and IgM memory B cells were found to be reduced in THI. Considering that the CD19 complex regulates the events following antigen stimulation, the change in CD19 complex detected in THI may be related to insufficiency of antibody production. PMID- 22820758 TI - Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin. AB - Particulate pollution is suspected to contribute to obstructive lung diseases characterized by chronic inflammation, mucus hypersecretion and bronchial remodeling. Our aim was to study the effect of real-world particulate matter (PM) on the expression of a mucin, MUC5AC, focusing on the role of the epidermal growth factor receptor (EGFR) pathway. MUC5AC induction was studied in vivo in mice trachea and in vitro in human bronchial epithelial cells (HBEC) exposed to urban fine PM. Fine PM were able to induce MUC5AC mRNA in mice trachea after 48 h of exposure (50 MUg PM/mouse), and MUC5AC mRNA and protein in HBEC after 24 h of exposure (from 5 MUg PM/cm(2)). It was associated with the increased expression of amphiregulin (AREG), an EGFR ligand. Experiments with conditioned media (media from PM-treated cells) demonstrated the involvement of AREG on MUC5AC induction as MUC5AC induction by media from PM-treated cells was prevented in the presence of either EGFR- or AREG-neutralizing antibodies. The effect of an inhibitor of a metalloprotease involved in the AREG shedding confirmed the autocrine loop made by AREG leading to MUC5AC induction by fine PM. We also demonstrated that IL-8 pro-inflammatory cytokine induction was dependent on the same autocrine mechanisms. We demonstrate for the first time that MUC5AC expression and production is increased by short-term exposure to fine PM through an autocrine effect of AREG. Our study provides mechanistic explanations to the exacerbation of obstructive lung diseases induced by particulate pollution characterized by mucus hypersecretion and chronic inflammation. PMID- 22820759 TI - Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses. AB - An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 MUg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans. PMID- 22820761 TI - Periodic overlayers and moire patterns: theoretical studies of geometric properties. AB - Single crystal surfaces with periodic overlayers, such as graphene on hexagonal metal substrates, are found to exhibit, apart from their intrinsic periodicity, additional long-range order expressed by approximate surface lattices with large lattice constants. This phenomenon can be described as geometrically analogous to lateral interference effects resulting in periodic moire patterns which are characterized by two-dimensional moire lattices. Here we discuss in detail the mathematical formalism determining such moire patterns based on concepts of two dimensional Fourier transformation including coincidence lattices. The formalism provides simple relations that allow one to calculate possible moire lattice vectors in their dependence on rotation angles alpha and scaling factors p1,p2 for periodic (p1 * p2)Ralpha overlayers on substrate surfaces described by general Bravais lattices. Specific emphasis will be given to hexagonal lattices where experimental data are available. PMID- 22820760 TI - A standardized laboratory and surgical method for in vitro culture isolation and expansion of primary human Tenon's fibroblasts. AB - Good manufacturing practices guidelines require safer and standardized cell substrates especially for those cell therapy products to treat ocular diseases where fibroblasts are used as feeder layers. However, if these are unavailable for stem cells culturing, murine fibroblasts are regularly used, raising critical issues as accidentally transplanting xenogenous graft and adversely affecting stem cell clinical trials. Moreover, human fibroblasts play a significant role in testing novel ophthalmologic drugs. Accordingly, we developed a standardized laboratory and surgical approach to isolate normal and undamaged Tenon's fibroblasts to implement the setting up of banks for both stem cells-based ocular cell therapy and in vitro drug testing. A 2-3 cm(2) undamaged Tenon's biopsy was surgically obtained from 28 patients without mutually correlated ocular diseases. Nineteen dermal biopsies were used as control. Fibroblasts were isolated with or without collagenase, cultured in autologous, fetal bovine or AB serum, tested for viability by trypan blue, vimentin expression and standardized until passage 6. Successful Tenon's fibroblasts isolation was age dependent (P = 0.001) but not sex, pathology or surgery related. A significant rate of successful cultures were obtained when biopsies were not digested by collagenase (P = 0.013). Moreover, cultures in autologous or fetal bovine serum had comparable proliferative properties (P = 0.77; P = 0.82). Through our surgical and laboratory standardized procedure, we elucidated for the first time key points of this human primary culture system, the role of the autologous serum, comparing Tenon's and dermal fibroblasts. Our protocol may be clinically useful to reduce the risk above mentioned and may be potentially more effective for ophthalmological clinical purposes. PMID- 22820764 TI - The cover. Retrovirus. PMID- 22820767 TI - Scientists investigate routing latent HIV from its reservoirs to achieve a cure. PMID- 22820768 TI - CDC pilot program will offer free rapid HIV tests through pharmacies. PMID- 22820769 TI - "Elite controllers" provide clues to keeping HIV infection in check. Interview by Tracy Hampton. PMID- 22820770 TI - HIV/AIDS: the state of the epidemic after 3 decades. PMID- 22820775 TI - Losartan vs candesartan for heart failure. PMID- 22820777 TI - Arrhythmia management in myotonic dystrophy type 1. PMID- 22820779 TI - Antitrust guidelines in health care markets. PMID- 22820781 TI - Sustained viral suppression in HIV-infected patients receiving antiretroviral therapy. PMID- 22820783 TI - Toward an AIDS-free generation. PMID- 22820784 TI - HIV/AIDS in 1990 and 2012: from San Francisco to Washington, DC. PMID- 22820785 TI - The future of HIV prevention in the United States. PMID- 22820786 TI - Aging and HIV-related cognitive loss. PMID- 22820787 TI - A piece of my mind. Forever young. PMID- 22820789 TI - Risk of cervical precancer and cancer among HIV-infected women with normal cervical cytology and no evidence of oncogenic HPV infection. AB - CONTEXT: US cervical cancer screening guidelines for human immunodeficiency virus (HIV)-uninfected women 30 years or older have recently been revised, increasing the suggested interval between Papanicolaou (Pap) tests from 3 years to 5 years among those with normal cervical cytology (Pap test) results who test negative for oncogenic human papillomavirus (HPV). Whether a 3-year or 5-year screening interval could be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown. OBJECTIVE: To determine the risk of cervical precancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as 2 separate end points, in HIV-infected women and HIV uninfected women who at baseline had a normal Pap test result and were negative for oncogenic HPV. DESIGN, SETTING, AND PARTICIPANTS: Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional US cohort of the Women's Interagency HIV Study, between October 1, 2001, and September 30, 2002, with follow-up through April 30, 2011. Semiannual visits at 6 clinical sites included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using polymerase chain reaction. The primary analysis was truncated at 5 years of follow-up. MAIN OUTCOME MEASURE: Five-year cumulative incidence of cervical precancer and cancer. RESULTS: No oncogenic HPV was detected in 369 (88% [95% CI, 84%-91%]) HIV-infected women and 255 (91% [95% CI, 88%-94%]) HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women, 2 cases of HSIL+ were observed; an HIV uninfected woman and an HIV-infected woman with a CD4 cell count of 500 cells/MUL or greater. Histologic data were obtained from 4 of the 6 clinical sites. There were 6 cases of CIN-2+ in 145 HIV-uninfected women (cumulative incidence, 5% [95% CI, 1%-8%]) and 9 cases in 219 HIV-infected women (cumulative incidence, 5% [95% CI, 2%-8%]). This included 1 case of CIN-2+ in 44 oncogenic HPV-negative HIV infected women with CD4 cell count less than 350 cells/MUL (cumulative incidence, 2% [95% CI, 0%-7%]), 1 case in 47 women with CD4 cell count of 350 to 499 cells/MUL (cumulative incidence, 2% [95% CI, 0%-7%]), and 7 cases in 128 women with CD4 cell count of 500 cells/MUL or greater (cumulative incidence, 6% [95% CI, 2%-10%]). One HIV-infected and 1 HIV-uninfected woman had CIN-3, but none had cancer. CONCLUSION: The 5-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment. PMID- 22820788 TI - Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. AB - CONTEXT: Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. OBJECTIVE: To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/MUL. INTERVENTION: Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. RESULTS: There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and 4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/MUL vs -23 cells/MUL at week 48; difference, -62 cells/MUL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03). CONCLUSION: Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN30019040. PMID- 22820790 TI - Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. AB - CONTEXT: Human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV) disease progression; however, the effect of liver disease stage and antiviral therapy on the risk of clinical outcomes is incompletely understood. OBJECTIVE: To determine the incidence of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death according to baseline hepatic fibrosis and antiviral treatment for HIV/HCV coinfected individuals. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 638 coinfected adults (80% black, 66% men) receiving care at the Johns Hopkins HIV clinic and receiving a liver biopsy and who were prospectively monitored for clinical events between July 1993 and August 2011 (median follow-up, 5.82 years; interquartile range, 3.42-8.85 years). Histological specimens were scored for hepatic fibrosis stage according to the METAVIR scoring system. MAIN OUTCOME MEASURE: Incidence of composite outcome of ESLD, HCC, or death. RESULTS: Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage (classification range, F0-F4): F0, 23.63 (95% CI, 16.80-33.24); F1, 36.33 (95% CI, 28.03-47.10); F2, 53.40 (95% CI, 33.65-84.76); F3, 56.14 (95% CI, 31.09 101.38); and F4, 79.43 (95% CI, 55.86-112.95) per 1000 person-years (P < .001). In multivariable negative binomial regression, fibrosis stages F2 through F4 and antiretroviral therapy were independently associated with composite ESLD, HCC, or all-cause mortality after adjustment for demographic characteristics, injection drug use, and CD4 cell count. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23-4.34; P = .009); F3, 3.18 (95% CI, 1.47-6.88; P = .003); and F4, 3.57 (95% CI, 2.06-6.19; P < .001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19-0.38; P < .001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86-1.86; P = .23). In contrast, no events were observed in the 51 patients with sustained virologic response (n = 36) and relapse (n = 15), including 19 with significant fibrosis. CONCLUSION: In this cohort of patients with HIV/HCV coinfection, hepatic fibrosis stage was independently associated with a composite outcome of ESLD, HCC, or death. PMID- 22820791 TI - Arterial inflammation in patients with HIV. AB - CONTEXT: Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. OBJECTIVE: To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). MAIN OUTCOME MEASURE: Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). RESULTS: Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/MUL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9 8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03 2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P <= .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV. CONCLUSION: Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation. PMID- 22820792 TI - Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. AB - CONTEXT: New trial data and drug regimens that have become available in the last 2 years warrant an update to guidelines for antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected adults in resource-rich settings. OBJECTIVE: To provide current recommendations for the treatment of adult HIV infection with ART and use of laboratory-monitoring tools. Guidelines include when to start therapy and with what drugs, monitoring for response and toxic effects, special considerations in therapy, and managing antiretroviral failure. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: Data that had been published or presented in abstract form at scientific conferences in the past 2 years were systematically searched and reviewed by an International Antiviral Society-USA panel. The panel reviewed available evidence and formed recommendations by full panel consensus. DATA SYNTHESIS: Treatment is recommended for all adults with HIV infection; the strength of the recommendation and the quality of the evidence increase with decreasing CD4 cell count and the presence of certain concurrent conditions. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor (raltegravir). Alternatives in each class are recommended for patients with or at risk of certain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored, as should engagement in care, ART adherence, HIV drug resistance, and quality-of-care indicators. Reasons for regimen switching include virologic, immunologic, or clinical failure and drug toxicity or intolerance. Confirmed treatment failure should be addressed promptly and multiple factors considered. CONCLUSION: New recommendations for HIV patient care include offering ART to all patients regardless of CD4 cell count, changes in therapeutic options, and modifications in the timing and choice of ART in the setting of opportunistic illnesses such as cryptococcal disease and tuberculosis. PMID- 22820793 TI - A crusted plaque on the right nipple. PMID- 22820794 TI - Inflammation, immune activation, and CVD risk in individuals with HIV infection. PMID- 22820795 TI - HIV/AIDS--increasing evidence, advancing ahead. PMID- 22820800 TI - JAMA patient page. HIV infection: the basics. PMID- 22820801 TI - Generative cell-specific activation of the histone gH2A gene promoter of Lilium longiflorum in tobacco. AB - The Lilium longiflorum gH2A promoter is active exclusively in the generative cells of mature pollen in transgenic tobacco expressing the gH2A promoter::GUS (beta-glucuronidase) construct as a reporter gene. Temporal and spatial aspects of gH2A promoter activity examined during pollen development in transgenic tobacco reveal that GUS reporter activity was not detected until developing pollen entered the early bicellular developmental stage. Activity was first detected in generative cells at early-mid stages and gradually increased to maximum levels at mid-bicellular stages. The patterns of appearance and longevity of GUS activity in tobacco were very similar to those of gH2A mRNA during pollen development in Lilium. Exogenous treatment with colchicine, a well-known microtubule depolymerize, blocked microspore mitosis and inhibited generative cell differentiation. No GUS signal was detected in the resulting anomalous pollen, which lacked generative cell differentiation. These data strongly suggest that normal generative cell development is essential for activation of the gH2A promoter. Furthermore, these results indicate that common transcriptional activator(s) of the gH2A promoter may be present in both Lilium and Nicotiana, and that such putative factor(s) activates the gH2A promoter only when generative cells undergo normal development. PMID- 22820802 TI - Characterization of peripheral and mucosal immune responses in rhesus macaques on long-term tenofovir and emtricitabine combination antiretroviral therapy. AB - BACKGROUND: The goal of antiretroviral therapy (ART) is to suppress virus replication to limit immune system damage. Some have proposed combining ART with immune therapies to boost antiviral immunity. For this to be successful, ART must not impair physiological immune function. METHODS: We studied the impact of ART (tenofovir and emtricitabine) on systemic and mucosal immunity in uninfected and simian immunodeficiency (SIV)-infected Chinese rhesus macaques. Subcutaneous ART was initiated 2 weeks after tonsillar inoculation with SIVmac239. RESULTS: There was no evidence of immune dysregulation as a result of ART in either infected or uninfected animals. Early virus-induced alterations in circulating immune cell populations (decreased central memory T cells and myeloid dendritic cells) were detected, but normalized shortly after ART initiation. ART-treated animals showed marginal SIV-specific T-cell responses during treatment, which increased after ART discontinuation. Elevated expression of CXCL10 in oral, rectal, and blood samples and APOBEC3G mRNA in oral and rectal tissues was observed during acute infection and was down regulated after starting ART. ART did not impact the ability of the animals to respond to tonsillar application of polyICLC with increased CXCL10 expression in oral fluids and CD80 expression on blood myeloid dendritic cells. CONCLUSION: Early initiation of ART prevented virus-induced damage and did not impede mucosal or systemic immune functions. PMID- 22820804 TI - Problematic prescription opioid use in an HIV-infected cohort: the importance of universal toxicology testing. AB - BACKGROUND: Providers treating chronic pain must attempt to relieve suffering, while minimizing problematic prescription opioid use, including addiction and diversion. Previously described risk factors for problematic use include history of substance use, younger age, male sex, psychiatric comorbidity, and lower education level. METHODS: We examined these risk factors in HIV-infected individuals, using cross-sectional and longitudinal data from the Manhattan HIV Brain Bank. Problematic use was defined as illicit substance use (documented by urine toxicology or structured psychiatric interview), while receiving prescription opioids. RESULTS: Among 173 participants prescribed opioids, 62% had problematic use, the majority of which was discovered by urine toxicology. Problematic use was associated with past substance use, current psychiatric disorder, and poorer adherence to antiretrovirals. However, when participants without problematic use at baseline were followed longitudinally, these factors were not predictive. Furthermore, the cumulative incidence of problematic use behaviors was no greater than in a similar group of participants who were not prescribed opioids. CONCLUSIONS: Problematic prescription opioid use is common among HIV-infected individuals and is associated with history of substance use, current psychiatric disorder, and poor adherence to antiretrovirals. However, these factors do not predict future problematic use in those who are not currently using illicit substances, and the prescription of an opioid does not seem to predispose patients toward a future substance use disorder. Rather than attempting to assess risk for problematic prescription opioid use in HIV-infected individuals, we recommend baseline and follow-up urine toxicology. PMID- 22820805 TI - What is the cost of providing outpatient HIV counseling and testing and antiretroviral therapy services in selected public health facilities in Nigeria? AB - BACKGROUND: Limited data on actual cost of providing HIV/AIDS services in Nigeria makes planning difficult. A study was conducted in 9 public health facilities supported by the Global HIV/AIDS Initiative Nigeria. The objective was to determine the cost of outpatient HIV Testing and Counseling (HTC) and antiretroviral therapy (ART) services per patient. METHODS: Two tertiary and 7 secondary facilities were purposively selected across the six geopolitical regions. Facilities were distributed in urban and rural settings. Utilization and cost data for a 12-month period (January to December 2010) were analyzed. Cost elements included consumables, human resources, infrastructure, trainings, facility management, and Global HIV/AIDS Initiative Nigeria technical support. Total costs were apportioned based on percentage utilization by services, and unit costs were derived by dividing resource inputs by service outputs. Data were analyzed using Microsoft Excel 2003. A sensitivity analysis was also conducted for key assumptions. RESULTS: Mean costs for HTC and ART were US $7.4 and US $209.0, respectively. Costs were higher in Northern facilities (US $6.9, US $250.8), compared with Southern ones (US $6.7, US $194.7); and in tertiary facilities ($18.5, $338.4), compared with secondary ones ($6.3, $204.9). Major cost drivers for HTC and ART were human resources--ranging from 62% to 50%, and ARV drugs--ranging from 54% to 31%, respectively. CONCLUSIONS: Governments' ability to negotiate lower priced antiretroviral drugs will be central to reducing the cost of ART. Additionally, use of lower cadre staff to provide HTC will reduce costs and improves efficiency. PMID- 22820803 TI - Outcomes following virological failure and predictors of switching to second-line antiretroviral therapy in a South African treatment program. AB - OBJECTIVES: Without resistance tests, deciding which patients with virological failure should switch to second-line antiretroviral therapy (ART) is difficult. The factors influencing this decision are poorly understood. We assess predictors of switching regimens after virological failure. DESIGN: Retrospective cohort study using clinical data from a South African ART program with 6-monthly viral load (VL) monitoring. METHODS: We constructed a dataset of patient visits occurring following first-line virological failure, and used random effects logistic regression (accounting for individual-level and clinic-level clustering) to assess predictors of switching at each visit. RESULTS: One thousand six hundred sixty-eight patients with virological failure (73% male, mean age 41 years, median CD4 184 cells/mm, mean log10 VL 4.3) contributed 1922 person-years of viremia. 12 months after failure, the cumulative incidence of switching regimen, viral resuppression, or death was 16.9%, 13.2%, and 4.6%, respectively. In adjusted analysis, switching was more likely at the third or subsequent visit after failure; in visits occurring in 2008 versus 2003 to 2007; and in patients with ART experience pre-programme, current high VL or low CD4 count. Switching was less likely in patients with no clinic contact for 4 months, or declining VL. Switching rates varied between clinics with clinic-level clustering evident in the final model (P <0.001). CONCLUSIONS: Despite 6-monthly virological monitoring and recommendations to switch after adherence interventions and confirmed viremia, patients experienced delayed switching. Individual-level covariates influenced switching but did not account for variable switching rates between clinics, suggesting differences in guideline implementation. In certain circumstances delays may be warranted; however understanding barriers to guideline implementation will limit unnecessary delays. PMID- 22820806 TI - Changes in the soluble mucosal immune environment during genital herpes outbreaks. AB - BACKGROUND: Genital tract secretions provide variable inhibitory activity against herpes simplex virus (HSV) ex vivo. We hypothesize that the anti-HSV activity may prevent the spread of virus from the more commonly affected sites, such as the external genitalia, to the upper genital tract. METHODS: The antimicrobial activity of cervicovaginal lavage (CVL) and concentrations of mucosal immune mediators were measured in 10 HIV-seronegative women with an active external herpetic lesion and compared with 10 HIV-seronegative women who were HSV-1 and HSV-2 seronegative. Samples were obtained at the time of a symptomatic external lesion (day 0), after 1 week of oral acyclovir (day 7), and 1 week after completing treatment (day 14). Controls were evaluated at parallel intervals. RESULTS: The anti-HSV activity was higher in CVL obtained from cases compared to controls at presentation (day 0) (54.3% vs. 28%), fell to similar levels on day 7, and then rebounded on day 14 (69% vs. 25%). The anti-HSV activity correlated positively and significantly with the concentrations of several inflammatory proteins; the concentrations of these proteins tended to be higher in cases compared with controls and followed a similar temporal pattern. CONCLUSIONS: Increases in inflammatory immune mediators and anti-HSV activity were detected in CVL at the time of clinical outbreaks and after completion of a short course of acyclovir. These mucosal responses may protect against HSV spread but could facilitate HIV infection and contribute to the clinical observation that, independent of clinical lesions, HSV-2 is a risk factor for HIV acquisition. PMID- 22820807 TI - Frequency and predictors for late start of antiretroviral therapy in primary care clinics, Kampala, Uganda. AB - BACKGROUND: Access to antiretroviral treatment (ART) has improved greatly in many parts of the world, including Uganda, yet, many patients delay to start ART even when registered within the HIV services. We assessed, in a routine ambulatory care setting, what proportion of patients start ART late and the associated factors. METHODS: We conducted a cross-sectional study from a cohort of adult, HIV-infected, ART-naive patients seeking care at 3 primary care centers in Kampala, Uganda. ART eligibility at the time was World Health Organization clinical stage 4 or CD4 <200 cells/MUL. We defined late start of ART as starting ART at CD4 count <100 cells/MUL and analyzed associated factors using multivariable logistic regression. RESULTS: Between May 2008 and August 2009, 326 adults were studied. Two hundred eighteen (67%) were women; the median age was 34 years (range, 18-71). The median CD4 count was 132 cells/MUL (range, 1-505). Thirty-one patients (10%) were in World Health Organization stage 4. One hundred twenty-three patients (37.7%) were initiated on ART with CD4 cells <100 cells/MUL. Being male [adjusted OR (aOR): 2.4; 95% confidence interval: 1.3 to 4.2, P = 0.002] and having no employment (aOR: 1.9; 95% confidence interval: 1.2 to 3.3, P = 0.012) were associated with late start of ART. Being older, being married, and showing signs of alcohol dependence were associated with an earlier start of ART. CONCLUSIONS: A considerable proportion of patients started ART at very low CD4 counts. Male and unemployed patients were more likely and married people and those aged 40 years or older were less likely to start ART late. PMID- 22820810 TI - Introduction of rapid syphilis testing within prevention of mother-to-child transmission of HIV programs in Uganda and Zambia: a field acceptability and feasibility study. AB - BACKGROUND: Given that integration of syphilis testing into prevention of mother to-child transmission of HIV (PMTCT) programs can prevent adverse pregnancy outcomes, this study assessed feasibility and acceptability of introducing rapid syphilis testing (RST) into PMTCT services. METHODS: RST was introduced into PMTCT programs in Zambia and Uganda. Using a pre-post intervention design, HIV and syphilis testing and treatment rates during the intervention were compared with baseline. RESULTS: In Zambia, comparing baseline and intervention, 12,761 of 15,967 (79.9%) and 11,460 of 11,985 (95.6%) first-time antenatal care (ANC) attendees were tested for syphilis (P < 0.0001), 523 of 12,761 (4.1%) and 1050 of 11,460 (9.2%) women tested positive (P < 0.0001); and 267 of 523 (51.1%) and 1000 of 1050 (95.2%) syphilis-positive women were treated (P < 0.0001), respectively. Comparing baseline and intervention, 7479 of 7830 (95.5%) and 11,151 of 11,409 (97.7%) of ANC attendees were tested for HIV (P < 0.0001) and 1303 of 1326 (98.3%) and 2036 of 2034 (100.1%) of those testing positive received combination antiretroviral drugs or single-dose nevirapine prophylaxis (P < 0.0001). In Uganda, 13,131 of 14,540 (90.3%) women were tested for syphilis during intervention, with 690 of 13,131 (5.3%) positive and 715 of 690 (103.6%) treated. Syphilis baseline data were collected, but not included in analysis, as ANC syphilis testing before the study was not consistently practiced. Comparing baseline and intervention, 6479 of 6776 (95.6%) and 11,192 of 11,610 (96.4%) ANC attendees were tested for HIV (P = 0.0009) and 570 of 726 (78.5%) and 964 of 1153 (83.6%) received combination or single-dose prophylaxis (P = 0.007). In Zambia, 254 of 1050 (24.2%) syphilis-positive pregnant women were HIV-positive and 99 of 690 (14.3%) in Uganda. CONCLUSIONS: Integrating RST in PMTCT programs increases screening and treatment for syphilis among HIV-positive pregnant women and does not compromise HIV services. PMID- 22820808 TI - Unhealthy alcohol and illicit drug use are associated with decreased quality of HIV care. AB - BACKGROUND: HIV-infected patients with substance use experience suboptimal health outcomes, possibly because of variations in care. OBJECTIVES: To assess the association between substance use and the quality of HIV care (QOC) received. RESEARCH DESIGN: Retrospective cohort study. SUBJECTS: HIV-infected patients enrolled in the Veterans Aging Cohort Study. MEASURES: We collected self-report substance use data and abstracted 9 HIV quality indicators (QIs) from medical records. Independent variables were unhealthy alcohol use (AUDIT-C score >=4) and illicit drug use (self-report of stimulants, opioids, or injection drug use in past year). Main outcome was the percentage of QIs received, if eligible. We estimated associations between substance use and QOC using multivariable linear regression. RESULTS: The majority of the 3410 patients were male (97.4%) and black (67.0%) with a mean age of 49.1 years (SD = 8.8). Overall, 25.8% reported unhealthy alcohol use, 22% illicit drug use, and participants received 81.5% (SD = 18.9) of QIs. The mean percentage of QIs received was lower for those with unhealthy alcohol use versus not (59.3% vs. 70.0%, P < 0.001) and those using illicit drugs vs. not (57.8% vs. 70.7%, P < 0.001). In multivariable models, unhealthy alcohol use (adjusted beta -2.74; 95% confidence interval: -4.23 to 1.25) and illicit drug use (adjusted beta -3.51; 95% CI: -4.99 to -2.02) remained inversely associated with the percentage of QIs received. CONCLUSIONS: Although the overall QOC for these HIV-infected Veteran patients was high, gaps persist for those with unhealthy alcohol and illicit drug use. Interventions that address substance use in HIV-infected patients may improve the QOC received. PMID- 22820809 TI - Prevalence and risk factors for HPV in HIV-positive young women receiving their first HPV vaccination. AB - BACKGROUND: The objectives of this study were to describe the prevalence and risk factors for HPV infection among HIV-infected young women receiving their first quadrivalent HPV (HPV-6, -11, -16, and -18) vaccine dose. METHODS: We recruited 16- to 23-year-old women from 14 sites for an HPV vaccine trial. At the first visit, they completed a questionnaire and were tested for cervicovaginal HPV DNA (41 types) and HPV serology (4 vaccine types). Factors associated with any HPV, type-specific HPV, and high-risk (cancer-associated) HPV infections were identified using univariate and multivariable logistic regression. RESULTS: The mean age of participants (N = 99) was 21.4 years, 30.3% were on antiretroviral therapy, 74.7% were positive for >=1 HPV DNA type, 53.5% for >=1 high-risk type, 12.1% for HPV-16, and 5.1% for HPV-18. Most were HPV DNA negative and seronegative for HPV-16 (55.6%) and HPV-18 (73.7%); 45.5% were HPV DNA negative and seronegative for both HPV-16 and -18. Three variables were associated with high-risk HPV DNA in multivariable analysis: non-Hispanic black versus Hispanic ethnicity (adjusted odds ratio [AOR]: 7.06, 95% CI: 1.63 to 30.5), HIV viral load >= 400 versus <400 copies/mL (AOR: 3.47, 95% CI: 1.28 to 9.43), and frequency of vaginal sex in the past 90 days (AOR: 5.82, 95% CI: 1.30 to 26.11 for >=6 vs 0 times). CONCLUSIONS: The prevalence of >=1 HPV type was high in these young women, demonstrating the importance of vaccinating before sexual initiation. However, most women were HPV DNA negative and seronegative for high-risk vaccine type HPV infection, supporting vaccination of sexually experienced HIV-positive young women. PMID- 22820811 TI - Comparison of the effects of different lens-cleaning solutions on the protein profiles of human conjunctival cells. AB - BACKGROUND: Many contact lens wearers suffer from dry eye syndrome. Previous studies show significant changes in the protein composition of the tears depending on the lens-cleaning solution used. Therefore, the aim of this study was to detect the influence of different lens solutions on conjunctival cells, cells also involved in tear film composition. METHODS: Conjunctival epithelium cells (HCjE; IOBA-NHC) were exposed to medium containing Complete(r) Multipurpose Solution Easy Rub(r) Formula (Complete) (AMO) or Opti-Free(r) Express Multipurpose Disinfecting Solution (Opti-Free) (Alcon) in different concentrations (0.1, 0.5, 1, 2.5 %) for 12 and 24 h. Apoptosis and necrosis using FACS and protein profiles of the cells using SELDI-TOF-MS and MALDI-TOF-MS were measured. Multivariate statistics were calculated to detect the most significant changes. RESULTS: Complex protein profiles were measured with SELDI-TOF-MS and MALDI-TOF-MS. Significant differences of protein profiles between control and treatment cells were detected after 12 and 24 h, although cells incubated with Complete showed significantly fewer changes than cells incubated with Opti-Free, also showing concentration-dependent changes of some significantly changed proteins, e.g., protein at 6,736 Da (p > 0.002). Cells incubated with Complete showed significantly less apoptosis or necrosis in comparison to control cells (p < 0.05), whereas cells incubated with Opti-Free showed significantly more (p < 0.05). CONCLUSIONS: We were able to demonstrate that Complete shows very little effect on the protein profiles of conjunctival cells in comparison to Opti-Free, where the cells showed very large protein profile changes, and apoptosis and necrosis of the cells was increased. These results are in concordance to clinical studies showing that the use of Complete solution made the tear film proteins similar to those of people not wearing contact lenses. Therefore, we believe that Complete is less aggressive and should provoke fewer side-effects, such as dry eye syndrome, for the users. PMID- 22820812 TI - A 7-year retrospective study for clinical features and visual outcome of chestnut burr-related ocular injuries. PMID- 22820814 TI - Ocular hypertension and glaucoma incidence in patients with scleritis. AB - BACKGROUND: Scleritis belongs to the group of chronic inflammatory eye diseases that may cause ocular hypertension (OHT) and secondary glaucoma (SG). Aim of this study was to identify the incidence and risk factors for OHT and SG with regard to the scleritis form. METHODS: Single-center retrospective analysis of all consecutive patients with scleritis. RESULTS: A total of 271 scleritis patients (161 women, mean age 51.0 +/- 16.9 years) were enrolled. The median follow-up was 17.0 +/- 21.4 months (range 6-116). Of these patients, 56 (21 %) showed an intraocular pressure (IOP) increase with an open chamber angle at any time during follow-up. Another four patients (7 %) had secondary angle-closure glaucoma. An increase in IOP was found more frequently in patients with necrotizing (42 %) than in those with posterior (30 %), nodular (18 %) or diffuse anterior scleritis (18 %, p = 0.022). Most patients (82 %) developed the pressure increase during acute scleritis episodes. Initially, 72 % of patients with increased IOP were classified as OHT; this figure had decreased to 56 % at the end of follow-up. In the course of disease, the IOP normalized in 13 %. The univariate analysis of risk factors showed an increased risk in the presence of anterior uveitis, peripheral ulcerative keratitis, posterior synechiae, and previous cataract surgery. CONCLUSIONS: An increase in IOP occurs in about one-fifth of patients with scleritis. The initial pressure elevation occurs mostly in the acute phase of disease. An increase in pressure is found most often in patients with necrotizing scleritis. PMID- 22820813 TI - Randomised comparison of three tools for improving compliance with occlusion therapy: an educational cartoon story, a reward calendar, and an information leaflet for parents. AB - BACKGROUND: We previously demonstrated that compliance with occlusion therapy for amblyopia was improved by the use of an educational programme, especially in children of parents of foreign origin and who spoke Dutch poorly. The programme consisted of: (i) a cartoon story for amblyopic children that explained without words why they should patch, (ii) a calendar with reward stickers, and (iii) an information leaflet for parents. In the current study, we assessed the individual effect of each component on compliance. METHODS: We recruited 120 3- to 6-year old children who lived in a low socio-economic status (SES) area in The Hague and were starting occlusion therapy for the first time. They were randomised to receive one of the components (three intervention groups), or a picture to colour (control group). The randomisation was blinded for treating orthoptist and researcher. Compliance was measured electronically using the Occlusion Dose Monitor (ODM). Primary outcome was percentage of compliance (actual/prescribed occlusion time). Secondary outcome was absolute occlusion hours per day. Parental fluency in Dutch was rated on a five-point scale. RESULTS: Compliance could be measured electronically in 88 of the 120 children; in 32 others, it failed for various reasons. Parental fluency in Dutch was moderate or worse in 36.4 % (p = 0.327). Average compliance was 55 % standard deviation (SD) 40 (n = 18) in the control group, 89 % SD 25 in the group receiving the educational cartoon (n = 25, P = 0.002 compared with control group), 67 % SD 33 (n = 24, P = 0.301) in the reward-calendar group and 73 % SD 40 (n = 21, P = 0.119) in the parent information-leaflet group. On average, children in the control group occluded 1:46 SD1:19 hours/day, 2:33 SD 1:18 hours/day in the group receiving the educational cartoon, 1:59 SD 1:13 hours/day in the reward-calendar group and 2:18 SD 1:13 hours/day in the parent-information-leaflet group. No child who received the cartoon story occluded less than 1 hour per day, against seven in the reward calendar group, five in the parent-information-leaflet group and five in the control group. CONCLUSIONS: Although all three components of the programme improved compliance with occlusion therapy in children in low-SES areas, the educational cartoon had the strongest effect, as it explained without words to a 4- to 5-year-old child why it should wear the eye patch. PMID- 22820815 TI - Associated factors and treatment outcome of presumed noninfectious endophthalmitis occurring after intravitreal triamcinolone acetonide injection. AB - BACKGROUND: To investigate the associated factors and treatment outcomes in patients with presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide (IVTA) injection. METHODS: Among 219 consecutive cases of 186 patients who had undergone IVTA injection for macular diseases, presumed noninfectious endophthalmitis was diagnosed if the patient showed severe inflammation in the anterior chamber and vitreous cavity within 7 days after injection but no organism was isolated on microbiological examination. Clinical features and previously performed surgical procedures were evaluated to assess their association with presumed noninfectious endophthalmitis using logistic regression. After surgical or medical treatment for endophthalmitis, the visual outcome was evaluated in all patients. RESULTS: Noninfectious endophthalmitis developed in six of 219 eyes (2.7 %). Previous vitrectomy, history of IVTA injection, and pseudophakia were significantly associated with the occurrence of presumed noninfectious endophthalmitis after IVTA injection (p = 0.049, 0.034, and 0.009, respectively). Internal limiting membrane (ILM) peeling during vitrectomy also showed statistically significant association (odds ratio = 13.6, p = 0.017). Five of six patients (83.3 %) regained pre-injection vision. CONCLUSION: In addition to previous vitrectomy, history of IVTA injection, internal limiting membrane (ILM) peeling, and pseudophakia may render the eye vulnerable to presumed noninfectious endophthalmitis following IVTA injection. Visual outcome shows generally good prognosis after treatment. PMID- 22820816 TI - Systemic vascular resistance is increased and associated with accelerated arterial stiffening change in patients with chronic cervical spinal cord injury. AB - BACKGROUND: Despite of stiffening change of conduit arteries, how total peripheral resistance (TPR) is adapted to chronic spinal cord injury (SCI) remains unclear. AIM: To investigate how chronic cervical SCI influences hemodynamic characteristics DESIGN: Cross-sectional, case-control study. SETTING: Rehabilitation department in the tertiary medical center. POPULATION: Twenty-one male patients with traumatic SCI resulting from cervical spine fracture were recruited. The injury occurred three to 289 months (46 months in average) previously. Twenty-one healthy male participants with matched age and body mass index were enrolled as control group. METHODS: The subjects were asked to maintain supine rest (SR) and then head-up tilt (HUT) at 60 degree for five minutes, respectively. A novel noninvasive bio-reactance device was employed to measure cardiac hemodynamics, whereas heart rate variability was used to determine cardiac autonomic activity. Additionally, the digital volume pulse analysis was applied to calculate arterial stiffness index (SI) and arteriolar reflection index (RI). RESULTS: SCI patients revealed less stroke volume and cardiac output (CO), as well as, greater total peripheral resistance (TPR) and SI during SR than normal subjects did. Moreover, the positive correlation between TPR and SI was observed in SCI patients rather than normal subjects. In SCI patients, HUT (1) markedly decreased TPR while CO and cardio-acceleration responses remained intact and (2) decreased HF power value but failed to change LF/HF ratio. Furthermore, the degree of orthostatic hypotension was correlated with the TPRHUT/TPRSR ratio but not the COHUT/COSR ratio. CONCLUSIONS: Chronic cervical SCI leads to a progressively accelerated increase in vascular stiffness, which is associated with increase in systemic vascular resistance. Furthermore, the cervical SCI-related orthostatic hypotension lies in the impairment of vasoconstriction without cardiac dysfunction. Clinical Rehabilitation Impact. SI, rather than blood pressure, reflects not only cardiovascular risk but also TPR in chronic cervical SCI. PMID- 22820818 TI - A systematic review on the effectiveness of medical training therapy for subacute and chronic low back pain. AB - Medical training therapy (MTT) to improve muscular strength and endurance follows evidence based guidelines and is increasingly recommended to patients suffering from subacute and chronic back pain (LBP). This study investigated whether MTT was effective in reducing pain and improving function in patients with subacute or chronic LBP. Data sources were MEDLINE, EMBASE, CINAHL, Pedro, Cochrane Central Register of Controlled Trials. We included RCTs that examined exercise or MTT in adult patients with LBP compared to placebo, no intervention or other interventions. Study outcomes had to include at least one of the following: pain intensity; functional status, absenteeism. Two independent reviewers performed quality assessment. Visual analogue scale ratings ranging from 0-10 MTT quantified the MTT aspects of the intervention. Studies with rating scores >7.5 were included. We identified only 2 studies that examined the effectiveness of MTT. Both trials, one was of high quality, found MTT to decrease pain and improve function significantly better than therapy of uncertain effectiveness. There is moderate evidence that would support the effectiveness of MTT in the treatment chronic LBP. Future high quality RCT will have to clarify whether MTT is effective and would be superior to other forms of therapeutic exercise. PMID- 22820817 TI - Pulmonary rehabilitation at home guided by telemonitoring and access to healthcare facilities for respiratory complications in patients with neuromuscular disease. AB - BACKGROUND: Pulmonary complications are the main cause of morbidity and mortality in neuromuscular patients. Aim of this study was to evaluate the feasibility of a home follow-up program combining telemonitoring and chest physiotherapy (CPT) in preventing acute respiratory episodes. DESIGN: Prospective observational study in a period of 24 months, and comparison with preintervention data of the same patients. SETTING: Outpatients and community. POPULATION: Neuromuscular patients. Enrolment criteria were: reduced efficacy of cough, high family support, long home-to-hospital distance. METHODS: Caregivers and patients had to register daily respiratory signs and symptoms. Each patient was equipped with a pulse oximeter with a modem for transmitting data to a remote control center, in charge of alerting the pulmonologist in case of sign and symptom deterioration. CPT interventions at home were planned after indication by the pulmonologist. The number of emergency room admissions or hospitalization following respiratory exacerbations were registered. RESULTS: Thirteen patients were enrolled. In the first year of monitoring, 18 alerts were transmitted to the pulmonologist, average 1.38+/-1.38 alert/patient. In the second year, the number of alerts were 5, average 0.38+/-0.65 alert/patient (P<0.01). In 24 months, 241 respiratory therapists' interventions were conducted on 11 patients. In the first 12 months there were four episodes of hospitalisation, none in the following 12 months. In the year prior to the project, there were seven cases of hospitalisation and one case of emergency room admission. CONCLUSION: The combination of telemonitoring and CPT at home is feasible in the long-term for patients with neuromuscular disease. CLINICAL REHABILITATION IMPACT: An apparent reduction of hospitalisation and emergency room admissions for respiratory complications can justify a randomized control trial to confirm efficacy and effectiveness. PMID- 22820819 TI - Pain and electrophysiological parameters are improved by combined 830-1064 high intensity LASER in symptomatic carpal tunnel syndrome versus Transcutaneous Electrical Nerve Stimulation. A randomized controlled study. AB - AIM: The aim of the study was to compare LASER versus transcutaneous electrical nerve stimulation (TENS) in reducing pain and paraesthesia; and in improving motor and sensory median nerve conduction parameters in mild to moderate carpal tunnel syndrome (CTS). DESIGN: Randomised blinded pilot study. Patients and staff administered treatments and outcome measures were blinded. SETTING: Outpatient; Research and Care Rehabilitation Institute. PARTICIPANTS: Twenty CTS symptomatic patients. INTERVENTIONS: Fifteen sessions of: 1) 100 Hz TENS (30 minutes; rectangular waves; 80 ms width, intensity below muscle contraction); 2) combined 830-1064 nm LASER (radiating dose: 250 J cm-2 delivered to the skin overlying the course of the median nerve at the wrist for 100 s at 25 W (18 W [1064 nm] + 7 W [830 nm]) via a fiber-optic probe with a spot size of ~1 cm2). Outcome measures. Visual analogue scale (VAS) for pain and paresthesia; median nerve distal motor latency and sensory nerve conduction velocity. RESULTS: LASER improved both positive and negative sensory symptoms. TENS induced clinical improvement but this was not statistically significant and was limited to pain reduction. LASER but not TENS favourably modified the neurophysiological parameters. CONCLUSION: High-intensity combined LASER wavelengths of 830 nm and 1064 nm, which produce a better transparency with less scattering and a high energy transfer, are better than TENS in improving both pain and paraesthesia as well as neurophysiological parameters in CTS. PMID- 22820820 TI - Role of spiritual beliefs on disability and health-related quality of life in acute inpatient rehabilitation unit. AB - BACKGROUND: The influence of spirituality and religious beliefs on health-related quality of life and disability in the rehabilitation field is discussed in literature. AIM: To describe the role of spiritual belief on functional recovery and health-related quality of life in acute inpatient rehabilitation ward. DESIGN: Observational cross sectional study. SETTING: Inpatients clinic of Physical Medicine and Rehabilitation Department, University Hospital. POPULATION: One hundred and four patients admitted to an inpatient acute rehabilitation ward, after a neurological or orthopedic disease. METHODS: Anamnestic and demographic data were reported on a standardized form. The Royal Free Interview for Spiritual and Religious Beliefs (RFI) and Cumulative Illness Rating Scale (CIRS) were performed on admission (T0). SF-36 item Short Form Health Survey Questionnaire (SF36) and the Barthel index (BI) were performed on admission (T0) and on discharge (T1). RESULTS: Statistical analysis was performed on 102 patients with spiritual belief divided in strong (55 cases) and weak (47 cases) spiritual belief. Change from baseline (T1-T0) of SF36 domains between groups showed a significant higher improvement in Physical Role and Physical Composite Score in the weak belief group than in the strong belief group. The latter presented an improvement (without statistical significance) in almost every emotional score. We found no significant difference in change from baseline of Barthel index between the groups. CONCLUSION: Strength of spiritual belief seems to influence some aspects of quality of life of acute inpatient in the rehabilitation setting. It seems that patients with less spiritual belief showed more improvement in physical role, after acute rehabilitation. PMID- 22820821 TI - Course of back complaints in older adults: a systematic literature review. AB - BACKGROUND: Back pain is a common musculoskeletal complaint seen in older people. It is important to get an insight in the course of back complaints and to identify factors associated with a chronic course. AIM: To describe the course of acute and subacute back complaints in older people (>= 45 years) and to identify prognostic factors for developing chronic back complaints. DESIGN: Systematic review of the literature. METHODS: A database search was conducted in MEDLINE, EMBASE, Cochrane library, CINAHL, PsycINFO and PEDro. Cohort studies or randomized controlled trials reporting on the course of acute or subacute back complaints in older people were included. The percentage of patients that developed chronic back complaints was calculated, if possible. RESULTS: The search yielded 9293 potentially relevant articles. Of these, 5 studies met all inclusion criteria. At 3 months follow-up 37-40% of the patients still had back complaints. At 12 months follow-up, the percentage ranged from 26-45%. Older age was frequently reported as a prognostic factor for developing chronic back complaints of the whole study population. No prognostic factors could be retrieved for patients aged 45 years and older. CONCLUSIONS: At 3 and 12 month follow-up, about 40% of the older people still reported back complaints. However, the heterogeneity of the studies made comparisons difficult. In order to get a clear insight in the course of back complaints in the older adult patients and to indentify prognostic factors for developing chronic back complaints in older people, high quality prospective cohort studies are needed. CLINICAL REHABILITATION IMPACT: More than one-third of the older patients with back pain still experience complaints after 3 and 12 months. PMID- 22820822 TI - Outpatients' perceptions of their experiences in musculoskeletal rehabilitation care. AB - BACKGROUND: While patients' satisfaction with rehabilitation care is often measured, the knowledge of their experiences during delivery of care and of which characteristics may lead them to experience problems remains largely undocumented. AIM: To assess the quality of patients' experiences receiving post acute care for musculoskeletal disorders in outpatient rehabilitation settings. To describe the extent to which variations in reported quality of patients' experiences were related to their characteristics. DESIGN: A cross sectional, self-reported survey. SETTING: 3 outpatient rehabilitation units. POPULATION: Four hundred sixty-five outpatients. Mean age 39.4 (SD=11.9). METHODS: A problem score (from 0 to 100%) of self-reported experiences was calculated on 7 specific aspects of care (belonging to organizational environment and professionals' attitudes and behaviors) and compared among participants' subgroups. RESULTS: Mean scores of the organizational environment area showed higher amount of problems (43.3%) than the professionals' attitudes and behaviours area (34.7%). Two multivariate linear regression models (with adjusted R(2) 9.3% and 4.9%) indicated that older patients and those with high global rating change were less likely to experience problems in the two areas. CONCLUSION: Problems on aspects of care were commonly experienced by patients with musculoskeletal disorders in outpatient rehabilitation settings. The age and health of patients were associated to these problems, but explained only a small variation in them. CLINICAL REHABILITATION IMPACT: Surveys measuring patients' experiences can be used to monitor the actual performance of rehabilitation settings and to pinpoint the exact issues needing to be addressed to improve quality as well as to make comparison among centres. PMID- 22820823 TI - The Locomotory Index in diplegic and hemiplegic children: the effects of age and speed on the energy cost of walking. AB - BACKGROUND: The energy cost of locomotion (C) is a useful tool for quantifying the level of walking disability in the clinical evaluation of patients with cerebral palsy (CP). In addition to clinical condition, also age and velocity (v) can influence C, a fact that is often overlooked. AIM: To show: i) that C differs in the clinical subtypes of CP (hemiplegia or diplegia) and ii) that C should be measured at comparable speeds in CP patients and controls (of the same age). DESIGN: Controlled study. SETTING: Pediatric Rehabilitation Unit of "E. Medea" Scientific Institute (Conegliano, TV); Exercise Physiology Lab of University of Verona. POPULATION: Forty-three CP children (32 diplegic: Dg; 11 hemiplegic: Hg) and 20 healthy children (Cg) with an age range of 4-14 years. METHODS: C was measured as the ratio of net oxygen uptake to walking speed (at v from 1 to 6 km.h(-1)). The Locomotory index (LI) was calculated as the ratio of C in Dg/Hg and Cg (of the same age) at the same speed. RESULTS: C decreases with increasing speed in all groups but evolves differently in Hg and Dg: in the former C decreases by increasing age, becoming similar to that of Cg at 12-14 years; in the latter C does not change as a function of age being always larger than in Cg. CONCLUSION AND CLINICAL REHABILITATION IMPACT: Our data highlight the reduction in C with increasing speed and suggest a better prognosis of locomotion for Hg compared to Dg. PMID- 22820824 TI - Deep heating therapy via microwave diathermy relieves pain and improves physical function in patients with knee osteoarthritis: a double-blind randomized clinical trial. AB - BACKGROUND: Deep heating therapy (DHT) has shown to improve pain and function in patients with knee osteoarthritis (OA) in the short term. Benefits of superficial heating therapy (SHT) are controversial. Long-term effects of both heating modalities have not yet been investigated. AIM: To compare the effects of DHT and SHT in patients with symptomatic knee OA, and to determine the long-term effects of heat therapy. DESIGN: Double-blind randomized clinical trial. SETTING: Outpatient clinic of Geriatrics and Physiatrics, University Hospital. POPULATION: Fifty-four patients with radiologically established diagnosis of moderate knee OA (Kellgren-Lawrence grade II or III) and pain lasting for at least three weeks. METHODS: DHT: local microwave diathermy (three 30-min sessions a week for four weeks); SHT: application of hot packs (three 30-min sessions a week for four weeks). PRIMARY OUTCOME MEASURE: Western Ontario and McMaster Universities (WOMAC) index for the assessment of joint pain, stiffness and physical function limitations. SECONDARY OUTCOME MEASURES: British Medical Research Council (BMRC) rating scale for the evaluation of muscle strength, and a visual analogue scale (VAS) for pain assessment. Follow up: 24 weeks for all outcome measures; 12 months for the primary outcome. RESULTS: Intention-to-treat analyses showed a treatment effect in favor of DHT for all outcome measures. No clinically relevant changes were observed in the SHT group. Benefits of DHT were maintained over 12 months of follow-up. CONCLUSIONS: DHT via localized microwave diathermy improves pain, muscle strength and physical function in patients affected by knee OA, with benefits maintained over the long term. No clinically relevant improvements were observed in patients who underwent SHT. CLINICAL REHABILITATION IMPACT: DHT via microwave diathermy delivered three times a week for four weeks significantly improves pain and function in patients affected by moderate knee OA, with benefits retained for at least 12 months. No clinically relevant changes are observed in knee OA patients treated with SHT. PMID- 22820826 TI - Postpartum coccydynia: a case series study of 57 women. AB - BACKGROUND: Although childbirth is a well-known cause of coccydynia, this condition has not been studied previously. AIM: To explore the characteristics of postpartum coccydynia and identify risk factors. DESIGN: A case series study. SETTING: A specialist coccydynia clinic in a department of physical medicine in a university hospital. METHODS: A series of 57 women suffering from postpartum coccydynia was analyzed and compared with a control group of 192 women suffering from coccydynia due to other causes. Dynamic radiography enabled a comparison of the coccygeal mobility in the two groups. RESULTS: 7.3% of the cases of coccydynia in female patients seen in our clinic were related to childbirth. The pain appeared as soon as the patient adopted the sitting position after delivery. The deliveries had often been performed with instruments (forceps deliveries: 50.8%; vacuum-assisted deliveries: 7.0%) or were spontaneous but described as "difficult" (12.3%). Luxation of the coccyx was observed in 43.9% of the cases and 17.0% of the controls. Fracture of the coccyx was involved in 5.3% of the cases. A body mass index >27 and >=2 vaginal deliveries were associated with a higher prevalence of luxation of the coccyx. CONCLUSION: Postpartum coccydynia is often associated with a difficult delivery, with the use of forceps in 50.8% of cases. Luxation and fracture of the coccyx are the two most characteristic lesions. CLINICAL REHABILITATION IMPACT: Our results bring a better knowledge and should allow a better management of this specific etiology of coccydynia. PMID- 22820825 TI - Symptomatic correlates of six-minute walk performance in persons with multiple sclerosis. AB - BACKGROUND: The six-minute walk (6MW) test has been identified as a valid, reliable, and reproducible measure of endurance walking performance that differentiates persons with multiple sclerosis (MS) and controls and correlates with disability and walking impairment. AIM: This study examined symptoms of fatigue, pain, and depression as correlates of 6MW performance and the possibility that such symptoms would account for the difference in 6MW distance between persons with MS and controls. DESIGN: Observational. SETTING: Research laboratory. POPULATION: Sixty-six persons, 33 with MS and 33 controls matched on age, sex, height, and weight. METHODS. Participants completed the fatigue severity scale (FSS), short-form of the McGill pain questionnaire (SF-MPQ), and depression items of the hospital anxiety and depression scale (HADS-D) and then performed the six-minute walk (6MW) in a rectangular corridor. RESULTS: There were statistically significant differences between groups in 6MW distance (p = 0.0001) and FSS (P=0.0001) and SF-MPQ (P=0.025), but not HADS-D (P>0.05), scores. 6MW distance was significantly correlated with FSS (P=-0.66), SF-MPQ (P=-0.38), and HADS-D (P=-0.33) scores in the overall sample, but 6MW distance was significantly correlated with only FSS scores in the separate samples of those with MS (P=-0.46) and controls (P=-0.46). Only group (beta=0.32) and FSS scores (beta=-0.53) explained variance in overall 6MW distance in a hierarchical, linear regression analysis. CONCLUSION: This study provides new insight into the symptomatic correlates of 6MW performance and identifies fatigue as a possible target of interventions designed to improve walking endurance in MS. CLINICAL REHABILITATION IMPACT: Clinicians and practitioners might consider targeting fatigue as a method of managing compromised endurance walking in persons with MS. PMID- 22820829 TI - Rehabilitation interventions in patients with acute demyelinating inflammatory polyneuropathy: a systematic review. AB - Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome, GBS) can be a significant cause of new long-term disability, which is thought to be amenable to rehabilitation. Rehabilitation is an expensive resource and the evidence to support its justification is urgently needed. This systematic review presents an evidence-based overview of the effectiveness of various rehabilitation interventions in adults with GBS and the outcomes that are affected. Medline, EMBASE, CINAHL, AMED, PEDro, LILACS and the Cochrane Library were searched up to March 2012 for studies reporting outcomes of GBS patients following rehabilitation interventions that addressed functional restoration and participation. Two reviewers applied the inclusion criteria to select potential studies and independently extracted data and assessed the methodological quality. Included studies were critically appraised using GRADE methodological quality approach. Formal levels of evidence of each intervention were assigned using a standard format defined by National Health and Medical Research Council. Fourteen papers (one systematic review, one randomized controlled trial, one case-control study, five cohort studies and six case series/reports) that described a range of rehabilitation interventions for persons with GBS were evaluated for the "best" evidence to date. One high quality randomised controlled trial demonstrated effectiveness of higher intensity multidisciplinary ambulatory rehabilitation in reducing disability in persons with GBS in the later stages of recovery, compared with lesser intensity rehabilitation intervention for up to 12 months. Four observational studies, further demonstrated some support for improved disability and quality of life following inpatient multidisciplinary rehabilitation up to 12 months. Evidence for uni-disciplinary rehabilitation interventions is limited, with 'satisfactory' evidence for physical therapy in reducing fatigue, improving function and quality of life in persons with GBS. This review provides "good" evidence to support multidisciplinary rehabilitative intervention in adults with GBS; and "satisfactory" evidence for physical therapy in these patients. Evidence for other uni-disciplinary interventions is limited or inconclusive. The gaps in existing research should not be interpreted as ineffectiveness of rehabilitation intervention in GBS. Further research is needed with appropriate study designs, outcome measurement, type of modalities and cost-effectiveness of these interventions. PMID- 22820827 TI - Exploring variables associated with rehabilitation length of stay in brain injuries patients. AB - BACKGROUND: The impact of outcome measure as early variables on rehabilitation length of stay (LOS) in traumatic brain injury (TBI) patients remains poorly investigated. AIM: To investigate: 1) the association between LOS and motor and functional outcomes; 2) the predictive factors of LOS in TBI patients admitted to a rehabilitation center. DESIGN: Retrospective study. SETTING: Inpatient TBI Rehabilitation Centre. POPULATIONS: 241 TBI patients (190 males and 51 females, mean age 43.61+/-19.4 years, initial Glasgow Coma Scale of 6.96+/-3.39). METHODS: We recorded demographic characteristics (age, sex, setting and LOS in the acute phase, rehabilitation LOS) and outcome measures (Glasgow Outcome Scale, Disability Rating Scale, Levels of Cognitive Functioning, Functional Independence Measure). RESULTS: Average rehabilitation LOS was 58.82+/-58 days; 191 (79%) subjects were discharged from the rehabilitation center within 90 days. Rehabilitation LOS was significantly correlated with acute-care LOS (P=0.001) and Glasgow Coma Scale, but not with patients' age (P=0.250) or sex (P= 0.348). Rehabilitation LOS was significantly correlated with functional and cognitive admission outcome scores but not with gains during rehabilitation. Rehabilitation LOS was significantly less in the group of patients that returned back home respect to others. Regression analysis also illustrated that longer acute-care LOS was independently associated with significantly increased rehabilitation LOS (P<0.001). CONCLUSION: Our retrospective study suggests that rehabilitation LOS in TBI patients is correlated with timing of and score at admission to the rehabilitation setting rather than with gains in functional outcome. CLINICAL REHABILITATION IMPACT: This result may help to optimize inpatient service utilization, especially in term of LOS. PMID- 22820830 TI - The techniques of soft tissue release and true socket reconstruction in total hip arthroplasty for patients with severe developmental dysplasia of the hip. AB - PURPOSE: Total hip arthroplasty (THA) is an effective procedure for developmental dysplasia of the hip (DDH); however, it is sometimes difficult to complete for severe cases because of femoral head dislocation, dysplasia of the acetabulum and the femur, disparity in limb length, soft tissue contraction, and muscular atrophy. We aimed at exploring the efficiency of the techniques of release and balance of soft tissues and reconstruction of true socket THA for patients with severe DDH. METHODS: From January 2000 to January 2009, 46 adult patients with severe DDH (50 hips) were included in this study. According to the classification system, there were 26 type III and 24 type IV. Among them there were 32 women and 14 men, aged from 38 to 77 years. THA was performed via a lateral approach. All acetabular sockets were reconstructed at the original anatomical location following a meticulous technique of soft tissue release and balance around the hip to restore limb length, to strengthen the abductor and improve its function. RESULTS: All patients had restoration of limb length (range, 2.5-5.5 cm; 30 limbs of more than 4 cm) without injury to the sciatic nerve. One postoperative dislocation occurred due to slight enlargement of the angle of abduction of the acetabulum. The follow-up ranged from 2.2 to 11.5 years (median 6.4 years) in 46 patients, and the Harris score increased from 40.2 preoperatively to 86.5 (P = 0.027). All hips were pain free with good function at the latest follow-up. CONCLUSION: The meticulous techniques of soft tissue release and balance can be recommended to ensure anatomical reconstruction of the true acetabular socket and to improve abductor function during arthroplasty for DDH. PMID- 22820832 TI - Chronic urogenital sinus expansion in reconstruction of high persistent cloaca. AB - OBJECTIVE: Soft tissue expansion is a technique useful in reconstruction when a shortage of tissue exists. This study presents an investigation on using chronic balloon expansion in the urethral and vaginal reconstruction of high persistent cloaca. METHODS: The common channel was expanded by a balloon, which was progressively inflated over 3-4 weeks at a pressure of 30-50 mmHg until an adequate amount of tissue was obtained. The expanded channel was longitudinally split into anterior and posterior segments: the former was approximated to form a neourethra in continuity with the reconstructed bladder neck and the latter was tubularized to form a vagina. RESULTS: Twenty-one patients underwent primary posterior sagittal urethro-vaginoplasty using the expanded urogenital sinus. Histologic examination demonstrated that the expanded tissue consisted of a dense fibrous wall lined with a stratified squamous non-cornified epithelium, which was characterized by active cell mitosis and angiogenesis. The patients were followed up for 0.6-9 year (mean 5.69 +/- 2.43 years). All reconstructed urethras, vaginas, and vulvas were satisfactory in color, texture match, and sensation. Urinary continence (grades I and II) was observed in all patients without intermittent catheterization. Two complications were encountered in our study. One patient showed a distal urethral dehiscence and a secondary urethroplasty was performed 6 months after the operation. Another patient developed a redundant urethra upon reaching puberty and urethroplasty was needed. CONCLUSION: Chronic balloon expansion allows the formation of adequate tissue similar in appearance and type to the vagina and urethra. It also provides a valuable surgical alternative for the management of high persistent cloaca. PMID- 22820831 TI - Platinum(II/IV) complexes containing ethylenediamine-N,N'-di-2/3-propionate ester ligands induced caspase-dependent apoptosis in cisplatin-resistant colon cancer cells. AB - Several new R(2)eddp (R = i-Pr, i-Bu; eddp = ethylenediamine-N,N'-di-3 propionate) esters and corresponding platinum(ii) and platinum(iv) complexes of the general formula [PtCl(n)(R(2)edda-type)] (n = 2, 4) were synthesized and characterized by spectroscopic methods (IR, (1)H and (13)C NMR) and elemental analysis. The crystal structure of platinum(iv) complex [PtCl(4){(c-Pe)(2)eddip}] (3a) was resolved and is given herein. Ligand precursors, platinum(ii), and platinum(iv) complexes were tested against eight tumor cell lines (CT26CL25, HTC116, SW620, PC3, LNCaP, U251, A375, and B16). Selectivity in the action of those compounds between tumor and two normal primary cells (fibroblasts and keratinocytes) are discussed. A structure-activity relationship of these compounds is discussed. Furthermore, cell cycle distribution, induction of necrosis, apoptosis, autophagy, anoikis, caspase activation, ROS, and RNS are presented on the cisplatin-resistant colon carcinoma HCT116 cell line. PMID- 22820833 TI - Severe hyperphosphatemia after administration of sodium-phosphate containing laxatives in children: case series and systematic review of literature. AB - INTRODUCTION: Sodium phosphate-containing laxatives are commonly used as first line treatment option for constipation in children and adolescents. Hyperphosphatemia is an infrequent, but potentially life-threatening complication of laxative application. METHODS: We report a case series of three children exhibiting severe hyperphosphatemia and hypocalcemia after utilization of sodium phosphate-containing laxatives, necessitating intensive care services in two of three cases. Additionally, we reviewed 32 case reports of similar occurrences. RESULTS: We identified 28 publications on the subject dating from 1968 to 2010. Mean age of all children in reports was 2.83 years; sex was approximately equally distributed. While 18 patients suffered from either pre-existing gastrointestinal comorbidity or other major systemic disease, no or only unrelated, minor conditions were present in ten children. One-third of patients received laxatives repeatedly before the incident. Findings associated with hyperphosphatemia include lethargy, dizziness, stiffness, tachypnea, tachycardia and severe dehydration in almost all cases, and tetany, carpopedal spasm, and prolonged QT interval in a subset. While about 80% of children recovered without residual findings, three deceased and one incurred persistent hypoxic brain damage. CONCLUSION: Physicians should be alerted to the possibility of phosphate toxicity in children and adolescents treated with laxatives. PMID- 22820834 TI - Favorable effects of explanatory illustrations attached to a self-administered questionnaire for upper extremity disorders. AB - PURPOSE: The Hand10 is a self-administered questionnaire for upper extremity disorders. This questionnaire consists of 10 short, easy-to-understand questions and explanatory illustrations. In the shortening and validation process, the Hand10 demonstrated high acceptability and reliability among elderly individuals, with the advantage of being compact. We hypothesized that attached illustrations may contribute to the ability to maintain the psychometric properties of a questionnaire and raise acceptability for the elderly. METHODS: A series of 106 elderly patients with upper extremity disorders, whose symptoms had been stable, completed the Hand10, the Japanese Society for Surgery of the Hand Version of Disability of the Arm, Shoulder and Hand, and the Revised Hasegawa's Dementia Scale. Participants were randomly allocated to receive either the illustrated Hand10 or the unillustrated Hand10. The potential advantages attributed to attached illustrations were investigated. RESULTS: No significant differences were found in baseline demographic data between subjects who received the illustrated and unillustrated questionnaires. The average percentage of items that the elderly patients left unanswered was 0.5 % for the illustrated Hand10 and 3.8 % for the unillustrated Hand10. Instrument test-retest reliability assessed with the intraclass correlation coefficient was 0.92 and 0.86, respectively. CONCLUSION: The use of explanatory illustrations attached to the Hand10 contributed to raise acceptability for elderly patients and were suggested to improve the reproducibility. PMID- 22820835 TI - Postoperative transarterial chemoembolization benefits patients with high gamma glutamyl transferase levels after curative hepatectomy for hepatocellular carcinoma: a survival stratification analysis. AB - Hepatocellular carcinoma (HCC) is the most common liver tumor in Asian countries, and hepatectomy is currently regarded as the optimal curative treatment for HCC; however, the postoperative outcome remains unsatisfactory. Aiming at further clarification of prognostic factors after hepatectomy, we adopted a detailed stratification on survival periods. A total of 428 HCC patients undergoing curative hepatectomy were firstly divided into two groups using 2-year survival as cutoff point. Multivariate analysis showed that tumor-related factors, including vascular invasion (P < 0.001), high Edmondson grade (P < 0.001), large tumor size (P < 0.001) and high serum alpha-fetoprotein level (P = 0.001), were significant determinants for early death within 2 years, while postoperative transarterial chemoembolization (TACE) was demonstrated a protective factor (P = 0.013). Then the 281 patients with survival > 2 years were divided into two subgroups according to survival or death during follow-up to examine the late death related factors. We found that high serum gamma-glutamyl transpeptidase (GGT), indicating severity of underlying liver disease, was significantly linked to death in this stage (P = 0.006). In further comparison of survival rates between subgroups stratified by early- and late-death indictors, we found the long-term outcomes of patients with high serum GGT were poor, regardless of the factors related with primary tumor. Furthermore, postoperative TACE decreased late death rate of patients with high GGT levels. In conclusion, despite the overwhelmed effects of primary tumor in the early stage after hepatectomy, postoperative TACE is beneficial for HCC patients with poor liver status. PMID- 22820837 TI - Silicene structures on silver surfaces. AB - In this paper we report on several structures of silicene, the analog of graphene for silicon, on the silver surfaces Ag(100), Ag(110) and Ag(111). Deposition of Si produces honeycomb structures on these surfaces. In particular, we present an extensive theoretical study of silicene on Ag(111) for which several recent experimental studies have been published. Different silicene structures were obtained only by varying the silicon coverage and/or its atomic arrangement. All the structures studied show that silicene is buckled, with a Si-Si nearest neighbor distance varying between 2.28 and 2.5 A. Due to the buckling in the silicene sheet, the apparent (lateral) Si-Si distance can be as low as 1.89 A. We also found that for a given coverage and symmetry, one may observe different scanning tunneling microscopy images corresponding to structures that differ by only a translation. PMID- 22820836 TI - Dance-related injuries in children and adolescents treated in US emergency departments in 1991-2007. AB - BACKGROUND: Dancing is one of the most physically strenuous activities on the musculoskeletal system. As other literature has previously described, the types, sites, and rates of dance-related injuries are similar to those suffered by athletes in traditional sports. METHODS: A retrospective analysis was conducted with data from the National Electronic Injury Surveillance System from 1991-2007. Sample weights were used to calculate national estimates of dance-related injuries. Trend significance of the numbers and age-adjusted rates of dance related injuries over time was analyzed using linear regression. RESULTS: An estimated 113,084 children and adolescents 3-19 years of age were treated in US emergency departments for dance-related injuries. Classical dance (ballet, jazz, tap, modern) accounted for 55.0% of dance-related injuries. Adolescents 15-19 years of age constituted 40.4% of the dance-related injury cases. The majority of injuries (58.1%) occurred to the lower extremities. Sprains or strains were the most common injury (52.4%) and falls were the most common mechanism of injury (44.8%). CONCLUSIONS: Dance-related injuries have distinct injury patterns and mechanisms of injury. Injury patterns differ by types of dance and by age. Further research is needed to identify injury prevention strategies specific to these age groups. PMID- 22820838 TI - Hydrogenolysis-hydrogenation of aryl ethers: selectivity pattern. AB - The selectivity pattern of nickel-catalyzed hydrogenolysis-hydrogenation of aryl ethers has been studied in the micellar media. The micellar conditions selectively formed arenes and alcohols with enhanced yields. PMID- 22820839 TI - A Brucella abortus cstA mutant is defective for association with endoplasmic reticulum exit sites and displays altered trafficking in HeLa cells. AB - Members of the genus Brucella are facultative intracellular pathogenic bacteria able to control maturation of their vacuoles. In several cell types, Brucella is able to reach a proliferation compartment derived from the endoplasmic reticulum (ER). Since ER exit site (ERES) functions are required for Brucella proliferation, we performed a yeast two-hybrid screen between human ERES associated proteins and the predicted brucella proteome. This screening led to the identification of CstA, a conserved protein that specifically interacts with Sec24A, a component of the ERES. We found that a tagged CstA is secreted in Brucella abortus culture medium. This secretion is independent of the type IV secretion system VirB and the flagellum, suggesting that CstA is secreted through another system. We also discovered that a B. abortus cstA mutant is impaired for its association with the Sec23 ERES marker. The B. abortus cstA mutant displayed peculiar trafficking, with reduced association with LAMP1 and Calnexin 12 h post infection in HeLa cells. However, its intracellular proliferation kinetics was not affected. The data reported here suggest that CstA could be directly or indirectly involved in the control of B. abortus intracellular trafficking in HeLa cells. PMID- 22820841 TI - Three pathway-specific regulators control streptolydigin biosynthesis in Streptomyces lydicus. AB - The streptolydigin biosynthetic gene cluster from Streptomyces lydicus NRRL 2433 contains three putative regulatory genes, slgR1, slgR2 and slgY, encoding proteins belonging to TetR and LuxR transcriptional regulator families and ATP/GTP-binding proteins of DNA and RNA helicase superfamily I, respectively. Inactivation of slgR1 or slgR2 resulted in the abolition of streptolydigin production, suggesting that these proteins are pathway-specific positive regulators. In the case of the slgR1 mutant, low amounts of streptolydigin C were produced instead of streptolydigin. RT-PCR transcription analysis of streptolydigin biosynthesis genes revealed a hierarchical regulation process. SlgY was found to control the expression of the regulator slgR2. SlgR2 regulates the expression of structural genes involved in the formation of the streptolydigin bicyclic ketal moiety, incorporation and processing of 3 methylaspartate, and the regulator slgR1. On the other hand, SlgR1 controls the expression of slgE1-E2, involved in the conversion of glutamate to 3 methylaspartate, and putative glycoside hydrolases slgC1 and slgC2. Ectopic expression of slgR1, slgR2 and slgY regulatory genes in S. lydicus led to considerable increases in streptolydigin yields, 18-, 11- and 8.5-fold, respectively. Ectopic expression of slgY in an slgR1 mutant led to a 14-fold increase of streptolydigin C yields, while no effect was observed to result from expression of slgR2. PMID- 22820840 TI - The non-classical ArsR-family repressor PyeR (PA4354) modulates biofilm formation in Pseudomonas aeruginosa. AB - PyeR (PA4354) is a novel member of the ArsR family of transcriptional regulators and modulates biofilm formation in Pseudomonas aeruginosa. Characterization of this regulator showed that it has negative autoregulatory properties and binds to a palindromic motif conserved among PyeR orthologues. These characteristics are in line with classical ArsR-family regulators, as is the fact that PyeR is part of an operon structure (pyeR-pyeM-xenB). However, PyeR also exhibits some atypical features in comparison with classical members of the ArsR family, as it does not harbour metal-binding motifs and does not appear to be involved in metal perception or resistance. Hence, PyeR belongs to a subgroup of non-classical ArsR family regulators and is the second ArsR regulator shown to be involved in biofilm formation. PMID- 22820843 TI - Successful treatment of intractable hiccups by oral application of lidocaine. AB - BACKGROUND: Persistent and intractable hiccups are a rather rare, but distressing gastrointestinal symptom found in palliative care patients. Although several recommendations for treatment are given, hiccups often persist. CASE REPORTS: We describe a new pharmacological approach for successfully treating hiccups in four cancer patients. In the first patient, chronic and intractable hiccups lasted for more than 18 months, but disappeared immediately after swallowing a viscous 2 % lidocaine solution for treatment of mucositis. Based on this experience, we successfully treated three further patients suffering from singultus using a lidocaine-containing gel. To our knowledge, this is the first report about managing hiccups by oral application of a lidocaine solution. PMID- 22820842 TI - Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21WAF1. AB - Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, which has been shown to ameliorate the development of pulmonary hypertension in animal model by suppression of pulmonary artery smooth muscle cells (PASMCs) proliferation, yet its underlying molecular mechanisms are not completely understood. In this study, we show that simvastatin dose-dependently inhibited serotonin-stimulated PASMCs proliferation. This was accompanied with the parallel induction of heme oxyganase-1 (HO-1) and upregulation of p21(WAF1). More importantly, we found that Tin-protoporphyrin (SnPP), a selective inhibitor of HO 1, could block the effect of simvastatin on inhibition of cell proliferation in response to serotonin and abolish simvastatin-induced p21(WAF1) expression. The inhibitive effect of simvastatin on cell proliferation was also significantly suppressed by silencing p21(WAF1) with siRNA transfection. The extent of effect of SnPP on inhibition of cell proliferation was similar to that of lack of p21(WAF1) by siRNA transfection. Taken together, our study suggests that simvastatin inhibits PASMCs proliferation by sequential upregulation of HO-1 and p21(WAF1) to benefit pulmonary hypertension. PMID- 22820844 TI - Boundary zone between northern and southern pig-tailed macaques and their morphological differences. AB - Based on previous conflicting reports that the two forms of pig-tailed macaque (northern and southern) exist as separate species, subspecies, or forms, and that their boundary zone lies in Thailand, a survey of the distribution range and morphology of pig-tailed macaques in Thailand was conducted during 2003-2010. We first conducted a questionnaire survey. Questionnaires were sent to 7,410 subdistricts throughout Thailand. We then traveled to 72 of the 123 subdistricts reporting the presence of pig-tailed macaques. However, due to a lack of reports of the presence of free-ranging pig-tailed macaques living south of the Isthmus of Kra, a survey of pet pig-tailed macaques was also conducted during 16-24 September 2011. Furthermore, 35 wild northern pig-tailed macaques inhabiting northern Thailand (13 degrees 13'N, 101 degrees 03'E) were temporarily caught and their morphological characters were measured and then compared to those of the southern form captured from Sumatra, Indonesia. Although largely allopatric, the ranges of the northern and southern pig-tailed macaques in Thailand were found to have a partially sympatric boundary at the Surat Thani-Krabi depression (8-9 degrees 30'N). Morphologically, these two forms were very distinctive, with different morphological characters such as the crown patch, the white color of the triangle above the eyes, the red streak at the external rim of the eyes, pelage color, ischial callosity, tail length and carriage, facial height, and limb length in both sexes, and patterns of sex skin swelling and reddening in females. These differences in morphological characters between the northern and southern forms should help settle the problems of their taxonomy. PMID- 22820845 TI - Evolutionary insights into the role of the essential centromere protein CAL1 in Drosophila. AB - Centromeres are essential cis-elements on chromosomes that are crucial for the stable transmission of genetic information during mitotic and meiotic cell divisions. Different species employ a variety of centromere configurations, from small genetically defined centromeres in budding yeast to holocentric centromeres that occupy entire chromosomes in Caenorhabditis, yet the incorporation of nucleosomes containing the essential centromere-specific histone H3 variant CENP A is a common feature of centromeres in all eukaryotes. In vertebrates and fungi, CENP-A is specifically deposited at centromeres by a conserved chaperone, called HJURP or Scm3, respectively. Surprisingly, homologs of these proteins have not been identified in Drosophila, Caenorhabditis, or plants. How CENP-A is targeted to centromeres in these organisms is not known. The Drosophila centromeric protein CAL1, found only in the Diptera genus, is essential for CENP-A localization, is recruited to centromeres at a similar time as CENP-A, and interacts with CENP-A in both chromatin and pre-nucleosomal complexes, making it a strong candidate for a CENP-A chaperone in this lineage. Here, we discuss the conservation and evolution of this essential centromere factor and report the identification of a "Scm3-domain"-like region with similarity to the corresponding region of fungal Scm3 as well as a shared predicted alpha-helical structure. Given the lack of common ancestry between Scm3 and CAL1, we propose that an optimal CENP-A binding region was independently acquired by CAL1, which caused the loss of an ancestral Scm3 protein from the Diptera lineage. PMID- 22820846 TI - Marked hyperglycemia attenuates anesthetic preconditioning in human-induced pluripotent stem cell-derived cardiomyocytes. AB - INTRODUCTION: Anesthetic preconditioning protects cardiomyocytes from oxidative stress-induced injury, but it is ineffective in patients with diabetes mellitus. To address the role of hyperglycemia in the inability of diabetic individuals to be preconditioned, we used human cardiomyocytes differentiated from induced pluripotent stem cells generated from patients with or without type 2 diabetes mellitus (DM-iPSC- and N-iPSC-CMs, respectively) to investigate the efficacy of preconditioning in varying glucose conditions (5, 11, and 25 mM). METHODS: Induced pluripotent stem cells were induced to generate cardiomyocytes by directed differentiation. For subsequent studies, cardiomyocytes were identified by genetic labeling with enhanced green fluorescent protein driven by a cardiac specific promoter. Cell viability was analyzed by lactate dehydrogenase assay. Confocal microscopy was utilized to measure opening of the mitochondrial permeability transition pore and the mitochondrial adenosine 5'-triphosphate sensitive potassium channels. RESULTS: Isoflurane (0.5 mM) preconditioning protected N-iPSC- and DM-iPSC-CMs from oxidative stress-induced lactate dehydrogenase release and mitochondrial permeability transition pore opening in 5 mM and 11 mM glucose. Isoflurane triggered mitochondrial adenosine-5' triphosphate-sensitive potassium channel opening in N-iPSC-CMs in 5 mM and 11 mM glucose and in DM-iPSC-CMs in 5 mM glucose; 25 mM glucose disrupted anesthetic preconditioning-mediated protection in DM-iPSC- and N-iPSC-CMs. CONCLUSIONS: The opening of mitochondrial adenosine 5'-triphosphate-sensitive potassium channels are disrupted in DM-iPSC-CMs in 11 mM and 25 mM glucose and in N-iPSC-CMs in 25 mM glucose. Cardiomyocytes derived from healthy donors and patients with a specific disease, such as diabetes in this study, open possibilities in studying genotype- and phenotype-related pathologies in a human-relevant model. PMID- 22820847 TI - Sodium nitrite mitigates ventilator-induced lung injury in rats. AB - BACKGROUND: Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. METHODS: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end expiratory pressure; n=10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n=14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 MUmol/kg IV; n=6-8); group 6: HVT+NaNO2+nitric oxide scavenger 2-(4 carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n=6); group 7: HVT+NaNO2+nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n=7); and group 8: HVT+NaNO2+xanthine oxidoreductase inhibitor allopurinol (n=6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. RESULTS: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 MUmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. CONCLUSIONS: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases. PMID- 22820848 TI - Roles of Gr-1+ leukocytes in postincisional nociceptive sensitization and inflammation. AB - BACKGROUND: Neutrophils are one of the predominant immune cells initially migrating to surgical wound edges. They produce mediators both associated with supporting (interleukin [IL]-1beta, C5a) and reducing (opioid peptides) pain. Studies demonstrate neutrophil depletion/blockade reduces nociceptive sensitization after nerve injury and carrageenan administration, but enhance sensitization in complete Freund's adjuvant inflammation. This research identifies the contribution of infiltrating neutrophils to incisional pain and inflammation. METHODS: Antibody-mediated Gr1 neutrophil depletion preceded hind paw incisions. Sensitization to mechanical and thermal stimuli, effects on edema and local levels of IL-1beta and C5a were measured. Local effects of C5a or IL-1 receptor antagonists PMX-53 and anakinra on sensitization after neutrophil depletion were examined. Groups of 4-8 mice were used. RESULTS: Anti-Gr1 antibody depleted more than 90% of circulating and infiltrating skin neutrophils after incision. Neutrophil depletion did not change magnitude or duration of mechanical hypersensitivity in incised mice. However, paw edema was significantly reduced and heat hypersensitivity was slightly increased in depleted animals. In depleted animals IL-1beta levels were half of controls 24 h after incision, whereas C5a levels were increased in both. Prominent IL-1beta immunohistochemical staining of epidermis was seen in both groups. PMX-53 and anakinra reduced incisional mechanical and heat nociceptive sensitization to the same extent, regardless of neutrophil depletion. CONCLUSIONS: Neutrophil-derived IL-1beta and C5a do not appear to contribute critically to peri-incisional nociceptive signaling. Other sources of mediators, such as epidermal cells, may need to be considered. Controlling inflammatory activation of resident cells in epidermis/deeper structures may show therapeutic efficacy in reducing pain from surgical incisions. PMID- 22820849 TI - Abdominal wall reconstruction by combined use of biological mesh and autogenous pedicled demucosalized small intestinal sheet: a case report. AB - Since abdominal wall defects pose a tough challenge to surgeons, methods to solve the problem are attractive. This case report concerns about the combined use of biological mesh and autogenous pedicled demucosalized small intestinal sheet for abdominal wall reconstruction. An 8-month follow-up revealed favorable outcome. Properties that make the method appealing include decreased infection risk, increased strength and viability. It is a novel, safe, and effective method for abdominal wall reconstruction but still requires further studies. PMID- 22820850 TI - Changes in genetic structure of Posidonia oceanica at Monterosso al Mare (Ligurian Sea) and its resilience over a decade (1998-2009). AB - Genetic differences in the Posidonia oceanica meadow of Monterosso al Mare (NW Mediterranean, Marine Protected Areas (MPAs) "Cinque Terre") were compared in three stations, at an increasing distance from a source of impact (beach nourishment) in the recent decade. Random amplified polymorphic DNA analysis showed a higher genetic variability (>20 %) in the area directly subjected to the stress, increasing with time. Clone integration, confirmed by phenotypic analysis, showed increases both in shoot density and leaf length connected to genetic differences observed in DNA fingerprints of new shoots. Analysis of molecular variance (AMOVA) showed 45 % individual differences within populations and 54 % among the populations. The fixation index (F (ST) = 0.54), of the genetic differentiation, showed a marked difference between the populations at different temporal scales. Over a decade AMOVA indicated genetic variations from 28 % (1998) to 54 % (2009). These results make it clear that in the P. oceanica population examined the environment had, in ten years, selected those clones which were more resistant to the anthropogenic impact, despite being subjected to the effects of the resuspension of fine sediments. These findings could help to explain both the survival of the regressed Mediterranean P. oceanica meadows in areas subjected to moderate impacts and the extreme variability in success of revegetation experiments. Management of the ecological disturbance here described indicates also the timescale in population response to stress and its increased resilience in MPAs. PMID- 22820852 TI - Contrast inversion of the h-BN nanomesh investigated by nc-AFM and Kelvin probe force microscopy. AB - Single sheets of hexagonal boron nitride (h-BN) on transition metals provide a model system for layered insulating materials as well as a functional substrate for molecules and metal clusters. The progress in the understanding of h-BN layers on transition metals was mainly driven by scanning tunnelling microscopy (STM) and photoelectron spectroscopy (PES) measurements within the last decade, while direct measurements of mechanical and electrical properties are still rare. Our investigations of the two-dimensional (2D) h-BN nanomesh on a Rh(111) substrate by high-resolution noncontact atomic force microscopy (nc-AFM) reveal a complex surface structure including a frequently observed contrast inversion. Detailed 2D force spectroscopy measurements are revealing towards a mechanical elastic deformation of the h-BN monolayer caused by the tip-sample interaction. Furthermore, Kelvin probe force microscopy (KPFM) and spectroscopy measurements show local work function variations of the nanomesh, proving the results obtained by PES but additionally providing detailed local information. PMID- 22820851 TI - Rhythm-induced spike-timing patterns characterized by 1D firing maps. AB - We explore patterns in the spike timing of neurons receiving periodic inputs, with an emphasis on stable characteristics which are realized in both models and in-vitro whole-cell recordings. We report on whole-cell recordings of pyramidal CA1 cells from rat hippocampus and entorhinal cortex and compare this data to model simulations. Cells were injected with a constant current to induce a steady firing rate and then a modest rhythm was added which altered the spike times and their corresponding phases relative to the rhythm. For both experiment and theory the relationship between consecutive spike phases is characterized by a probability distribution with peaks concentrated near a one-dimensional firing map. As is well-known, stable fixed points of this map correspond to the neuron phase-locking to the rhythm. We show that the interaction between noise and sufficiently steep maps can also cause a new kind of spike-time organization, in which consecutive spike time pairs organize into discrete clusters, with transitions between these clusters proceeding in a fixed sequence. This structure is not just a vestige of the noise-free dynamics. This slow dynamics and temporal organization in the relationship between consecutive spike phases is not evident in either the neuron's voltage traces or single phase or interspike interval histograms. Furthermore, the consecutive spike relationship is also evident in consecutive ISIs, and hence this ordering can be observed without detailed knowledge of the rhythm (e.g. without concurrent LFP recordings). PMID- 22820853 TI - A meta-analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. AB - Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). As a standard treatment regimen for remission induction of proliferative LN, intravenous cyclophosphamide (IVCYC) and corticosteroids has been widely accepted. However, cyclophosphamide (CYC) is associated with significant adverse effects. Tacrolimus, a T-cell-specific calcineurin inhibitor, shares similar immunosuppressive actions with cyclosporine. We performed a meta-analysis of randomized controlled trials (RCTs) to compare efficacy and safety between tacrolimus (oral administration and/or IV injection) and IVCYC in the induction treatment for LN. We identified 5 trials, including 225 patients. Meta-analysis showed that tacrolimus could significantly increase complete remission (RR 1.61, 95% CI, 1.17 to 2.23; P = 0.004), response rate (RR 1.25, 95% CI, 1.09 to 1.44; P = 0.001), serum albumin level (SMD 1.11, 95% CI, 0.17 to 2.06; P = 0.02) and anti-dsDNA negative conversion rate (RR 1.34, 95% CI, 1.01 to 1.78; P = 0.04), and decrease urine protein (SMD -0.52, 95% CI, -0.83 to -0.22; P = 0.0008), systemic lupus erythematosus disease activity index (SLE-DAI) (SMD -0.59, 95% CI, -1.00 to 0.19; P = 0.004) compared with that of IVCYC. The rates of gastrointestinal symptoms and irregular menstruation (or amenorrhea) were significantly lower in tacrolimus group than IVCYC group (RR 0.46, 95% CI, 0.22 to 0.93; P = 0.03 and RR 0.14, 95% CI, 0.04 to 0.50; P = 0.003). In conclusion, tacrolimus was found to be more effective and safer than IVCYC as an induction therapy for Chinese LN patients. PMID- 22820854 TI - PSA-negative/low prostate cancer cells: the true villains of CRPC? PMID- 22820855 TI - Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia. AB - Maturation arrest (MA) refers to failure of germ cell development leading to clinical nonobstructive azoospermia. Although the azoospermic factor (AZF) region of the human Y chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. We sought to identify single genes on the Y chromosome that may be implicated in the pathogenesis of nonobstructive azoospermia associated with MA in the American population. Genotype-phenotype analysis of 132 men with Y-chromosome microdeletions was performed. Protein coding genes associated with MA were identified by visual analysis of a genotype phenotype map. Genes associated with MA were selected as those genes within a segment of the Y chromosome that, when completely or partially deleted, were always associated with MA and absence of retrievable testicular sperm. Expression of each identified gene transcript was then measured with quantitative RT-PCR in testicular tissue from separate cohorts of patients with idiopathic MA and obstructive azoospermia. Ten candidate genes for association with MA were identified within an 8.4-Mb segment of the Y chromosome overlapping the AZFb region. CDY2 and HSFY were the only identified genes for which differences in expression were observed between the MA and obstructive azoospermia cohorts. Men with obstructive azoospermia had 12-fold higher relative expression of CDY2 transcript (1.33 +/- 0.40 vs. 0.11 +/- 0.04; P=0.0003) and 16-fold higher expression of HSFY transcript (0.78 +/- 0.32 vs. 0.05 +/- 0.02; P=0.0005) compared to men with MA. CDY2 and HSFY were also underexpressed in patients with Sertoli cell only syndrome. These data indicate that CDY2 and HSFY are located within a segment of the Y chromosome that is important for sperm maturation, and are underexpressed in testicular tissue derived from men with MA. These observations suggest that impairments in CDY2 or HSFY expression could be implicated in the pathogenesis of MA. PMID- 22820856 TI - Testosterone therapy and mortality in US veterans. PMID- 22820857 TI - Metallic gold slows disease progression, reduces cell death and induces astrogliosis while simultaneously increasing stem cell responses in an EAE rat model of multiple sclerosis. AB - Multiple sclerosis (MS) is the most common neurodegenerative disease in the Western world affecting younger, otherwise healthy individuals. Today no curative treatment exists. Patients suffer from recurring attacks caused by demyelination and underlying neuroinflammation, ultimately leading to loss of neurons. Recent research shows that bio-liberation of gold ions from metallic gold implants can ameliorate inflammation, reduce apoptosis and promote proliferation of neuronal stem cells (NSCs) in a mouse model of focal brain injury. Based on these findings, the present study investigates whether metallic gold implants affect the clinical signs of disease progression and the pathological findings in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Gold particles 20-45 MUm suspended in hyaluronic acid were bilaterally injected into the lateral ventricles (LV) of young Lewis rats prior to EAE induction. Comparing gold-treated animals to untreated and vehicle-treated ones, a statistically significant slowing of disease progression in terms of reduced weight loss was seen. Despite massive inflammatory infiltration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed reduced apoptotic cell death in disease foci in the brain stem of gold-treated animals, alongside an up regulation of glial fibrillary acidic protein-positive reactive astrocytes near the LV and in the brain stem. Cell counting of frizzled-9 and nestin-stained cells showed statistically significant up-regulation of NSCs migrating from the subventricular zone. Additionally, the neuroprotective proteins Metallothionein-1 and -2 were up-regulated in the corpus callosum. In conclusion, this study is the first to show that the presence of small gold implants affect disease progression in a rat model of MS, increasing the neurogenic response and reducing the loss of cells in disease foci. Gold implants might thus improve clinical outcome for MS patients and further research into the long-term effects of such localized gold treatment is warranted. PMID- 22820858 TI - Expression of the E-cadherin repressors Snail, Slug and Zeb1 in urothelial carcinoma of the urinary bladder: relation to stromal fibroblast activation and invasive behaviour of carcinoma cells. AB - Epithelial-mesenchymal transition (EMT) is regulated by interaction of carcinoma and stromal cells and crucial for progression of urinary bladder carcinoma (UBC). Therefore, the influence of activated fibroblasts on the expression of E-cadherin repressors as well as EMT and invasion in UBC was investigated. A correlative analysis of the immunohistochemical expression of fibroblast (ASMA, S100A4, FAP, SDF1, PDGFRbeta) and EMT (Snail, Slug, Zeb1, E-cadherin) markers was performed on 49 UBC cases of different stages. The impact of distinguishable growth factor stimulated fibroblasts on invasion, EMT, and E-cadherin repressor expression was investigated in an invasion model. In situ, invasiveness was significantly correlated to the loss of membranous E-cadherin (E-cad_m) and increased Snail, Slug, Zeb1 in tumour cells, as well as to increased ASMA, S100A4, and PDGFRbeta in stromal cells. A significant correlation to nodal metastasis could be evidenced for the loss of E-Cad_m, and for an increase in S100A4 and PDGFRbeta. Comparison of stromal and EMT markers revealed significant correlations of ASMA to Snail and Slug; of S100A4 to the loss of E-cad_m and Zeb1; and of PDGFRbeta to the loss of E-Cad_m, Slug and Zeb1. In vitro, TGFbeta1 induced myofibroblasts were the strongest attractants, while aFGF or TGFbeta1/aFGF stimulated fibroblasts were the most potent EMT inductors. As shown here for the first time, distinct sub-populations of fibroblasts are to various extents associated with EMT and tumour progression in UBC. These relevant findings might be the basis for the identification of new diagnostic markers and therapeutic targets selectively affecting tumour supporting CAF effects. PMID- 22820860 TI - Hopfield neural network: the hyperbolic tangent and the piecewise-linear activation functions. AB - This paper reports two-dimensional parameter-space plots for both, the hyperbolic tangent and the piecewise-linear neuron activation functions of a three dimensional Hopfield neural network. The plots obtained using both neuron activation functions are compared, and we show that similar features are present on them. The occurrence of self-organized periodic structures embedded in chaotic regions is verified for the two cases. PMID- 22820859 TI - Formation and migration of neural crest cells in the vertebrate embryo. AB - The neural crest is a stem cell population, unique to vertebrates, that gives rise to a vast array of derivatives, ranging from peripheral ganglia to the facial skeleton. This population is induced in the early embryo at the border of the neural plate, which will form the central nervous system (CNS). After neural tube closure, neural crest cells depart from the dorsal CNS via an epithelial to mesenchymal transition (EMT), forming a migratory mesenchymal cell type that migrates extensive to diverse locations in the embryo. Using in vivo loss-of function approaches and cis-regulatory analysis coupled with live imaging, we have investigated the gene regulatory network that mediates formation of this fascinating cell type. The results show that a combination of transcriptional inputs and epigenetic modifiers control the timing of onset of neural crest gene expression. This in turn leads to the EMT process that produces this migratory cell population. PMID- 22820861 TI - Antileukemic activity of combined epigenetic agents, DNMT inhibitors zebularine and RG108 with HDAC inhibitors, against promyelocytic leukemia HL-60 cells. AB - DNMT inhibitors are promising new drugs for cancer therapies. In this study, we have observed the antileukemic action of two diverse DNMT inhibitors, the nucleoside agent zebularine and the non-nucleoside agent RG108, in human promyelocytic leukemia (PML) HL-60 cells. Zebularine but not RG108 caused dose- and time-dependent cell growth inhibition and induction of apoptosis. However, co treatment with either drug at a non-toxic dose and all trans retinoic acid (RA) reinforced differentiation to granulocytes, while 24 or 48 h-pretreatment with zebularine or RG108 followed by RA alone or in the presence of HDAC inhibitors (sodium phenyl butyrate or BML-210) significantly accelerated and enhanced cell maturation to granulocytes. This occurs in parallel with the expression of a surface biomarker, CD11b, and early changes in histone H4 acetylation and histone H3K4me3 methylation. The application of both drugs to HL-60 cells in continuous or sequential fashion decreased DNMT1 expression, and induced E-cadherin promoter demethylation and reactivation at both the mRNA and the protein levels in association with the induction of granulocytic differentiation. The results confirmed the utility of zebularine and RG108 in combinations with RA and HDAC inhibitors to reinforce differentiation effects in promyelocytic leukemia. PMID- 22820862 TI - Cell surface carbohydrates evaluation via a photoelectrochemical approach. AB - A robust and specific photoelectrochemical approach for cell surface carbohydrates evaluation was achieved firstly based on carboxylic-group containing free-base-porphyrin bridged 3-aminophenylboronic acid and a titania biosensing interface. PMID- 22820863 TI - Conditionally replicative adenovirus-based mda-7/IL-24 expression enhances sensitivity of colon cancer cells to 5-fluorouracil and doxorubicin. AB - BACKGROUND: Multiple drug resistance (MDR) greatly limits the efficacy of chemotherapy for colon cancer. An adenovirus armed with Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24; abbreviated to 'IL-24' here) was shown to reverse the MDR of colon cancer cells to oxaliplatin and doxorubicin. However, the relatively low expression level of IL-24 mediated by a replication deficient adenoviral vector hindered its clinical application. METHODS: To enhance IL-24-dependentreversion of the MDR phenotype, we utilized a conditionally replicative adenoviral vector, AdBB-IL24, to express IL-24 at a high level for more efficient MDR reversion. RESULTS: An enzyme-linked immunosorbent assay (ELISA) suggested conditionally replicative adenoviral vector mediated IL-24 expression was elevated in comparison with that of a replication deficient adenoviral vector, Ad-IL24. AdBB-IL24 was shown to reverse MDR in colon cancer cells more potently than Ad-IL24. The AdBB-IL24-induced MDR reversion was linked to reduced P-glycoprotein (Pgp) and breast cancer resistance protein 1 (BCRP1) expression. Consistently, 5-fluorouracil and doxorubicin induced more apoptosis in AdBB-IL24-infected colon cancer cells compared with that in the Ad IL24-infected cells. A cell viability assay showed that AdBB-IL24 could enhance the growth-inhibitory effect of 5-fluorouracil and doxorubicin on colon cancer cells more effectively than Ad-IL24 in vitro. In a mouse model, we also found that the combination of 5-fluorouracil and doxorubicin with AdBB-IL24 completely inhibited the growth of colon cancer cells. CONCLUSION: We here provide evidence supporting conditionally replicative adenoviral vector-based gene therapy as a powerful strategy to enhance mda7/IL-24-dependent MDR reversion of colon cancer cells. PMID- 22820864 TI - Assistive/rehabilitation technology, disability, and service delivery models. AB - The United Nation's Millennium Development Goals do not explicitly articulate a focus on disability; similar failures in the past resulted in research, policy, and practice that are not generalizable and did not meet the needs of persons with disabilities since they were developed for an "average" population. Academics and professionals in health and other disciplines should have a knowledge base in evidence-based practices that improve well-being and participation of people with disabilities through effective service delivery of assistive technology. Grounded by a theoretical framework that incorporates a multivariate perspective of disability that is acknowledged in the convention on the rights of persons with disabilities and the World Health Organization's International Classification of Functioning, Disability and Health, we present a review of models of assistive technology service delivery and call for future syntheses of the fragmented evidence base that would permit a comparative effectiveness approach to evaluation. PMID- 22820865 TI - Hyperbole, abstract motion and spatial knowledge: sequential versus simultaneous scanning. AB - Hyperbole is an interesting trope in the perspective of Space Grammar, since it is related to the displacing of a limit (Lausberg in Elemente der literarischen Rhetorik. M.H. Verlag, Munchen 1967; see the Ancient Greek meaning 'to throw over' > 'exaggerate'). Hyperbole semantic mechanisms are related to virtual scanning (Holmqvist and Pluciennik in Imagery in language. Peter Lang, Frankfurt am Main, pp 777-785, 2004). Basic concepts of SIZE and QUANTITY, related image schemas (IS) and conceptual metaphors (UP IS MORE; IMPORTANT IS BIG: Lakoff 1987, Johnson 1987) are implied in hyperbole processing. The virtual scanning is the simulation of a perceptual domain (here, the vertically oriented space). The virtual limit is defined by expected values on the relevant scale. Since hyperbole is a form of intensification, its linguistic interest lies in cases involving the extremes of a scale, for which a limit can be determined (Schemann 1994). In this experimental study, we analyze the concept of 'limit' in terms of 'abstract motion' and 'oriented space' domains (Langacker 1990) with respect to hyperboles expressed by Italian Verbs of movement. The IS considered are PATH and SOURCE-PATH-GOAL. The latter corresponds to a virtual scale whose limit is arrived at, or overcome, in hyperboles. PMID- 22820867 TI - Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions. AB - RATIONALE: Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin(1A) receptors (5-HT(1A)R) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment resistant depressed patients. OBJECTIVES: Recently, we reported that intranasal administration of modified small interference RNA (siRNA) molecules targeting 5 HT(1A)R in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT(1A)R (1A-siRNA) to reduce directly the 5-HT(1A) autoreceptor expression and evaluate its biological consequences under basal conditions and in response to stressful situations. METHODS: Adult mice were locally infused with vehicle, nonsense siRNA, and 1A siRNA into dorsal raphe nucleus (DR). 5-HT(1A)R knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT(1A) autoreceptor knockdown. RESULTS: Intra-DR 1A-siRNA infusion selectively reduced 5-HT(1A)R mRNA and binding levels and canceled 8-OH-DPAT-induced hypothermia. Basal extracellular 5-HT in medial prefrontal cortex (mPFC) did not differ among treatments. However, 1A-siRNA-treated mice displayed less immobility in the tail suspension and forced swim tests, as did 1A-KO mice. This was accompanied by a greater increase in prefrontal 5-HT release during tail suspension test. Moreover, intra-DR 1A-siRNA infusion augmented the increase of extracellular 5-HT in mPFC evoked by fluoxetine, up to the level in 1A-KO mice. CONCLUSION: Together with our previous report, the present results indicate that acute suppression of 5-HT(1A) autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions. PMID- 22820868 TI - Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator. AB - RATIONALE: Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction. OBJECTIVES: Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior. METHODS: Rats were trained to self administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10, or 15 mg/kg intraperitoneal) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking. RESULTS: Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested. CONCLUSIONS: The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to nonspecific suppression of general appetitive behaviors. PMID- 22820869 TI - Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish. AB - In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal mediated metabolism might indirectly affect hepatocyte proliferation. PMID- 22820873 TI - "Tuning into Kids": reducing young children's behavior problems using an emotion coaching parenting program. AB - This study evaluated a 6-session group parenting program, Tuning into Kids (TIK), as treatment for young children (aged 4.0-5.11 years) with behavior problems. TIK targets parent emotion socialization (parent emotion awareness, regulation and emotion coaching skills). Fifty-four parents, recruited via a child behavior clinic, were randomized into intervention (TIK) or waitlist (clinical treatment as usual). Parents reported emotion awareness/regulation, emotion coaching, empathy and child behavior (pre-intervention, post-intervention, 6-month follow up); teachers reported child behavior and observers rated parent-child emotion coaching and child emotion knowledge (pre-intervention, follow-up). Data were analyzed using growth curve modeling and ANCOVA. Parents in both conditions reported less emotional dismissiveness and reduced child behavior problems; in the intervention group, parents also reported greater empathy and had improved observed emotion coaching skills; their children had greater emotion knowledge and reduced teacher-reported behavior problems. TIK appears to be a promising addition to treatment for child behavior problems. PMID- 22820871 TI - Survival benefit of palliative gastrectomy in gastric cancer patients with peritoneal metastasis. AB - BACKGROUND: The survival benefit of palliative gastrectomy in patients with peritoneal metastasis as a single incurable factor remains unclear. METHODS: A total of 148 gastric cancer patients with peritoneal metastasis underwent gastrectomy or chemotherapy at the Shizuoka Cancer Center between September 2002 and December 2008 and were included in this study. The effects of gastrectomy and chemotherapy on their long-term outcome were investigated. Multivariate analysis was also performed to identify independent prognostic factors. RESULTS: Gastrectomy was performed in 82 patients and subsequent chemotherapy was administered to 55. Chemotherapy was selected as an initial treatment for 66 patients. Median survival time (MST) was identical between patients with and without gastrectomy (13.1 vs. 12.0 months; P = 0.410). Conversely, MST was significantly longer in patients who received chemotherapy (13.7 months) than those who did not (7.1 months; P = 0.048). According to the results of multivariate analysis, chemotherapy (hazards ratio [HR] = 0.476; 95 % CI = 0.288 0.787) was selected as an independent prognostic factor, while gastrectomy was not. CONCLUSIONS: The results of the present study did not show a survival benefit of palliative gastrectomy in selected patients with peritoneal metastasis. Instead, chemotherapy has to be considered as an initial treatment for these patients. PMID- 22820874 TI - In vitro assessment of chelating agents with regard to their abstraction efficiency of Cd(2+) bound to plasma proteins. AB - The exposure of various human populations to Cd(2+) is of increasing health concern. After its gastrointestinal absorption into the bloodstream, Cd(2+) binds to alpha(2)-macroglobulin and serum albumin. Although animal studies have demonstrated that meso-2,3-dimercaptosuccinic acid (DMSA) and diethylenetriamine pentaacetic acid (DTPA) can effectively mobilize Cd(2+) to urine and decrease the Cd concentrations of the kidneys, the liver and the brain, not much is known about the abstraction of Cd(2+) from blood plasma proteins. We prepared a stock of Cd(2+) spiked rabbit plasma (2.0 MUg of Cd(2+)/mL) and analyzed aliquots by size exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) while simultaneously monitoring the emission lines of Ca, Cd, Cu, Fe, and Zn. After the addition of 0.33 mM, 0.66 mM or 0.99 mM of DMSA, DTPA, 2,3-dimercapto-1-propanesulfonic acid (DMPS) or N acetyl-l-cysteine (NAC) to plasma aliquots, the obtained mixtures were analyzed by SEC-ICP-AES after 5 min and 30 min. None of the investigated compounds adversely affected the plasma distribution of Fe at all investigated doses. At 0.33 mM, DTPA was most effective at mobilizing plasma protein bound Cd(2+) to a ~5 kDa Cd-species (100% removal), followed by DMPS (94%), DMSA (83%) and NAC (3%). All investigated compounds also mobilized Zn(2+) from plasma proteins to ~5 kDa Zn-species (DTPA: 80% removal; DMPS: 63%; DMSA: 29% and NAC: 3%). The addition of DTPA resulted in the dose-dependent elution of a [Ca-DTPA](3-) complex. Based on these results, 0.33 mM DMSA represents the best compromise that can be achieved between maximizing the abstraction of Cd(2+) from plasma proteins (83%), while minimizing the mobilization of Zn(2+) from plasma proteins (29%), and avoiding the complexation of Ca(2+). PMID- 22820870 TI - C3KO mouse expression analysis: downregulation of the muscular dystrophy Ky protein and alterations in muscle aging. AB - Mutations in CAPN3 gene cause limb-girdle muscular dystrophy type 2A (LGMD2A) characterized by muscle wasting and progressive degeneration of scapular and pelvic musculature. Since CAPN3 knockout mice (C3KO) display features of muscle pathology similar to those features observed in the earliest-stage or preclinical LGMD2A patients, gene expression profiling analysis in C3KO mice was performed to gain insight into mechanisms of disease. Two different comparisons were carried out in order to determine, first, the differential gene expression between wild type (WT) and C3KO soleus and, second, to identify the transcripts differentially expressed in aging muscles of WT and C3KO mice. The up/downregulation of two genes, important for normal muscle function, was identified in C3KO mice: the Ky gene, encoding a protease implicated in muscle development, and Park2 gene encoding an E3 ubiquitin ligase (parkin). The Ky gene was downregulated in C3KO muscles suggesting that Ky protease may play a complementary role in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity. Park2 was upregulated in the aged WT muscles but not in C3KO muscles. Taking into account the known functions of parkin E3 ligase, it is possible that it plays a role in ubiquitination and degradation of atrophy-specific and damaged proteins that are necessary to avoid cellular toxicity and a cellular stress response in aging muscles. PMID- 22820876 TI - Probing the electronic structure and optical response of a graphene quantum disk supported on monolayer graphene. AB - In this paper, we show that a graphene quantum disk (GQD) can be generated on monolayer graphene via structural modification using the electron beam. The electronic structure and local optical responses of the GQD, supported on monolayer graphene, were probed with electron energy-loss spectrum imaging on an aberration-corrected scanning transmission electron microscope. We observe that for small GQD, ~1.3 nm in diameter, the electronic structure and optical response are governed by the dominating edge states, and are distinctly different from either monolayer graphene or double-layer graphene. Highly localized plasmon modes are generated at the GQD due to the confinement from the edge of the GQD in all directions. The highly localized optical response from GQDs could find use in designing nanoscale optoelectronic and plasmonic devices based on monolayer graphene. PMID- 22820875 TI - Prognosis of resected pancreatic cancer: is the refined resection margin status dispensable? PMID- 22820877 TI - The AJH visits FDA. PMID- 22820879 TI - Are some "lone" atrial fibrillations caused by masked hypertension? PMID- 22820881 TI - Small RNAs: transmitting silence through generations. PMID- 22820888 TI - Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. AB - Ubiquitylation is one of the most abundant and versatile post-translational modifications (PTMs) in cells. Its versatility arises from the ability of ubiquitin to form eight structurally and functionally distinct polymers, in which ubiquitin moieties are linked via one of seven Lys residues or the amino terminus. Whereas the roles of Lys48- and Lys63-linked polyubiquitin in protein degradation and cellular signalling are well characterized, the functions of the remaining six 'atypical' ubiquitin chain types (linked via Lys6, Lys11, Lys27, Lys29, Lys33 and Met1) are less well defined. Recent developments provide insights into the mechanisms of ubiquitin chain assembly, recognition and hydrolysis and allow detailed analysis of the functions of atypical ubiquitin chains. The importance of Lys11 linkages and Met1 linkages in cell cycle regulation and nuclear factor-kappaB activation, respectively, highlight that the different ubiquitin chain types should be considered as functionally independent PTMs. PMID- 22820891 TI - Prenatal tobacco exposure predicts differential brain function during working memory in early adolescence: a preliminary investigation. AB - Children prenatally exposed to tobacco exhibit higher rates of learning and emotional-behavioral problems related to worse working memory performance. Brain function, however, among tobacco exposed children while performing a working memory task has not previously been examined. This study compared the brain function of tobacco-exposed (n = 7) and unexposed (n = 11) 12-year-olds during a number N-back working memory task using an event-related functional magnetic resonance imaging (fMRI) design. Prenatal alcohol exposure, neonatal medical problems, environmental risk, and sex were statistically controlled. Tobacco exposed children showed greater activation in inferior parietal regions, whereas unexposed children showed greater activation in inferior frontal regions. These differences were observed in the context of correct responses, suggesting that exposed and unexposed children use different brain regions and approaches to succeed in working memory tasks. Implications for future research and intervention are discussed. PMID- 22820890 TI - alpha-Lipoic acid ameliorates impaired glucose uptake in LYRM1 overexpressing 3T3 L1 adipocytes through the IRS-1/Akt signaling pathway. AB - Overexpression of the Homo sapiens LYR motif containing 1 (LYRM1) causes mitochondrial dysfunction and induces insulin resistance in 3T3-L1 adipocytes. alpha-Lipoic acid (alpha-LA), a dithiol compound with antioxidant properties, improves glucose transport and utilization in 3T3-L1 adipocytes. The aim of this study was to investigate the direct effects of alpha-LA on reactive oxygen species (ROS) production and insulin sensitivity in LYRM1 overexpressing 3T3-L1 adipocytes and to explore the underlying mechanism. Pretreatment with alpha-LA significantly increased both basal and insulin-stimulated glucose uptake and insulin-stimulated GLUT4 translocation, while intracellular ROS levels in LYRM1 overexpressing 3T3-L1 adipocytes were decreased. These changes were accompanied by a marked upregulation in expression of insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt following treatment with alpha-LA. These results indicated that alpha-LA protects 3T3-L1 adipocytes from LYRM1-induced insulin resistance partially via its capacity to restore mitochondrial function and/or increase phosphorylation of IRS-1 and Akt. PMID- 22820889 TI - Navigating the epigenetic landscape of pluripotent stem cells. AB - Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Recently developed high-throughput genomic tools greatly facilitate the study of epigenetic regulation in pluripotent stem cells. Increasing evidence suggests the existence of extensive crosstalk among epigenetic pathways that modify DNA, histones and nucleosomes. Novel methods of mapping higher-order chromatin structure and chromatin-nuclear matrix interactions also provide the first insight into the three-dimensional organization of the genome and a framework in which existing genomic data of epigenetic regulation can be integrated to discover new rules of gene regulation. PMID- 22820892 TI - The case against aldosterone: not proven. PMID- 22820894 TI - Coeliac disease and type 1 diabetes mellitus: epidemiology, clinical implications and effects of gluten-free diet. PMID- 22820895 TI - Proteasome inhibition decreases inflammation in human endothelial cells exposed to lipopolysaccharide. AB - BACKGROUND: The proteasome degrades ubiquitinated proteins and is the major pathway for intracellular protein degradation. The role of the proteasome in endothelial dysfunction observed in septic shock remains unknown. We stimulated primary cultures of human umbilical vein endothelial cells with lipopolysaccharide (LPS) and investigated effects on the proteasome. We hypothesized that proteasome inhibition would decrease endothelial cell activation, oxidative stress, and alter the proteome. METHODS: Endothelial cells were exposed to LPS (100 ng/mL) for 6 hours with or without lactacystin (5 mM), a proteasome inhibitor. Proteasome content and ubiquitinated proteins were measured by enzyme-linked immunosorbent assay and immunoblot, respectively. Markers of cellular activation, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, were measured by immunoblot and immunoassay. Superoxide anion production was determined by dihydroethidium assay, and nitrotyrosine (a marker of peroxynitrite) was visualized by immunofluoresence. The endothelial cell proteome was analyzed by 2D gel electrophoresis. RESULTS: LPS stimulation of endothelial cells significantly increased proteasome content, whereas the total levels of ubquitinated proteins decreased. This suggests that LPS activates the proteasome system in endothelial cells. LPS increased total content and cell surface expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, whereas proteasome inhibition ameliorated these increases. LPS increased both superoxide anion production and nitrotyrosine staining. Proteasome inhibition decreased both markers of cellular oxidative stress. Proteomic analysis identified two novel proteins upregulated by LPS and normalized with proteasome inhibition as follows: guanine nucleotide binding protein-1 and heterogeneous ribonucleoprotein K transcript variant. CONCLUSIONS: These results suggest that inhibition of the proteasome diminishes a number of markers of cellular stress induced by LPS. The proteasome may be a promising therapeutic target in clinical situations of severe pro-inflammatory stress. PMID- 22820893 TI - Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus. AB - Although type 2 diabetes mellitus (DM) is a chronic metabolic disorder with multiple etiologies, obesity has been constantly linked with insulin resistance and manifestation of type 2 DM. In addition, obesity is associated with hypertension, dyslipidemia, and fatty liver disease and is regarded as a subclinical inflammatory condition characterized by release of pro-inflammatory mediators such as cytokines from adipose tissue. Both, type 2 DM and obesity are considered as major risks for developing micro- and macrovascular diseases. Recent studies showed that impaired circulating levels of fetuin-A, which is involved in propagating insulin resistance as well as circulating levels of angiopoietins, which are growth factors promoting angiogenesis, were observed in patients with obesity, metabolic syndrome, and type 2 DM. However, independent of type 2 DM and obesity, defective regulation of fetuin-A and angiopoietin are playing a critical role in predisposing to coronary and peripheral vascular diseases. Therefore, mechanisms linking type 2 DM and obesity with fetuin-A and angiopoietins seem to be complex and are in need of further exploration. In this review, we aimed to present a summary concerning associations of type 2 diabetes, obesity, and vascular diseases with circulating levels of angiopoietins and fetuin-A. Furthermore, we aimed to focus on roles of fetuin-A and angiopoietins and to highlight the most plausible mechanisms that might explain their associations with type 2 DM and obesity. PMID- 22820896 TI - Evidence of a drug-drug interaction linked to inhibition of ester hydrolysis by orlistat. AB - : Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity. PMID- 22820898 TI - Cardiovascular safety of one-year escitalopram therapy in clinically nondepressed patients with acute coronary syndrome: results from the DEpression in patients with Coronary ARtery Disease (DECARD) trial. AB - BACKGROUND: Selective serotonin reuptake inhibitors are commonly used for treatment of depression in patients with cardiac diseases. However, evidence of cardiovascular (CV) safety from randomized trials is based on studies of no longer than 6-month duration. We examined the CV safety of 1-year treatment with Selective serotonin reuptake inhibitor escitalopram compared with placebo in patients with recent acute coronary syndrome (ACS). METHODS: The DECARD (DEpression in patients with Coronary ARtery Disease) trial assessed the prophylactic effect of escitalopram on depression after ACS. Two hundred forty patients were randomized to escitalopram 10-mg daily or matching placebo for 1 year. Serial measures of CV safety including clinical and biochemical parameters, 24-hour electrocardiogram monitor, resting electrocardiogram, and echocardiographic assessment were obtained. RESULTS: Escitalopram and placebo groups were comparable at baseline with regard to age, gender, sociodemography, depression score, risk factor profile, severity of heart disease, and medications. Dropout rates defined as withdrawal for any reason or lost to follow up during the 12-month study period was 27.2% in the escitalopram group and 23.4% in the placebo group (NS). There were no statistically significant differences between intervention groups in any of CV safety measures including the incidence of ventricular arrhythmia and episodes of ST-segment depression, length of QTc, and systolic and diastolic echocardiographic measures at the 12-month follow-up between groups. After 12 months, 16 and 13 major adverse events (death, recurrent ACS, or acute revascularization) were recorded in the escitalopram and placebo group, respectively (NS). CONCLUSIONS: One-year escitalopram treatment was safe and well tolerated in patients with recent ACS. PMID- 22820899 TI - Editor's note. PMID- 22820900 TI - The heart speaks II: embracing integrative medicine for heart health. PMID- 22820901 TI - Theoretical studies of HIV-1 reverse transcriptase inhibition. AB - Computational methods for accurately calculating the binding affinity of a ligand for a protein play a pivotal role in rational drug design. We herein present a theoretical study of the binding of five different ligands to one of the proteins responsible for the human immunodeficiency virus type 1 (HIV-1) cycle replication; the HIV-1 reverse transcriptase (RT). Two types of approaches are used based on molecular dynamics (MD) simulations within hybrid QM/MM potentials: the alchemical free energy perturbation method, FEP, and the pathway method, in which the ligand is physically pulled away from the binding site, thus rendering a potential of mean force (PMF) for the binding process. Our comparative analysis stresses their advantages and disadvantages and, although the results are not in quantitative agreement, both methods are capable of distinguishing the most and the less potent inhibitors of HIV-1 RT activity on an RNase H site. The methods can then be used to select the proper scaffold to design new drugs. A deeper analysis of these inhibitors through molecular electrostatic potential (MEP) and calculation of the binding contribution of the individual residues shows that, in a rational design, apart from the strong interactions established with the two magnesium cations present in the RNase H site, it is important to take into account interactions with His539 and with those residues that are anchoring the metals; Asp443, Glu478, Asp498 and Asp549. The MEPs of the active site of the protein and the different ligands show a better complementarity in those inhibitors that present higher binding energies, but there are still possibilities of improving the favourable interactions and decreasing those that are repulsive in order to design compounds with higher inhibitory activity. PMID- 22820902 TI - Environmental factors associated with the seroprevalence of Toxoplasma gondii in Wild Boars (Sus scrofa), France. AB - Toxoplasma gondii is a protozoan parasite infecting humans and animals. Wild boars Sus scrofa are a potential source of human infection and an appropriate biological model for analyzing T. gondii dynamics in the environment. Here, we aimed to identify environmental factors explaining the seroprevalence of toxoplasmosis in French wild boar populations. Considering 938 individuals sampled from 377 'communes', overall seroprevalence was 23% (95% confidence interval: [22-24]). Using a Poisson regression, we found that the number of seropositive wild boars detected per 'commune' was positively associated with the presence of European wildcats (Felis silvestris) and moderate winter temperatures. PMID- 22820903 TI - Preparation of a magnetic molecularly imprinted polymer with pseudo template for rapid simultaneous determination of cyromazine and melamine in bio-matrix samples. AB - A magnetic molecularly imprinted polymer (M-MIP) for cyromazine and melamine was prepared by simple suspension polymerization using a pseudo template, 2-(4,6 diamino-1,3,5-triazin-2-ylamino)ethanethiol disulfide. The M-MIP was characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy, and vibrating sample magnetometry. Molecular recognition properties and binding capability to cyromazine and melamine were evaluated by adsorption testing, which showed the M-MIP had better affinity and selectivity than the magnetic non-imprinted polymer (M-NIP) for cyromazine and melamine. A method based on molecularly imprinted solid-phase extraction assisted by magnetic separation was developed for extraction of cyromazine and melamine from bio matrix samples. Various conditions, for example desorption conditions, amount of M-MIP, extraction time, and sample pH were optimized. High-performance liquid chromatography with UV detection was used to determine cyromazine and melamine after extraction. The proposed method was successfully applied to determination of cyromazine and melamine in egg and milk samples. Recovery of standard spiked cyromazine and melamine from these samples was between 71.86 and 80.57%, with intraday and interday relative standard deviation ranging from 3.45 to 6.39% and from 3.95 to 7.84%, respectively. The results indicate that the pseudo template M MIP can be used for preconcentration, purification, and analysis of cyromazine and melamine in bio-matrix samples. PMID- 22820904 TI - Morpho-spectral imaging for investigation of disease progression. PMID- 22820905 TI - Surface-enhanced Raman scattering (SERS) revealing chemical variation during biofilm formation: from initial attachment to mature biofilm. AB - Surface-enhanced Raman scattering (SERS) has recently been proved to be a promising technique for characterizing the chemical composition of the biofilm matrix. In the present study, to fully understand the chemical variations during biofilm formation, SERS based on silver colloidal nanoparticles was applied to evaluate the chemical components in the matrix of biofilm at different growth phases, including initial attached bacteria, colonies, and mature biofilm. Meanwhile, atomic force microscopy was also applied to study the changes of biofilm morphology. Three model bacteria, including Escherichia coli, Pseudomonas putida, and Bacillus subtilis, were used to cultivate biofilms. The results showed that the content of carbohydrates, proteins, and nucleic acids in the biofilm matrix increased significantly along with the biofilm growth of the three bacteria judging from the intensities and appearance probabilities of related marker peaks in the SERS spectra. The content of lipids, however, only increased in the Gram-negative biofilms (E. coli and P. putida) rather than the Gram positive biofilm (B. subtilis). Our findings strongly suggest the SERS has significant potential for studying chemical variations during biofilm formation. PMID- 22820907 TI - Current understanding of TRPM7 pharmacology and drug development for stroke. AB - The initial excitement and countless efforts to find a pharmacological agent that disrupts the excitotoxic pathway of ischemic neuronal death have only led to disappointing clinical trials. Currently, a thrombolytic agent called recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment available for patients with acute ischemic stroke in most countries. Even though its efficacy has been confirmed repeatedly, rt-PA is considerably underused due to reasons including a short therapeutic window and repeated complications associated with its use. A search for alternative mechanisms that may operate dependently or independently with the well-established excitotoxic mechanism has led researchers to the discovery of newly described non-glutamate mechanisms. Among the latter, transient receptor potential melastatin 7 (TRPM7) is one of the important nonglutamate mechanisms in stroke, which has been evaluated in both in vitro and in-vivo. In this review, we will discuss the current state of pharmacological treatments of ischemic stroke and provide evidence that TRPM7 is a promising therapeutic target of stroke. PMID- 22820908 TI - Pharmacokinetic interactions between ilaprazole and clarithromycin following ilaprazole, clarithromycin and amoxicillin triple therapy. AB - AIM: To investigate the drug interactions between ilaprazole, a new proton pump inhibitor, and clarithromycin following ilaprazole, clarithromycin and amoxicillin combination therapy. METHODS: Twelve healthy Chinese volunteers were recruited in a randomized, open-label, 3-period crossover study. All subjects were administered ilaprazole (5 mg), clarithromycin (500 mg) or a triple therapy, including ilaprazole (5 mg), clarithromycin (500 mg) and amoxicillin (1 g), twice daily for 6 consecutive days. On the 7th day, the drugs were given once, and blood samples were collected and analyzed using a well-validated HPLC/MS/MS method. RESULTS: Following the triple therapy, the peak concentration (C(max)) and the area under the concentration-time curve from 0 h to 12 h (AUC(0->12)) of ilaprazole were significantly decreased, as compared with the single medication group (C(max):1025.0+/-319.6 vs 1452.3+/-324.6 ng/mL; AUC(0->12): 9777.7+/-3789.8 vs 11363.1+/-3442.0 ng.h/mL). Similar changes were found for ilaprazole sulfone (C(max): 5.9+/-0.5 vs 9.3+/-1.7 ng/mL; AUC(0->12): 201.4+/-32.1 vs 277.1+/-66.2 ng.h/mL). The triple therapy significantly elevated the C(max) of clarithromycin (3161.5+/-702.2 vs 2541.9+/-476.2 ng/mL). CONCLUSION: The H pylori eradication therapy with clarithromycin, amoxicillin and ilaprazole may cause pharmacokinetic interactions that decrease the amount of ilaprazole and its metabolites and elevate that of clarithromycin. PMID- 22820909 TI - The pharmacology and therapeutic potential of small molecule inhibitors of acid sensing ion channels in stroke intervention. AB - In the nervous system, a decrease in extracellular pH is a common feature of various physiological and pathological processes, including synaptic transmission, cerebral ischemia, epilepsy, brain trauma, and tissue inflammation. Acid-sensing ion channels (ASICs) are proton-gated cation channels that are distributed throughout the central and peripheral nervous systems. Following the recent identification of ASICs as critical acid-sensing extracellular proton receptors, growing evidence has suggested that the activation of ASICs plays important roles in physiological processes such as nociception, mechanosensation, synaptic plasticity, learning and memory. However, the over-activation of ASICs is also linked to adverse outcomes for certain pathological processes, such as brain ischemia and multiple sclerosis. Based on the well-demonstrated role of ASIC1a activation in acidosis-mediated brain injury, small molecule inhibitors of ASIC1a may represent novel therapeutic agents for the treatment of neurological disorders, such as stroke. PMID- 22820911 TI - Arecoline improves vascular endothelial function in high fructose-fed rats via increasing cystathionine-gamma-lyase expression and activating K(ATP) channels. AB - AIM: To investigate the effect of arecoline, a major component of betel nut, on vascular endothelial function in high fructose-fed rats and the potential mechanisms underlying the effect. METHODS: Male Wistar rats were fed a high fructose or control diet for 16 weeks. At the beginning of week 13, the rats were injected ip with low (0.5 mg.kg(-1).d(-1)), medium (1.0 mg.kg(-1).d(-1)) or high (5.0 mg.kg(-1).d(-1)) doses of arecoline for 4 weeks. At the termination of the treatments, blood was collected, fasting blood glucose (FBG) and serum insulin (FSI) levels were measured, and insulin sensitivity index (ISI) was calculated. The thoracic aortas were isolated and aortic rings were prepared for studying ACh induced endothelium-dependent vasorelaxation (EDVR). The mRNA and protein expression of cystathionine-gamma-lyase (CSE) in the thoracic aortas was analyzed using RT-PCR and Western blot analysis, respectively. RESULTS: In high fructose fed rats, the levels of FBG and FSI were remarkably increased, whereas the ISI and the mRNA and protein expression of CSE were significantly decreased. ACh induced EDVR in the aortic rings from high fructose-fed rats was remarkably reduced. These changes were reversed by treatment with high dose arecoline. Pretreatment of the aortic rings rings from high fructose-fed rats with the CSE inhibitor propargylglycine (10 mmol/L) or the ATP-sensitive potassium (K(ATP)) channel blocker glibenclamide (10 mmol/L) abolished the restoration of ACh induced EDVR by high dose arecoline. On the contrary, treatment with high dose arecoline significantly impaired ACh-induced EDVR in the aortic rings from control rats, and pretreatment with propargylglycine or glibenclamide did not cause further changes. CONCLUSION: Arecoline treatment improves ACh-induced EDVR in high fructose-fed rats, and the potential mechanism of action might be associated with increase of CSE expression and activation of K(ATP) channels by arecoline. PMID- 22820910 TI - Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia. AB - AIM: To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. METHODS: Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. RESULTS: A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. CONCLUSION: Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring. PMID- 22820912 TI - Effect of feeding olive-pulp ensiled with additives on feedlot performance and carcass attributes of fat-tailed lambs. AB - Feed cost has a significant effect on the economic efficiency of feedlot lambs; therefore, the use of low-cost non-conventional feedstuffs, such as olive pulp (OP), has the potential to decrease the production costs. Because optimum inclusion of OP-treated silages has not been determined in feedlot lambs, an experiment was conducted to determine the effect of inclusion of OP ensiled with additives in the diet on the feedlot performance and carcass attributes of feedlot lambs. Ram lambs of Mehraban and Ghezel breeds (n = 50 lambs per breed) were randomly allotted to 10 groups and fed with one of the nine diets containing OP silage or a control diet. Silage treatments were: (1) OP silage without additives (OPS), (2) OP ensiled with 8 % beet molasses and 0.4 % formic acid (OP MF), and (3) OP ensiled with 8 % beet molasses, 0.4 % formic acid and 0.5 % urea (OP-MFU). The control diet contained 50 % alfalfa hay and 50 % barley grain. Three levels from each silage were chosen to replace the barley grain (10, 20, or 30 % dry matter basis). The lambs were slaughtered after 92 days, and the average daily gain (ADG), feed conversion ratio (FCR), and carcass characteristics were determined. Feeding OPS to fat-tailed lambs, at an inclusion level of 30 %, decreased the carcass dressing percentage, mainly as a result of decreased brisket percentage, but the ADG and FCR values were not adversely affected. Ghezel lambs had higher ADG than Mehraban lambs, but the visceral fat weight percentage, flap weight percentage, and back fat depth were higher in Mehraban. The crude protein content in the longissimus dorsi (LD) muscle was higher in Ghezel, but the dry matter percentage was higher in Mehraban (P < 0.05). Other attributes were not significantly affected by breed (P > 0.05). Most carcass characteristics, including major cuts, were not affected by OPS feeding; therefore, feeding OPS (up to 30 %) can be economical for feedlot lambs. Most carcass characteristics, including major cuts, were not affected by OPS levels used in this experiment; therefore, inclusion of OPS (up to 30 %) in the diet may reduce the cost of raising feedlot lambs. This also could help alleviate the problem of storage of OP in oil factories. PMID- 22820914 TI - Internet use by parents of children attending a dedicated scoliosis outpatient clinic. AB - PURPOSE: No information exists on the level of internet use among parents of pediatric patients with scoliosis. The internet may represent a medium through which to provide information to augment the outpatient consultation. The aim of this research was to establish the prevalence of internet use amongst a cohort of parents attending a pediatric scoliosis outpatient clinic. METHODS: A previously used questionnaire (Baker et al., Eur Spine J, 19:1776-1779, 2010) was distributed to parents attending a dedicated scoliosis outpatient clinic with their children. Demographic data and details about use of the internet were collected. RESULTS: Fifty-eight percent of respondents had used the internet to search for information on scoliosis, and 94 % were interested in a local internet provided information provision. A positive history of corrective surgery and possession of health insurance were independent positive predictors of internet use. CONCLUSIONS: As surgeons we need to be aware of our patients' use of the internet, and there is the opportunity to use this medium to provide additional education. PMID- 22820913 TI - Involvement of TRPV1 and TRPV4 channels in migration of rat pulmonary arterial smooth muscle cells. AB - Pulmonary hypertension, the main disease of the pulmonary circulation, is characterized by an increase in pulmonary vascular resistance, involving proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). However, cellular and molecular mechanisms underlying these phenomena remain to be identified. In the present study, we thus investigated in rat intrapulmonary arteries (1) the expression and the functional activity of TRPV1 and TRPV4, (2) the PASMC migration triggered by these TRPV channels, and (3) the associated reorganization of the cytoskeleton. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated expression of TRPV1 and TRPV4 mRNA in rat intrapulmonary arteries. These results were confirmed at the protein level by western blot. Using microspectrofluorimetry (indo-1), we show that capsaicin and 4alpha-phorbol-12,13-didecanoate (4alpha-PDD), selective agonists of TRPV1 and TRPV4, respectively, increased the intracellular calcium concentration of PASMC. Furthermore, stimulation of TRPV1 and TRPV4 induced PASMC migratory responses, as assessed by two different methods (a modified Boyden chamber assay and a wound healing migration assay). This response cannot seem to be attributed to a proliferative effect as assessed by BrdU and Wst-1 colorimetric methods. Capsaicin- and 4alpha-PDD-induced calcium and migratory responses were inhibited by the selective TRPV1 and TRPV4 blockers, capsazepine and HC067047, respectively. Finally, as assessed by immunostaining, these TRPV-induced migratory responses were associated with reorganization of the F-actin cytoskeleton and the tubulin and intermediate filament networks. In conclusion, these data point out, for the first time, the implication of TRPV1 and TRPV4 in rat PASMC migration, suggesting the implication of these TRPV channels in the physiopathology of pulmonary hypertension. PMID- 22820915 TI - Ultrasonographic quantification of spinal cord and dural pulsations during cervical laminoplasty in patients with compressive myelopathy. AB - PURPOSE: Pulsatile movements of the dura mater have been interpreted as a sign that the cord is free within the subarachnoid space, with no extrinsic compression. However, the association between restoration of pulsation and adequate decompression of the spinal cord has not been established. The present study investigated the relationship between the extent of spinal cord decompression and spinal cord and dural pulsations based on quantitative analysis of intraoperative ultrasonography (US). METHODS: Eighty-five consecutive patients (55 males, 30 females; mean age, 64 +/- 13 years) who underwent cervical double door laminoplasty to relieve compressive myelopathy were enrolled. Spinal cord decompression status was classified as: Type 1 (non-contact), the subarachnoid space was retained on the ventral side of the cord, Type 2 (contact and apart), the cord showed both contact with and separation from the anterior element of the cervical spine, or Type 3 (contact), the cord showed continuous contact with the anterior element of the cervical spine. Spinal cord and dura mater dynamics were quantitatively analyzed using automatic video-tracking software. Furthermore, the intensity of spinal and dural pulsation was compared with the recovery of motor function at 1 year after surgery as measured by increase in the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). RESULTS: Spinal cord pulsation amplitude ranged from 0.01 to 0.84 mm (mean 0.30 +/- 0.16 mm) and dural pulsation amplitude ranged from 0.01 to 0.38 mm (mean 0.14 +/- 0.08 mm). Average spinal cord pulsation amplitude in Type 2 patients was significantly larger than that in the other groups, whereas, average dural pulsation amplitudes were similar for all three groups. There was a significant correlation between spinal cord and dural pulsation amplitudes in Type 1 patients, but not in Type 2 or Type 3 patients. Type 3 patients showed a particularly poor correlation between spinal cord and dural pulsations. Spinal cord pulsation amplitude was moderately correlated with the recovery of motor function evaluated by JOACMEQ. CONCLUSION: The present results suggest that restoration of dural pulsation is not an adequate indicator of sufficient decompression of the spinal cord following a surgical procedure. PMID- 22820916 TI - Development of endovascular vibrating polymer actuator probe for mechanical thrombolysis: in vivo study. AB - In this study, we propose a new method for the enhancement of intraarterial thrombolysis by use of an endovascular vibrating polymer actuator probe (VPAP), which is fabricated from an ionic polymer metal composite (IPMC) actuator. The endovascular VPAP was fabricated by combining 0.8 * 0.8 * 10 mm3 IPMC samples, 0.22 mm * 50 cm copper wires, and 40 cm of Teflon tube. The purpose of this study was to evaluate the thrombolysis efficiency of an endovascular VPAP in a dog model. Both renal arteries of the enrolled dogs (n = 5) were used in the current study. A distal portion of the renal artery in a mongrel dog was occluded by a blood clot from autologous venous whole blood. Intraarterial thrombolysis was performed by use of a VPAP without the actuation force (control group), by a VPAP only (VPAP-only group), or with a combination of recombinant tissue plasminogen activator (rtPA) and a VPAP (VPAP + rtPA group). The thrombolysis efficiency was evaluated by the modified Thrombolysis in Myocardial Infarction (TIMI) grading system based on the consensus between two radiologists. The grading scales were compared according to each intraarterial thrombolysis method. The VPAP + rtPA and VPAP-only groups showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP-only group also showed a significantly higher thrombolysis efficiency than did the control group (p < 0.05). The VPAP+ rtPA group showed a significantly higher thrombolysis efficiency than did the VPAP-only group (p < 0.05). The use of an endovascular VPAP was a feasible and useful method for intraarterial thrombolysis, and it enhanced the thrombolysis efficiency when combined with the thrombolytic agent rtPA. PMID- 22820917 TI - Liver support systems--a review. AB - Liver failure is associated with a high morbidity and mortality rate and is the seventh leading cause of death worldwide. Orthotopic liver transplantation remains the definitive treatment; however, because of the limited number of available organs many patients expire while on the transplant list. Currently, there are no established means for providing liver support as a means of bridging patients to transplantation or allowing for recovery from liver injury. Analogous to the clinical situation of renal failure, there is great interest in developing liver support systems that replace the metabolic and waste removal functions of the liver. These support systems are of two general types: artificial and bioartificial livers. In this review, based on a presentation from the 57th American Society of Artificial Internal Organs Annual Meeting (Washington, D.C., June 2011), we review the current status of liver support systems. PMID- 22820918 TI - Are blood stream infections associated with an increased risk of hemorrhagic stroke in patients with a left ventricular assist device? AB - Blood stream infections (BSIs) are an important cause of morbidity and mortality in patients with left ventricular assist devices (LVADs). The aim of this study was to examine the correlation between hemorrhagic cerebrovascular accident (CVA) and BSI after implantation of LVAD for advanced heart failure (HF). This was a retrospective descriptive review of 87 patients with end-stage HF, who underwent implantation of HeartMate II continuous-flow LVAD over a 4 year period. Blood stream infections were diagnosed by serial blood cultures, and suspected neurological complications including CVAs were confirmed by neuroimaging. Extensive patient chart review was performed, and descriptive characteristics were analyzed using SPSS statistical software. The mean age of our study population was 62.3 +/- 12.8 years, and the majority of our patients were males (n = 75, 86.2%). The baseline characteristics were comparable in the patients with and without CVAs. Patients with BSI had a much greater incidence of CVA compared to patients without BSI (n = 13, 43.3% vs. n = 5, 10.0%; p < 0.0001). There was an increased mortality in patients with BSI than those without (n = 57, 65.5% vs. n = 30, 34.5%; p = 0.003). The risk of all CVAs (hemorrhagic/ischemic) was eightfold (odds ratio [OR] = 7.9; 95% confidence interval [CI] = 2.4-25.5; p = 0.001] in patients with BSI. Patients with BSI had a >20-fold risk of hemorrhagic CVA (OR = 24; 95% CI = 2.8-201.1; p = 0.03). Advanced HF patients with LVAD support who developed BSI need urgent evaluation and close monitoring for suspected neurological complications, particularly hemorrhagic CVA. PMID- 22820919 TI - Glis3 regulates neurogenin 3 expression in pancreatic beta-cells and interacts with its activator, Hnf6. AB - The Kruppel-like zinc finger transcription factor, Glis3, has been associated with neonatal diabetes in humans and mice, and implicated in the regulation of pancreatic beta-cell generation. However, its precise function in the development of pancreatic beta-cells has not yet been elucidated. In this study, we provide evidence that Glis3 regulates Neurogenin 3 (Ngn3) through its distal promoter region. Previous studies showed that the distal region and proximal region of Ngn3 promoter contains various transcription binding sites, including binding sites for pancreatic and duodenal homeobox 1 (Pdx1), Hnf1beta and Hnf6. Interestingly, putative Glis3 binding sites (Glis3BS) were found in the distal region of Ngn3 promoter close to the Hnf6 binding sites. This suggested that along with Hnf6, Glis3 may also be involved in the regulation of Ngn3 expression. This hypothesis is supported by data showing that Glis3 can bind to the Ngn3 promoter directly and activate Ngn3 transcriptional activity. Additionally, Glis3 can interact directly with Hnf6 in vitro and in vivo. The amino-terminus in Glis3 and the homeodomain of Hnf6 are critical for this interaction. These data suggest that crosstalk between Glis3 and Hnf6 may play an important role in the regulation of Ngn3 during pancreatic endocrine progenitor cell specification and development. PMID- 22820921 TI - Structural characterization of an intrinsically unfolded mini-HBX protein from hepatitis B virus. AB - The hepatitis B virus x protein (HBX) is expressed in HBV-infected liver cells and can interact with a wide range of cellular proteins. In order to understand such promiscuous behavior of HBX we expressed a truncated mini-HBX protein (named Tr-HBX) (residues 18-142) with 5 Cys -> Ser mutations and characterized its structural features using circular dichroism (CD) spectropolarimetry, NMR spectroscopy as well as bioinformatics tools for predicting disorder in intrinsically unstructured proteins (IUPs). The secondary structural content of Tr-HBX from CD data suggests that Tr-HBX is only partially folded. The protein disorder prediction by IUPred reveals that the unstructured region encompasses its N-terminal ~30 residues of Tr-HBX. A two-dimensional (1)H-(15)N HSQC NMR spectrum exhibits fewer number of resonances than expected, suggesting that Tr HBX is a hybrid type IUP where its folded C-terminal half coexists with a disordered N-terminal region. Many IUPs are known to be capable of having promiscuous interactions with a multitude of target proteins. Therefore the intrinsically disordered nature of Tr-HBX revealed in this study provides a partial structural basis for the promiscuous structure-function behavior of HBX. PMID- 22820922 TI - A middle mesenteric artery. AB - In 114 cases of the transverse colon isolated from cadavers (50 male, 64 female), anatomical examinations of the arterial system of the colon were performed. Arteriograms were obtained after dissecting and contrasting the colonic vessels with Mixobar contrast. In one case, on arteriography of the colon with its mesentery isolated from a 55-year-old male cadaver, a rare anatomical variant was found. The third mesenteric artery originated directly from the aorta-halfway between the superior and inferior mesenteric arteries and ascended obliquely in the direction of the hepatic flexure of the colon. Supply area of the artery was typical for the middle colic branch of the superior mesenteric artery: the distal segment of the ascending colon and the transverse colon. Such a variation, although very rare, may have particular impact on diagnosis and even the method and range of surgery. PMID- 22820923 TI - Bacterial pathogenesis: The two faces of P. luminescens. PMID- 22820920 TI - Plant hormonal regulation of nitrogen-fixing nodule organogenesis. AB - Legumes have evolved symbiotic interactions with rhizobial bacteria to efficiently utilize nitrogen. Recent progress in symbiosis has revealed several key components of host plants required for nitrogen-fixing nodule organogenesis, in which complicated metabolic and signaling pathways in the host plant are reprogrammed to generate nodules in the cortex upon perception of the rhizobial Nod factor. Following the recognition of Nod factors, plant hormones are likely to be essential throughout nodule organogenesis for integration of developmental and environmental signaling cues into nodule development. Here, we review the molecular events involved in plant hormonal regulation and signaling cross-talk for nitrogen-fixing nodule development, and discuss how these signaling networks are integrated into Nod factor-mediated signaling during plant-microbe interactions. PMID- 22820924 TI - Short- and long-term efficacy of intragastric air-filled balloon (Heliosphere(r) BAG) among obese patients. AB - BACKGROUND: Obesity is an increasing health problem worldwide. The intragastric balloon as a temporary endoscopic treatment of obesity can play an important role among the aforementioned group of obese individuals. It can also be used as a preoperative test before subjecting patients to restrictive bariatric surgery. Furthermore, the intragastric device may be applied to patients affected by severe obesity as a "bridge treatment" before they undergo major surgery in order to reduce chances of operation-related risks. To date, there are insufficient data in the literature on the long-term results of the intragastric balloon. METHODS: Our study includes an analysis of our experience with Heliosphere(r) BAG from 2006 through to 2010, concerning early weight loss and weight loss maintenance over at least 18 months since the device's removal. The 32 patients who completed the 6-month treatment had recorded a mean weight loss of 12.66 kg and a mean overweight loss of 24.37 % (SD, 12.74). RESULTS: A total of 16 patients are subjected to an 18-month follow-up. Their pretreatment and long-term body mass index (BMI) were calculated: 6 months later, when devices were removed, they showed a mean weight of 99.75 kg (SD, 17.90; p < 0.001) and a mean weight loss of 13.62 kg and 26.14 % (SD, 12.79). 18 months after removing Heliosphere(r) BAG, the 16 patients' mean BMI was 37.28 kg/m2 (SD, 5.41; p = 0.004), with a mean weight of 103.56 kg (SD 17.25; p = 0.0125), and a mean weight loss of 9.8 kg or 18.2 % (SD, 12.07). CONCLUSIONS: Heliosphere(r) BAG enables modest short-term weight loss with little side effects, although mid/long-term follow-up may entail partial weight gain. We believe it can be considered a useful bridge treatment in bariatric surgery in order to reduce chances of preoperative risks. PMID- 22820925 TI - Deep and superficial fat ratio in dietary and surgically induced weight loss patients. AB - BACKGROUND: Architecture of abdominal fat above and below Scarpa's fascia is morphologically different. Little information is available about the relative distribution patterns of deep and superficial fat layers in massive weight loss (MWL) patients. This study aimed to evaluate the relative distribution patterns of deep and superficial abdominal fat layers in two groups of MWL patients presenting for abdominoplasty: (1) MWL via nutritional management and (2) MWL via bariatric surgery. METHODS: All MWL patients with stable body weight for a minimum of 24 months presenting for abdominal body contouring at Lausanne University Hospital, Department of Plastic Surgery between July 2008 and June 2009 were included. Patients with preexisting metabolic diseases were excluded. Patients with nutritional deficiencies were deferred until corrected. RESULTS: Nineteen consecutive patients were included in the study, 7 post-bariatric patients and 12 patients after dietary-induced weight loss (5 were males and 14 were females; average age 45.5 years, range 36-64 years), with an average weight loss of 48 kg (57 kg post-bariatric, 28 kg dietary induced) and a mean body mass index of 29.2 kg/m(2) (range 24.0-40.7) at the time of abdominoplasty. Morphologic evaluation yielded a relative distribution of deep to superficial fat layers of 42 to 58 % in the post-bariatric group versus 31 to 69 % (p < 0.05) in the nutritionally induced group. CONCLUSIONS: These data show that the morphologic distribution patterns of deep and superficial abdominal fat layers differ with regards to mode of weight loss. PMID- 22820926 TI - Crisis Intervention Team (CIT) programs in rural communities: a focus group study. AB - The Crisis Intervention Teams model (CIT) was originally developed as an urban model for police officers responding to calls about persons experiencing a mental illness crisis. Literature suggests that there is reason to believe that there may be unique challenges to adapting this model in rural settings. This study attempts to better understand these unique challenges. Thematic analysis of focus group interviews revealed that there were both external and internal barriers to developing CIT in their respective communities. Some of these barriers were a consequence of working in small communities and working within small police departments. Participants actively overcame these barriers through the realization that CIT was needed in their community, through collaborative efforts across disciplines, and through the involvement of mental health advocacy groups. These results indicate that CIT can be successfully implemented in rural communities. PMID- 22820928 TI - The impact of a mental health crisis respite upon clients' symptom distress. AB - This study examined clients who were admitted to a mental health respite program in the first 3 months of 2011 in order to identify the ability of the program to reduce symptom distress and to explore related psychosocial factors. Participants were provided with self-report questionnaires that included measurements of demographics, mental health status, symptom severity, and program satisfaction. Results indicate a significant improvement in symptom distress (p < 0.05), mental health confidence (p < 0.1), and self-esteem (p < 0.05) from admission to discharge. No change was detected in largely external measurements. PMID- 22820927 TI - Longitudinal association of therapeutic alliance and clinical outcomes in supported housing for chronically homeless adults. AB - General psychotherapy research has underscored the importance of the therapeutic alliance in client outcomes. This study examined the association between therapeutic alliance and client outcomes specifically between chronically homeless clients in a supported housing program and their case managers. Using data from a federal supported housing initiative, participants were categorized into those who rated their therapeutic alliance with case managers at 3 months as relatively high (top 75th percentile; n = 123), relatively low (bottom 25th percentile; n = 128), or did not identify any primary mental health provider at 3 months (n = 205). Controlling for baseline differences, there were no group differences on any outcomes, except that participants who rated high therapeutic alliance at 3 months reported the highest subjective quality of life and perceived social support. Client outcomes in supported housing may rely more on practical assistance and access to other services than the quality of the therapeutic relationship with their primary mental health provider. PMID- 22820929 TI - Attitudes and experience of youth and their parents with psychiatric medication and relationship to self-reported adherence. AB - Few studies have directly examined the interrelationship of teen and parent attitudes toward psychiatric medication and how this relates to medication adherence. In the current study, survey data from 19 parent-child dyads were analyzed to investigate the relationship of parent and teen attitudes toward medication, decision self-efficacy, and current involvement in decisions about psychiatric medication with self-reported adherence. Structural equation modeling techniques were used to fit actor-partner interdependence models to examine bidirectional effects of the dyadic relationships. Teens and parents had similarly positive attitudes toward medication, high levels of self-efficacy and self-reported adherence. Current involvement in decisions about medications was significantly lower for teens compared to their parents. The actor-partner interdependence models revealed that parent levels of decision self-efficacy were related to youth self-reported adherence (partner effect). Youth attitudes toward medications were related to youth self-reported adherence (actor effect). Parent and teen actor effects of decisional self-efficacy were significantly associated with current involvement. Providers need to be aware of the importance of engaging both teens and parents in decisions about psychiatric medication and recognize the need to explicitly elicit questions and concerns from young patients. PMID- 22820930 TI - Depressive symptoms among Jordanian youth: results of a national survey. AB - This study examines level of depression and factors associated with depression among female and male youth in Jordan. The study uses data from a cross-sectional survey conducted among a national sample of 14-25 year old youth attending educational institutions in Jordan (N = 8,129). On average, respondents reported frequently experiencing feelings of sadness (66 %), loss of joy (49 %) and loss of hope in living (43 %). Regression models demonstrated that higher levels of depressive symptoms were observed among females and among youth exposed to violence. Better parent-child relationships were associated with lower depression score. Among males depressive symptoms were associated with poor economic status, low assertiveness and a higher likelihood of alcohol use and smoking. There is a need for mental health prevention programs for youth in Jordan that enhance youth's social and emotional skills, strengthen parent-child relationships, and reduce violence in school, home and in the community. PMID- 22820931 TI - Course and predictors of physical aggressive behaviour after discharge from a psychiatric inpatient unit: 1 year follow-up. AB - The present study analyzes course and predictors of physically aggressive behaviour over a 1-year follow up in a sample of patients discharged from a psychiatric inpatient unit. One hundred and eighty-six patients discharged from a locked short-term Psychiatric Inpatient Unit at the Bologna University Hospital. After discharge, two data collection contacts at 1 month and at 1 year were scheduled. In particular, psychiatrists, nurses, and other professionals were interviewed by the research staff using the Overt Aggression Scale. About 20 % of discharged patients showed physical aggressiveness in subsequent follow-up contacts. Risk factors for physical violence in the short-time period were social problems and a longer time from the first psychiatric contact. Living in residential facilities and physical aggressiveness during hospitalization were correlated to violence in the long-time period. Risk factors for physically violent behaviour differed in the short-term and long-term follow-ups; different causes of violent behaviour could be hypothesized. PMID- 22820932 TI - Altered gene expression involved in insulin signaling pathway in type II diabetic osteoporosis rats model. AB - It is well established that both estrogen loss and type II diabetes mellitus (DMII) can impair bone metabolism, but whether estrogen loss exacerbates the effects of DMII is unclear. Therefore, we determined if ovariectomy (OVX) of rats on a long-term high-fat/sugar diet and injection of a low dose of streptozotocin (DMII) decreased bone mineral density (BMD) more than OVX or DMII alone. Bone insulin signaling is known to support bone metabolism; therefore, we also tested the hypothesis that OVX DMII rats (DOVX) would exhibit greater reductions in the expression of proteins important in insulin signaling, including IRS-1, IRS-2, and IGF-1. As hypothesized, BMD and plasma estrogen levels were decreased more in DOVX rats than in rats following OVX (NOVX) or DMII (DS) alone. IGF-1 expression was decreased in the liver, kidney, skeletal muscle, and bone of DOVX, DS, and NOVX rats; however, the decrease was larger and occurred sooner in DOVX rats. While IRS-1 and IRS-2 decreased in most groups in all tissues examined, the expression patterns differed in both a group- and tissue-dependent fashion. In conclusion, these data demonstrate that estrogen loss and DMII induced by a high fat/sugar diet interact to produce osteoporosis and support the hypothesis that the bone loss may be mediated at least in part by concurrent decreases in the insulin signaling proteins in bone. PMID- 22820934 TI - Developing and testing TEAM (Team Evaluation and Assessment Measure), a self assessment tool to improve cancer multidisciplinary teamwork. AB - BACKGROUND: Cancer multidisciplinary teams (MDTs) are well established worldwide and are an expensive resource yet no standardised tools exist to measure performance. We aimed to develop and test an MDT self-assessment tool underpinned by literature review and consensus from over 2000 UK MDT members about the "characteristics of an effective MDT." METHODS: Questionnaire items relating to all characteristics of MDTs (particularly Leadership and Chairing; Teamworking and Culture; Patient-centred care; Clinical decision-making process; and Organisation and administration during meetings) were developed by an expert panel. Acceptability, feasibility and psychometric properties were tested by online completion of the questionnaire by 23 MDTs from 4 UK NHS Trusts followed by interviews with 74 team members including members from all teams and nonresponders. 10 of the MDTs also completed questionnaires that directly translated each characteristic to an item (for the five domains above) to test content validity. RESULTS: A total of 47 items were created, each rated for agreement on a 5-point scale. A total of 329 (52 %) of 637 team members completed the questionnaire, including representation from medical, nursing and clerical MDT members. Responses correlated well with domain-specific questionnaires (r > 0.67, p = 0.01), most domain-scales had acceptable internal consistency (Cronbach alpha > 0.60), and good item discrimination (majority of items r < 0.20). Team members were positive about its value. CONCLUSIONS: Self-assessment of team performance using this tool may support MDT development. PMID- 22820933 TI - Diversity of P450 enzymes in the biosynthesis of natural products. AB - Diverse oxygenation patterns of natural products generated by secondary metabolic pathways in microorganisms and plants are largely achieved through the tailoring reactions catalysed by cytochrome P450 enzymes (P450s). P450s are a large family of oxidative hemoproteins found in all life forms from prokaryotes to humans. Understanding the reactivity and selectivity of these fascinating C-H bond activating catalysts will advance their use in generating valuable pharmaceuticals and products for medicine, agriculture and industry. A major strength of this P450 group is its set of established enzyme-substrate relationships, the source of the most detailed knowledge on how P450 enzymes work. Engineering microbial-derived P450 enzymes to accommodate alternative substrates and add new functions continues to be an important near- and long-term practical goal driving the structural characterization of these molecules. Understanding the natural evolution of P450 structure-function should accelerate metabolic engineering and directed evolutionary approaches to enhance diversification of natural product structures and other biosynthetic applications. PMID- 22820935 TI - Standards of outcome reporting in surgical oncology: a case study in esophageal cancer. AB - BACKGROUND: Multimodal strategies before surgery are often used to improve outcomes, but disease progression (precluding surgical resection) and inoperability at planned surgery still occur following neoadjuvant treatment. The standards of reporting of these outcomes have not previously been considered. This study examined reporting of rates of progression to surgical resection and inoperability at planned surgery following neoadjuvant treatment in surgical oncology, using esophageal cancer as a case study. METHODS: A systematic review identified randomized trials and prospective nonrandomized studies reporting short-term outcomes of neoadjuvant treatment and surgery for esophageal cancer. RESULTS: Of 4,763 abstracts, 224 papers were retrieved and 76 studies included (8 randomized trials and 68 cohort studies of 19,441 esophagectomies). Articles reported outcomes of preoperative chemotherapy (n = 33, 43.4 %), chemoradiotherapy (n = 13, 17.1 %), or both within one paper (n = 18, 23.7 %) and 12 (15.8 %) did not specify the type of neoadjuvant treatment. Also, 20 papers (26.3 %) reported numbers of patients not progressing to surgery after neoadjuvant treatment (with rates of nonprogression ranging between 2.0 and 35.3 %). In addition, 24 papers (31.6 %) reported rates of inoperability at planned surgery (with inoperability rates ranging between 0 and 26.2 %). More randomized controlled trials (RCTs) than observational studies reported nonprogression (4 randomized and 16 nonrandomized studies, 95 % CI -9.6 to 62.6 %, p = 0.108) and inoperability (6 randomized trials and 18 observational studies, 95 % CI 16.8 80.3 %, p = 0.005). Some 17 and 10 articles provided reasons for the observed rates of nonprogression and inoperability, respectively. CONCLUSIONS: Reporting rates of progression to surgery after neoadjuvant treatment and inoperability at planned surgery for esophageal cancer were poor, limiting data synthesis and comparisons. It is suggested that core outcome sets for trials in surgical oncology are developed with inclusion of these important endpoints. Collaboration between medical and surgical oncologists is necessary to achieve this. PMID- 22820936 TI - Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine tumor usually occurring on sun-exposed skin in elderly patients. Clinical and pathologic factors associated with disease progression and mortality in patients with MCC are poorly defined. Recently, it has been reported that p63 expression in primary MCC is strongly associated with clinical outcome. METHODS: MCC patients diagnosed between July 1, 1993 and July 31, 2009 were identified from the surgical pathology records of the Sydney South West Area Health Service. Clinical, pathologic, treatment, and survival data were obtained and immunohistochemical analyses for p53, p63, and Ki-67 were performed. The associations of clinical and pathologic features with disease-free and disease specific survival were analyzed. RESULTS: Ninety-five patients were identified (67 males, 28 females; median age at diagnosis of primary MCC 76 [range, 42-93] years). Increasing primary tumor thickness was significantly associated with poorer disease-free survival (5-year survival 18 % in tumors >10 mm thick compared with 69 % for patients with tumors <=10 mm thick, p = 0.002) and disease specific survival (5-year survival 74 % in tumors >10 mm thick compared with 97 % for patients with tumors <=10 mm thick, p = 0.006). There was a strong positive correlation between the Ki-67 index (proportion of Ki-67-positive tumor nuclei) and tumor thickness (r = 0.39, n = 45, p = 0.008). Positive staining for p63 in MCC was infrequent (9 % of primary MCC) and showed no significant association with disease outcome. CONCLUSIONS: Tumor thickness is significantly associated with disease-free survival in MCC. We recommend that primary tumor thickness be routinely recorded in the pathology reports of patients with primary MCC. PMID- 22820937 TI - Risk of locoregional recurrence in patients with false-negative frozen section or close margins of retroareolar specimen in nipple-sparing mastectomy. AB - BACKGROUND: Our purpose was to evaluate the locoregional recurrence (LRR) of patients with false-negative, frozen-section or close margins of retroareolar specimen in nipple-sparing mastectomy (NSM) procedure. METHODS: From 2002-2008, we recruited patients who had atypia or presence of cancer cells in definitive histology of retroareolar tissue despite of absence of tumor cell in intraoperative retroareolar frozen section. We also included the close margin cases defined as the presence of tumor cells at the first frozen section, but after deeper core out of retroareolar tissue were revealed free of malignancy. The incidence of LRR and NAC recurrence were reported, and the factors associated were analyzed. RESULTS: Of 948 NSM procedures, there were 88 false-negative, frozen-sections and 10 close margin cases. The 5-year cumulative incidence of LRR and NAC recurrence was 11.2 % (10/98 patients) and 2.4 % (2/98 patients), respectively. Analyzing the definitive results of retroareolar tissue, the 5-year cumulative incidence of LRR was 42.9 % (n = 4) for atypia, 10 % (n = 2) for lobular carcinoma in situ (LCIS), 10 % (n = 1) for close margins, 8.7 % (n = 3) for ductal carcinoma in situ (DCIS), and 0 % for invasive carcinoma. In situ carcinoma as a primary tumor was a significant predictor of NAC recurrence (P < 0.01). CONCLUSIONS: Despite a high reliability of frozen section, there is still a minority of false-negative results. Nevertheless, the LRR is considerably low. This fact suggests the possibility of preservation of the NAC after discussion with the patient. PMID- 22820938 TI - Changing behavior in clinical practice in response to the ACOSOG Z0011 trial: a survey of the American Society of Breast Surgeons. AB - BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in overall survival or local-regional recurrence rates between patients planned for breast conservation therapy including whole breast irradiation (WBI) with one or two positive sentinel lymph nodes (SLNs) randomly selected to undergo axillary lymph node dissection (ALND) versus no further surgery. The current study was undertaken to evaluate the impact of Z0011 on surgical practice nationally. METHODS: A survey was sent by e-mail to 2,759 members of the American Society of Breast Surgeons (ASBrS). Questions assessed the respondents' practice, familiarity with Z0011, and preferences for treating patients with one or two positive SLNs. RESULTS: Of those surveyed, 849 (30.8 %) responded. The majority (97 %) indicated familiarity with the data. Of those respondents, 468 (56.9 %) would not routinely perform ALND in patients planned to receive WBI, while 279 (36.0 %) would consider omission of completion ALND in patients planned to receive accelerated partial breast irradiation (APBI), and 218 (26.6 %) would consider omission of ALND in patients not planned to receive radiation. Academic and private practice surgeons were equally likely to incorporate Z0011 into practice. CONCLUSIONS: ACOSOG Z0011 has changed surgical practice. ASBrS respondents have embraced Z0011 and have changed their practice, omitting ALND in patients with one or two positive SLNs who will undergo WBI. However, many also omit ALND in patients undergoing surgery without radiation or with APBI. As these clinical scenarios were not studied in Z0011, further evaluation is required prior to changing clinical practice. PMID- 22820939 TI - Balancing venous thromboembolism and hematoma after breast surgery. AB - PURPOSE: The purposes of this study are (1) to determine our institution's rate of venous thromboembolic events (VTE) and hematomas following breast surgery, and (2) to compare our breast surgery VTE rate with both our general surgery population and the National surgical quality improvement program (NSQIP) dataset. METHODS: Prospectively collected NSQIP data from April 2006 to June 2010 were analyzed. Our institution's VTE rates, pharmacologic prophylaxis (PCP) utilization, and hematomas were reviewed for patients undergoing breast surgery. The VTE rate was compared with NSQIP patient populations. RESULTS: Among 4,579 breast operations at our institution over this time period, 988 (21.6 %) were analyzed through NSQIP. The VTE rate following breast operations was 4/988 (0.4 %): 0/236 for those with benign disease and 4/752 (0.5 %) for those with breast cancer (p = 0.58). PCP was received by 147/752 (19.5 %) cancer patients. In cancer patients, the hematoma rate requiring reoperation was 3/147 (2.0 %) in those receiving PCP and 12/605 (2.0 %) in those not receiving PCP (p = 1.0). Breast surgery patients had a similar VTE rate compared with the institutional general surgery population (0.7 %, p = 0.254) and versus national general surgery patients from NSQIP (0.7 %, p = 0.29). Our institution's VTE incidence for patients with breast cancer undergoing mastectomy was significantly higher than "like" NSQIP centers. CONCLUSIONS: Our breast surgery VTE rate was similar to our general surgery population. Our mastectomy population had a higher VTE incidence compared with other NSQIP sites. Patients undergoing mastectomy, especially if combined with axillary lymph node dissection or reconstruction, should be considered for routine PCP. PMID- 22820940 TI - Egg production, egg quality and crop content of Rhode Island Red hens grazing on natural tropical vegetation. AB - The aim of this experiment was to study the suitability of the outdoor system for Rhode Island Red hens under the tropical conditions of southern Mexico. Twelve floor pens, each containing four birds, were divided randomly into two groups. The first group was raised indoors only, while each of the second group replicates had access to an outdoor area with natural-grown vegetation from 0800 to 1700 hours daily. Both groups fed ad libitum on a commercial layers diet. The results revealed no differences in body weight between treatments. The outdoor group recorded significantly higher egg laying rate (86.90 vs. 78.05 %), higher egg mass (50.66 vs. 45.30 g egg/hen/day), and higher feed intake (103.70 vs. 97.67 g/day) versus the indoor group. The outdoor group had eggs with darker yellow yolks (9.46 vs. 5.46), lower yolk, and higher albumen proportions (P < 0.05) versus the indoor group. The crop content of the outdoor hens consisted of 86.55 % concentrated feed, 6.30 % plant material, 2.27 % grit stones, 1.69 % snails and oyster shells, 1.25 % seeds, 0.95 % farm wastes, and 0.99 % insects, worms, and larvae. Of the outdoor hens, 43.1 % was observed to be in the range at each scanning time. The outdoor system in the tropics had beneficial effects on Rhode Island Red hen performance, and the hens utilized the outdoor area effectively and obtained various feed items. PMID- 22820941 TI - Effect of timing of artificial insemination after synchronization of ovulation on reproductive performance in Holstein dairy cows. AB - The objective of this study was to determine the effect of timing of artificial insemination on pregnancy rates, calving rates, abortion rates, twinning rates, and calf gender ratio after synchronization of ovulation with Ovsynch protocol in Holstein dairy cows. The ovulation of 219 lactating Holstein dairy cows was synchronized using the Ovsynch protocol. Therefore, cows received an injection of GnRH followed by an injection of prostaglandin F(2alpha) 7 days later and a second treatment with GnRH 2 days later. Cows were artificially inseminated at 0, 12, or 24 h after the second injection of GnRH. Reproductive performance did not differ between cows inseminated at 0 h (n = 82), 12 h (n = 66), or 24 h (n = 71) after the last injection of GnRH (pregnancy rate: 0 h 48 %, 12 h 47 %, 24 h 52 %; abortion rate: 0 h 5 %, 12 h 0 %, 24 h 11 %; calving rate: 0 h 43 %, 12 h 47 %, 24 h 41 %; twinning rate: 0 h 2 %, 12 h 0 %, 24 h 0 %; calf gender ratio (F/M): 0 h 61:39 %, 12 h 48:52 %, 24 h 39:61 %; P > 0.05). Pregnancy rates for cows inseminated in postpartum times of 50-75, 76-100, and >100 days within the first and >= 3 parities were statistically similar (P > 0.05), but pregnancy rates for cows inseminated at different postpartum times of 50-75, 76-100, and >100 days within the second parity were different (P < 0.01). In general, pregnancy rates of cows inseminated at different postpartum times (P < 0.01) and parities (P < 0.001) differed. The findings of the current study showed that rates of pregnancy, abortion, calving, and twinning of Holstein dairy cows subjected to artificial insemination at different times after synchronization were similar. These results also indicate that the timing of artificial insemination after synchronization did not influence calf gender ratio. Furthermore, pregnancy rates of Holstein dairy cows inseminated after synchronization were significantly influenced by postpartum time and parity number. PMID- 22820942 TI - Productivity in different cattle production systems in Kenya. AB - Cattle are kept as an important source of livelihood in many Kenyan farming households whilst also having cultural and social value. A review was undertaken to estimate productivity in the three main Kenyan cattle production systems: small-scale dairy and meat; small-scale dairy; and large-scale dairy and meat. Data on production parameters were collected through a systematic literature search of electronic databases for peer reviewed and grey literature. The parameters included were reproductive rates, mortality rates and yields. Prices for livestock and livestock products were estimated from markets. The data were used to estimate net output from cattle using the Livestock Productivity Efficiency Calculator (LPEC), a deterministic steady state model which measures productivity as net output per megajoule (MJ) of metabolisable energy (ME). The estimated net outputs per livestock unit year(-1) were USD 146.6, USD 215.1 and USD 84.8 in the large-scale dairy and meat, small-scale dairy and meat and small scale dairy systems, respectively. Milk production contributed significantly to net output in all systems and was 91.8 % of total output in small-scale dairy. Cattle sales had the highest contribution to net output in large-scale dairy and meat system (45.1 %). Sensitivity analysis indicated that output was most affected by milk yield, age and weight at maturity and parturition rate. The productivity differences between the production systems call for more detailed research on the constraints to the production systems such as diseases, and to describe the benefits that farmers and society would obtain from disease control and improved management. PMID- 22820943 TI - An involvement of neurokinin-1 receptor in FcepsilonRIota-mediated RBL-2H3 mast cell activation. AB - OBJECTIVE AND DESIGN: To determine whether the neurokinin-1 receptor (NK1R) plays a role in the activation of RBL-2H3 mast cells after FcepsilonRIota aggregation. MATERIALS AND METHODS: NK1R expression in RBL-2H3 cells was inhibited by small hairpin RNA (shRNA) against NK1R, and determined by western blotting. For activation, both NK1R knockdown and control RBL-2H3 cells were sensitized by dinitrophenol (DNP)-specific IgE and stimulated with the antigen DNP-bovine serum albumin (BSA). Following the activation of RBL-2H3 cells, monocyte chemoattractant protein (MCP-1) production and intracellular calcium flux were monitored by ELISA and confocal microscopy assay, respectively. For investigation of the signaling mechanism, phosphorylation of mitogen-activated protein kinases (MAPKs) after RBL-2H3 cell activation was assessed by western blotting. RESULTS: shRNA-NK1R mediated an effective inhibition of NK1R expression in RBL-2H3 cells. Protein production of MCP-1 was reduced by more than 55 % in NK1R knockdown RBL 2H3 cells compared with control RBL-2H3 cells. In addition, both calcium mobilization and phosphorylation levels of MAPKs (Erk1/2, JNK, and p38) after DNP BSA stimulation (via FcepsilonRIota) were decreased due to the inhibition of NK1R expression. CONCLUSION: NK1R is required for the activation of RBL-2H3 cells following FcepsilonRIota engagement and involved in the regulation of MAPK signaling pathways. PMID- 22820944 TI - Overdose of the histamine H3 inverse agonist pitolisant increases thermal pain thresholds. AB - OBJECTIVE AND DESIGN: Pitolisant (BF2.649) is a selective inverse agonist for the histamine H(3) receptor and was developed for the treatment of excessive daytime sleepiness in Parkinson disease, narcolepsy, and schizophrenia. Since H(3) ligands can decrease inflammatory pain, we tested Pitolisant in inflammatory and neuropathic pain models. MATERIALS AND TREATMENTS: Behavioral effects of pitolisant and the structural different H(3) receptor inverse agonists ciproxifan and ST-889 were tested in zymosan-induced inflammation and the spared nerve injury model for neuropathic pain. METHODS: Responses to mechanical and thermal stimuli were determined. Calcium imaging was performed with primary neuronal cultures of dorsal root ganglions. RESULTS: Clinically relevant doses of pitolisant (10 mg/kg) had no relevant effect on mechanical or thermal pain thresholds in all animal models. Higher doses (50 mg/kg) dramatically increased thermal but not mechanical pain thresholds. Neither ciproxifan nor ST-889 altered thermal pain thresholds. In peripheral sensory neurons high concentrations of pitolisant (30-500 MUM), but not ciproxifan, partially inhibited calcium increases induced by capsaicin, a selective activator of transient receptor potential vanilloid receptor 1 (TRPV1). High doses of pitolisant induced a strong hypothermia. CONCLUSION: The data show a dramatic effect of high dosages of pitolisant on the thermosensory system, which appears to be H(3) receptor independent. PMID- 22820945 TI - Noise-mean relationship in mutated promoters. AB - Gene expression depends on the frequency of transcription events (burst frequency) and on the number of mRNA molecules made per event (burst size). Both processes are encoded in promoter sequence, yet their dependence on mutations is poorly understood. Theory suggests that burst size and frequency can be distinguished by monitoring the stochastic variation (noise) in gene expression: Increasing burst size will increase mean expression without changing noise, while increasing burst frequency will increase mean expression and decrease noise. To reveal principles by which promoter sequence regulates burst size and frequency, we randomly mutated 22 yeast promoters chosen to span a range of expression and noise levels, generating libraries of hundreds of sequence variants. In each library, mean expression (m) and noise (coefficient of variation, eta) varied together, defining a scaling curve: eta(2) = b/m + eta(ext)(2). This relation is expected if sequence mutations modulate burst frequency primarily. The estimated burst size (b) differed between promoters, being higher in promoter containing a TATA box and lacking a nucleosome-free region. The rare variants that significantly decreased b were explained by mutations in TATA, or by an insertion of an out-of-frame translation start site. The decrease in burst size due to mutations in TATA was promoter-dependent, but independent of other mutations. These TATA box mutations also modulated the responsiveness of gene expression to changing conditions. Our results suggest that burst size is a promoter-specific property that is relatively robust to sequence mutations but is strongly dependent on the interaction between the TATA box and promoter nucleosomes. PMID- 22820946 TI - Sister chromatid interactions in bacteria revealed by a site-specific recombination assay. AB - The process of Sister Chromosome Cohesion (SCC), which holds together sister chromatids upon replication, is essential for chromosome segregation and DNA repair in eukaryotic cells. Although cohesion at the molecular level has never been described in E. coli, previous studies have reported that sister sequences remain co-localized for a period after their replication. Here, we have developed a new genetic recombination assay that probes the ability of newly replicated chromosome loci to interact physically. We show that Sister Chromatid Interaction (SCI) occurs exclusively within a limited time frame after replication. Importantly, we could differentiate sister cohesion and co-localization since factors such as MatP and MukB that reduced the co-localization of markers had no effect on molecular cohesion. The frequency of sister chromatid interactions were modulated by the activity of Topo-IV, revealing that DNA topology modulates cohesion at the molecular scale in bacteria. PMID- 22820948 TI - High-throughput analysis of therapeutic and diagnostic monoclonal antibodies by multicapillary SDS gel electrophoresis in conjunction with covalent fluorescent labeling. AB - Capillary gel electrophoresis (CGE) in the presence of sodium dodecyl sulfate (SDS) is a well-established and widely used protein analysis technique in the biotechnology industry, and increasingly becoming the method of choice that meets the requirements of the standards of International Conference of Harmonization (ICH). Automated single channel capillary electrophoresis systems are usually equipped with UV absorbance and/or laser-induced fluorescent (LIF) detection options offering general applicability and high detection sensitivity, respectively; however, with limited throughput. This shortcoming is addressed by the use of multicapillary gel electrophoresis (mCGE) systems with LED-induced fluorescent detection (LED-IF), also featuring automation and excellent detection sensitivity, thus widely applicable to rapid and large-scale analysis of biotherapeutics, especially monoclonal antibodies (mAb). The methodology we report in this paper is readily applicable for rapid purity assessment and subunit characterization of IgG molecules including detection of non-glycosylated heavy chains (NGHC) and separation of possible subunit variations such as truncated light chains (Pre-LC) or alternative splice variants. Covalent fluorophore derivatization and the mCGE analysis of the labeled IgG samples with multi-capillary gel electrophoresis are thoroughly described. Reducing and non reducing conditions were both applied with and without peptide N-glycosidase F mediated deglycosylation. PMID- 22820947 TI - An N-terminal acidic region of Sgs1 interacts with Rpa70 and recruits Rad53 kinase to stalled forks. AB - DNA replication fork stalling poses a major threat to genome stability. This is counteracted in part by the intra-S phase checkpoint, which stabilizes arrested replication machinery, prevents cell-cycle progression and promotes DNA repair. The checkpoint kinase Mec1/ATR and RecQ helicase Sgs1/BLM contribute synergistically to fork maintenance on hydroxyurea (HU). Both enzymes interact with replication protein A (RPA). We identified and deleted the major interaction sites on Sgs1 for Rpa70, generating a mutant called sgs1-r1. In contrast to a helicase-dead mutant of Sgs1, sgs1-r1 did not significantly reduce recovery of DNA polymerase alpha at HU-arrested replication forks. However, the Sgs1 R1 domain is a target of Mec1 kinase, deletion of which compromises Rad53 activation on HU. Full activation of Rad53 is achieved through phosphorylation of the Sgs1 R1 domain by Mec1, which promotes Sgs1 binding to the FHA1 domain of Rad53 with high affinity. We propose that the recruitment of Rad53 by phosphorylated Sgs1 promotes the replication checkpoint response on HU. Loss of the R1 domain increases lethality selectively in cells lacking Mus81, Slx4, Slx5 or Slx8. PMID- 22820949 TI - Study of 1,4-naphthoquinone as a new useful derivatization reagent for LC analysis of aliphatic thiols in dietary supplements and pharmaceuticals. AB - The use of 1,4-naphthoquinone as an advantageous pre-column reagent for liquid chromatography analysis of aliphatic thiol compounds is proposed. The compound reacts selectively in mild conditions (5 min at room temperature; pH 7.5) with thiol function. The resulting adducts were separated under isocratic conditions by using a reversed-phase column (C-12n) with a mobile phase corresponding to methanol/triethylammonium phosphate buffer (pH 3; 0.05 mol L(-1)) 65:35, v/v, at a flow rate of 0.4 mL min(-1) in presence of quercetin as internal standard. Detection was set at a wavelength of 420 nm. The effect of the derivatization reaction conditions on the N-acetylcysteine (NAC) reaction yield was investigated by a series of experiments. The yield of NAC derivative was found to be quantitative at a reagent thiol molar ratio of about 3 by comparison with an authentic specimen of synthesized NAC adduct, which was characterized by (1) H NMR, IR, and UV. Similar linear responses were observed by standard and placebo solutions (determination coefficient, 0.9998). The within- and between-day standard deviations (RSD) were <=0.47 %. Recovery studies showed good results (100.03 %) with RSD 0.76 %. The limit of detection was about 20 pmol. The utility of the validated method for the determination of NAC in a new dietary supplement and commercial formulations is demonstrated. PMID- 22820950 TI - An electrochemical sensor for rapid determination of ractopamine based on a molecularly imprinted electrosynthesized o-aminothiophenol film. AB - A simple electrochemical sensor based on a molecularly imprinted polymer film as the recognition element was developed for ractopamine (RAC) detection. This is the first report of a RAC-imprinted film on a gold electrode surface, synthesized through an electrochemical method using o-aminothiophenol as the functional monomer. The imprinting mechanism and experimental parameters affecting the capability of the imprinted film are discussed here. The sensor was successfully applied with constant potential amperometry for RAC detection in an indirect process with potassium ferricyanide as an electrochemical probe. The sensor had a rapid equilibrium time (120 s), high binding affinity and selectivity towards RAC, and with good reproducibility and stability. Under the experimental conditions applied, a linear relationship between the relative amperometric response and RAC ranged from 2.0 * 10(-7) to 1.4 * 10(-6) mol L(-1), with a lower limit of detection (LOD) of 2.38 * 10(-8) mol L(-1) (signal to noise ratio = 3). The sensor was tested with feed samples spiked with trace amounts of RAC, with good recoveries between 87.4 and 90.5 %. PMID- 22820951 TI - Multi-oriented moire superstructures of graphene on Ir(111): experimental observations and theoretical models. AB - Six types of moire superstructures of graphene on Ir(111) with different orientations (labeled as R0, R14, R19, R23, R26 and R30) are investigated by low energy electron diffraction, scanning tunneling microscopy and first-principles calculations. The moire superstructure of R0 graphene has remarkable diffraction spots and deeper corrugation than that of the other superstructures. A high-order commensurate (HOC) method is applied to produce a list of all possible graphene moire superstructures on Ir(111). Several useful structural data including the precise matrices of the moire patterns are revealed. Density functional theory based first-principles calculations that include van der Waals interactions reveal the differences of the geometric environment and electronic structures of carbon atoms with respect to the underlying Ir(111) lattices for all the observed moire patterns. The further calculations of electronic properties at the graphene Ir interfaces show that the electron transfers for all superstructures are small and of the same order of magnitude, which demonstrates a weak interaction between graphene and the Ir(111) substrate, leading to the coexistence of multi-oriented moire superstructures. PMID- 22820952 TI - The use of antibiotic-impregnated fibrin sealant for the prevention of surgical site infection associated with spinal instrumentation. AB - PURPOSE: The purpose of this study was to determine if the use of antibiotic impregnated fibrin sealant (AFS) was effective in preventing surgical site infections (SSI) associated with spinal instrumentation. METHODS: In a preliminary study, five pieces of vancomycin-impregnated fibrin sealant, five nuts that were not treated with the sealant, and five nuts that were treated with the sealant were subjected to agar diffusion testing. In a clinical study, the rates of deep SSI were compared between 188 patients who underwent procedures involving spinal instrumentation without AFS (group 1) and 196 patients who underwent procedures involving spinal instrumentation with AFS (group 2). RESULTS: All five pieces of vancomycin-impregnated fibrin sealant and the five nuts treated with the sealant exhibited antimicrobial efficacy, while the five untreated nuts did not exhibit antimicrobial efficacy in the agar diffusion test. In the clinical study, 11 (5.8 %) of the 188 patients in group 1 acquired a deep SSI, while none (0 %) of the 196 patients in group 2 acquired a deep SSI. CONCLUSION: The present study demonstrated that the application of AFS to spinal instrumentation yielded good clinical outcomes in terms of the prevention of postoperative spinal infections. It is hoped that limiting AFS use to patients requiring spinal instrumentation and those with risk factors for SSI will reduce the overall costs while preventing SSIs. PMID- 22820953 TI - Effects of electroconvulsive therapy on brain functional activation and connectivity in depression. AB - OBJECTIVE: Past neuroimaging work has suggested that increased activation to cognitive and emotional tasks and decreased connectivity in frontal regions are related to cognitive inefficiency in depression; normalization of these relationships has been associated with successful treatment. The present study investigated brain function before and after electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD) and demonstrated the effect of treatment on cortical activation patterns. METHODS: Six ECT-naive patients with depression (mean +/- SD age, 39.0 +/- 5.4 years) were treated with ECT. Within 1 week before and 1 to 3 weeks after ECT, the patients underwent a magnetic resonance imaging session with functional magnetic resonance image scanning during working memory and affective tasks and during rest. Changes in voxelwise statistical maps of brain response to each task in regions identified to be relevant from past studies of depression were compared with changes in depression severity as measured by the Hamilton Depression Rating Score. Changes in functional connectivity between brain regions were also compared with changes in depression severity. RESULTS: Activation during both tasks was generally found to be decreased after ECT. Remission of depression was significantly associated with reduced affective deactivation after ECT in the orbitofrontal cortex (P = 0.03). Whole-brain functional connectivity of the anterior cingulate cortex showed a consistent increase in connectivity to the right dorsolateral prefrontal cortex and posterior cingulate cortex after ECT. CONCLUSIONS: These results suggest that successful ECT for MDD is associated with decreased activation to cognitive and emotional tasks and an increase in resting connectivity. PMID- 22820954 TI - Tuning the magnetic and transport properties of metal adsorbed graphene by co adsorption with 1,2-dichlorobenzene. AB - A fundamental understanding of the properties of various metal/graphene nanostructures is of great importance for realising their potential applications in electronics and spintronics. The electronic and magnetic properties of three metal/graphene adducts (metal = Li, Co or Fe) are investigated using first principles calculation. It is predicated that the metal/graphene adducts have strong affinity to aromatic molecule 1,2-dichlorobenzene (DCB), and the resultant DCB-metal/graphene sandwich structures are much more stable than the simple DCB/graphene adduct. Importantly, it is found that the adsorption of DCB slightly enhances the magnetic moment of the Co/graphene, but turns the Fe/graphene from magnetic to nonmagnetic. A detailed theoretical explanation of the different magnetic properties of the DCB/Co/graphene and DCB/Fe/graphene is achieved based on their different d-band splitting upon DCB adsorption. In addition, the transport property study indicates that the Fe/graphene is a better sensing material for DCB than the pristine graphene. PMID- 22820955 TI - Obesity and treatment meanings in bariatric surgery candidates: a qualitative study. AB - BACKGROUND: This study used a qualitative approach to comprehend how the morbid obese conceptualize and deal with obesity and obesity treatment, with the particular aim of exploring the expectations and beliefs about the exigencies and the impact of bariatric surgery. METHODS: The study population included 30 morbid obese patients (20 women and 10 men) with a mean age of 39.17 years (SD = 8.81) and a mean body mass index of 47.5 (SD = 8.2) (reviewer #2, comment #9) interviewed individually before surgery using open-ended questions. The interviews were audiotaped, transcribed, and then coded according to grounded analysis methodology. RESULTS: Three main thematic areas emerged from the data: obesity, eating behavior, and treatment. Obesity is described as a stable and hereditary trait. Although participants recognize that personal eating behavior exacerbates this condition, patients see their eating behavior as difficult to change and control. Food seems to be an ever-present dimension and a coping strategy, and to follow an adequate diet plan is described as a huge sacrifice. Bariatric surgery emerges as the only treatment for obesity, and participants highlight this moment as the beginning of a new life where health professionals have the main role. Bariatric surgery candidates see their eating behavior as out of their control, and to commit to its demands is seen as a big sacrifice. For these patients, surgery is understood as a miracle moment that will change their lives without requiring an active role or their participation. CONCLUSION: According to these results, it is necessary to validate them with qualitative and quantitative studies (reviewer #2, comment #3); it is necessary to promote a new awareness of the weight loss process and to empower patients before and after bariatric surgery. PMID- 22820957 TI - Patient safety: it is in our hands. PMID- 22820956 TI - Hematological variables and iron status in abdominoplasty after bariatric surgery. AB - BACKGROUND: Abdominoplasty, the treatment for abdominal wall deformity stemming from weight loss after bariatric surgery, can cause postoperative anemia. Moreover, bariatric surgery has been associated with iron deficiency, which by itself can compromise erythropoiesis. The objective of this research is to describe the development of anemia after postbariatric abdominoplasty. METHODS: The study group consisted of 32 adult women who had received bariatric surgery. Treatment group included 20 patients who were undergoing postbariatric abdominoplasty. Control group included 12 patients waiting for abdominoplasty. Values of hemoglobin, reticulocytes, iron, ferritin, and the transferrin saturation were obtained on the evening before abdominoplasty and during the first, fourth, and eighth postoperative weeks. Hemoglobin was measured at 48 h. RESULTS: Mean hemoglobin levels for treatment group decreased from 12.98 to 10.8 g/dL after 48 h, increased on day 7 to 11.53 g/dL, but did not increase further after day 7. The reticulocyte number increased in the first week. Serum iron and transferrin saturation index fell during the first week and remained low. Ferritin levels increased non-significantly from 29.77 to 37.24 ng/mL at week 1, then fell until they were decreased (16.44 ng/mL) by day 56. CONCLUSIONS: As expected, hemoglobin fell after abdominoplasty. However, after a one-third recovery of hemoglobin concentrations by week 1 postoperative, they failed to return to preoperative levels by the eighth week. Additionally, by the eighth postoperative week, 45 % of abdominoplasty patients had developed an iron deficiency and hemoglobin deficit that was higher than that of patients who maintained normal iron stocks. PMID- 22820961 TI - 3-day payment window policy q & a. PMID- 22820963 TI - Diagnosis and treatment of hand dermatitis. AB - PURPOSE: To enhance the learner's competence with knowledge of hand dermatitis. TARGET AUDIENCE: : This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: 1. Demonstrate knowledge of the pathophysiology and assessment of, and diagnostic testing for, hand dermatitis. 2. Apply knowledge of hand dermatitis to patient care scenarios for treatment recommendations and patient education. Hand dermatitis is a common disorder with different clinical presentations. Contact (irritant and allergic) dermatitis is the most common subtype with atopic dermatitis and dyshidrotic eczema as common differential diagnoses. The exact diagnosis and differential diagnoses (psoriasis, fungal infections) are important for specific investigations and treatment plans. PMID- 22820965 TI - Smart workflows support compliance. PMID- 22820962 TI - Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery. AB - This is the second of 2 articles that discuss the biology and pathophysiology of wound healing, reviewing the role that growth factors play in this process and describing the current methods for growth factor delivery into the wound bed. PMID- 22820966 TI - Quantitative assessment of the "inexplicability" of fibromyalgia patients: a pilot study of the fibromyalgia narrative of "medically unexplained" pain. AB - The purpose of this study was to quantify the degree to which fibromyalgia patients perceive the cause of their pain to be inexplicable or difficult to understand. The author developed two simple Likert scales, Understand Pain Scale and Explain Pain Scale, which ask the subject to indicate the degree to which they are able to, respectively, understand the cause of their pain and to explain the cause of their pain to others. A total of 104 subjects who met the 1990 American College of Rheumatology Diagnostic Criteria for fibromyalgia (FM group), and 272 subjects with widespread pain who did not meet these criteria (non-FM group) completed these two instruments. On the Understand Pain Scale, 67.3 % of FM subjects endorsed either the item "understand very little about the cause of my pain (the reason I have pain)" or "cannot understand at all the cause of my pain (the reason I have pain)". By comparison, 16.2 % of the non-FM group with widespread pain endorsed either of these Understand Pain Scale items. On the Explain Scale, 84.6 % of fibromyalgia subjects endorsed either the item "can very little or not very often explain the cause of my pain (the reason I have pain) to others" or "cannot at all explain the cause of my pain (the reason I have pain) to others". In contrast, 21.7 % of non-FM group subjects with widespread pain endorsed either of the aforementioned items. Compared to other patients with chronic, widespread pain, fibromyalgia patients report a much greater degree of difficulty in understanding the cause of their pain and explaining the cause of their pain to others. This phenomenon may reflect the narrative of "inexplicability" in fibromyalgia patients that distinguishes them from other widespread pain populations. PMID- 22820968 TI - Genetic counseling, activism and 'genotype-first' diagnosis of developmental disorders. AB - This paper presents a sociological examination of the role of genetic counselors as advocates, not only for patients and their families, but also for genetic conditions themselves. In becoming activists for new disorders, genetic counselors are helping to create new categories that will shape expectations and treatment regimens for both existing patients and those who are yet to be diagnosed. By virtue of their expertise and their position at the intersection of several key professions and constituencies, genetic counselors are likely to play a central role in the way the genetic testing technologies, and especially 'genotype-first' diagnosis, impacts the way we understand and categorize developmental difference. I outline some of the promises and dangers that this kind of activism holds for people with developmental disabilities, and particularly the challenge presented by systemic ascertainment bias in the face of genotype-phenotype uncertainty. I argue that new testing techniques like microarray analysis that do not need to be targeted on the basis of clinical presentation throw these challenges into sharp relief, and that the genetic counseling community should consider how to marry advocacy for new genetic conditions with an emphasis on the indeterminate developmental potential of every child. PMID- 22820967 TI - Systematic review of the literature and a case report informing biopsy-proven giant cell arteritis (GCA) with normal C-reactive protein. AB - Giant cell arteritis (GCA) is a vasculitis of large- vessels. A markedly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are characteristics of GCA, although temporal artery biopsy remains the gold standard for the diagnosis. We describe a case of biopsy-proven GCA showing a heavy infiltration of CD68 macrophages and CD3 T cells and with normal ESR and CRP levels at diagnosis. Key points (1) GCA may occur with normal ESR in a percentage of about 4 to 15 % (although the American College of Rheumatology classification criteria for giant cell arteritis include an ESR of 50 mm/h or more), while it can occur with normal ESR and normal CRP in a percentage of about 0.8 %. So, the clinical suspicion must be confirmed with a positive biopsy. (2) GCA patients with ESR >40 mm/h are characterized by higher incidence of headache and jaw claudication compared to patients with normal ESR. In our case, it occurred with normal ESR. (3) Color duplex ultrasonography is a noninvasive, easy, and inexpensive method for supporting a diagnosis of TA, with a high sensitivity and specificity. It can predict which patient will need TAB. PMID- 22820969 TI - Identifying loci influencing grain number by microsatellite screening in bread wheat (Triticum aestivum L.). AB - Grain number (GN) is one of three major yield-related components in wheat. We used the Chinese wheat mini core collection to undertake a genome-wide association analysis of grain number using 531 SSR markers randomly located on all 21 chromosomes. Grain numbers of all accessions were measured in four trials, i.e. two environments in four growing seasons. Association analysis based on a mixed linear model (MLM) revealed that 27 SSR loci were significantly associated with mean GN (MGN) estimated by the best linear unbiased predictor (BLUP) method. These included numerous breeder favorable alleles with strong positive effects at 23 loci. Significant or extremely significant differences were detected on MGN between varieties conveying favored allele and varieties with other alleles. Moreover, statistical simulation showed that the favored alleles have additive genetic effects. Although modern varieties combined larger numbers of favored alleles, the numbers of favored alleles were not significantly different from those in landraces, especially those alleles contributing mostly to the phenotypic variation. These results indicate that there is still considerable genetic potential for use of markers for genome selection of GN for high yield in wheat. PMID- 22820970 TI - Use of targeted therapy for refractory ALK-positive anaplastic large cell lymphoma as a bridging strategy prior to allogeneic transplantation. PMID- 22820971 TI - Fractionated doses of gemtuzumab ozogamicin combined with 3 + 7 induction chemotherapy as salvage treatment for young patients with acute myeloid leukemia in first relapse. AB - Current salvage therapies for relapsed acute myeloid leukemia (AML) are unsatisfactory. We retrospectively evaluated the efficacy and toxicity of fractionated doses of gemtuzumab ozogamicin (GO) combined with a standard 3 + 7 induction regimen in young patients with AML in first relapse. Salvage regimen consisted of GO 3 mg/m2 on days 1, 4, and 7; cytarabine, 200 mg/m2 on days 1-7; and daunorubicine, 60 mg/m2; or idarubicine, 12 mg/m2 on days 1-3. Fourteen patients were treated between April 2008 and April 2011. Median age was 46 years (29-58), median white blood cell count is 3.4 109/L (0.9-19), and median first complete remission (CR) duration is 11 months (1-42). All the patients had previously received high or intermediate doses of cytarabine as consolidation therapy. Salvage treatment was performed as scheduled for the 14 patients, using daunorubicine in 12 patients and idarubicine in two. Overall response rate was 79 % with six CR and five CR with incomplete platelet recovery. Median times to neutrophil (>0.5 109/L) and platelet (>20 109/L) recovery were 29 days (23-32) and 36 days (28-48), respectively. Allogeneic transplantation was performed in the 11 responding patients within a median time of 4 months (3-10). Three mild and one moderate veno-occlusive disease (VOD) occurred after salvage and two moderate VOD after transplantation. Median and 2-year overall survival (OS) were 10 months and 42 %, respectively. For responders, estimated 2-year OS was 53 % (median OS not reached). This salvage regimen seems safe and effective in younger patients with AML in first relapse allowing allogeneic transplantation in CR2 for most patients. PMID- 22820972 TI - Genetic services and testing in the Philippines. PMID- 22820973 TI - Factors influencing the health care expenditures of patients with laryngeal disorders. AB - OBJECTIVE: To identify factors related to the health care spending of patients with laryngeal disorders. STUDY DESIGN AND SETTING: Retrospective analysis of data from a large, nationally representative administrative US claims database. SUBJECTS AND METHODS: Patients with a laryngeal disorder based on International Classification of Diseases, Ninth Revision, Clinical Modification codes from January 1, 2004, to December 31, 2008, and who were continuously enrolled for 12 months were included. Age, sex, comorbidity, geography, provider type, visit type, and type of laryngeal pathology were collected. To identify which factors were related to the direct costs, a generalized linear regression with gamma distribution was used. RESULTS: Of almost 55 million individuals in the database, 309,300 patients with a laryngeal disorder and 12 months of follow-up data were identified (mean [SD] age, 47.3 [21.3] years; 63.5% female). Age, sex, geographic region, number of comorbid conditions, type of provider, visit type, and laryngeal pathology were significantly associated with the health care expenditures (all P values <.05). Costs increased with increasing age and were greater for male patients, higher in the South and Northeast compared with the West and North-central regions, greater in 2008 compared with 2004, higher for inpatient compared with outpatient care, higher with increasing number of comorbid conditions, and lower if a patient was treated by a primary care physician only. Among the various laryngeal pathologies, the greatest direct costs were for laryngeal cancer and patients with multiple diagnoses. CONCLUSION: This study identified multiple factors associated with the health care expenditures of patients with laryngeal disorders. PMID- 22820974 TI - Superhydrophobic-superhydrophilic binary micropatterns by localized thermal treatment of polyhedral oligomeric silsesquioxane (POSS)-silica films. AB - Surfaces patterned with alternating (binary) superhydrophobic-superhydrophilic regions can be found naturally, offering a bio-inspired template for efficient fluid collection and management technologies. We describe a simple wet processing, thermal treatment method to produce such patterns, starting with inherently superhydrophobic polysilsesquioxane-silica composite coatings prepared by spray casting nanoparticle dispersions. Such coatings become superhydrophilic after localized thermal treatment by means of laser irradiation or open-air flame exposure. When laser processed, the films are patternable down to ~100 MUm scales. The dispersions consist of hydrophobic fumed silica (HFS) and methylsilsesquioxane resin, which are dispersed in isopropanol and deposited onto various substrates (glass, quartz, aluminum, copper, and stainless steel). The coatings are characterized by advancing, receding, and sessile contact angle measurements before and after thermal treatment to delineate the effects of HFS filler concentration and thermal treatment on coating wettability. SEM, XPS and TGA measurements reveal the effects of thermal treatment on surface chemistry and texture. The thermally induced wettability shift from superhydrophobic to superhydrophilic is interpreted with the Cassie-Baxter wetting theory. Several micropatterned wettability surfaces demonstrate potential in pool boiling heat transfer enhancement, capillarity-driven liquid transport in open surface-tension confined channels (e.g., lab-on-a-chip), and select surface coating applications relying on wettability gradients. Advantages of the present approach include the inherent stability and inertness of the organosilane-based coatings, which can be applied on many types of surfaces (glass, metals, etc.) with ease. The present method is also scalable to large areas, thus being attractive for industrial coating applications. PMID- 22820975 TI - Stability-improved organic n-channel thin-film transistors with nm-thin hydrophobic polymer-coated high-k dielectrics. AB - We report on the fabrication of N,N'-ditridecyl-perylene-3,4:9,10-tetracarboxylic diimide-C13 (PTCDI-C13), n-channel organic thin-film transistors (OTFTs) with 30 nm Al(2)O(3) whose surface has been un-modified or modified with hexamethyldisilazane (HMDS) and thin hydrophobic CYTOP. Among all the devices, the OTFTs with CYTOP-modified dielectrics exhibit the most superior device performance and stability. The optimum post-annealing temperature for organic n channels on CYTOP was also found to be as low as 80 degrees C, although the post annealing was previously implemented at 120-140 degrees C for PTCDI domain growth in general. The low temperature of 80 degrees C hardly damages the CYTOP/n-channel organic interface which is deformed at a temperature higher than the glass transition temperature of CYTOP (~110 degrees C). The pentacenequinone passivation layer turned out to be helpful to keep the interfacial trap density minimum, according to the photo-excited charge collection spectroscopy results for our 80 degrees C-annealed OTFTs with CYTOP-modified dielectrics. PMID- 22820976 TI - ASCCP, moving forward. PMID- 22820979 TI - New guidelines on cervical cancer screening: more than just the end of annual Pap testing. PMID- 22820981 TI - Performance of combination drug and hygroscopic excipient submicrometer particles from a softmist inhaler in a characteristic model of the airways. AB - Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs. Both in vitro results and CFD simulations were in close agreement and indicated that EEG delivery of combination submicrometer particles could nearly eliminate MT deposition for inhaled pharmaceutical aerosols. Compared with current inhalers, the proposed delivery approach represents a 1-2 order of magnitude reduction in MT deposition. Transient inhalation was found to influence the final size of the aerosol based on changes in residence times and relative humidity values. Aerosol sizes following EEG when exiting the chamber (2.75-4.61 MUm) for all cases of initial submicrometer combination particles were equivalent to or larger than many conventional pharmaceutical aerosols that frequently have MMADs in the range of 2 3 MUm. PMID- 22820982 TI - Finite element strategies to satisfy clinical and engineering requirements in the field of percutaneous valves. AB - Finite element (FE) modelling can be a very resourceful tool in the field of cardiovascular devices. To ensure result reliability, FE models must be validated experimentally against physical data. Their clinical application (e.g., patients' suitability, morphological evaluation) also requires fast simulation process and access to results, while engineering applications need highly accurate results. This study shows how FE models with different mesh discretisations can suit clinical and engineering requirements for studying a novel device designed for percutaneous valve implantation. Following sensitivity analysis and experimental characterisation of the materials, the stent-graft was first studied in a simplified geometry (i.e., compliant cylinder) and validated against in vitro data, and then in a patient-specific implantation site (i.e., distensible right ventricular outflow tract). Different meshing strategies using solid, beam and shell elements were tested. Results showed excellent agreement between computational and experimental data in the simplified implantation site. Beam elements were found to be convenient for clinical applications, providing reliable results in less than one hour in a patient-specific anatomical model. Solid elements remain the FE choice for engineering applications, albeit more computationally expensive (>100 times). This work also showed how information on device mechanical behaviour differs when acquired in a simplified model as opposed to a patient-specific model. PMID- 22820980 TI - The Lower Anogenital Squamous Terminology Standardization Project for HPV Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. AB - The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care. PMID- 22820983 TI - Dynamic properties of human tympanic membrane based on frequency-temperature superposition. AB - The human tympanic membrane (TM) transfers sound in the ear canal into the mechanical vibration of the ossicles in the middle ear. The dynamic properties of TM directly affect the middle ear transfer function. The static or quasi-static mechanical properties of TM were reported in the literature, but the dynamic properties of TM over the auditory frequency range are very limited. In this paper, a new method was developed to measure the dynamic properties of human TM using the Dynamic-Mechanical Analyzer (DMA). The test was conducted at the frequency range of 1-40 Hz at three different temperatures: 5, 25, and 37 degrees C. The frequency-temperature superposition was applied to extend the testing frequency range to a much higher level (at least 3800 Hz). The generalized linear solid model was employed to describe the constitutive relation of the TM. The storage modulus E' and the loss modulus E" were obtained from 11 specimens. The mean storage modulus was 15.1 MPa at 1 Hz and 27.6 MPa at 3800 Hz. The mean loss modulus was 0.28 MPa at 1 Hz and 4.1 MPa at 3800 Hz. The results show that the frequency-temperature superposition is a feasible approach to study the dynamic properties of the ear soft tissues. The dynamic properties of human TM obtained in this study provide a better description of the damping behavior of ear tissues. The properties can be transferred into the finite element model of the human ear to replace the Rayleigh type damping. The data reported here contribute to the biomechanics of the middle ear and improve the accuracy of the FE model for the human ear. PMID- 22820984 TI - Free fatty acid derivative HUHS2002 potentiates alpha7 ACh receptor responses through indirect activation of CaMKII. AB - The present study examined the effect of 4-[4-(Z)-hept-1-enyl-phenoxy] butyric acid (HUHS2002), a free fatty acid derivative, on alpha7 acetylcholine (ACh) receptor responses. HUHS2002 potentiated whole-cell membrane currents through alpha7 ACh receptors expressed in Xenopus oocytes in a concentration (1-100 nM) dependent manner, reaching about 140 % of the original amplitude at 100 nM 50 min after a 10-min treatment. The HUHS2002 effect was prevented by KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), while it was not affected by GF109203X, an inhibitor of protein kinase C (PKC), or H-89, an inhibitor of protein kinase A (PKA). In the in situ CaMKII assay using cultured rat hippocampal neurons, HUHS2002 activated CaMKII and the activation was abolished by KN-93. In the cell-free assay of protein phosphatase 1 (PP1), HUHS2002 partially inhibited PP1 activity. Taken together, these results indicate that HUHS2002 potentiates alpha7 ACh receptor responses by indirectly activating CaMKII, possibly via inhibition of PP1. PMID- 22820985 TI - The physics of epitaxial graphene on SiC(0001). AB - Various physical properties of epitaxial graphene grown on SiC(0001) are studied. First, the electronic transport in epitaxial bilayer graphene on SiC(0001) and quasi-free-standing bilayer graphene on SiC(0001) is investigated. The dependences of the resistance and the polarity of the Hall resistance at zero gate voltage on the top-gate voltage show that the carrier types are electron and hole, respectively. The mobility evaluated at various carrier densities indicates that the quasi-free-standing bilayer graphene shows higher mobility than the epitaxial bilayer graphene when they are compared at the same carrier density. The difference in mobility is thought to come from the domain size of the graphene sheet formed. To clarify a guiding principle for controlling graphene quality, the mechanism of epitaxial graphene growth is also studied theoretically. It is found that a new graphene sheet grows from the interface between the old graphene sheets and the SiC substrate. Further studies on the energetics reveal the importance of the role of the step on the SiC surface. A first-principles calculation unequivocally shows that the C prefers to release from the step edge and to aggregate as graphene nuclei along the step edge rather than be left on the terrace. It is also shown that the edges of the existing graphene more preferentially absorb the isolated C atoms. For some annealing conditions, experiments can also provide graphene islands on SiC(0001) surfaces. The atomic structures are studied theoretically together with their growth mechanism. The proposed embedded island structures actually act as a graphene island electronically, and those with zigzag edges have a magnetoelectric effect. Finally, the thermoelectric properties of graphene are theoretically examined. The results indicate that reducing the carrier scattering suppresses the thermoelectric power and enhances the thermoelectric figure of merit. The fine control of the Fermi energy position is thought to be key for the practical use of graphene as a thermoelectric material, which could be achieved with epitaxial graphene. All of these results reveal that epitaxial graphene is physically interesting. PMID- 22820986 TI - Gliomatosis peritonei is associated with frequent recurrence, but does not affect overall survival in patients with ovarian immature teratoma. AB - Gliomatosis peritonei (GP) is commonly associated with ovarian teratoma and is not thought to have an adverse prognostic effect. However, the prognostic impact and characteristics of GP remain to be clarified. In this study, we investigated the clinicopathologic features of ovarian teratoma associated with GP, and we further compared ovarian immature teratoma (IT) with GP to ovarian IT without GP. During the study period, there were a total of 16 ovarian teratomas associated with GP. Among them, 15 cases were ovarian ITs of various grades. When ovarian IT with GP (n = 15) was compared to ovarian IT without GP (n = 27), it was found that ovarian IT patients with GP had larger tumor size (median, 19 vs. 13 cm; P < 0.001), more frequent recurrence (40 %, 6/15 vs. 3.7 %, 1/27; P = 0.005), and frequently elevated preoperative CA-125 level (100 %, 12/12 vs. 50 %, 10/20; P = 0.004). All recurrences occurred within 2 years of the initial surgery. Survival curves indicated that ovarian IT patients with GP had significantly shorter recurrence-free survival compared to those without GP (P = 0.002). The 2-year recurrence-free survival rates were 59.3 and 96.3 % in IT with GP and IT without GP, respectively. However, all but one case of IT with GP are currently alive. In conclusion, GP is an adverse prognostic factor characterized by frequent recurrence in patients with ovarian IT. PMID- 22820987 TI - BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression. AB - BRCA1 mutations have been associated with hereditary breast cancer only. Recent studies indicate that a subgroup of sporadic breast cancer might also be associated with reduction in BRCA1 mRNA levels and protein expression. However, the mechanism of reduced mRNA and protein expression is yet not fully elucidated. This study aims to assess BRCA1 protein expression and the role of BRCA1 promoter methylation in sporadic breast cancer in North Indian population and to correlate these with known prognostic factors and molecular profiles of breast cancer. BRCA1 protein expression was normal (>50 % tumour cells) in 41 (43 %) cases, reduced (20-50 % tumour cells) in 33 (35 %) cases and absent/markedly reduced (<20 % tumour cells) in 21 (22.1 %) cases. Cases which were negative for BRCA1 protein were more frequently positive for basal markers (29 versus 5 %) and were more often ER-negative (62 versus 39 %) than BRCA1-positive tumours. Methylation of BRCA1 promoter region was seen in 11/45 cases (24 %). All 11 cases showing BRCA1 methylation had absent (eight cases) or reduced (three cases) BRCA1 protein expression. BRCA1 protein-negative tumours were more frequently basal marker positive and ER-negative, highlighting the 'BRCAness' of sporadic breast cancer with loss of BRCA1 protein expression through promoter hypermethylation similar to hereditary breast cancer with BRCA1 mutations. Loss of BRCA1 in sporadic breast cancer suggests that therapeutics targeting BRCA1 pathway in hereditary breast cancer like PARP inhibitors might be used as therapeutic targets for sporadic breast tumours. PMID- 22820988 TI - Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. AB - The protein tyrosine kinase JAK2 mediates signaling through numerous cytokine receptors. JAK2 possesses a pseudokinase domain (JH2) and a tyrosine kinase domain (JH1). Through unknown mechanisms, JH2 regulates the catalytic activity of JH1, and hyperactivating mutations in the JH2 region of human JAK2 cause myeloproliferative neoplasms (MPNs). We showed previously that JAK2 JH2 is, in fact, catalytically active. Here we present crystal structures of human JAK2 JH2, including both wild type and the most prevalent MPN mutant, V617F. The structures reveal that JH2 adopts the fold of a prototypical protein kinase but binds Mg-ATP noncanonically. The structural and biochemical data indicate that the V617F mutation rigidifies alpha-helix C in the N lobe of JH2, facilitating trans phosphorylation of JH1. The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs. PMID- 22820989 TI - 5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. AB - Although the roles of 5-methylcytosine and 5-hydroxymethylcytosine in epigenetic regulation of gene expression are well established, the functional effects of 5 formylcytosine and 5-carboxylcytosine on the process of transcription are not clear. Here we report a systematic study of the effects of five different forms of cytosine in DNA on mammalian and yeast RNA polymerase II transcription, providing new insights into potential functional interplay between cytosine methylation status and transcription. PMID- 22820991 TI - Acoustic communication in crocodilians: information encoding and species specificity of juvenile calls. AB - In the Crocodylia order, all species are known for their ability to produce sounds in several communication contexts. Though recent experimental studies have brought evidence of the important biological role of young crocodilian calls, especially at hatching time, the juvenile vocal repertoire still needs to be clarified in order to describe thoroughly the crocodilian acoustic communication channel. The goal of this study is to investigate the acoustic features (structure and information coding) in the contact call of juveniles from three different species (Nile crocodile Crocodylus niloticus, Black caiman, Melanosuchus niger and Spectacled caiman, Caiman crocodilus). We have shown that even though substantial structural differences exist between the calls of different species, they do not seem relevant for crocodilians. Indeed, juveniles and adults from the species studied use a similar and non-species-specific way of encoding information, which relies on frequency modulation parameters. Interestingly, using conditioning experiments, we demonstrated that this tolerance in responses to signals of different acoustic structures was unlikely to be related to a lack of discriminatory abilities. This result reinforced the idea that crocodilians have developed adaptations to use sounds efficiently for communication needs. PMID- 22820990 TI - Direct sequencing of Arabidopsis thaliana RNA reveals patterns of cleavage and polyadenylation. AB - It has recently been shown that RNA 3'-end formation plays a more widespread role in controlling gene expression than previously thought. To examine the impact of regulated 3'-end formation genome-wide, we applied direct RNA sequencing to A. thaliana. Here we show the authentic transcriptome in unprecedented detail and describe the effects of 3'-end formation on genome organization. We reveal extreme heterogeneity in RNA 3' ends, discover previously unrecognized noncoding RNAs and propose widespread reannotation of the genome. We explain the origin of most poly(A)(+) antisense RNAs and identify cis elements that control 3'-end formation in different registers. These findings are essential to understanding what the genome actually encodes, how it is organized and how regulated 3'-end formation affects these processes. PMID- 22820992 TI - Culture, characterization and differentiation of cells from buffalo (Bubalus bubalis) amnion. AB - Stem cells present an important tool in livestock assisted reproduction and veterinary therapeutic field such as tissue engineering. We report for the first time isolation of pluripotent stem cell-like cells expressing pluripotency markers (alkaline phospahatase, OCT-4, NANOG and SOX-2) from the amnion of water buffalo (Bubalus bubalis). The cells showed no apparent abnormalities in their chromosomal profiles before and after cryopreservation. The cytochemical staining revealed that pluripotent cells were capable of undergoing directed differentiation in vitro into osteocytes. It could be inferred that amnion derived pluripotent stem cell-like cells can be isolated, cultured for many passages and differentiated into mesoderm lineage, and may be an alternative source to mesenchymal stem cells. These cells can have applications in assisted reproduction, developmental biological and regenerative medicine. PMID- 22820993 TI - Internal hernia projecting through a mesenteric defect to the lesser omental cleft following laparoscopic-assisted partial resection of the transverse colon: report of a case. AB - We herein report a case of an internal hernia projecting through a mesenteric defect following laparoscopic-assisted colectomy to the lesser omental cleft in a 61-year-old female. We performed laparoscopic-assisted partial resection of the transverse colon to treat transverse colon cancer. Three years and 6 months after the operation, the patient developed a bowel obstruction requiring surgical intervention. When we observed the intraperitoneal space under laparoscopy, we determined that the small intestine had passed into the bursa omentalis through the mesenteric defect. Additionally, an abnormal opening of the lesser omentum was present with a portion of the small intestine escaping into the space inferior to the liver. We performed reintegration of the escaped bowel and closed the mesenteric defect laparoscopically. This is the first case of an internal hernia projecting through a mesenteric defect following laparoscopic-assisted colectomy that we have experienced out of more than 2400 cases. Further research is needed to identify the patients who would benefit from the closure of mesenteric defects during laparoscopic-assisted colectomy. PMID- 22820995 TI - Gambling involvement and increased risk of gambling problems. AB - The opportunity to gamble has undergone rapid expansion with technology allowing for access to gambling products 24 h a day. This increased online availability challenges governments' abilities to restrict access to gambling. Indeed, the ready access to multiple forms of gambling may potentially contribute to impaired control over urges for problem gamblers. The present study considered whether problem gamblers manifested a tendency to engage in multiple forms of gambling and identified forms of gambling which were more strongly related to problem gambling. In reanalyses of two surveys (Sample 1, N = 464, Sample 2, N = 1141), significant relationships accounting for between 11.3 and 13.5% of the variance were found between the numbers of forms of gambling accessed and degree of problem. Participation in online poker, playing cards and sports wagering were linked to problem gambling. Access to multiple forms of gambling may pose difficulties for the tracking and control of gambling. PMID- 22820994 TI - Chronic intermittent stress-induced alterations in the spermatogenesis and antioxidant status of the testis are irreversible in albino rat. AB - The study was undertaken to find out whether or not chronic stress-induced alterations in spermatogenesis are accompanied by oxidative damage in the testis and reversibility of these effects. Adult male rats (n = 10) were subjected to restraint for 1 h and later after a gap of 4 h to forced swimming exercise for 15 min daily for 60 days and controls (n = 5) were maintained without disturbance. After treatment period, controls and 5 rats in stress group were killed and remaining rats in stress group were maintained without any treatment for 4 months and then autopsied to find out whether effects are reversible or not. The body and testicular weight, total sperm count, and mean number of type A spermatogonia, mid-pachytene spermatocytes, stage 7 spermatids, and elongated spermatids (cellular association in stage VII of spermatogenesis) showed a significant decrease whereas the abnormal sperm count and germ cell apoptosis were increased in stressed and recovery group rats compared to controls. Activities of testicular SOD, CAT, GPx, and GST were significantly decreased whereas MDA levels were significantly increased in stressed rats compared to controls. The SOD, GST, and CAT activities of recovery groups were significantly lower than controls, whereas MDA levels and GPx activity of these rats did not differ from controls. The results, for the first time, reveal that stress-induced loss of germ cells leading to decrease in sperm count may be due to oxidative damage caused by chronic stress and majority of these changes are not reversible. PMID- 22820996 TI - Partial replacement of dried Leucaena leucocephala (Lam.) de Wit leaves for noug (Guizotia abyssinica) (L.f.) Cass. seed cake in the diet of highland sheep fed on wheat straw. AB - This study investigated the effect of replacing noug (Guizotia abyssinica) (L.f.) Cass. seed cake by dried Leucaena leucocephala (Lam.) de Wit leaves on feed intake, live weight gain, nutrient digestibility, and nitrogen balance of highland sheep in Tigray Region in northern Ethiopia. Twenty intact yearling male highland sheep weighing 16.9 +/- 1.62 kg were used in a randomized complete block design and included the following four treatments: T1 (control, wheat straw ad libitum + 200 g noug seed cake (NSC) + 150 g wheat bran (WB)); T2 (wheat straw ad libitum + 170 g NSC + 44.3 g dried L. leucocephala (DLL) + 150 g WB); T3 (wheat straw ad libitum + 140 g NSC + 87.3 g DLL + 150 g WB); and T4 (wheat straw ad libitum + 110 g NSC + 130.2 g DLL + 150 g WB). Sheep fed on T4 diet consumed higher total dry matter (658 g/head/day) and recorded the highest average daily weight gain (59 g/head/day). Sheep fed on T4 diet had higher dry matter (61 %), organic matter (63 %), and crude protein (75 %) digestibility values than the other treatments. Sheep fed on T3 diet demonstrated higher feed conversion ratio (11.93) than sheep kept on the other treatments. All sheep exhibited positive nitrogen balance, with the highest nitrogen retention being measured in T4 (12 g/head/day). It is concluded that partially replacing NSC by DLL can improve total dry matter intake, digestibility of nutrients, and body weight gain in highland sheep fed on wheat straw as the basal diet. PMID- 22820998 TI - Diagnostic yield of electroencephalography in the medical and surgical intensive care unit. AB - BACKGROUND: To determine the incidence of electrographic seizures during continuous electroencephalography (cEEG) in the medical and surgical ICU. METHODS: We retrospectively reviewed the records of all adults who underwent cEEG in our medical and surgical ICU over a 4.5 year period. Patients with acute brain injury were excluded. Our primary outcome was cEEG documentation of an electrographic seizure, defined as a rhythmic discharge or spike and wave pattern demonstrating definite evolution and lasting at least 10 s. To assess inter-rater variability in cEEG interpretation, two electrophysiologists independently reviewed all available cEEGs of subjects with electrographic seizures documented on their clinical cEEG report and those of an equal number of randomly selected subjects from the remaining cohort. RESULTS: Kappa analysis showed a value of 0.88, indicating excellent inter-rater agreement. Electrographic seizures were identified in 12 of 105 patients (11 %, 95 % CI 5-18 %). This rate did not change after excluding patients with a history of seizure, remote brain injury, or seizure-like events before cEEG. In an ordinal logistic regression model controlling for age, sex, and SOFA score, electrographic seizures were associated with lower odds of good outcomes on the Glasgow Outcome Scale at discharge (OR 0.3, 95 % CI 0.1-0.8). CONCLUSION: In a tertiary care medical and surgical ICU, electrographic seizures were seen on 11 % of cEEGs ordered for the evaluation of encephalopathy, and were associated with worse functional outcomes at discharge. Our findings confirm the results of a prior study suggesting a substantial burden of electrographic seizures in critically ill encephalopathic patients. PMID- 22820997 TI - Bendamustine salvage for the treatment of relapsed Hodgkin's lymphoma after allogeneic bone marrow transplantation. PMID- 22820999 TI - Pt nanoparticles residing in the pores of porous LaNiO3 nanocubes as high efficiency electrocatalyst for direct methanol fuel cells. AB - Pt-filled porous LaNiO3 cubes are prepared through a facile route. The characterizations reveal that large numbers of pores (9-10 nm) are distributed homogeneously in porous LaNiO3 cubes. The Pt nanoparticles residing in the pores of porous LaNiO3 cubes are about 5 nm in size. The investigation on the electrocatalytic activity reveals that electrocatalytic activity of the obtained Pt loaded porous LaNiO3 nanocubes exhibit a significantly improved electrochemical active surface area (EASA) and a remarkably enhanced electrocatalytic performance toward methanol oxidation. The results are significant for improving the efficiency of Pt-based catalysts for DMFCs as well as the applications of perovskite compounds. PMID- 22821001 TI - Variability of GP6 gene in patients with sticky platelet syndrome and deep venous thrombosis and/or pulmonary embolism. AB - The GP6 gene encodes the GPVI, a crucial platelet membrane glycoprotein, for adequate platelet activation, adhesion and aggregation. The objectives of the present study were to assess the genetic variability of the GP6 gene in patients with platelet hyperaggregability phenotype, known as sticky platelet syndrome (SPS) manifesting as deep vein thrombosis (DVT), and/or pulmonary embolism, and in controls; and to evaluate its role in the pathogenesis of venous thromboembolism (VTE) in SPS. Seventy-seven patients with SPS and 77 healthy blood donors as controls were enrolled. Light transmission aggregometry was used to diagnose SPS according to the method of Mammen and Bick. Seven single nucleotide polymorphisms (SNPs) of the GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs12610286, rs1654431, rs1613662) were assessed using restriction fragment length polymorphism analysis. A significant association between 1613662 G [P < 0.05, odds ratio (OR) 2.087, confidence interval (CI) 1.049-4.148], 1654419-A (P < 0.05, OR 2.161, CI 1.020-4.577) and VTE was found in patients with SPS. The analysis based on SPS type revealed a significantly higher occurrence of 1671153-G (P < 0.05, OR 2.317, CI 1.103-4.865) and 1654419-A (P < 0.05, OR 2.317, CI 1.103-4.865) in the SPS type II compared to the control group. No association between the studied GP6 genotypes and the severity of VTE (pulmonary embolism vs. DVT) was found. In the patients, significant positive relationship between the 1671153-G, 1654419-A, 1613662-G alleles and male sex was observed. GP6 SNPs 1613662-G, 1671153-G and 1654419-A alleles are associated with an increased risk of VTE in SPS. They could contribute to the SPS phenotype. PMID- 22821002 TI - Impact of inherited bleeding disorders on pregnancy and postpartum hemorrhage. AB - Inherited bleeding disorders are caused by various genetic defects in the proteins involved in haemostasis. Female patients or carriers are faced with the risk of haemorrhage throughout life. During pregnancy and postpartum, this complication affects the health of either the mother or the baby, or both. This retrospective cohort study was designed to assess the occurrence of obstetric bleeding in the three trimesters of pregnancy, along with primary and secondary postpartum haemorrhage among 100 women with inherited bleeding disorders. A questionnaire was designed in order to collect historical data. The patients were evaluated in three groups: haemophilia carriers, von Willebrand disease (VWD) and rare bleeding disorders. In comparison with normal women, significantly severe bleeding was observed among patients in all of the five stages. VWD patients showed a higher frequency of bleeding in first trimester but the rate of miscarriage was lower. Haemophilia carriers were threatened with bleeding complications during the prenatal period, but they also had the highest frequency of postpartum haemorrhage. Based on our results, vaginal bleeding is a serious threat in all three patient groups, especially during the first trimester of pregnancy and in the postpartum period. PMID- 22821000 TI - Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). AB - Many components and pathways transducing multifaceted and deleterious effects of stress stimuli remain ill-defined. The Ran-binding protein 2 (RanBP2) interactome modulates the expression of a range of clinical and cell-context-dependent manifestations upon a variety of stressors. We examined the role of Ranbp2 haploinsufficiency on cellular and metabolic manifestations linked to tyrosine hydroxylase (TH(+)) dopaminergic neurons and glial cells of the brain and retina upon acute challenge to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonian neurotoxin, which models facets of Parkinson disease. MPTP led to stronger akinetic parkinsonism and slower recovery in Ranbp2 (+/-) than wild-type mice without viability changes of brain TH(+)-neurons of either genotype, with the exception of transient nuclear atypia via changes in chromatin condensation of Ranbp2 (+/-) TH(+)-neurons. Conversely, the number of wild-type retinal TH(+) amacrine neurons compared to Ranbp2 (+/-) underwent milder declines without apoptosis followed by stronger recoveries without neurogenesis. These phenotypes were accompanied by a stronger rise of EdU(+)-proliferative cells and non proliferative gliosis of GFAP(+)-Muller cells in wild-type than Ranbp2 (+/-) that outlasted the MPTP-insult. Finally, MPTP-treated wild-type and Ranbp2 (+/-) mice present distinct metabolic footprints in the brain or selective regions thereof, such as striatum, that are supportive of RanBP2-mediated regulation of interdependent metabolic pathways of lysine, cholesterol, free-fatty acids, or their beta-oxidation. These studies demonstrate contrasting gene-environment phenodeviances and roles of Ranbp2 between dopaminergic and glial cells of the brain and retina upon oxidative stress-elicited signaling and factors triggering a continuum of metabolic and cellular manifestations and proxies linked to oxidative stress, and chorioretinal and neurological disorders such as Parkinson. PMID- 22821003 TI - Determination of the anti-F10a or anti-F2a generation action of rivaroxaban or dabigatran. AB - Dabigatran and rivaroxaban are new oral inhibitors of the thrombin (F2a) and F10a, respectively. Both inhibitors decrease the extrinsic or intrinsic generation of F10a/F2a in plasma. An innovative test for extrinsic F10a/F2a generation is the extrinsic coagulation activity assay (EXCA). With the EXCA the action of all F10a/F2a generation inhibitors can be quantified. The present work aimed to establish the mean therapeutic ranges of these two new drugs, as determined in the EXCA. Forty microlitres reconstituted lyophilized commercial pooled normal plasma, that had been supplemented with 0-0.48 mg/l dabigatran or rivaroxaban, in high-quality polystyrene U-wells (Brand781600), were incubated with 4 MUl 1 ng/ml human placental tissue factor in 5% human albumin, 250 mmol/l CaCl2 (EXCA-trigger) for 1 min (EXCA-1) or 2 min (EXCA-2) at 37 degrees C. 80 MUl 2.5 mol/l arginine, 0.16% Triton X 100, pH 8.6, were added. After 3 min, 20 MUl 1 mmol/l CHG-Ala-Arg-pNA in 1.25 mol/l arginine was added and DeltaA/t was determined (37 degrees C). The mean therapeutic range (10-20% EXCA) of dabigatran is approximately 0.05-0.1 mg/l. The mean therapeutic range (10-20% EXCA) of rivaroxaban is approximately 0.13-0.22 mg/l. Mean prophylactic concentrations (20 40% EXCA) are approximately 0.02-0.05 mg/l dabigatran and approximately 0.05-0.13 mg/l rivaroxaban. These are the mean ranges. Individual plasma might well behave differently: either an individual patient could be more sensible or more resistant towards one or both of these drugs. It is suggested to perform EXCA tests for each individual patient to determine the real drug dosage he needs to reach 10-20% of normal EXCA for therapy or 20-40% of normal EXCA for prophylaxis. PMID- 22821005 TI - Quantifying barriers to monovalent anion transport in narrow non-polar pores. AB - The transport of anionic drinking water contaminants (fluoride, chloride, nitrate and nitrite) through narrow pores ranging in effective radius from 2.5 to 6.5 A was systematically evaluated using molecular dynamics simulations to elucidate the magnitude and origin of energetic barriers encountered in nanofiltration. Free energy profiles for ion transport through the pores show that energy barriers depend on pore size and ion properties and that there are three key regimes that affect transport. The first is where the ion can fit in the pore with its full inner hydration shell, the second is where the pore size is between the bare ion and hydrated radius, and the third is where the ion size approaches that of the pore. Energy barriers in the first regime are relatively small and due to rearrangement of the inner hydration shell and/or displacement of further hydration shells. Energy barriers in the second regime are due to partial dehydration and are larger than barriers seen in the first regime. In the third regime, the pore becomes too small for bare ions to fit regardless of hydration and thus energy barriers are very high. In the second regime where partial dehydration controls transport, the trend in the slopes of the change in energy barrier with pore size corresponds to the hydration strength of the anions. PMID- 22821004 TI - Atrial fibrillation and mortality in patients with acute myocardial infarction: a systematic overview and meta-analysis. AB - Atrial fibrillation (AF) confers an increased risk of mortality in patients hospitalized for acute myocardial infarction (AMI). However, it is unclear whether new-onset and preexisting AF portend a different risk. We extracted data from studies that evaluated in-hospital mortality in patients with AMI and included information on cardiac rhythm. Overall, the risk of mortality was higher in patients with AF than in those in sinus rhythm (OR 2.00, 95 % CI: 1.93-2.08; P < 0.0001). Compared with patients who remained in sinus rhythm, the risk of death was increased in patients with new AF certain (sinus rhythm on admission, new AF during hospitalization, and history of no evidence of prior AF; OR 3.38, 95 % CI: 2.98-3.83; P < 0.0001), new AF uncertain (sinus rhythm on admission, AF during hospitalization, but no clear information about previous history of AF; OR 1.90, 95 % CI:1.83-1.98; P < 0.0001), and permanent AF (AF before and during hospitalization; OR 2.01, 95 % CI:1.70-2.38;P < 0.0001). In a meta-regression analysis, the risk of death was 87 % higher in patients with new AF certain than in those with permanent AF (P = 0.013) or AF uncertain (P = 0.003), and not dissimilar in patients with new AF uncertain and permanent AF (P = 0.706). PMID- 22821006 TI - Prophylactic sesame oil attenuates sinusoidal obstruction syndrome by inhibiting matrix metalloproteinase-9 and oxidative stress. AB - BACKGROUND: Sinusoidal obstruction syndrome (SOS) occurs in patients undergoing hematopoietic cell transplantation and chemotherapy. The chemotherapeutic drugs oxaliplatin and cyclophosphamide cause SOS. Sesame oil is a nutrient-rich antioxidant popular in alternative medicine. It contains sesamin, sesamol, and sesamolin, all of which contribute to its antioxidant property. The authors investigated the protective effect of prophylactic sesame oil against monocrotaline-induced SOS in rats. METHODS: Male Sprague-Dawley rats were gavaged with a single dose of sesame oil (0.5, 1, 2, or 4 mL/kg). One hour later, those rats were gavaged with monocrotaline (90 mg/kg) to induce SOS. Control rats were treated with saline only. Aspartate transaminase, alanine transaminase, laminin, collagen, myeloperoxidase, nitrate content, lipid peroxidation, glutathione levels, matrix metalloproteinase (MMP)-9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were assessed 48 hours after the monocrotaline gavage. RESULTS: All tested parameters except TIMP-1, laminin, collagen, and glutathione were higher in monocrotaline-treated rats than in saline-only-treated control rats. In sesame oil-treated rats, all tested parameters except TIMP-1, laminin, collagen, and glutathione were significantly attenuated compared with monocrotaline-only-treated rats. Sesame oil downregulated MMP-9 expression but upregulated TIMP-1 expression in monocrotaline-only-treated rats. In addition, a histological analysis of liver tissue samples showed that sesame oil showed significant protection. CONCLUSION: A single prophylactic dose of sesame oil protects against SOS by downregulating MMP-9 expression, upregulating TIMP-1 expression, and inhibiting oxidative stress. PMID- 22821007 TI - Wild bearded capuchin (Sapajus libidinosus) select hammer tools on the basis of both stone mass and distance from the anvil. AB - Contemporary optimization models suggest that animals optimize benefits of foraging and minimize its costs. For wild bearded capuchins (Sapajus libidinosus), nut-cracking entails cost related to lifting the heavy stone and striking the nut and additional cost to transport the stone if it is not already on the anvil. To assess the role of stone mass and transport distance in capuchins' tool selection, we carried out three field experiments. In Experiment 1, we investigated whether transport distance affected choice of a tool by positioning two stones of the same mass close and far from the anvil. Capuchins consistently selected the closer stone, effectively reducing transport costs. In Experiment 2, we examined the trade-off between the cost of transport and the effectiveness in cracking by positioning two stones of different mass close and far from the anvil. Most subjects significantly preferred the closer stone, regardless of mass, whereas others preferred the heavier stone regardless of transport distance. In Experiment 3, we changed transport distance of both stones while maintaining the same distance ratios as in Experiment 2. Capuchins maintained the preferences expressed in Experiment 2, with the exception of one subject. Overall, our findings indicate that (1) individuals vary in their sensitivity to distance of transport, (2) a few meters are perceived as a substantive cost by some monkeys, and (3) monkeys' body mass affects their decisions. We also developed a non-dimensional Preference index (P) defined as a function of the stone mass and the transport distance to describe monkey's choice. PMID- 22821008 TI - Serum gamma-glutamyltransferase and the risk of hyperuricemia: a 6-year prospective study in Japanese men. AB - We conducted a longitudinal study to investigate whether increased serum gamma glutamyltransferase independently predicts subsequent development of hyperuricemia. The study participants included 3,310 Japanese men without hyperuricemia, aged 20-54 years. The participants had annual heath examinations for 6 years to assess incident hyperuricemia (defined as serum uric acid>416.4 MUmol/l and/or taking medication for hyperuricemia). The risk of incident hyperuricemia was compared in participants grouped according to their baseline serum gamma-glutamyltransferase level. During follow-up, there were 529 incident cases of hyperuricemia. A positive, dose-response relationship was observed between serum gamma-glutamyltransferase and the risk of incident hyperuricemia. The hazard ratios (95% confidence intervals) for hyperuricemia, compared with a serum gamma-glutamyltransferase level <=19 U/l, were 1.32 (1.05-1.67) for 20-39 U/l, 1.28 (0.90-1.83) for 40-59 U/l, 1.56 (0.98-2.47) for 60-79 U/l, and 1.57 (1.02-2.41) for >=80 U/l after adjustment for baseline serum uric acid, creatinine, total cholesterol, and glycated hemoglobin levels, ln(serum alanine aminotransferase), age, systolic blood pressure, medications for hypertension, hypercholesterolemia, and diabetes, body mass index, and smoking and exercise habits. A similar positive relationship was observed regardless of the presence or absence of alcohol drinking, obesity, metabolic disorders (any combination of hypertension, hypercholesterolemia and/or diabetes), or clinically high serum aminotransferases, without evidence of a significant interaction between increased serum gamma-glutamyltransferase and risk factors for incident hyperuricemia. These findings indicate that increased serum gamma glutamyltransferase is an independent predictor of subsequent development of hyperuricemia. PMID- 22821009 TI - Gamma paleohexaploidy in the stem lineage of core eudicots: significance for MADS box gene and species diversification. AB - Comparative genome biology has unveiled the polyploid origin of all angiosperms and the role of recurrent polyploidization in the amplification of gene families and the structuring of genomes. Which species share certain ancient polyploidy events, and which do not, is ill defined because of the limited number of sequenced genomes and transcriptomes and their uneven phylogenetic distribution. Previously, it has been suggested that most, but probably not all, of the eudicots have shared an ancient hexaploidy event, referred to as the gamma triplication. In this study, detailed phylogenies of subfamilies of MADS-box genes suggest that the gamma triplication has occurred before the divergence of Gunnerales but after the divergence of Buxales and Trochodendrales. Large-scale phylogenetic and K(S)-based approaches on the inflorescence transcriptomes of Gunnera manicata (Gunnerales) and Pachysandra terminalis (Buxales) provide further support for this placement, enabling us to position the gamma triplication in the stem lineage of the core eudicots. This triplication likely initiated the functional diversification of key regulators of reproductive development in the core eudicots, comprising 75% of flowering plants. Although it is possible that the gamma event triggered early core eudicot diversification, our dating estimates suggest that the event occurred early in the stem lineage, well before the rapid speciation of the earliest core eudicot lineages. The evolutionary significance of this paleopolyploidy event may thus rather lie in establishing a species lineage that was resilient to extinction, but with the genomic potential for later diversification. We consider that the traits generated from this potential characterize extant core eudicots both chemically and morphologically. PMID- 22821010 TI - Pervasive and ongoing positive selection in the vomeronasal-1 receptor (V1R) repertoire of mouse lemurs. AB - Chemosensory genes are frequently the target of positive selection and are often present in large gene families, but little is known about heterogeneity of selection in these cases and its relation to function. Here, we use the vomeronasal-1 receptor (V1R) repertoire of mouse lemurs (Microcebus spp.) as a model system to study patterns of selection of chemosensory genes at several different levels. Mouse lemurs are small nocturnal strepsirrhine primates and have a large (~200 loci) repertoire of V1R loci that are likely important for intraspecific pheromonal communication and interspecific interactions, for example, recognition of predator cues. We investigated signals and patterns of positive selection among the 105 identified full length V1R loci in the gray mouse lemur and within 7 V1R loci amplified across multiple mouse lemur species. Phylogenetic reconstructions of published sequences revealed at least nine monophyletic clusters of V1Rs in gray mouse lemurs that have diversified since the split between lemurs and lorisoid primates. A large majority of clusters evolved under significant positive selection. Similar results were found in V1Rs of closely related greater galagos. Comparison with function of related V1R clusters in mice suggested a potential relationship between receptor function and strength of selection. Interestingly, most codons identified as being under positive selection are located in the extracellular domains of the receptors and hence likely indicate the position of residues involved in ligand binding. Positive selection was also detected within five V1R loci (=71% of analyzed loci) sequenced from 6 to 10 mouse lemur species, indicating ongoing selection within the genus, which may be related to sexual selection and, potentially, speciation processes. Variation in strength of positive selection on V1Rs showed no simple relationship to cluster size. The diversity of V1R loci in mouse lemurs reflects their adaptive evolution and is most likely related to the fundamental relevance of olfactory communication and predator recognition in these primates. Overall, adaptive evolution is the predominant mode of evolution of V1R loci at all levels, and the substantial heterogeneity in the strength of selection may be related to receptor function. PMID- 22821012 TI - Phylogeny unites animal sodium leak channels with fungal calcium channels in an ancient, voltage-insensitive clade. AB - Proteins in the superfamily of voltage-gated ion channels mediate behavior across the tree of life. These proteins regulate the movement of ions across cell membranes by opening and closing a central pore that controls ion flow. The best known members of this superfamily are the voltage-gated potassium, calcium (Ca(v)), and sodium (Na(v)) channels, which underlie impulse conduction in nerve and muscle. Not all members of this family are opened by changes in voltage, however. NALCN (NA(+) leak channel nonselective) channels, which encode a voltage insensitive "sodium leak" channel, have garnered a growing interest. This study examines the phylogenetic relationship among Na(v)/Ca(v) voltage-gated and voltage-insensitive channels in the eukaryotic group Opisthokonta, which includes animals, fungi, and their unicellular relatives. We show that NALCN channels diverged from voltage-gated channels before the divergence of fungi and animals and that the closest relatives of NALCN channels are fungal calcium channels, which they functionally resemble. PMID- 22821013 TI - Genome reduction and co-evolution between the primary and secondary bacterial symbionts of psyllids. AB - Genome reduction in obligately intracellular bacteria is one of the most well established patterns in the field of molecular evolution. In the extreme, many sap-feeding insects harbor nutritional symbionts with genomes that are so reduced that it is not clear how they perform basic cellular functions. For example, the primary symbiont of psyllids (Carsonella) maintains one of the smallest and most AT-rich bacterial genomes ever identified and has surprisingly lost many genes that are thought to be essential for its role in provisioning its host with amino acids. However, our understanding of this extreme case of genome reduction is limited, as genomic data for Carsonella are available from only a single host species, and little is known about the functional role of "secondary" bacterial symbionts in psyllids. To address these limitations, we analyzed complete Carsonella genomes from pairs of congeneric hosts in three divergent genera within the Psyllidae (Ctenarytaina, Heteropsylla, and Pachypsylla) as well as complete secondary symbiont genomes from two of these host species (Ctenarytaina eucalypti and Heteropsylla cubana). Although the Carsonella genomes are generally conserved in size, structure, and GC content and exhibit genome-wide signatures of purifying selection, we found that gene loss has remained active since the divergence of the host species and had a particularly large impact on the amino acid biosynthesis pathways that define the symbiotic role of Carsonella. In some cases, the presence of additional bacterial symbionts may compensate for gene loss in Carsonella, as functional gene content indicates a high degree of metabolic complementarity between co-occurring symbionts. The genomes of the secondary symbionts also show signatures of long-term evolution as vertically transmitted, intracellular bacteria, including more extensive genome reduction than typically observed in facultative symbionts. Therefore, a history of co evolution with secondary bacterial symbionts can partially explain the ongoing genome reduction in Carsonella. However, the absence of these secondary symbionts in other host lineages indicates that the relationships are dynamic and that other mechanisms, such as changes in host diet or functional coordination with the host genome, must also be at play. PMID- 22821011 TI - Evolution of viral proteins originated de novo by overprinting. AB - New protein-coding genes can originate either through modification of existing genes or de novo. Recently, the importance of de novo origination has been recognized in eukaryotes, although eukaryotic genes originated de novo are relatively rare and difficult to identify. In contrast, viruses contain many de novo genes, namely those in which an existing gene has been "overprinted" by a new open reading frame, a process that generates a new protein-coding gene overlapping the ancestral gene. We analyzed the evolution of 12 experimentally validated viral genes that originated de novo and estimated their relative ages. We found that young de novo genes have a different codon usage from the rest of the genome. They evolve rapidly and are under positive or weak purifying selection. Thus, young de novo genes might have strain-specific functions, or no function, and would be difficult to detect using current genome annotation methods that rely on the sequence signature of purifying selection. In contrast to young de novo genes, older de novo genes have a codon usage that is similar to the rest of the genome. They evolve slowly and are under stronger purifying selection. Some of the oldest de novo genes evolve under stronger selection pressure than the ancestral gene they overlap, suggesting an evolutionary tug of war between the ancestral and the de novo gene. PMID- 22821016 TI - Evaluating the impact of a nurse residency program for newly graduated registered nurses. AB - Nurse residency programs are designed to support graduate nurses as they assume the professional role. Evaluation of these programs has been inconsistent. The purpose of this descriptive research study was to evaluate a year-long nurse residency program using a nonexperimental, repeated measures design with qualitative questions. Results showed statistically significant differences in new nurse confidence, skills, and abilities at 12 months. Nursing turnover was one third of the national average. The metatheme that emerged from the data was "I see that I am not the only one." PMID- 22821014 TI - Crystal structure and functional implication of the RUN domain of human NESCA. AB - NESCA, a newly discovered signaling adapter protein in the NGF-pathway, contains a RUN domain at its N-terminus. Here we report the crystal structure of the NESCA RUN domain determined at 2.0-A resolution. The overall fold of the NESCA RUN domain comprises nine helices, resembling the RUN domain of RPIPx and the RUN1 domain of Rab6IP1. However, compared to the other RUN domains, the RUN domain of NESCA has significantly different surface electrostatic distributions at the putative GTPase-interacting interface. We demonstrate that the RUN domain of NESCA can bind H-Ras, a downstream signaling molecule of TrkA, with high affinity. Moreover, NESCA RUN can directly interact with TrkA. These results provide new insights into how NESCA participates in the NGF-TrkA signaling pathway. PMID- 22821017 TI - Overcoming barriers to research utilization and evidence-based practice among staff nurses. AB - Several barriers exist to research utilization among staff nurses. Two barriers that appear in the research are lack of knowledge about research utilization and perceived lack of organizational support. The goal of this article is to present recommendations to overcome these barriers so that staff development educators can promote research utilization and evidence-based practice. PMID- 22821018 TI - Generational differences and learning style preferences in nurses from a large metropolitan medical center. AB - Nursing educators face the challenge of presenting educational programs to meet the learning needs of four diverse generational groups of nurses. This cross sectional survey examined if there is a relationship between staff nurses' generation and their learning styles. Results show that a combination of years in practice, time lapsed since last educational program ended, current school enrollment, degree earned, and generation influences preferred learning style. Implications for educators are discussed. PMID- 22821019 TI - Educating nurses about veno-thrombolytic events (VTE). AB - This study determined the effect of a computer-based educational program in preparing nurses to complete an assessment for veno-thrombotic risk on all patients admitted to a community hospital. The educational program included information on appropriate prophylaxis for patients at risk for veno-thrombolytic events (VTEs). Nurses were encouraged to work with physicians and pharmacists to obtain the appropriate VTE prophylaxis for all patients based on risk. Findings showed that one class may not be sufficient for long-term understanding of VTE risk and prophylaxis. PMID- 22821020 TI - Mentoring for evidence-based practice: a collaborative approach. AB - This article describes a collaborative project between clinical staff development professionals and a university associate professor of nursing to increase implementation of evidence-based practice in a clinical setting. The faculty member served as a mentor, helping nurses at the point of care who often lack the knowledge and skills to integrate evidence into practice. Outcomes of this project of benefit to staff development included education of the nurses on evidence-based practice, integration of evidence into policies, and development of a sustainable process to increase evidence-based practice. PMID- 22821021 TI - Nurses' barriers to learning: an integrative review. AB - This integrative review of the literature describes nurses' barriers to learning. Five major themes emerged: time constraints, financial constraints, workplace culture, access/relevance, and competency in accessing electronic evidence-based practice literature. The nurse educator must address these barriers for the staff to achieve learning and competency. PMID- 22821022 TI - Blended versus lecture learning: outcomes for staff development. AB - Critical care pharmacology education is crucial to safe patient care for nurses orienting to specialized areas. Although traditionally taught as a classroom lecture, it is important to consider effectiveness of alternative methods for education. This study provided experimentally derived evidence regarding effectiveness of blended versus traditional lecture for critical care pharmacology education. Regardless of learner demographics, the findings determined no significant differences in cognitive learning outcomes or learner satisfaction between blended versus lecture formats. PMID- 22821023 TI - Observed and self-perceived teamwork in a rapid response team. AB - Teamwork and communication between healthcare workers are vital for patient safety in the high-risk environment of health care. The purpose of this descriptive study was to measure the teamwork among members of the rapid response team (RRT) to design teamwork communication training for team members. Data were collected via live observation of RRT events and from RRT team member ratings of teamwork during events. PMID- 22821024 TI - Nursing professional development: stories, tips, and techniques. PMID- 22821025 TI - The power of "thank you": appreciation as a management strategy. PMID- 22821026 TI - Translating research into practice. PMID- 22821027 TI - Enhancing the effectiveness of nurse preceptors. AB - More than half of new graduate nurses start their careers in the hospital setting. Once there, they need an orientation that will help them make the transition from student to novice professional. It is just as important for experienced nurses transferring into another unit or hospital to be inculturated into the new work environment. In this study, academic and staff development educators collaborated to create the Nurse Preceptor Academy, a workshop that prepared over 700 nurse preceptors to be more effective in the preceptor role. PMID- 22821031 TI - Social therapy, the new anti-aging buzz? PMID- 22821029 TI - Subcellular localization of ERGIC-53 under endoplasmic reticulum stress condition. AB - Newly synthesized glycoproteins destined for secretion are transported from the endoplasmic reticulum (ER), through the Golgi and toward the cell surface. In this secretion pathway, several intracellular ER- or Golgi-resident transmembrane proteins serve as cargo receptors. ER-Golgi intermediate compartment (ERGIC)-53, VIP36 and VIPL, which have an L-type lectin domain within the luminal portion, participate in the vectorial transport of glycoproteins via sugar-protein interactions. To understand the nature of these receptors, monoclonal antibodies were generated against human ERGIC-53, VIP36 and VIPL using 293T cells expressing these receptors on cell surfaces. These cells were used to immunize rats and for screening antibody-producing clones. Flow cytometric analysis and immunoprecipitation studies showed that the obtained monoclonal antibodies bound specifically to the corresponding cargo receptors. Immunostaining of HeLa cells using the monoclonal antibodies showed that the localization of ERGIC-53 changed from relatively broad distribution in both the ER and the Golgi under normal conditions to a compact distribution in the Golgi under ER stress conditions. This redistribution was also observed by the overexpression of ERGIC-53 and abrogated by co-expression with VIPL but not VIP36. Real-time polymerase chain reaction revealed that ERGIC-53 along with several chaperone proteins was up regulated after tunicamycin treatment; however, the expression of VIPL was unchanged. Furthermore, ERGIC-53 co-precipitated with VIPL but not VIP36, indicating that ERGIC-53 may interact with VIPL in the ER, which may regulate the localization of ERGIC-53 inside cells. Taken together, these observations provide new insights into the regulation of these cargo receptors and the quality control of glycoproteins within cells. PMID- 22821032 TI - Viewing fat in zebrafish to study metabolism. PMID- 22821034 TI - Just one shot to make quitting a success. PMID- 22821035 TI - Tiny oxygen particles keep breathless animals alive. PMID- 22821037 TI - 2012 TriBranch Symposium. 11-13 June 2012. Atlantic City Convention Center, Atlantic City, NJ. PMID- 22821038 TI - Ferrets further disease research. PMID- 22821039 TI - Management of a holding protocol. PMID- 22821040 TI - Holding protocol represents risk. PMID- 22821041 TI - No delay. PMID- 22821042 TI - A word from OLAW and USDA. PMID- 22821043 TI - One person is the PI. PMID- 22821045 TI - Variability in intraosseous pressure induced by saline flush of an intraosseous cannula by multiple practitioners. AB - Intraosseous cannulation is an accepted means to achieve vascular access when peripheral venous access is not available. It is common practice to flush the intraosseous cannula with saline prior to establishing infusions. The objective of this study was to evaluate changes in intraosseous pressure during the flush procedure and to assess the variability of pressure changes induced by different practitioners. Two intraosseous cannulas were placed in an isolated cadaveric femur collected from a swine. Intraosseous pressure and the rate of change in pressure were recorded continuously during a series of saline flushes into a distal femoral intraosseous cannula by 21 members of the veterinary research staff at the authors' institution. Median peak intraosseous pressures exceeded 600 mmHg, and an inverse relationship was noted between peak intraosseous pressure and the duration of flush. Bone marrow fat emboli were grossly evident in flush effluents and their presence was confirmed by microscopic examination. Until the practitioners were informed of the pressure changes induced by the intraosseous cannula flush, few had appreciated the magnitude of the pressures that they had generated, suggesting that an instrumented intraosseous flush preparation like the one used in this study may prove useful as a training tool for flush procedures. PMID- 22821047 TI - Seeing animal welfare from two sides. PMID- 22821046 TI - A self-assessment survey of the Institutional Animal Care and Use Committee, Part 1: animal welfare and protocol compliance. AB - Nearly half of all external grants from the US National Institutes of Health require approval by the recipient organization's Institutional Animal Care and Use Committee (IACUC) before the funds can be used for research with animals. Given that large sums of money are spent annually on research involving animals, studies evaluating the strengths, weaknesses and overall effectiveness of IACUCs and similar animal welfare committees are needed. The authors designed and carried out a self-assessment survey on IACUC function and effectiveness. They found that 98% of all respondents believed that their IACUCs advanced animal welfare, but in many instances, veterinarians' responses to individual survey items were significantly different from those of other IACUC members. Protocol compliance, protocol review training and better understanding among non-committee members of the need for regulatory oversight are some areas where improvements could be made. Less than 50% of respondents stated that literature searches to find alternatives to animal use or painful or distressful procedures were helpful. PMID- 22821048 TI - First hospitalization after kidney transplantation. PMID- 22821049 TI - A novel and de novo deletion in the OCRL1 gene associated with a severe form of Lowe syndrome. AB - The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate (PIP2P) 5-phosphatase, is responsible for the phenotypic characteristics of the disease. We report a 22-year-old male with a severe form of OCRL syndrome, diagnosed on the basis of congenital cataracts, severe psychomotor and cognitive deficits, and renal tubular dysfunction without Fanconi syndrome. The patient presented low molecular weight proteinuria, nephrocalcinosis, nephrolithiasis, rickets, and growth retardation and developed progressive renal failure. Genetic analysis showed a novel and de novo deletion of exons 10-13 in the OCRL1 gene. PMID- 22821050 TI - Treating stress urinary incontinence in female patients with neuropathic bladder: the value of the autologous fascia rectus sling. AB - OBJECTIVE/BACKGROUND: The aim of this study was to evaluate the efficacy of the autologous fascia rectus sling in treating stress urinary incontinence in female patients with neuropathic bladder. Furthermore, correlations between preoperative parameters and outcome were evaluated. METHODS AND DESIGN: We retrospectively reviewed operative logs from a single surgeon (EM) of 33 female patients with neuropathic bladder treated over a 3-year period for stress urinary incontinence by implantation of an autologous fascia rectus sling. Efficacy was evaluated objectively in terms of the number of pads used per day, while subjective patient satisfaction was also recorded using a global assessment question. Possible correlations between age, obesity, preoperative Valsalva leak point pressure and incontinence severity and outcome were investigated using univariate analysis. OUTCOME MEASURES AND RESULTS: The mean follow-up time was 52 months, while the mean age of the patients was 37 years. Causes of neuropathic bladder were myelomeningocele in 21 (63.63 %) and spinal cord injury in 12 patients (36.36 %). A total of 30 patients were successfully treated and satisfied with the outcome of the operation (90.9 %). Twenty-five patients (75.75 %) were totally dry, while 5 patients (15.15 %) had markedly improved but still required one pad per day. The complication rate was 15.20 %. Univariate analysis failed to show any correlation between the final outcome and the checked parameters. CONCLUSION: The free autologous rectus fascia sling is a highly effective technique for the treatment of female stress incontinence in patients with neuropathic bladder, while the morbidity is mild. PMID- 22821051 TI - Alloplastic bladder substitution: are we making progress? AB - Radical cystectomy with lymphadenectomy and urinary diversion is the gold standard treatment for bladder cancer in organ-confined muscle-invasive disease and selected patients who have high-grade non-muscle-invasive disease or are non responders to BCG. The main and most morbid complications of this challenging surgery are related to the use of bowel for urinary tract reconstruction. For this reason, many past projects were devoted to finding an alternative to the use of bowel. The aim of this review is to provide a summary of the evolution of alloplastic bladder substitution. A comprehensive review of the literature was performed using the Medline National Library of Medicine database and Google Scholar. Keywords used were cystectomy and intestine/bowel, replacement, bladder substitution, organ replacement, artificial bladder, alloplastic material, biomaterial, and tissue engineering. Various prostheses have been proposed for replacement of the urinary bladder, silicone being the most frequently used material. The first published model of an alloplastic bladder was described by Bogash et al. in late 1959, while the last, in 1996, was suggested by Rohrmann. Interprofessional collaboration, recent advances in technology, and tissue engineering may help in developing suitable bladder prostheses. Urologists as well as engineers and the industry need to give this matter serious attention. PMID- 22821052 TI - Disaster preparedness and families of children with special needs: a geographic comparison. AB - Over eleven million children in the United States have special health care needs. These unique needs can burden community and emergency responders after a disaster, complicating rescue and recovery efforts and generating reunification needs. Family disaster preparedness can help to moderate the extent that community resources are utilized by preparing families to be self-sustaining after a disaster and streamline access to medical care when needed. This study explored differences in two populations of families of children with special health care needs to determine if geographic differences exist in preparedness levels and whether a brief education intervention would prove successful in increasing baseline preparedness levels across both populations. A brief education intervention was delivered by trained community health educators to 210 families of children with special health care needs. A quasiexperimental pre posttest design was used to compare baseline preparedness levels and 1 month follow-up levels. Although there was no difference in preparedness levels based on geographic location, both populations demonstrated a statistically significant increase in preparedness levels post-intervention. This study provides additional evidence that a brief education intervention helps to increase preparedness levels among families of children with special health care needs. PMID- 22821053 TI - Targeting HER2-positive cancer with dolastatin 15 derivatives conjugated to trastuzumab, novel antibody-drug conjugates. AB - PURPOSE: Targeting tubulin binders to cancer cells using antibody-drug conjugates (ADCs) has great potential to become an effective cancer treatment with low normal tissue toxicity. The nature of the linker used to tether the tubulin binder to the antibody and the conjugation sites on the antibody and the small molecule are important factors in the ADC stability and effectiveness. METHODS: We explored the use of tubulin-targeting dolastatin 15 derivatives (Dol15) tethered covalently to a representative antibody, trastuzumab, via cleavable and non-cleavable linkers at varying antibody reactive sites (i.e., lysine residues, partially reduced hinge region disulfide bonds) and drug coupling sites (i.e., C terminus, N-terminus), to investigate which constructs were more effective in killing HER2-positive cells in vitro and in vivo. RESULTS: We found that Dol15 conjugated to trastuzumab via lysine residues at the drug C-terminus using a non cleavable linker (trastuzumab-amide-C-term-Dol15) produced target-dependent growth inhibition of cells endogenously expressing high HER2 levels (i.e., SK-BR 3, SK-OV-3) in vitro. This ADC was effective at varying doses (i.e., 10 and 20 mg/kg) in the SK-OV-3 human ovarian cancer xenograft. CONCLUSIONS: Tethering Dol15 via partially reduced disulfide bonds at the drug C-terminus via a non cleavable linker (trastuzumab-MC-C-term-Dol15) resulted in an equally effective ADC in vitro, showing that site of antibody conjugation did not influence ADC activity. However, tethering Dol15 at the drug N-terminus using non-cleavable and cleavable linkers (trastuzumab-MC-N-term-Dol15 and trastuzumab-MC-VC-PABC-N-term Dol15, respectively) resulted in ineffective ADCs. Thus, Dol15 tethered at the C terminus may be a useful tubulin-targeting agent for conjugation at various antibody reactive sites. PMID- 22821054 TI - Differential effects of Oroxylum indicum bark extracts: antioxidant, antimicrobial, cytotoxic and apoptotic study. AB - Stem bark of Oroxylum indicum (L) (SBOI) is used by ethnic communities of North East India as health tonic and in treating diseases of humans and animals. The objective of this research was to carry out a detailed investigation including total phenolic and flavonoid content, antioxidant, antimicrobial, cytotoxic and apoptotic activities of different solvent extracts of SBOI and to establish correlation between some parameters. Among petroleum ether (PE), dichloromethane and methanol (MeOH) extract of SBOI, MeOH extract contained the highest amount of total phenolic (320.7 +/- 34.6 mg Gallic acid equivalent/g extract) and flavonoid (346.6 +/- 15.2 mg Quercetin equivalent/g extract) content. In vitro antioxidant activity (IC(50) 22.7 MUg/ml) was highest in MeOH extract (p > 0.05) and also a significant inverse correlation was observed between phenolic (r = 0.886)/flavonoid (r = 0.764) content and corresponding DPPH IC(50). Only MeOH extract inhibited both bacteria and fungi. Although, individual extract showed cytotoxicity on HeLa cells with characteristic features of apoptosis, PE extract caused maximum cytotoxicity (IC(50) of 112.3 MUg/ml, p < 0.05) and apoptotic activity (33.2 % sub-G0/G1 population) on HeLa cells. But, there was a significant non-inverse correlation of the MTT IC(50) with total phenolic (r = 0.812, p < 0.05)/flavonoid (r = 0.998, p < 0.05) content in the three solvent extracts. TLC analysis showed three unique compounds in PE extract which may have a role in apoptosis mediated cytotoxicity. These results called for futher chemical characterisation of MeOH and PE extract of SBOI for specific bioactivity. PMID- 22821055 TI - Saponin-rich fraction from Clematis chinensis Osbeck roots protects rabbit chondrocytes against nitric oxide-induced apoptosis via preventing mitochondria impairment and caspase-3 activation. AB - Our previous study reported that the saponin-rich fraction from Clematis chinensis Osbeck roots (SFC) could effectively alleviate experimental osteoarthritis induced by monosodium iodoacetate in rats through protecting articular cartilage and inhibiting local inflammation. The present study was performed to investigate the preventive effects of SFC on articular chondrocyte, and explore the underlying mechanisms. Primary rabbit chondrocytes were cultured and exposed to sodium nitroprusside (SNP), a NO donor. After treatment with different concentrations of SFC (30, 100, 300, 1,000 MUg/ml) for 24 h, nucleic morphology, apoptotic rate, mitochondrial function and caspase-3 activity of chondrocytes were examined. The results showed that SNP induced remarkable apoptosis of rabbit chondrocytes evidenced by Hoechst 33258 staining and flow cytometry analysis, and SFC prevented the apoptosis in a concentration-dependent manner. Further studies indicated that SFC could prevent the depolarization of mitochondrial membrane potential (?psim) in SNP-treated chondrocytes and suppress the activation of caspase-3. It can be concluded that the protection of SFC on articular chondrocytes is associated with the anti-apoptosis effects via inhibiting the mitochondrion impairment and caspase-3 activation. PMID- 22821056 TI - Extrapulmonary Small Cell Carcinoma of the Rectum. PMID- 22821057 TI - Dual-energy X-ray absorptiometry prediction of adipose tissue depots in children and adolescents. AB - BACKGROUND: The measurement of adipose tissue (AT) depots in vivo requires expensive imaging methods not accessible to most clinicians and researchers. The study aim was to derive mathematical models to predict total AT (TAT) and subdepots from total body fat derived from a dual-energy X-ray absorptiometry (DXA) scan. METHODS: Models were developed to predict magnetic resonance imaging derived TAT and subdepots subcutaneous AT, visceral AT, and intermuscular AT from DXA total body fat (Fat(DXA)) using cross-sectional data (time 0 (T0)) and validated results using 1 (T1) and 2 (T2) y follow-up data. Subjects were 176 multiethnic healthy children ages 5-17 y at T0. Twenty-two were measured at T1 and T2. TAT was compared with Fat(DXA). RESULTS: At T0, TAT was greater than Fat(DXA) (12.5 +/- 8.4 vs.12.0 +/- 9.4 kg; P < 0.0001), with a quadratic relationship between TAT and Fat(DXA) that varied by sex. Predicted mean TATs were not different from measured TATs: T1: (9.84 +/- 4.45 kg vs. 9.50 +/- 4.37 kg; P = 0.11); T2: (12.94 +/- 6.75 kg vs. 12.89 +/- 7.09 kg; P = 0.76). The quadratic relationship was not influenced by race or age. CONCLUSION: In general, the prediction equations for TAT and subdepots were consistent with the measured values using T1 and T2 data. PMID- 22821058 TI - Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic-ischemic brain injury in rats. AB - BACKGROUND: The endocannabinoids are emerging as natural brain protective substances that exert potentially beneficial effects in several neurological disorders by virtue of their hypothermic, immunomodulatory, vascular, antioxidant, and antiapoptotic actions. This study was undertaken to assess whether preventing the deactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG) with the monoacylglycerol lipase (MAGL) inhibitor URB602 can provide neuroprotective effects in hypoxia-ischemia (HI)-induced brain injury. METHODS: URB602 was administered into the right lateral ventricle 30 min before 7-day-old pup rats were subjected to HI. The neuroprotective effect was evaluated on postnatal day (PN) 14 or at adulthood (PN80) using behavioral and histological analyses. Activated caspase-3 expression and propidium iodide labeling were assessed as indexes of apoptotic and necrotic cell death, respectively. RESULTS: Pretreatment with URB602 reduced apoptotic and necrotic cell death, as well as the infarct volume measured at PN14. At adulthood, URB602-treated HI animals performed better at the T-maze and the Morris maze, and also showed a significant reduction of brain damage. CONCLUSION: These results demonstrate that a pretreatment with URB602 significantly reduces brain damage and improves functional outcome, indicating that endocannabinoid-degrading enzymes may represent an important target for neuroprotection in neonatal ischemic brain injury. PMID- 22821059 TI - Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS. AB - BACKGROUND: Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants. METHODS: Preterm lambs (126.8 +/- 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination. RESULTS: SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant. CONCLUSION: These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant. PMID- 22821060 TI - Temporary axillo-femoral bypass during open repair for abdominal aortic aneurysm: report of a case. AB - Open repair is the "gold standard" treatment for abdominal aortic aneurysm (AAA) and although considered safe, this operation is very invasive for high-risk patients with severe aortic valve stenosis (AS) because the left ventricular after-load changes sharply with the clamping and unclamping of the aorta. We prevented the change in left ventricular after-load by establishing a temporary axillo-bilateral femoral arterial shunt, which enabled us to perform open repair of an AAA safely in a patient with severe AS. PMID- 22821061 TI - Advanced colorectal polyp detection techniques. AB - A long-term follow-up of the landmark National Polyp Study recently showed that colonoscopy was associated with critical clinical benefit, including reduced overall death rate, colorectal cancer (CRC) death rate, and CRC incidence Zauber et al. (N Engl J Med 366(8):687-96, 2012). This and other recent studies emphasize the need for high-quality colonoscopy to realize maximal benefit. Adenoma detection has emerged as an important predictor of quality colonoscopy. Studies from Europe have shown that individuals whose colonoscopy was performed by a physician with high adenoma detection have a much lower likelihood of interval CRC. Studies now suggest that it is possible to train endoscopists to improve their adenoma detection rate. The specific methods associated with higher quality colonoscopy include careful inspection behind folds, washing the colon surface, adequate insufflation, and recognition of subtle flat polyps. Use of high-definition white light colonoscopy, chromoendoscopy, and cap-fitted colonoscopy has also been studied as potential methods for increasing adenoma detection. We will review these methods and techniques in this article. PMID- 22821062 TI - [Minimally invasive osteosynthesis. : even in talus fractures?]. AB - OBJECTIVE: Minimally invasive osteosynthesis of talar fractures. INDICATIONS: Minimally displaced fractures of the lateral process of the talus and talar neck fractures type 1 according to Hawkins classification. CONTRAINDICATIONS: Dislocated peripheral fractures. Displaced fractures of the talar neck or body. SURGICAL TECHNIQUE: For factures of the lateral process of the talus: short incision of skin over the lateral process of the talus. Gentle preparation and contact with the bone with scissors. Fragment reposition using a dentist's hook and Kirschner wire in a joy-stick technique under C-arm imaging. Stabilization with a miniscrew. For talar neck fracture Hawkins type 1: short incision of skin ventromedially and ventrolaterally. Blunt preparation of soft tissue and safe bone contact. Introduction of one small-fragment corticalis screw both medially and laterally under C-arm imaging. As an alternative, cannulated screws can also be used. POSTOPERATIVE MANAGEMENT: For fractures of the lateral process of the talus: postoperative protection in an ankle splint (air cast, gel cast) for 4 weeks. During this time moderate weight bearing is possible. For talar neck fractures Hawkins type 1: physiotherapy and only floor contact for 6 weeks. RESULTS: From January 1996 to December 2002, 44 talar fractures were operatively treated in our department. Six patients had talar neck fractures type 1 according the Hawkins classification and 3 patients showed fractures of the lateral process of the talus. From those injuries, 3 Hawkins type 1 fractures and 2 fractures of the lateral process were stabilized using minimally invasive osteosynthesis. The clinical outcomes were assessed using the Ankle Hindfoot Scale of the American Orthopedic Foot and Ankle Society. Both groups reached good cosmetic and functional results. We did not observe any avascular talar necrosis or nonunions in the two groups. PMID- 22821063 TI - Intrajejunal levodopa versus conventional therapy in Parkinson disease: motor and nonmotor effects. AB - Seventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care. PMID- 22821064 TI - The efficacy of primidone in reducing severe cerebellar tremors in patients with multiple sclerosis. AB - OBJECTIVES: Cerebellar tremor is a disabling sign of multiple sclerosis (MS), and various kinds of treatments have been proposed with different results. Primidone is one of the medications, mostly advised for essential tremor. The aim of our study was to determine the tolerability and efficacy of primidone in reducing severe cerebellar tremor in patients with MS. METHODS: Ten patients with severe cerebellar tremor were enrolled in this study. Primidone started with dose of 31.5 mg and gradually increased up to maximum of 750 mg/d. The severity of tremor was assessed with Activity of Daily Living (ADL), Nine-Hole Peg Test (NHPT), and Fahn Tremor Rating Scale (FTRS) at baseline and 2 follow-up studies after 6 and 12 weeks. RESULTS: All outcome measures including ADL, FTRS, and NHPT of dominant and nondominant hands improved. The mean ADL changed from 51.8 at baseline to 36.8 after 12 weeks. FTRS was 14.8 at baseline, which reduced to 9.5 during this period. These changes were statistically significant. Although the time of the NHPT showed some improvement, it did not reach a statistically significant point after 6 weeks.The drug was well tolerated in all patients, and mild drowsiness reported by the patients disappeared at the end of the study. CONCLUSIONS: Our study showed that primidone is tolerable in MS patients and effectively reduces severe cerebellar tremor in such patients. PMID- 22821066 TI - Ocean-atmosphere trace gas exchange. AB - The oceans contribute significantly to the global emissions of a number of atmospherically important volatile gases, notably those containing sulfur, nitrogen and halogens. Such gases play critical roles not only in global biogeochemical cycling but also in a wide range of atmospheric processes including marine aerosol formation and modification, tropospheric ozone formation and destruction, photooxidant cycling and stratospheric ozone loss. A number of marine emissions are greenhouse gases, others influence the Earth's radiative budget indirectly through aerosol formation and/or by modifying oxidant levels and thus changing the atmospheric lifetime of gases such as methane. In this article we review current literature concerning the physical, chemical and biological controls on the sea-air emissions of a wide range of gases including dimethyl sulphide (DMS), halocarbons, nitrogen-containing gases including ammonia (NH(3)), amines (including dimethylamine, DMA, and diethylamine, DEA), alkyl nitrates (RONO(2)) and nitrous oxide (N(2)O), non-methane hydrocarbons (NMHC) including isoprene and oxygenated (O)VOCs, methane (CH(4)) and carbon monoxide (CO). Where possible we review the current global emission budgets of these gases as well as known mechanisms for their formation and loss in the surface ocean. PMID- 22821067 TI - Recommended guidelines on using social networking technologies for HIV prevention research. PMID- 22821065 TI - Rifampicin and Parkinson's disease. AB - Rifampicin is a macrocyclic antibiotic used extensively for the treatment of Mycobacterium tuberculosis and other mycobacterial infections. Recently, it was discovered that rifampicin exhibits neuroprotective effects. It has been shown to protect PC12 cells against MPP(+)-induced apoptosis and inhibit the expression of alpha-synuclein multimers. In in vitro studies, rifampicin pretreatment protects PC12 cells against rotenone-induced cell death. Qualitative and quantitative analyses uncover that rifampicin significantly suppresses rotenone-induced apoptosis by ameliorating mitochondrial oxidative stress. It reduces microglial inflammation and improves neuron survival. Our results indicate that rifampicin is cytoprotective under a variety of experimental conditions, and suggest that it may be useful in PD therapeutics. It is the aim of this paper to review the experimental neuroprotection data reported using rifampicin with a focus on the molecular and cellular mechanisms of cytoprotective effect in in vitro models of PD. PMID- 22821068 TI - Electrochemical assembly of MnO2 on ionic liquid-graphene films into a hierarchical structure for high rate capability and long cycle stability of pseudocapacitors. AB - Hierarchical nanostructures are of prime importance due to their large surface area, easy accessibility to reaction sites, fast ion and electron transport, and mechanical integrity. Herein, we demonstrate the synthesis of hierarchically structured MnO2/ionic liquid-reduced graphene oxide (IL-RGO) nanocomposites through the electrochemical self-assembly. The structures of MnO2/IL-RGO nanocomposites and their formation mechanism are investigated by spectroscopic methods and as a consequence, correlated with the electrochemical behaviours. The specific capacitance (511 F g-1) of conformally MnO2-deposited IL-RGO composites is significantly higher than 159 F g-1 of pure MnO2 film. High rate capability (61% retention at 30 A g-1) of the MnO2/IL-RGO composite is attributed to the facilitated ion diffusion and electron transport, whereas its long cycle life (95% retention after 2000 cycles) is related to the mechanical robustness. These results provide a new insight into the rational design of hierarchical and complex heterostructures consisting of carbon nanomaterials and metal oxides for applications in energy conversion and storage. PMID- 22821069 TI - Identification of disease-associated DNA methylation in B cells from Crohn's disease and ulcerative colitis patients. AB - BACKGROUND: Changes in the methylation status of inflammatory bowel disease (IBD) associated genes could significantly alter levels of gene expression, thereby contributing to disease onset and progression. We previously identified seven disease-associated DNA methylation loci from intestinal tissues of IBD patients using the Illumina GoldenGate BeadArray assay. AIMS: In this study, we extended this approach to identify IBD-associated changes in DNA methylation in B cells from 18 IBD patients [9 Crohn's disease (CD) and 9 ulcerative colitis (UC)]. B cell DNA methylation markers are particularly favorable for diagnosis due to the convenient access to peripheral blood. METHODS: We examined DNA methylation profiles of B cell lines using the Illumina GoldenGate BeadArray assay. Disease associated CpGs/genes with changes in DNA methylation were identified by comparison of methylation profiles between B cell lines from IBD patients and their siblings without IBD. BeadArray data were validated using a bisulfite polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. To verify that observed changes in DNA methylation were not due to virus transformation, we compared specific CpG DNA methylation levels of GADD45A and POMC between B cell lines and matching peripheral blood B lymphocytes from five individuals. RESULTS: Using this approach with strict statistical analysis, we identified 11 IBD-associated CpG sites, 14 CD-specific CpG sites, and 24 UC specific CpG sites with methylation changes in B cells. CONCLUSIONS: IBD- and subtype-specific changes in DNA methylation were identified in B cells from IBD patients. Many of these genes have important immune and inflammatory response functions including several loci within the interleukin (IL)-12/IL-23 pathway. PMID- 22821070 TI - The effect of opioid use on workers' compensation claim cost in the State of Michigan. AB - OBJECTIVE: To investigate the association between opioid utilization and catastrophic claim (>=$100,000) cost. METHOD: A total of 12,226 workers' compensation indemnity claims that were opened and closed from January 1, 2006 to February 28, 2010 in the State of Michigan were selected for multivariate logistic regression analyses. RESULT: Controlling for sex, age, claim duration, number of distinct International Classification of Diseases-Ninth Revision codes per claim, and legal involvement, the presence of short-acting opioids on a claim were 1.76 (95% confidence interval: 1.23 to 2.51) and long-acting opioids 3.94 (95% confidence interval: 2.35 to 6.89) more likely to have a final cost $100,000 or more than a claim without any prescription. CONCLUSION: The use of opioid medications, particularly long-acting opioid medications, is an independent risk factor for the development of catastrophic claims. PMID- 22821071 TI - Work organization and musculoskeletal health: clinical findings from immigrant Latino poultry processing and other manual workers. AB - OBJECTIVE: To determine the potential role of differential exposure to work organization hazards in musculoskeletal disorders among immigrant Latino workers. METHOD: Self-reported work organization data were obtained from immigrant Latino workers in poultry processing and nonpoultry, manual occupations (N = 742). Clinical evaluations for epicondylitis, rotator cuff syndrome, and back pain were obtained from a subsample (n = 518). RESULTS: Several work organization hazards (eg, low job control, high psychological demands) were elevated among poultry processing workers. Job control predicted epicondylitis (odds ratio [OR] = 0.77) and rotator cuff syndrome (OR = 0.79); psychological demand predicted rotator cuff syndrome (OR = 1.30) and back pain (OR = 1.24); awkward posture and repeated movements predicted all three outcomes; and management safety commitment predicted rotator cuff syndrome (OR = 1.65) and back pain (OR = 1.81). DISCUSSION: Immigrant poultry processing workers are exposed to greater work organization hazards that may contribute to occupational health disparities. PMID- 22821072 TI - Comparison of job stress and obesity in nurses with favorable and unfavorable work schedules. AB - OBJECTIVES: To compare obesity-related factors between female nurses with favorable work schedules (WSs) and unfavorable WSs. METHODS: In a cross-sectional study, 1724 female nurses were stratified by WS (favorable vs unfavorable). For each schedule type, the odds of obesity were related to health behaviors, home demands, and job stress using logistic regression models. RESULTS: Among nurses with unfavorable WSs, healthy behaviors (exercise, sleep) were inversely associated with obesity, whereas for those with favorable WSs, obese nurses reported significantly more unhealthy behaviors (smoking, alcohol use; odds ratio [OR], 1.19; 95% confidence interval [CI], 1.02-1.38), more physical lifting of children/dependents (OR, 1.43; 95% CI, 1.06-1.93), having more nurse input into their jobs (OR, 1.21; 95% CI, 1.02-1.44), yet less boss support at work (OR, 0.83; 95% CI, 0.68-0.99). CONCLUSIONS: Considering impacts of WSs on obesity and potential obesity-related health outcomes, healthful scheduling should be provided to nurses. PMID- 22821073 TI - Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. AB - We investigated whether a young human leukocyte antigen (HLA)-matched unrelated donor (MUD) should be preferred as donor to an HLA-identical sibling (MRD) for older patients with myelodysplastic syndrome (MDS) (>= 50 years) who underwent allogeneic stem cell transplantation (AHSCT). Outcomes of 719 MDS patients with a median age of 58 years (range, 50-73 years) who received AHSCT from related (n=555) or unrelated (n=164) donors between 1999 and 2008 and reported to the European Group for Blood and Marrow Transplantation were analyzed. The median donor age of the MRD was 56 years (range: 35-78), in contrast to 34 years (range: 19-64) for the MUDs. Influence of donor's age on survival was not observed for MRD (hazard ratio (HR): 1.01 (95% confidence interval (CI): 0.99-1.02), P=0.2), but there was a significant impact of MUD's age on outcome (HR: 1.03 (95% CI: 1.01-1.06); P=0.02). Transplantation from younger MUDs (<30 years) had a significant improved 5-year overall survival in comparison with MRD and older MUDs (>30 years): 40% vs 33% vs 24% (P=0.04). In a multivariate analysis, AHSCT from young MUD (<30 years) remained a significant factor for improved survival in comparison with MRD (HR: 0.65 (95% CI: 0.45-0.95), P=0.03), which should be considered in donor selection for older patients. PMID- 22821074 TI - HIV/AIDS among African-born residents in the United States. AB - The number of African-born residents living in the United States (US) increased by more than 750 % between 1980 and 2009. HIV diagnosis rates in this population are six times higher than estimated incidence in the general US population. African-immigrants with HIV are also diagnosed at later stages of infection than US-born residents, but they paradoxically have lower mortality after diagnosis. There are higher rates of HIV among women, higher rates of heterosexual transmission, and lower rates of injection-drug-use-associated transmission among African-born residents in the US relative to the general US population. Despite this distinct epidemiologic profile, surveillance reports often group African born residents with US-born Blacks. The high rates of HIV among African-born residents in the US combined with increasing immigration and incomplete surveillance data highlight the need for more accurate epidemiologic data along with appropriate HIV service programs. PMID- 22821075 TI - Respiratory support practices in infants born at term in the United Kingdom. AB - Infants born at term requiring mechanical ventilation suffer significant mortality and morbidity, yet few studies have tried to identify the optimum respiratory support for such infants. We, therefore, hypothesised that practice would vary, particularly between different levels of neonatal care provision. The lead clinicians of all 212 UK neonatal units were asked to complete an electronic web-based survey regarding respiratory support practices for term-born infants. Survey questions included the level of neonatal care provided, number of term born infants ventilated per annum, initial and rescue ventilation modes and whether surfactant or inhaled nitric oxide (NO) were used. The overall response rate was 82 %. A greater proportion of neonatal intensive care units (NICUs) compared to local neonatal units (LNUs) stated that they used volume-targeting, particularly for infants with RDS (p = 0.0006) or congenital pneumonia (p = 0.0005). High-frequency oscillatory ventilation was stated as initial mode by a greater proportion of NICUs compared to LNUs and special care units (SCUs), particularly for respiratory distress syndrome (p < 0.0001) or persistent pulmonary hypertension of the newborn (p < 0.001). Continuous mandatory ventilation was stated to be the rescue mode by a greater proportion of LNUs/SCUs compared to NICUs (p < 0.0001). Surfactant was stated to be most commonly given for respiratory distress syndrome (79 % of units) and MAS (61 % of units); surfactant use was lowest in SCUs (p < 0.0001); inhaled NO was infrequently used by LNUs and SCUs. Conclusions There was considerable variation in respiratory support practices for term-born infants, particularly between different levels of neonatal care provision. PMID- 22821077 TI - Non-lateralized auditory input enhances averaged vectors in the oculomotor system. AB - The decision about which location should be the goal of the next eye movement is known to be determined by the interaction between auditory and visual input. This interaction can be explained by the vector theory that states that each element (either visual or auditory) in a scene evokes a vector in the oculomotor system. These vectors determine the direction in which the eye movement is initiated. Because auditory input is lateralized and localizable in most studies, it is currently unclear how non-lateralized auditory input interacts with the vectors evoked by visual input. In the current study, we investigated the influence of a non-lateralized auditory non-target on saccade accuracy (saccade angle deviation from the target) and latency in a single-target condition in Experiment 1 and a double-target condition in Experiment 2. The visual targets in Experiment 2 were positioned in such a way that saccades on average landed in between the two targets (i.e., a global effect). There was no effect of the auditory input on saccade accuracy in the single-target condition, but auditory input did influence saccade accuracy in the double-target condition. In both experiments, saccade latency increased when auditory input accompanied the visual target(s). Together, these findings show that non-lateralized auditory input enhances all vectors evoked by visual input. The results will be discussed in terms of their possible neural substrates. PMID- 22821078 TI - Loss of large-diameter nerve sensory input changes perceived posture. AB - Our previous studies (Inui et al. in J Physiol 589:5775-5784, 2011, Exp Brain Res 218:487-494, 2012) showed that a fully flexed or extended finger, wrist, and elbow became perceived as an extended or flexed 'phantom' hand and arm as ischemic anesthesia progressed. Here, we examined what happened if the wrist was fixed in full extension while the elbow was in full flexion before and during the anesthesia, and vice versa. Ten healthy participants demonstrated the perceived postures of their right wrist and elbow during an ischemic block of the right upper arm with the left hand and arm. If the actual wrist was fully extended while the actual elbow was fully flexed, then the perceived position of the wrist moved toward flexion and that of the elbow moved toward extension. Conversely, if the actual wrist was fully flexed while the actual elbow was fully extended, then the wrist was perceived to extend and the elbow was perceived to flex. Following the loss of the afferent signal coming from the main muscles acting at the two joints, the two perceived postures moved toward the opposite direction independently. The changes in the perceived postures are a shift in the body schema depending on the balance of the proprioceptive inputs that determine limb posture. PMID- 22821076 TI - The effect of extended wake on postural control in young adults. AB - The sleep-wake cycle is a major determinant of locomotor activity in humans, and the neural and physiological processes necessary for optimum postural control may be impaired by an extension of the wake period into habitual sleep time. There is growing evidence for such a contribution from sleep-related factors, but great inconsistency in the methods used to assess this contribution, particularly in control for circadian phase position. Postural control was assessed at hourly intervals across 14 h of extended wake in nine young adult participants. Force plate parameters of medio-lateral and anterior-posterior sway, centre of pressure (CoP) trace length, area, and velocity were assessed with eyes open and eyes closed over 3-min periods. A standard measure of psychomotor vigilance was assessed concurrently under constant routine conditions. After controlling for individual differences in circadian phase position, a significant effect of extended wake was found for anterior-posterior sway and for psychomotor vigilance. These data suggest that extended wake may increase the risk of a fall or other consequences of impaired postural control. PMID- 22821079 TI - Effects of stimulus duration on audio-visual synchrony perception. AB - The integration of visual and auditory inputs in the human brain occurs only if the components are perceived in temporal proximity, that is, when the intermodal time difference falls within the so-called subjective synchrony range. We used the midpoint of this range to estimate the point of subjective simultaneity (PSS). We measured the PSS for audio-visual (AV) stimuli in a synchrony judgment task, in which subjects had to judge a given AV stimulus using three response categories (audio first, synchronous, video first). The relevant stimulus manipulation was the duration of the auditory and visual components. Results for unimodal auditory and visual stimuli have shown that the perceived onset shifts to relatively later positions with increasing stimulus duration. These unimodal shifts should be reflected in changing PSS values, when AV stimuli with different durations of the auditory and visual components are used. The results for 17 subjects showed indeed a significant shift of the PSS for different duration combinations of the stimulus components. Because the shifts were approximately equal for duration changes in either of the components, no net shift of the PSS was observed as long as the durations of the two components were equal. This result indicates the need to appropriately account for unimodal timing effects when quantifying intermodal synchrony perception. PMID- 22821080 TI - Upper body 3-dimensional kinematics during gait in psychotic patients: a pilot study. AB - Gait is recognized as a key item related to mental function. Anomalous gait in psychotic individuals has been described for the lower extremities, whereas irregularities for upper body dynamics are not described, explained or verified with unbiased methods. Reduced walking velocity and increased somatic tension defined in this patient category may influence upper body dynamics during gait. The aim of this pilot-study was to describe upper body kinematics and investigate the biomechanical association with walking velocity and muscle tension. Twelve inpatients in a psychiatric ward with first-episode psychosis and 18 healthy control subjects walked at different self-chosen velocities. Movement and walking velocity were registered, and 3D kinematics was analysed for thorax and shoulder joint. Time-synchronized EMG from the trapezius muscle, chosen as indicator for general somatic tension, was analysed for maximal amplitude and variability. Results showed that patients walked with reduced arm swing at the shoulder joint and increased lateral thorax movements. Thorax rotations about the vertical axis, walking velocity and EMG measures were similar in patients and healthy subjects. The present study could not provide a biomechanical explanation for kinematic findings based on walking velocity or somatic tension. PMID- 22821083 TI - Impacts of an HIA on inter-agency and inter-sectoral partnerships and community participation: lessons from a local level HIA in the Republic of Ireland. AB - This study evaluates the impacts of a locally based health impact assessment (HIA) on community participation, inter-sectoral and inter-agency partnership in local decision and policy-making processes. The methods comprised a series of semi-structured interviews with key informants followed by thematic analysis of transcribed responses. The study revealed a number of positive impacts among both community and service providers. A particularly advantageous impact was the facilitation of community learning through a local action group formed as a recommendation of the HIA that provided community development and HIA training. During the HIA process all participants increased their knowledge of health determinants and recognized a broader range of evidence sources for local decision-making. Participants also developed a greater understanding of each other's roles and perspectives. Additionally, the study revealed a number of barriers to HIA. Differing views on the role of HIA were evident whereby community members tended to regard HIA as an advocacy tool for local issues impacting on health in their locality, while service providers perceived its role more in terms of networking and collaboration. A key area remaining to be tackled in terms of partnership working is the approach of service agencies to enabling meaningful community participation in local decision-making processes. In this respect, attention to the cultural dimension of inter-sectoral working, and the need for training for both service agency staff and community members prior to or at the initial stages of HIA are required. Such changes could facilitate more meaningful community inclusion and help to address the current power imbalance between these two sectors. PMID- 22821082 TI - Dissociable contributions of motor-execution and action-observation to intramanual transfer. AB - We examined the hypothesis that different processes and representations are associated with the learning of a movement sequence through motor-execution and action-observation. Following a pre-test in which participants attempted to achieve an absolute, and relative, time goal in a sequential goal-directed aiming movement, participants received either physical or observational practice with feedback. Post-test performance indicated that motor-execution and action observation participants learned equally well. Participants then transferred to conditions where the gain between the limb movements and their visual consequences were manipulated. Under both bigger and smaller transfer conditions, motor-execution and action-observation participants exhibited similar intramanual transfer of absolute timing. However, participants in the action-observation group exhibited superior transfer of relative timing than the motor-execution group. These findings suggest that learning via action-observation is underpinned by a visual-spatial representation, while learning via motor-execution depends more on specific force-time planning (feed forward) and afferent processing associated with sensorimotor feedback. These behavioural effects are discussed with reference to neural processes associated with striatum, cerebellum and motor cortical regions (pre-motor cortex; SMA; pre-SMA). PMID- 22821081 TI - Long-term behavioral and biochemical effects of an ultra-low dose of Delta9 tetrahydrocannabinol (THC): neuroprotection and ERK signaling. AB - We have previously reported that a single injection of an ultra-low dose of delta 9-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) protected the brain from pentylenentetrazole (PTZ)-induced cognitive deficits when applied 1-7 days before or 1-3 days after the insult. In the present study we expanded the protective profile of THC by showing that it protected mice from cognitive deficits that were induced by a variety of other neuronal insults, including pentobarbital-induced deep anesthesia, repeated treatment with 3,4 methylenedioxymethamphetamine (MDMA; "ecstasy") and exposure to carbon monoxide. The protective effect of THC lasted for at least 7 weeks. The same ultra-low dose of THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that produce the known acute effects of the drug in mice) induced long-lasting (7 weeks) modifications of extracellular signal-regulated kinase (ERK) activity in the hippocampus, frontal cortex and cerebellum of the mice. The alterations in ERK activity paralleled changes in its activating enzyme MEK and its inactivating enzyme MKP-1. Furthermore, a single treatment with the low dose of THC elevated the level of pCREB (phosphorylated cAMP response element-binding protein) in the hippocampus and the level of BDNF (brain-derived neurotrophic factor) in the frontal cortex. These long-lasting effects indicate that a single treatment with an ultra-low dose of THC can modify brain plasticity and induce long-term behavioral and developmental effects in the brain. PMID- 22821084 TI - Unexpected results of a nationwide, treatment-independent assessment of fecal incontinence in patients with anorectal anomalies. AB - PURPOSE: To determine the anorectal function in patients with anorectal malformations (ARM) in order to facilitate patient counseling and follow-up. METHODS: Data were collected by the German network for urorectal malformations (CURE-Net) according to the International Krickenbeck consensus. Questionnaires on bowel function and a defecation protocol were completed by the families/patients. The clinical findings were assessed from the patients' clinical records. RESULTS: Two hundred and ninety-seven patients with ARM were assessed, 175 patients gave complete data on continence, 52 of them were excluded due to mental retardation, age, and earlier type of pullthrough. Complete continence was found in 27 %, perineal fistula in 40 %, rectourethral/vesical in 10 %, vestibular in 24 %, cloaca in 0 %. Krickenbeck grade 1 soiling: 42 %, grade 2 and 3: 31 %. Forty-nine percent of the incontinent patients practiced bowel management, reaching continence in 19 %. The statement of constipation (67 %) was validated with the last clinical findings, showing coprostasis in 46 %, "Not suffering constipation" was confirmed in 61 % and falsified in 29 %. CONCLUSION: ARM patients in Germany, as assessed by independent researchers, show a high rate of fecal incontinence and insufficiently treated constipation. Parents should be counseled accordingly and motivated to engage in consequent follow-up. Intensified efforts in the conservative treatment of constipation and fecal incontinence are crucial to improvement. PMID- 22821085 TI - The ureteroscope-assisted "Mini-Perc" technique of placement of peritoneal dialysis catheters with a 16-Fr Peel-Away sheath: 3-year results in 47 patients. AB - OBJECTIVES: This study was undertaken to evaluate the clinical feasibility, safety and effect of the ureteroscope-assisted "Mini-Perc" technique with a 16-Fr Peel-Away sheath for insertion of peritoneal dialysis catheters in end-stage renal disease (ESRD) patients. PATIENTS AND METHODS: 47 consecutive ESRD patients underwent ureteroscope-assisted placement of peritoneal dialysis catheters via a 16-Fr Peel-Away sheath. Informed consent form was signed by patients under principle of voluntary. RESULTS: The mean duration of the operation was 40 min (range, 21-75 min). Seven patients (14.9 %) experienced mechanical complications: catheter tip migration in 1 patient (2.1 %), slightly bloody ascites in 4 patients (8.5 %) and catheter-related peritonitis in 2 patients (4.3 %). Two catheters (4.3 %) were removed after renal transplantation. One patient (2.1 %) died from heart failure. One catheter (2.1 %) was explanted because of malfunction. After a mean follow-up time of 15 months (range, 2-36 months), 42 catheters are still functioning properly. CONCLUSIONS: The ureteroscope-assisted "Mini-Perc" technique with a 16-Fr Peel-Away sheath is a simple, safe and effective method for placement of peritoneal dialysis catheters in ESRD patients. PMID- 22821086 TI - Molecular cloning, co-expression, and characterization of glycerol dehydratase and 1,3-propanediol dehydrogenase from Citrobacter freundii. AB - 1,3-Propanediol (1,3-PD), an important material for chemical industry, is biologically synthesized by glycerol dehydratase (GDHt) and 1,3-propanediol dehydrogenase (PDOR). In present study, the dhaBCE and dhaT genes encoding glycerol dehydratase and 1,3-propanediol dehydrogenase respectively were cloned from Citrobacter freundii and co-expressed in E. coli. Sequence analysis revealed that the cloned genes were 85 and 77 % identical to corresponding gene of C. freundii DSM 30040 (GenBank No. U09771), respectively. The over-expressed recombinant enzymes were purified by nickel-chelate chromatography combined with gel filtration, and recombinant GDHt and PDOR were characterized by activity assay, kinetic analysis, pH, and temperature optimization. This research may form a basis for the future work on biological synthesis of 1,3-PD. PMID- 22821088 TI - Feminine charm: an experimental analysis of its costs and benefits in negotiations. AB - The authors examined feminine charm, an impression management technique available to women that combines friendliness with flirtation. They asked whether feminine charm resolves the impression management dilemma facing women who simultaneously pursue task (i.e., economic) and social goals in negotiations. They compared women's social and economic consequences after using feminine charm versus a neutral interaction style. They hypothesized that feminine charm would create positive impressions of its users, thus partially mitigating the social penalties women negotiators often incur. They also expected that the degree to which females were perceived as flirtatious (signaling a concern for self), rather than merely friendly (signaling a concern for other), would predict better economic deals for females. Hypotheses were supported across a correlational study and three experiments. Feminine charm has costs and benefits spanning economic and social measures. Theoretical and practical implications are discussed. PMID- 22821089 TI - Heart failure in pregnancy. AB - With increasing maternal age and the presence of comorbid conditions such as hypertension, cardiovascular assessment and monitoring is the responsibility of all clinicians caring for pregnant patients. Furthermore, there are specific conditions, such as mitral stenosis, peripartum cardiomyopathy, and preeclampsia, that can be associated with heart failure and secondary maternal (and fetal) mortality and morbidity. The important causes of heart failure in pregnancy are discussed. PMID- 22821087 TI - Immunological mechanisms for desensitization and tolerance in food allergy. AB - Food allergy is a major public health concern in westernized countries, estimated to affect 5 % of children and 3-4 % of adults. Allergen-specific immunotherapy for food allergy is currently being actively evaluated, but is still experimental. The optimal protocol, in terms of the route of administration of the food, target maintenance dose, and duration of maintenance therapy, and the optimal patient for these procedures are still being worked out. The mechanisms underlying successful food desensitization are also unclear, in part, because there is no standard immunotherapy protocol. The mechanisms involved, however, may include mast cell and basophil suppression, development of food-specific IgG4 antibodies, reduction in the food-specific IgE/IgG4 ratio, up-regulation and expansion of natural or inducible regulatory T cells, a skewing from a Th2 to a Th1 profile, and the development of anergy and/or deletion in antigen-specific cells. Additional studies are required to elucidate and understand these mechanisms by which desensitization and tolerance are achieved, which may reveal valuable biomarkers for evaluating and following food allergic patients on immunotherapy. PMID- 22821090 TI - Fatal tumoral hemorrhage after stereotactic radiosurgery for metastatic brain tumors: report of three cases and review of literature. AB - Acute tumor hemorrhage occurring during stereotactic radiosurgery (SRS) for a metastatic lesion, or in the immediate post-treatment period, is believed to be extremely rare. The potential risk of hemorrhage related to SRS procedures in patients with metastatic brain tumors is not yet clearly understood. This case report describes three patients suffering acute fatal tumor hemorrhage during or immediately after SRS. One patient died within 2 weeks of treatment and the other patients were severely disabled as a result of the hemorrhage. The incidence of this complication was estimated as 0.52% per patient, 0.33% per intervention and 0.08% per lesion by reviewing our research database. Metastases from renal cell carcinoma, evidence of pre-radiosurgical peritumoral oozing of blood, anti coagulant and anti-platelet therapy were likely to be associated with tumor hemorrhage. Although this life-threatening complication is uncommon, extra caution should be exercised when treating patients with factors that could predispose to tumoral hemorrhage. PMID- 22821092 TI - [Laparoscopy-assisted versus open gastrectomy of advanced stomach cancer : a case control study]. PMID- 22821091 TI - [Surgery of gastric cancer in a medium volume center]. AB - BACKGROUND: The aim of the study was to evaluate prognostic factors for the surgical treatment of gastric cancer in a medium volume center. The investigation focused in particular on morbidity and mortality. PATIENTS AND METHODS: From January 2005 to August 2011 a total of 74 patients with gastric cancer were surgically treated in our medium volume center. The study of these patients included morbidity, mortality, UICC (International Union Against Cancer) stage, Lauren classification, surgical therapy procedure, American Society of Anesthesiologists (ASA) classification and duration of surgery. RESULTS: After surgery 11 patients suffered from complications with a morbidity of 14.9% and a mortality of 1.4% (n=1). No significant differences could be detected during the study period. CONCLUSION: In comparison to other studies the morbidity and mortality rates signify similar to better data than complications of high volume centers which might be due to the small group of surgeons who are specialized in gastric surgery. PMID- 22821093 TI - Association of blood group A with coronary artery disease in young adults in Taiwan. AB - OBJECTIVE: We aimed to investigate the association between the ABO blood groups and the risk of coronary artery disease (CAD) and myocardial infartion (MI) in a young Taiwanese population. METHODS: We retrospectively recruited 277 consecutive subjects (men younger than 45 years and women younger than 55 years) who underwent coronary angiography (136 with documented CAD and 129 without CAD) at our center, between 2005 and 2008. Their ABO blood groups were determined using standard agglutination techniques. RESULTS: Patients with CAD showed a significantly different blood group distribution (O, 30.1%; A, 39.7%; B, 26.5%; AB, 3.7%) than that shown by the controls (O, 42.6%; A, 24.0%; B, 27.1%; AB, 6.2%; p=0.032). Patients with blood group A had a greater risk of CAD and MI than those with non-A blood groups (OR=2.08, 95% CI=1.23-3.54; OR=2.21, 95% CI=1.19 4.09, respectively). After adjustment for common cardiovascular risk factors such as age, gender, hypertension, cigarette smoking, diabetes mellitus, body mass index, family history of CAD, and lipid profiles; blood group A remained significantly associated with an increased risk of CAD and MI (OR=2.61, 95% CI 1.11-6.14, p=0.028; OR=3.53, 95% CI=1.21-10.29, p=0.021, respectively). CONCLUSION: Our findings suggest that blood group A is an independent risk factor for CAD and MI in young people in Taiwan. PMID- 22821095 TI - Need for education on the differential diagnosis between chronic glomerulonephritis and nephrosclerosis, and treatment of both conditions to reduce the number of patients requiring hemodialysis in Wakayama. AB - OBJECTIVE: We investigated the present state of, and trends in, hemodialysis therapy in Wakayama, with the aim of identifying present and future problems. METHODS: We compared the number of patients on maintenance hemodialysis, patients newly commencing hemodialysis each year, and proportion of diseases prompting the initiation of hemodialysis, between Wakayama and all Japan from 2002 to 2009, using the CD-ROM, "An overview of dialysis treatment in Japan," published by the Japanese Society for Dialysis Therapy. RESULTS: The number of patients on maintenance hemodialysis per head of population was higher in Wakayama than in all Japan throughout the study period. The number of patients newly commencing hemodialysis per head of population was higher in Wakayama than in all Japan from 2002 to 2004, but no significant difference was seen after 2005. The proportion of patients with chronic glomerulonephritis as the causative disease for hemodialysis initiation was higher in Wakayama than in all Japan. However, nephrosclerosis was less common as the causative condition in Wakayama than in all Japan. The proportions of the different causative diseases were similar in all patients on maintenance hemodialysis in Wakayama as in the newly initiated patients. Accordingly, some patients diagnosed with chronic glomerulonephritis might actually have nephrosclerosis, or treatment may be inadequate. CONCLUSION: In order to reduce the number of patients requiring maintenance hemodailysis, it is important to accurately differentiate between chronic glomerulonephritis and nephrosclerosis, and also to treat patients with either disease appropriately. PMID- 22821094 TI - High body mass index is an important risk factor for the development of type 2 diabetes. AB - OBJECTIVE: The aim of this study was to establish a causal relationship between excess body weight and the onset of diabetes in a retrospective cohort study. METHODS: This 10-year observational cohort study investigated 969 men and 585 women (23 to 80 years of age), who underwent voluntary complete medical check-ups and an annual 75-g oral glucose tolerance test (75 g-OGTT). Participants with fasting plasma glucose >=126 mg/dL, 2-h glucose level in a 75 g-OGTT >=200 mg/dL and/or received medical treatment for type 2 diabetes during the previous year were considered as new-onset diabetics. We assessed the independent contribution of increased BMI to the risk of developing type 2 diabetes with Cox proportional hazard model. RESULT: During the follow-up period, we diagnosed 86 men and 49 women with new-onset type 2 diabetes. In the Cox proportional hazards model, the risk of diabetes mellitus increased with increasing BMI, even after adjusting for age, sex, blood pressure, metabolic profiles, and insulin resistance. In the final model, setting BMI less than 25 as a reference group, the Hazard ratios for diabetes mellitus was 3.12 for those with a BMI of 25-27.4 and it was increased to 3.80 for participants with a BMI of 27.5 or higher. CONCLUSION: Overweight/obesity (high BMI) is an independent and dose-dependent risk factor for type 2 diabetes in overweight Japanese patients. Our results confirmed the usefulness of BMI as a classic parameter, and the importance of lifestyle modification and better management among people with overweight/obesity for prevention of type 2 diabetes mellitus. PMID- 22821096 TI - The effect of comorbidity on the prognosis of acute lung injury and acute respiratory distress syndrome. AB - OBJECTIVE: We conducted a retrospective study assessing the relationship between comorbidity, using the Charlson Comorbidity Index (CCI), and the prognoses of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients. METHODS: We analyzed the data of 47 patients with ALI and ARDS who were admitted to our center between April 2004 and July 2009. The patients were classified into 2 groups (survival and non-survival) 3 months after diagnosis, and demographic and clinical characteristics were analyzed. We also evaluated the ROC curve and Akaike's information criterion (AIC) to determine the most appropriate cut-off level for the CCI at 3 months survival. The survival rate was estimated based on the AIC results. RESULTS: The mean age was 71.0 years; 25 (53%) of the patients died within 3 months of the diagnosis. Although age, etiology of ALI and ARDS, and APACHE II score did not differ between the two groups, smoking history, CCI, SOFA score, and steroid use were higher in the non-survival group than in the survival group. Age was not significantly correlated with CCI; however, CCI had weak, but statistically significant correlations with the APACHE II and SOFA scores (r=0.387, p<0.01 and r=0.288, p<0.05, respectively). AIC analysis revealed that a score of 4 on the CCI was the most appropriate cut off level for 3 months survival. The 3-month survival rate was lower in patients with a CCI>=4 than in those with a CCI<4 (9.5% vs. 55.5%, p<0.05). DISCUSSION: This study showed that the prognosis of ALI and ARDS was affected more by comorbidity than by age, and that the CCI was useful for assessing patient comorbidities in ALI and ARDS. We have to consider that patients with a CCI score of 4 or more are at risk of developing multi-organ failure and have a poor prognosis. PMID- 22821097 TI - Polymicrobial peritonitis following colonoscopic polypectomy in a peritoneal dialysis patient. AB - Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are at an increased risk of peritonitis following colonoscopy with or without polypectomy. Guidelines for peritoneal dialysis patients recommend administration of prophylactic antibiotics and drainage of the abdomen before colonoscopy. In this report, we describe a 53-year-old woman on CAPD who underwent colonoscopy with polypectomy and developed peritonitis within 24 hours. She presented with severe abdominal pain, typical rebounding tenderness, and turbid dialysate containing increased white blood cells with a predominance of neutrophils. A culture of the patient's peritoneal fluid grew polymicrobial species including Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis. She was treated with intraperitoneal and intravenous administration of combination antibiotics, and she fully recovered within 3 weeks. We suggest that nephrologists and endoscopists should be familiar with the risks and follow the guidelines to prevent such complications in CAPD patients. If peritonitis occurs, medical therapy with antibiotics should be considered before surgical intervention for catheter salvage. PMID- 22821098 TI - A survival case of cardiogenic shock due to left main coronary artery myocardial infarction: successful cooperation with on-site percutaneous coronary intervention and helicopter emergency medical service. AB - A 54-year-old man was referred to a local hospital, located about 90 km from our hospital, with cardiogenic shock due to left main coronary artery infarction (LMCA-MI). Percutaneous coronary intervention (PCI) was performed under intra aortic balloon pumping (IABP) support, but resulted in insufficient reperfusion and his condition worsened. The helicopter emergency medical service (HEMS) rapidly transported the patient to our hospital. After percutaneous cardio pulmonary support system (PCPS) insertion, PCI could establish the coronary flow. A series of intensive therapies saved the patient. The cooperation of medical and emergency service system following revascularization and intensive care saved the patient with LMCA-MI accompanied by cardiogenic shock. PMID- 22821100 TI - Long QT syndrome with nocturnal cardiac events caused by a KCNH2 missense mutation (G604S). AB - An 8-year-old boy suffered from an unconsciousness attack and torsade de pointes arrhythmia during sleep or at rest. His electrocardiogram showed prolonged QT intervals, but the T wave morphology was atypical for type 1, 2 or 3 congenital long-QT syndrome (LQTS). Intravenous epinephrine slightly prolonged the QT interval whereas mexiletine infusion shortened the QT interval. Although these clinical characteristics might suggest type 3 LQTS, a genetic analysis identified the G604S-KCNH2 mutation (type 2 LQTS). Because mismatches between the genotype and phenotype of LQTS are possible, genetic analysis of LQTS is important to identify the most appropriate therapeutic option and risk stratification. PMID- 22821099 TI - A case of paradoxical embolic ST-segment elevation myocardial infarction triggered by sleep apnea. AB - This report describes an obese 39-year-old man who experienced ST-segment elevation myocardial infarction with total thrombotic occlusion of the right coronary artery. Culprit vessel flow was improved by aspiration. Data suggested that myocardial infarction had resulted from paradoxical embolus via a patent foramen ovale triggered by the Mueller maneuver, which had induced negative intrathoracic pressure following an acute increase of right-heart volume in the context of obesity and sleep-disordered breathing (SDB). Obesity is increasing among younger populations and it represents a risk for SDB and thrombosis. Thus, this mechanism should be included within the differential diagnosis for myocardial infarction in young patients. PMID- 22821101 TI - Wolff-Parkinson-White syndrome concomitant with idiopathic ventricular fibrillation associated with inferior early repolarization. AB - We encountered a 39-year-old man with documented ventricular fibrillation (VF). His ECGs showed intermittent Wolff-Parkinson-White (WPW) syndrome pattern. During electrophysiological study, no ventricular preexcitation was observed. An accessory pathway located at the posterior mitral annulus was identified, and successfully eliminated by radiofrequency catheter ablation. VF was not induced. His ECGs in the absence of delta waves demonstrated early repolarization in the inferior leads. This case raises the possibility that patients with manifest WPW syndrome may have an arrhythmogenic substrate associated with early repolarization, and the characteristic J waves can be masked by the presence of ventricular preexcitation. PMID- 22821102 TI - Intracardiac thrombus in a young man: don't forget Behcet's disease! AB - Intracardiac thrombosis is an exceptional complication of Behcet's disease. The management of this involvement is difficult due to the risk of recurrence. We present the case of a young man admitted to our hospital for intermittent fever. The microbiologic investigations did not show any causative germ. We discovered a right ventricle thrombus on echocardiography. We confirmed the diagnosis of pulmonary embolism on CT angiogram. The patient developed oral and genital ulcerations which were consistent with Behcet's syndrome. The thrombus had disappeared after treatment with anticoagulant, corticosteroid and immunosuppressors. Intracardiac thrombosis can reveal Behcet's disease. An exhaustive examination and close monitoring should be performed in order to reveal pathognomonic signs as soon as possible and to promptly start the appropriate treatment. PMID- 22821103 TI - Severe hypocalcemia complicated by postsurgical hypoparathyroidism and hungry bone syndrome in a patient with primary hyperparathyroidism, Graves' disease, and acromegaly. AB - We herein report a case of severe postsurgical hypocalcemia associated with primary hyperparathyroidism (pHPT), Graves' disease (GD) and acromegaly (AC). A 54-year-old woman was referred to our clinic for treatment of pHPT and GD. She also had active AC and was clinically diagnosed as multiple endocrine neoplasm type 1 because of pHPT and AC. Two enlarged parathyroid glands were detected by preoperative examinations. We performed total parathyroidectomy and thyroidectomy. After the operation, she showed severe hypocalcemia induced by postsurgical hypoparathyroidism and hungry bone syndrome. This is a rare case of postsurgical severe hypocalcemia associated with pHPT, GD and AC. PMID- 22821104 TI - Case of type 1 diabetes mellitus following interferon beta-1a treatment for multiple sclerosis. AB - A 57-year-old woman who had been treated with interferon beta-1a (IFNbeta-1a) for multiple sclerosis was diagnosed with diabetic ketosis. Her fasting serum C peptide (F-CPR) was 1.9 ng/mL and her daily urinary C-peptide (U-CPR) was 24.1 ug/day. Her anti-glutamic acid decarboxylase (GAD) antibody was 3.5 U/mL. Seven months later, she was hospitalized with body weight loss and a high level of hemoglobin A1c [11.1% (JDS)]. Her F-CPR and U-CPR were very low (0.1 ng/mL and 8.35 ug/day, respectively), and anti-GAD antibody became distinctly positive (12.4 U/mL). She had HLA-DRB1*04:05, A24, and B54. For these reasons, IFNbeta-1a administration was considered a possible cause of type 1 diabetes mellitus in this case. PMID- 22821105 TI - A case of hereditary xanthinuria type 1 accompanied by bilateral renal calculi. AB - Hereditary xanthinuria is an extremely rare purine metabolism disorder caused by a genetic abnormality in xanthine dehydrogenase. A new case of hereditary xanthinuria type 1 accompanied by bilateral renal calculi was encountered. We performed an allopurinol loading test and diagnosed classical type 1 xanthinuria. Through genetic diagnosis, we identified a mutation site in the xanthine dehydrogenase gene. Genetic analysis revealed a homozygous deletion of cytosine 2,567 in the xanthine dehydrogenase gene, and as a result, a stop codon was formed at position 928. Renal failure caused by the deposition of xanthine crystals is a known complication because xanthine is poorly soluble in water. With high fluid intake and low purine diet, no significant increase in calculi has been observed in this patient for 2 years. PMID- 22821106 TI - Minimal change nephrotic syndrome complicated with malignant ascites in a patient with type II diabetes. AB - A large number of renal biopsy studies have shown the concurrent presence of non diabetic renal disease in diabetics. This report describes one such diabetic female patient with nephrotic syndrome due to minimal change glomerular disease who was successfully treated with prednisolone. Despite the remission of her nephrotic syndrome, she had gradual development of malignant ascites, which was finally interpreted to be linked to primary peritoneal carcinoma. It is necessary to bear in mind that malignancies may not only be the underlying etiology for paraneoplastic glomerular injuries, but also can be an independent pathogenic process, regardless of their nephrotic status during the overall management of the patients with ascites. PMID- 22821107 TI - Azathioprine hypersensitivity presenting as cardiogenic shock and Sweet's syndrome in a patient with microscopic polyangiitis. AB - Azathioprine hypersensitivity is a clinical syndrome which may manifest from isolated fever and rash to multi-organ failure. This rare condition is usually self-limiting following the discontinuation of azathioprine. Therefore, it is important to maintain a high index of clinical suspicion for hypersensitivity reactions with azathioprine therapy. We report a case of azathioprine hypersensitivity in a 69-year-old woman who developed cardiogenic shock and Sweet's syndrome following the initiation of azathioprine for her underlying autoantibodies to neutrophil cytoplasmic antigens (ANCA) associated microscopic polyangiitis. PMID- 22821108 TI - A case of combined sarcoidosis and usual interstitial pneumonia. AB - Sarcoidosis is a systemic granulomatous disease of unknown etiology with characteristic pulmonary lesions, which are often distributed in the upper lung fields. We describe a unique case of sarcoidosis with lower lung field-dominant reticular shadows. Three years after the diagnosis of sarcoidosis based on histologic findings of the mediastinal lymph nodes and transbronchial lung biopsy specimens, the patient developed acute respiratory failure and died. The autopsy showed usual interstitial pneumonia (UIP), with honeycombing and superimposed diffuse alveolar damage of the lungs. The findings suggest that the patient had both sarcoidosis and UIP, and that the UIP later progressed to acute exacerbation. PMID- 22821110 TI - Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis. AB - Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results. PMID- 22821109 TI - Thrombolytic therapy for cardiac arrest due to pulmonary embolism after varicose vein surgery. AB - Anticoagulant therapy is the mainstay in the management of venous thromboembolism. Nevertheless, the situation is entirely different in the patients with submassive or massive pulmonary embolism (PE) and cardiac arrest, and the diagnosis and therapy strategy for such conditions are lacking. This patient, who presented with a cardiac arrest event after varicose vein surgery, was diagnosed as acute pulmonary embolism. She survived after administration of 50 mg recombinant tissue plasminogen activator (rt-PA) for over half an hour, along with continued anticoagulant therapy. Unfortunately, gastrointestinal and cerebral hemorrhaging occurred during the process. PMID- 22821111 TI - FDG-PET and chemotherapy for successful diagnosis and treatment of cardiac metastasis from non-small cell lung cancer. AB - Non-small cell lung cancer was metastasized at the septal side of right atrium in 59-year-old woman who had undergone surgery for lung cancer 11 years ago. The cardiac metastasis was found by whole-body 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT), and cytologically confirmed by myocardial aspiration biopsy with right heart catheterization. The patient was treated with 4 cycles of carboplatin/pemetrexed followed by maintenance therapy with pemetrexed. The metastatic cardiac tumor shrank, and the atrioventricular (AV) block in ECG was improved. In this case, FDG-PET and chemotherapy were valuable for diagnosis and treatment of cardiac metastasis from non-small cell lung cancer. PMID- 22821112 TI - Isolated ACTH deficiency presenting with a glucocorticoid-responsive triphasic wave coma. AB - We report the case of a 58-year-old woman who presented with acutely developed coma characterized by electroencephalographic triphasic waves (TWs) in the absence of metabolic derangement. The patient's coma and TWs were promptly resolved after the administration of glucocorticoids, and thereafter isolated ACTH deficiency was diagnosed. Isolated ACTH deficiency may present with glucocorticoid-responsive acute encephalopathy without hypoglycemia, hyponatremia, or systemic hypotension. Electroencephalographic TWs or bursts of slow waves may be a clue to the diagnosis of this rare condition in patients with coma of unknown origin. PMID- 22821113 TI - Amyotrophic lateral sclerosis with demyelinating neuropathy. AB - Amyotrophic lateral sclerosis (ALS) with demyelinating polyneuropathy is a rare condition. We describe two ALS patients with demyelinating neuropathy. Immunomodulatory therapies brought slight symptomatic benefits to the patients, but the treatments could not halt the progression of ALS. Chance coincidence of the two diseases is unlikely in view of the low prevalence. ALS, mainly consisting of progressive axonal degeneration, might show temporal demyelinating features of peripheral nerves both electrophysiologically and pathologically. The pathomechanism for the demyelination in ALS remains to be elucidated. PMID- 22821114 TI - Pulmonary Mycobacterium kyorinense disease showed clinical improvement following combined therapy with clarithromycin and levofloxacin. AB - A 63-year-old man with a past history of resection of pulmonary adenocarcinoma and COPD visited our hospital because of fever, cough and purulent sputum. Chest CT showed an infiltration shadow with multiple bullae in the right lung. There was a slight elevation of the inflammatory response. We established a definitive diagnosis by frequent isolation of Mycobacterium kyorinense on a sputum culture test of acid-fast bacilli. Clarithromycin and levofloxacin were administered after identification of M. kyorinense using a 16S rRNA gene sequence. Subsequently his symptoms improved following combined therapy with clarithromycin and levofloxacin. PMID- 22821115 TI - Kikuchi-Fujimoto disease mimicking tuberculous lymphadenitis. AB - A 28-year-old woman was referred to our hospital for treatment of tuberculous lymphadenitis, after presenting with fever, left cervical lymphadenopathy, and a positive interferon-gamma release assay (QuantiFERON(r)-TB Gold In-Tube; QFT) result. Surprisingly, biopsy specimens of the cervical lymph nodes showed necrotic lesions with prominent nuclear debris and a proliferation of histiocytes, consistent with Kikuchi-Fujimoto disease (KFD). A diagnosis was made of KFD complicated by latent tuberculosis infection (LTBI), and all symptoms had resolved completely two months post-diagnosis. KFD may be misdiagnosed as tuberculous lymphadenitis, and antibiotics unnecessarily prescribed. Careful attention should therefore be paid when diagnosing cervical lymphadenopathy. PMID- 22821116 TI - Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccination. AB - Since the worldwide spread of the novel influenza type A virus in 2009, trivalent vaccines against H1N1 (pandemic) 09 and seasonal influenza have been used. We describe a 33-year-old woman who presented with hypoesthesia below the Th7 level fifteen days after vaccination without any preceding infection. Cerebrospinal fluid showed an increased level of myelin basic protein and positive oligoclonal IgG bands. Magnetic resonance imaging revealed disseminated lesions in the brain and thoracic cord. Steroid therapy improved her symptoms. She was diagnosed as having acute disseminated encephalomyelitis (ADEM) possibly related to the vaccination. As a potential adverse effect of the influenza vaccine, in addition to Guillain-Barre syndrome, ADEM should also be recognized. PMID- 22821117 TI - Syncope in a patient with giant bladder diverticulum. AB - Syncope is common in clinical practice, but the cause is often difficult to diagnose. We report a 75-year-old man who was referred to the emergency department because of syncope after an urgent sensation of urinating during jogging. He was finally diagnosed as having a giant bladder diverticulum due to prostatic hyperplasia accompanied by neurally mediated syncope. Excessive urinary retention is a possible cause of not only giant bladder diverticula but also syncope due to vagal enhancement. PMID- 22821118 TI - Takayasu arteritis. PMID- 22821119 TI - Angina as a manifestation of constrictive pericarditis. PMID- 22821120 TI - J-point elevation induced by double master two-step test. PMID- 22821121 TI - Thoracic aortic pseudoaneurysm which ruptured into the left lung. PMID- 22821122 TI - Intermittent blockade of a mechanical mitral valve prosthesis. PMID- 22821123 TI - Metastatic gastric cancer from squamous cell lung carcinoma. PMID- 22821124 TI - T2*-weighted MRI findings of superficial siderosis. PMID- 22821125 TI - Superficial siderosis due to pseudomeningocele. PMID- 22821126 TI - Micrographia and abulia due to frontal subcortical infarction. PMID- 22821127 TI - Clinicoradiological analysis of the oculomotor fasciculus. PMID- 22821129 TI - Covalent organic frameworks. AB - Covalent organic frameworks (COFs) are a class of crystalline porous polymers that allow the atomically precise integration of organic units to create predesigned skeletons and nanopores. They have recently emerged as a new molecular platform for designing promising organic materials for gas storage, catalysis, and optoelectronic applications. The reversibility of dynamic covalent reactions, diversity of building blocks, and geometry retention are three key factors involved in the reticular design and synthesis of COFs. This tutorial review describes the basic design concepts, the recent synthetic advancements and structural studies, and the frontiers of functional exploration. PMID- 22821130 TI - Evaluating medical marijuana dispensary policies: spatial methods for the study of environmentally-based interventions. AB - In 1996, California was the first state to pass a Compassionate Use Act allowing for the legal use of marijuana for medical purposes. Here we review several current policy and land use environmental interventions designed to limit problems related to the influx of medical marijuana dispensaries across California cities. Then we discuss the special challenges, solutions, and techniques used for studying the effects of these place-based policies. Finally, we present some of the advanced spatial analytic techniques that can be used to evaluate the effectiveness of environmental interventions, such as those related to reducing problems associated with the proliferation of medical marijuana dispensaries. Further, using data from a premise survey of all the dispensaries in Sacramento, this study will examine what characteristics and practices of these dispensaries are related to crime within varying distances from the dispensaries (e.g., 100, 250, 500, and 1,000 feet). We find that some security measures, such as security cameras and having a door man outside, implemented by medical marijuana dispensary owners might be effective at reducing crime within the immediate vicinity of the dispensaries. PMID- 22821132 TI - Organizations work to develop guidelines for survivorship care. National resource center, patient surveillance efforts planned. PMID- 22821131 TI - CD86 gene variants and susceptibility to pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. CD86 (B7-2) is a costimulatory molecule on antigen-presenting cells and plays critical roles in tumor immunity. It has been reported that polymorphisms in CD86 gene can be involved in the development of various cancers. Here, we investigated the association of two CD86 polymorphisms, +1057G/A (rs1129055) and +2379G/C (rs17281995), with pancreatic cancer in the Chinese population. METHODS: The two polymorphisms were identified in 369 pancreatic cancer patients and 412 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were analyzed by chi-square test and adjusted for body mass index, smoking, drinking, and diabetes status. RESULTS: Results showed that the frequency of the +1057A allele was significantly higher in pancreatic cancer cases than in controls (59.8 vs. 52.8 %, p = 0.021). Comparison of genotype frequencies showed that +1057GA and +1057AA genotypes were significantly increased in the pancreatic cancer group (odds ratio (OR) = 1.52; 95 % confidence interval (CI), 1.09-2.38; p = 0.026; and OR = 1.90; 95 % CI, 1.21-3.01; p = 0.007). We did not find any association between the +2379G/C polymorphism and pancreatic cancer. Analysis of haplotypes indicated that the AG (+1057, +2379) haplotype was correlated with the susceptibility to this disease (p = 0.019). CONCLUSIONS: These results suggest that the CD86 +1057G/A polymorphism and AG (+1057, +2379) haplotype are genetic risk factors for pancreatic cancer. PMID- 22821135 TI - Evaluation of bicinchoninic acid as a ligand for copper(I)-catalyzed azide-alkyne bioconjugations. AB - The Cu(I)-catalyzed cycloaddition of terminal azides and alkynes (click chemistry) represents a highly specific reaction for the functionalization of biomolecules with chemical moieties such as dyes or polymer matrices. In this study we evaluate the use of bicinchoninic acid (BCA) as a ligand for Cu(I) under physiological reaction conditions. We demonstrate that the BCA-Cu(I)-complex represents an efficient catalyst for the conjugation of fluorophores or biotin to alkyne- or azide-functionalized proteins resulting in increased or at least equal reaction yields compared to commonly used catalysts like Cu(I) in complex with TBTA (tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine) or BPAA (bathophenanthroline disulfonic acid). The stabilization of Cu(I) with BCA represents a new strategy for achieving highly efficient bioconjugation reactions under physiological conditions in many application fields. PMID- 22821136 TI - Public perception of Tourette syndrome on YouTube. AB - We sought to determine public perception surrounding Tourette syndrome through viewers' responses to videos on YouTube. The top 20 videos on YouTube for search terms Tourette's, Tourette's syndrome, Tourette syndrome and tics were selected. The portrayal of Tourette syndrome was assessed as positive, negative, or neutral. Top 10 comments for each video were graded as "sympathetic," "neutral," or "derogatory." A total of 14 970 hits were obtained and 41 videos were retained, with an average of 590 113 views (1369 to 13 747 069) and 1761 comments (0 to 35 241). Twenty-two percent of videos retained portrayed Tourette syndrome negatively, 20% were neutral and 59% positive. Negative portrayals were significantly associated with more views (Spearman correlation rho = -.46, P =.003) and comments (Spearman correlation rho = -.47, P = .002). Although excellent examples of Tourette syndrome are available on YouTube, the popularity of negative portrayals may reinforce existing stigma in society. PMID- 22821137 TI - Robert J. Joynt, MD, PhD: a tribute. PMID- 22821140 TI - Factors associated with complete local excision of small rectal carcinoid tumor. AB - PURPOSE: Although small rectal carcinoid tumors can be treated using local excision, complete resection can be difficult because tumors are located in the submucosal layer. We evaluate the factors associated with pathologically complete local resection of rectal carcinoid tumors. METHODS: Data were analyzed of 161 patients with 166 rectal carcinoid tumors who underwent local excision with curative intent from January 2001 to December 2010. A pathologically complete resection (P-CR) was defined as an en bloc resection with tumor-free lateral and deep margins. The study classified treatments into three categories for analysis: conventional polypectomy (including strip biopsy, snare polypectomy, and hot biopsy), advanced endoscopic techniques (including endoscopic mucosal resection with cap and endoscopic submucosal dissection), and surgical local excision (including transanal excision and transanal endoscopic microsurgery). We evaluated the P-CR rate according to treatment method, tumor size, initial endoscopic impression and the use of endoscopic ultrasound (EUS) or transrectal ultrasound (TRUS). RESULTS: The mean tumor size was 5.51 +/- 2.43 mm (range 2-18 mm) and all lesions were confined to the submucosal layer. The P-CR rates were 30.9, 72.0, and 81.8 % for conventional polypectomy, advanced endoscopic techniques, and surgical local excision, respectively. Univariate analysis showed that P-CR was associated with treatment method, use of EUS or TRUS, and initial endoscopic impression. Multivariate analysis showed that only treatment method was associated with P-CR. CONCLUSION: Pathologically complete resection of small rectal carcinoid tumors was more likely to be achieved when using advanced endoscopic techniques or surgical local excision rather than conventional polypectomy. PMID- 22821139 TI - Combining patient-level and summary-level data for Alzheimer's disease modeling and simulation: a beta regression meta-analysis. AB - Our objective was to develop a beta regression (BR) model to describe the longitudinal progression of the 11 item Alzheimer's disease (AD) assessment scale cognitive subscale (ADAS-cog) in AD patients in both natural history and randomized clinical trial settings, utilizing both individual patient and summary level literature data. Patient data from the coalition against major diseases database (3,223 patients), the Alzheimer's disease neruroimaging initiative study database (186 patients), and summary data from 73 literature references (representing 17,235 patients) were fit to a BR drug-disease-trial model. Treatment effects for currently available acetyl cholinesterase inhibitors, longitudinal changes in disease severity, dropout rate, placebo effect, and factors influencing these parameters were estimated in the model. Based on predictive checks and external validation, an adequate BR meta-analysis model for ADAS-cog using both summary-level and patient-level data was developed. Baseline ADAS-cog was estimated from baseline MMSE score. Disease progression was dependent on time, ApoE4 status, age, and gender. Study drop out was a function of time, baseline age, and baseline MMSE. The use of the BR constrained simulations to the 0-70 range of the ADAS-cog, even when residuals were incorporated. The model allows for simultaneous fitting of summary and patient level data, allowing for integration of all information available. A further advantage of the BR model is that it constrains values to the range of the original instrument for simulation purposes, in contrast to methodologies that provide appropriate constraints only for conditional expectations. PMID- 22821141 TI - Colon ischaemia following surgery for sigmoid colon and rectal cancer. PMID- 22821142 TI - Surgical management of rectal cancer in pregnancy. PMID- 22821144 TI - How perceived exposure to environmental harm influences environmental behavior in urban China. AB - Rapid environmental degradation in China makes understanding how perceived exposure to environmental harm influences environmental attitudes and participation in pro-environmental behaviors among the Chinese people crucial. We used a nation-wide survey dataset in urban China to test two hypotheses: experiencing environmental harm directly affects environmental behavior; environmental attitudes mediate the relationship between experiencing environmental harm and environmental behavior. We found respondents who experienced environmental harm had more pro-environmental attitudes. Experiencing environmental harm positively influenced pro-environmental behavior both directly and indirectly through the mediation of pro-environmental attitudes. Among the pro-environmental behaviors, environmental litigation was most strongly related with exposure to environmental harm. Our results suggest that more participation in pro-environmental behaviors may be expected as rapid economic development increases public exposure to environmental harm in urban China. PMID- 22821143 TI - The role of eNSCs in neurodegenerative disease. AB - Recent progress in biology has shown that many if not all adult tissues contain a population of stem cells. It is believed that these cells are involved in the regeneration of the tissue or organ in which they reside as a response to the natural turnover of differentiated cells or to injury. In the adult mammalian brain, stem cells in the subventricular zone and the dentate gyrus may also play a role in the replacement of neurons. A positive beneficial response to injury does not necessarily require cell replacement. New findings suggest that some populations of endogenous neural stem cells in the central nervous system may have adopted a function different from cell replacement and are involved in the protection of neurons in diverse paradigms of disease and injury. In this article, we will focus on the immature cell populations of the central nervous system and the signal transduction pathways that regulate them which suggest new possibilities for their manipulation in injury and disease. PMID- 22821145 TI - Reducing risks to rural water security in Africa. PMID- 22821146 TI - Where should the tip of the needle be located in ultrasound-guided peripheral nerve blocks? AB - PURPOSE OF REVIEW: Data now exist describing the appropriate positioning of the needle tip and pattern of local anaesthetic spread after injection. The recent literature has been analysed in search of studies on the optimal procedure for common approaches centred on block efficacy, performance time, and safety. RECENT FINDINGS: Large peripheral nerves are surrounded by a gliding layer, the adventitia or paraneurium. Ultrasonically, a circumneural spread corresponds to adventitial extraneural injection. Nerve expansion with fascicular separation matches intraneural injection. Deliberate intraneural injection remains controversial, and is not advisable at the present time. For popliteal sciatic nerve blocks, positioning the needle in the common nerve sheath between the tibial and peroneal components and obtaining a circumneural spread surrounding both divisions predict rapid surgical anaesthesia. Using axillary and infraclavicular approaches, ultrasound-guided perivascular injection aiming at circumferential spread around the artery appears a valuable alternative to individual targeted nerve injections. For single injection interscalene block, an injection into the fascial sheath but far from the plexus proved to be as effective as an injection adjacent to the nerve structures. Fascial plane approaches are appealing alternatives for thin nerves that run between muscles and cannot be regularly visualized with the current resolution of ultrasound systems. SUMMARY: The ultrasound appearance of nerves and target injections are better understood. The specific distributions of local anaesthetic spread that predict success are significantly different from one anatomical site to another. It seems advisable to avoid intraneural injection. PMID- 22821147 TI - Prehospital management of severe traumatic brain injury: concepts and ongoing controversies. AB - PURPOSE OF REVIEW: Prehospital management affects long-term outcome of patients with severe traumatic brain injury (TBI). This article reviews the current concepts and ongoing controversies of prehospital treatment of severe TBI. RECENT FINDINGS: Prehospital management focuses on the prevention of secondary brain injury and rapid transport to a neurotrauma center for definitive diagnosis and life- as well as brain-saving emergency treatment such as decompressive craniotomy. There is a broad consensus that adequate airway management, prevention of hypoxia, hypocapnia or hypercapnia, prevention of hypotension and control of hemorrhage represent preclinical therapeutic modalities that may contribute to improved survival in severe TBI. The precise role of prehospital endotracheal intubation, osmotic agents and early therapeutic hypothermia needs to be clarified in the context of time required for transportation, local infrastructure, geographical factors and availability of experienced emergency teams. SUMMARY: Prehospital management of TBI remains challenging. There are no universal objectives suitable to all patients. Randomized, controlled clinical trials are necessary for developing optimal protocols for paramedic and physician emergency medical teams. PMID- 22821148 TI - Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. AB - Anticancer properties of Garcinia indica-derived garcinol are just beginning to be elucidated. We have earlier reported its cancer cell-specific induction of apoptosis in breast cancer cells, which was mediated through the downregulation of NF-kappaB signaling pathway. To gain further mechanistic insight, here, we show for the first time that garcinol effectively reverses epithelial-to mesenchymal transition (EMT), that is, it induces mesenchymal-to-epithelial transition (MET) in aggressive triple-negative MDA-MB-231 and BT-549 breast cancer cells. This was associated with upregulation of epithelial marker E cadherin and downregulation of mesenchymal markers vimentin, ZEB-1, and ZEB-2. We also found that garcinol upregulates the expression of miR-200 and let-7 family microRNAs (miRNAs), which provides a molecular mechanism for the observed reversal of EMT to MET. Transfection of cells with NF-kappaB p65 subunit attenuated the effect of garcinol on apoptosis induction through reversal of MET to EMT. Forced transfection of p65 and anti-miR-200s could also reverse the inhibitory effect of garcinol on breast cancer cell invasion. Moreover, treatment with garcinol resulted in increased phosphorylation of beta-catenin concomitant with its reduced nuclear localization. The results were also validated in vivo in a xenograft mouse model where garcinol was found to inhibit NF-kappaB, miRNAs, vimentin, and nuclear beta-catenin. These novel findings suggest that the anticancer activity of garcinol against aggressive breast cancer cells is, in part, due to reversal of EMT phenotype, which is mechanistically linked with the deregulation of miR-200s, let-7s, NF-kappaB, and Wnt signaling pathways. PMID- 22821149 TI - BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. AB - Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC(50) values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials. PMID- 22821150 TI - Effect of laser preparation on bond strength of a self-adhesive flowable resin. AB - The aim of this in vitro study was to evaluate the effect of laser treatment on shear bond strength of a self-adhesive flowable resin composite to human dentin. Eighty extracted sound human molar teeth were used for the study. The teeth were sectioned mesiodistally and embedded in acrylic blocks. The dentin surfaces were ground wet with 600-grit silicon carbide (SiC) paper. They were randomly divided into two preparation groups: laser (Er:YAG laser, with 12 Hz, 350 mJ energy) and control (SiC). Each group was then divided into two subgroups according to the flowable resin composite type (n = 20). A self-adhesive flowable (Vertise Flow) and a conventional flowable resin (Premise Flow) were used. Flowable resin composites were applied according to the manufacturer's recommendations using the Ultradent shear bond Teflon mold system. The bonded specimens were stored in water at 37 degrees C for 24 h. Shear bond strength was tested at 1 mm/min. The data were logarithmically transformed and analyzed using two-way analysis of variance and Student-Newman-Keul's test at a significance level of 0.05. The self adhesive flowable resin showed significantly higher bond strength values to laser prepared surfaces than to SiC-prepared surfaces (p < 0.001). The conventional flowable resin did not show such differences (p = 0.224). While there was a significant difference between the two flowable resin composites in SiC-prepared surfaces (p < 0.001), no significant difference was detected in laser-prepared surfaces (p = 0.053). The bond strength of a self-adhesive flowable resin composite differs according to the type of dentin surface preparation. Laser treatment increased the dentin bonding values of the self-adhesive flowable resin. PMID- 22821151 TI - Isolation and characterization of Cyniclomyces guttulatus (Robin) Van Der Walt and Scott, 1971 in dogs in Brazil. AB - Vegetative cells of an ascomycetous yeast, morphologically consistent with published descriptions of Cyniclomyces guttulatus, were observed in large numbers in the feces and stomach washes of three dogs with a recurrent medical history characterized by vomiting and diarrhea. Nucleotide sequence analysis of an approximately 600 base pair fragment of the variable D1/D2 domain of large subunit (26S) ribosomal DNA of a pure culture, isolated from a Siberian Husky, revealed 98-99 % homology to sequences deposited in the GenBank as C. guttulatus. These data represent the first observation of C. guttulatus in association with canine gastrointestinal illness in the southern hemisphere and add weight to the hypothesis that this yeast may act as an opportunistic pathogen of dogs. An extended examination of wet mounts and smears prepared from feces collected from 63 dogs with no clinical symptoms of gastrointestinal illness, identified C. gluttulatus in 14 (22.2 %) of the animals, albeit at lower numbers than in diseased dogs, indicating that this yeast species is widely distributed as a component of the normal microflora of the canine gastrointestinal tract. PMID- 22821152 TI - [Therapy of lymphedema]. AB - Lymphedema is a chronic and progressive disease when untreated. It can be assumed that more than 5% of the population suffer from a form of lymphedema. The therapy options depend on the individual symptoms and the wishes of the patient and include conservative measures as well as surgery or a combination of both. PMID- 22821153 TI - Chronic myeloid leukemia: state of the art in 2012. AB - The prognosis of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) has been revolutionized since the discovery of the pathogenetic role of BCR-ABL and the invention of tyrosine kinase inhibitors (TKIs). With a follow-up of 8 years, patients had an OS of 85 % and, with second generation TKIs, dasatinib and nilotinib, almost 50 % of the resistant patients gained a remission with an OS over 90 % at 2 years. Currently the challenge is preventing resistance leading to progression to advance phases that have still few chances of effective treatment. Another objective, derived from the needs of our patients, beside the pride of the scientist, is the discontinuation of the treatment. Second generations TKIs applied to the first line setting seem to be a good option either to avoid progression and to achieve deeper rates of molecular response, necessary for the cure. PMID- 22821154 TI - [Evaluation of the detectability of vascular stenosis using non-contrast magnetic resonance angiography with various electrocardiographically-gated three dimensional fast spin echo sequences]. AB - Various three-dimensional fast spin echo (3D-FSE) sequences are used for non contrast magnetic resonance angiography (MRA). Differences in the ability to detect vascular stenosis using these sequences, however, have not yet been evaluated. The purpose of this study is to evaluate the usefulness of each sequence for the detection of vascular stenosis by using a vascular phantom. The phantom consisting of silicon tubes with 30% and 70% stenosis of luminal diameter and fluids close to T2 value of blood were used for the study. Non contrast MRA with half-Fourier acquisition single-shot turbo spin echo (HASTE) noncontrast magnetic resonance angiography of arteries and veins (NATIVE), sampling perfection with application optimized contrasts using different flip angle evolutions (SPACE)-NATIVE, fresh blood imaging (FBI) and triggered angiography non contrast enhanced (TRANCE) sequences was performed by using the phantom which can be varied in terms of the steady flow velocity. Each stenosis was quantitatively estimated by the stenosis index (SI) calculated from the signal intensities on acquired images. The signal intensity of the non-stenotic vascular site markedly decreased at more than a flow rate of 20 cm/s in all sequences. Significant decrease in the signal intensity was observed in the distal point from the stenosis area on these images acquired by using HASTE NATIVE and FBI sequences. FBI and TRANCE sequences showed a more accurate SI for 30% stenosis than HASTE-NATIVE and SPACE-NATIVE sequences. SI for 70% stenosis was overestimated in all sequences at 5 cm/s of diastolic flow rate. In conclusion, the ability to detect vascular stenosis on non-contrast MRA image using 3D-FSE sequences depends on the image quality during diastolic phase in the cardiac cycle. FBI and TRANCE sequences are useful to detect the mild arterial stenosis. PMID- 22821155 TI - [Influence of high-definition multileaf collimator for three-dimensional conformal radiotherapy and intensity-modulated radiotherapy of prostate cancer]. AB - The focus of this work is to evaluate the dosimetric impact of treatment planning for three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) of prostate cancer using Varian/BrainLAB 120-leaf high definition multileaf collimator (HD120 MLC) with 2.5 mm leaf width and Varian 120 leaf millennium multileaf collimator (M120 MLC) with 5 mm leaf width. We measured the leaf transmission and dosimetric leaf gap (DLG) of two multileaf collimator (MLC) systems using Farmer ionization chamber. The dosimetric impact of treatment planning for 3DCRT and IMRT of prostate cancer for ten clinical cases using two MLC systems was evaluated quantitatively. 3DCRT was divided to 3DCRT(middle) as fitting at middle of leaf tip and 3DCRT(outside) as fitting at outside of leaf tip. The leaf transmission factor and DLG of HD120 MLC for 6 and 10 MV X-ray decreased by 0.2% and 1 mm, respectively, compared to M120 MLC. The mean conformity index of PTV of treatment planning for prostate 3DCRT(middle), 3DCRT(outside) , and IMRT decreased by 0.9%, 6.6%, and 0.9% and the mean homogeneity index increased 2.3%, 13.0%, and 4.2%, respectively. The mean V20, V40, and V65 decreased by 2.4%, 6.6%, and 4.5% for bladder and 3.3%, 6.1%, and 5.9% for rectum, respectively. The results of this work demonstrated that the dose conformity of PTV improved and the dose of bladder and rectum decreased for 3DCRT and IMRT of prostate cancer using HD120 MLC compared to M120 MLC, because of reduction of leaf width, leaf transmission, and rounded leaf end transmission. PMID- 22821156 TI - [Estimating elapsed time of brain hemorrhage using computed tomography value based parameters]. AB - We measured the time-dependent change of computed tomography (CT) values for a blood sample in a syringe during 20 days expecting that the (average, maximum) CT values may be used to estimate the elapsed time after hemorrhage. The average CT value (CT(ave)) rapidly increased for the first 50 min. The maximum CT value (CT(max)) increased step by step to take the largest value (82.4 HU) one day later, and subsequently the CT(max) decreased slowly to become 72.0 HU 20 days later. We conclude that the rapid increase of the CT(ave) at the beginning is due to the fibrin generation, the increase of the CT(max) is a result of the formation of the fibrin net, and the subsequent decrease of CT(max) is caused by fibrinolysis. Tentative experimental formula for the time-dependent CT(max) change at each increasing stage and decreasing stage are given to estimate the elapsed time after hemorrhage. PMID- 22821157 TI - [Usefulness of lower extremity magnetic resonance venography with two-dimensional spiral gradient echo sequence and effect of patient positioning during the visualization of lower extremity veins]. AB - PURPOSE: We examined the two-dimensional-spiral-gradient-echo (2D-spiral-GRE) for magnetic resonance venography (MRV). In addition, five variations in patient positioning of the MRV were investigated to determine the best method of visualizing. METHODS: First, flow phantom experiments were performed on a 1.5 T scanner. Using a flow phantom, the authors aimed to (1) measure the optimal TR (40, 60, 140, 190 ms), (2) measure the flip angle (20-60 degrees) and (3) determine the optimal combination of saturation pulse (S, I, A, P, R, L) and half acquisition method for MRV. Secondly, ten volunteers without vessel disease were imaged by phase contrast sequence for measured mean value of the venous area and velocity of the femoral and popliteal vein. The volunteers' MRV images were compared qualitatively on visualization. RESULTS: There is better demonstration of the veins under the longer repetition time (TR), resulting in a setting of 2-3 acquisitions ordering. Because the fluid or blood has been irradiated with pulsed radiofrequency multiple times, optimal FA was about 40 degrees. Combination of saturation pulse was slightly effective and the best saturation effect was seen in the half acquisition method. Volunteer study patient positioning, which involves the slight lifting up of the upper half of the body and continuous warming of the feet, has brought about a larger area and a slower velocity in the lower extremity veins. The greater veins and peripheral veins were demonstrated more accurately. CONCLUSION: 2D-spiral-GRE sequence was a useful method for lower extremity MRV. Furthermore, the most effective patient positioning for the lower extremity MRV was slightly lifting up the upper half of the body and continuously warming the feet. These enabled the best results to be obtained in the lower extremity MRV. PMID- 22821159 TI - [Constructing a database that can input record of use and product-specific information]. AB - In Japan, patients were infected by viral hepatitis C generally by administering a specific fibrinogen injection. However, it has been difficult to identify patients who were infected as result of the injections due to the lack of medical records. It is still not a common practice by a number of medical facilities to maintain detailed information because manual record keeping is extremely time consuming and subject to human error. Due to these reasons, the regulator required Medical device manufacturers and pharmaceutical companies to attach a bar code called "GS1-128" effective March 28, 2008. Based on this new process, we have come up with the idea of constructing a new database whose records can be entered by bar code scanning to ensure data integrity. Upon examining the efficacy of this new data collection process from the perspective of time efficiency and of course data accuracy, "GS1-128" proved that it significantly reduces time and record keeping mistakes. Patients not only became easily identifiable by a lot number and a serial number when immediate care was required, but "GS1-128" enhanced the ability to pinpoint manufacturing errors in the event any trouble or side effects are reported. This data can be shared with and utilized by the entire medical industry and will help perfect the products and enhance record keeping. I believe this new process is extremely important. PMID- 22821158 TI - [Optimization of the chest computed tomography scan by varying the position of the arms]. AB - Computed tomography automatic exposure control (CT-AEC) technique is calculated from a localizer radiograph. When we perform neck and chest CT examination, at first, we acquire localizer radiograph and neck images by placing the arm in a lowered position. Next, the arm is raised for the chest scan. Therefore, the localizer radiograph and subject information are different in the chest scan. In this situation, the chest scan with the use of the CT-AEC causes radiation over dose. The purpose of this study is to optimize the CT-AEC by controlling noise index (NI), and make a chest CT scan condition considering the position of the arms. We measured the image noise (SD) in the phantom by using CT-AEC. In addition, dose length product (DLP) was recorded. Moreover, we examined the correlation with the clinical images. The results of our experiments show that radiation dose can be reduced with the image quality kept by controlling NI. PMID- 22821160 TI - [Fundamental study of three-dimensional coherent oscillatory state acquisition for the manipulation of image contrast: 3D-COSMIC in the spinal region]. AB - Balanced sequence, three-dimensional fast imaging employ steady state acquisition (3D-FIESTA) as an example, was often used for colangiopancretography and aortagraphy in the chest and the aorta, and venography in the extremity and other body parts, because this had the high signal to noise ratio and the short acquisition time. 3D-coherent oscillatory state acquisition for the manipulation of image contrast (COSMIC) developed recently is a sequence thought about based on 3D-FIESTA. We investigated the basic property of 3D-COSMIC compared with 3D FIESTA in phantom and volunteer scan image study. At result, 3D-COSMIC was superior to 3D-FIESTA at signal to noise ratio and contrast on phantom image, contrast and visual evaluation on volunteer scan image of detection of tissue on spinal region. 3D-COSMIC was useful sequence in spinal region. PMID- 22821161 TI - [Utility of sampling perfection with application optimized contrasts using different flip angle evolutions method in magnetic resonance imaging of carotid artery plaque]. AB - In the carotid artery plaque diagnosis, it is said that properties evaluation is important. For this inspection, it is general to use electrocardiogram (ECG) trigger-dark blood (DB)-fat suppression (fs)-turbo spin echo (TSE)-T1 weighted image (T1WI), T2WI, and magnetization prepared rapid gradient echo (MPRAGE) methods though many problems still remain. This time, a comparative study of the carotid artery plaque diagnosis that used the sampling perfection with application optimized contrasts was made. This used different flip angle evolutions method sampling perfection with application optimized contrasts using different flip angle evolutions (SPACE) method that was 3 dimension (3D) imaging procedure that used variable flip angle with the law so far. The subjects were normal volunteers, handmade phantoms changed by T1 and T2 value, and the five patients on five cases who had taken carotid endoarterectomy (CEA) (male, mean 70.6 yr). Findings by the pathologist were obtained for the CEA enforcement patient. There is an excellent result in the contrast ratio by phantom, the signal intensity ratio of a clinical patient, and the comparison with pathological findings. The SPACE method can solve various problems, be evaluated by a properties evaluation of the plaque, a grasp of the range, and an arbitrary section, and be devised as a useful imaging procedure. PMID- 22821162 TI - [Carotid plaque assessment using inversion recovery T1 weighted-3 dimensions variable refocus flip angle turbo spin echo sampling perfection with application optimized contrast using different angle evolutions black blood imaging]. AB - Vulnerable plaque can be attributed to induction of ischemic symptoms and magnetic resonance imaging of carotid artery is valuable to detect the plaque. Magnetization prepared rapid acquisition with gradient echo (MPRAGE) method could detect hemorrhagic vulnerable plaque as high intensity signal; however, blood flow is not sufficiently masked by this method. The contrast for plaque in T1 weighted image (T1WI) could not be obtained sufficiently with black blood image (BBI) by sampling perfection with application optimized contrast using different angle evolutions (SPACE) method as turbo spin echo (TSE). In addition, an appearance of artifact by slow flow is a problem. Considering these controversial situations in plaque imaging, we examined the modified BBI inversion recovery (IR)-SPACE in which IR was added for SPACE method so that the contrast for plaque in T1WI was optimized. We investigated the application of this method in plaque imaging. As a result of phantom imaging, the contrast for plaque in T1WI was definitely obtained by choosing an appropriate inversion time (TI) for the corresponding repetition time. In clinical cases, blood flow was sufficiently masked by IR-SPACE method and the plaque imaging was clearly obtained in clinical cases to the same extent as MPRAGE method. Since BBI with IR-SPACE method was derived from both IR pulse and flow void effect, this method could obtain the blood flow masking effect definitely. The present study suggested that SPACE method might be applicable to estimate properties of carotid artery plaque. PMID- 22821164 TI - [Application and measurement method of passive dosimeter]. PMID- 22821163 TI - [Internal exposure after the Fukushima Daiichi Nuclear Power Plant accident]. PMID- 22821165 TI - [Change of absorbed dose determination in external beam radiotherapy (sequel)]. PMID- 22821166 TI - [Photon-counting digital mammography]. PMID- 22821167 TI - [Quality control of PET imaging: from study to diagnosis]. PMID- 22821169 TI - [Introduction of the data book "Japan Medical Imaging and Radiological Systems Industries 2012"]. PMID- 22821170 TI - The twentieth century reversal of pink-blue gender coding: a scientific urban legend? PMID- 22821171 TI - A fluorophosphate-based inverse Keggin structure. AB - An unusual PFO(3)(2-)-templated "inverse Keggin" polyanion, [Mo(12)O(46)(PF)(4)](4-), has been isolated from the degradation reaction of an {Mo(132)}-type Keplerate to [PMo(12)O(40)](3-) by [Cu(MeCN)(4)](PF(6)) in acetonitrile. (31)P-NMR studies suggest a structure-directing role for [Cu(MeCN)(4)](+) in the formation of the highly unusual all-inorganic inverse Keggin structure. PMID- 22821172 TI - Efficacy of substituted 9-aminoacridine derivatives in small cell lung cancer. AB - Topoisomerase II (TopoII) plays a critical role in the processes of replication, transcription, and decantenation in the cell and is an important chemotherapeutic target in the treatment of small cell lung cancer (SCLC). Current treatment strategies for SCLC employ the use of topoII poisons which stabilize the topoII DNA transient covalent complex, inducing double stranded DNA damage and cellular death via apoptosis in cancer cells. Despite their effectiveness the topoII poisons are known to induce secondary malignancies in a small population of patients, stimulating the search for new compounds with less toxicity. Recently a small library of substituted 9-aminoacridine derivatives was discovered that displayed topoII catalytic inhibitory properties. In this work we assess their ability to inhibit proliferation and induce cellular death in SCLC. The results indicate effective inhibition of cellular proliferation at EC(50) values in the low MUM range. Western blot analysis of p62/LC3 levels, the AKT/mTOR pathway, and the ERK1/2 pathway indicate that autophagy is occurring as the primary mechanism of cell death; furthermore, the Guava Nexin and caspase 3/7 activation assays indicate that apoptosis does not occur. While it is unlikely that the active concentration of these compounds could be achieved in vivo, they show great promise for the use and effectiveness of acridine derivatives in the treatment of SCLC in the future. PMID- 22821174 TI - Intake of trans fatty acids from partially hydrogenated vegetable and fish oils and ruminant fat in relation to cancer risk. AB - Intake of trans fatty acids (TFA) may influence systemic inflammation, insulin resistance and adiposity, but whether TFA intake influences cancer risk is insufficiently studied. We examined the association between TFA intake from partially hydrogenated vegetable oils (PHVO-TFA), partially hydrogenated fish oils (PHFO-TFA), and ruminant fat (rTFA) and cancer risk in the Norwegian counties study, a large cohort study with a participation rate >80%. TFA intake was assessed three times in 1974-1988 by questionnaire. A total of 77,568 men and women were followed up through 2007, during which time 12,004 cancer cases occurred. Hazard ratios (HRs) and confidence intervals (CIs) were estimated with Cox regression for cancer sites with >=150 cases during follow-up. Significantly increased or decreased risks were found when comparing the highest and lowest intake categories (HRs, 95% CIs) for PHVO-TFA and pancreatic cancer in men (0.52, 0.31-0.87) and non-Hodgkin lymphoma (NHL) in both genders (0.70, 0.50-0.98); PHFO TFA and rectal cancer (1.43, 1.09-1.88), prostate cancer (0.82, 0.69-0.96), and multiple myeloma (2.02, 1.24-3.28); and rTFA and all cancers (1.09, 1.02-1.16), cancer of the mouth/pharynx (1.59, 1.08-2.35), NHL (1.47, 1.06-2.04) and multiple myeloma (0.45, 0.24-0.84). Furthermore, positive trends were found for PHFO-TFA and stomach cancer (p(trend) = 0.01) and rTFA and postmenopausal breast cancer (p(trend) = 0.03). Inverse trends were found for PHVO-TFA and all cancers (p(trend) = 0.006) and cancer of the central nervous system in women (p(trend) = 0.005). PHFO-TFA, but not PHVO-TFA, seemed to increase cancer risk. The increased risks observed for rTFA may be linked to saturated fat. PMID- 22821173 TI - The nucleoside antagonist cordycepin causes DNA double strand breaks in breast cancer cells. AB - The fungal drug cordycepin (3-deoxyadenosine) is known to exert anti-tumor activities, preferentially by interfering with RNA synthesis. We have investigated the effect of cordycepin on human breast epithelial cell lines, ranging from non-malignant MCF10A cells to highly de-differentiated MDA-MB-435 cancer cells. Treatment of human breast cancer cells with cordycepin caused either apoptosis or persistent cell cycle arrest that was associated with reduced clonal growth of cordycepin-treated breast cancer cells. Highly de-differentiated breast cancer cell lines, such as MDA-MB-231 and MDA-MB-435, reacted more sensitive to cordycepin than less aggressive breast cancer cell lines (MCF7, T47D) or non-malignant breast epithelial cells (MCF10A), which poorly reacted to cordycepin. In cordycepin-sensitive breast cancer cells, a marked induction of the DNA damage response (DDR), including the phosphorylation of ATM, ATR, and histone gammaH2AX could be observed. These data indicate that cordycepin, which was believed to cause cancer cell death by inhibition of RNA synthesis, induces DNA double strand breaks in breast cancer cells. The genotoxic effect of cordycepin on breast cancer cells indicates a new mechanism of cordycepin-induced cancer cell death, and its activity against highly undifferentiated breast cancer cells provides a new perspective of how cordycepin may be used in the treatment of advanced breast cancer. PMID- 22821175 TI - Gene expression changes of interconnected spared cortical neurons 7 days after ischemic infarct of the primary motor cortex in the rat. AB - After cortical injury resulting from stroke, some recovery can occur and may involve spared areas of the cerebral cortex reorganizing to assume functions previously controlled by the damaged cortical areas. No studies have specifically assessed gene expression changes in remote neurons with axonal processes that terminate in the infarcted tissue, i.e., the subset of neurons most likely to be involved in regenerative processes. By physiologically identifying the primary motor area controlling forelimb function in adult rats (caudal forelimb area = CFA), and injecting a retrograde tract-tracer, we labeled neurons within the non primary motor cortex (rostral forelimb area = RFA) that project to CFA. Then, 7 days after a CFA infarct (n = 6), we used laser capture microdissection techniques to harvest labeled neurons in RFA. Healthy, uninjured rats served as controls (n = 6). Biological interactions and functions of gene profiling were investigated by Affymetrix Microarray, and Ingenuity Pathway Analysis. A total of 143 up- and 128 down-regulated genes showed significant changes (fold change >=1.3 and p < 0.05). The canonical pathway, "Axonal Guidance Signaling," was overrepresented (p value = 0.002). Significantly overrepresented functions included: branching of neurites, organization of cytoskeleton, dendritic growth and branching, organization of cytoplasm, guidance of neurites, development of cellular protrusions, density of dendritic spines, and shape change (p = 0.000151 0.0487). As previous studies have shown that spared motor areas are important in recovery following injury to the primary motor area, the results suggest that these gene expression changes in remote, interconnected neurons may underlie reorganization and recovery mechanisms. PMID- 22821176 TI - Deficiency of the complex I of the mitochondrial respiratory chain but improved adenylate control over succinate-dependent respiration are human gastric cancer specific phenomena. AB - The purpose of study was to comparatively characterize the oxidative phosphorylation (OXPHOS) and function of respiratory chain in mitochondria in human gastric corpus mucosa undergoing transition from normal to cancer states and in human gastric cancer cell lines, MKN28 and MKN45. The tissue samples taken by endobiopsy and the cells were permeabilized by saponin treatment to assess mitochondrial function in situ by high-resolution oxygraphy. Compared to the control group of endobiopsy samples, the maximal capacity of OXPHOS in the cancer group was almost twice lower. The respiratory chain complex I-dependent respiration, normalized to complex II-dependent respiration, was reduced that suggests deficiency of complex I, but the respiratory control by ADP in the presence of succinate was increased. Similar changes were observed also in mucosa adjacent to cancer tissue. The respiratory capacity of MKN45 cells was higher than that of MKN28 cells, but both types of cells exhibited a deficiency of complex I of the respiratory chain which appears to be an intrinsic property of the cancer cells. In conclusion, human gastric cancer is associated with decreased respiratory capacity, deficiency of the respiratory complex I of mitochondria, and improved coupling of succinate oxidation to phosphorylation in tumor tissue and adjacent atrophic mucosa. Detection of these changes in endobiopsy samples may be of diagnostic value. PMID- 22821177 TI - Treatment of tobacco dependence in people with mental health and addictive disorders. AB - People with mental health and addictive disorders (MHADs) have higher rates of cigarette smoking, and less success in quitting smoking compared with the general population. Moreover, tobacco-related medical illness may be the leading cause of death in the MHAD population. We discuss the scope of this comorbidity, and approaches to the treatment of tobacco dependence in people with MHAD, including schizophrenia, mood disorders, anxiety disorders, and alcohol and substance use disorders. Finally, at the level of health systems, we emphasize the importance of integrated treatment of tobacco dependence in MHADs. PMID- 22821178 TI - Stress fracture risk factors in basic combat training. AB - This study examined demographic and physical risk factors for stress fractures in a large cohort of basic trainees. New recruits participating in US Army BCT from 1997 through 2007 were identified, and birth year, race/ethnicity, physical characteristics, body mass index, and injuries were obtained from electronic databases. Injury cases were recruits medically diagnosed with inpatient or outpatient stress fractures. There were 475 745 men and 107 906 women. Stress fractures incidences were 19.3 and 79.9 cases/1 000 recruits for men and women, respectively. Factors that increased stress fracture risk for both men and women included older age, lower body weight, lower BMI, and race/ethnicity other than black. Compared to Asians, those of white race/ethnicity were at higher stress fractures risk. In addition, men, but not women, who were taller or heavier were at increased stress fracture risk. Stress fracture risk generally increased with age (17-35 year range) at a rate of 2.2 and 3.9 cases/1 000 recruits per year for men and women, respectively. This was the largest sample of military recruits ever examined for stress fractures and found that stress fracture risk was elevated among recruits who were female, older, had lower body weight, had lower BMI, and/or were not of black race/ethnicity. PMID- 22821180 TI - Determination of amylopectin structure and physicochemical properties in rice endosperm starch of mutant lines derived from Malaysian rice cultivar MR219. AB - BACKGROUND: Characterization of starch properties and functionality can apply breeding program selection for desirable traits such as eating, cooking and processing qualities to meet consumer preference. Low amylose content is generally preferred in Malaysia because of cohesive, tender and glossy cooked rice. Rice high in short-chain amylopectin has a lower transition temperature of starch gelatinization. In the continuing search for improved starch quality in rice cultivars a study was carried out with new mutant lines MR219-4 and MR219-9, derived from MR219. RESULTS: MR219 and its mutant lines contain L-type amylopectin, being high in amylopectin of intermediate chain length with degree of polymerization 12-21. The apparent amylose content (AAC) in MR219-4 had lower AAC value (19.2%) compared to other lines. A strongly negative correlation was found between chain-length fraction of amylopectin and transition temperatures onset temperature peak temperature, and conclusion temperature (0.992, 0.958, 0.950; P < 0.01)-with fraction b1 (fb1), respectively. CONCLUSION: The Malaysian lines studied contain L-type amylopectin and offer a better understanding of grain quality improvement in terms of starch properties and functionality. This information will be directly applicable to select for desirable traits in future breeding programs. PMID- 22821179 TI - Combined Erlotinib and Cetuximab overcome the acquired resistance to epidermal growth factor receptors tyrosine kinase inhibitor in non-small-cell lung cancer. AB - PURPOSE: Non-small-cell lung cancer (NSCLC) cells with somatic mutations in epidermal growth factor receptors (EGFR) are initially susceptible to tyrosine kinase inhibitor (TKI); however, eventually resistance to TKI is developed in these cells, which leads to the failure of treatment. The most common mechanism of this acquired drug resistance is development of a secondary T790M mutation in EGFR. In this study, we investigated the effects of the combination of Erlotinib and Cetuximab on T790M and L858R mutation lung cancer cells lines (H1975), in the primary NSCLC cells with the T790M mutation and TKI-resistant EGFR mutations human tumor xenograft model (H1975). METHODS: The effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. Sensitivity of EGFR inhibitors was detected in the primary tumor cell suspension and human tumor xenograft model (H1975). RESULTS: Compared with single-agent treatment, the combination of Cetuximab and Erlotinib increased apoptosis of EGFR TKI-resistant NSCLC cells (H1975), resulting in more pronounced growth inhibition on cell proliferation and significant inhibition of EGFR-dependent signaling. CONCLUSIONS: These data suggest that treatment with a combination of Erlotinib and Cetuximab overcomes T790M-mediated drug resistance. PMID- 22821181 TI - Lymphatic complications in surgery: possibility of prevention and therapeutic options. AB - The problem of prevention of lymphatic complications in surgery is extremely important if we think about the frequency of both early complications such as lymphorrhea, lymphocele, wound dehiscence and infections and late complications such as lymphangitis and lymphedema. Nowadays, it is possible to identify risk patients and prevent these lesions or treat them at an early stage. This report helps to demonstrate how it is important to integrate diagnostic and clinical findings to better understand how to properly identify risk patients for lymphatic injuries and, therefore, when it is useful and proper to do prevention. Authors report their experiences in the prevention and treatment of lymphatic injuries after surgical operations and trauma. After an accurate diagnostic approach, prevention is based on different technical procedures among which microsurgical procedures. It is very important to follow-up the patient not only clinically but also by lymphoscintigraphy. A protocol of prevention of secondary limb lymphedema was proposed and it includes, from the diagnostic point of view, lymphoscintigraphy and, as concerns therapy, it recognizes also a role to early microsurgery. It is necessary to accurately follow-up the patient who has undergone an operation at risk for the appearance of lymphatic complications and, even better, to assess clinically and by lymphoscintigraphy the patient before surgical operation. PMID- 22821182 TI - Comparative study of clinical outcomes between laparoscopy-assisted proximal gastrectomy (LAPG) and laparoscopy-assisted total gastrectomy (LATG) for proximal gastric cancer. AB - BACKGROUND: The choice of surgical strategy for patients with proximal gastric cancer is controversial. The purpose of this study was to assess the feasibility, safety, and surgical and functional outcomes of laparoscopy-assisted proximal gastrectomy (LAPG) and laparoscopy-assisted total gastrectomy (LATG). METHODS: Between June 2003 and December 2009, 131 patients with proximal gastric cancer underwent LAPG (n = 50) or LATG (n = 81) at Seoul National University Bundang Hospital. We reviewed their medical and surgical records from our prospectively collected gastric cancer database. The clinicopathologic characteristics and short-term, long-term, and functional outcomes were compared between the 2 groups. RESULTS: There were no significant differences in demographics, T-stage, N-stage, or survival between the 2 groups. The LAPG group had a shorter operative time and lower estimated blood loss than the LATG group. The early complication rates after the LAPG and LATG procedures were 24.0 and 17.3%, respectively (p = 0.349). The incidence of reflux symptoms was significantly higher in the LAPG group (32.0 vs. 3.7%, p < 0.001). The parameters that reflected nutritional status were similar in the 2 groups. CONCLUSION: LAPG is a feasible and acceptable method for treating proximal early gastric cancer in terms of surgical and oncologic safety. However, esophagogastrostomy after LAPG was associated with an increased risk of reflux symptoms. Antireflux procedures should be considered to prevent reflux symptoms after LAPG. PMID- 22821183 TI - Development of a minigenome system for Andes virus, a New World hantavirus. AB - The development of reverse genetics systems for negative-stranded RNA viruses is a rapidly evolving field that has greatly advanced the study of the many different aspects of the viral life cycle. Andes virus (ANDV) is a highly pathogenic hantavirus found in South America that causes hantavirus pulmonary syndrome but to date remains poorly characterized due to the lack of a reverse genetics system for genetic manipulation. Here, we describe the first successful minigenome system for a New World hantavirus, as well as many of the obstacles that still exist in the development of such a system. PMID- 22821184 TI - Genome characterization of a novel porcine bocavirus. AB - Using a high-throughput DNA sequencing method, one DNA sequence (contig01006), suspected to belong to a novel porcine bocavirus (PBoV), was found with a high rate of detection (19.6 %) in fecal samples from healthy piglets. Moreover, a novel PBoV (tentatively named PBoV3C) with a nearly complete genome sequence (5235 bp) was identified. PBoV3C exhibits typical genome characteristics of bocaviruses and shows the highest genomic sequence identity (78 % to 81 %) to PBoV3A/B (PBoV3/4-UK) and PBoV3D/E (PBoV3/4-HK), respectively. Phylogenetic and recombination analysis indicated high diversity, prevalence and complexity among the PBoVs. The phospholipase A2 (PLA2) site of VP1 and the secondary structure of VP2 of PBoV3C were also analyzed. Additionally, we propose a uniform method of PBoV nomenclature based on the VP1 gene. PMID- 22821185 TI - Nickel complexes supported by quinoline-based ligands: synthesis, characterization and catalysis in the cross-coupling of arylzinc reagents and aryl chlorides or aryltrimethylammonium salts. AB - Lithium and nickel complexes bearing quinoline-based ligands have been synthesized and characterized. Reaction of 8-azidoquinoline with Ph(2)PNHR (R = p MeC(6)H(4), Bu(t)) affords N-(8-quinolyl)iminophosphoranes RNHP(Ph(2))=N(8 C(9)H(6)N) (1a, R = p-MeC(6)H(4); 1b, R = Bu(t). C(9)H(6)N = quinolyl)). Reaction of 1a with (DME)NiCl(2) generates a nickel complex [NiCl(2){N(8 C(9)H(6)N)=P(Ph(2))NH(p-MeC(6)H(4))}] (2a). Treatment of 1b with (DME)NiCl(2) and following with NaH produces [NiCl{(1,2-C(6)H(4))P(Ph)(NHBu(t))=N(8-C(9)H(6)N)}] (4). Complex 4 was also obtained by reaction of (DME)NiCl(2) with [Li{(1,2 C(6)H(4))P(Ph)(NHBu(t))=N(8-C(9)H(6)N)}] (5) prepared through lithiation of 1b. Reaction of 2-PyCH(2)P(Ph(2))=N(8-C(9)H(6)N) (6, Py = pyridyl) and PhN=C(Ph)CH(2)P(Ph(2))=N(8-C(9)H(6)N) (8), respectively, with (DME)NiCl(2) yields two five-coordinate N,N,N-chelate nickel complexes, [NiCl(2){2 PyCH(2)P(Ph(2))=N(8-C(9)H(6)N)}] (7) and [NiCl(2){PhN=C(Ph)CH(2)P(Ph(2))=N(8 C(9)H(6)N)}] (9). Similar reaction between Ph(2)PCH(2)P(Ph(2))=N(8-C(9)H(6)N) (10) and (DME)NiCl(2) results in five-coordinate N,N,P-chelate nickel complex [NiCl(2){Ph(2)PCH(2)P(Ph(2))=N(8-C(9)H(6)N)}] (11). Treatment of [(8 C(9)H(6)N)N=P(Ph(2))](2)CH(2) (12) [prepared from (Ph(2)P)(2)CH(2) and 2 equiv. of 8-azidoquinoline] with LiBu(n) and (DME)NiCl(2) successively affords [NiCl{(8 C(9)H(6)N)NP(Ph(2))}(2)CH] (13). The new compounds were characterized by (1)H, (13)C and (31)P NMR spectroscopy (for the diamagnetic compounds), IR spectroscopy (for the nickel complexes) and elemental analysis. Complexes 2a, 4, 7, 9, 11 and 13 were also characterized by single-crystal X-ray diffraction techniques. The nickel complexes were evaluated for the catalysis in the cross-coupling reactions of arylzinc reagents with aryl chlorides and aryltrimethylammonium salts. Complex 7 exhibits the highest activity among the complexes in catalyzing the reactions of arylzinc reagents with either aryl chlorides or aryltrimethylammonium bromides. PMID- 22821186 TI - Peripheral mitochondrial dysfunction in Alzheimer's disease: focus on lymphocytes. AB - Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction and increased oxidative stress. These changes are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and especially mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells especially in lymphocytes. We discuss recent not otherwise published findings on the level of complex activities of the respiratory chain comprising mitochondrial respiration and the mitochondrial membrane potential (MMP). We obtained decreased basal MMP levels in lymphocytes from AD patients as well as enhanced sensitivity to different complex inhibitors of the respiratory chain. These changes are in line with mitochondrial defects obtained in AD cell and animal models, and in post-mortem AD tissue. Importantly, these mitochondrial alterations where not only found in AD patients but also in patients with mild cognitive impairment (MCI). These new findings point to a relevance of mitochondrial function as an early peripheral marker for the detection of AD and MCI. PMID- 22821187 TI - Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques. AB - Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects. PMID- 22821189 TI - [Being old is occurring later. Age-related norms and self-concepts in the second half of life]. AB - Our contribution focuses on the question of how aging subjects experience and interpret biographic transitions into old age - specifically against the background of the current sociodiscursive revaluation of the so-called young old. The results of our qualitative interviews with elderly men and women in Germany indicate that the self-description "young elderly" does not play a role in identity-building in higher age, although norms of "active" or "productive aging" are widely accepted by the elderly. On the other hand, notions of "very old age" in need of care appear as something that can barely be integrated into the self concepts and life plans of the interviewees. The transition from adulthood into the "third" (i.e., old age) stage is, thus, subjectively being postponed by elderly people into the (imagined) very last stage of their lives. PMID- 22821188 TI - Nitric oxide in myogenesis and therapeutic muscle repair. AB - Nitric oxide is a short-lived intracellular and intercellular messenger. The first realisation that nitric oxide is important in physiology occurred in 1987 when its identity with the endothelium-derived relaxing factor was discovered. Subsequent studies have shown that nitric oxide possesses a number of physiological functions that are essential not only to vascular homeostasis but also to neurotransmission, such as in the processes of learning and memory and endocrine gland regulation, as well as inflammation and immune responses. The discovery in 1995 that a splice variant of the neuronal nitric oxide synthase is localised at the sarcolemma via the dystrophin-glycoprotein complex and of its displacement in Duchenne muscular dystrophy has stimulated a host of studies exploring the role of nitric oxide in skeletal muscle physiology. Recently, nitric oxide has emerged as a relevant messenger also of myogenesis that it regulates at several key steps, especially when the process is stimulated for muscle repair following acute and chronic muscle injuries. Here, we will review briefly the mechanisms and functions of nitric oxide in skeletal muscle and discuss its role in myogenesis, with specific attention to the promising nitric oxide-based approaches now being explored at the pre-clinical and clinical level for the therapy of muscular dystrophy. PMID- 22821190 TI - [Trauma surgery - a lasting motivation]. AB - Retirement is a caesura already determined on the day of assumption of office. With an abundance of tasks and a long period of enthusiasm the turning point slips out of memory or is simply repressed. We should have the good sense to think about alternatives in advance after running a hospital for so many years. There is an abundance of tasks within and outside the profession. The continuation of long established collegial alliances all over the world presents an excellent opportunity to maintain surgical skills as well as to retain motivation in trauma care and to obtain a broader view of human society. PMID- 22821192 TI - Hip fracture rates and bisphosphonate consumption in Spain. An ecologic study. AB - INTRODUCTION: Bisphosphonates are used worldwide to treat osteoporosis and, thus, to prevent fractures. Though they have been proven in clinical trials to avoid some fractures, their effectiveness in reducing hip fractures is unclear. The aim of the present study was to explore the relationship between bisphosphonate use and hip fracture trends in Spain. METHODS: For this purpose, an ecologic study spanning 2002 to 2008 was conducted in Spain. Consumption data were obtained from the Spanish Ministry of Health and Social Policy. The number of hip fractures was obtained from hospital discharges; annual hip fracture rates were determined and standardized using the Spanish 2002 population census. A linear regression was performed between fracture rate and use of bisphosphonates; R(2) and Pearson correlation coefficient were calculated. RESULTS: From 2002 to 2008, dispensed prescriptions of bisphosphonates in Spain increased from 3.28 to 17.66 DDD/1,000 inhabitants per day. In the same period, the crude hip fracture rate increased from 2.85 to 3.02 cases per 1,000 inhabitants older than 50 years; however, when age standardized rates were estimated, the rate declined from 2.85 to 2.79. Analyzed by sex, the standardized rate for men slightly increased from 1.45 to 1.48, while for women the rate significantly dropped from 4.00 to 3.91. CONCLUSION: A small effect of bisphosphonates on hip fracture rates can not be ruled out; however, other factors might partially explain this decline. Assuming this medication was the only cause for hip fracture rate reduction, the elevated medication cost to avoid a single hip fracture makes it necessary to explore less expensive interventions. PMID- 22821191 TI - [Bone substitute. Transplants and replacement materials--an update]. AB - Due to the special characteristics, autologous bone for bone grafting remains the gold standard for defect filling. Besides allogenic bone transplants, as an alternative a set of bone substitutes has been established. An overview of the bone substitutes presently on the market is almost lost due to the abundance of products. The present paper gives a review of the materials available on the market. Different classification systems regarding origin, vitality, biological priority and chemical composition are described as well as the individual materials including the advantages and disadvantages. Finally, a description of tissue engineering and gene therapy gives a view of future prospective. PMID- 22821193 TI - Enantioselective approach to functionalized quinolizidines: synthesis of (+) julandine and (+)-cryptopleurine. AB - An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched gamma-nitroketone, which is easily prepared by an organocatalytic ketone-nitroalkene Michael addition. Oxidative ring expansion of the nitroketone followed by reductive ring-opening leads to a suitably functionalized nitrodiol which is an intermediate to the title compounds. PMID- 22821195 TI - Protonation preferentially stabilizes minor tautomers of the halouracils: IRMPD action spectroscopy and theoretical studies. AB - Tautomerization induced by protonation of halouracils may increase their efficacy as anti-cancer drugs by altering their reactivity and hydrogen bonding characteristics, potentially inducing errors during DNA and RNA replication. The gas-phase structures of protonated complexes of five halouracils, including 5 fluorouracil, 5-chlorouracil, 5-bromouracil, 5-iodouracil, and 6-chlorouracil are examined via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical electronic structure calculations. IRMPD action spectra were measured for each complex in the IR fingerprint region extending from ~1000 to 1900 cm(-1) using the free electron laser (FELIX). Correlations are made between the measured IRMPD action spectra and the linear IR spectra for the stable low energy tautomeric conformations computed at the B3LYP/6-311+G(2d,2p)//B3LYP/6 31G* level of theory. Absence of an intense band(s) in the IRMPD spectrum arising from the carbonyl stretch(es) that are expected to appear near 1825 cm(-1) provides evidence that protonation induces tautomerization and preferentially stabilizes alternative, noncanonical tautomers of these halouracils where both keto functionalities are converted to hydroxyl groups upon binding of a proton. The weak, but measurable absorption, which does occur for these systems near 1835 cm(-1) suggests that in addition to the ground-state conformer, very minor populations of excited, low-energy conformers that contain keto functionalities are also present in these experiments. PMID- 22821196 TI - Gas-phase hydration thermochemistry of sodiated and potassiated nucleic acid bases. AB - Hydration reactions of sodiated and potassiated nucleic acid bases (uracil, thymine, cytosine, and adenine) produced by electrospray have been studied in a gas phase using the pulsed ion-beam high-pressure mass spectrometer. The thermochemical properties, DeltaH(o)(n), DeltaS(o)(n), and DeltaG(o)(n), for the hydrated systems were obtained from hydration equilibrium measurement. The structural aspects of the hydrated complexes are discussed in conjunction with available literature data. The correlation between water binding energies in the hydrated complexes and the corresponding metal ion affinities of nucleobases suggests that a significant (if not dominant) amount of the canonical structure of cytosine undergoes tautomerization during electrospray ionization, and the thermochemical values for cationized cytosine probably correspond to a mixture of tautomeric complexes. PMID- 22821197 TI - Characterization of the expression and cell-surface localization of transmembrane protein 132A. AB - Transmembrane protein 132A (TMEM132A, KIAA1583) was first isolated as a novel gene that is enriched during the embryonic and postnatal stages of rat brain development and interacts with GRP78. However, the biological functions of TMEM132A are scarcely characterized because the protein does not contain any known structural domains. Using a cell-surface biotinylation assay and immunocytochemical staining, we found that TMEM132A is a transmembrane glycoprotein consisting of a large extracellular domain in the N-terminal region and a small cytosolic domain in the C-terminal region. Partial deletions of the intracellular domain of TMEM132A had little effect on its expression level and cell-surface localization in transfected HEK293 cells, whereas deletions of the extracellular domain hampered transport to the cell surface. The expression pattern of each N-terminal mutant was immunocytochemically confirmed in HeLa cells transfected with the same constructs. Treatment with tunicamycin, an inhibitor of protein glycosylation, led to the accumulation of the unglycosylated form of TMEM132A in inverse proportion to the glycosylated form; however, both forms were localized at the cell surface at almost equal rates. In contrast, GRP78 overexpression led to the accumulation of unglycosylated TMEM132A, which was not detected on the cell surface. Inhibition of ER-Golgi transport by treatment with brefeldin A or the overexpression of mutant Sar1 attenuated the amount of cell-surface localized TMEM132A in HEK293 cells. Treatment with reagents disrupting intracellular calcium rapidly down-regulated the amount of TMEM132A protein in Neuro2a cells without affecting the expression level of its mRNA. Taken together, our data show that the novel cell-surface localized glycoprotein, TMEM132A, is regulated by several factors, including GRP78, Sar1, and intracellular calcium, in a post-transcriptional manner. PMID- 22821198 TI - The effects of homocysteine-related compounds on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart. AB - Research on the effects of homocysteine on the vascular wall, especially in endothelial and smooth muscle cells, has indicated that increased homocysteine levels lead to cellular stress and cell damage. Considering the adverse effects of homocysteine on vascular function and the role of oxidative stress in these mechanisms, the aim of this study was to estimate the influence of different homocysteine isoforms on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart. The hearts of male Wistar albino rats (n = 36, age 8 weeks, body mass 180-200 g), were excised and retrogradely perfused according to the Langendorff technique at a constant perfusion pressure (70 cmH(2)O) and administered with three isoforms of 10 MUM homocysteine [DL-Hcy, DL Hcy thiolactone-hydrochloride (TLHC) and L-Hcy TLHC). After the insertion and placement of the sensor in the left ventricle, the parameters of heart function: maximum rate of pressure development in the left ventricle (dP/dt max), minimum rate of pressure development in the left ventricle (dP/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean blood pressure (MBP) and heart rate (HR)] were continuously registered. Flowmetry was used to evaluate the coronary flow. Markers of oxidative stress: index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO(2)(-)), superoxide anion radical (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the coronary venous effluent were assessed spectrophotometrically. Our results showed that administration of Hcy compounds in concentration of 10 MUM induced depression of cardiac contractility, manifested by a decrease in dp/dt max after administration of any Hcy compound, decrease in dp/dt min after administration of L-Hcy TLHC, decrease in SLVP after administration of DL-Hcy TLHC and DL-Hcy, and the drop in CF after administration of any Hcy compound. Regarding the effects of Hcy on oxidative stress parameters, only L-Hcy TLHC significantly affected O(2)( ) release. L-Hcy TLHC showed a cardiotoxic effect by affecting heart contractility, but surprisingly, it decreased the release of O(2)(-). PMID- 22821199 TI - Reactive arthritis: developments and challenges in diagnosis and treatment. AB - Reactive arthritis (ReA) has traditionally been described as a nonseptic arthritis occurring in the joint following an extra-articular bacterial infection. This concept became clinically associated with antecedent infections of either the gastrointestinal or genitourinary tract. Yet this operational definition of ReA has led to diagnostic uncertainty in different clinical settings. There are several scenarios in which the ReA has been complex. One is in the SAPHO syndrome, which shares many features with ReA. Another is the development of arthritis after infection with atypical organisms such as Clostridium difficile and Giardia lamblia. Treatment of ReA remains an area of ongoing investigation. There has been a randomized controlled trial of combination antibiotics in Chlamydia-induced ReA, which reported a positive result. There are several uncontrolled reports of anti-TNF agents being used successfully in refractory ReA. These studies in treatment modalities require validation on larger samples but do provide some encouraging preliminary findings from which to develop new therapeutic approaches. PMID- 22821200 TI - Myelodysplasia and malignancy-associated vasculitis. AB - While the link between malignancy and vasculitis has been known for some time, the association of vasculitis and myelodysplastic syndrome (MDS) has only recently been reported. This article reviews the most current and landmark publications regarding MDS, as well as malignancy-associated vasculitis. We include theories of paraneoplastic associations, immune pathogenesis including an associated cytokine transcriptional factor (interferon regulatory factor-1 [IFN 1]), and the relationship to treatment. Key clinical features that suggest underlying malignancy in patients with vasculitis are highlighted. Although the association between vasculitis and malignancy is rare, leukocytoclastic vasculitis is the most common vasculitis associated with MDS, hematologic malignancies as well as solid tumors. We review several articles that demonstrate a paraneoplastic association between vasculitis and various malignancies, but overall, the connection is still unclear and not well defined. Certain features that suggest a true paraneoplastic association are outlined. Further studies are needed to advance our understanding of this complex topic. PMID- 22821201 TI - Complete genome sequence of a velogenic Newcastle disease virus isolated in Mexico. AB - In Mexico, the number of cases of the highly virulent Newcastle disease virus is increasing. In 2005, an outbreak of Newcastle disease occurred on an egg laying hen farm in the state of Puebla despite vaccination with the LaSota strain. Farmers experienced a major drop in egg production as a consequence of a field challenge virus. In this study, we characterize the virus, APMV1/chicken/Mexico/P05/2005, responsible for the outbreak. The virus is categorized as a velogenic virus with an intracranial pathogenicity index of 1.99 and a chicken embryo mean death time of 36 h. The complete genome length of the virus was sequenced as consisting of 15,192 bp. In addition, phylogenetic analysis classified the virus as a member of the class II, genotype V. The highly pathogenic nature of the virus has been linked to the amino acid sequence at the fusion protein cleavage site, which contains multiple basic amino acids (RRQKR?F). PMID- 22821202 TI - Green synthesis of Au nanoparticles immobilized on halloysite nanotubes for surface-enhanced Raman scattering substrates. AB - A facile and green route was introduced to synthesize Au nanoparticles immobilized on halloysite nanotubes (AuNPs/HNTs) used for surface-enhanced Raman scattering substrates. The naturally occurring HNTs were firstly functionalized with a large amount of -NH(2) groups by N-(beta-aminoethyl)-gamma-aminopropyl trimethoxysilane (AEAPTES), which possesses one lone electron pair and will "anchor" Au ions to form a chelate complex. Then, with the addition of tea polyphenols (TP), the Au ions were reduced on the surface of the previously formed Au-NH(2) chelate complex to form AuNPs. Transmission electron microscopy (TEM) and field emission scanning electron microscopy (FE-SEM) observations indicate that a large amount of AuNPs were synthesized on HNTs. The AuNPs are irregularly spherical and densely dispersed on HNTs and the diameter of the nanoparticles varies from 20 to 40 nm. The interactions between AuNPs and -NH(2) groups were verified by X-ray photoelectron spectroscopy (XPS) and the results showed that the functional groups can "anchor" AuNPs through the chelating effect. The as-prepared AuNPs/HNTs nanomaterials with several nanometers gaps among nanoparticles were used as a unique surface-enhanced Raman scattering substrate, which possessed strong and distinctive Raman signals for R6G, indicating the remarkable enhancement effect of the AuNPs/HNTs. PMID- 22821203 TI - Stereotypical rapid source level regulation in the harbour porpoise biosonar. AB - Some odontocetes and bats vary both click intensity and receiver sensitivity during echolocation, depending on target range. It is not known how this so called automatic gain control is regulated by the animal. The source level of consecutive echolocation clicks from a harbour porpoise was measured with a hydrophone array while the animal detected an aluminium cylinder at 2, 4 or 8 m distance in a go/no-go paradigm. On-axis clicks had source levels of 145-174 dB re 1 MUPa peak-to-peak. During target-present trials the click trains reached comparable source levels independent of the range to the target after three clicks. After an additional click, the source level was reduced for the 2 and 4 m trials until it equalled the one-way transmission loss. During target-absent trials, the source level remained high throughout the entire click train. Given typical values of harbour porpoise inter-click intervals, the source level reduction commenced within a few 100 ms from the first click in the click train. This may indicate a sub-cortically regulated source level regulation in the harbour porpoise. PMID- 22821204 TI - Influence of siderophore pyoverdine synthesis and iron-uptake on abiotic and biotic surface colonization of Pseudomonas putida S11. AB - Fluorescent pseudomonads produce a characteristic fluorescent pigment, pyoverdines as their primary siderophore for iron acquisition under iron-limiting conditions. Here, we report the identification of a random transposon mutant IST3 of Pseudomonas putida S11 showing tolerance to iron starvation stress condition and increased pyoverdine production. The insertion of the Tn5 transposon was found to be in pstS gene of pstSR operon encoding sensor histidine kinase protein of the two-component signal transduction system. A pyoverdine negative derivative of IST3 mutant constructed was sensitive to iron stress condition. It indicated that increased survival of IST3 under iron-limiting condition was due to higher pyoverdine production. The iron starvation tolerant mutant (IST3) exhibited enhanced pyoverdine-mediated iron uptake in minimal medium which significantly improved its biofilm formation, seed adhesion and competitive root colonization. PMID- 22821205 TI - Stoichiometric identification with maximum likelihood principal component analysis. AB - This study presents an effective procedure for the determination of a biologically inspired, black-box model of cultures of microorganisms (including yeasts, bacteria, plant and animal cells) in bioreactors. This procedure is based on sets of experimental data measuring the time-evolution of a few extracellular species concentrations, and makes use of maximum likelihood principal component analysis to determine, independently of the kinetics, an appropriate number of macroscopic reactions and their stoichiometry. In addition, this paper provides a discussion of the geometric interpretation of a stoichiometric matrix and the potential equivalent reaction schemes. The procedure is carefully evaluated within the stoichiometric identification framework of the growth of the yeast Kluyveromyces marxianus on cheese whey. Using Monte Carlo studies, it is also compared with two other previously published approaches. PMID- 22821206 TI - Integrate and fire neural networks, piecewise contractive maps and limit cycles. AB - We study the global dynamics of integrate and fire neural networks composed of an arbitrary number of identical neurons interacting by inhibition and excitation. We prove that if the interactions are strong enough, then the support of the stable asymptotic dynamics consists of limit cycles. We also find sufficient conditions for the synchronization of networks containing excitatory neurons. The proofs are based on the analysis of the equivalent dynamics of a piecewise continuous Poincare map associated to the system. We show that for efficient interactions the Poincare map is piecewise contractive. Using this contraction property, we prove that there exist a countable number of limit cycles attracting all the orbits dropping into the stable subset of the phase space. This result applies not only to the Poincare map under study, but also to a wide class of general n-dimensional piecewise contractive maps. PMID- 22821207 TI - A rigorous model study of the adaptive dynamics of Mendelian diploids. AB - Adaptive dynamics (AD) so far has been put on a rigorous footing only for clonal inheritance. We extend this to sexually reproducing diploids, although admittedly still under the restriction of an unstructured population with Lotka-Volterra like dynamics and single locus genetics (as in Kimura's in Proc Natl Acad Sci USA 54: 731-736, 1965 infinite allele model). We prove under the usual smoothness assumptions, starting from a stochastic birth and death process model, that, when advantageous mutations are rare and mutational steps are not too large, the population behaves on the mutational time scale (the 'long' time scale of the literature on the genetical foundations of ESS theory) as a jump process moving between homozygous states (the trait substitution sequence of the adaptive dynamics literature). Essential technical ingredients are a rigorous estimate for the probability of invasion in a dynamic diploid population, a rigorous, geometric singular perturbation theory based, invasion implies substitution theorem, and the use of the Skorohod M 1 topology to arrive at a functional convergence result. In the small mutational steps limit this process in turn gives rise to a differential equation in allele or in phenotype space of a type referred to in the adaptive dynamics literature as 'canonical equation'. PMID- 22821208 TI - SNR of DNA sequences mapped by general affine transformations of the indicator sequences. AB - The identification of gene coding regions of DNA sequences through digital signal processing techniques based on the so-called 3-base periodicity has been an emerging problem in bioinformatics. The signal to noise ratio (SNR) of a DNA sequence is computed after mapping the DNA symbolic sequence into numerical sequences. Typical mapping schemes include the Voss, Z-curve and tetrahedron representations and the like, which have been used to construct gene coding region detecting algorithms. In this paper, an extended definition of SNR is proposed, which has less computational cost and wider applicability than its original ones. Furthermore, we analyze the SNRs of different mapping schemes and derive the general relationship between Voss based SNR and that of its general affine transformations. We conclude that the SNRs of Z-curve and tetrahedron map are also linearly proportional to that of Voss map. Not only is our conclusion instructional for the design of other affine transformations, but it is also of much significance in understanding the role of the symbolic-to-numerical mapping in the detection of gene coding regions. PMID- 22821209 TI - Circulating microRNA profiles reflect the presence of breast tumours but not the profiles of microRNAs within the tumours. AB - BACKGROUND: Extra-cellular microRNAs have been identified within blood and their profiles reflect various pathologies; therefore they have potential as disease biomarkers. Our aim was to investigate how circulating microRNA profiles change during cancer treatment. Our hypothesis was that tumour-related profiles are lost after tumour resection and therefore that comparison of profiles before and after surgery would allow identification of biomarker microRNAs. We aimed to examine whether these microRNAs were directly derived from tumours, and whether longitudinal expression monitoring could provide recurrence diagnoses. METHODS: Plasma was obtained from ten breast cancer patients before and at two time-points after resection. Tumour tissue was also obtained. Quantitative PCR were used to determine levels of 367 miRNAs. Relative expressions were determined after normalisation to miR-16, as is typical in the field, or to the mean microRNA level. RESULTS: 210 microRNAs were detected in at least one plasma sample. Using miR-16 normalisation, we found few consistent changes in circulating microRNAs after resection, and statistical analyses indicated that this normalisation was not justifiable. However, using data normalised to mean microRNA expression we found a significant bias for levels of individual circulating microRNAs to be reduced after resection. Potential biomarker microRNAs were identified, including let-7b, let-7g and miR-18b, with higher levels associated with tumours. These microRNAs were over-represented within the more highly expressed microRNAs in matched tumours, suggesting that circulating populations are tumour-derived in part. Longitudinal monitoring did not allow early recurrence detection. CONCLUSIONS: We concluded that specific circulating microRNAs may act as breast cancer biomarkers but methodological issues are critical. PMID- 22821210 TI - Analytical sensitivity and stability of DNA methylation testing in stool samples for colorectal cancer detection. AB - BACKGROUND: Stool-based molecular tests hold large potential for improving colorectal cancer screening. Here, we investigated the analytical sensitivity of a DNA methylation assay on partial stool samples, and estimated the DNA degradation in stool over time. In addition, we explored the detection of DNA methylation in fecal immunochemical test (FIT) fluid. MATERIALS AND METHODS: Partial stool samples of colonoscopy-negative individuals were homogenized with stool homogenization buffer, spiked with different numbers of HCT116 colon cancer cells and kept at room temperature for 0, 24, 48, 72 and 144 h before DNA isolation. Analytical sensitivity was determined by the lowest number of cells that yielded positive test results by DNA methylation or mutation analysis. DNA methylation in FIT fluid was measured in 11 CRC patients and 20 control subjects. RESULTS: The analytical sensitivity for detecting DNA methylation was 3000 cells per gram stool, compared to 60000 cells per gram stool for detection of DNA mutations in the same stool samples. No degradation up to 72 h was noted when a conservation buffer was used. DNA methylation was detected in 4/11 CRC FIT samples and in none of the 20 control FIT samples. CONCLUSIONS: Methylation based stool DNA testing showed a high analytical sensitivity for tumor DNA in partial stool samples, which was hardly influenced by DNA degradation over time, provided an adequate buffer was used. The feasibility of detecting DNA methylation in FIT fluid demonstrates the opportunity to combine testing for occult blood with DNA methylation in the same collection device. PMID- 22821212 TI - PAH depositional history and sources in recent sediment core from Ukwa Ibom Lake, S. E. Nigeria. AB - Analyses of recent sediment core from the Ukwa Ibom Lake show evidence of aquatic production, terrigenous, combustion and petroleum inputs. Total organic carbon/total nitrogen values (>10) for the sediments indicate greater wash-in of land-plant organic matter relative to algal production. The characteristic combustion ratios, fluoranthene/fluoranthene + pyrene (>0.50), anthracene/anthracene + phenanthrene (>0.10), benzo(a)anthracene/benzo(a)anthracene + chrysene (>0.35) as well as 1,7/1,7 + 2,6 dimethylphenanthrene (>0.70) were observed for the top section only. These results coincided with the most recent pave-road extension exercise involving tree logging and burning of bush. The highest total PAH concentration (91.13 ng/g dry weight (dw)) observed for the bottom section coincided with the period of inhabitation of the lake catchments (~5 decades ago) when discharge to the Lake water of domestic sewage and mill waste water were prevalent. The regular decline in total PAH concentrations upcore is a reflection of the ban placed on indiscriminate dumping of wastes following relocation of the inhabitants of the catchments. Besides the local depositional history, the irregular decrease in unresolved complex mixture (UCM) profiles suggests regional contaminant influx from the adjacent upper Cross River estuary, especially during intense rainfall event. The non-uniformity in methylphenanthrene indices (MPI-1 and MPI-2) shows evidence of importation and utilization of petroleum products of different thermal maturity histories into the Nigerian economy. PMID- 22821211 TI - Oncogenic mutations in extramammary Paget's disease and their clinical relevance. AB - Extramammary Paget's disease (EMPD) is a rare cutaneous malignant neoplasm. The genetic alterations underlying its pathogenesis have less been described. Therefore, we analyzed the possible mutations in the KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, PIK3CA, AKT1, CTNNB1 and APC genes as well as methylation and expression of CDH1 in 144 EMPD cases and 42 matched normal skin tissues. A distinct mutation profile was identified in EMPDs with 27 (19%) cases mutant for RAS and RAF genes and 50 (35%) cases harboring oncogenic mutations in PIK3CA and AKT1. Moreover, a mutually exclusive pattern was observed in the genetic variants in these two signaling pathways. No mutation was detected in CTNNB1 and APC genes. High prevalence of low expression and hypermethylation of CDH1 gene was detected in 33 and 48% of the EMPD cases, respectively. Furthermore, PIK3CA and AKT1 mutations were significantly correlated with CDH1 hypermethylation which could explain why the majority of EMPD cases with mutant PIK3CA and AKT1 were invasive. Our study demonstrates that genetic variants associated with constitutive activation of RAS/RAF and PI3K/AKT pathways are involved in the pathogenesis of EMPD. This may represent novel therapeutic targets for this skin cancer. PMID- 22821213 TI - Highly luminescent Ru(II) metallopolymers: photonic and redox properties in solution and as thin films. AB - Highly luminescent metallopolymers have been prepared from condensation reactions between the primary alkyl amines contained within a poly(styrene-p (aminomethyl)styrene) polymer backbone and carboxylic acid groups on [Ru(bpy)(2)(CAIP)](ClO(4))(2), where CAIP is 2-(4-carboxyphenyl)imidazo[4,5 f][1,10]phenanthroline. The photophysical properties of these metallopolymers including emission and absorption spectroscopy, luminescent lifetimes and time resolved emission anisotropy show strong solvent and pH dependence. These properties are rather insensitive to the loading of the metal centres on the polymer backbone suggesting weak electronic interactions between adjacent centres and the polymer backbone. The polymers form continuous films when drop-cast at an indium tin oxide interface and retain their strong luminescence. This processability and intense luminescence make them potentially useful for sensing and display applications. PMID- 22821214 TI - Left cardiac sympathetic denervation for the management of life-threatening ventricular tachyarrhythmias in young patients with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome. AB - BACKGROUND: Left cardiac sympathetic denervation (LCSD) may be a therapeutic adjunct for young patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS) who are not fully protected by beta-blockade. OBJECTIVE: The objective of this analysis was to report our institutional experience with LSCD in young patients for the management of life threatening ventricular arrhythmias in CPVT and LQTS. METHODS: Ten young patients with CPVT and LQTS underwent transaxillary LSCD at our institution. Mean age at surgery was 14.0 (range 3.9-42) years, mean body weight was 45.7 (range 15.5-90) kg. Five patients had the clinical diagnosis of CPVT, three were genotype positive for a mutation in the ryanodine-receptor-2-gene. Four of five LQTS patients were genotype positive. Indications for LCSD were recurrent syncope, symptomatic episodes of ventricular tachycardias and/or internal cardioverter defibrillator (ICD) discharges, and aborted cardiac arrest despite high doses of beta-blockers. RESULTS: LCSD was performed via the transaxillary approach. No significant complications were observed. Two patients already had an ICD, 6 patients received an ICD at the same operation or shortly thereafter. Median length of follow-up after LCSD was 2.3 (range 0.6-3.9) years. After LCSD a marked reduction in arrhythmia burden and cardiac events was observed in all patients while medication was continued. None of the patients had any further ICD discharge for sustained VT. CONCLUSIONS: After LCSD, arrhythmia burden could significantly be reduced in all our young patients with CPVT and LQTS. PMID- 22821215 TI - Comparative analysis of periprostatic implantation and intracavernosal injection of human adipose tissue-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. AB - BACKGROUND: We compared periprostatic implantation (PPI) and intracavernosal injection (ICI) of human adipose tissue-derived stem cell (ADSC) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury. METHODS: Bilateral CN dissection (BCND) was induced in Sprague-Dawley rats. After BCND 10 rats each were treated with PPI and/or ICI of ADSCs. After 4 weeks erectile responses to electric pelvic ganglion stimulation were studied. Each penis was evaluated in terms of the expression of neuronal nitric oxide synthase and smooth muscle content. RESULTS: The ratio of maximal intracavernosal pressure to mean arterial pressure was significantly decreased in the BCND group (24.5%) compared to the sham group (64.2%). PPI and ICI significantly improved erectile function (46.7% and 47.9%, respectively) compared to the BCND group. A combination of PPI and ICI (42.5%) did not afford any incremental effect on erectile function. After stem cell therapy, the expression of neuronal nitric oxide synthase increased slightly in the ICI group without statistical relevance, whereas the PPI and combination groups showed marginally significant increases (P = 0.08). In both the PPI and ICI groups, the smooth muscle content was similar to the sham group. The combination group showed remarkable increase in smooth muscle content to an extent greater than that seen when either treatment was given alone, although statistically not significant. CONCLUSION: PPI or ICI of ADSCs in a rat model of CN injury were equally effective in recovering penile erection, but may address different types of pathophysiology. PMID- 22821216 TI - Enhanced killing effect of nanosecond pulse electric fields on PANC1 and Jurkat cell lines in the presence of Tween 80. AB - We investigated the effects of nanosecond pulse electric fields (nsPEFs) on Jurkat and PANC1 cells, which are human carcinoma cell lines, in the presence of Tween 80 (T80) at a concentration of 0.18% and demonstarted an enhanced killing effect. We used two biological assays to determine cell viability after exposing cells to nsPEFs in the presence of T80 and observed a significant increase in the killing effect of nsPEFs. We did not see a toxic effect of T80 when cells were exposed to surfactant alone. However, we saw a synergistic effect when cells exposed to T80 were combined with the nsPEFs. Increasing the time of exposure for up to 8 h in T80 led to a significant decrease in cell viability when nsPEFs were applied to cells compared to control cells. We also observed cell type-specific swelling in the presence of T80. We suggest that T80 acts as an adjuvant in facilitating the effects of nsPEFs on the cell membrane; however, the limitations of the viability assays were addressed. We conclude that T80 may increase the fragility of the cell membrane, which makes it more susceptible to nsPEF-mediated killing. PMID- 22821217 TI - Altering the Tat-derived peptide bioactivity landscape by changing the arginine side chain length. AB - Mutations of proteins with dual activities that lead to enhancement of one activity are frequently accompanied by attenuation of the other activity. However, this mutational negative trade-off phenomenon typically only involves the canonical 20 amino acids. To test the effect of non-canonical amino acids on the negative trade-off phenomenon, two bioactivities of HIV-1 Tat-derived peptides were monitored upon changing the Arg side chain length. In contrast to the expected mutational negative trade-off, shortening Arg by one methylene resulted in both higher TAR RNA binding specificity and higher cellular uptake. These results suggest that introducing previously unexploited building blocks, even if the difference is only one methylene, can alter the peptide bioactivity landscape leading to the enhancement of multiple bioactivities. PMID- 22821218 TI - Prevalence of parent-rated attention deficit hyperactivity disorder and associated parent-related factors in primary school children of Navi Mumbai--a school based study. AB - OBJECTIVES: To study the prevalence of parent-rated attention deficit hyperactivity disorder and associated parent-related factors in primary school children of Navi Mumbai. METHODS: One hundred twenty two children including both boys and girls aged between 6 y and 11 y were selected from a school at Navi Mumbai and their parents were given the National Innovative for Children's Healthcare Quality (NICHQ) Vanderbilt Assessment Scale to be filled and returned, which was subsequently analyzed using SPSS (version 16). RESULTS: The prevalence of attention deficit hyperactivity disorder was 12.3 % with boy to girl ratio of 3:2. It was more prevalent in nuclear type of family and in families where a single parent was working especially where the father was the sole breadwinner and doing semi-skilled or unskilled type of work. No significant relation was found between the numbers of work-related hours when parents were away from children and attention deficit hyperactivity disorder. CONCLUSIONS: Attention deficit hyperactivity disorder is prevalent in the primary school-going population of Navi Mumbai, especially in boys. The increased prevalence in nuclear families and families with single working parent should further be explored. Further studies with larger sample size and longer period of follow up may be recommended. The study also recommends screening of school children for symptoms of attention deficit hyperactivity disorder (ADHD) for early diagnosis and treatment. PMID- 22821219 TI - Leptospirosis in association with hemophagocytic syndrome: a rare presentation. PMID- 22821220 TI - Charges associated with pediatric head injuries: a five year retrospective review of 41 pediatric hospitals in the US. AB - BACKGROUND: Brain injuries are a significant public health problem, particularly among the pediatric population. Brain injuries account for a significant portion of pediatric injury deaths, and are the highest contributor to morbidity and mortality in the pediatric and young adult populations. Several studies focus on particular mechanisms of brain injury and the cost of treating brain injuries, but few studies exist in the literature examining the highest contributing mechanisms to pediatric brain injury and the billed charges associated with them. METHODS: Data were extracted from the Pediatric Health Information System (PHIS) from member hospitals on all patients admitted with diagnosed head injuries and comparisons were made between ICU and non-ICU admissions. Collected data included demographic information, injury information, total billed charges, and patient outcome. RESULTS: Motor vehicle collisions, falls, and assaults/abuse are the three highest contributors to brain injury in terms of total numbers and total billed charges. These three mechanisms of injury account for almost $1 billion in total charges across the five-year period, and account for almost half of the total charges in this dataset over that time period. CONCLUSIONS: Research focusing on brain injury should be tailored to the areas of the most pressing need and the highest contributing factors. While this study is focused on a select number of pediatric hospitals located throughout the country, it identifies significant contributors to head injuries, and the costs associated with treating them. (c) 2013 KUMS, All rights reserved. PMID- 22821221 TI - Effect of chitosan coating on maintenance of aril quality, microbial population and PPO activity of pomegranate (Punica granatum L. cv. Tarom) at cold storage temperature. AB - BACKGROUND: Chitosan edible coating was used in an attempt to extend the storage life of pomegranate arils during 12 days at 4 degrees C. Prior to storage, treated arils were dipped in 0.25, 0.5 and 1% (w/v) chitosan aqueous solutions and 1% (v/v) acetic acid for 1 min, while control arils were dipped in distilled water with 1% (v/v) acetic acid. RESULTS: Chitosan coating inhibited bacterial and fungal growth on the surface of arils. The water content of arils coated with 0.5 and 1% chitosan was maintained during 12 days of storage. Chitosan reduced the increase in total soluble solids (TSS) and titratable acidity (TA) of arils during storage. The lowest TSS and TA were detected in arils coated with 0.5 and 1% chitosan, which maintained the highest TSS/TA ratio after 12 days of storage. In contrast, application of chitosan delayed the decrease in total phenolics, total anthocyanins and antioxidant capacity during storage. The results also showed that chitosan coating suppressed the monophenolase activity of polyphenol oxidase (PPO) with pyrogallol substrate and the diphenolase activity of PPO with dopamine hydrochloride substrate, but the diphenolase activity of PPO with pyrocatechol substrate increased during storage. CONCLUSION: The results suggest that chitosan coating has the potential to extend the storage life of pomegranate arils by reducing the microbial population on their surface. PMID- 22821222 TI - Glasgow Prognostic Score as a useful prognostic factor after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Several previous studies have revealed that the Glasgow Prognostic Score (GPS) is a clinically useful scoring system to predict the prognosis of patients with various kinds of advanced cancers. However, there have been few reports on the relationship between the GPS and prognosis after hepatectomy for hepatocellular carcinoma (HCC). Therefore, we performed an analysis of the relationship between the GPS and prognosis after hepatectomy for HCC. METHODS: Between January 2005 and December 2009, 352 HCC patients underwent hepatectomy at Kumamoto University Hospital. Nineteen clinicopathologic factors were analyzed, using univariate and multivariate analyses. RESULTS: Univariate analysis showed that significant risk factors for poor survival included serum albumin level (<3.5 g/dL), tumor size (>35 mm), presence of ascites, portal vein invasion, operation time (>400 min), blood loss (>360 mL), requirement for blood transfusion, and GPS. Multivariate analysis revealed that tumor size [hazard ratio (HR) 3.355; p = 0.003], operation time (HR 2.634; p = 0.006), portal vein invasion (HR 2.419; p = 0.009), and GPS (HR 3.796; p < 0.001) were independent factors for poor prognosis. CONCLUSION: The GPS was demonstrated to be a statistically significant prognostic factor after hepatectomy for HCC. PMID- 22821223 TI - Effects of treatment with oral appliance on 24-h blood pressure in patients with obstructive sleep apnea and hypertension: a randomized clinical trial. AB - BACKGROUND: Continuous positive airway pressure treatment has been shown to lower blood pressure (BP) in patients with obstructive sleep apnea (OSA). The aims of the present pilot study were to evaluate the potential effects of oral appliance (OA) therapy on BP, to assess various outcome BP measures, and to inform sample size calculation. METHODS: Seventy-two patients with OSA and hypertension were randomly assigned to intervention with either an OA with mandibular advancement (active group) or an OA without advancement (control group). Before and after 3 months of treatment, the patients underwent nocturnal somnographic registration and 24-h ambulatory BP monitoring. RESULTS: Among the various BP measures, the largest trend toward effect of OA treatment was seen in 24-h mean systolic BP with a 1.8 mmHg stronger BP reduction in the active group compared with controls. A stronger trend toward effect was seen in a subgroup with baseline ambulatory daytime mean systolic BP >135/85 mmHg where the mean systolic BP fell, on average, 2.6 mmHg. Additional exclusion of patients with baseline apnea hypopnea index (AHI) <=15 gave a significant reduction in mean systolic BP of 4.4 mmHg (P = 0.044) in the active group compared with controls. CONCLUSIONS: In patients with OSA and hypertension, OA treatment had a modest trend toward effect on reducing BP. A stronger trend toward treatment effect was seen after excluding patients with normal baseline ambulatory BP. Additional exclusion of patients with baseline AHI <=15 showed a significant treatment effect. Data to inform sample size for an adequately powered randomized study are provided. PMID- 22821224 TI - Unmasking the Janus face of the association between psoriasis, metabolic syndrome and obstructive sleep apnea. PMID- 22821226 TI - Making incentives work: hospital organisation and performance. AB - AIMS: In 1997, financing of Norwegian hospitals was changed to a combination of block grants and activity-based reimbursements. Since then, many hospitals have also reorganised their internal structures, for instance by implementing activity based budgets at the departmental level. The purpose of this study is to investigate the impact of departmental activity-based budgets on overall hospital productivity and unit costs. METHODS: The analysis is based on register data on hospital admissions and hospital input factors, along with survey data on internal organisation of hospitals. Fixed-effects regression models are applied for the analysis. RESULTS: The main results indicate that hospitals with departmental activity-based budgets and department authority have higher productivity. The effect on unit costs is insignificant. CONCLUSIONS: The positive effect of the departmental activity-based budgets and departmental authority on productivity without increase in costs may indicate that providing incentives at lower hospital levels such as departments could be a useful tool for increasing overall hospital productivity and cost efficiency. PMID- 22821225 TI - Postoperative complications in obstructive sleep apnea. AB - STUDY OBJECTIVES: This study was conducted to determine whether postoperative complications are increased in patients with obstructive sleep apnea (OSA) and to study the impact of the severity of OSA and preoperative use of continuous positive airway pressure (CPAP) on the postoperative outcome. DESIGN AND SETTING: This study is retrospective in nature and was undertaken at the VA Medical Center. PARTICIPANTS AND METHODS: Three hundred seventy patients who had undergone both a major surgical procedure and a sleep study from 2000 to 2010 were identified. Patients were divided into four groups: OSA negative (apnea hypopnea index (AHI) < 5/h), OSA positive; mild: AHI 5 to <15/h; moderate: AHI 15 to <30/h; and severe: AHI >= 30/h. No intervention was made during the course of the study. Postoperative complications namely respiratory, cardiac, neurological, and unplanned intensive care unit transfers were collected. RESULTS: There were 284 (76.8 %) patients having OSA and 86 (23.2 %) without OSA. The overall incidence of total complications was significantly higher in the OSA patients compared with the control patients (48.9 vs. 31.4 %; odds ratio 2.09, 95 % CI 1.25-3.49). There was no significant difference in total complications between those using and not using CPAP prior to hospitalization. Patients with sleep apnea had a higher incidence of respiratory complications compared to patients without sleep apnea (40.4 vs. 23.2 %; odds ratio 2.24, 95 % CI 1.29-3.90). There was no significant difference in major cardiac complications in the OSA patients compared with the control patients (13.0 vs. 9.3 %; odds ratio 1.46, 95 % CI 0.65 3.26). CONCLUSION: OSA is associated with a significantly increased rate of postoperative complications. PMID- 22821227 TI - Healthcare spending in the case of a HPV16/18 population-wide vaccination programme. AB - BACKGROUND: The policy of population-wide human papillomavirus (HPV) vaccination has been debated as the introduction of such a programme in a low-resource country faces the risk of insufficient cost-effectiveness. OBJECTIVES: To assess the potential healthcare spending changes after the introduction of a HPV16/18 population-wide vaccination programme in Lithuania. STUDY DESIGN: For a cost effectiveness analysis, we used mathematical simulation and epidemiological data modelling based on a Lithuanian female population. We performed comparative analysis of an annual 12-year-old girls population-wide vaccination programme combined with cervical cancer screening programme compared to the screening programme strategy only. RESULTS: HPV vaccination would gain an average of 35.6 life years per death avoided or up to 284.8 thousand life years would be gained over 90 years in total. The programme costs would be 2932.58 EUR per life year gained. All costs associated with the introduction of the vaccination programme could be recovered in 48 years. The HPV vaccination programme in Lithuania has the potential to generate up to 40.07 million EUR of economic returns annually compared with the current practice of the cervical screening alone. CONCLUSIONS: In Lithuania the HPV16/18 vaccination programme would be economically effective only in the long term. The investment costs of HPV16/18 vaccination have the potential to be recovered. PMID- 22821228 TI - Consumption of traditional food and adherence to nutrition recommendations in Greenland. AB - AIMS: The purpose was to study the composition of the Inuit diet, to assess the adherence to nutritional recommendations among the Inuit in Greenland, and to discuss the potential role of traditional food in improving dietary quality. METHODS: Cross-sectional study of adult Inuit (18+ years) from Greenland (n=2752, 43% men). Data were collected by a food frequency questionnaire. Dietary contribution of nutrients was compared between quartiles of traditional food intake. A recommended macronutrient distribution range (RMDR) was constructed from the recommendations of Nordic Nutrition Recommendations (2004). The adherence to the RMDR was estimated and the food items' contribution to energy, macronutrients, subclasses of fats, fibres, and refined sugar were calculated. RESULTS: Consumption of refined sugar and saturated fat decreased by increasing consumption of traditional food whereas the fat profile improved due to increasing consumption of polyunsaturated fatty acids and monounsaturated fatty acids. Fibre intake decreased with increasing traditional food and 18% among both men and women complied to fibre recommendations. Compliance with polyunsaturated fatty acid recommendations was 27% for men and 36% for women. Compliance with n-3 fatty acids was 88% for men and 85% for women. CONCLUSIONS: Increasing consumption of traditional food could benefit the dietary fat profile but will result in low fibre intake. Promotion of healthy-fibre-dense and low-fat imported food will increase the compliance to the fibre recommendation while traditional food could stay an integrated part of the Inuit diet and provide less saturated fat. PMID- 22821229 TI - Introduction. Homology in developmental psychology. PMID- 22821230 TI - Does conservative management really benefit patients with OAB? AB - The benefit that patients with overactive bladder (OAB) experience with conservative management is an important aspect in the evaluation of this therapy. The first-line options include behavioral interventions, and several techniques are available. Clinical research indicates amelioration of individual symptoms with these techniques, but few studies have shown a positive effect on health related quality-of-life parameters. After failure of behavioral therapy or in combination with a training program, pharmacological therapy with anticholinergics is the next step. Extensive clinical research into different pharmacological compounds has shown significant effects on the symptomatic elements of OAB. The clinical relevance and the effects on quality-of-life parameters with pharmacological therapy have also been evaluated and show a significant effect on specific aspects. Recently, clinical research in conservative management of patients with OAB has focused more on evaluating patients' perceptions of their condition and the effects of treatment with patient-reported outcome instruments. Future studies should include these tools in the evaluation of any therapy in OAB. PMID- 22821231 TI - Adulticidal and repellent properties of Cassia tora Linn. (Family: Caesalpinaceae) against Culex quinquefasciatus, Aedes aegypti, and Anopheles stephensi. AB - Mosquitoes have developed resistance to various synthetic insecticides, making its control increasingly difficult. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. The adulticidal and repellent activities of crude hexane, chloroform, benzene, acetone, and methanol extracts of the leaf of Cassia tora were assayed for their toxicity against three important vector mosquitoes, viz., Culex quinquefasciatus, Aedes aegypti, and Anopheles stephensi. The adult mortality was observed after 24 h of exposure. All extracts showed moderate adulticidal effects; however, the highest adult mortality observed was found in methanol extract. The LC(50) and LC(90) values of C. tora leaf extracts against adulticidal activity of (hexane, chloroform benzene, acetone, and methanol) C. quinquefasciatus, A. aegypti, and A. stephensi were the following: C. quinquefasciatus LC(50) values were 338.81, 315.73, 296.13, 279.23, and 261.03 ppm and LC(90) values were 575.77, 539.31, 513.99, 497.06, and 476.03 ppm; A. aegypti LC(50) values were 329.82, 307.31, 287.15, 269.57, and 252.03 ppm and LC(90) values were 563.24, 528.33, 496.92, 477.61, and 448.05 ppm; and A. stephensi LC(50) values were 317.28, 300.30, 277.51, 263.35, and 251.43 ppm and LC(90) values were 538.22, 512.90, 483.78, 461.08, and 430.70 ppm, respectively. The results of the repellent activity of hexane, chloroform, benzene, acetone, and methanol extracts of C. tora plant at three different concentrations of 1.0, 2.5, and 5.0 mg/cm(2) were applied on skin of forearm in man and exposed against adult female mosquitoes. In this observation, this plant crude extracts gave protection against mosquito bites without any allergic reaction to the test person, and also, the repellent activity is dependent on the strength of the plant extracts. These results suggest that the leaf solvent plant extracts have the potential to be used as an ideal eco-friendly approach for the control of mosquitoes. This is the first report on mosquito adulticidal and repellent activities of the reported C. tora against mosquito vectors from Southern India. PMID- 22821233 TI - Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. AB - The adhesion G protein-coupled receptors (GPCRs) are a distinct family of more than 30 receptors in vertebrate genomes. These receptors have been shown to play pivotal roles in a diverse range of biological functions and are characterized by extremely large N termini featuring various adhesion domains capable of mediating cell-cell and cell-matrix interactions. The adhesion GPCR N termini also contain GPCR proteolytic site motifs that undergo autocatalytic cleavage during receptor processing to create mature GPCRs existing as noncovalently attached complexes between the N terminus and transmembrane regions. There is mounting evidence that adhesion GPCRs can couple to G proteins to activate a variety of different downstream signaling pathways. Furthermore, recent studies have demonstrated that adhesion GPCR N termini can bind to multiple ligands, which may differentially activate receptor signaling and/or mediate cell adhesion. In addition, studies on several distinct adhesion GPCRs have revealed that truncations of the N termini result in constitutively active receptors, suggesting a model of receptor activation in which removal of the N terminus may be a key event in stimulating receptor signaling. Because mutations to certain adhesion GPCRs cause human disease and because many members of this receptor family exhibit highly discrete distribution patterns in different tissues, the adhesion GPCRs represent a class of potentially important drug targets that have not yet been exploited. For this reason, understanding the mechanisms of activation for these receptors and elucidating their downstream signaling pathways can provide insights with the potential to lead to novel therapeutic agents. PMID- 22821235 TI - Uncommon formation of two antiparallel sperm bundles per cyst in tenebrionid beetles (Coleoptera). AB - Several species of Tenebrionidae are stored-grain pests. Since they belong to a specious family, the systematics of these beetles is still in doubt. In insects, spermatogenesis and the spermatozoa exhibit great diversity, and are therefore commonly used in phylogenetic and taxonomic analyses. During the spermatogenetic process in these organisms, the cells originating from a single spermatogonium develop synchronically in groups referred to as cysts. At the end of this process, there is usually only one sperm bundle per cyst, with all the cells in the same orientation. This paper details the spermiogenesis of the tenebrionid beetles Tenebrio molitor, Zophobas confusa, Tribolium castaneum and Palembus dermestoides using whole mount and histological sections of the cysts. In these species, spermatogenesis is similar to that which occurs in most insects. However, during spermiogenesis, the nuclei of the spermatids migrate to two opposite regions at the periphery of the cyst, leading to the uncommon formation of two bundles of spermatozoa per cyst. This feature is possibly an apomorphy for Tenebrionidae. PMID- 22821234 TI - Design and functional characterization of a novel, arrestin-biased designer G protein-coupled receptor. AB - Mutational modification of distinct muscarinic receptor subtypes has yielded novel designer G protein-coupled receptors (GPCRs) that are unable to bind acetylcholine (ACh), the endogenous muscarinic receptor ligand, but can be efficiently activated by clozapine-N-oxide (CNO), an otherwise pharmacologically inert compound. These CNO-sensitive designer GPCRs [alternative name: designer receptors exclusively activated by designer drug (DREADDs)] have emerged as powerful new tools to dissect the in vivo roles of distinct G protein signaling pathways in specific cell types or tissues. As is the case with other GPCRs, CNO activated DREADDs not only couple to heterotrimeric G proteins but can also recruit proteins of the arrestin family (arrestin-2 and -3). Accumulating evidence suggests that arrestins can act as scaffolding proteins to promote signaling through G protein-independent signaling pathways. To explore the physiological relevance of these arrestin-dependent signaling pathways, the availability of an arrestin-biased DREADD would be highly desirable. In this study, we describe the development of an M3 muscarinic receptor-based DREADD [Rq(R165L)] that is no longer able to couple to G proteins but can recruit arrestins and promote extracellular signal-regulated kinase-1/2 phosphorylation in an arrestin- and CNO-dependent fashion. Moreover, CNO treatment of mouse insulinoma (MIN6) cells expressing the Rq(R165L) construct resulted in a robust, arrestin-dependent stimulation of insulin release, directly implicating arrestin signaling in the regulation of insulin secretion. This newly developed arrestin biased DREADD represents an excellent novel tool to explore the physiological relevance of arrestin signaling pathways in distinct tissues and cell types. PMID- 22821236 TI - Reliable permeability assay system in a microfluidic device mimicking cerebral vasculatures. AB - Since most of the bioavailable drugs are impermeable through the blood-brain barrier (BBB), development of a rapid and reliable permeability assay system has been a challenge in drug discovery targeting central nervous system (CNS). Here, we designed a microfluidic device to monitor the drug permeability into the CNS. Human umbilical vein endothelial cells (HUVECs) were shortly (2 ~ 3 h) incubated with astrocyte-conditioned medium after being trapped on microholes in the microfluidic device and tested for chip-based permeability measurement of drugs. The measured permeability values were highly correlated with those measured by conventional in vitro methods and the brain uptake index representing the quantity of transported substances across the in vivo BBB of rats. Using the microfluidic device, we could easily monitor the effect of hydrogen peroxide on the trans-endothelial permeability, which are consistent with the finding that the same treatment disrupted the formation of tight junctions between endothelial cells. Considering relatively short period of time needed for endothelial cell culture and ability to monitor the BBB physiology continuously, we propose that this novel system can be used as an invaluable first-line tool for CNS-related drug development. PMID- 22821237 TI - Differential expression of HIF-1alpha in skin and mucosal wounds. AB - Despite accelerated epithelial closure, oral mucosal wounds exhibit lower levels of VEGF and a more refined angiogenic response than do skin wounds. The specific differences in angiogenesis suggest that skin and oral mucosal wounds may experience dissimilar levels of hypoxia and HIF-1alpha. Using a model of comparable wounds on murine dorsal skin and tongue, we determined levels of hypoxia and HIF-1alpha. Skin wounds were found to be significantly more hypoxic and had higher levels of HIF-1alpha than mucosal wounds. Furthermore, under stressed conditions, skin wounds, but not mucosal wounds, exhibited a further elevation of HIF-1alpha beyond that of non-stressed levels. To determine if manipulation of oxygen levels might equalize the repair response of each tissue, we exposed mice to hyperbaric oxygen treatment (HBOT) following wounding. HBOT did not significantly change HIF-1alpha or VEGF expression in either skin or mucosal wounds, nor did it alter wound bed vascularity. These studies suggest that skin wounds have higher levels of hypoxia than do mucosal wounds, along with a differential expression of HIF-1alpha. Interestingly, modulation of oxygen by HBOT does not ameliorate this difference. These results suggest that differential responses to hypoxia may underlie the distinctive wound-healing phenotypes seen in skin and oral mucosa. PMID- 22821238 TI - The natural history of dental caries lesions: a 4-year observational study. AB - Dental caries is a ubiquitous disease affecting all age groups and segments of the population. It is known that not all caries lesions progress to cavitation, but little is known regarding the progression pattern of caries lesions. This study's purpose was to evaluate the natural history of dental caries using a standardized, visually based system, the International Caries Detection and Assessment System (ICDAS). The study population consisted of 565 consenting children, who were enrolled and examined at baseline and at regular intervals over 48 months with ICDAS and yearly bitewing radiographs. Of these, 338 children completed all examinations. Not all lesions cavitated at the same rate, differing by surface type and baseline ICDAS severity score and activity status. With increasing severity, the percentage of lesions progressing to cavitation increased: 19%, 32%, 68%, and 66% for ICDAS scores 1, 2, 3, and 4, respectively. Lesions on occlusal surfaces were more likely to cavitate, followed by buccal pits, lingual grooves, proximal surfaces, and buccal and lingual surfaces. Cavitation was more likely on molars, followed by pre-molars and anterior teeth. Predictors of cavitation included age, gender, surfaces and tooth types, and ICDAS severity/activity at baseline. In conclusion, characterization of lesion severity with ICDAS can be a strong predictor of lesion progression to cavitation. PMID- 22821239 TI - Early maternal psychosocial factors are predictors for adolescent caries. AB - Few studies have investigated the role of early maternal enabling and psychosocial factors on subsequent adolescent caries experience. In this retrospective cohort study of 224 adolescents, we hypothesized that the causal pathway between early maternal enabling factors (education, cognitive abilities, psychological distress) and adolescent caries experience (DMFT) at age 14 yrs is mediated by maternal psychosocial factors (stress, coping, social support) and adolescent dental behavior/access. Maternal data on socio-demographic, medical, and psychosocial variables were measured when the child was 3, 8, and 14 yrs old. A structural equations model (SEM) evaluated the causal pathway, with latent variables for maternal enabling factors (MEF), stress, coping, and social support. Poor MEF was associated with increased stress and poorer coping when the child was 3 yrs old, which in turn affected adolescent dental visits and behavior. Greater social support at child's age 3 was directly associated with lower mean DMFT in adolescence. Maternal psychosocial factors measured when children are young are important mediators for adolescent mean DMFT, but these factors measured when children are adolescents are not. Better early and concurrent MEF, however, was associated directly/indirectly (through dental visits and insurance) with adolescent DMFT. Early maternal factors are important predictors for adolescent caries. PMID- 22821241 TI - A computational examination on the structure, spin-state energetics and spectroscopic parameters of high-valent Fe(IV)=NTs species. AB - The imidoiron(IV) species are relatively less explored compared to the oxoiron(IV) intermediates. Recently, generation and characterization of a novel imido/oxoiron(iv) species ([(N(4)Py)Fe(IV)=X](2+) X = NTs; 1, O; 2) has been reported with an S = 1 ground state. Although the ground state for 1 and 2 are the same, they are reported to be distinctly different in other aspects. Unlike the oxoiron(IV) species, the Fe(IV) and nitrene combination in 1 lead to eight different spin states. Bearing in mind the complexity arising here, we have undertaken a detailed DFT study on this transient intermediate and probed its electronic structure and bonding in comparison to the oxoiron(IV) unit. Our Molecular Orbital, Energy Decomposition Analysis, and Natural Bond Orbital analysis indicates a weaker sigma and non-degenerate pi* orbitals for 1 in comparison to a stronger sigma and degenerate pi* orbitals for 2. The implication of these intricate bonding differences in reactivity is discussed along with the computation of absorption and other spectral parameters. Our results broadly support the proposed S = 1 ground state for 1 and provides some useful insight into its electronic structure. PMID- 22821240 TI - HIV infection affects Streptococcus mutans levels, but not genotypes. AB - We report a clinical study that examines whether HIV infection affects Streptococcus mutans colonization in the oral cavity. Whole stimulated saliva samples were collected from 46 HIV-seropositive individuals and 69 HIV seronegative control individuals. The level of S. mutans colonization was determined by conventional culture methods. The genotype of S. mutans was compared between 10 HIV-positive individuals before and after highly active antiretroviral therapy (HAART) and 10 non-HIV-infected control individuals. The results were analyzed against viral load, CD4+ and CD8+ T-cell counts, salivary flow rate, and caries status. We observed that S. mutans levels were higher in HIV-infected individuals than in the non-HIV-infected control individuals (p = 0.013). No significant differences in S. mutans genotypes were found between the two groups over the six-month study period, even after HAART. There was a bivariate linear relationship between S. mutans levels and CD8+ counts (r = 0.412; p = 0.007), but not between S. mutans levels and either CD4+ counts or viral load. Furthermore, compared with non-HIV-infected control individuals, HIV infected individuals experienced lower salivary secretion (p = 0.009) and a positive trend toward more decayed tooth surfaces (p = 0.027). These findings suggest that HIV infection can have a significant effect on the level of S. mutans, but not genotypes. PMID- 22821243 TI - World blood donor day: the challenges ahead. PMID- 22821242 TI - A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis. AB - Oropharyngeal squamous cell carcinoma (SCC) is strongly associated with human papillomavirus (HPV) infection, which is distinctively different from most other head and neck cancers. However, a robust quantitative reverse transcription PCR (RT-qPCR) method for comprehensive expression profiling of HPV genes in routinely fixed tissues has not been reported. To address this issue, we have established a new real-time RT-PCR method for the expression profiling of the E6 and E7 oncogenes from 13 high-risk HPV types. This method was validated in cervical cancer and by comparison with another HPV RNA detection method (in situ hybridization) in oropharyngeal tumors. In addition, the expression profiles of selected HPV-related human genes were also analyzed. HPV E6 and E7 expression profiles were then analyzed in 150 archived oropharyngeal SCC samples and compared with other variables and with patient outcomes. Our study showed that RT qPCR and RNA in situ hybridization were 100% concordant in determining HPV status. HPV transcriptional activity was found in most oropharyngeal SCC (81.3%), a prevalence that is higher than in previous studies. Besides HPV16, three other HPV types were also detected, including 33, 35 and 18. Furthermore, HPV and p16 had essentially identical expression signatures, and both HPV and p16 were prognostic biomarkers for the prediction of disease outcome. Thus, p16 mRNA or protein expression signature is a sensitive and specific surrogate marker for HPV transcriptional activity (all genotypes combined). PMID- 22821244 TI - Do parents talk to their adolescent children about sex?--findings from a community survey in Singapore. AB - INTRODUCTION: Sexually transmitted infections have increased sharply among adolescents both locally and internationally in recent years. Parents play an important role in their children's sexual health development. An integral part of this includes effective parent-child sexuality communication. MATERIALS AND METHODS: A nationwide cross-sectional community-based household survey was conducted in Singapore between August 2008 and March 2009 to assess parents'/caregivers' attitudes and practices regarding caregiver-child sexuality communication. With an overall response rate of 81.4%, 1169 questionnaires from parents/caregivers of children aged 10 to 17 years were analysed. RESULTS: Almost all (94.2%) the caregivers were parents. A majority (>80%) of caregivers considered talking to their children about sexuality issues such as abstinence, consequences of premarital sex and condom use as important. However, a significantly lower percentage (about 60%) felt comfortable and confident doing so. Only 8.3% among them discussed sexual health issues with their children very often, 37.2% sometimes, 22.0% seldom/hardly ever (once or twice) and 32.5% never, in the past year. In the multivariate analysis, caregiver-child sexuality communication was significantly associated with caregivers' relationship to children, ethnicity, educational level, and their perceived levels of comfort and confidence in sexuality communication. CONCLUSION: Caregivers generally felt it was important but were significantly much less comfortable and confident talking about sexuality issues with their children, which leads to a lower frequency of caregiver-child sexuality communication. Educational programmes on adolescent sexual health targeting parents/caregivers are needed. They must be equipped with skills and provided with resources to enable them to talk to their adolescent children about sexuality. PMID- 22821245 TI - Male breast cancer in Singapore: 15 years of experience at a single tertiary institution. AB - INTRODUCTION: Male breast cancer is a rare disease entity, with little data from the Southeast Asian perspective. Hence, this study aims to review the data from our local experience in order to better delineate the disease characteristics in our population. MATERIALS AND METHODS: Male patients with histologically proven breast cancer were identified from a prospectively collected database. The clinical, histopathological and survival data were reviewed retrospectively and analysed. RESULTS: Twenty-one patients were identified. The median age at diagnosis was 68 years. Eighteen patients underwent simple mastectomy with curative intent, with the remaining patients having metastatic disease at presentation. Almost half of the patients presented with stage III or IV disease. At the time of analysis, median overall survival was 50 months and median disease free survival was 47.5 months. None of the patients had any documented family history or risk factors for male breast cancer. CONCLUSION: The disease appears to be a sporadic and rare occurrence in the local male population. A high index of suspicion should be maintained in males presented with a unilateral breast lump so that appropriate treatment can be instituted. PMID- 22821246 TI - Medium to long-term clinical outcomes with everolimus-eluting stents in real-life percutaneous coronary intervention. AB - INTRODUCTION: Everolimus eluting stents (EES) have demonstrated excellent re stenosis and thrombosis rates in a number of randomised controlled trials. This study reported the real world experience in a single tertiary centre with EES in predominantly acute coronary syndrome (ACS) patients and compared the outcomes in small and large vessels. We measured the medium to long-term major adverse cardiovascular events (MACE) defined as all-cause mortality, myocardial infarction (MI) and target vessel revascularisation (TVR) and stent thrombosis. MATERIALS AND METHODS: All consecutive patients underwent percutaneous coronary intervention (PCI) with EES (PROMUSTM, Boston Scientific, Natick USA; XIENCE VTM, Abbott Vascular, Santa Clara USA) between March 2007 and September 2009 recorded in our coronary intervention registry were included in this study. All patients were advised to stay on dual antiplatelet therapy with Aspirin 100 mg/day and Clopidogrel 75 mg/day. All patients had at least 6 months of clopidogrel, government funded and a further 6 months required self funding. RESULTS: Four hundred and six consecutive patients received EES during the study period; 403 were included in this study and 3 were lost to follow-up. Indications for PCI were stable angina in 11% of the patients, unstable angina in 38%, non-ST elevation myocardial infarction in 43%, and ST-elevation myocardial infarction in 8%. Procedural success was achieved in 99.5% of the cases. During a median follow up of 23 months, 3% of the patients had an MI, 3% underwent TVR, 5% all-cause mortality and 2 (0.5%) cases of definite or probable stent thrombosis. The Kaplan Meier 2-year survival and MACE free survival were 95% and 89% respectively. A subgroup analysis comparing MACE in patients who were treated with a single small (<= 2.75 mm; n = 91) or large (>= 3 mm; n = 118). EES did not show significant difference during the 2-year follow-up (12% vs 9%; P = 0.34). CONCLUSION: Everolimus eluting stent appears to be safe in a real world setting with satisfactory median-term outcomes which include low rates of TVR and other adverse events. EES appear to be equally effective in both small and large vessels. PMID- 22821247 TI - Policy implications of the Singapore Mental Health Study. AB - This paper discusses the implications of the key findings of the Singapore Mental Health Study (SMHS) in the context of the fi rst ever National Mental Health Policy and Blueprint (NMHPB). The SMHS was a cross-sectional epidemiological survey of the adult Singapore residents. The policy implications emanating from the findings of this study are discussed in this commentary. These pertain to initiatives to improve help-seeking behaviour, further developing the capability of the primary healthcare providers and the better integration of primary and specialist mental healthcare. Incorporation of mental health education and screening of mental disorders in the workforce should also be augmented with work practices that protect against discriminating those with mental disorders. PMID- 22821248 TI - Reverse Takotsubo pattern stress cardiomyopathy in a male patient induced during dobutamine stress echocardiography. PMID- 22821249 TI - Arthroscopic and magnetic resonance images of an inferiorly displaced meniscal flap tear. PMID- 22821250 TI - Primary intraventricular lymphoma with diffuse leptomeningeal spread at presentation. PMID- 22821251 TI - Mixed multilocular ectopic thymic cyst with parathyroid element presenting as neck mass. PMID- 22821252 TI - prognostic significance of vascular endothelial growth factor C in systemic malignancies besides non-small cell lung carcinomas. PMID- 22821253 TI - Clinical outcome following treatment of stable and unstable intertrochanteric fractures with dynamic hip screw. PMID- 22821254 TI - Recurrent abdominal pain in a young adult. PMID- 22821255 TI - Study of atmospheric stagnation, recirculation and ventilation potential at Narora Atomic Power Station NPP site. AB - The atmosphere is an important pathway to be considered in assessment of the environmental impact of radioactivity releases from nuclear facilities. The estimation of concentration of released effluents in air and possible ground contamination needs an understanding of relevant atmospheric dispersion. This paper describes the meteorological characteristics of Narora Atomic Power Station (NAPS) Nuclear Power Project site by using the integral parameters developed by Allwine and Whiteman (Atmospheric Environment 28(4):713-721, 1994). Meteorological data measured during the period 2006-2010 were analysed. The integral quantities related to the occurrence of stagnation, recirculation and ventilation characteristics were studied for the NAPS site to assess the dilution potential of the atmosphere. Wind run and recirculation factors were calculated for a 24-h transport time using 5 years of hourly surface measurements of wind speed and direction. The occurrence of stagnation, recirculation and ventilation characteristics during 2006-2010 at the NAPS site is observed to be 33.8, 19.5 and 34.7 % of the time, respectively. The presence of strong winds with predominant wind direction NW and WNW during winter and summer seasons leads to higher ventilation (48.1 and 44.3 %) and recirculation (32.6 % of the summer season). The presence of more dispersed light winds during pre-winter season with predominant wind directions W and WNW results in more stagnation (59.7 % of the pre-winter season). Thus, this study will serve as an essential meteorological tool to understand the transport mechanism of atmospheric radioactive effluent release from any nuclear industry during the pre-operational as well as operational phase. PMID- 22821258 TI - Kefir inhibits 3T3-L1 adipocyte differentiation through down-regulation of adipogenic transcription factor expression. AB - BACKGROUND: Kefir, a traditional fermented milk composed of microbial symbionts, is reported to have various health benefits such as anti-tumour, anti inflammatory, anti-neoplastic and pro-digestive effects. In this study, to elucidate the effects of kefir on adipocyte differentiation and lipid accumulation, three fractions were prepared from kefir culture broth. The inhibitory effects of kefir liquid culture broth fraction (Fr-1), soluble fraction (Fr-2) and insoluble fraction (Fr-3), prepared by sonication of kefir solid culture broth, on adipocyte differentiation in 3T3-L1 preadipocytes were examined. RESULTS: Fr-3 (0.1 mg mL(-1)) significantly decreased lipid accumulation and glycerol-3-phosphate dehydrogenase (GPDH) activity by 60 and 68% respectively without affecting cell viability. In addition, Fr-3 treatment down regulated the mRNA expression of adipogenic transcription factors including C/EBPalpha (32%), PPARgamma (46%) and SREBP-1c (34%) during adipocyte differentiation compared with untreated control cells. The mRNA expression of adipocyte-specific genes (aP2, FAS and ACC) was also clearly decreased. CONCLUSION: The results suggest that the insoluble fraction of kefir (Fr-3) mediates anti-adipogenic effects through the inhibition of adipocyte differentiation, partly via suppression of the C/EBPalpha-, SREBP-1c- and PPARgamma-dependent pathways. PMID- 22821259 TI - Ultrasonographic evaluation of the femoral cartilage thickness in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease with a broad spectrum of clinical and serological manifestations. Although articular involvement is known in SLE, articular cartilage has not been studied before. Therefore, in this study, we have evaluated the femoral cartilage by using ultrasonography. Twenty-nine SLE patients (5 M, 24 F) with a mean age of 37.93 +/- 10.66 years and mean disease duration of 3.69 +/- 3.24 years and 29 age , gender- and body mass index-matched healthy subjects were enrolled. Demographic and clinical characteristics of the patients were recorded. The thickness of the femoral articular cartilage was measured by using a 7- to 12-MHz linear probe. Three mid-point measurements were taken from each knee; from right lateral condyle, right intercondylar area (RIA), right medial condyle (RMC), left medial condyle, left intercondylar area (LIA) and left lateral condyle (LLC). Although SLE patients had thicker femoral cartilage values than those of the control group at all measurement sites, the differences were not statistically significant (all p > 0.05). Twenty-two patients (75.9 %) were using corticosteroids, and when those patients were compared with their healthy controls, the difference reached statistical significance at RIA (p = 0.022), LIA (p = 0.059) and LLC (p = 0.029). We found that SLE patients seem to have thicker femoral cartilage values and that this increase could be related with corticosteroid treatment. In addition to studies that have shown the favorable effects of corticosteroids on chondrogenesis, further studies are needed to clarify the scenario in SLE patients. PMID- 22821257 TI - Artificial DNA and surface plasmon resonance. AB - The combined use of surface plasmon resonance (SPR) and modified or mimic oligonucleotides have expanded diagnostic capabilities of SPR-based biosensors and have allowed detailed studies of molecular recognition processes. This review summarizes the most significant advances made in this area over the past 15 years. Functional and conformationally restricted DNA analogs (e.g., aptamers and PNAs) when used as components of SPR biosensors contribute to enhance the biosensor sensitivity and selectivity. At the same time, the SPR technology brings advantages that allows forbetter exploration of underlying properties of non-natural nucleic acid structures such us DNAzymes, LNA and HNA. PMID- 22821261 TI - Clinical remission in juvenile idiopathic arthritis after termination of etanercept. AB - Biologicals are very effective for inhibiting disease progression in active juvenile idiopathic arthritis (JIA). To date, there have been no recommendations on how and when to stop therapy with TNF inhibitors. Our objective was to analyze characteristics and the disease course of JIA patients who discontinued etanercept due to achievement of inactive disease. Data of 39 patients with JIA from two clinical pediatric rheumatology centers in Bydgoszcz and Lublin (Poland) were analyzed retrospectively. All patients discontinued etanercept due to a remission on treatment. Etanercept was started after a mean 33.7 +/- 36 (range 3 137) months of disease. The mean duration of therapy with etanercept was 34.7 +/- 16.7 (range 6-72) months, with a mean duration of remission on medication 21.3 +/ 9.6 (range 4-42) months before withdrawal of etanercept. The mean duration of remission after etanercept discontinuation was 14.2 +/- 12.1 (range of 1-60) months. Only 12/39 (30.8 %) patients did not develop a disease exacerbation until the end of the study. Early flares, that is less than 6 months after termination of etanercept, were observed in 15/39 (38.5 %) patients. Twelve (30.8 %) patients restarted etanercept after exacerbation-all patients responded satisfactorily. Our data show that etanercept discontinuation in a substantial proportion of JIA patients results in early disease exacerbation. In many cases, reintroduction of etanercept is needed. Patients, in whom etanercept was restarted, responded satisfactorily. PMID- 22821260 TI - The value of cartilage biomarkers in progressive knee osteoarthritis: cross sectional and 6-year follow-up study in middle-aged subjects. AB - To determine the possible diagnostic and prognostic value of cartilage biomarkers in early-stage progressive and nonprogressive knee osteoarthritis (OA) in a population-based cohort of middle-aged subjects with chronic knee pain. Design tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age at baseline, 45 +/- 6.2 years) in 2002, 2005, and 2008. Cartilage degradation was assessed by urinary C-telopeptide fragments of type II collagen (uCTx-II), synthesis by serum type II A procollagen N-terminal propeptide (sPIIANP), and articular tissue turnover in general by cartilage oligomeric matrix protein (sCOMP). Several diagnostic associations were found between all studied biomarkers and progressive osteophytosis. COMP and CTx-II had a predictive value for subsequent progressive osteophytosis in multiple knee compartments and in case of CTx-II-also for progressive JSN. Over the first 3 years (2002-2005), significant associations were observed between COMP and progressive osteophytosis, whereas 3 years later (2005-2008) between CTx-II and progressive JSN. Thus, the associations between cartilage markers (COMP, CTx-II) and progression of radiographic OA features--osteophytes and JSN--were different between 2002-2005 and 2005-2008. Logistic regression revealed that for every unit increase in COMP level, there was 33 % higher risk for TF osteophyte progression. During early-stage OA, the presence and progression of osteophytosis is accompanied by increased level of cartilage biomarkers. This is the first study to demonstrate biochemical differences over the course of knee OA, illustrating a phasic nonpersistent character of OA with periods of progression and stabilization. PMID- 22821262 TI - Characteristics of suckling stimulation determine the daily duration of mother young contact and milk output in rabbits. AB - Rabbits nurse inside a nest once/day for 3-5 min. We quantified mother's time inside the nest box (TINB) and milk output as we varied the number and age of pups across lactation. TINB was larger and milk output smaller on lactation days 2, 3, 7, or 8, when one pup (2-3 days old) was provided, but normal on Days 4-6, when suckling eight pups. Maintaining 1, 2, or 6-8 growing pups across 30 days increased TINB in the first two groups without modifying milk intake/pup. Substituting a 15 day-old for a newborn increased TINB (Days 15-20) and decreased milk intake/pup (Days 15-30). Substituting for a newborn on Days 5, 9, 13, 17, 21, 25, and 29 increased TINB on such days and revealed a gradual decline in TINB on the "non-switch" days. Litter size, age, and lactation stage interact to determine TINB and milk output. PMID- 22821263 TI - A conceptual and methodological framework for measuring and modulating the attentional blink. AB - The attentional blink (AB) is a transient attention cost that is shown when report accuracy for a second target (T2) is reduced when T2 is presented within approximately 500 ms of a first target (T1). Thus, by definition an AB is only observed when T2 accuracy is reduced at short relative to long T1-T2 separations, and the magnitude of the AB is reflected in the change in T2 performance across target separations. However, the designs, analyses, and interpretations of several studies of the AB have suggested a lack of clear definitions about what constitutes a demonstration of the AB, what constitutes a modulation of the AB across participant groups or manipulations, and how AB magnitude might best be represented accurately as a single value for a given individual. In this article, we discuss the important conceptual and methodological issues that should be considered when obtaining, analyzing, and interpreting AB data, and we discuss the pros and cons of various approaches while providing suggestions as to how best to validly represent the AB and its modulations. PMID- 22821264 TI - Analytical strategies for the global quantification of intact proteins. AB - The quantification of intact proteins is a relatively recent development in proteomics. In eukaryotic organisms, proteins are present as multiple isoforms as the result of variations in genetic code, alternative splicing, post translational modification and other processing events. Understanding the identities and biological functions of these isoforms and how their concentrations vary across different states is the central goal of proteomics. To date, the bulk of proteomics research utilizes a "bottom-up" approach, digesting proteins into their more manageable constitutive peptides, but sacrificing information about the specific isoform and combinations of post-translational modifications present on the protein. Very specific strategies for protein quantification such as the enzyme-linked immunosorbent assay and Western blot are commonplace in laboratories and clinics, but impractical for the study of global biological changes. Herein, we describe strategies for the quantification of intact proteins, their distinct advantages, and challenges to their employment. Techniques contained in this review include the more traditional and widely employed methodology of differential gel electrophoresis and more recently developed mass spectrometry-based techniques including metabolic labeling, chemical labeling, and label-free methodologies. PMID- 22821266 TI - Key issues in the acquisition and analysis of qualitative and quantitative mass spectrometry data for peptide-centric proteomic experiments. AB - Proteomic technologies have matured to a level enabling accurate and reproducible quantitation of peptides and proteins from complex biological matrices. Analysis of samples as diverse as assembled protein complexes, whole cell lysates or sub cellular proteomes from cell cultures, and direct analysis of animal and human tissues and fluids demonstrate the incredible versatility of the fundamental nature of the technique that forms the basis of most proteomic applications today (mass spectrometry). Determining the mass of biomolecules and their fragments or related products with high accuracy can convey a highly specific assay for detection and identification. Importantly, ion currents representative of these specifically identified analytes can be accurately quantified with the correct application of smart isobaric tagging chemistries, heavy and light isotopically derivatised samples or standards, or by careful application of workflows to compare unlabelled samples in so-called 'label-free' and targeted selected reaction monitoring experiments. In terms of exploring biology, a myriad of protein changes and modifications are being increasingly probed and quantified, including diverse chemical changes from relatively decisive modifications such as protein splicing and truncation, to more transient dynamic modifications such as phosphorylation, acetylation and ubiquitination. Proteomic workflows can be complex beasts and several key considerations to ensure effective applications have been outlined in the recent literature. The past year has witnessed the publication of several excellent reviews that thoroughly describe the fundamental principles underlying the state of the art. This review further elaborates on specific critical issues introduced by these publications and raises other important unaddressed considerations and new developments that directly impact on the effectiveness of proteomic technologies, in particular for, but not necessarily exclusive to peptide-centric experiments. These factors are discussed both in terms of qualitative analyses, including dynamic range and sampling issues, and developments to improve the translation of peptide fragmentation data into peptide and protein identities, as well as quantitative analyses, including data normalisation and the utility of ontology or functional annotation, the effects of modified peptides, and considered experimental design to facilitate the use of robust statistical methods. PMID- 22821265 TI - Quantitative proteomics to decipher ubiquitin signaling. AB - Ubiquitin signaling plays an essential role in controlling cellular processes in eukaryotes, and the impairment of ubiquitin regulation contributes to the pathogenesis of a wide range of human diseases. During the last decade, mass spectrometry-based proteomics has emerged as an indispensable approach for identifying the ubiquitinated proteome (ubiquitinome), ubiquitin modification sites, the linkages of complex ubiquitin chains, as well as the interactome of ubiquitin enzymes. In particular, implementation of quantitative strategies allows the detection of dynamic changes in the ubiquitinome, enhancing the ability to differentiate between function-relevant protein targets and false positives arising from biological and experimental variations. The profiling of total cell lysate and the ubiquitinated proteome in the same sets of samples has become a powerful tool, revealing a subset of substrates that are modulated by specific physiological and pathological conditions, such as gene mutations in ubiquitin signaling. This strategy is equally useful for dissecting the pathways of ubiquitin-like proteins. PMID- 22821267 TI - Advances in phosphopeptide enrichment techniques for phosphoproteomics. AB - Phosphoproteomics is increasingly used to address a wide range of biological questions. However, despite some success, techniques for phosphoproteomics are not without challenges. Phosphoproteins are present in cells in low abundance relative to their unphosphorylated counterparts; therefore phosphorylated proteins (or phosphopeptides after protein digestion) are rarely detected in standard shotgun proteomics experiments. Thus, extraction of phosphorylated polypeptides from complex mixtures is a critical step in the success of phosphoproteomics experiments. Intense research over the last decade has resulted in the development of powerful techniques for phosphopeptide enrichment prior to analysis by mass spectrometry. Here, we review how the development of IMAC, MOAC, chemical derivatization and antibody affinity purification and chromatography is contributing to the evolution of phosphoproteomics techniques. Although further developments are needed for the technology to reach maturity, current state-of the-art techniques can already be used as powerful tools for biological research. PMID- 22821269 TI - Analysing signalling networks by mass spectrometry. AB - Sequence analysis of the human genome and the association of genetic aberrations with diseases have provided a rough framework whereby the impact of individual genotypes can be assessed. To fully understand the effect of individual and co occurring genetic aberrations, as well as their individual and collected contribution to the development of diseases, it is critical to analyse the matching proteome and to determine how the organisation, expression level and function of protein networks are affected. Sensitive mass spectrometric platforms in combination with innovative workflows allow qualitative and quantitative analyses of the cellular as well as the extracellular proteome. Importantly, in addition to specifically identifying the content of the proteome, several aspects of the proteomic organisation can be analysed including protein complexes, protein modifications, enzymatic activities and subcellular/organelle localisation. Together, these measurements will provide novel insight into the biological effect of disease-causing mutations ultimately coupling genotype and phenotype. PMID- 22821270 TI - Analysis of the Plasmodium falciparum proteasome using Blue Native PAGE and label free quantitative mass spectrometry. AB - Detailed knowledge of the composition of protein complexes is crucial for the understanding of their structure and function; however, appropriate techniques for compositional analyses of complexes largely rely on elaborate tagging, immunoprecipitation, cross-linking and purification strategies. The proteasome is a prototypical protein complex and therefore an excellent model to assess new methods for protein complex characterisation. Here we evaluated the applicability of Blue Native (BN) PAGE in combination with label-free protein quantification and protein correlation profiling (PCP) for the investigation of proteasome complexes directly from biological samples. Using the purified human 20S proteasome we showed that the approach can accurately detect members of a complex by clustering their gel migration profiles. We applied the approach to address proteasome composition in the schizont stage of the malaria parasite Plasmodium falciparum. The analysis, performed in the background of the whole protein extract, revealed that all subunits comigrated and formed a tight cluster with a single maximum, demonstrating presence of a single form of the 20S proteasome. This study shows that BN PAGE in combination with label-free quantification and PCP is applicable to the analysis of multiprotein complexes directly from complex protein mixtures. PMID- 22821271 TI - Special issue in quantitative mass spectrometric proteomics. PMID- 22821268 TI - Current challenges in software solutions for mass spectrometry-based quantitative proteomics. AB - Mass spectrometry-based proteomics has evolved as a high-throughput research field over the past decade. Significant advances in instrumentation, and the ability to produce huge volumes of data, have emphasized the need for adequate data analysis tools, which are nowadays often considered the main bottleneck for proteomics development. This review highlights important issues that directly impact the effectiveness of proteomic quantitation and educates software developers and end-users on available computational solutions to correct for the occurrence of these factors. Potential sources of errors specific for stable isotope-based methods or label-free approaches are explicitly outlined. The overall aim focuses on a generic proteomic workflow. PMID- 22821272 TI - Forgotten atrial: driver of symptoms in heart failure with normal ejection fraction? PMID- 22821273 TI - Different cardiac biomarkers to detect peri-procedural myocardial infarction in contemporary coronary stent trials: impact on outcome reporting. AB - OBJECTIVE: To assess the differential implications of cardiac biomarker type on peri-procedural myocardial infarction (PMI) reporting. SETTING: The Resolute 'All Comers' stent trial. INTERVENTIONS: Blood samples for creatine kinase (CK), CK myoband (CK-MB) mass or cardiac troponin (cTn) (optional) were collected before and at 6, 12 and 18 h after the assigned percutaneous coronary intervention or at discharge. PMIs were adjudicated using either the 2007 universal definition of MI (type-4a) or the extended historical definition of MI. PATIENTS: 2121/2292 patients (92.5%) had an analysable dataset for either biomarker. 890/2121 patients (42%) presented with an acute coronary syndrome (ACS). 267/890 patients (30%) were within 24 h of an ST-segment elevation MI. MAIN OUTCOME MEASURES: Type 4a MI was diagnosed in 208/2121 patients (9.8%) when cTn was used (CK-MB mass if cTn not available), and in 93/2121 of patients (4.4%) when CK-MB mass was used (cTn if CK-MB mass not available). With the extended historical CK-based definition of MI, PMI was diagnosed in 65/2121 patients (3.1%). Adjudication of type-4a MI in patients with an ACS was problematic with <10% of the potential type-4a MI being confirmed as an event, as compared with approximately 95% in stable patients undergoing elective PCI. Type-4a MI was not associated with the subsequent hazard for cardiac mortality (p=0.6). CONCLUSIONS: The percentage of adjudicated PMI events is driven by the MI-definition criteria and biomarker type. Type-4a MI may not be a reliable component of the primary composite end point in coronary stent investigations which recruit patients with ACS. TRIAL REGISTRATION NUMBER: http://www.ClinicalTrials.gov; Unique identifier: NCT00617084. PMID- 22821274 TI - Temporal trends in the incidence and recurrence of hospitalised atherothrombotic disease in an Australian population, 2000-07: data linkage study. AB - OBJECTIVES: To examine temporal trends in the incidence and recurrence of hospitalised coronary heart disease (CHD), cerebrovascular disease (CeVD) and peripheral arterial disease (PAD) separately and combined, and by the history of all forms of atherothrombotic disease (ATD). DESIGN: Population-based longitudinal data linkage study. SETTING: Western Australia. PARTICIPANTS: All patients aged 35-84 years hospitalised in Western Australia for CHD, CeVD or PAD from 2000 to 2007. MAIN OUTCOME MEASURES: Age-standardised incidence and recurrence rates of CHD, CeVD and PAD stratified by ATD history, sex and age. RESULTS: 107 576 events (65.9% men) were identified; 70% of all admissions were for CHD. In patients without a history of any ATD, incidence rates declined significantly in all groups, although the reduction in incident CHD in women was marginal (-0.7%/year, 95% CI -1.5 to +0.1%). The largest annual reductions in incidence rates were for PAD (men, -6.4%/year, 95% CI -7.7 to -5.0%; women, 5.4%/year, 95% CI -7.2 to -3.6%) and CeVD in women (-4.0%/year, 95% CI -5.0 to 3.0%). Falls in overall recurrence rates were greatest for CeVD (men, -3.2%/year, 95% CI -4.7 to -1.6%; women -4.6%/year, 95% CI -6.4 to -2.7%). Trends across all categories of polyvascular ATD were generally downward, although not all changes were statistically significant. CONCLUSION: The incidence and recurrence rates of hospitalised ATD have decreased over time, including in patients with disease involving multiple vascular territories. This implies that primary and secondary prevention strategies have been broadly effective. However, high absolute rates of recurrence and limited reduction in 35-54-year-old individuals highlight patient groups to target to reduce further the burden of ATD. PMID- 22821275 TI - Successful treatment of resistant hypertension with percutaneous renal denervation therapy. PMID- 22821276 TI - Influence of age on the prognostic value of mid-regional pro-adrenomedullin in the general population. AB - OBJECTIVE: Experimental studies have shown that adrenomedullin (ADM) has an important role in circulatory homeostasis. Mid-regional pro-ADM (MR-proADM) is a stable form of ADM. Observational studies found an important association with age, body mass index and kidney function. The aim of this study was to evaluate the prognostic performance of MR-proADM in the general population, controlling for these potential confounders. METHODS: 7903 subjects (mean age 49 +/- 13 years, 49% male) from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort with a median follow-up of 10.5 years were enrolled in a prospective cohort study. RESULTS: Mean baseline MR-proADM was 0.39 +/- 0.14 nmol/l. In cross-sectional analyses, age, blood pressure, C reactive protein, cystatin-C, N-terminal pro-brain type natriuretic peptide and urinary albumin excretion remained as independent determinants of MR-proADM. In prospective analyses, MR-proADM was associated with the primary endpoint (combined cardiovascular mortality and cardiovascular morbidity), with event rates ranging from 8% in the lowest quintile to 45% in the highest quintile (p for trend <0.001) independent of age, sex, components of the Framingham risk score and other cardiovascular markers. Overall Net Reclassification Improvement against the Framingham risk score was 2.2%, which was non-significant. However, significant modification of the effect of MR-proADM on outcome by age was observed. In subjects aged <=70 years (N=7475), 8.8% were correctly reclassified in a higher risk category (p=0.017) and 3.4% in a lower risk category (p<0.001). In subjects aged >70 years (N=428) there was no improvement of reclassification (p=0.32). CONCLUSION: This study gives a detailed overview of the distribution of ADM in a general population and provides evidence that it is a potent and interesting biomarker in predicting cardiovascular events. These results seem especially applicable to younger subjects. PMID- 22821277 TI - A four-year retrospective study and review of selection criteria and post operative complications of stapled haemorrhoidopexy. AB - BACKGROUND: Severe life-threatening complications have been reported from the use of procedure for prolapsed haemorrhoids (PPH). First, we assessed post-operative complication rates over 4 years of PPH experience. We then sought to assess the impact of selection criteria for patients receiving PPH on post-operative complication rates and review our findings in the context of published literature. METHODS: Over a 4-year period 2006-2010 at Hinchingbrooke Hospital, all 118 patients receiving PPH were audited for readmissions with post-operative complications using the admission database. A further retrospective audit of 50 patients' notes assessed the impact of selection criteria for PPH on post operative complication rates. All PPH operations were performed by one of two senior colorectal consultants using the standard technique with a circular stapler. RESULTS: Of the 118 patients from the 4-year audit, 12 (10 %) patients were readmitted. Two (1.7 %) of these 12 patients had post-operative pain, six (5.1 %) had rectal bleeding, three (2.5 %) had urinary retention, and one (0.8 %) had localised infection. There was one (0.8 %) patient mortality resulting from severe sepsis from an infected intra-abdominal haemorrhagic collection. In the following audit of 50 patients' notes, 15 patients had internal prolapsed haemorrhoids alone, of which one (6.6 %) experienced post-operative complications compared with six (55 %) of the 11 patients who had haemorrhoids and skin tags. CONCLUSIONS: With careful selection of patients, PPH may be indicated for prolapsed internal haemorrhoids. More specific national guidelines are required with regard to contraindications to PPH. PMID- 22821280 TI - Sources of fluorescent dissolved organic matter in high salinity seawater (Bohai Bay, China). AB - Fluorescent dissolved organic matter (FDOM) identified in coastal waters within a large salinity range had been widely reported in previous studies, which stated that conservative mixing of terrestrially derived and river-transported FDOM by clear seawaters could account for the relatively low FDOM fluorescence signals in high salinity seawaters. This study aimed at testing the conservative mixing model in high salinity seawaters in a shallow bay (Bohai Bay, China) with low river flow in a dry season. The water showed high salinities varying in a narrow range (30.52 - 2.07), and salinity effects on fluorescence quantum yields therefore less likely introduced complications to fluorescence data analyses. By applying a parallel factor analysis to fluorescence excitation emission matrices of the water samples, we identified a tyrosine-like FDOM component, a tryptophan like FDOM component, and two humic substances-like FDOM components. Based on a theoretical analysis, we found that dissolved organic carbon concentrations and suspended solid concentrations of the bulk-water samples as well as the maximum fluorescence signals of each identified FDOM component showed spatial distributions that could not be accounted for by the conservative mixing model. Marine autochthonous processes including microbial activities and FDOM releasing from resuspended sediment were likely to be invoked. PMID- 22821279 TI - Screening of endocrine-disrupting phenols, herbicides, steroid estrogens, and estrogenicity in drinking water from the waterworks of 35 Italian cities and from PET-bottled mineral water. AB - We investigated contamination by endocrine-disrupting chemicals in drinking water from 35 major Italian cities and five popular Italian brands of bottled mineral water. The quality of Italian drinking water was assessed by combing chemical analysis with bioassay to quantify specific estrogenic contaminants and to characterize the actual biological effect of the mixture of chemicals present in drinking water including the contribution of not targeted compounds. The selected contaminants were natural and synthetic steroid estrogens, alkylphenols and bisphenol A, linuron, triazine herbicides, and their metabolites. A specific analytical method was developed based on solid phase extraction of 1 L of water and concentration to 100 MUL for quantification by electrospray ionization liquid chromatography tandem mass spectrometry, achieving quantification limits of 0.05 0.36 ng/L for herbicides and 0.64-7.70 ng/L for steroids and phenols. No steroid estrogens were detected in any of the samples, while bisphenol A and nonylphenols were detected in the ranges of 0.82-102.00 and 10.30-84.00 ng/L respectively. Herbicides and their degradation products, when present, were found from slightly above the quantification limits up to 49.91 ng/L, mainly from cities in northern Italy. Chemical analyses were complemented by the performance of a bioassay for the determination of the estrogenic activity in the extracts based on the transactivation of estrogen receptor alpha-transfected reporter HeLa-ERE Luciferase-Neomycin cell line. Activity was generally low with maximum estrogenicity of 13.6 pg/L estradiol equivalents. PMID- 22821278 TI - A survey of tissue-specific genomic imprinting in mammals. AB - In mammals, most somatic cells contain two copies of each autosomal gene, one inherited from each parent. When a gene is expressed, both parental alleles are usually transcribed. However, a subset of genes is subject to the epigenetic silencing of one of the parental copies by genomic imprinting. In this review, we explore the evidence for variability in genomic imprinting between different tissue and cell types. We also consider why the imprinting of particular genes may be restricted to, or lost in, specific tissues and discuss the potential for high-throughput sequencing technologies in facilitating the characterisation of tissue-specific imprinting and assaying the potentially functional variations in epigenetic marks. PMID- 22821282 TI - [Professional image and sector boundaries in a state of flux?]. PMID- 22821281 TI - Simultaneous removal of nitrate and pentachlorophenol from simulated groundwater using a biodenitrification reactor packed with corncob. AB - Both nitrate and pentachlorophenol (PCP) are familiar pollutants in aqueous environment. This research is focused on the simultaneous removal of nitrate and PCP from simulated contaminated groundwater using a laboratory-scale denitrification reactor packed with corncob as both carbon source and biofilm support. The reactor could be started up readily, and the removal efficiencies of nitrate and PCP reached up to approximately 98% and 40-45% when their initial concentrations were 50 mg N/L and 5 mg/L, respectively, after 15-day continuous operation at 10 h of hydraulic retention time (HRT) and 25 degrees C. Approximately 91% of PCP removal efficiency was achieved, with 2.47 mg/L of chloride ion release at 24 h of HRT. Eighty-two percent of chlorine in PCP removed was ionized. The productions of 3-chlorophenol and phenol and chloride ion release indicate that the reductive dechlorination reaction is a major degradation pathway of PCP under the experimental conditions. PMID- 22821283 TI - [Interdisciplinary treatment of urological tumors: a mixed-method study]. AB - From the medical viewpoint (oncology agreement) and also from that of patients (self-help groups) urological competence should be increased and the cooperation between medical disciplines should be improved. What does the medical cooperation really look like? The few studies which have been carried out concern the cooperation between general physicians and specialists although specialists, such as urologists and hemato-oncologists have not yet been investigated. These gaps should be closed by the study of interdisciplinary treatment of urological tumors (IBuTu study). PMID- 22821284 TI - Invasive meningococcal infection: analysis of 110 cases from a tertiary care centre in North East India. AB - OBJECTIVES: To report an outbreak of invasive meningococcal disease from Meghalaya, in the north east India, from January 2008 through June 2009. METHODS: Retrospective review of case sheets was done. One hundred ten patients with invasive meningococcal disease were included for the study. RESULTS: Of the total patients, 61.8 % were boys and 38.2 % were girls (boy to girl ratio = 1.62:1). The average age of presentation was 8.48 +/- 5.09 y. Meningococcal meningitis was seen in 61.8 % of cases, meningococcemia in 20 % and 18.2 % had both. Fever was the most common manifestation (100 %) followed by meningeal signs (78.2 %), headache (56.4 %), vomiting (53.6 %), shock (38.2 %), low Glasgow coma scale (GCS) (25.5 %), purpura and rashes (23.6 %), seizures (9.1 %), abdominal symptoms (4.5 %), irritability and excessive crying (4.5 %) and bulging anterior fontanalle (23 %) in those below 18 mo of age. Raised intracranial pressure (ICP) was the most common complication (28.2 %) followed by coagulopathy (16.4 %), hepatopathy (10 %), herpes labialis (9.1 %), syndrome of inappropriate ADH secretion (SIADH) (8 %), pneumonia (7 %), arthritis (6 %), purpura fulminans, respiratory failure, sixth nerve palsy and diabetes insipidus in 4.5 % each, subdural empyema, optic neuritis, ARDS and ARF in 1.8 % each, cerebral salt wasting syndrome, third nerve palsy, cerebritis and hearing impairment in 0.9 % each. Culture was positive in 35.5 %. Patients were treated initially with ceftriaxone and dexamethasone but later on with chloramphenicol due to clinical drug resistance. Mortality was 6.4 %. CONCLUSIONS: This is the first epidemic report of invasive meningococcal disease from the north east India. Chloramphenicol acts well in areas with penicillin or cephalosporin resistance. Mortality reduces significantly with early diagnosis and prompt intervention. PMID- 22821286 TI - Fatal pertussis in a preterm with hyperleukocytosis and necrotizing enterocolitis: considerations on pathogenesis and prevention. PMID- 22821285 TI - Long-term dietary intake of selenium, calcium, and dairy products is associated with improved capillary recruitment in healthy young men. AB - PURPOSE: To identify associations between long-term (1 year) food intake and skin nutritive microvascular function in healthy subjects. METHODS: This was a cross sectional study. A validated 88-item food-frequency questionnaire was administered to 39 healthy men aged 23.4 +/- 0.5 years and body mass index 23.3 +/- 2.3 kg/m2, who reported food intake during the last year and underwent videocapillaroscopy exams. The main outcome was the increase in functional capillary recruitment, that is, peak capillary density after post-occlusive reactive hyperemia subtracted from basal capillary density (caps/mm2). Associations between reported food intake and functional capillary recruitment were investigated. RESULTS: Daily average estimates of intake were: total energy (3,745 +/- 1,365 kcal), carbohydrates (60.1 +/- 5.9 %), lipids (22.1 +/- 4.4 %), proteins (17.8 +/- 4.1 %), fibers (33.9 +/- 18.5 g), and cholesterol (492.8 +/- 209.6 mg). Positive significant correlations with capillary recruitment were found for selenium (as MUg/day/1,000 kcal; rho = 0.3412, p = 0.038,) calcium (as mg/day/1,000 kcal; rho = 0.3390, p = 0.043), and percentage of total energy from dairy products (rho = 0.3660, p = 0.023). CONCLUSIONS: Long-term intakes of selenium, calcium, and dairy products were positively associated with capillary recruitment in skin nutritive microcirculation in healthy young men. The role of such dietary components is discussed and possible mechanisms for their effects should be further investigated. This evidence adds one more possible functional property of these nutrients and food items. PMID- 22821287 TI - Explanation of social inequalities in hyperactivity/inattention in children with prenatal alcohol exposure. AB - BACKGROUND: Hyperactivity and inattention are major effects of prenatal alcohol exposure (PAE). Although predominantly women from the high social class consume alcohol during pregnancy, children from the low social class are particularly affected by the adverse effects of PAE. This study aimed to test the hypothesis of a social gradient in hyperactivity/inattention in children with PAE. METHODS: Children with PAE (N=996) enrolled in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were studied. KiGGS was designed and conducted by Robert Koch Institute (RKI) as a nationwide representative survey on the health of German children and adolescents aged 0-17 years. The data include information given by parents and adolescents on the physical and mental health, sociodemographic features, life circumstances and conditions. RESULTS: PAE children with a middle and low parental socioeconomic status (SES) are on a higher risk of developing hyperactivity/inattention compared to those with high parental SES. Cultural-behavioral factors had the strongest effect in the explanation of social inequalities in hyperactivity/inattention among children with PAE. CONCLUSIONS: Cultural-behavioral factors, particularly health-related behaviors, need a significant improvement in children from the low and middle social class. To reduce social inequalities in hyperactivity in children with PAE, interventions have to focus on the dietary and television habits of the child by reaching parents from the low and middle social class. PMID- 22821288 TI - Human leukocyte antigen distribution in German Caucasians with advanced Ewing's sarcoma. AB - BACKGROUND: Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls. PATIENTS: HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients. RESULTS: After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05). CONCLUSION: We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups. PMID- 22821289 TI - Evaluation of functional MR-urography in complex obstructive uropathy of infants: comparison to the conventional diagnostic algorithm--a pilot study. AB - OBJECTIVES: To analyze the impact of functional magnetic resonance urography (fMRU) on the therapeutic management in infants with complex obstructive uropathy (OU) compared to the conventional diagnostic algorithm [CDA, ultrasound, radioisotope nephrography (RN)]. METHODS: Retrospective analysis on 10 consecutive infants [female, n=3; male, n=7; age, 10.7 (2-17) months] with OU. Patients were examined according to CDA. If CDA revealed inconclusive results, fMRU was performed additionally. Split kidney function was assessed by RN [single kidney function (SKF)] and fMRU [volumetric differential renal function (vDRF)]. Findings were presented to an interdisciplinary truth-panel in a 2-step decision process (with and without fMRU). Clinical decision was determined. RESULTS: CDA indicated surgical intervention in 8 patients and conservative treatment in 2. Information by fMRU changed treatment strategy in 3 patients and led to the modification of the initially chosen surgical approach in 8 cases. The comparison of SKF and vDRF was not possible in 1 patient, whereas concordance was observed in 7 patients. SKF and vDRF differed >5% in 2 patients. CONCLUSIONS: fMRU has potential to improve therapeutic management of OU in infants. If surgical treatment is advised, the morphological information by fMRU has to be emphasized. Regarding kidney function estimation preliminary results are encouraging. PMID- 22821290 TI - Holy water associated pulmonary infection with a multiresistant Acinetobacter baumanii in an 11-year-old child. PMID- 22821291 TI - Abdominal tuberculosis in children and adolescents: to this day a diagnostic challenge. PMID- 22821292 TI - Coincident diagnosis of a pulmonary abscess and ascaris lumbricoides infection: a possible causal connection? PMID- 22821293 TI - Near fatal physical neglect in a newborn with a three-year follow-up. PMID- 22821294 TI - Timely MMR vaccination in infancy: influence of attitudes and medical advice on the willingness to vaccinate. AB - In light of the failure to eliminate measles by 2010, the closure of any gaps in immunisation coverage is of paramount importance to interrupt transmission and to protect vulnerable individuals. Not only vaccination-critical attitudes of parents but furthermore the medical advice by physician in charge influence the vaccine uptake. 3 groups of factors which potentially influence parental decisions on child vaccination were analysed by univariable and multivariable logistic regression for the timely uptake of the first and the second dose of measles vaccination: parents' attitudes towards immunization, the influence of medical and laypersons and the influence of the advice of a medical doctor. A total of 3 041 children were eligible for the analysis. 53.0% of these received the first and 42.9% the second MMR dose in time. If parents considered that vaccinations are important and protective as well as the consulted physician advices towards vaccinations, children had significantly higher chances of a timely vaccination. Whereas, if parents were afraid of vaccinations or get advised by an alternative practitioner, the children had lower chances of being vaccinated in time. If medical providers help parents to reduce uncertainties about vaccination the chance for children to be vaccinated in time increased. It appeared that there still are unmet information needs after the medical consultation. By and large the medical advice plays an important role for vaccination uptake and its timing. In order to raise the vaccination rates further target-population specific approaches are needed. PMID- 22821295 TI - Bamboo nodes as a cause of juvenile dysphonia. PMID- 22821296 TI - [Congenital autosomal recessive Cutis laxa Type II A Wrinkly-Skin-Syndrome]. PMID- 22821297 TI - Frequency of symptomatic zinc deficiency in very low birth weight infants. AB - Current concepts on zinc requirements for premature infants rely on studies dating back more than 20 years. Given that nowadays more premature infants frequently survive we aimed to obtain recent frequency data on zinc deficiency in very low birth weight (VLBW) infants.226 VLBW infants born between July 2005 and December 2009 were retrospectively included in this study. Mean gestational age (GA) was 28.7 weeks (range 23+0 to 38+0) and mean birth weight 1120g (range 354 1495). All infants received zinc supplementation according to the ESPGHAN guidelines. 26 (11.5%) patients showed clinical signs for zinc deficiency of whom 15 had serum zinc concentrations < 50ug/dl, 9 between 50 and 70 ug/dl and 2 > 70 ug/dl. Infants presenting with dermatitis had significantly lower concentrations (mean 26.7 ug/dl, range 19-31) when compared to infants with diarrhoea or isolated peripheral oedema (35.3 ug/dl and 51.8 ug/dl respectively). Strongest independent risk factors were low GA, being small for GA and suffering from intestinal resection due to necrotizing enterocolitis. Frequency of zinc concentrations <50 ug/dl were calculated to be 6.6% in VLBW infants.Even though current guidelines for zinc supplementation were followed the frequency of zinc deficiency was found to be unexpectedly high in ELBW and SGA infants. Despite the retrospective nature of this single centre study, our data strongly suggest that recommendations on zinc supplementation in ELBW and SGA infants should be reviewed. PMID- 22821298 TI - [Genetic prognostic factors in childhood acute myeloid leukemia]. AB - The survival rate of children and adolescents suffering acute myeloid leukemia (AML) has been significantly improved within the last decades. This has been achieved by a continuously intensified therapy and progress in supportive care to prevent and treat complications. In Germany, the AML-BFM trials 98 (n=413) and 2004 (n=499) enrolled 912 children and adolescents as protocol patients (1998 2010). The 5-year-overall survival was 71+/-2%. In the previous studies prognosis and subsequent treatment stratification based on morphology, cytochemistry and white blood cell count. Today, the identification of new genetic aberrations in AML enables a genetically determined estimation of prognosis, although treatment response must be considered for treatment stratification. The group with a favorable prognosis summarized AML with t(8;21), inv(16), t(15;17), t(1;11), and AML with normal karyotype and NPM1-mutation (n=253; EFS 74+/-3%, OS 88+/-2%). A poor prognosis (HR-group) must be expected in AML with t(4;11), t(5;11), t(6;11), t(6;9), t(7;12), t(9;22), Monosomy 7, combined FLT3/WT1-mutation, and AML with der(12p)-aberration (n=101; EFS 30+/-5%; OS 56+/-5%). The intermediate group summarizes all other subgroups especially AML with normal karyotyp, AML with FLT3 ITD or t(9;11) (n=558; EFS 43+/-2%; OS 64+/-2%). The validation of the internationally identified, genetically determined prognostic factors within the AML-BFM (Germany) study population will support treatment recommendations. PMID- 22821299 TI - Death of an infant due to an undiagnosed congenital diaphragmatic hernia. PMID- 22821300 TI - Italian Mediterranean Index and risk of colorectal cancer in the Italian section of the EPIC cohort. AB - Colorectal cancer is among the commonest cancers worldwide. Dietary factors have been linked to colorectal cancer risk, however, few studies have evaluated the relationship between a priori dietary patterns and colorectal cancer risk. We evaluated the effect of adherence to a Mediterranean dietary pattern, as measured by the Italian Mediterranean Index, on the risk of colorectal cancer in the 45,275 participants of the Italian section of the EPIC study who completed a dietary questionnaire. Hazard ratios (HRs) with 95% confidence intervals (CIs) for colorectal cancer in relation to categories of Italian Mediterranean Index score were estimated by multivariate Cox models adjusted for known risk factors, on the whole cohort, on men and women and according to cancer subsite. During a mean follow-up of 11.28 years, 435 colorectal cancer cases were identified. The Italian Mediterranean Index was inversely associated with colorectal cancer risk (HR: 0.50; 95% CI: 0.35-0.71 for the highest category compared to the lowest, P trend: 0.043). Results did not differ by sex. Highest Italian Mediterranean Index score was also significantly associated with reduced risks of any colon cancer (HR: 0.54, 95% CI: 0.36-0.81), distal colon cancer (HR: 0.44, 95% CI: 0.26-0.75) and rectal cancer (HR: 0.41, 95% CI: 0.20-0.81), but not of proximal colon cancer. These findings suggest that adherence to a Mediterranean diet (as measured by the Italian Mediterranean Index) protects against colorectal cancer in general but not against cancer developing in the proximal colon. PMID- 22821301 TI - Consensus QSAR model for identifying novel H5N1 inhibitors. AB - Due to the importance of neuraminidase in the pathogenesis of influenza virus infection, it has been regarded as the most important drug target for the treatment of influenza. Resistance to currently available drugs and new findings related to structure of the protein requires novel neuraminidase 1 (N1) inhibitors. In this study, a consensus QSAR model with defined applicability domain (AD) was developed using published N1 inhibitors. The consensus model was validated using an external validation set. The model achieved high sensitivity, specificity, and overall accuracy along with low false positive rate (FPR) and false discovery rate (FDR). The performance of model on the external validation set and training set were comparable, thus it was unlikely to be overfitted. The low FPR and low FDR will increase its accuracy in screening large chemical libraries. Screening of ZINC library resulted in 64,772 compounds as probable N1 inhibitors, while 173,674 compounds were defined to be outside the AD of the consensus model. The advantage of the current model is that it was developed using a large and diverse dataset and has a defined AD which prevents its use on compounds that it is not capable of predicting. The consensus model developed in this study is made available via the free software, PaDEL-DDPredictor. PMID- 22821302 TI - Molecular mechanism of a novel CD59-binding peptide sp22 induced tumor cells apoptosis. AB - Some short peptides discovered by phage display are found to be able to inhibit cancer growth and induce cancer cell apoptosis. In this study, a novel cancer targeting short peptide which was composed of 22 amino acids (ACHWPWCHGWHSACDLPMHPMC, abbreviated as sp22) and specifically bound to human CD59 was screened from a M13 phage display library so as to counteract tumor immune escape activity. The mechanism of exogenous sp22 peptide in inducing apoptosis of MCF-7 cells was investigated. The results suggested that sp22 could lower CD59 expression level, downregulate Bcl-2 expression, activate Fas and caspase-3, and finally increase apoptotic cell numbers of MCF-7 cells. However, sp22 had no obvious influence on normal human embryonic lung cells. In addition, the effects of endogenous sp22 gene on CD59 expression and NKM cell apoptosis were explored using the recombinant plasmid sp22-PIRES. It showed that sp22 gene was efficiently expressed in transfected NKM cells. Compared with normal NKM cells, NKM cells transfected with sp22 displayed reduced mRNA and protein expression levels of CD59, increased sensitivity to complement-mediated cytolysis, decreased cell survival ratio, changes of the expression of apoptosis associated proteins, increased number of apoptotic cells and the appearance of apoptotic morphology. The results suggested that sp22 protein could bind to CD59 and inhibit the expression of CD59. The cytolytic activity of complement on tumor cells strengthened and apoptosis signal was stepwise transferred which might be a potential way to kill tumor cells. PMID- 22821303 TI - Medical social sciences. Their potential contributions to medical education reforms in Saudi Arabia. AB - This article emphasizes a holistic definition of health. It then introduces the concept of Medical social sciences, and drawing from the literature, argues for the inevitability of social sciences in medical education, especially in the health systems of developing countries including the Kingdom of Saudi Arabia (KSA). This is followed by a brief history of medical education in KSA, and an examination of some important social science issues. Finally, this article suggests how a holistic approach involving inputs from the social and behavioral sciences could be incorporated into undergraduate medical education to produce medical professionals who could better meet the community and public health needs of the country. PMID- 22821304 TI - Helicobacter pylori virulence markers in gastroduodenal disorders. Detection of cytotoxin-associated gene A and vacuolating cytotoxin-associated gene A genes in Saudi patients. AB - OBJECTIVE: To detect the presence of virulence markers cytotoxin-associated (cagA) and vacuolating cytotoxin-associated (vacA) genes in gastric biopsy specimens of patients with gastroduodenal disorders. METHODS: This study was conducted at the Department of Pathology, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between March 2008 and February 2009. A total of 118 gastric biopsy specimens from 81 males and 37 females (mean age: 55 +/- 18 years) with histological evidence for the presence of Helicobacter pylori (H. pylori) were included in the study. The H. pylori cagA and vacA genes were detected using polymerase chain reaction-enzyme-linked immunosorbent assay technique. RESULTS: Both H. pylori cagA and vacA genes were detected in 60 (51%) patients. Forty-one (35%) patients had active chronic gastritis, 22 (54%) harbored cagA, and 25 (61%) had vacA gene. Twenty-six (22%) patients had duodenal ulcer, 14 (54%) had cagA, and 15 (58%) had vacA genes. Eighteen (15%) patients had active acute gastritis, 8 (44%) carrying cagA gene, and 12 (67%) had vacA gene. The cagA and vacA genes co-existed in all the 17 (100%) patients with adenocarcinoma. These genes coexisted in 44% biopsies from active acute gastritis, and 46% each in duodenal ulcer and active chronic gastritis. CONCLUSION: The cagA and vacA genes as H. pylori virulence markers were detected in gastroduodenal disorders, and their remarkably high co-existence in adenocarcinoma prompt further investigations for evaluating H. pylori as a direct carcinogen. PMID- 22821305 TI - Effect of acrylamide on testis of albino rats. Ultrastructure and DNA cytometry study. AB - OBJECTIVE: To explore the harmful effects of acrylamide on the structure of testis in albino rats, in an attempt to clarify its potential risks on human health. METHODS: The present study was carried out in the Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia from December 2010 to December 2011. Forty-eight adult male albino rats (250-300 g) were divided randomly into 6 groups. Electron microscopy and histochemical techniques using Feulgen stain were used to conduct the morphological study. In addition, DNA cytometry method was used. RESULTS: Rats treated with acrylamide 25 mg/kg body weight for 10 days showed mild affection, whether acrylamide was administered orally or intraperitoneally. On the other hand, the testis of the group treated with a dose of 50 mg/kg/10 days showed damage, especially with intraperitoneal administration in comparison to oral treatment. This was in the form of degeneration of germ cells, numerous multinucleated giant cells with sloughed seminiferous epithelium, and vacuolation in-between the germ cells. CONCLUSION: Exposure to acrylamide produced degenerative changes in the testis, which were more prominent with a longer period of exposure. Recommendations are necessary to decrease acrylamide level in different foods, and ways to decrease acrylamide formation during preparation of different foods should be advertised. PMID- 22821306 TI - Biomechanical comparison of internal fixations in osteoporotic intertrochanteric fracture. A finite element analysis. AB - OBJECTIVE: To compare the biomechanical characteristics of dynamic hip screw (DHS) and proximal femoral nail anti-rotation (PFNA) for the treatment of 3 types of osteoporotic femoral intertrochanteric fracture (OFIF) by modeling, and virtual reduction with finite element analysis, and to provide some theoretical basis and reference to select the best internal fixation for clinical treatment of OFIF. METHODS: The experiment was conducted at the Laboratory of Biomechanics, Shanghai Institute of Orthopedics and Traumatology, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China from February to December 2011. The CT scan was performed in 3 cases with different types of OFIF (Evans-Jensen II, III, and IV). Upon validation, fracture models with different internal fixations were developed to simulate and analyze. Under the conditions of 7 different apparent bone densities and 3 different loads, the Von Mises stresses, and the failure rates were calculated, and the stress distribution patterns were compared. RESULTS: The PFNA internal fixation system has better stress distribution than DHS. The former has smaller maximum Von Mises stress of femur and internal fixation, and the femoral element failure rate, as well. The safety range of osteoporosis in PFNA is wider than the DHS. CONCLUSION: The experiment verifies, from the view of biomechanics, that PFNA should be taken into consideration firstly for OFIF (Evans-Jensen II, III, and IV). PMID- 22821307 TI - Vitamin D insufficiency and treatment with oral vitamin D3 in children with chronic kidney disease. AB - OBJECTIVE: To investigate the effects of oral cholecalciferol on the levels of vitamin D3 and intact parathyroid hormone (iPTH) in children with chronic kidney disease (CKD). METHODS: We conducted a prospective uncontrolled observational study at the Pediatric Nephrology Clinic of King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between January and October 2011 to assess serum 25-hydroxyvitamin D3 (25[OH]D) and iPTH in children with CKD stages 2-5. Children with low vitamin D3 levels were commenced on cholecalciferol, 2000 IU/day. Their 25(OH)D3 and iPTH levels were reassessed, first after 3 months, and then after 6 months. Data analysis was performed using the Statistical Package for Social Sciences. Paired t-test was used to compare results before and after treatment. RESULTS: Forty-five children (31 boys and 14 girls) were included in the study. Their mean+/-SD age was 9.6 +/- 4.6 years. There was significant improvement in 25(OH)D3 after 3 months (14.2 +/- 8.2 - 20 +/- 11.1 ng/mL) (p<0.001). However, only 5 children reached levels >/=30 ng/mL. There was no further improvement after 6 months of treatment (20.17 +/- 13.4 ng/mL) (p=0.65). There was no improvement in iPTH levels after 3 and 6 months. No changes were also observed in the levels of calcium, phosphate, alkaline phosphatase, or creatinine. CONCLUSION: The administration of oral vitamin D3 at 2000 IU/day resulted in significant improvement of vitamin D levels in children with CKD, but normalized only in 11% of the patients. The treatment had no effect on iPTH levels. PMID- 22821308 TI - Management of appendiceal abscess. A 10-year experience in Central Saudi Arabia. AB - OBJECTIVE: To study the outcome of patients with appendiceal abscess (AA) following immediate operative and non-operative management in terms of complications and hospital stay. METHODS: Medical records of all adult patients treated for AA between July 2002 and June 2011 in the Department of Surgery, King Saud Medical City, Riyadh, Kingdom of Saudi Arabia were reviewed. We identified 2 main groups of patients with the diagnosis of AA. The first group of patients were managed by CT-guided percutaneous drainage and parenteral antibiotics (non operative management [NOM group]). The second group were patients who underwent surgical intervention (operative management [OM]). The outcome was determined in terms of complications, recurrence rate, and hospital stay. RESULTS: Eighty AA patients were managed during the study period. Forty-two patients (52.5%) received NOM, while 38 patients (47.5%) underwent immediate OM. The complication rate was significantly higher in the OM group compared with the NOM group (44.7% versus 11.9%; p=0.0012). Successful NOM was achieved in 92.8% of patients. The overall mean hospital stay of the NOM group was 8.54+/-2.25, and the OM group was 10.86+/-4.32 days (p=0.003). CONCLUSION: Non-operative management is associated with significantly lower complication rate and shorter hospital stay than OM. PMID- 22821309 TI - Antimicrobial susceptibility patterns of multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii against carbapenems, colistin, and tigecycline. AB - OBJECTIVE: To examine susceptibility of Pseudomonas aeruginosa (P. aeruginosa) and Acinetobacter baumannii (A. baumannii ) against carbapenems along with colistin and tigecycline as alternative therapeutic options. METHODS: A total of 117 strains of multidrug-resistant (MDR) non-fermenting Gram negative bacteria isolated from non-duplicate samples were collected consecutively. We included one sample from each patient (84 isolates of A. baumannii and 33 isolates of P. aeruginosa isolated from patients seen at King Khalid University Hospital, Riyadh, Saudi Arabia, from June to December 2010). Isolates were identified by the MicroScan WalkAway 96 Plus system. The minimum inhibitory concentrations (MICs) were determined by E-test following the Clinical and Laboratory Standards Institute breakpoint recommendations. RESULTS: Most A. baumannii strains were resistant to imipenem (90.5%), meropenem (90.5%), and doripenem (77.4%). Whereas, a higher percentage of P. aeruginosa was resistant to imipenem (90.9%), and meropenem (81.8%), only 39.4% were resistant to doripenem. Colistin had excellent activity against both A. baumannii (100%) and P. aeruginosa (93.9%), while 89.3% of A. baumannii strains were susceptible to tigecycline. CONCLUSION: Among the carbapenems, doripenem was found to be the most potent antimicrobial agent against P. aeruginosa, whereas colistin proved to be an effective alternative antimicrobial agent for treatment of A. baumannii or P. aeruginosa. Tigecycline remains the best therapeutic option for MDR A. baumannii. PMID- 22821310 TI - Effectiveness of pharmaceutical care in an intensive care unit from China. A pre- and post-intervention study. AB - OBJECTIVE: To describe the development and implementation of pharmaceutical care services in an in-patient setting, and to examine the effectiveness of pharmacist interventions. METHODS: A single-center, 2-phase (pre-/post-intervention phase) design was performed in an intensive care unit (ICU) of a university-affiliated hospital. Patients in the post-intervention phase (March 2011 to June 2011) received pharmaceutical care from a clinical pharmacist, while patients in the pre-intervention phase (December 2010 to March 2011) received routine medical care. The pre- and post-intervention phases were then compared to evaluate the outcomes of pharmacist interventions. RESULTS: During the 3-month study period, the clinical pharmacist made 232 interventions for 416 admitted patients; of these, 202 (87.1%) were accepted by physicians or nurses, and dosage adjustment (n=83, [35.8%]) was the type of intervention implemented most often. In the group that received the participation of pharmacists, medication errors per patient decreased from 1.68 to 0.46 (p<0.001); medication errors, of incorrect dose or dosing interval, were markedly improved (decreased from 0.87 to 0.14; p<0.001), the drug cost per patient-day decreased from $347.43 to $307.36 (p=0.095), and the length of ICU stay did not change significantly (6.14 days versus 5.93 days; p=0.14). CONCLUSION: The presence of the pharmacist in the ICU resulted in significant reduction of medication errors and had potential drug-cost-saving effects, but did not have an influence on decreasing the length of ICU stay. PMID- 22821311 TI - Patients' preferences for physicians' attire in Saudi Arabia. AB - OBJECTIVE: To assess Saudi patients' preferences regarding Saudi physicians' attire, and its influence on patients' level of trust and confidence in their physician. METHODS: A cross-sectional survey was conducted from May to June 2011 among patients waiting to be seen by their physicians from the outpatient medical clinics of King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia. Patients were asked multiple questions, which included their choice of preference regarding the attire of male and female physicians. Additionally, patients were asked questions related to their preferences regarding their physician's gender, and the influence of physician's appearance on patient confidence. RESULTS: A total of 399 patients were interviewed (231 males, 168 females). The mean age was 37 years. Most of the patients (62%) preferred physicians' formal outfit, which was is defined as; tie, shirt, and trousers. Only 9.7% of the patients preferred national Saudi attire (thoab and shemagh). Most patients (73%) preferred long skirts to be worn by female doctors. Up to 85% of patients preferred the white coat to be worn by physicians. Approximately 50% of the patients expressed no preference regarding the gender of their physicians. Confidence in the physician's competence and experience was not significantly associated with the physician's attire or gender (p=0.238). CONCLUSION: Most patients prefer physicians to wear formal attire, however, the gender of the treating physician was not shown to be of particular importance. In addition, the level of trust in a physician is not related to his/her external appearance. PMID- 22821312 TI - Epidemiology of medico-legal litigations and related medical errors in Central and Northern Saudi Arabia. A retrospective prevalence study. AB - OBJECTIVE: To study medico-legal litigations and related medical errors in Central (Al-Qassim), and Northern (Hael) districts in the Kingdom of Saudi Arabia (KSA), and to identify types and causes of errors to reduce medical errors and patient harm. METHODS: This retrospective prevalence study was carried out between May 2010 and December 2011 to analyze medico-legal litigations in Al Qassim and Hael districts that were investigated by the Al-Qassim Medico-Legal Committee, Al-Qassim, KSA. Final verdicts issued between 1992 and 2009 included 293 cases. RESULTS: The patient's mean age was 29.5 years. Fifty-seven percent of the patients were females, and 92% were Saudis. The Obstetric and Gynecology department was involved in 29.7% of litigations followed by General Surgery, and Pediatrics (11.3% each). Of the 635 defendants, 90% were physicians, and 7.6% were nurses. Investigations showed no error in 47.1% of cases, error but no harm in 11.9%, and error resulted in harm in 39.6%. Errors were negligence (45.8%), wrong diagnosis (14.2%), surgical error (10.3%), and administrative error (5.2%). The average total duration of litigations was 13.9 months. Type of harm was the most significant predictor to determine a guilty decision (p<0.001). CONCLUSION: Obstetric practice in Al-Qassim and Hael districts and provider negligence contribute to a large portion of medico-legal litigations, and therefore this has to be further studied to recognize the specific causes and possible interventions. A systematic review of the medico-legal committee is needed to shorten the long duration of litigation. PMID- 22821313 TI - Evaluation of degenerative diseases of the lumbar spine with reformatted and 3 dimensional computed tomography images. AB - OBJECTIVE: To evaluate the identification of degenerative lesions of the lumbar spine with multiplanar reformatted images and 3-dimensional computed tomography (3DCT). METHODS: Fifty-three patients with degenerative spinal disease findings on lumbar CT scanning were reviewed in this retrospective study at the Department of Radiology, Medical Faculty, Sutcu Imam University, Kahramanmaras, Turkey between January 2006 to January 2009. Two-dimensional multiplanar reformatted and 3DCT images were obtained. First, the axial CT images, and then 2 dimensional multiplanar reformatted images (2DMPR) were evaluated. The findings seen on reformatted CT images that were not visualized, or visualized only in retrospect on axial images were recorded. Finally, the 3D images were evaluated by the same team. The results were again recorded in the same manner. RESULTS: When 53 patients were taken into account, the 2DMPR provided better visualization of lateral neural foraminal stenosis in 62%, bulging of the disc in 32%, degenerative retrolisthesis in 15%, and spondylolysis in 15% as compared to axial images. The 3DCT images clearly revealed the presence of lateral neural foraminal stenosis in 41%, degenerative retrolisthesis in 13%, lateral spondylolisthesis in 15% as compared to axial and 2DMPR. CONCLUSION: The 2DMPR and 3DCT images provide significant anatomic and diagnostic information not readily derived from axial CT. It is useful in detecting degenerative conditions of the spine and associated complications. PMID- 22821314 TI - Community acquired Klebsiella pneumoniae, K1 serotype. Invasive liver abscess with bacteremia and endophthalmitis. AB - A community-acquired syndrome of cryptogenic invasive Klebsiella pneumoniae (K. pneumoniae) liver abscess (CIKPLA) has been emerging worldwide over the past 3 decades, particularly in Taiwan and Korea. It is caused by highly virulent hypermucoviscous, rmpA positive K. pneumoniae serotype K1. This condition occurs in predominantly diabetic persons with no underlying hepatobiliary disease. Metastatic infections of the brain, meninges, lungs, pleura, bones, soft tissues, and eyes are unique features of this syndrome. We report a laboratory-confirmed regulator of mucoid phenotype (rmp)A-positive, K1 serotype K. pneumoniae from Saudi Arabia in 2 diabetic native Saudis presenting with community acquired, invasive liver abscess complicated in one by endogenous endophthalmitis. Following medical and surgical treatment, both patients were cured from liver abscesses, however there was unilateral permanent visual loss in one patient. PMID- 22821315 TI - Successful repair of a contained rupture of mycotic aortic aneurysm in an 8-year old child using polytetrafluoroethylene graft. AB - This study reports on a contained rupture of mycotic abdominal aortic aneurysm secondary to coagulase negative staph successfully repaired with aorto bi iliac polytetrafluoroethylene (PTFE) Gor-Tex graft. An 8-year-old Saudi male patient was found to have infective endocarditis by coagulase negative staph with mitral valve (MV) leaflet damage, which was repaired with mechanical MV. Post cardiac surgery, he complained of intermittent abdominal and back pain, until he became more symptomatic and had a sudden abdominal pain. Ultrasound showed abdominal aortic aneurysm (AAA), as well as the CT scan showed contained posterior rupture of AAA. He was operated immediately and the aorta was repaired with bifurcated PTFE Gor-Tex graft. He tolerated the operation, and he was given antibiotic coverage according to sensitivity. Tissue culture of the aorta confirmed coagulase negative staph. The strong relation between infective endocarditis and mycotic aneurysm should make a high index of suspicion of developing abdominal aortic aneurysm in children. Utilizing the PTFE graft with an omental patch is safe and life saving. PMID- 22821316 TI - Peripheral primitive neuroectodermal tumor of the pleura in a 41-year-old female. AB - Peripheral primitive neuroectodermal tumor (pPNET) is a rare, very aggressive neoplasm that belongs to a small round cell tumor, and most often arises from the chest wall. Here, we report a female case with proven pPNET who was treated in our institution. She presented with a history of left side chest pain, cough, and significant weight loss. Contrast enhanced CT imaging of the chest showed multiple left pleural-based enhancing masses with left diaphragmatic involvement. She underwent chemotherapy followed by tumor debulking through thoracotomy. However, she died of rapid growth from recurrent local tumors 3 months thereafter. PMID- 22821317 TI - Congenital pseudoarthrosis. PMID- 22821318 TI - Acute myocardial infarction in an adolescent. PMID- 22821319 TI - Safety of intradermal Bacillus Calmette-Guerin BCG vaccine for neonates in Eastern Saudi Arabia. PMID- 22821321 TI - Use of Sediment Quality Guidelines and pollution indicators for the assessment of heavy metal and PAH contamination in Greek surficial sea and lake sediments. AB - Eight different surface sediment samples (K1-K8) were collected from two separate areas of Lake Koumoundourou and two samples (E1 and E2) from one area of Elefsis Bay, Athens, Greece. The level of pollution attributed to heavy metals was evaluated using several pollution indicators. Degree of Contamination, Modified Contamination Degree and Geoaccumulation Indexes were applied in order to determine and assess the anthropogenic contribution of the selected six elements (Cr, Ni, Cu, Zn, As and Pb). Moreover, the adverse effects of the sediments to aquatic organisms, from both heavy metals and polycyclic aromatic hydrocarbons (PAHs), were determined by using Sediment Quality Guidelines. The results indicated that Lake Koumoundourou is contaminated with heavy metals in a moderate degree and almost 50 % of the sediments are associated with frequent observation of adverse effects, when it comes to Ni and occasional observation of adverse effects, when it comes to Cu, Zn and Pb. As far as PAHs are concerned, around 60 % of the samples can be occasionally associated to toxic biological effects according to the effect-range classification for phenanthrene, benzo(a)anthracene, chrysene and pyrene. Finally, samples taken from the north side of the lake are more contaminated with PAHs than the ones taken from the east side probably due to the existence of the water barrier which acts as a reservoir of PAHs. PMID- 22821320 TI - Handling of Astyanax sp. for biomonitoring in Canguiri Farm within a fountainhead (Irai River Environment Preservation Area) through the use of genetic biomarkers. AB - Aquatic environmental pollution may cause biodiversity loss. Thus, monitoring studies are very important because fish health reflects both quality and sustainability of the environment, as well as of the individuals that live there. In the present report, genetic biomarkers (piscine micronucleus test; comet assay with blood, liver, and kidney cells) were used in specimens of Astyanax sp. to analyze the contamination level of the Canguiri Farm through biomonitoring. The Canguiri Farm, the old school farm of the Federal University of Parana, is inside the Irai River Environment Preservation Area, created in 1996 to preserve the sources of public water supply in Curitiba and metropolitan area. We verified that the fishes collected within the Canguiri Farm area presented high damage levels, showing more environment contamination when compared to the specimens collected in the Costa Ecologic Park, used as reference in the present report. The results indicate that the Canguiri Farm, which is inside an environment protection area, created especially for the protection of the fountainhead for water supply, may be contaminated. These toxic residues, which were remarkably persistent in the environment, are possibly derived from agricultural activities in the wider area. Thus, we suggest the analysis of the area with other biomarkers and for a longer time period. PMID- 22821322 TI - Assessment of heavy metals in water samples and tissues of edible fish species from Awassa and Koka Rift Valley Lakes, Ethiopia. AB - The Ethiopian Rift Valley Lakes host populations of edible fish species including Oreochromis niloticus, Labeobarbus intermedius and Clarias gariepinus, which are harvested also in other tropical countries. We investigated the occurrence of six heavy metals in tissues of these fish species as well as in the waters of Lake Koka and Lake Awassa. Both lakes are affected by industrial effluents in their catchments, making them ideal study sites. Mercury concentrations were very low in the water samples, but concentrations in the fish samples were relatively high, suggesting a particularly high bioaccumulation tendency as compared with the other investigated metals. Mercury was preferentially accumulated in the fish liver or muscle. It was the only metal with species-specific accumulation with highest levels found in the predatory species L. intermedius. Lower mercury concentrations in O. niloticus could be attributed to the lower trophic level, whereas mercury values in the predatory C. gariepinus were unexpectedly low. This probably relates to the high growth rate of this species resulting in biodilution of mercury. Accumulation of lead, selenium, chromium, arsenic and cadmium did not differ between species, indicating that these elements are not biomagnified in the food chain. Values of cadmium, selenium and arsenic were highest in fish livers, while lead and chromium levels were highest in the gills, which could be related to the uptake pathway. A significant impact of the industrial discharges on the occurrence of metals in the lakes could not be detected, and the respective concentrations in fish do not pose a public health hazard. PMID- 22821323 TI - Spatial and temporal analysis of ground level ozone and nitrogen dioxide concentration across the twin cities of Pakistan. AB - The analyses presented in this paper include the concentration levels of NO2 and O3 measured during 2 successive years in twin cities (Rawalpindi and Islamabad) of Pakistan from November 2009 to March 2011. NO2 was determined using the passive sampling method, while ozone was determined by Model 400E ozone analyzer. The average NO2 and O3 concentration in twin cities of Pakistan was found to be 44 +/- 6 and 18.2 +/- 1.24 ppb, respectively. Results indicate that the concentration of NO2 and O3 show seasonal variations. Results also depict that NO2 and O3 concentration levels are high in areas of intense traffic flow and congestion. Rawalpindi has more elevated levels of NO2 and O3 as compared to the Islamabad due to the narrow roads, enclosing architecture of road network and congestion. Climatic variables also influenced the NO2 and O3 concentration, i.e., temperature is positively related with O3, while negatively related with NO2, relative humidity is directly related with NO2 and inversely related with O3, whereas rainfall show negative association with both NO2 and O3 concentration. Comparing the results with WHO standards reveals that NO2 concentration levels at all the sampling points are above the permissible limit, while ozone concentration is still lower than the WHO standards. Thus, there is a need to take appropriate steps to control these continuously increasing levels of NO2 and O3 before they become a serious hazard for the environment and people living in those areas. PMID- 22821324 TI - Seasonal and spatial distribution of 4-tert-octylphenol, 4-nonylphenol and bisphenol A in the Huangpu River and its tributaries, Shanghai, China. AB - The seasonal variations and spatial distributions of 4-tert-octylphenol (OP), 4 nonylphenol (NP) and bisphenol A (BPA) in surface waters, suspended solids and surface sediments in the Huangpu River and its tributaries (Suzhou River and Yunzao Brook) were firstly investigated. The mean concentrations of OP, NP and BPA in the three rivers were 10.59, 120.96 and 22.93 ng L(-1) in surface waters, 199.87, 2,300.87 and 84.11 ng g(-1) in suspended solids and 9.49, 119.44 and 7.13 ng g(-1) dry weight in surface sediments, respectively. The concentrations of NP and OP were higher in summer than in winter in the suspended solids and surface sediments, while the reverse was true in surface waters. Similarly, the levels of BPA were lower in summer than in winter in surface sediments, while the opposite was true in surface waters and suspended solids. These seasonal variations might be attributed to temperature and stream flows. High levels of OP, NP and BPA were found in surrounding river intersections, residential and industrial areas. Their concentrations decreased gradually with increasing distance from those areas, while the lowest levels were measured in near less urbanized and agricultural areas. These phenomena might indicate that the stream current and pollutant source were the major factors that affect the spatial distributions of OP, NP and BPA in the three rivers. Ecological risk assessment indicated that NP was the only one of the three pollutants with the potential to influence local aquatic organisms. The results of this study provide scientific support for control of these pollutants. PMID- 22821325 TI - Distribution characteristics of polycyclic aromatic hydrocarbons in sediments and biota from the Zha Long Wetland, China. AB - In this paper, the concentrations of polycyclic aromatic hydrocarbons (PAHs) were measured in biota (reed, grass, mussel, fish, and red-crowned crane) and sediments collected from seven locations in the Zha Long Wetland. PAHs were recovered from the sediments and biota by ultrasonic extraction and then analyzed by means of gas chromatography-mass spectrometry. The total PAH concentrations were 244-713 ng/g dw in sediments, 82.8-415 ng/g dw in plants and 207-4,780 ng/g dw in animals. The total sediment PAH concentrations were categorized as lower to moderate contamination compared with other regions of China and the world. In the plant samples, the accumulation abilities of reed roots and stems for PAHs were higher than those of grass roots. In addition, the concentration of individual PAHs in mussel muscles was the highest in all of the animal samples, followed by fish, feeding crane fetuses, and wild crane fetuses. Compositional analysis suggests that the PAHs in the sediments from the Zha Long Wetland were derived from incomplete biomass combustion. Risk assessment shows that the levels of PAHs in sediments are mostly lower than the effects range mean value (effects range mean), whereas only naphthalene in all sample sites was higher than the effects range low value. It is worthwhile to note that benzo(b)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene and benzo(ghi)perylene were detected in crane fetal, which have potential carcinogenicity for organisms from the Zha Long Wetland. PMID- 22821327 TI - An investigation of arsenic contamination in Peninsular Malaysia based on Centella asiatica and soil samples. AB - The first objective of this study was to provide data of arsenic (As) levels in Peninsular Malaysia based on soil samples and accumulation of As in Centella asiatica collected from 12 sampling sites in Peninsular Malaysia. The second objective was to assess the accumulation of As in transplanted C. asiatica between control and semi-polluted or polluted sites. Four sites were selected which were UPM (clean site), Balakong (semi-polluted site), Seri Kembangan (semi polluted site) and Juru (polluted site). The As concentrations of plant and soil samples were determined by Instrumental Neutron Activation Analysis. The As levels ranged from 9.38 to 57.05 MUg/g dw in soils, 0.21 to 4.33 MUg/g dw in leaves, 0.18 to 1.83 MUg/g dw in stems and 1.32-20.76 MUg/g dw in roots. All sampling sites had As levels exceeding the CCME guideline (12 MUg/g dw) except for Kelantan, P. Pauh, and Senawang with P. Klang having the highest As in soil (57.05 MUg/g dw). In C. asiatica, As accumulation was highest in roots followed by leaves and stems. When the As level in soils were higher, the uptake of As in plants would also be increased. After the transplantation of plants to semi polluted and polluted sites for 3 weeks, all concentration factors were greater than 50 % of the initial As level. The elimination factor was around 39 % when the plants were transplanted back to the clean sites for 3 weeks. The findings of the present study indicated that the leaves, stems and roots of C. asiatica are ideal biomonitors of As contamination. The present data results the most comprehensive data obtained on As levels in Malaysia. PMID- 22821326 TI - Genotoxic effects of the herbicide Roundup((r)) in the fish Corydoras paleatus (Jenyns 1842) after short-term, environmentally low concentration exposure. AB - The glyphosate-based herbicide, Roundup((r)), is one of the most used pesticides worldwide. In concert with the advent of transgenic crops resistant to glyphosate, the use of this pesticide has led to an increase in agricultural yields. The objective of this study was to evaluate the genotoxic effect that the herbicide Roundup((r)) (at a concentration of 6.67 MUg/L, corresponding to 3.20 MUg/L glyphosate) can have on the fish Corydoras paleatus. Treatment groups were exposed for 3, 6, and 9 days, and effects were analyzed using the piscine micronucleus test (PMT) and comet assay. A group subjected to filtered water only was used as a negative control. The PMT did not show differences between the control and exposed groups for any of the treatment times. In contrast, the comet assay showed a high rate of DNA damage in group exposed to Roundup((r)) for all treatment times, both for blood and hepatic cells. We conclude that for the low concentration used in this research, the herbicide shows potential genotoxic effects. Future research will be important in evaluating the effects of this substance, whose presence in the environment is ever-increasing. PMID- 22821328 TI - Assessment of the trophic status of four coastal lagoons and one estuarine delta, eastern Brazil. AB - Anthropogenic eutrophication of aquatic ecosystems continues to be one of the major environmental issues worldwide and also of Brazil. Over the last five decades, several approaches have been proposed to discern the trophic state and the natural and cultural processes involved in eutrophication, including the multi-parameter Assessment of Estuarine Trophic Status (ASSETS) index model. This study applies ASSETS to four Brazilian lagoons (Mundau, Manguaba, Guarapina, and Piratininga) and one estuarine delta (Paraiba do Sul River), set along the eastern Brazilian coast. The model combines three indices based on the pressure state-response (PSR) approach to rank the trophic status and forecast the potential eutrophication of a system, to which a final ASSETS grade is established. The lagoons were classified as being eutrophic and highly susceptible to eutrophication, due primarily to their longer residence times but also their high nutrient input index. ASSETS classified the estuary of the Paraiba do Sul river with a low to moderate trophic state (e.g., largely mesotrophic) and low susceptibility to eutrophication. Its nutrient input index was high, but the natural high dilution and flushing potential driven by river flow mitigated the susceptibility to eutrophication. Eutrophication forecasting provided more favorable trends for the Mundau and Manguaba lagoons and the Paraiba do Sul estuary, in view of the larger investments in wastewater treatment and remediation plans. The final ASSETS ranking system established the lagoons of Mundau as "moderate," Manguaba as "bad," Guarapina as "poor," and Piratininga as "bad," whereas the Paraiba do Sul River Estuary was "good." PMID- 22821330 TI - [2]Catenanes and inclusion complexes derived from self-assembled rectangular Pd(II) and Pt(II) metallocycles. AB - New inclusion complexes and [2]catenanes were self-assembled from a fluorescent diazapyrenium based ligand, a PdII or PtII complex, and cyclic or acyclic electron rich aromatic guests in aqueous and organic media. The molecular rectangles display a pi-deficient cavity suitable to incorporate pi-donor aromatic systems. The inclusion complexes between the metallocycles and phenylenic (2a,b) and naphthalenic (3a,b-5a,b) derivatives were studied by NMR, UV-vis and fluorescence spectroscopy. The crystal structure of (3b) ? 1a.6PF(6) confirmed the insertion of the guest into the cavity of the metallocycle. Following the same self-assembly strategy, the use of polyethers 6,7 as pi-donors resulted in the self-assembly of the [2]catenanes 1a(6,7).6PF(6). Single-crystal X-ray analysis of 1a(7).6PF6 revealed the [2]catenane structure being stabilized by pi-stacking and [C-H...O] interactions. PMID- 22821329 TI - Direct electrothermal atomic spectrometric determination of Ag in aqua regia extracts of soils, sediments, and sewage sludge with matrix modification. AB - Silver is subject to significant interferences caused by high chloride concentrations in electrothermal atomic absorption spectrometry, thus its direct determination in aqua regia leaches from soils, sediments, and sludges is very difficult, especially when using instrumentation equipped with deuterium-lamp background correction (D2). In this study, the interference of the aqua regia medium was successfully eliminated using Pd-citric acid chemical modifier. This chemical modifier was found to be the most advantageous in comparison with Pd mixture with ascorbic acid, tartaric acid, or citric acid-Li based on its ability to suppress the interference originating from different chloride matrix. Palladium increases the analyte stability; citric acid serves as a reducing reagent, and furthermore, it helps to remove the interfering chlorides by forming HCl, in the drying step of the electrothermal program. In the presence of the modifier, the pyrolysis temperature can be adjusted up to 1,000 degrees C with no loss of the analyte. The obtained limit of detection and characteristic mass were 5 ng g(-1) and 1.7 pg, respectively. The accuracy of the method was verified by means of six different reference samples and by comparing the results of the analysis of real samples with those obtained by inductively coupled plasma orthogonal acceleration time-of-flight mass spectrometer. The proposed method was applied to the Ag determination in soils, sediments, and sewage sludge samples from the Pardubice region in Czech Republic. PMID- 22821331 TI - A retrospective analysis of the effects of meloxicam on the longevity of aged cats with and without overt chronic kidney disease. AB - The study sought to examine the effect of long-term meloxicam treatment on the survival of cats with and without naturally-occurring chronic kidney disease at the initiation of therapy. The databases of two feline-only clinics were searched for cats older than 7 years that had been treated continuously with meloxicam for a period of longer than 6 months. Only cats with complete medical records available for review were recruited into the study.The median longevity in the renal group was 18.6 years [95% confidence interval (CI) 17.5-19.2] and the non renal group was 22 years [95% CI 18.5-23.8]. The median longevity after diagnosis of CKD was 1608 days [95% confidence interval 1344-1919] which compares favourably to previously published survival times of cats with CKD. In both groups the most common cause of death was neoplasia. Long-term treatment with oral meloxicam did not appear to reduce the lifespan of cats with pre-existent stable CKD, even for cats in IRIS stages II and III. Therefore, to address the need for both quality of life and longevity in cats with chronic painful conditions, meloxicam should be considered as a part of the therapeutic regimen. PMID- 22821332 TI - The HLA-Cw*06 allele and -1149 G/T polymorphism of extrapituitary promoter of PRL gene as a possible common genetic predisposing factors to psoriasis vulgaris and psoriatic arthritis in Czech population. AB - Psoriatic arthritis (PsA) affects approximately 30 % of patients suffering from psoriasis vulgaris (PsV), but the risk factors for its development have not been well elucidated yet. The HLA-Cw*06 allele was described as a predisposing factor to PsV. Prolactin is known as an immune response modulator, and its elevated levels present risk for PsV development. It is possible that these factors interact and together emphasize the predisposition to both diseases. We tested on an association of HLA-Cw alleles and functional polymorphism -1149 G/T in PRL gene extrapituitary promoter with PsV and PsA in Czech population. We found a statistically significant association between HLA-Cw*06 allele and PsV (P corrected = 0.0013) that was most prominent in early onset disease subtype (P corrected = 0.0013). The association between HLA-Cw*06 and PsA was low (P corrected = 0.0585) and restricted to PsA patients with early PsV onset (P corrected = 0.0195). We found no association of -1149 G/T PRL gene polymorphism with either PsV or PsA. PMID- 22821333 TI - The effectiveness of proprioceptive-based exercise for osteoarthritis of the knee: a systematic review and meta-analysis. AB - Osteoarthritis (OA) is a leading cause of functional impairment and pain. Proprioceptive defects may be associated with the onset and progression of OA of the knee. The purpose of this study was to determine the effectiveness of proprioceptive exercises for knee OA using meta-analysis. A systematic review was conducted on 12th December 2011 using published (Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, PubMed, PEDro) and unpublished/trial registry (OpenGrey, the WHO International Clinical Trials Registry Platform, Current Controlled Trials and the UK National Research Register Archive) databases. Studies were included if they were full publications of randomized or non-randomised controlled trials (RCT) comparing a proprioceptive exercise regime, against a non proprioceptive exercise programme or non-treatment control for adults with knee OA. Methodological appraisal was performed using the PEDro checklist. Seven RCTs including 560 participants (203 males and 357 females) with a mean age of 63 years were eligible. The methodological quality of the evidence base was moderate. Compared to a non-treatment control, proprioceptive exercises significantly improved functional outcomes in people with knee OA during the first 8 weeks following commencement of their exercises (p < 0.02). When compared against a general non-proprioceptive exercise programme, proprioceptive exercises demonstrated similar outcomes, only providing superior results with respect to joint position sense-related measurements such as timed walk over uneven ground (p = 0.03) and joint position angulation error (p < 0.01). Proprioceptive exercises are efficacious in the treatment of knee OA. There is some evidence to indicate the effectiveness of proprioceptive exercises compared to general strengthening exercises in functional outcomes. PMID- 22821335 TI - Awareness of diagnostic and clinical features of fibromyalgia among orthopedic surgeons. AB - Fibromyalgia Syndrome (FMS) is a chronic pain syndrome characterized by widespread musculoskeletal pain and fatigue. The current study was designed to evaluate the awareness and skills of orthopedic surgeons (OS) regarding FMS diagnosis and treatment. For the examination of awareness and familiarity of OS in Israel to Fibromyalgia, a questionnaire-based survey was conducted. Two hundred and nineteen OS, residents and specialists, were asked anonymously about awareness, knowledge, and treatment of FM. Multivariable statistical analysis was performed. 91 % (199) of responders reported that they recognized the disease. Notwithstanding, the mean knowledge score was 7.6 out of 17. In addition, OS who were trained in the south of Israel were found to have a better degree of knowledge about FM (9.7 vs. 7.4; p < 0.03). The awareness and knowledge among OS regarding FM needs to be improved. OS who were trained in the south of Israel were found to have better degree of knowledge regarding FM. PMID- 22821334 TI - Late appearance and exacerbation of primary Raynaud's phenomenon attacks can predict future development of connective tissue disease: a retrospective chart review of 3,035 patients. AB - To assess the prognostic value of the age at onset of Raynaud's (RP) and of a history of exacerbation of RP attacks for the development of connective tissue disease (CTD) in patients initially found to have primary Raynaud's. 3,035 patients with primary RP (2,702 women and 333 men) were followed for an average of 4.8 years (range from 1 to 10 years). At baseline and every 6 months, they were screened for signs and symptoms of CTD. At 4.8 years of follow-up, 54.7 % patients remained as primary RP, 8.1 % had developed suspected secondary RP, and 37.2 % had developed a definite CTD. Primary RP patients had an earlier onset of RP (mean age of 32.2 years) than those with suspected (mean age 36.5 years, P = .007) or definite secondary RP associated with CTD (mean age of 39.8 years, P = .004). RP beginning before the age of forty was not significantly associated with the development of CTD. Conversely, the appearance of RP after the age of 40 was significantly associated with the development of CTD (P = .00001). Worsening of RP attacks predicted the development of CTD, especially systemic sclerosis (relative risk [RR] of 1.42), scleroderma overlap syndrome (RR of 1.18), and mixed CTD (RR of 1.18). Patients whose onset of RP occurred past 40 years of age and those with worsening RP attacks were at risk for the future development of CTD. PMID- 22821336 TI - Critical points of Brazil nuts: a beginning for food safety, quality control and Amazon sustainability. AB - BACKGROUND: One difficulty of self-sustainability is the quality assurance of native products. This research was designed to study the risks and critical control points in the collection, handling and marketing of Brazil nuts from native forests and urban fairs in the Brazilian Amazon by characterisation of morphological aspects of fungi and posterior identification by molecular biology and determination of aflatoxins by high-performance liquid chromatography. RESULTS: Several corrective actions to improve product quality were found to be necessary in both sites. Growth of fungi was observed in 95% of fragments of Brazil nuts from both sites during the between-harvest period. Aflatoxin levels indicated that, although fungal growth was observed in both sites, only Brazil nuts from the native forest showed a high risk to human health (total aflatoxin level of 471.69 ug kg(-1)). CONCLUSION: This study has shown the main issues related to the process design of Brazil nuts, supporting the necessity for research on new strategies to improve the quality of nuts. Also, the habit of eating Brazil nuts stored throughout the year may represent a risk to farmers. PMID- 22821337 TI - [18F]FLT-PET to predict pharmacodynamic and clinical response to cetuximab therapy in Menetrier's disease. AB - Molecular imaging biomarkers of proliferation hold great promise for quantifying response to personalized medicine. One such approach utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[18F]-fluorothymidine ([18F]FLT), an investigational agent whose uptake reflects thymidine salvage-dependent DNA synthesis. The goal of this study was to evaluate [18F]FLT-PET in the setting of Menetrier's disease (MD), a rare, premalignant hyperproliferative disorder of the stomach treatable with cetuximab therapy. Over 15 months, a patient with confirmed MD underwent cetuximab therapy and was followed with sequential [18F]FLT-PET. For comparison to MD, an [18F]FLT-PET study was conducted in another patient to quantify uptake in a normal stomach. Prior to cetuximab therapy, stomach tissue in MD was easily visualized with [18F]FLT-PET, with pre treatment uptake levels exceeding normal stomach uptake by approximately fourfold. Diminished [18F]FLT-PET in MD was observed following the initial and subsequent doses of cetuximab and correlated with clinical resolution of the disease. To our knowledge, this study reports the first clinical use of [18F]FLT PET to assess proliferation in a premalignant disorder. We illustrate that the extent of MD involvement throughout the stomach could be easily visualized using [18F]FLT-PET, and that response to cetuximab could be followed quantitatively and non-invasively in sequential [18F]FLT-PET studies. Thus, [18F]FLT-PET appears to have potential to monitor response to treatment in this and potentially other hyperproliferative disorders. PMID- 22821338 TI - QTL mapping of yield-associated traits in Brassica juncea: meta-analysis and epistatic interactions using two different crosses between east European and Indian gene pool lines. AB - Genetic analysis of 12 yield-associated traits was undertaken by dissection of quantitative trait loci (QTL) through meta-analysis and epistatic interaction studies in Brassica juncea. A consensus (integrated) map in B. juncea was constructed using two maps. These were VH map, developed earlier in the laboratory by using a DH population from the cross between Varuna and Heera (Pradhan et al. in Theor Appl Genet 106:607-614, 2003; Ramchiary et al. in Theor Appl Genet. 115:807-817, 2007; Panjabi et al. in BMC Genomics 9:113, 2008), and the TD map, developed in the present study using a DH population of 100 lines from the cross between TM-4 and Donskaja-IV. The TD map was constructed with 911 markers consisting of 585 AFLP, 8 SSR and 318 IP markers covering a total genome length of 1,629.9 cM. The consensus map constructed by using the common markers between the two maps contained a total of 2,662 markers and covered a total genome length of 1,927.1 cM. Firstly, QTL analysis of 12 yield-associated traits was undertaken for the TD population based on three-environment phenotypic data. Secondly, the three-environment phenotypic data for the same 12 quantitative traits generated by Ramchiary et al. (2007) were re-analyzed for the QTL detection in the VH map. Comparative analysis identified both common and population-specific QTL. The study revealed the presence of QTL clusters on LG A7, A8 and A10 in both TD and VH maps. Meta-analyses resolved 187 QTL distributed over nine linkage groups of TD and VH maps into 20 meta-QTL. Maximum resolution was recorded for the LG A10 wherein all the 54 QTL were mapped to a single meta QTL within a confidence interval of 3.0 cM. Digenic epistatic interactions of QTL in both TD and VH maps revealed substantial additive * additive interactions showing a higher frequency of Type 1 and Type 2 interactions than Type 3 interactions. Some of the loci interacted with more than one locus indicating the presence of higher order epistatic interactions. These findings provided some detailed insight into the genetic architecture of the yield-associated traits in B. juncea. PMID- 22821339 TI - REST-dependent expression of TRF2 renders non-neuronal cancer cells resistant to DNA damage during oxidative stress. AB - REST is a neuronal gene silencing factor ubiquitously expressed in non-neuronal tissues. REST is additionally believed to serve as a tumor suppressor in non neuronal cancers. Conversely, recent findings on REST-dependent tumorigenesis in non-neuronal cells consistently suggest a potential role of REST as a tumor promoter. Here, we have uncovered for the first time the mechanism by which REST contributes to cancer cell survival in non-neuronal cancers. We observed abundant expression of REST in various types of non-neuronal cancer cells compared to normal tissues. The delicate roles of REST were further evaluated in HCT116 and HeLa, non-neuronal cancer cell lines expressing REST. REST silencing resulted in decreased cell survival and activation of the DNA damage response (DDR) through a decrease in the level of TRF2, a telomere-binding protein. These responses were correlated with reduced colony formation ability and accelerated telomere shortening in cancer cells upon the stable knockdown of REST. Interestingly, REST was down-regulated under oxidative stress conditions via ubiquitin proteasome system, suggesting that sustainability of REST expression is critical to determine cell survival during oxidative stress in a tumor microenvironment. Our results collectively indicate that REST-dependent TRF2 expression renders cancer cells resistant to DNA damage during oxidative stress, and mechanisms to overcome oxidative stress, such as high levels of REST or the stress-resistant REST mutants found in specific human cancers, may account for REST-dependent tumorigenesis. PMID- 22821340 TI - Effect of deposit age on adsorption and desorption behaviors of ammonia nitrogen on municipal solid waste. AB - Ammonia nitrogen pollution control is an urgent issue of landfill. This research aims to select an optimal refuse for ammonia nitrogen removal in landfill from the point of view of adsorption and desorption behavior. MSW (municipal solid waste) samples which deposit ages were in the range of 5 to 15 years (named as R(15), R(11), R(7), and R(5)) were collected from real landfill site. The ammonia nitrogen adsorption behaviors of MSW including equilibrium time, adsorption isotherms, and desorption behaviors including equilibrium time were determined. Furthermore, the effects of pH, OM, Cu(II), Zn(II), and Pb(II) on adsorption and desorption behavior of ammonia nitrogen were conducted by orthogonal experiment. The equilibrium time of ammonia nitrogen adsorption by each tested MSW was very short, i.e., 20 min, whereas desorption process needed 24 h and the ammonia nitrogen released from refuses was much lesser than that adsorbed, i.e., accounted for 3.20 % (R(15)), 14.32 % (R(11)), 20.59 % (R(7)), and 20.50 % (R(5)) of each adsorption quantity, respectively. The maximum adsorption capacity estimated from Langmuir isotherm appeared in R(15)-KCl, i.e., 25,000 mg kg(-1). The best condition for ammonia nitrogen removal from leachate was pH >7.5, OM 23.58 %, Cu(II) <5 mg L(-1), Zn(II) <10 mg L(-1), and Pb(II) <1 mg L(-1). Ammonia nitrogen in landfill leachate could be quickly and largely absorbed by MSW but slowly and infrequently released. The refuse deposited for 15 years could be a suitable material for ammonia nitrogen removal. PMID- 22821341 TI - Investigations into the differential reactivity of endogenous and exogenous mercury species in coastal sediments. AB - Stable isotopic tracer methodologies now allow the evaluation of the reactivity of the endogenous (ambient) and exogenous (added) Hg to further predict the potential effect of Hg inputs in ecosystems. The differential reactivity of endogenous and exogenous Hg was compared in superficial sediments collected in a coastal lagoon (Arcachon Bay) and in an estuary (Adour River) from the Bay of Biscay (SW France). All Hg species (gaseous, aqueous, and solid fraction) and ancillary data were measured during time course slurry experiments under variable redox conditions. The average endogenous methylation yield was higher in the estuarine (1.2 %) than in the lagoonal sediment (0.5 %), although both methylation and demethylation rates were higher in the lagoonal sediment in relation with a higher sulfate-reducing activity. Demethylation was overall more consistent than methylation in both sediments. The endogenous and exogenous Hg behaviors were always correlated but the exogenous inorganic Hg (IHg) partitioning into water was 2.0-4.3 times higher than the endogenous one. Its methylation was just slightly higher (1.4) in the estuarine sediment while the difference in the lagoonal sediment was much larger (3.6). The relative endogenous and exogenous methylation yields were not correlated to IHg partitioning, demonstrating that the bioavailable species distributions were different for the two IHg pools. In both sediments, the exogenous IHg partitioning equaled the endogenous one within a week, while its higher methylation lasted for months. Such results provide an original assessment approach to compare coastal sediment response to Hg inputs. PMID- 22821342 TI - Characterization of carbonic anhydrase II from Chlorella vulgaris in bio-CO2 capture. AB - Carbonic anhydrase II (CA II) can catalyze the reversible hydration reaction of CO(2) at a maximum of 1.4 * 10(6) molecules of CO(2) per second. The crude intracellular enzyme extract containing CA II was derived from Chlorella vulgaris. A successful CO(2) capture experiment with the presence of calcium had been conducted on the premise that the temperature was conditioned at a scope of 30-40 degrees C, that the biocatalyst-nurtured algal growth period lasted 3 days, and that pH ranged from7.5 to 8.5. Ions of K(+), Na(+), Ca(2+), Co(2+), Cu(2+), Fe(3+), Mg(2+), Mn(2+), and Zn(2+) at 0.01, 0.1, and 0.5 M were found to exhibit no more than 30 % inhibition on the residual activity of the biocatalyst. It is reasonable to expect that calcification catalyzed by microalgae presents an alternative to geological carbon capture and sequestration through a chain of fundamental researches carried on under the guidance of sequestration technology. PMID- 22821343 TI - Influence of Spartina alterniflora on the mobility of heavy metals in salt marsh sediments of the Yangtze River Estuary, China. AB - Using bio-disturbed sulphide to trace the mobility and transformation of Cu, Pb, Ni and Zn in the sediments of the Spartina alterniflora-dominated salt marsh in the Yangtze River Estuary, measurements were made of the seasonal variations of acid-volatile sulphide (AVS) and of the simultaneously extracted metals (SEM) in the rhizosphere sediments. Microcosm incubation experiments recreating flooding conditions were conducted to evaluate the effect of AVS and other metal binding phases upon the dynamics of Cu, Pb, Ni and Zn in the salt marsh sediments. The results demonstrate that the ratio values of SEM/AVS have a significant seasonal variation in the rhizosphere sediments and that the anoxic conditions in the sediments were likely enhanced by S. alterniflora during the summer and autumn compared with the anoxic conditions resulting from the native species Phragmites australis and Scirpus mariqueter. The incubation experiments suggest that Fe(III) and Mn(IV/III) (hydr)oxides provide important binding sites for heavy metals under oxic conditions, and sulphide provides important binding sites for the Cu and Pb under anoxic conditions. Our observations indicate that the mobility of heavy metals in the salt marsh sediments is strongly influenced by biogeochemical redox processes and that the invasive S. alterniflora may increase the seasonal fluctuation in heavy metal bioavailability in the salt marsh ecosystem. PMID- 22821344 TI - Characteristics of nano-/ultrafine particle-bound PAHs in ambient air at an international airport. AB - Concentrations of 22 polycyclic aromatic hydrocarbons (PAHs) were estimated for individual particle-size distributions at the airport apron of the Taipei International Airport, Taiwan, on 48 days in July, September, October, and December of 2011. In total, 672 integrated air samples were collected using a micro-orifice uniform deposition impactor (MOUDI) and a nano-MOUDI. Particle bound PAHs (P-PAHs) were analyzed by gas chromatography with mass selective detector (GC/MSD). The five most abundant species of P-PAHs on all sampling days were naphthalene (NaP), phenanthrene (PA), fluoranthene (FL), acenaphthene (AcP), and pyrene (Pyr). Total P-PAHs concentrations were 152.21, 184.83, and 188.94 ng/m(3) in summer, autumn, and winter, respectively. On average, the most abundant fractions of benzo[a]pyrene equivalent concentration (BaPeq) in different molecular weights were high-weight PAHs (79.29 %), followed by medium weight PAHs (11.57 %) and low-weight PAHs (9.14 %). The mean BaPeq concentrations were 1.25 and 0.94 (ng/m(3)) in ultrafine particles (<0.1 MUm) and nano-particles (<0.032 MUm), respectively. The percentages of total BaPeq in nano- and ultrafine particulate size ranges were 52.4 % and 70.15 %, respectively. PMID- 22821345 TI - Ten-year study of species distribution and antifungal susceptibilities of Candida bloodstream isolates at a Brazilian tertiary hospital. AB - To describe the incidence and susceptibility profile of Candida bloodstream infections in a tertiary-care hospital, we performed a retrospective observational study from 1998 to 2007. Comorbidities and risk factors were compiled from all cases. In vitro susceptibility testing to fluconazole, itraconazole, voriconazole, and amphotericin B was performed for 100 isolates, and caspofungin was tested for C. parapsilosis complex. In a ten-year evaluation of candidemias, 44 % were caused by C. albicans, and species of the C. parapsilosis complex were the second most frequent agents (37 %). Other species presented lower incidences (C. tropicalis, 13 %, C. glabrata, 5 %, and C. krusei, 1 %). Neither C. dubliniensis nor C. metapsilosis were observed in this study. C. orthopsilosis (3 %) and C. parapsilosis stricto sensu (34 %) were also found. Species distribution was independent of catheterization, mechanical ventilation, or previous use of antifungals or corticoids. Parenteral nutrition administration was strongly related to C. glabrata infection, and the highest mortality (80 %) was observed in patients infected by this species. All C. albicans isolates showed high susceptibility to all tested drugs. However, two C. parapsilosis stricto sensu isolates presented high minimum inhibitory concentration (MIC) (4 mg/L each) to fluconazole, and one exhibited voriconazole MIC of 0.25 mg/L, highlighting the cross-resistance to these azoles. All isolates of C. tropicalis and C. glabrata showed no resistance to any drug tested. No difference was noted between C. parapsilosis and C. orthopsilosis susceptibilities to caspofungin. Our results suggest that resistance to amphotericin B, fluconazole, voriconazole, itraconazole, and caspofungin in Brazilian Candida bloodstream isolates is still uncommon. PMID- 22821346 TI - Rapid identification of Histoplasma capsulatum directly from cultures by multiplex PCR. AB - The multiplex PCR developed from a suspension of the yeast fungi correctly identified fifty-one clinical of H. capsulatum var. capsulatum strains isolated from clinical samples and soil specimens. The multiplex PCR was developed by combining two pairs of primers, one of them was specific to the H. capsulatum and the other one, universal for fungi, turned out to be specific to H. capsulatum, regardless of the fungus isolate studied. Primers designed to amplify a region of about 390-bp (Hc I-Hc II) and a region of approximately 600-bp (ITS1-ITS4) were used to identify a yeast isolated as H. capsulatum when both regions could be amplified. Absolute agreement (100 % sensitivity) could be shown between this assay and the cultures of H. capsulatum according to their morphological characteristics. Failure to amplify the target DNA sequence by PCR with primers Hc I-Hc II in the presence of the ITS1-ITS4 amplicon in isolates of P. brasiliensis, Cryptococcus neoformans, Trichosporon spp, Candida glabrata, C. albicans, C. tropicalis, C. parapsilosis, C. krusei, or Penicillium marneffei was an unequivocal sign of the high specificity of this assay. The assay specificity was also found to be 100 %. Incipient yeast forms obtained from clinical samples were identified as H. capsulatum by the PCR assay described before the morphological characteristics were registered shortening the time of diagnosis. PMID- 22821347 TI - Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. AB - Efficacy of ischemic preconditioning is decreased in animal models of type 2 diabetes mellitus while the responses in humans with diabetes are contradictory. It is unknown whether attenuation is related to decreased release of a mediating humoral cardioprotective factor or reduced ability to respond in the target tissue. The aim of the present study was to investigate the release and effect of a circulating cardioprotective factor in type 2 diabetes mellitus patients. Blood samples were drawn from nine non-diabetic subjects, eight diabetic patients without peripheral neuropathy, and eight diabetic patients with peripheral neuropathy before (control) and after a remote ischemic preconditioning (rIPC) stimulus. Blood samples were dialyzed against Krebs-Henseleit buffer and the cardioprotective effects of the dialysates were tested in rabbit hearts mounted on a Langendorff model and subjected to 30-min global ischemia and 120-min reperfusion. rIPC dialysate from non-diabetic and diabetic subjects without peripheral neuropathy reduced infarct size and improved hemodynamic recovery compared to control dialysate from non-diabetic and diabetic subjects. However, in the subgroup of diabetic patients with neuropathy the cardioprotective effect was attenuated. These findings indicate that the release mechanism involves neural pathways. PMID- 22821348 TI - Discordance in TKA expectations between patients and surgeons. AB - BACKGROUND: Aligning patient and surgeon expectations preoperatively may lead to better postoperative medical and rehabilitation compliance and therefore improve outcomes and increase satisfaction. QUESTIONS/PURPOSES: We (1) determined the rate of discordantly high patient expectations compared with those of their surgeon in patients undergoing TKA; and (2) evaluated the impact of the preoperative educational class, patient characteristics, and functional status on the likelihood of having discordantly high patient expectations. METHODS: We enrolled 205 patients awaiting TKA. Each patient completed a validated questionnaire that addresses expectations of postoperative pain relief, function, and well-being as part of a preoperative assessment. The surgeon completed the same expectations questionnaire preoperatively blinded to their patient's response. Patients had discordantly high expectations if their scores were >= 7 points higher than the surgeon on a 0 to 100 score range. Regression analysis was performed to determine the effect of class, patient characteristics, and functional status on the likelihood of having discordantly high patient expectations. RESULTS: Thirty-seven percent of the patients had expectation scores >= 7 points higher than those of their surgeon. Patients were less likely to have discordantly higher expectations if they were female (OR, 0.56; CI, 0.32 0.97) and if their pain level was high (OR, 0.99; CI, 0.98-0.99). Patients were more likely to have discordantly higher expectations if they filled out the expectations survey before rather than after the preoperative educational class (OR, 1.80; CI, 1.08-3.01). CONCLUSIONS: With increasing TKA use, surgeons will likely encounter more patients with discordantly high expectations. The preoperative educational class can be used to target patients more likely to have discordantly high expectations. PMID- 22821349 TI - Biographical sketch: Thomas W. Huntington, MD (1849-1929). AB - This biographical sketch on Thomas Huntington corresponds to the historic text, The classic: case of bone transference. use of a segment of fibula to supply a defect in the tibia (1905), available at DOI 10.1007/s11999-012-2496-z . PMID- 22821350 TI - Heritability in the genome-wide association era. AB - Heritability, the fraction of phenotypic variation explained by genetic variation, has been estimated for many phenotypes in a range of populations, organisms, and time points. The recent development of efficient genotyping and sequencing technology has led researchers to attempt to identify the genetic variants responsible for the genetic component of phenotype directly via GWAS. The gap between the phenotypic variance explained by GWAS results and those estimated from classical heritability methods has been termed the "missing heritability problem". In this work, we examine modern methods for estimating heritability, which use the genotype and sequence data directly. We discuss them in the context of classical heritability methods, the missing heritability problem, and describe their implications for understanding the genetic architecture of complex phenotypes. PMID- 22821352 TI - Dissolved organic carbon modulates the effects of copper on olfactory-mediated behaviors of chinook salmon. AB - The modulation of Cu effects on olfactory-mediated behaviors by dissolved organic carbon (DOC) and Fe was examined in juvenile chinook salmon. Chinook were exposed to several concentrations of Cu, DOC, and Fe alone or in combination in a flow through system for either 4 d (acute exposure) or 14 d (subchronic exposure) and tested for their ability to detect and avoid the odorant L-histidine in an avoidance/preference trough assay. In both acute and subchronic exposures, Cu inhibited the ability of fish to detect this amino acid in a concentration dependent manner, and Cu toxicity (olfactory inhibition) decreased with increasing DOC concentration. In both acute and subchronic experiments including DOC, Cu-induced olfactory inhibition decreased in a linear fashion with increasing DOC concentration, although the modulation was lower in subchronic exposures. The protective effect of DOC on Cu olfactory inhibition was reduced only slightly in the presence of Fe, indicating that other metals can potentially affect the modulation of the olfactory inhibition of Cu through competition for DOC binding sites. The results of the present study clearly show the amelioration by DOC of the effects of Cu on juvenile chinook salmon olfaction at a behavioral level. These data further indicate that DOC concentrations should be considered when evaluating the potential impact of Cu on fish olfaction. PMID- 22821353 TI - Laryngeal aging and acoustic changes in male rat ultrasonic vocalizations. AB - This study examined changes in the acoustic and temporal structure of ultrasonic vocalizations as a function of age and correlated acoustic changes with vocal fold microstructure. Ultrasonic vocalizations were recorded in three age groups of male rats: aged (24-26 months), middle-aged (17-18 months), and young (4-5 months). Acoustic and structural changes in vocal fold tissue were evident by 18 months of age. Histological analyses revealed decreased density of elastin and hyaluronic acid and increased collagen density in the middle-aged and aged groups compared to the young rats. Laryngeal microstructure correlated with some of the ultrasonic acoustic features. These results show that male Long Evans rats experience changes in ultrasonic acoustic structure by middle age, and these changes correlate with deterioration in laryngeal microstructure. Ultrasonic vocalizations can be used as a model system for age-related degeneration in vocal fold structure and function. PMID- 22821354 TI - Effect of vancomycin on the cytoplasmic membrane fatty acid profile of vancomycin resistant and -susceptible isolates of Staphylococcus aureus. AB - This study was designed to analyze the effect of vancomycin on the cytoplasmic membrane fatty acid (FA) composition of vancomycin-resistant Staphylococcus aureus (VRSA), vancomycin-intermediate resistant S. aureus (VISA), and vancomycin susceptible S. aureus. One low-level vancomycin-resistant isolate (LLR-VRSA) termed CP2, along with two vancomycin intermediate-resistant S. aureus isolates (VISA-CP1) and Mu50 (ATCC #700699), were studied. The LLR-VRSA isolate CP2, recovered from the blood sample of a postoperative cardiac patient, exhibited vanA type vancomycin resistance [minimum inhibitory concentration (MIC) 16 MUg/ml], and the vanA cassette was located on a plasmid. CP1, isolated from the pus sample of the same patient, exhibited vancomycin intermediate resistance (MIC 8 MUg/ml) in the absence of the vanA, vanB, or vanC gene. As susceptible controls, we used PSA (vancomycin MIC 2 MUg/ml), which was isolated from the pus sample of a neonate, and S. aureus (ATCC# 29213). Membrane FA analysis was carried out using gas chromatography coupled with mass spectrometry. For this purpose, CP1, CP2, Mu50, and the susceptible control isolates were grown in the presence and absence of vancomycin. Comparative analysis showed an increase in the relative proportion of unsaturated FAs during growth under vancomycin stress. The isolate CP2 (LLR-VRSA) exhibited a higher MIC to vancomycin than the other isolates used in present study (16 MUg/ml) and under vancomycin stress conditions, quantitatively, it showed a high rate of conversion of saturated to unsaturated membrane FAs than CP1, Mu50 (VISA isolate) and the susceptible control PSA. The rate of saturated-to-unsaturated FA conversion increased as the concentration of vancomycin in the growth media was increased. Therefore, it is concluded that S. aureus tend to modify their membrane lipid chemistry from saturated to unsaturated in order to survive in a vancomycin stress environment. PMID- 22821355 TI - Estimation of two real-time RT-PCR assays for quantitation of hepatitis C virus RNA during PEG-IFN plus ribavirin therapy by HCV genotypes and IL28B genotype. AB - Hepatitis C virus (HCV) RNA values measured with two real-time PCR methods (Cobas Ampliprep/Cobas TaqMan, CAP/CTM, and the Abbott real-time PCR test, ART) vary among patients with genotype 1. We investigated HCV RNA values measured by two real-time PCR assays during pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. We evaluated 185 cases of chronic hepatitis C patients, among which 97 patients received the PEG-IFN/RBV therapy. HCV RNA values of CAP/CTM for genotype 1 were significantly higher than those of ART (p < 0.05) The difference in HCV RNA values (CAP/CTM minus ART) of genotype 1 was significantly higher than those in genotype 2 (p < 0.0001). The positive rate (>0) of the difference of HCV RNA values in genotype 1 was 100 % (55/55), which was significantly higher than the 78.6 % (33/42) of genotype 2 (p < 0.001). There was no difference between TT and TG/GG genotype groups in terms of difference of HCV RNA values (CAP/CTM minus ART). After PEG-IFN/RBV therapy was administered, reduction of HCV measurements was observed from day 1 for both assays regardless of genotype. The HCV value of CAP/CTM during PEG-IFN/RBV therapy was consistently higher than the value of ART, although the difference in these two values gradually became smaller during the course of therapy, and eventually no significant difference was observed near the detection level. No correlation was observed between the sustained virological response (SVR) rate and the difference between the CAP/CTM HCV values and the ART HCV value before treatment. PMID- 22821356 TI - gyrA and parC mutations in quinolone-resistant clinical isolates of Pseudomonas aeruginosa from Nini Hospital in north Lebanon. AB - The problem of Pseudomonas aeruginosa resistance to fluoroquinolones is of growing concern in hospitals. The major mechanism of the resistance of this bacterium to fluoroquinolones is the modification of type II topoisomerases (DNA gyrase and topoisomerase IV). In this study, we examined, using the technique of DNA pyrosequencing, mutations in the quinolone resistance-determining regions of the gyrA and parC genes of 38 clinical isolates of P. aeruginosa that were non susceptible to at least one of the three fluoroquinolones tested. The most common origin of the isolates was sputum (44.7 %), followed by wounds (11 %), urine (5 %), and ear discharge (5 %). Serotypes O:11 (21 %), O:2 (18.4 %), and O:6 (7.8 %), were the most predominant. Among these 38 isolates, 11 were susceptible, 22 were resistant, and 5 were intermediate-resistant to ciprofloxacin. We found that 19 (50 %) of these strains had a mutation in the gyrA gene (Thr 83 Ile), one of them presented a new mutation (His 80 Arg), 8 (21.05 %) strains had an additional mutation in the parC gene (Ser 80 Leu), and one of these strains had two new mutations not previously reported (Gln 84 Asp, Ala 85 Gly). The ciprofloxacin sensitive strains had no mutations in the sequence area examined. We found that 81.8 % of the isolates that were resistant to ciprofloxacin had a mutation in the gyrA gene. Some of these resistant strains also had a mutation in the parC gene. The results of this study suggest that pyrosequencing is a reliable technique for the determination of the antibiotic resistance pattern of a given bacterial strain. PMID- 22821357 TI - Flow diverters for unruptured aneurysms: are they safe enough? PMID- 22821359 TI - Persistent hypoglossal artery and its variants diagnosed by CT and MR angiography. AB - INTRODUCTION: Persistent hypoglossal artery (PHA) is the second most common anastomosis between the carotid and vertebrobasilar systems and demonstrates some variations. We evaluated the prevalence of PHA on computed tomography (CT) angiography. We also evaluated characteristic features of PHA and its variants on magnetic resonance (MR) angiography. METHODS: We retrospectively reviewed our database of 2,074 CT angiographic images obtained using either of two 64-slice multidetector CT scanners. We also reviewed our database of 7,646 MR angiographic images obtained using either of two 1.5-T or one 3.0-T imager. We could not determine the exact number of patients whose MR angiography included the hypoglossal canal. Most patients had or were suspected of having cerebrovascular diseases. RESULTS: We found six usual PHAs arising from the cervical internal carotid artery on CT angiography among 2,074 patients. On MR angiography, we also found six additional usual PHAs (total 12, right/left = 6/6, male/female = 3/9), three right PHAs originating from the external carotid artery (ECA), and two posterior inferior cerebellar arteries (PICAs) arising from the ECA without connection to the vertebral artery. CONCLUSIONS: The prevalence of usual PHA diagnosed by CT angiography was 0.29 %, slightly higher than that reported for angiography and may be due to selection bias in the examined patients. We propose naming usual PHA "type 1 PHA"; PHA originating from the ECA, of which we found three, "type 2 PHA"; and PICA arising from the ECA, of which we found two, "type 2 PHA variant." PMID- 22821360 TI - Molecular evidence for the subspecific differentiation of blue sheep (Pseudois nayaur) and polyphyletic origin of dwarf blue sheep (Pseudois schaeferi). AB - Blue sheep (Pseudois nayaur), a Central Asian ungulate with restricted geographic distribution, exhibits unclear variation in morphology and phylogeographic structure. The composition of species and subspecies in the genus Pseudois is controversial, particularly with respect to the taxonomic designation of geographically restricted populations. Here, 26 specimens including 5 dwarf blue sheep (Pseudois schaeferi), which were collected from a broad geographic region in China, were analyzed for 2 mitochondrial DNA fragments (cytochrome b and control region sequences). In a pattern consistent with geographically defined subspecies, we found three deeply divergent mitochondrial lineages restricted to different geographic regions. The currently designated two subspecies of blue sheep, Pseudois nayaur nayaur and Pseudois nayaur szechuanensis, were recognized in the phylogenetic trees. In addition, the Helan Mountain population showed distinct genetic characteristics from other geographic populations, and thus should be classified as a new subspecies. In contrast, dwarf blue sheep clustered closely with some blue sheep from Sichuan Province in the phylogenetic trees. Therefore, dwarf blue sheep appear to be a subset of Pseudois nayaur szechuanensis. After considering both population genetic information and molecular clock analysis, we obtained some relevant molecular phylogeographic information concerning the historical biogeography of blue sheep. These results also indicate that western Sichuan was a potential refugium for blue sheep during the Quaternary period. PMID- 22821363 TI - Distribution of lipid transfer protein 1 (LTP1) epitopes associated with morphogenic events during somatic embryogenesis of Arabidopsis thaliana. AB - Using immunocytochemical methods, at both the light and electron microscopic level, we have investigated the spatial and temporal distribution of lipid transfer protein 1 (LTP1) epitopes during the induction of somatic embryogenesis in explants of Arabidopsis thaliana. Immunofluorescence labelling demonstrated the presence of high levels of LTP1 epitopes within the proximal regions of the cotyledons (embryogenic regions) associated with particular morphogenetic events, including intense cell division activity, cotyledon swelling, cell loosening and callus formation. Precise analysis of the signal localization in protodermal and subprotodermal cells indicated that cells exhibiting features typical of embryogenic cells were strongly labelled, both in walls and the cytoplasm, while in the majority of meristematic-like cells no signal was observed. Staining with lipophilic dyes revealed a correlation between the distribution of LTP1 epitopes and lipid substances within the cell wall. Differences in label abundance and distribution between embryogenic and non-embryogenic regions of explants were studied in detail with the use of immunogold electron microscopy. The labelling was strongest in both the outer periclinal and anticlinal walls of the adaxial, protodermal cells of the proximal region of the cotyledon. The putative role(s) of lipid transfer proteins in the formation of lipid lamellae and in cell differentiation are discussed. Key message Occurrence of lipid transfer protein 1 epitopes in Arabidopsis explant cells accompanies changes in cell fate and may be correlated with the deposition of lipid substances in the cell walls. PMID- 22821362 TI - Isolation and expression analysis of a LEAFY/FLORICAULA homolog and its promoter from London plane (Platanus acerifolia Willd.). AB - The LEAFY/FLORICAULA (LFY/FLO) homologous genes are necessary for normal flower development in diverse angiosperm species. To understand the genetic and molecular mechanisms underlying floral initiation and development in Platanaceae, an early divergent eudicot family consisting of large monoecious trees, we isolated a homolog of LFY/FLO, PlacLFY, and its promoter from London plane (Platanus acerifolia). PlacLFY is 1,419 bp in length, with an ORF of 1,122 bp encoding a predicted polypeptide of 374 amino acids and 5'/3'-UTR of 54 and 213 bp, respectively. The putative PlacLFY protein showed a high degree of identity (56-84 %) with LFY/FLO homologs from other species, including two highly conserved regions, the N and C domains, and a less conserved amino-terminal proline-rich region. Real-time PCR analysis showed that PlacLFY was expressed mainly in male inflorescences from May of the first year to March of next year, with the highest expression level in December, and in female inflorescences from June to April of next year. PlacLFY mRNA was also detected strongly in subpetiolar buds of December from 4-year-old and adult trees, and slightly in stem of young seedling and young leaf of adult plant. Additionally, we cloned 1,138 bp promoter sequence of PlacLFY and we drove GUS expression in transgenic tobacco by the chimerical pPlacLFY::GUS construction. Histological GUS staining analysis indicated that PlacLFY promoter can drive GUS gene expression in shoot apex, stem, young leaf and petiole, flower stalk, petal tip, and young/semi mature fruits of transgenic tobacco, which is almost identical to the expression pattern of PlacLFY in London plane. The results revealed that the PlacLFY gene isolated from London plane is expressed not only in reproductive organ but also in vegetative organs. Moreover, this expression pattern is consistent with the expression pattern in tobacco of a GUS reporter gene under the control of the potential promoter region of PlacLFY. PMID- 22821364 TI - Loss of Dicer expression is associated with breast cancer progression and recurrence. AB - Dicer is a protein that plays a pivotal role in the final steps of the microRNA (miRNA) processing pathway, to produce mature miRNAs from their precursor molecules. The purpose of the current study was to assess the biological and prognostic value of Dicer protein expression in breast cancer (BC). Dicer protein expression was assessed immunohistochemically in two sets of BC: (1) full-face sections of selected BC series with distinct stages of tumour progression (normal, in situ (DCIS), primary invasive BC and nodal metastases) to evaluate its differential expression. (2) Tissue microarray comprising a large and well characterised series of unselected clinically annotated invasive BC (n = 1,174) to investigate its correlation with clinicopathological features and patient outcome. A gradual loss of Dicer protein expression was observed in malignant compared to normal breast tissues, with the loss being the least in DCIS and most prominent in metastatic malignant cells. In invasive BC, loss of Dicer expression was associated with features of aggressive behaviour including higher histological grade, loss of hormone receptor and BRCA1 protein expression and with shorter disease-free survival (DFS). Dicer expression was an independent predictor of recurrence in the aggressive HER2-positive subgroup. Moreover, loss of Dicer was predictive of better response to chemotherapy and to endocrine therapy. This study provides evidence that Dicer protein plays a role in human BC progression and behaviour, and assessment of its expression could provide prognostic information in BC including the HER2-positive class. PMID- 22821361 TI - A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. AB - Hepatitis C virus (HCV) infection recurs in liver recipients who are viremic at transplantation. We conducted a randomized, controlled trial to test the efficacy and safety of pretransplant pegylated interferon alpha-2b plus ribavirin (Peg-IFN alpha2b/RBV) for prevention of post-transplant HCV recurrence. Enrollees had HCV and were listed for liver transplantation, with either potential living donors or Model for End-Stage Liver Disease upgrade for hepatocellular carcinoma. Patients with HCV genotypes (G) 1/4/6 (n = 44/2/1) were randomized 2:1 to treatment (n = 31) or untreated control (n = 16); HCV G2/3 (n=32) were assigned to treatment. Overall, 59 were treated and 20 were not. Peg-IFN-alpha2b, starting at 0.75 MUg/kg/week, and RBV, starting at 600 mg/day, were escalated as tolerated. Patients assigned to treatment versus control had similar baseline characteristics. Combined virologic response (CVR) included pretransplant sustained virologic response and post-transplant virologic response (pTVR), defined as undetectable HCV RNA 12 weeks after end of treatment or transplant, respectively. In intent-to-treat analyses, 12 (19%) assigned to treatment and 1 (6%) assigned to control achieved CVR (P = 0.29); per-protocol values were 13 (22%) and 0 (0%) (P = 0.03). Among treated G1/4/6 patients, 23 of 30 received transplant, of whom 22% had pTVR; among treated G2/3 patients 21 of 29 received transplant, of whom 29% had pTVR. pTVR was 0%, 18%, and 50% in patients treated for <8, 8-16, and >16 weeks, respectively (P = 0.01). Serious adverse events (SAEs) occurred with similar frequency in treated versus untreated patients (68% versus 55%; P = 0.30), but the number of SAEs per patient was higher in the treated group (2.7 versus 1.3; P = 0.003). CONCLUSION: Pretransplant treatment with Peg-IFN-alpha2b/RBV prevents post-transplant recurrence of HCV in selected patients. Efficacy is higher with >16 weeks of treatment, but treatment is associated with increased risk of potentially serious complications. PMID- 22821365 TI - What primary care providers need to know about preexposure prophylaxis for HIV prevention: a narrative review. AB - As HIV prevalence climbs globally, including more than 50 000 new infections per year in the United States, we need more effective HIV prevention strategies. The use of antiretrovirals for preexposure prophylaxis (PrEP) among high-risk persons without HIV is emerging as one such strategy. Randomized, controlled trials have demonstrated that once-daily oral PrEP decreased HIV incidence among at-risk men who have sex with men and African heterosexuals, including serodiscordant couples. An additional randomized, controlled trial of a topical pericoital antiretroviral microbicide gel decreased HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population. The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee reviewed these studies and additional data in May 2012 and voted to advise the approval of oral tenofovir-emtricitabine for PrEP in high-risk populations. On 16 July 2012, the FDA recommended that this combination medication be approved for use as PrEP in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic. PMID- 22821366 TI - A cupric silver histochemical analysis of domoic acid damage to olfactory pathways following status epilepticus in a rat model for chronic recurrent spontaneous seizures and aggressive behavior. AB - The amnesic shellfish toxin, domoic acid, interferes with glutamatergic pathways leading to neuronal damage, most notably causing memory loss and seizures. In this study, the authors utilized a recently developed rat model for domoic acid induced epilepsy, an emerging disease appearing in California sea lions weeks to months after poisoning, to identify structural damage that may lead to a permanent epileptic state. Sprague Dawley rats were kindled with several low hourly intraperitoneal doses of domoic acid until a state of status epilepticus (SE) appears. This kindling approach has previously been shown to induce a permanent state of epileptic disease in 96% animals within 6 months. Three animals were selected for neurohistology a week after the initial SE. An amino cupric silver staining method using neutral red counterstain was used on every eighth 40 um coronal section from each brain to highlight neural degeneration from the olfactory bulb through the brain stem. The most extensive damage was found in the olfactory bulb and related olfactory pathways, including the anterior/medial olfactory cortices, endopiriform nucleus, and entorhinal cortex. These findings indicate that damage to olfactory pathways is prominent in a rat model for domoic acid-induced chronic recurrent spontaneous seizures and aggressive behavior. PMID- 22821367 TI - Immunohistochemical characterization of spontaneous and acrylonitrile-induced brain tumors in the rat. AB - Twenty-eight spontaneously occurring glial tumors (previously diagnosed as astrocytomas, oligodendrogliomas, and gliomas) and eleven granular cell tumors (GCTs) were selected for evaluation using a panel of immunohistochemistry (IHC) stains (Ricinus communis agglutinin type 1 [RCA-1], ionized calcium-binding adapter molecule 1 [Iba-1], OX-6/major immunohistocompatibility complex class II, oligodendrocytes transcription factor 2 [Olig2], glial fibrillary acidic protein [GFAP], S100 beta, glutamine synthetase, neurofilament, proliferating cell nuclear antigen). In addition, nine brain tumors from a 2-year drinking water study for acrylonitrile were obtained from the Acrylonitrile Group, Inc. Based on IHC staining characteristics, Olig2+ oligodendrogliomas were the most commonly diagnosed spontaneous tumor in these animals. Many of the spontaneous tumors previously diagnosed as astrocytomas were RCA-1+, Iba-1+ and negative for GFAP, S100beta, and glutamine synthetase; the diagnosis of malignant microglial tumor is proposed for these neoplasms. Three mixed tumors were identified with Olig2+ (oligodendrocytes) and Iba-1+ (macrophage/microglia) cell populations. The term mixed glioma is not recommended for these tumors, as it is generally used to refer to oligoastrocytomas, which were not observed in this study. GCT were positive for RCA-1 and Iba-1. All acrylonitrile tumors were identified as malignant microglial tumors. These results may indicate that oligodendrogliomas are more common as spontaneous tumors, while acrylonitrile-induced neoplasms are microglial/histiocytic in origin. No astrocytomas (GFAP, S100 beta, and/or glutamine synthetase-positive neoplasms) were observed. PMID- 22821368 TI - Regulatory forum opinion piece*: reversibility groups: the "hows" and "how-nots". AB - Adding a few animals to a toxicology study in order to document whether any lesions observed are reversible and at what level is a common practice but it is often unjustified, as most of the findings observed, particularly in the early stages of drug development, are easily categorized in regard to reversibility potential. The scientific application of all knowledge regarding the compound and the lesion in question is necessary to develop specific studies to address reversibility when this is a necessary step. PMID- 22821369 TI - Type 1 IFN inhibits the growth factor deprived apoptosis of cultured human aortic endothelial cells and protects the cells from chemically induced oxidative cytotoxicity. AB - It has been shown that the genesis of atherosclerotic lesions is resulted from the injury of vascular endothelial cells and the cell damage is triggered by oxygen radicals generated from various tissues. Human vascular endothelial cells can survive and proliferate depending on growth factors such as VEGF or basic FGF and are induced apoptosis by the deprivation of growth factor or serum. It was found that type 1 IFN inhibits the growth factor deprived cell death of human aortic endothelial cells (HAEC) and protects the cells from chemically induced oxidative cytotoxicity. The anti-apoptotic effects of type 1 IFN were certified by flow cytometry using annexin-V-FITC/PI double staining and cell cycle analysis, fluorescence microscopy using Hoechst33342 and PI, colorimetric assay for caspase-3 activity, p53 and bax mRNA expressions, and cell counts. It was considered that IFN-beta inhibits the executive late stage apoptosis from the results of annexin-V-FITC/PI double staining and the inhibition of caspase-3 activity, and that the anti-apoptotic effect might be owing to the direct inhibition of the apoptotic pathway mediated by p53 from the transient down regulation of bax mRNA expression. Whereas, type 1 IFN protected the cells from the oxidative cytotoxicity induced by tertiary butylhydroperoxide (TBH) under the presence of Ca(2+). The effects of IFN-beta is more potent inhibitor of cell death than IFN-alpha. These results indicate that type 1 IFN, especially IFN-beta may be useful for the diseases with vascular endothelium damage such as atherosclerosis or restenosis after angioplasty as a medical treatment or a prophylactic. PMID- 22821370 TI - Concerns regarding methodology and interpretation in the study of meat intake and incident diabetes. PMID- 22821371 TI - That it's red? Or what it was fed/how it was bred? The risk of meat. PMID- 22821374 TI - Automated algorithm for reconstruction of the complete spine from multistation 7T MR data. AB - Recent technical developments in high-field MRI have enabled high-resolution imaging of the whole spine within clinically acceptable times. However, analysis of such data requires intensity inhomogeneity correction and volume stitching, both of which are typically performed manually. In this work, an automated method for reconstruction of the complete spine from multistation 7T MR data is presented. The method consists of a number of image processing steps, in particular intensity inhomogeneity correction and image registration for recovery of unknown interscan bed translations, which result in high-quality spine volume reconstructions. The registration performance of the developed algorithm was validated on 18 datasets acquired in two or three stations. In all the test cases, our algorithm was able to produce correct reconstruction of the spine volume. The resulting mean registration error (0.53 mm) is found to be lower than the pixel size, demonstrating robustness and accuracy of the proposed method. PMID- 22821375 TI - Analysis of potential fumonisin-producing Fusarium species in corn products from three main maize-producing areas in eastern China. AB - BACKGROUND: Fusarium species are common fungal contaminants of maize and a number of them can produce mycotoxin fumonisins. China is one of the largest maize producers in the world. This study investigated the contamination of maize samples from three areas in eastern China by Fusarium and fumonisin-producing fungi as well as their fumonisin-producing potential. RESULTS: A total of 22 Fusarium strains were isolated, 19 of which were able to produce fumonisin. Among the 19 strains, 16 belonged to F. verticillioides, two to F. subglutinans and one to F. proliferatum. The majority (17/19) of the fumonisin-forming strains were high FB(1) producers, which is a potential health risk for the population in these areas. Fusarium contamination in samples from the mideastern area was the most serious (11 Fusarium strains, with nine producing fumonisin, isolated from 24 samples), followed by the northeastern area (nine Fusarium strains, with all nine producing fumonisin, isolated from 21 samples) and the southeastern area (two Fusarium strains, with one producing fumonisin, isolated from 19 samples). CONCLUSION: Although the overall levels of FBs and contamination by fumonisin producing fungi in corn samples were not serious, the contaminating Fusarium strains possessed fairly strong toxicogenic ability and potential risk for food safety. PMID- 22821376 TI - Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. AB - Heterogeneous ribonucleoprotein (hnRNP) A1 is a member of the A/B subfamily of ubiquitously expressed hnRNPs, which have a wide variety of functions in gene expression and signal transduction. To investigate the biological function and clinical significance of hnRNP A1 in hepatocellular carcinoma (HCC), we measured hnRNP A1 expression in four HCC cell lines and two independent cohorts of HCC patients. We found that hnRNP A1 was overexpressed in the highly metastatic HCC cell lines and in tumor tissues of patients with recurrent HCC. Knockdown of hnRNP A1 in highly metastatic HCC cells caused a significant decrease in cell invasion, while upregulation of hnRNP A1 in poorly metastatic HCC cells led to a significant increase in their invasive capacity. We found that this effect may occur through the regulation of CD44v6 expression by hnRNP A1 in HCC cells. Both quantitative reverse transcription-polymerase chain reaction (qRT-RCR) and immunohistochemistry revealed that hnRNP A1 was upregulated in HCC tissues and coincided with overexpression of CD44v6. HCC patients with high hnRNP A1 tended to have higher levels of CD44v6, shorter overall survival (OS) and higher rates of tumor recurrence. Multivariate analyses revealed that hnRNP A1 alone or in combination with CD44v6 were independent prognostic indicators for OS and time to recurrence and have potential as therapeutic targets. In conclusion, overexpression of hnRNP A1 promotes HCC invasion by regulating the level of CD44v6 and indicates a poor prognosis for HCC patients after curative resection. PMID- 22821378 TI - Modeling judgment of sequentially presented categories using weighting and sampling without replacement. AB - In a series of experiments, Kusev et al. (Journal of Experimental Psychology: Human Perception and Performance 37:1874-1886, 2011) studied relative-frequency judgments of items drawn from two distinct categories. The experiments showed that the judged frequencies of categories of sequentially encountered stimuli are affected by the properties of the experienced sequences. Specifically, a first run effect was observed, whereby people overestimated the frequency of a given category when that category was the first repeated category to occur in the sequence. Here, we (1) interpret these findings as reflecting the operation of a judgment heuristic sensitive to sequential patterns, (2) present mathematical definitions of the sequences used in Kusev et al. (Journal of Experimental Psychology: Human Perception and Performance 37:1874-1886, 2011), and (3) present a mathematical formalization of the first-run effect-the judgments-relative-to patterns model-to account for the judged frequencies of sequentially encountered stimuli. The model parameter w accounts for the effect of the length of the first run on frequency estimates, given the total sequence length. We fitted data from Kusev et al. (Journal of Experimental Psychology: Human Perception and Performance 37:1874-1886, 2011) to the model parameters, so that with increasing values of w, subsequent items in the first run have less influence on judgments. We see the role of the model as essential for advancing knowledge in the psychology of judgments, as well as in other disciplines, such as computer science, cognitive neuroscience, artificial intelligence, and human-computer interaction. PMID- 22821377 TI - Effects of 2-chlorodeoxyadenosine (Cladribine) on primary rat microglia. AB - 2-chlorodeoxyadenosine (CdA, Cladribine) is an immunosuppressant that has recently been shown to be effective in the treatment of multiple sclerosis (MS). There is extensive clinical experience with CdA for the treatment of neoplastic diseases, especially hematologic malignancies, due to its apoptotic effects on leukemic and several other neoplastic cells. Furthermore, CdA crosses the blood brain-barrier and thus may also exert its effects directly on cells of the central nervous system (CNS). Therefore, we have studied the effects of CdA on cultured primary rat microglia, the resident macrophage in the CNS, which is also thought to be involved in the pathogenesis of MS. Treatment of microglia with CdA inhibited their proliferation and induced apoptosis. Phosphorylation of CdA to CdATP was required for both effects and was inhibited by deoxycytidine. Furthermore, activation of caspase-3 and -9 revealed the involvement of the intrinsic mitochondrial mediated apoptotic pathway. However, the absence of caspase-8 activation specified independency from the extrinsic death receptor mediated apoptosis. The mitochondrial membrane potential was significantly reduced after CdA exposure and was not conserved with Bax or caspase-3 inhibition. Assessment of DNA fragmentation by TUNEL and DNA-release-assay showed microglia with fragmented nuclei. Other functions of microglia like phagocytosis and LPS-induced NO and TNF-alpha release were not affected by CdA. These data suggest a potential of CdA treatment to induce not only leukopenia but also apoptosis in microglia in the CNS. These results help to understand the mechanism of action of CdA in CNS diseases and may open the possibility to target microglia. PMID- 22821379 TI - Treatment of femoral head osteonecrosis with advanced cell therapy in sheep. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of core decompression associated with advanced cell therapy for the treatment of femoral head osteonecrosis in an established sheep model. METHODS: Early stage osteonecrosis of the right hip was induced cryogenically in 15 mature sheep. At 6 weeks, the sheep were divided into three groups, Group A: core decompression only; Group B: core decompression followed by implantation of an acellular bone matrix scaffold; Group C: core decompression followed by implantation of a cultured BMSC loaded bone matrix scaffold. At 12 weeks, MRI hip studies were performed and then the proximal femur was harvested for histological analysis. RESULTS: In the group of advanced cell therapy, Group C, there was a tendency to higher values of the relative surface of newly formed bone with a mean of 20.3 versus 11.27 % in Group A and 13.04 % in Group B but it was not statistically significant. However, the mean relative volume of immature osteoid was 8.6 % in Group A, 14.97 in Group B, and 53.49 % in Group C (p < 0.05), revealing a greater capacity of osteoid production in the sheep treated with BMSCs. MRI findings were not conclusive due to constant bone edema artifact in all cases. CONCLUSIONS: Our findings indicate that a BMCSs loaded bone matrix scaffold is capable of stimulating bone regeneration more effectively than isolated core decompression or in association with an acellular scaffold in a preclinical femoral head osteonecrosis model in sheep. PMID- 22821381 TI - Improved antimicrobial potency through synergistic action of chitosan microparticles and low electric field. AB - Techniques to inhibit gram-negative bacteria such as Shiga toxin-producing Escherichia coli are valuable as the prevalence of large-scale industrial food preparation increases the likelihood of contamination. Chitosan, the deacetylated derivative of chitin, has been demonstrated to inhibit bacteria growth in acidic environments, but is significantly less effective in preventing bacteria grown at pH >7.0. Pulsed electric fields, constituting another method of bacteria inhibition, are difficult to generate at sufficient strength due to the high electric potentials required. This study utilizes adsorption of particulate chitosan in a very low electric field for an increased inhibition of gram negative bacteria in neutral or alkaline pH conditions. Chitosan microparticles are demonstrated to flocculate E. coli, inhibit growth, and exhibit increased efficacy when combined with a low voltage electric field applied over 2-min intervals. Using sustained pulses of approximately 100 V/cm, it is demonstrated that bacteria viability is reduced by several orders of magnitude. The degree of bacterial inhibition is increased when chitosan microparticles are introduced to the system prior to imposing a small electric field. PMID- 22821380 TI - Increased interleukin-8 in epithelial lining fluid of collapsed lungs during one lung ventilation for thoracotomy. AB - The present study was designed to evaluate inflammatory changes in collapsed lungs during one-lung ventilation using the assistance of a bronchoscopic microsampling probe. Serial albumin and interleukin (IL)-8 concentrations in epithelial lining fluid (ELF) were measured in seven patients undergoing resection of lung tumors. The samples were taken after induction of anesthesia (baseline), 30 min after one-lung ventilation was started (point 2), just before resuming two-lung ventilation (point 3), and 30 min after two-lung ventilation was restarted (point 4). The albumin and IL-8 concentrations in ELF were significantly increased at point 2 and point 3, respectively, and remained to be high, compared to the baseline. The increase in IL-8 at point 3 was correlated with the interval of one-lung ventilation; however, none developed specific acute lung injury. These findings suggest that inflammatory changes can occur on the epithelium of a collapsed lung even in patients who underwent successful and standard thoracic surgery. PMID- 22821383 TI - Prospective, high-throughput molecular profiling of human gliomas. AB - Gliomas consist of multiple histologic and molecular subtypes with different clinical phenotypes and responsiveness to treatment. However, enrollment criteria for clinical trials still largely do not take into account these underlying molecular differences. We have incorporated a high-throughput tumor genotyping program based on the ABI SNaPshot platform as well as other molecular diagnostic tests into the standard evaluation of glioma patients in order to assess whether prospective molecular profiling would allow rational patient selection onto clinical trials. From 218 gliomas we prospectively collected SNaPshot genotyping data on 68 mutated loci from 15 key cancer genes along with data from clinical assays for gene amplification (EGFR, PDGFRA, MET), 1p/19q co-deletion and MGMT promoter methylation. SNaPshot mutations and focal gene amplifications were detected in 38.5 and 47.1 % of glioblastomas, respectively. Genetic alterations in EGFR, IDH1 and PIK3CA closely matched frequencies reported in recent studies. In addition, we identified events that are rare in gliomas although are known driver mutations in other cancer types, such as mutations of AKT1, BRAF and KRAS. Patients with genetic alterations that activate signaling pathways were enrolled onto genetically selective clinical trials for malignant glioma as well as for other solid cancers. High-throughput molecular profiling incorporated into the routine clinical evaluation of glioma patients may enable the rational selection of patients for targeted therapy clinical trials and thereby improve the likelihood that such trials succeed. PMID- 22821382 TI - Analysis of NADP+-dependent isocitrate dehydrogenase-1/2 gene mutations in pediatric brain tumors: report of a secondary anaplastic astrocytoma carrying the IDH1 mutation. AB - Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165 pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously been investigated. Mutation analysis was performed by use of pyrosequencing and, additionally, data were validated for a cohort of 70 gliomas from among the series by use of the arrayed primer extension technique. We identified one tumor which harbored mutation of IDH1 at codon 132 and no alteration was identified in the matched-germline DNA. No IDH2 mutations were detected. Most noteworthy, the IDH1 mutant tumor was an anaplastic astrocytoma involving the cortex in the left frontal lobe which appeared seven years after radiation treatment for an extensive sellar/suprasellar craniopharyngioma. This anaplastic astrocytoma was regarded as secondary to radiation treatment because it seemed to originate within the irradiation field that received a dose varying from a maximum of 30.6 Gy of 4 MV X-rays down to very few Gy of lower-energy scattered radiation. In this work our observations agree with those in previous reports showing the rarity of IDH1/2 mutations in childhood tumors. The interesting identification of an IDH1 mutation in a radiation-induced secondary malignant glioma raises the likelihood that these types of tumor may develop IDH1/2 mutations. Thus, caution is needed when dealing with these tumors, and further genetic analysis is warranted. PMID- 22821384 TI - Chronic cannabis abuse, delta-9-tetrahydrocannabinol and thyroid function. AB - OBJECTIVE: The aim of this study was to obtain rather rare information about the influence of chronic cannabis abuse on thyroid function. METHODS: Thyroid function tests (TSH, total T3, free T4) of 39 chronic cannabis-dependent subjects (ICD-10) were determined at admission (for in-patient detoxification). In a subgroup, serum levels of thyroid hormones were correlated with the serum levels of delta-9-tetrahydrocannabinol (THC, N=24) and its major metabolites, THC-OH (N=16) and THC-COOH (N=24). RESULTS: All of the tested patients were found to have TSH, total T3 and free T4 levels within the population reference range. The levels of thyroid hormones did not correlate significantly with levels of THC, THC-OH or THC-COOH in serum. CONCLUSION: These results argue against a relevant influence of chronic cannabis intake on thyroid function in humans. PMID- 22821385 TI - Delirium during i. v. citalopram treatment: a case report. AB - This paper reports the case of a 65-year-old depressed man without somatic illnesses in whom monotherapy with i. v. citalopram induced delirium. He was admitted to a closed geriatric ward as a psychotically depressed patient with somatic and depressive delusions, and suicidal thoughts. Because he rejected all oral medications, monotherapy was initiated with 20 mg of i. v. citalopram per day. After 3 days, he became delirious and physically aggressive. This description of acute hyperkinetic delirium associated with i. v. citalopram therapy is the first one of this kind addressing side effects of i. v. citalopram. PMID- 22821386 TI - Antipsychotics: a real or confounding risk factor for venous thromboembolism? AB - In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients. PMID- 22821387 TI - Amyloid beta modulated the selectivity of heme-catalyzed protein tyrosine nitration: an alternative mechanism for selective protein nitration. AB - Protein tyrosine nitration is a post-translational modification associated with numerous pathological conditions. The biological consequences of this modification strongly depend on the site selectivity. Unfortunately, to date there is still no reliable model for predicting the selectivity of protein tyrosine nitration. Previously, we found that amyloid beta (Abeta) changed the selectivity of enolase tyrosine nitration upon binding to heme. It seemed that there was a link between the hydrophilicity of Abeta and the site-specific tyrosine nitration. We further investigated the role of the hydrophilicity of the molecules that bind to heme in the selectivity of protein tyrosine nitration. We found that Abeta(1-16), Abeta(1-20), and Abeta(1-40), upon binding to heme and interacting with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a site specific manner, differently modulated the site selectivity of heme-catalyzed GAPDH tyrosine nitration. The modulation is associated with the hydrophilicity of the Abeta peptides, which changed the surrounding environment of the heme. At the same time, the Abeta-heme complexes were found to be more effective at inactivating GAPDH than heme alone, and the selective tyrosine nitration that was catalyzed by Abeta-heme played an important role. These findings suggest an alternative mechanism for the selectivity of protein tyrosine nitration, which may lead to a better understanding of the factors that influence protein tyrosine nitration selectivity and the important roles of Abeta and heme in the pathogenesis of Alzheimer's disease, where Abeta accumulation and Abeta-dependent protein nitration play central roles. PMID- 22821388 TI - Effects of road deicer (NaCl) and amphibian grazers on detritus processing in pond mesocosms. AB - Road deicers have been identified as potential stressors in aquatic habitats throughout the United States, but we know little regarding associated impacts to ecosystem function. A critical component of ecosystem function that has not previously been evaluated with respect to freshwater salinization is the impact on organic matter breakdown. The purpose of this study was to evaluate cumulative effects of road deicers and tadpole grazers on leaf litter breakdown rate (g d( 1) ) and microbial respiration (mg O(2) g leaf(-1) h(-1) ). To test this interaction, in May 2008 the authors added dry leaf litter (Quercus spp.) to forty 600-L pond mesocosms and inoculated each with algae and zooplankton. In a full-factorial design, they manipulated a realistic level of road salt (ambient or elevated at 645 mg L(-1) Cl(-) ) and tadpole (Hyla versicolor) presence or absence. The elevated chloride treatment reduced microbial respiration by 24% in the presence of tadpoles. The breakdown of leaf litter by tadpoles occurred 9.7% faster under ambient chloride conditions relative to the elevated chloride treatment. Results of the present study suggest that the microbial community is directly impacted by road deicers and heavy tadpole grazing under ambient conditions limits microbial capacity to process detritus. Road salts and tadpoles interact to limit microbial respiration, but to a lesser extent leaf mass loss rate, thereby potentially restricting energy flow from detrital sources in pond ecosystems. PMID- 22821390 TI - Staged single-tract minimally invasive percutaneous nephrolithotomy and flexible ureteroscopy in the treatment of staghorn stone in patients with solitary kidney. AB - The aim of this study was to evaluate the outcome of staged single-tract minimally invasive percutaneous nephrolithotomy (MPCNL) and flexible ureteroscopy as a minimally invasive option in the treatment of staghorn stone in patients with a solitary kidney. A total of 24 patients with staghorn stone in a solitary kidney were treated with single-tract MPCNL and flexible ureteroscopy by a single surgeon. All the patients underwent single-tract MPCNL through a 20 F tract and had most of the intrarenal calculi removed at the first stage. The second stage of retrograde flexible ureteroscopy was performed 3-5 days later, after the drainage was cleared. The preoperative patient, characteristics, stone size, operative time, renal functional status and postoperative outcomes were then evaluated. Sixteen patients were partial staghorn (66.7 %), and other eight were complete staghorn (33.3 %). The overall stone-free rate was 83.3 % after the second-stage procedures, and only four patients had significant residue. The hemoglobin drop ranged from 1.1 to 3.7 g/dl, and three patients required blood transfusion. The mean serum creatinine value was 1.7 +/- 0.5 mg/dl before surgery and 1.3 +/- 0.4 mg/dl at the end of the follow-up period with statistical significance (P < 0.05). None of the patients had increased serum creatinine, and needed dialysis at the end of the follow-up period. Staged single-tract MPCNL and flexible ureteroscopy are safe and effective for the management of staghorn stone in patients with a solitary kidney and even in patients with impaired renal functions. PMID- 22821389 TI - Polymorphisms of ERCC1 genotype associated with response to imatinib therapy in chronic phase chronic myeloid leukemia. AB - DNA repair machinery may contribute to the mechanism of the action in imatinib. We examined the association between the single nucleotide polymorphism (SNP) markers involved in the DNA repair enzyme pathway (ERCC1/2/4/5, XRCC1/2/4/5) and the clinical outcomes following an imatinib therapy in chronic phase chronic myeloid leukemia (CML) patients. A total of 169 Korean patients were included. Of the 19 SNPs from these patients, those with the TT genotype of ERCC1 (rs11615) showed a higher probability of achieving major cytogenetic response [P = 0.002, HR 5.14 (95 % CI 1.83-14.43)], complete cytogenetic response [P = 0.012, HR 3.47 (95 % CI 1.31-9.17)], and major molecular response [P = 0.001, HR 5.71 (95 % CI 2.13-15.30)] than those with CC or CT genotypes. This suggests that SNP markers on ERCC1 may predict the response to imatinib therapy, which proposes the potential involvement of the DNA repair machinery in the mechanism of imatinib action in chronic phase CML. PMID- 22821392 TI - The elevation of oxidative stress after the great East Japan earthquake. PMID- 22821391 TI - Positive C1q staining associated with poor renal outcome in membranoproliferative glomerulonephritis. AB - BACKGROUND: Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established. METHODS: We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed. RESULTS: Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04). CONCLUSIONS: C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria. PMID- 22821393 TI - Diagnostic relevance of high field MRI in clinical neuroradiology: the advantages and challenges of driving a sports car. AB - High field MRI operating at 3 T is increasingly being used in the field of neuroradiology on the grounds that higher magnetic field strength should theoretically lead to a higher diagnostic accuracy in the diagnosis of several disease entities. This Editorial discusses the exhaustive review by Wardlaw and colleagues of research comparing 3 T MRI with 1.5 T MRI in the field of neuroradiology. Interestingly, the authors found no convincing evidence of improved image quality, diagnostic accuracy, or reduced total examination times using 3 T MRI instead of 1.5 T MRI. These findings are highly relevant since a new generation of high field MRI systems operating at 7 T has recently been introduced. KEY POINTS: * Higher magnetic field strengths do not necessarily lead to a better diagnostic accuracy. * Disadvantages of high field MR systems have to be considered in clinical practice. * Higher field strengths are needed for functional imaging, spectroscopy, etc. * Disappointingly there are few direct comparisons of 1.5 and 3 T MRI. * Whether the next high field MR generation (7 T) will improve diagnostic accuracy has to be investigated. PMID- 22821394 TI - ADC maps in the prediction of pelvic lymph nodal metastatic regions in endometrial cancer. AB - OBJECTIVES: To evaluate the usefulness of apparent diffusion coefficient (ADC) in discriminating metastatic from non-metastatic pelvic lymph nodal sites in endometrial cancer. MATERIALS AND METHODS: This retrospective study included 40 patients with endometrial cancer who underwent MRI [T2-weighted, dynamic T1 weighted images and diffusion-weighted images with body background suppression (DWIBS), b-values 0 and 1,000 s/mm(2)], total hysterectomy and pelvic lymphadenectomy. Lymph nodes identifiable on DWIBS were evaluated, classified into six nodal regions, and for each node ADC values, short- and long-axis diameters were measured by two readers. Histopathological findings and follow-up information served as the reference standard. RESULTS: Average (+/- standard deviation) mean and minimum ADC region value (0.87 +/- 0.15 and 0.74 +/- 0.07 * 10(-3) mm(2)/s) of metastatic sites (n = 7) were significantly lower than those of non-metastatic ones (n = 89; 1.07 +/- 0.20 and 1.02 +/- 0.20; p-value = 0.010 and 0.0004). Mean short-axis and short-to-long axis ratios of metastatic nodes were 7.47 mm and 0.68. Using the minimum ADC region value with threshold 0.807 * 10(-3) mm(2)/s, sensitivity, specificity, positive and negative predictive value and accuracy were 100 %, 98.3 %, 63.6 %, 100 % and 98.3 %, respectively (reader 1). CONCLUSION: In endometrial cancer, mean and minimum ADC region values of metastatic nodal sites are significantly lower than those found at normal sites. PMID- 22821395 TI - Accuracy and speed of robotic assisted needle interventions using a modern cone beam computed tomography intervention suite: a phantom study. AB - OBJECTIVE: To analyse the feasibility and accuracy of robotic aided interventions on a phantom when using a modern C-arm-mounted cone beam computed tomography (CBCT) device in combination with needle guidance software. METHODS: A small robotic device capable of holding and guiding needles was attached to the intervention table. After acquiring a 3D data set the access path was planned on the CBCT workstation and shown on the intervention monitor. Then the robot was aligned to the live fluorosopic image. A total of 40 punctures were randomly conducted on a phantom armed with several targets (diameter 2 mm) in single and double oblique trajectory (n = 20 each). Target distance, needle deviation and time for the procedures were analysed. RESULTS: All phantom interventions (n = 40) could be performed successfully. Mean target access path within the phantom was 8.5 cm (min 4.2 cm, max 13.5 cm). Average needle tip deviation was 1.1 mm (min 0 mm, max 4.5 mm), time duration was 3:59 min (min 2:07 min, max 10:37 min). CONCLUSION: When using the proposed robot device in a CBCT intervention suite, highly accurate needle-based interventional punctures are possible in a reasonable timely manner in single as well as in double oblique trajectories. PMID- 22821396 TI - Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease. AB - The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 * 10(-4)) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Abeta(42) levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Abeta(42) levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Abeta(42) levels was independent of the APOE epsilon4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE epsilon4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 * 10(-13)). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE epsilon4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10(-6). Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 * 10(-9)). PMID- 22821397 TI - Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection. AB - Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the under-lying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4+ T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-gamma. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-gamma expressing, ESAT-6 specific CD4+CD45RO+CD27- T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions. PMID- 22821398 TI - Involvement of astrocytes in transmissible spongiform encephalopathies: a confocal microscopy study. AB - Astroglial proliferation associated with pathological prion protein (PrPsc) deposition is widely described in Transmissible Spongiform Encephalopathies (TSEs). However, little is known of the actual role played by glia in their pathogenesis. The aim of the study has been to determine whether PrPsc is located exclusively in neurons or in both neurons and glial cells present in the central nervous system in a natural Scrapie model. Samples of cerebellum from 25 Scrapie sheep from various flocks were sectioned. Following epitope retrieval with formic acid, proteinase K and heat treatment, primary antibody L42 and primary antibodies against glial fibrillary acidic protein were applied as prion- and astrocytic-specific markers, respectively. For visualization, a suitable mixture of fluorochrome-conjugated secondary antibodies was used. Relevant controls were processed in the same manner. As determined by confocal microscopy, PrPsc deposits co-localized with glial cells in all samples. Our results suggest that these cells can sustain active prion propagation, in agreement with similar findings from other studies of primary cell cultures and inoculated mice. Furthermore, despite ongoing debate regarding whether varied TSE sources show differences in their tropism for different cell lineages in the brains of affected animals, no differences in co-localization results were seen. PMID- 22821399 TI - The activity and safety of electrochemotherapy in persistent chest wall recurrence from breast cancer after mastectomy: a phase-II study. AB - Electrochemotherapy (ECT) represents an attractive locoregional therapy for unresectable chest wall recurrence (CWR) from breast cancer. Thirty-five patients with cutaneous CWR after mastectomy who experienced progression despite re irradiation and extensive systemic treatments were administered bleomycin-based ECT. Local response, toxicity, and superficial control were evaluated. Out of 516 metastases (median 15/patient, range 1-50), response was assessed on 196 target lesions (median size 20 mm, range 10-220). Patients received a median of 2 ECT courses (range 1-3). Two-month objective response was as follows: 54.3 % complete (19/35 patients), 37.1 % partial (13/35), and 8.6 % no change (3/35). Twenty three patients (65.7 %) developed new lesions (NL) after a median time of 6.6 months (range 2.3-29.5), therefore 1, 2, or 3 ECT cycles were required in 14, 15, and 6 patients, respectively. Median follow-up was 32 months (range 6-53) and the 3-year local control rate was 81 %. Related morbidity was mild, increased after retreatments and consisted primarily of pain (reported as "moderate"/"severe" by 6, 13, and 17 % of patients 1 month after the first, second, and third application, respectively) and dermatological toxicity (acute G3 skin ulceration in 14, 20, and 33 % of patients, respectively). Less than 10 metastases (P < 0.001), the narrower area of tumor spread on the chest wall (P = 0.022), complete response achievement (P = 0.019), and post-ECT endocrine instead of chemotherapy (P = 0.025) were associated to NL-free survival. Only fewer skin metastases, hazard ratio (HR) 0.122, 95 % confidence interval (CI) 0.037-0.397, P < 0.001, and contained superficial spread, HR 0.234, 95 % CI 0.067-0.818, P = 0.023, were predictors for longer NL-free survival. ECT showed a satisfactory activity in refractory breast cancer CWR, providing sustained local control. Patients with fewer and less scattered skin metastases are less likely to develop NL. Partial responders and NL can be handled with additional ECT albeit increasing local pain and skin toxicity. PMID- 22821400 TI - Impact of real-time virtual sonography, a coordinated sonography and MRI system that uses an image fusion technique, on the sonographic evaluation of MRI detected lesions of the breast in second-look sonography. AB - The aim of this study was to verify the utility of second-look sonography using real-time virtual sonography (RVS)-a coordinated sonography with an MRI system that uses an image fusion technique with magnetic navigation-on the sonographic evaluation of MRI-detected lesions of the breast. Of the 196 consecutive patients who were examined with breast MRI in our hospital from 2006 to 2009, those patients who underwent second-look sonography to identify MRI-detected lesions were enrolled in this study. MRI was performed using a 1.5-T imager with the patient in a supine position. To assess the efficacy benefits of RVS, the correlations between lesion detection rates, MRI features, distribution, and histopathological classification on second-look sonography using conventional B mode or RVS were analyzed. Of the 196 patients, 55 (28 %) demonstrated 67 lesions initially detected by MRI, followed by second-look sonography. Of the 67 MRI detected lesions, 18 (30 %) were identified with second-look sonography using conventional B-mode alone, whereas 60 (90 %) lesions were detected with second look sonography using RVS (p < 0.001). The detection rates of 16 focal lesions, 46 mass lesions, 16 lesions sized <5 mm, 45 lesions sized 5-10 mm, 26 lesions situated within the mammary gland, 41 lesions situated around mammary fascia, 24 malignant lesions, and 43 benign lesions were, respectively, 25, 26, 25, 24, 42, 17, 33, and 23 % by conventional B-mode, and were significantly higher, respectively, at 94, 89, 94, 89, 88, 90, 92, and 88 % by RVS. Of the seven lesions with no sonographic correlates, five could be biopsied by marking MRI information onto the body surface using RVS. Overall, 65 of 67 (97 %) MRI detected lesions were confirmed by histopathological results. Our results suggest that the additional use of RVS on second-look sonography significantly increases the sonographic detection rate of MRI-detected lesions without operator dependence. PMID- 22821402 TI - Why I voted "no" to Truvada PrEP. PMID- 22821401 TI - Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. AB - Bypassing estrogen receptor (ER) signaling during development of endocrine resistance remains the most common cause of disease progression and mortality in breast cancer patients. To date, the majority of molecular research on ER action in breast cancer has occurred in cell line models derived from late stage disease. Here we describe patient-derived ER+ luminal breast tumor models for the study of intratumoral hormone and receptor action. Human breast tumor samples obtained from patients post surgery were immediately transplanted into NOD/SCID or NOD/SCID/ILIIrg(-/-) mice under estrogen supplementation. Five transplantable patient-derived ER+ breast cancer xenografts were established, derived from both primary and metastatic cases. These were assessed for estrogen dependency, steroid receptor expression, cancer stem cell content, and endocrine therapy response. Gene expression patterns were determined in select tumors +/-estrogen and +/-endocrine therapy. Xenografts morphologically resembled the patient tumors of origin, and expressed similar levels of ER (5-99 %), and progesterone and androgen receptors, over multiple passages. Four of the tumor xenografts were estrogen dependent, and tamoxifen or estrogen withdrawal (EWD) treatment abrogated estrogen-dependent growth and/or tumor morphology. Analysis of the ER transcriptome in select tumors revealed notable differences in ER mechanism of action, and downstream activated signaling networks, in addition to identifying a small set of common estrogen-regulated genes. Treatment of a naive tumor with tamoxifen or EWD showed similar phenotypic responses, but relatively few similarities in estrogen-dependent transcription, and affected signaling pathways. Several core estrogen centric genes were shared with traditional cell line models. However, novel tumor-specific estrogen-regulated potential target genes, such as cancer/testis antigen 45, were uncovered. These results evoke the importance of mapping both conserved and tumor-unique ER programs in breast cancers. Furthermore, they underscore the importance of primary xenografts for improved understanding of ER+ breast cancer heterogeneity and development of personalized therapies. PMID- 22821404 TI - A viable isolated tissue system: a tool for detailed MR measurements and controlled perturbation in physiologically stable tissue. AB - In vivo magnetic resonance imaging (MRI) assessment of neuronal tissue is prone to artifacts such as movement, pulsatile flow, and tissue susceptibility. Furthermore, stable in vivo scans of over 3 h are difficult to achieve, experimental design is therefore limited. Using isolated tissue maintained in a viable physiological state can mitigate many of these in vivo issues. This work describes the fabrication and validation of an MRI compatible viable isolated tissue maintenance chamber. Parameters measured from maintained rat optic nerves did not change significantly over 10 h: (i) mean axon radius [electron microscopy -0 h: 0.75+/-0.46; 5 h: 0.74+/-0.35; 10 h: 0.76+/-0.35 MUm (P>>0.05, t-test], (ii) action potentials [grease-gap electrophysiology--4.89+/-0.16 mv, (P>>0.05, Pearson test], and (iii) diffusion tensor imaging parameters [fractional anisotropy: 0.86+/-0.02 (P>>0.05, Pearson test), mean diffusivity: 1.48E-06+/ 9.74E-08 cm2/s, (P>>0.05, Pearson test)]. In addition, a thorough diffusion weighted MR protocol demonstrated the comparable stability of viable isolated and chemically fixed rat optic nerve. This MRI compatible viable isolated tissue system allows researchers to probe neuronal physiology in a controlled environment by limiting in vivo artifacts and allowing extended MRI acquisitions. PMID- 22821403 TI - Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. AB - Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 * 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 * 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. CONCLUSION: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. PMID- 22821405 TI - Experience with daptomycin daily dosing in ICU patients undergoing continuous renal replacement therapy. AB - PURPOSE: For critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily. METHODS: The retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured. RESULTS: Daptomycin dose ranged from 3 to 8 mg/kg/q24 h in patients undergoing CRRT (n = 7) and 6 to 10 mg/kg/q24 h in patients without CRRT (n = 4). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (n = 6), coagulase-negative Staphylococcus (n = 2), Staphylococcus aureus (n = 2) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection. CONCLUSION: In critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRRT. PMID- 22821407 TI - Correlates of drug dealing in female methamphetamine users. AB - Female drug dealers have been a neglected population despite their potentially elevated risk for social, legal, family, and psychological health problems. This study examined correlates of drug-dealing behavior in a sample of 209 female methamphetamine users in San Diego, CA. Twenty-five percent of the sample reported dealing methamphetamine in the past 2 months. Women who dealt methamphetamine were significantly more likely than their nondealing counterparts to have started using illicit drugs before the age of 13 years (68 % versus 44.7 %, p = .003); to have been introduced to methamphetamine by a parent (15.1 % versus 5.8 %, p = .037); and to report currently using methamphetamine to stay awake (84.9 % versus 64.7 %, p = .004), enhance self-confidence (62.3 % versus 45.5 %, p = .025), and feel more attractive (54.7 % versus 38.5 %, p = .029). In a multivariate logistic regression, factors independently associated with methamphetamine dealing were: having a spouse or live-in partner (Adjusted Odds Ratio, AOR = 2.89), using methamphetamine with a broader range of types of person (AOR = 1.46), and reporting lower levels of emotional support (AOR = 0.57). These findings suggest that female methamphetamine dealers are in urgent need of access to substance use treatment, therapies to enhance self-worth and emotional support, and family-based substance use prevention interventions for dependent children and those at risk. PMID- 22821406 TI - Lipopolysaccharide-induced bacterial translocation is intestine site-specific and associates with intestinal mucosal inflammation. AB - The present study aimed to determine whether any specific intestinal site or intestinal mucosal inflammation is highly correlated with bacterial translocation (BT). Enterostomy tubes were surgically placed in adult male Sprague-Dawley rats 5 days before induction of experimental model. After surgery, sterile water containing kanamycin (25 mg/L) was injected into each intestinal segment through the tubes for 3 days. Green fluorescent protein (GFP)-transfected Escherichia coli (n = 30 for lipopolysaccharide (LPS) group, and n = 30 for control group) or 0.9 % saline (n = 30 for blank group) were injected into each intestinal segment through the tubes for two consecutive days. Rats were then subjected to LPS induced endotoxemia; lactulose and mannitol were injected into each intestinal segment through the tubes simultaneously. At 6 h after LPS injection, BT to distant organs and integrity of tight junctions (TJ) were examined by fluorescence and electron microscopy, respectively. The urinary excretion ratio of lactulose/mannitol (L/M) and intestinal mucosal cytokine levels were assessed. We found that the intestinal permeability, reflected by translocation rates of GFP-labeled E. coli, the levels of open TJ, the excretion ratio of L/M, and the inflammatory cytokine levels were higher in the LPS group than in the control and blank groups. The endotoxemia ileum showed the highest levels of both intestinal permeability and inflammatory cytokine, while the colon showed the lowest. The present study of endotoxemia rats suggests that LPS increases gut paracellular permeability and induces BT. The ileum is the site of greatest BT risk, while the colon is the lowest, and the difference in risk between these sites is correlated with intestinal mucosal inflammation. PMID- 22821408 TI - The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) for low back disorders: a validation study from Iran. AB - BACKGROUND: Lumbar disc hernia (LDH) and lumbar spinal stenosis (LSS) are the most common diagnoses of low back and leg pain symptoms. The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) is a measure of health related quality of life in these patients. This study aimed to cross-culturally translate and validate the JOABPEQ in Iran. METHODS: This was a prospective clinical validation study. The translation and cross-cultural adaptation of the original questionnaire was performed in accordance with published guidelines. A total of 103 patients with LDH or LSS were asked to respond to the questionnaire at two points in time: pre- and postoperative assessments (6 months follow-up). To test reliability, the internal consistency was assessed by Cronbach's alpha coefficient, and validity was assessed using convergent validity. Responsiveness to change was also assessed comparing patients' pre- and postoperative scores. RESULTS: The Cronbach's alpha coefficients for the JOABPEQ at pre- and postoperative assessments ranged from 0.71 to 0.81, indicating a good internal consistency for the questionnaire. In addition, the correlation of each item with its hypothesized subscale of the JOABPEQ showed satisfactory results, suggesting that the items had a substantial association with the subscale representing the concept. Further analysis also indicated that the questionnaire was responsive to change (P < 0.0001). CONCLUSIONS: In general, the Iranian version of JOABPEQ performed well, and the findings suggest that it is a reliable and valid measure of back pain evaluation among LDH and LCS patients. PMID- 22821409 TI - Author's reply to: Smoking at diagnosis and survival in cancer patients. PMID- 22821410 TI - Identification and expression of an APETALA2-like gene from Nelumbo nucifera. AB - Arabidopsis transcription factor APETALA2 (AP2) controls multiple aspects of plant growth and development, including seed development, stem cell maintenance, and specification of floral organ identity. Based on sequence similar of Arabidopsis AP2 and its homologues genes from other plant species, degenerate RT PCR and rapid amplification of cDNA ends assay were used to clone AP2 genes from lotus (Nelumbo nucifera). A 2,048-bp cDNA fragment was obtained, which contains a 1,536-bp open reading frame encoding a protein of 511 amino acids. The protein contains two AP2 domains that are conserved in AP2 proteins from other plant species, thus was named as N. nucifera APETALA2 (NnAP2). Quantitative RT-PCR revealed that NnAP2 gene was expressed in flowers, roots, leaves, and stems of N. nucifera, with flowers which have the highest transcript levels. Further analysis showed that in all five lotus cultivars examined, including "Zhongguogudailian," "Yaoniangyujiao," "Jinxia," "Hongtailian," and "Yiliangqianban," petals always have the highest expression levels when compared with the other four flower organs, though the number of petals in these cultivars ranged from simple to thousands. However, NnAP2 expression level in four nonsimple petal flower cultivars was higher than that in the simple petal flower cultivar Zhongguogudailian, indicating that NnAP2 may play a role in specification of petal identity during the evolutionary process of the ancient species N. nucifera. PMID- 22821411 TI - Reversine promotes porcine muscle derived stem cells (PMDSCs) differentiation into female germ-like cells. AB - A small molecular chemical-Reversine has been shown to promote cell reprogramming and induce dedifferentiation of multiple terminally differentiated mesodermal origin cells, and then differentiate into other cell types within mesodermal lineages as well as neuroectodermal. However, the possibilities of these cells to give rise to germ cell lineages have not been examined. The objective of the current study was to detect the effect of Reversine on PMDSCs differentiation into germ cells. PMDSCs from fetal porcine skeletal muscle and their potential of differentiation into germ cells in vitro were investigated. The phenotype, proliferation potential, characteristic markers of the first adhesion cells (pp1), and the purified 2 times cells (pp3) were analyzed by growth curve, FACS, and RT-PCR, respectively. Then, the purified cells were induced with 10% or 20% bovine follicular fluid (FF), the results showed that some of the induced pp3 cells were similar as porcine oocyte, and expressed germ cell and oocyte markers analyzed by semi-quantitative RT-PCR and immunofluorescent staining. Reversine clearly increased the potentiality of PMDSCs differentiation into large round germ-like cells in FF induction medium analyzed by morpholgogy, QRT-PCR and immunofluoresce. The BrdU labeled PMDSCs might differentiate into female germ like cells in recipient's kidney capsule, which were positive for germ cell and meiotic markers (Dazl, Vasa, Figla, Stra8, Scp3) and oocyte markers (Zp2, Zp3). These findings provided an efficient model to study the mechanism of cell proliferation and germ cell differentiation in livestock promoted by Reversine. PMID- 22821412 TI - 1-methylcyclopropene effects on temporal changes of aroma volatiles and phytochemicals of fresh-cut cantaloupe. AB - BACKGROUND: Orange-fleshed cantaloupe melons have intense aroma and flavor but are very perishable during storage life. Fresh-cut processing enhances ethylene mediated quality losses. Post-cutting 1-methylcyclopene (1-MCP) application to fresh-cut cantaloupe was evaluated for its effects on quality attributes, phytochemical content and aroma volatiles. RESULTS: Fresh-cut cantaloupe (Cucumis melo var. cantalupensis 'Fiesta') cubes treated with 1.0 uL L(-1) of 1-MCP for 24 h at 5 degrees C, packaged in vented plastic clamshells and stored under normal atmosphere at 5 degrees C for 9 days, preserved their soluble solids, total phenolics, total carotenoids and beta-carotene contents, but significant softening occurred. A significant increase of non-acetate esters and a decrease of aldehydes occurred during storage. Most quality attributes of fresh-cut cantaloupe were unaffected by the treatment with 1-MCP. 1-MCP-treated fresh-cut cantaloupe accumulated higher levels of propyl acetate, 2-methylbutyl acetate, methyl butanoate, methyl 2-methyl butanoate, methyl hexanoate, 2-methylbutyl alcohol and phenethyl alcohol, and lower levels of benzyl alcohol and heptanal than untreated controls. CONCLUSION: Post-cutting treatment with 1-MCP affected nine of the flavor-important volatiles, particularly those derived from the amino acids isoleucine and phenylalanine, but had no practical effect on phytochemicals or other quality attributes. PMID- 22821414 TI - Percutaneous distal metatarsal osteotomy versus distal chevron osteotomy for correction of mild-to-moderate hallux valgus deformity. AB - PURPOSE: A lot of procedures were described for managing hallux valgus deformity. Percutaneous metatarsal osteotomies have received increasing recognition in the previous decade. The proposed benefits revolve primarily around the shorter surgical time, lower incidence of complications, and higher patient satisfaction. However, there is insufficient evidence to determine whether this technique is comparable to traditional open approaches. MATERIALS AND METHODS: A total of 64 consecutive feet (53 patients) with mild-to-moderate symptomatic hallux valgus were randomly assigned into two groups to compare the results of percutaneous distal metatarsal osteotomy (group I, 31 feet) and distal chevron osteotomy (group II, 33 feet). All patients were clinically assessed using the American Orthopedic Foot and Ankle Society (AOFAS) scoring system. Radiographical assessment was done using the hallux valgus angle (HVA) and intermetatarsal angle (IMA). RESULTS: The mean correction of HVA and IMA achieved in group I was 14.4 degrees and 4.8 degrees , respectively, while in group II, it was 13.1 degrees and 3.9 degrees , respectively. The mean AOFAS score improved from a pre operative of 44.6 points to 90.2 points in group I, and from 47.5 points to 87.7 points in group II. In group I, 26/29 patients (89.6 %) were happy with the cosmetic results of the surgery, compared to 20/31 patients (64.5 %) in group II. CONCLUSION: The results of this study support the idea that percutaneous distal metatarsal osteotomy yields good functional and radiological result and is associated with a high degree of postoperative patient satisfaction. PMID- 22821413 TI - Response of biomarkers in amphibian larvae to in situ exposures in a fruit producing region in North Patagonia, Argentina. AB - The authors evaluated biomarker responses in caged larvae of the amphibian Rhinella arenarum in water channels during fruit production season and compared them with those elicited by a transient exposure to azinphos methyl (AzM) (0.02-2 mg/L; 4 h), the main pesticide applied in the Alto Valle region, Patagonia, Argentina, taking into account the maximum environmental concentration detected in superficial water (22.5 ug/L). The traditional biomarkers of organophosphate exposure, acetylcholinesterase (AChE) and carboxylesterase, were inhibited in tadpoles after one week of exposure in channels potentially receiving pesticide drift, whereas the antioxidant glutathione (GSH) and the detoxifying activity of GSH S-transferase (GST) were induced. In a two-week monitoring study, AChE activity was induced in larvae exposed at the agricultural site, and carboxylesterase showed an inhibition followed by return to control values, suggesting an exposure-recovery episode. Antioxidant glutathione levels were first depleted and then surpassed control levels, whereas GST activity was continuously induced. These responses were mimicked in the laboratory by 2 mg/L AzM-pulse exposure, which notably exceeds the expected environmental concentrations. The results draw attention to the complexity of responses after pesticide exposure, strongly depending on exposure time-concentration and recovery periods, among other possible factors, and support the necessity of the integrated use of biomarkers to assess exposure episodes in agricultural areas. PMID- 22821415 TI - A survey on causes of amputation in a 9-year period in Iran. AB - BACKGROUND: Limb loss occurs as a result of different causes and has been increasing in many countries. This study determines the demography of amputees in one of the relatively large cities of Iran. METHODS: This retrospective study was undertaken on all of the amputees between 2003 and 2011. Patients' demographics including age, sex, the limb that had undergone amputation, etiology of limb loss and side and level of amputation were recorded. Also, the level of amputation was recorded as minor (below wrist or ankle) or major (above wrist or ankle). RESULTS: In total, 624 patients were enrolled in the study. The number of amputees was from 53 to 118/year. Of the patients, 508 were male (81.4 %) and 118 were female (18.6 %). The men with amputation were younger on average than women; 61.9 % of the amputations (386) were major and 38.1 % were minor (238). Overall, the most common cause of amputation was trauma and the most common level was transmetatarsal. The most common level for major amputations was below knee. CONCLUSION: In contrast to similar studies in developed countries, trauma was found to be the major cause of all types of amputations and in all age groups, which emphasizes the need for preventive measures in the country. PMID- 22821416 TI - Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation. AB - Epigenetic control is crucial for the differentiation of a variety of cells including oligodendrocytes, the myelinating glial cells of the central nervous system. However, studies about the implication of epigenetic factors in peripheral nervous system maturation are just emerging. Here, we demonstrate for the first time the impact of a histone methyltransferase, encoded by the enhancer of zeste homolog 2 (EZH2) gene, on Schwann cell differentiation. In sciatic nerves, EZH2 expression was found in Schwann cells and to peak perinatally. Suppression of EZH2 expression in cultured primary rat Schwann cells reduced the length of cell processes. These morphological changes were accompanied by widespread alterations in the gene expression pattern, including downregulation of myelin genes and induction of p57kip2, which we have recently identified as an intrinsic inhibitory regulator of Schwann cell maturation. In addition, we show that EZH2 suppression in dorsal root ganglion cocultures interferes with in vitro myelination. Chromatin immunoprecipitation analysis revealed binding of EZH2 at the p57kip2 promoter and reduction of histone H3K27 trimethylation upon gene suppression. EZH2 suppression-dependent effects on morphology and myelin genes could be reversed by concomitant suppression of p57kip2, indicating that p57kip2 is a downstream effector of EZH2. Furthermore, we describe Hes5 as transcriptional repressor of myelin genes in Schwann cells, which was induced upon EZH2 suppression and downregulated in p57kip2-suppressed Schwann cells. Therefore, we have identified a molecular link between histone methylation and control of Schwann cell differentiation and demonstrate that this epigenetic mechanism is crucial for glial differentiation to proceed. PMID- 22821417 TI - Successful treatment of a newborn with acute myocardial infarction on the first day of life. AB - Cardiogenic shock occurring after acute neonatal myocardial infarction (MI) due to coronary artery thrombosis is very rarely encountered. Acute neonatal MI typically presents suddenly with usually a fatal outcome. Treatment options in patients with this condition are limited. There are previous case reports in the literature advocating the use of extracorporeal membrane oxygenation for hemodynamic support. In this report, we present a newborn with severe MI secondary to thrombus formation within the left anterior descending coronary artery. There also proved to be a Factor V Leiden heterozygotic mutation. The patient initially presented with cardiogenic shock. After resuscitation and thrombolytic therapy were administered, coronary artery patency was restored resulting in myocardial revitalization and recovery of left-ventricular function within 4 weeks. PMID- 22821418 TI - Memory enhancing activity of naringin in unstressed and stressed mice: possible cholinergic and nitriergic modulation. AB - The present study was designed to evaluate the effect of Naringin on memory of unstressed and stressed Swiss young albino mice. Naringin (80 mg/kg, i.p.) and donepezil (10 mg/kg) were administered for 21 successive days to separate groups of unstressed and stressed mice. The nootropic activity was evaluated using elevated plus maze and Hebbs Williams Maze. Brain acetylcholinesterase (AChE), brain nitrite and plasma corticosterone levels were also estimated. unpredictable chronic mild stress was produced by using different stressors. Naringin (80 mg/kg) and donepezil significantly showed memory enhancing activity in both unstressed and stressed mice. Naringin significantly reduced brain AChE activity and brain nitrite levels in both unstressed and stressed mice. Naringin (80 mg/kg) significantly reversed scopolamine-induced amnesia in unstressed and stressed mice. 7-Nitroindazole [a neuronal nitric oxide synthase (NOS) inhibitor] and aminoguanidine (an inducible NOS inhibitor) significantly enhanced memory improving activity and brain nitrite decreasing effect of naringin in unstressed and stressed mice respectively. Plasma corticosterone levels were significantly decreased by naringin (80 mg/kg) in stressed mice as compared to its control. Thus, naringin showed memory enhancing activity in unstressed mice probably by decreasing brain AChE activity and by inhibition of neuronal NOS. The memory enhancing activity of naringin in stressed mice might be due to decrease in brain AChE activity, inhibition of inducible NOS and also by decreasing the elevated plasma corticosterone levels. PMID- 22821419 TI - Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). AB - PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports. METHODS: Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs. RESULTS: We identified 635 PML cases in a total of 1,978,706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate. DISCUSSION: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies. PMID- 22821420 TI - A case of infantile Takayasu arteritis with a p.D382E NOD2 mutation: an unusual phenotype of Blau syndrome/early-onset sarcoidosis? AB - Blau syndrome/early-onset sarcoidosis (Blau/EOS) is an autoinflammatory disease characterized by granulomatous arthritis, uveitis, and skin rash. It has been shown that gain-of-function NOD2 mutations cause Blau/EOS. In this paper, we describe a patient with a gain-of-function NOD2 mutation who developed infantile Takayasu arteritis, which is rare in Blau/EOS, but who has not yet had significant granulomatous changes in joints, eyes, or skin. We suspect that this case is an unusual phenotype of Blau/EOS. PMID- 22821421 TI - Failure of conservative treatment for thoracic spine fracture in ankylosing spondylitis: delayed neurological deficit due to spinal epidural hematoma. AB - Patients with ankylosing spondylitis (AS) are prone to spinal fracture after even minor trauma. We report a case of thoracic spinal fracture in a patient with AS who developed a secondary neurological deficit due to delayed diagnosis and prolonged conservative treatment. When the neurological deficit occurred, the fractured segment showed no displacement, but a spinal epidural hematoma was present. Surgical treatment produced significant neurological improvement, although incomplete paralysis persisted. PMID- 22821422 TI - Biotic structure indirectly affects associated prey in a predator-specific manner via changes in the sensory environment. AB - Indirect effects, which can be either positive or negative, may be important in areas containing biotic structure, because such structure can provide refuge and habitat, produce additional sensory cues that may attract predators, and modify the sensory landscape in which predator-prey interactions occur. To determine the indirect effects of biotic structure on prey populations, we assessed predation on patches of hard clams (Mercenaria mercenaria) by large odor-mediated blue crab (Callinectes sapidus) and knobbed whelk (Busycon carica) predators at 0, 5, and 10 m from oyster reefs in intertidal salt marshes. Oyster reefs had an overall indirect negative effect on hard clams, with higher predation rates closer to the reef than farther away. Predator-specific patterns of predation showed that blue crabs consumed more clams very close to the reef, whereas whelks consumed more clams at intermediate distances. Laboratory flume experiments suggest that the oyster reef structure creates turbulence that diminishes predator foraging efficiency, particularly in rapidly mobile predators such as blue crabs, but that oyster reef chemicals ameliorate the negative impact of turbulence on foraging success for both predators. Changes in the sensory landscape, in combination with predator perceptual ability, will determine the positive and/or negative impacts of biotic structure on associated prey. Gaining an understanding of the context specificity of positive and negative sensory effects of biotic structure provides insights that are important for developing a predictive framework to assess the magnitude and distribution of indirect interactions in natural communities. PMID- 22821423 TI - C-terminal truncated hepatitis B virus x protein is associated with metastasis and enhances invasiveness by C-Jun/matrix metalloproteinase protein 10 activation in hepatocellular carcinoma. AB - Random integration of hepatitis B virus (HBV) DNA into the host genome is frequent in human hepatocellular carcinoma (HCC) and this leads to truncation of the HBV DNA, particularly at the C-terminal end of the HBV X protein (HBx). In this study, we investigated the frequency of this natural C-terminal truncation of HBx in human HCCs and its functional significance. In 50 HBV-positive patients with HCC, full-length HBx was detected in all nontumorous livers. However, full length HBx was found in only 27 (54%) of the HCC tumors, whereas natural carboxylic acid (COOH)-truncated HBx was found in the remaining 23 (46%) tumors. Upon clinicopathological analysis, the presence of natural COOH-truncated HBx significantly correlated with the presence of venous invasion, a hallmark of metastasis (P = 0.005). Inducible stable expression of the COOH-truncated HBx protein (with 24 amino acids truncated at the C-terminal end) enhanced the cell invasive ability of HepG2 cells, as compared to full-length HBx, using the Matrigel cell-invasion assay. It also resulted in increased C-Jun transcriptional activity and enhanced transcription of matrix metalloproteinase 10 (MMP10), whereas activation of the MMP10 promoter by COOH-truncated HBx was abolished when the activator protein 1-binding sites on the MMP10 promoter were mutated. Furthermore, silencing of MMP10 by short interfering RNA in HBxDeltaC1-expressing HepG2 cells resulted in significant reduction of cell invasiveness. CONCLUSIONS: Our data suggest that COOH truncation of HBx, particularly with 24 amino acids truncated at the C-terminal end, plays a role in enhancing cell invasiveness and metastasis in HCC by activating MMP10 through C-Jun. PMID- 22821424 TI - Green-lipped mussel extract (Perna canaliculus) and glucosamine sulphate in patients with knee osteoarthritis: therapeutic efficacy and effects on gastrointestinal microbiota profiles. AB - OBJECTIVE: To investigate how changes in the gastrointestinal tract (GIT) microbiota profile may influence nutraceutical efficacy in osteoarthritis (OA) and allow the formulation of a hypothesis that explains in part the inconsistent and contentious findings from OA clinical studies with green-lipped mussel (GLM) and glucosamine. METHODS: A non-blinded randomised clinical trial was conducted with 38 subjects diagnosed with knee OA. Each participant received either 3,000 mg/day of a whole GLM extract or 3,000 mg/day of glucosamine sulphate (GS), p.o. for 12 weeks. Faecal microbial analyses were carried out after collecting stools at T (0) and T (12) weeks. Additional pharmacometric measures were obtained from changes in arthritic scores in the Western Ontario McMaster Universities Arthritis Index (WOMAC) and the Lequesne algofunctional indices and the Gastrointestinal Symptom Rating Scale (GSRS). An intention-to-treat analysis was employed and participant data collected at T (0), T (6) and T (12) weeks. RESULTS: There were no statistically significant changes in bacterial growth patterns determined by the Wilcoxon test. In both groups there was a trend towards a decrease in Clostridium and Staphylococcus species and increase in Lactobacillus, Streptococcus and Eubacterium species. In the GLM group Bifidobacterium tended to increase and Enterococcus and yeast species to decrease. The GS-treated group demonstrated a trend towards a decrease in Bacteroides and an increase in yeasts and Coliforms species, most notably Escherichia coli. We further confirm significant improvement (p < 0.05) in all OA outcome measures from T (0) to T (12) weeks for both the GLM and GS groups. The GSRS scores indicated that GIT function significantly improved over the 12 weeks duration with GLM and GS supplementation. CONCLUSION: Both GLM and GS reduced OA symptoms and non-significantly altered the gut microbiota profile from baseline. Changes in the microbiota profiles occurred in both treatment groups; the most notable being a reduction in the Clostridia sp. This study suggests that nutritional supplements such as GLM and GS may regulate some of the metabolic and immunological activities of the GIT microbiota. The decrease in Clostridia, a potent modulator of colonic Th17 and CD4+ regulatory T cells, was consistent with a decrease in inflammation; improved GSRS scores and OA symptoms for these OA participants. The GIT microbiota may be important factor in the first-pass metabolism of these nutraceuticals. PMID- 22821425 TI - Cancer prevalence in Italy: an analysis of geographic variability. AB - PURPOSE: Statistics on cancer prevalence are scanty. The objectives of this study were to describe the cancer prevalence in Italy and to explore determinants of geographic heterogeneity. METHODS: The study included data from 23 population based cancer registries, including one-third of the Italian population. Five-year cancer prevalence was observed, and complete prevalence (i.e., all patients living after a cancer diagnosis) was estimated through sex-, age-, cancer site-, and observation period length-specific completeness indices by means of regression models. RESULTS: In 2006, 3.8 % of men and 4.6 % of women in Italy were alive after a cancer diagnosis, with a 5-year prevalence of 1.9 % and 1.7 % in men and women, respectively. A relevant geographic variability emerged for all major cancer sites. When compared to national pooled estimates, crude cancer prevalence proportions were 10 % higher in the north and 30 % lower in the south of Italy. However, these variations were consistently reduced after age adjustment and, in both sexes, largely overlapped those of incidence rates, with correlations >0.90 between variations of prevalence and incidence for all cancer sites and areas. CONCLUSIONS: Magnitude of the cancer prevalence and the geographic heterogeneity herein outlined in Italy will help in meeting the needs of specific population of survivor patients. PMID- 22821426 TI - Joint genotype calling with array and sequence data. AB - Analysis of rare variants is currently a major focus of genetic studies of human disease. Single-nucleotide polymorphism (SNP) genotypes can be assayed using microarray genotyping or by sequencing, but neither technology produces perfect genotype calls, especially at rare SNPs. Studies that collect both types of data are becoming increasingly common, so it may be possible to combine data types to increase accuracy. We present a method, called Chiamante, which calls genotypes on individuals with either array data, sequence data, or both. The model adapts to data quality and can estimate when either the array or the sequence data should be ignored when calling the genotypes at each SNP. As a special case, our method will call genotypes from only array data and outperforms existing methods in this scenario. We have applied our method to array and sequence data from Phase I of the 1000 Genomes Project and show that it provides improved performance, especially at rare SNPs. This method provides a foundation for future efforts to fuse genetic data from different sources, for example, when combining data from exome sequencing and exome microarrays. PMID- 22821427 TI - Transient hemiparesis in a 14-year-old boy with MYH9 disorders. PMID- 22821430 TI - Comparison of different live/dead stainings for detection and quantification of adherent microorganisms in the initial oral biofilm. AB - OBJECTIVES: The aim of the present study was to investigate different fluorescence-based, two-color viability assays for visualization and quantification of initial bacterial adherence and to establish reliable alternatives to the ethidium bromide staining procedure. MATERIALS AND METHODS: Bacterial colonization was attained in situ on bovine enamel slabs (n = 6 subjects). Five different live/dead assays were investigated (fluorescein diacetate (FDA)/propidium iodide (PI), Syto 9/PI (BacLight(r)), FDA/Sytox red, Calcein acetoxymethyl (AM)/Sytox red, and carboxyfluorescein diacetate (CFDA)/Sytox red). After 120 min of oral exposure, analysis was performed with an epifluorescence microscope. Validation was carried out, using the colony-forming units for quantification and the transmission electron microscopy for visualization after staining. RESULTS: The average number of bacteria amounted to 2.9 +/- 0.8 * 10(4) cm(-2). Quantification with Syto 9/PI and Calcein AM/Sytox red yielded an almost equal distribution of cells (Syto 9/PI 45% viable, 55% avital; Calcein AM/Sytox red 52% viable, 48% avital). The live/dead ratio of CFDA/Sytox red and FDA/Sytox red was 3:2. An aberrant dispersal was recorded with FDA/PI (viable 34%, avital 66%). The TEM analysis indicated that all staining procedures affect the structural integrity of the bacterial cells considerably. CONCLUSION: The following live/dead assays are reliable techniques for differentiation of viable and avital adherent bacteria: BacLight, FDA/Sytox red, Calcein AM/Sytox red, and CFDA/Sytox red. These fluorescence-based techniques are applicable alternatives to toxic and instable conventional assays, such as the staining procedure based on ethidium bromide. CLINICAL RELEVANCE: Differentiation of viable and avital adherent bacteria offers the possibility for reliable evaluation of different mouth rinses, oral medication, and disinfections. PMID- 22821429 TI - Clinical longevity of ceramic laminate veneers bonded to teeth with and without existing composite restorations up to 40 months. AB - OBJECTIVES: This study evaluated the survival rate of ceramic laminate veneers bonded to teeth with and without existing composite restorations (ECR). MATERIALS AND METHODS: Twenty patients (mean age: 49.7 years) received 92 feldspathic ceramic laminate veneers (Shofu Vintage AL) on the maxillary teeth (intact teeth: n = 26; teeth with ECR: n = 66). Preparations with incisal overlap were made, and ECR of good quality were not removed but conditioned using silica coating (CoJet) and silanization (ESPE-Sil). Enamel and dentin were etched with 38% H3PO4 for 15 30 s and rinsed 30 s; adhesive resin (Excite) was applied, and laminate veneers were then cemented (Variolink Veneer). Restorations were evaluated at baseline and thereafter every 6 months using modified United States Public Health Service criteria. RESULTS: Mean observation period was 21.6 months. Overall, five absolute failures were encountered (fractures: n = 3; chipping: n = 1; debonding: n = 1), resulting in a survival rate of 94.6% (Kaplan-Meier). Survival rates of the laminates bonded to teeth without (96%) and with ECR (93.5%) did not show significant differences (p > 0.05). Slight marginal defects (16 of 87 laminates) and slight marginal discoloration at the margins were noted (12 of 87 laminates) until the final recall. Secondary caries and endodontic complications were not detected in any of the teeth. CONCLUSION: The clinical survival of ceramic laminate veneers up to 40 months was not significantly influenced when they were bonded onto intact teeth or onto teeth with ECR. CLINICAL RELEVANCE: When no caries is present, it may not be necessary to replace existing composite restorations prior to cementation of ceramic laminate veneers. PMID- 22821431 TI - Cys-X-Cys ligand 9 might be an immunological factor in the pathogenesis of oral submucous fibrosis and its concomitant oral lichenoid lesion. AB - OBJECTIVES: Oral submucous fibrosis (OSF) is a chronic oral precancerous disease primarily caused by betel quid chewing. Some OSF patients are concomitant with oral lichenoid lesion (OLL), a white-streak lesion with a higher risk for cancerization, in OSF mucosa. Immunological reaction has been considered as one of their common pathogenic mechanisms. Cys-X-Cys ligand 9 (CXCL9) is an important factor to recruit effector neutrophils and lymphocytes in immunological reactions. However, the expression levels of CXCL9 in OSF and OLL remain unclear. MATERIALS AND METHODS: We investigated the expression levels of CXCL9 in 10 normal buccal mucosa (NBM) samples and 56 OSF concomitant with OLL patients, and evaluated the possible mechanism of CXCL9 on their pathogenesis. RESULTS: Our results showed NBM demonstrated negative CXCL9 expression. OSF stained positive CXCL9 mainly in the cytoplasm of inflammatory cells and endothelial cells throughout the superficial layer of connective tissue, while its concomitant OLL showed much stronger CXCL9 in all mononuclear cells of subepithelial inflammatory infiltration (p = 0.0006). There was an upregulated trend of CXCL9 expression from NBM to OSF to OLL. However, no significant association between CXCL9 expression and clinicopathologic parameters of patients was found. CONCLUSIONS: In conclusion, CXCL9 was found for the first time to contribute to the immunological pathogenesis for both OSF and its concomitant OLL, indicating a continuously enhanced intensity of immunoreactivity in their pathogenic process. CLINICAL RELEVANCE: CXCL9 might be a useful tool to monitor the phase and disease severity of OSF and OLL, and a potential target for further clinical therapy for both lesions. PMID- 22821428 TI - Association of levofloxacin resistance with mortality in adult patients with invasive pneumococcal diseases: a post hoc analysis of a prospective cohort. AB - OBJECTIVE: This study was conducted to identify risk factors for mortality and to evaluate the impact of antimicrobial resistance on outcome in adult patients with invasive pneumococcal disease (IPD). METHODS: A post hoc analysis of an observational cohort study on community-acquired pneumococcal infections was conducted and a total of 136 adult patients with IPD were analyzed in this study. RESULTS: Pneumonia was the most common type of infection (n = 84, 61.8 %), followed by primary bacteremia (n = 15, 11.0 %) and meningitis (n = 15, 11.0 %). One hundred and three patients (75.7 %) had concomitant pneumococcal bacteremia. The overall 30-day mortality rate was 26.5 % (36/136), and factors associated with 30-day mortality were corticosteroid use, presentation with septic shock, and development of acute respiratory distress syndrome (ARDS) (all P < 0.05). While penicillin and erythromycin resistance were associated with a lower mortality, an association between levofloxacin resistance and increased mortality was found in the univariate analysis; however, statistical significance was not reached (P = 0.083). Multivariable analysis showed that presentation with septic shock, corticosteroid use, development of ARDS, and levofloxacin resistance were independent factors associated with 30-day mortality. Of the five patients with IPD caused by levofloxacin-resistant Streptococcus pneumoniae, three (60 %) died within 30 days of diagnosis. CONCLUSION: Levofloxacin resistance was associated with increased mortality, along with septic shock, prior use of corticosteroids, and development of ARDS, in adult patients with IPD. Our data suggest that the emergence of levofloxacin resistance among invasive pneumococcal isolates is now becoming a challenge for clinicians managing community-acquired bacterial infections. PMID- 22821432 TI - In women with endometriosis anti-Mullerian hormone levels are decreased only in those with previous endometrioma surgery. AB - STUDY QUESTION: Are anti-Mullerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis? SUMMARY ANSWER: Endometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs. WHAT IS KNOWN ALREADY: The impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Operations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables. MAIN RESULTS AND THE ROLE OF CHANCE: The difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 +/- 3.1 versus 4.1 +/- 3.4 ng/ml, P = 0.06). Analysis of variance-covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30-34 years OR = 3.1, 95% CI: 1.5-6.4, P = 0.01; 35-39 years OR = 7.0, 95% CI: 3.5-14.1, P = 0.001; >=40 years OR = 20.8, 95% CI: 9.1-47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4 6.41, P = 0.01). LIMITATIONS, REASONS FOR CAUTION: The selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy. STUDY FUNDING/COMPETING INTERESTS: STUDY FUNDING: none. Potential competing interests: none. PMID- 22821433 TI - Effect of fixed orthodontic therapy on urinary nickel levels: a long-term retrospective cohort study. AB - Nickel constitutes about 8-60 % of orthodontic alloys. It is known as an allergenic/cytotoxic trace metal. Therefore, it should be investigated in patients undergoing orthodontic treatment which might last for 2 or 3 years. However, no controlled studies have assessed the influence of orthodontic treatments of longer than 5 months on its systemic levels. Thus, the aim of this retrospective cohort study was to evaluate systemic nickel in patients undergoing orthodontic therapy for a minimum period of 1 year. In this study, urinary nickel concentrations in 20 female and 10 male patients being treated with stainless steel appliances were measured using atomic absorption spectrophotometry. The same procedure was done on a control group of the patients' same-gender near-age siblings (n = 30). The effect of treatment and gender on urinary nickel levels were assessed using a repeated-measures two-way analysis of variance (ANOVA) and a Tukey test (alpha = 0.05). The mean treatment duration was 17.1 +/- 6.4 months (range, 12-21). The mean nickel concentrations in male and female patients were 9.67 +/- 3.25 and 9.9 +/- 3.83 MUg/L, respectively. These statistics for male and female control subjects were 6.65 +/- 2.57 and 8.43 +/- 2.94 MUg/L, respectively. The ANOVA showed a statistically significant difference between the urinary nickel levels of the treatment and the control groups (P = 0.009) but not between the genders (P = 0.194). The interaction between gender and treatment was also nonsignificant (P = 0.337). The Tukey test indicated that the increase in nickel was higher in male patients, in comparison to their brothers (P < 0.05). It could be concluded that orthodontic therapy for longer durations with stainless-steel archwires might elevate slightly, but significantly, urinary nickel levels. PMID- 22821434 TI - Current tobacco and water-pipe smoking enhance human cancer invasion and metastasis. PMID- 22821435 TI - Improvement in antioxidant activity, angiotensin-converting enzyme inhibitory activity and in vitro cellular properties of fermented pepino milk by Lactobacillus strains containing the glutamate decarboxylase gene. AB - BACKGROUND: The purpose of this study was to evaluate the functional potential of fermented pepino extract (PE) milk by Lactobacillus strains containing the glutamate decarboxylase (GAD) gene. Three Lactobacillus strains were selected, including L. brevis BCRC 12310, L. casei BCRC 14082 and L. salivarius subsp. salivarius BCRC 14759. The contents of free amino acids, total phenolics content, total carotenoids and the associated functional and antioxidant abilities were analyzed, including angiotensin-converting enzyme (ACE) inhibition activity, 1,1 diphenyl-2-picylhydrazyl (DPPH) radical-scavenging ability and oxygen radical absorbance capacity (ORAC). Cell proliferation of fermented PE milk was also evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS: Compared to the unfermented PE, fermented PE milk from Lactobacillus strains with the GAD gene showed higher levels of total phenolics, gamma-aminobutyric acid, ACE inhibitory activity, DPPH, and ORAC. The viability of human promyelocytic leukemia cells (HL-60) determined by the MTT method decreased significantly when the cells were incubated with the PE and the fermented PE milk extracts. CONCLUSION: The consumption of fermented PE milk from Lactobacillus strains with the GAD gene is expected to benefit health. Further application as a health food is worthy of investigation. (c) 2012 Society of Chemical Industry. PMID- 22821436 TI - CAP, a new human suspension cell line for influenza virus production. AB - Forced by major drawbacks of egg-based influenza virus production, several studies focused on the establishment and optimization of cell-based production systems. Among numerous possible host cell lines from duck, monkey, canine, chicken, mouse, and human origin, only a few will meet regulatory requirements, accomplish industrial standards, and result in high virus titers. From primary virus isolation up to large-scale manufacturing of human vaccines, however, the most logical choice seems to be the use of human cell lines. For this reason, we evaluated the recently established CAP cell line derived from human amniocytes for its potential in influenza virus production in suspension culture in small scale shaker flask and stirred tank bioreactor experiments. Different human and animal influenza viruses could be adapted to produce hemagglutination (HA) titers of at least 2.0 log(10) HA units/100 MUL without further process optimization. Adjusting trypsin activity as well as infection conditions (multiplicity of infection, infection medium) resulted in HA titers of up to 3.2 log(10) HA units/100 MUL and maximum cell-specific virus productivities of 6,400 virions/cell (for human influenza A/PR/8/34 as a reference). Surface membrane expression of sialyloligosaccharides as well as HA N-glycosylation patterns were characterized. Overall, experimental results clearly demonstrate the potential of CAP cells for achieving high virus yields for different influenza strains and the option to introduce a highly attractive fully characterized human cell line compliant with regulatory and industrial requirements as an alternative for influenza virus vaccine production. PMID- 22821437 TI - Constitutive high-level expression of a codon-optimized beta-fructosidase gene from the hyperthermophile Thermotoga maritima in Pichia pastoris. AB - Enzymes for use in the sugar industry are preferred to be thermotolerant. In this study, a synthetic codon-optimized gene encoding a highly thermostable beta fructosidase (BfrA, EC 3.2.1.26) from the bacterium Thermotoga maritima was expressed in the yeast Pichia pastoris. The gradual increase of the transgene dosage from one to four copies under the control of the constitutive glyceraldehyde 3-phosphate dehydrogenase promoter had an additive effect on BfrA yield without causing cell toxicity. Maximal values of cell biomass (115 g/l, dry weight) and overall invertase activity (241 U/ml) were reached at 72 h in fed batch fermentations using cane sugar as the main carbon source for growth. Secretion driven by the Saccharomyces cerevisiae alpha-factor signal peptide resulted in periplasmic retention (44 %) and extracellular release (56 %) of BfrA. The presence of N-linked oligosaccharides did not influence the optimal activity, thermal stability, kinetic properties, substrate specificity, and exo type action mode of the yeast-secreted BfrA in comparison to the native unglycosylated enzyme. Complete inversion of cane sugar at initial concentration of 60 % (w/v) was achieved by periplasmic BfrA in undisrupted cells reacting at pH 5.5 and 70 degrees C, with average productivity of 4.4 g of substrate hydrolyzed per grams of biomass (wet weight) per hour. The high yield of fully active glycosylated BfrA here attained by recombinant P. pastoris in a low-cost fermentation process appears to be attractive for the large-scale production of this thermostable enzyme useful for the manufacture of inverted sugar syrup. PMID- 22821438 TI - Induction of hexanol dehydrogenase in Geotrichum spp. by the addition of hexanol. AB - Excessive hexanol content distorts the flavor of foods and is harmful to human health. Previously, two strains of fungi were found capable of producing hexanol degrading enzymes. The current study identified these strains as Galactomyces geotrichum according to the gene sequence of the 26 S rDNA D1/D2 region (strain S12) and genus Geotrichum according to the gene sequence of ITS region (strain S13). Parallel analysis of extracellular and intracellular enzyme activities showed that the enzymes mainly accumulated intracellularly. Native polyacrylamide gel electrophoresis with reactive dyes showed the enzymes were alcohol dehydrogenases induced by the addition of hexanol. Hexanol was catalyzed into hexanoic acid and hexanal by strain S12 and into hexanoic acid by strain S13. The optimum conditions for the induction of enzymes were determined to be 6-9 h in the presence of 0.7 g/l hexanol. The identification of two strains capable of enzymatically degrading hexanol and optimum conditions for their induction will facilitate their use in industrial applications. PMID- 22821439 TI - Combining in the melt physical and biological properties of poly(caprolactone) and chlorhexidine to obtain antimicrobial surgical monofilaments. AB - Bacterial infections on a sutured wound represent a critical problem, and the preparation of suture threads possessing antimicrobial properties is valuable. In this work, poly(caprolactone) (PCL) monofilaments were compounded at the concentration of 1, 2 and 4 % (w/w), respectively, to the antiseptic chlorhexidine diacetate (CHX). The incorporation was carried out in the melt by a single-step methodology, i.e. "online" approach. Mechanical tests revealed that the incorporation of CHX does not significantly change tensile properties of PCL fibres as the thermal profile adopted to prepare the compounded fibres does not compromise the antibacterial activity of CHX. In fact, CHX confers to compounded PCL fibres' antimicrobial property even at the lowest CHX concentration as revealed by microbiological assays performed on Escherichia coli, Micrococcus luteus and Bacillus subtilis strains. The scanning electron microscope micrographs and energy-dispersive X-ray analysis of compounded threads revealed that CHX is uniformly distributed on fibre surface and that the overall amount of superficial CHX increases by increasing compounded CHX concentration. This distribution determines a biphasic CHX release kinetics characterized by an initial rapid solubilisation of superficial CHX micro-crystals, followed by a slow and gradual release of CHX incorporated in the bulk. Interestingly, the compounded threads did not show any toxic effect compromising cell viability of human fibroblasts in vitro, differently from that observed using an equal amount of pure CHX. Thus, this study originally demonstrated the effectiveness of an "online" approach to confer antimicrobial properties to an organic thermoplastic polymeric material commonly used for medical devices. PMID- 22821440 TI - Production of xylanase by an alkaline-tolerant marine-derived Streptomyces viridochromogenes strain and improvement by ribosome engineering. AB - Xylanase is the enzyme complex that is responsible for the degradation of xylan; however, novel xylanase producers remain to be explored in marine environment. In this study, a Streptomyces strain M11 which exhibited xylanase activity was isolated from marine sediment. The 16S rDNA sequence of M11 showed the highest identity (99 %) to that of Streptomyces viridochromogenes. The xylanase produced from M11 exhibited optimum activity at pH 6.0, and the optimum temperature was 70 degrees C. M11 xylanase activity was stable in the pH range of 6.0-9.0 and at 60 degrees C for 60 min. Xylanase activity was observed to be stable in the presence of up to 5 M NaCl. Antibiotic-resistant mutants of M11 were isolated, and among the various antibiotics tested, streptomycin showed the best effect on obtaining xylanase overproducer. Mutant M11-1(10) isolated from 10 MUg/ml streptomycin-containing plate showed 14 % higher xylanase activities than that of the wild-type strain. An analysis of gene rpsL (encoding ribosomal protein S12) showed that rpsL from M11-1(10) contains a K88R mutation. This is the first report to show that marine-derived S. viridochromogenes strain can be used as a xylanase producer, and utilization of ribosome engineering for the improvement of xylanase production in Streptomyces was also first successfully demonstrated. PMID- 22821441 TI - Persistent astroglial swelling accompanies rapid reversible dendritic injury during stroke-induced spreading depolarizations. AB - Spreading depolarizations are a key event in the pathophysiology of stroke, resulting in rapid dendritic beading, which represents acute damage to synaptic circuitry. The impact of spreading depolarizations on the real-time injury of astrocytes during ischemia is less clear. We used simultaneous in vivo 2-photon imaging and electrophysiological recordings in adult mouse somatosensory cortex to examine spreading depolarization-induced astroglial structural changes concurrently with signs of neuronal injury in the early periods of focal and global ischemia. Astrocytes in the metabolically compromised ischemic penumbra like area showed a long lasting swelling response to spontaneous spreading depolarizations despite rapid dendritic recovery in a photothrombotic occlusion model of focal stroke. Astroglial swelling was often facilitated by recurrent depolarizations and the magnitude of swelling strongly correlated with the total duration of depolarization. In contrast, spreading depolarization-induced astroglial swelling was transient in normoxic healthy tissue. In a model of transient global ischemia, the occurrence of a single spreading depolarization elicited by a bilateral common carotid artery occlusion coincided with astroglial swelling alongside dendritic beading. With immediate reperfusion, dendritic beading subsides. Astroglial swelling was either transient during short ischemic periods distinguished by a short-lasting spreading depolarization, or persistent during severe ischemia characterized by a long-lasting depolarization with the ultraslow negative voltage component. We propose that persistent astroglial swelling is initiated and exacerbated during spreading depolarization in brain tissue with moderate to severe energy deficits, disrupting astroglial maintenance of normal homeostatic function thus contributing to the negative outcome of ischemic stroke as astrocytes fail to provide neuronal support. PMID- 22821442 TI - Infliximab for Behcet disease with aortic involvement: two novel case reports without concurrent use of immunosuppressive agents or corticosteroids. PMID- 22821443 TI - Psychometric development of the Iceland-Family Perceived Support Questionnaire (ICE-FPSQ). AB - Valid and reliable instruments are needed to measure how family members perceive support from nurses when a family member is experiencing serious illness. The purpose of this article is to describe the development and psychometric testing of a new instrument, the Iceland-Family Perceived Support Questionnaire (ICE FPSQ). The concepts in the original version of the ICE-FPSQ (suggesting 24 items and 4 categories) were developed from the Calgary Family Intervention Model. In the first phase of the instrument construction, 179 family members answered the original ICE-FPSQ, and 236 answered the questionnaire in the second phase of testing. Principal Component Analysis (PCA) reduced the original questionnaire to 21 items. Cronbach's alpha = .959 explained 68% of the total variance, with three factors emerging: (a) emotional support (alpha = .925), (b) recognition of families' strengths (alpha = .926), and (c) cognitive support (alpha = .841). Confirmatory Factor Analyses (CFA) resulted in a final version of the questionnaire containing 14 items with total alpha of .961 and two factors: (a) cognitive support (alpha = .881) and (b) emotional support (alpha = .952). The instrument measures family's perceptions of support provided by nurses and will be helpful in examining the usefulness of family nursing interventions. PMID- 22821445 TI - Promoting consultation recording practice in oncology: identification of critical implementation factors and determination of patient benefit. AB - OBJECTIVE: The objectives of this implementation study were to (i) address the evidentiary, contextual, and facilitative mechanisms that serve to retard or promote the transfer and uptake of consultation recording use in oncology practice and (ii) follow patients during the first few days following receipt of the consultation recording to document, from the patient's perspective, the benefits realized from listening to the recording. METHODS: Nine medical and nine radiation oncologists from cancer centers in three Canadian cities (Calgary, Vancouver, and Winnipeg) recorded their primary consultations for 228 patients newly diagnosed with breast (n = 174) or prostate cancer (n = 54). The Digital Recording Use Semi-Structured Interview was conducted at 2 days and 1 week postconsultation. Each oncologist was provided a feedback letter summarizing the consultation recording benefits reported by their patients. RESULTS: Sixty-nine percent of patients listened to at least a portion of the recording within the first week following the consultation. Consultation recording favorableness ratings were high: 93.6% rated the intervention between 75 and 100 on a 100-point scale. Four main areas of benefit were reported: (i) anxiety reduction; (ii) enhanced retention of information; (iii) better informed decision making; and (iv) improved communication with family members. Eight fundamental components of successful implementation of consultation recording practice were identified. CONCLUSIONS: Further randomized trials are recommended, using standardized measures of the patient-reported benefit outcomes reported herein, to strengthen the evidence base for consultation recording use in oncology practice. PMID- 22821446 TI - Effects of environmental lead contamination on cattle in a lead/zinc mining area: changes in cattle immune systems on exposure to lead in vivo and in vitro. AB - The Republic of Zambia is rich in mineral resources, such as zinc (Zn) and lead (Pb), and mining is a key industry in Zambia. A previous study of Pb pollution in Kabwe, one of the main mining areas, found that soil was contaminated with high levels of toxic metals over a substantial area. In the present study, the authors focus on toxic metal pollution in cattle, one of the most important domestic animals in Zambia. Blood samples from cattle in Kabwe and a control area (Lusaka) were tested for toxic metal content. They also measured mRNA expression of metal responsive proteins and cytokines in white blood cells using real-time reverse transcriptase polymerase chain reaction. In the present in vitro study, The authors cultured peripheral blood mononuclear cells (PBMCs) from cattle, exposing them to Pb acetate for 24 h and analyzing mRNA expression of metal-responsive proteins and selected cytokines. Lead concentrations in cattle blood from Kabwe were significantly greater than those from Lusaka, as were the mRNA expressions of metallothionein-2 (MT-2), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-6, and inducible nitric oxide synthase (iNOS). The present in vitro study demonstrated that Pb exposure led to an increase in the expressions of MT-2, TNF-alpha, IL-1beta, and iNOS, similar to those found in vivo. These results indicate the possibility of immune system modulations in cattle from the Kabwe area. PMID- 22821447 TI - Analytical and experimental position stability of the abutment in different dental implant systems with a conical implant-abutment connection. AB - OBJECTIVES: Position stability of the abutment should be investigated in four implant systems with a conical implant-abutment connection. MATERIALS AND METHODS: Previously developed formulas and an established experimental setup were used to determine the position stability of the abutment in the four implant systems with a conical implant-abutment connection and different positional index designs: The theoretical rotational freedom was calculated by using the dimensions of one randomly selected implant per system for approximated geometric models. Experimentally, the rotation, the vertical displacement, and canting moments of the abutment after multiple repositioning and hand tightening of the abutment screw were investigated. RESULTS: The experimental rotation and vertical displacement differed between the implant systems tested. The analytical and experimental results for the rotation of the abutment clearly deviated in the three implant systems. CONCLUSIONS: Malpositioning of the abutment was possible in all the implant systems tested. Deviating theoretical and experimental results suggest high manufacturing tolerances during fabrication of the implant components. CLINICAL RELEVANCE: Position stability of the abutment is essential for precisely fitting implant-supported superstructures. PMID- 22821448 TI - Maternal over-control moderates the association between early childhood behavioral inhibition and adolescent social anxiety symptoms. AB - Behavioral inhibition (BI) and maternal over-control are early risk factors for later childhood internalizing problems, particularly social anxiety disorder (SAD). Consistently high BI across childhood appears to confer risk for the onset of SAD by adolescence. However, no prior studies have prospectively examined observed maternal over-control as a risk factor for adolescent social anxiety (SA) among children initially selected for BI. The present prospective longitudinal study examines the direct and indirect relations between these early risk factors and adolescent SA symptoms and SAD, using a multi-method approach. The sample consisted of 176 participants initially recruited as infants and assessed for temperamental reactivity to novel stimuli at age 4 months. BI was measured via observations and parent-report across multiple assessments between the ages of 14 months and 7 years. Maternal over-control was assessed observationally during parent-child interaction tasks at 7 years. Adolescents (ages 14-17 years) and parents provided independent reports of adolescent SA symptoms. Results indicated that higher maternal over-control at 7 years predicted higher SA symptoms and lifetime rates of SAD during adolescence. Additionally, there was a significant interaction between consistently high BI and maternal over-control, such that patterns of consistently high BI predicted higher adolescent SA symptoms in the presence of high maternal over-control. High BI across childhood was not significantly associated with adolescent SA symptoms when children experienced low maternal over-control. These findings have the potential to inform prevention and early intervention programs by identifying particularly at-risk youth and specific targets of treatment. PMID- 22821449 TI - Mother-stranger comparisons of social attention in jealousy context and attachment in HFASD and typical preschoolers. AB - Affective bonding, social attention, and intersubjective capabilities are all conditions for jealousy, and are deficient in autism. Thus, examining jealousy and attachment may elucidate the socioemotional deficit in autism spectrum disorders (ASD). Jealousy was provoked in 30 high-functioning children with ASD (HFASD) and 30 typical children (ages 3-6 years) through two triadic social (storybook-reading) scenarios - mother-child-rival and stranger-child-rival. A control nonsocial scenario included mother/stranger-book. For both groups, higher jealousy expressions emerged for mother than stranger, and for social than nonsocial scenarios. Attachment security (using Attachment Q-Set) was lower for HFASD than typical groups, but attachment correlated negatively with jealous verbalizations for both groups and with jealous eye gazes for HFASD. Implications for understanding jealousy's developmental complexity and the socioemotional deficit in ASD are discussed. PMID- 22821450 TI - Bidirectional relations between parenting practices and child externalizing behavior: a cross-lagged panel analysis in the context of a psychosocial treatment and 3-year follow-up. AB - In the current study, we examined longitudinal changes in, and bidirectional effects between, parenting practices and child behavior problems in the context of a psychosocial treatment and 3-year follow-up period. The sample comprised 139 parent-child dyads (child ages 6-11) who participated in a modular treatment protocol for early-onset ODD or CD. Parenting practices and child behavior problems were assessed at six time-points using multiple measures and multiple reporters. The data were analyzed using cross-lagged panel analyses. Results indicated robust temporal stabilities of parenting practices and child behavior problems, in the context of treatment-related improvements, but bidirectional effects between parenting practices and child behavior were less frequently detected. Our findings suggest that bidirectional effects are relatively smaller than the temporal stability of each construct for school-age children with ODD/CD and their parents, following a multi-modal clinical intervention that is directed at both parents and children. Implications for treatment and intervention are discussed. PMID- 22821451 TI - Evolutionary systems biology: historical and philosophical perspectives on an emerging synthesis. AB - Systems biology (SB) is at least a decade old now and maturing rapidly. A more recent field, evolutionary systems biology (ESB), is in the process of further developing system-level approaches through the expansion of their explanatory and potentially predictive scope. This chapter will outline the varieties of ESB existing today by tracing the diverse roots and fusions that make up this integrative project. My approach is philosophical and historical. As well as examining the recent origins of ESB, I will reflect on its central features and the different clusters of research it comprises. In its broadest interpretation, ESB consists of five overlapping approaches: comparative and correlational ESB; network architecture ESB; network property ESB; population genetics ESB; and finally, standard evolutionary questions answered with SB methods. After outlining each approach with examples, I will examine some strong general claims about ESB, particularly that it can be viewed as the next step toward a fuller modern synthesis of evolutionary biology (EB), and that it is also the way forward for evolutionary and systems medicine. I will conclude with a discussion of whether the emerging field of ESB has the capacity to combine an even broader scope of research aims and efforts than it presently does. PMID- 22821452 TI - Metabolic networks and their evolution. AB - Since the last decade of the twentieth century, systems biology has gained the ability to study the structure and function of genome-scale metabolic networks. These are systems of hundreds to thousands of chemical reactions that sustain life. Most of these reactions are catalyzed by enzymes which are encoded by genes. A metabolic network extracts chemical elements and energy from the environment, and converts them into forms that the organism can use. The function of a whole metabolic network constrains evolutionary changes in its parts. I will discuss here three classes of such changes, and how they are constrained by the function of the whole. These are the accumulation of amino acid changes in enzyme coding genes, duplication of enzyme-coding genes, and changes in the regulation of enzymes. Conversely, evolutionary change in network parts can alter the function of the whole network. I will discuss here two such changes, namely the elimination of reactions from a metabolic network through loss of function mutations in enzyme-coding genes, and the addition of metabolic reactions, for example through mechanisms such as horizontal gene transfer. Reaction addition also provides a window into the evolution of metabolic innovations, the ability of a metabolism to sustain life on new sources of energy and of chemical elements. PMID- 22821453 TI - Organization principles in genetic interaction networks. AB - Understanding how genetic modifications, individual or in combinations, affect phenotypes is a challenge common to several areas of biology, including human genetics, metabolic engineering, and evolutionary biology. Much of the complexity of how genetic modifications produce phenotypic outcomes has to do with the lack of independence, or epistasis, between different perturbations: the phenotypic effect of one perturbation depends, in general, on the genetic background of previously accumulated modifications, i.e., on the network of interactions with other perturbations. In recent years, an increasing number of high-throughput efforts, both experimental and computational, have focused on trying to unravel these genetic interaction networks. Here we provide an overview of how systems biology approaches have contributed to, and benefited from, the study of genetic interaction networks. We focus, in particular, on results pertaining to the global multilevel properties of these networks, and the connection between their modular architecture and their functional and evolutionary significance. PMID- 22821454 TI - Evolution of regulatory networks: nematode vulva induction as an example of developmental systems drift. AB - Changes in the developmental processes and developmental mechanisms can result in the modification of morphological structures and in the evolution of phenotypic novelty. But how do developmental processes evolve? One striking finding in modern biology is the confrontation of morphological diversity in multicellular organisms with the conserved blueprint of life-the small number of conserved signaling pathways and transcriptional regulators. Evolutionary developmental biology (evo-devo) tries to explain this discrepancy between macroscopic diversity and molecular uniformity. Selected case studies in evo-devo models allowed detailed insight into the mechanisms of evolutionary changes and might help solving this problem. Here, I compare the formation of vulva development between Caenorhabditis elegans and the evo-devo model Pristionchus pacificus. More than 3 decades of work in C. elegans and 15 years in P. pacificus provide an insight into the molecular mechanisms of developmental change during vulva evolution. C. elegans and P. pacificus differ first, in the type of the signaling system used for vulva induction; second, the cells required for the inductive interactions; third, the logic of the signal system, and finally, the sequence and structure of peptide domains in otherwise conserved proteins. Nonetheless, the vulva is formed from the same three cells in both nematodes. I discuss redundancy as an evolutionary mechanism to explain developmental systems drift, a theory predicting conserved morphological structures to be generated by diverse molecular regulatory networks. PMID- 22821455 TI - Life's attractors : understanding developmental systems through reverse engineering and in silico evolution. AB - We propose an approach to evolutionary systems biology which is based on reverse engineering of gene regulatory networks and in silico evolutionary simulations. We infer regulatory parameters for gene networks by fitting computational models to quantitative expression data. This allows us to characterize the regulatory structure and dynamical repertoire of evolving gene regulatory networks with a reasonable amount of experimental and computational effort. We use the resulting network models to identify those regulatory interactions that are conserved, and those that have diverged between different species. Moreover, we use the models obtained by data fitting as starting points for simulations of evolutionary transitions between species. These simulations enable us to investigate whether such transitions are random, or whether they show stereotypical series of regulatory changes which depend on the structure and dynamical repertoire of an evolving network. Finally, we present a case study-the gap gene network in dipterans (flies, midges, and mosquitoes)-to illustrate the practical application of the proposed methodology, and to highlight the kind of biological insights that can be gained by this approach. PMID- 22821456 TI - Evolutionary characteristics of bacterial two-component systems. AB - The evolution of biological systems is influenced by a number of factors and forces that have acted in different combinations at different times to give rise to extant organisms. Here we illustrate some of the issues surrounding the data driven evolutionary analysis of biological systems in the context of bacterial two-component systems (TCSs). TCSs are critical for bacteria to interact with their extracellular environment. A typical TCS consists of a histidine kinase on the membrane and a response regulator in the cytoplasm. Here we comprehensively characterise the extent to which these appear together across some 950 bacterial species and test for statistically significant patterns of correlated gain and loss. Our analysis provides evidence for correlated evolution but also a high level of evolutionary flexibility: at the sequence level, histidine kinases but especially response regulators belonging to different TCSs in a species show high levels of similarity, which may facilitate crosstalk as well as the recruitment of components into new compound signalling systems. We furthermore find that bacterial lifestyle has an overriding influence on the presence and absence of TCS; while in most TCSs either both or none of the two components are present, several TCSs tend to lose preferentially either the histidine kinase or response regulator component, which further supports the notion of reuse and reshuffling of these components in different TCS arrangements. We conclude by placing these findings in a wider context and discuss the implications for evolutionary systems biology more generally. PMID- 22821458 TI - Evolution in silico: from network structure to bifurcation theory. AB - I describe an evolutionary procedure in silico that creates small gene networks performing basic tasks. I use it to evolve a wide range of models for very different biological functions: multistability, adaptive networks and entire developmental programmes like somitogenesis and Hox gene pattern. In silico evolution finds both known and original network designs, and can be used to make predictions on biological behaviours. This computation illustrates how complex traits can evolve in an incremental way, and suggests that dynamical systems theory could be used to get new insights towards a predictive evolutionary theory. PMID- 22821459 TI - On the search for design principles in biological systems. AB - The search for basic concepts and underlying principles was at the core of the systems approach to science and technology. This approach was somehow abandoned in mainstream biology after its initial proposal, due to the rise and success of molecular biology. This situation has changed. The accumulated knowledge of decades of molecular studies in combination with new technological advances, while further highlighting the intricacies of natural systems, is also bringing back the quest-for-principles research program. Here, I present two lessons that I derived from my own quest: the importance of studying biological information processing to identify common principles in seemingly unrelated contexts and the adequacy of using known design principles at one level of biological organization as a valuable tool to help recognizing principles at an alternative one. These and additional lessons should contribute to the ultimate goal of establishing principles able to integrate the many scales of biological complexity. PMID- 22821457 TI - Comparative interaction networks: bridging genotype to phenotype. AB - Over the past decade, biomedical research has witnessed an exponential increase in the throughput of the characterization of biological systems. Here we review the recent progress in large-scale methods to determine protein-protein, genetic and chemical-genetic interaction networks. We discuss some of the limitations and advantages of the different methods and give examples of how these networks are being used to study the evolutionary process. Comparative studies have revealed that different types of protein-protein interactions diverge at different rates with high conservation of co-complex membership but rapid divergence of more promiscuous interactions like those that mediate post-translational modifications. These evolutionary trends have consistent genetic consequences with highly conserved epistatic interactions within complex subunits but faster divergence of epistatic interactions across complexes or pathways. Finally, we discuss how these evolutionary observations are being used to interpret cross species chemical-genetic studies and how they might shape therapeutic strategies. Together, these interaction networks offer us an unprecedented level of detail into how genotypes are translated to phenotypes, and we envision that they will be increasingly useful in the interpretation of genetic and phenotypic variation occurring within populations as well as the rational design of combinatorial therapeutics. PMID- 22821460 TI - Toward a theory of multilevel evolution: long-term information integration shapes the mutational landscape and enhances evolvability. AB - Most of evolutionary theory has abstracted away from how information is coded in the genome and how this information is transformed into traits on which selection takes place. While in the earliest stages of biological evolution, in the RNA world, the mapping from the genotype into function was largely predefined by the physical-chemical properties of the evolving entities (RNA replicators, e.g. from sequence to folded structure and catalytic sites), in present-day organisms, the mapping itself is the result of evolution. I will review results of several in silico evolutionary studies which examine the consequences of evolving the genetic coding, and the ways this information is transformed, while adapting to prevailing environments. Such multilevel evolution leads to long-term information integration. Through genome, network, and dynamical structuring, the occurrence and/or effect of random mutations becomes nonrandom, and facilitates rapid adaptation. This is what does happen in the in silico experiments. Is it also what did happen in biological evolution? I will discuss some data that suggest that it did. In any case, these results provide us with novel search images to tackle the wealth of biological data. PMID- 22821461 TI - Evolutionary principles underlying structure and response dynamics of cellular networks. AB - The network view in systems biology, in conjunction with the continuing development of experimental technologies, is providing us with the key structural and dynamical features of both cell-wide and pathway-level regulatory, signaling and metabolic systems. These include for example modularity and presence of hub proteins at the structural level and ultrasensitivity and feedback control at the level of dynamics. The uncovering of such features, and the seeming commonality of some of them, makes many systems biologists believe that these could represent design principles that underpin cellular systems across organisms. Here, we argue that such claims on any observed feature requires an understanding of how it has emerged in evolution and how it can shape subsequent evolution. We review recent and past studies that aim to achieve such evolutionary understanding for observed features of cellular networks. We argue that this evolutionary framework could lead to deciphering evolutionary origin and relevance of proposed design principles, thereby allowing to predict their presence or absence in an organism based on its environment and biochemistry and their effect on its future evolution. PMID- 22821462 TI - Phenotypic plasticity and robustness: evolutionary stability theory, gene expression dynamics model, and laboratory experiments. AB - Plasticity and robustness, which are two basic concepts in the evolution of developmental dynamics, are characterized in terms of the variance of phenotype distribution. Plasticity concerns the response of a phenotype against environmental and genetic changes, whereas robustness is the degree of insensitivity against such changes. Note that the sensitivity increases with the variance, and the inverse of the variance works as a measure of the robustness. First, it is found that the response ratio is proportional to the phenotype variance, as described by extending the fluctuation-response relationship in statistical physics. Next, it is shown that through the course of robust evolution, the phenotype variance caused by genetic change decreases in proportion to that by noise during the developmental process. This evolution, resulting in increased robustness, is achieved only when the noise in the developmental process is sufficiently large; in other words, robustness to noise leads to robustness to mutation. For a system that achieves robustness in the phenotype, it is also found that the proportionality between the two variances also holds across different phenotypic traits. These general relationships for plasticity and robustness in terms of fluctuations are demonstrated using macroscopic phenomenological theory, simulations of gene-expression dynamics models with regulation networks, and laboratory selection experiments. It is also shown that an optimal noise level compatibility between robustness and plasticity is achieved to cope with a fluctuating environment. PMID- 22821463 TI - Genetic redundancies and their evolutionary maintenance. AB - Genetic redundancy refers to the common phenomenon that deleting or mutating a gene from a genome has minimal or no impact on the phenotype or fitness of the organism because of functional compensation conferred by one or more other genes. Here I summarize studies of functional redundancies between duplicate genes and those among metabolic reactions that respectively represent genetic redundancies at the individual gene level and at the systems level. I discuss the prevalence of genetic redundancies in a genome, evolutionary origins of these redundancies, and mechanisms responsible for their stable maintenance. I show that genetic redundancies are highly abundant. While some of them may be evolutionarily transient, many are stable. The majority of the stable redundancies are likely to have been selectively kept, not because of their potential benefits in regard to future deleterious mutations, but because of their actual benefits at present or in the recent past. The rest are probably preserved by selection on nonredundant pleiotropic functions. The studies summarized here illustrate the utility of systems analysis for understanding evolutionary phenomena and the importance of evolutionary thinking in uncovering the functions and origins of systemic properties. PMID- 22821464 TI - Evolution of resource and energy management in biologically realistic gene regulatory network models. AB - We describe the use of computational models of evolution of artificial gene regulatory networks to understand the topologies of biological gene regulatory networks. We summarize results from three complementary approaches that explicitly represent biological processes of transcription, translation, metabolism and gene regulation: a fine-grained model that allows detailed molecular interactions, a coarse-grained model that allows rapid evolution of many generations, and a fixed-architecture model that allows for comparison of different hypotheses. In the first two cases, we are able to evolve networks towards the biological fitness objectives of survival and reproduction. A theme that emerges is that the control of cell energy and resources is a major driver of gene network topology and function. This is demonstrated in the fine-grained model with the emergence of biologically realistic mRNA and protein turnover rates that optimize energy usage and cell division time, and the evolution of basic repressor activities; in the fixed architecture model with a negative self regulating gene evolving major efficiencies in mRNA usage; and in the coarse grained model by the need for the inclusion of basal gene expression to obtain biologically plausible networks and the emergence of global regulators keeping all cellular systems under negative control. In summary, we demonstrate the value of biologically realistic computer evolution techniques, and the importance of energy and resource management in driving the topology and function of gene regulatory networks. PMID- 22821465 TI - Reverse Ecology: from systems to environments and back. AB - The structure of complex biological systems reflects not only their function but also the environments in which they evolved and are adapted to. Reverse Ecology an emerging new frontier in Evolutionary Systems Biology-aims to extract this information and to obtain novel insights into an organism's ecology. The Reverse Ecology framework facilitates the translation of high-throughput genomic data into large-scale ecological data, and has the potential to transform ecology into a high-throughput field. In this chapter, we describe some of the pioneering work in Reverse Ecology, demonstrating how system-level analysis of complex biological networks can be used to predict the natural habitats of poorly characterized microbial species, their interactions with other species, and universal patterns governing the adaptation of organisms to their environments. We further present several studies that applied Reverse Ecology to elucidate various aspects of microbial ecology, and lay out exciting future directions and potential future applications in biotechnology, biomedicine, and ecological engineering. PMID- 22821466 TI - Bacteria-virus coevolution. AB - Phages, viruses of bacteria, are ubiquitous. Many phages require host cell death to successfully complete their life cycle, resulting in reciprocal evolution of bacterial resistance and phage infectivity (antagonistic coevolution). Such coevolution can have profound consequences at all levels of biological organisation. Here, we review genetic and ecological factors that contribute to determining coevolutionary dynamics between bacteria and phages. We also consider some of the consequences of bacteria-phage coevolution, such as determining rates of molecular evolution and structuring communities, and how these in turn feedback into driving coevolutionary dynamics. PMID- 22821467 TI - The genotype-phenotype maps of systems biology and quantitative genetics: distinct and complementary. AB - The processes by which genetic variation in complex traits is generated and maintained in populations has for a long time been treated in abstract and statistical terms. As a consequence, quantitative genetics has provided limited insights into our understanding of the molecular bases of quantitative trait variation. With the developing technological and conceptual tools of systems biology, cellular and molecular processes are being described in greater detail. While we have a good description of how signaling and other molecular networks are organized in the cell, we still do not know how genetic variation affects these pathways, because systems and molecular biology usually ignore the type and extent of genetic variation found in natural populations. Here we discuss the quantitative genetics and systems biology approaches for the study of complex trait architecture and discuss why these two disciplines would synergize with each other to answer questions that neither of the two could answer alone. PMID- 22821468 TI - How evolutionary systems biology will help understand adaptive landscapes and distributions of mutational effects. AB - Population genetics and ecology have been modeling biological systems quantitatively for over 8 decades and their results have contributed greatly to our understanding of the natural world and its evolution. Theories in these areas necessarily had to focus on comparisons of the contribution of different individuals to changes in the bigger picture at the expense of ignoring much of the complexity that exists inside individuals. Current systems biology provides new insights into this complexity within organisms. Here I review developments in evolutionary systems biology that have the potential to lead to a more unified approach that integrates contributions from current systems biology and population genetics. Central integrative concepts in this approach are the adaptive landscape and distributions of mutational effects. Both capture our understanding of the fitness of individuals and how it can change. Fitness is frequently used in population genetics to summarize key properties of individuals. Such properties emerge from the complexity of molecular processes within individuals, often in interaction with the environment. The general principles of this approach are reviewed here. This work can open up new avenues for computing critical quantities for models of long-term evolution, including epistasis, the distribution of deleterious mutational effects, and the frequency of adaptive mutations. PMID- 22821469 TI - Building synthetic systems to learn nature's design principles. AB - Evolution undoubtedly shapes the architecture of biological systems, yet it is unclear which features of regulatory, metabolic, and signalling circuits have adaptive significance and how the architecture of these circuits constrains or promotes evolutionary processes, such as adaptation to new environments. Experimentally rewiring circuits using genetic engineering and constructing novel circuits in living cells allows direct testing and validation of hypotheses in evolutionary systems biology. Building synthetic genetic systems enables researchers to explore regions of the genotype-phenotype and fitness landscapes that may be inaccessible to more traditional analysis. Here, we review the strategies that allow synthetic systems to be constructed and how evolutionary design principles have advanced these technologies. We also describe how building small genetic regulatory systems can provide insight on the trade-offs that constrain adaptation and can shape the structure of biological networks. In the future, the possibility of building biology de novo at the genome scale means that increasingly sophisticated models of the evolutionary dynamics of networks can be proposed and validated, and will allow us to recreate ancestral systems in the lab. This interplay between evolutionary systems theory and engineering design may illuminate the fundamental limits of performance, robustness, and evolvability of living systems. PMID- 22821470 TI - The robustness continuum. AB - Organisms are subject to random changes in their external environments, as well as in their internal components. A central goal of evolutionary systems biology is to understand how living systems cope with-and in some cases exploit-this variation. Many cellular and developmental processes operate with high fidelity to produce stereotyped, irreversible outcomes despite environmental and genetic perturbation. These processes are said to be robust or insensitive to variation. Robustness can lead to single, invariant phenotypes, or it can take the form of phenotypic plasticity, in which different environmental conditions reproducibly induce distinct phenotypes. Some organisms cope with environmental variation not with robust responses but with stochastic, reversible fate decisions. In those organisms, lower robustness yields heterogeneity among individuals, which in turn serves as a bet-hedging mechanism for the population. Considering high-fidelity and bet-hedging processes together-as a robustness continuum-provides a unifying framework for analyzing and conceptualizing variation in complex evolving systems. This framework can be applied to understanding the architectures and dynamics of the regulatory networks that underlie fate decisions in microbes, plants, animals, and cancer cells. PMID- 22821471 TI - Analysis of blastocyst culture of discarded embryos and its significance for establishing human embryonic stem cell lines. AB - In recent years, applications of stem cells have already involved in all domains of life science and biomedicine. People try to establish human embryonic stem cell lines (hESCs) in order to carry out hESC-related studies. In this study, we explored what embryos are conducive to the establishment of hESCs. The discarded embryos from in vitro fertilization-embryo transfer (IVF-ET) cycles were sequentially incubated into blastocysts, and then the inner cell mass (ICM) was isolated and incubated in the mixed feeder layer. The cell lines which underwent serial passage were identified. After a total of 1,725 discarded embryos from 754 patients were incubated, 448 blastocysts were formed with 123 high-quality blastocysts. The blastulation rate was significantly higher in the discarded embryos with non-pronucleus (0PN) or 1PN than in the discarded embryos with 2PN or >=3PN. The blastulation rate of the D3 embryos with 7-9 blastomeres was higher. Among the originally incubated 389 ICMs, 22 hESCs with normal karyotype were established, and identified to be ESCs. Therefore, in establishing hESCs with discarded embryos, D(3) 0PN or 1PN embryos with 7-9 blastomeres should be first selected, because they can improve high-quality blastulation rate which can increase the efficiency of hESC establishment. PMID- 22821473 TI - Index of biventricular interdependence calculated using cardiac MRI: a proof of concept study in patients with and without constrictive pericarditis. AB - We sought to propose a magnetic resonance (MR) imaging-derived index of biventricular interdependence as a diagnostic parameter to distinguish patients with surgically-confirmed pericardial constriction from those without. Free breathing real time MR pulse sequences of seventeen subjects with surgically proven constrictive pericarditis and thirty-five patients referred for clinically indicated cardiac MR examinations but without documented constriction were analyzed using a novel index of biventricular interdependence. Cross-sectional biventricular areas at end diastole using the epicardial surface were traced at the mid left ventricular level at end-inspiration and end-expiration and an index of biventricular interdependence, defined as the ratio of (biventricular end diastolic area at end-inspiration)/(biventricular end-diastolic area at end expiration) was calculated for each subject. The mean index for both groups was calculated and results were statistically compared. The index of biventricular interdependence approximated unity (mean index 1.03 +/- 0.03 SD) in patients with surgically confirmed pericardial constriction, indicating similar biventricular area at end-inspiration and end-expiration, and was significantly lower than in individuals without constrictive pericarditis (mean index 1.28 +/- 0.10 SD; p < 0.0001). The MR-derived index of biventricular interdependence was significantly different between subjects with surgically-confirmed pericardial constriction and subjects where pericardial constraint was not suspected and may serve as a useful metric in the hemodynamic assessment of patients with a potential diagnosis of constrictive pericarditis. PMID- 22821472 TI - Heat shock protein production and immunity and altered fetal development in diabetic pregnant rats. AB - We evaluated associations between the concentrations of heat shock proteins (hsp60 and hsp70) and their respective antibodies, alterations in maternal reproductive performance, and fetal malformations in pregnant rats with hyperglycemia. Mild diabetes (MD) or severe diabetes (SD) was induced in Sprague Dawley rats prior to mating; non-treated non-diabetic rats (ND) served as controls. On day 21 of pregnancy, maternal blood was analyzed for hsp60 and hsp70 and their antibodies; and fetuses were weighed and analyzed for congenital malformations. Hsp and anti-hsp levels were correlated with blood glucose levels during gestation. There was a positive correlation between hsp60 and hsp70 levels and the total number of malformations (R = 0.5908, P = 0.0024; R = 0.4877, P = 0.0134, respectively) and the number of malformations per fetus (R = 0.6103, P = 0.0015; R = 0.4875, P = 0.0134, respectively). The anti-hsp60 IgG concentration was correlated with the number of malformations per fetus (R = 0.3887, P = 0.0451) and the anti-hsp70 IgG level correlated with the total number of malformations (R = 0.3999, P = 0.0387). Moreover, both hsp and anti-hsp antibodies showed negative correlations with fetal weight. The results suggest that there is a relationship between hsp60 and hsp70 levels and their respective antibodies and alterations in maternal reproductive performance and impaired fetal development and growth in pregnancies associated with diabetes. PMID- 22821475 TI - Dinuclear metalloradicals featuring unsupported metal-metal bonds. PMID- 22821474 TI - Gender differences in coronary plaque composition and burden detected in symptomatic patients referred for coronary computed tomographic angiography. AB - We assessed gender differences in coronary plaque burden and composition amongst symptomatic patients referred for coronary computed tomographic angiography (CCTA). Over all, 916 symptomatic patients who were referred for a clinically indicated CCTA were included in the study. CCTAs were interpreted on a per segment basis for plaque composition (non-calcified, calcified, or mixed) and stenosis severity. A stenosis of >=50 % was considered obstructive coronary artery disease. Among 916 patients, 498 (54.3 %) patients were women. Obstructive stenosis was found in 11 % of women compared to 21 % of men (p < 0.0001). Men had significantly higher plaque prevalence, 67.9 % versus 51.6 % in women (unadjusted OR 1.98; 95 % CI, 1.51-2.60). This remained significant after adjusting for age and potential confounders (adjusted OR 2.96; 95 % CI, 2.01-4.36). A similar relationship existed for all three plaque subtypes. Men were also more likely to have mixed plaque burden (adjusted OR 1.24; 95 % CI, 1.08-1.43) than women without any significant differences in regards to the other plaque sub-types. In conclusion, symptomatic women have a lower prevalence of obstructive coronary artery disease and are less likely to have mixed coronary plaque compared to symptomatic men. Future studies are needed to determine the prognostic implications of these findings. PMID- 22821476 TI - Technical and practical aspects of (19) F NMR-based screening: toward sensitive high-throughput screening with rapid deconvolution. AB - The technical and practical aspects of (19) F NMR-based screening against a macromolecular target are analyzed in detail. A novel method utilizing the relaxation of (19) F homonuclear double quantum coherence is proposed for performing NMR-based binding assays in a direct- or competition-mode format. A combined strategy based on (19) F NMR chemical shift prediction, 2D (19) F NMR DOSY, and 2D (19) F-(1) H NMR long-range COSY experiments is presented for the deconvolution of complex mixtures of fluorinated molecules generated by either addition of single compounds or by chemical synthesis. The approaches presented here allow the screening of complex mixtures, even in the case where the exact composition is not known, and the rapid identification of the binders contained in the mixtures. PMID- 22821478 TI - Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. AB - Protein tyrosine phosphatase receptor type O (PTPRO), one of the receptor types of phosphotyrosine phosphatases (PTP), was recently described as a tumor suppressor in various kinds of cancers. We aimed to clarify the role of PTPRO in hepatocellular carcinoma (HCC). It was demonstrated in 180 pairs (120 male and 60 female) of clinical HCC specimens that the PTPRO level was significantly reduced, as compared with adjacent tissue, and the PTPRO level in male adjacent tissue was lower than in female. We further found that estrogen receptor alpha (ERalpha) could up-regulate PTPRO expression as a transcription factor. Moreover, an in vitro study showed that cell proliferation was inhibited and apoptosis was promoted in PTPRO-transduced HCC cell lines, whereas an in vivo study represented that tumor number and size was increased in ptpro(-/-) mice. As a result of its tumor-suppressive position, PTPRO was proved to down-regulate signal transducers and activators of transcription (STAT3) activity dependent on Janus kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) dephosphorylation. CONCLUSIONS: PTPRO expression results in pathological deficiency and gender bias in HCC, which could be attributed to ERalpha regulation. The suppressive role of PTPRO in HCC could be ascribed to STAT3 inactivation. PMID- 22821477 TI - Differential toxicity of 6-hydroxydopamine in SH-SY5Y human neuroblastoma cells and rat brain mitochondria: protective role of catalase and superoxide dismutase. AB - Oxidative stress and mitochondrial dysfunction are two pathophysiological factors often associated with the neurodegenerative process involved in Parkinson's disease (PD). Although, 6-hydroxydopamine (6-OHDA) is able to cause dopaminergic neurodegeneration in experimental models of PD by an oxidative stress-mediated process, the underlying molecular mechanism remains unclear. It has been established that some antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) are often altered in PD, which suggests a potential role of these enzymes in the onset and/or development of this multifactorial syndrome. In this study we have used high-resolution respirometry to evaluate the effect of 6-OHDA on mitochondrial respiration of isolated rat brain mitochondria and the lactate dehydrogenase cytotoxicity assay to assess the percentage of cell death induced by 6-OHDA in human neuroblastoma cell line SH-SY5Y. Our results show that 6-OHDA affects mitochondrial respiration by causing a reduction in both respiratory control ratio (IC(50) = 200 +/- 15 nM) and state 3 respiration (IC(50) = 192 +/- 17 nM), with no significant effects on state 4(o). An inhibition in the activity of both complex I and V was also observed. 6-OHDA also caused cellular death in human neuroblastoma SH-SY5Y cells (IC(50) = 100 +/- 9 MUM). Both SOD and CAT have been shown to protect against the toxic effects caused by 6-OHDA on mitochondrial respiration. However, whereas SOD protects against 6-OHDA-induced cellular death, CAT enhances its cytotoxicity. The here reported data suggest that both superoxide anion and hydroperoxyl radical could account for 6-OHDA toxicity. Furthermore, factors reducing the rate of 6-OHDA autoxidation to its p-quinone appear to enhance its cytotoxicity. PMID- 22821482 TI - Dynamic manipulation of modes in an optical waveguide using dielectrophoresis. AB - The emergence of optofluidics has brought a high degree of tuneability and reconfigurability to optical devices. These possibilities are provided by characteristics of fluids including mobility, wide range of index modulation, and abrupt interfaces that can be easily reshaped. In this work, we created a new class of optofluidic waveguides, in which suspended mesoparticles were employed to greatly enhance the flexibility of the system. We demonstrated tuneable quasi single mode waveguides using spatially controllable mesoparticles in optofluidics. The coupling of waveguiding modes into the assembly of mesoparticles produces strong interactions and resonant conditions, which promote the transitions of the waveguiding modes. The modal response of the system depends on the distribution of packed particles above the polymeric rib waveguide which can be readily controlled under the appropriate combination of dielectrophoresis and hydrodynamic forces. PMID- 22821481 TI - Quantitative investigation of resolution increase of free-flow electrophoresis via simple interval sample injection and separation. AB - Interval free-flow zone electrophoresis (FFZE) has been used to suppress sample band broadening greatly hindering the development of free-flow electrophoresis (FFE). However, there has been still no quantitative study on the resolution increase of interval FFZE. Herein, we tried to make a comparison between bandwidths in interval FFZE and continuous one. A commercial dye with methyl green and crystal violet was well chosen to show the bandwidth. The comparative experiments were conducted under the same sample loading of the model dye (viz. 3.49, 1.75, 1.17, and 0.88 mg/h), the same running time (viz. 5, 10, 15, and 20 min), and the same flux ratio between sample and background buffer (= 10.64 * 10 3). Under the given conditions, the experiments demonstrated that (i) the band broadening was evidently caused by hydrodynamic factor in continuous mode, and (ii) the interval mode could clearly eliminate the hydrodynamic broadening existing in continuous mode, greatly increasing the resolution of dye separation. Finally, the interval FFZE was successfully used for the complete separation of two-model antibiotics (herein pyoluteorin and phenazine-1-carboxylic acid coexisting in fermentation broth of a new strain Pseudomonas aeruginosa M18), demonstrating the feasibility of interval FFZE mode for separation of biomolecules. PMID- 22821483 TI - The effect of solvent on the morphology of ZnO nanostructure assembly by dielectrophoresis and its device applications. AB - Different zinc oxide nanostructured morphologies were grown on photolithographically patterned silicon/silicon dioxide substrates by dielectrophoresis technique using different solvents, such as water and ethanol, obtaining rod-like and net-like nanostructures, respectively. The formation of continuous nanostructures was confirmed by scanning electron microscopic, atomic force microscopic images, and electrical characterizations. The rod-like zinc oxide nanostructures were observed in the 10 MUm gap between the fingers in the pattern, whereas net-like nanostructures were formed independently of microgap. A qualitative study about the mechanism for the assembly of zinc oxide continuous nanostructures was presented. Devices were electrically characterized, at room temperature, in controlled environment to measure the conductance behavior in ultraviolet and humidity environment. Devices based on zinc oxide nanostructures grown in ethanol medium show better responses under both ultraviolet and humidity, because of the net-like structure with high surface-to-volume ratio. PMID- 22821484 TI - Surfactant-induced electroosmotic flow in microfluidic capillaries. AB - Control of EOF in microfluidic devices is essential in applications such as protein/DNA sizing and high-throughput drug screening. With the growing popularity of poly(methyl methacrylate) (PMMA) as the substrate for polymeric based microfludics, it is important to understand the effect of surfactants on EOF in these devices. In this article, we present an extensive investigation exploring changes in EOF rate induced by SDS, polyoxyethylene lauryl ether (Brij35) and CTAB in PMMA microfluidic capillaries. In a standard protein buffer (Tris-Glycine), PMMA capillaries exhibited a cathodic EOF with measured mobility of 1.54 +/- 0.1 (* 10-4 cm2/V.s). In the presence of surfactant below a critical concentration, EOF was independent of surfactant concentration. At high concentrations of surfactants, the electroosmotic mobility was found to linearly increase/decrease as the logarithm of concentration before reaching a constant value. With SDS, the EOF increased by 257% (compared to buffer), while it was decreased by 238% with CTAB. In the case of Brij35, the electroosmotic mobility was reduced by 70%. In a binary surfactant system of SDS/CTAB and SDS/Brij35, addition of oppositely charged CTAB reduced the SDS-induced EOF more effectively compared to nonionic Brij35. We propose possible mechanisms that explain the observed changes in EOF and zeta potential values. Use of neutral polymer coatings in combination with SDS resulted in 50% reduction in the electroosmotic mobility with 0.1% hydroxypropyl methyl cellulose (HPMC), while including 2% poly (N,N-dimethylacrylamide) (PDMA) had no effect. These results will potentially contribute to the development of PMMA-based microfluidic devices. PMID- 22821485 TI - On the formation of carbonate adducts of fatty alcohols, sterols, and sugars in biological conditions. AB - The formation and properties of carbonate adducts of some organic hydroxy compounds in aqueous medium were investigated. Fatty alcohols and sugars were chosen as representative classes of biological interest, and the medium was carbonated aqueous solution with pH ranging from 3.0 to 8.3. Capillary electrophoresis with two capacitively coupled contactless conductivity detectors (C4 Ds) was used for quantitation and to obtain the mobility of the monoalkyl carbonates (MACs), which were used to determine the equilibrium and kinetic constants of the reaction as well as the diffusion coefficients. For increasing chain length of the alcohols, the equilibrium constant tends to the unit, which suggests that fatty alcohols can form the corresponding MACs. The formation of MACs for cyclohexanol and cyclopentanol also suggest the existence of similar species for sterols. Carbonate adducts of fructose, glucose, and sucrose were also detected, which suggests that these counterparts of the well-known phosphates can also occur in the cytosol. Our calculations suggest that one in 1000 to one in 10,000 molecules of these hydroxy compounds would be available as the corresponding MAC in such a medium. Experiments carried out at pH values less than 3.0 showed that there is a catalytic effect of hydronium on the interconversion of bicarbonate and a MAC. Taking into account the great number of hydroxy compounds similar to the ones investigated and that bicarbonate is ubiquitous in living cells, one can anticipate the existence of a whole new class of carbonate adducts of these metabolites. PMID- 22821486 TI - Capillary electrophoresis mass spectrometry with sheathless electrospray ionization for high sensitivity analysis of underivatized amino acids. AB - A high durability sheathless electrospray ionization interface of CE-MS is applied for the sensitive analysis of underivatized amino acids. The sheathless interface was realized using an ionophore membrane-packed electro-conduction channel. The interface functioned well with a volatile alkaline background electrolyte (BGE) and uncoated fused-silica capillaries for CE-MS analysis of underivatized amino acids. High electroosmotic flow with alkaline BGE facilitated high separation efficiency (>100,000 theoretical plates) and short analysis time (<15 min). Both the short-term stability and long-term durability are particularly suited for routine applications. Using electrokinetic injection and the multiple reaction monitoring (MRM) mode with a triple-quadrupole analyzer, high sensitivity was achieved, which yielded detection limits of 0.05-0.81 MUM. For the quantitation of underivatized amino acids, quantification precisions (RSDs) for intra- and inter-day analyses were less than 3%. Recoveries from serum were 96.3-101.8% for isotope dilution mass spectrometry (IDMS). When compared with HPLC-IDMS for human serum samples, highly agreeable (96.9-102.0%) results were obtained with the proposed CE-IDMS method. PMID- 22821487 TI - Quantitative SNP genotyping by affinity capillary electrophoresis using PEG oligodeoxyribonucleotide block copolymers with electroosmotic flow. AB - Quantitative SNP detection was demonstrated with an ACE using a PEG oligodeoxyribonucleotide block copolymer (PEG-b-ODN) as a probe in the presence of an EOF. The probe's PEG segment with large molecular weight and small polydispersity yielded a high resolution in the separation of a chemically synthesized 60-base ssDNA (WT) and its single-base-substituted mutant (MT). A mixture of WT and MT was clearly separated within 10 min by simultaneously using two types of PEG-b-ODN probes whose ODN segments were complementary to WT and MT and whose PEG segments were of different lengths. The peak area ratio between WT and MT was in good agreement with the feed ratio. The averaged difference between the feed and observed ratio of MT was determined to be 0.23%, which is lower than that of any other methods. The ACE using the PEG-b-ODN probes in the presence of EOF could be utilized as a facile method for estimating SNP allele frequency in various research fields. PMID- 22821488 TI - Alpha 1-antitrypsin: a novel tumor-associated antigen identified in patients with early-stage breast cancer. AB - Several studies have demonstrated that sera from patients with cancer contain antibodies that recognize a unique group of autologous antigens called tumor associated antigens (TAA). In the current study, we employed an immunoproteomic approach, combining 2DE, Western blot, and MALDI-MS to identify TAA in the sera of patients diagnosed with infiltrating ductal or in situ carcinoma breast cancer. Sera obtained from 25 newly diagnosed patients with stage II breast cancer and 20 healthy volunteers was evaluated for the presence of novel TAA. Alpha 1-antitrypsin (A1AT) antibodies were detected in 24 of 25 patients with breast cancer (96%) and in 2 of 20 controls (10%). Sensitivity of detection of autoantibodies against A1AT in patients with breast cancer was 96%. Our preliminary results suggest that A1AT and autoantibodies against alpha 1 antitrypsin may be useful serum biomarkers for early-stage breast cancer screening and diagnosis. PMID- 22821489 TI - SpectraBank: an open access tool for rapid microbial identification by MALDI-TOF MS fingerprinting. AB - MALDI-TOF MS has proved to be an accurate, rapid, and cost-effective technique for microbial identification in which the spectral fingerprint of an unknown strain can be compared to a database of spectra from reference strains. Most of the existing databases are private and often costly to access, and little spectral information is shared among researchers. The objective of the present communication is to introduce the SpectraBank database (http://www.spectrabank.org), which provides open access MALDI-TOF mass spectra from a variety of microorganisms. This work aims to familiarize readers with the SpectraBank database, from the sample preparation, data collection, and data analysis to how the spectral reference data can be used for microbial species identification. The database currently includes more than 200 MALDI-TOF MS spectra from more than 70 bacterial species and links to the freely available web based application SPECLUST (http://bioinfo.thep.lu.se/speclust.html) to allow comparisons of the obtained peak mass lists and evaluate phyloproteomic relationships. The SpectraBank database is intended to be expanded by the addition of new spectra from microbial strains, obtained in our laboratory and by other researchers. PMID- 22821490 TI - A rapid and simplified method for protein silver staining in polyacrylamide gels. AB - Silver staining is widely used to detect protein in polyacrylamide gels when high sensitivity is required. A simple and rapid protocol for silver staining of proteins following PAGE was developed in the present study. The number of steps was reduced compared to conventional protocol by combining fixing, rinsing, and soaking into a single impregnating step, thus achieving detection of proteins in 20 min. The present method is as sensitive as current protocols with the advantage of saving time and costs. PMID- 22821491 TI - A replaceable dual-enzyme capillary microreactor using magnetic beads and its application for simultaneous detection of acetaldehyde and pyruvate. AB - A novel replaceable dual-enzyme capillary microreactor was developed and evaluated using magnetic fields to immobilize the alcohol dehydrogenase (ADH)- and lactate dehydrogenase (LDH)-coated magnetic beads at desired positions in the capillary. The dual-enzyme assay was achieved by measuring the two consumption peaks of the coenzyme beta-nicotinamide adenine dinucleotide (NADH), which were related to the ADH reaction and LDH reaction. The dual-enzyme capillary microreactor was constructed using magnetic beads without any modification of the inner surface of the capillary, and showed great stability and reproducibility. The electrophoretic resolution for different analytes can be easily controlled by altering the relative distance of different enzyme-coated magnetic beads. The apparent K(m) values for acetaldehyde with ADH-catalyzed reaction and for pyruvate with LDH-catalyzed reaction were determined. The detection limits for acetaldehyde and pyruvate determination are 0.01 and 0.016 mM (S/N = 3), respectively. The proposed method was successfully applied to simultaneously determine the acetaldehyde and pyruvate contents in beer samples. The results indicated that combing magnetic beads with CE is of great value to perform replaceable and controllable multienzyme capillary microreactor for investigation of a series of enzyme reactions and determination of multisubstrates. PMID- 22821492 TI - Determination of peimine and peiminine in Bulbus Fritillariae Thunbergii by capillary electrophoresis by indirect UV detection using N-(1 naphthyl)ethylenediamine dihydrochloride as probe. AB - A simple and inexpensive CE method was developed for the determination of peimine and peiminine. Because of the lack of an UV chromophore of peimine and peiminine, the detection method chosen was indirect UV detection, with N-(1 naphthyl)ethylenediamine dihydrochloride (NED) as the UV absorbing probe. It was thought that NED, a chromophoric ion, may form hydrogen bonding pairs with the analytes to cause significant changes in separation selectivity. Additionally, the hydrophobic interactions between analytes and the probe also play a crucial role in achieving a resolution between the two analytes. The analyses were carried out with a background electrolyte composed of 66% MeOH-ACN (1:1, v/v), 34% aqueous buffer containing 15 mM NaH2PO4, 2.5 mM NED, 4 mM H3PO4. MeOH-ACN mixtures used as organic modifiers can not only reduce the adsorption of NED to the capillary wall, but also decrease the baseline noise and drift. The method provided a linear response ranging from 5 to 200 MUg/mL. The limits of detection (LODs) for peimine and peiminine were 3.9 and 4.1 MUg/mL, respectively. The repeatabilities (n = 3) reached relative standard deviation values (RSDs) of 3.4 and 4.1% for the peak areas, 4.0 and 4.4% for the peak heights, and 0.29 and 0.30% for the migration time of peimine and peiminine, respectively. Regression equations revealed linear relationships (r = 0.9995-0.9996) between the peak area of each analyte and the concentration. The method developed was successfully applied to quantify peimine and peiminine in chloroform extracts of the ground Bulbus Fritillariae Thunbergii. PMID- 22821493 TI - On-line preconcentration of perfluorooctanoic acid and perfluorooctanesulfonic acid by nonaqueous capillary electrophoresis. AB - Separation of major environmental pollutants as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) by capillary electrophoresis is reported for the first time. It is not possible to resolve the solutes in an aqueous media. However, the use of methanol and acetonitrile as the background electrolyte (BGE) solvents allowed their rapid separation in an uncoated capillary. A major effort was put into BGE optimization in respect to both separation efficiency and detection for further on-line preconcentration. 5 mmol.L-1 naphthalene-1-sulfonic acid and 10 mmol.L-1 triethylamine dissolved in ACN/MeOH (50:50 v/v) provided best separation and detection conditions. Next, the large-volume sample stacking and the field-amplified sample injection were applied and compared. Large-volume sample stacking improved limits of detection (LODs) with regard to the standard injection by 69 times for PFOA and 143 times for PFOS with LODs of 280 and 230 nmol.L-1, respectively. Field-amplified sample injection improved LODs 624 times for PFOAand 806 times for PFOS with LODs 31 and 40 nmol.L-1, respectively. Both preconcentration methods showed repeatabilities of migration times less than 1.2% RSD intraday and 6.6% RSD interday. The method was applied on PFOA and PFOS analysis in a sample of river water treated with solid-phase extraction, which further improved LOD toward 5.6 * 10-10 mol.L-1 for PFOS and 6.4 * 10-10 mol.L-1 for PFOA and allows the method to be used for river water contamination screening or decomposition studies. PMID- 22821494 TI - On-line sample concentration via micelle to solvent stacking of cations prepared with aqueous organic solvents in capillary electrophoresis. AB - In this paper, by injecting a SDS micellar plug before the sample prepared in aqueous organic solvents, we show the on-line sample preconcentration of cations via micelle to solvent stacking (MSS) using solvents of as low as 30%. This extends the choice of stacking techniques to include moderate amounts of organic solvent in the sample. The approach is akin to in-line solid phase extraction where the micellar plug acted as a transient micellar phase extractor. Basic studies were conducted (e.g. type and amount of organic solvent in the sample). The calculated sensitivity enhancement factors based on LOD obtained for the six test antipsychotic drugs were from 41 to 68. The peak signals were linear (R2 > 0.99) from 0.2 to 10.0 MUg/mL. The intraday and interday reproducibility (n = 10) for migration time, peak height, and corrected peak area were from 0.2 to 13.6%. The technique was also tested on spiked wastewater sample with minimal sample treatment (i.e. dilution and centrifugation). PMID- 22821495 TI - Vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction for the determination of triazine herbicides in water samples by microemulsion electrokinetic chromatography. AB - A novel method based on the combination of microemulsion electrokinetic chromatography (MEEKC) and vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction (VSLLME) was developed for the determination of five triazine herbicides (simazine, atrazine, ametryn, prometryn, and terbutryn) in water samples. The five triazine herbicides were baseline separated by using the microemulsion buffer containing a 10 mmol/L borate buffer at pH 9.5, 2.5% (w/v) SDS as surfactant, 0.8% (w/v) ethyl acetate as oil phase, and 6.0% (w/v) 1 butanol as cosurfactant. The optimum extraction conditions of VSLLME were as follows: 100 MUL chloroform was used as extraction solvent, 5.0 * 10-5 mol/L Tween-20 was chosen as the surfactant to enhance the emulsification, and the extraction process was carried out by vortex mixing for 3 min. Under these optimum experimental conditions, the calibration curve was linear in the range of 2.0-200.0 ng/mL, with the correlation coefficients (r2) varying from 0.9927 to 0.9958. The detection limits of the method varied from 0.41 to 0.62 ng/mL. The purposed method was applied to the determination of five triazine herbicides in real water samples, and the recoveries were between 80.6 and 107.3%. PMID- 22821496 TI - Hollow-fiber liquid-phase microextraction for the determination of pesticides and metabolites in soils and water samples using HPLC and fluorescence detection. AB - A new and simple method has been developed for the determination of a group of four benzimidazole pesticides (carbendazim/benomyl, thiabendazole, and fuberidazole), a carbamate (carbaryl), and an organophosphate (triazophos), together with two of their main metabolites (2-aminobenzimidazole, metabolite of carbendazim/benomyl, and 1-naphthol, metabolite of carbaryl) in soils. First, an ultrasound-assisted extraction (UAE) was performed, followed by evaporation and reconstitution in water. Then, extraction and preconcentration of the analytes was accomplished by two-phase hollow-fiber liquid-phase microextraction (HF-LPME) using 1-octanol as extraction solvent. Parameters that affect the extraction efficiency in HF-LPME technique (organic solvent, pH of the sample, extraction time, stirring speed, temperature, and ionic strength) were deeply investigated. Optimum HF-LPME conditions involved the use of a 2.0 cm polypropylene fiber filled with 1-octanol to extract 10 mL of an aqueous soil extract at pH 9.0 containing 20% (v/v) of NaCl for 30 min at 1440 rpm. Separation and quantification was achieved by HPLC with fluorescence detection (FD). The proposed optimum UAE-HF-LPME-HPLC-FD methodology provided good calibration, precision, and accuracy results for two soils of different physicochemical properties. LODs were in the range 0.001-6.94 ng/g (S/N = 3). With the aim of extending the validation, the HF-LPME method was also applied to different types of waters (Milli-Q, mineral and run-off), obtaining LODs in the range 0.0002-0.57 MUg/L. PMID- 22821497 TI - Determination of nicotinyl pesticide residues in vegetables by micellar electrokinetic capillary chromatography with quantum dot indirect laser-induced fluorescence. AB - A new assay was developed by use of micellar electrokinetic capillary chromatography with indirect LIF fluorescence for the determination of thiamethoxam, acetamiprid, and imidacloprid residues in vegetables, in which the cadmium telluride quantum dots (QDs) synthesized in aqueous phase were used as fluorescent background substance and their excitation and emission wavelengths matched with LIF detector by engineering their size. The factors that affected the peak height and the resolution were optimized. The running buffer was composed of 4.4 MUM cadmium telluride QDs as fluorescent background substance, 40 mM borate and 60 mM SDS, and its pH was adjusted to 8.0. The separation voltage was 25 kV. Under the optimum conditions, the detection limits were 0.05, 0.01, and 0.009 mg/kg; the linear dynamic ranges were 0.5-30, 0.1-30, and 0.1-30 mg/L; and the average recoveries of spiked samples were 72.0-101.2, 74.0-106.7, and 77.8-105.1% for thiamethoxam, acetamiprid, and imidacloprid, respectively. The assay can meet the requirement of maximum residue limits to these three pesticides in the regulations of European Union and Japan, and has been applied for determining their residues in vegetables. PMID- 22821503 TI - Long-term quality of life of donors after living donor liver transplantation. AB - The aims of this study were to investigate the long-term effects of living donor liver transplantation (LDLT) on the health-related quality of life (HRQOL) of donors with the Short Form 36 health survey and to determine the risk factors for poor outcomes. Between June 1990 and June 2004, LDLT was performed 1000 times at Kyoto University Hospital. In July 2005, 997 of the 1000 donors were contacted by mail so that data on their HRQOL could be collected. In all, 578 donors responded (ie, there was a 58.0% response rate). The norm-based HRQOL scores for donors were better than the scores for Japanese norms across all time periods. All scores were similar for left lobe donors (n = 367) and right lobe donors (n = 211). For all donors, a multivariate logistic regression analysis revealed that age, the number of months until recovery to the preoperative health status, hospital visits due to donation-related symptoms, rest from work related to donation in the past month, and the existence of 2 or more comorbidities were significantly associated with decreased HRQOL scores. Postoperative complications and recipient mortality were not predictors of poor HRQOL. In conclusion, HRQOL was better for both right lobe donors and left lobe donors versus the Japanese norm population in the long term (mean postdonation period = 6.8 years). However, the prolongation of symptoms or sequelae related to donation lowered mental health or social functioning. The emergence of comorbidities after donation also significantly affected HRQOL in the long term. Careful follow-up and sustained counseling are required for donors with risk factors for lower HRQOL. PMID- 22821504 TI - Selenium and psoriasis. AB - Psoriasis is a chronic, immune-mediated skin disease characterized by production of reactive oxygen species due to the activation of tumor necrosis factor alpha (TNF-alpha), which is thought to be an important factor in inducing and maintaining psoriatic lesions. As an external factor, ultraviolet B (UVB) radiation stimulates TNF-alpha production and secretion by human keratinocytes in vitro and can also reach the upper dermis and suppress endothelial cells in vitro. The selenium level in psoriatic patients has been found to be lower than expected, but studies on its role in the pathogenesis of the disease are scarce. Selenium can influence immune response by changing the expression of cytokines and their receptors or by making immune cells more resistant to oxidative stress. It was reported that selenium supplementation had inhibitory effects on TNF-alpha levels in patients with psoriasis, but the details are not completely elucidated. Selenium compounds are also known to prevent the in vitro release of UVB-induced proinflammatory cytokines by inhibition of mRNA in human keratinocytes. In the present review, the protective role of selenium in oxidative stress, lesions, and immune system regulation in patients with psoriasis is summarized. PMID- 22821505 TI - Fast reconstructed radiographs from octree-compressed volumetric data. AB - PURPOSE: Simulated 2D X-ray images called digitally reconstructed radiographs (DRRs) have important applications within medical image registration frameworks where they are compared with reference X-rays or used in implementations of digital tomosynthesis (DTS). However, rendering DRRs from a CT volume is computationally demanding and relatively slow using the conventional ray-casting algorithm. Image-guided radiation therapy systems using DTS to verify target location require a large number DRRs to be precomputed since there is insufficient time within the automatic image registration procedure to generate DRRs and search for an optimal pose. METHOD: DRRs were rendered from octree compressed CT data. Previous work showed that octree-compressed volumes rendered by conventional ray casting deliver a registration with acceptable clinical accuracy, but efficiently rendering the irregular grid of an octree data structure is a challenge for conventional ray casting. We address this by using vertex and fragment shaders of modern graphics processing units (GPUs) to directly project internal spaces of the octree, represented by textured particle sprites, onto the view plane. The texture is procedurally generated and depends on the CT pose. RESULTS: The performance of this new algorithm was found to be 4 times faster than that of a ray-casting algorithm implemented using NVIDIATMCompute Unified Device Architecture (CUDATM) on an equivalent GPU (~95 % octree compression). Rendering artifacts are apparent (consistent with other splatting algorithm), but image quality tends to improve with compression and fewer particles are needed. A peak signal-to-noise ratio analysis confirmed that the images rendered from compressed volumes were of marginally better quality to those rendered using Gaussian footprints. CONCLUSIONS: Using octree-encoded DRRs within a 2D/3D registration framework indicated the approach may be useful in accelerating automatic image registration. PMID- 22821506 TI - Evaluation of selected ultrasonographic parameters and marker levels in the preoperative differentiation of borderline ovarian tumors and ovarian cancers. AB - OBJECTIVES: In young patients with borderline tumors the fertility-sparing treatment is indicated, thus the preoperative investigation is important. The aim of this study was to perform a comparative assessment of sensitivity and specificity of selected ultrasonographic and clinical parameters for the diagnoses of borderline tumors and ovarian cancers. METHODS: We retrospectively analyzed 57 patients who underwent surgical treatment in the Maria Sklodowska Curie Memorial Cancer Center from Jan 01, 2008 to Dec 31, 2009. Ovarian cancers were diagnosed in 41 patients, and borderline ovarian tumors in 16 patients. Statistical model was developed to determine independent predictive factors that would be useful in preoperative differentiation between both tumors. The model included the following factors: menopausal status, tumor morphology, wall thickness (including outgrowths), septal thickness, echogenicity, resistive index, serum CA-125 level, and free fluid in the peritoneal cavity. RESULTS: Based on the statistical model developed, independent predictive factors in the differentiation between ovarian cancers and borderline tumors included the menopausal status (P=0.005), tumor echogenicity (P=0.047) and the presence of free fluid in the Douglas pouch (P=0.043). With the cutoff value of 13 (with scores below 13 indicating a borderline ovarian tumor, and scores of >=13 indicating ovarian cancer), sensitivity was 90.2% and specificity was 87%. CONCLUSIONS: Our proposed model of preoperative evaluation has a sensitivity of 90% in the differentiation between ovarian cancers and borderline tumors. When combined with intraoperative findings, it allows optimal surgical therapeutic decisions to be made in patients with borderline ovarian tumors. PMID- 22821507 TI - Young women with breast cancer: how many are actually candidates for fertility preservation? AB - PURPOSE: There are no data regarding the actual need for fertility preservation (FP) in breast cancer (BC) patients. Our study provides a practical needs assessment for reproductive medicine by analyzing an unselected cohort of young BC patients. This assessment considers oncological factors as well as the patient's obstetrical and gynecological history and reproductive outcome after BC diagnosis. We aimed to identify how many patients are actually potential candidates for FP and how many patients might consequently use their cryopreserved gametes to achieve pregnancy. METHODS: Based on a prospective BC database, we analyzed all patients who were <=40 years at initial diagnosis (time period of diagnosis: 1990-2007; n=100; 7.7% of the entire BC cohort; median age: 35.9 years). RESULTS: Using an algorithm of exclusion criteria considering disease-specific, therapy-specific and family history characteristics, 36 patients who received chemotherapy were identified as potential "classical" candidates for FP. After 5 years, 22 women were identified as potential candidates for using their cryopreserved gametes to achieve pregnancy; the majority of these patients were childless (n=16, 72.7%) and in their late reproductive years (n=12, 54.5%). CONCLUSIONS: Our study demonstrates that in a cohort of young BC patients only a minority of women are candidates for FP. Young BC patients who wish to have children in the future usually carry risk factors both from oncological and reproductive medicine perspective. Due to this high risk profile, the rarity of BC in young age and the limited number of patients who might actually have opted for FP, these women must be offered timely and multidisciplinary counseling in highly specialized centers. PMID- 22821508 TI - Evolving trends in maternal fetal medicine referrals in a rural state using telemedicine. AB - OBJECTIVE: To determine maternal fetal medicine (MFM) referral trends in a Medicaid population over time. STUDY DESIGN: Sixteen clinical guidelines and 23 clinical conditions were identified where co-management/consultation with MFM specialist is recommended. Linked Medicaid claims and birth certificate data for 2001-2006 were used to identify pregnancies with these conditions and whether they received co-management/consultation from a MFM specialist. RESULTS: Between 2001 and 2006, there were 108,703 pregnancies with delivery of 110,890 neonates. Forty-five percent had one or more of the conditions identified for co management/consultation. Overall pregnancies receiving MFM contact remained unchanged at 22.2% in 2001 and 22.1% in 2006. However, face to face contacts decreased from 14.6% (2001) to 8.7% (2006) while telemedicine consults increased from 7.6% (2001) to 13.3% (2006). Health departments were most likely and family practitioners least likely to refer to MFM (p<0.001). Pregnancy complications leading to MFM referrals include cardiac complications, renal disease, systemic disorders, PPROM, suspected fetal abnormalities, and cervical insufficiency. CONCLUSION: Referral of high-risk pregnancies to MFMs varies with the level of expertise at the primary prenatal site. Increased contact between MFMs and local providers increased MFM referrals. PMID- 22821509 TI - The role of insulin-like growth factors signaling in merlin-deficient human schwannomas. AB - Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell-matrix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) is caused by overexpression/activation of platelet-derived growth factor receptor-beta (PDGFR-beta) and ErbB2/3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR-beta and is completely independent of ErbB2/3. Moreover, the mechanisms underlying pathological cell-matrix adhesion and survival of schwannoma cells are still not fully understood. Here, we demonstrate that insulin-like growth factor I receptor (IGF-IR) is strongly overexpressed and activated in human primary schwannoma cells. IGF-I and -II are overexpressed and released from schwannoma cells. We show that ERK1/2 is relevant for IGF-I-mediated increase in proliferation and cell-matrix adhesion, c-Jun N-terminal kinases for increased proliferation and AKT for survival. We demonstrate new mechanisms involved in increased basal proliferation, cell-matrix adhesion, and survival of schwannoma cells. We identified therapeutic targets IGF-IR and downstream PI3K for treatment of schwannoma and other merlin-deficient tumors and show usefulness of small molecule inhibitors in our model. PI3K is relevant for both IGF-IR and previously described PDGFR-beta signaling in schwannoma. PMID- 22821510 TI - Optical trapping microrheology in cultured human cells. AB - We present the microrheological study of the two close human epithelial cell lines: non-cancerous HCV29 and cancerous T24. The optical tweezers tracking was applied to extract the several seconds long trajectories of endogenous lipid granules at time step of 1MUs. They were analyzed using a recently proposed equation for mean square displacement (MSD) in the case of subdiffusion influenced by an optical trap. This equation leads to an explicit form for viscoelastic moduli. The moduli of the two cell lines were found to be the same within the experimental accuracy for frequencies 10(2) - 10(5) Hz. For both cell lines subdiffusion was observed with the exponent close to 3/4, the value predicted by the theory of semiflexible polymers. For times longer than 0.1s the MSD of cancerous cells exceeds the MSD of non-cancerous cells for all values of the trapping force. Such behavior can be interpreted as a signature of the active processes and prevents the extraction of the low-frequency viscoelastic moduli for the living cells by passive microrheology. PMID- 22821511 TI - Near-field laser Doppler velocimetry measures near-wall velocities. AB - A new near-wall velocimetry technique is proposed, based on evanescent wave dynamic light scattering, which allows for the measurement of near-wall velocity profile (characterized by an apparent slip velocity and a shear rate) with a resolution of tens of nanometers. A full theoretical expression of the correlation function is derived for the case of linear flow with negligible Brownian motion. The technique is demonstrated for latex spheres dispersed in water-glycerol mixtures. PMID- 22821512 TI - SAP30L (Sin3A-associated protein 30-like) is involved in regulation of cardiac development and hematopoiesis in zebrafish embryos. AB - The Sin3A-associated proteins SAP30 and SAP30L share 70% sequence identity and are part of the multiprotein Sin3A corepressor complex. They participate in gene repression events by linking members of the complex and stabilizing interactions among the protein members as well as between proteins and DNA. While most organisms have both SAP30 and SAP30L, the zebrafish is exceptional because it only has SAP30L. Here we demonstrate that SAP30L is expressed ubiquitously in embryonic and adult zebrafish tissues. Knockdown of SAP30L using morpholino mediated technology resulted in a morphant phenotype manifesting as cardiac insufficiency and defective hemoglobinization of red blood cells. A microarray analysis of gene expression in SAP30L morphant embryos revealed changes in the expression of genes involved in regulation of transcription, TGF-beta signaling, Wnt-family transcription factors, and nuclear genes encoding mitochondrial proteins. The expression of the heart-specific nkx2.5 gene was markedly down regulated in SAP30L morphants, and the cardiac phenotype could be partially rescued by nkx2.5 mRNA. In addition, changes were detected in the expression of genes known to be important in hemoglobin synthesis and erythropoiesis. Our results demonstrate that SAP30L regulates several transcriptional pathways in zebrafish embryos and is involved in the development of cardiac and hematopoietic systems. PMID- 22821513 TI - An integrated chip for the high-throughput synthesis of transcription activator like effectors. AB - A TALE of two assays: Transcription activator-like effectors (TALEs) are programmable proteins that can specifically recognize a DNA sequence. Previous strategies for the synthesis of TALEs were complicated and time-consuming. The solid-phase synthesis strategy demonstrated here allows quick and simple purification of the ligation product. PMID- 22821515 TI - Application of confocal single-molecule FRET to intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) are characterized by a large degree of conformational heterogeneity. In such cases, classical experimental methods often yield only mean values, averaged over the entire ensemble of molecules. The microscopic distributions of conformations, trajectories, or sequences of events often remain unknown, and with them the underlying molecular mechanisms. Signal averaging can be avoided by observing individual molecules. A particularly versatile method is highly sensitive fluorescence detection. In combination with Forster resonance energy transfer (FRET), distances and conformational dynamics can be investigated in single molecules. This chapter introduces the practical aspects of applying confocal single-molecule FRET experiments to the study of IDPs. PMID- 22821514 TI - Immobilization of proteins for single-molecule fluorescence resonance energy transfer measurements of conformation and dynamics. AB - Fluorescence resonance energy transfer provides information about protein structure and dynamics. Single-molecule analysis can capture the information normally lost through ensemble averaging of heterogeneous and dynamic samples. Immobilization of single molecules, under conditions that retain their biological activity, allows for extended observation of the same molecule for tens of seconds. This can capture slow conformational transitions or protein binding and unbinding cycles. Using an open geometry for immobilization allows for direct observation of the response to changing solution conditions or adding ligands. Here we provide detailed methods for immobilization and observation of fluorescently labeled single proteins using total internal reflection microscopy that are widely applicable to the study of intrinsically disordered proteins. PMID- 22821516 TI - Single-molecule force spectroscopy of chimeric polyprotein constructs containing intrinsically disordered domains. AB - Here, we describe the single molecule force spectroscopy (SMFS)-based experimental protocol we have recently used to single out different classes of conformations in a chimeric multimodular protein containing an intrinsically disordered (human Alpha Synuclein) domain. Details are provided regarding cloning, expression and purification of the chimeric polyprotein constructs, optimal surface preparation, SMFS data collection and filtering. Although the specificity of the issue and the ensemble of nonstandard techniques needed to perform the described procedures render this a rather unorthodox protocol, it is relatively straightforward to adapt it to the study of other protein domains. PMID- 22821517 TI - Visualization of mobility by atomic force microscopy. AB - Intrinsically disordered regions (IDRs) of proteins are very thin and hence hard to be visualized by electron microscopy. Thus far, only high-speed atomic force microscopy (HS-AFM) can visualize them. The molecular movies identify the alignment of IDRs and ordered regions in an intrinsically disordered protein (IDP) and show undulation motion of the IDRs. The visualized tail-like structures contain the information of mechanical properties of the IDRs. Here, we describe methods of HS-AFM visualization of IDPs and methods of analyzing the obtained images to characterize IDRs. PMID- 22821518 TI - Unequivocal single-molecule force spectroscopy of intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) are predicted to represent about one third of the eukaryotic proteome. The dynamic ensemble of conformations of this steadily growing class of proteins has remained hardly accessible for bulk biophysical techniques. However, single-molecule techniques provide a useful means of studying these proteins. Atomic force microscopy (AFM)-based single molecule force spectroscopy (SMFS) is one of such techniques, which has certain peculiarities that make it an important methodology to analyze the biophysical properties of IDPs. However, several drawbacks inherent to this technique can complicate such analysis. We have developed a protein engineering strategy to overcome these drawbacks such that an unambiguous mechanical analysis of proteins, including IDPs, can be readily performed. Using this approach, we have recently characterized the rich conformational polymorphism of several IDPs. Here, we describe a simple protocol to perform the nanomechanical analysis of IDPs using this new strategy, a procedure that in principle can also be followed for the nanomechanical analysis of any protein. PMID- 22821519 TI - Sedimentation velocity analytical ultracentrifugation for intrinsically disordered proteins. AB - The size of intrinsically disordered proteins (IDPs) is large compared to their molecular mass and the resulting mass-to-size ratio is unusual. The sedimentation coefficient, which can be obtained from sedimentation velocity (SV) analytical ultracentrifugation (AUC), is directly related to this ratio and can be easily interpreted in terms of frictional ratio. This chapter is a step-by-step protocol for setting up, executing and analyzing SV experiments in the context of the characterization of IDPs, based on a real case study of the partially folded C terminal domain of Sendai virus nucleoprotein. PMID- 22821520 TI - Analysis of intrinsically disordered proteins by small-angle X-ray scattering. AB - Small-angle scattering of X-rays (SAXS) is a method for the low-resolution structural characterization of biological macromolecules in solution. The technique is highly complementary to the high-resolution methods of X-ray crystallography and NMR. SAXS not only provides shapes, oligomeric state, and quaternary structures of folded proteins and protein complexes but also allows for the quantitative analysis of flexible systems. Here, major procedures are presented to characterize intrinsically disordered proteins (IDPs) using SAXS. The sample requirements for SAXS experiments on protein solutions are given and the sequence of steps in data collection and processing is described. The use of the recently developed advanced computational tools to quantitatively characterize solutions of IDPs is presented in detail. Typical experimental and potential problems encountered during the use of SAXS are discussed. PMID- 22821521 TI - Small angle neutron scattering for the structural study of intrinsically disordered proteins in solution: a practical guide. AB - Small angle neutron scattering (SANS) allows studying bio-macromolecular structures and interactions in solution. It is particularly well-suited to study structural properties of intrinsically disordered proteins (IDPs) over a wide range of length-scales ranging from global aspects (radii of gyration and molecular weight) down to short-distance properties (e.g., cross-sectional analysis). In this book chapter, we provide a practical guide on how to carry out SANS experiments on IDPs and discuss the complementary aspects and strengths of SANS with respect to small angle X-ray scattering (SAXS). PMID- 22821522 TI - Dynamic and static light scattering of intrinsically disordered proteins. AB - Molecular parameters such as size, molar mass, and intermolecular interactions, which are important to identify and characterize intrinsically disordered proteins (IDPs), can be obtained from light scattering measurements. In this chapter, we discuss the physical basis of light scattering, experimental techniques, sample treatment, and data evaluation with special emphasis on studies on proteins. Static light scattering (SLS) is capable of measuring molar masses within the range 10(3)-10(8) g/mol and is therefore ideal for determining the state of association of proteins in solution. Since proteins are in general too small to obtain the geometric radius of gyration R (G) from SLS, it is more useful to determine the hydrodynamic Stokes radius, R (S), which can be obtained easily and quickly from dynamic light scattering (DLS) experiments. Accordingly, DLS is an appropriate technique to monitor expansion or compaction of protein molecules. This is especially important for IDPs, which can be recognized and characterized by comparing the measured Stokes radii with those calculated for particular reference states, such as the compactly folded and the fully unfolded states. The combined application of DLS and SLS improves measurements of the molar mass and is essential when changes in the molecular dimensions and molecular association/dissociation take place simultaneously. PMID- 22821523 TI - Estimation of intrinsically disordered protein shape and time-averaged apparent hydration in native conditions by a combination of hydrodynamic methods. AB - Size exclusion chromatography coupled online to a Tetra Detector Array in combination with analytical ultracentrifugation (or with quasi-elastic light scattering) is a useful methodology to characterize hydrodynamic properties of macromolecules, including intrinsically disordered proteins. The time-averaged apparent hydration and the shape factor of proteins can be estimated from the measured parameters (molecular mass, intrinsic viscosity, hydrodynamic radius) by these techniques. Here we describe in detail this methodology and its application to characterize hydrodynamic and conformational changes in proteins. PMID- 22821524 TI - Size-exclusion chromatography in structural analysis of intrinsically disordered proteins. AB - Gel-filtration chromatography, also known as size-exclusion chromatography (SEC) or gel-permeation chromatography, is a useful tool for structural and conformational analyses of intrinsically disordered proteins (IDPs). SEC can be utilized for the estimation of the hydrodynamic dimensions of a given IDP, for evaluation of the association state, for the analysis of IDP interactions with binding partners, and for the induced folding studies. It also can be used to physically separate IDP conformers based on their hydrodynamic dimensions, thus providing a unique possibility for the independent analysis of their physicochemical properties. PMID- 22821525 TI - Denaturant-induced conformational transitions in intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) differ from ordered proteins at several levels: structural, functional, and conformational. Amino acid biases also drive atypical responses of IDPs to changes in their environment. Among several specific features, the conformational behavior of IDPs is characterized by the low cooperativity (or the complete lack thereof) of the denaturant-induced unfolding. In fact, the denaturant-induced unfolding of native molten globules can be described by shallow sigmoidal curves, whereas urea- or guanidinium hydrochloride-induced unfolding of native pre-molten globules or native coils is a noncooperative process and typically is seen as monotonous feature-less changes in the studied parameters. This chapter describes some of the most characteristic features of the IDP conformational behavior. PMID- 22821526 TI - Identification of intrinsically disordered proteins by a special 2D electrophoresis. AB - Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure under physiological conditions. They constitute a significant fraction of various proteomes and have significant roles in key cellular processes. Here we report the development of a two-dimensional electrophoresis technique for their de novo recognition and characterization. This technique consists of the combination of native and 8 M urea electrophoresis of heat-treated proteins where IDPs are expected to run into the diagonal of the gel, whereas globular proteins either precipitate upon heat treatment or unfold and run off the diagonal in the second dimension. PMID- 22821527 TI - pH-induced changes in intrinsically disordered proteins. AB - Intrinsically disordered proteins are typically enriched in amino acids that confer a relatively high net charge to the protein, which is an important factor leading to the lack of a compact structure. There are many different approaches that can be used to experimentally confirm whether a protein is intrinsically disordered. One such approach takes advantage of the distinctive amino acid composition to test whether a protein is a genuine IDP. In particular, the conformation of the protein can be monitored at different pHs; as opposed to globular or ordered proteins, IDPs will typically gain structure under highly acidic or basic conditions. Here, we describe circular dichroism and fluorescence spectroscopic experimental approaches in which the conformation of proteins is monitored as pH is altered as a way of testing whether the protein behaves as an intrinsically disordered protein. PMID- 22821528 TI - Temperature-induced transitions in disordered proteins probed by NMR spectroscopy. AB - Intrinsically disordered proteins are abundant in nature and perform many important physiological functions. Multidimensional NMR spectroscopy has been crucial for the understanding of the conformational properties of disordered proteins and is increasingly used to probe their conformational ensembles. Compared to folded proteins, disordered proteins are more malleable and more easily perturbed by environmental factors. Accordingly, the experimental conditions and especially the temperature modify the structural and functional properties of disordered proteins. NMR spectroscopy allows analysis of temperature-induced structural changes at residue resolution using secondary chemical shift analysis, paramagnetic relaxation enhancement, and residual dipolar couplings. This chapter discusses practical aspects of NMR studies of temperature-induced structural changes in disordered proteins. PMID- 22821529 TI - Analyzing temperature-induced transitions in disordered proteins by NMR spectroscopy and secondary chemical shift analyses. AB - Intrinsically disordered proteins are abundant in nature and perform many important physiological functions. Multidimensional NMR spectroscopy has been crucial for the understanding of the conformational properties of disordered proteins and is increasingly used to probe their conformational ensembles. Compared to folded proteins, disordered proteins are more malleable and more easily perturbed by environmental factors. Accordingly, the experimental conditions and especially the temperature modify the structural and functional properties of disordered proteins. This chapter discusses practical aspects of NMR studies of temperature-induced structural changes in disordered proteins using chemical shifts. PMID- 22821530 TI - Osmolyte-, binding-, and temperature-induced transitions of intrinsically disordered proteins. AB - Structural studies of intrinsically disordered proteins (IDPs) entail unique experimental challenges due in part to the lack of well-defined three-dimensional structures exhibited by this class of proteins. Although IDPs can be studied in their native disordered conformations using a variety of ensemble and single molecule biophysical techniques, one particularly informative experimental strategy is to probe protein disordered states as part of folding-unfolding transitions. In this chapter, we describe solution methods for probing conformational properties of IDPs (and unfolded proteins, in general), including the use of naturally occurring osmolytes to force protein folding, the quantification of coupled folding and ligand binding of IDPs, and the structural interrogation of solvent- and/or binding-induced folded conformations by thermal perturbations. PMID- 22821531 TI - Laser temperature-jump spectroscopy of intrinsically disordered proteins. AB - Laser temperature-jump methods allow an experimenter to study the kinetics and dynamics of very rapid solution-phase processes, including conformational dynamics of biomolecules on time scales of nanoseconds and microseconds. The combination of laser temperature-jump (T-jump) excitation and appropriate optical detection techniques such as fluorescence energy transfer allows the study of intramolecular and intermolecular conformational changes and interactions that occur during protein folding and binding. This article describes the application of the laser temperature-jump method to UV-visible fluorescence studies of the coupled folding and binding of intrinsically disordered proteins. We emphasize the practical aspects of instrument alignment and optimization, sample preparation, and data collection using fluorescently labeled peptides with UV laser excitation. PMID- 22821532 TI - Differential scanning microcalorimetry of intrinsically disordered proteins. AB - Ultrasensitive differential scanning calorimetry (DSC) is an indispensable thermophysical technique enabling to get direct information on enthalpies accompanying heating/cooling of dilute biopolymer solutions. The thermal dependence of protein heat capacity extracted from DSC data is a valuable source of information on intrinsic disorder level of a protein. Application details and limitations of DSC technique in exploration of protein intrinsic disorder are described. PMID- 22821533 TI - Identifying disordered regions in proteins by limited proteolysis. AB - Limited proteolysis experiments can be successfully used to detect sites of disorder in otherwise folded globular proteins. The approach relies on the fact that the proteolysis of a polypeptide substrate requires its binding in an extended conformation at the protease's active site and thus an enhanced backbone flexibility or local unfolding of the site of proteolytic attack. A striking correlation was found between sites of limited proteolysis and sites of enhanced chain flexibility of the polypeptide chain, this last evaluated by the crystallographically determined B-factor. In numerous cases, it has been shown that limited proteolysis occurs at chain regions characterized by missing electron density and thus being disordered. Therefore, limited proteolysis is a simple and reliable experimental technique that can detect sites of disorder in proteins, thus complementing the results that can be obtained by the use of other physicochemical and computational approaches. PMID- 22821534 TI - The effect of counter ions on the conformation of intrinsically disordered proteins studied by size-exclusion chromatography. AB - Counter ions are able to change the conformation of intrinsically disordered proteins (IDPs) to a more compact structure via the reduction of electrostatic repulsion. When the extended IDP conformation is transformed into a more ordered one, the value of the Stokes radius should decrease. Size-exclusion chromatography is a simple method for the determination of the Stokes radius, which describes the hydrodynamic properties of protein molecules. In our paper size-exclusion chromatography experiments of Starmaker (a highly acidic IDP), in the presence of various counter ions, are presented as an example of a simple experimental method, which provides valuable information about subtle counter ions-induced conformational changes in IDP. PMID- 22821535 TI - Mean net charge of intrinsically disordered proteins: experimental determination of protein valence by electrophoretic mobility measurements. AB - Under physiological conditions, intrinsically disordered proteins (IDPs) are unfolded, mainly because of their low hydrophobicity and the strong electrostatic repulsion between charged residues of the same sign within the protein. Softwares have been designed to facilitate the computation of the mean net charge of proteins (formally protein valence) from their amino acid sequences. Nevertheless, discrepancies between experimental and computed valence values for several proteins have been reported in the literature. Hence, experimental approaches are required to obtain accurate estimation of protein valence in solution. Moreover, ligand-induced disorder-to-order transition is involved in the folding of numerous IDPs. Some of the ligands are cations or anions, which, upon protein binding, decrease the mean net charge of the protein, favoring its folding via a charge reduction effect. An accurate determination of the mean net charge of protein in both its ligand-free intrinsically disordered state and in its folded, ligand-bound state allows one to estimate the number of ligands bound to the protein in the holo-state. Here, we describe an experimental protocol to determine the mean net charge of protein, from its electrophoretic mobility, its molecular mass and its hydrodynamic radius. PMID- 22821536 TI - Protein characterization by partitioning in aqueous two-phase systems. AB - Protein partitioning in aqueous two-phase systems is a technique that enables one to monitor changes in the 3D structures of proteins in solution resulting from chemical modifications, conformational changes, and interactions with other proteins and ligands. The advantage of this technique is that it may be used to monitor the aforementioned changes for purified proteins as well as for proteins in biological fluids, and that it is readily adaptable to automated high throughput mode. PMID- 22821537 TI - Detection and characterization of large-scale protein conformational transitions in solution using charge-state distribution analysis in ESI-MS. AB - Ion charge-state distribution analysis in electro-spray ionization mass spectrometry (ESI-MS) is a robust and fast technique for direct detection and characterization of coexisting protein conformations in solution. Compact folded proteins give rise to ESI-generated ions carrying a relatively small number of charges, whereas less compact conformers accommodate upon ESI a larger number of charges depending on the extent of their unfolding. A chemometric approach [1] based upon factor analysis is applied to determine contributions from individual conformers to the overall CSD. Here we present basic guidelines for the use of this MS-based technique: from the preparation of suitable solutions for ESI-MS to the acquisition of reliable MS data and their subsequent analysis. PMID- 22821538 TI - Localizing flexible regions in proteins using hydrogen-deuterium exchange mass spectrometry. AB - Hydrogen-deuterium exchange (HDX) can provide invaluable structural information for proteins. The incorporation of deuterium into a protein's backbone amide is readily monitored by mass spectrometry (MS). Assuming that the molecular weight of the protein is not a limiting factor of the MS, HDXMS can be performed on intact proteins; however, digesting the protein prior to MS allows one to assign HDX information to specific peptides within the protein. Here, we describe HDXMS data collection and analysis to identify regions based on their degree of protection in the pharmaceutical protein glucocerebrosidase (GCase). PMID- 22821540 TI - Characterization of oligomerization-aggregation products of neurodegenerative target proteins by ion mobility mass spectrometry. AB - Protein amyloidogenesis is generally considered to be a major cause of two most severe neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). Formation and accumulation of fibrillar aggregates and plaques derived from alpha-synuclein (alpha-Syn) and beta-amyloid (Abeta) polypeptide in brain have been recognized as characteristics of Parkinson's disease and Alzheimer's disease. Oligomeric aggregates of alpha-Syn and Abeta are considered as neurotoxic intermediate products leading to progressive neurodegeneration. However, molecular details of the oligomerization and aggregation pathway(s) and the molecular structure details are still unclear. We describe here the application of ion-mobility mass spectrometry (IMS-MS) to the identification of alpha-Syn and Abeta oligomerization-aggregation products, and to the characterization of different conformational forms. IMS-MS is an analytical technique capable of separating gaseous ions based on their size, shape, and topography. IMS-MS studies of soluble alpha-Syn and Abeta-aggregates prepared by in vitro incubation over several days were performed on a quadrupole time of flight mass spectrometer equipped with a "travelling wave" ion mobility cell, and revealed the presence of different conformational states and, remarkably, truncation and proteolytic products of high aggregating reactivity. These results suggest that different polypeptide sequences may contribute to the formation of oligomeric aggregates of heterogeneous composition and distinct biochemical properties. PMID- 22821539 TI - Mass spectrometry tools for analysis of intermolecular interactions. AB - The small quantities of protein required for mass spectrometry (MS) make it a powerful tool to detect binding (protein-protein, protein-small molecule, etc.) of proteins that are difficult to express in large quantities, as is the case for many intrinsically disordered proteins. Chemical cross-linking, proteolysis, and MS analysis, combined, are a powerful tool for the identification of binding domains. Here, we present a traditional approach to determine protein-protein interaction binding sites using heavy water ((18)O) as a label. This technique is relatively inexpensive and can be performed on any mass spectrometer without specialized software. PMID- 22821541 TI - Identifying solubility-promoting buffers for intrinsically disordered proteins prior to purification. AB - Intrinsically disordered proteins are anticipated to be more prone to aggregation than folded, stable proteins. Chemical additives included in the buffer can help maintain proteins in a soluble, monomeric state. However, the array of chemicals that impact protein solubility is staggering, precluding iterative testing of chemical conditions during purification. Herein, we describe a filter-based aggregation assay to rapidly identify chemical additives that maintain solubility for a protein of interest. A hierarchical approach to buffer selection is provided, in which the type of chemical which best improves solubility is first determined, followed by identifying the optimal chemical and its most effective concentration. Finally, combinations of chemical additives can be assessed if necessary. Although this assay can be applied to purified protein, partially purified protein, or aggregated protein, this protocol specifically details the use of this assay for crude cell lysate. This approach allows identification of solubility-promoting buffers prior to the initial protein purification. PMID- 22821542 TI - Proteomic methods for the identification of intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) lack fixed 3D structure under physiological conditions, yet they often carry out critically important physiological functions. The first few disordered proteins have been discovered one-by-one from clues that suggested that a protein lacks structure. Since bioinformatic predictions suggest that a large portion of eukaryotic proteomes contains significant levels of protein disorder, a reliable method for the large scale separation and identification of these proteins is needed. IDPs do not undergo large-scale structural changes and aggregation at low pH or elevated temperatures. Thus, such proteins are likely to remain soluble under these extreme conditions, making acid treatment and/or heat treatment suitable for substantial enrichment of intrinsically unfolded proteins in the soluble fraction. PMID- 22821543 TI - Selective isotope labeling of recombinant proteins in Escherichia coli. AB - Selective stable-isotope labeling is a useful technique to study structures of proteins, especially intrinsically disordered proteins, by nuclear magnetic resonance spectroscopy. Here, we describe a simple method for amino acid selective isotope labeling of recombinant proteins in E. coli. This method only requires addition of an excess of unlabeled amino acids and, if necessary, enzyme inhibitors to the culture medium. Its efficiency has been demonstrated even in labeling with glutamine or glutamate that is easily converted to other amino acid types by the metabolic pathways of E. coli. PMID- 22821545 TI - Pelvic angiosarcoma occurring in a postmenopausal female: case report and review of the literature. PMID- 22821546 TI - Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9. AB - Semaphorin 5A, a member of semaphorin family, was originally identified as axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, its functional roles and mechanism(s) in invasion and metastasis of gastric cancer remain unclear. By using human gastric caner cell lines Parental SGC7901, SGC7901-siScrambled and SGC7901-siSema 5A, we found that semaphorin 5A significantly promoted the invasive and metastatic abilities of gastric cancer cell in vitro. Semaphorin 5A increased the expression of MMP9 by activating phosphorylated ErK1/2 in gastric cancer cell. Furthermore, MEK inhibitor PD98059 and MMP9 antibody (Ab) significantly inhibited in vitro invasive and metastatic abilities induced by semaphorin 5A. Taken together, the present work revealed a novel function of semaphorin 5A that the existence of semaphorin 5A could promote invasion and metastasis of gastric cancer by regulating MMP9 expression, at least partially, via the MEK/ERKs signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy. PMID- 22821547 TI - Macrocephaly, obesity, mental (intellectual) disability, and ocular abnormalities: alternative definition and further delineation of MOMO syndrome. AB - MOMO syndrome, previously defined as Macrosomia, Obesity, Macrocephaly, and Ocular abnormalities (OMIM 157980) is a rare intellectual disability syndrome of unknown cause. We describe two further patients with MOMO syndrome. Reported data of patients with MOMO syndrome and our own findings indicate that overgrowth does not appear to be a specific feature. We propose to form the acronym "MOMO" from Macrocephaly, Obesity, Mental (intellectual) disability, and Ocular abnormalities, excluding macrosomia from the syndrome name. The combination of obesity, macrocephaly, and colobomas is unique, therefore these features can be used as major diagnostic criteria of MOMO syndrome. PMID- 22821544 TI - Role of EphA/ephrin--a signaling in the development of topographic maps in mouse corticothalamic projections. AB - Corticothalamic (CT) feedback outnumbers thalamocortical projections and regulates sensory information processing at the level of the thalamus. It is well established that EphA7, a member of EphA receptor family, is involved in the topographic mapping of CT projections. The aim of the present study was to dissect the precise impact of EphA7 on each step of CT growth. We used in utero electroporation-mediated EphA7 overexpression in developing somatosensory CT axons to dissect EphA7/ephrin-A-dependent mechanisms involved in regulating both initial targeting and postnatal growth of the CT projections. Our data revealed that topographic maps of cortical afferents in the ventrobasal complex and medial part of the posterior complex in the thalamus become discernible shortly after birth and are fully established by the second postnatal week. This process starts with the direct ingrowth of the CT axons to the designated areas within target thalamic nuclei and by progressive increase of axonal processes in the terminal zones. Large-scale overproduction and elimination of exuberant widespread axonal branches outside the target zone was not observed. Each developmental event was coordinated by spatially and temporally different responsiveness of CT axons to the ephrin-A gradient in thalamic nuclei, as well as by the matching levels of EphA7 in CT axons and ephrin-As in thalamic nuclei. These results support the concept that the topographic connections between the maps in the cerebral cortex and corresponding thalamic nuclei are genetically prespecified to a large extent, and established by precise spatiotemporal molecular mechanisms that involve the Eph family of genes. PMID- 22821548 TI - Hepatic stellate cells and cirrhosis: fishing for cures. PMID- 22821549 TI - Overview of calpain-mediated regulation of bone and fat mass in osteoblasts. AB - The receptor for parathyroid hormone (PTH) and PTH-related peptide (PTH1R) belongs to the class II G protein-coupled receptor superfamily. The calpain small subunit encoded by the gene Capns1 is the second protein and the first enzyme identified by a yeast two-hybrid screen using the intracellular C-terminal tail of the rat PTH1R. The calpain regulatory small subunit forms a heterodimer with the calpain large catalytic subunit and modulates various cellular functions as a cysteine protease. To investigate a physiological role of the calpain small subunit in cells of the osteoblast lineage, we generated osteoblast-specific Capns1 knockout mouse models and characterized their bone phenotype. Molecular mechanisms by which calpain modulates cell proliferation of the osteoblast lineage were further examined in vitro. Moreover, we utilized the mutant mice as a disease model of osteoporosis accompanied with impaired bone resorptive function and suggested a possible clinical translation of our basic research finding. PMID- 22821550 TI - Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. AB - Treatment options for metastatic renal cell carcinoma (mRCC) have evolved very rapidly, as reflected by the approval of the many drugs that have shown efficacy in phase III studies. Approved drugs include tyrosine kinase inhibitors (TKI) such as sunitinib, sorafenib and pazopanib, vascular endothelial growth factor inhibitors such as bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus. These biological agents have toxicity profiles that differ from those accompanying current chemotherapeutic agents, but their novelty leads to a lack of exhaustive clinical data regarding related adverse events (AEs), whose symptoms may overlap with those of the chronic illnesses of patients with mRCC such as hypertension, hyperglycemia, and pneumonitis. Hypertension, hypothyroidism, hand-foot syndrome, and fatigue are AEs frequently associated with TKIs; whereas immunosuppression, stomatitis, metabolic alterations, and non-infectious pneumonitis are AEs of mTOR inhibitors. Recommendations for treating these adverse events in patients with mRCC are usually the same as those for the general population. Mild to moderate toxicities may be managed with supportive and pharmacologic interventions, but higher-grade toxicities usually require external specialist consultation, dose reductions, and treatment interruption or discontinuation. Some groups of patients with mRCC, such as frail, elderly patients, and patients with renal or liver dysfunction, require special management of AEs. PMID- 22821551 TI - Quantifying the eyeball test: sarcopenia, analytic morphomics, and liver transplantation. PMID- 22821553 TI - Olfactory disorders: distribution according to age and gender in 3,400 patients. AB - Aim of this investigation was to determine the distribution of gender and age with regard to major causes of olfactory loss, (1) trauma, (2) acute upper respiratory tract infections [URI], (3) sinunasal causes like sinusitis or nasal polyposis and (4) idiopathic. Data from more than 3,400 patients were used. In agreement with other studies, we found that (1) for trauma the female to male ratio was 0.80 and mean age was 46 years, (2) for URI the numbers were 2.39 and mean age was 57 years, (3) for sinunasal causes the numbers were 0.95 and 50 years, and (4) for idiopathic causes the female to male ratio was 1.13 and mean age was 57 years. These differences with regard to age and gender may indicate that hormonal changes may play a role in post-URI olfactory loss. PMID- 22821554 TI - Overdose of pegfilgrastim: case report. AB - BACKGROUND: Pegfilgrastim is a G-CSF that can be administered in a single dose 24 h after each cycle of chemotherapy. CASE: 59 years-old man with a stage III-B peripheral T lymphoma with CD4 expression. Dose-dense chemotherapy was started with CHOP-14 combined with pegfilgrastim as primary prophylaxis. An error in the dispensing system meant that the patient received pegfilgrastim for 4 consecutive days. He remained under observation in hospital. During the 3 days after the last dose of pegfilgrastim, the patient remained stable, with no remarkable symptoms or associated laboratory abnormalities, and was discharged. CONCLUSION: The case we describe and the available literature lead us to suggest close monitoring as the main measure to be adopted when treating a patient for pegfilgrastim overdose. PMID- 22821552 TI - Biglycan: a multivalent proteoglycan providing structure and signals. AB - Research over the past few years has provided fascinating results indicating that biglycan, besides being a ubiquitous structural component of the extracellular matrix (ECM), may act as a signaling molecule. Proteolytically released from the ECM, biglycan acts as a danger signal signifying tissue stress or injury. As a ligand of innate immunity receptors and activator of the inflammasome, biglycan stimulates multifunctional proinflammatory signaling linking the innate to the adaptive immune response. By clustering several types of receptors on the cell surface and orchestrating their downstream signaling events, biglycan is capable to autonomously trigger sterile inflammation and to potentiate the inflammatory response to microbial invasion. Besides operating in a broad biological context, biglycan also displays tissue-specific affinities to certain receptors and structural components, thereby playing a crucial role in bone formation, muscle integrity, and synapse stability at the neuromuscular junction. This review attempts to provide a concise summary of recent data regarding the involvement of biglycan in the regulation of inflammation and the musculoskeletal system, pointing out both a signaling and a structural role for this proteoglycan. The potential of biglycan as a novel therapeutic target or agent for the treatment of inflammatory diseases and skeletal muscular dystrophies is also addressed. PMID- 22821555 TI - Communication barriers in counselling foreign-language patients in public pharmacies: threats to patient safety? AB - BACKGROUND: Foreign-language (FL) patients are at increased risk for adverse drug events. Evidence regarding communication barriers and the safety of pharmaceutical care of FL patients in European countries is scarce despite large migrant populations. OBJECTIVE: To investigate Swiss public pharmacists' experiences and current practices in counselling FL patients with a focus on patient safety. METHOD: In a cross-sectional study heads of public pharmacies in Switzerland were surveyed using an electronic questionnaire. MAIN OUTCOME MEASURE: The survey assessed the frequency of communication barriers encountered in medication counselling of FL patients, perceptions of risks for adverse drug events, satisfaction with the quality of counselling provided to FL patients, current strategies to reduce risks, and preferences towards tools to improve safety for FL patients. RESULTS: 498 pharmacists completed the survey (43 % response rate). More than every second pharmacist reported at least weekly encounters at which they cannot provide good medication counselling to FL patients in the regional Swiss language. Ad-hoc interpreting by minors is also common at a considerable number of pharmacies (26.5 % reported at least one weekly occurrence). Approximately 10 % of pharmacies reported that they fail at least weekly to explain the essentials of drug therapy (e.g. dosing of children's medications) to FL patients. 79.8 % perceived the risk of FL patients for adverse drug events to be somewhat or much higher compared to other patients. 22.5 % of pharmacists reported being concerned at least monthly about medication safety when FL patients leave their pharmacy. However, the majority of pharmacists were satisfied with the quality of care provided to FL patients in their pharmacy [78.6 % (very) satisfied]. The main strategy used to improve counselling for FL patients was the employment of multilingual staff. Participants would use software for printing foreign-language labels (41.2 %) and multilingual package inserts (42.0 %) if these were available. CONCLUSION: Communication barriers with FL patients are frequent in Swiss pharmacies and pharmacists perceive FL patients to be at increased risk for adverse drug events. Development and dissemination of communication tools are needed to support pharmacists in counselling of a diverse migrant population. PMID- 22821556 TI - Comparison of human exposure pathways in an urban brownfield: reduced risk from paving roads. AB - Risk assessments often do not quantify the risk associated with soil inhalation. This pathway generally makes a negligible contribution to the cumulative risk, because soil ingestion is typically the dominant exposure pathway. Conditions in northern or rural centers in Canada characterized by large areas of exposed soil, including unpaved roads, favor the resuspension of soil particles, making soil inhalation a relevant risk pathway. The authors determined and compared human exposure to metals and polycyclic aromatic hydrocarbons (PAHs) from soil ingestion and inhalation and analyzed the carcinogenic and noncarcinogenic risks before and after roads were paved in a northern community. To determine the inhalation exposure, three size fractions of airborne particulate matter were collected (total suspended particulates [TSP], particulate matter with an aerodynamic diameter less than 10 um [PM10], and particulate matter with an aerodynamic diameter less than 2.5 um [PM2.5]) before and after roads were paved. Road paving reduced the concentration of many airborne contaminants by 25 to 75%, thus reducing risk. For example, before paving, the carcinogenic risk associated with inhalation of Cr was 3.4 excess cancers per 100,000 people exposed, whereas after paving, this risk was reduced to 1.6 in 100,000. Paving roads reduced the concentrations of total suspended particulates (TSP; p < 0.1) and PM10 (p < 0.05) but not PM25. Consequently, the ingestion of inhaled soil particles was substantially reduced. The authors conclude that resuspended soil is likely an important source of risk for many northern communities and that paving roads is an effective method of reducing risk from the inhalation of soil particles. PMID- 22821557 TI - Decision making, impulsivity, and addictions: do Parkinson's disease patients jump to conclusions? AB - Links between impulsive-compulsive behaviors (ICBs) in treated Parkinson's disease (PD), behavioral addictions, and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with PD with and without ICBs with illicit drug abusers, pathological gamblers, and age-matched healthy controls using the beads task, a test of reflection impulsivity, and a working memory task. We found that all patients with PD made more impulsive and irrational choices than the control group. PD patients who had an ICB showed similar behavior to illicit substance abusers, whereas patients without ICBs more closely resembled pathological gamblers. In contrast, we found no difference in working memory performance within the PD groups. However, PD patients without ICBs remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the PD patients with respect to whether or not they had an ICB by analyzing three trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3%, and we propose that this task may prove to be a powerful screening tool to detect an ICB in PD. Our results also suggest that intact cortical processing and less distractibility in PD patients without ICBs may protect them from developing behavioral addictions. PMID- 22821558 TI - Computational identification of new structured cis-regulatory elements in the 3' untranslated region of human protein coding genes. AB - Messenger ribonucleic acids (RNAs) contain a large number of cis-regulatory RNA elements that function in many types of post-transcriptional regulation. These cis-regulatory elements are often characterized by conserved structures and/or sequences. Although some classes are well known, given the wide range of RNA interacting proteins in eukaryotes, it is likely that many new classes of cis regulatory elements are yet to be discovered. An approach to this is to use computational methods that have the advantage of analysing genomic data, particularly comparative data on a large scale. In this study, a set of structural discovery algorithms was applied followed by support vector machine (SVM) classification. We trained a new classification model (CisRNA-SVM) on a set of known structured cis-regulatory elements from 3'-untranslated regions (UTRs) and successfully distinguished these and groups of cis-regulatory elements not been strained on from control genomic and shuffled sequences. The new method outperformed previous methods in classification of cis-regulatory RNA elements. This model was then used to predict new elements from cross-species conserved regions of human 3'-UTRs. Clustering of these elements identified new classes of potential cis-regulatory elements. The model, training and testing sets and novel human predictions are available at: http://mRNA.otago.ac.nz/CisRNA-SVM. PMID- 22821559 TI - Protein L5 is crucial for in vivo assembly of the bacterial 50S ribosomal subunit central protuberance. AB - In the present work, ribosomes assembled in bacterial cells in the absence of essential ribosomal protein L5 were obtained. After arresting L5 synthesis, Escherichia coli cells divide a limited number of times. During this time, accumulation of defective large ribosomal subunits occurs. These 45S particles lack most of the central protuberance (CP) components (5S rRNA and proteins L5, L16, L18, L25, L27, L31, L33 and L35) and are not able to associate with the small ribosomal subunit. At the same time, 5S rRNA is found in the cytoplasm in complex with ribosomal proteins L18 and L25 at quantities equal to the amount of ribosomes. Thus, it is the first demonstration that protein L5 plays a key role in formation of the CP during assembly of the large ribosomal subunit in the bacterial cell. A possible model for the CP assembly in vivo is discussed in view of the data obtained. PMID- 22821560 TI - Movement of DNA sequence recognition domains between non-orthologous proteins. AB - Comparisons of proteins show that they evolve through the movement of domains. However, in many cases, the underlying mechanisms remain unclear. Here, we observed the movements of DNA recognition domains between non-orthologous proteins within a prokaryote genome. Restriction-modification (RM) systems, consisting of a sequence-specific DNA methyltransferase and a restriction enzyme, contribute to maintenance/evolution of genomes/epigenomes. RM systems limit horizontal gene transfer but are themselves mobile. We compared Type III RM systems in Helicobacter pylori genomes and found that target recognition domain (TRD) sequences are mobile, moving between different orthologous groups that occupy unique chromosomal locations. Sequence comparisons suggested that a likely underlying mechanism is movement through homologous recombination of similar DNA sequences that encode amino acid sequence motifs that are conserved among Type III DNA methyltransferases. Consistent with this movement, incongruence was observed between the phylogenetic trees of TRD regions and other regions in proteins. Horizontal acquisition of diverse TRD sequences was suggested by detection of homologs in other Helicobacter species and distantly related bacterial species. One of these RM systems in H. pylori was inactivated by insertion of another RM system that likely transferred from an oral bacterium. TRD movement represents a novel route for diversification of DNA-interacting proteins. PMID- 22821561 TI - Trans-kingdom rescue of Gln-tRNAGln synthesis in yeast cytoplasm and mitochondria. AB - Aminoacylation of transfer RNA(Gln) (tRNA(Gln)) is performed by distinct mechanisms in different kingdoms and represents the most diverged route of aminoacyl-tRNA synthesis found in nature. In Saccharomyces cerevisiae, cytosolic Gln-tRNA(Gln) is generated by direct glutaminylation of tRNA(Gln) by glutaminyl tRNA synthetase (GlnRS), whereas mitochondrial Gln-tRNA(Gln) is formed by an indirect pathway involving charging by a non-discriminating glutamyl-tRNA synthetase and the subsequent transamidation by a specific Glu-tRNA(Gln) amidotransferase. Previous studies showed that fusion of a yeast non-specific tRNA-binding cofactor, Arc1p, to Escherichia coli GlnRS enables the bacterial enzyme to substitute for its yeast homologue in vivo. We report herein that the same fusion enzyme, upon being imported into mitochondria, substituted the indirect pathway for Gln-tRNA(Gln) synthesis as well, despite significant differences in the identity determinants of E. coli and yeast cytosolic and mitochondrial tRNA(Gln) isoacceptors. Fusion of Arc1p to the bacterial enzyme significantly enhanced its aminoacylation activity towards yeast tRNA(Gln) isoacceptors in vitro. Our study provides a mechanism by which trans-kingdom rescue of distinct pathways of Gln-tRNA(Gln) synthesis can be conferred by a single enzyme. PMID- 22821563 TI - Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. AB - Cells release RNA-carrying vesicles and membrane-free RNA/protein complexes into the extracellular milieu. Horizontal vesicle-mediated transfer of such shuttle RNA between cells allows dissemination of genetically encoded messages, which may modify the function of target cells. Other studies used array analysis to establish the presence of microRNAs and mRNA in cell-derived vesicles from many sources. Here, we used an unbiased approach by deep sequencing of small RNA released by immune cells. We found a large variety of small non-coding RNA species representing pervasive transcripts or RNA cleavage products overlapping with protein coding regions, repeat sequences or structural RNAs. Many of these RNAs were enriched relative to cellular RNA, indicating that cells destine specific RNAs for extracellular release. Among the most abundant small RNAs in shuttle RNA were sequences derived from vault RNA, Y-RNA and specific tRNAs. Many of the highly abundant small non-coding transcripts in shuttle RNA are evolutionary well-conserved and have previously been associated to gene regulatory functions. These findings allude to a wider range of biological effects that could be mediated by shuttle RNA than previously expected. Moreover, the data present leads for unraveling how cells modify the function of other cells via transfer of specific non-coding RNA species. PMID- 22821562 TI - PKC phosphorylates HEXIM1 and regulates P-TEFb activity. AB - The positive transcription elongation factor b (P-TEFb) regulates RNA polymerase II elongation. In cells, P-TEFb partitions between small active and larger inactive states. In the latter, HEXIM1 binds to 7SK snRNA and recruits as well as inactivates P-TEFb in the 7SK snRNP. Several stimuli can affect this P-TEFb equilibrium. In this study, we demonstrate that protein kinase C (PKC) phosphorylates the serine at position158 (S158) in HEXIM1. This phosphorylated HEXIM1 protein neither binds to 7SK snRNA nor inhibits P-TEFb. Phorbol esters or the engagement of the T cell antigen receptor, which activate PKC and the expression of the constitutively active (CA) PKCtheta protein, which is found in T cells, inhibit the formation of the 7SK snRNP. All these stimuli increase P TEFb-dependent transcription. In contrast, the kinase-negative PKCtheta and the mutant HEXIM1 (S158A) proteins block effects of these PKC-activating stimuli. These results indicate that the phosphorylation of HEXIM1 by PKC represents a major regulatory step of P-TEFb activity in cells. PMID- 22821564 TI - Structural and functional analysis of the transcriptional regulator Rv3066 of Mycobacterium tuberculosis. AB - The Mmr multidrug efflux pump recognizes and actively extrudes a broad range of antimicrobial agents, and promotes the intrinsic resistance to these antimicrobials in Mycobacterium tuberculosis. The expression of Mmr is controlled by the TetR-like transcriptional regulator Rv3066, whose open reading frame is located downstream of the mmr operon. To understand the structural basis of Rv3066 regulation, we have determined the crystal structures of Rv3066, both in the absence and presence of bound ethidium, revealing an asymmetric homodimeric two-domain molecule with an entirely helical architecture. The structures underscore the flexibility and plasticity of the regulator essential for multidrug recognition. Comparison of the apo-Rv3066 and Rv3066-ethidium crystal structures suggests that the conformational changes leading to drug-mediated derepression is primarily due to a rigid body rotational motion within the dimer interface of the regulator. The Rv3066 regulator creates a multidrug-binding pocket, which contains five aromatic residues. The bound ethidium is found buried within the multidrug-binding site, where extensive aromatic stacking interactions seemingly govern the binding. In vitro studies reveal that the dimeric Rv3066 regulator binds to a 14-bp palindromic inverted repeat sequence in the nanomolar range. These findings provide new insight into the mechanisms of ligand binding and Rv3066 regulation. PMID- 22821565 TI - Functional screening for miRNAs targeting Smad4 identified miR-199a as a negative regulator of TGF-beta signalling pathway. AB - The transforming growth factor-beta (TGF-beta) signalling pathway participates in various biological processes. Dysregulation of Smad4, a central cellular transducer of TGF-beta signalling, is implicated in a wide range of human diseases and developmental disorders. However, the mechanisms underlying Smad4 dysregulation are not fully understood. Using a functional screening approach based on luciferase reporter assays, we identified 39 microRNAs (miRNAs) as potential regulators of Smad4 from an expression library of 388 human miRNAs. The screening was supported by bioinformatic analysis, as 24 of 39 identified miRNAs were also predicted to target Smad4. MiR-199a, one of the identified miRNAs, was inversely correlated with Smad4 expression in various human cancer cell lines and gastric cancer tissues, and repressed Smad4 expression and blocked canonical TGF beta transcriptional responses in cell lines. These effects were dependent on the presence of a conserved, but not perfect seed paired, miR-199a-binding site in the Smad4 3'-untranslated region (UTR). Overexpression of miR-199a significantly inhibited the ability of TGF-beta to induce gastric cancer cell growth arrest and apoptosis in vitro, and promoted anchorage-independent growth in soft agar, suggesting that miR-199a plays an oncogenic role in human gastric tumourigenesis. In conclusion, our functional screening uncovers multiple miRNAs that regulate the cellular responsiveness to TGF-beta signalling and reveals important roles of miR-199a in gastric cancer by directly targeting Smad4. PMID- 22821566 TI - Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain. AB - Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the mouse liver, we show that the majority of genes were associated with a single prominent H2A.Z containing nucleosome in their promoter region. We classified genes into clusters depending on the proximity of H2A.Z to the TSS. The genes with no detectable H2A.Z showed lowest expression level, whereas H2A.Z was positioned closer to the TSS of genes with higher expression levels. We confirmed this relation between the proximity of H2A.Z and expression level in the brain. The proximity of histone variant H2A.Z, but not H3.3 to the TSS, over seven consecutive nucleosomes, was correlated with expression. Further, a nucleosome was positioned over the TSS of silenced genes while it was displaced to expose the TSS in highly expressed genes. Our results suggest that gene expression levels in vivo are determined by accessibility of the TSS and proximity of H2A.Z. PMID- 22821567 TI - MetaVelvet: an extension of Velvet assembler to de novo metagenome assembly from short sequence reads. AB - An important step in 'metagenomics' analysis is the assembly of multiple genomes from mixed sequence reads of multiple species in a microbial community. Most conventional pipelines use a single-genome assembler with carefully optimized parameters. A limitation of a single-genome assembler for de novo metagenome assembly is that sequences of highly abundant species are likely misidentified as repeats in a single genome, resulting in a number of small fragmented scaffolds. We extended a single-genome assembler for short reads, known as 'Velvet', to metagenome assembly, which we called 'MetaVelvet', for mixed short reads of multiple species. Our fundamental concept was to first decompose a de Bruijn graph constructed from mixed short reads into individual sub-graphs, and second, to build scaffolds based on each decomposed de Bruijn sub-graph as an isolate species genome. We made use of two features, the coverage (abundance) difference and graph connectivity, for the decomposition of the de Bruijn graph. For simulated datasets, MetaVelvet succeeded in generating significantly higher N50 scores than any single-genome assemblers. MetaVelvet also reconstructed relatively low-coverage genome sequences as scaffolds. On real datasets of human gut microbial read data, MetaVelvet produced longer scaffolds and increased the number of predicted genes. PMID- 22821568 TI - RNAsnapTM: a rapid, quantitative and inexpensive, method for isolating total RNA from bacteria. AB - RNAsnapTM is a simple and novel method that recovers all intracellular RNA quantitatively (>99%), faster (<15 min) and less expensively (~3 cents/sample) than any of the currently available RNA isolation methods. In fact, none of the bacterial RNA isolation methods, including the commercial kits, are effective in recovering all species of intracellular RNAs (76-5700 nt) with equal efficiency, which can lead to biased results in genome-wide studies involving microarray or RNAseq analysis. The RNAsnapTM procedure yields ~60 ug of RNA from 10(8) Escherichia coli cells that can be used directly for northern analysis without any further purification. Based on a comparative analysis of specific transcripts ranging in size from 76 to 5700 nt, the RNAsnapTM method provided the most accurate measure of the relative amounts of the various intracellular RNAs. Furthermore, the RNAsnapTM RNA was successfully used in enzymatic reactions such as RNA ligation, reverse transcription, primer extension and reverse transcriptase-polymerase chain reaction, following sodium acetate/ethanol precipitation. The RNAsnapTM method can be used to isolate RNA from a wide range of Gram-negative and Gram-positive bacteria as well as yeast. PMID- 22821569 TI - The role of patients' explanatory models and daily-lived experience in hypertension self-management. AB - BACKGROUND: Uncontrolled hypertension remains a significant problem for many patients. Few interventions to improve patients' hypertension self-management have had lasting effects. Previous work has focused largely on patients' beliefs as predictors of behavior, but little is understood about beliefs as they are embedded in patients' social contexts. OBJECTIVE: This study aims to explore how patients' "explanatory models" of hypertension (understandings of the causes, mechanisms or pathophysiology, course of illness, symptoms and effects of treatment) and social context relate to their reported daily hypertension self management behaviors. DESIGN: Semi-structured qualitative interviews with a diverse group of patients at two large urban Veterans Administration Medical centers. PARTICIPANTS (OR PATIENTS OR SUBJECTS): African-American, white and Latino Veterans Affairs (VA) primary care patients with uncontrolled blood pressure. APPROACH: We conducted thematic analysis using tools of grounded theory to identify key themes surrounding patients' explanatory models, social context and hypertension management behaviors. RESULTS: Patients' perceptions of the cause and course of hypertension, experiences of hypertension symptoms, and beliefs about the effectiveness of treatment were related to different hypertension self-management behaviors. Moreover, patients' daily-lived experiences, such as an isolated lifestyle, serious competing health problems, a lack of habits and routines, barriers to exercise and prioritizing lifestyle choices, also interfered with optimal hypertension self-management. CONCLUSIONS: Designing interventions to improve patients' hypertension self-management requires consideration of patients' explanatory models and their daily-lived experience. We propose a new conceptual model - the dynamic model of hypertension self-management behavior - which incorporates these key elements of patients' experiences. PMID- 22821570 TI - Insurance status, not race, is associated with mortality after an acute cardiovascular event in Maryland. AB - BACKGROUND: It is unclear how lack of health insurance or otherwise being underinsured contributes to observed racial disparities in health outcomes related to cardiovascular disease. OBJECTIVE: To determine the relative risk of death associated with insurance and race after hospital admission for an acute cardiovascular event. DESIGN: Prospective cohort study in three hospitals in Maryland representing different demographics between 1993 and 2007. PATIENTS: Patients with an incident admission who were either white or black, and had either private insurance, state-based insurance or were uninsured. 4,908 patients were diagnosed with acute myocardial infarction, 6,759 with coronary atherosclerosis, and 1,293 with stroke. MAIN MEASURES: Demographic and clinical patient-level data were collected from an administrative billing database and neighborhood household income was collected from the 2000 US Census. The outcome of all-cause mortality was collected from the Social Security Death Master File. KEY RESULTS: In an analysis adjusted for race, disease severity, location, neighborhood household income among other confounders, being underinsured was associated with an increased risk of death after myocardial infarction (relative hazard, 1.31 [95 % CI: 1.09, 1.59]), coronary atherosclerosis (relative hazard, 1.50 [95 % CI: 1.26, 1.80]) or stroke (relative hazard, 1.25 [95 % CI: 0.91, 1.72]). Black race was not associated with an increased risk of death after myocardial infarction (relative hazard, 1.03 [95 % CI: 0.85, 1.24]), or after stroke (relative hazard, 1.18 [95 % CI: 0.86, 1.61]) and was associated with a decreased risk of death after coronary atherosclerosis (relative hazard, 0.82 [95 % CI: 0.69, 0.98]). CONCLUSIONS: Race was not associated with an increased risk of death, before or after adjustment. Being underinsured was strongly associated with death among those admitted with myocardial infarction, or a coronary atherosclerosis event. Our results support growing evidence implicating insurance status and socioeconomic factors as important drivers of health disparities, and potentially racial disparities. PMID- 22821572 TI - PHOTO QUIZ. A man with AIDS and gastric ulcers. PMID- 22821571 TI - Clinician stress and patient-clinician communication in HIV care. AB - BACKGROUND: Clinician stress is common, but few studies have examined its relationship with communication behaviors. OBJECTIVE: To investigate associations between clinician stress and patient-clinician communication in primary HIV care. DESIGN: Observational study. PARTICIPANTS: Thirty-three primary HIV clinicians and 350 HIV-infected adult, English-speaking patients at three U.S. HIV specialty clinic sites. MAIN MEASURES: Clinicians completed the Perceived Stress Scale, and we categorized scores in tertiles. Audio-recordings of patient-clinician encounters were coded using the Roter Interaction Analysis System. Patients rated the quality of their clinician's communication and overall quality of medical care. We used regression with generalized estimating equations to examine associations between clinician stress and communication outcomes, controlling for clinician gender, clinic site, and visit length. KEY RESULTS: Among the 33 clinicians, 70 % were physicians, 64 % were women, 67 % were non-Hispanic white, and the mean stress score was 3.9 (SD 2.4, range 0-8). Among the 350 patients, 34 % were women, 55 % were African American, 23 % were non-Hispanic white, 16 % were Hispanic, and 30 % had been with their clinicians >5 years. Verbal dominance was higher for moderate-stress clinicians (ratio=1.93, p<0.01) and high-stress clinicians (ratio=1.76, p=0.01), compared with low-stress clinicians (ratio 1.45). More medical information was offered by moderate-stress clinicians (145.5 statements, p <0.01) and high-stress clinicians (125.9 statements, p=0.02), compared with low-stress clinicians (97.8 statements). High-stress clinicians offered less psychosocial information (17.1 vs. 19.3, p=0.02), and patients of high-stress clinicians rated their quality of care as excellent less frequently than patients of low-stress clinicians (49.5 % vs. 66.9 %, p<0.01). However, moderate-stress clinicians offered more partnering statements (27.7 vs. 18.2, p=0.04) and positive affect (3.88 vs. 3.78 score, p=0.02) than low-stress clinicians, and their patients' ratings did not differ. CONCLUSIONS: Although higher stress was associated with verbal dominance and lower patient ratings, moderate stress was associated with some positive communication behaviors. Prospective mixed methods studies should examine the complex relationships across the continuum of clinician well-being and health communication. PMID- 22821582 TI - "Mangrove 'killifish': an exemplar of integrative biology": introduction to the symposium. AB - The mangrove rivulus, Kryptolebias marmoratus, (hereafter, rivulus) is one of the only two vertebrates known to self-fertilize, with the other being a recently named close relative, Kryptolebias hermaphroditus (Tatarenkov et al. 2012). Rivulus is also the first fish species found to have environmental sex determination, whereby lower temperatures inhibit ovarian development, thus providing one potential route that avoids inbreeding depression (Harrington 1967; Conover 2004). Wild rivulus exist as androdioecious populations in which both hermaphrodites and, although relatively rare, males are found (Taylor 2000). In the laboratory, individual adult rivulus can produce isogenic embryos. Under as yet unknown environmental conditions, males develop and outcrossing between the hermaphrodites and males occurs (Taylor 2000; Mackiewicz et al. 2006a, 2006b). It is intriguing to consider the behavioral, neurological, and endocrinological control necessary to accommodate this reproductive strategy (Sakakura et al. 2006; Orlando et al. 2006; Earley et al. 2008). In addition to environmental sex determination and androdioecious reproduction, rivulus is also known to emerge from its aquatic surroundings and assume a transitory, terrestrial existence (Ong et al. 2007; Taylor et al. 2008; Cooper et al. 2012). Rivulus is an emerging and potentially powerful model for integrative and comparative biological research and, in part, this emergence has been catalyzed by this first symposium on its biology. The well-attended symposium comprised 11 speakers, which included four women and seven men, with academic ranks ranging from postdoctoral fellow to full professor, who came from four countries. This symposium will help drive future research within this taxon and will facilitate collaborations among researchers. It has already facilitated networking between heads of laboratories and current and potential future postdoctoral fellows and students. The organizing committee looks forward to the next rivulus symposium with great anticipation. PMID- 22821583 TI - Introduction to the symposium--barnacle biology: essential aspects and contemporary approaches. AB - Barnacles have evolved a number of specialized features peculiar for crustaceans: they produce a calcified, external shell; they exhibit sexual strategies involving dioecy and androdioecy; and some have become internal parasites of other Crustacea. The thoroughly sessile habit of adults also belies the highly mobile and complex nature of their larval stages. Given these and other remarkable innovations in their natural history, it is perhaps not surprising that barnacles present a spectrum of opportunities for study. This symposium integrates research on barnacles in the areas of larval biology, biofouling, reproduction, biogeography, speciation, population genetics, ecological genomics, and phylogenetics. Pioneering comparisons are presented of metamorphosis among barnacles from three major lineages. Biofouling is investigated from the perspectives of biochemical and biomechanical mechanisms. Tradeoffs in reproductive specializations are scrutinized through theoretical modeling and empirical validation. Patterns of endemism and diversity are delineated in Australia and intricate species boundaries in the genus Chthamalus are elucidated for the Indo-Pacific. General methodological concerns with population expansion studies in crustaceans are highlighted using barnacle models. Data from the first, draft barnacle genome are employed to examine location-specific selection. Lastly, barnacle evolution is framed in a deep phylogenetic context and hypothetical origins of defined characters are outlined and tested. PMID- 22821584 TI - Effects of capability for dispersal on the evolution of diversity in Antarctic benthos. AB - The likelihood of marine invertebrates to maintain large geographic ranges is widely dependent on the ability of their early ontogenetic stages to disperse over long distances. Marine benthic invertebrates inhabiting the cold stenothermal environment of the Southern Ocean are known for their overall reduced number of pelagic larvae, or drifting stages of any kind, when compared with organisms elsewhere in the sea. The diversity of organisms thriving in Antarctic waters is the result of evolution in situ and of the intrusion of species from surrounding seas. The reasons for a high level of endemism and a stunning diversity of benthic invertebrates found today are frequently discussed in the literature, but the mechanisms whereby diversity has been controlled over time remain largely theoretical. Here, I suggest that, indeed, early life-history patterns play a key role in defining the radiation and the speciation potential of Antarctic benthic invertebrates. In arguing this case, I synthesize the growing body of molecular studies on population connectivity in Antarctic benthic invertebrates, and compare this information with knowledge of their life histories and biogeography. I conclude that differences in early life-history patterns are key to the resilience potential of species in response to late Cenozoic glacial periods and propose that there is a direct relationship between rate of speciation and the ability of taxa to disperse. PMID- 22821581 TI - Extension of the CHARMM General Force Field to sulfonyl-containing compounds and its utility in biomolecular simulations. AB - Presented is an extension of the CHARMM General Force Field (CGenFF) to enable the modeling of sulfonyl-containing compounds. Model compounds containing chemical moieties such as sulfone, sulfonamide, sulfonate, and sulfamate were used as the basis for the parameter optimization. Targeting high-level quantum mechanical and experimental crystal data, the new parameters were optimized in a hierarchical fashion designed to maintain compatibility with the remainder of the CHARMM additive force field. The optimized parameters satisfactorily reproduced equilibrium geometries, vibrational frequencies, interactions with water, gas phase dipole moments, and dihedral potential energy scans. Validation involved both crystalline and liquid phase calculations showing the newly developed parameters to satisfactorily reproduce experimental unit cell geometries, crystal intramolecular geometries, and pure solvent densities. The force field was subsequently applied to study conformational preference of a sulfonamide based peptide system. Good agreement with experimental IR/NMR data further validated the newly developed CGenFF parameters as a tool to investigate the dynamic behavior of sulfonyl groups in a biological environment. CGenFF now covers sulfonyl group containing moieties allowing for modeling and simulation of sulfonyl-containing compounds in the context of biomolecular systems including compounds of medicinal interest. PMID- 22821585 TI - Reproductive output and duration of the pelagic larval stage determine seascape wide connectivity of marine populations. AB - Connectivity among marine populations is critical for persistence of metapopulations, coping with climate change, and determining the geographic distribution of species. The influence of pelagic larval duration (PLD) on connectivity has been studied extensively, but relatively little is known about the influence of other biological parameters, such as the survival and behavior of larvae, and the fecundity of adults, on population connectivity. Furthermore, the interaction between the seascape (habitat structure and currents) and these biological parameters is unclear. We explore these interactions using a biophysical model of larval dispersal across the Indo-Pacific. We describe an approach that quantifies geographic patterns of connectivity from demographically relevant to evolutionarily significant levels across a range of species. We predict that at least 95% of larval settlement occurs within 155 km of the source population and within 13 days irrespective of the species' life history, yet long distant connections remain likely. Self-recruitment is primarily driven by the local oceanography, larval mortality, and the larval precompetency period, whereas broad-scale connectivity is strongly influenced by reproductive output (abundance and fecundity of adults) and the length of PLD. The networks we have created are geographically explicit models of marine connectivity that define dispersal corridors, barriers, and the emergent structure of marine populations. These models provide hypotheses for empirical testing. PMID- 22821586 TI - Dynamic skeletogenesis in fishes: insight of exercise training on developmental plasticity. AB - BACKGROUND: Through developmental and evolutionary time, organisms respond variably to their environment not only in terms of size and shape but also in terms of timing. Developmental plasticity can potentially act on various aspects of the timing of developmental events (i.e., appearance, cessation, duration, sequence). In this study, we address the developmental plasticity of median fin endoskeleton by using exercise training on newly-hatched Arctic charr (Salvelinus alpinus). RESULTS: Developmental progress of cartilage formation (i.e., chondrification) in all fins is less influenced than ossification by an increase of water velocity. The most responsive elements, meaning those elements with greater onset plasticity owing to a water velocity increase, differ in terms of early versus late developmental events. The most responsive elements are those that chondrify and to a greater extent ossify later in the development. CONCLUSIONS: Plasticity is documented for the timing of appearance (i.e., onset) and the timing of transition from cartilage to bone (i.e., transitions of skeletal states) rather than the order of events within a sequence. Similarities of plastic response in developmental patterns could be used as a powerful criterion to strengthen the identification of phenotypic modules. PMID- 22821587 TI - Development, reliability, and validity of the Posttraumatic Stress Disorder Interview for Vietnamese refugees: a diagnostic instrument for Vietnamese refugees. AB - The Posttraumatic Stress Disorder Interview for Vietnamese Refugees (PTSD-IVR) was created specifically to assess for the presence of current and lifetime history of premigration, migration, encampment, and postmigration traumas in Vietnamese refugees. The purpose of the present study was to describe the development of and investigate the interrater and test-retest reliability of the PTSD-IVR and its validity in relation to the diagnoses obtained from the Longitudinal, Expert, and All Data (LEAD; Spitzer, 1983) standard. Clinicians conducted the diagnosis process with 127 Vietnamese refugees using the LEAD standard and the PTSD-IVR. Assessment of the reliability and validity of the PTSD IVR yielded good to excellent AUC (area under the receiver operating characteristic curve; .86, .87) and kappa values (.66, .74) indicating the reliability of the PTSD-IVR and the agreement between the LEAD procedure and the PTSD-IVR. The results of the present study suggest that the PTSD-IVR performs successfully as a diagnostic instrument specifically created for Vietnamese refugees in their native language. PMID- 22821589 TI - Cell perturbation screens for target identification by RNAi. AB - Over the last decade, cell-based screening has become a powerful method in target identification and plays an important role both in basic research and drug discovery. The availability of whole genome sequences and improvements in cell based screening techniques opened new avenues for high-throughput experiments. Large libraries of RNA interference reagents available for many organisms allow the dissection of broad spectrum of cellular processes. Here, we describe the current state of the large-scale phenotype screening with a focus on cell-based screens. We underline the importance and provide details of screen design, scalability, performance, data analysis, and hit prioritization. Similar to classical high-throughput in vitro screens with defined-target approaches in the past, cell-based screens depend on a successful establishment of robust phenotypic assays, the ability to quantitatively measure phenotypic changes and bioinformatics methods for data analysis, integration, and interpretation. PMID- 22821590 TI - Using functional genomics to identify drug targets: a Dupuytren's disease example. AB - Research into the molecular mechanism of Dupuytren's disease (DD) illustrates all the problems common to drug discovery in orphan diseases, but also in more commonly investigated ailments. Current findings characterize DD as a disease with complex molecular pathology, with changes in expression of multiple genes and proteins as well as many contributing risk factors. Some of the observed changes include genes and proteins that have been identified in a number of other pathological processes, such as TGF-beta, some which may be more specific to DD, such as ADAM12, and undoubtedly also some that have yet to be discovered in future studies. When all these results are taken into consideration, it can be deduced that DD is an end result of several pathological processes that can have many points of origin, and probably involves several subtypes that give rise to sufficiently similar clinical symptoms to be unified under a single medical term. Such breadth of view has become possible with the advent of functional genomics methods and system-wide overview of the molecular processes, which highlight molecular players and processes that might not be intuitively obvious from symptoms, as is the case with the observed parallels with wound-healing processes. As functional genomics methods allow researchers to compile a more complete image of the molecular mechanisms involved in DD pathogenesis, they also help to propose new drug targets that can be employed to develop an effective pharmacological treatment for DD. Identification of key molecular players in DD has already benefited from the integration of functional genomics and biocomputational methods, and such approach may reveal new ways how we can interfere with the emergence of the DD phenotype. PMID- 22821591 TI - Functional characterization of human genes from exon expression and RNA interference results. AB - Complex biological systems comprise a large number of interacting molecules. The identification and detailed characterization of the functions of the involved genes and proteins are crucial for modeling and understanding such systems. To interrogate the various cellular processes, high-throughput techniques such as the Affymetrix Exon Array or RNA interference (RNAi) screens are powerful experimental approaches for functional genomics. However, they typically yield long gene lists that require computational methods to further analyze and functionally annotate the experimental results and to gain more insight into important molecular interactions. Here, we focus on bioinformatics software tools for the functional interpretation of exon expression data to discover alternative splicing events and their impact on gene and protein architecture, molecular networks, and pathways. We additionally demonstrate how to explore large lists of candidate genes as they also result from RNAi screens. In particular, our exemplary application studies show how to analyze the function of human genes that play a major role in human stem cells or viral infections. PMID- 22821588 TI - Applicability of adult techniques for ovarian preservation to childhood cancer patients. AB - PURPOSE: To appraise the feasibility of current adult medical and surgical techniques for ovarian preservation in pre-pubertal and adolescent girls with cancer. METHODS: Literature search using PubMed and SCOPUS up to February 2012. In addition, the reference lists of selected studies and all identified systematic and narrative reviews were scanned for relevant references. Inclusion criteria were ovarian preservation and cancer. Exclusion criteria were non English publications, letters, personal communications, and ovarian preservation for conditions other than cancer. RESULTS: Data from the selected publications was interpreted and discussed in the relevant sections. Cryopreservation of ovarian tissue followed by autologous transplant represents the only surgical option available for pre-pubertal girls and adolescents who cannot delay the start of chemotherapy. Few studies report on pre-pubertal and adolescent girls undergoing ovarian preservation surgeries with good harvesting, and no follow-up has been conveyed, to date. Outcomes of ovarian function after ovarian suppression with GnRH-analogs in adults have been controversial and no reports are available for pre-pubertal girls. CONCLUSIONS: Autologous transplantation of cryopreserved ovarian cortex probably represents the best option for preservation of fertility and hormonal function in childhood cancer females; however, future research needs to address the safety of this technique, especially in patients with blood-borne cancers. Ovarian suppression with GnRH-analogs at the time of chemotherapy treatment has not proven to be superior to non-suppression for fertility preservation purposes in adults. Not enough evidence is presently available in childhood cancer patients. PMID- 22821592 TI - Barcode sequencing for understanding drug-gene interactions. AB - With the advent of next-generation sequencing (NGS) technology, methods previously developed for microarrays have been adapted for use by NGS. Here we describe in detail a protocol for Barcode analysis by sequencing (Bar-seq) to assess pooled competitive growth of individually barcoded yeast deletion mutants. This protocol has been optimized on two sequencing platforms: Illumina's Genome Analyzer IIx/HiSeq2000 and Life Technologies SOLiD3/5500. In addition, we provide guidelines for assessment of human knockdown cells using short-hairpin RNAs (shRNA) and an Illumina sequencing readout. PMID- 22821593 TI - High-throughput sequencing of the methylome using two-base encoding. AB - Methylation of Cytosine together with other epigenetic traits plays an important role in the development and regulation of both healthy and diseased cells. Changes in the methylation patterns have been shown to be associated with the development of cancer, growth, neurodevelopmental, and endocrine disorders (Laird PW, Nat Rev Genet 11:191-203, 2010; Tost J, Mol Biotechnol 44:71-81, 2010; Zuo T et al., Epigenomics 1:331-345, 2009). Thus, studying the methylation pattern can give important insights to the underlying causes of disease and development. A method for studying the methylome on a single base resolution is described, using bisulfite sequencing in combination with the high-throughput SOLiD(TM) sequencing technology. PMID- 22821594 TI - Applications and limitations of in silico models in drug discovery. AB - Drug discovery in the late twentieth and early twenty-first century has witnessed a myriad of changes that were adopted to predict whether a compound is likely to be successful, or conversely enable identification of molecules with liabilities as early as possible. These changes include integration of in silico strategies for lead design and optimization that perform complementary roles to that of the traditional in vitro and in vivo approaches. The in silico models are facilitated by the availability of large datasets associated with high-throughput screening, bioinformatics algorithms to mine and annotate the data from a target perspective, and chemoinformatics methods to integrate chemistry methods into lead design process. This chapter highlights the applications of some of these methods and their limitations. We hope this serves as an introduction to in silico drug discovery. PMID- 22821595 TI - Compound collection preparation for virtual screening. AB - Virtual screening is an established technique that has successfully been deployed in the identification of novel biologically active molecules. Whether for ligand based or for structure-based virtual screening, a chemical collection needs to be properly processed prior to in silico evaluation. Here we describe our step-by step procedure for handling large collections of compounds prior to virtual screening. PMID- 22821596 TI - Mapping between databases of compounds and protein targets. AB - Databases that provide links between bioactive compounds and their protein targets are increasingly important in drug discovery and chemical biology. They join the expanding universes of cheminformatics via chemical structures on the one hand and bioinformatics via sequences on the other. However, it is difficult to assess the relative utility of databases without the explicit comparison of content. We have exemplified an approach to this by comparing resources that each has a different focus on bioactive chemistry (ChEMBL, DrugBank, Human Metabolome Database, and Therapeutic Target Database) both at the chemical structure and protein levels. We compared the compound sets at different representational stringencies using NCI/CADD Structure Identifiers. The overlap and uniqueness in chemical content can be broadly interpreted in the context of different data capture strategies. However, we recorded apparent anomalies, such as many compounds-in-common between the metabolite and drug databases. We also compared the content of sequences mapped to the compounds via their UniProt protein identifiers. While these were also generally interpretable in the context of individual databases we discerned differences in coverage and the types of supporting data used. For example, the target concept is applied differently between DrugBank and the Therapeutic Target Database. In ChEMBL it encompasses a broader range of mappings from chemical biology and species orthologue cross screening in addition to drug targets per se. Our analysis should assist users not only in exploiting the synergies between these four high-value resources but also in assessing the utility of other databases at the interface of chemistry and biology. PMID- 22821597 TI - Predictive cheminformatics in drug discovery: statistical modeling for analysis of micro-array and gene expression data. AB - The vast amounts of chemical and biological data available through robotic high throughput assays and micro-array technologies require computational techniques for visualization, analysis, and predictive -modeling. Predictive cheminformatics and bioinformatics employ statistical methods to mine this data for hidden correlations and to retrieve molecules or genes with desirable biological activity from large databases, for the purpose of drug development. While many statistical methods are commonly employed and widely accessible, their proper use involves due consideration to data representation and preprocessing, model validation and domain of applicability estimation, similarity assessment, the nature of the structure-activity landscape, and model interpretation. This chapter seeks to review these considerations in light of the current state of the art in statistical modeling and to summarize the best practices in predictive cheminformatics. PMID- 22821598 TI - Advances in nuclear magnetic resonance for drug discovery. AB - Nuclear Magnetic Resonance (NMR) techniques are widely used in the drug discovery process. The primary feature exploited in these investigations is the large difference in mass between drugs and receptors (usually proteins) and the effect this has on the rotational or translational correlation times for drugs bound to their targets. Many NMR parameters, such as the diffusion coefficient, spin diffusion, nuclear Overhauser enhancement, and transverse and longitudinal relaxation times, are strong functions of either the overall tumbling or translation of molecules in solution. This has led to the development of a wide variety of NMR techniques applicable to the elucidation of protein and nucleic acid structure in solution, the screening of drug candidates for binding to a target of choice, and the study of the conformational changes which occur in a target upon drug binding. High-throughput screening by NMR methods has recently received a boost from the introduction of sophisticated computational techniques for reducing the time needed for the acquisition of the primary NMR data for multidimensional studies. PMID- 22821599 TI - Human ABC transporter ABCG2 in cancer chemotherapy: drug molecular design to circumvent multidrug resistance. AB - Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP) is critically involved in multidrug resistance of human cancer. This transporter exhibits broad substrate specificity toward structurally diverse compounds, as do other ABC transporters, such as ABCB1 (P-glycoprotein/MDR1), ABCC1 (MRP1/GS-X pump), and ABCC2 (MRP2/cMOAT). To gain insight into the relationship between the molecular structure of compounds and the ABCG2-mediated transport activity, we have developed a high-speed screening method to analyze the substrate specificity of ABCG2. In addition, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. This chapter presents our strategy of transport mechanism-based molecular design to circumvent multidrug resistance of cancer. PMID- 22821600 TI - Protein interactions: mapping interactome networks to support drug target discovery and selection. AB - Proteins are biomolecular structures that build the microscopic working machinery of any living system. Proteins within the cells and biological systems do not act alone, but rather team up into macromolecular structures enclosing intricate physicochemical dynamic connections to undertake biological functions. A critical step towards unraveling the complex molecular relationships in living systems is the mapping of protein-to-protein physical "interactions". The complete map of protein interactions that can occur in a living organism is called the "interactome". Achieving an adequate atlas of all the protein interactions within a living system should allow to build its interaction network and to identity the "central nodes" that can be critical for the function, the homeostasis, and the movement of such system. Focusing on human studies, the data about the human interactome are most relevant for current biomedical research, because it is clear that the location of the proteins in the interactome network will allow to evaluate their centrality and to redefine the potential value of each protein as a drug target. This chapter presents our current knowledge on the human protein protein interactome and explains how such knowledge can help us to select adequate targets for drugs. PMID- 22821601 TI - Linking variants from genome-wide association analysis to function via transcriptional network analysis. AB - We outline a strategy to use tissue-specific expression along with promoter module analysis to determine the putative functional context of candidate genes implicated in genome-wide association studies. First, genes are selected from candidate SNPs, followed by construction of a gene co-regulation network to expand the regulatory context of the candidate genes, functional analysis to determine putative functional roles, and subsequent analysis of regulatory elements. We describe these sub-strategies and variations, along with guidelines for alternatives in the overall analysis. PMID- 22821603 TI - Integration of multiple ubiquitin signals in proteasome regulation. AB - The ubiquitin-proteasome system has emerged in the last decades as a new paradigm in cell physiology. Ubiquitin is found in fundamental levels of cell regulation, as a target for degradation to the proteasome or as a signal that controls protein function in a complex manner. Even though many aspects of the ubiquitin system remain unexplored, the contributions on the field uncover that ubiquitin represents one of the most sophisticated codes in cellular biology. The proteasome is an ATP-dependent protease that degrades a large number of protein substrates in the cell. The proteasome recruits substrates by a number of receptors that interact with polyubiquitin. Recently, it has been shown that one of these receptors, Rpn10, is regulated by monoubiquitination. In this chapter, we show an overview of the central aspects of the pathway and describe the methodology to characterize in vitro the monoubiquitination of proteasome subunits. PMID- 22821602 TI - Models of excitation-contraction coupling in cardiac ventricular myocytes. AB - Excitation-contraction coupling describes the processes relating to electrical excitation through force generation and contraction in the heart. It occurs at multiple levels from the whole heart, to single myocytes and down to the sarcomere. A central process that links electrical excitation to contraction is calcium mobilization. Computational models that are well grounded in experimental data have been an effective tool to understand the complex dynamics of the processes involved in excitation-contraction coupling. Presented here is a summary of some computational models that have added to the understanding of the cellular and subcellular mechanisms that control ventricular myocyte calcium dynamics. Models of cardiac ventricular myocytes that have given insight into termination of calcium release and interval-force relations are discussed in this manuscript. Computational modeling of calcium sparks, the elementary events in cardiac excitation-contraction coupling, has given insight into mechanism governing their dynamics and termination as well as their role in excitation contraction coupling and is described herein. PMID- 22821604 TI - Supracondylar humerus fractures in children treated with closed reduction and percutaneous pinning. AB - Supracondylar fractures of the humerus in children are important for frequency and type of associated serious complications. The management of this kind of fractures is still controversial (Skaggs et al. in J Bone Joint Surg Am 86:702 707, 2004; Kalllio et al. in J Pediatr Orthop 12:11-15, 1992). We are going to present our experience in the treatment of supracondylar humeral fracture in children. In the Orthopedic Department of Pisa, we treated 150 cases from 1989 to 2006. We are used to perform, emergency or within 12 h, reduction and two lateral entry percutaneous pins fixation. The mean age was 7.5 years. We checked 125 cases, because we excluded all the cases with follow up less then 5 years. The mean follow up was 8.2 years. We used Gartland classification modified by Wilkins. We evaluated 125 cases by using the Flynn classification: 100 % of patients did not have impairment of the elbow joint mobility. We had seven valgus deviation, one of which was more then 10 degrees . We also had 17 varus deviations, 11 of which were not over 8 degrees and only 2 of them were 15 degrees . The average value of the joint Baumann angle was calculated as great as 16 degrees . The obtained results were classified as very good 80 %, good 11 %, sufficiently good 6 %, and bad 3 %. In our experience, all the fractures type II and III by Gartland have to be treated within 12 h, with closed reduction and stabilization with lateral-entry K-wire technique. The conservative treatment by cast is indicated only in type I fracture. The trans olecranic treatment is not realizable, for the stiffness which can occur, for the risk of iatrogenic ulnar nerve lesion, and for long-time hospitalization. The open reduction remains the first choice treatment for exposed or nonreducible fractures, and in cases of vascular injury. PMID- 22821605 TI - Dyschromatosis symmetrica hereditaria with long hair on the forearms, hypo/hyperpigmented hair, and dental anomalies: report of a novel ADAR1 mutation. AB - We report on a father and his two children who are affected with dyschromatosis symmetrica hereditaria (DSH). Mutation analysis of ADAR1 gene demonstrated a novel splice acceptor site mutation in intron 10, IVS10-2A>C. The hair on the forearm of the affected father became longer, larger in diameter, and hypopigmented (white) after age 40 years. Hyperpigmented hair was also found in normal and hypopigmented skin. The colors of the hair and the skin did not correlate. Transmission electron micrography of cortical keratinocytes of the hair follicles showed that normal hair contained more keratinocytes than those of hyperpigmented and hypopigmented hair. The keratinocytes of the hyperpigmented hair were larger than those of normal and hypopigmented hair and those of the normal hair were larger than those of the hypopigmented hair. The affected daughter had dens evaginatus of the mandibular right second premolar and the son had dens invaginatus of the maxillary permanent lateral incisors. Expression of Adar1 gene during mouse tooth development is demonstrated. PMID- 22821606 TI - Nonuniform distribution of contacts from noradrenergic and serotonergic boutons on the dendrites of cat splenius motoneurons. AB - The input-output properties of motoneurons are dynamically regulated. This regulation depends, in part, on the relative location of excitatory and inhibitory synapses, voltage-dependent and -independent channels, and neuromodulatory synapses on the dendritic tree. The goal of the present study was to quantify the number and distribution of synapses from two powerful neuromodulatory systems that originate from noradrenergic (NA) and serotonergic (5-HT) neurons. Here we show that the dendritic trees of motoneurons innervating a dorsal neck extensor muscle, splenius, in the adult cat are densely, but not uniformly innervated by both NA and 5-HT boutons. Identified splenius motoneurons were intracellularly stained with Neurobiotin. Using 3D reconstruction techniques we mapped the distributions of contacts formed by NA and 5-HT boutons on the reconstructed dendritic trees of these motoneurons. Splenius motoneurons received an average of 1,230 NA contacts (range = 647-1,507) and 1,582 5-HT contacts (range = 1,234-2,143). The densities of these contacts were 10 (NA) to 6 (5-HT) fold higher on small compared to large-diameter dendrites. This relationship largely accounts for the bias of NA and 5-HT contacts on distal dendrites and is partially responsible for the higher density of NA contacts on dendrites located more than 200 MUm dorsal to the soma. These results suggest that the neuromodulatory actions of NA and 5-HT are compartmentalized and regulate the input-output properties of motoneurons according to precisely arranged interactions with voltage-dependent and -independent channels that are primarily located on small-diameter dendrites. PMID- 22821607 TI - Diagnostic accuracy of nocturnal oximetry for detection of sleep apnea syndrome in stroke rehabilitation. AB - BACKGROUND AND PURPOSE: Sleep apnea syndrome (SAS) is a common sleep disorder in stroke patients and is associated with decreased recovery and increased risk of recurrent stroke and mortality. The standard diagnostic test for SAS is poly(somno)graphy, but this is often not feasible in stroke rehabilitation settings. This study investigated the diagnostic value of nocturnal oximetry for screening SAS in stroke rehabilitation. METHODS: Fifty-six stroke patients underwent nocturnal polygraphy and oximetry. Sensitivity, specificity, and positive and negative predictive values for the oxygen desaturation index were calculated. Patient and sleep characteristics were used to develop a predictive model of apnea-hypopnea index. RESULTS: Forty-six percent of the stroke patients had SAS. The majority of SAS patients was male, older, and had a higher body mass index than patients without SAS. Sensitivity, specificity, and positive and negative predictive values for the oxygen desaturation index >=15 were, respectively, 77%, 100%, 100%, and 83%. Oxygen desaturation index predicted 87% of the variance in the apnea-hypopnea index. Patient characteristics did not add significantly to the prediction model. CONCLUSIONS: Nocturnal oximetry is an accurate diagnostic screening instrument for the detection of SAS in stroke patients. PMID- 22821608 TI - Evaluating performance of the spetzler-martin supplemented model in selecting patients with brain arteriovenous malformation for surgery. AB - BACKGROUND AND PURPOSE: Our recently proposed point scoring model includes the widely-used Spetzler-Martin (SM)-5 variables, along with age, unruptured presentation, and diffuse border (SM-Supp). Here we evaluate the SM-Supp model performance compared with SM-5, SM-3, and Toronto prediction models using net reclassification index, which quantifies the correct movement in risk reclassification, and validate the model in an independent data set. METHODS: Bad outcome was defined as worsening between preoperative and final postoperative modified Rankin Scale score. Point scores for each model were used as predictors in logistic regression and predictions evaluated using net reclassification index at varying thresholds (10%-30%) and any threshold (continuous net reclassification index >0). Performance was validated in an independent data set (n=117). RESULTS: Net gain in risk reclassification was better using the SM-Supp model over a range of threshold values (net reclassification index=9%-25%) and significantly improved overall predictions for outcomes in the development data set, yielding a continuous net reclassification index of 64% versus SM-5, 67% versus SM-3, and 61% versus Toronto (all P<0.001). In the validation data set, the SM-Supp model again correctly reclassified a greater proportion of patients versus SM-5 (82%), SM-3 (85%), and Toronto models (69%). CONCLUSIONS: The SM-Supp model demonstrated better discrimination and risk reclassification than several existing models and should be considered for clinical practice to estimate surgical risk in patients with brain arteriovenous malformation. PMID- 22821609 TI - Time-dependent test characteristics of head computed tomography in patients suspected of nontraumatic subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: A recent study suggested that in patients with acute headache suspicious of nontraumatic subarachnoid hemorrhage (SAH), cerebrospinal fluid (CSF) analysis is not needed to rule out SAH if head CT performed <=6 hours after ictus is negative. Before implementation in daily practice, these results need replication. Therefore, we investigated test characteristics of head CT in patients with a clinical suspicion of SAH. METHODS: Patients suspicious of SAH and a normal level of consciousness presenting to our tertiary care hospital between 2005 and 2012 were included. All patients had a head CT interpreted by experienced neuroradiologists and CSF spectrophotometry if head CT was negative or inconclusive. We determined test characteristics with 95% confidence intervals (CI) for nontraumatic SAH of head CT performed <=6 or >6 hours after onset of headache. RESULTS: Sensitivity of head CT <=6 hours after ictus (n=137) was 98.5% (95% CI, 92.1%-100%), diagnosing all patients with aneurysmal and perimesencephalic SAH, but not with a cervical arteriovenous malformation. Sensitivity of head CT performed >6 hours after ictus (n=113) was 90.0% (95% CI, 76.3-97.2). After exclusion of patients with an atypical presentation without headache, sensitivity, specificity, negative predictive value, and positive predictive value of head CT <=6 hours were all 100%. CONCLUSIONS: In patients presenting with acute headache and a normal head CT <=6 hours after ictus, as interpreted by experienced neuroradiologists, there is no added value of CSF analysis. In patients with an atypical presentation without headache and in patients presenting >6 hours after ictus, CSF analysis is still indicated. PMID- 22821610 TI - Transient global amnesia, cerebral veins, and the need to find the 'smoking gun'. PMID- 22821611 TI - Ischemic brain injury after intracerebral hemorrhage: a critical review. PMID- 22821612 TI - Diagnosis of subarachnoid hemorrhage: time to change the guidelines? PMID- 22821613 TI - Determining stroke's rank as a cause of death using multicause mortality data. AB - BACKGROUND AND PURPOSE: Stroke has fallen from the second to the fourth leading cause of death in the United States without large declines in stroke incidence or case fatality. We explored whether this decline may be attributable to changes in mortality attribution methodology. METHODS: Multicause mortality files from 2000 to 2008 were used to compare changes in reporting of stroke as underlying cause of death (UCOD) with changes in death certificates reporting any mention (AMCOD) of stroke. In addition, the UCOD/AMCOD ratio was calculated for the 6 leading organ and disease-specific causes of death. If stroke mortality is underestimated by the system of mortality attribution, we hypothesized that we would find: (1) a greater decline in stroke as UCOD than as AMCOD; and (2) a decline in the UCOD/AMCOD ratio compared with other causes of death. RESULTS: Age-adjusted death rates for stroke as UCOD (61 per 100,000 in 2000 versus 41 in 2008) and AMCOD (102 per 100,000 versus 68) both declined by 33%. The ratio of UCOD to AMCOD for stroke did not change over time (0.595 in 2000 versus 0.598 in 2008). Changes in UCOD/AMCOD ratio for the diagnoses that surpassed stroke as UCOD were too small (no change for lung cancer and a slight increase from 0.49 to 0.52 for chronic lower respiratory diseases) to explain stroke's decline as UCOD. CONCLUSION: Changes in mortality attribution methodology are not likely responsible for stroke's decline as a leading cause of death. The discordant trends in incidence, case fatality, and mortality require further study. PMID- 22821614 TI - Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk: results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). AB - BACKGROUND AND PURPOSE: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated similar rates of the primary composite end point between carotid artery stenting (CAS) and carotid endarterectomy (CEA), although the risk of stroke was higher with CAS, and the risk of myocardial infarction was higher with CEA. Given the large number of patients who are candidates for these procedures, an understanding of their relative cost and cost effectiveness may have important implications for health care policy and treatment guidelines. METHODS: We performed a formal economic evaluation alongside the CREST trial. Costs were estimated from all trial participants over the first year of follow-up using a combination of resource use data and hospital billing data. Patient-level health use scores were obtained using data from the SF-36. We then used a Markov disease-simulation model calibrated to the CREST results to project 10-year costs and quality-adjusted life expectancy for the 2 treatment groups. RESULTS: Although initial procedural costs were $1025/patient higher with CAS, postprocedure costs and physician costs were lower such that total costs for the index hospitalization were similar for the CAS and CEA groups ($15 055 versus $14 816; mean difference, $239/patient; 95% CI for difference, $297 to $775). Neither follow-up costs after discharge nor total 1-year costs differed significantly. For the CREST population, model-based projections over a 10-year time horizon demonstrated that CAS would result in a mean incremental cost of $524/patient and a reduction in quality-adjusted life expectancy of 0.008 years compared with CEA. Probabilistic sensitivity analysis demonstrated that CEA was economically attractive at an incremental cost-effectiveness threshold of $50 000/quality-adjusted life-year gained in 54% of samples, whereas CAS was economically attractive in 46%. CONCLUSIONS: Despite slightly lower in-trial costs and lower rates of stroke with CEA compared with CAS, projected 10-year outcomes from this controlled clinical trial demonstrate only trivial differences in overall healthcare costs and quality-adjusted life expectancy between the 2 strategies. If the CREST results can be replicated in clinical practice, these findings suggest that factors other than cost-effectiveness should be considered when deciding between treatment options for carotid artery stenosis in patients at standard risk for surgical complications. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00004732. PMID- 22821615 TI - Broad spectrum of dystonia associated with a novel thanatosis-associated protein domain-containing apoptosis-associated protein 1 mutation in a Japanese family with dystonia 6, torsion. PMID- 22821616 TI - Importance of blood rheology in the pathophysiology of atherothrombosis. AB - Elevated blood viscosity is an integral component of vascular shear stress that contributes to the site specificity of atherogenesis, rapid growth of atherosclerotic lesions, and increases their propensity to rupture. Ex vivo measurements of whole blood viscosity (WBV) is a predictor of cardiovascular events in apparently healthy individuals and studies of cardiovascular disease patients. The association of an elevated WBV and incident cardiovascular events remains significant in multivariate models that adjust for major cardiovascular risk factors. These prospective data suggest that measurement of WBV may be valuable as part of routine cardiovascular profiling, thereby potentially useful data for risk stratification and therapeutic interventions. The recent development of a high throughput blood viscometer, which is capable of rapidly performing blood viscosity measurements across 10,000 shear rates using a single blood sample, enables the assessment of blood flow characteristics in different regions of the circulatory system and opens new opportunities for detecting and monitoring cardiovascular diseases. PMID- 22821617 TI - Iodine-125 seed implantation in the treatment of sacrococcygeal chordoma: a case report. AB - The objective of this was to summarize the efficacy and safety of iodine-125 seed implantation in the treatment of sacrococcygeal chordoma. CT-guided implantation of radioactive iodine-125 seed was applied in treating a patient with sacrococcygeal chordoma. The incidence of complications was recorded and the results were evaluated and analyzed, to compare the postoperative complications and recurrence rate of sacrococcygeal chordoma. The patient was followed up to 15 months after operation. The minimum peripheral dose was 180 Gy, and 8 months after the implantation, the tumor mass was reduced significantly. There was no serious complications detected during the follow-up period. Radioactive iodine 125 seed implantation can improve the target volume dose, with the high doses of radioactive iodine-125 seed, the tumor, which was refractory and insensitive to chemotherapy and radiotherapy, can be effectively controlled and complications are less than surgical treatment. However, the long-term efficacy of this treatment needs further follow-up. PMID- 22821618 TI - MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice. AB - Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work, and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1 Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 +/- 98 mmHg vs. 335 +/- 98, P < 0.05; 6.14 +/- 0.57 mmHg/ul vs. 3.92 +/ 0.60, P < 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1 Tg, demonstrated by reductions in chronic infarct size (28.5 +/- 3.1% vs. 47.8 +/- 3.2%), myocardial fibrosis (3.98 +/- 0.74% vs. 9.27 +/- 1.97%) and apoptosis (0.66 +/- 0.11% vs. 1.60 +/- 0.34%). Higher phosphorylation (i.e., activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e., inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1 Tg. MMP2 activity was higher in MEK1 Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium. PMID- 22821619 TI - Hemicrania continua in a headache clinic: referral source and diagnostic delay in a series of 22 patients. AB - Hemicrania continua (HC) is a unilateral and continuous primary headache with superimposed exacerbations frequently associated with autonomic features. Diagnostic criteria of HC, according to II Edition of International Classification of Headache Disorders require complete response to indomethacin. HC is probably misdiagnosed more often than other primary headaches. We aim to analyze characteristics of a series of 22 consecutive cases of HC. We recruited patients from a headache outpatient clinic in a tertiary hospital over a 3-year period (January 2008 to January 2011). We prospectively gathered demographic and nosological characteristics and considered referral source and delay between onset of headache and diagnosis of HC. Twenty-two patients (14 females, 8 males) out of 1,150, who attended the mentioned clinic during the inclusion period (1.9 %) were diagnosed with HC. All cases responded to indomethacin. No patient received a diagnosis of HC before attending our headache office. Mean latency of diagnosis was 86.1 +/- 106.5 months (range 3-360). 11 patients (50 %) were referred from primary care, with 9 (40.9 %) from other neurology clinics and 2 (9.1 %) from other specialities offices. According to our series, HC is not an infrequent diagnosis in a headache outpatient clinic. Diagnostic delay is comparable to data collected in previous studies. As HC is frequently misdiagnosed, we thing there is a need for increasing the understanding of this entity, potentially responsive to indomethacin. PMID- 22821620 TI - Epinephrine and phenylephrine pretreatments for preventing postreperfusion syndrome during adult liver transplantation. AB - Acute hypotension after reperfusion of the liver graft occurs frequently during liver transplantation. A randomized, prospective trial was performed to test the effects of epinephrine and phenylephrine pretreatments for attenuating postreperfusion syndrome (PRS). Ninety-three adult liver recipients were randomly allocated to receive an intravenous bolus of 10 MUg of epinephrine, 100 MUg of phenylephrine, or normal saline (the control group) at the time of graft reperfusion. The occurrence of PRS, the use of vasoactive drugs, and the postoperative courses were compared. The epinephrine and phenylephrine groups showed PRS less frequently (39% and 48%) than the control group (77%, P = 0.006) as well as higher mean arterial pressures (MAPs) immediately after reperfusion (P < 0.05). An overshoot of MAP was observed in one-third of the pretreated patients with minimal heart rate changes. Only 2 patients in each pretreatment group showed an increase in MAP that was greater than 20% of the baseline value. The intraoperative epinephrine and dopamine requirements were significantly lower in both pretreatment groups. Perioperative laboratory data, postoperative stays, and in-hospital mortality rates were similar for the 3 groups. In conclusion, pretreatment with 10 MUg of epinephrine or 100 MUg of phenylephrine significantly reduces the occurrence of PRS and vasopressor requirements without immediate or delayed adverse effects in adult liver transplantation. PMID- 22821621 TI - Cost effectiveness of three drugs for the treatment of S. aureus infections in Nigeria. AB - BACKGROUND: Resistance of microorganisms to existing antimicrobial agents threatens the effective utilization of available resources in sub-Saharan Africa. Cost-effective utilization of antibacterial agents is essential in effective health care delivery in Nigeria. OBJECTIVES: To determine the most cost effective antibacterial agent in the treatment of S. aureus infections in Lagos metropolis. SETTING: The study was carried out in a teaching hospital, a specialist hospital, a referral center and two private hospitals. METHODS: Cost effectiveness analysis of ciprofloxacin, cefuroxime and gentamicin identified to be most effective agent against 463 clinical isolates of S. aureus obtained from the five hospitals was carried out on the basis of societal, health care and third party perspectives using 'decision table" as an analytical model. Criteria considered in the model included degree of efficacy of the agents, adherence tendencies and tolerability. Both direct (cost of drugs, diagnosis/monitoring, personnel and transportation) and indirect (loss of productivity) costs were evaluated. MAIN OUTCOME MEASURES: These include economic outcome as total therapy cost, clinical outcomes as extent of antibacterial effectiveness obtained from degree of antibacterial efficacy, a proxy measurement of cure rates, and adherence tendency. Humanistic outcome was also measured as tolerability prorated from literature reported degree of adverse drug reactions events, risk of infection and pains from drug administration. RESULTS: Ciprofloxacin tablet is a dominant option and much more cost-effective than either cefuroxime or gentamicin in the treatment of S. aureus in Lagos. Regardless of the perspective of analysis, ciprofloxacin has the least cost effectiveness ratio of NGN4214.66 ($28.09), NGN2392.63 ($16.00) and NGN2048.66 ($13.65) from societal, health care and third party payer perspectives, respectively. Sensitivity analysis by increasing the effectiveness index of gentamicin injection-the least cost effective option to the value for the most cost effective option did not change the results. CONCLUSION: Ciprofloxacin should be used as first-line-treatment of S aureus in Lagos as it will lead to significant cost savings in the treatment of S. aureus infections. PMID- 22821622 TI - Retention of stereochemistry in gold-catalyzed formal [4+3] cycloaddition of epoxides with arenynamides. PMID- 22821624 TI - The development and classification accuracy of the life assessment questionnaire in the detection of pain-related malingering. AB - This paper describes three phases of the development and validation of the Life Assessment Questionnaire (LAQ), a multi-scale inventory for assessing potential malingering in adults reporting chronic pain. Study 1 involved scale construction and item analysis. Discriminant validity was investigated in Study 2 by comparing scores for the clinical reference group with participants instructed to simulate chronic pain. Study 3 examined the convergent validity of the LAQ with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and Behavioral Assessment of Pain (BAP). Results revealed that the simulation groups scored significantly higher than the clinical reference group across all scales. Receiver operating characteristic analysis revealed sensitivity and specificity scores ranging from 0.44 to 0.57 and 0.88 to 0.93, respectively. Positive predictive power values ranged between 0.79 and 0.88. Strong convergent validity was found for the LAQ. These studies demonstrated the effectiveness of the LAQ in classifying individuals who feign pain complaints, supporting the utility of the LAQ for reaching conclusions about the presence of malingering. PMID- 22821623 TI - Morphometry of structural disconnectivity indicators in subjects at risk and in age-matched patients with schizophrenia. AB - Structural disconnectivity has been hypothesized as being accountable for the pathophysiology of schizophrenia. Morphometric variables suitable for the empirical study of disconnectivity were studied aiming at the research question whether empirical indicators for disconnectivity are already informative in subjects at risk (SAR) and in young matched patients diagnosed with schizophrenia (SZ). In MRI data of subjects of the two diagnostic groups SZ and SAR, the size of the corpus callosum (CC) as indicator for interhemispherical long distance connections and the gyrification index (GI) as indicator for cortico-cortical connections were analyzed compared to a healthy controls (HC). Each subgroup consists of 21 subjects matched for sex and age. Measurements of the CC and GI were estimated in manually performed tracing procedures. GI data revealed significant differences between the diagnostic groups of both SAR and SZ as compared to HC in the frontal and parietal cortices. Measurements of total CC yielded no significant differences between diagnostic groups. The results are suggestive for impaired cortico-cortical connections as indicated by gyrification changes in SZ and also in SAR, whereas interhemispherical connectivity at the same time appears to be unaffected. PMID- 22821625 TI - Fluorescent silica nanoparticles improve optical imaging of stem cells allowing direct discrimination between live and early-stage apoptotic cells. AB - Highly bright and photostable cyanine dye-doped silica nanoparticles, IRIS Dots, are developed, which can efficiently label human mesenchymal stem cells (hMSCs). The application procedure used to label hMSCs is fast (2 h), the concentration of IRIS Dots for efficient labeling is low (20 MUg mL(-1) ), and the labeled cells can be visualized by flow cytometry, confocal microscopy, and transmission electron microscopy. Labeled hMSCs are unaffected in their viability and proliferation, as well as stemness surface marker expression and differentiation capability into osteocytes. Moreover, this is the first report that shows nonfunctionalized IRIS Dots can discriminate between live and early-stage apoptotic stem cells (both mesenchymal and embryonic) through a distinct external cell surface distribution. On the basis of biocompatibility, efficient labeling, and apoptotic discrimination potential, it is suggested that IRIS Dots can serve as a promising stem cell tracking agent. PMID- 22821627 TI - Chromosome 9p deletion syndrome and sex reversal: novel findings and redefinition of the critically deleted regions. AB - Deletions of the short arm of chromosome 9 are associated with two distinct clinical entities. Small telomeric 9p24.3 deletions cause genital anomalies in male subjects, ranging from disorder of gonadal sex to genital differentiation anomalies, while large terminal or interstitial deletions result in 9p malformation syndrome phenotype. The critical region for non-syndromic 46,XY sex reversal was assigned to a 1 Mb interval of chromosome 9p, extending from the telomere to the DMRT genes cluster. The 9p-syndrome was assigned to bands 9p22.3p24.1, but a phenotypic map has not been established for this condition, probably because of the lack of detailed molecular and/or phenotypic characterization, as well as frequent involvement of additional chromosome rearrangements. Here, we describe a unique patient with a small isolated 9p terminal deletion, characterized by array-CGH and FISH, who shows a complex phenotype with multiple physical anomalies, resembling the 9p-syndrome, disorder of sex development with gonadoblastoma, congenital heart defect and epilepsy. The observed deletion includes the 46,XY sex-reversal critical region, excluding the region so far associated with the 9p-syndrome. Genotype-phenotype correlations are tentatively established comparing our patient to seven other previously reported males with isolated terminal 9p deletions, finely defined at a molecular level. Our observations expand the 9p deletion clinical spectrum, and add significantly to the definition of a 9p-syndrome critical region. PMID- 22821626 TI - Fetal ductal constriction caused by maternal ingestion of green tea in late pregnancy: an experimental study. AB - OBJECTIVES: The aim of this study was to test the hypothesis that experimental maternal intake of green tea in late pregnancy causes fetal ductus arteriosus constriction, probably because of prostaglandin inhibition. METHODS AND RESULTS: Twelve fetal lambs (pregnancy > 120 days) were assessed before and after maternal administration of green tea (n = 8) or water (n = 4; controls) as the only source of liquid. After 1 week, echocardiography showed signs of constriction of the ductus arteriosus in all fetuses from mothers ingesting green tea, with increase in mean systolic velocity(from 0.70 +/- 0.19 m/s to 0.92 +/- 0.15 m/s, 31.4%, p = 0.001) and mean diastolic velocity (0.19 +/- 0.05 m/s to 0.31 +/- 0.01 m/s, 63.1%, p < 0.001), decrease of pulsatility index (2.2 +/- 0.4 to 1.8 +/- 0.3, 22.2%, p = 0.003) and increase of mean right ventricular/left ventricular diameter ratio (0.89 +/- 0.14 to 1.43 +/- 0.23, 60.6%, p < 0.001). In the four control fetuses, there were no significant changes. All lambs exposed to green tea also showed at autopsy dilated and hypertrophic right ventricles, which was not present in control fetuses. Histological analysis showed a significantly larger mean thickness of the medial avascular zone of the ductus arteriosus in fetuses exposed to green tea than in controls (747.6 +/- 214.6 um vs 255.3 +/- 97.9 um, p < 0.001). CONCLUSIONS: This study in fetal lambs shows a cause and effect relationship between experimental maternal exposure of green tea and fetal ductus arteriosus constriction in late pregnancy. PMID- 22821628 TI - High-mobility group box 1 (HMGB1)-Toll-like receptor (TLR)4-interleukin (IL)-23 IL-17A axis in drug-induced damage-associated lethal hepatitis: Interaction of gammadelta T cells with macrophages. AB - Acetaminophen overdose causes acute liver inflammation with neutrophil infiltration; however, the mechanism of damage-associated inflammation has not been elucidated. In this study we found that the HMGB1-TLR4-IL-23-IL-17A axis played a crucial role in acetaminophen-induced infiltration of neutrophils and liver injury. Notably, interleukin (IL)-17A and IL-23 significantly increased after acetaminophen challenge. A neutralizing antibody against IL-17A attenuated the recruitment of neutrophils, accompanied by reduced liver injury. Only IL 17A(+) CD3(+) gammadelta T cell receptor (TCR)(+) cells were significantly increased in the liver, and depletion of gammadelta T cells, but not CD4(+) T cells or natural killer (NK)T cells significantly reduced IL-17A production, attenuated liver injury, and decreased the number of neutrophils in the liver. Furthermore, a neutralizing IL-23 p19 antibody or p40-deficiency significantly decreased the levels of IL-17A and infiltration of neutrophils. After in vitro stimulation, the percentage of IL-17A-producing gammadelta T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified gammadelta T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL 17A were reduced after inhibition of macrophages and could not be induced in Toll like receptor TLR4(-/-) mice after acetaminophen challenge. Meanwhile, serum high mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4(+/+) but not by TLR4(-/-) macrophages. CONCLUSION: The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing gammadelta T cells, which mediates neutrophil infiltration and damage-induced liver inflammation. PMID- 22821629 TI - Cell in situ zymography: an in vitro cytotechnology for localization of enzyme activity in cell culture. AB - In situ zymography is a unique technique for detection and localization of enzyme substrate interactions majorly in histological sections. Substrate with quenched fluorogenic molecule is incorporated in gel over which tissue sections are mounted and then incubated in buffer. The enzymatic activity is observed in the form of fluorescent signal. With the advancements in the field of biological research, use of in vitro cell culture has become very popular and holds great significance in multiple fields including inflammation, cancer, stem cell biology and the still emerging 3-D cell cultures. The information on analysis of enzymatic activity in cell lines is inadequate presently. We propose a single step methodology that is simple, sensitive, cost-effective, and functional to perform and study the 'in position' activity of enzyme on substrate for in vitro cell cultures. Quantification of enzymatic activity to carry out comparative studies on cells has also been illustrated. This technique can be applied to a variety of enzyme classes including proteases, amylases, xylanases, and cellulases in cell cultures. PMID- 22821630 TI - Evaluation of cytotoxic compounds in different organs of the sea bream Sarpa salpa as related to phytoplankton consumption: an in vitro study in human liver cell lines HepG2 and WRL68. AB - The present study was aimed to assess the cytotoxic effects of not-yet identified compounds present in organ extracts of Sarpa salpa, collected in autumn, the period with a peak in health problems. In addition, we studied the cytotoxicity of extracts of epiphytes found in the stomach content of S. salpa collected in summer and of epiphytes collected from the sea in the Sfax area at the end of spring. We tested these fractions in two human hepatic cell lines: HepG2 and WRL68. We observed a significant loss of viable cells when HepG2 cells were exposed for 72 h to acetone extracts of livers of S. salpa at a concentration of 2.5 mg/ml protein. Proteins extracted from brain or muscle did not significantly induce cell death at the studied concentrations (<=10 mg/ml). There was a significant loss of viable cells when treated with liver extract of S. salpa dissolved in DMSO. Extracts of epiphytes collected in late spring showed a cytotoxic effect in a concentration-dependent manner. Moreover, we observed a significantly decreased cell viability of HepG2 at a dilution (1/40) of epiphyte extracts from stomach contents of two fish we had collected. The cytotoxic effect of the observed epiphyte extracts confirms the transfer of toxins originating from toxic dinoflagellates which live in epiphyte on the Posidonia oceanica leaves to fish organs by grazing. Hence, the liver of this fish can cause a threat to human health and consumption should for this reason be dissuaded. PMID- 22821631 TI - The plexiform neurofibroma microenvironment. AB - Dynamic interactions between tumorigenic cells and surrounding cells, including immunomodulatory hematopoietic cells, can dictate tumor initiation, progression, and transformation. Hematopoietic-stromal interactions underpin the plexiform neurofibroma, a debilitating tumor arising in individuals afflicted with Neurofibromatosis type 1 (NF1), a common genetic disorder resulting from mutations in the NF1 tumor suppressor gene. At the tissue level, plexiform neurofibromas demonstrate a complex microenvironment composed of Schwann cells, fibroblasts, perineural cells, mast cells, secreted collagen, and blood vessels. At the cellular level, specific interactions between these cells engender tumor initiation and progression. In this microenvironment hypothesis, tumorigenic Schwann cells secrete pathological concentrations of stem cell factor, which recruit c-kit expressing mast cells. In turn, activated mast cells release inflammatory effectors stimulating the tumorigenic Schwann cells and their supporting fibroblasts and blood vessels, thus promoting tumor expansion in a feed-forward loop. Bone marrow transplantation experiments in plexiform neurofibroma mouse models have shown that tumorigenesis requires Nf1 haploinsufficiency in the hematopoietic compartment, suggesting that tumor microenvironments can depend on intricate interactions at both cellular and genetic levels. Overall, our continued understanding of critical tumor-stromal interactions will illuminate novel therapeutic targets, as shown by the first ever successful medical treatment of a plexiform neurofibroma by targeted inhibition of the stem cell factor/c-kit axis. PMID- 22821632 TI - Genetic and environmental factors in late onset dementia: possible role for early parental death. AB - OBJECTIVE: We aimed to investigate three reports of a possible role of early parental death in late onset dementia. We tested a multivariate model of risk factors for late onset dementia that included established (female sex, a family history of dementia, APOE epsilon4) and putative influences (vascular risk factors, years of full-time education, parental ages at death, and childhood IQ) on dementia risk. METHODS: We examined contributions of early life and late life risk factors for dementia by using childhood social and family data and blood samples obtained at interview at age about 78 years. In 1997-1999, we recruited 281 subjects without dementia from a 1932 Scottish IQ survey of children born in 1921 and followed them up to 2010 (at age 88). Binary logistic regression and Bayesian structural equation modelling were used to model dementia risk. RESULTS: Risk of dementia was associated with increasing age from 77 to 88 years, female sex, death of either parent before age 11 and APOE epsilon4 genotype. Family history of dementia, childhood IQ, years of education and vascular risk factors did not contribute to the model. CONCLUSIONS: Our multivariate models of the possible causes of late onset dementia confirm previous associations of dementia with female sex and APOE epsilon4 genotype and supports earlier reports of a role for early parental death. PMID- 22821633 TI - WDR1 expression in normal and noise-damaged Sprague-Dawley rat cochleae. AB - WD40 repeat protein 1 (WDR1) has been suggested as a protective mechanism or a sign of regeneration in avian cochlea. However, its role in mammalian cochlea has yet to be determined. Hence, we investigated WDR1 expression in sound overstimulated Sprague-Dawley rats. Rats were divided into three groups (the permanent and temporary threshold shift [PTS and TTS] groups and the control group) according to the extent of noise exposure and euthanized immediately, 3, or 7 days after noise exposure for cochlear harvest. Immunocytochemistry localized WDR1 to outer hair cells, Deiter's cells, outer sulcus cells, and Reissner's membrane in the control group, and the PTS and TTS groups exhibited stronger WDR1 expression in the same cochlear regions than the controls. Moreover, WDR1 expression in these noise-exposed groups was extended to inner hair cells and basal cells of the stria vascularis. The expression of WDR1 in the PTS and TTS groups showed differences in intensity and shifts of localization, based on exposure length and recovery duration. Contrary to the avian cochlea, hair cell regeneration does not naturally occur in the acoustically damaged mammalian cochlea. Therefore, elevated WDR1 expression after acoustic overstimulation in the current experiments may provide a mechanism for protection against noise exposure. PMID- 22821634 TI - Outcome and complications after implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: systematic review and meta-analysis. AB - BACKGROUND: Previous observational studies demonstrated that patients with hypertrophic cardiomyopathy at risk for sudden cardiac death (SCD) may benefit from implantable cardioverter defibrillator (ICD) therapy. A complete overview of outcome and complications after ICD therapy is currently not available. This study pools data from published studies on outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. METHODS AND RESULTS: A PubMed database search returned 27 studies on 16 cohorts reporting outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. In case of >1 publications on a particular cohort, the publication with the largest number of patients was included in the meta-analysis. ICD interventions, complications, and mortality rates were extracted, pooled, and analyzed. There were 2190 patients (mean age, 42 years; 38% women), most of whom (83%) received an ICD for primary prevention of SCD. Risk factors for SCD were left ventricular wall thickness >=30 mm (20%), family history of SCD (43%), nonsustained ventricular tachycardia (46%), syncope (41%), and abnormal blood pressure response (25%). During the 3.7-year follow-up, the annualized cardiac mortality rate was 0.6%, the noncardiac mortality rate was 0.4%, and the appropriate ICD intervention rate was 3.3%. The annualized inappropriate ICD intervention rate was 4.8% and the annualized ICD-related complication rate was 3.4%. CONCLUSIONS: This meta-analysis demonstrates a low cardiac and noncardiac mortality rate after ICD therapy in patients with hypertrophic cardiomyopathy. Appropriate ICD intervention occurred at a rate of 3.3%/year, thereby, most probably, preventing SCD. Inappropriate ICD intervention and complications are not uncommon. PMID- 22821635 TI - The structure of peritraumatic dissociation: a cross validation in clinical and nonclinical samples. AB - Empirical data have challenged the unidimensionality of the Peritraumatic Dissociative Experiences Questionnaire (PDEQ), a widely used measure for peritraumatic dissociation. The aim of this study was to assess the factor structure of the PDEQ in 3 trauma-exposed samples: (a) trauma-exposed police officers (N = 219); (b) trauma-exposed civilians (N = 158); and (c) treatment seeking trauma-exposed civilians (N = 185). Confirmatory factor analyses using measurement invariance testing supported a 2-factor structure (CFIs .96-.98; RMSEAs .07-.09), but excluded 2 of the original items. Factor 1 was termed Altered Awareness; Factor 2 was termed Derealization. Altered Awareness reflected disturbances in information processing during the traumatic event, whereas Derealization reflected distortions in perception. Hierarchical linear regression analysis showed that Derealization predicted posttraumatic stress severity at 26.5 weeks follow-up only in the sample of police officers (R(2) = .45). Future longitudinal research shortly following trauma is required to elucidate causality and underlying mechanisms of peritraumatic dissociation, which may contribute to the development of more accurate screening strategies, as well as more effective strategies for prevention and early intervention. PMID- 22821636 TI - Concise review: a high-content screening approach to stem cell research and drug discovery. AB - High-throughput screening (HTS) is a technology widely used for early stages of drug discovery in pharmaceutical and biotechnology industries. Recent hardware and software improvements have enabled HTS to be used in combination with subcellular resolution microscopy, resulting in cell image-based HTS, called high content screening (HCS). HCS allows the acquisition of deeper knowledge at a single-cell level such that more complex biological systems can be studied in a high-throughput manner. The technique is particularly well-suited for stem cell research and drug discovery, which almost inevitably require single-cell resolutions for the detection of rare phenotypes in heterogeneous cultures. With growing availability of facilities, instruments, and reagent libraries, small-to moderate scale HCS can now be carried out in regular academic labs. We envision that the HCS technique will play an increasing role in both basic mechanism study and early-stage drug discovery on stem cells. Here, we review the development of HCS technique and its past application on stem cells and discuss possible future developments. PMID- 22821637 TI - Catalytic enantioselective synthesis of secondary alkylboronate building blocks with and without metals. AB - With or without you: Chiral secondary alkylboronates can now be accessed by highly enantioselective catalytic methods including conjugate addition under metal-free conditions with an NHC catalyst, and also iridium-catalyzed hydrogenation. These methods reinforce the potential of secondary alkylboronates as ideal and universal chiral building blocks for bond formation to sp(3) carbon atoms. PMID- 22821638 TI - Nail and phalangeal agenesis in a patient with 4pter and 9pter duplication. AB - We report on an 8-month-old girl with intra-uterine growth retardation, microcephaly, incomplete cleft lip, axial hypotonia, failure to thrive, and brachydactyly type B (phalangeal agenesis and absence of nails). She carried a supernumerary marker chromosome derived from chromosomes 4 and 9, leading to 4pter-q12 and 9pter-p21.2 duplication. The marker was derived from the 3:1 segregation of a maternal balanced translocation 46,XX, t(4;9)(q12;p21.2). The proposita is the first reported individual with distal phalangeal agenesis and anonychia, and trisomy 4p and partial trisomy 9p due to 3:1 segregation of a maternal reciprocal translocation. PMID- 22821639 TI - Serum C-reactive protein is a useful biomarker for predicting outcomes after liver transplantation in patients with hepatocellular carcinoma. AB - Liver transplantation (LT) is a curative modality for hepatocellular carcinoma (HCC), especially in patients with cirrhosis. However, there are still risks of recurrence. C-reactive protein (CRP), an acute-phase inflammatory reactant that is synthesized by hepatocytes, has been related to the prognosis of various malignancies, including HCC. In this study, we investigated the role of a high CRP level in predicting the posttransplant outcomes of HCC patients. We analyzed 85 patients undergoing LT between August 2000 and July 2010 whose pretransplant serum CRP levels were available. Only 2 patients underwent deceased donor LT, and the remaining patients underwent living donor LT. With 1 mg/dL used as a cutoff value, 27 patients showed high CRP levels (>=1 mg/dL) at the time of LT, and 58 showed low CRP levels (<1 mg/dL). The total bilirubin level, Child-Pugh grade, Model for End-Stage Liver Disease score, maximal tumor size, and frequency of intrahepatic metastasis were significantly higher in the high-CRP group. According to multivariate analyses, HCC beyond the Milan criteria, a high CRP level, and microvascular invasion were related to tumor recurrence, and a high CRP level and microvascular invasion were related to poor overall survival. When a subgroup analysis was performed according to the Milan criteria, a high CRP level was an independent factor for predicting poor outcomes in patients with HCC beyond the Milan criteria (P = 0.02 for recurrence and P < 0.001 for survival) but not in patients with HCC within the criteria. Serum CRP could be considered a useful and cost-effective biomarker for predicting outcomes after LT for HCC, particularly in patients beyond the Milan criteria. PMID- 22821640 TI - 'Click' preparation of CuPt nanorod-anchored graphene oxide as a catalyst in water. AB - In this paper, a simple and powerful method of producing nanoparticle-anchored graphene oxide (GO) composites using a 'click' reaction is demonstrated. This method affords a facile means of anchoring of nanoparticles with various shapes and sizes on the GO. CuPt nanorods with controlled size, aspect ratio (from 1 to 11), and uniformity are synthesized. Transmission electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy measurements are made to monitor the formation and characterize the properties of the CuPt nanorod-grafted GO composites. Their catalytic properties in the water phase are investigated using an o-phenylenediamine oxidation reaction. The results of this study clearly demonstrate that nonpolar CuPt nanorods immobilized on GO can function as a catalyst in an aqueous solution and that GO can be used as a catalytic nanorod support. PMID- 22821641 TI - Free jejunum reconstruction of upper esophageal defects. AB - The free jejunum has become an important method for reconstructing extensive oncologic defects of the upper esophagus and pharynx. The advantages of a single staged reconstruction with a low incidence of morbidity have generally outweighed criticisms such as the requirement for a laparotomy and poor voice quality. The aim of the study was to present the technique and outcomes of free jejunal reconstruction of the upper esophagus in 31 consecutive cases. We reviewed our experience of free jejunal flaps undertaken over a 6-year period. Our surgical approach, complications, and results of swallow and speech restoration are described. A functional swallow was achieved by 27/31 patients. However, satisfactory voice restoration was seen in only a small proportion of patients. Complications at the donor site occurred in just one patient. The current review confirms the jejunal flap as a reliable reconstructive option with minimal donor site morbidity. PMID- 22821642 TI - Scavenger receptor A restrains T-cell activation and protects against concanavalin A-induced hepatic injury. AB - Negative feedback immune mechanisms are essential for maintenance of hepatic homeostasis and prevention of immune-mediated liver injury. We show here that scavenger receptor A (SRA/CD204), a pattern recognition molecule, is highly up regulated in the livers of patients with autoimmune or viral hepatitis, and of mice during concanavalin A (Con A)-induced hepatitis (CIH). Strikingly, genetic SRA ablation strongly sensitizes mice to Con A-induced liver injury. SRA loss, increased mortality and liver pathology correlate with excessive production of IFN-gamma and heightened activation of T cells. Increased liver expression of SRA primarily occurs in mobilized hepatic myeloid cells during CIH, including CD11b(+) Gr-1(+) cells. Mechanistic studies establish that SRA on these cells functions as a negative regulator limiting T-cell activity and cytokine production. SRA-mediated protection from CIH is further validated by adoptive transfer of SRA(+) hepatic mononuclear cells or administration of a lentivirus expressing SRA, which effectively ameliorates Con A-induced hepatic injury. Also, CIH and clinical hepatitis are associated with increased levels of soluble SRA. This soluble SRA displays a direct T-cell inhibitory effect and is capable of mitigating Con A-induced liver pathology. CONCLUSION: Our findings demonstrate an unexpected role of SRA in attenuation of Con A-induced, T-cell-mediated hepatic injury. We propose that SRA serves as an important negative feedback mechanism in liver immune homeostasis, and may be exploited for therapeutic treatment of inflammatory liver diseases. PMID- 22821643 TI - Comparison of tacrolimus, fluorometholone, and saline in mild-to-moderate contact lens-induced papillary conjunctivitis. AB - INTRODUCTION: The purpose of this study was to compare the efficacy of tacrolimus, fluorometholone, and saline in the treatment of mild to moderate contact lens-induced papillary conjunctivitis (CLPC). METHODS: This was a double masked, randomized pilot study. A total of 18 soft contact lens users (n = 36 eyes) with mild to moderate papillary conjunctivitis were enrolled. Subjects were randomly assigned into three groups to receive tacrolimus 0.05%, fluorometholone 0.1%, or saline (sodium chloride 0.9%). Drugs were prescribed at the baseline visit (visit 1) and instilled twice daily for 4 weeks. Follow-up visits were taken at week 1 (visit 2), week 2 (visit 3), week 4 (visit 4, drug usage suspended at this visit), and week 6 (visit 5, 2 weeks after interrupting eye drops). Contact lens use was discontinued during the 6 weeks of the study, and variables assessed were symptoms and signs, tear film status, and intraocular pressures. Conjunctival impression cytology was performed at baseline and visit 5 to assess ocular surface status. RESULTS: Mean roughness and redness scores decreased significantly from visit 1 to visit 5, but the variation tendency was comparable in all groups (P = 0.180 and 0.889, respectively). Subjective symptom parameters were improved in all CLPC patients at visit 5, and there was no remarkable difference in symptom reduction in three groups. The mean Schirmer value and mean break-up time (BUT) did not change significantly in the three groups during the study. Ocular surface findings by impression cytology improved significantly after three treatments. Intraocular pressure fluctuation from baseline to 6-week follow-up was not statistically significant in all subjects. No adverse treatment-related event was observed in any study group. CONCLUSIONS: Tacrolimus 0.05% may be a safe and effective treatment for mild to moderate CLPC and is comparable with fluorometholone 0.1% in efficacy. Contact lens cessation accompanied with saline may also be effective in treating mild to moderate CLPC. PMID- 22821644 TI - Telmisartan at 80 mg/day increases high-molecular-weight adiponectin levels and improves insulin resistance in diabetic patients. AB - INTRODUCTION: The clinical dose of telmisartan necessary for activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) has not been established. The authors investigated the effect of high-dose telmisartan on serum levels of the high-molecular-weight (HMW) adiponectin in patients with diabetes and hypertension. METHODS: In this open-label, prospective, randomized study, patients with type 2 diabetes and hypertension with poor control of blood pressure by 40 mg/day telmisartan were randomly assigned into the telmisartan 80 mg/day (Tel80) group (dose increase from 40 to 80 mg/day) or the telmisartan 40 mg + amlodipine 5 mg (Tel40 + Aml5) group. Serum levels of HMW adiponectin and parameters of glucose and lipid metabolism were measured at baseline and end of 3 months of treatment. RESULTS: Although the antihypertensive effects of the two doses of telmisartan were similar, a significant increase in HMW adiponectin levels was noted only in the Tel80 group. The increase was evident particularly in a group of patients whose HMW adiponectin levels were less than 4.0 MUg/dL. A significant improvement in homeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was also observed in the Tel80 group only. CONCLUSIONS: In diabetic patients with hypertension, high-dose telmisartan increased HMW adiponectin levels and improved insulin resistance through activation of PPAR-gamma. PMID- 22821645 TI - Acromegalic patients lost to follow-up: a pilot study. AB - Approximately 50 % of all acromegalic patients will require lifelong medical treatment to normalize mortality rates and reduce morbidity. Thus, adherence to therapy is essential to achieve treatment goals. To date, no study has evaluated the frequency and reasons for loss to follow-up in the acromegalic population. The current study aimed at evaluating the frequency of acromegalic patient loss to follow-up in three reference centers and the reasons responsible for their low compliance with treatment. All of the files for the acromegalic patients in the three centers were reviewed. Those patients, who had not followed up with the hospital for more than a year, were contacted via phone and/or mail and invited to participate. Patients who agreed to participate were interviewed, and blood samples were collected. A total of 239 files were reviewed; from these 42 patients (17.6 %) were identified who were lost to follow-up. It was possible to contact 27 of these patients, 10 of whom did not attend the appointments for more than one time and 17 of whom agreed to participate in the study. Fifteen of these 17 patients had active disease (88.2 %), and all of the patients restarted treatment in the original centers. The main reason for loss to follow-up was an absence of symptoms. High-quality follow-up is important in acromegaly to successfully achieve the aims of the treatment. An active search for patients may allow the resumption of treatment in a significant proportion of these cases, contributing to reduced morbidity and mortality in this patient population. PMID- 22821646 TI - Association of beta(2)-adrenergic receptor polymorphisms with asthma in a North Indian population. AB - BACKGROUND: beta(2)-Adrenergic receptor (beta(2)AR), a G-protein coupled receptor, is present on the bronchial smooth muscle cells and results in bronchodilation upon activation. The genetic factors determining beta(2)AR expression and function may not only alter the response of an individual to the therapy but also may serve as predictive markers for response to the agonists used in the therapy. The present study aimed at evaluating the role of beta(2)AR 16 and beta(2)AR-27 gene polymorphisms in asthma. METHODS: A case-control study was performed with a total of 824 adult subjects, including 410 asthmatics and 414 healthy controls from regions of North India. The beta(2)AR-16 and beta(2)AR 27 polymorphisms were genotyped by PCR-RFLP. RESULTS: Statistical analysis for the beta(2)AR-16 polymorphism revealed that the mutant Gly16 allele was significantly associated with asthma, with OR = 0.80, 95 % CI = 0.65-0.99, and P = 0.032. The Gly16/Gly16 mutant genotype also confers decreased risk toward asthma, with OR = 0.65, 95 % CI = 0.41-1.02, and P = 0.049. However, the beta(2)AR-27 polymorphism was not associated with asthma as it did not reach statistical significance, with OR = 0.86, 95 % CI = 0.69-1.07, and P = 0.163. CONCLUSION: The beta(2)AR-16 polymorphism confers a decreased risk toward asthma while the beta(2)AR-27 polymorphism is not associated with asthma in the studied North Indian population. PMID- 22821647 TI - TOP2A amplification in breast cancer in the absence of that of HER-2: myth or reality? PMID- 22821648 TI - Prenatal diagnosis of hypoplastic left heart syndrome associated with Noonan Syndrome and de novo RAF1 mutation. PMID- 22821649 TI - Scheduled re-entry coil embolization before entry coverage of thoracic endovascular stent grafting for aneurysmal chronic type B aortic dissection. AB - Endovascular treatment for type B dissections is controversial. This therapy aims at complete occlusion and thrombosis of the false lumen of the aneurysm. We report a case where cessation of flow was achieved using covered stent grafts in conjunction with coil embolization of the false lumen. The use of scheduled coil re-entry embolization of the false lumen before endovascular entry coverage using a stent graft is a novel approach that could become a treatment option for aneurysmal type B dissection. PMID- 22821650 TI - In patients with corrosive oesophageal stricture for surgery, is oesophagectomy rather than bypass necessary to reduce the risk of oesophageal malignancy? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was, 'is there an increased risk of cancer in a non-resected corrosive oesophageal stricture?' Altogether, 133 papers were found using the reported search; six papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. From the studies, 198 consecutive patients had corrosive oesophageal stricture resulting from corrosive oesophageal injury, 50 of whom (25.3%) developed oesophageal cancer. The interval between the burn and the diagnosis of scar carcinoma was 46.1 years and ranged between 25 and 58 years. The incidence of carcinoma of the oesophagus among patients from the study was significantly higher than that of the general population. In one review, seven (13%) of 54 consecutive patients treated by conservative means for caustic oesophageal stricture (COS) developed oesophageal cancer, leading to the conclusion that simultaneous resection of the oesophagus with reconstruction for such patients would provide a better probability of being completely cured of the disease. Furthermore, in patients with COS in need of operation who had a bypass procedure, it was pointed out that malignancy may develop even years after the bypass operation in the remaining part of the oesophagus and so total oesophagectomy was suggested instead of bypass. In another study, as many as 10 (31.3%) of 32 patients with corrosive oesophageal stricture developed cancer. That gave further credence to the arguments against conservative treatment or bypassing of corrosive oesophageal strictures. The risk of morbidity for intrathoracic oesophageal replacement in uncomplicated cases was 2.4%. There were basically two things that were agreed from the studies: that corrosive-induced carcinoma can occur with a reasonably high incidence if part or all of the oesophagus was left during reconstructive surgery; and that simultaneous resection of the oesophagus at the time of reconstruction in a patient with corrosive stricture offered a better outcome. The limitations of the present review were the lack of randomized controlled trials and no close follow-up. PMID- 22821651 TI - Inferior vena cava thrombectomy in a patient with heparin-induced thrombocytopenia via inflow occlusion technique on beating heart. AB - Anticoagulation management of a patient complicated by heparin-induced thrombocytopenia is one of the challenging situations in open heart surgery. A 40 year old male receiving warfarin for anticoagulation was admitted to our clinic with a history of heparin-induced thrombocytopenia and a diagnosis of inferior caval thrombosis. He was scheduled for inferior vena cava thrombectomy via the inflow occlusion technique on the beating heart. Warfarin sodium was stopped three days prior to the operation while fondaparinux sodium was begun twice a day. The operation was successfully performed and no postoperative complications were observed. PMID- 22821652 TI - Complementary and alternative medicine: is it possible to be mainstream? PMID- 22821653 TI - The current acceptance, accessibility and recognition of Chinese and Ayurvedic medicine in the United States in the public, governmental, and industrial sectors. AB - To assess the current level of acceptance in the United States of complementary and alternative medicine, recent research into the prevalence, acceptance, accessibility, and recognition of complementary and alternative therapies were reviewed. Several signs point to an increasing acceptance of complementary and alternative medicine in the United States; the use of complementary and alternative medicine is significantly increasing, many aspects of Chinese medicine and Ayurveda are becoming mainstream, practitioners in the United States are beginning to be licensed, and insurance companies are beginning to cover some complementary and alternative therapies. Remaining challenges to true acceptance include the restrictive Western mindset, the absence of published studies, a lack of consistent manufacturing processes and quality standards, and a fear of adulteration. Although the field still faces many challenges, alternative and complementary medicine, including Chinese medicine and Ayurvedic medicine, is becoming more accepted and accessible in the United States. PMID- 22821655 TI - Effects of Pien Tze Huang on angiogenesis in vivo and in vitro. AB - OBJECTIVE: To investigate the anti-angiogenic effects of Pien Tze Huang in vivo and in vitro. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with 0 mg/mL, 0.25 mg/mL, 0.5 mg/mL, and 1 mg/mL of PZH for 24 h, 48 h and 72 h, respectively. Chicken embryo chorioallantoic membrane (CAM) model was used to evaluate in vivo angiogenesis. An ECMatrix gel system was used to evaluate in vitro angiogenesis by examining the tube formation of HUVECs. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine HUVEC viability. Cell density of HUVECs was observed by phase-contrast microscopy. HUVEC migration was determined by wound healing method. The mRNA and protein expression of vascular endothelial growth factor A (VEGF-A) and basic fibroblast growth factor (bFGF) in both HUVEC and human colon adenocarcinoma cells (HT-29) was examined by reverse transcription polymerase chain reaction (RT PCR) and enzyme linked immune sorbent assay (ELISA), respectively. RESULTS: PZH treatment significantly reduced the total number of blood vessels compared with the untreated control in the chicken embryos and resulted in a significant decrease in capillary tube formation and cell density of HUVECs (P<0.05). In addition, treatment with 0.25-1 mg/mL of PZH for 24 h, 48 h, and 72 h respectively reduced cell viability by 9%-52%, 24%-87% or 25%-87%, compared with the untreated control cells (P<0.05). Moreover, PZH treatment decreased the migration of HUVECs. Furthermore, PZH dose-dependently suppressed the expression of VEGF-A and bFGF on both mRNA and protein levels (P<0.05). CONCLUSION: PZH could inhibit angiogenesis in vivo in CAM model and in vitro on HUVECs, suggesting that inhibiting tumor angiogenesis might be one of the mechanisms by which PZH treats cancer. PMID- 22821654 TI - A survey of complementary and alternative medicine in Iran. AB - OBJECTIVE: To survey the use, capability and satisfaction of complementary and alternative medicine (CAM) in comparison with conventional medicine in Iran. METHODS: In this national survey, a cross-sectional study was designed, 5,000 people were surveyed to identify predictors of Iranian traditional medicine (ITM) use compared with conventional medicine. Data were collected through a questionnaire that covered three different predictor categories: demographic information, patient's viewpoint, and patients' experiences. RESULTS: Most of the participants preferred government owned hospitals rather than other places. Praying for one's own health was the most frequent and favorable ITM domain (P=0.017) based on patients' interests, both in low- (P=0.08) and high-level (P=0.011) educated subjects. Among the participants, 97.8% had previous conventional medicine history due to their chronic diseases CONCLUSIONS: Iranian patients resort to ITM as a choice at the late stage of the disease. Current deficiency in integration of CAM and conventional medicine is in contrast to the increasing demand on patients' side. Health care organizers should be facilitating the CAM services by tuition of CAM practitioners and supporting eligible CAM centers for diagnosis and treatment of patients. PMID- 22821658 TI - Effect of Huxin Formula on reverse cholesterol transport in ApoE-gene knockout mice. AB - OBJECTIVE: To observe the effect of Huxin Formula on expressions of the chief reverse cholesterol transport (RCT) associated genes, caveolin-1 and scavenger receptor-BI (SR-BI) in ApoE-gene knockout [ApoE (-/-)] mice. METHODS: Thirty ApoE (-/-) mice of 4-6 weeks old were randomly divided into three groups (A-C). After being fed with high-fat diet for 16 weeks, they were treated with HXF (1 mL/100 g), pravachol (0.3 mg/100 g), and saline in equal volume respectively for 16 weeks successively; in addition, a blank group was set up with 10 C57BL/6J mice of 6-week old received 16-week high-fat feeding and saline treatment. Animals were sacrificed at the termination of the experiment, their paraffin sections of aortic tissue were used to measure the size of plaque, expressions of cavolin-1 and SR-BI were detected by immunological histochemical method. RESULTS: As compared with the blank group, levels of caveolin-1 and SR-BI were increased in Groups A and B (P<0.01); but the increase in Group A was more significant than that in Group B (P<0.05). The plaque/aorta area ratio decreased significantly in Groups A and B, but showed insignificant difference between the two groups. CONCLUSION: HXF could obviously increase the expressions of RCT associated genes, caveolin-1 and SR-BI, promote the RCT process, so as to reduce the formation of aorta atherosclerotic plaque in ApoE (-/-) mice. PMID- 22821656 TI - Caffeic acid ester fraction from Erigeron breviscapus inhibits microglial activation and provides neuroprotection. AB - OBJECTIVE: To investigate the effects of caffeic acid ester fraction (Caf) from Erigeron breviscapus, mainly composed of dicaffeoylquinic acids (diCQAs), on microglial activation in vitro and focal cerebral ischemia in vivo. METHODS: The production of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and interleukin-1beta (IL-1beta) induced by lipopolysaccharide (LPS) treatment in rat primary cultured microglia were measured by Griess reaction or enzyme-linked immunosorbent assay. Cell viability of cortical neurons was measured using AlamarBlue reagent. The behavioral tests and the infarct area of brain were used to evaluate the damage to central nervous system in rat middle cerebral artery occlusion (MCAO) model of cerebral ischemia. Real time polymerase chain reaction was used to determine the expression of inducible nitric oxide synthase (iNOS), TNF-alpha and IL-1beta mRNA in ischemic cerebral tissues. RESULTS: Caf inhibited the production of NO, TNF-alpha and IL-1beta induced by LPS treatment in primary microglia in a dose-dependent manner. Exposure of cortical neurons to conditioned medium from Caf-treated microglia increased neuronal cell viability (P<0.01) compared with conditioned medium from LPS-treated alone. In MCAO rat model of cerebral ischemia, Caf could significantly improve neurobehavioural performance and reduce percentage infarct volume compared with the vehicle group (P<0.05). Caf could also significantly inhibit the up-regulation of iNOS, TNF-alpha, and IL 1beta gene expressions in ischemic cerebral tissues. CONCLUSION: Caf could suppress microglial activation, which may be one mechanism of its neuroprotective effect against ischemia. PMID- 22821657 TI - Effect of oxymatrine on hepatic gene expression profile in experimental liver fibrosis of rats. AB - OBJECTIVE: To investigate the effects of oxymatrine on hepatic gene expression profile in a rat model of liver fibrosis. METHODS: Forty healthy male SD rats were randomly divided into three groups, a normal group (n=8), a model group (n=16), and an oxymatrine treatment group (n=16). Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride (CCl(4)). The rats in the treatment group received oxymatrine via celiac injection at a dosage of 40 mg/kg once a day at the same time. The rats in the model and normal groups received saline at the same dosage via celiac injection. Serum levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (AKP), hyaluronic acid (HA), and laminin (LN) were assayed. The deposition of collagen was observed with HE and Masson staining. Effect of oxymatrine on hepatic gene expression profile was detected by oligonucleotide microarray analysis with Affymetrix gene chip rat U230A. Quantitative real-time polymerase chain reaction (QRT-PCR) was carried out to confirm the expression changes of six genes. RESULTS: Oxymatrine significantly improved liver function, lowered serum levels of HA and LN, and decreased the degree of liver fibrosis, compared with the model group (P<0.05). A total of 754 differentially expressed genes were identified by gene chip between the model group and the normal group, among which 438 genes increased and 316 genes decreased over two folds. Compared with the model group, 86 genes were downregulated markedly in the oxymatrine group (P<0.05), including collagen I and other genes related to extracellular material (ECM), integrin signal transduction genes, early growth response factor genes, and proinflammatory genes; 28 genes were upregulated significantly (P<0.05), including cytochrome P450 (CYP450) superfamily genes, glycolipids metabolism and biological transformation related genes. Six genes were confirmed with QRT-PCR, consistent with the result from microarray. CONCLUSION: Oxymatrine could affect the expression of many functional genes and may be useful in the prevention and treatment of liver fibrosis. PMID- 22821659 TI - Emotionless holism: factor and Rasch analysis of the Chinese Integrative Medicine Attitude Questionnaire. AB - OBJECTIVE: To examine the Eastern-Western difference in the interpretation of Integrative Medicine Attitude Questionnaire (IMAQ) by assessing the psychometric properties of a revised Chinese medicine (CM)-specific version of IMAQ (CM-IMAQ). METHODS: Factor and Rasch analysis were performed with data collected from a mail survey of 165 Hong Kong Western medical doctors (WMD) randomly sampled from the official registry. The structural validity, unidimensionality, item fit, and differential item functioning (DIF) of the Hong Kong CM-IMAQ were evaluated. RESULTS: Confirmatory factor analysis (CFA) demonstrated that the original IMAQ factor structure was not concordant with our data on Chinese WMD, and subsequent explanatory factor analysis (EFA) validated a new three-factor model for CM-IMAQ: (1) attitude towards "tonification", (2) attitude towards the effectiveness of CM, and (3) attitude towards CM knowledge. The original IMAQ factor on holism and doctor-patient relationship disappeared. Rasch analysis confirmed the unidimensionality of "tonification" and the effectiveness domains, but further refinement of the knowledge domain is needed. CONCLUSIONS: Cultural adaptation of the IMAQ has demonstrated differences between Eastern and Western doctors trained in allopathic medicine in their interpretations of holism in healthcare. For Chinese WMD, the emphasis of holistic care is placed on "tonifying" the body rather than on nurturing the mind and spirit. Confucian and Taoist conceptualizations of mental health as well as the persistent stigma towards mental illness within modern Chinese culture may explain why Chinese WMD do not regard mental health promotion as part of routine healthcare. PMID- 22821660 TI - Influence of Fuzheng Huayu Tablet on mental state and social function of patients with post-hepatitis B liver cirrhosis. AB - OBJECTIVE: To observe the influence of Fuzheng Huayu Tablet on mental state and social activity of patients with post-hepatitis B liver cirrhosis (LC-HB). METHODS: Adopting grouped randomized double-blinded control method, 180 LC-HB patients in 3 research centers were distributed to 2 groups, the treated group and the control group, 90 in each group. Patients in the treated group were administered with FZHYT; while those in the control group treated with conventional therapy combined with placebo, the course for all patients were 6 months. Their mental state and social activity were evaluated before treatment, after 3 months' treatment and at terminal of the 6-month therapeutic course by estimating with Zung self-rating anxiety scale (SAS), self-rating depression scale (SDS) and social deficit screening scale (SDSS). Additionally, the basic demographic materials, liver function, cirrhosis index, hepatic and splenic images, blood coagulation function, etc. in the patients were tested and compared as well. RESULTS: As compared with before treatment, the normal rate of SAS and SDS scores increased and the social deficit rate decreased in the treated group significantly after treatment, showing statistical significance (P<0.05 or P<0.01); while in the control group, change was only shown in the social deficit (P<0.01), inter-group comparisons after treatment showed significant differences in all the three indexes (P<0.05 or P<0.01). Additionally, after treatment, levels of liver function, cirrhosis, blood coagulation function and splenomegaly in the treated group were all improved significantly P<0.05 or P<0.01), and the improvements were better than those in the control group (P<0.01) in levels of total bilirubin (TBIL), albumin (ALB), type IV collagen (IV-C), prothrombin time (PT), prothrombin activity (PTA). CONCLUSION: Most patients of LC-HB have mental disturbance and social activity deficit, which could definitely be improved by intervention with Chinese FZHYT. PMID- 22821661 TI - Natural products: a safest approach for obesity. AB - Obesity is recognized as a social problem, associated with serious health risks and increased mortality. Numerous trials have been conducted to find and develop new anti-obesity drugs through herbal sources to minimize adverse reactions associated with the present anti-obesity drugs. The use of natural products as medicine has been documented for hundreds of years in various traditional systems of medicines throughout the world. This review focuses on the medicinal plants such as Achyranthus aspera, Camellia sinensis, Emblica officinalis, Garcinia cambogia, Terminalia arjuna, etc., being used traditionally in Ayurvedic, Unani, Siddha and Chinese, etc., systems of medicine. The review also highlights recent reported phytochemicals such as escins, perennisosides, dioscin, gracillin, etc., and the various extracts of the plants like Nelumbo nucifera, Panax japonicas, Cichorium intybus, Cyperus rotundus, Paeonia suffruticosa, etc., which have been successfully identified for the treatment of obesity. PMID- 22821662 TI - Hierarchical self-assembly of polycyclic heteroaromatic stars into snowflake patterns. AB - Seeing stars: The two-dimensional patterns of the polycyclic heteroaromatic star molecules 1 on graphite vary with the side chain length. For n=12, frustrated self-assembly leads to hierarchically organized superstructures: up to 10 molecules form triangular aggregates which pack densely into hexagonal patterns with very large (15.5 nm) lattice constants. PMID- 22821663 TI - The influence of comorbid MDD on outcome after residential treatment for veterans with PTSD and a history of TBI. AB - Among military personnel, posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and a history of traumatic brain injury (TBI) are frequently reported, highlighting the need for treatment outcome research with this population. This study examined the influence of the presence or absence of comorbid MDD on the outcome of a residential treatment program at the midpoint and end of the program for 47 male veterans with PTSD and a history of TBI. Results demonstrated significant decreases of self-reported symptoms on the PTSD Checklist-Stressor Specific Version (PCL-S; MDD, d = 1.19; No MDD, d = 1.17) and the Beck Depression Inventory-II (BDI-II; MDD, d = 0.98; No MDD, d = 1.09) following treatment for both groups. There were no differences in the rate of symptom reduction between groups. Individuals who also met criteria for MDD at pretreatment, however, evidenced higher scores on symptom measures at all assessment time points (ds = 0.60-1.25). PMID- 22821664 TI - Re: The extended diep flap: extending the possibilities for breast reconstruction with tissue from the lower abdomen. PMID- 22821665 TI - Dorsal-ventral patterning of the neural tube: a tale of three signals. AB - Development of the vertebrate nervous system begins with the acquisition of neural identity from the midline dorsal-ectodermal cells of the gastrulating embryos. The subsequent progressive specification of the neural plate along its anterior-posterior and dorsal-ventral (DV) axes allows the generation of the tremendous variety of neuronal and glial cells that compose the vertebrate central nervous system (CNS). Studies on the development of the spinal cord, the anatomically simplest part of the CNS, have generated most of our current knowledge on the signaling events and the genetic networks that orchestrate the DV patterning of the neural plate. In this review, we discuss the recent advances in our understanding of these events and highlight unresolved questions. We focused our attention on the activity and the integration of the three main instructive cues: Sonic hedgehog, the Wnts and the Bone Morphogenetic Proteins, giving particular attention to the less well understood dorsal signaling events. PMID- 22821666 TI - Selective expression of alpha-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea pig rectum and human colon. AB - Parkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated alpha synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express alpha-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed alpha-synuclein in their axons. alpha-Synuclein-immunoreactivity was present in 24 +/- 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 +/- 4.3% of substance P (SP)-IR varicosities and 9 +/- 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea pig rectal myenteric ganglia. However, alpha-synuclein-immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 +/- 3%, P < 0.001). Of SOM-IR, SP-IR, and VIP-IR varicosities that lacked VAChT immunoreactivity, only 1 +/- 0.3%, 0 +/- 0.3%, and 0% contained alpha-synuclein immunoreactivity, respectively. 71 +/- 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were alpha-synuclein-IR. In guinea pig rectal myenteric ganglia, alpha-synuclein- and VAChT-immunoreactivity coexisted in 15 +/- 1.4% of biotinamide-labeled extrinsic varicosities; only 1 +/- 0.3% of biotinamide labeled extrinsic varicosities contained alpha-synuclein-immunoreactivity without VAChT-immunoreactivity. alpha-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective alpha-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease. PMID- 22821667 TI - Further evidence of reliability and validity of the Huntington's disease quality of life battery for carers: Italian and French translations. AB - BACKGROUND: Existing research suggests that family caregivers of persons with Huntington's disease (HD) face a distinct series of problems, linked to the complex nature of the disease. Aubeeluck and Buchanan (Clin Genet, 71(5):434-445, 2007) developed and validated a disease-specific measure used to explore caregivers quality of life and assess the efficacy of therapeutic interventions. This current study builds on this research through the validation of French and Italian translations of the Huntington's disease quality of life battery for carers (HDQoL-C). METHOD: A total of 301 family carers completed the HDQoL-C. Participants were recruited through the "Euro-HDB" study which is measuring the burden in HD across Europe and the USA. RESULTS: Factor analysis demonstrated good internal consistency, reliability and congruent validity. Carers who cared for patients with less clinically severe symptoms reported significantly better QoL than carers of patients with more clinically severe symptoms. DISCUSSION: Findings indicate the HDQoL-C is multi-lingual, multi-cultural and easily applicable in other languages. PMID- 22821668 TI - Enhanced antigen retrieval of amyloid beta immunohistochemistry: re-evaluation of amyloid beta pathology in Alzheimer disease and its mouse model. AB - Senile plaques, extracellular deposits of amyloid beta peptide (Abeta), are one of the pathological hallmarks of Alzheimer disease (AD). As the standard immunohistochemical detection method for Abeta deposits, anti-Abeta immunohistochemistry combined with antigen retrieval (AR) by formic acid (FA) has been generally used. Here, we present a more efficient AR for Abeta antigen. On brain sections of AD and its mouse model, a double combination of either autoclave heating in EDTA buffer or digestion with proteinase K plus FA treatment reinforced Abeta immunoreactivity. A further triple combination of digestion with proteinase K (P), autoclave heating in EDTA buffer (A), and FA treatment (F), when employed in this order, gave a more enhanced immunoreactivity. Our PAF method prominently visualized various forms of Abeta deposits in AD that have not been clearly detected previously and revealed numerous minute-sized plaques both in AD and the mouse model. Quantification of Abeta loads showed that the AR effect by the PAF method was 1.86-fold (in the aged human brain) and 4.64-fold (in the mouse brain) higher than that by the FA method. Thus, the PAF method could have the potential to be the most sensitive tool so far to study Abeta pathology in AD and its mouse model. PMID- 22821670 TI - Alternation of fluorescent spectra of membrane markers DiI C18(3) and DiI C18(5) evoked by laser illumination. PMID- 22821671 TI - Doppler changes in the vertebral, middle cerebral, and umbilical arteries in fetuses delivered after 34 weeks: relationship to severity of growth restriction. AB - OBJECTIVE: To determine the association between Doppler changes in the fetal vertebral (VA), middle cerebral (MCA), and umbilical arteries (UA) and severity of growth restriction (FGR) in fetuses delivered after 34 weeks. METHOD: Five hundred seventy-one Doppler examinations of the VA, MCA, and UA were performed between 26 and 41 weeks of gestation. Values were converted into multiples of the median and divided into birth weight (BW) categories: BW>P10(th) , BWG (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q. PMID- 22821681 TI - Liver transplantation in septuagenarians receiving model for end-stage liver disease exception points for hepatocellular carcinoma: the national experience. PMID- 22821682 TI - Association of life threat and betrayal with posttraumatic stress disorder symptom severity. AB - The Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association [APA], 2000) emphasizes life threat as the defining feature of psychological trauma. Recent theoretical and empirical work, however, indicates the need to identify and evaluate other key aspects of trauma. Betrayal has been proposed as a pertinent, distinct, and complementary factor that can explain effects of trauma not accounted for by life threat alone. This study examined the relationship between injury, perceived life threat (PLT), and betrayal with posttraumatic stress disorder (PTSD) symptom severity. Trauma exposed college students (N = 185) completed self-report measures of trauma exposure and PTSD, as well as items regarding life threat, betrayal, and level of medical care received. In hierarchical regressions incorporating injury, PLT, and betrayal, betrayal was associated with all PTSD symptom clusters and PTSD total severity (f(2) = .08), whereas PLT was associated with hyperarousal (f(2) = .05) and PTSD total (f(2) = .03), and injury had no association with PTSD symptoms. In a revised model with trauma type as an additional variable, betrayal was associated with avoidance (f(2) = .03), numbing (f(2) = .04), and PTSD total (f(2) = .03), whereas PLT was associated with reexperiencing (f(2) = .04), hyperarousal (f(2) = .04), and PTSD total (f(2) = .03), and injury was associated with avoidance (f(2) = .03). These findings support the idea that betrayal is a core dimension of psychological trauma that may play an important role in the etiology of PTSD. PMID- 22821683 TI - Enantioselective synthesis of alpha-alkyl-beta-ketoesters: asymmetric Roskamp reaction catalyzed by an oxazaborolidinium ion. PMID- 22821684 TI - The oblique branch trap in the harvest of the anterolateral thigh myocutaneous flap. AB - A 67-year-old man with squamous cell carcinoma underwent reconstruction with a free anterolateral thigh myocutaneous flap. Unroofing the skin perforators found that the skin perforators originated from the oblique branch of the lateral circumflex femoral artery with no connections with the descending branch. Thus, the flap was harvested based on the oblique branch, leaving the descending branch in situ. Reconstruction was completed uneventfully and he had an excellent outcome at 1-year follow-up. The anterolateral thigh myocutaneous flap was reputed to be a technically easy flap to harvest. The perforators supplying the skin were visualized and a block of muscle incorporating the perforators harvested with the descending branch of the lateral circumflex femoral artery as the pedicle of the flap. However, not infrequently with this approach, the flap thus harvested has a well-perfused muscle component, whereas the skin component was not viable. This situation is explained anatomically by the potential occurrence of an alternative pedicle that supplies the anterolateral thigh flap, called the oblique branch of the lateral circumflex femoral artery. Our case presented here was a "classic" intraoperative finding of this potential trap and the importance of defining the anatomy before committing oneself to the harvest by unroofing all the skin perforators was emphasized. PMID- 22821685 TI - A cavitating pulmonary lesion with eosinophilia. PMID- 22821686 TI - Gains in language comprehension relating to working memory training in healthy older adults. AB - OBJECTIVE: A growing number of studies are focusing on cognitive training procedures to delay age-related decline. Given the crucial role of working memory (WM) in everyday life, some studies have recently analyzed gains deriving from WM training and their transfer and maintenance effects in older adults. METHOD: The present study investigates the efficacy of a verbal WM training program in 20 65 75 year old adults with no cognitive impairments, considering the specific training-related gains in a verbal WM task (criterion) and the transfer effects on measures of WM updating, reasoning, and on abilities related more to daily life, that is language comprehension. Maintenance of training benefits was also assessed after 6 months. RESULTS: The older adults given training performed better than controls in the criterion task and retained this benefit 6 months later. Immediate transfer effects were seen in most of the abilities considered (reasoning and language comprehension performance) and were substantially maintained at the 6-month follow-up. CONCLUSION: Our results suggest that WM training is a promising approach for preserving abilities relating to everyday activities, helping to prolong older adults' independence and well-being. PMID- 22821688 TI - Ultrastructure of a novel bacterial form located in Staphylococcus aureus in vitro and in vivo catheter-associated biofilms. AB - Bacterial biofilms are ubiquitous in nature, industry, and medicine, and understanding their development and cellular structure is critical in controlling the unwanted consequences of biofilm growth. Here, we report the ultrastructure of a novel bacterial form observed by scanning electron microscopy in the luminal vegetations of catheters from patients with active Staphylococcus aureus bacteremia. This novel structure had the general appearance of a normal staphylococcal cell but up to 10 to 15 times as large. Transmission electron microscopy indicated that these structures appeared as sacs enclosing multiple normal-sized (~0.6 um) staphylococcal forms. Using in vitro cultivated biofilms, cytochemical studies using fluorescent reagents revealed that these structures were rich in lipids and appeared within 15 min after S. aureus inoculation onto clinically relevant abiotic surfaces. Because they appeared early in biofilm development, these novel bacterial forms may represent an unappreciated mechanism for biofilm surface adherence, and their prominent lipid expression levels could explain the perplexing increased antimicrobial resistance of biofilm-associated bacteria. PMID- 22821689 TI - Science to practice: how will myocardial inflammation be imaged with MR imaging? AB - The elegant study by Naresh and colleagues (1) synthesizes many of the best aspects of molecular magnetic resonance(MR) imaging: Quantitative serial imaging of a well-defined molecular process is performed in vivo, and its results are correlated with sensitive measures of left ventricular function. The technique described adds a valuable tool to the molecular imaging armamentarium. How, then, will myocardial inflammation be imaged with MR imaging?The only clinical experience to date has been with iron oxide nanoparticles (2,3). Their excellent sensitivity, dynamic range, and safety record make them a highly appealing choice. It will be critical, however, for any iron oxide nanoparticle that is used clinically to be well studied and validated in animal models of the disease before it is used in humans. A "group effect" cannot be assumed, even in the case of fairly similar iron oxide nanoparticles. The use of MR imaging-detectable liposomes appears promising,and initial clinical studies with fluorine-containing liposomes are likely to begin shortly. The clinical use of gadolinium-labeled liposomes appears further away, and the approach described by Naresh and colleagues is thus likely to remain confined to preclinical investigation for the foreseeable future. The development of novel anti-inflammatory therapies, however, will require robust imaging tools to shepherd these agents through preclinical studies and into the clinical arena. The approach described by Naresh et al adds a valuable tool to the preclinical molecular imaging armamentarium. PMID- 22821687 TI - Mutation of the BiP/GRP78 gene causes axon outgrowth and fasciculation defects in the thalamocortical connections of the mammalian forebrain. AB - Proper development of axonal connections is essential for brain function. A forward genetic screen for mice with defects in thalamocortical development previously isolated a mutant called baffled. Here we describe the axonal defects of baffled in further detail and identify a point mutation in the Hspa5 gene, encoding the endoplasmic reticulum chaperone BiP/GRP78. This hypomorphic mutation of BiP disrupts proper development of the thalamocortical axon projection and other forebrain axon tracts, as well as cortical lamination. In baffled mutant brains, a reduced number of thalamic axons innervate the cortex by the time of birth. Thalamocortical and corticothalamic axons are delayed, overfasciculated, and disorganized along their pathway through the ventral telencephalon. Furthermore, dissociated mutant neurons show reduced axon extension in vitro. Together, these findings demonstrate a sensitive requirement for the endoplasmic reticulum chaperone BiP/GRP78 during axon outgrowth and pathfinding in the developing mammalian brain. PMID- 22821690 TI - Radiation risks of medical imaging: separating fact from fantasy. AB - During the past few years, several articles have appeared in the scientific literature that predict thousands of cancers and cancer deaths per year in the U.S. population caused by medical imaging procedures that use ionizing radiation. These predictions are computed by multiplying small and highly speculative risk factors by large populations of patients to yield impressive numbers of "cancer victims." The risk factors are acquired from the Biological Effects of Ionizing Radiation (BEIR) VII report without attention to the caveats about their use presented in the BEIR VII report. The principal data source for the risk factors is the ongoing study of survivors of the Japanese atomic explosions, a population of individuals that is greatly different from patients undergoing imaging procedures. For the purpose of risk estimation, doses to patients are converted to effective doses, even though the International Commission on Radiological Protection warns against the use of effective dose for epidemiologic studies or for estimation of individual risks. To extrapolate cancer incidence to doses of a few millisieverts from data greater than 100 mSv, a linear no-threshold model is used, even though substantial radiobiological and human exposure data imply that it is not an appropriate model. The predictions of cancers and cancer deaths are sensationalized in electronic and print public media, resulting in anxiety and fear about medical imaging among patients and parents. Not infrequently, patients are anxious about a scheduled imaging procedure because of articles they have read in the public media. In some cases, medical imaging examinations may be delayed or deferred as a consequence, resulting in a much greater risk to patients than that associated with imaging examinations. (c) RSNA, 2012. PMID- 22821691 TI - Automated data mining of exposure information for dose management and patient safety initiatives in medical imaging. PMID- 22821692 TI - Radiation exposure in CT scanning and risk: where are we? PMID- 22821693 TI - Imaging and genomics: is there a synergy? PMID- 22821694 TI - MR imaging of the small bowel. AB - Small-bowel radiology has undergone dramatic changes in the past 2 decades. Despite important recent advances in small-bowel endoscopy, radiologic imaging remains important for patients suspected of having or with established small bowel disease. Cross-sectional imaging techniques (computed tomography and magnetic resonance [MR] imaging), used to investigate both extraluminal abnormalities and intraluminal changes, have gradually replaced barium contrast examinations, which are, however, still used to examine early mucosal disease. MR imaging techniques clearly highlight endoluminal, mural and extramural enteric details and provide vascular and functional information, thereby enhancing the diagnostic value of these techniques in small-bowel diseases. Two MR imaging based techniques are currently utilized: MR enteroclysis and MR enterography. In enteroclysis, enteric contrast material is administered through a nasoenteric tube, whereas in enterography, large volumes of enteric contrast material are administered orally. MR enteroclysis ensures consistently better luminal distention than does MR enterography in both the jejunum and the ileum and more accurately depicts endoluminal abnormalities and early disease, particularly at the level of the jejunal loops. Moreover, MR enteroclysis provides a high level of accuracy in the diagnosis and exclusion of small-bowel inflammatory and neoplastic diseases and can be used for the first radiologic evaluation, while MR enterography may effectively be used to follow up both Crohn disease patients without jejunal disease and in pediatric patients where nasogastric intubation might be a problem. MR enteroclysis may also reveal subtle transition points or an obstruction in the lower small bowel, which may escape detection when more routine methods, including enterography, are used. MR imaging offers detailed morphologic information and functional data of small-bowel diseases and provides reliable evidence of normalcy, thereby allowing the diagnosis of early or subtle structural abnormalities and guiding treatment and decisions in patient care. PMID- 22821695 TI - Molecular body imaging: MR imaging, CT, and US. Part II. Applications. AB - Molecular imaging is expected to have a major impact on the early diagnosis of diseases and disease monitoring in the next decade. Traditionally, nuclear imaging techniques have been the mainstay of molecular imaging in the clinical arena. However, with continued development of molecularly targeted contrast agents for nonnuclear imaging techniques such as magnetic resonance (MR), computed tomography (CT), and ultrasonography (US), the spectrum of clinical molecular imaging applications is expanding. In the second part of this review series, an overview of applications of molecular MR imaging-, CT-, and US-based imaging strategies that show promise for clinical translation is presented, and key challenges that need to be addressed to successfully translate these promising techniques in the future are discussed. (c) RSNA, 2012. PMID- 22821697 TI - Case 184: ulcerative tracheobronchitis. PMID- 22821698 TI - Fractures: abuse or rickets? PMID- 22821699 TI - Fractures: abuse or rickets? PMID- 22821700 TI - The prevalence of selected potentially hazardous workplace exposures in the US: findings from the 2010 National Health Interview Survey. AB - OBJECTIVE: Assess the national prevalence of current workplace exposure to potential skin hazards, secondhand smoke (SHS), and outdoor work among various industry and occupation groups. Also, assess the national prevalence of chronic workplace exposure to vapors, gas, dust, and fumes (VGDF) among these groups. METHODS: Data were obtained from the 2010 National Health Interview Survey (NHIS). NHIS is a multistage probability sample survey of the civilian non institutionalized population of the US. Prevalence rates and their variances were calculated using SUDAAN to account for the complex NHIS sample design. RESULTS: The data for 2010 were available for 17,524 adults who worked in the 12 months that preceded interview. The highest prevalence rates of hazardous workplace exposures were typically in agriculture, mining, and construction. The prevalence rate of frequent handling of or skin contact with chemicals, and of non-smokers frequently exposed to SHS at work was highest in mining and construction. Outdoor work was most common in agriculture (85%), construction (73%), and mining (65%). Finally, frequent occupational exposure to VGDF was most common among mining (67%), agriculture (53%), and construction workers (51%). CONCLUSION: We identified industries and occupations with the highest prevalence of potentially hazardous workplace exposures, and provided targets for investigation and intervention activities. PMID- 22821701 TI - A novel sclerosing skeletal dysplasia with mixed sclerosing bone dysplasia, characteristic syndromic features, and clinical and radiographic evidence of male male transmission. AB - We report on a father and his 4-year-old son sharing a characteristic dysmorphic facial phenotype (including hyperteleroism, prominent forehead, and wide nasal bridge), macrocephaly, hearing loss, palatal clefting, developmental delay, hypotonia and bony abnormalities including marked cranial sclerosis and sclerosis of the ribs and long bones, which evolved in severity in the son between the ages of 2 and 4 years. The father's radiographs also showed prominent coarse striations, patchy metaphyseal sclerotic plaques, markedly increased bone density and cortical thickening of long bones, and significant degenerative changes in the thoracic spine. The son has an additional history of sleep apnea resulting from multi-level airway obstruction that includes adenoid hypertrophy, lingual tonsil hypertrophy, subglottic stenosis, and supra-arytenoid tissue consistent with laryngomalacia and tracheomalacia. The clinical, radiographic, and genetic findings in father and son are consistent with a sclerosing skeletal dysplasia syndrome with similarities to mixed sclerosing bone dysplasia (MSBD) including metaphyseal plaques, osteopathia striata, and cranial sclerosis (OS-CS). This family may represent one of the first descriptions of familial inheritance and evolving phenotype in MSBD. The evidence for male-male transmission would support the existence of an autosomal mechanism of inheritance for a novel form of MSBD with characteristic syndromic features. PMID- 22821703 TI - In-silico prediction of gas chromatographic retention indices of some terpenols. AB - A quantitative structure-retention relationship study based on multiple linear regression technique was carried out to investigate the gas chromatographic retention indices (RIs) of some terpenols on the HP 5 ms fused silica column. A collection of 75 terpene alcohols was chosen as dataset. The data were divided into two groups; a training set and a prediction set consist of 60 and 15 molecules, respectively. The best-selected descriptors that appear in the models are; the Randic index order 1, Kier shape index order 2, total charge weighted partial negatively charged surface area, and fractional atomic charge weighted partial positive surface area. These descriptors can encode different features of molecules that are responsible for their steric, electronic, and lipophilicity interactions. The best-obtained model had statistics of R(2)(t) = 0.959 and R(2)(p) = 0.952. The reliability of the model was evaluated by using the leave many-out cross-validation method (Q(2) = 0.957 and SPRESS = 46.427) as well as by y-scrambling and jackknife test. Furthermore, the chemical applicability domains of these models were determined via leverage approach. The simple developed four parameter linear model can predict the gas chromatographic RIs of terpenols. PMID- 22821702 TI - Spatial domains of progenitor-like cells and functional complexity of a stem cell niche in the neonatal rat spinal cord. AB - During spinal cord development, progenitors in the neural tube are arranged within spatial domains that generate specific cell types. The ependyma of the postnatal spinal cord seems to retain cells with properties of the primitive neural stem cells, some of which are able to react to injury with active proliferation. However, the functional complexity and organization of this stem cell niche in mammals remains poorly understood. Here, we combined immunohistochemistry for cell-specific markers with patch-clamp recordings to test the hypothesis that the ependyma of the neonatal rat spinal cord contains progenitor-like cells functionally segregated within specific domains. Cells on the lateral aspects of the ependyma combined morphological and molecular traits of ependymocytes and radial glia (RG) expressing S100beta and vimentin, displayed passive membrane properties and were electrically coupled via Cx43. Cells contacting the ventral and dorsal poles expressed the neural stem cell markers nestin and/or vimentin, had the typical morphology of RG, and appeared uncoupled displaying various combinations of K(+) and Ca(2+) voltage-gated currents. Although progenitor-like cells were mitotically active around the entire ependyma, the proliferative capacity seemed higher on lateral domains. Our findings represent the first evidence that the ependyma of the rat harbors progenitor-like cells with heterogeneous electrophysiological phenotypes organized in spatial domains. The manipulation of specific functional properties in the heterogeneous population of progenitor-like cells contacting the ependyma may in future help to regulate their behavior and lineage potential, providing the cell types required for the endogenous repair of the injured spinal cord. PMID- 22821704 TI - Multi-loci analysis reveals the importance of genetic variations in sensitivity of platinum-based chemotherapy in non-small-cell lung cancer. AB - Polymorphisms in DNA repair and apoptotic pathways may cause variations in chemosensitivity of non-small-cell lung cancer (NSCLC) through complex gene-gene and gene-environment interactions. A total of 200 advanced NSCLC patients who received platinum-based chemotherapies were recruited. The short-term clinical outcomes were classified as chemosensitive group, including complete remission (CR) and partial remission (PR), and chemoresistant group, namely stable disease (SD) and progression disease (PD) at the end of treatment. We applied multifactor dimensionality reduction (MDR), classification and regression tree (CART) and traditional logistic regression (LR) to explore high-order gene-gene and gene environment interactions among 11 functional single nucleotide polymorphisms (SNPs), smoking status, cancer stages and treatment regimens in the response to chemotherapy. Multi-loci analyses consistently indicated that interactions among XRCC1 Arg194Trp, XPC PAT, FAS G-1377A, and FASL T-844C were associated with sensitivity to platinum-based chemotherapy. In MDR analysis, the four-factor model yielded the highest test accuracy of 0.72 (permutation P = 0.001). In CART analysis, these four SNPs were the determinant nodes of the growth of regression tree. Patients carrying XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed completely no response to platinum, whereas patients with XRCC1 194Trp allele and XPC PAT +/+ had 68.8% response rate to platinum. In LR analysis, a significant gene-dosage effect was detected along with the increasing number of favorable genotypes of these four polymorphisms (P trend = 0.00002). Multi-loci analysis reveals the importance of genetic variations involved in DNA repair and apoptotic pathways in sensitivity of platinum-based chemotherapy in NSCLC. PMID- 22821705 TI - Enantioselective titanium(III)-catalyzed reductive cyclization of ketonitriles. AB - Reduction, please! The title reaction affords alpha-hydroxyketones, a common structural motif in biologically active natural products, in good yields and high enantioselectivities at room temperature. The commercially available ansa titanocene 1 was found to be an efficient catalyst for this process, which presumably proceeds by addition of a ketyl radical to a nitrile. PMID- 22821707 TI - Living donor safety during the performance of hepatectomy. PMID- 22821706 TI - Characterization of small-field bistratified amacrine cells in macaque retina labeled by antibodies against synaptotagmin-2. AB - Macaque retinae were immunostained with monoclonal antibodies directed against the protein synaptotagmin-2 (Syt2). Syt2 was localized in a population of small field amacrine cells, whose cell bodies formed a regular mosaic within the inner nuclear layer, indicating they represent a single amacrine cell type. The labeled amacrine cells had a bistratified appearance with a dense dendritic plexus in the OFF-layer and only a few lobular processes extending into the ON-layer of the inner plexiform layer, similar to A8 amacrine cells described in cat and human retina. Syt2-labeled cells were immunoreactive for glycine but lacked immunoreactivity for gamma-aminobutyric acid (GABA), suggesting they use glycine as their neurotransmitter. The density of these cells increases from ~200/mm(2) in peripheral retina to ~1,400/mm(2) in central retina. Their bipolar cell input was studied by immunolabeling experiments using various bipolar cell markers combined with CtBP2, a marker of presynaptic ribbons. Our data show that Syt2 labeled amacrine cells receive input from both OFF and ON cone bipolar cells, as well as from rod bipolar cells. The OFF input is dominated by the diffuse bipolar cell DB1 (44%) and the OFF midget bipolar cell (38%). Here we describe a population of bistratified small-field amacrine cells closely resembling A8 amacrine cells and their cone-dominated bipolar cell input. J. Comp. Neurol. 521:709-724, 2013. (c) 2012 Wiley Periodicals, Inc. PMID- 22821708 TI - Is adult stem cell aging driven by conflicting modes of chromatin remodeling? AB - Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long-term changes in DNA methylation and, accordingly, in gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences. PMID- 22821709 TI - Germline mosaicism of PHOX2B mutation accounts for familial recurrence of congenital central hypoventilation syndrome (CCHS). AB - Congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation, is caused by mutations in the PHOX2B gene. Most mutations occur de novo, but recent evidence suggests that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations. However, to date, germline mosaicism has not been reported. This report describes a family with recurrence of PHOX2B mutation-confirmed CCHS due to germline mosaicism. The first occurrence was a baby girl, noted on day 2 of life to have multiple episodes of apnea, bradycardia, and cyanosis while breathing room air. PHOX2B gene testing confirmed the diagnosis of CCHS with a heterozygous polyalanine repeat expansion mutation (PARM); genotype 20/27 (normal 20/20). Both parents tested negative for this mutation using fragment analysis (limit of detection<1%). Upon subsequent pregnancy [paternity confirmed using short tandem repeat (STR) analysis], amniocentesis testing identified the PHOX2B 20/27 genotype, confirmed with repeat testing. Elective abortion was performed at 21.5 weeks gestation. Testing of abortus tissue confirmed amniocentesis testing. The PHOX2B 20/27 expansion was not observed in a paternal sperm sample. This case represents the first reported family with recurrence of PHOX2B mutation-confirmed CCHS without detection of a parental carrier state or mosaicism, confirming the previously hypothesized possibility of germline mosaicism for PHOX2B mutations. This is an important finding for genetic counseling of CCHS families, suggesting that even if somatic mosaicism is not detected in parental samples, there is still reason for careful genetic counseling and consideration of prenatal testing during subsequent pregnancies. PMID- 22821710 TI - Transfer of two motor branches of the anterior obturator nerve to the motor portion of the femoral nerve: an anatomical feasibility study. AB - Femoral nerve lesions are uncommon, but very distressing at the functional level because of the absence of knee locking mechanism by the quadriceps muscle. We propose here a new neurotization procedure of obturator nerve motor branches to the motor portion of the femoral nerve in the thigh. This study was conducted on five cadavers. The motor portion of the femoral nerve and the motor branches of the obturator nerve, supplying the gracilis and adductor longus muscles, were isolated. The distance between nerve endings and diameter were measured to determine if a direct neurorrhaphy was possible between the femoral nerve and the two united branches of the obturator nerve. The overlap between the two nerve endings was 26 mm on average, and the mean diameter of the two nerve endings was 3.6 mm for the united branches of the obturator nerve and 3.7 mm for the femoral nerve. Thus, a direct suture was possible in all cases. In this anatomical study, access to the femoral nerve and two united branches of the obturator nerve was easy, in contrast to transfer in the pelvis. Moreover, direct suture without tension was possible in all cases. Thus, this transfer is simple and perfectly reproducible and may have a clinical application in proximal femoral nerve injuries. PMID- 22821711 TI - Longitudinal testing of visual perception in dementia with Lewy bodies and Alzheimer's disease. AB - OBJECTIVES: Visuo-perceptual abnormalities are a prominent feature in dementia with Lewy bodies (DLB) and also occur in Alzheimer's disease (AD) to a lesser extent. We studied the progression of visuo-perceptual abnormalities over a 12 month period in DLB and AD by using a novel computerised test battery. METHODS: Following our previous work using the Newcastle Visual Perception (NEVIP) battery, we re-assessed 16 AD, 12 DLB and 28 similar-aged comparison participants 12 months after initial baseline assessment. RESULTS: DLB visual perception at follow-up showed worse performance than AD (U = 43, p = 0.027); however, there were no significant changes in visuo-perceptual scores between baseline assessment and 12-month assessment within groups. A poor baseline score on the NEVIP predicted subsequent deterioration on the Bristol Activities of Daily Living Scale (rs = -0.725, p = 0.014) in DLB participants but not in the AD group. CONCLUSIONS: The NEVIP is a reliable test of visuo-perception, relatively independent of cognitive decline, with predictive value in identifying DLB participants at risk of functional decline. Visuo-perceptual dysfunction is a core feature of the disorder for some DLB patients and was stable over the 12 month period examined here. PMID- 22821712 TI - Occupation and the prevalence of current depression and frequent mental distress, WA BRFSS 2006 and 2008. AB - BACKGROUND: Workers with depression and frequent mental distress (FMD) have lost work productivity. Limited systematic comparisons exist for the prevalence of depression and FMD across occupational groups. METHODS: Using a state-added question for occupation coupled to measures of depression and FMD on the Washington State (WA) 2006 and 2008 Behavioral Risk Factor Surveillance System survey, we estimated the prevalence and odds ratios (ORs) among the 20,560 WA workers. RESULTS: The prevalences of current depression and FMD were 5.2% and 7.5%, respectively. The prevalence varied considerably across occupations. Compared with Management occupation, Truck drivers had significantly increased odds for both current depression [OR = 6.18, 95% confidence interval (CI): 2.52 15.16] and FMD (OR = 1.85, 95% CI: 1.01-3.41). Cleaning/Building services (OR = 1.95, 95% CI: 1.11-3.40) and Protective services (OR = 1.97, 95% CI: 1.19-3.27) were associated with increased FMD. CONCLUSIONS: These findings demonstrate the need for research on possible sources of the differences for current depression and FMD across occupations. PMID- 22821713 TI - Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development. AB - Congenital heart defects (CHDs) are the most prevalent human birth defects. More than 85% of CHDs are thought to result from a combination of genetic susceptibilities and environmental stress. However, the stress-related signalling pathways involved remain largely unknown. The p53 transcription factor is a key tumour suppressor and a central regulator of the cellular stress responses. p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post translational level. Here we used the Cre-loxP system to delete Mdm2 (Tie2Cre;Mdm2(FM/FM) ) or one copy of both Mdm2 and Mdm4 (Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) ) in endothelial/endocardial cells and their derivatives in mice to examine the regulation of the p53/Mdm2-Mdm4 pathway during vascular and cardiovascular development. The Tie2Cre;Mdm2(FM/FM) mice died before embryonic day 10.5 (E10.5) and displayed severe vascular defects. On the other hand, the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice displayed atrial and ventricular septal defects (ASD, VSD) of the heart, leading to severe heart dysfunction and postnatal death. During cardiac endocardial cushion morphogenesis, p53 activation was associated with defects in both the epithelial-mesenchymal transition (EMT) of the endocardial cells and the post-EMT proliferation of the mesenchymal cells, and the valvuloseptal phenotypes of the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) mice were fully rescued by deletion of one copy of p53. Strikingly, maternal exposure to low-dose X-rays in C57BL/6 mice mimicked the congenital heart malformations seen in the Tie2Cre;Mdm2(FM/+) ; Mdm4(+/-) model, which was also dependent on p53 status, establishing a link between maternal exposures and CHD susceptibility through the p53 pathway. These data revealed a new regulatory mechanism in cardiac endocardial cushion morphogenesis and suggested a possible cause of CHDs due to environmental stress. PMID- 22821714 TI - Methylated actinomycin D, a novel actinomycin D analog induces apoptosis in HepG2 cells through Fas- and mitochondria-mediated pathways. AB - Actinomycin D (Act D), a well known of clinical antitumor drug, has been used for the treatment of some highly malignant tumors, however, the clinical application was limited by its extreme cytotoxicity. In the present study, we reported that methylated actinomycin D (mAct D), a novel actinomycin D analog isolated from Streptomyces sp. KLBMP 2541 in our previous study, could not only exert stronger inhibitory effects on several human cancer cells than Act D in dose- and time dependent manner at ng concentrations, especially on HepG2 cells, but also lower cytotoxicity in normal cells (HL-7702). Base on these results, HepG2 cells were treated for further study to illustrate the potential mechanism of mAct D. The results of nuclei morphology examination, DNA fragmentation detection, sub-G1 analysis, annexin V-FITC/PI staining and activation of caspase-3 indicated mAct D significantly induced HepG2 cells apoptosis. Semiquantitative RT-PCR and Western blot analysis revealed that mAct D induced apoptosis in HepG2 cells through mitochondria-dependent pathway by increasing levels of caspase-9, Bax, Bak while decreasing levels of Bcl-2, Bid, and Fas-dependent pathway by increasing levels of Fas, FasL, FADD, and caspase-8. Subsequently, pretreatment with specific inhibitor of caspase-8 Z-LEHD-FMK and caspase-9 Z-LEHD-FMK significantly attenuated caspase-3 activity, the cleavage of caspase-3 and PARP, meanwhile increased the cell viability. In addition, p53 and mitochondrial transcription factor A (mtTFA) were also upregulated. Taken together, ng concentrations mAct D induces the apoptosis of HepG2 through Fas- and mitochondria-mediated pathway and presents a potential novel alternative agent for the treatment of human hepatic carcinoma. PMID- 22821716 TI - Reducing the load: the evolution and management of obesity and nonalcoholic steatohepatitis before liver transplantation. AB - KEY POINTS: 1. Obesity is common in patients with end-stage liver disease of any cause. 2. Obesity is associated with comorbidities that can affect liver transplant candidacy, such as metabolic syndrome (diabetes, hyperlipidemia, and hypertension), cardiovascular disease, pulmonary disorders (related to obstructive sleep apnea), renal dysfunction, and malignancies. 3. Nonalcoholic steatohepatitis is the only indication for transplantation that is increasing in frequency, and it may soon become the leading indication. 4. There is no set body mass index above which liver transplantation is contraindicated. Transplant candidacy and outcomes depend on the cumulative comorbidities of the individual patient. 5. Weight loss is an important component of metabolic syndrome management and is recommended before liver transplantation. 6. Bariatric surgery may be considered in carefully selected patients with well-compensated cirrhosis but is not recommended in patients with decompensated cirrhosis. PMID- 22821717 TI - Development and characterization of an automated high throughput screening method for optimization of protein refolding processes. AB - Optimization of protein refolding parameters by automated, miniaturized, and parallelized high throughput screening is a powerful approach to meet the demand for fast process development with low material consumption. In this study, we validated methods applicable on a standard liquid handling robot for screening of refolding process parameters by dilution of denatured lysozyme in refolding buffer systems. Different approaches for the estimation of protein solubility and folding were validated concerning resolution and compatibility with the robotic system and with the complex buffer and protein structure composition. We established an indirect method to assess soluble lysozyme concentration independent of matrix effects and protein structure varieties by automated separation of aggregated protein, resolubilization, and measurement of absorption at 280 nm. Using this nonspecific solubility assays the correlation between favorable parameters for high active and soluble lysozyme yields were evaluated. An overlap of good refolding buffer compositions was found provided that the redox environment was controlled with redox reagents. In addition, the need to control unfolding conditions like time, temperature, lysozyme, and dithiothreitol concentration was pointed out as different feedstocks resulted in different refolding yields. PMID- 22821715 TI - Corneal goblet cells and their niche: implications for corneal stem cell deficiency. AB - Goblet cells are terminally differentiated cells secreting mucins and antibacterial peptides that play an important role in maintaining the health of the cornea. In corneal stem cell deficiency, the progenitor cells giving rise to goblet cells on the cornea are presumed to arise from differentiation of cells that migrate onto the cornea from the neighboring conjunctiva. This occurs in response to the inability of corneal epithelial progenitor cells at the limbus to maintain an intact corneal epithelium. This study characterizes clusters of cells we refer to as compound niches at the limbal:corneal border in the unwounded mouse. Compound niches are identified by high expression of simple epithelial keratin 8 (K8) and 19 (K19). They contain variable numbers of cells in one of several differentiation states: slow-cycling corneal progenitor cells, proliferating cells, nonproliferating cells, and postmitotic differentiated K12+Muc5ac+ goblet cells. Expression of K12 differentiates these goblet cells from those in the conjunctival epithelium and suggests that corneal epithelial progenitor cells give rise to both corneal epithelial and goblet cells. After wounds that remove corneal epithelial cells near the limbus, compound niches migrate from the limbal:corneal border onto the cornea where K8+ cells proliferate and goblet cells increase in number. By contrast, no migration of goblet cells from the bulbar conjunctiva onto the cornea is observed. This study is the first description of compound niches and corneal goblet cells and demonstration of a role for these cells in the pathology typically associated with corneal stem cell deficiency. PMID- 22821718 TI - Research alone is not sufficient to prevent sports injury. PMID- 22821719 TI - Management of acute anterior shoulder dislocation. AB - Shoulder dislocation is the most common large joint dislocation in the body. Recent advances in radiological imaging and shoulder surgery have shown the potential dangers of traditional reduction techniques such as the Kocher's and the Hippocratic methods, which are still advocated by many textbooks. Many non specialists continue to use these techniques, unaware of their potential risks. This article reviews the clinical and radiographic presentation of dislocation; some common reduction techniques; their risks and success rate; analgesia methods to facilitate the reduction; and postreduction management. Many textbooks advocate methods that have been superceded by safer alternatives. Trainees should learn better and safer relocation methods backed up by the current evidence available. PMID- 22821720 TI - Clinical assessment of the scapula: a review of the literature. AB - Scientific evidence supporting a role for faulty scapular positioning in patients with various shoulder disorders is cumulating. Clinicians who manage patients with shoulder pain and athletes at risk of developing shoulder pain need to have the skills to assess static and dynamic scapular positioning and dynamic control. Several methods for the assessment of scapular positioning are described in scientific literature. However, the majority uses expensive and specialised equipment (laboratory methods), making their use in clinical practice nearly impossible. On the basis of biometric and kinematic studies, guidelines for interpreting the observation of static and dynamic scapular positioning pattern in patients with shoulder pain are provided. At this point, clinicians can use reliable clinical tests for the assessment of both static and dynamic scapular positioning in patients with shoulder pain. However, this review also provides clinicians several possible pitfalls when performing clinical scapular evaluation. On the basis of its clinical relevance, its proven reliability, its relation to body length and its applicability in a clinical setting, this review recommends to assess the scapula both static (visual observation and acromial distance or Baylor/double square method for shoulder protraction) and semidynamic (visual observation and inclinometry for scapular upward rotation). In addition, when the patient demonstrates with shoulder impingement symptoms, the scapular repositioning test and scapular assistant test are recommended for relating the patients' symptoms to the position or movement of the scapula. PMID- 22821721 TI - Liquid chromatography - tandem mass spectrometry for the simultaneous quantitation of glipizide, cilostazol and its active metabolite 3, 4-dehydro cilostazol in rat plasma: application for a pharmacokinetic study. AB - A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC ESI-MS/MS) method for the simultaneous quantitation of glipizide, cilostazol and 3, 4-dehydro-cilostazol in rat plasma was developed and validated. Glimepride was used as an internal standard (IS). The analytes were extracted by using liquid liquid extraction procedure and separated on a reverse phase C18 column (50 mm*4.6 mm i. d., 5 u) using acetonitrile: 2 mM ammonium acetate buffer, pH 3.2 (90:10, v/v) as mobile phase at a flow rate 0.4 mL/min in an isocratic mode. Selective reaction monitoring was performed using the transitions m/z 446.4>321.1, 370.2>288.3, 368.3>286.2, and 491.4>352.2 to quantify glipizide, cilostazol, 3, 4-dehydro-cilostazol and glimepride, respectively. Calibration curves were constructed over the range of 25-2 000 ng/mL for glipizide, cilostazol and 3, 4-dehydro-cilostazol. The lower limit of quantitation was 25 ng/mL for all the analytes. The recoveries from spiked control samples were>76% for all analytes and internal standard. Intra and inter day accuracy and precision of validated method were within the acceptable limits of at all concentration. The quantitation method was successfully applied for simultaneous estimation of glipizide, cilostazol and 3, 4-dehydro-cilostazol in a pharmacokinetic drug-drug interaction study in wistar rats. PMID- 22821722 TI - Pleural malignancy in a 22-year-old female with a chromosome 22q13 deletion. PMID- 22821723 TI - TEDE per cumulated activity for family members exposed to adult patients treated with 131I. AB - In 1997, the United States Nuclear Regulatory Commission amended its criteria under which patients administered radioactive materials could be released from the hospital. The revised criteria ensures that the total effective dose equivalent (TEDE) to any individual exposed to the released patient will not likely exceed 5 mSv. Licensees are recommended to use one of the three options to release the patient in accordance with these regulatory requirements: administered activity, measured dose rate, or patient-specific dose calculation. The NRC's suggested calculation method is based on the assumption that the patient (source) and a family member (target) are each considered to be points in space. This point source/target assumption has been shown to be conservative in comparison to more realistic guidelines. In this present study, the effective doses to family members were calculated using a series of revised Oak Ridge National Laboratory stylised phantoms coupled with a Monte Carlo radiation transport code. A set of TEDE per cumulated activity values were calculated for three different distributions of (131)I (thyroid, abdomen and whole body), various separation distances and two exposure scenarios (face-to-face standing and side-by-side lying). The results indicate that an overestimation of TEDE per cumulated activity based on the point source/target method was >2-fold. The values for paediatric phantoms showed a strong age-dependency, which showed that dosimetry for children should be separately considered instead of using adult phantoms as a substitute. On the basis of the results of this study, a licensee may use less conservative patient-specific release criteria and provide the patient and the family members with more practical dose avoidance guidelines. PMID- 22821724 TI - Switchable catalysis. PMID- 22821725 TI - Reliability and validity of swallows as a measure of breast milk intake in the first days of life. AB - BACKGROUND: Breastfeeding assessment in the hospital to determine adequacy of feeds remains controversial. Swallow evaluation is integral to current assessment tools, but the literature is not clear about whether the number of swallows is an accurate indicator of breast milk intake in early postpartum. OBJECTIVES: To determine the reliability and validity of swallows as a measure of breast milk intake in the first days of a newborn's life. METHODS: Thirty mother-baby dyads were observed at one breastfeeding; pre- and postfeed weights were done, bedside audible swallows were counted, and feeds were videotaped for independent rating. Milk intake was determined from weight change, adjusted for insensible water loss. RESULTS: Number of swallows was significantly and positively correlated with breast milk intake (r = .71). Number of swallows alone, however, accounted for only 50.8% (R (2) = .508) of the variation in milk intake. Infant age was the best predictor of milk intake (beta(age) = .56 vs beta(No. swallows) = .36), accounting for 68% of the variation in milk intake when combined with swallows. The majority of infants took in 10 g or less of breast milk (77%); length of feeds was variable. In-room (at bedside) lactation consultant (LC) and video rater LC swallow counts were significantly and positively correlated (r = .93; P < .01). However, the 2 lactation consultant swallow numbers include clinically important discrepancies in a Bland-Altman analysis. CONCLUSIONS: Number of swallows was not supported as a reliable or valid indicator of milk intake and adequacy of a feed in the first few days of life. PMID- 22821726 TI - Breastfeeding at NICU discharge: a multicenter Italian study. AB - BACKGROUND: Human milk is the optimal form of nutrition for infants, especially sick or compromised infants, yet international data suggest that breastfeeding (feeding at the breast) and the use of expressed human milk (mother's and donor's milk) are limited in patients cared for in the neonatal intensive care unit (NICU). OBJECTIVE: The goal of this study was to examine feeding status at hospital discharge among high risk infants. METHODS: We used the 1991 World Health Organization infant feeding definitions, applied to the 72 hour period preceding discharge from the NICU. The study sample consisted of all high risk infants discharged from July 1, 2005, to June 30, 2006 from 13 Italian NICUs. Data on infant feeding in the last 72 hours were collected at discharge from the medical records. RESULTS: We recorded data from 2948 subjects with a median gestational age of 35 weeks (IQR, 32-38), a median birth weight of 2200 g (IQR, 1630-2920) and a median length of stay of 16 days (IQR, 8-33). At discharge, 28% of all infants were fed exclusively with human milk: 31%, 25%, 22% and 33% respectively in the <1500 g, 1500-2000 g, 2000-2499 g and >= 2500 g birth weight categories. The proportion of infants not fed with human milk varied from 6 to 82% across different centers. CONCLUSION: Our study found limited breastfeeding and use of human milk among the NICU infants at discharge. At discharge, infants with a birth weight 1500-2499 g were fed exclusively with human milk less than those in higher or lower birth weight categories. PMID- 22821727 TI - Surgical strategies based on standard templates for microsurgical reconstruction of oral cavity and oropharynx soft tissue: a 20 years' experience. AB - BACKGROUND: Microsurgical reconstruction has become the worldwide gold standard for repairing surgical defects in head and neck cancer. The aim of this article is to describe a standardized reconstructive approach to the oral cavity and oropharynx soft tissue defects. PATIENTS AND METHODS: Since 1992, the authors have treated 163 patients affected by oral cavity and oropharynx cancer, performing a total of 175 flaps. A systematic postoperative functional study prompted a surgical strategy, in terms of flap choice, shape, and insetting. A two-dimensional template was used to obtain a three-dimensional reconstruction for the best functional and aesthetic outcome. To simplify preoperative planning, surgical resections were divided into a set number of classes. The templates, flap choice, and insetting are described for each region. RESULTS: Complications consisted of seven partial necroses of the flap which easily resolved with a local toilette and 12 complete necroses of the flap due to vascular thrombosis, these patients required a secondary reconstruction with another free flap. Functional results were systematically evaluated in the first 60 patients of our series with particular attention to the swallowing function, which was analyzed by both videofluoroscopy and functional endoscopic evaluation of swallowing. Results showed a good functional recovery with the described reconstructive techniques. CONCLUSION: A standardized surgical strategy based on reproducible templates might facilitate less experienced surgeons in analyzing the problem, choosing the best technical solution and foreseeing the functional outcomes. PMID- 22821728 TI - Nutritional status of community-dwelling older people with dementia: associations with individual and family caregivers' characteristics. AB - OBJECTIVE: The objective of this study was to explore the associations of individual characteristics of both older people with dementia and family caregivers with the nutritional status of older people with dementia. METHODS: This cross-sectional study comprising 56 community-dwelling older persons with dementia and 56 family caregivers was conducted at home by a psychogerontologist working for a community gerontological center. Older people with dementia were assessed with Mini mental state examination, Instrumental Activities of Daily Living, Activities of Daily Living (ADL), and NeuroPsychiatric Inventory (NPI) and family caregivers with the Burden Interview (Zarit scale), the State-Trait Anxiety Inventory, the Center for Epidemiologic Studies Depression Scale, and the emotional impact measure of NPI. For both, nutritional status was evaluated using the Mini Nutritional Assessment (MNA). RESULTS: Among older people with dementia, 58.9% were at risk of malnutrition and 23.2% presented a poor nutritional status, and among the family caregivers, 32.1% and 5.4%, respectively. The MNA score of older people with dementia was strongly and inversely associated with the ADL score and was strongly and positively associated with the MNA score of family caregiver. These two factors significantly explained 32% of variation of MNA score of older people with dementia. CONCLUSIONS: These findings confirm the value of investigating nutritional deficiencies in dementia within the caregiving dyad and suggest that the functional status of older people with dementia and the nutritional status of family caregivers should be carefully assessed. PMID- 22821729 TI - SP1 mediates the link between methylation of the tumour suppressor miR-149 and outcome in colorectal cancer. AB - Although recent studies indicate that DNA methylation contributes to the down regulation of microRNAs (miRNAs) in colorectal cancer (CRC), this field remains largely unexplored. To identify methylation-silenced miRNAs and clarify their role in CRC, we performed a microarray analysis and screened for miRNAs that were induced in CRC cells by 5-aza-2'-deoxycytidine treatment or by the knockdown of DNA methyltransferases. The DNA methylation status of the candidate miRNA was analysed by bisulphite sequencing PCR and methylation-specific PCR. We found that miRNA-149 (miR-149) was epigenetically silenced in CRC and down-regulation of miR 149 was associated with hypermethylation of the neighbouring CpG island (CGI). Quantitative RT-PCR analysis demonstrated that the miR-149 level was markedly reduced in 51.6% of the CRC tissues compared with matched non-cancerous tissues. In addition, low expression of miR-149 was associated with a greater depth of invasion (p = 0.012), lower 5-year survival rate (p = 0.025), and was found to be an independent prognostic factor for overall survival (p = 0.016) in a multivariate analysis. Moreover, transfection of miR-149 inhibited cell growth and invasion of CRC cells in vitro. We also identified mRNA for Specificity Protein 1 (SP1, Sp1), a potential oncogenic protein, as a target of miR-149. Our data suggest that, as a methylation-sensitive miRNA, miR-149 may play an important role as a tumour suppressor in CRC, which has prognostic and therapeutic implications. PMID- 22821730 TI - Efficacy of antiviral therapy for hepatitis C after liver transplantation with cyclosporine and tacrolimus: a systematic review and meta-analysis. AB - Cyclosporine A (CSA), but not tacrolimus (TAC), inhibits hepatitis C virus (HCV) replication in vitro. Clinical reports on the efficacy of interferon-alpha (IFNalpha)-based antiviral therapy (AVT) for recurrent HCV after liver transplantation (LT) with CSA and TAC are conflicting. Our aim was to assess whether AVT for recurrent HCV after LT is more effective with CSA or TAC. We performed an electronic database search (1995-2012) and a manual abstract search (2005-2012). The a priori defined eligibility criteria included the use of AVT for recurrent HCV with IFN (standard or pegylated) and ribavirin and the reporting of sustained virological response (SVR) rates with CSA and TAC (the primary outcome). Two authors identified and extracted data independently. Dichotomous data were expressed as relative risks (RRs) and 95% confidence intervals (CIs) with a random effects model. In all, 5058 references were retrieved, and 1 randomized controlled trial (RCT) and 17 observational studies (13 full-text articles) met the eligibility criteria; the meta-analysis was based on the latter studies. The pooled SVR rates were 42% (395/945) with CSA and 35% (471/1364) with TAC (RR = 1.18, 95% CI = 1.00-1.39, P = 0.05). Although the pooled data contained significant heterogeneity (I(2) = 45%, P = 0.02), the SVR rates in the RCT were comparable (39% with CSA and 35% with TAC). Limiting the analysis to the 7 studies reporting on 40 or more patients in each group (with 1634 patients in all) favored CSA (RR = 1.23, 95% CI = 1.09-1.38, P < 0.001), and heterogeneity disappeared (I(2) = 0%, P = 0.62). In conclusion, IFN-based AVT for recurrent HCV after LT seems marginally more effective with CSA versus TAC; the study heterogeneity, however, limits firm conclusions. PMID- 22821731 TI - The worker's ear: a history of noise-induced hearing loss. AB - Hearing loss afflicts millions of people throughout the world, and many of those millions are workers who have been exposed to excessive noise. People have always been surrounded by a variety of sounds in their environments, but the invention of gunpowder and the Industrial Revolution introduced new sounds of greater intensity than ever before. It is only within the past 40 years that serious efforts to reduce excessive noise at work sites have been initiated. In the latter half of the 20th century, many governments imposed regulations to limit workers' exposure to loud sounds. Because of this recent action, some people may believe that the recognition of occupational noise-induced hearing loss (NIHL) is relatively new. However, a review of selected historical and medical manuscripts, books, and articles show that the association of hearing changes with loud noise exposure was recognized for centuries before systematic attempts were made to limit the exposure. Delays in implementing controls to limit noise exposure were due to cultural reasons, technical problems in controlling noise generation, and a lack of understanding of the mechanics of hearing loss. A historical perspective on this issue may remind health care providers that they need to continue to emphasize hearing conservation measures as occupational noise exposures change with the shift of industrial activities between countries. PMID- 22821732 TI - Deficient DNA damage response and cell cycle checkpoints lead to accumulation of point mutations in human embryonic stem cells. AB - Human embryonic stem cells (hESCs) tend to lose genomic integrity during long periods of culture in vitro and to acquire a cancer-like phenotype. In this study, we aim at understanding the contribution of point mutations to the adaptation process and at providing a mechanistic explanation for their accumulation. We observed that, due to the absence of p21/Waf1/Cip1, cultured hESCs lack proper cell cycle checkpoints and are vulnerable to the kind of DNA damage usually repaired by the highly versatile nucleotide excision repair (NER) pathway. In response to UV-induced DNA damage, the majority of hESCs succumb to apoptosis; however, a subpopulation continues to proliferate, carrying damaged DNA and accumulating point mutations with a typical UV-induced signature. The UV resistant cells retain their proliferative capacity and potential for pluripotent differentiation and are markedly less apoptotic to subsequent UV exposure. These findings demonstrate that, due to deficient DNA damage response, the modest NER activity in hESCs is insufficient to prevent increased mutagenesis. This provides for the appearance of genetically aberrant hESCs, paving the way for further major genetic changes. PMID- 22821733 TI - Enantioseparation of chiral sulfonates by liquid chromatography and subcritical fluid chromatography. AB - Tert-butylcarbamoyl-quinine and -quinidine weak anion-exchange chiral stationary phases (Chiralpak(r) QN-AX and QD-AX) have been applied for the separation of sodium beta-ketosulfonates, such as sodium chalconesulfonates and derivatives thereof. The influence of type and amount of co- and counterions on retention and enantioresolution was investigated using polar organic mobile phases. Both columns exhibited remarkable enantiodiscrimination properties for the investigated test solutes, in which the quinidine-based column showed better enantioselectivity and slightly stronger retention for all analytes compared to the quinine-derived chiral stationary phase. With an optimized mobile phase (MeOH, 50 mM HOAc, 25 mM NH(3)), 12 of 13 chiral sulfonates could be baseline separated within 8 min using the quinidine-derivatized column. Furthermore, subcritical fluid chromatography (SubFC) mode with a CO(2)-based mobile phase using a buffered methanolic modifier was compared to HPLC. Generally, SubFC exhibited slightly inferior enantioselectivities and lower elution power but also provided unique baseline resolution for one compound. PMID- 22821734 TI - Pseudenhygromyxa salsuginis gen. nov., sp. nov., a myxobacterium isolated from an estuarine marsh. AB - A myxobacterial strain, designated SYR-2(T), was obtained from a mud sample from an estuarine marsh alongside the Yoshino River, Shikoku, Japan. It had rod-shaped vegetative cells and formed bacteriolytic enlarging colonies or so-called 'swarms' in the agar media. Fruiting-body-like globular to polyhedral cell aggregates and myxospore-like spherical to ellipsoidal cells within them were observed. Those features coincided with the general characteristics of myxobacteria. The strain was mesophilic and strictly aerobic. Growth of SYR-2(T) was observed at 18-40 degrees C (optimum, 30-35 degrees C), pH 5.5-8.3 (optimum, pH 7.0-7.5) and with 0.0-2.5 % (w/v) NaCl (optimum, 0.2-1.0 %). Both Mg(2+) and Ca(2+) were essential cations for the growth. The predominant fatty acids were iso-C15 : 0 (43.8 %), iso-C17 : 0 (22.4 %) and iso-C16 : 0 (9.6 %). A C20 : 4 fatty acid [arachidonic acid (4.3 %)], iso-C19 : 0 (1.5 %) and anteiso acids [ai-C15 : 0 (0.5 %), ai-C17 : 0 (0.3 %)] were also detected. The G+C content of the DNA was 69.7 mol%. The strain contained menaquinone-7 (MK-7) as the major respiratory quinone. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain SYR-2(T) belonged to the suborder Nannocystineae, order Myxococcales in the class Deltaproteobacteria, and the strain was most closely related to two type strains of marine myxobacteria, Enhygromyxa salina SHK-1(T) and Plesiocystis pacifica SIR-1(T), with 96.5 % and 96.0 % similarities, respectively. These characteristics determined in this polyphasic study suggested that strain SYR-2(T) represents a novel species in a new genus of myxobacteria. The name Pseudenhygromyxa salsuginis gen. nov., sp. nov. is proposed to accommodate this isolate, and the type strain of Pseudenhygromyxa salsuginis is SYR-2(T) ( = NBRC 104351(T) = DSM 21377(T)). PMID- 22821735 TI - Lysinimonas soli gen. nov., sp. nov., isolated from soil, and reclassification of Leifsonia kribbensis Dastager et al. 2009 as Lysinimonas kribbensis sp. nov., comb. nov. AB - A Gram-stain-positive, non-motile rod, designated strain SGM3-12(T), was isolated from paddy soil in Suwon, Republic of Korea. 16S rRNA gene sequence analysis revealed that the strain represented a novel member of the family Microbacteriaceae. The nearest phylogenetic neighbour was Leifsonia kribbensis MSL-13(T) (97.4 % 16S rRNA gene sequence similarity). Strain SGM3-12(T) and Leifsonia kribbensis MSL-13(T) formed a distinct cluster within the family Microbacteriaceae. Strain SGM3-12(T) contained MK-12(H2) and MK-11(H2) as the predominant menaquinones with moderate amounts of MK-12 and MK-11; anteiso-C15 : 0 and iso-C16 : 0 as the major cellular fatty acids (>10 % of total); and diphosphatidylglycerol, phosphatidylglycerol and unidentified glycolipids as the polar lipids. The peptidoglycan type of the isolate was B1delta with L-Lys as the diagnostic cell-wall diamino acid. On the basis of these results, strain SGM3 12(T) represents a novel species within a new genus, for which the name Lysinimonas soli gen. nov., sp. nov. is proposed (the type strain of the type species is SGM3-12(T) = KACC 13362(T) = NBRC 107106(T)). It is also proposed that Leifsonia kribbensis be transferred to this genus as Lysinimonas kribbensis comb. nov. (the type strain is MSL-13(T) = DSM 19272(T) = JCM 16015(T) = KACC 21108(T) = KCTC 19267(T)). PMID- 22821736 TI - Humitalea rosea gen. nov., sp. nov., an aerobic bacteriochlorophyll-containing bacterium of the family Acetobacteraceae isolated from soil. AB - A Gram-staining-negative, pale-pink-pigmented, non-motile, obligately aerobic and rod-shaped bacterium, designated strain W37(T), was isolated from soil and subjected to a taxonomic investigation using a polyphasic approach. The strain grew at 1-30 degrees C, oxidized thiosulfate and accumulated polyhydroxyalkanoates. Photosynthetic pigments were represented by bacteriochlorophyll a and carotenoids. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain W37(T) was most closely related to members of the genera Roseococcus and Rubritepida (with sequence similarities of <92.8 %) but formed a distinct lineage in the family Acetobacteraceae. The polar lipid profile comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, three unidentified aminolipids and one other unidentified lipid. The predominant cellular fatty acids were C18 : 1omega7c and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The DNA G+C content of strain W37(T) was 68.2 mol%. On the basis of phenotypic characteristics and phylogenetic analysis, strain W37(T) represents a novel species of a new genus in the family Acetobacteraceae, for which the name Humitalea rosea gen. nov., sp. nov. is proposed. The type strain of the type species is W37(T) ( = CIP 110261(T) = LMG 26243(T)). PMID- 22821738 TI - Direct growth of TiO2 nanosheet arrays on carbon fibers for highly efficient photocatalytic degradation of methyl orange. PMID- 22821737 TI - The Learning Disabilities Network (LeaDNet): using neurofibromatosis type 1 (NF1) as a paradigm for translational research. AB - Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for these phenotypes. The successes with NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments. PMID- 22821739 TI - Assessment of thought-shape fusion: initial validation of a short version of the trait thought-shape fusion scale. AB - OBJECTIVE: Thought-shape fusion (TSF) is a cognitive distortion that has been linked to eating pathology. Two studies were conducted to further explore this phenomenon and to establish the psychometric properties of a French short version of the TSF scale. METHOD: In Study 1, students (n = 284) completed questionnaires assessing TSF and related psychopathology. In Study 2, the responses of women with eating disorders (n = 22) and women with no history of an eating disorder (n = 23) were compared. RESULTS: The French short version of the TSF scale has a unifactorial structure, with convergent validity with measures of eating pathology, and good internal consistency. Depression, eating pathology, body dissatisfaction, and thought-action fusion emerged as predictors of TSF. Individuals with eating disorders have higher TSF, and more clinically relevant food-related thoughts than do women with no history of an eating disorder. DISCUSSION: This research suggests that the shortened TSF scale can suitably measure this construct, and provides support for the notion that TSF is associated with eating pathology. PMID- 22821740 TI - Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation. AB - It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, H(ex) , between an API-coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest H(ex) s with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates. PMID- 22821741 TI - A chemoenzymatic total synthesis of the neurogenic starfish ganglioside LLG-3 using an engineered and evolved synthase. AB - An LLG-3 oligosaccharide-fluoride can be assembled chemoenzymatically and readily coupled with various sphingosines by an engineered endoglycoceramidase glycosynthase. The lyso-ganglioside products are acylated to generate the individual isomers identified in the heterogeneous natural isolates, as well as modified glycosphingolipids. PMID- 22821742 TI - External validation of the updated Briganti nomogram to predict lymph node invasion in prostate cancer patients undergoing extended lymph node dissection. AB - PURPOSE: We aimed to test accuracy and generalizability of a recently updated nomogram to assess the probability of lymph node invasion (LNI), when applied to a different European cohort of men undergoing radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND). MATERIALS AND METHODS: The study cohort consisted of 1,282 men with clinically localized PCa who underwent RP and ePLND, including removal of obturator, external iliac, and hypogastric lymph nodes, between 01/2007 and 08/2011. Descriptive measurements included preoperative clinical and biopsy variables, such as prostate-specific antigen (PSA), clinical stage (CS), primary and secondary biopsy Gleason pattern, and percentage of positive cores. We used the area under curve (AUC) of the receiver operator characteristic analysis to quantify accuracy of the model to predict LNI. The extent of over- or under-estimation was explored graphically within loess calibration plots. RESULTS: The median number of removed lymph nodes was 15 with an interquartile range of 12-20. Twelve percent (n = 155) of men had LNI. Preoperative clinical and biopsy characteristics differed significantly (all P <= 0.002) between men with LNI and those without. External validation of the previously reported updated LNI nomogram showed very good accuracy (AUC: 0.829). A nomogram-derived cut-off of 4% could lead to a reduction of 48% of lymph node dissection, while missing 10% of patients with LNI. CONCLUSIONS: We report the external validation of an updated LNI nomogram, demonstrating accuracy and applicability in a different European cohort. A nomogram-derived cut-off of 4% confirmed good performance characteristics within a different external validation cohort. PMID- 22821744 TI - AEBP1 gene variants in infants with gastroschisis. AB - BACKGROUND: The AEBP1 (adipocyte enhancer binding protein) gene has two isoforms: AEBP1, the shorter of the two isoforms, and Aclp (aortic carboxypeptidase-like protein). Aclp(-/-) mice demonstrate a ventral wall defect that is similar to gastroschisis in humans. Aclp is a potential candidate gene because it is expressed in numerous tissues during early development in mice; it associates with the extracellular matrix; and is essential for abdominal wall development and wound healing. In contrast, AEBP1 encodes an intracellular protein involved in proinflammatory responses, and may play a critical role in apoptosis and cell survival. Gastroschisis is a severe abdominal wall defect more common in young women and recently associated with a genitourinary infection early in pregnancy. METHODS: We screened AEBP1 in 40 cases of gastroschisis and compared identified variants in a control population. RESULTS: We identified several novel variants in AEBP1, including synonymous and nonsynonymous single nucleotide substitutions and intronic indels. However, the frequency of these variants was not significantly different from that of the control group, and the associated amino acid changes were predicted to be benign by two prediction software programs. CONCLUSIONS: Gastroschisis remains an intriguing defect that, for an unknown reason, occurs more commonly in young women and after a genitourinary infection. Although we found many alterations in AEBP1 among the gastroschisis cases, they were predicted to be benign. However, this gene requires further understanding of its interaction with other genes involved in the immune response pathway. PMID- 22821743 TI - Vascular endothelial growth factor-loaded poly(lactic-co-glycolic acid) microspheres-induced lateral axonal sprouting into the vein graft bridging two healthy nerves: nerve graft prefabrication using controlled release system. AB - The most commonly used surgical technique for repairing segmental nerve defects is autogenous nerve grafting; however, this method causes donor site morbidity. In this study, we sought to produce prefabricated nerve grafts that can serve as a conduit instead of autologous nerve using a controlled release system created with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres. The study was performed in vitro and in vivo. For the in vitro studies, VEGF-loaded PLGA microspheres were prepared. Thirty rats were used for the in vivo studies. Vein grafts were sutured between the tibial and peroneal nerves in all animals. Three groups were created, and an epineural window, partial incision, and microsphere application were performed, respectively. Walking track analysis, morphologic, and electron microscopic assessment were performed at the end of the eight weeks. Microspheres were produced in spherical shapes as required. Controlled release of VEGF was achieved during a 30-days period. Although signs of nerve injury occurred initially in the partial incision groups according to the indexes of peroneal and tibial function, it improved gradually. The index values were not affected in the other groups. There were many myelinated fibers with large diameters in the partial incision and controlled release groups, while a few myelinated fibers that passed through vein graft in the epineural window group. Thereby, prefabrication was carried out for the second and third groups. It was demonstrated that nerve graft can be prefabricated by the controlled delivery of VEGF. PMID- 22821745 TI - E2-binding surface on Uba3 beta-grasp domain undergoes a conformational transition. AB - The covalent attachment of ubiquitin (Ub) and ubiquitin-like (Ubl) proteins to various eukaryotic targets plays critical roles in regulating numerous cellular processes. E1-activating enzymes are critical, because they catalyze activation of their cognate Ub/Ubl protein and are responsible for its transfer to the correct E2-conjugating enzyme(s). The activating enzyme for neural-precursor-cell expressed developmentally downregulated 8 (NEDD8) is a heterodimer composed of APPBP1 and Uba3 subunits. The carboxyl terminal ubiquitin-like beta-grasp domain of human Uba3 (Uba3-betaGD) has been suggested as a key E2-binding site defining E2 specificity. In crystal structures of free E1 and the NEDD8-E1 complex, the E2 binding surface on the domain was missing from the electron density. However, when complexed with various E2s, this missing segment adopts a kinked alpha helix. Here, we demonstrate that Uba3-betaGD is an independently folded domain in solution and that residues involved in E2 binding are absent from the NMR spectrum, indicating that the E2-binding surface on Uba3-betaGD interconverts between multiple conformations, analogous to a similar conformational transition observed in the E2-binding surface of SUMO E1. These results suggest that access to multiple conformational substates is an important feature of the E1-E2 interaction. PMID- 22821747 TI - Inorganic double-helix structures of unusually simple lithium-phosphorus species. PMID- 22821746 TI - Combination treatments with ABT-263 and an immunotoxin produce synergistic killing of ABT-263-resistant small cell lung cancer cell lines. AB - Synergistic killing was achieved when Small Cell Lung Cancer (SCLC) cell lines were incubated with ABT-263 and an immunotoxin directed to the transferrin receptor. SCLC lines are variably sensitive to the BH-3 only peptide mimetic, ABT 263. To determine their sensitivity to toxin-based reagents, we incubated four representative SCLC lines with a model Pseudomonas exotoxin-based immunotoxin directed to the transferrin receptor. Remarkably in 4-of-4 lines, there was little evidence of immunotoxin-mediated cytotoxicity despite near complete inhibition of protein synthesis. However, when combinations of ABT-263 and immunotoxin were added to the ABT-263-resistant cell lines (H196 and H69AR), there was synergistic killing as evidenced by increased activation of caspase 3/7, annexin V staining, and loss of cell integrity. Synergistic killing was evident at 6 hr and correlated with loss of Mcl-1. This synergy was also noted when the closely related compound ABT-737 was combined with the same immunotoxin. To establish that the synergy seen in tissue culture could be achieved in vivo, H69AR cells were grown as tumors in nude mice and shown to be susceptible to the killing action of an immunotoxin-ABT-737 combination but not to either agent alone. When immunotoxin-ABT combinations were added to ABT-263-sensitive lines (H146 and H1417), killing was additive. Our data support combination approaches for treating ABT-263-resistant SCLC with ABT-263 and a second agent that provides synergistic killing action. PMID- 22821748 TI - Biocompatibility of an experimental MTA sealer implanted in the rat subcutaneous: quantitative and immunohistochemical evaluation. AB - The tissue reaction promoted by an experimental mineral trioxide aggregate sealer (MTAS) in the rat subcutaneous was evaluated by morphological and morphometric analyses. In the animals from each group (n = 20), polyethylene tubes filled with MTAS, Portland cement (PC) or MTA were implanted in the dorsal subcutaneous. In the control group, empty tubes were implanted. After 7, 14, 30, and 60 days, the specimens were fixed and embedded in paraffin. In the HE-stained sections, the numerical density of inflammatory cells (IC) in the capsule was evaluated and statistical analyses performed (p <= 0.05). The expression of osteopontin (OPN) was evaluated by immunohistochemistry. The von Kossa method for detection of calcified structures was also performed. A moderate inflammatory process in the capsule was seen in all groups, at 7 and 14 days. At 60 days, significant reduction in the number of IC was verified in comparison to initial periods; however, significant differences were not verified among the groups. OPN immunolabeling was observed in the fibroblasts cytoplasm of the capsule next to the implants. Structures von Kossa-positive were observed in the capsule adjacent to all materials implanted at 7, 14, and 30 days. The results strongly indicate that MTAS presents biocompatibility similarly to MTA and PC. PMID- 22821749 TI - Cigarette butt littering in city streets: a new methodology for studying and results. AB - OBJECTIVES: The objectives of the present work were to (a) develop a relatively simple single-observer method for data collection on cigarette butt discarding; and (b) quantify cigarette butt discarding behaviour in city streets. METHODS: A method was developed, piloted and refined (with interobserver assessment). Cigarette butt discarding was systematically observed by a single data collector while walking a continuous circuit of busy downtown streets in a capital city (Wellington, New Zealand). RESULTS: The final method appeared feasible in this setting and seemed efficient (at 5.5 discarding events observed per hour). A clear majority (76.7%; 95% CI 70.8 to 82.0%) of the 219 smokers observed littered their cigarette butts. Butt littering was more common for those who did not extinguish their cigarette (94.4% vs 4.5%, p=0.003). Butt littering was more common in the evening versus lunchtime periods of observation (85.8% vs 68.1%, p=0.002, logistic regression analysis). Overall, most smokers (73.5%) did not extinguish their butts and some placed lit butts in bins (constituting a risk of bin fires). The context for this littering was a high density of rubbish bins on this circuit with a mean of 3.5 bins being in view and with a bin every 24 m on average. CONCLUSIONS: Butt littering behaviour appears to be the norm among smokers in this urban setting, even though rubbish bins were ubiquitous. One solution is stronger enforcement of littering laws. Nevertheless, in a society with a national smokefree goal (by year 2025 for New Zealand), it would probably be more logical and cost effective to move to smokefree policies for major city streets, which are used in a number of jurisdictions internationally. PMID- 22821750 TI - Awareness, perceptions and use of snus among young adults from the upper Midwest region of the USA. AB - BACKGROUND: Since its introduction in 2006, snus has been aggressively marketed by tobacco companies. However, little is known about the awareness, perceptions and use of snus among young adults after Camel and Marlboro snus were sold nationwide in 2010. METHODS: Data were collected from 2607 young adults (ages 20 28) who participated in the Minnesota Adolescent Community Cohort Study in 2010 2011. Data include awareness of snus, ever and past 30-day use, perceived potential of snus as a quit aid, and perceived harmfulness and addictiveness of snus relative to cigarettes. The authors assessed the associations between these outcome variables and socio-demographic characteristics. RESULTS: Overall, 64.8% of participants were aware of snus, 14.5% ever used snus and 3.2% used snus in the past 30 days. Men and participants who smoked >100 cigarettes in their lifetime were associated with these three outcomes (p<0.05). Among those who were aware of snus, 16.3% agreed snus can help people quit smoking, 17.3% agreed snus is less harmful than cigarettes and 11.3% agreed snus is less addictive than cigarettes. These perceptions were associated with ever use and the past 30-day use of snus (p<0.05). CONCLUSIONS: In this regional sample of US young adults, the majority of young adults were aware of snus, and over one in 10 had used snus. More young adults in the sample than the overall US adult population believed that snus is less harmful than cigarettes. Perceptions of snus are associated with snus use. Strategic health communication interventions targeting young adults to confront the positive perceptions associated with snus may be needed to curb the interest in snus. PMID- 22821751 TI - The analysis of mainstream smoke emissions of Canadian 'super slim' cigarettes. AB - BACKGROUND: Super slim cigarettes are a relatively new type of cigarette in Canada, and an analysis of select toxicants in the mainstream smoke emissions of the super slim cigarette was conducted. METHOD: The yields of selected toxicants in the mainstream smoke emissions of six brands of super slim cigarettes were compared with the Canadian Benchmark, which represents the cigarette designs most commonly found in Canada. A super slim cigarette was also compared with a 'Reference Cigarette' to study the impact of the significantly reduced circumference on mainstream smoke emissions. RESULTS: Compared with the Canadian Benchmark, the yields of carbon monoxide, the carbonyls, volatiles and the aromatic amines were significantly lower for the super slim cigarette, but the yields of formaldehyde and ammonia were significantly higher. For brands containing a mixed tobacco blend, the yields of tobacco-specific nitrosamines were increased significantly. The reduced circumference of the super slim cigarette resulted in a lower tobacco weight, which together with filter ventilation resulted in lower yields of many toxicants. However, the reduced circumference increased significantly the yields of formaldehyde and phenols in mainstream smoke emissions. CONCLUSIONS: The notably slimmer design of the super slim cigarette resulted in lower yields of some toxicants in the mainstream smoke emissions. However, there were also significant increases in some toxicant levels in the mainstream smoke emissions including formaldehyde, ammonia and the phenols. There are no changes in emission levels that have been shown to reduce exposure or risk in a way that is meaningful, and therefore, the super slim cigarette should not be considered a 'less harmful' cigarette. PMID- 22821752 TI - A catalytic asymmetric ring-expansion reaction of isatins and alpha-alkyl-alpha diazoesters: highly efficient synthesis of functionalized 2-quinolone derivatives. AB - Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N' dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl). PMID- 22821753 TI - Efficacy of family-based treatment for adolescents with eating disorders: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and quantitatively evaluate the efficacy of Family-Based Treatment (FBT) compared with individual treatment among adolescents with eating disorders. METHOD: The literature was reviewed using the MEDLINE search terms "family therapy AND Anorexia Nervosa," and "family therapy AND Bulimia Nervosa". This produced 12 randomized controlled trials involving adolescents with eating disorders and family therapy which were reviewed carefully for several inclusion criteria including: allocation concealment, intent-to-treat analysis, assessor blinding, behavioral family therapy compared with an individual therapy, and adolescent age group. References from these articles were searched. Only three studies met these strict inclusion criteria for meta-analysis. A random effects model and odds ratio was used for meta analysis, looking at "remission" as the outcome of choice. RESULTS: When combined in a meta-analysis, end of treatment data indicated that FBT was not significantly different from individual treatment (z = 1.62, p = 0.11). However, when follow-up data from 6 to 12 months were analyzed, FBT was superior to individual treatment (z = 2.94, p < 0.003), and heterogeneity was not significant (p = 0.59). DISCUSSION: Although FBT does not appear to be superior to individual treatment at end of treatment, there appear to be significant benefits at 6-12 month follow-up for adolescents suffering from eating disorders. PMID- 22821755 TI - Association between maternal age and birth defects of unknown etiology: United States, 1997-2007. AB - BACKGROUND: Birth defects affect 3% of babies born, and are one of the leading causes of infant mortality. Both younger and older maternal age may pose increased risks for certain birth defects. This study assessed the relationship between maternal age at the estimated delivery date and the risk for birth defects. METHODS: Data were obtained from the National Birth Defects Prevention Study, a population-based case-control study including mothers across 10 states. Maternal age was stratified into six categories: <20, 20 to 24, 25 to 29, 30 to 34, 35 to 39, and >=40 years, and also analyzed as a continuous variable. Logistic regression models adjusted formaternal race/ethnicity, education, body mass index (BMI), folic acid use, smoking, gravidity, and parental age difference were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: For maternal age <20 years, associations with total anomalous pulmonary venous return (aOR, 2.3; 95% CI, 1.3-4.0), amniotic band sequence (aOR, 2.4; 95% CI, 1.5-3.8), and gastroschisis (aOR, 6.1; 95% CI, 4.8-8.0) were observed. For the >=40 year age group, associations with several cardiac defects, esophageal atresia (aOR, 2.9; 95% CI, 1.7-4.9), hypospadias (aOR, 2.0; 95% CI, 1.4-3.0), and craniosynostosis (aOR, 1.6; 95% CI, 1.1-2.4) were observed. Results using maternal age as a continuous variable were consistent with those that used categorized maternal age. CONCLUSION: Elucidating risk factors specific to women ateither extreme of maternal age may offer prevention opportunities. All women should be made aware of prevention opportunities, such as folic acid supplementation, to reduce the occurrence of birth defects. PMID- 22821756 TI - Prostate health index (phi) and prostate cancer antigen 3 (PCA3) significantly improve diagnostic accuracy in patients undergoing prostate biopsy. AB - BACKGROUND: Prostate health index (phi) and prostate cancer antigen 3 (PCA3) have been recently proposed as novel biomarkers for prostate cancer (PCa). We assessed the diagnostic performance of these biomarkers, alone or in combination, in men undergoing first prostate biopsy for suspicion of PCa. METHODS: One hundred sixty male subjects were enrolled in this prospective observational study. PSA molecular forms, phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay), and other established biomarkers (tPSA, fPSA, and %fPSA) were assessed before patients underwent a 18-core first prostate biopsy. The discriminating ability between PCa-negative and PCa-positive biopsies of Beckman coulter phi and PCA3 score and other used biomarkers were determined. RESULTS: One hundred sixty patients met inclusion criteria. %p2PSA (p2PSA/fPSA * 100), phi and PCA3 were significantly higher in patients with PCa compared to PCa-negative group (median values: 1.92 vs. 1.55, 49.97 vs. 36.84, and 50 vs. 32, respectively, P <= 0.001). ROC curve analysis showed that %p2PSA, phi, and PCA3 are good indicator of malignancy (AUCs = 0.68, 0.71, and 0.66, respectively). A multivariable logistic regression model consisting of both the phi index and PCA3 score allowed to reach an overall diagnostic accuracy of 0.77. Decision curve analysis revealed that this "combined" marker achieved the highest net benefit over the examined range of the threshold probability. CONCLUSIONS: phi and PCA3 showed no significant difference in the ability to predict PCa diagnosis in men undergoing first prostate biopsy. However, diagnostic performance is significantly improved by combining phi and PCA3. PMID- 22821757 TI - Loss of SLC45A3 protein (prostein) expression in prostate cancer is associated with SLC45A3-ERG gene rearrangement and an unfavorable clinical course. AB - The majority of prostate cancer harbors recurrent gene fusions involving ETS transcription factors, most commonly ERG. The second most common 5' fusion partner after TMPRSS2 is SLC45A3. The aim of our study was to quantify the protein expression of ERG, TMPRSS2 and SLC45A3 in prostate cancer to assess for diagnostic or prognostic utility. Six hundred and forty consecutive prostate cancer cases in tissue microarray format were immunohistochemically analyzed for ERG, TMPRSS2 and SLC45A3 protein. Resultant protein expression data was correlated to the respective gene rearrangement status and clinico-pathological parameters including PSA follow up times. ERG showed no expression in benign prostate glands. In cancer tissue, ERG protein expression showed a high rate of concordance with an underlying ERG rearrangement (91.5%). SLC45A3 showed a weaker expression in cancer as compared to benign tissue, which was pronounced in cases with SLC45A3-ERG fusion. Importantly, SLC45A3 down regulation was significantly associated with shorter PSA-free survival times. In contrast, TMPRSS2 was neither differentially expressed nor did it show a correlation between protein expression and rearrangement status. This study provides first evidence that the expression of SLC45A3 protein is down regulated through SLC45A3-ERG fusion in prostate cancer. Moreover, these cases may represent a distinct molecular subclass of ERG rearranged prostate cancer with distinct clinical features. This study also confirms that ERG protein expression is predominantly found in prostate carcinomas with ERG gene rearrangement and does not occur in benign glands. PMID- 22821758 TI - Solvent-stabilized y-type oxotitanium phthalocyanine photoconductive nanoparticles: preparation and application in single-layered photoreceptors. PMID- 22821759 TI - Enhanced oral bioavailability of a cancer preventive agent (SR13668) by employing polymeric nanoparticles with high drug loading. AB - SR13668 [2,10-Dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole] has been proven effective in cancer prevention, but the limited bioavailability has hindered its clinical translation. In this study, we have developed a continuous, scalable process to form stable poly(lactic-co-glycolic acid) nanoparticles encapsulating SR13668, based on understanding of the competitive kinetics of nanoprecipitation and spray drying. The optimized formulation achieved high drug loading (33.3 wt %) and small particles (150 nm) with narrow size distribution. The prepared nanoparticle suspensions through flash nanoprecipitation were spray dried to achieve long-term stability and to conveniently adjust the nanoparticle concentration before use. In vitro release of SR13668 from the nanosuspensions was measured in a solution with separated organic and aqueous phases to overcome the limit of SR13668 low water solubility. Higher oral bioavailability of SR13668 by employing polymeric nanoparticles compared with the Labrasol(r) formulation was demonstrated in a mouse model. PMID- 22821760 TI - Asymmetric epoxidation of conjugated olefins with dioxygen. PMID- 22821761 TI - Combined use of free jejunum and pectoralis major muscle flap with skin graft for reconstruction after salvage total pharyngolaryngectomy. AB - Salvage total pharyngolaryngectomy after failed organ-preserving therapy often results in composite defects involving the alimentary tract, trachea, and neck skin. This retrospective study examined combined use of the free jejunum flap and the pectoralis major muscle flap with skin graft for such a complex reconstruction. We reviewed 11 patients who underwent free jejunum transfer for alimentary reconstruction and pedicled pectoralis major muscle flap transfer with a skin graft on the muscle for simultaneous neck skin resurfacing after salvage total pharyngolaryngectomy from 2005 through 2010. The operative morbidity rate was 27.3%. No pharyngocutaneous fistula developed in this series. Oral intake could be resumed within 3 weeks after surgery in all patients. Seven of 11 patients had a functional tracheostoma with adequate stomal patency. Combined use of free jejunum and pectoralis major muscle flap with skin graft provided secure wound closure even for complicated cases. PMID- 22821763 TI - Biodegradable composites with aligned hydroxyapatite nanoneedles. AB - We prepared an anisotropic bone graft composite to mimic the hierarchical structure of the natural bone in which aligned hydroxyapatite (HA) nanocrystals deposit along collagen fibers. To approach the modulus and strength of the bone, we incorporated synthesized HA nanoneedles and melt drawn poly(L-lactic acid) fibers in our composite as reinforcing components. Their preferred orientation was induced via a modified pultrusion process. The HA orientation distribution was examined using wide angle X-ray diffraction. Micromechanical Halpin-Tsai model predictions considering the amount, shape, and orientation distribution of HA were compared, favorably, with the experimental observations. PMID- 22821762 TI - Predicting Ca2+ -binding sites using refined carbon clusters. AB - Identifying Ca(2+) -binding sites in proteins is the first step toward understanding the molecular basis of diseases related to Ca(2+) -binding proteins. Currently, these sites are identified in structures either through X ray crystallography or NMR analysis. However, Ca(2+) -binding sites are not always visible in X-ray structures due to flexibility in the binding region or low occupancy in a Ca(2+) -binding site. Similarly, both Ca(2+) and its ligand oxygens are not directly observed in NMR structures. To improve our ability to predict Ca(2+) -binding sites in both X-ray and NMR structures, we report a new graph theory algorithm (MUG(C) ) to predict Ca(2+) -binding sites. Using carbon atoms covalently bonded to the chelating oxygen atoms, and without explicit reference to side-chain oxygen ligand co-ordinates, MUG(C) is able to achieve 94% sensitivity with 76% selectivity on a dataset of X-ray structures composed of 43 Ca(2+) -binding proteins. Additionally, prediction of Ca(2+) -binding sites in NMR structures was obtained by MUG(C) using a different set of parameters, which were determined by the analysis of both Ca(2+) -constrained and unconstrained Ca(2+) -loaded structures derived from NMR data. MUG(C) identified 20 of 21 Ca(2+) -binding sites in NMR structures inferred without the use of Ca(2+) constraints. MUG(C) predictions are also highly selective for Ca(2+) -binding sites as analyses of binding sites for Mg(2+) , Zn(2+) , and Pb(2+) were not identified as Ca(2+) -binding sites. These results indicate that the geometric arrangement of the second-shell carbon cluster is sufficient not only for accurate identification of Ca(2+) -binding sites in NMR and X-ray structures but also for selective differentiation between Ca(2+) and other relevant divalent cations. PMID- 22821764 TI - Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. AB - The results of recent clinical trials for the management of limited-stage Hodgkin lymphoma have led to considerable debate, especially regarding the role of radiation therapy. This review highlights those recent trials and provides perspectives regarding their interpretation from a radiation oncologist and a hematologist. The trial protocol is available at http://www.nejm.org/doi/suppl/10.1056/NEJMoa1111961/suppl_file/nejmoa1111961_prot col.pdf. PMID- 22821767 TI - Urine TMPRSS2:ERG fusion transcript integrated with PCA3 score, genotyping, and biological features are correlated to the results of prostatic biopsies in men at risk of prostate cancer. AB - BACKGROUND: Detection of fusion gene TMPRSS2:ERG transcripts in urine have been recently described in order to refine urine-based detection of prostate cancer (PCa), but data its clinical impact remain scarce. We aimed at investigating the correlation of TMPRSS2:ERG, prostate cancer antigen 3 (PCA3), prostate specific antigen (PSA) density, genetic variants, and androgenic status with outcome and pathological findings at prostatic biopsy. METHODS: Between 2007 and 2011, 291 patients at risk of PCa because of PSA > 3.0 ng/ml (55%) or candidate to active surveillance protocol justifying restaging biopsy management (45%) were recruited. TMPRSS2:ERG was detected by urine assay (ProgensaTM). PCA3-score, PSA level, bioavailable testosterone level, prostate volume, rs1447295 and rs6983267 genotypes were prospectively assessed. Univariate and multivariate analysis by logistic regression model (logit) were conducted to study the correlation of TMPRSS2:ERG status, PCA3, and PSA density with biopsy results, and Gleason score. RESULTS: Of 291 patients, 173 had PCa and 118 had negative biopsy. PCA3 score, PSA density and TMPRSS2:ERG-score were correlated with presence of PCa (P < 0.0001, P = 0.046, and P < 0.0001, respectively). This correlation remained strong on multivariable analysis model (area under curve 0.743). PCA3 score and PSA density were significantly associated with presence of Grade 4 through multivariable analysis. PCA3 score was also correlated to the percentage of positive cores at biopsy (P = 0.008). CONCLUSIONS: Integration of levels TMPRSS2:ERG transcripts in urine, with PCA3-score, androgenic status, genetic status and traditional clinical variables could significantly increase detection of high risk localized PCa. PMID- 22821768 TI - Parent reported inattention and hyperactivity/impulsivity as predictor of long term weight loss after inpatient treatment in obese adolescents. AB - OBJECTIVE: The long-term success of treatment for pediatric obesity is often unsatisfactory and variable. We aim to elucidate the influence of inattention and hyperactivity/impulsivity on weight loss after inpatient treatment for adolescent obesity. METHOD: We included 13-17 year old obese participants treated in three inpatient multidisciplinary treatment centers. At the beginning and end of treatment and at one year follow-up weight and height were measured. Inattention and hyperactivity/impulsivity was assessed with the hyperactivity/inattention (HI) subscale of the parent-rated Strengths and Difficulties Questionnaire. General linear models were used with the standard deviation scores of the body mass index (BMI-SDS) as dependent variable. RESULTS: Totally, 253 participants were included (65% female, age: 15.3 +/- 1.4 years, baseline BMI-SDS: 3.13 +/- 0.38 kg/m(2)). HI scores were associated with long-term (p < .001) but not short term (ns) weight loss. DISCUSSION: This indicates that inattention and hyperactivity/impulsivity is associated with reduced long-term weight loss success in adolescent inpatients. PMID- 22821765 TI - Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma. AB - The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138(+) MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific down-regulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome. PMID- 22821769 TI - Influence of having a home garden on personal UVR exposure behavior and risk of cutaneous malignant melanoma in Denmark. AB - There is a need for more knowledge concerning the association of higher socioeconomic status (SES) with cutaneous malignant melanoma (CMM). Having a home garden is associated with a higher SES. We aimed to study the influence of having a home garden on UVR exposure behavior and risk of CMM. Register study: We collected information from Danish national registers about gender, age, type of home and CMM among persons aged 16-75 in 2002-2006. A total of 5,118 CMM cases were identified. Risk of CMM of the trunk was increased by 46% (p < 0.001, 95% confidence interval (CI): 31-63) and risk of CMM of the extremities by 34% (p < 0.001, 95% CI: 20-49) among people with home gardens. Dosimeter study: During a summer season 194 participants living in the Capital area, Denmark, equally distributed in homes with and without a garden, wore personal electronic UVR dosimeters measuring time-stamped UVR doses continuously and filled in sun exposure diaries. While no difference was found in estimated yearly UVR dose between groups, participants with a home garden had more days exposing shoulders or upper body, and upper extremities outdoors than those without a garden (p = 0.026, age adjusted). People with a home garden are at increased risk of CMM of the trunk and extremities-body sites that seems to be exposed to a higher extent among people with home gardens. People with a higher SES are more likely to have a home garden. This may partly explain the well-known association of higher SES with CMM incidence. PMID- 22821770 TI - Association of microtia with maternal nutrition. AB - BACKGROUND: Few studies have investigated the potential association of maternal dietary intake and risk of microtia among offspring. METHODS: The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic cases of microtia were compared to nonmalformed, population-based, live-born control infants by estimating adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models that included maternal race or ethnicity, education, folic acid-containing supplement intake, fertility treatment, study site, and total energy intake. RESULTS: Comparing intake in the lowest 10th percentile versus the 10th to 90th percentiles, lower maternal intakes of carbohydrate (OR, 1.59; 95% CI, 1.07-2.38) and dietary folate (OR, 1.57; 95% CI, 1.09-2.25) were associated with elevated risk of microtia. In addition, results suggested that higher diet quality (as measured by the Diet Quality Index, and comparing the highest with the lowest quartile) was protective, but the CI did not exclude one (OR, 0.73; 95% CI, 0.50-1.07). Results were similar among obese and nonobese women. CONCLUSIONS: These data contribute to the limited body of evidence regarding the potential contribution of maternal nutrition to the etiology of microtia. PMID- 22821771 TI - Microfluidic control of the internal morphology in nanofiber-based macroscopic cables. PMID- 22821773 TI - Anti-inflammatory effects of anthocyanins from black soybean seed coat on the keratinocytes and ischemia-reperfusion injury in rat skin flaps. AB - Ischemia-reperfusion injury is a phenomenon that occurs when tissues are subjected to ischemia for a variable period of time, and then reperfused. Inflammatory reaction has been implicated as one of the most important mechanism of ischemia-reperfusion injury. The purpose of this study was to evaluate the anti-inflammatory effects of anthocyanins from black soybean seed coat on keratinocytes in vitro and ischemia-reperfusion injury in vivo. We investigated the inhibition, by anthocyanins, of the expression of various inflammatory genes associated with ischemia-reperfusion injury in the tumor necrosis factor-alpha treated (TNF-alpha) immortalized epidermal keratinocyte cell line (HaCaT). We also investigated the effects of anthocyanins on the survival of skin flaps after ischemia-reperfusion injury in the rats. According to Western blot analysis and a luciferase activity assay, anthocyanins inhibited TNF-alpha-induced intercellular adhesion molecule-1 and cyclooxygenase-2 (COX-2) levels through the NF-kappaB dependent pathway. Administration of anthocyanins (50 and 100 mg/kg) significantly improved the flap area survival in the 10-hour ischemic model from 62% to 74.5% and 83%, respectively (P = 0.001). The related cytokines in skin flap also changed as the same pattern as in vitro. Our results indicate that anthocyanins from black soybean seed coat had anti-inflammatory effects on the HaCaT cell line and increase the survival of skin flaps through anti-inflammatory properties against ischemia-reperfusion injury. PMID- 22821774 TI - Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: towards a global multi-step design space. AB - The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Similarly, process parameters that have a potential impact on critical quality attributes (CQAs) were also identified through a risk assessment. Critical process parameters were then evaluated for their impact on CQAs, individually and in interaction with each other, using multivariate design of experiment techniques during the process characterisation phase. The global multi-step Design Space, defining operational limits for the entire drug substance manufacturing process so as to ensure that the drug substance quality targets are met, was devised using predictive statistical models developed during the characterisation study. The validity of the global multi-step Design Space was then confirmed by performing the entire process, from cell bank thawing to final drug substance, at its limits during the robustness study: the quality of the final drug substance produced under different conditions was verified against predefined targets. An adaptive strategy was devised whereby the Design Space can be adjusted to the quality of the input material to ensure reliable drug substance quality. Finally, all the data obtained during the process described above, together with data generated during additional validation studies as well as manufacturing data, were used to define the control strategy for the drug substance manufacturing process using a risk assessment methodology. PMID- 22821775 TI - Amputation for pain in a thumb: not an advisable treatment. PMID- 22821776 TI - Acute carpal tunnel secondary to metallosis after total wrist arthroplasty. PMID- 22821777 TI - Flexor pollicis longus tendon repair in patients with Linburg-Comstock anomaly. PMID- 22821772 TI - Building bridges: leveraging interdisciplinary collaborations in the development of biomaterials to meet clinical needs. AB - Our laboratory at Rice University has forged numerous collaborations with clinicians and basic scientists over the years to advance the development of novel biomaterials and the modification of existing materials to meet clinical needs. This review highlights collaborative advances in biomaterials research from our laboratory in the areas of scaffold development, drug delivery, and gene therapy, especially as related to applications in bone and cartilage tissue engineering. PMID- 22821780 TI - With protective gowns, look beyond brand name. PMID- 22821778 TI - Neonatal repetitive needle pricking: plasticity of the spinal nociceptive circuit and extended postoperative pain in later life. AB - Repetitive exposure of neonates to noxious events is inherent to their health status monitoring in neonatal intensive care units (NICU). Altered basal nociception in the absence of an injury in later life has been demonstrated in ex NICU children, but the impact on pain hypersensitivity following an injury in later life is unknown. Also, underlying mechanisms for such long-term changes are relatively unknown. The objective of this study is to investigate acute and long term effects of neonatal repetitive painful skin-breaking procedures on nociception and to investigate plasticity of the nociceptive circuit. The repetitive needle prick animal model was used in which neonatal rats received four needle pricks into the left hind paw per day during the first postnatal week and control animals received nonpainful tactile stimuli. Repetitive needle pricking during the first week of life induced acute hypersensitivity to mechanical stimuli. At the age of 8 weeks, increased duration of postoperative hypersensitivity to mechanical stimuli after ipsilateral hind paw incision was shown in needle prick animals. Basal nociception from 3 to 8 weeks of age was unaffected by neonatal repetitive needle pricking. Increased calcitonin gene related peptide expression was observed in the ipsilateral and contralateral lumbar spinal cord but not in the hind paw of needle prick animals at the age of 8 weeks. Innervation of tactile Abeta-fibers in the spinal cord was not affected. Our results indicate both acute and long-term effects of repetitive neonatal skin breaking procedures on nociception and long-term plasticity of spinal but not peripheral innervation of nociceptive afferents. PMID- 22821781 TI - Group takes aim to carry on PSPC. PMID- 22821782 TI - Data-sharing project seeks to cut drug abuse, diversion. PMID- 22821783 TI - Alternative format for presenting research by pharmacy residents at national meetings. PMID- 22821784 TI - Alternative format for presenting research by pharmacy residents at national meetings. PMID- 22821785 TI - Handbook and website on HIV drug therapy. PMID- 22821786 TI - Effects of dark chocolate on blood pressure in patients with hypertension. PMID- 22821787 TI - Stem cell transplantation for treatment of sickle cell disease: bone marrow versus cord blood transplants. AB - PURPOSE: The transplantation of stem cells harvested from bone marrow and cord blood for the treatment of sickle cell disease (SCD) is reviewed. SUMMARY: Current treatment options have lengthened the lifespan of patients with SCD. Hydroxyurea is the standard of care for the management of SCD, but it does not prevent serious complications in all patients. For those patients with severe disease, stem cell transplantation may be an appropriate curative option. However, less than one third of these patients find an appropriate matched related bone marrow donor. Cord blood offers a more readily available source of stem cells for transplantation. Donor morbidity is eliminated, since the cells come from banked cords, and the harvesting process is noninvasive for the donor. Another advantage of cord blood transplantation is the lower occurrence of graft versus-host disease (GVHD). One disadvantage of transplantation with cord blood includes delayed time to engraftment. Due to the mortality associated with stem cell transplantation, it may be most appropriate to reserve the procedure for patients who have a more severe course of SCD. CONCLUSION: Although bone marrow, peripheral blood, and cord blood transplantation has been successfully performed in patients with SCD, data remain limited regarding the optimal preparative regimens, the most appropriate stem cell source, and the type of GVHD prophylaxis to be used after transplantation. More data are warranted before this treatment approach can be recommended as a standard of care for SCD. PMID- 22821788 TI - Encephalopathy associated with metoclopramide use in a patient with Parkinson's disease. AB - PURPOSE: The case of a patient with Parkinson's disease (PD) who experienced profound encephalopathy after short-term exposure to metoclopramide is described. SUMMARY: A 79-year-old man with PD received metoclopramide (10 mg i.v. every six hours) for stimulation of gastric motility after a colon resection; the first of three doses of the drug was administered about 30 minutes after completion of the afternoon procedure. The evening after surgery, the patient appeared to be resting comfortably without pain, although he was somewhat agitated; two more metoclopramide doses were administered during the night. Over the next several hours his mental status deteriorated, and the next morning he was found to be unresponsive and could not be aroused. Although the patient had received minimal narcotics, naloxone was administered but failed to produce an improvement in the patient's mental status. The results of laboratory tests, computer tomography scanning, and other diagnostic studies ruled out cardiac ischemia, infectious disease, and other potential causes of the abrupt change in mental status. Within eight days of the discontinuation of metoclopramide use, the patient gradually returned to his baseline mental status. The application of the algorithm of Naranjo et al. in this case indicated a possible adverse reaction to metoclopramide as the cause of acute metabolic encephalopathy, with the patient's underlying PD and PD-related dementia suspected to have been contributing factors. CONCLUSION: A 79-year-old man with long-term PD developed acute encephalopathy after the administration of i.v. metoclopramide. PMID- 22821789 TI - Hypotension associated with menaquinone. AB - PURPOSE: A case of mild symptomatic hypotension after treatment with menaquinone (vitamin K(2)) is reported. SUMMARY: A 62-year-old white man with a medical history of hyperlipidemia, coronary artery disease, and benign prostatic hyperplasia was started on a regimen of menaquinone 100 MUg daily as a supplement to his medications for coronary artery disease. Approximately two hours after taking the first dose of menaquinone, the patient experienced sudden weakness and dizziness. At that time, his blood pressure was 110/55 mm Hg. On day 2 of treatment, his blood pressure was 105/50 mm Hg two hours after taking menaquinone; however the patient was asymptomatic. On day 3, the patient's blood pressure was 100/50 mm Hg two hours after menaquinone ingestion, with symptoms of generalized weakness and dizziness, at which point menaquinone was discontinued. All of the patient's heart rate measurements were within normal limits during this time. The day after discontinuing menaquinone, the patient's blood pressure was 115/65 mm Hg, after which his readings were within normal limits on subsequent days. After a 10-day menaquinone-free period, the patient was rechallenged. On rechallenge day 1, the patient's blood pressure was 115/60 mm Hg two hours after menaquinone ingestion; on rechallenge day 2, his blood pressure was 100/55 mm Hg. The patient was asymptomatic on both days of the rechallenge. The Naranjo et al. adverse drug reaction probability scale score was 7, indicating a probable adverse reaction to menaquinone. The drug interaction probability scale score for this case was 6, indicating that a drug interaction was probable. CONCLUSION: A 62-year-old white man developed mild symptomatic hypotension while receiving menaquinone therapy. PMID- 22821790 TI - Effect of a pharmacist intervention in Spanish community pharmacies on blood pressure control in hypertensive patients. AB - PURPOSE: The effect of a protocol-based pharmacist intervention on blood pressure (BP) control among treated hypertensive patients who use community pharmacies was studied. METHODS: A quasi-experimental study with a control group was conducted at 13 community pharmacies in Jaen and Granada in Spain. Hypertensive patients over age 18 years who were receiving antihypertensive treatment were eligible for participation. The protocol-based intervention consisted of three components: (1) patient education about hypertension, (2) home blood pressure monitoring (HBPM), and (3) referral to a physician through personalized reports when necessary. The control group received the standard of care. BP control was assessed at the beginning and end of the study. Results Data were collected from 176 patients. In the intervention group (n = 87), significant baseline-to-endpoint reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were observed: 6.8 mm Hg (p < 0.001) and 2.1 mm Hg (p = 0.032), respectively. The changes in SBP and DBP in the intervention group at the end of the study were significantly greater than those in the control group (difference between adjusted mean change, 5.7 mm Hg for SBP [p = 0.001] and 2.6 mm Hg for DBP [p = 0.013]). The odds of achieving BP control in the intervention group was 2.46 times higher than in the control group (95% confidence interval, 1.15-5.24; p = 0.020). CONCLUSION: A protocol-based community pharmacist intervention in combination with HBPM significantly reduced SBP and DBP and increased the percentage of patients with controlled BP compared with patients receiving the standard of care. PMID- 22821792 TI - Leadership at all levels. PMID- 22821791 TI - Development of criteria for gentamicin monitoring in a neonatal intensive care unit. AB - PURPOSE: The results of a study to identify factors associated with serum gentamicin levels outside the therapeutic range in a neonatal population are reported. METHODS: A single-center retrospective chart review was conducted to identify cases involving gentamicin use in the neonatal intensive care unit; a sample of cases sufficient for risk-factor analysis (n = 225) was selected for evaluation. In all evaluated cases, gentamicin was administered according to a standardized dosing protocol based on gestational age and weight. Selected clinical factors and laboratory values potentially associated with undesirably high or low serum drug levels were analyzed. RESULTS: Of the 225 patient cases included in the analysis, 184 (82%) involved appropriate (i.e., per protocol) gentamicin dosing. Of the 41 doses classified as inappropriate, 33 were higher and 8 were lower than those recommended by the protocol. Six (18%) of the newborns who received doses classified as inappropriately high had supratherapeutic serum trough concentrations, and 3 (9%) had subtherapeutic trough values. Among the neonates with supratherapeutic peak values, none had an elevated trough value and only 1 received a gentamicin dose deemed to be inappropriately high. Factors associated with an increased relative risk (RR) of a supratherapeutic trough included inappropriate dosing (RR, 2.9; 95% confidence interval [CI], 1.18-6.9), an elevated serum creatinine (SCr) concentration (>0.8 mg/dL) on the day of blood sampling for drug level assessment (RR, 25.6; 95% CI, 9.1-71.4), low urine output (<1 mL/kg/hr) on the day of blood sampling (RR, 7.8; 95% CI, 3.0-15.4), and shock (RR, 3.16; 95% CI, 1.32-7.57). CONCLUSION: When adhering to a weight-based gentamicin dosing protocol, the SCr level and urine output are the best indicators for identifying neonatal patients at risk for supratherapeutic gentamicin trough levels. Shock and inappropriate dosing strategies also put patients at increased risk for supratherapeutic troughs. PMID- 22821794 TI - Pharmacists' role in procedural sedation and analgesia in the emergency department. PMID- 22821793 TI - Droplet-size distribution and stability of commercial injectable lipid emulsions containing fish oil. AB - PURPOSE: The droplet size of commercial fish oil-containing injectable lipid emulsions, including conformance to United States Pharmacopeia (USP) standards on fat-globule size, was investigated. METHODS: A total of 18 batches of three multichamber parenteral products containing the emulsion SMOFlipid as a component were analyzed. Samples from multiple lots of the products were evaluated to determine compliance with standards on the volume-weighted percentage of fat exceeding 0.05% (PFAT(5)) specified in USP chapter 729 to ensure the physical stability of i.v. lipid emulsions. The products were also analyzed to determine the effects of various storage times (3, 6, 9, and 12 months) and storage temperatures (25, 30, and 40 degrees C) on product stability. Larger-size lipid particles were quantified via single-particle optical sensing (SPOS). The emulsion's droplet-size distribution was determined via laser light scattering. RESULTS: SPOS and light-scattering analysis demonstrated mean PFAT(5) values well below USP-specified globule-size limits for all the tested products under all study conditions. In addition, emulsion aging at any storage temperature in the range studied did not result in a significant increase of PFAT(5) values, and mean droplet-size values did not change significantly during storage of up to 12 months at temperatures of 25-40 degrees C. CONCLUSION: PFAT(5) values were below the USP upper limits in SMOFlipid samples from multiple lots of three multichamber products after up to 12 months of storage at 25 or 30 degrees C or 6 months of storage at 40 degrees C. PMID- 22821795 TI - Understanding bioactivity and polarizability of hydroxyapatite doped with tungsten. AB - This study investigates the use of hydroxyapatite (HAp) doped with hexavalent tungsten to improve its interaction with bone cells and to influence the polarizing capacity of HAp. Increases in dopant concentration increased the beta TCP phases and decreased the HAp phases in sintered samples. Results of thermally stimulated depolarization current measurements suggested that doped HAp had stored fewer charge compared with pure HAp. However, the decrease in stored charge was related to fraction of HAp or beta-TCP phases present in sintered samples. Activation energy of dipole relaxation and stored charge was used to examine the mechanism of polarization. The charge stored in doped samples due to polarization was attributed to the migration of H(+) ions in HAp phases and O(2-) or Ca(2+) ions in beta-TCP phases. Hindrance of ion migration due to the presence of different phases appeared to lower charge storage ability in doped samples. In vitro study revealed an increase in bioactivity of doped HAp when compared with pure HAp. Polarization further improved the bioactivity of doped HAp. Results of our study provide evidence for the use of higher valent cations to improve biological performance of HAp ceramics. PMID- 22821796 TI - When trade law meets public health evidence: the World Trade Organization and clove cigarettes. AB - A recent trade dispute between the USA and Indonesia, overseen by the World Trade Organization, challenges piecemeal approaches to tobacco regulation. PMID- 22821797 TI - Menthol use among smokers with psychological distress: findings from the 2008 and 2009 National Survey on Drug Use and Health. AB - OBJECTIVE: The Food and Drug Administration is considering regulation of menthol cigarettes. While persons with mental distress are known to smoke cigarettes at high rates, little is known about their use of menthol. The authors examined the association of psychological distress and menthol use in a national sample of adult smokers. METHODS: Data were from the 2008 and 2009 National Survey on Drug Use and Health. Past month smokers (N=24,157) were categorised for menthol or non menthol use. Psychological distress was categorised as none/mild, moderate or severe on the Kessler six-item scale. RESULTS: The prevalence of menthol use was higher among individuals with severe psychological distress, women, young adults, African-Americans, Native Hawaiians/Pacific Islanders, persons with fewer years of education and lower income, and the unmarried and uninsured. In a multivariate model controlling for socio-demographic factors, smoking intensity and time to first cigarette, smokers with severe (adjusted OR (AOR) 1.23, 95% CI 1.04 to 1.46, p=0.02) but not moderate (AOR 1.03, 95% CI 0.92 to 1.15, p=0.58) psychological distress were significantly more likely to smoke menthols compared with smokers with none/mild distress. CONCLUSION: An elevated prevalence of menthol use was found among persons with severe psychological distress, suggesting another group that could potentially benefit from the regulation of menthol cigarettes. PMID- 22821800 TI - A mesoporous anisotropic n-type Bi2Te3 monolith with low thermal conductivity as an efficient thermoelectric material. PMID- 22821798 TI - Dead-end elimination with perturbations (DEEPer): a provable protein design algorithm with continuous sidechain and backbone flexibility. AB - Computational protein and drug design generally require accurate modeling of protein conformations. This modeling typically starts with an experimentally determined protein structure and considers possible conformational changes due to mutations or new ligands. The DEE/A* algorithm provably finds the global minimum energy conformation (GMEC) of a protein assuming that the backbone does not move and the sidechains take on conformations from a set of discrete, experimentally observed conformations called rotamers. DEE/A* can efficiently find the overall GMEC for exponentially many mutant sequences. Previous improvements to DEE/A* include modeling ensembles of sidechain conformations and either continuous sidechain or backbone flexibility. We present a new algorithm, DEEPer (Dead-End Elimination with Perturbations), that combines these advantages and can also handle much more extensive backbone flexibility and backbone ensembles. DEEPer provably finds the GMEC or, if desired by the user, all conformations and sequences within a specified energy window of the GMEC. It includes the new abilities to handle arbitrarily large backbone perturbations and to generate ensembles of backbone conformations. It also incorporates the shear, an experimentally observed local backbone motion never before used in design. Additionally, we derive a new method to accelerate DEE/A*-based calculations, indirect pruning, that is particularly useful for DEEPer. In 67 benchmark tests on 64 proteins, DEEPer consistently identified lower-energy conformations than previous methods did, indicating more accurate modeling. Additional tests demonstrated its ability to incorporate larger, experimentally observed backbone conformational changes and to model realistic conformational ensembles. These capabilities provide significant advantages for modeling protein mutations and protein-ligand interactions. PMID- 22821801 TI - Self-reported maternal smoking during pregnancy by source in Utah, 2003-2007. AB - BACKGROUND: Maternal self-report is the most common method for assessment of past cigarette exposure to assess birth defect risk. This study compared maternal smoking prior to and during pregnancy based on self-reports obtained from the medical records abstracted for the Utah Birth Defect Network (UBDN), the birth certificate, and the computer-assisted telephone interview (CATI) in the National Birth Defects Prevention Study (NBDPS). The study also investigated how the different sources for maternal smoking data affect estimates in an empirical study. METHODS: A total of 1774 case and 618 control mothers who had participated in the NBDPS and whose live born infants were delivered between January 1, 2003, and December 31, 2007, were included in this study. Among the case mothers, we compared data from all three sources, whereas for control mothers only two data sources were available for comparison (i.e., birth certificate and CATI). RESULTS: Smoking prevalence was highest in the CATI. Compared to the CATI, data from the UBDN had a higher sensitivity (61.3%) and better agreement (kappa = 0.63) than birth certificates (51.8%; kappa = 0.56). Adjusted odds ratios for all and specific birth defects (i.e., holoprosencephaly, hydrocephalus, anophthalmia/microphthalmia, anotia/microtia, total anomalous pulmonary venous return/partial anomalous pulmonary venous return [TAPVR/PAPVR], heterotaxy, and gastroschisis) were different between the birth certificate and CATI. The change in the effect estimates between the two sources ranged from 19% to 56%. CONCLUSIONS: Based on our findings, maternal smoking exposure from interview data was shown to be of higher quality with less misclassification compared to data obtained from medical records or birth certificates. PMID- 22821802 TI - Use of beta-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. AB - BACKGROUND: Experimental evidence suggests a role for the beta(2) -adrenergic receptor pathway in prostate cancer (PCa). We have investigated the association of beta-blocker use with PCa incidence and survival in a Norwegian cohort. METHODS: Data from the Oslo II study in 2000 (n = 6515) were linked with information from the Cancer Registry of Norway and Statistics Norway. PCa risk and overall- and PCa-specific mortality were analyzed using uni- and multi variable Cox- and competing risk regression models. RESULTS: At baseline, 776 men (11.9%) reported using a beta-blocker. 212 men (3.3%) were diagnosed with PCa before the survey, leaving 6,303 eligible for incidence analysis. During a median follow-up of 122 months, 448 (7.1%) men were diagnosed with PCa. beta-blocker use was not associated with PCa risk [hazard ratio (HR): 1.05, 95% CI: 0.79-1.40]. For all patients (n = 655; including med diagnosed before the survey), beta blocker use was not associated with PCa-specific mortality (HR: 0.55, 95% CI 0.24 1.26, P = 0.16). However, in the subgroup of men planned to receive androgen deprivation therapy (ADT), as reported to the Cancer Registry (n = 263), beta blocker use was associated with reduced PCa-specific mortality (HR: 0.14, 95% CI 0.02-0.85, P = 0.032). No effect on overall mortality was seen (HR, all patients: 0.88, 95% CI 0.56-1.38, P = 0.57). beta-blocker use did not appear to affect PSA level, Gleason score, or T-stage at diagnosis; however, these variables were missing for many cases. CONCLUSIONS: Our findings demonstrate a possible benefit of beta-blocker use for men treated with ADT, suggesting the need for investigation in larger cohorts. PMID- 22821803 TI - GRecon: a method for the lipid reconstitution of membrane proteins. PMID- 22821804 TI - Absence of seasonal pattern of birth in patients with anorexia nervosa. AB - OBJECTIVE: An excess of spring births has been suggested in patients with anorexia nervosa (AN), especially in the restricting subtype, but most of the research has been carried out inside the United Kingdom. The aim of this study was to assess whether there is a seasonal pattern of birth in a representative sample of patients with AN in a different latitude in the northern hemisphere. METHOD: We examined the month of birth in a sample of 210 female patients with a DSM-IV diagnosis of AN at first presentation to a specialized eating disorders service in Spain. RESULTS: We found no evidence of significant variation in month or season of birth in AN when compared to general population. DISCUSSION: There is not enough evidence of a season of birth bias under the latitude of the United Kingdom in the risk of developing AN. PMID- 22821805 TI - Subacute and delayed period microsurgical management of traumatic extremity injuries in pediatric population. AB - The purpose of the present report is to evaluate the outcome of subacute and delayed period microsurgical reconstructions of traumatic extremity defects of the pediatric patients. Eighteen free tissue transfers had been performed in 18 patients. Patients ranged in age from 5 to 17 years of age and had a median age of 12.05 years. The time between trauma and free flap transfer varied between 8 and 86 days (mean, 30.8 days). Hospital stay ranged from 8 to 90 days, with a mean stay of 38.7 days. Postoperative complications were seen in 8 of 18 patients (44.4%). Re-exploration for venous thrombosis was necessary in two patients, and total flap loss occurred in one case. The average follow-up time was 34 months. One could conclude from our report and the reference literature that the frequently quoted dogma of a definitive defect closure within 7 days may have lost much of its justification. The final results obtained after delayed definitive soft tissue reconstruction compare favorably with results previously reported in the literature from patient groups whose wounds could be closed in the early period within 7 days. PMID- 22821807 TI - Incomplete degeneration versus enhanced regeneration in skeletal muscle. PMID- 22821806 TI - Immune Reconstitution Inflammatory Syndrome (IRIS) with acute tuberculous osteomyelitis and disseminated mutilating tuberculous dactylitis in a person living with HIV and AIDS (PLHA): a case report. AB - HIV infection changed the scenario of infectious diseases. The pre-HAART (highly active antiretroviral therapy) era had resulted in new opportunistic infections. HIV and tuberculosis together had high mortality in countries with high prevalence of tuberculosis. Disseminated and extra pulmonary tuberculosis is common in PLHA (People Living with HIV and AIDS). IRIS (Immune Reconstitution Inflammatory Syndrome) after HAART is common (10% to 25%) in PLHA. Pott's spine is the most common presentation in PLHA of bone and skeletal system. IRIS tuberculosis, especially extra pulmonary tuberculosis, is the most common. In this case, we are presenting an IRIS disseminated tuberculosis in the form of acute osteomyelitis and mutilating dactylitis involving many joints of the fingers. Of 37 cases (9 from India) reported worldwide multiple dactylitis was never presented in the medical journals. This might be the first multiple dactylitis with extensive mutilation to the dactyls due to IRIS in a patient on ART. PMID- 22821808 TI - Tunicamycin inhibits PDGF-BB-induced proliferation and migration of vascular smooth muscle cells through induction of HO-1. AB - The abnormal proliferation and migration of vascular smooth muscle cell (VSMC), which is triggered by various external stimuli, contributes importantly to the pathogenesis of atherosclerosis and restenosis. Recent studies indicate that the endoplasmic reticulum (ER) stress is intensively involved in the pathophysiological changes of VSMCs by various stimuli. However, the direct effects of ER stress on VSMC proliferation and migration remain unknown. In this study, we found that pretreatment with tunicamycin (Tm), an ER stress inducer, significantly inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and migration in a dose-dependent manner without causing significant apoptosis. Tm stimulated the expression of the antioxidant gene heme oxygenase-1 (HO-1) both at the transcriptional and translational levels, while reducing phosphorylation and activation of mitogen-activated protein (MAP) kinases. The negative regulative effects of Tm were associated with a decrease in cyclins and cyclin-dependent kinases (CDKs) activation. More importantly, HO-1 siRNA partially abolished the beneficial effects of Tm on VSMCs. These results indicate that Tm-induced ER stress provides protection against the abnormal VSMC activation by PDGF-BB, which may be mediated by the induction of HO-1 and blockade of cell cycle reentry. PMID- 22821809 TI - Relation between flexibility and positively selected HIV-1 protease mutants against inhibitors. AB - The antiretroviral chemotherapy helps to reduce the mortality of HIVs infected patients. However, RNA dependant virus replication has a high mutation rate. Human immunodeficiency virus Type 1 protease plays an essential role in viral replication cycle. This protein is an important target for therapy with viral protein inhibitors. There are few works using normal mode analysis to investigate this problem from the structural changes viewpoint. The investigation of protein flexibility may be important for the study of processes associated with conformational changes and state transitions. The normal mode analysis allowed us to investigate structural changes in the protease (such as flexibility) in a straightforward way and try to associate these changes with the increase of fitness for each positively selected HIV-1 mutant protease of patients treated with several protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir, and tripanavir) in combination or separately. These positively selected mutations introduce significant flexibility in important regions such as the active site cavity and flaps. These mutations were also able to cause changes in accessible solvent area. This study showed that the majority of HIV-1 protease mutants can be grouped into two main classes of protein flexibility behavior. We presented a new approach to study structural changes caused by positively selected mutations in a pathogen protein, for instance the HIV-1 protease and their relationship with their resistance mechanism against known inhibitors. The method can be applied to any pharmaceutically relevant pathogen proteins and could be very useful to understand the effects of positively selected mutations in the context of structural changes. PMID- 22821810 TI - Enzyme-specific activation versus leaving group ability. AB - Enzyme-specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme--at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance. To this end we used both experimental and computational methods: 1) synthesis of close analogues of OGp, and their evaluation in a dipeptide synthesis assay with trypsin, 2) molecular docking studies to provide insights into the binding mode, and 3) ab initio calculations to evaluate their electronic properties. PMID- 22821811 TI - High-optical-quality blends of anionic polymethine salts and polycarbonate with enhanced third-order non-linearities for silicon-organic hybrid devices. AB - A series of anionic polymethine dyes with different aromatic counterions are prepared to improve their compatibility as guests in an amorphous polycarbonate host. When they are used as the cladding material for silicon hybrid slot waveguides, four-wave mixing wavelength conversion and two-photon absorption based optical-power modulation are observed. Such guest-host materials may be attractive candidates for all-optical signal-processing applications. PMID- 22821812 TI - Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer. AB - Bone marrow-derived mesenchymal stem cells (MSCs) are reported to contribute to formation of tumor-promoting stromal cells. We reported recently that, in an orthotopic nude mice model of colon cancer, MSCs traveled to tumor stroma, where they differentiated into carcinoma-associated fibroblast (CAF)-like cells. We also found that CAFs express platelet-derived growth factor receptor (PDGFR) at a high level and that imatinib therapy targeting PDGFR in CAFs inhibits growth and metastasis of human colon cancer. These findings led us to examine whether the tumor-promoting effect of MSCs is impaired by blockade of PDGFR signaling achieved with imatinib. Orthotopic transplantation and splenic injection of human MSCs along with KM12SM human colon cancer cells, in comparison with transplantation of KM12SM cells alone, resulted in significantly greater promotion of tumor growth and liver metastasis. The KM12SM + MSC xenograft enhanced cell proliferation and angiogenesis and inhibited tumor cell apoptosis. When tumor-bearing animals were treated with imatinib, there was no significant increase in primary tumor volume or total volume of liver metastases, despite the KM12SM+MSC xenograft, and survival in the mixed-cell group was prolonged by imatinib treatment. Moreover, the ability of MSCs to migrate to tumor stroma was impaired, and the number of MSCs surviving in the tumor microenvironment was significantly decreased. In in vitro experiments, treatment with imatinib inhibited migration of MSCs. Our data suggest that blockade of PDGF signaling pathways influences the interaction between bone marrow-derived MSCs and tumor cells in the tumor microenvironment and, hence, inhibits the progressive growth of colon cancer. PMID- 22821813 TI - Histocompatibility and in vivo signal throughput for PEDOT, PEDOP, P3MT, and polycarbazole electrodes. AB - Stimulation and recording of the in vivo electrical activity of neurons are critical functions in contemporary biomedical research and in treatment of patients with neurological disorders. The electrodes presently in use tend to exhibit short effective lifespans due to degradation of signal transmission resulting from the tissue response at the electrode-brain interface, with signal throughput suffering most at the low frequencies relevant for biosignals. To overcome these limitations, new electrode designs to minimize tissue responses, including conducting polymers (CPs) have been explored. Here, we report the short term histocompatibility and signal throughput results comparing platinum and CP modified platinum electrodes in a Sprague-Dawley rat model. Two of the polymers tested elicited significantly decreased astrocyte responses relative to platinum. These polymers also showed improved signal throughput at low frequencies and comparable signal-to-noise ratios during targeted intracranial electroencephalograms. These results suggest that CP electrodes may present viable alternatives to the metal electrodes that are currently in use. PMID- 22821815 TI - The evolution, development and skeletal identity of the crocodylian pelvis: revisiting a forgotten scientific debate. AB - Unlike most tetrapods, in extant crocodylians the acetabulum is formed by only two of the three skeletal elements that constitute the pelvis, the ilium, and ischium. This peculiar arrangement is further confused by various observations that suggest the crocodylian pelvis initially develops from four skeletal elements: the ilium, ischium, pubis, and a novel element, the prepubis. According to one popular historical hypothesis, in crocodylians (and many extinct archosaurs), the pubis fuses with the ischium during skeletogenesis, leaving the prepubis as a distinct element, albeit one which is excluded from the acetabulum. Whereas the notion of a distinct prepubic element was once a topic of considerable interest, it has never been properly resolved. Here, we combine data gleaned from a developmental series of Alligator mississippiensis embryos, with a revised interpretation of fossil evidence from numerous outgroups to Crocodylia. We demonstrate that the modern crocodylian pelvis is composed of only three elements: the ilium, ischium, and pubis. The reported fourth pelvic element is an unossified portion of the ischium. Interpretations of pelvic skeletal homology have featured prominently in sauropsid systematics, and the unambiguous identification of the crocodylian pubis provides an important contribution to address larger scale evolutionary questions associated with locomotion and respiration. PMID- 22821814 TI - Polyvinyl alcohol-polyvinyl pyrrolidone thin films provide local short-term release of anti-inflammatory agents post spinal cord injury. AB - Spinal cord injury (SCI) triggers a large inflammatory response that results in exacerbated tissue damage. Locally delivering anti-inflammatory drugs could mitigate this secondary wave of degeneration. The mitogen-activated protein kinase family members p38 and c-Jun N-terminal kinase (JNK) play important roles in the inflammatory response and cell death. We propose that the use of polymer thin films, made of polyvinyl alcohol and polyvinyl pyrrolidone blends (PVA-PVP), can be used to provide local release of inhibitors to p38 and JNK post-SCI. Release studies performed in vitro confirmed the inhibitors could be released from the film for up to 7 days. The thin film was also tested for its surgical feasibility using a cervical contusion model of SCI in adult female rats. Films with or without the inhibitors were placed subdurally over the injury site immediately following SCI. Animals were sacrificed 5 days post-SCI and spinal cord tissue above and below the injury site was harvested. Additionally, films were removed for analysis. Scanning electron microscopy confirmed the anti fouling properties of the PVA-PVP film. Tissue histology confirmed that the films themselves did not generate a large immune response, but they did compress the tissue slightly at its placement above the injury site. Finally, quantitative Western blot analysis determined the films loaded with p38 and JNK inhibitors delivered bioactive agents to the injury site and resulted in a significantly decreased amount of pro-cell death proteins. These data indicate that PVA-PVP films can be used to effectively deliver drugs to a SCI site. PMID- 22821816 TI - Isolation and characterization of stable iron(I) sulfide complexes. PMID- 22821818 TI - Targeted glycomics by selected reaction monitoring for highly sensitive glycan compositional analysis. AB - The development of glycomics increasingly requires the detection and quantification of large numbers of glycans, which is only partially achieved by current glycomics approaches. Taking advantage of selected reaction monitoring to enhance both sensitivity and selectivity, we report here a strategy termed targeted glycomics that enables highly sensitive and consistent identification and quantification of diverse glycans across multiple samples at the same time. In this proof-of-principle study, we validated the method by analyzing global N glycans expressed in different systems: single proteins, cancer cells, and serum samples. A dynamic range of three orders of magnitude was obtained for the detection of all five glycans released from ribonuclease B. The limit of detection of 80 attomole for Man(9)GlcNAc(2) demonstrated the excellent sensitivity of the method. The capability of the strategy to identify diverse glycans was demonstrated by identification and detection of 162 different glycans and isomers from pancreatic cancer cells. The sensitivity of the method was illustrated further by the ability to detect eight glycans from 250 cancer cells and five glycans released from 100 cancer cells. In serum obtained from rabbits fed control diet or diet enriched with 2% cholesterol, differences to 42 glycans were accurately measured and this indicates that this strategy might find use in studies of biomarker discovery and validation. PMID- 22821819 TI - Composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin allotransplantation model of bone marrow transplantation. AB - Cellular and vascularized bone marrow cells have been used to induce donor specific chimerism in various models of composite tissue allotransplantation. Although thymus transplantation has been reported in the literature, the effect of thymus transplantation on chimerism levels in vascularized bone containing composite tissue allotransplantation has not been reported. In this study, a new method for composite vascularized sternal bone marrow transplant model is descried that can be applied to augment chimerism after transplantation. A total of seven composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin transplantations were performed in two groups. The first group (n = 5) was designed as an allotransplantation group and the second group (n = 2) was designed as an isotransplantation group. Composite osseomusculocutaneous sternum, ribs, thymus, and pectoralis muscles allografts were harvested on the common carotid artery and external jugular vein and a heterotopic transplantation was performed to the inguinal region of the recipient rat. Cyclosporine A monotherapy was administered in order to prevent acute and chronic allograft rejection. Animals sacrificed when any sign of rejection occurred. The longest survival was 156 day post-transplant. Assessment of bone marrow cells within sternum bone component and flow cytometry analysis of donor-specific chimerism in the peripheral blood of recipients were evaluated. Our results showed that this composite allograft carried 7.5 * 10(6) of viable hematopoietic cells within the sternum component. At day 7 post-transplant chimerism was developed in T-cell population and mean level was assessed at 2.65% for RT1(n) /CD4 and at 1.0% for RT1(n) /CD8. In this study, a new osseomusculocutaneous sternum, ribs, thymus, pectoralis muscle, and skin allotransplantation model is reported which can be used to augment hematopoietic activity for chimerism induction after transplantation. PMID- 22821817 TI - The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way. AB - BACKGROUND: The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known. METHODS: We analyzed potential signaling pathways associated with AR V7 constitutive activation in PTEN (-) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway. RESULTS: In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation. CONCLUSIONS: Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration-resistant PC. PMID- 22821820 TI - Enhancement of the substrate scope of transketolase. AB - To enhance the activity of transketolase towards nonphosphorylated substrates and enlarge the scope of its substrates, notably to long polyol aldehyde acceptors (D ribose or D-glucose), a rational design-supported evolution strategy was applied. By using docking experiments, an in silico library, and iterative mutagenesis, libraries of single- and double-point mutants were designed and generated. A double-screening approach was implemented, coupling a preselection activity assay (HPLC method) and a selective assay (GC method) to find the best enzymes. Several mutants (R526N, R526Q, R526Q/S525T, R526K/S525T) showed improved activities towards nonphosphorylated substrates as the coupled products of lithium hydroxypyruvate (HPA) with glycolaldehyde (GO), D-ribose or D-glucose. These mutated enzymes were further characterised. They were shown to be up to four times more active than the wild-type (mutant R526Q/S525T) for nonphosphorylated substrates LiHPA/GO (V(m) /K(m) for LiHPA = 92.4 instead of 28.8*10(-3) min(-1) for the wild-type) and 2.6 times more active for substrates LiHPA/rib. PMID- 22821821 TI - Reply: To PMID 21901857. PMID- 22821822 TI - Behavior of poly(glycerol sebacate) plugs in chronic tympanic membrane perforations. AB - The tympanic membrane (TM), separating the external and middle ear, consists of fibrous connective tissue sandwiched between epithelial layers. To treat chronic ear infections, tympanostomy drainage tubes are placed in surgically created holes in TMs which can become chronic perforations upon extrusion. Perforations are repaired using a variety of techniques, but are limited by morbidity, unsatisfactory closure rates, or minimal regeneration of the connective tissue. A more effective, minimally-invasive therapy is necessary to enhance the perforation closure rate. Current research utilizing decellularized or alignate materials moderately enhance closure but the native TM architecture is not restored. Poly(glycerol sebacate) (PGS) is a biocompatible elastomer which supports cell migration and enzymatically degrades in contact with vascularized tissue. PGS spool-shaped plugs were manufactured using a novel process. Using minimally invasive procedures, these elastomeric plugs were inserted into chronic chinchilla TM perforations. As previously reported, effective perforation closure occurred as both flange surfaces were covered by confluent cell layers; >90% of perforations were closed at 6-week postimplantation. This unique in vivo environment has little vascularized tissue. Consequently, PGS degradation was minimal over 16-week implantation, hindering regeneration of the TM fibrous connective tissue. PGS degradation must be enhanced to promote complete TM regeneration. PMID- 22821824 TI - A new and useful method to prevent spasm of microvascular anastomosis in the postoperative period. PMID- 22821825 TI - Use of the bioaccumulation factor to screen chemicals for bioaccumulation potential. AB - The fish bioconcentration factor (BCF), as calculated from controlled laboratory tests, is commonly used in chemical management programs to screen chemicals for bioaccumulation potential. The bioaccumulation factor (BAF), as calculated from field-caught fish, is more ecologically relevant because it accounts for dietary, respiratory, and dermal exposures. The BCFBAFTM program in the U.S. Environmental Protection Agency's Estimation Programs Interface Suite (EPI SuiteTM Ver 4.10) screening-level tool includes the Arnot-Gobas quantitative structure-activity relationship model to estimate BAFs for organic chemicals in fish. Bioaccumulation factors can be greater than BCFs, suggesting that using the BAF rather than the BCF for screening bioaccumulation potential could have regulatory and resource implications for chemical assessment programs. To evaluate these potential implications, BCFBAF was used to calculate BAFs and BCFs for 6,034 U.S. high- and medium-production volume chemicals. The results indicate no change in the bioaccumulation rating for 86% of these chemicals, with 3% receiving lower and 11% receiving higher bioaccumulation ratings when using the BAF rather than the BCF. All chemicals that received higher bioaccumulation ratings had log K(OW ) values greater than 4.02, in which a chemical's BAF was more representative of field-based bioaccumulation than its BCF. Similar results were obtained for 374 new chemicals. Screening based on BAFs provides ecologically relevant results without a substantial increase in resources needed for assessments or the number of chemicals screened as being of concern for bioaccumulation potential. PMID- 22821823 TI - Bioinspired controlled release of CCL22 recruits regulatory T cells in vivo. PMID- 22821826 TI - Polymer micelles for delayed release of therapeutics from drug-releasing surfaces with nanotubular structures. AB - A new approach to engineer a local drug delivery system with delayed release using nanostructured surface with nanotube arrays is presented. TNT arrays electrochemically generated on a titanium surface are used as a model substrate. Polymer micelles as drug carriers encapsulated with drug are loaded at the bottom of the TNT structure and their delayed release is obtained by loading blank micelles (without drug) on the top. The delayed and time-controlled drug release is successfully demonstrated by controlling the ratio of blank and drug loaded micelles. The concept is verified using four different polymer micelles (regular and inverted) loaded with water-insoluble (indomethacin) and water-soluble drugs (gentamicin). PMID- 22821827 TI - Two-dimensional infrared correlation spectroscopy and principal component analysis on the carbonation of sterically hindered alkanolamines. AB - Despite the academic and industrial importance of the chemical reaction between carbon dioxide (CO(2)) and alkanolamine, the delicate and precise monitoring of the reaction dynamics by conventional one-dimensional (1D) spectroscopy is still challenging, due to the overlapped bands and the restricted static information. Herein, we report two-dimensional infrared correlation spectroscopy (2D IR COS) and principal component analysis (PCA) on the reaction dynamics of a sterically hindered amine, 2-[(1,1-dimethylethyl)amino]ethanol (TBAE) and CO(2). The formation of carbonate rather than carbamate species, which contribute to the unusual high working capacity of ~1 mole CO(2) per mole of TBAE at 40 degrees C, occurs through deprotonation of the hydroxyl group, protonation on the nitrogen atom of the amino group, and formation of a carbonate species due to the steric hindrance of the tert-butyl group. In particular, PCA captures the chemical transition into a carbonate species and the main contributions of nu(CO(2)), nu(OH), nu(C - N), and nu(C=O) bands to the carbonation, while 2D IR COS verifies the interrelation of four bands and their changes. Therefore, these results provide a powerful analytic method to understand the complex and abnormal reaction dynamics as well as the rational design strategy for the CO(2) absorbents. PMID- 22821828 TI - Sulfatide negatively regulates the fusion process of human parainfluenza virus type 3. AB - Sulfatide (HSO(3)-3-galactosylceramide), which enriched in lipid rafts of plasma membranes in various epithelial cell lines, is a critical component of host cells for effective production of influenza A virus. However, the function of sulfatide in other virus infections targeting epithelial cells remains unknown. In this study, the effect of sulfatide on infection of human parainfluenza virus type 3 (hPIV3) was demonstrated by using genetically produced sulfatide-enriched cells and by treatment of hPIV3-infected cells with anti-sulfatide monoclonal antibody (GS-5) as well as by addition of sulfatide to the cells. hPIV3 was found to bind to sulfatide in a virus overlay assay and a solid-phase binding assay. Genetic expression of sulfatide in COS-7 cells defective in sulfatide suppressed initial hPIV3 infection and formation of multinucleate virus-infected cells. Treatment of virus-infected LLC-MK2 cells with GS-5 promoted formation of multinucleate cells. In contrast, exogenous addition of sulfatide to hPIV3-infected COS-7 cells and cells expressing the hPIV3-hemagglutinin-neuraminidase (HN) gene and fusion (F) gene conspicuously reduced the formation of multinucleate cells. The results suggest that sulfatide negatively regulates the fusion process of hPIV3, possibly through interaction with HN or F glycoprotein on the cell surface. PMID- 22821829 TI - Spermiogenesis in the Australian cockatiel Nymphicus hollandicus. AB - Information on the ultrastructure of parrot spermatids and spermatozoa is limited to only four species with no comprehensive study of spermiogenesis conducted within the order Psittaciformes. The present study was undertaken to describe the development of the cockatiel spermatid using electron microscopy. Four phases of spermatid maturation were documented on the basis of nuclear morphology, development of the acrosome, perforatorium, and axial filament. These phases included 1) round nuclei, 2) irregular nuclei, 3) elongated nuclei with granular chromatin, and 4) elongated nuclei with homogenous chromatin. While development of the cockatiel spermatid was comparable to that of other domestic avian species, we have noted the hollow nature of some chromatin granules, an abnormal formation of the axoneme, the absence of the fibrous sheath around the axoneme of the principal piece, and the absence of an annulus. PMID- 22821830 TI - Facilitated substrate channeling in a self-assembled trifunctional enzyme complex. PMID- 22821831 TI - Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. AB - MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (EMT). Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Panc1 cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer. PMID- 22821832 TI - Effect of load on the repair of osteochondral defects using a porous polymer scaffold. AB - The aim of the present study was to evaluate if a porous polymer scaffold, currently used for partial meniscal replacement in clinical practice, could initiate regeneration and repair of osteochondral defects, and if regeneration and repair were related to mechanical stimulation. Two equally sized osteochondral defects were created bilaterally in each trochlear groove of 16 adult female New Zealand White rabbits. The defects were filled with polycaprolactone-polyurethane scaffolds of either 3 or 4 mm in height. Regeneration and repair of the defects were evaluated after 8 (n = 8) and 14 weeks (n = 8). After 8 weeks of implantation, both the 3- and 4-mm scaffolds were flush with the native cartilage. The amount of cartilaginous tissue was similar in both scaffold types. Pores located in the more central zones of the scaffolds contained less cartilaginous tissue when compared with pores located in the more superficial zones. After 14 weeks, significantly more cartilaginous tissue was present in 4 mm scaffolds when compared with the 3-mm scaffolds (p = 0.03). In the 4-mm scaffolds, progression of cartilaginous tissue from the surface of the scaffold toward the center was observed over time, whereas in the 3-mm scaffold, the percentage of cartilaginous tissue in the central zones was not different from the situation after 8 weeks. Osteochondral defects might be treated using porous polymer scaffolds currently used for partial meniscus replacement, although several limitations need yet to be overcome. The results suggest that mechanical forces may not have to be applied over long periods of time to accelerate tissue formation and increase cartilage repair longevity. PMID- 22821833 TI - Solution structure and siRNA-mediated knockdown analysis of the mitochondrial disease-related protein C12orf65. AB - Loss of function of the c12orf65 gene causes a mitochondrial translation defect, leading to encephalomyopathy. The C12orf65 protein is thought to play a role similar to that of ICT1 in rescuing stalled mitoribosomes during translation. Both proteins belong to a family of Class I peptide release factors (RFs), all characterized by the presence of a GGQ motif. Here, we determined the solution structure of the GGQ-containing domain (GGQ domain) of C12orf65 from mouse by NMR spectroscopy, and examined the effect of siRNA-mediated knockdown of C12orf65 on mitochondria in HeLa cells using flow cytometry. The GGQ domain, comprising residues 60-124 of the 184-residue full-length protein, forms a structure with a 3(10) -beta1-beta2-beta3-alpha1 topology that resembles the GGQ domain structure of RF more closely than that of ICT1. Thus, the GGQ domain structures of this protein family can be divided into two types, depending on the region linking beta2 and beta3; the C12orf65/RF type having a 6-residue pi-HB turn and the ICT1 type having an alpha-helix. Knockdown of C12orf65 resulted in increased ROS production and apoptosis, leading to inhibition of cell proliferation. Substantial changes in mitochondrial membrane potential and mass in the C12orf65 knockdown cells were observed compared with the control cells. These results indicate that the function of C12orf65 is essential for cell vitality and mitochondrial function. Although similar effects were observed in ICT1 downregulated cells, there were significant differences in the range and pattern of the effects between C12orf65- and ICT1-knockdown cells, suggesting different roles of C12orf65 and ICT1 in rescuing stalled mitoribosomes. PMID- 22821836 TI - Too many children with autism miss genetics evaluations: parents and other medical specialties and professionals need education, study says. PMID- 22821837 TI - More states screen for severe combined immunodeficiency: screening finds other genetic syndromes marked by immunodeficiency. PMID- 22821839 TI - Compartment syndrome at the fibula flap's donor site and salvage by anerolateral thigh chimeric flap. PMID- 22821841 TI - Spectral diffusion of single dibenzoterrylene molecules in 2,3 dimethylanthracene. AB - We study single dibenzoterrylene molecules embedded in the dipolar disordered crystal 2,3-dimethylanthracene at 1.25 K. Broad linewidths (about 1 GHz, ~30 times broader than in the anthracene crystal), high saturation excitation intensities (~1000 times larger than in anthracene), as well as strong spectral diffusions are observed. Additionally, spectral jumping is studied by varying the excitation intensity and the temperature. We propose that the spectral diffusion and dynamic disorder in this system arise from the combination of a static disorder with slight reorientations of the methyl groups of the host molecules. PMID- 22821840 TI - Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF. AB - Hypoxic microenvironment plays an important role in determining stem cell fates. However, it is controversial to which direction between self-renewal and differentiation the hypoxia drives the stem cells. Here, we investigated whether a short exposure to hypoxia (termed 'hypoxic-priming') efficiently directed and promoted mouse embryonic stem cells (mESCs) to differentiate into vascular lineage. During spontaneous differentiation of embryoid bodies (EBs), hypoxic region was observed inside EB spheroids even under normoxic conditions. Indeed, hypoxia-primed EBs more efficiently differentiated into cells of vascular lineage, than normoxic EBs did. We found that hypoxia suppressed Oct4 expression via direct binding of HIF-1 to reverse hypoxia-responsive elements (rHREs) in the Oct4 promoter. Furthermore, vascular endothelial growth factor (VEGF) was highly upregulated in hypoxia-primed EBs, which differentiated towards endothelial cells in the absence of exogenous VEGF. Interestingly, this differentiation was abolished by the HIF-1 or VEGF blocking. In vivo transplantation of hypoxia primed EBs into mice ischemic limb elicited enhanced vessel differentiation. Collectively, our findings identify that hypoxia enhanced ESC differentiation by HIF-1-mediated inverse regulation of Oct4 and VEGF, which is a novel pathway to promote vascular-lineage differentiation. PMID- 22821842 TI - Clinical predictors of nasal continuous positive airway pressure requirement in acute bronchiolitis. PMID- 22821843 TI - Oxytetracycline interactions at the soil-water interface: effects of environmental surfaces on natural transformation and growth inhibition of Azotobacter vinelandii. AB - The mechanism of oxytetracycline (OTC) adsorption to a silty clay loam soil was investigated using sorption isotherm experiments, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction spectroscopy (XRD). Sorption data fit well to a cation-exchange capacity sorption model. Spectroscopic data indicate that the interactions between oxytetracycline and silty clay loam soil were primarily through electrostatic interactions between the protonated dimethylamino group of OTC and the negatively charged moieties on the surface of the soil. Based on XRD results, OTC adsorption appeared to inhibit the ethylene glycol solvation of the expandable clay minerals, suggesting that OTC had diffused into the clay interlayer space. The presence of adsorbed OTC did not significantly affect the transformation frequency of the soil bacterium Azotobacter vinelandii with plasmid DNA (soil alone 3 * 10(6) +/- 4 * 10(6) and soil with adsorbed OTC 4 * 10(6) +/- 0.5 * 10(6) ). Growth was inhibited by adsorbed OTC, although a greater mass of adsorbed OTC was required to achieve the same degree of inhibition as the system of dissolved OTC alone. These results suggest that the interactions of tetracyclines at the soil-water interface will affect the growth of sensitive microorganisms in soil microbial communities. PMID- 22821844 TI - Ovarian follicular development in the hawksbill turtle (Cheloniidae: Eretmochelys imbricata L.). AB - Ovarian follicular development is an essential process in the determination of maturation stages associated with size. This association acquires importance when managing populations of threatened species. We histologically processed 11 prepubescent ovaries, four pubescent ovaries, and one breeding adult ovary with vitellogenic follicles using specific staining techniques to identify the follicular stages of Eretmochelys imbricata. Follicular stages were compared with maturation stages [including straight carapace length (SCL)]. The ovary presented several germinal beds and a lacunar system less histochemically and morphologically heterogeneous than that of crocodiles. During previtellogenesis (four stages), the oocyte grows rapidly due to the strong transcriptional activity of lampbrush chromosomes and numerous nucleoli, and the strong metabolism associated with lipid synthesis. The Stage III ooplasm showed a Sudan positive band. This stage was the most frequent in all ovarian sections and it was independent of maximal follicular stage. Stage IV, more frequent in pubescent and adult ovaries, presented a lipid vacuole-rich ooplasm and a broadening of the zona pellucida and the theca. The vitellogenesis begins with the penetration and accumulation of spherical glycoprotein yolk platelets and chemically neutral lipid droplets which are observed to be mixed, but spatially and chemically segregated. Both the yolk platelets and lipid droplets increase in size, density, and proximity to the periphery of the oocyte due to their coalescence. The SCL of the immature females did not determine the maximal follicular stage nor its frequency in the ovaries. Straight carapace length turned out to be an imprecise measure in identifying the presence of follicular stages in females larger than the minimum legal size limit in Cuba. Consequently, for a national conservation program to be successful, it must emphasize the critically endangered status of E. imbricata, as well as the maturity of the most frequent hawksbill sizes encountered in the Cuban archipelago fishery. PMID- 22821845 TI - Dual functionalization of titanium with vascular endothelial growth factor and beta-defensin analog for potential application in keratoprosthesis. AB - Functionalization of material surfaces can improve their biointegration and bactericidal effect. To expand the biomedical applications of titanium in artificial cornea implantation surgery, titanium alloy substrates were coated with polydopamine and dual bound with recombinant vascular endothelial growth factor (VEGF) and anti-microbial peptide (AMP), SESB2V. Successful chemical binding was assessed with attenuated total reflectance-Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Coating thickness was assessed by atomic force microscopy. Cellular studies revealed that the functionalized substrates displayed the abilities to enhance primary human corneal fibroblast adhesion, proliferation, and viability. Angiogenesis assay with human mesenchymal stem cells was used to verify the biological functions of immobilized VEGF while bactericidal assay was evaluated for the anti-microbial activities of immobilized SESB2V peptide. We found that the titanium surface that was sequentially functionalized with VEGF and SESB2V had enhanced fibroblast proliferation and anti-microbial properties. The incorporation of such peptides into an artificial cornea implant is important for implant-tissue integration and wound healing. This may improve implant integration and reduce the risk of device infection following artificial cornea implantation. PMID- 22821846 TI - [Ge9{Si(SiMe3)3}3{SnPh3}]: a tetrasubstituted and neutral deltahedral nine-atom cluster. AB - Reaching neutral territory: The title compound, the first tetrasubstituted deltahedral Zintl cluster, is no longer an ion (see picture; Ge green, Si purple, Sn blue). It is a neutral molecule formed by a reaction of the trisilylated anion with Ph(3) SnCl. PMID- 22821847 TI - A three-dimensional stereoscopic monitor system in microscopic vascular anastomosis. AB - Microvascular procedures not only demand precise movements but also usually require a long operation time. Using a conventional surgical microscope, microvascular surgeons need to keep the neck in a fixed flexion posture, which can lead to physical fatigue. Thus, our aim was to develop a three-dimensional (3D) monitoring system to improve the microsurgery environment. It consists of four main parts: the surgical microscope, the charge-coupled devices, the 3D multiplexer, and the 3D monitor. Two patients with head and neck cancers who underwent tumor resections were reconstructed with free flap microsurgeries. Both artery anastomoses were completed successfully and the postoperative courses of the two patients were smooth. Vascular anastomosis can be performed successfully with the help of the new 3D display system. Although the artery anastomosis procedures took longer than under a surgical microscope, the 3D system offers another option to improve the working environment for surgeons. PMID- 22821848 TI - Disclosure of child sexual abuse by adolescents: a qualitative in-depth study. AB - This qualitative study aimed to study the process of disclosure by examining adolescents from the general population who had experienced child sexual abuse (CSA). Twenty-six sexually victimized adolescents (23 girls, 3 boys; age: 15-18 years) participated in a qualitative face-to-face in-depth interview on different aspects of disclosure. A qualitative content analysis was conducted following Mayring and using the qualitative data analysis program Atlas.ti. In addition, quantitative correlation analyses were calculated to identify factors associated with disclosure. Less than one third of participants immediately disclosed CSA to another person. In most cases, recipients of both immediate and delayed disclosure were peers. More than one third of participants had never disclosed the abuse to a parent. Main motives for nondisclosure to parents were lack of trust or not wanting to burden the parents. Factors that correlated positively with disclosure were extrafamilial CSA, single CSA, age of victim at CSA, and having parents who were still living together. Negative associations with disclosure were found for feelings of guilt and shame and the perpetrator's age. Many adolescent survivors of CSA have serious concerns about disclosure to their parents and consider friends as more reliable confidants. These findings have two main implications for prevention: (1) In order to facilitate disclosure to parents, the strengthening of the child-parent relationship should be given specific attention in prevention programs, and (2) prevention programs should aim at teaching adolescents how they can help a victim if they become a recipient of disclosure. PMID- 22821849 TI - Cannabinoid receptor antagonist-induced striated muscle toxicity and ethylmalonic adipic aciduria in beagle dogs. AB - Ibipinabant (IBI), a potent cannabinoid-1 receptor (CB1R) antagonist, previously in development for the treatment of obesity, causes skeletal and cardiac myopathy in beagle dogs. This toxicity was characterized by increases in muscle-derived enzyme activity in serum and microscopic striated muscle degeneration and accumulation of lipid droplets in myofibers. Additional changes in serum chemistry included decreases in glucose and increases in non-esterified fatty acids and cholesterol, and metabolic acidosis, consistent with disturbances in lipid and carbohydrate metabolism. No evidence of CB1R expression was detected in dog striated muscle as assessed by polymerase chain reaction, immunohistochemistry, Western blot analysis, and competitive radioligand binding. Investigative studies utilized metabonomic technology and demonstrated changes in several intermediates and metabolites of fatty acid metabolism including plasma acylcarnitines and urinary ethylmalonate, methylsuccinate, adipate, suberate, hexanoylglycine, sarcosine, dimethylglycine, isovalerylglycine, and 2 hydroxyglutarate. These results indicated that the toxic effect of IBI on striated muscle in beagle dogs is consistent with an inhibition of the mitochondrial flavin-containing enzymes including dimethyl glycine, sarcosine, isovaleryl-CoA, 2-hydroxyglutarate, and multiple acyl-CoA (short, medium, long, and very long chain) dehydrogenases. All of these enzymes converge at the level of electron transfer flavoprotein (ETF) and ETF oxidoreductase. Urinary ethylmalonate was shown to be a biomarker of IBI-induced striated muscle toxicity in dogs and could provide the ability to monitor potential IBI-induced toxic myopathy in humans. We propose that IBI-induced toxic myopathy in beagle dogs is not caused by direct antagonism of CB1R and could represent a model of ethylmalonic-adipic aciduria in humans. PMID- 22821850 TI - Characterization of mitophagy in the 6-hydoxydopamine Parkinson's disease model. AB - In the present study, the activation of autophagy and its interaction with the mitochondrial fission machinery was investigated in an experimental model of Parkinson's disease. The addition of 50uM 6-hydroxydopamine (6-OHDA) to the dopaminergic cell line SH-SY5Y profoundly stimulated formation of autophagosomes within 12h. Under these conditions, mitochondrial fission was also activated in a sustained manner, but this occurred at earlier time points (after 3h). Upon 6 OHDA treatment, dynamin-related protein 1 (Drp1) transiently translocated to mitochondria, with increased levels of mitochondrial Drp1 being observed after 3 and 9h. Pharmacological inhibition of Drp1, through treatment with the mitochondrial-division inhibitor-1 (mdivi-1), resulted in the abrogation of mitochondrial fission and in a decrease of the number of autophagic cells. In addition, 6-OHDA failed to induce the expression of the proapoptotic protein Bax in total cellular extracts although it did induce its migration to mitochondria. In our model, Bax migrated later than Drp1. However, Drp1 inhibition did not block Bax migration. These results show that reactive oxygen species but not quinone derivates act as mediators of autophagy at an early stage of the process. 6-OHDA induces hydrogen peroxide production, which was placed upstream of mitochondrial fission, given that mdivi-1 did not abrogate this increase. Furthermore, the 6-OHDA-induced activation of autophagy was also suppressed by addition of the free radical scavengers TEMPOL and MnTBAP. This effect could be reproduced by the addition of hydrogen peroxide, but not with aged 6-OHDA. To our knowledge, this is the first detailed study highlighting the various mediators that are implicated in mitochondrial alterations and autophagy of cells in response to 6-OHDA. PMID- 22821851 TI - The effects of maternal exposure to bisphenol A on allergic lung inflammation into adulthood. AB - Bisphenol A (BPA) is a high-production volume chemical classified as an environmental estrogen and used primarily in the plastics industry. BPA's increased usage correlates with rising BPA levels in people and a corresponding increase in the incidence of asthma. Due to limited studies, the contribution of maternal BPA exposure to allergic asthma pathogenesis is unclear. Using two established mouse models of allergic asthma, we examined whether developmental exposure to BPA alters hallmarks of allergic lung inflammation in adult offspring. Pregnant C57BL/6 dams were gavaged with 0, 0.5, 5, 50, or 500 MUg BPA/kg/day from gestational day 6 until postnatal day 21. To induce allergic inflammation, adult offspring were mucosally sensitized with inhaled ovalbumin containing low-dose lipopolysaccharide or ip sensitized using ovalbumin with alum followed by ovalbumin aerosol challenge. In the mucosal sensitization model, female offspring that were maternally exposed to >= 50 MUg BPA/kg/day displayed enhanced airway lymphocytic and lung inflammation, compared with offspring of control dams. Peritoneally sensitized, female offspring exposed to <= 50 MUg BPA/kg/day presented dampened lung eosinophilia, compared with vehicle controls. Male offspring did not exhibit these differences in either sensitization model. Our data demonstrate that maternal exposure to BPA has subtle and qualitatively different effects on allergic inflammation, which are critically dependent upon route of allergen sensitization and sex. However, these subtle, yet persistent changes due to developmental exposure to BPA did not lead to significant differences in overall airway responsiveness, suggesting that early life exposure to BPA does not exacerbate allergic inflammation into adulthood. PMID- 22821852 TI - Nablus mask-like facial syndrome: deletion of chromosome 8q22.1 is necessary but not sufficient to cause the phenotype. AB - Nablus mask-like facial syndrome (NMLFS) has many distinctive phenotypic features, particularly tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. Over the last few years, several individuals with NMLFS have been reported to have a microdeletion of 8q21.3q22.1, demonstrated by microarray analysis. The minimal overlapping region is 93.98-96.22 Mb (hg19). Here we present clinical and microarray data from five singletons and two mother-child pairs who have heterozygous deletions significantly overlapping the region associated with NMLFS. Notably, while one mother and child were said to have mild tightening of facial skin, none of these individuals exhibited reduced facial expression or the classical facial phenotype of NMLFS. These findings indicate that deletion of the 8q21.3q22.1 region is necessary but not sufficient for development of the NMLFS. We discuss possible genetic mechanisms underlying the complex pattern of inheritance for this condition. PMID- 22821853 TI - Extracts of Cordyceps militaris lower blood glucose via the stimulation of cholinergic activation and insulin secretion in normal rats. AB - Previous studies have shown that Cordyceps militaris (CM) has a hypoglycemic effect, but the actual mechanism remains unclear. This study explored the hypoglycemic mechanism of aqueous extracts of CM in normal Wistar rats. First, the optimal dose of CM for lowering plasma glucose and insulin secretion was tested. Further, atropine and hemicholinium-3 (HC-3) were injected and a western blot was used to investigate insulin signaling. It was found that 10 mg/kg CM extracts had a stronger hypoglycemic effect than a higher dose (100 mg/kg); therefore, a dose of 10 mg/kg was used in subsequent experiments. In normal rats, CM extracts decreased plasma glucose by 21.0% and induced additional insulin secretion by 54.5% after 30 min. When atropine or HC-3 was injected, CM induced a hypoglycemic effect, but the enhancement of insulin secretion was blocked. By western blotting, significant increases in the insulin receptor substrate 1 (IRS 1) and glucose transporter 4 (GLUT-4) were observed after CM feeding. However, the elevation of these signaling proteins was abolished by atropine or HC-3. Taken together, these findings indicate that CM can lower plasma glucose via the stimulation of insulin secretion and cholinergic activation involved in the hypoglycemic mechanism of normal Wistar rats. PMID- 22821854 TI - Xanthine oxidase inhibitors from Vietnamese Blumea balsamifera L. AB - From the MeOH extract of the aerial part of Blumea balsamifera L., a new dihydroflavonol, (2R,3S)-(-)-4'-O-methyldihydroquercetin (1), together with seven known compounds has been isolated. Their structures were elucidated on the basis of spectroscopic data. Compounds 1-4 and 6-8 displayed significant xanthine oxidase inhibitory activity in a concentration-dependent manner, and compounds 1, 6 and 8 showed more potent inhibitory activity, with IC50 values ranging from 0.23 to 1.91 uM, than that of a positive control allopurinol (IC50 2.50 uM). PMID- 22821855 TI - Antiosteoporotic activity of Saururus chinensis extract in ovariectomized rats. AB - Recent studies suggest that phytoestrogens may exert a protective effect against osteoporosis. This study examined whether treatment with phytoestrogen extracts from Saururus chinensis (SC) exerted a preventive effect on estrogen-deficiency induced osteoporosis. Six- to seven-month-old female Sprague-Dawley rats were randomly assigned into either a sham-operated group or one of three ovariectomy (OVX) subgroups: OVX treated with vehicle, OVX with alendronate, and OVX with SC extract (SC). Rats began receiving treatment 4 weeks before the OVX treatment and continued receiving treatment for an additional 10 weeks after OVX (for a combined total of 14 weeks). The results showed that the SC treatment prevented loss of femur bone mineral density after OVX, as determined by a significant decrease in the levels of serum bone turnover markers osteocalcin and alkaline phosphatase as well as urinary deoxypyridinoline. Micro-computed tomography analysis showed that the SC treatment significantly prevented decreases in bone volume/tissue volume, trabecular number and trabecular thickness, while also preventing an increase in trabecular separation. It was concluded that SC treatment could prevent OVX-induced loss of bone mass and deterioration in trabecular microarchitecture by suppressing bone turnover, thereby maintaining bone structural integrity. Further, no stimulation of proliferation of uterine tissue was noted. Therefore, it is suggested that treatment with S. chinensis extracts might be a potential alternative therapy for treating postmenopausal osteoporosis. PMID- 22821856 TI - Navigating motherhood choices in the context of rheumatoid arthritis: women's stories. AB - OBJECTIVE: Planning a family is a complex decision. For women with chronic conditions such as rheumatoid arthritis (RA), there are additional concerns about their own and their baby's health. This qualitative study examined women's experiences of negotiating their family decisions in the context of RA. METHODS: A qualitative study was conducted in 14 women who provided a written account of their motherhood decisions and experiences. Those 'stories' were then thematically analysed. RESULTS: RA was found to affect women's motherhood decisions and experiences. Three key themes were identified for both the process of decision making and the experience of that decision: capacity, uncertainty and acceptance. Only two of the women decided not to have children, while for others the decision centred on changing expectations from the number of children they planned to have, to parenting within the restrictions of their physical abilities. CONCLUSION: While many women struggled through the negotiations of their motherhood choices, those who chose to have children reported great joy in that experience. The challenges faced by women with RA contemplating motherhood, however, highlight the need for understanding and support from health professionals and the provision of resources so that women can make informed choices. PMID- 22821857 TI - Transcriptional responses in Enchytraeus albidus (Oligochaeta): comparison between cadmium and zinc exposure and linkage to reproduction effects. AB - Metal ecotoxicity to soil organisms (for example, in enchytraeids) has been addressed mainly by assessing effects on survival and reproduction, but very little is known about the underlying molecular mechanisms of responses. The main purpose of the present study was to assess and compare the transcriptional responses of Enchytraeus albidus to an essential (Zn) and a nonessential (Cd) metal. Exposure was performed with two concentrations with a known effect on reproduction (effective concentration for 50% [EC50] and 90% [EC90]) at three time points (2, 4, and 8 d). Results showed that transcriptional responses were influenced by exposure duration but, independently of that, the mechanisms of response to Cd and Zn were consistently different. Both metals affected pathways related to the regulation of gene expression, calcium homeostasis, and cellular respiration. Mechanisms of toxicity that were exclusively associated with Cd exposures were the inhibition of DNA repair and the impairment of ubiquitin mediated proteolysis. The microarray for E. albidus was a useful tool for detecting molecular pathways affected by metal exposures. Transcriptional responses strongly correlated with known mechanisms of Cd and Zn responses in other organisms, suggesting cross-species conserved mechanisms of action. It should be highlighted not only that the authors could retrieve mechanistic information but also that genes responded within 2 to 8 d of exposure. This represents an additional advantage of using such molecular endpoints as a complement to the traditional, more time-consuming endpoints. PMID- 22821858 TI - High-resolution functional MRI at 3 T: 3D/2D echo-planar imaging with optimized physiological noise correction. AB - High-resolution functional MRI (fMRI) offers unique possibilities for studying human functional neuroanatomy. Although high-resolution fMRI has proven its potential at 7 T, most fMRI studies are still performed at rather low spatial resolution at 3 T. We optimized and compared single-shot two-dimensional echo planar imaging (EPI) and multishot three-dimensional EPI high-resolution fMRI protocols. We extended image-based physiological noise correction from two dimensional EPI to multishot three-dimensional EPI. The functional sensitivity of both acquisition schemes was assessed in a visual fMRI experiment. The physiological noise correction increased the sensitivity significantly, can be easily applied, and requires simple recordings of pulse and respiration only. The combination of three-dimensional EPI with physiological noise correction provides exceptional sensitivity for 1.5 mm high-resolution fMRI at 3 T, increasing the temporal signal-to-noise ratio by more than 25% compared to two-dimensional EPI. PMID- 22821860 TI - Temporal bone arrangements in turtles: an overview. AB - The temporal region of turtles is characterized by significant anatomical diversity. Turtles show a pure anapsid morphotype that exhibits various different marginal reductions known as emarginations. As a result of this diversity, turtles can be taken as a model by which to understand the processes that may have resulted in the highly debated anatomy of the amniote temporal region in general. In this review on almost forgotten literature, I summarize ten potential factors that may act on the skull to shape the temporal region of turtles. These are: (1) phylogenetic constraints, (2) skull weights, (3) type of food, (4) skull dimensions, (5) muscle bulging, (6) ear anatomy and jaw muscle bending mechanisms, (7) extent and nature of muscle attachment sites, (8) internal forces within the jaw adductor chamber, (9) environmental pressure, and (10) neck bending mechanisms. Particular focus is laid on the interrelationship of the jaw musculature and the dermatocranial armour, which were assumed to influence each other to a certain degree. In the literature, cranial dimensions were assumed to influence temporal bone formation within major tetrapod groups. Among these, turtles seem to represent a kind of intermixture, a phenomenon that may be reflected in their specific anatomy. The references presented should be understood as product of the scientific environment in which they developed and the older literature does not always insist current empirical demands. However, the intuitive and creative ideas and the comprehensive anatomical considerations of these authors may inspire future studies in several fields related to this topic. PMID- 22821861 TI - Expression of calcium transport proteins in the extraembryonic membranes of a viviparous snake, Virginia striatula. AB - Yolk is the primary source of calcium for embryonic growth and development for most squamates, irrespective of mode of parity. The calcified eggshell is a secondary source for embryonic calcium in all oviparous eggs, but this structure is lost in viviparous lineages. Virginia striatula is a viviparous snake in which embryos obtain calcium from both yolk and placental transport of uterine calcium secretions. The developmental pattern of embryonic calcium acquisition in V. striatula is similar to that for oviparous snakes. Calbindin-D(28K) is a marker for epithelial calcium transport activity and plasma membrane Ca(2+)-ATPase (PMCA) provides the energy to catalyze the final step in calcium transport. Expression of calbindin-D(28K) and PMCA was measured by immunoblotting in yolk sac splanchnopleure and chorioallantois of a developmental series of V. striatula to test the hypothesis that these proteins mediate calcium transport to embryos. In addition, we compared the expression of calbindin-D(28K) in extraembryonic membranes of V. striatula throughout development to a previously published expression pattern in an oviparous snake to test the hypothesis that the ontogeny of calcium transport function is independent of reproductive mode. Expression of calbindin-D(28K) increased in yolk sac splanchnopleure and chorioallantois coincident with calcium mobilization from yolk and uterine sources and with embryonic growth. The amount of PMCA in the chorioallantois did not change through development suggesting its expression is not rate limiting for calcium transport. The pattern of expression of calbindin-D(28K) and PMCA confirms our initial hypothesis that these proteins mediate embryonic calcium uptake. In addition, the developmental pattern of calbindin-D(28K) expression in V. striatula is similar to that of an oviparous snake, which suggests that calcium transport mechanisms and their regulation are independent of reproductive mode. PMID- 22821859 TI - Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer. AB - Pancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures whose origin and significance are currently unknown. We show here that cell-in-cells form after homotypic cell cannibalism (HoCC). We found PDAC patients whose tumours display HoCC develop less metastasis than those without. In vitro, HoCC was promoted by inactivation of the nuclear protein 1 (Nupr1), and was enhanced by treatment with transforming growth factor beta. HoCC ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for HoCC in PDAC and identifies Nupr1 as a molecular regulator of this process. PMID- 22821862 TI - The "eyes absent" (eya) gene in the eye-bearing hydrozoan jellyfish Cladonema radiatum: conservation of the retinal determination network. AB - Eyes absent (Eya) is a member of the Retinal Determination Gene Network (RDGN), a set of genes responsible for eye specification in Drosophila. Eya is a dual function protein, working as a transcription factor in the nucleus and as a tyrosine phosphatase in the cytoplasm. It had been shown that Pax and Six family genes, main components of the RDGN, are present in the hydrozoan Cladonema radiatum and that they are expressed in the eye. However, nothing had been known about the Eya family in hydrozoan jellyfish. Here we report the presence of an Eya homologue (CrEya) in Cladonema. Real-time PCR analysis and in situ hybridization showed that CrEya is expressed in the eye. Furthermore, the comprehensive survey of eukaryote genomes revealed that the acquisition of the N terminal transactivation domain, including the EYA Domain 2 and its adjacent sequence shared by all eumetazoans, happened early in evolution, before the separation of Cnidaria and Bilateria. Our results uncover the evolution of the two domains and show a conservation of the expression pattern of the Eya gene between Cnidaria and Bilateria, which, together with previous data, supports the hypothesis of the monophyletic origin of metazoans eyes. We additionally show that CrEya is also expressed in the oocytes, where two other members of the RDGN, CrPaxB, and Six4/5-Cr, are known to be expressed. These data suggest that several members of the RDGN have begun to be localized also into the different context of egg development early in the course of metazoan evolution. PMID- 22821863 TI - Sexually dimorphic levels of color trait integration and the resolution of sexual conflict in Lake Malawi cichlids. AB - East African cichlids are renowned for their propensity to radiate, and variation in color patterns accounts for much of endemic cichlid diversity. Sexual dimorphism in color among cichlid species likely represents the outcome of different selective regimes acting on each sex, and is a classic example of sexual conflict. It is generally assumed that this conflict has been mitigated through the evolution of sex-linked color polymorphisms. Here, we propose that the evolution of sex-specific differences in levels of color trait integration may represent an additional mechanism through which sexual conflict has been resolved in this group. Specifically, we predict: (1) that general patterns of integration are influenced by early developmental events and thus conserved across sexes and (2) that male color is less integrated than females, and thus more evolvable in terms of producing an elaborate palette (i.e., in response to sexual selection), whereas female color is more integrated, facilitating wholesale shifts in color for background matching (i.e., in response to natural selection for crypsis). We tested these hypotheses using an F(2) design to compare the segregation of male and female color patterns. Both exploratory methods and hypothesis-driven analyses of integration demonstrate that the covariance structure of color traits in males and females is distinct, and that males are significantly less integrated than females. We suggest that the ability of species to promote different levels, and to a lesser extent patterns, of phenotypic integration between males and females may have contributed to the evolutionary success of this group. PMID- 22821865 TI - The Pere David's deer MHC class I genes show unexpected diversity patterns, with monomorphic classical genes but polymorphic nonclassical genes and pseudogenes. AB - Pere David's deer (Elaphurus davidianus) is a highly inbred species that arose from 11 founders but now comprises a population of about 3,000 individuals, making it interesting to investigate the adaptive variation of this species from the major histocompatibility complex (MHC) perspective. In this study, we isolated Elda-MHC class I loci using magnetic bead-based cDNA hybridization, and examined the molecular variations of these loci using single-strand conformation polymorphism (SSCP) and sequence analysis. We obtained seven MHC class I genes, which we designated F1, F12, G2, I7, AF, I8, and C1. Our analyses of stop codons, phylogenetic trees, amino acid conservation, and G+C content revealed that F1, F12, G2, and I7 were classical genes, AF was a nonclassical gene, and I8 and C1 were pseudogenes. Our subsequent molecular examinations showed that the diversity pattern in the Pere David's deer was unusual. Most mammals have more polymorphic classical class I loci vs. the nonclassical and neutral genes. In contrast, the Pere David's deer was found to be monomorphic at classical genes F1, F12, G2, and I7, dimorphic at the nonclassical AF gene, dimorphic at pseudogene I8, and tetramorphic at pseudogene C1. The adverse polymorphism patterns of Elda-I genes might provide evidence for selection too faster deplete MHC variation than drift in the bottlenecked populations, while the postbottleneck tetramorphism of the C1 pseudogene appears to be evidence of strong historical balancing selection. PMID- 22821864 TI - Disparate Igf1 expression and growth in the fore- and hind limbs of a marsupial mammal (Monodelphis domestica). AB - Proper regulation of growth is essential to all stages of life, from development of the egg into an embryo to the maintenance of normal cell cycle progression in adults. However, despite growth's importance to basic biology and health, little is known about how mammalian growth is regulated. In this study, we investigated the molecular basis of the highly disparate growth of opossum fore- and hind limbs in utero. We first used a novel, opossum-specific microarray to identify several growth-related genes that are differentially expressed in opossum fore- and hind limbs of comparable developmental stages. These genes included Igf1. Given Igf1's role in the growth of other systems, we further investigated the role of Igf1 in opossum limb growth. Supporting the microarray results, RT-PCR indicated that Igf1 levels are approximately two times higher in opossum fore- than hind limbs. Consistent with this, while Igf1 transcripts were readily detectable in opossum forelimbs using whole-mount in situ hybridization, they were not detectable in opossum hind limbs. Furthermore, opossum limbs treated with exogenous Igf1 protein experienced significantly greater cellular proliferation and growth than control limbs in vitro. Taken together, results suggest that the differential expression of Igf1 in developing opossum limbs contributes to their divergent rate of growth, and the unique limb phenotype of opossum newborns. This study establishes the opossum limb as a new mammalian model system for study of organ growth. PMID- 22821866 TI - A novel pattern of placental leucine transfer during mid to late gestation in a highly placentotrophic viviparous lizard. AB - Placentotrophy is the nourishment of embryos by resources provided via the placenta during gestation. The magnitude and timing of placental nutrient support during pregnancy are important for embryonic growth, especially in highly placentotrophic animals such as mammals. However, no study has yet investigated how placental organic nutrient support may change during pregnancy in highly placentotrophic viviparous reptiles. Amino acids are essential nutrients for embryonic growth and leucine is a common amino acid. The magnitude and timing of placental leucine transfer may affect embryonic growth and mass and, therefore, offspring phenotype. In this study, female Pseudemoia entrecasteauxii, a highly placentotrophic viviparous skink, were collected throughout gestation. We injected (3)H-leucine into these gravid females and assessed the transfer of (3)H leucine into maternal compartments (i.e., the blood and the liver), and into embryonic compartments (i.e., the embryo, the yolk, and the amniotic fluid). At either 60 or 120 min post-injection, the radioactivity in each sample was extracted and then counted, and the transfer ratio was calculated. Our results provide direct evidence that circulating maternal leucine passes through the placenta into the embryos in this species. The relative rate of placental leucine transfer did not alter during mid to late gestation. This suggests the steady somatic growth of the embryos during mid-late pregnancy is dependent upon the placental transfer of nutrients rather than yolk stores. This pattern of placental nutrient support may determine offspring body size at birth and, therefore, offspring fitness in P. entrecasteauxii. PMID- 22821867 TI - Differential expression and regulation of angiopoietin-3 in mouse uterus during preimplantation period. AB - Angiogenesis is necessary for successful implantation and decidualization. This study was to investigate the differential expression of angiopoietin-3 (Ang-3) in mouse uterus during early pregnancy and its regulation by steroid hormones using in situ hybridization and reverse transcription polymerase chain reaction (RT PCR). There was no detectable Ang-3 mRNA signal on days 1-5 of pregnancy by in situ hybridization. On day 6 of pregnancy, a low level of Ang-3 mRNA signal was seen in the primary decidua. Ang-3 mRNA expression gradually increased on days 7 and 8 of pregnancy along with the development of decidua, and its expression scope was also expanded. The RT-PCR result indicated that Ang-3 mRNA expression was low on days 1-4 of pregnancy. On day 5, as embryo implanted, Ang-3 mRNA was highly expressed in mouse uterus, and the expression gradually increased on days 6-8 of pregnancy, with peak level on day 8 of pregnancy. Similarly, Ang-3 mRNA was also strongly expressed in decidualized cells under artificial decidualization. Compared with the delayed uterus, a high level of Ang-3 mRNA expression was detected in activated implantation uterus by RT-PCR. In the ovariectomized mouse uterus, Ang-3 mRNA expression increased and reached the highest level at 12 hr after injection of estrogen, progesterone, and estrogen plus progesterone, respectively. These results suggest that Ang-3 may play an important role during the process of mouse decidualization. Both estrogen and progesterone can induce the expression of Ang-3 in ovariectomized mouse uterus. PMID- 22821869 TI - Growth in individuals with Majewski osteodysplastic primordial dwarfism type II caused by pericentrin mutations. AB - Microcephalic primordial dwarfism (MPD) is a class of disorders characterized by intrauterine growth restriction (IUGR), impaired postnatal growth and microcephaly. Majewski osteodysplastic primordial dwarfism type II (MOPD II) is one of the more common conditions within this group. MOPD II is caused by truncating mutations in pericentrin (PCNT) and is inherited in an autosomal recessive manner. Detailed growth curves for length, weight, and OFC are presented here and derived from retrospective data from 26 individuals with MOPD II confirmed by molecular or functional studies. Severe pre- and postnatal growth failure is evident in MOPD II patients. The length, weight, and OFC at term (when corrected for gestational age) were -7.0, -3.9, and -4.6 standard deviation (SD) below the population mean and equivalent to the 50th centile of a 28-29-, 31-32-, and 30-31-week neonate, respectively. While at skeletal maturity, the height, weight, and OFC were -10.3, -14.3, and -8.5 SD below the population mean and equivalent to the size of 3-year 10- to 11-month-old, a 5-year 2- to 3-month-old, and 5- to 6-month-old, respectively. During childhood, MOPD II patients grow with slowed, but fairly constant growth velocities and show no evidence of any pubertal growth spurt. Treatment with human growth hormone (n = 11) did not lead to any significant improvement in final stature. The growth charts presented here will be of assistance with diagnosis and management of MOPD II, and should have particular utility in nutritional management of MOPD II during infancy. PMID- 22821870 TI - Acute psychosis related to use of trimethoprim/sulfamethoxazole in the treatment of HIV-infected patients with Pneumocystis jirovecii pneumonia: a multicentre, retrospective study. AB - OBJECTIVES: A recent study reported that trimethoprim/sulfamethoxazole caused acute psychosis in four renal transplant patients with Pneumocystis jirovecii pneumonia. We aimed to investigate the incidence of and factors associated with trimethoprim/sulfamethoxazole-related acute psychosis in HIV-infected patients with P. jirovecii pneumonia. METHODS: We reviewed the medical records of HIV infected patients who presented with P. jirovecii pneumonia and received trimethoprim/sulfamethoxazole at six major hospitals in Taiwan from July 2009 to May 2011. Acute psychosis was defined as the occurrence of hallucinations or delusions following the initiation of trimethoprim/sulfamethoxazole during hospitalization. RESULTS: During the study period, 135 patients receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia were enrolled and 16 (11.9%; 95% CI, 6.3%-17.4%) developed acute psychosis after a median duration of 5 days of trimethoprim/sulfamethoxazole treatment (range, 3-11 days). The incidence increased from 0% (0/16) in patients who received a daily trimethoprim dose of <=12 mg/kg to 23.5% (4/17) in those who received a daily trimethoprim dose of >18 mg/kg. In multivariate logistic regression analysis, a higher daily dose of trimethoprim/sulfamethoxazole (OR, per 1 mg increase of trimethoprim, 1.40; 95% CI, 1.12-1.76; P = 0.0035) and use of adjunctive steroids (OR, 4.43; 95% CI, 1.14-17.15; P = 0.031) were associated with acute psychosis. CONCLUSIONS: In this case series, 11.9% of HIV-infected patients developed acute psychosis while receiving trimethoprim/sulfamethoxazole for P. jirovecii pneumonia. While the study was limited by its retrospective design, the risk appeared to increase with increasing daily dose of trimethoprim/sulfamethoxazole in those vulnerable patients with multiple risks for acute psychosis. PMID- 22821871 TI - Microfluidic synthesis of palladium nanocrystals assisted by supercritical CO2: tailored surface properties for applications in boron chemistry. AB - On the surface: A library of organic-inorganic hybrid palladium nanocrystals was synthesized using continuous supercritical microfluidic technology. The nanocatalysts show moderate to excellent activities towards C(Ar)-B and C(Ar) C(Ar) bond-forming reactions, thus illustrating the relationship between surface properties and modulated catalytic activity. PMID- 22821872 TI - First-in-human valve-in-valve implantation of a 20 mm balloon expandable transcatheter heart valve. AB - An 86-year-old lady with recurrent admissions for heart failure due to a severely regurgitant aortic bioprosthesis (SJM Epic 19 mm) was not a candidate for re operation due to age and frailty. Her small ilio-femoral arteries precluded a transfemoral transcatheter valve-in-valve (VIV) approach. The small internal diameter of her bioprosthesis (16 mm) forbids the implantation of the smallest available transapical transcatheter heart valve (THV). We, therefore, decided to perform a first-in-human transapical aortic VIV implantation using a 20 mm balloon expandable THV and a transfemoral delivery system. The procedure was successfully performed under general anesthesia, without any contrast dye and under fluoroscopy as well as transesophageal echocardiography guidance. The post procedural transvalvular gradient was 15 mm Hg (pre-procedural 14 mm Hg). At 30 day follow-up, the lady was living independently at home without shortness of breath during her daily activities. If redo-surgery for prosthetic regurgitation is not an option, VIV implantation in very small surgical bioprosthesis is feasible and leads to acceptable hemodynamics and clinical improvement. PMID- 22821875 TI - Influence of humic acid on the uptake of aqueous metals by the killifish Fundulus heteroclitus. AB - The role of humic acids, over a concentration range of 0 to 20 mg L(-1) , was investigated in the uptake of three metals (Cd, Cr, and Hg-as both inorganic Hg [Hg(II)] and methylmercury [MeHg]) and a metalloid (As) from the aqueous phase by the killifish (Fundulus heteroclitus). Cadmium uptake showed no relationship with humic acid concentration, whereas Cr, Hg(II), and MeHg uptake showed an inverse relationship, and As uptake increased with increasing humic acid concentration. Concentration factors were >1 for Cd, Hg(II), and MeHg at all humic acid concentrations, indicating killifish were more enriched in the metal than the experimental media, whereas As and Cr generally had concentration factors <1 at the end of a 72-h exposure. The uptake of As and Cr reached steady state within the 72-h exposure, whereas uptake of Cd, Hg(II), and MeHg did not. Uptake rate constants (k(u) s; ml g(-1) d(-1) ) were highest for MeHg (91-3,936), followed by Hg(II), Cd, and Cr, and lowest for As (0.17-0.29). Dissection data revealed that the gills generally had the highest concentration of all metals under all humic acid treatments. The present study concludes that changes in humic acid concentration can influence the accumulation of aqueous metals in killifish and should be considered when modeling metal bioaccumulation. PMID- 22821874 TI - Calcium binding and allosteric signaling mechanisms for the sarcoplasmic reticulum Ca2+ ATPase. AB - The sarcoplasmic reticulum Ca2+ ATPase (SERCA) is a membrane-bound pump that utilizes ATP to drive calcium ions from the myocyte cytosol against the higher calcium concentration in the sarcoplasmic reticulum. Conformational transitions associated with Ca2+-binding are important to its catalytic function. We have identified collective motions that partition SERCA crystallographic structures into multiple catalytically-distinct states using principal component analysis. Using Brownian dynamics simulations, we demonstrate the important contribution of surface-exposed, polar residues in the diffusional encounter of Ca2+. Molecular dynamics simulations indicate the role of Glu309 gating in binding Ca2+, as well as subsequent changes in the dynamics of SERCA's cytosolic domains. Together these data provide structural and dynamical insights into a multistep process involving Ca2+ binding and catalytic transitions. PMID- 22821877 TI - Therapeutic application of MicroRNAs against human cancers. AB - MicroRNAs (miRNAs) are deregulated in human cancers. A large number of studies have shown that miRNAs play critical roles in tumorigenesis, either as oncogenes or tumor suppressors. This review provides an overview of current research on the roles of miRNA in cancer development. Furthermore, we also discuss the current progress and limitation of therapeutic application of miRNAs in preclinical studies. PMID- 22821878 TI - DOTAM-type ligands possessing arginine pendant groups for use in PARACEST MRI. AB - A synthetic methodology was developed for the preparation of metal-chelating ligands that possess arginine pendant groups relying on the alkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with arginine-containing electrophiles. Conditions for the selective trialkylation or peralkylation of cyclen are described, the outcome being dependent on the nature of the arginine-derived electrophile and the solvent used for the reaction. Lanthanide metal complexes of the ligands prepared by the described route were evaluated for their suitability as PARACEST contrast agents for use in magnetic resonance imaging. The Dy(3+) and Tm(3+) complexes display CEST effects that are associated with the amide protons proximate to the metal center. These signals exhibit pH dependence in the range of 6.0-8.0 and thus may have the potential for pH measurement in physiological range. PMID- 22821876 TI - Anti-influenza drug discovery: identification of an orally bioavailable quinoline derivative through activity- and property-guided lead optimization. AB - From a high-throughput screening (HTS) hit with inhibitory activity against virus induced cytophathic in the low micromolar range, we have developed a potent anti influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit. PMID- 22821873 TI - Autotaxin/ENPP2 regulates oligodendrocyte differentiation in vivo in the developing zebrafish hindbrain. AB - During development, progenitors that are committed to differentiate into oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated within discrete regions of the neuroepithelium. More specifically, within the developing spinal cord and hindbrain ventrally located progenitor cells that are characterized by the expression of the transcription factor olig2 give temporally rise to first motor neurons and then oligodendrocyte progenitors. The regulation of this temporal neuron-glial switch has been found complex and little is known about the extrinsic factors regulating it. Our studies described here identified a zebrafish ortholog to mammalian atx, which displays evolutionarily conserved expression pattern characteristics. Most interestingly, atx was found to be expressed by cells of the cephalic floor plate during a time period when ventrally-derived oligodendrocyte progenitors arise in the developing hindbrain of the zebrafish. Knock-down of atx expression resulted in a delay and/or inhibition of the timely appearance of oligodendrocyte progenitors and subsequent developmental stages of the oligodendrocyte lineage. This effect of atx knock-down was not accompanied by changes in the number of olig2-positive progenitor cells, the overall morphology of the axonal network or the number of somatic abducens motor neurons. Thus, our studies identified Atx as an extrinsic factor that is likely secreted by cells from the floor plate and that is involved in regulating specifically the progression of olig2-positive progenitor cells into lineage committed oligodendrocyte progenitors. PMID- 22821879 TI - In vivo monitoring of antiangiogenic therapy by magnetic resonance and bioluminescence imaging in an M21 tumor model through activation of an hsp70 promoter-luciferase reporter construct. AB - We have investigated the effect of targeted gene therapy on the melanoma cell line M21, using a combination of bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). M21 cells transfected with a plasmid containing either an hsp70 (Hspa1b) or a CMV promoter fragment, along with the luciferase reporter gene, were grown to a tumor size of 900 mm(3) . Five mice in each group were intravenously treated every 72 h with a complex consisting of a nanoparticle, an Arg-Gly-Asp-peptide, and a dominant negative mutant protein kinase inhibitor gene. BLI and MRI were performed at specific time intervals. The MRI scan protocol included T(1) -weighted-spin-echo +/- contrast medium, T(2) -weighted fast-spin-echo, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted stimulated-echo-acquisition-mode-sequence. The T(2) times were obtained using a 1.5 T GE MRI scanner. The size of the treated M21 tumors remained almost constant during the treatment phase (837.8 +/- 133.4 vs 914.8 +/- 134.4 mm(3) ). BLI showed that, if transcription was controlled by the CMV promoter, the luciferase activity decreased to 51.1 +/- 8.3%. After transcription was controlled by the hsp70 promoter, the highest luciferase activity (4.4 +/- 0.3 fold) was seen after 24 h. The signal-to-noise ratio (SNR; T(2) -weighted images) of the tumors was 36.7 +/- 0.6 and subsequently dropped to 31.2 +/- 4.4 (p=0.004). DCE-MRI showed a reduction of the slope and the Ak(ep) of 67.8% +/- 4.3 and 64.8% +/- 3.3%, respectively, compared with the baseline. The SNR value (T(1) -weighted images) of the tumors was 42.3 +/- 1.9 immediately following contrast medium application and subsequently dropped to 28.5 +/- 3.0 (p<0.001). In the treatment group, the diffusion coefficient increased significantly under therapy (0.66 +/- 0.05 vs the pretreatment value of 0.54 +/- 0.009 p<0.01). Thus, we observed that targeted antiangiogenic therapy can induce activation of the hsp70 promoter through a heat shock/luciferase reporter system. Moreover, MRI showed a significant reduction of the contrast medium uptake parameters and an increase in the diffusion coefficient of the tumors. PMID- 22821880 TI - Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T(2) contrast agent with tunable proton relaxivities. AB - Monodisperse mesoporous silica (mSiO(2) ) coated superparamagnetic iron oxide (Fe(3) O(4) @mSiO(2) ) nanoparticles (NPs) have been developed as a potential magnetic resonance imaging (MRI) T(2) contrast agent. To evaluate the effect of surface coating on MRI contrast efficiency, we examined the proton relaxivities of Fe(3) O(4) @mSiO(2) NPs with different coating thicknesses. It was found that the mSiO(2) coating has a significant impact on the efficiency of Fe(3) O(4) NPs for MRI contrast enhancement. The efficiency increases with the thickness of mSiO(2) coating and is much higher than that of the commercial contrast agents. Nuclear magnetic resonance (NMR) relaxometry of Fe(3) O(4) @mSiO(2) further revealed that mSiO(2) coating is partially permeable to water molecules and therefore induces the decrease of longitudinal relaxivity, r(1) . Biocompatibility evaluation of various sized (ca. 35-95 nm) Fe(3) O(4) @mSiO(2) NPs was tested on OC-k3 cells and the result showed that these particles have no negative impact on cell viability. The enhanced MRI efficiency of Fe(3) O(4) @mSiO(2) highlights these core-shell particles as highly efficient T(2) contrast agents with high biocompatibility. PMID- 22821881 TI - Hyperpolarized (13) C-labelled anhydrides as DNP precursors of metabolic MRI agents. AB - The extraordinary enhancement of the nuclear magnetic resonance (NMR) signal that can be obtained by dynamic nuclear polarization (DNP) techniques is prompting new avenues of research based on the in vivo detection of metabolic abnormalities associated with the onset and progression of human diseases. (13) C-labelled short-chain fatty acids appear to be interesting candidates for this novel class of metabolic-active contrast agents (MCAs), as they have been shown to report on metabolic differences between healthy and ischaemic tissues in mice. In spite of their promising biological efficacy, the formulations of short-chain fatty acids that fulfil the many technical constraints of the DNP procedure, as it is today, may limit their clinical potential. New solutions have been sought to circumvent technology-related challenges and facilitate clinical translation of these molecules. In particular, it has been shown that, by using symmetric anhydrides as chemical precursors for short-chain fatty acids, no glass-forming additives are needed in the DNP formulations. Furthermore, novel esterified trityl radicals and lipophilic gadolinium complexes allow easy removal of the polarization promoting additives at the end of the DNP process. By applying the three concepts reported, we have succeeded in preparing aqueous formulations of short-chain fatty acids for pharmaceutical use that have favourable properties compared with those obtained from current procedures. The use of organic derivatives as chemical precursors of the MCA of interest appears to be a generally valid concept, not restricted to symmetric anhydrides of fatty acids, which can markedly improve the clinical potential of other (13) C-labelled compounds. PMID- 22821882 TI - A smart (19) F and (1) H MRI probe with self-immolative linker as a versatile tool for detection of enzymes. AB - Here we report on a dual-modal (19) F and (1) H MRI paramagnetic probe with a self-immolative linker, Gd-DOMF-Gal. The enzymatic conversion of this probe by beta-galactosidase resulted in a simultaneous turning on of the fluorine signal and changed ability of the Gd(3+) complex to modulate the (1) H MR signal intensity of the surrounding water molecules. A versatile imaging platform for monitoring a variety of enzymes by (19) F and (1) H MRI using this molecular design is proposed. PMID- 22821884 TI - A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development. AB - Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or Gly(13) in >90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other HRAS codons were reported in patients with an attenuated or mild phenotype. Disease-associated HRAS missense mutations result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT signal flow. Here we report on a novel heterozygous HRAS germline alteration, c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural effusion, followed by a more benign postnatal course. A sibling with the same mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C>G change. By functional analyses we identified reduced levels of active HRAS(S89C) and diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) , which represent novel consequences of disease-associated HRAS mutations. Given our patients' difficult neonatal course and presence of this change in their asymptomatic father, we hypothesize that its harmful consequences may be time limited, with the late fetal stage being most sensitive. Alternatively, the phenotype may develop only in the presence of an additional as-yet-unknown genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline HRAS mutations. PMID- 22821885 TI - Catalytic asymmetric Claisen rearrangement of enolphosphonates: construction of vicinal tertiary and all-carbon quaternary centers. PMID- 22821887 TI - Mouse lines with photo-activatable mitochondria to study mitochondrial dynamics. AB - Many pathological states involve dysregulation of mitochondrial fusion, fission, or transport. These dynamic events are usually studied in cells lines because of the challenges in tracking mitochondria in tissues. To investigate mitochondrial dynamics in tissues and disease models, we generated two mouse lines with photo activatable mitochondria (PhAM). In the PhAM(floxed) line, a mitochondrially localized version of the photo-convertible fluorescent protein Dendra2 (mito Dendra2) is targeted to the ubiquitously expressed Rosa26 locus, along with an upstream loxP-flanked termination signal. Expression of Cre in PhAM( floxed) cells results in bright mito-Dendra2 fluorescence without adverse effects on mitochondrial morphology. When crossed with Cre drivers, the PhAM(floxed) line expresses mito-Dendra2 in specific cell types, allowing mitochondria to be tracked even in tissues that have high cell density. In a second line (PhAM(excised) ), the expression of mito-Dendra2 is ubiquitous, allowing mitochondria to be analyzed in a wide range of live and fixed tissues. By using photo-conversion techniques, we directly measured mitochondrial fusion events in cultured cells as well as tissues such as skeletal muscle. These mouse lines facilitate analysis of mitochondrial dynamics in a wide spectrum of primary cells and tissues, and can be used to examine mitochondria in developmental transitions and disease states. PMID- 22821889 TI - The system N transporter SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors. AB - Activation of NMDA receptor requires two co-agonists, glutamate and glycine. Despite its intrinsic role in brain functions molecular mechanisms involved in glutamate replenishment and identification of the origin of glycine have eluded characterization. We have performed direct measurements of glycine flux by SN2 (Slc38a5; also known as SNAT5), executed extensive electrophysiological characterization as well as implemented ratiometric analyses to show that SN2 transport resembles SN1 in mechanism but differ in functional implications. We report that rat SN2 mediates electroneutral and bidirectional transport of glutamine and glycine at perisynaptic astroglial membranes. Sophisticated coupled and uncoupled movements of H(+) differentially associate with glutamine and glycine transport by SN2 and regulate pH(i) and the release mode of the transporter. Consequently, SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors. PMID- 22821886 TI - Familial secondary erythrocytosis due to increased oxygen affinity is caused by destabilization of the T state of hemoglobin Brigham (alpha2beta2(Pro100Leu)). AB - Hemoglobin Brigham (beta Pro100 to Leu) was first reported in a patient with familial erythrocytosis. Erythrocytes of an affected individual from the same family contain both HbA and Hb Brigham and exhibit elevated O2 affinity compared with normal cells (P50 = 23 mm Hg vs. 31 mmHg at pH 7.4 at 37 degrees C). O2 affinities measured for hemolysates were sensitive to changes in pH or chloride concentrations, indicating little change in the Bohr and Chloride effects. Hb Brigham was separated from normal HbA by nondenaturing cation exchange liquid chromatography, and the amino acid substitution was verified by mass spectrometry. The properties of Hb Brigham isolated from the patient's blood were then compared with those of recombinant Hb Brigham expressed in Escherichia coli. Kinetic experiments suggest that the rate constants for ligand binding and release in the high (R) and low (T) affinity quaternary states of Hb Brigham are similar to those of native hemoglobin. However, the Brigham mutation decreases the T to R equilibrium constant (L) which accelerates the switch to the R state during ligand binding to deoxy-Hb, increasing the rate of association by approximately twofold, and decelerates the switch during ligand dissociation from HbO2, decreasing the rate approximately twofold. These kinetic data help explain the high O2 affinity characteristics of Hb Brigham and provide further evidence for the importance of the contribution of Pro100 to intersubunit contacts and stabilization of the T quaternary structure. PMID- 22821890 TI - Effects of deletion and duplication in a patient with a 46,XX,der(7)t(7;17)(q36;p13)mat karyotype. AB - Exact breakpoint determination by DNA-array has dramatically improved the analysis of genotype-phenotype correlations in chromosome aberrations. It allows a more exact definition of the most relevant genes and particularly their isolated or combined impact on the phenotype in an unbalanced state. Here, we report on a 21-year-old female with severe growth retardation, severe intellectual disability, hypoplasia of the corpus callosum, unilateral sacral hypoplasia, tethered cord, various minor facial dysmorphisms, and a telomeric deletion of about 4.4 Mb in 7q36.2->qter combined with a telomeric duplication of about 8 Mb in 17pter->p13.1. Fine mapping was achieved with the Illumina(r) Infinium HumanOmni1-Quad v1.0 BeadChip. Most of the major clinical features correspond to the well-known effects of haploinsufficiency of the MNX1 and SHH genes. In addition, review of the literature suggests an association of the 17p duplication with specific facial dysmorphic features and skeletal anomalies, but also an aggravating effect of the duplication-deletion for severe growth retardation as well as sacral and corpus callosum hypoplasia by one or more genes located on the proximal half of the segmental 17p duplication could be elaborated by comparison with other patients from the literature carrying either the deletion or the duplication found in our patient. PMID- 22821891 TI - Fatigue-free, electrically reliable copper electrode with nanohole array. AB - Design and fabrication of reliable electrodes is one of the most important challenges in flexible devices, which undergo repeated deformation. In conventional approaches, mechanical and electrical properties of continuous metal films degrade gradually because of the fatigue damage. The designed incorporation of nanoholes into Cu electrodes can enhance the reliability. In this study, the electrode shows extremely low electrical resistance change during bending fatigue because the nanoholes suppress crack initiation by preventing protrusion formation and damage propagation by crack tip blunting. This concept provides a key guideline for developing fatigue-free flexible electrodes. PMID- 22821892 TI - Runx2 isoform I controls a panel of proinvasive genes driving aggressiveness of papillary thyroid carcinomas. AB - CONTEXT: The ability of tumor cells to invade adjacent tissues is governed by a complicated network of molecular signals, most of which have not yet been identified. In a recent work, we reported that the transcriptional regulator Id1 contributes to thyroid cancer progression by powering the invasion capacity of tumor cells. OBJECTIVE: The intent of this work was to further investigate the biology of invasive thyroid tumors, through the analysis of the molecular interactions existing between Id1 and some of its target genes and through the characterization of the function of these factors in the progression of thyroid tumors. RESULTS: We showed that Id1 controls the expression of the Runx2 isoform I and that this transcription factor plays a central role in mediating the Id1 proinvasive function in thyroid tumor cells. We demonstrated that Runx2 regulates proliferation, migration, and invasiveness by activating a panel of genes involved in matrix degradation and cellular invasion, which we previously identified as Id1 target genes in thyroid tumor cells. Finally, we show that Runx2 is strongly expressed in metastatic human thyroid tumors both at the primary site and in metastases. CONCLUSION: Overall, our experiments demonstrate the existence of a previously unknown molecular axis that controls thyroid tumor invasiveness by altering the ability of tumor cells to interact with the surrounding microenvironment. These factors could prove to be valuable markers that permit early diagnosis of aggressive thyroid tumors. PMID- 22821893 TI - Microarchitectural abnormalities are more severe in postmenopausal women with vertebral compared to nonvertebral fractures. AB - BACKGROUND: Abnormal bone microarchitecture predisposes postmenopausal women to fragility fractures. Whether women with vertebral fractures have worse microarchitecture than those with nonvertebral fractures is unknown. METHODS: Postmenopausal women with a history of low trauma vertebral fracture (n=30) and nonvertebral fracture (n=73) and controls (n=120) had areal bone mineral density of lumbar spine, total hip, femoral neck, 1/3 radius, and ultradistal radius measured by dual-energy x-ray absorptiometry. Trabecular and cortical volumetric bone mineral density and microarchitecture were measured by high-resolution peripheral quantitative computed tomography of the distal radius and tibia. Finite element analysis estimated whole bone stiffness. RESULTS: Mean age of subjects was 68+/-7 yr. Groups were similar with respect to age, race, and body mass index. Mean T-scores did not differ from controls at any site except the ultradistal radius (vertebral fracture, 0.6 sd lower; nonvertebral fracture, 0.4 sd lower). Compared to controls, women with vertebral fractures had lower total, cortical, and trabecular volumetric density, lower cortical thickness, trabecular number and thickness, greater trabecular separation and network heterogeneity, and lower stiffness at both radius and tibia. Differences between women with nonvertebral fractures and controls were similar but less pronounced. Compared to women with nonvertebral fractures, women with vertebral fractures had lower total and trabecular density, lower cortical thickness and trabecular number, and greater trabecular separation and heterogeneity at the tibia. Whole bone stiffness tended to be lower (P=0.06). Differences between fracture groups at the radius were not statistically significant. CONCLUSION: Women with vertebral fractures have more severe trabecular and cortical microarchitectural deterioration than those with nonvertebral fractures, particularly at the tibia. PMID- 22821894 TI - Pituitary function in patients with normal pressure hydrocephalus before and after neurosurgical correction. AB - INTRODUCTION: Little is known about pituitary function in patients with normal pressure hydrocephalus (NPH). This study evaluated pituitary function in a large series of patients awaiting neurosurgical correction for NPH. We also sought to ascertain whether surgical correction of hydrocephalus would result in improvement of any noted pituitary dysfunction. METHODS: Patients with NPH referred for neurosurgical evaluation between February 2010 and January 2011 were eligible for recruitment. Pituitary endocrine evaluation including serum prolactin, free thyroid hormone, TSH, IGF-I, FSH, LH, estradiol, testosterone, cortisol, and ACTH was preformed at baseline and 1 and 3 months after surgery. RESULTS: Of the 63 patients referred for possible NPH, 32 met study criteria, 20 could provide informed consent, and laboratory evaluation was obtainable in 16. The mean age of these patients was 62+/-14 yr, and 75% were men. The overall incidence of NPH-associated pituitary dysfunction was 31% (five of 16 patients) at baseline laboratory assessment. Hypogonadism was the most common type of pituitary dysfunction detected. CONCLUSION: NPH is associated with pituitary dysfunction, observed in a significant proportion (31%) of patients. As such, we recommend that pituitary screening should be considered in all NPH patients. In two patients with hypogonadism, surgical correction of NPH was associated with improved testosterone levels. Therefore, not all patients with NPH-associated pituitary dysfunction will require hormone replacement therapy because surgical correction may correct pituitary deficiencies in some instances. PMID- 22821896 TI - Alcohol and intellectual disability: personal problem or cultural exclusion? AB - The small number of studies on alcohol use among adults with intellectual disabilities shows their usage is significantly less than average, with very high levels of abstinence. Despite this, the literature focuses almost to exclusion on the very small number of people who do have problems, and neglects to question the possible reasons for this differential pattern of consumption. This article reviews the extant literature, showing that it constructs an inherently pathological view of drinking in people with intellectual disabilities, framing it entirely within a discourse of risk and as a personal behaviour, rather than as a social and cultural one. As a counter to this perspective, the article opens up new lines of exploration around the significance of abstinence, why it might occur to such a high degree and whether, in fact, it might itself be and also point towards the cultural exclusion of people with intellectual disabilities. PMID- 22821895 TI - Neonatal body composition according to the revised institute of medicine recommendations for maternal weight gain. AB - BACKGROUND: In 2009, the Institute of Medicine (IOM) released revised pregnancy weight gain guidelines. There are limited data regarding the effect of maternal weight gain on newborn adiposity. OBJECTIVE: The aim of this study was to estimate neonatal fat mass, lean body mass, and percentage body fat according to current Institute of Medicine (IOM) pregnancy weight gain guidelines. DESIGN: This is a secondary analysis of a prospective observational cohort study of neonates delivered at least 36 wk gestation and evaluated for fat mass, lean body mass, and percentage body fat. Women with abnormal glucose tolerance testing and other known medical disorders or pregnancies with known fetal anomalies were excluded. Pregravid body mass index (BMI) was categorized as normal weight (<25 kg/m2), overweight (25-30 kg/m2), or obese (>30 kg/m2). Maternal weight gain was quantified as less than, equal to, or greater than current IOM guidelines. Newborn body composition measurements were compared according to weight gain and BMI categories. RESULTS: A total of 439 maternal-newborn pairs were evaluated; 19.8% (n=87) of women gained less than IOM guidelines; 31.9% (n=140), equal to IOM guidelines; and 48.3% (n=212), greater than IOM guidelines. Significant differences for each component of body composition were found when evaluated by IOM weight gain categories (all ANOVA, P<0.001). When controlling for pregravid BMI, only weight gain for women who were of normal weight before pregnancy remained significant. CONCLUSION: Maternal weight gain during pregnancy is a significant contributor to newborn body composition, particularly for women who are of normal weight before pregnancy. PMID- 22821897 TI - Discotic ionic liquid crystals of triphenylene as dispersants for orienting single-walled carbon nanotubes. AB - Orient and conduct: Triphenylene-based discotic ionic liquid crystals (ILCs) with six imidazolium ion pendants can disperse pristine single-walled carbon nanotubes (SWNTs). When the ILC is columnarly assembled, doping with SWNTs results in macroscopic homeotropic columnar orientation. Combination of shear and annealing treatments gives rise to three different orientation states, which determine the anisotropy of electrical conduction. PMID- 22821898 TI - Surface functionalization of poly(ether imide) membranes with linear, methylated oligoglycerols for reducing thrombogenicity. AB - Materials for biomedical applications are often chosen for their bulk properties. Other requirements such as a hemocompatible surface shall be fulfilled by suitable chemical functionalization. Here we show, that linear, side-chain methylated oligoglycerols (OGMe) are more stable to oxidation than oligo(ethylene glycol) (OEG). Poly(ether imide) (PEI) membranes functionalized with OGMes perform at least as good as, and partially better than, OEG functionalized PEI membranes in view of protein resistance as well as thrombocyte adhesion and activation. Therefore, OGMes are highly potent surface functionalizing molecules for improving the hemocompatibility of polymers. PMID- 22821899 TI - Is liver transplantation a risk factor for cardiovascular disease? A meta analysis of observational studies. AB - Up to two-thirds of patients develop metabolic syndrome within the first 5 years after orthotopic liver transplantation (OLT). However, data on overall cardiovascular (CV) morbidity and mortality among OLT recipients and particularly those who develop metabolic syndrome remain elusive. A literature search using MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and meeting abstracts (along with their bibliographies) was performed to identify studies. Data on ischemic CV events were extracted from each study and were used for pooled analyses. Overall pooled estimates and 95% confidence intervals (CIs) for the incidence of CV events and deaths were obtained with a random effects model. Twelve observational studies reporting CV outcomes for 4792 post-OLT recipients who were followed for 28,783 person-years were included. Pooled estimates showed that the 10-year risk of developing CV events among the post-OLT recipients was 13.6% (95% CI = 9%-8.1%). Pooled estimates from case-control studies showed that the post-OLT group had an approximately 64% greater risk of experiencing CV events than controls (standardized incidence ratio = 1.64, 95% CI = 1.18-2.20). Among OLT recipients, those with metabolic syndrome were approximately 4 times more likely to have a CV event [odds ratio (OR) = 4.01, 95% CI = 1.94-8.32] without any significant increase in all-cause mortality (OR = 1.15, 95% CI = 0.63-2.10). In conclusion, this systematic review suggests that OLT recipients and particularly those with metabolic syndrome have a high risk for CV events. However, the literature is limited and lacks high-quality studies. Future prospective studies are warranted to confirm these findings and determine whether aggressive risk-reduction strategies can attenuate the increased CV risk seen in this population. PMID- 22821901 TI - N,N-Diphenylpyridin-4-amine as a bipolar core structure of high-triplet-energy host materials for blue phosphorescent organic light-emitting diodes. PMID- 22821900 TI - Chronic tibial nonunion in a Rothmund-Thomson syndrome patient. AB - Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by biallelic mutations in RECQL4, a helicase involved with chromosomal instability and DNA repair. Patients typically present with a poikilodermatous facial rash, photosensitivity, congenital bony abnormalities, short stature, and have a predilection for osteosarcoma and cutaneous malignancies. We present a 34-year old male RTS patient, previously diagnosed with osteosarcoma of the right forearm which was successfully treated with resection and chemotherapy, who has had multiple tibial fractures and has suffered from chronic nonunion of the proximal tibias bilaterally for greater than 9 years. The patient subsequently developed generalized lower extremity osteopenia with normal calcium homeostasis and calcitriol levels. As the RTS population continues to reach greater ages we must be mindful of other health concerns that may develop. Bone health is one considerable concern with a large portion of patients having congenital bony abnormalities and many receiving chemotherapy for osteosarcoma. We conclude that screening for bone health and supplementation with calcium and vitamin D may be warranted in RTS patients with a history of fractures and osteosarcoma treatment. PMID- 22821902 TI - Size-controlled single-crystal perovskite PbTiO3 nanofibers from edge-shared TiO6 octahedron columns. PMID- 22821903 TI - Redox mediating epigenetic changes confer metabolic memories. PMID- 22821904 TI - Role of microparticles as messengers enhancing stem cell activity after genetic engineering. PMID- 22821905 TI - Whither art thou, SCN10A, and what art thou doing? PMID- 22821906 TI - Inflame on!: mitochondrial escape provokes cytokine storms that doom the heart. AB - Mitochondria are derived from primordial bacterial endosymbionts and retain partial genomes. In mammalian cells, damaged or dysfunctional mitochondria are recognized, targeted for elimination, then neatly packaged and eliminated via mitophagy. A recent paper from Oka et al describes how interrupting normal mitophagic mitochondrial DNA degradation after pressure overload can activate Toll-like receptor-9 mediated innate immunity, causing myocardial inflammation that contributes to cardiomyopathic decompensation. PMID- 22821907 TI - Antibodies to PCSK9: a superior way to lower LDL cholesterol? AB - Lowering of LDL cholesterol, predominantly accomplished clinically by statins, is one of the key components of both the prevention and medical management of coronary atherosclerosis; however, additional or alternative cholesterol lowering agents are needed for patients who fail to achieve goals or have adverse effects on statins. Owing to relatively rapid translation of basic science research on a novel regulatory pathway of the LDL receptor by PCSK9, a new class of such drugs with a different mode of action, and potentially better tolerance and less off target effects may be just over the horizon. PMID- 22821908 TI - Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: a methods overview. AB - Since human embryonic stem cells were first differentiated to beating cardiomyocytes a decade ago, interest in their potential applications has increased exponentially. This has been further enhanced over recent years by the discovery of methods to induce pluripotency in somatic cells, including those derived from patients with hereditary cardiac diseases. Human pluripotent stem cells have been among the most challenging cell types to grow stably in culture, but advances in reagent development now mean that most laboratories can expand both embryonic and induced pluripotent stem cells robustly using commercially available products. However, differentiation protocols have lagged behind and in many cases only produce the cell types required with low efficiency. Cardiomyocyte differentiation techniques were also initially inefficient and not readily transferable across cell lines, but there are now a number of more robust protocols available. Here, we review the basic biology underlying the differentiation of pluripotent cells to cardiac lineages and describe current state-of-the-art protocols, as well as ongoing refinements. This should provide a useful entry for laboratories new to this area to start their research. Ultimately, efficient and reliable differentiation methodologies are essential to generate desired cardiac lineages to realize the full promise of human pluripotent stem cells for biomedical research, drug development, and clinical applications. PMID- 22821912 TI - N-heterocyclic carbene catalyzed homoenolate-addition reaction of enals and nitroalkenes: asymmetric synthesis of 5-carbon-synthon delta-nitroesters. PMID- 22821909 TI - The emerging paradigm of network medicine in the study of human disease. AB - The molecular pathways that govern human disease consist of molecular circuits that coalesce into complex, overlapping networks. These network pathways are presumably regulated in a coordinated fashion, but such regulation has been difficult to decipher using only reductionistic principles. The emerging paradigm of "network medicine" proposes to utilize insights garnered from network topology (eg, the static position of molecules in relation to their neighbors) as well as network dynamics (eg, the unique flux of information through the network) to understand better the pathogenic behavior of complex molecular interconnections that traditional methods fail to recognize. As methodologies evolve, network medicine has the potential to capture the molecular complexity of human disease while offering computational methods to discern how such complexity controls disease manifestations, prognosis, and therapy. This review introduces the fundamental concepts of network medicine and explores the feasibility and potential impact of network-based methods for predicting individual manifestations of human disease and designing rational therapies. Wherever possible, we emphasize the application of these principles to cardiovascular disease. PMID- 22821910 TI - Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor. AB - Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are inherited diseases with a high incidence of death due to electric abnormalities or outflow tract obstruction. In many of the families afflicted with either disease, causative mutations have been identified in various sarcomeric proteins. In this review, we focus on mutations in the cardiac muscle molecular motor, myosin, and its associated light chains. Despite the >300 identified mutations, there is still no clear understanding of how these mutations within the same myosin molecule can lead to the dramatically different clinical phenotypes associated with HCM and DCM. Localizing mutations within myosin's molecular structure provides insight into the potential consequence of these perturbations to key functional domains of the motor. Review of biochemical and biophysical data that characterize the functional capacities of these mutant myosins suggests that mutant myosins with enhanced contractility lead to HCM, whereas those displaying reduced contractility lead to DCM. With gain and loss of function potentially being the primary consequence of a specific mutation, how these functional changes trigger the hypertrophic response and lead to the distinct HCM and DCM phenotypes will be the future investigative challenge. PMID- 22821913 TI - A rare case of gastric MALT lymphoma resistant to multiple treatment regimens. PMID- 22821914 TI - Identification of the mechanism underlying a human chimera by SNP array analysis. AB - Human chimerism resulting from the fusion of two different zygotes is a rare phenomenon. Two mechanisms of chimerism have been hypothesized: dispermic fertilization of an oocyte and its second polar body and dispermic fertilization of two identical gametes from parthenogenetic activation, and these can be identified and discriminated using DNA polymorphism. In the present study we describe a patient with chimerism presenting as a true hermaphrodite and applied single nucleotide polymorphism array analysis to demonstrate dispermic fertilization of two identical gametes from parthenogenetic activation as the underlying mechanism at the whole chromosome level. We suggest that application of genotyping array analysis to the diagnostic process in patients with disorders of sex development will help identify more human chimera patients and increase our understanding of the underlying mechanisms. PMID- 22821915 TI - New insights into the functions and localization of nuclear CCT protein complex in K562 leukemia cells. AB - PURPOSE: The eukaryotic cytosolic chaperonin containing TCP-1 (CCT) plays an important role in maintaining cellular homeostasis by assisting the folding of many proteins and is also well known for the critical roles in disease. However, the functions of CCT complex have not been established globally, especially when translocating into nuclear. The purpose of this study is to explore the function of CCT in nuclear and present a strategy in clinical proteomics studies. EXPERIMENTAL DESIGN: Blue native polyacrylamide gel electrophoresis (BN-PAGE) combined with mass spectrometry was applied to separate and identify CCT protein complexes. RESULTS: We isolated the CCT complex in K562 nucleus and identified a novel CCT complex containing 40 protein components involved in protein folding, RNA processing, apoptosis, and cell metabolism. The interactions between four candidate proteins and CCT were confirmed by immunoblotting. Computational biological analyses and independent biochemical assays validated the overall quality of interactions. CONCLUSIONS AND CLINICAL RELEVANCE: Our results support clues that CCT might play an unexpected role in various biological processes including RNA processing. And we envision future applications for this system searching for new clues of CCT in disease and readily be applied to the clinic. PMID- 22821916 TI - MR spectroscopy of the fetal brain: is it possible without sedation? AB - BACKGROUND AND PURPOSE: The quality of spectroscopic studies may be limited because of unrestricted fetal movement. Sedation is recommended to avoid motion artefacts. However, sedation involves side effects. The aim of this study was to assess the feasibility and quality of brain (1)H-MR spectroscopy in unsedated fetuses and to evaluate whether quality is dependent on the type of spectra, fetal presentation, GA, and/or fetal pathology. MATERIALS AND METHODS: Seventy five single-voxel spectroscopic studies of the fetal brain, performed at gestational weeks 19-38 at 1.5T, were evaluated retrospectively. A PRESS (TE = 144 or 35 ms) was used. Fetal presentation, GA, and kind of pathology were recorded. The quality of the spectra was assessed by reviewing the spectral appearance (line width, signal-to-noise) of the creatine resonance obtained relative to concentrations (ratios-to-creatine) of choline, myo-inositol, and NAA. RESULTS: Of 75 studies, 50 (66.6%) were rated as readable: short TE = 17/50 (34%), long TE = 33/50 (66%), cephalic presentation in 36/50 (72%) studies, breech in 10/50 (20%) studies, and "other" presentation in 4/50 (8%) studies (mean GA, 31.0 weeks). Twenty-eight of 50 fetuses (56%) showed normal development (short TE = 12/28, long TE = 16/28), and 22/50 (44%) showed pathology. Of the 75 studies, 25 (33.3%) were not readable: short TE = 14/25 (56%), long TE = 11/25 (44%), cephalic presentation in 20/25 (80%) studies, breech in 4/25 (16%) studies, and other presentation in 1 study (4%) (mean GA, 30.1 week). Thirteen of 25 fetuses (52%) showed normal development; 12/25 (48%) showed pathology. Statistical analysis revealed no impact of the different parameters on the quality of spectra. CONCLUSIONS: Single-voxel spectroscopy can be performed in approximately two-thirds of unsedated fetuses, regardless of the type of spectra, fetal presentation, GA, and pathology. PMID- 22821917 TI - Structural brain MR imaging changes associated with obsessive-compulsive disorder in patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: Psychiatric symptoms occur in approximately 30% of patients with MS. Such symptoms include OCD, which may interfere heavily with the patient's daily life. We hypothesized that the widespread involvement of both GM and WM, which characterizes MS, may be responsible for the occurrence of OCD when specific brain structures are affected. The aim of this study was to evaluate the relationship between GM and WM tissue damage and OCD in patients with MS. MATERIALS AND METHODS: We evaluated 16 patients with relapsing-remitting MS who had been diagnosed with OCD on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th edition) and 15 age- and sex-matched patients with relapsing-remitting MS with no psychiatric disorders as a CG. The MR study (1.5T) included 3D T1-weighted fast-field echo sequences, DTI (32 directions), and conventional MRI. Images were processed using SPM5, FSL, and Jim 5.0 software to evaluate VBM, TBSS, and global and regional LV, respectively. RESULTS: The VBM analysis revealed a set of clusters of reduced GM volume in the OCD group, compared with the CG, located in the right inferior and middle temporal gyri and in the inferior frontal gyrus. TBSS did not detect any differences in the FA values between the 2 groups; global and regional LV values also did not differ significantly between the 2 groups. CONCLUSIONS: Our study suggests that OCD in MS may be caused by damage in the right frontotemporal cortex. PMID- 22821918 TI - Diffusion tensor imaging correlates with the clinical assessment of disease severity in cervical spondylotic myelopathy and predicts outcome following surgery. AB - BACKGROUND AND PURPOSE: CSM is a common neurologic disease that results in progressive disability and eventual paralysis without appropriate treatment. Imaging plays a significant role in the evaluation of CSM and has evolved with recent technical advances. We sought to systematically explore the relationship between clinical disease severity and DTI in CSM, and to investigate the potential use of DTI in surgical decision-making models. MATERIALS AND METHODS: MR imaging studies and clinical assessments were prospectively collected on 30 patients with CSM. Spearman correlations were used to investigate associations between clinical disease severity and FA at the time of diagnosis. Clinical assessment was performed using mJOA, Nurick, Short Form-36, and NDI scores. Fifteen patients with CSM subsequently underwent decompressive surgery; Spearman correlation and logistic regression were applied to this cohort to study the relationship between baseline DTI measurements and postoperative outcome. Conventional imaging (spinal cord T2 signal intensity and degree of stenosis) was evaluated for comparison with DTI. RESULTS: At diagnosis, FA demonstrated a strong correlation with baseline mJOA (r = 0.62, P < .01) and Nurick (r = -0.46, P = .01) scores. After surgery, recovery of function demonstrated by improvement in NDI score was associated with higher FA values on preoperative DTI (r = -0.61, P = .04). Severely affected patients with CSM with disproportionately high FA tended to achieve greater mJOA scores after surgery compared with subjects with lower FA (P = .08). T2 signal intensity was associated with functional status at baseline but did not predict postoperative outcome; degree of stenosis lacked any significant correlation with clinical parameters. CONCLUSIONS: DTI may be a useful diagnostic tool for assessing disease severity in CSM. The predictive value of DTI regarding postoperative outcome may improve surgical decision-making and facilitate health care outcomes research. PMID- 22821919 TI - Reduced diffusion in neurocysticercosis: circumstances of appearance and possible natural history implications. AB - BACKGROUND AND PURPOSE: Few studies discuss DWI findings in patients with NCC, and their conclusions are variable and contradictory. The aim of our study was to describe DWI findings of a cohort of patients with NCC, emphasizing the frequency of reduced diffusion. MATERIALS AND METHODS: This retrospective study included 48 patients with NCC. Two neuroradiologists analyzed MR images regarding location, number, and stage of NCC lesions. On the basis of visual analysis, they defined, by consensus, the presence of high signal within NCC lesions on DWI and measured their ADC values when feasible. RESULTS: The total number of lesions was 342: parenchymal (263), subarachnoid (65), and intraventricular (14); 83 were DWI hyperintense. The first pattern was a small eccentric hyperintense dot/curvilinear structure on DWI (representing the scolex) noted in intraparenchymal lesions in vesicular (41 lesions, 29%) and colloidal vesicular (18 lesions, 19%) stages, in 14 (22%) subarachnoid lesions, and 2 (14%) intraventricular lesions; rADC calculations were hampered by the intrinsic small dimensions of this finding. The second pattern was the presence of total/subtotal DWI hyperintensity in intraparenchymal lesions, 5 in the colloidal vesicular stage (5%) and 1 in the granular nodular phase (3%). Two subarachnoid lesions also showed the same presentation; in this second pattern, reduced diffusion was present in different degrees, measured by rADC calculations. CONCLUSIONS: DWI may identify the scolex, increasing diagnostic confidence for NCC. Total/subtotal DWI hyperintensity, related to the stage of the lesion, though uncommon, allows including NCC as a consideration in the differential diagnosis of lesions with reduced diffusion and ring enhancement. PMID- 22821920 TI - The U sign: tenth landmark to the central region on brain surface reformatted MR imaging. AB - BACKGROUND AND PURPOSE: Identification of the central region is of special importance to avoid neurologic deficits in brain surgery. Brain surface reformatted images (Mercator view) map the frontoparietal brain surface in 1 view and provide a synopsis of the most important landmarks. In this view, the U shaped subcentral gyrus appears as a distinctive anatomic structure enclosing the Sylvian end of the central sulcus. The purpose of this study was to add the subcentral gyrus as a new landmark to the central region (U sign) and to compare its frequency and applicability with common landmarks in healthy hemispheres. MATERIALS AND METHODS: Mercator views of 178 hemispheres in 100 patients were generated from 3D MR imaging datasets. The hemispheres were evaluated on Mercator views for the presence or absence of each of the 9 common landmarks and the new U sign identifying the central region. RESULTS: The new landmark U sign was most common (96.6%), followed by the thin postcentral gyrus sign (95.5%). The least common landmark was the Omega-shaped handknob (54.5%). None of the landmarks could be identified in all hemispheres. All landmarks could be identified bilaterally in only 1.3% of patients. CONCLUSIONS: On the Mercator view, the new U sign is an applicable and even the most frequent landmark to identify the central region. Considering the variability of the anatomic structures of the brain, including the motor hand area, the synopsis of all 10 landmarks on this surface-reformatting projection is a helpful adjunct to standard MR imaging projections to identify the central region. PMID- 22821921 TI - Treatment of intracranial aneurysms using the pipeline flow-diverter embolization device: a single-center experience with long-term follow-up results. AB - BACKGROUND AND PURPOSE: Flow-diverting devices now offer a new treatment alternative for cerebral aneurysms. We present the results of a large single center series of patients treated with the PED, including long-term follow-up. MATERIALS AND METHODS: Between November 2008 and September 2011, sidewall aneurysms with a wide neck (>=4 mm) or unfavorable dome-neck ratio (<=1.5); large/giant, fusiform, dissecting, blister-like, and recurrent sidewall aneurysms; aneurysms at difficult angles; and aneurysms in which a branch was originating directly from the sac were treated with the PED. Patients were premedicated with dual antiplatelet medications. Data, including demographics, aneurysm features, clinical presentation, complications, results, and follow-up information, for up to 2 years are presented. RESULTS: Two hundred fifty-one aneurysms in 191 patients were treated. Of these, 96 (38.3%) were large or giant (>=10 mm). In 34/251 (13.5%), PEDs were used for retreatment. Adjunctive coiling was performed in 11 aneurysms (2.1%). The mean number of devices per aneurysm was 1.3. One aneurysm ruptured in the fourth month posttreatment (0.5%), and symptomatic in-construct stenosis was detected in 1 patient (0.5%) treated with percutaneous transarterial angioplasty. Any event rate was 27/191 (14.1%), with a permanent morbidity of 1% and mortality of 0.5%. Control angiography was available in 182 (95.3%) patients with 239 (95.2%) aneurysms. In 121 aneurysms (48.2%), 1- to 2-year control angiography was available. The aneurysm occlusion rate was 91.2% in 6 months, increasing to 94.6%. CONCLUSIONS: Use of the PED is safe, efficacious, and durable in cerebral aneurysm treatment, with low morbidity mortality and high occlusion rates as confirmed with mid- to long-term control angiography. PMID- 22821922 TI - Microcatheter to recanalization (procedure time) predicts outcomes in endovascular treatment in patients with acute ischemic stroke: when do we stop? AB - BACKGROUND AND PURPOSE: Endovascular treatment for acute ischemic stroke consists of various mechanical and pharmacologic modalities used for recanalization of arterial occlusions. We performed this study to determine the relationship among procedure time, recanalization, and clinical outcomes in patients with acute ischemic stroke undergoing endovascular treatment. MATERIALS AND METHODS: We analyzed data from consecutive patients with acute ischemic stroke who underwent endovascular treatment during a 6-year period. Demographic characteristics, NIHSS score before and 24 hours after the procedure, and discharge mRS score were ascertained. Procedure time was defined by the time interval between microcatheter placement and recanalization or completion of the procedure. We estimated the procedure time after which favorable clinical outcome was unlikely, even after adjustment for age, time from symptom onset, and admission NIHSS scores. RESULTS: We analyzed 209 patients undergoing endovascular treatment (mean age, 65 +/- 16 years; 109 [52%] men; mean admission/preprocedural NIHSS score, 15.3 +/- 6.8). Complete or partial recanalization was observed in 176 (84.2%) patients, while unfavorable outcome (mRS 3-6) was observed in 138 (66%) patients at discharge. In univariate analysis, patients with procedure time <=30 minutes had lower rates of unfavorable outcome at discharge compared with patients with procedure time >=30 minutes (52.3% versus 72.2%, P = .0049). In our analysis, the rates of favorable outcomes in endovascularly treated patients after 60 minutes were lower than rates observed with placebo treatment in the Prourokinase for Acute Ischemic Stroke Trial. In logistic regression analysis, unfavorable outcome was positively associated with age (P = .0012), admission NIHSS strata (P = .0017), and longer procedure times (P = .0379). CONCLUSIONS: Procedure time in patients with acute ischemic stroke appears to be a critical determinant of outcomes following endovascular treatment. This highlights the need for procedure time guidelines for patients being considered for endovascular treatment in acute ischemic stroke. PMID- 22821923 TI - Mechanical thrombectomy in acute stroke: prospective pilot trial of the solitaire FR device while under conscious sedation. AB - BACKGROUND AND PURPOSE: The best approach between general anesthesia and conscious sedation to perform mechanical thrombectomy remains unknown. The goal of our study was to evaluate the feasibility, safety, and efficacy of mechanical thrombectomy under conscious sedation in patients with acute ischemic stroke, using the Solitaire FR device, in a prospective, single-center, single-arm study. MATERIALS AND METHODS: The study included consecutive patients with acute ischemic stroke due to a large artery occlusion within 6 hours of symptom onset for the anterior circulation, and within 24 hours for the posterior circulation. After intravenous thrombolysis (when no contraindications), thrombectomy was performed with the Solitaire device in patients under conscious sedation. Primary efficacy and safety end points were good functional outcome (mRS <=2) at 3 months and mortality at 3 months. Secondary end points were recanalization (TICI >=2) and failure rate. RESULTS: From May 2010 to July 2011, 36 patients were treated. Median baseline NIHSS score was 17.5. The occlusion site was MCA in 21 patients (58.4%), ICA-MCA tandem occlusion in 9 patients (25.0%), terminal ICA in 2 patients (5.5%), and basilar artery in 4 patients (11.1%). Twenty-three patients (63.9%) received intravenous thrombolysis. Superselective catheterization of the occluded vessel was not feasible in 5/36 cases (13.9%). Successful revascularization was achieved in 28/36 patients (77.8%). After 3 months, 22 patients (61.1%) showed good functional outcome (mRS <=2) and the median NIHSS score was 8.5. Overall mortality rate at 3 months was 22.2% (8/36). CONCLUSIONS: In acute ischemic stroke, mechanical thrombectomy while under conscious sedation is feasible in a large percentage of cases (86.1%) and is associated with a short procedure delay and a high percentage of good functional outcomes at 3 months (61.1%). PMID- 22821924 TI - Imaging changes in very young children with brain tumors treated with proton therapy and chemotherapy. AB - SUMMARY: PT promises to reduce side effects in children with brain tumors by sparing normal tissue compared with 3D conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in 8 very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging, which were consistent with radiation-induced effects on normal appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report, we describe the time course of these PT-related imaging findings and correlate them with treatment and clinical outcomes. PMID- 22821926 TI - Pharmacist credentialing in pain management and palliative care. AB - A credential is documented evidence of a pharmacist's qualifications; while credentialing is the method used to acquire, confirm, determine, and document a pharmacist's qualifications to practice. Voluntary credentials are important in clinical pharmacy specialties to ensure proficiency in caring for patients with complex pharmacotherapy needs. This article discusses current and future pharmacy pain management and palliative care credentialing opportunities. Pharmacists wishing to pursue voluntary pain management and palliative care credentialing may elect to take a multidisciplinary pain credentialing exam offered by the American Society of Pain Educators (ASPE) or American Academy of Pain Management (AAPM) and/or complete an American Society of Health System Pharmacists (ASHP) Postgraduate Year 2 (PGY2) pain management and palliative care pharmacy residency. A palliative care credentialing exam is not currently available to pharmacists. Efforts are underway within the pharmacy profession to standardize the board certification process, design a pain and palliative certificate program, and create a specialty pain management and palliative care board certification examination. PMID- 22821925 TI - Ultrasound guided versus CT-controlled pararadicular injections in the lumbar spine: a prospective randomized clinical trial. AB - BACKGROUND AND PURPOSE: Injection therapies play a major role in the treatment of lower back pain and are to date performed mainly under CT- or fluoroscopic guidance. We conducted this study to evaluate the accuracy, time savings, radiation doses, and pain relief of US-guided pararadicular injections versus CT controlled interventions in the lumbar spine in a prospective randomized clinical trial. MATERIALS AND METHODS: Forty adult patients were consecutively enrolled and assigned to a US or CT group. US-guided pararadicular injections were performed on a standard US device by using a broadband curved-array transducer (9 4 or 5-1 MHz). In the in-plane technique, the needle was advanced through the respective segmental intertransverse ligament. The needle tip position was verified by CT. The CT-guided approaches were performed under standardized procedures by using the CT-positioning laser function. RESULTS: The accuracy of US-guided interventions was 90%. The mean time to final needle placement in the US group was 4.0 +/- 1.8 minutes, and in the CT group, 7.6 +/- 2.1 minutes. The mean radiation doses, including CT confirmation for study purposes only, were 20.3 +/- 9.0 mGy cm for the US group and 42.6 +/- 36.1 mGy cm for the CT group. Both groups showed the same significant pain relief (P < .05) without relevant "intermethodic" differences of pain relief (P > .05). CONCLUSIONS: US-guided pararadicular injections show a therapeutic effect similar to that in the time consuming, expensive, ionizing CT or fluoroscopically guided pararadicular injections and result in a significant reduction of procedure time expenditure and avoidance of radiation. PMID- 22821927 TI - How to get proteomics to the clinic? Issues in clinical proteomics, exemplified by CE-MS. AB - Clinical proteomics is defined as application of proteome analysis aiming at improving the current clinical situation. As such, the success of clinical proteomics should be assessed based on the clinical impact following implementation of the findings. While we have experienced significant technological advancements in mass spectrometry in the last years, based on the above measure, this has not at all resulted in similar advancements in clinical proteomics. Although a large number of proteomic biomarkers have been described, most of them were not subsequently validated, and certainly have had no impact in clinical decision making as yet. Under the current conditions, it appears likely that the situation will not change significantly: we will be flooded by reports on biomarkers, but not see any implementation. In this article, some key issues in proteomic biomarker research are pinpointed, based on the experience with CE MS, likely also holding true for biomarkers resulting from other analysis domains. PMID- 22821928 TI - Transesterification of diethyl oxalate with phenol over sol-gel MoO(3)/TiO(2) catalysts. AB - The transesterification of diethyl oxalate (DEO) with phenol to form diphenyl oxalate (DPO) has been carried out in the liquid phase over very efficient MoO(3)/TiO(2) solid-acid sol-gel catalysts. A selectivity of 100 % with a remarkable maximum yield of 88 % were obtained, which opens the route to downstream phosgene-free processes for the synthesis of polycarbonates. Interpretation of the results of various acidity measurements (NH(3) and pyridine desorption, methanol oxidation as a probe reaction) allowed us to identify the catalytic sites as Lewis acid sites. PMID- 22821929 TI - Microfluidic single-cell analysis shows that porcine induced pluripotent stem cell-derived endothelial cells improve myocardial function by paracrine activation. AB - RATIONALE: Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large-animal iPSC models. OBJECTIVE: To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia. METHODS AND RESULTS: Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction. Compared with control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2+/-1.3% versus 22.3+/ 1.1%; P<0.001) and MRI (ejection fraction at week 4: 45.8+/-1.3% versus 42.3+/ 0.9%; P<0.05). Quantitative protein assays and microfluidic single-cell PCR profiling showed that piPSC-ECs released proangiogenic and antiapoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery. CONCLUSIONS: In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function after myocardial infarction via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the clinical translation of autologous iPSC-based therapy. PMID- 22821930 TI - Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair. AB - RATIONALE: Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the function of the cells is missing. OBJECTIVE: Here, we investigated the effects of heparin and the thrombin inhibitor bivalirudin on bone marrow-derived mononuclear cell (BMC) functional activity and homing capacity. METHODS AND RESULTS: Heparin, but not bivalirudin profoundly and dose dependently inhibited basal and stromal cell-derived factor 1 (SDF-1)-induced BMC migration. Incubation of BMCs with 20 U/mL heparin for 30 minutes abrogated SDF-1 induced BMC invasion (16+/-8% of control; P<0.01), whereas no effects on apoptosis or colony formation were observed (80+/-33% and 100+/-44% of control, respectively). Pretreatment of BMCs with heparin significantly reduced the homing of the injected cells in a mouse ear-wound model (69+/-10% of control; P<0.05). In contrast, bivalirudin did not inhibit in vivo homing of BMCs. Mechanistically, heparin binds to both, the chemoattractant SDF-1 and its receptor, chemokine receptor 4 (CXCR4), blocking CXCR4 internalization as well as SDF-1/CXCR4 signaling after SDF-1 stimulation. CONCLUSIONS: Heparin blocks SDF-1/CXCR4 signaling by binding to the ligand as well as the receptor, thereby interfering with migration and homing of BMCs. In contrast, the thrombin inhibitor bivalirudin did not interfere with BMC homing or SDF-1/CXCR4 signaling. These findings suggest that bivalirudin but not heparin might be recommended as an anticoagulant for intracoronary infusion of BMCs for cell therapy after cardiac ischemia. PMID- 22821931 TI - Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. AB - RATIONALE: We and others have demonstrated that anthocyanins have antiatherogenic capability. Because intact anthocyanins are absorbed very poorly, the low level of circulating parent anthocyanins may not fully account for their beneficial effect. We found recently that protocatechuic acid (PCA), a metabolite of cyanidin-3 to 0-beta-glucoside (Cy-3-G), has a remarkable antiatherogenic effect. OBJECTIVE: To investigate whether mouse gut microbiota metabolizes Cy-3-G into PCA and to determine whether and how PCA contributes to the antiatherogenic potency of its precursor, Cy-3-G. METHODS AND RESULTS: PCA was determined as a gut microbiota metabolite of Cy-3-G in ApoE(-/-) mice, verified by the utilization of antibiotics to eliminate gut microbiota and further microbiota acquisition. PCA but not Cy-3-G at physiologically reachable concentrations promoted cholesterol efflux from macrophages and macrophage ABCA1 and ABCG1 expression. By conducting a miRNA microarray screening, we revealed that expression of miRNA-10b in macrophages can be reduced by PCA. Functional analyses demonstrated that miRNA-10b directly represses ABCA1 and ABCG1 and negatively regulates cholesterol efflux from murine- and human-derived macrophages. Further in vitro and ex vivo analyses verified that PCA accelerates macrophage cholesterol efflux, correlating with the regulation of miRNA-10b-ABCA1/ABCG1 cascade, whereas Cy-3-G consumption promoted macrophage RCT and regressed atherosclerotic lesion in a gut microbiotaendependent manner. CONCLUSIONS: PCA, as the gut microbiota metabolite of Cy-3-G, exerts the antiatherogenic effect partially through this newly defined miRNA-10b-ABCA1/ABCG1-cholesterol efflux signaling cascade. Thus, gut microbiota is a potential novel target for atherosclerosis prevention and treatment. PMID- 22821933 TI - Progress towards less invasive veterinary surgery. PMID- 22821932 TI - Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. AB - RATIONALE: A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS). OBJECTIVE: To determine the pathogenic role of TRIM63 in human hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Sequencing of TRIM63 gene in 302 HCM probands (250 white individuals) and 339 control subjects (262 white individuals) led to identification of 2 missense (p.A48V and p.I130M) and a deletion (p.Q247*) variants exclusively in the HCM probands. These 3 variants were absent in 751 additional control subjects screened by TaqMan assays. Likewise, rare variants were enriched in the white HCM population (11/250, 4.4% versus 3/262, 1.1%, respectively, P=0.024). Expression of the mutant TRIM63 was associated with mislocalization of TRIM63 to sarcomere Z disks, impaired auto-ubiquitination, reduced ubiquitination and UPS-mediated degradation of myosin heavy chain 6, cardiac myosin binding protein C, calcineurin (PPP3CB), and p-MTOR in adult cardiac myocytes. Induced expression of the mutant TRIM63 in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of the hypertrophic markers, which were normalized on turning off expression of the mutant protein. CONCLUSIONS: TRIM63 mutations, identified in patients with HCM, impart loss-of-function effects on E3 ligase activity and are probably causal mutations in HCM. The findings implicate impaired protein degradation in the pathogenesis of HCM. PMID- 22821934 TI - Responsibility for assessing the risk of spread of Schmallenberg virus. PMID- 22821935 TI - Control of off-label use of medicines. PMID- 22821936 TI - Religious slaughter in context. PMID- 22821937 TI - In a poetic vein. PMID- 22821938 TI - Embryo growth, testa permeability, and endosperm weakening are major targets for the environmentally regulated inhibition of Lepidium sativum seed germination by myrigalone A. AB - Myrigalone A (MyA) is a rare flavonoid in fruit leachates of Myrica gale, a deciduous shrub adapted to flood-prone habitats. As a putative allelochemical it inhibits seed germination and seedling growth. Using Lepidium sativum as a model target species, experiments were conducted to investigate how environmental cues modulate MyA's interference with key processes of seed germination. Time course analyses of L. sativum testa and endosperm rupture under different light conditions and water potentials were combined with quantifying testa permeability, endosperm weakening, tissue-specific gibberellin (GA) and abscisic acid (ABA) contents, as well as embryo growth and apoplastic superoxide production important for cell expansion growth. Lepidium sativum testa permeability and early water uptake by imbibition is enhanced by MyA. During late germination, MyA inhibits endosperm weakening and embryo growth, both processes required for endosperm rupture. Inhibition of embryo cell expansion by MyA depends on environmental cues, which is evident from the light-modulated severity of the MyA-mediated inhibition of apoplastic superoxide accumulation. Several important key weakening and growth processes during early and late germination are targets for MyA. These effects are modulated by light conditions and ambient water potential. It is speculated that MyA is a soil seed bank-destroying allelochemical that secures the persistence of M. gale in its flood-prone environment. PMID- 22821939 TI - Overexpression of the wheat salt tolerance-related gene TaSC enhances salt tolerance in Arabidopsis. AB - A novel gene named TaSC was cloned from salt-tolerant wheat. Northern blot showed that the expression of TaSC in salt-tolerant wheat was up-regulated after salt stress. Real-time quantitative PCR analyses showed that TaSC expression was induced by salt and ABA in wheat. Localization analysis showed that TaSC proteins were localized to the plasma membrane in transgenic Arabidopsis thaliana. The overexpression of TaSC in Col-0 and atsc (SALK_072220) Arabidopsis strains resulted in increased salt tolerance of the transgenic plants. TaSC overexpression in Col-0 and atsc significantly up-regulated the expression of AtFRY1, AtSAD1, and AtCDPK2. AtCDPK2 overexpression in atsc rescued the salt sensitive phenotype of atsc. The TaSC gene may improve plant salt tolerance by acting via the CDPK pathway. PMID- 22821940 TI - Isolation of Arabidopsis ahg11, a weak ABA hypersensitive mutant defective in nad4 RNA editing. AB - The phytohormone abscisic acid (ABA) plays pivotal roles in the regulation of developmental and environmental responses in plants. Identification of cytoplasmic ABA receptors enabled the elucidation of the main ABA signalling pathway, connecting ABA perception to either nuclear events or the action of several transporters. However, the physiological functions of ABA in cellular processes largely remain unknown. To obtain greater insight into the ABA response, genetic screening was performed to isolate ABA-related mutants of Arabidopsis and several novel ABA-hypersensitive mutants were isolated. One of those mutants--ahg11--was characterized further. Map-based cloning showed that AHG11 encodes a PPR type protein, which has potential roles in RNA editing. An AHG11-GFP fusion protein indicated that AHG11 mainly localized to the mitochondria. Consistent with this observation, the nad4 transcript, which normally undergoes RNA editing, lacks a single RNA editing event conferring a conversion of an amino acid residue in ahg11 mutants. The geminating ahg11 seeds have higher levels of reactive-oxygen-species-responsive genes. Presumably, partial impairment of mitochondrial function caused by an amino acid conversion in one of the complex I components induces redox imbalance which, in turn, confers an abnormal response to the plant hormone. PMID- 22821941 TI - Epidemiology of 10,000 high school football injuries: patterns of injury by position played. AB - BACKGROUND: With more than 1.1 million high school athletes playing annually during the 2005-06 to 2009-10 academic years, football is the most popular boys' sport in the United States. METHODS: Using an internet-based data collection tool, RIO, certified athletic trainers (ATs) from 100 nationally representative US high schools reported athletic exposure and football injury data during the 2005-06 to 2009-10 academic years. RESULTS: Participating ATs reported 10,100 football injuries corresponding to an estimated 2,739,187 football-related injuries nationally. The injury rate was 4.08 per 1000 athlete-exposures (AEs) overall. Offensive lineman collectively (center, offensive guard, offensive tackle) sustained 18.3% of all injuries. Running backs (16.3%) sustained more injuries than any other position followed by linebackers (14.9%) and wide receivers (11.9%). The leading mechanism of injury was player-player contact (64.0%) followed by player-surface contact (13.4%). More specifically, injury occurred most commonly when players were being tackled (24.4%) and tackling (21.8%). CONCLUSIONS: Patterns of football injuries vary by position. Identifying such differences is important to drive development of evidence-based, targeted injury prevention efforts. PMID- 22821942 TI - Coronary microvascular dysfunction induced by primary hyperparathyroidism is restored after parathyroidectomy. AB - BACKGROUND: Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality. However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset. METHODS AND RESULTS: We studied 100 PHPT patients (80 women; age, 58+/-12 years) without cardiovascular disease and 50 control subjects matched for age and sex. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. CFR was lower in PHPT patients than in control subjects (3.0+/-0.8 versus 3.8+/-0.7; P<0.0001) and was abnormal (<=2.5) in 27 patients (27%) compared with control subjects (4%; P=0.0008). CFR was inversely related to parathyroid hormone (PTH) levels (r=-0.3, P<0.004). In patients with CFR <=2.5, PTH was higher (26.4 pmol/L [quartiles 1 and 3, 16 and 37 pmol/L] versus 18 [13-25] pmol/L; P<0.007), whereas calcium levels were similar (2.9+/-0.1 versus 2.8+/-0.3 mmol/L; P=0.2). In multivariable linear regression analysis, PTH, age, and heart rate were the only factors associated with CFR (P=0.04, P=0.01, and P=0.006, respectively). In multiple logistic regression analysis, only PTH increased the probability of CFR <=2.5 (P=0.03). In all PHPT patients with CFR <=2.5, parathyroidectomy normalized CFR (3.3+/-0.7 versus 2.1+/-0.5; P<0.0001). CONCLUSIONS: PHPT patients have coronary microvascular dysfunction that is completely restored after parathyroidectomy. PTH independently correlates with the coronary microvascular impairment, suggesting a crucial role of the hormone in explaining the increased cardiovascular risk in PHPT. PMID- 22821943 TI - Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. AB - BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH >=10 and <0.10 mIU/L. PMID- 22821944 TI - Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. AB - Although hepatic encephalopathy (HE) is linked to the gut microbiota, stool microbiome analysis has not found differences between HE and no-HE patients. This study aimed to compare sigmoid mucosal microbiome of cirrhotic patients to controls, between HE vs. no-HE patients, and to study their linkage with cognition and inflammation. Sixty cirrhotic patients (36 HE and 24 no-HE) underwent cognitive testing, stool collection, cytokine (Th1, Th2, Th17, and innate immunity), and endotoxin analysis. Thirty-six patients (19 HE and 17 no HE) and 17 age-matched controls underwent sigmoid biopsies. Multitag pyrosequencing (including autochthonous genera, i.e., Blautia, Roseburia, Fecalibacterium, Dorea) was performed on stool and mucosa. Stool and mucosal microbiome differences within/between groups and correlation network analyses were performed. Controls had significantly higher autochthonous and lower pathogenic genera compared with cirrhotic patients, especially HE patients. HE patients had worse MELD (model for end-stage liver disease) score and cognition and higher IL-6 and endotoxin than no-HE. Mucosal microbiota was different from stool within both HE/no-HE groups. Between HE/no-HE patients, there was no difference in stool microbiota but mucosal microbiome was different with lower Roseburia and higher Enterococcus, Veillonella, Megasphaera, and Burkholderia abundance in HE. On network analysis, autochthonous genera (Blautia, Fecalibacterium, Roseburia, and Dorea) were associated with good cognition and decreased inflammation in both HE/no-HE, whereas genera overrepresented in HE (Enterococcus, Megasphaera, and Burkholderia) were linked to poor cognition and inflammation. Sigmoid mucosal microbiome differs significantly from stool microbiome in cirrhosis. Cirrhotic, especially HE, patients' mucosal microbiota is significantly different from controls with a lack of potentially beneficial autochthonous and overgrowth of potentially pathogenic genera, which are associated with poor cognition and inflammation. PMID- 22821945 TI - CD18 is required for optimal lymphopenia-induced proliferation of mouse T cells. AB - Lymphocyte numbers are tightly regulated; with acute lymphopenia, T cell numbers are reestablished through lymphopenia-induced proliferation. In contrast to the costimulation requirements of antigen-driven proliferation, a number of costimulatory molecules are not required for lymphopenia-induced proliferation. However, the requirement for major histocompatibility complex (MHC)-T cell receptor (TCR) interactions and the enhanced lymphopenia-induced proliferation in T cells with higher TCR affinity argue for a role for surface molecules that contribute to efficient MHC-TCR interactions, in particular adhesion molecules. CD18 is an integrin that contributes to the activation of peripheral and intestinal T cells through adhesive and costimulatory mechanisms. We found that CD18 is required for optimal polyclonal and monoclonal CD4+ T cell lymphopenia induced proliferation in recombination-activating gene 1-deficient (RAG-1-/-) mice; this requirement persisted over time. Uniquely, the dependency on CD18 in CD4+ T cells is in the rapid proliferation in RAG-1-/- recipients and in the slow homeostatic proliferation in irradiated Balb/c recipients. Consistent with the proposed role for intestinal microbiota in lymphopenia-induced rapid proliferation in RAG-/- mice, we observed a significant reduction in rapid proliferation upon treatment of mice with antibiotics; however, the dependency on CD18 for optimal lymphopenia-induced proliferation persisted. Moreover, the dependency for CD18 is maintained over a wide range of numbers of initially transferred T cells, including a low number of initially transferred T cells, when the drive for proliferation is very strong and proliferation is more rapid. Overall, these data argue for an essential and broad role for CD18 in lymphopenia induced proliferation. PMID- 22821946 TI - Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation. AB - The premature activation of digestive enzyme zymogens in the pancreatic acinar cell is an important initiating event in acute pancreatitis. We have previously demonstrated that vacuolar ATPase (vATPase) activity is required for zymogen activation. Adenosine monophosphate-activated protein kinase (AMPK) regulates vATPase function in kidney and epididymal clear cells. To determine whether AMPK could affect pancreatitis responses, its effects were first examined in a cellular model of pancreatitis, cerulein-hyperstimulated (100 nM) pancreatic acini. This treatment caused a prominent increase in trypsin and chymotrypsin activities. Pretreatment with AICAR or metformin (AMPK activators) or compound C (an AMPK inhibitor) reduced or increased cerulein-induced zymogen activation, respectively. The association of the vATPase E subunit with membranes, a marker of its activation, tended to be inversely related to AMPK activity (assessed by AICAR and compound C treatments). Cerulein treatment did not change AMPK (alpha and beta) levels but did lead to an increase in its activation (phosphorylation of Thr172) and induced the time-dependent translocation of the enzyme to a Triton insoluble compartment. Basal in vivo studies showed that AMPK was widely distributed between membrane and soluble fractions generated by differential centrifugation. After cerulein hyperstimulation, AMPK levels selectively decreased in fractions containing the highest levels of active zymogens. These studies suggest that AMPK activity has a protective role in the pancreatic acinar cell that inhibits zymogen activation in the basal state, and this AMPK effect is reduced during pancreatitis. Therapies that prevent the selective reduction of AMPK in compartments that support zymogen activation could reduce injury during pancreatitis. PMID- 22821947 TI - Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum. AB - Intestinal endocrine cells release gut hormones, including glucagon-like peptides (GLPs), in response to luminal nutrients. Luminal L-glutamate (L-Glu) and 5' inosine monophosphate (IMP) synergistically increases duodenal HCO3- secretion via GLP-2 release. Since L cells express the bile acid receptor TGR5 and dipeptidyl peptidase (DPP) IV rapidly degrades GLPs, we hypothesized that luminal amino acids or bile acids stimulate duodenal HCO3- secretion via GLP-2 release, which is enhanced by DPPIV inhibition. We measured HCO3- secretion with pH and CO2 electrodes using a perfused rat duodenal loop under isoflurane anesthesia. L Glu (10 mM) and IMP (0.1 mM) were luminally coperfused with or without luminal perfusion (0.1 mM) or intravenous (iv) injection (3 MUmol/kg) of the DPPIV inhibitor NVP728. The loop was also perfused with a selective TGR5 agonist betulinic acid (BTA, 10 MUM) or the non-bile acid type TGR5 agonist 3-(2 chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide (CCDC; 10 MUM). DPPIV activity visualized by use of the fluorogenic substrate was present on the duodenal brush border and submucosal layer, both abolished by the incubation with NVP728 (0.1 mM). An iv injection of NVP728 enhanced L-Glu/IMP induced HCO3- secretion, whereas luminal perfusion of NVP728 had no effect. BTA or CCDC had little effect on HCO3- secretion, whereas NVP728 iv markedly enhanced BTA- or CCDC-induced HCO3- secretion, the effects inhibited by a GLP-2 receptor antagonist. Coperfusion of the TGR5 agonist enhanced L-Glu/IMP-induced HCO3- secretion with the enhanced GLP-2 release, suggesting that TGR5 activation amplifies nutrient sensing signals. DPPIV inhibition potentiated luminal L Glu/IMP-induced and TGR5 agonist-induced HCO3- secretion via a GLP-2 pathway, suggesting that the modulation of the local concentration of the endogenous secretagogue GLP-2 by luminal compounds and DPPIV inhibition helps regulate protective duodenal HCO3- secretion. PMID- 22821948 TI - Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis. AB - Pomegranate seed oil (PSO), which is the major source of conjugated linolenic acids such as punicic acid (PuA), exhibits strong anti-inflammatory properties. Necrotizing enterocolitis (NEC) is a devastating disease associated with severe and excessive intestinal inflammation. The aim of this study was to evaluate the effects of orally administered PSO on the development of NEC, intestinal epithelial proliferation, and cytokine regulation in a rat model of NEC. Premature rats were divided into three groups: dam fed (DF), formula-fed rats (FF), or rats fed with formula supplemented with 1.5% of PSO (FF + PSO). All groups were exposed to asphyxia/cold stress to induce NEC. Intestinal injury, epithelial cell proliferation, cytokine production, and trefoil factor 3 (Tff3) production were evaluated in the terminal ileum. Oral administration of PSO (FF+PSO) decreased the incidence of NEC from 61 to 26%. Feeding formula with PSO improved enterocyte proliferation in the site of injury. Increased levels of proinflammatory IL-6, IL-8, IL-12, IL-23, and TNF-alpha in the ileum of FF rats were normalized in PSO-treated animals. Tff3 production in the FF rats was reduced compared with DF but not further affected by the PSO. In conclusion, administration of PSO protects against NEC in the neonatal rat model. This protective effect is associated with an improvement of intestinal epithelial homeostasis and a strong anti-inflammatory effect of PSO on the developing intestinal mucosa. PMID- 22821951 TI - Comparison of GT3X accelerometer and YAMAX pedometer steps/day in a free-living sample of overweight and obese adults. AB - BACKGROUND: The purpose of this study was to compare steps/day detected by the YAMAX SW-200 pedometer versus the Actigraph GT3X accelerometer in free-living adults. METHODS: Daily YAMAX and GT3X steps were collected from a sample of 23 overweight and obese participants (78% female; age = 52.6 +/- 8.4 yr.; BMI = 31.0 +/- 3.7 m.kg-2). Because a pedometer is more likely to be used in a community based intervention program, it was used as the standard for comparison. Percent difference (PD) and absolute percent difference (APD) were calculated to examine between-instrument agreement. In addition, days were categorized based on PD: a) under-counting (> -10 PD), b) acceptable counting (-10 to 10 PD), and c) over counting (> 10 PD). RESULTS: The YAMAX and GT3X detected 8,025 +/- 3,967 and 7131 +/- 3066 steps/day, respectively, and the outputs were highly correlated (r = .87). Average PD was -3.1% +/- 30.7% and average APD was 23.9% +/- 19.4%. Relative to the YAMAX, 53% of the days detected by the GT3X were classified as under-counting, 25% acceptable counting, and 23% over-counting. CONCLUSION: Although the output of these 2 instruments is highly correlated, caution is advised when directly comparing or using their output interchangeably. PMID- 22821953 TI - Prediction of maximal oxygen uptake from a 3-minute walk based on gender, age, and body composition. AB - BACKGROUND: The purpose was to develop new maximal oxygen uptake (VO2max) prediction models using a perceptually regulated 3-minute walk test. METHODS: VO2max was measured with a maximal incremental cycle test in 283 Japanese adults. A 3-minute walk test was conducted at a self-regulated intensity corresponding to ratings of perceived exertion (RPE) 13. RESULTS: A 3-minute walk distance (3MWD) was significantly related to VO2max (r = .60, P < .001). Three prediction models were developed by multiple regression to estimate VO2max using data on gender, age, 3MWD, and either BMI [BMI model, multiple correlation coefficients (R) = .78, standard error of estimate (SEE) = 5.26 ml.kg-1.min-1], waist circumference (WC model, R = .80, SEE = 5.04 ml.kg-1.min-1), or body fat percentage (%Fat model, R = .84, SEE = 4.57 ml.kg-1.min-1), suggesting that the %Fat model is the best model [VO2max = 37.501 + 0.463 * Gender (0 = women, 1 = men) - 0.195 * Age - 0.589 * %Fat + 0.053 * 3MWD]. Cross-validation by using the predicted residual sum of squares (PRESS) procedures demonstrated a high level of cross-validity of all prediction models. CONCLUSIONS: The new VO2max prediction models are reasonably applicable to estimating VO2max in Japanese adults and represent a quick, low-risk, and convenient means for estimating VO2max in the field. PMID- 22821949 TI - Medicinal lavender modulates the enteric microbiota to protect against Citrobacter rodentium-induced colitis. AB - Inflammatory bowel disease, inclusive of Crohn's disease and ulcerative colitis, consists of immunologically mediated disorders involving the microbiota in the gastrointestinal tract. Lavender oil is a traditional medicine used to relieve many gastrointestinal disorders. The goal of this study was to examine the therapeutic effects of the essential oil obtained from a novel lavender cultivar, Lavandula*intermedia cultivar Okanagan lavender (OLEO), in a mouse model of acute colitis caused by Citrobacter rodentium. In colitic mice, oral gavage with OLEO resulted in less severe disease, including decreased morbidity and mortality, reduced intestinal tissue damage, and decreased infiltration of neutrophils and macrophages, with reduced levels of TNF-alpha, IFN-gamma, IL-22, macrophage inflammatory protein-2alpha, and inducible nitric oxide synthase expression. This was associated with increased levels of regulatory T cell populations compared with untreated colitic mice. Recently, we demonstrated that the composition of the enteric microbiota affects susceptibility to C. rodentium-induced colitis. Here, we found that oral administration of OLEO induced microbiota enriched with members of the phylum Firmicutes, including segmented filamentous bacteria, which are known to protect against the damaging effects of C. rodentium. Additionally, during infection, OLEO treatment promoted the maintenance of microbiota loads, with specific increases in Firmicutes bacteria and decreases in gamma Proteobacteria. We observed that Firmicutes bacteria were intimately associated with the apical region of the intestinal epithelial cells during infection, suggesting that their protective effect was through contact with the gut wall. Finally, we show that OLEO inhibited C. rodentium growth and adherence to Caco-2 cells, primarily through the activities of 1,8-cineole and borneol. These results indicate that while OLEO promoted Firmicutes populations, it also controlled pathogen load through antimicrobial activity. Overall, our results reveal that OLEO can protect against colitis through the microbial-immunity nexus and that a pharmacological agent, in this case OLEO, alters the normal enteric microbiota. PMID- 22821954 TI - County-level effects of green space access on physical activity. AB - BACKGROUND: Parks and other forms of green space are among the key environmental supports for recreational physical activity. Measurements of green space access have provided mixed results as to the influence of green space access on physical activity. METHODS: This cross-sectional study uses a geographical information system (GIS) to examine the relationships between the amount of and distance to green space and county-level (n = 67) moderate and vigorous physical activity (MVPA) in the state of Florida. RESULTS: The gross amount of green space in a county (P < .05) and the amount of green space within defined distances of where people live (1/4 mile, P < .01; 1/2 mile, P < .05; 1 mile, P < .01) were positively associated with self-reported levels of MVPA. Distance to the nearest green space and the amount of green space furthest from where people live (10 miles) were not significantly associated with MVPA. All measures were weighted by the population living in census tracts. CONCLUSIONS: The results suggest that there is an association between the accessibility created by having more green space closer to home and MVPA, but this holds only for areas up to and including 1 mile from home. PMID- 22821955 TI - Relation of aortic calcification, wall thickness, and distensibility with severity of coronary artery disease: evaluation with coronary CT angiography. AB - BACKGROUND: Three known risk factors for aortic atherosclerosis predict the severity of coronary artery disease (CAD): aortic calcification (AC), aortic wall thickness (AWT), and aortic distensibility (AD). PURPOSE: To determine the relationship of AC, AWT, and AD with the severity of CAD. MATERIAL AND METHODS: A total of 104 patients who underwent both coronary CT angiography (CCTA) and invasive coronary angiography were enrolled. The severity of CAD was assessed by three methods: the segment involvement score (SIS), the segment stenosis score (SSS), and the modified Gensini score (mG). We quantified AC using the Agatston method on low-dose ungated chest CT (LDCT). We measured AWT at the thickest portion of the descending thoracic aorta on CCTA. AD was calculated as the difference between the maximum and minimum areas of the ascending aorta and the pulse pressure. The relationships between the severity of CAD and the three aortic factors were assessed. RESULTS: The AC and AWT of the thoracic aorta were significantly higher in the occlusive CAD (OCAD) group (1984.21 +/- 2986.10 vs. 733.00 +/- 1648.71, P = 0.01; 4.13 +/- 1.48 vs. 3.40 +/- 1.01, P = 0.22). Patients with OCAD had more than one epicardial coronary artery with >50% luminal stenosis. The AC (r = 0.453 with SIS; r = 0.454 with SSS; r = 0.427 with mG) and the AWT (r = 0.279 with SIS; r = 0.324 with SSS; r = 0.304 with mG) were significantly correlated with all three methods, and the AD was negatively correlated with the SIS (r = - 0.221, P < 0.05, respectively) in the unadjusted model. After adjustment for cardiovascular risk factors, only the correlations between AC and all three methods assessing CAD remained significant. CONCLUSION: There are significant relationships between AC, AWT and AD and severity of CAD. In particular, AC measured on LDCT is the most consistent predictor of severity of CAD. PMID- 22821956 TI - Introducer curving technique to reduce tilting of transfemoral Gunther Tulip IVC filter: in vitro study. AB - BACKGROUND: Severe tilting of Gunther Tulip filter (GTF) may be associated with difficulty in retrieval. PURPOSE: To determine if an introducer curving technique of GTF can decrease the tilting degree of GTF in a caval model. MATERIAL AND METHODS: The model was constructed by placing Dacron grafts in bifurcated glass tubes. The study included three groups: Right Straight Group (G(1)), Left Straight Group (G(2)), and Left Curved Group (G(3)). In G(3), a 10-20 degrees angle was curved on the metal introducer before insertion to decrease the angle between inferior vena cava axes and metal introducer (A(CM)). Before GTF was released, the distance between the caval right wall and the apical hook (D(CH1)), and A(CM) were measured. The tilt angle of GTF (A(CF)) was also measured. RESULTS: In G(1), GTF apex tended to center compared to G(2) (59% vs. 36%, P < 0.01). In G(3), GTF apex tended to center compared to G(2) (71% vs. 36%, P < 0.01). The differences of A(CF) between G(1) and G(2) (2.66 +/- 1.80 vs. 4.13 +/- 2.07, P < 0.01) and between G(2) and G(3) (4.13 +/- 2.07 vs. 2.39 +/- 1.79, P < 0.01) were statistically significant. There were significant positive correlations between A(CM) and A(CF), whereas significant negative correlations were detected between D(CH1) and A(CF) in each group. CONCLUSION: The oblique course of GTF delivery system relative to the axis of the cava causes filter tilt, and thus, curving the introducer prior to its introduction helps to reduce the filter tilt. We recommend a clinical study to determine whether the introducer curving technique improves filter centering and its retrievability. PMID- 22821957 TI - Detection of flat colorectal polyps at screening CT colonography in comparison with conventional polypoid lesions. AB - BACKGROUND: Although the screening of small, flat polyps is clinically important, the role of CT colonography (CTC) screening in their detection has not been thoroughly investigated. PURPOSE: To evaluate the detection capability and usefulness of CTC in the screening of flat and polypoid lesions by comparing CTC with optic colonoscopy findings as the gold standard. MATERIAL AND METHODS: We evaluated the CTC detection capability for flat colorectal polyps with a flat surface and a height not exceeding 3 mm (n = 42) by comparing to conventional polypoid lesions (n = 418) according to the polyp diameter. Four types of reconstruction images including multiplanar reconstruction, volume rendering, virtual gross pathology, and virtual endoscopic images were used for visual analysis. We compared the abilities of the four reconstructions for polyp visualization. RESULTS: Detection sensitivity for flat polyps was 31.3%, 44.4%, and 87.5% for lesions measuring 2-3 mm, 4-5 mm, and >=6 mm, respectively; the corresponding sensitivity for polypoid lesions was 47.6%, 79.0%, and 91.7%. The overall sensitivity for flat lesions (47.6%) was significantly lower than polypoid lesions (64.1%). Virtual endoscopic imaging showed best visualization among the four reconstructions. Colon cancers were detected in eight patients by optic colonoscopy, and CTC detected colon cancers in all eight patients. CONCLUSION: CTC using 64-row multidetector CT is useful for colon cancer screening to detect colorectal polyps while the detection of small, flat lesions is still challenging. PMID- 22821958 TI - Survey of pediatric MDCT radiation dose from university hospitals in Thailand: a preliminary for national dose survey. AB - BACKGROUND: Increasing pediatric CT usage worldwide needs the optimization of CT protocol examination. Although there are previous published dose reference level (DRL) values, the local DRLs should be established to guide for clinical practice and monitor the CT radiation. PURPOSE: To determine the multidetector CT (MDCT) radiation dose in children in three university hospitals in Thailand in four age groups using the CT dose index (CTDI) and dose length product (DLP). MATERIAL AND METHODS: A retrospective review of CT dosimetry in pediatric patients (<15 years of age) who had undergone head, chest, and abdominal MDCT in three major university hospitals in Thailand was performed. Volume CTDI (CTDI(vol)) and DLP were recorded, categorized into four age groups: <1 year, 1-< 5 years, 5-<10 years, and 10-<15 years in each scanner. Range, mean, and third quartile values were compared with the national reference dose levels for CT in pediatric patients from the UK and Switzerland according to International Commission on Radiological Protection (ICRP) recommendation. Results Per age group, the third quartile values for brain, chest, and abdominal CTs were, respectively, in terms of CTDI(vol): 25, 30, 40, and 45 mGy; 4.5, 5.7, 10, and 15.6 mGy; 8.5, 9, 14, and 17 mGy; and in terms of DLP: 400, 570, 610, and 800 mGy cm; 80, 140, 305, and 470 mGy cm; and 190, 275, 560,765 mGy cm. CONCLUSION: This preliminary national dose survey for pediatric CT in Thailand found that the majority of CTDI(vol) and DLP values in brain, chest, and abdominal CTs were still below the diagnostic reference levels (DRLs) from the UK and Switzerland regarding to ICRP recommendation. PMID- 22821959 TI - A new manganese-based oral contrast agent (CMC-001) for liver MRI: pharmacological and pharmaceutical aspects. AB - Manganese is one of the most abundant metals on earth and is found as a component of more than 100 different minerals. Besides being an essential trace element in relation to the metabolic processes in the body, manganese is also a paramagnetic metal that possesses similar characteristics to gadolinium with regards to T1 weighted (T1-w) magnetic resonance imaging (MRI). Manganese, in the form of manganese (II) chloride tetrahydrate, is the active substance in a new targeted oral contrast agent, currently known as CMC-001, indicated for hepatobiliary MRI. Under physiological circumstances manganese is poorly absorbed from the intestine after oral intake, but by the use of specific absorption promoters, L-alanine and vitamin D(3), it is possible to obtain a sufficiently high concentration in the liver in order to achieve a significant signal enhancing effect. In the liver manganese is exposed to a very high first-pass effect, up to 98%, which prevents the metal from reaching the systemic circulation, thereby reducing the number of systemic side-effects. Manganese is one of the least toxic trace elements, and due to its favorable safety profile it may be an attractive alternative to gadolinium-based contrast agents for patients undergoing an MRI evaluation for liver metastases in the future. In this review the basic pharmacological and pharmaceutical aspects of this new targeted oral hepatobiliary specific contrast agent will be discussed. PMID- 22821960 TI - Acquisition of MHC:peptide complexes by dendritic cells contributes to the generation of antiviral CD8+ T cell immunity in vivo. AB - There is an increasing body of evidence suggesting that the transfer of preformed MHC class I:peptide complexes between a virus-infected cell and an uninfected APC, termed cross-dressing, represents an important mechanism of Ag presentation to CD8+ T cells in host defense. However, although it has been shown that memory CD8+ T cells can be activated by uninfected dendritic cells (DCs) cross-dressed by Ag from virus-infected parenchymal cells, it is unknown whether conditions exist during virus infection in which naive CD8+ T cells are primed and differentiate to cytolytic effectors through cross-dressing, and indeed which DC subset would be responsible. In this study, we determine whether the transfer of MHC class I:peptide complexes between infected and uninfected murine DC plays a role in CD8+ T cell priming to viral Ags in vivo. We show that MHC class I:peptide complexes from peptide-pulsed or virus-infected DCs are indeed acquired by splenic CD8alpha- DCs in vivo. Furthermore, the acquired MHC class I:peptide complexes are functional in that they induced Ag-specific CD8+ T cell effectors with cytolytic function. As CD8alpha- DCs are poor cross-presenters, this may represent the main mechanism by which CD8alpha- DCs present exogenously encountered Ag to CD8+ T cells. The sharing of Ag as preformed MHC class I:peptide complexes between infected and uninfected DCs without the restraints of Ag processing may have evolved to accurately amplify the response and also engage multiple DC subsets critical in the generation of strong antiviral immunity. PMID- 22821961 TI - The bone marrow functions as the central site of proliferation for long-lived NK cells. AB - NK cells play an important role in the early defense against invading pathogens. Although it is well established that infection leads to a substantial, local increase in NK cell numbers, little is known about the mechanisms that trigger their proliferation and migration. In this study, we investigated the dynamics of NK cell responses after intranasal respiratory virus infection. We show that NK cell numbers increased in the airways after influenza virus infection but find no evidence of proliferation either at the site of infection or in the draining lymph nodes. Instead, we find that the bone marrow (BM) is the primary site of proliferation of both immature and mature NK cells during infection. Using an adoptive transfer model, we demonstrate that peripheral, long-lived and phenotypically mature NK cells migrate back to the BM and proliferate there, both homeostatically and in response to infection. Thus, the BM is not only a site of NK cell development but also an important site for proliferation of long-lived mature NK cells. PMID- 22821962 TI - Cytokine secretion by CD4+ T cells at the immunological synapse requires Cdc42 dependent local actin remodeling but not microtubule organizing center polarity. AB - Cytokine secretion by T lymphocytes plays a central role in mounting adaptive immune responses. However, little is known about how newly synthesized cytokines, once produced, are routed within T cells and about the mechanisms involved in regulating their secretions. In this study, we investigated the role of cytoskeleton remodeling at the immunological synapse (IS) in cytokine secretion. We show that a key regulator of cytoskeleton remodeling, the Rho GTPase Cdc42, controls IFN-gamma secretion by primary human CD4+ T lymphocytes. Surprisingly, microtubule organizing center polarity at the IS, which does not depend on Cdc42, is not required for cytokine secretion by T lymphocytes, whereas microtubule polymerization is required. In contrast, actin remodeling at the IS, which depends on Cdc42, controls the formation of the polymerized actin ring at the IS, the dynamic concentration of IFN-gamma-containing vesicles inside this ring, and the secretion of these vesicles. These results reveal a previously unidentified role of Cdc42-dependent actin remodeling in cytokine exocytosis at the IS. PMID- 22821964 TI - Negative impact of IFN-gamma on early host immune responses to retroviral infection. AB - The immune system is tasked with defending against a myriad of microbial infections, and its response to a given infectious microbe may be strongly influenced by coinfection with another microbe. It was shown that infection of mice with lactate dehydrogenase-elevating virus (LDV) impairs early adaptive immune responses to Friend virus (FV) coinfection. To investigate the mechanism of this impairment, we examined LDV-induced innate immune responses and found LDV specific induction of IFN-alpha and IFN-gamma. LDV-induced IFN-alpha had little effect on FV infection or immune responses, but unexpectedly, LDV-induced IFN gamma production dampened Th1 adaptive immune responses and enhanced FV infection. Two distinct effects were identified. First, LDV-induced IFN-gamma signaling indirectly modulated FV-specific CD8+ T cell responses. Second, intrinsic IFN-gamma signaling in B cells promoted polyclonal B cell activation and enhanced early FV infection, despite promotion of germinal center formation and neutralizing Ab production. Results from this model reveal that IFN-gamma production can have detrimental effects on early adaptive immune responses and virus control. PMID- 22821963 TI - CD8+CD45RA+CCR7+FOXP3+ T cells with immunosuppressive properties: a novel subset of inducible human regulatory T cells. AB - CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-15 retain a naive phenotype with expression of CD45RA, CD28, CD27, and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8+CCR7+ regulatory T cells (Tregs) express FOXP3 and prevent CD4 T cells from responding to TCR stimulation and entering the cell cycle. Naive CD4 T cells are more susceptible to inhibition than memory cells. The suppressive activity of CD8+CCR7+ Tregs is not mediated by IL-10, TGF-beta, CTLA-4, CCL4, or adenosine and relies on interference with very early steps of the TCR signaling cascade. Specifically, CD8+CCR7+ Tregs prevent TCR-induced phosphorylation of ZAP70 and dampen the rise of intracellular calcium in CD4 T cells. The inducibility of CD8+CCR7+ Tregs is correlated with the age of the individual with PBLs of donors older than 60 y yielding low numbers of FOXP3(low) CD8 Tregs. Loss of CD8+CCR7+ Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation. PMID- 22821965 TI - Practice observed. PMID- 22821966 TI - Rethinking the evolution of single-stranded RNA (ssRNA) bacteriophages based on genomic sequences and characterizations of two R-plasmid-dependent ssRNA phages, C-1 and Hgal1. AB - We have sequenced and characterized two R-plasmid-dependent single-stranded RNA bacteriophages (RPD ssRNA phages), C-1 and Hagl1. Phage C-1 requires a conjugative plasmid of the IncC group, while Hgal1 requires the IncH group. Both the adsorption rate constants and one-step growth curves are determined for both phages. We also empirically confirmed the lysis function of the predicted lysis genes. Genomic sequencing and phylogenetic analyses showed that both phages belong to the Levivirus group and are most closely related to another IncP plasmid-dependent ssRNA phage, PRR1. Furthermore, our result strongly suggests that the stereotypical bauplans of genome organization found in Levivirus and Allolevivirus predate phage specialization for conjugative plasmids, suggesting that the utilization of conjugative plasmids for cell attachment and entry comprises independent evolutionary events for these two main clades of ssRNA phages. Our result is also consistent with findings of a previous study, making the Levivirus-like genome organization ancestral and the Allolevivirus-like genome derived. To obtain a deeper insight into the evolution of ssRNA phages, more phages specializing for various conjugative plasmids and infecting different bacterial species would be needed. PMID- 22821967 TI - Evidence for cyclic Di-GMP-mediated signaling in Bacillus subtilis. AB - Cyclic di-GMP (c-di-GMP) is a second messenger that regulates diverse cellular processes in bacteria, including motility, biofilm formation, cell-cell signaling, and host colonization. Studies of c-di-GMP signaling have chiefly focused on Gram-negative bacteria. Here, we investigated c-di-GMP signaling in the Gram-positive bacterium Bacillus subtilis by constructing deletion mutations in genes predicted to be involved in the synthesis, breakdown, or response to the second messenger. We found that a putative c-di-GMP-degrading phosphodiesterase, YuxH, and a putative c-di-GMP receptor, YpfA, had strong influences on motility and that these effects depended on sequences similar to canonical EAL and RxxxR D/NxSxxG motifs, respectively. Evidence indicates that YpfA inhibits motility by interacting with the flagellar motor protein MotA and that yuxH is under the negative control of the master regulator Spo0A~P. Based on these findings, we propose that YpfA inhibits motility in response to rising levels of c-di-GMP during entry into stationary phase due to the downregulation of yuxH by Spo0A~P. We also present evidence that YpfA has a mild influence on biofilm formation. In toto, our results demonstrate the existence of a functional c-di-GMP signaling system in B. subtilis that directly inhibits motility and directly or indirectly influences biofilm formation. PMID- 22821969 TI - Virulence or niche factors: what's in a name? AB - The increasing interest in the human microbiota raises some interesting questions about the terminology we use to describe some of the structures and strategies employed by commensal and pathogenic microbes to compete in these complex biological ecosystems. For example, all microbes arriving in the alimentary tract face the task of surviving passage through the stomach, coping with bile, interacting with the immune system, competing with the established microbiota, and obtaining sufficient nutrients to gain a foothold in this hostile environment. It is not surprising then that many gastrointestinal microbes (both pathogens and commensals) use similar strategies to overcome the challenges associated with this particular biological niche. Given that many of these structures and strategies were discovered and characterized in pathogens and because they often play important roles in establishing and maintaining an infection, they have often been characterized as virulence factors. It would be misleading to describe the same strategies and structures found in harmless commensals as "virulence factors," since they represent a sine qua non for life in the gastrointestinal tract. It may be time to reconsider and refer to them as "niche factors," both in terms of providing scientific accuracy but also in light of the growing interest in using gut microbes as probiotics, where the distinction between virulence factors and niche factors is likely to be very important from a regulatory perspective. PMID- 22821968 TI - Characterization of the organic hydroperoxide resistance system of Brucella abortus 2308. AB - The organic hydroperoxide resistance protein Ohr has been identified in numerous bacteria where it functions in the detoxification of organic hydroperoxides, and expression of ohr is often regulated by a MarR-type regulator called OhrR. The genes annotated as BAB2_0350 and BAB2_0351 in the Brucella abortus 2308 genome sequence are predicted to encode OhrR and Ohr orthologs, respectively. Using isogenic ohr and ohrR mutants and lacZ promoter fusions, it was determined that Ohr contributes to resistance to organic hydroperoxide, but not hydrogen peroxide, in B. abortus 2308 and that OhrR represses the transcription of both ohr and ohrR in this strain. Moreover, electrophoretic mobility shift assays and DNase I footprinting revealed that OhrR binds directly to a specific region in the intergenic region between ohr and ohrR that shares extensive nucleotide sequence similarity with so-called "OhrR boxes" described in other bacteria. While Ohr plays a prominent role in protecting B. abortus 2308 from organic hydroperoxide stress in in vitro assays, this protein is not required for the wild-type virulence of this strain in cultured murine macrophages or experimentally infected mice. PMID- 22821970 TI - The primosomal protein DnaD inhibits cooperative DNA binding by the replication initiator DnaA in Bacillus subtilis. AB - DnaA is an AAA+ ATPase and the conserved replication initiator in bacteria. Bacteria control the timing of replication initiation by regulating the activity of DnaA. DnaA binds to multiple sites in the origin of replication (oriC) and is required for recruitment of proteins needed to load the replicative helicase. DnaA also binds to other chromosomal regions and functions as a transcription factor at some of these sites. Bacillus subtilis DnaD is needed during replication initiation for assembly of the replicative helicase at oriC and during replication restart at stalled replication forks. DnaD associates with DnaA at oriC and at other chromosomal regions bound by DnaA. Using purified proteins, we found that DnaD inhibited the ability of DnaA to bind cooperatively to DNA and caused a decrease in the apparent dissociation constant. These effects of DnaD were independent of the ability of DnaA to bind or hydrolyze ATP. Other proteins known to regulate B. subtilis DnaA also affect DNA binding, whereas much of the regulation of Escherichia coli DnaA affects nucleotide hydrolysis or exchange. We found that the rate of nucleotide exchange for B. subtilis DnaA was high and not affected by DnaD. The rapid exchange is similar to that of Staphylococcus aureus DnaA and in contrast to the low exchange rate of Escherichia coli DnaA. We suggest that organisms in which DnaA has a high rate of nucleotide exchange predominantly regulate the DNA binding activity of DnaA and that those with low rates of exchange regulate hydrolysis and exchange. PMID- 22821971 TI - Basis for the essentiality of H-NS family members in Pseudomonas aeruginosa. AB - Members of the histone-like nucleoid-structuring (H-NS) family of proteins have been shown to play important roles in silencing gene expression and in nucleoid compaction. In Pseudomonas aeruginosa, the two H-NS family members MvaT and MvaU are thought to bind the same AT-rich regions of the chromosome and function coordinately to control a common set of genes. Here we present evidence that the loss of both MvaT and MvaU cannot be tolerated because it results in the production of Pf4 phage that superinfect and kill cells or inhibit their growth. Using a ClpXP-based protein depletion system in combination with transposon mutagenesis, we identify mutants of P. aeruginosa that can tolerate the depletion of MvaT in an DeltamvaU mutant background. Many of these mutants contain insertions in genes encoding components, assembly factors, or regulators of type IV pili or contain insertions in genes of the prophage Pf4. We demonstrate that cells that no longer produce type IV pili or that no longer produce the replicative form of the Pf4 genome can tolerate the loss of both MvaT and MvaU. Furthermore, we show that the loss of both MvaT and MvaU results in an increase in expression of Pf4 genes and that cells that cannot produce type IV pili are resistant to infection by Pf4 phage. Our findings suggest that type IV pili are the receptors for Pf4 phage and that the essential activities of MvaT and MvaU are to repress the expression of Pf4 genes. PMID- 22821972 TI - The small RNA RteR inhibits transfer of the Bacteroides conjugative transposon CTnDOT. AB - CTnDOT is a 65-kb conjugative transposon present in Bacteroides spp. that confers resistance to erythromycin [erm(F)] and tetracycline [tet(Q)]. An interesting feature of CTnDOT is that both excision from the chromosome and transfer of CTnDOT are stimulated by exposure to tetracycline. However, when no tetracycline is present, transfer of CTnDOT is not detectable. Previous studies suggested that a region containing a small RNA, RteR, appeared to mediate repression of CTnDOT transfer; however, virtually nothing was known about RteR. We have demonstrated that RteR is a 90-nucleotide transcript that is not further processed. RteR inhibits conjugative transfer of CTnDOT by targeting the transfer region, a 13-kb operon that encodes the tra genes required to assemble the mating apparatus. We report here that RteR interacts with the region downstream of traA. Levels of the downstream tra mRNA are dramatically reduced when RteR is present. Further, RteR does not appear to decrease the half-life of the tra mRNA transcript, suggesting that RteR does not bind to the transcript to initiate RNase-dependent decay, similar to other trans-acting small RNAs. We predict that RteR may act to enhance termination of the tra operon within traB, which could account for the decreased abundance of the tra transcript downstream of traA and explain why the tra mRNA has the same half-life whether or not RteR is present. RteR is the only small RNA that has been characterized so far within the Bacteroidetes phylum. PMID- 22821973 TI - Cell wall amidase AmiC1 is required for cellular communication and heterocyst development in the cyanobacterium Anabaena PCC 7120 but not for filament integrity. AB - Filamentous cyanobacteria of the order Nostocales display typical properties of multicellular organisms. In response to nitrogen starvation, some vegetative cells differentiate into heterocysts, where fixation of N(2) takes place. Heterocysts provide a micro-oxic compartment to protect nitrogenase from the oxygen produced by the vegetative cells. Differentiation involves fundamental remodeling of the gram-negative cell wall by deposition of a thick envelope and by formation of a neck-like structure at the contact site to the vegetative cells. Cell wall-hydrolyzing enzymes, like cell wall amidases, are involved in peptidoglycan maturation and turnover in unicellular bacteria. Recently, we showed that mutation of the amidase homologue amiC2 gene in Nostoc punctiforme ATCC 29133 distorts filament morphology and function. Here, we present the functional characterization of two amiC paralogues from Anabaena sp. strain PCC 7120. The amiC1 (alr0092) mutant was not able to differentiate heterocysts or to grow diazotrophically, whereas the amiC2 (alr0093) mutant did not show an altered phenotype under standard growth conditions. In agreement, fluorescence recovery after photobleaching (FRAP) studies showed a lack of cell-cell communication only in the AmiC1 mutant. Green fluorescent protein (GFP)-tagged AmiC1 was able to complement the mutant phenotype to wild-type properties. The protein localized in the septal regions of newly dividing cells and at the neck region of differentiating heterocysts. Upon nitrogen step-down, no mature heterocysts were developed in spite of ongoing heterocyst-specific gene expression. These results show the dependence of heterocyst development on amidase function and highlight a pivotal but so far underestimated cellular process, the remodeling of peptidoglycan, for the biology of filamentous cyanobacteria. PMID- 22821974 TI - Primer on agar-based microbial imaging mass spectrometry. AB - Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) applied directly to microbes on agar-based medium captures global information about microbial molecules, allowing for direct correlation of chemotypes to phenotypes. This tool was developed to investigate metabolic exchange factors of intraspecies, interspecies, and polymicrobial interactions. Based on our experience of the thousands of images we have generated in the laboratory, we present five steps of microbial IMS: culturing, matrix application, dehydration of the sample, data acquisition, and data analysis/interpretation. We also address the common challenges encountered during sample preparation, matrix selection and application, and sample adherence to the MALDI target plate. With the practical guidelines described herein, microbial IMS use can be extended to bio-based agricultural, biofuel, diagnostic, and therapeutic discovery applications. PMID- 22821975 TI - Cellulose degradation by Sulfolobus solfataricus requires a cell-anchored endo beta-1-4-glucanase. AB - A sequence encoding a putative extracellular endoglucanase (sso1354) was identified in the complete genome sequence of Sulfolobus solfataricus. The encoded protein shares signature motifs with members of glycoside hydrolases family 12. After an unsuccessful first attempt at cloning the full-length coding sequences in Escherichia coli, an active but unstable recombinant enzyme lacking a 27-residue N-terminal sequence was generated. This 27-amino-acid sequence shows significant similarity with corresponding regions in the sugar binding proteins AraS, GlcS, and TreS of S. solfataricus that are responsible for anchoring them to the plasma membrane. A strategy based on an effective vector/host genetic system for Sulfolobus and on expression control by the promoter of the S. solfataricus gene which encodes the glucose binding protein allowed production of the enzyme in sufficient quantities for study. In fact, the enzyme expressed in S. solfataricus was stable and highly thermoresistant and showed optimal activity at low pH and high temperature. The protein was detected mainly in the plasma membrane fraction, confirming the structural similarity to the sugar binding proteins. The results of the protein expression in the two different hosts showed that the SSO1354 enzyme is endowed with an endo-beta-1-4-glucanase activity and specifically hydrolyzes cellulose. Moreover, it also shows significant but distinguishable specificity toward several other sugar polymers, such as lichenan, xylan, debranched arabinan, pachyman, and curdlan. PMID- 22821976 TI - Identification and characterization of the functional toxboxes in the Vibrio cholerae cholera toxin promoter. AB - Following the consumption of contaminated food or water by a human host, the Vibrio cholerae bacterium produces virulence factors, including cholera toxin (CT), which directly causes voluminous diarrhea, producing cholera. A complex regulatory network controls virulence gene expression and responds to various environmental signals and transcription factors. Ultimately, ToxT, a member of the AraC/XylS transcription regulator family, is responsible for activating the transcription of the virulence genes. ToxT-regulated promoters all contain one or more copies of the toxbox, a 13-bp DNA sequence which ToxT recognizes. Nucleotides 2 through 7 of the toxbox sequence are well conserved and contain an invariant tract of four consecutive T nucleotides, whereas the remainder of the toxbox sequence is not highly conserved other than being A/T rich. The binding of ToxT to toxboxes is required to activate the transcription of virulence genes, and toxboxes in several virulence gene promoters have been characterized. However, the toxboxes required for the activation of transcription from the cholera toxin promoter PctxAB have not been identified. PctxAB contains a series of heptad repeats (GATTTTT), each of which matches the 5' end of the toxbox consensus sequence and is a potential binding site for ToxT. Using site-directed mutagenesis and high-resolution copper-phenanthroline footprinting, we have identified the functional toxboxes required for the ToxT activation of PctxAB. Our findings suggest that ToxT binds to only two toxboxes within PctxAB, despite the presence of several other potential ToxT binding sites within the promoter. Both toxboxes are essential for DNA binding and the full activation of ctxAB transcription. PMID- 22821977 TI - Characterization of a new GlnR binding box in the promoter of amtB in Streptomyces coelicolor inferred a PhoP/GlnR competitive binding mechanism for transcriptional regulation of amtB. AB - The transcription of amtB in Streptomyces coelicolor has been proposed to be counter-regulated by GlnR (a global regulator for nitrogen metabolism) and PhoP (a global regulator for phosphate metabolism). However, the GlnR-protected region, which was deduced to be two 22-bp GlnR binding boxes (gTnAc-n6-GaAAc-n6 GtnAC-n6-GAAAc-n6, abbreviated as a1-b1 and a2-b2), was separated from the PhoP protected region in the promoter of amtB, leaving the mechanism for this regulation undefined. In this study, another 22-bp GlnR binding box, which consisted of a3-site-n6-b3-site (a3-b3) overlapping with the PhoP-binding sequences, was identified in the promoter region of amtB by a DNase I footprinting assay. An electrophoretic mobility shift assay (EMSA) using purified recombinant GlnR and the synthetic amtB promoter fragments with the three GlnR binding boxes individually mutated demonstrated that every box was involved in GlnR binding in vitro. Further in vivo assays using the egfp reporter gene fused to various kinds of mutated promoter regions of amtB demonstrated that all of the three GlnR binding boxes were required for GlnR-mediated activation of amtB transcription under the nitrogen-limited condition. The results of EMSA using the amtB promoter with mixtures of recombinant His-tagged GlnR and Trx-His-S-tagged PhoP inferred that PhoP might compete against GlnR from binding at the a3-b3 site, attributable to the PhoP/GlnR counter-regulatory function subjected to further experimental proof. PMID- 22821978 TI - VirB-mediated positive feedback control of the virulence gene regulatory cascade of Shigella flexneri. AB - Shigella flexneri is a facultative intracellular pathogen that relies on a type III secretion system and its associated effector proteins to cause bacillary dysentery in humans. The genes that encode this virulence system are located on a 230-kbp plasmid and are transcribed in response to thermal, osmotic, and pH signals that are characteristic of the human lower gut. The virulence genes are organized within a regulatory cascade, and the nucleoid-associated protein H-NS represses each of the key promoters. Transcription derepression depends first on the VirF AraC-like transcription factor, a protein that antagonizes H-NS-mediated repression at the intermediate regulatory gene virB. The VirB protein in turn remodels the H-NS-DNA nucleoprotein complexes at the promoters of the genes encoding the type III secretion system and effector proteins, causing these genes to become derepressed. In this study, we show that the VirB protein also positively regulates the expression of its own gene (virB) via a cis-acting regulatory sequence. In addition, VirB positively regulates the gene coding for the VirF protein. This study reveals two hitherto uncharacterized feedback regulatory loops in the S. flexneri virulence cascade that provide a mechanism for the enhanced expression of the principal virulence regulatory genes. PMID- 22821980 TI - Will the initiator of fatty acid synthesis in Pseudomonas aeruginosa please stand up? PMID- 22821979 TI - Seventeen Sxy-dependent cyclic AMP receptor protein site-regulated genes are needed for natural transformation in Haemophilus influenzae. AB - Natural competence is the ability of bacteria to actively take up extracellular DNA. This DNA can recombine with the host chromosome, transforming the host cell and altering its genotype. In Haemophilus influenzae, natural competence is induced by energy starvation and the depletion of nucleotide pools. This induces a 26-gene competence regulon (Sxy-dependent cyclic AMP receptor protein [CRP-S] regulon) whose expression is controlled by two regulators, CRP and Sxy. The role of most of the CRP-S genes in DNA uptake and transformation is not known. We have therefore created in-frame deletions of each CRP-S gene and studied their competence phenotypes. All but one gene (ssb) could be deleted. Although none of the remaining CRP-S genes were required for growth in rich medium or survival under starvation conditions, DNA uptake and transformation were abolished or reduced in most of the mutants. Seventeen genes were absolutely required for transformation, with 14 of these genes being specifically required for the assembly and function of the type IV pilus DNA uptake machinery. Only five genes were dispensable for both competence and transformation. This is the first competence regulon for which all genes have been mutationally characterized. PMID- 22821981 TI - Hfq influences multiple transport systems and virulence in the plant pathogen Agrobacterium tumefaciens. AB - The Hfq protein mediates gene regulation by small RNAs (sRNAs) in about 50% of all bacteria. Depending on the species, phenotypic defects of an hfq mutant range from mild to severe. Here, we document that the purified Hfq protein of the plant pathogen and natural genetic engineer Agrobacterium tumefaciens binds to the previously described sRNA AbcR1 and its target mRNA atu2422, which codes for the substrate binding protein of an ABC transporter taking up proline and gamma aminobutyric acid (GABA). Several other ABC transporter components were overproduced in an hfq mutant compared to their levels in the parental strain, suggesting that Hfq plays a major role in controlling the uptake systems and metabolic versatility of A. tumefaciens. The hfq mutant showed delayed growth, altered cell morphology, and reduced motility. Although the DNA-transferring type IV secretion system was produced, tumor formation by the mutant strain was attenuated, demonstrating an important contribution of Hfq to plant transformation by A. tumefaciens. PMID- 22821982 TI - TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. AB - Host protection from infection relies on the recognition of pathogens by innate pattern-recognition receptors such as Toll-like receptors (TLRs). Here, we show that the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA (rRNA) sequence that is the binding site of macrolide, lincosamide, and streptogramin group (MLS) antibiotics (including erythromycin) in bacteria. Notably, 23S rRNA from clinical isolates of erythromycin-resistant Staphylococcus aureus and synthetic oligoribonucleotides carrying methylated adenosine or a guanosine mimicking a MLS resistance-causing modification failed to stimulate TLR13. Thus, our results reveal both a natural TLR13 ligand and specific mechanisms of antibiotic resistance as potent bacterial immune evasion strategy, avoiding recognition via TLR13. PMID- 22821983 TI - A single progenitor population switches behavior to maintain and repair esophageal epithelium. AB - Diseases of the esophageal epithelium (EE), such as reflux esophagitis and cancer, are rising in incidence. Despite this, the cellular behaviors underlying EE homeostasis and repair remain controversial. Here, we show that in mice, EE is maintained by a single population of cells that divide stochastically to generate proliferating and differentiating daughters with equal probability. In response to challenge with all-trans retinoic acid (atRA), the balance of daughter cell fate is unaltered, but the rate of cell division increases. However, after wounding, cells reversibly switch to producing an excess of proliferating daughters until the wound has closed. Such fate-switching enables a single progenitor population to both maintain and repair tissue without the need for a "reserve" slow-cycling stem cell pool. PMID- 22821984 TI - A reversible and higher-rate Li-O2 battery. AB - The rechargeable nonaqueous lithium-air (Li-O(2)) battery is receiving a great deal of interest because, theoretically, its specific energy far exceeds the best that can be achieved with lithium-ion cells. Operation of the rechargeable Li O(2) battery depends critically on repeated and highly reversible formation/decomposition of lithium peroxide (Li(2)O(2)) at the cathode upon cycling. Here, we show that this process is possible with the use of a dimethyl sulfoxide electrolyte and a porous gold electrode (95% capacity retention from cycles 1 to 100), whereas previously only partial Li(2)O(2) formation/decomposition and limited cycling could occur. Furthermore, we present data indicating that the kinetics of Li(2)O(2) oxidation on charge is approximately 10 times faster than on carbon electrodes. PMID- 22821986 TI - Earthquake in a maze: compressional rupture branching during the 2012 M(w) 8.6 Sumatra earthquake. AB - Seismological observations of the 2012 moment magnitude 8.6 Sumatra earthquake reveal unprecedented complexity of dynamic rupture. The surprisingly large magnitude results from the combination of deep extent, high stress drop, and rupture of multiple faults. Back-projection source imaging indicates that the rupture occurred on distinct planes in an orthogonal conjugate fault system, with relatively slow rupture speed. The east-southeast-west-northwest ruptures add a new dimension to the seismotectonics of the Wharton Basin, which was previously thought to be controlled by north-south strike-slip faulting. The rupture turned twice into the compressive quadrant, against the preferred branching direction predicted by dynamic Coulomb stress calculations. Orthogonal faulting and compressional branching indicate that rupture was controlled by a pressure insensitive strength of the deep oceanic lithosphere. PMID- 22821985 TI - Drosophila dosage compensation involves enhanced Pol II recruitment to male X linked promoters. AB - Through hyperacetylation of histone H4 lysine 16 (H4K16), the male-specific lethal (MSL) complex in Drosophila approximately doubles transcription from the single male X chromosome in order to match X-linked expression in females and expression from diploid autosomes. By obtaining accurate measurements of RNA polymerase II (Pol II) occupancies and short promoter-proximal RNA production, we detected a consistent, genome-scale increase in Pol II activity at the promoters of male X-linked genes. Moreover, we found that enhanced Pol II recruitment to male X-linked promoters is largely dependent on the MSL complex. These observations provide insights into how global modulation of chromatin structure by histone acetylation contributes to the precise control of Pol II function. PMID- 22821987 TI - Strategy-dependent encoding of planned arm movements in the dorsal premotor cortex. AB - The kinematic strategy encoded in motor cortical areas for classic straight-line reaching is remarkably simple and consistent across subjects, despite the complicated musculoskeletal dynamics that are involved. As tasks become more challenging, however, different conscious strategies may be used to improve perceived behavioral performance. We identified additional spatial information that appeared both in single neurons and in the population code of monkey dorsal premotor cortex when obstacles impeded direct reach paths. The neural correlate of movement planning varied between subjects in a manner consistent with the use of different strategies to optimize task completion. These distinct planning strategies were manifested in the timing and strength of the information contained in the neural population code. PMID- 22821988 TI - Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity. AB - Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4 42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = 0.30; all P <= 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors. PMID- 22821990 TI - Adaptive changes of mesenteric arteries in pregnancy: a meta-analysis. AB - The vascular response to pregnancy has been frequently studied in mesenteric artery models by investigating endothelial cell (EC)- and smooth muscle cell (SMC)-dependent responses to mechanical (flow-mediated vasodilation, myogenic reactivity, and vascular compliance) and pharmacological stimuli (G protein coupled receptor responses: Gq(EC), Gs(SMC), Gq(SMC)). It is unclear to what extent these pathways contribute to normal pregnancy-induced vasodilation across species, strains, and/or gestational age and at which receptor level pregnancy affects the pathways. We performed a meta-analysis on responses to mechanical and pharmacological stimuli associated with pregnancy-induced vasodilation of mesenteric arteries and included 55 (188 responses) out of 398 studies. Most included studies (84%) were performed in Wistar and Sprague-Dawley rats (SDRs) and compared late gestation versus nonpregnant controls (80%). Pregnancy promotes flow-mediated vasodilation in all investigated species. Only in SDRs, pregnancy additionally stimulates both vasodilator Gq(EC) sensitivity (EC(50) reduced by 0.76 [-0.92, -0.60] log[M]) and Gs(SMC) sensitivity (EC(50) reduced by -0.51 [ 0.82, -0.20] log[M]), depresses vasopressor Gq(SMC) sensitivity (EC(50) increase in SDRs by 0.23 [0.16, 0.31] log[M]), and enhances arterial compliance. We conclude that 1) pregnancy facilitates flow-mediated vasodilation at term among all investigated species, and the contribution of additional vascular responses is species and strain specific, and 2) late pregnancy mediates vasodilation through changes at the receptor level for the substances tested. The initial steps of vasodilation in early pregnancy remain to be elucidated. PMID- 22821989 TI - TNF-alpha impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity. AB - We tested the hypothesis that high fat (HF) feeding results in endothelial dysfunction in resistance arteries of epididymal white adipose tissue (eWAT) and is mediated by adipose tissue inflammation. When compared with normal chow (NC) fed mice (n = 17), HF-fed male B6D2F1 mice were glucose intolerant and insulin resistant as assessed by glucose tolerance test (area under the curve; HF, 18,174 +/- 1,889 vs. NC, 15,814 +/- 666 mg.dl(-1).min(-1); P < 0.05) and the homeostatic model assessment (HF, 64.1 +/- 4.3 vs. NC, 85.7 +/- 6.4; P = 0.05). HF diet induced metabolic dysfunction was concomitant with a proinflammatory eWAT phenotype characterized by greater macrophage infiltration (HF, 3.9 +/- 0.8 vs. NC, 0.8 +/- 0.4%; P = 0.01) and TNF-alpha (HF, 22.6 +/- 4.3 vs. NC, 11.4 +/- 2.5 pg/dl; P < 0.05) and was associated with resistance artery dysfunction, evidenced by impaired endothelium-dependent dilation (EDD) (maximal dilation; HF, 49.2 +/- 10.7 vs. NC, 92.4 +/- 1.4%; P < 0.01). Inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl ester (L-NAME) reduced dilation in NC (28.9 +/- 6.3%; P < 0.01)- and tended to reduce dilation in HF (29.8 +/- 9.9%; P = 0.07)-fed mice, eliminating the differences in eWAT artery EDD between NC- and HF fed mice, indicative of reduced NO bioavailability in eWAT resistance arteries after HF feeding. In vitro treatment of excised eWAT arteries with recombinant TNF-alpha (rTNF) impaired EDD (P < 0.01) in NC (59.7 +/- 10.9%)- but not HF (59.0 +/- 9.3%)-fed mice. L-NAME reduced EDD in rTNF-treated arteries from both NC (21.9 +/- 6.4%)- and HF (29.1 +/- 9.2%)-fed mice (both P < 0.01). In vitro treatment of arteries with a neutralizing antibody against TNF-alpha (abTNF) improved EDD in HF (88.2 +/- 4.6%; P = 0.05)-fed mice but was without effect on maximal dilation in NC (89.0 +/- 5.1%)-fed mice. L-NAME reduced EDD in abTNF treated arteries from both NC (25.4 +/- 7.5%)- and HF (27.1 +/- 16.8%)-fed mice (both P < 0.01). These results demonstrate that inflammation in the visceral adipose tissue resulting from diet-induced obesity impairs endothelial function and NO bioavailability in the associated resistance arteries. This dysfunction may have important implications for adipose tissue blood flow and appropriate tissue function. PMID- 22821991 TI - Nonviral gene therapy targeting cardiovascular system. AB - The goal of gene therapy is either to introduce a therapeutic gene into or replace a defective gene in an individual's cells and tissues. Gene therapy has been urged as a potential method to induce therapeutic angiogenesis in ischemic myocardium and peripheral tissues after extensive investigation in recent preclinical and clinical studies. A successful gene therapy mainly relies on the development of the gene delivery vector. Developments in viral and nonviral vector technology including cell-based gene transfer will further improve transgene delivery and expression efficiency. Nonviral approaches as alternative gene delivery vehicles to viral vectors have received significant attention. Recently, a simple and safe approach of gene delivery into target cells using naked DNA has been improved by combining several techniques. Among the physical approaches, ultrasonic microbubble gene delivery, with its high safety profile, low costs, and repeatable applicability, can increase the permeability of cell membrane to macromolecules such as plasmid DNA by its bioeffects and can provide as a feasible tool in gene delivery. On the other hand, among the promising areas for gene therapy in acquired diseases, ischemic cardiovascular diseases have been widely studied. As a result, gene therapy using advanced technology may play an important role in this regard. The aims of this review focus on understanding the cellular and in vivo barriers in gene transfer and provide an overview of currently used chemical vectors and physical tools that are applied in nonviral cardiovascular gene transfer. PMID- 22821992 TI - Assessment of cerebral autoregulation: the quandary of quantification. AB - We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal P(CO2) (P(ET)(CO2) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in P(ET)(CO2) were positively related to coherence [LF: beta = 0.0065 arbitrary units (AU)/mmHg and VLF: beta = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: beta = -0.026 rad/mmHg and VLF: beta = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: beta = -0.042%/mmHg(2) and VLF: beta = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: beta = 0.0070 cm.s(-1).mmHg( 2), P < 0.05; and VLF: beta = 0.014 cm.s(-1).mmHg(-2), P < 0.01). Thus, during changes in P(ET)(CO2), LF phase was inversely related to LF gain (beta = -0.29 cm.s(-1).mmHg(-1).rad(-1), P < 0.01) but positively related to LF normalized gain (beta = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously. PMID- 22821993 TI - Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes. AB - Optical mapping has become an increasingly important tool to study cardiac electrophysiology in the past 20 years. Multiple methods are used to process and analyze cardiac optical mapping data, and no consensus currently exists regarding the optimum methods. The specific methods chosen to process optical mapping data are important because inappropriate data processing can affect the content of the data and thus alter the conclusions of the studies. Details of the different steps in processing optical imaging data, including image segmentation, spatial filtering, temporal filtering, and baseline drift removal, are provided in this review. We also provide descriptions of the common analyses performed on data obtained from cardiac optical imaging, including activation mapping, action potential duration mapping, repolarization mapping, conduction velocity measurements, and optical action potential upstroke analysis. Optical mapping is often used to study complex arrhythmias, and we also discuss dominant frequency analysis and phase mapping techniques used for the analysis of cardiac fibrillation. PMID- 22821994 TI - The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface. AB - The bicuspid aortic valve (BAV) is a common congenital malformation of the aortic valve (AV) affecting 1% to 2% of the population. The BAV is predisposed to early degenerative calcification of valve leaflets, and BAV patients constitute 50% of AV stenosis patients. Although evidence shows that genetic defects can play a role in calcification of the BAV leaflets, we hypothesize that drastic changes in the mechanical environment of the BAV elicit pathological responses from the valve and might be concurrently responsible for early calcification. An in vitro model of the BAV was constructed by surgically manipulating a native trileaflet porcine AV. The BAV valve model and a trileaflet AV (TAV) model were tested in an in vitro pulsatile flow loop mimicking physiological hemodynamics. Laser Doppler velocimetry was used to make measurements of fluid shear stresses on the leaflet of the valve models using previously established methodologies. Furthermore, particle image velocimetry was used to visualize the flow fields downstream of the valves and in the sinuses. In the BAV model, flow near the leaflets and fluid shear stresses on the leaflets were much more unsteady than for the TAV model, most likely due to the moderate stenosis in the BAV and the skewed forward flow jet that collided with the aorta wall. This additional unsteadiness occurred during mid- to late-systole and was composed of cycle-to-cycle magnitude variability as well as high-frequency fluctuations about the mean shear stress. It has been demonstrated that the BAV geometry can lead to unsteady shear stresses under physiological flow and pressure conditions. Such altered shear stresses could play a role in accelerated calcification in BAVs. PMID- 22821995 TI - The severity of shock is associated with impaired rates of net alveolar fluid clearance in clinical acute lung injury. AB - The rate of alveolar fluid clearance (AFC) is associated with mortality in clinical acute lung injury (ALI). Patients with ALI often develop circulatory shock, but how shock affects the rate of AFC is unknown. To determine the effect of circulatory shock on the rate of AFC in patients with ALI, the rate of net AFC was measured in 116 patients with ALI by serial sampling of pulmonary edema fluid. The primary outcome was the rate of AFC in patients with shock compared with those without shock. We also tested the effects of shock severity and bacteremia. Patients with ALI and shock (n = 86) had significantly slower rates of net AFC compared with those without shock (n = 30, P = 0.03), and AFC decreased significantly as the number of vasopressors increased. Patients with positive blood cultures (n = 21) had slower AFC compared with patients with negative blood cultures (n = 96, P = 0.023). In addition, the edema fluid-to plasma protein ratio, an index of alveolar-capillary barrier permeability, was highest in patients requiring the most vasopressors (P < 0.05). Patients with ALI complicated by circulatory shock and bacteremia had slower rates of AFC compared with patients without shock or bacteremia. An impaired capacity to reabsorb alveolar edema fluid may contribute to high mortality among patients with sepsis induced ALI. These findings also suggest that vasopressor use may be a marker of alveolar-capillary barrier permeability in ALI and provide justification for new therapies that enhance alveolar epithelial and endothelial barrier integrity in ALI, particularly in patients with shock. PMID- 22821996 TI - Does the F508-CFTR mutation induce a proinflammatory response in human airway epithelial cells? AB - In the clinical setting, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene enhance the inflammatory response in the lung to Pseudomonas aeruginosa (P. aeruginosa) infection. However, studies on human airway epithelial cells in vitro have produced conflicting results regarding the effect of mutations in CFTR on the inflammatory response to P. aeruginosa, and there are no comprehensive studies evaluating the effect of P. aeruginosa on the inflammatory response in airway epithelial cells with the DeltaF508/DeltaF508 genotype and their matched CF cell line rescued with wild-type (wt)-CFTR. CFBE41o cells (DeltaF508/DeltaF508) and CFBE41o- cells complemented with wt-CFTR (CFBE wt-CFTR) have been used extensively as an experimental model to study CF. Thus the goal of this study was to examine the effect of P. aeruginosa on gene expression and cytokine/chemokine production in this pair of cells. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2 and TNF-alpha) in CFBE-wt-CFTR cells compared with CFBE-DeltaF508 CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o DeltaF508/DeltaF508-CFTR cells. Taken together with other published studies, our data demonstrate that there is no compelling evidence to support the view that mutations in CFTR induce a hyperinflammatory response in human airway epithelial cells in vivo. Although the lungs of patients with CF have abundant levels of proinflammatory cytokines and chemokines, because the lung is populated by immune cells and epithelial cells there is no way to know, a priori, whether airway epithelial cells in the CF lung in vivo are hyperinflammatory in response to P. aeruginosa compared with non-CF lung epithelial cells. Thus studies on human airway epithelial cell lines and primary cells in vitro that propose to examine the effect of mutations in CFTR on the inflammatory response to P. aeruginosa have uncertain clinical significance with regard to CF. PMID- 22821998 TI - The wound healing chronicles. AB - In this issue of Blood, Willenborg and colleagues uncover the timeline of monocyte/macrophage involvement during sequential phases of skin wound healing. The CCR2-mediated recruitment of a vascular endothelial growth factor A(VEGF-A) expressing inflammatory monocyte subset is critical for early vascular sprouting, while epidermal-derived VEGF-A mediates vascularization in the late wound healing phases (see figure). PMID- 22821999 TI - Predicting individual risk of venous thrombosis. AB - de Haan et al have developed a risk score algorithm that is able to improve the individual prediction of venous thrombosis, taking into account information from multiple risk SNPs in addition to clinical data. PMID- 22821997 TI - Dual targeting of mTOR and aurora-A kinase for the treatment of uterine Leiomyosarcoma. AB - PURPOSE: The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. EXPERIMENTAL DESIGN: Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo. RESULTS: Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. CONCLUSIONS: mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS. PMID- 22822000 TI - Liberating R169 promotes anticoagulant protein C. AB - In this issue of Blood, Pozzi et al demonstrate that removing an anionic cage promotes exposure of R169 thereby generating a protein C (PC) that is far more readily activated. PMID- 22822002 TI - The alpha4beta7 integrin binds HIV envelope but does not mediate bystander killing of gammadelta T cells. PMID- 22822001 TI - Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia. PMID- 22822003 TI - Further examination of BAFF SNPs in cGVHD. PMID- 22822005 TI - Necrotising fasciitis. PMID- 22822004 TI - H5N1 virus causes significant perturbations in host proteome very early in influenza virus-infected primary human monocyte-derived macrophages. AB - H5N1 influenza viruses, which cause disease in humans, have unusually high pathogenicity. The temporal response of primary human monocyte-derived macrophages infected with highly pathogenic H5N1 and seasonal H1N1 influenza viruses was evaluated using mass spectrometry-based quantitative proteomic profiling. This was done in order to demonstrate significant perturbation of the host proteome upon viral infection, as early as 1 hour after infection. This early host response distinguished H5N1 infection from H1N1 infection, the latter inducing less of a response. The most pronounced effect was observed on the translational machinery, suggesting that H5N1 might gain advantage in replication by using the cell protein synthesis machinery early in the infection. PMID- 22822006 TI - Will the revolution in genetics improve healthcare? PMID- 22822008 TI - UK economy can withstand a doubling in health spending in next 50 years, conference hears. PMID- 22822007 TI - Effect of communicating DNA based risk assessments for Crohn's disease on smoking cessation: randomised controlled trial. AB - OBJECTIVE: To test the hypothesis that communicating risk of developing Crohn's disease based on genotype and that stopping smoking can reduce this risk, motivates behaviour change among smokers at familial risk. DESIGN: Parallel group, cluster randomised controlled trial. SETTING: Families with Crohn's disease in the United Kingdom. PARTICIPANTS: 497 smokers (mean age 42.6 (SD 14.4) years) who were first degree relatives of probands with Crohn's disease, with outcomes assessed on 209/251 (based on DNA analysis) and 217/246 (standard risk assessment). INTERVENTION: Communication of risk assessment for Crohn's disease by postal booklet based on family history of the disease and smoking status alone, or with additional DNA analysis for the NOD2 genotype. Participants were then telephoned by a National Health Service Stop Smoking counsellor to review the booklet and deliver brief standard smoking cessation intervention. Calls were tape recorded and a random subsample selected to assess fidelity to the clinical protocol. MAIN OUTCOME MEASURE: The primary outcome was smoking cessation for 24 hours or longer, assessed at six months. RESULTS: The proportion of participants stopping smoking for 24 hours or longer did not differ between arms: 35% (73/209) in the DNA arm versus 36% (78/217) in the non-DNA arm (difference -1%, 95% confidence interval -10% to 8%, P=0.83). The proportion making a quit attempt within the DNA arm did not differ between those who were told they had mutations putting them at increased risk (36%), those told they had none (35%), and those in the non-DNA arm (36%). CONCLUSION: Among relatives of patients with Crohn's disease, feedback of DNA based risk assessments does not motivate behaviour change to reduce risk any more or less than standard risk assessment. These findings accord with those across a range of populations and behaviours. They do not support the promulgation of commercial DNA based tests nor the search for gene variants that confer increased risk of common complex diseases on the basis that they effectively motivate health related behaviour change. TRIAL REGISTRATION: Current Controlled Trials ISRCTN21633644. PMID- 22822009 TI - Effects of IFN-gamma on intracellular trafficking and activity of macrophage NADPH oxidase flavocytochrome b558. AB - Flavocytochrome b(558), the catalytic core of the phagocyte NADPH oxidase (NOX2), mediates electron transfer from NADPH to molecular oxygen to generate superoxide, the precursor of highly ROS for host defense. Flavocytochrome b(558) is an integral membrane heterodimer consisting of a large glycosylated subunit, gp91(phox), and a smaller subunit, p22(phox). We recently showed in murine macrophages that flavocytochrome b(558) localizes to the PM and Rab11-positive recycling endosomes, whereas in primary hMDMs, gp91(phox) and p22(phox) reside in the PM and the ER. The antimicrobial activity of macrophages, including ROS production, is greatly enhanced by IFN-gamma, but how this is achieved is incompletely understood. To further define the mechanisms by which IFN-gamma enhances macrophage NADPH oxidase activity, we evaluated changes in flavocytochrome b(558) expression and localization, along with NADPH oxidase activity, in IFN-gamma stimulated RAW 264.7 cells and primary murine BMDMs and hMDMs. We found that enhanced capacity for ROS production is, in part, a result of increased protein expression of gp91(phox) and p22(phox) but also demonstrate that IFN-gamma induced a shift in the predominant localization of gp91(phox) and p22(phox) from intracellular membrane compartments to the PM. Our results are the first to show that a cytokine can change the distribution of macrophage flavocytochrome b(558) and provide a potential, new mechanism by which IFN-gamma modulates macrophage antimicrobial activity. Altogether, our data suggest that the mechanisms by which IFN-gamma regulates antimicrobial activity of macrophages are more complex than previously appreciated. PMID- 22822011 TI - Is long-term prediction in membranous nephropathy (MGN) better than the weatherman's forecast capacity? PMID- 22822010 TI - A randomized trial comparing buttonhole with rope ladder needling in conventional hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Buttonhole needling is reported to be associated with less pain than standard needling. The purpose of this study was to compare patient perceived pain and fistula complications in buttonhole and standard needling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 140 conventional hemodialysis patients were randomly assigned to buttonhole or standard needling. The primary outcome was patient perceived pain with needling at 8 weeks. Fistula complications of hematoma, bleeding postdialysis, and infection were tracked. RESULTS: Median pain score at 8 weeks using a visual analog scale from 0 to 10 cm was similar for standard and buttonhole needling (1.2 [0.4-2.4] versus 1.5 [0.5-3.4]; P=0.57). Rate of hematoma formation in standard needling was higher (436 versus 295 of 1000 hemodialysis sessions; P=0.03). Rate of no bleeding postdialysis was 23.6 and 28.3 per 1000 in standard and buttonhole needling, respectively (P=0.40). Rate of localized signs of infection in standard versus buttonhole needling was 22.4 versus 50 per 1000 (P=0.003). There was one episode of Staphylococcal aureus bacteremia during the 8 weeks with buttonhole needling and no episodes with standard needling (P=1.00). Within 12 months of follow-up, another two buttonhole needling episodes developed S. aureus bacteremia, and nine buttonhole needling episodes had needling site abscesses requiring intravenous antibiotics versus zero standard needling episodes (P=0.003). CONCLUSIONS: Patients had no difference in pain between buttonhole and standard needling. Although fewer buttonhole needling patients developed a hematoma, there was an increased risk of bacteremia and localized signs of infection. Routine use of buttonhole needling is associated with increased infection risk. PMID- 22822012 TI - Monitoring quality of care at dialysis facilities: a case for regulatory parsimony--and beyond. AB - With the issuance of the new Conditions for Coverage in 2008 and the implementation of the Prospective Payment System in 2011, the Centers for Medicare & Medicaid Services has fundamentally altered the regulatory landscape of quality in the ESRD program. Although these changes-largely through use of tools comparing individual facility performance to regional and national quality expectations-have increased facility accountability for the quality of patient care in many quarters, they have also complicated both substance and process of facility adherence to quality rules in that component of the program. This editorial critically assesses the main quality tools now in use for dialysis facilities and reviews the issues arising from their conjoint use. A scheme for improving the effectiveness of each quality tool is proposed, and an assessment of their future value and effectiveness in quality improvement is offered. PMID- 22822013 TI - Troponin T for the detection of dialysis-induced myocardial stunning in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Circulating troponin T levels are frequently elevated in patients undergoing long-term dialysis. The pathophysiology underlying these elevations is controversial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 70 prevalent hemodialysis (HD) patients, HD-induced myocardial stunning was assessed echocardiographically at baseline and after 12 months. Nineteen patients were not available for the follow-up analysis. The extent to which predialysis troponin T was associated with the occurrence of HD-induced myocardial stunning was assessed as the primary endpoint. RESULTS: The median troponin T level in this hemodialysis cohort was 0.06 ng/ml (interquartile range, 0.02-0.10). At baseline, 64% of patients experienced myocardial stunning. These patients showed significantly higher troponin T levels than patients without stunning (0.08 ng/ml [0.05-0.12] versus 0.02 ng/ml [0.01-0.05]). Troponin T levels were significantly correlated to measures of myocardial stunning severity (number of affected segments: r=0.42; change in ejection fraction from beginning of dialysis to end of dialysis: r=-0.45). In receiver-operating characteristic analyses, predialytic troponin T achieved an area under the curve of 0.82 for the detection of myocardial stunning. In multivariable analysis, only ultrafiltration volume (odds ratio, 4.38 for every additional liter) and troponin T (odds ratio, 9.33 for every additional 0.1 ng/ml) were independently associated with myocardial stunning. After 12 months, nine patients had newly developed myocardial stunning and showed a significant increase in troponin T over baseline (0.03 ng/ml at baseline versus 0.05 ng/ml at year 1). CONCLUSIONS: Troponin T levels in HD patients are associated with the presence and severity of HD-induced myocardial stunning. PMID- 22822015 TI - Getting excited about exit sites in peritoneal dialysis? PMID- 22822014 TI - Hemodialysis-induced regional left ventricular systolic dysfunction: prevalence, patient and dialysis treatment-related factors, and prognostic significance. AB - BACKGROUND AND OBJECTIVES: The hemodialysis procedure may acutely induce regional left ventricular systolic dysfunction. This study evaluated the prevalence, time course, and associated patient- and dialysis-related factors of this entity and its association with outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hemodialysis patients (105) on a three times per week dialysis schedule were studied between March of 2009 and March of 2010. Echocardiography was performed before dialysis, at 60 and 180 minutes intradialysis, and at 30 minutes postdialysis. Hemodialysis-induced regional left ventricular systolic dysfunction was defined as an increase in wall motion score in more than or equal to two segments. RESULTS: Hemodialysis-induced regional left ventricular systolic dysfunction occurred in 29 (27%) patients; 17 patients developed regional left ventricular systolic dysfunction 60 minutes after onset of dialysis. Patients with hemodialysis-induced left ventricular systolic dysfunction were more often male, had higher left ventricular mass index, and had worse predialysis left ventricular systolic function (left ventricular ejection fraction). The course of blood volume, BP, heart rate, electrolytes, and acid-base parameters during dialysis did not differ significantly between the two groups. Patients with hemodialysis-induced regional left ventricular systolic dysfunction had a significantly higher mortality after correction for age, sex, dialysis vintage, diabetes, cardiovascular history, ultrafiltration volume, left ventricular mass index, and predialysis wall motion score index. CONCLUSIONS: Hemodialysis induces regional wall motion abnormalities in a significant proportion of patients, and these changes are independently associated with increased mortality. Hemodialysis induced regional left ventricular systolic dysfunction occurs early during hemodialysis and is not related to changes in blood volume, electrolytes, and acid-base parameters. PMID- 22822016 TI - Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. AB - BACKGROUND AND OBJECTIVES: Little is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors >=5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes. RESULTS: At a median age of 19.3 years (interquartile range, 15.6-24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8-17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR <90 ml/min per 1.73 m(2). Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4-21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63-9.19), as did male sex, higher body mass index, and longer time since cancer treatment. CONCLUSION: Almost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage. PMID- 22822018 TI - Evolution and revolution: the formation of Today's American Thoracic Society, Part 2. AB - The major event in the recent history of the American Thoracic Society (ATS) is its separation from the American Lung Association (ALA), resulting in the Society's independence. The seeds of the separation were sown over the course of many years. The fundamental reason driving the separation was the organizational structure of the ALA, with the ATS being a division within the larger organization and having neither the standing to make independent decisions nor the ability to respond effectively to the expectations of a growing and diverse membership. Additional important factors included continual organizational conflicts; ongoing struggles over finances; reluctance by the ALA to provide what the ATS considered to be appropriate support for research; divergence of areas of interest as the Society became more broad based to include critical care and sleep medicine, as well as concerns with medical practice issues; and internationalization of the Society, with an increasing proportion of members residing outside the United States. Once it was decided that the ATS could only exist as an independent organization, the separation agreement was negotiated in less than 3 years. Although there were substantial unknowns immediately after the separation, a unified leadership, a strongly supportive membership, and a skilled and dedicated staff guided the organization through this difficult period, from which the Society emerged as a strong independent professional organization that remains true to the public-minded spirit that guided its formation 107 years ago. PMID- 22822017 TI - Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study. AB - BACKGROUND AND OBJECTIVES: Prescription patterns for hemodialysis patients with secondary hyperparathyroidism have varied widely since market introduction of cinacalcet. This study examined associations between prescription patterns and subsequent laboratory values. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients subcohort, 1716 prevalent hemodialysis patients (4048 sets for repeated measures between January 2008 and July 2009) with an intact parathyroid hormone (iPTH) level >180 pg/ml who used intravenous vitamin D receptor activator (VDRA) without cinacalcet were selected. Prescription patterns were defined based on cinacalcet administration (starting or not) and VDRA dosage change (decreased [< 25%], stable [-25% to 25%], or increased [>25%]). Proportion differences (PDs) were determined for decreasing iPTH levels by at least one category (<180, 180 299, 300-499, and >=500 pg/ml) and for achieving target phosphorus (3.5-6.0 mg/dl) and calcium (8.4-10.0 mg/dl) levels, adjusting for potential confounders. RESULTS: The starting cinacalcet and increased VDRA patterns were associated with decreasing iPTH levels (PD, 0.25 and 0.13; 95% confidence intervals [95% CIs], 0.19-0.31 and 0.09-0.17, respectively); combination use had an additive association (PD, 0.34; 95% CI, 0.20-0.42). The starting cinacalcet and decreased VDRA combination was associated with simultaneously achieving target phosphorus (PD, 0.12; 95% CI: 0.04-0.20) and calcium (PD, 0.09; 95% CI, 0.01-0.17) levels. CONCLUSIONS: Certain combinations of cinacalcet and VDRA were associated with decreasing iPTH and achieving targets for phosphorus and calcium. Combinations may prove advantageous versus VDRA alone in managing secondary hyperparathyroidism. PMID- 22822019 TI - Influences of spinal anesthesia on exercise tolerance in patients with chronic obstructive pulmonary disease. AB - RATIONALE: Lower limb muscle dysfunction contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). We hypothesized that signaling from lower limb muscle group III/IV sensory afferents to the central motor command could be involved in premature cycling exercise termination in COPD. OBJECTIVES: To evaluate the effects of spinal anesthesia, which presumably inhibited central feedback from the lower limb muscle group III/IV sensory afferents on exercise tolerance and cardiorespiratory response during constant work-rate cycling exercise in patients with COPD. METHODS: In a crossover and double-blind randomized design, eight patients with COPD (FEV(1), 67 +/- 8% predicted) completed a constant work-rate cycling exercise after sham (NaCl, interspinous L(3)-L(4)) or active (fentanyl 25 MUg, intrathecal L(3)-L(4)) spinal anesthesia. MEASUREMENTS AND MAIN RESULTS: When compared with placebo, endurance time was significantly prolonged after spinal anesthesia with fentanyl (639 +/- 87 s vs. 423 +/- 38 s [mean +/- SEM]; P = 0.01). Ventilation and respiratory rate were reduced at isotime points under the fentanyl condition, whereas ventilatory efficiency and dead space ventilation were improved. Patients exhibited less dynamic hyperinflation at isotime points with spinal anesthesia. Consequently, the rise in dyspnea was significantly flatter during the fentanyl condition than with placebo. CONCLUSIONS: Spinal anesthesia enhanced cycling exercise tolerance in patients with COPD, mostly by reducing ventilatory response and dyspnea during exercise; these effects were possibly mediated through the inhibition of group III/IV lower limb sensory muscle afferents. PMID- 22822020 TI - The facilitated values history: helping surrogates make authentic decisions for incapacitated patients with advanced illness. AB - Many patients who develop incapacitating illness have not expressed clear treatment preferences. Therefore, surrogate decision makers are asked to make judgments about what treatment pathway is most consistent with the patient's values. Surrogates often struggle with such decisions. The difficulty arises because answering the seemingly straightforward question, "What do you think the patient would choose?" is emotionally, cognitively, and morally complex. There is little guidance for clinicians to assist families in constructing an authentic picture of the patient's values and applying them to medical decisions, in part because current models of medical decision making treat the surrogate as the expert on the patient's values and the physician as the expert on technical medical considerations. However, many surrogates need assistance in identifying and working through the sometimes conflicting values relevant to medical decisions near the end of life. We present a framework for clinicians to help surrogates overcome the emotional, cognitive, and moral barriers to high-quality surrogate decision making for incapacitated patients. PMID- 22822021 TI - Evolution and revolution: the formation of today's American Thoracic Society, part 1. AB - The American Thoracic Society (ATS), the preeminent professional organization in the field of respiratory, critical care, and sleep medicine, is now 107 years old. For the most part, the Society's administrative and medical-scientific interests evolved in an orderly fashion, but two "revolutions" took place that should be remembered. What ultimately metamorphosed into the ATS in 1960 began in 1905 as the 34-member American Sanatorium Association, which in 1915 became the medical section of the National Association for the Study and Prevention of Tuberculosis (NASPT). In 1918, the NASPT became the National Tuberculosis Association and in 1939, the ASA became the American Trudeau Society, cosmetic revisions having no effect on either the medical section-parent relationship or the one-disease orientation of both organizations. After World War II, the narrow focus of the ATS on tuberculosis was progressively enlarged through coalescence of several factors that transformed the practice of pulmonary medicine: the growth of intensive care units and pulmonary function laboratories and the advent of fiberoptic bronchoscopy; the rise of asthma, chronic obstructive pulmonary disease, and lung cancer coincident with the withering of tuberculosis; and the arrival of pulmonary physician-scientists who sought enrichment through a professional society. The newcomers found a home in the ATS, but it was slow to fulfill their needs for scientific communication and administrative responsibility. The first revolution, the formation of Scientific Assemblies, got the job done quickly and well, as described in Part 1 of this perspective. The second revolution, separation from the American Lung Association, is described in Part 2. PMID- 22822023 TI - Vitamin D deficiency, smoking, and lung function in the Normative Aging Study. AB - RATIONALE: Vitamin D has immunomodulatory and antiinflammatory effects that may be modified by cigarette smoke and may affect lung function. OBJECTIVES: To examine the effect of vitamin D deficiency and smoking on lung function and lung function decline. METHODS: A total of 626 men from the Normative Aging Study had 25-hydroxyvitamin D levels measured at three different times between 1984 and 2003 with concurrent spirometry. Vitamin D deficiency was defined as serum level <= 20 ng/ml. Statistical analysis was performed using multivariable linear regression and mixed effects models. MEASUREMENTS AND MAIN RESULTS: In the overall cohort, there was no significant effect of vitamin D deficiency on lung function or on lung function decline. In both cross-sectional and longitudinal multivariable models, there was effect modification by vitamin D status on the association between smoking and lung function. Cross-sectional analysis revealed lower lung function in current smokers with vitamin D deficiency (FEV(1), FVC, and FEV(1)/FVC; P <= 0.0002), and longitudinal analysis showed more rapid rates of decline in FEV(1) (P = 0.023) per pack-year of smoking in subjects with vitamin D deficiency as compared with subjects who were vitamin D sufficient. CONCLUSIONS: Vitamin D deficiency was associated with lower lung function and more rapid lung function decline in smokers over 20 years in this longitudinal cohort of elderly men. This suggests that vitamin D sufficiency may have a protective effect against the damaging effects of smoking on lung function. Future studies should seek to confirm this finding in the context of smoking and other exposures that affect lung function. PMID- 22822024 TI - Reversal of immunoparalysis in humans in vivo: a double-blind, placebo controlled, randomized pilot study. AB - RATIONALE: Reversal of sepsis-induced immunoparalysis may reduce the incidence of secondary infections and improve outcome. Although IFN-gamma and granulocyte macrophage colony-stimulating factor (GM-CSF) restore immune competence of ex vivo stimulated leukocytes of patients with sepsis, effects on immunoparalysis in vivo are not known. OBJECTIVES: To investigate the effects of IFN-gamma and GM CSF on immunoparalysis in vivo in humans. METHODS: We performed a double-blind, placebo-controlled, randomized study in 18 healthy male volunteers that received Escherichia coli endotoxin (LPS; 2 ng/kg, intravenously) on days 1 and 7 (visits 1 and 2). On days 2, 4, and 6, subjects received subcutaneous injections of IFN gamma (100 MUg/day; n = 6), GM-CSF (4 MUg/kg/day; n = 6), or placebo (NaCl 0.9%; n = 6). MEASUREMENTS AND MAIN RESULTS: In the placebo group, immunoparalysis was illustrated by a 60% (48-71%) reduction of LPS-induced tumor necrosis factor (TNF)-alpha plasma concentrations during visit 2 (P = 0.03), whereas the antiinflammatory IL-10 response was not significantly attenuated (39% [2-65%]; P = 0.15). In contrast, in the IFN-gamma group, TNF-alpha concentrations during visit 2 were not significantly attenuated (28% [1-47%]; P = 0.09), whereas the IL 10 response was significantly lower (reduction of 54% [47-66%]; P = 0.03). Compared with the placebo group, the reduction in the LPS-induced TNF-alpha response during visit 2 was significantly less pronounced in the IFN-gamma group (P = 0.01). Moreover, compared with placebo, treatment with IFN-gamma increased monocyte HLA-DR expression (P = 0.02). The effects of GM-CSF tended in the same direction as IFN-gamma, but were not statistically significant compared with placebo. CONCLUSIONS: IFN-gamma partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-gamma is a promising treatment option to reverse sepsis-induced immunoparalysis. PMID- 22822022 TI - Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury. AB - RATIONALE: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. OBJECTIVES: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. METHODS: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2(hi) monocytes. MEASUREMENTS AND MAIN RESULTS: PBMs play a critical role in regulating neutrophil emigration in established murine LPS induced lung injury. Gr1(hi) and Gr1(lo) PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. CONCLUSIONS: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI. PMID- 22822025 TI - Variation in PTX3 is associated with primary graft dysfunction after lung transplantation. AB - RATIONALE: Elevated long pentraxin-3 (PTX3) levels are associated with the development of primary graft dysfunction (PGD) after lung transplantation. Abnormalities in innate immunity, mediated by PTX3 release, may play a role in PGD pathogenesis. OBJECTIVES: Our goal was to test whether variants in the gene encoding PTX3 are risk factors for PGD. METHODS: We performed a candidate gene association study in recipients from the multicenter, prospective Lung Transplant Outcomes Group cohort enrolled between July 2002 and July 2009. The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD within 72 hours of transplantation. Targeted genotyping of 10 haplotype-tagging PTX3 single-nucleotide polymorphisms (SNPs) was performed in lung transplant recipients. The association between PGD and each SNP was evaluated by logistic regression, adjusting for pretransplantation lung disease, cardiopulmonary bypass use, and population stratification. The association between SNPs and plasma PTX3 levels was tested across genotypes in a subset of recipients with idiopathic pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: Six hundred fifty-four lung transplant recipients were included. The incidence of PGD was 29%. Two linked 5' region variants, rs2120243 and rs2305619, were associated with PGD (odds ratio, 1.5; 95% confidence interval, 1.1 to 1.9; P = 0.006 and odds ratio, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.007, respectively). The minor allele of rs2305619 was significantly associated with higher plasma PTX3 levels measured pretransplantation (P = 0.014) and at 24 hours (P = 0.047) after transplantation in patients with idiopathic pulmonary fibrosis. CONCLUSIONS: Genetic variants of PTX3 are associated with PGD after lung transplantation, and are associated with increased PTX3 plasma levels. PMID- 22822026 TI - Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ current. AB - RATIONALE: Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown. OBJECTIVES: To understand the cellular basis of CO-induced arrhythmias and to identify an effective therapeutic approach. METHODS: Patch-clamp electrophysiology and confocal Ca(2+) and nitric oxide (NO) imaging in isolated ventricular myocytes was performed together with protein S-nitrosylation to investigate the effects of CO at the cellular and molecular levels, whereas telemetry was used to investigate effects of CO on electrocardiogram recordings in vivo. MEASUREMENTS AND MAIN RESULTS: CO increased the sustained (late) component of the inward Na(+) current, resulting in prolongation of the action potential and the associated intracellular Ca(2+) transient. In more than 50% of myocytes these changes progressed to early after-depolarization-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na(+) channel, Na(v)1.5. All proarrhythmic effects of CO were abolished by the NO synthase inhibitor l-NAME, and reversed by ranolazine, an inhibitor of the late Na(+) current. Ranolazine also corrected QT variability and arrhythmias induced by CO in vivo, as monitored by telemetry. CONCLUSIONS: Our data indicate that the proarrhythmic effects of CO arise from activation of NO synthase, leading to NO mediated nitrosylation of Na(V)1.5 and to induction of the late Na(+) current. We also show that the antianginal drug ranolazine can abolish CO-induced early after depolarizations, highlighting a novel approach to the treatment of CO-induced arrhythmias. PMID- 22822027 TI - Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists. AB - Atherosclerosis is a chronic inflammatory vascular disease. Toll-like receptors (TLRs) are major initiators of inflammation. TLR2 promotes atherosclerosis in LDL receptor (LDLr)-deficient mice fed a high-fat diet (HFD). TLR2 forms heterodimers with TLR1 or TLR6 to enable inflammatory responses in the presence of distinct ligands. Here we asked whether TLR1 and/or TLR6 are required. We studied atherosclerotic disease using either TLR1- or TLR6-deficient mice. Deficiency of TLR1 or TLR6 did not diminish HFD-driven disease. When HFD-fed LDLr-deficient mice were challenged with Pam3 or MALP2, specific exogenous ligands of TLR2/1 or TLR2/6, respectively, atherosclerotic lesions developed with remarkable intensity in the abdominal segment of the descending aorta. In contrast to atherosclerosis induced by the endogenous agonists, these lesions were diminished by deficiency of either TLR1 or TLR6. The endogenous ligand(s) that arise from consumption of a HFD and promote disease via TLR2 are unknown. Either TLR1 or TLR6 are redundant for this endogenous ligand detection, or they are both irrelevant to endogenous ligand detection. However, the exogenous ligands Pam3 and MALP2 promote severe abdominal atherosclerosis in the descending aorta that is dependent on TLR1 and TLR6, respectively. PMID- 22822028 TI - Targeted profiling of circulating and hepatic bile acids in human, mouse, and rat using a UPLC-MRM-MS-validated method. AB - Bile acids (BAs) are a group of chemically related steroids recognized as regulatory molecules whose profiles can change in different physio-pathological situations. We have developed a sensitive, fast, and reproducible ultraperformance liquid chromatography/multiple reaction monitoring/mass spectrometry method to determine the tissue and sera BA profiles in different species (human, rat, and mouse) by quantifying 31 major and minor BA species in a single 21-min run. The method has been validated according to FDA guidelines, and it generally provides good results in terms of intra- and interday precision (less than 8.6% and 16.0%, respectively), accuracy (relative error measurement between -11.9% and 8.6%), and linearity (R(2) > 0.996 and dynamic ranges between two and four orders of magnitude), with limits of quantification between 2.5 and 20 nM. The new analytical approach was applied to determine BA concentrations in human, rat, and mouse serum and in liver tissue. Our comparative study confirmed and extended previous reports, showing marked interspecies differences in circulating and hepatic BA composition. The targeted analysis revealed the presence of unexpected minoritary BAs, such as tauro-alpha-Muricholic acid in human serum, thus allowing us to obtain a thorough profiling of human samples. Its great sensitivity, low sample requirements (25 ul of serum, 5 mg of tissue), and comprehensive capacity to profile a considerable number of BAs make the present method a good choice to study BA metabolism in physiological and pathological situations, particularly in toxicological studies. PMID- 22822030 TI - GPs are outnumbered on boards of clinical commissioning groups. PMID- 22822031 TI - Government targets on obesity remain a challenge, says spending watchdog. PMID- 22822029 TI - CD11c(+)/CD11b(+) cells are critical for organic dust-elicited murine lung inflammation. AB - Organic dust exposure in the agricultural industry results in significant lung disease. Macrophage infiltrates are increased in the lungs after organic dust exposures, yet the phenotype and functional importance of these cells remain unclear. Using an established intranasal inhalation murine model of dust-induced lung inflammation, animals were treated once or daily for 3 weeks with swine confinement organic dust extract (DE). Repetitive DE treatment for 3 weeks resulted in significant increases in CD11c(+)/CD11b(+) macrophages in whole lung associated tissue. These cells displayed increased costimulatory molecule (CD80 and CD86) expression, enhanced phagocytic ability, and an increased production of IL-6, CXCL1, and CXCL2. Similar findings were observed with the CD11c(+)/CD11b(+) macrophage infiltrate after repetitive exposure to peptidoglycan, a major DE component. To determine the functional importance of macrophages in mediating DE induced airway inflammation, lung macrophages were selectively depleted using a well-established intranasal clodronate liposome depletion/suicide strategy. First, macrophage depletion by clodronate liposomes resulted in significant reductions in airway neutrophil influx and TNF-alpha and IL-6 production after a single exposure to DE. In contrast, after repetitive 3-week exposure to DE, airway lavage fluid and lung tissue neutrophils were significantly increased in clodronate liposome-treated mice compared with control mice. A histological examination of lung tissue demonstrated striking increases in alveolar and bronchiolar inflammation, as well as in the size and distribution of cellular aggregates in clodronate-liposome versus saline-liposome groups repetitively exposed to DE. These studies demonstrate that DE elicits activated CD11c(+)/CD11b(+) macrophages in the lung, which play a critical role in regulating the outcome of DE-induced airway inflammation. PMID- 22822032 TI - NHS structural upheaval threatens already variable quality of essential data. PMID- 22822033 TI - Case against paediatric cardiologist will go ahead without him after his refusal to attend. PMID- 22822034 TI - Landmark study identifies major gaps in Australian healthcare. PMID- 22822035 TI - Mechanistic studies on the absorption and disposition of scutellarin in humans: selective OATP2B1-mediated hepatic uptake is a likely key determinant for its unique pharmacokinetic characteristics. AB - Scutellarin [scutellarein-7-O-glucuronide (S-7-G)] displayed a unique pharmacokinetic profile in humans after oral administration: the original compound was hardly detected, whereas its isomeric metabolite isoscutellarin [scutellarein-6-O-glucuronide (S-6-G)] had a markedly high exposure. Previous rat study revealed that S-7-G and S-6-G in the blood mainly originated from their aglycone in enterocytes, and that the S-7-G/S-6-G ratio declined dramatically because of a higher hepatic elimination of S-7-G. In the present study, metabolite profiling in human excreta demonstrated that the major metabolic pathway for S-6-G and S-7-G was through further glucuronidation. To further understand the cause for the exposure difference between S-7-G and S-6-G in humans, studies were conducted to uncover mechanisms underlying their formation and elimination. In vitro metabolism study suggested that S-7-G was formed more easily but metabolized more slowly in human intestinal and hepatic microsomes. Efflux transporter study showed that S-6-G and S-7-G were good substrates of breast cancer resistance protein and multidrug resistance-associated protein (MRP) 2 and possible substrates of MRP3; however, there was no preference great enough to alter the S-7-G/S-6-G ratio in the blood. Among the major hepatic anion uptake transporters, organic anion-transporting polypeptide (OATP) 2B1 played a predominant role in the hepatic uptake of S-6-G and S-7-G and showed greater preference for S-7-G with higher affinity than S-6-G (K(m) values were 1.77 and 43.9 MUM, respectively). Considering the low intrinsic permeability of S-6-G and S-7-G and the role of OATP2B1 in the hepatic clearance of such compounds, the selective hepatic uptake of S-7-G mediated by OATP2B1 is likely a key determinant for the much lower systemic exposure of S-7-G than S-6-G in humans. PMID- 22822036 TI - Glycemic control and chronic dosing of rhesus monkeys with a fusion protein of iduronidase and a monoclonal antibody against the human insulin receptor. AB - Hurler's syndrome, or mucopolysaccharidosis type I, is a lysosomal storage disorder caused by mutations in the gene encoding the lysosomal enzyme iduronidase (IDUA). The disease affects both peripheral tissues and the central nervous system (CNS). Recombinant IDUA treatment does not affect the CNS, because IDUA does not cross the blood-brain barrier (BBB). To enable BBB penetration, human IDUA was re-engineered as an IgG-IDUA fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb penetrates the brain from the blood via transport on the endogenous BBB insulin receptor and acts as a molecular Trojan horse to deliver the fused IDUA to the brain. Before human testing, the HIRMAb-IDUA fusion protein was evaluated in a 6-month weekly dosing toxicology study at doses of 0, 3, 9, and 30 mg/kg/week of the fusion protein administered to 40 rhesus monkeys. The focus of the present study is the effect of chronic high dose administration of this fusion protein on plasma glucose and long-term glycemic control. The results show that the HIRMAb has weak insulin agonist activity and causes hypoglycemia at the high dose, 30 mg/kg, after intravenous infusion in normal saline. When dextrose is added to the saline infusion solution, no hypoglycemia is observed at any dose. An intravenous glucose tolerance test performed at the end of the 6 months of chronic treatment showed no change in glucose tolerance at any dose of the HIRMAb-IDUA fusion protein. PMID- 22822037 TI - A novel biotinylated lipid raft reporter for electron microscopic imaging of plasma membrane microdomains. AB - The submicroscopic spatial organization of cell surface receptors and plasma membrane signaling molecules is readily characterized by electron microscopy (EM) via immunogold labeling of plasma membrane sheets. Although various signaling molecules have been seen to segregate within plasma membrane microdomains, the biochemical identity of these microdomains and the factors affecting their formation are largely unknown. Lipid rafts are envisioned as submicron membrane subdomains of liquid ordered structure with differing lipid and protein constituents that define their specific varieties. To facilitate EM investigation of inner leaflet lipid rafts and the localization of membrane proteins therein, a unique genetically encoded reporter with the dually acylated raft-targeting motif of the Lck kinase was developed. This reporter, designated Lck-BAP-GFP, incorporates green fluorescent protein (GFP) and biotin acceptor peptide (BAP) modules, with the latter allowing its single-step labeling with streptavidin gold. Lck-BAP-GFP was metabolically biotinylated in mammalian cells, distributed into low-density detergent-resistant membrane fractions, and was readily detected with avidin-based reagents. In EM images of plasma membrane sheets, the streptavidin-gold-labeled reporter was clustered in 20-50 nm microdomains, presumably representative of inner leaflet lipid rafts. The utility of the reporter was demonstrated in an investigation of the potential lipid raft localization of the epidermal growth factor receptor. PMID- 22822038 TI - Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation. AB - We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic 'butterfly'-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term 'diencephalic-mesencephalic junction dysplasia' to characterize this autosomal recessive malformation. PMID- 22822039 TI - The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. AB - The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor 1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma. PMID- 22822040 TI - Reducing patient re-identification risk for laboratory results within research datasets. AB - OBJECTIVE: To try to lower patient re-identification risks for biomedical research databases containing laboratory test results while also minimizing changes in clinical data interpretation. MATERIALS AND METHODS: In our threat model, an attacker obtains 5-7 laboratory results from one patient and uses them as a search key to discover the corresponding record in a de-identified biomedical research database. To test our models, the existing Vanderbilt TIME database of 8.5 million Safe Harbor de-identified laboratory results from 61 280 patients was used. The uniqueness of unaltered laboratory results in the dataset was examined, and then two data perturbation models were applied-simple random offsets and an expert-derived clinical meaning-preserving model. A rank-based re identification algorithm to mimic an attack was used. The re-identification risk and the retention of clinical meaning for each model's perturbed laboratory results were assessed. RESULTS: Differences in re-identification rates between the algorithms were small despite substantial divergence in altered clinical meaning. The expert algorithm maintained the clinical meaning of laboratory results better (affecting up to 4% of test results) than simple perturbation (affecting up to 26%). DISCUSSION AND CONCLUSION: With growing impetus for sharing clinical data for research, and in view of healthcare-related federal privacy regulation, methods to mitigate risks of re-identification are important. A practical, expert-derived perturbation algorithm that demonstrated potential utility was developed. Similar approaches might enable administrators to select data protection scheme parameters that meet their preferences in the trade-off between the protection of privacy and the retention of clinical meaning of shared data. PMID- 22822041 TI - Identifying primary and recurrent cancers using a SAS-based natural language processing algorithm. AB - OBJECTIVE: Significant limitations exist in the timely and complete identification of primary and recurrent cancers for clinical and epidemiologic research. A SAS-based coding, extraction, and nomenclature tool (SCENT) was developed to address this problem. MATERIALS AND METHODS: SCENT employs hierarchical classification rules to identify and extract information from electronic pathology reports. Reports are analyzed and coded using a dictionary of clinical concepts and associated SNOMED codes. To assess the accuracy of SCENT, validation was conducted using manual review of pathology reports from a random sample of 400 breast and 400 prostate cancer patients diagnosed at Kaiser Permanente Southern California. Trained abstractors classified the malignancy status of each report. RESULTS: Classifications of SCENT were highly concordant with those of abstractors, achieving kappa of 0.96 and 0.95 in the breast and prostate cancer groups, respectively. SCENT identified 51 of 54 new primary and 60 of 61 recurrent cancer cases across both groups, with only three false positives in 792 true benign cases. Measures of sensitivity, specificity, positive predictive value, and negative predictive value exceeded 94% in both cancer groups. DISCUSSION: Favorable validation results suggest that SCENT can be used to identify, extract, and code information from pathology report text. Consequently, SCENT has wide applicability in research and clinical care. Further assessment will be needed to validate performance with other clinical text sources, particularly those with greater linguistic variability. CONCLUSION: SCENT is proof of concept for SAS-based natural language processing applications that can be easily shared between institutions and used to support clinical and epidemiologic research. PMID- 22822043 TI - Accuracy of non-invasive measurement of haemoglobin concentration by pulse co oximetry during steady-state and dynamic conditions in liver surgery. AB - BACKGROUND: The Masimo Radical 7 (Masimo Corp., Irvine, CA, USA) pulse co oximeter((r)) calculates haemoglobin concentration (SpHb) non-invasively using transcutaneous spectrophotometry. We compared SpHb with invasive satellite-lab haemoglobin monitoring (Hb(satlab)) during major hepatic resections both under steady-state conditions and in a dynamic phase with fluid administration of crystalloid and colloid solutions. METHODS: Thirty patients undergoing major hepatic resection were included and randomized to receive a fluid bolus of 15 ml kg(-1) colloid (n=15) or crystalloid (n=15) solution over 30 min. SpHb was continuously measured on the index finger, and venous blood samples were analysed in both the steady-state phase (from induction until completion of parenchymal transection) and the dynamic phase (during fluid bolus). RESULTS: Correlation was significant between SpHb and Hb(satlab) (R(2)=0.50, n=543). The modified Bland Altman analysis for repeated measurements showed a bias (precision) of -0.27 (1.06) and -0.02 (1.07) g dl(-1) for the steady-state and dynamic phases, respectively. SpHb accuracy increased when Hb(satlab) was <10 g dl(-1), with a bias (precision) of 0.41 (0.47) vs -0.26 (1.12) g dl(-1) for values >10 g dl(-1), but accuracy decreased after colloid administration (R(2)=0.25). CONCLUSIONS: SpHb correlated moderately with Hb(satlab) with a slight underestimation in both phases in patients undergoing major hepatic resection. Accuracy increased for lower Hb(satlab) values but decreased in the presence of colloid solution. Further improvements are necessary to improve device accuracy under these conditions, so that SpHb might become a sensitive screening device for clinically significant anaemia. PMID- 22822042 TI - Challenges to nurses' efforts of retrieving, documenting, and communicating patient care information. AB - OBJECTIVE: To examine information flow, a vital component of a patient's care and outcomes, in a sample of multiple hospital nursing units to uncover potential sources of error and opportunities for systematic improvement. DESIGN: This was a qualitative study of a sample of eight medical-surgical nursing units from four diverse hospitals in one US state. We conducted direct work observations of nursing staff's communication patterns for entire shifts (8 or 12 h) for a total of 200 h and gathered related documentation artifacts for analyses. Data were coded using qualitative content analysis procedures and then synthesized and organized thematically to characterize current practices. RESULTS: Three major themes emerged from the analyses, which represent serious vulnerabilities in the flow of patient care information during nurse hand-offs and to the entire interdisciplinary team across time and settings. The three themes are: (1) variation in nurse documentation and communication; (2) the absence of a centralized care overview in the patient's electronic health record, ie, easily accessible by the entire care team; and (3) rarity of interdisciplinary communication. CONCLUSION: The care information flow vulnerabilities are a catalyst for multiple types of serious and undetectable clinical errors. We have two major recommendations to address the gaps: (1) to standardize the format, content, and words used to document core information, such as the plan of care, and make this easily accessible to all team members; (2) to conduct extensive usability testing to ensure that tools in the electronic health record help the disconnected interdisciplinary team members to maintain a shared understanding of the patient's plan. PMID- 22822044 TI - Closed-loop neural stimulation for pentylenetetrazole-induced seizures in zebrafish. AB - Neural stimulation can reduce the frequency of seizures in persons with epilepsy, but rates of seizure-free outcome are low. Vagus nerve stimulation prevents seizures by continuously activating noradrenergic projections from the brainstem to the cortex. Cortical norepinephrine then increases GABAergic transmission and increases seizure threshold. Another approach, responsive nervous stimulation, prevents seizures by reactively shocking the seizure onset zone in precise synchrony with seizure onset. The electrical shocks abort seizures before they can spread and manifest clinically. The goal of this study was to determine whether a hybrid platform in which brainstem activation triggered in response to impending seizure activity could prevent seizures. We chose the zebrafish as a model organism for this study because of its ability to recapitulate human disease, in conjunction with its innate capacity for tightly controlled high throughput experimentation. We first set out to determine whether electrical stimulation of the zebrafish hindbrain could have an anticonvulsant effect. We found that pulse train electrical stimulation of the hindbrain significantly increased the latency to onset of pentylenetetrazole-induced seizures, and that this apparent anticonvulsant effect was blocked by noradrenergic antagonists, as is also the case with rodents and humans. We also found that the anticonvulsant effect of hindbrain stimulation could be potentiated by reactive triggering of single pulse electrical stimulations in response to impending seizure activity. Finally, we found that the rate of stimulation triggering was directly proportional to pentylenetetrazole concentration and that the stimulation rate was reduced by the anticonvulsant valproic acid and by larger stimulation currents. Taken as a whole, these results show that that the anticonvulsant effect of brainstem activation can be efficiently utilized by reactive triggering, which suggests that alternative stimulation paradigms for vagus nerve stimulation might be useful. Moreover, our results show that the zebrafish epilepsy model can be used to advance our understanding of neural stimulation in the treatment of epilepsy. PMID- 22822045 TI - Altered inflammation, paraoxonase-1 activity and HDL physicochemical properties in obese humans with and without Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) represents the most common form of genetic obesity. Several studies confirm that obesity is associated with inflammation, oxidative stress and impairment of antioxidant systems; however, no data are available concerning PWS subjects. We compared levels of plasma lipids and C-reactive protein (CRP) in 30 subjects of 'normal' weight (18.5-25 kg/m(2)), 15 PWS obese (>30 kg/m(2)) subjects and 13 body mass index (BMI)-matched obese subjects not affected by PWS. In all subjects, we evaluated the levels of lipid hydroperoxides and the activity of paraoxonase-1 (PON1), an enzyme involved in the antioxidant and anti-inflammatory properties exerted by high-density lipoproteins (HDLs). Furthermore, using the fluorescent molecule of Laurdan, we investigated the physicochemical properties of HDLs isolated from normal weight and obese individuals. Altogether, our results demonstrated, for the first time, higher levels of lipid hydroperoxides and a lower PON1 activity in plasma of obese individuals with PWS with respect to normal-weight controls. These alterations are related to CRP levels, with a lower PON1:CRP ratio in PWS compared with non PWS obese subjects. The study of Laurdan fluorescence parameters showed significant modifications of physicochemical properties in HDLs from PWS individuals. Whatever the cause of obesity, the increase of adiposity is associated with inflammation, oxidative stress and alterations in HDL compositional and functional properties. PMID- 22822046 TI - Induction of oxazolone-mediated features of atopic dermatitis in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells. AB - Animal models mimicking human diseases have been used extensively to study the pathogenesis of autoimmune diseases and the efficacy of potential therapeutics. They are, however, limited with regard to their similarity to the human disease and cannot be used if the antagonist and its cognate receptor require high similarity in structure or binding. Here, we examine the induction of oxazolone mediated features of atopic dermatitis (AD) in NOD-scid IL2Rgamma(null) mice engrafted with human peripheral blood mononuclear cells (PBMC). The mice developed the same symptoms as immunocompetent BALB/c mice. Histological alterations induced by oxazolone were characterized by keratosis, epithelial hyperplasia and influx of inflammatory cells into the dermis and epidermis. The cellular infiltrate was identified as human leukocytes, with T cells being the major constituent. In addition, oxazolone increased human serum IgE levels. The response, however, required the engraftment of PBMC derived from patients suffering from AD, which suggests that this model reflects the immunological status of the donor. Taken together, the model described here has the potential to evaluate the efficacy of therapeutics targeting human lymphocytes in vivo and, in addition, might be developed further to elucidate molecular mechanisms inducing and sustaining flares of the disease. PMID- 22822047 TI - DPP4 inhibitor vildagliptin preserves beta-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice. AB - The development of type 2 diabetes is accompanied by a progressive decline in beta-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on beta cells was studied in diabetic mice. Diabetic pancreatic beta cell-specific C/EBPB transgenic (TG) mice exhibit decreased beta-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on beta cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased beta-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in beta cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in beta cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic beta cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes. PMID- 22822048 TI - Biomarkers of aggressive pituitary adenomas. AB - Pituitary adenomas exhibit a wide range of behaviors. The prediction of aggressive or malignant behavior in pituitary adenomas remains challenging; however, the utility of biomarkers is rapidly evolving. In this review, we discuss potential biomarkers as they relate to aggressive behavior in pituitary adenomas. While detailed histological subtyping remains the best independent predictor of aggressive behavior in the majority of cases, evidence suggests that the additional analyses of FGFR4, MMP, PTTG, Ki-67, p53, and deletions in chromosome 11 may contribute to decisions concerning management of aggressive pituitary adenomas. PMID- 22822049 TI - Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells. AB - Embryonic, adult, artificially reprogrammed, and cancer...- there are various types of cells associated with stemness. Do they have something fundamental in common? Are we applying a common name to very different entities? In this review, we will revisit the characteristics that define 'pluripotency', the main property of stem cells (SCs). For each main type of physiological (embryonic and adult) or synthetic (induced pluripotent) SCs, markers and functional behavior in vitro and in vivo will be described. We will review the pioneering work that has led to obtaining human SC lines, together with the problems that have arisen, both in a biological context (DNA alterations, heterogeneity, tumors, and immunogenicity) and with regard to ethical concerns. Such problems have led to proposals for new operative procedures for growing human SCs of sufficiently high quality for use as models of disease and in human therapy. Finally, we will review the data from the first clinical trials to use various types of SCs. PMID- 22822051 TI - Cochrane review finds that use of cardiotocograph on admission to the labour ward, rather than intermittent auscultation of the fetal heart rate, may increase risk of caesarean in low-risk women. PMID- 22822050 TI - IDO is a nodal pathogenic driver of lung cancer and metastasis development. AB - Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, interleukin (IL)-6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of protumorigenic myeloid-derived suppressor cells (MDSC), as restoration of IL-6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization, and immune escape to license primary and metastatic tumor outgrowth. SIGNIFICANCE: This study provides preclinical, genetic proof-of-concept that the immunoregulatory enzyme IDO contributes to autochthonous carcinoma progression and to the creation of a metastatic niche. IDO deficiency in vivo negatively impacted both vascularization and IL-6 dependent, MDSC-driven immune escape, establishing IDO as an overarching factor directing the establishment of a protumorigenic environment. PMID- 22822052 TI - Nuclear calcium signaling controls methyl-CpG-binding protein 2 (MeCP2) phosphorylation on serine 421 following synaptic activity. AB - The function of MeCP2, a methylated DNA-interacting protein that may act as a global chromatin modifier, is controlled by its phosphorylation on serine 421. Here we show that in hippocampal neurons, nuclear calcium signaling controls synaptic activity-induced phosphorylation of MeCP2 on serine 421. Pharmacological inhibition of calcium/calmodulin-dependent protein (CaM)kinases blocked activity induced MeCP2 serine 421 phosphorylation. CaM kinase II (CaMKII) but not CaMKIV, the major nuclear CaM kinase in hippocampal neurons, appeared to mediate this phosphorylation event. Biochemical subcellular fractionations and immunolocalization studies revealed that several isoforms of CaMKII (i.e. CaMKIIalpha, -beta, -gamma, and -delta) are expressed in the cytosol but are also detectable in the cell nucleus of hippocampal neurons, suggesting that nuclear CaMKII catalyzes MeCP2 serine 421 phosphorylation. Thus, in addition to the classical nuclear calcium-CaMKIV-CREB/CBP (cAMP-response element-binding protein/CREB-binding protein) pathway that regulates transcription of specific target genes, nuclear calcium may also modulate genome-wide the chromatin state in response to synaptic activity via nuclear CaMKII-MeCP2 signaling. PMID- 22822054 TI - Introduction to thematic minireview series on calcium. PMID- 22822053 TI - Influenza A virus infection of human respiratory cells induces primary microRNA expression. AB - The cellular response to virus infection is initiated by recognition of the invading pathogen and subsequent changes in gene expression mediated by both transcriptional and translational mechanisms. In addition to well established means of regulating antiviral gene expression, it has been demonstrated that RNA interference (RNAi) can play an important role in antiviral responses. Virus derived small interfering RNA (siRNA) is a primary antiviral response exploited by plants and invertebrate animals, and host-encoded microRNA (miRNA) species have been clearly implicated in the regulation of innate and adaptive immune responses in mammals and other vertebrates. Examination of miRNA abundance in human lung cell lines revealed endogenous miRNAs, including miR-7, miR-132, miR 146a, miR-187, miR-200c, and miR-1275, to specifically accumulate in response to infection with two influenza A virus strains, A/Udorn/72 and A/WSN/33. Known antiviral response pathways, including Toll-like receptor, RIG-I-like receptor, and direct interferon or cytokine stimulation did not alter the abundance of the tested miRNAs to the extent of influenza A virus infection, which initiates primary miRNA transcription via a secondary response pathway. Gene expression profiling identified 26 cellular mRNAs targeted by these miRNAs, including IRAK1, MAPK3, and other components of innate immune signaling systems. PMID- 22822055 TI - Calcium channels and pumps in cancer: changes and consequences. AB - Increases in intracellular free Ca(2+) play a major role in many cellular processes. The deregulation of Ca(2+) signaling is a feature of a variety of diseases, and modulators of Ca(2+) signaling are used to treat conditions as diverse as hypertension to pain. The Ca(2+) signal also plays a role in processes important in cancer, such as proliferation and migration. Many studies in cancer have identified alterations in the expression of proteins involved in the movement of Ca(2+) across the plasma membrane and subcellular organelles. In some cases, these Ca(2+) channels or pumps are potential therapeutic targets for specific cancer subtypes or correlate with prognosis. PMID- 22822056 TI - Endoplasmic reticulum stress induces a caspase-dependent N-terminal cleavage of RBX1 protein in B cells. AB - Endoplasmic reticulum (ER) stress develops when the ER is overloaded with too many proteins to fold. This elicits a signaling pathway called the unfolded protein response. The unfolded protein response is physiologically required for the terminal development of B cells into antibody-secreting plasma cells. Ring Box Protein 1 (RBX1) is a 14-kDa protein necessary for ubiquitin ligation activity of the multimeric cullin ring ubiquitin ligases (CRLs). As RBX1 is shared by a large number of CRLs, alterations in its activity may lead to global changes in protein stability. We discovered that RBX1 is cleaved in the course of LPS-induced plasma cell differentiation and in multiple myeloma cell lines upon induction of pharmacological ER stress. The cleavage is executed by several caspase proteases that cleave RBX1 eight amino acids from the N terminus. To address the possible implication of RBX1 cleavage for CRL activity, we replaced the endogenous RBX1 homolog of the yeast Saccharomyces cerevisiae, Roc1, with the wild type or the N-terminal Delta8 mutant human RBX1. We show that yeast expressing the cleaved RBX1 are hypersensitive to ER stress and are impaired in CRL-mediated ubiquitination and degradation. We propose a model by which N terminal cleavage of RBX1 impairs its activity and promotes susceptibility to ER stress induction. PMID- 22822057 TI - CYP90A1/CPD, a brassinosteroid biosynthetic cytochrome P450 of Arabidopsis, catalyzes C-3 oxidation. AB - Brassinosteroids (BRs) are steroidal phytohormones that regulate plant growth and development. Whereas in Arabidopsis the network-like routes of BR biosynthesis have been elucidated in considerable detail, the roles of some of the biosynthetic enzymes and their participation in the different subpathways remained to be clarified. We investigated the function of the cytochrome P450 monooxygenase CYP90A1/CPD, which earlier had been proposed to act as a BR C-23 hydroxylase. Our GC-MS and genetic analyses demonstrated that the cpd mutation arrests BR synthesis upstream of the DET2-mediated 5alpha reduction step and that overexpression of the C-23 hydroxylase CYP90C1 does not alleviate BR deficiency in the cpd mutant. In line with these results, we found that CYP90A1/CPD heterologously expressed in a baculovirus-insect cell system catalyzes C-3 oxidation of the early BR intermediates (22S)-22-hydroxycampesterol and (22R,23R) 22,23-dihydroxycampesterol, as well as of 6-deoxocathasterone and 6 deoxoteasterone. Enzyme kinetic data of CYP90A1/CPD and DET2, together with those of the earlier studied CYP90B1, CYP90C1, and CYP90D1, suggest that BR biosynthesis proceeds mainly via the campestanol-independent pathway. PMID- 22822058 TI - Ca2+-dependent transcriptional control of Ca2+ homeostasis. AB - Intracellular free Ca(2+) ions regulate many cellular functions, and in turn, the cell devotes many genes/proteins to keep tight control of the level of intracellular free Ca(2+). Here, we review recent work on Ca(2+)-dependent mechanisms and effectors that regulate the transcription of genes encoding proteins involved in the maintenance of the homeostasis of Ca(2+) in the cell. PMID- 22822059 TI - Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1beta-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets. AB - Arachidonic acid is converted to prostaglandin E(2) (PGE(2)) by a sequential enzymatic reaction performed by two isoenzyme groups, cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin E synthases (cPGES, mPGES-1, and mPGES-2). mPGES-1 is widely considered to be the final enzyme regulating COX-2-dependent PGE(2) synthesis. These generalizations have been based in most part on experiments utilizing gene expression analyses of cell lines and tumor tissue. To assess the relevance of these generalizations to a native mammalian tissue, we used isolated human and rodent pancreatic islets to examine interleukin (IL) 1beta-induced PGE(2) production, because PGE(2) has been shown to mediate IL 1beta inhibition of islet function. Rat islets constitutively expressed mRNAs of COX-1, COX-2, cPGES, and mPGES-1. As expected, IL-1beta increased mRNA levels for COX-2 and mPGES-1, but not for COX-1 or cPGES. Basal protein levels of COX-1, cPGES, and mPGES-2 were readily detected in whole cell extracts but were not regulated by IL-1beta. IL-1beta increased protein levels of COX-2, but unexpectedly mPGES-1 protein levels were low and unaffected. In microsomal extracts, mPGES-1 protein was barely detectable in rat islets but clearly present in human islets; however, in neither case did IL-1beta increase mPGES-1 protein levels. To further assess the importance of mPGES-1 to IL-1beta regulation of an islet physiologic response, glucose-stimulated insulin secretion was examined in isolated islets of WT and mPGES-1-deficient mice. IL-1beta inhibited glucose stimulated insulin secretion equally in both WT and mPGES-1(-/-) islets, indicating that COX-2, not mPGES-1, mediates IL-1beta-induced PGE(2) production and subsequent inhibition of insulin secretion. PMID- 22822061 TI - Leucine-rich repeat 11 of Toll-like receptor 9 can tightly bind to CpG-containing oligodeoxynucleotides, and the positively charged residues are critical for the high affinity. AB - TLR9 is a receptor for sensing bacterial DNA/CpG-containing oligonucleotides (CpG ODN). The extracellular domain (ECD) of human TLR9 (hTLR9) is composed of 25 leucine-rich repeats (LRR) contributing to the binding of CpG ODN. Herein, we showed that among LRR2, -5, -8, and -11, LRR11 of hTLR9 had the highest affinity for CpG ODN followed by LRR2 and -5, whereas LRR8 had almost no affinity. In vitro, preincubation with LRR11 more significantly decreased CpG ODN internalization, subsequent NF-kappaB activation, and cytokine release than with LRR2 and -5 in mouse peritoneal macrophages treated with CpG ODN. The LRR11 deletion mutant of hTLR9 conferred decreased cellular responses to CpG ODN. Single- or multiple-site mutants at five positively charged residues of LRR11 (LRR11m1-9), especially Arg-337 and Lys-367, were shown to contribute to hTLR9 binding of CpG ODN. LRR11m1-9 showed reduced inhibition of CpG ODN internalization and CpG ODN/TLR9 signaling, supporting the above findings. Prediction of whole hTLR9 ECD-CpG ODN interactions revealed that Arg-337 and Lys 338 directly contact CpG ODN through hydrogen bonding, whereas Lys-347, Arg-348, and His-353 contribute to stabilizing the shape of the ligand binding region. These findings suggested that although all five positively charged residues within LRR11 contributed to its high affinity, only Arg-337 and Lys-338 directly interacted with CpG ODN. In conclusion, the results suggested that LRR11 could strongly bind to CpG ODN, whereas mutations at the five positively charge residues reduced this high affinity. LRR11 may be further investigated as an antagonist of hTLR9. PMID- 22822060 TI - Catalytic convergence of manganese and iron lipoxygenases by replacement of a single amino acid. AB - Lipoxygenases (LOXs) contain a hydrophobic substrate channel with the conserved Gly/Ala determinant of regio- and stereospecificity and a conserved Leu residue near the catalytic non-heme iron. Our goal was to study the importance of this region (Gly(332), Leu(336), and Phe(337)) of a lipoxygenase with catalytic manganese (13R-MnLOX). Recombinant 13R-MnLOX oxidizes 18:2n-6 and 18:3n-3 to 13R , 11(S or R)-, and 9S-hydroperoxy metabolites (~80-85, 15-20, and 2-3%, respectively) by suprafacial hydrogen abstraction and oxygenation. Replacement of Phe(337) with Ile changed the stereochemistry of the 13-hydroperoxy metabolites of 18:2n-6 and 18:3n-3 (from ~100% R to 69-74% S) with little effect on regiospecificity. The abstraction of the pro-S hydrogen of 18:2n-6 was retained, suggesting antarafacial hydrogen abstraction and oxygenation. Replacement of Leu(336) with smaller hydrophobic residues (Val, Ala, and Gly) shifted the oxygenation from C-13 toward C-9 with formation of 9S- and 9R-hydroperoxy metabolites of 18:2n-6 and 18:3n-3. Replacement of Gly(332) and Leu(336) with larger hydrophobic residues (G332A and L336F) selectively augmented dehydration of 13R-hydroperoxyoctadeca-9Z,11E,15Z-trienoic acid and increased the oxidation at C-13 of 18:1n-6. We conclude that hydrophobic replacements of Leu(336) can modify the hydroperoxide configurations at C-9 with little effect on the R configuration at C-13 of the 18:2n-6 and 18:3n-3 metabolites. Replacement of Phe(337) with Ile changed the stereospecific oxidation of 18:2n-6 and 18:3n-3 with formation of 13S-hydroperoxides by hydrogen abstraction and oxygenation in analogy with soybean LOX-1. PMID- 22822062 TI - Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. AB - TDP2 is a multifunctional enzyme previously known for its role in signal transduction as TRAF and TNF receptor-associated protein (TTRAP) and ETS1 associated protein 2 (EAPII). The gene has recently been renamed TDP2 because it plays a critical role for the repair of topoisomerase II cleavage complexes (Top2cc) and encodes an enzyme that hydrolyzes 5'-tyrosine-DNA adducts that mimic abortive Top2cc. Here we further elucidate the DNA-processing activities of human recombinant TDP2 and its biochemical characteristics. The preferred substrate for TDP2 is single-stranded DNA or duplex DNA with a four-base pair overhang, which is consistent with the known structure of Top2cc or Top3cc. The k(cat)/K(m) of TDP1 and TDP2 was determined. It was found to be 4 * 10(5) s(-1)M(-1) for TDP2 using single-stranded 5'-tyrosyl-DNA. The processing of substrates as short as five nucleotides long suggests that TDP2 can directly bind DNA ends. 5' Phosphodiesterase activity requires a phosphotyrosyl linkage and tolerates an extended group attached to the tyrosine. TDP2 requires Mg(2+) or Mn(2+) for efficient catalysis but is weakly active with Ca(2+) or Zn(2+). Titration with Ca(2+) demonstrates a two-metal binding site in TDP2. Sequence alignment suggests that TDP2 contains four conserved catalytic motifs shared by Mg(2+)-dependent endonucleases, such as APE1. Substitutions at each of the four catalytic motifs identified key residues Asn-120, Glu-152, Asp-262, and His-351, whose mutation to alanine significantly reduced or completely abolished enzymatic activity. Our study characterizes the substrate specificity and kinetic parameters of TDP2. In addition, a two-metal catalytic mechanism is proposed. PMID- 22822063 TI - Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger. AB - The mitochondrial membrane potential that powers the generation of ATP also facilitates mitochondrial Ca(2+) shuttling. This process is fundamental to a wide range of cellular activities, as it regulates ATP production, shapes cytosolic and endoplasmic recticulum Ca(2+) signaling, and determines cell fate. Mitochondrial Ca(2+) transport is mediated primarily by two major transporters: a Ca(2+) uniporter that mediates Ca(2+) uptake and a Na(+)/Ca(2+) exchanger that subsequently extrudes mitochondrial Ca(2+). In this minireview, we focus on the specific role of the mitochondrial Na(+)/Ca(2+) exchanger and describe its ion exchange mechanism, regulation by ions, and putative partner proteins. We discuss the recent molecular identification of the mitochondrial exchanger and how its activity is linked to physiological and pathophysiological processes. PMID- 22822064 TI - Ryanodine receptors: structure and function. AB - Ryanodine receptors (RyRs) are huge ion channels that are responsible for the release of Ca(2+) from the sarco/endoplasmic reticulum. RyRs form homotetramers with a mushroom-like shape, consisting of a large cytoplasmic head and transmembrane stalk. Ca(2+) is a major physiological ligand that triggers opening of RyRs, but a plethora of modulatory proteins and small molecules in the cytoplasm and sarco/endoplasmic reticulum lumen have been recognized. Over 300 mutations in RyRs are associated with severe skeletal muscle disorders or triggered cardiac arrhythmias. With the advent of high-resolution structures of individual domains, many of these can be mapped onto the three-dimensional structure. PMID- 22822065 TI - Euglycemic agent-mediated hypothalamic transcriptomic manipulation in the N171 82Q model of Huntington disease is related to their physiological efficacy. AB - Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171 82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD. PMID- 22822067 TI - Ca2+ regulation of ion transport in the Na+/Ca2+ exchanger. AB - The binding of Ca(2+) to two adjacent Ca(2+)-binding domains, CBD1 and CBD2, regulates ion transport in the Na(+)/Ca(2+) exchanger. As sensors for intracellular Ca(2+), the CBDs form electrostatic switches that induce the conformational changes required to initiate and sustain Na(+)/Ca(2+) exchange. Depending on the presence of a few key residues in the Ca(2+)-binding sites, zero to four Ca(2+) ions can bind with affinities between 0.1 to 20 MUm. Importantly, variability in CBD2 as a consequence of alternative splicing modulates not only the number and affinities of the Ca(2+)-binding sites in CBD2 but also the Ca(2+) affinities in CBD1. PMID- 22822066 TI - Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization. AB - Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate were discovered >2 decades ago. That they are second messengers for mobilizing Ca(2+) stores has since been firmly established. Separate stores and distinct Ca(2+) channels are targeted, with cyclic ADP-ribose acting on the ryanodine receptors in the endoplasmic reticulum, whereas nicotinic acid adenine dinucleotide phosphate mobilizes the endolysosomes via the two-pore channels. Despite the structural and functional differences, both messengers are synthesized by a ubiquitous enzyme, CD38, whose crystal structure and catalytic mechanism have now been well elucidated. How this novel signaling enzyme is regulated remains largely unknown and is the focus of this minireview. PMID- 22822068 TI - Two ATPases. AB - In this article, I reflect on research on two ATPases. The first is F(1)F(0) ATPase, also known as ATP synthase. It is the terminal enzyme in oxidative phosphorylation and famous as a nanomotor. Early work on mitochondrial enzyme involved purification in large amount, followed by deduction of subunit composition and stoichiometry and determination of molecular sizes of holoenzyme and individual subunits. Later work on Escherichia coli enzyme utilized mutagenesis and optical probes to reveal the molecular mechanism of ATP hydrolysis and detailed facets of catalysis. The second ATPase is P-glycoprotein, which confers multidrug resistance, notably to anticancer drugs, in mammalian cells. Purification of the protein in large quantity allowed detailed characterization of catalysis, formulation of an alternating sites mechanism, and recently, advances in structural characterization. PMID- 22822069 TI - Redefinition of the carbohydrate binding specificity of Helicobacter pylori BabA adhesin. AB - Certain Helicobacter pylori strains adhere to the human gastric epithelium using the blood group antigen-binding adhesin (BabA). All BabA-expressing H. pylori strains bind to the blood group O determinants on type 1 core chains, i.e. to the Lewis b antigen (Fucalpha2Galbeta3(Fucalpha4)GlcNAc; Le(b)) and the H type 1 determinant (Fucalpha2Galbeta3GlcNAc). Recently, BabA strains have been categorized into those recognizing only Le(b) and H type 1 determinants (designated specialist strains) and those that also bind to A and B type 1 determinants (designated generalist strains). Here, the structural requirements for carbohydrate recognition by generalist and specialist BabA were further explored by binding of these types of strains to a panel of different glycosphingolipids. Three glycosphingolipids recognized by both specialist and generalist BabA were isolated from the small intestine of a blood group O pig and characterized by mass spectrometry and proton NMR as H type 1 pentaglycosylceramide (Fucalpha2Galbeta3GlcNAcbeta3Galbeta4Glcbeta1Cer), Globo H hexaglycosylceramide (Fucalpha2Galbeta3GalNAcbeta3Galalpha4Galbeta4Glcbeta1Cer), and a mixture of three complex glycosphingolipids (Fucalpha2Galbeta4GlcNAcbeta6(Fucalpha2Galbeta3GlcNAcbeta3)Galbeta3GlcNAcbeta3Gal eta4Glcbeta1Cer, Fucalpha2Galbeta3GlcNAcbeta6(Fucalpha2Galbeta3GlcNAcbeta3)Galbeta3GlcNAcbeta3Galb ta4Glcbeta1Cer, and Fucalpha2Galbeta4(Fucalpha3)GlcNAcbeta6(Fucalpha2Galbeta3GlcNAcbeta3)Galbeta3GlcN cbeta3Galbeta4Glcbeta1Cer). In addition to the binding of both strains to the Globo H hexaglycosylceramide, i.e. a blood group O determinant on a type 4 core chain, the generalist strain bound to the Globo A heptaglycosylceramide (GalNAcalpha3(Fucalpha2)Galbeta3GalNAcbeta3Galalpha4Galbeta4Glcbeta1Cer), i.e. a blood group A determinant on a type 4 core chain. The binding of BabA to the two sets of isoreceptors is due to conformational similarities of the terminal disaccharides of H type 1 and Globo H and of the terminal trisaccharides of A type 1 and Globo A. PMID- 22822070 TI - The role of heterodimeric AP-1 protein comprised of JunD and c-Fos proteins in hematopoiesis. AB - Activator protein-1 (AP-1) regulates a wide range of cellular processes including proliferation, differentiation, and apoptosis. As a transcription factor, AP-1 is commonly found as a heterodimer comprised of c-Jun and c-Fos proteins. However, other heterodimers may also be formed. The function of these dimers, specifically the heterodimeric AP-1 comprised of JunD and c-Fos (AP-1(JunD/c-Fos)), has not been elucidated. Here, we identified a function of AP-1(JunD/c-Fos) in Xenopus hematopoiesis. A gain-of-function study performed by overexpressing junD and c fos and a loss-of-function study using morpholino junD demonstrate a critical role for AP-1(JunD/c-Fos) in hematopoiesis during Xenopus embryogenesis. Additionally, we confirmed that JunD of AP-1(JunD/c-Fos) is required for BMP-4 induced hematopoiesis. We also demonstrated that BMP-4 regulated JunD activity at the transcriptional regulation and post-translational modification levels. Collectively, our findings identify AP-1(JunD/c-Fos) as a novel hematopoietic transcription factor and the requirement of AP-1(JunD/c-Fos) in BMP-4-induced hematopoiesis during Xenopus hematopoiesis. PMID- 22822071 TI - Stimulation of histone deacetylase activity by metabolites of intermediary metabolism. AB - Histone deacetylases (HDACs) function in a wide range of molecular processes, including gene expression, and are of significant interest as therapeutic targets. Although their native complexes, subcellular localization, and recruitment mechanisms to chromatin have been extensively studied, much less is known about whether the enzymatic activity of non-sirtuin HDACs can be regulated by natural metabolites. Here, we show that several coenzyme A (CoA) derivatives, such as acetyl-CoA, butyryl-CoA, HMG-CoA, and malonyl-CoA, as well as NADPH but not NADP(+), NADH, or NAD(+), act as allosteric activators of recombinant HDAC1 and HDAC2 in vitro following a mixed activation kinetic. In contrast, free CoA, like unconjugated butyrate, inhibits HDAC activity in vitro. Analysis of a large number of engineered HDAC1 mutants suggests that the HDAC activity can potentially be decoupled from "activatability" by the CoA derivatives. In vivo, pharmacological inhibition of glucose-6-phosphate dehydrogenase (G6PD) to decrease NADPH levels led to significant increases in global levels of histone H3 and H4 acetylation. The similarity in structures of the identified metabolites and the exquisite selectivity of NADPH over NADP(+), NADH, and NAD(+) as an HDAC activator reveal a previously unrecognized biochemical feature of the HDAC proteins with important consequences for regulation of histone acetylation as well as the development of more specific and potent HDAC inhibitors. PMID- 22822072 TI - High conformational stability of secreted eukaryotic catalase-peroxidases: answers from first crystal structure and unfolding studies. AB - Catalase-peroxidases (KatGs) are bifunctional heme enzymes widely spread in archaea, bacteria, and lower eukaryotes. Here we present the first crystal structure (1.55 A resolution) of an eukaryotic KatG, the extracellular or secreted enzyme from the phytopathogenic fungus Magnaporthe grisea. The heme cavity of the homodimeric enzyme is similar to prokaryotic KatGs including the unique distal (+)Met-Tyr-Trp adduct (where the Trp is further modified by peroxidation) and its associated mobile arginine. The structure also revealed several conspicuous peculiarities that are fully conserved in all secreted eukaryotic KatGs. Peculiarities include the wrapping at the dimer interface of the N-terminal elongations from the two subunits and cysteine residues that cross link the two subunits. Differential scanning calorimetry and temperature- and urea-mediated unfolding followed by UV-visible, circular dichroism, and fluorescence spectroscopy combined with site-directed mutagenesis demonstrated that secreted eukaryotic KatGs have a significantly higher conformational stability as well as a different unfolding pattern when compared with intracellular eukaryotic and prokaryotic catalase-peroxidases. We discuss these properties with respect to the structure as well as the postulated roles of this metalloenzyme in host-pathogen interactions. PMID- 22822073 TI - Quantitation of the effect of ErbB2 on epidermal growth factor receptor binding and dimerization. AB - The epidermal growth factor (EGF) receptor is a member of the ErbB family of receptors that also includes ErbB2, ErbB3, and ErbB4. These receptors form homo- and heterodimers in response to ligand with ErbB2 being the preferred dimerization partner. Here we use (125)I-EGF binding to quantitate the interaction of the EGF receptor with ErbB2. We show that the EGFR/ErbB2 heterodimer binds EGF with a 7-fold higher affinity than the EGFR homodimer. Because it cannot bind a second ligand, the EGFR/ErbB2 heterodimer is not subject to ligand-induced dissociation caused by the negatively cooperative binding of EGF to the second site on the EGFR homodimer. This increases the stability of the heterodimer relative to the homodimer and is associated with enhanced and prolonged EGF receptor autophosphorylation. These effects are independent of the kinase activity of ErbB2 but require back-to-back dimerization of the EGF receptor with ErbB2. Back-to-back dimerization is also required for phosphorylation of ErbB2. These findings provide a molecular explanation for the apparent preference of the EGF receptor for dimerizing with ErbB2 and suggest that the phosphorylation of ErbB2 occurs largely in the context of the EGFR/ErbB2 heterodimer, rather than through lateral phosphorylation of isolated ErbB2 subunits. PMID- 22822074 TI - Biochemical analysis of hypermutation by the deoxycytidine deaminase APOBEC3A. AB - APOBEC3A belongs to a family of single-stranded DNA (ssDNA) DNA cytosine deaminases that are known for restriction of HIV through deamination-induced mutational inactivation, e.g. APOBEC3G, or initiation of somatic hypermutation and class switch recombination (activation-induced cytidine deaminase). APOBEC3A, which is localized to both the cytoplasm and nucleus, not only restricts HIV but can also initiate catabolism of cellular DNA. Despite being ascribed these roles, there is a paucity of data available on the biochemical mechanism by which APOBEC3A deaminates ssDNA. Here we assessed APOBEC3A deamination activity on ssDNA and in dynamic systems modeling HIV replication (cytoplasmic event) and DNA transcription (nuclear event). We find that APOBEC3A, unlike the highly processive APOBEC3G, exhibits low or no processivity when deaminating synthetic ssDNA substrates with two cytosines located 5-63 nucleotides apart, likely because of an apparent K(d) in the micromolar range (9.1 MUm). APOBEC3A was able to deaminate nascently synthesized (-)DNA in an in vitro model HIV replication assay but induced fewer mutations overall in comparison to APOBEC3G. However, the data indicate that the target deamination motif (5'-TC for APOBEC3A and 5'-CC for APOBEC3G) and not the number of mutations best predicted the ability to mutationally inactivate HIV. We further assessed APOBEC3A for the ability to deaminate dsDNA undergoing transcription, which could allow for collateral deaminations to occur in genomic DNA similar to the action of activation-induced cytidine deaminase. That APOBEC3A was able to deaminate dsDNA undergoing transcription suggests a genomic cost of a deamination-based retroviral restriction system. PMID- 22822075 TI - Effects of phosphate binders in moderate CKD. AB - Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain. PMID- 22822076 TI - MicroRNA-324-3p promotes renal fibrosis and is a target of ACE inhibition. AB - The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated. In situ hybridization localized miR-324-3p to glomerular podocytes, parietal cells of Bowman's capsule, and most abundantly, cortical tubules. A predicted target of miR-324-3p is prolyl endopeptidase (Prep), a serine peptidase involved in the metabolism of angiotensins and the synthesis of the antifibrotic peptide N-acetyl seryl-aspartyl-lysyl-proline (Ac-SDKP). In cultured tubular cells, transient transfection with a miR-324-3p mimic reduced Prep protein and activity, validating Prep as a target of this miRNA. In MWF rats, upregulation of miR-324 3p associated with markedly reduced expression of Prep in both glomeruli and tubules, low urine Ac-SDKP, and increased deposition of collagen. ACE inhibition downregulated glomerular and tubular miR-324-3p, promoted renal Prep expression, increased plasma and urine Ac-SDKP, and attenuated renal fibrosis. In summary, these results suggest that dysregulation of the miR-324-3p/Prep pathway contributes to the development of fibrosis in progressive nephropathy. The renoprotective effects of ACE inhibitors may result, in part, from modulation of this pathway, suggesting that it may hold other potential therapeutic targets. PMID- 22822078 TI - How to use near-patient capillary ketone meters. PMID- 22822079 TI - The child with a limp: a symptom and not a diagnosis. PMID- 22822077 TI - Rituximab in idiopathic membranous nephropathy. AB - Selective depletion of B cells with the mAb rituximab may benefit the autoimmune glomerular disease idiopathic membranous nephropathy (IMN). Here, we describe our experience treating 100 consecutive IMN patients with persistent nephrotic syndrome with rituximab. We defined complete remission as persistent proteinuria <0.3 g/24 h and partial remission as persistent proteinuria <3 g/24 h, each also having >50% reduction in proteinuria from baseline. During a median follow-up of 29 months after rituximab administration, 65 patients achieved complete or partial remission. The median time to remission was 7.1 months. All 24 patients who had at least 4 years of follow-up achieved complete or partial remission. Rates of remission were similar between patients with or without previous immunosuppressive treatment. Four patients died and four progressed to ESRD. Measured GFR increased by a mean 13.2 (SD 19.6) ml/min per 1.73 m(2) among those who achieved complete remission. Serum albumin significantly increased and albumin fractional clearance decreased among those achieving complete or partial remission. Proteinuria at baseline and the follow-up duration each independently predicted the decline of proteinuria. Furthermore, the magnitude of proteinuria reduction significantly correlated with slower GFR decline (P=0.0001). No treatment-related serious adverse events occurred. In summary, rituximab achieved disease remission and stabilized or improved renal function in a large cohort of high-risk patients with IMN. PMID- 22822080 TI - How to use toxicology screening tests. PMID- 22822082 TI - Oxidation-mediated DNA cross-linking contributes to the toxicity of 6-thioguanine in human cells. AB - The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders. PMID- 22822081 TI - Negative regulators of integrin activity. AB - Integrins are heterodimeric transmembrane adhesion receptors composed of alpha- and beta-subunits. They are ubiquitously expressed and have key roles in a number of important biological processes, such as development, maintenance of tissue homeostasis and immunological responses. The activity of integrins, which indicates their affinity towards their ligands, is tightly regulated such that signals inside the cell cruicially regulate the switching between active and inactive states. An impaired ability to activate integrins is associated with many human diseases, including bleeding disorders and immune deficiencies, whereas inappropriate integrin activation has been linked to inflammatory disorders and cancer. In recent years, the molecular details of integrin 'inside out' activation have been actively investigated. Binding of cytoplasmic proteins, such as talins and kindlins, to the cytoplasmic tail of beta-integrins is widely accepted as being the crucial step in integrin activation. By contrast, much less is known with regard to the counteracting mechanism involved in switching integrins into an inactive conformation. In this Commentary, we aim to discuss the known mechanisms of integrin inactivation and the molecules involved. PMID- 22822083 TI - Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response. AB - Ectopic expression of the mitochondrial F(1)F(0)-ATP synthase on the plasma membrane has been reported to occur in cancer, but whether it exerts a functional role in this setting remains unclear. Here we show that ectopic ATP synthase and the electron transfer chain exist on the plasma membrane in a punctuated distribution of lung adenocarcinoma cells, where it is critical to support cancer cell proliferation. Applying ATP synthase inhibitor citreoviridin induced cell cycle arrest and inhibited proliferation and anchorage-independent growth of lung cancer cells. Analysis of protein expression profiles after citreoviridin treatment suggested this compound induced the unfolded protein response (UPR) associated with phosphorylation the translation initiation factor 2alpha (eIF2alpha), triggering cell growth inhibition. Citreoviridin-enhanced eIF2alpha phosphorylation could be reversed by siRNA-mediated attenuation of the UPR kinase PKR-like endoplasmic reticulum kinase (PERK) combined with treatment with the antioxidant N-acetylcysteine, establishing that reactive oxygen species (ROS) boost UPR after citreoviridin treatment. Thus, a coordinate elevation of UPR and ROS initiates a positive feedback loop that convergently blocks cell proliferation. Our findings define a molecular function for ectopic ATP synthase at the plasma membrane in lung cancer cells and they prompt further study of its inhibition as a potential therapeutic approach. PMID- 22822084 TI - Identifying key juxtamembrane interactions in cell membranes using AraC-based transcriptional reporter assay (AraTM). AB - Dimerization is a key regulatory mechanism in activation of transmembrane (TM) receptors during signal transduction. This process involves a coordinated interplay between extracellular (EX), TM, and cytoplasmic (CYTO) regions to form a specific interface required for both ligand binding and intracellular signaling to occur. While several transcriptional activator-based methods exist for investigating TM interactions in bacterial membranes, expression of TM chimera in these methods occurs in a reverse orientation, and are limited to only TM domains for proper membrane trafficking and integration. We therefore developed a new, AraC-based transcriptional reporter assay (AraTM) that expresses EX-TM-CYTO chimera in their native orientation, thereby enabling membrane trafficking to occur independent of the TM chimera used as well as permitting analysis of EX-TM CYTO interactions in biological membranes. Using integrin alpha(IIb) TM-CYTO as a model, we observe a large increase in homodimerization for the constitutively active TM mutant L980A relative to wild-type in the TM-CYTO construct (A963 E1008). We also characterized the receptor for advanced glycation endproducts (RAGE), whose homooligomeric state is critical in ligand recognition, and find the specific juxtamembrane region within the CYTO (A375-P394) mediates homodimerization, and is dominant over effects observed when the extracellular C2 domain is included. Furthermore, we find good agreement between our AraTM measurements in bacterial membranes and BRET measurements made on corresponding RAGE constructs expressed in transfected HEK293 cells. Overall, the AraTM assay provides a new approach to identify specific interactions between receptor EX-TM CYTO domains in biological membranes that are important in regulation of signal transduction. PMID- 22822085 TI - Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. AB - In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that must be balanced to regulate cell death and survival. Here we identify the low-density lipoprotein receptor-related protein-1 (LRP1) as the VacA receptor for toxin-induced autophagy in the gastric epithelial cell line AZ-521, and show that VacA internalization through binding to LRP1 regulates the autophagic process including generation of LC3-II from LC3-I, which is involved in formation of autophagosomes and autolysosomes. Knockdown of LRP1 and Atg5 inhibited generation of LC3-II as well as cleavage of PARP, a marker of apoptosis, in response to VacA, whereas caspase inhibitor, benzyloxycarbonyl-VAD fluoromethylketone (Z-VAD-fmk), and necroptosis inhibitor, Necrostatin-1, did not inhibit VacA-induced autophagy, suggesting that VacA-induced autophagy via LRP1 binding precedes apoptosis. Other VacA receptors such as RPTPalpha, RPTPbeta, and fibronectin did not affect VacA-induced autophagy or apoptosis. Therefore, we propose that the cell surface receptor, LRP1, mediates VacA-induced autophagy and apoptosis. PMID- 22822086 TI - Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid. AB - Phosphatidylinositol transfer proteins (PITPs) are versatile proteins required for signal transduction and membrane traffic. The best characterized mammalian PITPs are the Class I PITPs, PITPalpha (PITPNA) and PITPbeta (PITPNB), which are single domain proteins with a hydrophobic cavity that binds a phosphatidylinositol (PI) or phosphatidylcholine molecule. In this study, we report the lipid binding properties of an uncharacterized soluble PITP, phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) (alternative name, RdgBbeta), of the Class II family. We show that the lipid binding properties of this protein are distinct to Class I PITPs because, besides PI, RdgBbeta binds and transfers phosphatidic acid (PA) but hardly binds phosphatidylcholine. RdgBbeta when purified from Escherichia coli is preloaded with PA and phosphatidylglycerol. When RdgBbeta was incubated with permeabilized HL60 cells, phosphatidylglycerol was released, and PA and PI were now incorporated into RdgBbeta. After an increase in PA levels following activation of endogenous phospholipase D or after addition of bacterial phospholipase D, binding of PA to RdgBbeta was greater at the expense of PI binding. We propose that RdgBbeta, when containing PA, regulates an effector protein or can facilitate lipid transfer between membrane compartments. PMID- 22822088 TI - Time-dilation and time-contraction in an anisochronous and anisometric visual scenery. AB - Several studies show that visual stimuli traveling at higher velocities are overestimated with respect to slower, or stationary, stimuli of equivalent physical duration. This effect-time dilation-relates more in general to several accounts highlighting a quantitative relationship between the amount of changes a stimulus is subject to and the perceived duration: faster stimuli, subject to a greater number of changes in space, lead to overestimated durations of displacement. In the present paper we provide evidence of a new illusory effect, in which the apparent duration of a sensory event is affected by the way a constant number of changes are delivered in time, or in time and space. Participants judged accelerating and decelerating sequences of stationary flickering stimuli (Experiments 1 and 3) and accelerating and decelerating horizontally drifting visual stimuli (Experiment 2) on the fronto-parallel plane. Acceleration and deceleration were achieved by irregular sequencing of events in time (anisochronous flicker rate) or irregular sequencing of events in time and space (anisochronous and/or anisometric drift). Despite being characterized by the same amounts of visual changes, accelerating and decelerating sequences lead to opposite duration biases (underestimation and overestimation errors, respectively). We refer to this effect in terms of ATI: Aniso-Time-Illusion. This bias was observed in both subsecond (760 ms) and suprasecond ranges (1900 ms). These data highlight how the spatio-temporal evolution of dynamic visual events, asides the overall quantity of changes they are subject to, affect the perceived amount of time they require to unfold. PMID- 22822089 TI - A generalized magnitude system for space, time, and quantity? A cautionary note. AB - We investigated the claim that larger stimuli are perceived to last longer (Xuan, Zhang, He, & Chen, 2007). This claim, along with other similar claims of interactions between magnitude representations, is frequently used to support the generalized magnitude system hypothesis-the suggestion that the brain represents information about different magnitudes (e.g., time, space, and quantity) via a common mechanism. It is not clear, however, whether the size of a stimulus genuinely affects the perceived duration of the stimulus or simply biases decisions about duration. This was addressed using duration "equality judgments," which have been proposed to measure perceived duration unconfounded by decisional bias-in contrast to "comparative judgments," which are generally considered bias prone. Using equality judgments, we failed to find support for the claim that larger stimuli are perceived to last longer, despite replicating the original effect reported by Xuan et al. (2007) using comparative judgments. Instead, unexpectedly, larger stimuli were judged-though not necessarily perceived-as shorter in duration. This result casts doubt on the conclusions of a significant body of behavioral interference studies using comparative judgments, which support a generalized magnitude system. We also identify a hitherto unrecognized potential source of decisional bias associated with equality judgments. PMID- 22822087 TI - Protein carbonylation and adipocyte mitochondrial function. AB - Carbonylation is the covalent, non-reversible modification of the side chains of cysteine, histidine, and lysine residues by lipid peroxidation end products such as 4-hydroxy- and 4-oxononenal. In adipose tissue the effects of such modifications are associated with increased oxidative stress and metabolic dysregulation centered on mitochondrial energy metabolism. To address the role of protein carbonylation in the pathogenesis of mitochondrial dysfunction, quantitative proteomics was employed to identify specific targets of carbonylation in GSTA4-silenced or overexpressing 3T3-L1 adipocytes. GSTA4 silenced adipocytes displayed elevated carbonylation of several key mitochondrial proteins including the phosphate carrier protein, NADH dehydrogenase 1alpha subcomplexes 2 and 3, translocase of inner mitochondrial membrane 50, and valyl tRNA synthetase. Elevated protein carbonylation is accompanied by diminished complex I activity, impaired respiration, increased superoxide production, and a reduction in membrane potential without changes in mitochondrial number, area, or density. Silencing of the phosphate carrier or NADH dehydrogenase 1alpha subcomplexes 2 or 3 in 3T3-L1 cells results in decreased basal and maximal respiration. These results suggest that protein carbonylation plays a major instigating role in cytokine-dependent mitochondrial dysfunction and may be linked to the development of insulin resistance in the adipocyte. PMID- 22822090 TI - Detection of linear ego-acceleration from optic flow. AB - Human observers are able to estimate various ego-motion parameters from optic flow, including rotation, translational heading, time-to-collision (TTC), time-to passage (TTP), etc. The perception of linear ego-acceleration or deceleration, i.e., changes of translational velocity, is less well understood. While time-to passage experiments indicate that ego-acceleration is neglected, subjects are able to keep their (perceived) speed constant under changing conditions, indicating that some sense of ego-acceleration or velocity change must be present. In this paper, we analyze the relation of ego-acceleration estimates and geometrical parameters of the environment using simulated flights through cylindrical and conic (narrowing or widening) corridors. Theoretical analysis shows that a logarithmic ego-acceleration parameter, called the acceleration rate rho, can be calculated from retinal acceleration measurements. This parameter is independent of the geometrical layout of the scene; if veridical ego-motion is known at some instant in time, acceleration rate allows updating of ego-motion without further depth-velocity calibration. Results indicate, however, that subjects systematically confuse ego-acceleration with corridor narrowing and ego deceleration with corridor widening, while veridically judging ego-acceleration in straight corridors. We conclude that judgments of ego-acceleration are based on first-order retinal flow and do not make use of acceleration rate or retinal acceleration. PMID- 22822091 TI - The global role of kidney transplantation. AB - World Kidney Day on March 8(th) 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end-stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end-stage kidney disease include the economic limitations which, in some countries, place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high-income countries, the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 22822092 TI - Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. AB - BACKGROUND: Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. METHODS: An 8 week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40,000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25 OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). RESULTS: Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. CONCLUSIONS: 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment. PMID- 22822093 TI - Improving quality of life in patients with chronic kidney disease: influence of acceptance and personality. AB - BACKGROUND: A low health-related quality of life (HQL) is associated with the evolution of chronic kidney disease (CKD) and mortality in patients in end-stage of the disease. Therefore research on psychological determinants of HQL is emerging. We investigate whether acceptance of the disease contributes to a better physical and mental health-related quality of life (PHQL and MHQL). We also examine the impact of personality characteristics on acceptance, PHQL and MHQL. METHODS: In this cross-sectional study, patients from an outpatient clinic of nephrology completed self-report questionnaires on quality of life, acceptance and personality characteristics. We performed correlations, regression analyses and a path analysis. RESULTS: Our sample of 99 patients had a mean duration of CKD of 10.81 years and a mean estimated Glomerular Filtration Rate (eGFR) by Modification of Diet in Renal Disease (MDRD)-formula of 34.49 ml/min (SD 21.66). Regression analyses revealed that acceptance had a significant positive contribution to the prediction of PHQL and MHQL. Neuroticism was negatively associated with acceptance and MHQL. Path analysis showed that 37% of the total effect of neuroticism on MHQL was mediated by acceptance. CONCLUSIONS: Acceptance is an important positive variable in accounting for HQL, however, clinicians must be aware that if patients have a high level of neuroticism they are likely to have more difficulties with this coping strategy. These results provide a better understanding of psychological determinants of HQL in CKD, which can initiate another approach of these patients by nephrologists, specific psychological interventions, or other supporting public health services. PMID- 22822094 TI - ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis. AB - Garlic-derived organosulfur compounds including diallyl polysulfides are well known for various health-beneficial properties and recent reports even point to a potential role of diallyl polysulfides as chemopreventive and therapeutic agents in cancer treatment due to their selective antiproliferative effects. In this respect, diallyl tri- and tetrasulfide are reported as strong inducers of an early mitotic arrest and subsequent apoptosis, but the underlying molecular mechanisms and the link between these two events are not yet fully elucidated. Our data revealed that diallyl tetrasulfide acts independently of reactive oxygen species and tubulin represents one of its major cellular targets. Tubulin depolymerization prevents the formation of normal spindle microtubules, thereby leading to G2/M arrest. Here, we provide evidence that c-jun N-terminal kinase, which is activated early in response to diallyl tetrasulfide treatment, mediates multisite phosphorylation and subsequent proteolysis of the anti-apoptotic protein B-cell lymphoma 2. As the latter event occurs concomitantly with the onset of apoptosis and the chemical c-jun N-terminal kinase inhibitor SP600125 not only prevented B-cell lymphoma 2 phosphorylation and proteolysis but also apoptosis following diallyl tetrasulfide treatment, we suggest that these c-jun N terminal kinase-mediated modulations of B-cell lymphoma 2 represent the missing link connecting early microtubule inactivation to the induction of apoptosis. PMID- 22822095 TI - Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta. AB - DNA polymerase eta (pol eta) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol eta in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol eta deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol eta. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol eta or harboured a pol eta deletion. Pol eta deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol eta demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol eta-deficient cells as compared with pol eta-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol eta deficiency. We propose that pol eta protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control. PMID- 22822096 TI - Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case-control study. AB - Red meat, processed and unprocessed, has been considered a potential prostate cancer (PCA) risk factor; epidemiological evidence, however, is inconclusive. An association between meat intake and PCA may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures. We investigated the association between red meat and poultry intake and localized and advanced PCA taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats. We analyzed data for 1096 controls, 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We examined nutrient density-adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes: GSTP1, PTGS2, CYP1A2, CYP2E1, EPHX1, CYP1B1, UGT1A6, NAT2, GSTM1 and GSTT1. We observed a positive association between risk of advanced PCA and high intake of red meat cooked at high temperatures (trend P = 0.026), cooked by pan-frying (trend P = 0.035), and cooked until well-done (trend P = 0.013). An inverse association was observed for baked poultry and advanced PCA risk (trend P = 0.023). A gene-by-diet interaction was observed between an SNP in the PTGS2 gene and the estimated levels of meat mutagens (interaction P = 0.008). Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential PCA risk factors, and may support a role for heterocyclic amines (HCAs) in PCA etiology. PMID- 22822098 TI - Functional study of risk loci of stem cell-associated gene lin-28B and associations with disease survival outcomes in epithelial ovarian cancer. AB - Several single-nucleotide polymorphisms (SNPs) of the stem cell-associated gene lin-28B have been identified in association with ovarian cancer and ovarian cancer-related risk factors. However, whether these SNPs are functional or might be potential biomarkers for ovarian cancer prognosis remains unknown. The purposes of this study were to investigate the functional relevance of the identified lin-28B SNPs, as well as the associations of genotype and phenotype with epithelial ovarian cancer (EOC) survival. We analyzed five SNPs and mRNA levels of lin-28B in 211 primary EOC tissues using Taqman((r)) SNP genotyping assays and SYBR green-based real-time PCR, respectively. The RNA secondary structures at the region of a genome-wide association-identified intronic rs314276 were analyzed theoretically with mfold and experimentally with circular dichroism spectroscopy. We found that rs314276 was a cis-acting expression quantitative trait locus (eQTL) in both additive and dominant models, while rs7759938 and rs314277 were significant or of borderline significance in dominant models only. The rs314276 variant significantly affects RNA secondary structure. No SNPs alone were associated with patient survival. However, we found that among patients initially responding to chemotherapy, those with higher lin-28B expression had higher mortality risk (hazard ratio =3.27, 95% confidence interval: 1.63-6.56) and relapse risk (hazard ratio = 2.53, 95% confidence interval: 1.41-4.54) than those with lower expression, and these associations remained in multivariate analyses. These results suggest that rs314276 alters RNA secondary structure and thereby influences gene expression, and that lin-28B is a cancer stem cell-associated marker, which may be a pharmaceutical target in the management of EOC. PMID- 22822099 TI - HIF-1alpha and paradoxical phenomena in cardioprotection. PMID- 22822097 TI - The rebel angel: mutant p53 as the driving oncogene in breast cancer. AB - Breast cancer is the most frequent invasive tumor diagnosed in women, causing over 400 000 deaths yearly worldwide. Like other tumors, it is a disease with a complex, heterogeneous genetic and biochemical background. No single genomic or metabolic condition can be regarded as decisive for its formation and progression. However, a few key players can be pointed out and among them is the TP53 tumor suppressor gene, commonly mutated in breast cancer. In particular, TP53 mutations are exceptionally frequent and apparently among the key driving factors in triple negative breast cancer -the most aggressive breast cancer subgroup-whose management still represents a clinical challenge. The majority of TP53 mutations result in the substitution of single aminoacids in the central region of the p53 protein, generating a spectrum of variants ('mutant p53s', for short). These mutants lose the normal p53 oncosuppressive functions to various extents but can also acquire oncogenic properties by gain-of-function mechanisms. This review discusses the molecular processes translating gene mutations to the pathologic consequences of mutant p53 tumorigenic activity, reconciling cell and animal models with clinical outcomes in breast cancer. Existing and speculative therapeutic methods targeting mutant p53 are also discussed, taking into account the overlap of mutant and wild-type p53 regulatory mechanisms and the crosstalk between mutant p53 and other oncogenic pathways in breast cancer. The studies described here concern breast cancer models and patients-unless it is indicated otherwise and justified by the importance of data obtained in other models. PMID- 22822101 TI - Effects of phosphate on vascular function under normal conditions and influence of the uraemic state. AB - AIMS: Increased serum phosphorus levels are associated with cardiovascular disease in patients with chronic kidney disease (CKD) and in the general population. High phosphate levels may play a direct role in vascular dysfunction. We investigated here the effects of phosphate loading and of the phosphate binder sevelamer-HCl on vascular function. METHODS AND RESULTS: CKD and non-CKD C57/BL6 mice were used to study the effects of CKD, phosphate, and sevelamer-HCl on vascular function and structure. In vitro, phosphate exhibited a direct vasoconstrictor effect on aortic rings. This effect was smaller in vessels from CKD than non-CKD mice and it was abolished by reactive oxygen species inhibitor dimethylthiourea. A high-phosphate diet (1.3%) increased phenylephrine-induced contraction and lowered acetylcholine-induced relaxation of aortic rings ex vivo, both in non-CKD and CKD mice. It also induced endothelial cell detachment. Sevelamer-HCl exposure in vitro normalized the endothelial dysfunction induced by 3.0 mM phosphate and restored endothelial integrity. Sevelamer-HCl treatment of CKD mice under normal diet (0.65% phosphate) improved the endothelial dysfunction, aortic systolic expansion rate, and pulse wave velocity, and it reduced the endothelial expression of adhesion molecules. CONCLUSION: Changes in extracellular phosphorus concentrations may directly modulate vascular function and thereby modulate the vascular smooth muscle response to physiological or pathological stimuli in normal and CKD mice. Whether serum phosphorus lowering and/or dietary phosphate restriction can improve arterial function in humans remains to be established. PMID- 22822102 TI - Personalized medicine and the role of induced pluripotent stem cells. PMID- 22822103 TI - Does TRPC3 macrodominate the myoendothelial gap junction microdomain? PMID- 22822104 TI - Mitral valve replacement following a failed MitraClip procedure. AB - While mitral valve surgery remains the gold standard for mitral regurgitation (MR), recent innovative and less invasive procedures like percutaneous MitraClip insertion make treatment options open to patients with end-stage dilated cardiomyopathy and poor left ventricular function, since such a cohort of patients invariably represents a high surgical risk. Enthusiasts of this procedure advocate the use of MitraClip as a primary procedure for patients with Type 1 MR and end-stage cardiomyopathy. Valve repair could be reserved for those patients with ongoing regurgitation following MitraClip insertion. We describe a patient treated by MitraClip insertion in whom the unsuccessful mid-term result necessitated surgery. In this patient, damage to the mitral valve from the MitraClip insertion produced a central leaflet perforation, which precluded repair, and thereby, the patient received a mechanical valve replacement. The enthusiasm for a less invasive initial approach in such patients must be balanced against the risk of failure of the primary procedure so that the patient is not denied the prospect of repair in the first instance. PMID- 22822105 TI - Contralateral mediastinal lymph node micrometastases assessed by video-assisted thoracoscopic surgery in stage I non-small cell left lung cancer. AB - OBJECTIVES: Survival of patients with left-sided stage I non-small cell lung cancer (NSCLC) is unsatisfactory, probably because of the high incidence of contralateral mediastinal node involvement. In this study, occult micrometastases to the right upper mediastinal nodes were retrospectively investigated in patients with left-sided stage I NSCLC. METHODS: Nineteen patients with clinical stage I NSCLC underwent video-assisted thoracoscopic lobectomy and bilateral mediastinal node dissection (BMD). Clinical data and survival of patients with BMD were compared with those of 25 left-unilateral mediastinal node dissection (UMD) patients. Occult micrometastases were detected using the cytokeratin 19 mRNA reverse transcription-polymerase chain reaction method. RESULTS: Pathological N2 disease was found in 1 patient, and 18 had pN0 disease. The operative time, blood loss, duration of chest tube drainage and duration of postoperative hospital stay were not different between BMD and UMD patients. Nodal micrometastases were detected in 11/19 (57.8%) patients. Skip micrometastases to the level N3 nodes without N1 and N2 node involvement were observed in 8/11 (72.7%) patients. Patients with BMD are all alive and have had no recurrence during the median follow-up period of 21.4 months. Overall 3-year survival and disease-free 3-year survival were not significantly different between the two groups. CONCLUSION: In this preliminary study, occult micrometastases to the level N3 nodes occurred frequently in patients with left sided clinical N0 stage I NSCLC. Postoperative survival of patients with occult micrometastases to the level N3 node does not appear to be poor. Further follow up and work are needed. PMID- 22822106 TI - Off-pump transapical mitral valve-in-ring implantation. AB - OBJECTIVES: The study aimed to evaluate the feasibility of off-pump transapical mitral valve-in-ring implantation and to test the performance of a custom-made self-expandable stent valve, in comparison with the standard SAPIEN valve. METHODS: Acute experiments were performed in five pigs. Animals (mean weight 58.4 +/- 7.3 kg) underwent mitral valve annuloplasties under cardiopulmonary bypass using 26-mm rings (SJMTM). Then, a 30-mm custom-made self-expandable stent valve or a 23-mm balloon-expandable transcatheter heart valve (Edwards SAPIEN XTTM) was deployed within the annuloplasty rings through a transatrial access and under direct vision. Subsequently, the stent valves were inserted transapically under fluoroscopic guidance and off pump. RESULTS: The procedural success of transatrial and transapical mitral valve-in-ring procedures was 100% (10 of 10). Mean transatrial and transapical procedure time was 2.0 +/- 1.1 and 22.0 +/- 5.7 min, respectively. Haemodynamic status during transapical implantation remained stable, and differences in data collected before and after the stent-valve deployment were not statistically significant. Mean mitral annulus diameter and mean mitral orifice area in the group of self-expandable stent valves were 2.60 +/- 0.02 cm and 4.16 +/- 0.48 cm(2), respectively, whereas in the SAPIEN group they were 1.95 +/- 0.18 cm and 2.26 +/- 0.20 cm(2), respectively. Trace or mild regurgitation was detected only in the self-expandable stent-valve group. Mean gradients were 4.1 +/- 4.5 mmHg across the self-expandable stent valves and 1.0 +/- 0 mmHg across the SAPIEN valves. Postmortem examination confirmed adequate positioning of the self-expandable valves and the SAPIEN valves within the annuloplasty ring. CONCLUSIONS: Off-pump transapical mitral valve-in-ring implantation is safe and feasible. Transapical access may represent the ideal option for valve-in-ring procedures in cases of recurrent mitral regurgitation after mitral valve repair, in high-risk patients. Owing to the supra-annular profile of the valve components, our custom-made nitinol stent valve provides nearer to normal functional area than the SAPIEN valve. PMID- 22822107 TI - Stentless aortic bioprostheses: their role in the treatment of aortic endocarditis should not be underestimated. PMID- 22822108 TI - Accuracy, calibration and clinical performance of the new EuroSCORE II risk stratification system. AB - OBJECTIVES: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) has been used for many years since its introduction in 1999. Recently, a new EuroSCORE (EuroSCORE II) has been developed to update the previous version. The EuroSCORE II includes some different predictors and/or introduces a new classification of the already existing predictors. This study presents a validation series for the EuroSCORE II compared with the previous additive and the logistic EuroSCORE and with the Age, Creatinine and Ejection Fraction (ACEF) score. METHODS: A total of 1090 consecutive adult patients operated on at our institution from September 2010 to October 2011 were admitted to this retrospective study. All the patients received a risk stratification based on the EuroSCORE II and the other scores considered. Accuracy, calibration and clinical performance of the various risk models were assessed. RESULTS: The accuracy of the EuroSCORE II was good (c-statistic 0.81) but not significantly higher than the other scores (range 0.78-0.8). Calibration at the Hosmer-Lemeshow statistic was good for all the scores; the difference between observed (3.75%) and predicted mortality in the overall population was not significant for the EuroSCORE II (3.1%) and the ACEF score (3.4%), whereas the additive EuroSCORE (5.8%) and the logistic EuroSCORE (7.3%) significantly overestimated the risk. In patients at low, mild moderate and high mortality risk, the EuroSCORE II provided a risk prediction not significantly different from the observed mortality rate, whereas in very high-risk patients (observed mortality rate 11%), it significantly underestimated (6.5%) the mortality risk. The accuracy of the EuroSCORE II was acceptable in isolated coronary surgery, and good or excellent in the other operations. CONCLUSIONS: The EuroSCORE II represents a useful update of the previous EuroSCORE version, with a much better clinical performance and the same good level of accuracy. It is possible that for the risk stratification of very high-risk patients, other factors (rare but associated with a mortality rate >50%) should be included in the future models. PMID- 22822109 TI - The first reported case of non-compacted cardiomyopathy in a preterm infant with Ebstein's anomaly. AB - Non-compaction of the ventricular myocardium is a congenital dysfunction of ventricular morphogenesis caused by the arrest of normal embryogenesis of the ventricles. It is considered as a rare disease and can involve both ventricles but commonly the left ventricle. It is classified into isolated non-compaction of the ventricles and non-compaction associated with other congenital heart defects. Its association with Ebstein's anomaly is very rare. We are reporting a rare case of severe heart failure and complex cardiac anomaly including biventricular non compaction cardiomyopathy, Ebstein's anomalies and large patent ductus arteriosus with severe persistent pulmonary hypertension in a 31-weeks-old preterm infant. The infant recovered smoothly and continued to be asymptomatic and off medications throughout his 2 years follow-up period. Up to our knowledge, this is the youngest and first patient yet reported to have this disease at this age with good recovery. PMID- 22822110 TI - An unusual cause of a non-functioning stoma in an 87-year-old gentleman. AB - Gallstone ileus is a rare but significant cause of intestinal obstruction particularly among the elderly population. Symptoms are often vague and therefore a high suspicious index is required for successful diagnosis. In this report, we present the case of an 87-year-old gentleman with a background history of cholelithiasis and ileostomy for ulcerative colitis who was admitted with a 24-h history of his stoma not functioning. He had an abdominal x-ray and CT which were consistent with small bowel obstruction with no identifiable cause. He underwent an examination of his stoma under general anaesthesia which revealed a 2.5 cm gallstone wedged several centimetres near the entry point of the stoma. The purpose of this report is to highlight the importance of considering gallstones as a potential cause of a non-functioning stoma in any patient with a significant history of cholelithiasis. PMID- 22822111 TI - Fulminant inflammatory neuropathy mimicking cerebral death. AB - We report a case of a 44-year-old woman who developed rapidly progressive tetraparesis followed by respiratory failure and abolition of brainstem reflexes. Electrodiagnostic studies excluded the possibility of cerebral death and confirmed the diagnosis of acute motor-sensory axonal neuropathy. The initial fulminant course of the disease was followed by slow recovery to independence in daily activities. PMID- 22822112 TI - Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes. AB - OBJECTIVE: Increased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance. DESIGN: We performed both cross-sectional and longitudinal (diet-induced weight loss) studies. METHODS: Circulating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (S(I), Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19). RESULTS: Circulating calprotectin was significantly increased in IGT-T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin with S(I) was independent of BMI and age. In fact, S(I) together with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR. CONCLUSION: These findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity. PMID- 22822114 TI - Modeling human disease. PMID- 22822113 TI - Limited PSA testing in indigent men in South Texas: an appropriate care or missing a prevention opportunity? AB - BACKGROUND: No previous study has examined racial ethnic differences in prostate specific antigen (PSA) testing and followup in primary care practices serving an indigent population. METHODS: From electronic medical records of primary care practices affiliated with one health care system in San Antonio, we identified 9,267 men aged 50 to 74 with 2+ clinic visits from 2008 through 2010 and no prior prostate cancer diagnosis. Logistic regression was used to examine the association of race ethnicity with the use of PSA testing and, if tested, with an abnormal result (>=4 ng/mL) adjusted for demographics, health care, and clinical factors. Time to a follow-up activity after an abnormal PSA was assessed using Cox proportional models. RESULTS: The race ethnicity of this cohort was 63% Hispanic, 27% non-Hispanic white, 7% African-American, and 3% other. In a 3-year period, 26.8% of men had at least one PSA test. Compared with African-Americans, non-Hispanic whites were less likely to be tested [OR, 0.68; 95% confidence interval (CI), 0.55-0.83] but Hispanics did not differ (OR = 0.95; 95% CI 0.79 1.15). African-Americans were more likely to have an abnormal PSA than others (12.4% vs. 5.2%, P < 0.001) and the shortest adjusted time to follow-up (P = 0.004). CONCLUSIONS: In this 3-year indigent cohort, about one quarter had a PSA test, approximately half of the national testing rate. IMPACT: African-Americans were more likely to be tested than non-Hispanic whites but had more abnormal results, raising concerns about missed prevention opportunities. African Americans with high PSA results had the shortest time until follow-up, reflecting awareness of the threat of prostate cancer for African-Americans by physicians. PMID- 22822118 TI - Patents. U.S. appeals court hears gene patent arguments. PMID- 22822119 TI - Science funding. Stability at last for Australian Synchrotron? PMID- 22822120 TI - Ecology. The Metatron: experimental ecology gets connected. PMID- 22822121 TI - Training and workforce. What if the science pipeline isn't really leaking? PMID- 22822122 TI - Commercializing research. NSF program offers start-up 101 to its grantees. PMID- 22822124 TI - Ecology. Taking the measure of Madidi. PMID- 22822123 TI - Profile: Bert Vogelstein. Cancer genetics with an edge. PMID- 22822125 TI - Ecology. Probing diversity's complexity. PMID- 22822126 TI - European Association for South Asian Archaeology and Art meeting. The ingredients for a 4000-year-old proto-curry. PMID- 22822127 TI - European Association for South Asian Archaeology and Art meeting. Diving into the Indian Ocean's past. PMID- 22822128 TI - European Association for South Asian Archaeology and Art meeting meeting. Persians made the Afghan desert bloom. PMID- 22822129 TI - Retraction. PMID- 22822130 TI - Human conflict: beware politicized science. PMID- 22822131 TI - Human conflict: pacifists at heart. PMID- 22822132 TI - Human conflict: targeting natural resources. PMID- 22822134 TI - Comment on "Illusions promote mating success in great bowerbirds". AB - Kelley and Endler (Reports, 20 January 2012, p. 335) claim that male great bowerbirds construct a visual illusion, using display object gradients, that affects mating success. We argue that they provide inadequate statistical support for their hypothesis, inappropriately exclude important data, and do not consider other display traits that explain mating success. We propose a more plausible alternative hypothesis to explain display object patterns. PMID- 22822136 TI - Plant science. Defining the plant germ line--nature or nurture? PMID- 22822137 TI - Chemistry. Molecule formation in ultrahigh magnetic fields. PMID- 22822138 TI - Chemistry. Nanomaterials for drug delivery. PMID- 22822139 TI - Geochemistry. The marine sulfur cycle, revisited. PMID- 22822140 TI - Ecology. The art of ecological modeling. PMID- 22822141 TI - Applied physics. Spin twists in a transistor. PMID- 22822142 TI - Retrospective. Aaron Shatkin (1934-2012). PMID- 22822143 TI - The exploration of hot nuclear matter. AB - When nuclear matter is heated beyond 2 trillion degrees, it becomes a strongly coupled plasma of quarks and gluons. Experiments using highly energetic collisions between heavy nuclei have revealed that this new state of matter is a nearly ideal, highly opaque liquid. A description based on string theory and black holes in five dimensions has made the quark-gluon plasma an archetypical strongly coupled quantum system. Open questions about the structure and theory of the quark-gluon plasma are under active investigation. Many of the insights are also relevant to ultracold fermionic atoms and strongly correlated condensed matter. PMID- 22822144 TI - Imaging the impact of single oxygen atoms on superconducting Bi(2+y)Sr(2 y)CaCu2O(8+x). AB - High-temperature cuprate superconductors display unexpected nanoscale inhomogeneity in essential properties such as pseudogap energy, Fermi surface, and even superconducting critical temperature. Theoretical explanations for this inhomogeneity have ranged from chemical disorder to spontaneous electronic phase separation. We extend the energy range of scanning tunneling spectroscopy on Bi(2+y)Sr(2-y)CaCu(2)O(8+x), allowing a complete mapping of two types of interstitial oxygen dopants and vacancies at the apical oxygen site. We show that the nanoscale spatial variations in the pseudogap states are correlated with disorder in these dopant concentrations, particularly that of apical oxygen vacancies. PMID- 22822145 TI - Spin-transistor action via tunable Landau-Zener transitions. AB - Spin-transistor designs relying on spin-orbit interaction suffer from low signal levels resulting from low spin-injection efficiency and fast spin decay. Here, we present an alternative approach in which spin information is protected by propagating this information adiabatically. We demonstrate the validity of our approach in a cadmium manganese telluride diluted magnetic semiconductor quantum well structure in which efficient spin transport is observed over device distances of 50 micrometers. The device is turned "off" by introducing diabatic Landau-Zener transitions that lead to a backscattering of spins, which are controlled by a combination of a helical and a homogeneous magnetic field. In contrast to other spin-transistor designs, we find that our concept is tolerant against disorder. PMID- 22822146 TI - A paramagnetic bonding mechanism for diatomics in strong magnetic fields. AB - Elementary chemistry distinguishes two kinds of strong bonds between atoms in molecules: the covalent bond, where bonding arises from valence electron pairs shared between neighboring atoms, and the ionic bond, where transfer of electrons from one atom to another leads to Coulombic attraction between the resulting ions. We present a third, distinct bonding mechanism: perpendicular paramagnetic bonding, generated by the stabilization of antibonding orbitals in their perpendicular orientation relative to an external magnetic field. In strong fields such as those present in the atmospheres of white dwarfs (on the order of 10(5) teslas) and other stellar objects, our calculations suggest that this mechanism underlies the strong bonding of H(2) in the (3)Sigma(u)(+)(1sigma(g)1sigma(u)*) triplet state and of He(2) in the (1)Sigma(g)(+)(1sigma(g)(2)1sigma(u)(*2)) singlet state, as well as their preferred perpendicular orientation in the external field. PMID- 22822147 TI - Sulfate burial constraints on the Phanerozoic sulfur cycle. AB - The sulfur cycle influences the respiration of sedimentary organic matter, the oxidation state of the atmosphere and oceans, and the composition of seawater. However, the factors governing the major sulfur fluxes between seawater and sedimentary reservoirs remain incompletely understood. Using macrostratigraphic data, we quantified sulfate evaporite burial fluxes through Phanerozoic time. Approximately half of the modern riverine sulfate flux comes from weathering of recently deposited evaporites. Rates of sulfate burial are unsteady and linked to changes in the area of marine environments suitable for evaporite formation and preservation. By contrast, rates of pyrite burial and weathering are higher, less variable, and largely balanced, highlighting a greater role of the sulfur cycle in regulating atmospheric oxygen. PMID- 22822148 TI - Rapid variability of seawater chemistry over the past 130 million years. AB - Fluid inclusion data suggest that the composition of major elements in seawater changes slowly over geological time scales. This view contrasts with high resolution isotope data that imply more rapid fluctuations of seawater chemistry. We used a non-steady-state box model of the global sulfur cycle to show that the global delta(34)S record can be explained by variable marine sulfate concentrations triggered by basin-scale evaporite precipitation and dissolution. The record is characterized by long phases of stasis, punctuated by short intervals of rapid change. Sulfate concentrations affect several important biological processes, including carbonate mineralogy, microbially mediated organic matter remineralization, sedimentary phosphorous regeneration, nitrogen fixation, and sulfate aerosol formation. These changes are likely to affect ocean productivity, the global carbon cycle, and climate. PMID- 22822149 TI - Sex-specific adaptation drives early sex chromosome evolution in Drosophila. AB - Most species' sex chromosomes are derived from ancient autosomes and show few signatures of their origins. We studied the sex chromosomes of Drosophila miranda, where a neo-Y chromosome originated only approximately 1 million years ago. Whole-genome and transcriptome analysis reveals massive degeneration of the neo-Y, that male-beneficial genes on the neo-Y are more likely to undergo accelerated protein evolution, and that neo-Y genes evolve biased expression toward male-specific tissues--the shrinking gene content of the neo-Y becomes masculinized. In contrast, although older X chromosomes show a paucity of genes expressed in male tissues, neo-X genes highly expressed in male-specific tissues undergo increased rates of protein evolution if haploid in males. Thus, the response to sex-specific selection can shift at different stages of X differentiation, resulting in masculinization or demasculinization of the X chromosomal gene content. PMID- 22822151 TI - Diversity of interaction types and ecological community stability. AB - Ecological theory predicts that a complex community formed by a number of species is inherently unstable, guiding ecologists to identify what maintains species diversity in nature. Earlier studies often assumed a community with only one interaction type, either an antagonistic, competitive, or mutualistic interaction, leaving open the question of what the diversity of interaction types contributes to the community maintenance. We show theoretically that the multiple interaction types might hold the key to understanding community dynamics. A moderate mixture of antagonistic and mutualistic interactions can stabilize population dynamics. Furthermore, increasing complexity leads to increased stability in a "hybrid" community. We hypothesize that the diversity of species and interaction types may be the essential element of biodiversity that maintains ecological communities. PMID- 22822150 TI - Hypoxia triggers meiotic fate acquisition in maize. AB - Evidence from confocal microscopic reconstruction of maize anther development in fertile, mac1 (excess germ cells), and msca1 (no germ cells) flowers indicates that the male germ line is multiclonal and uses the MAC1 protein to organize the somatic niche. Furthermore, we identified redox status as a determinant of germ cell fate, defining a mechanism distinct from the animal germ cell lineage. Decreasing oxygen or H(2)O(2) increases germ cell numbers, stimulates superficial germ cell formation, and rescues germinal differentiation in msca1 flowers. Conversely, oxidizing environments inhibit germ cell specification and cause ectopic differentiation in deeper tissues. We propose that hypoxia, arising naturally within growing anther tissue, acts as a positional cue to set germ cell fate. PMID- 22822154 TI - Abnormal early diastolic intraventricular flow 'kinetic energy index' assessed by vector flow mapping in patients with elevated filling pressure. AB - AIMS: Recently developed vector flow mapping (VFM) enables evaluation of local flow dynamics without angle dependency. This study used VFM to evaluate quantitatively the index of intraventricular haemodynamic kinetic energy in patients with left ventricular (LV) diastolic dysfunction and to compare those with normal subjects. METHODS AND RESULTS: We studied 25 patients with estimated high left atrial (LA) pressure (pseudonormal: PN group) and 36 normal subjects (control group). Left ventricle was divided into basal, mid, and apical segments. Intraventricular haemodynamic energy was evaluated in the dimension of speed, and it was defined as the kinetic energy index. We calculated this index and created time-energy index curves. The time interval from electrocardiogram (ECG) R wave to peak index was measured, and time differences of the peak index between basal and other segments were defined as DeltaT-mid and DeltaT-apex. In both groups, early diastolic peak kinetic energy index in mid and apical segments was significantly lower than that in the basal segment. Time to peak index did not differ in apex, mid, and basal segments in the control group but was significantly longer in the apex than that in the basal segment in the PN group. DeltaT-mid and DeltaT-apex were significantly larger in the PN group than the control group. Multiple regression analysis showed sphericity index, E/E' to be significant independent variables determining DeltaT apex. CONCLUSION: Retarded apical kinetic energy fluid dynamics were detected using VFM and were closely associated with LV spherical remodelling in patients with high LA pressure. PMID- 22822152 TI - LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. AB - Defective catabolite export from lysosomes results in lysosomal storage diseases in humans. Mutations in the cystine transporter gene CTNS cause cystinosis, but other lysosomal amino acid transporters are poorly characterized at the molecular level. Here, we identified the Caenorhabditis elegans lysosomal lysine/arginine transporter LAAT-1. Loss of laat-1 caused accumulation of lysine and arginine in enlarged, degradation-defective lysosomes. In mutants of ctns-1 (C. elegans homolog of CTNS), LAAT-1 was required to reduce lysosomal cystine levels and suppress lysosome enlargement by cysteamine, a drug that alleviates cystinosis by converting cystine to a lysine analog. LAAT-1 also maintained availability of cytosolic lysine/arginine during embryogenesis. Thus, LAAT-1 is the lysosomal lysine/arginine transporter, which suggests a molecular explanation for how cysteamine alleviates a lysosomal storage disease. PMID- 22822155 TI - Myocardium at risk can be determined by ex vivo T2-weighted magnetic resonance imaging even in the presence of gadolinium: comparison to myocardial perfusion single photon emission computed tomography. AB - AIMS: Determination of the myocardium at risk (MaR) and final infarct size by cardiac magnetic resonance imaging (CMR) enables calculation of salvaged myocardium in acute infarction. T2-weighted imaging is performed prior to the administration of gadolinium, since gadolinium affects T2 tissue properties. This is, however, difficult in an ex vivo model since gadolinium must be administered for determination of infarct size by CMR. We aimed to test the ability of ex vivo T2-weighted imaging to assess MaR using myocardial perfusion single photon emission computed tomography (SPECT) as reference and to investigate whether MaR could be assessed by ex vivo T2-weighted imaging after injection of gadolinium. Materials and methods In 18 domestic pigs, the left anterior descending artery was occluded for either 30 or 40 min, followed by 4 h of reperfusion. After explantation of the hearts, myocardial perfusion SPECT and T2-weighted imaging were performed for determination of MaR, either with or without gadolinium. Infarct size was determined by T1-weighted imaging and by triphenyl tetrazolium chloride (TTC) staining. RESULTS: T2-weighted imaging agreed with myocardial perfusion SPECT, both with and without gadolinium (r(2)= 0.70, P < 0.01) with a bias of 2.6 +/- 5.1% (P = 0.04). Infarct size was 15.4 +/- 5.3 and 22.1 +/- 5.6% with TTC and T1-weighted imaging, respectively (P = 0.008) in nine pigs who had both infarct measures. CONCLUSION: T2-weighted CMR imaging can be used to determine MaR in an ex vivo experimental model, both with and without the presence of gadolinium. Thus, CMR alone can be used to assess myocardial salvage in experimental studies. PMID- 22822156 TI - Anomalous origin of right coronary artery from left coronary sinus. PMID- 22822157 TI - Apico-aortic valved conduit for the treatment of severe aortic stenosis and porcelain aorta. PMID- 22822158 TI - Trends in hospice referral and length of stay at a veterans hospital over the past decade. AB - INTRODUCTION: Hospice decreases the fear of dying alone, reduces the agony of death, and helps in maintaining dignity at the end of life. Physicians are encouraged to offer hospice to terminally ill patients early on in their end-of life care to maximize these benefits. However, there is limited data on the changes and characteristics of hospice utilization. We performed a study to determine the changes in the hospice utilization over the last decade in our hospital. METHODS: A chart review of all veterans referred to hospice during the years 2001 and 2010 was performed and subsequently analyzed. Analyses were performed with SPSS 19.0 for Windows. RESULTS: Referral to hospice increased significantly but the duration of stay did not change in 2010 in comparison with 2001. Factors associated with increased length of stay were full-code status, receiving hospice at home, hospitalization during enrollment in hospice, referral to hospice by oncologist, and a diagnosis of cancer. CONCLUSION: Hospice referrals need to be considered earlier in their disease process for terminally ill patients. In addition, requirement of a do-not-resuscitate order as a condition for hospice at some agencies needs to be revisited, and patients should not be discouraged to seek treatment for reversible medical conditions even when enrolled in hospice. PMID- 22822159 TI - A clinical deterioration prediction tool for internal medicine patients. AB - Many early warning models for hospitalized patients use variables measured on admission to the hospital ward; few have been rigorously derived and validated. The objective was to create and validate a clinical deterioration prediction tool using routinely collected clinical and nursing measurements. Multivariate regression analysis was used to determine clinical variables statistically associated with clinical deterioration; subsequently, the model tool was retrospectively validated using a different cohort of medical inpatients. The Braden Scale (P = .01; odds ratio [OR] = 0.91; confidence interval [CI] = 0.84 0.98), respiratory rate (P < .01; OR = 1.08; CI = 1.04-1.13), oxygen saturation (P < .01; OR = 0.97; CI = 0.96-0.99), and shock index (P < .01; OR = 2.37; CI = 1.14-3.98) were predictive of clinical deterioration 2-12 hours in the future. When applied to the validation cohort, the tool demonstrated fair concordance with actual outcomes. This tool created using routinely collected clinical measurements can serve as a very early warning system for hospitalized medical patients. PMID- 22822160 TI - Topiramate treatment improves hypothalamic insulin and leptin signaling and action and reduces obesity in mice. AB - Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action, or neuropeptide expression in the hypothalamus of mice fed with a high-fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhancing the leptin-induced leptin receptor/Janus kinase 2/signal transducer and activator of transcription 3 pathway and the insulin-induced insulin receptor substrate/Akt/forkhead box O1 pathway in parallel to reduced phosphatase protein expression in the hypothalamus of obese mice. These effects were independent of body weight. TPM also raised anorexigenic neuropeptides such as POMC, TRH, and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in peroxisome proliferator-activated receptor-coactivator alpha and uncoupling protein 1 protein levels in brown adipose tissue. Furthermore, TPM increased AMP activated protein kinase and acetyl-coenzyme A carboxylase phosphorylation in peripheral tissues, which may help improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity. PMID- 22822161 TI - Neurokinin B and the control of the gonadotropic axis in the rat: developmental changes, sexual dimorphism, and regulation by gonadal steroids. AB - Neurokinin B (NKB), encoded by Tac2 in rodents, and its receptor, NK3R, have recently emerged as important regulators of reproduction; NKB has been proposed to stimulate kisspeptin output onto GnRH neurons. Accordingly, NKB has been shown to induce gonadotropin release in several species; yet, null or even inhibitory effects of NKB have been also reported. The basis for these discrepant findings, as well as other key aspects of NKB function, remains unknown. We report here that in the rat, LH responses to the NK3R agonist, senktide, display a salient sexual dimorphism, with persistent stimulation in females, regardless of the stage of postnatal development, and lack of LH responses in males from puberty onward. Such dimorphism was independent of the predominant sex steroid after puberty, because testosterone administration to adult females failed to prevent LH responses to senktide, and LH responsiveness was not restored in adult males treated with estradiol or the nonaromatizable androgen, dihydrotestosterone. Yet, removal of sex steroids by gonadectomy switched senktide effects to inhibitory, both in adult male and female rats. Sexual dimorphism was also evident in the numbers of NKB-positive neurons in the arcuate nucleus (ARC), which were higher in adult female rats. This is likely the result of differences in sex steroid milieu during early periods of brain differentiation, because neonatal exposures to high doses of estrogen decreased ARC NKB neurons at later developmental stages. Likewise, neonatal estrogenization resulted in lower serum LH levels that were normalized by senktide administration. Finally, we document that the ability of estrogen to inhibit hypothalamic Tac2 expression seems region specific, because estrogen administration decreased Tac2 levels in the ARC but increased them in the lateral hypothalamus. Altogether, our data provide a deeper insight into relevant aspects of NKB function as major regulator of the gonadotropic axis in the rat, including maturational changes, sexual dimorphism, and differential regulation by sex steroids. PMID- 22822162 TI - Glucose transporter 8 (GLUT8) regulates enterocyte fructose transport and global mammalian fructose utilization. AB - Enterocyte fructose absorption is a tightly regulated process that precedes the deleterious effects of excess dietary fructose in mammals. Glucose transporter (GLUT)8 is a glucose/fructose transporter previously shown to be expressed in murine intestine. The in vivo function of GLUT8, however, remains unclear. Here, we demonstrate enhanced fructose-induced fructose transport in both in vitro and in vivo models of enterocyte GLUT8 deficiency. Fructose exposure stimulated [(14)C]-fructose uptake and decreased GLUT8 protein abundance in Caco2 colonocytes, whereas direct short hairpin RNA-mediated GLUT8 knockdown also stimulated fructose uptake. To assess GLUT8 function in vivo, we generated GLUT8 deficient (GLUT8KO) mice. GLUT8KO mice exhibited significantly greater jejunal fructose uptake at baseline and after high-fructose diet (HFrD) feeding vs. wild type mice. Strikingly, long-term HFrD feeding in GLUT8KO mice exacerbated fructose-induced increases in blood pressure, serum insulin, low-density lipoprotein and total cholesterol vs. wild-type controls. Enhanced fructose uptake paralleled with increased abundance of the fructose and glucose transporter, GLUT12, in HFrD-fed GLUT8KO mouse enterocytes and in Caco2 cultures exposed to high-fructose medium. We conclude that GLUT8 regulates enterocyte fructose transport by regulating GLUT12, and that disrupted GLUT8 function has deleterious long-term metabolic sequelae. GLUT8 may thus represent a modifiable target in the prevention and treatment of malnutrition or the metabolic syndrome. PMID- 22822164 TI - Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain. AB - Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones. We used single-probe microdialysis to measure directly the free corticosterone levels in the blood of freely behaving rats. Free corticosterone in the blood shows a distinct circadian and ultradian rhythm with a pulse frequency of approximately one pulse per hour together with an increase in hormone levels and pulse height toward the active phase of the light/dark cycle. Similar rhythms were also evident in the subcutaneous tissue, demonstrating that free corticosterone rhythms are transferred from the blood into peripheral target tissues. Furthermore, in a dual probe microdialysis study, we demonstrated that the circadian and ultradian rhythms of free corticosterone in the blood and the subcutaneous tissue were highly synchronized. Moreover, free corticosterone rhythms were also synchronous between the blood and the hippocampus. These data demonstrate for the first time an ultradian rhythm of free corticosterone in the blood that translates into synchronized rhythms of free glucocorticoid hormone in peripheral and central tissues. The maintenance of ultradian rhythms across tissue barriers in both the periphery and the brain has important implications for research into aberrant biological rhythms in disease and for the development of improved protocols for glucocorticoid therapy. PMID- 22822165 TI - INSL5-deficient mice display an alteration in glucose homeostasis and an impaired fertility. AB - Insulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and beta-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and beta-cell homeostasis. PMID- 22822163 TI - Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1. AB - GnRH neurons are essential for reproduction, being an integral component of the hypothalamic-pituitary-gonadal axis. Progesterone (P4), a steroid hormone, modulates reproductive behavior and is associated with rapid changes in GnRH secretion. However, a direct action of P4 on GnRH neurons has not been previously described. Receptors in the progestin/adipoQ receptor family (PAQR), as well as progesterone receptor membrane component 1 (PgRMC1) and its partner serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1) mRNA binding protein 1 (SERBP1), have been shown to mediate rapid progestin actions in various tissues, including the brain. This study shows that PgRMC1 and SERBP1, but not PAQR, are expressed in prenatal GnRH neurons. Expression of PgRMC1 and SERBP1 was verified in adult mouse GnRH neurons. To investigate the effect of P4 on GnRH neuronal activity, calcium imaging was used on primary GnRH neurons maintained in explants. Application of P4 significantly decreased the activity of GnRH neurons, independent of secretion of gamma-aminobutyric acidergic and glutamatergic input, suggesting a direct action of P4 on GnRH neurons. Inhibition was not blocked by RU486, an antagonist of the classic nuclear P4 receptor. Inhibition was also maintained after uncoupling of the inhibitory regulative G protein (G(i/o)), the signal transduction pathway used by PAQR. However, AG-205, a PgRMC1 ligand and inhibitor, blocked the rapid P4-mediated inhibition, and inhibition of protein kinase G, thought to be activated downstream of PgRMC1, also blocked the inhibitory activity of P4. These data show for the first time that P4 can act directly on GnRH neurons through PgRMC1 to inhibit neuronal activity. PMID- 22822168 TI - Association between conformity with performance measures and 1-year postdischarge survival in patients with acute decompensated heart failure. AB - Recognition of the treatment gap in patients with heart failure (HF) led to the development of a set of process-of-care measures to improve the quality of care. To assess the association of established and emerging process-of-care measures with 1-year postdischarge survival, 496 patients with acute decompensated HF were studied. After adjustment for established prognostic factors, the relative risk (RR) for mortality in patients eligible for treatment was as follows: 0.49 (P < .001) for discharge prescription of renin-angiotensin system inhibitors (RAS-Is), 0.59 (P = .015) for beta-blockers, 0.44 (P < .001) for combination therapy (ie, a beta-blocker and a RAS-I), 0.87 (P nonsignificant) for aldosterone antagonists, and 0.49 (P nonsignificant) for planned cardioverter-defibrillator implantation. After adjustment for propensity scores, the RR was 0.49 (P < .001) for RAS-Is, 0.67 (P = .04) for beta-blockers, and 0.57 (P < .001) for combination therapy. The data suggest that performance measures for RAS-Is, beta-blockers, and combination therapy are strongly associated with improved 1-year survival. PMID- 22822169 TI - A national study of nurse leadership and supports for quality improvement in rural hospitals. AB - This study assessed the perceptions and actions of rural hospital nurse executives with regard to patient safety and quality improvement (QI). A national sample of rural hospital nurse executives (n = 300) completed a survey measuring 4 domains related to patient safety and QI: (a) patient "Safety Culture," (b) adequacy of QI "Resources," (c) "Barriers" related to QI, and (d) "Nurse Leader Engagement" in activities supporting QI. Perceptions of Safety Culture were strong but 47% of the Resources needed to carry out QI were inadequate, 29% of Barriers were moderate to major, and 25% of Nurse Leader Engagement activities were performed infrequently. Nurse Leader Engagement in quality-related activities was less frequent among nurses in isolated and small rural town hospitals compared with large rural city hospitals. To further QI, rural nurse executives may need to use their communications and actions to raise the visibility of QI. PMID- 22822170 TI - Commentary: reducing hospital readmissions: aligning financial and quality incentives. PMID- 22822171 TI - Improved patient safety and outcomes with a comprehensive interdisciplinary improvement initiative in kidney transplant recipients. AB - Although kidney transplant recipients at the authors' institution had a short length of stay (LOS), delayed discharges and early readmissions were common; medication use and safety were at the core of these issues. A multidisciplinary quality improvement initiative was developed that targeted eliminating these issues. The team developed key initiatives including improved medication reconciliation, development of a diabetes management service, and improved discharge medication dispensing, delivery, education, and scrutiny. Follow-up analysis demonstrated reduced medication discrepancies by >2 per patient and obtaining 100% adherence with reconciliation. Pharmacists reviewed discharge medications, reaching 100% by study end, leading to a 40% reduction in medication safety issues. LOS remained short, and delayed discharges were reduced by 14%; 7 day readmission rates decreased by 50%. Acute rejection and infection rates also significantly decreased. In conclusion, a multidisciplinary quality improvement initiative can improve medication safety in kidney transplant patients, which can lead to improved clinical outcomes. PMID- 22822173 TI - Development and validation of new anxiety and bipolar symptom scales for an expanded version of the IDAS (the IDAS-II). AB - The original Inventory of Depression and Anxiety Symptoms (IDAS) contains 11 nonoverlapping scales assessing specific depression and anxiety symptoms. In creating the expanded version of the IDAS (the IDAS-II), our goal was to create new scales assessing other important aspects of the anxiety disorders as well as key symptoms of bipolar disorder. Factor analyses of the IDAS-II item pool led to the creation of seven new scales (Traumatic Avoidance, Checking, Ordering, Cleaning, Claustrophobia, Mania, Euphoria) plus an expanded version of Social Anxiety. These scales are internally consistent and show strong convergent and significant discriminant validity in relation to other self-report and interview based measures of anxiety, depression, and mania. Furthermore, the scales demonstrate substantial criterion and incremental validity in relation to interview-based measures of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) symptoms and disorders. Thus, the expanded IDAS-II now assesses a broad range of depression, anxiety, and bipolar symptoms. PMID- 22822175 TI - Transdiagnostic treatment of bipolar disorder and comorbid anxiety with the unified protocol: a clinical replication series. AB - Bipolar disorder (BD) is a chronic, debilitating disorder with recurrent manic and depressive episodes. More than 75% of bipolar patients have a current or lifetime diagnosis of a comorbid anxiety disorder. Comorbid anxiety in BD is associated with greater illness severity, greater functional impairment, and poorer illness-related outcomes. Effectively treating comorbid anxiety in individuals with BD has been recognized as one of the biggest unmet needs in the field of BD. Recently, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) was developed to be applicable to the full range of anxiety and mood disorders, based on converging evidence from genetics, cognitive and affective neuroscience, and behavioral research suggesting common, core emotion-related pathology. Here, the authors present a preliminary evaluation of the efficacy of the UP for the treatment of BD with comorbid anxiety, in a clinical replication series consisting of three cases. PMID- 22822174 TI - Obesity and all-cause mortality among black adults and white adults. AB - In recent pooled analyses among whites and Asians, mortality was shown to rise markedly with increasing body mass index (BMI; weight (kg)/height (m)(2)), but much less is known about this association among blacks. This study prospectively examined all-cause mortality in relation to BMI among 22,014 black males, 9,343 white males, 30,810 black females, and 14,447 white females, aged 40-79 years, from the Southern Community Cohort Study, an epidemiologic cohort of largely low income participants in 12 southeastern US states. Participants enrolled in the cohort from 2002 to 2009 and were followed up to 8.9 years. Hazard ratios and 95% confidence intervals for mortality were obtained from sex- and race-stratified Cox proportional hazards models in association with BMI at cohort entry, adjusting for age, education, income, cigarette smoking, and alcohol consumption. Elevated BMI was associated with increased mortality among whites (hazard ratios for BMI >40 vs. 20-24.9 = 1.37 (95% confidence interval (CI): 1.02, 1.84) and 1.47 (95% CI: 1.15, 1.89) for white males and white females, respectively) but not significantly among blacks (hazard ratios = 1.13 (95% CI: 0.89, 1.43) and 0.87 (95% CI: 0.72, 1.04) for black males and black females, respectively). In this large cohort, obesity in mid-to-late adulthood among blacks was not associated with the same excess mortality risk seen among whites. PMID- 22822176 TI - Development of a quality of patient-health care provider communication scale from the perspective of patients with rheumatoid arthritis. AB - OBJECTIVES: To devise a patient-perspective driven measure of the quality of patient-health care provider communication and to evaluate the psychometric properties of this scale in a sample of 150 patients with rheumatoid arthritis. METHODS: Items were developed from interviews with 15 patients with rheumatoid arthritis. Two rheumatologists, a behavioral scientist, and a nurse researcher provided item feedback. Exploratory factor analysis with Oblimin rotation was used to examine the dimensionality of the newly developed Patient-Health Care Provider Communication Scale (PHCPCS). Cronbach's alpha was computed to assess internal consistency. Test-retest reliability was determined using the intraclass correlation coefficient. Construct validity was tested by comparing the PHCPCS with the Perceived Involvement in Care Scale (PICS) using correlation analysis. RESULTS: The PHCPCS measured two dimensions of the quality of patient-health care provider communication [Quality Communication (alpha = 0.94) and Negative Patient Health Care Provider Communication (alpha = 0.73)]. The total PHCPCS score and its Quality Communication Subscale were positively correlated with the total score on the PICS and with the doctor facilitation subscale of the PICS. DISCUSSION: This new measure of the quality of patient-health care provider communication has the potential for use in clinical practice, provider education, and further studies to improve health care to patients with rheumatoid arthritis. PMID- 22822178 TI - Outcomes of autologous chondrocyte implantation in study of the treatment of articular repair (STAR) patients with osteochondritis dissecans. AB - BACKGROUND: This is an analysis of the prospective Study of the Treatment of Articular Repair (STAR) to evaluate the effectiveness of autologous chondrocyte implantation (ACI) in a subset of adult patients with osteochondritis dissecans (OCD) knee lesions. HYPOTHESIS: Autologous chondrocyte implantation can improve clinical outcomes in patients with at least 1 chronic OCD lesion of the knee who failed a previous non-ACI cartilage repair treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Forty patients with at least one failed non-ACI treatment for an OCD knee lesion received ACI in a multicenter study. The modified Cincinnati Knee Rating System, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Short-Form 36 Health Survey (SF-36) were used to assess patient outcomes at baseline and periodically to 48 months. Treatment failures, serious adverse events, and subsequent surgical procedures were recorded. RESULTS: Thirty-two (80%) patients completed the 48-month study. Autologous chondrocyte implantation treatment was successful in 85% of patients. Mean (+/- standard deviation) overall knee condition score (modified Cincinnati) was 3.1 +/- 1.1 at baseline and 6.8 +/- 2.0 at month 48. Clinically and statistically significant (P < .001) mean improvements from baseline to month 48 for the KOOS were as follows: 51.5 to 79.5 (pain), 54.8 to 77.9 (symptoms), 27.5 to 63.6 (sports and recreation ability), 63.5 to 86.7 (activities of daily living), and 21.9 to 59.6 (knee-related quality of life). The mean improvement (P < .001) in overall health assessed by the SF-36 was 35.4 to 45.5. Thirty-five percent (n = 14/40) of patients had a subsequent surgical procedure, most frequently debridement of the cartilage lesion. Treatment failure occurred in 6 of 32 (19%) patients. CONCLUSION: Patients with OCD of the knee had statistically significant pain reduction and functional improvement for up to 48 months after ACI, despite the complexity and severity of the osteochondral lesions. PMID- 22822177 TI - The biomechanical and histologic effects of platelet-rich plasma on rat rotator cuff repairs. AB - BACKGROUND: Rotator cuff tears are common injuries that are often treated with surgical repair. Because of the high concentration of growth factors within platelets, platelet-rich plasma (PRP) has the potential to enhance healing in rotator cuff repairs. HYPOTHESIS: Platelet-rich plasma would alter the biomechanical and histologic properties of rotator cuff repair during an acute injury response. STUDY DESIGN: Controlled laboratory study. METHODS: Platelet rich plasma was produced from inbred donor rats. A tendon-from-bone supraspinatus tear was created surgically and an immediate transosseous repair performed. The control group underwent repair only. The PRP group underwent a repair with PRP augmentation. Rats in each group were sacrificed at 7, 14, and 21 days. The surgically repaired tendons underwent biomechanical testing, including failure load, stiffness, failure strain, and stress relaxation characteristics. Histological analysis evaluated the cellular characteristics of the repair tissue. RESULTS: At 7- and 21-day periods, augmentation with PRP showed statistically significant effects on the biomechanical properties of the repaired rat supraspinatus tear, but failure load was not increased at the 7-, 14-, or 21 day periods (P = .688, .209, and .477, respectively). The control group had significantly higher stiffness at 21 days (P = .006). The control group had higher failure strain at 7 days (P = .02), whereas the PRP group had higher failure strain at 21 days (P = .008). Histologically, the PRP group showed increased fibroblastic response and vascular proliferation at each time point. At 21 days, the collagen fibers in the PRP group were oriented in a more linear fashion toward the tendon footprint. CONCLUSION: In this controlled, rat model study, PRP altered the tissue properties of the supraspinatus tendon without affecting the construct's failure load. CLINICAL RELEVANCE: The decreased tendon tissue stiffness acutely and failure to enhance tendon-to-bone healing of repairs should be considered before augmenting rotator cuff repairs with PRP. Further studies will be necessary to determine the role of PRP in clinical practice. PMID- 22822179 TI - The HeartQoL: Part I. Development of a new core health-related quality of life questionnaire for patients with ischemic heart disease. AB - BACKGROUND: Evaluation of health-related quality of life (HRQL) is important in improving the quality of patient care. METHODS: The HeartQoL Project, with cross sectional and longitudinal phases, was designed to develop a core ischemic heart disease (IHD) specific HRQL questionnaire, to be called the HeartQoL, for patients with angina, myocardial infarction (MI), or ischemic heart failure. Patients completed a battery of questionnaires and Mokken scaling analysis was used to identify items in the HeartQoL questionnaire. RESULTS: We enrolled 6384 patients (angina, n = 2111, 33.1%; MI, n = 2351, 36.8%; heart failure, n = 1922, 30.1%) across 22 countries and 15 languages. The HeartQoL questionnaire comprises 14-items with 10-item physical and 4-item emotional subscales which are scored from 0 (poor HRQL) to 3 (better HRQL) with a global score if needed. The mean baseline HeartQoL global score was 2.2 (+/-0.5) in the total group and was different (p < 0.001) by diagnosis (MI, 2.4 +/- 0.5; angina, 2.2 +/- 0.6; and heart failure, 2.1 +/- 0.6). CONCLUSION: The HeartQoL questionnaire, with global and subscale scores, has the potential to allow clinicians and researchers to (a) assess baseline HRQL, (b) make between-diagnosis comparisons of HRQL, and (c) evaluate change in HRQL in patients with angina, MI, or heart failure with a single IHD-specific HRQL instrument. PMID- 22822180 TI - The HeartQoL: part II. Validation of a new core health-related quality of life questionnaire for patients with ischemic heart disease. AB - BACKGROUND: Evaluation of health-related quality of life (HRQL) is important in improving the quality of patient care. The aim of this study was to determine the psychometric properties of the HeartQoL in patients with ischemic heart disease (IHD), specifically angina, myocardial infarction (MI), or ischemic heart failure. METHODS: Data for the interim validation of the HeartQoL questionnaire were collected in (a) a cross-sectional survey and (b) a prospective substudy of patients undergoing either a percutaneous coronary intervention (PCI) or referred to cardiac rehabilitation (CR) and were then analyzed to determine the reliability, validity, and responsiveness of the HeartQoL questionnaire. RESULTS: We enrolled 6384 patients (angina, n = 2111, 33.1%; MI, n = 2351, 36.8%; heart failure, n = 1922, 30.1%) across 22 countries speaking 15 languages in the cross sectional study and 730 patients with IHD in the prospective substudy. The HeartQoL questionnaire comprises 14-items with physical and emotional subscales and a global score (range 0-3 (poor to better HRQL). Cronbach's alpha was consistently >=0.80; convergent validity correlations between similar HeartQoL and SF-36 subscales were significant (r >= 0.60, p < 0.001); discriminative validity was confirmed with predictor variables: health transition, anxiety, depression, and functional status. HeartQoL score changes following either PCI or CR were significant (p < 0.001) with effect sizes ranging from 0.37-0.64. CONCLUSION: The HeartQoL questionnaire is reliable, valid, and responsive to change allowing clinicians and researchers to (a) assess baseline HRQL, (b) make between-diagnosis comparisons of HRQL, and (c) evaluate change in HRQL in patients with angina, MI, or heart failure with a single IHD-specific HRQL instrument. PMID- 22822172 TI - Time scales of divergence and speciation among natural populations and subspecies of Arabidopsis lyrata (Brassicaceae). AB - PREMISE OF THE STUDY: Plant populations that face new environments adapt and diverge simultaneously, and both processes leave footprints in their genetic diversity. Arabidopsis lyrata is an excellent species for studying these processes. Pairs of populations and subspecies of A. lyrata represent different stages of divergence. These populations are also known to be locally adapted and display various stages of emerging reproductive isolation. METHODS: We used nucleotide diversity data from 19 loci to estimate divergence times and levels of diversity among nine A. lyrata populations. Traditional distance-based methods and model-based clustering analysis were used to supplement pairwise coalescence based analysis of divergence. KEY RESULTS: Estimated divergence times varied from 130,000 generations between North American and European subspecies to 39,000 generations between central European and Scandinavian populations. In concordance with previous studies, the highest level of diversity was found in Central Europe and the lowest in North America and a diverged Russian Karhumaki population. Local adaptation among Northern and central European populations has emerged during the last 39,000 generations. Populations that are reproductively isolated by prezygotic mechanisms have been separated for a longer time period of ~70,000 generations but still have shared nucleotide polymorphism. CONCLUSIONS: In A. lyrata, reproductively isolated populations started to diverge ~70,000 generations ago and more closely related, locally adapted populations have been separate lineages for ~39,000 generations. However, based on the posterior distribution of divergence times, the processes leading to reproductive isolation and local adaptation are likely to temporally coincide. PMID- 22822181 TI - Aquatic exercise in a chest-high pool for hormone therapy-induced arthralgia in breast cancer survivors: a pragmatic controlled trial. AB - OBJECTIVE: To investigate the impact of aquatic exercise on pressure pain threshold in breast cancer survivors with hormone therapy-associated arthralgia. DESIGN: Single-blind, controlled trial. SETTING: Two major metropolitan hospitals and a Sport and Spa Club in Granada, Spain. SUBJECTS: Forty women aged 29-71 years with stage I-III breast cancer who reported arthralgia. INTERVENTION: Patients were allocated alternately to either aquatic exercise in a chest-high pool or usual care while on the waiting list; control patients received treatment later. The two-month hydrotherapy intervention consisted of 24 sessions 3 days per week. Each session included 5 minutes of warm-up, 15-20 minutes of aerobic exercise, 15 minutes of mobility exercise and 20 minutes of recovery techniques. MAIN MEASURES: Pressure pain threshold at neck, shoulder, hand and leg were evaluated as primary outcomes. Cancer-related fatigue, as measured by the Piper Fatigue Scale, body mass index and waist circumference were secondary outcomes. A 2 * 2 repeated-measure ANCOVA was used in this study. RESULTS: No adverse events or development of worsening of pain was observed. Almost all the participants in the intervention group (89%) adhered to the hydrotherapy programme. Participants experienced a decrease in pressure pain threshold measured in neck, hand, shoulder and leg, as measured by algometry pressure, and waist circumference; all P < 0.05. Cancer-related fatigue (P = 0.06) and body mass index (P = 0.42) did not show significant improvement. CONCLUSIONS: These data suggest that hydrotherapy in a chest-high pool may reduce the pain threshold and waist circumference in breast cancer survivors with hormone therapy-associated arthralgia. PMID- 22822183 TI - The Greek population is iodine sufficient and not at risk of iodine-induced hyperthyroidism. PMID- 22822182 TI - Attenuated response to methamphetamine sensitization and deficits in motor learning and memory after selective deletion of beta-catenin in dopamine neurons. AB - In the present study, we analyzed mice with a targeted deletion of beta-catenin in DA neurons (DA-betacat KO mice) to address the functional significance of this molecule in the shaping of synaptic responses associated with motor learning and following exposure to drugs of abuse. Relative to controls, DA-betacat KO mice showed significant deficits in their ability to form long-term memories and displayed reduced expression of methamphetamine-induced behavioral sensitization after subsequent challenge doses with this drug, suggesting that motor learning and drug-induced learning plasticity are altered in these mice. Morphological analyses showed no changes in the number or distribution of tyrosine hydroxylase labeled neurons in the ventral midbrain. While electrochemical measurements in the striatum determined no changes in acute DA release and uptake, a small but significant decrease in DA release was detected in mutant animals after prolonged repetitive stimulation, suggesting a possible deficit in the DA neurotransmitter vesicle reserve pool. However, electron microscopy analyses did not reveal significant differences in the content of synaptic vesicles per terminal, and striatal DA levels were unchanged in DA-betacat KO animals. In contrast, striatal mRNA levels for several markers known to regulate synaptic plasticity and DA neurotransmission were altered in DA-betacat KO mice. This study demonstrates that ablation of beta-catenin in DA neurons leads to alterations of motor and reward-associated memories and to adaptations of the DA neurotransmitter system and suggests that beta-catenin signaling in DA neurons is required to facilitate the synaptic remodeling underlying the consolidation of long-term memories. PMID- 22822185 TI - Driving forces of proteasome-catalyzed peptide splicing in yeast and humans. AB - Proteasome-catalyzed peptide splicing (PCPS) represents an additional activity of mammalian 20S proteasomes recently identified in connection with antigen presentation. We show here that PCPS is not restricted to mammalians but that it is also a feature of yeast 20S proteasomes catalyzed by all three active site beta subunits. No major differences in splicing efficiency exist between human 20S standard- and immuno-proteasome or yeast 20S proteasome. Using H(2)(18)O to monitor the splicing reaction we also demonstrate that PCPS occurs via direct transpeptidation that slightly favors the generation of peptides spliced in cis over peptides spliced in trans. Splicing efficiency itself is shown to be controlled by proteasomal cleavage site preference as well as by the sequence characteristics of the spliced peptides. By use of kinetic data and quantitative analyses of PCPS obtained by mass spectrometry we developed a structural model with two PCPS binding sites in the neighborhood of the active Thr1. PMID- 22822186 TI - Proteomic analysis of menstrual blood. AB - Menstruation is the expulsion of the endometrial lining of the uterus following a nearly month long preparation for embryo implantation and pregnancy. Increasingly, the health of the endometrium is being recognized as a critical factor in female fertility, and proteomes and transcriptomes from endometrial biopsies at different stages of the menstrual cycle have been studied for both diagnostic and therapeutic purposes (1 Kao, L. C., et al. 2003 Endocrinology 144, 2870-2881; Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; DeSouza, L., et al. 2005 Proteomics 5, 270-281). Disorders of the uterus ranging from benign to malignant tumors, as well as endometriosis, can cause abnormal menstrual bleeding and are frequently diagnosed through endometrial biopsy (Strowitzki, Tet al. 2006 Hum. Reprod. Update 12, 617-630; Ferenczy, A. 2003 Maturitas 45, 1-14). Yet the proteome of menstrual blood, an easily available noninvasive source of endometrial tissue, has yet to be examined for possible causes or diagnoses of infertility or endometrial pathology. This study employed five different methods to define the menstrual blood proteome. A total of 1061 proteins were identified, 361 were found by at least two methods and 678 were identified by at least two peptides. When the menstrual blood proteome was compared with those of circulating blood (1774 proteins) and vaginal fluid (823 proteins), 385 proteins were found unique to menstrual blood. Gene ontology analysis and evaluation of these specific menstrual blood proteins identified pathways consistent with the processes of the normal endometrial cycle. Several of the proteins unique to menstrual blood suggest that extramedullary uterine hematopoiesis or parenchymal hemoglobin synthesis may be occurring in late endometrial tissue. The establishment of a normal menstrual blood proteome is necessary for the evaluation of its usefulness as a diagnostic tool for infertility and uterine pathologies. Identification of unique menstrual blood proteins should aid the forensic community in distinguishing menstrual blood from circulating blood. PMID- 22822187 TI - The association between nitrous oxide and postoperative mortality and morbidity after noncardiac surgery. AB - BACKGROUND: Nitrous oxide (N2O) has been widely used in clinical anesthesia for >150 years. However, use of N2O has decreased in recent years because of concern about the drug's metabolic side effects. But evidence that routine use of N2O causes clinically important toxicity remains elusive. We therefore evaluated the relationship between intraoperative N2O administration and 30-day mortality as well as a set of major inpatient postoperative complications (including mortality) in adults who had general anesthesia for noncardiac surgery. METHODS: We evaluated 49,016 patients who had noncardiac surgery at the Cleveland Clinic between 2005 and 2009. Among 37,609 qualifying patients, 16,961 were given N2O ("nitrous," 45%) and 20,648 were not ("nonnitrous," 55%). Ten thousand seven hundred fifty-five nitrous patients (63% of the total) were propensity score matched with 10,755 nonnitrous patients. Matched nitrous and nonnitrous patients were compared on 30-day mortality and a set of 8 in-hospital morbidity/mortality outcomes. RESULTS: Inhalation of N2O intraoperatively was associated with decreased odds of 30-day mortality (odds ratio [OR]: 97.5% confidence interval, 0.67, 0.46-0.97; P = 0.02). Furthermore, nitrous patients had an estimated 17% (OR: 0.83, 0.74-0.92) decreased odds of experiencing major in-hospital morbidity/mortality than nonnitrous (P < 0.001). Among the individual morbidities, intraoperative N2O use was only associated with significantly lower odds of having pulmonary/respiratory morbidities (OR, 95% Bonferroni-adjusted CI: 0.59, 0.44-0.78). CONCLUSIONS: Intraoperative N2O administration was associated with decreased odds of 30-day mortality and decreased odds of in-hospital mortality/morbidity. Aside from its specific and well-known contraindications, the results of this study do not support eliminating N2O from anesthetic practice. PMID- 22822188 TI - Change in heparin potency and effects on the activated clotting time in children undergoing cardiopulmonary bypass. AB - BACKGROUND: Heparin is the anticoagulant most commonly used for cardiopulmonary bypass (CPB), and the activated clotting time (ACT) is its primary monitor. In October 2009, the Food and Drug Administration changed the United States Pharmacopeia (USP) monograph for unfractionated heparin to incorporate new quality tests and a new potency assay and reference standard. This latter change was anticipated by in vitro tests to reduce heparin potency by 10% in each USP unit dose. After integration of the "new" heparin into our practice, we subjectively noticed less prolongation of the ACT with our routine heparin bolus before the initiation of CPB. We performed this investigation to provide objective evidence of a reduction in the level of anticoagulation achieved with use of the new heparin as assessed by ACT values and to document the occurrence of having an ACT below our institutional threshold before the initiation of CPB. METHODS: A retrospective chart review was performed on all children who underwent CPB at Children's Healthcare of Atlanta between July 1, 2008, and June 30, 2009, before the release of the new heparin ("old heparin" [OH] group) and between June 1, 2010, and May 31, 2011, after complete integration of the new heparin ("new heparin" [NH] group). Baseline ACTs and ACTs after the administration of 400 U/kg of heparin were recorded for both the OH and NH groups. We determined the number of patients in each group having an ACT <480 seconds after the initial heparin bolus but before the initiation of CPB. Additionally, patients were divided into 3 age groups (<1 month, 1 to 12 months, and >1 year) to analyze similar ACT changes. RESULTS: Postheparin ACTs were significantly lower in the NH group than in the OH group. There were significantly more patients having an ACT <480 seconds after the initial heparin bolus in the NH group (OH: 68 of 557 [12.2%] versus NH: 140 of 491 patients [28.5%]; P < 0.0001). The change remained significant when assessed across the age groups. CONCLUSIONS: In this investigation we provide objective evidence that the level of anticoagulation after the initial pre-CPB heparin bolus as assessed by the ACT is significantly less with use of the new heparin. This reduction remained consistent across 3 age groups and was associated with a more frequent occurrence of ACTs below our institutional threshold for the initiation of CPB. Consideration should be given to increasing the initial weight-based heparin dose administered before CPB. PMID- 22822190 TI - Transthoracic echocardiography simulation is an efficient method to train anesthesiologists in basic transthoracic echocardiography skills. AB - BACKGROUND: The clinical utility of focused transthoracic echocardiography (TTE) is increasingly recognized in perioperative medicine. However its use is limited among anesthesiologists because of a lack of training. The most efficient training methods have not been determined. We hypothesized that simulation-based TTE training would be more effective than traditional lecture-based methods for teaching basic TTE skills to the anesthesiology residents. METHODS: In this prospective randomized study, 61 anesthesiology residents (in anesthesia clinical training years 1 to 3) were randomized to either control (n = 30) or simulation groups (n = 31) for TTE training. A standardized pretest was administered before TTE training sessions of 45 minutes each. The first training session used a lecture-based video didactic in the control group or a TTE simulator in the simulation group. Comprehension in both groups was then assessed using a written posttest and by performing a TTE examination on a volunteer subject. TTE examinations were graded on the ability to acquire the correct image, image quality, anatomy identification, and time required to attain proper imaging by 2 blinded experts. A second training session incorporating "hands-on" training with a volunteer subject was conducted in a subset of 21 residents (n = 11 control, n = 10 simulation). The simulation group included additional simulator training. After the second session, another posttest on a volunteer subject was administered. RESULTS: Pretest scores revealed similar preintervention knowledge among residents (56.0% +/- 11.9% vs 59.3% +/- 11.0%, P = 0.25; control versus simulator group, respectively). The simulation group scored higher on all criteria after the first training session: written posttest (57.9% +/- 8.8% vs 68.2% +/- 10.1%; P < 0.001), volunteer subject posttest image quality scores (0 to 25 scale) (6.4 +/- 3.5 vs 12.4 +/- 4.2; P = 0.003), anatomy identification scores (0 to 25 scale) (8.3 +/- 6.6 vs 17.8 +/- 6.6; P = 0.003), and percentage correct views (50 +/- 19 vs 78 +/- 21; P < 0.001). After the second session, all scores were again improved in the simulation group: volunteer subject posttest image quality scores (9.6 +/- 3.3 vs 15.6 +/- 2.8; P = 0.002), anatomy identification scores: (17.6 +/- 3.8 vs 22.8 2.4; P = 0.003), and percentage correct views (80 +/- 16 vs 96 +/- 8; P = 0.007). DISCUSSION: This prospective randomized study demonstrated that anesthesiology residents trained with simulation acquired better skills in TTE image acquisition and anatomy identification on volunteer subjects. The educational benefit of simulation persisted even with introduction of hands-on instruction with volunteer subjects in both groups. The impact of these short-term educational approaches on longer term retention and actual clinical application warrants further investigation. PMID- 22822189 TI - Local neurotoxicity and myotoxicity evaluation of cyclodextrin complexes of bupivacaine and ropivacaine. AB - BACKGROUND: Bupivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures. In previous studies, inclusion complexes of BVC or RVC in hydroxypropyl-beta-cyclodextrin (HP-beta-CD) increased differential nervous blockade, compared to the plain anesthetic solutions. In this study we evaluated the local neural and muscular toxicity of these new formulations containing 0.5% BVC or RVC complexed with HP-beta-CD (BVC(HP-beta-CD) and RVC(HP beta-CD)). METHODS: Schwann cell viability was assessed by determination of mitochondrial dehydrogenase activity, and histopathological evaluation of the rat sciatic nerve was used to identify local neurotoxic effects (48 hours and 7 days after the treatments). Evaluations of serum creatine kinase levels and the histopathology of rat gastrocnemius muscle (48 hours after treatment) were also performed. RESULTS: Schwann cell toxicity evaluations revealed no significant differences between complexed and plain local anesthetic formulations. However, use of the complexed local anesthetics reduced serum creatine kinase levels 5.5 fold, relative to the plain formulations. The differences were significant at P < 0.05 (BVC) and P < 0.01 (RVC). The histopathological muscle evaluation showed that differences between groups treated with local anesthetics (BVC or RVC) and their respective complexed formulations (BVC(HP-beta-CD) or RVC(HP-beta-CD)) were significant (P < 0.05). CONCLUSIONS: We concluded that the new formulations presented a lower myotoxicity and a similar cytotoxic effect when compared to plain local anesthetic solutions. PMID- 22822191 TI - Patient warming excess heat: the effects on orthopedic operating room ventilation performance. AB - BACKGROUND: Patient warming has become a standard of care for the prevention of unintentional hypothermia based on benefits established in general surgery. However, these benefits may not fully translate to contamination-sensitive surgery (i.e., implants), because patient warming devices release excess heat that may disrupt the intended ceiling-to-floor ventilation airflows and expose the surgical site to added contamination. Therefore, we studied the effects of 2 popular patient warming technologies, forced air and conductive fabric, versus control conditions on ventilation performance in an orthopedic operating room with a mannequin draped for total knee replacement. METHODS: Ventilation performance was assessed by releasing neutrally buoyant detergent bubbles ("bubbles") into the nonsterile region under the head-side of the anesthesia drape. We then tracked whether the excess heat from upper body patient warming mobilized the "bubbles" into the surgical site. Formally, a randomized replicated design assessed the effect of device (forced air, conductive fabric, control) and anesthesia drape height (low-drape, high-drape) on the number of bubbles photographed over the surgical site. RESULTS: The direct mass-flow exhaust from forced air warming generated hot air convection currents that mobilized bubbles over the anesthesia drape and into the surgical site, resulting in a significant increase in bubble counts for the factor of patient warming device (P < 0.001). Forced air had an average count of 132.5 versus 0.48 for conductive fabric (P = 0.003) and 0.01 for control conditions (P = 0.008) across both drape heights. Differences in average bubble counts across both drape heights were insignificant between conductive fabric and control conditions (P = 0.87). The factor of drape height had no significant effect (P = 0.94) on bubble counts. CONCLUSIONS: Excess heat from forced air warming resulted in the disruption of ventilation airflows over the surgical site, whereas conductive patient warming devices had no noticeable effect on ventilation airflows. These findings warrant future research into the effects of forced air warming excess heat on clinical outcomes during contamination-sensitive surgery. PMID- 22822192 TI - Characteristics of distribution of morphine and metabolites in cerebrospinal fluid and plasma with chronic intrathecal morphine infusion in humans. AB - BACKGROUND: Despite widespread use of chronic intrathecal (IT) infusions of morphine, there is little systematic human work evaluating the steady state morphine concentrations or cerebrospinal (CSF) chemistry after long-term IT morphine delivery. We sought to address these issues in patients receiving chronic IT morphine infusion. METHODS: Pain patients with implanted catheters and pumps (range: 127 to 2165 days), receiving a stable dosing (>1 week) of IT morphine by infusion, were entered into the study. The following sequence was performed: (1) estimation of pain score; (2) radiograph localization of catheter tip; (3) percutaneous sampling of lumbar CSF at the L4 to 5 or L5-S1 space. CSF/plasma samples were assayed for chemistry, and morphine and its 3/6 glucuronide metabolites (M3G, M6G) by liquid chromatography mass spectrometry. RESULTS: Nineteen patients were enrolled. CSF samples were obtained from 16 subjects. Three patients were not included in the primary analysis because 1 catheter was epidural, 1 catheter was fractured, and 1 had a granuloma at the catheter tip. Of the 13 sampled patients, the range of daily doses, rates, and concentrations were 1.6 to 25 mg/d and 0.1 to 1 mL/d, 5 to 50 mg/mL, respectively. The principal observations were as follows: (i) morphine, M3G, and M6G were present in the CSF and plasma and showed a significant regression slope when plotted versus daily dose; (ii) in contrast, the regression slope of the group ratio morphine:M3G:M6G plotted versus daily dose in CSF or plasma was not different from zero; (iii) plotting "normalized" CSF analyte concentration (e.g., concentration at site/daily IT morphine dose) against the segmental distance of the sampling site from the catheter tip revealed a significant decline in concentration of morphine, but not of conjugates as a function of distance from the catheter tip; (iv) plotting CSF protein, glucose, and red and white cell counts versus daily morphine dose or morphine concentration at the sampling site revealed no significant regression; and (v) patients with a catheter failure or a granuloma showed reduced concentrations of morphine in their CSF. CONCLUSION: Chronic infusion of morphine shows high concentrations, which correlate with the infusion dose and the proximity of the sampling site to the infusion site with no effects on CSF chemistry. PMID- 22822193 TI - Different roles of peripheral mitogen-activated protein kinases in carrageenan induced arthritic pain and arthritis in rats. AB - BACKGROUND: Accumulating evidence suggests that extracellular signal-regulated protein kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) might be involved in hypersensitivity of various pain models. However, there is a lack of direct evidence for actual involvement of peripheral ERK, p38, and JNK in induction and maintenance of arthritic pain and the development of arthritis. METHODS: We evaluated the effects of preemptive and therapeutic intra-articular administration of selective inhibitors of p38 (SB203580) and JNK (SP600125), and indirect inhibition of ERK with a blocker (PD98059) of the kinase that activates ERK (i.e., MEK, the mitogen-activated protein kinase [MAPK]/ERK kinase), on arthritic pain-related behavior such as reduction of weight load and the inflammatory responses such as neutrophil infiltration into the synovium and knee joint diameter in rats. In addition, arthritis-induced phosphorylation of ERK, p38, and JNK in synovium of knee joint was examined. RESULTS: Pretreatments with PD98059, SB203580, and SP600125 prevented the reduction of weight load induced by the carrageenan injected into the knee joint cavity, but their effects showed different time course patterns. Therapeutic administration of PD98059 and SB203580 partially reversed carrageen-induced reduction of weight load, and their effects showed a similar time course pattern. However, therapeutic administration of SP600125 had no effect on the reduction of weight load. Hematoxylin and eosin staining revealed that carrageenan-induced neutrophil infiltration into the synovium was inhibited by pretreatment with SB203580 or SP600125, but not PD98059. Western blot measurements showed distinct expression of phosphorylated ERK, p38, and JNK in the synovium at different time points after carrageenan injection. CONCLUSION: These results suggest that ERK, p38, and JNK signaling pathways at the peripheral level may play different roles in arthritic pain and arthritis of the knee joint. PMID- 22822194 TI - Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy. AB - BACKGROUND: Hemostatic disorders are common in obstetric complications. Thromboelastography (TEG(r)) simultaneously measures coagulation and fibrinolysis within 10 to 20 minutes. Our primary aim in this prospective longitudinal study was to obtain knowledge about physiological changes in TEG(r) variables during normal pregnancy and 8 weeks postpartum. The secondary aims were to compare TEG(r) variables during pregnancy with TEG(r) variables 8 weeks postpartum and gestational weeks 10 to 15 and to correlate TEG(r) variables to standard laboratory analyses. METHODS: Blood samples were collected from 45 healthy pregnant women at gestational weeks 10 to 15, 20 to 22, 28 to 30, and 38 to 40, and at 8 weeks postpartum. The following TEG(r) analyses were performed: time until start of clotting (TEG(r)-R), time until 20-mm clot firmness (TEG(r)-K), angle of clotting (TEG(r)-Angle), maximum amplitude (TEG(r)-MA), and lysis after 30 minutes (TEG(r)-LY30). Activated partial thromboplastin time, prothrombin time, soluble fibrin, antithrombin, D-dimer, and platelet count were analyzed. RESULTS: Compared to 8 weeks postpartum TEG(r)-R was at least 0.9 minutes shorter (upper limit 99% confidence intervals) until gestational weeks 28 to 30 and the mean reduction varied between 23%-26%. TEG(r)-K was at least 0.1 minutes shorter throughout pregnancy and the mean reduction varied between 18%-35%. TEG(r)-Angle was at least 2.5 degrees greater during pregnancy and the mean increase varied between 12%-20%. TEG(r)-MA was also at least 0.4 mm greater during pregnancy and the mean increase varied between 6%-8%. TEG(r)-LY30 was at least 0.03% lower during gestational weeks 28 to 30 and 38 to 40 and the mean reduction varied between 67%-73%. The routine coagulation laboratory values were within normal pregnant limits. There were no or weak correlations between TEG(r) and the laboratory variables. CONCLUSIONS: TEG(r) demonstrates increased coagulability and decreased fibrinolysis during pregnancy. There was a faster initiation of hemostasis, with a minor increase in clot strength. Fibrinolysis decreased during late pregnancy. Alternative cutoff limits for TEG(r) variables may be required during pregnancy. Standard hemostatic laboratory tests were as expected during pregnancy. Future studies are needed to ascertain whether viscoelastic methods are preferable to standard hemostatic tests for the diagnosis of coagulopathy during obstetric hemorrhage. PMID- 22822195 TI - Lumbar plexus blockade reduces pain after hip arthroscopy: a prospective randomized controlled trial. AB - BACKGROUND: Hip arthroscopy causes moderate to severe postoperative pain. We hypothesized that performance of a lumbar plexus block (LPB) would reduce postoperative pain in the postanesthesia care unit (PACU) for patients discharged home on the day of surgery. METHODS: Patients received a combined spinal epidural with IV sedation, ondansetron, and ketorolac. Half of the patients (n = 42) also underwent a single-injection bupivacaine LPB. Postoperative analgesia (PACU and after discharge) was provided with oral hydrocodone/acetaminophen (5/500 mg) and an oral nonsteroidal antiinflammatory drug. IV hydromorphone was given as needed in the PACU. RESULTS: The LPB reduced pain at rest in the PACU (GEE: beta estimate of the mean on a 0 to 10 scale = -0.9; 95% confidence interval = -1.7 to -0.1; P = 0.037). Mean PACU pain scores at rest were reduced by the LPB from 4.2 to 3.3 (P = 0.048, 95% confidence interval for difference = 0.007-1.8; uncorrected for multiple values per patient, using independent samples t test for preliminary evaluation comparing pain between the groups). There were no statistically significant differences in PACU analgesic usage, PACU pain with movement, and patient satisfaction. No permanent adverse events occurred, but 2 LPB patients fell in the PACU bathroom, without injury. Three unplanned admissions occurred; one LPB patient was admitted for epidural spread and urinary retention. Two control patients were admitted, one for oxygen desaturation and one for pain and nausea. CONCLUSION: LPB resulted in statistically significant reductions in PACU resting pain after hip arthroscopy, but the absence of improvement in most secondary outcomes suggests that assessment of risks and benefits of LPB should be individualized. PMID- 22822196 TI - Echocardiographic assessment of atrial septal defects. PMID- 22822197 TI - A method for ultrasonographic visualization and injection of the superior laryngeal nerve: volunteer study and cadaver simulation. AB - Superior laryngeal nerve block is a valuable technique for provision of upper airway anesthesia. In bilateral scans of 20 volunteers, we developed a technique for ultrasonographic visualization of the superior laryngeal nerve and key anatomical structures using a hockey stick-shaped 8 to 15 MHz transducer (HST15 to 8/20 linear probe, Ultrasonix, Richmond, BC, Canada). Subsequently, we simulated superior laryngeal nerve scanning and injection in bilateral injections in 2 cadavers. Ultrasound-guided in-plane advancement of a needle toward the superior laryngeal nerve and injection of 1 mL of green dye was achieved in all 4 attempts and confirmed by a postprocedural dissection performed by an anatomist. We conclude that ultrasound-guided superior laryngeal nerve block in humans may be feasible. PMID- 22822198 TI - Volumetric three-dimensional ultrasound imaging of the anatomy relevant for thoracic paravertebral block. AB - BACKGROUND: While ultrasound imaging of the thoracic paravertebral space in 2 dimensional (D) mode allows examination of the paravertebral anatomy in the transverse or sagittal axis, volumetric 3D ultrasound imaging provides multiplanar images in several orthogonal (perpendicular) planes and may provide additional anatomical information. In this imaging study we assessed the feasibility of 3D ultrasound imaging of the anatomical area relevant to the thoracic paravertebral block. METHODS: Four healthy young adult volunteers were recruited. With the volunteer in the sitting position, the C7 spinous process and the spinous processes of the T1 to 5 vertebra were identified. All images were obtained using a Philips iU22 ultrasound system with a high-frequency 3D 4D volume linear array transducer (13 to 5 MHz). A 3D volumetric scan of the right thoracic paravertebral region was performed with the sagittal plane as the data acquisition plane. RESULTS: With 3D multiplanar scanning, the sagittal, transverse, and coronal views of the paravertebral anatomy were simultaneously visualized in all subjects. Unlike 2D images, the articulation between the neck of the rib and the transverse process was well delineated in the sagittal and coronal images of the multiplanar scans. The rendered 3D volume allowed an in depth view of the paravertebral anatomy from all sides (i.e., top, bottom, front, back, left, and right). CONCLUSIONS: Volumetric 3D ultrasound imaging of the thoracic paravertebral space is feasible and provides more detailed spatial anatomical information than 2D ultrasound imaging. PMID- 22822199 TI - DNA and chromatin modification networks distinguish stem cell pluripotent ground states. AB - Pluripotent stem cells are capable of differentiating into all cell types of the body and therefore hold tremendous promise for regenerative medicine. Despite their widespread use in laboratories across the world, a detailed understanding of the molecular mechanisms that regulate the pluripotent state is currently lacking. Mouse embryonic (mESC) and epiblast (mEpiSC) stem cells are two closely related classes of pluripotent stem cells, derived from distinct embryonic tissues. Although both mESC and mEpiSC are pluripotent, these cell types show important differences in their properties suggesting distinct pluripotent ground states. To understand the molecular basis of pluripotency, we analyzed the nuclear proteomes of mESCs and mEpiSCs to identify protein networks that regulate their respective pluripotent states. Our study used label-free LC-MS/MS to identify and quantify 1597 proteins in embryonic and epiblast stem cell nuclei. Immunoblotting of a selected protein subset was used to confirm that key components of chromatin regulatory networks are differentially expressed in mESCs and mEpiSCs. Specifically, we identify differential expression of DNA methylation, ATP-dependent chromatin remodeling and nucleosome remodeling networks in mESC and mEpiSC nuclei. This study is the first comparative study of protein networks in cells representing the two distinct, pluripotent states, and points to the importance of DNA and chromatin modification processes in regulating pluripotency. In addition, by integrating our data with existing pluripotency networks, we provide detailed maps of protein networks that regulate pluripotency that will further both the fundamental understanding of pluripotency as well as efforts to reliably control the differentiation of these cells into functional cell fates. PMID- 22822200 TI - Participants' responsibilities in clinical research. AB - Discussions on the ethics and regulation of clinical research have a great deal to say about the responsibilities of investigators, sponsors, research institutions and institutional review boards, but very little about the responsibilities of research participants. In this article, we discuss the responsibilities of participants in clinical research. We argue that competent adult participants are responsible for complying with study requirements and fulfilling other obligations they undertake when they make an informed choice to enroll in a study. These responsibilities are based on duties related to promise keeping, avoiding harm to one's self or others, beneficence and reciprocity. Investigators and research staff should inform participants about their responsibilities during the consent process, and should stress the importance of fulfilling study requirements. They should address any impediments to compliance, and they may provide participants with financial incentives for meeting study requirements. In very rare cases, coercive measures may be justified to prevent immanent harm to others resulting from non-compliance with study requirements. PMID- 22822202 TI - Functional analyses of the plant photosystem I-light-harvesting complex II supercomplex reveal that light-harvesting complex II loosely bound to photosystem II is a very efficient antenna for photosystem I in state II. AB - State transitions are an important photosynthetic short-term response that allows energy distribution balancing between photosystems I (PSI) and II (PSII). In plants when PSII is preferentially excited compared with PSI (State II), part of the major light-harvesting complex LHCII migrates to PSI to form a PSI-LHCII supercomplex. So far, little is known about this complex, mainly due to purification problems. Here, a stable PSI-LHCII supercomplex is purified from Arabidopsis thaliana and maize (Zea mays) plants. It is demonstrated that LHCIIs loosely bound to PSII in State I are the trimers mainly involved in state transitions and become strongly bound to PSI in State II. Specific Lhcb1-3 isoforms are differently represented in the mobile LHCII compared with S and M trimers. Fluorescence analyses indicate that excitation energy migration from mobile LHCII to PSI is rapid and efficient, and the quantum yield of photochemical conversion of PSI-LHCII is substantially unaffected with respect to PSI, despite a sizable increase of the antenna size. An updated PSI-LHCII structural model suggests that the low-energy chlorophylls 611 and 612 in LHCII interact with the chlorophyll 11145 at the interface of PSI. In contrast with the common opinion, we suggest that the mobile pool of LHCII may be considered an intimate part of the PSI antenna system that is displaced to PSII in State I. PMID- 22822203 TI - Cyclic peptides arising by evolutionary parallelism via asparaginyl-endopeptidase mediated biosynthesis. AB - The cyclic miniprotein Momordica cochinchinensis Trypsin Inhibitor II (MCoTI-II) (34 amino acids) is a potent trypsin inhibitor (TI) and a favored scaffold for drug design. We have cloned the corresponding genes and determined that each precursor protein contains a tandem series of cyclic TIs terminating with the more commonly known, and potentially ancestral, acyclic TI. Expression of the precursor protein in Arabidopsis thaliana showed that production of the cyclic TIs, but not the terminal acyclic TI, depends on asparaginyl endopeptidase (AEP) for maturation. The nature of their repetitive sequences and the almost identical structures of emerging TIs suggest these cyclic peptides evolved by internal gene amplification associated with recruitment of AEP for processing between domain repeats. This is the third example of similar AEP-mediated processing of a class of cyclic peptides from unrelated precursor proteins in phylogenetically distant plant families. This suggests that production of cyclic peptides in angiosperms has evolved in parallel using AEP as a constraining evolutionary channel. We believe this is evolutionary evidence that, in addition to its known roles in proteolysis, AEP is especially suited to performing protein cyclization. PMID- 22822204 TI - A genome-wide regulatory framework identifies maize pericarp color1 controlled genes. AB - Pericarp Color1 (P1) encodes an R2R3-MYB transcription factor responsible for the accumulation of insecticidal flavones in maize (Zea mays) silks and red phlobaphene pigments in pericarps and other floral tissues, which makes P1 an important visual marker. Using genome-wide expression analyses (RNA sequencing) in pericarps and silks of plants with contrasting P1 alleles combined with chromatin immunoprecipitation coupled with high-throughput sequencing, we show here that the regulatory functions of P1 are much broader than the activation of genes corresponding to enzymes in a branch of flavonoid biosynthesis. P1 modulates the expression of several thousand genes, and ~1500 of them were identified as putative direct targets of P1. Among them, we identified F2H1, corresponding to a P450 enzyme that converts naringenin into 2-hydroxynaringenin, a key branch point in the P1-controlled pathway and the first step in the formation of insecticidal C-glycosyl flavones. Unexpectedly, the binding of P1 to gene regulatory regions can result in both gene activation and repression. Our results indicate that P1 is the major regulator for a set of genes involved in flavonoid biosynthesis and a minor modulator of the expression of a much larger gene set that includes genes involved in primary metabolism and production of other specialized compounds. PMID- 22822205 TI - PROTON GRADIENT REGULATION5 is essential for proper acclimation of Arabidopsis photosystem I to naturally and artificially fluctuating light conditions. AB - In nature, plants are challenged by constantly changing light conditions. To reveal the molecular mechanisms behind acclimation to sometimes drastic and frequent changes in light intensity, we grew Arabidopsis thaliana under fluctuating light conditions, in which the low light periods were repeatedly interrupted with high light peaks. Such conditions had only marginal effect on photosystem II but induced damage to photosystem I (PSI), the damage being most severe during the early developmental stages. We showed that PROTON GRADIENT REGULATION5 (PGR5)-dependent regulation of electron transfer and proton motive force is crucial for protection of PSI against photodamage, which occurred particularly during the high light phases of fluctuating light cycles. Contrary to PGR5, the NAD(P)H dehydrogenase complex, which mediates cyclic electron flow around PSI, did not contribute to acclimation of the photosynthetic apparatus, particularly PSI, to rapidly changing light intensities. Likewise, the Arabidopsis pgr5 mutant exhibited a significantly higher mortality rate compared with the wild type under outdoor field conditions. This shows not only that regulation of PSI under natural growth conditions is crucial but also the importance of PGR5 in PSI protection. PMID- 22822206 TI - The Arabidopsis mediator subunit MED25 differentially regulates jasmonate and abscisic acid signaling through interacting with the MYC2 and ABI5 transcription factors. AB - Transcriptional regulation plays a central role in plant hormone signaling. At the core of transcriptional regulation is the Mediator, an evolutionarily conserved, multisubunit complex that serves as a bridge between gene-specific transcription factors and the RNA polymerase machinery to regulate transcription. Here, we report the action mechanisms of the MEDIATOR25 (MED25) subunit of the Arabidopsis thaliana Mediator in regulating jasmonate- and abscisic acid (ABA) triggered gene transcription. We show that during jasmonate signaling, MED25 physically associates with the basic helix-loop-helix transcription factor MYC2 in promoter regions of MYC2 target genes and exerts a positive effect on MYC2 regulated gene transcription. We also show that MED25 physically associates with the basic Leu zipper transcription factor ABA-INSENSITIVE5 (ABI5) in promoter regions of ABI5 target genes and shows a negative effect on ABI5-regulated gene transcription. Our results reveal that underlying the distinct effects of MED25 on jasmonate and ABA signaling, the interaction mechanisms of MED25 with MYC2 and ABI5 are different. These results highlight that the MED25 subunit of the Arabidopsis Mediator regulates a wide range of signaling pathways through selectively interacting with specific transcription factors. PMID- 22822207 TI - Arabidopsis JAGGED LATERAL ORGANS acts with ASYMMETRIC LEAVES2 to coordinate KNOX and PIN expression in shoot and root meristems. AB - Organ initiation requires the specification of a group of founder cells at the flanks of the shoot apical meristem and the creation of a functional boundary that separates the incipient primordia from the remainder of the meristem. Organ development is closely linked to the downregulation of class I KNOTTED1 LIKE HOMEOBOX (KNOX) genes and accumulation of auxin at sites of primordia initiation. Here, we show that Arabidopsis thaliana JAGGED LATERAL ORGANS (JLO), a member of the LATERAL ORGAN BOUNDARY DOMAIN (LBD) gene family, is required for coordinated organ development in shoot and floral meristems. Loss of JLO function results in ectopic expression of the KNOX genes SHOOT MERISTEMLESS and BREVIPEDICELLUS (BP), indicating that JLO acts to restrict KNOX expression. JLO acts in a trimeric protein complex with ASYMMETRIC LEAVES2 (AS2), another LBD protein, and AS1 to suppress BP expression in lateral organs. In addition to its role in KNOX regulation, we identified a role for AS2 in regulating PINFORMED (PIN) expression and auxin transport from embryogenesis onwards together with JLO. We propose that different JLO and AS2 protein complexes, possibly also comprising other LBD proteins, coordinate auxin distribution and meristem function through the regulation of KNOX and PIN expression during Arabidopsis development. PMID- 22822208 TI - Interspecific RNA interference of SHOOT MERISTEMLESS-like disrupts Cuscuta pentagona plant parasitism. AB - Infection of crop species by parasitic plants is a major agricultural hindrance resulting in substantial crop losses worldwide. Parasitic plants establish vascular connections with the host plant via structures termed haustoria, which allow acquisition of water and nutrients, often to the detriment of the infected host. Despite the agricultural impact of parasitic plants, the molecular and developmental processes by which host/parasitic interactions are established are not well understood. Here, we examine the development and subsequent establishment of haustorial connections by the parasite dodder (Cuscuta pentagona) on tobacco (Nicotiana tabacum) plants. Formation of haustoria in dodder is accompanied by upregulation of dodder KNOTTED-like homeobox transcription factors, including SHOOT MERISTEMLESS-like (STM). We demonstrate interspecific silencing of a STM gene in dodder driven by a vascular-specific promoter in transgenic host plants and find that this silencing disrupts dodder growth. The reduced efficacy of dodder infection on STM RNA interference transgenics results from defects in haustorial connection, development, and establishment. Identification of transgene-specific small RNAs in the parasite, coupled with reduced parasite fecundity and increased growth of the infected host, demonstrates the efficacy of interspecific small RNA-mediated silencing of parasite genes. This technology has the potential to be an effective method of biological control of plant parasite infection. PMID- 22822209 TI - A ubiquitin ligase of symbiosis receptor kinase involved in nodule organogenesis. AB - The symbiosis receptor kinase (SymRK) is required for morphological changes of legume root hairs triggered by rhizobial infection. How protein turnover of SymRK is regulated and how the nodulation factor signals are transduced downstream of SymRK are not known. In this report, a SymRK-interacting E3 ubiquitin ligase (SIE3) was shown to bind and ubiquitinate SymRK. The SIE3-SymRK interaction and the ubiquitination of SymRK were shown to occur in vitro and in planta. SIE3 represents a new class of plant-specific E3 ligases that contain a unique pattern of the conserved CTLH (for C-terminal to LisH), CRA (for CT11-RanBPM), and RING (for Really Interesting New Gene) domains. Expression of SIE3 was detected in all tested tissues of Lotus japonicus plants, and its transcript level in roots was enhanced by rhizobial infection. The SIE3 protein was localized to multiple subcellular locations including the nuclei and plasma membrane, where the SIE3 SymRK interaction took place. Overexpression of SIE3 promoted nodulation in transgenic hairy roots, whereas downregulation of SIE3 transcripts by RNA interference inhibited infection thread development and nodule organogenesis. These results suggest that SIE3 represents a new class of E3 ubiquitin ligase, acts as a regulator of SymRK, and is involved in rhizobial infection and nodulation in L. japonicus. PMID- 22822210 TI - A structural basis for the biosynthesis of the major chlorogenic acids found in coffee. AB - Chlorogenic acids (CGAs) are a group of phenolic secondary metabolites produced by certain plant species and an important component of coffee (Coffea spp.). The CGAs have been implicated in biotic and abiotic stress responses, while the related shikimate esters are key intermediates for lignin biosynthesis. Here, two hydroxycinnamoyl-coenzyme A shikimate/quinate hydroxycinnamoyl transferases (HCT/HQT) from coffee were biochemically characterized. We show, to our knowledge for the first time, that in vitro, HCT is capable of synthesizing the 3,5-O dicaffeoylquinic acid diester, a major constituent of the immature coffee grain. In order to further understand the substrate specificity and catalytic mechanism of the HCT/HQT, we performed structural and mutagenesis studies of HCT. The three dimensional structure of a native HCT and a proteolytically stable lysine mutant enabled the identification of important residues involved in substrate specificity and catalysis. Site-directed mutagenesis confirmed the role of residues leucine-400 and phenylalanine-402 in substrate specificity and of histidine-153 and the valine-31 to proline-37 loop in catalysis. In addition, the histidine-154-asparagine mutant was observed to produce 4-fold more dichlorogenic acids compared with the native protein. These data provide, to our knowledge, the first structural characterization of a HCT and, in conjunction with the biochemical and mutagenesis studies presented here, delineate the underlying molecular-level determinants for substrate specificity and catalysis. This work has potential applications in fine-tuning the levels of shikimate and quinate esters (CGAs including dichlorogenic acids) in different plant species in order to generate reduced or elevated levels of the desired target compounds. PMID- 22822211 TI - MEDIATOR25 acts as an integrative hub for the regulation of jasmonate-responsive gene expression in Arabidopsis. AB - The PHYTOCHROME AND FLOWERING TIME1 gene encoding the MEDIATOR25 (MED25) subunit of the eukaryotic Mediator complex is a positive regulator of jasmonate (JA) responsive gene expression in Arabidopsis (Arabidopsis thaliana). Based on the function of the Mediator complex as a bridge between DNA-bound transcriptional activators and the RNA polymerase II complex, MED25 has been hypothesized to function in association with transcriptional regulators of the JA pathway. However, it is currently not known mechanistically how MED25 functions to regulate JA-responsive gene expression. In this study, we show that MED25 physically interacts with several key transcriptional regulators of the JA signaling pathway, including the APETALA2 (AP2)/ETHYLENE RESPONSE FACTOR (ERF) transcription factors OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59 and ERF1 as well as the master regulator MYC2. Physical interaction detected between MED25 and four group IX AP2/ERF transcription factors was shown to require the activator interaction domain of MED25 as well as the recently discovered Conserved Motif IX-1/EDLL transcription activation motif of MED25-interacting AP2/ERFs. Using transcriptional activation experiments, we also show that OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59- and ERF1-dependent activation of PLANT DEFENSIN1.2 as well as MYC2-dependent activation of VEGETATIVE STORAGE PROTEIN1 requires a functional MED25. In addition, MED25 is required for MYC2 dependent repression of pathogen defense genes. These results suggest an important role for MED25 as an integrative hub within the Mediator complex during the regulation of JA-associated gene expression. PMID- 22822212 TI - Lipid profiling of the Arabidopsis hypersensitive response reveals specific lipid peroxidation and fragmentation processes: biogenesis of pimelic and azelaic acid. AB - Lipid peroxidation (LPO) is induced by a variety of abiotic and biotic stresses. Although LPO is involved in diverse signaling processes, little is known about the oxidation mechanisms and major lipid targets. A systematic lipidomics analysis of LPO in the interaction of Arabidopsis (Arabidopsis thaliana) with Pseudomonas syringae revealed that LPO is predominantly confined to plastid lipids comprising galactolipid and triacylglyceride species and precedes programmed cell death. Singlet oxygen was identified as the major cause of lipid oxidation under basal conditions, while a 13-lipoxygenase (LOX2) and free radical catalyzed lipid oxidation substantially contribute to the increase upon pathogen infection. Analysis of lox2 mutants revealed that LOX2 is essential for enzymatic membrane peroxidation but not for the pathogen-induced free jasmonate production. Despite massive oxidative modification of plastid lipids, levels of nonoxidized lipids dramatically increased after infection. Pathogen infection also induced an accumulation of fragmented lipids. Analysis of mutants defective in 9 lipoxygenases and LOX2 showed that galactolipid fragmentation is independent of LOXs. We provide strong in vivo evidence for a free radical-catalyzed galactolipid fragmentation mechanism responsible for the formation of the essential biotin precursor pimelic acid as well as of azelaic acid, which was previously postulated to prime the immune response of Arabidopsis. Our results suggest that azelaic acid is a general marker for LPO rather than a general immune signal. The proposed fragmentation mechanism rationalizes the pathogen induced radical amplification and formation of electrophile signals such as phytoprostanes, malondialdehyde, and hexenal in plastids. PMID- 22822213 TI - Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. AB - Mitochondrial ability of shaping Ca(2+) signals has been demonstrated in a large number of cell types, but it is still debated in heart cells. Here, we take advantage of the molecular identification of the mitochondrial Ca(2+) uniporter (MCU) and of unique targeted Ca(2+) probes to directly address this issue. We demonstrate that, during spontaneous Ca(2+) pacing, Ca(2+) peaks on the outer mitochondrial membrane (OMM) are much greater than in the cytoplasm because of a large number of Ca(2+) hot spots generated on the OMM surface. Cytoplasmic Ca(2+) peaks are reduced or enhanced by MCU overexpression and siRNA silencing, respectively; the opposite occurs within the mitochondrial matrix. Accordingly, the extent of contraction is reduced by overexpression of MCU and augmented by its down-regulation. Modulation of MCU levels does not affect the ATP content of the cardiomyocytes. Thus, in neonatal cardiac myocytes, mitochondria significantly contribute to buffering the amplitude of systolic Ca(2+) rises. PMID- 22822214 TI - Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors. AB - The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal gamma oscillations--a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal gamma oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases gamma oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG 1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for gamma oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in gamma oscillation power. This unique link between D4R and ErbB4 signaling on gamma oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and gamma oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits. PMID- 22822215 TI - Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) dimerization and its roles in chromatinized DNA repair. AB - UV light-induced photoproducts are recognized and removed by the nucleotide excision repair (NER) pathway. In humans, the UV-damaged DNA-binding protein (UV DDB) is part of a ubiquitin E3 ligase complex (DDB1-CUL4A(DDB2)) that initiates NER by recognizing damaged chromatin with concomitant ubiquitination of core histones at the lesion. We report the X-ray crystal structure of the human UV-DDB in a complex with damaged DNA and show that the N-terminal domain of DDB2 makes critical contacts with two molecules of DNA, driving N-terminal-domain folding and promoting UV-DDB dimerization. The functional significance of the dimeric UV DDB [(DDB1-DDB2)(2)], in a complex with damaged DNA, is validated by electron microscopy, atomic force microscopy, solution biophysical, and functional analyses. We propose that the binding of UV-damaged DNA results in conformational changes in the N-terminal domain of DDB2, inducing helical folding in the context of the bound DNA and inducing dimerization as a function of nucleotide binding. The temporal and spatial interplay between domain ordering and dimerization provides an elegant molecular rationale for the unprecedented binding affinities and selectivities exhibited by UV-DDB for UV-damaged DNA. Modeling the DDB1 CUL4A(DDB2) complex according to the dimeric UV-DDB-AP24 architecture results in a mechanistically consistent alignment of the E3 ligase bound to a nucleosome harboring damaged DNA. Our findings provide unique structural and conformational insights into the molecular architecture of the DDB1-CUL4A(DDB2) E3 ligase, with significant implications for the regulation and overall organization of the proteins responsible for initiation of NER in the context of chromatin and for the consequent maintenance of genomic integrity. PMID- 22822216 TI - Direct observation of kinetic traps associated with structural transformations leading to multiple pathways of S-layer assembly. AB - The concept of a folding funnel with kinetic traps describes folding of individual proteins. Using in situ Atomic Force Microscopy to investigate S-layer assembly on mica, we show this concept is equally valid during self-assembly of proteins into extended matrices. We find the S-layer-on-mica system possesses a kinetic trap associated with conformational differences between a long-lived transient state and the final stable state. Both ordered tetrameric states emerge from clusters of the monomer phase, however, they then track along two different pathways. One leads directly to the final low-energy state and the other to the kinetic trap. Over time, the trapped state transforms into the stable state. By analyzing the time and temperature dependencies of formation and transformation we find that the energy barriers to formation of the two states differ by only 0.7 kT, but once the high-energy state forms, the barrier to transformation to the low-energy state is 25 kT. Thus the transient state exhibits the characteristics of a kinetic trap in a folding funnel. PMID- 22822217 TI - Protein folding kinetics and thermodynamics from atomistic simulation. AB - Advances in simulation techniques and computing hardware have created a substantial overlap between the timescales accessible to atomic-level simulations and those on which the fastest-folding proteins fold. Here we demonstrate, using simulations of four variants of the human villin headpiece, how simulations of spontaneous folding and unfolding can provide direct access to thermodynamic and kinetic quantities such as folding rates, free energies, folding enthalpies, heat capacities, Phi-values, and temperature-jump relaxation profiles. The quantitative comparison of simulation results with various forms of experimental data probing different aspects of the folding process can facilitate robust assessment of the accuracy of the calculations while providing a detailed structural interpretation for the experimental observations. In the example studied here, the analysis of folding rates, Phi-values, and folding pathways provides support for the notion that a norleucine double mutant of villin folds five times faster than the wild-type sequence, but following a slightly different pathway. This work showcases how computer simulation has now developed into a mature tool for the quantitative computational study of protein folding and dynamics that can provide a valuable complement to experimental techniques. PMID- 22822218 TI - Aortic dissection associated with right pulmonary artery compression. PMID- 22822219 TI - An octogenarian with painless type A aortic dissection and cardiac tamponade. PMID- 22822220 TI - Giant left atrium: a forgotten cause of cardiomegaly. PMID- 22822221 TI - Comparative outcomes of total hip and knee arthroplasty: a prospective cohort study. AB - PURPOSE: The comparative outcome of primary hip and knee arthroplasty is not well understood. This study aimed to investigate the outcome and satisfaction of these procedures and determine predictive models for 1 year patient outcome with a view to informing surgical management and patient expectations. STUDY DESIGN: Prospective cohort study of all primary hip and knee arthroplasty procedures performed at the Royal Infirmary of Edinburgh between January 2006 and November 2008. General health (SF-12) and joint specific function (Oxford Score) was assessed pre-operatively and at 6 and 12 months post-operatively. Patient satisfaction was assessed at 12 months. RESULTS: 1410 total hip arthroplasty (THA) and 1244 total knee arthroplasty (TKA) procedures were assessed. Oxford Score improved by 4.9 points more in THA patients than in TKA patients. SF-12 physical scores were on average 2.7 points greater in the THA patients at one year. Satisfaction was also greater (91%) following THA compared with TKA (81%). Regression modelling was not able to predict individual patient outcome; however, mean pre-operative Oxford Scores were found to be strong predictors of mean post operative Oxford Scores for each procedure. Age, gender and pre-operative general health scores did not influence these models. CONCLUSIONS: Both THA and TKA confer substantial improvement in patient outcome; however, greater joint specific, general health and satisfaction scores are reported following THA. This difference is physical in nature. Regression models are presented that can be applied to predict mean hip/knee arthroplasty outcome based on preoperative values. PMID- 22822222 TI - Improving outcome in severe trauma: what's new in ABC? Imaging, bleeding and brain injury. AB - Appropriate imaging is critical in the initial assessment of patients with severe trauma. Plain radiographs remain integral to the primary survey. Focused ultrasonography is useful for identifying intraperitoneal fluid likely to represent haemorrhage in patients who are shocked and also has a role in identifying intrathoracic pathology. Modern scanners permit a greater role for CT, being more rapid and exposing the patient to less ionising radiation. 'Whole body' (head to pelvis) CT scanning has been shown to identify injuries missed by 'traditional' focused assessment and may be associated with an improved outcome. CT identifies more spinal injuries than plain radiographs, is the gold standard for diagnosing blunt aortic injury and facilitates non-operative management of solid organ injury and other bleeding. Coagulopathy occurs early in trauma as a direct result of injury and hypoperfusion. Damage control resuscitation with blood components is associated with an improved outcome in patients with trauma with massive haemorrhage. Packed cells and fresh frozen plasma should be used in a 1:1 to 1:2 ratio. Bedside measures of coagulopathy may prove useful. Adjuvant early treatment with tranexamic acid is of benefit in reducing blood loss and reducing mortality. Limited 'damage control surgery' with early optimisation of physiology augmented by interventional radiology to control haemorrhage is preferable to early definitive care. Limiting haemorrhage by correction of anticoagulation and minimising secondary brain injury through optimal supportive care is critical to improving outcome in neurotrauma. PMID- 22822223 TI - Fertility: role of repressor of estrogen receptor activity. PMID- 22822225 TI - Republished: from coronary care unit to acute cardiac care unit: the evolving role of specialist cardiac care. PMID- 22822224 TI - Sugar making sugar: gluconeogenesis triggered by fructose via a hypothalamic adrenal-corticosterone circuit. PMID- 22822226 TI - Republished: which questions of two commonly used multidimensional palliative care patient reported outcome measures are most useful? Results from the European and African PRISMA survey. AB - AIM: To evaluate the views of clinicians and researchers on their use of outcome measures and which questions are most important in palliative and end-of-life care. METHODS: Online survey of professionals working in clinical care, clinical audit and research in palliative care across Europe and Africa identified through national and international associations and databases. Questions focused on measures used, reasons and which questions were important in two commonly used multidimensional measures, the Palliative care Outcome Scale (POS) and the Support Team Assessment Schedule (STAS). RESULTS: The overall completion rate was 59% (392/663). Three outcome measures were commonly used by over one in four respondents for clinical practice and over one in 10 for research: the Karnofsky Performance Scale (KPS), followed by the Edmonton Symptom Assessment Scale (ESAS) and the POS. Measures were used twice as often in clinical practice as in research. The main uses were similar: assessing patients' symptoms/needs (88% and 85% of POS and STAS users, respectively), monitoring changes (62%, 58%), evaluating care (61%, 48%) and assessing family needs (59%, 60%). Respondents rated the most important questions as pain, symptoms, emotional and family aspects. There were no differences in the choice of the most important questions between doctors and nurses or between researchers and clinicians. CONCLUSIONS: In palliative care, outcome measures often used in clinical practice are also often used in research. Questions relating to pain, symptoms, emotional needs and family concerns are consistently considered the most useful and important in palliative patient reported outcome measures (PROMs). PMID- 22822227 TI - After treat-to-target: can a targeted ultrasound initiative improve RA outcomes? AB - For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network - the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA. PMID- 22822228 TI - Improving outpatient services: the Southampton IBD virtual clinic. AB - The follow-up of inflammatory bowel disease (IBD) patients is challenging due to the relapsing remitting nature of the diseases, the wide spectrum of severity and complexity as well as the need for monitoring of long-term complications and drug treatments. Conventional outpatient follow-up lacks flexibility for patients and there are competing pressures for clinic time. Alternative follow-up pathways include telephone clinics, self-management programmes or discharging patients. The IBD virtual clinic (VC) is a further option. Patients with an established diagnosis for >2 years, who have been stable for >1 year, do not have primary sclerosing cholangitis and who give their consent, are entered into the VC system. Two months before their annual follow-up is due patients are sent blood test forms and a simple questionnaire with an information sheet. If they meet any of the criteria on the questionnaire, they are asked to contact the IBD specialist nursing team to discuss their situation. The blood test results and the patient's database entry are reviewed to ensure that they are not due surveillance investigations. The patients and their GPs then receive a letter informing them of their management plan. We currently follow-up 20% of the Southampton IBD cohort using the VC. The VC system is an innovative, efficient and patient-responsive method for following up mild to moderate IBD. It is well liked by patients but is dependent on a well-maintained database with good integration of IT systems and requires both clerical and IBD nurse specialist support. PMID- 22822229 TI - The birch field. PMID- 22822231 TI - The immediate and delayed cardiovascular benefits of forgiving. AB - BACKGROUND: The putative health benefits of forgiveness may include long-term buffering against cardiovascular reactivity associated with rumination. Although studies show short-term benefits of adopting a forgiving perspective, it is uncertain whether this perspective protects against repeated future rumination on offenses, which may be necessary for long-term health benefits. Also unclear is whether forgiveness offers unique benefits beyond simple distraction. METHODS: Cardiovascular parameters (systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate) were measured while 202 participants thought about a previous offense from an angry or forgiving perspective or were distracted. All participants were then distracted for 5 minutes, after which they freely ruminated on the offense. RESULTS: Angry rumination initially yielded the greatest increase in blood pressure from baseline (mean [M] [standard deviation {SD}]: SBP = 9.24 [11.16]; M [SD]: DBP = 4.69 [7.48]) compared with forgiveness (M [SD]: SBP = 3.30 [6.48]; M [SD]: DBP = 1.51 [4.94]) and distraction (M [SD]: SBP = 4.81 [6.28]; M [SD]: DBP = 1.75 [3.80]), which did not differ from each other (p > .30). During free rumination, however, those who had previously focused on forgiveness showed less reactivity (M [SD]: SBP = 7.33 [9.61]; M [SD]: DBP = 4.73 [7.33]) than those who had been distracted (M [SD]: SBP = 10.50 [7.77]; M [SD]: DBP = 7.71 [6.83]) and those who previously focused on angry rumination (M [SD]: SBP = 12.04 [11.74]; M [SD]: DBP = 8.64 [12.63]). There were no differences for heart rate. CONCLUSIONS: Forgiveness seems to lower reactivity both during the initial cognitive process and, more importantly, during mental recreations of an offense soon thereafter, potentially offering sustained protection, whereas effects of distraction appear transient. PMID- 22822230 TI - Indirect effects of elevated body mass index on memory performance through altered cerebral metabolite concentrations. AB - OBJECTIVE: Elevated body mass index (BMI) at midlife is associated with increased risk of cognitive decline in later life. The goal of the current study was to assess mechanisms of early brain vulnerability by examining if higher BMI at midlife affects current cognitive performance through alterations in cerebral neurochemistry. METHODS: Fifty-five participants, aged 40 to 60 years, underwent neuropsychological testing, health screen, and proton magnetic resonance spectroscopy examining N-acetylaspartate, creatine (Cr), myo-inositol (mI), choline, and glutamate concentrations in occipitoparietal gray matter. Concentrations of N-acetylaspartate, choline, mI, and glutamate were calculated as a ratio over Cr and examined in relation to BMI using multivariate regression analyses. Structural equation modeling was used to determine if BMI had an indirect effect on cognition through cerebral metabolite levels. RESULTS: Higher BMI was associated with elevations in mI/Cr (F(5,45) = 3.843, p = .006, beta = 0.444, p = .002), independent of age, sex, fasting glucose levels, and systolic blood pressure. Moreover, a chi(2) difference test of the direct and indirect structural equation models revealed that BMI had an indirect effect on global cognitive performance (Deltachi(2) = 19.939, df = 2, p < .001). Subsequent follow up analyses revealed that this effect was specific to memory (Deltachi(2) = 22.027, df = 2, p < .001). CONCLUSIONS: Higher BMI was associated with elevations in mI/Cr concentrations in the occipitoparietal gray matter and indirectly related to poorer memory performance through mI/Cr levels, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain vulnerability. PMID- 22822232 TI - Sex differences in the association of childhood socioeconomic status with adult blood pressure change: the CARDIA study. AB - OBJECTIVE: To examine sex differences in the relation of childhood socioeconomic status (CSES) to systolic (SBP) and diastolic blood pressure (DBP) trajectories during 15 years, spanning young (mean [M] [standard deviation {SD}] = 30 [3] years) and middle (M [SD] = 45 [3] years) adulthood, independent of adult SES. METHODS: A total of 4077 adult participants reported father's and mother's educational attainments at study enrollment (Year 0) and own educational attainment at enrollment and at all follow-up examinations. Resting BP also was measured at all examinations. Data from examination Years 5 (when participant M [SD] age = 30 [3] years), 7, 10, 15, and 20 are examined here. Associations of own adult (Year 5), mother's, and father's educations with 15-year BP trajectories were examined in separate multilevel models. Fully controlled models included time-invariant covariates (age, sex, race, recruitment center) and time varying covariates that were measured at each examination (marital status, body mass, cholesterol, oral contraceptives/hormones, and antihypertensive drugs). Analyses of parental education controlled for own education. RESULTS: When examined without covariates, higher education - own (SBP gamma = -0.03, DBP gamma = -0.03), mother's (SBP gamma = -0.02, DBP gamma = -0.02), and father's (SBP gamma = -0.02, DBP gamma = -0.01) - were associated with attenuated 15-year increases in BP (p < .001). Associations of own (but not either parent's) education with BP trajectories remained independent of standard controls. Sex moderated the apparent null effects of parental education, such that higher parental education-especially mother's, predicted attenuated BP trajectories independent of standard covariates among women (SBP gamma = -0.02, p = .02; DBP gamma = -0.01, p = .04) but not men (SBP gamma = 0.02, p = .06; DBP gamma = 0.005, p = .47; p interaction SBP < .001, p interaction DBP = .01). CONCLUSIONS: Childhood socioeconomic status may influence women's health independent of their own adult status. PMID- 22822233 TI - Cardiovascular and cortisol reactions to acute psychological stress and adiposity: cross-sectional and prospective associations in the Dutch Famine Birth Cohort Study. AB - OBJECTIVE: In recent analyses of data from a large community sample, negative cross-sectional and prospective associations between cardiac stress reactivity and obesity were observed. The present study reexamined the association between cardiovascular reactivity and adiposity in the Dutch Famine Birth Cohort, with the additional aim of examining the association between cortisol reactivity and adiposity. METHODS: Blood pressure, heart rate, and salivary cortisol were measured at rest and in response to standard laboratory stress tasks in 725 adults. Height, weight, waist-and-hip circumference, and skinfold thickness were measured. Between 4 to 7 years later, 460 participants reported current height and weight. Obesity was defined as a body mass index of 30 kg/m(2) or higher. RESULTS: Those with a greater body mass index (beta = -0.39 beats per minute (bpm)), waist-to-hip ratio (beta = -0.15 bpm), and triceps and subscapular skinfold thicknesses (beta = -1.0 and -1.8 bpm) or who were categorized as obese (-3.9 bpm) displayed smaller cardiac reactions to acute stress (all p < .001). With the exception of waist-to-hip ratio, the same negative associations emerged for cortisol reactivity (all p <= .01). In prospective analyses, low cardiac reactivity was associated with an increased likelihood of becoming or remaining obese in the subsequent 4 to 7 years (odds ratio = 1.03, p = .01). All associations withstood adjustment for a range of possible confounders. CONCLUSIONS: The present analyses provide additional support for the hypothesis that it is low not high cardiac and cortisol stress reactivity that is related to adiposity. PMID- 22822235 TI - Extended exercise rehabilitation after hip fracture improves patients' physical function: a systematic review and meta-analysis. AB - BACKGROUND: Although the principal goal of hip fracture management is a return to the pre-event functional level, most survivors fail to regain their former levels of autonomy. One of the most effective strategies to mitigate the fracture's consequences is therapeutic exercise. PURPOSE: The purpose of this study was to review and quantify the reported effects of an extended exercise rehabilitation program offered beyond the regular rehabilitation period on improving physical functioning for patients with hip fractures. SOURCES: The Cochrane libraries, PubMed, CINAHL, PEDro, and EMBASE were searched to April 2012. STUDY SELECTION: All randomized controlled trials comparing extended exercise programs with usual care for community-dwelling people after hip fracture were included in the review. DATA EXTRACTION AND SYNTHESIS: Two reviewers conducted each step independently. The data from the included studies were summarized, and pooled estimates were calculated for 11 functional outcomes. RESULTS: Thirteen trials were included in the review and 11 in the meta-analysis. The extended exercise program showed modest effect sizes (ESs), which reached significance, under random theory, for knee extension strength for the affected and nonaffected sides (ES=0.47, 95% confidence interval [CI]=0.27-0.66, and ES=0.45, 95% CI=0.16-0.74, respectively), balance (ES=0.32, 95% CI=0.15-0.49), physical performance-based tests (ES=0.53, 95% CI=0.27-0.78), Timed "Up & Go" Test (ES=0.83, 95% CI=0.28 1.4), and fast gait speed (ES=0.42, 95% CI=0.11-0.73). Effects on normal gait speed, Six-Minute Walk Test, activities of daily living and instrumental activities of daily living, and physical function subscale of the 36-Item Short Form Health Survey (SF-36-PF) did not reach significance. Community-based programs had larger ESs compared with home-based programs. CONCLUSIONS: To the authors' knowledge, this is the first meta-analysis to provide evidence that an extended exercise rehabilitation program for patients with hip fractures has a significant impact on various functional abilities. The focus of future research should go beyond just effectiveness and study the cost-effectiveness of extended programs. PMID- 22822234 TI - Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus. AB - Heat shock protein 90 (Hsp90) is a eukaryotic molecular chaperone. Its involvement in the resistance of Candida albicans to azole and echinocandin antifungals is well established. However, little is known about Hsp90's function in the filamentous fungal pathogen Aspergillus fumigatus. We investigated the role of Hsp90 in A. fumigatus by genetic repression and examined its cellular localization under various stress conditions. Failure to generate a deletion strain of hsp90 suggested that it is essential. Genetic repression of Hsp90 was achieved by an inducible nitrogen-dependent promoter (pniiA-Hsp90) and led to decreased spore viability, decreased hyphal growth, and severe defects in germination and conidiation concomitant with the downregulation of the conidiation-specific transcription factors brlA, wetA, and abaA. Hsp90 repression potentiated the effect of cell wall inhibitors affecting the beta-glucan structure of the cell wall (caspofungin, Congo red) and of the calcineurin inhibitor FK506, supporting a role in regulating cell wall integrity pathways. Moreover, compromising Hsp90 abolished the paradoxical effect of caspofungin. Pharmacological inhibition of Hsp90 by geldanamycin and its derivatives (17-AAG and 17-DMAG) resulted in similar effects. C-terminal green fluorescent protein (GFP) tagging of Hsp90 revealed mainly cytosolic distribution under standard growth conditions. However, treatment with caspofungin resulted in Hsp90 accumulation at the cell wall and at sites of septum formation, further highlighting its role in cell wall stress compensatory mechanisms. Targeting Hsp90 with fungal-specific inhibitors to cripple stress response compensatory pathways represents an attractive new antifungal strategy. PMID- 22822236 TI - Personal health behaviors and role-modeling attitudes of physical therapists and physical therapist students: a cross-sectional study. AB - BACKGROUND: Physical therapists have been encouraged to engage in health promotion practice. Health professionals who engage in healthy behaviors themselves are more apt to recommend those behaviors, and patients are more motivated to change their behaviors when their health care provider is a credible role model. OBJECTIVE: The purpose of this study was to describe the health behaviors and role-modeling attitudes of physical therapists and physical therapist students. DESIGN: This study was a descriptive cross-sectional survey. METHODS: A national sample of 405 physical therapists and 329 physical therapist students participated in the survey. Participants' attitudes toward role modeling and behaviors related to physical activity, fruit and vegetable consumption, abstention from smoking, and maintenance of a healthy weight were measured. Wilcoxon rank sum tests were used to examine differences in attitudes and behaviors between physical therapists and physical therapist students. RESULTS: A majority of the participants reported that they engage in regular physical activity (80.8%), eat fruits and vegetables (60.3%), do not smoke (99.4%), and maintain a healthy weight (78.7%). Although there were no differences in behaviors, physical therapist students were more likely to believe that role modeling is a powerful teaching tool, physical therapist professionals should "practice what they preach," physical activity is a desirable behavior, and physical therapist professionals should be role models for nonsmoking and maintaining a healthy weight. LIMITATIONS: Limitations of this study include the potential for response bias and social desirability bias. CONCLUSIONS: Physical therapists and physical therapist students engage in health-promoting behaviors at similarly high rates but differ in role-modeling attitudes. PMID- 22822238 TI - Factors associated with physical therapy services received for individuals with cerebral palsy in an outpatient pediatric medical setting. AB - BACKGROUND: Limited information is available regarding physical therapy use for individuals with cerebral palsy (CP). OBJECTIVES: The purpose of this study was to evaluate the association of Gross Motor Function Classification System (GMFCS) level, age, race, sex, and type of insurance with the total physical therapy units received over a 1-year period for individuals with CP in this outpatient pediatric medical setting. DESIGN: This was a cross-sectional study. METHODS: Four hundred twenty-five individuals with CP (GMFCS level I, 36%; level II, 15%; level III, 13%; level IV, 19%; and level V, 17%) were identified retrospectively through their electronic medical records. A one-way analyses of variance (ANOVA) was performed for each explanatory variable followed by a multiway ANOVA that adjusted for other variables to find the best model to explain total physical therapy units received. RESULTS: A significant difference in total therapy units received was found among GMFCS levels (F=6.91; df=4,420; P<.001), age groups (F=4.76; df=3,421; P=.028), and type of insurance (F=8.09; df=2,422; P=.004). No significant difference in physical therapy received was found for the factors of sex and race. The final multifactorial model indicates a significant main effect of insurance and a GMFCS by age interaction accounting for 19% of the variability (F=4.45; df=21,403; P<.001). LIMITATIONS: This study is cross-sectional and examines physical therapy services received in a pediatric medical setting in 1 geographic region of the United States. CONCLUSIONS: The results of this study provide insight into how therapy received varies for individuals with CP. Future studies should evaluate additional variables that may affect physical therapy services received. PMID- 22822239 TI - Self-reported uptake of recommendations after dissemination of medication incident alerts. AB - INTRODUCTION: In the Netherlands, a Central Medication Incidents Registration (CMR) system is operational. To prevent recurrence of reported medication incidents the CMR sends medication incident alerts with recommendations. It is up to the healthcare workers whether or not to implement the recommendations in clinical practice, which may lead to variations in degrees of uptake of the recommendations. OBJECTIVE: The aim of this study was to explore the degree of self-reported uptake of the recommendations and to identify potential determinants associated with successful uptake. DESIGN: This is a cross-sectional study conducted within a convenience sample of 33 Dutch hospital pharmacies. The study was carried out from April 2009 to September 2010. MEASUREMENTS: Three alerts were selected for the study: administration of methotrexate in a dosage of once a day instead of once a week, administration of undiluted potassium-sodium phosphate concentrate, and administration of glucose 50% instead of 5%. The primary outcome was the degree of self-reported uptake of the specific recommendations and the associations of the degree of uptake with several potential determinants. RESULTS: Twenty-one hospitals (63.6%) had adopted all recommendations about methotrexate. A quarter of the hospitals (24.2%) had adopted all recommendations related to potassium-sodium-phosphate concentrate. For the alert about glucose 50%, none of the hospitals had implemented all the recommendations. No statistically significant associations between potential determinants and the degree of uptake were found. CONCLUSIONS: This study is the first to investigate the degree of uptake of the recommendations of three different CMR alerts. The alerts varied in the degrees of self-reported uptake of the recommendations, with the methotrexate alert having the highest degree of uptake. No significant associations with potential determinants were found. PMID- 22822240 TI - Removal of doctors from practice for professional misconduct in Australia and New Zealand. AB - OBJECTIVE: To examine how disciplinary tribunals assess different forms of misconduct in deciding whether to remove doctors from practice for professional misconduct. DESIGN AND SETTING: Multivariable regression analysis of 485 cases in which tribunals found doctors guilty of professional misconduct. The cases came from four Australian states (New South Wales, Victoria, Queensland and Western Australia) and New Zealand and were decided over a 10-year period (1 January 2000 - 30 September 2009). MAIN OUTCOME MEASURES: Type of misconduct, the tribunal's explanation for why the misconduct occurred, and the disciplinary measure imposed. RESULTS: 43% of the cases resulted in removal of the offending doctor from practice, 37% in restrictions on practice and 19% in non-restrictive sanctions. The odds of removal were very high in cases involving sexual relationships with patients (OR 22.59; 95% CI 10.18 to 50.14) and moderately high in cases involving inappropriate sexual conduct (not in the context of a relationship), commission of criminal offences, and forms of inappropriate conduct unrelated to patients. Cases in which the misconduct was judged to be due to willful wrongdoing (OR 17.14; 95% CI 8.62 to 34.09), incompetence (OR 6.02; 95% CI 2.87 to 12.63) and issues in the doctor's personal life (OR 4.17; 95% CI 2.07 to 8.41) also had higher odds removal from practice. CONCLUSION: Tribunals in Australia and New Zealand tend to remove doctors from practice for behaviours indicative of character flaws and lack of insight, rather than behaviours exhibiting errors in care delivery, poor clinical judgement or lack of knowledge. The generalisability of these findings to regulatory regimes for health practitioners in other countries should be tested. PMID- 22822237 TI - Exercise for people in early- or mid-stage Parkinson disease: a 16-month randomized controlled trial. AB - BACKGROUND: Exercise confers short-term benefits for individuals with Parkinson disease (PD). OBJECTIVE: The purpose of the study was to compare short- and long term responses among 2 supervised exercise programs and a home-based control exercise program. DESIGN: The 16-month randomized controlled exercise intervention investigated 3 exercise approaches: flexibility/balance/function exercise (FBF), supervised aerobic exercise (AE), and home-based exercise (control). SETTING: This study was conducted in outpatient clinics. PATIENTS: The participants were 121 individuals with PD (Hoehn & Yahr stages 1-3). INTERVENTIONS: The FBF program (individualized spinal and extremity flexibility exercises followed by group balance/functional training) was supervised by a physical therapist. The AE program (using a treadmill, bike, or elliptical trainer) was supervised by an exercise trainer. Supervision was provided 3 days per week for 4 months, and then monthly (16 months total). The control group participants exercised at home using the National Parkinson Foundation Fitness Counts program, with 1 supervised, clinic-based group session per month. MEASUREMENTS: Outcomes, obtained by blinded assessors, were determined at 4, 10, and 16 months. The primary outcome measures were overall physical function (Continuous Scale-Physical Functional Performance [CS-PFP]), balance (Functional Reach Test [FRT]), and walking economy (oxygen uptake [mL/kg/min]). Secondary outcome measures were symptom severity (Unified Parkinson's Disease Rating Scale [UPDRS] activities of daily living [ADL] and motor subscales) and quality of life (39-item Parkinson's Disease Quality of Life Scale [PDQ-39]). RESULTS: Of the 121 participants, 86.8%, 82.6%, and 79.3% completed 4, 10, and 16 months, respectively, of the intervention. At 4 months, improvement in CS-PFP scores was greater in the FBF group than in the control group (mean difference=4.3, 95% confidence interval [CI]=1.2 to 7.3) and the AE group (mean difference=3.1, 95% CI=0.0 to 6.2). Balance was not different among groups at any time point. Walking economy improved in the AE group compared with the FBF group at 4 months (mean difference=-1.2, 95% CI=-1.9 to -0.5), 10 months (mean difference=-1.2, 95% CI= 1.9 to -0.5), and 16 months (mean difference=-1.7, 95% CI=-2.5 to -1.0). The only secondary outcome that showed significant differences was UPDRS ADL subscale scores: the FBF group performed better than the control group at 4 months (mean difference=-1.47, 95% CI=-2.79 to -0.15) and 16 months (mean difference=-1.95, 95% CI=-3.84 to -0.08). LIMITATIONS: Absence of a non-exercise control group was a limitation of the study. CONCLUSIONS: Findings demonstrated overall functional benefits at 4 months in the FBF group and improved walking economy (up to 16 months) in the AE group. PMID- 22822241 TI - Diagnostic errors in the intensive care unit: a systematic review of autopsy studies. AB - CONTEXT: Misdiagnoses may be an underappreciated cause of preventable morbidity and mortality in the intensive care unit (ICU). Their prevalence, nature, and impact remain largely unknown. OBJECTIVES: To determine whether potentially fatal ICU misdiagnoses would be more common than in the general inpatient population (~5%), and would involve more infections or vascular events. DATA SOURCES: Systematic review of studies identified by electronic (MEDLINE, etc.) and manual searches (references in eligible articles) without language restriction (1966 through 2011). STUDY SELECTION AND DATA ABSTRACTION: Observational studies examining autopsy-confirmed diagnostic errors in the adult ICU were included. Studies analysing misdiagnosis of one specific disease were excluded. Study results (autopsy rate, misdiagnosis prevalence, Goldman error class, diseases misdiagnosed) were abstracted and descriptive statistics calculated. We modelled the prevalence of Class I (potentially lethal) misdiagnoses as a non-linear function of the autopsy rate. RESULTS: Of 276 screened abstracts, 31 studies describing 5863 autopsies (median rate 43%) were analysed. The prevalence of misdiagnoses ranged from 5.5%-100% with 28% of autopsies reporting at least one misdiagnosis and 8% identifying a Class I diagnostic error. The projected prevalence of Class I misdiagnoses for a hypothetical autopsy rate of 100% was 6.3% (95% CI 4.0% to 7.5%). Vascular events and infections were the leading lethal misdiagnoses (41% each). The most common individual Class I misdiagnoses were PE, MI, pneumonia, and aspergillosis. CONCLUSIONS: Our data suggest that as many as 40,500 adult patients in an ICU in USA may die with an ICU misdiagnoses annually. Despite this, diagnostic errors receive relatively little attention and research funding. Future studies should seek to prospectively measure the prevalence and impact of diagnostic errors and potential strategies to reduce them. PMID- 22822242 TI - Quality improvement collaboratives in the age of health informatics--new wine in new wineskins. PMID- 22822244 TI - Bears "Count" Too: Quantity Estimation and Comparison in Black Bears (Ursus Americanus). AB - Studies of bear cognition are notably missing from the comparative record despite bears' large relative brain size and interesting status as generalist carnivores facing complex foraging challenges, but lacking complex social structures. We investigated the numerical abilities of three American black bears (Ursus Americanus) by presenting discrimination tasks on a touch-screen computer. One bear chose the larger of two arrays of dot stimuli, while two bears chose the smaller array of dots. On some trials the relative number of dots was congruent with the relative total area of the two arrays. On other trials number of dots was incongruent with area. All of the bears were above chance on trials of both types with static dots. Despite encountering greater difficulty with dots that moved within the arrays, one bear was able to discriminate numerically larger arrays of moving dots, and a subset of moving dots from within the larger array, even when area and number were incongruent. Thus, although the bears used area as a cue to guide responding, they were also able to use number as a cue. The pattern of performance was similar to that found previously with monkeys, and suggests that bears may also show other forms of sophisticated quantitative abilities. PMID- 22822243 TI - Impact of a hospital-wide hand hygiene initiative on healthcare-associated infections: results of an interrupted time series. AB - BACKGROUND: Evidence that hand hygiene (HH) reduces healthcare-associated infections has been available for almost two centuries. Yet HH compliance among healthcare professionals continues to be low, and most efforts to improve it have failed. OBJECTIVE: To improve healthcare workers' HH, and reduce healthcare associated infections. DESIGN: 3-year interrupted time series with multiple sequential interventions and 1-year post-intervention follow-up. SETTING: Teaching hospital in rural New Hampshire. INTERVENTIONS: In five categories: (1) leadership/accountability; (2) measurement/feedback; (3) hand sanitiser availability; (4) education/training; and (5) marketing/communication. MEASUREMENT: Monthly changes in observed HH compliance (%) and rates of healthcare-associated infection (including Staphylococcus aureus infections, Clostridium difficile infections and bloodstream infections) per 1000 inpatient days. The subset of S aureus infections attributable to the operating room served as a tracer condition. We used statistical process control charts to identify significant changes. RESULTS: HH compliance increased significantly from 41% to 87% (p<0.01) during the initiative, and improved further to 91% (p<0.01) the following year. Nurses achieved higher HH compliance (93%) than physicians (78%). There was a significant, sustained decline in the healthcare-associated infection rate from 4.8 to 3.3 (p<0.01) per 1000 inpatient days. The rate of S aureus infections attributable to the operating room rose, while the rate of other S aureus infections fell. CONCLUSIONS: Our initiative was associated with a large and significant hospital-wide improvement in HH which was sustained through the following year and a significant, sustained reduction in the incidence of healthcare-associated infection. The observed increased incidence of the tracer condition supports the assertion that HH improvement contributed to infection reduction. Persistent variation in HH performance among different groups requires further study. PMID- 22822245 TI - Adjusting for covariate effects on classification accuracy using the covariate adjusted receiver operating characteristic curve. AB - Recent scientific and technological innovations have produced an abundance of potential markers that are being investigated for their use in disease screening and diagnosis. In evaluating these markers, it is often necessary to account for covariates associated with the marker of interest. Covariates may include subject characteristics, expertise of the test operator, test procedures or aspects of specimen handling. In this paper, we propose the covariate-adjusted receiver operating characteristic curve, a measure of covariate-adjusted classification accuracy. Nonparametric and semiparametric estimators are proposed, asymptotic distribution theory is provided and finite sample performance is investigated. For illustration we characterize the age-adjusted discriminatory accuracy of prostate-specific antigen as a biomarker for prostate cancer. PMID- 22822246 TI - Bayesian analysis of matrix normal graphical models. AB - We present Bayesian analyses of matrix-variate normal data with conditional independencies induced by graphical model structuring of the characterizing covariance matrix parameters. This framework of matrix normal graphical models includes prior specifications, posterior computation using Markov chain Monte Carlo methods, evaluation of graphical model uncertainty and model structure search. Extensions to matrix-variate time series embed matrix normal graphs in dynamic models. Examples highlight questions of graphical model uncertainty, search and comparison in matrix data contexts. These models may be applied in a number of areas of multivariate analysis, time series and also spatial modelling. PMID- 22822248 TI - Penalized Bregman divergence for large-dimensional regression and classification. AB - Regularization methods are characterized by loss functions measuring data fits and penalty terms constraining model parameters. The commonly used quadratic loss is not suitable for classification with binary responses, whereas the loglikelihood function is not readily applicable to models where the exact distribution of observations is unknown or not fully specified. We introduce the penalized Bregman divergence by replacing the negative loglikelihood in the conventional penalized likelihood with Bregman divergence, which encompasses many commonly used loss functions in the regression analysis, classification procedures and machine learning literature. We investigate new statistical properties of the resulting class of estimators with the number p(n) of parameters either diverging with the sample size n or even nearly comparable with n, and develop statistical inference tools. It is shown that the resulting penalized estimator, combined with appropriate penalties, achieves the same oracle property as the penalized likelihood estimator, but asymptotically does not rely on the complete specification of the underlying distribution. Furthermore, the choice of loss function in the penalized classifiers has an asymptotically relatively negligible impact on classification performance. We illustrate the proposed method for quasilikelihood regression and binary classification with simulation evaluation and real-data application. PMID- 22822247 TI - Semiparametric methods for evaluating risk prediction markers in case-control studies. AB - The performance of a well-calibrated risk model for a binary disease outcome can be characterized by the population distribution of risk and displayed with the predictiveness curve. Better performance is characterized by a wider distribution of risk, since this corresponds to better risk stratification in the sense that more subjects are identified at low and high risk for the disease outcome. Although methods have been developed to estimate predictiveness curves from cohort studies, most studies to evaluate novel risk prediction markers employ case-control designs. Here we develop semiparametric methods that accommodate case-control data. The semiparametric methods are flexible, and naturally generalize methods previously developed for cohort data. Applications to prostate cancer risk prediction markers illustrate the methods. PMID- 22822249 TI - On the asymptotic behaviour of the pseudolikelihood ratio test statistic with boundary problems. AB - This paper considers the asymptotic distribution of the likelihood ratio statistic T for testing a subset of parameter of interest theta, theta = (gamma, eta), H(0) : gamma = gamma(0), based on the pseudolikelihood L(theta, phi), where phi is a consistent estimator of phi, the nuisance parameter. We show that the asymptotic distribution of T under H(0) is a weighted sum of independent chi squared variables. Some sufficient conditions are provided for the limiting distribution to be a chi-squared variable. When the true value of the parameter of interest, theta(0), or the true value of the nuisance parameter, phi(0), lies on the boundary of parameter space, the problem is shown to be asymptotically equivalent to the problem of testing the restricted mean of a multivariate normal distribution based on one observation from a multivariate normal distribution with misspecified covariance matrix, or from a mixture of multivariate normal distributions. A variety of examples are provided for which the limiting distributions of T may be mixtures of chi-squared variables. We conducted simulation studies to examine the performance of the likelihood ratio test statistics in variance component models and teratological experiments. PMID- 22822250 TI - Detecting simultaneous changepoints in multiple sequences. AB - We discuss the detection of local signals that occur at the same location in multiple one-dimensional noisy sequences, with particular attention to relatively weak signals that may occur in only a fraction of the sequences. We propose simple scan and segmentation algorithms based on the sum of the chi-squared statistics for each individual sample, which is equivalent to the generalized likelihood ratio for a model where the errors in each sample are independent. The simple geometry of the statistic allows us to derive accurate analytic approximations to the significance level of such scans. The formulation of the model is motivated by the biological problem of detecting recurrent DNA copy number variants in multiple samples. We show using replicates and parent-child comparisons that pooling data across samples results in more accurate detection of copy number variants. We also apply the multisample segmentation algorithm to the analysis of a cohort of tumour samples containing complex nested and overlapping copy number aberrations, for which our method gives a sparse and intuitive cross-sample summary. PMID- 22822251 TI - Sufficient cause interactions for categorical and ordinal exposures with three levels. AB - Definitions are given for weak and strong sufficient cause interactions in settings in which the outcome is binary and in which there are two exposures of interest that are categorical or ordinal. Weak sufficient cause interactions concern cases in which a mechanism will operate under certain values of the two exposures but not when one or the other of the exposures takes some other value. Strong sufficient cause interactions concern cases in which a mechanism will operate under certain values of the two exposures but not when one or the other of the exposures takes any other value. Empirical conditions are derived for such interactions when exposures have two or three levels and are related to regression coefficients in linear and log-linear models. When the exposures are binary, the notions of a weak and a strong sufficient cause interaction coincide, but not when the exposures are categorical or ordinal. The results are applied to examples concerning gene-gene and gene-environment interactions. PMID- 22822252 TI - Analysis of cohort studies with multivariate and partially observed disease classification data. AB - Complex diseases like cancers can often be classified into subtypes using various pathological and molecular traits of the disease. In this article, we develop methods for analysis of disease incidence in cohort studies incorporating data on multiple disease traits using a two-stage semiparametric Cox proportional hazards regression model that allows one to examine the heterogeneity in the effect of the covariates by the levels of the different disease traits. For inference in the presence of missing disease traits, we propose a generalization of an estimating equation approach for handling missing cause of failure in competing risk data. We prove asymptotic unbiasedness of the estimating equation method under a general missing-at-random assumption and propose a novel influence function-based sandwich variance estimator. The methods are illustrated using simulation studies and a real data application involving the Cancer Prevention Study II nutrition cohort. PMID- 22822253 TI - Estimating species richness by a Poisson-compound gamma model. AB - We propose a Poisson-compound gamma approach for species richness estimation. Based on the denseness and nesting properties of the gamma mixture, we fix the shape parameter of each gamma component at a unified value, and estimate the mixture using nonparametric maximum likelihood. A least-squares crossvalidation procedure is proposed for the choice of the common shape parameter. The performance of the resulting estimator of N is assessed using numerical studies and genomic data. PMID- 22822254 TI - Noncrossing quantile regression curve estimation. AB - Since quantile regression curves are estimated individually, the quantile curves can cross, leading to an invalid distribution for the response. A simple constrained version of quantile regression is proposed to avoid the crossing problem for both linear and nonparametric quantile curves. A simulation study and a reanalysis of tropical cyclone intensity data shows the usefulness of the procedure. Asymptotic properties of the estimator are equivalent to the typical approach under standard conditions, and the proposed estimator reduces to the classical one if there is no crossing. The performance of the constrained estimator has shown significant improvement by adding smoothing and stability across the quantile levels. PMID- 22822255 TI - Nonparametric Bayesian density estimation on manifolds with applications to planar shapes. AB - Statistical analysis on landmark-based shape spaces has diverse applications in morphometrics, medical diagnostics, machine vision and other areas. These shape spaces are non-Euclidean quotient manifolds. To conduct nonparametric inferences, one may define notions of centre and spread on this manifold and work with their estimates. However, it is useful to consider full likelihood-based methods, which allow nonparametric estimation of the probability density. This article proposes a broad class of mixture models constructed using suitable kernels on a general compact metric space and then on the planar shape space in particular. Following a Bayesian approach with a nonparametric prior on the mixing distribution, conditions are obtained under which the Kullback-Leibler property holds, implying large support and weak posterior consistency. Gibbs sampling methods are developed for posterior computation, and the methods are applied to problems in density estimation and classification with shape-based predictors. Simulation studies show improved estimation performance relative to existing approaches. PMID- 22822257 TI - Nonparametric inference for competing risks current status data with continuous, discrete or grouped observation times. AB - New methods and theory have recently been developed to nonparametrically estimate cumulative incidence functions for competing risks survival data subject to current status censoring. In particular, the limiting distribution of the nonparametric maximum likelihood estimator and a simplified naive estimator have been established under certain smoothness conditions. In this paper, we establish the large-sample behaviour of these estimators in two additional models, namely when the observation time distribution has discrete support and when the observation times are grouped. These asymptotic results are applied to the construction of confidence intervals in the three different models. The methods are illustrated on two datasets regarding the cumulative incidence of different types of menopause from a cross-sectional sample of women in the United States and subtype-specific HIV infection from a sero-prevalence study in injecting drug users in Thailand. PMID- 22822256 TI - A note on overadjustment in inverse probability weighted estimation. AB - Standardized means, commonly used in observational studies in epidemiology to adjust for potential confounders, are equal to inverse probability weighted means with inverse weights equal to the empirical propensity scores. More refined standardization corresponds with empirical propensity scores computed under more flexible models. Unnecessary standardization induces efficiency loss. However, according to the theory of inverse probability weighted estimation, propensity scores estimated under more flexible models induce improvement in the precision of inverse probability weighted means. This apparent contradiction is clarified by explicitly stating the assumptions under which the improvement in precision is attained. PMID- 22822258 TI - Time-dependent cross ratio estimation for bivariate failure times. AB - In the analysis of bivariate correlated failure time data, it is important to measure the strength of association among the correlated failure times. One commonly used measure is the cross ratio. Motivated by Cox's partial likelihood idea, we propose a novel parametric cross ratio estimator that is a flexible continuous function of both components of the bivariate survival times. We show that the proposed estimator is consistent and asymptotically normal. Its finite sample performance is examined using simulation studies, and it is applied to the Australian twin data. PMID- 22822259 TI - Bayesian isotonic density regression. AB - Density regression models allow the conditional distribution of the response given predictors to change flexibly over the predictor space. Such models are much more flexible than nonparametric mean regression models with nonparametric residual distributions, and are well supported in many applications. A rich variety of Bayesian methods have been proposed for density regression, but it is not clear whether such priors have full support so that any true data-generating model can be accurately approximated. This article develops a new class of density regression models that incorporate stochastic-ordering constraints which are natural when a response tends to increase or decrease monotonely with a predictor. Theory is developed showing large support. Methods are developed for hypothesis testing, with posterior computation relying on a simple Gibbs sampler. Frequentist properties are illustrated in a simulation study, and an epidemiology application is considered. PMID- 22822260 TI - A class of mixtures of dependent tail-free processes. AB - We propose a class of dependent processes in which density shape is regressed on one or more predictors through conditional tail-free probabilities by using transformed Gaussian processes. A particular linear version of the process is developed in detail. The resulting process is flexible and easy to fit using standard algorithms for generalized linear models. The method is applied to growth curve analysis, evolving univariate random effects distributions in generalized linear mixed models, and median survival modelling with censored data and covariate-dependent errors. PMID- 22822261 TI - Conditional Akaike information under generalized linear and proportional hazards mixed models. AB - We study model selection for clustered data, when the focus is on cluster specific inference. Such data are often modelled using random effects, and conditional Akaike information was proposed in Vaida & Blanchard (2005) and used to derive an information criterion under linear mixed models. Here we extend the approach to generalized linear and proportional hazards mixed models. Outside the normal linear mixed models, exact calculations are not available and we resort to asymptotic approximations. In the presence of nuisance parameters, a profile conditional Akaike information is proposed. Bootstrap methods are considered for their potential advantage in finite samples. Simulations show that the performance of the bootstrap and the analytic criteria are comparable, with bootstrap demonstrating some advantages for larger cluster sizes. The proposed criteria are applied to two cancer datasets to select models when the cluster specific inference is of interest. PMID- 22822262 TI - On protected estimation of an odds ratio model with missing binary exposure and confounders. AB - We describe an estimator of the parameter indexing a model for the conditional odds ratio between a binary exposure and a binary outcome given a high dimensional vector of confounders, when the exposure and a subset of the confounders are missing, not necessarily simultaneously, in a subsample. We argue that a recently proposed estimator restricted to complete-cases confers more protection to model misspecification than existing ones in the sense that the set of data laws under which it is consistent strictly contains each set of data laws under which each of the previous estimators are consistent. PMID- 22822263 TI - The price of maturity: Aging populations mean countries have to find new ways to support their elderly. PMID- 22822264 TI - Target Detection via Network Filtering. AB - A method of 'network filtering' has been proposed recently to detect the effects of certain external perturbations on the interacting members in a network. However, with large networks, the goal of detection seems a priori difficult to achieve, especially since the number of observations available often is much smaller than the number of variables describing the effects of the underlying network. Under the assumption that the network possesses a certain sparsity property, we provide a formal characterization of the accuracy with which the external effects can be detected, using a network filtering system that combines Lasso regression in a sparse simultaneous equation model with simple residual analysis. We explore the implications of the technical conditions underlying our characterization, in the context of various network topologies, and we illustrate our method using simulated data. PMID- 22822265 TI - On a Class of Admissible Constitutive Behaviors in Free-Floating Engineered Tissues. AB - A commonly used assay for studying cell - matrix interactions is the free floating fibroblast populated collagen lattice, which was introduced in 1979. Briefly, fibroblasts are seeded within an initially thin, amorphous, untethered, circular gel consisting of reconstituted fibrillar collagen. Although the gel remains traction free and circular, the cells typically contract the gel to less than 50% of its original diameter within hours to days. Cellular mechanotransduction mechanisms are fundamental to this contraction, but there has not been a careful study of the associated mechanics. In this paper, we model the initial contraction of a circular gel by assuming a homogeneous, axisymmetric finite deformation while allowing possible radial variations in material properties, including material symmetry. We show that trivial solutions alone (i.e., no deformation, no contraction) are admitted by equilibrium and boundary conditions unless radial variations exist in the material behavior, including cell contraction. Although more complete data are needed to model better this initial-boundary value problem, the present results are consistent with both the salient features of the gel assay and recent observations reported in the literature that cells often introduce regional variations in tissue properties in vivo in an attempt to achieve, maintain, or restore mechanical homeostasis. PMID- 22822266 TI - Thermodynamic Analysis of Thermal Hysteresis: Mechanistic Insights into Biological Antifreezes. AB - Antifreeze proteins (AFPs) bind to ice crystal surfaces and thus inhibit the ice growth. The mechanism for how AFPs suppress freezing is commonly modeled as an adsorption-inhibition process by the Gibbs-Thomson effect. Here we develop an improved adsorption-inhibition model for AFP action based on the thermodynamics of impurity adsorption on the crystal surfaces. We demonstrate the derivation of a realistic relationship between surface protein coverage and the protein concentration. We show that the improved model provides a quantitatively better fit to the experimental antifreeze activities of AFPs from distinct structural classes, including fish and insect AFPs, in a wide range of concentrations. Our theoretical results yielded the adsorption coefficients of the AFPs on ice, suggesting that, despite the distinct difference in their antifreeze activities and structures, the affinities of the AFPs to ice are very close and the mechanism of AFP action is a kinetically controlled, reversible process. The applications of the model to more complex systems along with its potential limitations are also discussed. PMID- 22822267 TI - A FRAMEWORK TO EXAMINE GATEWAY RELATIONS IN DRUG USE: A N APPLICATION OF LATENT TRANSITION ANALYSIS. AB - A progressive and hierarchical sequence of drug use suggests that a sequence of stages of drug use can describe the order by which adolescents try drugs. We propose an operational definition to test gateway relations by providing a framework with the aim of describing a set of conditions to guide the evaluation of whether a drug serves as a gateway for another drug. We used data from the National Longitudinal Study of Adolescent Health to demonstrate how using latent transition analysis we can estimate the odds of using a drug at a later time conditional on having used a gateway drug at an earlier time. We provide three empirical demonstrations for testing the gateway relations using a national and longitudinal data of adolescents (e.g., gateway relation between cigarettes and marijuana, alcohol and marijuana, and alcohol and cigarettes). PMID- 22822268 TI - Partnering Across the Life Course: Sex, Relationships, and Mate Selection. AB - Marital delay, relationship dissolution and churning, and high divorce rates have extended the amount of time individuals in search of romantic relationships spend outside of marital unions. The scope of research on intimate partnering now includes studies of "hooking up," Internet dating, visiting relationships, cohabitation, marriage following childbirth, and serial partnering, as well as more traditional research on transitions into marriage. Collectively, we know much more about relationship formation and development, but research often remains balkanized among scholars employing different theoretical approaches, methodologies, or disciplinary perspectives. The study of relationship behavior is also segmented into particular life stages, with little attention given to linkages between stages over the life course. Recommendations for future research are offered. PMID- 22822269 TI - A Predictive Approach to Nonparametric Inference for Adaptive Sequential Sampling of Psychophysical Experiments. AB - We present a predictive account on adaptive sequential sampling of stimulus response relations in psychophysical experiments. Our discussion applies to experimental situations with ordinal stimuli when there is only weak structural knowledge available such that parametric modeling is no option. By introducing a certain form of partial exchangeability, we successively develop a hierarchical Bayesian model based on a mixture of Polya urn processes. Suitable utility measures permit us to optimize the overall experimental sampling process. We provide several measures that are either based on simple count statistics or more elaborate information theoretic quantities. The actual computation of information theoretic utilities often turns out to be infeasible. This is not the case with our sampling method, which relies on an efficient algorithm to compute exact solutions of our posterior predictions and utility measures. Finally, we demonstrate the advantages of our framework on a hypothetical sampling problem. PMID- 22822270 TI - Speeding up Evolutionary Search by Small Fitness Fluctuations. AB - We consider a fixed size population that undergoes an evolutionary adaptation in the weak mutation rate limit, which we model as a biased Langevin process in the genotype space. We show analytically and numerically that, if the fitness landscape has a small highly epistatic (rough) and time-varying component, then the population genotype exhibits a high effective diffusion in the genotype space and is able to escape local fitness minima with a large probability. We argue that our principal finding that even very small time-dependent fluctuations of fitness can substantially speed up evolution is valid for a wide class of models. PMID- 22822271 TI - Response to Comment on "Dynamic Shifts of Limited Working Memory Resources in Human Vision" AB - Cowan & Rouder suggest that a modification to the four-slot model of visual working memory fits the available data better than our distributed resource model. However their comparisons of statistical fit are biased in favour of the slot model. Here we compare the predictions of the two models and present further evidence against the division of visual memory into slots. PMID- 22822272 TI - Relationship between side-chain branching and stoichiometry in beta(3)-peptide bundles. AB - The stability and stoichiometry of beta(3)-peptide bundles is influenced by side chain identity. beta(3)-peptides containing beta(3)-homoleucine on one helical face assemble into octamers, whereas those containing beta(3)-homovaline form tetramers. From a structural perspective, the side chains of beta(3)-homoleucine and beta(3)-homovaline differ in terms of both side-chain length and gamma-carbon branching. To evaluate the extent to which these two parameters control beta(3) peptide bundle stoichiometry, we synthesized the beta(3)-peptide Acid-3Y, which contains beta(3)-homoisoleucine in place of beta(3)-homoleucine or beta(3) homovaline. Acid-3Y assembles into a stable tetramer whose stability resembles that of the previously characterized Acid-VY tetramer. These results suggest that beta(3)-peptide bundle stoichiometry is dominated by the presence or absence of gamma-carbon branching on core side chains. PMID- 22822273 TI - Application of Chemoenzymatic Hydrolysis in the Synthesis of 2-Monoacylglycerols. AB - The selective biocatalyzed synthesis of 2-monoacylglycerols (2-MAGs) through the use of commercially available immobilized Candida antarctica (Novozym435) and Rhizomucor miehei is explored. Reactions at room temperature result in the formation of a 2-MAG and a corresponding ethyl ester of the fatty acid with immobilized Candida antarctica within 2h with yields ranging from 36%-83%. Similar reaction conditions with immobilized Rhizomucor miehei yielded exclusively the 2-MAG after 24h with yields ranging from 37% to 88%. Yields vary on the acyl group at the sn-2 position and choice of enzyme involved. PMID- 22822274 TI - Facile Synthesis of Mutagen X (MX): 3-Chloro-4-(dichloromethyl)-5-hydroxy-5H furan-2-one. AB - 3-Chloro-4-(dichloromethyl)-5-hydroxy-5H-furan-2-one (Mutagen X, MX) was synthesized in six steps from commercially-available and inexpensive starting materials (27% overall yield). This synthesis enables the preparation of MX analogs and does not require the use of chlorine gas, as do previously reported methods. PMID- 22822275 TI - Synthesis and Biological Evaluation of Cremastrine and an Unnatural Analogue. AB - In this Letter, we describe the first total synthesis of cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata, with anticholinergic activity as well as an unnatural analogue. The streamlined synthesis proceeds in 9 steps, 7 steps longest linear sequence, in 25.2% overall yield, and features novel methodology to construct the pyrrolizidine core. Biological evaluation of cremastrine and the unnatural analogue indicated that both are pan-mAChR functional antagonists. PMID- 22822276 TI - Synthesis and characterization of membrane stable bis(arylimino)isoindole dyes and their potential application in nano-biotechnology. AB - A synthetic methodology of preparing novel membrane stable, responsive dyes is revealed in this manuscript. 1,3-bis(arylimino)isoindole dyes were synthesized and their properties to undergo intramolecular hydrogen bonding was studied with fluorescence spectroscopy in varying solvent polarities. Based on the functional moieties, compound that is capable of hydrogen donor and acceptor interactions produces predominant photoexcitation in comparison to the responsive dyes that lack these functionalities. These dyes, by the virtue of the presence of long chain acyl groups could be incorporated stably within the phospholipids membrane of core-shell nanoparticles. Nanoparticle was 'cracked' to release the dye from a hydrophobic to a hydrophilic environment, A significant change in florescence intensity was then observed, indicating the direct change in effect of intramolecular hydrogen bonding based on solvent polarity changes. This unique study provided implications of many further applications towards nanomedicine and nano-biotechnology. PMID- 22822278 TI - Personality Trait Development and Social Investment in Work. AB - A longitudinal study of employed individuals was used to test the relationship between social investment at work-the act of cognitively and emotionally committing to one's job-and longitudinal and cross-sectional personality trait development. Participants provided ratings of personality traits and social investment at work at two time-points, separated by approximately three years. Data were analyzed using latent change models. Cross-sectional results showed that extraversion, agreeableness, conscientiousness and emotional stability were related to social investment at work. Additionally, a positive association was found between longitudinal change in social investment in work and change in personality traits-especially conscientiousness. Finally, the correlated changes in social investment and personality traits were invariant across age groups, suggesting that personality traits remain malleable across the lifespan. PMID- 22822277 TI - CHILD DISRUPTIVE BEHAVIOR AND PARENTING EFFICACY: A COMPARISON OF THE EFFECTS OF TWO MODELS OF INSIGHTS. AB - In this article, we investigate the effectiveness of INSIGHTS into Children's Temperament (INSIGHTS), a temperament-based preventive intervention, in reducing the disruptive behavior problems of young children from low-income, urban families. Results indicate that children enrolled in INSIGHTS evidenced a decrease in disruptive behavior problems over the course of the intervention, with children with high maintenance temperaments evidencing the most rapid rates of decline. In addition, children in a collaborative version of the program with joint parent and teacher sessions demonstrated more rapid decreases in disruptive behavior than children in a parallel version with separate parent and teacher sessions. Furthermore, high maintenance children in the collaborative intervention evidenced lower levels of disruptive behaviors at the end of the intervention than their peers in the parallel version. Increases in parenting efficacy appeared to be the mechanism through which INSIGHTS reduced child disruptive behavior. PMID- 22822279 TI - Positive mood is associated with the implicit use of distraction. AB - Previous research demonstrates that individuals in a positive mood are differentially distracted by irrelevant information during an ongoing task (Rowe et al. in Proc Natl Acad Sci 104:383-388, 2007). The present study investigated whether susceptibility to distraction shown by individuals in a positive mood results in greater implicit memory for that distraction. Participants performed a similarity-judgment task on pictures that were superimposed with distracting words. When these previously distracting words could be used as solutions on a delayed implicit task administered several minutes later, performance was positively correlated with pleasantness of mood. Individuals in a positive mood are more likely than others to use previously irrelevant information to facilitate performance on a subsequent implicit task, a finding with implications for the relationship between positive mood and creativity. PMID- 22822280 TI - Mean-level change and intraindividual variability in self-esteem and depression among high-risk children. AB - This study investigated mean-level changes and intraindividual variability of self-esteem among maltreated (n=142) and nonmaltreated (n=109) school-aged children from low-income families. Longitudinal factor analysis revealed higher temporal stability of self-esteem among maltreated children compared to nonmaltreated children. Cross-domain latent growth curve models indicated that nonmaltreated children showed higher initial levels and greater increases in self esteem than maltreated children, and that the initial levels of self-esteem were significantly associated with depressive symptoms among maltreated and nonmaltreated children. The average level (mean of repeated measurements) of self esteem was predictive of depression at the final occasion for both maltreated and nonmaltreated children. For nonmaltreated children intraindividual variability of self-esteem had a direct contribution to prediction of depression. The findings enhance our understanding of developmental changes in self-esteem and the role of the average level and within-person variability of self-esteem in predicting depressive symptoms among high-risk children. PMID- 22822281 TI - Dimensions of social capital and life adjustment in the transition to early adulthood. AB - The predictive relations between social capital depth (high-quality relationships across contexts) and breadth (friendship network extensivity) and early-adult, life adjustment outcomes were examined using data from a prospective longitudinal study. Interviews at age 22 yielded (a) psychometrically sound indexes of relationship quality with parents, peers, and romantic partners that served as indicators of a latent construct of social capital depth, and (b) a measure of number of close friends. In follow-up interviews at age 24, participants reported on their behavioral adjustment, educational attainment, and arrests and illicit substance use. Early-adolescent assessments of behavioral adjustment and academic performance served as controls; data on what were construed as interpersonal assets (teacher-rated social skills) and opportunities (family income) were also collected at this time. Results showed that depth was associated with overall better young-adult adjustment, net of prior adjustment, and assets and opportunities. Breadth was only modestly associated with later outcomes, and when its overlap with depth was taken into account, breadth predicted higher levels of subsequent externalizing problems. These findings are consistent with the notion that social capital is multidimensional and that elements of it confer distinct benefits during an important life transition. PMID- 22822282 TI - Handshape monitoring: Evaluation of linguistic and perceptual factors in the processing of American Sign Language. AB - We investigated the relevance of linguistic and perceptual factors to sign processing by comparing hearing individuals and deaf signers as they performed a handshape monitoring task, a sign-language analogue to the phoneme-monitoring paradigms used in many spoken-language studies. Each subject saw a series of brief video clips, each of which showed either an ASL sign or a phonologically possible but non-lexical "non-sign," and responded when the viewed action was formed with a particular handshape. Stimuli varied with respect to the factors of Lexicality, handshape Markedness (Battison, 1978), and Type, defined according to whether the action is performed with one or two hands and for two-handed stimuli, whether or not the action is symmetrical.Deaf signers performed faster and more accurately than hearing non-signers, and effects related to handshape Markedness and stimulus Type were observed in both groups. However, no effects or interactions related to Lexicality were seen. A further analysis restricted to the deaf group indicated that these results were not dependent upon subjects' age of acquisition of ASL. This work provides new insights into the processes by which the handshape component of sign forms is recognized in a sign language, the role of language experience, and the extent to which these processes may or may not be considered specifically linguistic. PMID- 22822283 TI - AFDC/TANF Exits and Re-entries for Families Raising Children with Educational Disabilities. AB - Having a child with a disability is considered a barrier to self-sufficiency among welfare recipients. This study examines the impact of children's educational disability on single-mother families' welfare exits and re-entries for a cohort of children in a metropolitan region in Missouri, who were born between 1982 and 1994, and received AFDC/TANF at least once from 1990 through 2008 (N=4,928). A semiparametric proportional hazards model for recurrent events is used to analyze the relationship between a child's educational disability and family welfare exit and re-entry. Results show that families with children with disabilities (the disability group) are less likely to exit and more likely to re enter the welfare system than families with children without disabilities (the nondisability group). After the 1996 welfare reform, the welfare exit rate increases more for the disability group than for the nondisability group, while the welfare re-entry rate decreases less for the disability group than for the nondisability group. PMID- 22822284 TI - Union Type and Depressive Symptoms Among Mexican Adults. AB - Diversity in union type is increasing around the world as cohabitation and higher order unions become more prevalent in developing and developed countries. This necessitates a more nuanced understanding of how different union types relate to individual well-being across social settings. In this study, the authors analyze nationally-representative data from Mexico in cross-sectional and change models to evaluate differences in depressive symptoms across union type (marital vs. cohabiting and first vs. higher order unions) among Mexican men and women. The findings suggest that cohabiting unions do not provide the same mental health benefits as marital unions (especially for men). Repartnering is also associated with higher depressive symptoms (especially for women), which indicates possible lasting mental health disadvantages of divorce/separation or entrance into lower quality second unions. These results suggest that the changing family context in Mexico, which includes increasing cohabitation and union instability, may have important consequences for individuals' psychological well-being. PMID- 22822285 TI - The Specter of Divorce: Views From Working- and Middle-Class Cohabitors. AB - Young Americans increasingly express apprehension about their ability to successfully manage intimate relationships. Partially in response, cohabitation has become normative over the past few decades. Little research, however, examines social class distinctions in how emerging adults perceive challenges to sustaining intimate unions. We examine cohabitors' views of divorce and how these color their sentiments regarding marriage. Data are from in-depth interviews with 122 working- and middle-class cohabitors. More than two thirds of respondents mentioned concerns with divorce. Working-class women, in particular, view marriage less favorably than do their male and middle-class counterparts, in part because they see marriage as hard to exit and are reluctant to assume restrictive gender roles. Middle-class cohabitors are more likely to have concrete wedding plans and believe that marriage signifies a greater commitment than does cohabitation. These differences in views of marriage and divorce may help explain the bifurcation of cohabitation outcomes among working- and middle-class cohabitors. PMID- 22822286 TI - A Developmental Process Analysis of Cross-Generational Continuity in Educational Attainment. AB - In this prospective longitudinal study (N = 585) we examined intergenerational links in level of educational attainment. Of particular interest was whether family background characteristics, parenting in early childhood and early adolescence, and school adjustment and performance in middle childhood accounted for (i.e., mediated) continuity and amplified or attenuated (i.e., moderated) continuity. Family background data, including mother education level, were collected when the children were age 5 years; parenting was assessed at ages 5 and 12; and school adjustment data (behavior problems, peer acceptance, academic performance) were collected in the first four years of elementary school. Cross generational continuity in educational attainment was moderate (r = .38) and largely indirect via children's academic performance in elementary school and mothers' academic involvement in early adolescence. Moderator analyses indicated greater cross-generational continuity in single-parent families; in families low in proactive teaching, monitoring, and academic involvement; and in families with lower-IQ children who performed poorly in school and were disliked by peers, These findings suggest that distal and proximal family and child characteristics may serve as crucial processes in the intergenerational transmission of low educational attainment. PMID- 22822287 TI - Parent Personality and Positive Parenting as Predictors of Positive Adolescent Personality Development Over Time. AB - We investigated the degree to which parent positive personality characteristics in terms of conscientiousness, agreeableness and emotional stability predict similar adolescent personality traits over time as well as the role played by positive parenting in this process. Mothers and fathers of 451 White adolescents (52% female, mean age = 13.59 years) were assessed on three occasions, with 2 year lags between each assessment. Parent personality and observed positive parenting both predicted 12(th) graders personality. Additionally, we found evidence for an indirect link between parent personality and later adolescent personality through positive parenting. The results suggest that parents may play a significant role in the development of adolescent personality traits that promote competence and personal well-being across the life course. PMID- 22822288 TI - Double Jeopardy: Child and School Characteristics That Predict Aggressive Disruptive Behavior in First Grade. AB - High rates of aggressive-disruptive behavior exhibited by children during their initial years of elementary school increase their risk for significant behavioral adjustment problems with teachers and peers. The purpose of the present study was to examine the unique and combined contributions of child vulnerabilities and school context to the development of aggressive-disruptive student behavior during first grade. Parent ratings and child interviews assessed three child characteristics associated with risk for the development of aggressive behavior problems in elementary school (aggressive-disruptive behaviors at home, attention problems, and social cognitions) in a sample of 755 first-grade children in four demographically diverse American communities. Two school characteristics associated with student aggressive-disruptive behavior problems (low-quality classroom context, school poverty levels) were also assessed. Linear and multilevel analyses showed that both child and school characteristics made independent and cumulative contributions to the development of student aggressive disruptive behavior at school. Although rates of student aggressive-disruptive behavior varied by gender and race, the predictive model generalized across all groups of children in the study. PMID- 22822289 TI - Walk the line-dispersal movements of gray mouse lemurs (Microcebus murinus). AB - Despite the importance of dispersal for individuals and populations, little is known about the actual dispersal process in most species. We observed 90 subadult gray mouse lemurs-small, arboreal, nocturnal primates-in Kirindy Forest in western Madagascar, to determine the behavioral processes underlying natal dispersal. Twelve radio-collared males dispersed over distances between 180 and 960 m (~1-7 home range diameters) away from their presumed natal ranges. Dispersal forays were fast and highly directed, and thus distinct from routine movements. Contrary to expectations of current hypotheses on potential differences between different types of dispersal movements, their special movement style did not prevent dispersers from interrupting forays to exploit resources they encountered during their forays. Data from a translocation experiment indicated that highly directed dispersal or search forays reflect a general strategy for large-scale exploration away from familiar sites in this species. A prolonged transfer phase was also observed, with regular commuting between old and new sites for up to 14 days, which probably served to moderate costs of unfamiliarity with a new site. In conclusion, the dispersal process of gray mouse lemurs is characterized by high intra- and interindividual consistency in movement strategies, but variation in the duration of the transfer phase. The observed dispersal movement style represents an effective strategy balancing costs of dispersal with the need to gather an appropriate level of information about potential dispersal target sites. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00265-012-1371-y) contains supplementary material, which is available to authorized users. PMID- 22822290 TI - Age-Related Effects of Study Time Allocation on Memory Performance in a Verbal and a Spatial Task. AB - Past studies have suggested that study time allocation partially mediates age relations on memory performance in a verbal task. To identify whether this applied to a different material modality, participants ages 20-87 completed a spatial task in addition to a traditional verbal task. In both the verbal and the spatial task, increased age was associated with poorer utilization of study time, suggesting that age differences in study time allocation are qualitatively similar across material modality. Furthermore, age differences in how individuals allocated their study time partially mediated the age relations on memory performance in both tasks, indicating the importance of effective regulation of study time when learning information. Finally, age differences in study time allocation did not appear to be due to differences in awareness of performance. When a subset of participants was asked about their prior performance, awareness of previous performance was not associated with study time allocation on either task. Interestingly, asking participants about their prior performance tended to decrease recall performance. Overall, these results illustrate that how one allocates study time is related to subsequent memory performance in both a verbal and spatial modality, but knowledge about prior performance is not associated with study time utilization, and inquiring about past performance during study may disrupt rather than facilitate learning. PMID- 22822291 TI - Generating Conflict for Greater Good: Utilizing Contingency Theory to Assess Black and Mainstream Newspapers as Public Relations Vehicles to Promote Better Health among African Americans. AB - The potential use of strategic conflict management ( Wilcox and Cameron, 2006; Cameron, Wilcox, Reber and Shin ( in press) as a health advocacy tool in US African-American and mainstream newspapers, arguing that escalation of conflict can increase effectiveness of health-related news releases. For health communicators focusing on at-risk populations with poor health outcomes, such goals would include increased awareness of health problems and solutions, along with increased motivation arising from indignation over health disparities. Content analysis of 1,197 stories in 24 Black and 12 mainstream newspapers showed that more conflict factors were present in Black vs. mainstream newspapers, suggesting a way to strategically place health messages in news releases disseminated to newspapers that motivate at-risk publics to better health. The findings suggest that conflict factors such as racial disparity data regarding health issues may enhance media advocacy. PMID- 22822292 TI - Characterization of localized surface plasmon resonance transducers produced from Au(25) nanoparticle multilayers. AB - This article reports the preparation of gold plasmonic transducers using a nanoparticle self-assembly/heating method and the characterization of the films using scattering-type scanning near-field optical microscopy (s-SNOM). Nanoparticle-polymer multilayer films were prepared by the layer-by-layer assembly on glass slides by alternating exposures to monodisperse Au(25) nanoparticles and ionic polymer linkers. Thermal evaporation of organic matters from the nanoparticle-polymer multilayer films at 600 degrees C allowed the nanoparticles to coalescence and form nanostructured films. Characterization of the nanostructured films generated from Au(25) nanoparticles using atomic force microscopy (AFM) showed that the films have rounded, small, island-like morphologies (d: 30-50 nm) with a pit in the center of many islands. However, further characterizations with s-SNOM revealed that the produced nanoislands contain a single gold cluster in a pit surrounded by donut-shaped dielectric species. Formation of such a structure is thought to be resulted from the embedding of gold clusters under the reorganized polysiloxane binder coatings and glass surfaces during heat treatment of the Au(25) nanoparticle multilayer films. The nanostructured films displayed strong surface plasmon resonance bands in UV vis spectra with a peak absorbance occurring at ~545-550 nm. The optical sensing capability of the films was examined using D-glucose-functionalized gold island films with the interaction of Concanavalin A (ConA). The result showed that the adsorption of ConA on island films causes a large change in the LSPR band intensity. PMID- 22822293 TI - The impact of herpes zoster and post-herpetic neuralgia on quality of life: patient-reported outcomes in six European countries. AB - AIM: To investigate the impact of an entire episode of herpes zoster (HZ) or post herpetic neuralgia (PHN) on an individual's quality of life (QoL). SUBJECTS AND METHODS: Individuals aged >=50 years with painful HZ in the previous 5 years were identified across six European countries (Spain, Portugal, The Netherlands, Belgium, Sweden and Switzerland). They participated in a survey comprising bespoke questions to evaluate their previous HZ/PHN episode. RESULTS: A total of 1,005 individuals participated, 874 (87%) having had HZ, and 13% having had PHN. Generally, pain and QoL outcomes were similar irrespective of when HZ was diagnosed (<=12 versus 13-60 months) and age (50-59 versus >=60 years). Mean pain scores were significantly higher in those with PHN versus HZ both on average (7.2 versus 6.4) and at worst (8.3 versus 7.4). PHN had a significantly higher impact on patients' perception of their overall QoL, with 37% reporting a high impact (HZ: 19%). Pain restrictions in the following QoL domains significantly impacted on the respondents' perception of QoL: enjoyment of life (level of impact, 31%), general activity (29%), mood (25%), sleep (8%) and walking ability (8%), and were significantly higher in those with PHN than in those with HZ. Sleep was the area worst affected. CONCLUSION: HZ, and particularly PHN, is associated with considerable levels of pain that have a significant impact on the QoL of participants across six European countries. PMID- 22822294 TI - Surface area and pore size characteristics of nanoporous gold subjected to thermal, mechanical, or surface modification studied using gas adsorption isotherms, cyclic voltammetry, thermogravimetric analysis, and scanning electron microscopy. AB - Nitrogen adsorption/desorption isotherms are used to investigate the Brunauer, Emmett, and Teller (BET) surface area and Barrett-Joyner-Halenda (BJH) pore size distribution of physically modified, thermally annealed, and octadecanethiol functionalized np-Au monoliths. We present the full adsorption-desorption isotherms for N(2) gas on np-Au, and observe type IV isotherms and type H1 hysteresis loops. The evolution of the np-Au under various thermal annealing treatments was examined using scanning electron microscopy (SEM). The images of both the exterior and interior of the thermally annealed np-Au show that the porosity of all free standing np-Au structures decreases as the heat treatment temperature increases. The modification of the np-Au surface with a self assembled monolayer (SAM) of C(18)-SH (coverage of 2.94 * 10(14) molecules cm(-2) based from the decomposition of the C(18)-SH using thermogravimetric analysis (TGA)), was found to reduce the strength of the interaction of nitrogen gas with the np-Au surface, as reflected by a decrease in the 'C' parameter of the BET equation. From cyclic voltammetry studies, we found that the surface area of the np-Au monoliths annealed at elevated temperatures followed the same trend with annealing temperature as found in the BET surface area study and SEM morphology characterization. The study highlights the ability to control free-standing nanoporous gold monoliths with high surface area, and well-defined, tunable pore morphology. PMID- 22822295 TI - Parents' Marital Status, Conflict, and Role Modeling: Links With Adult Romantic Relationship Quality. AB - This study investigated three parental marital statuses and relationship quality among unmarried, but dating adults ages 18 to 35 (N = 1153). Those whose parents never married one another tended to report the lowest relationship quality (in terms of relationship adjustment, negative communication, commitment, and physical aggression) compared to those with divorced or married biological parents. In addition, those with divorced parents reported lower relationship adjustment and more negative communication than those with married parents. Parental conflict and the degree to which participants rated their parents' relationship as a healthy model for their own relationships partially explained the associations between parental marital status and relationship outcomes. We suggest that this particular family type (i.e., having parents who never marry one another) needs greater attention in this field in terms of research and intervention. PMID- 22822296 TI - The Trajectories of Adolescents' Perceptions of School Climate, Deviant Peer Affiliation, and Behavioral Problems During the Middle School Years. AB - This longitudinal study examined trajectories of change in adolescents' perceptions of four dimensions of school climate (academic support, behavior management, teacher social support, peer social support) and the effects of such trajectories on adolescent problem behaviors. We also tested whether school climate moderated the associations between deviant peer affiliation and adolescent problem behaviors. The 1,030 participating adolescents from 8 schools were followed from 6th through 8th grades (54% female; 76% European American). Findings indicated that all the dimensions of school climate declined and behavioral problems and deviant peer affiliation increased. Declines in each of the dimensions were associated with increases in behavioral problems. The prediction of problem behavior from peer affiliation was moderated by adolescents' perceptions of school climate. PMID- 22822297 TI - Efficient Markov Network Structure Discovery Using Independence Tests. AB - We present two algorithms for learning the structure of a Markov network from data: GSMN* and GSIMN. Both algorithms use statistical independence tests to infer the structure by successively constraining the set of structures consistent with the results of these tests. Until very recently, algorithms for structure learning were based on maximum likelihood estimation, which has been proved to be NP-hard for Markov networks due to the difficulty of estimating the parameters of the network, needed for the computation of the data likelihood. The independence based approach does not require the computation of the likelihood, and thus both GSMN* and GSIMN can compute the structure efficiently (as shown in our experiments). GSMN* is an adaptation of the Grow-Shrink algorithm of Margaritis and Thrun for learning the structure of Bayesian networks. GSIMN extends GSMN* by additionally exploiting Pearl's well-known properties of the conditional independence relation to infer novel independences from known ones, thus avoiding the performance of statistical tests to estimate them. To accomplish this efficiently GSIMN uses the Triangle theorem, also introduced in this work, which is a simplified version of the set of Markov axioms. Experimental comparisons on artificial and real-world data sets show GSIMN can yield significant savings with respect to GSMN*, while generating a Markov network with comparable or in some cases improved quality. We also compare GSIMN to a forward-chaining implementation, called GSIMN-FCH, that produces all possible conditional independences resulting from repeatedly applying Pearl's theorems on the known conditional independence tests. The results of this comparison show that GSIMN, by the sole use of the Triangle theorem, is nearly optimal in terms of the set of independences tests that it infers. PMID- 22822299 TI - Food-Sharing Networks in Lamalera, Indonesia: Status, Sharing, and Signaling. AB - Costly signaling has been proposed as a possible mechanism to explain food sharing in foraging populations. This sharing-as-signaling hypothesis predicts an association between sharing and status. Using exponential random graph modeling (ERGM), this prediction is tested on a social network of between-household food sharing relationships in the fishing and sea-hunting village of Lamalera, Indonesia. Previous analyses (Nolin 2010) have shown that most sharing in Lamalera is consistent with reciprocal altruism. The question addressed here is whether any additional variation may be explained as sharing-as-signaling by high status households. The results show that high-status households both give and receive more than other households, a pattern more consistent with reciprocal altruism than costly signaling. However, once the propensity to reciprocate and household productivity are controlled, households of men holding leadership positions show greater odds of unreciprocated giving when compared to households of non-leaders. This pattern of excessive giving by leaders is consistent with the sharing-as-signaling hypothesis. Wealthy households show the opposite pattern, giving less and receiving more than other households. These households may reciprocate in a currency other than food or their wealth may attract favor seeking behavior from others. Overall, status covariates explain little variation in the sharing network as a whole, and much of the sharing observed by high status households is best explained by the same factors that explain sharing by other households. This pattern suggests that multiple mechanisms may operate simultaneously to promote sharing in Lamalera and that signaling may motivate some sharing by some individuals even within sharing regimes primarily maintained by other mechanisms. PMID- 22822298 TI - Adolescent Brain Development and Drugs. AB - New scientific discoveries have put a much different perspective on our understanding of adolescent behavior. Research now suggests that the human brain is still maturing during the adolescent years. The developing brain may help explain why adolescents sometimes make decisions that are risky and can lead to safety or health concerns, including unique vulnerabilities to drug abuse. This new science can be useful in revising prevention strategies to be more effective. PMID- 22822300 TI - Bequest Motives and the Annuity Puzzle. AB - Few retirees annuitize any wealth, a fact that has so far defied explanation within the standard framework of forward-looking, expected utility-maximizing agents. Bequest motives seem a natural explanation. Yet the prevailing view is that people with plausible bequest motives should annuitize part of their wealth, and thus that bequest motives cannot explain why most people do not annuitize any wealth. I show, however, that people with plausible bequest motives are likely to be better off not annuitizing any wealth at available rates. The evidence suggests that bequest motives play a central role in limiting the demand for annuities. PMID- 22822301 TI - Sulfation of fulvestrant by human liver cytosols and recombinant SULT1A1 and SULT1E1. AB - Fulvestrant (FaslodexTM) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with K(m) of 4.2 +/- 0.99 and 0.2 +/- 0.16 MUM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with beta naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001), but not with 17beta-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10). Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023) and copy number (P < 0.0001). These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy. PMID- 22822302 TI - Factors influencing societal response of nanotechnology: an expert stakeholder analysis. AB - Nanotechnology can be described as an emerging technology and, as has been the case with other emerging technologies such as genetic modification, different socio-psychological factors will potentially influence societal responses to its development and application. These factors will play an important role in how nanotechnology is developed and commercialised. This article aims to identify expert opinion on factors influencing societal response to applications of nanotechnology. Structured interviews with experts on nanotechnology from North West Europe were conducted using repertory grid methodology in conjunction with generalized Procrustes analysis to examine the psychological constructs underlying societal uptake of 15 key applications of nanotechnology drawn from different areas (e.g. medicine, agriculture and environment, chemical, food, military, sports, and cosmetics). Based on expert judgement, the main factors influencing societal response to different applications of nanotechnology will be the extent to which applications are perceived to be beneficial, useful, and necessary, and how 'real' and physically close to the end-user these applications are perceived to be by the public. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11051-012-0857-x) contains supplementary material, which is available to authorized users. PMID- 22822303 TI - Criterion validity of the Pittsburgh Sleep Quality Index: Investigation in a non clinical sample. AB - The objective of this study was to investigate the reliability and validity of the Pittsburgh Sleep Quality Index (PSQI) in a non-clinical sample consisting of younger and older adults. There has been little research validating the PSQI with respect to multinight recording as with actigraphy, and more validation is needed in samples not specifically selected for clinical disturbance. Also, the degree to which the PSQI scores may reflect depressive symptoms versus actual sleep disturbance remains unclear. One-hundred and twelve volunteers (53 younger and 59 older) were screened for their ability to perform treadmill exercises; inclusion was not based on sleep disturbance or depression. Internal homogeneity was evaluated by correlating PSQI component scores with the global score. Global and component scores were correlated with a sleep diary, actigraphy, and centers for epidemiological studies - depression scale scores to investigate criterion validity. Results showed high internal homogeneity. PSQI global score correlated appreciably with sleep diary variables and the depression scale, but not with any actigraphic sleep variables. These results suggest that the PSQI has good internal homogeneity, but may be less reflective of actual sleep parameters than a negative cognitive viewpoint or pessimistic thinking. The sleep complaints measured may often be more indicative of general dissatisfaction than of any specifically sleep-related disturbance. PMID- 22822305 TI - From The Editor's Desk. PMID- 22822306 TI - Assuring quality patient care and quality education. PMID- 22822304 TI - Health Care Reform and Concurrent Curative Care for Terminally Ill Children: A Policy Analysis. AB - Within the Patient Protection and Affordable Care Act of 2010 or health care reform, is a relatively small provision about concurrent curative care that significantly affects terminally ill children. Effective on March 23, 2010, terminally ill children, who are enrolled in a Medicaid or state Children's Health Insurance Plans (CHIP) hospice benefit, may concurrently receive curative care related to their terminal health condition. The purpose of this article was to conduct a policy analysis of the concurrent curative care legislation by examining the intended goals of the policy to improve access to care and enhance quality of end of life care for terminally ill children. In addition, the policy analysis explored the political feasibility of implementing concurrent curative care at the state-level. Based on this policy analysis, the federal policy of concurrent curative care for children would generally achieve its intended goals. However, important policy omissions focus attention on the need for further federal end of life care legislation for children. These findings have implications nurses. PMID- 22822307 TI - Venous thromboembolic disease. AB - Physicians understand the importance of prompt diagnosis and therapy of venous thromboembolism. This is a common and potentially deadly disease. Many patients may have no symptoms of this disorder, yet face a significant risk of serious complications if undiagnosed and untreated. Venous duplex ultrasonography has become the diagnostic test of choice for deep venous thrombosis. Quantitative d dimer levels may be very helpful in establishing the diagnosis of venous thrombosis. Helical (spiral) computed tomographic scans have replaced nuclear medicine ventilation-perfusion imaging for pulmonary embolus. So, the evolution of diagnostic methods has helped to identify patients with venous thromboembolism at an earlier stage of the disease. Treatment of venous thromboembolism has rapidly evolved over the past 40 years. Patients are often treated with subcutaneous low-molecular-weight heparins as outpatients, rather than admitted to hospital for continuous intravenous infusions of unfractionated heparin. This change in practice grew from a body of scientific literature supporting this advance. PMID- 22822308 TI - A history of the diagnosis and treatment of venous thrombosis and pulmonary embolism. AB - The history of venous thrombosis and pulmonary embolism echoes the naes of Harvey, Virchow, Margagni, Lannec, Trendelenberg, Ochsner DeBakey, Murray and many other famous figures in medicine. Through anatomical observation, physiologic experimentation, and laboratory or clinical investigation, they individually and collectively contributed to our current knowledge and approach to the treatment of these common and often life-threatening maladies. This article chronicles the important historical milestones in the understanding and development of current surgical and medical management of thromboembolic disease. PMID- 22822309 TI - Deep vein thrombosis: diagnosis of a comon clinical problem. AB - Ultrasound is recognized as a very accurate first line diagnostic tool when a patient presents with a symptomatic lower extremity suggesting acute venous thrombus. Advantages of ultrasound are that it does not involve using radiation or contrast and can be performed portably, generally with no complications. In many patients, other abnormalities such as Baker's cysts, arterial aneurysms, or hematomas can be detected and can explain the symptoms. Some limitations are that ultrasound is dependent on the skills of the sonographer and is very limited in visualization of iliac and abdominal veins. We are currently investigating computed tomography (CT) venography, which appears to be an accurate alternative, particularly for obese patients or when pelvic or abdominal thrombus is suspected. PMID- 22822310 TI - Pulmonary thromboembolic disease: a new role for computed tomography. AB - Over the past few years, computed tomography (CT) has emerged as a common noninvasive, definitive, alternative to ventilation-perfusion scintigraphy scan and pulmonary angiography in the evaluation of patients suspected of having pulmonary emboli. Additionally, recent articles have investigated the possibility of using CT to identify deep venous thrombi following a spiral CT pulmonary angiogram. Using the same bolus of contrast as that administered for a CT pulmonary angiogram, the ultimate goal is to design a single test that defines both aspects of pulmonary thromboembolic disease. More studies are needed and controversy exists, but CT's role in the evaluation of pulmonary thromboembolic disease appears promising. PMID- 22822311 TI - Management and prevention of venous thromboembolism including surgery and the pregnant state. AB - As the spectrum of venous thromboembolic disease states demanding both pharmacologic and non-pharmacologic prophylactic modalities continues to expand, the determination of the appropriate preventive regimen is of paramount importance. As a consensus develops regarding the clinical efficacy and safety of various antithrombotics for medical, surgical, and pregnant patients, clinicians must rely on existing evidence. For many populations, a definitive statement is difficult due to the heterogeneity of available study parameters. The development of a risk stratification may help to identify patients who will benefit from prophylaxis. PMID- 22822312 TI - Mechanical interventions and thrombolytic therapy in venous thrombosis and pulmonary embolism. AB - Venous thromboembolism is associated with significant morbidity and mortality. Anticoagulation with heparin and warfarin has favorably altered the natural history of untreated venous thromboembolism. The role of thrombolysis and interventional therapy in the management of venous thromboembolism is less well appreciated. This review evaluates the role of thrombolytic therapy and mechanical interventions in the management of deep vein thrombosis and pulmonary embolism. PMID- 22822313 TI - The comprehensive management of anticoagulation: ochsner coumadin clinic. AB - Clinical privileging of pharmacists and the effective use of support staff and information technology have helped create an efficient pharmacist-operated anticoagulation clinic at Ochsner Clinic Foundation that will support future growth efforts for improved patient care. Developed by Ochsner's Department of Cardiology, the pharmacist-operated anticoagulation clinic cares for 2000 patients with a clinical pharmacist, staff pharmacist, registered nurse, and medical assistants. Patients are managed by face-to-face and telephone encounters. The pharmacists are privileged by medical staff to write prescriptions for warfarin, adjust warfarin doses, and conduct appropriate laboratory monitoring. Patients attend a mandatory initial visit where they are given medication instructions and educational materials. The pharmacist determines the treatment dose and schedules follow-up appointments. A software system developed by Ochsner's Information Services Department imports patient data from the institution's central computer system, allowing for a limited electronic patient record. Once fully implemented, this program will allow for more specific patient tracking and assist with quality improvement efforts. At present, approximately 68% of our patient population is within therapeutic range. PMID- 22822314 TI - The new heparins. PMID- 22822315 TI - Alton Ochsner, MD: Physician. PMID- 22822316 TI - Scanning the literature. PMID- 22822319 TI - Ongoing clinical protocols at ochsner. PMID- 22822317 TI - About ochsner. PMID- 22822320 TI - From The Editor's Desk. PMID- 22822321 TI - Medical informatics: where are we in 2002? PMID- 22822322 TI - Adolescent tobacco use: prevention and cessation. AB - Smoking is an important cause of morbidity and mortality. Preventing and halting tobacco use are worthy strategies to improve the overall health of any population. Smoking and tobacco use begin during early adolescence, and most smokers try their first cigarette by age 12. A variety of psychosocial factors are involved in the initiation of tobacco use by adolescents. Strategies to prevent tobacco use should address these factors. Cessation efforts are hampered by nicotine addiction, which occurs in adolescents in a manner comparable to adults. Physicians and health care providers can assist adolescents in their attempts to quit tobacco use. A combination of counseling, peer and family support and, for some, nicotine replacement therapy, is the best approach to tobacco cessation. This paper reviews the findings of the major epidemiologic surveys of adolescent tobacco use and suggests strategies that health care providers can employ to reduce tobacco use among their adolescent patients. PMID- 22822323 TI - Fish oil in cardiovascular prevention. AB - The potential benefits of fish oil have been touted for several decades. The authors review evidence from epidemiologic, retrospective, and controlled prospective clinical trials demonstrating the effects of omega-3 fatty acids (fish oil) for the prevention of major cardiovascular events including myocardial infarction and stroke in primary and especially secondary prevention settings. Fish oil's efficacy in reducing total mortality and sudden cardiac death appears particularly promising, probably due to potent antiarrhythmic effects. We believe it is now time to consider fish oil therapy, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), for most patients with known cardiovascular disease and for patients at increased risk for cardiovascular disease, particularly patients at increased risk of sudden cardiac death. PMID- 22822324 TI - Nonalcoholic Fatty liver disease from the perspective of an internist. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as one of the most common causes of chronic hepatitis. While it has an indolent course in most patients, progression to cirrhosis is seen in some. Epidemiological data suggest that NAFLD may be the underlying disease in some patients with so called cryptogenic cirrhosis. Its incidence is likely to increase along with the current epidemiological trends in obesity. An increasing number of observations link insulin resistance as the central mechanism for hepatic steatosis. The factors that determine the progression of the disease, however, remain unclear. A clinical diagnosis is possible in most patients and liver biopsy is seldom required. While weight loss remains the most effective treatment, trials with insulin sensitizing agents are underway. There are some animal data as well as preliminary human data showing that metformin might offer some benefit in NAFLD. Liver transplantation is the treatment of choice for patients with decompensated cirrhosis. PMID- 22822325 TI - Approach to end of life care. AB - End of life care is often overlooked in busy day-to-day medical practice. Physicians need to recognize that death is inevitable for many medical conditions despite aggressive treatment. Optimal end of life care begins with an honest discussion of disease progression and prognosis. By coordinating the care with the family and a hospice program, terminally ill patients can achieve relief of pain and other unwanted symptoms, leading to a good quality of life during their remaining days. PMID- 22822326 TI - Joining the personal digital assitant revolution. AB - Personal Digital Assistants (PDAs), also known as handheld computers, are being increasingly adopted by physicians, many of whom find the PDA to be an indispensable part of their medical practice. With limited time and expense, an interested physician can choose and purchase a PDA, connect it to a computer, and fill it with useful medical software, much of which is available at little or no cost on the Internet. At its most basic, the PDA allows for the access of medical reference material at the point of care. Physicians interested in going to the next level can use the PDA for electronic prescribing, charge capture, or to customize documents or databases to meet the specific needs of their practice. PMID- 22822328 TI - Guy Alvin Caldwell, MD: Physician and Administrator. PMID- 22822329 TI - Scanning the literature. PMID- 22822327 TI - Immune disorders and susceptibility to neoplasms. PMID- 22822330 TI - Case studies. PMID- 22822331 TI - About ochsner. PMID- 22822334 TI - From The Editor's Desk. PMID- 22822335 TI - Academic affairs. PMID- 22822336 TI - Hereditary aspects of colon cancer. AB - Inherited colorectal cancer syndromes are responsible for a small percentage of all colorectal cancers, but affected individuals are at increased risk of gastrointestinal and extraintestinal malignancies. Gene testing plays an important diagnostic role and guides continued care to the patient and family members. Predisposition to colorectal cancer outside these inherited syndromes is less well defined, but recently established screening guidelines should prove to reduce the incidence of colorectal cancer in those with a familial risk. Colorectal cancer is preventable through recognition, treatment, and proper screening of those at risk. PMID- 22822337 TI - The case for universal screening colonoscopy. AB - The mortality related to colorectal malignancy each year remains significant. Although improvements in chemotherapy and surgical management may allow for some improvement, any profound impact must come through the implementation of appropriate screening. Several strategies for screening are available and widely practiced, but this review focuses on the concept of universal screening colonoscopy for the average-risk patient and addresses whether this is the appropriate recommendation in terms of safety, medicolegal, reimbursement and manpower issues, effectiveness and cost-effectiveness, patient acceptance, and appropriate intervals. PMID- 22822338 TI - The role of positron emission tomography in colorectal carcinoma. AB - Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is a functional imaging modality that provides mapping of glucose metabolism in the whole body. The glucose analogue fluorodeoxyglucose is labeled with the cyclotron produced, positron-emitting radioisotope fluorine-18. The resulting radiopharmaceutical FDG is a substrate for glucose transport proteins (Glut) in cell membranes and accumulates intracellularly. Increased metabolic activity in malignant tissue is accompanied by increased glucose uptake relative to that of surrounding normal tissue. This focal increase in glucose uptake can be identified with FDG PET, which allows identification of malignant tumor foci. Multiple reports have shown that positron emission tomography with 18F fluorodeoxyglucose scanning (FDG-PET) is highly accurate in detecting early localized tumor recurrence with a sensitivity and specificity in the mid nineties. FDG-PET scanning evaluates abdomen, chest, and pelvis in one examination setting, permiting identification of local recurrence as well as distant metastasis. FDG-PET is also highly sensitive in detecting hepatic and extra-hepatic metastasis. Finally, FDG-PET scanning can distinguish post treatment (postoperative and postradiation therapy) scarring from recurrent tumors since malignant tumors are metabolically active and FDG-avid on PET imaging and scar tissue is not. This high accuracy in identifying early stage recurrent tumors with FDG-PET is crucial for potential surgical cure and improving patient outcomes. PMID- 22822339 TI - Surgical management of colon and rectal cancer. AB - Adenocarcinoma, the most common malignant lesion of the colon and rectum, accounts for approximately 148,000 diagnosed cases and 56,000 deaths per year. Management of this disease comprises a large portion of the practice of colorectal surgery. This article describes the current concepts of surgical management of adenocarcnoma of the colon and rectum. Surgical options are reviewed following a brief discussion of diagnosis. PMID- 22822340 TI - The role of chemotherapy in colon cancer. AB - Chemotherapy is effective in the treatment of colon cancer when used both as adjuvant therapy and for metastatic disease. It has also been shown to improve survival. Novel therapies are currently being evaluated in clinical trials. To continue our progress, it is important that clinical trials be offered to patients undergoing treatment for colon cancer. PMID- 22822341 TI - Adjuvant and neoadjuvant treatment of resectable, locally advanced, rectal carcinoma with radiation therapy and chemotherapy. AB - Patients who undergo apparently curative low anterior or abdominal-perineal resection of locally advanced carcinoma of the rectum have a significant rate of local pelvic recurrence and death from cancer in the years following surgery. Pre and postoperative irradiation and chemotherapy in various combinations and schedules have been recommended to improve the outcome for these patients. Several randomized trials have evaluated the effectiveness of adjuvant and neoadjuvant treatments in improving survival and reducing the rate of pelvic recurrence with a combination of radiation and chemotherapy. There is some evidence that preoperative treatment with radiation is more effective than postoperative treatment. The treatment program preferred at Ochsner is described. PMID- 22822343 TI - Edgar burns. PMID- 22822342 TI - Cyclooxygenase 2 inhibitors and colon cancer. PMID- 22822344 TI - Scanning the literature. PMID- 22822345 TI - Ochsner colorectal cancer screening frequency study presented at american society of colon and rectal surgeons annual meeting. PMID- 22822347 TI - Ongoing clinical protocols at ochsner. PMID- 22822348 TI - The Leaf Fell (the Leaf): The Online Processing of Unaccusatives. AB - According to the Unaccusative Hypothesis, unaccusative subjects are base generated in object position and move to subject position. We examined this hypothesis using the cross-modal lexical priming technique, which tests whether and when an antecedent is reactivated during the online processing of a sentence. We compared sentences containing unergative verbs with sentences containing unaccusatives, both alternating and nonalternating, and found that subjects of unaccusatives reactivate after the verb, while subjects of unergatives do not. Alternating unaccusatives showed a mixed pattern of reactivation. The research directly supports the Unaccusative Hypothesis. PMID- 22822349 TI - Overview of Reviews The prevention of eczema in infants and children: an overview of Cochrane and non-Cochrane reviews. AB - BACKGROUND: Eczema is the most common inflammatory skin disease of childhood, characterized by an itchy red rash that usually involves the face and skin folds. There is currently no curative treatment for eczema, so the reduction of eczema incidence through disease prevention is a desirable goal. Potential interventions for preventing eczema include exclusive breastfeeding, hydrolysed protein formulas and soy formulas when bottle feeding, maternal antigen avoidance, omega oil supplementation, prebiotics and probiotics. OBJECTIVES: This overview of reviews aims to present the current body of data from Cochrane and non-Cochrane reviews to provide the most up-to-date evidence on the efficacy and safety of interventions to prevent eczema in infants and children at different risk levels for developing allergic disease. METHODS: Our pool of Cochrane and non-Cochrane reviews came from the 2010 United Kingdom National Health Service (NHS) Evidence Skin Disorders Annual Evidence Updates Mapping Exercise on Atopic Eczema. This group used a comprehensive search strategy last conducted in August 2010 to identify all systematic reviews on eczema prevention. We identified all reviews that met our pre-specified inclusion criteria, and data were extracted, analysed, compiled into tables and synthesized using quantitative and qualitative methods. MAIN RESULTS: Seven systematic reviews containing 39 relevant trials with 11 897 participants were included in this overview. Overall, there was no clear evidence that any of the main interventions reviewed reduced eczema incidence. In subgroup analyses of infants at high risk of allergic disease, an observational study found that exclusive breastfeeding for at least six months compared with introduction of solids at three to six months decreased the incidence of eczema by 60% (risk ratio (RR): 0.40; 95% confidence interval (CI): 0.21, 0.78), and a randomized controlled trial found that prebiotics compared with no prebiotics decreased incidence by 58% (RR: 0.42; 95% CI: 0.21, 0.84). However, each of these findings was based on the results of a single small trial, and no intervention reduced eczema incidence beyond the first two years of life. Although we pre specified incidence of atopic eczema (i.e. eczema associated with immunoglobulin E (IgE) sensitization) as a primary outcome, data on whether participants diagnosed with eczema were truly atopic were largely lacking from systematic reviews. Similarly, data on atopy, measured using skin prick tests or specific IgE tests to allergens, were not reported in many reviews. No interventions were found to decrease atopy when reported. Adverse events data were generally lacking, but data from a trial of probiotics versus no probiotics showed significantly more spitting up in the first one (RR: 1.88; 95% CI: 1.03, 3.45) and two (RR: 1.69; 95% CI: 1.02, 2.80) months of life, but no overall increase in risk of gastrointestinal symptoms in the first year. AUTHORS#ENTITYSTARTX02019; CONCLUSIONS: Although there is currently no clear evidence showing that any of the interventions examined in this overview prevent eczema in participants not selected for risk of allergic disease, there is some evidence that exclusive breastfeeding for at least six months and prebiotics might reduce eczema incidence in high-risk participants. However, these conclusions are based on limited evidence with methodological shortcomings. Future research on prevention of eczema is needed and should examine different types of hydrolysed formulas, prebiotics and probiotics, as well as enhancement of the skin barrier and other novel approaches in infants at different risk levels for developing allergic disease. PMID- 22822351 TI - Cytotoxic sesterterpenoids from a sponge Hippospongia sp. AB - One new pentacyclic sesterterpene, hippospongide A (1), and one new scalarane sesterterpenoid, hippospongide B (2), along with six previously reported known scalarane-type sesterterpenes (3-8), were isolated from a sponge Hippospongia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. These metabolites are the first pentacyclic sesterterpene and scalarane-type sesterterpenes to be reported from this genus. Compounds 3-5 exhibited significant cytotoxicity against DLD-1, HCT-116, T-47D and K562 cancer cell lines. PMID- 22822350 TI - Bioactive peptides and depsipeptides with anticancer potential: sources from marine animals. AB - Biologically active compounds with different modes of action, such as, antiproliferative, antioxidant, antimicrotubule, have been isolated from marine sources, specifically algae and cyanobacteria. Recently research has been focused on peptides from marine animal sources, since they have been found as secondary metabolites from sponges, ascidians, tunicates, and mollusks. The structural characteristics of these peptides include various unusual amino acid residues which may be responsible for their bioactivity. Moreover, protein hydrolysates formed by the enzymatic digestion of aquatic and marine by-products are an important source of bioactive peptides. Purified peptides from these sources have been shown to have antioxidant activity and cytotoxic effect on several human cancer cell lines such as HeLa, AGS, and DLD-1. These characteristics imply that the use of peptides from marine sources has potential for the prevention and treatment of cancer, and that they might also be useful as molecular models in anticancer drug research. This review focuses on the latest studies and critical research in this field, and evidences the immense potential of marine animals as bioactive peptide sources. PMID- 22822352 TI - Dietary carotenoids regulate astaxanthin content of copepods and modulate their susceptibility to UV light and copper toxicity. AB - High irradiation and the presence of xenobiotics favor the formation of reactive oxygen species in marine environments. Organisms have developed antioxidant defenses, including the accumulation of carotenoids that must be obtained from the diet. Astaxanthin is the main carotenoid in marine crustaceans where, among other functions, it scavenges free radicals thus protecting cell compounds against oxidation. Four diets with different carotenoid composition were used to culture the meiobenthic copepod Amphiascoides atopus to assess how its astaxanthin content modulates the response to prooxidant stressors. A. atopus had the highest astaxanthin content when the carotenoid was supplied as astaxanthin esters (i.e., Haematococcus meal). Exposure to short wavelength UV light elicited a 77% to 92% decrease of the astaxanthin content of the copepod depending on the culture diet. The LC(50) values of A. atopus exposed to copper were directly related to the initial astaxanthin content. The accumulation of carotenoids may ascribe competitive advantages to certain species in areas subjected to pollution events by attenuating the detrimental effects of metals on survival, and possibly development and fecundity. Conversely, the loss of certain dietary items rich in carotenoids may be responsible for the amplification of the effects of metal exposure in consumers. PMID- 22822353 TI - Briacavatolides A-C, new briaranes from the Taiwanese octocoral Briareum excavatum. AB - In order to search for novel bioactive substances from marine organisms, we have investigated the organic extracts of the Taiwanese octocoral Briareumexcavatum collected at Orchid Island. Three new briarane-type diterpenoids, briacavatolides A-C (1-3) as well as two known briaranes, briaexcavatolide U (4) and briaexcavatin L (5) were isolated from the acetone extract. The structures of these compounds were elucidated by extensive NMR spectroscopic analysis and physical data. The anti-HCMV (human cytomegalovirus) activity of 1-5 and their cytotoxicity against selected cancer cell lines were evaluated. PMID- 22822355 TI - Antibacterial secondary metabolites from the cave sponge Xestospongia sp. AB - Chemical investigation of the cave sponge Xestospongia sp. resulted in the isolation of three new polyacetylenic long chain compounds along with two known metabolites. The structures of the new metabolites were established by NMR and MS analyses. The antibacterial activity of the new metabolites was also evaluated. PMID- 22822354 TI - Woodylides A-C, new cytotoxic linear polyketides from the South China Sea sponge Plakortis simplex. AB - Three new polyketides, woodylides A-C (1-3), were isolated from the ethanol extract of the South China Sea sponge Plakortis simplex. The structures were elucidated by spectroscopic data (IR, 1D and 2D NMR, and HRESIMS). The absolute configurations at C-3 of 1 and 3 were determined by the modified Mosher's method. Antifungal, cytotoxic, and PTP1B inhibitory activities of these polyketides were evaluated. Compounds 1 and 3 showed antifungal activity against fungi Cryptococcus neoformans with IC50 values of 3.67 and 10.85 ug/mL, respectively. In the cytotoxicity test, compound 1 exhibited a moderate effect against the HeLa cell line with an IC50 value of 11.2 ug/mL, and compound 3 showed cytotoxic activity against the HCT-116 human colon tumor cell line and PTP1B inhibitory activity with IC50 values of 9.4 and 4.7 ug/mL, respectively. PMID- 22822356 TI - Accumulation, biotransformation, histopathology and paralysis in the Pacific calico scallop Argopecten ventricosus by the paralyzing toxins of the dinoflagellate Gymnodinium catenatum. AB - The dinoflagellate Gymnodinium catenatum produces paralyzing shellfish poisons that are consumed and accumulated by bivalves. We performed short-term feeding experiments to examine ingestion, accumulation, biotransformation, histopathology, and paralysis in the juvenile Pacific calico scallop Argopecten ventricosus that consume this dinoflagellate. Depletion of algal cells was measured in closed systems. Histopathological preparations were microscopically analyzed. Paralysis was observed and the time of recovery recorded. Accumulation and possible biotransformation of toxins were measured by HPLC analysis. Feeding activity in treated scallops showed that scallops produced pseudofeces, ingestion rates decreased at 8 h; approximately 60% of the scallops were paralyzed and melanin production and hemocyte aggregation were observed in several tissues at 15 h. HPLC analysis showed that the only toxins present in the dinoflagellates and scallops were the N-sulfo-carbamoyl toxins (C1, C2); after hydrolysis, the carbamate toxins (epimers GTX2/3) were present. C1 and C2 toxins were most common in the mantle, followed by the digestive gland and stomach-complex, adductor muscle, kidney and rectum group, and finally, gills. Toxin profiles in scallop tissue were similar to the dinoflagellate; biotransformations were not present in the scallops in this short-term feeding experiment. PMID- 22822357 TI - Optimization of hydrolysis conditions for the production of angiotensin-I converting enzyme-inhibitory peptides and isolation of a novel peptide from lizard fish (Saurida elongata) muscle protein hydrolysate. AB - Lizard fish (Saurida elongata) muscle protein was hydrolyzed using neutral protease to produce protein hydrolysate (LFPH), and the hydrolysis conditions were investigated using response-surface methodology. The optimum conditions for producing peptides with the highest angiotensin-I converting enzyme (ACE) inhibitory activity were the following: enzyme-to-substrate ratio of 10,000 U/g, temperature of 48 degrees C, pH 7.0, and hydrolysis time of 2 h. Under these conditions, the ACE-inhibitory activity of LFPH and the degree of hydrolysis were 84% and 24%, respectively. A novel ACE-inhibitory peptide was isolated from LFPH using ultrafiltration, Sephadex G-15, and high-performance liquid chromatography. The amino acid sequence of the ACE-inhibitory peptide was identified as Ser-Pro Arg-Cys-Arg (SPRCR), and its IC50 was 41 +/- 1 uM. PMID- 22822358 TI - Pullularins E and F, two new peptides from the endophytic fungus Bionectria ochroleuca isolated from the mangrove plant Sonneratia caseolaris. AB - Chemical investigation of the EtOAc extract of the endophytic fungus Bionectria ochroleuca, isolated from the inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae) from Hainan island (China), yielded two new peptides, pullularins E and F (1 and 2) together with three known compounds (3-5). The structures of the new compounds were unambiguously determined on the basis of one and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configurations of amino acids were determined by HPLC analysis of acid hydrolysates using Marfey's method. The isolated compounds exhibited pronounced to moderate cytotoxic activity against the mouse lymphoma cells (L5178Y) with EC50 values ranging between 0.1 and 6.7 ug/mL. PMID- 22822359 TI - Structure elucidation and anticancer activity of 7-oxostaurosporine derivatives from the Brazilian endemic tunicate Eudistoma vannamei. AB - The present study reports the identification of two new staurosporine derivatives, 2-hydroxy-7-oxostaurosporine (1) and 3-hydroxy-7-oxostaurosporine (2), obtained from mid-polar fractions of an aqueous methanol extract of the tunicate Eudistoma vannamei, endemic to the northeast coast of Brazil. The mixture of 1 and 2 displayed IC50 values in the nM range and was up to 14 times more cytotoxic than staurosporine across a panel of tumor cell lines, as evaluated using the MTT assay. PMID- 22822360 TI - Geographic variability and anti-staphylococcal activity of the chrysophaentins and their synthetic fragments. AB - Drug-resistant Staphylococcus aureus is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple S. aureus strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga Chrysophaeum taylori that inhibit the growth of S. aureus and methicillin resistant S. aureus (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in C. taylori located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse S. aureus strains. We find that the chrysophaentins show similar activity against all S. aureus strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs. PMID- 22822361 TI - Biochemical studies of the lagunamides, potent cytotoxic cyclic depsipeptides from the marine cyanobacterium Lyngbya majuscula. AB - Lagunamides A (1) and B (2) are potent cytotoxic cyclic depsipeptides isolated from the filamentous marine cyanobacterium, Lyngbya majuscula, from Pulau Hantu, Singapore. These compounds are structurally related to the aurilide-class of molecules, which have been reported to possess exquisite antiproliferative activities against cancer cells. The present study presents preliminary findings on the selectivity of lagunamides against various cancer cell lines as well as their mechanism of action by studying their effects on programmed cell death or apoptosis. Lagunamide A exhibited a selective growth inhibitory activity against a panel of cancer cell lines, including P388, A549, PC3, HCT8, and SK-OV3 cells, with IC50 values ranging from 1.6 nM to 6.4 nM. Morphological studies showed blebbing at the surface of cancer cells as well as cell shrinkage accompanied by loss of contact with the substratum and neighboring cells. Biochemical studies using HCT8 and MCF7 cancer cells suggested that the cytotoxic effect of 1 and 2 might act via induction of mitochondrial mediated apoptosis. Data presented in this study warrants further investigation on the mode of action and underscores the importance of the lagunamides as potential anticancer agents. PMID- 22822362 TI - Preclinical evaluation of anticancer efficacy and pharmacological properties of FBA-TPQ, a novel synthetic makaluvamine analog. AB - We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development. PMID- 22822363 TI - Briarenolides F and G, new briarane diterpenoids from a Briareum sp. octocoral. AB - Two new briarane diterpenoids, briarenolides, F (1) and G (2), were isolated from an octocoral identified as Briareum sp. The structures of briaranes 1 and 2 were established by spectroscopic methods and by comparison of the spectroscopic data with those of known briarane analogues. Briarenolide F was proven to be the first 6-hydroperoxybriarane derivative and this compound displayed a significant inhibitory effect on the generation of superoxide anion by human neutrophils. PMID- 22822364 TI - Bioactive compounds from a gorgonian coral Echinomuricea sp. (Plexauridae). AB - A new labdane-type diterpenoid, echinolabdane A (1), and a new sterol, 6-epi yonarasterol B (2), were isolated from a gorgonian coral identified as Echinomuricea sp. The structures of metabolites 1 and 2 were elucidated by spectroscopic methods. Echinolabdane A (1) possesses a novel tetracyclic skeleton with an oxepane ring jointed to an alpha,beta-unsaturated-gamma-lactone ring by a hemiketal moiety, and this compound is the first labdane-type diterpenoid to be obtained from marine organisms belonging to the phylum Cnidaria. 6-epi Yonarasterol B (2) is the first steroid derivative to be isolated from gorgonian coral belonging to the genus Echinomuricea, and this compound displayed significant inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils. PMID- 22822365 TI - Chemical profiles and identification of key compound caffeine in marine-derived traditional Chinese medicine Ostreae concha. AB - To compare the chemical differences between the medicinal and cultured oyster shells, their chemical profiles were investigated. Using the ultra performance liquid chromatography-electron spraying ionization-mass spectrometry (UPLC-ESI MS), combined with principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA), the discrimination of the chemical characteristics among the medicinal and cultured oyster shells was established. Moreover, the chemometric analysis revealed some potential key compounds. After a large-scale extraction and isolation, one target key compound was unambiguously identified as caffeine based on extensive spectroscopic data analysis (1D and 2D NMR, MS, and UV) and comparison with literature data. PMID- 22822366 TI - Diversity of nonribosomal peptide synthetase genes in the microbial metagenomes of marine sponges. AB - Genomic mining revealed one major nonribosomal peptide synthetase (NRPS) phylogenetic cluster in 12 marine sponge species, one ascidian, an actinobacterial isolate and seawater. Phylogenetic analysis predicts its taxonomic affiliation to the actinomycetes and hydroxy-phenyl-glycine as a likely substrate. Additionally, a phylogenetically distinct NRPS gene cluster was discovered in the microbial metagenome of the sponge Aplysina aerophoba, which shows highest similarities to NRPS genes that were previously assigned, by ways of single cell genomics, to a Chloroflexi sponge symbiont. Genomic mining studies such as the one presented here for NRPS genes, contribute to on-going efforts to characterize the genomic potential of sponge-associated microbiota for secondary metabolite biosynthesis. PMID- 22822367 TI - Simplexins P-S, eunicellin-based diterpenes from the soft coral Klyxum simplex. AB - Four new eunicellin-based diterpenes, simplexins P-S (1-4), and the known compound simplexin A (5), have been isolated from the soft coral Klyxum simplex. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly 1D and 2D NMR experiments. Compounds 1 and 3 5 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines, 3 being the most cytotoxic. PMID- 22822368 TI - Mycalamide A shows cytotoxic properties and prevents EGF-induced neoplastic transformation through inhibition of nuclear factors. AB - Mycalamide A, a marine natural compound previously isolated from sponges, is known as a protein synthesis inhibitor with potent antitumor activity. However, the ability of this compound to prevent malignant transformation of cells has never been examined before. Here, for the first time, we report the isolation of mycalamide A from ascidian Polysincraton sp. as well as investigation of its cancer preventive properties. In murine JB6 Cl41 P(+) cells, mycalamide A inhibited epidermal growth factor (EGF)-induced neoplastic transformation, and induced apoptosis at subnanomolar or nanomolar concentrations. The compound inhibited transcriptional activity of the oncogenic nuclear factors AP-1 and NF kappaB, a potential mechanism of its cancer preventive properties. Induction of phosphorylation of the kinases MAPK p38, JNK, and ERK was also observed at high concentrations of mycalamide A. The drug shows promising potential for both cancer-prevention and cytotoxic therapy and should be further developed. PMID- 22822369 TI - Microbial regulation in gorgonian corals. AB - Gorgonian corals possess many novel natural products that could potentially mediate coral-bacterial interactions. Since many bacteria use quorum sensing (QS) signals to facilitate colonization of host organisms, regulation of prokaryotic cell-to-cell communication may represent an important bacterial control mechanism. In the present study, we examined extracts of twelve species of Caribbean gorgonian corals, for mechanisms that regulate microbial colonization, such as antibacterial activity and QS regulatory activity. Ethanol extracts of gorgonians collected from Puerto Rico and the Florida Keys showed a range of both antibacterial and QS activities using a specific Pseudomonas aeruginosa QS reporter, sensitive to long chain AHLs and a short chain N-acylhomoserine lactones (AHL) biosensor, Chromobacterium violaceium. Overall, the gorgonian corals had higher antimicrobial activity against non-marine strains when compared to marine strains. Pseudopterogorgia americana, Pseusopterogorgia acerosa, and Pseudoplexuara flexuosa had the highest QS inhibitory effect. Interestingly, Pseudoplexuara porosa extracts stimulated QS activity with a striking 17-fold increase in signal. The stimulation of QS by P. porosa or other elements of the holobiont may encourage colonization or recruitment of specific microbial species. Overall, these results suggest the presence of novel stimulatory QS, inhibitory QS and bactericidal compounds in gorgonian corals. A better understanding of these compounds may reveal insight into coral-microbial ecology and whether a therapeutic potential exists. PMID- 22822370 TI - Conotoxins that confer therapeutic possibilities. AB - Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt((r)); Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring omega-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred. PMID- 22822371 TI - Purpurogemutantin and purpurogemutantidin, new drimenyl cyclohexenone derivatives produced by a mutant obtained by diethyl sulfate mutagenesis of a marine-derived Penicillium purpurogenum G59. AB - Two new drimenyl cyclohexenone derivatives, named purpurogemutantin (1) and purpurogemutantidin (2), and the known macrophorin A (3) were isolated from a bioactive mutant BD-1-6 obtained by random diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. Structures and absolute configurations of 1 and 2 were determined by extensive spectroscopic methods, especially 2D NMR and electronic circular dichroism (ECD) analysis. Possible biosynthetic pathways for 1-3 were also proposed and discussed. Compounds 1 and 2 significantly inhibited human cancer K562, HL-60, HeLa, BGC-823 and MCF-7 cells, and compound 3 also inhibited the K562 and HL-60 cells. Both bioassay and chemical analysis (HPLC, LC-ESIMS) demonstrated that the parent strain G59 did not produce 1-3, and that DES-induced mutation(s) in the mutant BD-1-6 activated some silent biosynthetic pathways in the parent strain G59, including one set for 1-3 production. PMID- 22822372 TI - New 19-oxygenated steroids from the soft coral Nephthea chabrolii. AB - In order to search for novel bioactive substances from marine organisms, we investigated the acetone extract of the soft coral Nephthea chabrolii collected at San-Hsian-Tai, Taitong County, Taiwan. From this extract three new 19 oxygenated steroids, nebrosteroids N-P (1-3) were isolated. The structures of these compounds were elucidated by extensive spectroscopic analyses. PMID- 22822373 TI - Quinazolin-4-one coupled with pyrrolidin-2-iminium alkaloids from marine-derived fungus Penicillium aurantiogriseum. AB - Three new alkaloids, including auranomides A and B (1 and 2), a new scaffold containing quinazolin-4-one substituted with a pyrrolidin-2-iminium moiety, and auranomide C (3), as well as two known metabolites auranthine (4) and aurantiomides C (5) were isolated from the marine-derived fungus Penicillium aurantiogriseum. The chemical structures of compounds 1-3 were elucidated by extensive spectroscopic methods, including IR, HRESIMS and 2D NMR spectroscopic analysis. The absolute configurations of compounds 1-3 were suggested from the perspective of a plausible biosynthesis pathway. Compounds 1-3 were subjected to antitumor and antimicrobial screening models. Auranomides A-C exhibited moderate cytotoxic activity against human tumor cells. Auranomides B was the most potent among them with an IC(50) value of 0.097 MUmol/mL against HEPG2 cells. PMID- 22822374 TI - Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways. AB - Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways. PMID- 22822375 TI - New Briarane diterpenoids from the gorgonian coral Junceella juncea. AB - Chemical investigation of Junceella juncea has resulted in the isolation of three new briaranes designated juncenolides M-O (1-3). The structures of these compounds were determined by spectroscopic analysis including 2D-NMR (COSY, HMBC and NOESY) and HRMS. Compound 1 is a new chlorinated briarane while compound 3 contains a rare methyl ester at C-16. The anti-inflammatory activities tested on superoxide anion generation and elastase release by human neutrophils in response to FMLP/CB were evaluated. PMID- 22822376 TI - Sinularones A-I, new cyclopentenone and butenolide derivatives from a marine soft coral Sinularia sp. and their antifouling activity. AB - Nine new compounds, namely sinularones A-I (1-9), characterized as cyclopentenone and butenolide-type analogues, were isolated from a soft coral Sinularia sp., together with a known butenolide (10). Their structures were elucidated by means of spectroscopic (IR, MS, 1D and 2D NMR, CD) analysis. The absolute configurations were determined on the basis of CD and specific rotation data in association with the computed electronic circular dichroism (ECD) by time dependent density functional theory (TD DFT) at 6-31+G(d,p)//DFT B3LYP/6 31+G(d,p) level. Compounds 1-2 and 7-10 showed potent antifouling activities against the barnacle Balanus amphitrite. PMID- 22822377 TI - SD118-xanthocillin X (1), a novel marine agent extracted from Penicillium commune, induces autophagy through the inhibition of the MEK/ERK pathway. AB - A compound named SD118-xanthocillin X (1) (C(18)H(12)N(2)O(2)), isolated from Penicillium commune in a deep-sea sediment sample, has been shown to inhibit the growth of several cancer cell lines in vitro. In the present study, we employed a growth inhibition assay and apoptotic analysis to identify the biological effect and detailed mechanism of SD118-xanthocillin X (1) in human hepatocellular carcinoma (HepG2) cells. SD118-xanthocillin X (1) demonstrated a concentration dependent inhibitory effect on the growth of HepG2 cells and caused slight cellular apoptosis and significantly induced autophagy. Autophagy was detected as early as 12 h by the conversion of microtubule-associated protein 1 light chain 3 (LC3-I) to LC3-II, following cleavage and lipid addition to LC3-I. The pharmacological autophagy inhibitor 3-methyladenine largely attenuates the growth inhibition and autophagic effect of SD118-xanthocillin X (1) in HepG2 cells. Our data also indicated that the autophagic effect of SD118-xanthocillin X (1) occurs via the down-regulation of the MEK/ERK signaling pathway and the up-regulated class III PI3K/Beclin 1 signaling pathway. PMID- 22822378 TI - Production and isolation of azaspiracid-1 and -2 from Azadinium spinosum culture in pilot scale photobioreactors. AB - Azaspiracid (AZA) poisoning has been reported following consumption of contaminated shellfish, and is of human health concern. Hence, it is important to have sustainable amounts of the causative toxins available for toxicological studies and for instrument calibration in monitoring programs, without having to rely on natural toxin events. Continuous pilot scale culturing was carried out to evaluate the feasibility of AZA production using Azadinium spinosum cultures. Algae were harvested using tangential flow filtration or continuous centrifugation. AZAs were extracted using solid phase extraction (SPE) procedures, and subsequently purified. When coupling two stirred photobioreactors in series, cell concentrations reached 190,000 and 210,000 cell . mL(-1) at steady state in bioreactors 1 and 2, respectively. The AZA cell quota decreased as the dilution rate increased from 0.15 to 0.3 day(-1), with optimum toxin production at 0.25 day(-1). After optimization, SPE procedures allowed for the recovery of 79 +/- 9% of AZAs. The preparative isolation procedure previously developed for shellfish was optimized for algal extracts, such that only four steps were necessary to obtain purified AZA1 and -2. A purification efficiency of more than 70% was achieved, and isolation from 1200 L of culture yielded 9.3 mg of AZA1 and 2.2 mg of AZA2 of >95% purity. This work demonstrated the feasibility of sustainably producing AZA1 and -2 from A. spinosum cultures. PMID- 22822379 TI - Chalinulasterol, a chlorinated steroid disulfate from the Caribbean sponge Chalinula molitba. Evaluation of its role as PXR receptor modulator. AB - Chalinulasterol (1) a new chlorinated sterol disulfate was isolated from the Caribbean sponge Chalinula molitba. Its structure was elucidated using mass spectrometry and NMR experiments. The possible role of chalinulasterol as modulator of the PXR nuclear receptor was investigated but, in spite of the close structural relationship with the PXR agonist solomonsterol A (2), it showed no activity. The structural requirements for the PXR nuclear receptor activity were discussed. PMID- 22822380 TI - Anti-oxidative, anti-tumor-promoting, and anti-carcinogensis activities of nitroastaxanthin and nitrolutein, the reaction products of astaxanthin and lutein with peroxynitrite. AB - Astaxanthin captured peroxynitrite to form nitroastaxanthins. 15-Nitroastaxanthin was a major reaction product of astaxanthin with peroxynitrite. Here, the anti oxidative, anti-tumor-promoting, and anti-carcinogensis activities of 15 nitroastaxanthin were investigated. In addition to astaxanthin, 15 nitroastaxanthin showed excellent singlet oxygen quenching activity. Furthermore, 15-nitroastaxanthin showed inhibitory effects of in vitro Epstein-Barr virus early antigen activation and two-stage carcinogensis on mouse skin papillomas. These activities were slightly higher than those of astaxanthin. Similar results were obtained for the 15-nitrolutein, a major reaction product of lutein with peroxynitrite. PMID- 22822381 TI - Pigmentation and spectral absorbance signatures in deep-water corals from the Trondheimsfjord, Norway. AB - The pigmentation and corresponding in vivo and in vitro absorption characteristics in three different deep-water coral species: white and orange Lophelia pertusa, Paragorgia arborea and Primnoa resedaeformis, collected from the Trondheimsfjord are described. Pigments were isolated and characterized by High-Performance Liquid Chromatography (HPLC) analysis and High-Performance Liquid Chromatography Time-Of-Flight Mass Spectrometer (LC-TOF MS). The main carotenoids identified for all three coral species were astaxanthin and a canthaxanthin-like carotenoid. Soft tissue and skeleton of orange L. pertusa contained 2 times more astaxanthin g(-1) wet weight compared to white L. pertusa. White and orange L. pertusa were characterized with in vivo absorbance peaks at 409 and 473 nm, respectively. In vivo absorbance maxima for P. arborea and P. resedaeformis was typically at 475 nm. The shapes of the absorbance spectra (400 700 nm) were species-specific, indicated by in vivo, in vitro and the corresponding difference spectra. The results may provide important chemotaxonomic information for pigment when bonded to their proteins in vivo, bio prospecting, and for in situ identification, mapping and monitoring of corals. PMID- 22822382 TI - Total synthesis of a marine alkaloid--rigidin E. AB - In the present paper, we report an efficient total synthesis of a marine alkaloid, rigidin E. The key tetrasubstituted 2-amino-3-carboxamidepyrrole intermediate was synthesized by cascade Michael addition/intramolecular cyclization between N-(2-(4-(benzyloxy)phenyl)-2-oxoethyl)methanesulfonamide and 3-(4-(benzyloxy)phenyl)-2-cyano-N-methylacrylamide. Subsequent carbonylation with triphosgene catalyzed by I(2) and deprotection of benzyl groups afforded rigidin E in 21% overall yield. This strategy has the merits of metal-free reactions, low cost, mild reaction protocols, and easy access to diversity-oriented derivatives for potential structure-activity relationship investigation. PMID- 22822383 TI - In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome. AB - Using high-resolution molecular karyotyping with SNP arrays to identify candidate genes for etiologically unexplained intellectual disability, we identified a 32 kb de novo in-frame deletion of the C-terminal helicase domain of the SMARCA2 gene in a patient with severe intellectual disability, epilepsy, sparse hair, prominent joints, and distinct facial anomalies. Sequencing of the gene in patients with a similar phenotype revealed de novo missense mutations in this domain in 2 further patients, pointing to a crucial role of the SMARCA2 C terminal helicase domain. The clinical features observed in all 3 patients are typical of Nicolaides-Baraitser syndrome, an only rarely reported syndrome with mainly moderate to severe intellectual disability. Notably, one of our patients with a p.Gly1132Asp mutation showed typical morphological features but an exceptional good development with borderline overall IQ and learning difficulties, thus expanding the phenotypic spectrum of Nicolaides-Baraitser syndrome. PMID- 22822385 TI - LEOPARD Syndrome Caused by Tyr279Cys Mutation in the PTPN11 Gene. AB - LEOPARD syndrome (LS) is an acronym consisting of lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness. However, hypertrophic cardiomyopathy, the most frequent cause of sudden cardiac death in young people, is the most common cardiovascular manifestation in LS patients and the major determinant of mortality and morbidity. In approximately 85% of the patients with a definite diagnosis of LS, a missense mutation is found in the protein-tyrosine phosphatase non-receptor type 11 (PTPN11) gene located on chromosome 12q24.1. We report the case of an asymptomatic 17-year-old male with a missense mutation (c.836A>G) in exon 7 (Tyr279Cys) of the PTPN11 gene and a non obstructive asymmetric anteroseptal hypertrophic cardiomyopathy. PMID- 22822384 TI - A 380-kb Duplication in 7p22.3 Encompassing the LFNG Gene in a Boy with Asperger Syndrome. AB - De novo genomic aberrations are considered an important cause of autism spectrum disorders. We describe a de novo 380-kb gain in band p22.3 of chromosome 7 in a patient with Asperger syndrome. This duplicated region contains 9 genes including the LNFG gene that is an important regulator of NOTCH signaling. We suggest that this copy number variation has been a contributive factor to the occurrence of Asperger syndrome in this patient. PMID- 22822386 TI - Novel Compound Heterozygous Mutations in the Cathepsin K Gene in Japanese Female Siblings with Pyknodysostosis. AB - We report on female siblings with pyknodysostosis who showed common clinical and radiographic features including disproportionate short stature, dental abnormalities, increased bone density, open fontanelle, and acroosteolysis. Sequence analysis of the cathepsin K (CTSK) gene demonstrated compound heterozygous mutations (935 C>T, A277V and 489 G>C, R122P) in the affected siblings and a heterozygous mutation in their parents. The former missense mutation has previously been reported in 6 unrelated patients, and the latter seemed to be a novel mutation. Atomic model assessment of the CTSK gene revealed that the R122P mutant could disrupt hydrogen bonds binding with chondroitin 4 sulfate leading to a decrease in the collagen-degrading activity of cathepsin K. PMID- 22822387 TI - Delayed Diagnosis of Potocki-Shaffer Syndrome in a Woman with Multiple Exostoses and Mental Retardation. AB - We describe the case of an adult patient affected by multiple exostoses, severe mental retardation, epilepsy and facial dysmorphisms with a deletion of ~2.3 Mb on chromosome 11p11.21, correlated to Potocki-Shaffer syndrome (PSS). PSS is a rare contiguous gene deletion syndrome, mainly characterized by multiple exostoses and bilateral parietal foramina. Mental retardation and craniofacial dysmorphisms have often been reported, too. Although the patient showed many signs of PSS since early childhood, the diagnosis was suggested only when we examined her at adult age. This case highlights how frequently rare diseases remain undiagnosed till adulthood and is an excellent example of the need for a timely and correct diagnosis. PMID- 22822388 TI - Is a 4-bit synaptic weight resolution enough? - constraints on enabling spike timing dependent plasticity in neuromorphic hardware. AB - Large-scale neuromorphic hardware systems typically bear the trade-off between detail level and required chip resources. Especially when implementing spike timing dependent plasticity, reduction in resources leads to limitations as compared to floating point precision. By design, a natural modification that saves resources would be reducing synaptic weight resolution. In this study, we give an estimate for the impact of synaptic weight discretization on different levels, ranging from random walks of individual weights to computer simulations of spiking neural networks. The FACETS wafer-scale hardware system offers a 4-bit resolution of synaptic weights, which is shown to be sufficient within the scope of our network benchmark. Our findings indicate that increasing the resolution may not even be useful in light of further restrictions of customized mixed signal synapses. In addition, variations due to production imperfections are investigated and shown to be uncritical in the context of the presented study. Our results represent a general framework for setting up and configuring hardware constrained synapses. We suggest how weight discretization could be considered for other backends dedicated to large-scale simulations. Thus, our proposition of a good hardware verification practice may rise synergy effects between hardware developers and neuroscientists. PMID- 22822389 TI - EEG oscillations reveal neural correlates of evidence accumulation. AB - Recent studies have begun to elucidate the neural correlates of evidence accumulation in perceptual decision making, but few of them have used a combined modeling-electrophysiological approach to studying evidence accumulation. We introduce a multivariate approach to EEG analysis with which we can perform a comprehensive search for the neural correlate of dynamics predicted by accumulator models. We show that the dynamics of evidence accumulation are most strongly correlated with ramping of oscillatory power in the 4-9 Hz theta band over the course of a trial, although it also correlates with oscillatory power in other frequency bands. The rate of power decrease in the theta band correlates with individual differences in the parameters of drift diffusion models fitted to individuals' behavioral data. PMID- 22822391 TI - Individual differences in risky decision-making among seniors reflect increased reward sensitivity. AB - Increasing age is associated with subtle but meaningful changes in decision making. It is unknown, however, to what degree these psychological changes are reflective of age-related changes in decision quality. Here, we investigated the effect of age on latent cognitive processes associated with risky decision-making on the Balloon Analog Risk Task (BART). In the BART, participants repetitively inflate a balloon in order to increase potential reward. At any point, participants can decide to cash-out to harvest the reward, or they can continue, risking a balloon pop that erases all earnings. We found that among seniors, increasing age was associated with greater reward-related risk taking when the balloon has a higher probability of popping (i.e., a "high risk" condition). Cognitive modeling results from hierarchical Bayesian estimation suggested that performance differences were due to increased reward sensitivity in high risk conditions in seniors. PMID- 22822390 TI - Prefrontal and striatal activity related to values of objects and locations. AB - The value of an object acquired by a particular action often determines the motivation to produce that action. Previous studies found neural signals related to the values of different objects or goods in the orbitofrontal cortex, while the values of outcomes expected from different actions are broadly represented in multiple brain areas implicated in movement planning. However, how the brain combines the values associated with various objects and the information about their locations is not known. In this study, we tested whether the neurons in the dorsolateral prefrontal cortex (DLPFC) and striatum in rhesus monkeys might contribute to translating the value signals between multiple frames of reference. Monkeys were trained to perform an oculomotor intertemporal choice in which the color of a saccade target and the number of its surrounding dots signaled the magnitude of reward and its delay, respectively. In both DLPFC and striatum, temporally discounted values (DVs) associated with specific target colors and locations were encoded by partially overlapping populations of neurons. In the DLPFC, the information about reward delays and DVs of rewards available from specific target locations emerged earlier than the corresponding signals for target colors. Similar results were reproduced by a simple network model built to compute DVs of rewards in different locations. Therefore, DLPFC might play an important role in estimating the values of different actions by combining the previously learned values of objects and their present locations. PMID- 22822392 TI - Complementary neural correlates of motivation in dopaminergic and noradrenergic neurons of monkeys. AB - Rewards have many influences on learning, decision-making, and performance. All seem to rely on complementary actions of two closely related catecholaminergic neuromodulators, dopamine (DA), and noradrenaline (NA). We compared single unit activity of dopaminergic neurons of the substantia nigra pars compacta (SNc) and noradrenergic neurons of the locus coeruleus (LC) in monkeys performing a reward schedule task. Their motivation, indexed using operant performance, increased as they progressed through schedules ending in reward delivery. The responses of dopaminergic and noradrenergic neurons around the time of major task events, visual cues predicting trial outcome and operant action to complete a trial were similar in that they occurred at the same time. They were also similar in that they both responded most strongly to the first cues in schedules, which are the most informative cues. The neuronal responses around the time of the monkeys' actions were different, in that the response intensity profiles changed in opposite directions. Dopaminergic responses were stronger around predictably rewarded correct actions whereas noradrenergic responses were greater around predictably unrewarded correct actions. The complementary response profiles related to the monkeys operant actions suggest that DA neurons might relate to the value of the current action whereas the noradrenergic neurons relate to the psychological cost of that action. PMID- 22822393 TI - Are NCAM deficient mice an animal model for schizophrenia? AB - Genetic and biomarker studies in patients have identified the Neural Cell Adhesion Molecule (NCAM) and its associated polysialic acid (PSA) as a susceptibility factors for schizophrenia. NCAM and polysialtransferase mutant mice have been generated that may serve as animal models for this disorder and allow to investigate underlying neurodevelopmental alterations. Indeed, various schizophrenia-relevant morphological, cognitive and emotional deficits have been observed in these mutants. Here we studied social interaction and attention of NCAM null mutant (NCAM(-/-)) mice as further hallmarks of schizophrenia. Nest building, which is generally associated with social behavior in rodents, was severely impaired, as NCAM(-/-) mice continuously collected smaller amounts of nest building material than their wild type littermates and built nests of poorer quality. However, social approach tested in a three-compartment-box was not affected and latent inhibition of Pavlovian fear memory was not disturbed in NCAM(-/-) mice. Although NCAM deficient mice do not display a typical schizophrenia-like phenotype, they may be useful for studying specific endophenotypes with relevance to the disease. PMID- 22822394 TI - Neglect and extinction depend greatly on task demands: a review. AB - This review illustrates how, after unilateral brain damage, the presence and severity of spatial awareness deficits for the contralesional hemispace depend greatly on the quantity of attentional resources available for performance. After a brief description of neglect and extinction, different frameworks accounting for spatial and non-spatial attentional processes will be outlined. The central part of the review describes how the performance of brain-damaged patients is negatively affected by increased task demands, which can result in the emergence of severe awareness deficits for contralesional space even in patients who perform normally on paper-and-pencil tests. Throughout the review neglect is described as a spatial syndrome that can be exacerbated in the presence and severity by both spatial and non-spatial tasks. The take-home message is that the presence and degree of contralesional neglect and extinction can be dramatically overlooked based on standard clinical (paper-and-pencil) testing, where patients can easily compensate for their deficits. Only tasks where compensation is made impossible represent an appropriate approach to detect these disabling contralesional deficits of awareness when they become subtle in post-acute stroke phases. PMID- 22822395 TI - Talking to the senses: modulation of tactile extinction through hypnotic suggestion. AB - Following brain damage, typically of the right hemisphere, patients can show reduced awareness of sensory events occurring in the space contralateral to the brain damage. The present work shows that a hypnotic suggestion can temporarily reduce tactile extinction to double bilateral stimulation, i.e., a loss of contralesional stimuli when these are presented together with ipsilesional ones. Patient EB showed an improved detection of contralesional targets after a single 20-min hypnosis session, during which specific suggestions were delivered with the aim of increasing her insight into somatosensory perception on both sides of the body. Simple overt attention orienting toward the contralesional side, or a hypnotic induction procedure not accompanied by specifically aimed suggestions, were not effective in modulating extinction. The present result is the first systematic evidence that hypnosis can temporarily improve a neuropsychological condition, namely Extinction, and may open the way for the use of this technique as a fruitful rehabilitative tool for brain-damaged patients affected by neuropsychological deficits. PMID- 22822396 TI - Neuroscience of human social interactions and adult attachment style. AB - Since its first description four decades ago, attachment theory (AT) has become one of the principal developmental psychological frameworks for describing the role of individual differences in the establishment and maintenance of social bonds between people. Yet, still little is known about the neurobiological underpinnings of attachment orientations and their well-established impact on a range of social and affective behaviors. In the present review, we summarize data from recent studies using cognitive and imaging approaches to characterize attachment styles and their effect on emotion and social cognition. We propose a functional neuroanatomical framework to integrate the key brain mechanisms involved in the perception and regulation of social emotional information, and their modulation by individual differences in terms of secure versus insecure (more specifically avoidant, anxious, or resolved versus unresolved) attachment traits. This framework describes how each individual's attachment style (built through interactions between personal relationship history and predispositions) may influence the encoding of approach versus aversion tendencies (safety versus threat) in social encounters, implicating the activation of a network of subcortical (amygdala, hippocampus, striatum) and cortical (insula, cingulate) limbic areas. These basic and automatic affective evaluation mechanisms are in turn modulated by more elaborate and voluntary cognitive control processes, subserving mental state attribution and emotion regulation capacities, implicating a distinct network in medial prefrontal cortex (mPFC), superior temporal sulcus (STS), and temporo-parietal junction (TPJ), among others. Recent neuroimaging data suggest that affective evaluation is decreased in avoidantly but increased in anxiously attached individuals. In turn, although data on cognitive control is still scarce, it points toward a possible enhancement of mental state representations associated with attachment insecurity and particularly anxiety. Emotion regulation strategies such as reappraisal or suppression of social emotions are also differentially modulated by attachment style. This research does not only help better understand the neural underpinnings of human social behavior, but also provides important insights on psychopathological conditions where attachment dysregulation is likely to play an important (causal) role. PMID- 22822397 TI - P300 brain computer interface: current challenges and emerging trends. AB - A brain-computer interface (BCI) enables communication without movement based on brain signals measured with electroencephalography (EEG). BCIs usually rely on one of three types of signals: the P300 and other components of the event-related potential (ERP), steady state visual evoked potential (SSVEP), or event related desynchronization (ERD). Although P300 BCIs were introduced over twenty years ago, the past few years have seen a strong increase in P300 BCI research. This closed-loop BCI approach relies on the P300 and other components of the ERP, based on an oddball paradigm presented to the subject. In this paper, we overview the current status of P300 BCI technology, and then discuss new directions: paradigms for eliciting P300s; signal processing methods; applications; and hybrid BCIs. We conclude that P300 BCIs are quite promising, as several emerging directions have not yet been fully explored and could lead to improvements in bit rate, reliability, usability, and flexibility. PMID- 22822398 TI - Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis. AB - Cystic Fibrosis (CF) is the most common autosomal recessive lethal disorder among Caucasian populations. CF results from mutations and resulting dysfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a cyclic AMP dependent chloride channel that is localized to the apical membrane in epithelial cells where it plays a key role in salt and water homeostasis. An intricate network of molecular chaperone proteins regulates CFTR's proper maturation and trafficking to the apical membrane. Understanding and manipulation of this network may lead to therapeutics for CF in cases where mutant CFTR has aberrant trafficking. PMID- 22822399 TI - Alzheimer's disease, neuroprotection, and CNS immunosenescence. AB - This review is focused on discussing in some detail possible neuroprotective functions of microglial cells. We strive to explain how loss of these essential microglial functions might contribute toward the development of characteristic neuropathological features that characterize Alzheimer's disease. The conceptual framework guiding our thinking is provided by the hypothesis that microglial senescence accounts for impaired neuronal protection and consequent neurodegeneration. PMID- 22822402 TI - PowerPoint((r)) Presentation Flaws and Failures: A Psychological Analysis. AB - Electronic slideshow presentations are often faulted anecdotally, but little empirical work has documented their faults. In Study 1 we found that eight psychological principles are often violated in PowerPoint((r)) slideshows, and are violated to similar extents across different fields - for example, academic research slideshows generally were no better or worse than business slideshows. In Study 2 we found that respondents reported having noticed, and having been annoyed by, specific problems in presentations arising from violations of particular psychological principles. Finally, in Study 3 we showed that observers are not highly accurate in recognizing when particular slides violated a specific psychological rule. Furthermore, even when they correctly identified the violation, they often could not explain the nature of the problem. In sum, the psychological foundations for effective slideshow presentation design are neither obvious nor necessarily intuitive, and presentation designers in all fields, from education to business to government, could benefit from explicit instruction in relevant aspects of psychology. PMID- 22822400 TI - New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment. AB - Processes such as cell proliferation, angiogenesis, apoptosis, or invasion are strongly influenced by the surrounding microenvironment of the tumor. Therefore, the ability to change these surroundings represents an important property through which tumor cells are able to acquire specific functions necessary for tumor growth and dissemination. Matrix metalloproteinases (MMPs) constitute key players in this process, allowing tumor cells to modify the extracellular matrix (ECM) and release cytokines, growth factors, and other cell-surface molecules, ultimately facilitating protease-dependent tumor progression. Remodeling of the ECM by collagenolytic enzymes such as MMP1, MMP8, MMP13, or the membrane-bound MT1-MMP as well as by other membrane-anchored proteases is required for invasion and recruitment of novel blood vessels. However, the multiple roles of the MMPs do not all fit into a simple pattern. Despite the pro-tumorigenic function of certain metalloproteinases, recent studies have shown that other members of these families, such as MMP8 or MMP11, have a protective role against tumor growth and metastasis in animal models. These studies have been further expanded by large scale genomic analysis, revealing that the genes encoding metalloproteinases, such as MMP8, MMP27, ADAM7, and ADAM29, are recurrently mutated in specific tumors, while several ADAMTSs are epigenetically silenced in different cancers. The importance of these proteases in modifying the tumor microenvironment highlights the need for a deeper understanding of how stroma cells and the ECM can modulate tumor progression. PMID- 22822403 TI - Affective Primacy vs. Cognitive Primacy: Dissolving the Debate. AB - When people see a snake, they are likely to activate both affective information (e.g., dangerous) and non-affective information about its ontological category (e.g., animal). According to the Affective Primacy Hypothesis, the affective information has priority, and its activation can precede identification of the ontological category of a stimulus. Alternatively, according to the Cognitive Primacy Hypothesis, perceivers must know what they are looking at before they can make an affective judgment about it. We propose that neither hypothesis holds at all times. Here we show that the relative speed with which affective and non affective information gets activated by pictures and words depends upon the contexts in which stimuli are processed. Results illustrate that the question of whether affective information has processing priority over ontological information (or vice versa) is ill-posed. Rather than seeking to resolve the debate over Cognitive vs. Affective Primacy in favor of one hypothesis or the other, a more productive goal may be to determine the factors that cause affective information to have processing priority in some circumstances and ontological information in others. Our findings support a view of the mind according to which words and pictures activate different neurocognitive representations every time they are processed, the specifics of which are co determined by the stimuli themselves and the contexts in which they occur. PMID- 22822401 TI - Resveratrol: French paradox revisited. AB - Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the "French paradox," which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed. PMID- 22822404 TI - Substrate-specific pressure-dependence of microbial sulfate reduction in deep-sea cold seep sediments of the Japan Trench. AB - The influence of hydrostatic pressure on microbial sulfate reduction (SR) was studied using sediments obtained at cold seep sites from 5500 to 6200 m water depth of the Japan Trench. Sediment samples were stored under anoxic conditions for 17 months in slurries at 4 degrees C and at in situ pressure (50 MPa), at atmospheric pressure (0.1 MPa), or under methanic conditions with a methane partial pressure of 0.2 MPa. Samples without methane amendment stored at in situ pressure retained higher levels of sulfate reducing activity than samples stored at 0.1 MPa. Piezophilic SR showed distinct substrate specificity after hydrogen and acetate addition. SR activity in samples stored under methanic conditions was one order of magnitude higher than in non-amended samples. Methanic samples stored under low hydrostatic pressure exhibited no increased SR activity at high pressure even with the amendment of methane. These new insights into the effects of pressure on substrate specific sulfate reducing activity in anaerobic environmental samples indicate that hydrostatic pressure must be considered to be a relevant parameter in ecological studies of anaerobic deep-sea microbial processes and long-term storage of environmental samples. PMID- 22822405 TI - Does cholesterol play a role in the bacterial selectivity of antimicrobial peptides? PMID- 22822406 TI - Myeloid-derived suppressor cells: mechanisms of action and recent advances in their role in transplant tolerance. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses in infection, chronic inflammation, cancer, and autoimmunity. In this paper, we review recent findings detailing their mode of action and discuss recent reports that suggest that MDSC are also expanded during transplantation and that modulation of MDSC can participate in preventing graft rejection as well as graft versus-host disease. PMID- 22822407 TI - Measures of light in studies on light-driven plant plasticity in artificial environments. AB - Within-canopy variation in light results in profound canopy profiles in foliage structural, chemical, and physiological traits. Studies on within-canopy variations in key foliage traits are often conducted in artificial environments, including growth chambers with only artificial light, and greenhouses with and without supplemental light. Canopy patterns in these systems are considered to be representative to outdoor conditions, but in experiments with artificial and supplemental lighting, the intensity of artificial light strongly deceases with the distance from the light source, and natural light intensity in greenhouses is less than outdoors due to limited transmittance of enclosure walls. The implications of such changes in radiation conditions on canopy patterns of foliage traits have not yet been analyzed. We developed model-based methods for retrospective estimation of distance vs. light intensity relationships, for separation of the share of artificial and natural light in experiments with combined light and for estimation of average enclosure transmittance, and estimated daily integrated light at the time of sampling (Q(int,C)), at foliage formation (Q(int,G)), and during foliage lifetime (Q(int,av)). The implications of artificial light environments were analyzed for altogether 25 studies providing information on within-canopy gradients of key foliage traits for 70 species * treatment combinations. Across the studies with artificial light, Q(int,G) for leaves formed at different heights in the canopy varied from 1.8- to 6.4-fold due to changing the distance between light source and growing plants. In experiments with combined lighting, the share of natural light at the top of the plants varied threefold, and the share of natural light strongly increased with increasing depth in the canopy. Foliage nitrogen content was most strongly associated with Q(int,G), but photosynthetic capacity with Q(int,C), emphasizing the importance of explicit description of light environment during foliage lifetime. The reported and estimated transmittances of enclosures varied between 0.27 and 0.85, and lack of consideration of the reduction of light compared with outdoor conditions resulted in major underestimation of foliage plasticity to light. The study emphasizes that plant trait vs. light relationships in artificial systems are not directly comparable to natural environments unless modifications in lighting conditions in artificial environments are taken into account. PMID- 22822408 TI - Cerebrovascular function in aging and dementia: a systematic review of transcranial Doppler studies. AB - BACKGROUND/AIM: The contribution of cerebrovascular dysfunction to the manifestation of dementia and cognitive decline in late life is gaining increased attention. We aimed to systematically review evidence for associations between dementia or aging and cerebrovascular function as measured using transcranial Doppler (TCD) examination. METHODS: A total of 1,172 articles were retrieved from PsychInfo and PubMed searches, and 34 relevant articles were identified using a variety of TCD methods. RESULTS: The pulsatility index (vessel resistance), spontaneous emboli and cerebrovascular reactivity to hyper-/hypocapnia appeared good discriminators of dementia. Aging was associated with a slowing in blood flow velocity. CONCLUSION: TCD ultrasonography is inexpensive, portable and well tolerated by aged and demented subjects. The technique stands to make a valuable contribution to the knowledge regarding the underlying functional biology of age related cognitive change and dementia. PMID- 22822409 TI - Ion Electrodiffusion Governs Silk Electrogelation. AB - Silk electrogelation involves the transition of an aqueous silk fibroin solution to a gel state (E-gel) in the presence of an electric current. The process is based on local pH changes as a result of water electrolysis - generating H(+) and OH(-) ions at the (+) and (-) electrodes, respectively. Silk fibroin has a pI=4.2 and when local pH2000 m). Moreover, a separation of the northern Turkish population from the southern Turkish populations was observed using both markers. CONCLUSIONS: Morphological variation together with genetic and biogeographic studies make an effective tool for detecting relict plant populations and also populations subjected to more intensive selection. PMID- 22822423 TI - Borrelidin modulates the alternative splicing of VEGF in favour of anti angiogenic isoforms. AB - The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning of a phage display library of colon tumor cell cDNAs identified the tandem WW domains of spliceosome-associated protein formin binding protein 21 (FBP21) as a novel molecular target of borrelidin, suggesting that borrelidin may act as a modulator of alternative splicing. In support of this idea, 1, and its more selective analog 2, bound to purified recombinant WW domains of FBP21. They also altered the ratio of vascular endothelial growth factor (VEGF) isoforms in retinal pigmented endothelial (RPE) cells in favour of anti-angiogenic isoforms. Transfection of RPE cells with FBP21 altered the ratio in favour of pro-angiogenic VEGF isoforms, an effect inhibited by 2. These data implicate FBP21 in the regulation of alternative splicing and suggest the potential of borrelidin analogs as tools to deconvolute key steps of spliceosome function. PMID- 22822424 TI - Transducing methyltransferase activity into electrical signals in a carbon nanotube-DNA device(). AB - This study creates a device where the DNA is electronically integrated to serve as both the biological target and electrical transducer in a CNT-DNA-CNT device. We detect DNA binding and methylation by the methyltransferase M.SssI at the single molecule level. We demonstrate sequence-specific, reversible binding of M.SssI and protein-catalyzed methylation that alters the protein-binding affinity of the device. This device, which relies on the exquisite electrical sensitivity of DNA, represents a unique route for the specific, single molecule detection of enzymatic activity. PMID- 22822425 TI - Collective behavior in the spatial spreading of obesity. AB - Obesity prevalence is increasing in many countries at alarming levels. A difficulty in the conception of policies to reverse these trends is the identification of the drivers behind the obesity epidemics. Here, we implement a spatial spreading analysis to investigate whether obesity shows spatial correlations, revealing the effect of collective and global factors acting above individual choices. We find a regularity in the spatial fluctuations of their prevalence revealed by a pattern of scale-free long-range correlations. The fluctuations are anomalous, deviating in a fundamental way from the weaker correlations found in the underlying population distribution indicating the presence of collective behavior, i.e., individual habits may have negligible influence in shaping the patterns of spreading. Interestingly, we find the same scale-free correlations in economic activities associated with food production. These results motivate future interventions to investigate the causality of this relation providing guidance for the implementation of preventive health policies. PMID- 22822427 TI - On creative machines and the physical origins of freedom. AB - We discuss the possibility of free behavior in embodied systems that are, with no exception and at all scales of their body, subject to physical law. We relate the discussion to a model of an artificial agent that exhibits a primitive notion of creativity and freedom in dealing with its environment, which is part of a recently introduced scheme of information processing called projective simulation. This provides an explicit proposal on how we can reconcile our understanding of universal physical law with the idea that higher biological entities can acquire a notion of freedom that allows them to increasingly detach themselves from a strict dependence on the surrounding world. PMID- 22822426 TI - A Bayesian analysis of the chromosome architecture of human disorders by integrating reductionist data. AB - In this paper, we present a Bayesian approach to estimate a chromosome and a disorder network from the Online Mendelian Inheritance in Man (OMIM) database. In contrast to other approaches, we obtain statistic rather than deterministic networks enabling a parametric control in the uncertainty of the underlying disorder-disease gene associations contained in the OMIM, on which the networks are based. From a structural investigation of the chromosome network, we identify three chromosome subgroups that reflect architectural differences in chromosome disorder associations that are predictively exploitable for a functional analysis of diseases. PMID- 22822428 TI - Alternative strategies of seed predator escape by early-germinating oaks in Asia and North America. AB - Early germination of white oaks is widely viewed as an evolutionary strategy to escape rodent predation; yet, the mechanism by which this is accomplished is poorly understood. We report that chestnut oak Quercus montana (CO) and white oak Q. alba (WO) (from North America), and oriental cork oak Q. variabilis (OO) and Mongolian oak Q. mongolica (MO) (from Asia) can escape predation and successfully establish from only taproots. During germination in autumn, cotyledonary petioles of acorns of CO and WO elongate and push the plumule out of the cotyledons, whereas OO and MO extend only the hypocotyls and retain the plumule within the cotyledons. Experiments showed that the pruned taproots (>6 cm) of CO and WO acorns containing the plumule successfully germinated and survived, and the pruned taproots (>=12 cm) of OO and MO acorns without the plumule successfully regenerated along with the detached acorns, thus producing two seedlings. We argue that these two distinct regeneration morphologies reflect alternative strategies for escaping seed predation. PMID- 22822429 TI - Incorrect handling of calibration information in divergence time inference: an example from volcanic islands. AB - Divergence time studies rely on calibration information from several sources. The age of volcanic islands is one of the standard references to obtain chronological data to estimate the absolute times of lineage diversifications. This strategy assumes that cladogenesis is necessarily associated with island formation, and punctual calibrations are commonly used to date the splits of endemic island species. Here, we re-examined three studies that inferred divergence times for different Hawaiian lineages assuming fixed calibration points. We show that, by permitting probabilistic calibrations, some divergences are estimated to be significantly younger or older than the age of the island formation, thus yielding distinct ecological scenarios for the speciation process. The results highlight the importance of using calibration information correctly, as well as the possibility of incorporating volcanic island studies into a formal, biogeographical hypothesis-testing framework. PMID- 22822430 TI - Modeling climate change impacts on overwintering bald eagles. AB - Bald eagles (Haliaeetus leucocephalus) are recovering from severe population declines, and are exerting pressure on food resources in some areas. Thousands of bald eagles overwinter near Puget Sound, primarily to feed on chum salmon (Oncorhynchus keta) carcasses. We used modeling techniques to examine how anticipated climate changes will affect energetic demands of overwintering bald eagles. We applied a regional downscaling method to two global climate change models to obtain hourly temperature, precipitation, wind, and longwave radiation estimates at the mouths of three Puget Sound tributaries (the Skagit, Hamma Hamma, and Nisqually rivers) in two decades, the 1970s and the 2050s. Climate data were used to drive bald eagle bioenergetics models from December to February for each river, year, and decade. Bald eagle bioenergetics were insensitive to climate change: despite warmer winters in the 2050s, particularly near the Nisqually River, bald eagle food requirements declined only slightly (<1%). However, the warming climate caused salmon carcasses to decompose more rapidly, resulting in 11% to 14% less annual carcass biomass available to eagles in the 2050s. That estimate is likely conservative, as it does not account for decreased availability of carcasses due to anticipated increases in winter stream flow. Future climate-driven declines in winter food availability, coupled with a growing bald eagle population, may force eagles to seek alternate prey in the Puget Sound area or in more remote ecosystems. PMID- 22822431 TI - Altruism and the evolution of resource generalism and specialism. AB - The evolution of resource specialism and generalism has attracted widespread interest. Evolutionary drivers affecting niche differentiation and resource specialization have focused on the role of trade-offs. Here, however, we explore how the role of cooperation, mediated through altruistic behaviors, and classic resource-consumer dynamics can influence the evolution of resource utilization. Using an evolutionary invasion approach, we investigate how critical thresholds in levels of altruism are needed for resource specialization to arise and be maintained. Differences between complementary (essential) and substitutable resources affect the evolution of resource generalists. The strength of resource preferences coupled with the levels of altruism are predicted to influence the evolution of generalism. Coupling appropriate evolutionary game and ecological dynamics lead to novel expectations in the feedbacks between social behaviors and population dynamics for understanding classic ecological problems. PMID- 22822432 TI - Negative density-dependent dispersal in the American black bear (Ursus americanus) revealed by noninvasive sampling and genotyping. AB - Although the dispersal of animals is influenced by a variety of factors, few studies have used a condition-dependent approach to assess it. The mechanisms underlying dispersal are thus poorly known in many species, especially in large mammals. We used 10 microsatellite loci to examine population density effects on sex-specific dispersal behavior in the American black bear, Ursus americanus. We tested whether dispersal increases with population density in both sexes. Fine scale genetic structure was investigated in each of four sampling areas using Mantel tests and spatial autocorrelation analyses. Our results revealed male biased dispersal pattern in low-density areas. As population density increased, females appeared to exhibit philopatry at smaller scales. Fine-scale genetic structure for males at higher densities may indicate reduced dispersal distances and delayed dispersal by subadults. PMID- 22822433 TI - Dispersal limitation and the assembly of soil Actinobacteria communities in a long-term chronosequence. AB - It is uncertain whether the same ecological forces that structure plant and animal communities also shape microbial communities, especially those residing in soil. We sought to uncover the relative importance of present-day environmental characteristics, climatic variation, and historical contingencies in shaping soil actinobacterial communities in a long-term chronosequence. Actinobacteria communities were characterized in surface soil samples from four replicate forest stands with nearly identical edaphic and ecological properties, which range from 9500 to 14,000 years following glacial retreat in Michigan. Terminal restriction fragment length polymorphism (TRFLP) profiles and clone libraries of the actinobacterial 16S rRNA gene were constructed in each site for phenetic and phylogenetic analysis to determine whether dispersal limitation occurred following glacial retreat, or if community composition was determined by environmental heterogeneity. At every level of examination, actinobacterial community composition most closely correlated with distance, a surrogate for time, than with biogeochemical, plant community, or climatic characteristics. Despite correlation with leaf litter C:N and annual temperature, the significant and consistent relationship of biological communities with time since glacial retreat provides evidence that dispersal limitation is an ecological force structuring actinobacterial communities in soil over long periods of time. PMID- 22822434 TI - Genetic signatures of a demographic collapse in a large-bodied forest dwelling primate (Mandrillus leucophaeus). AB - It is difficult to predict how current climate change will affect wildlife species adapted to a tropical rainforest environment. Understanding how population dynamics fluctuated in such species throughout periods of past climatic change can provide insight into this issue. The drill (Mandrillus leucophaeus) is a large-bodied rainforest adapted mammal found in West Central Africa. In the middle of this endangered monkey's geographic range is Lake Barombi Mbo, which has a well-documented palynological record of environmental change that dates to the Late Pleistocene. We used a Bayesian coalescent-based framework to analyze 2,076 base pairs of mitochondrial DNA across wild drill populations to infer past changes in female effective population size since the Late Pleistocene. Our results suggest that the drill underwent a nearly 15-fold demographic collapse in female effective population size that was most prominent during the Mid Holocene (approximately 3-5 Ka). This time period coincides with a period of increased dryness and seasonality across Africa and a dramatic reduction in forest coverage at Lake Barombi Mbo. We believe that these changes in climate and forest coverage were the driving forces behind the drill population decline. Furthermore, the warm temperatures and increased aridity of the Mid Holocene are potentially analogous to current and future conditions faced by many tropical rainforest communities. In order to prevent future declines in population size in rainforest-adapted species such as the drill, large tracts of forest should be protected to both preserve habitat and prevent forest loss through aridification. PMID- 22822435 TI - Concurrent habitat and life history influences on effective/census population size ratios in stream-dwelling trout. AB - Lower effective sizes (N(e)) than census sizes (N) are routinely documented in natural populations, but knowledge of how multiple factors interact to lower N(e)/N ratios is often limited. We show how combined habitat and life-history influences drive a 2.4- to 6.1-fold difference in N(e)/N ratios between two pristine brook trout (Salvelinus fontinalis) populations occupying streams separated by only 750 m. Local habitat features, particularly drainage area and stream depth, govern trout biomass produced in each stream. They also generate higher trout densities in the shallower stream by favoring smaller body size and earlier age-at-maturity. The combination of higher densities and reduced breeding site availability in the shallower stream likely leads to more competition among breeding trout, which results in greater variance in individual reproductive success and a greater reduction in N(e) relative to N. A similar disparity between juvenile or adult densities and breeding habitat availability is reported for other species and hence may also result in divergent N(e)/N ratios elsewhere. These divergent N(e)/N ratios between adjacent populations are also an instructive reminder for species conservation programs that genetic and demographic parameters may differ dramatically within species. PMID- 22822436 TI - Contemporary and historical evolutionary processes interact to shape patterns of within-lake phenotypic divergences in polyphenic pumpkinseed sunfish, Lepomis gibbosus. AB - Historical and contemporary evolutionary processes can both contribute to patterns of phenotypic variation among populations of a species. Recent studies are revealing how interactions between historical and contemporary processes better explain observed patterns of phenotypic divergence than either process alone. Here, we investigate the roles of evolutionary history and adaptation to current environmental conditions in structuring phenotypic variation among polyphenic populations of sunfish inhabiting 12 postglacial lakes in eastern North America. The pumpkinseed sunfish polyphenism includes sympatric ecomorphs specialized for littoral or pelagic lake habitats. First, we use population genetic methods to test the evolutionary independence of within-lake phenotypic divergences of ecomorphs and to describe patterns of genetic structure among lake populations that clustered into three geographical groupings. We then used multivariate analysis of covariance (MANCOVA) to partition body shape variation (quantified with geometric morphometrics) among the effects of evolutionary history (reflecting phenotypic variation among genetic clusters), the shared phenotypic response of all populations to alternate habitats within lakes (reflecting adaptation to contemporary conditions), and unique phenotypic responses to habitats within lakes nested within genetic clusters. All effects had a significant influence on body form, but the effects of history and the interaction between history and contemporary habitat were larger than contemporary processes in structuring phenotypic variation. This highlights how divergence can be better understood against a known backdrop of evolutionary history. PMID- 22822437 TI - Uncertainty analysis of vegetation distribution in the northern high latitudes during the 21st century with a dynamic vegetation model. AB - This study aims to assess how high-latitude vegetation may respond under various climate scenarios during the 21st century with a focus on analyzing model parameters induced uncertainty and how this uncertainty compares to the uncertainty induced by various climates. The analysis was based on a set of 10,000 Monte Carlo ensemble Lund-Potsdam-Jena (LPJ) simulations for the northern high latitudes (45(o)N and polewards) for the period 1900-2100. The LPJ Dynamic Global Vegetation Model (LPJ-DGVM) was run under contemporary and future climates from four Special Report Emission Scenarios (SRES), A1FI, A2, B1, and B2, based on the Hadley Centre General Circulation Model (GCM), and six climate scenarios, X901M, X902L, X903H, X904M, X905L, and X906H from the Integrated Global System Model (IGSM) at the Massachusetts Institute of Technology (MIT). In the current dynamic vegetation model, some parameters are more important than others in determining the vegetation distribution. Parameters that control plant carbon uptake and light-use efficiency have the predominant influence on the vegetation distribution of both woody and herbaceous plant functional types. The relative importance of different parameters varies temporally and spatially and is influenced by climate inputs. In addition to climate, these parameters play an important role in determining the vegetation distribution in the region. The parameter-based uncertainties contribute most to the total uncertainty. The current warming conditions lead to a complexity of vegetation responses in the region. Temperate trees will be more sensitive to climate variability, compared with boreal forest trees and C3 perennial grasses. This sensitivity would result in a unanimous northward greenness migration due to anomalous warming in the northern high latitudes. Temporally, boreal needleleaved evergreen plants are projected to decline considerably, and a large portion of C3 perennial grass is projected to disappear by the end of the 21st century. In contrast, the area of temperate trees would increase, especially under the most extreme A1FI scenario. As the warming continues, the northward greenness expansion in the Arctic region could continue. PMID- 22822438 TI - Do allopatric male Calopteryx virgo damselflies learn species recognition? AB - There is a growing amount of empirical evidence that premating reproductive isolation of two closely related species can be reinforced by natural selection arising from avoidance of maladaptive hybridization. However, as an alternative for this popular reinforcement theory, it has been suggested that learning to prefer conspecifics or to discriminate heterospecifics could cause a similar pattern of reinforced premating isolation, but this possibility is much less studied. Here, we report results of a field experiment in which we examined (i) whether allopatric Calopteryx virgo damselfly males that have not encountered heterospecific females of the congener C. splendens initially show discrimination, and (ii) whether C. virgo males learn to discriminate heterospecifics or learn to associate with conspecifics during repeated experimental presentation of females. Our experiment revealed that there was a statistically nonsignificant tendency for C. virgo males to show initial discrimination against heterospecific females but because we did not use sexually naive individuals in our experiment, we were not able to separate the effect of innate or associative learning. More importantly, however, our study revealed that species discrimination might be further strengthened by learning, especially so that C. virgo males increase their association with conspecific females during repeated presentation trials. The role of learning to discriminate C. splendens females was less clear. We conclude that learning might play a role in species recognition also when individuals are not naive but have already encountered potential conspecific mates. PMID- 22822439 TI - Population-based resequencing revealed an ancestral winter group of cultivated flax: implication for flax domestication processes. AB - Cultivated flax (Linum usitatissimum L.) is the earliest oil and fiber crop and its early domestication history may involve multiple events of domestication for oil, fiber, capsular indehiscence, and winter hardiness. Genetic studies have demonstrated that winter cultivated flax is closely related to oil and fiber cultivated flax and shows little relatedness to its progenitor, pale flax (L. bienne Mill.), but winter hardiness is one major characteristic of pale flax. Here, we assessed the genetic relationships of 48 Linum samples representing pale flax and four trait-specific groups of cultivated flax (dehiscent, fiber, oil, and winter) through population-based resequencing at 24 genomic regions, and revealed a winter group of cultivated flax that displayed close relatedness to the pale flax samples. Overall, the cultivated flax showed a 27% reduction of nucleotide diversity when compared with the pale flax. Recombination frequently occurred at these sampled genomic regions, but the signal of selection and bottleneck was relatively weak. These findings provide some insight into the impact and processes of flax domestication and are significant for expanding our knowledge about early flax domestication, particularly for winter hardiness. PMID- 22822440 TI - Spatial and temporal determinants of genetic structure in Gentianella bohemica. AB - The biennial plant Gentianella bohemica is a subendemic of the Bohemian Massif, where it occurs in seminatural grasslands. It has become rare in recent decades as a result of profound changes in land use. Using amplified fragment length polymorphisms (AFLP) fingerprint data, we investigated the genetic structure within and among populations of G. bohemica in Bavaria, the Czech Republic, and the Austrian border region. The aim of our study was (1) to analyze the genetic structure among populations and to discuss these findings in the context of present and historical patterns of connectivity and isolation of populations, (2) to analyze genetic structure among consecutive generations (cohorts of two consecutive years), and (3) to investigate relationships between intrapopulational diversity and effective population size (N(e)) as well as plant traits. (1) The German populations were strongly isolated from each other (pairwise F(ST)= 0.29-0.60) and from all other populations (F(ST)= 0.24-0.49). We found a pattern of near panmixis among the latter (F(ST)= 0.15-0.35) with geographical distance explaining only 8% of the genetic variance. These results were congruent with a principal coordinate analysis (PCoA) and analysis using STRUCTURE to identify genetically coherent groups. These findings are in line with the strong physical barrier and historical constraints, resulting in separation of the German populations from the others. (2) We found pronounced genetic differences between consecutive cohorts of the German populations (pairwise F(ST)= 0.23 and 0.31), which can be explained by local population history (land use, disturbance). (3) Genetic diversity within populations (Shannon index, H(Sh)) was significantly correlated with N(e) (R(S)= 0.733) and reflected a loss of diversity due to several demographic bottlenecks. Overall, we found that the genetic structure in G. bohemica is strongly influenced by historical periods of high connectivity and isolation as well as by marked demographic fluctuations in declining populations. PMID- 22822441 TI - The impact of Pleistocene climate change on an ancient arctic-alpine plant: multiple lineages of disparate history in Oxyria digyna. AB - The ranges of arctic-alpine species have shifted extensively with Pleistocene climate changes and glaciations. Using sequence data from the trnH-psbA and trnT trnL chloroplast DNA spacer regions, we investigated the phylogeography of the widespread, ancient (>3 million years) arctic-alpine plant Oxyria digyna (Polygonaceae). We identified 45 haplotypes and six highly divergent major lineages; estimated ages of these lineages (time to most recent common ancestor, T(MRCA)) ranged from ~0.5 to 2.5 million years. One lineage is widespread in the arctic, a second is restricted to the southern Rocky Mountains of the western United States, and a third was found only in the Himalayan and Altai regions of Asia. Three other lineages are widespread in western North America, where they overlap extensively. The high genetic diversity and the presence of divergent major cpDNA lineages within Oxyria digyna reflect its age and suggest that it was widespread during much of its history. The distributions of individual lineages indicate repeated spread of Oxyria digyna through North America over multiple glacial cycles. During the Last Glacial Maximum it persisted in multiple refugia in western North America, including Beringia, south of the continental ice, and within the northern limits of the Cordilleran ice sheet. Our data contribute to a growing body of evidence that arctic-alpine species have migrated from different source regions over multiple glacial cycles and that cryptic refugia contributed to persistence through the Last Glacial Maximum. PMID- 22822442 TI - Subtle genetic structure reveals restricted connectivity among populations of a coral reef fish inhabiting remote atolls. AB - We utilized a spatial and temporal analyses of genetic structure, supplemented with ecological and oceanographic analysis, to assess patterns of population connectivity in a coral reef fish Chromis margaritifer among the unique and remote atolls in the eastern Indian Ocean. A subtle, but significant genetic discontinuity at 10 microsatellite DNA loci was detected between atoll systems corresponding with a low (<= 1%) probability of advection across the hundreds of kilometers of open ocean that separates them. Thus, although genetic connections between systems are likely maintained by occasional long-distance dispersal of C. margaritifer larvae, ecological population connectivity at this spatial scale appears to be restricted. Further, within one of these atoll systems, significant spatial differentiation among samples was accompanied by a lack of temporal pairwise differentiation between recruit and adult samples, indicating that restrictions to connectivity also occur at a local scale (tens of kilometers). In contrast, a signal of panmixia was detected at the other atoll system studied. Lastly, greater relatedness and reduced genetic diversity within recruit samples was associated with relatively large differences among them, indicating the presence of sweepstakes reproduction whereby a small proportion of adults contributes to recruitment in the next generation. These results are congruent with earlier work on hard corals, suggesting that local production of larvae drives population replenishment in these atoll systems for a range of coral reef species. PMID- 22822444 TI - The effect of three gums on the retrogradation of indica rice starch. AB - Retrograded starch (RS(3)) was produced from indica rice starch with three kinds of gums (konjac glucomannan, KGM; carrageenan, CA, USA; and gellan, GA, USA) by autoclaving, respectively, and the effect of the gums on the retrogradation behavior of starch was estimated. The influences of polysaccharide concentration, sodium chloride concentration, autoclaving time, refrigerated time, and pH value on RS(3) formation were discussed. Except for sodium chloride's persistent restraint on RS(3), the others all forced RS(3) yields higher at first, but lowered it after the peak value. The influencing sequence of these impact factors was: sodium chloride concentration > polysaccharide concentration > autoclaving time > refrigerated time > pH value. The results also proved that in the three gums, KGM plays the most significant role in RS(3) changing. It was concluded that the incorporation of each of these three gums into starch, especially KGM, results in an increase or decrease of RS(3) under different conditions. This phenomenon could be taken into consideration when developing starchy food with appropriate amount of RS(3). PMID- 22822445 TI - Neonatal phosphate nutrition alters in vivo and in vitro satellite cell activity in pigs. AB - Satellite cell activity is necessary for postnatal skeletal muscle growth. Severe phosphate (PO(4)) deficiency can alter satellite cell activity, however the role of neonatal PO(4) nutrition on satellite cell biology remains obscure. Twenty-one piglets (1 day of age, 1.8 +/- 0.2 kg BW) were pair-fed liquid diets that were either PO(4) adequate (0.9% total P), supra-adequate (1.2% total P) in PO(4) requirement or deficient (0.7% total P) in PO(4) content for 12 days. Body weight was recorded daily and blood samples collected every 6 days. At day 12, pigs were orally dosed with BrdU and 12 h later, satellite cells were isolated. Satellite cells were also cultured in vitro for 7 days to determine if PO(4) nutrition alters their ability to proceed through their myogenic lineage. Dietary PO(4) deficiency resulted in reduced (P < 0.05) sera PO(4) and parathyroid hormone (PTH) concentrations, while supra-adequate dietary PO(4) improved (P < 0.05) feed conversion efficiency as compared to the PO(4) adequate group. In vivo satellite cell proliferation was reduced (P < 0.05) among the PO(4) deficient pigs, and these cells had altered in vitro expression of markers of myogenic progression. Further work to better understand early nutritional programming of satellite cells and the potential benefits of emphasizing early PO(4) nutrition for future lean growth potential is warranted. PMID- 22822446 TI - Dietary zinc deficiency in rodents: effects on T-cell development, maturation and phenotypes. AB - Zinc deficiency is one of the leading risk factors for developing disease and yet we do not have a clear understanding of the mechanisms behind the increased susceptibility to infection. This review will examine the interrelationships among the hypothalamus-pituitary-adrenal stress axis, p56(lck), and T-cell maturation in both zinc deficiency and responses during zinc repletion. We will highlight differences between the adult mouse model (wasting malnutrition) and growing rat model (stunting malnutrition) of dietary zinc deficiency and discuss the use of various controls to separate out the effects of zinc deficiency from the associated malnutrition. Elevated serum corticosterone in both zinc deficient and pair-fed rats does not support the hypothesis that zinc deficiency per se leads to corticosterone-induced apoptosis and lymphopenia. In fact, the zinc deficient rat does not have lymphopenia. Thymocytes from zinc deficient mice and rats have elevated levels of p56(lck), a signalling protein with a zinc clasp structure, but this does not appear to affect thymocyte maturation. However, post thymic T-cell maturation appears to be altered based on the lower proportion of splenic late thymic emigrants in zinc deficient rats. Fewer new T-cells in the periphery could adversely affect the T-cell repertoire and contribute to immunodeficiency in zinc deficiency. PMID- 22822448 TI - The impact of Ramadan observance upon athletic performance. AB - Ramadan observance requires a total abstention from food and drink from sunrise to sunset for a period of one month. Such intermittent fasting has only minor effects upon the overall nutrition and physiological responses of the general sedentary population. Larger meals are consumed at night and in the early morning. Body mass usually remains unchanged, the total energy intake remains roughly constant, and there is little alteration in the relative consumption of protein, fats and carbohydrates. However, Ramadan observance may be of greater consequence for the training and performance of the competitive athlete, particularly when the festival is celebrated in the hotter part of the year and daylight hours are long, as is the case for the 2012 Summer Olympic Games in London, England. The normal sleeping time then tends to be shortened, and blood sugar and tissue hydration decrease progressively throughout the hours of daylight. Some limitation of anaerobic effort, endurance performance and muscle strength might be anticipated from the decrease in muscle glycogen and body fluid reserves, and a reduced blood glucose may cause a depressed mood state, an increased perception of effort, and poorer team work. This review considers empirical data on the extent of such changes, and their likely effect upon anaerobic, aerobic and muscular performance, suggesting potential nutritional and behavioral tactics for minimizing such effects in the Muslim competitor. PMID- 22822449 TI - Nutrition education by a registered dietitian improves dietary intake and nutrition knowledge of a NCAA female volleyball team. AB - Eleven female participants from a NCAA Division I volleyball team were evaluated for adequate energy and macronutrient intake during two off-seasons. Total energy and macronutrient intake were assessed by food records and results were compared against estimated needs using the Nelson equation. Dietary intervention was employed regarding the individual dietary needs of each athlete as well as a pre- and post-sports nutrition knowledge survey. Post dietary intervention, total energy, and macronutrient intake improved, as well as a significant improvement in sports nutrition knowledge (p < 0.001). Nutrition education is useful in improving dietary intake and nutrition knowledge of female athletes. PMID- 22822447 TI - Plasma and tissue concentrations of alpha-tocopherol and delta-tocopherol following high dose dietary supplementation in mice. AB - Vitamin E isoforms are essential nutrients that are widely used as dietary supplements and therapeutic agents for a variety of diseases. However, their pharmacokinetic (PK) properties remain poorly characterized, and high dosage animal studies may provide further information on their in vivo functions and pharmacological effects. In this study, alpha-tocopherol (alpha-toc) and delta tocopherol (delta-toc) levels were measured in mouse plasma and tissues following their high dosage dietary supplementation. Average alpha-toc levels at 5, 10 and 20 g alpha-toc/kg diet increased over baseline levels 6-fold in plasma, 1.6-fold in brain, and 4.9-fold in liver. These elevated alpha-toc concentrations remained constant from 5 to 20 g alpha-toc/kg diet, rather than showing further increases across these dosages. No alpha-toc-related toxicity occurred at these high dosages, and strain-specific differences in liver and brain alpha-toc levels between Balb/cJ and C57Bl/6J mice were observed. Relatively high-dosage administration of dietary delta-toc for 1 or 4 weeks resulted in 6-30-fold increases in plasma and liver levels between dosages of 0.33 and 1.67 g delta toc/kg diet. Co-administration of sesamin with delta-toc further increased delta toc levels between 1.3- and 14-fold in plasma, liver, and brain. These results provide valuable PK information on high dosage alpha-toc and delta-toc in mouse and show that supplementation of sesamin with delta-toc further increases delta toc levels over those seen with delta-toc supplementation alone. PMID- 22822450 TI - Zinc biofortification of rice in China: a simulation of zinc intake with different dietary patterns. AB - A cross-sectional survey of 2819 adults aged 20 years and above was undertaken in 2002 in Jiangsu Province. Zinc intake was assessed using a consecutive 3-day 24-h dietary recall method. Insufficient and excess intake was determined according to the Chinese Dietary Recommended Intakes. Four distinct dietary patterns were identified namely "traditional", "macho", "sweet tooth", and "healthy". Intake of zinc from biofortified rice was simulated at an intermediate zinc concentration (2.7 mg/100 g) and a high zinc concentration (3.8 mg/100 g) in rice. Average total zinc intake was 12.0 +/- 3.7 mg/day, and insufficiency of zinc intake was present in 15.4%. Simulated zinc intake from biofortified rice with intermediate and high zinc concentration decreased the prevalence of low zinc intake to 6.5% and 4.4%, respectively. The effect was most pronounced in the "traditional" pattern, with only 0.7% of insufficiency of zinc intake remaining in the highest quartile of the pattern. Zinc intake was inversely associated with the "sweet tooth" pattern. Zinc biofortifed rice improves dietary zinc intake and lowers risk for insufficient zinc intake, especially for subjects with a more "traditional" food pattern, but less for subjects with a "sweet tooth" food pattern. PMID- 22822451 TI - Effects of a leucine and pyridoxine-containing nutraceutical on fat oxidation, and oxidative and inflammatory stress in overweight and obese subjects. AB - Leucine stimulates tissue protein synthesis and may also attenuate adiposity by increasing fatty acid oxidation and mitochondrial biogenesis in muscle and adipocytes. Accordingly, the effects of a nutraceutical containing 2.25 g leucine and 30 mg pyridoxine (Vitamin B6) (NuFit active blend) were tested in cell culture and in a clinical trial. 3T3L1 adipocytes were treated with leucine (0.25 mM or 0.5 mM) and/or Pyridoxal Phosphate (PLP) (50 nM or 100 nM) for 48 h. For the clinical trial, twenty overweight or obese subjects received the NuFit active blend or placebo three times/day for 4 weeks without energy restriction. Leucine decreased fatty acid synthase (FAS) expression and triglyceride content in adipocytes, and PLP addition significantly augmented this effect. Administration of NuFit active blend in the clinical trial increased fat oxidation by 33.6 g/day (p < 0.04), decreased respiratory quotient, improved HOMA(IR), reduced oxidative and inflammatory biomarkers (plasma MDA, 8-isoprostane-F(2alpha), TNF-alpha, C reactive protein), and increased the anti-inflammatory marker adiponectin. These data indicate that the NuFit active blend significantly increased fat oxidation and insulin sensitivity, and reduced oxidative and inflammatory stress. Therefore, the NuFit active blend appears to be a useful nutraceutical in the management of obesity and associated co-morbidities. PMID- 22822452 TI - Changes in the amino acid composition of Bogue (Boops boops) fish during storage at different temperatures by 1H-NMR spectroscopy. AB - Nuclear magnetic resonance spectroscopy was employed to obtain information about the changes occurring in Bogue (Boops boops) fish during storage. For this purpose, (1)H-NMR spectra were recorded at 600 MHz on trichloroacetic acid extracts of fish flesh stored over a 15 days period both at 4 degrees C and on ice. Such spectra allowed the identification and quantification of amino acids, together with the main organic acids and alcohols. The concentration of acidic and basic free amino acids was generally found to increase and decrease during storage, respectively. These concentration changes were slow during the first days, as a consequence of protein autolysis, and at higher rates afterward, resulting from microbial development. Two of the amino acids that showed the greatest concentration change were alanine and glycine, known to have a key role in determining the individual taste of different fish species. The concentration of serine decreased during storage, as highlighted in the literature for frozen fish samples. Differences in the amino acids concentration trends were found to be related to the different storage temperatures from day 4 onwards. PMID- 22822453 TI - Everyday eating experiences of chocolate and non-chocolate snacks impact postprandial anxiety, energy and emotional states. AB - Social and psychological stressors are both a part of daily life and are increasingly recognized as contributors to individual susceptibility to develop diseases and metabolic disorders. The present study investigated how snacks differing in sensory properties and presentation can influence ratings of affect in consumers with different levels of dispositional anxiety. This study examines the relationships between a pre-disposition to anxiety and food using a repeated exposures design with three interspersed test days over a period of two weeks. The study was conducted on ninety free-living male (n = 28) and female (n = 62) Dutch participants aged between 18 and 35 years old, with a BMI between 18 and 25 kg/m(2) and different anxiety trait levels assessed using State-Trait Anxiety Inventory tests. The study was randomized by age, gender, anxiety trait score, and followed a parallel open design. Three test products: dark chocolate, a milk chocolate snack and crackers with cheese spread (control), which differed in composition, sensory properties and presentation, were evaluated. Changes in self reported anxiety, emotion, and energetic states were assessed as a function of eating the snacks just after consumption and up to one hour. The repeated exposure design over a period of two weeks enabled the investigations of potential cumulative effects of regular consumption of the food products. The milk chocolate snack resulted in the decrease of anxiety in high anxiety trait subjects, whereas dark chocolate and cheese and crackers respectively improved the anxiety level and the energetic state of low anxiety trait participants. The mood effects were not altered with repeated exposure, and the magnitude of changes was similar on each test day, which illustrates the repeatability of the effects of the food on subjective measures of postprandial wellness. PMID- 22822454 TI - Effects of cyanobacterial lipopolysaccharides from microcystis on glutathione based detoxification pathways in the zebrafish (Danio rerio) embryo. AB - Cyanobacteria ("blue-green algae") are recognized producers of a diverse array of toxic secondary metabolites. Of these, the lipopolysaccharides (LPS), produced by all cyanobacteria, remain to be well investigated. In the current study, we specifically employed the zebrafish (Danio rerio) embryo to investigate the effects of LPS from geographically diverse strains of the widespread cyanobacterial genus, Microcystis, on several detoxifying enzymes/pathways, including glutathione-S-transferase (GST), glutathione peroxidase (GPx)/glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT), and compared observed effects to those of heterotrophic bacterial (i.e., E. coli) LPS. In agreement with previous studies, cyanobacterial LPS significantly reduced GST in embryos exposed to LPS in all treatments. In contrast, GPx moderately increased in embryos exposed to LPS, with no effect on reciprocal GR activity. Interestingly, total glutathione levels were elevated in embryos exposed to Microcystis LPS, but the relative levels of reduced and oxidized glutathione (i.e., GSH/GSSG) were, likewise, elevated suggesting that oxidative stress is not involved in the observed effects as typical of heterotrophic bacterial LPS in mammalian systems. In further support of this, no effect was observed with respect to CAT or SOD activity. These findings demonstrate that Microcystis LPS affects glutathione-based detoxification pathways in the zebrafish embryo, and more generally, that this model is well suited for investigating the apparent toxicophore of cyanobacterial LPS, including possible differences in structure activity relationships between heterotrophic and cyanobacterial LPS, and teleost fish versus mammalian systems. PMID- 22822455 TI - Toxins for transgenic resistance to hemipteran pests. AB - The sap sucking insects (Hemiptera), which include aphids, whiteflies, plant bugs and stink bugs, have emerged as major agricultural pests. The Hemiptera cause direct damage by feeding on crops, and in some cases indirect damage by transmission of plant viruses. Current management relies almost exclusively on application of classical chemical insecticides. While the development of transgenic crops expressing toxins derived from the bacterium Bacillus thuringiensis (Bt) has provided effective plant protection against some insect pests, Bt toxins exhibit little toxicity against sap sucking insects. Indeed, the pest status of some Hemiptera on Bt-transgenic plants has increased in the absence of pesticide application. The increased pest status of numerous hemipteran species, combined with increased prevalence of resistance to chemical insecticides, provides impetus for the development of biologically based, alternative management strategies. Here, we provide an overview of approaches toward transgenic resistance to hemipteran pests. PMID- 22822456 TI - Monoclonal antibodies and toxins--a perspective on function and isotype. AB - Antibody therapy remains the only effective treatment for toxin-mediated diseases. The development of hybridoma technology has allowed the isolation of monoclonal antibodies (mAbs) with high specificity and defined properties, and numerous mAbs have been purified and characterized for their protective efficacy against different toxins. This review summarizes the mAb studies for 6 toxins- Shiga toxin, pertussis toxin, anthrax toxin, ricin toxin, botulinum toxin, and Staphylococcal enterotoxin B (SEB)--and analyzes the prevalence of mAb functions and their isotypes. Here we show that most toxin-binding mAbs resulted from immunization are non-protective and that mAbs with potential therapeutic use are preferably characterized. Various common practices and caveats of protection studies are discussed, with the goal of providing insights for the design of future research on antibody-toxin interactions. PMID- 22822458 TI - A method for multiple mycotoxin analysis in wines by solid phase extraction and multifunctional cartridge purification, and ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. AB - An analytical method using two solid phase extractions and ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was developed for the identification and quantification of 14 mycotoxins (patulin, deoxynivalenol, aflatoxins B(1), B(2), G(1), G(2), M(1), T-2 toxin, HT-2 toxin, zearalenone, fumonisins B(1), B(2), B(3), and ochratoxin A) in domestic and imported wines. Mycotoxins were purified with an Oasis HLB cartridge, followed by a MultiSep(TM) #229 Ochra. As a result, sufficient removal of the pigments and highly polar matrices from the red wines was achieved. UHPLC conditions were optimized, and 14 mycotoxins were separated in a total of 13 min. Determinations performed using this method produced high correlation coefficients for the 14 mycotoxins (R > 0.990) and recovery rates ranging from 76 to 105% with good repeatability (relative standard deviation RSD < 12%). Twenty-seven samples of domestic and imported wines were analyzed using this method. Although ochratoxin A (OTA) and fumonisins (FMs) were detected in several samples, the FM levels were less than limits of quantification (LOQs) (1 MUg/L), and even the largest of the OTA levels was below the EU regulatory level (2 MUg/L). These results suggest that the health risk posed to consumers from the wines available in Japan is relatively low. PMID- 22822459 TI - Urine from Sexually Mature Intact Male Mice Contributes to Increased Cardiovascular Responses during Free-Roaming and Restrained Conditions. AB - Pheromones in the urine regulate aggression of male mice and castrated males produce less of these pheromones. We tested the hypothesis that pheromones in the urine of sexually mature-intact (SMI) males placed in the cage bedding of an individually housed male mouse or in a mouse restrainer would contribute to a significant increase in mean arterial pressure (MAP), heart rate (HR), and activity. Sexually mature male C57BL/6 mice were implanted with a biotelemetry transmitter to measure MAP, HR, and activity. Urine (200 MUL) from SMI mice placed in the cages of singularly housed male mice caused significant changes above baseline values for MAP (21 +/- 4 mmHg), HR (145 +/-25 bpm), and activity (9 2 counts) when compared to urine from castrated mice-induced MAP (11 +/- 3 mmHg), HR (70 +/- 15 bpm), and activity (5 +/- 1 counts). Pretreatment with terazosin significantly reduced the change in MAP (9 +/- 3 mmHg), heart rate (90 +/- 15 bpm), and activity (4 +/- 2 counts) responses to urine from SMI males. Saline did not significantly increase MAP, HR, or activity in any group. During restraint, urine from SMI mice caused a significant change in MAP (5 +/-0.4 mmHg) and HR (17 +/-1 bpm); urine from castrated mice did not cause a significant increase in MAP and HR. Our results demonstrate that a significant increase in MAP, HR, and activity occurs when male mice are exposed to urine pheromones from SMI males. In summary, pheromones in the urine of SMI male excreted in the cage bedding and mouse restrainers contribute to a significant increase in cardiovascular responses in the absence of direct physical contact with a different male mouse or animal handler. PMID- 22822457 TI - Multimodal protein constructs for herbivore insect control. AB - Transgenic plants expressing combinations of microbial or plant pesticidal proteins represent a promising tool for the efficient, durable control of herbivorous insects. In this review we describe current strategies devised for the heterologous co-expression of pesticidal proteins in planta, some of which have already shown usefulness in plant protection. Emphasis is placed on protein engineering strategies involving the insertion of single DNA constructs within the host plant genome. Multimodal fusion proteins integrating complementary pesticidal functions along a unique polypeptide are first considered, taking into account the structural constraints associated with protein or protein domain grafting to biologically active proteins. Strategies that allow for the co- or post-translational release of two or more pesticidal proteins are then considered, including polyprotein precursors releasing free proteins upon proteolytic cleavage, and multicistronic transcripts for the parallel translation of single protein-encoding mRNA sequences. PMID- 22822460 TI - From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers. AB - Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, efforts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting. PMID- 22822461 TI - Reappraisal of intergender differences in the urethral striated sphincter explains why a completely circular arrangement is difficult in females: a histological study using human fetuses. AB - To investigate why the development of a completely circular striated sphincter is so rare, we examined histological sections of 11 female and 11 male mid-term human fetuses. In male fetuses, the striated muscle initially extended in the frontal, rather than in the horizontal plane. However, a knee-like portion was absent in the female fetal urethra because, on the inferior side of the vaginal end, a wide groove for the future vestibule opened inferiorly. Accordingly, it was difficult for the developing striated muscle to surround the groove, even though there was not a great difference in width or thickness between the female vestibule and the male urethra. The development of a completely circular striated sphincter seems to be impossible in females because of interruption of the frontal plane by the groove-like vestibule. However, we cannot rule out the possibility that before descent of the vagina, the urethral striated muscle extends posteriorly. PMID- 22822462 TI - Vasculosyncytial membrane in relation to syncytial knots complicates the placenta in preeclampsia: a histomorphometrical study. AB - The vasculosyncytial membrane (VSM), primary site of fetomaternal exchange is formed when syncytiotrophoblast surrounds the terminal villi and make a close contact with capillaries. Some syncytiotrophoblast forms thin single layer of villous and some syncytial nuclei become piled up to form the syncytial knots (SKs). Undoubtedly there is a clear-cut inverse relation between villous VSM and fetal hypoxia. In preeclampsia (PE) the hypoxia injury disrupts the syncytial architecture which in turn initiates other complications of PE. Present study was designed to observe the morphological and histomorphometric features of 84 placentas from control and PE (42 each) collected from Department of Obstetrics and Gynecology. Neonatal weight and placental weight were reduced in PE than the controls but the feto-placental index did not differ. The SK density and VSM thickness was found to be increased and was statistically significant in PE cases. In relation to SKs, the VSM thickness was twofold increased than the controls and was statistically significant. The SKs in the present study were classified as type-1, 2a, 2b, and 3. Type 1 was found to be 62% in control and 47% in PE, type 2a and 2b were 38% in control and 37% in PE, and type 3 was in 8% of PE cases. All the parameters of present study reveal the adverse effects of PE influencing on both morphological and microscopical features of the placenta resulting in fetal hypoxia. PMID- 22822463 TI - Protective effects of Ginkgo biloba extract (EGB 761) on astrocytes of rat hippocampus after exposure with scopolamine. AB - The regular extract of Ginkgo biloba has been shown to possess neuroprotective properties in disorders like hypoxia, ischemia, seizure activity and peripheral nerve damage. Also, G. biloba has received attention as a potential cognitive enhancer for the treatment of Alzheimer's disease, but there is not any documentation about the effect of an extract of G. biloba on astrocytes. Therefore, the aim of this study was examined the effects of G. biloba extract on the rat's hippocampal astrocytes after scopolamine based amnesia. In this study, 36 adult male Wistar rats were used. Rats were randomly distributed into control, sham, protective and treatment groups. The rats in the sham group only received scopolamine hydrobromide (3 mg/kg) intraperitoneally. The rats in the protective and treatment groups received G. biloba extract (40, 80 mg/kg) for 7 days intraperitoneally before and after scopolamine injection. Forty eight hours after the last injection, the brains of the rats were withdrawn and fixed with paraformaldehide, and then after histological processing, the slices were stained with phosphotungstic acid-haematoxylin for astrocytes. Data were analyzed by the analysis of variance (ANOVA) post hoc Tukey test; P<0.05 was considered significant. Results showed that scopolamine can reduce the number of astrocytes in all areas of hippocampal formation compared with the control. However, G. biloba extract can compensate for the reduction in the number of astrocytes in the hippocampus before or after the encounter with scopolamine. We concluded that a pretreatment and treatment injection of G. biloba extract can have a protective effect for astrocytes in all areas of hippocampal formation. PMID- 22822464 TI - Differential expression levels of synaptophysin through developmental stages in hippocampal region of mouse brain. AB - The formation of neural synapses according to the development and growth of neurite were usually studied with various markers. Of these markers, synaptophysin is a kind of synaptic protein located in the synaptic vesicle of neuron or neuroendocrine cell known to be distributed consistently in all neural synapses. The purpose of this study was to investigate differential expression levels and patterns of synaptic marker (synaptophysin) in the mouse hippocampal region according to the developmental stages of embryonic, neonatal, and adulthood respectively. In the embryonic and neonatal groups, synaptophysin immunofluorescence was almost defined to cornu ammonis subfields (CA1 and CA3) of hippocampus and subiculum proper in the hippocampal region. However in dentate gyrus, synaptophysin immunoreactivities were insignificant or absent in all developmental stages. In embryonic and neonatal hippocampus, the intensities of immunofluorescence were significantly different between molecular and oriens layers. Furthermore, those intensities were decreased considerably in both layers of neonatal group compared to embryonic. The results from this study will contribute to characterizing synaptogenic activities in the central nervous system through developmental stages. PMID- 22822465 TI - Protective efficacy of an Ecklonia cava extract used to treat transient focal ischemia of the rat brain. AB - Phlorotannins (marine algal polyphenols) have been reported to exhibit beneficial biological activities, serving as both antioxidants and anti-inflammatory agents. Among marine algae, Ecklonia cava, a member of the Laminariaceae, is a very popular food regarded as healthy in Korea and Japan. Recently, benefits afforded by phlorotannins in the treatment of various clinical conditions have been reported, but any therapeutic effects of such materials in the treatment of neurodegenerative diseases such as stroke remain unclear. Also, the mechanisms of action of the algal components remain poorly understood. In the present in vivo study, administration of Ecklonia cava polyphenols (ECP) at 10 mg/kg and 50 mg/kg intraperitoneally (i.p.) significantly decreased infarct size and the extent of brain edema in the rat after induction of transient focal ischemia via middle cerebral artery occlusion (MCAO). Further, terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) assay revealed dose-dependent blockage of neuronal apoptosis upon intravenous ECP treatment. Neurobehavioral tests performed over the 6 days after MCAO revealed a reduction in neurological motor performance in control animals, but administration of ECP (50 mg/kg i.p.) prevented this decline. In vitro, a significant neuroprotective effect of ECP was evident when cell viability was assayed after induction of H(2)O(2)-mediated oxidative stress, upon retinoic acid treatment, in the differentiated neuroblastoma cell line SH-SY5Y. Interestingly, ECP blocked the rise in cytosolic calcium, in a dose-dependent manner, in differentiated SH-SY5Y cells exposed to H(2)O(2). Together, the results suggest that ECP exerts neuroprotective effects in the focally ischemic brain by reducing Ca(2+)-mediated neurotoxicity. PMID- 22822466 TI - Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats. AB - Arginine vasopressin (AVP) is a neuropeptide with vasoconstrictive, antidiuretic, cardiovascular regulative and hepatic glycogenolysis effects, that also affects other behaviors including modulating learning. A number of studies on AVP regulation have been conducted in various metabolic diseases (disorders). In this study, the immunoreactivities of AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and mRNA expressions in the hypothalamus were investigated by immunohistochemistry and quantitative real-time PCR (RT-qPCR) in stroke-prone spontaneously hypertensive rats at different ages (i.e., at postnatal months [PM] 1, 8, and 12). Blood glucose levels in the PM 8 group were higher than in the other groups. However, cresyl violet positive neurons were detected in the PVN and SON of all animals, and numbers of cresyl violet positive neurons were similar in all aged groups. In addition, AVP immunoreactivity was detected in the PVN and SON of all age groups, and AVP immunoreactivity and mRNA expression levels were found to be increased in proportion to age by immunohistochemistry and RT-qPCR. These results suggest that the diabetic condition is temporally generated after hypertension has developed. Furthermore, our findings suggest that increased AVP expressions in the hypothalamic PVN and SON are associated with hypertension by age. PMID- 22822467 TI - Purkinje cells loss in off spring due to maternal morphine sulfate exposure: a morphometric study. AB - The toxic effects of morphine sulfate in the adult cerebral cortex and one-day neonatal cerebellum have been studied. This study was carried out to evaluate the effect of maternal morphine exposure during gestational and lactation period on the Purkinje cells and cerebellar cortical layer in 18- and 32-day-old mice offspring. Thirty female mice were randomly allocated into cases and controls. In cases, animals received morphine sulfate (10 mg/kg/body weight intraperitoneally) during the 7 days before mating, gestational day (GD 0-21) 18 or 32. The controls received an equivalent volume of saline. The cerebellum of six infants for each group was removed and each was stained with cresyl violet. Quantitative computer assisted morphometric study was done on cerebellar cortex. The linear Purkinje cell density in both experimental groups (postnatal day [P]18, 23.40+/-0.5; P32, 23.45+/-1.4) were significantly reduced in comparison with the control groups (P18, 28.70+/-0.9; P32, 28.95+/-0.4) (P<0.05). Purkinje cell area, perimeter and diameter at apex and depth of simple lobules in the experimental groups were significantly reduced compared to the controls (P<0.05). The thickness of the Purkinje layer of the cerebellar cortex was significantly reduced in morphine treated groups (P<0.05). This study reveals that morphine administration before pregnancy, during pregnancy and during the lactation period causes Purkinje cells loss and Purkinje cell size reduction in 18- and 32-day-old infant mice. PMID- 22822468 TI - Three types of the serial segmented images suitable for surface reconstruction. AB - Stereoscopic surface models of human organs can be manipulated in real time. This is a significant feature of an interactive simulation system used for clinical practice. Objective surface models are obtainable from the accumulation of each structure's serial outlines, followed by surface reconstruction. The segmented images including the outlines can be divided into outlined images, white-filled images, and color-filled images. The purpose of this study was to report the benefits of the three types of segmented images for surface reconstruction. For the raw data, sectioned images of a male cadaver head were used. In the sectioned images, 91 structures were delineated for the preparation of 234 serial outlined images. The outlined images were converted into white-filled and color-filled images; the reverse conversion was also possible. The outlined images, including the original sectioned images, could be the source not only of surface models but also of volume models. The white-filled images, with a minimal file size, were preferred for separate surface reconstruction of the individual structures. The color-filled images, which allowed for recognition of the entire outlined structures simultaneously, were regarded as a good choice for the construction of several surface models. For the process, we employed a variety of software packages including those for animation, where the images were compatible. This information can be used by other investigators to build their own three dimensional models. In addition, the surface models of detailed structures in the head, accompanied by the corresponding sectioned and segmented images, will hopefully contribute to various simulations that can be useful to clinicians. PMID- 22822469 TI - Four-headed biceps brachii, three-headed coracobrachialis muscles associated with arterial and nervous anomalies in the upper limb. AB - A four-headed biceps brachii muscle and three-headed coracobrachialis muscle, high-originated radial artery and communication between the median and musculocutaneous nerves have been well documented in the available literature. However co-existence of these variations is rare. In this study we aimed to describe multiple variations in the upper limb and discuss their co-existence from clinical and embryological points of view. PMID- 22822470 TI - Reproductive Decision Making and Genetic Predisposition to Sudden Cardiac Death. AB - BACKGROUND: With current genetic technology, it is possible to detect mutations associated with long QT syndrome (LQTS), a hereditary cardiac arrhythmia syndrome. As a result, prospective parents diagnosed with LQTS will have to decide whether or not to prevent its transmission to future generations, either by not procreating or through the use of assisted reproductive technologies or prenatal testing. This paper explores how a hereditary predisposition to sudden cardiac death can influence reproductive decision making. METHODS: This study draws from interviews and focus groups with individuals who have personal or family histories of cardiac arrhythmia or sudden death. A keyword search was conducted on interview transcripts to identify quotes for analysis. RESULTS: Participants expressed complex, often ambivalent attitudes about the prospect of having a child with a predisposition to sudden cardiac death. Their comments reveal conflicting understandings of genetic responsibility and reflect the variable effects of personal experience on reproductive decision making. This paper compares attitudes towards LQTS and other genetic conditions in analyzing the themes that emerged in interviews and focus groups. CONCLUSIONS: The "disability critique" of prenatal testing should be applied carefully to a context of genetic predisposition to sudden cardiac death in order to understand reproductive decision making. Firsthand experience with the condition, among other factors, can weigh heavily in those decisions. PMID- 22822472 TI - Gene expression changes in the MAPK pathway in both Fragile X and Down syndrome human neural progenitor cells. AB - The two most common genetic developmental disorders that cause intellectual disability are Down syndrome (DS) and Fragile X syndrome (FXS). Although the genetics and behavioral hallmarks of these two disorders are distinct, common underlying defects in neural development may lead to the cognitive impairment characteristic of both. Human neural progenitor cells (hNPCs) enable the study of prenatal human brain development in these developmental disorders. We therefore tested whether there are common affected molecular pathways in FXS and DS hNPCs that may be indicators of the fundamental developmental causes of intellectual disability. Comparison of gene expression data from FXS and DS (disorder group) hNPCs to unaffected hNPCs indicated genes in specific signal transduction cascades are dysregulated. Importantly, altered expression of genes in these signaling pathways did not emerge when the two disorder hNPCs were analyzed separately. Specifically, genes in the mitogen-activated protein kinases (MAPK/ERK) and calcium signaling pathways are mis-expressed in disorder hNPCs. These results suggest that DS and FXS hNPCs do not communicate or respond appropriately to extracellular cues during neural development. These results validate the use of hNPCs as a tool to assess complex cell functions during neural development and suggest that defects in the pathways identified could have profound effects on how neural progenitor cells survive, proliferate and differentiate, thereby leading to intellectual disability. PMID- 22822473 TI - Health Evaluation of Experimental Laboratory Mice. AB - Good science and good animal care go hand in hand. A sick or distressed animal does not produce the reliable results that a healthy and unstressed animal produces. This unit describes the essentials of assessing mouse health, colony health surveillance, common conditions, and determination of appropriate endpoints. Understanding the health and well-being of the mice used in research enables the investigator to optimize research results and animal care. PMID- 22822471 TI - New Genetic Insights into Congenital Heart Disease. AB - There has been remarkable progress in understanding the genetic basis of cardiovascular malformations. Chromosome microarray analysis has provided a new tool to understand the genetic basis of syndromic cardiovascular malformations resulting from microdeletion or microduplication of genetic material, allowing the delineation of new syndromes. Improvements in sequencing technology have led to increasingly comprehensive testing for aortopathy, cardiomyopathy, single gene syndromic disorders, and Mendelian-inherited congenital heart disease. Understanding the genetic etiology for these disorders has improved their clinical recognition and management and led to new guidelines for treatment and family-based diagnosis and surveillance. These new discoveries have also expanded our understanding of the contribution of genetic variation, susceptibility alleles, and epigenetics to isolated congenital heart disease. This review summarizes the current understanding of the genetic basis of syndromic and non syndromic congenital heart disease and highlights new diagnostic and management recommendations. PMID- 22822475 TI - In vitro antiviral activity of honey against varicella zoster virus (VZV): A translational medicine study for potential remedy for shingles. AB - OBJECTIVES: The aim of this study was to determine the in vitro anti-viral effect of honey on varicella zoster virus. METHODS: Manuka and clover honeys were used at concentrations ranging from 0-6% wt/vol. A clinical VZV isolate was obtained from a zoster vesicle and used at low passage. Various concentrations of manuka and clover honey were added to the tissue culture medium of VZV-infected human malignant melanoma (MeWo) cells. RESULTS: Both types of honey showed antiviral activity against varicella zoster virus with an approximate EC50 = 4.5 % (wt/vol). CONCLUSIONS: Our results showed that honey has significant in vitro anti-VZV activity. As, honey is convenient for skin application, is readily available and inexpensive, honey may be an excellent remedy to treat zoster rash in developing countries where antiviral drugs are expensive or not easily available. PMID- 22822474 TI - Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-beta precursor protein dimerization. AB - The amyloid beta precursor protein (APP) is a single-pass transmembrane glycoprotein that is ubiquitously expressed in many cell types, including neurons. Amyloidogenic processing of APP by beta- and gamma-secretases leads to the production of amyloid-beta (Abeta) peptides that can oligomerize and aggregate into amyloid plaques, a characteristic hallmark of Alzheimer's disease (AD) brains. Multiple reports suggest that dimerization of APP may play a role in Abeta production; however, it is not yet clear whether APP dimers increase or decrease Abeta and the mechanism is not fully understood. To better understand the relationship between APP dimerization and production of Abeta, a high throughput screen for small molecule modulators of APP dimerization was conducted using APP-Firefly luciferase enzyme complementation to detect APP dimerization. Selected modulators identified from a compound library of 77,440 compounds were tested for their effects on Abeta generation. Two molecules that inhibited APP dimerization produced a reduction in Abeta levels as measured by ELISA. The inhibitors did not change sAPPalpha or gamma-CTF levels, but lowered sAPPbeta levels, suggesting that blocking the dimerization is preventing the cleavage by beta-secretase in the amyloidogenic processing of APP. To our knowledge, this is the first High Throughput Screen (HTS) effort to identify small molecule modulators of APP dimerization. Inhibition of APP dimerization has previously been suggested as a therapeutic target in AD. The findings reported here further support that modulation of APP dimerization may be a viable means of reducing the production of Abeta. PMID- 22822477 TI - Inflammatory mimetic microfluidic chip by immobilization of cell adhesion molecules for T cell adhesion. AB - Leukocyte adhesion to adhesion molecules on endothelial cells is important in immune function, cancer metastasis and inflammation. This cell-cell binding is mediated via cell adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) found on endothelial cells. Because these adhesion molecules on endothelial cells vary significantly across several disease conditions such as autoimmune diseases, inflammation or cancer metastasis, investigations of therapeutic agents that down regulate leukocyte-endothelial interactions have been based on in vitro models using endothelial cell lines. Here we report a new model, an inflammatory mimetic microfluidic chip, which emulates leukocyte binding to cell adhesion molecules (CAM) by controlling the types and ratio of adhesion molecules. In our model, E selectin was essential for the synergic binding of Jurkat T cells. Immunosuppressive drugs, such as tacrolimus (FK506) and cyclosporine A (CsA), were used to inhibit T cell interactions under the physiologic model of T cell migration at a ratio of 5 : 4.3 : 3.9 (E-selectin : ICAM-1 : VCAM-1). Our results support the potential usefulness of the inflammatory mimetic microfluidic chip as a T cell adhesion assay tool with modified adhesion molecules for applications such as immunosuppressive drug screening. The inflammatory mimetic microfluidic chip can also be used as a biosensor in clinical diagnostics, drug efficacy tests and high throughput drug screening due to the dynamic monitoring capability of the microfluidic chip. PMID- 22822476 TI - The promyelocytic leukemia zinc finger protein: two decades of molecular oncology. AB - The promyelocytic leukemia zinc finger (PLZF) protein, also known as Zbtb16 or Zfp145, was first identified in a patient with acute promyelocytic leukemia, where a reciprocal chromosomal translocation t(11;17)(q23;q21) resulted in a fusion with the RARA gene encoding retinoic acid receptor alpha. The wild-type Zbtb16 gene encodes a transcription factor that belongs to the POK (POZ and Kruppel) family of transcriptional repressors. In addition to nine Kruppel-type sequence-specific zinc fingers, which make it a member of the Kruppel-like zinc finger protein family, the PLZF protein contains an N-terminal BTB/POZ domain and RD2 domain. PLZF has been shown to be involved in major developmental and biological processes, such as spermatogenesis, hind limb formation, hematopoiesis, and immune regulation. PLZF is localized mainly in the nucleus where it exerts its transcriptional repression function, and many post translational modifications affect this ability and also have an impact on its cytoplasmic/nuclear dissociation. PLZF achieves its transcriptional regulation by binding to many secondary molecules to form large multi-protein complexes that bind to the regulatory elements in the promoter region of the target genes. These complexes are also capable of physically interacting with its target proteins. Recently, PLZF has become implicated in carcinogenesis as a tumor suppressor gene, since it regulates the cell cycle and apoptosis in many cell types. This review will examine the major advances in our knowledge of PLZF biological activities that augment its value as a therapeutic target, particularly in cancer and immunological diseases. PMID- 22822478 TI - A facile graphene oxide-based DNA polymerase assay. AB - The DNA polymerase assay is fundamental for related molecular biology investigations and drug screenings, however, the commonly used radioactive method is laborious and restricted. Herein, we report a novel, simple and cost-effective fluorometric DNA polymerase detection method by utilizing graphene oxide (GO) as a signal switch. In this strategy, in the absence of DNA polymerase, the fluorophore-labeled template ssDNA could be strongly adsorbed and almost entirely quenched by GO. However, as DNA polymerase exists, the polymerized dsDNA product might lead to a much lower quenching efficiency after addition of GO due to the much weaker interaction of dsDNA with GO than ssDNA, thus resulting in a much higher fluorescence signal detected. As proof of concept, the quantitative DNA polymerase activity assay was performed using the Klenow fragment exo(-) (KF(-)) as a model. It was confirmed that, after optimization of detection conditions, KF(-) activity could be sensitively detected through facile fluorescence measurements, with a detection limit of 0.05 U mL(-1) and a good linear correlation between 0.05-2.5 U mL(-1) (R(2) = 0.9928). In addition, this GO-based method was further inspected to evaluate the inhibitive behaviors of several drugs toward KF(-) activity, the result of which firmly demonstrated its potential application in polymerization-targeted drug screening. PMID- 22822479 TI - A Zn2+ specific triazole based calix[4]arene conjugate (L) as a fluorescence sensor for histidine and cysteine in HEPES buffer milieu. AB - A highly fluorescent Zn(2+) complex of the triazole linked salicyl-imino thiophenyl conjugate of calix[4]arene, [ZnL] has been demonstrated to be a chemo sensing ensemble for the recognition of His and Cys among the naturally occurring amino acids in HEPES buffer milieu. The recognition behaviour of the [ZnL] towards these amino acids has been shown on the basis of fluorescence, absorption and visual fluorescent colour changes. The species of recognition were shown by ESI MS titrations, AFM & TEM microscopy and cell studies. PMID- 22822481 TI - New opportunities in crystal engineering--the role of atomic force microscopy in studies of molecular crystals. AB - Here, we highlight recent research involving atomic force microscopy investigations of molecular crystals, and focus particularly on the latest relevant advances in our knowledge of crystal-growth mechanisms and structure property relationships in organic crystals. This brief survey features the importance of incorporating AFM into solid-state research as an essential tool for the informed design and construction of crystalline materials. PMID- 22822480 TI - A "zig-zag" naphthodithiophene core for increased efficiency in solution processed small molecule solar cells. AB - A solution-processed small molecule utilizing a novel 5,10-bis((2-ethylhexyl)oxy) naphtho[2,3-b:6,7-b0]dithiophene [corrected] "zig-zag" core (zNDT) exhibits high hole mobility, upshifted frontier MO energies, and enhanced photovoltaic cell short-circuit currents, fill-factors, and power conversion efficiencies (4.7%) versus the linear NDT isomer. PMID- 22822482 TI - Ligand effects on the stereochemistry of Stille couplings, as manifested in reactions of Z-alkenyl halides. AB - Unexpected losses in stereochemistry from Stille reactions involving Z-alkenyl halides have been shown to be ligand dependent. A new set of reaction conditions has been developed that, in most cases, leads to highly stereoselective cross couplings under mild conditions, along with improved yields. PMID- 22822483 TI - Time-gated luminescence microscopy with responsive nonmetal probes for mapping activity of protein kinases in living cells. AB - A photoluminescence probe ARC-1185, possessing both high affinity towards basophilic protein kinases (PKs) and microsecond-scale luminescence lifetime when associated with a kinase, was used for the mapping of ARC-1185-PK complexes in living cells with time-gated luminescence microscopy. PMID- 22822484 TI - Benzothiazolium-functionalized tetraphenylethene: an AIE luminogen with tunable solid-state emission. AB - Melding a benzothiazolium unit with tetraphenylethene generates a new hemicyanine luminogen with aggregation-induced emission characteristics; the luminogen exhibits crystochromism and its solid-state emission can be repeatedly tuned from yellow or orange to red by grinding-fuming or grinding-heating processes due to the transformation from the crystalline to the amorphous state and vice versa. PMID- 22822485 TI - Enhanced water splitting activity of M-doped Ta3N5 (M = Na, K, Rb, Cs). AB - We use a highly aligned Ta(2)O(5) nanochannel structure to fabricate alkali metal ion (Na, K, Rb or Cs) doped Ta(3)N(5)via solution seeding and thermal conversion in NH(3). Under optimized conditions the resulting doped structures show a strongly enhanced visible light water splitting performance in comparison to undoped Ta(3)N(5). PMID- 22822486 TI - Monodispersity and size control in the synthesis of 20-100 nm quasi-spherical silver nanoparticles by citrate and ascorbic acid reduction in glycerol-water mixtures. AB - A simple two-step seed-mediated synthesis of monodisperse quasi-spherical silver nanoparticles by citrate and ascorbic acid reduction is presented. Control over monodispersity is achieved by a variety of compounds with hydroxyl groups such as glycerol, ethylene glycol, agarose, or sucrose. The latter can also be used as a matrix for storage. PMID- 22822487 TI - Oxidative transformation of aryls using molybdenum pentachloride. AB - Molybdenum pentachloride combines a strong Lewis acid character with an unusually high oxidation potential creating a powerful reagent for oxidative transformations. Since the oxidative coupling reaction of aryls is induced at an extraordinarily high reaction rate, a variety of labile groups, e.g. iodo, tert alkyl, etc., are tolerated on the aromatic core. Furthermore, the co-formed molybdenum salts can either be exploited for template effects to obtain uncommon geometries in a preferred manner, or redox-play starts after aqueous workup. Therefore MoCl(5) represents a unique and easily available reagent. PMID- 22822488 TI - A general synthetic method for MPO4 (M = Co, Fe, Mn) frameworks using deep eutectic solvents. AB - A general approach was developed to synthesize a series of cobalt, manganese, and iron phosphate frameworks in deep-eutectic solvents through tuning important reaction parameters including temperature, time, and addition of water. PMID- 22822489 TI - Multifunctional switching of a photo- and electro-chemiluminescent iridium dithienylethene complex. AB - Optical or electrochemical excitation of an Ir(III) cyclometalated complex bearing photochromic and acid-sensitive dithienylethene ligands generates phosphorescence emission that can be switched on/off by light and chemical stimulation. PMID- 22822491 TI - L-dopa impairs proteasome activity in Parkinsonism through D1 dopamine receptor. PMID- 22822490 TI - [See you soon in Interlaken]. PMID- 22822494 TI - Insights on the role of adhesion related molecules on stem cells. PMID- 22822500 TI - Recent progress in cancer therapy with radiolabeled monoclonal antibodies. AB - "Progress in the use of RAIT for cancer therapy has been slow but steady, involving the reengineerin1g of antibodies (reducing murine component, altering size and clearance properties), and pretargeting methods for improvving tumor:blood and tumor:organ ratios are continuing to evolve". PMID- 22822501 TI - Gene delivery the key to gene therapy: the case for foamy viruses. AB - "There have been rare cases of zoonotic transmission of foamy virus from monkeys to humans, but despite keeping these cases under close scrutiny for years no pathology has ever been detected...". PMID- 22822502 TI - Oral delivery of poorly soluble compounds by supersaturated systems. AB - "New formulation and manufacturing methods are now available to efficiently and effectively increase solubility and maintain the supersaturation of a thermodynamically metastable state". PMID- 22822503 TI - Second world conference on nanomedicine and drug delivery. AB - The Institute of Holistic Medical Sciences (IHMS, Kottayam, Kerala, India); the Institute of Macromolecular Science and Engineering (IMSE, Kottayam, Kerala, India) and Mathew Ayurveda und Venen Klinik (MUVK, Klegenfurt, Austria) have jointly conducted a 3-day world conference on Nanomedicine and Drug Delivery (WCN 2011) in Kottayam, Kerala, India from 11-13 March 2011. Application of nanotechnology for treatment, diagnosis, monitoring and control of biological systems has been referred to as 'nanomedicine' by the NIH. Research into the rational delivery and targeting of pharmaceutical, therapeutic, and diagnostic agents is at the forefront of projects in nanomedicine. Nanotechnology will also provide devices to examine tissues in minute detail. Biosensors that are smaller than a cell would give us an inside look at cellular function. Tissues could be analyzed down to the molecular level, giving a completely detailed 'snapshot' of cellular, subcellular, and molecular activities. Today, nanotechnology and nanoscience approaches to particle design and formulation are beginning to expand the market for many drugs and are forming the basis for a highly profitable niche within the industry, but some predicted benefits are hyped. This article gives an outlook of the ongoing research projects conducted all over the world, presented at the conference that highlight rational approaches in design and surface engineering of nanoscale vehicles and entities for site-specific drug delivery and medical imaging after parenteral administration. Potential pitfalls or side effects associated with nanoparticles were also discussed. PMID- 22822504 TI - MagnetofectionTM platform: from magnetic nanoparticles to novel nucleic acid therapeutics. AB - Nucleic acid delivery to cells to make them produce a desired protein or to shut down the expression of endogenous genes opens unique possibilities for research and therapy. During the last decade, to realize the potential of this approach, nanomagnetic methods for delivering and targeting nucleic acids have been developed, methods which are often referred to as Magnetofection. Our research group at the Institute of Experimental Oncology and Therapy Research, located at the University Hospital Klinikum rechts der Isar in the center of Munich, Germany, develops new magnetic nanomaterials and, their formulations with gene delivery vectors and technologies to allow localized and efficient gene delivery in vitro and in vivo for a variety of research, diagnostic and therapeutic applications. PMID- 22822505 TI - Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. AB - AIM: The majority of the subcutaneously injected monoclonal antibodies already on the market achieve 50-65% bioavailability, yet the fate of the portion that is lost remains unknown. This consistently incomplete systemic absorption affects the efficacy, safety and overall cost of the drug product. There are many potential factors that might influence the absorption, such as charge, hydrophobicity, formulation variables and the depth and volume of the injection. MATERIALS & METHODS: To explore the possibility that the charge of the injected protein and/or formulation components is partially responsible for drug retention at the subcutaneous site, an ex vivo study, where the monoclonal antibodies were exposed to homogenized rat subcutaneous tissue, was performed. RESULTS & CONCLUSION: It was found that positively charged monoclonal antibodies bind to subcutaneous tissue in a manner that is dependent on ionic strength and pH, suggesting the electrostatic nature of the interaction. As expected, saturation of both nonspecific and electrostatic subcutaneous binding sites was observed after incubation with highly concentrated monoclonal antibody solutions. Additionally, it was demonstrated using model proteins that electrostatic effects of buffer components depend on ionic strength of ions bearing opposite charge rather than total ionic strength of the solution. These results suggest that electrostatic interactions may play a role in absorption processes of positively charged therapeutic proteins after subcutaneous administration. PMID- 22822506 TI - Surface modification and drug delivery for biointegration. AB - Biointegration refers to the interconnection between a biomedical device and the recipient tissue. In many implant devices, the lack of proper biointegration can cause device failure and potentially serious medical problems. This review summarizes the recent progress in surface chemistry, drug delivery and antifouling methods to improve the biointegration of implants. Much progress has been made as our understanding of biological systems and material properties expands and as new technologies become available. This article addresses methods of enhancing biointegration by means of modifying implant surface chemistry and by drug-delivery approaches. PMID- 22822507 TI - Inhaled therapies for tuberculosis and the relevance of activation of lung macrophages by particulate drug-delivery systems. AB - Pathogenic strains of Mycobacterium tuberculosis (Mtb) induce 'alternative activation' of lung macrophages that they colonize, in order to create conditions that promote the establishment and progression of infection. There is some evidence to indicate that such macrophages may be rescued from alternative activation by inhalable microparticles containing a variety of drugs. This review summarizes the experience of various groups of researchers, relating to observations of induction of a number of classical macrophage activation pathways. Restoration of a 'respiratory burst' and upregulation of reactive oxygen species and nitrogen intermediates through the phagocyte oxidase and nitric oxide synthetase enzyme systems; induction of proinflammatory macrophage cytokines; and finally induction of apoptosis rather than necrosis of the infected macrophage are discussed. It is suggested that there is scope to co-opt host responses in the management of tuberculosis, through the route of pulmonary drug delivery. PMID- 22822508 TI - Antibody delivery of drugs and radionuclides: factors influencing clinical pharmacology. AB - The therapeutic rationale of antibody conjugates is the selective delivery of a cytotoxin to tumor cells via binding and internalization of the monoclonal antibodies to a specific cell-surface antigen, thereby enhancing the therapeutic index of the cytotoxin. The key structural and functional components of an antibody conjugate are the antibody, the linker and the cytotoxin (chemical or radionuclide) with each component being critical for the successful development of the conjugate. Considerable efforts have been made in understanding the pharmacokinetics, pharmacodynamics, tissue distribution, metabolism and pharmacologic effects of these complex macromolecular entities. The purpose of this article is to discuss the properties and various structural components of antibody conjugates that influence their clinical pharmacology. PMID- 22822509 TI - Arsenic and its combinations in cancer therapeutics. AB - Arsenic is a metalloid that is considered to be a paradox in terms of its role both as a carcinogen and as a therapeutic agent. Chronic exposure to arsenic in drinking water has been linked with the development of various pathological conditions including cancer. Nevertheless, the therapeutic potential of arsenic and its derivatives in a variety of diseases have been exploited in the past. However, its role and mechanism of action as a therapeutic agent still remain an active area of research and investigation. Our ongoing work also suggests varied responses in cancer cells exposed to lower versus higher concentrations of arsenic. Furthermore, the arsenic combinations with chemopreventive or anticancer agents have been observed to sensitize the cell for cell-cycle arrest and cell death. Here, we have provided the account of recent updates on the mechanism of action of arsenic and its derivatives that lead to various disorders, and its role as a therapeutic agent both as a single agent as well as in combination chemotherapy. PMID- 22822510 TI - Local drug delivery to the inner ear using biodegradable materials. AB - The lack of an effective method of drug delivery has been a considerable obstacle in the development of novel therapeutics for inner ear diseases. However, several strategies have been investigated to achieve drug delivery to the inner ear, particularly for local application. Here, we review recent advances in the development of inner ear drug-delivery systems, focusing on biodegradable materials. Both synthetic and natural biodegradable materials have shown efficacy for inner ear drug delivery, resulting in an attenuation of hearing loss in animal models. We expect the further development of such drug-delivery systems to help translate the findings of experimental studies to clinical applications. PMID- 22822511 TI - Targeted magnetic hyperthermia. AB - Many nanotechnologies, which enable unique approaches to treat cancer, have been developed based upon non-toxic organic and inorganic materials to improve current cancer treatments. The use of inorganic materials to form magnetic nanoparticles for hyperthermia therapy is of great interest for localized treatment of cancers without effecting adjacent healthy tissue. Extensive clinical trials have begun using magnetic hyperthermia in animal models. The purpose of this article is to address different factors that affect targeting, heating and biodistribution to safely control the therapeutic efficacy of targeted magnetic hyperthermia. This method involves accumulation of magnetic nanoparticles at a tumor site and then manipulating the magnetic properties of the nanoparticles to heat the targeted tissues. PMID- 22822512 TI - Peripheral neuropathy. PMID- 22822513 TI - Neurologic complications of systemic cancer. PMID- 22822514 TI - [Securing A4 and A5 for resection of the medial lobe when facing incomplete lobation]. PMID- 22822515 TI - [My first experience with MICS (minimally invasive cardiac surgery)]. PMID- 22822517 TI - Letter from the editors. PMID- 22822516 TI - Occurrence of antibodies to low-incidence antigens among a cohort of multiply transfused patients with sickle cell disease. AB - Data from an immunohematology reference laboratory were compiled retrospectively to determine the occurrence of the formation of alloantibodies to low-incidence antigens associated with the African American population (AA-LIAs) among patients with sickle cell disease (SCD). The AA-LIAs under study were V, VS, Js(a), and Go(a). The records from 137 recurrently transfused patients with SCD were selected on the basis of transfusion activity from the 2009 calendar year. We found that 13 patients (9.49%) exhibited one or more antibodies to AA-LIAs, and a total of 17 antibodies to these AA-LIAs have been developed by these patients. The occurrence of antibody formation to AA-LIAs is significantly greater than that of alloantibodies to low-incidence antigens in the general population. Considering the possibility of the presence of antibodies to AA-LIAs in multiply transfused patients with SCD is warranted. PMID- 22822518 TI - Transfusion protocols for patients with sickle cell disease: working toward consensus? PMID- 22822519 TI - [Diagnostic imaging Q & A. Intralobar sequestration]. PMID- 22822520 TI - Multiple testing in candidate gene situations: a comparison of classical, discrete, and resampling-based procedures. AB - In candidate gene association studies, usually several elementary hypotheses are tested simultaneously using one particular set of data. The data normally consist of partly correlated SNP information. Every SNP can be tested for association with the disease, e.g., using the Cochran-Armitage test for trend. To account for the multiplicity of the test situation, different types of multiple testing procedures have been proposed. The question arises whether procedures taking into account the discreteness of the situation show a benefit especially in case of correlated data. We empirically evaluate several different multiple testing procedures via simulation studies using simulated correlated SNP data. We analyze FDR and FWER controlling procedures, special procedures for discrete situations, and the minP-resampling-based procedure. Within the simulation study, we examine a broad range of different gene data scenarios. We show that the main difference in the varying performance of the procedures is due to sample size. In small sample size scenarios,the minP-resampling procedure though controlling the stricter FWER even had more power than the classical FDR controlling procedures. In contrast, FDR controlling procedures led to more rejections in higher sample size scenarios. PMID- 22822521 TI - Skip the screen. Experts say blood tests for prostate cancer don't save lives. PMID- 22822522 TI - Stress-responsive hypothalamic-nucleus accumbens regulation may vary depending on stressors. AB - This study was conducted to determine if the stress-responsive hypothalamic nucleus accumbens (NAc) regulation is a stressor specific event. Male SD rats were subjected to restraint or cold stress for 2 h, and then mRNA expression of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) was examined by in situ hybridization and the plasma corticosterone levels by radioimmunoassay. Neuronal activations in the PVN and the NAc were examined by c-Fos immunohistochemistry and the brain GABA contents by HPLC. Both restraint and cold stresses increased c-Fos expression in the PVN and the plasma corticosterone; however, CRH expression in PVN was increased only by restraint, but not by cold, stress. Restraint stress significantly increased the NAc neuronal activation, but cold stress failed to do so. Restraint stress increased the NAc-GABA contents and cold stress did the hypothalamic GABA. Results suggest that the HPA axis regulation responding to restraint stress, but not cold stress, may involve the NAc neuronal activation in relation with GABAergic neurotransmission. Additionally, CRH expression in the PVN may not play a major role in the elevation of plasma corticosterone responding to cold stress. PMID- 22822523 TI - Effect of ANXA2 gene single nucleotide polymorphism (SNP) on the development of osteonecrosis in Indian sickle cell patient: a PCR-RFLP approach. AB - Osteonecrosis is a serious complication in sickle cell patients. The common sites of the necrosis are femoral head, head of the humerus and acetabulam. Annexin A2 (ANXA2) protein mainly functions in bone formation and bone resorption. Alteration of ANXA2 gene may affect the manifestations of osteonecrosis in the patients. PCR-RFLP is a common applicable technique for the detection of known mutation/polymorphisms. Here we are presenting application of the PCR-RFLP technique for determination of the ANXA2 gene single nucleotide polymorphism frequency and their clinical association among Indian sickle cell patients. Five known SNPs of ANXA2 gene (rs7170178, rs73435133, rs73418020, rs72746635 and rs73418025) were determined using the HpyCH4V, DdeI, HpyCH4III and Sau 961 restriction enzyme respectively. Restriction enzyme DdeI was common for rs73435133 and rs72746635 SNP. Only the rs7170178 SNP was detected among patient and control and the other four SNPs were absent in the studied groups. The frequency of ANXA2 gene rs7170178 SNP (A/G, G/G) was comparatively higher in sickle cell patients than controls and it was clinically associated with sickle cell osteonecrosis. The P value of heterozygotes (A/G) and homozygotes (G/G) genotypes were <0.001 and 0.001 respectively, which were highly significant. This study established the application of PCR-RFLP in detection of ANXA2 SNPs in sickle cell patients. PMID- 22822524 TI - Production and characterization of monoclonal antibodies against a local isolate of classical swine fever virus. AB - Monoclonal antibodies (mAbs) against a classical swine fever virus (CSFV; subgenogroup 1:1) isolate from Assam, India were produced and characterized. Four fusions of myeloma cells (SP2/0Ag) were made with spleenocytes of 8-10 weeks old BALB/C mice immunized with the viral antigen. Several hybridoma clones secreting antibodies to the virus were obtained after four fusions, but five hybridoma clones secreting antibody specific to the virus could be stabilized. All the mAbs belong to the IgG2a isotype. Except one, none of the four mAbs showed cross reaction with bovine viral diarrhoea virus and border disease virus (BDV). One mAb showed cross reaction with BDV. All the four mAbs specific to CSFV showed reactivity with the parental virus in immunoperoxidase test (IPT) and with a single protein band (molecular weight 55 kD approximately) of the virus in western blotting. In neutralization peroxidase linked assay (NPLA) all the mAbs reacted with 13 CSFV local isolates as well as with the cell culture adapted lapinized vaccine virus strain belonging to the subgenogroup 1:1. This is the first report on production and characterization of mAbs against CSFV in India. PMID- 22822525 TI - Anticancer activity of sclerotiorin, isolated from an endophytic fungus Cephalotheca faveolata Yaguchi, Nishim. & Udagawa. AB - Biodiversity provides critical support for drug discovery. A significant proportion of drugs are derived, directly or indirectly, from biological sources. Through high throughput screening (HTS) and bioassay-guided isolation, bioactive compound sclerotiorin has been isolated from an endophytic fungus Cephalotheca faveolata. Sclerotiorin was found to be potent anti-proliferative against different cancer cells. In this study sclerotiorin has been found to induce apoptosis in colon cancer (HCT-116) cells through the activation of BAX, and down regulation of BCL-2, those further activated cleaved caspase-3 causing apoptosis of cancer cells. PMID- 22822526 TI - Asparagus racemosus Willd (Liliaceae) ameliorates early diabetic nephropathy in STZ induced diabetic rats. AB - Diabetic nephropathy is a major "microvascular" complication of diabetes, differs from other causes of chronic kidney diseases in its predictability, with well defined functional progression from hyperfiltration to micro- to macroalbuminuria to renal failure. The present study was undertaken to investigate the effect of Asparagus racemosus Willd (Liliaceae) on streptozotocin-induced early diabetic nephropathy. Single i.p injection of streptozotocin (55 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats and thereafter treated orally with ethanolic extract of Asparagus racemosus (EEAR) at a dose level of 100 and 250 mg/kg daily for 4 weeks. The efficacy of extract was compared with diabetic control rats. A. racemosus treatment significantly decreased plasma glucose, creatinine, urea nitrogen, total cholesterol and triglyceride levels. Renal hypertrophy, polyuria, hyperfiltration, microalbuminuria and abnormal changes in the renal tissue as well as oxidative stress were effectively attenuated by EEAR treatment. Basement membrane thickening and mesangial proliferation formation without nodules were seen in diabetic rats, whereas these structural changes were reduced in EEAR treated groups. Results of this study suggested that A. racemosus has beneficial effect in the treatment of diabetic PMID- 22822527 TI - Anti-obese activity of Butea monosperma (Lam) bark extract in experimentally induced obese rats. AB - To study the efficacy of ethanolic extract of B. monosperma bark in cafeteria and atherogenic diet fed rats and monosodium glutamate (MSG) obese rats, different doses (200, 400 and 800 mg/kg) of ethanolic extract of B. monosperma bark showed dose dependent decrease in body weight, daily food intake, glucose, lipids, internal organs' weight and fat pad weight in cafeteria and atherogenic diet fed rats and monosodium glutamate obese rats. The results suggested that B. monosperma has significant anti-obese activity. PMID- 22822528 TI - Carbohydrate and elicitor enhanced withanolide (withaferin A and withanolide A) accumulation in hairy root cultures of Withania somnifera (L.). AB - Leaves of Withania somnifera contained more withaferin A and withanolide A than roots indicating that these compounds mainly accumulate in leaves. With an increase in age of the plant, withaferin A was enhanced with a corresponding decrease in withanolide A. Hairy root cultures were induced from leaf explants using Agrobacterium rhizogenes and the transgenic nature of hairy roots was confirmed by partial isolation and sequencing of rolB gene, which could not be amplified in untransformed plant parts. In hairy roots, withaferin A accumulated at 2, 3 and 4% but not at 6% sucrose, the highest amount being 1733 microg/g dry weight at 4% level. High and equal amounts of withaferin A and withanolide A accumulated (890 and 886 microg/g dry tissue respectively) only at 3% sucrose. Increasing concentrations of glucose enhanced withaferin A and it peaked at 5% level (3866 microg/g dry tissue). This amount is 2842 and 34% higher compared to untransformed roots and leaves (collected from 210-day-old plants) respectively. Withanolide A was detected at 5% glucose but not at other concentrations. While chitosan and nitric oxide increased withaferin A, jasmonic acid decreased it. Acetyl salicylic acid stimulated accumulation of both withaferin A and withanolide A at higher concentrations. Triadimefon, a fungicide, enhanced withaferin A by 1626 and 3061% (not detected earlier) compared to hairy and intact roots respectively. PMID- 22822529 TI - Degradation of bacterial DNA by a natural antimicrobial agent with the help of biomimetic membrane system. AB - The antimicrobial efficacy of methylglyoxal (MG) against several gram-negative bacteria including Escherichia coli has been reported. To determine the mechanism of action of MG, molecular interactions between lipid and MG within the liposomal membrane were also investigated. Multilamellar and unilamellar vesicles were prepared from 1, 2-dipalmitoyl-snglycero-3-phosphocholine (DPPC). The effect of MG on DPPC liposomal membrane was studied by fluorescence spectroscopy and differential scanning calorimetry. The results indicate that MG interacts mainly with the DPPC head group that produces a significant increase in the fluidity of liposomal vesicles, which could be the cause of a fusion/aggregation effect in microbial cells. The agarose gel electrophoresis study with the genomic DNA extracted from E. coli ATCC 25922 revealed that addition of MG could completely degrade this DNA within 1 h, pointing out to their distinctly high degree of sensitivity towards MG. Further, the drug was able to cross the cell membranes, penetrating into the interior of the cell and interacting with DNA for demonstrating antibacterial activity of MG. PMID- 22822530 TI - Synergistic effect of calcium stearate and photo treatment on the rate of biodegradation of low density polyethylene spent saline vials. AB - The biodegradation of spent saline bottles, a low density polyethylene product (LDPE) by two selected Arthrobacter sp. under in vitro conditions is reported. Chemical and UV pretreatment play a vital role in enhancing the rate of biodegradation. Treated LDPE film exhibits a higher weight loss and density when compared to untreated films. Arthrobacter oxydans and Arthrobacter globiformis grew better in medium containing pretreated film than in medium containing untreated film. The decrease in density and weight loss of LDPE was also more for pretreated film when compared to untreated film indicating the affect of abiotic treatment on mechanical properties of LDPE. The decrease in the absorbance corresponding to carbonyl groups and double bonds that were generated during pretreatment suggest that some of the double bonds were cut by Arthrobacter species. Since Arthrobacter sp. are capable of degrading urea, splitting of urea group were also seen in FTIR spectrum indicating the evidence of biodegradation after microbial incubation. The results indicated that biodegradation rate could be enhanced by exposing LDPE to calcium stearate (a pro-oxidant) which acts as an initiator for the oxidation of the polymers leading to a decrease of molecular weight and formation of hydrophilic group. Therefore, the initial step for biodegradation of many inert polymers depends on a photo-oxidation of those polymers. The application in sufficient details with improved procedures utilizing recombinant microorganism with polymer degradation capacity can lead to a better plastic waste management in biomedical field. The present plastic disposal trend of waste accumulation can be minimized with this promising eco friendly technique. PMID- 22822531 TI - Biodiesel production from seed oil of Cleome viscosa L. AB - Edible oil seed crops, such as rapeseed, sunflower, soyabean and safflower and non-edible seed oil plantation crops Jatropha and Pongamia have proved to be internationally viable commercial sources of vegetable oils for biodiesel production. Considering the paucity of edible oils and unsustainability of arable land under perennial plantation of Jatropha and Pongamia in countries such as India, the prospects of seed oil producing Cleome viscosa, an annual wild short duration plant species of the Indogangetic plains, were evaluated for it to serve as a resource for biodiesel. The seeds of C. viscosa resourced from its natural populations growing in Rajasthan, Haryana and Delhi areas of Aravali range were solvent extracted to obtain the seed oil. The oil was observed to be similar in fatty acid composition to the non-edible oils of rubber, Jatropha and Pongamia plantation crops and soybean, sunflower, safflower, linseed and rapeseed edible oil plants in richness of unsaturated fatty acids. The Cleome oil shared the properties of viscosity, density, saponification and calorific values with the Jatropha and Pongamia oils, except that it was comparatively acidic. The C. viscosa biodiesel had the properties of standard biodiesel specified by ASTM and Indian Standard Bureau, except that it had low oxidation stability. It proved to be similar to Jatropha biodiesel except in cloud point, pour point, cold filter plugging point and oxidation stability. In view of the annual habit of species and biodiesel quality, it can be concluded that C. viscosa has prospects to be developed into a short-duration biodiesel crop. PMID- 22822532 TI - The hedgehog signaling pathway, a new therapeutic target for treatment of ischemic heart disease. AB - The hedgehog (Hh) protein is involved in angiogenesis and cardiovascular development via activation of the classical ligand-dependent signaling transduction. So its potential therapeutic meaning of Hh signaling proteins to the ischemic heart diseases has been greatly explored. Recent studies show that up-regulated expression of hypoxia-induced factor-1 (HIF-1) and inflamemation in ischemic tissues activate the Hh signaling cascade in a GLI-dependent or independent way, resulting in elevated expression levels of pro-angiogenic and agiogenic factors to facilitate angiogenesis. In addition, Hh signaling pathway activation can promote residual myocardial progenitors, endogenous EPCs and MSCs differentiating into cardiomyocytes, inhibit cardiomyocyte apoptosis; thirdly, high level of exogenous Hh signaling can reduce myocardial ischemic/reperfusion injuries(I/R). In conclusion, three kinds of mechanisms induced by Hh signaling pathway participate in the heart repair after myocardial ischemia. Therefore, Hh agonists including Hh protein, Hh gene transfer and small molecule agonist could be part of a potential therapeutic strategy for acute or chronic ischemic heart disease. PMID- 22822533 TI - Monitoring of methylergometrine in human breast milk by solid-phase extraction and high-performance liquid chromatography with fluorimetric detection. AB - A high-performance liquid chromatographic assay has been developed for the detection and quantification of the conventional postnatal uterotonic drug, methylergometrine, in human breast milk using a C-18 reversed-phase column by isocratic elution. The analytical method consisted of sample clean-up by solid phase extraction, and the fluorescence detection required only 8.5 min per sample for separation and quantitation. This assay gave intra- and inter-assay coefficients of variation of less than 7.9% and 7.7%, respectively, and the detection limit was approximately 50 pg/ml. This method was applied for drug level monitoring in the breast milk of patients given methylergometrine. PMID- 22822534 TI - Simultaneous determination of dextromethorphan and dextrophan in rat plasma by LC MS/MS and its application to a pharmacokinetic study. AB - A highly selective and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for quantitating dextromethorphan (DXM) and its metabolite dextrophan (DXO) in rat plasma using pirfenidone as an internal standard. Protein precipitation with acetonitrile was employed for the sample preparation. Chromatographic separation was achieved on a SB-C18 column at 25 degrees C, with a gradient elution programme of which acetonitrile-0.1% formic acid in water as mobile phase. The flow rate was 0.4 mL/min. Detection is carried out by multiple reaction monitoring (MRM) on a ion-trap LC-MS/MS system with an electrospray ionization interface. The assay is linear over the range 1-500 ng/mL for DXM and 1-250 ng/mL for DXO, with a lower limit of quantitation of 1 ng/mL for both. Intra- and inter-day precision of the assay were less than 9.80% and the accuracy were in the range 96.35-106.39%. The developed method was successfully applied to analyze the drug in samples of rat plasma for pharmacokinetic study. PMID- 22822535 TI - Photodegradation kinetics, cytotoxicity assay and determination by stability indicating HPLC method of mianserin hydrochloride. AB - A stability-indicating HPLC method for the determination of mianserin hydrochloride in coated tablets was developed and validated. Also, drug photodegradation kinetics and cytotoxicity were determined. Chromatographic analyses were performed in an Ace RP-18 octadecyl silane column (250 mm x 4.6 mm i.d., particle size 5 microm) maintained at ambient temperature (25 degrees C). The mobile phase was composed of methanol, 50 mM monobasic potassium phosphate buffer and 0.3% triethylamine solution adjusted to pH 7.0 with phosphoric acid 10% (85:15, v/v) in isocratic mode at a flow rate of 1.0 mL x min(-1). The performed degradation conditions were: acid and basic media with HCl 1.0 M and NaOH 1.0 M, respectively, oxidation with H2O2 3% and the exposure to UV-C light. No interference in the mianserin hydrochloride elution was verified by degradation products formed. Linearity was assessed and ANOVA showed non significant linearity deviation (p > 0.05). Adequate results were obtained for repeatability, intermediate precision, accuracy and robustness. The photodegradation kinetics of mianserin hydrochloride was evaluated in methanol. The degradation of mianserin could be better described as zero order kinetic (r = 0.9982). The UV-C degraded samples of mianserin hydrochloride were also studied in order to determine the preliminary cytotoxicity in vitro against mononuclear cells. PMID- 22822536 TI - Isolation and characterization of a degradation product of deflazacort. AB - Deflazacort (DFZ) is an oxazoline derivative of prednisolone with anti inflammatory and immunosuppressive activity. The aim of this study was to investigate and to identify the main degradation product of DFZ, and to evaluate the anti-inflammatory effect of both DFZ and its major degradation product (namely DDP1). DFZ was subjected to alkaline and acid degradation. In 0.1 N NaOH, DFZ was immediately degraded and 99.0% of product DDP1 was detected by high performance liquid chromatography (HPLC). The HPLC method was ideal to separate the primary and other minor degradation products and was carried out using C18 column, mobile phase consisting of water: acetonitrile: (60:40, v/v) with flow rate of 1.0 mL/min and detection at 244 nm. DDP1 was isolated and identified as 21-hydroxy deflazacort (21-OH-DFZ) by NMR, IR and LCMS. The in vivo pharmacological assays showed that both DFZ as 21-OH-DFZ are active in in vivo and in vitro inflammatory models, but 21-OH-DFZ is more potent than DFZ. PMID- 22822537 TI - Evaluation of the disintegration properties of microcrystalline cellulose II and commercial disintegrants. AB - This study was conducted to assess the disintegration properties of cellulose II excipients named as spray-dried cellulose II (SDCII) and non spray-dried cellulose II (MCCII) in comparison with commercial disintegrants. Swelling and water sorption characteristics were determined by conventional methods. The swelling values, water uptake and percentage of compact volume expansion all suggested that SDCII and MCCII compacts disintegrate by a wicking mechanism similar to that of Polyplasdone-XL, whereas a swelling mechanism dominates for Primojel and Ac-Di-Sol. With commercial binders, SDCII, MCCII and Polyplasdone-XL produced strong, but fast disintegrating tablets. At high levels, their performance as a disintegrant was superior compared to Primojel and Ac-Di-Sol. Disintegration times of the pure excipients revealed SDCII and MCCII to be comparable to Polyplasdone-XL, but faster than Primojel and Ac-Di-Sol. Ibuprofen tablets prepared using disintegrants at all levels released 80% of the drug within 60 min. SDCII and MCCII offer potential for use as a disintegrant in the design and development of solid dosage forms. PMID- 22822538 TI - Multivesicular liposomes for the sustained release of thymopentin: stability, pharmacokinetics and pharmacodynamics. AB - The objective of the present study was to investigate the storage stability of thymopentin multivesicular liposomes (TP5-MVLs) prepared with different emulsifiers, and to study the pharmacokinetics and pharmacodynamics of the produced TP5-MVLs in vivo. The stability studies of TP5-MVLs indicated that MVLs particles prepared with mixed emulsifiers (Myrj52:solutolHS15 = 2:3) were stable at the storage temperature of 4 +/- 2 degrees C within 3 months. In addition, FITC-TP5-loaded MVLs was prepared for pharmacokinetic studies that after subcutaneous administration, the fluorescence signal lasted for about 5 days in plasma demonstrating that the rate of drug release from MVLs was very slow. The pharmacodynamic studies indicated that the therapeutic efficacy of TP5-MVLs after subcutaneous administration once every four days was the same as free TP5 solution after intravenous or subcutaneous administration once daily. In conclusion, MVLs, which possessed great storage stability, can be utilized to reduce the administration frequency of TP5, and therefore, served as a promising sustained release delivery system for polypeptide. PMID- 22822539 TI - Powder and compaction characteristics of pregelatinized starches. AB - Pregelatinized starch is widely used as a pharmaceutical aid, especially as a filler-binder. It is known that the tableting performance of excipients could be affected by their source. The aim of this study was to evaluate the powder and tableting properties of pregelatinized starches obtained from yucca, corn and rice and compare those properties with those of Starch 1500. This material had the lowest particle size, and porosity and largest density and best flow. However, yucca starch and corn starch showed an irregular granule morphology, better compactibility and compressibility than Starch 1500. Their onset of plastic deformation and their strain rate sensitivity was comparable to that of Starch 1500. These two materials showed compact disintegration slower that Starch 1500. Conversely, rice starch showed a high elasticity, and friability, low compactibility, which are undesirable for direct compression. This study demonstrated the potential use of pregelatinized starches, especially those obtained from yucca and corn as direct compression filler-binders. PMID- 22822541 TI - Chitosan microparticles for oral bioavailability improvement of the hydrophobic drug curcumin. AB - The aim of this study was to assess the feasibility of microparticles for dissolution enhancement and oral bioavailability of curcumin (Cur). Microparticles were prepared by the ionic crosslinking interaction with the use of tripolyphosphate (TPP) and chitosan (Cs). The physicochemical characteristics of microparticles were investigated. The in vivo performance was assessed by a pharmacokinetic study. The microparticles had an average diameter of 58.50 microm. Acceptable drug loading and encapsulation efficiency of microparticles were obtained to be 33.5% and 85.2%, respectively. Dissolution of Cur enhanced in the microparticles in comparison with pure drug. Drug release profile of Cur from microparticles fitted the first-order model. Microparticles provided improved pharmacokinetic parameters (Cmax 270.24 ng/ml, T(max) 1.30 h) in rats as compared with pure drug (C(max) 87.06 nglml, Tmax 0.66 h). The AUC value of microparticles was 8.4 fold that of the pure drug. The information from this study suggests that the developed microparticles successfully enhanced dissolution of the poorly water-soluble drug Cur, and eventually, improved its oral bioavailability effectively. PMID- 22822540 TI - Physiological barriers to the oral delivery of curcumin. AB - Curcumin, a principal component from Curcuma longa, with antioxidant and anti inflammatory activities was proposed as a potential candidate for the preventation and/or treatment of cancer and chronic diseases. However, curcumin could not achieve its expected therapeutic outcome in clinical trials due to its low solubility and poor bioavailability. The actual intestinal physiological barriers limiting curcumin absorption after oral administration have not been fully investigated. To identify the main barriers curtailing its absorption, in vitro permeability of curcumin and flux of its glucuronide were monitored in rat jejunum and Transwell grown Caco-2 cells. Curcumin was more permeable under acidic conditions, but the permeability was substantially below the permeability of highly permeable standards. Its efflux could not be inhibited by specific Pgp and MRP inhibitors. BCRP was found to participate in curcumin transport, but the Organic Anion Transporting Polypeptide (OATP) did not. The permeability of curcumin significantly increased when the structure of mucus was compromised. The inhibitor of curcumin metabolism, piperin, failed to act as a permeability enhancer. Piperin inhibited Pgp and MRP transporters and decreased the amount of glucuronide transported back into the intestine. Inclusion of piperin in curcumin containing formulations is highly recommended as to inhibit curcumin glucuronidation and to increase the transport of formed glucuronides into the plasma, therefore increasing the probability of glucuronide distribution into target tissue and inter-convertion to curcumin. It would also be beneficial, if curcumin delivery systems could reversibly compromise the mucous integrity to minimize the non-specific binding of curcumin to its constituents. PMID- 22822543 TI - Development of a difenoconazole/propiconazole microemulsion and its antifungal activities against Rhizoctonia solani AG1-IA. AB - According to its physical and chemical properties, the composition of difenoconazole/propiconazole microemulsion was as follows: xylene as solvent, emulsifier HSH as surfactant and methanol as cosurfactant. The optimal formulation of difenoconazole/propiconazole microemulsion was oil/SAA/water = 1/2/5 (w/w), in which the SAA consisted of emulsifier HSH and methanol with ratio of 3/2 (w/w). The cloud point of difenoconazole/propiconazole microemulsion was 70 degrees C and its effective ingredient content was 2.5% measured by High Performance Liquid Chromatography (HPLC). Its heat storage stability was studied according to the standards. The decomposition rates of the difenoconazole/propiconazole microemulsion were merely 2.45%, 2.63% respectively and met the Food and Agriculture Organization (FAO) standards of pesticide microemulsion. Investigated by Transmission Electron Microscopy (TEM) the particle size of difenoconazole/propiconazole microemulsion was 90-140 nm and its antifungal activities against Rhizoctonia solani AG1-IA were tested and compared with that of Meiyu. We found that the inhibition rates in the difenoconazole/propiconazole microemulsion treatment group were significantly higher than that of the emulsion group with the same content of effective ingredients and the study also revealed that its inhibiting ability on the formation and germination of sclerotia was significant. PMID- 22822542 TI - Pharmacokinetics, excretion, and distribution of combretastatin A4 phosphate in rats. AB - In order to characterize the pharmacokinetics, excretion, and distribution of combretastatin A4 phosphate (CA4P) and its active metabolite, combretastatin A4 (CA4), in rats, a reliable gradient HPLC-based method has been developed and validated. The pharmacokinetic profiles of CA4P and CA4 in rats after CA4P intravenous injection at doses of 0.7, 1 and 4 mg x kg(-1) were best described by a two-compartment model. The terminal half-lives of CA4P or CA4 were similar at different CA4P dose levels, 5-9 min for CA4P and 39-60 min for CA4, while t1/2alpha, and Vd of CA4P or CA4 were very different. CA4 was largely distributed to the heart, intestine, lung, spleen and liver during 15 to 40 min after intravenous injection of CA4P. CA4P was predominantly excreted into urine (10.72%) and feces (9.703%) and to a lesser extent into bile (0.897%), whereas a greater portion of CA4 were excreted into feces (6.235%) and to a lesser extent into urine (0.782%) and bile (0.496%) during 0-28 h after intravenous injection of 1 mg x kg(-1) to rats. This is the first study to characterize the distribution of the active CA4P metabolite, CA4, in rat. PMID- 22822544 TI - Hypopigmentary effects of 4-n-butylresorcinol and resveratrol in combination. AB - In the present study, the effects of 4-n-butylresorcinol and/or resveratrol on melanogenesis were studied. To achieve synergistic effects and avoid potential adverse effects, combinations of the agents in low concentrations were investigated. Our results show that 1 microM of 4-n-butylresorcinol and 1 microM of resveratrol did not individually inhibit melanin synthesis. However, the combination of 4-n-butylresorcinol (1 microM) and resveratrol (1 microM) significantly reduced melanin synthesis. Furthermore, 4-n-butylresorcinol (10 microM) and resveratrol (10 microM) decreased melanogenesis much stronger. 4-n Butylresorcinol is reported to directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, without changing tyrosinase levels. Our results also showed that resveratrol did not directly inhibit tyrosinase at 0.1-10 microM. Literature has reported that resveratrol led to post-transcriptional regulation of tyrosinase. However, Western blot analysis showed that neither 4-n butylresorcinol nor resveratrol alone decreased tyrosinase protein levels. Surprisingly, the combination of 4-n-butylresorcinol and resveratrol reduced tyrosinase levels. Therefore, these results indicate that the synergistic hypopigmentary effect of 4-n-butylresorcinol and resveratrol results from a decreased level of tyrosinase possibly resulting from synergistic action of 4-n butylresorcinol on tyrosinase alteration by resveratrol. PMID- 22822545 TI - Combined effects of the ATP-sensitive potassium channel opener pinacidil and simvastatin on pulmonary vascular remodeling in rats with monocrotaline-induced pulmonary arterial hypertension. AB - The drugs that are currently used to treat pulmonary hypertension (PH) lack the ability to inhibit or reverse the pulmonary vascular remodeling that occurs during the course of the disease. We propose a novel method that combines the therapeutic powers of the potassium channel opener pinacidil and the statin drug simvastatin. These two drugs do not share similar mechanisms of treating PH. We used rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) as a model and examined the combined effects of pinacidil and simvastatin on pulmonary vascular remodeling. A series of indicators, including those for pulmonary vascular obstruction, proliferation, and cell phenotype, pulmonary vascular matrix and pulmonary vascular smooth muscle cell phenotype were used to monitor changes in pulmonary structure over the course of disease and treatment in normal controls, untreated PAH rats, pinacidil-treated subjects, simvastatin treated subjects, and combination-treated subjects. We found that levels of mPAP, right ventricle Fulton index, pulmonary arteriolar wall thickness and muscularization, cell growth rate, transforming growth factor beta (TGF-beta), lung tissue matrix metalloproteinase-2 (MMP-2), MMP-9 and lung tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), vascular smooth muscle cell (VSMC) contractile protein SM-alpha-actin, and SM-alpha-actin mRNA of these different groups were all significantly lower in the combination-treated group than in the untreated group. Subjects in the combination-treated group also showed lower levels than those in either the pinacidil-treated or simvastatin-treated group. These results support our hypothesis and provide basis for a new, more effective therapeutic methods of treating PAH in human patients. PMID- 22822546 TI - Osteopontin is required for angiotensin II-induced migration of vascular smooth muscle cells. AB - Migration and proliferation of vascular smooth muscle cells (VSMCs) play a prominent role in the development of atherosclerotic plaques and restenosis lesions. Angiotensin II (Ang-II) is typically associated with excessive proliferation and migration of VSMCs and vascular remodeling. High levels of osteopontin (OPN) mRNA and protein were reported in human atherosclerotic plaque from the aorta, carotid and coronary arteries. However whether OPN plays a role in VSMCs migration induced by Ang-II is unknown. Here we show that, in primary cultured rat VSMCs, Ang-II exhibits chemotactic effect on cultured VSMCs and induces OPN expression dose-dependently. With a lentiviral shRNA specifically targeting OPN and transwell migration assay, we find that blockade of OPN with shRNA inhibits Ang-II-induced MMP9 upregulation and VSMCs migration. Our results demonstrated that OPN is required for Ang-II to induce VSMCs migration and suggested OPN as a potential target in preventing atherosclerotic development. PMID- 22822547 TI - Ethanol extract of Piper longum L. attenuates gentamicin-induced hair cell loss in neonatal cochlea cultures. AB - Piper longum L. (PL), also as known as long pepper, a well-known spice and traditional medicine in Asia and Pacific islands, has been reported to exhibit wide spectrum activity including antioxidant activity. However, little information is available on its protective effect on gentamicin (GM) induced ototoxicity which is commonly regarded as being mediated by reactive oxygen species and reactive nitrogen species. This study was undertaken to investigate the protective effect of PL ethanol extract on gentamicin-induced hair cell loss in neonatal cochlea cultures. Cochlea cultures from postnatal day 2-3 mice were used for analysis of the protective effects of PL against gentamicin-induced hair cell loss by phalloidin staining. E. coil cultures were used to determine whether PL interferes with the antibiotic activity of GM. Nitric oxide (NO)-scavenging activity of PL was also measured in vitro. GM induced significant dose-dependent hair cell loss in cochlea cultures. However, without interfering with the antibiotic activity of GM, PL showed a significant and concentration-dependent protective effect against GM-induced hair cell loss, and hair cells retained their stereocilia well. In addition, PL expressed direct scavenging activity toward NO radical liberated within solution of sodium nitroprusside. These findings demonstrate the protective effect of PL on GM-induced hair cell loss in neonatal cochlea cultures, and suggest that it might be of therapeutic benefit for treatment of GM-induced ototoxicity. PMID- 22822548 TI - Stimulation of lysozyme release by selected microbial preparations. AB - Lysozyme is an important factor of innate immunity and a unique enzybiotic in that it exerts not only antibacterial activity, but also antiviral, anti inflammatory, anticancer, and immunomodulatory activities. The purpose of the present study was to investigate whether in vitro exposure to microbial preparations can affect the release and production of lysozyme activity in human monocytic cell line THP-1. Lysozyme activity levels in cell culture fluids were measured using highly sensitive fluorescence-based lysozyme activity assay. Different preparations of bacteria and ascomycetes stimulated lysozyme release result in a higher lysozyme activity after one hour exposure. The demonstrated ability of selected microbial preparations to enhance the release of lysozyme activity can present a new mechanism contributing to explaining biological characteristics of microbial preparations, including their antibacterial and immune-stimulating properties. PMID- 22822549 TI - Adhesion testing of polyurethane matrix patches for transdermal delivery of testosterone. AB - The 180 degrees peel test was applied to measure adhesion of three experimental polyurethane (PU) matrix patches and one commercial patch, Testopatch, on human volunteers skin. Comparing the results with those measurements on stainless steel or leather, a significant correlation between the leather data and the skin measurements was found. In contrary to results from stainless steel tests, all of the PU patches achieved better adhesion on skin than the commercial patch. PMID- 22822550 TI - We can do better. PMID- 22822551 TI - Moving beyond the illusion. PMID- 22822552 TI - In search of a best practice model for the hospital-foundation relationship, part II: continuing the dialogue. PMID- 22822553 TI - Relationships matter. PMID- 22822554 TI - Powerful mission storytelling. PMID- 22822555 TI - What is it about a pie? PMID- 22822556 TI - The perioperative nurse's role in patient-focused funding. AB - All provinces across Canada are currently struggling with long surgery wait times. British Columbia (BC) has recently implemented an improvement strategy called patient focused funding (PFF) whereby health authorities are offered additional money for completing extra surgeries. System wide change, when made without engagement by all involved parties, rarely achieves expected outcomes suggesting PFF would benefit from the participation of the entire operating room (OR) team. Perioperative nurses, in the role of patient advocate, are well suited to observe and report patient focused outcomes thereby limiting the unintended and negative consequences associated with proposed changes. This article seeks to inform Canadian perioperative nurses about PFF and explain why it is important for nurses to participate. At the time of writing, Ontario and Alberta had also announced plans to implement some form of PFE It is anticipated that, if proven successful, BC's experience will likely be duplicated in other provinces. PMID- 22822558 TI - Spotlight on ORNAC members. Interview by Catherine Harley. PMID- 22822557 TI - Historical trends influencing the future of perioperative nursing. AB - This paper explores the historical trends that have shaped the perioperative nursing specialty. The educational, societal, and political influences are examined through different historical periods. After, initially, being the first recognized nursing specialty operating room nursing was later removed from the nursing education curriculum. A debate as to whether perioperative nursing was simply a technical skill or actually "real" nursing was beginning and it continues to this day. Today, students' lack of exposure to the operating room, unsuccessful preceptorship programs, and poor working conditions are creating major recruitment and retention challenges. Because these historical trends have led to the decline of perioperative nursing, it is crucial for modern nurses to understand the factors that are influencing our practice and to make collective efforts to positively influence the future of our specialty. PMID- 22822559 TI - [The general practitioner faced with memory problems in the aged patient in Luxembourg: a study of the management employed, the experience of the physicians and the perception of the specific treatment]. AB - Memory impairments are common in elderly. General practitioners are in first line to detect and manage these troubles, for which many countries published recommendations. For Alzheimer disease there are currently four treatments, none of which is healing. Some countries limited the first prescription of those medicines to specialists whereas in Luxembourg, every practitioner is allowed to prescribe them, but has to ask health insurance first. Consequently, it is important that general practitioners know what to do. The aim of our paper is to study the management done by the general practitioners in Luxembourg, the way they feel about it and the way they see the specific medicines for Alzheimer disease. Therefore, we have sent a questionnaire to every general practitioner in Luxembourg. We found that 87% of the practitioners realize at least one cognitive impairment test. More than half of them check for depression and 22.6% also add an autonomy assessment scale, even though all these tests are done by the dependence insurance. The involvement of general practitioners in the diagnosis of dementia is important as more than half of them have a statistically adequate number of demented patients. About two third of the practitioners do systematically start a specific medicine for Alzheimer disease. The management of cognitive impairment is difficult for general practitioners of Luxembourg, particularly the disclosure of diagnosis and management of behavioural and psychological symptoms. PMID- 22822560 TI - [Can one authorize oocyte donation in the Grand Duchy of Luxembourg?]. AB - In the case of early ovary extinction, the only way to have a child is either adoption or egg/embryo reception by donation. To day, egg donation is prohibited in Luxembourg by ministerial decision in 2003. Germ cell donation is part of artificial reproductive therapy. Oocyte donation, in particular, needs to be done by IVF treatment, which makes it more complicated then sperm donation What makes it more difficult is the fact that there are no oocyte bank yet. Today, prohibition encourages procreative tourism what only wealthy people can afford. Although donation programs are well established many questions arise about egg donation such as refunds, divulging information, women's age limit, health insurance participation. PMID- 22822561 TI - [The dependence level of the elderly person influences the risk of infection]. AB - OBJECTIVE: Assess the impact of the reduction or loss of autonomy of the elderly in the nosocomial infection risk. METHOD: Using Karnosfsky scale (KPS). This study involved 163 patients aged 65 and over hospitalized for medical reasons. DATA COLLECTION: KPS index, body mass index, Index Norton, bladder's drainage system at the entrance and during hospitalization, colonization of resistant bacteria (BMR) at entry and during hospitalization, antibiotic use at entry and during hospitalization, infection at entry and during hospitalization. RESULTS: There is a statistically significant relationship between the degree of autonomy and the index of risk of pressure ulcers (Norton), between the degree of autonomy and the use of bladder's drainage system, between the degree of autonomy and risk acquisition of BMR, between the degree of autonomy and the nosocomial infection risk. CONCLUSION: The level of dependence increases the risk of infection nosocomial: loss of autonomy is a risk factor for infection. The evaluation of the degree o autonomy of elderly patients at entry and at regular intervals is essential in ou view a policy of reducing nosocomial infections. PMID- 22822562 TI - [The OPTIMISE study (Optimal Type 2 Diabetes Management Including Benchmarking and Standard Treatment]. Results for Luxembourg]. AB - The OPTIMISE study (NCT00681850) has been run in six European countries, including Luxembourg, to prospectively assess the effect of benchmarking on the quality of primary care in patients with type 2 diabetes, using major modifiable vascular risk factors as critical quality indicators. Primary care centers treating type 2 diabetic patients were randomized to give standard care (control group) or standard care with feedback benchmarked against other centers in each country (benchmarking group). Primary endpoint was percentage of patients in the benchmarking group achieving pre-set targets of the critical quality indicators: glycated hemoglobin (HbAlc), systolic blood pressure (SBP) and low-density lipoprotein (LDL) cholesterol after 12 months follow-up. In Luxembourg, in the benchmarking group, more patients achieved target for SBP (40.2% vs. 20%) and for LDL-cholesterol (50.4% vs. 44.2%). 12.9% of patients in the benchmarking group met all three targets compared with patients in the control group (8.3%). In this randomized, controlled study, benchmarking was shown to be an effective tool for improving critical quality indicator targets, which are the principal modifiable vascular risk factors in diabetes type 2. PMID- 22822563 TI - [The Luxembourg Society for Sports Medicine (SLM) after 60 years]. AB - This review will mainly focus the last 10 years of the society's history because several important changes occurred during this relatively short period. The most important was the creation of the first clinical sports medicine department in Luxembourg in 2004. This modern new infrastructure was made possible by the recruitment of 2 highly competent sports physicians, the excellent collaboration of the governing board of the Centre Hospitalier de Luxembourg (CHL) and the support of the sports minister. In 2008 the new department received the label "Medical Olympic Centre of Luxembourg". One year later a Research Lab of Sports Medicine (CRP-Sante) completed the new concept. Thus within 4 years the structure of Luxembourgish sports medicine was completely rearranged and includes today orthopaedic surgery and traumatology, functional rehabilitation, sports cardiology, exercise physiology, physiotherapy and specific sports medicine research. An important new challenge of the SLMS will be to integrate the external sports physicians into this new infrastructure. Another ongoing mission of the SLMS will be the education and training of new young sports medicine specialists. Here the new department could play an outstanding role and the SLMS is in close negotiations with the University of Luxembourg, in charge of academic education in Luxembourg. A recruitment of new young sports physicians is necessary to perpetuate the routine sports medicine exams in the 15 regional centres in Luxembourg, where such an exam is mandatory in order to get an official sports licence. Since 2010 an ECG exam has been added for all new licence candidates, according to the recent recommendations of the scientific societies. New young sports physicians will also be needed to assure the medical attendance of the different national teams of Luxembourg. Until 1985 these activities were confined only to the Olympic teams every 4 years, but since the implementation of the Games of the Small European Countries in 1985, where rather big teams represent Luxembourg every two years, this mission has become more important. The history of the SLMS reflects the development both of sports and sports medicine during the last 60 years. At the beginning of the 21.century sports medicine is well settled in the Grand-duchy of Luxembourg. PMID- 22822564 TI - Impact of initial intervention on long-term neurological recovey after cardiac arrest: data from the Luxembourg "North Pole" cohort. AB - BACKGROUND: Prognosis after cardiac arrest is variable and difficult to predict. Early prognostic markers would facilitate the care of these patients. AIMS: Therefore, we evaluated the impact of initial interventions after resuscitation on neurological outcome at 6 months. MATERIAL AND METHODS: We conducted a retrospective analysis of the patient charts from consecutive cardiac arrest patients admitted to our intensive care unit and treated with induced hypothermia. RESULTS: Over a 3-year period, 90 patients were included in our study. Sixty-four percent of the patients had bystander cardio-pulmonary resuscitation. An automated external defibrillator (AED) was used in 19% of the patients and the mean time to first defibrillation was 11 +/- 8.9 minutes. Patients being resuscitated and defibrillated by bystanders did better than those who had CPR only and far better than those patients in whom no rescue measures where attempted at all (73% vs. 56% vs. 32% for good neurological outcome, respectively, p= 0.03). Witnessed cardiac arrest was more frequent in patients with a good outcome than in those who collapsed without a witness (91% vs 75%, p = 0.03). In 76% of the patients with good outcome, CPR was performed whereas only 52% benefited from these measures in the bad outcome group (p = 0.01). Although the use of an AED was not significantly different between good and bad outcome groups (26% vs. 11%, p = 0.06), time to first defibrillation was significantly lower in patients with good outcome (8.7 +/- 6.3 vs. 13.3 +/- 11.3 minutes, p = 0.05). In the 17 patients in whom an AED was used, 12 (71%) recovered without major sequelae whereas in the 73 cases where no AED was used, only 34 (47%) had a good outcome (p = 0.06). At 6 months follow-up, 46 (51%) survivors had a good outcome (cerebral performance category 1-2), 5 (6%) survived with severe neurological sequelae or stayed in coma and 39 (43%) died. CONCLUSIONS: Our local data confirm that early interventions have a major impact on survival of cardiac arrest patients. Efforts should concentrate on delivering rapid and high quality CPR as well as early defibrillation by AED's to every patient in cardiac arrest. Besides large scale Basic life support training, the introduction of dispatcher assisted CPR and the implementation and use of public AED's could considerably help to improve outcome in these patients. PMID- 22822565 TI - The effect of smoking on fracture healing and on various orthopaedic procedures. AB - Ten percent of all fractures lead to problems with healing. Smoking is said to be a cause. There are 13.5 million smokers in the U.K. Healing of tibial fractures, for instance, requires two more months in smokers. Nicotine, carbon monoxide and hydrogen cyanide are most often seen as the offenders, among the 4000 chemicals found in cigarettes. Many studies plead for the negative effect of smoking in general, yet there is uncertainty as to the precise role of nicotine. The authors recommend that patients should attempt smoking cessation therapy before elective orthopaedic treatment. PMID- 22822566 TI - Chronic anterior shoulder dislocation: aspects of current management and potential complications. AB - Chronic unreduced anterior dislocations of the shoulder are rare. Arterial and neurological complications in chronic glenohumeral dislocations are even less frequent. We report three cases of old anterior shoulder dislocations. Open reduction is indicated for most chronic shoulder dislocations. Arterial lesions require urgent intervention with reconstruction. Conservative treatment is advised for most neurological complications. PMID- 22822567 TI - Latissimus dorsi transfer: L'Episcopo versus Herzberg technique. AB - The purpose of this study was to compare the clinical results of two different techniques of latissimus dorsi transfer used in 28 patients, either a modified single incision mini-invasive Herzberg transfer (HT) or a combined latissimus dorsi and teres major transfer according to L'Episcopo (LE). Twenty-eight patients fulfilled the inclusion criteria. Minimum follow-up was 24 months. Sixteen patients were treated with the Herzberg transfer (HT group) and 12 patients had the L'Episcopo technique (LE group). The Constant score rose from 272 initially to 73.5 four years post-operatively in the LE group and from 32.2 to 76 three years and 3 months post-operatively in the HE group (statistically similar). The pre-operative acromiohumeral distance remained unchanged statistically. Radiological signs of osteoarthritis increased. Constant-Murley score, acromiohumeral distance and progression of rotator cuff tear arthropathy were not significantly different between the two groups. PMID- 22822568 TI - Thermal capsulorrhaphy in internal shoulder impingement: a 7-year follow-up study. AB - This study aimed to evaluate the long-term results of arthroscopic thermal shrinkage of the anterior capsule in athletes with internal shoulder impingement. In recent years, opinion with regards to the aetiology of internal shoulder impingement has changed significantly. The traditional treatment of internal impingement consisted of debridement of labral and/or undersurface cuff lesions. The use of concomitant thermal capsulorrhaphy, based on the concept of anteroinferior laxity, has also been advocated with excellent short-term results. In this study we investigated the long-term effects of this technique. Twelve overhead athletes with internal impingement underwent traditional arthroscopic treatment plus thermal capsulorrhaphy for internal impingement. All patients were evaluated 1, 2 and 7 years postoperatively using a questionnaire regarding their sports activity, and the modified Rowe score. At 1, 2 and 7 years postoperatively there was a significant improvement in the modified Rowe score when compared to the preoperative scores. However, follow-up at 7 years showed a significant deterioration of the initial 1 and 2 year results (p < 0.001), with only 25% of the athletes able to perform sports at their preoperative level. CONCLUSION: Excellent short-term results with thermal capsulorrhaphy, in addition to traditional arthroscopic treatment, in patients with internal shoulder impingement were not sustained over time. After 7 years, only 25% of the athletes were able to perform sports at their preoperative level. PMID- 22822569 TI - Distal radius volar locking plates: does a variable angle locking system confer a clinical advantage? AB - This retrospective study compared clinical, radiological and subjective outcomes between patients with a distal radius fracture fixed with a variable angle or fixed angle volar locking plate. Radiological parameters were assessed between initial and final post-operative films. Post-operative clinical range of motion as a proportion of that in the opposite wrist was assessed clinically, and satisfaction and subjective outcomes were assessed by questionnaire. One hundred and seven patients were included in the study; 65 underwent fixation with a variable angle and 42 with a fixed angle locking plate. There were five complications and secondary operations in each group. There was no significant difference between the groups in radiological parameters measured or the proportional range of motion. Visual analogue scale, Mayo Wrist and Quick DASH scores were not significantly different between the groups. Neither the subjective nor clinical outcomes of this study demonstrated clinical superiority of either plate system. PMID- 22822570 TI - Ulna-shortening osteotomy: subjective appreciation and long-term functional outcome. AB - Ulna-shortening osteotomy is a therapeutic option for ulnar impaction syndrome. We aimed to assess the long-term subjective and functional outcome after ulna shorteming osteotomy. We conducted a retrospective study of 18 patients presenting with ulnar impaction syndrome of various aetiologies, with an average follow-up of 5.9 +/- 3.4 years. Seventeen patients (94.4%) were satisfied and would undergo the operation again. Although most patients reported residual complaints (833%) such as weakness (38%) or pain under given specific circumstances, objective measurements of wrist function were good. The average Mayo Wrist Score was 75.9 +/- 13.4 (n=16) and the average DASH score was 18.0 +/- 13 (n=12). Comparison of the operated and healthy limb did not show any significant difference in strength or range of motion, except for significantly reduced flexion on the operated side (p < 0.05). In this study, ulna-shortening osteotomy provided a good functional outcome and high subjective satisfaction over the long term. PMID- 22822571 TI - Ulnar shortening or arthroscopic wafer resection for ulnar impaction syndrome. AB - The outcome of ulnar shortenings was compared to the outcome after arthroscopic wafer resections for ulnar impaction (or abutment) syndrome in patients with a positive ulnar variance. Both surgical techniques are described. The outcome was measured by the DASH score, the visual analogue score for pain and the working incapacity. The mean DASH score in the ulnar shortening group was 26, in the wafer group it was 36. The VAS were respectively 4.4 and 4.6. The working incapacity was 7 months in the ulnar shortening group and 6.1 months in the wafer group. The differences between the two groups were not statistically significant. PMID- 22822572 TI - Range of motion in femoroacetabular impingement. AB - Recent epidemiological studies have demonstrated that radiographic features specific to femoroacetabular impingement appear far more frequently in healthy and asymptomatic cohorts than previously anticipated. It remains unclear how incidental findings should be interpreted clinically. In addition, several authors have suggested that a decreased range of motion is part of the clinical presentation of femoroacetabular impingement. The purpose of the present study was to describe and analyze differences in range of motion between femoroacetabular impingement patients, asymptomatic individuals with incidental radiographic findings and healthy controls, using a validated electromagnetic tracking system. Furthermore, it was evaluated which motions were clinically relevant and could be used to differentiate between these three groups. We found all evaluated motions to differ significantly between patients and controls. The anterior impingement test showed a significant difference between patients and asymptomatic cases. In conclusion, functional evaluation of the range of motion appeared in this study as a useful tool in the diagnostic work-up of femoracetabular impingement. PMID- 22822573 TI - Total hip arthroplasty after ipsilateral intra-articular steroid injection: 8 years follow up. AB - The purpose of the study was to assess the safety of Intra-articular steroid hip injections (IASHI), prior to ipsilateral total hip arthroplasty (THA). We investigated whether there was an excess of infection in such a group 7-10 years after total hip arthroplasty. A database of 49 patients who had undergone IASHI followed by ipsilateral THA was reviewed. The mean length of time between injection and arthroplasty was 12.1 months (5.1-19 months). We found 7 major complications. Ten patients died with no further hip surgery at a mean of 28 months from surgery ; 3 were lost to follow-up. The remaining group (36) were contacted by telephone at a mean of 97.8 (85-117) months from their surgery. No objective signs of joint infection were found. We believe our results show that ipsilateral steroid injection does not confer an increased risk of complications following subsequent THA, over an extended follow up. PMID- 22822574 TI - Advancement of the vastus lateralis muscle for irreparable hip abductor tears: clinical and morphological results. AB - Outcome after advancement of the vastus lateralis muscle for irreparable disruption of the hip abductor mechanism was evaluated in 9 patients. Seven to 10 cm defects were bridged without complications. After a mean follow-up of 33 months (range: 12-60 months), the majority of patients reported a 69% satisfaction and a reduction of both pain medication and gait assists. Six out of 9 patients would undergo the same treatment again and one was undecided. On physical examination hip function was significantly improved but still poor. A significant loss of quadriceps muscle strength was the only donor site morbidity encountered. Overall, very modest but relevant improvement of hip function can be achieved with this procedure without relevant donor site morbidity and complications. PMID- 22822575 TI - Digital templating facilitates accurate leg length correction in total hip arthroplasty. AB - Digital templating of pre-operative radiographs is increasingly utilised by surgeons before total hip arthroplasty (THA) as part of an adequate preoperative preparation to minimise complications. Templating can accurately predict the required implant sizes but its use in facilitating correction of leg length discrepancy (LLD) has been underreported in the literature. We performed a retrospective analysis of a cohort of consecutive patients undergoing primary THA. A comparison was made of the implant sizes templated with actual sizes used. In addition, pre-operative leg-length discrepancy (LLD) was noted and compared with intra-operative measurement of LLD correction and post-operative LLD correction seen on postoperative radiographs, as measured by two independent observers. Statistical analysis was performed to investigate the correlation between pre- and postoperative measurements. Fifty nine patients that had primary THA were investigated, 42 with hybrid replacements, 17 with cemented replacements. Spearman's-rho 2-tailed correlation between templated and implanted femoral offset, stem size and acetabular cup size was 0.850, 0.709 and 0.834 respectively (p < 0.01 for all). Correlation between the pre-operative templated LLD and the measured post-operative corrected LLD was 0.841 (p < 0.01). No difference existed between hybrid and cemented hips or the presence or absence of a contralateral hip replacement. In this study, templating for THA was significantly accurate in predicting the required femoral and acetabular implant sizes. In addition, the correction of pre-operative LLD was accurately performed, as evidenced by measurement on post-operative films. The results of this study support the pre-operative digital templating of radiographs in total hip arthroplasty. PMID- 22822576 TI - Radiographic analysis of a bone plug in 275 primary cemented total hip arthroplasties. AB - Various designs of cement restrictors for total hip arthroplasty have shown a variability in resistance to intramedullary pressure and migration. The performance of a conical bone plug was studied in 275 cemented total hip arthroplasties with a followup between 5 and 19 years. In a radiographic analysis the relation between the plug position and the cement mantle quality was investigated. The results were compared to the performance of other cement restrictors as reported in the literature. Good to excellent cement mantles were observed in 80% of the femurs. A significant correlation between the stability of the plug and the quality of the cement mantle was found. Forty-nine percent of the plugs were within 1 to 3 centimetres of the Exeter stem hollow centraliser. We also demonstrated that bone plugs performed almost always better than polyethylene or gelatine restrictors reported in other studies. PMID- 22822577 TI - Early complications after revision total hip arthroplasty with cemented dual mobility socket and reinforcement ring. AB - Encouraged by the success of dual-mobility sockets in achieving implant stability in primary hip replacement, surgeons have started to use the implant in revision hip arthroplasty. However, very little is known yet about the postoperative complication rate of this type of implant when fixation in a reinforcement ring is required. In our department, 37 dual-mobility sockets were cemented in a reinforcement ring for revision hip arthroplasty in 36 patients over a period of two years. The mean follow-up period was 16 months (range, 6-27 months). Indications for revision hip arthroplasty included, among others, recurrent dislocation (3 cases) and implant loosening (9 cases) with extensive bone loss. We observed two single re-dislocations (5.40%), one infection and one mechanical failure of the reinforcement ring; the literature mentions dislocation rates of 2.7 to 10.6% after revisions not specifically for recurrent dislocation. Revision hip arthoplasty combining dual-mobility sockets with reinforcement ring fixation thus had a relatively low early postoperative complication rate in this challenging group of patients. The design therefore seems to be a valid alternative to constrained implants, especially in high-risk revision cases. Despite the short follow-up period, cemented dual-mobility sockets seem to be a valuable option when reinforcement rings need to be used, with an acceptable dislocation rate in this challenging group of patients. But long-term survival studies are mandatory to evaluate stability and fixation longevity. PMID- 22822578 TI - Basal medial opening wedge first metatarsal osteotomy stabilized with a low profile wedge plate. AB - Twenty patients underwent 25 basal medial opening wedge osteotomies of the first metatarsal stabilized using a low-profile wedge plate in combination with a distal soft tissue release, distal metatarsal osteotomy and Akin osteotomy as required for correction of a hallux valgus deformity. The mean clinical and radiographic follow-up was 12.2 months. Pre- and post operative radiographs available in 15 cases showed that the median hallux valgus angle (HVA), intermetatarsal angle (IMA) and distal metatarsal articular angle (DMAA) were corrected from 45.5 to 13.1, 17.7 to 9.2 and 243 to 10.0 degrees respectively (p < 0.001). Final radiographic assessment for the whole series showed a median final HVA and IMA of 14.1 and 9.1 respectively. Radiographic union was noted in all but one case which was asymptomatic. One wound infection was treated with oral antibiotics, one hallux varus deformity required soft tissue reconstruction and there was one recurrence. The outcome was reported as good or satisfactory by the patients for 20 of 25 feet. Three patients reported stiffness in the first MTP joint, which improved with joint injection and manipulation. Two plates were removed for prominence. The basal medial opening wedge osteotomy stabilized with a low profile wedge plate was an effective addition for correcting a moderate to severe hallux valgus deformity as part of a double or triple first ray osteotomy. PMID- 22822579 TI - Quality of life and radiological outcome after cervical cage fusion and cervical disc arthroplasty. AB - In this retrospective comparative study, 42 patients with single-level cervical radiculopathy were operated upon, either with Shell cage fusion (23 patients) or with Prestige cervical disc arthroplasty (19 patients). The mean follow-up (FU) was 17.5 months (range: 5.6-42.1 months). Both treatments significantly improved all clinical parameters (VAS, ODI, SF36) (p < 0.001), without statistically relevant differences between the two groups. From a radiological viewpoint there was an obvious but statistically non-significant increase in the segmental height for both treatment groups. Segmental angle also increased in both groups, and the increase was significant (p < 0.05). As expected, range of motion (ROM) decreased significantly (p < 0.05) in the fusion group, while it was preserved in the arthroplasty group. Significantly more (p < 0.05) adjacent level degeneration class 1 to 4 was evident in the fusion group (8/23 or 34.8%) than in the arthroplasty group (3/19 or 15.8%). Two fusion patients (2/23 or 8.7%) developed painful clinical adjacent level disease requiring arthroplasty. The major conclusion was that significant adjacent level degenerative changes occurred in the cage group. Retained motion at the operative site seems to decrease the incidence of adjacent level degeneration. Implant subsidence was recorded at FU in 8 out of 42 patients (19%). It occurred significantly (p < 0.05) more often in the fusion group (6/23 or 26.1%) than in the arthroplasty group (2/19 or 10.5%), but it did not cause clinical symptoms. As in other studies, there is no explanation as to why better radiological results did not translate into better clinical outcomes within the time limits of the study. PMID- 22822580 TI - Percutaneous minimally invasive instrumentation for traumatic thoracic and lumbar fractures: a prospective analysis. AB - Open posterior instrumentation is still the standard procedure for unstable traumatic thoracic and lumbar fractures. There is a general tendency towards minimally invasive approaches in various surgical disciplines. The Sextant II Rod Insertion system is one of these. The authors prospectively studied this system in 51 patients with thoracic and lumbar fractures, between October 2007 and January 2011. Most fractures (31/51) were situated at the lumbar level. In 7 older patients the technique was combined with kyphoplasty and/or cement augmentation of the pedicle screws. The median operative time was 61 minutes (range: 26-130). The median fluoroscopy time was 132 seconds (range: 24-414). Most pedicle screws were correctly placed: 197 out of 204 screws. All fractures showed bony union after 6 weeks, but the multiaxial pedicle screws were not able to conserve the slight correction obtained peroperatively via positioning and longitudinal traction. Percutaneous minimally invasive stabilization of the spine needs further improvement. PMID- 22822581 TI - The role of surgery for haematologic neoplasms of bone. AB - We report on 205 patients with haematologic neoplasms of bone treated from 1985 to 2009. There were 77 patients with primary bone lymphoma, 77 with myeloma and 51 with plasmacytoma. All patients had medical treatments; 43 patients had wide and 162 intralesional surgery. Mean follow-up was 5 years (median, 3.5 years); 11 patients were lost to followup. At the latest examination, 99 patients were alive without disease, 20 were alive with disease and 75 were dead of disease; 13 patients (6.7%) had local recurrence; 12 patients (24%) with plasmacytoma developed myeloma. Survival to death was significantly higher after wide resection for lymphoma and plasmacytoma, but not for myeloma. Survival to local recurrence was not statistically different between wide and intralesional surgery for any haematologic neoplasm. Surgical complications including aseptic loosening, infection, neurological deficits and breakage of implants occurred in 21 patients (11%). PMID- 22822582 TI - Iliosacral fixation after type-1 hemipelvectomy: a novel technique. AB - Involvement of the iliac bone and a sacroiliac joint with malignant tumours is not uncommon; treatment is difficult due to the anatomy of the pelvis. Resection of the tumour mass must be extensive in order to achieve safe margins, but this may lead to instability and poor results. We present a new technique for reconstruction after resection of the iliac bone and sacroiliac joint including a sacral ala, and we present two illustrative cases, with 2 years follow-up. Following en bloc resection of a chondrosarcoma in the iliac bone, two or three polyaxial pedicle screws were placed transversly into the sacrum. Two polyaxial pedicle screws were also inserted into the remaining pubic and ischial bone respectively. After completion of the construct with rods, a cortical strut graft from the ipsilateral fibula was placed between the rods. Next a split mesh was placed around the implants and was filled with 60 cc bone chips allografts. Both patients were mobilized with crutches and partial weight bearing for 4 weeks and then full-weight bearing. After two years follow-up, they were ambulatory without external support and their radiological results remained satisfactory. This technique for reconstruction after type I pelvic resection is advantageous in that it saves mobile lumbar segments. PMID- 22822583 TI - A safe and effective method of acquiring morcelised cancellous bone graft from frozen femoral head allograft. PMID- 22822584 TI - Anatomical reconstruction of the medial collateral ligament and the posterior oblique ligament of the knee. AB - Chronic medial knee instability is frequently due to a combination of superficial medial collateral ligament (sMCL) and posterior oblique ligament (POL) insufficiency. We present a new technique for simultaneous anatomical reconstruction of sMCL and POL, using an anterior tibialis tendon allograft with three reconstruction tunnels. PMID- 22822585 TI - Pediatric odontoid fracture causing Brown-Sequard syndrome: a case report. AB - An odontoid fracture leading to Brown-Sequard syndrome (BSS) is an uncommon condition with only seven cases reported to date. To our knowledge, there are no reports of occurrence in paediatric patients. We report a paediatric odontoid fracture leading to Brown-Sequard syndrome (BSS) with satisfactory recovery following surgical treatment. Odontoid fractures may lead to Brown-Sequard syndrome in cases of high-energy trauma in paediatric patients. Direct anterior screw fixation may be a treatment of choice in paediatric odontoid fractures of the comminuted, displaced type when occurring in conjunction with neurologic injuries. PMID- 22822586 TI - Acute traumatic spinal injury following bicycle accidents: a report of three cases. AB - Although the vast majority of injuries suffered while cycling are minor, acute spinal injuries have been reported. We describe three cases of acute spinal injury occurring while cycling. All three patients reported being thrown over the handlebars, while travelling downhill at speed. Two of the cases resulted in profound neurological deficit. These cases show that there is a spectrum of spinal injury due to bicycle accidents, ranging from no neurological deficit to profound insult, and from high cervical injury to mid-thoracic spinal injury. In cases of bicycle accidents, increased awareness of the possibility of such spinal injury is advisable. PMID- 22822587 TI - Chondroblastoma of the femoral head disrupting the articular cartilage. Description of a novel surgical technique. AB - Chondroblastoma is a rare benign tumour. Involvement of the femoral head may often lead to a delayed diagnosis. We present the case of a 15-year-old patient with right hip pain which was first attributed to adductor tendinitis. Following aggravation of the symptoms, thorough investigation including a CT-guided biopsy, revealed the diagnosis of chondroblastoma of the femoral head. Removal of the lesion based on the techniques described in literature was not possible, mainly because the articular cartilage was breached. A novel surgical technique was used in order to address the rare location and behaviour of the tumour. This technique offered the patient pain relief and return to his previous every day and sports activities. No recurrence was seen at two years follow-up. PMID- 22822588 TI - Paraganglioma in the cauda equina. A case report. AB - Paraganglioma of the cauda equina is rare, and diagnosis is difficult. A 47-year old woman presented with backache, with a 2-year history of pain radiating in her right lower extremity. Initial neurologic examination revealed mild hypaesthesia in the L4 dermatome on both sides. Spine MRI showed a well-delinated intradural extramedullary mass compressing the spinal cord. It extended from L2 to L4, with anterior compression of the spinal cord which was displaced posteriorly. Clinical and radiological findings suggested an ependymoma. Surgical decompression was performed from L2 to L4 through lumbar laminectomy under microscope. Intraoperatively, the patient experienced unexplained paroxysmal hypertension while manipulating the tumour, which was not relieved by hypotensive medication but resolved immediately after resection of the mass. Postoperatively, the neurologic status improved and the radiating pain was relieved. Histopathologic examination showed cellular perivascular arrangement which looked like 'pseudorosettes'. Taken together, these histologic and radiologic findings suggested a benign myxopapillary ependymoma. However, immunohistochemical examination showed reactivity with synaptophysin and chromogranin. Finally, histological examination of the specimen revealed a 'Zellballen' pattern of paraganglioma, and the final diagnosis of paraganglioma with secreting function was confirmed. Paraganglioma is a rare tumour that can exhibit a secreting function causing paroxysmal hypertension which may be life threatening. Therefore, the differential diagnosis is important. The diagnosis is based on close examination of the clinical, radiologic and pathologic findings. PMID- 22822589 TI - Compare and contrast. PMID- 22822590 TI - Ipilimumab. Immunostimulant; more assessment needed. AB - In patients with inoperable or metastatic melanoma, first-line cytotoxic drugs have no proven impact on survival, which is generally limited to only a few months. There is no standard second-line treatment. Ipilimumab, a monoclonal antibody, stimulates T lymphocyte proliferation and activation. It has been authorised in the European Union for melanoma patients in whom one or more lines of chemotherapy have failed. Clinical evaluation is based on a double-blind randomised trial in 676 patients comparing ipilimumab + gp 100, ipilimumab + placebo, and 100 gp + placebo. Gp 100 is an experimental mixture of proteins being tested in melanoma. The median overall survival time was significantly longer among patients treated with ipilimumab, with or without gp 100 (about 10 months), than among those receiving gp 100 + placebo (about 6 months). In another trial, involving previously untreated melanoma patients, adding ipilimumab (at a dose 3 times higher than in the previous trial) to dacarbazine prolonged median overall survival by 2 months. The main adverse effects of ipilimumab are immune related adverse reactions, and include gastrointestinal, cutaneous and endocrine disorders (enterocolitis with or without perforation, dermatitis, hypopituitarism and hepatitis). In practice, in patients with metastatic melanoma in whom one or more treatments have failed, the use of ipilimumab should be restricted to well designed clinical trials designed to better assess the survival benefit, serious adverse effects, and the optimal dosage. PMID- 22822592 TI - Drugs for Alzheimer's disease: best avoided. No therapeutic advantage. AB - The French Pharmacoeconomic Committee that assesses the medical benefit of new drugs and provides recommendations about reimbursement has downgraded its rating of the medical benefit (SMR, service mddical rendu) provided by cholinesterase inhibitors and memantine in Alzheimer's disease from "major" to "low". PMID- 22822591 TI - Abiraterone. After prostate cancer treatment failure: 4-month survival advantage. AB - There is no standard treatment for metastatic prostate cancer that progresses despite castration and cytotoxic chemotherapy. Abiraterone inhibits both testicular and extratesticular androgen synthesis. It has been approved in the European Union for use in this situation, in which treatment options are extremely limited. Clinical evaluation is based on a double-blind comparative trial of good methodological quality that included 1195 patients. The median overall survival time was 4 months longer in the group treated with abiraterone + prednisone (or prednisolone) than in the group treated with placebo + prednisone (or prednisolone): 15.8 versus 11.2 months. The addition of prednisone (or prednisolone) reduced but did not eliminate the effects of hyperaldosteronism induced by abiraterone; oedema occurred in 26.7% of patients, arterial hypertension in 8.5%, and hypokalaemia in 17.1%. Moderate hepatotoxicity was reported with abiraterone and needs to be better assessed. Abiraterone was also associated with cardiac arrhythmias (7.2% versus 4.6% with placebo) and heart failure (1% versus 0.3%). Abiraterone is metabolised by cytochrome P450 isoenzyme CYP3A4 and inhibits isoenzyme CYP2D6, resulting in a high potential for drug interactions. Treatment is somewhat inconvenient. Abiraterone must be taken between meals, serum potassium levels must be monitored, and care must be taken to avoid interactions. Overall, the known risks of abiraterone appear to be acceptable in view of its efficacy, but patients must be carefully monitored. Abiraterone is one option to discuss with patients with metastatic prostate cancer after other treatments fail. PMID- 22822593 TI - Gabapentin and pregabalin: abuse and addiction. AB - In Europe, in mid-2011, about 30 cases of dependence, abuse or withdrawal symptoms attributed to pregabalin had been reported to Swedish and French pharmacovigilance centres and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). About 20 cases of gabapentin addiction were published in detail. The most frequently reported disorders were withdrawal symptoms. More than half of the patients were hospitalised for withdrawal. Cases of excessive increases in the doses of gabapentin or pregabalin, unauthorised routes of administration, and combination with other substances were also reported. Some patients had no known history of substance abuse. In practice, it is better to avoid exposing patients to these risks when the expected benefits are not properly documented. Healthcare professionals should take care to prevent and detect addiction to pregabalin or gabapentin. When necessary, assistance with tapering off the medication should be offered. PMID- 22822594 TI - HPV vaccines and pregnancy: the situation in early 2012. AB - Vaccines against human papillomavirus (HPV) types 6/11/16/18 (Gardasil) and 16/18 (Cervarix) are non-viable vaccines composed of recombinant HPV proteins. As a precaution, they should not be given during pregnancy. However, some women are vaccinated shortly before conceiving or early during an undiagnosed pregnancy. What are the risks for the unborn child exposed in utero to these vaccines? We examined data available in late 2011. After in utero exposure to the HPV 6/11/16/18 vaccine during the first trimester, animal studies, only conducted in rats, showed no increase in the risk of malformations. Five clinical trials and the latest annual update of the Pregnancy Registry for Gardasil, released in 2010 and including more than 1000 vaccinated pregnant women, showed no particular pattern of malformations with the quadrivalent vaccine. A few reports of very rare abnormalities are troubling, but they do not clearly implicate the vaccine. Most data on the HPV 16/18 vaccine come from two clinical trials comparing this vaccine with hepatitis A vaccine or placebo vaccination. Fewer than 400 pregnancies exposed to the HPV 16/18 vaccine have been studied. The rate of congenital malformations was similar to that in the control population. In practice, there are few data on exposure to HPV vaccines during the first trimester of pregnancy. There are more, relatively reassuring, data on the HPV 6/11/16/18 vaccine. Women who are vaccinated just before conceiving or early in pregnancy should receive appropriate information. Active pharmacovigilance must continue. PMID- 22822595 TI - Treatment of non-localised, non-metastatic rectal cancer. AB - The standard treatment for rectal cancer is surgical removal of the rectum and mesorectum. Is the prognosis for non-metastatic rectal cancer that extends beyond the bowel wall improved by adding radiotherapy and/or chemotherapy to surgery? To answer this question, we conducted a review of the literature using the standard Prescrire methodology. Randomised trials conducted before optimal surgery was developed showed that, compared with surgery alone, postoperative radiotherapy reduced the risk of local recurrence and possibly increased overall survival. In the only randomised trial in which the mesorectum was systematically removed, preoperative radiotherapy had no impact on overall survival but reduced the risk of local recurrence (5% at 10 years, versus 11% without radiation therapy).This result was statistically significant in patients with lymph node involvement. Radiotherapy for rectal cancer carries a risk of faecal incontinence (about 50% of patients), small bowel occlusion, and secondary cancers (about 1 in 15 patients). In patients who receive neither radiotherapy nor chemotherapy before surgery, postoperative chemotherapy based on fluorouracil or the tegafur + uracil combination increases overall survival by about 5% at 5 years, in absolute numbers, but carries a risk of serious adverse effects, including haematological and gastrointestinal disorders. Eight randomised trials suggest that the beneficial effects of post-operative chemotherapy and radiotherapy persist and are additive. However, the same is true for adverse effects. In four randomised trials, adding chemotherapy to preoperative radiotherapy roughly halved the risk of local recurrence. In three randomised trials, preoperative chemoradiotherapy appeared to be slightly more effective than postoperative chemoradiotherapy in terms of recurrence, and to carry a similar or lower risk of serious adverse effects, without improving overall survival. Preoperative chemoradiotherapy carries a risk of unnecessarily exposing between 8% and 18% of patients to adverse effects, as their tumour is found to be less extensive than initially thought. There is no firm evidence that postoperative chemotherapy is beneficial after preoperative radiotherapy. Preoperative treatments do not prevent removal of the anal sphincter. The probable benefits of adjuvant therapies in surgical patients must be weighed, on a case by case basis, against the potential risk of serious adverse effects and complications. PMID- 22822596 TI - Key opinion leaders: used as a marketing tool by drug companies. AB - In marketing, "key opinion leaders" are used to influence purchasing behaviour through their perceived position of authority. In drug marketing, key opinion leaders are renowned physicians and other healthcare professionals on whom the medical profession rely when forming an opinion on a drug or practice. Pharmaceutical companies use key opinion leaders as marketing tools to promote their drugs or influence the decisions of regulatory agencies and other institutions. Opinion leaders are carefully handled and their management is often outsourced to specialised marketing agencies. PMID- 22822597 TI - Lessons from the other side of the Atlantic. AB - In the United States, bevacizumab was approved for use in combination with paclitaxel for the treatment of metastatic breast cancer on the basis of a single trial showing a beneficial impact on progression-free survival, a surrogate endpoint. The indication in breast cancer was withdrawn in 2011 when a new review of the data showed no increase in overall survival. In the European Union, bevacizumab was approved for use in combination with paclitaxel or docetaxel, again based on an improvement in progression-free survival. Following a review of clinical trials using this same endpoint, the indication for combination with paclitaxel was maintained while the indication for combination with docetaxel was withdrawn in 2011. Furthermore, bevacizumab was approved for use in combination with capecitabine on the basis of progression-free survival data. PMID- 22822598 TI - [The association of oral microbiota and general health]. AB - Mouth is in direct contact with the outside world of the body and therefore abundant microflora sets there already in childhood. Even in a healthy mouth there is a plethora of bacteria, viruses and fungi. Oral microbial diseases usually arise from growth of opportunistic pathogens. Predisposing factors for oral infections are contact with pathogen carriers, impaired immune system, poor oral hygiene, and smoking. In chronic periodontitis tooth attachment is lost as a result of inflammation, and pockets formed between the tooth and gingiva. Chronic periodontitis is associated with an increased risk for cardiovascular diseases, pulmonary infections, and poor glycemic control of diabetes. This may be due to constant release of pathogenic bacteria and proinflammatory cytokines into the bloodstream. PMID- 22822599 TI - [Proctocolectomy and ileoanal anastomosis as a treatment of ulcerative colitis]. AB - Proctocolectomy and ileoanal anastomosis as a treatment of ulcerative colitis Sphincter-saving proctocolectomy, construction of ileal pouch (J pouch) and associated ileoanal anastomosis constitute an established surgical procedure in the treatment of patients having ulcerative colitis. The procedure has been found to improve the condition: the patient is usually relieved of medications and possible associated adverse effects, the cancer risk associated with the disease is minimized and the quality of life will improve. The most common complication is inflammation of the ileal pouch, developing in half of the patients. PMID- 22822600 TI - [Hepatic porphyrias with cutaneous symptoms]. AB - Hepatic porphyrias with cutaneous symptoms Cutaneous symptoms of porphyrias are initiated from a phototoxic reaction caused by sunlight and circulating porphyrins in the vascular walls of the skin. This leads in fragility, blistering and scarring of the skin on light-exposed areas. There are approximately 200 patients having hepatic porphyrias with cutaneous symptoms in Finland. Cutaneous symptoms of variegate porphyria and porphyria cutanea tarda are indistinguishable, but an effective treatment is available only for the latter. Differential diagnosis is important due to acute episodes occurring in variegate porphyria. PMID- 22822601 TI - [Erythropoietic porphyrias]. AB - Erythropoietic, i.e., myelogenous porphyrias include erythropoietic protoporphyria and the very rare congenital protoporphyria and X-linked protoporphyria. Of these, in Finland only erythropoietic protoporphyria has been diagnosed, in which pain and swelling in the skin upon sunlight exposure are the most typical symptoms. A high protoporphyrin level in erythrocytes and a typical peak in the plasma porphyrin spectrum lead to diagnosis. PMID- 22822602 TI - [Initiation and monitoring of contraception]. AB - The majority of those requiring contraception may safely use any available contraceptive method. Each method has, however, its particular contraindications, which should be screened by applying careful anamnesis and focused status, when contraception is being initiated. Gynecologic examination is not a prerequisite for the initiation of hormonal contraception, but measurement and monitoring of blood pressure is important. Testing for sexually transmitted diseases is readily worthwhile. Follow-up visits provide a chance for comprehensive support for a woman or a young person concerning sexual health. PMID- 22822603 TI - [Newborn infants treated with hypothermia therapy]. AB - Perinatal asphyxia may lead to neurologic injury and death of the newborn infant. Hypothermia therapy seems to lower this risk. For the present retrospective study, the patient record data of both the mother and the child were collected for the newborn infants treated with hypothermia therapy in 2007-2010 in Helsinki University Central Hospital. Of the 61 children treated with hypothermia therapy, 12 died. Resuscitation response, severity of hypoxic-ischemic encephalopathy, EEG and MRI findings may provide more information than the baseline condition about the prognosis of infants treated with hypothermia therapy. PMID- 22822604 TI - [Intensive care of a person refusing blood products]. AB - In cases with severe anemia and significant hemorrhages, intensive care of a person refusing blood products is challenging. Owing to ethical aspects associated with conviction, treatment is easily subject to prejudice. Research data on this particular topic are insufficient, thus, treatment decisions are based on case reports. Treatment modalities that can be approved by the patients should be scrutinized as early as possible and individuality taken into consideration. Epoetin, iron and vitamins are readily started. Attempts have to be made to guarantee adequate blood volume, oxygen transport and hemostasis. Mechanical ventilation, high fraction of inspired oxygen and sedation are utilized as supportive treatments, when severe anemia is improving. PMID- 22822605 TI - [Mediastinitis in a patient with eating disorder]. AB - Mediastinitis is a rare but life-threatening disorder. This infection, spreading from outside of the chest to the mediastinum, is most commonly derived from the pharynx or the teeth. In our patient, mediastinitis resulted from an eating disorder. She attempted to control her body weight by vomiting and damaged her pharynx by provoking vomiting. Eating disorder is exceptional as a cause of mediastinitis. This condition should be kept in mind in some common somatic symptoms and findings. An example of these is vomiting induced hypokalemia. PMID- 22822606 TI - [Update on current care guidelines: ovarian cancer]. AB - Ovarian cancer is the most lethal gynaecological cancer. It appears that seemingly ovarian or primary peritoneal carcinomas, in fact, originate from fimbriae. BRCA1/2 mutation carriers are recommended for the removal of ovaries and fimbriae, to reduce the risk of cancer. Treatment of epithelial ovarian cancer is based on the combination of surgery and chemotherapy. The residual tumour volume at the primary operation is the most important predictive factor of survival. The best response at the primary treatment is observed with combination chemotherapy with taxane and platinum. Adding bevacitzumab to first line chemotherapy may improve survival. PMID- 22822607 TI - [The presence of the corpse and semiotic effectiveness in Geoffrey Chaucer and Cain in Mctatio Abel]. AB - This article grapples with the question of the corpse through two particular literary texts. Rather than an elucidation of the physiological principle of the human body by means of dissection, the play Mactatio Abel, written in England in the 15th century, stages the difficulty of the relation to the corpse, via an amplification of the biblical narrative of Abel's murder by Cain. As for Chaucer's work, The Book of the Duchess, it rewrites Ovid's and Machaut's texts featuring the figure of Morpheus in a way that distinguishes between an imitation of the living and its simulacrum in the sense Wolfgang Iser gives this concept. Chaucer's Morpheus, instead of promoting verisimilitude, forbids it. Indeed, he animates a corpse from within instead of simulating an apparition of the deceased. The simulacrum, rather than a mimetic copy of the real, blocks all representational illusion, in order to formulate absence. The readability of the corpse in both works is relational. Both literary texts express the corpse as being always already grounded in a relational and narratorial space. PMID- 22822608 TI - Pioneers in the anti-malaria battle in Greece (1900-1930). AB - The aim of the study is to present the efforts of the Greek physicians to introduce a malaria control and eradication program in Greece. It is based on the proceedings of the Greek Anti-Malaria League and on medicohistorical studies. Due to political, economic and military reasons the Greek State seemed weak to develop a dedicated plan to eradicate malaria. Hence, the Greek Anti-Malaria League in 1905 was founded by a group of eminent citizens who took the initiative to organize a campaign against the disease. Constantinos Savvas, Professor of Hygiene and Microbiology and President of the League, as well as the pediatrician Dr. Ioannis Kardamatis were among the most influential personalities in the Greek society at that time. Due to the massive use of quinine the burden of the disease decreased significantly. But, the national disaster of 1922, however, during the Greek-Turkish War and the wave of one million Greek refugees from Asia Minor to Greece modified the epidemiological map of malaria. The heritage of the epidemiological studies undertaken by the League was the basis for the new campaign undertaken during the 1930s by the Greek State and the Rockefeller Foundation. The new structure of the Sanitary Services, the legacy of the League's experience and the knowledge of the Greek trainees of the Rockefeller Foundation, served as the starting-point for the final eradication of malaria after World War II. PMID- 22822609 TI - [Occult medicine in the 20th century: pharmacotherapy by Demeter Georgievitz Weitzer, known as Surya (1873 - 1949)]. AB - Demeter Georgievitz-Weitzer (1873-1949), called "Surya", Sanskrit for "sun", was an important representative of medical occultism in the first half of the 20th century. He worked as a journal editor and published a 13-volume book series about occult medicine, mainly written by himself. His hypotheses were closely related to the "Lebensreform" movement around 1900. Regarding diagnostics, he relied on astrology, cheiromancy, and clairvoyance, while therapeutics were dominated by diet and spagyric remedies according to Cesare Mattei (1809-1896) and Carl-Friedrich Zimpel (1801-1879). In his later years, he developed his own healing system, initially comprising eight, later only two preparations. Surya remedies were commercially available until the end of the 20th century, PMID- 22822610 TI - "The sixth sense": towards a history of muscular sensation. AB - This paper outlines the history of knowledge about the muscular sense and provides a bibliographic resource for further research. A range of different topics, questions and approaches have interrelated throughout this history, and the discussion clarifies this rather than presenting detailed research in any one area. Part I relates the origin of belief in a muscular sense to empiricist accounts of the contribution of the senses to knowledge from Locke, via the iddologues and other authors, to the second half of the nineteenth century. Analysis paid much attention to touch, first in the context of the theory of vision and then in its own right, which led to naming a distinct muscular sense. From 1800 to the present, there was much debate, the main lines of which this paper introduces, about the nature and function of what turned out to be a complex sense. A number of influential psycho-physiologists, notably Alexander Bain and Herbert Spencer, thought this sense the most primitive and primary of all, the origin of knowledge of world, causation and self as an active subject. Part II relates accounts of the muscular sense to the development of nervous physiology and of psychology. In the decades before 1900, the developing separation of philosophy, psychology and physiology as specialised disciplines divided up questions which earlier writers had discussed under the umbrella heading of muscular sensation. The term'kinaesthesia' came in 1880 and 'proprio ception' in 1906. There was, all the same, a lasting interest in the argument that touch and muscular sensation are intrinsic to the existence of embodied being in the way the other senses are not. In the wider culture--the arts, sport, the psychophysiology of labour and so on--there were many ways in which people expressed appreciation of the importance of what the anatomist Charles Bell had called 'the sixth sense'. PMID- 22822612 TI - Left ventricular and left atrial thrombi in sinus rhythm patients with dilated ischemic cardiomyopathy. AB - INTRODUCTION: Ischemic dilated cardiomyopathy offers a favorable terrain for left ventricular (LV) thrombus formation; however, left artial appendage (LAA) may be an additional source of thrombi in patients with dilated heart. The main objectives of this study were to determine the prevalence of LV and LAA thrombi in patients with chronic ischemic dilated cardiomyopathy in sinus rhythm, as well as to reveal echocardiographic predictors for thrombus formation. METHODS: The study included 57 patients with chronic dilated ischemic cardiomyopathy in sinus rhythm, who were not under oral anticoagulation therapy. Exclusion criteria included patients with: swallowing problems, acute myocardial infarction, idiopathic and/or non-ischemic dilated cardiomyopathy, atrial fibrillation/flatter, severe systolic dysfunction. Transthoracic echocardiography and transesophageal echocardiography were obtained for each patient. RESULTS: Mean patient age was 62 +/- 10.5 years, mean LV end diastolic diameter was 67.2 +/- 5.8 mm, whereas mean LV ejection fraction (EF) was 37.1 +/- 4.3%. LV thrombus was detected in 11 (19.3%) patients; while 23 (40.3%) patients had LAA thrombus. In a multiple regression analysis LV size (p = 0.05) and lack of aspirin therapy (p = 0.02) showed to be independent LV thrombus predictors, whereas lower LV EF (p = 0.02) and larger LAA maximal area (p = 0.004) demonstrated to be independent predictors of LAA thrombus. CONCLUSIONS: We consider that our study sheds light to the high possibility of LAA thrombi formation in addition to LV thrombi in patients with chronic dilated ischemic cardiomyopathy in sinus rhythm. LV size, LV EF, LAA maximal area and lack of aspirin therapy are shown to be independent predictors of left heart chamber thrombi in this patient category. PMID- 22822611 TI - Conflict of interest policies and disclosure requirements among European Society of Cardiology National Cardiovascular Journals. PMID- 22822614 TI - Monitoring and treatment of acute gastrointestinal bleeding. AB - Acute gastrointestinal bleeding-massive acute bleeding from gastrointestinal section is one of the most frequent forms of acute abdomen. The mortality degree in emergency surgery is about 10%. It's very difficult to identify the place of bleeding and etiology. PURPOSE: The important purpose of this research is to present the cases of acute gastrointestinal bleeding from the patients which were monitored and treated at The University Clinical Center of Kosova-Emergency Center in Pristina. MATERIAL AND METHODS: These inquests included 137 patients with acute gastrointestinal bleeding who were treated in emergency center of The University Clinical Center in Pristina for the period from January 2005 until December 2006. RESULTS AND DISCUSSION: From 137 patients with acute gastrointestinal bleeding 41% or 29% was female and 96% or 70.1% male. Following the sex we gained a high significant difference of statistics (p < 0.01). The gastrointestinal bleeding was two times more frequent in male than in female. Also in the age-group we had a high significant difference of statistics (p < 0.01) 63.5% of patients were over 55 years old. The mean age of patients with an acute gastrointestinal bleeding was 58.4 years SD 15.8 age. The mean age for female patients was 56.4 age SD 18.5 age. The patients with arterial systolic pressure under 100 mmHg have been classified as patients with hypovolemic shock. They participate with 17.5% in all prevalence of acute gastrointestinal bleeding. From the number of prevalence 2 {1.5%} patients have been diagnosed with peptic ulcer, 1 {0.7%} as gastric perforation and 1 {0.7%} with intestine ischemia. Abdominal Surgery and Intensive Care 2 or 1.5% died, 1 at intensive care unit and 1 at nephrology. CONCLUSION: As we know the severe condition of the patients with gastrointestinal bleeding and etiology it is very difficult to establish, we need to improve for the better conditions in our emergency center for treatment and initiation base of clinic criteria. PMID- 22822613 TI - Correlation of CRP and serum level of fibrinogen with severity of disease in chronic obstructive pulmonary disease patients. AB - BACKGROUND AND OBJECTIVES: Data of a previously published study have shown that chronic obstructive pulmonary disease (COPD) patients have increased serum levels of CRP and fibrinogen. The aim of this work is to investigate if there was any correlation between inflammation factors and severity of COPD. DESIGN AND SETTINGS: A case control study conducted on 43 COPD patients and 40 healthy controls. PATIENTS AND METHODS: COPD were selected according to GOLD criteria. Exclusion criteria were acute exacerbation of disease in the past 4 weeks, usage of oral corticosteroids and presence of any comorbidity which could raise level of inflammatory proteins. Control group were healthy individuals. Serum levels of CRP and fibrinogen were measured. RESULTS: The mean serum level of CRP in COPD patients was significantly higher than that of controls (p = 0.03). No significant difference was found in the mean serum level of fibrinogen between cases and controls. Also, there were no significant correlation between the serum level of CRP or fibrinogen and severity of the disease and arterial 02 saturation. CONCLUSION: According to our study results, COPD, per se, can increase serum CRP level. Attenuation of systemic inflammation may offer new perspectives in the management of COPD and its comorbidities. PMID- 22822615 TI - Recovery of liver function after surgical procedure of penetrative and nonpenetrative liver injury. AB - AIMS: Determination of degree of liver function damadge after nonpentrative and penetrative injury as well as degree of postoperative recovery of liver function after surgical procedure of penetrative and non-penetrative injury. METHODS: 60 patients were analised by retrospective-prospective study after surgery performed on University-Clinical Centre Tuzla in period from March 2008 to June 2011, out of which 30 of them were surgicaly treated for non-penetrative and 30 for penetrative liver injury. All patients were determined for values of total billirubine, direct billirubine, albumins, aspartat aminotransferasis (AST), alanin aminotransferasis (ALT) in preoperative period and in two weeks of postoperative recovery. In statistical data processing T-test of independent variables was used along with methods of descriptive statistical analysis. the difference on level p < 0,05 is statisticaly significant. RESULTS: Significant difference of values in direct billirubine, total proteins, albumins, AST, ALT was found by analysis of paremeters in liver function in preoperative period and among values in total and direct billirubine, total proterins, albumins, AST, ALT on 7th and 15th postoperative day among tested groups. CONCLUSION: Liver function damaged is larger after non-pentrative liver trauma in comparing to penetrative one. Liver function recovery is longer after surgical procedure of penetrative liver injury in comparing to non-pentrative liver injury. PMID- 22822616 TI - The results of treatment of basoceltular carcinomas of the head skin. AB - INTRODUCTION: Basocellular skin carcinoma (BCC) is the most common cancer in the human population. BCC almost appeared at adult's people, but it can be found at children, too. THE AIM: The aim of this study was to determine which the position of BCC on the head skin is the most difficult for the treatment and what the reasons are for it. METHODS: With the prospective study, from June 2004 to June 2011, were compared the results of treatment of basocellular carcinomas (BCC) of the head skin. The examinees were divided into 3 groups. The first group, the group A (38 patients) was consisted of examinees treated of BCC on the nose. In the second group, the group B (42 patients) was classified of examinees treated of BCC on the face, temple, eyelids and forehead, while the third group, group C (35 patients) was classified of examinees treated of BCC on the scalp. The parameters for comparison the results of treatment were the method of treatment, number of the relapse, elapsed time from surgery to relapse and consequently defacement. RESULTS: There was found a statistical significant difference in terms of choice of methods of operative treatment for the significantly higher number of operations on the scalp operated with cutaneous transplants. It was confirmed that the localization of the tumors on the scalp, and then on the nose are with the highest incidence of the relapse, whereas the postoperative defacement is mostly on the scalp after skin graft placement. Key PMID- 22822617 TI - Efficacy and safety of tamsulosin in the treatment of benign prostatic hyperplasia. AB - INTRODUCTION/OBJECTIVE: The alpha-adrenergic receptor antagonists represent the most frequently prescribed first line treatment for benign prostatic hyperplasia. Tamsulosin is a uroselective alpha1A/alpha1D adrenergic receptor antagonist. The objective of this study is to establish the efficacy and safety of a daily dose of tamsulosin 0.4 mg in patients with functional symptoms of benign prostatic hyperplasia through an evaluation of reduction of subjective symptoms, quantified through the International Prostate Symptom Score. MATERIALS AND METHODS: 45 patients with lower urinary tract symptoms caused by benign prostatic hyperplasia used tamsulosin 0.4 mg over the course of 12 weeks; their International Prostate Symptom Score (IPSS) value was > or =8 points, while their Quality of Life Index (QLI) value was > or =3 points. Checkups were scheduled 4 and 12 weeks following the initiation of treatment, during which the values for IPSS and disease specific quality of life (QLI) were obtained. RESULTS: At the beginning of tamsulosin treatment, the total IPSS was 24.95 points. After the 4- and 12-week checkups, the total IPSS fell to 16.09 and 11.20 points, respectively. The reduction in symptoms, quantified through IPSS, was 35.51% after 4 weeks of treatment, and 55.11% after 12 weeks. The Quality of Life Index was initially 4.49 points, it decreased to 2.49 points after 4 weeks, and to 1.40 points after 12 weeks, marking an improvement of 44.54% after 4 weeks and 68.82% after 12 weeks. There was a statistically significant difference between the initial values for IPSS and QLI and their values after both checkups (p < 0.05). Side effects were observed in three patients (6.66%), with one (2.22%) experiencing problems with ejaculation and the other two (4.44%) having vasodilatatory effects such as vertigo and headache. CONCLUSION: Clinical response to a 12-week tamsulosin treatment improved during the course of treatment, reflected in a reduction in all of the lower urinary tract symptoms, with rare and insignificant side effects. PMID- 22822618 TI - Correlation between parathormone and sexual hormones in patients on haemodialysis. AB - INTRODUCTION: Chronic renal failure is associated with endocrine abnormalities, which in some cases cause polyendocrinopathy responsible for the symptoms and complications. The consequence of secondary hyperparathyroidism is not only bone disease but may be cardiovascular disorders, peripheral nerve damage and impact on the level of sex hormones. THE AIM: To evaluate the interactions between parathyroid hormone and sexual hormones and the effect of elevated levels of parathyroid hormone secretion on various sexual hormones. The study included 72 patients who were undergoing chronic hemodialysis program 3 times a week at the clinic for hemodialysis. Patients were divided into two groups according to parathyroid hormone values and child-bearing age. The study is a retrospective prospective and lasted for 1 year. At the beginning, after 6 months, and at the end of the study were determined the PTH, FSH, LH, progesterone, testosterone, beta-estradiol, prolactin. RESULTS: During the study period followed are the values of sexual hormones and PTH in 72 patients of which 41 men and 31 women. Of these 33.3% (24) men were in the reproductive age, and 23.6% (17) were women in the reproductive age. The mean age of patients was 53.2 +/- 12.16, and the average duration of hemodialysis was 7.57 +/- 4.0. PTH showed a slight tendency to increase 274.45 +/- 220.74 pg/dL at baseline, at the end of study 383 +/- 313.2 also increased during the study was recorded and the values progesterone. Statistically significant effect of PTH showed the FSH p < 0.01 LH p < 0.05 and prolactin p < 0.01. On average, patients who have elevated PTH levels have lower values of FSH and LH, but higher prolactin values. Parathormone also shows the effect on beta estradiol at level p < 0.01, patients with higher PTH values have lower levels of beta estradiol. CONCLUSION: The increase in the number of younger people with terminal renal insufficiency treated by repeated hemodialysis, often have endocrine disorders and elevated PTH. Normalization of PTH levels affects the normalization of sexual hormone levels and improves quality of life of patients on hemodialysis. PMID- 22822619 TI - Correlation of pathohistotogical changes and serology parameters in chronic hepatitis C. AB - INTRODUCTION: Viral Hepatitis C, formerly known as non A-non B hepatitis, as a separate clinical entity described in 1975 is most often reported in patients who received blood transfusions, and also called it post transfusion hepatitis. AIM OF THE STUDY: Goal was to quantify the number of HCV RNA copies by PCR method, histologically determine the stage of fibrosis and degree of necroinflammatory activity in biopsies of liver parenchyma, and compare the histopathological changes with the number of the virus copies. MATERIAL AND METHODS: The study was prospective and involved 50 patients suffering from chronic hepatitis C of viral etiology. All patients underwent liver biopsy and the specimens were patohistologically investigated to determine the stage of fibrosis score, and necroinflammatory activities. In every case was determined the concentration of AST, ALT, bilirubin, CBC, DR, and all underwent percutaneous ultrasonography and gastroscopy. We performed genotyping of viruses and virus quantification of HCV RNA-PCR. RESULTS: The study showed that women were older than men. The stage of fibrosis and degree of necroinflammatory activities were higher in women than men, meaning that older people carry the virus longer, increasing the number of virus copies the disease lasted longer. According to the etiology of infection the patients who were infected by blood transfusions had a higher stage of fibrosis. Score of necroinflammatory activity was significantly dependent on variables AST with p = 0.02 and ALT with p = 0026. CONCLUSION: Our research has shown that the stage of fibrosis was significantly dependent on alanine aminotransferases, duration of infection, number of virus copies and mode of infection. Patients who received blood transfusions, had the longest duration of infection, higher stage of fibrosis and degree necroinflammatory activity. PMID- 22822620 TI - The significance of the influence of aging and infravesical obstruction caused by benign prostatic enlargement on detrusor impairment. AB - OBJECTIVE: to analyze the influence of aging and infravesical obstruction on cystometric characteristics of patients with lower urinary tract symptoms (LUTS) and proven benign prostatic enlargement (BPE). METHODOLOGY: A retrospective analysis was performed of basic characteristics of randomly chosen 213 patients with LUTS caused by BPE and urodynamic findings made in period 2005-2009 at the Urology Department of the Sarajevo University Clinical Center. The patients were divided into groups based on their age (<60 years/46 patients, 60-69 years/95 pat., and >70 years/72 pat.), and the degree of bladder compliance loss (<20 ml/cmH2O-76 patients, 20-40 ml/cmH2O-57 pat., and >40 ml/cmH2O-80 pat.). All patients had International Prostate Symptom Score (IPS-S) completed, prostate volume measured transabdominally, free uroflowmetry, as well as complete urodynamic study (UDS) findings--cystometry and pressure/flow studies (PFS). The PFS data were plotted on L-PURR, URA and ICS nomogram, bladder contractility index (BCI) and obstruction coefficient (OCO) were calculated for each patient. RESULTS: There was no statistically significant difference of IPS-S, prostate volume and postvoid residual urine among the age groups. Qmax (ml/sec.) declines significantly with age (mean 11.9 vs. 10.3 vs. 7.9, ANOVA p < 0.001), along with statistically significant decrease of cystometric capacity (mean 331 ml vs. 293 mi vs. 264 ml, p = 0.001), bladder compliance (BC-ml/cmH2O) (mean 35.3 vs. 31 vs. 26.5, p = 0.013), with increased incidence of detrusor overactivity (DO) (21.7% vs. 32.6% vs. 45.8%, chi2 test for trend p = 0.006), followed by a higher incidence of obstruction (URA > or = 29 cmH2O) (37% patients vs. 61% patients vs. 72.2% patients Chi2 for trend=13.8; p = 0.0002), along with noticeable reduction of BCI (117 vs. 121 vs. 106; p = 0.02). Patients with severe BC damage (<20 ml/cmH2O) showed a difference with respect to the degree of obstruction and age, along with decreased cystometric capacity and higher incidence of DO, while the difference in IPP-S was insignificant. OCO with cut-off point of 1 showed significant difference with regard to age (66.3 vs. 66.6 years, T test, p = 0.015), prostate volume (45 cc vs. 51.8 cc, p = 0.007) and incidence of DO (26% vs. 43.4%, p = 0.02). CONCLUSION: the degree of bladder compliance loss and incidence of obstruction increase with age, as reflected in decreased bladder capacity, decreased urine voided volume and increased incidence of DO, along with noticeably impaired detrusor contractility. PMID- 22822621 TI - Retrocaecal appendix position--findings during the clasic appendectomy. AB - INTRODUCTION: Appendicitis is one of the most common diseases that require urgent surgical intervention. Due to its position, the inflamed appendix can cause many complications in abdominal cavity. Most of these complications are based on the anatomical position of the appendix. According to world literature over 65% of the anatomical positions of appendix is retrocaecal position, followed paracaecal and then the other positions of the appendix in different percentages. GOAL: The main goal of this research is to shown that anatomical retrocaecal position of the appendix can lead to prolonged hospitalization and more often occurrence of appendicitis complications. MATERIAL AND METHODS: The research is based on patients who had appendectomy during 2009 at the Cantonal Hospital Zenica and General Hospital Tesanj. The study included approximately 400 respondents and the method of research was of retrospective, descriptive and analytical type. RESULTS AND DISCUSSION: According to the results of this research we can conclude that in our country is not devoted enough attention to the anatomic position of the appendix and that we are not using enough diagnostic methods such as ultrasound and CT in determining the anatomic position to help determine the course of the disease. CONCLUSIONS: Retrocaecal appendix position according to the obtained data from this study did not cause many complications in classical appendectomy but this can be attributed to insufficient observation of the anatomical position of the appendix. PMID- 22822622 TI - Anterior cervical discectomy, drainage and non-instrumented cortico-cancellous allograft fusion: a treatment option for ventral cervical spinal epidural abscess. AB - INTRODUCTION: Ventral cervical spinal epidural abscess is a very rare clinical condition with a relatively high morbidity and mortality. Due to the paucity of reported cases there is heterogeneity and no clear "gold standard" in the treatment of these patients. OBJECTIVE: The authors report four consecutive patients with ventral cervical spinal epidural abscess treated with anterior cervical discectomy, abscess drainage and original non-instrumented cortico cancellous allograft spinal fusion. METHODS: The authors retrospectively reviewed a series of four patients treated for ventral cervical epidural spinal abscess. All patients were treated with an urgent operation. Anterior cervical discectomy, abscess drainage, and non-instrumented cortico-cancellous allograft spinal fusion followed by cervical immobilization and systemic antibiotic treatment were utilized. RESULTS: The bone fusion occurred within a mean of 3.5 months of follow up. No significant radiologic or clinical evidence of graft subsidence was noted after a minimum of 2.5 years follow-up. All patients resolved infection and were neurologically intact. No complications of treatment were noted. CONCLUSION: Urgent operative treatment with anterior cervical discectomy, abscess drainage and non-instrumented cortico-cancellous allograft spinal fusion, followed by immobilization and the appropriate systemic antibiotic treatment is an effective original modification for the treatment and resolution of ventral cervical epidural spinal abscess. PMID- 22822623 TI - Clinical evaluation of Nigella sativa seeds for the treatment of hyperlipidemia: a randomized, placebo controlled clinical trial. AB - BACKGROUND: Natural products are proved to play a good role as an alternative to synthetic chemicals in many clinical conditions. Hypercholesterolemia is the most important risk factor for atherosclerosis. Previous studies showed that Nigella sativa L. has both antioxidant and lipid lowering potentials. THE AIM OF THIS STUDY: To evaluate the efficacy of the seeds of Nigella sativa on the treatment of hyperlipidemia. METHODS: In this randomized, placebo controlled clinical trial which was conducted in Isfahan city (Iran), 88 subjects aged > or =18 years with a total cholesterol concentration >200 mg/dl were included. According to the patients" profiles number, they were randomized to receive either N. sativa capsules or the matching placebo. Each N sativa capsule contained 500 +/- 10 mg N. sativa crushed seeds, and patients had to take 2 g N. sativa per day for 4 weeks. Fasting baseline laboratory values (fasting blood sugar, total cholesterol, low density lipoprotein, high density lipoprotein and triglyceride) were obtained for all parameters on each subject prior to the start of the study and at the end of 4 weeks. RESULTS: In our study a significant decrease was observed in the concentration of total cholesterol (4.78%), Low density lipoprotein (7.6%) and Triglyceride (16.65%), and this decrease was more significant for TG concentration. N. sativa had not any beneficial effects on Fasting blood sugar and High density lipoprotein. CONCLUSION: According to the results of our present study it seems that N. sativa may have some beneficial therapeutic effects in the treatment of hyperlipidemia. However, further investigations with a larger sample size are necessary. PMID- 22822624 TI - Avoiding parental distress when discussing about SUDEP: the Albanian experience. AB - INTRODUCTION: Pediatric SUDEP (Sudden Unexpected Death in Epilepsy) is an uncommon event, but its unpredictability has rendered the issue very important to be addressed, under all points of view: medical, moral and legal one. The death of a child has been always considered a dramatic event for the Albanian families, and when it overcomes unexpectedly the emotional reactions might even be more exaggerated. DISCUSSION: Debates about truth-telling on the prognosis, or even on the probability of a sudden death related to the main diagnosis (epilepsy) are old and controversial. Risk factors for SUDEP have been formulated and strategies to confront them have been put in place; however medical (pharmacological) compliance seems by large the most important protective factor. CONCLUSION: To our opinion, disclosing the risk of a sudden death to the family on a child suffering from epilepsy is a necessary act; timing and ways of disclosure are details that need to be refined case-by-case, in a situation where a general consensus or guidelines are lacking. A step-by-step approach and a gradual informing are helpful and psychologically acceptable from the parents or other relatives. PMID- 22822625 TI - The secondary composite temporoparietal lobe-modification. AB - Orbital defects after malignant tumor removal represent a major problem for satisfactory reconstruction. Treatment and surgical reconstruction according to the regular surgical protocol improves with each new case contributing to continuous improvement of surgical techniques in order to achieve better reconstruction of the defect. In our modification in 20 patients there was presented a new method of reconstruction of the defect where the orbits included also a part of the muscle (sternocleidomastoid muscle) for better stabilization at the desired position on the immediate ocular prosthesis installation site in order to quickly overcome the postoperative defect after orbital exenteration. Application of modified temporoparietal slice gives good functional and cosmetic results, and is recommended to be used for reconstruction of defects after orbital exenteration. PMID- 22822626 TI - Penile duplication in newborn with multiple anomalies. AB - We present a case of male, premature born child with multiple anomalies. The physical status was dominated by penile duplication, with additional, abortion scrotum in the median line, without palpable content and omphalocele with semi septum of the anus. By ultrasound examination of internal organs, we found a complex congenital heart anomaly, multiple anomalies in abdomen and micro calcifications in the central nervous system. General condition of the child required a prolonged mechanical ventilation and intensive care, so with clinical picture of liver failure at the age of 45 days occurred fetal outcome. PMID- 22822627 TI - Prolonged spasm of the left anterior descending coronary artery. AB - Coronary artery spasm is one of the well-known causes of anginal chest pain. We presented the case of prolonged spasm of the left anterior descending coronary artery which happened during coronary angiography leading to pulse less state and low blood pressure with syncope and appearing of ventricular fibrillation on ECG. During one hour of successful cardiopulmonary resuscitation, the patient had again normal pulse and blood pressure. Coronary angiography performed immediately after DC's showed normal coronary angiogram. After two days the patient left the hospital without brain disorders. PMID- 22822628 TI - An unusual case of hydroa vacciniforme with ocular involvement. AB - Hydroa vacciniforme (HV) is a sporadic, rare and idiopathic chronic photodermatosis characterized by recurrent vesicles and crust formation on a sun exposed skin, typically resulting in vacciniform or varioliform scarring. Herein, we report on a 18-year-old boy who presented with rare ocular involvement in HV. PMID- 22822629 TI - V-type mini sternotomy in aortic valve replacement. AB - As patients and their physicians become more demanding, the desire to make the procedures "minimally invasive" is growing constantly. In short, "minimally invasive" is a code phrase for life saving procedures which in same time disrupt our quality of life the least. Its goals include reducing incision size, decreasing surgical trauma and pain, and improving cosmesits, patient satisfaction, and recovery times. However, the most important goal of minimally invasive aortic valve surgery must be to maintain or improve the efficacy and safety of conventional aortic valve surgery. In this report we would like to present operative technique of minimally invasive aortic valve replacement (MIAVR) we use in our hospital. PMID- 22822630 TI - Childhood obesity: time to act? PMID- 22822631 TI - Continuing challenges in haemodialysis treatment. PMID- 22822632 TI - Childhood obesity--prevalence among 7 and 8 year old primary school students in Kota Kinabalu. PMID- 22822633 TI - In-centre intermittent peritoneal dialysis: a viable interim option to an eventual definitive renal replacement therapy? AB - In-centre intermittent peritoneal dialysis (IPD), a decade-old modality commonly associated with acute (stab) PD, continues to play an undeniably important role of providing "temporary" renal replacement therapy (RRT) in Malaysia. In our center, IPD is commenced after insertion of Tenckhoff catheter by interventional nephrologists as an interim option until a definitive RRT is established. This study aims to describe our experience and evaluate the viability of this modality as a bridging therapy. We retrospectively analyzed 39 IPD patients from January 2007 to December 2009; looking at demographics, cause of end-stage renal disease, duration on the program, length of hospitalization, PD-related infection profile, biochemical parameters and clinical outcomes. We accumulated a total experience of 169 patient-months, the average age of patients was 54.6 +/- 11.6 years, 84.6% of them diabetics. The median duration of a patient in the program was 88 days with accumulated in-hospital stay of 45 days. Eventually 48.7% of the patients secured placement for long-term haemodialysis while 20.5% were converted to CAPD. The mortality rate was 7.7% while the peritonitis rate was at 1 per 18.8 patient months. Our study shows that IPD is a viable interim option with a low infection rate and good clinical outcome. PMID- 22822634 TI - Changes in salivary immunoglobulin A (IgA) following match-play and training among English premiership footballers. AB - Decreased salivary immunoglobulin A (sIgA), a component of mucosal immunity, is associated with intensive physical activity: suggesting that sIgA may be used for the monitoring of mucosal immunity with footballers. We investigated changes in sIgA in elite footballers, in response to training and match-play. There was a decrease in sIgA following training, with a return to pre-training levels after 18 hours of rest. This return to resting levels was not observed following competitive match-play. Overnight rest was sufficient for mucosal IgA recovery following training but not following two successive matches, suggesting that sIgA may be used to monitor training in multi-sprint sports. PMID- 22822635 TI - Clinical profile and aetiology of optic neuritis in Hospital Universiti Sains Malaysia--5 years review. AB - Although few studies concerning optic neuritis (ON) in Asian countries have been reported, there is no report about ON in Malaysia particularly within the Malay population. We aimed to determine the clinical manifestation, visual outcome and aetiology of ON in Malays, and discussed the literature of ON studies in other Asian populations. This was a retrospective study involving 31 consecutive patients (41 eyes) with ON treated at Hospital Universiti Sains Malaysia commencing from July 2005 till January 2010 with a period of follow-up ranging from 18-60 months. The clinical features, laboratory results, possible aetiology, and visual acuity after one year were analysed. Females were the predominant group. The age of the patients ranged between 3-55 years and peaked between 21-30 years old. 67.7% of the patients had unilateral involvement. Pain on ocular movement was observed in 31.7% of the affected eyes. 73.3% of 41 involved eyes showed visual acuity equal 6/60 or worse on presentation. Paracentral scotoma was the most common visual field defect noted. Optic disc papillitis proved more widespread compared to the retrobulbar type of ON. The aetiology was idiopathic in more than 50%, while the risk of multiple sclerosis was extremely low (3.2%) in our series. 66.0% demonstrating visual acuity improved to 6/12 or better at one year after the attack. 16.1% showed evidence of recurrence during follow-up. In conclusion, the clinical profile and aetiology of ON in Malay patients are comparable to other ON studies reported by other Asian countries. PMID- 22822636 TI - Predictors for failure to mature of autogenous arteriovenous fistulae: Alor Setar experience. PMID- 22822637 TI - Iatrogenic ureter injuries: eleven years experience in a tertiary hospital. AB - Iatrogenic ureteric injuries are rare complications of abdomino-pelvic surgery but associated with high morbidity from infection and possible loss of renal function. A successful repair is related to the timing of diagnosis, site of injury and method of repair. This study was a retrospective review of outcomes of iatrogenic ureteric injury and factors contributing to successful operative repair. Twenty consecutive cases referred to the Urology Unit of the UKM Medical Center during an 11-year period from 1998 to 2009 were reviewed. Thirteen patients were diagnosed intraoperatively and underwent immediate repair. Seven patients had delayed diagnosis but also underwent immediate repair. In our series, there was no significant difference in outcome between injuries diagnosed intraoperatively versus injuries with delayed diagnosis. There was significant difference in the outcomes between methods of ureteric repair where ureter reimplantation via psoas hitch or Boari flap yielded better results than primary end-to-end anastomosis Three patients suffered loss of renal function from unsuccessful ureter repair. We conclude that all iatrogenic ureteric injury should be repaired immediately in the absence of overt sepsis. Ureter reimplantation using a Boari flap or psoas hitch is preferred to the end-to-end anastomosis especially when there is delayed diagnosis PMID- 22822638 TI - Outcome of coronary artery bypass grafting in end stage renal disease patients. AB - INTRODUCTION: End stage renal disease (ESRD) patients have a much higher rate of cardiac disease and cardiac mortality as compared with the general population. Revascularisation such as coronary artery bypass grafting (CABG) may also carry a higher rate of complications and morbidity. We compared our ESRD patients who underwent CABG with the general population and ESRD population. METHODS: This is an observational study of ESRD patients who underwent CABG in our centre from 2003-2009 with case-control matching comparison with non-ESRD patients for ICU and hospital stay; and ESRD patients without CABG for survival. Patients with concomitant valvular operation were excluded. The primary outcomes were peri operative complications and survival. RESULTS: Eleven patients with mean age of 57.5 +/- 8.5 were included. All except 1 were diabetics. One patient had excessive haemorrhage requiring immediate re-thoracotomy, and this was complicated with thrombosed AVF. Four patients experienced intradialytic hypotension postoperatively but all resolved within 1 week. Both ESRD and non ESRD patients had equal number of ICU stay (3.1 versus 3.2 days, p = 0.906) and hospital stay (7.6 versus 6.9 days, p = 0.538). With average of 3.3 years follow up (range from 1 to 7 years), 4 deaths were observed but only one from cardiac cause. Both ESRD cohorts with or without CABG have compatible left ventricular mass: 295 +/- 86 vs 343 +/- 113 g (p=0.226) and left ventricular mass: 174 +/- 54 vs. 206 +/- 63 g/m2 (p = 0.157). The outcome of CABG ESRD patients was comparable to matched ESRD patients without CABG with 90.9 % versus 91.9% 1 year survival, 95.5% versus 77.7% 2 year survival, 71.4% versus 70.3% 3 year and 40.0% versus 40.3% at 5 year survival (p = 0.627, 0.386, 0.659 and 0.683 respectively). CONCLUSION: CABG in ESRD patients carries an acceptable perioperative complication rate. They have acceptable ICU and hospitalization duration in comparison to non-ESRD patients. Their long term survival was at least as good as matched ESRD patients without CABG. PMID- 22822639 TI - An early single institutional experience in sutureless total thyroidectomy. PMID- 22822641 TI - Cognitive impairment among the elderly Malays living in rural Malaysia. AB - Cognitive impairment is a common psychiatric problem among the elderly. The objective of the study was to determine the prevalence of cognitive impairment among the elderly Malays living in a rural community in north Malaysia. A cross sectional study was conducted among the elderly population of 22 villages in north Malaysia. Elderly cognitive assessment questionnaire was used to determine the cognition status. Analysis was done using SPSS version 13. The prevalence of cognitive impairment among the older adults in these villages was 11% (n=46). There was an increasing prevalence of cognitive impairment with increasing age (p < 0.05). Being unmarried (OR 2.31), unemployed (OR 2.74) and living alone (OR 2.32) were significantly associated with the risk of being cognitively impairment. Being unemployed (OR 2.29) was a significant predictor variable for cognitive impairment. Similar to other studies conducted in Malaysia the prevalence of cognitive impairment was high. PMID- 22822640 TI - Prevalence of sleep disordered breathing symptoms among Malay school children in a primary school in Malaysia. AB - Sleep disordered breathing (SDB) is increasingly being diagnosed in children. However, there is no prevalence study done in Malaysia. The study objective was to evaluate the prevalence of SDB symptoms based on parental reports and associated risk factors among Malay school children aged 6 to 10 years old in a primary school using a translated University Michigan Paediatric Sleep Questionnaire (Malay UM-PSQ). The children whose parents responded to the questionnaire and consented were examined, documenting height, weight, skin fold thickness, neck and abdominal circumference, tonsillar size, nostril examination and presence of micrognathia or retrognathia. There were 550 respondents. The prevalence of parental report of SDB symptoms was 14.9 % (95 % CI 11.9, 17.9). Two hundred and eighty-five (51.8%) school children were males with mean age of 8.5 years (SD 1.1). The associated risk factors for SDB symptoms are male, obesity, large neck and waist circumference, positive history of asthma, history of recurrent tonsillitis, enlarged tonsil (> 4+) and enlarged nasal turbinate. Multivariate analysis showed that male gender is the only significant independent risk factor of SDB symptoms PMID- 22822642 TI - Clinicians' knowledge, beliefs and acceptance of intravenous-to-oral antibiotic switching, Hospital Pulau Pinang. AB - A cross-sectional study was conducted to explore clincians' baseline knowledge, practice beliefs and acceptance of intravenous (IV)-to-oral antibiotic switching practice in Hospital Pulau Pinang. The factors most highly rated for antibiotic conversion were the ability to maintain oral intake (85.6%) and microbiology etiology (85.0%). Majority of the clinicians (76%) agreed with the traditional clinical rule that "patient should be afebrile for 24 hours before IV-to-oral switch". Specialists and consultants had the highest knowledge score among the clinicians. However, they were generally less positive about a guideline being integrated into practice. PMID- 22822643 TI - Mixed-genotypes infections with hepatitis C virus in hemodialysis subjects. AB - Mixed-genotypes hepatitis C virus (HCV) infections are normally ignored in chronic hemodialysis patients. The aim of this study is to investigate the prevalence of mixed-genotypes infections among hemodialysis patients in Pahang province, Malaysia. Reverse-transcription and polymerase chain reaction methods were performed using two different sets of primers, targeting the 5' untranslated region and nonstructural 5B region. Target region base sequences were obtained by direct sequencing. Discrepancy in outcomes from phylogenetic analysis of both regions suggests double infections. Of 40 subjects in eight hemodialysis centres, evidence of mixed-genotypes infections was found in 5 subjects (12.5%) from three different centres. Four patients were infected with mixed genotypes 3 and 1 and one with genotypes 3 and 4. Cases of mixed HCV genotypes infection were considered high among hemodialysis patients in Pahang. However, further investigation is needed to confirm whether they are true mixed infections or perhaps infection with recombinant virus and also to assess the clinicopathologic characteristics of the infection. PMID- 22822644 TI - Methacholine challenge test as an adjunctive investigative tool in patients with asthma-like symptoms: the Sabah experience. AB - INTRODUCTION: Patients with asthma-like symptoms pose a diagnostic dilemma when physical examination is normal. The usual practice in Malaysia would be to give empirical asthma treatment. Bronchial challenge test (BCT) is widely used in many countries to diagnose asthma objectively but it is not widely available in Malaysia. OBJECTIVE: To describe our experience with BCT using methacholine at Queen Elizabeth Hospital as a supporting tool in the investigation of patients with asthma-like symptoms. METHODOLOGY: Review of case notes of patients who underwent BCT from July 2008 till April 2009. BCT was performed via dosimeter technique. Results were classified as high hyper responsiveness if the provocative dose of methacholine required to achieve 20% fall in FEV1 (PD20) was less than or equal to 0.125 micromol, moderate hyper responsiveness if PD20 was between 0.125 to 1.99 micromol or mild hyper responsiveness if PD20 was between 2.00 to 6.6 micromol. PD20 of more than 6.6 micromol constitutes a negative MCT. RESULTS: 29 patients had BCT during the study period. 19 cases were included in this review. The age ranged from 13 to 70 years old. There were 12 males and 7 females. Duration of symptoms ranged from 2 weeks to 23 years. BCT was positive (mild or moderate hyper responsiveness) in 10 out of 19 patients. No patient had high bronchial hyper responsiveness. CONCLUSIONS: BCT is a useful adjunctive tool in the investigation of patients presenting with asthma-like symptoms. This test obviates empirical asthma treatment. BCT should be made available in all major hospitals in Malaysia. PMID- 22822645 TI - Intramedullary cervical spine germinoma: a case report. AB - Primary intramedullary germinoma arising in the cervical spinal cord is a very rare entity. We present one such case arising in a young man who presented with radiculopathy and myelopathy, which was partially excised. Upon histological confirmation, he was treated successfully with radiotherapy alone. To our knowledge, this is only the second reported case worldwide which is histologically confirmed. Although extremely rare, differential diagnosis for intramedullary spinal cord tumor should include germinoma. PMID- 22822646 TI - Pancreatic metastases from ovarian carcinoma--diagnosis by endoscopic ultrasound guided fine needle aspiration. AB - Pancreatic metastases are very uncommon and originate most commonly from lung, colon, breast and kidney cancer. Ovarian adenocarcinoma has been reported as a primary site of pancreatic metastasis, but its diagnosis has rarely being reported by endoscopic ultrasound guided fine needle aspiration (EUS-FNA). We report a case of multiple metastases to the pancreas from ovarian carcinoma occurring four years after original resection of the primary tumour. Our patient presented with severe epigastric pain which was initially treated as acute pancreatitis. Further imaging modalities showed multiple large pseudocystic lesions in the pancreatic head and body. Subsequent EUS-FNA confirmed that the lesions were metastatic disease from an advanced ovarian carcinoma. She underwent palliative chemotherapy and the pancreatic lesion showed receding size. PMID- 22822647 TI - Superglue accidentally used as ear drops. AB - Superglue in the ear as a foreign body is an uncommon presentation. We report the case of a lady who accidentally instilled superglue directly onto her tympanic membrane and presented five days later. We successfully removed the glue with acetone and managed to preserve the integrity of the tympanic membrane. PMID- 22822648 TI - CNS toxoplasmosis presenting with obstructive hydrocephalus in patients of retroviral disease--a case series. AB - CNS toxoplasmosis presenting as hydrocephalus is a very rare entity. We present three cases of HIV positive patients whose brain imaging revealed hydrocephalus and who improved with anti toxoplasma medication along with intravenous steroids and did not require any CSF shunting procedures. The mechanism of hydrocephalus in CNS toxoplasmosis is usually due to compression of CSF outflow pathway by ring enhancing lesions but even in their absence hydrocephalus can be rarely seen due to ventriculitis. Hence in HIV positive patients with unexplained hydrocephalus CNS toxoplasmosis should be considered and such patients if started on treatment early have a good prognosis without requiring neurosurgical intervention. PMID- 22822649 TI - Cholesterol granuloma in a post-mastoidectomy for cholesteatoma. AB - Cholesterol granuloma is a histological term used to describe the foreign body reaction towards cholesterol crystals causing granuloma. We report a case of cholesterol granuloma in a patient who presented with a mass in her ear after 6 years of mastoidectomy. The diagnosis has been confirmed by MRI and postoperative findings. The difference between cholesterol granuloma and the other entities especially cholesteatoma and meningoencephalic herniation must be made in view of its implications and surgical management of each lesion. PMID- 22822650 TI - A young patient with history of Kawasaki disease presenting with triple vessel disease. AB - Kawasaki disease is primarily a condition that affects young children and it is associated with cardiac morbidity and mortality. This disease has been known to cause coronary artery aneurysms which occurs as a sequelae of vasculitis. The progression of triple vessel disease in adult which results from cardiac complications from Kawasaki disease is rare. We report a case of a young man with history of Kawasaki disease at infancy presenting with triple vessel disease requiring cardiac bypass surgery at the age of 20 years old. PMID- 22822651 TI - Cutaneous side-effects of epidermal growth factor receptor-tyrosine kinase inhibitor (TKI) in the treatment of lung cancer: description and its management. AB - Epidermal growth factor receptor (EGFR)--tyrosine kinase inhibitors (TKI) like erlotinib and gefitinib have been approved as monotherapy for the treatment of patients with locally advanced or metastatic non small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. The use of EGFR-TKI is associated with unique and dramatic dermatologic side effects. We report 2 patients with NSCLC developing a typical acneiform (papulo-pustular) eruption shortly after initiation of EGFR-TKI. PMID- 22822652 TI - Resection and reconstruction of malignant tumor involving sternum. AB - We present a series of four cases of chest wall tumor, which underwent sternum resection. The methods of resection and reconstruction chest wall defect are discussed and the final outcome highlighted. PMID- 22822653 TI - Single stage minimally invasive bilateral video assisted thoracoscopic surgery for simultaneous bilateral primary spontaneous pneumothorax. AB - Simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare life threatening condition that requires rapid diagnosis and treatment. Most cases are secondary to various underlying lung pathology but a primary SBSP may occur due to rupture of subpleural blebs or bullae. Surgery via an open or minimally invasive approach provides definitive treatment and can be undertaken as a staged or simultaneous procedure. We report our experience with two such rare cases utilizing a single stage minimally invasive bilateral video assisted thoracoscopic (VATS) approach. The pathogenesis of this rare condition and intra operative technical considerations for a successful outcome are discussed. PMID- 22822654 TI - Severe diabetic papillopathy mimicking non-arteritic anterior ischemic optic neuropathy (NAION) in a young patient. AB - With the pathophysiology not clearly understood and fewer than 130 cases having been reported in the literature, diabetic papillopathy presents a special challenge to the ophthalmologist. We report a case of a young patient with more than 12 years of type 1 diabetes mellitus (T1DM) on insulin with poor compliance to treatment who presented with sudden bilateral loss of vision. Ocular examination, fluorescence angiography (FA) and systemic signs were conclusive of diabetic papillopathy. His fasting blood sugar level was high and serum glycosylated haemoglobin (HbA1c) indicated a long term fluctuating blood glucose control. His vision initially improved with treatment, but later deteriorated with tight glycemic control. PMID- 22822655 TI - New estimates of CMV seroprevalence in Malaysia. Where do we go from here? PMID- 22822656 TI - Evidence-based medicine, Cochrane reviews and open-access journals. PMID- 22822657 TI - Prevalence of melanocortin receptor 4 (MC4R) V103I gene variant and its association with obesity among the Kampar Health Clinic cohort, Perak, Malaysia. AB - This study investigated the prevalence of the Melanocortin receptor 4 (MC4R) V1031 gene variant and its association with obesity among a cohort of 254 patients (101 males; 118 obese) attending the Kampar Health Clinic. Genotyping revealed the mutated I allele frequency of 0.02, no homozygous mutated (II), and similar distribution of V and I alleles across BMI groups, genders and ethnic groups. No significant difference was found for the means of anthropometric measurements between alleles. Prevalence of this gene variant among the Malaysian cohort was similar with previous populations (2-4% of mutated allele carrier), but was not associated with obesity. PMID- 22822658 TI - Non-invasive investigation of chronic stable angina--a practical overview for medical practitioners. AB - How does one decide on the best non-invasive test to investigate stable coronary ischaemia? This is a very common question faced by many medical practitioners. Chronic stable angina is a common presentation encountered in general practitice. Upon clinical assessment and risk stratification the patient needs to be investigated further to confirm the diagnosis. The first investigational modality involves a non-invasive test. It is important that practitioners possess a practical knowledge of the array of different tests that are available so that the best suited one for each patient can be chosen. This article aims to compare the efficacy and accuracy and the practical utility of the different non-invasive tests for coronary ischaemia and aid the practitioner in making sound decisions in this regard. PMID- 22822659 TI - [Callus induction of Liriope muscari and its dynamic accumulation of polysaccharide]. AB - OBJECTIVE: To study the induction rate of callus tissue in four different explants of stem, root, leaf and fruit of Liriope muscari. METHODS: The effect of 2,4-D, sugar and illumination on callus succeeding preservation was analyzed. The dynamic accumlation of polysaccharide in callus was described. The polysaccharide content among callus, tissue culture seedings and field seedings was compared. RESULTS AND CONCLUSION: The callus induction rate of stem was the highest. The optimal concentration range of 2,4-D was 1.5-2.0 mg/L, then the induction rate was 87.5%. When the 2,4-D conncentration was 0.5-1.0 mg/L, and the sucrose concentration was 20 g/L, the multiplication coefficient was highest. The illumination condition did not influence the effect of callus succeeding preservation. The content of callus polysaccharide continuously increased for 60 d. The growth rate of callus was reached the highest level from 40 d to 60 d. Polysaccharide content in root of tissue culture seeding was higher than that of the field seeding. PMID- 22822660 TI - [Study on the HPLC fingerprint of toad skin from different regions]. AB - OBJECTIVE: To study the HPLC fingerprint of toad skin and provide a reliable method for quality control and identification. METHODS: It used HPLC for detection and computer aided similarity evaluation system for processing and analysing HPLC fingerprint. RESULTS: The common pattern of HPLC fingerprint of toad skin was astablished, 29 peaks were identified as the characteristic fingerprints, in which 9 peaks corresponded to 9 bufogenins. (2) Each samples' similarity of relative retention time was all above 0.99, but the similarity of relative peak areas was low. CONCLUSION: (1) The method is accurate and with good reproducibility. The fingerprints can be used for the identification and quality control of toad skin. (2) The toad skin from different regions are stable in composition, but the contents of the components are different. PMID- 22822661 TI - [Genetic diversity and volatile components of Asarum sieboldii in Qin-ba region]. AB - OBJECTIVE: To analyze the genetic diversity and the volatile components of Asarum sieboldii from seven habitats in Qin-ba region. METHODS: The genetic diversity of the herb was analyzed by ISSR (inter simple sequence repeat) markers; The relative content volatile components of the herb were dectected by head space solid-phase microextraction gas chromatogrphy-mass spectrometry (HS-SPME-GC-MS). The contents of the 3 main components were analyzed by steam distillation gas chromatography-mass spectrometry (GC-MS). RESULTS: 57 bands were amplified from 7 populations by 6 reliable primers, 51 of which were polymorphic (89.47% of the total). The cluster analysis presented that these resources were divided into two main groups. There were differences in the chemical components and the contents of Asarum sieboldii from the 6 wild habitats. Except for some same components, many unique components were identified in them respectively. In addition, some components could be detected only in some populations which had smaller genetic distance. CONCLUSION: Cluster analysis shows no direct correlation between genetic distance and geographic distance of Asarum sieboldii in Qin-ba region. The accumulations of some volatile components of Asarum sieboldii are possibly related to genetic diversity. PMID- 22822662 TI - [The analysis of allozymic variation and genetic diversity in different Prunus mongolica population]. AB - OBJECTIVE: To evaluate the allozymic variation and genetic diversity from four wild population of Prunus mongolica. METHODS: The technique of polyacrylamide gel electrophoresis was used. RESULTS: The percentage of loci polymorphic (P) was 77.78%. The mean number of alleles per locus (A) was 1.7916. The mean observed heterozygosity per locus ( H ) was 0.4009 and the mean expected heterozygosity per locus (He) was 0.4898. The coefficient of gene differentiation (G(ST)) was 0.0693 which explained that 6.93% of the total genetic diversity was distributed within populations. The gene flow (Nm) was 3. 3575, which indicated the gene flow took place among populations. The fixation index (F) was 0.0896 which indicated a slight excess of homozygote within populations and a little insufficiency of heterozygosity. CONCLUSION: Considering the relatively high level of genetic diversity in Prunus mongolica regenerating in the largest population, we recommend in situ conservation to maintain viable Prunus mongolica populations in their original habitats. PMID- 22822663 TI - [Study on HPLC characteristic fingerprint of Yunnan Dipsacus asper]. AB - OBJECTIVE: To study the HPLC fingerprint of yunnan Dipsacus asper and provide a reliable method for sciencetific evaluation and quality control. METHODS: 16 batches of Dipsacus asper were collected from 11 counties (cities, districts) of 5 prefectures or municipals in Yunnan provinice, which were the mainly distribution region of Dipsacus asper. Samples were analyzed on an Aglient Zorbax SB-18 (4.6 mm x 250 mm, 5 microm) eluted with methanol (A) and water (B) as mobile phase in gradient clution. The flow rate was 1 ml/min, and the column temperature was set at 38 degrees C. The detector wavelength was 220 nm. RESULTS: A HPLC fingerprint method was established, 14 common peaks were selected and the similarity ranged from 0.674 to 0.965, cluster analysis could classified these 16 batches of Dipsacus asper into 2 groups. CONCLUSION: Dipsacus japonicus is found for the first time in yunnan. The fingerprint of Dipsacus asper in different origin have a extremely high similarity;The method is accurate and reliable. PMID- 22822664 TI - [Fingerprint analysis of Glehniae Radix by TLC]. AB - OBJECTIVE: To establish TLC fingerprint of Glehniae Radix for the identification and quality control of the drug. METHODS: 10 batches of Glehniae Radix commercial drugs collected from different gathering areas and 3 batches from Laiyang, Shandong were used as qualitative identification samples. Falcarindiol, scopoletin umbelliferone and isoimperatorin were used as the chemical reference substances. Double wavelength TLCS was performed with petroleum and ethyl acetate (4:1) as developer,detection wavelength at 300 nm and reference wavelength at 260 nm. RESULTS: TLC chromatogram of 13 samples had 8 well-resolved characteristic peaks, in which 4 peaks were falcarindiol, umbelliferone, scopoletin and isoimperatorin, respectively. CONCLUSION: The method is accurate and simple, and can be used for the quality control of Glehniae Radix. PMID- 22822665 TI - [Pharmacognosy identification of Embelia parviflora]. AB - OBJECTIVE: To study the morphological character and microscopic identification of Embelia parviflora. METHODS: Researches on the morphological character and microscopic identification of roots and stems of Embelia parviflora were carried on respectively. RESULTS: Significant microscopic characteristics of Embelia parviflora were confirmed. Such as single stone cells scattered in the root cortical, lots of stone cell groups and fiber bundles scattered in the column parts and became ring intermittently. Stem phloem was broad, large scale secretory cells scattered near cambium region and stone cell groups in ray parts. Crystal stone cells of thick and thin could be seen in powder. CONCLUSION: These features can be used as the reference for quality standard of Embelia parviflora. PMID- 22822666 TI - [Chemical constituents of Berchemia lineate]. AB - OBJECTIVE: To investigate the chemical constituents of the roots of Berchemia lineate as a medicinal plant of Yao nationality in China. METHODS: Compounds were isolated by various column chromatography and elucidated by physicochemical and spectral analysis. RESULTS: Nine compounds were isolated from the 95% ethanol extract of the roots of Berchemia lineate and their structures were identified as palmitic acid (1), octadecanoic acid (2), beta-sitosterol (3), stigmasterol (4), fernenol (5), chrysophanol (6), physcion (7), floribundiquinone D (8), 2 acetylphyscion(9) respectively. CONCLUSION: Compounds 1-4,7-9 are isolated from this plant for the first time,and compounds land 2 are firstly isolated from this genus. PMID- 22822667 TI - [Study on the alkaloids constituents from Voacanga africana]. AB - OBJECTIVE: To study the alkaloids of Voacanga africana. METHODS: The alkaloids were isolated by normal phase silica gel and Sephadex LH-20 column chromatography. Their structures were elucidated by analysis of spectroscopic data. RESULTS: Eight alkaloids were isolated and their structures were elucidated as voacangine(1), voacangine hydroxyindolenine(2), 19R-epi-voacristine(3), epi ibogaine(4), vobasine(5), 19-epi-heyneanine(6), vobtusine(7) and voacamine(8). CONCLUSION: Compounds 2-4 and 6 are isolated from this plant for the first time. PMID- 22822668 TI - [Study on chemical constituents of the ethyl acetate extract from Blumea aromatica]. AB - OBJECTIVE: To study the chemical constituents of the ethyl acetate extract from Blumea aromatica. METHODS: Column chromatographic techniques were used for the isolation and purification. Spectroscopic techniques were used for the identification of structures. RESULTS: Seven compounds were isolated from the ethyl acetate extract of 80% alcohol extract of the whole plant, and their structures were identified as xanthoxylin(1), dibutyl phthalate(2), luteolin 3',4',7-trimethyl ether(3), rubiadin(4), eriodictyol(5), kaempherol(6), luteolin 7,3'-dimethyl ether(7). CONCLUSION: All the compounds are isolated from this plant for the first time. Among them, compounds 2,4 and 7 are isolated from this genus for the first time. PMID- 22822669 TI - [Water-soluble chemical constituents in flower buds of Lonicera macranthoides]. AB - OBJECTIVE: To study the water-soluble chemical constituents of the flower buds of Lonicera macranthoides. METHODS: The chemical constituents were isolated and purified by means of chromatographic techniques and their structures were elucidated by spectroscopic methods. RESULTS: Six compounds were isolated and identified as trans-linalool-3,7-oxide-6-O-beta-D-glucopyranoside(1), secol oganoside(2), secoxyloganin(3),chlorogenic acid(4), caffeic acid(5), sucrose(6). CONCLUSION: Compound 1 is isolated from nature as a single compound for the first time, compounds 2-3 are isolated from this plant for the first time. PMID- 22822670 TI - [Analysis on volatile constituents of Semen Ziziphi Spinosae by HS-SPME-GC-MS]. AB - OBJECTIVE: To establish a rapid and simple method for the determination of volatile constituents in Semen Ziziphi Spinosae. METHODS: The volatile constituents in Semen Ziziphi Spinosae were extracted by head space solid-phase microextraction (HS-SPME) and analysed by GC-MS. RESULTS: Powder of sample was pre-heated for 30 min at 90 degrees C, then headspace-extracted with 65 microm PDMS/DVB fiber for 50 min. After desorbed for 5 min at 250 degrees C, the separation was well completed on a Rxi -50 capillary column. 126 kinds of volatile compounds were isolated and 116 compounds were identified. The amounts of compound from the volatile constituents were determined by area normalization method. The main components extracted by HS-SPME were alkane (32.08%), terpenoid and derivatives of oxygenated terpenoid (27.06%). CONCLUSION: The method is simple, fast and accurate, and it is suitable for the determination of the volatile constituents in fruit of Ziziphus jujuba. PMID- 22822671 TI - [Analysis of head volatile constituents of Polyonum cuspidatum flower by HS GC/MS]. AB - OBJECTIVE: To analyze the floral volatiles of Polyonum cuspidatum flower. METHODS: The floral volatiles of P. cuspidaturn flower were investigated by Headspace Sampler GC/MS. RESULTS: 21 compounds were separated and determined from P. cuspidatumrn, which amounted to 99.29% of the total volatiles. 5 compounds including (E)-2-hyexenoic acid methyl ester, 1-phenyl-l-pentanone, (E)-4-hexenoic acid methyl ester, 3-hexenoic acid methyl ester, 2-methyl-6-methylene-1 and 7 octadien-3-one were the main constituents existed in P. cuspidatum flower, which amounted to 63.23% of the total volatiles. Organic ester compounds amounted to 52.09% of the total volatiles. Hexenoic acid methyl ester compounds were most, which amounted to 85.66% of the total organic ester compounds. In addition, the 1 phenyl-1-pentanone and acetophenone were 16.30% and 4.33%, which amounted to 20.63% of the total volatiles. CONCLUSION: The result of this research provides a scientific method for the reasonable exploitation and utilization of P. cuspidatum flower. PMID- 22822672 TI - [Effects of secoisolariciresinol diglucoside combined with bortezomib on induction of apoptosis in lung cancer cell line A549]. AB - OBJECTIVE: To study the influence of Secoisolariciresinol Diglucoside (SDG) combined with Bortezomib on induction of apoptosis in lung cancer cell line A549 and its relative mechanisms. METHODS: The effect on proliferation was evaluated by MTT assay. The cell apoptosis was studied by flow cytometry and Hoechst 33342 staining. Colorimetric method was used to detect the activity of Caspase-3. Real time PCR was used to detect the expression of Caspase-3, BCL-2 and BAX mRNA. Western blot was used to determine the change of p-JNK, BCL-2 and BAX protein expression in A549 cells. RESULTS: The cell growth was significantly slowed down and the cell apoptosis was induced after the combined treatment. Meanwhile the Caspase-3 activity and the expression of Caspase-3 mRNA were obviously increased, the expression of BCL-2 mRNA and protein were significantly down regulated and the expression of BAX. p-JNK mRNA and protein were significantly up regulated after the combined treatment. CONCLUSION: The results demonstrate that SDG combined with Bortezomib can significantly induce apoptosis of A549 cells, its mechanisms may be involved in activation of the JNK pathway. PMID- 22822674 TI - [Time-effect and dose-effect relationships study on the effect of tonifying kidney and activating blood formulas contained serum on MSCs proliferation and osteogenic differentiation]. AB - OBJECTIVE: To screen the optimal cell proliferation and osteogenic differentiation concentration of SD rats' Mesenchymal stem cells (MSCs) affected by compound Bushenhuoxue (CB) contained serum. METHODS: 30 SD female rats, aged 10 months, were randomly divided into low-dose (11.6 g/kg), medium dose (34.8 g/kg) and high dose CB group (104.4 g/kg), 10 rats in each group (qd, 12 d). Rats blood of three groups were taken respectively in 0.5, 1.0, 1.5, 2.0, 3.0 h after the last intragastric infusion, blood serum was separated, and different concentrations of CB contained serum were given to MSCs form SD female rats aged 3 months. MTT method was used to determine the effect of CB on MSCs proliferation. Alkaline phosphatase (ALP) was detected to determine the osteogenic differentiation of MSCs from each group. RESULTS: The 25% concentration of CB contained serum collected from SD rats one hour after intragastric infusion with low dose CB was proved to be the most effective concentration on the proliferation of MSCs; The 25%-30% concentration of CB contained serum collected from SD rats one hour after intragastric infusion with high dose CB was proved to be the most effective concentration on the differentiations of MSCs into osteoblast. CONCLUSION: CB contained serum could promote the proliferation and osteogenic differentiation of MSCs. PMID- 22822673 TI - [Effect of shengbanfang on CYP3A1 activities of Sprague-Dawley rat]. AB - OBJECTIVE: To study the influences of Shengbanfang on CYP3A1 activities of SD rat and provide suggestions for drug combinations. METHODS: 25 male SD rats were devided into 5 groups randomly,and treated with saline( NS, ig, 10 mg/(kg/d) ,qd,14 d), dexamethasone (DEX, ig, 100 mg/(kg x d), qd, 3 d), high dose of Shengbanfang (HD, ig, 8.645 g/kg, bid, 14 d), middle dose of Shengbanfang (MD, ig, 4.322 g/kg, bid, 14 d) and low dose of Shengbanfang (LD, ig, 2.161 g/kg, bid, 14 d), respectively. The HPLC method was established and validated to determine the productive velocity of 6beta-hydroxytestosterone and measure the activity of CYP3Al. RESULTS: Under the optimized incubation conditions, the productive rates of 6beta-hydroxytestosterone of HD, MD, LD, NS and DEX, groups were (55.82 +/- 5.97), (65.10 +/- 6.83), (60.89 +/- 6.53), (62.17 +/- 6.55), (126.73 +/- 15.40) micromol/(L x mg pro x min). There were significant differences between Shengbanfang groups compared with dexamethasone group, but there was no significant difference between Shengbanfang groups and the control group (NS). CONCLUSION: Shengbanfang has no induce effect on the enzymic activity of CYP3Al in SD rats. PMID- 22822675 TI - [Study on the effect of grape seed proanthocyanidins on increasing the radiosensitivity for X-ray]. AB - OBJECTIVE: To investigate the effect of Grape Seed Proanthocyanidins (GSPs) on enhancing the radiosensitivity of human hepatic carcinoma cell line HepG2, human cervical cancer cell line Hela and human leukemia cell line K562 for X-ray in vitro. METHODS: The killing effect of GSPs combined with X-ray on cells was evaluated by SRB and clone formation assay. RESULTS: The GSPs had obvious cytotoxicity on three cell lines in a dose-dependent and time-dependent manners. However, inhibition rate of different cell line were quite different, the strongest one was human leukemia K562 cells and the others were weak. The sensitization ranges calculated by univariate analysis were 6.25-12.5 microg/mL for human leukemia K562 cells. Sensitization enhancement ratio was 1.94 using curve fitting method for K562 cells. CONCLUSION: GSPs can obviously enhance the radiosensitivity of cancer cells in vitro. The mechanism of sensitization effect may be related to the effects of GSPs on oxygen balance and cell cycle. PMID- 22822676 TI - [Comparative study of Radix Hedyseri as sulstitute for Radix Astragali of yupingfeng oral liquid on cellular immunity in immunosuppressed mice]. AB - OBJECTIVE: To study on Radix Hedyseri as substitute for Radix Astragali of Yupingfeng oral liquid on cellular immunity in immunosuppressed mice. METHODS: The model of immunosuppression mice were induced by Cyclophosphamide. And the same dose of Radix Hedyseri and Radix Astragali alternative Yupingfeng oral liquid was intragastric administrated into mice; Antagonistic experiments were observed in vivo. Determined the thymus gland index, spleen index, phagocytosis of the macrophage, proliferation index of T lymphocyte, kill and wound activity, T lymphocyte subgroup, and content of IL-13 of serum. RESULTS: Yupingfeng oral liquid and Yuping-feng aqueous extract of Radix Hedyseri substitute Radix Astragali both could significant raise thymus gland index and spleen index, and clearly increase the phagocytosis of the macrophage. They both could antagonize immunosuppressive action caused by Cyclophosphamide, which could promote T lymphocyte proliferation, kill and wound activity, quantity of T lymphocyte subgroup, and production of IL-1beta with different degree. And Yupingfeng aqueous extract of Radix Hedyseri substitute Radix Astragali increased spleen index and T lymphocyte proliferation was better than those of Yupingfeng oral liquid. CONCLUSION: Radix Hedyseri and Radix Saposhnikoviae, compatible with Rhizoma Atractylodis Macrocephalae compared with Yupingfeng oral liquid in cell immunity regulation has a similar role, and better in the recovery of spleen weight and T cell proliferation. PMID- 22822677 TI - [Preparation and physiochemical properties of curcumin-loaded lipid cubic liquid crystalline nanoparticles]. AB - OBJECTIVE: To prepare curcumin-loaded lipid cubic liquid crystalline nanoparticles and evaluate its physiochemical properties. METHODS: The nanoparticles were prepared using hot and high-pressure homogenization. The prescription and preparation process were optimized by uniform design with drug loading and entrapment efficiency as indexes. RESULTS: The nanoparticles were spherical under transmission electron microscope (TEM) with average particle size of 176.1 nm, zeta potential of -25.19 mV, average drug loading of (1.5 +/- 0.2)% and entrapment efficiency of (95 +/- 1.8)%. The release equation: In (1-Q) = 0.0251t-0.0075. The cumulative release percentage was 60% at 36 h in vitro. CONCLUSION: The obtained curcumin-loaded lipid cubic liquid crystalline nanoparticles shows high entrapment efficiency and good sustain release property. PMID- 22822678 TI - [Optimization for supercritical CO2 extraction with response surface methodology and component analysis of Sapindus mukorossi oil]. AB - OBJECTIVE: To study the extraction conditions of Sapindus mukorossi oil by Supercritical CO2 Extraction and identify its components. METHODS: Optimized SFE CO2 Extraction by response surface methodology and used GC-MS to analysie Sapindus mukorossi oil compounds. RESULTS: Established the model of an equation for the extraction rate of Sapindus mukorossi oil by Supercritical CO2 Extraction, and the optimal parameters for the Supercritical CO2 Extraction determined by the equation were: the extraction pressure was 30 MPa, temperature was 40 degrees C; The separation I pressure was 14 MPa, temperature was 45 degrees C; The separation II pressure was 6 MPa, temperature was 40 degrees C; The extraction time was 60 min and the extraction rate of Sapindus mukorossi oil of 17.58%. 22 main compounds of Sapindus mukorossi oil extracted by supercritical CO2 were identified by GC-MS, unsaturated fatty acids were 86.59%. CONCLUSION: This process is reliable, safe and with simple operation, and can be used for the extraction of Sapindus mukorossi oil. PMID- 22822679 TI - [Enzymatic extraction and antibacterial activity of aucubin from Eucommia ulmoides leaves]. AB - OBJECTIVE: To investigate the technology of Aucubin in Eucommia ulmoides leaves extracted by enzymatic method and its antibacterial activity. METHODS: Aucubin in Eucommia ulmoides leaves was extracted by cellulase method. The extraction technology was optimized using the content of Aucubin as index. The antibacterial activity of Aucubin was determined. RESULTS: The results showed that the optimum technology was as follows; The solid-liquid ratio was 1:12, extracted for 50 min by 0.4% enzyme at 50 degrees C in pH 6.0. The extraction rate of Aucubin was as high as 17.892 mg/g. The Aucubin extracted could obviously inhibit the growth of Escherichia coli and Staphylococcus aureus, the MIC of Aucubin against Staphylococcus aureus and Escherichia coli were 4.832 mg/mL and 9.664 mg/mL respectively. However, Aucubin presented weak inhibitory effect on Streptococcus pneumonia and MG-hemolytic streptococcus, the MIC of Aucubin against them were all 28.946 mg/mL. CONCLUSION: The extraction technology obtained in this experiment is reasonable and feasible with high extraction rate, and the Aucubin has some antibacterial activity. PMID- 22822680 TI - [Study on purification of total organic acid and chlorogenic acid in Herba Artemisiae scopariae with macroporous adsorption resin]. AB - OBJECTIVE: To optimize the technological parameters of the purification process for total organic acid and chlorogenic acid in Herba Artemisiae scopariae with macroporous adsorption resin. METHODS: Static and dynamic adsorption-desorption methods were adopted to choose the optimal type of resin. Then orthogonal design L9 (3(4)) and single factor experiment were used to select the optimum purification process conditions. RESULTS: The optimal purification process for total organic acid and chlorogenic acid with HPD200A macroporous adsorption resin were as follows: the diameter height ratio of the resin was 1:6, the sample concentration was 1 g/mL, the absorption velocity was 1 BV/h (1 BV represented one column volume), the ratio of sample to HPD200A macroporous adsorption resin was 1.5:1 (W/W), 3 BV of water was used as purificant and 2 BV of 90% ethanol was used as eluant. Under these conditions, the purity of total organic acid and chlorogenic acid was 588.74% and 567.89%, respectively. CONCLUSION: The established purification process for total organic acid and chlorogenic acid in Herba Artemisiae scopariae with HPD200A macroporous adsorption resin is simple and stable and can be used in industrial production. PMID- 22822681 TI - The sweet smell of ... implicit helping: effects of pleasant ambient fragrance on spontaneous help in shopping malls. AB - Some studies have shown that pleasant scent encourages the prosocial behavior of people requested for help. However, the effect of pleasant ambient odor on spontaneous helping has never been tested. Male and female confederates accidentally dropped a glove on the floor while walking in places with pleasant ambient odors (e.g., pastries) and in places with no odor. The confederate continued his/her walk, seemingly unaware of his/her loss. It was found that passers-by helped the confederates more favorably in the pleasant-smelling areas. Positive mood induced by ambient smell was used to explain such results. PMID- 22822682 TI - Choking under the pressure of a positive stereotype: gender identification and self-consciousness moderate men's math test performance. AB - Choking under pressure occurs when an individual underperforms due to situational pressure. The present study examined whether being the target of a positive social stereotype regarding math ability causes choking among men. Gender identification and self-consciousness were hypothesized to moderate the effect of math-gender stereotypes on men's math test performance. Men high in self consciousness but low in gender identification significantly underperformed when exposed to gender-relevant test instructions. No significant effects were found under a gender-irrelevant condition. These findings are discussed in the contexts of research on stereotype threat, stereotype lift, and choking under pressure. PMID- 22822683 TI - Primacy of warmth versus competence: a motivated bias? AB - In line with previous results that challenge the traditional primacy of warmth over competence in outgroup perception, we propose to bridge elements from stereotype content model and social identity theory: Perceivers will use the competence and warmth dimensions differentially when interpreting higher or lower status outgroup members' behavior. We test the hypothesis that the dimension that is less favorable for the outgroup and more favorable for the ingroup will be used. In particular, we investigate whether the warmth dimension would better predict the interpretation of higher status outgroup members' behavior than the competence dimension, whereas the competence dimension would better predict the interpretation of lower status outgroup members' behavior than the warmth dimension. Two studies separately test these effects. Results suggest the existence of a motivated bias in interpreting outgroup members' behavior, especially when there is ingroup identification. PMID- 22822684 TI - Relationships between leaders' and subordinates' emotion regulation and satisfaction and affect at work. AB - The study examined relationships between leaders' emotion regulation and leaders' and subordinates' work-related outcomes. Fifty-one school directors and 281 teachers reported on their strategies of emotion regulation (reappraisal, suppression), job satisfaction, and affect at work. For subordinates, suppression was negatively related to job satisfaction and was positively related to negative affect and emotional exhaustion, and reappraisal was positively related to job satisfaction and negatively to negativ affect. In contrast, multilevel analyses found that directors' use of reappraisal was neg atively related to subordinates' job satisfaction, and directors' use of suppression wa positively related to subordinates' positive affect. Leaders' suppression interacted wit group cohesion to predict subordinates' negative affect. This is one of the first studies to find evidence for the possible tension between leaders' emotion regulation competencie and organizational-role interests. PMID- 22822685 TI - Attitudes toward cosmetic surgery patients: the role of culture and social contact. AB - Cosmetic surgery is increasingly popular globally, but how cosmetic surgery patients are socially evaluated is largely unknown. The present research documents attitudes toward these patients in multiple cultures (Hong Kong, Japan, and the United States). Across these cultures, attitudes toward cosmetic surgery patients were predominantly negative: Participants ascribed more negative attributes to cosmetic surgery patients and found cosmetic surgery not acceptable. Also, participants in Hong Kong and Japan were not willing to form social relationships, particularly intimate ones, with these patients. These attitudes were less negative in the United States than in Hong Kong and Japan, partly because social contact, which reduced negativity in attitudes toward cosmetic surgery patients, was more prevalent in the United States. These findings bear important implications for the subjective well-being of cosmetic surgery patients, who very often expect improvement in their social relationships through the surgery. PMID- 22822686 TI - Social-cognitive predictors of intention to vaccinate against the human papillomavirus in college-age women. AB - This study examined social-cognitive predictors of college-age women's intentions to obtain the human papillomavirus (HPV) vaccine using the Health Belief Model (HBM) and Theory of Planned Behavior (TBP) as theoretical guides. Questionnaire data were collected from 143 women at a Midwestern university. Among the HBM variables, perceived susceptibility to HPV, perceived benefits of the vaccine, and self-efficacy to obtain the vaccine were significant predictors. Among the TPB variables, positive attitudes toward the vaccine and beliefs that important others would support vaccination predicted intentions. A model with all HBM and TPB variables explained nearly 60% of the variance in intentions. Comparison of the theories suggests that the TPB is a better predictor of intentions than the HBM. Results suggest that targeting personal beliefs about the vaccine, and increasing acceptance for the vaccine among social network members, may increase vaccination intentions among college-age women. PMID- 22822687 TI - Butting in vs. being a friend: cultural differences and similarities in the evaluation of imposed social support. AB - Imposed social support can be more harmful than helpful due to its potential to threaten the recipient's autonomy. These findings may reflect cultural contexts that foster autonomy (e.g., European American [EA]). Imposed social support may be interpreted more positively in cultural contexts that place emphasis on mutual responsibility for solving problems (e.g., Russian [RU]). We compared EA (n = 128) and RU (n = 125) young adults' reports of recent episodes of support. EAs were more likely than RUs to be satisfied with these interactions, a difference mediated by levels of nondirective support. Cultural differences emerged in interpretations of support. Unsolicited support from family was interpreted more positively by RUs than by EAs. Thus, although nondirective support contributed to support satisfaction across cultural groups, cultural context influenced young adults' interpretations of imposed support. PMID- 22822688 TI - Identity practices, ingroup projection, and the evaluation of subgroups: a study among Turkish-Dutch Sunnis. AB - This research focuses on religious subgroup evaluations by examining the attitude of Turkish-Dutch Sunni Muslims towards Alevi and Shiite Muslims. Following the Ingroup Projection Model, it was expected that Sunni participants who practice Islam will project their self-defining subgroup practices on the superordinate Muslim category, which will be related to more ingroup bias towards Alevis, a Muslim subgroup that performs different religious practices. Two studies yielded consistent evidence that practicing Islam increased ingroup bias towards Alevis. Furthermore, in Study 2, we found evidence that the effect of practicing Islam on ingroup bias was mediated by relative ingroup prototypicality (RIP). Moreover, practicing Islam did not affect RIP in relation to Shiites who perform the same religious practices that we examined. These findings support the Ingroup Projection Model. PMID- 22822689 TI - Methodological coherence: establishing a unified research frame. PMID- 22822690 TI - The relationship between sensory processing patterns and sleep quality in healthy adults. AB - BACKGROUND: Sleep quality affects a person's performance and quality of life. Poor sleep was recently associated with hyperarousability and difficulties in processing sensory input. PURPOSE: To examine the relationships between sensory processing difficulties (SPD) and sleep quality in healthy adults. METHODS: The 185 participants, aged 21 to 60 (mean 33.64 +/- 8.69), completed the Adolescent/Adult Sensory Profile (AASP) and the Pittsburgh Sleep Quality Index (PSQI). FINDINGS: Sleep quality significantly correlated with sensory-processing patterns characterized by hypersensitivity. These patterns were manifested in specific modalities (tactile, visual, and auditory), which significantly predicted sleep quality. IMPLICATIONS: Sleep quality may be related to predisposing, sensory-processing patterns, particularly to hypersensitivity. Occupational therapists should refer to the possible relationship between SPD and sleep quality when treating individuals with SPD or poor sleepers. This may assist in implementing the optimal intervention based on the person's specific needs and contribute to performance and quality of life. PMID- 22822691 TI - A phenomenological study of occupational engagement in recovery from mental illness. AB - BACKGROUND: Recovery from mental illness has been described as a process involving personal growth and a search for meaning. Occupation is a primary medium for human development as well as the creation of life meaning, suggesting the exploration of recovery from an occupational perspective is warranted. PURPOSE: To explore the experience and meaning of occupation for 713 people who self-identified as being in recovery from mental illness. METHODS: Recovery narratives were collected from participants in conversational interviews that were recorded and transcribed. The transcripts were analysed using hermeneutic phenomenology. FINDINGS: A range of experiences were evident in the recovery narratives, from complete disengagement to full engagement in occupations. Insights into the experience and meaning of different states of occupation were revealed. IMPLICATIONS: All forms of occupational engagement, including disengagement, can be meaningful in the recovery process. Increased understanding of different modes of occupational engagement will assist therapists to support recovery more effectively. PMID- 22822692 TI - A critical reflection on the concept of cultural safety. AB - BACKGROUND: Cultural safety broadens and transforms the discourse on culture and health inequities as experienced by diverse populations. PURPOSE: To critically analyze cultural safety in terms of its clarity, simplicity, generality, accessibility, and importance. KEY ISSUES: Whilst the clarity and generality of cultural safety remain contentious, there is emerging evidence of its capacity to promote a more critical discourse on culture, health, and health care inequities and how they are shaped by historical, political, and socioeconomic circumstances. IMPLICATIONS: Cultural safety promotes a more critical and inclusive perspective of culture. As an analytical lens in occupational therapy practice and research, it has the potential to reveal and generate broader understandings of occupation and health from individuals or groups in society who are traditionally silenced or marginalized. In relation to Aboriginal peoples, it clearly situates health and health inequities within the context of their colonial, socioeconomic, and political past and present. PMID- 22822693 TI - Terms used to describe pediatric videofluoroscopic feeding studies: a Delphi survey. AB - BACKGROUND: The prevalence of pediatric feeding and swallowing disorders is high in the special needs population. Videofluoroscopic feeding studies (VFFS) are used to assess feeding, but the accurate interpretation of VFFS depends on consistent use of terminology for describing a physiological swallow. No consensus exists regarding the terminology used for reporting VFFS findings. PURPOSE: The goal of this study was to achieve consensus among pediatric therapists on definitions for terminology used to describe the results of VFFS. METHODS: Using a Delphi process, therapists from British Columbia rated definitions most appropriate for each term. They also were asked to add definitions that they thought would more accurately describe the terms. FINDINGS. Consensus was achieved on at least one definition for each of the terms used to describe the results of VFFS. IMPLICATIONS: Accurate interpretation of swallowing issues may improve the care of infants and children with feeding and swallowing difficulties. PMID- 22822694 TI - Comparing the responsiveness of the assessment of motor and process skills and the functional independence measure. AB - BACKGROUND: Selecting and utilizing appropriate assessments to evaluate outcomes is an important aspect of evidence-based occupational therapy practice. The Functional Independence Measure (FIM), to which occupational therapists contribute motor and cognitive scores, is currently the only required assessment for evaluating change from admission to discharge on an inpatient rehabilitation unit. However, occupational therapists are also using the motor and process scales from the Assessment of Motor and Process Skills (AMPS) to assess clients and evaluate change. PURPOSE: To compare responsiveness of the AMPS and the FIM on an inpatient rehabilitation unit. METHODS: A retrospective chart review of AMPS measures and FIM scores at admission and discharge was undertaken. Standardized response means and effect sizes were calculated to estimate responsiveness. FINDINGS: No significant difference was found in the ability of the AMPS motor and FIM motor scales to detect change. The AMPS process scale was more responsive to change than the FIM cognitive scale. IMPLICATIONS: Using the AMPS as an assessment to evaluate outcomes allows practitioners to detect changes that may not be detected through the exclusive use of the FIM. PMID- 22822695 TI - Curriculum evaluation: linking curriculum objectives to essential competencies. AB - BACKGROUND: The essential competencies of occupational therapy practice are agreed upon and documented (ACOTRO, 2003), yet they have not been used to evaluate educational programs. PURPOSE: To evaluate the match between the planned curriculum and the nationally recognized competencies that define safe, effective, and ethical practice. METHODS: Utilizing a comparative and systematic approach, course learning objectives in the approved curriculum map were matched to the ACOTRO (2003) competencies. FINDINGS: A total of 218 links were made between the 179 learning objectives and the 30 essential competencies. There were no links to three competencies. Learning objectives were not equally represented across the ACOTRO units; initial analyses indicate the distribution is likely appropriate. IMPLICATIONS: This novel evaluative process allowed critical appraisal and subsequent minor revision of Dalhousie curriculum. The appropriate, relative weighting of curriculum content is unknown and is a professional issue for discussion by regulators, educators, and the profession at large. PMID- 22822696 TI - A scoping review of the Photovoice method: implications for occupational therapy research. AB - BACKGROUND: Photovoice is a participatory action research method combining photography and group work to give people an opportunity to record and reflect on their daily lives. PURPOSE: To review the use of Photovoice in health research and consider the implications for occupational therapy research. METHODS: Literature review, guided by a scoping framework, reveals the purposes, rationales and populations with whom Photovoice has been used. FINDINGS: From 351 documents retrieved, 191 original studies were surveyed; 68% were peer-reviewed. The majority of studies (76%) occurred within the public health domain and a smaller percentage (24%) with individuals experiencing a specific illness and/or disability, with very few (2%) documented in the occupational therapy literature. IMPLICATIONS: Photovoice provides a useful framework to apply a participant centred research approach on occupational participation. It is important to consider and further examine ethical and methodological issues related to stigma, physical and cognitive capacities, mobility and technical accessibility related to using this method. PMID- 22822697 TI - How should careproviders respond to patients' requests that may be refused? AB - Some requests made to careproviders by patients may be of great personal importance to patients. Careproviders may assign proportionally greater weight to these exceptional requests, and may choose to take exceptional measures to assist. A strong trust relationship may be formed with patients as a result. PMID- 22822698 TI - Living donation and cosmetic surgery: a double standard in medical ethics? AB - The commitment of transplant physicians to protect the physical and psychological health of potential donors is fundamental to the process of living donor organ transplantation. It is appropriate that strict regulations to govern an individual's decision to donate have been developed. Some may argue that adherence to such regulations creates a doctor-patient relationship that is rooted in paternalism, which is in drastic contrast with a doctor-patient relationship that is rooted in patients' autonomy, characteristic of most other operative interventions. In this article we analyze the similarities between cosmetic plastic surgery and living donor surgery as examples of surgeries governed by different ethical principles. It is interesting that, while the prevailing ethical approach in living donor surgery is based on paternalism, the ethical principle guiding cosmetic surgery is respect for patients' autonomy. The purpose of this article is not to criticize either practice, but to suggest that, given the similarities between the two procedures, both operative interventions should be guided by the same ethical principle: a respect for patients' autonomy. We further suggest that if living organ donation valued donors' autonomy as much as cosmetic plastic surgery does, we might witness a wider acceptance of and increase in living organ donation. PMID- 22822699 TI - Different standards are not double standards: all elective surgical patients are not alike. AB - Testa and colleagues argue that evaluation for suitability for living donor surgery is rooted in paternalism in contrast with the evaluation for most operative interventions, which is rooted in the autonomy of patients. We examine two key ethical concepts that Testa and colleagues use: paternalism and autonomy, and two related ethical concepts: moral agency and shared decision making. We show that by moving the conversation from paternalism, negative autonomy, and informed consent to moral agency, relational autonomy, and shared decision making, one better understands why the arguments given by Testa and colleagues fail. We argue (1) why the hurdles that one must overcome to become a living donor are appropriate; and (2) that the similarities between living donor transplant surgery and cosmetic plastic surgery that the authors describe are inaccurate. Finally, we consider the recommendation to treat plastic surgery patients and living donors more similarly. We argue that any change should not be in the direction of becoming less protective of living donors, but more protective of cosmetic plastic surgery candidates. PMID- 22822700 TI - The effect of completing a surrogacy information and decision-making tool upon admission to an intensive care unit on length of stay and charges. AB - BACKGROUND AND PURPOSE: Many critically ill patients in intensive care units (ICUs) are unable to communicate their wishes about goals of care, particularly about the use of life-sustaining treatments. Surrogates and clinicians struggle with medical decisions because of a lack of clarity regarding patients' preferences, leading to prolonged hospitalizations and increased costs. This project focused on the development and implementation of a tool to facilitate a better communication process by (1) assuring the early identification of a surrogate if indicated on admission and (2) clarifying the decision-making standards that the surrogate was to use when participating in decision making. Before introducing the tool into the admissions routine, the staff were educated about its use and value to the decision-making process. PROJECT AND METHODS: The study was to determine if early use of a simple method of identifying a patient's surrogate and treatment preferences might impact length of stay (LOS) and total hospital charges. A pre- and post-intervention study design was used. Nurses completed the surrogacy information tool for all patients upon admission to the neuroscience ICU. Subjects (total N = 203) were critically ill patients who had been on a mechanical ventilator for 96 hours or longer, or in the ICU for seven days or longer.The project included staff education on biomedical ethics, critical communication skills, early identification of families and staff in crisis, and use of a simple tool to document patients' surrogates and previously expressed care wishes. Data on hospital LOS and hospital charges were collected through a retrospective review of medical records for similar four-month time frames pre- and post-implementation of the assessment tool. RESULTS: Significant differences were found between pre- and post-groups in terms of hospital LOS (F = 6.39, p = .01) and total hospital charges (F = 7.03, p = .009). CONCLUSIONS: Project findings indicate that the use of a simple admission assessment tool, supported by staff education about its completion, use, and available resources, can decrease LOS and lower total hospital charges. The reasons for the difference between the pre- and post-intervention groups remain unclear. Further research is needed to evaluate if the quality of communications between patients, their legally authorized representatives, and clinicians--as suggested in the literature--may have played a role in decreasing LOS and total hospital charges. PMID- 22822701 TI - Training in clinical ethics: launching the clinical ethics immersion course at the Center for Ethics at the Washington Hospital Center. AB - In May 2011, the clinical ethics group of the Center for Ethics at Washington Hospital Center launched a 40-hour, three and one-half day Clinical Ethics Immersion Course. Created to address gaps in training in the practice of clinical ethics, the course is for those who now practice clinical ethics and for those who teach bioethics but who do not, or who rarely, have the opportunity to be in a clinical setting. "Immersion" refers to a high-intensity clinical ethics experience in a busy, urban, acute care hospital. During the Immersion Course, participants join clinical ethicists on working rounds in intensive care units and trauma service. Participants engage in a videotaped role-play conversation with an actor. Each simulated session reflects a practical, realistic clinical ethics case consultation scenario. Participants also review patients' charts, and have small group discussions on selected clinical ethics topics. As ethics consultation requests come into the center, Immersion Course participants accompany clinical ethicists on consultations. Specific to this pilot, because participants' evaluations and course faculty impressions were positive, the Center for Ethics will conduct the course twice each year. We look forward to improving the pilot and establishing the Immersion Course as one step towards addressing the gap in training opportunities in clinical ethics. PMID- 22822702 TI - Training in clinical ethics consultation: the Washington Hospital Center course. AB - How can one be trained to enter the evolving field of clinical ethics consultation? The classroom is not the proper place to teach clinical ethics consultation; it is best done in a clinical setting. The author maps the elements that might be included in an apprenticeship, and sets out propositions for debate regarding the training needed for clinical ethics consultants and directors of clinical ethics consultation services. I was invited to be an observer of the first Intensive Course in Clinical Ethics at the Washington Hospital Center (WHC). I had no input into the planning. Having been present at a meeting of the Clinical Ethics Consultation Affinity Group of the American Society of Bioethics and Humanities (ASBH) when the issue of a lack of training programs was discussed, I was acutely aware of the need. Knowing how popular the various four day intensive courses in bioethics have been, held at Georgetown University first, and then in Seattle and locations in the Midwest, it seemed time to have a four-day intensive course that was devoted to clinical ethics. The differences between bioethics and clinical ethics is substantial and largely unappreciated by those in bioethics. So when the WHC team agreed to take on the task of offering an intensive in clinical ethics, it was an important step for the field. PMID- 22822703 TI - Truly intensive clinical ethics immersion at the Washington Hospital Center. AB - Opportunities for practical, hospital-based training in those skills demanded by clinical ethics consultation (CEC) have been limited. Given the number of individuals who provide part-time CEC, greater access to condensed, practical training such as the clinical ethics immersion course offered by the Washington Hospital Center, is necessary. Two participants in the initial cohort evaluate their CE training at a busy, urban referral center, exploring prior expectations, perceptions of its utility and suggestions for improvement. Such training will prove valuable not only for bioethicists who lack practical CEC experience "at the bedside" but also for ethics consultants whose ethics services have a low consult volume who wish to sharpen their skills. PMID- 22822704 TI - Credentialing the clinical ethics consultant: an academic medical center affirms professionalism and practice. AB - In response to national trends calling for increasing accountability and an emerging dialogue within bioethics, we describe an effort to credential clinical ethicists at a major academic medical center.This effort is placed within the historical context of prior calls for credentialing and certification and efforts currently underway within organized bioethics to engage this issue.The specific details, and conceptual rationale, behind the NewYork-Presbyterian Hospital's graduated credentialing plan are shared as is their evolution and ratification within the context of institutional policy. While other programs will design their credentialing schema consistent with their local context and demographics, the description of one such effort is offered to be instructive to others who want to bring additional standardization to the assessment of the readiness and credentials of those who will engage in the practice of clinical ethics case consultation. PMID- 22822705 TI - Ethics been very good to us. AB - This commentary asks whether ongoing efforts to accredit, certify, and credential hospital ethics consultants are nothing other than an illegal restraint on trade masquerading as an effort to protect the public from harm. PMID- 22822706 TI - Inside baseball and ethics consultation: a comment on "ethics been very good to us". AB - In response to the article by Scofield, I consider the that, how, and why of ethics consultation, moral expertise, and the rules of the game. The question still to be engaged is, how does all of this work out for patients and families? PMID- 22822707 TI - Credentialing and certification in ethics consultation: lessons from palliative care. AB - In response to an article by Acres and colleagues, "Credentialing the Clinical Ethics Consultant: An Academic Medical Center Affirms Professionalism and Practice:" the authors urge continued action for the credentialing and certification of clinical ethics consultants. They also promote a vigorous and engaged model for ethics consultation. PMID- 22822708 TI - Always on call: thoughts from a neophyte physician. AB - This commentary describes a new physician who encountered a patient in crisis in a nonmedical environment. It discusses professional obligations, ethical principles, errors committed, and reasoning behind such errors. Unusual circumstances, uncertainty about how to properly identify oneself as a physician, self-doubt, and discomfort with practicing outside one's scope of training are recognized as reasons behind these errors. Medical students should be reminded of their ethical obligation to offer emergency care within their limitations, instructed how to identify themselves, and guided to become competent team leaders. Resident doctors should continue to receive instruction as they internalize ethical principles and identify their scopes of practice. Practicing physicians should be competent in offering basic emergency care if needed. PMID- 22822709 TI - Legal briefing: The unbefriended: making healthcare decisions for patients without surrogates (Part 2). AB - This issue's "Legal Briefing" column continues coverage of recent legal developments involving medical decision making for unbefriended patients. These patients have neither decision-making capacity nor a reasonably available surrogate to make healthcare decisions on their behalf. This topic has been the subject of recent articles in JCE. It has been the subject of major policy reports. Indeed, caring for the unbefriended has even been described as the "single greatest category of problems" encountered in bioethics consultation. Moreover, the scope of the problem continues to expand, especially with rapid growth in the elderly population and with an increased prevalence of dementia. Unfortunately, most U.S.jurisdictions have failed to adopt effective healthcare decision-making systems or procedures for the unbefriended. "Existing mechanisms to address the issue of decision making for the unbefriended are scant and not uniform." Most providers are "muddling through on an ad hoc basis." Still, over the past several months, a number of state legislatures have finally addressed the issue. These developments and a survey of the current landscape are grouped into the following 14 categories. The first two categories define the problem of medical decision making for the unbefriended.The remaining 12 describe different solutions to the problem. The first six categories were covered in Part 1 of this article; the last eight categories are covered in this issue (Part 2). 1. Who are the unbefriended? 2. Risks and problems of the unbefriended. 3. PREVENTION: advance care planning, diligent searching, and careful capacity assessment. 4. Decision-making mechanisms and standards. 5. Emergency exception to informed consent. 6. Expanded default surrogate lists: close friends. 7. Private guardians. 8. Volunteer guardians. 9. Public guardians. 10. Temporary and emergency guardians. 11. Attending physicians. 12. Other clinicians, individuals, and entities. 13. Institutional committees. 14. External committees. PMID- 22822710 TI - Structural basis for efficient chromophore communication and energy transfer in a constructed didomain protein scaffold. AB - The construction of useful functional biomolecular components not currently part of the natural repertoire is central to synthetic biology. A new light-capturing ultra-high-efficiency energy transfer protein scaffold has been constructed by coupling the chromophore centers of two normally unrelated proteins: the autofluorescent protein enhanced green fluorescent protein (EGFP) and the heme binding electron transfer protein cytochrome b(562) (cyt b(562)). Using a combinatorial domain insertion strategy, a variant was isolated in which resonance energy transfer from the donor EGFP to the acceptor cyt b(562) was close to 100% as evident by virtually full fluorescence quenching on heme binding. The fluorescence signal of the variant was also sensitive to the reactive oxygen species H(2)O(2), with high signal gain observed due to the release of heme. The structure of oxidized holoprotein, determined to 2.75 A resolution, revealed that the two domains were arranged side-by-side in a V-shape conformation, generating an interchromophore distance of ~17 A (14 A edge-to edge). Critical to domain arrangement is the formation of a molecular pivot point between the two domains as a result of different linker sequence lengths at each domain junction and formation of a predominantly polar interdomain interaction surface. The retrospective structural analysis has provided an explanation for the basis of the observed highly efficient energy transfer through chromophore arrangement in the directly evolved protein scaffold and provides an insight into the molecular principles by which to design new proteins with coupled functions. PMID- 22822711 TI - Medication overuse headache in school-aged children: more common than expected? AB - OBJECTIVE: To investigate the prevalence of medication overuse headache (MOH) in a group of children and adolescents seen for headache in a third-level center in Italy. BACKGROUND: Epidemiological studies indicate a prevalence of MOH in children and adolescents between 0.3 and 0.5%; no data are available for the Italian population. METHODS: We studied a group of first-seen children and adolescents (118 patients, 43.2% male and 56.8% female, mean age: 11.9 years). A detailed history was taken, using criteria defined by Olesen et al to assess the presence of MOH. Statistical correlations between demographic and diagnostic variables were assessed. RESULTS: Eleven (9.3%) of our patients presented MOH; in the group with chronic daily headache, the prevalence raised to 20.8%. At follow up, after introduction of a more rationale treatment, most patients improved, but 2 of them reported a worsening of their headache. CONCLUSIONS: We believe that a strong warning regarding medication overuse in headache therapy is essential for pediatricians and neuropsychiatrists. PMID- 22822713 TI - Resistance to thyroid hormone and Down syndrome: coincidental association or genetic linkage? PMID- 22822712 TI - Dried blood spots and sparse sampling: a practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants. AB - AIMS: Dried blood spots (DBS) alongside micro-analytical techniques are a potential solution to the challenges of performing pharmacokinetic (PK) studies in children. However, DBS methods have received little formal evaluation in clinical settings relevant to children. The aim of the present study was to determine a PK model for caffeine using a 'DBS/microvolume platform' in preterm infants. METHODS: DBS samples were collected prospectively from premature babies receiving caffeine for treatment of apnoea of prematurity. A non-linear mixed effects approach was used to develop a population PK model from measured DBS caffeine concentrations. Caffeine PK parameter estimates based on DBS data were then compared with plasma estimates for agreement. RESULTS: Three hundred and thirty-eight DBS cards for caffeine measurement were collected from 67 preterm infants (birth weight 0.6-2.11 kg). 88% of cards obtained were of acceptable quality and no child had more than 10 DBS samples or more than 0.5 ml of blood taken over the study period. There was good agreement between PK parameters estimated using caffeine concentrations from DBS samples (CL = 7.3 ml h-1 kg-1; V = 593 ml kg-1; t(1/2) = 57 h) and historical caffeine PK parameter estimates based on plasma samples (CL = 4.9-7.9 ml h-1 kg-1; V = 640-970 ml kg-1; t(1/2) = 101-144 h). We also found that changes in blood haematocrit may significantly confound estimates of caffeine PK parameters based on DBS data. CONCLUSIONS: This study demonstrates that DBS methods can be applied to PK studies in a vulnerable population group and are a practical alternative to wet matrix sampling techniques. PMID- 22822714 TI - Synthesis and evaluation of novel alpha-fluorinated (E)-3-((6-methylpyridin-2 yl)ethynyl)cyclohex-2-enone-O-methyl oxime (ABP688) derivatives as metabotropic glutamate receptor subtype 5 PET radiotracers. AB - In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five alpha-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI alpha fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K(i) of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K(i) = 31.2 nM), and successful radiosynthesis afforded (E)-[(18)F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[(18)F]-16 (K(d) = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro. PMID- 22822715 TI - Comment on "condensation of excitons in a trap". PMID- 22822717 TI - How similar are those molecules after all? Use two descriptors and you will have three different answers. AB - IMPORTANCE OF THE FIELD: Molecular similarity searching (ligand-based virtual screening) is one of the routine computational techniques used in drug discovery and pharmacological research. However, while a large number of descriptors exist, there are no general guidelines whatsoever which descriptors work better and which descriptors should be used in the different cases. AREAS COVERED IN THIS REVIEW: This review provides a brief overview of current molecular descriptors and databases used for their evaluation, followed by a critical discussion of their differences. WHAT THE READER WILL GAIN: After reading this review, the reader will be aware of how very differently molecular descriptors assess similarities of molecules, and the performance that can be realistically expected from them. TAKE HOME MESSAGE: Molecular descriptors come in a variety of forms, and they show vast differences in assessing the similarity between molecules. Virtual screening performance of many descriptors is often lower than expected, compared to 'dumb' descriptors while some simple methods such as circular fingerprints offer surprisingly good performance in many cases. The choice of the right benchmark library is crucial, many of which are summarized in this review. PMID- 22822716 TI - A case of Trichophyton mentagrophytes infection in a fennec fox (Vulpes zerda). AB - A 2-year-old male fennec fox presented with a 4 month history of nonpruritic, crusty skin lesions on the forehead, the pinnae and the tail tip. Initial investigations, including routine haematology, biochemistry profile, multiple skin scrapings, trichoscopic examination, Wood's lamp examination and fungal culture, failed to reveal any abnormalities. Histopathological examination of a first set of skin biopsies showed an interface dermatitis pattern, with lymphocyte infiltration in the basal layer, a significant lymphocytic exocytosis and occasional apoptotic basal epidermal keratinocytes; periodic acid Schiff stain did not reveal any fungal elements. On further biopsies, there was a pustular neutrophilic dermatitis, with numerous crusts containing high numbers of arthrospores and fungal hyphae. Trichophyton mentagrophytes infection was confirmed on fungal culture and PCR. The fennec fox received oral itraconazole (5 mg/kg once daily for 6 weeks) combined with a miconazole and chlorhexidine shampoo applied on affected areas once weekly, followed with an enilconazole dip. The fox improved dramatically, and a fungal culture performed at 6 weeks was negative. Unfortunately, a few days later the fennec fox developed anorexia, icterus and died. To the authors' knowledge, this is the first report of Trichophyton infection in a fennec fox and, although a postmortem examination was not performed, this is possibly the first report of fatal acute liver failure associated with itraconazole in a canid. PMID- 22822718 TI - The woodchuck hepatitis B virus infection model for the evaluation of HBV therapies and vaccine therapies. AB - Studies focused on the understanding of the molecular mechanisms involved in recovery or progression to chronicity of HBV may take advantage of natural and experimental models that mimic its properties. This is also of relevance for associated diseases such as cirrhosis and hepatocellulocarcinoma. The eastern woodchuck (Marmota monax) infected by the hepadnavirus woodchuck Hepatitis B virus (WHV) has been applied as a predictive model to support development of new HBV vaccines, antivirals, immunotherapies and combination therapies. This report summarizes studies carried out by our and other groups, with the application of this model in natural and experimental infections. Using standardized viral inocula in neonate and adult animals and newly established assays, the presence of the specific patterns of markers of acute, chronic and resolved infections and their relationships in the different virus-host interactions have been shown. B and T cell responses and T(H)1 cytokine expression have been shown to play a crucial role in the outcome of infection. The availability of the WHV/Marmota monax model and specific standardized assays may allow evaluation of new formulations of multimodal therapeutic strategies based on antiviral chemotherapy and immunomodulation. These may also include specifically targeted immunocomplexes. Such therapies could constitute new frontiers for the treatment of HBV chronic disease. PMID- 22822719 TI - Models and screening assays for drug discovery in osteoporosis. AB - IMPORTANCE OF THE FIELD: Osteoporosis affects nearly 100 million people in Europe, Japan and the US, and the number is increasing due to aging of the population. Preclinical efficacy studies performed according to regulatory guidelines are large, long and expensive, and there is a need for guidance and recommendations on how to perform preliminary studies prior to the regulatory studies. AREAS COVERED IN THIS REVIEW: We review research models that can be used for preclinical efficacy testing of new drug candidates for osteoporosis. Our focus is on testing compounds targeted to directly decrease osteoclastic bone resorption or increase osteoblastic bone formation. WHAT THE READER WILL GAIN: We provide an overview of in vitro bone cell culture systems and osteoporosis animal models useful for preclinical efficacy studies and a step-by-step approach on how the most interesting compound can be selected from thousands of drug candidates. Different approaches for testing anti-catabolic and anabolic compounds are provided. TAKE HOME MESSAGE: Efficacy of new osteoporosis drug candidates can be first proven conveniently using in vitro bone cell cultures and then confirmed in short-term animal studies, followed by more extensive animal studies, and finally a regulatory study performed according to the guidelines of regulatory authorities. PMID- 22822720 TI - How can high-throughput screening deliver drugs to treat atherosclerosis? AB - IMPORTANCE OF THE FIELD: Atherosclerosis is a progressive disease that is characterized by the accumulation of lipid-rich plaques within the artery walls. Despite the past 3 decades witnessing the most significant advances in the pharmacotherapy of atherosclerosis with statins, atherosclerosis is still one of the leading causes of mortality in industrialized and developing nations. The applications of high-throughput screening (HTS) have retrieved hits and lead compounds which may be further developed to new promising therapeutics to achieve more effective reductions in the risk of cardiovascular morbidity and mortality. AREAS COVERED IN THIS REVIEW: The review provides a summary of potential drug targets other than HMG-CoA reductase (primary target of statins) and their application in biochemical or cell-based HTS assays used by pharmaceutical companies and academic laboratories for anti-atherosclerotic drug discovery. WHAT THE READER WILL GAIN: The reader will gain an overview of the HTS strategies currently used in the development of anti-atherosclerotic agents. The reader is also provided with some abortive examples in anti-atherosclerotic drug discovery as well as the associated limitations and challenges of the process that HTS delivers new drugs to treat atherosclerosis. TAKE HOME MESSAGE: HTS can assist in the efficient discovery of new drugs towards the potential targets involved in the progress of atherosclerosis. PMID- 22822722 TI - The ubiquitin-proteasome system and assays to determine responses to inhibitors. AB - IMPORTANCE OF THE FIELD: Proteasome inhibition is an important therapeutic modality. Additionally, given the toxicities of direct proteasome inhibition, interest is increasing in modulating the ubiquitin ligases in the ubiquitin proteasome system (UPS). AREAS COVERED IN THIS REVIEW: A detailed examination of the ubiquitin-proteasome pathway and an examination of methods of inhibiting this pathway from a variety of targets including the proteasome, the ubiquitin ligases and molecular biology techniques. Special attention is given to the assays used to measure modulation of the ubiquitin-proteasome pathway. WHAT THE READER WILL GAIN: A thorough examination of the UPS and its role in cells and disease and an overview of several assays for analyzing the effect of inhibitors on the UPS. Significant detail is given to assays of the ligase system and molecular approaches. These assays have their own advantages and disadvantages and will allow investigators to make informed choices on investigating the UPS. TAKE HOME MESSAGE: Interrupting the UPS can have profound consequences for cellular health and disease progression. The ubiquitin-proteasome pathway contains multiple activities that cannot be definitively assayed by a single technique. Assaying the UPS requires investigators to use multiple corroborating techniques and avoid confounding issues within each technique. PMID- 22822723 TI - Simultaneous liver-kidney transplantation summit: current state and future directions. AB - Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver-kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed. PMID- 22822721 TI - Development of drugs for Epstein-Barr virus using high-throughput in silico virtual screening. AB - IMPORTANCE OF THE FIELD: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ~ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases. AREAS COVERED IN THIS REVIEW: In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease. WHAT THE READER WILL GAIN: The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process. TAKE HOME MESSAGE: Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease. PMID- 22822724 TI - Implant removal rate from infection after tibial plateau leveling osteotomy in dogs. AB - OBJECTIVE: To determine implant removal rate associated with infection after tibial plateau leveling osteotomy (TPLO) in dogs and to report antimicrobial susceptibility patterns for isolates. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 255; 282 TPLO). METHODS: Medical records (April 2006-April 2008) for dogs that had TPLO with >= 18 month follow-up were reviewed. Dogs that had implant removal with confirmed bacterial isolation from the implant were studied. Cefazolin (22 mg/kg intravenously) was administered before anesthesia induction for TPLO, every 2 hours intraoperatively, and every 6 or 8 hours until the next morning. Antimicrobial susceptibility testing was performed on isolates. RESULTS: Twenty-one (7.4%) of 282 TPLO required implant removal because of infection. Bacterial species isolated were Actinomyces spp. (1), Corynebacterium spp. (1), Enterococcus spp. (3), hemolytic Staphylococcus coagulase negative (2), nonhemolytic Staphylococcus coagulase negative (3), Staphylococcus spp. coagulase positive (7), methicillin-oxacillin-resistant Staphylococcus coagulase positive (2), and Serratia marcesens (2). Of the antibiotics that had >=10 isolates tested against them, gentamicin had the highest susceptibility rate (94%), followed by tribrissen (71%), and amoxicillin/clavulanic acid (67%). CONCLUSION: Staphylococcus spp. was reported in 14 of the 21 infections cultured in this study. Based on antimicrobial susceptibility testing, amoxicillin/clavulanic acid would be the best empirical treatment. PMID- 22822725 TI - A case of wrist tenosynovitis caused by Mycobacterium kansasii in a renal transplant recipient. AB - Mycobacterial infection in an organ transplant recipient is a diagnostic and therapeutic challenge. Diagnosis is often delayed, resulting in significant morbidity. Anti-microbial chemotherapy needs careful selection to prevent potentially significant complications, such as organ rejection and dose-related toxicities. We present the case of a 61-year-old Caucasian male kidney transplant recipient with chronic tenosynovitis of the left wrist. Histological findings of the synovial biopsy revealed multinucleated giant cell epithelioid granuloma. Culture of synovial fluid grew Mycobacterium kansasii. Treatment with rifampicin, ethambutol, and clarithromycin proved curative, but the patient developed irreversible ethambutol-related optic neuritis. PMID- 22822726 TI - Reference values for within-breath pulmonary impedance parameters in asymptomatic elderly. AB - INTRODUCTION: A new application for the forced oscillation technique (FOT) has been described by Dellaca et al. using sinusoidal pressure variations at 5 Hz to detect expiratory flow limitation by measuring the within-breath reactance [termed difference between inspiratory and expiratory X5 (DX5)]. Few studies have been performed on respiratory phase differences in the elderly. OBJECTIVE: Our aim was to present reference values for within-breath impedance measurements and to examine how the earlier mentioned method performs in a study population of asymptomatic elderly. METHODS: An age- and sex-stratified random sample was drawn from the elderly population of Bergen, Norway. Among the healthy non-smoking responders from a postal questionnaire study, 148 were selected to perform FOT measurements using an impulse oscillometry system (IOS). Seventy five of these participants had a normal spirometry and were able to perform at least two valid FOT measurements. Predictive equations for men and women were created for FOT parameters by linear multiple regression analysis. DX5 was calculated from the within-breath variation of reactance at 5 Hz. RESULTS/CONCLUSION: This study presents reference values for whole-breath and within-breath impedance parameters in asymptomatic elderly aged >70 years using the IOS method. We found higher resistance measurements than what is reported in previous studies and significantly larger frequency dependence. PMID- 22822771 TI - Experiences and psychosocial adjustment of Darfuri female students affected by war: an exploratory study. AB - This paper presents the personal accounts of Darfuri students studying at Ahfad University for Women in Omdurman, Sudan. Their war-related exposure, current ongoing life challenges, emotional distress, and coping strategies were explored using a semistructured interview protocol with a sample of 20 students. Through interpretative phenomenological analysis (IPA), the Darfuri students' stories illustrated that they were exposed to an array of traumatic war events, including personal experiences of parental separation, injury and death of family members, and shortages of essential life-sustaining supplies in internally displaced camps. Also, they were confronted with myriad current life hassles and urban cultural challenges, including being physically distant from their families, and losing the shelter of parents, the encouragement of extended family members, and their rich and familiar social support networks. Urban-cultural challenges and lack of environmental mastery applied to most Darfuri participants as they relocated to Omdurman city, which included negotiating an unfamiliar transport system, learning the routes and directions to important city landmarks, and insufficient funds for basic hygienic essentials. Emotional distress reactions were coded by forming two distinct lists: directly mentioned by the participant; and observations of emotional manifestation during the interview. Patterns emerged that may be similar to symptoms of mood and anxiety disorders; for example, the DSM-IV criteria for symptoms of generalized anxiety disorder and major depression. Strong religious practices and beliefs (such as praying and reading the Quran), ability to form interpersonal relationships, availability of social support networks, and a positive future outlook seemed to augment their ability to cope with their subsequent emotional distress owing to war-related exposures, current ongoing life hassles and urban-cultural challenges. PMID- 22822770 TI - Short communication: emerging transmitted HIV type 1 drug resistance mutations among patients prior to start of first-line antiretroviral therapy in middle and low prevalence sites in China. AB - It is known that transmitted drug resistance (TDR) will most likely emerge in regions where antiretroviral therapy (ART) has been widely available for years. However, after a decade of rapid scale-up of ART in China, there are few data regarding TDR among HIV-infected patients prior to initiating first-line ART in China. A prospective, observational cohort study was performed at sentinel sites in five provinces or municipalities. Study participants were recruited at the county- or city-level centers for disease control (CDCs), during routine monitoring visits following referral from diagnosing parties (e.g., hospitals). Each province or municipality recruited 140 patients through sequential sampling throughout the 2011 calendar year. A total of 627 eligible subjects were included in the analysis. the median CD4(+) cell count was 206 cells/ml at the baseline survey. The majority of patients (93.5%) had plasma HIV viral load >=1,000 copies/ml. Of the 627 patients, 17 (2.7%) had drug resistance mutations for any type of HIV drugs. The prevalence of drug resistance mutations to nonnucleoside reverse transcriptase inhibitor (NNRTI) drugs (8/627, 1.3%) was higher than to nucleoside reverse transcriptase inhibitor (NRTI) drugs (5/627, 0.8%) and protease inhibitor (PI) drugs (4/627, 0.6%). A logistic regression model showed that the only predictive factor was the route of infection through homosexual intercourse, i.e., men who have sex with men (MSM) status. As HIV prevalence is rising rapidly among Chinese MSM, it is essential to continue surveying this risk group and related high-risk populations with low awareness of HIV, and to develop new public health interventions that help to reduce the spread of drug-resistant HIV. PMID- 22822772 TI - Sandimmun((r)) (ciclosporin, Cyclosporin A) Past experience and present uses in autoimmune diseases. AB - Sandimmun (cyclosporin) is the established therapy to prevent graft rejection of all transplanted organs. The drug is also effective in several autoimmune diseases. Uveitis was the first clinical indication tested with Sandimmun systematically in the early eighties. Its use has been widely accepted particularly for the treatment of Behcet uveitis. However, in long-term use at high doses, biopsy-proven kidney deterioration in some patients led to a reduction in recommended doses. With close monitoring of renal dysfunction and a starting dose not exceeding 5 mg/kg, Sandimmun has since been shown to be effective in controlled trials in severe rheumatoid arthritis, severe psoriasis and treatment-resistant atopic dermatitis. Sandimmun has also been shown to be of benefit in patients with nephrotic syndrome, SLE and primary biliary cirrhosis among other indications. Based on extended clinical trials and numerous publications, it can be concluded that the use of Sandimmun in selected autoimmune diseases is of benefit to patients if the risks are adequately controlled by following established safety monitoring rules. PMID- 22822773 TI - Low-dose Cyclosporin a in uveitis a long-term follow-up. AB - Seventy patients suffering from bilateral endogenous chronic uveitis or ocular Behcet's disease have been treated with 5 mg/kg/day Cyclosporin A. All patients were followed at regular intervals for up to eight years. In this group of patients, we observed that CsA is an effective drug for the treatment of intraocular inflammation. Patients have needed continuous treatment with CsA for an average period of 31 months. Exacerbations of the inflammatory processes have been observed in 95% of the patients on initial attempts to lower the CsA dosage. These exacerbations were controlled either by local treatment or a combination of low-dose systemic corticosteroids. Elevation of the serum creatinine was initially observed in all patients when under the higher doses of CsA. However, only 15 patients (21.4%) had levels which were higher than the upper normal limit. Elevation of the bilirubin level of 50% or more above baseline was observed in 45 patients (64.3%) but only 11 patients (15.7%) showed levels which were above the upper normal limit. During this period of follow-up, cure was achieved in 25 patients and no exacerbations were observed up to five years after discontinuation of treatment. PMID- 22822774 TI - Effect of Cyclosporin A, Rapamycin, and FK-506 on corneal epithelial cells and lymphocyte proliferation. AB - The proliferation of corneal epithelial cells in vitro is relatively resistant to the addition of immunomodulating drugs to the cultures. Cyclosporin A, FK-506, and Rapamycin cause minimal or no inhibition of corneal epithelial cells proliferation in concentrations of up to 500 ng/ml. At concentrations of 5000 ng/ml, all drugs induce an inhibitory effect. In this system, Rapamycin induces the strongest inhibition in most cases. Nonetheless, a residual activity of more than 50% is recorded even at the highest concentrations. On the lymphocytes, both FK-506 and Rapamycin show marked inhibitory effects at 0.5 ng/ml, while CsA shows significant inhibition only at the level of 50 ng/ml or higher. These data can be interpreted to indicate a possible large therapeutic window (marked inhibition of lymphocyte proliferation at drug concentrations which do not have any effect on epithelial cell proliferation) of these drugs for topical use in external ocular diseases. PMID- 22822775 TI - Comparison of the anti-inflammatory potency and local tolerance of diclofenac and indomethacin eye drops in the postoperative management of patients undergoing ECCE with PCL. AB - Prostaglandins have been shown to mediate various manifestations of ocular inflammation. Diclofenac and indomethacin are thought to inhibit cyclooxygenase, an enzyme necessary for prostaglandin biosynthesis. The anti-inflammatory effect and subjective tolerance of topical diclofenac 0.1% and indomethacin 0.1% were examined in the postoperative treatment of 64 patients undergoing extracapsular cataract surgery with IOL implantation in a prospective, comparative, single masked study. Patients with preexisting ocular disease or whose intraoperative course was complicated were excluded from the study. Ophthalmologic examinations were performed preoperatively and at days: 1, 4-6, and 28-30 post surgery. Tolerance was assessed by subjective patient evaluation. There was no significant difference (p < 0.05) in postoperative inflammation among the two treatment groups. There was a trend for more severe corneal edema on day 4-6 in the indomethacin group. Diclofenac was slightly better tolerated. PMID- 22822776 TI - Subclinical inflammatory reaction induced by phakic anterior chamber lenses for the correction of high myopia. AB - To ascertain the potential that phakic anterior chamber lenses (PACL) used for the surgical correction of high myopia have for the induction of chronic subclinical inflammatory reaction, the authors have studied prospectively in one year of surgery the presence of subclinical inflammation in the anterior chamber in 18 clinically controlled cases. Nine of them were implanted with the Baik off ZB5M Domilens type and nine with the Fechner-Worst iris claw type. Clinical follow-up and objective measurements were taken with the Laser Flare Cell Meter Kowa FC-1000. In one year of an uncomplicated follow-up flare measurements were 722.52 +/- 639.21 (range 0 to 1557.6) for the iris claw and 42.38 +/- 91.67 (range 0 to 228.7) for the ZB5M lens (p < 0.01, Mann-Whitney test). Cell measurements were 34.52 +/- 22.08 (range 5 to 54.8) for the iris claw and 9.3 +/- 11.74 (range 0 to 31.8) for the ZB5M type (p < 0.05 Mann Whitney test). It is concluded that the PACL model ZB5M type is well tolerated in one year of surgery with the induction of marginal levels of flare and cell levels. The Fechner-Worst iris claw type induces unacceptable levels of chronic intraocular inflammation and does not seem suitable for the surgical correction of high myopia. This is the first study that shows that subclinical intraocular inflammation may be present in some models of PACL. PMID- 22822777 TI - Histopathology and ultrastructure of rabbit lenses exposed 'in vitro' to lysophosphatidylcholine (LPC). AB - Permeability changes which take place in the lens in the course of uveitis are probably due to 'Lens Permeability Factors' present in the inflammatory aqueous. One of these 'factors', lysophosphatidyl-choline (LPC), has been shown to damage the lens in vitro: a leakage of Rb(86) and proteins, and an increase of Na(+) and water content indicate a dose-related membrane lytic effect. Damaging levels of LPC (up to 10MUg/ml of aqueous humor) were found in the anterior chamber of inflamed eyes in the course of experimental uveitis in rabbits, and also in humans during uveitis. This report deals with an ultrastructural investigation on the damaging effect of different concentrations of LPC on rabbit lenses in culture. Concentrations of LPC higher than 12MUg/ml caused signs of degeneration immediately below the capsule. Scanning electron microscopy revealed grossly enlarged lens fibers, globular structures of different size and widespread water vacuoles. Transmission electron microscopy showed inter- and intracellular changes in the epithelium and the outer cortex, swollen lens epithelial cells, fiber cells separation, vacuoles, and areas of decreased electron density. The overall structure of the lens fibers in the inner cortex and in the nucleus was always intact. PMID- 22822778 TI - Skin biopsies in the evaluation of atypical optic neuropathies. AB - Patients with atypical clinical presentations of common optic neuropathies such as optic neuritis (ON), anterior ischemic optic neuropathy (AION), or optic neuropathy of unknown etiology (UON) are difficult to distinguish from inflammatory autoimmune optic neuropathy (AON) which is typically associated with a poor visual prognosis, unless treated with high doses of corticosteroids and/or immunosuppressive agents. The authors retrospectively evaluated 34 patients [AON (n = 12); AION (n = 5); ON (n = 9); UON (n = 8)] with visual loss which deteriorated over weeks to months or followed an atypical course, for the presence of immunological markers suggestive of AON. These markers included serological testing for antiphospholipid (APA) and antinuclear (ANA) antibodies, and evaluation of histopathologic and immunofluorescent staining of skin biopsies. All patients underwent a skin biopsy. Four of the 12 patients with AON had urticarial cutaneous lesions which revealed leukocytoclastic and/or lymphohistiocytic vasculitis. Seven of the remaining eight AON patients had skin biopsies of non-lesional skin which revealed immunoreactant deposition. Seven of the 21 skin biopsies obtained from the non-AON patients had findings of vacuolization or mild perivascular infiltration of lymphocytes (n = 5) and immunofluorescent deposits (n = 2). Abnormal skin biopsies (92%;p = 0.0009) and circulating APA (82%; p = 0.013) were common in AON patients while ANA was not statistically increased in AON patients (p = 0.06) when compared to the remaining patients as a whole. AON patients typically demonstrate evidence of systemic autoimmune involvement, as manifested by cutaneous abnormalities such as urticarial vasculitis and/or immunoreactant deposition and circulating APA. These may serve as markers for identifying AON patients who may be treated with immunomodulatory agents. PMID- 22822779 TI - Treatment of vernal keratoconjunctivitis a double-masked study. AB - Thirty-one children aged five to 14 years with severe vernal keratoconjunctivitis (VKC) were enrolled in a double-masked study evaluating the efficacy of three ophthalmic preparations: cromolyn sodium (Opticrom) 2%, artificial tears and fluorometholone 0.1% (FML). These drugs were coded respectively as A, B, C, and dispensed in similar bottles. Both eyes were treated, and drug assignment was made at random. Objective assessment of the disease activity was done under slit lamp by two ophthalmologists according to a five-point scale. The results were tabulated and the chi-square test performed. Decoding of the drugs was done only after completion of the statistical analysis. FML was found effective with a statistically significant difference from the other two drugs, both after the first week on the initially assigned treatment (p = 0.05) and on completion of the treatment period according to protocol (p = 0.005). Although several patients improved under cromolyn sodium, there was no statistically significant difference between cromolyn sodium 2% and artificial tears. All the preparations were well tolerated. One patient developed bilateral allergic blepharitis when treated with FML during the study. Another patient who responded well to FML developed posterior subcapsular cataract while continuing treatment with corticosteroids a few months after completion of the study. PMID- 22822780 TI - Visual prognosis in Behcet's disease. AB - In the pre-cyclosporin therapy era, BenEzra and Cohen(1) reported an appalling visual prognosis of patients with Behcet's disease, with 74% of eyes losing useful vision six to ten years after diagnosis. This experience was in a population largely of Mediterranean origin and it has been suggested that different ethnic groups may have different rates of ocular disease progression. In addition, newer immunosuppressive agents, e.g. cyclosporin, have been widely used in the last few years in the acute management of patients with Behcet's disease though their long term effect on the visual prognosis has not been established. The authors report the visual findings in a cohort of 28 patients of mixed ethnic extraction with Behcet's disease and ocular involvement who have been followed-up for an average of six years. Posterior segment disease relapse was treated aggressively with high dose corticosteroids, cyclosporin, azathioprine, cyclophosphamide, or chlorambucil in varying combinations. At present, approximately 60% of patients have visual acuity of +/- 6/9 in the better eye, 21% are 6/12 to 6/60, and 18% worse than 6/60. These findings, albeit relatively short term at present, are encouraging enough to continue this aggressive therapeutic management in the belief that the depressing figures in the literature reflect the past and not the present. PMID- 22822781 TI - Inflammatory cellular kinetics in sympathetic ophthalmia a study of 29 traumatized (exciting) eyes. AB - An immunohistochemical study was conducted on 29 cases of sympathetic ophthalmia (SO). Monoclonal antibodies against T, B, NK cells, macrophages, and MHC class II antigen (HLA-DR) were used. The choroidal infiltrate in 20 eyes was predominantly T cell while B cell predominated in four cases. All eyes with a B cell predominance came from males. A predominance of B cells was correlated to a longer duration of the disease (> 9 months) and in eyes showing phthisical changes. There was no correlation between a predominance of B cells with age, race, corticosteroid treatment or histological type (typical or atypical). These findings suggest that, although SO is a T cell mediated disease, the predominance of B cells in some cases may represent the end stage of the disease process, or seems a secondary pathological process. The kinetic change in cell populations during the disease may have therapeutic implication. PMID- 22822782 TI - Cytomegalovirus retinitis in children following bone marrow transplantation. AB - The authors describe three children, aged one, 13 and 24 months, who developed cytomegalovirus (CMV) retinitis seven to 18 months following allogeneic BMT. The underlying disease in two patients was severe combined immunodeficiency disease (SCID) and acute myeloid leukemia (AML) M5 in the third. All three patients developed chronic graft-versus-host-disease (GVHD) and received massive immunosuppressive therapy. The CMV retinitis was treated with ganciclovir. Clinical improvement was observed in the two SCID patients. The AML patient whose acute inflammatory retinitis was controlled, nevertheless developed optic atrophy in both eyes and VEP and ERG responses disappeared. The incidence of cytomegalovirus retinitis in our pediatric population of bone marrow transplant (BMT) recipients in the last three years was higher than expected: 3/85 (3.5%). Alertness to the possibility of intraocular complications is advocated. Early detection of CMV retinitis and intensive treatment with ganciclovir can save vision. It is therefore suggested to perform ocular examinations as part of the routine follow-up of BMT patients, especially in children with profound immune deficiency. PMID- 22822783 TI - Inhibition of cellular transfer of experimental autoimmune uveoretinitis by Rapamycin. AB - The crucial role of CD4(+) T cells in mediating uveitis is well recognized. One treatment strategy of non-infectious uveitis therefore seeks to inhibit T cell function. For that purpose the authors have evaluated the efficacy of Rapamycin (RAPA), an inhibitor of lymphocyte response to growth factors. To reproduce as best as possible the immune system condition during active disease, the adoptive transfer of activated T cells was used to induce experimental autoimmune uveoretinitis (EAU). Treatment with RAPA was delivered by continuous intravenous infusion. The results showed a complete inhibition of EAU transfer at the RAPA dose of 0.1 mg/kg/day. They indicate that RAPA could be a useful immunosuppressant for uveitis therapy. PMID- 22822784 TI - HTLV-I uveitis in a rabbit. AB - An animal model of HTLV-I associated uveitis was created. One rabbit developed bilateral uveitis 3,5 years after being injected with blood from an HTLV-I infected rabbit. The proviral DNA of HTLV-I was detected by polymerase chain reaction and dot-blot hybridization in the aqueous humor of the anterior chamber and the vitreous body. Histopathological examination revealed marked corneal opacity with neovascularization and infiltration of inflammatory cells, mainly plasma cells, into the iris, ciliary body, and choroid. Complicated cataracts were also seen. The retinas were destroyed and replaced by gliosis. This is the first animal model of HTLV-I-associated disease to be reported. PMID- 22822785 TI - The effect of intraperitoneal and topic sodium diclofenac on the arachidonic acid metabolism in endotoxin-induced uveitis in the rabbit. AB - Endotoxin-induced uveitis (EIU) was produced in albino rabbits by intravitreal injection in the right eye of 10 ng of salmonella endotoxin in 5 +/- l of saline solution by a Hamilton syringe. PGE2 and LTB4 were measured in the aqueous humor by the R.I.A. method 24 hours after endotoxin injection in order to examine the activity of the arachidonic acid metabolism. The authors have used seven groups of 12 animals each. The control group was injected with saline (5 +/- l) and the endotoxin group (ET) with 10 ng of endotoxin. One experimental group was injected with the same amount of ET and treated with three intraperitoneal injections ( 2h, 0h, 12h) of DFNa (32 mg/kg). Another group (ET+S) was injected with ET and treated with saline intraperitoneally (-2h, 0h, 12h). The topically treated groups received ET and topic DFNa (0.1%) every 6h, 4h and 2h respectively. Mean aqueous PGE2 concentration of the negative control group (0.03 +/- 0.02 ng/ml) was significantly lower (p < 0.01) than in the ET group (7.26 +/- 4.16). All the treated groups showed a statistical difference as compared to the ET group (p < 0.01, Student test). Mean LTB4 concentration of the negative control group (4.44 +/- 0.33 ng/ml) was also significantly lower (p<0.01) than in the ET group (5.10 +/- 0.61). Treatment with DFNa did not result in a decrease of the aqueous LTB4 levels. It is concluded that topical DFNa results in a decrease of aqueous PGE(2), without affecting LTB levels. To the best of our knowledge, such an effect of topical DFNa has not been reported previously. PMID- 22822786 TI - S-antigen-like protein in porcine ciliary epithelium. AB - A soluble protein with a molecular weight of approximately 52,000 Da (from SDS polyacrylamide gel electrophoresis) was purified from porcine ciliary body, vitreous body and retina by ammonium sulfate fractionation, Sephacryl S-300 gel filtration, and DEAE-cellulose ion exchange chromatography. The protein has a higher molecular weight than bovine S-antigen which is a highly pathogenic retinal antigen, and was eluted from DEAE-cellulose at a slightly higher NaCl concentration than the concentration at which bovine S-antigen was eluted. By reaction with anti-bovine S-antigen polyclonal antibodies, the porcine protein and bovine S-antigen showed full immunological identity. Using a panel of five monoclonal antibodies (MAbs) directed against epitopes spanning the entire length of bovine S-antigen, the porcine protein was analyzed by the enzyme immunoassay and found to react with all MAbs except one that is specific for a species specific epitope of bovine S-antigen. Immunocytochemical labeling of porcine ciliary body using all of the MAbs demonstrated that the 52,000-Da protein was primarily localized to the nonpigmented epithelial cells rather than the pigmented epithelial cells. Consistent with this localization, the 52,000-Da protein was synthesized by in vitro translation of mRNA extracted from the nonpigmented cells. When injected into Lewis rats, the porcine protein was found to be far less effective in inducing uveoretinitis than native bovine S-antigen. PMID- 22822787 TI - Serum sex steroid hormones and frailty in older American men of the Third National Health and Nutrition Examination Survey (NHANES III). AB - OBJECTIVE: To determine whether frailty is associated with circulating total and free testosterone, total and free estradiol, and sex hormone-binding globulin (SHBG) in older men. METHODS: With NHANES III data of 461 men aged 60 years and older, we used logistic regression to analyze the associations between serum concentrations of sex steroid hormones, SHBG and frailty. Participants meeting any three or more of the five frailty criteria were classified as "frail", all others were considered as non-frail. RESULTS: 2.5% of men were frail. Men with SHBG >=66 nmol/L had three times the odds of frailty (OR = 2.97; 95% CI 1.28 6.86) compared to men with SHBG <66 nmol/L. Men with free testosterone levels below 243 pmol/L had an increased odds of frailty (OR = 3.92; 95% CI 1.29-11.89). None of these associations was statistically significant after additionally adjusting for body mass index, smoking and history of cardiovascular diseases (CVD). Total testosterone, and total and free estradiol serum levels were not statistically significantly associated with frailty. CONCLUSIONS: In this US nationally representative study of older men, low free testosterone and high SHBG serum levels were associated with a significantly increased odds of frailty after adjustment for age and race/ethnicity. These associations may, however, be explained by confounding due to obesity, smoking, and the higher prevalence of CVD in frail men or by low hormones or high SHBG mediating the association between obesity, smoking, CVD and frailty. PMID- 22822788 TI - Trial of labor and vaginal delivery rates in women with a prior cesarean. AB - OBJECTIVE: To evaluate evidence on trial of labor (TOL) and vaginal delivery rates in women with a prior cesarean and to understand the characteristics of women offered a trial of labor. DATA SOURCES: MEDLINE, DARE, and Cochrane databases were searched for articles evaluating mode of delivery for women with a prior cesarean delivery published between 1980 and September 2009. STUDY SELECTION: Studies were included if they involved human participants, were in English, conducted in the United States or in developed countries, and if they were rated fair or good base on U.S. Preventive Services Task Force (USPSTF) criteria. DATA EXTRACTION AND SYNTHESIS: The search yielded 3,134 abstracts: 69 full-text papers on TOL and vaginal birth after cesarean (VBAC) rates and 10 on predictors of TOL. The TOL rate in U.S. studies was 58% (95% CI [52, 65]) compared with 64% (95% CI [59, 70]) in non U.S. STUDIES: The TOL rate in the U.S. was 62% (95% CI [57, 66]) for studies completed prior to 1996 and dropped to 44% (95% CI [34, 53]) in studies launched after 1996, p = .016. In U.S. studies, 74% (95% CI [72, 76]) of women who had a TOL delivered vaginally. Women who had a prior vaginal birth or delivered at a large teaching hospital were more likely to be offered a TOL. CONCLUSIONS: Although the TOL rate has dropped since 1996, the rate of vaginal delivery after a TOL has remained constant. Efforts to increase rates of TOL will depend on patients understanding the risks and benefits of both options. Maternity providers are well positioned to provide key education and counseling when patients are not informed of their options. PMID- 22822789 TI - Cultural identity and mental health: differing trajectories among Asian and Latino youth. AB - Asians and Latinos are the 2 fastest growing immigrant populations in the United States. In this 3-year longitudinal study, we explored trajectories of mental health symptoms (withdrawn/depressed and somatic symptoms) among 163 first- and second-generation Asian (n = 76) and Latino (n = 97) adolescents. The focus of the study was to examine how ethnic identity and U.S. identity, as 2 separate processes of identity development, affect mental health symptoms, and whether these relationships are moderated by ethnic group, Asian or Latino. Participants were recruited when they entered 10th grade, and 2 additional waves of data were gathered at 12-month intervals. Results revealed that somatic and depressed symptoms decreased over time for both groups. Similarly, for both groups, U.S. identity and ethnic identity increased over time. Ethnic identity was associated with lower levels of withdrawn/depressed symptoms for both Latino and Asian youth. Ethnic identity was associated with lower levels of somatic symptoms for Asian youth, but not for Latino youth. U.S. identity was not associated with reduced levels of somatic or withdrawn/depressed symptoms for either group. Implications for clinicians are discussed. PMID- 22822790 TI - Real-time tele-echocardiography: diagnosis and management of a pericardial effusion secondary to pericarditis at an Antarctic research station. AB - The McMurdo Research Station medical facility functions at the level of a rural community hospital emergency department. Telehealth technology has played an increasingly important role in providing intercontinental tertiary healthcare consultations, particularly for assistance with diagnostically challenging cases or cases involving complicated medical management. The role of telehealth in Antarctica is vital given the harsh and remote environment. The following case discusses a real-time tele-ultrasound consultation between the station physician and a patient with pericarditis at the McMurdo Medical Clinic in Antarctica and a team of cardiology consultants at the University of Texas Medical Branch, Galveston, TX. The use of teleheath technologies prevented an unnecessary intercontinental medical evacuation and allowed the patient to receive treatment at the McMurdo Research Station. This case report demonstrates that real-time tele-ultrasound can serve as an important diagnostic resource in the delivery of healthcare to isolated populations in remote environments. PMID- 22822900 TI - Making dendritic cells that turn immune responses off. PMID- 22822901 TI - The study of time perception in migraineurs. AB - OBJECTIVE: The study aimed to explore the impairment of time perception in migraineurs. BACKGROUND: Headache is the most common pain syndrome in middle-aged adults, and migraine is highly prevalent and severely disabling. Although the mechanisms of and the therapies for migraines have long been explored, less is known about the functional impairments associated with them, especially the impairment in time perception, that is, the ability to estimate the passage of time. METHODS: In this study, we used a temporal reproduction task to assess the estimation of the duration of visual stimulus in 27 migraine patients. The stimulus was delivered at different intervals over the milliseconds and seconds range. RESULTS: In the setting of an interstimulus interval for 1 second and an interstimulus interval for 5 seconds in the 600-millisecond-duration reproduction task, the migraineurs showed impairment in time perception, and in that they significantly overestimated the duration, as compared with the healthy subjects. When compared with the healthy controls for the 3-second and 5-second duration reproduction task, migraineurs in the setting of an interstimulus interval for 1 second and an interstimulus interval for 5 seconds did not show impairment in time perception. CONCLUSIONS: This study indicates that not only is time perception impaired in migraineurs, but that this impairment is exhibited for durations in the milliseconds range, and not the seconds range. PMID- 22822902 TI - Intensification of insulin therapy in patients with type 2 diabetes mellitus: an algorithm for basal-bolus therapy. AB - The incidence of diabetes mellitus is projected to continue to increase worldwide over the next 20 years leading to increased costs in the management of the disease and its associated co-morbidities. Insulin replacement is one of many treatment options that can help to bring about near normoglycemia in the patient with type 2 diabetes mellitus (T2DM). Glycemic control as close to normoglycemia as possible can help to reduce the risk of microvascular and macrovascular complications, yet less than one-half of patients with T2DM achieve glycemic targets as recommended by practice guidelines. The purpose of this review is to provide guidance to primary care physicians for the initiation and intensification of basal-bolus insulin therapy in patients with T2DM. Two treatment algorithms that can be both patient- and physician-driven are proposed: a stepwise approach and a multiple daily injections approach. Evidence shaping the two approaches will be discussed alongside management issues that surround the patient treated with insulin: hypoglycemia, weight gain, patient education, and quality of life. PMID- 22822903 TI - Acute exudative paraneoplastic polymorphous vitelliform maculopathy in five cases. AB - BACKGROUND AND OBJECTIVE: To evaluate clinical features, course, and outcome of patients with acute exudative paraneoplastic polymorphous vitelliform maculopathy (AEPPVM). PATIENTS AND METHODS: Retrospective case series of 5 patients. RESULTS: There were 3 males and 2 females, with a median age of 74 years. The primary neoplasms were cutaneous melanoma (n = 2), choroidal melanoma (n = 1), lung adenocarcinoma (n = 1), and lung plus breast adenocarcinoma (n = 1). The mean interval between the diagnosis of the primary neoplasm and the diagnosis of AEPPVM was 42 months. The presenting symptom was blurred vision in all cases. Ophthalmoscopy disclosed multifocal localized shallow serous detachments of the post-equatorial neurosensory retina with yellow-white subretinal debris confirmed by optical coherence tomography (OCT). There was a mean of 21 individual sites of detachment per eye, each measuring a mean of approximately 0.8 millimeter in diameter. Fundus autofluorescence depicted hyperautofluorescence corresponding to the detachments. After mean follow-up of 5 months, three patients had died of metastases. Of the two survivors, one showed resolution of lesions and the other was unchanged. CONCLUSION: AEPPVM is a paraneoplastic retinopathy found in patients with metastatic melanoma or carcinoma. The most salient feature is reduced visual acuity from multifocal shallow retinal detachments less than 1-mm diameter, best depicted on OCT. PMID- 22822904 TI - Noninvasive imaging of mitochondrial dysfunction in dry age-related macular degeneration. AB - BACKGROUND AND OBJECTIVE: Oxidative stress and mitochondrial dysfunction are implicated in the pathogenesis of age-related macular degeneration (AMD). Because increased flavoprotein fluorescence (FPF) is indicative of mitochondrial dysfunction, the authors attempted to detect mitochondrial dysfunction in eyes with AMD using FPF. PATIENTS AND METHODS: Six nonexudative eyes with AMD, including three with geographic atrophy (GA), and age-matched control eyes were imaged with a FPF device. Qualitative and quantitative analyses were conducted on the FPF images. RESULTS: Five eyes with AMD, including all three eyes with GA, showed qualitative and/or quantitative FPF heterogeneity that was not present in control eyes. Mean FPF average intensities of eyes with AMD with (P = .044) and without (P = .00060) GA were significantly greater than those of control eyes. The standard deviations of FPF images were greater in eyes with AMD (P = .020). CONCLUSION: In this small cluster of patients with AMD, retinal FPF is increased, suggesting elevated mitochondrial dysfunction. FPF heterogeneity indicates that an increased variability in mitochondrial dysfunction seems to be present in eyes with advanced disease. PMID- 22822905 TI - Air bubbles emanating from the vitrector probe port during vitrectomy. AB - The Constellation Vision System (Alcon Laboratories, Fort Worth, TX) introduces advanced technology with its new microsurgical platform that is growing in popularity. One significant obstacle noted with initial use is a frequent efflux of bubbles from the vitrector that sometimes appears like frothing from the port. Although seemingly innocuous, these bubbles rise in the vitreous cavity and obstruct the surgeon's view of the retina. This frequently necessitates increased surgical time to allow bubble evacuation to restore a clear view to the retina. This report serves to raise surgeon awareness of bubbling at the vitrector port as more surgeons transition to the Constellation Vision System. PMID- 22822906 TI - Religious and national group identification in adolescence: a study among three religious groups in Mauritius. AB - Religious group identification is an important but understudied social identity. The present study investigates religious group identification among adolescents of different faiths (Hindu, Muslim, Christian) living in multicultural Mauritius. It further explores how religious and national group identities come together among religious majority and minority adolescents. For three age groups (11 to 19 years, N = 2152) we examined the strength of adolescents' religious and national group identification, the associations between these two identities, and the relationships to global self-esteem. Across age and religious group, participants reported stronger identification with their religious group than with the nation. Identification with both categories declined with age, with the exception of Muslims, whose strong religious identification was found across adolescence. The association between religious and national identification was positive, albeit stronger for the majority group of Hindus and for early adolescents. We examined the manner in which religious and national identities come together using a direct self-identification measure and by combining the separate continuous measures of identification. Four distinct clusters of identification (predominant religious identifiers, dual identifiers, neutrals, and separate individuals) that were differently associated with global self-esteem were found. Dual identifiers reported the highest level of global self-esteem. The clusters of identification did not fully correspond to the findings for the direct self-identification measure. The results are discussed in terms of the meaning of dual identity and the positive manner in which adolescents can manage their multiple identities while taking into account the ideological framework in which those identities are played out. PMID- 22822907 TI - T regulatory cells play a significant role in modulating MHC class I antibody induced obliterative airway disease. AB - The molecular mechanisms leading to the development of chronic lung allograft dysfunction following de novo development of antibodies to mismatched donor MHC remain undefined. We demonstrated that intrabronchial administration of antibodies to MHC class I resulted in induction of both innate and adaptive cellular immune responses characterized by a predominance of Th17 specific to lung associated self-antigens Kalpha1-tubulin and Collagen-V leading to the development of obliterative airway lesions (OAD), correlate of chronic rejection following human lung transplantation. To determine the role of regulatory T cells (Treg) in the pathogenesis of OAD, we administered anti-MHC class I to mice, in which Treg were depleted by conditional ablation of FoxP3+cells. Under this condition, we observed a threefold increase in pulmonary cellular infiltration, luminal occlusion and fibrous deposition when compared anti-MHC class I Ab administered mice maintaining FoxP3. OAD lesions were accompanied with enhanced accumulation of neutrophils along with self-antigen-specific Th17 and humoral responses. However, IL-17-blockade or adoptive transfer of Treg abrogated OAD. We conclude that Treg exerts a suppressive effect on anti-MHC induced IL-8-mediated neutrophil infiltration and innate immune responses that leads to inhibition of Th17 immune responses to lung associated self-antigens which is critical for development of OAD. PMID- 22822909 TI - Bismuth-catalyzed and doped silicon nanowires for one-pump-down fabrication of radial junction solar cells. AB - Silicon nanowires (SiNWs) are becoming a popular choice to develop a new generation of radial junction solar cells. We here explore a bismuth- (Bi-) catalyzed growth and doping of SiNWs, via vapor-liquid-solid (VLS) mode, to fabricate amorphous Si radial n-i-p junction solar cells in a one-pump-down and low-temperature process in a single chamber plasma deposition system. We provide the first evidence that catalyst doping in the SiNW cores, caused by incorporating Bi catalyst atoms as n-type dopant, can be utilized to fabricate radial junction solar cells, with a record open circuit voltage of V(oc) = 0.76 V and an enhanced light trapping effect that boosts the short circuit current to J(sc) = 11.23 mA/cm(2). More importantly, this bi-catalyzed SiNW growth and doping strategy exempts the use of extremely toxic phosphine gas, leading to significant procedure simplification and cost reduction for building radial junction thin film solar cells. PMID- 22822908 TI - Antiproliferative and antimigratory actions of synthetic long chain n-3 monounsaturated fatty acids in breast cancer cells that overexpress cyclooxygenase-2. AB - Cyclooxygenase-2 (COX-2) is overexpressed in many human cancers and converts the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid to prostaglandin E(2) (PGE(2)), which drives tumorigenesis; in contrast, n-3 PUFA inhibit tumorigenesis. We tested the hypothesis that these antitumor actions of n-3 PUFA may involve the n-3 olefinic bond. n-3 Monounsaturated fatty acids (MUFAs) of chain length C16-C22 were synthesized and evaluated in MDA-MB-468 breast cancer cells that stably overexpressed COX-2 (MDA-COX-2 cells). Longer chain (C19-C22) n 3 MUFAs inhibited proliferation, activated apoptosis, decreased PGE(2) formation, and decreased cell invasion; C16-C18 analogues were less active. Molecular modeling showed that interactions of Arg120, Tyr355, and several hydrophobic amino acid residues in the COX-2 active site with C19-C22 MUFA analogues were favored. Thus, longer-chain n-3 MUFAs may be prototypes of novel anticancer agents that decrease the formation of PGE(2) in tumor cells that contain high levels of COX-2. PMID- 22822910 TI - Virtual drug discovery: beyond computational chemistry? AB - This editorial looks at how a fully integrated structure that performs all aspects in the drug discovery process, under one company, is slowly disappearing. The steps in the drug discovery paradigm have been slowly increasing toward virtuality or outsourcing at various phases of product development in a company's candidate pipeline. Each step in the process, such as target identification and validation and medicinal chemistry, can be managed by scientific teams within a 'virtual' company. Pharmaceutical companies to biotechnology start-ups have been quick in adopting this new research and development business strategy in order to gain flexibility, access the best technologies and technical expertise, and decrease product developmental costs. In today's financial climate, the term virtual drug discovery has an organizational meaning. It represents the next evolutionary step in outsourcing drug development. PMID- 22822911 TI - Building a disease knowledge environment to lay the foundations for in silico drug discovery and translational medicine. AB - The number of new drug approvals per year has been decreasing consistently over the past decade. Although this is due in part to an increase in regulatory requirements, it should also be recognized that the pharmaceutical industry is struggling to feed R&D pipelines with novel molecular entities. The innovation gap is widening as the density and complexity of biomedical information often prevents researchers from efficiently extracting relevant knowledge to foster innovation and support informed decision making. In this article, we discuss how a biomedical knowledge compilation strategy focused around disease can provide a framework to enhance productivity within the pharmaceutical industry. The aim is to systematically structure multidisciplinary data in a pathophysiologically relevant context in order to maximize its therapeutic potential. We predict that in this way the industry should finally be able to leverage on a return on investment from the -omics fields and high-throughput technologies that have failed to live up to its expectations in recent years. Furthermore, we expect that the proposed strategic change in the way biomedical information is managed will support the development of future in silico and systems biology approaches and promote translational research. PMID- 22822912 TI - When analoging is not enough: scaffold discovery in medicinal chemistry. AB - IMPORTANCE OF THE FIELD: As an integral part of lead generation and optimization, scaffold discovery has broad implications in drug discovery. Currently available chemical scaffolds might be inadequate to provide drug-like ligands for new targets such as phosphatases and protein-protein interactions and therapeutically useful chemical space needs to be continuously explored. New scaffolds are often desired to overcome major hurdles (e.g., potency plateau, selectivity, pharmacokinetics, etc.) in lead generation and optimization. Timely discovery of proof-of-concept compounds facilitates target validation, diversifies clinical candidates and improves the overall success rate of drug discovery. AREAS COVERED IN THIS REVIEW: This analysis discusses the strategies involved in finding new scaffolds (i.e., fragment-, ligand- and structure-based design) and their applications (e.g., improve potency/selectivity, multiple ligand design, protein protein interactions, etc.) in drug discovery. WHAT THE READER WILL GAIN: The readers will learn the strategies involved in scaffold design and the problems that they solve. They will also gain the understanding of the circumstances suitable for using scaffold design. TAKE HOME MESSAGE: Scaffold is defined by the authors as a biological target dependent concept. Therapeutically useful scaffolds are limited and the identification of new scaffolds is sometimes required to overcome major optimization hurdles. However, depending on the promiscuity of the binding pocket of the target and the validity of the optimization protocol, finding better scaffolds can be a challenging task. Several strategies in scaffold discovery have emerged or matured owing to recent trends such as pursuit of targets from new proteomic families, lack of validated targets, advances in synthesis and biological assays and adoption of in vitro activity-driven screening paradigms. PMID- 22822913 TI - High-content screening for the discovery of pharmacological compounds: advantages, challenges and potential benefits of recent technological developments. AB - IMPORTANCE OF THE FIELD: Screening compounds with cell-based assays and microscopy image-based analysis is an approach currently favored for drug discovery. Because of its high information yield, the strategy is called high content screening (HCS). AREAS COVERED IN THIS REVIEW: This review covers the application of HCS in drug discovery and also in basic research of potential new pathways that can be targeted for treatment of pathophysiological diseases. HCS faces several challenges, however, including the extraction of pertinent information from the massive amount of data generated from images. Several proposed approaches to HCS data acquisition and analysis are reviewed. WHAT THE READER WILL GAIN: Different solutions from the fields of mathematics, bioinformatics and biotechnology are presented. Potential applications and limits of these recent technical developments are also discussed. TAKE HOME MESSAGE: HCS is a multidisciplinary and multistep approach for understanding the effects of compounds on biological processes at the cellular level. Reliable results depend on the quality of the overall process and require strong interdisciplinary collaborations. PMID- 22822914 TI - Discovery of novel antibacterials. AB - IMPORTANCE OF THE FIELD: Antibiotics have existed in the environment for millennia, but it has only been in the past 80 years that humans have used them systematically to treat infections. This battle between humans and bacteria has led to an alarming increase in resistance to all clinically useful antibacterial agents. Thus, there is an imperative need for new agents to combat these resistant strains of bacteria. AREAS COVERED IN THIS REVIEW: The topics covered include natural product screening, identification and validation of new antibacterial targets and approaches for the discovery and optimization of antibacterial compounds. Last, an assessment of the major challenges facing antibacterial discovery is presented. WHAT THE READER WILL GAIN: The current strategies and methodologies for discovering and designing new antibacterial agents are evaluated as to their potential for generating the next round of therapeutics. Each topic is presented in a general, basic manner and will hopefully be a useful resource for students and newcomers to the field. TAKE HOME MESSAGE: New antibacterial agents are desperately needed to fight the increasing number of antibiotic resistant pathogenic bacteria. New methodologies as well as traditional approaches should both be used for discovering antibiotics to meet this serious medical need. PMID- 22822915 TI - Identification of targets and inhibitors of protein palmitoylation. AB - IMPORTANCE OF THE FIELD: Palmitoylation is the post-translational addition of a 16-carbon fatty acid, palmitate, to specific cysteines of proteins via a labile thioester bond. The transfer of palmitate to a substrate is mediated by palmitoyl acyltransferases (PATs). Nearly a third of the 23 genes that encode PATs are linked to human diseases, in particular cancer, and as such represent important targets for drug development. AREA COVERED IN THIS REVIEW: In this review, we summarize recent technical advances in the field of palmitoylation, how they will affect our ability to understand palmitoylation-related signaling, and outline a general strategy for the discovery of selective and potent palmitoylation inhibitors. WHAT THE READER WILL GAIN: The goals of this review are to increase awareness of the importance of palmitoylation in disease as well as our general lack of understanding of the complexity of the fundamental mechanisms of PAT regulation and specificity, and finally to suggest general strategies for the development of PAT inhibitors. TAKE HOME MESSAGE: Any reasonable hope of developing therapeutically useful, pharmacological modulators of palmitoylation will require that they be developed within the context of PAT-related signaling systems that are more extensively characterized than any we currently know. The successful creation of potent, specific drugs in other similarly complex systems suggests that development of useful drugs targeting PATs is certain. PMID- 22822916 TI - Non-mammalian animal models of Parkinson's disease for drug discovery. AB - IMPORTANCE OF THE FIELD: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of predominantly elderly individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. Compounding this problem is the current lack of a truly representative mammalian model of PD. However, a number of non-mammalian models of PD have been created in recent years that hold tremendous promise to accelerate our understanding of the disease as well as to transform the drug discovery process. AREAS COVERED IN THIS REVIEW: This review provides an overview of the various Caenorhabditis elegans and Drosophila genetic models of PD that have been generated to date and discusses the utility of these model systems in the identification of molecules of potential therapeutic value for the PD patient. WHAT THE READER WILL GAIN: Readers will appreciate the strengths (and limitations) of C. elegans and Drosophila in modeling salient features of the disease as well as their usefulness in uncovering novel gene-gene interaction and pathways relevant to PD pathogenesis. Readers will also appreciate how technological advancements have allowed the direct evaluation of novel compounds in these living models of PD in a virtually high-throughput manner. TAKE HOME MESSAGE: Non-mammalian models of PD provide a valuable in vivo platform for drug screening. Unlike cell-based systems, these living models with an intact nervous system allow for a more meaningful evaluation of the neuroprotective properties of genetic and chemical modifiers to be conducted. PMID- 22822917 TI - Gene expression profiling to identify druggable targets in prion diseases. AB - IMPORTANCE OF THE FIELD: Despite many recent advances in prion research, the molecular mechanisms by which prions cause neurodegeneration have not been established. In fact, the complexity and the novelty characterizing this class of disorders pose a huge challenge to drug discovery. Pharmacogenomics has recently adopted high-throughput transcriptome analyses to predict potential drug target candidates, with promising results in various fields of medicine. AREAS COVERED IN THIS REVIEW: The present work offers an overview of the transcriptional alterations induced by prion infection in different biological systems. Hereafter, therapeutic approaches are discussed in light of the identified altered processes. WHAT THE READER WILL GAIN: This review offers readers a detailed overview on microarray analyses, taking into account their advantages and limitations. Our work can help readers, from many research areas, to design a suitable microarray experiment. TAKE HOME MESSAGE: So far, drugs acting on the pathways identified by microarray analysis have not been found to be effective in prion diseases therapy. An integration of gene expression profiling, proteomics and physiology should be applied to pursue this aim. PMID- 22822918 TI - Seed-litter-position drives seedling establishment in grassland species under recurrent drought. AB - Changes in land use and climate interfere with grassland ecosystem processes. Here I experimentally investigated the combined effects of land-use change related litter cover and contrasting water supply on seedling emergence. In this context, the role of the initial relative position of seeds, i.e. seeds on top of the litter versus seeds beneath the litter in interaction with water supply has not been investigated so far. I hypothesised that facilitative effects of litter on seedling emergence occur when seeds are covered by litter and deteriorate when litter covers the ground and seeds fall on it (seeds on top of the litter). Further, I hypothesised that the importance of seed position for seedling emergence will increase under conditions of recurrent drought. I performed a controlled pot experiment on seedling emergence of three common European grassland species (Pimpinella saxifraga, Leontodon autumnalis, Sanguisorba officinalis) by experimental manipulations of litter and water availability. Seedling emergence under moist conditions showed no significant differences between each litter position compared to the control across species. In contrast, under recurrent drought, seedling emergence was significantly higher below the litter compared to seeds on top of the litter and the control (i.e. no litter). In abandoned land, seedling emergence may be limited when seeds fall on ground covering litter. In contrast, in grasslands with regular low-intensity land use, seedling emergence may be enhanced when a moderate level of litter covers seeds at the end of the growing season. Protective mechanisms that occur with seeds positioned beneath litter are particularly important under recurrent drought. PMID- 22822920 TI - A comparison of heparin-coated and uncoated intraocular lenses in glaucoma patients undergoing combined cataract extraction and trabeculectomy and in diabetic patients undergoing cataract extraction. AB - The postoperative course of cataract extraction and IOL implantation combined with trabeculectomy in glaucoma patients and of cataract extraction with intraocular lens (IOL) in diabetic patients is more complicated than that of cataract extraction with IOL implantation in otherwise healthy eyes. The main complications are fibrin in the anterior chamber, pigment dispersion, and posterior synechiae. In an attempt to determine whether heparin-coated lenses reduce the rate of these complications, a prospective study was conducted on 19 glaucomatous eyes of 19 patients who underwent a combined procedure of trabeculectomy and extracapsular cataract extraction with IOL and 20 eyes of 20 diabetic patients subjected to extracapsular cataract extraction with IOL. In each category of patients, the early postoperative course in those who received heparin-coated lenses and those who received regular polymethyl methacrylate (PMMA) lenses was compared with respect to the inflammatory reaction, assessed by the amounts of cells and flare, and complications in terms of fibrin, posterior synechiae and pigment dispersion. The results of this preliminary study indicate a slightly higher rate of early postoperative complications with the heparin coated lenses as compared to PMMA lenses. PMID- 22822919 TI - Controlling air pollution from straw burning in China calls for efficient recycling. PMID- 22822921 TI - Von Willebrand factor, endothelial damage and ocular disease. AB - Plasma von Willebrand factor (vWF), a marker for vascular damage, was measured in patients with giant cell arteritis (GCA), central retinal vein occlusion (CRVO), and active intraocular inflammation (AII), vWF was highest in GCA (median 3.52 kIU/L) relative to age matched controls (1.08 kIU/L, p<0.0001), with elevated levels in 75% of patients, the highest values found at disease presentation. Longitudinal measurements showed prolonged elevation of vWF, and increased levels were also found in 50% of patients with clinically inactive disease. In CRVO, raised levels were found in 53% of patients (median 2.32 kIU/L, p = 0.0002), but could not differentiate between an ischaemic and non-ischaemic sub-group. There was no statistical difference between those patients with and without systemic disease. Although vWF was raised in 34% of patients with AII (median 1.26 kIU/L, p = 0.0114), it was not different in uveitis (median 1.26 kIU/L), as compared to retinal vasculitis (median 1.58 kIU/L) or in those patients with and without systemic disease. vWF did not correlate with C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) in any of the groups studied. It appears a sensitive test for detecting vascular damage in GCA and may have a role in monitoring the disease where either a prolonged elevation or alteration of vWF levels may be of importance, particularly if ESR and CRP levels are normal. vWF measurement may be limited to more widespread vascular disease, such as in GCA as it was unable to differentiate between different types of CRVO or AII. PMID- 22822922 TI - Passive transfer of the ocular late-phase reaction. AB - The authors report a series of conjunctival provocation tests in a single allergic patient indicating that tears collected during the late phase of a conjunctival reaction induced by allergen challenge, can act as inducers of a new late-phase reaction when applied again to the eye of the same patient. This short report is aimed at stimulating more extensive investigations to confirm the authors' observation and to prove the hypothesis here suggested that soluble mediators present in tears during the late-phase conjunctival reaction can act as inducers of a de novo recruitment of inflammatory cells. PMID- 22822923 TI - Vitronectin: Possible contribution to the closed-eye external host-defense mechanism. AB - Eye closure causes a shift in the preocular tear film, from a reflex tear-rich layer which is in dynamic equilibrium to a secretory IgA-rich layer which is stagnant in nature. This is accompanied by complement conversion and plasminogen activation, followed by polymorphonuclear (PMN) cell recruitment. It is suggested that this shift to a secretory IgA and PMN cell-rich layer serves to protect the ocular surfaces from trapped microorganisms. The mechanisms whereby autologous damage is avoided are uncertain. In other tissues, vitronectin (VN) may be an inhibitor of complement and plasmin induced autolytic damage and a potentiator of microbial phagocytosis. Its presence in the external ocular environment is unknown. To screen for VN, normal human reflex (R), open-eye (O) and closed-eye (C) tear samples were collected, separated by SDS PAGE, and immunoblot probed. Detection was carried out using monoclonal antibodies (MAbs) raised against human VN, coupled to an avidin biotin conjugate-horseradish peroxidase amplification system. Quantitative analysis was carried out using a sandwich ELISA assay. Bovine corneas were sectioned and immunohistochemically stained with MAbs to bovine VN. Results revealed that in going from R to O to C tear fluid there is a marked progressive increase in VN (0.08, 0.75, 3.65 MU/ml). This is accompanied by a shift from the intact 75kDa molecule to the 65kDa breakdown product which is still biologically active, with further degradation occasionally encountered. Immunohistochemical staining of bovine cornea revealed that VN is localized in the corneal epithelium and stromal keratocytes. These findings are compatible with either a local or serological origin for VN, and support the contention that VN may be a component in the external closed-eye host-defense system. PMID- 22822924 TI - The antiinflammatory effect of nordihydroguaiaretic acid in endotoxin induced uveitis in rabbits. AB - The authors evaluated the anti-inflammatory effect of nordihydroguaiaretic acid (NDGA) and dexamethasone on an endotoxin induced uveitis (EIU) model, in rabbits. Six groups of 12 rabbits were formed. In groups II to V a uveitis was induced by an intravitreal injection of 5 ul of saline, containing 10 ng of endotoxin of Salmonella typhi. In group I, which is considered as the control, an intravitreal injection of 5 ul of saline was given. Each group received a different treatment and the inflammatory reaction was evaluated after 24 hours, quantifying the following parameters: clinical scoring, cells, proteins, PGE2, LTB4 in the aqueous and histopathological scoring. Compared to group II (non treated), group VI (treated with intraperitoneal 2 mg/kg dexamethasone) showed a decrease of 61% of proteins and LTB4, and a decrease of more than 90% of the other parameters studied. All these differences are statistically significant (p < 0.001). In groups III (intraperitoneal NDGA 10 mg/kg), IV and V (NDGA 1% topically every two and four hours respectively), the proteins showed a change of less than 5.5% and the PGE2 was reduced to around 50% compared to group II; these changes are not statistically significant (p > 0.05). The authors observed an important and significant decrease of the other parameters when compared to group II (p < 0.001). It can be concluded that at the doses given here, NDGA shows an effective action on the lipoxygenase pathway without an increase of the production of PGE2. PMID- 22822925 TI - Transforming growth factor-beta levels in aqueous humor during experimentally induced uveitis. AB - The anterior chamber of the eye is known to be a site of immune privilege. Particularly, the aqueous humor (AqH) appears to possess unique immunoregulatory properties. The authors have previously shown that human AqH (HAqH) may increase or decrease the proliferation of different cell types. Although no single factor has been established as solely responsible for these effects, much attention has been given to the 24-30 kD fraction of AqH, where transforming growth factor-beta (TGF-beta) is found. The purpose of this study was to determine the changes occurring in the rabbit AqH (RAqH) in relation to intraocular inflammation. Heterologous lens or human serum albumin (HSA) immunization-induced uveitis models were used in two groups of New Zealand albino rabbits to study the relationship between uveitis and TGF-beta. AqH and serum samples were obtained serially before, during and after the induction of ocular inflammation. Systemic humoral immunity to HSA or lens antigens was monitored using enzyme-linked immunosorbent assay (ELISA). A mink lung epithelial cell (CCL-64) bioassay for TGF-beta was used to quantify the amount of this cytokine in RAqH. TGF-beta levels in RAqH increased fourfold after the first immunization. A sharp decrease in RAqH TGF-beta levels was found in association with the development of acute intraocular inflammation. The implications of this finding to the etiology of uveitis are discussed. PMID- 22822926 TI - Aetiological distribution of uveitis patients in Southern Turkey. AB - A prospective study was conducted involving 363 patients seen in the UveaImmunology Clinic of the Department of Ophthalmology, Cukurova University Medical Faculty, to determine the aetiological distribution of uveitis in this region. The results of the study were compared with previous studies carried out on different populations, and the significance of geographical, cultural and genetic factors in the occurrence of uveitis was discussed. In the authors' study group an aetiological diagnosis was established in 68.3% of the patients, whereas 115 cases (31.7%) were diagnosed as idiopathic uveitis. 203 cases (55.9%) were found to be associated with systemic diseases and 45 patients (12.4%), who had a well established clinical uveitis without a recognizable systemic disorder were diagnosed as having primary ocular syndromes. Although the aetiological distribution of the patients in our study group was found to be similar to that of other populations living in different regions in Turkey, it was completely different from the results of studies performed on populations living in different geographical areas of the world, who have different cultural and genetic characteristics. In the authors' study an associated condition was found in a high percentage of the patients, the most frequent of which was Behcet's disease (32.5%). PMID- 22822927 TI - Determinants of asthma control and quality of life in stable asthma: evaluation of two new cough provocation tests. AB - INTRODUCTION: Asthma control and quality of life are poorly associated with traditional asthma biomarkers. OBJECTIVES: In the present study, we evaluated two new cough provocation tests in this respect. METHODS: Asthma Control Questionnaire and Leicester Cough Questionnaire were completed by 36 stable asthmatics. Cough provocation tests with hypertonic saline and isocapnic hyperpnoea of dry air were performed, as well as spirometry, ambulatory peak expiratory flow (PEF) monitoring and exhaled nitric oxide (eNO) measurement. RESULTS: Leicester Cough Questionnaire score correlated closely with cough responsiveness to hypertonic saline and isocapnic hyperpnoea (R = -0.66, P < 0.001 and R = -0.49, P = 0.002, respectively). Asthma Control Questionnaire score also correlated with the cough responsiveness to these tests (R = 0.52, P = 0.001 and R = 0.43, P = 0.008, respectively). Forced expiratory volume in 1 s (%predicted), diurnal PEF variation and eNO did not correlate with cough-related quality of life but showed some association with asthma control. There was a significant correlation between Leicester Cough Questionnaire and Asthma Control Questionnaire (R = -0.54, P = 0.001). CONCLUSIONS: Asthma control and cough related quality of life are more closely associated with cough responsiveness to the investigated cough provocation tests than to eNO and traditional indices of bronchial obstruction. Cough is a major contributor to poor asthma control. PMID- 22822928 TI - Flurbiprofen concentration in soft tissues is higher after topical application than after oral administration. AB - AIM: To compare tissue concentrations of flurbiprofen resulting from topical application and oral administration according to the regulatory approved dosing guidelines. METHOD: Sixteen patients were included in this study. Each patient was randomly assigned to the topical application or oral administration group. In each group, a pair of tapes or a tablet, containing a total of 40 mg flurbiprofen, was administered twice at 16 and 2 h before the surgery. RESULTS: The flurbiprofen concentration in the fat, tendon, muscle and periosteum tissues was significantly higher (P < 0.0330) after topical application (992 ng g-1 [95% CI 482, 1503], 944 [95% CI 481, 1407], 492 [95% CI 248, 735], and 455 [95% CI 153, 756], respectively) than after oral administration (150 ng g-1 [95% CI 84, 217], 186 [95% CI 118, 254], 82 [95% CI 49, 116],and 221 [95% CI, 135, 307], respectively). CONCLUSION: Topical application is an effective method to deliver flurbiprofen to the human body, particularly to soft tissues near the body surface. PMID- 22822929 TI - The challenges and realties of diaper area cleansing for parents. AB - OBJECTIVE: To explore the complexities of diaper area cleansing reported by women participating in a randomized controlled trial designed to compare optimally formulated baby wipes (Johnson's Baby Skincare fragrance free wipe) with cotton wool and water. DESIGN: A mixed-method design incorporating quantitative and qualitative methods to explore maternal views and experiences of using baby wipes or cotton wool and water to cleanse their newborn's diaper area over an 8-week period. SETTING: Participants were recruited from a large regional maternity hospital in Northern England. PARTICIPANTS: Participants included 280 women and their healthy term newborns; 252 provided 4-week data (90.0%) and 237 provided 8 week data (85.0%). METHODS: Data from diaries and structured face-to-face interviews at 4 weeks and telephone interviews at 8 weeks were transcribed and thematically analyzed to identify themes. Quantitative data were compared between randomized groups using descriptive statistics and two-group tests, where appropriate. RESULTS: Major themes identified highlighted the practical realities of diaper area cleansing, diaper area cleansing and everyday life, and living with the rhetoric that water is best. Baby wipes were perceived as more convenient efficient at cleansing. Some women using cotton wool and water did not cleanse skin after urination alone. Diaper changing was significantly more frequent in the baby wipes group at 4 weeks, but there was no significant difference between the groups at 8 weeks. CONCLUSION: Women are faced with a complex environment regarding diaper area cleansing and need clear evidence-based advice and guidance on effective diaper area cleansing. PMID- 22822931 TI - The use of lexical and referential cues in children's online interpretation of adjectives. AB - Recent research on moment-to-moment language comprehension has revealed striking differences between adults and preschool children. Adults rapidly use the referential principle to resolve syntactic ambiguity, assuming that modification is more likely when there are 2 possible referents for a definite noun phrase. Young children do not. We examine the scope of this phenomenon by exploring whether children use the referential principle to resolve another form of ambiguity. Scalar adjectives (big, small) are typically used to refer to an object when contrasting members of the same category are present in the scene (big and small coins). In the present experiment, 5-year-olds and adults heard instructions like "Point to the big (small) coin" while their eye-movements were measured to displays containing 1 or 2 coins. Both groups rapidly recruited the meaning of the adjective to distinguish between referents of different sizes. Critically, like adults, children were quicker to look to the correct item in trials containing 2 possible referents compared with 1. Nevertheless, children's sensitivity to the referential principle was substantially delayed compared to adults', suggesting possible differences in the recruitment of this top- down cue. The implications of current and previous findings are discussed with respect to the development of the architecture of language comprehension. PMID- 22822930 TI - Developmental regulation across the life span: toward a new synthesis. AB - How can individuals regulate their own development to live happy, healthy, and productive lives? Major theories of developmental regulation across the life span have been proposed (e.g., dual-process model of assimilation and accommodation; motivational theory of life-span development; model of selection, optimization, and compensation), but they have rarely been integrated. We provide an integration of key processes and predictions postulated by the 3 theories. Moreover, we present evidence from 2 age-heterogeneous, cross-sectional studies showing that the different processes of developmental regulation proposed by the different theories center around 3 key processes (i.e., goal engagement, goal disengagement, and metaregulation), which are positively associated with age and well-being. We conclude by proposing an agenda for future research. PMID- 22822932 TI - The role of symbol-based experience in early learning and transfer from pictures: evidence from Tanzania. AB - Extensive exposure to representational media is common for infants in Western culture, and previous research has shown that soon after their 1st birthday, infants can acquire and extend new information from pictures to real objects. Here we explore the extent to which lack of exposure to pictures during infancy affects children's learning from pictures. Infants were recruited from a rural village in Tanzania and had no prior experience with pictures. After a picture book interaction during which a novel depicted object was labeled, we assessed infants' learning and transfer of the label from pictures to their referents. In a 2nd study, we assessed infants' learning and generalization of new names using real objects, rather than pictures. Tanzanian infants demonstrated a similar pattern of learning and generalization from real objects, when compared with infants in Western culture. However, there was a significant difference in learning and generalization from pictures to real objects. These findings provide evidence for the important role of early experience with representational media in children's ability to use pictures as a source of information about the world. PMID- 22822933 TI - Children's use of information quality to establish speaker preferences. AB - Knowledge transfer is most effective when speakers provide good quality (in addition to accurate) information. Two studies investigated whether preschool- (4 5 years old) and school-age (6-7 years old) children prefer speakers who provide sufficient information over those who provide insufficient (yet accurate) information. Children were provided clues to the location of hidden dots by speakers who varied in quality and accuracy. Subsequently, children decided from whom they would like to receive additional information. In Study 1, when the outcome of the clue was clear, preschool- (n = 40) and school-age (n = 42) children chose to solicit information from sufficient rather than from insufficient speakers. In Study 2, when not provided with information about the outcome of the speakers' clues, school-age (n = 22), but not preschool-age (n = 19), children preferred sufficient relative to insufficient speakers. Results highlight a developmental progression in children's use of information quality as a cue to determining that individuals are preferable informants. PMID- 22822934 TI - Social goals, social behavior, and social status in middle childhood. AB - This study examines motivational precursors of social status and the applicability of a dual-component model of social competence to middle childhood. Concurrent and longitudinal relationships between self-reported social goals (social development, demonstration-approach, demonstration-avoid goal orientations), teacher-rated prosocial and aggressive behavior, and peer nominations of social status (preference, popularity) were examined over the course of an academic year among 980 3rd- to 5th-grade children. Findings support dual-component expectations. Confirmatory factor analyses verified the expected 3 factor structure of social goals and 2-factor structure of social status. Structural equation modeling (SEM) found that (a) social development goals were associated with prosocial behavior and increased preference, and (b) demonstration-approach goals were associated with aggressive behavior and increased popularity. Demonstration-avoid goals were associated with a popularity decrease. SEMs were invariant across grade, gender, and ethnicity. Discussion concerns the potential risks of high social status, extensions to the dual component model, and the generality of an achievement goal approach to child social development. PMID- 22822935 TI - "Shall we blick?" Novel words highlight actors' underlying intentions for 14 month-old infants. AB - By 14 months, infants have become exquisite observers of others' behavior and successful word learners. But do they coordinate their early observational and language capacities to gain insight into the intentions of others? Building upon Gergely, Bekkering, and Kiraly's (2002) classic head-touch phenomenon, we consider the contribution of language to 14-month-old infants' imitation of an unconventional behavior (turning on a light with one's forehead, rather than hand). Providing a novel word ("I'm going to blick the light!") prompted infants to imitate; simply drawing attention to the action ("Look at this!"; "Look at what I'm doing!") did not. Thus, by 14 months, infants gain insight into the intentions of others by considering not only what we do but also what we say. PMID- 22822936 TI - The effect of verbal reminders on memory reactivation in 2-, 3-, and 4-year-old children. AB - For adults, verbal reminders provide a powerful key to unlock our memories. For example, a simple question, such as "Do you remember your wedding day?" can reactivate rich memories of the past, allowing us to recall experiences that may have occurred days, weeks, and even decades earlier. The ability to use another person's language to access our memory of a prior experience is considered to be one of the hallmarks in human memory development, but surprisingly, little is known about the ontogeny of this fundamental ability. Prior research has shown that by 4 years of age, children can use a simple verbal reminder (e.g., "Do you remember coming here before?") to reactivate an otherwise inaccessible memory of a unique visual stimulus. Given that language comprehension precedes production, it has been hypothesized that the ability to use verbal reminders may emerge well before 4 years of age. In the present experiment, we tested this hypothesis by examining whether a verbal reminder reactivated memory in 2-, 3-, and 4-year-old children who were tested using the visual-paired comparison (VPC) paradigm. Our findings showed that the ability to exploit a simple verbal reminder emerges by at least 2 years of age. PMID- 22822937 TI - Reading to learn: prereaders' and early readers' trust in text as a source of knowledge. AB - Literacy gives children an opportunity to benefit from others' knowledge and experience that far exceeds what they can achieve when reliant on learning orally via personal encounters. Little is known about young children's understanding and use of print as a source of knowledge. Three experiments investigated children's use and understanding of printed names as sources of information about the identity of unfamiliar targets. Children in Experiment 1 (N = 34, ages 5 years 5 months to 7 years 5 months) proactively used printed labels to correct their guesses. In Experiment 2 (N = 86, ages 3 years 7 months to 6 years 2 months), early readers offered a picture strip with labels (illegible to them) rather than one without labels to help a doll identify the target. Younger prereaders showed no such preference. In Experiment 3 (N = 69, ages 3 years 2 months to 6 years 2 months), early readers believed oral suggestions backed up with labels (illegible to them) over suggestions without such backing. Younger prereaders less frequently showed such trust in the reliability of information gained via print. Children may treat print as a reliable source of knowledge as soon as they can decode print for themselves, but not before. PMID- 22822938 TI - Pragmatic inference, not semantic competence, guides 3-year-olds' interpretation of unknown number words. AB - Before children learn the specific meanings of numerals like six, do they know that they represent precise quantities? Previous studies have reported conflicting evidence and have found that children expect numerals to label precise quantities in some tasks but not in others (Condry & Spelke, 2008; Sarnecka & Gelman, 2004). In this article, we present evidence that some of children's apparent successes are best explained not by domain-specific semantic understanding of number but instead by language-general pragmatic abilities. In Experiment 1, we replicated the findings of the previous studies in a within subject design. When 3-year-olds saw a set labeled with a number (e.g., five) and an item was added, they preferred a new label (six) over the old one, as though they believed that number words have precise meanings. However, when 1 of 2 sets was labeled (e.g., as five) and children were asked to find the same quantity (five) or a new quantity (six), they performed identically whether the original set was changed in quantity or merely rearranged. Thus, when 2 numerals were offered as alternative labels for 1 set, children behaved as though they had precise meanings, whereas when they were asked to determine which of 2 sets a single numeral referred to, they did not. In Experiment 2, children were tested using similar methods but with novel nouns and objects that were transformed, instead of sets. Children showed the identical pattern of results despite lacking meanings for these words, suggesting that their judgments for numerals may not have relied on semantic knowledge that numerals have precise meanings. We propose that children's behavior can be explained by the use of domain-general pragmatic inference and does not require positing domain-specific numerical knowledge. PMID- 22822939 TI - Evaluation of blind thoracoscopic-assisted placement of three double-lumen endobronchial tube designs for one-lung ventilation in dogs. AB - OBJECTIVE: To describe a technique for blind thoracoscopic-assisted double-lumen endobronchial tube (DLT) placement for achieving one-lung ventilation (OLV) using 3 different DLT designs and to evaluate whether thoracic auscultation could reliably confirm OLV in dogs. STUDY DESIGN: Prospective randomized study. ANIMALS: Mature female hound dogs (n = 6). METHODS: Physical examination, baseline blood work and thoracic radiography confirmed the absence of preexisting disease in all dogs. Thoracoscopic observation was established through a subxiphoid portal and used for evaluation of differential lung lobe ventilation. Each dog was sequentially intubated using 1 of 3 DLT designs in random order; Robertshaw left-sided tube (RS-L), Carlens left-sided tube (C-L), Dr. White right sided tube (DW-R). Incidence of initial and overall (after a maximum of 3 DLT manipulations) correct and complete OLV (CC-OLV) was recorded. After each blind thoracoscopic-assisted DLT placement, bronchoscopic evaluation was performed to document correct DLT position. RESULT: Blind DLT placement achieved overall CC OLV in all dogs using RS-L, 66% using C-L, and all using DW-R. Successful initial left-sided OLV (L-OLV) was statistically more likely when RS-L DLTs were used compared to C-L or DW-R. Of cases where overall CC-OLV was achieved, correct DLT position was present in only 44% of intubations. CONCLUSIONS: Blind DLT placement produced successful CC-OLV in all dogs using at least one DLT design evaluated. Use of thoracoscopic assistance may obviate the need for bronchoscopic observation during DLT placement in dogs. However, bronchoscopic observation may still refine DLT positioning in dogs after blind thoracoscopic-assisted DLT placement. PMID- 22822940 TI - Rural inpatient telepharmacy consultation demonstration for after-hours medication review. AB - OBJECTIVE: Medication errors contribute to a significant number of fatal and nonfatal adverse medical events each year. Many actions, from both a policy and innovation standpoint, have been taken to reduce medication errors in the inpatient setting; yet, these actions often target larger urban hospitals. Rural hospitals face many more challenges in implementing these changes due to fewer resources and lower patient volumes. Our article discusses the implementation and results of a telepharmacy demonstration implemented between the University of California Davis Health System and six rural hospitals. MATERIALS AND METHODS: A retrospective chart review obtained baseline medication errors for comparison with the prospective review of medication orders through telepharmacy. Medication orders from rural hospitals were transmitted via fax to the University of California Davis Pharmacy for after-hours review. If a medication required after hours removal from the pharmacy, it was requested that video verification by a telepharmacist be used to verify that the correct medication was removed from the pharmacy. RESULTS: Baseline findings from the retrospective chart review indicated that 30.0% of patients had one or more medication errors and that these errors occurred in 7.2% of the medication orders. None of these errors were found to have resulted in harm to the patients. During the telepharmacy demonstration, 2,378 medication orders were screened from 504 independent order review requests. In total, 58 (19.2%) patients had one or more medication errors. The errors from the telepharmacy demonstration represented potential errors that were identified through telepharmacy medication review. CONCLUSIONS: Telepharmacy represents a potential alternative to around-the-clock on-site pharmacist medication review for rural hospitals. PMID- 22822941 TI - Pro-inflammatory role of angiotensin II in mercuric chloride-induced nephropathy in rats. AB - Mercuric chloride (HgCl2), which induces kidney toxicity, constitutes a potential threat to human health. In addition to direct toxic effects, kidney inflammatory events take place during the HgCl2-induced nephropathy. There is no information currently available about the role of angiotensin II (Ang II) in this inflammatory process. Accordingly, the aim of this study was to determine the expression of Ang II and Ang II-associated inflammatory molecules, i.e. intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS), and mono-cyte/macrophage infiltration (ED-1), in HgCl2-induced nephropathy. Three groups of Sprague Dawley rats that were to receive HgCl2 (2.5 mg HgCl2/kg BW, by gavage) were utilized: one had received Losartan at 30 mg/kg BW; one had received Enalapril at 30 mg/kg BW; and one had received distilled water, in each case daily for 3 days prior to the HgCl2 exposure. For these studies, an extra set of controls treated with saline solution in place of HgCl2 and water in place of the test drugs was employed. Renal biopsies were obtained 96 h after HgCl2 injection and the expressions of Ang II, ICAM-1, iNOS, and ED-1 were analyzed by indirect immunoflourescence while tubular damage was assessed via histopathology. An increased expression of Ang II, ICAM-1, iNOS, and ED-1 as well as increases in tubular necrosis were observed in all HgCl2-animals. Treatments with Losartan or Enalapril diminished the induced expressions as well as the extent of tubular damage. The data here suggest that Ang II is involved in the pro-inflammatory events during HgCl2-induced nephropathy, and that this is probably mediated, in part, by Ang II receptors Type 1 (AT-1). PMID- 22822989 TI - Dispositional optimism and physical wellbeing: the relevance of culture, gender, and socioeconomic status. AB - The present study examined the relationship between dispositional optimism and physical wellbeing (as reflected in physical symptom reporting) in two groups of American and Jordanian college students. It also assessed moderation effects of culture, gender, and socioeconomic status (SES). Participants were administered a questionnaire consisting of items pertaining to dispositional optimism (as measured by the Revised Life Orientation Test, LOT-R) along with items assessing physical symptom reporting and sociodemographic factors (e.g., gender, socioeconomic status). The results revealed significant negative correlations between dispositional optimism and physical symptom reporting for both American and Jordanian participants, although the magnitude of the correlation for the American group was noticeably larger than that for the Jordanian group. The results also showed that women, especially Jordanians, were more likely than men to report physical symptoms. Among Jordanians, physical symptom reporting was more common among those of lower SES. No statistically significant differences in physical symptom reporting were found between American men and women or between the two cultural groups. Multiple regression analyses revealed no statistically significant interactions between optimism and cultural background, optimism and gender, or optimism and SES. Overall, the results suggest that optimism is the factor most predictive of physical symptom reporting, followed by SES and gender. These results corroborate previous findings on the relationship between dispositional optimism and physical wellbeing, and point to crosscultural differences in relationship patterns. These differences suggest that although personality characteristics such as optimism may play an important role in the physical wellbeing of both Western and non-Western groups, the influence of sociodemographic factors such as gender and SES and their interaction with cultural variables must not be overlooked. PMID- 22822991 TI - Effect of lidocaine- and prilocaine-based topical anesthetics on the inflammatory exudates in subcutaneous tissue of rats. AB - The aim of this present study was to evaluate the irritative potential of 2 topical anesthetics used in intrapocket anesthesia for periodontal scaling/root planing when applied in subcutaneous tissue of rats. Sixty animals were divided into 4 groups: group 1, saline solution (control); group 2, poloxamer gel (thermosetting vehicle); group 3, lidocaine and prilocaine poloxamer thermosetting gel; group 4: EMLA, a lidocaine and prilocaine dermatological cream. Injections of 2% Evans blue were administrated intravenously into the lateral caudal vein. In order to analyze vascular permeability, the tested substances were injected intradermally. The rats were sacrificed 3, 6, and 9 hours after injection of the substances. The dorsal skin was dissected and removed. The vascular permeability was evaluated by the measurement of area of dye extravasation and the dye was subsequently extracted after immersion in formamide. Statistical analyses were made by ANOVA with Bonferroni's post hoc test and Pearson correlation. The 2 methods to analyze the exudative phase of the inflammatory process showed statistically significant difference among the groups and periods of evaluation (P < .05). Both methods had a significant correlation (P < .0001). Under the tested conditions, the anesthetic agents showed mild initial inflammatory response when implanted in subcutaneous connective tissue. PMID- 22822992 TI - A comparison of dexmedetomidine sedation with and without midazolam for dental implant surgery. AB - Dexmedetomidine (DEX) has a minimal respiratory depressive effect, which is beneficial for dentistry; however, it has the disadvantage of permitting an intraoperative arousal response such that the patient appears to be suddenly no longer sedated, and it has a variable amnestic effect. Since midazolam (MDZ) in an appropriate dose has a profound amnesic effect, we investigated whether additional MDZ compensates for the disadvantage of DEX and enables a better quality of sedation. Forty-three subjects were randomly divided into 4 groups. In group 1, MDZ (0.02 mg/kg) was administered intravenously, followed by a dose of 0.01 mg/kg every 45 minutes. After the first dose of MDZ, preloading with DEX (2 ug/kg/h for 10 minutes) was started and maintained with a dosage of 0.5 ug/kg/h. In group 2, MDZ was infused in the same manner as in group 1, followed by preloading with DEX (1 ug/kg/h for 10 minutes) and maintenance (0.3 ug/kg/h). In group 3, MDZ was infused 0.03 mg/kg, and a dose of 0.01 mg/kg was given every 30 minutes; DEX was administered at the same as in group 2. In group 4, DEX was infused using the same method as in group 1 without MDZ. The sedation levels, amnesia, and patient satisfaction were also investigated. Group 2 had a lower sedation level and a poor evaluation during the first half of the operation. Group 4 did not exhibit an amnesic effect at the beginning of the operation. An evaluation of the degree of patient satisfaction did not reveal any differences among the groups. Optimal sedation was achieved through the combined use of MDZ (0.02 mg/kg with the addition of 0.01 mg/kg every 45 minutes) and DEX (2 ug/kg/h for 10 minutes followed by 0.5 ug/kg/h). PMID- 22822993 TI - The effect of anesthetic technique on recovery after orthognathic surgery: a retrospective audit. AB - We audited the recovery characteristics of 51 patients who had undergone orthognathic maxillofacial surgery at a single center. Patients whose anesthesia had been maintained with intravenous propofol and remifentanil (n = 21) had significantly higher pain scores during the first 4 hours after surgery than those whose anesthesia was maintained with volatile inhalational agents and longer-acting opioids (n = 30) (P = .016). There was a nonsignificant trend towards shorter recovery times in the former group, while there were no differences in early postoperative opioid usage, hemodynamic parameters, or postoperative nausea and vomiting . Given that our data were collected retrospectively and without the ability to control for potential confounders, we interpret the results with caution. Notwithstanding these limitations, we believe this is the first report comparing the effects of different opioid-based anesthetic regimens on early recovery from orthognathic surgery, and we believe this report may be used as the starting point for a controlled study. PMID- 22822994 TI - The local pharmacokinetics of 3H-ropivacaine and 14C-lidocaine after maxillary infiltration anesthesia in rats. AB - The effects of infiltration anesthesia with ropivacaine on the dental pulp are considered to be weak. This may be partly associated with its permeation into the oral tissue. With the objective of investigating the local pharmacokinetics of ropivacaine and lidocaine following infiltration anesthesia, we injected (3)H ropivacaine or (14)C-lidocaine to the palatal mucosa in rats, measured distributions of radioactivity in the maxilla, and compared the local pharmacokinetics of these agents. The animals were sacrificed at various times and the maxillas were removed. The palatal mucosa and maxillary nerve were resected, and the bone was divided into 6 portions. We measured radioactivity in each tissue and calculated the level of each local anesthetic (n = 8). Lidocaine diffused to the surrounding tissue immediately after the injection, whereas ropivacaine tended to remain in the palatal mucosa for a longer period. Lidocaine showed a higher affinity for the maxillary bone than ropivacaine. There was a correlation between the distribution level of local anesthetics in the maxillary bone and that in the maxillary nerve. The lower-level effects of infiltration anesthesia with ropivacaine on the dental pulp may be because ropivacaine has a high affinity for soft tissue, and its transfer to bone is slight. PMID- 22822995 TI - Complicated airway due to unexpected lingual tonsil hypertrophy. AB - We report an unexpected failed laryngeal mask airway in a patient with unrecognized lingual tonsil hypertrophy (LTH). A 19-year-old obese woman presented for extraction of multiple teeth via intravenous general anesthesia. Surgery was interrupted due to a laryngospasm midway through the procedure. The laryngospasm required the existing laryngeal mask airway to be removed so the patient could be suctioned. Although it is unclear the extent of obstruction caused by LTH, the surgery had to be postponed due to the discovery of enlarged lingual tonsils, which prevented endotracheal intubation. One reason for unexpected difficult airways is attributed to LTH. It is recognized that LTH is more common in patients with obstructive sleep apnea; however, LTH also has an increased prevalence in obese children with prior palatine tonsillectomies or adenoidectomies. Unexpected LTH can complicate general anesthesia by making placement of a laryngeal mask airway difficult. Thus, further research needs to be conducted to gain a deeper understanding on how to reduce the risks presented by LTH during sedation surgeries. PMID- 22822996 TI - Dual bougie technique for nasotracheal intubation. AB - We read with great interest the anesthetic technique of using a gum elastic bougie (GEB) for nasal intubation in a recent issue of Anesthesia Progress. The authors recommend the use of GEB for the first attempt of nasotracheal intubation in patients with a difficult airway. We agree that this is an excellent alternative. We also have found an excellent variation of this method that utilizes a double bougie technique for insertion of a nasotracheal tube if the difficult airway can be secured initially with an orotracheal tube. PMID- 22822997 TI - Anesthetic considerations for masticatory muscle tendon-aponeurosis hyperplasia: a report of 24 cases. AB - Masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) is a new disease entity characterized by limited mouth opening due to contracture of the masticatory muscles, resulting from hyperplasia of tendons and aponeuroses. In this case series, we report what methods of airway establishment were conclusively chosen after rapid induction of anesthesia. We had 24 consecutive patients with MMTAH who underwent surgical release of its contracture under general anesthesia. Rapid induction of anesthesia with propofol and rocuronium was chosen for all the cases. In 7 cases, intubation using the Macintosh laryngoscopy was attempted; however, 2 of those cases failed to be intubated on the first attempt. Finally, intubation using the McCoy laryngoscopy or fiber-optic intubation was alternatively used in these 2 cases. In 7 cases, the Trachlight was used. In the remaining 10 cases, fiber-optic intubation was used. Limited mouth opening in patients with MMTAH did not improve with muscular relaxation. "Square mandible" has been reported to be one of the clinical features in this disease; however, half of these 24 patients lacked this characteristic, which might affect a definitive diagnosis of this disease for anesthesiologists. An airway problem in patients with MMTAH should not be underestimated, which means that other intubation methods rather than direct laryngoscopy had better be considered. PMID- 22822998 TI - Local anesthetics: review of pharmacological considerations. AB - Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article. PMID- 22823001 TI - Control of lateral dimension in metal-catalyzed germanium nanowire growth: usage of carbon sheath. AB - We report on the catalytic growth of thin carbon sheathed single crystal germanium nanowires (GeNWs), which can solve the obstacles that have disturbed a wide range of applications of GeNWs. Single crystal Ge NW core and amorphous carbon sheath are simultaneously grown via vapor-liquid-solid (VLS) process. The carbon sheath completely blocks unintentional vapor deposition on NW surface, thus ensuring highly uniform diameter, dopant distribution, and electrical conductivity along the entire NW length. Furthermore, the sheath not only inhibits metal diffusion but also improves the chemical stability of GeNWs at even high temperatures. PMID- 22823000 TI - Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). AB - The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those >= 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious. PMID- 22823002 TI - Monitoring of immunoglobulin levels identifies kidney transplant recipients at high risk of infection. AB - We aimed to analyze the incidence, risk factors and impact of hypogammaglobulinemia (HGG) in 226 kidney transplant (KT) recipients in which serum immunoglobulin (Ig) levels were prospectively assessed at baseline, month 1 (T(1) ), and month 6 (T(6) ). The prevalence of IgG HGG increased from 6.6% (baseline) to 52.0% (T(1) ) and subsequently decreased to 31.4% (T(6) ) (p < 0.001). The presence of IgG HGG at baseline (odds ratio [OR] 26.9; p = 0.012) and a positive anti-HCV status (OR 0.17; p = 0.023) emerged as risk factors for the occurrence of posttransplant IgG HGG. Patients with HGG of any class at T(1) had higher incidences of overall (p = 0.018) and bacterial infection (p = 0.004), bacteremia (p = 0.054) and acute pyelonephritis (p = 0.003) in the intermediate period (months 1-6). Patients with HGG at T(6) had higher incidences of overall (p = 0.004) and bacterial infection (p < 0.001) in the late period (>6 month). A complementary log-log model identified posttransplant HGG as an independent risk factor for overall (hazard ratio [HR] 2.03; p < 0.001) and bacterial infection (HR 2.68; p < 0.0001). Monitoring of humoral immunity identifies KT recipients at high risk of infection, offering the opportunity for preemptive immunoglobulin replacement therapy. PMID- 22823003 TI - Attitudes to brain donation for Parkinson's research and how to ask: a qualitative study with suggested guidelines for practice. AB - AIM: To describe factors people consider important in deciding whether or not to donate their brain for research after death. BACKGROUND: Brain tissue retrieved at post-mortem is needed to further research into neurological conditions such as Parkinson's disease. Previous research has focussed mainly on attitudes to organ donation for transplantation. DESIGN: Data were gathered and analysed using a qualitative approach based on grounded theory. METHODS: Nineteen people who had made a decision about brain donation, five people with Parkinson's and 14 unaffected individuals, were identified through theoretical sampling. Interviews conducted between September 2007-January 2008 were analysed to identify themes representing the concerns of participants, when making a decision. FINDINGS: The three main themes identified were views and beliefs about post-mortem, the importance of family and the things people do not talk about. Although participants were more familiar with the concept of organ donation for transplantation, unanimous support was expressed for brain donation for research. However, beliefs about death and post-mortem, influence of family and the difficulty in talking and thinking about things to do with death all posed barriers to consent when actually asked to make a decision. For some, however, being asked had acted as a catalyst, transforming previously held positive attitudes into a decision to consent. CONCLUSION: Guidelines for asking developed from these findings highlight the importance of discussing the issue to raise awareness in potential donors, involving family members, and giving accurate and appropriate information to inform, reassure and to dispel misconceptions. PMID- 22823004 TI - Intergenerational transmission and transition to fatherhood: a mediated moderation model of paternal engagement. AB - The aim of this longitudinal study on determinants of parenting was to test a mediated-moderation model of fathers' postnatal engagement with their children in the context of the transition to fatherhood. More precisely, the model postulated that men's marital status (marriage vs. cohabitation) moderated the relation between one characteristic of the family of origin, maternal physical affection, and their level of postnatal engagement and that this interaction effect was mediated by men's involvement during pregnancy. A sample of 158 Canadian men participated in the study during the third trimester of pregnancy and at 6 months postpartum. As expected, results revealed that cohabiting fathers, as compared to married fathers, showed lower levels of postnatal engagement with their newborns when they had received less physical affection from their mothers during their childhood and adolescence. This result was explained by the fact that these men were less involved as future fathers during their partner's pregnancy. Results are discussed in terms of multiplicative effects of risk factors and in terms of intergenerational continuity in parenting. PMID- 22823005 TI - Family carers' perspectives on post-school transition of young people with intellectual disabilities with special reference to ethnicity. AB - BACKGROUND: School leavers with intellectual disabilities (ID) often face difficulties in making a smooth transition from school to college, employment or more broadly to adult life. The transition phase is traumatic for the young person with ID and their families as it often results in the loss of friendships, relationships and social networks. METHOD: The aim of this study was to explore the family carers' views and experiences on transition from school to college or to adult life with special reference to ethnicity. Forty-three families (consisting of 16 White British, 24 Pakistani, 2 Bangladeshi and one Black African) were interviewed twice using a semi-structured interview schedule. The carers were interviewed twice, Time 1 (T1) and Time 2 (T2), T2 being a year later to observe any changes during transition. RESULTS: The findings indicate that although transition planning occurred it was relatively later in the young person's school life. Parents were often confused about the process and had limited information about future options for their son or daughter. All family carers regardless of ethnicity, reported lack of information about services and expressed a sense of being excluded. South Asian families experienced more problems related to language, information about services, culture and religion. CONCLUSIONS: The majority of families lacked knowledge and awareness of formal services and the transition process. Socio-economic status, high levels of unemployment and caring for a child with a disability accounted for similar family experiences, regardless of ethnic background. The three key areas relevant for ethnicity are interdependence, religion and assumptions by service providers. PMID- 22823006 TI - The pre-emptive analgesic effect of a cyclooxygenase-2 inhibitor in a rat model of acute postoperative pain. AB - We examined the pre-emptive analgesic effect of a cyclooxygenase (COX)-2 inhibitor in a rat surgical pain model and characterised the changes in cutaneous COX-2 around a surgical site. Thermal hyperalgesia and mechanical allodynia were tested in the rats for three days after incision and skin tissues were collected for analysis of COX-2. There was decreased expression of cutaneous COX-2 one day after surgical incision. Pre-incision injection of the COX-2 inhibitor significantly inhibited expression of COX-2 and also reduced thermal hyperalgesia (but not mechanical allodynia) compared with the post-incision COX-2-inhibitor injection group, one day after incision. PMID- 22823007 TI - Restriction of transpiration rate under high vapour pressure deficit and non limiting water conditions is important for terminal drought tolerance in cowpea. AB - Drought stress is a major constraint on cowpea productivity, since the crop is grown under warm conditions on sandy soils having low water-holding capacity. For enhanced performance of crops facing terminal drought stress, like cowpea, water saving strategies are crucial. In this work, the growth and transpiration rate (TR) of 40 cowpea genotypes with contrasting response to terminal drought were measured under well-watered conditions across different vapour pressure deficits (VPD) to investigate whether tolerant and sensitive genotypes differ in their control of leaf water loss. A method is presented to indirectly assess TR through canopy temperature (CT) and the index of canopy conductance (Ig). Overall, plants developed larger leaf area under low than under high VPD, and there was a consistent trend of lower plant biomass in tolerant genotypes. Substantial differences were recorded among genotypes in TR response to VPD, with tolerant genotypes having significantly lower TR than sensitive ones, especially at times with the highest VPD. Genotypes differed in TR response to increasing VPD, with some tolerant genotypes exhibiting a clear VPD breakpoint at about 2.25 kPa, above which there was very little increase in TR. In contrast, sensitive genotypes presented a linear increase in TR as VPD increased, and the same pattern was found in some tolerant lines, but with a smaller slope. CT, estimated with thermal imagery, correlated well with TR and Ig and could therefore be used as proxy for TR. These results indicate that control of water loss discriminated between tolerant and sensitive genotypes and may, therefore, be a reliable indicator of terminal drought stress tolerance. The water-saving characteristics of some genotypes are hypothesised to leave more soil water for pod filling, which is crucial for terminal drought adaptation. PMID- 22823009 TI - Pedicle screw-rod fixation of the canine lumbosacral junction. AB - OBJECTIVE: To assess pedicle screw-rod fixation (PSRF) of the canine lumbosacral junction (LSJ) ex vivo and in vivo. STUDY DESIGN: Ex vivo cadaver study and in vivo pilot study. SAMPLE POPULATION: Six canine cadaveric lumbosacral spinal specimens and 3 Greyhound dogs diagnosed with degenerative lumbosacral stenosis (DLSS). METHODS: Ex vivo study: PSRF of the LSJ was performed in 6 spinal specimens using guidelines and was evaluated by radiography, computed tomography, and magnetic resonance imaging. In vivo study: 3 Greyhounds diagnosed with DLSS had dorsal laminectomy and partial discectomy combined with PSRF of the LSJ. Curettage of the endplates with insertion of an autologous cancellous bone graft was performed to promote spinal fusion. During 18-month follow-up, dogs were monitored by clinical evaluation, diagnostic imaging, and force plate analysis. Dogs were euthanatized for reasons unrelated to PSRF or their lumbosacral disease, and postmortem imaging and histopathologic investigations of the LSJ were performed. RESULTS: Ex vivo study: Sixteen of 24 inserted screws had an acceptable placement. In vivo study: Ten of 12 inserted screws had acceptable placement. Clinical signs of ''lower'' back pain resolved at 4 weeks after surgery. Diagnostic imaging and histopathology showed no bony spinal fusion of the LSJ. Force plate analysis revealed a trend toward improved pelvic limb function relative to preoperative function. CONCLUSIONS: PSRF of the LSJ of large breed dogs is technically possible. Improvements to the surgical technique to induce spinal fusion and assessment in a larger sample size are required before it can be recommended. PMID- 22823008 TI - Six-minute walk distance and dyspnoea scores to assess the course of COPD exacerbation in elderly patients. AB - INTRODUCTION: While the severity of stable chronic obstructive pulmonary disease (COPD) has been defined in a valid and relevant prognostic manner, parameters that describe the course of COPD exacerbations are not yet established. Physical performance and dyspnoea are of prognostic relevance in stable COPD. The issue investigated was to assess the course of COPD exacerbations to find parameters that describe this situation better. METHODS: In 82 hospitalised patients with acute exacerbation of COPD who responded to intensified medical treatment (age 67.3 +/- 9.5 years; forced expiratory volume in 1 s 1.0l, 40% predicted), we measured the 6-min walk distance and the visual analogue scale dyspnoea scores before the start of treatment, prior to discharge and after a 4-week stable period. Additionally, the conventional clinical parameters of COPD and quality of life were documented. RESULTS: The 6-min walk distance was significantly increased from 97 +/- 114 m to 290 +/- 106 m. After 4 weeks of outpatient treatment in clinically stable patients, the 6-min walk distance fell non significantly to 270 +/- 120 m. The increment in walk distance fell significantly with advancing severity of COPD: from 112 +/- 68 m for grade I and II to 56 +/- 88 m for grade IV. Resting as well as exertional dyspnoea scores were significantly reduced (resting dyspnoea from 4 to 2 and exertional dyspnoea from 8 to 6). CONCLUSION: We were able to demonstrate that 6-min walk test and dyspnoea scores, but not pulmonary function test, are suitable parameters to assess the course of COPD exacerbations. PMID- 22823010 TI - Recent developments in the immunopathology of intra-ocular inflammation. PMID- 22823011 TI - Choroidal mast cell dynamics during experimental autoimmune uveoretinitis in rat strains of differing susceptibility. AB - Choroidal mast cells have been implicated in the pathogenesis of experimental autoimmune uveoretinitis (EAU). The aim of the present study was to examine the dynamics of choroidal mast cells during the course of EAU in rat strains of varying susceptibility. Histochemical staining showed choroidal mast cell degranulation in Lewis rats, a highly susceptible strain, commenced nine days post-immunisation, and peaked at day 11, at which time the percentage of degranulated choroidal mast cells (32. 5+/- 4%) was significantly higher than controls (15. 3 +/- 3%; p <0.05). At day 14, mean choroidal mast cell density was significantly reduced (from 23. 6 +/- 1/mm(2) tot 16. 2 +/- 2/mm(2); p<0.05) and early signs of choroidal mast cell regeneration were evident. Immunisation of PVG/C (moderate susceptibility) and Brown Norway (very low susceptibility) rats produced a similar pattern of morphological changes. Onset of clinical signs in Lewis rats, which possess approximately 1100 to 1800 choroidal mast cells per eye, occurred one day following commencement of choroidal mast cell degranulation but prior to the peak of degranulation. However, in PVG/C and Brown Norway rats, which possess only approximately 70 and 110 choroidal mast cells per eye respectively, onset of disease was not temporally linked to commencement of degranulation. Production of antigen-specific IgE during the course of EAU was extremely low in all three strains. These results indicate that choroidal mast cells may be important in the pathogenesis of EAU in Lewis rats but not in PVG/C or Brown Norway rats and that non-IgE mediated degranulation may play a role in disease induction. PMID- 22823012 TI - S-antigen immunoreactivity in tumors of the choroid plexus. AB - Using monoclonal antibodies (MAbs) directed against retinal S-antigen, the authors demonstrated the presence of S-antigen immunoreactivity in six of six (100%) tumors of the human choroid plexus, a tissue rich in beta-adrenergic receptor activity. An anti-retinal S-antigen MAb F4C1, showed S-antigen immunoreactivity in one papilloma of the choroid plexus and in five of five (100%) carcinomas of the choroid plexus. In contrast, a papillary ependymoma of the spinal cord, an astrocytoma, an oligodendroglioma, metastatic oat cell carcinoma and metastatic adenocarcinoma to the brain did not stain. Our study indicates that MAb F4C1 may prove to be a useful immunohistochemical marker of tumors originating from the choroid plexus. PMID- 22823013 TI - Conjunctival instillation of retinal antigens induces tolerance Does it invoke mucosal tolerance mediated via conjunctiva associated lymphoid tissues (CALT)? AB - Conjunctiva associated lymphoid tissue (CALT) is histologically very similar to other mucosa associated lymphoid tissue (MALT) like gut associated lymphoid tissue (GALT) and bronchus associated lymphoid tissue (BALT), and forms an integral part of the mucosal immune system. Several studies have shown that antigens encountered by GALT and BALT, induce a state of tolerance rather than sensitization. This MALT induced suppression of immune responses against antigen is manifest in both the humoral and cell mediated components of the immune system. The phenomenon of mucosa induced tolerance to a variety of antigens, including retinal antigens, has been well documented with regard to GALT and BALT. However, similar information concerning CALT is not available. In this preliminary study, using retinal antigens and the experimental autoimmune uveitis (EAU) model, we were able to demonstrate that antigen specific tolerance to two retinal antigens, S-antigen and interphotoreceptor retinol-binding protein (IRBP), could be effectively induced by instillation of the antigens into the conjunctival sac for ten days prior to challenge with the respective antigen. It is likely that tolerance induction by this mode involves CALT. PMID- 22823014 TI - Quantification of transforming growth factor-beta in aqueous humor. AB - The use of biological assays in research often creates complex Problems of data analysis. Due to the nature of bioassays which respond to the intricate interplay between multiple factors that may either increase or decrease the readout, simple arithmetic or standard linear regression analysis often fails to provide accurate values when extrapolation from a standard curve is employed. Non-linear polynomial analysis could provide a better way for expressing such complex relationships. Using a bioassay for transforming growth factor-beta (TGF-beta) employing the mink lung epithelium cell line CCL-64, the authors present a new way to analyze experimental data based on non-linear polynomial statistics to provide accurate quantitative results when other simpler techniques have failed. This technique for data analysis provided accurate consistent results with acceptably small experimental variance. Using this approach, the bioactive concentration of TGF-beta in normal rabbit aqueous humor was found to be 2.72 +/- 0.61 ng/ml, that is, corresponding to 2. 72 ng of PURE TGF-beta2, when referring to a standard curve. PMID- 22823015 TI - Endogenous endophthalmitis due to Listeria monocytogenes. AB - The authors report a case of Listeria monocytogenes endophthalmitis in a patient who had undergone cardiac revascularization surgery and was receiving systemic corticosteroids. The organism was isolated both in the aqueous humor and in blood culture. The infection was successfully treated with intravenous crystalline penicillin, but the patient developed a bullous keratopathy and secondary glaucoma, resulting in poor visual acuity (counting fingers at 0.5 m). The visual acuity recovered to 20/30 after a penetrating keratoplasty and the glaucoma was controlled with a Molteno implant and a trabeculectomy combined with administration of mitomycin. Listeria monocytogenes endogenous endophthalmitis should be suspected in any immunosuppressed patient with severe anterior uveitis, especially when a brown hypopyon, high intraocular pressure and corneal edema are present. PMID- 22823016 TI - Coats' disease and Fuchs' heterochromic cyclitis. AB - The authors present an interesting case of a young boy with unilateral Coats' disease who after ten years of follow-up developed Fuchs' heterochromic cyclitis in the same eye. PMID- 22823017 TI - Letters to the editor. PMID- 22823018 TI - Pharmacophore-based virtual screening: a review of recent applications. AB - IMPORTANCE OF THE FIELD: In research relating to the development of new drugs, hit identification and validations are critical for successful optimization of candidates. To achieve rapid identification of new lead compounds, high throughput screening assays have been employed in many pharmaceutical companies and laboratories. However, their success depends on the assay system relevant to in vivo conditions and they are physically limited by the repertoire of compounds. As an alternative or complementary approach to high-throughput screening assays, virtual screening is an efficient method to identify drug candidates in silico from large chemical compound databases. Its usefulness has been verified by current applications that successfully retrieved hit and lead identifications against various disease targets. However, for better application, the scoring functions for distinguishing possible active and inactive compounds must beimproved. AREAS COVERED IN THIS REVIEW: In this review, we provide an overview of pharmacophore-based virtual screening methods with a special focus on their successful application towards finding hits against various diseasetargets. WHAT THE READER WILL GAIN: Readers will rapidly gain insight into the recent successful applications of pharmacophore-based virtual screening. They will acknowledge that this technique is a powerful and cost-effective alternative to high-throughput assays. TAKE HOME MESSAGE: Although there are many hurdles yet to be resolved, virtual screening techniques will emerge as essential infrastructure and as a prerequisite for developing new lead compounds with therapeuticapplications. PMID- 22823020 TI - Lipophilicity in drug discovery. AB - IMPORTANCE OF THE FIELD: The role of lipophilicity in determining the overall quality of candidate drug molecules is of paramount importance. Recent developments suggest that, as well as determining pre-clinical ADMET (absorption, distribution, metabolism, elimination and toxicology) properties, compounds of optimal lipophilicity might have increased chances of success in development. AREAS COVERED IN THIS REVIEW: The review covers aspects of methods of prediction of lipophilicity in frequent use and describes the most relevant literature analyses linking individual ADMET parameters and more composite measures of overall compound 'quality' with lipophilicity. WHAT THE READER WILL GAIN: The aim is to provide an overview of the relevant literature in an attempt to summarise where the optimum region of lipophilicity lies and to highlight which particular issues and risks might be expected when operating outside this region. TAKE HOME MESSAGE: The review of the data shows that this optimal space is defined by a narrow range of logD between ~ 1 and 3. Some of the implications of this for medicinal chemistry optimisation are discussed. PMID- 22823019 TI - Cell viability assessment: toward content-rich platforms. AB - IMPORTANCE OF THE FIELD: Monitoring cell viability in vitro is critical in many areas of biomedical research, and the ultimate goal in drug discovery is the ability to predict the in vivo toxicology of drug candidates based on their toxicity profile in vitro. Over the last decade, the contribution of high throughput screening toward this goal has been tremendous, providing the ability to screen compounds in parallel against multiple cell types. However, the toxic effects of drug candidates uncovered during clinical trials are by far the main reason for their failure. Over the same period, our understanding of programmed cell death has evolved dramatically with the identification of critical control points in the cell death pathways. As a result, cell viability should no longer be characterized solely on the basis of discrete end point measurements such as membrane permeability. AREAS COVERED IN THIS REVIEW: This review summarizes the traditional viability assays currently commercially available, focusing on methods amenable to high density format. Assays categorized into the following classes are discussed: dye exclusion assays, DNA condensation-based assays and assays monitoring a metabolic function. WHAT THE READER WILL GAIN: We describe current approaches for assessing cell viability and, using case studies, emphasize their limitations. As an alternative, we propose the use of live, multiplexed readouts to accurately record cell death induction. TAKE HOME MESSAGE: Current low-content methods based on single parameter readouts are prone to error due to the heterogeneity of cell populations and the multi-faceted nature of cell death. High-content approaches based on continuous, multiplexed readouts are becoming increasingly important for monitoring multiple markers of cell death induction simultaneously on a cell by cell basis. The use of such content-rich platforms is a necessity to predict the toxicology of drug candidates accurately. PMID- 22823021 TI - Practical metabolomics in drug discovery. AB - IMPORTANCE OF THE FIELD: Metabolomics is increasingly becoming an important field in the pharmaceutical industry to support the discovery and development of therapeutic agents. It allows the comprehensive and simultaneous profiling of hundreds of discrete biologically important molecules, including amino acids, sugars, lipids and exogenous substances from biological fluids and tissues. Metabolomics is the 'omics' field that most represents the interplay of internal biological regulation and external environmental influences on disease, thereby being of particular importance to disease mitigation and management. AREAS COVERED IN THIS REVIEW: Technological advances in the experimental work flow, analytical detection strategies and bioinformatics tools have enabled metabolomics studies to become increasingly comprehensive, robust and informative for the understanding of disease, drug action and the development of biomarkers. This review will focus on the practical aspects of metabolomics studies as they have been applied to the study of mammalian biological systems, specifically targeted to the steps of experimental design with regard to sample preparation, sample analysis and data analysis of both polar and non-polar metabolites. WHAT THE READER WILL GAIN: The reader will gain an overview of the field of metabolomics as it applies to drug development and the practical issues involved with experimental design. We will discuss the various methods of sample preparation and analysis as they apply to different classes of metabolites and highlight recent advances in the field that illustrate these methods. TAKE HOME MESSAGE: The field of metabolomics is a rapidly expanding discipline that is being applied to various aspects of drug development. The large diversity of metabolites found in nature dictates that different methods be developed for the investigation of different classes of metabolites. As the field of metabolomics continues to mature, it is likely that it will play an increasingly important role in the characterization of disease and the future development of biomarkers to assess drug efficacy and safety. PMID- 22823022 TI - Parathyroid gland regulation: contribution of the in vivo and in vitro models. AB - IMPORTANCE OF THE FIELD: The current regulation of parathyroid hormone (PTH) and the development of parathyroid disorders in chronic kidney disease involve complex mechanisms. Factors such as calcium, phosphorous, calcitriol, vitamin D receptor, calcium-sensing receptor and fibroblast growth factor 23 play a key role in the regulatory process in the pathogenesis of secondary hyperparathyroidism. AREAS COVERED IN THIS REVIEW: This review provides an analysis of published results related to the different models and approaches used to study the mechanisms involved in the pathogenesis of secondary hyperparathyroidism. The review includes clinical studies, animal and ex vivo/in vitro models which have been extensively used in this area. WHAT THE READER WILL GAIN: Readers will have an overview of the main findings and progress achieved in the knowledge of the parathyroid function combining the results obtained from the different models used to understand the parathyroid gland regulation. TAKE HOME MESSAGE: Each of the available models used to study the complex system of parathyroid regulation has advantages and limitations; therefore, it is necessary to combine the information obtained from more than one model in order to have a more complete knowledge of the mechanisms involved in PTH regulation. PMID- 22823023 TI - Human kinome drug discovery and the emerging importance of atypical allosteric inhibitors. AB - IMPORTANCE OF THE FIELD: Protein kinases are important targets for drug discovery because they possess critical roles in many human diseases. Several protein kinase inhibitors have entered clinical development with others having already been approved for treating a host of diseases. However, many kinase inhibitors suffer from non-selectivity because they interact with the ATP binding region which has similar structures amongst the protein kinases and this non-selectivity sometimes can cause side effects. As a consequence, there is much interest in developing drugs that inhibit kinases through non-classical mechanisms with the hope of avoiding the side effects of previous kinase drugs. AREAS COVERED IN THIS REVIEW: This review covers emerging information on kinase biology and discusses new approaches to design selective inhibitors that do not compete with ATP. WHAT THE READER WILL GAIN: The reader will gain a better understanding of the importance of the field of allosteric inhibitor drug discovery and how this has required the adoption of a new generation of high-throughput screening techniques. TAKE HOME MESSAGE: Discovery and development of allosteric modulators will result in a family of novel kinase therapies with greater selectivity and more varied ways to control activity of disease causing kinase targets. PMID- 22823024 TI - The role and future potential of fluorinated biomarkers in positron emission tomography. AB - IMPORTANCE OF THE FIELD: Positron emission tomography (PET) is rapidly emerging as the functional imaging method of choice for in vivo imaging applications in a number of key areas of drug discovery and clinical pathology, but especially in oncology. One key limitation of PET is the requirement for rapid synthesis and purification of biomarker/drug molecules regiospecifically labelled with short lived positron-emitting isotopes. AREAS COVERED IN THIS REVIEW: In this review, we focus on the role of (18)F-labelled molecules in PET, presenting a perspective on the challenges associated with the synthesis and future clinical utility of a range of labelled small molecules and macromolecular structures. Further preclinical method development for the regiospecific synthesis of fluorinated biomarkers under mild conditions is required before a wide range of (18)F labelled molecules take their place alongside clinically established oncology biomarkers such as (18)FDG and (18)FLT. WHAT THE READER WILL GAIN: In this review, we offer insights into current and future chemical methods for the efficient synthesis of fluorinated PET biomarkers, featuring modern technologies such as microwave-promoted chemistries and microfluidic reactors, both of which possess the capability to routinely and rapidly produce the small quantities of PET-labelled molecules under the mild and efficient conditions that are required for PET tracer synthesis. TAKE HOME MESSAGE: (18)F PET is a flourishing field with many applications in drug discovery and development, through radiolabelling of drug molecules or use of fluorinated disease biomarkers. PMID- 22823025 TI - The use of mobile phone cameras in guiding treatment decisions for laceration care. AB - OBJECTIVES: Mobile phone technology may be useful in helping to guide medical decisions for lacerations. We examined whether emergency department (ED) provider opinions on which lacerations require repair differed using mobile phone generated images compared with in-person evaluations. SUBJECTS AND METHODS: Patients presenting to an urban ED for initial and follow-up laceration care were prospectively enrolled. Patients took four mobile phone pictures of their laceration and provided a medical history. Cases were reviewed by ED providers who assessed image quality and made a recommendation about whether the laceration needed repair. The same provider then assessed the patient in-person. Concordant decision-making between mobile phone and in-person assessments was calculated as well as the degree of undertriage. RESULTS: In total, 94 patients were included over an 8-month period. There was complete agreement in 87% of cases (kappa statistic=0.65). Of the 13 patients with discrepant decisions, 6 were due to poor image quality, in 3 the images did not properly represent the problem, in 3 others there were historical findings that altered care, and for 1 the image looked worse than the actual injury in-person. In total, 5 of 94 (5%) of cases would have been undertriaged using only the mobile phone recommendation. Median image quality was 6 out of 10 (with 10 being the best) (interquartile range, 4 8). CONCLUSIONS: There are high rates of agreement when providers use mobile phone images to assess lacerations for possible repair in the ED. Image quality is in general good but highly variable and may drive incorrect assessments. PMID- 22823026 TI - Eudesmane-type sesquiterpenoid and guaianolides from Kandelia candel in a screening program for compounds to overcome TRAIL resistance. AB - In a screening program for natural products that can overcome TRAIL resistance, a new eudesmane-type sesquiterpenoid (1), three new guaianolides, mehirugins A-C (2 4), and two known guaianolides (5 and 6) were isolated from a MeOH extract of Kandelia candel leaves. Compounds 1 and 3-6 in combination with TRAIL showed cytotoxic activity in sensitizing TRAIL-resistant human gastric adenocarcinoma cells. PMID- 22823028 TI - DSAEK for implantable collamer lens dislocation and corneal decompensation 6 years after implantation. AB - A 39-year-old woman with a history of high myopia underwent uneventful implantation of phakic posterior chamber implantable collamer lenses (ICLs) 6 years earlier in both eyes with a visual acuity of 20/20 bilaterally. The patient presented as an emergency with sudden decreased vision in her right eye after blunt trauma. Slit-lamp examination showed a partially dislocated ICL in the anterior chamber, associated with ocular hypertension. It was decided to treat her with topical ocular hypotensive agents and surgical repositioning of the ICL. There was a progressive loss of endothelial cells and decreased visual acuity. Descemet stripping automated endothelial keratoplasty was needed to correct the endothelial failure. This case presents a potential complication of the ICL several years after implantation, and should be considered in these types of procedures. PMID- 22823027 TI - A randomized trial of Raltegravir replacement for protease inhibitor or non nucleoside reverse transcriptase inhibitor in HIV-infected women with lipohypertrophy. AB - Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT) quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m(2). After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol (p=0.04), self reported belly size (p=0.02) and composite body size (p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm. PMID- 22823029 TI - Macular infarction following intravitreal bevacizumab for treatment of central retinal vein occlusion. AB - Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is widely used for the treatment of macular edema associated with central retinal vein occlusion (CRVO). The authors present a series of three patients with CRVO who suffered apparent macular infarction within weeks of intravitreal administration of bevacizumab. Of the nearly 200 patients undergoing intravitreal injections of bevacizumab for this indication over a surveillance period of 3 years, this event occurred in three patients. This has not been described in the natural history of the disease and is associated with poor visual outcomes. PMID- 22823057 TI - Successful treatment of acquired haemophilia in a patient with bullous pemphigoid with single-dosing regimen of rituximab. PMID- 22823058 TI - Spectrophotometric analysis of coronal discolouration induced by grey and white MTA. AB - AIM: To evaluate the specific alterations in tooth colour with white and grey MTA when used to fill pulp chambers. METHODOLOGY: Forty-five fully developed, intact, mandibular third molars were sectioned 1 mm below their cemento-enamel junction (CEJ). Their pulp chambers were chemo-mechanically debrided, and the specimens were randomly assigned into three groups: Group 1-white MTA (Angelus(TM)), Group 2-grey MTA (Angelus(TM)) and Group 3-negative control (unfilled). During the experimental period, specimens were immersed in vials containing distilled water up to the CEJ (37+/-1 degrees C). Spectral reflectance lines were recorded by utilizing a UV-vis spectrophotometer equipped with an integration sphere in the visual spectrum, at baseline, 1 week and 1, 2 and 3 months after placement of the materials. Data were transformed into values of the CIE L*a*b* colour system, and the corresponding DeltaEpsilon values were calculated. The results were analysed using two-way mixed anova models, whilst pairwise comparisons were conducted with Bonferroni's method at P < 0.05 level of significance. RESULTS: Both types of MTA induced significant decreases in L*, a* and b* values. The colour change was greater with grey MTA. Grey MTA led to clinically perceptible crown discolouration after 1 month, whilst the total colour change caused by white MTA exceeded the perceptible threshold for the human eye after 3 months. CONCLUSIONS: The application of both grey and white MTA formulations induced a decrease in lightness and reduction in redness and yellowness in teeth. The present findings suggest that application of grey MTA in the aesthetic zone should be avoided, whilst white MTA should be used with caution when filling pulp chambers with the materials. PMID- 22823059 TI - Intracerebral alveolar echinococcosis. PMID- 22823060 TI - Extracurricular activities in young applicants' resumes: what are the motives behind their involvement? AB - Applicants use resumes to demonstrate their knowledge, skills, abilities, and other personal characteristics (KSAOs) to recruiters, through education and job related or non-job-related experiences. But research suggests that the situation for young applicants is especially competitive, since they increasingly enter the labour market with similar educational credentials and limited job-related experience. They may thus use non-job-related experiences, such as participation in extracurricular activities (ECAs) during their studies, to demonstrate KSAOs to recruiters, but also to add distinction and value to their credentials. ECAs may therefore become more important in the selection of young applicants. Yet few studies have undertaken a comprehensive and systematic analysis of the relationships students have with these activities. The purpose of this study was to investigate to what extent students' involvement in ECAs is due to internal (e.g., passion) or external (e.g., resume-building) motives, and what factors influence these motives. Results from a study with 197 students suggest that students engage in ECAs mainly out of internal motives. But external motives are stronger for activities started closer to entering the labour market, for students active in associative or volunteering activities (as compared to sports or artistic activities), and for students holding leadership positions in their activities. Our results suggest that labour market pressure may be a key component of applicants' involvement in ECAs. Also, organizations and recruiters may want to consider that students tend not to engage in ECAs purely out of internal motives, but also to add value to their credentials and match employers' expectations. The authors thank Anna Ambrosetti for her help with the data collection. PMID- 22823061 TI - p27(Kip1) V109G polymorphism and cancer risk: a systematic review and meta analysis. AB - Relationship between the p27Kip1 (here after referred to as p27) V109G polymorphism and cancer risk has been extensively studied; however, results from different studies were not fully consistent. Therefore, we carried out a meta analysis to comprehensively assess the correlation between the p27V109G polymorphism and the cancer risk. Articles on the relationship of the p27V109G polymorphism with cancer risk were searched from Medline, Pub Med, and Web of science databases. A total of eight eligible studies with 3591 cases and 3799 controls were included in this meta-analysis. Overall, it seemed that the G allele was not associated with the elevated cancer risk (pooled odds ratio [OR]=0.98, 95% confidence interval [CI]: 0.88-1.09, p=0.68, fixed effects). Analyses in different populations revealed that no statistically significant associations between the G allele and cancer risk were demonstrated in Caucasians or Asians. When analyzed in different types of cancer that, from two studies, the G allele was found to be associated with a decreased risk of prostate cancer in a dominant genetic model (pooled OR=0.60, 95% CI=0.36-0.98, p=0.04, fixed effects), but did not alter the breast cancer risk from four studies. In conclusion, this meta-analysis indicated that the p27V109G polymorphism did not correlate with the overall cancer risk in the general population. PMID- 22823062 TI - Excellent clinical outcomes from a national donation-after-determination-of cardiac-death lung transplant collaborative. AB - Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 +/- 4.0 min (range 18 89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs. PMID- 22823063 TI - The effect of delivery method on breastfeeding initiation from the The Ontario Mother and Infant Study (TOMIS) III. AB - OBJECTIVE: To report on the relationship between delivery method (cesarean vs. vaginal) and type (planned vs. unplanned) and breastfeeding initiation in hospital and continuation to 6 weeks postpartum as self-reported by study participants. DESIGN: Quantitative sequential mixed methods design. SETTING: Women were recruited from 11 hospital sites in Ontario, Canada. PARTICIPANTS: Participants included 2,560 women age 16 years or older who delivered live, full term, singleton infants. METHODS: Data were collected from an in-hospital questionnaire, hospital records, and a 6-week postpartum interview. RESULTS: Ninety-two percent of women reported initiating breastfeeding, and 74% continued to 6 weeks. The method of delivery, when defined as cesarean versus vaginal, was not a determining factor in breastfeeding initiation in hospital or in the early postdischarge period. An unexpected delivery method (i.e., unplanned cesarean or instrument-assisted vaginal deliveries) was associated, at a statistically significant level, with an increased likelihood of initiating breastfeeding and continuation to 6 weeks postdischarge. CONCLUSION: Breastfeeding can be considered a coping strategy that serves to normalize an abnormal experience and allows the individual to once again assume control. These unexpected results warrant further investigation to understand why women make the decision to initiate breastfeeding, why they choose to continue breastfeeding, and how they can be supported to achieve exclusive breastfeeding as recommended for infants in the first 6 months. PMID- 22823064 TI - CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder? AB - BACKGROUND: In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2. METHOD: In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels. RESULTS: In all patients' salivary melatonin levels at noon were >50 or melatonin half time was > 5 h. A SNP was found in eight of 15 patients. The allele 1C was found in two patients and in six patients the 1F allele was found. CONCLUSIONS: Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic-type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism. PMID- 22823065 TI - In memory of deceased chairmen of the Asian Dermatological Association. PMID- 22823066 TI - Synergistic effects from graphene and carbon nanotubes enable flexible and robust electrodes for high-performance supercapacitors. AB - Flexible and lightweight energy storage systems have received tremendous interest recently due to their potential applications in wearable electronics, roll-up displays, and other devices. To manufacture such systems, flexible electrodes with desired mechanical and electrochemical properties are critical. Herein we present a novel method to fabricate conductive, highly flexible, and robust film supercapacitor electrodes based on graphene/MnO(2)/CNTs nanocomposites. The synergistic effects from graphene, CNTs, and MnO(2) deliver outstanding mechanical properties (tensile strength of 48 MPa) and superior electrochemical activity that were not achieved by any of these components alone. These flexible electrodes allow highly active material loading (71 wt % MnO(2)), areal density (8.80 mg/cm(2)), and high specific capacitance (372 F/g) with excellent rate capability for supercapacitors without the need of current collectors and binders. The film can also be wound around 0.5 mm diameter rods for fabricating full cells with high performance, showing significant potential in flexible energy storage devices. PMID- 22823067 TI - Predicting adult physical illness from infant attachment: a prospective longitudinal study. AB - OBJECTIVE: Recent epidemiological and longitudinal studies indicate that attachment relationships may be a significant predictor of physical health in adulthood. This study is among the few to prospectively link attachment classifications assessed in infancy to physical health outcomes 30 years later in adulthood, controlling for various health-related confounds. METHODS: Participants were 163 individuals involved in a 32-year longitudinal study of risk and adaptation who have been followed since birth. Attachment classifications were assessed at ages 12 and 18 months using the Ainsworth Strange Situation Procedure. Stability of attachment security was derived from these assessments. At age 32, participants completed a questionnaire asking about the presence of or treatment for current physical illnesses. RESULTS: Binary logistic regression analyses controlling for health-related confounds at age 32 indicated that individuals who were insecurely attached (i.e., anxious-resistant or anxious-avoidant) during infancy were more likely to report an inflammation based illness in adulthood than those classified as securely attached during infancy. There also was a trend whereby individuals classified as anxious resistant reported more nonspecific symptoms in adulthood than those classified as either anxious-avoidant or secure. Individuals who were continuously insecure during infancy were more likely to report all types of physical illness in adulthood. CONCLUSION: These findings reveal the lasting effect of early interpersonal relationships on physical health and suggests that infancy may be a fruitful point for prevention efforts. The widespread influence that attachment has on endogenous and exogenous health-related processes may make it particularly potent in the prevention of later physical health problems. PMID- 22823068 TI - Rumination and anxiety mediate the effect of loneliness on depressed mood and sleep quality in college students. AB - OBJECTIVE: We examined the mechanisms that underlie the observed relationships between loneliness and depressed mood and poor sleep quality in college students. This study was the first to investigate whether rumination and trait anxiety are psychological mechanisms that mediate this relationship. METHODS: In Study 1 (n = 1,244), using factor analysis with cross-sectional data, we established that loneliness and rumination are distinct constructs. We then collected survey data in two cross-sectional samples (ns = 300 and 218) and one prospective (n = 334) sample to test whether rumination and anxiety were mediators of the relationship between loneliness and depressed mood and poor sleep quality. Structural equation modeling was used to test the proposed relationships. Participants completed self report measures of loneliness, rumination, trait anxiety, depressed mood, and sleep quality. In addition, measures of hostility, neuroticism, negative affect, and tobacco use were also assessed and tested as mediators, while social support was assessed and tested as a moderator. RESULTS: Consistent across the three studies, we found that rumination and trait anxiety fully mediated the associations between loneliness and depressed mood as well as poor sleep quality; these relationships held after testing all other factors. CONCLUSION: This study helps explain how loneliness dynamics relate to poor health and suggests specific points of departure for the development of interventions. PMID- 22823069 TI - Randomized controlled trial testing an internet physical activity intervention for sedentary adults. AB - OBJECTIVE: Internet-based physical activity (PA) interventions have shown promise, although findings remain equivocal. We used formative research to enhance a previously demonstrated program (Step into Motion) with the goal of developing an Internet program poised for dissemination. METHODS: We conducted focus groups to identify Internet features targeted to theoretical constructs (social cognitive theory) predictive of PA behavior and rated as "useful for increasing PA." We identified 5 theory-targeted Internet features as useful for increasing PA: (1) a PA tracking/logging calendar targeting self-monitoring and goal setting; (2) geographic mapping tools targeting perceived environment; (3) a discussion forum targeting social support; (4) exercise videos targeting observational learning; and (5) regular updates of peer PA progress targeting situation. We then tested the efficacy of the enhanced program (enhanced Internet, EI; N = 25) in relation to publicly available PA Websites (standard Internet, SI; N = 28) among 53 participants in a randomized controlled trial. RESULTS: The EI arm increased PA in relation to the SI arm at 3 months (18.4 to 186.0 min/wk vs. 20.9 to 57.3 min/wk; p = .03) but between-groups differences were not observed at 6 months (176.8 vs. 133.5 min/wk; p = .44). EI participants maintained PA from 3 to 6 months (186.0 to 176.8 min/wk), and the SI group increased PA (57.3 to 133.5 min/wk). CONCLUSION: The EI program was efficacious at improving PA levels in relation to publicly available Websites initially, but differences in PA levels were not maintained at 6 months. Future research should identify Internet features that promote long-term maintenance. PMID- 22823070 TI - Mother-father informant discrepancies regarding diabetes management: associations with diabetes-specific family conflict and glycemic control. AB - OBJECTIVE: To examine the relationship of mother-father informant discrepancies regarding diabetes management to diabetes-specific family conflict and glycemic control. METHODS: One hundred thirty-six mothers and fathers of youth with Type 1 diabetes reported on the youth's diabetes management, diabetes-specific family conflict, and amount of paternal involvement in diabetes care. Glycosylated hemoglobin A1c (HbA1c) was used to measure glycemic control. RESULTS: As hypothesized, mother-father discrepancies regarding diabetes management were positively associated with frequency of diabetes-specific family conflict. Contrary to hypotheses, mother-father discrepancies regarding diabetes management predicted poorer glycemic control for youth with less involved fathers only. CONCLUSIONS: Results highlight the importance of caregivers being consistent about pediatric illness management and support the idea that informant discrepancies represent an important window into the functioning of the family system. PMID- 22823071 TI - Thoracic epidural catheter placement using a paramedian approach with cephalad angulation in three dogs. AB - OBJECTIVE: To describe a technique for insertion of a thoracic epidural catheter. STUDY DESIGN: Clinical report. ANIMALS: Dogs (n = 3) undergoing thoracic wall resection and thoracotomy. METHODS: A paramedian approach with cephalic angulation was used to place a 24-g epidural catheter in 3 dogs. Dogs 1 and 2 had left caudal thoracic wall resection and dog 3 had left thoracotomy. In dog 1, the epidural catheter was inserted at L2-L3 intervertebral space and the tip of the catheter advanced to the level of T13 vertebral body. In dog 2, the epidural catheter was inserted at T12-T13 intervertebral space and the tip of the catheter was advanced to the level of T8 vertebral body. In dog 3, the epidural catheter was inserted at T13-L1 intervertebral space and its tip advanced until reaching the vertebral body of T10. All dogs were administered a combination of bupivacaine and morphine through the epidural catheter to provide intra- and postoperative analgesia. RESULTS: The peridural space was identified and the tip of the catheter was positioned where intended in all dogs. Dog 1 developed transient Horner's syndrome and dog 3 required intraoperative fentanyl during the first part of the procedure. CONCLUSION: Paramedian approach with cephalad angulation is a suitable technique to place thoracic epidural catheters in dogs. PMID- 22823072 TI - Beyond the pollination syndrome: nectar ecology and the role of diurnal and nocturnal pollinators in the reproductive success of Inga sessilis (Fabaceae). AB - Inga species present brush-type flower morphology allowing them to be visited by distinct groups of pollinators. Nectar features in relation to the main pollinators have seldom been studied in this genus. To test the hypothesis of floral adaptation to both diurnal and nocturnal pollinators, we studied the pollination ecology of Inga sessilis, with emphasis on the nectar secretion patterns, effects of sequential removals on nectar production, sugar composition and the role of diurnal and nocturnal pollinators in its reproductive success. Inga sessilis is self-incompatible and pollinated by hummingbirds, hawkmoths and bats. Fruit set under natural conditions is very low despite the fact that most stigmas receive polyads with sufficient pollen to fertilise all ovules in a flower. Nectar secretion starts in the bud stage and flowers continually secreting nectar for a period of 8 h. Flowers actively reabsorbed the nectar a few hours before senescence. Sugar production increased after nectar removal, especially when flowers were drained during the night. Nectar sugar composition changed over flower life span, from sucrose-dominant (just after flower opening, when hummingbirds were the main visitors) to hexose-rich (throughout the night, when bats and hawkmoths were the main visitors). Diurnal pollinators contributed less than nocturnal ones to fruit production, but the former were more constant and reliable visitors through time. Our results indicate I. sessilis has floral adaptations, beyond the morphology, that encompass both diurnal and nocturnal pollinator requirements, suggesting a complementary and mixed pollination system. PMID- 22823073 TI - Abstracts of the Royal Australian and New Zealand College of Radiologists (RANZCR) 63rd Annual Scientific Meeting, and the Asian Oceanian Congress of Radiology (AOCR), August 30-September 2, 2012, Sydney, Australia and the Faculty of Radiation Oncology Scientific Meeting, July 26-28, 2012, Queensland, Australia. PMID- 22823075 TI - Effects of 2 different prior endurance exercises on whole-body fat oxidation kinetics: light vs. heavy exercise. AB - This study aimed to compare the effects of 2 different prior endurance exercises on subsequent whole-body fat oxidation kinetics. Fifteen men performed 2 identical submaximal incremental tests (Incr2) on a cycle ergometer after (i) a ~40-min submaximal incremental test (Incr1) followed by a 90-min continuous exercise performed at 50% of maximal aerobic power-output and a 1-h rest period (Heavy); and (ii) Incr1 followed by a 2.5-h rest period (Light). Fat oxidation was measured using indirect calorimetry and plotted as a function of exercise intensity during Incr1 and Incr2. A sinusoidal equation, including 3 independent variables (dilatation, symmetry and translation), was used to characterize the fat oxidation kinetics and to determine the intensity (Fat(max)) that elicited the maximal fat oxidation (MFO) during Incr. After the Heavy and Light trials, Fat(max), MFO, and fat oxidation rates were significantly greater during Incr2 than Incr1 (p < 0.001). However, Delta (i.e., Incr2-Incr1) Fat(max), MFO, and fat oxidation rates were greater in the Heavy compared with the Light trial (p < 0.05). The fat oxidation kinetics during Incr2(Heavy) showed a greater dilatation and rightward asymmetry than Incr1(Heavy), whereas only a greater dilatation was observed in Incr2(Light) (p < 0.05). This study showed that although to a lesser extent in the Light trial, both prior exercise sessions led to an increase in Fat(max), MFO, and absolute fat oxidation rates during Incr2, inducing significant changes in the shape of the fat oxidation kinetics. PMID- 22823076 TI - Total and femoral neck bone mineral density and physical activity in a sample of men and women. AB - Physical activity (PA), total body fat (TBF), and lean body mass (LBM) are associated with bone mineral density (BMD). However, the independent influence of PA on BMD, while controlling for body composition is not understood as well and is the purpose of the current study. Whole-body BMD (g.cm-2), femoral neck BMD (g.cm-2), TBF (kg), and LBM (kg) were measured with dual-energy X-ray absorptiometry. PA levels (total, work, sport, non-sport) were estimated using the Baecke questionnaire. General linear models determined the independent effects of PA on BMD (whole-body and femoral neck), with adjustment for age, sex, ethnicity, smoking, menopausal status (as appropriate), LBM, and TBF. These associations were also examined by sex and age group (20-34, 35-49, and 50-64 years). The sample included 802 adults (65% women; 13% African American) from the Pennington Center Longitudinal Study that were 20 to 64 years of age (mean +/- SD: 46.9 +/- 11.0 years). Higher sports scores were associated with higher femoral neck BMD in the total group, men and women, and in 20- to 34-year-olds and 35- to 49-year-olds, but not significant in those 50-64 years of age. Similar significant associations were found for sports score with total body BMD; however, this relationship was not significant for women or for those 50-64 years of age. Total PA had inconsistent relationships with both femoral neck BMD and total body BMD. Higher levels of sport-related PA are associated with higher femoral neck BMD; however, these relationships vary by PA domain and site of BMD measurement. PMID- 22823077 TI - Telemedicine--a complement to traditional referrals in oral medicine. AB - INTRODUCTION: Introducing telemedicine into clinical practice has not been without difficulties. Within the framework of the European Union project "Health Optimum," telemedicine consultations with specialists at the Department of Oral & Maxillofacial Surgery at Uppsala University Hospital (Uppsala, Sweden) have been offered to dentists in the public dental health service. The aim is to streamline the consultation process, improve/develop the skills of the participating dentists and dental hygienists, and save time and money for patients, healthcare authorities, and society. SUBJECTS AND METHODS: Patient records are collected in a database for demonstration and discussion, and the system is also available for referrals. Both medical and dental photographs and x-rays are digitized in the same system. These can be viewed during telemedicine rounds and by the consultants at the hospital prior to a consultation. Secure, interactive conferencing software is used, which provides a quick, easy, and effective way to share video and data over the Internet. Both parties can demonstrate different parts of an image using a pointer or a drawing system. Conference phones are presently used for verbal communication. RESULTS: Ten patients were discussed during telemedicine rounds (3 males and 7 females), all of whom would normally have been referred to a specialist. As a result of the telemedicine round, 2 were referred to a specialist, whereas diagnoses were made for the other 8, and treatment was suggested. The dental health clinic could thus provide treatment without the need for referral to a consultant. CONCLUSIONS: The telemedicine system described here allows patient care to be provided rapidly and more economically. Future plans include "live" rounds using a videocamera, providing the possibility to relay real-time information about the intraoral situation. A camera is being developed and should preferably be permanently installed chair side. PMID- 22823078 TI - Role of HLA and T lymphocytes in the immune response. AB - Human leukocyte antigens (HLA) play a role in the pathogenesis of diseases involving an immune response. Because HLA are strongly associated with ophthalmologic diseases such as Behcet's disease, VogtKoyanagi-Harada's disease and birdshot retinochoroidopathy, an understanding of HLA is essential in analyzing the immunogenetic mechanisms underlying many diseases. Recent advances in molecular biology have made it possible to characterize the HLA gene region at the DNA level. This paper provides a comprehensive overview of the etiology of various immunologic disorders with emphasis on the role of HLA, a self/not-self discrimination mechanism, and of T lymphocytes. PMID- 22823079 TI - Tear IgE detected by a new method: Stallerdiag-IgE. AB - A new method for the tear IgE measurement Stallerdiag-IgE is presented. For this assay, the tears are collected on a strip of filter paper introduced into the conjunctival cul-de-sac. Then the IgE are measured by a simple enzymo immunological assay. Tear IgE were determined in a normal population and in three groups of patients with keratoconjunctivitis. In the normal population, the tear IgE level is 0.37+/-0.66 kIU/1. The IgE level observed in the patients with vernal keratoconjunctivitis (19.6+/-21.5 kIU/1) or chronic allergic keratoconjunctivitis (11.1+/-16.2 kIU/1) is significantly different (p<0.0005) from the IgE level measured in the patients suffering from non-allergic keratoconjunctivitis (3.4+/-10.4 kIU/1). By comparison with a non-allergic group, the sensitivity is 80%, the specificity is 89% giving an overall efficiency of 83%. PMID- 22823080 TI - Sjogren's syndrome (SS) and Epstein-Barr virus (EBV) reactivation. AB - Recent reports have shown that dry eye in Sjogren's syndrome (SS) is associated with reactivation of Epstein-Barr virus (EBV) in lacrimal glands. However, the number of patients examined were few and it has not been determined whether dry eye in the absence of SS is also related to EBV reactivation. The authors examined the serum antibody titers to EBV in three groups of patients: (1) simple dry eye (SDE)-dry eye with no circulating autoantibodies (n = 157), (2) autoimmune positive dry eye (ADE)-dry eye with circulating autoantibodies (n = 68), and (3) Sjogren's syndrome (SS)-dry eye associated with Sjogren's syndrome (n = 62). Healthy volunteers were recruited as controls (n = 47). In SS, the mean antibody titers to EBV nuclear antigen (anti-EBNA), early antigen (anti-EA IgG), and virus capsid antigen (anti-VCA-IgG) were significantly elevated compared to those of controls. No significant differences in antibody titers were found among ADE, SDE, and the controls. The EBV reactivated pattern was found in 17.7% of SS, which was significantly higher than the 4.4% in ADE, 1.9% in SDE, 0% in controls. These findings suggest an association of EBV with SS, but not ADE or SDE. PMID- 22823081 TI - Recurrent uveitis, cystoid macular edema and pericarditis in Lyme disease. AB - Lyme disease has been associated with many systemic and ocular complications. The authors' patient, a 26-year-old man, developed recurrent pars planitis with two episodes of acute pericarditis. Extensive medical investigations were negative except for a highly positive western blot for Borrelia burgdorferi. Specific antibiotic treatment for Lyme disease was followed by a long lasting period without any relapse. PMID- 22823082 TI - American uveitis society meeting summary november 15, 1993 hyatt regency, chicago, IL, USA. PMID- 22823083 TI - The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety. AB - The extent and duration of pharmacological action is determined by the lifetime of drug occupancy on a molecular target. This lifetime is defined by dynamic processes that control the rates of drug association and dissociation from the target. Recently, the term residence time has been coined to describe experimental measurements that can be related to the lifetime of the binary drug target complex, and this in turn to durable, pharmacodynamic activity. The residence time concept and its impact on drug optimization are reviewed here. Examples are provided that demonstrate how a long residence time can improve drug efficacy in vivo. Additionally, optimization of drug-target residence time can help to mitigate off-target mediated toxicity, hence, improving drug safety and tolerability. Recent applications of the residence time concept to both drug discovery and development are also presented. PMID- 22823084 TI - The current role of model-based drug development. AB - IMPORTANCE OF THE FIELD: Current drug discovery and development programs are under growing scrutiny for low productivity and escalating costs. Model-based drug development (MBDD) has been recognized as a promising tool to address some of the related challenges. AREAS COVERED IN THIS REVIEW: This review introduces the concept of MBDD and the associated quantitative pharmacology-based iterative 'learn and confirm' paradigm in the drug discovery and development process to provide concise information for rational decision making. It summarizes the evolving role of MBDD in drug development programs and outlines the full armamentarium of modeling and simulation approaches utilized to facilitate its application. WHAT THE READER WILL GAIN: Different aspects and applications of MBDD are introduced to the reader and illustrated in prime examples. The reader is provided with an understanding of potential applications of MBDD in drug development as well as the associated limitations and challenges in its implementation. TAKE HOME MESSAGE: MBDD is a tool that is increasingly used throughout the drug discovery and development continuum to support fast and rationale decision making and has thereby the potential to accelerate and increase the cost-effectiveness of the drug development process. PMID- 22823085 TI - Mining protein lists from proteomics studies: applications for drug discovery. AB - IMPORTANCE OF THE FIELD: In recent years, proteomics has become a common technique applied to a wide spectrum of scientific problems, including the identification of diagnostic biomarkers, monitoring the effects of drug treatments or identification of chemical properties of a protein or a drug. Although being significantly different in scientific essence, the ultimate result of the majority of proteomics studies is a protein list. Thousands of independent proteomics studies have reported protein lists in various functional contexts. AREAS COVERED IN THIS REVIEW: We review here the spectrum of scientific problems where proteomics technology was applied recently to deliver protein lists. The available bioinformatics methods commonly used to understand the properties of the protein lists are compared. WHAT THE READER WILL GAIN: The types and common functional properties of the reported protein lists are discussed. The range of scientific problems where this knowledge could be potentially helpful with a focus on drug discovery issues is explored. TAKE HOME MESSAGE: Reported protein lists represent a valuable resource which can be used for a variety of goals, ranging from biomarkers discovery to identification of novel therapeutic implications of known drugs. PMID- 22823086 TI - The GRID/CPCA approach in drug discovery. AB - IMPORTANCE OF THE FIELD: Bimolecular recognition is the basis for almost all processes in biological systems. The geometrical and chemical complementarity of small molecule ligands and their macromolecular biological targets, matching paired interacting parts, can result in binding that will eventually yield a biological response. AREAS COVERED IN THIS REVIEW: The topics covered include the integration of molecular interaction fields and chemometrics, via the GRID/CPCA (consensus principal component analysis) method that is actively contributing to the optimization of potency and selectivity of ligands towards a chosen target. Key applications that hallmark the usefulness of the method are critically presented. By comparison of the GRID/CPCA and GRID/PCA, the breakthroughs and challenges are highlighted. WHAT THE READER WILL GAIN: Molecular recognition studies support the development of pharmacophore-based descriptors, which provide the means to identify new ligand templates ('scaffold-hopping'). The GRID/CPCA approach can simultaneously reveal common trends in more than one block of data for more than two target proteins, with several three-dimensional structures per protein. It offers the benefit of improving the weighting between different interaction energy probes within the GRID parameterization. An important consequence is that hydrophobic interactions can be assessed for selectivity between proteins. TAKE HOME MESSAGE: Molecular-field-based methods along with CPCA analysis are extremely powerful to understand bimolecular interactions. Because drug discovery and development is a costly, time consuming and high-risk activity and GRID/CPCA is at the forefront of the computer-aided design, it should be used as early as possible for discovering new drugs. PMID- 22823087 TI - Tackling the challenges posed by target flexibility in drug design. AB - IMPORTANCE OF THE FIELD: Current computational docking methods are often effective in predicting accurate drug-binding geometries in cases of relatively rigid target structures. However, binding of drug-like ligands to protein receptor molecules frequently involves or even requires conformational adaptation. Realistic prediction of ligand-receptor binding geometries and complex stability needs in many cases an appropriate inclusion of conformational changes, not only for the ligand, but also for the receptor molecule. AREAS COVERED IN THIS REVIEW: Recent approaches to efficiently account for target receptor flexibility during docking simulations are reviewed. WHAT THE READER WILL GAIN: The reader will gain insights into methods to efficiently treat protein side-chain flexibility and approaches for continuous adaptation of backbone conformations in pre-calculated essential or soft collective degrees of freedom. In addition, molecular dynamics or Monte Carlo based methods providing simultaneous inclusion of receptor and ligand flexibility are discussed as well as promising new developments to generate conformationally diverse ensembles of a protein structure. The large variety of possible conformational changes in proteins on ligand binding is illustrated for the enzyme reverse transcriptase of HIV-1, which is an important drug target. TAKE HOME MESSAGE: If the backbone conformation of the binding site does not change, current docking programs can perform well by taking side-chain reorientations into account only. Future progress to account for full target flexibility in docking requires both accurate prediction of the essential modes of backbone motion and improvements in scoring to enhance selectivity. Thus, the scoring function should realistically cover energetic and particularly entropic contributions to binding, which would allow more realistic estimates of binding free energies. PMID- 22823088 TI - Use of phage display technology for the determination of the targets for small molecule therapeutics. AB - IMPORTANCE OF THE FIELD: Target discovery of drug-like small-molecules contributes to our understanding of biological phenomena at the molecular level as well as elucidating the mode of action of bioactive compounds. Research in this field is of high value because, in addition to basic observations, the data can be used to directly identify molecular targets or investigate pharmacokinetic characteristics of drugs in clinical use. AREAS COVERED IN THIS REVIEW: In addition to providing a brief overview of phage display (PD) technology, we discuss screening platforms, different types of phage libraries and the application of this method to the determination of targets for small-molecule therapeutics over the past decade. WHAT THE READER WILL GAIN: Readers will gain an understanding of the basis of PD technology through successful examples of the use of this method for the determination of targets for small-molecule therapeutics. They will learn what kinds of small-molecules were used to identify their binding partner, what characteristics and drawbacks are present in the use of small-molecule as bait, and what kinds of approaches were introduced in order to improve the technique to overcome the limitations of conventional strategies. TAKE HOME MESSAGE: A suitable combination of diverse technologies from various different fields can act synergistically to increase throughput and enhance the efficiency of PD technology for the determination of targets for small-molecule therapeutics. The most suitable method for successful target identification of small-molecules of interest using PD technology can often be determined by referring to past examples. PMID- 22823089 TI - Platforms for the identification of GPCR targets, and of orthosteric and allosteric modulators. AB - AREAS COVERED IN THIS REVIEW: The review provides a summary of old and new approaches for GPCR target identification and for the screening of molecules acting on GPCR targets. The new findings in the field are presented as well as an opinion about how these developments may help GPCR drug discovery. Importance in the field: GPCRs have been the most useful family of proteins in terms of targets for drug discovery. The expectations for GPCR target identification and discovery of new drugs acting on 'old' or 'new' GPCR targets are very high. Given the fact that the pace at which new 'GPCR drugs' appear in the market is decreasing and since the new developments in the field are not being translated into drug discovery there is a need to review the field from a critical perspective. TAKE HOME MESSAGE: To overcome the limitation of the old approaches used in GPCR target identification and drugs discovery new approaches are required. In particular successful approaches in GPCR drug discovery should take into account that the real GPCR targets for a given disease are not GPCR monomers but GPCR heteromers. WHAT THE READER WILL GAIN: The reader will gain an overview of the strategies currently used and their pros and cons. The reader will also understand that new strategies may help in accelerating the access of GPCR into the market, and also notice that successful strategies should take advantage of the new findings in the field of GPCRs. PMID- 22823090 TI - Association between early methylmercury exposure and functional health among residents of the Shiranui Sea communities in Japan. AB - The objective of this study was to evaluate the effect of estimated historical methylmercury exposure on the functional health of residents living in the Shiranui Sea communities in Japan. Functional health was measured by self reported activities of daily living (ADL). Study areas were categorized into high, medium and low methylmercury exposure areas according to their location or distance from the Shiranui Sea. We estimated the adjusted prevalence odds ratios of impaired ADL in relation to exposure using a logistic regression model. Compared with residents in the low-exposure area, residents in the high-exposure area were significantly associated with a higher prevalence odds ratio (OR) for impaired ADL after adjustment for confounding factors (adjusted ORs = 2.8, 95% CI: 1.3-6.2). These results showed strong dose-response relationships (p for trend = 0.0050). Our findings suggest that historical methylmercury exposure might cause functional impairment in later in life depending on the exposure level. PMID- 22823092 TI - E-mental health - a land of unlimited possibilities. PMID- 22823091 TI - Impact of a randomized campus/community trial to prevent high-risk drinking among college students. AB - BACKGROUND: High-risk drinking by college students continues to pose a significant threat to public health. Despite increasing evidence of the contribution of community-level and campus-level environmental factors to high risk drinking, there have been few rigorous tests of interventions that focus on changing these interlinked environments. The Study to Prevent Alcohol Related Consequences (SPARC) assessed the efficacy of a comprehensive intervention using a community organizing approach to implement environmental strategies in and around college campuses. The goal of SPARC was to reduce high-risk drinking and alcohol-related consequences among college students. METHODS: Ten universities in North Carolina were randomized to an Intervention or Comparison condition. Each Intervention school was assigned a campus/community organizer. The organizer worked to form a campus-community coalition, which developed and implemented a strategic plan to use environmental strategies to reduce high-risk drinking and its consequences. The intervention was implemented over a period of 3 years. Primary outcome measures were assessed using a web-based survey of students. Measures of high-risk drinking included number of days alcohol was consumed, number of days of binge drinking, and greatest number of drinks consumed (all in the past 30 days); and number of days one gets drunk in a typical week. Measures of alcohol-related consequences included indices of moderate consequences due to one's own drinking, severe consequences due to one's own drinking, interpersonal consequences due to others' drinking, and community consequences due to others' drinking (all using a past 30-day time frame). Measure of alcohol-related injuries included (i) experiencing alcohol-related injuries and (ii) alcohol related injuries caused to others. RESULTS: We found significant decreases in the Intervention group compared with the Comparison group in severe consequences due to students' own drinking and alcohol-related injuries caused to others. In secondary analyses, higher levels of implementation of the intervention were associated with reductions in interpersonal consequences due to others' drinking and alcohol-related injuries caused to others. CONCLUSIONS: A community organizing approach promoting implementation of environmental interventions can significantly affect high-risk drinking and its consequences among college students. PMID- 22823093 TI - The impact of social anxiety on student learning and well-being in higher education. AB - BACKGROUND: This paper reports findings from two complementary web-surveys conducted in the UK, in which 787 university students described their experiences of social anxiety. AIMS: The aim was to explore the impact of social anxiety on student learning and well-being in the context of higher education. METHOD: Participants self-selected using a screening tool and completed a web-based questionnaire. RESULTS: The findings are consistent with previous research on social anxiety and suggest that for a significant minority of students, social anxiety is a persistent, hidden disability that impacts on learning and well being. CONCLUSIONS: The findings highlight the need for enhanced pedagogic support for students with social anxiety. PMID- 22823094 TI - e-Psychonauts: conducting research in online drug forum communities. AB - BACKGROUND: "Legal highs" are becoming increasingly common features of the recreational drug market. The Internet has emerged as an important resource for technical and pharmacological knowledge in the absence of evidence-based literature, and for identifying emerging trends. Self-established drug-related Internet forums have emerged as particularly useful sources of information. AIMS: It was the aim of this study to explore the key features of drug-related Internet forums and the drug forum communities. METHODS: Within the framework of the larger Psychonaut Web Mapping project, eight English-language drug forums were assessed, and key features, categories, themes and attributions were identified. RESULTS: The results are reported taking into account ethical issues, such as anonymity and confidentiality, associated with research in online communities. CONCLUSIONS: This study identified strong, unified and unique communities of recreational drug users that can provide an insight into the growing market in new drugs and drug compounds, and may be key components in future research, harm reduction and prevention strategies. PMID- 22823097 TI - Polymeric modification and its implication in drug delivery: poly-epsilon caprolactone (PCL) as a model polymer. AB - Biodegradable polymers provided the opportunity to explore beyond conventional drug delivery and turned out to be the focus of current drug delivery. In spite of availability of diverse class of polymers, several of these polymers lack important physicochemical and biological properties, limiting their widespread application in pharmaceutical drug delivery. However, most polymers in the form of blends, copolymers and functionally modified polymers have exhibited their applicability to overcome specific limitations and to produce novel and/or functionalized formulations for drug delivery as well as tissue engineering. This review aims to provide the need of polymeric modification, approaches adopted to modify and their scope. Special emphasis has been given to synthetic polyester PCL, as it is widely demonstrated in its modified form to overcome its problem of hydrophobicity and much slower degradation over the past decade. Past studies show a significantly higher utility of modified form of PCL in comparison to its native form. From the statistical analysis of these modifications and the formulations prepared, we present a basic understanding of the impact of selective modifications on the formulation design. In conclusion, we remark that a thorough understanding of the polymer and its modification has a huge potential to be the future trend for drug delivery and tissue engineering applications. PMID- 22823099 TI - Contrasting effects of climatic variability on the demography of a trans equatorial migratory seabird. AB - Large-scale seasonal climatic indices, such as the North Atlantic Oscillation (NAO) index or the Southern Oscillation Index (SOI), account for major variations in weather and climate around the world and may influence population dynamics in many organisms. However, assessing the extent of climate impacts on species and their life-history traits requires reliable quantitative statistical approaches. We used a new analytical tool in mark-recapture, the multi-event modelling, to simultaneously assess the influence of climatic variation on multiple demographic parameters (i.e. adult survival, transient probability, reproductive skipping and nest dispersal) at two Mediterranean colonies of the Cory's shearwater Calonectris diomedea, a trans-equatorial migratory long-lived seabird. We also analysed the impact of climate in the breeding success at the two colonies. We found a clear temporal variation of survival for Cory's shearwaters, strongly associated to the large-scale SOI especially in one of the colonies (up to 66% of variance explained). Atlantic hurricane season is modulated by the SOI and coincides with shearwater migration to their wintering areas, directly affecting survival probabilities. However, the SOI was a better predictor of survival probabilities than the frequency of hurricanes; thus, we cannot discard an indirect additive effect of SOI via food availability. Accordingly, the proportion of transients was also correlated with SOI values, indicating higher costs of first reproduction (resulting in either mortality or permanent dispersal) when bad environmental conditions occurred during winter before reproduction. Breeding success was also affected by climatic factors, the NAO explaining c. 41% of variance, probably as a result of its effect in the timing of peak abundance of squid and small pelagics, the main prey for shearwaters. No climatic effect was found either on reproductive skipping or on nest dispersal. Contrarily to what we expect for a long-lived organism, large-scale climatic indexes had a more pronounced effect on survival and transient probabilities than on less sensitive fitness parameters such reproductive skipping or nest dispersal probabilities. The potential increase in hurricane frequency because of global warming may interact with other global change agents (such as incidental bycatch and predation by alien species) nowadays impacting shearwaters, affecting future viability of populations. PMID- 22823098 TI - The Eurotransplant donor risk index in liver transplantation: ET-DRI. AB - Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. From 5723 patients follow up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET-DRI). Concordance-index calculation shows this ET-DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET-DRI for risk indication and possibly for allocation purposes within the Eurotrans-plant region. PMID- 22823100 TI - Microscale investigation of anaerobic biogas production under various hydrodynamic conditions. AB - This work presents an investigation at microscale of various mechanisms affecting anaerobic reactions within the microdevices. In particular, the effect of different hydrodynamic conditions associated with the granular particles' size and density on the biogas production was studied in order to intensify the performance of the anaerobic reactor. The image analysis techniques offer an opportunity to observe and quantify the nucleation and growth of biogas bubble at microscale on a single granule. In addition, the flow conditions were perfectly controlled in the microdevice, and the liquid flow fields were measured by a microparticle image velocimetry (micro-PIV) system. The effect of real hydrodynamic conditions exerted directly on granules onto the maximum biogas production rate was described for the first time. Finally, the role of hydrodynamic conditions on the biogas production at microscale is discussed through a straightforward relationship between the shear rates exerted on the granule and the optimal biogas production rate. The investigation reveals that big granules could have satisfactory biogas production ability under relatively weak hydrodynamic conditions. Thus they would be priority selection for industrial reactors. PMID- 22823102 TI - Intercultural caring from the perspectives of immigrant new mothers. AB - OBJECTIVE: To describe and interpret the perceptions and experiences of caring of immigrant new mothers from an intercultural perspective in maternity care in Finland. DESIGN: Descriptive interpretive ethnography using Eriksson's theory of caritative caring. SETTING: A maternity ward in a medium-sized hospital in western Finland. PARTICIPANTS: Seventeen mothers from 12 countries took part in the study. METHODS: Interviews, observations, and field notes were analyzed and interpreted. RESULTS: Most mothers were satisfied with the equal access to high quality maternity care in Finland, although the stereotypes and the ethnocentric views of some nurses negatively influenced the experiences of maternity care for some mothers. The cultural background of the mother, as well as the Finnish maternity care culture, influenced the caring. Four patterns were found. There were differences between the expectations of the mothers and their Finnish maternity care experience of caring. Caring was related to the changing culture. Finnish maternity care traditions were sometimes imposed on the immigrant new mothers, which likewise influenced caring. However, the female nurse was seen as a professional friend, and the conflicts encountered were resolved, which in turn promoted caring. CONCLUSION: The influence of Finnish maternity care culture on caring is highlighted from the perspective of the mothers. Intercultural caring was described as universal, cultural, contextual, and unique. Women were not familiar with the Finnish health care system, and many immigrant mothers lacked support networks. The nurse/patient relationship could partly replace their support if the relationship was perceived as caring. The women had multiple vulnerabilities and were prone to isolation and discrimination if they experienced communication problems. PMID- 22823103 TI - Validity evidence for the situational judgment test paradigm in emotional intelligence measurement. AB - To date, various measurement approaches have been proposed to assess emotional intelligence (EI). Recently, two new EI tests have been developed based on the situational judgment test (SJT) paradigm: the Situational Test of Emotional Understanding (STEU) and the Situational Test of Emotion Management (STEM). Initial attempts have been made to examine the construct-related validity of these new tests; we extend these findings by placing the tests in a broad nomological network. To this end, 850 undergraduate students completed a personality inventory, a cognitive ability test, a self-report EI test, a performance-based EI measure, the STEU, and the STEM. The SJT-based EI tests were not strongly correlated with personality and fluid cognitive ability. Regarding their relation with existing EI measures, the tests did not capture the same construct as self-report EI measures, but corresponded rather to performance based EI measures. Overall, these results lend support for the SJT paradigm for measuring EI as an ability. PMID- 22823101 TI - Reduced ethanol consumption and preference in cocaine- and amphetamine-regulated transcript (CART) knockout mice. AB - Cocaine- and amphetamine-regulated transcript (CART) is a neuropeptide implicated in addiction to drugs of abuse. Several studies have characterized the role of CART in addiction to psychostimulants, but few have examined the role of CART in alcohol use disorders including alcoholism. The current study utilized a CART knockout (KO) mouse model to investigate the role of CART in ethanol appetitive behaviors. A two-bottle choice, unlimited-access paradigm was used to compare ethanol appetitive behaviors between CART wild type (WT) and KO mice. The mice were presented with an ethanol solution (3%-21%) and water, each concentration for 4 days, and their consumption was measured daily. Consumption of quinine (bitter) and saccharin (sweet) solutions was measured following the ethanol preference tests. In addition, ethanol metabolism rates and ethanol sensitivity were compared between genotypes. CART KO mice consumed and preferred ethanol less than their WT counterparts in both sexes. This genotype effect could not be attributed to differences in bitter or sweet taste perception or ethanol metabolism rates. There was also no difference in ethanol sensitivity in male mice; however, CART KO female mice showed a greater ethanol sensitivity than the WT females. Taken together, these data demonstrate a role for CART in ethanol appetitive behaviors and as a possible therapeutic drug target for alcoholism and abstinence enhancement. PMID- 22823104 TI - Qualitative research as methodical hermeneutics. AB - The proportion of publications of qualitative research in mainstream psychology journals is small. Thus, in terms of this important criterion, despite its recent rapid growth, qualitative research is marginalized in psychology. The author suggests that contributing to this situation is the lack of a coherent and unifying methodology of qualitative research methods that elucidates their credibility. He groups the many qualitative research methods into 3 main kinds, then applies to them 4 propositions offered as such a methodology: (1) Qualitative research is hermeneutical, entailing application of the method of the hermeneutic circle to text about experience and/or action. (2) Implicit in the use of the hermeneutic circle method is the activity of educing and articulating the meaning of text, an activity that modifies and interacts with C. S. Peirce's (1965, 1966) logical operations of abduction, theorematic deduction, and induction. (3) The cycling of these 4 moments enables demonstration, achieved rhetorically, of the validity of the understandings resulting from the exegesis of the text under study. (4) This demonstrative rhetoric is enhanced when researchers disclose reflexively those aspects of their perspectives they judge to have most relevant bearing on their understandings. The author compares abduction as formulated here with other recent uptakes of it. As an installment on the generality of the methodology, he explores its fit with the descriptive phenomenological psychological method, conversation analysis, and thematic analysis. PMID- 22823105 TI - Crystallinity control of ferromagnetic contacts in stressed nanowire templates and the magnetic domain anisotropy. AB - We report the controlled growth of single-crystalline ferromagnetic contacts through solid state reaction at nanoscale. Single-crystal Mn(5)Si(3) and Fe(5)Ge(3) contacts were grown within stressed Si and Ge nanowire templates, where oxide-shells were used to exert compressive stress on the silicide or germanide. Compared to polycrystalline silicide and germanide structures observed within bare nanowires, the built-in high strain in the oxide-shelled nanostructures alters the nucleation behavior of the ferromagnetic materials, leading to single crystal growth in the transverse/radial direction. Interestingly, the compressive stress is also found to affect the magnetic anisotropy of the ferromagnetic contacts. In-plane and out-of-plane magnetization were observed in Fe(5)Ge(3) for different crystal orientations, showing distinctly preferred domain orientations. These interesting results display the capability to control both the crystallinity and the magnetic anisotropy of ferromagnetic contacts in engineered nanostructures. PMID- 22823106 TI - Physical education teachers' attitudes towards children with intellectual disability: the impact of time in service, gender, and previous acquaintance. AB - BACKGROUND: This study investigated attitudes towards teaching students with intellectual disability (ID) within a representative sample of secondary school physical education (PE) teachers, and to determine the effects of age, gender, teaching experience, and having acquaintance with ID and students with ID on their attitudes. METHODS: Participants were 729 secondary school PE teachers who worked in 81 major cities of Turkey. The Teachers Attitudes towards Children with Intellectual Disability Scale was administered. RESULTS: The statistical analysis revealed that there was no significant effect on factors and total attitudes scores of gender and having students with ID. Significant effects on factors and total attitudes score were found in teaching experiences and having acquaintance with ID. CONCLUSIONS: It is encouraged to maintain and further develop in-service education programmes of adapted physical activity for PE teachers. PMID- 22823107 TI - Assessment of the probiotic potential of a dairy product fermented by Propionibacterium freudenreichii in piglets. AB - Dairy propionibacteria, including Propionibacterium freudenreichii , display promising probiotic properties, including immunomodulation. These properties are highly strain-dependent and rarely studied in a fermented dairy product. We screened 10 strains, grown in a newly developed fermented milk ultrafiltrate, for immunomodulatory properties in vitro. The most anti-inflammatory strain, P. freudenreichii BIA129, was further tested on piglets. P. freudenreichii fermented product improved food intake and growth of piglets. Colonic mucosa explants of treated pigs secreted less interleukin 8 (-25%, P < 0.05) and tumor necrosis factor alpha (-20%, P < 0.05), either in basal conditions or after a lipopolysaccharide challenge. By contrast, the gut structure, barrier function (measured ex vivo in Ussing chambers), microbial diversity (assessed by 16S rRNA pyrosequencing), and colonic short-chain fatty acid content were unchanged, assuming maintenance of normal intestinal physiology. In conclusion, this work confirms in vivo probiotic properties of dairy propionibacteria-fermented products, which are promising for the prevention or healing of inflammatory bowel diseases. PMID- 22823108 TI - Effect of external rotational humeral osteotomy on the contact mechanics of the canine elbow joint. AB - OBJECTIVE: To evaluate the effect of 15 degrees external rotational humeral osteotomy (ERHO) on canine elbow joint contact mechanics. STUDY DESIGN: Ex vivo biomechanical study. SAMPLE POPULATION: Unpaired cadaveric canine thoracic limbs (n = 8) METHODS: Digital pressure sensors placed in a subchondral osteotomy distal to the elbow joint were used to measure contact area, peak and mean contact pressure, peak pressure location, center of pressure, and total force in the subchondral bone of the radius and the ulna. Measurements were taken in the following sequence: (i) neutral and (ii) after 15 degrees external rotation. The distal aspect of the humerus was externally rotated by a middiaphyseal osteotomy and stabilized with an internal fixator. Data were normalized and analyzed using paired t-tests; P <= .05 was considered significant. RESULTS: Peak pressure location and center of pressure shifted 37.5 +/- 15.9% and 21.5 +/- 6.8% laterally after ERHO (P < .001 for both). Both were situated over the subchondral bone of the ulna in neutral position and over the radius after rotation in all 8 specimens (P < .001). Pressure measured in the ulnar part of the osteotomy was reduced from 58.7 +/- 9.1% to 27.1% after ERHO (P < .001). Contact area, peak and mean contact pressure, and total force did not vary significantly between conditions. CONCLUSION: ERHO shifts the peak pressure location and the center of pressure laterally, toward the radial head and reduced the pressure acting on the ulna. The lateral shift of peak pressure may be beneficial in dogs with medial compartment disease. PMID- 22823109 TI - Treatment of advanced stage Hodgkin lymphoma--it's all about risk-benefit. PMID- 22823110 TI - Selenium nanoparticles as a carrier of 5-fluorouracil to achieve anticancer synergism. AB - A simple method for preparing 5-fluorouracil surface-functionalized selenium nanoparticles (5FU-SeNPs) with enhanced anticancer activity has been demonstrated in the present study. Spherical SeNPs were capped with 5FU through formation of Se-O and Se-N bonds and physical adsorption, leading to the stable structure of the conjugates. 5FU surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. A panel of five human cancer cell lines was shown to be susceptible to 5FU-SeNPs, with IC(50) values ranging from 6.2 to 14.4 MUM. Despite this potency, 5FU-SeNP possesses great selectivity between cancer and normal cells. Induction of apoptosis in A375 human melanoma cells by 5FU-SeNPs was evidenced by accumulation of sub-G1 cell population, DNA fragmentation, and nuclear condensation. The contribution of the intrinsic apoptotic pathway to the cell apoptosis was confirmed by activation of caspase-9 and depletion of mitochondrial membrane potential. Pretreatment of cells with a general caspase inhibitor z-VAD-fmk significantly prevented 5FU-SeNP-induced apoptosis, indicating that 5FU-SeNP induced caspase-dependent apoptosis in A375 cells. Furthermore, 5FU-SeNP-induced apoptosis was found dependent on ROS generation. Our results suggest that the strategy to use SeNPs as a carrier of 5FU could be a highly efficient way to achieve anticancer synergism. 5FU-SeNPs may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially melanoma. PMID- 22823112 TI - Behaviour of pollinator insects within inflorescences of Scrophularia species from Iberian Peninsula. AB - Several hypotheses have been proposed to explain the pattern of pollinator visits to vertical inflorescences. These range from a response to a pattern of resources to merely instinctive behaviour. In dichogamous plants, such behaviour has been associated with promoting outcrossing and avoiding geitonogamy. We here analyse behaviour of the principal pollinator groups in five protogynous species of Scrophularia with different flower sizes (S. sambucifolia, S. grandiflora, S. lyrata, S. scorodonia and S. canina), and the distribution of sexual phases along the inflorescences. The results in all cases show that pollinators follow a pattern of ascending visits accompanied by movements between flowers of the same whorl (horizontal movements). The relative frequency of these horizontal movements depends on the flower size, with a higher frequency in species with large flowers. In vertical movements of the three more common pollinator groups to several plant species (bumblebees, wasps and small bees), the behaviour was essentially independent of flower size, with bumblebees having the highest ratio of ascents to descents. Behaviour of the pollinators, together with the absence of a definite pattern of distribution of the sexual phases along the inflorescence, implies that geitonogamy is not avoided in any of the Scrophularia species studied. PMID- 22823113 TI - Atopic keratoconjunctivitis. AB - Atopic keratoconjunctivitis (AKC) is a potentially blinding disease characterized by a bilateral chronic keratoconjunctivitis associated with atopic dermatitis. The disease usually manifests as severe itching and burning, excessive tearing, foreign body sensation, and mucoid discharge. The clinical characteristics of AKC show a broad spectrum including lid dermatitis, chronic blepharitis, cicatrizing conjunctivitis with fornix foreshortening and symblepharon formation, punctate epithelial keratitis, persistent epithelial defects, corneal scarring and neovascularization, lipid keratopathy, conjunctivalization of peripheral cornea, and peripheral ulcerative keratitis. The underlying pathophysiologic mechanism in AKC involves a combination of type-I IgE-mediated, and type-IV delayed hypersensitivity reactions. The immunoregulatory defect responsible for the overproduction of allergen-specific IgE antibody, the key component responsible for antigen binding, and subsequent mast cell degranulation, is probably multifactorial. The histopathologic characteristics of the conjunctiva in AKC include a mast cell and eosinophil invasion of the epithelium, epithelial pseudotubule formation, and prominent mast cell and mononuclear cell infiltration of the substantia propria. A number of ocular conditions have been reported to be associated with AKC, including keratoconus, herpes simplex keratitis, and cataracts. Successful long-term control of this potentially blinding disease requires a multidisciplinary approach involving systemic and environmental aspects. Scrupulous long-term environmental control of allergens is the single most important aspect in the management of patients with AKC. Systemic anti histamine therapy, and long-term topical mast cell stabilizing therapy are also mandatory. Topical steroids should be reserved for exacerbations of the disease. PMID- 22823114 TI - The influence of cyclosporin A on proteininduced uveitis in the rabbit. AB - Until now immunosuppressive drugs have mainly been used to treat ocular diseases considered to have an autoimmune pathogenesis. The authors investigated whether cyclosporin A (CsA) could also prevent intraocular inflammation mediated by a foreign antigen. To this purpose, uveitis was induced by injection of human serum albumin (HSA) into the vitreous of rabbits. Subcutaneous injection of CsA prevented the induction of uveitis. Treatment of CsA had to be started at the time of intravitreal antigen injection and did not suppress the reaction when started at the onset of uveitis. Suppression of uveitis correlated with an inhibition of the antibody response against the injected HSA. Animals in which uveitis was suppressed by CsA did not develop a recurrent uveitis after intravenous challenge with the antigen, but did develop a primary inflammatory response after a repeated injection of HSA into the vitreous. The most likely interpretation of the findings presented in this paper are as follows. CsA blocks T helper cells through an inhibition of IL-2 gene activation. This in turn blocks release of other T helper cell cytokines which are essential for the activation of B lymphocytes into antibody producing plasma cells. These observations thus show that CsA can suppress both cell-mediated as well as antibody-mediated models of uveitis. PMID- 22823115 TI - Immunohistochemical localization of T lymphocytes and macrophages and expression of interferon gamma and defensin in uveitis. AB - Cytokines play important roles in the pathogenesis of uveitis. In order to characterize the role of T cells, macrophages, and their cytokines in uveitis, the authors examined iris biopsies from eight patients with chronic, quiescent anterior uveitis and five subjects with cataracts. All except one iris biopsy from uveitic patients demonstrated the presence of T cells and macrophages following avidin-biotin-complex immunoperoxidase staining. The most striking feature was the consistent spatial correlation between the presence of T cells and localized tissue staining for interferon gamma, and between the presence of macrophages and tissue staining for defensins. This study showed that T cells and macrophages were part of the inflammatory response in uveitis and that they secreted interferon gamma and defensin respectively. PMID- 22823116 TI - Heparin surface modified intraocular lenses in uveitis. AB - A retrospective analysis of the results of cataract surgery using heparin surface modified intraocular lenses (HSM-IOL) performed on patients with uveitis between August 1989 and July 1993 was undertaken. In total, 32 eyes of 28 patients with various types of uveitis underwent extracapsular cataract extraction and implantation of a posterior chamber HSM-IOL. In four patients, cataract extraction was combined with trabeculectomy. The post-operative follow-up period ranged from two to 51 months (average 16 months). The visual acuity improved in 31 of 32 eyes (96.8%) with 28 eyes (87.5%) seeing 6/18 or better. In four eyes (12.5%), the visual acuity was only 6/60 due to longstanding, pre-operative cystoid macular oedema. Posterior synechiae developed in eight eyes (25%), inflammatory deposits were noticed on the IOL surface in five eyes (15.6%), and three eyes (9.3%) required YAG laser posterior capsulotomy. These results suggest that HSM lenses are associated with minimal post-operative complications and appear safe to be used in human uveitic eyes. PMID- 22823117 TI - Epidemiology of uveitis in Switzerland. AB - During the period from January 1990 to December 1993, 558 new patients (250 female and 308 male, mean age 44 years; range 5-92) were seen at the Uveitis Clinic of the Hopital Jules Gonin. These 558 patients (740 eyes) were subdivided into anterior uveitis (343 patients-61%), intermediate uveitis (57 patients-10%), posterior uveitis (118 patients-21 %) and panuveitis (40 patients-7%). The incidence of uveitis for the referral area considered was calculated to be 17.5 per 100,000 inhabitants per year. A specific diagnosis was found in 386 cases (69%). The most frequently diagnosed entities were HLA-B27-associated acute anterior uveitis (89 cases-15.9%), uveitis associated with acute herpes zoster ophthalmicus (54 cases-9.7%), toxoplasmosis (53 cases-9.5%), sarcoidosis (33 cases-5.9%), typical pars planitis (31 cases-5.6%), Fuchs' heterochromic cyclitis (30 cases-5.4%), herpetic anterior uveitis (23 cases-4.1 %) and acute retinal necrosis (13 cases-2.3%). Incidence and distribution of most disease entities correspond to those of other European and American series. PMID- 22823118 TI - Nedocromil sodium treats symptoms of perennial allergic conjunctivitis not fully controlled by sodium cromoglycate A double-masked placebo controlled group comparative study. AB - In a double-masked group comparative study, 20 patients received 2% nedocromil sodium four times daily and 23 placebo eye drops, for treatment of perennial allergic conjunctivitis (PAC). All had at least a one-year diagnosis of bilateral PAC and remained symptomatic despite using 2% sodium cromoglycate eye drops four times daily for at least 14 days Symptom severity (0-4) during sodium cromoglycate monotherapy was then recorded in a one-week baseline prior to randomisation, a minimum total score of 11 being mandatory. During the trial, no eye medication was allowed other than the test treatment. Clinic examinations were made before and after baseline and after one, three and six weeks' treatment, and patients kept daily diary cards of eye symptom severity. Compared to placebo, nedocromil sodium significantly (p<0.05) improved diary scores for itching (weeks 3, 4, 5, 6), total symptoms (weeks 5, 6) and general eye condition (week 6). Mean scores over the final four weeks, allowing a two-week washout, showed similar improvements in itching (p = 0.01), total symptoms (p = 0.05) and general eye condition (p = 0.04). Clinical assessments again favoured nedocromil sodium, which improved itching (week 3, p = 0.002), burning (week 6, p = 0.007), overall eye condition (weeks 3-6, p<0.05). and conjunctival thickening and hyperaemia (weeks 3-6, p<0.05). Finally, both patient (p = 0.02) and clinician (p = 0.0015) opinions of efficacy favoured nedocromil sodium over placebo. These results show nedocromil sodium to be effective in controlling symptoms of perennial allergic conjunctivitis which persisted during treatment with sodium cromoglycate. PMID- 22823119 TI - Fuchs'heterochromic uveitis and Coats' disease. PMID- 22823120 TI - Seasonal variation in competition and coexistence of Aedes mosquitoes: stabilizing effects of egg mortality or equalizing effects of resources? AB - Theory shows that fluctuation of environmental conditions can produce temporal niches for inferior competitors that mitigate effects of interspecific competition and facilitate long-term persistence of poor competitors. In south Florida, the mosquitoes Aedes albopictus and Aedes aegypti often co-occur in water-filled containers despite A. albopictus being competitively superior to A. aegypti. We tested the hypothesis that seasonal fluctuation in environmental conditions reduces or reverses competitive asymmetry between the species and contributes to persistence of the poorer competitor via stabilizing or equalizing effects. During the Florida wet and dry seasons, we manipulated mosquito egg exposure to desiccation before inducing hatching and allowing surviving larvae to compete for 59 days. The effect of season also incorporated seasonal fluctuations in resource input to experimental containers. For both species, composite index of population performance (lambda') was greater in the dry season than in the wet season, indicating strong seasonal effects on population dynamics. Aedes albopictus was not affected by competition in either season. Aedes aegypti was negatively affected by interspecific competition in the wet season. Aedes aegypti egg survival was unaffected by exposure to the different experimental environments. There was a small reduction in A. albopictus egg survival in the wet season, but this reduction was unrelated to effects on lambda', indicating fluctuation in the egg environment did not contribute to dry season release from competition. Detritus resource inputs were over three times greater in the dry season than in the wet season. Given the relatively small effect of environment on egg survival, these results suggest that seasonal differences in population performance are driven primarily by per-capita food availability. Large inputs of detritus in the dry season appear to reduce competition and produce similar responses in both species. This result suggests that seasonal variation contributes to coexistence of A. albopictus and A. aegypti as a fitness equalizing factor. PMID- 22823121 TI - Photo-inactivation of Bacillus endospores: inter-specific variability of inactivation efficiency. AB - The aims of this work were to (a) evaluate the susceptibility of endospores of Bacillus cereus, B. licheniformis, B. sphaericus and B. subtilis to photodynamic inactivation using a tricationic porphyrin as photosensitizer, (b) assess the efficiency of adsorption of the photosensitizer in endospore material as a determinant of the susceptibility of endospores of different Bacillus species to photo-inactivation, (c) determine the value of B. cereus as a model organism for studies of antimicrobial photodynamic inactivation of bacterial endospores. The results of irradiation experiments with endospores of four species of Bacillus showed that B. cereus was the only species for which efficient endospore photo inactivation (> 3 log reduction) could be achieved. Endospores of B. licheniformis, B. sphaericus and B. subtilis were virtually resistant to photo inactivation with tricationic porphyrin. The amount of porphyrin bound to endospore material was not significantly different between species, regardless of the presence of an exosporium or exosporium-like outer layer. The sensitivity of endospores to photodynamic inactivation with a tricationic porphyrin is highly variable among different species of the genus Bacillus. The presence of an exosporium in endospores of B. cereus and B. sphaericus, or an exosporium-like glycoprotein layer in endospores of B. subtilis, did not affect the amount of bound photosensitizer and did not explain the inter-species variability in susceptibility to photodynamic inactivation. The results imply that the use of B. cereus as a more amenable surrogate of the exosporium-producing B. anthracis must be carefully considered when testing new photosensitizers for their antimicrobial photo-inactivation properties. PMID- 22823124 TI - The genetic aetiology of cannabis use initiation: a meta-analysis of genome-wide association studies and a SNP-based heritability estimation. AB - While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic aetiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with > 10 000 individuals. None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic aetiology of cannabis use. PMID- 22823126 TI - Fragment-based QSAR strategies in drug design. AB - Recently, fragment-based drug design has been established as a crucial strategy for hit identification and lead generation, which has strongly encouraged the development of approaches to specifically recognize and evaluate molecular fragments or structural scaffolds that preferentially interact with particular sites of important biological targets. In this context, fragment-based quantitative structure-activity relationship (FB-QSAR) has emerged as a versatile tool to explore the chemical and biological space of data sets of compounds. FB QSAR approaches have evolved from a classical use in the generation of standard QSAR models into advanced drug design tools for database mining, pharmacokinetic property prediction and optimization of multiple parameters. This paper provides a brief perspective on the evolution and current status of FB-QSAR, highlighting new opportunities in drug design. PMID- 22823127 TI - The use of web ontology languages and other semantic web tools in drug discovery. AB - IMPORTANCE OF THE FIELD: To optimize drug development processes, pharmaceutical companies require principled approaches to integrate disparate data on a unified infrastructure, such as the web. The semantic web, developed on the web technology, provides a common, open framework capable of harmonizing diversified resources to enable networked and collaborative drug discovery. AREAS COVERED IN THIS REVIEW: We survey the state of art of utilizing web ontologies and other semantic web technologies to interlink both data and people to support integrated drug discovery across domains and multiple disciplines. Particularly, the survey covers three major application categories including: i) semantic integration and open data linking; ii) semantic web service and scientific collaboration and iii) semantic data mining and integrative network analysis. WHAT THE READER WILL GAIN: The reader will gain: i) basic knowledge of the semantic web technologies; ii) an overview of the web ontology landscape for drug discovery and iii) a basic understanding of the values and benefits of utilizing the web ontologies in drug discovery. TAKE HOME MESSAGE: i) The semantic web enables a network effect for linking open data for integrated drug discovery; ii) The semantic web service technology can support instant ad hoc collaboration to improve pipeline productivity and iii) The semantic web encourages publishing data in a semantic way such as resource description framework attributes and thus helps move away from a reliance on pure textual content analysis toward more efficient semantic data mining. PMID- 22823125 TI - Differential effect of alcoholism and HIV infection on visuomotor procedural learning and retention. AB - BACKGROUND: Selective declarative memory processes are differentially compromised in chronic alcoholism (ALC) and HIV infection (HIV) and likely reflect neuropathology associated with each condition: frontocerebellar dysfunction in ALC and frontostriatal dysfunction in HIV infection. Evidence for disease overlap derives from observed exacerbated impairments in these declarative memory processes in ALC-HIV comorbidity. Less is known about nondeclarative memory processes in these disease conditions. Examination of visuomotor learning in chronic ALC and HIV infection could provide insight into the differential and combined contribution of selective disease-related injury to visuomotor procedural memory processes. METHODS: We examined component processes of visuomotor learning and retention on the rotary pursuit task in 29 ALC, 23 HIV, 28 ALC + HIV, and 20 control subjects. Participants were given 4 rotary pursuit learning sessions over 2 testing days, typically separated by 1 week, to assess visuomotor learning and retention patterns. Ancillary measures of simple motor, psychomotor, explicit memory, and balance abilities were administered to test which component processes independently predicted visuomotor learning. RESULTS: All clinical groups showed visuomotor learning across rotary pursuit testing sessions, despite impairment in visuomotor speed in the HIV groups and impairment in explicit memory and psychomotor speed in the alcohol groups. The 2 alcoholic groups showed retention and consolidation over time (i.e., improved performance without further training), whereas the HIV-infected group showed learning and retention but no consolidation effect. The comorbid group shared impairments associated with the ALC-only group (explicit memory and psychomotor speed) and the HIV-only group (visuomotor speed), although there was no clear compounded effect of alcohol and HIV infection on visuomotor learning performance. CONCLUSIONS: This study supports the hypothesis that ALC and HIV infection exert differential effects on components of visuomotor procedural learning. Further, the results provide behavioral evidence for dissociable influences of frontocerebellar and frontostriatal disruption to visuomotor procedural learning and retention. PMID- 22823128 TI - Systems biology visualization tools for drug target discovery. AB - IMPORTANCE OF THE FIELD: Post-genome drug development has been driven by the need to study biological perturbations at the molecular system level. Systems biology visualization tools can help researchers extract hidden patterns from complex and large Omics data sets, model disease molecular mechanisms, and identify drug targets and drugs with good pharmacological and toxicological profiles. AREAS COVERED IN THIS REVIEW: This review covers basic concepts in developing and applying information visualization tools to systems biology. We describe a framework and basic data representation schemes for visual data analysis in systems biology. We review major application areas of these visualization tools within drug discovery by focusing on early-stage drug discovery tasks such as disease biology modeling, target identifications and lead identification. We also show case studies and summarize our experience using visualization tools as lessons to our readers. WHAT THE READER WILL GAIN: The reader will understand what visualization tools are available for diverse types of systems biology studies in drug discovery and understand how these tools can help advance drug development. TAKE HOME MESSAGE: In spite of the complexity inherent in systems biology, proper use of information visualization tools may reveal emerging properties hidden in the data and enhance chances of success for drug discovery. PMID- 22823129 TI - Pharmacophore models for GABA(A) modulators: implications in CNS drug discovery. AB - IMPORTANCE OF THE FIELD: GABA(A) ion channel is a validated drug target, implicated in the pathophysiology of various neurological and psychiatric disorders. Structural investigations on GABA(A) are currently precluded in the absence of experimentally resolved structure. Pharmacophore modeling circumvents such issues and proves to be a powerful and successful method in drug discovery. AREAS COVERED IN THIS REVIEW: The present reviews encompass pharmacophoric models available in the literature for the orthosteric GABA and the allosteric benzodiazepine binding site. Success stories from these simplistic pharmacophore models in scaffold hopping and strategic lead optimization have been highlighted. Recent advances in pharmacophore modeling that can leverage CNS drug discovery programs and deliver astounding results have been reviewed. WHAT THE READER WILL GAIN: Readers are bound to gain a comprehensive insight on different computational techniques used by different groups to arrive at simple, yet sophisticated pharmacophore models. In the absence of experimentally unresolved active site geometry of GABA(A), these models will provide the reader an opportunity to translate these pharmacophoric features to the microscopic phenomenon of supramolecular ligand interaction. TAKE HOME MESSAGE: Pharmacophore modeling has now evolved as a mainstay approach for lead generation and optimization in drug discovery programs. Of late, many advances in pharmacophore perception have emerged. Such advancements should be used to confront activity profiling and early stage risk assessment in a high-throughput fashion. Extending such technologies has the potential not only to reduce time and cost, but also to prevent late stage attrition in drug discovery. PMID- 22823130 TI - Heterodimerisation of G protein-coupled receptors: implications for drug design and ligand screening. AB - IMPORTANCE OF THE FIELD: In recent times many G protein-coupled receptors (GPCRs) have been shown to dimerise/oligomerise and, in some cases, such structural organization has been found to be essential for receptor function or to play a modulatory role in living cells. The fact that these complexes may display differential pharmacology through, for example, the formation of a new binding pocket or signalling properties, as well as different functions or regulation in physiological tissues, offers novel opportunities for drug discovery. As a consequence, it seems necessary to develop new approaches suitable for GPCR heterodimer identification and selective ligand screening. AREAS COVERED IN THIS REVIEW: This review gives an overview of new strategies that have been developed in an effort to incorporate the possibilities added by GPCR hetero oligomerisation on the screening of compounds as drug candidates. WHAT THE READER WILL GAIN: The reader will gain a wider knowledge about how the current understanding of GPCR oligomeric structure and function has mandated that hetero oligomeric receptors must be considered as novel targets in the identification of future lead compounds. TAKE HOME MESSAGE: For the improvement of novel drug discovery, more structural and functional information on the process of receptor oligomerisation is needed, and the realisation that the function of GPCRs can be greatly influenced by other interacting receptors or proteins also demands consideration in the lead-compound developing process in order to achieve better therapeutic agents. PMID- 22823131 TI - Advances in LC platforms for drug discovery. AB - IMPORTANCE OF THE FIELD: The major application areas of liquid chromatography (LC) in modern drug discovery are the identification and structural characterization of new potential lead compounds from natural and/or synthetic sources and the determination of their physico-chemical and pharmacokinetic properties. AREAS COVERED IN THIS REVIEW: Significant advances in terms of LC platforms achieved in the last 5 years are highlighted in this review. Special attention is paid to novel LC strategies used in the discovery of new bioactive molecules and the determination of lipophilicity, pK(a) values, passive drug permeability and in vitro metabolism of new chemical entities. WHAT THE READER WILL GAIN: Many improvements were achieved in terms of LC instrumentation, columns technology and analytes detection to attain ultra-fast and/or high resolution chromatographic separations. These advances are particularly beneficial to face the complexity and high number of samples studied in the early phases of the discovery process. Advantages and drawbacks of each strategy are discussed. TAKE HOME MESSAGE: LC and ultra high pressure liquid chromatography coupled with mass spectrometry detection constitute the most promising strategies to achieve high-throughput and/or high-resolution analyses in a drug discovery environment. PMID- 22823132 TI - Methods for the quantitative evaluation and prediction of CYP enzyme induction using human in vitro systems. AB - IMPORTANCE OF THE FIELD: For successful drug development, it is important to investigate the potency of candidate drugs causing drug-drug interactions (DDI) during the early stages of development. The most common mechanisms of DDIs are the inhibition and induction of CYP enzymes. Therefore, it is important to develop co.mpounds with lower potencies for CYP enzyme induction. AREAS COVERED IN THIS REVIEW: The aim of the present paper is to present an overview of the current knowledge of CYP induction mechanisms, particularly focusing on the transcriptional gene activation mediated by pregnane X receptor, aryl hydrocarbon receptor and constitutive androstane receptor. The adoptable options of in vitro assay methods for evaluating CYP induction are also summarized. Finally, we introduce a method for the quantitative prediction of CYP3A4 induction considering the turnover of CYP3A4 mRNA and protein in hepatocytes based on the data obtained from a reporter gene assay. WHAT THE READER WILL GAIN: In order to predict in vivo CYP enzyme induction quantitatively based on in vitro information, an understanding of the physiological induction mechanisms and the features of each in vitro assay system is essential. We also present the estimation method of in vivo CYP induction potency of each compound based on the in vitro data which are routinely obtained but not necessarily utilized maximally in pharmaceutical companies. TAKE HOME MESSAGE: It is desirable to select compounds with lower potencies for the inductive effect. For this purpose, an accurate prioritization procedure to evaluate the induction potency of each compound in a quantitative manner considering the pharmacologically effective concentration of each compound is necessary. PMID- 22823133 TI - Massive intravascular hemolysis with mechanical rheolytic thrombectomy of a hemodialysis arteriovenous fistula. AB - A 57-year-old man with chronic kidney disease stage 5 presented for ambulatory evaluation of his arteriovenous fistula. He underwent rheolytic thrombectomy with tissue plasminogen activator infusion, angioplasty, and brachial artery stenting under local sedation. His immediate postoperative course was complicated by hypotension, cardiac dysrhythmias and hyperkalemia requiring emergent hemodialysis, due to severe intravascular hemolysis. This case illustrates that mechanical thrombectomy can cause clinically significant intravascular hemolysis, thus careful postoperative monitoring is recommended. PMID- 22823134 TI - Grief and joy: emotion word comprehension in the dementias. AB - OBJECTIVE: Word comprehension deficits in neurodegenerative conditions are most striking in the syndrome of semantic dementia. Tests of word comprehension typically examine concrete and abstract nonemotion words. Whether or not understanding of words describing emotion concepts (e.g., insulted, fascinated) is also impaired in the dementias has not been systematically investigated. METHOD: Patients with semantic dementia (SD; n = 8), behavioral-variant frontotemporal dementia (bvFTD; n = 8), Alzheimer's disease (AD; n = 12), as well as healthy controls (n = 15) completed newly designed emotion word comprehension tasks. Participants also undertook the Graded Synonyms Test, an abstract and concrete nonemotion word comprehension measure. RESULTS: Degradation of knowledge about negative and positive emotion words was most impaired in SD. Correlation analyses in the SD group also showed that knowledge of emotion words correlated with the understanding of abstract nonemotion words. The bvFTD group was impaired only when making associations for emotion words. The AD cohort did not differ from controls on any measures of word comprehension. CONCLUSIONS: Impairment in word knowledge is greatest in the syndrome of SD, compared with bvFTD and AD, and includes concrete words, abstract words as well as emotion words. Importantly, word comprehension deficits affect positive and negative emotions. PMID- 22823135 TI - Covert recognition relies on affective valence in developmental prosopagnosia: evidence from the skin conductance response. AB - OBJECTIVE: It has traditionally been thought that covert face recognition cannot be observed in developmental cases of prosopagnosia, because the phenomenon is thought to rely on the activation of face representations created during a period of normal processing. Yet, recent studies have provided evidence of covert recognition in some developmental cases, and critically the findings of one study suggest that these individuals might be processing faces on an affective dimension rather than a familiarity dimension. The current study aimed to examine this possibility using a physiological measure of covert recognition, the skin conductance response (SCR). METHOD: One 61-year-old male with developmental prosopagnosia and 10 age-matched (M = 59.80 years, SD = 4.02) controls (5 men) took part in this study. Participants viewed a set of 15 famous faces intermixed with 30 novel faces, and the SCR was recorded throughout. RESULTS: Although control participants demonstrated an increased SCR for famous faces in comparison with novel faces, t(9) = 2.112, p = .032, d = .382, the same finding was not observed in Patient WS. However, when WS' increase in SCR was correlated with his affective ratings of the celebrities from name cues, a strong negative correlation was observed (r = -.614, n = 34, p = .020). CONCLUSION: This pattern of findings was interpreted as evidence that WS is covertly processing faces on an affective dimension rather than a familiarity dimension, and fits well with recent neurophysiological findings that support hypotheses for independent processing of cognitive and affective information. PMID- 22823137 TI - Color matrix refractive index sensors using coupled vertical silicon nanowire arrays. AB - Vivid colors are demonstrated in silicon nanowires with diameters ranging from 105 to 346 nm. The nanowires are vertically arranged in a square lattice with a pitch of 400 nm and are electromagnetically coupled to each other, resulting in frequency-dependent reflection spectra. Since the coupling is dependent on the refractive index of the medium surrounding the nanowires, the arrays can be used for sensing. A simple sensor is demonstrated by observing the change in the reflected color with changing refractive index of the surrounding medium. A refractive index resolution of 5 * 10(-5) is achieved by analyzing bright-field images captured with an optical microscope equipped with a charge coupled device camera. PMID- 22823136 TI - Cognitive deficits in the remitted state of unipolar depressive disorder. AB - BACKGROUND: Patients with unipolar depressive disorder may present with cognitive deficits in the remitted state, and the aim of the present study was to investigate whether cognitive deficits within specific cognitive domains are present. METHOD: Via the Danish registers (Civil Person Register, Danish Psychiatric Register) we identified individuals between 40 and 80 years of age with a diagnosis of unipolar disorder at their first discharge from a psychiatric hospital, and a gender- and age-matched control group. Particular emphasis was placed on assuring that patients were in a remitted state. Cognitive function was assessed with a broad range of neuropsychological tests. RESULTS: A total of 88 patients and 50 controls were included in the study. In multiple linear regression analyses with simultaneous adjustment for age, gender, education level, premorbid IQ, and residual depressive symptoms, a diagnosis of unipolar disorder predicted lower performance on the Trail Making Test, the Symbol Digit Modalities Test, and on the Stroop test. CONCLUSION: Cognitive deficits are present in patients with unipolar disorder in the remitted state. The deficits seem to reside more within the cognitive domain of attention than within other domains, and may be characterized by impairment of processing speed and cognitive flexibility. PMID- 22823138 TI - Therapy in virtual environments--clinical and ethical issues. AB - BACKGROUND: As virtual reality and computer-assisted therapy strategies are increasingly implemented for the treatment of psychological disorders, ethical standards and guidelines must be considered. This study determined a set of ethical and legal guidelines for treatment of post-traumatic stress disorder (PTSD)/traumatic brain injury (TBI) in a virtual environment incorporating the rights of an individual who is represented by an avatar. MATERIALS AND METHODS: A comprehensive literature review was undertaken. An example of a case study of therapy in Second Life (a popular online virtual world developed by Linden Labs) was described. RESULTS: Ethical and legal considerations regarding psychiatric treatment of PTSD/TBI in a virtual environment were examined. The following issues were described and discussed: authentication of providers and patients, informed consent, patient confidentiality, patient well-being, clinician competence (licensing and credentialing), training of providers, insurance for providers, the therapeutic environment, and emergencies. Ethical and legal guidelines relevant to these issues in a virtual environment were proposed. CONCLUSIONS: Ethical and legal issues in virtual environments are similar to those that occur in the in-person world. Individuals represented by an avatar have the rights equivalent to the individual and should be treated as such. PMID- 22823139 TI - |SE|S|AM|E| Barcode: NGS-oriented software for amplicon characterization- application to species and environmental barcoding. AB - Progress in NGS technologies has opened up new opportunities for characterizing biodiversity, both for individual specimen identification and for environmental barcoding. Although the amount of data available to biologist is increasing, user friendly tools to facilitate data analysis have yet to be developed. Our aim, with |SE|S|AM|E| Barcode, is to provide such support through a unified platform. The sequences are analysed through a pipeline that (i) processes NGS amplicon runs, filtering markers and samples, (ii) builds reference libraries and finally (iii) identifies (barcodes) the sequences in each amplicon from the reference library. We use a simulated data set for specimen identification and a recently published data set for environmental barcoding to validate the method. The results obtained are consistent with the expected characterizations (in silico and previously published, respectively). |SE|S|AM|E| Barcode and its documentation are freely available under the Creative Commons Attribution NonCommercial-ShareAlike 3.0 Unported Licence for Windows and Linux from http://www1.montpellier.inra.fr/CBGP/NGS/. PMID- 22823140 TI - Intrinsic dynamics of DNA-polymer complexes: a mechanism for DNA release. AB - The transfer of genetic material into cells using nonviral vectors offers unique potential for therapeutics; however, the efficacy of delivery depends upon a poorly understood, multistep pathway, limiting the prospects for successful gene delivery. Mechanistic insight into DNA association and release has been hampered by a lack of atomic resolution structural and dynamic information for DNA-polymer complexes (polyplexes). Here, we report a dendrimer-based polyplex system containing poly(ethyleneglycol) (PEG) arms that is suitable for atomic-level characterization by solution NMR spectroscopy. NMR chemical shift, line width, and proton transverse relaxation rate measurements reveal that free and dendrimer bound polyplex DNA exchange rapidly relative to the NMR time scale ( C57BL6 cardiac transplant model. Moreover, the combination of MyD88 and TRIF siRNA along with a low dose of rapamycin further extended the allograft survival (88.8 +/- 7.1 days). Tissue histopathology demonstrated an overall reduction in lymphocyte interstitium infiltration, vascular obstruction and hemorrhage in mice treated with MyD88 and TRIF siRNA vector plus rapamycin. Furthermore, treatment was associated with an increase in the numbers of CD4(+) CD25(+) FoxP3(+) regulatory T cells and Th2 deviation. To our knowledge, this study is the first demonstration of prolonging the survival of allogeneic heart grafts through gene silencing of TLR signaling adaptors, highlighting the therapeutic potential of siRNA in clinical transplantation. PMID- 22823143 TI - Nicotine metabolism and addiction among adolescent smokers. AB - AIMS: The purpose of this study was to determine the association between the nicotine metabolic rate and smoking behavior, including addiction, in adolescent smokers. DESIGN: Baseline data from a prospective study of adolescent smoking behaviors and nicotine metabolism. SETTING: The setting was an out-patient university hospital in San Francisco. PARTICIPANTS: Adolescent smokers (n = 164) aged 13-17 years old. MEASUREMENTS: Participants completed self-report measures of smoking behavior and nicotine dependence (modified Fagerstrom Tolerance Questionnaire: mFTQ). The nicotine metabolite ratio (NMR), a phenotypic marker of the rate of nicotine metabolism, was calculated using the ratio of concentrations of deuterium-labeled 3'-hydroxycotinine to cotinine-d(4) . FINDINGS: Participants reported smoking a mean of 2.86 cigarettes per day (CPD) [median = 1.78, standard deviation (SD) = 3.35] for 1.37 years (median = 1.0, SD = 1.36). Results from multivariate analyses accounting for age, race/ethnicity, gender and duration of smoking indicated that slower metabolizers smoked more CPD than faster metabolizers (the NMR was inversely related to CPD; P = 0.02). Slower metabolizers also showed greater dependence on the mFTQ (NMR was negatively associated with the mFTQ; P = 0.02). CONCLUSIONS: In adolescence, slower clearance of nicotine may be associated with greater levels of addiction, perhaps mediated by a greater number of cigarettes smoked. PMID- 22823146 TI - Development of singlet oxygen absorption capacity (SOAC) assay method. 3. Measurements of the SOAC values for phenolic antioxidants. AB - Measurements of the singlet oxygen ((1)O(2)) quenching rates (k(Q) (S)) and the relative singlet oxygen absortpion capacity (SOAC) values were performed for 16 phenolic antioxidants (tocopherol derivatives, ubiquinol-10, caffeic acids, and catechins) and vitamin C in ethanol/chloroform/D(2)O (50:50:1, v/v/v) solution at 35 degrees C. It has been clarified that the SOAC method is useful to evaluate the (1)O(2)-quenching activity of lipophilic and hydrophilic antioxidants having 5 orders of magnitude different rate constants from 1.38 * 10(10) M(-1) s(-1) for lycopene to 2.71 * 10(5) for ferulic acid. The logarithms of the k(Q) (S) and the SOAC values for phenolic antioxidants were found to correlate well with their peak oxidation potentials (E(p)); the antioxidants that have smaller E(p) values show higher reactivities. In previous works, measurements of the k(Q) (S) values for many phenolic antioxidants were performed in ethanol. Consequently, measurements of the k(Q) (S) and relative SOAC values were performed for eight carotenoids in ethanol to investigate the effect of solvent on the (1)O(2) quenching rate. The k(Q) (S) values for phenolic antioxidants and carotenoids in ethanol were found to correlate linearly with the k(Q) (S) values in ethanol/chloroform/D(2)O solution with a gradient of 1.79, except for two catechins. As the relative rate constants (k(Q)(AO) (S)/k(Q)(alpha-Toc) (S)) of antioxidants (AO) are equal to the relative SOAC values, the SOAC values do not depend on the kinds of solvent used, if alpha-tocopherol is used as a standard compound. In fact, the SOAC values obtained for carotenoids in mixed solvent agreed well with the corresponding ones in ethanol. PMID- 22823148 TI - Pollen dispersal and fruit production in Vaccinium oxycoccos and comparison with its sympatric congener V. uliginosum. AB - Investigating plant-pollinator interactions and pollen dispersal are particularly relevant for understanding processes ensuring long-term viability of fragmented plant populations. Pollen dispersal patterns may vary strongly, even between similar congeneric species, depending on the mating system, pollinator assemblages and floral traits. We investigated pollen dispersal and fruit production in a population of Vaccinium oxycoccos, an insect-pollinated shrub, and compared the pollen dispersal pattern with a co-flowering, sympatric congener, V. uliginosum. We examined whether they share pollinators (through interspecific fluorescent dye transfers) and may differently attract pollinators, by comparing their floral colour as perceived by insects. Fluorescent dyes were mainly dispersed over short distances (80% within 40.4 m (max. 94.5 m) for V. oxycoccos and 3.0 m (max. 141.3 m) for V. uliginosum). Dye dispersal in V. oxycoccos was not significantly affected by plant area, floral display or the proximity to V. uliginosum plants. Interspecific dye transfers were observed, indicating pollinator sharing. The significantly lower dye deposition on V. oxycoccos stigmas suggests lower visitation rates by pollinators, despite higher flower density and local abundance. The spectral reflectance analysis indicates that bees are unlikely to be able to discriminate between the two species based on floral colour alone. Fruit production increased with increasing floral display, but was not affected by proximity to V. uliginosum plants. Our study highlights that fragmented populations of V. oxycoccos, when sympatric with co flowering V. uliginosum, might incur increased competition for the shared pollinators in the case of pollination disruption, which might then reduce outcrossed seed set. PMID- 22823149 TI - The pattern of the ocular late phase reaction induced by allergen challenge in hay fever conjunctivitis. AB - The purpose of this study was to describe the pattern of the ocular late phase reaction in patients with ocular hay fever. The authors monitored the clinical and cytological conjunctival response after topical allergen challenge. A conjunctival provocation test was performed in six ryegrass-sensitive patients and six healthy volunteers with 320,000 Biological Units (Pharmacia, Uppsala) of ryegrass antigen, diluted in albumin, in one eye; albumin diluent alone was used in the second (control) eye. Clinical symptoms were evaluated before challenge after 20 min, then hourly for 12 hours and 24 hours after challenge. Cell counts in the tear fluid were performed at the same time interval The results obtained show a significant clinical reaction during the entire period, differing in peaks in individual cases. This reaction was associated with a persistent inflammation, with neutrophils in the early phase and eosinophils and lymphocytes in the late phase period The data thus show that ocular challenge with high allergen doses induces clinical and cellular evidence of an ocular late phase reaction and suggest that the conjunctival provocation test may be used for a better understanding of the pathogenesis of mild but persistent ocular inflammation in ocular hay fever. PMID- 22823150 TI - Survival of corneal grafts after severe burns of the eye. AB - The authors investigated 32 human corneal buttons of patients suffering from severe eye burns. The keratoplasties were performed in different periods after the burn and collected within five years. Grafts were followed-up until they failed because of ulceration or until rehabilitating keratoplasties were performed. Early (up to six months after the burn) and late (more than 12 months after the burn) obtained corneas showed different cellular reactions in the corneal stroma. Inflammatory cells such as granulocytes and lymphocytes decreased with increasing periods after the burn. More than 12 months after the burn, minor inflammatory cellular reactions but increasing scar formation could be found. Four out of 19 early-, two out of eight intermediate- (between six and 12 months after the burn) and one of the late performed keratoplasties failed and had to be replaced by new corneal grafts. Due to the conditions in the graft beds the explanted corneal grafts showed a cellular reaction in the stroma comparable to the previously explanted burnt corneae. Further complications occurred because of problems concerning the ocular surface. After preliminary therapeutical keratoplasties rehabilitating keratoplasties could be successfully performed in four cases between 19 and 39 months. PMID- 22823151 TI - Systemic steroid prophylaxis for cataract surgery in patients with posterior uveitis. AB - Cataract remains difficult to manage in patients with uveitis affecting the posterior segment of the eye due to the high risk of postoperative complications, especially cystoid macular oedema, even in eyes in which inflammation has been completely suppressed preoperatively. A standard regimen of preoperative and perioperative systemic steroid prophylaxis was introduced into the uveitis clinic in order to prevent uveitis-related cystoid macular oedema in the postoperative period. The aim of this study was to assess if this policy resulted in an improvement in the visual recovery. Data from a single consecutive clinical series of 30 extracapsular cataract extraction procedures performed in 24 patients with posterior uveitis were collected retrospectively. Nineteen procedures were performed before and 11 after the introduction of the regimen of steroid prophylaxis. Success was graded according to the Snellen acuity at six months, the number of lines improvement in visual acuity by six months and the time from the operation date for acuity to recover to its best postoperative level. The median visual acuity after six months was 20/30 in the prophylaxis group compared with 20/80 in the controls (p = 0.052), representing a median improvement of five lines in the prophylaxis group and three lines in the controls (not significant). The eyes receiving prophylaxis achieved their best acuity in 1.8 months (median) compared with 5.9 months for the control group (p<0.01). This was not attributable to the longer period of follow-up in the control group and was independent of IOL implantation or the influence of any individual postoperative complication. When pseudophakic eyes were considered in isolation, the median acuity at six months was also better in the prophylaxis group (p = 0.023). The results suggest that preoperative systemic steroid prophylaxis may benefit the patient by hastening postoperative visual recovery independently of IOL implantation. PMID- 22823152 TI - Expression of the interleukin 1 receptor antagonist in the normal human cornea. AB - The human cornea has been shown to express a number of inflammatory cytokines including IL-1, IL-6 and IL-8. In view of the potent proinflammatory activities of interleukin-1 (IL-1), regulatory mechanisms should be present in the human cornea to control IL-1 mediated inflammatory and immune responses. This is important for the maintenance of the integrity and transparency of the cornea. To test this hypothesis, the authors determined the presence of IL-1 receptor antagonist (IL-tra) in the normal human cornea using an enzyme-linked immunosorbent assay (ELISA). IL-tra is a natural antagonist of IL-1 and competes with IL-1 for the binding to its receptors thereby blocking the inflammatory response. Corneas were either tested immediately or after a 24-hour culture period. Furthermore, the authors separately analyzed the three layers of the cornea. Their results present evidence for the constitutive expression of the IL tra protein in the normal human cornea and show that both epithelial and stromal cells produce IL-1ra. The epithelial cells are the major source of corneal IL-1ra immunoreactivity, and secrete IL-1ra during culture. Stromal cells contain detectable, albeit low amounts of cell associated IL-1ra. No IL-1ra was detected in the endothelial cell layer. A more accurate understanding of the balance between IL-1 and IL-1ra in ocular tissues and the role of the IL-1ra under physiologie and pathophysiologic conditions will be necessary for an eventual use of IL-1 receptor antagonist as a therapeutical tool. PMID- 22823153 TI - Comparison of uveitis induced by interleukin-8 (IL-8) and endotoxin in rabbits. AB - IL-8 is a potent chemoattractant which has been postulated to play a role in the cytokine cascade associated with uveitis. The authors studied the effect of intravitreal IL-8 on the induction of uveitis in the rabbit. IL-8 at varying concentrations (1 ng, 10 ng or 100 ng) or endotoxin (100 ng) was injected intravitreally within the rabbit eye. At 6, 24 and 48 hours following injection the induction of uveitis was evaluated by clinical scoring, anterior chamber (AC) leukocyte count, AC protein concentration and histopathology in 15 rabbits. Only the 100 ng concentration of IL-8 induced uveitis at 6 and 24 hours by clinical scoring and AC leukocyte count; the AC protein concentration remained normal. In contrast, endotoxin caused a severe uveitis with a significant increase in all the parameters evaluated. The authors conclude that intravitreal IL-8, in the concentrations studied, induces a limited uveitis which is detectable at six hours and resolves within 48 hours. It is characterized by leukocyte infiltration without an increased AC protein concentration. Thus, IL-8 may play a role in the cytokine cascade involved in the induction of uveitis. PMID- 22823154 TI - Ginkgo biloba extract (EGb 761) and a platelet-activating factor antagonist protect the retina in experimental autoimmune uveoretinitis. AB - Oxygen-free radical toxicity is an important factor of tissue necrosis in the eye, especially in the retina. Activation of synthesis and release of platelet activating factor (PAF) by ocular inflammatory cells and resident cells initiates cascades of mediators and cytokines which contribute to tissue damage in several ocular pathologies. The authors studied the therapeutic effectiveness of Ginkgo biloba extract (EGb 761), a potent free radical scavenger with anti-PAF activity, and of BN 50730, a specific PAF antagonist, on acute experimental autoimmune uveoretinitis induced in rats by S-antigen immunization. These treatments slightly delayed disease onset but had little effect on the severity of uveal inflammation. However, they significantly reduced inflammatory cell infiltration of the retina and the damage of the outer retinal layers. These drugs should become useful adjuvants in the therapy of posterior uveitis and other disorders that might damage the retina. PMID- 22823155 TI - American uveitis society spring meeting sarasota, Florida, april 30, 1994. PMID- 22823156 TI - Uveitis in china. PMID- 22823157 TI - FDG-PET guided diagnosis of vaginal intravascular diffuse large B-cell lymphoma. PMID- 22823158 TI - Explicit and implicit stigma towards peers with mental health problems in childhood and adolescence. AB - BACKGROUND: Children and adolescents with mental health problems are widely reported to have problems with peer relationships; however, few studies have explored the way in which these children are regarded by their peers. For example, little is known about the nature of peer stigmatisation, and no published research has investigated implicit attitudes thus ensuring that stigma is not well understood. To address this issue, the current study explored patterns of explicit and implicit stigmatisation of peers with depression and attention deficit hyperactivity disorder (ADHD). METHODS: The sample was 385 children (M = 10.21 years) and adolescents (M = 15.36 years). Participants completed a questionnaire assessing explicit stigma towards an age- and gender matched peer with ADHD or depression and another peer with 'normal issues' who were described in vignettes. They also completed a modified version of the implicit association test (IAT) that explored implicit attitudes towards the target peers. RESULTS: Questionnaire data indicated that the peer with ADHD was perceived more negatively than the peer with depression on all dimensions of stigma, except perceived dangerousness and fear. In contrast, the IAT findings suggest that some participants had more negative views of the peer with depression than the peer with ADHD. Specifically, the findings demonstrate that adolescent males demonstrated significantly stronger negative implicit evaluations of depression compared with younger males and adolescent females. CONCLUSIONS: Children and adolescents demonstrate stigmatising responses to peers with common mental health problems. The nature and extent of these responses depends on the type of problem and the type of measurement used. The findings highlight the importance of using both explicit and implicit measures of stigma. PMID- 22823159 TI - Graphene-based aptamer logic gates and their application to multiplex detection. AB - In this work, a GO/aptamer system was constructed to create multiplex logic operations and enable sensing of multiplex targets. 6-Carboxyfluorescein (FAM) labeled adenosine triphosphate binding aptamer (ABA) and FAM-labeled thrombin binding aptamer (TBA) were first adsorbed onto graphene oxide (GO) to form a GO/aptamer complex, leading to the quenching of the fluorescence of FAM. We demonstrated that the unique GO/aptamer interaction and the specific aptamer target recognition in the target/GO/aptamer system were programmable and could be utilized to regulate the fluorescence of FAM via OR and INHIBIT logic gates. The fluorescence changed according to different input combinations, and the integration of OR and INHIBIT logic gates provided an interesting approach for logic sensing applications where multiple target molecules were present. High throughput fluorescence imagings that enabled the simultaneous processing of many samples by using the combinatorial logic gates were realized. The developed logic gates may find applications in further development of DNA circuits and advanced sensors for the identification of multiple targets in complex chemical environments. PMID- 22823160 TI - Optogenetic inhibition of cocaine seeking in rats. AB - Inhibitory optogenetics was used to examine the roles of the prelimbic cortex (PL), the nucleus accumbens core (NAcore) and the PL projections to the NAcore in the reinstatement of cocaine seeking. Rats were microinjected into the PL or NAcore with an adeno-associated virus containing halorhodopsin or archaerhodopsin. After 12 days of cocaine self-administration, followed by extinction training, animals underwent reinstatement testing along with the presence/absence of optically induced inhibition via laser light. Bilateral optical inhibition of the PL, NAcore or the PL fibers in the NAcore inhibited the reinstatement of cocaine seeking. PMID- 22823162 TI - Intranasal administration of the TLR2 agonist Pam2Cys provides rapid protection against influenza in mice. AB - The protective role played by the innate immune system during early stages of infection suggests that compounds which stimulate innate responses could be used as antimicrobial or antiviral agents. In this study, we demonstrate that the Toll like receptor-2 agonist Pam2Cys, when administered intranasally, triggers a cascade of inflammatory and innate immune signals, acting as an immunostimulant by attracting neutrophils and macrophages and inducing secretion of IL-2, IL-6, IL-10, IFN-gamma, MCP-1 and TNF-alpha. These changes provide increased resistance against influenza A virus challenge and also reduce the potential for transmission of infection. Pam2Cys treatment also reduced weight loss and lethality associated with virulent influenza virus infection in a Toll-like receptor-2-dependent manner. Treatment did not affect the animals' ability to generate an adaptive immune response, measured by the induction of functional influenza A virus-specific CD8(+) T cells following exposure to virus. Because this compound demonstrates efficacy against distinct strains of influenza, it could be a candidate for development as an agent against influenza and possibly other respiratory pathogens. PMID- 22823164 TI - Advances in visual representation of molecular potentials. AB - IMPORTANCE OF THE FIELD: The recent advances in visual representations of molecular properties in 3D space are summarized, and their applications in molecular modeling study and rational drug design are introduced. The visual representation methods provide us with detailed insights into protein-ligand interactions, and hence can play a major role in elucidating the structure or reactivity of a biomolecular system. AREAS COVERED IN THIS REVIEW: Three newly developed computation and visualization methods for studying the physical and chemical properties of molecules are introduced, including their electrostatic potential, lipophilicity potential and excess chemical potential. The newest application examples of visual representations in structure-based rational drug are presented. WHAT THE READER WILL GAIN: The 3D electrostatic potentials, calculated using the empirical method (EM-ESP), in which the classical Coulomb equation and traditional atomic partial changes are discarded, are highly consistent with the results by the higher level quantum chemical method. The 3D lipophilicity potentials, computed by the heuristic molecular lipophilicity potential method based on the principles of quantum mechanics and statistical mechanics, are more accurate and reliable than those by using the traditional empirical methods. The 3D excess chemical potentials, derived by the reference interaction site model-hypernetted chain theory, provide a new tool for computational chemistry and molecular modeling. TAKE HOME MESSAGE: For structure based drug design, the visual representations of molecular properties will play a significant role in practical applications. It is anticipated that the new advances in computational chemistry will stimulate the development of molecular modeling methods, further enriching the visual representation techniques for rational drug design, as well as other relevant fields in life science. PMID- 22823163 TI - Candida krusei: biotechnological potentials and concerns about its safety. AB - Yeasts have a tradition in biotechnological applications, and Saccharomyces species are the most dominating representatives. Among the yeast species, Candida krusei has been isolated from different habitats, and in recent years, it has gained increased interest because of its diverse biotechnological role. It is found in many fermented food items and dairy products and has also been exploited for production of biochemicals and enzymes. However, because of its opportunistic pathogenic nature, it draws scientific attention regarding the safety of its industrial exploitation. Candida krusei generally causes infections in immunocompromised patients, such as those suffering from Human immunodeficiency virus - acquired immune deficiency syndrome, and also in cancer patients. The recent increase in the use of immunosuppressive drugs has increased the chances of C. krusei infections. Candida krusei possesses an intrinsic resistance to many triazole antifungal drugs, especially fluconazole, which is a main drug used in antifungal therapy; therefore, there is serious concern regarding its safe industrial use. PMID- 22823161 TI - A prospective cohort study of the prevalence of growth, facial, and central nervous system abnormalities in children with heavy prenatal alcohol exposure. AB - BACKGROUND: Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited. METHODS: This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status. RESULTS: One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome. CONCLUSIONS: After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure. PMID- 22823165 TI - Advances in 2D fingerprint similarity searching. AB - IMPORTANCE TO THE FIELD: Similarity searching is one of the premier approaches for computational hit identification. Fingerprints are bit string representations of molecular structure and properties and rather simplistic search tools. Nevertheless, they are widely used and often surprisingly successful in drug discovery applications. AREAS COVERED IN THIS REVIEW: Herein we discuss recent research efforts that have helped to better understand fingerprint search performance, design new fingerprints and search strategies, or modify standard fingerprints for specific applications. Key publications of the past ~ 20 years are covered and major emphasis is put on reviewing fingerprint studies published during the past 5 years. WHAT THE READER WILL GAIN: The reader is provided with an overview of the state-of-the-art fingerprint design and search strategies developed. It will be possible to rationalize opportunities and limitations of 2D fingerprint similarity searching. Take home messages: Fingerprint search calculations are more complex than it might appear at first glance and susceptible to complications that are often overlooked in practical applications. Fingerprint search performance typically only depends on relatively small subsets of bit positions. Recently, different fingerprint engineering strategies have been applied to 'tune' existing fingerprints in a compound class-directed manner. Fingerprints have substantial scaffold hopping potential, despite the simplicity of their design. PMID- 22823166 TI - Rational design of CCR2 antagonists: a survey of computational studies. AB - IMPORTANCE OF THE FIELD: CC-chemokine receptor 2 (CCR2) belongs to the GPCR superfamily and is the primary receptor for monocyte chemoattractant protein-1 (MCP-1), also known as chemokine ligand CCL2. Studies indicate the possible involvement of MCP-1 and CCR2 in various disease conditions, such as rheumatic arthritis, multiple sclerosis, vascular diseases, obesity and diabetes, via the inflammatory pathway. MCP-1 and CCR2 knockout mice under a broad range of stimuli exhibit deficient monocyte recruitment suggesting its potential role in inflammation. Overall, there is evidence that an impairment of monocyte trafficking in inflammation models occurs when there is a loss of MCP-1 effector function. This makes its receptor, CCR2, an attractive target for pharmaceutical research. Several small molecular CCR2 antagonists have been developed, particularly in the industry. AREAS COVERED IN THIS REVIEW: In this article, we have summarized the in silico work carried out in the area of CCR2 and reviewed mainly the computer aided drug design (CADD) studies reported on quantitative structure-activity relationship, homology modeling, molecular docking and virtual screening. WHAT THE READER WILL GAIN: A survey of computational studies for the rational design and development of CCR2 antagonists. TAKE HOME MESSAGE: CADD tools can be used to rationalize the identification of the potential leads and these techniques can be effectively applied in the rapid searching of novel and potent CCR2 antagonists. PMID- 22823167 TI - Current strategies for drug discovery through natural products. AB - IMPORTANCE TO THE FIELD: Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Areas to be covered: Current drug discovery strategies involving natural products are described in three sections: developments from traditionally used medicines, random testing of natural compounds on biological assays and use of virtual screening techniques with structures of natural products. WHAT THE READER WILL GAIN: The reader will gain an insight into the potential for natural products in current drug discovery paradigms, particularly in the value of using natural products in virtual screening approaches. TAKE HOME MESSAGE: Drug discovery would be enriched if fuller use was made of the chemistry of natural products. PMID- 22823168 TI - Micropatterned surfaces: techniques and applications in cell biology. AB - IMPORTANCE OF THE FIELD: Engineering of cell culture substrates provides a unique opportunity for precise control of the cellular microenvironment with both spatial as well as temporal resolutions. This greatly enhances studies of cell cell, cell-matrix and cell-factor interaction studies in vitro. AREAS COVERED IN THIS REVIEW: The technologies used for micropatterning in the biological field over the last decade and new applications in the last few years for dynamic control of surfaces, tissue engineering, drug discovery, cell-cell interactions and stem cell studies are presented. WHAT THE READER WILL GAIN: The reader will gain knowledge on the state of the art in micropatterning and its wide ranging applications in cell patterning, with new pathways to control the cell environment. TAKE HOME MESSAGE: Micropatterning of cells has been studied and developed enough to be widely applied ranging from single cell assays to tissue engineering. Techniques have evolved from many-step processes to direct writing of biologically selective patterns. PMID- 22823169 TI - Cell-based apoptosis assays in oncology drug discovery. AB - IMPORTANCE OF THE FIELD: Screening compounds with a cell-based phenotypic approach complements target-based discovery programs because of the opportunity to investigate targets in the context of the cellular milieu and to discover novel targets. AREAS COVERED IN THIS REVIEW: Utilizing a cell-based apoptotic phenotype screen for discovery and optimization of apoptosis inducers and affirming activity as potential anticancer agents in vivo with xenograft models. Subsequently, chemical genetic tools are utilized to identify and validate previously unrecognized cancer targets. Case studies showing the various multidisciplinary approaches utilized for several years are reviewed. WHAT THE READER WILL GAIN: The interactive nature of the drug and target discovery processes, and insights that come from integration of cellular biology, medicinal chemistry and animal research. TAKE HOME MESSAGE: Phenotype proapoptotic screen followed by chemical genetics is useful for anticancer drug research, for the discovery of potential drugs and identification of druggable targets. PMID- 22823170 TI - The Asian perspective to the International Diabetes Federation's position statement on bariatric surgery for diabetes. PMID- 22823171 TI - A new approach for posterior mediastinal tumors: thoracoscopic resection in the prone position. AB - Video-assisted thoracoscopic surgery in the lateral position has been the standard surgical approach for posterior mediastinal tumors. Herein, we report the successful thoracoscopic resection of a posterior mediastinal tumor with the patient in the prone position. The patient was a 62-year-old man with a posterior mediastinal mass. We were able to completely extirpate the posterior mediastinal tumor by means of thoracoscopic resection, with the patient in the prone position, much in the manner of solo surgery. The prone position has the potential to become the standard thoracoscopic surgical approach for posterior mediastinal tumors because it provides excellent exposure of the posterior mediastinum. PMID- 22823172 TI - Diaphragmatic repair of hepatic hydrothorax with VATS after abdominal insufflation with CO(2). AB - Hepatic hydrothorax is defined as the presence of a significant pleural effusion that develops in a patient with cirrhosis of the liver who does not have an underlying cardiac or pulmonary disease. There have been few published case reports dealing with hepatic hydrothorax treated surgically. Recently, we treated a patient with refractory hepatic hydrothorax by directly suturing the diaphragmatic defect during VATS. During surgery, the diaphragmatic defect was identified by using abdominal insufflation with CO(2) . The defect was sutured and the diaphragm was covered by polyglycolic acid felt and fibrin glue. After surgery, the patient's pleural effusion improved, his postoperative course was uneventful and he did not require a drainage tube at discharge. PMID- 22823173 TI - Thoracoscopic pericardiotomy for management of purulent pneumococcal pericarditis in a child. AB - Purulent pericarditis is an extremely rare complication of pneumococcal pneumonia in children that may result in to cardiac tamponade. While image-guided pericardiocentesis is the treatment of choice for such a condition, it may fail in the presence of thick pus; loculations and thoracoscopic pericardiotomy are useful procedures for such situations. Herein, we report such a case involving a 6-year-old boy who presented with purulent pneumococcal pericarditis that was managed with thoracoscopic pericardiotomy and who recovered well. Thoracoscopic pericardiotomy is a safe procedure that allows effective drainage under vision, pericardial biopsy for diagnosis, and a simultaneous opportunity to perform thoracoscopic pleural drainage. PMID- 22823174 TI - Reversed intestinal malrotation with concurrent cecal carcinoma. AB - A 57-year-old man was admitted with a type 2 (ulcerated with clear margin) cancer in the cecum. Contrast-enhanced CT showed that the superior mesenteric vein was anterior to the superior mesenteric artery, and the patient was suspected of having intestinal malrotation. A laparoscopic-assisted ileocecal resection was performed. At operation, the cecum and the transverse colon passed through the root of the mesentery behind the superior mesenteric artery with the duodenum. Therefore, this was thought to be a reversed-type intestinal malrotation. After the operation, 3D-CT colonography with duodenography images were reconstructed to retrospectively confirm the diagnosis of a reversed malrotation. These images clearly demonstrated the abnormal anatomy and overall orientation of the intestine. Patients with a reversed intestinal malrotation and concurrent cecal cancer are extremely rare. Herein, we present a patient who underwent a laparoscopic-assisted ileocecal resection for cecal cancer that presented concurrently with a reversed intestinal malrotation. PMID- 22823175 TI - Finger-assisted totally extra-peritoneal laparoscopic hernia repair: a simple aid to unfolding the mesh for the novice. PMID- 22823176 TI - Vitamin D nutritional status and antenatal depressive symptoms in African American women. AB - BACKGROUND: Vitamin D deficiency is associated with depression; however, no studies have examined the relationship of vitamin D and antenatal depression. Antenatal depression increases the risk of adverse birth outcomes and poorer postpartum maternal and infant health. African American women are at increased risk for vitamin D deficiency and antenatal depression. Thus, we examined if early pregnancy vitamin D nutrition (VDN) was associated with antenatal depressive symptoms among African American women in the second trimester of pregnancy. METHODS: Women (n=178) were recruited from obstetrics clinics of a large health system. VDN was assessed by serum 25-hydroxyvitamin D (25-OHD). Depression symptoms were measured with the Center for Epidemiological Studies Depression (CES-D) scale; CES-D>=16 equates with criteria for clinical depression. Logistic regression was used to examine the association of log transformed 25-OHD and elevated depression symptoms (CES-D>=16). RESULTS: Mean 25 OHD was 13.4+/-8.4 ng/mL; most women (82.6%, n=147) were vitamin D inadequate or deficient (25-OHD<20 ng/mL). Mean CES-D was 15.2+/-10.7, and 74 (41.6%) women had a CES-D>=16, suggestive of clinical depression. A significant inverse relationship was found between log (25-OHD) and CES-D>=16 (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.29-0.99, p=0.046). For every 1-unit increase in log (25-OHD) (corresponding to ~2.72 ng/mL increase in 25-OHD), the odds of CES D>=16 decreased by 46%. CONCLUSIONS: African American women with lower VDN exhibit increased depressive symptoms. Research on vitamin D supplementation for reducing antenatal depressive symptoms is needed. PMID- 22823177 TI - The road to hell is paved with good intentions. PMID- 22823178 TI - Racial/ethnic disparities in HIV infection among people who inject drugs: an international systematic review and meta-analysis. AB - AIMS: The Ethnic Minority Meta-Analysis (EMMA) aims to assess racial/ethnic disparities in HIV infection among people who inject drugs (PWID) across various countries. This is the first report of the data. METHODS: Standard systematic review/meta-analysis methods were utilized, including searching for, screening and coding published and unpublished reports and meta-analytical statistics. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for reporting methods. Disparities were measured with the odds ratio (OR) for HIV prevalence among ethnic minority PWID compared to ethnic majority PWID; an OR >1.0 indicated higher prevalence among ethnic minorities. RESULTS: Racial/ethnic disparities in HIV prevalence among PWID were examined in 131 prevalence reports, with 214 racial/ethnic minority to majority comparisons, comprising 106 715 PWID. Overall, the pooled OR indicates an increased likelihood of higher HIV prevalence among racial/ethnic minority compared to racial/ethnic majority PWID [OR = 2.09, 95% confidence interval (CI): 1.92-2.28]. Among 214 comparisons, 106 produced a statistically significant higher OR for minorities; in 102 comparisons the OR was not significantly different from 1.0; six comparisons produced a statistically significant higher OR for majority group members. Disparities were particularly large in the United States, pooled OR = 2.22 (95% CI: 2.03-2.44). There was substantial variation in ORs-I(2) = 75.3%: interquartile range = 1.38-3.56-and an approximate Gaussian distribution of the log ORs. CONCLUSIONS: Among people who inject drugs, ethnic minorities are approximately twice as likely to be HIV seropositive than ethnic majorities. The great heterogeneity and Gaussian distribution suggest multiple causal factors and a need to tailor interventions to local conditions. PMID- 22823179 TI - Sulfate-reducing bacteria lower sulfur-mediated pitting corrosion under conditions of oxygen ingress. AB - The effect of oxygen ingress into sour water containing dissolved sulfide on the production of sulfur and polysulfide (S-PS) and associated iron corrosion was investigated. Biotic (active SRB present), abiotic (autoclaved SRB present), and chemical (no bacteria present) conditions were compared. Under biotic conditions formation of S-PS was only seen at a high ratio of oxygen to sulfide (R(OS)) of 1 to 2.4. General corrosion rates increased 10-fold to 0.10 mm/yr under these conditions. Under abiotic and chemical conditions S-PS formation increased over the entire range of R(OS) with general corrosion rates reaching 0.06 mm/yr. Although general corrosion rates were thus highest under biotic conditions, biotically corroded coupons showed much less pitting corrosion. Maximum pit depth increased to 40-80 MUm with increasing R(OS) for coupons incubated for 1 month under abiotic or chemical conditions but not for biotically incubated coupons (10 MUm). This appeared to be related to the properties and size of the sulfur formed, which was hydrophobic and in excess of 10 MUm under chemical or abiotic conditions and hydrophilic and 0.5 to 1 MUm under biotic conditions. Hence, perhaps contrary to expectation, SRB lowered pitting corrosion rates under conditions of oxygen ingress due to their ability to respire oxygen and produce a less aggressive form of sulfur. Microbial control, which is usually required in sour systems, may be counterproductive under these conditions. PMID- 22823181 TI - High carrier mobility in single ultrathin colloidal lead selenide nanowire field effect transistors. AB - Ultrathin colloidal lead selenide (PbSe) nanowires with continuous charge transport channels and tunable bandgap provide potential building blocks for solar cells and photodetectors. Here, we demonstrate a room-temperature hole mobility as high as 490 cm(2)/(V s) in field effect transistors incorporating single colloidal PbSe nanowires with diameters of 6-15 nm, coated with ammonium thiocyanate and a thin SiO(2) layer. A long carrier diffusion length of 4.5 MUm is obtained from scanning photocurrent microscopy (SPCM). The mobility is increased further at lower temperature, reaching 740 cm(2)/(V s) at 139 K. PMID- 22823180 TI - Effect of an employer-sponsored health and wellness program on medical cost and utilization. AB - The objective of this study was to examine the impact of PepsiCo's health and wellness program on medical cost and utilization. The authors analyzed health plan and program data of employees and dependents 19-64 years of age, who had 2 years of baseline data (2002 and 2003) and at least 1 year of data from the intervention period (2004 to 2007), resulting in a sample of 55,030 members. Program effects were measured using a difference-in-difference approach based on a multivariate regression model with an individual-level random effect. In its first year, the program was associated with a relative increase in per member per month (PMPM) cost ($66, P<0.01); a relative reduction in PMPM costs of $76 (P<0.01) and $61 (P<0.01) was seen in the second and third year, respectively. Over all 3 years, the program was associated with reduced PMPM costs of $38 (P<0.01), a decrease of 50 emergency room visits per 1000 member years (P<0.01), and a decrease of 16 hospital admissions per 1000 member years (P<0.01). The disease management component reduced PMPM costs by $154 (P<0.01), case management increased PMPM costs by $2795 (P<0.01), but no significant effects were observed for lifestyle management over the 3 intervention years. The implementation of a comprehensive health and wellness program was associated with a cost increase in the first year, followed by a decrease in the following years. These results highlight the importance of taking a long-term perspective when implementing such programs and evaluating their effectiveness. PMID- 22823182 TI - Factors influencing scores on the social responsiveness scale. AB - BACKGROUND: The Social Responsiveness Scale (SRS) is a parent-completed screening questionnaire often used to measure autism spectrum disorders (ASD) severity. Although child characteristics are known to influence scores from other ASD symptom measures, as well as parent-questionnaires more broadly, there has been limited consideration of how non-ASD-specific factors may affect interpretation of SRS scores. Previous studies have explored effects of behavior problems on SRS specificity, but have not addressed influences on the use of the SRS as a quantitative measure of ASD-symptoms. METHOD: Raw scores (SRS-Raw) from parent completed SRS were analyzed for 2,368 probands with ASD and 1,913 unaffected siblings. Regression analyses were used to assess associations between SRS scores and demographic, language, cognitive, and behavior measures. RESULTS: For probands, higher SRS-Raw were associated with greater non-ASD behavior problems, higher age, and more impaired language and cognitive skills, as well as scores from other parent report measures of social development and ASD-symptoms. For unaffected siblings, having more behavior problems predicted higher SRS-Raw; male gender, younger age, and poorer adaptive social and expressive communication skills also showed small, but significant effects. CONCLUSIONS: When using the SRS as a quantitative phenotype measure, the influence of behavior problems, age, and expressive language or cognitive level on scores must be considered. If effects of non-ASD-specific factors are not addressed, SRS scores are more appropriately interpreted as indicating general levels of impairment, than as severity of ASD-specific symptoms or social impairment. Additional research is needed to consider how these factors influence the SRS' sensitivity and specificity in large, clinical samples including individuals with disorders other than ASD. PMID- 22823183 TI - Aging and emotion recognition: not just a losing matter. AB - Past studies on emotion recognition and aging have found evidence of age-related decline when emotion recognition was assessed by having participants detect single emotions depicted in static images of full or partial (e.g., eye region) faces. These tests afford good experimental control but do not capture the dynamic nature of real-world emotion recognition, which is often characterized by continuous emotional judgments and dynamic multimodal stimuli. Research suggests that older adults often perform better under conditions that better mimic real world social contexts. We assessed emotion recognition in young, middle-aged, and older adults using two traditional methods (single emotion judgments of static images of faces and eyes) and an additional method in which participants made continuous emotion judgments of dynamic, multimodal stimuli (videotaped interactions between young, middle-aged, and older couples). Results revealed an Age * Test interaction. Largely consistent with prior research, we found some evidence that older adults performed worse than young adults when judging single emotions from images of faces (for sad and disgust faces only) and eyes (for older eyes only), with middle-aged adults falling in between. In contrast, older adults did better than young adults on the test involving continuous emotion judgments of dyadic interactions, with middle-aged adults falling in between. In tests in which target stimuli differed in age, emotion recognition was not facilitated by an age match between participant and target. These findings are discussed in terms of theoretical and methodological implications for the study of aging and emotional processing. PMID- 22823185 TI - Enzymatic synthesis of piceid glucosides using maltosyltransferase from Caldicellulosiruptor bescii DSM 6725. AB - Piceid is widely used in food, cosmetics, and pharmaceuticals because of its therapeutic benefits. However, the use of piceid as a drug is limited because of its low solubility. To increase solubility, we synthesized piceid glucosides using maltosyltransferase from Caldicellulosiruptor bescii. The MTase gene was cloned and expressed in Escherichia coli. The enzyme had a unique transfer specificity to the transfer of maltosyl units. Four piceid transglycosylation products were present and identified by thin-layer chromatography and recycling preparative high-performance liquid chromatography. The major product was purified by C(18) and gel filtration chromatography, and its molecular structure was determined using nuclear magnetic resonance spectroscopy to be alpha-D maltosyl-(1->4)-piceid. The solubility of maltosyl piceid was 8.54 * 10(3) and 1.86 * 10(3) times those of natural resveratrol and piceid, respectively, suggesting that the transglycosylation greatly increased the water solubility. This suggests that dietary intake of this compound can enhance the bioavailability of resveratrol in the human body. PMID- 22823188 TI - I. Introduction. PMID- 22823189 TI - IV. Non-infectious conjunctivitis (NIC). PMID- 22823186 TI - Building a nanostructure with reversible motions using photonic energy. AB - Recently, the specific hybridization of DNA molecules has been used to construct self-assembled devices, such as the mechanical device to mimic cellular protein motors in nature. Here, we present a new light-powered DNA mechanical device based on the photoisomerization of azobenzene moieties and toehold-mediated strand displacement. This autonomous and controllable device is capable of moving toward either end of the track, simply by switching the wavelength of light irradiation, either UV (365 nm) or visible (>450 nm). This light-controlled strategy can easily solve one main technical challenge for stepwise walking devices: the selection of routes in multipath systems. The principle employed in this study, photoisomerization-induced toehold length switching, could be further useful in the design of other mechanical devices, with the ultimate goal of rivaling molecular motors for cargo transport and macroscopic movement. PMID- 22823187 TI - Scrotal flap for closure of perineal skin defects in dogs. AB - OBJECTIVE: To describe the use of a scrotal flap for covering perineal skin defects in dogs. STUDY DESIGN: Experimental study. ANIMALS: Male Beagles (n = 5). METHODS: A scrotal flap was created by making a U-shaped incision around the scrotum, with the base of the flap at its rostral border. Orchiectomy was performed through this incision and the scrotum was undermined from the underlying tissue. A small median longitudinal incision in the caudal aspect of the scrotum eliminated its curvature. A skin defect, comparable to the size of the scrotal flap, was created in the perineum extending from the caudal side of the scrotum toward the anus. The scrotal flap covered the defect and was sutured in place. RESULTS: By 5-7 days, all flaps had ~27% necrosis on their caudal border. The necrotic area was surgically excised and the defect was covered completely again by the remaining healthy flap. One year after surgery, wound healing was normal and flap survival was complete, providing full coverage of the perineal skin defect. CONCLUSION: A scrotal flap can be used to reconstruct perineal skin defects ventral to the anus. PMID- 22823191 TI - V. Occupational conjunctivitis (OC). PMID- 22823190 TI - II. Clinical signs of conjunctivitis. PMID- 22823184 TI - Characterization of norovirus infections in Seoul, Korea. AB - The present study has determined the detection rate of norovirus (NoV) with acute gastroenteritis (AGE) in hospitalized children and describes the molecular epidemiology of NoV circulating in Seoul, Korea. Six hundred and eighty-three (9.8%) of samples were positive for NoV. Of these, the NoV GII genogroup was the most commonly found, with a prevalence of 96.2% (683 of 710). Only 27 samples were positive for the NoV GI genogroup. Ten kinds of GI genotype (GI/1, GI/2, GI/3, GI/4, GI/5, GI/6, GI/7, GI/9, GI/12, and GI/13) and eight kinds of GII genotype (GII/2, GII/3, GII/4, GII/8, GII/14, GII/15, GII/16, and GII/17) were identified in children with AGE during the years 2008-2011. PMID- 22823193 TI - VII. Mechanical conjunctivitis (MC). PMID- 22823192 TI - VI. latrogenic conjunctivitis (IAC). PMID- 22823194 TI - VIII. Appendices. PMID- 22823195 TI - IX. Figures. PMID- 22823196 TI - Bibliography. PMID- 22823197 TI - III. Infectious conjunctivitis (IC). PMID- 22823200 TI - Myeloperoxidase: a leukocyte-derived protagonist of inflammation and cardiovascular disease. AB - SIGNIFICANCE: The heme-enzyme myeloperoxidase (MPO) is one of the major neutrophil bactericidal proteins and is stored in large amounts inside azurophilic granules of neutrophils. Upon cell activation, MPO is released and extracellular MPO has been detected in a wide range of acute and chronic inflammatory conditions. Recent ADVANCES AND CRITICAL ISSUES: Apart from its role during infection, MPO has emerged as a critical modulator of inflammation throughout the last decade and is currently discussed in the initiation and propagation of cardiovascular diseases. MPO-derived oxidants (e.g., hypochlorous acid) interfere with various cell functions and contribute to tissue injury. Recent data also suggest that MPO itself exerts proinflammatory properties independent of its catalytic activity. Despite advances in unraveling the complex action of MPO and MPO-derived oxidants, further research is warranted to determine the precise nature and biological role of MPO in inflammation. FUTURE DIRECTIONS: The identification of MPO as a central player in inflammation renders this enzyme an attractive prognostic biomarker and a potential target for therapeutic interventions. A better understanding of the (patho-) physiology of MPO is essential for the development of successful treatment strategies in acute and chronic inflammatory diseases. PMID- 22823199 TI - Application of incoherent inelastic neutron scattering in pharmaceutical analysis: relaxation dynamics in phenacetin. AB - This study centers on the use of inelastic neutron scattering as an alternative tool for physical characterization of solid pharmaceutical drugs. On the basis of such approach, relaxation processes in the pharmaceutical compound phenacetin (p ethoxyacetanilide, C(10)H(13)NO(2)) were evidenced on heating between 2 and 300 K. By evaluating the mean-square displacement obtained from the elastic fixed window approach, using the neutron backscattering technique, a crossover of the molecular fluctuations between harmonic and nonharmonic dynamical regimes around 75 K was observed. From the temperature dependence of the quasi-elastic line width, summed over the total Q range explored by the time-of-flight technique, it was possible to attribute the onset of this anharmonicity to methyl group rotations. Finally, using density functional theory-based methods, we were able to calculate the lattice vibrations in the harmonic approximation. The overall spectral profile of the calculated partial contributions to the generalized density of states compares satisfactorily to the experimental spectra in the region of the lattice modes where the intermolecular interactions are expected to play an important role. This study contributes to understanding the relationships between intermolecular hydrogen bonds, intramolecular dynamics, and conformational flexibility in pharmaceuticals on a molecular level, which can help in evaluating phase stability with respect to temperature variations on processing or on storage, and is related to control of polymorphism and pseudopolymorphism. PMID- 22823201 TI - Andromonoecy in an Old World Papilionoid legume, Erophaca baetica. AB - Andromonoecy (i.e. the occurrence on individual plants of hermaphroditic and male flowers) is a rare sexual system among the angiosperms, regarded by some authors as a transitional stage from hermaphroditism to monoecy. Having discovered the occurrence of andromonoecy in Erophaca baetica (a Mediterranean shrubby legume with two subspecies), a novelty for Old World papilionoid legumes, we investigated the morpho-functional correlates and the geographical distribution of this phenomenon in the species. The relative frequencies of hermaphrodite and male flowers were determined in two field and 111 herbarium populations. Biomass allocation within flowers, pollen production and viability, pollen tube growth, nectar production and the temporal pattern of male flower production were also studied in two nearby southern Spanish populations. Virtually all of the studied populations were andromonoecious. Male flowers tended to appear at apical positions within the inflorescence, and became more abundant by the end of the flowering season. Male flowers were externally similar to hermaphroditic flowers (although with less biomass and smaller parts) and released equivalent amounts of pollen and nectar; however, their pollen germinated significantly better. Erophaca is the first example of an andromonecious Papilionoid in the Old World. Since the main difference among floral morphs in this species is functional (i.e. pollen germination rate) rather than morphological, andromonoecy is not readily noticeable, and very careful inspection may be required to reveal it. The potential effect of andromonoecy in enhancing outcrossing rate in this species is discussed. PMID- 22823203 TI - Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates. AB - As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate. PMID- 22823202 TI - Chronic hepatitis e in heart transplant recipients. AB - Chronic courses of hepatitis E virus (HEV) infections have been described in immunosuppressed patients. We aimed to study the role of HEV infections in heart transplant recipients (HTR). 274 HTR were prospectively screened for HEV infection using an anti-HEV-IgG ELISA and HEV-PCR. In addition, 137 patients undergoing cardiac surgery (non-HTR) and 537 healthy subjects were studied cross sectionally. The anti-HEV-IgG seroprevalence was 11% in HTR, 7% in non-HTR and 2% in healthy controls (HTR vs. healthy controls p<0.0001; non-HTR vs. healthy controls p<0.01). Anti-HEV tested positive in 4.0% in control cohorts of other immunocompromised patients (n = 474). Four HTR (1.5%) were chronically infected with HEV as shown by HEV-PCR and all four patients had liver transaminases of >200 IU/L and histological or clinical evidence of advanced liver disease. In three patients ribavirin treatment was successful with a sustained biochemical and virological response while treatment failed in one cirrhotic patient after ribavirin dose reduction. Heart transplant recipients and patients undergoing cardiac surgery have an increased risk for HEV infections. Chronic hepatitis E may explain elevated liver enzymes in heart transplant recipients. Treatment of HEV infection with ribavirin is effective but the optimal dose and duration of ribavirin therapy remains to be determined. PMID- 22823204 TI - Advances in computational methods to predict the biological activity of compounds. AB - IMPORTANCE OF THE FIELD: The past decade had witnessed remarkable advances in computer science which had given rise to many new possibilities including the ability to simulate and model life's phenomena. Among one of the greatest gifts computer science had contributed to drug discovery is the ability to predict the biological activity of compounds and in doing so drives new prospects and possibilities for the development of novel drugs with robust properties. AREAS COVERED IN THIS REVIEW: This review presents an overview of the advances in the computational methods utilized for predicting the biological activity of compounds. WHAT THE READER WILL GAIN: The reader will gain a conceptual view of the quantitative structure-activity relationship paradigm and the methodological overview of commonly used machine learning algorithms. TAKE HOME MESSAGE: Great advancements in computational methods have now made it possible to model the biological activity of compounds in an accurate manner. To obtain such a feat, it is often necessary to forgo several data pre-processing and post-processing procedures. A wide range of tools are available to perform such tasks; however, the proper selection and piecing together of complementary components in the prediction workflow remains a challenging and highly subjective task that heavily relies on the experience and judgment of the practitioner. PMID- 22823205 TI - Improvement of drug-like properties of peptides: the somatostatin paradigm. AB - IMPORTANCE OF THE FIELD: Peptides are promising candidates as therapeutic agents due to their wide involvement in physiological processes. However, their often non-selective activity and their poor drug-like properties, mainly their inherent low stability to enzymatic degradation and poor oral bioavailability, limit their clinical potential. Somatostatin is a peptide hormone involved in many different biological functions. The role of its five different receptor subtypes and their interplay in medicinal processes is only partially understood. In addition, it suffers from poor drug-like properties. AREAS COVERED IN THIS REVIEW: We review several promising chemical modifications, including head-to-tail and backbone cyclization as well as N-methylation, which were applied throughout the years in the development of various somatostatin analogs. WHAT THE READER WILL GAIN: These modifications led to enhanced metabolic stability and intestinal permeability. In addition, several analogs exhibited specific receptor subtype activation. TAKE HOME MESSAGE: The results presented in this review suggest a potential use of these chemical modifications in order to achieve required characteristics for a bioactive peptide, mainly for clinical usage. PMID- 22823206 TI - Opportunities and limits of cell-based assay miniaturization in drug discovery. AB - IMPORTANCE OF THE FIELD: Miniaturization is a significant driver for many life science applications and a key technology for personalized medicine. Innovations in microfluidics will make ex vivo testing in in vivo-like environment possible, thus, allowing novel pathways for drug discovery. AREAS COVERED IN THIS REVIEW: This review covers the application of miniaturization technologies, namely microfluidics for cell-based assay development. We highlight the use of microfluidics in sample preparation and clinical trials, review the progress towards in vivo-like test environments and point out practical challenges in the work with microfluidic systems. WHAT THE READER WILL GAIN: The reader will gain an overview of the different application areas of miniaturized systems for cell based assay-methods and the technologies involved in how they can be applied in the drug discovery process is given. Examples of clinical applications are pointed out. TAKE HOME MESSAGE: Miniaturization is a key technology driver for methodological progress in drug discovery. The enabling nature of this technology is reflected in the multitude of applications covering all aspects of the drug discovery process. PMID- 22823207 TI - Exemplification of the challenges associated with utilising fluorescence intensity based assays in discovery. AB - IMPORTANCE OF THE FIELD: Despite the advances in the understanding of biological processes, significant challenges still face those engaged in small molecule drug discovery. To complicate matters further, researchers are often overwhelmed with a range of off-the-shelf as well as bespoke assay formats to choose from when initiating a drug discovery programme. Although fluorescence intensity based assays have traditionally been adopted in drug discovery programmes for a wide range of target classes, it is essential to fully validate the chosen readouts to confirm that they accurately reflect the underlying biological mechanism under investigation. AREAS COVERED IN THIS REVIEW: This review exemplifies the challenges that are often encountered with fluorescence intensity based assays and particular attention is paid to compound interference, the protease, deacetylating enzyme and kinase enzyme target classes. WHAT THE READER WILL GAIN: Designing a critical path in early stage drug discovery, which combines several diverse and minimally overlapping readout modes, will maximise the chance that compound activities will translate between the primary assay (utilised in the initial screening campaign) and secondary assay (utilised to evaluate the confirmed hits identified in the primary assay, usually a cell based assay) formats in a meaningful way. However, this is not always the case as is amply demonstrated across both academia and the pharmaceutical industry. Paying insufficient attention to these points can lead to the early termination of drug discovery programmes, not for want of resources or confidence in the rationale underlying the target, but instead because decision making has been driven by assay data originating from a different biological mechanism than the one under investigation. TAKE HOME MESSAGE: Although fluorescence intensity based assays are likely to remain popular for many target classes in drug discovery, in particular in small molecule screening campaigns, it is essential that at the outset they are sufficiently well validated so that compounds are likely to exhibit profiles that are confirmed in subsequent assays. PMID- 22823208 TI - The alluring potential of functionalized carbon nanotubes in drug discovery. AB - IMPORTANCE OF THE FIELD: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses. AREAS COVERED IN THIS REVIEW: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy. WHAT THE READER WILL GAIN: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed. TAKE HOME MESSAGE: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining - and in some cases improving - their therapeutic efficacy. PMID- 22823209 TI - The Maniapure Program--lessons learned from a rural experience: two decades delivering primary healthcare through telemedicine. AB - OBJECTIVE: Latin American healthcare has a common characteristic in the way countries provide assistance to the majority of their population, often represented by limitations in investment and most frequently by assigning funds to the wrong sectors of the system, which will never reach the neediest segments of the society. We want to share some lessons learned in nearly two decades serving the poorest segments of the society, despite limited funding, through the use of communication and information technologies. MATERIALS AND METHODS: The data analyzed come from the accumulated experience in a remote rural center in southern Venezuela (La Milagrosa Health Center in Maniapure, Bolivar State) and further experience in over 20 similar rural clinics replicated from that case. The methodology has been a retrospective evaluation of results with a constantly maturing and dynamic practice at three levels of care: (1) remote (basic clinic), (2) a virtual triage center, and (3) a specialty level. RESULTS: We analyzed qualitative results on access to specialty care of previously excluded communities (populations) and the significant cost reduction (social and financial) by avoiding unnecessary travel for the majority of consulting patients. In cases needing subspecialty care that require travel, the effectiveness of such activity is optimized in time and service. CONCLUSIONS: Communication and information technologies can provide significant savings to society and improve healthcare with the use of common and relatively inexpensive consumer-level devices if used in a basic, coordinated system of services with adequate training and follow-up. PMID- 22823212 TI - Management and leadership at the bedside. PMID- 22823211 TI - Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation. AB - The main outcomes of the Programa Espanol para Tratamiento de Hemopatias (PETHEMA)-acute lymphoblastic leukaemia (ALL)-Ph-08 trial were described and compared with those of the historical PETHEMA-CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL-Ph-08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant-related mortality observed in the ALL-Ph-08 trial resulted in an improved 2-year event-free survival (63% vs. 37%, P = 0.009). PMID- 22823210 TI - HIF-1 expression is associated with CCL2 chemokine expression in airway inflammatory cells: implications in allergic airway inflammation. AB - BACKGROUND: The pathogenesis of allergic airway inflammation in asthmatic patients is complex and characterized by cellular infiltrates and activity of many cytokines and chemokines. Both the transcription factor hypoxia inducible factor-1 (HIF-1) and chemokine CCL2 have been shown to play pivotal roles in allergic airway inflammation. The interrelationship between these two factors is not known. We hypothesized that the expression of HIF-1 and CCL2 may be correlated and that the expression of CCL2 may be under the regulation of HIF-1. Several lines of evidence are presented to support this hypothesis. METHODS: The effects of treating wild-type OVA (ovalbumin)-sensitized/challenged mice with ethyl-3,4-dihydroxybenzoate (EDHB), which upregulate HIF, on CCL2 expression, were determined. Mice conditionally knocked out for HIF-1beta was examined for their ability to mount an allergic inflammatory response and CCL2 expression in the lung after intratracheal exposure to ovalbumin. The association of HIF-1alpha and CCL2 levels was also measured in endobronchial biopsies and bronchial fluid of asthma patients after challenge. RESULTS: We show that both HIF-1alpha and CCL2 were upregulated during an OVA (ovalbumin)-induced allergic response in mice. The levels of HIF-1alpha and CCL2 were significantly increased following treatment with a pharmacological agent which upregulates HIF-1alpha, ethyl-3,4 dihydroxybenzoate (EDHB). In contrast, the expression levels of HIF-1alpha and CCL2 were decreased in the lungs of mice that have been conditionally knocked out for ARNT (HIF-1beta) following sensitization with OVA when compared to levels in wild type mice. In asthma patients, the levels of HIF-1alpha and CCL2 increased after challenge with the allergen. CONCLUSIONS: These data suggest that CCL2 expression is regulated, in part, by HIF-1 in the lung. These findings also demonstrate that both CCL2 and HIF-1 are implicated in the pathogenesis of allergic airway inflammation. PMID- 22823213 TI - Change-related expectations and commitment to change of nurses: the role of leadership and communication. AB - AIM: The purpose of this study was to test a theoretical model linking the impact of expectations on commitment to change and to explore whether change-related communication is a mediating variable between leader-member exchange and expectations. BACKGROUND: Expectations for change outcomes are an important condition to increase nurses' commitment to change. To understand the role of leadership and communication in expectations development is crucial to promote commitment to change. METHOD: A predictive, non-experimental design was used in a random sample of 395 nurses. Structural equation modelling was used to analyse the hypothesized model. RESULTS: Positive expectations had a direct effect on affective commitment to change, whereas negative expectation had a direct effect on continuance commitment to change. Leader-member exchange and communication influenced nurse's expectations about change. Communication partially mediated the relationship between Leader-member exchange and expectations. CONCLUSION: These findings suggested that nurses' expectation about change were strongly linked to commitment to change. Furthermore, the enhancement of communication and relationship with leader contributed to the development of positive and negative expectations. IMPLICATIONS FOR NURSING MANAGEMENT: Strategies to promote commitment to change include developing positive expectations about change outcomes and building high-quality leadership style oriented to the communication. PMID- 22823214 TI - Achieving the 'perfect handoff' in patient transfers: building teamwork and trust. AB - AIMS: To use the philosophy and methodology of Appreciative Inquiry (AI) in the investigation of unit to unit transfers to determine aspects which are working well and should be incorporated into standard practice. BACKGROUND: Handoffs can result in threats to patient safety and an atmosphere of distrust and blaming among staff can be engendered. As the majority of handoffs go well, an alternative is to build on successful handoffs. EVALUATION: The AI methodology was used to discover what was currently working well in unit to unit transfers. The data from semi-structured interviews that were conducted with staff, patients, and family informed structural process improvements. KEY ISSUES: Themes extracted from the interviews focused on the situational variables necessary for the perfect transfer, the mode and content of transfer-related communication, and important factors in communication with the patient and family. CONCLUSIONS: This project was successful in demonstrating the usefulness of AI as both a quality improvement methodology and a strategy to build trust among key stakeholders. IMPLICATIONS FOR NURSING MANAGEMENT: Giving staff members the opportunity to contribute positively to process improvements and share their ideas for innovation has the potential to highlight expertise and everyday accomplishments enhancing morale and reducing conflict. PMID- 22823215 TI - Strengthening communication to overcome lateral violence. AB - AIM: This quality improvement project aims to reduce nurse-to-nurse lateral violence and create a more respectful workplace culture through a series of workshops. BACKGROUND: Lateral violence is common and pervasive in nursing, with detrimental physical, psychological and organizational consequences. METHODS: This project describes the organization-wide pre- and post-intervention survey of registered nurses' perception of lateral violence and turnover. RESULTS: After the workshop series, nurses who reported experiencing verbal abuse fell from 90 to 76%. A greater percentage of nurses perceived a workplace that was respectful to others and in which it was safe to express opinions. After the workshop series, a greater percentage of nurses felt determined to solve the problem after an incident of lateral violence, while a smaller percentage felt powerless. Nursing turnover and vacancy rates dropped. CONCLUSIONS: Educational workshops that enhanced awareness of lateral violence and improved assertive communication resulted in a better working environment, reduction in turnover and vacancy rates, and reduced incidence of lateral violence. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers must raise awareness of lateral violence with individual and organizational consequences. Nursing leadership can effect organizational change to lesson lateral violence and enhance a healthy workplace culture by replicating our intervention or components of our workshops. PMID- 22823216 TI - Comparison of self-assessed competence and experience among critical care nurses. AB - AIM: To determine the level of self-assessed nursing competence and the relationship to age and experience in nursing. BACKGROUND: Nursing competence is a concern for all health-care stakeholders. Methods to measure competence have been evaluated worldwide. There is little agreement about the development or reliable measure of competence. Exploring these relationships can identify strategies for education, retention, professional growth and potentially affect patient outcome measures. METHOD: The Nurse Competence Scale (NCS) was completed by 101 critical care nurses. Statistical methods were used to analyse the data. RESULTS: The nurses self-assessed level of competence ranged from good to excellent along with an increased frequency of using competencies. Statistically significant relationships were found among the variables. CONCLUSIONS: Measurable, significant relationships exist among the variables. The NCS proved to be a valid and reliable instrument to measure competence. IMPLICATIONS FOR NURSING MANAGEMENT: Objective and reliable assessment of nursing competence is an important measure for leadership and education. Further studies to identify other factors affecting the nurses' experience and the effect on competence will help to develop and promote supportive strategies. PMID- 22823217 TI - Transition support for the newly licensed nurse: a programme that made a difference. AB - AIM: To describe and evaluate a collaborative programme that supports newly licensed registered nurses (RNs). BACKGROUND: New RN transition is recognized globally as a challenge. Nurse managers desire successful programmes that support transition into professional practice. One community developed and implemented an on-going programme that supported the new RNs transition and leadership development. METHODS: One hundred and nine newly licensed nurses participated in a 10-month programme. Quantitative data were collected and analysed. The present study reports on the evaluation of the programme. RESULTS: Skill acquisition occurred, retention improved, and transition was supported. Leadership development and psychosocial and technical skills sets improved for participants involved with the programme. CONCLUSIONS AND IMPLICATIONS FOR NURSING MANAGEMENT: The results of the present study suggest that transition support is valuable. Enhanced retention, improved transition and leadership development were noted. Newly licensed RNs gained leadership, patient care and professionalism skills, and were supported with their transition. The results demonstrate that Nurse Managers need to consider opportunities to offer their newly licensed nurses a programme that is targeted for transition support and leadership development. PMID- 22823218 TI - Family-centred care in the paediatric intensive care unit. AB - AIM: The aim was to assess emotional support given to mothers of children in intensive care units (ICUs) and make recommendations to nurse managers regarding family-centred nursing care in paediatric ICUs in South Africa. BACKGROUND: Family-centred care is an essential component of paediatric care. Nurse managers should enhance implementation and sustainability to ensure quality care. METHODS: A quantitative descriptive research design was used. Structured interviews using questionnaires were conducted with 62 mothers whose children were nursed in ICUs in Bloemfontein. FINDINGS: Fifteen stressors for mothers were identified and emotional support for mothers in ICU's was assessed and described. Analysis indicated that COPE (Creating Opportunities for Parent Empowerment) can be used within the South African context to enhance family-centred paediatric nursing care. CONCLUSION: Competencies of nurse practitioners and other staff involved must be improved and the seriousness and importance of emotional support as part of family-centred care should be emphasized. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers should take responsibility for the training of staff in implementing COPE as a possible empowerment programme in Paediatric ICUs to ensure that emotional support is not neglected. PMID- 22823219 TI - Leadership qualities when providing therapy for women who suffer from eating difficulties. AB - AIM: The aim of this study was to reflect on aspects of mental health nursing leadership qualities with special focus on the therapeutic process for women who suffer from eating difficulties (ED). BACKGROUND: Therapy for patients with ED involves motivating them to make meaningful changes. Leadership qualities in MHN should focus on the relationship with the patient and positive empowerment processes. METHODS: In-depth interviews were conducted with six women suffering from ED who had participated in art therapy. The interviews were analysed by means of an interpretative hermeneutic approach. RESULTS: A main theme 'The mental health nurse as a formative and mindful leader in a group therapeutic relationship' and two themes 'Leading sensitively towards awakening the patients' awareness of their pre-understanding' and 'Leading dialectically towards solving patients' existential dilemmas' were developed and comprised two aspects of leadership. CONCLUSION: The nurse-patient relationship is influenced by the patients' pre-understanding and existential dilemmas. Leadership qualities associated with being formative and mindful represent important aspects of this relationship and should be investigated and thematically described in greater detail in future research. IMPLICATIONS FOR NURSING MANAGEMENT: The nurse-patient relationship should focus on clinical supervision, in order to strengthen the nurses' leadership qualities in terms of being aware and dialectical. PMID- 22823220 TI - Staff attitudes towards older patients with cognitive impairment: need for improvements in acute care. AB - AIM: To explore the attitudes held by staff working in acute care units towards patients aged 70 years or older with cognitive impairment, and to explore factors associated with negative attitudes. BACKGROUND: Hospital staff attitudes towards older patients with cognitive impairment are of concern as older people are the main hospital users, and because staff attitudes influence care quality and uptake of evidence-based care. METHOD: A cross-sectional survey design was used to collect data from staff (n = 391). RESULTS: Staff attitudes were not explicitly negative. However, higher perceived strain in caring for older patients with cognitive impairment, higher perceived prevalence of these patients in the ward, being younger and working as an assistant nurse were associated with negative attitudes. A majority of staff reported that these patients received the best possible care, but few reported formally assessing cognitive status or working with evidence-based care protocols. CONCLUSION: Staff characteristics associated with negative attitudes were described and staff perception that patients received best hospital care, despite limited cognitive assessments and care guidelines, indicate areas for improvement. IMPLICATIONS FOR NURSING MANAGEMENT: Supporting young staff and assistant nurses, and implementing cognitive assessments and evidence-based guidelines can promote positive attitudes and best practice. PMID- 22823221 TI - Attitudes towards the Infection Prevention and Control Nurse: an interview study. AB - AIM: A study was undertaken involving nursing students and nurse mentors to investigate the experiences and learning needs of nursing students in relation to infection prevention. One of the objectives was to consider the views of both nursing students and mentors towards the Infection Prevention and Control Nurse (IPCN) as an important staff member in infection prevention and control. BACKGROUND: Infection prevention and control is a national and international priority but compliance with precautions can be low. One reason for this is staff attitudes. Infection Prevention and Control Nurses have an important role to play in the management of patient care through clinical staff and it is therefore important that they are seen as approachable and effective in their role. METHODS: Using a qualitative approach, data were obtained through semistructured interviews with 31 nursing students and 32 nurse mentors. Interviews were recorded, transcribed and analysed using framework analysis. FINDINGS: Three themes emerged: attitudes towards the IPCN, effects of the presence of the IPCN and preferred qualities in IPCNs. CONCLUSIONS: Areas for future research are identified and recommendations made to address areas where attitudes may affect both clinical practice and the education of nursing students in clinical placements. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse specialists or practitioners, who are often seen within a management role, need to consider how they work with clinical staff in order to foster more collaborative relationships. PMID- 22823222 TI - The relationship between social skills and early resignation in Japanese novice nurses. AB - AIM: The aim of this study was to reveal the relationship between social skills and early resignation in Japanese novice nurses. BACKGROUND: The early resignation of novice nurses has become increasingly prevalent in recent years. This study was conducted to investigate the relationship between the personal sociality of novice nurses and their early resignation. METHODS: We surveyed 272 nurses with 1-3 years of experience. Instances of early resignation were studied by using a questionnaire, and their social skills were measured using Kikuchi's Scale of Social Skills:18 items (KiSS-18), a tool developed by Kikuchi to estimate sociality. RESULTS: Nurses with low sociality were more likely to resign than those with higher sociality. The lack of advanced social skills was closely associated with a higher likelihood of early resignation. CONCLUSION: The presence of advanced social skills appeared to potentially prevent resignation among novice nurses. Further investigation is needed to determine the causal relationship between sociality and early resignation. IMPLICATIONS FOR NURSING MANAGEMENT: Social skills training for novice nurses may be of benefit in preventing early resignation. PMID- 22823223 TI - The impact of leadership styles on nurses' satisfaction and intention to stay among Saudi nurses. AB - AIM: To examine the impact of leadership styles of nurse managers on Saudi nurses' job satisfaction and their intent to stay at work. BACKGROUND: Increasing nurses' satisfaction is one of the key elements in meeting challenges of quality outcomes, patient satisfaction and retention of staff nurses in hospitals. METHODS: This study used a descriptive correlational design. The Multifactor Leadership Questionnaire (MLQ-5X), Job Satisfaction Survey (JSS), the McCain's Intent to Stay Scale and a demographic form were used to collect the data from a convenience sample of 308 Saudi nurses. RESULTS: Saudi nurses were moderately satisfied in their jobs. In addition, nurses were more satisfied with leaders who demonstrated transformational leadership styles, and those who were more satisfied with their jobs intended to say at work. The background variables, the transformational leadership style and the transactional style explained 32% of the variation in job satisfaction. CONCLUSIONS: The results of the study emphasized the importance of transformational leadership, which indicates the need for further attention to training and development of effective leadership behaviours. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse administrators in Saudi Arabia should capitalize on the importance of transformational leadership style in enhancing the level of job satisfaction. PMID- 22823224 TI - Structural empowerment and anticipated turnover among behavioural health nurses. AB - AIM: The aim of this pilot study was to examine the relationship between structural empowerment and anticipated turnover among behavioural health nurses. BACKGROUND: There have been several studies relating structural empowerment to a range of organizational characteristics and personal attributes of nurses themselves. There are also previous studies linking the key variables in the present study, but no previous research of behavioural health nurses was available. METHODS: A quantitative design was used for this cross-sectional pilot study. All registered nurses (RN) working on inpatient units in the study facility were invited to participate (n = 97). An anonymous survey was sent to all potential participants. RESULTS: The response rate was 53% (n = 50). The majority of participants perceived themselves as moderately empowered. There was a significant negative correlation between empowerment and anticipated turnover. CONCLUSION: The results of this pilot study among behavioural health nurses are similar to the results among nurses working in other clinical areas. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers should be cognizant of the factors that enhance nurses' perceptions of empowerment, particularly related to issues of retention and anticipated turnover among behavioural health nurses. PMID- 22823225 TI - Practice environment, job satisfaction and burnout of critical care nurses in South Africa. AB - AIM: To describe the practice environment, job satisfaction and burnout of critical-care nurses (CCNs) in South Africa (SA) and the relationship between these variables. BACKGROUND: CCNs are more sensitive to job satisfaction and burnout, and several studies have been published on the relationship between these variables. However, the research that was undertaken did not focus exclusively on the practice environment of CCNs or the context of SA. METHOD: The RN4CAST survey was used. A stratified sample of 55 private hospitals and seven national referral hospitals were included in the study. A total of 935 CCNs completed the survey. RESULTS: The practice environment is positive, except for staffing and resource adequacy, and governance. The greatest job dissatisfaction is experienced with regard to wages, opportunities for advancement and study leave. CCNs have a high degree of burnout. CONCLUSION: The high degree of burnout is related to dissatisfaction with wages, opportunities for advancement, study leave and a practice environment with inadequate staffing and resources, and lack of nurse participation in hospital affairs. IMPLICATIONS FOR NURSING MANAGEMENT: Managers should ensure that adequate numbers of CCNs are on the staff allocation and provide opportunities for CCNS to participate in policy and governance of the hospital, while giving attention to good salaries and providing opportunities for advancement and study leave. PMID- 22823226 TI - Exploring the key predictors of retention in emergency nurses. AB - AIM: To explore the factors that predict the retention of nurses working in emergency departments. BACKGROUND: The escalating shortage of nurses is one of the most critical issues facing specialty areas, such as the emergency department. Therefore, it is important to identify the key influencing and intermediary factors that affect emergency department nurses' intention to leave. METHODS: As part of a larger study, a cross-sectional survey was completed by 261 registered nurses working in the 12 designated emergency departments within rural, urban community and tertiary hospitals in Manitoba, Canada. RESULTS: Twenty-six per cent of the respondents will probably/definitely leave their current emergency department jobs within the next year. Engagement was the key predictor of intention to leave (P < 0.001). Engagement was also associated with job satisfaction, compassion satisfaction, compassion fatigue, and burnout (P < 0.05). In an ordinal least-squares model (R(2) = 0.44), nursing management, professional practice, collaboration with physicians, staffing resources and shift work emerged as significant influencing factors for engagement. CONCLUSIONS: Engagement plays a central role in emergency department nurses intention to leave. Addressing the factors that influence engagement may reduce emergency department nurses' intention to leave. IMPLICATIONS FOR NURSING MANAGEMENT: This study highlights the value of research-based evidence as the foundation for developing innovative strategies for the retention of emergency department nurses. PMID- 22823227 TI - Cost savings associated with an education campaign on the diagnosis and management of sleep-disordered breathing: a retrospective, claims-based US study. AB - This economic evaluation takes the perspective of a health plan provider. The primary objective was to determine if medical expenses of members enrolled in the not-for-profit, US-based Union Pacific Railroad Employes Health Systems (UPREHS) health plan were reduced after implementing a low-cost, patient-focused education campaign on sleep-disordered breathing (SDB). The authors reviewed medical claims records of all members (N=22,275) from 2 years before (2005-2006) and 2 years after (2007-2008) the campaign. Members were assigned to a non-SDB (did not seek diagnosis or not diagnosed with SDB), an SDB-NT (diagnosed with SDB but not on therapy), or an SDB-PAP (diagnosed with SDB and on positive airway pressure [PAP] therapy) group. The authors assessed overall medical and inpatient hospital costs (calculated as annual per member per month [PMPM] costs), and number of hospital admissions. The percentage of members with SDB was 11.1% (2350/21,185) in 2005 and 10.5% (2385/22,639) in 2008. During the study, the percentage of members with SDB receiving PAP increased 145% (2005: 23%, 517/2350; 2008: 54.3%, 1265/2385). After the campaign was initiated, overall medical PMPM costs were significantly lower for the SDB-PAP than the SDB-NT group (2007: $572.10 vs. $720.27, P=0.0006; 2008: $645.66 vs. $846.58, P=0.0009), resulting in a differential cost savings of $4.9 million for the study period. In addition, inpatient hospital PMPM costs and the number of hospital admissions also were lower for the SDB-PAP group than for the SDB-NT group. These findings suggest that an SDB education campaign can improve health care outcomes and reduce medical expenses. PMID- 22823228 TI - Starting dialysis early: no survival, quality of life, or cost advantages. PMID- 22823229 TI - Modulation of interferon-gamma-induced glial cell activation by transforming growth factor beta1: a role for STAT1 and MAPK pathways. AB - Overactivated glial cells can produce neurotoxic oxidant molecules such as nitric oxide (NO.) and superoxide anion (O(2).(-)). We have previously reported that transforming growth factor beta1 (TGFbeta1) released by hippocampal cells modulates interferon-gamma (IFNgamma)-induced production of O(2).(-) and NO. by glial cells. However, underlying molecular mechanisms are not completely understood, thereby, the aim of this work was to study the effect of TGFbeta1 on IFNgamma-induced signaling pathways. We found that costimulation with TGFbeta1 decreased IFNgamma-induced phosphorylation of signal transducer and activator of transcription-type-1 (STAT1) and extracellular signal-regulated kinase (ERK), which correlated with a reduced O(2).(-) and NO. production in mixed and purified glial cultures. Moreover, IFNgamma caused a decrease in TGFbeta1-mediated phosphorylation of P38, whereas pre-treatment with ERK and P38 inhibitors decreased IFNgamma-induced phosphorylation of STAT1 on serine727 and production of radical species. These results suggested that modulation of glial activation by TGFbeta1 is mediated by deactivation of MAPKs. Notably, TGFbeta1 increased the levels of MAPK phosphatase-1 (MKP-1), whose participation in TGFbeta1-mediated modulation was confirmed by MKP-1 siRNA transfection in mixed and purified glial cultures. Our results indicate that the cross-talk between IFNgamma and TGFbeta1 might regulate the activation of glial cells and that TGFbeta1 modulated IFNgamma induced production of neurotoxic oxidant molecules through STAT1, ERK, and P38 pathways. PMID- 22823230 TI - Racial differences in the development of impulsivity and sensation seeking from childhood into adolescence and their relation to alcohol use. AB - BACKGROUND: Pronounced differences in drinking behavior exist between African Americans and European Americans. Disinhibited personality characteristics are widely studied risk factors for alcohol use outcomes. Longitudinal studies of children have not examined racial differences in these characteristics and in their rates of change or whether these changes differentially relate to adolescent alcohol use. METHODS: Latent growth curve modeling was performed on 7 annual waves of data on 447 African American and European American 8- and 10-year old children followed into adolescence as part of the Tween to Teen Project. Both mother and child data were examined. RESULTS: European Americans had higher initial levels of (beta = 0.22, p < 0.001) and greater growth in sensation seeking (beta = 0.16, p < 0.05) compared with African Americans. However, African American children had higher initial levels of impulsivity compared with European American children (beta = -0.27 and -0.16, p < 0.01). Higher initial levels of sensation seeking (beta = 0.18, p < 0.01) and greater growth in both sensation seeking (beta = 0.24, p < 0.01) and impulsivity (beta = 0.30 to 0.34, p < 0.01) related to subsequent frequency of alcohol use. The association between race and alcohol use was partially mediated by initial levels of sensation seeking (beta = 0.04, p < 0.05; 95% CI: 0.004 to 0.078). Additionally, sharper increases in sensation seeking predicted greater levels of subsequent alcohol use for European Americans (beta = 0.33, p < 0.001) but not for African Americans (beta = -0.15, ns). CONCLUSIONS: This study revealed different developmental courses and important racial differences for sensation seeking and impulsivity. Findings highlight the possibility that sensation seeking at least partly drives early alcohol use for European American but not for African American adolescents. PMID- 22823231 TI - Refining the phenotype of borderline personality disorder: Diagnostic criteria and beyond. AB - Borderline personality disorder (BPD) is a heterogeneous disorder, and previous analyses have parsed its phenotype in terms of subtypes or underlying traits. We refined the BPD construct by testing a range of latent variable models to ascertain whether BPD is composed of traits, latent classes, or both. We also tested whether subtypes of BPD could be distinguished by anger, aggressiveness, antisocial behavior, and mis-trustfulness, additional putative indicators drawn from Kernberg's (1967, 1975) theory of BPD. In a mixed clinical and nonclinical sample (N = 362), a factor mixture model consisting of two latent classes (symptomatic and asymptomatic) and a single severity dimension fit the BPD criteria, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), data better than latent class or factor analytic approaches. In the second analytic phase, finite mixture modeling of the symptomatic latent class (n = 100) revealed four BPD subtypes: angry/aggressive, angry/mistrustful, poor identity/low anger, and prototypical. Our results support a hybrid categorical-dimensional model of the BPD DSM-IV criteria. The BPD subtypes emerging from this model have important implications for treatment and etiological research. PMID- 22823232 TI - The role of fearless dominance in psychopathy: confusions, controversies, and clarifications. AB - Based on their 2011 meta-analysis of the correlates of the Psychopathic Personality Inventory (PPI), Miller and Lynam (An examination of the Psychopathic Personality Inventory's nomological network: A meta-analytic review, Personality Disorders: Theory, Research, and Treatment, 3, 305-326) conclude that its Fearless Dominance (PPI-FD) higher-order dimension exhibits weak construct validity, leading them to question the relevance of boldness to the conceptualization and assessment of psychopathy. We examine their assertions in light of the clinical, conceptual, and empirical literatures on psychopathy. We demonstrate that Miller and Lynam's assertions (a) are sharply at odds with evidence that well-validated psychopathy measures detect both secondary and primary subtypes, the latter of which is linked to social poise and immunity to psychological distress, (b) are inconsistent with most classic clinical descriptions of psychopathy, in which fearless dominance plays a key role, (c) presume an a priori nomological network of psychopathy that leaves scant room for adaptive functioning and renders psychopathy largely equivalent to antisocial personality disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, (d) are premised on a misunderstanding of the role of Cleckley's "mask" of healthy adjustment in psychopathy, and (e) are contradicted by data-some reported elsewhere by Miller and Lynam themselves-that PPI-FD is moderately to highly associated with scores on several well-validated psychopathy measures, as well as with personality traits and laboratory markers classically associated with psychopathy. A scientific approach to psychopathy requires the question of whether its subdimensions are linked to adaptive functioning to be adjudicated by data, not by fiat. PMID- 22823233 TI - Fearless dominance and psychopathy: a response to Lilienfeld et al. AB - We respond to criticisms raised by Lilienfeld et al. (2012, The role of fearless dominance in psychopathy: Confusions, controversies, and clarifications. Personality Disorders: Theory, Research, and Treatment, 3, 327-340) about our meta-analysis (Miller & Lynam, 2012, An examination of the Psychopathic Personality Inventory's nomological network: A meta-analytic review. Personality Disorders: Theory, Research, and Treatment, 3, 305-326). We argue that Lilienfeld et al. commit multiple logical and scientific errors throughout their response: minimizing the centrality of antisocial behavior in previous conceptions of psychopathy, magnifying the role of psychological health in these same conceptions, ignoring the relative sizes of relations, and selective reporting of studies and specific findings within studies. We identify two points of agreement with Lilienfeld et al.: (a) the presence of fearless dominance (FD) traits is not sufficient to indicate the presence of psychopathy; and (b) traits related to FD may have a role to play in psychopathy. Beyond these points of agreement, we find Lilienfeld et al.'s response to be less than compelling. We reiterate our main conclusions that Psychopathic Personality Inventory's FD subscale assesses stable extraversion and is, at best, considered a diagnostic specifier rather than an essential feature. PMID- 22823234 TI - Imaging wellbore cement degradation by carbon dioxide under geologic sequestration conditions using X-ray computed microtomography. AB - X-ray microtomography (XMT), a nondestructive three-dimensional imaging technique, was applied to demonstrate its capability to visualize the mineralogical alteration and microstructure changes in hydrated Portland cement exposed to carbon dioxide under geologic sequestration conditions. Steel coupons and basalt fragments were added to the cement paste in order to simulate cement steel and cement-rock interfaces. XMT image analysis showed the changes of material density and porosity in the degradation front (density: 1.98 g/cm(3), porosity: 40%) and the carbonated zone (density: 2.27 g/cm(3), porosity: 23%) after reaction with CO(2)-saturated water for 5 months compared to unaltered cement (density: 2.15 g/cm(3), porosity: 30%). Three-dimensional XMT imaging was capable of displaying spatially heterogeneous alteration in cement pores, calcium carbonate precipitation in cement cracks, and preferential cement alteration along the cement-steel and cement-rock interfaces. This result also indicates that the interface between cement and host rock or steel casing is likely more vulnerable to a CO(2) attack than the cement matrix in a wellbore environment. It is shown here that XMT imaging can potentially provide a new insight into the physical and chemical degradation of wellbore cement by CO(2) leakage. PMID- 22823236 TI - Multiple recurrences in melanin-protein-induced uveitis in the rat. AB - The purpose of the present study was to investigate the occurrence and sequelae of multiple recurrences in experimental melanin-protein-induced uveitis (EMIU). Lewis rats were immunized with purified bovine choroidal melanin granules, and the development of EMIU was studied during six months. Multiple recurrences were observed in virtually all rats that developed primary EMIU. The spontaneous recurrences exhibited an increasingly mild character and a decreasing frequency over time. They occurred one to four times per eye with intervals of five to six weeks. If the inflammations were more severe or chronic the uveal tissues were more seriously damaged. The anterior uvea became slender by loss of cells and stroma during the process suggesting a role as target. Unlike in primary EMIU, the retina finally exhibited areas with damage of the photoreceptor and pigment epithelial cells. Mononuclear cells were the predominant inflammatory cell type in the entire uvea in eyes with serious recurrences or chronic uveitis. The number of recurrences per se did not correlate with the extent of tissue damage but the overall severity of the disease over six months did. In rats recovered from mild recurrences, a single injection of pertussis toxin, or melanin granules emulsified in Freund's incomplete adjuvant was sufficient to reinduce severe EMIU with extensive damage of the uvea. Hence, specific as well as aspecific stimulation of the immune system caused severe recurrences of this type of uveitis. EMIU resembles non-infectious human anterior uveitis in several respects, even in its multiple recurrences. PMID- 22823235 TI - Surface-Enhanced Raman scattering-based detection of the interactions between the essential cell division FtsZ protein and bacterial membrane elements. AB - Surface-enhanced Raman scattering (SERS) spectroscopy has been applied to detect the interaction of the FtsZ protein from Escherichia coli, an essential component of the bacterial division machinery, with either a soluble variant of the ZipA protein (that provides membrane tethering to FtsZ) or the bacterial membrane (containing the full-length ZipA naturally incorporated), on silver-coated polystyrene micrometer-sized beads. The engineered microbeads were used not only to support the bilayers but also to offer a stable support with a high density of SERS hot spots, allowing the detection of ZipA structural changes linked to the binding of FtsZ. These changes were different upon incubating the coated beads with FtsZ polymers (GTP form) as compared to oligomers (GDP form) and more pronounced when the plasmonic sensors were coated with natural bacterial membranes. PMID- 22823237 TI - Clinical course, immune response, and histopathology of a simplified model of experimental lens induced endophthalmitis in rats. AB - YAG laser capsulotomy 14 days after one-shot immunization of bovine lens soluble protein with Freund's complete adjuvant and simultaneous intravenous injection of Bordettella pertussis caused lens induced endophthalmitis (LIE) in Lewis rats. Exudate first appeared in the anterior chamber eight hours after capsulotomy. In the cases of low dose (20MUg/rat) immunization, exudative change was localized around the ruptured lens surface. On the other hand, the anterior chamber was filled with thick exudate in high dose (200MUg/rat) immunized rats. By ELISA and lymphocyte proliferation assay, serum and lymphocyte from LIE rats reacted with bovine uvea as well as bovine lens, but showed no cross-reactivity with bovine retina. Histopathological finding in the low-dose immunized rats was granulomatous inflammation localized to the anterior eye segment, but high dose immunized rats developed severe panophthalmitis and showed epithelioid granulomas in disorganized retina. The authors think this low dose model can contribute to therapeutic or suppressive studies. PMID- 22823238 TI - Primary trabeculectomy with 5-fluorouracil for glaucoma secondary to uveitis. AB - Raised intraocular pressure occurs in a significant proportion of patients with uveitis, and may lead to glaucomatous visual loss. Medical therapy often proves inadequate in controlling intraocular pressure, necessitating surgical intervention but conventional filtering procedures such as trabeculectomy are known to fail more frequently in this group than in non-inflamed eyes. Adjunctive subconjunctival 5-fluorouracil (5-FU) has been shown to improve the success of trabeculectomy in a variety of secondary glaucomas. This retrospective study examined the effect of postoperative 5-FU administration on the outcome of trabeculectomy in uveitis-related glaucoma in 28 eyes of 26 patients. Eyes treated with adjunctive 5-FU showed a more prolonged control of intraocular pressure, and a longer median time to failure of control than untreated eyes. Trabeculectomy failure was more common and occurred earlier when a limbus-based conjunctival flap had been used, in patients of black ethnic origin, and if there had been previous intraocular surgery. Additional hypotensive therapy with topical beta-blockers was required more frequently in eyes which had not received 5-FU, and where a limbus-based conjunctival flap had been employed, all eyes in the latter group requiring beta-blockers one year after surgery. Intraocular inflammation was under satisfactory control in all patients at the time of surgery, and no deleterious effect on control of uveitis in relation to surgical intervention was observed. PMID- 22823239 TI - Immunochemical evaluation of S-antigen of rabbit pineal gland. AB - Purified S-antigen of photoreceptor cells induces experimental autoimmune uveoretinitis (EAU) and experimental autoimmune pinealitis (EAP) in laboratory animals. However, in rabbits, S-antigen induces only EAU without EAP. To evaluate this difference, the authors studied immunochemical reactivity of rabbit pineal gland with a panel of anti-S-antigen monoclonal antibodies (MAb). Rabbit pineal gland reacted with the MAbs by ELISA and immunoblot but not by immunohistochemistry. In contrast, rabbit retina like guinea pig retina, guinea pig pineal gland and bovine retina reacted with these MAbs by immunohistochemistry as well as by ELISA and immunoblot. Also, S-antigen purified from rabbit retina reacted as did bovine and guinea pig S-antigen. Therefore, S antigen in situ in rabbit pineal gland is different from S-antigen of rabbit retina and different from S-antigen of pineal gland and retina of other species. Just as the MAbs did not react with S-antigen in rabbit pineal gland, it is possible that S-antigen activated lymphocytes may not recognize S-antigen in rabbit pineal gland and thereby not induce EAP. PMID- 22823240 TI - Stromelysin (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase (TIMP-1) mRNA expression in scleritis. AB - Scleritis is a severe and destructive inflammatory eye disease characterized by extensive extracellular matrix degradation. As in rheumatoid arthritis (RA), tissue destruction in scleritis may be mediated in part by matrix metalloproteinases such as collagenase (MMP-1) and stromelysin (MMP-3) which are normally kept in balance by endogenous inhibitors, such as tissue inhibitor of metalloproteinase (TIMP-1). To test this hypothesis, in situ hybridization was used to localize MMP-1, MMP-3 and TIMP-1 mRNA in diseased and normal scleral tissue using digoxigenin labelled probes. Strong expression of MMP-3 and TIMP-1 mRNA, but not MMP-1, was observed in the diseased scleral tissue. Infiltrating inflammatory cells such as macrophages and scleral fibroblasts were the primary source of MMP-3 and TIMP-1 expression. There was also relatively less TIMP-1 compared with MMP-3 mRNA expression in the inflammatory cells in scleritis tissue. In order to study regulation of metalloproteinase expression in ocular cells the authors established human scleral fibroblasts (HSF) in primary culture. Northern blot analysis was performed on total RNA extracted from HSF grown in serum free media. MMP-1 MMP-3 and TIMP-1 were constitutively expressed in these cells. Stimulation of HSF with pro-inflammatory cytokines likely to be present in scleritis, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), significantly induced MMP-3 and TIMP-1 mRNA expression. Using culture supernatants derived from the same cytokine stimulated scleral fibroblast the authors were able to detect MMP-3 protein production by Western blot analysis. They conclude that matrix metalloproteinase-3 mRNAs are present in scleritis tissue and may be induced by cytokines produced in the inflammatory process. PMID- 22823241 TI - Synergism between corticosteroids and Rapamycin for the treatment of intraocular inflammation. AB - The authors studied the combination effect of corticosteroids with the new immunosuppressant Rapamycin for the treatment of intraocular inflammation. A median-effect analysis, of the combined effect of Rapamycin and dexamethasone, was performed on the inhibition of lymphocyte proliferation in culture. The mathematical formulas allowed for the calculation of combination indices and dose reduction factors. On the basis of these in-vitro results, treatment with reduced doses of drugs in combination was evaluated in the rat model of experimental autoimmune uveoretinitis. The results showed that Rapamycin and dexamethasone were synergistic over a wide concentration range. The calculated dose reduction factors indicated that an equivalent inhibition of lymphocyte proliferation was achieved with a combination of Rapamycin and dexamethasone reduced by 5-7 and 3-6 fold respectively, compared to the concentration required when each drug was used alone. In animals, there was a significant reduction of the incidence and severity of ocular inflammation with low doses of the drugs in combination. The authors conclude that the observed synergistic effect between Rapamycin and dexamethasone suggests that the use of this drug combination might be advantageous in the treatment of patients with severe uveitis. PMID- 22823242 TI - Aqueous humor cytokine profile in patients with chronic uveitis. AB - There is increasing evidence that cytokines play an important role in the pathogenesis of uveitis. The aim of this study was to determine the presence of cytokines in the aqueous humor (AH) of patients with chronic idiopathic uveitis (CU). Patients with uveitis (n=10) were compared to those undergoing cataract surgery (n=1) for non-inflammatory eye diseases. ELISA's for the detection of cytokines (IL-1, IL-2, IL-6, TNF-alpha) in aqueous humor were developed that allowed the measurement of multiple cytokines present in low concentrations. Interleukin-6 was found to be elevated in the aqueous humor of two patients (20%) with CU, but in none of the controls. Interleukin-1-alpha, Interleukin-2 and TNF alpha were not detected in the AH of patients or controls. TGF-beta was detected in the aqueous of all patients and controls, using a bioassay. PMID- 22823243 TI - Trabeculectomy in uveitis Are antimetabolites necessary at the first procedure? AB - A retrospective study was undertaken analysing the results of trabeculectomy without antimetabolites in 33 eyes with uveitis compared to 33 eyes with primary open angle glaucoma (POAG). Both groups were matched for surgeon with a median follow-up of 19 months (range 2-44 months) for the uveitis group and 24 months (range 6-92 months) for the POAG group. The overall one and two year success (IOP +/- 21 mmHg with or without medication) was 92% and 83% respectively for the uveitis group and 96% for both years for the POAG group (p = 0.241, Mantel Haenszel test). These results indicate that the success of trabeculectomy in patients with inflammatory glaucoma compares well with that of the POAG group. In the absence of other risk factors, primary trabeculectomy without the use of antimetabolites should be considered as the first choice of surgical treatment for raised intraocular pressure in patients with intraocular inflammatory disease. PMID- 22823244 TI - American uveitis society meeting october 31, 1994 san francisco, california. AB - 1 Ophthalmic manifestations of presumed rifabutin-related uveitis. Arevalo JF, Freeman WR, La Jolla, CA, USA. 2 Diagnosis of toxoplasmosis acute anterior uveitis by PCR. Cano J, Diaz M, Navee A, Maldonado M, Barcelona, Spain. 3 Neuroretinits in patients with AIDS. Berger B, Austin TX, USA. 4 Presumed varicella zoster retinitis in a pediatric patient with AIDS. El Baba F, Nachman S, Stony Brook, NY, USA. 5 ARN with hypopyon caused by EVB and herpes type VI viruses. Cano J, Diaz M, Navea A, Maldonado MJ, Barcelona, Spain. 6 CD8(+) T lymphocytes and ocular infections in HIV(+) patients. Lowder CY, Butler CP, Dodds EM, Recillas-Gispert C, Cleveland, OH, USA. 7 Intravitreal foscanet for persistent CMV. Lieberman RM, Orellana J, New York, NY, USA. 8 Perfluorocarbon liquid versus air-fluid exchange during surgical repair of retinal detachment caused by cytomegalovirus retinitis in patients with AIDS. Sery T, Gomes J, Sando R, Dua H, Donoso L, Vrabec T, Philadelphia, PA, USA. 9 Endogenous ophthalmitis simulating retinoblastoma: a report of six cases. Shields J, Shields C, Eagle R, Barrett J, DePotter P, Philadelphia, PA, USA. 10 Ocular lymphoma resembling chronic postoperative endophthalmitis. Fox G, Chan CC, Whitcup SM, Nussenblatt R, Bethesda, MD, USA. 11 A phase II trial of combination chemotherapy for primary central nervous system lymphoma. Whitcup SM, Stark-Vanes V, Nussenblatt RB, Heiss H, Witte R, Bethesda, MD, USA. 12 Cancer-induced autoimmune retinopathy. Thirkill C, Sacramento, CA, USA. 13 Leukocytoclastic vasculitis. Tessler H. Chicago, IL, USA. 14 Bilateral choroidal neovascular membranes after Candida albicans chorioretinitis. Dodds E, Townsend-Pico W, Lowder CY, Lewis H, Cleveland, OH, USA. 15 An unusual complications of Toxoplasma retinochoroiditis. Gormley PD, Flaxel CJ, Pavesio CE, Conrad DK, Lightman S, London, UK. 16 Surgical removal of a choroidal neovascular membrane in sympahtetic ophthalmia. Conrad DK, McCluskey PJ, Schwartz S, Gregor Z. Lightman S, London, UK. 17 Peripheral laser scatter ablation in pars planitia. Park SE, Mieler WF, Pulido JS, Milwaukee, WI, USA. PMID- 22823245 TI - Nanowire arrays in multicrystalline silicon thin films on glass: a promising material for research and applications in nanotechnology. AB - Silicon nanowires (SiNW) were formed on large grained, electron-beam crystallized silicon (Si) thin films of only ~6 MUm thickness on glass using nanosphere lithography (NSL) in combination with reactive ion etching (RIE). Electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) studies revealed outstanding structural properties of this nanomaterial. It could be shown that SiNWs with entirely predetermined shapes including lengths, diameters and spacings and straight side walls form independently of their crystalline orientation and arrange in ordered arrays on glass. Furthermore, for the first time grain boundaries could be observed in individual, straightly etched SiNWs. After heat treatment an electronic grade surface quality of the SiNWs could be shown by X-ray photoelectron spectroscopy (XPS). Integrating sphere measurements show that SiNW patterning of the multicrystalline Si (mc-Si) starting thin film on glass substantially increases absorption and reduces reflection, as being desired for an application in thin film photovoltaics (PV). The multicrystalline SiNWs directly mark a starting point for research not only in PV but also in other areas like nanoelectronics, surface functionalization, and nanomechanics. PMID- 22823246 TI - Identification and quantitative analysis of carotenoids and their esters from sarsaparilla (Smilax aspera L.) berries. AB - The carotenoid composition of sarsaparilla ( Smilax aspera L.) berries has been analyzed for the first time. Lycopene was found to be the main carotenoid (242.44 MUg/g fresh wt) in the pulp, followed by beta-carotene (65.76 MUg/g fresh wt) and beta-cryptoxanthin (42.14 MUg/g fresh wt; including the free and esterified forms). Other minor carotenoids were lycophyll (13.70 MUg/g fresh wt), zeaxanthin (8.56 MUg/g fresh wt; including the free and esterified forms), lutein (0.94 MUg/g fresh wt), and antheraxanthin (0.58 MUg/g fresh wt). beta-Cryptoxanthin and zeaxanthin were present in free and esterified forms. beta-Cryptoxanthin was mainly esterified with saturated fatty acids (capric, lauric, myristic, palmitic, and stearic), although a low amount of beta-cryptoxanthin oleate was also detected. In the case of zeaxanthin, only a monoester with myristic acid (zeaxanthin monomyristate) was identified. The diverse carotenoid profile, some with provitamin A activity, together with the relatively high content, up to 375 MUg/g fresh wt, makes sarsaparilla berries a potential source of carotenoids for the food, animal feed, and pharmaceutical industries. PMID- 22823247 TI - Soybean oleosomes behavior at the air-water interface. AB - Soy milk is a highly stable emulsion, the stability being mainly due to the presence of oleosomes or oil bodies, spherical structures filled with triacylglycerides (TAGs) and surrounded by a monolayer of phospholipids and proteins called oleosins. For oleosomes purified from raw soymilk, surface pressure investigations and Brewster angle microscopy have been performed to unveil their adsorption, rupture and structural changes over time at different subphase conditions (pH, ionic strength). Such investigations are important for (industrial) food applications of oleosomes, but are also useful for the understanding of the general behavior of proteins and phospholipids at interfaces. In addition a better comprehension of the highly stable oleosomes can lead to advancements in liposome manufacturing, e.g., for storage and transport applications. Although oleosomes have their origin in food systems, their unique stability and physical behavior show transferable characteristics which lead to a much better understanding of the description of any kind of emulsion. This study is one of the first steps toward the comparison of natural emulsification concepts based on different physical structures: e.g., the animals' low density lipoproteins, where apolipoproteins with phospholipids are located only at the interface and plant oleosomes with its oleosins, which are embedded in a phospholipid monolayer and reach deep inside the oil phase. PMID- 22823248 TI - Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma. PMID- 22823249 TI - Impact of genetic epistasis on emotion and executive function: methodological issues and generalizability of findings. PMID- 22823250 TI - Congenital nevus of the nail apparatus--diagnostic approach of a case through dermoscopy. AB - Melanonychia striata in childhood is primarily due to congenital nevi, but melanoma should be excluded. We report a case in which dermoscopy was used in an attempt to avoid incisional biopsy. PMID- 22823251 TI - Expression of anatomical leaf traits in homoploid hybrids between deciduous and evergreen species of Vaccinium. AB - We investigated the anatomical expression of leaf traits in hybrids between evergreen Vaccinium vitis-idaea and deciduous V. myrtillus. We compared parents from four populations with their respective F1 hybrids and tested whether (i) transgression can be the source of novel anatomical traits in hybrids; (ii) expression of transgressive traits is more probable for traits with similar values in parents and intermediate for more distinct values, as predicted by theory; and (iii) independent origin of hybrids leads to identical trait expression profiles among populations. We found that anatomical leaf traits can be divided into four categories based on their similarity to parents: intermediate, parental-like, transgressive and non-significant. Contrary to the common view, parental-like trait values were equally important in shaping the hybrid profile, as were intermediate traits. Transgression was revealed in 17/144 cases and concerned mainly cell and tissue sizes. As predicted by theory, we observed transgressive segregation more often when there was little phenotypic divergence, but intermediate values when parental traits were differentiated. It is likely that cell and tissue sizes are phylogenetically more conserved due to stabilising selection, whereas traits such as leaf thickness and volume fraction of the intercellular spaces, showing a consistent intermediate pattern across populations, are more susceptible to directional selection. Hybrid populations showed little similarity in expression profile, with only three traits identically expressed across all populations. Thus local adaptation of parental species and specific genetic background may be of importance. PMID- 22823252 TI - The IDEAL trial: a closer look. PMID- 22823253 TI - Comparison of physiological and behavioral responses to fresh and thawed breastmilk in premature infants--a preliminary study. AB - BACKGROUND: Breastmilk is usually frozen for premature infants when they are unable to feed orally. However, thawed breastmilk may have altered odor and taste from its original form. Few studies have investigated whether premature infants respond differently to fresh and thawed breastmilk. The purpose of this study was to examine the physiological and behavior responses of premature infants alternately fed fresh and thawed breastmilk. SUBJECTS AND METHODS: An experimental, crossover study using random assignment was conducted. A convenience sample of 18 premature infants less than 37 weeks gestational age at birth with the capability of oral feeding was studied. The premature infants were fed with fresh and thawed breastmilk during two consecutive meals in a random order. Infants' heart rate and oxygen saturation levels were measured baseline and during feeding, as well as observed feeding cues during the feeding period. RESULTS: Premature infants showed significant differences in heart rate when fed thawed, as opposed to fresh, breastmilk. Premature infants demonstrated more stress cues when fed thawed compared with fresh breastmilk (p=0.007). For infants with postmenstrual ages greater than 36 weeks gestation, feeding with thawed breastmilk showed more stress cues and greater effect on heart rate activity compared with fresh breastmilk (p<0.05). CONCLUSIONS: Older premature infants demonstrate more stress when fed with thawed breastmilk. Preterm infants should be directly breastfed or fed with nonfrozen breastmilk, when they show stress behaviors in being fed with thawed breastmilk. PMID- 22823255 TI - Readmission risk factors after hospital discharge among the elderly. AB - Hospital readmission rates among the elderly are attracting increasing attention. Readmission is costly, especially as proposed new guidelines could deny reimbursement for readmissions. Identifying key factors at discharge that can serve as prognostic indicators for readmission is an important step toward developing and targeting interventions to reduce hospital readmissions rates. Published literature has listed predominantly demographic, clinical, and health care utilization characteristics to describe the factors that put the elderly at risk. However, additional factors are proposed that include social, clinical, individual-level, environmental, and system-level factors. Multimodal interventions have been tested and some reduction in readmissions has been shown. Whether these additional factors might lead to a further reduction remains unclear. In addition to possible factors at discharge, factors identified after the patient has been discharged also must be identified and addressed. The patient safety literature characterizes factors that put the elderly at risk for adverse drug events, which function as antecedent factors for readmission and likely include the environmental and system-level factors. Synthesizing these factors from the readmission and patient safety literature provides the basis to develop a more comprehensive conceptual framework to identify research gaps aimed at reducing hospital readmissions among the elderly. PMID- 22823254 TI - Chronic ethanol feeding alters miRNA expression dynamics during liver regeneration. AB - BACKGROUND: Adaptation to chronic ethanol (EtOH) treatment of rats results in a changed functional state of the liver and greatly inhibits its regenerative ability, which may contribute to the progression of alcoholic liver disease. METHODS: In this study, we investigated the effect of chronic EtOH intake on hepatic microRNA (miRNA) expression in male Sprague-Dawley rats during the initial 24 hours of liver regeneration following 70% partial hepatectomy (PHx) using miRNA microarrays. miRNA expression during adaptation to EtOH was investigated using RT-qPCR. Nuclear factor kappa B (NFkappaB) binding at target miRNA promoters was investigated with chromatin immunoprecipitation. RESULTS: Unsupervised clustering of miRNA expression profiles suggested that miRNA expression was more affected by chronic EtOH feeding than by the acute challenge of liver regeneration after PHx. Several miRNAs that were significantly altered by chronic EtOH feeding, including miR-34a, miR-103, miR-107, and miR-122 have been reported to play a role in regulating hepatic metabolism and the onset of these miRNA changes occurred gradually during the time course of EtOH feeding. Chronic EtOH feeding also altered the dynamic miRNA profile during liver regeneration. Promoter analysis predicted a role for NFkappaB in the immediate early miRNA response to PHx. NFkappaB binding at target miRNA promoters in the chronic EtOH-fed group was significantly altered and these changes directly correlated with the observed expression dynamics of the target miRNA. CONCLUSIONS: Chronic EtOH consumption alters the hepatic miRNA expression profile such that the response of the metabolism-associated miRNAs occurs during long term adaptation to EtOH rather than as an acute transient response to EtOH metabolism. Additionally, the dynamic miRNA program during liver regeneration in response to PHx is altered in the chronically EtOH-fed liver and these differences reflect, in part, differences in miRNA expression between the EtOH adapted and control livers at the baseline state prior to PHx. PMID- 22823256 TI - How to conduct research in the pharmaceutical industry? Facing the dilemma: small, autonomous teams versus large, integrated centers. AB - The million dollar question in the pharmaceutical industry today is: how can better productivity be ensured which guarantees that a higher number of valuable medicines are made available to meet patients' needs? The current productivity crisis we are facing is not new; on the contrary, historical data tracing back to the early 1950s show that in spite of our access to much more advanced technologies and understanding of disease mechanisms in combination with the huge efforts that are invested (> $70 billion/annum across the entire pharma business), the output in terms of new drugs is disappointingly low (a total of only 51 new chemical entities globally in 2009). With this challenging state in mind, there are major initiatives underway aiming at defining new organizational models, ways of working, strategies, development concepts and so on to improve the situation and turn the wheel around to take the industry towards a more prosperous future. A key question that has often been asked in this context is whether small teams in charge of R&D activities will perform more efficiently than an organization of an opposite character operating in a large and centralized structure? Whilst the general trend is probably leaning more towards the former, if nothing else than driven by the pronounced downsizing that currently is the prevailing direction, it is crucial not to adopt a one-size-fits all approach but rather to address the specific needs in a given setting and design tailor-made solutions that stand a chance of being successful. PMID- 22823257 TI - Antibiotic biosynthesis following horizontal gene transfer: new milestone for novel natural product discovery? AB - Bacteria obtain a significant proportion of their genetic diversity via acquisition of DNA from distantly related organisms, a phenomenon known as horizontal gene transfer. The focus of horizontal gene transfer investigations has been primarily on the impact of this phenomenon on the ecological and/or pathogenic characteristics of bacterial species, with very little effort devoted to investigating horizontal gene transfer as a means of drug discovery. Here, we describe a novel approach to harness the power of horizontal gene transfer to produce novel chemotherapeutic molecules, a process that is easily scalable. We describe the state of the art in this field and discuss the current limiting factors associated with this phenomenon. Utilising a horizontal gene transfer method, we have identified and characterised a novel antimicrobial compound. Production of this antibiotic, termed rhodostreptomycin, is associated with the transfer of DNA from a species of Streptomyces to Rhodococcus by an as yet identified mechanism. We believe that horizontal gene transfer may represent the future of natural product discovery and engineering. PMID- 22823258 TI - Advances in flow cytometry for drug screening. AB - IMPORTANCE OF THE FIELD: Flow cytometry is considered today as a mature technology. Recently, it has become an accurate tool for screening applications. Yet, not many studies have been published emphasizing flow cytometry as a tool of choice for drug screening except multiplex bead assay. AREAS COVERED IN THIS REVIEW: Scanning the literature for technology breakouts in screening by flow is not an easy task. When a private industry has an accurate and fast screening technology on hands, why should they make public a tool precious for their screening applications? On the European academic side, there are regrettably few grants to help develop and publish screening methodologies. So, a less scientific way to find out is a close market survey seeking new instruments and associated kits or new methods. From here, can one expect flow cytometry to be a tool with new potential for drug discovery? WHAT THE READER WILL GAIN: As the machines are getting simpler to use, a need for plug-and-analyze software has emerged. New analysis tools remain an important step as they will permit to analyze and compare several parameters in a multi-well format simultaneously and this for several cell types for cytomics: a multiparametric, dynamic approach to cell research as cytomics has a practical role to play in drug discovery within the immediate limitations of cell-based analyses. TAKE HOME MESSAGE: Developing new software with multi-well comparison capabilities and most importantly real-time interaction on cytograms can easily circumvent the lack of fluorescent channels on small bench top machines. PMID- 22823259 TI - Bioluminescence assays: multicolor luciferase assay, secreted luciferase assay and imaging luciferase assay. AB - IMPORTANCE OF THE FIELD: By selecting the most appropriate bioluminescence assay, the researcher can study the underlying molecular mechanisms of a physiological system and the effects of a drug throughout the body. AREAS COVERED IN THIS REVIEW: This review covers three luciferase assay systems: the multicolor luciferase assay, secreted luciferase assay and imaging luciferase assay. These assays are applied to drug screening in vitro, in cellulo and in vivo. WHAT THE READER WILL GAIN: Different solutions for reporter assay in vitro, in cellulo and in vivo are presented. A suitable bioluminescence system depending on the assay purpose is also discussed. TAKE HOME MESSAGE: Bioluminescence is a manifold system based on the different types of luciferin and its luciferase. Namely, luciferin catalyzed by corresponding luciferases resulted in the production of different color lights. We must understand the manifold mechanisms of bioluminescence reaction. PMID- 22823260 TI - Orthotopic mouse models expressing fluorescent proteins for cancer drug discovery. AB - IMPORTANCE OF THE FIELD: Currently used rodent tumor models, including transgenic tumor models, or subcutaneously growing human tumors in immunodeficient mice, do not sufficiently represent clinical cancer, especially with regard to metastasis and drug sensitivity. AREAS COVERED IN THIS REVIEW: To obtain clinically accurate models, we have developed the technique of surgical orthotopic implantation (SOI) to transplant histologically intact fragments of human cancer, including tumors taken directly from the patient, to the corresponding organ of immunodeficient rodents. SOI allows the growth and metastatic potential of the transplanted tumors to be expressed and reflects clinical cancer of all types. Effective drugs can be discovered and evaluated in the SOI models utilizing human tumor cell lines and patient tumors. Visualization of many aspects of cancer initiation and progression in vivo has been achieved with fluorescent proteins. Tumors and metastases in the SOI models that express fluorescent proteins can be visualized noninvasively in intact animals, greatly facilitating drug discovery. WHAT THE READER WILL GAIN: This review will provide information on the imageable mouse models of cancer that are clinically relevant, especially regarding metastasis and their use for drug discovery and evaluation. TAKE HOME MESSAGE: SOI mouse models of cancer reproduce the features of clinical cancer. PMID- 22823261 TI - Targeting kinases for the treatment of inflammatory diseases. AB - IMPORTANCE OF THE FIELD: Inflammatory diseases are one of the major health issues and have become a major focus in the pharmaceutical and biotech industries. To date, drugs prescribed for treatment of these diseases target enzymes that are not specific to the immune system resulting in adverse effects. The main challenge of this research field is, therefore, identifying targets that act specifically on the diseased tissue. AREAS COVERED IN THIS REVIEW: This review summarizes drug discovery efforts on kinases that have been identified as key players mediating inflammation and autoimmune disorders. In particular, we discuss recent developments on well-established targets such as mammalian target of rapamycin, JAK3, spleen tyrosine kinase, p38alpha and lymphocyte specific kinase but provide also a perspective on emerging targets. WHAT THE READER WILL GAIN: The reader will obtain an overview of drug discovery efforts on kinases in inflammation, recent clinical and preclinical data and developed inhibitor scaffolds. In addition, the reader will be updated on issues in target validation of current drug targets and the potential of selected novel kinase targets in this important disease area. TAKE HOME MESSAGE: Cellular signaling networks that regulate inflammatory response are still poorly understood making rational selection of targets challenging. Recent data suggest that kinase targets that are specific to the immune system and mediate signals immediately downstream of surface receptors are most efficacious in the clinic. PMID- 22823262 TI - Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance. AB - IMPORTANCE OF THE FIELD: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) expanded spectrum of activity and iii) reduced potential for generating bacterial resistance. AREAS COVERED IN THIS REVIEW: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compounds with emphases on their potential to reduce resistance development. WHAT THE READER WILL GAIN: Recently developed synergistic and antagonistic antibacterial drug drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Additionally, we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances. TAKE HOME MESSAGE: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compounds are entering clinical trials. However, the key challenge in this area should be a broader experimental demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug. PMID- 22823263 TI - Lab-on-a-Chip European Congress 2010. AB - On 25 and 26 May 2010, the fourth Lab-on-a-Chip European Congress took place in Dublin, Ireland. This article reviews some key presentations as well as the overall trends observed in the field of microfluidics as presented in this conference. While, as in most microfluidic conferences, no spectacular innovations have been presented indicating a certain maturing of the technology, the widening impact of microfluidics technology in a large variety of application fields can be observed. This was reflected in the multitude of applications presented covering fields as diverse as sport science, protein crystallisation, biosensors in a large variety, cell-based assays and point-of-care diagnostics. PMID- 22823264 TI - Erratum. PMID- 22823266 TI - Predicting possible effects of H2S impurity on CO2 transportation and geological storage. AB - For CO(2) geological storage, permitting impurities, such as H(2)S, in CO(2) streams can lead to a great potential for capital and energy savings for CO(2) capture and separation, but it also increases costs and risk management for transportation and storage. To evaluate the cost-benefits, using a recently developed model (Ji, X.; Zhu, C. Geochim. Cosmochim. Acta 2012, 91, 40-59), this study predicts phase equilibria and thermodynamic properties of the system H(2)S CO(2)-H(2)O-NaCl under transportation and storage conditions and discusses potential effects of H(2)S on transportation and storage. The prediction shows that inclusion of H(2)S in CO(2) streams may lead to two-phase flow. For H(2)S CO(2) mixtures, at a given temperature, the bubble and dew pressures decrease with increasing H(2)S content, while the mass density increases at low pressures and decreases at high pressures. For the CO(2)-H(2)S-H(2)O system, the total gas solubility increases while the mass density of the aqueous solution with dissolved gas decreases. For the CO(2)-H(2)S-H(2)O-NaCl system, at a given temperature, pressure and NaCl concentration, the solubility of the gas mixture in aqueous phase increases with increasing H(2)S content and then decreases, while the mass density of aqueous solution decreases and may be lower than the mass density of the solution without gas dissolution. PMID- 22823265 TI - Bioinformatic analysis of responsive genes in two-dimension and three-dimension cultured human periodontal ligament cells subjected to compressive stress. AB - BACKGROUND AND OBJECTIVE: Analyzing responses of human periodontal ligament cells to mechanical stress and mechanotransduction is important for understanding periodontal tissue physiology and remodeling. It has been shown that the cellular response to mechanical stress can vary according to the type and duration of force and to extracellular attachment conditions. This study investigated the gene-expression profile of human periodontal ligament cells cultured in two dimension (2D) and three-dimension (3D) conditions after application of compressive stress for 2 and 48 h. MATERIAL AND METHODS: Human primary periodontal ligament cells were obtained from premolars extracted for orthodontic purposes. Cells were cultured in a conventional 2D culture dish or in 3D collagen gel and compressive stress was applied for 2 and 48 h. Control cells were cultured under identical conditions but without the application of compressive stress. After the application of compressive stress, total RNA was extracted and a cDNA microarray was performed. Microarray data were analyzed using statistical methods, including david and gene set enrichment analysis to identify significant signaling pathways. Real-time PCR was performed for five mRNAs in order to confirm the cDNA microarray results. RESULTS: The cDNA microarray analysis revealed that after application of compressive stress for 2 h, 191 and 553 genes showed changes in their expression levels in 2D and 3D cultured cells, respectively. After application of compressive stress for 48 h, 280 and 519 genes showed changes in their expression levels in 2D and 3D cultured cells, respectively. Euclidean clustering method was used to demonstrate the gene expression kinetics. CONCLUSION: Analysis of the results showed that several signaling pathways, including the MAPK pathway and the focal adhesion kinase pathway are relevant to the compressive force-induced cellular response. 2D and 3D cultured cells showed significantly different gene-expression profiles, suggesting that cellular attachment to extracellular matrix influences cellular responses to mechanical stresses. PMID- 22823267 TI - Enantioselective rhodium-catalyzed synthesis of alpha-chloromethylene-gamma butyrolactams from N-allylic alkynamides. AB - The first enantioselective cycloisomerization with intramolecular halogen migration of various 1,6-enynes promoted by a cationic Rh-Synphos catalyst is reported. This method provides an efficient route to enantiomerically enriched gamma-butyrolactam derivatives, which are important core scaffolds found in numerous natural products and biologically active molecules. Good yields and enantiomeric excesses up to 96% are achieved. PMID- 22823268 TI - Force-induced selective dissociation of noncovalent antibody-antigen bonds. AB - Specific noncovalent binding between antibody and antigen molecules is the basis for molecular recognition in biochemical processes. Quantitative investigation of the binding forces could lead to molecular specific analysis and potentially mechanical manipulation of these processes. Using our force-induced remnant magnetization spectroscopy, we revealed a well-defined binding force for the bonds between mouse immunoglobulin G and magnetically labeled alpha-mouse immunoglobulin G. The force was calibrated to be 120 +/- 15 pN. In comparison, the binding force was only 17 +/- 3 pN for physisorption and much higher than 120 pN for biotin-streptavidin bonds. A unique rebinding method was used to confirm the dissociation of the antibody-antigen bonds. A well-defined and molecule specific binding force opens a new avenue for distinguishing different noncovalent bonds in biochemical processes. PMID- 22823269 TI - Pattern of adhesion molecule expression in labial salivary glands from patients with primary Sjogren's syndrome. AB - The aim of this work was to examine the pattern of distribution of adhesion molecules in minor salivary glands from patients with primary Sjogren's syndrome (SS). Labial salivary gland (LSG) biopsies from 31 patients with primary SS and 21 normal subjects were examined. Cryostat sections were examined with monoclonal antibodies to different adhesion molecules using an indirect immunoperoxidase technique. There was an increased expression of ICAM-1, class IMHC, HLA-DR & DQ (p<0.05) on endothelial cells, lymphocytes, fibroblasts and salivary epithelial cells (HLA-DR far exceeds ICAM-1 (limited) epithelial expression). ELAM-1 and to a lesser extent VCAM-1 were demonstrated over some of the endothelial cells in patients, but not in controls (p<0.01). Many of the endothelial cells expressing ICAM-1, DR, DQ, ELAM-1 were high endothelial venules. CD44 was strongly expressed over epithelial cells, endothelial and infiltrating mononuclear cells, while LFA 3 was present mainly on epithelial cells, and faintly on infiltrating inflammatory cells. There was no difference between patients and controls with regard to CD44 or LFA-3 expression. The ligands for the above mentioned adhesion molecules, namely LFA-1alpha, LFA-1beta, LECAM-1, VLA-4beta(CD49d), CD44 and CD2 were demonstrated (variably) on the surface of infiltrating lymphocytes. CD11b and CD11c were detected over monocytes/macrophages. A proportion of lymphocytes expressed VCAM-1 and CD11c and may function as antigen presenting cells. In some biopsies these molecules were localized at the center of lymphoid follicles with the appearance of dendritic cells. Although the majority of lymphocytes were activated and strongly expressing DR and ICAM-1, they were IL-2Ralpha (CD25) negative. We conclude that adhesion molecules are prominent in LSG of patients with primary SS. They may play a major role by mediating the lymphocytic infiltration to the glands, retaining the lymphocytes in the glands and regulating the different immune responses in the local microenvironment of this chronic inflammatory disease. PMID- 22823270 TI - Clinical study on patients with Behcet's disease in Hokkaido. AB - Behcet's disease is the most frequently encountered form of endogenous uveitis in Japan. The authors examined the clinical manifestations in cases with Behcet's disease over six years (1987-1992), and compared the results with those of a previous study (1978-1983). In the more recent study the number of new patients who visited our clinic was 54, compared to 180 in the previous study. As for the frequencies of the four major symptoms in the recent study, oral aphtha were seen in 100%, skin lesions in 88.9%, ocular lesions in 74.0%, and genital ulcers in 61.1% of the patients. The frequencies of these major symptoms were not significantly different between the two time periods investigated. Analysis of the type of ocular involvement showed that 94.4% of the patients in the more recent study belonged to the uveoretinitis type and 5.6% of the patients belonged to the iridocyclitis type, whereas in the previous study the figures were 71.5% and 28.5%, respectively. The ratio of the patients with severe eye involvement has increased recently. However the visual prognosis of patients was better in the more recent study than in the previous study. In the previous study a marked decrease in visual acuity was observed during a two-year follow-up, whereas in the 1987-1992 period it was observed that visual acuity hardly changed over two years. The observed improvement in the visual prognosis may be due to the fact that the treatment of Behcet's disease has become more effective in recent years. PMID- 22823271 TI - Intraocular contamination during extracapsular cataract extraction with intraocular lens implantation. AB - Ocular bacterial contamination has been studied in 45 eyes that underwent cataract surgery. The following samples were taken: (1) eyelid margin swab; (2) conjunctival swab; (3) aqueous humor after initial anterior chamber penetration; (4) anterior capsule fragment after capsulorrhexis or capsulotomy; (5) cortical lens material; (6) anterior chamber fluid after lens implantation. The percentages of contaminated samples were 15.5, 13.3, 0.0, 11.1, 13.3 and 6.6, respectively. There was a significant difference between the incidence of positive cultures in the aqueous humor at the time of incision and in subsequent intraocular samples. Positive cultures were found in 13 out of 45 eyes, only gram positive organisms were recovered and coagulase-negative staphylococci were the most common (78.5% of the isolates). These results confirm previous reports on intraocular contamination during cataract surgery. PMID- 22823272 TI - Analysis of neutralizing antibodies to Enterovirus 70 and Coxsackievirus A24 variant, levels of immunoglobulins and total protein in tears of patients with acute hemorrhagic conjunctivitis. AB - Tear samples were collected from 37 residents of the Dominican Republic <5 d post onset (p.o.) of symptoms (mean 1.73+/-1.17 d p.o.) of acute hemorrhagic conjunctivitis (AHC). Sixty-two percent (23/37) of the patients had bilateral infections. Anti-enterovirus 70 (EV70) tear neutralizing activity (TNA) (10(2 >3.5) U/ml) and anti-Coxsackievirus A24 variant (CA24v) TNA (10(<1-3) U/ml), but no anti-poliovirus (PV) TNA was detected. The anti-EV70 TNA in pooled tear samples sedimented in sucrose density gradient fractions that corresponded to 19 7S serum anti-PV immunoglobulin (1g). Anti-CA24v TNA sedimented as 7S1g. 1gG levels (mean, 3.13+/-4.2mg/ml) were higher than 1gA levels (mean, 0.92+/-0.98 mg/ml) in 21 of 27 tear samples. 1gG levels in tears from six patients with bilateral AHC were associated with total tear protein (p=0.003), but not with the levels of TNA or interferon (IFN). The total protein in AHC tears (5.13+/-1.72 mg/ml) was two-fold less than the total protein in normal tears (11.2+/-3.25 mg/ml). 1gA levels increased from 0.31+/-.3 to 1.34+/-1.28 mg/ml in tears collected up to 3 d p.o. of AHC. 1gM was not detected (<0.01 mg/ml). EV70 was isolated from the tears of one patient. Taken together, our results suggest that EV70 and CA24v are endemic in the Dominican Republic and that the 1992 epidemic of AHC was due to EV70. The detection of 19S (IgM) and high levels of 7S (IgG) TNA to EV70<1 d p.o. of AHC indicate a rapid ocular immune response to EV70 and suggests that virus-specific TNAs inhibit AHC virus infection. PMID- 22823273 TI - Retinal antigen-specific T cells mediate experimental autoimmune uveoretinitis (EAU) in PVG rat a model for tracking antigen-specific CD4(+) T cells in the inflamed eye. AB - Experimental autoimmune uveoretinitis (EAU) is a CD(4)(+) T cell mediated organ specific model of autoimmune disease and is considered a good model of posterior uveitis in man. Previously it has been shown that EAU may be induced in Lewis rats by adoptive transfer of small numbers of retinal antigen-specific CD(4)(+) T cell lines where recruitment of naive T cells is integral to the pathogenesis of uveitis. In order to assess the role of antigen-specific CD(4)(+) T cells in EAU, a model of passively induced EAU has been developed in which retinal extract specific T cell lines were generated from lymph nodes of immunised PVG-RT(7)(b) rats and maintained with alternating cycles of stimulation with retinal extract presented on syngeneic accessory cells and proliferation in IL-2 rich media. The antigen-specific cell line can be categorised phenotypically by the CD(4)(+) IL 2R(+) OX(42)-OX8- cell surface expression. All cells expressed on their cell surface RT7.2 allotype of CD(45) antigen specific for PVG-RT(7)(b) strain, so that when EAU was induced by adoptive transfer with as little as 5X10(6) cells to PVG-RT(7)(a) recipients, antigen-specific cells of donor allotype (CD(4)(+) RT(7.2)(+)) may be tracked in the recipient (RT(7.1)(+) allotype). This preliminary report describes the isolation of antigen-specific (donor) T cells from the retina in early stages of passively-induced EAU, a model which can now be adopted to investigate the role different populations of cells play in the pathogenesis of EAU. PMID- 22823274 TI - American Uveitis Society Meeting, May 13,1995 Fort Lauderdale, FL, USA. AB - 1 Confirmation of Bartonella henselae as the cause of cat scratch related acute neuroretinitis and prospective observation to its response to oral doxycycline and rifampin. Reed B, Smith R, Dolan M, Wong M, Scales D, Department of Ophthalmology & Infectious Disease, Wilford Hall Medical Center, Lackland AFB, TX, USA. 2 Recurrence rate of CMV retinitis in patients following pars plana vitrectomy and silicone oil injection. Marx JL, Thach AB, Reingold W, Terry B, Rao NA, Chong LP. Doheny Eye Institute, Los Angeles, CA, USA. 3 A PCR based assay for the diagnosis of AIDS related VZV retinitis. Margolis T, Short G, Schwartz D, Irvine A, Martin D, Francis I. Proctor Foundation, San Francisco, CA, USA. 4 Presumptive ocular sarcoidosis. Dodds EM, Lowder CY, Meisler DM. Division of Ophthalmology, Cleveland, OH, USA. 5 Prevalence of uveitis in an outpatient juvenile arthritis clinic. Akduman L, Tychsen L, Kaplan HJ, Washington University, St. Louis, MO, USA. 6 The role of choroidal dendritic cells in the pathogenesis of experimental autoimmune uveoretinitis. Choudhury A, Padhye NS, Caspi RR, Bowers WE, University of South Carolina School of Medicine, Columbia, S.C. and The National Eye Institute, Bethesda, MD, USA. PMID- 22823275 TI - From whispering to RoAring: engaging undergraduate nursing students in research. PMID- 22823276 TI - Graphene: the game changer? PMID- 22823278 TI - Metabolism and metabolites of dithiocarbamates in the plant pathogenic fungus Leptosphaeria maculans. AB - Synthetic compounds containing a dithiocarbamate group are known to have a variety of biological effects and applications including antifungal, herbicidal, and insecticidal application. Leptosphaeria maculans is a fungal pathogen of crucifers able to detoxify efficiently the only plant natural product containing a dithiocarbamate group, the phytoalexin brassinin. To evaluate the effects of dithiocarbamates on L. maculans, a number of structurally diverse S-methyl dithiocarbamates containing indolyl, biphenyl, and benzimidazolyl moieties were synthesized, and their antifungal activities and metabolism by L. maculans were investigated. All dithiocarbamates were transformed by L. maculans through hydrolysis to the corresponding amines, which were less antifungal than the parent compounds. Two dithiocarbonates were shown to be much less antifungal than the corresponding dithiocarbamates. Results of this investigation indicate that S methyl dithiocarbamates are not useful inhibitors of L. maculans and that their rates of transformation by L. maculans did not correlate with the antifungal activity of the particular compound. PMID- 22823279 TI - What are the symptoms of internal rectal prolapse? AB - AIM: Although high-grade internal rectal prolapse is believed to cause functional symptoms such as obstructed defaecation, little has been published on the exact distribution and frequency of symptoms. The aim of this study was to identify the most common symptoms of patients with high-grade internal rectal prolapse. METHOD: Patients were diagnosed with high-grade prolapse (grade 3 and 4) on proctography using the Oxford Rectal Prolapse Grade. Information from a prospectively collected database was supplemented by a retrospective case note review. RESULTS: Eighty eight patients (94% of them women) were included for analysis. Faecal incontinence (56%) was the most common symptom at presentation. Symptoms related to obstructed defaecation syndrome were the next most common, including incomplete evacuation (45%), straining (34%), digital assistance (34%) and repetitive toilet visits (33%). CONCLUSION: A variety of symptoms may be caused by high-grade internal rectal prolapse Although symptoms of obstructed defaecation were frequent, urge faecal incontinence was the most common. PMID- 22823280 TI - Ablation of atrial flutter in severe pulmonary hypertension: pushing the outside of the envelope. PMID- 22823281 TI - Invasive lymphatic malformation (gorham-stout) of the pelvis with prominent skin involvement. AB - Gorham-Stout syndrome is a rare disease characterized by progressive osteolysis leading to disappearance of the bone. Vascular proliferations have been implicated in the pathogenesis of this syndrome. The case of a 7-year-old girl with a prominent invasive lymphatic malformation on the lumbosacral area and massive osteolysis of the pelvic girdle is reported. PMID- 22823282 TI - A text-mining system for extracting metabolic reactions from full-text articles. AB - BACKGROUND: Increasingly biological text mining research is focusing on the extraction of complex relationships relevant to the construction and curation of biological networks and pathways. However, one important category of pathway - metabolic pathways - has been largely neglected.Here we present a relatively simple method for extracting metabolic reaction information from free text that scores different permutations of assigned entities (enzymes and metabolites) within a given sentence based on the presence and location of stemmed keywords. This method extends an approach that has proved effective in the context of the extraction of protein-protein interactions. RESULTS: When evaluated on a set of manually-curated metabolic pathways using standard performance criteria, our method performs surprisingly well. Precision and recall rates are comparable to those previously achieved for the well-known protein-protein interaction extraction task. CONCLUSIONS: We conclude that automated metabolic pathway construction is more tractable than has often been assumed, and that (as in the case of protein-protein interaction extraction) relatively simple text-mining approaches can prove surprisingly effective. It is hoped that these results will provide an impetus to further research and act as a useful benchmark for judging the performance of more sophisticated methods that are yet to be developed. PMID- 22823283 TI - Laboratory evaluation of rapid test kits to detect hepatitis C antibody for use in predonation screening in emergency settings. AB - BACKGROUND: Emergency whole blood transfusion is a lifesaving procedure employed on modern battlefields. Rapid device tests (RDTs) are frequently used to mitigate transfusion-transmitted infection risks. STUDY DESIGN AND METHODS: A limited evaluation of the RDT formerly used on battlefields was performed using 50 donor plasma samples and commercially available panels. Five hepatitis C virus (HCV) RDTs with sufficient stated sensitivity and thermostability were assessed using 335 HCV-positive and 339 HCV-negative donor plasma samples, 54 seroconversion panel plasma samples, and 84 HCV-positive and 84 HCV-negative spiked whole blood under normal, hot, and cold storage conditions and normal and hot test conditions, plus an ease-of-use survey. RESULTS: BioRapid HCV test sensitivity on donor plasma was 84% (95% confidence interval [CI], 70.9%-92.8%). Using all positive plasma samples, OraQuick HCV sensitivity exceeded all comparators (99.4%, 95% CI, 98.0%-99.9%, p<0.05). Specificity was consistently high, led by OraQuick HCV at 99.7% (95% CI, 98.6%-100%), statistically superior only to Axiom HCV (p<0.05). Using seroconversion panels, only OraQuick HCV showed equivalent or earlier HCV detection compared to the gold standard. Using spiked whole blood, specificity was consistently high, and sensitivity ranged significantly from 34.5% (95% CI, 25.0%-45.1%) for CORE HCV to 98.8% (95% CI, 94.3%-99.9%) for OraQuick HCV. All comparator RDTs were significantly less sensitive than OraQuick HCV at one or more stress condition. CONCLUSION: This HCV RDT comparison identified significant sensitivity differences, particularly using whole blood under extreme storage and testing conditions. These data support OraQuick HCV superiority and illustrate the value of RDT evaluation under simulated field conditions. PMID- 22823285 TI - Understanding solvent effects in vibrational circular dichroism spectra: [1,1' binaphthalene]-2,2'-diol in dichloromethane, acetonitrile, and dimethyl sulfoxide solvents. AB - We present a combined experimental and computational investigation of the vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of [1,1'-binaphthalene]-2,2'-diol. First, the sensitive dependence of the experimental VA and VCD spectra on the solvent is demonstrated by comparing the experimental spectra measured in CH(2)Cl(2), CD(3)CN, and DMSO-d(6) solvents. Then, by comparing calculations performed for the isolated solute molecule to calculations performed for molecular complexes formed between solute and solvent molecules, we identify three main types of perturbations that affect the shape of the VA and VCD spectra when going from one solvent to another. These sources of perturbations are (1) perturbation of the Boltzmann populations, (2) perturbation of the electronic structure, and (3) perturbation of the normal modes. PMID- 22823284 TI - Secondary organic aerosol formation from intermediate-volatility organic compounds: cyclic, linear, and branched alkanes. AB - Intermediate volatility organic compounds (IVOCs) are an important class of secondary organic aerosol (SOA) precursors that have not been traditionally included in chemical transport models. A challenge is that the vast majority of IVOCs cannot be speciated using traditional gas chromatography-based techniques; instead they are classified as an unresolved complex mixture (UCM) that is presumably made up of a complex mixture of branched and cyclic alkanes. To better understand SOA formation from IVOCs, a series of smog chamber experiments was conducted with different alkanes, including cyclic, branched, and linear compounds. The experiments focused on freshly formed SOA from hydroxyl (OH) radical-initiated reactions under high-NO(x) conditions at typical atmospheric organic aerosol concentrations (C(OA)). SOA yields from cyclic alkanes were comparable to yields from linear alkanes three to four carbons larger in size. For alkanes with equivalent carbon numbers, branched alkanes had the lowest SOA mass yields, ranging between 0.05 and 0.08 at a C(OA) of 15 MUg m(-3). The SOA yield of branched alkanes also depends on the methyl branch position on the carbon backbone. High-resolution aerosol mass spectrometer data indicate that the SOA oxygen-to-carbon ratios were largely controlled by the carbon number of the precursor compound. Depending on the precursor size, the mass spectrum of SOA produced from IVOCs is similar to the semivolatile-oxygenated and hydrocarbon like organic aerosol factors derived from ambient data. Using the new yield data, we estimated SOA formation potential from diesel exhaust and predict the contribution from UCM vapors to be nearly four times larger than the contribution from single-ring aromatics and comparable to that of polycyclic aromatic hydrocarbons after several hours of oxidation at typical atmospheric conditions. Therefore, SOA from IVOCs may be an important contributor to urban OA and should be included in SOA models; the yield data presented in this study are suitable for such use. PMID- 22823286 TI - Striking a balance. PMID- 22823287 TI - Getting the most out of living abroad: biculturalism and integrative complexity as key drivers of creative and professional success. AB - The current research investigated how patterns of home and host cultural identification can explain which individuals who have lived abroad achieve the greatest creative and professional success. We hypothesized that individuals who identified with both their home and host cultures (i.e., biculturals) would show enhanced creativity and professional success compared with individuals who identified with only a single culture (i.e., assimilated and separated individuals). Further, we expected that these effects would be driven by biculturals' greater levels of integrative complexity, an information processing capacity that involves considering and combining multiple perspectives. Two studies demonstrated that biculturals exhibited more fluency, flexibility, and novelty on a creative uses task (Study 1) and produced more innovations at work (Study 2) than did assimilated or separated individuals. Study 3 extended these findings to general professional outcomes: Bicultural professionals achieved higher promotion rates and more positive reputations compared with assimilated or separated individuals. Importantly, in all 3 studies, integrative complexity mediated the relationship between home/host identification and performance. Overall, the current results demonstrate who is most likely to achieve professional and creative success following experiences abroad and why. PMID- 22823288 TI - Fearless dominance and the U.S. presidency: implications of psychopathic personality traits for successful and unsuccessful political leadership. AB - Although psychopathic personality (psychopathy) is marked largely by maladaptive traits (e.g., poor impulse control, lack of guilt), some authors have conjectured that some features of this condition (e.g., fearlessness, interpersonal dominance) are adaptive in certain occupations, including leadership positions. We tested this hypothesis in the 42 U.S. presidents up to and including George W. Bush using (a) psychopathy trait estimates derived from personality data completed by historical experts on each president, (b) independent historical surveys of presidential leadership, and (c) largely or entirely objective indicators of presidential performance. Fearless Dominance, which reflects the boldness associated with psychopathy, was associated with better rated presidential performance, leadership, persuasiveness, crisis management, Congressional relations, and allied variables; it was also associated with several largely or entirely objective indicators of presidential performance, such as initiating new projects and being viewed as a world figure. Most of these associations survived statistical control for covariates, including intellectual brilliance, five factor model personality traits, and need for power. In contrast, Impulsive Antisociality and related traits of psychopathy were generally unassociated with rated presidential performance, although they were linked to some largely or entirely objective indicators of negative job performance, including Congressional impeachment resolutions, tolerating unethical behavior in subordinates, and negative character. These findings indicate that the boldness associated with psychopathy is an important but heretofore neglected predictor of presidential performance, and suggest that certain features of psychopathy are tied to successful interpersonal behavior. PMID- 22823289 TI - Analysis of sensitive questions across cultures: an application of multigroup item randomized response theory to sexual attitudes and behavior. AB - Answers to sensitive questions are prone to social desirability bias. If not properly addressed, the validity of the research can be suspect. This article presents multigroup item randomized response theory (MIRRT) to measure self reported sensitive topics across cultures. The method was specifically developed to reduce social desirability bias by making an a priori change in the design of the survey. The change involves the use of a randomization device (e.g., a die) that preserves participants' privacy at the item level. In cases where multiple items measure a higher level theoretical construct, the researcher could still make inferences at the individual level. The method can correct for under- and overreporting, even if both occur in a sample of individuals or across nations. We present and illustrate MIRRT in a nontechnical manner, provide WinBugs software code so that researchers can directly implement it, and present 2 cross national studies in which it was applied. The first study compared nonstudent samples from 2 countries (total n = 927) on permissive sexual attitudes and risky sexual behavior and related these to individual-level characteristics such as the Big Five personality traits. The second study compared nonstudent samples from 17 countries (total n = 6,195) on risky sexual behavior and related these to individual-level characteristics, such as gender and age, and to country-level characteristics, such as sex ratio. PMID- 22823290 TI - Binds and bounds of communion: effects of interpersonal values on assumed similarity of self and others. AB - Assumed similarity refers to ascribing similar attributes to the self and others. Because self-other similarity facilitates communion, people who value communion should be prone to assume self-other similarity; but because self-other similarity also evokes obligation, they may be prone to assume similarity only with others with whom they are or would feel comfortable being interconnected. We tested these hypotheses in 5 studies (total N = 1,709). In Study 1, students indicated their political preferences and estimated other students' preferences. In Studies 2-5, students described their personality and the personalities of the following targets: actual or imagined romantic partners in Study 2; ingroup members (students from the respondents' university) and outgroup members (students from a foreign university) in Studies 3-4; and specific liked and disliked others in Study 5. As hypothesized, people with stronger communal values were more likely to assume self-other similarity with liked others, romantic partners, and ingroup members, but not with disliked others and outgroup members. These effects replicated across different cultures (India, Korea, and the United States) and remained significant when controlling for self-esteem, national identification, and attribute desirability. Although people who valued communion tended to depict themselves and liked and ingroup others in relatively normative (typical) ways, which partially explained assumptions of similarity and indicated that those assumptions were to some extent accurate, communal values continued to predict distinctive self-other similarity or "false consensus" even after controlling for the normative prevalence of attributes. PMID- 22823291 TI - Enjoying life in the face of death: East-West differences in responses to mortality salience. AB - Five experiments explored the hypothesis that thinking about one's own death activates thoughts about enjoying one's life as moderated by culture. Given that Eastern cultures, relative to Western ones, are more holistic and endorse notions of "yin and yang" (e.g., where "good" and "bad" coexist in all things), we hypothesized that East Asians would be more likely than European Americans to think about life and strive more to enjoy life when mortality salience (MS) is evoked. As predicted, MS led East Asians, but not European Americans, to (a) activate more life-related thoughts (Study 1); (b) express greater interest in enjoyable daily life activities (Study 2); and (c) report enjoying daily life activities more (Study 3). Cultural differences in holism mediated the tendency to enjoy life in the face of death (Study 4), and experimental induction of holism caused greater life enjoyment in response to MS (Study 5). Implications for terror management theory and culture are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22823292 TI - Refining the theory of basic individual values. AB - We propose a refined theory of basic individual values intended to provide greater heuristic and explanatory power than the original theory of 10 values (Schwartz, 1992). The refined theory more accurately expresses the central assumption of the original theory that research has largely ignored: Values form a circular motivational continuum. The theory defines and orders 19 values on the continuum based on their compatible and conflicting motivations, expression of self-protection versus growth, and personal versus social focus. We assess the theory with a new instrument in 15 samples from 10 countries (N = 6,059). Confirmatory factor and multidimensional scaling analyses support discrimination of the 19 values, confirming the refined theory. Multidimensional scaling analyses largely support the predicted motivational order of the values. Analyses of predictive validity demonstrate that the refined values theory provides greater and more precise insight into the value underpinnings of beliefs. Each value correlates uniquely with external variables. PMID- 22823293 TI - Sex begets violence: mating motives, social dominance, and physical aggression in men. AB - There are sizable gender differences in aggressive behavior, with men displaying a much higher propensity for violence than women. Evolutionary theories suggest that men's more violent nature derives in part from their historically greater need to compete over access to potential mates. The current research investigates this link between mating and male violence and provides rigorous experimental evidence that mating motives cause men to behave violently toward other men. In these studies, men and women were primed with a mating motive and then performed a noise-blast aggression task. Being primed with mating led men, but not women, to deliver more painful blasts of white noise to a same-sex partner (but not an opposite-sex partner). This effect was particularly pronounced among men with an unrestricted sociosexual orientation, for whom competition over access to new mates is an especially relevant concern. Findings also suggest that mating induced male violence is motivated by a desire to assert one's dominance over other men: when men were given feedback that they had won a competition with their partner (and thus had achieved dominance through nonaggressive means), the effect of the mating prime on aggression was eliminated. These findings provide insight into the motivational roots of male aggression and illustrate the value of testing theories from evolutionary biology with rigorous experimental methods. PMID- 22823294 TI - Does co-payment rate influence the relationship between monthly salary and health care service demand among the insured of health insurance societies in Japan? AB - The co-payment rate for health care services for insured people increased from 10% to 20% in 1997, and then to 30% in 2003 under the Employed Health Insurance System in Japan. The purpose of this study is to quantify the relationship between average monthly salary and health care service demand by different co payment rates among the insured of health insurance societies in Japan. Data from the National Federation of Health Insurance Societies from 1996, 2002, and 2007 were analyzed. Indicators of health care service demand included case rates and number of service days per case for inpatient, outpatient, and dental services. The authors evaluated the relationship of average monthly salary with these indicators using multiple regression analyses for each of the 3 years. In the study, the average monthly salary showed a high positive correlation with outpatient and dental case rates for all 3 years. The magnitude of the relationship of average monthly salary to health care service demand was intensified as patient co-payment increased from 10% to 20%. However, it did not change when the co-payment increased from 20% to 30%. The increase in patient co payment rate from 20% to 30% did not intensify the relationship between average monthly salary and health care service demand among the insured of health insurance societies in Japan. PMID- 22823323 TI - Absolute configurations of unique harziane diterpenes from Trichoderma species. AB - Harzianone (2), a new harziane diterpene, was isolated from an alga-endophytic isolate of Trichoderma longibrachiatum. The structure and absolute configuration of 2 were unambiguously identified by NMR and mass spectrometric methods as well as quantum chemical calculations. The absolute configuration of harziandione (1) was supported by calculation of optical rotation, and the structure of isoharziandione was revised to 1 on the basis of (13)C NMR data comparison and calculation. PMID- 22823322 TI - Glutamatergic input to the lateral hypothalamus stimulates ethanol intake: role of orexin and melanin-concentrating hormone. AB - BACKGROUND: Glutamate (GLUT) in the lateral hypothalamus (LH) has been suggested to mediate reward behaviors and may promote the ingestion of drugs of abuse. This study tested the hypothesis that GLUT in the LH stimulates consumption of ethanol ( EtOH ) and that this effect occurs, in part, via its interaction with local peptides, hypocretin/orexin (OX), and melanin-concentrating hormone (MCH). METHODS: In Experiments 1 and 2, male Sprague-Dawley rats, after being trained to drink 9% EtOH , were microinjected in the LH with N-methyl-d-aspartate (NMDA) or its antagonist, D-AP5, or with alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid (AMPA) or its antagonist, CNQX-ds. Consumption of EtOH , chow, and water was then measured. To provide an anatomical control, a separate set of rats was injected 2 mm dorsal to the LH. In Experiment 3, the effect of LH injection of NMDA and AMPA on the expression of OX and MCH was measured using radiolabeled in situ hybridization (ISH) and also using digoxigenin-labeled ISH, to distinguish effects on OX and MCH cells in the LH and the nearby perifornical area (PF) and zona incerta (ZI). RESULTS: When injected into the LH, NMDA and AMPA both significantly increased EtOH intake while having no effect on chow or water intake. The GLUT receptor antagonists had the opposite effect, significantly reducing EtOH consumption. No effects were observed with injections 2 mm dorsal to the LH. In addition to these behavioral effects, LH injection of NMDA significantly stimulated expression of OX in both the LH and PF while reducing MCH in the ZI, whereas AMPA increased OX only in the LH and had no effect on MCH. CONCLUSIONS: Glutamatergic inputs to the LH, acting through NMDA and AMPA receptors, appear to have a stimulatory effect on EtOH consumption, mediated in part by increased OX in LH and PF and reduced MCH in ZI. PMID- 22823324 TI - Peripheral corneal endotheliopathy and pars planitis. AB - A peripheral corneal endotheliopathy (PCE), named autoimmune endotheliopathy was described in association with corneal graft rejection and as an isolated corneal alteration unrelated to surgery, trauma, or infection. It has also been found in patients with pars planitis (PP), but the significance of this association is unknown. The authors retrospectively reviewed the clinical charts of 53 PP patients (106 eyes) examined at the Uveitis Clinic from 1988 to 1993. Special attention was paid to the description of corneal clinical findings. PCE was found in 18.8+ of the eyes, and of these, 70+ showed bilateral involvement. The presence of PCE was not related to PP severity, but PCE was more frequently seen in younger patients. This descriptive study shows that identification of PCE may aid in the diagnosis of childhood PP. PMID- 22823325 TI - Nicardipine inhibits acute rise of aqueous flare and intraocular pressure induced by argon laser photocoagulation. AB - The purpose of this study was to examine the anti-inflammatory effect of the calcium channel blocker nicardipine. Intraocular inflammation was induced by argon laser photocoagulation of the iris of pigmented rabbits and was assessed by measuring aqueous flare and intraocular pressure. This resulted in a marked increase in the aqueous flare that peaked at approximately one hour following coagulation and returning to the original values after six hours. Intraocular pressure increased within 15 minutes following laser treatment and returned to baseline levels at 60 minutes. Pre-treatment of the rabbits with an intravenous injection of 2 mg/kg of nicardipine completely abolished both the increase in aqueous flare and intraocular pressure induced by laser photocoagulation as compared to the control experiment. Earlier work from the author's group has shown that nicardipine can also block aqueous flare and intraocular pressure increases induced by topical administration of prostaglandin E2. From these combined experiments they would like to draw the conclusion that the inflammatory reaction induced by photocoagulation of the iris is partly mediated by prostaglandins and that blockade of calcium channels by nicardipine can inhibit the effects induced by prostaglandin E2. PMID- 22823326 TI - Hormonal support of lacrimal function, primary lacrimal deficiency, autoimmunity, and peripheral tolerance in the lacrimal gland. AB - Several causes of lacrimal insufficiency have been recognized, including Sjogren's syndrome and other immune-related processes as well as a disparate group of non-immune related disorders. However, the mechanisms underlying primary lacrimal deficiency (PLD), the most common cause of dry eye, have remained obscure. After summarizing mechanisms of lacrimal secretion and stimulus secretion coupling, the authors review the thesis that optimal lacrimal gland function depends on a hormonal milieu in which androgens play a crucial role. According to this thesis, simple acquired PLD results when bioavailable androgen levels decrease below critical values. However, it is noted that PLD also may be complicated by local autoimmune processes, and hypothetical pathways leading to such processes are discussed. Cell death following withdrawal of hormonal support may lead to processing and presentation of parenchymal cell antigens. Normal intracellular membrane traffic patterns may cause acinar cells to secrete autoantigens into the interstitium. When acinar cells have been induced to express major histocompatibility complex Class II molecules, their intracellular membrane traffic may allow them to process and present autoantigens, essentially mimicking the functions of professional antigen presenting cells. The possibility is discussed that perturbations of the spectra of released and presented autoantigens upset the equilibria of idiotypic networks arising to establish peripheral tolerance. The resulting incremental increases in lymphocytic infiltration are suggested to represent essentially cryptic autoimmune processes which may impair lacrimal secretory function and regeneration. Failure to establish peripheral tolerance is predicted to permit unrestrained CD(4) cell proliferation and an environment favoring B cell activation. Recruitment of B lymphocytes, perhaps in events influenced by re-activated viruses, is predicted to lead to Sjogren's autoimmunity as recognized by stringent diagnostic criteria. Finally, the possibility is discussed that androgen supplementation or hormone replacement therapy might prevent simple PLD and avoid the initiation of autoimmune processes. PMID- 22823328 TI - Breastfeeding among high-risk inner-city African-American mothers: a risky choice? AB - OBJECTIVE: This study identified barriers to breastfeeding among high-risk inner city African-American mothers. SUBJECTS AND METHODS: We used audiotaped focus groups moderated by an experienced International Board Certified Lactation Consultant, with recruitment supported by the community partner MomsFirstTM (Cleveland Department of Public Health, Cleveland, OH). Institutional Review Board approval and written informed consent were obtained. Notes-based analysis was conducted with use of a prior analytic structure called Factors Influencing Beliefs (FIBs), redefined with inclusion/exclusion criteria to address breastfeeding issues. RESULTS: Three focus groups included 20 high-risk inner city expectant and delivered mothers. Relevant FIBs domains were as follows: Risk Appraisal, Self Perception, Relationship Issues/Social Support, and Structural/Environmental Factors. Risk Appraisal themes included awareness of benefits, fear of pain, misconceptions, and lack of information. Self Perception themes included low self-efficacy with fear of social isolation and limited expression of positive self-esteem. Relationship Issues/Social Support themes included formula as a cultural norm, worries about breastfeeding in public, and challenging family relationships. Structural/Environmental Factors themes included negative postpartum hospital experiences and lack of support after going home. CONCLUSIONS: Several findings have been previously reported, such as fear of pain with breastfeeding, but we identified new themes, including self-esteem and self-efficacy, and new concerns, for example, that large breasts would suffocate a breastfeeding infant. The FIBs analytic framework, as modified for breastfeeding issues, creates a context for future analysis and comparison of related studies and may be a useful tool to improve understanding of barriers to breastfeeding among high-risk inner-city women. PMID- 22823329 TI - Its ovr b/n u n me: technology use, attachment styles, and gender roles in relationship dissolution. AB - Relationship dissolution now occurs through technologies like text messaging, e mail, and social networking sites (SNS). Individuals who experience relationship dissolution via technology may differ in their attachment pattern and gender role attitudes from those who have not had that experience. One hundred five college students (males=21 and females=84) completed an online questionnaire about technology-mediated breakups, attachment style, and gender role attitudes. More than a quarter of the sample had experienced relationship dissolution via technology. Attachment anxiety predicted those subject to technology-mediated breakups. Attachment avoidance and less traditional gender roles were associated with increased likelihood of technology use in relationship dissolution. Implications are discussed in regards to future research and practice. PMID- 22823330 TI - Synchrotron small-angle X-ray scattering studies of hemoglobin nonaggregation confined inside polymer capsules. AB - The effect of confinement on the structure of hemoglobin (Hb) within polymer capsules was investigated here. Hemoglobin transformed from an aggregated state in solution to a nonaggregated state when confined inside the polymer capsules. This was directly confirmed using synchrotron small-angle X-ray scattering (SAXS) studies. The radius of gyration (R(g)) and polydispersity (p) of the proteins in the confined state were smaller compared to those in solution. In fact, the R(g) value is very similar to theoretical values obtained using protein structures generated from the Protein Databank. In the temperature range (25-85 degrees C, Tm 59 degrees C), the R(g) values for the confined Hb remained constant. This observation is in contrary to the increasing R(g) values obtained for the bare Hb in solution. This suggested higher thermal stability of Hb when confined inside the polymer capsule than when in solution. Changes in protein configuration were also reflected in the protein function. Confinement resulted in a beneficial enhancement of the electroactivity of Hb. While Hb in solution showed dominance of the cathodic process (Fe(3+) -> Fe(2+)), efficient reversible Fe(3+)/Fe(2+) redox response is observed in the case of the confined Hb. This has important protein functional implications. Confinement allows the electroactive heme to take up positions favorable for various biochemical activities such as sensing of analytes of various sizes from small to macromolecules and controlled delivery of drugs. PMID- 22823331 TI - Building multivalent iminosugar-based ligands on calixarene cores via nitrone cycloadditions. AB - A novel and challenging approach for the construction of multivalent iminosugar architectures directly on calixarene scaffolds is presented, which exploits multiple cycloaddition reactions of a carbohydrate-derived nitrone on diversely functionalized calix[4]arenes. Regardless of the 4-fold reiteration on a single calixarene, the reactions take place with high regio- and stereoselectivity, demonstrating this method as an appealing one for the synthesis of calixarene based neoglycoconjugates. PMID- 22823332 TI - Effects of premature lure stimuli on 2nd-target identification in rapid serial visual presentation: inhibition induced by lures or by 1st target? AB - In many rapid serial presentation tasks, two targets ("T1" and "T2") have to be distinguished from background stimuli. Here, digits ("lures") were interspersed among the background letters, differing from the T2 digit by occurring before rather than after T1. The resulting inhibitory effects on T2 identification may either be evoked directly by the lures or be triggered by T1, interfering with positive priming of lures on T2. To distinguish between these two alternatives, lures, T1, and T2 were presented in two different simultaneously running streams, T2 was or was not the same digit as a lure, and EEG potentials related to lures, T1, and T2 were recorded. Effects on T2 identification better fit the view that lures exerted positive priming interrupted by T1. Recurrence of lures in the trial led to abridged duration of the lure-evoked N2pc, and T2-evoked N2pc was reduced after lures. Also these N2pc effects may reflect positive priming. PMID- 22823333 TI - Characterization of Miscanthus giganteus lignin isolated by ethanol organosolv process under reflux condition. AB - Miscanthus giganteus lignin was extracted by an organosolv process under reflux conditions (4 h) with varying concentrations of ethanol (65%, 75%, 85%, 95%) and 0.2 M hydrochloric acid as catalyst. The resulting lignin was extensively characterized by size exclusion chromatography (SEC), Fourier-transform infrared spectroscopy (FTIR), gas chromatography-mass spectrometry (GC/MS), two dimensional nuclear magnetic resonance spectroscopy (2D-NMR), and chemical analysis (residual sugars, Klason lignin, ash). The predominant linkage units present were beta-O-4' (82-84%), resinol (6-7%), and phenylcoumaran (10-11%). The 65% ethanol solvent system gave the lowest lignin yield (14% of starting biomass) compared to 29-32% of the other systems. Increasing ethanol concentration resulted in decreasing carbohydrate content of the lignins (3.6-1.1%), a higher solubility in tetrahydrofuran (THF), a slight reduction of the molecular weight (M(w) 2.72-2.25 KDa), an increasing alpha-ethoxylation, and an increase in ethoxylated phenylpropenoic compounds (p-coumaric and ferulic acid), but the S/G ratio of the monolignols (0.63, GC/MS) and Klason lignin content (86-88%) were unaffected. An extraction method for these ethyl-esterified phenylpropenoids and smaller molecular weight lignin compounds was developed. The effect of reaction time (2, 4, and 8 h) was investigated for the 95% ethanol solvent system. Besides increased lignin yield (13-43%), a slight increase in M(w) (2.21-2.38 kDa) and S/G ratio (0.53-0.68, GC-MS) was observed. Consecutive extractions suggested that these changes were not from lignin modifications (e.g., condensations) but rather from extraction of lignin of different composition. The results were compared to similar solvent systems with 95% acetone and 95% dioxane. PMID- 22823334 TI - The influence of different convergence angles and resin cements on the retention of zirconia copings. AB - PURPOSE: This in vitro study aimed to determine the ability of three resin cements to retain zirconia copings under two clinically simulated conditions. MATERIALS AND METHODS: Extracted human molars (72) were collected, cleaned, and divided into two groups. All teeth were prepared with a 15 degrees total convergence angle for group 1 and a 30 degrees total convergence angle for group 2, a flat occlusal surface, and approximately 4-mm axial length. Each group was divided by surface area into three subgroups (n = 12). All zirconia copings were abraded with 50-MUm Al(2)O(3), then cemented using Panavia F 2.0 (PAN-1) (PAN-2) Rely X Unicem (RXU-1) (RXU-2), and Clearfil SA (CSA-1) (CSA-2). After cementation, the copings were thermocycled for 5000 cycles between 5 degrees C and 55 degrees C with a 15-second dwell time. Then the copings were subjected to dislodgment force in a universal testing machine at 0.5 mm/min. The force of removal was recorded, and the dislodgement stress was calculated. A Kruskal Wallis test (nonparametric ANOVA) was used to analyze the data (alpha= 0.05), and the nature of failure was also recorded. RESULTS: The mean (SD) coping removal stresses (MPa) were as follows: PAN-1: 6.0 (1.3), CSA-1: 4.8 (1.4), RXU-1: 5.5 (2.3), PAN-2: 2.8 (1.1), CSA-2: 3.0 (1.25), and RXU-2: 2.6 (1.2). The Kruskal Wallis test was significant. Mann-Whitney pairwise comparisons of the subgroups were significant (p < 0.05) for the comparisons between subgroups of group 1 and group 2. Mode of failure was mixed, with cement remaining principally on the tooth for PAN. For CSA and RXU, mode of failure was mixed with cement remaining principally on the zirconia copings. CONCLUSIONS: Retention values of zirconia copings with three different resin cements were not significantly different. Retention of zirconia copings cemented on the teeth with adequate resistance and retention form was higher than that cemented on teeth lacking these forms. The cement remained mostly on the tooth with the adhesive resin cement with a dentin bonding system. The cement remained mostly on the coping with the self-adhesive resin cement. PMID- 22823335 TI - Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction. AB - BACKGROUND AND PURPOSE: Curcumin, the natural yellow pigment extracted from the rhizomes of the plant curcuma longa, has been demonstrated to exhibit a variety of potent beneficial effects, acting as an antioxidant, anti-inflammatory and anti-fibrotic. In this study we tested the hypothesis that curcumin attenuates maladaptive cardiac repair and improves cardiac function after ischaemia and reperfusion by reducing degradation of extracellular matrix (ECM) and inhibiting synthesis of collagens via TGFbeta/Smad-mediated signalling pathway. EXPERIMENTAL APPROACH: Sprague-Dawley rats were subjected to 45 min of ischaemia followed by 7, 21 and 42 days of reperfusion respectively. Curcumin was fed orally at a dose of 150 mg.kg(-1) .day(-1) only during reperfusion. KEY RESULTS: Curcumin reduced the level of malondialdehyde, inhibited activity of MMPs, preserved ECM from degradation and attenuated collagen deposition, as it reduced the extent of collagen-rich scar and increased mass of viable myocardium. In addition to reducing collagen synthesis and fibrosis in the ischaemic/reperfused myocardium, curcumin significantly down-regulated the expression of TGFbeta1 and phospho Smad2/3, and up-regulated Smad7 and also increased the population of alpha-smooth muscle actin expressing myofibroblasts within the infarcted myocardium relative to the control. Echocardiography showed it significantly improved left ventricular end-diastolic volume, stroke volume and ejection fraction. The wall thickness of the infarcted middle anterior septum in the curcumin group was also greater than that in the control group. CONCLUSION AND IMPLICATIONS: Dietary curcumin is effective at inhibiting maladaptive cardiac repair and preserving cardiac function after ischaemia and reperfusion. Curcumin has potential as a treatment for patients who have had a heart attack. PMID- 22823336 TI - The management of infantile extravasation injury using maternal platelet-rich plasma. AB - Accidental leakage of infusions into surrounding tissue is an adverse event that commonly occurs in preterm infants in the intensive care unit. Although most of these extravasations do not cause severe damage, a small number progress to tissue necrosis, and extensive tissue loss can sometimes occur. Platelet-rich plasma (PRP) consists of a high concentration of platelets in a small volume of plasma and can be prepared easily from peripheral blood. Its wound healing effect is well known. We report the successful healing of extensive tissue necrosis with maternal PRP and suggest that the application of maternal PRP may be an easy and effective treatment option for infant wound management in selected cases that merits further investigation. PMID- 22823338 TI - Semiclassical hybrid approach to condensed phase molecular dynamics: application to the I2Kr17 cluster. AB - We study the vibrational decoherence dynamics of an iodine molecule in a finite krypton cluster comprising the first solvation shell. A normal mode analysis allows us to successively increase the complexity of the description. For the ground state dynamics, comparison with experimental matrix results shows that already four degrees of freedom are sufficient to capture the main decoherence mechanism. For electronically excited iodine, we model the vibrational dynamics of initial Schrodinger cat-like states by the semiclassical hybrid dynamics [Grossmann, F. J. Chem. Phys. 2006, 125, 014111] and full quantum calculations, where available. Good agreement of the results is found for a reduced model with three degrees of freedom. We find non-Gaussian distortions of the bath density matrix, which is a necessary condition, if Schrodinger catlike states in the bath are to be identified. However, in contrast to the experiment [Segale, D.; et al. J. Chem. Phys. 2005, 122, 111104], we observe only incoherent superpositions of bath vibrational states. PMID- 22823337 TI - Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. AB - BACKGROUND: Today, recognition and classification of sequence motifs and protein folds is a mature field, thanks to the availability of numerous comprehensive and easy to use software packages and web-based services. Recognition of structural motifs, by comparison, is less well developed and much less frequently used, possibly due to a lack of easily accessible and easy to use software. RESULTS: In this paper, we describe an extension of DeepView/Swiss-PdbViewer through which structural motifs may be defined and searched for in large protein structure databases, and we show that common structural motifs involved in stabilizing protein folds are present in evolutionarily and structurally unrelated proteins, also in deeply buried locations which are not obviously related to protein function. CONCLUSIONS: The possibility to define custom motifs and search for their occurrence in other proteins permits the identification of recurrent arrangements of residues that could have structural implications. The possibility to do so without having to maintain a complex software/hardware installation on site brings this technology to experts and non-experts alike. PMID- 22823340 TI - Improved health behaviors persist over two years for employees in a worksite wellness program. AB - This study evaluates whether improvements in health behaviors related to a worksite wellness program persist through 2 years. The program was designed to build behavioral capability and self-efficacy by yielding immediately applicable skills and tools and segmenting the behavior change process into weekly, manageable doses. Analyses are based on 267 individuals employed from 2009 through 2011. Significant improvements were observed in the frequency and volume of exercise, and the consumption of vegetables and fruits over 12 and 24 months. Requests for health coaching significantly increased over the study period. Thus, the type of wellness program evaluated in this study produced sustainable health behaviors through 24 months, which likely will translate into future positive health outcomes and improved employee productivity. PMID- 22823339 TI - Age- and ethanol concentration-dependent effects of acute binge drinking in the HIV-1 transgenic rat. AB - BACKGROUND: Binge drinking is common in young people. Alcoholic beverages vary significantly in their ethanol (EtOH) concentration (alcohol by volume). We previously showed EtOH concentration-dependent activation of the hypothalamic supraoptic nucleus. In the HIV-infected population, incidence of alcohol abuse is close to 50%. We found age-dependent expression of HIV-1 viral proteins in the HIV-1 transgenic (HIV-1Tg) rat. Thus, we hypothesized that there are age- and EtOH concentration-dependent effects of binge drinking in HIV-1-positive individuals. METHODS: Blood ethanol concentration was measured in adult F344 rats after gavage (i.g.) administration of water, 20% EtOH, or 52% EtOH. We also compared expression of the HIV-1 viral protein Tat in the brain, spleen, and liver of adult and adolescent HIV-1Tg rats following binge i.g. administration of water, 20% EtOH, or 52% EtOH for 3 days (4.8 g/kg/d) using absolute quantitative real-time reverse transcription-polymerase chain reaction. In a parallel study, we assessed age-dependent motor function in the HIV-1Tg rats 1 day after exposure to 20% EtOH using the open-field test. RESULTS: Blood ethanol concentration was significantly higher in the 52% EtOH-treated F344 rats compared to the 20% EtOH animals at 90 minutes posttreatment. In the adult HIV-1Tg rats, HIV-1 Tat expression (copies per microgram of total RNA) was significantly increased in the brain, liver, and spleen of the 52% EtOH group, but not in the 20% EtOH group. However, in the adolescent animals, HIV-1 Tat expression in the 52% EtOH group was increased in the brain and liver, but not in the spleen. A significant reduction in locomotor activity occurred in 20% EtOH-treated adult HIV-1Tg rats compared to the water control, although no difference was observed in the adolescent HIV-1Tg animals. CONCLUSIONS: Our data indicate that binge alcohol drinking can have age- and EtOH concentration-dependent effects in the presence of HIV-1 infection. PMID- 22823341 TI - Investigation of the reaction of dithiocarbamic acid salts with aromatic aldehydes. AB - A reaction of dithiocarbamic acid salts with carbonyl compounds was investigated for the first time in the presence of BF(3).OEt(2). The reaction is temperature dependent and gives gem-bis(dithiocarbamates) at 35-45 degrees C as a molecule with high equivalents of dithiocarbamate groups. At lower temperatures (15-20 degrees C), the 2-iminium-1,3-dithietane is obtained as the only product. The structure of a 2-iminium-1,3-dithietane was accomplished by X-ray crystallographic analysis. PMID- 22823342 TI - Enantio- and regioselective epoxidation of olefinic double bonds in quinolones, pyridones, and amides catalyzed by a ruthenium porphyrin catalyst with a hydrogen bonding site. AB - An array of differently substituted 3-alkenylquinolones was synthesized, and the enantio- and regioselectivity of their Ru-catalyzed epoxidation were studied. A precursor ruthenium(II) complex with a chiral tricyclic gamma-lactam skeleton (octahydro-1H-4,7-methanoisoindol-1-one) was available by Sonogashira cross coupling with a monobromo-substituted ruthenium(II) porphyrin. Enantioselective epoxidation reactions (60-83% yield, 85-98% ee) were achieved with this catalyst, and it was shown that the enantioselectivity depends critically on the presence of a two-point hydrogen bond interaction between the gamma-lactam site of the catalyst and the delta-lactam (quinolone) site of the substrate. DFT calculations support the hypothesis that the reaction occurs via a hydrogen-bound transition state, in which the 3-alkenylquinolone adopts an s-trans conformation. The calculations further revealed that this transition state is preferred over a competing s-cis transition state because it exerts less strain in the rigid backbone and because the hydrogen bond interaction is more stable. The catalyst loading required for complete conversion was low (<0.2 mol %), and turnover numbers exceeding 4000 were recorded. It was shown that there is little, if any, inhibition of the catalytic process by other quinolones, which could potentially compete with the binding site. A mechanistic model for the catalytic reaction is presented. In accordance with this model 3-alkenylpyridones reacted with similar enantioselectivities as the respective quinolones. The epoxidation products were unstable, however, and the enantiomeric purity (77-87% ee) of the products could be established only after derivatization. Primary alkenoic acid amides also underwent the epoxidation but gave the respective products in lower enantioselectivities (70% and 45% ee), presumably because the enantioface differentiation is hampered by the increased flexibility of the substrates, which exhibit two or three rotatable single bonds between the binding site and the reactive olefinic double bond. PMID- 22823343 TI - The activity of ferulic and gallic acids in biofilm prevention and control of pathogenic bacteria. AB - The activity of two phenolic acids, gallic acid (GA) and ferulic acid (FA) at 1000 MUg ml(-1), was evaluated on the prevention and control of biofilms formed by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes. In addition, the effect of the two phenolic acids was tested on planktonic cell susceptibility, bacterial motility and adhesion. Biofilm prevention and control were tested using a microtiter plate assay and the effect of the phenolic acids was assessed on biofilm mass (crystal violet staining) and on the quantification of metabolic activity (alamar blue assay). The minimum bactericidal concentration for P. aeruginosa was 500 MUg ml(-1) (for both phenolic acids), whilst for E. coli it was 2500 MUg ml(-1) (FA) and 5000 MUg ml( 1) (GA), for L. monocytogenes it was >5000 MUg ml(-1) (for both phenolic acids), and for S. aureus it was 5000 MUg ml(-1) (FA) and >5000 MUg ml(-1) (GA). GA caused total inhibition of swimming (L. monocytogenes) and swarming (L. monocytogenes and E. coli) motilities. FA caused total inhibition of swimming (L. monocytogenes) and swarming (L. monocytogenes and E. coli) motilities. Colony spreading of S. aureus was completely inhibited by FA. The interference of GA and FA with bacterial adhesion was evaluated by the determination of the free energy of adhesion. Adhesion was less favorable when the bacteria were exposed to GA (P. aeruginosa, S. aureus and L. monocytogenes) and FA (P. aeruginosa and S. aureus). Both phenolics had preventive action on biofilm formation and showed a higher potential to reduce the mass of biofilms formed by the Gram-negative bacteria. GA and FA promoted reductions in biofilm activity >70% for all the biofilms tested. The two phenolic acids demonstrated the potential to inhibit bacterial motility and to prevent and control biofilms of four important human pathogenic bacteria. This study also emphasizes the potential of phytochemicals as an emergent source of biofilm control products. PMID- 22823344 TI - Effects of prenatal and/or postnatal (maternal and/or child) folic acid supplementation on the mental performance of children. AB - It has been suggested that a deficiency in folic acid during early, critical central nervous system development may result in persistent cognitive and behavioral effects. The purpose of this systematic review was to evaluate evidence regarding whether folic acid supplementation during pregnancy and early life influences mental performance outcomes in children. The following electronic databases were searched through December 2009 for studies relevant to mental performance and folic acid: MEDLINE, EMBASE and The Cochrane Library; additional references were obtained from reviewed articles. Only randomized controlled trials (RCTs) were included. Of 8 RCTs identified, only 2 met the inclusion criteria. Both studies involved periconceptional, multivitamin-containing, folic acid supplementation. Evidence from these 2 RCTs suggests that such supplementation does not affect the postnatal mental development of infants at a mean age of 11 mo, the developmental quotient (DQ) at 2 y of age, or the intelligence quotient (IQ) and Goodenough man drawing test quotient (DrQ) at 6 y of age. We conclude that the use of multivitamin-containing folic acid supplementation during pregnancy is associated with no benefit to the mental performance of children. These findings should be interpreted with caution due to the very limited number of studies included in this systemic review. PMID- 22823345 TI - A pursuit of the functional nutritional and bioactive properties of canola proteins and peptides. AB - This review focuses on updated information about canola proteins and peptides, their functional, nutritional, and bioactive properties, safety aspects, and potential application in foods. Attention is paid to gelation, emulsion, thermal, and water holding capacities of crude and pure proteins and peptides isolated from canola meal. Various factors affecting these properties are discussed. This paper provides an overview of use of canola meal as a protein source in animal diets and their digestibility in vivo. Their effects on a range of health outcomes including ACE inhibition, hypocholesterolemic effects, cancer prevention, anti-viral and anti-diabetic properties are reviewed on the basis of the available in vitro and in vivo animal and human data. The review also focuses on the safety aspects and selected food applications of canola proteins and peptides. PMID- 22823346 TI - Vitamin D and multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system and characterized by neurological and cognitive manifestations. The disease is more common in populations living in high altitudes with low sun exposure, women more than men, and certain ethnic backgrounds more than others. The etiology of MS is yet unknown, although several factors have been implicated in its development. These include genetic factors and environmental factors as well as dietary components and their interactions. Among the dietary components that have recently attracted the attention is vitamin D. This mini-review summarizes current knowledge on the potential use of vitamin D in the protection and treatment of MS. In addition, the mechanism(s) by which vitamin D plays a role in the development and/or protection from MS are discussed. PMID- 22823347 TI - Steviol glycosides from Stevia: biosynthesis pathway review and their application in foods and medicine. AB - Stevia rebaudiana, a perennial herb from the Asteraceae family, is known to the scientific world for its sweetness and steviol glycosides (SGs). SGs are the secondary metabolites responsible for the sweetness of Stevia. They are synthesized by SG biosynthesis pathway operating in the leaves. Most of the genes encoding the enzymes of this pathway have been cloned and characterized from Stevia. Out of various SGs, stevioside and rebaudioside A are the major metabolites. SGs including stevioside have also been synthesized by enzymes and microbial agents. These are non-mutagenic, non-toxic, antimicrobial, and do not show any remarkable side-effects upon consumption. Stevioside has many medical applications and its role against diabetes is most important. SGs have made Stevia an important part of the medicinal world as well as the food and beverage industry. This article presents an overview on Stevia and the importance of SGs. PMID- 22823348 TI - Principles and applications of hyperspectral imaging in quality evaluation of agro-food products: a review. AB - The requirements of reliability, expeditiousness, accuracy, consistency, and simplicity for quality assessment of food products encouraged the development of non-destructive technologies to meet the demands of consumers to obtain superior food qualities. Hyperspectral imaging is one of the most promising techniques currently investigated for quality evaluation purposes in numerous sorts of applications. The main advantage of the hyperspectral imaging system is its aptitude to incorporate both spectroscopy and imaging techniques not only to make a direct assessment of different components simultaneously but also to locate the spatial distribution of such components in the tested products. Associated with multivariate analysis protocols, hyperspectral imaging shows a convinced attitude to be dominated in food authentication and analysis in future. The marvellous potential of the hyperspectral imaging technique as a non-destructive tool has driven the development of more sophisticated hyperspectral imaging systems in food applications. The aim of this review is to give detailed outlines about the theory and principles of hyperspectral imaging and to focus primarily on its applications in the field of quality evaluation of agro-food products as well as its future applicability in modern food industries and research. PMID- 22823350 TI - Application of hyperspectral imaging in food safety inspection and control: a review. AB - Food safety is a great public concern, and outbreaks of food-borne illnesses can lead to disturbance to the society. Consequently, fast and nondestructive methods are required for sensing the safety situation of produce. As an emerging technology, hyperspectral imaging has been successfully employed in food safety inspection and control. After presenting the fundamentals of hyperspectral imaging, this paper provides a comprehensive review on its application in determination of physical, chemical, and biological contamination on food products. Additionally, other studies, including detecting meat and meat bone in feedstuffs as well as organic residue on food processing equipment, are also reported due to their close relationship with food safety control. With these applications, it can be demonstrated that miscellaneous hyperspectral imaging techniques including near-infrared hyperspectral imaging, fluorescence hyperspectral imaging, and Raman hyperspectral imaging or their combinations are powerful tools for food safety surveillance. Moreover, it is envisaged that hyperspectral imaging can be considered as an alternative technique for conventional methods in realizing inspection automation, leading to the elimination of the occurrence of food safety problems at the utmost. PMID- 22823349 TI - Vacuum cooling of meat products: current state-of-the-art research advances. AB - Vacuum cooling (VC) is commonly applied for cooling of several foodstuffs, to provide exceptionally rapid cooling rates with low energy consumption and resulting in high-quality food products. However, for products such as meat and cooked meat products, the higher cooling loss of vacuum cooling compared with established methods still means lower yields, and important meat quality parameters can be negatively affected. Substantial efforts during the past ten years have aimed to improve the technology in order to offer the meat industry, especially the cooked meat industry, optimized production in terms of safety regulations and guidelines, as well as meat quality. This review presents and discusses recent VC developments directed to the cooked meat industry. The principles of VC, and the basis for improvements of this technology, are firstly discussed; future prospects for research and development in this area are later explored, particularly in relation to cooling of cooked meat and meat products. PMID- 22823351 TI - Raw material consumption of the European Union--concept, calculation method, and results. AB - This article presents the concept, calculation method, and first results of the "Raw Material Consumption" (RMC) economy-wide material flow indicator for the European Union (EU). The RMC measures the final domestic consumption of products in terms of raw material equivalents (RME), i.e. raw materials used in the complete production chain of consumed products. We employed the hybrid input output life cycle assessment method to calculate RMC. We first developed a highly disaggregated environmentally extended mixed unit input output table and then applied life cycle inventory data for imported products without appropriate representation of production within the domestic economy. Lastly, we treated capital formation as intermediate consumption. Our results show that services, often considered as a solution for dematerialization, account for a significant part of EU raw material consumption, which emphasizes the need to focus on the full production chains and dematerialization of services. Comparison of the EU's RMC with its domestic extraction shows that the EU is nearly self-sufficient in biomass and nonmetallic minerals but extremely dependent on direct and indirect imports of fossil energy carriers and metal ores. This implies an export of environmental burden related to extraction and primary processing of these materials to the rest of the world. Our results demonstrate that internalizing capital formation has significant influence on the calculated RMC. PMID- 22823385 TI - ViSA: a neurodynamic model for visuo-spatial working memory, attentional blink, and conscious access. AB - Two separate lines of study have clarified the role of selectivity in conscious access to visual information. Both involve presenting multiple targets and distracters: one simultaneously in a spatially distributed fashion, the other sequentially at a single location. To understand their findings in a unified framework, we propose a neurodynamic model for Visual Selection and Awareness (ViSA). ViSA supports the view that neural representations for conscious access and visuo-spatial working memory are globally distributed and are based on recurrent interactions between perceptual and access control processors. Its flexible global workspace mechanisms enable a unitary account of a broad range of effects: It accounts for the limited storage capacity of visuo-spatial working memory, attentional cueing, and efficient selection with multi-object displays, as well as for the attentional blink and associated sparing and masking effects. In particular, the speed of consolidation for storage in visuo-spatial working memory in ViSA is not fixed but depends adaptively on the input and recurrent signaling. Slowing down of consolidation due to weak bottom-up and recurrent input as a result of brief presentation and masking leads to the attentional blink. Thus, ViSA goes beyond earlier 2-stage and neuronal global workspace accounts of conscious processing limitations. PMID- 22823386 TI - Hepatitis C virus spontaneous clearance: immunology and genetic variance. AB - Hepatitis C virus (HCV) infection is one of the most common chronic viral infections in the world. Approximately 80-90% of acutely infected individuals develop persistent infection, which is a major risk for liver cirrhosis and liver cancer. However, a small portion of patients (10-20%) clear the virus. Clinical outcomes of HCV infection are determined by the interplay between the host immune response, and viral and environmental factors. In regulating immune responses, cytokines play an indispensable role that controls the underlying pathogenesis and the resulting outcome of HCV infection. Cytokines themselves are manipulated by polymorphisms in their genes. In fact, the majority of genetic variants that apparently confer a significant risk for chronic HCV infection have been localized in genes involved in cytokine synthesis and the ultimate immune response. So far, treatment strategies for HCV infection have remained controversial. Genotyping of different polymorphisms will aid clinical decision making for both current standard and personalized care. Genotyping can potentially be useful for future integration of other agents, which provides an opportunity for clinicians to personalize treatment regimens for HCV patients. This review summarizes findings of different studies on host immune responses after HCV infection and the association between cytokine gene polymorphisms and the likelihood of HCV clearance. PMID- 22823387 TI - Expression and functions of MU-opioid receptors and cannabinoid receptors type 1 in T lymphocytes. AB - Opioids and cannabinoids modulate T lymphocyte functions. Many effects of the drugs are mediated by MU-opioid receptor and cannabinoid receptor type 1 (CB1), respectively. These two receptors are strikingly similar with respect to their expression in T cells and the mechanisms by which they mediate modulation of T cell activity. Thus, MU-opioid receptors and CB1 not expressed in resting primary human and Jurkat T cells. However, in response to the cytokine IL-4, the epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A, and activation of T cells, functional MU-opioid receptors and CB1 are induced. The induced receptors mediate inhibition of T cell signaling and, thereby, IL-2 production, a hallmark of activated T cells. Although coupled to inhibitory G proteins, MU opioid receptors and CB1 produce a remarkable increase in cAMP levels in T cells stimulated with opioids and cannabinoids, which is a key mechanism for the inhibition of T cell signaling. PMID- 22823388 TI - Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function. AB - Immune cells, including lymphocytes, express muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs, respectively), and agonist stimulation of these AChRs causes functional and biochemical changes in the cells. The origin of the ACh that acts on immune cell AChRs has remained unclear until recently, however. In 1995, we identified choline acetyltransferase mRNA and protein in human T cells, and found that immunological T cell activation potentiated lymphocytic cholinergic transmission by increasing ACh synthesis and AChR expression. We also found that M(1) /M(5) mAChR signaling upregulates IgG(1) and proinflammatory cytokine production, whereas alpha7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts as an autocrine and/or paracrine factor via AChRs on immune cells to modulate immune function. In addition, a recently discovered endogenous allosteric alpha7 nAChR ligand, SLURP-1, also appears to be involved in modulating normal T cell function. PMID- 22823389 TI - T cells affect central and peripheral noradrenergic mechanisms and neurotrophin concentration in the spleen and hypothalamus. AB - Interactions between T cells and noradrenergic pathways were investigated using athymic nude mice as a model. Higher noradrenaline (NA) concentrations and increased density of noradrenergic fibers were found in the spleen and hypothalamus, but not in the kidney, of 21-day-old Foxn1(n) (athymic) mice, compared with Foxn1(n) /Foxn1(+) (heterozygous) littermates. Although no differences in nerve growth factor concentrations were detected, significantly higher brain-derived neurotrophic factor concentrations were found in the spleen and hypothalamus of athymic mice compared with the controls. All of these alterations were abrogated in Foxn1(n) mice reconstituted by thymus transplantation at birth. These results suggest that T lymphocytes or their products can induce (1) a decrease in the number and activity in splenic sympathetic nerve fibers; (2) a decrease in NA content in the hypothalamus, which, in turn, may influence the pituitary-adrenal axis and the descending neural pathways associated with the autonomic nervous system; and (3) changes in neurotrophin concentration in the spleen and hypothalamus. PMID- 22823390 TI - Sympathetic nerve fiber repulsion: testing norepinephrine, dopamine, and 17beta estradiol in a primary murine sympathetic neurite outgrowth assay. AB - Loss of sympathetic nerve fibers (SNFs) occurs in inflamed tissue; and select semaphorins, upregulated during inflammation, stimulate repulsion/loss of SNFs. However, it is unknown whether other factors released locally in inflamed tissue, such as norepinephrine, dopamine, and 17beta-estradiol, are also repellent. In order to study the effects of hormones on SNF repulsion, an SNF outgrowth assay was used. The repellent activity of semaphorins 3C was weaker than of semaphorin 3F. Tumor necrosis factor alpha (TNF-alpha) repelled nerve fibers with moderate to strong effects (from 0-100% repulsion). High concentrations of dopamine and norepinephrine (10(-6) M) induced weak but significant nerve fiber repulsion (up to 20%). Norepinephrine at 10(-8) M was comparable with 10(-6) M at inducing nerve fiber outgrowth. Stimulation with low concentrations of 17beta-estradiol (10(-10) M, but not 10(-8) M) repelled SNFs. These results demonstrate that not only specific axon guidance molecules, such as semaphorins 3F and 3C, but also hormonal factors and TNF-alpha influence SNF repulsion and outgrowth. PMID- 22823391 TI - Glucocorticoid-catecholamine interplay within the composite thymopoietic regulatory network. AB - This paper highlights the multiple putative thymic and extrathymic points of intersection and interaction between glucocorticoids (GCs) and catecholamines (CAs)--the end-point mediators of the major routes of communication between the brain and the immune system--in the context of intricate thymic T cell developmental tuning. More specifically, we discuss in detail findings indicating that adrenal GCs can influence thymopoiesis by adjusting directly and/or indirectly (through modulation of pituitary and local ACTH synthesis) not only thymic GC synthesis, in a cell type-specific manner, but also thymic CA bioavailability (via altering CA outflow from sympathetic nerve endings and local CA synthesis), beta and alpha(1) -adrenoceptor (AR) expression, and/or AR mediated intracellular signal transduction in thymic cells. In addition, this short review points to GC- and CA-sensitive stages along the multistep T cell developmental journey and the possible effects of altered GC, and consequently CA signaling, on thymopoietic efficiency. PMID- 22823392 TI - Presentation of neuroendocrine self in the thymus: a necessity for integrated evolution of the immune and neuroendocrine systems. AB - During evolution, from ancestor thymoids scattered in gill baskets of the lamprey, the first unique thymus appeared in jawed cartilaginous fishes around 450-500 millions years ago, concomitantly or shortly after the emergence of recombinase-dependent adaptive immunity. The major biological function of the thymus is to generate a diverse repertoire of T cell receptors that are self tolerant. The thymus achieves this role by using two complementary and intimately associated mechanisms: apoptotic deletion of T cell clones bearing a TCR with high affinity for self-antigens presented by MHC proteins on thymic epithelial cells (TECs) and dendritic cells (DCs); and generation of self-antigen-specific natural regulatory T (nT(reg)) cells. Moreover, the escape from thymic central self-tolerance plays a primary role in the development of autoimmune diseases that are a significant burden for the quality of life and health-care cost. Our new knowledge in thymus physiology and physiopathology is currently translated into innovative therapeutic strategies against these devastating chronic diseases. PMID- 22823393 TI - Growth hormone modulates migration of thymocytes and peripheral T cells. AB - In the context of immunoneuroendocrine cross talk, growth hormone (GH) exerts pleiotropic effects in the immune system. For example, GH-transgenic mice, as well as animals and humans treated with GH, exhibit enhanced cellularity in the thymus. GH also stimulates the thymic microenvironment, augmenting chemokine and extracellular matrix (ECM) production, with consequent increase in ECM- and chemokine-driven thymocyte migratory responses. Peripheral T cell migration triggered by laminin or fibronectin was enhanced in cells from GH-transgenic versus wild-type control adult mice, as seen for CD4(+) and CD8(+) T cells from mesenteric lymph nodes. Migration of these T lymphocytes, triggered by the chemokine CXCL12, in conjunction with laminin or fibronectin, was also enhanced compared with control counterparts. Considering that GH can be used as an adjuvant therapy in immunodeficiencies, including AIDS, the concepts defined herein, that GH enhances developing and peripheral T cell migration, provide new clues for future GH-related immune interventions. PMID- 22823395 TI - Hsp72, inflammation, and aging: causes, consequences, and perspectives. AB - Although aging is an inexorable component of life, its progress depends on how cumulative disruptions of homeostasis are compensated. Cumulative oxidative and inflammatory processes must be controlled to maintain successful aging. Heat shock proteins, such as those of the Hsp70 family, can be considered a danger signal, and their effects can either support longevity by neutralizing danger or can become detrimental when their production is not balanced. Here, we discuss evidence indicating that these highly conserved proteins can favor longevity when such balance is achieved. We emphasize mechanisms affected by Hsp72 that can interfere with effects of excessive oxidative stress and subtle inflammation and, acting either directly or by affecting neuro-immune-endocrine interactions, can mediate metabolic, neuroprotective, and behavioral adjustments during the aging process. PMID- 22823396 TI - Regulation of intestinal morphology and GALT by pituitary hormones in the rat. AB - Here, the effects of neurointermediate (NIL), anterior (AL), and total hypophysectomy (HYPOX) on ileal mucosa cells and gut-associated lymphoid tissue (GALT) are reported. Compared with the sham-operated (SHAM) rats, the villi height and goblet cells numbers were significantly decreased in all groups. Lamina propria area decreased in AL and HYPOX, but not in NIL animals. CD8(+) but not CD4(+) lymphocytes decreased in the HYPOX and NIL groups. Paneth cells did not change, while IgA cells, IgM cells, and secretory IgA were significantly decreased in all groups. NIL but not AL animals lost significant numbers of IgA cells and secretory IgA. In summary, pituitary hormones exert lobe-specific regulatory effects on the gut and on GALT. PMID- 22823394 TI - Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. AB - Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress-related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress-related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed. PMID- 22823398 TI - Role of interleukin-6 in stress, sleep, and fatigue. AB - Chronic low-grade inflammation, in particular increased concentrations of proinflammatory cytokines such as interleukin (IL)-6 in the circulation, is observed with increasing age, but it is also as a consequence of various medical and psychological conditions, as well as life-style choices. Since molecules such as IL-6 have pleiotropic effects, consequences are wide ranging. This short review summarizes the evidence showing how IL-6 elevations in the context of inflammatory disease affect the organism, with a focus on sleep-related symptoms and fatigue; and conversely, how alterations in sleep duration and quality stimulate increased concentrations of IL-6 in the circulation. Research showing that acute as well as chronic psychological stress also increase concentrations of IL-6 supports the notion of a close link between an organism's response to physiological and psychological perturbations. The findings summarized here further underscore the particular importance of IL-6 as a messenger molecule that connects peripheral regulatory processes with the CNS. PMID- 22823397 TI - Transforming growth factor-beta inhibits the expression of clock genes. AB - Disturbances of sleep-wake rhythms are an important problem in Alzheimer's disease (AD). Circadian rhythms are regulated by clock genes. Transforming growth factor-beta (TGF-beta) is overexpressed in neurons in AD and is the only cytokine that is increased in cerebrospinal fluid (CSF). Our data show that TGF-beta2 inhibits the expression of the clock genes Period (Per)1, Per2, and Rev-erbalpha, and of the clock-controlled genes D-site albumin promoter binding protein (Dbp) and thyrotroph embryonic factor (Tef). However, our results showed that TGF-beta2 did not alter the expression of brain and muscle Arnt-like protein-1 (Bmal1). The concentrations of TGF-beta2 in the CSF of 2 of 16 AD patients and of 1 of 7 patients with mild cognitive impairment were in the dose range required to suppress the expression of clock genes. TGF-beta2-induced dysregulation of clock genes may alter neuronal pathways, which may be causally related to abnormal sleep-wake rhythms in AD patients. PMID- 22823399 TI - Role of sleep in the regulation of the immune system and the pituitary hormones. AB - Sleep is characterized by a reduced response to external stimuli and a particular form of electroencephalographic (EEG) activity. Sleep is divided into two stages: REM sleep, characterized by muscle atonia, rapid eye movements, and EEG activity similar to wakefulness, and non-REM sleep, characterized by slow EEG activity. Around 80% of total sleep time is non-REM. Although it has been intensely studied for decades, the function (or functions) of sleep remains elusive. Sleep is a highly regulated state; some brain regions and several hormones and cytokines participate in sleep regulation. This mini-review focuses on how pituitary hormones and cytokines regulate or affect sleep and how sleep modifies the plasma concentration of hormones as well as cytokines. Also, we review the effects of hypophysectomy and some autoimmune diseases on sleep pattern. Finally, we propose that one of the functions of sleep is to maintain the integrity of the neuro immune-endocrine system. PMID- 22823400 TI - Foreword for Neuroimmunomodulation in health and disease. PMID- 22823401 TI - Ground-state properties of a polymer chain in an attractive sphere. AB - We analyze the structural formation of a polymer chain inside of an attractive sphere depending on the attraction strength. Our model is composed of a coarse grained polymer and an attractive sphere potential. Within this frame, multicanonical Monte Carlo simulations are employed to identify the global minimum energies for a polymer chain interacting with the attractive inner wall of the sphere. Different compact structures are found with varying attraction strengths, among which are spherical, three/two, or monolayer. The conformational properties of these structures are presented. PMID- 22823402 TI - Isolation, characterization, and NO inhibitory activities of sesquiterpenes from Blumea balsamifera. AB - Blumea balsamifera belongs to the family Compositae, and its leaves have been used as a flavoring ingredient and a tea. A phytochemical investigation of the aerial parts of B. balsamifera led to the isolation of 10 new (1-10) and 1 known (11) sesquiterpenes. Their structures were elucidated on the basis of extensive one- and two-dimensional nuclear magnetic resonance (heteronuclear multiple-quantum coherence, heteronuclear multiple-bond correlation, (1)H-(1)H correlation spectroscopy, and nuclear Overhauser effect spectrometry) spectroscopic data analyses, and the structure of compound 1 was confirmed by X ray crystallography. The inhibitory activities on lipopolysaccharide-induced NO production in murine microglial BV-2 cells of these sesquiterpenes were evaluated, and all of the compounds showed inhibitory effects. PMID- 22823403 TI - Pals in power armor: attribution of human-like emotions to video game characters in an ingroup/outgroup situation. AB - Previous research has demonstrated the tendency for humans to anthropomorphize computers-that is, to react to computers as social actors, despite knowing that the computers are mere machines. In the present research, we examined the attribution of both primary (non-uniquely human) and secondary (human-like) emotions to ingroup (teammate) and outgroup (opponent) computer-controlled characters in a video game. We found that participants perceived the teammate character as experiencing more secondary emotions than the opponent character, but that they perceived the teammate and opponent character as experiencing equal levels of primary emotions. Thus, participants anthropomorphized the ingroup character to a greater extent than the outgroup character. These results imply that computers' "emotions" are treated with a similar ingroup/outgroup social regard as the emotions of actual humans. PMID- 22823404 TI - Clinical judgment: good but not enough. PMID- 22823405 TI - A novel hierarchical clustering algorithm for gene sequences. AB - BACKGROUND: Clustering DNA sequences into functional groups is an important problem in bioinformatics. We propose a new alignment-free algorithm, mBKM, based on a new distance measure, DMk, for clustering gene sequences. This method transforms DNA sequences into the feature vectors which contain the occurrence, location and order relation of k-tuples in DNA sequence. Afterwards, a hierarchical procedure is applied to clustering DNA sequences based on the feature vectors. RESULTS: The proposed distance measure and clustering method are evaluated by clustering functionally related genes and by phylogenetic analysis. This method is also compared with BlastClust, CD-HIT-EST and some others. The experimental results show our method is effective in classifying DNA sequences with similar biological characteristics and in discovering the underlying relationship among the sequences. CONCLUSIONS: We introduced a novel clustering algorithm which is based on a new sequence similarity measure. It is effective in classifying DNA sequences with similar biological characteristics and in discovering the relationship among the sequences. PMID- 22823406 TI - Dissociative benzyl cation transfer versus proton transfer: loss of benzene from protonated N-benzylaniline. AB - In collisional activation of protonated N-benzylaniline, the benzene loss from the benzyl moiety is actually not the result of dissociative proton transfer (PT). In fact, benzyl cation transfer (BCT) from the nitrogen to the anilinic ring (ortho or para position) is the key step for benzene loss. Such dissociation occurs only after the benzyl group migrating from the site with the highest benzylation nucleophilicity (nitrogen) to a different one (aromatic ring carbon), which is described as dissociative benzyl cation transfer. PMID- 22823407 TI - Kinetic modelling of central carbon metabolism in Escherichia coli. AB - In the present study, we developed a detailed kinetic model of Escherichia coli central carbon metabolism. The main model assumptions were based on the results of metabolic and regulatory reconstruction of the system and thorough model verification with experimental data. The development and verification of the model included several stages, which allowed us to take into account both in vitro and in vivo experimental data and avoid the ambiguity that frequently occurs in detailed models of biochemical pathways. The choice of the level of detail for the mathematical description of enzymatic reaction rates and the evaluation of parameter values were based on available published data. Validation of the complete model of the metabolic pathway describing specific physiological states was based on fluxomics and metabolomics data. In particular, we developed a model that describes aerobic growth of E. coli in continuous culture with a limiting concentration of glucose. Such modification of the model was used to integrate experimental metabolomics data obtained in steady-state conditions for wild-type E. coli and genetically modified strains, e.g. knockout of the pyruvate kinase gene (pykA). Following analysis of the model behaviour, and comparison of the coincidence between predicted and experimental data, it was possible to investigate the functional and regulatory properties of E. coli central carbon metabolism. For example, a novel metabolic regulatory mechanism for 6 phosphogluconate dehydrogenase inhibition by phosphoenolpyruvate was hypothesized, and the flux ratios between the reactions catalysed by enzyme isoforms were predicted. DATABASE: The mathematical model described here has been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at http://jjj.biochem.sun.ac.za/database/peskov/index.html PMID- 22823408 TI - An empirically optimized classical force-field for molecular simulations of 2,4,6 trinitrotoluene (TNT) and 2,4-dinitrotoluene (DNT). AB - An empirical classical all-atom specific force-field for use in molecular dynamics simulations (MD) has been developed to reproduce the experimental densities and structures of trinitrotoluene (TNT) in its crystalline and liquid phases at six different temperatures, as well as its enthalpies of sublimation and fusion. The average structural parameters and partial charges were obtained from density functional theory optimizations of single molecules at the B3LYP/6 311+G** level. The other constants for the potential were adjusted in order to obtain a classical force-field, which is able to reproduce the aforementioned properties for TNT with a high degree of accuracy. This force-field was also found to predict closely the experimental densities and structures of 2,4 dinitrotoluene (2,4-DNT) in its crystalline and liquid phases as well as its enthalpy of sublimation. It was a bit less successful for its enthalpy of fusion, but it still remained reasonable, and the model mechanical properties were of the right order of magnitude. As such, this fairly simple force-field can be used for MD simulations of both TNT and 2,4-DNT nitroaromatic compounds. PMID- 22823409 TI - Exome sequencing overrides formal genetics: ASPM mutations in a case study of apparent X-linked microcephalic intellectual deficit. PMID- 22823410 TI - A novel framework to eliminate the effects of casting distortion when fabricating a fixed, detachable screw-retained prosthesis. AB - The ideal fixed, detachable framework sits passively on the implants and does not introduce any stress. Several techniques in the literature compensate for an ill fitting framework. These techniques require extra visits, chairtime, and laboratory time and only mitigate the stress; the stress is not eliminated. A framework is presented here that eliminates the stress transmitted to the implants by encircling the abutment cylinders and not directly incorporating them into the framework. Furthermore, the framework mitigates the stress from the polymerization distortion of acrylic when processing the acrylic onto the prosthesis. PMID- 22823411 TI - Should diabetes retinal screening intervals change? AB - There is accumulating evidence that the natural history of diabetic eye disease is sufficiently slow that 2-yearly retinal screening, or even longer, may be safe for some patients with diabetes. The information technology underpinning call recall systems within screening programmes permits a more sophisticated approach to organizing retinal screening, as directed by the clinical evidence. This commentary explores the evidence for moving towards a biennial retinal screening programme for patients with Type 2 diabetes and diabetes duration of less than 10 years. Such an approach may allow capacity to introduce 6-monthly screening for high-risk patients, a targeted approach to recurrent defaulters and possible introduction of new aspects of screening such as optical coherence tomography, in addition to accommodating for the expanding number of patients with diabetes. A UK-four nations group is now critically looking at the evidence for any such changes. PMID- 22823412 TI - Towards bloodless cystectomy: a 10-year experience of intra-operative cell salvage during radical cystectomy. AB - Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Guidance from the UK National Institute for Health and Clinical Excellence (NICE) on the use of intraoperative cell savage (ICS) has been in place for over 3 years and recommends its routine usage in all patients undergoing radical pelvic urological surgery. The current series describes the contribution of ICS to contemporary blood conservation strategies and the goal of 'bloodless' cystectomy. OBJECTIVE: * To describe a 10-year experience of intra-operative cell salvage (ICS) during radical cystectomy at a regional cancer centre. PATIENTS AND METHODS: * Between 1(st) January 2001 and 31(st) December 2010, 213 consecutive patients underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer, with an ICS suction device used in theatre. * Surgery was performed by one of three consultant surgeons using an open technique with lymph node clearance to the iliac bifurcation. Orthotopic bladder substitution was performed in 25% of patients overall. * ICS data were collected prospectively on an electronic database and the institutional database was then cross-referenced with a complete review of patients' medical records, laboratory results and radiological investigations retrospectively. * Data collected included patient demographics, haemoglobin levels before and after surgery, the volume of ICS blood collected and re-infused, complications related to ICS usage, the volume of allogeneic red blood cells (RBCs) transfused, length of stay and overall patient survival at 3 and 5 years after surgery. RESULTS: * In all 213 cases described, ICS was used without complication, with no recorded episodes of device failure and no complications related to the use of cell salvage. * Overall, 91% of patients received ICS blood and 28% of patients avoided any further transfusion products. * The median (range) follow-up for the cohort was 24 (9-119) months. * Seventy percent of the transfusion requirement for patients who underwent surgery in 2001 was met using allogeneic RBC transfusion but by 2010, as blood loss markedly reduced, ICS blood was able to provide ~70% of overall transfusion requirements. As a consequence, the percentage of patients avoiding an allogeneic RBC transfusion significantly increased during the 10-year period, such that 70% of patients avoided allogeneic RBC transfusion in 2010 compared with only 10-20% in the period 2001-2003 * The overall survival rate at 3 and 5 years was 58% and 49%, respectively. CONCLUSIONS: * In conclusion, the use of ICS during radical cystectomy is safe; it is capable of meeting the majority of or, in some cases, the total blood product requirement for individual patients. As a result, it decreases the need for allogeneic RBC transfusion and hence the associated risks. Current follow-up shows no apparent risk of decreased long-term survival from an oncological perspective. * The authors advocate routine availability of ICS for all major urological oncology cases. PMID- 22823413 TI - Improving the efficiency of telephone-based disease management programs: getting the population and the timing right using hospital admission data. AB - Telephone-based disease management (DM) programs can improve health outcomes and provide a positive return on investment to funders. However, there is scant evidence about how to use hospital admission episode data to identify patients who are most likely to participate in a DM program. The objective of this study was to use hospital admission episode data held by health insurers to determine those factors that predict members with chronic disease joining and remaining in a DM program for at least 6 months. A multivariable logistic regression model was constructed to determine predictors of participating in a DM program for an insured population who had been admitted to hospital for congestive heart failure, coronary artery disease, or chronic obstructive pulmonary disease. The outcome variable was binary: did the member both opt into the DM program and remain in the program for at least 6 months? The study population included 9874 private health fund members. Time from a related hospital admission was a significant predictor, with those offered the program within 3 to 6 months being 71% more likely (95% confidence interval [CI]: 33%, 113%) to participate. The length of time from offer to commencement also was a significant predictor, with those commencing within 3 to 4 months being 75% (95% CI: 44%, 112%) as likely to remain in the program. It is possible to predict which individuals are most likely to participate in a telephone-based DM program using hospital admission episode data. Once individuals are identified, timely commencement of a DM program is an important predictor of success. PMID- 22823414 TI - A one-pot-three-step route to triazolotriazepinoindazolones from oxazolino-2H indazoles. AB - A one-pot-three-step method has been developed for the conversion of oxazolino-2H indazoles into triazolotriazepinoindazolones with three points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the Davis-Beirut reaction) to give an N(1) (propargyl)-N(2)-(2-bromoethyl)-disubstituted indazolone, which then undergoes CH(2)Br -> -CH(2)N(3) displacement (step two) followed by an uncatalyzed intramolecular azide-alkyne 1,3-dipolar cycloaddition (step three) to form the target heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling chemistry, as reported here. PMID- 22823416 TI - Exploring the role of laparoscopic surgery in two-stage hepatectomy for bilobar colorectal liver metastases. AB - BACKGROUND: The role of laparoscopy in two-stage hepatectomy for bilobar colorectal liver metastases (CRLMs) has not yet been extensively investigated. PATIENTS AND METHODS: We reviewed a prospectively collected database of 302 consecutive patients undergoing laparoscopic liver resection at our institution between 2003 and 2011. RESULTS: Eight patients undergoing laparoscopic first/second-stage hepatectomy for bilobar CRLMs (male/female 6:2; median age, 64 years) were analyzed. The first stage consisted of laparoscopic clearance of the left lobe in all patients with no postoperative morbidity and mortality. Seven patients underwent portal vein embolization or ligation. The median interval between first- and second-stage hepatic resections was 89 days (range, 36-123 days). Second-stage hepatectomy with right lobar clearance (open, n=5; laparoscopic, n=2; laparoscopic to open, n=1) was associated with no mortality and an operative morbidity rate of 50%. Adhesions were judged to be minimal or absent during the second-stage procedure. Complications included intra-abdominal collection (n=2), bleeding requiring re-operation (n=1), and bile leak (n=1). R0 resection was obtained in 7 of 8 cases after first-stage resection and in 8 of 8 cases after second-stage resection. Three patients (38%) died from disease recurrence. Of the remaining 5 patients, 4 are disease-free at a median follow-up of 24 months (range, 9-27 months). CONCLUSIONS: The well-recognized advantages of laparoscopy may play a favorable role in the management of patients with bilobar CRLMs candidate for a two-stage resection. The first-stage laparoscopic clearance of the left lobe could progressively become the "gold standard." Laparoscopic second-stage hepatectomy should be limited to selected cases. PMID- 22823415 TI - Perceived access to reinforcers as a function of alcohol consumption among one First Nation group. AB - BACKGROUND: Spillane and Smith (2007, Psychol Bull 133:395-418) postulated that high levels of problem drinking in some First Nation (FN) communities resulted in part from the perception that there is low access to alternative reinforcers (e.g., jobs, friendships, family relationships, and financial security), that many alternative reinforcers are less contingent on sobriety, and that others are available regardless of drinking status for reserve-dwelling FN members. METHODS: This study examined perceptions of access to alternative reinforcers and the extent to which access varied as a function of drinking in 211 FN members living on 1 reserve in Canada, 138 middle socioeconomic status Caucasians (MCCs), and 98 low socioeconomic status Caucasians (LCCs). RESULTS: The FN group expected less access to employment, quality family and friend relationships, and financial security compared with the MCC group. After controlling for perceived access in general, gender, and age, the FN group reported that drinking would not cause a decrease in access to employment, family relationships, friendships, and finances as compared to the MCC group. The FN group did not differ from the LCC group in the degree to which they expected drinking to cost access to family relationships or finances, but the LCC group expected drinking to have less of an impact on access to jobs and friendships as compared to the FN group. CONCLUSIONS: The results provide initial support for the Spillane and Smith theory of problem drinking among this 1 FN group. The results suggest that increasing access to these reinforcers may reduce problematic drinking in this FN group. PMID- 22823417 TI - Implications of neurophysiological parameters in persons with severe brain injury with respect to improved patient outcomes: a retrospective review. AB - PRIMARY OBJECTIVE: To determine whether neurophysiologic parameters-intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), partial brain tissue oxygenation (PbtO(2)) and pressure reactivity index (PRx, calculated)-captured during the management of traumatic brain injury (TBI) have a relationship to patient outcome. RESEARCH DESIGN: A retrospective analysis of neurophysiologic data collected from persons under medical management of TBI per Conemaugh Memorial Medical Center (CMMC) standard treatment algorithms. METHODS AND PROCEDURES: Nine patients' medical records that matched International Statistical Classification of Diseases and Related Health Problems (ICD-9) code for head injury and a Current Procedural Terminology (CPT) code for an ICP monitoring device or ventriculostomy were analysed on the aforementioned parameters. MAIN OUTCOMES AND RESULTS: Statistical significance by mortality (alpha = 0.05) was found for ICP, CPP and PbtO(2). PRx showed a pattern of significance over the last 72 hours. The couplets (CPP & ICP) and (CPP & MAP) demonstrated significant correlations. CONCLUSIONS: Improved autoregulation was associated with PRx values near zero. Controlling those parameters that affect PRx, namely MAP, ICP and CPP and more importantly cerebral oxygen perfusion (COP), would likely increase the probability of a better outcome while guarding against secondary insult. PMID- 22823418 TI - Linz-Donawitz steel slag for the removal of hydrogen sulfide at room temperature. AB - Slags collected from the basic oxygen furnaces of two Linz-Donawitz steel making plants were tested as adsorbents for H(2)S removal at room temperature (298 K). Two different particle size fractions, namely <212 and 212-500 MUm, were selected from the original slag samples. Dynamic adsorption tests were carried out using a column-bed configuration and retention capacities were calculated after bed exhaustion. Retention capacities as high as 180 mg of H(2)S g(-1) of slag were attained, in spite of the very low specific surface area of the steel slags. As expected, humidity played a crucial role in the removal of H(2)S. Particle size had also an important effect on the capacity of the adsorption beds. Analysis of the exhausted slags revealed considerable amounts of elemental sulfur on the surface of the particles. Sulfates were also found on the exhausted slags, especially on the 212-500 MUm size fractions. The characterization of the slags prior and after the H(2)S adsorption experiments allowed us to postulate plausible mechanisms to understand the outstanding capacity of these steel byproduct for H(2)S adsorption. PMID- 22823419 TI - Generalization decrement and not overshadowing by associative competition among pairs of landmarks in a navigation task. AB - When they are trained in a Morris water maze to find a hidden platform, whose location is defined by a number of equally spaced visual landmarks round the circumference of the pool, rats are equally able to find the platform when tested with any two of the landmarks (Prados, & Trobalon, 1998; Rodrigo, Chamizo, McLaren, & Mackintosh, 1997). This suggests that none of the landmarks was completely overshadowed by any of the others. In Experiment 1 one pair of groups was trained with four equally salient visual landmarks spaced at equal intervals around the edge of the pool, while a second pair was trained with two landmarks only, either relatively close to or far from the hidden platform. After extensive training, both male and female rats showed a reciprocal overshadowing effect: on a test with two landmarks only (either close to or far from the platform), rats trained with four landmarks spent less time in the platform quadrant than those trained with only two. Experiment 2 showed that animals trained with two landmarks and then tested with four also performed worse on test than those trained and tested with two landmarks only. This suggests that generalization decrement, rather than associative competition, provides a sufficient explanation for the overshadowing observed in Experiment 1. Experiment 3 provided a within experiment replication of the results of Experiments 1 and 2. Finally, Experiment 4 showed that rats trained with a configuration of two landmarks learn their identity. PMID- 22823420 TI - Goal-directed and transfer-cue-elicited drug-seeking are dissociated by pharmacotherapy: evidence for independent additive controllers. AB - According to contemporary learning theory, drug-seeking behavior reflects the summation of 2 dissociable controllers. Whereas goal-directed drug-seeking is determined by the expected current incentive value of the drug, stimulus-elicited drug-seeking is determined by the expected probability of the drug independently of its current incentive value, and these 2 controllers contribute additively to observed drug-seeking. One applied prediction of this model is that smoking cessation pharmacotherapies selectively attenuate tonic but not cue-elicited craving because they downgrade the expected incentive value of the drug but leave expected probability intact. To test this, the current study examined whether nicotine replacement therapy (NRT) nasal spray would modify goal-directed tobacco choice in a human outcome devaluation procedure, but leave cue-elicited tobacco choice in a Pavlovian to instrumental transfer (PIT) procedure intact. Smokers (N= 96) first underwent concurrent choice training in which 2 responses earned tobacco or chocolate points, respectively. Participants then ingested either NRT nasal spray (1 mg) or chocolate (147 g) to devalue 1 outcome. Concurrent choice was then tested again in extinction to measure goal-directed control of choice, and in a PIT test to measure the extent to which tobacco and chocolate stimuli enhanced choice of the same outcome. It was found that NRT modified tobacco choice in the extinction test but not the extent to which the tobacco stimulus enhanced choice of the tobacco outcome in the PIT test. This dissociation suggests that the propensity to engage in drug-seeking is determined independently by the expected value and probability of the drug, and that pharmacotherapy has partial efficacy because it selectively effects expected drug value. PMID- 22823421 TI - Effects of thinning the rate at which the alternative behavior is reinforced on resurgence of an extinguished instrumental response. AB - Three experiments with rats examined the effects of thinning the rate of reinforcement for the alternative behavior in the resurgence paradigm. In all experiments, pressing one lever (L1) was first reinforced and then extinguished while pressing a second alternative lever (L2) was then reinforced. When L2 responding was then extinguished, L1 responses "resurged." Resurgence was always observed when L2 was reinforced on an unchanging reinforcement schedule during Phase 2. However, other rats received systematic decreases in the rate of L2 reinforcement before extinction of L2 began. Such a "thinning" procedure was predicted to reduce final resurgence by associating L1 extinction with longer and longer periods without a reinforcer. The procedure did reduce the resurgence effect observed when L2 was put on extinction (Experiment 3). However, in each experiment, thinned groups also returned to L1 responding, and continued to make L1 responses, while the reinforcement schedule for L2 was being thinned. Fine grained analysis of behavior in time suggested that this early resurgence was not due to adventitious reinforcement of L1, occasion setting of L1 by reinforcer presentation, or the entrainment of L1 as a schedule-induced interim behavior. The results are overall consistent with the hypothesis that resurgence is a renewal effect in which extinguished L1 responding recovers when the context provided by the L2 reinforcement schedule is changed. Challenges for this view are also discussed. PMID- 22823422 TI - Towards a mathematical model of within-session operant responding. AB - Operant response rate changes within the course of a typical free-operant experimental session. These changes are orderly, and reliably demonstrated with subjects from different species, responding under different experimental conditions. Killeen (1995) postulated that the response rate changes are a function of the interplay between arousal and satiation and offered a mathematical model for this hypothesis. Here we analyze Killeen's model, demonstrating that, although solid in its principles, it presents some flaws in its implementation. Then, based on the same principles, we build and test a new model of within-session motivation dynamics. We also demonstrate that, by representing arousal as a variable that ranges between 0 and 1, we can obtain a surprisingly simple model of free-operant response rate. PMID- 22823423 TI - A category-overshadowing effect in pigeons: support for the Common Elements Model of object categorization learning. AB - A model proposing error-driven learning of associations between representations of stimulus properties and responses can account for many findings in the literature on object categorization by nonhuman animals. Furthermore, the model generates predictions that have been confirmed in both pigeons and people, suggesting that these learning processes are widespread across distantly related species. The present work reports evidence of a category-overshadowing effect in pigeons' categorization of natural objects, a novel behavioral phenomenon predicted by the model. Object categorization learning was impaired when a second category of objects provided redundant information about correct responses. The same impairment was not observed when single objects provided redundant information, but the category to which they belonged was uninformative, suggesting that this effect is different from simple overshadowing, arising from competition among stimulus categories rather than individual stimuli during learning. PMID- 22823424 TI - Effects of nitrite on development of embryos and early larval stages of the zebrafish (Danio rerio). AB - Epidemiological studies suggest that high nitrate levels in food and water may cause birth defects or spontaneous abortions in humans. Experimental mammalian studies show that high nitrite levels adversely affect reproductive outcomes, but have not shown congenital malformations. Consequently, the teratogenic potential of nitrite is unclear. In this study, the effects of nitrite on development of zebrafish embryos and early larval stages were investigated. Eggs were exposed to ethanol (a known teratogen), nitrite, or nitrate for 24 or 96 hours, and larvae examined at 120 hours. Sublethal exposure to 300 mM ethanol for 24 hours caused severe pericardial and yolk sac edema, craniofacial and axial malformations, and swim bladder noninflation. The 96 hour LC(50) for nitrite was 411 mg/L. Less severe edema, craniofacial (but not axial) malformations, swim bladder noninflation, and immobility were observed after sublethal exposure to nitrite between 10 and 300 mg/L for 96 hours. Exposure to nitrite for 24 hours at concentrations as high as 2000 mg/L was not lethal. Only axial malformations and swim bladder noninflation were observed at 1500 mg/L. The results demonstrate that sublethal nitrite concentrations cause developmental defects. The type and magnitude of these defects differed after 24 and 96 hours of exposure. PMID- 22823425 TI - Molecular modeling to provide insight into the substrate binding and catalytic mechanism of human biliverdin-IXalpha reductase. AB - Human biliverdin-IXalpha reductase (hBVR-A) catalyzes the conversion of biliverdin-IXalpha to bilirubin-IXalpha in the last step of heme degradation and is a key enzyme in regulating a wide range of cellular responses. Though the X ray structure of hBVR-A is available including cofactor, a crystal structure with a bound substrate would be even more useful as a starting point for protein structure-based inhibitor design, but none have been reported. The present study employed induced fit docking (IFD) to study the substrate binding modes to hBVR-A of biliverdin-IXalpha and four analogues. The proposed substrate binding modes were examined further by performing molecular dynamics (MD) simulations followed by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The predicted binding free energies for the five biliverdin-IXalpha analogues match well with the relative potency of their reported experimental binding affinities, supporting that the proposed binding modes are reasonable. Furthermore, the ternary complex structure of hBVR-A binding with biliverdin-IXalpha and the electron donor cofactor NADPH obtained from MD simulations was exploited to investigate the catalytic mechanism, by calculating the reaction energy profile using the quantum mechanics/molecular mechanics (QM/MM) method. On the basis of our calculations, the energetically preferred pathway consists of an initial protonation of the pyrrolic nitrogen on the biliverdin substrate followed by hydride transfer to yield the reduction product. This conclusion is consistent with a previous mechanistic study on human biliverdin IXbeta reductase (hBVR-B). PMID- 22823426 TI - Three-dimensional location of the retaining screw axis for a cemented single tooth implant restoration. AB - Retrievability is a major concern with cemented versus screw-retained implant restorations. This article describes the use of cone beam radiography to help target and create a precise screw access opening for a loosened implant-supported single crown retained by cement to its abutment. PMID- 22823427 TI - Functional roles of H98 and W99 and beta2alpha2 loop dynamics in the alpha-l arabinofuranosidase from Thermobacillus xylanilyticus. AB - This study is focused on the elucidation of the functional role of the mobile beta2alpha2 loop in the alpha-L-arabinofuranosidase from Thermobacillus xylanilyticus, and particularly on the roles of loop residues H98 and W99. Using site-directed mutagenesis, coupled to characterization methods including isothermal titration calorimetry (ITC) and saturation transfer difference nuclear magnetic resonance (STD-NMR) spectroscopy, and molecular dynamics simulations, it has been possible to provide a molecular level view of interactions and the consequences of mutations. Binding of para-nitrophenyl alpha-L-arabinofuranoside (pNP-alpha-l-Araf) to the wild-type arabinofuranosidase was characterized by K(d) values (0.32 and 0.16 mm, from ITC and STD-NMR respectively) that highly resembled that of the arabinoxylo-oligosaccharide XA(3)XX (0.21 mm), and determination of the thermodynamic parameters of enzyme : pNP-alpha-L-Araf binding revealed that this process is driven by favourable entropy, which is linked to the movement of the beta2alpha2 loop. Loop closure relocates the solvent-exposed W99 into a buried location, allowing its involvement in substrate binding and in the formation of a functional active site. Similarly, the data underline the role of H98 in the 'dynamic' formation and definition of a catalytically operational active site, which may be a specific feature of a subset of GH51 arabinofuranosidases. Substitution of H98 and W99 by alanine or phenylalanine revealed that mutations affected K(M) and/or k(cat). Molecular dynamics performed on W99A implied that this mutation causes the loss of a hydrogen bond and leads to an alternative binding mode that is detrimental for catalysis. STD-NMR experiments revealed altered binding of the aglycon motif in the active site, combined with reduced STD intensities of the alpha-L arabinofuranosyl moiety for W99 substitutions. PMID- 22823428 TI - Infrared spectra of CH3-MH through methane activation by laser-ablated Sn, Pb, Sb, and Bi atoms. AB - Methane activation has been carried out by laser-ablated Sn, Pb, Sb, and Bi atoms. All four metals generate the insertion complex (CH(3)-MH), but subsequent H-migration from C to M to form CH(2)-MH(2) and CH-MH(3) complexes is not observed. Our previous and present experimental and computational results indicate that the higher oxidation state complexes become less favored with increasing atomic mass in groups 14 and 15, which is opposite the general trend found for transition metals. The C-H bond insertion evidently occurs during reaction on sample condensation, and the product dissociates on broad-band photolysis afterward. The insertion complex contains a near right angle C-M-H moiety because of high p contribution from the metal center to the C-M and M-H bonds unlike many transition-metal analogues. The computed methylidene structures for these main group metals are not agostic possibly because of the absence of valence d-orbitals. PMID- 22823429 TI - TGF-beta neutralization abrogates the inhibited DHEA production mediated by factors released from M. tuberculosis-stimulated PBMC. AB - Supernatants (SN) from cultures of peripheral blood mononuclear cells (PBMC) of tuberculosis (TB) patients inhibit dehydroepiandrosterone (DHEA) secretion by the adrenal cell line NCI-H295R. To analyze whether TGF-beta is involved in this effect, SN of PBMC from healthy controls or patients with severe TB infections, stimulated or not with Mycobacterium tuberculosis (Mtb SN), were added to adrenal cells under basal conditions or following stimulation with forskolin. Cortisol and DHEA concentrations were evaluated in supernatants of the adrenal cells cultured with or without the addition of anti-TGF-beta. Treatment with Mtb SN from TB inhibited DHEA production, and this effect was reversed when SN were treated with anti-TGF-beta. The increase in cortisol production induced by SN from TB patients was not affected by TGF-beta neutralization. Mediators released during the anti-TB immune response differentially modulate steroid production by adrenal cells, and TGF-beta is a cytokine implicated in the inhibition of DHEA production observed in TB. PMID- 22823430 TI - Changes in the immune and endocrine responses of patients with pulmonary tuberculosis undergoing specific treatment. AB - We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1beta, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects. PMID- 22823431 TI - Sex steroids, immune system, and parasitic infections: facts and hypotheses. AB - It has been widely reported that the incidence and the severity of natural parasitic infections are different between males and females of several species, including humans. This sexual dimorphism involves a distinct exposure of males and females to various parasite infective stages, differential effects of sex steroids on immune cells, and direct effects of these steroids on parasites, among others. Typically, for a large number of parasitic diseases, the prevalence and intensity is higher in males than females; however, in several parasitic infections, males are more resistant than females. In the present work, we review the effects of sex hormones on immunity to protozoa and helminth parasites, which are the causal agents of several diseases in humans, and discuss the most recent research related to the role of sex steroids in the complex host-parasite relationship. PMID- 22823432 TI - Extrathymic CD4+CD8+ lymphocytes in Chagas disease: possible relationship with an immunoendocrine imbalance. AB - Double-positive (DP) CD4(+) CD8(+) T cells normally represent a thymic subpopulation that is developed in the thymus as a precursor of CD4(+) or CD8(+) single-positive T cells. Recent evidence has shown that DP cells with an activated phenotype can be tracked in secondary lymph organs. The detection of an activated DP population in the periphery, a population that expresses T cell receptors unselected during thymic negative selection in murine models of Trypanosoma cruzi infection and in humans with Chagas disease, raise new questions about the relevance of this population in the pathogenesis of this major parasitic disease and its possible link with immunoendocrine alterations. PMID- 22823433 TI - Different peripheral neuroendocrine responses to Trypanosoma cruzi infection in mice lacking adaptive immunity. AB - Trypanosoma cruzi infection in mice triggers neuroendocrine responses that affect the course of the disease. To analyze the contribution of adaptive immunity to these responses, comparative studies between normal C57Bl/6J and recombinase activator gene 1 (RAG-1)-deficient mice, which lack mature B and T lymphocytes, were performed. There was no difference between both types of mice in basal body weight. Following infection, higher parasitemia, increased IL-1beta and IL-6 blood levels, less marked changes in lymphoid organs weight, no cardiomegaly, and earlier mortality were observed in RAG-1-deficient, compared with normal mice. The response of the hypothalamus-pituitary-adrenal axis after infection occurred earlier and was more intense in RAG-1-deficient mice than in normal mice. Noradrenaline concentration and serotonergic metabolism in the spleen, lymph nodes, and heart differed between RAG-1-deficient and normal mice. Our studies indicate that the absence of adaptive immunity to T. cruzi influences the neuroendocrine response to the infection with this parasite. PMID- 22823434 TI - Thymic atrophy in acute experimental Chagas disease is associated with an imbalance of stress hormones. AB - Disorders in the hypothalamic-pituitary-adrenal axis are associated with the pathogenesis of Trypanosoma cruzi infection. During the acute phase of this disease, increased levels of circulating glucocorticoids (GCs) correlate with thymic atrophy. Recently, we demonstrated that this phenomenon is paralleled by a decrease of prolactin (PRL) secretion, another stress hormone that seems to counteract many immunosuppressive effects of GCs. Both GCs and PRL are intrathymically produced and exhibit mutual antagonism through the activation of their respective receptors, GR, and PRLR. Considering that GCs induce apoptosis and inhibit double-positive (DP) thymocyte proliferation and that PRL administration prevents these effects, it seems plausible that a local imbalance of GR-PRLR crosstalk underlies the thymic involution occurring in acute T. cruzi infection. In this respect, preserving PRLR signaling seems to be crucial for protecting DP from GC-induced apoptosis. PMID- 22823435 TI - Endocrine, metabolic, and immunologic components of HIV infection. AB - It is generally accepted that the progression of HIV infection is the consequence of increased HIV virus load and defective CD4(+) T cell-mediated immunity. Previous studies have shown that T helper-directed cellular immunity is suppressed in hypercortisolemic HIV patients, while it is activated in cortisol resistant HIV patients. This is suggestive of a cytokine system intimately linked with cortisol and its receptors. Highly active antiretroviral therapy is an important advance in the treatment of HIV infection, but the suppression of viral replication is not associated with reconstitution of the immune function. This would account for reduced control of inflammation and the activation of 11beta hydroxysteroid dehydrogenase type 1(11beta-HSD1) and increases in glucocorticoid and mineralocorticoid production in peripheral tissues. Such hormonal activation may cause insulin resistance and cardiometabolic complications. Therapeutic approaches with 11beta-HSD1 inhibitors, aldosterone antagonists, type 1 angiotensin receptor blockers, or renin inhibitors are suggested. PMID- 22823436 TI - Autoimmune diseases and infections as risk factors for schizophrenia. AB - Immunological hypotheses have become increasingly prominent when studying the etiology of schizophrenia. Autoimmune diseases, and especially the number of infections requiring hospitalization, have been identified as significant risk factors for schizophrenia in a dose-response relationship, which seem compatible with an immunological hypothesis for subgroups of patients with schizophrenia. Inflammation and infections may affect the brain through many different pathways that are not necessarily mutually exclusive and can possibly increase the risk of schizophrenia in vulnerable individuals. However, the findings could also be an epiphenomenon and not causal, due to, for instance, common genetic vulnerability, which could be supported by the observations of an increased prevalence of autoimmune diseases and infections in parents of patients with schizophrenia. Nevertheless, autoimmune diseases and infections should be considered in the treatment of individuals with schizophrenia symptoms, and further research is needed of the immune system's possible contributing pathogenic factors in the etiology of schizophrenia. PMID- 22823437 TI - Antidepressants prevent hierarchy destabilization induced by lipopolysaccharide administration in mice: a neurobiological approach to depression. AB - In spite of the high prevalence and negative impact of depression, little is known about its pathophysiology. Basic research on depression needs new animal models in order to increase knowledge of the disease and search for new therapies. The work presented here aims to provide a neurobiologically validated model for investigating the relationships among sickness behavior, antidepressants treatment, and social dominance behavior. For this purpose, dominant individuals from dyads of male Swiss mice were treated with the bacterial endotoxin lipopolysaccharide (LPS) to induce social hierarchy destabilization. Two groups were treated with the antidepressants imipramine and fluoxetine prior to LPS administration. In these groups, antidepressant treatment prevented the occurrence of social destabilization. These results indicate that this model could be useful in providing new insights into the understanding of the brain systems involved in depression. PMID- 22823438 TI - Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer's disease. AB - Neurodegenerative diseases such as Alzheimer's disease (AD) can be understood in the context of the aging of neuroimmune communication. Although the contribution to AD of the immune cells present in the brain is accepted, the role of the peripheral immune system is less well known. The present review examines the behavior and the function and redox state of peripheral immune cells in a triple transgenic mouse model (3*Tg-AD). These animals develop both beta-amyloid plaques and neurofibrillary tangles with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We have observed age and sex-related changes in several aspects of behavior and immune cell functions, which demonstrate premature aging. Lifestyle strategies such as physical exercise and environmental enrichment can improve these aspects. We propose that the analysis of the function and redox state of peripheral immune cells can be a useful tool for measuring the progression of AD. PMID- 22823439 TI - Effects of plasmalogens on systemic lipopolysaccharide-induced glial activation and beta-amyloid accumulation in adult mice. AB - Neuroinflammation essentially involves an activation of glial cells as the cause/effect of neurodegenerative diseases such as Alzheimer's disease (AD). Plasmalogens (Pls) are glycerophospholipids constituting cellular membranes and play significant roles in membrane fluidity and cellular processes like vesicular fusion and signal transduction. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 250 MUg/kg) for 7 days resulted in the morphological changes and increase in number of Iba-1(+) microglia showing neuroinflammation in the adult mouse hippocampus. The LPS-induced activation of glial cells was significantly attenuated by i.p. pretreatment with Pls dissolved in corn oil. In addition, systemic injection of LPS induced Abeta(1-16) (+) neurons in the hippocampus were also abolished by application of Pls. Finally, contents of Pls in the hippocampus decreased after LPS injection, and the reduction was suppressed by administration of Pls. These findings suggest an antiamyloidogenic effect of Pls, implicating a possible therapeutic application of Pls against AD. PMID- 22823440 TI - Biological memory of childhood maltreatment: current knowledge and recommendations for future research. AB - Child maltreatment (CM) not only has detrimental and lifelong psychological consequences, but also can lead to lasting alterations in core physiological systems--a biological memory of CM. Furthermore, some of these alterations might even be transmitted to the next generation. This article describes current knowledge about the effects of CM on the stress system (i.e., the hypothalamus pituitary-adrenal axis), on cellular aging (i.e., telomere length and telomerase activity), and on the immune system. Furthermore, we want to initiate research on the question of transmission of the described physiological alterations subsequent to CM to the next generation--possibly through epigenetic imprinting. As diverse neurobiological factors and epigenetics are closely linked, these different research fields should join forces to gain a deeper understanding of the biological determinants and sequelae of CM and its transmission. PMID- 22823442 TI - Experimental endotoxemia as a model to study neuroimmune mechanisms in human visceral pain. AB - The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well-established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. This knowledge gap is particularly striking in the context of visceral pain in functional as well as chronic-inflammatory gastrointestinal disorders. Although inflammatory processes have been implicated in the pathophysiology of visceral pain, it remains incompletely understood how inflammatory mediators interact with bottom-up (i.e., increased afferent input) and top-down (i.e., altered central pain processing) mechanisms of visceral hyperalgesia. Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions. PMID- 22823441 TI - Chronic neuropathic pain-like behavior and brain-borne IL-1beta. AB - Neuropathic pain in animals results in increased IL-1beta expression in the damaged nerve, the dorsal root ganglia, and the spinal cord. Here, we discuss our results showing that this cytokine is also overexpressed at supraspinal brain regions, in particular in the contralateral side of the hippocampus and prefrontal cortex and in the brainstem, in rats with neuropathic pain-like behavior. We show that neuropathic pain degree and development depend on the specific nerve injury model and rat strain studied, and that there is a correlation between hippocampal IL-1beta expression and tactile sensitivity. Furthermore, the correlations between hippocampal IL-1beta and IL-1ra or IL-6 observed in control animals, are disrupted in rats with increased pain sensitivity. The lateralization of increased cytokine expression indicates that this alteration may reflect nociception. The potential functional consequences of increased IL-1beta expression in the brain during neuropathic pain are discussed. PMID- 22823443 TI - The neuroimmune connection interferes with tissue regeneration and chronic inflammatory disease in the skin. AB - Research over the past decades has revealed close interactions between the nervous and immune systems that regulate peripheral inflammation and link psychosocial stress with chronic somatic disease. Besides activation of the sympathetic and the hypothalamus-pituitary-adrenal axis, stress leads to increased neurotrophin and neuropeptide production in organs at the self environment interface. The scope of this short review is to discuss key functions of these stress mediators in the skin, an exemplary stress-targeted and stress sensitive organ. We will focus on the skin's response to acute and chronic stress in tissue regeneration and pathogenesis of allergic inflammation, psoriasis, and skin cancer to illustrate the impact of local stress-induced neuroimmune interaction on chronic inflammation. PMID- 22823444 TI - 17alpha-androstenediol-mediated oncophagy of tumor cells by different mechanisms is determined by the target tumor. AB - Delta5-androstene-3beta,17alpha-diol (17alpha-AED) mediates oncophagy of human myeloid, glioma, and breast tumor cells by apoptotic- and autophagic-programmed cell death pathways, whereas the 17beta-epimer does not. In hematologically derived myeloid tumor cells, 17alpha-AED induced apoptosis, as determined by TUNEL staining, caspase, PARP activation, and electron microscopy. In contrast, 17alpha-AED treatment of glioma cells of neuroectodermal lineaged induced autophagy, evident by the presence of acidic vesicular organelles, LC3 processing, and upregulation of beclin-1. Proliferation inhibition studies on primary and established glioma cells demonstrated that the IC-50 of the steroid is ~15 MUM. In the case of breast cancer cells, the bioactivity of 17alpha-AED is independent of the expression of estrogen or androgen receptors. Collectively, oncophagy is induced by 17alpha-AED treatment in human tumor cells and proceeds by the induction of either autophagy or apoptosis. The neoplastic cell determines which oncophagic pathway is utilized. PMID- 22823446 TI - Neuroimmunomodulation in health and disease. PMID- 22823445 TI - Cellular and molecular players in the atherosclerotic plaque progression. AB - Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed. PMID- 22823447 TI - Electronic transport in two stacked graphene monolayers. AB - We report on interlayer and lateral electronic transport measurements in two stacked graphene monolayers which have separate electrical contacts. The current voltage characteristic across the two layers shows linear Ohmic behavior at zero magnetic field. At high magnetic fields, sequences of quantum Hall plateaus of the overlap region with filling factors 4, 8, and 12 are observed which can be explained by equilibration of the edge channel potentials of the individual graphene layers. An anomaly is observed at total filling factors +/-2 in the overlap region. The I-V characteristic for interlayer transport turns nonlinear, and the Hall signal vanishes, indicating a magnetic field induced electrical decoupling of the two graphene layers. PMID- 22823448 TI - Patterns of choices on video game genres and Internet addiction. AB - In this study, we attempt to identify motives pivotal in choices made regarding online and offline game genres and assess whether they are meaningful predictors of Internet addiction. A separate goal was to determine how an assessment of Internet-related cognitions compares to criteria-based research instruments on Internet addiction, and demonstrate its clinical usefulness. We are using data from a cross-sectional study of the entire adolescent student population aged 12 18 of the island of Kos. Results indicate that specific game genres and motives for choosing a game are important predictors of Internet addiction, even after accounting for sociodemographic and Internet-use-related variables. Gender differences are not statistically important when we account for genre choices and motives for choosing them. Boys' thought content tends to revolve more around their Internet use compared to girls. Several patterns of motives to play specific genres were identified with the help of a canonical correlation analysis, demonstrating the fact that the simple observation of overt behavior is not enough to deduce the meaning of these actions for the individual. Using multiple measures of online addiction, examining genre preferences and underlying motives for choosing a game can be helpful in reaching a better understanding of the individual game player. PMID- 22823449 TI - Safety and long-term outcome of modified intracardiac echocardiography-assisted "no-balloon" sizing technique for transcatheter closure of ostium secundum atrial septal defect. AB - BACKGROUND: The need for sizing the secundum atrial septal defect (ASD) with the balloon sizing technique is still debated at least in adult patients. We sought to prospectively evaluate the effectiveness of intracardiac echocardiography (ICE)-aided sizing technique for transcatheter closure of secundum ASD, without using a balloon sizing. METHODS: In a prospective 5-year registry, we enrolled 81 patients (mean age 48 +/- 13.7 years, 54 females) who had been referred to three different centers for atheter-based closure of secundum ASD. Eligible patients underwent ICE study and closure attempt. In a preliminary group of 21 patients, sizing balloon was performed under ICE guidance to assess the value of rim thickness necessary for device anchorage. In the remaining 60 patients, the retrieved value of the rim thickness was measured on ICE and used as key points to measure the defect and select the device. RESULTS: In the preliminary group of patients, the value of thickness at point of initial deflection by the balloon was 1.23 +/- 0.1 mm. ASD diameter in the study group was measured at the point of rim with at least 1.2 mm and the mean ASD diameter was 26.2 +/- 10.1 mm. Rates of procedural success, predischarge occlusion, and major complications rate were 100%, 93.3%, and 0%, respectively. On mean follow-up of 5.4 +/- 1.8 years, the occlusion rate was 98.7% with no long-term complications. CONCLUSIONS: Our novel ICE-sizing technique appears to be safe and effective in adult patients, thus eventually minimizing overestimation, costs, and potential complications of balloon sizing. PMID- 22823450 TI - Setting research priorities for Type 1 diabetes. AB - AIMS: Research priorities are often set by academic researchers or the pharmaceutical industry. The interests of patients, carers and clinicians may therefore be overlooked and research questions that matter may be neglected. The aims of this study were to collect uncertainties about the treatment of Type 1 diabetes from patients, carers and health professionals, and to collate and prioritize these uncertainties to develop a top 10 list of research priorities, using a structured priority-setting partnership of patients, carers, health professionals and diabetes organizations, as described by the James Lind Alliance. METHODS: A partnership of interested organizations was set up, and from this a steering committee of 10 individuals was formed. An online and paper survey was used to identify uncertainties. These were collated, and the steering group carried out an interim priority-setting exercise with partner organizations. This group of uncertainties was then voted on to give a smaller list that went forward to the final priority-setting workshop. At this meeting, a final list of the top 10 research priorities was agreed. RESULTS: An initial 1141 uncertainties were described. These were reduced to 88 indicative questions, 47 of which went out for voting. Twenty-four were then taken forward to a final priority-setting workshop. This workshop resulted in a list of top 10 research priorities in Type 1 diabetes. CONCLUSION: We have shown that it is possible using the James Lind Alliance process to develop an agreed top 10 list of research priorities for Type 1 diabetes from health professionals, patients and carers. PMID- 22823451 TI - Multianalysis of 35 mycotoxins in traditional Chinese medicines by ultra-high performance liquid chromatography-tandem mass spectrometry coupled with accelerated solvent extraction. AB - A generic procedure, which involved accelerated solvent extraction and homemade cleanup cartridges, has been developed for the extraction and purification of 35 mycotoxins in various traditional Chinese medicine (TCM) matrixes, i.e., rhizomes and roots, seeds, flowers, and grasses and leaves, for subsequent analysis by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS). All target analytes could be simultaneously quantitated in less than 17 min per run, showing narrow symmetrical peaks. The developed method was also successfully applied in routine monitoring programs, which implied a significant reduction of both effort and time, to investigate the contamination of TCMs. Among 60 commercial TCMs analyzed, 50 were positive. The achieved data underpin the practical application of the UHPLC-MS/MS method as a valuable tool for the trace analysis of multiple mycotoxins in TCMs. PMID- 22823452 TI - Assessment of required nodal yield in a high risk cohort undergoing extended pelvic lymphadenectomy in robotic-assisted radical prostatectomy and its impact on functional outcomes. AB - OBJECTIVES: To establish a minimal lymph node yield (LNY) necessary for accurate staging in a high risk cohort, since no consensus exists as to the optimal extent of pelvic lymph node dissection (PLND) needed during radical prostatectomy in high risk patients. To investigate the impact of an extended PLND on urinary and sexual function. PATIENTS AND METHODS: In all, 760 men underwent robotic-assisted radical prostatectomy from January 2010 to May 2011 by a single surgeon (AKT). Low and intermediate risk groups (as defined by the D'Amico classification) underwent a minimum of a limited PLND (obturator/external iliac packets) and high risk patients underwent an extended PLND (as limited plus hypogastric, triangle of Marcille and common iliac packets up to the level of the ureteric crossing). In order to analyse LNY for staging purposes, the high risk group (n = 82) was subdivided into patients with >=13 LNY vs <13 LNY and the incidence of lymph node (LN) invasion was compared between these groups. To study the impact of extended PLND on functional outcomes, we evaluated patients from our total cohort who were preoperatively potent (Sexual Health Inventory for Men >=17), continent and who received bilateral nerve-sparing surgery. Return to potency at 26 weeks postoperatively was defined as a score of >=3 on questions 2 and 3 of the Sexual Health Inventory for Men questionnaire, and continence was defined as zero pads per day or one pad for security per day. RESULTS: Median LNYs in the low, intermediate and high risk groups were (interquartile range [IQR]) 5 (2-10), 7 (3 12) and 13 (6-20) (P < 0.001); LN positivity was 0% (0 of 309), 0.8% (3 of 369) and 13.4% (11 of 82) in the three respective groups (P < 0.001). Median LNYs (IQR) among the high risk LN positive and negative patients were 20 (13-22) and 11 (5-18) (P = 0.05); 5% of the patients had positive LNs in the <13 LNY group vs 21% of patients in the >13 LNY group (P = 0.036). Median (IQR) console time was significantly different, at 120 min (95-137) for the >=13 LNY group vs 100 min (85-120) for the <13 LNY group (P = 0.04). Among patients who fitted the inclusion criteria for functional outcomes (n = 561), 55.2% (16 of 29) with >=20 LNs removed recovered potency at a median follow-up of 6 months postoperatively vs 70% of patients with <20 LNs (301 of 430) (P = 0.020). There was no significant difference in continence recovery between the groups. CONCLUSIONS: High risk patients should undergo an extended dissection with at least 13 LNs removed for accurate staging. Extended PLND with LNYs of >=20 is associated with worse potency outcomes. With LN positivity occurring rarely in low risk patients, extended PLND may be of little oncological benefit but with significant functional compromise in this cohort. PMID- 22823453 TI - P-chiral phosphine-sulfonate/palladium-catalyzed asymmetric copolymerization of vinyl acetate with carbon monoxide. AB - Utilization of palladium catalysts bearing a P-chiral phosphine-sulfonate ligand enabled asymmetric copolymerization of vinyl acetate with carbon monoxide. The obtained gamma-polyketones have head-to-tail and isotactic polymer structures. The origin of the regio- and stereoregularities was elucidated by stoichiometric reactions of acylpalladium complexes with vinyl acetate. The present report for the first time demonstrates successful asymmetric coordination-insertion (co)polymerization of vinyl acetate. PMID- 22823454 TI - Ultrasensitive electrochemical detection of nucleic acids by template enhanced hybridization followed with rolling circle amplification. AB - An ultrasensitive protocol for electrochemical detection of DNA is designed with quantum dots (QDs) as a signal tag by combining the template enhanced hybridization process (TEHP) and rolling circle amplification (RCA). Upon the recognition of the molecular beacon (MB) to target DNA, the MB hybridizes with assistants and target DNA to form a ternary ''Y-junction''. The target DNA can be dissociated from the structure under the reaction of nicking endonuclease to initiate the next hybridization process. The template enhanced MB fragments further act as the primers of the RCA reaction to produce thousands of repeated oligonucleotide sequences, which can bind with oligonucleotide functionalized QDs. The attached signal tags can be easily read out by square-wave voltammetry after dissolving with acid. Because of the cascade signal amplification and the specific TEHP and RCA reaction, this newly designed protocol provides an ultrasensitive electrochemical detection of DNA down to the attomolar level (11 aM) with a linear range of 6 orders of magnitude (from 1 * 10(-17) to 1 * 10(-11) M) and can discriminate mismatched DNA from perfect matched target DNA with high selectivity. The high sensitivity and specificity make this method a great potential for early diagnosis in gene-related diseases. PMID- 22823455 TI - The burden and management of dyslipidemia: practical issues. AB - The objective of this study is to describe briefly the burden of dyslipidemia, and to discuss and present strategies for health professionals to improve dyslipidemia management, based on a review of selected literature focusing on interventions for dyslipidemia treatment adherence. Despite the availability of effective lifestyle and pharmaceutical therapies for dyslipidemias, they continue to present a significant economic burden in the United States. Adherence to evidence-based guidelines for the treatment of dyslipidemias is unsatisfactory. The reasons for medication nonadherence are complex and specific to each patient. The lack of progress in achieving optimal lipid targets is caused by many factors: patient (medication adherence, cost of medication, literacy), medication (adverse effects, complexity of regimen), provider (lack of adherence to evidence based practice guidelines, poor communication), and the US healthcare system (being focused on acute care rather than prevention, lack of continuity of care, general lack of use of an electronic health record). Combined interventions that target each part of the system have been effective in improving treatment adherence and achieving lipid goals. Patients, providers, pharmacists, and employers all play a role in management of dyslipidemia. No single approach will solve the complex issue of improving dyslipidemia management. The required lifestyle changes are known and effective medications are available. The challenge is for all interested parties-including nurses, nurse practitioners, doctors, pharmacists, other health care professionals, employers, and health plans-to help patients achieve behavioral changes. PMID- 22823456 TI - Maternal effects on male weaponry: female dung beetles produce major sons with longer horns when they perceive higher population density. AB - BACKGROUND: Maternal effects are environmental influences on the phenotype of one individual that are due to the expression of genes in its mother, and are expected to evolve whenever females are better capable of assessing the environmental conditions that their offspring will experience than the offspring themselves. In the dung beetle Onthophagus taurus, conditional male dimorphism is associated with alternative reproductive tactics: majors fight and guard females whereas minors sneak copulations. Furthermore, variation in dung beetle population density has different fitness consequences for each male morph, and theory predicts that higher population density might select for a higher frequency of minors and/or greater expenditure on weaponry in majors. Because adult dung beetles provide offspring with all the nutritional resources for their development, maternal effects strongly influence male phenotype. RESULTS: Here we tested whether female O. taurus are capable of perceiving population density, and responding by changing the phenotype of their offspring. We found that mothers who were reared with other conspecifics in their pre-mating period produced major offspring that had longer horns across a wider range of body sizes than the major offspring of females that were reared in isolation in their pre-mating period. Moreover, our results indicate that this maternal effect on male weaponry does not operate through the amount of dung provided by females to their offspring, but is rather transmitted through egg or brood mass composition. Finally, although theory predicts that females experiencing higher density might produce more minor males, we found no support for this, rather the best fitting models were equivocal as to whether fewer or the same proportions of minors were produced. CONCLUSIONS: Our study describes a new type of maternal effect in dung beetles, which probably allows females to respond to population density adaptively, preparing at least their major offspring for the sexual competition they will face in the future. This new type of maternal effect in dung beetles represents a novel transgenerational response of alternative reproductive tactics to population density. PMID- 22823457 TI - Small-angle neutron scattering study of protein crowding in liquid and solid phases: lysozyme in aqueous solution, frozen solution, and carbohydrate powders. AB - The structure, interactions, and interprotein configurations of the protein lysozyme were studied in a variety of phases. These properties have been studied under a variety of solution conditions before, during, and after freezing and after freeze-drying in the presence of glucose and trehalose. Contrast variation experiments have also been performed to determine which features of the scattering in the frozen solutions are from the protein and which are from the ice structure. Data from lysozyme at concentrations ranging from 1 to 100 mg/mL in solution and water ice with NaCl concentrations ranging from 0 to 0.4 mol/L are fit to model small-angle neutron scattering (SANS) intensity functions consisting of an ellipsoidal form factor and either a screened-Coulomb or hard sphere structure factor. Parameters such as protein volume fraction and long dimension are followed as a function of temperature and salt concentration. The SANS results are compared to real space models of concentrated lysozyme solutions at the same volume fractions obtained from Monte Carlo simulations. A cartoon representation of the frozen lysozyme solution in 0 mol/L NaCl is presented based on the SANS and Monte Carlo results, along with those obtained from other complementary methods. PMID- 22823458 TI - Single molecule force spectroscopy reveals critical roles of hydrophobic core packing in determining the mechanical stability of protein GB1. AB - Understanding molecular determinants of protein mechanical stability is important not only for elucidating how elastomeric proteins are designed and functioning in biological systems but also for designing protein building blocks with defined nanomechanical properties for constructing novel biomaterials. GB1 is a small alpha/beta protein and exhibits significant mechanical stability. It is thought that the shear topology of GB1 plays an important role in determining its mechanical stability. Here, we combine single molecule atomic force microscopy and protein engineering techniques to investigate the effect of side chain reduction and hydrophobic core packing on the mechanical stability of GB1. We engineered seven point mutants and carried out mechanical phi-value analysis of the mechanical unfolding of GB1. We found that three mutations, which are across the surfaces of two subdomains that are to be sheared by the applied stretching force, in the hydrophobic core (F30L, Y45L, and F52L) result in significant decrease in mechanical unfolding force of GB1. The mechanical unfolding force of these mutants drop by 50-90 pN compared with wild-type GB1, which unfolds at around 180 pN at a pulling speed of 400 nm/s. These results indicate that hydrophobic core packing plays an important role in determining the mechanical stability of GB1 and suggest that optimizing hydrophobic interactions across the surfaces that are to be sheared will likely be an efficient method to enhance the mechanical stability of GB1 and GB1 homologues. PMID- 22823459 TI - Epimediphine, a novel alkaloid from Epimedium koreanum inhibits acetylcholinesterase. AB - A novel aporphine alkaloid was isolated from the leaves of Epimedium koreanum Nakai during activity-guided fractionation in search of compounds with an anticholinesterase activity. The structure of the new compound was assigned as 1,10-methoxy-7-hydroxy-aporphine (1), which we have named epimediphine. Unambiguous (1)H-NMR and (13)C-NMR data for epimediphine are described. Epimediphine inhibited an acetylcholinesterase (AchE) activity in a dose dependent manner with an IC50 value of 3.1 uM. Meanwhile, tacrine, dehydroevodiamine and physostigmine, which are therapeutic drugs or candidates for AD, exhibited an anti-AchE activity with IC50 values of 0.4, 37.9 and 0.12 uM, respectively. PMID- 22823460 TI - A nondysraphic paraspinal mass and a ventricular septal defect: unusual components of diabetes-induced mesodermal derangement. AB - Solitary paraspinal masses in the pediatric age group commonly occur secondary to spinal dysraphism, chronic inflammatory conditions, and tumors. We describe the unusual case of a 10-year-old boy with a nondysraphic, paraspinal mass that had occurred secondary to congenital spinal epidural lipomatosis (SEL) in the setting of poorly controlled maternal type-I diabetes mellitus. The mass was picked up along with a ventricular septal defect (VSD) on an antenatal ultrasonogram. This is the first report in literature of SEL presenting as a solitary paraspinal mass at birth, and in the unusual setting of an antenatal mesodermal derangement that simultaneously engendered a VSD. PMID- 22823461 TI - Structural origin of polymorphism of Alzheimer's amyloid beta-fibrils. AB - Formation of senile plaques containing amyloid fibrils of Abeta (amyloid beta peptide) is a pathological hallmark of Alzheimer's disease. Unlike globular proteins, which fold into unique structures, the fibrils of Abeta and other amyloid proteins often contain multiple polymorphs. Polymorphism of amyloid fibrils leads to different toxicity in amyloid diseases and may be the basis for prion strains, but the structural origin for fibril polymorphism is still elusive. In the present study we investigate the structural origin of two major fibril polymorphs of Abeta40: an untwisted polymorph formed under agitated conditions and a twisted polymorph formed under quiescent conditions. Using electron paramagnetic resonance spectroscopy, we studied the inter-strand side chain interactions at 14 spin-labelled positions in the Abeta40 sequence. The results of the present study show that the agitated fibrils have stronger inter strand spin-spin interactions at most of the residue positions investigated. The two hydrophobic regions at residues 17-20 and 31-36 have the strongest interactions in agitated fibrils. Distance estimates on the basis of the spin exchange frequencies suggest that inter-strand distances at residues 17, 20, 32, 34 and 36 in agitated fibrils are approximately 0.2 A (1 A=0.1 nm) closer than in quiescent fibrils. We propose that the strength of inter-strand side-chain interactions determines the degree of beta-sheet twist, which then leads to the different association patterns between different cross beta-units and thus distinct fibril morphologies. Therefore the inter-strand side-chain interaction may be a structural origin for fibril polymorphism in Abeta and other amyloid proteins. PMID- 22823462 TI - Adult human progenitor cells from the temporal lobe: another source of neuronal cells. AB - OBJECTIVES: In the adult human brain, neurogenesis occurs in the SVZ and the dentate gyrus of the hippocampus, but it is still unclear whether persistent neural progenitor/stem cells are also present in other brain areas. The present work studies the possibility of obtaining neural progenitor/stem cells from the temporal lobe and investigates their potential to differentiate into neuronal cells. METHODS: Human biopsies from the temporal lobe of epileptic patients were used to isolate potential neural progenitors. Differentiation was induced in the presence of different agents (NGF, NT3, RA) and immunocytochemistry was then performed for quantitative analysis. RESULTS: It was shown that a significant number of cells in the temporal lobe are also capable of expansion and multi potency. These cells can be amplified as neurospheres and have the potential to differentiate naturally in vitro into neurons, astrocytes and oligodendrocytes. Quantitative analyses show that the progenitor cells of the temporal lobe exhibit a better rate of neuronal differentiation in vitro than the cells from the SVZ, particularly in the presence of NGF. CONCLUSION: This study indicates that neural progenitors are also present in the human temporal lobe. Studying them could be of great interest for cell therapy in neurological disorders. PMID- 22823463 TI - Reactivity of alkynyl metal carbenoids: DFT study on the Pt-catalyzed cyclopropanation of propargyl ester containing 1,3-diynes. AB - DFT/M06 calculations were performed to investigate the mechanism of the Pt catalyzed intermolecular cyclopropanation of propargyl ester containing diynes with styrene. The results show that the alkynyl Pt-carbenoid formed from proximal activation of the diyne is a more favorable productive intermediate for cyclopropanation, which occurs preferentially at the distal sp-hybridized carbon via an S(N)2'-type olefin addition. Notably, the widely accepted [1,3] metallotropic shift of such an alkynyl metal carbenoid is found to be energetically demanding. PMID- 22823464 TI - Transcranial magnetic stimulation on the modulation of gamma oscillations in schizophrenia. AB - Cognitive dysfunction is suggested to be the best predictor of functional outcome in schizophrenia. Therefore, new diagnostic and treatment strategies are needed to both ascertain the biological underpinning of cognitive deficits and to restore them. Modulation of gamma oscillations (30-50 Hz) has been associated with cognitive performance, particularly in the dorsolateral prefrontal cortex (DLPFC). In this manuscript, we review evidence for gamma modulation deficits during cognitive performance in schizophrenia. We demonstrate that transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) is a reliable method that permits systematic quantification of gamma modulation in the cortex. Using TMS-EEG, we show that patients with schizophrenia have selective gamma inhibition deficits in the DLPFC. Finally, we demonstrate that repetitive TMS therapy over the DLPFC can normalize excessive gamma oscillations and ultimately cognitive performance in patients. We suggest that restoring gamma impairments in the DLPFC may be a potential strategy for improving cognitive deficits in schizophrenia. PMID- 22823465 TI - Thoracoscopic repair of recurrent bochdalek diaphragmatic hernias in children. AB - BACKGROUND: Recurrent herniation is a well-known complication following the initial repair of congenital diaphragmatic hernias (CDHs). The role of minimally invasive surgical techniques in recurrent CDH remains undefined. The purpose of this study was to evaluate our early experience with thoracoscopic repair compared with traditional open repair in children with recurrent CDH. SUBJECTS AND METHODS: We retrospectively reviewed all recurrent Bochdalek CDH cases (n=24) managed at a single tertiary-care referral center between January 1990 and March 2011. Children who underwent thoracoscopic repair for recurrent CDH were identified, and their data were compared by the unpaired t test and the two-sided Fisher's exact test, as appropriate, with those of children who underwent open repair. Significance was defined as P<.05. RESULTS: Thoracoscopic repair was attempted in 6 (25%) children with recurrent CDH. Four (67%) repairs were successfully completed without conversion to an open procedure. The mean age at thoracoscopic repair was 11.5 months (range, 8.1-16.1 months). The mean operative time was 191 minutes (range, 94-296 minutes), and all children were extubated within 24 hours. The mean hospital length of stay was 3.75 days (range, 1-6 days). There were no deaths or subsequent recurrences after a mean follow-up of 26.5 months (range, 14.3-41.3 months). There were no statistical differences in any of the measured outcome variables when compared with the open repair group. CONCLUSIONS: Our initial experience suggests that thoracoscopic repair is a feasible alternative to open repair in selected children with recurrent Bochdalek diaphragmatic hernias. PMID- 22823466 TI - Novel dynamic flux chamber for measuring air-surface exchange of Hg(o) from soils. AB - Quantifying the air-surface exchange of Hg(o) from soils is critical to understanding the cycling of mercury in different environmental compartments. Dynamic flux chambers (DFCs) have been widely employed for Hg(o) flux measurement over soils. However, DFCs of different sizes, shapes, and sampling flow rates yield distinct measured fluxes for a soil substrate under identical environmental conditions. In this study, we performed an integrated modeling, laboratory and field study to design a DFC capable of producing a steady and uniform air flow over a flat surface. The new DFC was fabricated using polycarbonate sheets. The internal velocity field was experimentally verified against model predictions using both theoretical and computational fluid dynamics techniques, suggesting fully developed flow with velocity profiles in excellent agreement with model results. Laboratory flux measurements demonstrated that the new design improves data reproducibility as compared to a conventional DFC, and reproduces the model predicted flux trend with increasing sampling flow. A mathematical relationship between the sampling flow rate and surface friction velocity, a variable commonly parametrized in atmospheric models, was developed for field application. For the first time, the internal shear property of a DFC can be precisely controlled using the sampling flow rate, and the flux under atmospheric condition can be inferred from the measured flux and surface shear property. The demonstrated methodology potentially bridges the gap in measured fluxes obtained by the DFC method and the micrometeorological methods. PMID- 22823467 TI - Continuous objective monitoring of alcohol use: twenty-first century measurement using transdermal sensors. AB - Transdermal alcohol sensors continuously collect reliable and valid data on alcohol consumption in vivo over the course of hours to weeks. Transdermal alcohol readings are highly correlated with breath alcohol measurements, but transdermal alcohol levels lag behind breath alcohol levels by one or more hours owing to the longer time required for alcohol to be expelled through perspiration. By providing objective information about alcohol consumption, transdermal alcohol sensors can validate self-report and provide important information not previously available. In this article, we describe the development and evaluation of currently available transdermal alcohol sensors, present the strengths and limitations of the technology, and give examples of recent research using the sensors. PMID- 22823468 TI - Am I my avatar? A tool to investigate virtual body image representation in adolescence. AB - The assessment of body image in adolescence plays a key role in investigating self-esteem development and social adjustment. In particular, these days, adolescents use more and more online tools to communicate with other people, and virtual body image represents a critical aspect for understanding the avatar development. This study aims at investigating the virtual body representation by using the "Drawing Me" graphical test with a group of Italian adolescents. Specifically, we compared body image representation in real (drawings) and virtual (avatar) life by taking gender differences into consideration. Results show that virtual body representation is more characterized by the sexual features related to body, face, and clothes and by a major number of context elements than real body representation. Gender differences confirm that girls tend to represent themselves in greater detail than boys and their avatars are rich with sexual characters. To conclude, our study illustrates that the Drawing Me test is an effective tool that analyzes the virtual body representation in an unobtrusive way, and intervention implications are discussed. PMID- 22823469 TI - Theoretical study of the reaction of ethane with oxygen molecules in the ground triplet and singlet delta states. AB - Quantum chemical calculations are carried out to study the reaction of ethane with molecular oxygen in the ground triplet and singlet delta states. Transition states, intermediates, and possible products of the reaction on the triplet and singlet potential energy surfaces are identified on the basis of the coupled cluster method. The basis set dependence of coupled-cluster energy values is estimated by the second-order perturbation theory. The values of energy barriers are also refined by using the compound CBS-Q and G3 techniques. It was found that the C(2)H(6) + O(2)(X(3)Sigma(g)(-)) reaction leads to the formation of C(2)H(5) and HO(2) products, whereas the C(2)H(6) + O(2)(a(1)Delta(g)) process produces C(2)H(4) and H(2)O(2) molecules. The appropriate rate constants of these reaction paths are estimated on the basis of variational and nonvariational transition state theories assuming tunneling and possible nonadiabatic transitions in the temperature range 500-4000 K. The calculations showed that the rate constant of the C(2)H(6) + O(2)(a(1)Delta(g)) reaction path is much greater than that of the C(2)H(6) + O(2)(X(3)Sigma(g)(-)) one. At the same time, the singlet and triplet potential surface intersection is detected that leads to the appearance of the nonadiabatic quenching channel O(2)(a(1)Delta(g)) + C(2)H(6) -> O(2)(X (3)Sigma(g)(-)) + C(2)H(6). The rate constant of this process is estimated with the use of the Landau-Zener model. It is demonstrated that, in the case of the existence of thermal equilibrium in the distribution of molecules over the electronic states, at low temperatures (T < 1200 K) the main products of the reaction of C(2)H(6) with O(2) are C(2)H(4) and H(2)O(2), rather than C(2)H(5) and HO(2). At higher temperature (T > 1200 K) the situation is inverted. PMID- 22823470 TI - Influence of grape maturity and maceration length on color, polyphenolic composition, and polysaccharide content of Cabernet Sauvignon and Tempranillo wines. AB - The aim of this paper was to study how maturity and maceration length affect color, phenolic compounds, polysaccharides, and sensorial quality of Cabernet Sauvignon and Tempranillo wines at three stages of grape ripening. Ripeness increased color extractability, phenolic compounds, and polysaccharide concentrations. Moreover, the proanthocyanidin mean degree of polymerization (mDP) and the percentage of prodelphinidins also increased with maturity, whereas the percentage of galloylation decreased. In general, wines from riper grapes contain higher proportions of skin proanthocyanidins. Color and anthocyanin concentration decreased when the maceration was longer, whereas polysaccharide and proanthocyanidin concentrations did the opposite. It was also detected that the mDP and the percentage of prodelphinidins decreased when the maceration was extended, whereas the percentage of galloylation increased. These data seem to indicate that proanthocyanidin extraction from seeds is clearly increased throughout the maceration time. PMID- 22823471 TI - The application of rapid prototyping in prosthodontics. AB - Dentists have used rapid prototyping (RP) techniques in the fields of oral maxillofacial surgery simulation and implantology. With new research emerging for molding materials and the forming process of RP techniques, this method is becoming more attractive in dental prosthesis fabrication; however, few researchers have published material on the RP technology of prosthesis pattern fabrication. This article reviews and discusses the application of RP techniques for prosthodontics including: (1) fabrication of wax pattern for the dental prosthesis, (2) dental (facial) prosthesis mold (shell) fabrication, (3) dental metal prosthesis fabrication, and (4) zirconia prosthesis fabrication. Many people could benefit from this new technology through various forms of dental prosthesis production. Traditional prosthodontic practices could also be changed by RP techniques in the near future. PMID- 22823472 TI - Off-trial evaluation of the B cell-targeting treatment in the refractory cases of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: long-term follow-up from a single centre. AB - The aim of the study was to evaluate long-term clinical and immunological effects of anti-B cell treatment in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis refractory to conventional immunosuppressive treatment. Rituximab (RTX) was added to the ongoing immunosuppressive treatment in 29 patients with refractory ANCA-associated vasculitis. The disease activity was measured using Birmingham Vasculitis Activity Score/Wegener's granulomatosis (BVAS/WG score), and clinical laboratory variables were recorded. The median BVAS/WG score before treatment was 6 (IQR 3-8), and 28 patients (97%) had disease flare classified either severe (62%) or limited (34%). Six of 29 patients (21%) achieved a complete remission, and 12 (41%) had a treatment response with >=50% decrease in BVAS/WG score at 6 months. Fourteen patients (64%) with kidney involvement achieved remission, and in seven patients (50%), no flare was seen during the follow-up period. Three patients had renal flare and were successfully re-treated with RTX. Seventeen patients had disease symptoms from airways and eyes at RTX initiation, whereas only 29% displayed >=50% treatment response. Limited clinical improvement was seen in patients with endobronchial lesions and trachea-subglottic granulomatous disease. RTX is a potent therapeutic option for ANCA-associated vasculitis refractory to conventional treatment. Best response may be expected in patients with vasculitic manifestations. PMID- 22823473 TI - The role of conserved inulosucrase residues in the reaction and product specificity of Lactobacillus reuteri inulosucrase. AB - The probiotic bacterium Lactobacillus reuteri 121 produces two fructosyltransferase enzymes, a levansucrase and an inulosucrase. Although these two fructosyltransferase enzymes share high sequence similarity, they differ significantly in the type and size distribution of fructooligosaccharide products synthesized from sucrose, and in their activity levels. In order to examine the contribution of specific amino acids to such differences, 15 single and four multiple inulosucrase mutants were designed that affected residues that are conserved in inulosucrase enzymes, but not in levansucrase enzymes. The effects of the mutations were interpreted using the 3D structures of Bacillus subtilis levansucrase (SacB) and Lactobacillus johnsonii inulosucrase (InuJ). The wild type inulosucrase synthesizes mostly fructooligosaccharides up to a degree of polymerization of 15 and relatively low amounts of inulin polymer. In contrast, wild-type levansucrase produces mainly levan polymer and fructooligosaccharides with a degree of polymerization < 5. Although most of the inulosucrase mutants in this study behaved similarly to the wild-type enzyme, the mutation G416E, at the rim of the active site pocket in loop 415-423, increased the hydrolytic activity twofold, without significantly changing the transglycosylation activity. The septuple mutant GM4 (T413K, K415R, G416E, A425P, S442N, W486L, P516L), which included two residues from the above-mentioned loop 415-423, synthesized 1 kestose only, but at low efficiency. Mutation A538S, located behind the general acid/base, increased the enzyme activity two to threefold. Mutation N543S, located adjacent to the +1/+2 sub-site residue R544, resulted in synthesis of not such a wide variety of fructooligosaccharides than the wild-type enzyme. The present study demonstrates that the product specificity of inulosucrase is easily altered by protein engineering, obtaining inulosucrase variants with higher transglycosylation specificity, higher catalytic rates and different fructooligosaccharide size distributions, without changing the beta(2-1) linkage type in the product. PMID- 22823474 TI - Development and characterization of an implantable biosensor for telemetric monitoring of ethanol in the brain of freely moving rats. AB - Ethanol is one of the most widespread psychotropic agents in western society. While its psychoactive effects are mainly associated with GABAergic and glutamatergic systems, the positive reinforcing properties of ethanol are related to activation of mesolimbic dopaminergic pathways resulting in a release of dopamine in the nucleus accumbens. Given these neurobiological implications, the detection of ethanol in brain extracellular fluid (ECF) is of great importance. In this study, we describe the development and characterization of an implantable biosensor for the amperometric detection of brain ethanol in real time. Ten different designs were characterized in vitro in terms of Michaelis-Menten kinetics (V(MAX) and K(M)), sensitivity (linear region slope, limit of detection (LOD), and limit of quantification (LOQ)), and electroactive interference blocking. The same parameters were monitored in selected designs up to 28 days after fabrication in order to quantify their stability. Finally, the best performing biosensor design was selected for implantation in the nucleus accumbens and coupled with a previously developed telemetric device for the real time monitoring of ethanol in freely moving, untethered rats. Ethanol was then administered systemically to animals, either alone or in combination with ranitidine (an alcohol dehydrogenase inhibitor) while the biosensor signal was continuously recorded. The implanted biosensor, integrated in the low-cost telemetry system, was demonstrated to be a reliable device for the short-time monitoring of exogenous ethanol in brain ECF and represents a new generation of analytical tools for studying ethanol toxicokinetics and the effect of drugs on brain ethanol levels. PMID- 22823475 TI - Interventional catheterization after total cavopulmonary connection: experience in 68 patients. AB - BACKGROUND: Total cavopulmonary connection (TCPC) is performed in patients having a single ventricle to allow the passive flow of systemic venous blood to the lungs. Interventional catheterization is needed to treat residual defects or complications. AIMS: We discuss our results concerning 68 patients who had had TCPC from January 1995 to December 2010. METHODS: Initial and follow-up catheterization data were reviewed retrospectively. Mid-term results were evaluated by means of angiography and/or CT scan. RESULTS: Mean age at TCPC was 5 years (2.5-18); mean interval between TCPC and catheterization was 5.6 years (1.5-15). Sixty-nine catheterizations were performed in 53 patients. Eleven patients (21%) had low venous pressure, did not display a right-to-left shunt, and did not need any intervention. Fifteen patients (28%) had low venous pressure and only needed the closure of the fenestration. The remaining 27 patients (51%) needed the following interventions: embolization of venous vessels prompting right-to-left shunt (n = 15), stenting or reconnection of pulmonary arteries (n = 5), stenting or recanalization of systemic veins (n = 11), other procedures (n = 5). In 3 patients the fenestration could not be closed due to high venous pressure. After the interventions oxygen saturation increased from 90.5%+/- 4.8% to 94.7% +/- 3.6% (P = 0.002). CONCLUSIONS: Our data show that 49% of patients with TCPC are in good condition late after surgery. However, half of these patients continue to need interventions generally aimed at suppressing stenoses at various levels of TCPC or at occluding vessels prompting right-to-left shunt. This population should enter a multicenter program aimed at identifying patients at risk. PMID- 22823476 TI - Farm elders define health as the ability to work. AB - Thirty percent of America's 2.2 million farms are operated by individuals older than 65 years. This study examined how older farmers define health and determined whether demographic characteristics, farm work, and physical and mental health status predict health definition. Data were collected via telephone and mailed surveys during the baseline wave of data collection in a longitudinal study of family farmers residing in two southern states (n=1,288). Nearly 42% defined health as the "ability to work" compared to a physical health-related definition. Predictors of defining health as the ability to work included being White, performing more farm tasks in the past week, taking prescription medications daily, and having minimal health-related limitations to farm work. Health behaviors are centered on the individual's perception of health. Understanding the defining attributes of health can support better approaches to health care and health promotion, particularly among rural subcultures such as farmers, whose identity is rooted in their work. PMID- 22823478 TI - Delayed auditory feedback in repetitive tapping: a role for the sensory goal. AB - The open-loop model by Wing and Kristofferson has successfully explained many aspects of movement timing. A later adaptation of the model assumes that timing processes do not control the movements themselves, but the sensory consequences of the movements. The present study tested direct predictions from this "sensory goals model". In two experiments, participants were instructed to produce regular intervals by tapping alternately with the index fingers of the left and the right hand. Auditory feedback tones from the taps of one hand were delayed. As a consequence, regular intervals between taps resulted in irregular intervals between feedback tones. Participants compensated for this auditory irregularity by changing their movement timing. Compensation effects increased with the magnitude of feedback delay (Experiment 1) and were also observed in a unimanual variant of the task (Experiment 2). The pattern of effects in alternating tapping suggests that compensation processes were anticipatory--that is, compensate for upcoming feedback delay rather than being reactions to delay. All experiments confirmed formal model predictions. Taken together, the findings corroborate the sensory-goals adaptation of the Wing-Kristofferson model. PMID- 22823477 TI - Does early intensive multifactorial treatment reduce total cardiovascular burden in individuals with screen-detected diabetes? Findings from the ADDITION-Europe cluster-randomized trial. AB - AIMS: To describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non-traumatic amputation) in individuals with screen-detected diabetes in the ADDITION-Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years. METHODS: In a pragmatic, cluster-randomized, parallel-group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target-driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method. RESULTS: Over 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person-years were 14.6 (12.8-16.6) and 20.4 (18.2-22.6), respectively. There were non-significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65-1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43-1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58-1.02). CONCLUSIONS: Early intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service. PMID- 22823479 TI - Ancestral polymorphism and recent invasion of transposable elements in Drosophila species. AB - BACKGROUND: During the evolution of transposable elements, some processes, such as ancestral polymorphisms and horizontal transfer of sequences between species, can produce incongruences in phylogenies. We investigated the evolutionary history of the transposable elements Bari and 412 in the sequenced genomes of the Drosophila melanogaster group and in the sibling species D. melanogaster and D. simulans using traditional phylogenetic and network approaches. RESULTS: Maximum likelihood (ML) phylogenetic analyses revealed incongruences and unresolved relationships for both the Bari and 412 elements. The DNA transposon Bari within the D. ananassae genome is more closely related to the element of the melanogaster complex than to the sequence in D. erecta, which is inconsistent with the species phylogeny. Divergence analysis and the comparison of the rate of synonymous substitutions per synonymous site of the Bari and host gene sequences explain the incongruence as an ancestral polymorphism that was inherited stochastically by the derived species. Unresolved relationships were observed in the ML phylogeny of both elements involving D. melanogaster, D. simulans and D. sechellia. A network approach was used to attempt to resolve these relationships. The resulting tree suggests recent transfers of both elements between D. melanogaster and D. simulans. The divergence values of the elements between these species support this conclusion. CONCLUSIONS: We showed that ancestral polymorphism and recent invasion of genomes due to introgression or horizontal transfer between species occurred during the evolutionary history of the Bari and 412 elements in the melanogaster group. These invasions likely occurred in Africa during the Pleistocene, before the worldwide expansion of D. melanogaster and D. simulans. PMID- 22823480 TI - Alfaxalone compared with ketamine for induction of anaesthesia in horses following xylazine and guaifenesin. AB - OBJECTIVE: To compare anaesthesia induced with either alfaxalone or ketamine in horses following premedication with xylazine and guaifenesin. STUDY DESIGN: Randomized blinded cross-over experimental study. ANIMALS: Six adult horses, five Standardbreds and one Thoroughbred; two mares and four geldings. METHODS: Each horse received, on separate occasions, induction of anaesthesia with either ketamine 2.2 mg kg(-1) or alfaxalone 1 mg kg(-1) . Premedication was with xylazine 0.5 mg kg(-1) and guaifenesin 35 mg kg(-1) . Incidence of tremors/shaking after induction, recovery and ataxia on recovery were scored. Time to recovery was recorded. Partial pressure of arterial blood oxygen (PaO(2) ) and carbon dioxide (PaO(2) ), arterial blood pressures, heart rate (HR) and respiratory rates were recorded before premedication and at intervals during anaesthesia. Data were analyzed using Wilcoxon matched pairs signed rank test and are expressed as median (range). RESULTS: There was no difference in the quality of recovery or in ataxia scores. Horses receiving alfaxalone exhibited a higher incidence of tremors/shaking on induction compared with those receiving ketamine (five and one of six horses respectively). Horses recovered to standing similarly [28 (24-47) minutes for alfaxalone; 22 (18-35) for ketamine] but took longer to recover adequately to return to the paddock after alfaxalone [44 (38-67) minutes] compared with ketamine [35 (30-47)]. There was no statistical difference between treatments in effect on HR, PaO(2) or PaCO(2) although for both regimens, PaO(2) decreased with respect to before premedication values. There was no difference between treatments in effect on blood pressure. CONCLUSIONS AND CLINICAL RELEVANCE: Both alfaxalone and ketamine were effective at inducing anaesthesia, although at induction there were more muscle tremors after alfaxalone. As there were no differences between treatments in relation to cardiopulmonary responses or quality of recovery, and only minor differences in recovery times, both agents appear suitable for this purpose following the premedication regimen used in this study. PMID- 22823481 TI - Topiramate as an adjunctive treatment in patients with refractory status epilepticus: an observational cohort study. AB - BACKGROUND: Refractory status epilepticus (RSE) is the most severe manifestation of status epilepticus (SE), often requiring intensive care and therapeutic coma. It is associated with prolonged intensive care unit (ICU) and hospital stays, as well as increased morbidity and mortality. Treatment involves both intravenous anaesthetics and antiepileptic drugs (AEDs) that can be administrated intravenously, by nasogastric tube or by percutaneous endoscopic gastrostomy. Experience with some of the newer AEDs for the treatment of RSE is restricted and higher-class evidence regarding tolerability and efficacy is lacking. Topiramate is a potent broad-spectrum AED with several modes of action, including blockade of the ionotropic glutamatergic AMPA receptor, which is likely to be an important mechanism for the treatment of SE. While there is no commercially available intravenous formulation, topiramate can be administered enterally, which may make it suitable for the treatment of RSE. OBJECTIVE: The objective of this study was to evaluate the tolerability, safety profile and efficacy of adjunctive and enterally administered topiramate in patients with RSE. METHODS: A medical chart review was performed of all consecutive patients treated for RSE between August 2004 and December 2011 at the ICU of the University Hospital Basel (Basel, Switzerland). RESULTS: 113 (43%) of all consecutive 268 patients with SE developed RSE. Of those, 35 (31%) were treated with topiramate. Median age was 60.5 years. Topiramate was used as an add-on treatment after 1-6 (median 4) prior administered AEDs had failed. It was introduced after a median of 2 (range 2-23) days for a duration of 1-24 (median 3) days. The response rate after topiramate administration as the third AED was 86% (6/7 patients), and remained stable at 67% after administration as the fourth, fifth, sixth or seventh AED when the groups of successfully and probably successfully treated patients were pooled. Overall, RSE was terminated in 71% of patients within 72 hours after first administration of topiramate, in 9% of patients, within 24 hours (none in the 800 mg/day group; 9% in the 400-799 mg/day group; and 11% in the <400 mg/day group). Mortality was 31% and was not strictly dependent on failure to terminate RSE, but also on the underlying aetiology of RSE. There were no serious or fatal adverse events directly attributable to topiramate. Adverse effects included slight hyperchloremic acidosis and hyperammonemia (all associated with co-medication with valproic acid). CONCLUSION: Treatment with enterally administered topiramate was feasible, well tolerated and had a good safety profile in patients with RSE in this observational, single-centre, cohort study. Refractory SE was terminated in the majority of patients within 3 days after initiation of topiramate. Prospective studies are warranted to further evaluate topiramate for the treatment of RSE. PMID- 22823483 TI - Label-free detection of prion protein with its DNA aptamer through the formation of T-Hg2+-T configuration. AB - Though rapid tests were developed for mass screening of prion diseases in the last century, bovine spongiform encephalopathy (BSE) was still epidemic in some European countries. The main reason is that the sensitivity of such tests is insufficient for detecting animals that are incubating with prion diseases at the presymptomatic stage. Driven by this, in this contribution, we developed a novel sensitive label-free method taking advantage of DNA aptamer for prion proteins (PrP) detection through the formation of T-Hg(2+)-T configuration. In the presence of Hg(2+) ions, double-strand structures formed due to the strong binding affinity of Hg(2+) ions to the T bases of DNA aptamer, which dramatically enhanced the fluorescence of Syber Green I, a double-strand indicator. With the addition of prion protein, however, the specific interaction between prion protein and its aptamer forced the destruction of the double-strand structures, and thus the fluorescence of Syber Green I decreased. It was found that there is a linear relationship between the decreased fluorescence intensities and prion protein concentration ranging from 13.0 to 156.0 nmol/L. Compared with other methods, the method presented here holds the advantages of being label-free, rapid, highly sensitive, and selective, which shows great promise for clinical application. PMID- 22823482 TI - Acute treatment of migraines. AB - Migraine is a prevalent and disabling brain disorder that costs billions of dollars annually in direct healthcare costs, and school and work absenteeism and presenteeism. The objective of acute treatment is a cost-effective, rapid restoration of functional ability, with minimal recurrence and adverse effects. The acute treatment of migraine includes specific drugs, which currently all have vasoconstrictive effects (dihydroergotamine and triptans), and nonspecific drugs that include paracetamol (acetaminophen), combination analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), dopamine antagonists, narcotics and corticosteroids. NSAIDs have both peripheral and central effects on reversing migraine, and so may represent the best alternative for patients who cannot use triptans and ergots due to vascular contraindications. Narcotics and habituating medications should be avoided in the acute treatment of migraine, as the risk for transformation to chronic daily headache is excessively high at a relatively infrequent rate of exposure. PMID- 22823484 TI - The impact of obesity on learning laparoscopic surgery for colon cancer. AB - OBJECTIVE: This study evaluated the impact of obesity on learning to perform laparoscopic surgery for colon cancer. SUBJECTS AND METHODS: We compared the outcomes for 72 patients with colon cancer treated by a single surgeon between June 2005 and July 2008. The first 36 patients who underwent surgery were considered to be during the "early period," and the other 36 patients who underwent surgery as the "late period," and the patients with a body mass index (BMI) >=25 kg/m(2) were defined as being obese. RESULTS: During the early period, the tumor stages of obese patients were less advanced than those of nonobese patients, whereas the length of the operation, surgical blood loss, and wound diameter of obese patients were worse than those of nonobese patients. Furthermore, the tumor stages in the obese patients during the late period were more advanced than those in obese patients during the early period, whereas the length of the operation and number of dissected lymph nodes in the obese patients during the late period were better than those in obese patients during the early period. CONCLUSIONS: We demonstrated that the differences of the surgical outcomes between obese and nonobese patients undergoing laparoscopic colon resection decreased as the surgeon's experience increased. PMID- 22823485 TI - Comparative and dispositional optimism as separate and interactive predictors. AB - Comparative optimism and dispositional optimism are typically studied separately and little is known regarding their unique and combined predictive abilities. We examined how these two types of optimism predict cognitive and affective reactions following unpleasant dental health feedback (Studies 1 and 2) and neutral feedback (Study 2). In Study 1, dispositional optimism and a measure of dental health comparative optimism interacted to predict appraisals of dental health feedback. In Study 2, dispositional optimism and dental health comparative optimism interacted to predict appraisals of new dental health information following negative dental health feedback - but not following neutral feedback. Individuals scoring high in dispositional optimism and low in dental health comparative optimism were more interested in and receptive to the dental health feedback than those scoring high in both types of optimism. Finally, greater dental health comparative optimism was associated with less negative affect following the dental health feedback, whereas dispositional optimism was associated with greater positive affect under all conditions. The results indicate that comparative and dispositional optimism are unique as well as interactive predictors. PMID- 22823486 TI - Challenges to deep brain stimulation: a pragmatic response to ethical, fiscal, and regulatory concerns. AB - In response to the early success of deep brain stimulation, we offer some common sense strategies to sustain the work, addressing the need to do so in a fiscally workable, ethically transparent, and scientifically informed manner. After delineating major threats, we will suggest reforms in both the legislative and regulatory spheres that might remediate these challenges. We will recommend (1) revisions to the Bayh-Dole Act of 1980, which governs intellectual property exchange resulting from federally funded research; (2) revisions to the Association of American Medical Colleges recommendations concerning the management of conflicts of interest when scientists with an intellectual property interest participate in clinical research in tandem; (3) revisions to the Food and Drug Administration's pre-market approval process for new devices, including a proposal for a mini-investigational device exemption; and (4) the establishment of a public-private partnership to build ethical and sustainable synergies between the scientific community, industry, and government that would foster discovery and innovation. PMID- 22823487 TI - The shift length, fatigue, and safety conundrum in EMS. PMID- 22823488 TI - A ruthenocene-PNA bioconjugate--synthesis, characterization, cytotoxicity, and AAS-detected cellular uptake. AB - Labeling of peptide nucleic acids (PNA) with metallocene complexes is explored herein for the modulation of the analytical characteristics, as well as biological properties of PNA. The synthesis of the first ruthenocene-PNA conjugate with a dodecamer, mixed-sequence PNA is described, and its properties are compared to a ferrocene-labeled analogue as well as an acetylated, metal-free derivative. The synthetic characteristics, chemical stability, analytical and thermodynamic properties, and the interaction with cDNA were investigated. Furthermore, the cytotoxicity of the PNA conjugates is determined on HeLa, HepG2, and PT45 cell lines. Finally, the cellular uptake of the metal-containing PNAs was quantified by high-resolution continuum source atomic absorption spectrometry (HR-CS AAS). An unexpectedly high cellular uptake to final concentrations of 4.2 mM was observed upon incubation with 50 MUM solutions of the ruthenocene-PNA conjugate. The ruthenocene label was shown to be an excellent label in all respects, which is also more stable than its ferrocene analogue. Because of its high stability, low toxicity, and the lack of a natural background of ruthenium, it is an ideal choice for bioanalytical purposes and possible medicinal and biological applications like, e.g., the development of gene-targeted drugs. PMID- 22823490 TI - Morally disengaged and unempathic: do cyberbullies fit these definitions? An exploratory study. AB - In recent years, the phenomenon of cyberbullying has been gaining scholars' growing interest under various aspects, including its overlap with face-to-face bullying. Nevertheless, its relationships with cognitive and affective empathy, proactive and reactive aggression, and moral disengagement, constructs that proved to be crucial in distinguishing aggressive subjects from their targets and nonaggressive peers in traditional bullying, still represent, to some extent, an unexplored domain. The main purpose of the present exploratory study was to investigate the associations between cyberbullying and the mentioned constructs among Italian adolescents. 819 high-school students (mean age 16.08) were administered a battery of standardized tools, along with Cyberties, a new instrument created to assess the prevalence of (and the type of involvement in) different forms of electronic assaults. Analyses of variance were conducted to compare four roles ("pure" bullies, "pure" victims, bully victims, and noninvolved subjects). Participants who identified themselves as cyberbullies or cyberbully victims showed significantly higher levels of overall moral disengagement and of both types of aggression. Cyberbullies also displayed a lack of affective empathy. Our findings are in line with the ones in extant literature about correlates of traditional and electronic forms of bullying. Implications for prevention strategies are discussed. PMID- 22823492 TI - In vivo phosphorylation of FtsZ2 in Arabidopsis thaliana. AB - The tubulin-like FtsZ protein initiates assembly of the bacterial and plastid division machineries. In bacteria, phosphorylation of FtsZ impairs GTPase activity, polymerization and interactions with other division proteins. Using a proteomics approach, we have shown that AtFtsZ2 is phosphorylated in vivo in Arabidopsis and that PGK1 (phosphoglycerate kinase 1) interacts with AtFtsZ2 in planta, suggesting a possible role in FtsZ phosphorylation. PMID- 22823491 TI - Distinct pattern of immunophenotypic features of innate and adaptive immunity as a putative signature of clinical and laboratorial status of patients with localized cutaneous leishmaniasis. AB - In this study, we have analysed the phenotypic features of innate/adaptive immunity of patients with localized cutaneous leishmaniasis (LCL), categorized according to their clinical/laboratorial status, including number of lesion (L1; L2-4), days of illness duration (<=60;>60) and positivity in the Montenegro skin test (MT-;MT+). Our findings highlighted a range of phenotypic features observed in patients with LCL (?%HLA-DR+ neutrophils; ?CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio; ?HLA-DR in B lymphocytes, ?%CD23+ neutrophils, monocytes and B cells; ?alpha-Leishmania IgG and ?serum NO2- + NO3-). Selective changes were observed in L1 (?%HLA-DR+ neutrophils, ?CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio and ?serum NO2 + NO3-) as compared to L2-4 (?%CD5- B cells; ?CD23+ B cells and ?alpha Leishmania IgG). Whilst <=60 presented a mixed profile of innate/adaptive immunity (?%CD28+ neutrophils and ?%CD4+ T cells), >60 showed a well-known leishmanicidal events (?CD8+ T cells; ?serum NO2- + NO3- and ?alpha-Leishmania IgG). MT+ patients showed increased putative leishmanicidal capacity (?%HLA-DR+ neutrophils; ?%CD23+ monocytes; ?CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio and ? serum NO2- + NO3-). Overall, a range of immunological biomarkers illustrates the complex immunological network associated with distinct clinical/laboratorial features of LCL with applicability in clinical studies. PMID- 22823489 TI - Evidence for possible period 2 gene mediation of the effects of alcohol exposure during the postnatal period on genes associated with maintaining metabolic signaling in the mouse hypothalamus. AB - BACKGROUND: Animals exposed to alcohol during the developmental period develop circadian disturbances and metabolic problems that often persist during their adult period. In order to study whether alcohol and the circadian clock interact to alter metabolic signaling in the hypothalamus, we determined whether postnatal alcohol feeding in mice permanently alters metabolic sensing in the hypothalamus. Furthermore, we evaluated whether the effect of circadian disruption via Period 2 (Per2) gene mutation prevents alcohol's effects on metabolic signaling in the hypothalamus. METHODS: Per2 mutant and wild-type male and female mice of the same genetic background were given a milk formula containing ethanol (EtOH; 11.34% vol/vol) from postnatal day (PD) 2 to 7 and used for gene expression and peptide level determinations in the hypothalamus at PD7 and PD90. RESULTS: We report here that postnatal alcohol feeding reduces the expression of proopiomelanocortin (Pomc) gene and production of beta-endorphin and alpha-melanocyte stimulating hormone (alpha-MSH) in the hypothalamus that persists into adulthood. In addition, expressions of metabolic sensing genes in the hypothalamus were also reduced as a consequence of postnatal alcohol exposure. These effects were not sex-specific and were observed in both males and females. Mice carrying a mutation of the Per2 gene did not show any reductions in hypothalamic levels of Pomc and metabolic genes and beta-endorphin and alpha-MSH peptides following alcohol exposure. CONCLUSIONS: These data suggest that early-life exposure to alcohol alters metabolic sensing to the hypothalamus possibly via regulating Per2 gene and/or the cellular circadian clock mechanism. PMID- 22823493 TI - Do nonbonded H--H interactions in phenanthrene stabilize it relative to anthracene? A possible resolution to this question and its implications for ligands such as 2,2'-bipyridyl. AB - The problem of whether interactions between the hydrogen atoms at the 1,10 positions in the "cleft" of the "bent" phenanthrene stabilize the latter molecule thermodynamically relative to "linear" anthracene, or whether the higher stability of phenanthrene is due to a more energetically favorable pi-system, is considered. DFT calculations at the X3LYP/cc-pVTZ(-f)++ level of the ground state energies (E) of anthracene, phenanthrene, and the set of five benzoquinolines are reported. In the gas phase, "bent" phenanthrene was computed to be thermodynamically more stable than "linear" anthracene by -28.5 kJ mol(-1). This fact was attributed predominantly to the phenomenon of higher aromatic stabilization of the pi-system of phenanthrene relative to anthracene, and not to the stabilizing influence of the nonbonding H--H interactions in its cleft. In fact, these interactions in phenanthrene were shown to be destabilizing. Similar calculations for five benzoquinolines (bzq) indicate that DeltaE values vary as: 6,7-bzq (linear) <= 2,3-bzq (linear) < 5,6-bzq (bent) <= 3,4-bzq (bent) < 7,8-bzq (bent, no H--H nonbonding interactions in cleft), supporting the idea that it is a more stable pi-system that favors 7,8-bzq over 2,3-bzq and 6,7-bzq, and that the H--H interactions in the clefts of 3,4-bzq and 5,6-bzq are destabilizing. Intramolecular hydrogen bonding in the cleft of 7,8-bzq plays a secondary role in its stabilization relative 6,7-bzq. The question of whether H--H nonbonded interactions between H atoms at the 3 and 3' positions of 2,2'-bipyridyl (bpy) coordinated to metal ions are stabilizing or destabilizing is then considered. The energy of bpy is scanned as a function of N-C-C-N torsion angle (chi) in the gas-phase, and it is found that the trans form is 32.8 kJ mol(-1) more stable than the cis conformer. A relaxed coordinate scan of energy of bpy in aqueous solution as a function of chi is modeled using the PBF approach, and it is found that the trans conformer is still more stable than the cis, but now only by 5.34 kJ mol(-1). The effect that the latter energy has on the thermodynamic stability of complexes of metal ions with bpy in aqueous solution is discussed. PMID- 22823494 TI - Usefulness of a collateral channel dilator for antegrade treatment of chronic total occlusion of a coronary artery. AB - OBJECTIVES: The aim of this study was to clarify the effectiveness of a collateral channel dilator microcatheter in antegrade percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) of a coronary artery. BACKGROUND: The Corsair microcatheter, which was originally developed as a collateral channel dilator, has been reported to be useful for retrograde CTO PCI. METHODS: We compared the success rate of the Corsair microcatheter collateral channel dilator for antegrade CTO-PCI with a previously available microcatheter. We analyzed the data from 27 patients (32 CTOs) using the FinecrossMG (Finecross group) and the data from 31 patients (34 CTOs) using the Corsair (Corsair group). RESULTS: There were no significant differences in the clinical or lesion characteristics between the 2 groups. The success rate for crossing the CTO by the microcatheter was 62.5% in the Finecross group and 85.3% in the Corsair group (P < 0.05). After the Corsair crossed the CTO, a 2-mm diameter balloon catheter crossed the lesion in all the cases, but it crossed the lesion in only 17 of 20 cases in the Finecross group (85.0%, P < 0.05). The number of balloon catheters used for predilation was significantly less in the Corsair group compared with the Finecross group (P < 0.05). CONCLUSIONS: The success rate for crossing of the microcatheters and the balloon catheters through the occlusion in antegrade CTO-PCI was better with the Corsair than with the FinecrossMG. In addition, the use of the Corsair reduced the number of balloon catheters used for predilation in antegrade CTO-PCI. PMID- 22823495 TI - Geogenic sources of benzene in aquifers used for public supply, California. AB - Statistical evaluation of two large statewide data sets from the California State Water Board's Groundwater Ambient Monitoring and Assessment Program (1973 wells) and the California Department of Public Health (12,417 wells) reveals that benzene occurs infrequently (1.7%) and at generally low concentrations (median detected concentration of 0.024 MUg/L) in groundwater used for public supply in California. When detected, benzene is more often related to geogenic (45% of detections) than anthropogenic sources (27% of detections). Similar relations are evident for the sum of 17 hydrocarbons analyzed. Benzene occurs most frequently and at the highest concentrations in old, brackish, and reducing groundwater; the detection frequency was 13.0% in groundwater with tritium <1 pCi/L, specific conductance >1600 MUS/cm, and anoxic conditions. This groundwater is typically deep (>180 m). Benzene occurs somewhat less frequently in recent, shallow, and reducing groundwater; the detection frequency was 2.6% in groundwater with tritium >=1 pCi/L, depth <30 m, and anoxic conditions. Evidence for geogenic sources of benzene include: higher concentrations and detection frequencies with increasing well depth, groundwater age, and proximity to oil and gas fields; and higher salinity and lower chloride/iodide ratios in old groundwater with detections of benzene, consistent with interactions with oil-field brines. PMID- 22823496 TI - Penetrating brain injury caused by nail guns: two case reports and a review of the literature. AB - BACKGROUND: To the best of the authors' knowledge, there are few case reports of penetrating brain injuries (PBI) caused by nail guns and these have usually involved incomplete penetration of the skull. Complete penetration of a nail into the intracranial cavity is extremely rare. CASE STUDY: Here, two such cases are presented. In the first, the nail entered through the right temporal bone, lodged in the right temporal lobe and was removed via craniotomy with intra-operative ultrasound guidance. In the second, the nail destroyed the left parietal bone, damaged the left internal capsule and lodged in the left temporal lobe near the left petrous apex and the brain stem. According to the latest literature retrieval, this is the first reported case of nail-gun injury to the internal capsule. The position of the nail precluded removal without further neurologic damage. Treatment strategies designed to optimize outcome, with or without surgery, and possible complications are discussed in this report. PMID- 22823498 TI - On the determinants of the conjunction fallacy: probability versus inductive confirmation. AB - Major recent interpretations of the conjunction fallacy postulate that people assess the probability of a conjunction according to (non-normative) averaging rules as applied to the constituents' probabilities or represent the conjunction fallacy as an effect of random error in the judgment process. In the present contribution, we contrast such accounts with a different reading of the phenomenon based on the notion of inductive confirmation as defined by contemporary Bayesian theorists. Averaging rule hypotheses along with the random error model and many other existing proposals are shown to all imply that conjunction fallacy rates would rise as the perceived probability of the added conjunct does. By contrast, our account predicts that the conjunction fallacy depends on the added conjunct being perceived as inductively confirmed. Four studies are reported in which the judged probability versus confirmation of the added conjunct have been systematically manipulated and dissociated. The results consistently favor a confirmation-theoretic account of the conjunction fallacy against competing views. Our proposal is also discussed in connection with related issues in the study of human inductive reasoning. PMID- 22823497 TI - Rapid, sensitive detection of neurotransmitters at microelectrodes modified with self-assembled SWCNT forests. AB - Carbon nanotube (CNT) modification of microelectrodes can result in increased sensitivity without compromising time response. However, dip coating CNTs is not very reproducible and the CNTs tend to lay flat on the electrode surface which limits access to the electroactive sites on the ends. In this study, aligned CNT forests were formed using a chemical self-assembly method, which resulted in more exposed CNT ends to the analyte. Shortened, carboxylic acid functionalized single walled CNTs were assembled from a dimethylformamide (DMF) suspension onto a carbon-fiber disk microelectrode modified with a thin iron hydroxide-decorated Nafion film. The modified electrodes were highly sensitive, with 36-fold higher oxidation currents for dopamine using fast-scan cyclic voltammetry than bare electrodes and 34-fold more current than electrodes dipped in CNTs. The limit of detection (LOD) for dopamine was 17 +/- 3 nM at a 10 Hz repetition rate and 65 +/ 7 nM at 90 Hz. The LOD at 90 Hz was the same as a bare electrode at 10 Hz, allowing a 9-fold increase in temporal resolution without a decrease in sensitivity. Similar increases were observed for other cationic catecholamine neurotransmitters, and the increases in current were greater than for anionic interferents such as ascorbic acid and 3,4-dihydroxyphenylacetic acid (DOPAC). The CNT forest electrodes had high sensitivity at 90 Hz repetition rate when stimulated dopamine release was measured in Drosophila . The sensitivity, temporal resolution, and spatial resolution of these CNT forest modified disk electrodes facilitate enhanced electrochemical measurements of neurotransmitter release in vivo. PMID- 22823499 TI - Healing rate calculation in the diabetic foot ulcer: comparing different methods. AB - The determination of healing rate in the diabetic foot wound is an important assessment parameter that is part of the overall clinical decision-making process in wound treatment. A number of methods that have been used to calculate healing, ranging from length and width measurement, surface area measure changes expressed as a function of time and linear advancement of the wound edge. The objective of this study was to compare surface area measures to linear advancement of the wound edge in 228 diabetic foot ulcers. Each wound was measured using the two methods and analyzed using linear regression to determine the best modeling of the healing process in these wounds. Results indicated that the total surface area change per day was superior to the linear advancement parameter in this group of wounds and that the area measurement was significantly more likely to predict the healing trajectory in the subgroup of wounds that took more than 28 days to heal. Contrary to expectations, the linear advancement method was correlated to initial wound size in the longer duration wounds suggesting that in these chronic wounds, differing healing phases render the surface area calculation method superior to the linear advancement parameter. PMID- 22823500 TI - Overexpression of melatonin membrane receptors increases calcium-binding proteins and protects VSC4.1 motoneurons from glutamate toxicity through multiple mechanisms. AB - Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 MUm) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor beta (ERbeta): estrogen receptor alpha (ERalpha) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50. PMID- 22823501 TI - Chemical immobilization of chimpanzees (Pan troglodytes) using a combination of detomidine and ketamine. AB - OBJECTIVE: To determine if a combination of detomidine and ketamine can be used for effective chemical immobilization of chimpanzees. STUDY DESIGN: Observational study. ANIMALS: Twenty-one adult captive chimpanzees (12 males, nine females), age 8-46 years, weighing 40.4-68.4 kg. METHODS: The chimpanzees were immobilized with intramuscular (IM) detomidine and ketamine by a darting system. Based on estimated weights, doses administered were 50 MUg kg(-1) detomidine and 4 mg kg( 1) ketamine in groups 1 and 2, and 60 MUg kg(-1) and 5 mg kg(-1) respectively in group 3. Eight minutes in group 1 and 15 minutes in groups 2 and 3 were allowed from the time of apparent immobilization before removing the animals from their enclosures. Body temperature, arterial haemoglobin saturation and pulse rate were measured. The time from injection to induction (recumbency and absence of voluntary movement), total anaesthetic and recovery times (with or without atipamezole) were recorded. RESULTS: Immobilization occurred within 5 minutes after darting in most animals. Early handling of the chimpanzees often resulted in arousal and required further doses of ketamine IM. Most animals were hypoxaemic and hypothermic. Occasionally, bradycardia was observed. Atipamezole resulted in an acceptable quality of recovery 10 minutes after IM injection. The duration of immobilization varied widely when no antagonist was administered. CONCLUSIONS AND CLINICAL RELEVANCE: The combination detomidine (60 MUg kg(-1) ) and ketamine (5-6 mg kg(-1) ) can be used for the immobilization of chimpanzees for non- to minimally invasive procedures. A period of 15 minutes should be allowed before handling to avoid unwanted arousal. Oxygen administration is recommended to reduce hypoxaemia. Administration of atipamezole is justified to hasten recovery. PMID- 22823502 TI - Incidence and economic burden of adverse drug reactions among elderly patients in Ontario emergency departments: a retrospective study. AB - BACKGROUND: The rapid rise in the availability and use of pharmaceutical agents, and particularly polypharmacy, directly increases the risk for patients to experience adverse drug reactions (ADRs). There are few studies on the overall incidence and costs of ADRs. OBJECTIVE: The aim of this study was to estimate the incidence and costs of emergency department (ED) visits related to ADRs for patients greater than 65 years of age using administrative data, and to describe risk factors for experiencing severe ADRs. METHODS: We employed a retrospective cohort design based on population-based healthcare administrative clinical databases. Identification of ADR-related ED visits from the administrative database was based on International Classification of Diseases, 10th Revision Canadian Enhancement (ICD-10-CA) codes for each ED visit. The incidence and costs of ADR-related ED visits and subsequent hospital admissions were estimated for all adults aged 66 years and above for the period April 2003-March 2008. Costs were standardized and reported in 2008 Canadian dollars. Logistic regression was used to detect risk factors for severe ADRs. RESULTS: Approximately 0.75% of total annual ED visits among adults aged 66 years and above were found to be ADR related, and among these patients 21.6% were hospitalized. In 2007, the cost of ADR-related visits was $333 per ED visit and $7528 per hospitalization for a total annual cost of $13.6 million in Ontario, or an estimated $35.7 million in Canada. Severe ADRs were associated with sex, age, comorbid disease burden, multiple drugs, multiple pharmacies, newly prescribed drugs, recent ED visit, recent hospitalization and long-term care (LTC) residence. CONCLUSIONS: ADRs are an important public health issue that threaten the safety of drug therapy and results in significant economic burden to the healthcare system. ED visits related to ADRs may be underestimated in retrospective studies using administrative data compared with prospective studies. Further research is needed to better understand the risk of experiencing severe ADRs among LTC residents. PMID- 22823503 TI - Impact of ionic liquid pretreatment conditions on cellulose crystalline structure using 1-ethyl-3-methylimidazolium acetate. AB - Ionic liquids (ILs) have been shown to affect cellulose crystalline structure in lignocellulosic biomass during pretreatment. A systematic investigation of the swelling and dissolution processes associated with IL pretreatment is needed to better understand cellulose structural transformation. In this work, 3-20 wt % microcrystalline cellulose (Avicel) solutions were treated with 1-ethyl-3 methylimidazolium acetate ([C(2)mim][OAc]) and a mixture of [C(2)mim][OAc] with the nonsolvent dimethyl sulfoxide (DMSO) at different temperatures. The dissolution process was slowed by decreasing the temperature and increasing cellulose loading, and was further retarded by addition of DMSO, enabling in depth examination of the intermediate stages of dissolution. Results show that the cellulose I lattice expands and distorts prior to full dissolution in [C(2)mim][OAc] and that upon precipitation the former structure leads to a less ordered intermediate structure, whereas fully dissolved cellulose leads to a mixture of cellulose II and amorphous cellulose. Enzymatic hydrolysis was more rapid for the intermediate structure (crystallinity = 0.34) than for cellulose II (crystallinity = 0.54). PMID- 22823505 TI - Reactive solid surface morphology variation via ionic diffusion. AB - In gas-solid reactions, one of the most important factors that determine the overall reaction rate is the solid morphology, which can be characterized by a combination of smooth, convex and concave structures. Generally, the solid surface structure varies in the course of reactions, which is classically noted as being attributed to one or more of the following three mechanisms: mechanical interaction, molar volume change, and sintering. Here we show that if a gas-solid reaction involves the outward ionic diffusion of a solid-phase reactant then this outward ionic diffusion could eventually smooth the surface with an initial concave and/or convex structure. Specifically, the concave surface is filled via a larger outward diffusing surface pointing to the concave valley, whereas the height of the convex surface decreases via a lower outward diffusion flux in the vertical direction. A quantitative 2-D continuum diffusion model is established to analyze these two morphological variation processes, which shows consistent results with the experiments. This surface morphology variation by solid-phase ionic diffusion serves to provide a fourth mechanism that supplements the traditionally acknowledged solid morphology variation or, in general, porosity variation mechanisms in gas-solid reactions. PMID- 22823504 TI - A multi-locus species phylogeny of African forest duikers in the subfamily Cephalophinae: evidence for a recent radiation in the Pleistocene. AB - BACKGROUND: Duikers in the subfamily Cephalophinae are a group of tropical forest mammals believed to have first originated during the late Miocene. However, knowledge of phylogenetic relationships, pattern and timing of their subsequent radiation is poorly understood. Here we present the first multi-locus phylogeny of this threatened group of tropical artiodactyls and use a Bayesian uncorrelated molecular clock to estimate divergence times. RESULTS: A total of 4152 bp of sequence data was obtained from two mitochondrial genes and four nuclear introns. Phylogenies were estimated using maximum parsimony, maximum likelihood, and Bayesian analysis of concatenated mitochondrial, nuclear and combined datasets. A relaxed molecular clock with two fossil calibration points was used to estimate divergence times. The first was based on the age of the split between the two oldest subfamilies within the Bovidae whereas the second was based on the earliest known fossil appearance of the Cephalophinae and molecular divergence time estimates for the oldest lineages within this group. Findings indicate strong support for four major lineages within the subfamily, all of which date to the late Miocene/early Pliocene. The first of these to diverge was the dwarf duiker genus Philantomba, followed by the giant, eastern and western red duiker lineages, all within the genus Cephalophus. While these results uphold the recognition of Philantomba, they do not support the monotypic savanna-specialist genus Sylvicapra, which as sister to the giant duikers leaves Cephalophus paraphyletic. BEAST analyses indicate that most sister species pairs originated during the Pleistocene, suggesting that repeated glacial cycling may have played an important role in the recent diversification of this group. Furthermore, several red duiker sister species pairs appear to be either paraphyletic (C.callipygus/C. ogilbyi and C. harveyi/C. natalensis) or exhibit evidence of mitochondrial admixture (C. nigrifrons and C. rufilatus), consistent with their recent divergence and/or possible hybridization with each other. CONCLUSIONS: Molecular phylogenetic analyses suggest that Pleistocene-era climatic oscillations have played an important role in the speciation of this largely forest-dwelling group. Our results also reveal the most well supported species phylogeny for the subfamily to date, but also highlight several areas of inconsistency between our current understanding of duiker taxonomy and the evolutionary relationships depicted here. These findings may therefore prove particularly relevant to future conservation efforts, given that many species are presently regulated under the Convention for Trade in Endangered Species. PMID- 22823506 TI - The caregiving process of the family unit caring for a frail older family member at home: a grounded theory study. AB - AIMS AND OBJECTIVES: To explore the caregiving process of family units caring for a frail older family member at home. BACKGROUND: Previous research on family caregiving has demonstrated the interdependence between individual members' health and family status and suggested the importance of support provided to the family as a unit. However, little research that could be used as the basis for nursing interventions has focused on the caregiving process of the family unit caring for a frail older family member in the community. DESIGN: The grounded theory approach was applied in this study. METHODS: Eighteen families were recruited using the method of theoretical sampling. Data were collected through face-to-face semi-structured interviews. Constant comparative analysis proceeded with data collection. FINDINGS: Two core categories were identified: 'degree of routinisation of daily life' and 'degree of minimisation of competing needs within the family'. The caregiving process was classified according to the core categories into the following four phases: confusion, fluctuating disharmony, stable disharmony and stable harmony. The conditions for the routinisation and the competing needs and coping strategies of the family were also clarified. CONCLUSIONS: To lead a stable family life, families caring for a frail older member try to control the competing needs among members and routinise by adopting various strategies. Nurses should support or enhance such family action and interactions. IMPLICATIONS FOR PRACTICE: The degrees of daily life routinisation and of minimising competing needs within a family can be used to assess families caring for a frail older member. Nurses can determine the current state of the caregiving family from these two aspects and support family strategies that build daily routines and regulate their competing needs. PMID- 22823507 TI - Bytes, and pixels and pieces of information. PMID- 22823508 TI - Feasibility and safety of laparoscopic nephrectomy for nonfunctioning kidney in patients with previous renal surgery. AB - PURPOSE: Performing laparoscopic nephrectomy in the setting of previous renal surgery may be challenging and associated with a higher complication rate. We conducted this study to assess the feasibility and safety of laparoscopic nephrectomy among patients with a history of ipsilateral renal surgery. PATIENTS AND METHODS: We reviewed the chart of 193 patients who underwent transperitoneal laparoscopic nephrectomy for nonfunctioning kidney between April 2007 and March 2011. The study population was divided into two groups: Group 1 comprised 37 patients with a history of ipsilateral renal surgery, and Group 2 consisted of 156 patients with no history of previous renal surgery. RESULTS: Baseline characteristics and preoperative variables were similar in both groups. Mean operative time, complication rate, and hospital stay were comparable between the two groups. A nonstatistically significant trend toward a higher transfusion rate was noted in Group 1 patients. The operation was converted to open nephrectomy in 1 (2.7%) and 3 (1.9%) patients of Groups 1 and 2, respectively (P=.765). CONCLUSIONS: Laparoscopic nephrectomy of the nonfunctioning kidney is a feasible and safe procedure in the setting of previous renal surgery and is not associated with a significant increase in operative time and complication rate compared with patients with no prior ipsilateral renal surgery. PMID- 22823510 TI - Sourcing and using stem cell lines for radiation research: Potential, challenges and good stem cell culture practice. AB - PURPOSE: Exposition of best practice in management and experimental use of human stem cell lines in radiobiological research. This paper outlines the key challenges to be addressed by radiobiologists wishing to use human pluripotent stem cell (hPSC) lines in their research including human embryonic stem cell (hESC) lines and human induced pluirpotency stem (hiPSC) lines. It emphasises the importance of guidance already established for cell culture in general and outlines some further considerations specific to the culture of human pluripotent stem cell lines which may impact on the interpretation of data from radiobiological studies using these cells. Fundamental standards include obtaining cells from bona fide suppliers with suitable quality controls, screening cell lines to ensure absence of mycoplasma and authentication of cell lines by DNA profiling. For hESC and hiPSC lines, it is particularly important to recognise the significance of phenotypic and genetic stability and this paper will address approaches to reduce their impact. Quality assured banking of these two types of stem cell lines will facilitate reliable supply of quality controlled cells that can provide standardisation between laboratories and in the same laboratory over time. CONCLUSIONS: hPSC lines could play an important role in future radiobiological research providing certain fundamental principles of good stem cell culture practice are adopted at the outset of such work. PMID- 22823509 TI - Twin studies of pain. AB - Twin studies provide a method for estimating the heritability of phenotypes and for examining genetic and environmental relationships between phenotypes. We conducted a systematic review of twin studies of pain, including both clinical and experimental pain phenotypes. Fifty-six papers were included, whereof 52 addressed clinical phenotypes. Of the most comprehensively studied phenotypes, available data indicates heritability around 50% for migraine, tension-type headache and chronic widespread pain, around 35% for back and neck pain, and around 25% for irritable bowel syndrome. However, differences in phenotype definitions make these results somewhat uncertain. All clinical studies relied on dichotomous outcomes and none used pain intensity as continuous phenotype. This is a major weakness of the reviewed studies and gives reason to question their validity with respect to pain mechanisms. Experimental pain studies indicate large differences in heritability across pain modalities. Whereas there is evidence for substantial common genetic risk across many clinical pain conditions, different experimental pain phenotypes appear to be associated with different genetic factors. Recommendations for future research include inclusion of pain intensity scaling and number of pain sites in phenotyping. Furthermore, studies examining the genetic relationships between pain phenotypes, in particular between clinical and experimental phenotypes, should be prioritized. PMID- 22823511 TI - Erythrophagocytosis by neutrophils in paroxysmal cold haemoglobinuria. PMID- 22823513 TI - Effects of L-cysteine on reinstatement of ethanol-seeking behavior and on reinstatement-elicited extracellular signal-regulated kinase phosphorylation in the rat nucleus accumbens shell. AB - BACKGROUND: Alcoholism is a neuroadaptive disorder, and the understanding of the mechanisms of the high rates of relapse, which characterize it, represents one of the most demanding challenges in alcoholism and addiction research. The extracellular signal-regulated kinase (ERK) is an intracellular kinase, critical for neuroplasticity in the adult brain that is suggested to play a fundamental role in the molecular mechanisms underlying drug addiction and relapse. We previously observed that a nonessential amino acid, L-cysteine, significantly decreases oral ethanol (EtOH) self-administration, reinstatement of EtOH-drinking behavior, and EtOH self-administration break point. METHODS: Here, we tested whether L-cysteine can affect the ability of EtOH priming to induce reinstatement of EtOH-seeking behavior. In addition, we determined the ability of EtOH priming to induce ERK phosphorylation as well as the ability of L-cysteine to affect reinstatement-elicited ERK activation. To these purposes, Wistar rats were trained to nose-poke for a 10% v/v EtOH solution. After stable drug-taking behavior was obtained, nose-poking for EtOH was extinguished, and reinstatement of drug seeking, as well as reinstatement-elicited pERK, was determined after an oral, noncontingent, priming of EtOH (0.08 g/kg). Rats were pretreated with either saline or L-cysteine (80 to 120 mg/kg) 30 minutes before testing for reinstatement. RESULTS: The findings of this study confirm that the noncontingent delivery of a nonpharmacologically active dose of EtOH to rats, whose previous self-administration behavior had been extinguished, results in significant reinstatement into EtOH-seeking behavior. In addition, the results indicate that reinstatement selectively activates ERK phosphorylation in the shell of the nucleus accumbens (Acb) and that pretreatment with L-cysteine reduces either reinstatement of EtOH seeking and reinstatement-elicited pERK in the AcbSh. CONCLUSIONS: Altogether, these results indicate that L-cysteine could be an effective pharmacological agent for the prevention of behavioral and molecular correlates of EtOH-primed reinstatement of EtOH seeking and that the shell of the Acb represents a critical neural substrate for priming-elicited reinstatement mechanisms involving ERK phosphorylation. PMID- 22823512 TI - Deep brain stimulation for movement and other neurologic disorders. AB - Deep brain stimulation (DBS) was introduced as a treatment for patients with parkinsonism and other movement disorders in the early 1990s. The technique rapidly became the treatment of choice for these conditions, and is now also being explored for other diseases, including Tourette syndrome, gait disorders, epilepsy, obsessive-compulsive disorder, and depression. Although the mechanism of action of DBS remains unclear, it is recognized that DBS works through focal modulation of functionally specific circuits. The fact that the same DBS parameters and targets can be used in multiple diseases suggests that DBS does not counteract the pathophysiology of any specific disorder, but acts to replace pathologic activities in disease-affected brain circuits with activity that is more easily tolerated. Despite the progress made in the use of DBS, much remains to be done to fully realize the potential of this therapy. We describe some of the most active areas of research in this field, both in terms of exploration of new targets and stimulation parameters, and in terms of new electrode or stimulator designs. PMID- 22823514 TI - Antitumor agents 295. E-ring hydroxylated antofine and cryptopleurine analogues as antiproliferative agents: design, synthesis, and mechanistic studies. AB - Various E-ring hydroxylated antofine and cryptopleurine analogues were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of nonsmall cell lung cancer (NSCLC) cell lines in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down regulate HSP90 and beta-catenin in A549 lung adenocarcinoma cells in a dose dependent manner, suggesting a potential use for treating hedgehog pathway-driven tumorigenesis. PMID- 22823516 TI - Interface driven energy filtering of thermoelectric power in spark plasma sintered Bi(2)Te(2.7)Se(0.3) nanoplatelet composites. AB - Control of competing parameters such as thermoelectric (TE) power and electrical and thermal conductivities is essential for the high performance of thermoelectric materials. Bulk-nanocomposite materials have shown a promising improvement in the TE performance due to poor thermal conductivity and charge carrier filtering by interfaces and grain boundaries. Consequently, it has become pressingly important to understand the formation mechanisms, stability of interfaces and grain boundaries along with subsequent effects on the physical properties. We report here the effects of the thermodynamic environment during spark plasma sintering (SPS) on the TE performance of bulk-nanocomposites of chemically synthesized Bi(2)Te(2.7)Se(0.3) nanoplatelets. Four pellets of nanoplatelets powder synthesized in the same batch have been made by SPS at different temperatures of 230, 250, 280, and 350 degrees C. The X-ray diffraction, transmission electron microscopy, thermoelectric, and thermal transport measurements illustrate that the pellet sintered at 250 degrees C shows a minimum grain growth and an optimal number of interfaces for efficient TE figure of merit, ZT~0.55. For the high temperature (350 degrees C) pelletized nanoplatelet composites, the concurrent rise in electrical and thermal conductivities with a deleterious decrease in thermoelectric power have been observed, which results because of the grain growth and rearrangements of the interfaces and grain boundaries. Cross section electron microscopy investigations indeed show significant grain growth. Our study highlights an optimized temperature range for the pelletization of the nanoplatelet composites for TE applications. The results provide a subtle understanding of the grain growth mechanism and the filtering of low energy electrons and phonons with thermoelectric interfaces. PMID- 22823515 TI - Caring for children with physical disability in Kenya: potential links between caregiving and carers' physical health. AB - BACKGROUND: The health of a carer is a key factor which can affect the well-being of the child with disabilities for whom they care. In low-income countries, many carers of children with disabilities contend with poverty, limited public services and lack assistive devices. In these situations caregiving may require more physical work than in high-income countries and so carry greater risk of physical injury or health problems. There is some evidence that poverty and limited access to health care and equipment may affect the physical health of those who care for children with disabilities. This study seeks to understand this relationship more clearly. METHODS: A mixed methods study design was used to identify the potential physical health effects of caring for a child with moderate-severe motor impairments in Kilifi, Kenya. Qualitative data from in depth interviews were thematically analysed and triangulated with data collected during structured physiotherapy assessment. RESULTS: Carers commonly reported chronic spinal pain of moderate to severe intensity, which affected essential activities. However, carers differed in how they perceived their physical health to be affected by caregiving, also reporting positive benefits or denying detrimental effects. Carers focussed on support in two key areas; the provision of simple equipment and support for their children to physically access and attend school. CONCLUSIONS: Carers of children with moderate-severe motor impairments live with their own physical health challenges. While routine assessments lead to diagnosis of simple musculoskeletal pain syndromes, the overall health status and situation of carers may be more complex. As a consequence, the role of rehabilitation therapists may need to be expanded to effectively evaluate and support carers' health needs. The provision of equipment to improve their child's mobility, respite care or transport to enable school attendance is likely to be helpful to carers and children alike. PMID- 22823517 TI - The relationships between Internet addiction, subjective vitality, and subjective happiness. AB - The aim of the present study is to examine the relationships between Internet addiction, subjective vitality, and subjective happiness. The participants were 328 university students who completed a questionnaire package that included the Online Cognition Scale, the Subjective Vitality Scale, and the Subjective Happiness Scale. According to the results, subjective vitality and subjective happiness were negatively predicted by Internet addiction. On the other hand, subjective happiness was positively predicted by subjective vitality. In addition, subjective vitality mediated the relationship between Internet addiction and subjective happiness. Results were discussed in light of the literature. PMID- 22823518 TI - Volatile kinetic capillary electrophoresis for studies of protein-small molecule interactions. AB - Kinetic capillary electrophoresis (KCE) is a toolset of homogeneous affinity methods for studying kinetics of noncovalent binding. Sensitive KCE measurements are typically done with fluorescence detection and require a fluorescent label on a smaller-sized binding partner. KCE with fluorescence detection is difficult to use for study of protein-small molecule interactions since labeling small molecules is cumbersome and can affect binding. A combination of KCE with mass spectrometry (KCE-MS) has been recently suggested for label-free studies of protein-small molecule interactions. The major obstacle for studies by KCE-MS is a buffer mismatch between KCE and MS; MS requires volatile buffers while KCE of protein-ligand interactions is always run in near-physiological buffers. Here we asked a simple question: can protein-ligand interactions be studied with KCE in a volatile buffer? We compared three volatile buffers (ammonium acetate, ammonium bicarbonate, and ammonium formate) with a near-physiological buffer (Tris acetate) for three protein-ligand pairs. The volatile buffers were found not to significantly affect protein-ligand complex stability; moreover, when used as CE run buffers, they facilitated good-quality separation of free ligands from the protein-ligand complexes. The use of volatile buffers instead of Tris-acetate in detection of small molecules by MS improved the detection limit by approximately 2 orders of magnitude. These findings prove the principle of "volatile" KCE, which can be easily coupled with MS to facilitate label-free kinetic studies of protein-small molecule interactions. PMID- 22823519 TI - Exploring the potential of doped zero-dimensional cages for proton transfer in fuel cells: a computational study. AB - Calculations with density functional theory (DFT) and MP2 have been done to investigate the potential of recently synthesized durable zero-dimensional (OD) nitrogen-based cage structures to perform as efficient proton-exchange membranes (PEMs) in fuel cells. Our calculations suggest that the hydrogenated 0-D cages, in combination with hydrogen-bonding 1,2,3- and 1,2,4-triazole molecules, would perform as highly efficient PEMs. The results are important in the context of the need for efficient PEMs for fuel cells, especially at higher temperatures (greater than 120 degrees C) where conventional water-based PEMs such as Nafion have been found to be ineffective. PMID- 22823520 TI - Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components. AB - Mitochondrial protein tyrosine phosphorylation is an important mechanism for the modulation of mitochondrial functions. In the present study, we have identified novel substrates of c-Src in mitochondria and investigated their function in the regulation of oxidative phosphorylation. The Src family kinase inhibitor PP2 {amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4d] pyrimidine} exhibits significant reduction of respiration. Similar results were obtained from cells expressing kinase-dead c-Src, which harbours a mitochondrial-targeting sequence. Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. Comparison of cells expressing wild-type proteins and their mutants reveals that NDUFV2 phosphorylation is required for NADH dehydrogenase activity, affecting respiration activity and cellular ATP content. SDHA phosphorylation shows no effect on enzyme activity, but perturbed electron transfer, which induces reactive oxygen species. Loss of viability is observed in T98G cells and the primary neurons expressing these mutants. These results suggest that mitochondrial c-Src regulates the oxidative phosphorylation system by phosphorylating respiratory components and that c-Src activity is essential for cell viability. PMID- 22823521 TI - Patient preferences for community pharmacy asthma services: a discrete choice experiment. AB - BACKGROUND: Specialized community pharmacy services, involving the provision of disease state management and care by pharmacists, have been developed and trialled and have demonstrated very good health outcomes. Most of these services have been developed from a healthcare professional perspective. However, for the future uptake and long-term sustainability of these services as well as for better and sustained health outcomes for patients, it is vital to gain an understanding of patients' preferences. We can then structure healthcare services to match these preferences and needs rather than around clinical viewpoints alone. OBJECTIVE: The aim of this study was to elicit patient preferences for pharmacy-based specialized asthma services using a discrete choice experiment and to explore the value/importance that patients place on the different attributes of the asthma service. The existence of preference heterogeneity in the population was also investigated. METHODS: The study was conducted with asthma patients who had recently experienced a specialized asthma management service at their pharmacy in New South Wales, Australia. Pharmacists delivering the asthma service mailed out the discrete choice questionnaires to participating patients at the end of 6 months of service provision. A latent class (LC) model was used to investigate each patient's strength of preference and preference heterogeneity for several key attributes related to asthma service provision: frequency of visits, access to pharmacist, interaction with pharmacy staff, availability of a private area for consultation, provision of lung function testing, type and depth of advice provision, number of days with asthma symptoms and cost of service. RESULTS: Eighty useable questionnaires (of 170 questionnaires sent out) were received (response rate 47.1%). The study identified various key elements of asthma services important to patients. Further, the LC analysis revealed three classes with differing patient preferences for levels of asthma service provision. Patients in the Minimalistic Model class valued provision of lung function testing and preferred more frequent service visits. Cost of service had a negative effect on service preference for patients in this class. Patients in the Partial Model class mainly derived utility from the provision of lung function testing and comprehensive advice at the pharmacy and also wanted more frequent service visits. The Holistic Model class patients considered all attributes of the service to be important when making a choice. While the majority of the service attributes had a positive effect on preference for patients in this class, cost of service and days with symptoms of asthma had a negative effect on service preference. These patients also preferred fewer service visits. CONCLUSION: The study identified various key attributes that are important to patients with respect to community pharmacy-based asthma services. The results also demonstrate the existence of preference heterogeneity in the population. Asthma service providers need to take these findings into consideration in the design and development of future service models so as to increase their uptake and ensure their long-term sustainability. PMID- 22823522 TI - Angiogenin expression in burn blister fluid: implications for its role in burn wound neovascularization. AB - Deep partial thickness burn (DPTB) wound fluids have a greater propensity for establishing neovascularization than did superficial partial thickness burn (SPTB) wound fluids in our previous study. To investigate the factors responsible for this activity, cytokine array and enzyme-linked immunosorbent assay were used to perform an expression analysis of angiogenic factors in burn fluid. Although present in approximately equal amounts in both SPTB and DPTB blister fluids from burn patients, angiogenin does appear to be involved in the ability of DPTB blister fluid to promote neovascularization in vitro and in vivo. Angiogenin alone was sufficient to induce endothelial differentiation of circulating angiogenic cells (CAC) without vascular endothelial growth factor A involvement. In addition, angiogenin was positively associated with CAC differentiation in the burn blister fluid. Blocking the effect of angiogenin in burn blister fluids resulted in a significant reduction of endothelial cell proliferation, CAC differentiation, and new blood vessels formation in vivo. Moreover, immunohistochemistry revealed that high angiogenin expression colocalizes with high vascularity in human burn wounds at day 7, further supporting our hypothesis that angiogenin is involved in burn wound neovascularization. PMID- 22823524 TI - Capillary condensation hysteresis in overlapping spherical pores: a Monte Carlo simulation study. AB - The mechanisms of hysteretic phase transformations in fluids confined to porous bodies depend on the size and shape of pores, as well as their connectivity. We present a Monte Carlo simulation study of capillary condensation and evaporation cycles in the course of Lennard-Jones fluid adsorption in the system of overlapping spherical pores. This model system mimics pore shape and connectivity in some mesoporous materials obtained by templating cubic surfactant mesophases or colloidal crystals. We show different mechanisms of capillary hysteresis depending on the size of the window between the pores. For the system with a small window, the hysteresis cycle is similar to that in a single spherical pore: capillary condensation takes place upon achieving the limit of stability of adsorption film and evaporation is triggered by cavitation. When the window is large enough, the capillary condensation shifts to a pressure higher than that of the isolated pore, and the possibility for the equilibrium mechanism of desorption is revealed. These finding may have important implications for practical problems of assessment of the pore size distributions in mesoporous materials with cagelike pore networks. PMID- 22823525 TI - Concurrent separation of CO2 and H2O from air by a temperature-vacuum swing adsorption/desorption cycle. AB - A temperature-vacuum swing (TVS) cyclic process is applied to an amine functionalized nanofibrilated cellulose sorbent to concurrently extract CO(2) and water vapor from ambient air. The promoting effect of the relative humidity on the CO(2) capture capacity and on the amount of coadsorbed water is quantified. The measured specific CO(2) capacities range from 0.32 to 0.65 mmol/g, and the corresponding specific H(2)O capacities range from 0.87 to 4.76 mmol/g for adsorption temperatures varying between 10 and 30 degrees C and relative humidities varying between 20 and 80%. Desorption of CO(2) is achieved at 95 degrees C and 50 mbar(abs) without dilution by a purge gas, yielding a purity exceeding 94.4%. Sorbent stability and a closed mass balance for both H(2)O and CO(2) are demonstrated for ten consecutive adsorption-desorption cycles. The specific energy requirements of the TVS process based on the measured H(2)O and CO(2) capacities are estimated to be 12.5 kJ/mol(CO2) of mechanical (pumping) work and between 493 and 640 kJ/mol(CO2) of heat at below 100 degrees C, depending on the air relative humidity. For a targeted CO(2) capacity of 2 mmol/g, the heat requirement would be reduced to between 272 and 530 kJ/mol(CO2), depending strongly on the amount of coadsorbed water. PMID- 22823523 TI - Comparative metagenomics of three Dehalococcoides-containing enrichment cultures: the role of the non-dechlorinating community. AB - BACKGROUND: The Dehalococcoides are strictly anaerobic bacteria that gain metabolic energy via the oxidation of H2 coupled to the reduction of halogenated organic compounds. Dehalococcoides spp. grow best in mixed microbial consortia, relying on non-dechlorinating members to provide essential nutrients and maintain anaerobic conditions.A metagenome sequence was generated for the dechlorinating mixed microbial consortium KB-1. A comparative metagenomic study utilizing two additional metagenome sequences for Dehalococcoides-containing dechlorinating microbial consortia was undertaken to identify common features that are provided by the non-dechlorinating community and are potentially essential to Dehalococcoides growth. RESULTS: The KB-1 metagenome contained eighteen novel homologs to reductive dehalogenase genes. The metagenomes obtained from the three consortia were automatically annotated using the MG-RAST server, from which statistically significant differences in community composition and metabolic profiles were determined. Examination of specific metabolic pathways, including corrinoid synthesis, methionine synthesis, oxygen scavenging, and electron-donor metabolism identified the Firmicutes, methanogenic Archaea, and the ? Proteobacteria as key organisms encoding these pathways, and thus potentially producing metabolites required for Dehalococcoides growth. CONCLUSIONS: Comparative metagenomics of the three Dehalococcoides-containing consortia identified that similarities across the three consortia are more apparent at the functional level than at the taxonomic level, indicating the non-dechlorinating organisms' identities can vary provided they fill the same niche within a consortium. Functional redundancy was identified in each metabolic pathway of interest, with key processes encoded by multiple taxonomic groups. This redundancy likely contributes to the robust growth and dechlorination rates in dechlorinating enrichment cultures. PMID- 22823526 TI - Exploring interpretation of complexity and typicality in narratives and statistical images about the social determinants of health. AB - This article explores public responses to narratives and statistical images, predominantly graphs and maps, designed to raise awareness of social determinants of health and health disparities. We focus particular attention on respondents' interpretation of the complexity of health causality and the typicality of the situations described. We conducted 24 focus groups with liberal and conservative adults (n = 180 participants) living in a large U.S. northeastern state. Although some narratives showed potential for communicating the complex causality connecting social determinants of health (SDH) to health outcomes, contextual details sometimes disrupted generalization to a broader thematic message. Statistical images often prompted useful speculation about how the factors portrayed might be related, but tended to be regarded with suspicion and criticized for oversimplifying what were perceived to be extremely complex issues. These findings lend theoretical insight to narrative and visual persuasion in the context of social issues with complex causation. We discuss practical implications for those seeking to communicate about the social determinants of health. PMID- 22823527 TI - Older people's dependence on caregivers' help in their own homes and their lived experiences of their opportunity to make independent decisions. AB - AIM: The aim of this study was to illuminate the meaning of older people's dependence on caregivers' help, and of their opportunity to make independent decisions. BACKGROUND: Throughout the world, the older population is growing, and in Sweden, the system of care for older people is currently undergoing change. Older people in the need of care are expected to live at home for as long as possible. DESIGN: A qualitative and life world approach was used. METHODS: Audio taped interviews were conducted with twelve older persons living at home, dependent on daily municipal home help service. A phenomenological hermeneutic method was utilised to disclose the meanings of lived experiences. FINDING: The findings revealed three themes: being facilitated to make one's own decisions, being hindered from making one's own decisions, struggling for vs. resigning oneself to losing the opportunity to make one's own decisions. The comprehensive understanding revealed that as older people become more dependent on caregivers' help, their opportunity to self-determine is challenged and this is stressful for them. CONCLUSION: The older persons assess their opportunity to self-determine differently, depending on who they are as a person. The caregivers need an awareness of this, and further research is needed to gain knowledge and understanding of how caregivers can improve the way they support and enhance older people's opportunity to decide for themselves. IMPLICATIONS FOR PRACTICE: The findings revealed older persons need to exercise more self-determination and caregivers' need for knowledge to enable this. Further, it indicates a move towards a person-centred approach to focus on persons as individuals and see them as interdependent. The findings contribute to improvements in similar contexts worldwide. PMID- 22823529 TI - Screening electronic veterans' health records for medication discontinuation. AB - OBJECTIVES: Determine the viable yield of screening electronic Veterans Health Administration (VHA) records to identify patients who stop taking a long-term medication for reasons that might be addressed by healthcare providers. STUDY DESIGN: Prospectively screened cohort with mailed follow-up of positive screens. METHODS: Electronic healthcare records were screened to identify patients receiving care in a Veterans Administration (VA) Health Care System who became past due for resupply of medication (statin) prescribed to reduce cholesterol and risks of adverse cardiovascular events. Subsequently, administrative data were used to classify and characterize patients as true or false positive screens. A follow-up survey mailed to the first 1000 positive screens asked them if they were still taking a statin provided by the VHA, and if not, why? RESULTS: From February to July 2010, 1000 (4.6%) of the statin-recipient cohort of 21,935 became past due for a resupply. Subsequently 824 (3.8%; 95% confidence interval [CI] 3.5%-4.0%) were classified as true positives (positive predictive value 82%; 95% CI 80%-85%), and 176 (0.8%; 95% CI 0.7%-0.9%) as false positives. However, the 824 true positives included 95 deceased, 17 long-term care residents, 302 who reported good reasons for no longer getting the statin, and 208 who eventually got another supply. The overall yield of good candidates for efforts to reinstate long-term use of statins was only 20%. CONCLUSIONS: The viable yield from electronically screening VA healthcare records to find patients who stopped taking statins was low. More complete records and sophisticated screening programs are needed to improve the yield. PMID- 22823528 TI - Treatment utilization and unmet treatment need among Hispanics following brief intervention. AB - BACKGROUND: In a large randomized trial examining ethnic differences in response to a brief alcohol intervention following an alcohol-related injury, we showed that Hispanics, but not non-Hispanics, were more likely to reduce alcohol intake in comparison with treatment as usual (Addiction 105:62, 2010). The current study evaluates whether the observed improvements in drinking outcomes previously reported among Hispanics following brief intervention might be related to prior or subsequent treatment utilization. METHODS: This study is a secondary analysis of data collected in a randomized clinical trial that evaluated ethnic differences in the effect of a brief motivational intervention (BMI) on alcohol use among medical inpatients admitted for alcohol-related injury. For this study, statistical analyses were carried out to compare alcohol use, alcohol problems, treatment utilization, and unmet treatment need between Hispanic (n = 537) and non-Hispanic White (n = 668) inpatients. In addition, we examined the relationship between prior treatment utilization and unmet treatment need and alcohol use outcomes following brief intervention and the impact of brief intervention on subsequent treatment utilization and unmet treatment need. RESULTS: In comparison with non-Hispanic Whites, Hispanics at baseline reported heavier drinking, more alcohol problems, greater unmet treatment need, and lower rates of treatment utilization. Among Hispanics, multilevel analyses showed that prior treatment utilization or unmet treatment need did not moderate the effect of BMI on alcohol outcomes. Furthermore, BMI did not significantly impact subsequent treatment utilization or unmet treatment need among Hispanics. Finally, treatment utilization and unmet treatment need at 6 months were not significant mediators between BMI and alcohol use outcomes at follow-up. CONCLUSIONS: The benefits of brief intervention among Hispanics do not appear to be better explained by subsequent engagement in mutual help groups or formal substance abuse treatment. Prior history of treatment, regardless of the severity of alcohol problems, does not appear to influence the impact of brief intervention on alcohol use among Hispanics. These findings support prior results reporting the benefits of brief intervention among Hispanics and demonstrate that these improvements are not related to prior or subsequent treatment utilization. PMID- 22823530 TI - Gender differences in healthcare utilization of patients with diabetes. AB - OBJECTIVES: To examine gender differences in healthcare utilization including outpatient and inpatient medical care for patients with type 2 diabetes mellitus (T2DM), despite participation in T2DM-specific disease management programs (DMP DM). STUDY DESIGN: Baseline data from a cohort study in southwest Germany including 1146 patients with T2DM recruited between October 2008 and March 2010 were used. METHODS: After bivariate analyses, multivariate Poisson and logistic regression models were used to estimate the effect of sex on the number of general practitioner (GP) and medical specialist appointments, prescribed medications, hospitalizations, and inpatient rehabilitations, with additional consideration of glycemic control levels. Poor glycemic control (PGC) was defined as glycated hemoglobin >=7.5%. RESULTS: In total, 905 participants had acceptable glycemic control and 237 participants had poor glycemic control. PGC was more prevalent in men than in women (23% vs 18%). Bivariate analyses among participants with PGC showed significantly fewer GP and medical specialist appointments, a lower number of medications, and longer rehabilitation stays in men than in women. Multivariate regression analyses among participants with PGC confirmed statistically significant gender differences for GP appointments and number of prescribed medications (P <.05) for men compared with women. Gender differences regarding inpatient care were less evident. CONCLUSIONS: Our data disclosed major gender differences in healthcare utilization of diabetes patients in Germany despite a high DMP-DM rate. Future research should focus attention on gender-specific approaches to healthcare delivery to improve quality and access to care. PMID- 22823531 TI - Automated phone and mail population outreach to promote colorectal cancer screening. AB - OBJECTIVES: To evaluate a population outreach program to promote screening for colorectal cancer (CRC) among average-risk insured men and women. STUDY DESIGN: In 2008, 58,440 Kaiser Permanente Colorado members unscreened for CRC received an interactive voice response (IVR) call followed by mailed fecal immunochemical test (FIT), or colonoscopy if requested. We used a quasi-experimental design with staged implementation, in which a random subset of eligible members was selected each week to receive the intervention. This design allowed the entire group to ultimately receive the intervention. METHODS: Survival models summarized time specific comparisons of screening behaviors for members who received immediate outreach compared with those who had not yet received it. RESULTS: A total of 26,003 (45%) of the unscreened population completed screening, predominately due to the mailed kits. The unadjusted hazard ratio (HR) for the outreach effect on screening completion was 4.08 (95% confidence interval: 3.93-4.25) and adjusted HR was 3.75 (3.60-3.91). Lower levels of screening were seen in African Americans (HR 0.83; 0.77-0.90) and Hispanics (HR 0.84; 0.80-0.88) compared with whites, and in smokers (HR 0.77; 0.74-0.80) compared with nonsmokers. The outreach had greater impact among those without a primary care (HR 4.5 vs 3.0, P <.0001) or specialty care (HR 5.2 vs 3.5, P <.0001) visit compared with those with 1 or more visits. CONCLUSIONS: The rate of colorectal cancer screening in members after mailed FIT with IVR was almost 4 times higher than usual care, particularly in those without an office visit. Targeted approaches are needed for groups at risk for not screening. PMID- 22823532 TI - Incidence and cost of CAP in a large working-age population. AB - OBJECTIVES: To estimate incidence rates and quantify excess medical and productivity cost of community-acquired pneumonia (CAP) in a commercially insured, working-age population. METHODS: Using the Thomson Reuters MarketScan Commercial Claims and Encounters Database, we estimated the annual incidence of CAP from 2003 through 2007 and evaluated its excess direct medical and productivity costs due to short-term disability and workplace absenteeism for adult patients aged 18 to 64 years. A cohort of CAP patients was 1:3 propensity score matched to a control cohort without pneumonia. Both excess direct medical costs and excess productivity costs were estimated in multivariate ordinary least squares (OLS) and generalized linear model (GLM) adjusting for demographic and clinical characteristics. RESULTS: A total of 402,831 patients with CAP and 1,208,231 matched controls were included. Overall annual CAP incidence was 4.89 cases per 1000 person-years. Excess annual medical cost of CAP ranged from $7220 by OLS to $11,443 by GLM. Inpatient costs, outpatient costs, and pharmacy costs explained 34%, 51%, and 15% of this excess cost of the GLM models, respectively. CAP patients had an additional productivity cost of $2391. Among adults younger than 65 years, these estimates imply an incidence of CAP of 950,000 annual cases at a cost of $10.6 billion (range: $9.04-$13.1), of which 80% are direct medical costs and 20% are productivity costs. CONCLUSIONS: CAP is a frequent and costly event in a working-age population with a national cost of $10.6 billion. Interventions that could successfully prevent CAP could have a significant impact on healthcare costs and productivity. PMID- 22823534 TI - Response to temperature stress in rhizobia. AB - It is well established that soil is a challenging environment for bacteria, where conditions may change rapidly and bacteria have to acclimate and adapt in order to survive. Rhizobia are an important group of soil bacteria due to their ability to establish atmospheric nitrogen-fixing symbioses with many legume species. Some of these legumes are used to feed either humans or cattle and therefore the use of rhizobia can reduce the need for synthetic N-fertilizers. Several environmental factors shape the composition and the activity of rhizobia populations in the rhizosphere. Soil pH and temperature are often considered to be the major abiotic factors in determining the bacterial community diversity. The present review focuses on the current knowledge on the molecular bases of temperature stress response in rhizobia. The effects of temperature stress in the legume-rhizobia symbioses are also addressed. PMID- 22823533 TI - Chromosome cohesion decreases in human eggs with advanced maternal age. AB - Aneuploidy in human eggs increases with maternal age and can result in infertility, miscarriages, and birth defects. The molecular mechanisms leading to aneuploidy, however, are largely unknown especially in the human where eggs are exceedingly rare and precious. We obtained human eggs from subjects ranging from 16.4 to 49.7 years old following in vitro maturation of oocyte-cumulus complexes isolated directly from surgically removed ovarian tissue. A subset of these eggs was used to investigate how age-associated aneuploidy occurs in the human. The inter-kinetochore distance between sister chromatids increased significantly with maternal age, indicating weakened cohesion. Moreover, we observed unpaired sister chromatids from females of advanced age. We conclude that loss of cohesion with increasing maternal age likely contributes to the well-documented increased incidence of aneuploidy. PMID- 22823535 TI - MicroRNA155 in the growth and invasion of salivary adenoid cystic carcinoma. AB - BACKGROUND: The carcinogenesis mechanism of adenoid cystic carcinoma (ACC) of the salivary gland is poorly understood. MicroRNA155 (miRNA155) has been involved in the carcinogenesis of many malignant tumors. The present study aims to examine the role of miRNA155 in tumor growth and invasion of ACC. METHODS: MiRNA155 expression was determined in ACC specimens along with normal salivary glands by quantitative PCR. Using ACC-2 cells as a model for ACC, cell proliferation was examined by MTT assay after knocking down miRNA155 expression, and cell cycle analysis was performed. Invasive capacity of ACC-2 cells was examined by a Transwell culture assay. The effect of miRNA155 on tumor growth was also examined in vivo using mouse models. The effect of miRNA155 on epidermal growth factor receptor (EGFR)/NF-kappaB was studied by quantitative PCR and electrophoretic mobility shift assay. RESULTS: MiRNA155 was over-expressed in ACC. Proliferation of ACC-2 cells was markedly inhibited by knocking down miRNA155, resulting from a blockade of cell cycle in the G1 phase. Inhibition of miRNA155 significantly suppressed the invasive capacity of ACC-2 cells. In vivo growth of ACC-2 cell derived tumors was significantly slower by inhibition of miRNA155. Inhibition of miRNA155 also resulted in decreased expression of EGFR and RelA (NF-kappaB). CONCLUSION: The results suggest that miRNA155 facilitates cell cycle progression and promotes invasion in ACC and that the EGFR/NF-kappaB pathway might participate in mediating the effects of miRNA155. This study has provided insights into the carcinogenic mechanisms of ACC and identified new targets for intervention of salivary ACC. PMID- 22823536 TI - Liquid plasmonics: manipulating surface plasmon polaritons via phase transitions. AB - This paper reports the manipulation of surface plasmon polaritons (SPPs) in a liquid plasmonic metal by changing its physical phase. Dynamic properties were controlled by solid-to-liquid phase transitions in 1D Ga gratings that were fabricated using a simple molding process. Solid and liquid phases were found to exhibit different plasmonic properties, where light coupled to SPPs more efficiently in the liquid phase. We exploited the supercooling characteristics of Ga to access plasmonic properties associated with the liquid phase over a wider temperature range (up to 30 degrees C below the melting point of bulk Ga). Ab initio density functional theory-molecular dynamic calculations showed that the broadening of the solid-state electronic band structure was responsible for the superior plasmonic properties of the liquid metal. PMID- 22823537 TI - Life-bombing-injury-life: a qualitative follow-up study of Oklahoma City bombing survivors with TBI. AB - PRIMARY OBJECTIVE: To learn about and come to an understanding of the recovery process and outcomes experienced by the survivors of the 1995 Oklahoma City bombing, who sustained a traumatic brain injury (TBI) along with other injuries in the blast. RESEARCH DESIGN: A phenomenological study was conducted using in person interviews, document and video-tape review, internet communication and researcher journals as the primary data set. METHODS AND PROCEDURES: A total of 20 of the 46 bombing survivors with TBI (44%) agreed to be a part of the study. The data collection process focused on stories about service needs, services accessed and long-term outcomes of the participants. MAIN OUTCOME AND RESULTS: The researchers' data analysis yielded four themes (Trauma-Healing-Support; What TBI?; How I went back to work and life; Now I really need assistance!) that represented the content and meanings of the interviews and supplemental data. CONCLUSIONS: A common thread running through the interviews of survivors with TBI was their portrayal of life-long medical, emotional, vocational and residential needs since the bombing. What they experienced in the months--extending into years--after the bombing was beyond their own anticipation and that of their families and healthcare professionals. PMID- 22823538 TI - Predicting pesticide attenuation in a fractured aquifer using lumped-parameter models. AB - Neighboring springs draining fractured-rock aquifers can display large differences in water quality and flow regime, depending on local variations of the connectivity and the aperture size distribution of the fracture network. Consequently, because homogeneous equivalent parameters cannot be assumed a priori for the entire regional aquifer, the vulnerability to pollution of such springs has to be studied on a case by case basis. In this paper, a simple lumped parameter model usually applied to estimate the mean transit time of water (or tracer) is presented. The original exponential piston-flow model was modified to take land-use distribution into account and applied to predict the evolution of atrazine concentration in a series of springs draining a fractured sandstone aquifer in Luxembourg, where despite a nationwide ban in 2005, atrazine concentrations still had not begun to decrease in 2009. This persistence could be explained by exponentially distributed residence times in the aquifer, demonstrating that in some real world cases, models based on the groundwater residence time distribution can be a powerful tool for trend reversal assessments as recommended for instance by current European Union guidelines. PMID- 22823539 TI - Three wavelength substrate system of neutrophil serine proteinases. AB - Neutrophil serine proteases, including elastase, proteinase 3, and cathepsin G, are closely related enzymes stored in similar amounts in azurophil granules and released at the same time from triggered neutrophils at inflammatory sites. We have synthesized new fluorescence resonance energy transfer (FRET) substrates with different fluorescence donor-acceptor pairs that allow all three proteases to be quantified at the same time and in the same reaction mixture. This was made possible because the fluorescence emission spectra of the fluorescence donors do not overlap and because the values of the specificity constants were in the same range. Thus, similar activities of proteases can be measured with the same sensitivity. In addition, these substrates contain an N-terminal 2-(2-(2 aminoethoxy)ethoxy)acetic acid (PEG) moiety that makes them cell permeable. Using the mixture of these selected substrates, we were able to detect the neutrophil serine protease (NSP) activity on the activated neutrophil membrane and in the neutrophil lysate in a single measurement. Also, using the substrate mixture, we were in a position to efficiently determine NSP activity in human serum of healthy individuals and patients with diagnosed Wegener disease or microscopic polyangiitis. PMID- 22823540 TI - Effect of 5-hydroxytryptamine (serotonin) receptor inhibitors on the radiation induced bystander effect. AB - PURPOSE: To test the importance of serotonin as a signaling molecule involved in the production and response of radiation-induced bystander effects. MATERIALS AND METHODS: HPV-G human keratinocyte cultures were spiked with various concentrations of Granisetron or Ketanserin and subject to either 0 Gy or 0.5 Gy X-irradiation to observe the inhibitor's effects on bystander signal production. Medium from these cultures was harvested and introduced to non- irradiated cultures of the same cell line to determine the clonogenic bystander response. Separate HPV-G cultures were set up for subsequent calcium measurements in response to irradiated cell conditioned medium (ICCM) in the presence or absence of Granisetron in an attempt to block bystander signal response. RESULTS: Granisetron and Ketanserin produced a dose-dependent propagation of the bystander effect in recipient cultures. Granisetron completely abolished the characteristic calcium pulse observed when non-irradiated cultures are exposed to irradiated cell medium in the presence of this drug. CONCLUSIONS: Serotonin-dependent mechanisms appear to be involved in bystander signal production and response to radiation in this system. PMID- 22823541 TI - Rapid diagnosis of two facial papules using ex vivo fluorescence confocal microscopy: toward a rapid bedside pathology. PMID- 22823542 TI - Awareness and knowledge of developmental co-ordination disorder among physicians, teachers and parents. AB - BACKGROUND: Obtaining a diagnosis of developmental co-ordination disorder (DCD) is a long, inconsistent and frustrating journey for families, with apparently little awareness of DCD in schools or the medical community. METHODS: An online survey was completed by 1297 participants: parents (n = 501), teachers (n = 202), family/general physicians (n = 339) and paediatricians (n = 255). RESULTS: Only 20% of the sample had knowledge of DCD, with 41% of the paediatricians and 23% of family/general physicians familiar. Of participants who have awareness, only 11 59% have knowledge of the impact of DCD on social, emotional and physical health. Less than 30% of physicians have awareness of the secondary consequences. Few physicians diagnose DCD and less than one-third believe it is easy to make a diagnosis; this is in contrast to the fact that most parents report confidence in their physician's ability to make a timely diagnosis. CONCLUSIONS: If less than one-half of physicians have knowledge of DCD and even fewer are knowledgeable of the secondary consequences of the condition, it is not surprising that DCD is infrequently diagnosed and that families need to search for support. This survey confirms observations that the condition is not well known and there is a need for greater awareness of DCD. PMID- 22823544 TI - The context of desire to use marijuana: momentary assessment of young people who frequently use marijuana. AB - Drawing on factors identified in the literature, this study explored in-the moment associations of social, emotional, and temporal contexts and perceived marijuana availability with desire to use the drug, using momentary sampling methodology with young people who frequently use marijuana. Forty-one adolescent/young adult medical outpatients aged 15 to 24 years who reported using marijuana at least twice a week completed 2,912 brief questionnaires on a handheld computer in response to signals emitted at random four to six times a day for 2 weeks. The questionnaires assessed, for the moment when signaled, desire to use marijuana, location, companionship, perceived ease of getting marijuana (availability), positive affect, and negative affect. Participants reported any desire to use marijuana on 1,528 reports (55%). Companionship, perceived availability, and positive affect were independently associated with having any desire to use marijuana. Once desire to use marijuana was present, time of day, positive affect, and negative affect were independently associated with strength of desire. By collecting data in real time, in real life, this study highlights the importance of examining and intervening on emotional, environmental, and temporal contexts for youth who frequently use marijuana in order to reduce their desire to use the drug. PMID- 22823543 TI - Burkholderia pseudomallei transcriptional adaptation in macrophages. AB - BACKGROUND: Burkholderia pseudomallei is a facultative intracellular pathogen of phagocytic and non-phagocytic cells. How the bacterium interacts with host macrophage cells is still not well understood and is critical to appreciate the strategies used by this bacterium to survive and how intracellular survival leads to disease manifestation. RESULTS: Here we report the expression profile of intracellular B. pseudomallei following infection of human macrophage-like U937 cells. During intracellular growth over the 6 h infection period, approximately 22 % of the B. pseudomallei genome showed significant transcriptional adaptation. B. pseudomallei adapted rapidly to the intracellular environment by down regulating numerous genes involved in metabolism, cell envelope, motility, replication, amino acid and ion transport system and regulatory function pathways. Reduced expression in catabolic and housekeeping genes suggested lower energy requirement and growth arrest during macrophage infection, while expression of genes encoding anaerobic metabolism functions were up regulated. However, whilst the type VI secretion system was up regulated, expression of many known virulence factors was not significantly modulated over the 6hours of infection. CONCLUSIONS: The transcriptome profile described here provides the first comprehensive view of how B. pseudomallei survives within host cells and will help identify potential virulence factors and proteins that are important for the survival and growth of B. pseudomallei within human cells. PMID- 22823545 TI - A prospective test of the influence of negative urgency and expectancies on binge eating and purging. AB - It has been proposed that both trait negative urgency (NU; the tendency to act rashly when distressed) and learned outcome expectancies for eating and restricting behavior contribute to the development of symptoms of bulimia nervosa (BN). The current study provides the first prospective test of whether these factors, and their interaction, predict increases in bulimic symptoms over time. In a sample of 355 first-year college women assessed at the start and then at the end of the first semester, prospective tests indicated that (a) baseline NU and eating expectancy endorsement predicted increased odds of binge eating at Time 2; (b) and baseline NU and thinness/restricting expectancies interacted to predict increased frequency of purging at Time 2. These findings are consistent with the hypothesis that NU and learned expectancies together increase risk for symptoms of BN. PMID- 22823546 TI - Feasibility and utility of momentary sampling of sex events in young couples. AB - Research on couples' sexual behaviors is limited because most studies collect data from only one person, rely on retrospective recall, and lack ecological validity. This study explored the feasibility of using momentary sampling (MS) methods to collect sex event data from both members of heterosexual young adult couples. Over two weeks, 40 participants (20 couples) were asked to use a handheld computer to respond to random auditory signals each day and self initiate a report as soon as possible after sex. Couples were randomized into two groups: (a) both partners reported after sex events, or (b) one partner reported after sex events during Week 1 and the other during Week 2 (randomized by gender). Descriptive statistics examined protocol compliance, partner agreement on whether an event occurred, condom use, and reason for sex, as well as partner involvement in reporting, comfort with reporting after sex, and study burden. Results indicated that couples were willing and able to adhere to the protocol. Partners agreed on condom use for nearly all sex events, but frequently reported different reasons for sex events. The use of MS methods to collect information about sex events within couples is a promising approach to the study of sexual behavior. PMID- 22823547 TI - Pickering emulsions stabilized by nanoparticle surfactants. AB - Amphiphilic gold nanoparticles are demonstrated to effectively stabilize emulsions of hexadecane in water. Nanoparticle surfactants are synthesized using a simple and scalable one-pot method that involves the sequential functionalization of particle surfaces with thiol-terminated polyethylene glycol (PEG) chains and short alkane-thiol molecules. The resulting nanoparticles are shown to be highly effective emulsifying agents due to their strong adsorption at oil-water and air-water interfaces. The original nonfunctionalized gold nanoparticles are unable to effectively stabilize oil-water emulsions due to their small size and low adsorption energy. Small-angle X-ray scattering and electron microscopy are used to demonstrate the formation of nanoparticle stabilized colloidosomes that are stable against coalescence and show significant shifts in plasmon resonance enhancing the near-infrared optical absorption. PMID- 22823549 TI - Increasing the validity of experimental models for depression. AB - Major depressive disorder (MDD) is a central nervous system disorder characterized by the culmination of profound disturbances in mood and affective regulation. Animal models serve as a powerful tool for investigating the neurobiological mechanisms underlying this disorder; however, little standardization exists across the wide range of available modeling approaches most often employed. This review will illustrate some of the most challenging obstacles faced by investigators attempting to associate depressive-like behaviors in rodents with symptoms expressed in MDD. Furthermore, a novel series of depressive-like criteria based on correlating behavioral endophenotypes, novel in vivo neurophysiological measurements, and molecular/cellular analyses within multiple brain are proposed as a potential solution to overcoming this barrier. Ultimately, linking the neurophysiological and cellular/biochemical actions that contribute to the expression of a defined MDD-like syndrome will dramatically extend the translational value of the most valid animal models of MDD. PMID- 22823548 TI - Microglia play a role in ethanol-induced oxidative stress and apoptosis in developing hypothalamic neurons. AB - BACKGROUND: Animals exposed to alcohol during the developmental period develop many physiological and behavioral problems because of neuronal loss in various brain areas including the hypothalamus. Because alcohol exposure is known to induce oxidative stress in developing neurons, we tested whether hypothalamic cells from the fetal brain exposed to ethanol (EtOH) may alter the cell-cell communication between neurons and microglia, thereby leading to increased oxidative stress and the activation of apoptotic processes in the neuronal population in the hypothalamus. METHODS: Using enriched neuronal and microglial cells from fetal rat hypothalami, we measured cellular levels of various oxidants (O2 -, reactive oxygen species, nitrite), antioxidants (glutathione [GSH]), antioxidative enzymes (glutathione peroxidase [GSH-Px], catalase, superoxide dismutase) and apoptotic death in neurons in the presence and absence of EtOH or EtOH-treated microglial culture medium. Additionally, we tested the effectiveness of antioxidative agents in preventing EtOH or EtOH-treated microglial conditioned medium actions on oxidative stress and apoptosis in neuronal cell cultures. RESULTS: Neuronal cell cultures showed increased oxidative stress, as demonstrated by higher cellular levels of oxidants but lower levels of antioxidant and antioxidative enzymes, as well as, increased apoptotic death following treatment with EtOH. These effects of EtOH on oxidative stress and cell death were enhanced by the presence of microglia. Antioxidative agents protected developing hypothalamic neurons from oxidative stress and cellular apoptosis which is caused by EtOH or EtOH-treated microglial culture medium. CONCLUSIONS: These data suggest that exposure of developing hypothalamic neurons to EtOH increases cellular apoptosis via the effects on oxidative stress of neurons directly and via increasing production of microglial-derived factor(s). PMID- 22823550 TI - Bridging the gap on Facebook: assessing intergroup contact and its effects for intergroup relations. AB - In line with Allport's contact hypothesis, previous research showed that direct intergroup contact can reduce prejudices. However, establishing face-to-face contact is not always feasible. We postulate that Facebook-groups are a setting where direct and observed intergroup contact can develop, reducing prejudices and increasing mutual acceptance. Analyzing the comments of nine Facebook-groups with the destructive and constructive conflict scale, our results indicated that the expression of prejudices decreased and that of mutual acceptance increased over time, both for in- and outgroup members of the Facebook-groups. Only the expression of less prejudices, but not that of more mutual acceptance was predicted by intergroup contact. The influence of group-based motivations on the engagement in intergroup contact is discussed, and the overall findings are integrated in Steele and Brown's process model of media practices. PMID- 22823551 TI - Role of pharmaceuticals in value-based healthcare: a framework for success. PMID- 22823552 TI - Patient safety-focused medication therapy management: challenges affecting future implementation. AB - OBJECTIVES/BACKGROUND: Lessons learned from the implementation of a pharmacist delivered medication therapy management (MTM) intervention in primary care (PC) can inform future MTM studies and be adopted into real-world clinical settings. We sought to describe the variations and challenges of patient recruitment, enrollment, MTM pharmacist visits, and telephone follow-up in a 3-arm randomized trial of MTM interventions conducted at 3 health centers. STUDY DESIGN/METHODS: Using a post-study structured interview, we interviewed study personnel, clinical pharmacists, and investigators about 5 study domains: recruitment, enrollment visits, MTM pharmacist visits, telephone follow-up, and data collection. RESULTS: All centers screened clinic schedules and conducted queries of administrative databases to identify eligible participants. Patients were recruited either during existing primary care visits or by mailing letters with telephone follow up. Patients with many medical problems, with transportation difficulties, or who were unaccompanied by a family member were less likely to enroll. MTM visits scheduled separately from other clinic appointments had higher cancellation or no show rates. Provider response to pharmacist recommendations was low overall but better when the provider was acquainted with the pharmacist who was making contact. CONCLUSIONS: Off-site implementation of MTM services results in lower participation by patients and providers. Future MTM studies should consider integrating MTM services within the clinic during existing appointments by a pharmacist familiar to the primary care provider. PMID- 22823553 TI - Association between personal health record enrollment and patient loyalty. AB - OBJECTIVES: To examine the association between patient loyalty, as measured by member retention in the health plan, and access to My Health Manager (MHM), Kaiser Permanente's PHR, which is linked to its electronic health record, KP HealthConnect. DESIGN: We conducted a retrospective cohort observational quality improvement project from the third quarter of 2005 to the fourth quarter of 2008 for approximately 394,000 Kaiser Permanente Northwest members. METHODS: To control for self-selection bias, we used propensity scores to perform exact 1-to 1 matching without replacement between MHM users and nonusers. We estimated retention rates of the matched data and assessed the association between MHM use and retention versus voluntary termination. We also estimated odds ratios of significant variables impacting member retention. RESULTS: The probability of remaining a member or being involuntarily terminated versus voluntary termination was 96.7% for users (95% confidence interval [CI], 96.6%-96.7%) and 92.2% for nonusers (95% CI, 92.1%-92.4%; P <.001). In the logistic model, MHM use was a significant predictor; only tenure and illness burden were stronger predictors. Users were 2.578 (95% CI, 2.487%-2.671%) times more likely to choose to remain members than were nonusers. The impact was more substantial among newer members. CONCLUSIONS: MHM use was significantly associated with voluntary membership retention. An indicator of patient loyalty, retention is critical to healthcare organizations. PMID- 22823554 TI - Exploring health plan perspectives in collecting and using data on race, ethnicity, and language. AB - OBJECTIVES: To explore why health plans collect or forgo data collection efforts on race, ethnicity, and language (REL), and the challenges encountered in collecting and using data for quality improvement. STUDY DESIGN: In-depth interviews with 15 health plans were conducted between June and August 2009. METHODS: Fifteen health plans participated and were divided into 2 groups: Plans that collect and use REL data (n = 10), and plans that do not collect REL data (n = 5). A structured interview guide was developed that included questions about REL data collection efforts, leadership support, collaboration with external partners, and challenges and opportunities in the collection and use of REL information. For plans not collecting REL data, questions were also asked regarding reasons to forgo data collection and existing health equity efforts. A summary report, based on audiotapes, interview notes, and input from the research team, was developed and analyzed. RESULTS: The interviews highlight the need for new partnerships and coordinated efforts to improve healthcare equity through disseminating best practices and tools that help expand such activities. Barriers noted include the costs associated with adapting information technology systems to accommodate new functions, such as new data fields, appropriate software and analytical tools, and the lack of standard codes for race and ethnicity. CONCLUSIONS: Health plans are eager to collaborate with new partners and share strategies to collect REL data as a foundation to reduce disparities. Opportunities exist to collaborate with employers and purchasers to improve the extent and quality of REL data and can ultimately lead to designing and implementing culturally appropriate programs in the workforce. PMID- 22823555 TI - Standardizing primary care physician panels: is age and sex good enough? AB - OBJECTIVES: To determine if patient clinical conditions need to be considered when assessing primary care physician (PCP) workload in the context of standardizing panel sizes. STUDY DESIGN: Work resource value units (wRVUs) were used to standardize PCP panel workload. Standardized panels were created using (1) age and sex- and (2) clinical condition-based risk indicators. Billing data were used for all patients, regardless of insurance, for PCPs in a group practice (n = 190). Weighting methods were assessed for subgroups based on PCP specialty (family medicine, internal medicine, and pediatrics) and patient age (adults vs children) and for different levels of aggregation (patient vs PCP). METHODS: Groupwide weights based on wRVUs of all primary care services delivered during the year were applied to individual patients and then aggregated to PCP panels. For age/sex weighting, only patient age and sex were taken into account. For condition-based weighting, 1275 disease categories, based on a combination of episode treatment groups (ETGs) and age and/or sex, were used. RESULTS: As expected, at the patient level, condition-based weights were far more discriminative than age/sex. At the PCP level, this discrimination was less important; panel weights varied 1.9- (age/sex-based) to 2.6-fold (condition based) across PCPs. Correlations between the 2 weighting methods were high (r = 0.93) for child panels and moderate (r = 0.71) for adult panels (all P <.001). CONCLUSIONS: The heterogeneity of PCP panels should be considered when assessing PCP workload for panel management. Panel variability in workload is well captured by age/sex-based weights for children, but for adults condition-based adjustment may be necessary. PMID- 22823557 TI - Pulsed laser deposition of CdSe Quantum dots on Zn2SnO4 nanowires and their photovoltaic applications. AB - In this work we report a physical deposition-based, one-step quantum dot (QD) synthesis and assembly on ternary metal oxide nanowires for photovoltaic applications. Typical solution-based synthesis of colloidal QDs for QD sensitized solar cells involves nontrivial ligand exchange processing and toxic wet chemicals, and the effect of the ligands on carrier transport has not been fully understood. In this research using pulsed laser deposition, CdSe QDs were coated on Zn(2)SnO(4) nanowires without ligand molecules, and the coverage could be controlled by adjusting the laser fluence. Growth of QDs in dense nanowire network structures was also achieved, and photovoltaic cells fabricated using this method exhibited promising device performance. This approach could be further applied for the assembly of QDs where ligand exchange is difficult and could possibly lead to reduced fabrication cost and improved device performance. PMID- 22823558 TI - Ultradian corticosterone secretion is maintained in the absence of circadian cues. AB - Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity. Two approaches were used to dissociate the hypothalamic-pituitary adrenal (HPA) axis from normal circadian input in rats: (i) exposure to a constant light (LL) environment and (ii) electrolytic lesioning of the SCN. Blood was sampled using an automated sampling system. As expected, both treatments resulted in a loss of the circadian pattern of corticosterone secretion. Ultradian pulsatile secretion of corticosterone however, was maintained across the 24 h in all animals. Furthermore, the loss of SCN input revealed an underlying relationship between locomotor and HPA activity. In control (LD) rats there was no clear correlation between ultradian locomotor activity and hormone secretion, whereas, in LL rats, episodes of ultradian activity were consistently followed by periods of increased pulsatile hormone secretion. These data clearly demonstrate that the ultradian rhythm of corticosterone secretion is generated through a mechanism independent of the SCN input, supporting recent evidence for a sub-hypothalamic pulse generator. PMID- 22823559 TI - Potential effect of the New York City policy regarding sugared beverages. PMID- 22823560 TI - Redox status evaluation in dogs affected by mast cell tumour. AB - Oxidative stress status has been evaluated in depth in human medicine and its role in carcinogenesis has been clearly established. The purpose of this prospective study was to evaluate antioxidant concentrations and oxidative stress in dogs with mast cell tumours (MCTs) that had received no previous treatments, and to compare them to healthy controls. In 23 dogs with mast cell tumour and 10 healthy controls, oxidative status was assessed using the Reactive Oxygen Metabolites-derived compounds (d-ROMs) test, antioxidant activity was measured by the Biological Antioxidant Potential (BAP) test, and alpha-tocopherol levels were evaluated using high-performance liquid chromatography and ultraviolet analysis. At baseline, dogs with MCT had significantly higher d-ROMs (P < 0.00001) and lower BAP (P < 0.0002) compared with healthy controls. However, no significant difference was observed for alpha-tocopherol (P = 0.95). Results suggest that oxidative stress pattern and oxidative defence barrier are altered in dogs with newly diagnosed MCT compared with control dogs. Future studies are needed in order to assess the prognostic role of oxidative stress and to evaluate the impact of different therapeutic approaches. PMID- 22823561 TI - Altered cingulostriatal coupling in obsessive-compulsive disorder. AB - Neurobiological models of obsessive-compulsive disorder (OCD) assume abnormalities in corticostriatal networks involving cingulate and orbitofrontal cortices, but the connectivity within these systems is rarely addressed in experimental imaging studies in this patient group. Using an established monetary reinforcement paradigm known to involve the cingulate cortex and the ventral striatum, the present study sought to test for altered corticostriatal coupling in OCD patients anticipating potential punishment. The anterior midcingulate cortex (aMCC), a region integrating negative emotion, pain, and cognitive control, was chosen as a seed region due to its particular relevance in OCD, representing the neurosurgical target for cingulotomy, and showing increased responses to errors in OCD patients. Results from psychophysiological interaction analyses revealed that significantly altered, inverse coupling occurs between the aMCC and the ventral striatum when OCD patients anticipate potential punishment. This abnormality links the two major contemporary neurosurgical OCD target sites, and provides direct experimental evidence of altered corticostriatal connectivity in OCD. Noteworthy, an abnormal aMCC coupling with cortical areas outside of traditional corticostriatal circuitry was identified besides the alteration in the cingulostriatal pathway. In conclusion, these findings support the importance of applying connectivity methods to study corticostriatal networks in OCD, and favor the application of effective connectivity methods to study corticostriatal abnormalities in OCD patients performing tasks that involve symptom provocation and reinforcement learning. PMID- 22823562 TI - Resourcefulness, positive cognitions, relocation controllability and relocation adjustment among older people: a cross-sectional study of cultural differences. AB - BACKGROUND: The population of older people in both the United States and Egypt is expected to double by the year 2030. With ageing, chronic illnesses increase and many older people need to relocate to retirement communities. Research has shown that positive cognitions and resourcefulness are positively correlated with adaptive functioning and better adjustment. AIMS AND OBJECTIVES: The purpose of this study was to examine and compare relocation controllability, positive cognitions, resourcefulness and relocation adjustment between American and Egyptian older people living in retirement communities. The purpose of this cultural comparison is to gain insight into influencing factors in each culture that might lead to interventions to help relocated older adults in both cultures adjust to their new surroundings. DESIGN AND METHOD: A cross-sectional, descriptive design was used to compare relocation controllability, positive cognitions, resourcefulness and relocation adjustment of a convenience sample of American older people (n = 104) and a convenience sample of Egyptian older people (n = 94). The study was a secondary analysis of two studies of older people residing in six retirement communities in Northeast Ohio and in five retirement communities in Alexandria, Egypt. RESULTS: Examination of mean scores and standard deviations on the measure of positive cognitions using independent sample t-tests indicated that on average, the American older people reported more positive cognitions (t (131.16) = 11.29, P < 0.001), more relocation controllability (t (196) = -6.78, P < 0.001) and more relocation adjustment (t (196) = 9.42, P < 0.001) than the Egyptian older people. However, there was no significant difference between Egyptians and Americans in resourcefulness (t (174.16) = -0.97, P > 0.05). CONCLUSION: The results provide direction for the development of positive cognition interventions and engaging older people in the decision-making process to help them to adjust to relocation. Implications for practice. Positive thinking and resourcefulness training interventions can be used by nurses to help relocated older people to adjust to the stress of relocation to retirement communities. These interventions can be used on primary, secondary, and tertiary levels. Primary interventions can help to prevent the stress of relocation before happening by helping older people to use their positive thinking and their resources and work with them before relocating to retirement communities. Secondary prevention can be used by nurses to help older people who have already relocated to retirement communities and have already experienced stress of relocation to help them out by decreasing the stress that they are suffering. Tertiary prevention can be used to prevent further stress and deterioration for those who have suffered physical and psychological symptoms as a result of relocation. PMID- 22823563 TI - Conserving and extending the useful life of the largest aquifer in North America: the future of the High Plains/Ogallala aquifer. AB - The water-level decline of the High Plains/Ogallala aquifer is one of the largest water management concerns in the United States. The economy and livelihood of people living in that vast region depend almost exclusively on water extracted from that aquifer. A debate about its future is ongoing, and questions remain as to how best to conserve the groundwater resource. Maintaining the aquifer will require reductions in pumping and irrigated hectarage and adopting additional conservation measures. Eventually, the agricultural system will have to be based dominantly on the renewable water resources of the region. In effect, this means a limited-irrigation and/or dry-farming regime. What Kansas is currently doing to further extend the life of the aquifer is presented here together with additional measures that could be taken. A key management approach to help sustain the aquifer in western Kansas is to divide the aquifer into subunits on which to base localized management decisions. Another recently adopted measure is the establishment of local enhanced management areas, which would allow locally agreed upon specific corrective controls in those areas. History has shown that incentive and voluntary plans alone have not been successful in halting water level declines. Thus, limits and timelines need to be set and checks must be in place to enforce strict administration of conservation measures. It is advocated that water laws be reformed and modernized so that "water rights" are constrained by the current availability of water and the preservation of the resource base for future generations. PMID- 22823564 TI - Allocating the unexpected kidney. PMID- 22823565 TI - Imaging of desmoid tumor located in renal hilum. PMID- 22823566 TI - Iodine isotopes (127I and 129I) in aerosols at high altitude Alp stations. AB - Concentrations of gases and particulate matter have been proven to be affected by meteorological and geographical variables from urban locations to high mountain clean air sites. Following our previous research in Vienna, we summarize here new findings about concentration levels of iodine isotopes in aerosols collected at two Alpine meteorological stations, Sonnblick (Austria) and Zugspitze (Germany) during 2001. The present study mainly focuses on the effect of altitude on the anthropogenic concentration of (129)I and on the isotopic ratio (129)I/(127)I. Iodine was separated from matrix elements by using either an anion exchange method or solvent extraction, and was analyzed by ICP-MS and AMS. Over the altitude change from Vienna to Zugspitze and Sonnblick (202 m to 2962 m and 3106 m above sea level), stable iodine level decreased from an average of 0.94 ng m( 3) to 0.52 ng m(-3) and 0.62 ng m(-3), respectively. Similarly, (129)I concentrations at both Alpine stations were about 1 order of magnitude lower (10(4) atoms m(-3)) than values obtained for Vienna (10(5) atoms m(-3)) and reveal a strong vertical concentration gradient of (129)I. A high degree of variability is observed, which is due to wide variation in the origin of air masses. Furthermore, air trajectory analysis demonstrates the importance of large scale air transport mostly from southeast Europe for influencing Sonnblick whereas influence from northwest Europe is strong at Zugspitze. In contrast to (129)I, a higher concentration of (7)Be was found at higher altitude stations compared to Vienna which probably results from its production in the upper atmosphere. PMID- 22823567 TI - Z- and enantioselective ring-opening/cross-metathesis with enol ethers catalyzed by stereogenic-at-Ru carbenes: reactivity, selectivity, and Curtin-Hammett kinetics. AB - The first instances of Z- and enantioselective Ru-catalyzed olefin metathesis are presented. Ring-opening/cross-metathesis (ROCM) reactions of oxabicyclic alkenes and enol ethers and a phenyl vinyl sulfide are promoted by 0.5-5.0 mol % of enantiomerically pure stereogenic-at-Ru complexes with an aryloxy chelate tethered to the N-heterocyclic carbene. Products are formed efficiently and with exceptional enantioselectivity (>98:2 enantiomer ratio). Surprisingly, the enantioselective ROCM reactions proceed with high Z selectivity (up to 98% Z). Moreover, reactions proceed with the opposite sense of enantioselectivity versus aryl olefins, which afford E isomers exclusively. Preliminary DFT calculations in support of Curtin-Hammett kinetics as well as initial models that account for the stereoselectivity levels and trends are provided. PMID- 22823568 TI - Strategy for optimizing LC-MS data processing in metabolomics: a design of experiments approach. AB - A strategy for optimizing LC-MS metabolomics data processing is proposed. We applied this strategy on the XCMS open source package written in R on both human and plant biology data. The strategy is a sequential design of experiments (DoE) based on a dilution series from a pooled sample and a measure of correlation between diluted concentrations and integrated peak areas. The reliability index metric, used to define peak quality, simultaneously favors reliable peaks and disfavors unreliable peaks using a weighted ratio between peaks with high and low response linearity. DoE optimization resulted in the case studies in more than 57% improvement in the reliability index compared to the use of the default settings. The proposed strategy can be applied to any other data processing software involving parameters to be tuned, e.g., MZmine 2. It can also be fully automated and used as a module in a complete metabolomics data processing pipeline. PMID- 22823571 TI - Thermal effusivity changes as a precursor to moist desquamation. AB - Skin toxicity is a ubiquitous side effect in radiotherapy and can be difficult to predict. Moist desquamation in cancer patients can decrease quality of life and occasionally demand unplanned treatment breaks thus worsening outcome. In breast cancer patients, moist desquamation occurs approximately one-third of the time, and while avenues such as intensity-modulated radiation therapy exist to decrease skin side effects, they may be prohibitively expensive to distribute widely. To selectively target patients who are at risk for high skin toxicity, toxicity prediction beyond heuristics is required. This study presents 3D thermal tomography, a translation technology that employs active thermal imaging to map the thermal effusivity of skin. Irradiated mice were imaged throughout reaction development to establish a correlation between effusivity changes and eventual toxicity severity. Female hairless mice (n = 11) were anesthetized and irradiated to 40 Gy in one fraction using a 1 cm Leipzig brachytherapy applicator with an Ir 192 source. After irradiation, thermal imaging was conducted daily with a flash lamp and infrared camera. Effusivity was calculated using custom software and tracked within irradiated and contralateral control regions. Mice were retrospectively grouped into high-grade (moist desquamation present, n = 6) and low-grade (n = 5). All mice showed an increase in the relative average effusivity difference among the treated and control regions between irradiation and peak reaction between 12 and 15 days after irradiation. The high-grade group showed an earlier increase in relative average effusivity difference (mean 1.7 days after irradiation versus 4.4 days after irradiation) than the low-grade group, and had a significantly greater relative average effusivity difference between 2-5 days after irradiation. We concluded that 3D thermal tomography is quick, non invasive, non-ionizing and exhibited a correlative difference between mice that eventually developed moist desquamation and those that only presented dry desquamation. With further development, it may prove to be a useful tool in the clinic for differentiating patients who require preventative measures to reduce skin toxicity. PMID- 22823570 TI - Novel fluorescent biosensor for alpha-glucosidase inhibitor screening based on cationic conjugated polymers. AB - A new fluorescent biosensor has been designed to screen alpha-glucosidase inhibitors (AGIs) sensitively by utilizing signal amplification effect of conjugated polymers. The fluorescence of cationic poly(fluorenylene phenylene) (PFP) was quenched in the presence of para-nitrophenyl-alpha-d-glucopyranoside and alpha-glucosidase, and turned on upon addition of AGIs. Thus, a new method was developed for AGIs screening based on the fluorescence turn-off/turn-on. The IC(50) values obtained for inhibitors were compared with that reported using absorption spectroscopy. All results present the new method is more sensitive and promising in screening AGIs and inhibitors of other enzymes whose hydrolysis product is 4-nitrophenol. PMID- 22823569 TI - Characterization of the small RNA component of leaves and fruits from four different cucurbit species. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of non-coding small RNAs involved in post-transcriptional regulation of gene expression critical for plant growth and development, stress responses and other diverse biological processes in plants. The Cucurbitaceae or cucurbit family represents some of economically important species, particularly those with edible and medicinal fruits. Genomic tools for the molecular analysis of members of this family are just emerging. Partial draft genome sequence became available recently for cucumber and watermelon facilitating investigation of the small RNA component of the transcriptomes in cucurbits. RESULTS: We generated four small RNA libraries from bottle gourd (Lagenaria siceraria), Cucurbita moschata, Cucurbita pepo, and, watermelon (Citrullus lanatus var. lanatus) in order to identify conserved and novel lineage specific miRNAs in these cucurbits. Deep sequencing of small RNA libraries from these species resulted in 1,597,263, 532,948, 601,388, and 493,384 unique sRNA reads from bottle gourd, moschata, pepo and watermelon, respectively. Sequence analysis of these four libraries resulted in identification of 21 miRNA families that are highly conserved and 8 miRNA families that are moderately conserved in diverse dicots. We also identified 4 putative novel miRNAs in these plant species. Furthermore, the tasiRNAs were identified and their biogenesis was determined in these cucurbits. Small RNA blot analysis or q-PCR analyses of leaf and fruit tissues of these cucurbits showed differential expression of several conserved miRNAs. Interestingly, the abundance of several miRNAs in leaves and fruits of closely related C. moschata and C. pepo was also distinctly different. Target genes for the most conserved miRNAs are also predicted. CONCLUSION: High throughput sequencing of small RNA libraries from four cucurbit species has provided a glimpse of small RNA component in their transcriptomes. The analysis also showed considerable variation within four cucurbit species with regards to expression of individual miRNAs. PMID- 22823572 TI - A focused scanning vertical beam for charged particle irradiation of living cells with single counted particles. AB - The Surrey vertical beam is a new facility for targeted irradiation of cells in medium with singly counted ions. A duo-plasmatron ion source and a 2 MV TandemTM accelerator supply a range of ions from protons to calcium for this beamline and microscope endstation, with energy ranges from 0.5 to 12 MeV. A magnetic quadrupole triplet lens is used to focus the beam of ions. We present the design of this beamline, and early results showing the capability to count single ions with 98% certainty on CR-39 track etch. We also show that the beam targeting accuracy is within 5 MUm and selectively target human fibroblasts with a <5 MUm carbon beam, using gamma-H2AX immunofluorescence to demonstrate which cell nuclei were irradiated. We discuss future commissioning steps necessary to achieve submicron targeting accuracy with this beamline. PMID- 22823573 TI - Serum nitric oxide synthase activity is a novel predictor of impaired vasorelaxation in rats. AB - 1. It is well documented that both acetylcholine (ACh)-evoked arterial relaxation and brachial artery flow-mediated vasodilatation are blunted in hypercholesterolaemic patients. However, there are no simple diagnostic methods to detect the pathology of blood vessels of patients. 2. To establish the use of serum nitric oxide synthase (NOS) activity as a diagnostic parameter for impaired vasorelaxation, animals with different levels of vascular healthiness were made by feeding Sprague-Dawley rats a normal diet, a high-cholesterol diet (HCD) or an HCD supplemented with 10 mg/kg per day, p.o., simvastatin, a cholesterol-lowering drug, for 30 days. Serum total cholesterol levels, serum NOS activity and ACh induced vasorelaxation of the isolated aorta were determined at the end of the experiment. 3. Consumption of HCD for 30 days resulted in an increase in serum total cholesterol, attenuated ACh-induced nitric oxide/endothelium-dependent aortic relaxation and decreased NOS activity. Concomitant administration of simvastatin lowered the elevated blood cholesterol levels with complete reversal of the attenuated ACh-induced aortic relaxation and serum NOS activity. An attempt was made to correlate serum NOS activity and the magnitude of ACh elicited vascular relaxation among the different groups. A positive correlation (r = 0.8329; P < 0.001; n = 30) was found between serum NOS activity and vascular relaxation. 4. This finding is a good foundation for the development of a simple and low-cost alternative for diagnosing vascular diseases and evaluating the effectiveness of drugs on the vascular system in patients. PMID- 22823575 TI - Noncooperative metalation of metallothionein 1a and its isolated domains with zinc. AB - Mammalian metallothioneins (MTs) are a family of small cysteine-rich proteins capable of binding 7 Zn(2+) or Cd(2+) ions into two distinct domains: an N terminal beta-domain that binds 3 Zn(2+) or Cd(2+) and a C-terminal alpha-domain that binds 4 Zn(2+) or Cd(2+). MT has been implicated in a number of physiological functions, including metal ion homeostasis, toxic metal detoxification, and as a protective agent against oxidative stress. Conventionally, MT has been understood to coordinate metal ions in a cooperative fashion. Under this mechanism of metalation, the only species of biological relevance would be the metal-free (apo-) form of the protein and the fully metalated (holo-) form of the protein. However, an increasing body of evidence suggests that metalation occurs in a noncooperative manner. If this latter mechanism is correct, then partially metalated forms of the protein will be stable and able to take part in cellular chemistry. We report in this paper conclusive evidence that shows that biologically essential zinc binds to MT in a noncooperative manner. In addition, we report for the first time the stability of a Zn(5)-MT species. The implications of these findings are discussed in terms of the mechanism of metalation. PMID- 22823574 TI - Self-assembled supramolecular gels of reverse poloxamers and cyclodextrins. AB - A series of supramolecular aggregates were prepared using a poly(propylene oxide) poly(ethylene oxide)-poly(propylene oxide) (PPO-PEO-PPO) block copolymer and beta or alpha-cyclodextrins (CD). The combination of beta-CD and the copolymer yields inclusion complexes (IC) with polypseudorotaxane structures. These are formed by complexation of the PPO blocks with beta-CD molecules producing a powder precipitate with a certain crystallinity degree that can be evaluated by X-ray diffraction (XRD). In contrast, when combining alpha-CD with the block copolymer, the observed effect is an increase in the viscosity of the mixtures yielding fluid gels. Two cooperative effects come into play: the complexation of PEO blocks with alpha-CD and the hydrophobic interactions between PPO blocks in aqueous media. These two combined interactions lead to the formation of a macromolecular network. The resulting fluid gels were characterized using different techniques such as differential scanning calorimetry (DSC), viscometry, and XRD measurements. PMID- 22823576 TI - Levetiracetam in the treatment of alcohol dependence: toward the end of the story? AB - BACKGROUND: Levetiracetam exhibited 2 promising results in preclinical studies as well as in treating alcohol withdrawal in humans. Two open-label trials suggested that levetiracetam may be efficient in alcohol-related disorder. METHODS: The study by Fertig and colleagues (2012) examines the effects of levetiracetam using a double-blind, placebo-controlled design including 130 participants. Fertig and colleagues' study included alcohol-dependent participants drinking heavily. Double-blind medication was dispensed for 16 weeks, with a target dose of 2,000 mg per day from week 5 to week 14, and then tapered. RESULTS: The results are negative both on the primary and on the secondary outcomes, except from lower alcohol-related consequences in the levetiracetam extended-release (XR) group, and a trend for a lower quality of life in the levetiracetam XR group. These last 2 results would have been nonsignificant after controlling for multiple testing. CONCLUSIONS: By conducting a state-of-the-art randomized-controlled clinical trial with negative results, Fertig and colleagues have filled an important gap in the existing literature. PMID- 22823578 TI - Staphylococcal skin diseases in animals. PMID- 22823577 TI - Parents, peers and pornography: the influence of formative sexual scripts on adult HIV sexual risk behaviour among Black men in the USA. AB - Black men in the USA experience disproportionately high rates of HIV infection, particularly in the Southeastern part of the country. We conducted 90 qualitative in-depth interviews with Black men living in the state of Georgia and analysed the transcripts using Sexual Script Theory to: (1) characterise the sources and content of sexual scripts that Black men were exposed to during their childhood and adolescence and (2) describe the potential influence of formative scripts on adult HIV sexual risk behaviour. Our analyses highlighted salient sources of cultural scenarios (parents, peers, pornography, sexual education and television), interpersonal scripts (early sex- play, older female partners, experiences of child abuse) and intrapsychic scripts that participants described. Stratification of participant responses based on sexual-risk behaviour revealed that lower- and higher-risk men described exposure to similar scripts during their formative years; however, lower-risk men reported an ability to cognitively process and challenge the validity of risk-promoting scripts that they encountered. Implications for future research are discussed. PMID- 22823579 TI - Are all meticillin-resistant Staphylococcus aureus (MRSA) equal in all hosts? Epidemiological and genetic comparison between animal and human MRSA. AB - Meticillin-resistant Staphylococcus aureus (MRSA) continues to pose a major threat to human health. In animals, MRSA has become established as a veterinary pathogen in pets and horses; in livestock, it presents a concern for public health as a reservoir that can infect humans and as a source of transferrable resistance genes. Genetic analyses have revealed that the epidemiology of MRSA is different in different animal hosts. While human hospital-associated MRSA lineages are most commonly involved in pet infection and carriage, horse-specific MRSA most often represent 'traditional' equine S. aureus lineages. A recent development in the epidemiology of animal MRSA is the emergence of pig-adapted strains, such as CC398 and CC9, which appear to have arisen independently in the pig population. Recent insight into the genome structure and the evolution of S. aureus has helped to explain key aspects of these three distinct epidemiological scenarios. This nonsystematic literature review summarizes the structure and variations of the S. aureus genome and gives an overview of the current distribution of MRSA lineages in various animal species. It also discusses present knowledge about the emergence and evolution of MRSA in animals, adaptation to different host species and response to selective pressure from animal-specific environments. An improved understanding of the genetics and selective pressure that underpin the adaptive behaviour of S. aureus may be used in the future to predict new developments in staphylococcal diseases and to investigate novel control strategies required at a time of increasing resistance to antimicrobial agents. PMID- 22823580 TI - Staphylococcal skin disease in livestock. AB - This review covers cutaneous manifestations of staphylococcal infection in livestock species. CATTLE: In cattle, staphylococcal infections may present as folliculitis or as impetigo. Both may present as mild forms of a group of conditions loosely termed udder dermatitis, which has various clinical presentations and does not always involve staphylococci. GOATS: In goats, staphylococcal infection may be secondary to chorioptic mange or contagious pustular dermatitis (parapox virus infection). While Staphylococcus aureus is usually implicated, infection with Staphylococcus chromogenes and Staphylococcus hyicus have also been reported. SHEEP: Ovine staphylococcal dermatitis typically involves the head. Trauma due to the close contact of heads over feeding troughs and abrasive plants at pasture may be predisposing factors. PIGS: In pigs, the most common cause of staphylococcal skin disease is S. hyicus, although other bacteria, including Staphylococcus sciuri, Staphylococcus chromogenes and meticillin-resistant S. aureus (MRSA), have also been isolated from some cases of greasy pig disease (exudative epidermitis). DIAGNOSIS: Routine culture methods are increasingly supplemented by molecular methods to characterize staphylococci. MANAGEMENT: As commensal bacteria, staphylococcal skin infection is presumed to develop because of predisposing factors. While topical and systemic therapies can be effective, it is important to control for predisposing factors so that recurrences can be prevented. LIVESTOCK-ASSOCIATED MRSA: In recent years, MRSA strains have emerged, particularly in pigs and cattle. While they rarely cause skin disease, they do pose a significant concern for public health authorities. Studies on livestock-associated MRSA may help to progress our understanding of staphylococci in livestock, especially how they spread between animals and humans. PMID- 22823581 TI - Examining retaliatory responses to justice violations and recovery attempts in teams. AB - We examine the effect of supervisor injustice directed toward 1 team member and argue not only that the violated member will retaliate against the supervisor but that team members will band together as a collective in order to retaliate. However, we argue that effects depend on which member is violated, such that violating a strategic core member will result in greater retaliation. We then test the effect of a supervisor recovery attempt, hypothesizing that a recovery will negatively impact retaliation and that the coreness of the violated member moderates this effect, such that it is more important to recover a core member. We test our hypotheses utilizing 64 teams engaged in a command-and-control simulation. Results generally support our hypotheses for retaliation in the form of fewer supervisor-directed organizational citizenship behaviors but are less supportive for retaliation in the form of lower supervisor performance evaluations. PMID- 22823582 TI - Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives--an update. AB - Since the original publication of the article "Development of the IL-12/23 antagonist ustekinumab in psoriasis: Past, present and future perspectives" in March 2011 (see Appendix),(1) there have been several new publications and developments of note. A number of new reports from the ustekinumab psoriasis clinical development program have been published. The analysis of efficacy and safety in the PHOENIX 1 long-term extension demonstrated that continuous stable maintenance dosing of ustekinumab was generally well tolerated and sustained durable efficacy through up to three years of treatment.(2) Pooled safety data from the phase 2 and phase 3 global trials showed that the safety profile of long term continuous ustekinumab treatment through up to three years(3,4) and four years(5) of follow-up was favorable and comparable to what has been reported previously in the shorter-term ustekinumab psoriasis studies.(6-8) This represents the greatest exposure and longest follow-up of psoriasis patients treated with a biologic published to date. Additional phase 3 trials in Asian populations demonstrated similar high levels of efficacy and favorable safety profiles in Japanese,(9,10) Korean,(11,12) and Taiwanese(11,12) patients as those observed in trials conducted in mostly White populations in North America and Europe.(6-8) These data support the positive benefit:risk profile and consistency of response to ustekinumab over years of usage, and in multiple ethnic groups. Results from up to five years of treatment with ustekinumab in the long-term extensions of the phase 3 trials, and the efficacy, safety, and effect on quality of life in Chinese patients will be available in 2012. In addition to clinical trials of ustekinumab for the treatment of psoriasis, 24-week data from one phase 3 study of ustekinumab for the treatment of psoriatic arthritis has recently been presented(13) and another study is ongoing. A Phase 2b trial in Crohn's disease has also been presented,(14) and three phase 3 studies in Crohn's disease are currently in progress. PMID- 22823584 TI - The production of erotica: photobooks of teenage models in Hong Kong. AB - This article examines the production of erotica in a Chinese cultural context. It takes the photo books featuring teenage models published in Hong Kong in 2010 as case studies in which a total of 2,205 photographs of teenage models were analyzed. In-depth interviews were conducted with six producers of these images. It was found that the set of erotic pictures was characterized by three distinctive features. First, they emphasized a look of innocence that suggested purity, fragility, and delicacy. Second, albeit being sexy and desirable, the girls were often presented as if they were unaware of their sexiness. The implication was that their sexiness was unintentional and, thus, the girls were not to blame. Finally, a sense of intimacy was purposefully built between the models and readers by constituting a direct gaze and presenting models as ordinary "girls next door." All these echoed the emphasis of female chastity in Chinese culture. It appears that in Hong Kong, where sexuality issues often provoke debates, the producers of sexy images have benefited from media controversies. By heightening expectations of potential customers, they fuel the "erotic" imagination of the readers. The production of erotica is, hence, completed through a collaboration between teenage models, producers, marketers, and consumers. PMID- 22823583 TI - Does Traditional Chinese Medicine pattern affect acupoint specific effect? Analysis of data from a multicenter, randomized, controlled trial for primary dysmenorrhea. AB - OBJECTIVES: This study assessed the importance of the Traditional Chinese Medicine (TCM) pattern on an acupoint-specific effect. DESIGN: This was a TCM pattern subdivision analysis of the first intervention data from a multicenter, randomized, controlled trial (ISRCTN24863192) (the main trial). SETTINGS: The main trial recruited participants from six hospitals in three provinces in China. SUBJECTS: Five hundred and one (501) participants diagnosed with primary dysmenorrhea (PD) were enrolled in the main trial. INTERVENTIONS: The main trial randomly and equally divided participants into three treatment groups with bilateral electroacupuncture at three sites, respectively: Sanyinjiao (SP6), Xuanzhong (GB39), and an adjacent nonacupoint. Participants were diagnosed with TCM patterns before the treatment. The intervention was carried out when the visual analogue scale (VAS) score of participant's menstrual pain was >= 40 mm on the first day of menstruation and lasted for 30 minutes. OUTCOME MEASURES: The immediate improvement of pain was measured with a 100-mm VAS before the intervention, at 5 minutes, 10 minutes, and 30 minutes during the intervention, and at 30 minutes after the completion of this intervention. RESULTS: Three (3) TCM patterns (n=320) were eligible for analysis, including Cold and Dampness Stagnation pattern (n=184), Qi and Blood Stagnation pattern (n=84), and Qi and Blood Deficiency pattern (n=52). In Cold and Dampness Stagnation pattern, the SP6 group had a significant reduction in VAS scores compared with the GB39 group (mean difference -7.6 mm) and the nonacupoint group (mean difference -8.2 mm), respectively. There was no difference between the latter two groups. There were no group differences in VAS scores in the other two patterns. CONCLUSIONS: It suggested that TCM pattern might affect acupoint specific effect on the immediate pain relief obtained for participants with PD. PMID- 22823585 TI - Factors associated with resident aggression toward caregivers in nursing homes. AB - PURPOSE: Caregivers in nursing homes often experience aggressive behavior of residents. The aim of this study was to explore the caregivers' experiences with aggressive behavior from residents and to identify environmental factors as well as caregiver and resident characteristics related to aggressive behavior in Swiss nursing homes. DESIGN: A retrospective cross-sectional survey was conducted between November 2010 and April 2011 with a sample of caregivers working in various nursing homes in the German-speaking part of Switzerland. In total, 814 caregivers (response rate 51.8%) of 21 nursing homes participated in the study. METHODS: Data were collected using the German version of the Survey of Violence Experienced by Staff (SOVES-G-R). Standard descriptive statistics were used to describe and summarize the date. To identify risk factors related to the experience of aggression by residents, multilevel logistic regression analysis was applied. FINDINGS: The prevalence of participants reporting an aggressive incident during the 12-month period prior to data collection was 81.6%. Of these, 76.5% had experienced verbal aggression, 27.6% threats, and 54.0% physical aggression. The predictive variables in the multiple regression model for physical aggression were: staff education level (odds ratio [OR]= 1.82), gender (OR = 1.82), age (< 30 years vs. 30-45 years: OR = 1.46; < 30 years vs. > 45 years: OR = 2.13), and confidence in managing physical aggression (OR = 1.49). The predictive variables for threatening behavior were staff education level (registered nurses vs. non-registered nurses: OR = 1.70; nonstudent vs. student: OR = 1.89) and age (< 30 years vs. 30-45 years: OR = 2.00; < 30 years vs. > 45 years: OR = 2.04). CONCLUSIONS: Caregivers in nursing homes are at high risk for experiencing aggressive behavior. The identified risk factors are in line with earlier investigations, but some contradictory results also were observed. CLINICAL RELEVANCE: The high risk for registered nurses exposed to aggressive behavior and the increased risk for caregivers who feel confident in managing aggressive behavior cast a critical light on the content and aim on present programs for management of aggressive behavior. Caregivers in nursing homes should be qualified in understanding resident aggression in a comprehensive way. A critical point in this topic seems to be the interaction between caregiver and resident during basic care activities. This topic should be investigated in further research projects. PMID- 22823587 TI - Diameter-dependent or independent: toward a mechanistic understanding of the vapor-liquid-solid Si nanowire growth rate. AB - Si nanowires have received continued increased attention because they keep the promise of monolithic integration of high-performance semiconductors with new functionality into existing silicon technology. Most Si nanowires are grown by vapor-liquid-solid mechanism, and despite many years of study, this growth mechanism remains under lively debate. For instance, contradictory results have been reported on the effect of diameter size on nanowire growth rate. Here, we developed a universal kinetic model of Si nanowire growth based on surface diffusion which takes into account adatom diffusion from the sidewall and substrate surface into the liquid droplet as well as the Gibbs-Thomson effect. Our analysis shows that the diameter independence for Si nanowires is affected by the interplay between the Gibbs-Thomson effect and the surface diffusion, whereas the diameter dependence is mainly influenced by the Gibbs-Thomson effect. The results based on the proposed model are in good agreement with experimental data. PMID- 22823586 TI - MiR-146a polymorphism is associated with asthma but not with systemic lupus erythematosus and juvenile rheumatoid arthritis in Mexican patients. AB - Extensive research has shown that aberrant expression of microRNAs (miRNAs) plays an important role in innate and adaptive immune responses. The rs2910164 polymorphism has been identified as a functional variant, which affects the transcription and expression level of miR-146a and, thereby, contributes to the pathogenesis of several inflammatory and autoimmune diseases. To investigate whether the rs2910164 G/C polymorphism was associated with asthma, systemic lupus erythematosus (SLE) or juvenile rheumatoid arthritis (JRA), we performed an association study in a pediatric Mexican cohort. We included 979 pediatric patients (asthma: 402, SLE: 367 and JRA: 210) and 531 control subjects without inflammatory or immune diseases. Genotyping was performed using the 5' exonuclease technique. The genotype distribution of the rs2910164 polymorphism was in Hardy-Weinberg equilibrium in each group. No significant differences were detected in the distribution of this polymorphism between cases and controls (P = 0.108, 0.609 and 0.553 for subjects with asthma, JRA and SLE, respectively). However, stratification by gender showed a statistically significant difference between asthmatic and control females, where the C allele was significantly associated with protection to asthma (odds ratio = 0.694, 95% confidence interval 0.519-0.929, P = 0.0138). Our results provide evidence that rs2910164 may play a role in the susceptibility to childhood-onset asthma, but not SLE or JRA in Mexicans. Further association studies may contribute to determining the role of miR-146a single-nucleotide polymorphisms in immune-mediated diseases. PMID- 22823588 TI - Public experiences of mass casualty decontamination. AB - In this article, we analyze feedback from simulated casualties who took part in field exercises involving mass decontamination, to gain an understanding of how responder communication can affect people's experiences of and compliance with decontamination. We analyzed questionnaire data gathered from 402 volunteers using the framework approach, to provide an insight into the public's experiences of decontamination and how these experiences are shaped by the actions of emergency responders. Factors that affected casualties' experiences of the decontamination process included the need for greater practical information and better communication from responders, and the need for privacy. Results support previous findings from small-scale incidents that involved decontamination in showing that participants wanted better communication from responders during the process of decontamination, including more practical information, and that the failure of responders to communicate effectively with members of the public led to anxiety about the decontamination process. The similarity between the findings from the exercises described in this article and previous research into real incidents involving decontamination suggests that field exercises provide a useful way to examine the effect of responder communication strategies on the public's experiences of decontamination. Future exercises should examine in more detail the effect of various communication strategies on the public's experiences of decontamination. This will facilitate the development of evidence-based communication strategies intended to reduce anxiety about decontamination and increase compliance among members of the public during real-life incidents that involve mass decontamination. PMID- 22823590 TI - Convalescent resting tachycardia predicts unfavorable outcome of anorexia nervosa. AB - BACKGROUND: In patients with anorexia nervosa (AN) who have tachycardia during the clinical course, difficulty in treatment has been observed. The purpose of the present study was to evaluate the association between heart rate (HR) in the weight loss and weight recovery periods, and outcome. METHODS: The subjects consisted of 40 girls with AN (age at onset, 8-16 years). The outcome 1-5 years after the initiation of treatment was regarded as favorable for both bodyweight within 15% of the standard weight and regular menstruation during the last 6 months, and unfavorable for bodyweight <85% of the standard weight and absent or nearly always absent menstruation. HR during the weight loss period was obtained at the outpatient clinic on the first visit. For HR during the weight recovery period, we used the resting and peak HR obtained in exercise tolerance test, which was performed when the bodyweight successfully increased along with improvement in physical complications. The association between each HR and outcome was evaluated. RESULTS: Favorable outcomes were observed in 19 of the 40 patients after the 1 year follow up but in 32 after the 5 year follow up. Resting HR during the weight recovery period was higher throughout the 5 years in the unfavorable than in the favorable outcome group, with significant differences after the 2, 4, and 5 year follow ups. CONCLUSION: In AN, resting tachycardia during the convalescent period is associated with unfavorable outcome. PMID- 22823591 TI - Synthesis, structure, and properties of the new mixed-valent dodecahalogenotrimetallate In4Ti3Br12 and its relation to compounds A3Ti2X9 (A = K, In; X = Cl, Br). AB - Black single crystals of the new dodecahalogenotrimetallate In(4)Ti(3)Br(12) were obtained by reacting InBr(3) with Ti-wire at 450 degrees C in a silica tube sealed under vacuum. In(4)Ti(3)Br(12) (Pearson symbol hR57, space group R3m, Z = 3, a = 7.3992(8) A, c = 36.673(6) A, 643 refl., 25 param., R(1)(F) = 0.025; wR(2)(F(2)) = 0.046) is a defect variant of a 12 L-perovskite. In(+) cations are 12-fold coordinated in two different ways: In1 as an anticuboctahedron and In2 as a cuboctahedron. In both cases the 5s(2) configuration results in 3 short, 6 medium, and 3 long In-Br distances which might be explained as lone pair effect or second order Jahn-Teller instability. Furthermore there are isolated linear trimers [Ti(3)Br(12)](4-) consisting of facesharing octahedra similar to [Ru(3)Cl(12)](4-). The [Ti(3)Br(12)](4-)-unit has to be described as a mixed valent d(1)-d(2)-d(1) system. According to magnetic measurements, the Ti-atoms in In(4)Ti(3)Br(12) show strong antiferromagnetic interactions (Theta = -1216(6) K) which might be addressed as weak Ti(3+)-Ti(2+)-Ti(3+) bonds. For comparison, single crystals of K(3)Ti(2)X(9) (X = Cl, Br) were synthesized and their structures refined. The rotation of the Ti(2)X(9)(3-) dimers reduced the symmetry of the well-known Cs(3)Cr(2)Cl(9) type from P6(3)/mmc to P6(3)/m and resulted in the formation of merohedral twins. According to the unit cell volumes In(+) is smaller than K(+) in all cases. PMID- 22823589 TI - Differential gene expression profiling of porcine epithelial cells infected with three enterotoxigenic Escherichia coli strains. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is one of the most important pathogenic bacteria causing severe diarrhoea in human and pigs. In ETEC strains, the fimbrial types F4 and F18 are commonly found differently colonized within the small intestine and cause huge economic losses in the swine industry annually worldwide. To address the underlying mechanism, we performed a transcriptome study of porcine intestinal epithelial cells (IPEC-J2) with and without infection of three representative ETEC strains. RESULTS: A total 2443, 3493 and 867 differentially expressed genes were found in IPEC-J2 cells infected with F4ab ETEC (C(F4ab)), with F4ac ETEC (C(F4ac)) and with F18ac ETEC (C(F18ac)) compared to the cells without infection (control), respectively. The number of differentially expressed genes between C(F4ab) and C(F4ac), C(F4ab) and C(F18ac), and C(F4ac) and C(F18ac) were 77, 1446 and 1629, respectively. The gene ontology and pathway analysis showed that the differentially expressed genes in C(F4ab)vs control are significantly involved in cell-cycle progress and amino acid metabolism, while the clustered terms of the differentially expressed genes in C(F4ac)vs control comprise immune, inflammation and wounding response and apoptosis as well as cell cycle progress and proteolysis. Differentially expressed genes between C(F18ac)vs control are mainly involved in cell-cycle progression and immune response. Furthermore, fundamental differences were observed in expression levels of immune-related genes among the three ETEC treatments, especially for the important pro-inflammatory molecules, including IL 6, IL-8, TNF-alpha, CCL20, CXCL2 etc. CONCLUSIONS: The discovery in this study provides insights into the interaction of porcine intestinal epithelial cells with F4 ETECs and F18 ETEC, respectively. The genes induced by ETECs with F4 versus F18 fimbriae suggest why ETEC with F4 may be more virulent compared to F18 which seems to elicit milder effects. PMID- 22823592 TI - A self-assembled delivery platform with post-production tunable release rate. AB - Self-assembly of three molecular components results in a delivery platform, the release rate of which can be tuned after its production. A fluorophore-conjugated gelator can be hydrolyzed by an enzyme, resulting in the release of a fluorescent small molecule. To allow the release to be tunable, the enzyme is entrapped in liposomes and can be liberated by heating the system for a short period. Crucially, the heating time determines the amount of enzyme liberated; with that, the release rate can be tuned by the time of heating. PMID- 22823593 TI - Distributed parallel computing in stochastic modeling of groundwater systems. AB - Stochastic modeling is a rapidly evolving, popular approach to the study of the uncertainty and heterogeneity of groundwater systems. However, the use of Monte Carlo-type simulations to solve practical groundwater problems often encounters computational bottlenecks that hinder the acquisition of meaningful results. To improve the computational efficiency, a system that combines stochastic model generation with MODFLOW-related programs and distributed parallel processing is investigated. The distributed computing framework, called the Java Parallel Processing Framework, is integrated into the system to allow the batch processing of stochastic models in distributed and parallel systems. As an example, the system is applied to the stochastic delineation of well capture zones in the Pinggu Basin in Beijing. Through the use of 50 processing threads on a cluster with 10 multicore nodes, the execution times of 500 realizations are reduced to 3% compared with those of a serial execution. Through this application, the system demonstrates its potential in solving difficult computational problems in practical stochastic modeling. PMID- 22823594 TI - CNS effects of indomethacin: should patients be cautioned about decreased mental alertness and motor coordination? AB - AIMS: In many European countries as well as in the USA, the leaflet, or even the packaging of indomethacin, contains a specific warning to refrain from activities requiring mental alertness and motor coordination, such as driving a car. In this placebo-controlled randomized study with a crossover design we attempted to find evidence for that warning. METHODS: Indomethacin 75 mg slow release or a visually identical placebo with similar flavour was taken orally twice daily for 2.5 days. It was suggested that indomethacin affects the motor coordination required to avoid obstacles successfully during walking and that this effect will be even stronger when simultaneously performing a cognitive task that puts mental alertness to the test. Nineteen healthy middle-aged individuals (60 +/- 4.7 years, eight female) performed an obstacle avoidance task on a treadmill), combined with a cognitive secondary task. Biceps femoris (BF) muscle response times, obstacle avoidance failure rates and composite scores ((100 * accuracy)/verbal response time) were used to evaluate the data. RESULTS: No differences between indomethacin and placebo were found on the outcome measures regarding motor coordination, avoidance failure rates (P = 0.81) and BF response times (P = 0.47), nor on the performance on the secondary cognitive task (P = 0.12). CONCLUSIONS: Even though surrogate methods were used, the current study provides evidence to suggest that there might be no need to caution patients who experience CNS side effects after indomethacin use to avoid activities requiring quick and adequate reactions, such as walking under challenging circumstances and maybe also driving a car. PMID- 22823595 TI - Pacific-wide simplified syndromic surveillance for early warning of outbreaks. AB - The International Health Regulations require timely detection and response to outbreaks. Many attempts to set up an outbreak early warning system in Pacific island countries and territories (PICTs) have failed. Most were modelled on systems from large countries; large amounts of data often overwhelmed small public health teams. Many conditions required overseas laboratory confirmation, further reducing timeliness and completeness. To improve timeliness and reduce the data burden, simplified surveillance was proposed, with case definitions based on clinical signs and symptoms without the need for laboratory confirmation or information on symptoms, location, sex and age. After trials in three PICTs, this system was implemented throughout the Pacific. Enthusiastic adoption by public health staff resulted in 20 of 22 PICTs reporting weekly to the World Health Organization within 12 months of starting to use the system. In the first year, the system has detected many infectious disease outbreaks and facilitated timely implementation of control measures. For several Pacific countries and territories, this is the first functional and timely infectious disease surveillance system. When outbreak detection is the principal objective, simplification of surveillance should be a priority in countries with a limited public health system capacity. PMID- 22823597 TI - Cognitive frameworks of virginity and first intercourse. AB - Research has begun to examine the subjective meanings of virginity and first coitus, but little is known about how these understandings influence the first sexual intercourse event. The purpose of this study was to investigate the relationship between virginity scripts and the approach taken and decisions made during first coitus. A quantitative measure of virginity interpretations (as gift, stigma, or process) was developed based on Carpenter's ( 2001 , 2005 ) qualitative interviews. Participants were university students (184 women and 31 men), all of whom had experienced consensual first penile-vaginal intercourse. Participants completed a quantitative questionnaire in the lab. Fifty-four percent of participants classified themselves as process oriented, 37.7% as gift oriented, and 8.4% as stigma oriented at the time of first coitus. The virginity scripts or frameworks were found to be related to age at first coitus, partner choice, length of relationship with first partner, planning, affective reaction to first coitus, and perceived impact on life. Virginity frameworks were unrelated to contraceptive use at first coitus. Results from this study suggest that Carpenter's virginity frameworks can be successfully translated into quantitative measures that support links between how individuals interpret their virginity and the decisions they make at first coitus. PMID- 22823596 TI - The tick-derived inhibitor Ixolaris prevents tissue factor signaling on tumor cells. AB - BACKGROUND: Tissue factor (TF) is frequently overexpressed in cancer cells and correlated with more aggressive tumor phenotypes and poor prognosis. In addition to promoting coagulation-dependent metastasis and cancer-associated thrombosis, tumor cell-expressed TF mediates direct cell signaling involving the protease activated receptor (PAR) 2. Ixolaris is a tick-derived inhibitor of the TF-factor (F)VIIa-Xa coagulation initiation complex which blocks primary tumor growth and angiogenesis in glioblastoma and melanoma models. METHODS: In this study we address the anti-tumor effects of Ixolaris in TF-VIIa-PAR2 signaling-dependent breast cancer models, a xenograft model of highly aggressive human MDA-MB-231 mfp cells and a syngeneic model of PAR2-deficient and replete PyMT mouse mammary carcinoma cells. RESULTS: Ixolaris potently inhibited the procoagulant activity of human MDA-MB-231mfp or murine PyMT breast cancer cells. Ixolaris blocked signaling by the ternary TF-FVIIa-FXa complex, and, surprisingly, at higher concentrations also the binary TF-FVIIa complex on MDA-MB-231 cells. We show that Ixolaris interacts with certain residues in the human VIIa protease domain that are involved in PAR2 cleavage. In contrast to human VIIa, Ixolaris was a poor inhibitor of murine TF-FVIIa signaling and did not attenuate PAR2-dependent tumor growth in a syngeneic mouse model of breast cancer progression. CONCLUSION: These data show that Ixolaris inhibits PAR2 cleavage specifically by human TF signaling complexes and suggest that Ixolaris may block tumor growth of human cell models with ectopic FVIIa expression through inhibition of direct TF-FVIIa-PAR2 signaling as well as its anticoagulant activity. PMID- 22823598 TI - Technological advancements and Internet sexuality: does private access to the Internet influence online sexual behavior? AB - The aim of this study was to investigate whether demographic characteristics and sexual behavior online and offline were associated with private, respectively, nonprivate access to the Internet in a Web sample of people who use the Internet for sexual purposes. A total of 1,913 respondents completed an online questionnaire about Internet sexuality, and 1,614 reported using the Internet for sexual purposes. The majority of these respondents reported having access to an Internet-connected computer no one else had access to (62 percent women and 70 percent men). The results showed that it is possible to differentiate between those who have access to an Internet-connected computer no one else has access to and those who have shared access to an Internet-connected computer. Not only did they differ in demographic characteristics, but also in the sexual activities they engaged in on the Internet. Different patterns were found for women and men. For example, men who had private access to Internet-connected computers were more likely than those who had shared access to seek information about sexual issues. Thus, having access to Internet computers no one else has access to may promote sexual knowledge and health for men. The results of this study along with the technological development implies that in future research, attention should be paid to where and how people access the Internet in relation to online behavior in general and online sexual behavior in particular. PMID- 22823599 TI - The HAWK2 program: a computer-based drug prevention intervention for Native American youth. AB - BACKGROUND: American Indians and Alaska Natives (AI/ANs) have some of the highest rates of substance use compared with other ethnic groups. Native American youth start experimenting with drugs at younger ages, continue to use them after initial experimentation, and thus seem to mirror the same drug use patterns as their older peers. Despite the seriousness of the problem, there is a lack of evidence-based drug prevention interventions for AI/AN youth. OBJECTIVES: This review article describes the process by which an existing evidence-based, culturally relevant drug prevention intervention was transformed into a low-cost, computerized intervention digitized in order to extend its reach to Native American youth in reservations and rural locations. METHODS: The intervention, titled HAWK(2) (Honoring Ancient Wisdom and Knowledge(2): Prevention and Cessation) is aimed at young Native children in elementary school settings (grades 4 and 5) and uses engaging multimedia features such as games, animations, and video clips to impart substance abuse prevention knowledge and skills training. The development of this intervention was a collaborative process involving the participation of community experts, research scientists, school teachers, and practitioners, as well as Native youth. Specific examples are provided to illustrate the development processes. RESULTS: Initial feedback from practitioners and youth suggest the feasibility and acceptability of computer based interventions by Native youth and practitioners. SCIENTIFIC SIGNIFICANCE: Computer-based interventions are a cost-effective way of engaging youth in prevention programming. Future studies of HAWK(2) will provide an important means of testing the long-term effectiveness of self-administered, computer-based interventions for AI/AN youth. PMID- 22823600 TI - Guidance for storing blood samples in laboratories performing complete blood count with differential. AB - INTRODUCTION: The complete blood count (CBC) with differential leukocyte count (DIFF) is an important part of clinical laboratory analyses and provides crucial data for clinicians. Delivery time after blood collection and conditions of storage is known to affect the reliability of results of some hematologic parameters. The aim of this study was to assess the variations of hematologic parameters over time and the influence of storage temperature. METHODS: Blood samples were randomly selected from hospitalized patients and stored at room temperature and at 4 degrees C. CBC and DIFF were performed on an automated hematology analyzer and the results between the two groups were compared. RESULTS: Samples stored at room temperature showed an important increase in mean corpuscular volume and hematocrit and a decrease in mean corpuscular hemoglobin concentration. Neutrophil counts tended to increase, whereas monocyte counts tended to decrease. CONCLUSION: Storing samples at 4 degrees C improved reproducibility over time of all quantitative and qualitative parameters. We also observed that NEUT-X, a routine parameter useful in detecting myelodysplastic syndrome, became unreliable when analyzed 24 h after sample collection. Our results led us to recommend that samples should be analyzed within 6 h, particularly if samples are transported at room temperature. We also recommend storing samples at 4 degrees C in case of remote CBC analysis, especially in the context of clinical trials. PMID- 22823737 TI - Normograde and retrograde pinning of the distal fragment in humeral fractures of the dog. AB - OBJECTIVE: To determine if normograde and retrograde pinning of the distal humeral fragment, to maximize pin purchase in this fragment, would damage vital structures in and around the elbow and shoulder joints in dogs. STUDY DESIGN: Anatomic study. SAMPLE POPULATION: Cadaveric dogs (n = 12; 12 thoracic limb pairs). METHODS: Twelve thoracic limb pairs were harvested from cross-breed dogs and 1 thoracic limb from each pair was allocated to 1 of 3 groups. A transverse osteotomy was created at the junction of the middle and distal thirds in the diaphyseal fracture group (n = 8) and proximal to the supracondylar foramen in the metaphyseal fracture group (n = 8). The humeri in the normograde group (n = 8) were left intact. In all specimens in the distal and supracondylar fracture groups, retrograde pinning of the distal fragment was performed with the elbow flexed. The pins were driven into the medial epicondyle until they exited the skin caudal to the elbow. Dissection of the soft tissues around the exit tract of the pin was performed. The fracture was then reduced and the pin was advanced until it exited the proximal humeral fragment. In the specimens in the normograde group, pinning was initiated on the distal aspect of the medial epicondyle. The pin was directed parallel to the caudal aspect of the medial epicondyle and driven proximally into the humerus until it exited the proximal humerus. RESULTS: Pins exiting the distal aspect of the medial epicondyle passed through muscle origins in 7 specimens in the diaphyseal osteotomy group and in all 8 specimens in the metaphyseal group. The ulnar nerve was entrapped in 1 specimen in the metaphyseal osteotomy group; however, it was not entrapped in any of the specimens in the diaphyseal osteotomy group. The articular cartilage of the trochlea was damaged in 2 specimens in each of the retrograde pinned groups. There was no damage to articular or periarticular structures by pins exiting the proximal humerus. CONCLUSION: Retrograde pinning of the distal fragment in humeral fractures in the dog may damage the articular cartilage and cannot be recommended. PMID- 22823738 TI - Losses as modulators of attention: review and analysis of the unique effects of losses over gains. AB - It has been shown that in certain situations losses exert a stronger effect on behavior than respective gains, and this has been commonly explained by the argument that losses are given more weight in people's decisions than respective gains. However, although much is understood about the effect of losses on cognitive processes and behavior, 2 major inconsistencies remain. First, recent empirical evidence fails to demonstrate that people avoid incentive structures that carry equivalent gains and losses. Second, findings in experience-based decision tasks indicate that following losses, increased arousal is observed simultaneously with no behavioral loss aversion. To account for these findings, we developed an attention-allocation model as a comprehensive framework for the effect of losses. According to this model losses increase on-task attention, thereby enhancing the sensitivity to the reinforcement structure. In the current article we examine whether this model can account for a broad range of empirical phenomena involving losses. We show that as predicted by the attentional model, asymmetric effects of losses on behavior emerge where gains and losses are presented separately but not concurrently. Yet, even in the absence of loss aversion, losses have distinct effects on performance, arousal, frontal cortical activation, and behavioral consistency. The attentional model of losses thus explains some of the main inconsistencies in previous studies of the effect of losses. PMID- 22823739 TI - Structure of surfaces and interfaces of poly(N,N-dimethylacrylamide) hydrogels. AB - We investigated the surface structure of hydrogels of poly(N,N dimethylacrylamide) (PDMA) hydrogels synthesized and cross-linked simultaneously by redox free radical polymerization. We demonstrate the existence of a less cross-linked layer at the surface of the gel at least at two different length scales characterized by shear rheology and by neutron reflectivity, suggesting the existence of a gradient in cross-linking. The composition of the layer is shown to depend on the degree of hydrophobicity of the mold surface and is weaker for more hydrophobic molds. While the macroscopic tests proved the existence of a relatively thick under-cross-linked layer, we also demonstrated by neutron reflectivity that the gel surface at the submicrometric scale (500 nm) was also affected by the surface treatment of the mold. These results should have important implications for the measurement of macroscopic surface properties of these hydrogels such as friction or adhesion. PMID- 22823741 TI - Abstracts of the 7th World Congress of Veterinary Dermatology. July 24-28, 2012. Vancouver, Canada. PMID- 22823742 TI - Bipolar resistive switching of single gold-in-Ga2O3 nanowire. AB - We have fabricated single nanowire chips on gold-in-Ga(2)O(3) core-shell nanowires using the electron-beam lithography techniques and realized bipolar resistive switching characteristics having invariable set and reset voltages. We attribute the unique property of invariance to the built-in conduction path of gold core. This invariance allows us to fabricate many resistive switching cells with the same operating voltage by simple depositing repetitive metal electrodes along a single nanowire. Other characteristics of these core-shell resistive switching nanowires include comparable driving electric field with other thin film and nanowire devices and a remarkable on/off ratio more than 3 orders of magnitude at a low driving voltage of 2 V. A smaller but still impressive on/off ratio of 10 can be obtained at an even lower bias of 0.2 V. These characteristics of gold-in-Ga(2)O(3) core-shell nanowires make fabrication of future high-density resistive memory devices possible. PMID- 22823743 TI - Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. AB - Gelastic epilepsy are focal seizures manifesting as recurrent brief seizures starting as laughter or grimaces. They are most commonly associated with other types of seizures and can be secondary to infectious, malformative, metabolic, or neoplastic processes involving the central nervous system. We report on an 18 month-old girl who presented since the age of 2 months with multiple, recurrent, unprovoked episodes of stereotypical laughter. Brain magnetic resonance study revealed an hypothalamic hamartoma. Endoscopic tumor disconnection of the hamartoma resulted in rapid resolution of neurological symptomatology. PMID- 22823744 TI - Ba2Ti2Fe2As4O: A new superconductor containing Fe2As2 layers and Ti2O sheets. AB - We have synthesized a new oxypnictide, Ba2Ti2Fe2As4O, via a solid-state reaction under a vacuum. The compound crystallizes in a body-centered tetragonal lattice, which can be viewed as an intergrowth of BaFe2As2 and BaTi2As2O, thus containing Fe2As2 layers and Ti2O sheets. Bulk superconductivity at 21 K is observed after annealing the as-prepared sample at 773 K for 40 h. In addition, an anomaly in resistivity and magnetic susceptibility around 125 K is revealed, suggesting a charge- or spin-density wave transition in the Ti sublattice. PMID- 22823745 TI - Synthesis and characterization of Li11Nd18Fe4O(39-delta). AB - Li(11)Nd(18)Fe(4)O(39-delta) has been synthesized by the solid-state reaction of pellets, covered with powder of the same composition to avoid lithium loss, with a final reaction temperature of 950 degrees C. This phase has been reported previously to have various stoichiometries: Li(5)Nd(4)FeO(10), Li(8)Nd(18)Fe(5)O(39), and Li(1.746)Nd(4.494)FeO(9.493). The crystal structure of Li(11)Nd(18)Fe(4)O(39-delta) is closely related to that reported previously for two of the other three compositions but contains extra Li and differences in Li/Fe site occupancies. Fe is present in a mixture of 3+ and 4+ oxidation states, as confirmed by Mossbauer spectroscopy. The oxygen content of 39 - delta is variable, depending on the processing conditions. Samples slow-cooled in air from 800 degrees C are semiconducting, attributed to the presence of Fe(4+) ions, whereas samples quenched from 950 degrees C in N(2) are insulating. PMID- 22823746 TI - Simultaneous oral therapeutic and intravenous 14C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin. AB - AIM: To determine the absolute oral bioavailability (F(p.o.) ) of saxagliptin and dapagliflozin using simultaneous intravenous 14C-microdose/therapeutic oral dosing (i.v.micro + oraltherap). METHODS: The F(p.o.) values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography-tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively. RESULTS: The geometric mean point estimates (90% confidence interval) F(p.o) . values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap. CONCLUSIONS: Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability. PMID- 22823747 TI - Toward a network model of dystonia. AB - Dystonia has generally been considered a basal ganglia (BG) disorder. Early models hypothesized that dystonia occurred as the result of reduced mean discharge rates in the internal segment of the globus pallidus (GPi). Increasing evidence suggests a more systemwide disruption of the basal ganglia thalamic circuit (BGTC) resulting in altered firing patterns, synchronized oscillations, and widened receptive fields. A model of dystonia incorporating these changes within the BGTC is presented in which we postulate that this pathophysiology arises from disruptions within the striatum. Alterations in the cerebellothalamocortical (CBTC) pathway to the development of dystonia may also play a role. However, the contribution of CBTC abnormalities to dystonia remains unclear and may vary with different etiologies of dystonia. Finally, the relevance of established and emerging theories related to the pathophysiology of dystonia is addressed within the context of improving conventional approaches for deep brain stimulation (DBS) treatment strategies. PMID- 22823748 TI - Pulsatile pump decreases risk of delayed graft function in kidneys donated after cardiac death. AB - Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0-3.5). PP kidneys had less DGF (AOR 0.59; 0.56-0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7-1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43-5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters. PMID- 22823750 TI - Influence of pressure change during hydraulic tests on fracture aperture. AB - In a series of field experiments, we evaluate the influence of a small water pressure change on fracture aperture during a hydraulic test. An experimental borehole is instrumented at the Korea Atomic Energy Research Institute (KAERI) Underground Research Tunnel (KURT). The target fracture for testing was found from the analyses of borehole logging and hydraulic tests. A double packer system was developed and installed in the test borehole to directly observe the aperture change due to water pressure change. Using this packer system, both aperture and flow rate are directly observed under various water pressures. Results indicate a slight change in fracture hydraulic head leads to an observable change in aperture. This suggests that aperture change should be considered when analyzing hydraulic test data from a sparsely fractured rock aquifer. PMID- 22823749 TI - Comparison of the QuantiFERON-TB Gold In-Tube test with the tuberculin skin test for detecting latent tuberculosis infection prior to hematopoietic stem cell transplantation. AB - A total of 244 patients including 100 (41%) autologous hematopoietic stem cell transplant (HCT) recipients and 144 (59%) allogeneic HCT recipients were enrolled over a 28-month period. During the study period, no prophylaxis for latent tuberculosis (TB) infection was administrated. Of these, 201 (82%) had Bacillus Calmette-Guerin (BCG) scars or prior histories of BCG vaccination. The tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT) test were performed simultaneously in all 244 patients. TST indurations were >= 5 mm in 39 of these patients (15%), and in 25 (10%) indurations were >= 10 mm. In addition, 40 (16%) had positive QFT-GIT outcomes, and 34 (14%) indeterminate outcomes. If the 34 patients with indeterminate QFT-GIT results were excluded from the overall agreement analysis, the agreement between the TST results (induration size >= 5 mm) and the QFT-GIT results in the 210 patients with clear QFT results was poor (kappa = 0.08, 95% confidence interval [CI] -0.06 to 0.24), as it was for the patients with indurations >= 10 mm (kappa = 0.15, 95% CI -0.004 to 0.31). During follow up, 2 patients developed TB after HCT. The incidence of TB in the patients with positive QFT-GIT outcomes was 2.80 per 100 person-years (95% CI 0.07-15.81), whereas among those with positive TST (>= 5 mm) results, it was 0 per 100 person years (95% CI 0-8.00). However, this finding should be cautiously interpreted because of the relatively short follow up and the fact that the sample size of the study cohort did not have adequate power. In conclusion, our data show that, although the frequencies of positive outcomes in the 2 TB screening tests were similar, the overall agreement between the TST and the QFT-GIT test was poor, regardless of BCG vaccination history. PMID- 22823752 TI - Framing risk in pandemic influenza policy and control. AB - This article explores differing understandings of 'risk' in relation to pandemic influenza policy and control. After a preliminary overview of methodological and practical problems in risk analysis, ways in which risk was framed and managed in three historical cases were examined. The interdependence between scientific empiricism and political decision-making led to the mismanagement of the 1976 swine influenza scare in the USA. The 2004 H5N1 avian influenza outbreak in Thailand, on the other hand, was undermined by questions of national economic interest and concerns over global health security. Finally, the recent global emergency of pandemic influenza H1N1 in 2009 demonstrated the difficulties of risk management under a context of pre-established perceptions about the characteristics and inevitability of a pandemic. Following the analysis of these cases, a conceptual framework is presented to illustrate ways in which changing relationships between risk assessment, risk perception and risk management can result in differing policy strategies. PMID- 22823751 TI - Genomic and proteomic characterization of SuMu, a Mu-like bacteriophage infecting Haemophilus parasuis. AB - BACKGROUND: Haemophilus parasuis, the causative agent of Glasser's disease, is prevalent in swine herds and clinical signs associated with this disease are meningitis, polyserositis, polyarthritis, and bacterial pneumonia. Six to eight week old pigs in segregated early weaning herds are particularly susceptible to the disease. Insufficient colostral antibody at weaning or the mixing of pigs with heterologous virulent H. parasuis strains from other farm sources in the nursery or grower-finisher stage are considered to be factors for the outbreak of Glasser's disease. Previously, a Mu-like bacteriophage portal gene was detected in a virulent swine isolate of H. parasuis by nested polymerase chain reaction. Mu-like bacteriophages are related phyologenetically to enterobacteriophage Mu and are thought to carry virulence genes or to induce host expression of virulence genes. This study characterizes the Mu-like bacteriophage, named SuMu, isolated from a virulent H. parasuis isolate. RESULTS: Characterization was done by genomic comparison to enterobacteriophage Mu and proteomic identification of various homologs by mass spectrometry. This is the first report of isolation and characterization of this bacteriophage from the Myoviridae family, a double stranded DNA bacteriophage with a contractile tail, from a virulent field isolate of H. parasuis. The genome size of bacteriophage SuMu was 37,151 bp. DNA sequencing revealed fifty five open reading frames, including twenty five homologs to Mu-like bacteriophage proteins: Nlp, phage transposase-C-terminal, COG2842, Gam-like protein, gp16, Mor, peptidoglycan recognition protein, gp29, gp30, gpG, gp32, gp34, gp36, gp37, gpL, phage tail tube protein, DNA circulation protein, gpP, gp45, gp46, gp47, COG3778, tail fiber protein gp37-C terminal, tail fiber assembly protein, and Com. The last open reading frame was homologous to IS1414. The G + C content of bacteriophage SuMu was 41.87% while its H. parasuis host genome's G + C content was 39.93%. Twenty protein homologs to bacteriophage proteins, including 15 structural proteins, one lysogeny-related and one lysis related protein, and three DNA replication proteins were identified by mass spectrometry. One of the tail proteins, gp36, may be a virulence-related protein. CONCLUSIONS: Bacteriophage SuMu was characterized by genomic and proteomic methods and compared to enterobacteriophage Mu. PMID- 22823753 TI - A modified laryngeal tie-forward procedure using metallic implants for treatment of dorsal displacement of the soft palate in horses. AB - OBJECTIVE: To describe a modified laryngeal tie-forward procedure (LTFP) using metallic implants. STUDY DESIGN: Retrospective case series. POPULATION: Twenty seven horses (including 24 race horses) with dorsal displacement of the soft palate (DDSP) or palatal instability (PI) diagnosed using high-speed treadmill endoscopy (n = 15), history and resting examination (n = 8), or dynamic endoscopy over ground (n = 4). METHODS: All horses underwent the modified LTFP. Modifications of the surgical procedure consisted in the use of 3 metallic stents called Suture Button(TM) through which the sutures are threaded and in a tying technique that involved a single knot connecting left and right suture loops (versus tying each separately). Lateral radiographs were taken 24 hours after surgery. Follow-up was obtained by telephone communication with trainers or owners. RESULTS: Surgery was performed without complications on all horses. The 3 metallic buttons were clearly visible on the postoperative radiographic examination. No evidence of suture breakage was observed 24 hours postoperatively based on radiographs. CONCLUSION: In other aspects, this technique is not very different from that originally described by Ducharme et al; it is an innovation that could offer some advantages to the surgeons and increase suture resistance to pullout from the thyroid cartilage. Our technique was used without complication in a small group of horses and return to performance may be similar to the original technique. PMID- 22823754 TI - Prevalence of diabetes in Asian Indians based on glycated hemoglobin and fasting and 2-H post-load (75-g) plasma glucose (CURES-120). AB - OBJECTIVE: With the introduction of glycated hemoglobin (A1c) as a method of screening for diabetes, it is essential to study how use of A1c would affect the prevalence of diabetes in different ethnic groups. We compared the prevalence of diabetes by fasting (FPG) and 2-h post-load (75-g) plasma glucose (2-h PG) and A1c criteria in an Asian Indian population. RESEARCH DESIGN AND METHODS: Subjects (n=2,188) without known diabetes were drawn from the Chennai Urban Rural Epidemiological Study, a population-based study in Chennai, South India. FPG, 2-h PG, and A1c estimations were carried out. Prevalence rates of diabetes were compared using as cut points FPG >=7 mmol/L (126 mg/dL), 2-hr PG >=11.1 mmol/L (200 mg/dL), or A1c >=6.5% criteria. RESULTS: Prevalence of diabetes was 6.1% (n=134) using the FPG criterion, 10.1% (n=221) by the 2-h PG criterion, and 12.8% (n=281) by the A1c criterion. Thus the prevalence of diabetes by the A1c criterion was 110% and 27% higher than the FPG and 2-hr PG criteria, respectively. Only 121 of these subjects were identified by all three criteria. Subjects diagnosed by the A1c criteria had the lowest FPG, 2-h PG, A1c, and serum triglyceride levels. CONCLUSIONS: In Asian Indians, use of A1c criteria would result in markedly higher prevalence rates of diabetes. It also identifies a different set of individuals with milder glucose intolerance and lower serum triglyceride levels. PMID- 22823755 TI - Transmitted antiretroviral drug resistance in newly HIV-infected and untreated patients in Segou and Bamako, Mali. AB - The WHO recommends regular surveillance for transmitted antiretroviral drug resistant viruses in HIV antiretroviral treatment (ART)-naive patients in resource-limited settings. This study aimed to assess the prevalence of mutations associated with resistance in ART-naive patients newly diagnosed with HIV in Bamako and Segou in Mali. HIV-positive patients who never received ART were recruited in Bamako and Segou, Mali. The reverse transcriptase (RT) and protease (PR) genes of these patients were sequenced by the "ViroSeq" method. Analysis and interpretation of the resistance were made according to the WHO 2009 list of drug resistance mutations. In all, 51/54 (94.4%) sample patients were sequenced. The median age (IQR) of our patients was 24 (22-27) years and the median CD4 count was 380 (340-456) cells/mm(3). The predominant subtype was recombinant HIV-1 CRF02_AG (66.7%) followed by CRF06_cpx (12%) and CRF09_cpx (4%). Four patients had mutations associated with resistance, giving an overall prevalence of resistance estimated at 7.9%. There were two (4%) patients with nucleoside reverse transcriptase inhibitor (NRTI) mutations (one M184V and one T215Y), two (4%) with non-NRTI mutations (two K103N), and one (2%) with a protease inhibitor mutation (one I54V). The prevalence of primary resistance in newly infected patients in Mali is moderate (7.9%). This indicates that the standard NNRTI-based first-line regimen used in Mali is suboptimal for some patients. This study should be done regularly to inform clinical practice. PMID- 22823856 TI - Indicated prevention and early intervention for childhood anxiety: a randomized trial with Caucasian and Hispanic/Latino youth. AB - OBJECTIVE: This trial of a randomized indicated anxiety prevention and early intervention explored initial program effects as well as the role of ethnicity and language on measured outcomes. METHOD: A total of 88 youth (M = 10.36 years; 45 girls, 52 Latino) received 1 of 2 protocols with varying degrees of parent involvement, and response was measured at posttest and 6-month follow-up. RESULTS: Findings showed that child anxiety symptoms improved significantly across protocols, although additional gains were found for children in the child plus parent condition. Program effects did not vary by Latino ethnicity or Spanish language use in the intervention. CONCLUSIONS: The cognitive and behavioral strategies established for Caucasian children may be promising for Hispanic/Latino children when applied in a culturally responsive manner. PMID- 22823855 TI - A randomized controlled trial of event-specific prevention strategies for reducing problematic drinking associated with 21st birthday celebrations. AB - OBJECTIVE: While research has documented heavy drinking practices and associated negative consequences of college students turning 21, few studies have examined prevention efforts aimed at reducing high-risk drinking during 21st birthday celebrations. The present study evaluated the comparative efficacy of a general prevention effort (i.e., Brief Alcohol Screening and Intervention for College Students, or BASICS) and event-specific prevention in reducing 21st birthday drinking and related negative consequences. Furthermore, this study evaluated inclusion of peers in interventions and mode of intervention delivery (i.e., in person vs. via the Web). METHOD: Participants included 599 college students (46% male): men who intended to consume at least 5 drinks and women who intended to consume at least 4 drinks on their 21st birthday. After completing a screening/baseline assessment approximately 1 week before turning 21, participants were randomly assigned to 1 of 6 conditions: 21st birthday in-person BASICS, 21st birthday web BASICS, 21st birthday in-person BASICS plus friend intervention, 21st birthday web BASICS plus friend intervention, BASICS, or an attention control. A follow-up assessment was completed approximately 1 week after students' birthdays. RESULTS: Results indicated a significant intervention effect for BASICS in reducing blood alcohol content reached and number of negative consequences experienced. All 3 in-person interventions reduced negative consequences experienced. Results for the web-based interventions varied by drinking outcome and whether a friend was included. CONCLUSIONS: Overall, results provide support for both general intervention and ESP approaches across modalities for reducing extreme drinking and negative consequences associated with turning 21. These results suggest there are several promising options for campuses seeking to reduce both use and negative consequences associated with 21st birthday celebrations. PMID- 22823858 TI - Moderators and non-specific predictors of treatment outcome for anxiety disorders: a comparison of cognitive behavioral therapy to acceptance and commitment therapy. AB - OBJECTIVE: Understanding for whom, and under what conditions, treatments exert their greatest effects is essential for developing personalized medicine. Research investigating moderators of outcome among evidence-based treatments for anxiety disorders is lacking. The current study examined several theory-driven and atheoretical putative moderators of outcome in cognitive behavioral therapy (CBT) and acceptance and commitment therapy (ACT). METHOD: Eighty-seven patients with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) anxiety disorder completed 12 sessions of ACT or CBT and were assessed with a self-report measure of anxiety at baseline, post-treatment, and 6- and 12-month follow-up assessments. RESULTS: CBT outperformed ACT among those at moderate levels of baseline anxiety sensitivity, and among those with no comorbid mood disorder. ACT outperformed CBT among those with comorbid mood disorders. Higher baseline neuroticism was associated with poorer outcome across treatment conditions. Neither moderation nor general prediction was observed for baseline anxiety disorder comorbidity, race/ethnicity, gender, age, or baseline severity of the principal anxiety disorder. When including all randomized participants who completed the pre treatment assessment (N = 121), a similar pattern was observed. CONCLUSIONS: Prescriptive recommendations for clinical practice and directions for future research are discussed. PMID- 22823857 TI - The role of personality pathology in depression treatment outcome with psychotherapy and pharmacotherapy. AB - BACKGROUND: Depressed patients with comorbid personality pathology may fare worse in treatment for depression than those without this additional pathology, and comorbid personality pathology may be associated with superior response in one form of treatment relative to another, though recent findings have been mixed. We aimed to evaluate the effect of personality pathology on time to remission of patients randomly assigned to 1 of 2 treatment strategies for depression and to determine whether personality pathology moderated the effect of treatment assignment on outcome. METHOD: Individuals undergoing an episode of unipolar major depression (n = 275) received interpersonal psychotherapy (Klerman, Weissman, Rounsaville, & Chevron, 1984) or selective serotonin reuptake inhibitor (SSRI) pharmacotherapy for depression. Depressive symptoms were measured with the HRSD-17. Remission was a mean HRSD-17 score of 7 or below over a period of 3 weeks. Personality disorders were measured according to SCID-II diagnoses, and personality pathology was measured dimensionally by summing the positive probes on the SCID-II. RESULTS: The presence of at least 1 personality disorder was not a significant predictor of time to remission, but a higher level of dimensionally measured personality pathology and the presence of borderline personality disorder were associated with a longer time to remission. Personality pathology did not moderate the effect of treatment assignment on time to remission. CONCLUSIONS: The findings suggest that depressed individuals with comorbid personality pathology generally fare worse in treatment for depression, although in this report, the effect of personality pathology did not differ by the type of treatment received. PMID- 22823859 TI - National dissemination of cognitive behavioral therapy for depression in the Department of Veterans Affairs health care system: therapist and patient-level outcomes. AB - OBJECTIVE: The Department of Veterans Affairs (VA) health care system is nationally disseminating and implementing cognitive behavioral therapy for depression (CBT-D). The current article evaluates therapist and patient-level outcomes associated with national training in and implementation of CBT-D in the VA health care system. METHOD: Therapist competencies were assessed with the Cognitive Therapy Rating Scale (CTRS). Patient outcomes were assessed with the Beck Depression Inventory-II and the World Health Organization Quality of Life BREF. Therapeutic alliance was assessed with the Working Alliance Inventory-Short Revised. Two-hundred twenty-one therapists have received training, and 356 veteran patients have received treatment through the VA CBT-D Training Program. RESULTS: Of therapists who have participated in the program, 182 (82%) completed all training requirements and achieved competency, reflected by a score of 40 on the CTRS. Of 356 patients, nearly 70% completed 10 or more sessions or improved sufficiently to stop therapy before the 10th session. Mean depression scores decreased by approximately 40% from initial to later treatment phase. Effect sizes of changes ranged from d = 0.39 to d = 0.74 for quality of life and from d = 0.47 to d = 0.66 for therapeutic alliance measures. CONCLUSION: National training in and implementation of CBT-D within the VA health care system is associated with significant, positive therapist training outcomes, as evidenced by increases in CBT core competencies. The implementation of the protocol by newly trained CBT-D therapists is associated with significantly improved patient outcomes, as evidenced by large decreases in depression and improvements in quality of life. PMID- 22823860 TI - The relationship between experiences of discrimination and mental health among lesbians and gay men: An examination of internalized homonegativity and rejection sensitivity as potential mechanisms. AB - OBJECTIVE: The current study used path analysis to examine potential mechanisms through which experiences of discrimination influence depressive and social anxiety symptoms. METHOD: The sample included 218 lesbians and 249 gay men (total N = 467) who participated in an online survey about minority stress and mental health. The proposed model included 2 potential mediators-internalized homonegativity and rejection sensitivity-as well as a culturally relevant antecedent to experiences of discrimination-childhood gender nonconformity. RESULTS: Results indicated that the data fit the model well, supporting the mediating roles of internalized homonegativity and rejection sensitivity in the associations between experiences of discrimination and symptoms of depression and social anxiety. Results also supported the role of childhood gender nonconformity as an antecedent to experiences of discrimination. Although there were not significant gender differences in the overall model fit, some of the associations within the model were significantly stronger for gay men than lesbians. CONCLUSIONS: These findings suggest potential mechanisms through which experiences of discrimination influence well-being among sexual minorities, which has important implications for research and clinical practice with these populations. PMID- 22823862 TI - Obese children suffer more often from migraine. AB - AIM: To determine a possible relationship between migraine and body mass index. METHODS: Migraine shows a wide spectrum of comorbidities, including cardiocerebral, vascular, psychiatric, metabolic, neurological as well as other pathologies. Recent researches suggest that obesity was significantly correlated with migraine frequency and disability in children, as well as in adult population studies. We reviewed data from the literature to clarify this possible relationship. RESULTS: Translational and basic science research shows multiple areas of overlap between migraine pathophysiology and the central and peripheral pathways regulating feeding. Specifically, neurotransmittors such as serotonin, peptides such as orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and migraine. A relationship between migraine and body mass index exists, and therefore, interventions to modify body mass index may provide a useful treatment model for investigating whether modest weight loss reduces headache frequency and severity in obese migraineurs. CONCLUSION: The effect of obesity and weight change on headache outcomes may have important implications for clinical care. PMID- 22823863 TI - Tribute to Israel E. Ashkenazi 1934-2011. PMID- 22823864 TI - Low-carbohydrate, high-protein diet affects rhythmic expression of gluconeogenic regulatory and circadian clock genes in mouse peripheral tissues. AB - Recent studies have demonstrated that metabolic changes in mammals induce feedback regulation of the circadian clock. The present study evaluates the effects of a low-carbohydrate high-protein diet (HPD) on circadian behavior and peripheral circadian clocks in mice. Circadian rhythms of locomotor activity and core body temperature remained normal in mice fed with the HPD diet (HPD mice), suggesting that it did not affect the central clock in the hypothalamus. Two weeks of HPD feeding induced mild hypoglycemia without affecting body weight, although these mice consumed more calories than mice fed with a normal diet (ND mice). Plasma insulin levels were increased during the inactive phase in HPD mice, but increased twice, beginning and end of the active phase, in ND mice. Expression levels of the key gluconeogenic regulatory genes PEPCK and G6Pase were significantly induced in the liver and kidneys of HPD mice. The HPD appeared to induce peroxisome proliferator-activated receptor alpha (PPARalpha) activation, since mRNA expression levels of PPARalpha and its typical target genes, such as PDK4 and Cyp4A10, were significantly increased in the liver and kidneys. Circadian mRNA expression of clock genes, such as BMAL1, Cry1, NPAS2, and Rev erbalpha, but not Per2, was significantly phase-advanced, and mean expression levels of BMAL1 and Cry1 mRNAs were significantly elevated, in the liver and kidneys of HPD mice. These findings suggest that a HPD not only affects glucose homeostasis, but that it also advances the molecular circadian clock in peripheral tissues. PMID- 22823865 TI - Chronomics of pressure overload-induced cardiac hypertrophy in mice reveals altered day/night gene expression and biomarkers of heart disease. AB - There is critical demand in contemporary medicine for gene expression markers in all areas of human disease, for early detection of disease, classification, prognosis, and response to therapy. The integrity of circadian gene expression underlies cardiovascular health and disease; however time-of-day profiling in heart disease has never been examined. We hypothesized that a time-of-day chronomic approach using samples collected across 24-h cycles and analyzed by microarrays and bioinformatics advances contemporary approaches, because it includes sleep-time and/or wake-time molecular responses. As proof of concept, we demonstrate the value of this approach in cardiovascular disease using a murine Transverse Aortic Constriction (TAC) model of pressure overload-induced cardiac hypertrophy in mice. First, microarrays and a novel algorithm termed DeltaGene were used to identify time-of-day differences in gene expression in cardiac hypertrophy 8 wks post-TAC. The top 300 candidates were further analyzed using knowledge-based platforms, paring the list to 20 candidates, which were then validated by real-time polymerase chain reaction (RTPCR). Next, we tested whether the time-of-day gene expression profiles could be indicative of disease progression by comparing the 1- vs. 8-wk TAC. Lastly, since protein expression is functionally relevant, we monitored time-of-day cycling for the analogous cardiac proteins. This approach is generally applicable and can lead to new understanding of disease. PMID- 22823866 TI - Circadian system functionality, hippocampal oxidative stress, and spatial memory in the APPswe/PS1dE9 transgenic model of Alzheimer disease: effects of melatonin or ramelteon. AB - Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes beta amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (tau) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24 h. Whereas melatonin maintained tau at 24 h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswe/PS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD. PMID- 22823867 TI - Differential involvement of the suprachiasmatic nucleus in lipopolysaccharide induced plasma glucose and corticosterone responses. AB - The hypothalamic suprachiasmatic nucleus (SCN) is an essential component of the circadian timing system, and an important determinant of neuroendocrine and metabolic regulation. Recent data indicate a modulatory role for the immune system on the circadian timing system. The authors investigated how the circadian timing system affects the hypothalamo-pituitary-adrenal (HPA) axis and glucose regulatory responses evoked by an immune challenge induced by lipopolysaccharide (LPS). LPS-induced increases in corticosterone were minimal during the trough of the daily corticosterone rhythm; in contrast, LPS effects on glucose, glucagon, and insulin did not vary across time-of-day. Complete ablation of the SCN resulted in increased corticosterone responses but did not affect LPS-induced hyperglycemia. The paraventricular nucleus (PVN) of the hypothalamus is an important neuroendocrine and autonomic output pathway for hypothalamic information, as well as one of the main target areas of the SCN. Silencing the neuronal activity in the PVN did not affect the LPS-induced corticosterone surge and only slightly delayed the LPS-induced plasma glucose and glucagon responses. Finally, surgical interruption of the neuronal connection between hypothalamus and liver did not affect the corticosterone response but slightly delayed the LPS induced glucose response. Together, these data support the previously proposed circadian modulation of LPS-induced neuroendocrine responses, but they are at variance with the suggested major role for the hypothalamic pacemaker on the autonomic output of the hypothalamus, as reflected by the effects of LPS on glucose homeostasis. The latter effects are more likely due to direct interactions of LPS with peripheral tissues, such as the liver. PMID- 22823868 TI - Winter day lengths counteract stimulatory effects of apomorphine and yohimbine on sexual behavior of male Syrian hamsters. AB - Yohimbine and apomorphine selectively act on noradrenergic and dopaminergic neural substrates to augment male sexual behavior (MSB) in several rodent species. The present study assessed whether these drugs can overcome the suppressive effects of short winter-like day lengths on MSB. Yohimbine treatments that markedly increase copulatory behavior of male hamsters in long days were completely ineffective in facilitating MSB when injected after gonadal regression induced by 16 wks of short day lengths and after complete gonadal recrudescence after 32 wks of short days; apomorphine was similarly ineffective. The brain circuit that mediates MSB either may be less responsive to yohimbine and apomorphine in short than long days, or these drugs may not produce equivalent neurotransmitter changes in the two day lengths. After 32 wks of short-day treatment, all males had undergone testicular recrudescence and successfully ejaculated on initial tests with sexually receptive females after a hiatus of at least 4 mo during which they were denied mating opportunities. This suggests that overwintering males in the field are in a state of reproductive readiness at the outset of spring conditions favorable for survival of offspring. PMID- 22823869 TI - Evidence for a plastic dual circadian rhythm in the oyster Crassostrea gigas. AB - Although a significant body of literature has been devoted to the chronobiology of aquatic animals, how biological rhythms function in molluscan bivalves has been poorly studied. The first objective of this study was to determine whether an endogenous circadian rhythm does exist in the oyster, Crassostrea gigas. The second objective was to characterize it in terms of robustness. To answer these questions, the valve activity of 15 oysters was continuously recorded for 2 mo in the laboratory under different entrainment and free-running regimes using a high frequency noninvasive valvometer. The present work demonstrates the presence of a circadian rhythm in the oyster Crassostrea gigas. First, oysters were entrained by 12 L:12 D conditions. Then, free-running conditions (D:D and L:L) indicated that the most frequently observed period ranged from 20 to 28 h, the circadian range. That endogenous circadian rhythm was characterized as weak. Indeed, the period (tau) of the individual animals exhibited high plasticity in D:D and L:L, and the animals immediately followed a 4-h phase advance or delay. Additionally, C. gigas appeared as a dual organism: all oysters were nocturnal at the beginning of the laboratory experiment (January), whereas they were diurnal at the end (March). That shift was progressive. Comparison with a full-year in situ record showed the same behavioral duality as observed in the laboratory: the animals were nocturnal in autumn-winter and diurnal in spring-summer. The significant advantage of a plastic and dual circadian rhythm in terms of adaptability in a highly changing environment is discussed. PMID- 22823870 TI - Identification of human plasma metabolites exhibiting time-of-day variation using an untargeted liquid chromatography-mass spectrometry metabolomic approach. AB - Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD +/- 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation <10%. A total of 1069 metabolite features were detected and 203 (19%) showed significant time-of-day variation. Of these, 34 metabolites were identified using a combination of accurate mass, tandem MS, and online database searches. These metabolites include corticosteroids, bilirubin, amino acids, acylcarnitines, and phospholipids; of note, the magnitude of the 24-h variation of these identified metabolites was large, with the mean ratio of oscillation range over MESOR (24-h time series mean) of 65% (95% confidence interval [CI]: 49-81%). Importantly, several of these human plasma metabolites, including specific acylcarnitines and phospholipids, were hitherto not known to be 24-h variant. These findings represent an important baseline and will be useful in guiding the design and interpretation of future metabolite-based studies. PMID- 22823871 TI - The effect of time-of-day and sympathetic alpha1-blockade on orthostatic tolerance. AB - Tolerance time to a standardized orthostatic stressor is markedly reduced in normotensive individuals in the morning. However, the physiological mechanisms that underpin this phenomenon are unknown. The purpose of this study was to examine the role of alpha(1)-adrenergic activity on orthostatic tolerance and associated cardiorespiratory and cerebrovascular responses, and to determine whether its endogenous modulation is important in the diurnal variation of orthostatic tolerance. In a four-trial, randomized placebo-controlled crossover experiment, 12 normotensive volunteers (aged 25 +/- 1 yrs; mean +/- SE) completed a 60 degrees head-upward tilt (HUT; 15 min or until onset of presyncope) at 06:00 and 16:00 h, 90 min after the administration of either alpha(1)-blockade (prazosin, 1 mg/20 kg body weight) or placebo. Continuous beat-to-beat measurements of middle cerebral blood flow velocity (transcranial Doppler), blood pressure (Finometer), heart rate, stroke volume, cardiac output, and end-tidal carbon dioxide were obtained. Independent of time-of-day, alpha(1)-blockade markedly reduced the ability to tolerate a 15-min 60 degrees HUT; tolerance time was 229% shorter compared with the placebo condition (p <= .0001). Moreover, a marked diurnal variation in orthostatic tolerance was evident following alpha(1) adrenergic blockade; e.g., tolerance time in the morning (176 +/- 30 s) was lower than in the afternoon (354 +/- 75 s; p = .04). These findings highlight an important role of alpha(1)-sympathetic vasoconstrictor activity in acutely regulating blood pressure and offsetting syncope, especially in the early morning. PMID- 22823872 TI - The 3111T/C polymorphism interacts with stressful life events to influence patterns of sleep in females. AB - Genetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n = 415). Gene-environment (G * E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G * E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G * E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females. PMID- 22823873 TI - Morningness: protective factor for sleep-related and emotional problems in childhood and adolescence? AB - The relationship between morningness/eveningness, sleep, and psychological problems is well documented in adults as well as in adolescents. However, research on the circadian orientation and its concomitants in younger children is scarce. The authors investigated the distribution of morningness/eveningness and its connection to sleeping and psychological problems in 91 children and 151 adolescents in Austria. The authors found that morning (M) types had less sleep related and psychological problems than intermediate (I) and evening (E) types, respectively. Among children, M-types suffered less from daytime sleepiness (females: chi(2)((2)) = 8.1, p = .017; males: chi(2)((2)) = 14.8, p = .001). Among adolescents, M-types showed fewer sleep-wake problems (females: chi(2)((2)) = 17.5, p < .001; males: chi(2)((2)) = 19.8, p < .001), and female M-types showed less externalizing (chi(2)((2)) = 8.7, p = .013) as well as internalizing problem behavior (chi(2)((2)) = 9.0, p = .011). In conclusion, these findings indicate that morningness may act as a protective factor against the development of sleep related problems in childhood and sleep-related and psychological problems in adolescence, especially in females. PMID- 22823874 TI - Alterations of locomotor activity rhythm and sleep parameters in patients with advanced glaucoma. AB - The aim of this study was to evaluate the effect of advanced glaucoma on locomotor activity rhythms and related sleep parameters. Nine normal subjects and nine age-matched patients with bilateral advanced primary open-angle glaucoma, >10 yrs since diagnosis, were included in this observational, prospective, case control study. Patients were required to record the timing and duration of their sleep and daily activities, and wore an actigraph on the wrist of the nondominant arm for 20 d. Activity rhythm period, MESOR (24-h time-series mean), amplitude (one-half peak-to-trough variation), and acrophase (peak time), plus long sleep episodes during the wake state, sleep duration, efficiency, and latency, as well as mean activity score, wake minutes, and mean wake episodes during the sleep interval were assessed in controls and glaucomatous patients. Glaucomatous patients exhibited significant decrease in nighttime sleep efficiency, and significant increase in the mean activity score, wake minutes, and mean wake episode during the night. These results suggest that alterations of circadian physiology could be a risk to the quality of life of patients with glaucoma. PMID- 22823875 TI - Tendency toward eveningness is associated with unhealthy dietary habits. AB - Subjects with higher preference for evening hours in daily activities (eveningness) have been repeatedly shown to practice adverse health behaviors as compared to those preferring morning hours (morningness). However, associations between chronotype and dietary intake have not been explored intensively. The authors explored whether the human chronotype is associated with food and nutrient intakes in a random sample of the population aged 25 to 74 yrs. The cross-sectional study included 4493 subjects from the National FINRISK 2007 Study. Chronotype was assessed using a shortened version of Horne and Ostberg's Morningness-Eveningness Questionnaire. Diet was assessed using a validated food frequency questionnaire. Associations between morningness-eveningness (ME) score and dietary intakes were analyzed by linear regression and difference between lowest (eveningness) and highest (morningness) ME score quintiles by Tukey's test. In the multivariable model, intakes of whole grain, rye, potatoes, and vegetables and roots decreased, whereas those of wine and chocolate increased with lower ME scores. Participants in the lowest ME score quintile consumed less fish (p < .001) and fruits (p = .025) and more chocolate (p = .001) and soft drinks (p = .015) compared to the highest quintile. No linear association was found between ME score and total energy intake. In regression analyses, intake of alcohol (as a percentage of total energy intake; E%) and sucrose (E%) increased, whereas intake of carbohydrates (E%), protein (E%), fiber, folic acid, and sodium decreased with lower ME scores. Furthermore, participants in the lowest ME score quintile ingested more fat (E%) (p < .001) and less vitamin D (p < .001) compared to the highest quintile, even though no linear trend between ME score and these nutrients emerged. In conclusion, these results support existing evidence that individuals with circadian preference toward eveningness have less healthy lifestyles, such as unfavorable dietary habits, than those with tendency toward morningness, which could put them at higher risk of several chronic diseases. PMID- 22823876 TI - Circadian phase, sleepiness, and light exposure assessment in night workers with and without shift work disorder. AB - Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean +/- SD] age: 39.2 +/- 12.5 yrs; mean yrs on shift = 9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6 +/- 8.6 yrs; mean years on shift = 8.4) participated. All participants were admitted to the sleep center at 16:00 h, where they stayed in a dim light (<10 lux) private room for the study period of 25 consecutive hours. Saliva samples for melatonin assessment were collected at 30-min intervals. Circadian phase was determined from circadian rhythms of salivary melatonin onset (dim light melatonin onset, DLMO) calculated for each individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00 h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42 +/- 3.25 h, whereas in the SWD group it was 20:42 +/- 2.21 h (z = 2.4; p < .05). Sleep did not differ between groups, except the SWD group showed an earlier bedtime on off days from work relative to that in ANW group. The MSLT corresponding to night work time (01:00-09:00 h) was significantly shorter (3.6 +/- .90 min: [M +/- SEM]) in the SWD group compared with that in ANW group (6.8 +/- .93 min). DLMO was significantly correlated with insomnia severity (r = -.68; p < .03), indicating that the workers with more severe insomnia symptoms had an earlier timing of DLMO. Finally, SWD subjects were exposed to more morning light (between 05:00 and 11:00 h) as than ANW ones (798 vs. 180 lux [M +/- SD], respectively z = -1.7; p < .05). These data provide evidence of an internal physiological delay of the circadian pacemaker in asymptomatic night-shift workers. In contrast, individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule. PMID- 22823877 TI - A reliability and validity study of the Bergen Shift Work Sleep Questionnaire in nurses working three-shift rotations. AB - The "Bergen Shift Work Sleep Questionnaire" (BSWSQ) was developed to systematically assess discrete sleep problems related to different work shifts (day, evening, night shifts) and rest days. In this study, we assessed the psychometric properties of the BSWSQ using a sample of 760 nurses, all working in a three-shift rotation schedule: day, evening, and night shifts. BSWSQ measures insomnia symptoms using seven questions: >30-min sleep onset latency, >30-min wake after sleep onset, >30-min premature awakenings, nonrestorative sleep, being tired/sleepy at work, during free time on work days, and when not working/on vacation. Symptoms are assessed separately for each work shift and rest days, as "never," "rarely," "sometimes," "often," "always," or "not applicable." We investigated the BSWSQ model fit, reliability (test-retest of a subsample, n = 234), and convergent and discriminant validity between the BSWSQ and Epworth Sleepiness Scale, Fatigue Questionnaire, and Hospital Anxiety Depression Scale. We also investigated differences in mean scores between the different insomnia symptoms with respect to different work shifts and rest days. BSWSQ demonstrated an adequate model fit using structural equation modeling: root mean square error of approximation = .071 (90% confidence interval [CI] = .066-.076), comparative fit index = .91, and chi-square/degrees of freedom = 4.41. The BSWSQ demonstrated good reliability (test-retest coefficients p < .001). We found good convergent and discriminant validity between BSWSQ and the other scales (all coefficients p < .001). There were significant differences between the overall/composite scores of the various work shifts. Night shift showed the highest score compared to day and evening shifts as well as to rest days (all post hoc comparisons p < .001). Mean scores of different symptoms also varied significantly within the individual work shifts. We conclude that the BSWSQ meets the necessary psychometric standards, enabling systematic study of discrete insomnia symptoms in different work shifts. PMID- 22823878 TI - Subjective sleep quality exclusively mediates the relationship between morningness-eveningness preference and self-perceived stress response. AB - Eveningness preference has been associated with lower sleep quality and higher stress response compared with morningness preference. In the current study, female morning (n = 27) and evening (n = 28) types completed the Pittsburgh Sleep Quality Index (PSQI) and were additionally challenged with an arithmetic stress induction task. Evening types reported lower subjective sleep quality and longer sleep latency than morning types. Furthermore, evening types reported higher self perceived stress after the task than morning types. Subjective sleep quality fully mediated the relationship between morningness-eveningness preference and stress response. Poor sleep quality may, therefore, contribute to the elevated health risk in evening types. PMID- 22823881 TI - Direct evidence of the left caudate's role in bilingual control: an intra operative electrical stimulation study. AB - Bilinguals need control mechanisms in order to switch between languages in different communication contexts (Green, 1998, Bilingualism: Language and Cognition, 1; Price, Green, & von Studnitz, 1999, Brain, 122). There has been neural evidence showing competition to control output in L2 vs. L1 in both cortical and sub-cortical areas, when language selection is carried out (Abutalebi & Green, 2007, Journal of Neurolinguistics, 20). Here we use intra operative direct electrical stimulation to demonstrate that the head of the left caudate is critical not only in language switching tasks but other control tasks. A bilingual Chinese-English patient was instructed to perform both language switching and switching in color-shape naming tasks during awake glioma surgery. When stimulation was applied on the left caudate, failures or difficulties in both language switching and color-shape naming were observed, with the effects greater on language switching. Stimulation to neighboring brain regions either did not affect performance or generated mild problems specific to language switching. The results provide direct evidence of the necessary role of the left caudate in language control. PMID- 22823883 TI - Highly ordered, accessible and nanocrystalline mesoporous TiO2 thin films on transparent conductive substrates. AB - Highly porous (V(mesopore) = 25-50%) and ordered mesoporous titania thin films (MTTF) were prepared on ITO (indium tin oxide)-covered glass by a fast two-step method. The effects of substrate surface modification and thermal treatment on pore order, accessibility and crystallinity of the MTTF were systematically studied for MTTF deposited onto bare and titania-modified ITO. MTTF exposed briefly to 550 degrees C resulted in highly ordered films with grid-like structures, enlarged pore size, and increased accessible pore volume when prepared onto the modified ITO substrate. Mesostructure collapse and no significant change in pore volume were observed for MTTF deposited on bare ITO substrates. Highly crystalline anatase was obtained for MTTF prepared on the modified-ITO treated at high temperatures, establishing the relationship between grid-like structures and titania crystallization. Photocatalytic activity was maximized for samples with increased crystallization and high accessible pore volume. In this manner, a simple way of designing materials with optimized characteristics for optoelectronic applications was achieved through the modification of the ITO surface and a controlled thermal treatment. PMID- 22823882 TI - Large-scale identification of N-glycosylated proteins of mouse tissues and construction of a glycoprotein database, GlycoProtDB. AB - Protein glycosylation is a common post-translational modification that plays important roles in terms of protein function. However, analyzing the relationship between glycosylation and protein function remains technically challenging. This problem arises from the fact that the attached glycans possess diverse and heterogeneous structures. We believe that the first step to elucidate glycan function is to systematically determine the status of protein glycosylation under physiological conditions. Such studies involve analyzing differences in glycan structure on cell type (tissue), sex, and age, as well as changes associated with perturbations as a result of gene knockout of glycan biosynthesis-related enzyme, disease and drug treatment. Therefore, we analyzed a series of glycoproteomes in several mouse tissues to identify glycosylated proteins and their glycosylation sites. Comprehensive analysis was performed by lectin- or HILIC-capture of glycopeptide subsets followed by enzymatic deglycosylation in stable isotope labeled water (H218O, IGOT) and finally LC-MS analyses. In total, 5060 peptides derived from 2556 glycoproteins were identified. We then constructed a glycoprotein database, GlycoProtDB, using our experimental-based information to facilitate future studies in glycobiology. PMID- 22823884 TI - Burning Man 2011: mass gathering medical care in an austere environment. AB - INTRODUCTION: Burning Man is a large weeklong outdoor arts festival held annually in the rugged and austere Black Rock Desert in northern Nevada. The 2011 event presented several unusual challenges in terms of emergency medical services (EMS) and medical care provision. OBJECTIVE: This paper details the planning and subsequent emergency medical care for Burning Man 2011. METHODS: This was a retrospective, observational review of the preparation, management, and medical care at Burning Man 2011. RESULTS: Attendance at Burning Man 2011 was 53,735. Of these attendees, 2,307 were treated in the field hospital. While most patients had minor injuries, 33 were subsequently transported to a hospital (28 by ambulance and five by helicopter). The most common conditions treated were soft tissue injuries, dehydration, eye problems, and urinary tract infections. There was one death (subarachnoid hemorrhage) and one patient in cardiac arrest (thoracic aortic dissection) who was successfully resuscitated and transferred. Burning Man 2011 presented numerous challenges in provision of EMS and medical care because of attendance size, the austere environment, and significant distance (150 miles) to definitive medical care. EMS operations included six dedicated ambulances, three quick-response vehicles, two first-aid stations, and a physician-staffed field hospital. The hospital had limited diagnostic capabilities (e.g., x-ray, ultrasound, basic laboratory analysis) and a limited formulary. We found that the use of physicians was necessary because much of the care provided was beyond the scope of paramedics. CONCLUSIONS: We describe the preparation and medical care for a large outdoor mass-gathering event held in a remote and austere environment. We met the stated goals of providing needed medical care while minimizing the need to transport attendees offsite for additional care. Our experience with Burning Man 2011 may aid planners with similar events. PMID- 22823885 TI - Study on the subgel-phase formation using an asymmetric phospholipid bilayer membrane by high-pressure fluorometry. AB - The myristoylpalmitoylphosphatidylcholine (MPPC) bilayer membrane shows a complicated temperature-pressure phase diagram. The large portion of the lamellar gel (L(beta)'), ripple gel (P(beta)'), and pressure-induced gel (L(beta)I) phases exist as metastable phases due to the extremely stable subgel (L(c)) phase. The stable L(c) phase enables us to examine the properties of the L(c) phase. The phases of the MPPC bilayers under atmospheric and high pressures were studied by small-angle neutron scattering (SANS) and fluorescence spectroscopy using a polarity-sensitive fluorescent probe Prodan. The SANS measurements clearly demonstrated the existence of the metastable L(beta)I phase with the smallest lamellar repeat distance. From a second-derivative analysis of the fluorescence data, the line shape for the L(c) phase under high pressure was characterized by a broad peak with a minimum of ca. 460 nm. The line shapes and the minimum intensity wavelength (lambda"(min)) values changed with pressure, indicating that the L(c) phase has highly pressure-sensible structure. The lambda"(min) values of the L(c) phase spectra were split into ca. 430 and 500 nm in the L(beta)I phase region, which corresponds to the formation of a interdigitated subgel L(c) (L(c)I) phase. Moreover, the phase transitions related to the L(c) phase were reversible transitions under high pressure. Taking into account the fluorescence behavior of Prodan for the L(c) phase, we concluded that the structure of the L(c) phase is highly probably a staggered structure, which can transform into the L(c)I phase easily. PMID- 22823886 TI - Phase behavior of a lattice hydrophobic oligomer in explicit water. AB - We investigate the thermodynamics of hydrophobic oligomer collapse using a water explicit, three-dimensional lattice model. The model captures several aspects of protein thermodynamics, including the emergence of cold- and thermal-unfolding, as well as unfolding at high solvent density (a phenomenon akin to pressure induced denaturation). We show that over a range of conditions spanning a ~14% increase in solvent density, the oligomer transforms into a compact, strongly water-penetrated conformation at low temperature. This contrasts with thermal unfolding at high temperature, where the system "denatures" into an extended random coil conformation. We report a phase diagram for hydrophobic collapse that correctly captures qualitative aspects of cold and thermal unfolding at low to intermediate solvent densities. PMID- 22823887 TI - Associations between factors within the home setting and screen time among children aged 0-5 years: a cross-sectional study. AB - BACKGROUND: Excessive engagement in screen time has several immediate and long term health implications among pre-school children. However, little is known about the factors that influence screen time in this age group. Therefore, the purpose of this study was to use the Ecologic Model of Sedentary Behavior as a guide to examine associations between intrapersonal, interpersonal, and physical environment factors within the home setting and screen time among pre-school children. METHODS: Participants were 746 pre-school children (<= 5 years old) from the Kingston, Ontario, Canada area. From May to September, 2011, parents completed a questionnaire regarding several intrapersonal (child demographics), interpersonal (family demographics, parental cognitions, parental behavior), and physical environment (television, computer, or video games in the bedroom) factors within the home setting. Parents also reported the average amount of time per day their child spent watching television and playing video/computer games. Associations were examined using linear and logistic regression models. RESULTS: Most participants (93.7%) watched television and 37.9% played video/computer games. Several intrapersonal, interpersonal, and physical environment factors within the home setting were associated with screen time. More specifically, age, parental attitudes, parental barriers, parental descriptive norms, parental screen time, and having a television in the bedroom were positive predictors of screen time; whereas, parental education, parental income, and parental self efficacy were negative predictors of screen time in the linear regression analysis. Collectively these variables explained 64.2% of the variance in screen time. Parental cognitive factors (self-efficacy, attitudes, barriers, descriptive norms) at the interpersonal level explained a large portion (37.9%) of this variance. CONCLUSIONS: A large proportion of screen time in pre-school children was explained by factors within the home setting. Parental cognitive factors at the interpersonal level were of particular relevance. These findings suggest that interventions aiming to foster appropriate screen time habits in pre-school children may be most effective if they target parents for behavioral change. PMID- 22823888 TI - Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue - a GC-TOFMS based metabolomics study. AB - BACKGROUND: Changes in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far. RESULTS: A cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5 monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%. CONCLUSIONS: For the first time, a comprehensive metabolic map of breast cancer was constructed by GC TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology. PMID- 22823889 TI - Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients. AB - Oral consumption of freeze-dried black raspberries attenuated neoplastic changes in colorectal tissue markers of apoptosis, cell proliferation, and angiogenesis in colorectal cancer (CRC) patients. To determine whether plasma concentrations of interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL-10, IL-12p70, granulocyte macrophage colony stimulating factor (GM-CSF), interferon-gamma, and tumor necrosis factor-alpha (TNF-alpha) were associated with berry treatment and changes in colorectal tissue markers of apoptosis, cell proliferation, and angiogenesis, plasma and biopsy samples of adenocarcinoma and adjacent normal appearing colorectal tissue were collected before and during berry treatment from 24 CRC patients who had not received prior therapy and drank a slurry of black raspberry powder (20 g in 100 ml drinking water) 3 times a day for 1 to 9 wk. Plasma concentrations of GM-CSF (+0.12 +/- 0.04 pg/mL; P = 0.01) and IL-8 (-1.61 +/- 0.71 pg/mL; P = 0.04) changed in patients receiving berries for more than 10 days. These changes were correlated with beneficial changes in markers of proliferation (r(DeltaGM-CSF, DeltaKi67 carcinoma - normal) = -0.51) and apoptosis (r(DeltaIL-8, DeltaTUNEL carcinoma - normal) = -0.52) observed in colorectal tissue taken within the same week. Plasma concentrations of GM-CSF and IL-8 may serve as noninvasive indicators to monitor tissue response to berry based interventions for CRC. PMID- 22823890 TI - Association between pregnancy intention and optimal breastfeeding practices in the Philippines: a cross-sectional study. AB - BACKGROUND: The effect of pregnancy intention on post-natal practices like breastfeeding is still poorly understood in the Philippines. In this light, this study aims to determine the association between pregnancy intention and optimal breastfeeding practices in the Philippines. METHODS: This is a cross-sectional study design using the 2003 Philippine National Demographic and Health Survey. Logistic regression analysis was used to determine the independent association of pregnancy intention and optimal breastfeeding practices. The study includes 3,044 last-born children aged 6-36 months at the time of survey. Dead children were also included as long as their age of death satisfies the age criterion. RESULTS: Children born from mistimed pregnancies are more likely to have late breastfeeding initiation compared to children born from wanted pregnancies (OR = 1.44; 90%CI: 1.17-1.78). However, this occurs only among children belonging to households with low socio-economic status. Among children belonging to households with high socio-economic status, no significant effect of pregnancy intention on breastfeeding initiation was observed. Children born from unwanted pregnancies are less likely to have short breastfeeding duration (OR = 0.60; 90%CI: 0.48 0.76). However, this occurs only among children belonging to households with high socioeconomic status. No significant effect of pregnancy intention on breastfeeding duration was observed among children belonging to households with low socio-economic status. CONCLUSION: The findings of this study suggest that there are different effects of pregnancy intention on the two types of optimal breastfeeding practices examined. With regards to breastfeeding duration, it was found that among infants belonging to high SES, the odds of having short breastfeeding duration is lower among children born from unwanted pregnancies compared to children born from wanted one. Conversely, children belonging to low SES household, the odds of having late breastfeeding initiation among children born from mistimed pregnancies are higher compared to children born from wanted pregnancies. PMID- 22823891 TI - Biocompatibility of mesoporous silica nanoparticles. AB - In this review, recent reports on the biocompatibility of mesoporous silica nanoparticles (MSNs) are reviewed, with special emphasis being paid to the correlations between MSNs' structural and compositional features and their biological effects on various cells and tissues. First, the different synthetic routes used to produce the most common types of MSNs and the various methods employed to functionalize their surfaces are discussed. This is, however, done only briefly because of the focus of the review being the biocompatibility of the materials. Similarly, the biological applications of MSNs in areas such as drug and gene delivery, biocatalysis, bioimaging, and biosensing are briefly introduced. Many examples have also been mentioned about the biological applications of MSNs while discussing the materials' biocompatibility. The cytotoxicity of different types of MSNs and the effects of their various structural characteristics on their biological activities, which are the focus of this review, are then described in detail. In addition, synthetic strategies developed to reduce or eliminate any possible negative biological effects associated with MSNs or to improve their biocompatibility, as necessary, are illustrated. At the same time, recent reports on the interactions between MSNs and various in vivo or in vitro biological systems, plus our opinions and remarks on what the future may hold for this field, are included. PMID- 22823893 TI - In vivo drug release and antibacterial properties of vancomycin loaded hydroxyapatite/chitosan composite. AB - The present study was designed to investigate the in vivo drug release and antibacterial properties of a novel mesoporous hydroxyapatite/chitosan (mesoHA CS) composite loaded with vancomycin (VCM). VCM-mesoHA/CS composite was prepared via a freeze-drying method. The successful loading of VCM in the composite scaffold was verified by FT IR analyses. SEM observation revealed the mesoporous structure of the VCM-mesoHA/CS composite with the pore size of 50-100 um. Medicated composites were then implanted into the muscular pockets of extremity in rabbits. The results demonstrated that local VCM concentration in muscle tissue could maintain higher than the minimum inhibitory concentration at the site of implantation for long time (i.e. 4 weeks). As a result, the number of viable methicillin-resistant Staphylococcus aureus (MRSA) on mesoHA/CS could be significantly suppressed after the VCM-mesoHA/CS implantation. These results indicated that the mesoHA/CS composite may be promising scaffold as drug storage and release vehicle applied for local antibacterial drug release and bone repair. PMID- 22823892 TI - Preparation of the thienopyridine derivatives loaded liposomes and study on the effect of compound-lipid interaction on release behavior. AB - The article describes characterization of two liposome formulations containing thienopyridine derivatives, namely TP-58 and TP-67. By preparing the liposomes, the concentration of the two compounds in ultrapure water was increased up to three orders of magnitude. After i.v. administration of the liposomes in rats, the initial compound plasma concentrations were enhanced more than fifty times relative to that after i.g. administration of the compound suspensions. It was found out that the release rate of TP-67 from the liposome both in vitro and in vivo was not significantly different from that of TP-58. TP-58 was more lipophilic than TP-67 according to partition coefficiency, and TP-67 had greater polarity than TP-58 based on polar surface area (PSA). With DSC, it was found out that the interaction magnitude between TP-67 and the lipid bilayer was not significantly different from that between TP-58 and the lipid bilayer, which accounted for the similarity of the two compounds in release rate both in vitro and in vivo. It indicated liposome can be used as a potential carrier for broading the application of TP-58 and TP-67. Interaction between the thienopyridine derivatives and the lipid bilayer is probably the decisive factor for compound release from the liposomes. PMID- 22823894 TI - Thermally reversible xyloglucan gels as vehicles for nasal drug delivery. AB - The aim of this study was to investigate the potential application of thermosensitive gels formed by a xyloglucan polysaccharide derived from tamarind seed for nasal drug delivery. Xyloglucan that had been partially degraded by beta galactosidase to eliminate 45% of galactose residues formed gels at concentrations of 2.5% w/w at gelation temperatures decreasing over the range 27 28 degrees C. The in vitro release of ondansetron hydrochloride from the enzyme degraded xyloglucan gels followed higuchi kinetics over a period of 5 h at 34 degrees C by anomalous transport mechanism. The ex vivo permeation of ondansetron hydrochloride from the gels was sustained. Histological examination of nasal mucosa following a single administration of the gels showed no evidence of mucosal damage. Finally, the bioavailability study in rabbits revealed that the absolute bioavailability of ondansetron hydrochloride was significantly increased from 28.64% in the case of the oral drug solution to 52.79% in the case of the nasal in situ gel. The results of this study suggest the potential of the enzyme degraded xyloglucan gels as vehicles for nasal delivery of drugs. PMID- 22823895 TI - Transplant organizational structures: viewpoints from established centers. AB - This personal viewpoint report summarizes the responses of a survey targeting established transplant programs with a structured framework, such as center, institute, or department, and stability of leadership to assure valuable experiential observations. The 18-item survey was sent to 20 US institutions that met inclusion criteria. The response rate was 100%. Seventeen institutions had a distinct transplant governance structure. A majority of respondents perceived that their type of transplant structure was associated with enhanced recognition within their institution (85%), improved regulatory compliance (85%), transplant volume growth (75%), improved quality outcomes (75%) and increased funding for transplant-related research (75%). The prevailing themes in respondents' remarks were the perceived need for autonomy of the transplant entity, alignment among services and finances and alignment of authority with responsibility. Many respondents suggested that a dialogue be opened about effective transplant infrastructure that overcomes the boundaries of traditional academic department silos. PMID- 22823896 TI - Reversible solvatomagnetic effect in novel tetranuclear cubane-type Ni4 complexes and magnetostructural correlations for the [Ni4(MU3-O)4] core. AB - A new family of tetranuclear nickel cube complexes [Ni(4)L(4)(solv)(4)] (1, solv = MeOH; 2, solv = H(2)O; H(2)L = pyrazole-based tridentate {ONO} ligand) has been studied in detail, in particular by X-ray diffraction and superconducting quantum interference device (SQUID) magnetometry. Different solvates 1.H(2)O, 2.4C(3)H(6)O, 2.CH(2)Cl(2), and 2.H(2)O were obtained in crystalline form. Only small structural variations were found for the Ni-O-Ni angles of the [Ni(4)O(4)] cores of those compounds, but these slight variations have dramatic consequences for the magnetic properties. [Ni(4)L(4)(MeOH)(4)].H(2)O (1.H(2)O) and [Ni(4)L(4)(H(2)O)(4)].H(2)O (2.H(2)O) can be reversibly interconverted in the solid state by exposure to the respective solvent, MeOH or H(2)O, and this goes along with a switching of the spin ground state from magnetic (S(T) = 4) to diamagnetic (S(T) = 0). Likewise the (irreversible) loss of lattice solvent in [Ni(4)L(4)(H(2)O)(4)].4C(3)H(6)O (2.4C(3)H(6)O) to give 2.2C(3)H(6)O changes the ground state from S(T) = 4 to S(T) = 0. In view of these dramatic solvatomagnetic effects for the present [Ni(4)L(4)(solv)(4)] complexes, which occur upon extrusion of lattice solvent or facile exchange of coordinated solvent molecules while keeping the robust [Ni(4)O(4)] core intact, a note of care is issued: whenever magnetic data are obtained for powdered material or for crystals that easily loose lattice solvent molecules, the magnetic properties may not necessarily reflect the situation observed in the corresponding single crystal diffraction study. Finally, a thorough analysis of the present series of complexes as well as other {Ni(4)(MU(3)-OR)(4)} cubes reported in the literature confirms that a correlation between the (Ni-O-Ni)(av) bond angle and J in [Ni(4)O(4)] cubane complexes does indeed exist. PMID- 22823897 TI - Soleus activity in post-stroke subjects: movement sequence from standing to sitting. AB - INTRODUCTION: The beginning of the movement sequence from standing to sitting requires the modulation of plantar flexors activity, including the soleus muscle (SOL), to allow the forward translation of the tibia in relation to the foot, preserving its antigravity function. PURPOSE: To analyze the SOL activity during the initial phase of standing to sitting in stroke subjects. METHODS: Two groups of ten subjects each participated in this study, one composed of healthy subjects and the other with subjects with a history of stroke. Electromyographic activity (EMGa) of SOL was analyzed in the ipsilateral (IPSI) and contralateral (CONTRA) limb to side lesion in stroke subjects, and in one limb in healthy subjects during the initial phase of standing to sitting. A force plate was used to identify the movement sequence phase. RESULTS: The mean values of SOL EMGa were higher in healthy subjects than the ones obtained in the IPSI and CONTRA limb in stroke subjects. Significant differences were only observed between the IPSI and healthy limb (p=0.035). CONCLUSION: When compared to the healthy subjects, stroke subjects showed a decreased SOL EMGa in the IPSI limb, which suggests that therapeutic decisions must consider the need to promote a better postural control also in the IPSI limb. PMID- 22823898 TI - Fatal human metapneumovirus and influenza B virus coinfection in an allogeneic hematopoietic stem cell transplant recipient. AB - Human metapneumovirus (hMPV) infection can occur in all age groups with significant morbidity and mortality. Coinfection with influenza virus occurs mainly with influenza type A and all reported cases recovered completely. We report the case of a 61-year-old man who had hematopoietic stem cell transplant for myelodysplastic syndrome. He was admitted to hospital for septic shock and neutropenia, and blood culture was positive for Pseudomonas aeruginosa. He rapidly developed respiratory failure and required ventilator support. His respiratory culture grew P. aeruginosa and hMPV. His course was complicated by persistent shock requiring vasopressor support, and repeat nasopharyngeal swab was positive for influenza type B and hMPV. His condition rapidly deteriorated, his family elected comfort care, and the patient died shortly thereafter. Coinfection with hMPV and influenza virus type B may have a poor outcome and can be fatal, especially in immunocompromised patients. PMID- 22823899 TI - Short hairpin-looped oligodeoxynucleotides reduce hepatitis C virus replication. AB - BACKGROUND: Persistent infection with hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Standard therapy consists of a combination of interferon-alpha and ribavirin, but many patients respond poorly, especially those infected with HCV genotypes 1 and 4. Furthermore, standard therapy is associated with severe side-effects. Thus, alternative therapeutic approaches against HCV are needed. FINDINGS: Here, we studied the effect of a new class of antiviral agents against HCV, short, partially double-stranded oligodeoxynucleotides (ODNs), on viral replication. We targeted the 5' nontranslated region (5' NTR) of the HCV genome that has previously been shown as effective target for small interfering RNAs (siRNAs) in vitro. One of the investigated ODNs, ODN 320, significantly and efficiently reduced replication of HCV replicons in a sequence-, time- and dose-dependent manner. ODN 320 targets a genomic region highly conserved among different HCV genotypes and might thus be able to inhibit a broad range of genotypes and subtypes. CONCLUSIONS: ODNs provide an additional approach for inhibition of HCV, might be superior to siRNAs in terms of stability and cellular delivery, and suitable against HCV resistant to standard therapy. This study underlines the potential of partially double-stranded ODNs as antiviral agents. PMID- 22823900 TI - Training on a new, portable, simple simulator transfers to performance of complex bronchoscopy procedures. AB - INTRODUCTION: Virtual-reality (VR) simulation provides a safe and effective learning environment prior to practicing on patients. However, existing bronchoscopy simulators are expensive and not easily portable. OBJECTIVES: The aim of this study was to assess the effect of self-directed training on a new, portable, simple simulator measured by transfer of skills to performance of more complex bronchoscopy procedures on an advanced VR simulator. METHODS: Twenty medical students participated in the study. After a general introduction to bronchoscopy, they were randomised into two groups, receiving either self directed bronchoscopy training using a portable, simple simulator or no manual training. Subsequently, all participants were tested on complex scenarios in an advanced VR simulator using a validated bronchoscopy quality test. Bronchoscopy quality scores were compared using independent samples t-test and correlated with a previously established pass-fail standard. RESULTS: The intervention group spent an average of 71-min training on the new simulator. The intervention group performed significantly better than the control group, mean bronchoscopy quality score 0.55 [standard deviation (SD) 0.16] vs 0.36 (SD 0.10), P = 0.005, effect size = 1.47. Eight out of 10 participants in the intervention group passed the test compared with only 1 out of 10 in the control group. CONCLUSION: The effect of a brief, self-directed training session using a portable, simple simulator was substantial and transferred to performance of more complex skills. PMID- 22823901 TI - Migraine among Norwegian neurologists. AB - BACKGROUND: Previous studies have shown a high prevalence of migraine among neurologists. The main objective of this study was to assess the prevalence of migraine and its subtypes among neurologists in Norway. METHOD: Questionnaire based cross-sectional study among every Norwegian neurologist registered on March 19, 2010. RESULTS: Among the 384 neurologists, 245 (64%) participated. Of these, 95 (39%) reported having experienced migraine aura, and 86 having experienced migraine headache (35%). By employing the International Headache Society criteria for migraine with regard to the number of attacks, the gender-adjusted lifetime and 1-year prevalence was 38.7% (95% CI 30.3-47.7) and 33.8% (95% CI 25.9-47.2), respectively. Age-adjusted 1-year prevalence of migraine headache (not including subjects experiencing visual aura only) for men was 15.9% and for women 36.7%, which gives an overall age and gender-adjusted prevalence of 26.3% (95% CI 18.5 34.2). Solitary auras were experienced by 83 (34%), of which 73 (30%) had experienced this twice or more frequently. The majority of the neurologists thought that migraine was underdiagnosed and undertreated, 70% and 68%, respectively. CONCLUSION: The study confirms the results of previous studies, indicating that migraine, including visual aura, is more common among neurologists than what would be expected from population-based studies. Because this group, through professional experience with the condition, can make accurate diagnoses in themselves, and will have fewer problems with recalling headache episodes, the prevalence figures obtained may give the most precise estimate of the true population prevalence. PMID- 22823902 TI - Excess of the endocannabinoid anandamide during lactation induces overweight, fat accumulation and insulin resistance in adult mice. AB - BACKGROUND: Environmental conditions in early life can induce permanent physiological changes, sometimes increasing the risk of chronic diseases during adulthood. Neural and peripheral circuits controlling energy balance may be modulated during such a critical period. Since type 1 cannabinoid receptors (CB1R) have recently emerged as targets for modulating energy balance, their premature chronic activation during early life may result in long-term metabolic consequences associated to overweight/obesity. Endogenous activation of CB1R mainly occurs after binding to the endocannabinoid Anandamide (AEA). OBJECTIVE: To evaluate long-term effects of AEA treatment during lactation on body weight, epididymal fat accumulation and related metabolic parameters during adulthood. DESIGN: Male mice pups were orally treated with a solution of AEA (20 MUg/g body weight in soy oil) or vehicle during the whole lactation period. After weaning, food intake and body weight were recorded every 10 days. Adult animals were subjected to glucose and insulin tolerance tests. Subsequently, animals were sacrificed and epididymal fat pads were extracted. Circulating levels of plasma insulin, leptin, non-sterified fatty acids (NEFA), triglyceride and cholesterol were also evaluated. RESULTS: AEA-treated mice during lactation showed a significant increase in accumulated food intake, body weight and epididymal fat during adulthood when compared to control mice. When evaluating CB1R protein expression in epididymal fat, the AEA-treated group showed a 150 % increase in expression compared to the control mice. This group also displayed significantly higher levels of circulating glucose, insulin, leptin, triglycerides, cholesterol and NEFA. Moreover, a marked state of insulin resistance was an important finding in the AEA-treated group. CONCLUSION: This study showed that overweight, accumulation of visceral fat and associated metabolic disturbances, such as a higher lipid profile and insulin resistance, can be programmed by a treatment with the endocannabinoid AEA during lactation in adult mice. PMID- 22823903 TI - Responsiveness and validity of the SCORFAD, an extent and severity scale for feline hypersensitivity dermatitis. AB - BACKGROUND: Hypersensitivity (allergic) dermatitis (HD) is commonly seen in cats, causing pruritus and various patterns of skin lesions, including at least one of the following: head and neck excoriations, self-induced alopecia, eosinophilic plaques and miliary dermatitis. Few studies have evaluated the efficacy of therapeutic interventions for feline HD, and although various scales have been considered, none has been formally validated for the assessment of disease severity and its response to therapy. OBJECTIVE: To design and validate a novel scale (SCORing Feline Allergic Dermatitis; SCORFAD) to assess the value of different criteria used as outcome measures for the treatment of feline HD and to set minimal thresholds for defining the clinical success of tested interventions. ANIMALS: One hundred client-owned cats. METHODS: The SCORFAD scale was designed to include the four most frequently identified lesion types in feline HD (eosinophilic plaque, head and neck excoriations, self-induced alopecia and miliary dermatitis) across 10 body regions. The extent and severity of each lesion type were graded prior to inclusion and after 3 and 6 weeks in a clinical study to compare the efficacy of two doses of ciclosporin with placebo. RESULTS: The SCORFAD scale was found to exhibit satisfactory content, construct, criterion and sensitivity to change. The percentage reduction in SCORFAD from baseline was determined to be the most valid assessment of clinical response. Inter- and intra observer reliability was not assessed. CONCLUSIONS AND CLINICAL IMPORTANCE: The SCORFAD scale is proposed for use as a validated tool for the assessment of disease severity and response to therapeutic interventions in clinical trials for feline HD. PMID- 22823905 TI - Pressure-induced crystal structure and spin-state transitions in magnetite (Fe3O4). AB - High pressure is an important dimension for the emergent phenomena in transition metal oxides, including high-temperature superconductivity, colossal magnetoresistance, and magnetoelectric coupling. In these multiply correlated systems, the interplay between lattice, charge, orbital, and spin is extremely susceptible to external pressure. Magnetite (Fe(3)O(4)) is one of the oldest known magnetic materials and magnetic minerals, yet its high pressure behaviors are still not clear. In particular, the crystal structure of the high-pressure phase has remained contentious. Here, we investigate the pressure-induced phase transitions in Fe(3)O(4) from first-principles density-functional theory. It is revealed that the net magnetic moment, arising from two ferrimagnetically coupled sublattices in Fe(3)O(4), shows an abrupt drop when entering into the high pressure phase but recovers finite value when the pressure is beyond 65.1 GPa. The origin lies in the redistribution of Fe 3d orbital occupation with the change of crystal field, where successive structural transitions from ambient pressure phase Fd3[combining overline]m to high pressure phase Pbcm (at 29.7 GPa) and further to Bbmm (at 65.1 GPa) are established accurately. These findings not only explain the experimental observations on the structural and magnetic properties of the highly compressed Fe(3)O(4) but also suggest the existence of highly magnetized magnetite in the Earth's lower mantle. PMID- 22823904 TI - Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study. AB - BACKGROUND: Aim of this pilot study is to examine the effects of myo-inositol administration on ovarian response and oocytes and embryos quality in non PolyCystic Ovary Syndrome (PCOS) patients undergoing multiple follicular stimulation and in vitro insemination by conventional in vitro fertilization or by intracytoplasmic sperm injection. METHODS: One hundred non-PCOS women aged <40 years and with basal FSH <10 mUI/ml were down-regulated with triptorelin acetate from the mid-luteal phase for 2 weeks, before starting the stimulation protocol for oocytes recovery. All patients received rFSH, at a starting dose of 150 IU for 6 days. The dose was subsequently adjusted according to individual response. Group B (n=50) received myo-inositol and folic acid for 3 months before the stimulation period and then during the stimulation itself. Group A (n-50) received only folic acid as additional treatment in the 3 months before and through treatment. RESULTS: Total length of the stimulation was similar between the two groups. Nevertheless, total amount of gonadotropins used to reach follicular maturation was found significantly lower in group B. In addition, the number of oocytes retrieved was significantly reduced in the group pretreated with myo-inositol. Clinical pregnancy and implantation rate were not significantly different in the two groups. CONCLUSIONS: Our findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients. PMID- 22823906 TI - Colovesical fistula causing an uncommon reason for failure of computed tomography colonography: a case report. AB - INTRODUCTION: Computed tomography colonography, or virtual colonoscopy, is a good alternative to optical colonoscopy. However, suboptimal patient preparation or colon distension may reduce the diagnostic accuracy of this imaging technique. CASE PRESENTATION: We report the case of an 83-year-old Caucasian woman who presented with a five-month history of pneumaturia and fecaluria and an acute episode of macrohematuria, leading to a high clinical suspicion of a colovesical fistula. The fistula was confirmed by standard contrast-enhanced computed tomography. Optical colonoscopy was performed to exclude the presence of an underlying colonic neoplasm. Since optical colonoscopy was incomplete, computed tomography colonography was performed, but also failed due to inadequate colon distension. The insufflated air directly accumulated within the bladder via the large fistula. CONCLUSIONS: Clinicians should consider colovesical fistula as a potential reason for computed tomography colonography failure. PMID- 22823908 TI - "Keep up the good work"! A case study of the effects of a specific cognitive training in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative condition characterized by significant impairment in multiple cognitive domains. In recent years, the development of cognitive trainings in AD has received significant attention. In the present case study we designed a cognitive training program (GEO, Geographical Exercises for cognitive Optimization) based on an errorless paradigm and tailored to the patient's cultural interests. The aim of this training was to investigate the potential for acquiring and possibly retaining both procedural and verbal knowledge in early-stage AD. This study involved an 80-year-old female patient diagnosed with early-stage AD, and 10 matched healthy subjects. Participants were asked to perform the two GEO training tasks: a "puzzle-like" task for procedural memory, and an "association" task for verbal memory. Both the patient and the healthy controls were subsequently trained with GEO using the same two tasks for 2 months. Although the patient's performance before training in both tasks was poor compared to healthy controls, after the training these differences disappeared. Our results showed that the patient was able to acquire new procedural abilities and verbal knowledge, and that her achievements were stable at the follow-up testing scheduled 3 months after the end of the intervention. This case study suggests a potentially useful strategy for cognitive training in AD. PMID- 22823907 TI - A microRNA activity map of human mesenchymal tumors: connections to oncogenic pathways; an integrative transcriptomic study. AB - BACKGROUND: MicroRNAs (miRNAs) are nucleic acid regulators of many human mRNAs, and are associated with many tumorigenic processes. miRNA expression levels have been used in profiling studies, but some evidence suggests that expression levels do not fully capture miRNA regulatory activity. In this study we integrate multiple gene expression datasets to determine miRNA activity patterns associated with cancer phenotypes and oncogenic pathways in mesenchymal tumors - a very heterogeneous class of malignancies. RESULTS: Using a computational method, we identified differentially activated miRNAs between 77 normal tissue specimens and 135 sarcomas and we validated many of these findings with microarray interrogation of an independent, paraffin-based cohort of 18 tumors. We also showed that miRNA activity is imperfectly correlated with miRNA expression levels. Using next-generation miRNA sequencing we identified potential base sequence alterations which may explain differential activity. We then analyzed miRNA activity changes related to the RAS-pathway and found 21 miRNAs that switch from silenced to activated status in parallel with RAS activation. Importantly, nearly half of these 21 miRNAs were predicted to regulate integral parts of the miRNA processing machinery, and our gene expression analysis revealed significant reductions of these transcripts in RAS-active tumors. These results suggest an association between RAS signaling and miRNA processing in which miRNAs may attenuate their own biogenesis. CONCLUSIONS: Our study represents the first gene expression-based investigation of miRNA regulatory activity in human sarcomas, and our findings indicate that miRNA activity patterns derived from integrated transcriptomic data are reproducible and biologically informative in cancer. We identified an association between RAS signaling and miRNA processing, and demonstrated sequence alterations as plausible causes for differential miRNA activity. Finally, our study highlights the value of systems level integrative miRNA/mRNA assessment with high-throughput genomic data, and the applicability of paraffin-tissue-derived RNA for validation of novel findings. PMID- 22823909 TI - Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study. AB - BACKGROUND: 1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. METHODS: Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. RESULTS: Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05). CONCLUSIONS: Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV. PMID- 22823910 TI - Discovery of ligands for ADP-ribosyltransferases via docking-based virtual screening. AB - The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. By using virtual screening, we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8. PMID- 22823911 TI - Engineering the interface characteristics of ultrananocrystalline diamond films grown on Au-coated Si substrates. AB - Enhanced electron field emission (EFE) properties have been observed for ultrananocrystalline diamond (UNCD) films grown on Au-coated Si (UNCD/Au-Si) substrates. The EFE properties of UNCD/Au-Si could be turned on at a low field of 8.9 V/MUm, attaining EFE current density of 4.5 mA/cm(2) at an applied field of 10.5 V/MUm, which is superior to that of UNCD films grown on Si (UNCD/Si) substrates with the same chemical vapor deposition process. Moreover, a significant difference in current-voltage curves from scanning tunneling spectroscopic measurements at the grain and the grain boundary has been observed. From the variation of normalized conductance (dI/dV)/(I/V) versus V, bandgap of UNCD/Au-Si is measured to be 2.8 eV at the grain and nearly metallic at the grain boundary. Current imaging tunneling spectroscopy measurements show that the grain boundaries have higher electron field emission capacity than the grains. The diffusion of Au into the interface layer that results in the induction of graphite and converts the metal-to-Si interface from Schottky to Ohmic contact is believed to be the authentic factors, resulting in marvelous EFE properties of UNCD/Au-Si. PMID- 22823912 TI - Enhancing organ pool by statins: is this the future? PMID- 22823913 TI - Portal hypertension in nodular regenerative hyperplasia: a mixed bag! PMID- 22823914 TI - Lactulose in the treatment of hepatic encephalopathy: new evidence for an old modality. PMID- 22823915 TI - Getting most out of SpyGlass cholangio-pancreatoscopy: how and when? PMID- 22823917 TI - Education and gastrointestinal imaging: case of early-stage squamous cell carcinoma of the anal canal diagnosed using narrow-band imaging system with magnification. PMID- 22823916 TI - Education and Imaging. Gastrointestinal: gastric incarceration in parastomal hernia. PMID- 22823918 TI - Education and Imaging. Gastrointestinal: small bowel lymphangioma diagnosed by single-balloon enteroscopy. PMID- 22823919 TI - Education and Imaging. Hepatobiliary and pancreatic: hepatocellular carcinoma supplied by portal blood after repeated transcatheter arterial chemoembolization. PMID- 22823920 TI - Education and Imaging. Hepatobiliary and pancreatic: falciform ligament necrosis. PMID- 22823923 TI - A policy analysis of the implementation of a Reproductive Health Vouchers Program in Kenya. AB - BACKGROUND: Innovative financing strategies such as those that integrate supply and demand elements like the output-based approach (OBA) have been implemented to reduce financial barriers to maternal health services. The Kenyan government with support from the German Development Bank (KfW) implemented an OBA voucher program to subsidize priority reproductive health services. Little evidence exists on the experience of implementing such programs in different settings. We describe the implementation process of the Kenyan OBA program and draw implications for scale up. METHODS: Policy analysis using document review and qualitative data from 10 in-depth interviews with facility in-charges and 18 with service providers from the contracted facilities, local administration, health and field managers in Kitui, Kiambu and Kisumu districts as well as Korogocho and Viwandani slums in Nairobi. RESULTS: The OBA implementation process was designed in phases providing an opportunity for learning and adapting the lessons to local settings; the design consisted of five components: a defined benefit package, contracting and quality assurance; marketing and distribution of vouchers and claims processing and reimbursement. Key implementation challenges included limited feedback to providers on the outcomes of quality assurance and accreditation and budgetary constraints that limited effective marketing leading to inadequate information to clients on the benefit package. Claims processing and reimbursement was sophisticated but required adherence to time consuming procedures and in some cases private providers complained of low reimbursement rates for services provided. CONCLUSIONS: OBA voucher schemes can be implemented successfully in similar settings. For effective scale up, strong partnership will be required between the public and private entities. The government's role is key and should include provision of adequate funding, stewardship and looking for opportunities to utilize existing platforms to scale up such strategies. PMID- 22823925 TI - Case report: Spontaneous remission of metastatic endometrial carcinoma through the Lim Lifestyle. AB - This case report records 2 discrete episodes of spontaneous remission of metastatic endometrial cancer (into peritoneum and omentum) in a 41-yr-old female following the "Lim Lifestyle" therapy alone. This lifestyle is an originally formulated holistic approach toward cancer consisting of nutritional, spiritual, and mental therapies. Cancer regression was measured symptomatologically, serologically, and radiologically (resolved ascites and reduced omental cake). PMID- 22823926 TI - A case-control study on cortical thickness in episodic cluster headache. AB - OBJECTIVE: This study aims at investigating cortical thickness in cluster headache patients as compared with a healthy control group. BACKGROUND: The pathobiology of cluster headache is not yet fully understood, although a dysfunction of the hypothalamus has been suggested to be causal. Previous studies in migraine and trigeminal neuropathic pain have demonstrated changes in cortical thickness using cortex segmentation techniques, but no data have been published on cluster headache. METHODS: We investigated 12 men with episodic cluster headache during a phase without acute headache as well as age and sex-matched healthy controls using high resolution T1-weighted magnetic resonance imaging acquired at 3T and performed a categorical whole-brain surface-based comparison of cortical thickness between groups. Furthermore, a correlation analysis of disease duration and cortical thickness was conducted. RESULTS: In comparison with control subjects, we found a reduction of cortical thickness in the angular gyrus and the precentral gyrus in cluster headache patients contralaterally to the headache side. These reductions did not correlate with disease duration. The cortical thickness of an area within the primary sensory cortex correlated with disease duration. CONCLUSIONS: This study demonstrates alterations in cortical thickness in cluster headache patients suggesting a potential role of cortical structures in cluster headache pathogenesis. However, it cannot be determined from this study whether the changes are cause or consequence of the disorder. The correlation of cortical thickness with disease duration in the somatosensory cortex may suggest disease-related plasticity in the somatosensory system. PMID- 22823927 TI - Weight status of adolescents in secondary schools in port Harcourt using Body Mass Index (BMI). AB - BACKGROUND: Adolescent weight status is a cumulative effect of health and nutritional problems. Adolescent weight problems often go unnoticed as weight assessment is not considered a priority in adolescents. OBJECTIVES: To determine the weight status of adolescents using BMI and to identify the contributing factors to adolescent weight problems. METHODS: In April 2010, 960 adolescents aged 10-19 years in secondary schools in Port Harcourt were selected for the study using a stratified multi-staged sampling method. Structured questionnaires were filled by the investigators while weight and height were measured. BMI was calculated using the formula weight/height2 (kg/m2). RESULTS: The prevalence of underweight, overweight, obesity and stunting were 6.4%, 6.3%, 1.8% and 5.4% respectively. Factors which were commoner in overweight adolescents were high socioeconomic class, higher maternal education, spending > 3 hours a day watching television and frequent ingestion of snacks. CONCLUSION: There is a need for periodic weight assessment of adolescents and health education to promote healthy eating habits and regular physical exercise as part of the School Health Programme. PMID- 22823929 TI - Women's knowledge of and attitude towards disability in rural Nepal. AB - PURPOSE: What is perceived to be a disability is both culturally specific and related to levels of development and modernity. This paper explores knowledge and attitudes towards people with disabilities among rural women in Nepal, one of the poorer countries in South Asia. METHOD: Four hundred and twelve married women of reproductive age (aged 15-49 years), from four villages in two different parts of Nepal, who had delivered a child within the last 24 months preceding the study, completed a standard questionnaire. RESULTS: The majority of the participants only considered physical conditions that limit function of an individual and are visible to naked eyes, such as missing a leg or arm, to be disability. Attitudes towards people with disability were generally positive, for example most women believed that disabled people should have equal rights and should be allowed to sit on committees or get married. Most respondents thought that disability could result from: (i) accidents; (ii) medical conditions; or (iii) genetic inheritance. Fewer women thought that disability was caused by fate or bad spirits. CONCLUSIONS: There is need to educate the general population on disability, especially the invisible disabilities. There is also a need for further research on disability and its social impact. IMPLICATIONS FOR REHABILITATION: * There is need to educate the general population on disability, especially the invisible disabilities and its rehabilitation. There is also a need for further research on disability and its social impact. PMID- 22823924 TI - Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data. AB - Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is coadministered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contribute half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database. A total of 38 multi P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450s, were identified. Seventeen (45%) multi P450 inhibitors were strong inhibitors of at least one P450, and an additional 12 (32%) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam, while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine, and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate studies with the same inhibitors. The results of this study suggest that inhibition of multiple clearance pathways in vivo is clinically relevant, and the risk of DDIs with object drugs may be best evaluated in studies using multi-P450 inhibitors. PMID- 22823928 TI - Mycobacterium kansasii pericarditis in a kidney transplant recipient: a case report and comprehensive review of the literature. AB - Mycobacterium kansasii is the second most common non-tuberculous mycobacteria in kidney transplant recipients (KTRs) and has been reported to cause disseminated infection in KTRs. We report the first case to our knowledge of M. kansasii pericarditis after kidney transplantation in a 54-year-old man. The patient was admitted with a 2-month history of intermittent fever and myalgia, treated with oral prednisolone and mycophenolate mofetil prior to admission. Chest computed tomography showed enlarged mediastinal lymph node and small amount of pericardial effusion. Mediastinoscopic biopsy of mediastinal lymph node revealed reactive hyperplasia, without evidence of granuloma, but acid-fast bacilli stain of pericardial fluid reported positive finding and pericardial fluid culture identified M. kansasii. The patient has been treated successfully with rifabutin based combination therapy. All available cases of M. kansasii infection in kidney transplant patients and M. kansasii pericarditis in human immunodeficiency virus infected patients are comprehensively reviewed. PMID- 22823930 TI - The quality of antenatal care in rural Tanzania: what is behind the number of visits? AB - BACKGROUND: Antenatal care (ANC) provides an important opportunity for pregnant women with a wide range of interventions and is considered as an important basic component of reproductive health care. METHODS: In 2008, severe maternal morbidity audit was established at Saint Francis Designated District Hospital (SFDDH), in Kilombero district in Tanzania, to ascertain substandard care and implement interventions. In addition, a cross-sectional descriptive study was carried out in 11 health facilities within the district to assess the quality of ANC and underlying factors in a broader view. RESULTS: Of 363 severe maternal morbidities audited, only 263 (72%) ANC cards were identified. Additionally, 121 cards (with 299 ANC visits) from 11 facilities were also reviewed. Hemoglobin and urine albumin were assessed in 22% - 37% and blood pressure in 69% - 87% of all visits. Fifty two (20%) severe maternal morbidities were attributed to substandard ANC, of these 39 had severe anemia and eclampsia combined. Substandard ANC was mainly attributed to shortage of staff, equipment and consumables. There was no significant relationship between assessment of essential parameters at first ANC visit and total number of visits made (Spearman correlation coefficient, r = 0.09; p = 0.13). Several interventions were implemented and others were proposed to those in control of the health system. CONCLUSIONS: This article reflects a worrisome state of substandard ANC in rural Tanzania resulting from inadequate human workforce and material resources for maternal health, and its adverse impacts on maternal wellbeing. These results suggest urgent response from those in control of the health system to invest more resources to avert the situation in order to enhance maternal health in this country. PMID- 22823931 TI - Barriers to and enablers for prehospital analgesia for pediatric patients. AB - OBJECTIVE: To identify and investigate the barriers and enablers perceived by paramedics regarding the administration of analgesia to pediatric emergency medical services (EMS) patients. METHODS: This was a qualitative study in which in-depth semistructured interviews of a purposively-sampled group of 16 paramedics were performed before achieving redundancy. The interviews were structured and the data were thematically analyzed. Emerging themes were categorized into four domains, and novel themes were identified and further explored. RESULTS: Thirteen of 16 paramedics reported success with analgesia in children at least once in their careers. Provider anxiety, unfamiliarity and discomfort with pediatrics, unfamiliarity with the protocol, insufficient didactic and clinical education, and concern for adverse effects from analgesic agents were perceived as barriers to pediatric pain management. The paramedics had differing beliefs about the importance of pain control, the role of parents in medical care for children, and the paramedic's ability to assess pediatric patients. Having a positive relationship with online medical control and using commercially available assistive guides were viewed as enablers for pediatric pain management. The response from paramedic supervisors and emergency department staff, unwanted attention from authority figures, perceived superiority of hospital care, difficulty obtaining intravenous access, and overall culture of stinginess in medication administration played important roles in an overall preference to defer pediatric analgesia. Some paramedics mentioned a specific experience or mentoring relationship with a more seasoned provider who taught them the importance of pain management. Paramedics reported various effects of transport distance on their decision to administer analgesia. CONCLUSIONS: We have identified a number of previously unrecognized barriers to and enablers for prehospital pediatric analgesia. The majority of these factors lead to an overall preference of paramedics to defer administration of analgesic agents. A number of educational and EMS system changes could be made to address these barriers and increase the frequency of appropriate pediatric prehospital analgesia. PMID- 22823932 TI - Mechanism of cellular uptake of genotoxic silica nanoparticles. AB - Mechanisms for cellular uptake of nanoparticles have important implications for nanoparticulate drug delivery and toxicity. We have explored the mechanism of uptake of amorphous silica nanoparticles of 14 nm diameter, which agglomerate in culture medium to hydrodynamic diameters around 500 nm. In HT29, HaCat and A549 cells, cytotoxicity was observed at nanoparticle concentrations >= 1 MUg/ml, but DNA damage was evident at 0.1 MUg/ml and above. Transmission electron microscopy (TEM) combined with energy-dispersive X-ray spectroscopy confirmed entry of the silica particles into A549 cells exposed to 10 MUg/ml of nanoparticles. The particles were observed in the cytoplasm but not within membrane bound vesicles or in the nucleus. TEM of cells exposed to nanoparticles at 4 degrees C for 30 minutes showed particles enter cells when activity is low, suggesting a passive mode of entry. Plasma lipid membrane models identified physical interactions between the membrane and the silica NPs. Quartz crystal microbalance experiments on tethered bilayer lipid membrane systems show that the nanoparticles strongly bind to lipid membranes, forming an adherent monolayer on the membrane. Leakage assays on large unilamellar vesicles (400 nm diameter) indicate that binding of the silica NPs transiently disrupts the vesicles which rapidly self-seal. We suggest that an adhesive interaction between silica nanoparticles and lipid membranes could cause passive cellular uptake of the particles. PMID- 22823933 TI - Modeling the signatures of hydrides in metalloenzymes: ENDOR analysis of a Di iron Fe(MU-NH)(MU-H)Fe core. AB - The application of 35 GHz pulsed EPR and ENDOR spectroscopies has established that the biomimetic model complex L(3)Fe(MU-NH)(MU-H)FeL(3) (L(3) = [PhB(CH(2)PPh(2))(3)](-)) complex, 3, is a novel S = (1)/(2) type-III mixed valence di-iron II/III species, in which the unpaired electron is shared equally between the two iron centers. (1,2)H and (14,15)N ENDOR measurements of the bridging imide are consistent with an allyl radical molecular orbital model for the two bridging ligands. Both the (MU-H) and the proton of the (MU-NH) of the crystallographically characterized 3 show the proposed signature of a 'bridging' hydride that is essentially equidistant between two 'anchor' metal ions: a rhombic dipolar interaction tensor, T ~ [T, -T, 0]. The point-dipole model for describing the anisotropic interaction of a bridging H as the sum of the point dipole couplings to the 'anchor' metal ions reproduces this signature with high accuracy, as well as the axial tensor of a terminal hydride, T ~ [-T, -T, 2T], thus validating both the model and the signatures. This validation in turn lends strong support to the assignment, based on such a point-dipole analysis, that the molybdenum-iron cofactor of nitrogenase contains two [Fe-H(-)-Fe] bridging hydride fragments in the catalytic intermediate that has accumulated four reducing equivalents (E(4)). Analysis further reveals a complementary similarity between the isotropic hyperfine couplings for the bridging hydrides in 3 and E(4). This study provides a foundation for spectroscopic study of hydrides in a variety of reducing metalloenzymes in addition to nitrogenase. PMID- 22823934 TI - A microarray analysis of gnotobiotic mice indicating that microbial exposure during the neonatal period plays an essential role in immune system development. AB - BACKGROUND: Epidemiological studies have suggested that the encounter with commensal microorganisms during the neonatal period is essential for normal development of the host immune system. Basic research involving gnotobiotic mice has demonstrated that colonization at the age of 5 weeks is too late to reconstitute normal immune function. In this study, we examined the transcriptome profiles of the large intestine (LI), small intestine (SI), liver (LIV), and spleen (SPL) of 3 bacterial colonization models-specific pathogen-free mice (SPF), ex-germ-free mice with bacterial reconstitution at the time of delivery (0WexGF), and ex-germ-free mice with bacterial reconstitution at 5 weeks of age (5WexGF)-and compared them with those of germ-free (GF) mice. RESULTS: Hundreds of genes were affected in all tissues in each of the colonized models; however, a gene set enrichment analysis method, MetaGene Profiler (MGP), demonstrated that the specific changes of Gene Ontology (GO) categories occurred predominantly in 0WexGF LI, SPF SI, and 5WexGF SPL, respectively. MGP analysis on signal pathways revealed prominent changes in toll-like receptor (TLR)- and type 1 interferon (IFN)-signaling in LI of 0WexGF and SPF mice, but not 5WexGF mice, while 5WexGF mice showed specific changes in chemokine signaling. RT-PCR analysis of TLR related genes showed that the expression of interferon regulatory factor 3 (Irf3), a crucial rate-limiting transcription factor in the induction of type 1 IFN, prominently decreased in 0WexGF and SPF mice but not in 5WexGF and GF mice. CONCLUSION: The present study provides important new information regarding the molecular mechanisms of the so-called "hygiene hypothesis". PMID- 22823935 TI - Comparison of once-daily versus twice-weekly terbinafine administration for the treatment of canine Malassezia dermatitis - a pilot study. AB - BACKGROUND: Terbinafine, an allylamine antifungal, is used in pulsatile dose regimens for superficial mycoses in human medicine. OBJECTIVES: To compare the clinical efficacy of twice-weekly versus once-daily terbinafine administration to determine whether preliminary proof-of-concept evidence exists for pulsatile administration of terbinafine in the treatment of canine Malassezia dermatitis and to determine whether twice-weekly treatment results in fewer clinical and owner-perceived adverse events. ANIMALS: Twenty client-owned dogs with Malassezia dermatitis. METHODS: In this randomized, single-blinded clinical trial, dogs were randomly assigned to receive terbinafine (30 mg/kg) either once daily for 21 days (n = 10) or once daily on two consecutive days per week for six doses (n = 10). On day 0 and day 21, a mean yeast count was calculated from eight anatomical locations via adhesive tape-strip cytology, clinical lesion scores were assigned to the same locations, and owners assessed pruritus using a visual analog scale. RESULTS: There was no significant difference between treatment groups with respect to the reduction in mean yeast count (P = 0.343) and clinical lesion scores (P = 0.887). Pruritus measured by visual analog scale was significantly decreased in the twice-weekly treatment group compared with the daily treatment group (P = 0.047). Seven of 20 dogs had a clinically measurable or owner-reported adverse event during treatment that included gastrointestinal disturbances, excessive panting and elevated hepatic enzymes, with no significant difference noted between treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: This pilot study indicates that twice-weekly terbinafine administration may be an effective alternative treatment for canine Malassezia dermatitis and merits further investigation. PMID- 22823936 TI - Asymmetric formal carbonyl-ene reactions of formaldehyde tert-butyl hydrazone with alpha-keto esters: dual activation by bis-urea catalysts. AB - The dual activation of alpha-keto esters and formaldehyde tert-butyl hydrazone by BINAM-derived bis-ureas is the key to achieve high reactivity and excellent enantioselectivities in nucleophilic addition (formal carbonyl-ene reaction) to functionalized tertiary carbinols. Ensuing high-yielding diazene-to-aldehyde tranformations and subsequent derivatizations provides a direct entry to a variety of densely functionalized products. PMID- 22823937 TI - Production and characterisation of monoclonal antibodies for the quantification of potentially allergenic xylanase from Aspergillus niger. AB - Xylanase from Aspergillus niger (ANX) is widely used in bakeries as a processing aid since it stabilises and improves dough quality. An association between allergic symptoms among bakery workers and sensitisation to ANX has been reported, indicating that this enzyme is an occupational allergen. The presence of ANX in dough improvers and semi-finished goods is often hidden due to incomplete and unclear labelling. The quantification of microbial enzymes in these products is necessary and the determination of the actual concentration of ANX in workplaces is therefore essential to assess the occupational risk. To this purpose we have developed and characterised monoclonal antibodies to ANX. The monoclonal antibodies do not show any cross-reaction with other commonly used microbial enzymes, and they allow the detection of ANX in complex mixtures by ELISA inhibition assays down to the concentration limit of approximately 10 ug kg(-1). These mAbs are a valuable tool to detect and quantify ANX and to investigate its allergenic potential in the workplace. PMID- 22823940 TI - Oxalate nephropathy induced by octreotide treatment for acromegaly: a case report. AB - INTRODUCTION: Oxalate nephropathy has various etiologies and remains a rare cause of renal failure. To the best of our knowledge, we report the first case of oxalate nephropathy following octreotide therapy. CASE PRESENTATION: We report the case of a 78-year-old Caucasian man taking chronic octreotide treatment for acromegaly who presented with acute oxalate nephropathy after antibiotic therapy. The diagnosis was confirmed by urinary analysis and a kidney biopsy. The recovery of renal function was favorable after hydration and withdrawal of octreotide therapy. CONCLUSIONS: Oxalate nephropathy should be suspected in patients at risk who present with acute kidney injury after prolonged antibiotic treatment. This diagnosis should be distinguished from immuno-allergic interstitial nephritis and requires specific care. The evolution of this condition may be favorable if the pathology is identified correctly. Octreotide therapy should be considered a risk factor for enteric oxaluria. PMID- 22823938 TI - A survey of putative secreted and transmembrane proteins encoded in the C. elegans genome. AB - BACKGROUND: Almost half of the Caenorhabditis elegans genome encodes proteins with either a signal peptide or a transmembrane domain. Therefore a substantial fraction of the proteins are localized to membranes, reside in the secretory pathway or are secreted. While these proteins are of interest to a variety of different researchers ranging from developmental biologists to immunologists, most of secreted proteins have not been functionally characterized so far. RESULTS: We grouped proteins containing a signal peptide or a transmembrane domain using various criteria including evolutionary origin, common domain organization and functional categories. We found that putative secreted proteins are enriched for small proteins and nematode-specific proteins. Many secreted proteins are predominantly expressed in specific life stages or in one of the two sexes suggesting stage- or sex-specific functions. More than a third of the putative secreted proteins are upregulated upon exposure to pathogens, indicating that a substantial fraction may have a role in immune response. Slightly more than half of the transmembrane proteins can be grouped into broad functional categories based on sequence similarity to proteins with known function. By far the largest groups are channels and transporters, various classes of enzymes and putative receptors with signaling function. CONCLUSION: Our analysis provides an overview of all putative secreted and transmembrane proteins in C. elegans. This can serve as a basis for selecting groups of proteins for large-scale functional analysis using reverse genetic approaches. PMID- 22823939 TI - Evaluation of developmental changes in bovine in vitro produced embryos following exposure to bovine Herpesvirus type 5. AB - BACKGROUND: Bovine Herpesvirus type-5 (BoHV-5) is a neurovirulent alpha Herpesvirus which is potentially pathogenic for cows and suspected to be associated with reproductive disorders. Interestingly, natural transmission of BoHV-5 by contaminated semen was recently described in Australia. Additionally, BoHV-5 was also isolated from the semen of a healthy bull in the same country and incriminated in a natural outbreak of reproductive disease after artificial insemination. In contrast with BoHV-1, experimental exposure of in vitro produced bovine embryos to BoHV-5 does not affect embryo viability and seems to inhibit some pathways of apoptosis. However, the mechanisms responsible for these phenomena are poorly understood. In this study, we examined mitochondrial activity, antioxidant protection, stress response and developmental rates of in vitro produced bovine embryos that were exposed and unexposed to BoHV-5. METHODS: For this purpose, bovine embryos produced in vitro were assayed for cell markers after experimental infection of oocytes (n = 30; five repetitions), in vitro fertilization and development. The indirect immunofluorescence was employed to measure the expression of superoxide dismutase 1 (SOD1), anti-oxidant like protein 1 (AOP-1), heat shock protein 70.1 (Hsp 70.1) and also viral antigens in embryos derived from BoHV-5 exposed and unexposed oocytes. The determination of gene transcripts of mitochondrial activity (SOD1), antioxidant protection (AOP-1) and stress response (Hsp70.1) were evaluated using the reverse transcriptase polymerase chain reaction (RT-PCR). MitoTracker Green FM, JC-1 and Hoechst 33342 staining were used to evaluate mitochondrial distribution, segregation patterns and embryos morphology. The intensity of labeling was graded semi-quantitatively and embryos considered intensively marked were used for statistical analysis. RESULTS: The quality of the produced embryos was not affected by exposure to BoHV 5. Of the 357 collected oocytes, 313 (+/- 6.5; 87.7%) were cleaved and 195 (+/- 3.2; 54.6%) blastocysts were produced without virus exposure. After exposure, 388 oocytes were cleaved into 328 (+/- 8.9, 84.5%), and these embryos produced 193 (+/- 3.2, 49.7%) blastocysts. Viral DNA corresponding to the US9 gene was only detected in embryos at day 7 after in vitro culture, and confirmed by indirect immunofluorescence assay (IFA). These results revealed significant differences (p < 0.05) between exposed and unexposed oocytes fertilized, as MitoTracker Green FM staining Fluorescence intensity of Jc-1 staining was significantly higher (p < 0.005) among exposed embryos (143 +/- 8.2). There was no significant difference between the ratios of Hoechst 33342-stained nuclei and total cells in good quality blastocysts (in both the exposed and unexposed groups). Using IFA and reverse transcriptase polymerase chain reaction (RT-PCR) for the set of target transcripts (SOD1, AOP-1 and Hsp 70.1), there were differences in the mRNA and respective proteins between the control and exposed embryos. Only the exposed embryos produced anti-oxidant protein-like 1 (AOP-1). However, neither the control nor the exposed embryos produced the heat shock protein Hsp 70.1. Interestingly, both the control and the exposed embryos produced superoxide dismutase (SOD1), revealing intense mitochondrial activity. CONCLUSION: This is the first demonstration of SOD1 and AOP-1 production in bovine embryos exposed to BoHV-5. Intense mitochondrial activity was also observed during infection, and this occurred without interfering with the quality or number of produced embryos. These findings further our understanding on the ability of alpha-Herpesviruses to prevent apoptosis by modulating mitochondrial pathways. PMID- 22823941 TI - Attitudes towards mental illness in Malawi: a cross-sectional survey. AB - BACKGROUND: Stigma and discrimination associated with mental illness are strongly linked to suffering, disability and poverty. In order to protect the rights of those with mental disorders and to sensitively develop services, it is vital to gain a more accurate understanding of the frequency and nature of stigma against people with mental illness. Little research about this issue has been conducted in Sub- Saharan Africa. Our study aimed to describe levels of stigma in Malawi. METHODS: A cross-sectional survey of patients and carers attending mental health and non-mental health related clinics in a general hospital in Blantyre, Malawi. Participants were interviewed using an adapted version of the questionnaire developed for the "World Psychiatric Association Program to Reduce Stigma and Discrimination Because of Schizophrenia". RESULTS: 210 participants participated in our study. Most attributed mental disorder to alcohol and illicit drug abuse (95.7%). This was closely followed by brain disease (92.8%), spirit possession (82.8%) and psychological trauma (76.1%). There were some associations found between demographic variables and single question responses, however no consistent trends were observed in stigmatising beliefs. These results should be interpreted with caution and in the context of existing research. Contrary to the international literature, having direct personal experience of mental illness seemed to have no positive effect on stigmatising beliefs in our sample. CONCLUSIONS: Our study contributes to an emerging picture that individuals in Sub Saharan Africa most commonly attribute mental illness to alcohol/ illicit drug use and spirit possession. Our work adds weight to the argument that stigma towards mental illness is an important global health and human rights issue. PMID- 22823943 TI - Epidemiology of acute otitis media among young children: a multiple database study in Taiwan. AB - BACKGROUND/PURPOSE: Acute otitis media (AOM) is a common complication of upper respiratory tract infection (URTI) among children. The purpose of this study was to evaluate the epidemiology of AOM among young children in Taiwan, including the age incidence and seasonality by combining multiple databases. METHODS: Two country-based questionnaire survey studies had been conducted to evaluate the experience of otitis media (OM) among young children: one in 2007 and the other between 2005 and 2010. The number of OM cases (5% of population younger than 7 years) in 2005 and annual visiting rates for URTI from 2005 to 2010 obtained from the National Health Insurance Research Database of Taiwan were collected and comprised the third database. The fourth database comprised ambulatory visits of children with OM to a medical center in central Taiwan between 2005 and 2010. RESULTS: Data from a total of 1099 questionnaires were entered into Database I in 2007, and data from 9705 questionnaires between 2005 and 2010 comprised Database II. There were 86,702 children (younger than 7 years, representing 5% of the whole population for this age group) retrieved from Database III in 2007, and 5,904 cases of OM in children between 2005 and 2010 in a hospital. In Database I, 7.46% children experienced at least one episode of AOM compared with 9.21% in Database II for children aged 5 years and younger. In Database III, 13.2% children younger than 7 years had AOM in 2005. The peak season of AOM among children was from March to May (Databases III and IV). CONCLUSION: AOM was thought to be a very common disease among children; however, this comparative analysis showed that the overall prevalence of AOM among children younger than 5 years was only 20%, much lower than in other countries. AOM was more prevalent during the spring season, and still was similarly common after age 2 years. PMID- 22823942 TI - Sign language aphasia from a neurodegenerative disease. AB - While Alois Alzheimer recognized the effects of the disease he described on speech and language in his original description of the disease in 1907, the effects of Alzheimer's disease (AD) on language in deaf signers has not previously been reported. We evaluated a 55-year-old right-handed congenitally deaf woman with a 2-year history of progressive memory loss and a deterioration of her ability to communicate in American Sign Language, which she learned at the age of eight. Examination revealed that she had impaired episodic memory as well as marked impairments in the production and comprehension of fingerspelling and grammatically complex sentences. She also had signs of anomia as well as an ideomotor apraxia and visual-spatial dysfunction. This report illustrates the challenges in evaluation of a patient for the presence of degenerative dementia when the person is deaf from birth, uses sign language, and has a late age of primary language acquisition. Although our patient could neither speak nor hear, in many respects her cognitive disorders mirror those of patients with AD who had normally learned to speak. PMID- 22823944 TI - Effects of microbubbles on transcranial Doppler ultrasound-assisted intracranial urokinase thrombolysis. AB - INTRODUCTION: To evaluate the efficacy of microbubbles in transcranial Doppler ultrasound (TCD)-assisted urokinase thrombolysis. MATERIALS AND METHODS: Male New Zealand white rabbits (N=32) were randomly divided into 2 groups, a urokinase group and a combined urokinase plus microbubble group. The middle cerebral artery (MCA) was occluded by injecting autologous blood clots through the carotid artery. In the urokinase plus microbubble group, sulfur hexafluoride (SonoVue) microbubbles were injected intravenously immediately after intravenous injection of urokinase. The 2 groups were monitored by TCD from before until 2h after thrombolysis, and the hemodynamic changes and infarct size were recorded. RESULTS: The urokinase alone group had 1 case of complete recanalization and 4 cases of partial recanalization (recanalization rate, 31.3%). The urokinase plus microbubble group had 3 cases of complete recanalization and 6 cases of partial recanalization (recanalization rate, 56.3%). The average size of the infarction foci was 13.9% in the urokinase group and 9.1% in the urokinase plus microbubble group (P=0.025). Pathological examination revealed no cerebral hemorrhage in either group. CONCLUSIONS: The addition of microbubbles enhanced the effects of transcranial Doppler ultrasound-assisted urokinase thrombolysis. PMID- 22823945 TI - Trends in malaria cases, hospital admissions and deaths following scale-up of anti-malarial interventions, 2000-2010, Rwanda. AB - BACKGROUND: To control malaria, the Rwandan government and its partners distributed insecticide-treated nets (ITN) and made artemisinin-based combination therapy (ACT) widely available from 2005 onwards. The impact of these interventions on malaria cases, admissions and deaths was assessed using data from district hospitals and household surveys. METHODS: District records of ITN and ACT distribution were reviewed. Malaria and non-malaria indictors in 30 district hospitals were ascertained from surveillance records. Trends in cases, admissions and deaths for 2000 to 2010 were assessed by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period, 2000-2005. Changes were estimated by comparing trends in post intervention (2006-2010) with that of pre-intervention (2000-2005) period. All cause deaths in children under-five in household surveys of 2005 and 2010 were also reviewed to corroborate with the trends of deaths observed in hospitals. RESULTS: The proportion of the population potentially protected by ITN increased from nearly zero in 2005 to 38% in 2006, and 76% in 2010; no major health facility stock-outs of ACT were recorded following their introduction in 2006. In district hospitals, after falling during 2006-2008, confirmed malaria cases increased in 2009 coinciding with decreased potential ITN coverage and declined again in 2010 following an ITN distribution campaign. For all age groups, from the pre-intervention period, microscopically confirmed cases declined by 72%, (95% Confidence Interval [CI], 12-91%) in 2010, slide positivity rate declined 58%, (CI, 47%-68%), malaria inpatient cases declined 76% (CI, 49%-88%); and malaria deaths declined 47% (CI, 47%-81%). In children below five years of age, malaria inpatients decreased 82% (CI, 61%-92%) and malaria hospital deaths decreased 77% (CI, 40%-91%). Concurrently, outpatient cases, admissions and deaths due to non-malaria diseases in all age groups either increased or remained unchanged. Rainfall and temperature remained favourable for malaria transmission. The annual all-cause mortality in children under-five in household surveys declined from 152 per 1,000 live births during 2001-2005, to 76 per 1,000 live births in 2006-2010 (55% decline). The five-year cumulative number of all-cause deaths in hospital declined 28% (8,051 to 5,801) during the same period. CONCLUSIONS: A greater than 50% decline in confirmed malaria cases, admissions and deaths at district hospitals in Rwanda since 2005 followed a marked increase in ITN coverage and use of ACT. The decline occurred among both children under five and in those five years and above, while hospital utilization increased and suitable conditions for malaria transmission persisted. Declines in malaria indicators in children under 5 years were more striking than in the older age groups. The resurgence in cases associated with decreased ITN coverage in 2009 highlights the need for sustained high levels of anti-malarial interventions in Rwanda and other malaria endemic countries. PMID- 22823946 TI - Field airway management of a construction worker with an impaling rebar injury to the neck and brain. AB - This article discusses a case of airway management by air ambulance emergency medical services (EMS) providers in a 22-year-old man impaled through the neck into the brain with 0.5-inch rebar. Penetrating neck injuries (PNIs) with impalement are extraordinarily rare. It is important for EMS providers and emergency medicine physicians to have an understanding of the initial management of an impaled patient with PNI, including having an organized approach to establishing a definitive airway and recognizing the airway complications that PNI may cause. This article discusses out-of-hospital management of impaled patients. PMID- 22823948 TI - Molecular characterization of the horse isolate of Echinococcus granulosus in Turkey. AB - Cystic echinococcosis is one of the most important helminthozoonoses, affecting various species of intermediate hosts and humans. In this report, we present Echinococcus granulosus infection in a horse and its molecular characterization. Polymerase chain reaction (PCR) amplification of mitochondrial 12S rRNA (mt-12S rRNA) and partial sequencing of mitochondrial cytochrome c oxidase subunit 1 (mt CO1) genes were performed. According to the mt-12S rRNA-PCR result, the horse isolate was grouped with E. granulosus sensu stricto (G1-G3) and the partial mt CO1 sequence corresponded to the G1 strain. This is the first study of the molecular characterization of the horse isolate of E. granulosus in Turkey. PMID- 22823947 TI - Clostridium thermocellum ATCC27405 transcriptomic, metabolomic and proteomic profiles after ethanol stress. AB - BACKGROUND: Clostridium thermocellum is a candidate consolidated bioprocessing biocatalyst, which is a microorganism that expresses enzymes for both cellulose hydrolysis and its fermentation to produce fuels such as lignocellulosic ethanol. However, C. thermocellum is relatively sensitive to ethanol compared to ethanologenic microorganisms such as yeast and Zymomonas mobilis that are used in industrial fermentations but do not possess native enzymes for industrial cellulose hydrolysis. RESULTS: In this study, C. thermocellum was grown to mid exponential phase and then treated with ethanol to a final concentration of 3.9 g/L to investigate its physiological and regulatory responses to ethanol stress. Samples were taken pre-shock and 2, 12, 30, 60, 120, and 240 min post-shock, and from untreated control fermentations for systems biology analyses. Cell growth was arrested by ethanol supplementation with intracellular accumulation of carbon sources such as cellobiose, and sugar phosphates, including fructose-6-phosphate and glucose-6-phosphate. The largest response of C. thermocellum to ethanol shock treatment was in genes and proteins related to nitrogen uptake and metabolism, which is likely important for redirecting the cells physiology to overcome inhibition and allow growth to resume. CONCLUSION: This study suggests possible avenues for metabolic engineering and provides comprehensive, integrated systems biology datasets that will be useful for future metabolic modeling and strain development endeavors. PMID- 22823950 TI - Issues to be considered when studying cancer in vitro. AB - Various cancer treatment approaches have shown promising results when tested preclinically. The results of clinical trials, however, are often disappointing. While searching for the reasons responsible for their failures, the relevance of experimental and preclinical models has to be taken into account. Possible factors that should be considered, including cell modifications during in vitro cultivation, lack of both the relevant interactions and the structural context in vitro have been summarized in the present review. PMID- 22823949 TI - Prevalence of overweight, obesity and thinness in 9-10 year old children in Mauritius. AB - OBJECTIVE: To document the prevalence of overweight, obesity and thinness in 9-10 year old children in Mauritius. METHODS: 412 boys and 429 girls aged 9-10 years from 23 primary schools were selected using stratified cluster random sampling. All data was cross-sectional and collected via anthropometry and self administered questionnaire. Outcome measures were BMI (kg/m2), prevalence of overweight, obesity (International Obesity Task Force definitions) and thinness (low BMI for age). Linear and logistic regression analyses, accounting for clustering at the school level, were used to assess associations between gender, ethnicity, school location, and school's academic performance (average) to each outcome measure. RESULTS: The distribution of BMI was marginally skewed with a more pronounced positive tail in the girls. Median BMI was 15.6 kg/m2 in boys and 15.4 kg/m2 in girls, respectively. In boys, prevalence of overweight was 15.8% (95% CI: 12.6, 19.6), prevalence of obesity 4.9% (95% CI: 3.2, 7.4) and prevalence of thinness 12.4% (95% CI: 9.5, 15.9). Among girls, 18.9% (95% CI: 15.5, 22.9) were overweight, 5.1% (95% CI: 3.4, 7.7) were obese and 13.1% (95% CI: 10.2, 16.6) were thin. Urban children had a slightly higher mean BMI than rural children (0.5 kg/m2, 95% CI: 0.01, 1.00) and were nearly twice as likely to be obese (6.7% vs. 4.0%; adjusted odds ratio 1.6; 95% CI: 0.9, 3.5). Creole children were less likely to be classified as thin compared to Indian children (adjusted odds ratio 0.3, 95% CI: 0.2, 0.6). CONCLUSION: Mauritius is currently in the midst of nutritional transition with both a high prevalence of overweight and thinness in children aged 9-10 years. The coexistence of children representing opposite sides of the energy balance equation presents a unique challenge for policy and interventions. Further exploration is needed to understand the specific causes of the double burden of malnutrition and to make appropriate policy recommendations. PMID- 22823951 TI - Cancer-associated genodermatoses: skin neoplasms as clues to hereditary tumor syndromes. AB - Characteristic skin neoplasms are associated with a large number of hereditary tumor syndromes and their knowledge and early detection may facilitate the diagnosis of the underlying malignancies. We will review the clinical and dermatopathological aspects of cutaneous and visceral lesions and the recent progresses in understanding the etiology, pathogenesis and therapies of selected tumor syndromes. The skin neoplasms we chose to consider are multiple neurofibromas in neurofibromatosis, cylindromas and trichoepitheliomas in Broke Spiegler syndrome, sebaceous tumors and keratoacanthomas in Muir-Torre syndrome, Gardner fibromas in Gardner syndrome, multiple basal cell carcinomas in nevoid basal cell carcinoma (Gorlin) syndrome, multiple tricholemmomas in Cowden syndrome, multiple fibrofolliculomas in Birt-Hogg-Dube syndrome and multiple leiomyomas in hereditary leiomyomatosis and renal cell cancer. Hereditary cancers have distinct biological and clinical features as compared to their sporadic counterparts; for this reason, we are now able to experiment new treatment approaches involving not only tumor detection and prevention, but also tailored therapeutic strategies focusing on the peculiar druggable molecular targets. PMID- 22823953 TI - WIP: WASP-interacting proteins at invadopodia and podosomes. AB - Regulated cell invasion resulting from migratory and matrix-degrading events is an essential step in physiological processes such as the inflammatory response and tissue repair. Cell invasion is also thought to be a critical parameter in pathological conditions such as cancer metastasis. The migration of normal and cancer cells is largely driven by the actin cytoskeleton, which controls cell shape, adhesion and contractility. Podosomes and invadopodia are actin-rich protrusions that drive invasion in normal and cancer cells. These structures protrude from the basal region of the cell facing the extracellular matrix, where they adhere to and degrade the matrix, thus facilitating invasive migration. WASP (Wiskott-Aldrich syndrome protein) and WIP (WASP-interacting protein) localise to the actin rich core of podosomes and play a critical role in their formation. More recently, studies performed on microarray data sets from cancer patients of several tumour categories show a strong correlation between reduced WIP expression and improved prognosis. In this article, we identify endogenous WIP at the distal tips of cancer cell invasive protrusions and we summarise recent advances in the study of the roles of WIP- and WASP-protein families during migration and invasion of normal and cancer cells related to podosome and invadopodium generation. PMID- 22823954 TI - Electronic restoration of vision in those with photoreceptor degenerations. AB - Complete loss of vision is one of the most feared sequelae of retinal disease. Currently, there are few if any treatment options available to patients that may slow or prevent blindness in diseases caused by photoreceptor loss, such as retinitis pigmentosa and age-related macular degeneration. Electronic restoration of vision has emerged over recent years as a safe and viable option for those who have lost substantial numbers of photoreceptors and who are severely vision impaired. Indeed, there has been a dramatic increase in our understanding of what is required to restore vision using an electronic retinal prosthesis. Recent reports show that for some patients, restoration of vision to the point of reading large letters is possible. In this review, we examine the types of implants currently under investigation and the results these devices have achieved clinically. We then consider a range of engineering and biological factors that may need to be considered to improve the visual performance of newer generation devices. With added research, it is hoped that the level of vision achieved with newer generation devices will steadily improve, resulting in enhanced quality of life for those with severe vision impairment. PMID- 22823955 TI - Work-ability assessment in young adults with disabilities applying for disability benefits. AB - PURPOSE: To investigate the impact of diagnosis, co-morbidity, secondary conditions (e.g. learning problems, subclinical mental and somatic complaints, addictions, and socio-emotional and behavioral problems) and problems in social context on work ability as assessed by Insurance Physicians (IPs) in young adults applying for a disability benefit. METHOD: IPs of the Social Security Institute assessed young adults with disabilities (aged 15-27) applying for a disability benefit (n = 1755). Data were analyzed with multilevel ordinal regression techniques. RESULTS: Primary diagnosis, co-morbidity and subclinical mental complaints were associated with IP-assessed work ability. Persons with mental health conditions as primary diagnosis were less likely to reach a higher work ability than persons with somatic diseases. Young adults with two or more co morbid conditions and those with psychiatric or developmental co-morbidity were less likely to reach a higher work ability level than persons without co morbidity. Young adults with subclinical mental complaints were half as likely to reach a higher IP-assessed work ability than young adults without this condition. CONCLUSION: Primary diagnosis, type and number of co-morbid conditions and subclinical mental complaints are associated with IP-assessed work ability. Work ability assessments among adolescents with disabilities applying for disability benefits still focus mainly on medical factors. PMID- 22823956 TI - Immigration and changes in the epidemiology of hemoglobin disorders in Italy : an emerging public health burden. AB - BACKGROUND: In the last years Italy is confronting with massive migratory movements from developing countries where hemoglobinopathies are widespread. This is causing a large diffusion and a changing spectrum in the epidemiology of hemoglobin disorders in Italy. METHODS: Investigations recently published in Italy on hemoglobinopathies among immigrants were revised in order to appreciate the impact of immigration from developing countries on epidemiology of these pathologies and to outline adequate guidelines of prevention. RESULTS: Although in Italy there is a limited number of investigations regarding the relation between immigration and hemoglobin disorders, published data show that in our Nation there is a changing and increasing spectrum of hemoglobinopathies linked to immigration. CONCLUSIONS: Prospective and retrospective actions of public healthy preventive policy are requested, based upon information (health educational programs for immigrants and caregivers), screenings among immigrants (school screening, pre-marital, preconception and early pregnancy screening, newborn screening), counseling for foreign at-risk couples and healthy carriers. PMID- 22823952 TI - Spatiotemporal regulation of Src and its substrates at invadosomes. AB - In the past decade, substantial progress has been made in understanding how Src family kinases regulate the formation and function of invadosomes. Invadosomes are organized actin-rich structures that contain an F-actin core surrounded by an adhesive ring and mediate invasive migration. Src kinases orchestrate, either directly or indirectly, each phase of the invadosome life cycle including invadosome assembly, maturation and matrix degradation and disassembly. Complex arrays of Src effector proteins are involved at different stages of invadosome maturation and their spatiotemporal activity must be tightly regulated to achieve effective invasive migration. In this review, we highlight some recent progress and the challenges of understanding how Src is regulated temporally and spatially to orchestrate the dynamics of invadosomes and mediate cell invasion. PMID- 22823958 TI - Parvalbumin in fish skin-derived gelatin: is there a risk for fish allergic consumers? AB - The major allergen parvalbumin was purified from cod muscle tissues, and polyclonal antibodies were raised towards it. The antibodies were tested for specificity and an enzyme-linked immunosorbent assay (ELISA) was developed using these antibodies. The ELISA was applied to measure parvalbumin in cod skin, the starting material for fish gelatin made from deep sea, wild fish. The ELISA was sufficiently sensitive (LLOQ = 0.8 ng ml(-1) in extracts, corresponding to 0.02 ug of parvalbumin per g of tissue), and did not cross-react with common food constituents. Fish gelatin, wine and beer, matrices for the potential use of this ELISA, did not cause disturbance of the assay performance. The data show that the parvalbumin content in cod muscle tissue is 6.25 mg g(-1), while the skins contained considerably less, 0.4 mg g(-1). Washing of the skins, a common industrial procedure during the manufacturing of fish gelatin, reduced the level of parvalbumin about 1000-fold to 0.5 ug g(-1), or 0.5 ppm. From 95 commercial lots of fish gelatin it is shown that 73 are below 0.02 ug g(-1) parvalbumin. From the other 22 lots, the one with the highest concentration contained 0.15 ug g(-1) of parvalbumin. These levels are generally assumed to be safe for fish allergic individuals. PMID- 22823957 TI - Wnt/beta-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia. AB - BACKGROUND: The advanced phases of chronic myeloid leukemia (CML) are known to be more resistant to therapy. This resistance has been associated with the overexpression of ABCB1, which gives rise to the multidrug resistance (MDR) phenomenon. MDR is characterized by resistance to nonrelated drugs, and P glycoprotein (encoded by ABCB1) has been implicated as the major cause of its emergence. Wnt signaling has been demonstrated to be important in several aspects of CML. Recently, Wnt signaling was linked to ABCB1 regulation through its canonical pathway, which is mediated by beta-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/beta-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several beta-catenin binding sites. beta-catenin is the mediator of canonical Wnt signaling, which is important for CML progression. METHODS: In this work we used the K562 cell line and its derived MDR-resistant cell line Lucena (K562/VCR) as CML study models. Real time PCR (RT-qPCR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), flow cytometry (FACS), western blot, immunofluorescence, RNA knockdown (siRNA) and Luciferase reporter approaches were used. RESULTS: beta-catenin was present in the protein complex on the basal promoter of ABCB1 in both cell lines in vitro, but its binding was more pronounced in the resistant cell line in vivo. Lucena cells also exhibited higher beta-catenin levels compared to its parental cell line. Wnt1 and beta-catenin depletion and overexpression of nuclear beta-catenin, together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling. CONCLUSIONS: These results suggest, for the first time, that the Wnt/beta-catenin pathway regulates ABCB1 in CML. PMID- 22823959 TI - Isothermal close space sublimation for II-VI semiconductor filling of porous matrices. AB - Isothermal close space sublimation, a simple and low-cost physical vapour transport technique, was used to infiltrate ZnTe and CdSe semiconductors in porous silicon. The structure of the embedded materials was determined by X-ray diffraction analysis while Rutherford backscattering spectra allowed determining the composition profiles of the samples. In both cases, a constant composition of the II-VI semiconductors throughout the porous layer down to the substrate was found. Resonance Raman scattering of the ZnTe samples indicates that this semiconductor grows in nanostructured form inside the pores. Results presented in this paper suggest that isothermal close space sublimation is a promising technique for the conformal growth of II-VI semiconductors in porous silicon. PMID- 22823960 TI - Where is the evidence for emergency planning: a scoping review. AB - BACKGROUND: Recent terrorist attacks and natural disasters have led to an increased awareness of the importance of emergency planning. However, the extent to which emergency planners can access or use evidence remains unclear. The aim of this study was to identify, analyse and assess the location, source and quality of emergency planning publications in the academic and UK grey literature. METHODS: We conducted a scoping review, using as data sources for academic literature Embase, Medline, Medline in Process, Psychinfo, Biosis, Science Citation Index, Cinahl, Cochrane library and Clinicaltrials.gov. For grey literature identification we used databases at the Health Protection Agency, NHS Evidence, British Association of Immediate Care Schemes, Emergency Planning College and the Health and Safety Executive, and the websites of UK Department of Health Emergency Planning Division and UK Resilience.Aggregative synthesis was used to analyse papers and documents against a framework based on a modified FEMA Emergency Planning cycle. RESULTS: Of 2736 titles identified from the academic literature, 1603 were relevant. 45% were from North America, 27% were commentaries or editorials and 22% were event reports.Of 192 documents from the grey literature, 97 were relevant. 76% of these were event reports.The majority of documents addressed emergency planning and response. Very few documents related to hazard analysis, mitigation or capability assessment. CONCLUSIONS: Although a large body of literature exists, its validity and generalisability is unclear There is little evidence that this potential evidence base has been exploited through synthesis to inform policy and practice. The type and structure of evidence that would be of most value of emergency planners and policymakers has yet to be identified. PMID- 22823961 TI - Mobility training using a bionic knee orthosis in patients in a post-stroke chronic state: a case series. AB - INTRODUCTION: An emerging area of neurorehabilitation is the use of robotic devices to enhance the efficiency and effectiveness of lower extremity physical therapy post-stroke. Many of the robotic devices currently available rely on computer-driven locomotive algorithms combined with partial bodyweight-supported treadmill training that drive reflex stepping with minimal patient intention during therapy. In this case series, we examined the effect of task-oriented mobility training in patients in a post-stroke chronic state using a novel, wearable, mobile, intention-based robotic leg orthosis. CASE PRESENTATION: Three individuals, all of whom had reached a plateau with conventional bodyweight supported treadmill training, participated in task-oriented mobility therapy (1.5 hours, two to four times per week for four weeks) with a robotic leg orthosis under supervision by a physical therapist. Participant 1 was a 59-year-old Caucasian man, who had an ischemic left stroke six years previously with resultant right hemiparesis. Participant 2 was a 42-year-old Caucasian woman with left hemiparesis after a right stroke 15 months previously. Participant 3 was a 62-year-old Caucasian woman with a history of a right middle cerebral artery aneurysm with third degree sub-arachnoid hemorrhage 10 years ago.Immediately after training, all participants demonstrated improved gait speed (10 meter walk), stride length and walking endurance (6 minute walk) compared with baseline measurements. Improvements were maintained one month after training. Timed up and go and five times sit-to-stand were maintained for all three participants, with only one individual remaining outside the safety performance norm. CONCLUSIONS: Lower extremity training integrating an intention-based robotic leg orthosis may improve gait speed, endurance and community levels of participation in select patients in a post-stroke chronic state after plateauing within a bodyweight supported treadmill training program. The wearable, mobile assistive robotic device safely supplemented supervised physical therapy including mobility and balance skill training. PMID- 22823962 TI - Does instruction in semantic clustering and switching enhance verbal fluency in children? AB - This study investigated (1) test-retest reliabilities of Verbal Fluency (VF) outcome measures (i.e., word productivity, clustering, and switching) and (2) the effects of a brief training on semantic clustering to improve performance on a VF task. A total of 81 children enrolled in grades 3-6 completed a traditional VF task twice. In between task administrations half of the children were given instruction on using semantic clustering and switching to improve their VF, while the other half served as a control group. Test-retest reliability coefficients of the control group (N = 40) were substantial for "word productivity over 60 seconds" (riccs varied between 0.45 and 0.64) but only moderate for "clustering" (0.31) and "switching" (0.31). Next only the older children improved on VF after instruction on semantic clustering; the younger children appeared to understand the instruction but had to use up a great deal of cognitive load trying to implement this new strategy. This paper describes (1) the impact of strategy instruction on performance and (2) the need to analyze, at a process level, multi factorial tasks, so as to gain a better understanding of their functional components. PMID- 22823963 TI - EMS providers and exception from informed consent research: benefits, ethics, and community consultation. AB - BACKGROUND: As attention to, and motivation for, emergency medical services (EMS) related research continues to grow, particularly exception from informed consent (EFIC) research, it is important to understand the thoughts, beliefs, and experiences of EMS providers who are actively engaged in the research. OBJECTIVE: We explored the attitudes, beliefs, and experiences of EMS providers regarding their involvement in prehospital emergency research, particularly EFIC research. METHODS: Using a qualitative design, 24 participants were interviewed including nationally registered paramedics and Virginia-certified emergency medical technicians employed at Richmond Ambulance Authority, the participating EMS agency. At the time of our interviews, the EMS agency was involved in an EFIC trial. Transcribed interview data were coded and analyzed for themes. Findings were presented back to the EMS agency for validation. RESULTS: Overall, there appeared to be support for prehospital emergency research. Participants viewed research as necessary for the advancement of the field of EMS. Improvement in patient care was identified as one of the most important benefits. A number of ethical considerations were identified: individual risk versus public good and consent. The EMS providers in our study were open to working with EMS researchers throughout the community consultation and public disclosure process. CONCLUSION: The EMS providers in our study valued research and were willing to participate in studies. Support for research was balanced with concerns and challenges regarding the role of providers in the research process. PMID- 22823964 TI - Potential novel therapeutic strategies in cystic fibrosis: antimicrobial and anti biofilm activity of natural and designed alpha-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. AB - BACKGROUND: Treatment of cystic fibrosis-associated lung infections is hampered by the presence of multi-drug resistant pathogens, many of which are also strong biofilm producers. Antimicrobial peptides, essential components of innate immunity in humans and animals, exhibit relevant in vitro antimicrobial activity although they tend not to select for resistant strains. RESULTS: Three alpha helical antimicrobial peptides, BMAP-27 and BMAP-28 of bovine origin, and the artificial P19(9/B) peptide were tested, comparatively to Tobramycin, for their in vitro antibacterial and anti-biofilm activity against 15 Staphylococcus aureus, 25 Pseudomonas aeruginosa, and 27 Stenotrophomonas maltophilia strains from cystic fibrosis patients. All assays were carried out in physical-chemical experimental conditions simulating a cystic fibrosis lung. All peptides showed a potent and rapid bactericidal activity against most P. aeruginosa, S. maltophilia and S. aureus strains tested, at levels generally higher than those exhibited by Tobramycin and significantly reduced biofilm formation of all the bacterial species tested, although less effectively than Tobramycin did. On the contrary, the viability-reducing activity of antimicrobial peptides against preformed P. aeruginosa biofilms was comparable to and, in some cases, higher than that showed by Tobramycin. CONCLUSIONS: The activity shown by alpha-helical peptides against planktonic and biofilm cells makes them promising "lead compounds" for future development of novel drugs for therapeutic treatment of cystic fibrosis lung disease. PMID- 22823965 TI - Did the first Global Fund grant (2003-2006) contribute to malaria control and health system strengthening in Timor-Leste? AB - BACKGROUND: In 2003, Timor-Leste successfully obtained its first Global Fund grant for a three-year programme for malaria control. The grant aimed to reduce malaria-related morbidity and mortality by 30 % by the end of the implementation. METHODS: A mixed-methods approach was used to assess the impact of the grant implementation. Fifty-eight in-depth interviews, eight group interviews, 16 focus group discussions, and on-site observations were used. Morbidity data reported to the Ministry of Health were also examined to assess trends. RESULTS: The National Malaria Programme with funding support from the Global Fund grant and other development partners contributed considerably to strengthening malaria control and the general health system. It also brought direct and indirect benefits to pregnant women and to the community at large. However, it failed to achieve the stated objective of reducing malaria morbidity and mortality by 30 %. The implementation was hampered by inadequate human resources, the rigidity of Global Fund rules, weak project management and coordination, and inadequate support from external stakeholders. CONCLUSION: Despite limitations, the grant was implemented until the agreed closing date. Considerable contributions to malaria control, health system, and the community have been made and the malaria programme was sustained. PMID- 22823967 TI - The underestimated impact of cachexia. AB - This editorial contains views on the importance of animal research in the field of cachexia, a crippling syndrome associated with almost all chronic diseases that dramatically impact on quality of life and survival of the patient. Unfortunately, it is infrequently identified or diagnosed and too rarely treated. Even if treated, the treatment options are extremely limited, as no truly successful therapies have been established so far. Therefore, research in animal models is of outmost importance, but care should be taken in designing these pre clinical studies. We propose a design as close to clinical trials as possibly and to use primary endpoints that are of clinical relevance. PMID- 22823966 TI - Assessing the effect of high-repetitive single limb exercises (HRSLE) on exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD): study protocol for randomized controlled trial. AB - BACKGROUND: Single-limb knee extension exercises have been found to be effective at improving lower extremity exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Since the positive local physiological effects of exercise training only occur in the engaged muscle(s), should upper extremity muscles also be included to determine the effect of single limb exercises in COPD patients. METHODS/DESIGN: TRIAL DESIGN: a prospective, assessor-blind, block randomized controlled, parallel-group multicenter trial. PARTICIPANTS: stage II-IV COPD patients, > 40 years of age, ex-smokers, with stable medical treatment will be included starting May 2011. Recruitment at three locations in Sweden. INTERVENTIONS: 1) high-repetitive single limb exercise (HRSLE) training with elastic bands, 60 minutes, three times/week for 8 weeks combined with four sessions of 60 minutes patient education, or 2) the same patient education alone. OUTCOMES: Primary: determine the effects of HRSLE on local muscle endurance capacity (measured as meters walked during 6-minute walk test and rings moved on 6-minute ring and pegboard test) and quality of life (measured as change on the Swedish version of the Chronic Respiratory Disease Questionnaire). Secondary: effects on maximal strength, muscular endurance, dyspnea, self-efficacy, anxiety and depression. The relationship between changes in health-related variables and changes in exercise capacity, sex-related differences in training effects, feasibility of the program, strategies to determine adequate starting resistance and provide accurate resistance for each involved movement and the relationship between muscle fatigue and dyspnea in the different exercise tests will also be analyzed. Randomization: performed by a person independent of the recruitment process and using a computer random number generator. Stratification by center and gender with a 1:1 allocation to the intervention or control using random block sizes. Blinding: all outcome assessors will be blinded to group assignment. DISCUSSION: The results of this project will contribute to increase the body of knowledge regarding COPD and HRSLE. PMID- 22823968 TI - Structural basis for computational screening of non-steroidal androgen receptor ligands. AB - IMPORTANCE OF THE FIELD: Deep structural and chemical understanding of the protein target and computational methods for detection of receptor-selective ligands are important for the early drug discovery in the steroid receptor field. AREAS COVERED IN THIS REVIEW: This review focuses on the use of currently available structural information of the androgen receptor (AR) and known AR ligands to make computational strategies for the discovery of AR ligands in order to offer new chemical platforms for drug development. WHAT THE READER WILL GAIN: AR is a challenging target for drug discovery and modeling even if there is a wealth of experimental data available. First, only the active structure of AR is currently known, which hampers the design of AR antagonists. Second, the structural similarity between the ligand-binding sites of AR and its mutated forms and closely related steroid receptors (SRs) such as progesterone receptors presents challenges for the development of drugs with receptor-selective function. TAKE HOME MESSAGE: Research indicates that a very small chemical change in the structure of a non-steroidal ligand can cause a complete change in its activity. One source of this effect arises from binding to similar binding sites in related SRs and other proteins in the signaling pathway. Currently, computational methods are not able to predict the subtle differences between AR ligand activities but modeling does offer the possibility of generating new lead structures that might have the desired properties. PMID- 22823969 TI - Discovery of estrogen receptor modulators: a review of virtual screening and SAR efforts. AB - IMPORTANCE OF THE FIELD: Virtual screening (VS) coupled with structural biology is a significantly important approach to increase the number and enhance the success of projects in lead identification stage of drug discovery process. Recent advances and future directions in estrogen therapy have resulted in great demand for identifying the potential estrogen receptor (ER) modulators with more activity and selectivity. AREAS COVERED IN THIS REVIEW: This review presents the current state of the art in VS and structure-activity relationship of ER modulators in recent discovery, and discusses the strengths and weaknesses of the technology. WHAT THE READER WILL GAIN: Readers will gain an overview of the current platforms of in silico screening for discovery of ER modulators; they will learn which structural information is significantly correlated with the bioactivity of ER modulators and what novel strategies should be considered for the creation of more effective chemical structures. TAKE HOME MESSAGE: With the goal of reducing toxicity and/or improving efficacy, challenges to the successful modeling of endocrine agents are proposed, providing new paradigms for the design of ER inhibitors. PMID- 22823970 TI - Quantum mechanical effect in protein-ligand interaction. AB - IMPORTANCE OF THE FIELD: The development of quantum mechanics (QM) was perhaps the greatest intellectual achievement of the 20th century. Recently, QM-based methods have come to attention with the applications of studying QM effects in protein-ligand interactions. The QM-based methods give molecular-level insights into protein-ligand interactions and these can play a major role in the elucidation of the structure or reactivity of a biomolecular system. AREAS COVERED IN THIS REVIEW: In this review article, we present three examples to illustrate applications of QM-based methods in protein-ligand interactions. First, the QM calculation based on the density functional theory has been used to study the simplified active site model of CYP450 with an ethanol molecule. Second, a combined QM and molecular mechanical method, the generalized hybrid orbital approach, was applied to explore the identity of the fourth ligand of zinc in metalloproteins. Third, by the molecular fractionation with conjugate caps approach with full QM calculations; we obtained the interaction energies of thrombin-inhibitor complexes. WHAT THE READER WILL GAIN: Readers will gain an overview of development of QM-based methods. We summarize results from three applications of QM-based methods, each using a different method for a different system. These results show that studies of protein-ligand interactions based on QM calculations provide further descriptions of biochemical mechanisms, structures and particular interaction energies. TAKE HOME MESSAGE: For the structure-based drug design, the QM-based methods will have significant applications. QM-based methods have been, and will continue to be, important tools in the study of biological systems; moreover, development of a more accurate and more efficient QM-based method is still worth waiting for. PMID- 22823971 TI - Capillary microfluidic electrophoretic mobility shift assays: application to enzymatic assays in drug discovery. AB - IMPORTANCE OF THE FIELD: Microfluidic electrophoretic mobility shift assays are becoming increasingly popular with screening groups throughout the pharmaceutical industry due to their excellent data quality and target flexibility. AREAS COVERED IN THIS REVIEW: This review summarizes our experience of the microfluidic electrophoretic mobility shift technique at Merck Serono as well as from the published literature. We assess the advantages and limitations of electrophoretic mobility shift assays in this context. WHAT THE READER WILL GAIN: Published literature on the topic is scarce. The reader will gain an insight into the techniques and issues with the use of this technology in a pharmaceutical setting. TAKE HOME MESSAGE: This technology has reached maturity, providing reliable and robust results. Current limitations are the lower-than-desired throughput capacity for primary screening campaigns, and its current restriction to enzyme classes catalyzing a significant change in mass/charge of the substrate. PMID- 22823972 TI - In vivo models of cardiac diseases: application to drug development and screening. AB - Cardiac disease is the top cause of human mortality in the Western world. Current drug therapy for cardiac disease has been established via experimental studies using a variety of in vivo animal models. The purpose of this review is to discuss the features (advantages and limitations) of the mainly used in vivo models of cardiac disease and provide the reader with an overview of how they can be utilized in the development and screening of cardiac drugs. A search for articles focusing on and including in vivo models for the main areas of cardiac diseases was performed on PubMed. We also searched the reference lists of identified articles for further original articles. Large and small animal models including genetically modified ones have made accomplishments in the process of cardiac drug development with different clinical relevance. However, there is still a clear need for lessening the gap between human and experimental models by improving in vivo models. PMID- 22823973 TI - Challenges of general safety evaluations of biologics compared to small molecule pharmaceuticals in animal models. AB - IMPORTANCE OF THE FIELD: The prediction of human toxicity by employing animal models for nonclinical safety evaluation of pharmaceuticals poses numerous challenges. Each type, biologics, vaccines and small molecules, has unique features, which may impact the ability to effectively assess safety. AREAS COVERED IN THIS REVIEW: The importance of taking a case-by-case approach is highlighted in this review of the challenges encountered in general safety evaluations for biologics and vaccines compared to small molecules. WHAT THE READER WILL GAIN: The reader will gain insights in specific issues related to building a successful predictive nonclinical safety program for biologics. TAKE HOME MESSAGE: While there is fair concordance for small molecules, animal models used for the safety evaluation of biologics may have limitations with regard to human relevance. For small molecules, this is commonly because of differences in metabolism profiles or off-target effects. For biologics, which are highly targeted molecules, it may be because of differences in physiological processes or biologic pathways that limit pharmacologic relevance. For vaccines or immunomodulatory biologics, it may be related to the complexities of modeling the human immune system in a nonhuman species. While international guidances are available to govern the nonclinical safety assessment process for human pharmaceuticals (such as ICH M3), in many instances a case-by-case approach is employed for novel agents. PMID- 22823974 TI - GlycoFi's technology to control the glycosylation of recombinant therapeutic proteins. AB - IMPORTANCE OF THE FIELD: Therapeutic properties of many glycoproteins strongly depend on the composition of their glycans. Most of the current approved glycoproteins are produced in mammalian cell lines, which yield mixture of different glycoforms close to the human one but not fully identical. Glyco engineering is being developed as a method to control the composition of carbohydrates. Many alternative glycoprotein productions systems are actively investigated including new-engineered yeast strains, as developed by GlycoFi, a biotech company fully owned by Merck & Co. since 2006. AREAS COVERED IN THIS REVIEW: The objectives of this opinion paper is to present a comprehensive overview of the technological breakthrough developed by GlycoFi to produce recombinant human proteins with controlled glycosylation patterns in yeast, in comparison to other glyco-engineering technologies and to discuss the application to large-scale manufacturing of biologicals. WHAT THE READER WILL GAIN: Research papers and recent review articles on protein glycosylation and glyco-engineering, and in-depth search of the bibliography by the GlycoFi's research team, summary of recent meetings discussing the biosimilar topic were analyzed by the authors and will help the reader to gain insight in the field. TAKE HOME MESSAGE: The glyco-engineering technology of the Pichia pastoris N-glycosylation pathway developed by GlycoFi allows producing human proteins with complex N-glycosylation modifications, which are similar to the ones performed in human. Moreover, more homogeneous glycosylation patterns are observed, as opposed to the large heterogeneity of glycan moieties that are found naturally in mammals or in other production systems such as Chinese hamster ovary and NS0 cell lines. These properties associated with the perspective to industrialize the manufacturing process of Pichia makes it a very promising expression system to produce large scale batches of therapeutics at a lower cost. PMID- 22823975 TI - Osteoradionecrosis of the external auditory canal: three cases involving reconstruction with transposition of a split temporalis muscle flap. AB - OBJECTIVE: Osteoradionecrosis of the temporal bone is an uncommon but well documented finding after radiotherapy in the head and neck region, and results in exposed, necrotic bone with a soft tissue defect in the external auditory canal. The defect can be treated either conservatively or surgically. This paper aims to describe the results of reconstruction of the external auditory canal by transpositioning of the superficial layer of either the anterior or posterior part of the temporalis muscle to cover the defect. PATIENTS AND METHODS: Three patients with large, symptomatic defects in the external auditory canal were treated with transposition of the superficial layer of the temporalis muscle. RESULTS: The duration of follow up was 4 to 16 months. No complications occurred. In all patients, re-epithelialisation was complete within 3 months. CONCLUSION: During reconstruction of the external auditory canal, transposition of the superficial layer of the temporalis muscle provides a reliable flap with a satisfactory outcome. PMID- 22823976 TI - Electrocardiographic and enzymatic correlations with outcome in neonates with hypoxic-ischemic encephalopathy. AB - BACKGROUND: Perinatal asphyxia leading to hypoxic-ischemic encephalopathy (HIE) is a common problem causing multi organ dysfunction including myocardial involvement which can affect the outcome. OBJECTIVE: To evaluate the myocardial dysfunction in neonates having HIE by electrocardiographic(ECG) and cardiac enzymes (CK Total, CK-MB and Troponin I) and find out the relationship with HIE and outcome. DESIGN/METHODS: This was a hospital based prospective study. Sixty term neonates who had suffered perinatal asphyxia and developed HIE were enrolled. Myocardial involvement was assessed by clinical, ECG, and CK Total, CK MB and Troponin I measurements. RESULTS: Of 60 cases, 13(21.7%) were in mild, 27(45%) in moderate and 20(33.3%) belonged to severe,HIE. ECG was abnormal in 46 (76.7%); of these 19 (41.3%) had grade I, 13 (28.2%) grades II and III each and 1 (2.1%) with grade IV changes. Serum levels of CK Total, CK- MB and Troponin I were raised in 54 (90%), 52 (86.6%) and 48 (80%) neonates, respectively. ECG changes and enzymatic levels showed increasing abnormalities with severity of HIE, and the differences among different grades were significant (p = 0.002, 0.02, <0.001 and 0.004, respectively). Nineteen (32%) cases died during hospital stay. The non- survivors had high proportion of abnormal ECG (p = 0.024), raised levels of CK-MB (p = 0.018) and Troponin I (p = 0.008) in comparison to survivors. CONCLUSIONS: Abnormal ECG and cardiac enzymes levels are found in HIE and can lead to poor outcome due to myocardial damage Early detection can help in better management and survival of these neonates. PMID- 22823978 TI - Selective emitter using a screen printed etch barrier in crystalline silicon solar cell. AB - The low level doping of a selective emitter by etch back is an easy and low cost process to obtain a better blue response from a solar cell. This work suggests that the contact resistance of the selective emitter can be controlled by wet etching with the commercial acid barrier paste that is commonly applied in screen printing. Wet etching conditions such as acid barrier curing time, etchant concentration, and etching time have been optimized for the process, which is controllable as well as fast. The acid barrier formed by screen printing was etched with HF and HNO3 (1:200) solution for 15 s, resulting in high sheet contact resistance of 90 Omega/sq. Doping concentrations of the electrode contact portion were 2 * 1021 cm-3 in the low sheet resistance (Rs) region and 7 * 1019 cm-3 in the high Rs region. Solar cells of 12.5 * 12.5 cm2 in dimensions with a wet etch back selective emitter Jsc of 37 mAcm-2, open circuit voltage (Voc) of 638.3 mV and efficiency of 18.13% were fabricated. The result showed an improvement of about 13 mV on Voc compared to those of the reference solar cell fabricated with the reactive-ion etching back selective emitter and with Jsc of 36.90 mAcm-2, Voc of 625.7 mV, and efficiency of 17.60%. PMID- 22823979 TI - Takotsubo cardiomyopathy complicating thyroidectomy for Graves' disease. PMID- 22823977 TI - Myeloid malignancies: mutations, models and management. AB - Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach. PMID- 22823980 TI - Breast systemic follicular lymphoma in a man: a case report. AB - INTRODUCTION: Breast involvement by non-Hodgkin lymphoma is particularly rare in men. We describe the case of a patient with a rapidly growing, painless gynecomastia-like nodule in the left breast. On ultrasonography, the nodule was suspicious for breast carcinoma. CASE PRESENTATION: A breast biopsy from a 54 year-old Caucasian man showed the morphoimmunophenotypical features of grade 3 follicular lymphoma. Moreover, fluorescence in situ hybridization analysis showed a t(14,18) translocation suggesting breast involvement by a systemic lymphoma rather than a primary breast lymphoma. The histological diagnosis was subsequently confirmed after nodule excision. Mediastinal and abdominal node involvement was then identified on computed tomography and positron emission tomography scans during staging examinations. Our patient was treated with chemotherapy. After three years our patient experienced a right retro-areolar relapse. He then received two further cycles of chemotherapy but developed a myeloid acute leukemia and, as a result of this, he subsequently died. CONCLUSIONS: The rarity of breast lymphomas, especially in men, and the problems related to the therapeutic choices with these tumors require molecular techniques in association with classical histological diagnosis. PMID- 22823981 TI - Adverse pregnancy outcomes in rural Maharashtra, India (2008-09): a retrospective cohort study. AB - BACKGROUND: The study was carried out to record adverse pregnancy outcomes and to obtain information about sex ratio at birth in rural especially tribal areas in the State of Maharashtra, India. Although the tribal population is considered vulnerable to innumerable adversities, regretfully information about pregnancy wastage among them is not available. About 10% population of the state is tribal. The study of sex ratio at birth was planned as the overall sex ratio and child sex ratio had declined in the state. METHODS: The cohort of antenatal cases registered in rural areas of Maharashtra in the calendar year 2008 was followed up to study the pregnancy outcomes. A retrospective study was carried out from October 2009 to August 2010. The outcomes of all the registered antenatal cases were recorded by the Auxiliary Nurse Midwives. The summary sheets were obtained by Block Medical Officers. The data was entered at the block level by trained data entry operators in specially designed web-based software. Adverse pregnancy outcome was categorized in two groups abortions and stillbirths. RESULTS: About 1.1 million registered pregnancies were followed up. In the state 5.34% registered pregnancies ended in abortions. In tribal PHCs the relative risk of spontaneous abortion and induced abortion was 0.91 and 0.38 respectively. It was also revealed that about 1.55% pregnancies culminated in stillbirth. The relative risk of stillbirths in tribal PHCs was 1.33. The sex ratio at birth in the state was 850. The ratio was 883 in the tribal PHCs. Correlation was observed between sex ratio at birth and induced abortion rate. CONCLUSIONS: The study indicates that women from tribal PHCs are exposed to higher risk of adverse pregnancy outcome in the form of stillbirths. In non-tribal areas high induced abortion rate and poor sex ratio at birth is observed. These two indicators are correlated. The correlation may be explained by the unscrupulous practice of sex selective abortion. PMID- 22823982 TI - Characterisation of MRSA strains isolated from patients in a hospital in Riyadh, Kingdom of Saudi Arabia. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is spreading worldwide and poses a serious public health problem, being present in hospital settings and communities. However, from the Middle East and the Arabian Peninsula few molecular typing data on MRSA strains are currently available. In order to obtain data on the population structure of MRSA in Riyadh, Saudi Arabia, 107 clinical and environmental MRSA isolates were genotyped using a microarray-based assay. RESULTS: Five major MRSA strains from four clonal complexes were identified CC8/ST239-III (20.75%), PVL-positive as well as -negative CC22-IV (18.87% and 9.43%, respectively), PVL-positive CC30-IV (12.26%) and PVL-positive CC80-IV (17.92%). Minor strains, which accounted for less than 3% each, included CC1-IV/SCCfus, PVL-positive CC1/ST772-V, PVL-positive as well as- negative CC5 IV, CC5-IV/SCCfus, CC5-V, CC6-IV, CC45-IV, PVL-negative CC80-IV, PVL-positive CC88-IV, CC97-V and a CC9/ST834-MRSA strain. CONCLUSIONS: Typing of MRSA strains from Riyadh revealed a high diversity of clonal complexes. The prevalence of the genes encoding the Panton-Valentine leukocidin was surprisingly high (54.21%), and a significant rate of resistance markers was detected also in strains considered as community-associated. PMID- 22823983 TI - Estimating malaria parasite density: assumed white blood cell count of 10,000/MUl of blood is appropriate measure in Central Ghana. AB - BACKGROUND: White blood cells count (WBCc) is a bedrock in the estimation of malaria parasite density in malaria field trials, interventions and patient management. White blood cells are indirectly and relatively used in microscopy to estimate the density of malaria parasite infections. Due to frequent lack of facilities in some malaria-endemic countries, in order to quantify WBCc of patients, an assumed WBCc of 8.0 X 10(9)/L has been set by the World Health Organization to help in estimating malaria parasite densities. METHODS: This comparative analysis study, in Central Ghana, compiled laboratory data of 5,902 Plasmodium falciparum malaria parasite positive samples. Samples were obtained from consented participants of age groups less than five years. Full blood counts (FBC) of participants' samples were analysed using the ABX Micros 60 Haematology Analyzer. Blood slides were read by two competent microscopists to produce concordant results. All internal and external quality control measures were carried out appropriately. Parasite densities were calculated using participants' absolute WBCc and assumed WBCc of 5,000 to 10,000 per microlitre of blood. RESULTS: From the 5,902 Pf malaria positive samples, the mean (SD) WBCc and geometric mean parasite density were 10.4 (4.6) * 10(9)/L and 7,557/MUL (95% CI 7,144/MUL to 7,994/MUL) respectively. The difference in the geometric mean parasite densities calculated using absolute WBCs and compared to densities with assumed WBCs counts were significantly lower for 5.0 * 10(9)/L; 3,937/MUL, 6.0 * 10(9)/L; 4,725/MUL and 8.0 * 10(9)/L; 6,300/MUL. However, the difference in geometric mean parasite density, 7,874/MUL (95 % CI, 7,445/MUL to 8,328/MUL), with assumed WBCc of 10.0 * 10(9)/L was not significant. CONCLUSION: Using the assumed WBCc of 8.0 X 10(9)/L or lower to estimate malaria parasite densities in Pf infected children less than five years old could result in significant underestimation of parasite burden. Assumed WBCc of 10.0 * 10(9)/L at 95 % CI of geometric mean of parasite density statistically agreed with the parasite densities produce by the absolute WBCc of participants. The study suggests where resources are limited, use of assumed WBCc of 10.0 * 10(9)/L of blood to estimate malaria parasite density in central Ghana. Preferably, absolute WBCc should be used in drug efficacy and vaccine trials. PMID- 22823984 TI - Potential utility of near-infrared spectroscopy in out-of-hospital cardiac arrest: an illustrative case series. AB - OBJECTIVE: We evaluated the measurement of tissue oxygen content (StO(2)) by continuous near-infrared spectroscopy (NIRS) during and following cardiopulmonary resuscitation (CPR) and compared the changes in StO(2) and end-tidal carbon dioxide (ETCO(2)) as a measure of return of spontaneous circulation (ROSC) or rearrest. METHODS: This was a case series of five patients who experienced out-of hospital cardiac arrest. Patients included those who had already experienced ROSC, who were being transported to the hospital, or who were likely to have a reasonable amount of time remaining in the resuscitation efforts. Patients were continuously monitored from the scene using continuous ETCO(2) monitoring and a NIRS StO(2) monitor until they reached the hospital. The ETCO(2) and StO(2) values were continuously recorded and analyzed for comparison of the time points when patients were clinically identified to have ROSC or rearrest. RESULTS: Four of five patients had StO(2) and EtCO(2) recorded during an episode of CPR and all were monitored during the postarrest period. Three patients experienced rearrest en route to the hospital. Downward trends were noted in StO(2) prior to each rearrest, and rapid increases were noted after ROSC. The StO(2) data showed less variance than the ETCO(2) data in the periarrest period. CONCLUSIONS: This preliminary study in humans demonstrates that StO(2) dynamically changes during periods of hemodynamic instability in postarrest patients. These data suggest that a decline in StO(2) level may correlate with rearrest and may be useful as a tool to predict rearrest in post-cardiac arrest patients. A rapid increase in StO(2) was also seen upon ROSC and may be a better method of identifying ROSC during CPR than pauses for pulse checks or ETCO(2) monitoring. PMID- 22823986 TI - Neuroendocrine carcinoma of the ethmoid sinuses treated with radiotherapy alone. AB - OBJECTIVE: We present the first report of a case of neuroendocrine carcinoma of the paranasal sinuses treated successfully with radiotherapy alone. METHOD: A case report and literature review are presented. RESULTS: Fewer than 50 cases of paranasal sinus neuroendocrine carcinoma have been reported. We present an 82 year-old man referred with recurrent epistaxis. He was investigated by biopsy, computed tomography and magnetic resonance imaging, and was found to have a rare neuroendocrine carcinoma. He declined any surgery or chemotherapy but consented to radiotherapy. Thirty months later, he remained clinically free from cancer. CONCLUSION: There is no consensus for the management of paranasal sinus neuroendocrine carcinoma. Most cases are treated with surgery with or without chemoradiotherapy. This case shows that radiotherapy alone may be a viable treatment option for some cases. PMID- 22823985 TI - Comparison of serological assays for detecting antibodies in ducks exposed to H5 subtype avian influenza virus. AB - BACKGROUND: Chicken red blood cells (RBCs) are commonly used in hemagglutination inhibition (HI) tests to measure hemagglutinating antibodies against influenza viruses. The use of horse RBCs in the HI test can reportedly increase its sensitivity when testing human sera for avian influenza antibodies. This study aims to compare the proportion of positives detected and the agreement between two HI tests using either chicken or horse red blood cells for antibody detection in sera of ducks experimentally infected or naturally exposed to Indonesian H5 subtype avian influenza virus. In addition, comparison with a virus neutralisation (VN) test was conducted with the experimental sera. RESULTS: In the experimental study, the proportion of HI antibody-positive ducks increased slightly, from 0.57 when using chicken RBCs to 0.60 when using horse RBCs. The HI tests indicated almost perfect agreement (kappa = 0.86) when results were dichotomised (titre >= 4 log2), and substantial agreement (weighted kappa = 0.80) for log titres. Overall agreements between the two HI tests were greater than between either of the HI tests and the VN test. The use of horse RBCs also identified a higher proportion of antibody positives in field duck sera (0.08, compared to chicken RBCs 0.02), with also almost perfect agreements for dichotomized results (Prevalence and bias adjusted Kappa (PABAK) = 0.88) and for log titres (weighted PABAK = 0.93), respectively. Factors that might explain observed differences in the proportion of antibody-positive ducks and in the agreements between HI tests are discussed. CONCLUSION: In conclusion, we identified a good agreement between HI tests. However, when horse RBCs were used, a higher proportion of sera was positive (titre >= 4 log2) than using chicken RBCs, especially during the early response against H5N1 virus. The HRBC-HI might be more responsive in identifying early H5N1 HPAI serological response and could be a recommended assay for avian influenza sero-surveillance in both wild and domestic birds. PMID- 22823987 TI - Adult neurogenesis and neural stem cells as a model for the discovery and development of novel drugs. AB - Neurogenesis occurs in discrete regions of the adult brain, particularly the hippocampus. It is enhanced in the hippocampus of animal models and patients with neurological diseases and disorders, such as Alzheimer's disease (AD) and epilepsy. Adult hippocampal neurogenesis is modulated by drugs used for treating AD and depression, particularly galantamine, memantine and fluoxetine. This reveals that adult neurogenesis and newly generated neuronal cells of the adult hippocampus are involved in neurological diseases and disorders and that adult neurogenesis and neural stem cells (NSCs) of the adult hippocampus are the target of drugs used for treating AD and depression. Hence, adult neurogenesis and NSCs open new opportunities for our understanding of the pathology of the nervous system and new avenues to discover and develop novel drugs for treating neurogical diseases and disorders; drugs that would target specifically the NSCs of the neurogenic regions in the adult brain, or neurogenic drugs, and that would reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. Adult NSCs represent a model to discover and develop novel drugs for treating neurological diseases and disorders. These drugs may also have potential for regenerative medicine and the treatment of brain tumors. PMID- 22823988 TI - Rebinding: or why drugs may act longer in vivo than expected from their in vitro target residence time. AB - IMPORTANCE OF THE FIELD: It is well established that the in vivo duration of drug action not only depends on macroscopic pharmacokinetic properties like its plasma half-life, but also on the residence time of the drug-target complexes. However, drug 'rebinding' (i.e., the consecutive binding of dissociated drug molecules to the original target and/or targets nearby) can be influential in vivo as well. AREAS COVERED IN THIS REVIEW: Information about rebinding is available since the 1980s but it is dispersed in the life sciences literature. This review compiles this information. In this respect, neurochemists and biopohysicians advance the same equations to describe drug rebinding. WHAT THE READER WILL GAIN: The rebinding mechanism is explained according to the prevailing viewpoint in different life science disciplines. There is a general consensus that high target densities, high association rates and local phenomena that hinder the diffusion of free drug molecules away from their target all promote rebinding. TAKE HOME MESSAGE: Simulations presented here for the first time suggest that rebinding may increase the duration and even the constancy of the drug's clinical action. Intact cell radioligand dissociation and related ex vivo experiments offer useful indications about a drug's aptitude to experience target rebinding. PMID- 22823989 TI - Biasing conformational ensembles towards bioactive-like conformers for ligand based drug design. AB - IMPORTANCE OF THE FIELD: In silico or virtual screening has become a common practice in contemporary computer-aided drug discovery efforts and currently constitutes a reasonably mature paradigm. Application of ligand-based approaches to virtual screening requires the ability to identify the bioactive conformers of drug-like compounds as these conformers are expected to elicit the biological activity. However, given the complexity of the energy potential surfaces of such ligands and in particular those exhibiting some degree of flexibility and the limitation of contemporary energy functions, this is not an easy task. AREAS COVERED IN THIS REVIEW: The current contribution provides an in-depth review of recent developments in the field of generating conformational ensembles of drug like compounds with a particular emphasis of focusing such ensembles on bioactive conformers using both energy and structural criteria. The literature reviewed in this manuscript roughly covers the last decade. WHAT THE READER WILL GAIN: Readers of this review will gain an appreciation for the complexity of identifying bioactive conformers of drug-like compounds and an exposure to the different computational methods which were developed in order to tackle this problem as well as to the remaining challenges in this field. TAKE HOME MESSAGE: The identification of ensembles of bioactive conformers of drug-like compounds is far from being a solved problem. Recent research has advanced the field to the point where bioactive conformers could be readily identified from within conformational ensembles generated by contemporary computational tools. However, as such conformers are inevitably accompanied by many other non-relevant conformations, a focusing mechanism is required. New methods in this field are showing promise but more work is clearly needed. New research lines are proposed which are believed to enhance the performances and with it the usefulness of 3D ligand-based methods in drug discovery and development. PMID- 22823990 TI - Recent advances in the discovery and evaluation of fatty acid amide hydrolase inhibitors. AB - IMPORTANCE OF THE FIELD: Cannabis has been used for both medicinal and recreational purposes since ancient times. Although cannabinoid-based medicines hold great promise in several challenging therapeutic areas such as pain management and mode control, their development has been hampered by psychoactive and other CNS-related side effects. The identification of fatty acid amide hydrolase (FAAH), a key enzyme responsible for the degradation of endocannabinoids, has brought in tremendous opportunities in that inhibition of FAAH leads to local elevation of endocannabinoids under certain stimuli, thus, avoiding the side effects from global activation of cannabinoid receptors by exogenous cannabimimetic compounds. The search for selective FAAH inhibitors has thus become a strong focus in current drug discovery. AREAS COVERED IN THIS REVIEW: This review summarizes our current understanding of FAAH including its structure, catalytic mechanism and biological functions with emphases on its role in the regulation of endocannabinoids and other signaling lipids. The review then highlights the most recent discovery and biological activities of different classes of FAAH inhibitors. Last, the review discusses challenges and potential drawbacks in the development of FAAH inhibitor-based therapy. WHAT THE READER WILL GAIN: Readers will have an overview of FAAH and obtain a rationale on FAAH as an attractive therapeutic target for the development of medicines for treating pain, inflammation, anxiety and other diseases. More importantly, readers will gain knowledge on various newly established FAAH inhibitor scaffolds and their development potentials, and such information will hopefully stimulate ideas for the designing of new inhibitors with superior activity profiles. The discussions on the potential challenges in developing FAAH inhibitors will impose more caution in the decision-making process, thus, lowering the possibility of late stage failure. TAKE HOME MESSAGE: FAAH is an attractive target for modulating the endocannabinoid system, thus, treating many disease conditions including pain and mode control without the CNS side effects associated with cannabis usage. In recent years, tremendous effort has been focused in the FAAH inhibitor research field, and consequently many novel chemical templates have been discovered. FAAH hydrolyzes several important signaling lipids, but the long-term effects of FAAH inhibition in humans remain to be seen. While it is challenging to identify the right molecule with the right level of intervention of the FAAH function for treating a disease condition, it is possible to avoid mechanism-related undesired effects. With the entry of several compounds into clinical trials, FAAH inhibitor based medicines are on the horizon. PMID- 22823991 TI - Advances in functional assays for high-throughput screening of ion channels targets. AB - IMPORTANCE OF THE FIELD: Ion channels are important targets for many disease areas but are challenging to screen due to lack of technologies enabling robust high-throughput assays, particularly for state-dependent interactions. AREAS COVERED IN THIS REVIEW: Current assay technologies used to measure ion channel function are reviewed and assessed for use in high-throughput screening (HTS). An iterative approach to screening is evaluated as an alternative to full collection screening in order to take advantage of low-throughput, high cost assays that yield high quality data. WHAT THE READER WILL GAIN: The reader will gain an understanding of the advantages and disadvantages of various assay techniques used to screen ion channels and their suitability for use in HTS. TAKE HOME MESSAGE: Assays that directly measure ion channel function are prone to less artifact and higher hit confirmation in screening than those using an indirect measure but they are usually lower throughput. However, an iterative approach to screening can make the relatively lower throughput techniques amenable for use in interrogating large collections of compounds. PMID- 22823992 TI - Opioid receptor targeting ligands for pain management: a review and update. AB - IMPORTANCE OF THE FIELD: Discovery and synthesis of analgesic ligands can potentially improve analgesia, reduce side effects, minimize psychologic dependence and delay analgesic tolerance. AREAS COVERED IN THIS REVIEW: This review covers opioid peptides and analogs and bifunctional opioid ligands, and bifunctional opioid/non-opioid ligands as new, potentially useful analgesics. Several lines of investigation have resulted in potentially useful agents. WHAT THE READER WILL GAIN: Modifications of peptide structures have improved opioid receptor affinity, efficacy, stability, half-life and CNS penetrations. Opioid MU receptor agonists have been used to form multi-targeted directed ligands (MDL), which in animal models improve the therapeutic index of the analgesic relative to monovalent potent MU receptor agents. These new opioid ligands are reviewed in detail. TAKE HOME MESSAGE: Modified opioid peptides and MDL ligands are potentially better analgesics than morphine. PMID- 22823993 TI - Infantile colic, facts and fiction. AB - Infantile colic is one of the major challenges of parenthood. It is one of the common reasons parents seek medical advice during their child's first 3 months of life. It is defined as paroxysms of crying lasting more than 3 hours a day, occurring more than 3 days in any week for 3 weeks in a healthy baby aged 2 weeks to 4 months. Colic is a poorly understood phenomenon affecting up to 30% of babies, underlying organic causes of excessive crying account for less than 5%. Laboratory tests and radiological examinations are unnecessary if the infant is gaining weight normally and has a normal physical examination. Treatment is limited and drug treatment has no role in management. Probiotics are now emerging as promising agents in the treatment of infantile colic. Alternative medicine (Herbal tea, fennel, glucose and massage therapy) have not proved to be consistently helpful and some might even be dangerous. In conclusion infantile colic is a common cause of maternal distress and family disturbance, the cornerstone of management remains reassurance of parents regarding the benign and self-limiting nature of the illness. There is a critical need for more evidence based treatment protocols. PMID- 22823994 TI - Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): study protocol for a randomized phase II trial. AB - BACKGROUND: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone. METHODS: After stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy. DISCUSSION: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study. PMID- 22823995 TI - Increased type 3 deiodinase expression in papillary thyroid carcinoma. AB - BACKGROUND: Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid hormone-inactivating type 3 deiodinase (DIO3, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated DIO3 expression in human papillary thyroid carcinoma (PTC). METHODS: Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records. DIO3 mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of DIO3 gene regulation were performed in a human PTC derived cell line (K1 cells). BRAF(V600E) mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody. RESULTS: Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells, DIO3 transcripts were further upregulated by the transforming growth factor beta1 (TGFbeta1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased DIO3 mRNA levels and blocked the TGFbeta1-induced increase in DIO3 transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly, DIO3 mRNA and activity levels were significantly higher in BRAF(V600E)-mutated samples (p=0.001). Increased D3 activity was correlated with tumor size (r=0.68, p=0.003), and associated with lymph node (p=0.03) or distant metastasis (p=0.006) at diagnosis. Conversely, decreased levels of the thyroid hormone-activating type 2 deiodinase (DIO2) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples. CONCLUSIONS: These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in DIO3 and DIO2 expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation. PMID- 22823996 TI - Photoacoustic effects in nanocomposite structure 'porous silicon-liquid'. AB - Photoacoustic effect in nanocomposite structure 'porous silicon-liquid' has been investigated. Main mechanisms involved in the formation of photoacoustic signal in such structures have been experimentally studied. Liquids with different viscosity (ethanol and acetone) filling the nanopores have been used. A proposed mathematical model describing the photoacoustic signal formation was found to be in good agreement with the experimental results. The role of thermally induced pressures provoked by the liquids confined inside the nanopores in the photoacoustic process has been analyzed. PMID- 22823997 TI - Effects of sleep deprivation on central auditory processing. AB - BACKGROUND: Sleep deprivation is extremely common in contemporary society, and is considered to be a frequent cause of behavioral disorders, mood, alertness, and cognitive performance. Although the impacts of sleep deprivation have been studied extensively in various experimental paradigms, very few studies have addressed the impact of sleep deprivation on central auditory processing (CAP). Therefore, we examined the impact of sleep deprivation on CAP, for which there is sparse information. In the present study, thirty healthy adult volunteers (17 females and 13 males, aged 30.75+/-7.14 years) were subjected to a pure tone audiometry test, a speech recognition threshold test, a speech recognition task, the Staggered Spondaic Word Test (SSWT), and the Random Gap Detection Test (RGDT). Baseline (BSL) performance was compared to performance after 24 hours of being sleep deprived (24hSD) using the Student's t test. RESULTS: Mean RGDT score was elevated in the 24hSD condition (8.0+/-2.9 ms) relative to the BSL condition for the whole cohort (6.4+/-2.8 ms; p=0.0005), for males (p=0.0066), and for females (p=0.0208). Sleep deprivation reduced SSWT scores for the whole cohort in both ears [(right: BSL, 98.4%+/-1.8% vs. SD, 94.2%+/-6.3%. p=0.0005)(left: BSL, 96.7%+/-3.1% vs. SD, 92.1%+/-6.1%, p<0.0001)]. These effects were evident within both gender subgroups [(right: males, p=0.0080; females, p=0.0143)(left: males, p=0.0076; females: p=0.0010). CONCLUSION: Sleep deprivation impairs RGDT and SSWT performance. These findings confirm that sleep deprivation has central effects that may impair performance in other areas of life. PMID- 22823998 TI - Spatial-temporal analysis of malaria and the effect of environmental factors on its incidence in Yongcheng, China, 2006-2010. AB - BACKGROUND: In 2003, Plasmodium vivax malaria has re-emerged in central eastern China including Yongcheng prefecture, Henan Province, where no case has been reported for eleven years. Our goals were to detect the space-time distribution pattern of malaria and to determine significant environmental variables contributing to malaria incidence in Yongcheng from 2006 to 2010, thus providing scientific basis for further optimizing current malaria surveillance and control programs. METHODS: This study examined the spatial and temporal heterogeneities in the risk of malaria and the influencing factors on malaria incidence using geographical information system (GIS) and time series analysis. Univariate analysis was conducted to estimate the crude correlations between malaria incidence and environmental variables, such as mosquito abundance and climatic factors. Multivariate analysis was implemented to construct predictive models to explore the principal environmental determinants on malaria epidemic using a Generalized Estimating Equation (GEE) approach. RESULTS: Annual malaria incidence at town-level decreased from the north to south, and monthly incidence at prefecture-level demonstrated a strong seasonal pattern with a peak from July to November. Yearly malaria incidence had a visual spatial association with yearly average temperature. Moreover, the best-fit temporal model (model 2) (QIC = 16.934, P<0.001, R2 = 0.818) indicated that significant factors contributing to malaria incidence were maximum temperature at one month lag, average humidity at one month lag, and malaria incidence of the previous month. CONCLUSIONS: Findings supported the effects of environment factors on malaria incidence and indicated that malaria control targets should vary with intensity of malaria incidence, with more public resource allocated to control the source of infections instead of large scale An. sinensis control when malaria incidence was at a low level, which would benefit for optimizing the malaria surveillance project in China and some other countries with unstable or low malaria transmission. PMID- 22823999 TI - Dried Plasmodium falciparum-infected samples as positive controls for malaria rapid diagnostic tests. AB - BACKGROUND: Rapid diagnostic tests (RDTs) are central to fulfilling the WHO's recommendation for parasitologic confirmation of all suspected cases of malaria. RDT performance may be compromised when exposed to the high temperature conditions typical of most malaria endemic regions. However, a systematic method to monitor RDT quality and performance in endemic countries is lacking at the present time. Current methods to monitor RDT performance in the field include comparing results from RDTs to diagnoses made by light microscopy and observing health workers perform tests. These methods are not substitutes for direct quality control. In this study, the suitability of dried Plasmodium falciparum infected blood as quality control samples for malaria RDTs was evaluated. METHODS: Three cultured strains of P. falciparum at 200 and 2,000 parasites/MUl were tested on 10 brands of RDT. After baseline testing to determine initial reactivity, aliquots of parasite-infected blood were air dried, stored at 35 degrees C, room temperature (~25 degrees C) or 4 degrees C for one, four and 12 weeks and were then tested on the 10 RDTs after rehydration. Extended stability testing of dried blood stored at 4 degrees C was done using P. falciparum strain 3D7 at 1,000 and 2,000 parasites/MUl. RESULTS: All dried blood samples at 2,000 parasites/MUl retained reactivity (100% sensitivity) at all three temperatures and time points for all nine RDT brands that detect histidine-rich protein-2 (HRP2). The dried blood samples with 200 parasites/MUl were detected by six of the nine HRP2-based RDTs at all storage temperatures and time points. The sensitivity for two of the three remaining HRP2-based RDTs was 100% up to four weeks of storage at all temperatures but dropped to 87.5% at week 12. Of the four RDTs that detect plasmodium lactate dehydrogenase (pLDH) in a pan-specific manner, alone or in combination with HRP2, the detection of pLDH in samples with 2,000 parasites/MUL was 100% for two RDTs and 80% for the other two RDTs. The mean level for detection of pLDH at 200 parasites/MUl was low (29%), with a range of 0% to100%, which was partly attributable to weak initial baseline reactivity. Reactivity of dried 3D7 at 1,000 and 2,000 parasites/MUl stored at 4 degrees C was retained at 100% for up to 52 weeks for both HRP2 and pLDH. CONCLUSIONS: In the absence of native or recombinant positive control antigens, well-standardized P. falciparum-infected dried blood samples can be used as positive control samples for monitoring RDT performance, particularly with HRP2-detecting tests. PMID- 22824000 TI - Temperature dependence of ssrA-tag mediated protein degradation. AB - : Building synthetic gene networks with highly transient dynamics requires rapid protein degradation. We show that the degradation conferred by two commonly used ssrA tags is highly temperature dependent. Synthetic gene networks are being used increasingly in real-world applications where they may be subjected to variable conditions, and be required to display precise, quantitative dynamics, which will be more susceptible to environmental changes than the general qualitative dynamics focussed on so far. PMID- 22824001 TI - Histological observations in the Hawaiian reef coral, Porites compressa, affected by Porites bleaching with tissue loss. AB - The scleractinian finger coral Porites compressa is affected by the coral disease Porites bleaching with tissue loss (PBTL). This disease initially manifests as bleaching of the coenenchyme (tissue between polyps) while the polyps remain brown with eventual tissue loss and subsequent algal overgrowth of the bare skeleton. Histopathological investigation showed a loss of symbiont and melanin containing granular cells which was more pronounced in the coenenchyme than the polyps. Cell counts confirmed a 65% reduction in symbiont density. Tissue loss was due to tissue fragmentation and necrosis in affected areas. In addition, a reduction in putative bacterial aggregate densities was found in diseased samples but no potential pathogens were observed. PMID- 22824002 TI - Cloning eleven midgut trypsin cDNAs and evaluating the interaction of proteinase inhibitors with Cry1Ac against the tobacco budworm, Heliothis virescens (F.) (Lepidoptera: Noctuidae). AB - Midgut trypsins are associated with Bt protoxin activation and toxin degradation. Proteinase inhibitors have potential insecticidal toxicity against a wide range of insect species. This study was conducted to evaluate the interaction of proteinase inhibitors with Bt toxin and to examine midgut trypsin gene profile of Heliothis virescens. A sublethal dose (15 ppb) of Cry1Ac, 0.75% soybean trypsin inhibitor, and 0.1% and 0.2% N-alpha-tosyl-L-lysine chloromethyl ketone significantly suppressed midgut proteinase activities, and resulted in reductions in larval and pupal size and mass. The treatment with inhibitor+Bt suppressed approximately 65% more larval body mass and 21% more enzymatic activities than the inhibitor-only or Bt-only. Eleven trypsin-like cDNAs were sequenced from the midgut of H. virescens. All trypsins contained three catalytic center residues (H(73), D(153), and S(231)), substrate specificity determinant residues (D(225), G(250), and G(261)), and six cysteines for disulfide bridges. These putative trypsins were separated into three distinct groups, indicating the diverse proteinases evolved in this polyphagous insect. These results indicated that the insecticidal activity of proteinase inhibitors may be used to enhance Bt toxicity and delay resistance development. PMID- 22824003 TI - High stability and no fitness costs of the resistance of codling moth to Cydia pomonella granulovirus (CpGV-M). AB - Resistance against the biocontrol agent Cydia pomonella granulovirus (CpGV-M) was previously observed in field populations of codling moth (CM, C. pomonella) in South-West Germany. Incidental observations in a laboratory reared field colony (CpR) indicated that this resistance is rather stable, even in genetically heterogeneous CM colonies consisting of both susceptible and resistant individuals. To test this hypothesis, the resistance level of CpR that was 1000times less susceptible to CpGV-M was followed for more than 60 generations of rearing. Even without virus selection pressure, the high level of resistance, expressed as median lethal concentration, remained stable for more than 30 generations and declined only by a factor of 10 after 60 generations. When cohorts of the F32 and F56 generations of the same colony were selected to CpGV-M for five and two generations, respectively, the resistance level increased to factor of >1,000,000 compared to a susceptible control colony. Laboratory reared colonies of CpR, did not exhibit any measurable fitness costs under laboratory conditions in terms of fecundity and fertility. Resistance testing of seven selected codling moth field populations collected between 2003 and 2008 in commercial orchards in Germany that were repeatedly sprayed with CpGV products gave evidence of different levels of resistance and a more than 20-fold increase of the resistance in 1-3 years when selection by CpGV-M was continued. A maximum 1,000,000-fold level of resistance to CpGV-M that could be induced in the laboratory under virus pressure had been also observed in one field population. The high stability of resistance observed in the genetically heterogenous colony CpR indicates that resistance to CpGV-M is not very costly. PMID- 22824004 TI - Retraction of mechanistic basis for Epstein-Barr Virus ribonucleotide-reductase small-subunit function. PMID- 22824005 TI - Anti-Mullerian hormone plasma concentration in prepubertal ewe lambs as a predictor of their fertility at a young age. AB - BACKGROUND: In mammals, the ovarian follicular reserve is highly variable between individuals and impacts strongly on ovarian function and fertility. Nowadays, the best endocrine marker of this reserve in human, mouse and cattle is the anti Mullerian hormone (AMH). The objectives of this work were to determine whether AMH could be detected in the plasma of prepubertal ewe lambs and to assess its relationship with their fertility at a young age. RESULTS: Plasma was taken from 76 Rasa Aragonesa ewe lambs at 3.6 months of age for AMH determination. Simultaneously, 600 IU equine chorionic gonadotropin (eCG) was administered and the number of ovulations recorded 6 days later. AMH was detected in 93% of the lambs, and the concentrations were about 3-4-fold higher in ovulating than in non ovulating lambs (P < 0.004). Ewes aged around 10 months were mated, giving an overall fertility of 29%, and those failing to conceive were mated again 4 months later. Fertility at first mating was significantly correlated with plasma AMH concentration at 3.6 months (Spearman's rho = 0.34; P < 0.01). To use plasma AMH concentration as a screening test, a value of 97 pg/mL was determined as the optimum cutoff value to predict fertility at first mating (sensitivity = 68.2%; specificity = 72.2%). Fertility at first mating was 34.8 percentage points higher in ewe lambs with an AMH >= 97 pg/mL than in those with lower AMH concentrations (50% vs. 15%; P < 0.001). CONCLUSIONS: Plasma AMH concentration might be a reliable marker of the ovarian status of prepubertal ewe lambs, reflecting their ability to respond to eCG stimulation. A single AMH measurement performed on ewe lambs early in age could be useful to select for replacement ewes with a higher predicted fertility at first mating. PMID- 22824006 TI - Impact of delayed and infrequent administration of vasopressors on return of spontaneous circulation during out-of-hospital cardiac arrest. AB - INTRODUCTION: Epinephrine and vasopressin are the only vasopressors associated with return of spontaneous circulation (ROSC). While current guidelines recommend rapid and frequent vasopressor administration during cardiac arrest, delays in their administration in the out-of- hospital setting remain a concern. OBJECTIVE: This study evaluated delays in vasopressor administration and their effect on field ROSC. METHODS: This retrospective review included all adult patients who experienced cardiac arrest of medical origin and received field resuscitative efforts among 10 emergency medical services (EMS) systems. Data were abstracted from the EMS medical record and included response time intervals, calculated first-dose and interdosing intervals of vasopressors, and ROSC. Data were analyzed using Mann-Whitney tests, chi-square tests, and t-tests, survival analysis, and logistic regression, with p <= 0.05 indicating significance. RESULTS: A total of 660 cardiac arrest patients were enrolled in the study. The mean EMS response time was 8.8 minutes; 52.7% of patients had witnessed cardiac arrests, 46.2% received bystander cardiopulmonary resuscitation (CPR), 23.0% had shockable initial rhythms, and 19.5% experienced field ROSC. In total, 1,913 doses of epinephrine and 111 doses of vasopressin were administered, with mean and 90th-percentile scene arrival-to-first drug intervals of 9.5 and 17 minutes, respectively. The mean and 90th-percentile interdosing intervals were 6.1 and 10 minutes, respectively. Patients experiencing ROSC had shorter scene arrival-to first drug intervals than those without ROSC (8.1 vs. 9.8 min, p < 0.01), but there was no difference in the mean interdosing interval (6.8 vs. 6.0 min, p = 0.57). In the logistic regression analysis of ROSC, the adjusted odds ratio for call receipt-to-first drug interval <=10 minutes was 1.91 (p = 0.04). Patients receiving advanced airway control prior to vasopressor administration were less likely to have a call receipt-to-first drug interval within 10 minutes (4.0% vs. 17.3%, p < 0.01) and were less likely to attain ROSC (15.7% vs. 25.4%, p < 0.01). CONCLUSION: The interval between scene arrival and first administration of vasopressors is significantly shorter among patients who experience ROSC compared with those who do not. Airway control procedures delay vasopressor administration and reduce the likelihood of ROSC. Although the interdosing intervals of most patients were not consistent with current recommendations, there was no difference in the mean interdosing times between those who achieved ROSC and those who did not. PMID- 22824007 TI - [Allgrove syndrome (triple A). Finding of a mutation not described in the AAAS gene]. AB - Allgrove syndrome (triple A) is a rare autosomal recessive disease. The classic triad includes, congenital adrenal insufficiency due to ACTH resistance, achalasia of the cardia and alacrimia. Neurological abnormalities are associated with autonomic neuropathy, sensory and motor defects, deafness, mental retardation, Parkinsonism and dementia. The gene responsible is the ADRACALIN or AAAS encoding a protein called ALADIN. We report a case of a 19 year-old male, assessed when he was 10 years old in our department due to suspected storage disease. Mild mental and language retardation, hypernasal voice, sensory-motor neuropathy with autonomic involvement and signs of spastic paraparesis, alacrimia. gastroesophageal reflux, and achalasia. Molecular studies showed to mutations, the undescribed p.Tyr 19 Cys, and IVS14 +1 G. PMID- 22824008 TI - Silk ionomers for encapsulation and differentiation of human MSCs. AB - The response of human bone marrow derived human mesenchymal stem cells (hMSCs) encapsulated in silk ionomer hydrogels was studied. Silk aqueous solutions with silk-poly-L-lysine or silk-poly-L-glutamate were formed into hydrogels via ultrasonication in situ with different net charges. hMSCs were encapsulated within the hydrogels and the impact of matrix charge was assessed over weeks in osteogenic, adipogenic and maintenance growth media. These modified silk charged polymers supported cell viability and proliferative potential, and the hMSCs were able to differentiate toward osteogenic or adipogenic lineages in the corresponding differentiation media. The silk/silk-poly-L-lysine hydrogels exhibited a positive effect on selective osteogenesis of hMSCs, inducing differentiation toward an osteogenic lineage even in the absence of osteogenic supplements, while also inhibiting adipogenesis. In contrast, silk/silk fibroin poly-L-glutamate hydrogels supported both osteogenic and adipogenic differentiation of hMSCs when cultured under induction conditions. The results demonstrate the potential utility of silk-based ionomers in gel formats for hMSCs encapsulation and for directing hMSCs long term functional differentiation toward specific lineages. PMID- 22824009 TI - Does the home environment and the sex of the child modify the adverse effects of prenatal exposure to chlorpyrifos on child working memory? AB - Prenatal exposure to chlorpyrifos (CPF), an organophosphorus insecticide, has long been associated with delayed neurocognitive development and most recently with decrements in working memory at age 7. In the current paper, we expanded the previous work on CPF to investigate how additional biological and social environmental factors might create or explain differential neurodevelopmental susceptibility, focusing on main and moderating effects of the quality of the home environment (HOME) and child sex. We evaluate how the quality of the home environment (specifically, parental nurturance and environmental stimulation) and child sex interact with the adverse effects of prenatal CPF exposure on working memory at child age 7years. We did not observe a remediating effect of a high quality home environment (either parental nurturance or environmental stimulation) on the adverse effects of prenatal CPF exposure on working memory. However, we detected a borderline significant interaction between prenatal exposure to CPF and child sex (B (95% CI) for interaction term=-1.714 (-3.753 to 0.326)) suggesting males experience a greater decrement in working memory than females following prenatal CPF exposure. In addition, we detected a borderline interaction between parental nurturance and child sex (B (95% CI) for interaction term=1.490 (-0.518 to 3.499)) suggesting that, in terms of working memory, males benefit more from a nurturing environment than females. To our knowledge, this is the first investigation into factors that may inform an intervention strategy to reduce or reverse the cognitive deficits resulting from prenatal CPF exposure. PMID- 22824010 TI - Emerging roles of PKM2 in cell metabolism and cancer progression. AB - Increased conversion of glucose to lactate is a key feature of many cancer cells that promotes rapid growth. Pyruvate kinase M2 (PKM2) expression is increased and facilitates lactate production in cancer cells. Modulation of PKM2 catalytic activity also regulates the synthesis of DNA and lipids that are required for cell proliferation, and of NADPH that is required for redox homeostasis. In addition to its role as a pyruvate kinase, PKM2 also functions as a protein kinase and as a transcriptional coactivator. These biochemical activities are controlled by allosteric regulators and post-translational modifications of PKM2 that include acetylation, oxidation, phosphorylation, prolyl hydroxylation, and sumoylation. Given its pleiotropic effects on cancer biology, PKM2 represents an attractive target for cancer therapy. PMID- 22824038 TI - A treacherous impediment to duodenoscopy in a woman with pancreatic cancer. PMID- 22824011 TI - The immunopathogenesis of cow's milk protein allergy (CMPA). AB - The most frequent symptoms among the manifestations of cow milk protein allergy (CMPA) are gastrointestinal. CMPA pathogenesis involves immunological mechanisms with participation of immunocompetent cells and production of immunoglobulin E (IgE). Nevertheless, recent studies have been focused on the description of other forms of CMPA, not-mediated by IgE reactions, mostly involving the T lymphocite immune system. Thus, in this field it is important to note how different kind of cells are involved in the immunopathogenesis of CMPA, such as antigen-specific T cells, T regulatory cells, cytokines secreted by the different T lymphocite subsets, B lymphocytes, antingen-presenting cells, mast cells, that together orchestrate the complex mechanism leading to the phenotipic expression of CMPA.The progress in the diagnosis of immunologic disorders allowed the recent literature to develop new models for immuno-mediate disorders, involving new cells (such as Treg cells) and thus allowing the acquisition of a new vision of the pathogenesis of atopic diseases.The aim of this review is to describe the immunopathogenetic aspects of CMPA in view of these new discoveries in the immunologic field, considering the immunologic pathway at the basis of both IgE- and not-IgE mediated CMPA. PMID- 22824039 TI - Continuing attrition of physician-scientists (CAPS): a preventable syndrome? PMID- 22824040 TI - The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. AB - BACKGROUND: Tumor associated macrophages (TAMs) are alternatively activated macrophages that enhance tumor progression by promoting tumor cell invasion, migration and angiogenesis. TAMs have an anti-inflammatory function resembling M2 macrophages. CD163 is regarded as a highly specific monocyte/macrophage marker for M2 macrophages. In this study we evaluated the specificity of using the M2 macrophage marker CD163 as a TAM marker and compared its prognostic value with the more frequently used pan-macrophage marker CD68. We also analyzed the prognostic value of the localization of CD163(+) and CD68(+) myeloid cells in human breast cancer. METHODS: The extent of infiltrating CD163(+) or CD68(+) myeloid cells in tumor nest versus tumor stroma was evaluated by immunohistochemistry in tissue microarrays with tumors from 144 breast cancer cases. Spearman's Rho and chi(2) tests were used to examine the correlations between CD163(+) or CD68(+) myeloid cells and clinicopathological parameters. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the impact of CD163(+) and CD68(+) myeloid cells in tumor stroma and tumor nest, respectively, on recurrence free survival, breast cancer specific and overall survival. RESULTS: We found that infiltration of CD163(+) and CD68(+) macrophages into tumor stroma, but not into tumor nest, were of clinical relevance. CD163(+) macrophages in tumor stroma positively correlated with higher grade, larger tumor size, Ki67 positivity, estrogen receptor negativity, progesterone receptor negativity, triple-negative/basal-like breast cancer and inversely correlated with luminal A breast cancer. Some CD163(+) areas lacked CD68 expression, suggesting that CD163 could be used as a general anti-inflammatory myeloid marker with prognostic impact. CD68(+) macrophages in tumor stroma positively correlated to tumor size and inversely correlated to luminal A breast cancer. More importantly, CD68 in tumor stroma was an independent prognostic factor for reduced breast cancer specific survival. CONCLUSION: These findings highlight the importance of analyzing the localization rather than merely the presence of TAMs as a prognostic marker for breast cancer patients. PMID- 22824042 TI - The efficacy of endoscopic ultrasound for the diagnosis of common bile duct stones as compared to CT, MRCP, and ERCP. PMID- 22824043 TI - Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL-17-producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL-17 and IL-23, two Th17-related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. METHODS: This cross-sectional study included 49 AS patients and 25 healthy control subjects. The serum IL-17 and IL-23 levels were measured using enzyme-linked immunosorbent assay kits. At the same time, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. RESULTS: The serum IL-17 and IL-23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL-17 or IL-23 levels (IL-17, r = 0.351, p = 0.014; IL 23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL-17 or IL-23 correlate to the BASFI, BAS-G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL-17 and IL-23 levels act better in discriminating patients with BASDAI>=4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). CONCLUSION: Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS. PMID- 22824041 TI - Exercise training and PI3Kalpha-induced electrical remodeling is independent of cellular hypertrophy and Akt signaling. AB - In contrast with pathological hypertrophy, exercise-induced physiological hypertrophy is not associated with electrical abnormalities or increased arrhythmia risk. Recent studies have shown that increased cardiac-specific expression of phosphoinositide-3-kinase-alpha (PI3Kalpha), the key mediator of physiological hypertrophy, results in transcriptional upregulation of ion channel subunits in parallel with the increase in myocyte size (cellular hypertrophy) and the maintenance of myocardial excitability. The experiments here were undertaken to test the hypothesis that Akt1, which underlies PI3Kalpha-induced cellular hypertrophy, mediates the effects of augmented PI3Kalpha signaling on the transcriptional regulation of cardiac ion channels. In contrast to wild-type animals, chronic exercise (swim) training of mice (Akt1(-/-)) lacking Akt1 did not result in ventricular myocyte hypertrophy. Ventricular K(+) current amplitudes and the expression of K(+) channel subunits, however, were increased markedly in Akt1(-/-) animals with exercise training. Expression of the transcripts encoding inward (Na(+) and Ca(2+)) channel subunits were also increased in Akt1(-/-) ventricles following swim training. Additional experiments in a transgenic mouse model of inducible cardiac-specific expression of constitutively active PI3Kalpha (icaPI3Kalpha) revealed that short-term activation of PI3Kalpha signaling in the myocardium also led to the transcriptional upregulation of ion channel subunits. Inhibition of cardiac Akt activation with triciribine in this (inducible caPI3Kalpha expression) model did not prevent the upregulation of myocardial ion channel subunits. These combined observations demonstrate that chronic exercise training and enhanced PI3Kalpha expression/activity result in transcriptional upregulation of myocardial ion channel subunits independent of cellular hypertrophy and Akt signaling. PMID- 22824044 TI - Five-year experience of peritoneal dialysis catheter placement. AB - BACKGROUND: Peritoneal dialysis (PD) is a widely used renal replacement therapy for end-stage renal disease (ESRD) patients. Using laparoscopic guidance for PD catheter placement, we have designed a safe method that resulted in a reduction in catheter migration. METHODS: We retrospectively reviewed 250 consecutive patients who underwent PD catheter placement from January 2005 to December 2009. The patients were divided into two groups: the conventional open surgery group and the laparoscopic group. All patients received Tenckhoff straight catheters. In the laparoscopic group, the catheter was additionally fixed to the ventral abdominal wall. Data were collected and a statistical analysis was performed to compare patient characteristics, surgical complications and catheter removal between the groups. RESULTS: Overall surgical complications in the laparoscopic group were lower than those in the conventional group (3.8% vs. 19.4%, p < 0.001), and the majority of catheter migrations and omental wraps occurred in the conventional group. Patients in the conventional group had higher American Society of Anesthesiologists scores than those in the laparoscopic group. There was no difference in the incidence of previous abdominal operation or follow-up periods in the groups. CONCLUSION: Our laparoscopy-assisted PD catheter insertion method using an intraperitoneal fixation loop is safeand can be a valuable tool in prevention of catheter migration and omental wraps. PMID- 22824046 TI - Stent-assisted coil embolization of intracranial aneurysms: a single center experience. AB - BACKGROUND: Endovascular detachable coil embolization has become an important method in the management of intracranial aneurysms. However, coil embolization alone may fail to treat some wide-neck aneurysms. Herein, we report our experience with and outcome of stent-assisted coil embolization (SACE) of intracranial aneurysms. METHODS: Over a 5-year period, a total of 59 patients diagnosed with 63 intracranial aneurysms underwent SACE. Of the total 63 aneurysms, 6 aneurysms were treated by SACE as a salvageable procedure because of coil instability after detachment. There were 17 men and 42 women enrolled in the study, with ages ranging from 24 to 86 years (mean: 60 years). We retrospectively assessed the clinical data, aneurysm characteristics, and angiographic and clinical outcomes of all patient cases. RESULTS: The mean aneurysm size was 9.4 mm, and the mean neck size was 5.5 mm. Clinical and angiographic follow-up exceeding 6 months were available in 51 and 40 patients, respectively. The mean clinical follow-up time was 28 months (range: 6-49 months). Successful stent deployment was found in 60 aneurysms (95%). Midterm total or subtotal angiographic aneurismal occlusion was obtained in 56 aneurysms (89%), with further thrombosis of the aneurismal sac occurring in 4 (10%). Stable coiling aneurysm was found in 24 (78%), aneurysm recurrence was observed in 5 (13%), and permanent procedural morbidity was observed in two patients (3.4%). During the follow-up period, there were no hemorrhagic events and no stent displacement. CONCLUSION: Despite a modest procedural complication rate, and some evidence of aneurismal recurrence, SACE was proved to be both effective and safe in managing wide-neck intracranial aneurysms. Our results also demonstrated the midterm durability and stability of aneurysm treated by SACE. Furthermore, SACE can be a salvageable procedure in cases with coil instability after detachment. PMID- 22824045 TI - Generalized depletion of free nerve endings and decrease of cutaneous nervous innervation in streptozotocin-induced painful and painless diabetic rats. AB - BACKGROUND: The loss of peripheral nerve fiber is evident in chronic painful diabetic neuropathy. However, the correlation between peripheral fiber loss and the genesis of pain is unclear. Using the streptozotocin-induced diabetic rat model and focusing on free nerve endings, we attempted to investigate the peripheral changes that elicit pain syndromes in diabetes. METHODS: Diabetes was induced in rats using 75 mg/kg streptozotocin, while controls received saline solution. "Painful" rats with thermal or mechanical hypersensitivity and "painless" rats (without significant threshold changes) were enrolled. The peripheral nerve endings were immunostained using protein gene product 9.5 in footpad skin sections. The peripheral nerve densities in each behavior group were calculated and averaged. RESULTS: A progressive loss of protein gene product 9.5 blotted nerve fibers was noted after diabetes was induced and as the duration of hyperglycemia proceeded. Painful and painless diabetic rats have similar histological nerve fiber loss including depleted epidermal free nerve endings. CONCLUSION: The results indicated that there are undiscovered pathological changes that are sensitizing the injured nerve fiber in periphery. PMID- 22824047 TI - New therapeutic strategy for treating otitis media with effusion in postirradiated nasopharyngeal carcinoma patients. AB - BACKGROUND: Postirradiation otitis media with effusion (OME) is the most common radiotherapy-associated otologic complication associated with nasopharyngeal carcinoma (NPC). This study's aim was to evaluate the efficacy of laser myringotomy followed by intratympanic steroid injection (LMIS) for treating OME in postirradiated NPC patients. METHODS: From August 2002 to January 2006, 27 newly diagnosed NPC patients who developed OME after a full course of radiotherapy were enrolled. Laser myringotomy was performed followed by once weekly administration of steroids (0.5mL dexamethasone at a concentration of 5.0mg/mL) into the middle ear for 3 consecutive weeks. The success rate of dry eardrum perforation and the prognostic factors associated with OME resolution were analyzed. RESULTS: The procedure was performed on 44 ears of 27 patients. The mean follow-up period was 37 weeks. Of the 44 ears, 23 (52.3%) developed persistent eardrum perforation, 18 (40.9%) developed recurrent OME, and three (6.8%) were disease-free on follow-up. Of the 23 ears with persistent eardrum perforation, 18 (78.3%) were diagnosed as dry perforation. The absence of pretreatment mastoiditis was an independent factor associated with OME resolution (p<0.001). CONCLUSION: LMIS is a quick, minimally invasive, office-based technique that can be repeatedly performed to treat highly recurrent postirradiation OME, and it results in relatively slight pain to NPC patients. Long-lasting dry eardrum perforation allows for adequate middle ear ventilation and drainage and guarantees sustained relief from symptoms. The absence of preoperative mastoiditis is a favorable prognostic factor associated with OME resolution. PMID- 22824048 TI - Opposite associations of osteoprotegerin and ZBTB40 polymorphisms with bone mineral density of the hip in postmenopausal Taiwanese women. AB - BACKGROUND: An elevated annual incidence rate of hip fracture has been reported among elderly Taiwanese. Moreover, bone mineral density (BMD) is the single most reliable predictor of fragility fractures. We aimed to identify the association between gene sequence variants and hip BMD in postmenopausal Taiwanese women. METHODS: We prospectively analyzed data from 163 postmenopausal Taiwanese women to test an association between rs7524102, rs6696981, or rs6993813 single nucleotide polymorphisms (SNPs) and hip BMD. RESULTS: Our study showed that rs6993813 (osteoprotegerin gene) and rs6696981 (ZBTB40 gene) SNPs have an opposite association with hip BMD. For rs6993813 genotypic frequencies, the adjusted odds ratio for hip osteoporosis was 9.53 for individuals with T/T minor allele homozygotes, compared with that of participants with C/C wild-type homozygotes. Hip BMD also had an association with rs6993813 SNPs, especially in T/T minor allele homozygotes. For rs6696981 SNPs, hip BMD in G/T heterozygotes and at least one mutated T allele was higher than that in wild-type G/G homozygotes. CONCLUSION: The gene sequence variant rs6993813 reduced hip BMD and increased the risk of hip osteoporosis, whereas rs6696981 increased hip BMD in postmenopausal Taiwanese women. This indicated that the two SNPs may provide some explanation for the high risk of hip fracture in this population. PMID- 22824049 TI - Integration of fuzzy set theory and TOPSIS into HFMEA to improve outpatient service for elderly patients in Taiwan. AB - BACKGROUND: Taiwan became a World Health Organization-defined aging country in 1993, and it is estimated to become an aged country by 2017, surpassing Japan as the fastest aging country in the world. However, healthcare services in Taiwan need a wide range of improvements to cope with the challenges of population aging. METHODS: Healthcare failure mode and effects analysis (HFMEA) developed by the Department of Veterans Affairs' National Center for Patient Safety (NCPS) was used to evaluate the inconvenience of outpatient registration process for elderly patients. Also, fuzzy set theory was used along with technique for order preference by similarity to ideal solution (TOPSIS) method in multiple criteria decision making (MCDM) to rank the failure risks in the HFMEA. RESULTS: The top three failure modes ranked by the TOPSIS method were "short consultation time," "possible complications of the checkup or treatment were not told," and "opinions and feelings of patients and relatives were not respected." Based on those failure modes, improvements were proposed and results were feedback to hospitals. A random sample of 40 elderly patients was selected for interview at the outpatient department of a tertiary medical center in Taiwan. Thirty-seven out of the 40 elderly patients (92.5%) agreed with the executive expert team. This meant the improvement proposals were effective. CONCLUSION: In this study, HFMEA was extended to explore the impacts of geriatric outpatient service process failures on elderly patients. Using fuzzy set theory and the TOPSIS method in multiple criteria decision making to rank the severity of the failure modes, the risk assessment of the geriatric outpatient service process was more objective when analyzed with quantitative data. PMID- 22824050 TI - Atrial myxoma presenting as total occlusion of the abdominal aorta and its major four branches. AB - The presentations of cardiac myxoma are diverse, from asymptomatic to a variety of symptoms due to embolization. Occlusion of abdominal aortic bifurcation by straddled myxoma is not common; however, obstructive level above renal artery is very rare. We present a patient with cardiac myxoma who presented with acute onset of paraplegia. The aorta was occluded from the level of the liver dome to the renal arteries, and catastrophic outcome (ischemia/reperfusion) following its removal. PMID- 22824051 TI - Spontaneous perforation of the bile duct in a neonate: drainage or resection? AB - Spontaneous perforation of the bile duct is a rare disease, and delayed diagnosis without optimal treatment can be fatal. Abdominal drainage with or without repair of perforation seems to be adequate in most case series. We report on a 10-day old female neonate with spontaneous perforation of the bile duct over the junction of cystic duct and common hepatic duct, who recovered uneventfully with follow-up for 3 years after receiving a single-stage operation of cholecystectomy and biliary reconstruction. Drainage only or resection of the gall bladder or bile duct should depend on the patient's clinical conditions and intraoperative findings. PMID- 22824052 TI - Confluent focal nodular hyperplasia mimicking liver cancer: value of liver specific contrast-enhanced MRI for diagnosis. AB - Focal nodular hyperplasia is the second most common benign hepatic tumor. Unlike adenoma as well as the malignant neoplasms, focal nodular hyperplasia can often be managed successfully without surgery. Use of liver-specific contrast-enhanced magnetic resonance imaging allows clinicians to confirm the diagnosis noninvasively in some patients, allowing select patients to avoid surgery. We report a case of a patient who presented with the rare profile of multiple, confluent lesions that were diagnosed, using magnetic resonance imaging with gadolinium-dimeglumine, as focal nodular hyperplasia. This complicated case was managed successfully and noninvasively based on algorithm found in the recent literature that allows patients to avoid unnecessary surgery. PMID- 22824053 TI - Development of a scale to measure consumer perception of the risks involved in consuming raw vegetable salad in full-service restaurants. AB - The importance of the number of meals taken away-from-home represents an opportunity to promote consumption of vegetables in this context. However, the perception of risk may interfere with the food consumption behavior. The objective of this research was to develop a scale to measure consumer perception of the risks involved in consuming raw vegetable salad in full-service restaurants. The following research steps were carried out: item elaboration; content validity; scale purification (item-total correlation, internal consistency and exploratory factor analysis); and construct validity (confirmatory factor analysis). Non-probabilistic samples of consumers were interviewed (a total of 672 individuals) in the city of Campinas, Brazil. Several analyses were carried out using the Predictive Analytics Software 18.0 and LISREL 8.80. The final scale contained 26 items with an adequate content validity index (0.97) and Cronbach's alpha coefficient (0.93). The confirmatory factor analysis validates a six risk type factor model: physical, psychological, social, time, financial and performance (chi-square/degrees of freedom=2.29, root mean square error of approximation - RMSEA=0.060 and comparative fit index - CFI=0.98). The scale developed presented satisfactory reliability and validity results and could therefore be employed in further studies. PMID- 22824054 TI - Food cravings and food cue responding across the menstrual cycle in a non-eating disordered sample. AB - The study aim was to examine changes in food cue-elicited cravings and the macronutrient content of craved foods across menstrual cycle phases in a non eating disordered sample. Thirty-five college females attended laboratory sessions in the late follicular and late luteal phases. In each session they completed a measure of state food craving before and after exposure to preferred, high fat/high sugar chocolate candy. Candy consumption following cue exposure was measured during an ad libitum "taste test." Additionally, participants rated their desire to eat foods differing systematically and significantly in macronutrient content. Ovulation was confirmed with luteinizing hormone detection kits. Results show that whereas the food cue increased cravings, this effect did not differ between cycle phases examined. The macronutrient content of foods desired also did not differ significantly between cycle phases, however, a non significant trend suggested that high fat/high complex carbohydrate and low fat/high protein foods were more strongly desired in the late luteal phase. Amount of chocolate candy eaten did not differ between cycle phases. These results suggest that cravings for high fat/high sugar foods do not differ between menstrual cycle phases examined, whereas cravings for other foods may fluctuate across cycle phases in non-eating disordered women. PMID- 22824055 TI - Differential changes in impulsivity and sensation seeking and the escalation of substance use from adolescence to early adulthood. AB - Recent evidence suggests that impulsivity and sensation seeking are not stable risk factors for substance use among adolescents and early adults but rather that they undergo significant developmental maturation and change. Further, developmental trends of both personality facets may vary across individuals. In the current investigation, we used longitudinal data from ages 15 to 26 on 5,632 individuals drawn from the offspring generation of the National Longitudinal Survey of Youth to examine whether interindividual differences in intraindividual change in impulsivity and sensation seeking predicted the escalation of alcohol, marijuana, and cigarette use in adolescence and early adulthood. Latent growth curve models revealed significant individual differences in rates of change in both personality and substance use. Age-related changes in personality were positively associated with individual differences in substance-use change. Individuals who declined more slowly in impulsivity increased in alcohol, marijuana, and cigarette more rapidly, whereas individuals who declined more slowly in sensation seeking increased more rapidly in alcohol use only. Although risk for substance use across the population may peak during adolescence and early adulthood, this risk may be highest among those who decline more gradually in impulsivity. PMID- 22824056 TI - Duodopa(r) treatment for advanced Parkinson's disease: a review of efficacy and safety. AB - Enterally administered levodopa/carbidopa gel (Duodopa(r)) is used for the treatment of advanced Parkinson's disease (PD) in patients with motor fluctuations and dyskinesias. This review summarizes the current efficacy and safety data on this drug. Clinically important differences (CID) have been used to assess whether statistical improvements in symptoms translate into meaningful improvements for the patients. A PubMed search in February 2012 found 23 papers with efficacy data and 33 with safety data. Of 11 studies reporting Unified Parkinson's Disease Rating Scale (UPDRS) III scores, 10 found improvements that met the CID of 10.8 points. Of 7 studies reporting UPDRS IV scores, 5 found improvements meeting the CID of 2.3 points. Quality of life (QoL) was assessed in 6 studies using the 8- or 39-question version of the Parkinson's disease Questionnaire, and all reported improvements meeting the CID (10 points). Due to the nature of the data, it is not possible to give exact numbers for the frequency of adverse events. However, the findings seem to be in line with a previous report stating the majority of adverse events were related to the infusion system or surgical procedure rather than the drug. In conclusion, the large majority of studies have reported that Duodopa(r) is clinically effective in relieving the symptoms of advanced PD and improving QoL in comparison with conventional therapy. High-quality randomized trials with larger patient numbers will yield greater insights into the efficacy and safety of this treatment. PMID- 22824058 TI - Feasibility of filamentous fungi for biofuel production using hydrolysate from dilute sulfuric acid pretreatment of wheat straw. AB - BACKGROUND: Lipids produced from filamentous fungi show great promise for biofuel production, but a major limiting factor is the high production cost attributed to feedstock. Lignocellulosic biomass is a suitable feedstock for biofuel production due to its abundance and low value. However, very limited study has been performed on lipid production by culturing oleaginous fungi with lignocellulosic materials. Thus, identification of filamentous fungal strains capable of utilizing lignocellulosic hydrolysates for lipid accumulation is critical to improve the process and reduce the production cost. RESULTS: The growth performances of eleven filamentous fungi were investigated when cultured on glucose and xylose. Their dry cell weights, lipid contents and fatty acid profiles were determined. Six fungal strains with high lipid contents were selected to culture with the hydrolysate from dilute sulfuric acid pretreatment of wheat straw. The results showed that all the selected fungal strains were able to grow on both detoxified liquid hydrolysate (DLH) and non-detoxified liquid hydrolysate (NDLH). The highest lipid content of 39.4% was obtained by Mortierella isabellina on NDLH. In addition, NDLH with some precipitate could help M. isabellina form pellets with an average diameter of 0.11 mm. CONCLUSION: This study demonstrated the possibility of fungal lipid production from lignocellulosic biomass. M. isabellina was the best lipid producer grown on lignocellulosic hydrolysates among the tested filamentous fungi, because it could not only accumulate oils with a high content by directly utilizing NDLH to simplify the fermentation process, but also form proper pellets to benefit the downstream harvesting. Considering the yield and cost, fungal lipids from lignocellulosic biomass are promising alternative sources for biodiesel production. PMID- 22824057 TI - New highly sensitive rodent and human tests for soluble amyloid precursor protein alpha quantification: preclinical and clinical applications in Alzheimer's disease. AB - BACKGROUND: Amyloid precursor protein (APP), a key molecule in Alzheimer's disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPPalpha). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPPalpha in CSF as a biomarker has not been clearly established. sAPPalpha has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required. METHODS: The tests are based on homogenous time-resolved fluorescence and require no washing steps. RESULTS: We describe two new rapid and sensitive tests for quantifying mouse and human sAPPalpha. These 20 MUl-volume tests quantify the levels of: i) endogenous mouse sAPPalpha in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPPalpha in the CSF of AD mouse models, and iii) human sAPPalpha in the CSF of AD and non-AD patients. These tests require only 5 MUl of conditioned medium from 5 * 10(4) mouse primary neurons, 1 MUl of CSF from wild-type and transgenic mice, and 0.5 MUl of human CSF. CONCLUSIONS: The high sensitivity of the mouse sAPPalpha test will allow high throughput investigations of molecules capable of increasing the secretion of endogenous sAPPalpha in primary neurons, as well as the in vivo validation of molecules of interest through the quantification of sAPPalpha in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPPalpha in the CSF through the progression of the disease. Finally, the human sAPPalpha test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies. PMID- 22824060 TI - Enterocytozoon bieneusi at the wildlife/livestock interface of the Kruger National Park, South Africa. AB - This study investigates the presence of Enterocytozoon bieneusi in domestic and wild animals living in the wildlife/livestock interface area of the Kruger National Park (KNP) in South Africa. Fifty fecal samples from domestic calves in rural communities and 142 fecal samples from impala (Aepyceros melampus) and buffalo (Syncerus caffer) in the KNP were analysed for Enterocytozoon bieneusi, using a nested PCR targeting the internal transcribed spacer of the rRNA gene. All wildlife samples were negative for E. bieneusi, whereas nine (18%) calf samples were positive. Three cattle specific genotypes (group 2) were identified, belonging to the known genotypes BEB4 and I, and one novel genotype (BEB3-like). One human-pathogenic genotype (D) was detected in one calf. This is the first study on microsporidia performed in a wildlife/livestock interface area of sub Saharan Africa. Our findings show that at least one genotype of zoonotic importance is circulating in native cattle in the study area and the rest of the identified microsporidia were host-specific genotypes. Larger studies in domestic animals, humans and wildlife are necessary to assess the public health significance of E. bieneusi in that interface area. PMID- 22824059 TI - Open-label trial with artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria three years after its broad introduction in Jimma Zone, Ethiopia. AB - BACKGROUND: In Jimma Zone, Ethiopia, the first-line treatment of uncomplicated falciparum malaria has been changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (AL) in 2006. The objective of this study was to assess the effectiveness of AL in Jimma Zone two to three years after its broad introduction. METHODS: An open-label, single-arm, 42-day study of AL against falciparum malaria was conducted in four areas with moderate transmission in Jimma Zone between November 2008 and January 2009 and between August and December 2009. Patients (one-81 years) with uncomplicated Plasmodium falciparum mono infection were consecutively enrolled. Follow-up visits were at day 2, 3, 7, 28 and 42 or any other day if symptoms reoccurred. Primary and secondary endpoints were PCR-corrected and uncorrected cure rates (molecular differentiation between recrudescence and re-infection) on days 28 and 42. Other secondary endpoints were gametocytaemia at day 7 and day 28, parasitaemia at day 2 and 3, and re-infection rates at day 28 and day 42. RESULTS: Of 348 enrolled patients, 313 and 301 completed follow-up at day 28 and at day 42, respectively. No early treatment failure occurred. For per protocol analysis, PCR-uncorrected cure rates at day 28 and 42 were 99.1% (95% CI 98.0-100.0) and 91.1% (95% CI 87.9-94.3), respectively. PCR-corrected cure rates at day 28 and 42 were 99.4% (95% CI 98.5-100.0) and 94.7% (95% CI 92.2-97.2), respectively. PCR-corrected cure rate at day 42 for children <= 5 years was 90.6% (95% CI 82.4-98.7) only. Adverse events were in general mild to moderate. Incidence of new infections was 3.4% during 42 days, no new infections with Plasmodium vivax were observed. Microscopically detected gametocytaemia was reduced by 80% between day 0 and day 7. CONCLUSION: In general, AL was effective and well tolerated in Jimma Zone, Ethiopia. However, the PCR-corrected recrudescence rate per-protocol at day 42 for children <= 5 years was 9.4%. Therefore, further development should be monitored on a regular basis as recommended by WHO. PMID- 22824062 TI - First case report of infection caused by Encephalitozoon intestinalis in a domestic cat and a patient with AIDS. AB - Microsporidia are eukaryotic, intracellular obligate parasites that infect invertebrate and vertebrate animals, and have emerged as important opportunistic parasites in AIDS patients. We used light microscopy to detect microsporidial spores in stool samples of a domestic cat confirmed as Encephalitozoon intestinalis by PCR, owned by an AIDS patient with chronic diarrhea and E. intestinalis infection. Cats can be considered hosts of E. intestinalis. PMID- 22824061 TI - A multicentre prevalence study in Europe on Giardia duodenalis in calves, with molecular identification and risk factor analysis. AB - The present study aimed to obtain data on the occurrence of Giardia duodenalis in calves in four major cattle rearing countries in Europe (Germany, UK, France and Italy), along with genotyping data and risk factors associated with these infections. A total of 2072 calves were sampled on 207 farms. The majority of the animals were Holstein dairy or mixed Holstein calves (n=1565 or 75.5%), and were female (n=1640 or 79.1%). The average age was 7.8 weeks (SD=4.1; median=7; range=2-16 weeks). All fecal samples were tested using a commercially available monoclonal antibody-based ELISA. The overall apparent prevalence of G. duodenalis for the four countries was 45.4% (n=942/2072) and the overall farm prevalence was 89.9% (186/207), with differences in both animal and farm prevalence between the four countries. The prevalence was significantly higher in animals up to 8 weeks (OR=1.88; P<0.001) compared to older calves, and several management factors including contact with the Dam, Frequency of cleaning of the Maternity Pens, and Disinfection of the Calf Housing were found to be associated with infection. Positive samples were withheld for genotyping using the beta-giardin and triose phosphate isomerase gene: G. duodenalis assemblage E was most prevalent, although 43% of the isolates were typed as assemblage A, with differences in between countries. Furthermore, 32% of the examined samples was found to be a mixed assemblage A and E infection, which is consistent with previous reports. The results of the present study confirm previous findings in other European countries that G. duodenalis infections are common in calves. The infection especially occurs in animals younger than 2 months, and the proportion of positive animals gradually decreased with increasing age. PMID- 22824063 TI - Evaluation of plant species used traditionally to treat myiasis for activity on the survival and development of Lucilia cuprina and Chrysomya marginalis (Diptera: Calliphoridae). AB - Myiasis is a common parasitic problem of livestock responsible for severe economic losses in developing and developed countries. There are a number of challenges with the current control strategy, which depends largely on the use of pharmaceutical chemicals. These include inaccessibility, the increasing concern about pesticide accumulation in the environment and potential development of insecticide resistance in the devastating myiasis-causing flies. Consequently the search for alternatives is important. The use of plants in the treatment of wound myiasis in livestock as an alternative to commercial insecticides has been reported in resource poor areas worldwide. We therefore, undertook a study to establish the biological activity of seven plant species used against blowflies in southern Africa. A larvicidal assay was carried out in which third instar larvae of blowfly were fed meat treated with acetone leaf extracts of selected plant species. Four of the species, Aloe zebrina, Clausena anisata, Erythrina lysistemon and Spirostachys africana, induced developmental anomalies in the blowfly such as paralysis, prolongation of the prepuparium stage, reduced pupation rates, pupal malformations and reduced adult emergence. These results suggest that the plants may contain compounds that interfere with the neuroendocrine control mechanisms in the blowfly. PMID- 22824064 TI - Dependence of viscosity of suspensions of ceramic nanopowders in ethyl alcohol on concentration and temperature. AB - : This work presents results of measurements of viscosity of suspensions including yttrium oxide (Y2O3), yttrium aluminum garnet (Y3Al5O12) and magnesium aluminum spinel (MgAl2O4) nanopowders in ethanol. Nanoparticles used in our research were either commercially available (Baikowski) or nanopowders newly developed in the Institute of Ceramics and Building Materials in Warsaw, Poland. The study was conducted in a wide range of shear rates (0.01 to 2,000 s-1) and temperature interval from -15 degrees C to 20 degrees C. A Haake Mars 2 rheometer from Thermo Fisher, Germany, was used in the Biophysics Laboratory at Rzeszow University of Technology. Most of the samples show a non-Newtonian behaviour. It was confirmed with a Rheo-NMR system from Bruker that 10% by weight of Y2O3 suspension is a non-Newtonian fluid. In this work, we also report an unexpected behaviour of the viscosity of some samples (Y2O3 and Y3Al5O12) due to sedimentation effect. PMID- 22824065 TI - Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment. AB - BACKGROUND: Several studies suggest an increase of oxidative stress and a reduction of endothelial function in obstructive sleep apnoea syndrome (OSAS). We assessed the association between OSAS, endothelial dysfunction and oxidative stress. Further aim was to evaluate the effect of nasal continuous positive airway pressure (nCPAP) on oxidative stress and arterial dysfunction. METHODS: We studied 138 consecutive patients with heavy snoring and possible OSAS. Patients underwent unattended overnight home polysomnography. Ten patients with severe OSAS were revaluated after 6 months of nCPAP therapy. To assess oxidative stress in vivo, we measured urinary 8-iso-PGF2alpha and serum levels of soluble NOX2 derived peptide (sNOX2-dp). Serum levels of nitrite/nitrate (NOx) were also determined. Flow-mediated brachial artery dilation (FMD) was measured to asses endothelial function. RESULTS: Patients with severe OSAS had higher urinary 8-iso PGF2alpha (p<0.001) and serum NOX2 and lower NOx. A negative association was observed between FMD and OSA severity. Apnea/hypopnea index was significantly correlated with the indices of central obesity and with urinary 8-isoprostanes (r=0.298, p<0.001). The metabolic syndrome (t=-4.63, p<0.001) and urinary 8 isoprostanes (t=-2.02, p<0.05) were the only independent predictors of FMD. After 6-months nCPAP treatment, a significant decrease of serum NOX2, (p<0.005) and urinary 8-iso-PGF2alpha (p<0.01) was observed, while serum NOx showed only a minor increase. A statistically significant increase of FMD was observed (from 3.6% to 7.0%). CONCLUSIONS: The results of our study indicate that patients with OSAS and cardiometabolic comorbidities have increased oxidative stress and arterial dysfunction that are partially reversed by nCPAP treatment. PMID- 22824066 TI - A natural vanishing act: the enzyme-catalyzed degradation of carbon nanomaterials. AB - Over the past three decades, revolutionary research in nanotechnology by the scientific, medical, and engineering communities has yielded a treasure trove of discoveries with diverse applications that promise to benefit humanity. With their unique electronic and mechanical properties, carbon nanomaterials (CNMs) represent a prime example of the promise of nanotechnology with applications in areas that include electronics, fuel cells, composites, and nanomedicine. Because of toxicological issues associated with CNMs, however, their full commercial potential may not be achieved. The ex vitro, in vitro, and in vivo data presented in this Account provide fundamental insights into the biopersistence of CNMs, such as carbon nanotubes and graphene, and their oxidation/biodegradation processes as catalyzed by peroxidase enzymes. We also communicate our current understanding of the mechanism for the enzymatic oxidation and biodegradation. Finally, we outline potential future directions that could enhance our mechanistic understanding of the CNM oxidation and biodegradation and could yield benefits in terms of human health and environmental safety. The conclusions presented in this Account may catalyze a rational rethinking of CNM incorporation in diverse applications. For example, armed with an understanding of how and why CNMs undergo enzyme-catalyzed oxidation and biodegradation, researchers can tailor the structure of CNMs to either promote or inhibit these processes. In nanomedical applications such as drug delivery, the incorporation of carboxylate functional groups could facilitate biodegradation of the nanomaterial after delivery of the cargo. On the other hand, in the construction of aircraft, a CNM composite should be stable to oxidizing conditions in the environment. Therefore, pristine, inert CNMs would be ideal for this application. Finally, the incorporation of CNMs with defect sites in consumer goods could provide a facile mechanism that promotes the degradation of these materials once these products reach landfills. PMID- 22824068 TI - Variants of CD38 gene and lipid metabolism: a link in chronic lymphocytic leukemia? PMID- 22824067 TI - Growth and development of the ovary and small follicle pool from mid fetal life to pre-puberty in the African elephant (Loxodonta africana). AB - BACKGROUND: Follicle numbers and developing ovarian morphology, particularly with reference to the presence of interstitial tissue, are intimately linked within the ovary of the African elephant during the period spanning mid-gestation to puberty. These have not been previously quantified in any studies. The collection of 7 sets of elephant fetal ovaries between 11.2 and 20.2 months of gestation, and 29 pairs of prepubertal calf ovaries between 2 months and 9 years of age during routine management off-takes of complete family groups in private conservancies in Zimbabwe provided an opportunity for a detailed study of this period. RESULTS: The changing morphology of the ovary is described as the presumptive cortex and medulla components of the fetal ovary settled into their adult form. Interstitial tissue dominated the ovary in late fetal life and these cells stained strongly for 3beta-hydroxysteroid dehydrogenase. This staining continued postnatally through to 4.5 years of age suggesting continued secretion of progestagens by the ovary during this period. The considerable growth of antral follicles peaked at 28% of ovarian volume at around 16.7 months of fetal age. The numbers of small follicles (primordial, early primary and true primary), counted in the cortex using stereological protocols, revealed fewer small follicles in the ovaries of animals aged 0 to 4.5 years of age than during either late fetal life or prepubertal life. CONCLUSIONS: The small follicle populations of the late-fetal and prepubertal ovaries of the African elephant were described along with the changing morphology of these organs. The changes noted represent a series of events that have been recorded only in the elephant and the giraffe species to date. The expansion of the interstitial tissue of the fetal ovary and its continued presence in early post natal life may well contribute to the control of follicle development in these early years. Further research is required to determine the reasons behind the variation of numbers of small follicles in the ovaries of prepubertal calves. PMID- 22824069 TI - Shedding of genes that interfere with the pathogenic lifestyle: the Shigella model. AB - Pathoadaptive mutations are evolutionary events leading to the silencing of specific anti-virulence loci. This reshapes the core genome of a novel pathogen, adapts it to the host and boosts its harmful potential. A paradigmatic case is the emergence of Shigella, the causative agent of bacillary dysentery, from its innocuous Escherichia coli ancestor. Here we summarize current views on how pathoadaptation has allowed Shigella to progressively increase its virulence. In this context, modification of the polyamine pattern emerges as a crucial step towards full expression of the virulence program in Shigella. PMID- 22824070 TI - Megraft: a software package to graft ribosomal small subunit (16S/18S) fragments onto full-length sequences for accurate species richness and sequencing depth analysis in pyrosequencing-length metagenomes and similar environmental datasets. AB - Metagenomic libraries represent subsamples of the total DNA found at a study site and offer unprecedented opportunities to study ecological and functional aspects of microbial communities. To examine the depth of a community sequencing effort, rarefaction analysis of the ribosomal small subunit (SSU/16S/18S) gene in the metagenome is usually performed. The fragmentary, non-overlapping nature of SSU sequences in metagenomic libraries poses a problem for this analysis, however. We introduce a software package - Megraft - that grafts SSU fragments onto full length SSU sequences, accounting for observed and unobserved variability, for accurate assessment of species richness and sequencing depth in metagenomics endeavors. PMID- 22824071 TI - Er:YAG lasers versus ultrasonic and hand instruments in periodontal therapy: clinical parameters, intracrevicular micro-organism and leukocyte counts. AB - OBJECTIVE: The aim of this study was to compare the clinical parameters and crevicular cell population, particularly leukocyte counts, changes after initial periodontal therapy with different instruments by a chairside laboratory technique, in severe periodontitis patients. BACKGROUND DATA: Although scaling and root planing (SRP) with hand curettes or ultrasonic scalers may alter the subgingival microbial composition and improve clinical parameters, it is known that this effect decreases as the pocket depth (PD) increases. MATERIAL AND METHODS: Thirty systemically healthy subjects with severe chronic periodontitis were randomly assigned to three groups (n=10), and were treated either with hand curettes, ultrasonic scalers, or Er:YAG laser alone. Clinical measurements were made before and 90 days after treatment. A total of four subgingival plaque samples were collected from pockets with a PD 4-6 and >=7 mm and were analyzed with a phase-contrast microscopy for microorganism proportions and leukocyte counts at baseline and 7 and 90 days after treatment. RESULTS: From day 0 to day 90, clinical parameters were significantly improved in all groups (p<0.01), but there were no significant differences among groups. Laboratory assessments revealed significant differences in all groups between baseline, day 7, and day 90. However, considering changes from day 7 to day 90, hand curettes were the most successful for maintaining the levels of micro-organisms and leukocytes. CONCLUSIONS: Although Er:YAG lasers are promising in treating periodontitis, the results of this study favor finishing SRP with hand curettes. Moreover, as there is a similar tendency between micro-organism and leukocyte count changes, leukocyte counts may be used as chairside marker to evaluate the efficacy of SRP. PMID- 22824072 TI - The effect of quercetin on human neutrophil elastase-induced mucin5AC expression in human airway epithelial cells. AB - Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. Mucus hypersecretion is a common pathological change in chronic inflammatory diseases of the airway. We investigated the effect of quercetin on mucin 5AC (MUC5AC) expression induced by human neutrophil elastase (HNE) in airway epithelial cells and its molecular mechanisms. Human airway epithelial (HBE16) cells were pretreated with quercetin and were treated with HNE. We found that HNE induced a significant increase in the levels of MUC5AC and EGFR in cells treated only with HNE. Quercetin suppressed gene transcription and protein expression of MUC5AC in a dose-dependent manner, with significant inhibition from 40 MUM. mRNA and protein expressions of EGFR decreased markedly when pretreated with quercetin. Among three MAPK proteins, only phosphorylated ERK1/2 protein expression increased significantly after treatment with HNE alone and decreased significantly after pretreatment with quercetin. HNE also activated phosphorylated PKC protein expression which was attenuated when pretreated with quercetin. These results suggest that quercetin can inhibit HNE-induced MUC5AC expression in human airway epithelial cells through PKC/EGFR/ERK signal transduction pathway. In the future, quercetin might be a valuable treatment for mucin hypersecretion in chronic inflammatory airway diseases in clinic. PMID- 22824073 TI - Sauchinone suppresses lipopolysaccharide-induced inflammatory responses through Akt signaling in BV2 cells. AB - Activated microglial cells play an important role in inflammatory responses in the central nervous system (CNS) that are involved in neurodegenerative diseases. Sauchinone has been shown to modulate the expression of inflammatory factors through nuclear factor-kappa B (NF-kappaB) signaling pathway. Here, we examined the effect of sauchinone on the inflammatory responses of microglia cells induced by lipopolysaccharide (LPS) and explored the mechanism underlying action of sauchinone. BV2 cells treated with LPS showed an up-regulation of nitric oxide (NO) and prostaglandin (PGE(2)) release, whereas sauchinone suppressed this up regulation. Sauchinone inhibited both mRNA and protein expression of COX-2, iNOS, TNF-alpha and IL-1beta. In addition, sauchinone blocked the activation of NF kappaB through its inhibition of I-kappaB phosphorylation. Interestingly, sauchinone had no effect on the LPS-induced phosphorylation of mitogen activated protein kinases (MAP kinases; ERK1/2, p38, JNK), but it did inhibit Akt phosphorylation. These results suggest that the inhibitory effect of sauchinone on the LPS-induced production of inflammatory mediator in BV2 cells is associated with the suppression of the NF-kappaB and Akt signaling pathways. Therefore, sauchinone may be a useful treatment for neurodegenerative disease by inhibiting inflammatory responses in activated microglia. PMID- 22824074 TI - The volatile anesthetic sevoflurane inhibits activation of neutrophil granulocytes during simulated extracorporeal circulation. AB - Extracorporeal circulation (ECC) is an essential tool for the execution of cardiac operations. However, ECC is also associated with undesirable side effects. These include the induction of a systemic inflammatory response associated with leukocyte activation and cytokine release as well as potentially life-threatening complications. The volatile anesthetic sevoflurane has been reported to exert anti-ischemic and anti-inflammatory effects. We therefore investigated whether sevoflurane modulates the ECC-triggered inflammatory response. Heparinized human blood was circulated for 90 min in a normothermic (37 degrees C) ex vivo ECC circuit. An air-oxygen mixture was administered via an oxygenator in controls (n=5). Sevoflurane (2 vol.%) was added to the gas mixture in a second group (n=5). At baseline and after 30, 60 and 90 min of ECC, blood samples were taken. In each sample whole blood counts were determined. Expression of the activation-indicating Mac-1 receptor on granulocytes and monocytes as well as leukocyte-platelet aggregate formation was measured in flow cytometry. Levels of the granulocyte activation marker PMN-elastase and of the cytokines IL-1beta, IL-8 and TNF-alpha were analyzed using ELISA. ECC induced significant increases in Mac-1 expression on granulocytes (p<0.001) and PMN-elastase release (p<0.001). Sevoflurane decreased granulocyte Mac-1 expression during ECC (p<0.05) and inhibited the ECC-induced PMN-elastase release (p<0.05). Sevoflurane had no effect on whole blood cell counts, leukocyte-platelet aggregate formation and cytokine release during ECC. Sevoflurane inhibits granulocyte activation during ex vivo ECC and therefore has the potential to decrease the ECC-triggered inflammatory response. This promising finding warrants further investigation under clinical conditions. PMID- 22824076 TI - Analysis of plasma indices of redox homeostasis in dairy cows reared in polluted areas of Piedmont (northern Italy). AB - Steel manufacturing is responsible for the emission of pollutants, including dioxins and transition metals, inducing reactive oxygen species generation and DNA damage. Dioxin pollution represents the major cause of milk and dairy product contamination, in Italy, and is associated with oxidative stress-related processes, that may impair health and performance of cows. We evaluated the effect of exposure to different concentrations of pollutants derived from steel manufacturing on blood redox homeostasis of bovine cows. We analyzed two groups of dairy cows (A, B), reared in two different polluted areas, and a control group of cows bred in an industry free area. The extent of exposure to contaminants was defined by measuring dioxin level in bulk milk samples collected from animals of each farm. This level was lower in milk of group A than in group B. Plasma concentrations of retinol, alpha-tocopherol and ascorbate, the total antioxidant capacity, and the activities of superoxide dismutase and glutathione peroxidase were higher in control group than in exposed groups. In particular, retinol and tocopherol levels were higher in the group with lower milk dioxin level. Plasma titers of protein-bound carbonyls (PC), nitro-tyrosine, and hydroperoxides were lower in control group than in A or B. Hydroperoxides and PC plasma concentrations were increased in the group with higher milk concentration of dioxin. Our results demonstrate that, irrespective of the nature of chemicals inducing oxidative modifications, the extent of damage to plasma protein and lipid, is correlated with the concentration of dioxin in milk. So, the characterization of blood redox status might be a useful tool for identifying animals exposed to environmental pollutants. Plasma concentrations of retinol, alpha-tocopherol, PC and hydroperoxides could therefore represent good indices of the extent of animal exposure, as they significantly change in groups with different milk concentrations of dioxin. PMID- 22824075 TI - Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays. AB - With the discovery that the hereditary cancer susceptibility disease Lynch syndrome (LS) is caused by deleterious germline mutations in the DNA mismatch repair (MMR) genes nearly 20 years ago, genetic testing can now be used to diagnose this disorder in patients. A definitive diagnosis of LS can direct how clinicians manage the disease as well as prevent future cancers for the patient and their families. A challenge emerges, however, when a germline missense variant is identified in a MMR gene in a suspected LS patient. The significance of a single amino acid change in these large repair proteins is not immediately obvious resulting in them being designated variants of uncertain significance (VUS). One important strategy for resolving this uncertainty is to determine whether the variant results in a non-functional protein. The ability to reconstitute the MMR reaction in vitro has provided an important experimental tool for studying the functional consequences of VUS. However, beyond this repair assay, a number of other experimental methods have been developed that allow us to test the effect of a VUS on discrete biochemical steps or other aspects of MMR function. Here, we describe some of these assays along with the challenges of using such assays to determine the functional consequences of MMR VUS which, in turn, can provide valuable insight into their clinical significance. With increased gene sequencing in patients, the number of identified VUS has expanded dramatically exacerbating this problem for clinicians. However, basic science research laboratories around the world continue to expand our knowledge of the overall MMR molecular mechanism providing new opportunities to understand the functional significance, and therefore pathogenic significance, of VUS. PMID- 22824077 TI - Distribution and characterization of organochlorine pesticides and polycyclic aromatic hydrocarbons in surface sediment from Poyang Lake, China. AB - The concentrations of organochlorine pesticides (OCPs) and 16 priority polycyclic aromatic hydrocarbons (PAHs) were investigated in the sediments from Poyang Lake, the largest freshwater lake in China. The results showed that the total concentrations of four hexachlorocyclohexane (HCH) isomers (alpha-HCH, beta-HCH, gamma-HCH, delta-HCH), three dichlorodiphenyltrichloroethane (DDT) homologs and their metabolites (p,p'-DDD, o,p'-DDD, p,p'-DDE, p,p'-DDT, o,p'-DDT, o,p'-DDE), sodium pentachlorophenate and PAHs varied from 0.536+/-0.330 to 6.937+/-2.655, 14.421+/-5.260 to 82.871+/-31.258, 15.346+/-6.935 to 48.254+/-16.836, and 33.0+/ 11.5 to 369.1+/-138.5 MUg/kg, respectively. The concentrations of HCH isomers followed the order: gamma-HCH>beta-HCH>delta-HCH>alpha-HCH. The most dominant gamma-HCH ranged from 0.253+/-0.155 to 3.465+/-1.010 MUg/kg, suggesting a recent input of lindane. p,p'-DDD was the most dominant pollutant of DDTs, with a mean concentration of 31.684+/-13.530 MUg/kg. The ratios of (DDE+DDD)/DDT ranged from 75+/-24 to 360+/-115, indicating no recent input of DDTs. The PAHs were mainly originated from liquid fossil fuel combustion and leakage, except at Pojiang River estuary, where the pyrogenic source (coal, grass and wood combustion) was dominant. Several PAH metabolites were identified and the possible degradation pathways were proposed. PMID- 22824078 TI - Aerosol ionic components at Mt. Heng in central southern China: abundances, size distribution, and impacts of long-range transport. AB - Water-soluble ions in PM(2.5) were continuously measured, along with the measurements of many other species and collection of size-resolved aerosol samples, at the summit of Mt. Heng in the spring of 2009, to understand the sources of aerosols in rural central southern China. The mean concentrations of SO(4)(2-), NH(4)(+) and NO(3)(-) in PM(2.5) were 8.02, 2.94 and 1.47 MUg/m(3), indicating a moderate aerosol pollution level at Mt. Heng. Water-soluble ions composed approximately 40% of the PM(2.5) mass on average. PM(2.5) was weakly acidic with about 66% of the samples being acidic. SO(4)(2-), NO(3)(-) and NH(4)(+) exhibited similar diurnal patterns with a broad afternoon maximum. SO(4)(2-) and NH(4)(+) were mainly present in the fine aerosols with a peak in the droplet mode of 0.56-1 MUm, suggesting the important role of cloud processing in the formation of aerosol sulfate. NO(3)(-) was largely distributed in the coarse particles with a predominant peak in the size-bin of 3.2-5.6 MUm. Long distance transport of processed air masses, dust aerosols, and cloud/fog processes were the major factors determining the variations of fine aerosol at Mt. Heng. The results at Mt. Heng were compared with those obtained from our previous study at Mt. Tai in north China. The comparison revealed large differences in the aerosol characteristics and processes between southern and northern China. Backward trajectories indicated extensive transport of anthropogenic pollution from the coastal regions of eastern/northern China and the Pearl River Delta (PRD) to Mt. Heng in spring, highlighting the need for regionally coordinated control measures for the secondary pollutants. PMID- 22824079 TI - A randomized phase II trial to elucidate the efficacy of capecitabine plus cisplatin (XP) and S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment vs. SP randomized PII trial (XParTS II). AB - BACKGROUND: On the basis of international clinical trials, capecitabine plus cisplatin (XP) as a first-line treatment of advanced gastric cancer is considered a global standard regimen. However, the usefulness of XP as compared with S-1 plus cisplatin (SP), which is considered standard therapy in Japan, has not yet been assessed. METHODS/DESIGN: This is a multicenter randomized phase II trial to elucidate the efficacy of XP as compared with SP for first-line treatment of advanced gastric cancer. Patients with unresectable metastatic or recurrent gastric cancer, 20-74 years of age and human epidermal growth factor 2 (HER2) negative status, will be assigned in a 1:1 ratio to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3 week cycle. Patients will be also asked to the analysis of tumor tissues for translational investigations. The Primary endpoint is progression-free survival and secondary endpoints are overall survival, time to treatment failure, tumor response rate and safety. These comparisons will also be evaluated in terms of biomarkers. Planned sample size is 100 (50 in each arm), which is appropriate for this trial. DISCUSSION: Fluoropyrimidine plus cisplatin combination is the standard regimen of the first line treatment for advanced gastric cancer. Both S 1 and capecitabine are the prodrug of 5-FU but differ from their process of metabolism. Result of this trial and translational research will provide the important clues to prepare the individualized therapy for advanced gastric cancer in the near future. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01406249. PMID- 22824080 TI - [Reporting and grading of complications after urologic surgical procedures: an ad hoc EAU guidelines panel assessment and recommendations]. AB - CONTEXT: The incidence of postoperative complications is still the most frequently used surrogate marker of quality in surgery, but no standard guidelines or criteria exist for reporting surgical complications in the area of urology. OBJECTIVE: To review the available reporting systems used for urologic surgical complications, to establish a possible change in attitude towards reporting of complications using standardised systems, to assess systematically the Clavien-Dindo system when used for the reporting of complications related to urologic surgical procedures, to identify shortcomings in reporting complications, and to propose recommendations for the development and implementation of future reporting systems that are focused on patient-centred outcomes. EVIDENCE ACQUISITION: Standardised systems for reporting and classification of surgical complications were identified through a systematic review of the literature. To establish a possible change in attitude towards reporting of complications related to urologic procedures, we performed a systematic literature search of all papers reporting complications after urologic surgery published in European Urology, Journal of Urology, Urology, BJU International, and World Journal of Urology in 1999-2000 and 2009-2010. Data identification for the systematic assessment of the Clavien-Dindo system currently used for the reporting of complications related to urologic surgical interventions involved a Medline/Embase search and the search engines of individual urologic journals and publishers using Clavien, urology, and complications as keywords. All selected papers were full-text retrieved and assessed; analysis was done based on structured forms. EVIDENCE SYNTHESIS: The systematic review of the literature for standardised systems used for reporting and classification of surgical complications revealed five such systems. As far as the attitude of urologists towards reporting of complications, a shift could be seen in the number of studies using most of the Martin criteria, as well as in the number of studies using either standardised criteria or the Clavien-Dindo system. The latter system was not properly used in 72 papers (35.3%). CONCLUSIONS: Uniformed reporting of complications after urologic procedures will aid all those involved in patient care and scientific publishing (authors, reviewers, and editors). It will also contribute to the improvement of the scientific quality of papers published in the field of urologic surgery. When reporting the outcomes of urologic procedures, the committee proposes a series of quality criteria. PMID- 22824081 TI - [Acute arthritis secondary to intravesical bacillus Calmette-Guerin for bladder cancer]. AB - INTRODUCTION: We sought to identify the prevalence, presentation, treatment, and prognosis of acute arthritis secondary to intravesical bacilli Calmette-Guerin (BCG) therapy for bladder cancer. METHODS: We performed a structured, systematic review of the English language literature pertaining to BCG and reactive arthritis among bladder cancer patients. We extracted data pertaining to prevalence, presentation, management, and prognosis. RESULTS: We extracted 23 individual case reports and 4 review articles. Thirty-nine patients -31 (80%) male and 8 (20%) female- were described in these publications; we also identified 1 patient from our institution. Although prevalence estimates of reactive arthritis range from 0.5 to 1.0% of all bladder cancer patients receiving BCG, the true prevalence remains unclear. Polyarthritis (68%) and fever (58%) were the most common presenting symptoms. Among patients presenting with joint pain, the knees (41%), ankles (26%), and wrists (19%) were most often affected. The most common time of presentation was immediately following the 4th instillation of a 6 week induction course (25%). Initial therapy in 100% of patients was discontinuation of BCG. Other therapies included nonsteroidal anti-inflammatory drugs (NSAIDs) (25%); steroids (8%); anti-tubercular medications (8%); and combined NSAIDs, steroids, and anti-tubercular medications (20%). CONCLUSIONS: Reactive arthritis is an infrequent but potentially severe complication of intravesical BCG for bladder cancer that typically presents with polyarthritis and fever during induction. The most common treatments include immediate discontinuation of BCG and systemic anti-inflammatory therapy. Further studies are needed to determine prevalence, pathophysiology, and long-term prognosis. PMID- 22824082 TI - Sepsis: will awareness improve outcome? PMID- 22824083 TI - The early phase of human sepsis is characterized by a combination of apoptosis and proliferation of T cells. AB - PURPOSE: T cell activation as well as unresponsiveness has been described in separate studies in sepsis. Our aim was to establish the coexistence of both T cell fate in human sepsis. PATIENTS AND METHODS: This is a cross-sectional study of 48 patients presenting with severe sepsis or septic shock and 15 healthy controls. Cytofluorometric techniques were used to quantify T cell activation, apoptosis, proliferation, expression of costimulatory molecules, and cytokine secretion. RESULTS: Patients with sepsis were characterized by a significant increase in the percentage of activated T cell subsets, as measured using CD69 marker, compared with healthy controls (P<.05). T cell proliferation as measured through Ki67 expression was obvious in infected patients for both CD4 and CD8 T cell subsets compared with controls (P <=.006). T cell subset apoptosis as measured using Hoechst dye was also increased in infected patients compared with controls (P <=.002). CD4 T cell proliferation was correlated with interleukin 2 secretion (R(2)=0.84, P<.001), whereas up-regulation of CD4 T cell apoptosis was correlated with CTLA-4 expression (R(2)=0.24, P=.001). No such similar relationship was observed for CD8(+) T cells. CONCLUSIONS: Concomitant T cell proliferation and T cell apoptosis are observed in human sepsis, being related to a different pathway. PMID- 22824084 TI - Stop sepsis-save lives: A call to join the global coalition for the World Sepsis Day. PMID- 22824085 TI - Efficacy of information interventions in reducing transfer anxiety from a critical care setting to a general ward: a systematic review and meta-analysis. AB - PURPOSE: Our aim was to undertake a comprehensive systematic review on the efficacy of information interventions on reducing anxiety in patients and family members on transfer from a critical care setting to a general ward. MATERIALS AND METHODS: MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Google Scholar databases from 1990 to January 1, 2011, were searched. Bibliographies of identified articles were reviewed. Only high-quality randomized controlled trials comparing an intervention to reduce transfer anxiety with standard care, where transfer anxiety is measured by the validated State Trait Anxiety Inventory, were included. Data were extracted to estimate standard mean differences (SMDs), pooled odds ratios (ORs), and 95% confidence intervals (CIs) using both fixed and random effects model. RESULTS: Of 266 studies identified in the primary search, 5 studies enrolling 629 participants met the inclusion criteria, family members' transfer anxiety was significantly reduced in the intervention arm of information provision (OR, 1.70; 95% CI, 1.15-2.52; P = .01) compared with those who received standard care (OR, 0.42; 95% CI; 0.276-0.625; P < .001), and patients' transfer anxiety was significantly reduced in one study. CONCLUSIONS: Providing information to understand a future ward environment can significantly reduce patients' and family members' transfer anxiety from the critical care setting when compared with standard care. PMID- 22824087 TI - Aqueous extract of Artemisia iwayomogi Kitamura attenuates cholestatic liver fibrosis in a rat model of bile duct ligation. AB - Cholestatic liver fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins, is associated with bile acid-induced oxidative stress and lipid peroxidation. We evaluated the therapeutic or protective effect of an aqueous extract of Artemisia iwayomogi Kitamura (WAI) in a rat bile duct ligation (BDL)-induced hepatic fibrogenesis model. After BDL, rats were treated once daily with 25 or 50 mg/kg of WAI for 2weeks. The serum bilirubin, aspartate transaminase, alanine transaminase, malondialdehyde, and liver hydroxyproline levels were drastically increased in the BDL group. WAI administration significantly reduced these markers and restored BDL-induced depletion of glutathione content and glutathione peroxidase activity. Cholestatic liver injury and collagen deposition were markedly attenuated by WAI treatment, and these changes were paralleled by significantly suppressed gene and protein expression of fibrogenic factors, including hepatic alphasmooth muscle actin, platelet-derived growth factor, and transforming growth factor beta. Our data suggest that WAI may have antifibrotic properties via both improvement of antioxidant activities and inhibition of ECM protein production in the rat model of BDL. PMID- 22824086 TI - Target binding to S100B reduces dynamic properties and increases Ca(2+)-binding affinity for wild type and EF-hand mutant proteins. AB - Mutations in the second EF-hand (D61N, D63N, D65N, and E72A) of S100B were used to study its Ca(2+) binding and dynamic properties in the absence and presence of a bound target, TRTK-12. With (D63N)S100B as an exception ((D63N)K(D)=50+/-9 MUM), Ca(2+) binding to EF2-hand mutants were reduced by more than 8-fold in the absence of TRTK-12 ((D61N)K(D)=412+/-67 MUM, (D65N)K(D)=968+/-171 MUM, and (E72A)K(D)=471+/-133 MUM), when compared to wild-type protein ((WT)K(D)=56+/-9 MUM). For the TRTK-12 complexes, the Ca(2+)-binding affinity to wild type ((WT+TRTK)K(D)=12+/-10 MUM) and the EF2 mutants was increased by 5- to 14-fold versus in the absence of target ((D61N+TRTK)K(D)=29+/-1.2 MUM, (D63N+TRTK)K(D)=10+/-2.2 MUM, (D65N+TRTK)K(D)=73+/-4.4 MUM, and (E72A+TRTK)K(D)=18+/-3.7 MUM). In addition, R(ex), as measured using relaxation dispersion for side-chain (15)N resonances of Asn63 ((D63N)S100B), was reduced upon TRTK-12 binding when measured by NMR. Likewise, backbone motions on multiple timescales (picoseconds to milliseconds) throughout wild type, (D61N)S100B, (D63N)S100B, and (D65N)S100B were lowered upon binding TRTK-12. However, the X ray structures of Ca(2+)-bound (2.0A) and TRTK-bound (1.2A) (D63N)S100B showed no change in Ca(2+) coordination; thus, these and analogous structural data for the wild-type protein could not be used to explain how target binding increased Ca(2+)-binding affinity in solution. Therefore, a model for how S100B-TRTK-12 complex formation increases Ca(2+) binding is discussed, which considers changes in protein dynamics upon binding the target TRTK-12. PMID- 22824088 TI - Study on chemical composition, anti-inflammatory and anti-microbial activities of extracts from Chinese pear fruit (Pyrus bretschneideri Rehd.). AB - Pyrus bretschneideri Rehd. belongs to the genus Pyrus, a member of Rosaceae family. It is a routine edible fruit, and also used as a folk medicine to treat cough, eliminate constipation, and relieve alcoholism. In order to clarify the active compounds of P. bretschneideri, the phytochemical study were performed. Five compounds were isolated and identified as 2beta,19alpha-dihydroxy ursolic acid, quercitrin, dibutyl phthalate, diisobutyl phthalate and alpha-amyrin. Additionally, we investigate the anti-inflammatory and anti-microbial effects of the fractions of P. bretschneideri partitioned with petroleum ether, ethyl acetate and n-butanol, respectively. In the carrageenan-induced rat paw edema test, the EtOAc fraction showed the strongest inhibition of edema formation 0.5-5 h after edema induction, followed by n-butanol. EtOAc also displayed potent anti inflammatory activity against xylene-induced ear edema (22.03% and 43.69%, respectively) and acetic acid-induced extravasation of Evan's blue dye (39.58% and 49.92%, respectively) at the dose of 200 and 400 mg/kg. While, the anti microbial results showed that ethyl acetate and n-butanol fractions exhibited strong activity against the bacteria strains. Moreover, 2beta,19alpha-dihydroxy ursolic acid, alpha-amyrin and quercitrin could significantly inhibit the ear edema induced by xylene at the dose of 20 mg/kg, and exhibited moderate anti microbial activities against the bacteria strains. PMID- 22824089 TI - Bamboo salt reduces allergic responses by modulating the caspase-1 activation in an OVA-induced allergic rhinitis mouse model. AB - Bamboo salt (BS) is a specially processed salt according to the traditional recipe using sun-dried salt (SDS) and bamboo in Korea. The present study investigated the effects and mechanism of BS, SDS, NaCl, or mineral mixture (containing zinc, magnesium, and potassium) on ovalbumin (OVA)-induced allergic rhinitis (AR) animal model. The increased number of rubs was inhibited by the oral administration of BS, SDS, NaCl, mineral mixture, or nose inhalation of BS. The increased levels of IgE, histamine, and interleukin (IL)-1beta in serum were reduced by BS. The level of interferon-gamma was increased, whereas the level of IL-4 was reduced on the spleen tissue of BS-treated mice. In the BS-treated mice, the number of eosinophils and mast cells infiltration increased by OVA sensitization were also decreased. Protein levels of inflammatory cytokines were reduced by BS or NaCl administration in the nasal mucosa of the AR mice. In addition, BS inhibited caspase-1 activity in the nasal mucosa tissue. In activated human mast cells, BS significantly inhibited the production of IL-1beta and thymic stromal lymphopoietin and activation of caspase-1. Our data indicate that BS has anti-allergic and anti-inflammatory effects by regulating of caspase 1 activation in AR mice and in vitro models. PMID- 22824091 TI - Job satisfaction and associated variables among nurse assistants working in residential care. AB - BACKGROUND: While the work situation for nurse assistants in residential care is strenuous, they themselves often state that they are satisfied with their job. More knowledge is clearly needed of the interrelationship of variables associated with job satisfaction. This study aims to investigate job satisfaction and explore associated variables among nurse assistants working in residential care. METHODS: A total of 225 respondents completed a questionnaire measuring general job satisfaction, satisfaction with nursing-care provision and measures concerning person-centered care, work climate, leadership, and health complaints. Job satisfaction was the outcome measure and comparisons were made among those reporting low, moderate, and high levels of job satisfaction; multiple regression analyses were used to explore associated variables. RESULTS: The caring climate and personalized care provision were associated with general job satisfaction. High levels of satisfaction with nursing-care provision were also associated with the general work climate, organizational and environmental support, and leadership. Low job satisfaction was mainly associated with health complaints. CONCLUSIONS: Nurse assistants working in a positive work climate, caring climate, with a positive attitude to their leaders, who receive organizational and environmental support, provide person-centered care and experience a higher degree of job satisfaction. It seems essential, however, to include both general and context-specific measures when investigating job satisfaction in this field as they reveal different aspects of the nurse assistant's work situation. PMID- 22824092 TI - Luteinizing hormone, sex steroids and extracorporeal circulation - a promising link to treat retroperitoneal sarcomas. A reconsideration of cancer treatment. AB - Retroperitoneal sarcomas are rare and aggressive tumors with a negative prognosis as there is currently no satisfactory treatment for them. The only proven factor that can significantly increase the otherwise poor survival of sarcoma patients is the radically of resection. However, the completeness of resection is hindered by the hypervascularized nature of sarcomas and the frequent involvement of major blood vessels. In this context, we propose to operate on retroperitoneal sarcomas only with the use of extracorporeal circulation, applying vascular clamps above and below the tumor, even with short periods of hypothermic circulatory arrest in complex cases. This technique would allow the surgeon to achieve complete tumor resections, approach large blood vessels easier and perform sofisticated vascular reconstructions with no fear of hemorrhage which is fundamental to achieve a bloodless surgical field. Also, we speculate on the etiology of retroperitoneal sarcomas that appear mostly during the period of menopause/andropause. Although both estrogens and androgens have been incriminated in inducing various cancer types, including sarcomas, an endogenous estradiol cathabolyte has been shown to have anti-tumor effects. Considering that during menopause/andropause sex steroid levels actually decrease, our second working hypothesis is that the increasing follicle-stimulating hormone (FSH) and especially luteinizing hormone (LH) levels, together with the relative estrogen/androgen imbalance, may be the triggering cause. Also, a certain level of estrogens (Methoxyestradiol) may be essential in limiting tumor development and dedifferentiation. Given that extragonadal sarcomas appear to behave as endocrine tumors, a targeted hormonal therapy, together with controlled radical resections in complex cases of tumor vascular involvement, would certainly provide a strong link to both prevention and treatment of retroperitoneal sarcomas and even of cancer in general. PMID- 22824090 TI - Characterization of a putative grapevine Zn transporter, VvZIP3, suggests its involvement in early reproductive development in Vitis vinifera L. AB - BACKGROUND: Zinc (Zn) deficiency is one of the most widespread mineral nutritional problems that affect normal development in plants. Because Zn cannot passively diffuse across cell membranes, it must be transported into intracellular compartments for all biological processes where Zn is required. Several members of the Zinc-regulated transporters, Iron-regulated transporter like Protein (ZIP) gene family have been characterized in plants, and have shown to be involved in metal uptake and transport. This study describes the first putative Zn transporter in grapevine. Unravelling its function may explain an important symptom of Zn deficiency in grapevines, which is the production of clusters with fewer and usually smaller berries than normal. RESULTS: We identified and characterized a putative Zn transporter from berries of Vitis vinifera L., named VvZIP3. Compared to other members of the ZIP family identified in the Vitis vinifera L. genome, VvZIP3 is mainly expressed in reproductive tissue - specifically in developing flowers - which correlates with the high Zn accumulation in these organs. Contrary to this, the low expression of VvZIP3 in parthenocarpic berries shows a relationship with the lower Zn accumulation in this tissue than in normal seeded berries where its expression is induced by Zn. The predicted protein sequence indicates strong similarity with several members of the ZIP family from Arabidopsis thaliana and other species. Moreover, VvZIP3 complemented the growth defect of a yeast Zn-uptake mutant, ZHY3, and is localized in the plasma membrane of plant cells, suggesting that VvZIP3 has the function of a Zn uptake transporter. CONCLUSIONS: Our results suggest that VvZIP3 encodes a putative plasma membrane Zn transporter protein member of the ZIP gene family that might play a role in Zn uptake and distribution during the early reproductive development in Vitis vinifera L., indicating that the availability of this micronutrient may be relevant for reproductive development. PMID- 22824093 TI - Eukaryotic initiation factor 5B: a new player for the anti-hepatitis C virus effect of ribavirin? AB - The addition of the broad-spectrum antiviral agent ribavirin (RBV), a synthetic guanosine analog, to interferon-alpha (IFNalpha) monotherapy has been a major breakthrough in the treatment of patients with hepatitis C virus (HCV), as it greatly improved treatment response rates. Although several mechanisms of action have been proposed for RBV's antiviral activity, each with some experimental evidence, the precise mechanism by which it acts synergistically with IFNalpha has remained elusive. A cornerstone of the antiviral IFNalpha response is phosphorylation of the alpha subunit of eukaryotic initiation factor (eIF)2. This limits the availability of eIF2?GTP?Met-tRNA(i)(Met) ternary complexes, reduces formation of the 43S preinitiation complexes, ultimately blocking viral (and most cellular) mRNA translation. However recent studies indicated that translation driven by the HCV internal ribosome entry site (IRES) is insensitive to eIF2alpha phosphorylation. Particularly, in addition to the general eIF2-dependent pathway of translation, the HCV IRES makes use of a bacterial-like, eIF2-independent pathway requiring as initiation factors only eIF5B (an analog of bacterial IF2) and eIF3. Together, these observations support a model in which cellular stresses that induce eIF2alpha phosphorylation (e.g. treatment with IFNalpha) cause HCV IRES-directed translation to switch from an eIF2-dependent mode to an eIF5B dependent mode, defining a tactic used by HCV to evade the INFalpha response. Eukaryotic eIF5B is a ribosome-dependent GTPase that is responsible for 80S complex formation in translation initiation but shows much lower affinities for GTP than to other GTPases, thus suggesting that it may mis-incorporate the RBV triphosphate (RTP) in place of GTP even at the RBV concentrations achieved in clinical use. Consequently, we theorize that RTP bound to eIF5B lowering its affinity for ribosome, blocks the 80S complex formation on HCV IRES inhibiting the eIF5B-dependent translation used by HCV to elude IFNalpha response. In conclusion, our hypothesis provides a mechanistic explanation for the phenomenon of RBV enhancement in INFalpha-based therapy. PMID- 22824094 TI - Integrating guideline development and implementation: analysis of guideline development manual instructions for generating implementation advice. AB - BACKGROUND: Guidelines are important tools that inform healthcare delivery based on best available research evidence. Guideline use is in part based on quality of the guidelines, which includes advice for implementation and has been shown to vary. Others hypothesized this is due to limited instructions in guideline development manuals. The purpose of this study was to examine manual instructions for implementation advice. METHODS: We used a directed and summative content analysis approach based on an established framework of guideline implementability. Six manuals identified by another research group were examined to enumerate implementability domains and elements. RESULTS: Manuals were similar in content but lacked sufficient detail in particular domains. Most frequently this was Accomodation, which includes information that would help guideline users anticipate and/or overcome organizational and system level barriers. In more than one manual, information was also lacking for Communicability, information that would educate patients or facilitate their involvement in shared decision making, and Applicability, or clinical parameters to help clinicians tailor recommendations for individual patients. DISCUSSION: Most manuals that direct guideline development lack complete information about incorporating implementation advice. These findings can be used by those who developed the manuals to consider expanding their content in these domains. It can also be used by guideline developers as they plan the content and implementation of their guidelines so that the two are integrated. New approaches for guideline development and implementation may need to be developed. Use of guidelines might be improved if they included implementation advice, but this must be evaluated through ongoing research. PMID- 22824095 TI - Postmortem stability of brain GABAergic and glutamatergic receptors and enzymes under ecological conditions. AB - Neurochemical biomarkers have emerged as useful tools for assessing the subclinical neurological impacts of environmental toxicants in birds and other wildlife. Careful consideration of biomarker stability is necessary before implementing their use on tissues from ecological studies, as receptors and enzymes in the brain may be affected by postmortem conditions. The goal of this study was to evaluate the postmortem stability of key GABAergic and glutamatergic receptors (N-methyl-D-aspartate (NMDA), gamma-aminobutyric acid (GABAA benzodiazepine)) and enzymes (glutamine synthetase (GS), glutamic acid decarboxylase (GAD)) under environmentally relevant field and storage conditions to determine their suitability as biomarkers. We exposed chicken embryo brains to postmortem environmental and storage conditions typical for ecological studies (12, 24, and 48 h at 7 degrees C or 25 degrees C; 1, 4, and 8 weeks at -80 degrees C or -20 degrees C; 1 or 2 freeze thaw cycles), and measured [3H] MK-801 binding to the NMDA receptor, [3H] flunitrazipam binding to the GABAA benzodiazepine receptor, GS activity, and GAD activity. We found that [3H] MK-801 binding is stable under all conditions studied. GAD activity was fairly stable under each storage and environmental temperatures for all durations, but was significantly less stable when stored at -20 degrees C than at -80 degrees C. [3H] flunitrazipam binding and GS activity were both impacted by environmental and storage temperature and duration, and might best be utilized in studies of samples with similar histories. Our findings here demonstrate that caution is warranted when comparing samples with different collection and storage histories, but that some biomarkers are fairly stable under various conditions. PMID- 22824097 TI - Prevalence of vertebral fractures in a disease activity steered cohort of patients with early active rheumatoid arthritis. AB - OBJECTIVE: To determine the prevalence of vertebral fractures (VFs) after 5 years of disease activity score (DAS)-steered treatment in patients with early rheumatoid arthritis (RA) and to investigate the association of VFs with disease activity, functional ability and bone mineral density (BMD) over time. METHODS: Five-year radiographs of the spine of 275 patients in the BeSt study, a randomized trial comparing four treatment strategies, were used. Treatment was DAS-steered (DAS <= 2.4). A height reduction >20% in one vertebra was defined a vertebral fracture. With linear mixed models, DAS and Health Assessment Questionnaire (HAQ) scores over 5 years were compared for patients with and without VFs. With generalized estimating equations the association between BMD and VFs was determined. RESULTS: VFs were observed in 41/275 patients (15%). No difference in prevalence was found when stratified for gender, prednisone use and menopausal status. Disease activity over time was higher in patients with VFs, mean difference 0.20 (95% CI: 0.05-0.36), and also HAQ scores were higher, independent of disease activity, with a mean difference of 0.12 (95% CI: 0.02 0.2). Age was associated with VFs (OR 1.06, 95% CI: 1.02-1.09), mean BMD in spine and hip over time were not (OR 95% CI, 0.99: 0.78-1.25 and 0.94: 0.65-1.36, respectively). CONCLUSION: After 5 years of DAS-steered treatment, 15% of these RA patients had VFs. Higher age was associated with the presence of VFs, mean BMD in hip and spine were not. Patients with VFs have greater functional disability over time and a higher disease activity, suggesting that VFs may be prevented by optimal disease activity suppression. PMID- 22824098 TI - Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients. AB - The aim of the present study was to combine vibrational spectroscopy and chemometrics for investigating excipient-induced disproportionation of the calcium salt of atorvastatin into the corresponding free acid form in environments relevant to manufacturing and storage of solid dosage formulations. Of the excipients investigated, citric acid and polyacrylic acid were found to induce disproportionation. Moreover, it was also observed that exposure to high relative humidity, elevated temperatures, and milling all promoted disproportionation. The results suggest that disproportionation of drug salts in powders happens via a solution-mediated mechanism and that the choice of excipient has a considerable impact on the extent of disproportionation observed. Thus, careful attention must be paid to excipient selection during pharmaceutical development and exposure to stresses such as high humidity and mechanical activation should be minimized. PMID- 22824099 TI - Suppurative granulomatous inflammation in the ileo-anal pouch. AB - Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is commonly performed for medically refractory ulcerative colitis (UC), however with multiple possible complications, most notably pouchitis, cuffitis, Crohn's disease of the pouch and irritable pouch syndrome. We present a unique case of suppurative granulomatous inflammation in the ileal pouch mucosa, most likely infective in nature, that is unrelated to recognised causes of such pathology, especially yersiniosis. PMID- 22824100 TI - Genome-wide analysis of the sox family in the calcareous sponge Sycon ciliatum: multiple genes with unique expression patterns. AB - BACKGROUND: Sox genes are HMG-domain containing transcription factors with important roles in developmental processes in animals; many of them appear to have conserved functions among eumetazoans. Demosponges have fewer Sox genes than eumetazoans, but their roles remain unclear. The aim of this study is to gain insight into the early evolutionary history of the Sox gene family by identification and expression analysis of Sox genes in the calcareous sponge Sycon ciliatum. METHODS: Calcaronean Sox related sequences were retrieved by searching recently generated genomic and transcriptome sequence resources and analyzed using variety of phylogenetic methods and identification of conserved motifs. Expression was studied by whole mount in situ hybridization. RESULTS: We have identified seven Sox genes and four Sox-related genes in the complete genome of Sycon ciliatum. Phylogenetic and conserved motif analyses showed that five of Sycon Sox genes represent groups B, C, E, and F present in cnidarians and bilaterians. Two additional genes are classified as Sox genes but cannot be assigned to specific subfamilies, and four genes are more similar to Sox genes than to other HMG-containing genes. Thus, the repertoire of Sox genes is larger in this representative of calcareous sponges than in the demosponge Amphimedon queenslandica. It remains unclear whether this is due to the expansion of the gene family in Sycon or a secondary reduction in the Amphimedon genome. In situ hybridization of Sycon Sox genes revealed a variety of expression patterns during embryogenesis and in specific cell types of adult sponges. CONCLUSIONS: In this study, we describe a large family of Sox genes in Sycon ciliatum with dynamic expression patterns, indicating that Sox genes are regulators in development and cell type determination in sponges, as observed in higher animals. The revealed differences between demosponge and calcisponge Sox genes repertoire highlight the need to utilize models representing different sponge lineages to describe sponge development, a prerequisite for deciphering evolution of metazoan developmental mechanisms. PMID- 22824101 TI - Relationships between glucose, energy intake and dietary composition in obese adults with type 2 diabetes receiving the cannabinoid 1 (CB1) receptor antagonist, rimonabant. AB - BACKGROUND: Weight loss is often difficult to achieve in individuals with type 2 diabetes and anti-obesity drugs are often advocated to support dietary intervention. Despite the extensive use of centrally acting anti-obesity drugs, there is little evidence of how they affect dietary composition. We investigated changes in energy intake and dietary composition of macro- and micronutrients following therapy with the endocannabinoid receptor blocker, rimonabant. METHODS: 20 obese patients with type 2 diabetes were studied before and after 6 months dietary intervention with rimonabant. Dietary intervention was supervised by a diabetes dietician. Five-day food diaries were completed at baseline and at 6 months and dietary analysis was performed using computer software (Dietplan 6). RESULTS: After 6 months, (compared with baseline) there were reductions in weight (107 +/- 21Kg versus 112 +/- 21, p < 0.001, 4% body weight reduction), and improvements in HbA1c (7.4 +/- 1.7 versus 8.0 +/- 1.6%, p < 0.05) and HDL cholesterol. Intake of energy (1589 +/- 384 versus 2225 +/- 1109 kcal, p < 0.01), carbohydrate (199 +/- 74 versus 273 +/- 194 g, p < 0.05), protein (78 +/- 23 versus 98 +/- 36 g, p < 0.05), fats (55 +/- 18 versus 84 +/- 39 g, p < 0.01) and several micronutrients were reduced. However, relative macronutrient composition of the diet was unchanged. Improvement in blood glucose was strongly correlated with a reduction in carbohydrate intake (r = 0.76, p < 0.001). CONCLUSIONS: In obese patients with type 2 diabetes, rimonabant in combination with dietary intervention led to reduced intake of energy and most macronutrients. Despite this, macronutrient composition of the diet was unaltered. These dietary changes (especially carbohydrate restriction) were associated with weight loss and favourable metabolic effects. PMID- 22824096 TI - Molecular and cellular mechanisms of pulmonary fibrosis. AB - Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID- 22824102 TI - Demonstration of photon Bloch oscillations and Wannier-Stark ladders in dual periodical multilayer structures based on porous silicon. AB - : Theoretical demonstration and experimental evidence of photon Bloch oscillations and Wannier-Stark ladders (WSLs) in dual-periodical (DP) multilayers, based on porous silicon, are presented. An introduction of the linear gradient in refractive indices in DP structure, which is composed by stacking two different periodic substructures N times, resulted in the appearance of WSLs. Theoretical time-resolved reflection spectrum shows the photon Bloch oscillations with a period of 130 fs. Depending on the values of the structural parameters, one can observe the WSLs in the near infrared or visible region which may allow the generation of terahertz radiation with a potential applications in several fields like imaging. PMID- 22824103 TI - Antitumor activity of zoledronic acid in primary breast cancer cells determined by the ATP tumor chemosensitivity assay. AB - BACKGROUND: The NeoAzure study has demonstrated that the use of the bisphosphonate zoledronic acid (Zol) in the neoadjuvant setting increases the rate of complete response in primary breast cancer and therefore indicates direct antitumor activity. The purpose of this study was to compare the antitumor effect of Zol with standard chemotherapy in primary breast cancer cells using ATP-tumor chemosensitivity assay (ATP-TCA). METHODS: Breast cancer specimens were obtained from patients with breast cancer who underwent primary breast cancer surgery at the Department of Obstetrics and Gynecology, Tubingen, Germany, between 2006 through 2009. Antitumor effects of Zol, TAC (Docetaxel, Adriamycin, Cyclophosphamide) and FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) were tested in 116 fresh human primary breast cancer specimens using ATP-TCA. ATP-TCA results were analyzed with different cut-off levels for the half maximal inhibitory concentration (IC50), for IC90 and for the sensitivity index (IndexSUM). Each single agent or combination was tested at six doubling dilutions from 6.25, 12.5, 25, 50, 100, and 200% of test drug concentrations (TDC) derived from the plasma peak concentrations determined by pharmacokinetic data. The assay was carried out in duplicate wells with positive and negative controls. RESULTS: The median IndexSUM value was lower for Zol than for the combined regimen FEC (36.8%) and TAC (12.9%), respectively, indicating increased antitumor activity of Zol in primary breast cancer cells. The difference regarding Zol and FEC was significant (p < 0.05). The median IC50 value for Zol (8.03% TDC) was significantly lower than the IC50 values for FEC (33.5% TDC) and TAC (19.3% TDC) treatment (p < 0.05). However, the median IC90 value for Zol (152.5% TDC) was significantly higher than the IC90 value obtained with TAC (49.5% TDC; p < 0.05), but similar to the IC90 value for FEC (180.9% TDC). In addition a significant positive correlation was observed for the IndexSum of Zol and the ER status (p < 0.01). CONCLUSION: Zoledronic acid has a strong antitumor effect on primary breast cancer cells in vitro which is equal or superior to commonly used chemotherapeutic regimens for treating breast cancer. PMID- 22824104 TI - Biomarkers in cardiovascular diseases: how can the "-omics" revolution be applicable at the bedside. Introduction. PMID- 22824106 TI - Why are some studies of cardiovascular markers unreliable? The role of measurement variability and what an aspiring clinician scientist can do before it is too late. AB - Cardiology research suffers from the scourge of unreliable results, despite honest conduct. Investigators' prior belief, compromised blinding, and scope for measurement variability are a fatally synergistic combination. Can we stop these threats ruining the results? First, clinical researchers must realize that healthy clinical practice (including intelligently integrating all available information) may be catastrophic to research. Second, experienced clinicians know that variability may necessitate remeasurement to obtain a clinically correct result but must learn that doing so in research can cause surprisingly severe distortions of correlations or differences between groups. For example, a "best of-four" approach in comparing two 50-patient groups that are in reality identical, with a variable whose intraclass correlation is 0.8, easily generates highly significant P values. Clinicians may be habituated to poorly reproducible clinical measurements and falsely reassured by their effectiveness for group mean effects in blinded randomized controlled trials. We need a more critical approach to clinical tests if we care about evaluating individual patients reliably or want our research to be reliable. Simple steps shown here, addressed during study design, will increase the reliability of research-if considered by researchers or the juniors whom they nurture. PMID- 22824105 TI - Clinical adoption of prognostic biomarkers: the case for heart failure. AB - The recent explosion of scientific knowledge and technological progress has led to the discovery of a large array of circulating molecules commonly referred to as biomarkers. Biomarkers in heart failure (HF) research have been used to provide pathophysiologic insights, aid in establishing the diagnosis, refine prognosis, guide management, and target treatment. However, beyond diagnostic applications of natriuretic peptides, there are currently few widely recognized applications for biomarkers in HF. This represents a remarkable discordance considering the number of molecules that have been shown to correlate with outcomes, refine risk prediction, or track disease severity in HF in the past decade. In this article, we use a broad framework proposed for cardiovascular risk markers to summarize the current state of biomarker development for patients with HF. We use this framework to identify the challenges of biomarker adoption for risk prediction, disease management, and treatment selection for HF and suggest considerations for future research. PMID- 22824107 TI - Methodological and analytic considerations for blood biomarkers. AB - Biomarkers typically evolve from a research setting to use in clinical care as evidence for their independent contribution to patient management accumulates. This evidence relies heavily on knowledge of the preanalytical, analytical, and postanalytical characteristics of the biomarker's measurement. For the preanalytical phase, considerations such specimen type, acceptable anticoagulants for blood samples, biologic variation and stability of the biomarker under various conditions are key. The analytical phase entails critical details for development and maintenance of assays having performance characteristics that are "fit for service" for the clinical application at hand. Often, these characteristics describe the ability to measure minute quantities in the biologic matrix used for measurement. Although techniques such as mass spectrometry are used effectively for biomarker discovery, routine quantification often relies on use of immunoassays; early in development, the most common immunoassay used is the enzyme-linked immunosorbent assay format. As biomarkers evolve successfully, they will be adapted to large main laboratory platforms or, depending on the need for speed, point-of-care devices. Users must pay particular attention to performance parameters of assays they are considering for clinical implementation. These parameters include the limit of blank, a term used to describe the limit of analytical noise for an assay; limit of detection, which describes the lowest concentration that can reliably be discriminated from analytical noise; and perhaps most importantly, the limit of quantitation, which is the lowest concentration at which a biomarker can be reliably measured within some predefined specifications for total analytical error that is based on clinical requirements of the test. The postanalytical phase involves reporting biomarker values, which includes reporting units, any normalization factors, and interpretation. Standardization, a process that involves metrological traceability to a primary reference material and definitive measurement method, is important to assure that all biomarker values are transferable in the literature and across institutions. In the absence of standardization, assays can be harmonized using secondary reference materials so that biomarker values can be combined for meta-analysis and interpreted clinically with common reference and decision limit values. PMID- 22824109 TI - Urinary proteins in heart failure. AB - Renal insufficiency is common in patients with heart failure (HF), with both acute kidney injury and worsening renal function being associated with poor prognosis. The interplay between cardiac and renal failure has been termed the cardiorenal syndrome and is currently the subject of intense investigation. Urinary biochemistry has several advantages over blood or serum analyses, including lower costs, better patient comfort, and higher sensitivity to renal injury. However, urinalysis is currently not part of routine daily practice in cardiology. Recent advances in proteomics have allowed identification of numerous novel urinary biomarkers, many of which show promise in HF populations. In this review, we aim to provide an overview of both traditional and novel urinary biomarkers, examining evidence for diagnostic and prognostic value in HF as well as potential clinical utility. PMID- 22824108 TI - Cardiovascular biomarkers in exhaled breath. AB - With each breath that we exhale, thousands of molecules are expelled in our breath, giving individuals a "breath-print" that can tell a lot about them and their state of health. Breath analysis is rapidly evolving as the new frontier in medical testing. The end of the 20th century and the beginning of the 21st century have arguably witnessed a revolution in our understanding of the constituents of exhaled breath and the development of the field of breath analysis and testing. Thanks to major breakthroughs in new technologies (infrared, electrochemical, chemiluminescence, and others) and the availability of mass spectrometers, the field of breath analysis has made considerable advances in the 21st century. Several methods are now in clinical use or nearly ready to enter that arena. Breath analysis has the potential to offer relatively inexpensive, rapid, noninvasive methods for detecting and/or monitoring a variety of diseases. Breath analysis also has applications in fields beyond medicine, including environmental monitoring, security, and others. This review will focus on exhaled breath as a potential source of biomarkers for medical applications with specific attention to applications (and potential applications) in cardiovascular disease. PMID- 22824110 TI - Exploring predisposition and treatment response--the promise of genomics. AB - Spurred by large-scale public and private efforts as well as technological developments, the last few years have seen a major leap forward in our understanding of the genetic basis of cardiovascular disease. This revolution is in its infancy and will continue to alter the medical landscape for years to come. There is a need within the general cardiology community to develop a better understanding about how these developments may alter routine clinical care. In this review, we will provide an overview of the current state of genetics as pertains to rare cardiovascular diseases and then review advances in the discovery of the genetic basis of common disease with the potential for improved risk assessment and drug development. We will also outline a few recent examples of pharmacogenetic advances that are already starting to become a part of clinical management and finally discuss the promise as well as the challenges in using next-generation sequencing technologies to provide personalized cardiovascular care. PMID- 22824111 TI - Transcriptomic biomarkers of cardiovascular disease. AB - Transcriptomics is the study of how our genes are regulated and expressed in different biological settings. Technical advances now enable quantitative assessment of all expressed genes (ie, the entire "transcriptome") in a given tissue at a given time. These approaches provide a powerful tool for understanding complex biological systems and for developing novel biomarkers. This chapter will introduce basic concepts in transcriptomics and available technologies for developing transcriptomic biomarkers. We will then review current and emerging applications in cardiovascular medicine. PMID- 22824112 TI - Translating metabolomics to cardiovascular biomarkers. AB - Metabolomics is the systematic study of the unique chemical fingerprints of small molecules or metabolite profiles that are related to a variety of cellular metabolic processes in a cell, organ, or organism. Although messenger RNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures. PMID- 22824114 TI - Exposure to 1-bromopropane induces microglial changes and oxidative stress in the rat cerebellum. AB - 1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, is reported to exhibit neurotoxicity and reproductive toxicity in animals and humans. However, the underlying mechanism of the toxicity remains elusive. This study was designed to identify the microglial changes and oxidative stress in the central nervous system (CNS) after 1-BP exposure. Four groups of Wistar-ST rats (n=12 each) were exposed to 0, 400, 800 and 1000ppm of 1-BP, 8h/day for 28 consecutive days. The cerebellum was dissected out in 9 rats of each group and subjected to biochemical analysis, while the brains of the remaining 3 rats were examined immunohistochemically. Exposure to 1-BP increased the levels of oxidative stress markers [thiobarbituric acid reactive substances (TBARS), protein carbonyl and reactive oxygen species (ROS)] in a dose-dependent manner. Likewise, there was also 1-BP dose-dependent increase in nitric oxide (NO) and dose-dependent decrease in protein concentrations in the cerebellum. Immunohistochemical studies showed 1-BP-induced increase in cd11b/c-positive microglia area in the white matter of the cerebellar hemispheres. The results showed that exposure to 1-BP induced morphological change in the microglia and oxidative stress, suggesting that these effects are part of the underlying neurotoxic mechanism of 1-BP in the CNS. PMID- 22824116 TI - Letter from the guest editor: errors and malpractice in radiology. PMID- 22824115 TI - N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents. AB - Potent aryl hydrocarbon receptor agonists like PCB 126 (3,3',4,4',5 pentachlorobiphenyl) cause oxidative stress and liver pathology, including fatty liver. Our question was whether dietary supplementation with N-acetylcysteine (NAC), an antioxidant, can prevent these adverse changes. Male Sprague-Dawley rats were fed a standard AIN-93G diet (sufficient in cysteine) or a modified diet supplemented with 1.0% NAC. After one week, rats on each diet were exposed to 0, 1, or 5MUmol/kg body weight PCB 126 by i.p. injection (6 rats per group) and euthanized two weeks later. PCB-treatment caused a dose-dependent reduction in growth, feed consumption, relative thymus weight, total glutathione and glutathione disulfide (GSSG), while relative liver weight, glutathione transferase activity and hepatic lipid content were dose-dependently increased with PCB dose. Histologic examination of liver tissue showed PCB 126-induced hepatocellular steatosis with dose dependent increase in lipid deposition and distribution. Dietary NAC resulted in a reduction in hepatocellular lipid in both PCB groups. This effect was confirmed by gravimetric analysis of extracted lipids. Expression of CD36, a scavenger receptor involved in regulating hepatic fatty acid uptake, was reduced with high dose PCB treatment but unaltered in PCB treated rats on NAC-supplemented diet. These results demonstrate that NAC has a protective effect against hepatic lipid accumulation in rats exposed to PCB 126. The mechanism of this protective effect appears to be independent of NAC as a source of cysteine/precursor of glutathione. PMID- 22824113 TI - Disturbances in calcium metabolism and cardiomyocyte necrosis: the role of calcitropic hormones. AB - A synchronized dyshomeostasis of extra- and intracellular Ca(2+), expressed as plasma ionized hypocalcemia and excessive intracellular Ca(2+) accumulation, respectively, represents a common pathophysiologic scenario that accompanies several diverse disorders. These include low-renin and salt-sensitive hypertension, primary aldosteronism and hyperparathyroidism, congestive heart failure, acute and chronic hyperadrenergic stressor states, high dietary Na(+), and low dietary Ca(2+) with hypovitaminosis D. Homeostatic responses are invoked to restore normal extracellular [Ca(2+)](o), including increased plasma levels of parathyroid hormone and 1,25(OH)(2)D(3). However, in cardiomyocytes these calcitropic hormones concurrently promote cytosolic free [Ca(2+)](i) and mitochondrial [Ca(2+)](m) overloading. The latter sets into motion organellar based oxidative stress, in which the rate of reactive oxygen species generation overwhelms their detoxification by endogenous antioxidant defenses, including those related to intrinsically coupled increments in intracellular Zn(2+). In turn, the opening potential of the mitochondrial permeability transition pore increases, allowing for osmotic swelling and ensuing organellar degeneration. Collectively, these pathophysiologic events represent the major components to a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis. From necrotic cells, there follows a spillage of intracellular contents, including troponins, and a subsequent wound healing response with reparative fibrosis or scarring. Taken together, the loss of terminally differentiated cardiomyocytes from this postmitotic organ and the ensuing replacement fibrosis each contribute to the adverse structural remodeling of myocardium and progressive nature of heart failure. In conclusion, hormone-induced ionized hypocalcemia and intracellular Ca(2+) overloading comprise a pathophysiologic cascade common to diverse disorders and that initiates a mitochondriocentric pathway to nonischemic cardiomyocyte necrosis. PMID- 22824117 TI - The concept of error and malpractice in radiology. AB - Since the early 1970s, physicians have been subjected to an increasing number of medical malpractice claims. Radiology is one of the specialties most liable to claims of medical negligence. The etiology of radiological error is multifactorial. Errors fall into recurrent patterns. Errors arise from poor technique, failures of perception, lack of knowledge, and misjudgments. Every radiologist should understand the sources of error in diagnostic radiology as well as the elements of negligence that form the basis of malpractice litigation. Errors are an inevitable part of human life, and every health professional has made mistakes. To improve patient safety and reduce the risk from harm, we must accept that some errors are inevitable during the delivery of health care. We must play a cultural change in medicine, wherein errors are actively sought, openly discussed, and aggressively addressed. PMID- 22824118 TI - Missed lung cancer on chest radiography and computed tomography. AB - Missed lung cancer raises an important medicolegal issue and contributes to one of the most common causes for malpractice actions against radiologists. Lung cancer may be missed on either chest radiography or computed tomography. Although most malpractice cases involve lesions overlooked on the former, a small and increasing portion of cases are related to chest computed tomography scan. Factors contributing to overlooked lung cancer can be attributed to observer performance, lesion characteristics, and technical considerations. PMID- 22824119 TI - Difficulties and errors in diagnosis of breast neoplasms. AB - Many perceptual and interpretive factors influence the radiologic detection and assessment of breast neoplasms. Diagnostic problems can be divided into errors of detection and errors of assessment and management. Detection issues may relate to inherent features of the tumor or surrounding tissue, technical problems, or human error. Even when lesions are successfully detected, errors in assessment or management recommendations can cause diagnostic delays. Improper breast imaging reporting and data system (BI-RADS) usage or failure to integrate mammographic, ultrasonography (US), and magnetic resonance imaging (MRI) findings with clinical findings, all lead to interpretive errors. This article reviews factors affecting the detection and diagnosis of breast cancer, to improve radiologic interpretation, benefit patients by earlier cancer detection, and lessen medicolegal exposure from a missed or delayed cancer diagnosis. Mammography is the primary imaging modality for population-based breast cancer screening, and it is also the usual initial examination performed for diagnostic evaluation of clinical or screen-detected breast abnormalities in women aged 40 years and older. Mammography is supplemented by breast US and/or breast MRI in some cases. This article will, therefore, focus on mammography in reviewing difficulties and errors in cancer diagnosis, with supplemental discussion of breast US and breast MRI. PMID- 22824120 TI - Errors in the radiological evaluation of the alimentary tract: part I. AB - Physicians are subjected to an increasing number of medical malpractice claims, and radiology is one of the specialties most liable to claims of medical negligence The etiology of radiological error is multifactorial, deriving by poor technique, failures of perception, lack of knowledge, and misjudgments. Reducing errors will improve patient care, may reduce costs, and will improve the image of the hospital. The main reason for studying medical errors is to try to prevent them. This article focuses on the spectrum of diagnostic errors in radiology, including a classification of the errors, and highlights the malpractice issues in methods for functional alimentary tract examination: swallowing act study, 3 dimensional endoanal ultrasound, defecography, and defecography in magnetic resonance. PMID- 22824121 TI - Errors in the radiological evaluation of the alimentary tract: part II. AB - Plain abdominal radiography and computed tomographic (CT) enteroclysis are 2 essential radiological investigations in the study of gastrointestinal tract. Errors in patient preparation, execution, and interpretation may lead to severe consequences in the diagnosis and thus in patient outcome. Abdominal radiography is one of the most frequently requested radiographic examinations, and has an established role in the assessment of the acute abdomen. CT enteroclysis has revolutionized the assessment of small-bowel pathology, especially in patients with inflammatory bowel. The purpose of this article is to describe the pitfalls in the execution and interpretation of plain abdominal film and CT enteroclysis. PMID- 22824122 TI - Diagnostic errors in the evaluation of nontraumatic aortic emergencies. AB - Nontraumatic aortic emergencies (NTAE) are a complex and dynamic group of serious, potentially fatal conditions affecting the aorta. These entities most often present in the emergency department setting, and include aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, as well as aortic rupture and impending rupture. The radiologist plays a critical role in prompt diagnosis and evaluation since presenting signs and symptoms are often nonspecific. This article focuses on the potential sources of error in the imaging evaluation of patients presenting with NTAE. PMID- 22824123 TI - Errors in imaging assessment of polytrauma patients. AB - Although the use of multidetector computed tomography (MDCT) has increased the diagnostic quality by reducing the number of missed diagnoses in polytraumatized patients, errors remain a common phenomenon in emergency room setting. MDCT errors, contributing more commonly to missed or delayed diagnoses in polytrauma patients, are diagnostic errors commonly related to perceptual errors or to nonvisual errors. However, in some cases, misdiagnoses can be attributed to technical and methodological errors leading to incomplete or poor-quality imaging. Knowledge of common patterns of error is the most effective way to avoid future errors. The purpose of this article is to highlight the most frequent types of diagnostic errors in evaluating with MDCT of polytrauma patients. PMID- 22824124 TI - Errors in imaging of emergencies in pregnancy. AB - There is evidence that emergencies in pregnancy are subject to mismanagement; however, the percentage of error in the diagnosis of emergencies in pregnancies has not been studied in-depth. The purpose of this article is to review the most common emergencies in pregnancies, focusing the attention on errors in images. The topics covered are divided into gynecological and nongynecological, and for each pathology, the possible errors in the diagnostic pathway, the possible technical errors in the execution of the examination, and in the end, the possible errors in interpretation of the images have been dealt with. These last two entities are often connected, in the fact that a substandard examination can stem interpretation errors, but the systemization of the error is a valid approach in helping to learn from these errors, reducing the possibility that the same error can represent itself. PMID- 22824125 TI - Errors and malpractice in interventional radiology. AB - Interventional radiology is an invasive specialty with the potential for errors as with other invasive specialties. A critical analysis of the different types of errors may help radiologist undertake the corrective measures. Standardize interventional procedures with protocols applicable to clinical practice are necessary to avoid the malpractice and, therefore, the related medical-legal issues. In this article, we present an overview of principal differences between errors and malpractice with particular regard to the issues in interventional radiology. Specific topics discussed in this article are the approaches to preventing errors and, thus, to avoiding the malpractice in interventional radiology. PMID- 22824126 TI - Communication of findings of radiologic examinations: medicolegal considerations. AB - Radiologists receive little formal training regarding the structure of the radiology report and its importance as a medicolegal document; failure to communicate, in fact, represents one of the main problems facing the modern radiologists' activity. Duty to the patient does not end anymore with the written report; the paradox is that we are so advanced in imaging technology, but not in communicating imaging findings. Communication must be timely, appropriate, and fully documented. There is an increasing trend to communicate results directly to the patients; radiologists have the greatest problem when communicating unexpected findings. To improve patient care and reduce the risk of being sued, radiologists should follow shared report guidelines and be more familiar with their professional responsibilities. PMID- 22824127 TI - Learning from errors in radiology: a comprehensive review. AB - An important goal of error analysis is to create processes aimed at reducing or preventing the occurrence of errors and minimizing the degree of harm. The discovery of any errors presents an opportunity to study the types that occur and to examine their sources and develop measures to prevent them from recurring. The development of an effective system for detecting and appropriately managing errors is essential to substantially attenuate their consequences. At this stage, the error analysis process identifies contributing factors to enable the implementation of concrete steps to prevent such errors from occurring in the future. Active and comprehensive management of errors and adverse events requires ongoing surveillance processes. Educational programs, morbidity and mortality meetings, and a comprehensive and respected root cause analysis process are also essential components of this comprehensive approach. To reduce the incidence of errors, health care providers must identify their causes, devise solutions, and measure the success of improvement efforts. Moreover, accurate measurements of the incidence of error, based on clear and consistent definitions, are essential prerequisites for effective action. PMID- 22824129 TI - Effect of ractopamine hydrochloride (Optaflexx) dose on live animal performance, carcass characteristics and tenderness in early weaned beef steers. AB - Study objectives were to evaluate ractopamine hydrochloride's (RAC) effect on performance, carcass characteristics, and tenderness of early weaned beef steers. Steers were assigned to a control diet (0 mg RAC.steer-1.d-1), 200 mg RAC mg.steer-1.d-1, or 300 mg RAC.steer-1.d-1. Steers fed 200 and 300 mg RAC.steer 1.d-1 gained 14.84 kg and 14.57 kg more live weight and produced 13.22 and 14.90 kg more hot carcass weight, respectively, than controls. Feed conversions for steers fed 200 or 300 mg RAC.steer-1.d-1 of RAC increased 45.2% and 47.3% and average daily gain increased 55.5% and 54.5% compared to controls, respectively. Feeding either dose of RAC increased (P<0.05) loin muscle area and increased (P<0.05) Warner-Bratzler shear force (WBSF) values compared to controls, however the magnitude of WBSF difference diminished (P>0.05) over 14 days of postmortem aging. Results of this study confirm that RAC increases weight gain and feed efficiency, minimally impacts carcass quality and has manageable impacts on tenderness when fed at either 200 or 300 mg steer-1.d-1. PMID- 22824131 TI - Polyalkoxy substituted 4H-chromenes: synthesis by domino reaction and anticancer activity. AB - A series of 4H-chromenes containing various modifications in the ring B and polyalkoxy substituents in the ring E has been synthesized by Knoevenagel-Michael hetero-Thorpe-Ziegler three-component domino reaction with the overall yield of 45-82%. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antimitotic and microtubule destabilizing activity. The most active compounds 5{1,5} and 5{5,5} featured sesamol-derived ring B and m-methoxyphenyl or m-methoxymethylenedioxyphenyl ring E. Compounds 5{3,1}, 5{1,2}, 5{5,4}, 5{1,5}, and 5{5,5} exhibited strong cytotoxicity in the NCI60 human tumor cell line anticancer drug screen. Surprisingly, cell growth inhibition caused by these agents was more pronounced in the multidrug resistant NCI/ADR-RES cells than the parent OVCAR-8 cell line. The results suggest that polyalkoxy substited 4H chromenes may prove to be advantageous for further design as anticancer agents. PMID- 22824130 TI - Genetics of sudden cardiac death in children and young athletes. AB - Sudden cardiac death is a rare but socially devastating event. The most common causes of sudden cardiac death are congenital electrical disorders and structural heart diseases. The majority of these diseases have an incomplete penetrance and variable expression; therefore, patients may be unaware of their illness. In several cases, physical activity can be the trigger for sudden cardiac death as first symptom. Our purpose is to review the causes of sudden cardiac death in sportive children and young adults and its genetic background. Symptomatic individuals often receive an implantable cardioverter-defibrillator, the preventive treatment for sudden cardiac death in most of cases due to channelopathies, which can become a challenging option in young and active patients. The identification of one of these diseases in asymptomatic patients has similarly a great impact on their everyday life, especially on their ability to undertake competitive physical activities, and the requirement of prophylactic treatment. We review main causes of sudden cardiac death in relation to its genetics and diagnostic work-up PMID- 22824132 TI - [Non-atherosclerotic acute myocardial infarction: coronary artery embolism]. PMID- 22824128 TI - Transcript profiling of cytokinin action in Arabidopsis roots and shoots discovers largely similar but also organ-specific responses. AB - BACKGROUND: The plant hormone cytokinin regulates growth and development of roots and shoots in opposite ways. In shoots it is a positive growth regulator whereas it inhibits growth in roots. It may be assumed that organ-specific regulation of gene expression is involved in these differential activities, but little is known about it. To get more insight into the transcriptional events triggered by cytokinin in roots and shoots, we studied genome-wide gene expression in cytokinin-treated and cytokinin-deficient roots and shoots. RESULTS: It was found by principal component analysis of the transcriptomic data that the immediate early response to a cytokinin stimulus differs from the later response, and that the transcriptome of cytokinin-deficient plants is different from both the early and the late cytokinin induction response. A higher cytokinin status in the roots activated the expression of numerous genes normally expressed predominantly in the shoot, while a lower cytokinin status in the shoot reduced the expression of genes normally more active in the shoot to a more root-like level. This shift predominantly affected nuclear genes encoding plastid proteins. An organ-specific regulation was assigned to a number of genes previously known to react to a cytokinin signal, including root-specificity for the cytokinin hydroxylase gene CYP735A2 and shoot specificity for the cell cycle regulator gene CDKA;1. Numerous cytokinin-regulated genes were newly discovered or confirmed, including the meristem regulator genes SHEPHERD and CLAVATA1, auxin-related genes (IAA7, IAA13, AXR1, PIN2, PID), several genes involved in brassinosteroid (CYP710A1, CYP710A2, DIM/DWF) and flavonol (MYB12, CHS, FLS1) synthesis, various transporter genes (e.g. HKT1), numerous members of the AP2/ERF transcription factor gene family, genes involved in light signalling (PhyA, COP1, SPA1), and more than 80 ribosomal genes. However, contrasting with the fundamental difference of the growth response of roots and shoots to the hormone, the vast majority of the cytokinin regulated transcriptome showed similar response patterns in roots and shoots. CONCLUSIONS: The shift of the root and shoot transcriptomes towards the respective other organ depending on the cytokinin status indicated that the hormone determines part of the organ-specific transcriptome pattern independent of morphological organ identity. Numerous novel cytokinin-regulated genes were discovered which had escaped earlier discovery, most probably due to unspecific sampling. These offer novel insights into the diverse activities of cytokinin, including crosstalk with other hormones and different environmental cues, identify the AP2/ERF class of transcriptions factors as particularly cytokinin sensitive, and also suggest translational control of cytokinin-induced changes. PMID- 22824133 TI - A dosimetric comparison of 3D conformal vs intensity modulated vs volumetric arc radiation therapy for muscle invasive bladder cancer. AB - BACKGROUND: To compare 3 Dimensional Conformal radiotherapy (3D-CRT) with Intensity Modulated Radiotherapy (IMRT) with Volumetric-Modulated Arc Therapy (VMAT) for bladder cancer. METHODS: Radiotherapy plans for 15 patients with T2 T4N0M0 bladder cancer were prospectively developed for 3-DCRT, IMRT and VMAT using Varian Eclipse planning system. The same radiation therapist carried out all planning and the same clinical dosimetric constraints were used. 10 of the patients with well localised tumours had a simultaneous infield boost (SIB) of the primary tumour planned for both IMRT and VMAT. Tumour control probabilities and normal tissue complication probabilities were calculated. RESULTS: Mean planning time for 3D-CRT, IMRT and VMAT was 30.0, 49.3, and 141.0 minutes respectively. The mean PTV conformity (CI) index for 3D-CRT was 1.32, for IMRT 1.05, and for VMAT 1.05. The PTV Homogeneity (HI) index was 0.080 for 3D-CRT, 0.073 for IMRT and 0.086 for VMAT. Tumour control and normal tissue complication probabilities were similar for 3D-CRT, IMRT and VMAT. The mean monitor units were 267 (range 250-293) for 3D-CRT; 824 (range 641-1083) for IMRT; and 403 (range 333 489) for VMAT (P < 0.05). Average treatment delivery time were 2:25min (range 2:01-3:09) for 3D-CRT; 4:39 (range 3:41-6:40) for IMRT; and 1:14 (range 1:13 1:14) for VMAT. In selected patients, the SIB did not result in a higher dose to small bowel or rectum. CONCLUSIONS: VMAT is associated with similar dosimetric advantages as IMRT over 3D-CRT for muscle invasive bladder cancer. VMAT is associated with faster delivery times and less number of mean monitor units than IMRT. SIB is feasible in selected patients with localized tumours. PMID- 22824135 TI - Optimal control in microgrid using multi-agent reinforcement learning. AB - This paper presents an improved reinforcement learning method to minimize electricity costs on the premise of satisfying the power balance and generation limit of units in a microgrid with grid-connected mode. Firstly, the microgrid control requirements are analyzed and the objective function of optimal control for microgrid is proposed. Then, a state variable "Average Electricity Price Trend" which is used to express the most possible transitions of the system is developed so as to reduce the complexity and randomicity of the microgrid, and a multi-agent architecture including agents, state variables, action variables and reward function is formulated. Furthermore, dynamic hierarchical reinforcement learning, based on change rate of key state variable, is established to carry out optimal policy exploration. The analysis shows that the proposed method is beneficial to handle the problem of "curse of dimensionality" and speed up learning in the unknown large-scale world. Finally, the simulation results under JADE (Java Agent Development Framework) demonstrate the validity of the presented method in optimal control for a microgrid with grid-connected mode. PMID- 22824134 TI - Polymorphism in glutamate cysteine ligase catalytic subunit (GCLC) is associated with sulfamethoxazole-induced hypersensitivity in HIV/AIDS patients. AB - BACKGROUND: Sulfamethoxazole (SMX) is a commonly used antibiotic for prevention of infectious diseases associated with HIV/AIDS and immune-compromised states. SMX-induced hypersensitivity is an idiosyncratic cutaneous drug reaction with genetic components. Here, we tested association of candidate genes involved in SMX bioactivation and antioxidant defense with SMX-induced hypersensitivity. RESULTS: Seventy seven single nucleotide polymorphisms (SNPs) from 14 candidate genes were genotyped and assessed for association with SMX-induced hypersensitivity, in a cohort of 171 HIV/AIDS patients. SNP rs761142 T > G, in glutamate cysteine ligase catalytic subunit (GCLC), was significantly associated with SMX-induced hypersensitivity, with an adjusted p value of 0.045. This result was replicated in a second cohort of 249 patients (p = 0.025). In the combined cohort, heterozygous and homozygous carriers of the minor G allele were at increased risk of developing hypersensitivity (GT vs TT, odds ratio = 2.2, 95% CL 1.4-3.7, p = 0.0014; GG vs TT, odds ratio = 3.3, 95% CL 1.6 - 6.8, p = 0.0010). Each minor allele copy increased risk of developing hypersensitivity 1.9 fold (95% CL 1.4 - 2.6, p = 0.00012). Moreover, in 91 human livers and 84 B lymphocytes samples, SNP rs761142 homozygous G allele carriers expressed significantly less GCLC mRNA than homozygous TT carriers (p < 0.05). CONCLUSIONS: rs761142 in GCLC was found to be associated with reduced GCLC mRNA expression and with SMX-induced hypersensitivity in HIV/AIDS patients. Catalyzing a critical step in glutathione biosynthesis, GCLC may play a broad role in idiosyncratic drug reactions. PMID- 22824136 TI - Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: implications for epileptogenesis. AB - Hippocampal sclerosis, the main pathological sign of chronic temporal lobe epilepsy (TLE), is associated with oxidative injury, altered N-methyl d-aspartate receptor (NMDAR) stoichiometry, and loss of hippocampal neurons. However, the mechanisms that drive the chronic progression of TLE remain elusive. Our previous studies have shown that NADPH oxidase activation and ERK 1/2 phosphorylation are required for the up-regulation of the predominantly pre-synaptic NR2B subunit auto-receptor in both in vitro and in vivo pilocarpine (PILO) models of TLE. To provide further understanding of the cellular responses during the early-stages of hyper excitability, we investigated the role of oxidative damage and altered NR2B functions. In rat primary hippocampal cultures, we found that N acetylcysteine (NAC) prevented PILO-mediated thiol oxidation, apoptosis, cell death and NR2B subunit over-expression. Interestingly, NAC did not block thiol oxidation when added to the neurons 6h after the PILO exposure, suggesting that disulfide formation could rapidly become an irreversible phenomenon. Moreover, NAC pre-treatment did not prevent PILO-induced NR2A subunit over-expression, a critical event in hippocampal sclerosis. Pre-treatment with the highly specific NR2B subunit inhibitor, ifenprodil, partially decreased PILO-mediated thiol oxidation and was not effective in preventing apoptosis and cell death. However, if acutely administered 48h after PILO exposure, ifenprodil blocked glutamate induced aberrant calcium influx, suggesting the crucial role of NR2B over expression in triggering neuronal hyper-excitability. Furthermore, ifenprodil treatment was able to prevent NR2A subunit over-expression by means of ERK1/2 phosphorylation. Our findings indicate oxidative stress and NR2B/NMDA signaling as promising therapeutic targets for co-treatments aimed to prevent chronic epilepsy following the seizure onset. PMID- 22824137 TI - The expression of Delta ligands in the sponge Amphimedon queenslandica suggests an ancient role for Notch signaling in metazoan development. AB - BACKGROUND: Intercellular signaling via the Notch pathway regulates cell fate, patterning, differentiation and proliferation, and is essential for the proper development of bilaterians and cnidarians. To investigate the origins of the Notch pathway, we are studying its deployment in a representative of an early branching lineage, the poriferan Amphimedon queenslandica. The A. queenslandica genome encodes a single Notch receptor and five membrane-bound Delta ligands, as well as orthologs of many genes that enact and regulate canonical Notch signaling events in other animals. METHODS: In the present report we analyze the structure of the five A. queenslandica Deltas using bioinformatic methods, and characterize their developmental expression via whole mount in situ hybridization and histological staining. RESULTS: Sequence analysis of the A. queenslandica Delta ligands highlights the conservation of their extracellular domains. This contrasts with the divergence of their intracellular regions, each of which is predicted to bear a unique repertoire of protein interaction motifs. In keeping with this diversity, these ligands are expressed differentially and dynamically throughout A. queenslandica embryogenesis, both in cell type specific patterns and broader regional domains. Notably, this expression coincides with the development of the photosensitive larval pigment ring, the non-ciliated cuboidal cells located at the anterior pole of the larva, and the intraepithelial flask cells and globular cells that are presumed to have sensory and/or secretory roles. CONCLUSIONS: Based on the dynamic and complex patterns of expression of these Delta ligands and the Notch receptor, we propose that the Notch signaling pathway is involved in regulating the development of diverse cell types in A. queenslandica. From these observations we infer that Notch signaling is a conserved feature of metazoan development, ancestrally contributing to cell determination, patterning and differentiation processes. PMID- 22824138 TI - Finding the probability of infection in an SIR network is NP-Hard. AB - It is the purpose of this article to review results that have long been known to communications network engineers and have direct application to epidemiology on networks. A common approach in epidemiology is to study the transmission of a disease in a population where each individual is initially susceptible (S), may become infective (I) and then removed or recovered (R) and plays no further epidemiological role. Much of the recent work gives explicit consideration to the network of social interactions or disease-transmitting contacts and attendant probability of transmission for each interacting pair. The state of such a network is an assignment of the values {S,I,R} to its members. Given such a network, an initial state and a particular susceptible individual, we would like to compute their probability of becoming infected in the course of an epidemic. It turns out that this and related problems are NP-hard. In particular, it belongs in a class of problems for which no efficient algorithms for their solution are known. Moreover, finding an efficient algorithm for the solution of any problem in this class would entail a major breakthrough in computer science. PMID- 22824139 TI - Evidence theoretic protein fold classification based on the concept of hyperfold. AB - In current computational biology, assigning a protein domain to a fold class is a complicated and controversial task. It can be more challenging in the much harder task of correct identification of protein domain fold pattern solely through using extracted information from protein sequence. To deal with such a challenging problem, the concepts of hyperfold and interlaced folds are introduced for the first time. Each hyperfold is a set of interlaced folds with a centroid fold. These concepts are used to construct a framework for handling the uncertainty involved with the fold classification problem. In this approach, an unknown query protein is assigned to a hyperfold rather than a single fold. Ten different sequence based features are used to predicting the correct hyperfold. This architecture is featured by the Dempster-Shafer theory of evidence through the bodies of evidence and Dempster's rule of combination to combine the hyperfolds. The classification architecture thus developed was applied for identifying protein folds among the 27 famous SCOP fold patterns from a stringent well-known dataset. Compared with the existing predictors tested by the same benchmark dataset, our approach might achieve the better results. PMID- 22824140 TI - Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid. AB - BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) are diseases which result in the degeneration of the joint surface articular cartilage. Matrix metalloproteinases (MMPs) are enzymes that aid in the natural remodelling of tissues throughout the body including cartilage. However, some MMPs have been implicated in the progression of OA and RA as their expression levels and activation states can change dramatically with the onset of disease. Yet, it remains unknown if normal and arthritic joints demonstrate unique MMPs expression profiles, and if so, can the MMP expression profile be used to identify patients with early OA. In this study, the synovial fluid protein expression levels for MMPs 1, 2, 3, 7, 8, 9, 12 & 13, as well as those for the Tissue Inhibitors of MMPs (TIMPs) 1, 2, 3, & 4 were examined in highly characterized normal knee joints, and knee joints with clinically diagnosed OA (early and advanced) or RA. The purpose of this study was to determine if normal, OA, and RA patients exhibit unique expression profiles for a sub-set of MMPs, and if early OA patients have a unique MMP expression profile that could be used as an early diagnostic marker. METHODS: Synovial fluid was aspirated from stringently characterized normal knee joints, and in joints diagnosed with either OA (early and advanced) or RA. Multiplexing technology was employed to quantify protein expression levels for 8 MMPs and 4 TIMPs in the synovial fluid of 12 patients with early OA, 17 patients diagnosed with advanced OA, 15 with RA and 25 normal knee joints. Principle component analysis (PCA) was used to reveal which MMPs were most influential in the distinction between treatment groups. K - means clustering was used to verify the visual grouping of subjects via PCA. RESULTS: Significant differences in the expression levels of MMPs and TIMPs were observed between normal and arthritic synovial fluids (with the exception of MMP 12). PCA demonstrated that MMPs 2, 8 & 9 can be used to effectively separate individuals diagnosed with advanced arthritis from early osteoarthritic and normal individuals, however, these MMP profiles do not separate early OA from normal synovial fluid. An apparent separation between advanced OA and RA subjects was also revealed through PCA. K means clustering verified the presence of 3 clusters: normal joints clustered with early OA, and separate clusters of advanced OA or RA. CONCLUSIONS: This study demonstrates that unique MMP and TIMP expression profiles are present within normal, advanced OA and RA synovial fluid. These MMP profiles can be used to distinguish advanced OA & RA synovial fluid from early OA & normal synovial fluid, and even between synovial fluid samples from OA and RA joints. Although this methodology cannot be used for the diagnosis of early OA, high throughput multiplex technology of MMPs and TIMPs in synovial fluid may prove useful in determining the severity of the disease state, and/or quantifying the response of individuals to disease interventions. PMID- 22824141 TI - The plastid-dividing machinery: formation, constriction and fission. AB - Plastids divide by constriction of the plastid-dividing (PD) machinery, which encircles the division site. The PD machinery consists of the stromal inner machinery which includes the inner PD and filamenting temperature-sensitive mutant Z (FtsZ) rings and the cytosolic outer machinery which includes the outer PD and dynamin rings. The major constituent of the PD machinery is the outer PD ring, which consists of a bundle of polyglucan filaments. In addition, recent proteomic studies suggest that the PD machinery contains additional proteins that have not been characterized. The PD machinery forms from the inside to the outside of the plastid. The constriction seems to occur by sliding of the polyglucan filaments of the outer PD ring, aided by dynamin. The final fission of the plastid is probably promoted by the 'pinchase' activity of dynamin. PMID- 22824142 TI - Regulation of transposable elements in maize. AB - Maize is a typical plant with respect to the proportion of its genome that is composed of transposable elements (TEs), but it is unusual in the number of well characterized active TEs that it hosts. This has made it possible to examine in some detail the factors responsible for regulating the activity of these elements, particularly the means by which they are recognized and epigenetically silenced. That analysis has revealed that TE silencing is a complex process that involves careful distinctions of different developmental times and tissue types. The available evidence from maize and other species suggests that these distinctions are made in order to generate information in somatic tissues that can be used to induce or reinforce silencing in germinal tissues. PMID- 22824144 TI - Ge/Si(001) heterostructures with dense arrays of Ge quantum dots: morphology, defects, photo-emf spectra and terahertz conductivity. AB - : Issues of Ge hut cluster array formation and growth at low temperatures on the Ge/Si(001) wetting layer are discussed on the basis of explorations performed by high resolution STM and in-situ RHEED. Dynamics of the RHEED patterns in the process of Ge hut array formation is investigated at low and high temperatures of Ge deposition. Different dynamics of RHEED patterns during the deposition of Ge atoms in different growth modes is observed, which reflects the difference in adatom mobility and their 'condensation' fluxes from Ge 2D gas on the surface for different modes, which in turn control the nucleation rates and densities of Ge clusters. Data of HRTEM studies of multilayer Ge/Si heterostructures are presented with the focus on low-temperature formation of perfect films.Heteroepitaxial Si p-i-n-diodes with multilayer stacks of Ge/Si(001) quantum dot dense arrays built in intrinsic domains have been investigated and found to exhibit the photo-emf in a wide spectral range from 0.8 to 5 MUm. An effect of wide-band irradiation by infrared light on the photo-emf spectra has been observed. Photo-emf in different spectral ranges has been found to be differently affected by the wide-band irradiation. A significant increase in photo-emf is observed in the fundamental absorption range under the wide-band irradiation. The observed phenomena are explained in terms of positive and neutral charge states of the quantum dot layers and the Coulomb potential of the quantum dot ensemble. A new design of quantum dot infrared photodetectors is proposed.By using a coherent source spectrometer, first measurements of terahertz dynamical conductivity (absorptivity) spectra of Ge/Si(001) heterostructures were performed at frequencies ranged from 0.3 to 1.2 THz in the temperature interval from 300 to 5 K. The effective dynamical conductivity of the heterostructures with Ge quantum dots has been discovered to be significantly higher than that of the structure with the same amount of bulk germanium (not organized in an array of quantum dots). The excess conductivity is not observed in the structures with the Ge coverage less than 8 A. When a Ge/Si(001) sample is cooled down the conductivity of the heterostructure decreases. PMID- 22824143 TI - Ephrin-A1 inhibits NSCLC tumor growth via induction of Cdx-2 a tumor suppressor gene. AB - BACKGROUND: Tumor formation is a complex process which involves constitutive activation of oncogenes and suppression of tumor suppressor genes. Receptor EphA2 and its ligand ephrin-A1 form an important cell communication system with its functional role in cell-cell interaction and tumor growth. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential. Claudins, the integrated tight junction (TJ) cell-cell adhesion proteins located on the apico-lateral portion of epithelial cells, functions in maintaining cell polarity. There is extensive evidence implicating Eph receptors and ephrins in malignancy, but the mechanisms how these molecular players affect TJ proteins and regulate tumor growth are not clear. In the present study we hypothesized that EphA2 signaling modulates claudin-2 gene expression via induction of cdx-2, a tumor suppressor gene in NSCLC cells. METHODS: The expression of EphA2, claudin-2 was determined in various NSCLC cell lines by using real-time quantitative polymerase chain reaction and Western blot analysis. The claudin-2 expression was also analyzed by immunofluorescence analysis. EphA2 and erk1/erk2 phosphorylation in ephrin-A1 activated cells was evaluated by Western blot analysis. The cell proliferation and tumor colony formation were determined by WST-1 and 3-D matrigel assays respectively. RESULTS: NSCLC cells over expressed receptor EphA2 and claudin-2. Ephrin-A1 treatment significantly down regulated the claudin-2 and EphA2 expression in NSCLC cells. The transient transfection of cells with vector containing ephrin-A1 construct (pcDNA-EFNA1) decreased the expression of claudin-2, EphA2 when compared to empty vector. In addition ephrin-A1 activation increased cdx-2 expression in A549 cells. In contrast over-expression of EphA2 with plasmid pcDNA-EphA2 up regulated claudin-2 mRNA expression and decreased cdx-2 expression. The transient transfection of cells with vector containing cdx-2 construct (pcMV-cdx-2) decreased the expression of claudin-2 in A549 cells. Moreover, silencing the expression of receptor EphA2 by siRNA significantly reduced claudin-2 expression and decreased cell proliferation and tumor formation. Furthermore, silencing cdx-2 gene expression before ephrin-A1 treatment increased claudin-2 expression along with increased cell proliferation and tumor growth in A549 cells. CONCLUSIONS: Our study suggests that EphA2 signaling up-regulates the expression of the TJ-protein claudin-2 that plays an important role in promoting cell proliferation and tumor growth in NSCLC cells. We conclude that receptor EphA2 activation by ephrin-A1 induces tumor suppressor gene cdx-2 expression which attenuates cell proliferation, tumor growth and thus may be a promising therapeutic target against NSCLC. PMID- 22824145 TI - Food insecurity and associated factors among HIV-infected individuals receiving highly active antiretroviral therapy in Jimma zone Southwest Ethiopia. AB - BACKGROUND: In resource limited settings, many People Living with HIV/AIDS (PLWHA) lack access to sufficient quantities of nutritious foods, which poses additional challenges to the success of antiretroviral therapy (ART). Maintaining adequate food consumption and nutrient intake levels and meeting the special nutritional needs to cope up with the disease and the ART are critical for PLWHA to achieve the full benefit of such a treatment. OBJECTIVE: To determine the prevalence and correlates of food insecurity among HIV-infected individuals receiving highly active antiretroviral therapy in resource-limited settings. METHODS: A cross sectional study was carried out from January 1, 2009 to March 3, 2009 at ART clinic at Jimma University specialized hospital (JUSH) in Ethiopia. We used multivariable logistic regression model to compare independent risk factors by food insecurity status among 319 adult PLWHA (>= 18 years) attending ART Clinic. RESULTS: A total of 319 adult PLWHA participated in the study giving a response rate of 100%. Out of 319 PLWHA the largest numbers of participants, 46.4% were in the age group of 25-34 years. The overall 201(63.0%) PLWHA were food insecure. Educational status of elementary or lower [OR = 3.10 (95%CI; (1.68 5.71)], average family monthly income <100 USD [OR = 13.1 (95% CI; (4.29-40.0)] and lower food diversity [OR = 2.18 (95%CI; (1.21-3.99)] were significantly and independently associated with food insecurity. CONCLUSION: Food insecurity is a significant problem among PLWHA on HAART. Lower educational status and low family income were the predictors of food insecurity. Food security interventions should be an integral component of HIV/AIDS care and support programs. Special attention need to be given to patients who have lower educational status and are members of households with low income. PMID- 22824146 TI - Increased expression of OCT4 is associated with low differentiation and tumor recurrence in human hepatocellular carcinoma. AB - Octamer binding transcription factor 4 (OCT4), a key transcription factor required to maintain self-renewal and pluripotency of human and mouse embryonic stem cells, has been recently identified to be associated with tumorigenesis and malignant transformation of many types of cancers. This study was to determine the roles of OCT4 in HCC recurrence and their impact on the clinical outcome of HCC patients. Western blot and immunohistochemical stains were used to detect the expression of OCT4 protein in 152 HCC tissues and 40 cirrhosis tissues, as well as in 6 human HCC cell lines and normal hepatocytes. OCT4 expression in HCC cell lines and tumor tissues was higher than in normal hepatocytes and cirrhosis tissues. Overexpression of OCT4 was significantly associated with low differentiation and tumor recurrence. Patients with elevated expression of OCT4 protein usually carried a poor overall survival and high recurrence rate. Multivariate analysis showed that OCT4 expression was an independent predictive factor for HCC patients survival. OCT4 might serve as a promising biomarker for the diagnosis of highly recurrent cases of HCC and could be used as a valuable indicator for predicting the prognosis of HCC. PMID- 22824147 TI - Cathepsin D as a potential prognostic marker for lung adenocarcinoma. AB - We previously identified cathepsin D as a possible marker for lung adenocarcinoma (AD). The purpose of the present study is to evaluate the correlation between cathepsin D expression and clinicopathological findings or prognosis. We conducted immunohistochemistry (IHC) to assess 150 AD tissues. For these 150 tumors, TTF-1 expression, EGFR and KRAS gene mutations, and ALK rearrangements had already been examined. Cathepsin D expression was detected in 44% (66 of 150, IHC score >=1+) and 27.3% (41 of 150, IHC score >=2+). Cathepsin D-positive (IHC score >=2+) tumors were more poorly differentiated than cathepsin D-negative ones, while all lepidic predominant invasive adenocarcinomas showed no cathepsin D expression. Univariate analysis revealed a poor prognosis for cathepsin D positive lung AD patients with an IHC score >=2+ (P=0.044). Cathepsin D expression was more frequent in TTF-1-negative than in TTF-1-positive ADs (P=0.034), and more frequent in ADs with EGFR wild genotype than mutant EGFR (P<0.001). Regarding AD patients with ALK rearrangements, 4 were positive for Cathepsin D, while 2 were negative. Cathepsin D expression is indicated to be a possible prognostic marker for lung AD and to correlate with a more poorly differentiated form. PMID- 22824148 TI - Expression and prognostic significance of MAP4K4 in lung adenocarcinoma. AB - Accumulating evidence indicates that mitogen-activated protein 4 kinase 4 (MAP4K4) is frequently overexpressed in many types of human cancers, and plays important roles in transformation, invasiveness, adhesion, and cell migration. The aim of the present study was to explore the expression and prognostic significance of MAP4K4 in lung adenocarcinoma. The results of real-time quantitative PCR and Western blotting analysis revealed an enhanced expression of MAP4K4 in lung adenocarcinomas relative to adjacent non-tumorous lung tissues at both transcriptional and translational levels. Immunohistochemistry showed that 130 of 309 (42%) lung adenocarcinomas had high expression of MAP4K4. MAP4K4 overexpression was significantly correlated with histological grade (p=0.027), pT status (p=0.048), pN status (p=0.006), and pleural invasion (p=0.024). Patients with high MAP4K4 expression had a shorter overall survival compared with those with low MAP4K4 expression, regardless of histological grade, pT status, pN status, or pleural invasion status. Multivariate analysis identified MAP4K4 as an independent prognostic factor for lung adenocarcinoma. In conclusion, our results demonstrate that elevated MAP4K4 expression is closely associated with lung adenocarcinoma progression and has an independent prognostic value in predicting overall survival for patients with lung adenocarcinoma. PMID- 22824149 TI - The role of p21-activated kinase in the initiation of atherosclerosis. AB - BACKGROUND: p21-activated kinase (PAK) has been implicated in the inflammatory activation of endothelial cells by disturbed fluid shear stress, which is the initiating stimulus in atherosclerosis. The study addresses whether PAK1 contributes to inflammatory marker expression in endothelial cells at atherosclerosis-susceptible regions of arteries in vivo. METHOD: Aortas from WT and PAK1-/- C57BL/6J mice on a normal chow diet were fixed, dissected and processed for immunohistochemistry using a panel of inflammatory markers. We visualized and quantified staining in the endothelium at the greater and lesser curvatures of the arch of aorta, as atherosclerosis-resistant and susceptible regions, respectively. RESULTS: Fibronectin, VCAM-1 and the activated RelA NF kappaB subunit were localized to the lesser curvature and decreased in PAK1-/- mice. The activated RelB NF-kappaB subunit was also localized to the lesser curvature but was increased in PAK1-/- mice. Low levels of staining for ICAM-1 and the monocyte/macrophage marker Mac2 indicated that overall inflammation in this tissue was minimal. CONCLUSION: These data show that PAK1 has a significant pro-inflammatory function at atherosclerosis-prone sites in vivo. These effects are seen in young mice with very low levels of inflammation, suggesting that inflammatory activation of the endothelium is primarily biomechanical. Activation involves NF-kappaB, expression of leukocyte recruitment receptors and fibronectin deposition. These results support and extend in vitro studies demonstrating that PAK contributes to activation of inflammatory pathways in endothelial cells by fluid shear stress. PMID- 22824150 TI - What does make an amyloid toxic: morphology, structure or interaction with membrane? AB - The toxicity of amyloids is a subject under intense scrutiny. Many studies link this toxicity to the existence of various intermediate structures prior to the fiber formation and/or their specific interaction with membranes. Membranes can also be a catalyst of amyloidogenesis and the composition or the charge of membrane lipids may be of particular importance. Despite intensive research in the field, such intermediates are not yet fully characterized probably because of the lack of adapted methods for their analyses, and the mechanisms of interaction with the membrane are far to be understood. The purpose of this mini-review is to highlight some in vitro characteristics that seem to be convergent to explain the toxicity observed for some amyloids. Based on a comparison between the behavior of a model non-toxic amyloid (the Prion Forming Domain of HET-s) and its toxic mutant (M8), we could establish that short oligomers and/or fibers assembled in antiparallel beta-sheets strongly interact with membrane leading to its disruption. Many recent evidences are in favor of the formation of antiparallel toxic oligomers assembled in beta-helices able to form pores. We may also propose a new model of amyloid interaction with membranes by a "raft-like" mode of insertion that could explain important destabilization of membranes and thus amyloid toxicity. PMID- 22824151 TI - [Primary care resources available in digital libraries in Spanish Autonomous Regions]. AB - The Statement by the Spanish Society of Family and Community Medicine (SemFYC) on access to scientific information, highlights the need for providing digital libraries with certain resources in Autonomous Regions. The primary goal is to study the evidence-based medicine (EBM) coverage that SemFYC recommends regional virtual libraries. The regional health virtual libraries were identified and the access provided to health professionals, Internet presence, remote access and resources were studied. The results suggest there is ample coverage in 8 Autonomous Regions. At the top of the list was, Health Sciences Virtual Library of Navarre, the Balearic Islands Health Sciences Virtual Library, and Virtual Library of the Andalusian Public Health System. The present study needs to be extended to the other biomedical sciences, in order to obtain more accurate results. PMID- 22824152 TI - [Criteria for referral between levels of care of patients with peripheral vascular disease. SEMFYC-SEACV consensus document]. AB - Coordination between care levels is essential to increase the efficiency of the Health System; vascular disease has an important role in this respects, as it includes frequent, serious and vulnerable conditions. Consensus documents are an essential tool to obtain these aims. This document is not expected to replace the Clinical Guidelines, but tries to establish the basis of the shared management of the patient with vascular disease (peripheral arterial disease, diabetic foot, and chronic venous insufficiency) in three ways: to determine the profile of the patient who should receive priority follow-up at every level; to establish the skills that every professional must have, and to set and to prioritise the referral criteria in both directions. PMID- 22824153 TI - Ambidentate H-bonding of NO and O2 in heme proteins. AB - The affinity and reactivity of the gaseous molecules CO, NO and O(2) (XO) in heme protein adducts are controlled by secondary interactions, especially by H-bonds donated from distal protein residues. Vibrational spectroscopy, supported by DFT (Density Functional Theory) modeling, has revealed that for NO and O(2), but not for CO, a critical issue is whether the H-bond is donated to the outer or inner atom of the bound diatomic ligand. DFT modeling shows that bound NO and O(2) are ambidentate, both atoms separately acting as H-bond acceptors. This is not the case for CO, whose pi* orbital acts as a delocalized H-bond acceptor. Vibrational spectra of heme-XO adducts reveal a general pattern of backbonding variations, marked by families of negative correlations between frequencies associated with FeX and XO bond stretches. For heme-CO adducts, H-bonding increases backbonding, the nuFeX/nuXO points moving up the backbonding correlation established with model compounds. For NO and O(2) adducts, however, increased backbonding is only observed when the outer atom is the H-bond acceptor. H-bonding to the inner (X) atom instead produces a positive nuFeX/nuXO correlation. This effect can be reproduced by DFT modeling. Its mechanism is polarization of the sp(2) orbital on the X atom, on the back side of the bent FeXO unit, drawing electrons from both the FeX and XO bonds and weakening them together. Thus, the positioning of H-bond donors in the protein differentially affects bonding and reactivity in heme adducts of NO and O(2). PMID- 22824154 TI - Silica xerogels and hydroxyapatite nanocrystals for the local delivery of platinum-bisphosphonate complexes in the treatment of bone tumors: a mini-review. AB - The present review focuses on the "drug targeting and delivery" approach of the selective transportation of cisplatin to bone tumors and bone metastases. This aim is realized by binding cisplatin to (bis)phosphonate ligands or their derivatives. Geminal bisphosphonates are in clinical use in the treatment of several bone-related diseases because of their high affinity for calcium ions and hence for bones. Platinum-bisphosphonate complexes may be easily loaded onto calcium-containing inorganic matrices, such as calcium-doped sol-gel derived silica xerogels and hydroxyapatite nanocrystals, for local administration at the site of the bone malignancy. The composites may be used as bone-filler materials that, in addition to their action as bone substitutes, can also act as controlled platinum-drug releasing agents. The release kinetics of the drug can be tailored for specific therapeutic applications modulating the physico-chemical features of the inorganic matrices. Moreover, apatite nanocrystals loaded with platinum bisphosphonate prodrugs can be used as injectable material for nanomedical applications (e.g. intracellular drug delivery). PMID- 22824155 TI - The reactivity of macrocyclic Fe(II) paraCEST MRI contrast agents towards biologically relevant anions, cations, oxygen or peroxide. AB - The reactivity of four macrocyclic Fe(II) complexes (L1-L4) is studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) magnetic resonance imaging (MRI) contrast agents for in vivo studies. (L1 = 1,4,7 tris(carbamoylmethyl)-1,4,7-triazacyclononane; L2 = 1,4,7-tris[(5-methyl-2 pyridyl)methyl]-1,4,7-triazacyclononane; L3 = 1,4,7-tris[(2-pyridyl)methyl]-1,4,7 triazacyclononane; L4 = 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10 tetraazacyclododecane). The Fe(II) complexes remain intact in the presence of 25 mM carbonate, 0.40 mM phosphate and 100mM NaCl for 12h at 37 degrees C, consistent with their moderately high formation constants (log K=13.5, 19.2, 7.50 for [Fe(L1)](2+), [Fe(L3)](2+) and [Fe(L4)](2+), respectively). [Fe(L4)](2+), [Fe(L2)](2+) and [Fe(L3)](2+) do not dissociate over 12h in the presence of excess Cu(II) at 37 degrees C. None of the complexes show appreciable redox cycling as measured by consumption of ascorbate in the presence of oxygen, corresponding to their highly stabilized Fe(II) oxidation state (E(o)=860, 930, 970, and 800 mV versus NHE for [Fe(L1)](2+), [ [Fe(L2)](2+), [Fe(L3)](2+) and [Fe(L4)](2+). None of the Fe(II) complexes produce appreciable amounts of hydroxyl radical in the presence of peroxide and ascorbate as shown by limited hydroxylation of benzoate. Fe(II) complexes of L1, L2, and L3 show 25-28% cleavage of supercoiled plasmid DNA in the presence of peroxide and ascorbate over 2h at 37 degrees C while [Fe(L4)](2+) shows 6% cleavage. PMID- 22824156 TI - Metalloprotein active site structure determination: synergy between X-ray absorption spectroscopy and X-ray crystallography. AB - Structures of metalloprotein active sites derived from X-ray crystallography frequently contain chemical anomalies such as unexpected atomic geometries or elongated bond-lengths. Such anomalies are expected from the known errors inherent in macromolecular crystallography (ca. 0.1-0.2A) and from the lack of appropriate restraints for metal sites which are often without precedent in the small molecule structure literature. Here we review the potential of X-ray absorption spectroscopy to provide information and perspective which could aid in improving the accuracy of metalloprotein crystal structure solutions. We also review the potential problem areas in analysis of the extended X-ray absorption fine structure (EXAFS) and discuss the use of density functional theory as another possible source of geometrical restraints for crystal structure analysis of metalloprotein active sites. PMID- 22824157 TI - A comparison and evaluation of five biclustering algorithms by quantifying goodness of biclusters for gene expression data. AB - BACKGROUND: Several biclustering algorithms have been proposed to identify biclusters, in which genes share similar expression patterns across a number of conditions. However, different algorithms would yield different biclusters and further lead to distinct conclusions. Therefore, some testing and comparisons between these algorithms are strongly required. METHODS: In this study, five biclustering algorithms (i.e. BIMAX, FABIA, ISA, QUBIC and SAMBA) were compared with each other in the cases where they were used to handle two expression datasets (GDS1620 and pathway) with different dimensions in Arabidopsis thaliana (A. thaliana)GO (gene ontology) annotation and PPI (protein-protein interaction) network were used to verify the corresponding biological significance of biclusters from the five algorithms. To compare the algorithms' performance and evaluate quality of identified biclusters, two scoring methods, namely weighted enrichment (WE) scoring and PPI scoring, were proposed in our study. For each dataset, after combining the scores of all biclusters into one unified ranking, we could evaluate the performance and behavior of the five biclustering algorithms in a better way. RESULTS: Both WE and PPI scoring methods has been proved effective to validate biological significance of the biclusters, and a significantly positive correlation between the two sets of scores has been tested to demonstrate the consistence of these two methods.A comparative study of the above five algorithms has revealed that: (1) ISA is the most effective one among the five algorithms on the dataset of GDS1620 and BIMAX outperforms the other algorithms on the dataset of pathway. (2) Both ISA and BIMAX are data-dependent. The former one does not work well on the datasets with few genes, while the latter one holds well for the datasets with more conditions. (3) FABIA and QUBIC perform poorly in this study and they may be suitable to large datasets with more genes and more conditions. (4) SAMBA is also data-independent as it performs well on two given datasets. The comparison results provide useful information for researchers to choose a suitable algorithm for each given dataset. PMID- 22824158 TI - Long-term results of curative intraluminal high dose rate brachytherapy for endobronchial carcinoma. AB - BACKGROUND: The treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma. METHOD: Sixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy. RESULTS: Median follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea. CONCLUSIONS: ILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication. PMID- 22824159 TI - The effect of in situ augmentation on implant anchorage in proximal humeral head fractures. AB - INTRODUCTION: Fracture fixation in patients suffering from osteoporosis is difficult as sufficient implant anchorage is not always possible. One method to enhance implant anchorage is implant/screw augmentation with PMMA-cement. The present study investigated the feasibility of implant augmentation with PMMA cement to enhance implant anchorage in the proximal humerus. MATERIALS AND METHODS: A simulated three part humeral head fracture was stabilised with an angular stable plating system in 12 pairs of humeri using six head screws. In the augmentation group the proximal four screws were treated with four cannulated screws, each augmented with 0.5ml of PMMA-cement, whereas the contra lateral side served as a non-augmented control. Specimens were loaded in varus-bending or axial-rotation using a cyclic loading protocol with increasing load magnitude until failure of the osteosynthesis occurred. RESULTS: Augmented specimens showed a significant higher number of load cycles until failure than non-augment specimens (varus-bending: 8516 (SD 951.6) vs. 5583 (SD 2273.6), P=0.014; axial rotation: 3316 (SD 348.8) vs. 2050 (SD 656.5), P=0.003). Non-augmented specimens showed a positive correlation of load cycles until failure and measured bone mineral density (varus-bending: r=0.893, P=0.016; axial-rotation: r=0.753, P=0.084), whereas no correlation was present in augmented specimens (varus bending: r=0,258, P=0.621; axial-rotation r=0.127, P=0.810). CONCLUSION: These findings suggest that augmentation of cannulated screws is a feasible method to enhance implant/screw anchorage in the humeral head. The improvement of screw purchase is increasing with decreasing bone mineral density. PMID- 22824160 TI - Osteoarthritis year 2012 in review: imaging. AB - PURPOSE: This article reviews original publications related to imaging in osteoarthritis (OA) published in English from September 2011 through March 2012. In vitro data and animal studies are not covered. METHODS: To extract relevant studies, an extensive PubMed database search was performed using the query terms "osteoarthritis" in combination with "MRI", "imaging", "radiography", "ultrasound", "computed tomography" and "nuclear medicine". Publications were sorted according to relevance based on potential impact to the OA research community with the over all goal of a balanced overview of all aspects of imaging. Focus was on publications in high-impact special-interest journals. The literature will be presented by topics covering radiography, morphologic magnetic resonance imaging (MRI), compositional and high-field MRI, quantitative MRI, ultrasound, other joints and systematic reviews. Original research that was presented as a podium or poster presentation at osteoarthritis research society international (OARSI) 2012 will not be included. RESULTS AND CONCLUSIONS: For the search topics "MRI" and "osteoarthritis" a decrease in overall publications was observed over the 6 months following September 2011 when compared to the previous 6 months (-38.1%). For the terms "radiography" and "osteoarthritis" a decrease of 56.9% was noted. The 6 months since the last OARSI conference were characterized by several MRI-based studies dealing with epidemiologic and methodologic aspects of disease. Other modalities such as radiography or ultrasound received much less attention. Most imaging research is still concentrated on the knee although interest in other sites, especially the hand, has increased since the last OARSI meeting. PMID- 22824161 TI - Cardiac performance and quality of life in patients who have undergone the Fontan procedure with and without prior superior cavopulmonary connection. AB - BACKGROUND: A superior cavopulmonary connection is commonly performed before the Fontan procedure in patients with a functionally univentricular heart. Data are limited regarding associations between a prior superior cavopulmonary connection and functional and ventricular performance late after the Fontan procedure. METHODS: We compared characteristics of those with and without prior superior cavopulmonary connection among 546 subjects enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study. We further compared different superior cavopulmonary connection techniques: bidirectional cavopulmonary anastomosis (n equals 229), bilateral bidirectional cavopulmonary anastomosis (n equals 39), and hemi-Fontan (n equals 114). RESULTS: A prior superior cavopulmonary connection was performed in 408 subjects (75%); the proportion differed by year of Fontan surgery and centre (p-value less than 0.0001 for each). The average age at Fontan was similar, 3.5 years in those with superior cavopulmonary connection versus 3.2 years in those without (p-value equals 0.4). The type of superior cavopulmonary connection varied by site (p-value less than 0.001) and was related to the type of Fontan procedure. Exercise performance, echocardiographic variables, and predominant rhythm did not differ by superior cavopulmonary connection status or among superior cavopulmonary connection types. Using a test of interaction, findings did not vary according to an underlying diagnosis of hypoplastic left heart syndrome. CONCLUSIONS: After controlling for subject and era factors, most long-term outcomes in subjects with a prior superior cavopulmonary connection did not differ substantially from those without this procedure. The type of superior cavopulmonary connection varied significantly by centre, but late outcomes were similar. PMID- 22824162 TI - Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. AB - Biomarkers of infection, namely C-reactive protein and procalcitonin (PCT), are potentially useful in the diagnosis of infection as well as in the assessment of its response to antibiotic therapy. C-reactive protein variations overtime appears to have a good performance for the diagnosis of infection. Procalcitonin shows a better correlation with clinical severity. In addition, to overcome the worldwide problem of antibiotic overuse as well as misuse, biomarker guidance of antibiotic stewardship represents a promising new approach. In several randomized, controlled trials, including adult critically ill patients, PCT guidance was repeatedly associated with a decrease in the duration of antibiotic therapy. However, these trials present several limitations, namely high rate of patients' exclusion, high rate of algorithm overruling, long duration of antibiotic therapy in the control group, disregard the effect of renal failure on PCT level, and above all a possible higher mortality and higher late organ failure in the PCT arm. In addition, some infections (e.g., endocarditis) as well as frequent nosocomial bacteria (e.g., Pseudomonas aeruginosa) are not suitable to be assessed by PCT algorithms. Therefore, the true value of PCT-guided algorithm of antibiotic stewardship in assisting the clinical decision-making process at the bedside remains uncertain. Future studies should take into account the issues identified in the present review. PMID- 22824163 TI - Classification of edible oils and modeling of their physico-chemical properties by chemometric methods using mid-IR spectroscopy. AB - This research work describes two studies for the classification and characterization of edible oils and its quality parameters through Fourier transform mid infrared spectroscopy (FT-mid-IR) together with chemometric methods. The discrimination of canola, sunflower, corn and soybean oils was investigated using SVM-DA, SIMCA and PLS-DA. Using FT-mid-IR, DPLS was able to classify 100% of the samples from the validation set, but SIMCA and SVM-DA were not. The quality parameters: refraction index and relative density of edible oils were obtained from reference methods. Prediction models for FT-mid-IR spectra were calculated for these quality parameters using partial least squares (PLS) and support vector machines (SVM). Several preprocessing alternatives (first derivative, multiplicative scatter correction, mean centering, and standard normal variate) were investigated. The best result for the refraction index was achieved with SVM as well as for the relative density except when the preprocessing combination of mean centering and first derivative was used. For both of quality parameters, the best results obtained for the figures of merit expressed by the root mean square error of cross validation (RMSECV) and prediction (RMSEP) were equal to 0.0001. PMID- 22824165 TI - Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice. AB - To date, fewer than 50 mutagens have been studied for their ability to cause heritable mutations. The majority of those studied are classical mutagens like radiation and anti-cancer drugs. Very little is known about the dietary variables influencing germline mutation rates. Folate is essential for DNA synthesis and methylation and can impact chromatin structure. We therefore determined the effects of folic acid-deficient (0mg/kg), control (2mg/kg) and supplemented (6mg/kg) diets in early development and during lactation or post-weaning on mutation rates and chromatin quality in sperm of adult male Balb/c mice. The sperm chromatin structure assay and mutation frequencies at expanded simple tandem repeats (ESTRs) were used to evaluate germline DNA integrity. Treatment of a subset of mice fed the control diet with the mutagen ethylnitrosourea (ENU) at 8 weeks of age was included as a positive control. ENU treated mice exhibited decreased cauda sperm counts, increased DNA fragmentation and increased ESTR mutation frequencies relative to non-ENU treated mice fed the control diet. Male mice weaned to the folic acid deficient diet had decreased cauda sperm numbers, increased DNA fragmentation index, and increased ESTR mutation frequency. Folic acid deficiency in early development did not lead to changes in sperm counts or chromatin integrity in adult mice. Folic acid supplementation in early development or post-weaning did not affect germ cell measures. Therefore, adequate folic acid intake in adulthood is important for preventing chromatin damage and mutation in the male germline. Folic acid supplementation at the level achieved in this study does not improve nor is it detrimental to male germline chromatin integrity. PMID- 22824164 TI - Detection of acetaldehyde derived N(2)-ethyl-2'-deoxyguanosine in human leukocyte DNA following alcohol consumption. AB - Epidemiological studies have shown an association between alcohol (ethanol) consumption and increased cancer risk. The effect of alcohol consumption on the levels and persistence of N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) formed by acetaldehyde, the oxidative metabolite of ethanol, in human leukocyte DNA was investigated. DNA was isolated from venous blood samples obtained from 30 male non-smoking individuals before consumption of alcohol (0h) and subsequently at 3-5h following the consumption of 150mL of vodka (containing 42% pure ethanol). Additional samples were collected 24h and 48h post-alcohol consumption. The levels of N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) in the DNA were determined following reduction of N(2)-ethylidene-dG with sodium cyanoborohydride using a liquid chromatography-tandem mass spectrometry selected reaction monitoring method. A slight time-dependent trend showing an increase and decrease in the levels of N(2)-ethyl-dG was observed following consumption of alcohol compared to time 0h, however, the differences were not statistically significant. The average levels of N(2)-ethyl-dG observed at 0h, 3-5h, 24h and 48h time points following ingestion of alcohol were 34.6+/-21.9, 35.1+/-21.0, 36.8+/-20.7 and 35.6+/-21.1 per 10(8) 2'-deoxynucleosides, respectively. In conclusion, alcohol consumption that could be encountered under social drinking conditions, does not significantly alter the levels of the acetaldehyde derived DNA adduct, N(2)-ethyl dG in human leukocyte DNA from healthy individuals. PMID- 22824166 TI - Anti-TNFalpha therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a pilot study. AB - BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti tumor necrosis factor-alpha (anti-TNFalpha) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. METHODS: Twenty-three RA patients starting on anti-TNFalpha treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. RESULTS: Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. CONCLUSION: Anti-TNFalpha therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function. PMID- 22824168 TI - L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN)--a randomized multicentre trial. AB - BACKGROUND: Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia. FINDINGS: We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 +/- 2.5 (SEM) kg. During treatment body-mass-index increased by 3.4 +/- 1.4% under L Carnitine and decreased (-1.5 +/- 1.4%) in controls (p < 0.05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 +/- 50 d versus 399 +/- 43 d, not significant) and towards a reduced hospital-stay (36 +/- 4d versus 41 +/- 9d,n.s.). CONCLUSION: While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L Carnitine. PMID- 22824169 TI - Graphite/InP and graphite/GaN Schottky barriers with electrophoretically deposited Pd or Pt nanoparticles for hydrogen detection. AB - Large attention has been devoted worldwide to the investigation of hydrogen sensors based on various Schottky diodes. We prepared graphite semimetal Schottky contacts on polished n-InP and n-GaN wafers partly covered with nanoparticles of catalytic metals Pd or Pt by applying colloidal graphite. Metal nanoparticles were deposited electrophoretically from colloids prepared beforehand. Deposited nanoparticles were imaged by scanning electron microscopy, atomic force microscopy, and scanning tunneling microscopy on the as-made and annealed-in vacuum samples. Current-voltage characteristics of prepared Schottky diodes had very high rectification ratios, better than 107 at 1 V. It was shown that the barrier heights of these diodes were equal to the difference between the electron affinity of InP or GaN and the electron work function of the metal Pd or Pt (Schottky-Mott limit). That was a good precondition for the high sensitivity of the diodes to hydrogen, and indeed, high sensitivity to hydrogen, with the detection limit better than 1 ppm, was proved. PMID- 22824167 TI - Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome. AB - BACKGROUND: Renal cell carcinoma (RCC) is characterized by a number of diverse molecular aberrations that differ among individuals. Recent approaches to molecularly classify RCC were based on clinical, pathological as well as on single molecular parameters. As a consequence, gene expression patterns reflecting the sum of genetic aberrations in individual tumors may not have been recognized. In an attempt to uncover such molecular features in RCC, we used a novel, unbiased and integrative approach. METHODS: We integrated gene expression data from 97 primary RCC of different pathologic parameters, 15 RCC metastases as well as 34 cancer cell lines for two-way nonsupervised hierarchical clustering using gene groups suggested by the PANTHER Classification System. We depicted the genomic landscape of the resulted tumor groups by means of Single Nuclear Polymorphism (SNP) technology. Finally, the achieved results were immunohistochemically analyzed using a tissue microarray (TMA) composed of 254 RCC. RESULTS: We found robust, genome wide expression signatures, which split RCC into three distinct molecular subgroups. These groups remained stable even if randomly selected gene sets were clustered. Notably, the pattern obtained from RCC cell lines was clearly distinguishable from that of primary tumors. SNP array analysis demonstrated differing frequencies of chromosomal copy number alterations among RCC subgroups. TMA analysis with group-specific markers showed a prognostic significance of the different groups. CONCLUSION: We propose the existence of characteristic and histologically independent genome-wide expression outputs in RCC with potential biological and clinical relevance. PMID- 22824171 TI - Is it really getting easier to assess mitral regurgitation using the proximal isovelocity surface area? PMID- 22824172 TI - Quantitative echocardiography in pediatrics--are we there yet? PMID- 22824170 TI - Regional variations in early and late survival after out-of-hospital cardiac arrest. AB - BACKGROUND: While prior studies highlight regional variations in out-of-hospital cardiac arrest (OHCA) survival, the underlying reasons remain unknown. We sought to characterize regional variations early and later survival to hospital discharge after OHCA. METHODS: We studied adult, non-traumatic OHCA treated by 10 regional sites of the Resuscitation Outcomes Consortium (ROC) during 12/01/2005 6/30/2007. We compared (1) early survival (up to one calendar day after arrest) and (2) later conditional survival to hospital discharge (early survivors progressing to eventual hospital discharge) between ROC regional sites. RESULTS: Among 3763 VF/VT with complete covariates, site unadjusted early survival varied from 11.3 to 54.3%, and site unadjusted later survival varied from 33.3 to 70.5%. Compared with the largest site, adjusted VF/VT survival varied across sites: early survival OR 0.33 (95% CI: 0.17, 0.65) to 2.87 (2.20, 3.73), overall site variation p<0.001; later survival OR 0.29 (0.14, 0.59) to 1.21 (0.73, 2.00), p<0.001. Among 10,879 non-VF/VT with complete covariates, site unadjusted early survival varied from 6.6 to 14.3%, and site unadjusted later survival varied from 4.5 to 39.6%. Compared with the largest site, adjusted non-VF/VT survival varied across sites: early survival OR 1.02 (0.63, 1.64) to 2.43 (1.91, 3.12), p<0.001; later survival OR 0.11 (0.01, 0.82) to 1.56 (0.90, 2.70), p=0.02. CONCLUSIONS: In this prospective multicenter North American series, there were regional disparities in early and later survival after OHCA, suggesting that there are underlying regional differences in out-of-hospital and post-arrest care beyond traditional Utstein predictors. Community efforts to improve OHCA survival must address both out-of-hospital and in-hospital care. PMID- 22824173 TI - Marked variations in serial coronary artery diameter measures in Kawasaki disease: a new indicator of coronary involvement. AB - BACKGROUND: The long-term risk of patients with Kawasaki disease is not well defined. A great proportion of patients with Kawasaki disease have important variation of their coronary artery (CA) diameters, but the significance of this variation is not known. The aim of this study was to test the hypothesis that patients within the normal range of CA diameters but with important Z-score variation have a stronger inflammatory response and increased resistance to treatment than those without such Z-score variation. METHODS: A retrospective study was conducted in 197 patients with Kawasaki disease with serial echocardiograms up to 12 months after diagnosis. Patients with occult CA dilatation (variation > 2 Z-score units but within the normal range) were compared with patients with definite CA dilatation (Z score > 2.5) and with patients with normal CA for resistance to treatment and systemic inflammatory parameters. RESULTS: A total of 63 patients (32.0%) were identified with Z scores always within the normal range but with important variation of CA diameter during follow-up (occult dilatation). There was a strong statistically significant trend of increasing inflammatory marker levels across patient categories (normal > occult dilatation > definite dilatation). Furthermore, resistance to intravenous immunoglobulin therapy was significantly increased in patients with occult dilatation compared with patients with normal CAs (relative risk, 2.6; 95% confidence interval, 1.21-5.44; P = .006). CONCLUSIONS: The suggested definition of occult CA dilatation identified patients with CA involvement currently unrecognized per the current guidelines. These patients might be at a higher CA risk than previously thought. PMID- 22824175 TI - Echocardiography here, there, and everywhere. PMID- 22824174 TI - Left ventricular function and the systemic arterial vasculature: remembering what we have learned. PMID- 22824176 TI - Changing staff assignments. PMID- 22824177 TI - Can a handheld handle vascular? Contemplation of the vascular system in miniature. PMID- 22824178 TI - [Analysis of costs and cost-effectiveness of the preferred treatments by GESIDA/National plan for AIDS for initial antiretroviral therapy in 2012]. PMID- 22824179 TI - Phase I study of photodynamic therapy using talaporfin sodium and diode laser for local failure after chemoradiotherapy for esophageal cancer. AB - BACKGROUND: Photodynamic therapy (PDT) is a less invasive and effective salvage treatment for local failure after chemoradiotherapy (CRT) for esophageal cancer, however it causes a high rate of skin phototoxicity and requires a long sun shade period. Talaporfin sodium is a rapidly cleared photosensitizer that is expected to have less phototoxicity. This study was undertaken to clarify the optimum laser fluence rate of PDT using talaporfin sodium and a diode laser for patients with local failure after CRT or radiotherapy (RT) for esophageal cancer. METHODS: This phase I, laser dose escalation study used a fixed dose (40 mg/m2) of intravenous talaporfin sodium administered 4 to 6 hours before irradiation in patients with local failure limited to T2 after CRT or RT (>= 50 Gy). The primary endpoint was to assess the dose limiting toxicity (DLT) of PDT, and the secondary endpoints were to evaluate the adverse events and toxicity related to PDT. The starting fluence of the 664 nm diode laser was 50 J/cm2, with an escalation plan to 75 J/cm2 and 100 J/cm2. RESULTS: 9 patients with local failure after CRT or RT for ESCC were enrolled and treated in groups of 3 individuals to the third fluence level. No DLT was observed at any fluence level. Phototoxicity was not observed, but one subject had grade 1 fever, three had grade 1 esophageal pain, and 1 had grade 1 dysphagia. Five of 9 patients (55.6%) achieved a complete response after PDT. CONCLUSIONS: PDT using talaporfin sodium and a diode laser was safe for local failure after RT in patients with esophageal cancer. The recommended fluence for the following phase II study is 100 J/cm2. PMID- 22824180 TI - Phage display identifies an Eastern equine encephalitis virus glycoprotein E2 specific B cell epitope. AB - The present study identified a linear B-cell epitope in the Eastern equine encephalitis virus (EEEV) E2 glycoprotein by screening a phage-displayed random 12-mer peptide library using an EEEV E2 specific monoclonal antibody (mAb) 7C11 and defined L/F-E/R-Y-T-W-G/R-N-H/W-P as the consensus binding motif. A sequence ((321)EGLEYTWGNHPP(332)) encompassing this consensus motif was found in the EEEV E2 glycoprotein and synthesized for further epitope confirmation. Meanwhile, the corresponding epitope peptides in E2 protein of associated alphaviruses were synthesized for specificity identification. Results showed the mAb 7C11 and murine antisera all reacted strongly against the synthesized polypeptide of EEEV antigen complex, but no reaction with Western equine encephalitis virus (WEEV) and Venezuelan equine encephalitis virus (VEEV) was detected. The knowledge and reagents generated in this study may have potential applications in differential diagnosis and the development of epitope-based marker vaccines against EEEV. PMID- 22824181 TI - Evaluation of qPCR reference genes in two genotypes of Populus for use in photoperiod and low-temperature studies. AB - BACKGROUND: Quantitative PCR (qPCR) is a widely used technique for gene expression analysis. A common normalization method for accurate qPCR data analysis involves stable reference genes to determine relative gene expression. Despite extensive research in the forest tree species Populus, there is not a resource for reference genes that meet the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) standards for qPCR techniques and analysis. Since Populus is a woody perennial species, studies of seasonal changes in gene expression are important towards advancing knowledge of this important developmental and physiological trait. The objective of this study was to evaluate reference gene expression stability in various tissues and growth conditions in two important Populus genotypes (P. trichocarpa "Nisqually 1" and P. tremula x P. alba 717 1-B4) following MIQE guidelines. RESULTS: We evaluated gene expression stability in shoot tips, young leaves, mature leaves and bark tissues from P. trichocarpa and P. tremula. x P. alba grown under long-day (LD), short-day (SD) or SD plus low-temperatures conditions. Gene expression data were analyzed for stable reference genes among 18S rRNA, ACT2, CDC2, CYC063, TIP4 like, UBQ7, PT1 and ANT using two software packages, geNorm(PLUS) and BestKeeper. GeNorm(PLUS) ranked TIP4-like and PT1 among the most stable genes in most genotype/tissue combinations while BestKeeper ranked CDC2 and ACT2 among the most stable genes. CONCLUSIONS: This is the first comprehensive evaluation of reference genes in two important Populus genotypes and the only study in Populus that meets MIQE standards. Both analysis programs identified stable reference genes in both genotypes and all tissues grown under different photoperiods. This set of reference genes was found to be suitable for either genotype considered here and may potentially be suitable for other Populus species and genotypes. These results provide a valuable resource for the Populus research community. PMID- 22824182 TI - Factors predicting pathologic significance among women with atypical glandular cells on liquid-based cytology. AB - OBJECTIVE: To determine incidence, originating organ, and factors predicting significant histopathology (premalignant and malignant lesions) among women with atypical glandular cells (AGCs) on liquid-based cytology (LBC). METHODS: In a retrospective study at Siriraj Hospital, Bangkok, Thailand, clinical and histologic data were reviewed for women with AGCs who underwent appropriate examinations from January 2007 to December 2010. RESULTS: There were 284 women with AGC cytology (mean age, 51.2 years). The incidence of significant pathology and invasive cancer was 43.3% and 34.5%, respectively. The most common malignant organ was the uterus (64/123, 52%). Predictors of serious pathology were AGC favor neoplasia (AGC-FN) endocervical (odds ratio [OR], 5.64; 95% confidence interval [CI], 1.62-19.57), AGC-FN endometrial (OR, 4.11; 95% CI, 1.27-13.32), AGC-FN glandular (OR, 8.23; 95% CI, 2.02-33.49) subtypes, and bleeding (OR, 2.88; 95% CI, 1.47-5.65). Combining patient age and AGC subtype, there were no serious cervical lesions among women aged 50 years or younger with AGC-FN glandular subtype, or serious non-cervical neoplasia among women aged 50 years or younger with AGC not otherwise specified (AGC-NOS) or AGC-FN endocervical subtypes. CONCLUSION: AGC subcategories defined from LBC, alone or combined with patient age, might be predictors of significant histopathology, cancer incidence, and originating organ. PMID- 22824183 TI - Metallothionein 2A genetic polymorphisms and risk of prostate cancer in a Polish population. AB - Metallothionein 2A (MT2A) is the most expressed metallothionein (MT) isoform in prostate cells. A number of studies have demonstrated altered MT2A expression in various human tumors, including prostate cancer. We conducted an association study to examine whether MT2A gene polymorphisms are associated with a risk of prostate cancer. Genotyping was conducted using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Three single nucleotide polymorphisms (SNPs), rs28366003, rs1610216, and rs10636, were genotyped in 358 prostate cancer cases and 406 population controls. One SNP in MT2A (rs28366003) showed a positive association with prostate cancer. Compared to homozygous common allele carriers, heterozygosity for the G variant (odds ratio (OR)=2.30, 95% confidence interval (CI): 1.50-3.47, P-trend<0.0001; the OR assuming a dominant model 2.43 (95% CI: 1.62-3.61, P(dominant)=0.001) after adjustment for age) had a significantly increased risk of prostate cancer in a Polish population. Our data suggest that the rs28366003 SNP in MT2A is associated with the risk of prostate cancer in a Polish population. PMID- 22824184 TI - Serum IgG responses against Aspergillus proteins before hematopoietic stem cell transplantation or chemotherapy identify patients who develop invasive aspergillosis. AB - The ability to identify patients at particularly low risk for invasive aspergillosis (IA) would facilitate more efficient targeting of antifungal prophylaxis. We measured baseline serum immunoglobulin responses against 6 purified recombinant Aspergillus fumigatus proteins before hematopoietic stem cell transplantation (HSCT) or chemotherapy in 73 subjects, including 19 patients who subsequently developed proven or probable IA and 54 uninfected controls. We also assessed responses at the time of IA diagnosis and 4 weeks later (acute and convalescent sera, respectively). Baseline IgG responses against enolase, Ahp1, Hsp90, Crf1, and Cdc37 were significantly higher in the patients with IA compared with controls (P < .05). Cutoff concentrations identified by receiver-operating characteristic curve analysis were 67%-84% sensitive and 52%-67% specific. In a population with a 15% likelihood of developing IA, positive and negative predictive values would be 22%-26% and 92%-95%, respectively. Positive IgG responses against Hsp90, Pep2, Crf1, and Cdc37 were specifically associated with early-onset IA (<40 days) rather than late-onset IA (P <= .009). Increased IgG concentrations against Hsp90, Pep2, and Crf1 in convalescent sera versus baseline sera were more likely in the patients with IA who survived (P <= .01). IgG responses in acute sera were not correlated with outcomes, and IgM and IgA responses did not differ in baseline, acute, or convalescent sera between the patients and controls. In conclusion, baseline IgG responses against Aspergillus proteins may be useful screening tests for patients at low risk for IA. Our data suggest that some patients with IA have significant colonization or ongoing Aspergillus infections before immunosuppression. As such, IA may reflect unique predispositions to infection and/or progression from endogenous sources. PMID- 22824185 TI - Allogeneic hematopoietic stem cell transplantation in adolescent and adult patients with high-risk T cell acute lymphoblastic leukemia. AB - Allogeneic hematopoietic stem cell transplantation (allo-SCT) is often recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (>=CR2) and sometimes in high-risk (HR) patients in first complete remission (CR1). Between January 1995 and July 2009, 53 patients with HR T-ALL underwent allo-SCT at our institution. Median age was 18 years (range, 14-51). Thirty-two patients (60.3%) were in CR1, 18 (34%) were in >=CR2, and 3 (5.7%) were in relapse. The cumulative incidence of nonrelapse mortality at 5 years was 22.5%. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 40.2%, and that of chronic GVHD was 43.7%. The majority of relapses (88.9%) occurred within 1 year after SCT. The cumulative incidence of relapse (CIR) at 5 years was 35.6%. CIR was 29.8% in patients in CR1, 35.3% in patients in >=CR2 and all patients transplanted in relapse had disease recurrence post-allo-SCT (P = .000). Overall survival (OS) and disease free survival (DFS) at 5 years were 43.5% and 41.8%, respectively. The 5-year OS was 53.5% (95% CI 34.5%-72.5%) and 5-year DFS was 52% (95% CI 33%-71%) in patients who underwent allo-SCT in CR1, compared with 31.9% (95% CI, 9%-54.8%) and 29.4% (95% CI 7.6%-51.2%) in those who underwent allo-SCT in >=CR2. On multivariate analysis, disease status at SCT remained significantly associated with OS (P = .007), DFS (P = .002), and CIR (P = .000). The presence of extramedullary disease at diagnosis had no effect on the different outcomes. Grade II-IV acute GVHD was significantly associated with a lower OS (P = .006) and DFS (P = .01). Our data indicate that allo-SCT represents an effective treatment for HR T-ALL, particularly when performed in CR1. PMID- 22824186 TI - Quantitative analysis of multiphoton excitation autofluorescence and second harmonic generation imaging for medical diagnosis. AB - In recent years, two-photon excitation fluorescence and second harmonic generation microscopy has become an important tool in biomedical research. The ability of two-photon microscopy to achieve optical sectioning with minimal invasiveness is particularly advantageous for biomedical diagnosis. Advances in the miniaturization of the imaging system have increased its clinical potential, together with the development of quantitative technique for the analysis of data acquired using these imaging modalities. We present a review of the quantitative analysis techniques that have been used successfully with two-photon excitation fluorescence and SHG imaging. Specifically, quantification techniques using ratiometric, morphological, and structural differences to analyze two-photon images will be discussed, and their effectiveness at evaluating dermal and corneal pathologies and cancerous tumor growth will be described. PMID- 22824187 TI - Artificial neural networks versus proportional hazards Cox models to predict 45 year all-cause mortality in the Italian Rural Areas of the Seven Countries Study. AB - BACKGROUND: Projection pursuit regression, multilayer feed-forward networks, multivariate adaptive regression splines and trees (including survival trees) have challenged classic multivariable models such as the multiple logistic function, the proportional hazards life table Cox model (Cox), the Poisson's model, and the Weibull's life table model to perform multivariable predictions. However, only artificial neural networks (NN) have become popular in medical applications. RESULTS: We compared several Cox versus NN models in predicting 45 year all-cause mortality (45-ACM) by 18 risk factors selected a priori: age; father life status; mother life status; family history of cardiovascular diseases; job-related physical activity; cigarette smoking; body mass index (linear and quadratic terms); arm circumference; mean blood pressure; heart rate; forced expiratory volume; serum cholesterol; corneal arcus; diagnoses of cardiovascular diseases, cancer and diabetes; minor ECG abnormalities at rest. Two Italian rural cohorts of the Seven Countries Study, made up of men aged 40 to 59 years, enrolled and first examined in 1960 in Italy. Cox models were estimated by: a) forcing all factors; b) a forward-; and c) a backward-stepwise procedure. Observed cases of deaths and of survivors were computed in decile classes of estimated risk. Forced and stepwise NN were run and compared by C-statistics (ROC analysis) with the Cox models. Out of 1591 men, 1447 died. Model global accuracies were extremely high by all methods (ROCs > 0.810) but there was no clear-cut superiority of any model to predict 45-ACM. The highest ROCs (> 0.838) were observed by NN. There were inter-model variations to select predictive covariates: whereas all models concurred to define the role of 10 covariates (mainly cardiovascular risk factors), family history, heart rate and minor ECG abnormalities were not contributors by Cox models but were so by forced NN. Forced expiratory volume and arm circumference (two protectors), were not selected by stepwise NN but were so by the Cox models. CONCLUSIONS: There were similar global accuracies of NN versus Cox models to predict 45-ACM. NN detected specific predictive covariates having a common thread with physical fitness as related to job physical activity such as arm circumference and forced expiratory volume. Future attention should be concentrated on why NN versus Cox models detect different predictors. PMID- 22824188 TI - Medical Priority Dispatch System breathing problems protocol key question combinations are associated with patient acuity. AB - INTRODUCTION: The Breathing Problems Chief Complaint (CC) protocol in the Medical Priority Dispatch System (MPDS) was the system's most frequently used protocol. While "severe breathing problems" is a significant predictor of cardiac arrest (CA), previous data have demonstrated that the DELTA-level determinant codes in this CC contain patients across a wide spectrum of acuity. HYPOTHESIS: The hypothesis in this study was that certain combinations of caller answers to the breathing problems protocol key questions (KQs) are correlated with different but specific patient acuities. METHODS: This was a retrospective study conducted at one International Academies of Emergency Dispatch (IAED) Accredited Center of Excellence. Key Question combinations were generated and analyzed from 11 months of dispatch data, and extracted from MPDS software and the computer assisted dispatch system. Descriptive statistics were used to evaluate measures between study groups. RESULTS: Forty-two thousand cases were recorded; 52% of patients were female and the median age was 61 years. Overall, based on the original MPDS Protocol (before generating KQ combinations), patients with abnormal breathing and clammy conditions were the youngest. The MPDS DELTA-level constituted the highest percentage of cases (74.0%) and the difficulty speaking between breaths (DSBB) condition was the most prevalent (50.3%). Ineffective breathing and not alert conditions had the highest cardiac arrest quotient (CAQ). Based on the KQ combinations, the CA patients who also had the not alert condition were significantly older than other patients. The percentage of CA outcomes in asthmatic patients was significantly higher in DSBB plus not alert; DSBB plus not alert plus changing color; and DSBB plus not alert plus clammy conditions cases, compared to asthmatic abnormal breathing cases. CONCLUSIONS: The study findings demonstrated that MPDS KQ answer combinations relate to patient acuity. Cardiac arrest patients are significantly less likely to be asthmatic than those without CA, and vice versa. Using a prioritization scheme that accounts for the presence of either single or multiple signs and/or symptom combinations for the Breathing Problems CC protocol would be a more accurate method of assigning DELTA-level cases in the MPDS. PMID- 22824189 TI - Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents. AB - Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic alpha(1), alpha(2c), 5-HT(2A) 5-HT7, moderate affinity for adrenergic alpha(2a) and D2 receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT7 receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22824190 TI - Establishing a probabilistic reversal learning test in mice: evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin. AB - Valid animal models of psychopathology need to include behavioural readouts informed by human findings. In the probabilistic reversal learning (PRL) task, human subjects are confronted with serial reversal of the contingency between two operant stimuli and reward/punishment and, superimposed on this, a low probability (0.2) of punished correct responses/rewarded incorrect responses. In depression, reward-stay and reversals completed are unaffected but response-shift following punished correct response trials, referred to as negative feedback sensitivity (NFS), is increased. The aims of this study were to: establish an operant spatial PRL test appropriate for mice; obtain evidence for the processes mediating reward-stay and punishment-shift responding; and assess effects thereon of genetically- and pharmacologically-altered serotonin (5-HT) function. The study was conducted with wildtype (WT) and heterozygous mutant (HET) mice from a 5-HT transporter (5-HTT) null mutant strain. Mice were mildly food deprived and reward was sugar pellet and punishment was 5-s time out. Mice exhibited high motivation and adaptive reversal performance. Increased probability of punished correct response (PCR) trials per session (p = 0.1, 0.2 or 0.3) led to monotonic decrease in reward-stay and reversals completed, suggesting accurate reward prediction. NFS differed from chance-level at p PCR = 0.1, suggesting accurate punishment prediction, whereas NFS was at chance-level at p = 0.2-0.3. At p PCR = 0.1, HET mice exhibited lower NFS than WT mice. The 5-HTT blocker escitalopram was studied acutely at p PCR = 0.2: a low dose (0.5-1.5 mg/kg) resulted in decreased NFS, increased reward-stay and increased reversals completed, and similarly in WT and HET mice. This study demonstrates that testing PRL in mice can provide evidence on the regulation of reward and punishment processing that is, albeit within certain limits, of relevance to human emotional-cognitive processing, its dysfunction and treatment. PMID- 22824191 TI - Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. AB - Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether propranolol, a beta-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence accelerated mouse prone-8 (SAMP8). Propranolol administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Abeta(42) levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by propranolol treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3beta phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment. Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22824192 TI - The radiographic quantification of scapular malalignment after malunion of displaced clavicular shaft fractures. AB - BACKGROUND: Malunion after displaced fractures of the clavicle can result in varying degrees of scapular malalignment and potentially scapular winging. The purpose of our study was to quantify the scapular malalignment in patients with midshaft clavicle malunions showing scapular winging. METHODS: Eighteen patients with symptomatic midshaft clavicle malunions showing scapular winging were identified and underwent standardized computed tomography scanning of the thorax. Specific bony landmarks on the clavicle and scapula were digitized, allowing generation of 3-dimensional points. These points were acquired bilaterally so that relative translations comparing the malunited side with the contralateral side could be obtained. Statistical analysis using a paired t test was performed. RESULTS: The mean time from fracture to examination was 42.9 months. There were 15 men and 3 women with a mean age of 41.6 years. The mean clavicular shortening was 21.1 mm (P = .0000004). The acromion of the affected scapula on average translated 24.3 mm. The components of this translation were medial, 11.9 mm (P = .00008); inferior, 20.7 mm (P = .0009); and anterior, 4.6 mm (P = .02). Posterior bony landmarks on the scapula including the superior and inferior angles of the scapula translated a total of 9.9 mm and 5.9 mm, respectively. CONCLUSION: This is the first study to document the degree of scapular malalignment in patients with symptomatic clavicle malunions showing scapular winging. The acromion closely follows the distal clavicular fragment and translates medially, inferiorly, and anteriorly. The translations of the superior and inferior angles of the scapula are quite variable in magnitude and direction, and on average, these angles translate substantially less than the acromion. PMID- 22824193 TI - Therapeutic anticoagulation can be safely accomplished in selected patients with traumatic intracranial hemorrhage. AB - INTRODUCTION: Therapeutic anticoagulation is an important treatment of thromboembolic complications, such as DVT, PE, and blunt cerebrovascular injury. Traumatic intracranial hemorrhage has traditionally been considered to be a contraindication to anticoagulation. HYPOTHESIS: Therapeutic anticoagulation can be safely accomplished in select patients with traumatic intracranial hemorrhage. METHODS: Patients who developed thromboembolic complications of DVT, PE, or blunt cerebrovascular injury were stratified according to mode of treatment. Patients who underwent therapeutic anticoagulation with a heparin infusion or enoxaparin (1 mg/kg BID) were evaluated for neurologic deterioration or hemorrhage extension by CT scan. RESULTS: There were 42 patients with a traumatic intracranial hemorrhage that subsequently developed a thrombotic complication. Thirty-five patients developed a DVT or PE. Blunt cerebrovascular injury was diagnosed in four patients. 26 patients received therapeutic anticoagulation, which was initiated an average of 13 days after injury. 96% of patients had no extension of the hemorrhage after anticoagulation was started. The degree of hemorrhagic extension in the remaining patient was minimal and was not felt to affect the clinical course. CONCLUSION: Therapeutic anticoagulation can be accomplished in select patients with intracranial hemorrhage, although close monitoring with serial CT scans is necessary to demonstrate stability of the hemorrhagic focus. PMID- 22824194 TI - How many risks-of-bias and comorbidity scales do we need? PMID- 22824195 TI - Estimates of prospective change in self-rated health in older people were biased owing to potential recalibration response shift. AB - OBJECTIVE: Evidence shows that self-rated health (SRH) remains remarkably stable during aging. Individuals may change their conceptualization of health or revise their standard of good health when facing health decline. Although this "response shift" phenomenon is potentially beneficial to the individual, it also challenges comparison of SRH assessments over time. The present study investigates this response shift. STUDY DESIGN AND SETTING: Data come from two waves (T1 and T2) of the Longitudinal Aging Study Amsterdam (N: 1,274; age: 55-89 years; mean follow up: 3.6 years). Linear regression models were used for predicting SRH at T1 and T2. To capture changes in individual health standards, we administered a then test at T2, asking respondents to retrospectively rate their health at T1 again. RESULTS: No support was found for a changed conceptualization of SRH after health decline: predictive models for SRH at T1 and T2 were not significantly different. In the subgroup that reported identical SRH at T1 and T2, participants who experienced incident diseases were three times more likely to retrospectively overrate health at T1 with the then-test, suggesting that they had a lowered health standard. CONCLUSION: Older people's concept of health remains stable when they encounter significant health problems, but they potentially lower their standard of good health over time. PMID- 22824196 TI - A comparison between the VIPS model and the ICF for expressing nursing content in the health care record. AB - BACKGROUND: Multi-professional standardized terminologies are needed that cover common as well as profession-specific care content in order to obtain a full coverage and description of the contributions from different health professionals' perspectives in health care. Implementation of terminologies in clinical practice that do not cover professionals' needs for communication might jeopardize the quality of care. PURPOSE: The aim of the study was to compare the structure and content of the Swedish VIPS model for nursing documentation and the international classification of function, disability and health (ICF). METHOD: Mapping was performed between key words and prototypical examples for patient status in the VIPS model and terms in the ICF and its framework of domains, chapters and specific terms. The study had two phases. In the first phase 13 key words for patient status in the VIPS model and the 289 terms (prototypical examples) describing related content were mapped to comparable terms in the ICF. In phase two, 1424 terms on levels 2-4 in the ICF were mapped to the key words for patient status in the VIPS model. RESULTS: Differences in classification structures and content were found, with a more elaborated level of detail displayed in the ICF than in the VIPS model. A majority of terms could be mapped, but several essential nursing care concepts and perspectives identified in the VIPS model were missing in the ICF. Two-thirds of the content in the ICF could be mapped to the VIPS' key words for patient status; however, the remaining terms in the ICF, describing body structure and environmental factors, are not part of the VIPS model. CONCLUSION: Despite that a majority of the nursing content in the VIPS model could be expressed by terms in the ICF, the ICF needs to be developed and expanded to be functional for nursing practice. The results have international relevance for global efforts to implement unifying multi professional terminologies. In addition, our results underline the need for sufficient coverage and level of detail to support different professional perspectives in health care terminologies. PMID- 22824197 TI - NCI Surveillance, Epidemiology & End Results (SEER) registry. Foreword. PMID- 22824198 TI - The effects of noise reduction by earmuffs on the physiologic and behavioral responses in very low birth weight preterm infants. AB - OBJECTIVE: Preterm infants are exposed to loud noises during their stay in the neonatal intensive care unit which can lead to physiologic and behavioral alterations and even hearing loss. The use of earmuffs can reduce sound level and these changes. The objective of the present study is to evaluate the effectiveness of the earmuffs in preterm infants solely cared for in closed incubators. METHODS: A comparative prospective study comprising 20 clinically stable preterm infants weighing less than 1500 g cared in closed incubator was conducted. Preterm infants acted as their own controls whereby they were observed without earmuffs (Group 1) for 2 days and with earmuffs (Group 2) on consecutive 2 days. The preterm infants' physiologic responses and Anderson Behavioral State Scoring System (ABSS) scores were assessed over 30s every 2h for 8h during daytime for 4 days. RESULTS: Out of 20 preterm infants, 6 were male and 14 female with a mean birth weight of 1220 +/- 209 g, gestational age of 29.9 +/- 2.1 weeks. The total number of measurements was 320. The mean ABSS scores of Group 1 and 2 were 3.07+/-1.1 and 1.34 +/- 0.3, respectively. Statistically significant difference was noted between the means of ABSS scores (p<0.001). Preterm infants with earmuffs (87.5%) were more frequently observed in a quiet sleep state of ABSS compared with those without earmuffs (29.4%). CONCLUSIONS: Noise level reduction was associated with significant improvement in behavioral states of ABSS. We suggest that noise reduction in preterm infants with earmuffs is helpful by improving sleep efficiency and increasing time of quiet sleep. PMID- 22824199 TI - Motor proficiency and dynamic visual acuity in children with bilateral sensorineural hearing loss. AB - AIMS AND OBJECTIVES: Due to the close relationship between the cochlea and the peripheral vestibular system, the function of the vestibular system may be impaired in children with sensorineural hearing loss. The aims of this study were to determine the prevalence of impairments of motor performance and dynamic visual acuity, and the nature and extent of interaction between these in children with sensorineural hearing loss between the ages of 4 and 14 years. METHODS: This research utilized a correlational, cross-sectional, descriptive design. Thirty two children with sensorineural hearing loss were matched according to age and gender with children with no hearing impairment. Motor performance was evaluated by means of the Movement Assessment Battery for Children-2 and dynamic visual acuity was evaluated with the dynamic visual acuity test. The performances of the two groups on the different tests were then compared. DATA ANALYSIS: The one sided chi-square test or Fisher's exact test was used to determine whether there was any association between sensorineural hearing loss, impaired motor performance and poor dynamic visual acuity. The Mann-Whitney U-test was used to determine the difference between children with sensorineural hearing loss and those with normal hearing on the Movement Assessment Battery for Children-2. Forward stepwise regression was used to establish the predictors of the Movement Assessment Battery for Children-2 total standard score. The Kruskal-Wallis test was used to compare scores of children with normal hearing and those with a mild to moderate sensorineural hearing loss on the Movement Assessment Battery for Children-2. RESULTS: Reduced dynamic visual acuity is associated with sensorineural hearing loss (p=0.026). Motor performance is dependent on dynamic visual acuity and severity of sensorineural hearing loss (r(2)=0.41, p=0.001). CONCLUSIONS: The results of this study indicate that in children with sensorineural hearing loss, the prevalence of reduced dynamic visual acuity is 15.6% and of motor impairment is 65.6%. Both abnormal dynamic visual acuity and motor impairment are associated with sensorineural hearing loss. It is important to evaluate children with sensorineural hearing loss for the presence of abnormal dynamic visual acuity as well as motor impairment, because it can have serious implications for the safety, education and general well being of these children. PMID- 22824200 TI - A comparative 18F-FDG PET/CT imaging of experimental Staphylococcus aureus osteomyelitis and Staphylococcus epidermidis foreign-body-associated infection in the rabbit tibia. AB - BACKGROUND: 18F-FDG-PET imaging has emerged as a promising method in the diagnosis of chronic osteomyelitis commonly due to Staphylococcus aureus. The inaccuracy of 18 F-FDG-PET in the detection of periprosthetic joint infections may be related to the predominance of low-virulent S. epidermidis strains as the causative pathogen. We have compared the18F-FDG-PET characteristics of S. aureus osteomyelitis and foreign-body-associated S. epidermidis infections under standardized laboratory conditions. METHODS: Twenty-two rabbits were randomized into three groups. In group 1, a localized osteomyelitis model induced with a clinical strain of S. aureus was applied. In groups 2 and 3, a foreign-body associated infection model induced with a clinical or laboratory strain of S. epidermidis was applied. A small block of bone cement was surgically introduced into the medullary cavity of the proximal tibia followed by peri-implant injection of S. aureus (1 * 105 CFU/mL) or one of the two S. epidermidis (1 * 109 CFU/mL) strains with an adjunct injection of aqueous sodium morrhuate. In group 1, the cement block was surgically removed at 2 weeks but left in place in groups 2 and 3 in order to mimic foreign-body-associated S. epidermidis infections. At 8 weeks, the animals were imaged using 18 F-FDG PET/CT. The presence of bacterial infection was confirmed by cultures, and the severity of bone infections was graded by means of radiography, peripheral quantitative CT, and semi-quantitative histology. RESULTS: The S. aureus strain caused constantly culture-positive osteomyelitis. The clinical S. epidermidis strain resulted in foreign-body associated infections, while the laboratory S. epidermidis strain (ATCC 35983) induced only occasionally culture-positive infections. There was a correlation (r = 0.645; P = 0.013) between semi-quantitative score of leukocyte infiltration and the 18 F-FDG uptake in animals with positive cultures. Standardized uptake value (SUV) of the infected bones was twofold (P < 0.001) in S. aureus animals compared with S. epidermidis animals, but there was only a trend (P = 0.053, ANOVA) in the differences of the corresponding SUV ratios. This was due to the altered 18 F-FDG uptake of the contralateral tibias probably reflecting a systemic impact of severe osteomyelitis. CONCLUSION: The peri-implant inoculation of S. epidermidis, reflecting low virulence of the pathogen and limited leukocyte infiltration, was characterized by low 18 F-FDG uptake. PMID- 22824201 TI - Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial. AB - BACKGROUND: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus. RESULTS: The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% +/- 98.3%, +22.4% +/- 17.2%, and -15.7% +/- 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. CONCLUSIONS: In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship. PMID- 22824202 TI - The implementation of the functional task exercise programme for elderly people living at home. AB - BACKGROUND: The Functional Task Exercise programme is an evidence-based exercise programme for elderly people living at home. It enhances physical capacity with sustainable effects. FTE is provided by physiotherapists and remedial therapists. Although the intervention was found to be effective in a Randomised Controlled Trial, we may not assume that therapists will automatically supply the programme or that elderly people will automatically join the programme. This study protocol focuses on identifying determinants of implementation, developing implementation strategies and studying the effects of the implementation in daily practice. METHODS/DESIGN: Phase 1: The systematic identification of determinants of the implementation of FTE among therapists and the elderly. A questionnaire study was conducted in a random sample of 100 therapists, and interviews took place with 23 therapists and 8 elderly people (aged 66 to 80 years). The determinants were broken down into four categories: the characteristics of the environment, the organisation, the therapists, and the training programme.Phase 2: Developing and applying strategies adapted to the determinants identified. Fifteen physiotherapists will be trained to provide FTE and to recruit elderly people living at home. The therapists will then deliver the 12-week programme to two groups of elderly, each consisting of six to twelve people aged 70 years or older.Phase 3: Study of implementation and the impact. To study the actual use of FTE: 1) therapists record information about the selection of participants and how they apply the key features of FTE, 2) the participating elderly will keep an exercise logbook, 3) telephone interviews will take place with the therapists and the elderly and there will be on-site visits. The effects on the elderly people will be studied using: 1) the Patient-Specific Questionnaire, the Timed Up and Go test and a two performance tests. All tests will be performed at the start of the FTE programme, half way through, and at the end of the programme. DISCUSSION: The number of older people will increase in many countries in the years to come and so the project outcomes will be of interest to policy-makers, insurance companies, health-care professionals and implementation researchers. PMID- 22824204 TI - A highly selective structure-based virtual screening model of Palm I allosteric inhibitors of HCV Ns5b polymerase enzyme and its application in the discovery and optimization of new analogues. AB - First structure-based activity prediction model of topologically diverse inhibitors of Palm I allosteric site of HCV NS5b polymerase enzyme is reported here. The model is a workflow of structure-based pharmacophore followed by guided docking. The pharmacophore was constructed using a novel procedure which includes PLIF (protein ligand interaction fingerprint), Hypogen, contact-based pharmacophore and shape constraints. The guided docking was tweaked using both a scoring function of high correlation with activity (ChemPLP) and essential pharmacophore features. Statistically, ROC analysis for the workflow, deploying the novel technique of virtual decoys, yielded AUC of 0.947. Experimentally, the model was used to screen Asinex GOLD database yielding a new hit with a different scaffold which was further confirmed by synthesis and biological evaluation. PMID- 22824203 TI - Allergic predisposition modifies the effects of pet exposure on respiratory disease in boys and girls: the seven northeast cities of China (SNECC) study. AB - BACKGROUND: The relationship between pet exposure and the respiratory disease in childhood has been a controversial topic, much is still unknown about the nature of the associations between pet exposure and children's respiratory health stratified by gender and allergic predisposition. The objective of the present study was to assess the relationship between pet exposure and respiratory symptoms in Chinese children, and to investigate the modified effects of gender and allergic predisposition on such relationship. METHODS: 31,049 children were selected from 25 districts of 7 cities in Northeast China in 2009. Information on respiratory health and exposure to home environmental factors was obtained via a standard questionnaire designed by the American Thoracic Society. RESULTS: Children with an allergic predisposition were found to have more frequent exposure to pets than those without an allergic predisposition (18.5% vs. 15.4%). In children without an allergic predisposition, pet exposure was associated with increased susceptibility to respiratory symptoms/diseases, with girls being more susceptible than boys. No association was found between pet exposure and respiratory symptoms/diseases in boys with an allergic predisposition. In girls with an allergic predisposition, association was found between doctor-diagnosed asthma and pet exposure of their mother during pregnancy (adjusted odds ratio (ORs)=2.03; 95% confidence interval (CI): 1.01-4.33), and their current pet exposure (ORs=1.37; 95%CI: 1.00-1.88). CONCLUSIONS: Pet exposure in children without an allergic predisposition was associated with increased susceptibility to respiratory disease, with girls being more susceptible than boys. PMID- 22824205 TI - Synthesis and antiviral activity of substituted bisaryl amide compounds as novel influenza virus inhibitors. AB - The influenza virus is a persistent cause of mortality and morbidity on an annual basis and thus presents itself as an important target for pharmaceutical investigation. In this work, substituted bisaryl amide compounds were found to be a new class of potential anti-influenza agents, and a series of substituted bisaryl amide compounds were synthesised and evaluated for their anti-influenza virus activities. The analysis of the results produced a preliminary structure activity relationship study (SAR). Compounds 1a, 1g, 1h, 1j, 1l and 1n exhibited clear antiviral activities against the influenza A (A/Guangdong Luohu/219/2006, H1N1) virus with 50% inhibitory concentrations (IC(50)) for virus growth ranging from 12.5 to 59.0 MUM. Specifically, compound 1j also possessed antiviral activity against both oseltamivir-resistant influenza (A/Jinnan/15/2009) virus and influenza B (B/Jifang/13/97) virus with IC(50) values of 9.2 MUM and 21.4 MUM, respectively. Compound 1j is thus worth further investigation as an anti influenza virus candidate. PMID- 22824206 TI - Silicon-based photonic crystals fabricated using proton beam writing combined with electrochemical etching method. AB - A method for fabrication of three-dimensional (3D) silicon nanostructures based on selective formation of porous silicon using ion beam irradiation of bulk p type silicon followed by electrochemical etching is shown. It opens a route towards the fabrication of two-dimensional (2D) and 3D silicon-based photonic crystals with high flexibility and industrial compatibility. In this work, we present the fabrication of 2D photonic lattice and photonic slab structures and propose a process for the fabrication of 3D woodpile photonic crystals based on this approach. Simulated results of photonic band structures for the fabricated 2D photonic crystals show the presence of TE or TM gap in mid-infrared range. PMID- 22824207 TI - ACPYPE - AnteChamber PYthon Parser interfacE. AB - BACKGROUND: ACPYPE (or AnteChamber PYthon Parser interfacE) is a wrapper script around the ANTECHAMBER software that simplifies the generation of small molecule topologies and parameters for a variety of molecular dynamics programmes like GROMACS, CHARMM and CNS. It is written in the Python programming language and was developed as a tool for interfacing with other Python based applications such as the CCPN software suite (for NMR data analysis) and ARIA (for structure calculations from NMR data). ACPYPE is open source code, under GNU GPL v3, and is available as a stand-alone application at http://www.ccpn.ac.uk/acpype and as a web portal application at http://webapps.ccpn.ac.uk/acpype. FINDINGS: We verified the topologies generated by ACPYPE in three ways: by comparing with default AMBER topologies for standard amino acids; by generating and verifying topologies for a large set of ligands from the PDB; and by recalculating the structures for 5 protein-ligand complexes from the PDB. CONCLUSIONS: ACPYPE is a tool that simplifies the automatic generation of topology and parameters in different formats for different molecular mechanics programmes, including calculation of partial charges, while being object oriented for integration with other applications. PMID- 22824208 TI - The Kiss2 receptor (Kiss2r) gene in Southern Bluefin Tuna, Thunnus maccoyii and in Yellowtail Kingfish, Seriola lalandi - functional analysis and isolation of transcript variants. AB - The kisspeptin system plays an essential role in reproductive function in vertebrates, particularly in the onset of puberty. We investigated the kisspeptin system in two Perciform teleosts, the Southern Bluefin Tuna (SBT; Thunnus maccoyii), and the Yellowtail Kingfish (YTK; Seriola lalandi), by characterising their kisspeptin 2 receptor (Kiss2r) genes. In addition to the full length Kiss2r cDNA sequences, we have isolated from SBT and YTK a transcript variant that retained an intron. We have further obtained three ytkKiss2r transcript variants that contained deletions. In vitro functional analysis of the full length SBT and YTK Kiss2r showed higher response to Kiss2-10 than to Kiss1-10, with stronger transduction via PKC than PKA. The full length ytkKiss2r and two deletion variants were differentially expressed in the brain of male, but not in female, juvenile YTK treated with increasing doses of Kiss2-10 peptide. In the gonads, the expression level of the ytkKiss2r transcripts did not vary significantly either in the male or female fish. This is the first time that transcript variants of the Kiss2r gene that contain deletions and show responsiveness to treatments with kisspeptin have been reported in any teleost. PMID- 22824209 TI - Increased 18F FDG uptake in an unusual localization of giant cell tumor of the tendon sheath. PMID- 22824210 TI - Assessment of oxidative stress markers and prostaglandins after chronic training of triathletes. AB - The present study established the pattern of isoprostanes (IsoPs) and prostaglandins metabolites (PGMs) in urine after triathlon training. Fifteen Caucasian triathletes - 5 women and 10 men - performed 793 and 1603 Objective Load Scales, respectively. The optimization of urine hydrolysis conditions, concerning to the type of buffer, the units of hydrolytic enzyme added, and the pH, allowed precise quantification of these metabolites by UPLC-MS/MS, avoiding the under-estimation of their concentrations that occurred in previous studies. Their rate of conjugation ranged between 36% and 100%. This implies significant importance since it supposes non-detection of some IsoPs and PGMs totally conjugated with glucuronic acid developed by other previous methodologies. Among the 13 compounds analyzed, this assay detected and characterized 4 IsoPs and 3 PGMs in the triathletes' urine. The PGMs tetranor-PGEM and 11beta-PGF(2alpha) and the IsoP 8-iso-PGF(2alpha), showed lower concentrations after the training program, whereas the PGMs 6-keto-PGF(1alpha) increased (vascular PGI(2) metabolite). In fact, their pattern in the triathletes' urine indicated that their variation may have been related with the physical activity. Due to its high variation, 6-keto PGF(1alpha) stood out as a useful marker of the vasodilation and inhibition of the platelet aggregation of the PGI(2) linked to the physical exercise. The data obtained provided a global picture of changes in lipid peroxidation and vascular events as a consequence of chronic exercise. PMID- 22824211 TI - Identification of a human Th1-like IFNgamma-secreting Treg subtype deriving from effector T cells. AB - Characteristics and function of effector T-cells with regulatory properties (induced Treg, "iTreg") in humans are ill defined. Here we report that a proportion of activated, initially CD4(+)CD25(-)CD127(+) effector T-cells from human peripheral blood can convert into T-cells with regulatory activity while concomitantly secreting IFNgamma. Upon short-term culture in vitro these cells expressed a panel of common Treg markers, including FOXP3, CD25, GITR, HLA-DR and CTLA-4 in parallel with the Th1-specific transcription factor T-bet. Despite their own IFNgamma secretion they effectively suppressed IFNgamma secretion in effector T cells in parallel with inhibition of their proliferation. Highly purified IFNgamma(+)iTreg shared many functional properties with nTreg: Their suppressive activity was antigen-independent, contact-mediated and cytokine independent. Of note, in contrast to nTreg an inhibitor of TGF-beta1 signalling promoted the proliferation of IFNgamma(+)iTreg, without abrogating their suppressive function. In addition in vivo in tonsils of patients with chronic tonsillitis an IFNgamma-secreting subpopulation of the CD4(+)CD25( )CD127(+)CD45RA(-) memory T helper cell population was detected, which exhibited regulatory properties as well. Our results support the existence of Th1-like adaptive Tregs in humans that express a robust regulatory phenotype, comparable to nTreg and at the same time share characteristics of Th1 cells. According to our in vitro data IFNgamma(+)iTreg can emerge from activated effector T cells and downregulate Th1-mediated immune responses, supporting the hypothesis of effector T cell plasticity as a means for proper initiation and self regulation of inflammatory processes. This report characterizes a new subpopulation of human adaptive regulatory T-cells that derive from effector Th-cells and concomitantly express Th1-specific T-bet and IFNgamma with Foxp3. PMID- 22824212 TI - Calcium-induced cardiac mitochondrial dysfunction is predominantly mediated by cyclosporine A-dependent mitochondrial permeability transition pore. AB - BACKGROUND AND AIMS: Cardiac mitochondrial Ca(2+) overload plays a critical role in mechanical and electrical dysfunction leading to cardiac cell death and fatal arrhythmia. Because Ca(2+) overload is related to mitochondrial permeability transition, reactive oxygen species (ROS) production and membrane potential (DeltaPsim) dissipation, we probed the mechanistic association between Ca(2+) overload, oxidative stress, mitochondrial permeability transition pore (mPTP) and mitochondrial calcium uniporter (MCU) in isolated cardiac mitochondria. METHODS: Various concentrations of Ca(2+) (5-200 MUM) were used to induce mitochondrial dysfunction. Cyclosporin A (CsA, an mPTP blocker) and Ru360 (an MCU blocker) were used to test its protective effects on Ca(2+)-induced mitochondrial dysfunction. RESULTS: High concentrations of Ca(2+) (>=100 MUM) caused overt mitochondrial swelling and DeltaPsim collapse. However, only slight increases in ROS production were detected. Blocking the MCU by Ru360 is less effective in protecting mitochondrial dysfunction. CONCLUSIONS: A dominant cause of Ca(2+)-induced cardiac mitochondrial dysfunction was mediated through the mPTP rather than MCU. Therefore, CsA could be more effective than Ru360 in preventing Ca(2+)-induced cardiac mitochondrial dysfunction. PMID- 22824213 TI - Association study of sirtuin 1 polymorphisms with bone mineral density and body mass index. AB - BACKGROUND AND AIMS: Sirtuin 1, encoded by the SIRT1 gene, is an emerging modulator of carbohydrate and lipid metabolism and may also influence the differentiation of bone cells. Our objective was to test the hypothesis that polymorphisms of SIRT1 are associated with body mass index (BMI) and bone mineral density (BMD). METHODS: We carried out a cross-sectional genetic association study with genotyping of ten single nucleotide polymorphisms of the SIRT1 region. The discovery cohort included 1394 individuals (342 males, 1052 females). Significant results were replicated in an independent cohort of 408 males. RESULTS: We did not find a significant association of genotypes with BMD. There were also no significant BMI differences across genotypes in females. However, in males, two polymorphisms tended to be associated with BMI in the discovery cohort (p 0.03 and 0.05). A similar trend was also observed in the replication cohort. Thus, in the combined analysis of both cohorts, males with C alleles at the rs12049646 locus had a lower BMI than TT homozygotes, with a mean difference of 0.82 kg/m(2) (95% confidence interval 0.15-1.48; p = 0.016). Differences in the DNA binding of nuclear proteins between C and T alleles were also observed in vitro. CONCLUSIONS: These results suggest that common variants of the SIRT1 gene influence BMI but not BMD. PMID- 22824214 TI - Treatment of craniopharyngioma in adults: systematic analysis of a 25-year experience. AB - BACKGROUND AND AIMS: Craniopharyngioma is a rare and mostly benign epithelial tumor of the central nervous system, mostly affecting children. Considering that most of the published series of craniopharyngioma are based on pediatric populations, studies in adults gain importance based mainly on the reduced number of cases and the possible differences emerging from a mostly different histological type. We undertook this study to establish the pattern of presentation, morphological features and specific characteristics of craniopharyngioma in an adult Mexican population, as well as discussing the long term outcome and how it may be influenced by surgical, anatomic and clinical factors. METHODS: A total of 153 adult patients (16 years or older) underwent transcranial and transsphenoidal surgery between January 1985 and December 2009, all with histological confirmation of craniopharyngioma. Hypothalamic involvement, surgical complications, rate of tumor resection and endocrinological outcome were evaluated. RESULTS: Seventy nine males (51.6%) and 74 females (48.4%) were included. Mean age at diagnosis was 32.4 years (range: 16-77 years). Mean initial tumor volume was 28.44 mL (range: 0.18-100.44 mL). Partial or complete hypothalamic involvement (Samii Grades III, IV and V) was found in 90.2%. The overall rate of new endocrinopathies was 37.25% after surgery (95% CI = 33.9-41.2). CONCLUSIONS: Gross total removal of craniopharyngiomas with large hypothalamic involvement was related to poor neuroendocrine outcome in adults. Partial removal should be indicated, associated with adjuvant therapy, in order to improve postoperative neuroendocrine status. PMID- 22824215 TI - Development of a sensitive and robust liquid chromatography coupled with tandem mass spectrometry and a pressurized liquid extraction for the determination of aflatoxins and ochratoxin A in animal derived foods. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a pressurized liquid extraction (PLE) was developed for the simultaneous determination of aflatoxins B1, B2, G1, G2, M1 and M2, and ochratoxin A in the muscle, liver, kidney and fat of swine, bovine and sheep, muscle and liver of chicken, muscle and skin of fish, as well as in hen eggs and dairy milk. Samples were extracted with PLE and cleaned-up with solid phase extraction (SPE) on HLB cartridges. The optimum extraction conditions were obtained as a 11 ml ASE cell, acetonitrile/hexane as the extraction solvent, 1500 psi, 100 degrees C, a 5 min static time and a 60% flush volume. A cheaper and widely used SPE column (Oasis HLB) was applied during clean up. The detection and quantification of the 7 mycotoxins were performed by a reversed-phase liquid chromatography coupled with electrospray ionization triple quadrupole mass spectrometry (LC/ESI-MS/MS). The limits of detection defined as CCalpha varied from 0.07 MUg/kg to 0.59 MUg/kg. The recoveries of spiked samples from 0.25 MUg/kg to 1 MUg/kg ranged from 68.3% to 105.7% with the relative standard deviations of less than 17.6%. Performances of the whole analytical procedure met the criteria established by the European Commission for mass spectrometric detection. PMID- 22824216 TI - Hollow-fiber liquid-phase microextraction of amphetamine-type stimulants in human hair samples. AB - A fast method was optimized and validated in order to quantify amphetamine-type stimulants (amphetamine, AMP; methamphetamine, MAMP; fenproporex, FPX; 3,4 methylenedioxymethamphetamine, MDMA; and 3,4-methylenedioxyamphetamine, MDA) in human hair samples. The method was based in an initial procedure of decontamination of hair samples (50 mg) with dichloromethane, followed by alkaline hydrolysis and extraction of the amphetamines using hollow-fiber liquid phase micro extraction (HF-LPME) in the three-phase mode. Gas chromatography-mass spectrometry (GC-MS) was used for identification and quantification of the analytes. The LoQs obtained for all amphetamines (around 0.05 ng/mg) were below the cut-off value (0.2 ng/mg) established by the Society of Hair Testing (SoHT). The method showed to be simple and precise. The intra-day and inter-day precisions were within 10.6% and 11.4%, respectively, with the use of only two deuterated internal standards (AMP-d5 and MDMA-d5). By using the weighted least squares linear regression (1/x2), the accuracy of the method was satisfied in the lower concentration levels (accuracy values better than 87%). Hair samples collected from six volunteers who reported regular use of amphetamines were submitted to the developed method. Drug detection was observed in all samples of the volunteers. PMID- 22824217 TI - Hollow fibre liquid-phase microextraction of functionalised carboxylic acids from atmospheric particles combined with capillary electrophoresis/mass spectrometric analysis. AB - A method was developed to enrich various mono- and dicarboxylic acids from aqueous extracts of atmospheric particles by three-phase hollow fibre liquid phase microextraction. Analysis was performed by capillary electrophoresis/electrospray ionisation mass spectrometry applying a previously reported separation method. Several extraction parameters (pH of donor and acceptor phase, composition of supported liquid membrane, shaking speed, and extraction time) were tested for their influence on analyte recovery. A strong dependence of the recovery on the acceptor phase pH was observed. The final method consisted of 10% (w/v) trioctylphosphine oxide in dihexylether as supported liquid membrane, 1.8 ml aqueous particle extract, acidified by sulfuric acid to a pH of 2 as donor phase, and 15 MUl of 50 mM aqueous ammonia solution as acceptor phase. The extraction devices were shaken at 2200 rpm for 2 h. With this method, the recoveries from aqueous standards were between 10 and 80% with a repeatability of 4-14% for most compounds. Generally, more polar compounds were extracted less efficient than less polar ones. A few of the most polar compounds showed recoveries <10% with a repeatability of 20-55%. The enrichment factor was typically 10-100. The analyte recovery from real samples was found to strongly depend on the sample matrix due to co-extraction of mineral acids and organic acidic material present in atmospheric particles. Quantification was achieved by the method of standard addition. The easy handling of the hollow fibre devices, the low costs per extraction and the possibility to do many extractions in parallel allowed for an application of the developed method to a large set of real samples. PMID- 22824218 TI - Development of coatings for automated 96-blade solid phase microextraction-liquid chromatography-tandem mass spectrometry system, capable of extracting a wide polarity range of analytes from biological fluids. AB - This work presents the development and evaluation of biocompatible polyacrylonitrile-polystyrene-divinylbenzene (PAN-PS-DVB) and polyacrylonitrile phenylboronic acid (PAN-PBA) coatings for automated 96-blades (thin-film) solid phase microextraction (SPME) system, using high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS). The SPME condition was optimized for 60 min equilibrium extraction and 40 min desorption for PAN-PS-DVB, and 120 min equilibrium extraction and 60 min desorption for PAN-PBA for parallel sample preparation of up to 96 samples. The thin film geometry of the SPME blades provided good extraction efficiency due to the larger surface area of the coating, and simultaneous sample preparation provided fast and accurate analysis. The PAN-PS-DVB and PAN-PBA 96-blade SPME coatings were evaluated for extraction of analytes in a wide range of polarity (log P=2.8 to -3.7), and they demonstrated efficient extraction recovery (3.5-98.9% for PAN-PS-DVB and 4.0 74.1% for PAN-PBA) for both polar and non-polar groups of compounds. Reusability, reproducibility, and reliability of the system were evaluated. The results demonstrated that both coatings presented chemical and mechanical stability and long-lasting extraction efficiency for more than 100 usages in phosphate-buffered saline (PBS) and human plasma. PMID- 22824219 TI - Monitoring potential prostate cancer biomarkers in urine by capillary electrophoresis-tandem mass spectrometry. AB - Current prostate cancer (PCa) diagnosis based on prostate-specific antigen (PSA) has been gradually losing its credibility over the last decade due to contradictory results in published literature and clinical practice. Recently, a group of potential PCa biomarkers in urine, particularly sarcosine, was found to increase significantly as the cancer progressed to metastasis. We report a simple, robust, and reproducible CE-ESI-MS/MS method for the determination of sarcosine and other representative potential biomarkers in pooled urine. The pooled urine was obtained from 20 healthy adult volunteers between the ages of 23 30 years old. A solid phase extraction (SPE) technique was optimized for maximum recovery of sarcosine. With no derivatization step, excellent resolution between sarcosine and its isomers (alpha-alanine and beta-alanine) was achieved. A separate non-SPE method was also developed for quantitative determination of highly concentrated urinary metabolites. CE separation was performed on a positively-charged, polyethyleneimine (PEI)-coated capillary using 0.4-2% formic acid in 50% methanol. Precision for intra- and inter-day standard addition calibration of sarcosine were found to be within 15%, whereas intra-day precisions for the rest of the metabolites varied from 0.03 to 13.4%. Acceptable intra-day and inter-day accuracies, ranging from 80 to 124%, were obtained for sarcosine and the other metabolites. PMID- 22824220 TI - Hyphenated dimensions in separation science. PMID- 22824221 TI - Comparison of supercritical fluid extraction and ultrasound-assisted extraction of fatty acids from quince (Cydonia oblonga Miller) seed using response surface methodology and central composite design. AB - Fatty acids of Cydonia oblonga Miller cultivated in Iran were obtained by supercritical (carbon dioxide) extraction and ultrasound-assisted extraction methods. The oils were analyzed by capillary gas chromatography using mass spectrometric detections. The compounds were identified according to their retention indices and mass spectra (EI, 70eV). The experimental parameters of SFE such as pressure, temperature, modifier volume, static and dynamic extraction time were optimized using a Central Composite Design (CCD) after a 2(5) factorial design. Pressure and dynamic extraction time had significant effect on the extraction yield, while the other factors (temperature, static extraction time and modifier volume) were not identified as significant factors under the selected conditions. The results of chemometrics analysis showed the highest yield for SFE (24.32%), which was obtained at a pressure of 353bar, temperature of 35 degrees C, modifier (methanol) volume of 150MUL, and static and dynamic extraction times of 10 and 60min, respectively. Ultrasound-assisted extraction (UAE) of Fatty acids from C. oblonga Miller was optimized, using a rotatable central composite design. The optimum conditions were as follows: solvent (n hexane) volume, 22mL; extraction time, 30min; and extraction temperature, 55 degrees C. This resulted in a maximum oil recovery of 19.5%. The extracts with higher yield from both methods were subjected to transesterification and GC-MS analysis. The results show that the oil obtained by SFE with the optimal operating conditions allowed a fatty acid composition similar to the oil obtained by UAE in optimum condition and no significant differences were found. The major components of oil extract were Linoleic, Palmitic, Oleic, Stearic and Eicosanoic acids. PMID- 22824222 TI - Electrochemical methods in conjunction with capillary and microchip electrophoresis. AB - Electromigrative techniques such as capillary and microchip electrophoresis (CE and MCE) are inherently associated with various electrochemical phenomena. The electrolytic processes occurring in the buffer reservoirs have to be considered for a proper design of miniaturized electrophoretic systems and a suitable selection of buffer composition. In addition, the control of the electroosmotic flow plays a crucial role for the optimization of CE/MCE separations. Electroanalytical methods have significant importance in the field of detection in conjunction with CE/MCE. At present, amperometric detection and contactless conductivity detection are the predominating electrochemical detection methods for CE/MCE. This paper reviews the most recent trends in the field of electrochemical detection coupled to CE/MCE. The emphasis is on methodical developments and new applications that have been published over the past five years. A rather new way for the implementation of electrochemical methods into CE systems is the concept of electrochemically assisted injection which involves the electrochemical conversions of analytes during the injection step. This approach is particularly attractive in hyphenation to mass spectrometry (MS) as it widens the range of CE-MS applications. An overview of recent developments of electrochemically assisted injection coupled to CE is presented. PMID- 22824223 TI - Physico-chemical characterization of liposomes and drug substance-liposome interactions in pharmaceutics using capillary electrophoresis and electrokinetic chromatography. AB - Liposomes are self-assembled phospholipid vesicles and have numerous research and therapeutic applications. In the pharmaceutical and biomedical sciences liposomes find use as models of biological membranes, partitioning medium and as drug carriers. The present review addresses the use of capillary electrophoresis and liposome electrokinetic chromatography for the characterization of liposomes in a pharmaceutical context. Capillary electrophoretic techniques have been used for the measurement of electrophoretic mobility, which provides information on liposome surface charge, size and membrane permeability of liposomes. The use of liposome electrokinetic chromatography and capillary electrophoresis for determination of liposome/water partitioning and characterization of drug liposome interactions is reviewed. A number of studies indicate that capillary electrophoresis may have a role in the characterization of liposome drug delivery systems, e.g., for the investigation of encapsulation efficiency and drug leakage. The well-known characteristics of capillary electrophoresis, i.e., low sample volume requirement, high separation efficiency in aqueous media without a stationary phase, minimal sample preparation, and a high degree of automation, makes it an attractive approach in liposome research. PMID- 22824224 TI - Atmospheric pressure gas chromatography with quadrupole time of flight mass spectrometry for simultaneous detection and quantification of polycyclic aromatic hydrocarbons and nitro-polycyclic aromatic hydrocarbons in mosses. AB - Within the family of polycyclic aromatic hydrocarbons (PAHs), nitrated derivatives are of particular interest in environmental science because they have well-known carcinogenic and mutagenic effects. They are in fact more toxic than their parent PAHs. One valuable diagnosis of atmospheric pollution can be obtained using biomonitors such as mosses. These biomonitors can provide information about air pollution over long periods of time in wilderness areas. Thus, they can serve as monitors of the atmospheric transport of pollutants. In this study, atmospheric pressure gas chromatography coupled to a quadrupole hyphenated to a time of flight mass spectrometer (APGC-MS/Q-TOF) has been examined for the identification of target analytes (15 PAHs and 8 NPAHs) for subsequent use in the analysis of mosses. Working ranges in low MUg g(-1) concentration levels were obtained with most correlation coefficients higher than 0.999. All LODs were in the 0.007-0.035MUg g(-1) range and higher LODs (0.035MUg g(-1)) were obtained for the less volatile PAHs with higher mass and retention times: benzo(g,h,i)perylene, dibenz(a,h)anthracene and indeno(1,2,3-c,d)pyrene. These LODs are of importance for the intended use, biomonitoring, especially taking into account that NPAHs are commonly found at very low concentration levels. Recoveries from mosses ranged from 75 to 98%. Intraday and interday precision ranged from 1.8 to 11.1% RSD and from 2.4 to 16.7% RSD, respectively. Very low concentrations of NPAHs were found in mosses compared to those of PAHs. All these data were used for pattern recognition of the pollutant source. The results are shown and discussed. PMID- 22824225 TI - How pragmatic or explanatory is the randomized, controlled trial? The application and enhancement of the PRECIS tool to the evaluation of a smoking cessation trial. AB - BACKGROUND: Numerous explanatory randomized trials support the efficacy of chronic disease interventions, including smoking cessation treatments. However, there is often inadequate adoption of these interventions for various reasons, one being the limitation of generalizability of the explanatory studies in real world settings. Randomized controlled trials can be rated as more explanatory versus pragmatic along 10 dimensions. Pragmatic randomized clinical trials generate more realistic estimates of effectiveness with greater relevance to clinical practice and for health resource allocation decisions. However, there is no clear method to scale each dimension during the trial design phase to ensure that the design matches the intended purpose of the study. METHODS: We designed a pragmatic, randomized, controlled study to maximize external validity by addressing several barriers to smoking cessation therapy in ambulatory care. We analyzed our design and methods using the recently published 'Pragmatic Explanatory Continuum Indicatory Summary (PRECIS)' tool, a qualitative method to assess trial design across 10 domains. We added a 20-point numerical rating scale and a modified Delphi process to improve consensus in rating these domains. RESULTS: After two rounds of review, there was consensus on all 10 domains of study design. No single domain was scored as either fully pragmatic or fully explanatory; but overall, the study scored high on pragmatism. CONCLUSIONS: This addition to the PRECIS tool may assist other trial designers working with interdisciplinary co-investigators to rate their study design while building consensus. PMID- 22824226 TI - Single oral doses of (+/-) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations. AB - Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5 HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury. PMID- 22824227 TI - Development of post-pericardiotomy syndrome is preceded by an increase in pro inflammatory and a decrease in anti-inflammatory serological markers. AB - The post-pericardiotomy syndrome (PPS) is a common complication after cardiac surgery, occuring in 10-40% of patients. PPS may prolong hospitalization, and even serious complications like tamponade and constrictive pericarditis may occur. Early diagnosis and treatment may reduce morbidity. In 50 patients transferred to our hospital after cardiac surgery we found an increase in pro inflammatory and a decrease in anti-inflammatory cytokines at admission in the patients later developing PPS compared to the patients who did not develop PPS. If confirmed in larger studies, these findings may prove useful in early identification of and targeted treatment in patients developing PPS. PMID- 22824228 TI - Fulminant myocarditis and viral infection. PMID- 22824229 TI - Herpes zoster: family history and psychological stress-case-control study. AB - BACKGROUND: Several studies have reported risk factors for herpes zoster (HZ), but their results remain controversial and difficult to compare because of their limitations regarding sampling and design. OBJECTIVES: This study was aimed to determine risk factors in ambulatory patients aged 50 years or more, by consulting general practitioners (GPs) in France. STUDY DESIGN: A prospective, national, matched case-control study was conducted. It involved 121 GPs who recruited 250 cases of HZ and 500 controls (matched by age and sex), aged 50 years and older, between April 2009 and September 2010. GP and patient questionnaires explored the following risk factors: family history of HZ, comorbidities, depression, anxiety, negative life events, physical trauma, alcohol and tobacco consumption, level of education, and various protective factors (such as exposure to children). Odds ratios were estimated using conditional logistic regression. RESULTS: In multivariate adjusted analysis, a family history of HZ (OR 3.69, 95% CI 1.81-7.51), a HAD depressive score>=8 (OR 4.15, 95% CI 1.88-9.16), and a recent negative life event (OR 3.40, 95% CI 1.67 6.93) were all significantly associated with HZ. CONCLUSIONS: This case-control study conducted in ambulatory patients in general practice reinforced the hypothesis that, in addition to the age-related decline in VZV-specific T-cell mediated immunity, depression negative life event and familiar history of zoster increase the risk of occurrence of herpes zoster. In people with familiar history, this risk could be prevented by vaccination. PMID- 22824230 TI - Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc. AB - BACKGROUND: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop. OBJECTIVES: To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials. STUDY DESIGN: Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff. RESULTS: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed. CONCLUSIONS: In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility. PMID- 22824231 TI - Characterization of a novel gyrovirus in human stool and chicken meat. AB - BACKGROUND: Sequence-independent amplification of clinical specimens can lead to the identification of novel pathogens. OBJECTIVES: To identify novel viruses in human stool specimens from patients with diarrhea and to investigate the ecology and clinical significance of such viruses. STUDY DESIGN: Nucleic acid extracted from stool specimens from patients with diarrhea with no known etiology were subjected to random PCR amplification and Roche/454 pyrosequencing. Novel viruses identified were genetically and epidemiologically characterized. RESULTS: Four gyroviruses, chicken anemia virus (CAV), human gyrovirus (HGV)/avian gyrovirus 2 (AGV2), gyrovirus 3 (GyV3) and a novel gyrovirus (tentatively designated as gyrovirus 4 (GyV4)) were identified in human stool specimens. GyV4, as well as CAV and AGV2/HGV were also detected in chicken skin and meat used for human consumption. CONCLUSIONS: A novel gyrovirus (GyV4) was identified in human stool and in chicken meat sold for human consumption. This virus was phylogenetically distinct from previously reported gyroviruses in chicken and humans (chicken anemia virus, human gyrovirus, avian gyrovirus 2 and recently reported gyrovirus 3). The epidemiology and pathogenesis of this virus in humans and in chicken needs to be further investigated. PMID- 22824232 TI - A new control center for dopaminergic systems: pulling the VTA by the tail. AB - The tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), is a recently defined midbrain structure considered to exert a major inhibitory drive on dopamine systems. In view of its connectivity, tVTA is well placed to convey salient positive and negative signals to dopamine cells and participate in adaptative behavioral responses. This structure could act as a hub converging and integrating widespread multimodal signals toward dopamine systems. The tVTA participates in prediction error, motor control, and responses to aversive stimuli and drugs of abuse. In light of the crucial role of the tVTA in the opiate control of dopamine activity, a neuroanatomical update of the disinhibition model of morphine action is proposed. PMID- 22824233 TI - Major depressive disorder as a predictor of a worse seizure outcome one year after surgery in patients with temporal lobe epilepsy and mesial temporal sclerosis. AB - PURPOSE: The association between pre-surgical psychiatric disorders (PDs) and worse seizure outcome in patients with refractory epilepsy submitted to surgery has been increasingly recognized in the literature. The present study aimed to verify the impact of pre- and post-surgical PD on seizure outcome in a series of patients with refractory temporal lobe epilepsy and mesial temporal sclerosis (TLE-MTS). METHOD: Data from 115 TLE-MTS patients (65 females; 56.5%) who underwent cortico-amygdalohippocampectomy (CAH) were analyzed. Pre- and post surgical psychiatric evaluations were performed using DSM-IV and ILAE criteria. The outcome subcategory Engel IA was considered as corresponding to a favorable prognosis. A multivariate logistic regression model was applied to identify possible risk factors associated with a worse seizure outcome. RESULTS: Pre surgical PDs, particularly major depressive disorder (MDD), anxiety and psychotic disorders, were common, being found in 47 patients (40.8%). Fifty-six patients (48.7%) were classified as having achieved an Engel IA one year after CAH. According to the logistic regression model, the presence of pre-surgical MDD (OR=5.23; p=0.003) appeared as the most important risk factor associated with a non-favorable seizure outcome. CONCLUSION: Although epilepsy surgery may be the best treatment option for patients with refractory TLE-MTS, our findings emphasize the importance of performing a detailed psychiatric examination as part of the pre-surgical evaluation protocol. PMID- 22824234 TI - Looking at the brains behind figurative language--a quantitative meta-analysis of neuroimaging studies on metaphor, idiom, and irony processing. AB - A quantitative, coordinate-based meta-analysis combined data from 354 participants across 22 fMRI studies and one positron emission tomography (PET) study to identify the differences in neural correlates of figurative and literal language processing, and to investigate the role of the right hemisphere (RH) in figurative language processing. Studies that reported peak activations in standard space contrasting figurative vs. literal language processing at whole brain level in healthy adults were included. The left and right IFG, large parts of the left temporal lobe, the bilateral medial frontal gyri (medFG) and an area around the left amygdala emerged for figurative language processing across studies. Conditions requiring exclusively literal language processing did not activate any selective regions in most of the cases, but if so they activated the cuneus/precuneus, right MFG and the right IPL. No general RH advantage for metaphor processing could be found. On the contrary, significant clusters of activation for metaphor conditions were mostly lateralized to the left hemisphere (LH). Subgroup comparisons between experiments on metaphors, idioms, and irony/sarcasm revealed shared activations in left frontotemporal regions for idiom and metaphor processing. Irony/sarcasm processing was correlated with activations in midline structures such as the medFG, ACC and cuneus/precuneus. To test the graded salience hypothesis (GSH, Giora, 1997), novel metaphors were contrasted against conventional metaphors. In line with the GSH, RH involvement was found for novel metaphors only. Here we show that more analytic, semantic processes are involved in metaphor comprehension, whereas irony/sarcasm comprehension involves theory of mind processes. PMID- 22824235 TI - Oscillatory dynamics related to the Unagreement pattern in Spanish. AB - Unagreement patterns consist in a person feature mismatch between subject and verb that is nonetheless grammatical in Spanish. The processing of this type of construction gives new insights into the understanding of agreement processes during language comprehension. Here, we contrasted oscillatory brain activity triggered by Unagreement in different EEG bands with those triggered by Standard Agreement and Person Mismatch sentences. In Spectral Power analysis, a similar pattern for Unagreement to that elicited by Person Mismatch was found in lower beta and alpha bands, approximately around 600ms. This suggests that fast oscillations reflect the evaluation of the feature match between two structurally related constituents (independently of its grammaticality). In an equivalent time window, the Unagreement condition behaves similarly to the Standard Agreement condition in the theta band, but different from the Person Mismatch condition that shows an enhanced spectral power. In addition, an enhanced phase synchrony in lower beta frequency around 600ms is associated to standard agreement patterns, while beta-high frequencies at 800ms characterize processing of Unagreement sentences. These results support the functional dissociation between the evaluation of the feature match between two structurally related constituents (independently of its grammaticality-in fast oscillatory bands) and integration of linguistic material in working memory (reflected by theta oscillations). Successful resolution of an agreement dependency is better reflected in phase synchronizations at beta band. PMID- 22824236 TI - First description of Escherichia coli producing CTX-M-15- extended spectrum beta lactamase (ESBL) in out-patients from south eastern Nigeria. AB - We studied the presence of extended spectrum beta lactamases (ESBLs) in 44 clinical isolates of Escherichia coli collected from out-patients in two university teaching hospitals in South-Eastern Nigeria. Species identification was performed by standard microbiology methods and re-confirmed by MALDI-TOF technology. Phenotypic characterization of ESBL enzymes was done by double disc synergy test and presence of ESBL genes was determined by specific PCR followed by sequencing. Transfer of plasmid DNA was carried out by transformation using E. coli DH5 as recipient strain. Phenotypic characterization identified all isolates to be ESBL positive. 77% of strains were from urine, 13.6% from vaginal swabs and 9.0% from wound swabs. 63.6% were from female patients, 68% were from outpatients and 95.5% from patients younger than 30 years. All ESBL producers were positive in a PCR for bla(CTX-M-1) cluster, in exemplary strains bla(CTX-M-15) was found by sequencing. In all strains ISEcp1 was found upstream and ORF477 downstream of bla(CTX-M). PCR for bla(TEM) and bla(OXA-1) was positive in 93.1% of strains, whereas bla(SHV) was not detected, aac(6')-Ib-cr was found in 97.7% of strains. RAPD analysis revealed seven different clonal groups named A through G with the majority of the strains (65.9%) belonging to clone A. Transfer of an ESBL plasmid with co-resistance to gentamicin, kanamycin, tobramycin, doxycycline and trimethropim-sulfamethoxazole was successful in 19 (43.2%) strains. This study showed a high rate of CTX-M-1 cluster - ESBLs in South-Eastern Nigeria and further confirms the worldwide spread of CTX-M ESBL in clinical isolates. PMID- 22824237 TI - The 2011 ESPEN Arvid Wretlind lecture: cancer cachexia: the potential impact of translational research on patient-focused outcomes. AB - Cancer cachexia is a multifactorial syndrome characterised by loss of skeletal muscle that cannot be fully reversed by conventional nutritional support. Uncertainty continues as to its precise mediators and mechanisms. The pathophysiology is characterised by a variable combination of reduced food intake and abnormal metabolism. Recent evidence has suggested that there may be a genetic component to cachexia with emphasis on genes linked to systemic inflammation. Loss of skeletal muscle mass and function is a major contributor to the excess frailty, disability and increased mortality in cancer cachexia. Whilst muscle mass per se has been considered a key outcome measure in treating cachexia, it might be more rationale to choose a patient-centred outcome such as physical activity. Beyond good medical management, it is important that trials establish basic management for all patients (nutrition, exercise and anti inflammatory treatment). Specific therapies for cachexia should focus on the key issues of reduced food intake and abnormal metabolism. Whilst combination regimens to treat these issues continue to be explored, there is also interest in biological therapies that target conserved molecular mechanisms of muscle growth/atrophy. The combination of approaches promises a new era for the management of cachexia in the context of supportive oncology. PMID- 22824238 TI - The effect of smoking and alcohol consumption on markers of systemic inflammation, immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis. AB - INTRODUCTION: The purpose of this research was to study the influence of cigarette smoking and alcohol consumption on immune response to heptavalent pneumococcal conjugate vaccine, immunoglobulin levels (Ig) and markers of systemic inflammation in patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA). METHODS: In total, 505 patients were vaccinated. Six pre-specified groups were enrolled: RA on methotrexate (MTX) treatment in some cases other disease-modifying antirheumatic drugs (DMARDs) (I); RA on anti-tumour necrosis factor (TNF) as monotherapy (II); RA on anti-TNF+MTX+ possibly other DMARDs (III); SpA on anti-TNF as monotherapy (IV); SpA on anti-TNF+MTX+ possibly other DMARDs (V); and SpA on nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesics (VI). Smoking (pack-years) and alcohol consumption (g/week) were calculated from patient questionnaires. Ig, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at vaccination. IgG antibodies against serotypes 23F and 6B were measured at vaccination and after four to six weeks using standard ELISA. Immune response (ratio between post- and pre-vaccination antibodies; immune response (IR)) and positive immune response (>=2-fold increase in pre-vaccination antibodies; posIR) were calculated. RESULTS: Eighty-eight patients (17.4%) were current smokers. Smokers had higher CRP and ESR, lower IgG and lower IR for both serotypes (P between 0.012 and 0.045). RA patients on MTX who smoked >=1pack-year had lower posIR for both serotypes (P = 0.021; OR 0.29; CI 0.1 to 0.7) compared to never-smokers. Alcohol consumption was associated with lower CRP (P = 0.05) and ESR (P = 0.003) but did not influence IR or Ig levels. CONCLUSION: Smoking predicted impaired immune response to pneumococcal conjugate vaccine in RA patients on MTX. Smokers with arthritis had higher inflammatory markers and lower IgG regardless of diagnosis and treatment. Low to moderate alcohol consumption was related to lower levels of inflammation markers but had no impact on immune response. TRIAL REGISTRATION: EudraCT EU 2007-006539-29 and NCT00828997. PMID- 22824240 TI - Effects of the fungicide tebuconazole on microbial capacities for litter breakdown in streams. AB - Streams draining agricultural basins are subjected to the input of fungicides which can affect aquatic microbial communities. We analyzed the effect of the fungicide tebuconazole (TBZ) on Alnus glutinosa and Populus nigra litter breakdown by aquatic microorganisms. For six weeks, fungal and bacterial responses were analyzed in indoor stream channels subjected to TBZ-contaminated (33.1+/-12.4 MUg L(-1)) and uncontaminated conditions. Litter breakdown rates decreased in presence of TBZ. The decrease was explained by reductions in microbial biomass development and shifts in community structure. At the same time, TBZ modified the kinetics of beta-glucosidase, beta-xylosidase and cellobiohydrolase enzymes resulting in lower affinities for cellulose and hemicellulose decomposition in leaves. These alterations were modulated by the litter quality; the greatest structural impairment was observed in Populus whereas Alnus were more affected in terms of leaf breakdown rate. Our results suggest that chronic exposure to TBZ can affect aquatic microbial communities and their capacity to break down leaf litter in streams. PMID- 22824241 TI - ADAMTS5: A New Player in the Vascular Field. AB - This Commentary highlights the article by Kumar et al, showing that ADAMTS5 suppresses tumor growth by down-regulating other angiogenesis-inducing factors in addition to VEGF and that the central TSR1 domain of ADAMTS5 is required in this function. PMID- 22824239 TI - Drosophila larvae lacking the bcl-2 gene, buffy, are sensitive to nutrient stress, maintain increased basal target of rapamycin (Tor) signaling and exhibit characteristics of altered basal energy metabolism. AB - BACKGROUND: B cell lymphoma 2 (Bcl-2) proteins are the central regulators of apoptosis. The two bcl-2 genes in Drosophila modulate the response to stress induced cell death, but not developmental cell death. Because null mutants are viable, Drosophila provides an optimum model system to investigate alternate functions of Bcl-2 proteins. In this report, we explore the role of one bcl-2 gene in nutrient stress responses. RESULTS: We report that starvation of Drosophila larvae lacking the bcl-2 gene, buffy, decreases survival rate by more than twofold relative to wild-type larvae. The buffy null mutant reacted to starvation with the expected responses such as inhibition of target of rapamycin (Tor) signaling, autophagy initiation and mobilization of stored lipids. However, the autophagic response to starvation initiated faster in larvae lacking buffy and was inhibited by ectopic buffy. We demonstrate that unusually high basal Tor signaling, indicated by more phosphorylated S6K, was detected in the buffy mutant and that removal of a genomic copy of S6K, but not inactivation of Tor by rapamycin, reverted the precocious autophagy phenotype. Instead, Tor inactivation also required loss of a positive nutrient signal to trigger autophagy and loss of both was sufficient to activate autophagy in the buffy mutant even in the presence of enforced phosphoinositide 3-kinase (PI3K) signaling. Prior to starvation, the fed buffy mutant stored less lipid and glycogen, had high lactate levels and maintained a reduced pool of cellular ATP. These observations, together with the inability of buffy mutant larvae to adapt to nutrient restriction, indicate altered energy metabolism in the absence of buffy. CONCLUSIONS: All animals in their natural habitats are faced with periods of reduced nutrient availability. This study demonstrates that buffy is required for adaptation to both starvation and nutrient restriction. Thus, Buffy is a Bcl-2 protein that plays an important non-apoptotic role to promote survival of the whole organism in a stressful situation. PMID- 22824242 TI - A systematic review on 'Foveal Crowding' in visually impaired children and perceptual learning as a method to reduce Crowding. AB - BACKGROUND: This systematic review gives an overview of foveal crowding (the inability to recognize objects due to surrounding nearby contours in foveal vision) and possible interventions. Foveal crowding can have a major effect on reading rate and deciphering small pieces of information from busy visual scenes. Three specific groups experience more foveal crowding than adults with normal vision (NV): 1) children with NV, 2) visually impaired (VI) children and adults and 3) children with cerebral visual impairment (CVI). The extent and magnitude of foveal crowding as well as interventions aimed at reducing crowding were investigated in this review. The twofold goal of this review is : [A] to compare foveal crowding in children with NV, VI children and adults and CVI children and [B] to compare interventions to reduce crowding. METHODS: Three electronic databases were used to conduct the literature search: PubMed, PsycINFO (Ovid), and Cochrane. Additional studies were identified by contacting experts. Search terms included visual perception, contour interaction, crowding, crowded, and contour interactions. RESULTS: Children with normal vision show an extent of contour interaction over an area 1.5-3* as large as that seen in adults NV. The magnitude of contour interaction normally ranges between 1-2 lines on an acuity chart and this magnitude is even larger when stimuli are arranged in a circular configuration. Adults with congenital nystagmus (CN) show interaction areas that are 2* larger than those seen adults with NV. The magnitude of the crowding effect is also 2* as large in individuals with CN as in individuals with NV. Finally, children with CVI experience a magnitude of the crowding effect that is 3* the size of that experienced by adults with NV. CONCLUSIONS: The methodological heterogeneity, the diversity in paradigms used to measure crowding, made it impossible to conduct a meta-analysis. This is the first systematic review to compare crowding ratios and it shows that charts with 50% interoptotype spacing were most sensitive to capture crowding effects. The groups that showed the largest crowding effects were individuals with CN, VI adults with central scotomas and children with CVI. Perceptual Learning seems to be a promising technique to reduce excessive foveal crowding effects. PMID- 22824243 TI - Tobacco smoke biomarkers and cancer risk among male smokers in the Shanghai cohort study. AB - Metabolites of tobacco smoke constituents can be quantified in urine and other body fluids providing a realistic measure of carcinogen and toxicant dose in a smoker. Many previous studies have demonstrated that these metabolites - referred to as biomarkers in this paper - are related to tobacco smoke exposure. The studies reviewed here were designed to answer another question: are these substances also biomarkers of cancer risk? Using a prospective study design comparing biomarker levels in cancer cases and controls, all of whom were smokers, the results demonstrate that several of these biomarkers - total cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), r-1-,t 2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), and total N' nitrosonornicotine (NNN) - are biomarkers of cancer risk. Therefore, these biomarkers have the potential to become part of a cancer risk prediction algorithm for smokers. PMID- 22824244 TI - Ovarian ascites-derived Hospicells promote angiogenesis via activation of macrophages. AB - Within the microenvironment, Carcinoma-associated mesenchymal stem cells (Hospicells) are able to influence ovarian tumor development via, among others, the facilitation of angiogenesis in the tumor site allowing an accelerated tumor growth. We demonstrate the presence of a chemotactism between endothelial cells and Hospicells, and a cell line specific increased secretion of pro-angiogenic cytokines such as IL-6, IL-8 and VEGF from ovarian adenocarcinoma cells. Hospicells are also able to attract and activate macrophages to a M2 phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested. PMID- 22824245 TI - [Fungal invasion of connective tissue in patients with gingival-periodontal disease]. AB - BACKGROUND: In the last few years unusual microorganisms have been isolated from subgingival biofilm, as possible initiators or contributors to periodontal disease, especially in patients who show no improvement during treatment. AIMS: To study the Candida invasion of the connective tissue in relation to subgingival biofilm presence. METHODS: A total of 55 immunocompetent patients of both sexes, between 21 and 55 years of age, non-smokers, without previous antimicrobial treatment, suffering periodontal diseases, were studied. Soft tissues, supragingival and subgingival plaque samples, and periodontal pocket biopsies were taken. Microscopic studies, cultures, assimilation profiles, and DNA amplifications were performed. RESULTS: In 35% of the samples, different species of Candida were isolated in cultures, especially Candida albicans. Hyphae invasions in the connective tissue were observed, in association with anaerobic microorganisms (Porphyromonas gingivalis, Prevotella intermedia and Aggregatibacter actinomycetemcomitans) in patients with periodontitis. CONCLUSIONS: Different species of Candida could be part of the periodontal plaque and could play an important role in the adherence to soft tissues, allowing deep invasion. They also could infect gingival pockets in patients with gingivitis, even in healthy locations, playing a commensal or opportunist role. PMID- 22824246 TI - Prediction of width of un-erupted incisors, canines and premolars in a Ugandan population: a cross sectional study. AB - BACKGROUND: Accurate prediction of the space forms an important part of an orthodontic assessment in the mixed dentition. However the most commonly used methods of space analysis are based on data developed on Caucasian populations. In order to provide more accurate local data we set out to develop a formula for predicting the widths of un-erupted canines and premolars for a Ugandan population and to compare the predicted widths of the teeth from this formula with those obtained from Moyers' tables, and Tanaka and Johnston's equations. METHODS: Dental casts were prepared using mandibular and maxillary arch impressions of 220 children (85 boys/135 girls) aged 12-17 years recruited from schools in Kampala, Uganda. The mesio-distal width of the mandibular incisors, mandibular and maxillary canines and premolars were measured with a pair of digital calipers. Based on regression analysis, predictive equations were derived and the findings were compared with those presented in Moyers' probability tables, and Tanaka and Johnston's equations. RESULTS: There were no statistically significant differences between the tooth widths predicted by our equations and those from Moyers' probability tables at the 65th and 75th percentile probabilities for the girls and at 75th level in boys in the mandibular arch. While in the maxillary arch no statistically significant differences at the 75th and 95th levels were noted in girls. There were statistically significant differences between predicted tooth sizes using equations from the present study and those predicted from the Tanaka and Johnston regression equations. CONCLUSIONS: In this Ugandan population, Moyers' probability tables could be used to predict tooth widths at specific percentile probabilities, but generally, Tanaka and Johnston technique tends to overestimate the tooth widths. PMID- 22824247 TI - Consultation performance of general practitioners when supported by an asthma/COPDC-service. AB - BACKGROUND: General practitioners (GPs) can refer patients to an asthma/COPD service (AC-service) for diagnostic assessment of spirometry and medical history and for asthma or COPD monitoring. The AC-service reports diagnostic results and additional information about disease burden (BORG-score for complaints, MRC dyspnoea score, exacerbation rate), life style, medication and compliance, to the patient's GP. This study explores how GPs use this additional information when discussing the patient's disease burden and how this influences GPs' information and education provision during consultations with asthma/COPD patients. METHOD: Patients with (a suspicion of) asthma or COPD were referred to an AC-service and consulted their GPs after they had received a report from the AC-service. Retrospectively patients answered questions about their GPs' performance during these consultations. Performances were compared with performances of the same GPs during consultations without support of the AC-service (usual care), earlier that year. RESULTS: Of consultations not initiated by an AC-service check-up, 91% focussed on complaints, the initial reason for the consultation. In AC-service supported follow-up consultations, GPs explored disease burden when the (BORG )score for complaints was high - as reported by the AC-service - even when patients themselves thought it was irrelevant. GPs put significantly less effort in exploring disease burden when the Borg-score was low (BORG 3-4: 69%; BORG1-2: 51%, p = 0,01). GPs mostly ignored MRC-dyspnoea scores: attention to dyspnoea was 18% for MRC-score <3 and 25% for MRC-score >=3 (p = 0,63). GPs encouraged physical fitness in 13% of patients. Smoking behaviour was discussed with 66% of the actual smokers but only 14% remembered a stop smoking advice. Furthermore, pharmacotherapeutic management education in AC-service supported consultations did not differ from performance in usual care according to patient evaluations. CONCLUSION: Other than taking into account the severity of complaints, there was no difference between GPs' performance in AC-service supported and in usual care consultations. AC-service reports are thus not effective by themselves. GPs should be encouraged to use the information better and systematically check all relevant aspects that characterize the disease burden of their patients. PMID- 22824249 TI - Thickness of buccal bone in the mandible and its clinical significance in mono cortical screws placement. A CBCT analysis. AB - The aim of this study was to determine the safest length of monocortical screws that can be inserted for the treatment of mandibular fractures following Champy's technique. Fifty cone-beam computed tomography (CBCT) scans of hemi-mandibles were studied. Linear measurements were taken from the buccal cortical plate to the tooth apex, from the canine to the second premolar, and from the buccal cortical plate to the tooth apex and the inferior alveolar canal in the molar area. The minimum values of the horizontal distances both at the level of the apex and the inferior alveolar canal at the second molar were found to be 4 mm, which is greater than those of the first molar. At the canine, first premolar and second premolars, the minimum values of the horizontal distances at the level of the apex was found to be 2 mm, 2.33 mm and 2 mm, respectively. Stabilizing miniplates using 4 mm screws both at the level of the apex and the inferior alveolar canal is safe in the second molar area, anterior to this, there is a risk of injury to tooth root and inferior alveolar nerve. PMID- 22824248 TI - Role of social support in predicting caregiver burden. AB - OBJECTIVE: To examine the unique contribution of social support to burden in caregivers of adults aging with spinal cord injury (SCI). DESIGN: Secondary analyses of cross-sectional data from a large cohort of adults aging with SCI and their primary caregivers. SETTING: Multiple community locations. PARTICIPANTS: Caregivers of community-dwelling adults aging with SCI (n=173) were interviewed as part of a multisite randomized controlled trial. The mean age +/- SD of caregivers was 53+/-15 years and of care-recipients, 55+/-13 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was caregiver burden measured with the Abridged Version of the Zarit Burden Interview. A hierarchical multiple regression analysis examined the effects of social supports (social integration, received social support, and negative social interactions) on burden in caregivers of adults aging with SCI while controlling for demographic characteristics and caregiving characteristics. RESULTS: After controlling for demographic characteristics and caregiving characteristics, social integration (beta=-.16, P<.05), received social support (beta=-.15, P<.05), and negative social interactions (beta=.21, P<.01) were significant independent predictors of caregiver burden. CONCLUSIONS: Findings demonstrate that social support is an important factor associated with burden in caregivers of adults aging with SCI. Social support should be considered for assessments and interventions designed to identify and reduce caregiver burden. PMID- 22824250 TI - Odor-structure relationship studies of tetralin and indan musks. AB - A list of 147 tetralin- and indan-like compounds was compiled from the literature for investigating the relationship between molecular structure and musk odor. Each compound in the data set was represented by 374 CODESSA and 970 TAE descriptors. A genetic algorithm (GA) for pattern recognition analysis was used to identify a subset of molecular descriptors that could differentiate musks from nonmusks in a plot of the two largest principal components (PCs) of the data. A PC map of the 110 compounds in the training set using 45 molecular descriptors identified by the pattern recognition GA revealed an asymmetric data structure. Tetralin and indan musks were found to occupy a small, but well-defined region of the PC (descriptor) space, with the nonmusks randomly distributed in the PC plot. A three-layer feed-forward neural network trained by back propagation was used to develop a discriminant that correctly classified all the compounds in the training set as musk or nonmusk. The neural network was successfully validated using an external prediction of 37 compounds. PMID- 22824251 TI - Variation in the gene TAS2R13 is associated with differences in alcohol consumption in patients with head and neck cancer. AB - Variation in responsiveness to bitter-tasting compounds has been associated with differences in alcohol consumption. One strong genetic determinant of variation in bitter taste sensitivity is alleles of the TAS2R gene family, which encode chemosensory receptors sensitive to a diverse array of natural and synthetic compounds. Members of the TAS2R family, when expressed in the gustatory system, function as bitter taste receptors. To better understand the relationship between TAS2R function and alcohol consumption, we asked if TAS2R variants are associated with measures of alcohol consumption in a head and neck cancer patient cohort. Factors associated with increased alcohol intake are of strong interest to those concerned with decreasing the incidence of cancers of oral and pharyngeal structures. We found a single nucleotide polymorphism (SNP) located within the TAS2R13 gene (rs1015443 [C1040T, Ser259Asn]), which showed a significant association with measures of alcohol consumption assessed via the Alcohol Use Disorders Identification Test (AUDIT). Analyses with other SNPs in close proximity to rs1015443 suggest that this locus is principally responsible for the association. Thus, our results provide additional support to the emerging hypothesis that genetic variation in bitter taste receptors can impact upon alcohol consumption. PMID- 22824252 TI - Left ventricular partitioning device in a patient with chronic heart failure: short-term clinical follow-up. PMID- 22824253 TI - Angina pectoris in women: focus on microvascular disease. AB - Ischemic heart disease (IHD) is the leading cause of death among women in Western countries, and it is associated with higher morbidity and mortality than in men. Nevertheless, IHD in women remains underdiagnosed and undertreated, and the misperception that females are "protected" against cardiovascular disease leads to underestimation of their cardiovascular risk; instead, women with chest pain have a high risk of cardiovascular events. Women suffering from angina pectoris tend to have different characteristics compared to men, with a high prevalence of non-significant coronary artery disease. Angina in women is more commonly microvascular in origin than in men, and therefore standard diagnostic algorithms may be suboptimal for women. This different pathophysiology impacts clinical management of IHD in women. While response to medical therapy may differ in women, they are scarcely represented in clinical trials. Therefore, solid data in terms of gender efficacy of antianginal drugs are lacking, and particularly when angina is microvascular in origin women often continue to be symptomatic despite maximal therapy with classical antianginal drugs. Recently, new molecules have shown promising results in women. In conclusion, women with angina are a group of patients in whom it seems appropriate to concentrate efforts aimed at reducing morbidity and improving quality of life. PMID- 22824254 TI - Transient elimination of circulating bovine viral diarrhoea virus by colostral antibodies in persistently infected calves: a pitfall for BVDV-eradication programs? AB - Infections with bovine viral diarrhoea virus (BVDV) cause substantial economic losses to cattle industries. Rapid detection of persistently BVDV infected (PI) calves is of utmost importance for the efficacy of BVDV control programs. Blood and ear skin biopsy samples are conveniently used for early mass screening of newborns. However, little is known about the impact of colostral antibodies on the outcome of relevant analyses. Here, we rigorously tested a series of samples obtained from five colostrum-fed PI calves from birth until they reached the status of seronegativity for NS3-specific antibodies. We comparatively quantified virus loads in blood samples and dried skin biopsies as detected with BVDV-NS3-, Erns-capture ELISA and RT-qPCR. Monitoring of NS3-positive leukocytes was done with flow cytometry. Within seven days after colostrum intake, BVDV infected leukocytes disappeared for a three- to eight-week period. Immediately after colostrum ingestion, detectable Erns antigen levels dropped 10-100-fold in biopsy samples and in sera detection of Erns failed for one to two weeks. Virus demonstration in biopsy samples with a NS3-antigen-ELISA failed until days 90-158 after birth. Specific antibodies against BVDV also impaired the detection of viral RNA in leukocytes and blood. Mean RNA levels of the five calves were reduced in sera 2.500-fold and in leukocytes 400-fold, the lowest values were at week three of live. In contrast, levels of measurable viral RNA in biopsy samples remained constant during the observation period. PMID- 22824255 TI - Isolation and molecular characterization of a second serotype of the encephalomyocarditis virus. AB - Encephalomyocarditis virus (EMCV) and Theilovirus are the two species of the Cardiovirus genus. Whereas theiloviruses comprise several sero-/genotypes, all known EMCV isolates are serologically very similar and are thought to belong to one serotype, named EMCV-1. Here, a novel EMCV type is described. Strain RD 1338 (D28/05) was isolated from a wood mouse (Apodemus sylvaticus) in Germany and can be distinguished from EMCV-1 by serological and molecular means. Failure of EMCV 1 specific hyperimmune sera to neutralize RD 1338 suggests a distinct serotype. The viral genome was de novo sequenced using next-generation Illumina/Solexa technologies. Considerable differences of the BC-loop/loop I/loop II sequences of VP1, the VP2 puff and the VP3 knob provide a structural basis for deviant serological properties. Sequence alignments reveal amino acid identities of 75 percent for the P1 region and 84 percent for the P2 and P3 regions when comparing RD 1338 to EMCV-1 strains and some 60 percent and less than 50 percent amino acid identities, respectively, for comparisons with theilovirus strains. Phylogenetic analyses of the P1, 2C and 3CD gene regions support the establishment of an EMCV 2 serotype. In contrast to the theilovirus sero-/genotypes that show a narrow host range, EMCV-1 infects a wide variety of hosts. The host range of EMCV-2 remains to be determined. PMID- 22824256 TI - Efficient isolation of avian bornaviruses (ABV) from naturally infected psittacine birds and identification of a new ABV genotype from a salmon-crested cockatoo (Cacatua moluccensis). AB - Avian bornaviruses (ABV) have been discovered in 2008 as the causative agent of proventricular dilatation disease (PDD) in psittacine birds. To date, six ABV genotypes have been described in psittacines. Furthermore, two additional but genetically different ABV genotypes were recognized in non-psittacine birds such as canary birds and wild waterfowl. This remarkable genetic diversity poses a considerable challenge to ABV diagnosis, since polymerase chain reaction (PCR) assays may fail to detect distantly related or as yet unknown genotypes. In this study we investigated the use of virus isolation in cell culture as a strategy for improving ABV diagnosis. We found that the quail fibroblast cell line CEC-32 allows very efficient isolation of ABV from psittacine birds. Isolation of ABV was successful not only from organ samples but also from cloacal and pharyngeal swabs and blood samples collected intra vitam from naturally infected parrots. Importantly, using this experimental approach we managed to isolate a new ABV genotype, termed ABV-7, from a salmon-crested cockatoo (Cacatua moluccensis). Phylogenetic analysis showed that ABV-7 is most closely related to the psittacine genotypes ABV-1, -2, -3, and -4 and clearly distinct from genotypes ABV-5 and -6. Our successful identification of ABV-7 emphasizes the necessity to consider the high genetic diversity when trying to diagnose ABV infections with high reliability and further shows that classical virus isolation may represent a useful diagnostic option, particularly for the detection of new ABV genotypes. PMID- 22824257 TI - Synthesis of submicron spherical Fe-MCM-48 with actual gyroid like structure. AB - Highly ordered submicron spherical Fe-MCM-48 was successfully synthesized by a mixed surfactant method using cheap water glass as silica source. The gyroid like structure of MCM-48 was captured by a TEM image for the first time, and it was corresponded well to the previous simulated gyroid model. A tentative mechanism of homogenization cooperative process involving the Helmholtz double electrical layer was purposed. After the loading of metal Ag, the resulting Ag/Fe-MCM-48 catalyst showed good catalytic performance in the catalytic combustion of benzene. PMID- 22824258 TI - Schistosoma haematobium infections in preschool children from two rural communities in Ijebu East, south-western Nigeria. AB - There is an urgent need for information on schistosomiasis in preschool children, who are often excluded in mass treatment programmes. The prevalence and intensity of Schistosoma haematobium infection were determined in preschool children aged <= 6 years in two rural communities in Ijebu East, south-western Nigeria. Two urine samples each were collected from 83 preschool children from the two communities, tested for microhaematuria using reagent strips and then processed and examined with a microscope for S. haematobium eggs. Focus group discussions on perceptions of the disease and water contact practices were held in the communities with their guardians, caregivers and preschool children, using an interview guide. The prevalence of S. haematobium in the two communities was 14 (16.9%), with no significant differences (P = 0.661) in infection rate between boys (18.4%) and girls (14.7%). Both prevalence and intensity of infection did not increase significantly with age in both Korede and Obada community. However, there were significant differences in prevalence of infection between the two communities (P = 0.035). There was no association (P = 0.750) between intensity in boys (0.176 eggs/10 ml urine) and girls (0.110 eggs/10 ml urine). Focal group discussions with guardians and caregivers revealed that preschool children acquired infection early in their lives through exposure to infected stream water by their mothers, while the older children visit the stream for playing, bathing and swimming. It has therefore become imperative for preschool children to be included in the planning of schistosomiasis intervention programmes as a means of reducing transmission. PMID- 22824259 TI - Seasonal development and pathological changes associated with the parasitic nematode Philometroides sanguineus in wild crucian carp Carassius carassius (L.) in England. AB - Pathological changes associated with the parasitic nematode Philometroides sanguineus (Rudolphi, 1819) are described for the first time from observations of infections in wild crucian carp Carassius carassius (L.) in England. The damage caused by P. sanguineus was influenced strongly by host size, parasite development and the seasonal migrations of female nematodes within host tissues. Male and unfertilized female nematodes located on the swim-bladder wall caused only minor, localized changes. In contrast, the migration of gravid female nematodes into the fins during autumn provoked an acute inflammatory response comprising neutrophils, eosinophils and lymphocytes. This was accompanied by fin distortion, swelling of the dorsal and caudal tissues, degenerative changes and localized oedema. The encapsulation of female nematodes in connective tissue throughout winter limited additional tissue damage. The emergence of gravid nematodes from the fins in spring to facilitate larval dispersal caused necrosis, hyperplasia and loss of skin integrity. This activity was again accompanied by acute inflammatory reactions. Pathological changes were more severe in crucian carp measuring less than 60 mm in length, with no signs of debilitation in larger fish. These observations suggest that any impact of P. sanguineus is strictly seasonal and may be limited to fry. Lesions caused by this parasite, only recently recorded in Britain, may represent an additional pressure upon wild crucian carp populations already threatened by hybridization, competition and habitat loss. PMID- 22824260 TI - Metabolic fingerprinting of hard and semi-hard natural cheeses using gas chromatography with flame ionization detector for practical sensory prediction modeling. AB - Metabolic fingerprinting using gas chromatography with flame ionization detector (GC/FID) was used to generate a practical metabolomics-based tool for quality evaluation of natural cheese. Hydrophilic low molecular weight components, relating to sensory characteristics, including amino acids, fatty acids, amines, organic acids, and saccharides, were extracted and derivatized prior to the analysis. Data on 12 cheeses, six Cheddar cheeses and six Gouda cheeses, were analyzed by multivariate analysis. Prediction models for two sensory attributes relating to maturation, "Rich flavor" and "Sour flavor", were constructed with 4199 data points from GC/FID, and excellent predictability was validated. Chromatograms from GC/FID and gas chromatography/time-of-flight-mass spectrometry (GC/TOF-MS) were comparable when the same column was used. Although GC/FID alone cannot identify peaks, the mutually complementary relationship between GC/FID and GC/MS does allow peak identification. Compounds contributing significantly to the sensory predictive models included lactose, succinic acid, L-lactic acid, and aspartic acid for "Rich flavor", and lactose, L-lactic acid, and succinic acid for "Sour flavor". Since similar model precision was obtained using GC/FID and GC/TOF-MS, metabolic fingerprinting using GC/FID, which is a relatively inexpensive instrument compared with GC/MS, is easy to maintain and operate, and is a valid alternative when metabolomics (especially using GC/MS) is to be used in a practical setting as a novel quality evaluation tool for manufacturing processes or final products. PMID- 22824261 TI - The chemokine receptor cxcr5 regulates the regenerative neurogenesis response in the adult zebrafish brain. AB - BACKGROUND: Unlike mammals, zebrafish exhibits extensive neural regeneration after injury in adult stages of its lifetime due to the neurogenic activity of the radial glial cells. However, the genes involved in the regenerative neurogenesis response of the zebrafish brain are largely unknown. Thus, understanding the underlying principles of this regeneration capacity of the zebrafish brain is an interesting research realm that may offer vast clinical ramifications. RESULTS: In this paper, we characterized the expression pattern of cxcr5 and analyzed the function of this gene during adult neurogenesis and regeneration of the zebrafish telencephalon. We found that cxcr5 was upregulated transiently in the RGCs and neurons, and the expression in the immune cells such as leukocytes was negligible during both adult neurogenesis and regeneration. We observed that the transgenic misexpression of cxcr5 in the ventricular cells using dominant negative and full-length variants of the gene resulted in altered proliferation and neurogenesis response of the RGCs. When we knocked down cxcr5 using antisense morpholinos and cerebroventricular microinjection, we observed outcomes similar to the overexpression of the dominant negative cxcr5 variant. CONCLUSIONS: Thus, based on our results, we propose that cxcr5 imposes a proliferative permissiveness to the radial glial cells and is required for differentiation of the RGCs to neurons, highlighting novel roles of cxcr5 in the nervous system of vertebrates. We therefore suggest that cxcr5 is an important cue for ventricular cell proliferation and regenerative neurogenesis in the adult zebrafish telencephalon. Further studies on the role of cxcr5 in mediating neuronal replenishment have the potential to produce clinical ramifications in efforts for regenerative therapeutic applications for human neurological disorders or acute injuries. PMID- 22824262 TI - Assessment of performance of survival prediction models for cancer prognosis. AB - BACKGROUND: Cancer survival studies are commonly analyzed using survival-time prediction models for cancer prognosis. A number of different performance metrics are used to ascertain the concordance between the predicted risk score of each patient and the actual survival time, but these metrics can sometimes conflict. Alternatively, patients are sometimes divided into two classes according to a survival-time threshold, and binary classifiers are applied to predict each patient's class. Although this approach has several drawbacks, it does provide natural performance metrics such as positive and negative predictive values to enable unambiguous assessments. METHODS: We compare the survival-time prediction and survival-time threshold approaches to analyzing cancer survival studies. We review and compare common performance metrics for the two approaches. We present new randomization tests and cross-validation methods to enable unambiguous statistical inferences for several performance metrics used with the survival time prediction approach. We consider five survival prediction models consisting of one clinical model, two gene expression models, and two models from combinations of clinical and gene expression models. RESULTS: A public breast cancer dataset was used to compare several performance metrics using five prediction models. 1) For some prediction models, the hazard ratio from fitting a Cox proportional hazards model was significant, but the two-group comparison was insignificant, and vice versa. 2) The randomization test and cross-validation were generally consistent with the p-values obtained from the standard performance metrics. 3) Binary classifiers highly depended on how the risk groups were defined; a slight change of the survival threshold for assignment of classes led to very different prediction results. CONCLUSIONS: 1) Different performance metrics for evaluation of a survival prediction model may give different conclusions in its discriminatory ability. 2) Evaluation using a high-risk versus low-risk group comparison depends on the selected risk-score threshold; a plot of p-values from all possible thresholds can show the sensitivity of the threshold selection. 3) A randomization test of the significance of Somers' rank correlation can be used for further evaluation of performance of a prediction model. 4) The cross-validated power of survival prediction models decreases as the training and test sets become less balanced. PMID- 22824263 TI - Live-cell fluorescence microscopy with molecular biosensors: what are we really measuring? AB - Engineered protein biosensors, such as those based on Forster resonance energy transfer, membrane translocation, or solvatochromic shift, are being used in combination with live-cell fluorescence microscopy to reveal kinetics and spatial localization of intracellular processes as they occur. Progress in the application of this approach has been steady, yet its general suitability for quantitative measurements remains unclear. To address the pitfalls of the biosensor approach in quantitative terms, simple reaction-diffusion models were analyzed. The analysis shows that although high-affinity molecular recognition allows robust detection of the fluorescence readout, either of two detrimental effects is fostered. Binding of an intramolecular biosensor or of a relatively abundant intermolecular biosensor introduces observer effects in which the dynamics of the target molecule under study are significantly perturbed, whereas binding of a sparingly expressed intermolecular biosensor is subject to a saturation effect, where the pool of unbound biosensor is significantly depleted. The analysis explores how these effects are manifest in the kinetics and spatial gradients of the biosensor-target complex. A sobering insight emerges: the observer or saturation effect is always significant; the question is whether or not it can be tolerated or accounted for. The challenge in managing the adverse effects is that specification of the biosensor-target affinity to within a certain order of magnitude is required. PMID- 22824264 TI - Computational analysis of the regulation of EGFR by protein tyrosine phosphatases. AB - The tyrosine phosphorylated epidermal growth factor receptor (EGFR) initiates numerous cell signaling pathways. Although EGFR phosphorylation levels are ultimately determined by the balance of receptor kinase and protein tyrosine phosphatase (PTP) activities, the kinetics of EGFR dephosphorylation are not well understood. Previous models of EGFR signaling have generally neglected PTP activity or computed PTP activity by considering data that do not fully reveal the kinetics and compartmentalization of EGFR dephosphorylation. We developed a compartmentalized, mechanistic model to elucidate the kinetics of EGFR dephosphorylation and the coupling of this process to phosphorylation-dependent EGFR endocytosis. Model regression against data from HeLa cells for EGFR phosphorylation response to EGFR activation, PTP inhibition, and EGFR kinase inhibition led to the conclusion that EGFR dephosphorylation occurs at the plasma membrane and in the cell interior with a timescale that is smaller than that for ligand-mediated EGFR endocytosis. The model further predicted that sufficiently rapid dephosphorylation of EGFR at the plasma membrane could potentially impede EGFR endocytosis, consistent with recent experimental findings. Overall, our results suggest that PTPs regulate multiple receptor-level phenomena via their action at the plasma membrane and cell interior and point to new possibilities for targeting PTPs for modulation of EGFR dynamics. PMID- 22824265 TI - Phosphorylation primes vinculin for activation. AB - Vinculin phosphorylation has been implicated as a potential mechanism for focal adhesion growth and maturation. Four vinculin residues-Y100, S1033, S1045, and Y1065-are phosphorylated by kinases during focal adhesion maturation. In this study, phosphorylation at each of these residues is simulated using molecular dynamics models. The simulations demonstrate that once each phosphorylated vinculin structure is at equilibrium, significant local conformational changes result that may impact either vinculin activation or vinculin binding to actin and PIP2. Simulation of vinculin activation after phosphorylation shows that the added phosphoryl groups can prime vinculin for activation. It remains to be seen if vinculin can be phosphorylated at S1033 in vivo, but these simulations highlight that in the event of a S1033 phophorylation vinculin will likely be primed for activation. PMID- 22824266 TI - Lipid sorting by ceramide and the consequences for membrane proteins. AB - We mimicked the effect of sphingomyelinase activity on lipid mixtures of palmitoyl-oleoyl-phosphatidylcholine, sphingomyelin, ceramide, and 10 mol % cholesterol. Using x-ray diffraction experiments in combination with osmotic stress we found, in agreement with previous studies, that ceramide induces a coexistence of L(alpha) and L(beta) domains. A detailed structural analysis of the coexisting domains demonstrated an increase of lipid packing density and membrane thickness in the L(alpha) domains upon increasing overall ceramide levels. This provides evidence for a ceramide-driven accumulation of cholesterol in the L(alpha) domains, in support of previous reports. We further determined the bending rigidities of the coexisting domains and found that the accumulation of cholesterol in the L(alpha) domains stabilizes their bending rigidity, which experiences a dramatic drop in the absence of cholesterol. Deriving experimental estimates for the spontaneous curvature and Gaussian modulus of curvature, we show, using a simple geometric model for ion channels, that in this way changes in the conformational equilibrium of membrane proteins can be kept small. PMID- 22824267 TI - Sodium accumulation in SERCA knockout-induced heart failure. AB - In cardiomyocytes, a major decrease in the level of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) can severely impair systolic and diastolic functions. In mice with cardiomyocyte-specific conditional excision of the Serca2 gene (SERCA2 KO), end-stage heart failure developed between four and seven weeks after gene deletion combined with [Na(+)](i) elevation and intracellular acidosis. In this study, to investigate the underpinning changes in Ca(2+) dynamics and metabolic homeostasis, we developed data-driven mathematical models of Ca(2+) dynamics in the ventricular myocytes of the control, four-week, and seven-week SERCA2 knockout (KO) mice. The seven-week KO model showed that elevated [Na(+)](i) was due to increased Na(+) influxes through the Na(+)/Ca(2+) exchanger (NCX) and the Na(+)/H(+) exchanger, with the latter exacerbated by intracellular acidosis. Furthermore, NCX upregulation in the seven-week KO model resulted in increased ATP consumption for ion transport. Na(+) accumulation in the SERCA KO due to NCX upregulation and intracellular acidosis potentially play a role in the development of heart failure, by initiating a reinforcing cycle involving: a mismatch between ATP demand and supply; an increasingly compromised metabolism; a decreased pH(i); and, finally, an even greater [Na(+)](i) elevation. PMID- 22824268 TI - The molecular mechanism by which PIP(2) opens the intracellular G-loop gate of a Kir3.1 channel. AB - Inwardly rectifying potassium (Kir) channels are characterized by a long pore comprised of continuous transmembrane and cytosolic portions. A high-resolution structure of a Kir3.1 chimera revealed the presence of the cytosolic (G-loop) gate captured in the closed or open conformations. Here, we conducted molecular dynamics simulations of these two channel states in the presence and absence of phosphatidylinositol bisphosphate (PIP(2)), a phospholipid that is known to gate Kir channels. Simulations of the closed state with PIP(2) revealed an intermediate state between the closed and open conformations involving direct transient interactions with PIP(2), as well as a network of transitional inter- and intrasubunit interactions. Key elements in the G-loop gating transition involved a PIP(2)-driven movement of the N-terminus and C-linker that removed constraining intermolecular interactions and led to CD-loop stabilization of the G-loop gate in the open state. To our knowledge, this is the first dynamic molecular view of PIP(2)-induced channel gating that is consistent with existing experimental data. PMID- 22824269 TI - On the mechanism of gating charge movement of ClC-5, a human Cl(-)/H(+) antiporter. AB - ClC-5 is a Cl(-)/H(+) antiporter that functions in endosomes and is important for endocytosis in the proximal tubule. The mechanism of transport coupling and voltage dependence in ClC-5 is unclear. Recently, a transport-deficient ClC-5 mutant (E268A) was shown to exhibit transient capacitive currents. Here, we studied the external and internal Cl(-) and pH dependence of the currents of E268A. Transient currents were almost completely independent of the intracellular pH. Even though the transient currents are modulated by extracellular pH, we could exclude that they are generated by proton-binding/unbinding reactions. In contrast, the charge movement showed a nontrivial dependence on external chloride, strongly supporting a model in which the movement of an intrinsic gating charge is followed by the voltage-dependent low-affinity binding of extracellular chloride ions. Mutation of the external Glu-211 (a residue implicated in the coupling of Cl(-) and proton transport) to aspartate abolished steady-state transport, but revealed transient currents that were shifted by ~150 mV to negative voltages compared to E268A. This identifies Glu(ext) as a major component of the gating charge underlying the transient currents of the electrogenic ClC-5 transporter. The molecular events underlying the transient currents of ClC-5 emerging from these results can be explained by an inward movement of the side chain of Glu(ext), followed by the binding of extracellular Cl(-) ions. PMID- 22824270 TI - Probing tubulin-blocked state of VDAC by varying membrane surface charge. AB - Reversible blockage of the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane by dimeric tubulin is being recognized as a potent regulator of mitochondrial respiration. The tubulin-blocked state of VDAC is impermeant for ATP but only partially closed for small ions. This residual conductance allows studying the nature of the tubulin-blocked state in single channel reconstitution experiments. Here we probe this state by changing lipid bilayer charge from positive to neutral to negative. We find that voltage sensitivity of the tubulin-VDAC blockage practically does not depend on the lipid charge and salt concentration with the effective gating charge staying within the range of 10-14 elementary charges. At physiologically relevant low salt concentrations, the conductance of the tubulin-blocked state is decreased by positive and increased by negative charge of the lipids, whereas the conductance of the open channel is much less sensitive to this parameter. Such a behavior supports the model in which tubulin's negatively charged tail enters the VDAC pore, inverting its anionic selectivity to cationic and increasing proximity of ion pathways to the nearest lipid charges as compared with the open state of the channel. PMID- 22824271 TI - Accumulated bending energy elicits neutral sphingomyelinase activity in human red blood cells. AB - We propose that accumulated membrane bending energy elicits a neutral sphingomyelinase (SMase) activity in human erythrocytes. Membrane bending was achieved by osmotic or chemical processes, and SMase activity was assessed by quantitative thin-layer chromatography, high-performance liquid chromatography, and electrospray ionization-mass spectrometry. The activity induced by hypotonic stress in erythrocyte membranes had the pH dependence, ion dependence, and inhibitor sensitivity of mammalian neutral SMases. The activity caused a decrease in SM contents, with a minimum at 6 min after onset of the hypotonic conditions, and then the SM contents were recovered. We also elicited SMase activity by adding lysophosphatidylcholine externally or by generating it with phospholipase A(2). The same effect was observed upon addition of chlorpromazine or sodium deoxycholate at concentrations below the critical micellar concentration, and even under hypertonic conditions. A unifying factor of the various agents that elicit this SMase activity is the accumulated membrane bending energy. Both hypo and hypertonic conditions impose an increased curvature, whereas the addition of surfactants or phospholipase A(2) activation increases the outer monolayer area, thus leading to an increased bending energy. The fact that this latent SMase activity is tightly coupled to the membrane bending properties suggests that it may be related to the general phenomenon of stress-induced ceramide synthesis and apoptosis. PMID- 22824272 TI - Cholesterol superlattice modulates CA4P release from liposomes and CA4P cytotoxicity on mammary cancer cells. AB - Liposomal drugs are a useful alternative to conventional drugs and hold great promise for targeted delivery in the treatment of many diseases. Most of the liposomal drugs on the market or under clinical trials include cholesterol as a membrane stabilizing agent. Here, we used liposomal CA4P, an antivascular drug, to demonstrate that cholesterol content can actually modulate the release and cytotoxicity of liposomal drugs in a delicate and predictable manner. We found that both the rate of the CA4P release from the interior aqueous compartment of the liposomes to the bulk aqueous phase and the extent of the drug's cytotoxicity undergo a biphasic variation, as large as 50%, with liposomal cholesterol content at the theoretically predicted C(r), e.g., 22.0, 22.2, 25.0, 33.3, 40.0, and 50.0 mol % cholesterol for maximal superlattice formation. It appears that at C(r), CA4P can be released from the liposomes more readily than at non-C(r), probably due to the increased domain boundaries between superlattice and nonsuperlattice regions, which consequently results in increased cytotoxicity. The idea that the increased domain boundaries at C(r) would facilitate the escape of molecules from membranes was further supported by the data of dehydroergosterol transfer from liposomes to MbetaCD. These results together show that the functional importance of sterol superlattice formation in liposomes can be propagated to distal targeted cells and reveal a new, to our knowledge, mechanism for how sterol content and membrane lateral organization can control the release of entrapped or embedded molecules in membranes. PMID- 22824273 TI - Effect of calcium and magnesium on phosphatidylserine membranes: experiments and all-atomic simulations. AB - It is known that phosphatidylserine (PS(-)) lipids have a very similar affinity for Ca(2+) and Mg(2+) cations, as revealed by electrokinetic and stability experiments. However, despite this similar affinity, experimental evidence shows that the presence of Ca(2+) or Mg(2+) induces very different aggregation behavior for PS(-) liposomes as characterized by their fractal dimensions. Also, turbidity measurements confirm substantial differences in aggregation behavior depending on the presence of Ca(2+) or Mg(2+) cations. These puzzling results suggest that although these two cations have a similar affinity for PS(-) lipids, they induce substantial structural differences in lipid bilayers containing each of these cations. In other words, these cations have strong ion-specific effects on the structure of PS(-) membranes. This interpretation is supported by all-atomic molecular-dynamics simulations showing that Ca(2+) and Mg(2+) cations have different binding sites and induce different membrane hydration. We show that although both ions are incorporated deep into the hydrophilic region of the membrane, they have different positions and configurations at the membrane. Absorbed Ca(2+) cations present a peak at a distance ~2 nm from the center of the lipid bilayer, and their most probable binding configuration involves two oxygen atoms from each of the charged moieties of the PS molecule (phosphate and carboxyl groups). In contrast, the distribution of absorbed Mg(2+) cations has two different peaks, located a few angstroms before and after the Ca(2+) peak. The most probable configurations (corresponding to these two peaks) involve binding to two oxygen atoms from carboxyl groups (the most superficial binding peak) or two oxygen atoms from phosphate groups (the most internal peak). Moreover, simulations also show differences in the hydration structure of the membrane: we obtained a hydration of 7.5 and 9 water molecules per lipid in simulations with Ca(2+) and Mg(2+), respectively. PMID- 22824274 TI - Dynamics and size of cross-linking-induced lipid nanodomains in model membranes. AB - Changes of membrane organization upon cross-linking of its components trigger cell signaling response to various exogenous factors. Cross-linking of raft gangliosides GM1 with cholera toxin (CTxB) was shown to cause microscopic phase separation in model membranes, and the CTxB-GM1 complexes forming a minimal lipid raft unit are the subject of ongoing cell membrane research. Yet, those subdiffraction sized rafts have never been described in terms of size and dynamics. By means of two-color z-scan fluorescence correlation spectroscopy, we show that the nanosized domains are formed in model membranes at lower sphingomyelin (Sph) content than needed for the large-scale phase separation and that the CTxB-GM1 complexes are confined in the domains poorly stabilized with Sph. Forster resonance energy transfer together with Monte Carlo modeling of the donor decay response reveal the domain radius of ~8 nm, which increases at higher Sph content. We observed two types of domains behaving differently, which suggests a dual role of the cross-linker: first, local transient condensation of the GM1 molecules compensating for a lack of Sph and second, coalescence of existing nanodomains ending in large-scale phase separation. PMID- 22824275 TI - Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor. AB - The G-protein-coupled receptors (GPCRs) are a ubiquitous family of signaling proteins of exceptional pharmacological importance. The recent publication of structures of several GPCRs cocrystallized with ligands of differing activity offers a unique opportunity to gain insight into their function. To that end, we performed microsecond-timescale simulations of the A(2A) adenosine receptor bound to either of two agonists, adenosine or UK432097. Our data suggest that adenosine is highly dynamic when bound to A(2A), in stark contrast to the case with UK432097. Remarkably, adenosine finds an alternate binding pose in which the ligand is inverted relative to the crystal structure, forming relatively stable interactions with helices I and II. Our observations suggest new experimental tests to validate our predictions and deepen our understanding of GPCR signaling. Overall, our data suggest an intriguing hypothesis: that the 100- to 1000-fold greater efficacy of UK432097 relative to adenosine arises because UK432097 stabilizes a much tighter neighborhood of active conformations, which manifests as a greater likelihood of G-protein activation per unit time. PMID- 22824276 TI - Acyl-chain correlation in membrane fusion intermediates: x-ray diffraction from the rhombohedral lipid phase. AB - We have studied the acyl-chain conformation in stalk phases of model membranes by x-ray diffraction from oriented samples. As an equilibrium lipid phase induced by dehydration, the stalk or rhombohedral phase exhibits lipidic passages (stalks) between adjacent bilayers, representing a presumed intermediate state in membrane fusion. From the detailed analysis of the acyl-chain correlation peak, we deduce the structural parameters of the acyl-chain fluid above, at, and below the transition from the lamellar to rhombohedral state, at the molecular level. PMID- 22824277 TI - Accelerating membrane insertion of peripheral proteins with a novel membrane mimetic model. AB - Characterizing atomic details of membrane binding of peripheral membrane proteins by molecular dynamics (MD) has been significantly hindered by the slow dynamics of membrane reorganization associated with the phenomena. To expedite lateral diffusion of lipid molecules without sacrificing the atomic details of such interactions, we have developed a novel membrane representation, to our knowledge, termed the highly mobile membrane-mimetic (HMMM) model to study binding and insertion of various molecular species into the membrane. The HMMM model takes advantage of an organic solvent layer to represent the hydrophobic core of the membrane and short-tailed phospholipids for the headgroup region. We demonstrate that using these components, bilayer structures are formed spontaneously and rapidly, regardless of the initial position and orientation of the lipids. In the HMMM membrane, lipid molecules exhibit one to two orders of magnitude enhancement in lateral diffusion. At the same time, the membrane atomic density profile of the headgroup region produced by the HMMM model is essentially identical to those obtained for full-membrane models, indicating the faithful representation of the membrane surface by the model. We demonstrate the efficiency of the model in capturing spontaneous binding and insertion of peripheral proteins by using the membrane anchor (gamma-carboxyglutamic-acid-rich domain; GLA domain) of human coagulation factor VII as a test model. Achieving full insertion of the GLA domain consistently in 10 independent unbiased simulations within short simulation times clearly indicates the robustness of the HMMM model in capturing membrane association of peripheral proteins very efficiently and reproducibly. The HMMM model will provide significant improvements to the current all-atom models by accelerating lipid dynamics to examine protein-membrane interactions more efficiently. PMID- 22824278 TI - Impact of methylation on the physical properties of DNA. AB - There is increasing evidence for the presence of an alternative code imprinted in the genome that might contribute to gene expression regulation through an indirect reading mechanism. In mammals, components of this coarse-grained regulatory mechanism include chromatin structure and epigenetic signatures, where d(CpG) nucleotide steps are key players. We report a comprehensive experimental and theoretical study of d(CpG) steps that provides a detailed description of their physical characteristics and the impact of cytosine methylation on these properties. We observed that methylation changes the physical properties of d(CpG) steps, having a dramatic effect on enriched CpG segments, such as CpG islands. We demonstrate that methylation reduces the affinity of DNA to assemble into nucleosomes, and can affect nucleosome positioning around transcription start sites. Overall, our results suggest a mechanism by which the basic physical properties of the DNA fiber can explain parts of the cellular epigenetic regulatory mechanisms. PMID- 22824279 TI - Single-molecule experiments reveal the flexibility of a Per-ARNT-Sim domain and the kinetic partitioning in the unfolding pathway under force. AB - Per-ARNT-Sim (PAS) domains serve as versatile binding motifs in many signal transduction proteins and are able to respond to a wide spectrum of chemical or physical signals. Despite their diverse functions, PAS domains share a conserved structure. It has been suggested that the structure of PAS domains is flexible and thus adaptable to many binding partners. However, direct measurement of the flexibility of PAS domains has not yet been provided. Here, we quantitatively measure the mechanical unfolding of a PAS domain, ARNT PAS-B, using single molecule atomic force microscopy. Our force spectroscopy results indicate that the structure of ARNT PAS-B can be unraveled under mechanical forces as low as ~30 pN due to its broad potential well for the mechanical unfolding transition of ~2 nm. This allows the PAS-B domain to extend by up to 75% of its resting end-to end distance without unfolding. Moreover, we found that the ARNT PAS-B domain unfolds in two distinct pathways via a kinetic partitioning mechanism. Sixty seven percent of ARNT PAS-B unfolds through a simple two-state pathway, whereas the other 33% unfolds with a well-defined intermediate state in which the C terminal beta-hairpin is detached. We propose that the structural flexibility and force-induced partial unfolding of PAS-B domains may provide a unique mechanism for them to recruit diverse binding partners and lower the free-energy barrier for the formation of the binding interface. PMID- 22824280 TI - From static structure to living protein: computational analysis of cytochrome c oxidase main-chain flexibility. AB - Crystallographic structure and deuterium accessibility comparisons of CcO in different redox states have suggested conformational changes of mechanistic significance. To predict the intrinsic flexibility and low energy motions in CcO, this work has analyzed available high-resolution crystallographic structures with ProFlex and elNemo computational methods. The results identify flexible regions and potential conformational changes in CcO that correlate well with published structural and biochemical data and provide mechanistic insights. CcO is predicted to undergo rotational motions on the interior and exterior of the membrane, driven by transmembrane helical tilting and bending, coupled with rocking of the beta-sheet domain. Consequently, the proton K-pathway becomes sufficiently flexible for internal water molecules to alternately occupy upper and lower parts of the pathway, associated with conserved Thr-359 and Lys-362 residues. The D-pathway helices are found to be relatively rigid, with a highly flexible entrance region involving the subunit I C-terminus, potentially regulating the uptake of protons. Constriction and dilation of hydrophobic channels in RsCcO suggest regulation of the oxygen supply to the binuclear center. This analysis points to coupled conformational changes in CcO and their potential to influence both proton and oxygen access. PMID- 22824281 TI - Role of elongation and secondary pathways in S6 amyloid fibril growth. AB - The concerted action of a large number of individual molecular level events in the formation and growth of fibrillar protein structures creates a significant challenge for differentiating between the relative contributions of different self-assembly steps to the overall kinetics of this process. The characterization of the individual steps is, however, an important requirement for achieving a quantitative understanding of this general phenomenon which underlies many crucial functional and pathological pathways in living systems. In this study, we have applied a kinetic modeling approach to interpret experimental data obtained for the aggregation of a selection of site-directed mutants of the protein S6 from Thermus thermophilus. By studying a range of concentrations of both the seed structures, used to initiate the reaction, and of the soluble monomer, which is consumed during the growth reaction, we are able to separate unambiguously secondary pathways from primary nucleation and fibril elongation. In particular, our results show that the characteristic autocatalytic nature of the growth process originates from secondary processes rather than primary nucleation events, and enables us to derive a scaling law which relates the initial seed concentration to the onset of the growth phase. PMID- 22824282 TI - Studies on the dissociation and urea-induced unfolding of FtsZ support the dimer nucleus polymerization mechanism. AB - FtsZ is a major protein in bacterial cytokinesis that polymerizes into single filaments. A dimer has been proposed to be the nucleating species in FtsZ polymerization. To investigate the influence of the self-assembly of FtsZ on its unfolding pathway, we characterized its oligomerization and unfolding thermodynamics. We studied the assembly using size-exclusion chromatography and fluorescence spectroscopy, and the unfolding using circular dichroism and two photon fluorescence correlation spectroscopy. The chromatographic analysis demonstrated the presence of monomers, dimers, and tetramers with populations dependent on protein concentration. Dilution experiments using fluorescent conjugates revealed dimer-to-monomer and tetramer-to-dimer dissociation constants in the micromolar range. Measurements of fluorescence lifetimes and rotational correlation times of the conjugates supported the presence of tetramers at high protein concentrations and monomers at low protein concentrations. The unfolding study demonstrated that the three-state unfolding of FtsZ was due to the mainly dimeric state of the protein, and that the monomer unfolds through a two-state mechanism. The monomer-to-dimer equilibrium characterized here (K(d) = 9 MUM) indicates a significant fraction (~10%) of stable dimers at the critical concentration for polymerization, supporting a role of the dimeric species in the first steps of FtsZ polymerization. PMID- 22824283 TI - Geometry-induced bursting dynamics in gene expression. AB - In prokaryotes and eukaryotes, genes are transcribed stochastically according to various temporal patterns that range from simple first-order kinetics to marked bursts, resulting in temporal and cell-to-cell variations of mRNA and protein levels. Here, we consider the effect of the transport of regulatory molecules on the noise in gene expression by taking into account explicitly the dynamics of a finite number of transcription factors confined in the cell. We calculate analytically time-dependent correlation functions of mRNA levels for a wide range of transport mechanisms and find that in the limit of small-transcription-factor copy number, the results differ significantly from standard approaches, which ignore confinement. It is shown how such dynamical quantities, which can now be obtained experimentally, can be used to identify the underlying mechanisms of transcription. Of particular importance, it is demonstrated that the geometry of transcription-factor trajectories in the cellular environment plays a key role in transcription kinetics, and can intrinsically generate the observed various transcription patterns ranging from simple first-order kinetics to bursts. PMID- 22824284 TI - Self-association of the histidine kinase CheA as studied by pulsed dipolar ESR spectroscopy. AB - Biologically important protein complexes often involve molecular interactions that are low affinity or transient. We apply pulsed dipolar electron spin resonance spectroscopy and site-directed spin labeling in what to our knowledge is a new approach to study aggregation and to identify regions on protein surfaces that participate in weak, but specific molecular interactions. As a test case, we have probed the self-association of the chemotaxis kinase CheA, which forms signaling clusters with chemoreceptors and the coupling protein CheW at the poles of bacterial cells. By measuring the intermolecular dipolar interactions sensed by spin-labels distributed over the protein surface, we show that the soluble CheA kinase aggregates to a small extent through interactions mediated by its regulatory (P5) domain. Direct dipolar distance measurements confirm that a hydrophobic surface at the periphery of P5 subdomain 2 associates CheA dimers in solution. This result is further supported by differential disulfide cross linking from engineered cysteine reporter sites. We suggest that the periphery of P5 is an interaction site on CheA for other similar hydrophobic surfaces and plays an important role in structuring the signaling particle. PMID- 22824285 TI - Reference-free alignment and sorting of single-molecule force spectroscopy data. AB - Single-molecule force spectroscopy has become a versatile tool for investigating the (un)folding of proteins and other polymeric molecules. Like other single molecule techniques, single-molecule force spectroscopy requires recording and analysis of large data sets to extract statistically meaningful conclusions. Here, we present a data analysis tool that provides efficient filtering of heterogeneous data sets, brings spectra into register based on a reference-free alignment algorithm, and determines automatically the location of unfolding barriers. Furthermore, it groups spectra according to the number of unfolding events, subclassifies the spectra using cross correlation-based sorting, and extracts unfolding pathways by principal component analysis and clustering methods to extracted peak positions. Our approach has been tested on a data set obtained through mechanical unfolding of bacteriorhodopsin (bR), which contained a significant number of spectra that did not show the well-known bR fingerprint. In addition, we have tested the performance of the data analysis tool on unfolding data of the soluble multidomain (Ig27)(8) protein. PMID- 22824286 TI - Tracking UNC-45 chaperone-myosin interaction with a titin mechanical reporter. AB - Myosins are molecular motors that convert chemical energy into mechanical work. Allosterically coupling ATP-binding, hydrolysis, and binding/dissociation to actin filaments requires precise and coordinated structural changes that are achieved by the structurally complex myosin motor domain. UNC-45, a member of the UNC-45/Cro1/She4p family of proteins, acts as a chaperone for myosin and is essential for proper folding and assembly of myosin into muscle thick filaments in vivo. The molecular mechanisms by which UNC-45 interacts with myosin to promote proper folding of the myosin head domain are not known. We have devised a novel approach, to our knowledge, to analyze the interaction of UNC-45 with the myosin motor domain at the single molecule level using atomic force microscopy. By chemically coupling a titin I27 polyprotein to the motor domain of myosin, we introduced a mechanical reporter. In addition, the polyprotein provided a specific attachment point and an unambiguous mechanical fingerprint, facilitating our atomic force microscopy measurements. This approach enabled us to study UNC 45-motor domain interactions. After mechanical unfolding, the motor domain interfered with refolding of the otherwise robust I27 modules, presumably by recruiting them into a misfolded state. In the presence of UNC-45, I27 folding was restored. Our single molecule approach enables the study of UNC-45 chaperone interactions with myosin and their consequences for motor domain folding and misfolding in mechanistic detail. PMID- 22824287 TI - Polarization-resolved second-harmonic generation in tendon upon mechanical stretching. AB - Collagen is a triple-helical protein that forms various macromolecular organizations in tissues and is responsible for the biomechanical and physical properties of most organs. Second-harmonic generation (SHG) microscopy is a valuable imaging technique to probe collagen fibrillar organization. In this article, we use a multiscale nonlinear optical formalism to bring theoretical evidence that anisotropy of polarization-resolved SHG mostly reflects the micrometer-scale disorder in the collagen fibril distribution. Our theoretical expectations are confirmed by experimental results in rat-tail tendon. To that end, we report what to our knowledge is the first experimental implementation of polarization-resolved SHG microscopy combined with mechanical assays, to simultaneously monitor the biomechanical response of rat-tail tendon at macroscopic scale and the rearrangement of collagen fibrils in this tissue at microscopic scale. These experiments bring direct evidence that tendon stretching corresponds to straightening and aligning of collagen fibrils within the fascicle. We observe a decrease in the SHG anisotropy parameter when the tendon is stretched in a physiological range, in agreement with our numerical simulations. Moreover, these experiments provide a unique measurement of the nonlinear optical response of aligned fibrils. Our data show an excellent agreement with recently published theoretical calculations of the collagen triple helix hyperpolarizability. PMID- 22824288 TI - On resistance to virus entry into host cells. AB - In this article, we adopt a continuum model from Sun and Wirtz (2006. Biophys. J. 90:L10-L12) to show that, for the enveloped virus entry into host cells, the binding energy of the receptor-ligand complex can drive the engulfment of the viral particle to overcome the resistance alternatively dominated by the membrane deformation and cytoskeleton deformation at a different engulfing stage. This is contrary to the conclusions by Sun and Wirtz that the cytoskeleton deformation is always dominant. This discrepancy occurs because the energy of membrane deformation in their article is incorrect. Such an unfortunate small error has led to a severe underestimation of the contribution from membrane deformation to the total energy of the system, which then led them to improperly conclude that the cytoskeleton deformation plays the dominant role in the virus entry into host cell. By using the correct energy expression, our conclusion is justified by energy comparisons under a large range of virus sizes and Young's moduli of cytoskeleton. We even find that a critical radius of virus exists, beyond which the resistance to the virus engulfment becomes dominated by the membrane deformation during the whole stage, contrary to the point of view of Sun and Wirtz. PMID- 22824289 TI - Current concepts and significance of estrogen receptor beta in prostate cancer. AB - An increasing amount of evidence points at important roles for estrogen receptors in prostate carcinogenesis and progression. Of the two estrogen receptors, estrogen receptor beta is the most prominent within the prostate gland. Although there is much yet to be known, the findings from the discovery of the receptor in 1996 until now point at a role of the receptor in maintaining differentiation and reducing cellular proliferation in the prostate. Moreover, estrogen receptor beta is the main target for phytoestrogens, perhaps at least partially explaining the difference in incidence of prostate cancer in the Western world compared to Asia where the intake of soy-based, phytoestrogen-rich food is higher. The tumor suppressive capability of estrogen receptor beta makes it a promising drug target for the treatment and prevention of prostate cancer. This review will focus on different aspects of estrogen receptor signaling and prostate cancer. PMID- 22824290 TI - Ice-like encapsulated water by two cholic acid moieties. AB - Starting from the structure of ice (in which each water molecule is surrounded by other four water molecules forming a tetrahedron with a value of 4.51A for the edge O-O distance), and the knowledge that this value also corresponds to the O7 O12 distance of the skeleton of cholic acid, it is hypothesized that two steroid cholic acid moieties, with an appropriate steroid-steroid distance and a belly-to belly orientation, could encapsulate a single water molecule between them. To check this hypothesis two succinyl derivatives of cholic acid (a monomer and the related head-head dimer in which the succinyl group is the linking bridge) were designed. The expected "ice-like" structure is found in the crystal of the dimer. There is a hydrogen bond synergy between those participating in the "ice-like" structure, and those in which the bridge is involved with the O7-H hydroxy group and the side chain of the steroid. PMID- 22824291 TI - Design and studies of novel polyoxysterol-based porphyrin conjugates. AB - New types of steroid-porphyrin conjugates derived from 20-hydroxyecdysone (20E) and 24-epibrassinolide (EBl) were synthesized. An exceptional regioselectivity in the reaction of both steroids with porphyrin boronic acids was found to give side chain-conjugated boronic esters as sole products. UV-Vis-, fluorescence and NMR spectroscopy yielded similar data for all the studied compounds confirming the solvent driven supramolecular assembly with formation of J-aggregates. CD measurements of water diluted solutions showed a clear difference between 20E and EBl conjugates. The latter showed a strong supramolecular chirality, whereas 20E J-aggregates did not. PMID- 22824292 TI - Analysis of IgG4 class switch-related molecules in IgG4-related disease. AB - INTRODUCTION: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs. The purpose of this study was to determine the mechanism of upregulation of IgG4 class switch recombination in IgG4-RD. METHODS: We extracted RNA from peripheral blood mononuclear cells (PBMCs) of patients with IgG4-RD (n = 6), Sjogren syndrome (SS) (n = 6), and healthy controls (n = 8), from CD3-positive T cells and CD20-positive B cells sorted from PBMCs of patients with IgG4-RD (n = 3), SS (n = 4), and healthy controls (n = 4), as well as from labial salivary glands (LSGs) of patients with IgG4-RD (n = 11), SS (n = 13), and healthy controls (n = 3). The mRNA expression levels of IgG4-specific class switch-related molecules, such as Th2 cytokines (IL 4 and IL-13), Treg cytokines (IL-10 and TGF-beta), and transcriptional factors (GATA3 and Foxp3) were examined with quantitative polymerase chain reaction (PCR). IgG4-nonspecific class switch-related molecules, such as CD40, CD154, BAFF, APRIL, IRF4, and AID, were also examined. RESULTS: The expression levels of Treg cytokines (IL-10 and TGF-beta) and AID were significantly higher in LSGs of IgG4-RD than in SS and the controls (P < 0.05, each). In contrast, those of CD40 and CD154 were significantly lower in PBMCs of IgG4-RD than in SS (P < 0.05, each), whereas CD40 in CD20-positive B cells and CD154 in CD3-positive T cells were comparable in the three groups. CONCLUSION: Overexpression of IL-10, TGF beta, and AID in LSGs might play important roles in the pathogenesis of IgG4-RD, such as IgG4-specific class-switch recombination and fibrosis. IgG4 class-switch recombination seems to be mainly upregulated in affected organs. PMID- 22824294 TI - The impact of rural hospital closures on equity of commuting time for haemodialysis patients: simulation analysis using the capacity-distance model. AB - BACKGROUND: Frequent and long-term commuting is a requirement for dialysis patients. Accessibility thus affects their quality of lives. In this paper, a new model for accessibility measurement is proposed in which both geographic distance and facility capacity are taken into account. Simulation of closure of rural facilities and that of capacity transfer between urban and rural facilities are conducted to evaluate the impacts of these phenomena on equity of accessibility among dialysis patients. METHODS: Post code information as of August 2011 of all the 7,374 patients certified by municipalities of Hiroshima prefecture as having first or third grade renal disability were collected. Information on post code and the maximum number of outpatients (capacity) of all the 98 dialysis facilities were also collected. Using geographic information systems, patient commuting times were calculated in two models: one that takes into account road distance (distance model), and the other that takes into account both the road distance and facility capacity (capacity-distance model). Simulations of closures of rural and urban facilities were then conducted. RESULTS: The median commuting time among rural patients was more than twice as long as that among urban patients (15 versus 7 minutes, p<0.001). In the capacity-distance model 36.1% of patients commuted to the facilities which were different from the facilities in the distance model, creating a substantial gap of commuting time between the two models. In the simulation, when five rural public facilitiess were closed, Gini coefficient of commuting times among the patients increased by 16%, indicating a substantial worsening of equity, and the number of patients with commuting times longer than 90 minutes increased by 72 times. In contrast, closure of four urban public facilities with similar capacities did not affect these values. CONCLUSIONS: Closures of dialysis facilities in rural areas have a substantially larger impact on equity of commuting times among dialysis patients than closures of urban facilities. The accessibility simulations using the capacity-distance model will provide an analytic framework upon which rational resource distribution policies might be planned. PMID- 22824295 TI - Sleep apnea and heart failure. AB - Sleep apnea is frequently observed in patients with heart failure (HF). In general, sleep apnea consists of two types: obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from upper airway collapse, whereas CSA arises from reductions in central respiratory drive. In patients with OSA, blood pressure is frequently elevated as a result of sympathetic nervous system overactivation. The generation of exaggerated negative intrathoracic pressure during obstructive apneas further increases left ventricular (LV) afterload, reduces cardiac output, and may promote the progression of HF. Intermittent hypoxia and post-apneic reoxygenation cause vascular endothelial damage and possibly atherosclerosis and consequently coronary artery disease and ischemic cardiomyopathy. CSA is also characterized by apnea, hypoxia, and increased sympathetic nervous activity and, when present in HF, is associated with increased risk of death. In patients with HF, abolition of coexisting OSA by continuous positive airway pressure (CPAP) improves LV function and may contribute to the improvement of long-term outcomes. Although treatment options of CSA vary compared with OSA treatment, CPAP and other types of positive airway ventilation improve LV function and may be a promising adjunctive therapy for HF patients with CSA. Since HF remains one of the major causes of mortality in the industrialized countries, the significance of identifying and managing sleep apnea should be more emphasized to prevent the development or progression of HF. PMID- 22824293 TI - Antitumor activity of phenethyl isothiocyanate in HER2-positive breast cancer models. AB - BACKGROUND: HER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells. METHODS: MDA-MB-231 and MCF-7 breast cancer cells stably transfected with HER2 (high HER2 (HH)) were used in this study. The effect of PEITC was evaluated using cytotoxicity and apoptosis assay in these syngeneic cells. Western blotting was used to delineate HER2 signaling. SCID/NOD mice were implanted with MDA-MB-231 (HH) xenografts. RESULTS: Our results show that treatment of MDA-MB-231 and MCF-7 cells with varying concentrations of PEITC for 24 h extensively reduced the survival of the cells with a 50% inhibitory concentration (IC50) of 8 MUM in MDA MB-231 and 14 MUM in MCF-7 cells. PEITC treatment substantially decreased the expression of HER2, epidermal growth factor receptor (EGFR) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr-705. The expression of BCL-2-associated * (BAX) and BIM proteins were increased, whereas the levels of B cell lymphoma-extra large (BCL-XL) and X-linked inhibitor of apoptosis protein (XIAP) were significantly decreased in both the cell lines in response to PEITC treatment. Substantial cleavage of caspase 3 and poly-ADP ribose polymerase (PARP) were associated with PEITC-mediated apoptosis in MDA-MB 231 and MCF-7 cells. Notably, transient silencing of HER2 decreased and overexpressing HER2 increased the effects of PEITC. Furthermore, reactive oxygen species (ROS) generation, mitochondrial depolarization and apoptosis by PEITC treatment were much higher in breast cancer cells expressing higher levels of HER2 (HH) as compared to parent cell lines. The IC50 of PEITC following 24 h of treatment was reduced remarkably to 5 MUM in MDA-MB-231 (HH) and 4 MUM in MCF-7 (HH) cells, stably overexpressing HER2. Oral administration of 12 MUM PEITC significantly suppressed the growth of breast tumor xenografts in SCID/NOD mice. In agreement with our in vitro results, tumors from PEITC-treated mice demonstrated reduced HER2, EGFR and STAT3 expression and increased apoptosis as revealed by cleavage of caspase 3 and PARP. In addition our results show that PEITC can enhance the efficacy of doxorubicin. CONCLUSIONS: Our results show a unique specificity of PEITC in inducing apoptosis in HER2-expressing tumor cells in vitro and in vivo and enhancing the effects of doxorubicin. This unique specificity of PEITC offers promise to a subset of breast cancer patients overexpressing HER2. PMID- 22824296 TI - The risk of obesity by assessing infant growth against the UK-WHO charts compared to the UK90 reference: findings from the Born in Bradford birth cohort study. AB - BACKGROUND: The new growth charts in the UK, the UK-WHO charts, comprise prescriptive data from the WHO standard between two weeks and four years of age. Little is known about the development of obesity risk in normal UK infants, who are necessarily not fed according to the WHO recommendations and do not live in constraint-free environments (the selection criteria of the WHO standard source sample), using the new charts. Here, we investigated infant growth trajectories and traits indicative of childhood obesity using the UK-WHO charts, with the aim to clearly document the implications of adopting the new charts on UK growth monitoring practice. METHODS: Mixed effects models were applied to serial weight and length data from 2181 infants (1187 White; 994 Pakistani) in the Born in Bradford birth cohort study to produce curves from 10 days to 15 months of age. Individual monthly estimates were converted to Z-scores and were plotted by sex and ethnic group. The relative risks (RR) of traits indicative of childhood obesity, including high BMI and rapid weight gain, using the UK-WHO charts compared to the previously used UK90 reference were calculated for all infants together and for White and Pakistani infants separately. RESULTS: Both ethnic groups demonstrated patterns of growth similar to the UK-WHO charts in length but not in weight. The resulting pattern for BMI was remarkable, with an average gain of 1.0 Z-score between two and 12 months of age. The UK-WHO charts were significantly (p < 0.05) more likely than the UK90 reference to classify BMI above the 91st centile after age six months (RR 1.427-2.151) and weight and BMI gain between birth (one month for BMI) and 12 months of age greater than two centile bands (RR 1.214 and 1.470, respectively). CONCLUSIONS: The change to the UK-WHO charts means that normal UK infants risk being diagnosed as being on a trajectory toward childhood obesity. National estimates of obesity will have to be recalculated for previous years to allow longitudinal comparison. The new charts do not allow a focused prevention effort for targeting programmes at infants most at risk of becoming obese, because the use of the 91st or 98th centile on the UK-WHO charts will identify many more infants as being at risk than the same centiles on the UK90 reference. Now more than ever, research is needed to develop a large scale childhood obesity prevention programme which could ideally be integrated with routine infant growth monitoring practice. PMID- 22824297 TI - Alcohol and energy drinks: a pilot study exploring patterns of consumption, social contexts, benefits and harms. AB - BACKGROUND: Young people around the world are increasingly combining alcohol with energy drinks (AEDs). However, as yet, limited research has been conducted examining this issue, particularly in terms of exploring patterns of consumption, social practices and the cultural contexts of AED consumption. We sought to understand how AEDs are used and socially constructed among young people. METHODS: We conducted 25 hours of observation in a variety of pubs, bars and nightclubs, as well as in-depth interviews with ten young people who regularly consumed AEDs during a session of alcohol use. RESULTS: In this pilot study, participants were highly organised in their AED consumption practices and reported rarely altering this routine. Some young people consumed upwards of eight AEDs on a typical night, and others limited their use to between three and five AEDs to avoid unpleasant consequences, such as sleep disturbances, severe hangovers, heart palpitations and agitation. Wakefulness and increased energy were identified as the primary benefits of AEDs, with taste, reduced and increased intoxication, and sociability reported as additional benefits. Young AED users were brand sensitive and responded strongly to Red Bull imagery, as well as discounted AEDs. Finally, some young people reported substituting illicit stimulants with energy drinks. CONCLUSIONS: Combining energy drinks with alcohol is now a normalised phenomenon and an integral and ingrained feature of the night time economy. Despite this, many young people are unaware of recommended daily limits or related harms. While some young people consume AEDs to feel less drunk (consistent with motivations for combining alcohol with illicit stimulants), others report using AEDs to facilitate intoxication. While preliminary, our findings have relevance for potential policy and regulatory approaches, as well as directions for future research. PMID- 22824299 TI - Membrane structure and interactions of peptide hormones with model lipid bilayers. AB - In this work, the behavior of the neurohypophyseal hormones and their selected analogs was studied in the presence of membrane models in an attempt to correlate their activities with a distinct behavior at a level of peptide-lipid interactions. The influence of the peptides studied on the lipid acyl chain order was determined using FTIR spectroscopy. Conformational changes in the peptides upon binding to liposomes were examined using CD spectra. Attempts were also made to determine the binding parameters of the peptides to lipids using isothermal titration calorimetry (ITC). The results show unambiguously that the neurohyphophyseal hormone-like peptides interact with lipids, being a model of a eukaryotic cell membrane. Moreover, hydrophobic interactions between the peptides and liposomes are likely to determine the overall conformation of the peptide, especially below the temperature of the main phase transition (T(m)). Thus, the bulky and hydrophobic nature of the residues incorporated into the N-terminal part of neurohyphophyseal hormones is an important factor for both restriction of peptide mobility and the interaction of the analog with biomembrane. In turn, above T(m), the electrostatic interactions become also relevant for the conformation of the acyclic tail of the AVP-like peptides. PMID- 22824298 TI - Cation selectivity is a conserved feature in the OccD subfamily of Pseudomonas aeruginosa. AB - To achieve the uptake of small, water-soluble nutrients, Pseudomonas aeruginosa, a pathogenic Gram-negative bacterium, employs substrate-specific channels located within its outer membrane. In this paper, we present a detailed description of the single-channel characteristics of six members of the outer membrane carboxylate channel D (OccD) subfamily. Recent structural studies showed that the OccD proteins share common features, such as a closely related, monomeric, 18 stranded beta-barrel conformation and large extracellular loops, which are folded back into the channel lumen. Here, we report that the OccD proteins displayed single-channel activity with a unitary conductance covering an unusually broad range, between 20 and 670pS, as well as a diverse gating dynamics. Interestingly, we found that cation selectivity is a conserved trait among all members of the OccD subfamily, bringing a new distinction between the members of the OccD subfamily and the anion-selective OccK channels. Conserved cation selectivity of the OccD channels is in accord with an increased specificity and selectivity of these proteins for positively charged, carboxylate-containing substrates. PMID- 22824300 TI - Mitochondrial dynamics is affected by 17beta-estradiol in the MCF-7 breast cancer cell line. Effects on fusion and fission related genes. AB - Mitochondrial dynamics, specifically fusion and fission processes, maintain mitochondria integrity and function, yet at this time, effect of estrogens on fusion and fission in breast cancer cell lines has not been studied. The aim of this study was to characterize the effect of 17beta-estradiol on fusion and fission-related genes, as well as on mitochondria proliferation and function. We used MCF-7 breast cancer cell line, which is estrogen sensitive (estrogen receptor positive). Cells were grown in Dulbecco's modified Eagle medium charcoal stripped fetal bovine serum and treated with 1nM of 17beta-estradiol and with/without 100nM of ICI 182,780, a drug that caused rapid degradation of estrogen receptor. mRNA levels of fusion (mfn1, mfn2, opa1) and fission-related genes (drp1 and fis1) were examined by RT-PCR, cardiolipin content by N-acridyl orange fluorescence and oxidative phosphorylation protein levels, as well as, the major fusion and fission related protein levels, by Western blot. mRNA expression of fusion-related genes increased after 17beta-estradiol-treatment for 4h; however fis1 fission-related gene expression decreased. All these effects were not found in cells pre-treated with ICI 182,780, save for the changes in mfn-1, conferring them the effects of 17beta-estradiol to estrogen receptor. The changes in protein levels were less prominent, but in the same way, than in mRNA levels, showing an increase in Mfn1 and Mfn2, as well as in Drp1, but there was no change in Fis1 protein levels. Mitochondrial biogenesis was also affected by 17beta estradiol, showing an increase in mtDNA but with no change in N-acridyl-orange fluorescence. On the whole, our results suggest an imbalance in the fusion/fission ratio, with a high fusion by 17beta-estradiol-estrogen receptor action, which can affect to mitochondrial biogenesis, concretely in mitochondria proliferation. According to this information, 17beta-estradiol would modify mitochondrial dynamics, biogenesis and metabolism, and thus compromise the normal development and function of mitochondria in cancer affected tissues. PMID- 22824302 TI - Postural control strategy during standing is altered in patients with multiple sclerosis. AB - Disturbances in balance are one of the first reported symptoms of Multiple Sclerosis (MS), yet limited research has been performed to classify the postural control deficits in this population. This study investigated the variability present in the sway patterns during quiet standing in patients with MS (PwMS) and healthy controls. Subjects were assessed (eyes open, closed) standing on a force platform. Variability of the sway patterns was quantified using a measure of amount of variability (root mean square; RMS) and two measures of temporal structure of variability (Lyapunov Exponent - LyE; Approximate Entropy - ApEn). RMS results revealed significantly higher amount of variability in the sway patterns of PwMS. PwMS also exhibit increased regularity (decreased ApEn) and decreased divergence (decreased LyE) during standing compared to healthy controls. Removing vision resulted in significantly decreased divergence (decreased LyE) in the MS subject group. These changes in the temporal structure correspond well with the theoretical model of the optimal movement variability hypothesis and the results support using variability measures to understand the mechanisms that underline postural control in PwMS and possibly other neurodegenerative disease pathologies. PMID- 22824301 TI - RecQL4 cytoplasmic localization: implications in mitochondrial DNA oxidative damage repair. AB - RecQL4, one of the five human RecQ helicases, is crucial for genomic stability and RecQL4 when mutated leads to premature aging phenotypes in humans. Unlike other human RecQ helicases, RecQL4 is found both in the nucleus and the cytoplasm. While the nuclear localization signal (NLS) and the retention domain at the N-terminus are responsible for the nuclear localization of RecQL4, the signal for its cytoplasmic localization is essentially unknown. In this study, two functional nuclear exporting signals (NESs; pNES2 and pNES3) were identified at the C-terminus of RecQL4. Deletion of pNES2 drastically diminished the cytoplasmic localization of RecQL4. Strikingly, addition of ubiquitination tail at the C-terminus of RecQL4 substantially enriched the cytoplasmic fraction of RecQL4 only in the presence of functional pNES2. Immunofluorescence studies revealed that the cytoplasmic RecQL4 was localized in mitochondria. Consistent with its mitochondrial localization, a regulatory role for RecQL4 in the maintenance of mitochondrial DNA (mtDNA) copy number was demonstrated. Elevation of ectopic expression of RecQL4 increased the mtDNA copy number in HEK293 cells while RecQL4 knock down markedly decreased the mtDNA copy number in U2OS cells. Additionally, a substantially increased level of mitochondrial superoxide production, and a markedly decreased repair capacity for oxidative DNA damage were observed in the mitochondria of both RecQL4 deficient human fibroblasts and RecQL4-suppressed cancer cells. These data strongly suggest a regulatory role for RecQL4 in mitochondrial stability and function. Collectively, our study demonstrates that NES-mediated RecQL4 export to the cytoplasm is essential for the maintenance of mitochondrial genome stability. PMID- 22824303 TI - Effect of isoflurane on brain tissue oxygen tension and cerebral autoregulation in rabbits. AB - Oxygen tension (PO(2)) was measured in rabbit whisker barrel cortex using oxygen sensitive electrodes to investigate the impact of isoflurane anesthesia on oxygen autoregulation. Responses to 90s episodes of 100% oxygen inspiration were obtained from rabbits before anesthesia, and then when the animals were anesthetized with 0.5% or 1.5% isoflurane. For each episode, DeltaPO(2) (i.e., hyperoxic PO(2) minus baseline PO(2)) was computed. Compared to the conscious state, brain DeltaPO(2) increased during anesthesia with 1.5% isoflurane (0.73 MAC) by an average of 116%, whereas 0.5% isoflurane produced an insignificant average increase of 31%. The results suggest that moderate levels of isoflurane impaired autoregulation of brain tissue oxygen tension. PMID- 22824304 TI - Partial change in EphA4 knockout mouse phenotype: loss of diminished GFAP upregulation following spinal cord injury. AB - In a previous study we found that the EphA4 receptor inhibits regeneration following spinal cord injury by blocking regrowth of axons and regulation of astrocyte reactivity. In our original studies using EphA4 null mice [Goldshmit et al., J. Neurosci., 2004] we found attenuated astrocyte reactivity following spinal cord injury. Several other studies have now supported the role of EphA4 in regulating neural regeneration but a recent study [Herrmann et al., Exp. Neurol., 2010] did not find an effect of EphA4 on astrocyte reactivity. Re-examination of astrocytic gliosis following injury in our current cohort of EphA4 null mice revealed that they no longer showed attenuation of astrocyte reactivity, however other EphA4 null mouse phenotypes, such as decreased size of the dorsal funiculus were unaltered. We hypothesised that long-term breeding on the C57Bl/6 background may influence the EphA4-mediated astrocyte phenotype and compared astrocytic gliosis at 4 days following spinal cord injury in wildtype and EphA4 null mice on the C57Bl/6 background and backcrossed C57Bl/6*129Sv(F2) mice, as well as wildtype 129Sv mice. 129Sv mice had increased GFAP expression and increased numbers of reactive GFAP astrocytes compared to C57Bl/6 mice. There was no significant effect of EphA4 deletion on GFAP expression in C57Bl/6 mice or the F2 crosses other than a moderately decreased number of EphA4 null astrocytes in C57Bl/6 mice using one of two antibodies. Therefore, there has been an apparent change in EphA4-mediated astroglial phenotype associated with long term breeding of the EphA4 colony but it does not appear to be influenced by background mouse strain. PMID- 22824305 TI - Long-term nerve excitability changes by persistent Na+ current blocker ranolazine. AB - The persistent Na(+) current (Na(p)) in peripheral axons plays an important functional role in controlling the axonal excitability. Abnormal Na(p) is believed to contribute to neurodegeneration and neuropathic pain, and thus it is an attractive therapeutic target. To assess the chronic behavior of selective Na(p) blockade, axonal excitability testing was performed in vivo in normal male mice exposed to ranolazine by recording the tail sensory nerve action potentials (SNAPs). Seven days after administering ranolazine i.p. (50mg/kg) daily for 1 week, nerve excitability testing showed decreased strength-duration time constant in the ranolazine group in comparison to the control (P<0.03). This change is explained by the long-term effects of ranolazine on Na(p). Importantly, ranolazine showed no effect on other ion channels that influence axonal excitability. Further study is needed to assess the chronic Na(p) blockade as a useful therapy in peripheral nerve diseases associated with abnormal nerve excitability. PMID- 22824306 TI - Whole plant based treatment of hypercholesterolemia with Crataegus laevigata in a zebrafish model. AB - BACKGROUND: Consumers are increasingly turning to plant-based complementary and alternative medicines to treat hypercholesterolemia. Many of these treatments are untested and their efficacy is unknown. This multitude of potential remedies necessitates a model system amenable to testing large numbers of organisms that maintains similarity to humans in both mode of drug administration and overall physiology. Here we develop the larval zebrafish (4-30 days post fertilization) as a vertebrate model of dietary plant-based treatment of hypercholesterolemia and test the effects of Crataegus laevigata in this model. METHODS: Larval zebrafish were fed high cholesterol diets infused with fluorescent sterols and phytomedicines. Plants were ground with mortar and pestle into a fine powder before addition to food. Fluorescent sterols were utilized to optically quantify relative difference in intravascular cholesterol levels between groups of fish. We utilized the Zeiss 7-Live Duo high-speed confocal platform in order to both quantify intravascular sterol fluorescence and to capture video of the heart beat for determination of cardiac output. RESULTS: In this investigation we developed and utilized a larval zebrafish model to investigate dietary plant-based intervention of the pathophysiology of hypercholesterolemia. We found BODIPY cholesterol effectively labels diet-introduced intravascular cholesterol levels (P < 0.05, Student's t-test). We also established that zebrafish cardiac output declines as cholesterol dose increases (difference between 0.1% and 8% (w/w) high cholesterol diet-treated cardiac output significant at P < 0.05, 1-way ANOVA). Using this model, we found hawthorn leaves and flowers significantly reduce intravascular cholesterol levels (P < 0.05, 1-way ANOVA) and interact with cholesterol to impact cardiac output in hypercholesterolemic fish (2-way ANOVA, P < 0.05 for interaction effect). CONCLUSIONS: The results of this study demonstrate that the larval zebrafish has the potential to become a powerful model to test plant based dietary intervention of hypercholesterolemia. Using this model we have shown that hawthorn leaves and flowers have the potential to affect cardiac output as well as intravascular cholesterol levels. Further, our observation that hawthorn leaves and flowers interact with cholesterol to impact cardiac output indicates that the physiological effects of hawthorn may depend on diet. PMID- 22824307 TI - The treatable intellectual disability APP www.treatable-id.org: a digital tool to enhance diagnosis & care for rare diseases. AB - BACKGROUND: Intellectual disability (ID) is a devastating and frequent condition, affecting 2-3% of the population worldwide. Early recognition of treatable underlying conditions drastically improves health outcomes and decreases burdens to patients, families and society. Our systematic literature review identified 81 such inborn errors of metabolism, which present with ID as a prominent feature and are amenable to causal therapy. The WebAPP translates this knowledge of rare diseases into a diagnostic tool and information portal. METHODS & RESULTS: Freely available as a WebAPP via http://www.treatable-id.org and end 2012 via the APP store, this diagnostic tool is designed for all specialists evaluating children with global delay / ID and laboratory scientists. Information on the 81 diseases is presented in different ways with search functions: 15 biochemical categories, neurologic and non-neurologic signs & symptoms, diagnostic investigations (metabolic screening tests in blood and urine identify 65% of all IEM), therapies & effects on primary (IQ/developmental quotient) and secondary outcomes, and available evidence For each rare condition a 'disease page' serves as an information portal with online access to specific genetics, biochemistry, phenotype, diagnostic tests and therapeutic options. As new knowledge and evidence is gained from expert input and PubMed searches this tool will be continually updated. The WebAPP is an integral part of a protocol prioritizing treatability in the work-up of every child with global delay / ID. A 3-year funded study will enable an evaluation of its effectiveness. CONCLUSIONS: For rare diseases, a field for which financial and scientific resources are particularly scarce, knowledge translation challenges are abundant. With this WebAPP technology is capitalized to raise awareness for rare treatable diseases and their common presenting clinical feature of ID, with the potential to improve health outcomes. This innovative digital tool is designed to motivate health care providers to search actively for treatable causes of ID, and support an evidence based approach to rare metabolic diseases. In our current -omics world with continuous information flow, the effective synthesis of data into accessible, clinical knowledge has become ever more essential to bridge the gap between research and care. PMID- 22824308 TI - Short-term memory, executive control, and children's route learning. AB - The aim of this study was to investigate route-learning ability in 67 children aged 5 to 11years and to relate route-learning performance to the components of Baddeley's model of working memory. Children carried out tasks that included measures of verbal and visuospatial short-term memory and executive control and also measures of verbal and visuospatial long-term memory; the route-learning task was conducted using a maze in a virtual environment. In contrast to previous research, correlations were found between both visuospatial and verbal memory tasks-the Corsi task, short-term pattern span, digit span, and visuospatial long term memory-and route-learning performance. However, further analyses indicated that these relationships were mediated by executive control demands that were common to the tasks, with long-term memory explaining additional unique variance in route learning. PMID- 22824309 TI - Deglycosylation effect of the mammalian sperm maturation antigen (SMA2) on serological reaction and acrosome reaction. AB - Spermatozoal membrane proteins are considered to possess several immunological unique characteristics as the cell is formed behind the blood-testes barriers. Major goat sperm maturation antigen (SMA2) contains one hexosamine along with mannose, galactose and glucose. In the present study, effects of deglycosylation of SMA2 antigen on immuno-reactivity and the serological activity was investigated. SMA2 glycoantigen showed positive immunoreactivity after treatment with sodium borohydride (NaBH(4)) and moreover this generated a 44 kDa protein band which was negative for periodic acid Schiff reagent. Trifluoromethanesulfonic acid (TFMS) caused aggregation and restricted the free mobility of the treated antigen on SDS-PAGE and the protein band generated by TFMS treatment also showed positive immuno-reactivity. The results supported the views that the protein portion retains its immuno-reactivity even after oxidation of the vicinal hydroxyl group of saccharide component of SMA2 antigen. These data suggest that immunodominent epitopes exist on the core protein by which the SMA2 antigen retains its immuno-reactivity even after disruption of the saccharide portion. Additional experiments demonstrate that protein epitopes have a role in capacitation and the acrosome reaction (AR) in presence of antibody which is raised against this protein part of SMA2 using the negative staining of FITC-PSA (fluorescein isothiocyanate-labeled Pisum sativum agglutinin) probe. Altogether these findings indicate that the protein portion of SMA2 might fulfill the serological activity of the antigen as well as the protein epitope affects the acrosome reaction. In view of this property, we propose that the protein portion of SMA2 antigen might be considered as a potential antigenic target for an immune response. PMID- 22824310 TI - Minimally-invasive catheter drainage of submandibular abscesses. PMID- 22824311 TI - Translating the PLAYgrounds program into practice: a process evaluation using the RE-AIM framework. AB - OBJECTIVES: To present the results of the process evaluation of the PLAYgrounds program, using the RE-AIM framework. DESIGN: This study provides information regarding Reach, Adoption, Implementation and Maintenance. METHODS: The PLAYgrounds program promotes increasing levels of physical activity in 6-12 years old children and was evaluated using the RE-AIM framework in 4 intervention schools. Data collection consisted of a physical activity questionnaire with children (n=765, Reach), SOPLAY observations (Implementation and Maintenance), questionnaires on the satisfaction of the implemented elements with teachers (n=59) and children (n=730, Implementation) and interviews for increased depth of information. In addition a simple counting of participating schools, describing of non-participating reasons and characteristics of the schools were documented (Adoption). RESULTS: Reach of the target population (i.e. inactive children) was 60.7% (n=464) and the target population was representative for populations in low SES neighbourhoods. The PLAYgrounds program was adopted by 4 schools (80%), at which 5 (from 7) program elements were successfully implemented. At 18 months follow-up, 3 of those 5 elements were completely maintained. CONCLUSIONS: Adoption, Implementation, and Maintenance proved to be very high. Most likely due to the PLAYgrounds program being a complete intervention package that included financial, material, and staff support. Therefore, it is recommended to retain this high level of support when introducing the PLAYgrounds (or any other intervention) program in schools. In the future it would be recommended to evaluate the PLAYgrounds program on maintenance in schools where the key-person is employed at the school and funding is not available. PMID- 22824312 TI - Physical fitness predicts adiposity longitudinal changes over childhood and adolescence. AB - OBJECTIVES: The purpose of this study was to examine the influence of physical fitness (PF) on the development of subcutaneous adipose tissue in children followed longitudinally over a 9 year period ranging from childhood to adolescence. DESIGN: This longitudinal study followed 518 healthy participants (262 boys, 256 girls) over a 9-year period ranging from childhood (age 6) to adolescence (age 15). Adiposity (triceps and subscapular skinfolds), and fitness (60s sit-ups, flexed arm hang, standing long jump, 50m dash, 10m shuttle run, sit and-reach, and 20m pacer run) were assessed at four annual time points during primary school, and on a follow up, 6 years later, during secondary school. METHODS: Growth in subcutaneous fat was modeled within a HLM statistical framework, using fitness components as time changing predictors. RESULTS: Flexed arm hang (beta=-0.059; p=0.000), standing long jump (beta=-0.072; p=0.000), 60s sit-ups (beta=-0.041; p=0.040), 50m dash (beta=0.956; p=0.000), and 20m PACER (beta=-0.077; p=0.000) tests, were found to predict changes on body fat growth over the years, independently of sex. CONCLUSIONS: Improving PF individual levels can positively influence adiposity deposition over the time period covering childhood and adolescence. That occurs independently of the typical sex differentiated adiposity growth. PMID- 22824313 TI - Re-examination of the post half-time reduction in soccer work-rate. AB - OBJECTIVES: To re-examine the work-rate of soccer players immediately after a passive half-time interval with an alternative approach to data reduction and statistical contrasts. DESIGN: Time-motion analysis data (5Hz global positioning system), were collected from 20 elite youth players (age: 17+/-1 years) during 21 competitive league fixtures (5+/-3 matches per player). METHODS: Physical performances were categorised into total distance covered, total low-speed running (0-14.9kmh(-1)) and total high-speed running (15.0-35.0kmh(-1)). These dependent variables were subsequently time averaged into pre-determined periods of 5-, 15- and 45-min duration, and expressed in relative (mmin(-1)) terms to allow direct comparisons between match periods of different lengths. During the 15-min half-time interval players were passive (seated rest). RESULTS: There was a large reduction in relative total distance covered (effect size - standardised mean difference - 1.85), low-speed running (effect size -1.74) and high-speed running (effect size -1.37) during the opening 5-min phase of the second half (46 50min) when compared to the first half mean (0-45min). When comparing the 51-55 and 56-60-min periods, effect sizes were trivial for relative total distance covered (effect size -0.13; -0.04), low-speed running (effect size -0.10; -0.11) and small/trivial for high-speed running (-0.39; 0.11). CONCLUSIONS: Using a more robust analytical approach, the findings of this study support and extend previous research demonstrating that players work-rate was markedly lower in the first 5-min after a passive half-time interval, although we observed this phenomenon to be transient in nature. Time-motion analysts might re-consider their data reduction methods and comparators to distinguish within-match player work-rate trends. PMID- 22824314 TI - Do not jump too quickly to conclusions. AB - A great deal of misinformation has been promulgated about mammography screening. For example, there is no biological or scientific support for the use of the age of 50 years as a threshold for screening. Mammography screening can reduce deaths from breast cancer even if the rate of advanced cancers is not decreased. The suggestion that screening results in massive amounts of overdiagnosis is based upon faulty methodology. The results reported in the recent study by Nederend and colleagues may be due to the screening interval and thresholds used for intervention. What is clear, however, is that they do not show that screening is ineffective. PMID- 22824318 TI - Dorsomedial fracture dislocation of the first ray and medial cuneiform: a case report. AB - Isolated dislocation of the medial cuneiform is a rare injury. A favorable outcome relies on an accurate and stable reduction. Evidence of residual instability can be subtle. We present 1 such injury whose true extent was not fully appreciated at presentation, despite multiple plain films. Occult fracture of the medial cuneiform contributed to residual instability of the first ray and persistent and progressive symptoms and ultimately necessitated operative stabilization of the medial arch. We recommend the use of computed tomography as an adjunct to plain radiography for all midfoot dislocations to more accurately define the extent of the injury. PMID- 22824319 TI - A prospective series of patients with chronic Achilles tendinopathy treated with autologous-conditioned plasma injections combined with exercise and therapeutic ultrasonography. AB - Chronic Achilles tendinopathy is a difficult problem to manage, because it can result in significant patient morbidity. We conducted a prospective case series involving 26 patients (2 bilateral cases) with painful and ultrasound-confirmed Achilles tendinopathy for a minimum duration of 6 months. Our objective was to assess whether this condition can be effectively treated with a treatment protocol combining an intratendinous autologous-conditioned plasma injection followed by a standardized rehabilitation protocol. The rehabilitation protocol consisted of full weightbearing in a pneumatic cast boot for 6 weeks, therapeutic ultrasound treatment, and an eccentric exercise program. Our results showed statistically significant improvements in terms of pain (p < .0001), other symptoms (p = .0003), activities of daily living (p = .0002), sports activities (p = .0001), and quality of life (p = .0002). We believe that the use of autologous-conditioned plasma can provide a potential treatment solution for chronic Achilles tendinopathy. PMID- 22824320 TI - Modulation of the neurotensin solution structure in the presence of ganglioside GM1 bicelle. AB - Neurotensin (NT) is an endogenous tridecapeptide neurotransmitter that shows multiple biological function in central and peripheral nervous systems. Gangliosides are glycosphingolipids, most abundant in the plasma membrane of nerve cells. Here we investigate the change of neurotensin solution structure induced by isotropic CHAPS-PC bicelles with and without ganglioside GM1 using solution state NMR spectroscopy. In aqueous solution the peptide is predominately unstructured. In the presence of bicelle overall structure of the peptide is stabilized. In CHAPS-PC bicelle neurotensin adopts 3(10) helical structure. In the presence of GM1 containing bicelle, the peptide adopts predominately 3(10) helical structures with small amount of alpha-helical structure. These results are consistent with the CD spectroscopic results. Neurotensin interacts better with GM1 containing bicelle than that of the CHAPS-PC bicelle. Docking studies between the Neurotensin Receptor3 (NTS3) and different NT conformations also indicated better binding of the NT conformation obtained in presence of GM1 containing bicelles. PMID- 22824321 TI - First successful curative use of digoxin-specific Fab antibody fragments in a life-threatening coconut crab (Birgus latro L.) poisoning. AB - We wish to report the first curative use of digoxin-specific Fab antibody fragments in a coconut crab Birgus latro L. poisoning in New Caledonia. The female patient, aged sixty-three with a previous history of cardiovascular and metabolic dysfunctions, showed marked first-degree atrio-ventricular block and several atrial pauses, and was given 760 mg of digoxin-specific Fab antibody fragments. Shortly after the perfusion her electrocardiogram returned to close to normal with only slight first-degree atrio-ventricular block and no more atrial pauses. Neriifolin LC-MS/MS tests performed on the patient's serum and urine samples confirmed cardenolide poisoning. Another, younger patient, with high neriifolin levels in her serum and urine samples only experienced gastro intestinal symptoms and was discharged without specific treatment. The consumption of coconut crab in New Caledonia should be avoided even though the first of the two cases reported suggests that digoxin-specific Fab antibody fragments can be effective in the treatment of life-threatening poisoning caused by the ingestion of this crustacean. PMID- 22824322 TI - What does a modified-Fibonacci dose-escalation actually correspond to? AB - BACKGROUND: In most phase I oncology trials, it is often stated that the dose increments follow a "modified-Fibonacci sequence". This term, however, is vague. METHODS: To better characterize this sequence, we reviewed 81 phase I trials based on this concept. RESULTS: Out of 198 phase I oncology trials, 81 (41%) are based on modified-Fibonacci series. Actual incremental ratios varied in a large range from 0.80 to 2.08. The median of actual increments was about 2.00, 1.50, 1.33, 1.33, 1.33, 1.33, 1.30, 1.35.... The "modified Fibonacci-sequence" gathers heterogeneous variation of the genuine sequence, which does not tend to a constant number at higher dose-levels. CONCLUSION: This confusing term should be avoided. PMID- 22824323 TI - Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. AB - BACKGROUND: Emerging evidence indicates that reactive microglia-initiated inflammatory responses are responsible for secondary damage after primary traumatic spinal cord injury (SCI); epidermal growth factor receptor (EGFR) signaling may be involved in cell activation. In this report, we investigate the influence of EGFR signaling inhibition on microglia activation, proinflammatory cytokine production, and the neuronal microenvironment after SCI. METHODS: Lipopolysaccharide-treated primary microglia/BV2 line cells and SCI rats were used as model systems. Both C225 and AG1478 were used to inhibit EGFR signaling activation. Cell activation and EGFR phosphorylation were observed after fluorescent staining and western blot. Production of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) was tested by reverse transcription PCR and ELISA. Western blot was performed to semi-quantify the expression of EGFR/phospho-EGFR, and phosphorylation of Erk, JNK and p38 mitogen activated protein kinases (MAPK). Wet-dry weight was compared to show tissue edema. Finally, axonal tracing and functional scoring were performed to show recovery of rats. RESULTS: EGFR phosphorylation was found to parallel microglia activation, while EGFR blockade inhibited activation-associated cell morphological changes and production of IL-1 beta and TNF alpha. EGFR blockade significantly downregulated the elevated MAPK activation after cell activation; selective MAPK inhibitors depressed production of cytokines to a certain degree, suggesting that MAPK mediates the depression of microglia activation brought about by EGFR inhibitors. Subsequently, seven-day continual infusion of C225 or AG1478 in rats: reduced the expression of phospho-EGFR, phosphorylation of Erk and p38 MAPK, and production of IL-1 beta and TNF alpha; lessened neuroinflammation-associated secondary damage, like microglia/astrocyte activation, tissue edema and glial scar/cavity formation; and enhanced axonal outgrowth and functional recovery. CONCLUSIONS: These findings indicate that inhibition of EGFR/MAPK suppresses microglia activation and associated cytokine production; reduces neuroinflammation-associated secondary damage, thus provides neuroprotection to SCI rats, suggesting that EGFR may be a therapeutic target, and C225 and AG1478 have potential for use in SCI treatment. PMID- 22824325 TI - The relationship between attention deficit hyperactivity disorder and premature infants in Taiwanese: a case control study. AB - BACKGROUND: Preterm survivors from the neonatal intensive care unit (NICU) are considered to be at risk for some neurobehavioral disorders such as attention deficit/hyperactivity disorder (ADHD). The current study aimed to explore the relationship between ADHD and premature infants in Taiwan. METHODS: A total of 195 children (157 males and 38 females) diagnosed with ADHD based on DSM-IV and aged between 6 to 12 years and a control group of 212 (164 males, 48 females) age and sex-matched healthy children were enrolled. The ADHD-Rating scale and CGI severity were performed by child psychiatrists. Demographic data of the children, including birth history, perinatal neurological and respiratory problems were collected to facilitate the investigation of whether a correlation exists between ADHD and prematurity. RESULTS: The ADHD group had a significantly higher rate of prematurity and significantly higher rate of low birth body weight (defined as <2500 g) than the control group (both P=0.003). Pearson correlation showed a significantly negative correlation between gestational age and ADHD-RS score, inattentive score, hyperactivity and CGI-S score (P=0.004, 0.013, 0.015 and 0.002, respectively). However, only a CGI-S score (P=0.018) showed a significantly correlation between low birth weight and ADHD. CONCLUSIONS: Premature infants have significantly more severe symptoms of ADHD at school age and they were highly correlated. Further study is necessary to determine the main effect and pathogenesis of moderate as well as extreme preterm birth on the development of ADHD. PMID- 22824326 TI - Antiepileptic drugs, hyperhomocysteinemia and B-vitamins supplementation in patients with epilepsy. AB - Homocysteine (Hcy) is a sulfur-containing, nonprotein amino acid reversibly formed and secreted during metabolism of methionine. Elevated total Hcy levels (hyper-tHcy) have been associated with cardiovascular disease in multiple large scale epidemiologic studies and, in particular, patients with epilepsy exhibit elevated plasma tHcy levels more frequently than the general population caused by polymorphisms in the MTHFR gene and chronic treatment with older antiepileptic drugs. Folic acid alone or folic acid combined with other B-vitamins have all been shown to reduce tHcy concentration in patients on chronic treatment with antiepileptic drugs, however, which is the most appropriate supplementation scheme of folic acid and/or B-vitamins in patients with epilepsy still remains matter of debate. We review the latest findings on the role of supra physiological tHcy concentrations as vascular risk factor in patients with epilepsy and discuss the possible role played by folate and other B-vitamins supplementation in epileptic patient with hyper-tHcy. PMID- 22824324 TI - Modulation of paraoxonases during infectious diseases and its potential impact on atherosclerosis. AB - The paraoxonase (PON) gene family includes three members, PON1, PON2 and PON3, aligned in tandem on chromosome 7 in humans and on chromosome 6 in mice. All PON proteins share considerable structural homology and have the capacity to protect cells from oxidative stress; therefore, they have been implicated in the pathogenesis of several inflammatory diseases, particularly atherosclerosis. The major goal of this review is to highlight the modulation of each of the PONs by infective (bacterial, viral and parasitic) agents, which may shed a light on the interaction between infectious diseases and PONs activities in order to effectively reduce the risk of developing atherosclerosis. PMID- 22824327 TI - An electroclinical study of absence seizures in Dravet syndrome. AB - We studied clinical and EEG manifestations of absence seizures (AS) in children with Dravet syndrome (DS) to clarify their characteristic features and differences from those of typical AS (TAS). The subjects were 12 children with DS. We retrospectively analyzed electroclinical characteristics of AS. We analyzed a total of 102 ictal EEGs characterized by generalized spike-and-wave (GSW) and semiology of 78 video-taped AS. The mean age at the onset of AS and at the time of the study was 16.2+/-7.1 months and 40.3+/-22.1 months, respectively. Ictal EEG showed the focality of initial discharge in 49/102 (48%), a duration ranging from 2 to 180 s (mean: 10.2+/-22.6 s; median: 4.0 s), frequency ranging from 2 to 4 Hz (median=3.0 Hz), and irregular and disorganized GSW morphology in 66/102 (65%). AS manifested with eyelid-myoclonus and generalized myoclonus in 9/54 (17%) and 34/78 (44%), respectively. In conclusion, AS in DS were characterized by an early-onset age, a high incidence of irregular and disorganized 3 Hz GSW morphology, and the frequent association of generalized myoclonic movement as well as the absence of automatism as compared to TAS. The results should be appreciated in the differential diagnosis of early-onset AS, the treatment of AS in DS and also a further clinical and genetic study for DS. PMID- 22824329 TI - Analysis of volatile components in Curcuma rhizome by microemulsion electrokinetic chromatography. AB - Volatile chemicals are a group of very important compounds in natural products. Curcuma rhizome, which contains many bioactive volatile compounds, is a traditional Chinese medicine that has long been used for the treatment of several diseases. In the present study, a microemulsion electrokinetic chromatography (MEEKC) method was developed for the analysis of four volatile components in Curcuma rhizome, including germacrone, furanodiene, curcumenol and curdione. Experimental parameters, including the pH, type and concentrations of background electrolyte, and microemulsion compositions (type and concentrations of surfactant, co-surfactant and oil phase) were intensively investigated. Finally, the primary compounds in the methanol extract of Curcuma rhizome were separated within 30 min using a running buffer composed of 2.31% w/v (80 mmol/L) sodium dodecyl sulfate (SDS), 0.91% w/v (80 mmol/L) 1-octane, 6.95% w/v (937.5 mmol/L) 1 butanol and 1.88% w/v (312.5 mmol/L) propanol in a 5-mM borate buffer (pH 8.1). The contents of the four investigated compounds were determined in the rhizome from C. phaeocaulis. The results showed that the developed MEEKC method provided an alternative tool for the analysis of volatile components, especially those of heat-sensitive compounds from natural products. PMID- 22824328 TI - Genome-wide matching of genes to cellular roles using guilt-by-association models derived from single sample analysis. AB - BACKGROUND: High-throughput methods that ascribe a cellular or physiological function for each gene product are useful to understand the roles of genes that have not been extensively characterized by molecular or genetic approaches. One method to infer gene function is "guilt-by-association", in which the expression pattern of a poorly characterized gene is shown to co-vary with the expression of better-characterized genes. The function of the poorly characterized gene is inferred from the known function(s) of the well-described genes. For example, genes co-expressed with transcripts that vary during the cell cycle, development, environmental stresses, and with oncogenesis have been implicated in those processes. FINDINGS: While examining the expression characteristics of several poorly characterized genes, we noted that we could associate each of the genes with a cellular phenotype by correlating individual gene expression changes with gene set enrichment scores from individual samples. We evaluated the effectiveness of this approach using a modest sized gene expression data set (expO) and a compendium of gene expression phenotypes (MSigDBv3.0). We found the transcripts that correlated best with enrichment in mitochondrial and lysosomal gene sets were mostly related to those processes (89/100 and 44/50, respectively). The reciprocal evaluation, ranking gene sets according to correlation of enrichment with an individual gene's expression, also reflected known associations for prominent genes in the biomedical literature (16/19). In evaluating the model, we also found that 4% of the genome encodes proteins that are associated with small molecule and small peptide signal transduction gene sets, implicating a large number of genes in both internal and external environmental sensing. CONCLUSIONS: Our results show that this approach is useful to infer functions of disparate sets of genes. This method mirrors the biological experimental approaches used by others to associate individual genes with defined gene expression changes. Moreover, the approach can be used beyond discovering genes related to a cellular process to discover meaningful expression phenotypes from a compendium that are associated with a given gene. The effectiveness, versatility, and breadth of this approach make possible its application in a variety of contexts and with a variety of downstream analyses. PMID- 22824330 TI - High-performance liquid chromatography-electrospray ionization time-of-flight mass spectrometry analysis of Radix Saposhnikoviae for metabolomic research. AB - In this study, metabolite profiling of Radix Saposhnikoviae from different geographical locations was performed using high-performance liquid chromatography electrospray ionization time-of-flight mass spectrometry (HPLC-ESI-TOFMS) and multivariate statistical analysis technique. Principle component analysis (PCA) of the data shows that these samples could be roughly separated into three groups: Guan Fangfeng, Kou Fangfeng and Chuan Fangfeng. The potential chemical markers were discovered through the loading plot of PCA. Based on accurate mass measurements and subsequent fragment ions of TOFMS after in-source collision induced dissociation, as well as matching of empirical molecular formulae with those of published components in the in-house chemical library, 10 potential markers, such as 4'-O-glucosyl-5-O-methylvisamminol, cimifugin, prim-O glucosylcimifugin and 3'-O-angeloylhammaudol, were tentatively identified and partially verified by the available reference standards. The results of this study indicate that it is an effective and novel approach to identify traditional Chinese medicine (TCM) from different sources, and that performing quantity determination of corresponding marker compounds could optimize the quality control of TCM. PMID- 22824331 TI - Effect of intracortical vascular endothelial growth factor infusion and blockade during the critical period in the rat visual cortex. AB - VEGF is the major angiogenic and vascular permeability factor in health and disease. Vascular development depends on function, and in sensory areas is experience-dependent. Our aim was to investigate, qualitatively and quantitatively, the effects of intracortical infusion and neutralisation of VEGF during the first days of the critical visual period, when peak levels of endogenous VEGF secretion are reached. VEGF was intracortically delivered into middle cortical layers of P18 Long-Evans rats. Another cohort received anti-VEGF. Vehicle (PBS)-infused and non-operated animals were used as controls. Various immunopathological analyses were performed: Endothelial Barrier Antigen (EBA) for the BBB integrity and GFAP for astroglial response. Vascular density was measured by Butyryl Cholinesterase Histochemistry, neuronal density by NeuN immunohistochemistry and apoptosis by TUNEL staining. VEGF levels were measured by Western Blot. Decreased vascular permeability was evoked in VEGF-infused rats whilst EBA expression remained constant, suggesting a preserved BBB function. When VEGF was blocked, tissue showed a higher degree of extravasation and a decreased number of EBA-positive vessels surrounding the injury. Lesion induced by cannula implantation annulled the normal increase in vascular density and the decrease in neuronal density during this time. VEGF rescued in part the vascular increase, and also prevented physiological and pathological neuronal death. VEGF blockade induced a higher amount of neural loss and lower astrocytic reaction. Our results support the role of VEGF as extending beyond vascularization, preventing physiological and pathological neuronal death, not only in the injured hemisphere but also in the intact one suggesting a process of transhemispheric diaschisis. PMID- 22824332 TI - Visual sampling during walking in people with Parkinson's disease and the influence of environment and dual-task. AB - Visuospatial dysfunction may play a crucial role in gait disturbance in Parkinson's disease (PD), in particular how visual exploration of the environment is integrated into gait control. In this study, we tested the hypothesis that people with PD would visually sample their environment less frequently than controls when walking under different levels of environmental complexity and dual task. We also explored associations between saccadic outcomes and clinical measures. Visual sampling (saccadic frequency) and gait were measured concurrently for 21 people with PD and 12 age-matched controls during a series of walking tasks using electrooculography (EOG) synchronised with 3D motion analysis (VICON). Participants walked under four environmental conditions during single and dual-task. Saccade frequency and task duration were measured. PD participants took longer to complete all tasks than controls (p =.004). Environment and dual task impacted on saccadic frequency especially for PD. For both groups, saccadic frequency increased when approaching a turn compared with straight walking. Prior to turning, PD made less frequent early preparatory saccades than controls (p =.012). Under dual-task conditions, people with PD made less frequent saccades than controls when walking straight ahead (p =.040) and in preparation for a turn (p =.032). Increased saccadic frequency was related to poorer attention, cognition and spatial memory in controls and people with PD for single-task conditions but not dual-task conditions. Impaired visual sampling may contribute to the gait disorder in PD, especially when navigating through complex environments and when distracted. PMID- 22824333 TI - Masked repetition priming of letter-in-string identification: an ERP investigation. AB - In a post-cued letter identification task, participants were presented with 7 letter nonword target stimuli that were formed of a random string of consonants (DCMFPLR) or a pronounceable sequence of consonants and vowels (DAMOPUR). Targets were preceded by briefly presented pattern-masked primes that could be the same sequence of letters as the target, composed of seven different letters, or sharing either the first or last five letters of the target. There was some evidence for repetition priming effects that were independent of target type in an early component, the N/P150, thought to reflect the mapping of visual features onto letter representations, and that is insensitive to orthographic structure. Following this, pronounceable nonwords showed significantly greater repetition priming effects than consonant strings, in line with the behavioral results. Initial versus final overlap only started to influence target processing at around 200-250ms post-target onset, at about the same time as the effects of target type emerged. The results are in line with a model where the initial parallel mapping of visual features onto a location-specific orthographic code is followed by the subsequent activation of location-invariant orthographic and phonological codes. PMID- 22824334 TI - Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats. AB - Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Phytoestrogens are naturally occurring plant-derived compounds that are present in the human diet and are considered selective estrogen receptor (ER) modulators. The phytoestrogen coumestrol is a potent isoflavonoid, with binding affinities for both ER-alpha and ER-beta that are comparable to those of 17 b-estradiol. The present study examined the hypothesis that coumestrol protects hippocampal neurons in ovariectomized rats in a model of cerebral global ischemia. Ovariectomized rats were subjected to global ischemia (10 min) or sham surgery and received a single intracerebroventricular or peripheral infusion of 20 MUg of coumestrol, 20 MUg of estradiol or vehicle 1h before ischemia or 0 h, 3h, 6h or 24h after reperfusion. Estradiol and coumestrol afforded significant neuroprotection in all times of administration, with the exception of estradiol given 24h after the ischemic insult. Animals received icv infusion of the broad-spectrum ER antagonist ICI 182,780 (50 MUg) or vehicle into the lateral ventricle just before the E2 or coumestrol administration. The ER antagonist abolished estradiol protection, consistent with a role of classical ERs. In contrast, ICI 182,780 effected only partial reversal of the neuroprotective actions of coumestrol, suggesting that other cellular mediators in addition to classical ERs may be important. Additional research is needed to determine the molecular targets mediating the neuroprotective action of coumestrol and the therapeutic potential of this phytoestrogen in the mature nervous system. PMID- 22824335 TI - Stem cell regulation by the Hippo pathway. AB - BACKGROUND: The Hippo pathway coordinates cell proliferation, apoptosis, and differentiation, and has emerged as a major regulator of organ development and regeneration. Central to the mammalian Hippo pathway is the action of the transcriptional regulators TAZ (also known as WWTR1) and YAP, which are controlled by a kinase cascade that is sensitive to mechanosensory and cell polarity cues. SCOPE OF REVIEW: We review recent studies focused on the Hippo pathway in embryonic and somatic stem cell renewal and differentiation. MAJOR CONCLUSIONS: Accurate control of TAZ and YAP is crucial for the self-renewal of stem cells and in guiding distinct cell fate decisions. In vivo studies have implicated YAP as a key regulator of tissue-specific progenitor cell proliferation and tissue regeneration. Misappropriate activation of nuclear TAZ and YAP transcriptional activity drives tissue overgrowth and is implicated in cancer stem cell-like properties that promote tumor initiation. GENERAL SIGNIFICANCE: Understanding the activity and regulation of Hippo pathway effectors will offer insight into human pathologies that evolve from the deregulation of stem cell populations. Given the roles of the Hippo pathway in directing cell fate and tissue regeneration, the discernment of Hippo pathway regulatory cues will be essential for the advancement of regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22824336 TI - Molecular tools for the detection and identification of Ichthyobodo spp. (Kinetoplastida), important fish parasites. AB - Ichthyobodo spp. are ectoparasitic flagellates of fish that may cause disease (ichthyobodosis), a common problem affecting the aquaculture industry worldwide. Ichthyobodosis in farmed fish is often associated with a range of other infectious agents and diagnosis in for example gill disease may be difficult. Sensitive and effective methods for detection and identification of Ichthyobodo spp. are needed to aid diagnosis of ichthyobodosis and epizootiological studies on Ichthyobodo spp. We have designed a specific quantitative real-time PCR assay targeting SSU rDNA for the detection of Ichthyobodo spp. infections. Also, several novel primer sets are presented for use in identification of Ichthyobodo spp. through PCR and sequencing. These PCR methods have been optimized and tested on samples from wild caught and farmed fish from different geographical areas in Norway. The real-time PCR assay has been tested for sensitivity and efficiency, and we present data demonstrating its use for absolute quantification of Ichthyobodo salmonis in tissue samples through RT-qPCR and qPCR. We demonstrate the use of the described set of molecular tools for the detection and sequencing of Ichthyobodo spp. from farmed and wild fish, and also show that they may aid the discovery of new Ichthyobodo species. The detection of light Ichthyobodo spp. infections through microscopy is time consuming and less sensitive compared to PCR methods. Initial real-time PCR testing and subsequent sequencing of positive samples is a powerful method that will increase diagnostic precision, aid carrier detection and promote species discoveries in the Ichthyobodonidae. Our preliminary observations indicate a high Ichthyobodo spp. diversity. PMID- 22824337 TI - Genetic diversity of nuclear ITS1-5.8S-ITS2 rDNA sequence in Clonorchis sinensis Cobbold, 1875 (Trematoda: Opisthorchidae) from the Russian Far East. AB - The present study examined the molecular organisation and sequence variation in the nuclear ribosomal DNA (rDNA) region, including the two internal transcribed spacers (ITS1 and ITS2) and the 5.8S gene of the Clonorchis sinensis from the Russian Far East. The relevant sequences from other parts of this species' area were downloaded from GenBank. The results showed 100% identity for all investigated 5.8S-ITS2 rDNA sequences. In contrast, two levels of intraspecific variations were revealed in the complete ITS1 sequences. The intra-genomic variation resulted from a C/T polymorphism in a single position. The inter individual differences between the ITS1 sequences were both due to nucleotide and size polymorphisms resulting from a varying number of five-nucleotide repeats and followed by two ITS1 length variants. These variant frequencies correlate with the clonorchiasis level in some geographical localities. ITS1 differences, both in the mutation profile and mutation localisation, were revealed between northern and southern geographical samples. The presence of GC boxes that are identical to known regulatory motifs in eukaryotes was detected within the ITS1 sub-repeats. The predicted secondary structures for ITS1 consist of two large branches, one of which was invariable, while another depended on ITS1 length. The predicted secondary structure for ITS2 includes four helices around the core. The main differences between C. sinensis and other opisthorchids were localised on the tops of helices 2, 3, and 4. A phylogenetic MST reconstruction subdivided all ITS1 sequences into two well differentiated clusters, each with the major widespread ribotype, and showed that ribotype diversity in both Russia and Korea is much lower than in China. The results obtained demonstrate the feasibility of complete ITS1 sequences in C. sinensis population genetics and can be considered as a basis for further studies of the parasite infection because they may help to elucidate the molecular mechanisms of pathogen evolution and adaptation. PMID- 22824338 TI - Assessing basic life support skills without an instructor: is it possible? AB - BACKGROUND: Current methods to assess Basic Life Support skills (BLS; chest compressions and ventilations) require the presence of an instructor. This is time-consuming and comports instructor bias. Since BLS skills testing is a routine activity, it is potentially suitable for automation. We developed a fully automated BLS testing station without instructor by using innovative software linked to a training manikin. The goal of our study was to investigate the feasibility of adequate testing (effectiveness) within the shortest period of time (efficiency). METHODS: As part of a randomised controlled trial investigating different compression depth training strategies, 184 medicine students received an individual appointment for a retention test six months after training. An interactive FlashTM (Adobe Systems Inc., USA) user interface was developed, to guide the students through the testing procedure after login, while Skills StationTM software (Laerdal Medical, Norway) automatically recorded compressions and ventilations and their duration ("time on task"). In a subgroup of 29 students the room entrance and exit time was registered to assess efficiency. To obtain a qualitative insight of the effectiveness, student's perceptions about the instructional organisation and about the usability of the fully automated testing station were surveyed. RESULTS: During testing there was incomplete data registration in two students and one student performed compressions only. The average time on task for the remaining 181 students was three minutes (SD 0.5). In the subgroup, the average overall time spent in the testing station was 7.5 minutes (SD 1.4). Mean scores were 5.3/6 (SD 0.5, range 4.0-6.0) for instructional organisation and 5.0/6 (SD 0.61, range 3.1-6.0) for usability. Students highly appreciated the automated testing procedure. CONCLUSIONS: Our automated testing station was an effective and efficient method to assess BLS skills in medicine students. Instructional organisation and usability were judged to be very good. This method enables future formative assessment and certification procedures to be carried out without instructor involvement. TRIAL REGISTRATION: B67020097543. PMID- 22824339 TI - Assessment of root uptake and systemic vine-transport of Salmonella enterica sv. Typhimurium by melon (Cucumis melo) during field production. AB - Among melons, cantaloupes are most frequently implicated in outbreaks and surveillance-based recalls due to Salmonella enterica. There is limited but compelling evidence that associates irrigation water quality as a significant risk of preharvest contamination of melons. However, the potential for root uptake from water and soil and subsequent systemic transport of Salmonella into melon fruit is uncharacterized. The aim of this work was to determine whether root uptake of S. enterica results in systemic transport to fruit at high doses of applied inoculum through sub-surface drip and furrow irrigation during field production of melons. Cantaloupe and honeydew were grown under field conditions, in a silt clay loam soil using standard agronomic practices for California. An attenuated S. enterica sv. Typhimurium strain was applied during furrow irrigation and, in separate plots, buried drip-emitter lines delivered the inoculum directly into the established root zone. Contamination of the water resulted in soil contamination within furrows however Salmonella was not detected on top of the beds or around melon roots of furrow-irrigated rows demonstrating absence of detectable lateral transfer across the soil profile. In contrast, positive detection of the applied isolate occurred in soil and the rhizosphere in drip injected plots; survival of Salmonella was at least 41 days. Despite high populations of the applied bacteria in the rhizosphere, after surface disinfection, internalized Salmonella was not detected in mature melon fruit (n=485). Contamination of the applied Salmonella was detected on the rind surface of melons if fruit developed in contact with soil on the sides of the inoculated furrows. Following an unusual and heavy rain event during fruit maturation, melons collected from the central area of the beds, were shown to harbor the furrow-applied Salmonella. Delivery of Salmonella directly into the peduncle, after minor puncture wounding, resulted in detection of applied Salmonella in the sub-rind tissue below the fruit abscission zone. Results indicate that Salmonella internalization from soil and vascular systemic transport to fruit is unlikely to occur from irrigation water in CA production regions, even if substantially above normal presumptive levels of contamination. Although contaminated irrigation water and subsequently soil in contact with fruit remains a concern for contamination of the external rind, results suggest an acceptable microbial indicator threshold and critical limit for the presence of Salmonella in applied water may be possible by defining appropriate microbiological standards for melon irrigation in California and regions with similar climate, soil texture, and crop management practices. PMID- 22824340 TI - Antimicrobial assays of natural extracts and their inhibitory effect against Listeria innocua and fish spoilage bacteria, after incorporation into biopolymer edible films. AB - The antimicrobial activity of twelve natural extracts was tested against two fish spoilage bacteria (Pseudomonas fluorescens and Aeromonas hydrophila/caviae) and Listeria innocua, in order to assess their potential utilization in the preservation and safety of minimally processed fish products. After a screening of the active extracts by agar diffusion and vapour diffusion methods, oregano and thyme essential oils and citrus extract were selected. The minimum inhibitory concentration (MIC) of the selected extracts was determined by disc diffusion method against target bacteria and at two temperatures: bacteria's optimal growth temperature (30 degrees C or 37 degrees C) and refrigeration temperature (4 degrees C). Due to its better solubility, lack of odour and greater inhibitory effect obtained against L. innocua at refrigerated temperature, citrus extract was selected and incorporated at 1% (v/v) into different biopolymer film forming solutions (gelatin, methyl cellulose and their blend 50:50 w/w). The antimicrobial activity of the developed films was then evaluated, just after preparation of the films and after one month of storage at 43+/-3% relative humidity and 24+/-3 degrees C. Regardless of the biopolymer matrix, all the developed films showed antimicrobial activity against the target bacteria. The most sensitive bacterium towards active films was L. innocua while P. fluorescens appeared as the most resistant one, in accordance with the previously performed antimicrobial tests for pure extracts. The differences in activity of the films between the tested two temperatures were not significant except for L. innocua, for which three times higher inhibition diameters were observed at refrigerated temperature. The inhibitory effectiveness of the films against the tested strains was maintained regardless of the biopolymer matrix for at least one month. Therefore, these edible films show potential for their future use in fresh fish fillets preservation. PMID- 22824341 TI - Identification of novel human receptor activator of nuclear factor-kB isoforms generated through alternative splicing: implications in breast cancer cell survival and migration. AB - INTRODUCTION: The receptor activator of nuclear factor-kB (NF-kB) (RANK)/receptor activator of NF-kB ligand (RANKL) axis emerges as a key regulator of breast cancer initiation, progression and metastasis. RANK receptor is a tumor necrosis superfamily member, which upon ligand binding transduces a variety of survival, proliferation, differentiation and migration signals. The majority of these intracellular cues merge through the NF-kB transcription machinery. METHODS: TNFRSF11A (RANK) variants were identified and cloned in mammalian expression vectors. Their expression was analyzed using real time PCR on RNA from normal tissue, cell lines and breast cancer specimens. Western blot analysis and immunofluoresence stainings were used to study expression and localization of protein isoforms in a panel of breast cancer cell lines and in transfected 293T cells. Luciferase assays were employed to assess the contribution of each isoform alone or in combinations on NF-kB activation. Isoform effect on cell survival after doxorubicin treatment was analyzed through MTT assay. Wound healing and transwell assays were employed to evaluate the effect of TNFRSF11A isoforms on migration of MDA-MB-231 and 293T cells. RESULTS: We report the identification of three novel TNFRSF11A (RANK) variants, named TNFRSF11A_Delta9, TNFRSF11A_Delta8,9 and TNFRSF11A_Delta7,8,9 which result from the alternative splicing of exons 7 to 9. Interestingly, variant TNFRSF11A_Delta7,8,9 was found to be upregulated in breast cancer cells lines and its expression inversely correlated with tumor grade and proliferation index. TNFRSF11A_Delta7,8,9 encodes a 40-45 kDa protein, we named RANK-c, which lacks the transmembrane domain and most of the intracellular part of the wild type receptor. Furthermore, we showed that RANK-c could act as a dominant negative regulator of RANK-dependent NF-kB activation, affecting cell survival after apoptosis induction. In addition, RANK-c suppresses cell migration and represses the tumorigenic properties of invasive breast carcinoma cells. CONCLUSIONS: In this study, we provide evidence of a complex regulatory network of RANK receptor splice variants with a role in breast cancer. We identify that the RANK-c isoform is expressed in breast cancer samples and its expression reversely correlates with histological grade. Finally, isoform RANK-c seems to have the capacity to regulate signaling through wild type RANK and moreover to inhibit cell motility and migration of breast cancer cells. PMID- 22824342 TI - Association of polymorphisms of cytokine and TLR-2 genes with long-term immunity to hepatitis B in children vaccinated early in life. AB - Hepatitis B vaccine is effective in preventing hepatitis B virus (HBV) infection. However, 5-10% of vaccinees fail to produce sufficient antibody against hepatitis B surface antigen (anti-HBs). In this study, we investigated the association of genetic polymorphisms with long-term response to hepatitis B vaccine in 301 children who received the vaccine 5-7 years ago. Of them, 86 (28.6%) had anti-HBs <10 mIU/ml (group A) and 215 (71.4%) had anti-HBs >=10 mIU/ml (group B). While the frequencies of T allele and TT genotype in single nucleotide polymorphisms (SNP) rs2243250 and rs2070874 of interleukin (IL)-4 in group A were higher than those in group B (all P<0.05 and q<0.2), the frequency of C allele in SNP rs2243250, rs2070874 and rs2227284 of IL-4 in group B was higher than that in group A (all P<0.05 and q<0.2). None of 11 other SNP in IL-2, IL-10, IL-1beta, IL 13, IL-12B, tumor necrosis factor-alpha, and toll-like receptor-2 genes was found to associate with anti-HBs response. SNP rs2070874 was associated with humoral response to hepatitis B vaccine after analyzed by multivariable logistic regression analysis (P=0.015). The haplotype TT defined by SNP rs2243250 and rs2070874 in IL-4 was associated with the poor humoral response (adjusted P=0.037). Our findings demonstrate that IL-4 gene polymorphisms may affect the long-term immune response to hepatitis B vaccine. PMID- 22824343 TI - Characteristics of serology-based vaccine potency models for foot-and-mouth disease virus. AB - BACKGROUND: Foot-and-mouth disease (FMD) vaccine potency testing involves hundreds of animals each year. Despite considerable efforts during the past decades, a challenge-free alternative vaccine potency test to replace the European protective dose 50% test (PD(50)) has not been implemented yet. The aim of the present study was to further characterize the properties of serological vaccine potency models. METHODS: Logistic regression models were built for 5 serological assays from 3 different laboratories. The serum samples originated from 5 repeated PD(50) vaccine potency trials with a highly potent A/IRN/11/96 vaccine. Receiver Operating Characteristic analysis was used to determine a serological pass mark for predicting in vivo protected animals. Subsequently, an estimated PD(50) was calculated and the serotype dependency of the logistic models was investigated. RESULTS: Although differences were observed between the laboratories and the serological assays used, the logistic models accurately predicted the in vivo protection status of the animals in 74-93% of the cases and the antibody pass levels corresponded to 84-97% of protection, depending on the serological assay used. For logistic models that combine different serotypes, the model fit can be increased by inclusion of a serotype factor in the logistic regression function. CONCLUSIONS: The in vitro estimated PD(50) method may be at least as precise as the in vivo PD(50) test and may accurately predict the PD(50) content of a vaccine. However, the laboratory-effect and the serotype-dependency should be further investigated. PMID- 22824344 TI - Ex vivo transfection of trout pronephros leukocytes, a model for cell culture screening of fish DNA vaccine candidates. AB - DNA vaccination opened a new era in controlling and preventing viral diseases since DNA vaccines have shown to be very efficacious where some conventional vaccines have failed, as it occurs in the case of the vaccines against fish novirhabdoviruses. However, there is a big lack of in vitro model assays with immune-related cells for preliminary screening of in vivo DNA vaccine candidates. In an attempt to solve this problem, rainbow trout pronephros cells in early primary culture were transfected with two plasmid DNA constructions, one encoding the green fluorescent protein (GFP) and another encoding the viral haemorrhagic septicaemia virus (VHSV) glycoprotein G (G(VHSV)) - the only viral antigen which has conferred in vivo protection. After assessing the presence of GFP- and G(VHSV)-expressing cells, at transcription and protein levels, the immune response in transfected pronephros cells was evaluated. At 24h post-transfection, G(VHSV) up-regulated migm and tcr transcripts expression, suggesting activation of B and T cells, as well, a high up-regulation of tnfalpha gene was observed. Seventy-two hours post-transfection, we detected the up-regulation of mx and tnfalpha genes transcripts and Mx protein which correlated with the induction of an anti-VHSV state. All together we have gathered evidence for successful transfection of pronephros cells with pAE6G, which correlates with in vivo protection results, and is less time-consuming and more rapid than in vivo assays. Therefore, this outcome opens the possibility to use pronephros cells in early primary culture for preliminary screening fish DNA vaccines as well as to further investigate the function that these cells perform in fish immune response orchestration after DNA immunisation. PMID- 22824346 TI - Desmoid tumour of the thoracic outlet in a 70 year-old man successfully removed through cervico-thoracic Dartevelle approach. AB - Desmoid tumours have a strong tendency for local invasion and recurrence. A 70 year-old male presented with cervical and left shoulder pain associated with a supraclavicular mass. The computed-tomography showed an expansive lesion measuring 10 cm * 6 cm * 5.5 cm in the left supraclavicular space. At magnetic resonance imaging the subclavian vessels and the brachial plexus were dislocated anteriorly but not infiltrated. An incisional biopsy suggested a desmoid tumour. An anterior cervicothoracic approach was used to remove the tumour. The chest wall was reconstructed with titanium bars and a polytetrafluoroethylene-patch. The clavicle was fixed using a titanium clip. The post-operative course was uneventful. The patient was treated with adjuvant radiation therapy. After six months the patient is in good clinical condition free from disease recurrence. In conclusion, desmoid tumour of the thoracic outlet is a challenging situation. Wide radical resection should be attempted whenever possible. The Dartevelle approach gives an optimal surgical field with direct control of vessels and nerve roots facilitating tumour dissection and radical resection en-bloc with the chest wall. The chest wall reconstruction with titanium bars and clips is a simple and effective method to guarantee good respiratory function and to stabilise the shoulder girdle. PMID- 22824345 TI - Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with alpha-synuclein at the single molecule level. AB - BACKGROUND: Fibrillar amyloid-like deposits and co-deposits of tau and alpha synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and alpha-synuclein are not well understood. RESULTS: We used a novel approach applying confocal single particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with alpha-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3beta exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of alpha synuclein in pre-formed tau oligomers. CONCLUSIONS: Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration. PMID- 22824347 TI - The relative position of paired valves at venous junctions suggests their role in modulating three-dimensional flow pattern in veins. AB - PURPOSE: The aim of the study is to investigate the relative position of orifices of two valves within the most proximal segments of the great saphenous vein (GSV), and the femoral vein (FV). METHODS: A total of 15 volunteers with no signs or symptoms of venous disease and 13 unaffected limbs of patients with unilateral primary chronic venous disease (CVD) were included. Two most proximal valves of the GSV and the FV were identified. The angle between the two valves, and the distance between the valves were measured. RESULTS: The mean distance between the two valves in the GSV was 3.8 +/- 0.4 cm, and in the FV was 4.6 +/- 0.3 cm. In one limb, the distance between the FV valves was 1 cm less than GSV valves, and in two limbs the distances were equal. In the remaining 12 limbs available for comparison, the valves in the FV were 1-2 cm further apart compared to the GSV (P = 0.002, paired t-test). All studied pairs of valves were positioned at a minimum 60 degrees angle to each other. The mean angle between the two valves was 84.3 +/- 8.4 degrees in the GSV, and 88.3 +/- 6.7 degrees in the FV (P = 0.24). The angle between the two valves correlated with the distance between the valves (r = 0.68, P = 0.000005). No significant relations were found between the diameter of the studied vein, and the angle between the two valves. There was no difference in valve orientation between volunteers and unaffected limbs of the patients with CVD. CONCLUSION: When two valves are present in the areas of venous junctions, they consistently positioned at a significant angle to each other. A hypothesis that venous valves at the junctions increase efficiency of venous return by creating a helical flow pattern can be postulated and deserves further investigation. PMID- 22824348 TI - Effects of statin therapy on abdominal aortic aneurysm growth: a meta-analysis and meta-regression of observational comparative studies. AB - OBJECTIVE: To determine whether statin therapy reduces the growth rate of small abdominal aortic aneurysms (AAAs). DESIGN: A meta-analysis and a meta-regression of comparative studies. MATERIALS: Eligible studies were randomized controlled trials or observational comparative studies of statin therapy versus placebo or no statin, enrolling individuals with small (<55 mm in diameter) AAAs and reporting AAA growth rate as an outcome. METHODS: Study-specific estimates (standardized mean differences [SMDs]) were combined in the fixed- and random effects model. RESULTS: Seven adjusted and 4 unadjusted observational comparative studies enrolling 4647 patients with a small AAA were identified. Pooled analysis of all 11 studies suggested a significant reduction in AAA growth rate among patients assigned to statin therapy versus no statin (SMD, -0.420; 95% confidence interval [CI], -0.651 to -0.189). Combining the 7 high-quality studies providing adjusted data for growth rates generated an attenuated but still statistically significant result favoring statin therapy (SMD, -0.367; 95% CI, -0.566 to 0.168). The meta-regression coefficient for the baseline diameter was statistically significant (-0.096; 95% CI, -0.132 to -0.061). CONCLUSION: Statin therapy is likely effective in prevention of the growth of small AAAs, and may be more beneficial as the baseline diameter increases. PMID- 22824349 TI - The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate. AB - In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naive PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. PMID- 22824351 TI - Multifocal fixed drug eruption probably induced by mefenamic acid. PMID- 22824352 TI - Hand eczema due to hygiene and antisepsis products: not only an irritative etiology. PMID- 22824353 TI - Hyperkeratosis and Scaling in Identical Twins. PMID- 22824354 TI - Association of hemodialysis central venous catheter use with ipsilateral arteriovenous vascular access survival. AB - BACKGROUND: Central venous catheters frequently are used for hemodialysis vascular access while patients await placement and maturation of an arteriovenous fistula or graft. Catheters may cause central vein stenosis, which can adversely affect vascular access outcomes. We compared vascular access outcomes in patients with a history of ipsilateral and contralateral dialysis catheters. STUDY DESIGN: Retrospective analysis of a prospective computerized vascular access database. SETTING & PARTICIPANTS: Patients at a large medical center who initiated hemodialysis therapy with a catheter and subsequently received a fistula (n = 233) or graft (n = 89). PREDICTOR: History of central venous catheter placement ipsilateral versus contralateral to the arteriovenous fistula or graft. OUTCOME & MEASUREMENTS: Primary access failure (access never suitable for dialysis) and cumulative access survival (time from successful cannulation until permanent access failure). RESULTS: For patients receiving a fistula, the primary failure rate was similar for those with ipsilateral and contralateral catheters (50% vs 53%; HR, 0.94; 95% CI, 0.71-1.26; P = 0.7), and time to fistula maturation was similar (101 +/- 41 vs 107 +/- 39 days; P = 0.5). However, cumulative fistula survival was inferior in patients with ipsilateral catheters (HR, 2.48; 95% CI, 1.33-7.33; P = 0.009). For patients receiving a graft, the primary failure rate was similar for those with ipsilateral and contralateral catheters (35% vs 38%; HR, 0.92; 95% CI, 0.49-1.73; P = 0.8), but cumulative graft survival tended to be shorter with ipsilateral catheters (HR, 2.04; 95% CI, 0.92-5.38; P = 0.07). LIMITATIONS: Retrospective analysis, single medical center. CONCLUSIONS: The primary failure rate of fistulas and grafts is not affected by the presence of an ipsilateral catheter. However, cumulative access survival is inferior in patients with prior ipsilateral catheters. Avoidance of ipsilateral catheters may improve long-term vascular access survival. PMID- 22824366 TI - Tyrosol, a main phenol present in extra virgin olive oil, increases lifespan and stress resistance in Caenorhabditis elegans. AB - Extra virgin olive oil (EVOO) consumption has been traditionally related to a higher longevity in the human population. EVOO effects on health are often attributed to its unique mixture of phenolic compounds with tyrosol and hydroxityrosol being the most biologically active. Although these compounds have been extensively studied in terms of their antioxidant potential and its role in different pathologies, their actual connection with longevity remains unexplored. This study utilized the nematode Caenorhabditis elegans to investigate the possible effects of tyrosol in metazoan longevity. Significant lifespan extension was observed at one specific tyrosol concentration, which also induced a higher resistance to thermal and oxidative stress and delayed the appearance of a biomarker of ageing. We also report that, although tyrosol was efficiently taken up by these nematodes, it did not induce changes in development, body length or reproduction. In addition, lifespan experiments with several mutant strains revealed that components of the heat shock response (HSF-1) and the insulin pathway (DAF-2 and DAF-16) might be implicated in mediating tyrosol effects in lifespan, while caloric restriction and sirtuins do not seem to mediate its effects. Together, our results point to hormesis as a possible mechanism to explain the effects of tyrosol on longevity in C. elegans. PMID- 22824367 TI - Spatial clusters of suicide in Australia. AB - BACKGROUND: Understanding the spatial distribution of suicide can inform the planning, implementation and evaluation of suicide prevention activity. This study explored spatial clusters of suicide in Australia, and investigated likely socio-demographic determinants of these clusters. METHODS: National suicide and population data at a statistical local area (SLA) level were obtained from the Australian Bureau of Statistics for the period of 1999 to 2003. Standardised mortality ratios (SMR) were calculated at the SLA level, and Geographic Information System (GIS) techniques were applied to investigate the geographical distribution of suicides and detect clusters of high risk in Australia. RESULTS: Male suicide incidence was relatively high in the northeast of Australia, and parts of the east coast, central and southeast inland, compared with the national average. Among the total male population and males aged 15 to 34, Mornington Shire had the whole or a part of primary high risk cluster for suicide, followed by the Bathurst-Melville area, one of the secondary clusters in the north coastal area of the Northern Territory. Other secondary clusters changed with the selection of cluster radius and age group. For males aged 35 to 54 years, only one cluster in the east of the country was identified. There was only one significant female suicide cluster near Melbourne while other SLAs had very few female suicide cases and were not identified as clusters. Male suicide clusters had a higher proportion of Indigenous population and lower median socio-economic index for area (SEIFA) than the national average, but their shapes changed with selection of maximum cluster radii setting. CONCLUSION: This study found high suicide risk clusters at the SLA level in Australia, which appeared to be associated with lower median socio-economic status and higher proportion of Indigenous population. Future suicide prevention programs should focus on these high risk areas. PMID- 22824368 TI - Bioactivity of Samsum ant (Pachycondyla sennaarensis) venom against lipopolysaccharides through antioxidant and upregulation of Akt1 signaling in rats. AB - BACKGROUND: This study aimed at investigating the oxidative stress ameliorating effect, lipids profile restoration, and the anti-inflammatory effect of Samsum Ant Venom (SAV) in induced endotoxemic male rats, injected with bacterial lipopolysaccharides (LPS). RESULTS: Results revealed that LPS significantly increased the oxidative stress indications in LPS-injected rats. A significant increase of both malondialdehyde (MDA), and advanced oxidative protein products (AOPP), as well as a significant suppression of glutathione were all detected. Treatment with 100 MUg/kg dose of SAV significantly restored the oxidative stress normal indications and increased the total glutathione levels. Treatment of the LPS-rats with 100 MUg/kg dose of SAV showed a clear anti-inflammatory function; as the histological architecture of the hepatic tissue was partially recovered, along with a valuable decrease in the leukocytes infiltrated the hepatic tissues. Treatment of some rat groups with 600 MUg/kg dose of SAV after LPS injection induced a severe endotoxemia that resulted in very high mortality rates. SAV versus the effects of LPS on AKT1, Fas, TNF-alpha and IFN-gamma mRNA expression. SAV was found to significantly lower Fas gene expression comparing to the LPS group and restore the level of IFN-gamma mRNA expression to that of the control group. CONCLUSION: In conclusion, SAV, at the dose of 100 MUg/kg body weight, maintained and restored the oxidative stability, the anti-inflammatory, and the hypolipidemic bioactivity in rats after induced disruption of these parameters by LPS injection. This improvement by SAV was mediated by upregulation of AKT1. PMID- 22824370 TI - Antibiotic resistance: understanding how to control it. PMID- 22824369 TI - Who does not participate in a follow-up postal study? a survey of infertile couples treated by in vitro fertilization. AB - BACKGROUND: A good response rate has been considered as a proof of a study's quality. Decreasing participation and its potential impact on the internal validity of the study are of growing interest. Our objective was to assess factors associated with contact and response to a postal survey in a epidemiological study of the long-term outcome of IVF couples. METHODS: The DAIFI study is a retrospective cohort including 6,507 couples who began an IVF program in 2000-2002 in one of the eight participating French IVF centers. Medical data on all 6,507 couples were obtained from IVF center databases, and information on long-term outcome was available only for participants in the postal survey (n = 2,321). Logistic regressions were used to assess firstly factors associated with contact and secondly factors associated with response to the postal questionnaire among contacted couples. RESULTS: Sixty-two percent of the 6,507 couples were contacted and 58% of these responded to the postal questionnaire. Contacted couples were more likely to have had a child during IVF treatment than non contactable couples, and the same was true of respondents compared with non respondents. Demographic and medical characteristics were both associated with probability of contact and probability of response. After adjustment, having a live birth during IVF treatment remained associated with both probabilities, and more strongly with probability of response. Having a child during IVF treatment was a major factor impacting on participation rate. CONCLUSIONS: Non-response as well as non-contact were linked to the outcome of interest, i.e. long-term parenthood success of infertile couples. Our study illustrates that an a priori hypothesis may be too simplistic and may underestimate potential bias. In the context of growing use of analytical methods that take attrition into account (such as multiple imputation), we need to better understand the mechanisms that underlie attrition in order to choose the most appropriate method. PMID- 22824371 TI - Antibiotic therapy for inducible AmpC beta-lactamase-producing Gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? AB - Some bacteria that possess chromosomally determined AmpC beta-lactamases may express these enzymes at a high level following exposure to beta-lactams, either by induction or selection for derepressed mutants. This may lead to clinical failure even if an isolate initially tests susceptible in vitro, a phenomenon best characterised by third-generation cephalosporin therapy for Enterobacter bacteraemia or meningitis. Several other Enterobacteriaceae, such as Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (often termed the 'ESCPM' group), may also express high levels of AmpC. However, the risk of clinical failure with beta-lactams that test susceptible in vitro is less clear in these species than for Enterobacter. Laboratories frequently do not report beta-lactam or beta-lactamase inhibitor combination drug susceptibilities for ESCPM organisms, encouraging alternative therapy with quinolones, aminoglycosides or carbapenems. However, quinolones and carbapenems present problems with selective pressure for multiresistant organisms, and aminoglycosides with potential toxicity. The risk of emergent AmpC-mediated resistance for non-Enterobacter spp. appears rare in clinical studies. Piperacillin/tazobactam may remain effective and may be less selective for AmpC derepressed mutants than cephalosporins. The potential roles for agents such as cefepime or trimethoprim/sulfamethoxazole are also discussed. Clinical studies that better define optimal treatment for this group of bacteria are required. PMID- 22824373 TI - Lower omega-3 fatty acid intake and status are associated with poorer cognitive function in older age: A comparison of individuals with and without cognitive impairment and Alzheimer's disease. AB - OBJECTIVES: Various strands of evidence suggest that low intake of omega-3 fatty acids increases risk of cognitive decline and dementia. The present study investigated differences in dietary intake and blood plasma content of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) in individuals with cognitive impairment no dementia (CIND), individuals with Alzheimer's disease (AD), and healthy volunteers (HV). METHODS: A total of 135 individuals aged between 55 and 91 years (19 AD, 55 CIND, and 61 HV) were assessed predominantly within a hospital setting. RESULTS: Compared with age and sex-matched HV, individuals with AD or CIND performed poorly on a majority of tests of cognitive function. Impairment was greatest for delayed and verbal recognition memory. CIND individuals were less impaired than AD individuals. Omega-3 intake and the percentage of EPA and DHA in plasma phosphatidylcholine (PC) showed a similar pattern (AD < HV, with intermediate scores for CIND). Across the whole sample, and after controlling for age, years of education, level of socio-economic deprivation, and gender, omega-3 intake, plasma PC DHA, and plasma PC EPA were all significant positive predictors of memory functioning. DISCUSSION: These results are consistent with the possibility that omega-3 fatty acid nutrition has an impact on cognitive decline, but could equally be explained by dietary changes that occurred after onset of cognitive decline. It is also possible that the results could be explained by unknown confounding factors. PMID- 22824374 TI - Hormonal therapies for new onset and relapsed depression during perimenopause. AB - In recent years the perimenopause has become recognised as a 'window of vulnerability' for women's mood. The risk of depression during perimenopause is high and treatment failure is common. Perimenopausal depression encompasses both new onset (first episode) depression occurring during perimenopause as well as a relapse during perimenopause in women with a history of depression. Perimenopausal depression is increasingly recognised as a new subtype of depression with specific clinical characteristics. Current treatments for perimenopausal depression have high failure rates, multiple adverse effects and potentially damaging long term consequences. This review examines both new onset and relapsed depression during perimenopause, biological mechanisms of perimenopausal depression, and the role of hormonal therapies. PMID- 22824372 TI - Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. AB - BACKGROUND: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer's disease (AD). METHODS: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. RESULTS: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. CONCLUSIONS: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife. PMID- 22824375 TI - Effect of sawdust addition on composting of separated raw and anaerobically digested pig manure. AB - Manures need the addition of carbon-rich bulking agents to conserve N during composting, which increases the cost of the composting process. The recommended proportion of manure/sawdust, based on a carbon (C):nitrogen (N) ratio, is approximately 3:2. Two composting experiments were conducted to determine the impact of varying the proportion of sawdust to either separated raw, or separated anaerobically digested pig manures. To determine stability and maturity of the final compost, oxygen uptake rate (OUR) and germination index (GI) tests were conducted. For both experiments, three treatments were employed: manure-only (Treatment A), manure/sawdust mixed 4:1, fresh weight (Treatment B), and manure/sawdust mixed 3:2, fresh weight (Treatment C). The mixtures were composted in tumblers for 56 days with regular turning. The composting material was tested over the study duration for temperature, pH, water content, organic matter, C:N ratio and bulk density. For both Treatments B and C, the GI indicated low levels of phytotoxicity, and OUR values were lower than the recommended Irish threshold of 13 mmol O(2) kg OM(-1) h(-1), indicating that a high quality compost was produced. The proportion of sawdust to separated manure used can be reduced to make a cost saving, while still producing a stable end-product: 60% less sawdust is required to compost at a manure-to-sawdust ratio of 4:1 compared to the previously recommended ratio of 3:2. PMID- 22824376 TI - Exploring how IBCLCs manage ethical dilemmas: a qualitative study. AB - BACKGROUND: Professional health care practice should be based on ethical decisions and actions. When there are competing ethical standards or principles, one must choose between two or more competing options. This study explores ethical dilemmas experienced by International Board Certified Lactation Consultants. METHODS: The investigator interviewed seven International Board Certified Lactation Consultants and analyzed the interviews using qualitative research methods. RESULTS: "Staying Mother-Centred" emerged as the overall theme. It encompassed six categories that emerged as steps in managing ethical dilemmas: 1) recognizing the dilemma; 2) identifying context; 3) determining choices; 4) strategies used; 5) results and choices the mother made; and 6) follow-up. The category, "Strategies used", was further analyzed and six sub-themes emerged: building trust; diffusing situations; empowering mothers; finding balance; providing information; and setting priorities. CONCLUSIONS: This study provides a framework for understanding how International Board Certified Lactation Consultants manage ethical dilemmas. Although the details of their stories changed, the essence of the experience remained quite constant with the participants making choices and acting to support the mothers. The framework could be the used for further research or to develop tools to support IBCLCs as they manage ethical dilemmas and to strengthen the profession with a firm ethics foundation. PMID- 22824377 TI - Phospholipid sources for adrenic acid mobilization in RAW 264.7 macrophages. Comparison with arachidonic acid. AB - Cells metabolize arachidonic acid (AA) to adrenic acid (AdA) via 2-carbon elongation reactions. Like AA, AdA can be converted into multiple oxygenated metabolites, with important roles in various physiological and pathophysiological processes. However, in contrast to AA, there is virtually no information on how the cells regulate the availability of free AdA for conversion into bioactive products. We have used a comparative lipidomic approach with both gas chromatography and liquid chromatography coupled to mass spectrometry to characterize changes in the levels of AA- and AdA-containing phospholipid species in RAW 264.7 macrophage-like cells. Incubation of the cells with AA results in an extensive conversion to AdA but both fatty acids do not compete with each other for esterification into phospholipids. AdA but not AA, shows preference for incorporation into phospholipids containing stearic acid at the sn-1 position. After stimulation of the cells with zymosan, both AA and AdA are released in large quantities, albeit AA is released to a greater extent. Finally, a variety of phosphatidylcholine and phosphatidylinositol molecular species contribute to AA; however, AdA is liberated exclusively from phosphatidylcholine species. Collectively, these results identify significant differences in the cellular utilization of AA and AdA by the macrophages, suggesting non-redundant biological actions for these two fatty acids. PMID- 22824378 TI - New pieces of a puzzle: the current biological picture of MPN. AB - Over the last years, we have witnessed significant improvement in our ability to elucidate the genetic events, which contribute to the pathogenesis of acute and chronic leukemias, and also in patients with myeloproliferative neoplasms (MPN). However, despite significant insight into the role of specific mutations, including the JAK2V617F mutation, in MPN pathogenesis, the precise mechanisms by which specific disease alleles contribute to leukemic transformation in MPN remain elusive. Here we review recent studies aimed at understanding the role of downstream signaling pathways in MPN initiation and phenotype, and discuss how these studies have begun to lead to novel insights with biologic, clinical, and therapeutic relevance. PMID- 22824379 TI - Lack of association between the rs2294008 polymorphism in the prostate stem cell antigen gene and colorectal neoplasia: a case-control and immunohistochemical study. AB - BACKGROUND: Prostate stem cell antigen (PSCA) has been implicated in the pathogenesis of several solid tumours, either due to changes in protein expression, or through association with the rs2294008 polymorphism in the PSCA gene. To our knowledge, the role of PSCA in the development of colorectal neoplasia has not been explored. We performed a genotyping study to assess for associations between the rs2294008 polymorphism and risk of adenomatous polyps and colorectal cancer. DNA samples were available from 388 individuals with colorectal neoplasia and 496 controls, all of whom had undergone screening colonoscopy. In addition, we performed immunohistochemical staining for PSCA in colonic tissue representing all stages of the adenoma-carcinoma sequence. RESULTS: No genotypic associations were found between the rs2294008 polymorphism and the risk of colorectal adenomata or cancer. Immunohistochemical staining did not reveal any alteration in PSCA expression accompanying the adenoma-carcinoma sequence. CONCLUSION: From these data it seems unlikely that PSCA has a role in the initiation or progression of colorectal neoplasia. PMID- 22824380 TI - Sets2Networks: network inference from repeated observations of sets. AB - BACKGROUND: The skeleton of complex systems can be represented as networks where vertices represent entities, and edges represent the relations between these entities. Often it is impossible, or expensive, to determine the network structure by experimental validation of the binary interactions between every vertex pair. It is usually more practical to infer the network from surrogate observations. Network inference is the process by which an underlying network of relations between entities is determined from indirect evidence. While many algorithms have been developed to infer networks from quantitative data, less attention has been paid to methods which infer networks from repeated co occurrence of entities in related sets. This type of data is ubiquitous in the field of systems biology and in other areas of complex systems research. Hence, such methods would be of great utility and value. RESULTS: Here we present a general method for network inference from repeated observations of sets of related entities. Given experimental observations of such sets, we infer the underlying network connecting these entities by generating an ensemble of networks consistent with the data. The frequency of occurrence of a given link throughout this ensemble is interpreted as the probability that the link is present in the underlying real network conditioned on the data. Exponential random graphs are used to generate and sample the ensemble of consistent networks, and we take an algorithmic approach to numerically execute the inference method. The effectiveness of the method is demonstrated on synthetic data before employing this inference approach to problems in systems biology and systems pharmacology, as well as to construct a co-authorship collaboration network. We predict direct protein-protein interactions from high-throughput mass spectrometry proteomics, integrate data from Chip-seq and loss-of-function/gain of-function followed by expression data to infer a network of associations between pluripotency regulators, extract a network that connects 53 cancer drugs to each other and to 34 severe adverse events by mining the FDA's Adverse Events Reporting Systems (AERS), and construct a co-authorship network that connects Mount Sinai School of Medicine investigators. The predicted networks and online software to create networks from entity-set libraries are provided online at http://www.maayanlab.net/S2N. CONCLUSIONS: The network inference method presented here can be applied to resolve different types of networks in current systems biology and systems pharmacology as well as in other fields of research. PMID- 22824381 TI - A rapidly progressing lymphocyte exhaustion after severe sepsis. AB - Septic syndromes induce immune alterations that have long been considered solely an overwhelming pro-inflammatory response. Increasing evidence now suggests that, after the first pro-inflammatory hours, sepsis is accompanied by the occurrence of a systemic immune failure. Here, novel perspectives regarding sepsis-induced lymphocyte alterations will be discussed in the context of a recently published study investigating overtime evolution of co-inhibitory lymphocyte receptor expressions in patients with severe sepsis. PMID- 22824382 TI - Efflux of glutathione and glutathione complexes from human erythrocytes in response to vanadate. AB - The main objective of the present study was to investigate if vanadate is extruded from the cells in a glutathione dependent manner resulting in the appearance of extracellular glutathione and complexes of glutathione with vanadium. Vanadate significantly depleted intracellular non-protein sulfhydryl (NPSH) levels in a time- and concentration-dependent manner. The intracellular NPSH level was decreased to 0.0 +/- 0.0 MUmol/ml erythrocyte when exposed to 10 mM of vanadate for 4h. Extracellular NPSH level was increased concomitantly with the intracellular decrease and reached to 0.1410 +/- 0.005 MUmol/ml erythrocyte in 4h. Intracellular decrease and extracellular increase in NPSH levels were significantly inhibited in the presence of DIDS, a chloride-bicarbonate exchanger which also mediates phosphate and arsenate transport in erythrocytes. In parallel with the increase in extracellular NPSH levels, significant increases in extracellular glutathione levels were detected following exposure to vanadate. Extracellular glutathione levels reached to 0.0150 +/- 0.0.001, 0.0330 +/- 0.001, and 0.0576 +/- 0.002 MUmol/ml erythrocyte with 1, 5, and 10 mM of vanadate respectively. Dimercaptosuccinic acid treatment of supernatants significantly increased the glutathione levels measured in the extracellular media. Utilization of MK571 an MRP inhibitor decreased the rate of glutathione efflux from erythrocytes suggesting a role for this membrane transporter in the process. A known methylation inhibitor periodate oxidized adenosine decreased the rate of glutathione efflux from erythrocytes. This observed decrease in extracellular GSH levels suggests that GSH release partly requires a proper cellular methylation process and that part of GSH detected in the extracellular media may arise from GSH-vandium complexes. The results of the present study indicate that human erythrocyte efflux glutathione in reduced free form and in conjugated form/s that can be recovered with dimercaptosuccinic acid when exposed to vanadate. PMID- 22824383 TI - Generation and characterization of submicron size bubbles. AB - A baffled high intensity agitation (BHIA) cell was used to generate submicron size bubbles of an average diameter around 500nm by hydrodynamic cavitation. The generation of submicron size bubbles by BHIA cell was found to be largely dependent on the agitation speed of impellers. The duration of agitation and temperature showed only a marginal effect on generation of submicron size bubbles. Surface properties such as zeta-potential and stability of submicron size bubbles were found to be highly dependent on the chemistry of solutions in which the bubbles are generated. The presence of surfactant and frother in water was found to be beneficial for generating a larger number of submicron size bubbles that are more stable, having a life time of up to 24h. PMID- 22824384 TI - The analytical model of nanoparticle recovery by microflotation. AB - A model of collision and collection of Brownian submicron particles based on the creation of a convective-diffusion layer near a bubble surface and overcoming the energy barrier created by particle/bubble interaction is developed. Simple analytical expressions describing the rate of collision and collection efficiency are obtained. The collision and collection minimums and the limits of theory applicability are analysed. PMID- 22824411 TI - Increased mechanically-induced ectopy in the hypertrophied heart. AB - INTRODUCTION: Left ventricular hypertrophy (LVH) predisposes patients to arrhythmias, but the mechanism of these arrhythmias is unclear. Here we show that hearts from spontaneously hypertensive rats (SHR) have a lower threshold for induction mechanically induced arrhythmias compared to age matched Wistar-Kyoto (WKY). METHODS: Recordings were made from isolated hearts from nine month old SHR (n = 18) and WKY (n = 17) rats. A water filled balloon in the left ventricle had its volume controlled by a servo-driven syringe. LVEDP was abruptly increased in increments until an ectopic beat was detected by an epicardial MAP electrode. Alternatively, LVEDP was abruptly reduced back to 5 mm Hg from an elevated pressure. RESULTS: SHR hearts had a lower threshold for stretch induced ectopics (29.87 +/- 2.79 mm Hg vs. 42.23 +/- 2.33 mm Hg, p < 0.01) and for release induced ectopics (24.09 +/- 1.40 vs. 37.23 +/- 3.22, p < 0.01). Perfusion with 100 MUM streptomycin increased threshold for stretch induced ectopics in both strains (from 49.4 +/- 4.7 to 69.5 +/- 6.9 mm Hg in WKY; p < 0.05 and from 21.2 +/- 3.5 to 39.7 +/- 9.0 mm Hg in SHR; p = 0.07). 100 MUM streptomycin also increased threshold for release induced ectopics in SHR (from 23.5 +/- 3.6 to 32.6 +/- 4.9 mm Hg; p < 0.05) but not in WKY. Perfusion with 0.01 MUM isoprenaline decreased the threshold for stretch induced ectopics in both strains (from 40.6 +/- 5.0 to 22.6 +/- 2.5 mm Hg in WKY; not significant at p < 0.05; p = 0.07 and from 31.0 +/ 5.5 to 14.3 +/- 2.5 mm Hg in SHR; p < 0.05). CONCLUSIONS: Hearts from SHR are more susceptible to both stretch-induced and release-induced arrhythmia. PMID- 22824385 TI - The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain. AB - BACKGROUND: High-mobility group box-1 protein (HMGB1) is a nuclear protein that regulates gene expression throughout the body. It can also become cytoplasmic and function as a neuromodulatory cytokine after tissue damage or injury. The manner in which HMGB1 influences the peripheral nervous system following nerve injury is unclear. The present study investigated the degree to which HMGB1 signaling contributes to the maintenance of neuropathic pain behavior in the rodent. RESULTS: Redistribution of HMGB1 from the nucleus to the cytoplasm occurred in both sensory neurons derived from a tibial nerve injured (TNI) rat and in a sensory neuron-like cell line following exposure to a depolarizing stimulus. We also observe that exogenous administration of HMGB1 to acutely dissociated sensory neurons derived from naive or TNI rodents elicit increased excitability. Furthermore systemic injection of glycyrrhizin (50 mg/kg; i.p.), a known inhibitor of HMGB1, reversed TNI-induced mechanical hyperalgesia at fourteen days and three months following nerve injury. CONCLUSIONS: We have identified that a persistent endogenous release of HMGB1 by sensory neurons may be a potent, physiologically relevant modulator of neuronal excitability. More importantly, the use of the anti-inflammatory compound and known inhibitor of HMGB1, glycyrrhizin, has the ability to diminish persistent pain behavior in a model of peripheral neuropathy, presumably through its ability to neutralize the cyotkine. The identification of HMGB1 as a potential therapeutic target may contribute to a better understanding of mechanisms associated with chronic pain syndromes. PMID- 22824412 TI - 'Information on the fly': Challenges in professional communication in high technological nursing. A focus group study from a radiotherapy department in Sweden. AB - BACKGROUND: Radiotherapy (RT) units are high-tech nursing environments. In Sweden, RT registered nurses (RNs) provide and manage RT in close collaboration with other professional groups, as well as providing nursing care for patients with cancer. Communication demands on these RNs are thus particularly complex. In this study, we aimed to better understand problems, strengths and change needs related to professional communication with and within the RT department, as a basis for developing a situation-specific intervention. METHODS: Focus groups discussions (FGDs) were conducted with different professional (RNs, assistant nurses, physicians, engineers and physicists) and user stakeholders. Transcripts of the FGDs were inductively analyzed by a team of researchers, to generate clinically relevant and useful data. RESULTS: These findings give insight into RT safety climate and are presented under three major headings: Conceptualization of professional domains; Organization and leadership issues; and Communication forms, strategies and processes. The impact of existing hierarchies, including how they are conceptualized and acted out in practice, was noted throughout these data. Despite other differences, participating professionals agreed about communication problems related to RT, i.e. a lack of systems and processes for information transfer, unclear role differentiation, a sense of mutual disrespect, and ad hoc communication taking place 'on the fly'. While all professional groups recognized extensive communication problems, none acknowledged the potential negative effects on patient safety or care described in the FGD with patient representatives. While RNs often initially denied the existence of a hierarchy, they placed themselves on a hierarchy in their descriptions, describing their own role as passive, with a sense of powerlessness. Potential safety hazards described in the FGDs include not reporting medical errors and silently ignoring or actively opposing new guidelines and regulations. CONCLUSIONS: There is a risk that RNs who view themselves as disenfranchised within an organization will act with passive resistance to change, rather than as change promoters. As interventions to strengthen teams cannot be stronger than the weakest link, RNs may need support in the transition "from silence to voice" in order to take a position of full professional responsibility in a multi-professional health care team. PMID- 22824413 TI - Analyzing repeated data collected by mobile phones and frequent text messages. An example of low back pain measured weekly for 18 weeks. AB - BACKGROUND: Repeated data collection is desirable when monitoring fluctuating conditions. Mobile phones can be used to gather such data from large groups of respondents by sending and receiving frequently repeated short questions and answers as text messages.The analysis of repeated data involves some challenges. Vital issues to consider are the within-subject correlation, the between measurement occasion correlation and the presence of missing values.The overall aim of this commentary is to describe different methods of analyzing repeated data. It is meant to give an overview for the clinical researcher in order for complex outcome measures to be interpreted in a clinically meaningful way. METHODS: A model data set was formed using data from two clinical studies, where patients with low back pain were followed with weekly text messages for 18 weeks. Different research questions and analytic approaches were illustrated and discussed, as well as the handling of missing data. In the applications the weekly outcome "number of days with pain" was analyzed in relation to the patients' "previous duration of pain" (categorized as more or less than 30 days in the previous year).Research questions with appropriate analytical methods 1: How many days with pain do patients experience? This question was answered with data summaries. 2: What is the proportion of participants "recovered" at a specific time point? This question was answered using logistic regression analysis. 3: What is the time to recovery? This question was answered using survival analysis, illustrated in Kaplan-Meier curves, Proportional Hazard regression analyses and spline regression analyses. 4: How is the repeatedly measured data associated with baseline (predictor) variables? This question was answered using generalized Estimating Equations, Poisson regression and Mixed linear models analyses. 5: Are there subgroups of patients with similar courses of pain within the studied population? A visual approach and hierarchical cluster analyses revealed different subgroups using subsets of the model data. CONCLUSIONS: We have illustrated several ways of analysing repeated measures with both traditional analytic approaches using standard statistical packages, as well as recently developed statistical methods that will utilize all the vital features inherent in the data. PMID- 22824414 TI - Hippocampal volume and internalizing behavior problems in adolescence. AB - Adolescence is characterized by dynamic changes in structural brain maturation. At the same time, adolescence is a critical time for the development of affective and anxiety-related disorders. Individual differences in typically developing children and adolescents may prove more valuable for identifying which brain regions correspond with internalizing behavior problems (i.e., anxious/depressive, withdrawal and somatic symptoms) on a continuous scale compared to clinical studies. Participants were 179 (92 males, 87 females) typically developing children and adolescents between ages 8 and 17. Hippocampal and amygdala volumes were measured automatically with FreeSurfer. Internalizing behavior was assessed with the Child Behavior Checklist (CBCL) completed by the parent, and associated with hippocampal and amygdala volumes. Hippocampal volume was inversely related with the total internalizing problems scale of the CBCL, irrespective of gender, age, or informant (mother or father). The effects were most prominent for the withdrawal and anxiety/depression subscales and the left hippocampus: more withdrawal and anxiety/depression was related to smaller left hippocampal volume. No associations were found between internalizing behavior and amygdala volume. This study shows that typically developing children and adolescents with high internalizing behavior share some of the neuroanatomical features of adult depression and anxiety-related disorders. PMID- 22824415 TI - Physical and psychosocial work environment factors and their association with health outcomes in Danish ambulance personnel - a cross-sectional study. AB - BACKGROUND: Reviews of the literature on the health and work environment of ambulance personnel have indicated an increased risk of work-related health problems in this occupation. The aim of this study was to compare health status and exposure to different work environmental factors among ambulance personnel and the core work force in Denmark. In addition, to examine the association between physical and psychosocial work environment factors and different measures of health among ambulance personnel. METHODS: Data were taken from a nationwide sample of ambulance personnel and fire fighters (n = 1,691) and was compared to reference samples of the Danish work force. The questionnaire contained measures of physical and psychosocial work environment as well as measures of musculoskeletal pain, mental health, self-rated health and sleep quality. RESULTS: Ambulance personnel have half the prevalence of poor self-rated health compared to the core work force (5% vs. 10%). Levels of mental health were the same across the two samples whereas a substantially higher proportion of the ambulance personnel reported musculoskeletal pain (42% vs. 29%). The ambulance personnel had higher levels of emotional demands and meaningfulness of and commitment to work, and substantially lower levels of quantitative demands and influence at work. Only one out of ten aspects of physical work environment was consistently associated with higher levels of musculoskeletal pain. Emotional demands was the only psychosocial work factor that was associated with both poorer mental health and worse sleep quality. CONCLUSIONS: Ambulance personnel have similar levels of mental health but substantially higher levels of musculoskeletal pain than the work force in general. They are more exposed to emotional demands and these demands are associated with higher levels of poor mental health and poor sleep quality. To improve work environment, attention should be paid to musculoskeletal problems and the presence of positive organizational support mechanisms that can prevent negative effects from the high levels of emotional demands. PMID- 22824416 TI - Genetic diversity of Theileria orientalis in tick vectors detected in Hokkaido and Okinawa, Japan. AB - In the present study, we investigated the possible tick vectors that can transmit Theileria orientalis in eastern Hokkaido, Japan. Questing ticks collected from three different districts, Taiki, Otofuke, and Shin-Hidaka, of Hokkaido included Ixodes persulcatus, Haemaphysalis megaspinosa, Haemaphysalis douglasi, and Ixodes ovatus, while all the ticks collected from Yonaguni island of Okinawa were identified as Haemaphysalis longicornis. When the ticks were screened by polymerase chain reaction (PCR) for T. orientalis, the parasite was commonly detected among all tick species. Genotype-specific PCR assays revealed that all tick species in Hokkaido were predominantly detected with type 2, while ticks collected from Okinawa (H. longicornis) were predominantly detected with type 1. Consistent with the genetic diversity of T. orientalis in ticks, genotyping PCR assays from cattle grazed in the same Hokkaido sampling locations identified type 2 as the most prevalent genotype. This study provides the first identification of I. persulcatus, H. megaspinosa, H. douglasi, and I. ovatus as possible tick vectors of T. orientalis, and finds that the variety of vectors apparently capable of transmitting T. orientalis is wider in Japan than expected. The authors suggest that tick control strategies should be modified in Hokkaido based on the seasonal activities of ticks identified in the present study. PMID- 22824417 TI - Phylogenetic analysis of isolates from new cases of HBV infection in Southern Italy. AB - The level of endemicity of hepatitis B virus (HBV) infections in Italy is low and genotype D infections predominant. New HBV strains may however be introduced as a result of movements of people from regions of high endemicity. The aim of the present study was to determine whether strains from new cases of acute hepatitis B detected in southern Italy were due to endemic or new HBV strains. We studied 34 isolates from patients with acute hepatitis B infection, and 35 from chronic hepatitis B patients. A phylogenetic analysis of preS/S region was done by comparing the sequences from the acute and chronic cases with references sequences. The study showed that 44% of strain from acute hepatitis B patients were of genotype A, 53% of genotype D, and 3% of genotype E. The molecular analysis of isolates from acute hepatitis B patients from Sicily showed a change in the local epidemiology of this infection, with an increase in HBV/A infections and a clustering effect for HBV D2, possibly correlated to immigration. The introduction of new genotypes , could have an effect on HBV-correlated diseases due to the different association between genotype, liver disease and response to antiviral therapy. PMID- 22824418 TI - Multilocus PCR-RFLP profiling in Trypanosoma cruzi I highlights an intraspecific genetic variation pattern. AB - Chagas disease represents a serious problem in public health. This zoonotic pathology is caused by the kinetoplastid Trypanosoma cruzi which displays a high genetic diversity falling into six Discrete Typing Units (TcI-TcVI). In Colombia, the prevalent DTU is TcI with findings of TcII, TcIII and TcIV in low proportions. The aim of this work was to observe the genetic variability within TcI using a multilocus PCR-RFLP strategy. We analyzed 70 single-celled clones from triatomines, reservoirs and humans that were amplified and restricted via ten PCR-RFLPs targets across TcI genome, the restriction fragments were used to construct phylograms according to calculated genetic distances. We obtained five polymorphic targets (1f8, HSP60, HSP70, SAPA and H1) and the consensus tree constructed according to these regions allowed us to observe two well-defined groups with close association to the transmission cycles (domestic/peridomestic and sylvatic) of Chagas disease in Colombia. Our findings allowed us to corroborate the previous reported genotypes based on the intergenic region of mini-exon gene. More studies examining the genetic diversity among T. cruzi I populations must be conducted in order to obtain a better understanding in regions where this DTU is endemic. PMID- 22824419 TI - Eimeria that infect fish are diverse and are related to, but distinct from, those that infect terrestrial vertebrates. AB - The Eimeria are ubiquitous parasites (Phylum: Apicomplexa; family: Coccidia) of the gut epithelium of vertebrates which complete their development in a single host species and whose sporocysts may be recognized by the presence of a Stieda body through which their sporozoites excyst. Their diversity and relationship to other kinds of coccidia have been successfully explored by molecular systematic studies based on the sequencing the 18S ribosomal DNA. To date, most attention has been paid to the diversity and evolutionary relationships of Eimeria spp. parasitizing terrestrial vertebrates, most especially those species infecting domesticated birds and mammals. Regrettably, no Eimeria have yet been considered from the Earth's first vertebrates: the fish. If Eimeria first evolved in fish, then extant piscine parasites should comprise a deeply branching assemblage at the base of well-constructed phylogenetic trees. Here, we sequenced portions of ribosomal DNA from several such isolates (from Eimeria anguillae, Eimeria daviesae, Eimeria percae, Eimeria variabilis, Eimeria rutili and Eimeria nemethi) and compared them to one another as well as to other available sequences from the parasites of fish and terrestrial vertebrates, in order to better understand their diversity and origins. By establishing that such piscine parasites comprise a deeply branching clade at the base of the Eimeriidae, these data substantiate the hypothesis that Eimeria may have originated in fish. Plainly, a great deal of coccidian diversity awaits future discovery and description. PMID- 22824420 TI - Sex differences in the response of the alveolar macrophage proteome to treatment with exogenous surfactant protein-A. AB - BACKGROUND: Male wild type (WT) C57BL/6 mice are less capable of clearing bacteria and surviving from bacterial pneumonia than females. However, if an oxidative stress (acute ozone exposure) occurs before infection, the advantage shifts to males who then survive at higher rates than females. We have previously demonstrated that survival in surfactant protein-A (SP-A) knockout (KO) mice compared to WT was significantly reduced. Because the alveolar macrophage (AM) is pivotal in host defense we hypothesized that SP-A and circulating sex hormones are responsible for these sex differences. We used 2D-DIGE to examine the relationship of sex and SP-A on the AM proteome. The role of SP-A was investigated by treating SP-A KO mice with exogenous SP-A for 6 and 18 hr and studying its effects on the AM proteome. RESULTS: We found: 1) less variance between KO males and females than between the WT counterparts by principal component analysis, indicating that SP-A plays a role in sex differences; 2) fewer changes in females when the total numbers of significantly changing protein spots or identified whole proteins in WT or 18 hr SP-A-treated males or females were compared to their respective KO groups; 3) more proteins with functions related to chaperones or protease balance and Nrf2-regulated proteins changed in response to SP-A in females than in males; and 4) the overall pattern of SP-A induced changes in actin-related proteins were similar in both sexes, although males had more significant changes. CONCLUSIONS: Although there seems to be an interaction between sex and the effect of SP-A, it is unclear what the responsible mechanisms are. However, we found that several of the proteins that were expressed at significantly higher levels in females than in males in WT and/or in KO mice are known to interact with the estrogen receptor and may thus play a role in the SP-A/sex interaction. These include major vault protein, chaperonin subunit 2 (beta) (CCT2), and Rho GDP alpha dissociation inhibitor. We conclude that sex differences exist in the proteome of AM derived from male and female mice and that SP-A contributes to these sex differences. PMID- 22824421 TI - Multiple independent analyses reveal only transcription factors as an enriched functional class associated with microRNAs. AB - BACKGROUND: Transcription factors (TFs) have long been known to be principally activators of transcription in eukaryotes and prokaryotes. The growing awareness of the ubiquity of microRNAs (miRNAs) as suppressive regulators in eukaryotes, suggests the possibility of a mutual, preferential, self-regulatory connectivity between miRNAs and TFs. Here we investigate the connectivity from TFs and miRNAs to other genes and each other using text mining, TF promoter binding site and 6 different miRNA binding site prediction methods. RESULTS: In the first approach text mining of PubMed abstracts reveal statistically significant associations between miRNAs and both TFs and signal transduction gene classes. Secondly, prediction of miRNA targets in human and mouse 3'UTRs show enrichment only for TFs but not consistently across prediction methods for signal transduction or other gene classes. Furthermore, a random sample of 986 TarBase entries was scored for experimental evidence by manual inspection of the original papers, and enrichment for TFs was observed to increase with score. Low-scoring TarBase entries, where experimental evidence is anticorrelated miRNA:mRNA expression with predicted miRNA targets, appear not to select for real miRNA targets to any degree. Our manually validated text-mining results also suggests that miRNAs may be activated by more TFs than other classes of genes, as 7% of miRNA:TF co occurrences in the literature were TFs activating miRNAs. This was confirmed when thirdly, we found enrichment for predicted, conserved TF binding sites in miRNA and TF genes compared to other gene classes. CONCLUSIONS: We see enrichment of connections between miRNAs and TFs using several independent methods, suggestive of a network of mutual activating and suppressive regulation. We have also built regulatory networks (containing 2- and 3-loop motifs) for mouse and human using predicted miRNA and TF binding sites and we have developed a web server to search and display these loops, available for the community at http://rth.dk/resources/tfmirloop. PMID- 22824422 TI - Identity and diversity of blood meal hosts of biting midges (Diptera: Ceratopogonidae: Culicoides Latreille) in Denmark. AB - BACKGROUND: Host preference studies in haematophagous insects e.g. Culicoides biting midges are pivotal to assess transmission routes of vector-borne diseases and critical for the development of veterinary contingency plans to identify which species should be included due to their risk potential. Species of Culicoides have been found in almost all parts of the world and known to live in a variety of habitats. Several parasites and viruses are transmitted by Culicoides biting midges including Bluetongue virus and Schmallenberg virus. The aim of the present study was to determine the identity and diversity of blood meals taken from vertebrate hosts in wild-caught Culicoides biting midges near livestock farms. METHODS: Biting midges were collected at weekly intervals for 20 weeks from May to October 2009 using light traps at four collection sites on the island Sealand, Denmark. Blood-fed female biting midges were sorted and head and wings were removed for morphological species identification. The thoraxes and abdomens including the blood meals of the individual females were subsequently subjected to DNA isolation. The molecular marker cytochrome oxidase I (COI barcode) was applied to identify the species of the collected biting midges (GenBank accessions JQ683259-JQ683374). The blood meals were first screened with a species-specific cytochrome b primer pair for cow and if negative with a universal cytochrome b primer pair followed by sequencing to identify mammal or avian blood meal hosts. RESULTS: Twenty-four species of biting midges were identified from the four study sites. A total of 111,356 Culicoides biting midges were collected, of which 2,164 were blood-fed. Specimens of twenty species were identified with blood in their abdomens. Blood meal sources were successfully identified by DNA sequencing from 242 (76%) out of 320 Culicoides specimens. Eight species of mammals and seven species of birds were identified as blood meal hosts. The most common host species was the cow, which constituted 77% of the identified blood meals. The second most numerous host species was the common wood pigeon, which constituted 6% of the identified blood meals. CONCLUSIONS: Our results suggest that some Culicoides species are opportunistic and readily feed on a variety of mammals and birds, while others seems to be strictly mammalophilic or ornithophilic. Based on their number, dispersal potential and blood feeding behaviour, we conclude that Culicoides biting midges are potential vectors for many pathogens not yet introduced to Denmark. PMID- 22824423 TI - Plasma suPAR levels are associated with mortality, admission time, and Charlson Comorbidity Index in the acutely admitted medical patient: a prospective observational study. AB - INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is the soluble form of the membrane-bound receptor (uPAR) expressed predominantly on various immune cells. Elevated plasma suPAR concentration is associated with increased mortality in various patient groups, and it is speculated that suPAR is a low-grade inflammation marker reflecting on disease severity. The aim of this prospective observational study was to determine if the plasma concentration of suPAR is associated with admission time, re-admission, disease severity/Charlson Comorbidity Index Score, and mortality. METHODS: We included 543 patients with various diseases from a Danish Acute Medical Unit during a two month period. A triage unit ensured that only medical patients were admitted to the Acute Medical Unit. SuPAR was measured on plasma samples drawn upon admission. Patients were followed-up for three months after inclusion by their unique civil registry number and using Danish registries to determine admission times, readmissions, International Classification of Diseases, 10th Edition (ICD-10) diagnoses, and mortality. Statistical analysis was used to determine suPAR's association with these endpoints. RESULTS: Increased suPAR was significantly associated with 90 day mortality (4.87 ng/ml in survivors versus 7.29 ng/ml in non-survivors, P < 0.0001), higher Charlson Score (P < 0.0001), and longer admission time (P < 0.0001), but not with readmissions. The association with mortality remained when adjusting for age, sex, C-reactive protein (CRP), and Charlson Score. Furthermore, among the various Charlson Score disease groups, suPAR was significantly higher in those with diabetes, cancer, cardiovascular disease, and liver disease compared to those without comorbidities. CONCLUSIONS: SuPAR is a marker of disease severity, admission time, and risk of mortality in a heterogeneous cohort of patients with a variety of diseases. The independent value of suPAR suggests it could be of value in prognostic algorithms. PMID- 22824424 TI - Physiological and biochemical responses of transgenic potato plants with altered expression of PSII manganese stabilizing protein. AB - Manganese-stabilizing protein (MSP) represents a key component of the oxygen evolving complex (OEC). Transgenic potato plants with both enhanced (sense) and reduced (anti-sense) MSP expression levels were generated to investigate the possible physiological role of MSP in overall plant growth, particularly in tuber development. MSP antisense plants exhibited both higher tuberization frequency and higher tuber yield with increased total soluble carbohydrates. The photosynthetic efficiencies of the plants were examined using the OJIP kinetics; MSP-antisense plants were photosynthetically more active than the MSP-sense and UT (untransformed) control plants. The oxygen measurements indicated that the relative oxygen evolution was directly proportional to the MSP expression, as MSP antisense plants showed much lower oxygen evolution compared to MSP-sense as well as UT plants. MSP-sense plants behaved like the UT plants with respect to morphology, tuber yield, and photosynthetic performance. Chlorophyll a fluorescence analyses indicate a possible lack of intact Oxygen Evolving Complexes (OECs) in MSP antisense plants, which allow access to internal non water electron donors (e.g., ascorbate and proline) and consequently increase the Photosystem II (PSII) activity of those plants. These findings further indicate that this altered photosynthetic machinery may be associated with early tuberization and increased tuberization frequency. PMID- 22824426 TI - Germ cells are not the primary factor for sexual fate determination in goldfish. AB - The presence of germ cells in the early gonad is important for sexual fate determination and gonadal development in vertebrates. Recent studies in zebrafish and medaka have shown that a lack of germ cells in the early gonad induces sex reversal in favor of a male phenotype. However, it is uncertain whether the gonadal somatic cells or the germ cells are predominant in determining gonadal fate in other vertebrate. Here, we investigated the role of germ cells in gonadal differentiation in goldfish, a gonochoristic species that possesses an XX-XY genetic sex determination system. The primordial germ cells (PGCs) of the fish were eliminated during embryogenesis by injection of a morpholino oligonucleotide against the dead end gene. Fish without germ cells showed two types of gonadal morphology: one with an ovarian cavity; the other with seminiferous tubules. Next, we tested whether function could be restored to these empty gonads by transplantation of a single PGC into each embryo, and also determined the gonadal sex of the resulting germline chimeras. Transplantation of a single GFP-labeled PGC successfully produced a germline chimera in 42.7% of the embryos. Some of the adult germline chimeras had a developed gonad on one side that contained donor derived germ cells, while the contralateral gonad lacked any early germ cell stages. Female germline chimeras possessed a normal ovary and a germ-cell free ovary-like structure on the contralateral side; this structure was similar to those seen in female morphants. Male germline chimeras possessed a testis and a contralateral empty testis that contained some sperm in the tubular lumens. Analysis of aromatase, foxl2 and amh expression in gonads of morphants and germline chimeras suggested that somatic transdifferentiation did not occur. The offspring of fertile germline chimeras all had the donor-derived phenotype, indicating that germline replacement had occurred and that the transplanted PGC had rescued both female and male gonadal function. These findings suggest that the absence of germ cells did not affect the pathway for ovary or testis development and that phenotypic sex in goldfish is determined by somatic cells under genetic sex control rather than an interaction between the germ cells and somatic cells. PMID- 22824425 TI - Hox proteins coordinate peripodial decapentaplegic expression to direct adult head morphogenesis in Drosophila. AB - The Drosophila BMP, decapentaplegic (dpp), controls morphogenesis of the ventral adult head through expression limited to the lateral peripodial epithelium of the eye-antennal disc by a 3.5 kb enhancer in the 5' end of the gene. We recovered a 15 bp deletion mutation within this enhancer that identified a homeotic (Hox) response element that is a direct target of labial and the homeotic cofactors homothorax and extradenticle. Expression of labial and homothorax are required for dpp expression in the peripodial epithelium, while the Hox gene Deformed represses labial in this location, thus limiting its expression and indirectly that of dpp to the lateral side of the disc. The expression of these homeodomain genes is in turn regulated by the dpp pathway, as dpp signalling is required for labial expression but represses homothorax. This Hox-BMP regulatory network is limited to the peripodial epithelium of the eye-antennal disc, yet is crucial to the morphogenesis of the head, which fate maps suggest arises primarily from the disc proper, not the peripodial epithelium. Thus Hox/BMP interactions in the peripodial epithelium of the eye-antennal disc contribute inductively to the shape of the external form of the adult Drosophila head. PMID- 22824427 TI - Small GTPase Rab4b participates in the gene transcription of 20-hydroxyecdysone and insulin pathways to regulate glycogen level and metamorphosis. AB - The insulin and 20-hydroxyecdysone (20E) pathways coordinately regulate insect growth and metamorphosis. However, the molecular mechanism of the interaction of these two pathways in regulating insect development is not well understood. In the present study, we found that a small GTPase Rab4b from a lepidopteran insect Helicoverpa armigera participates in gene transcription in the two pathways. The results show that RNA interference of Rab4b in larvae results in a decrease in glycogen levels, small pupae, abnormal metamorphic transition, or larval death. The molecular mechanisms are demonstrated that knockdown of Rab4b in the larvae suppresses the transcription of glycogen synthase (GS), as well as the metamorphic-initiating factor (Br) and hormone receptor 3 (HR3), but increases the transcription of Forkhead box class O (FOXO). Further studies in the cell line confirm that Rab4b is necessary for gene transcription in the insulin and 20E pathways. Rab4b locates in the cytoplasm and takes part in regulation on FOXO cytoplasmic location by insulin induction, but travels toward the cell membrane upon 20E induction without affecting the FOXO location. The transcription of Rab4b could be upregulated by insulin injection or glucose feeding to the larvae, but not by 20E or juvenile hormone analogy methoprene. Our data suggest that Rab4b takes part in metamorphosis by regulating gene transcription and glycogen level in the insulin and 20E pathways. PMID- 22824428 TI - A1 adenosine receptor modulation of chemically and electrically evoked lumbar locomotor network activity in isolated newborn rat spinal cords. AB - It is not well-studied how the ubiquitous neuromodulator adenosine (ADO) affects mammalian locomotor network activities. We analyzed this here with focus on roles of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)-sensitive A(1)-type ADO receptors. For this, we recorded field potentials from ventral lumbar nerve roots and electrically stimulated dorsal roots in isolated newborn rat spinal cords. At >= 25MUM, bath-applied ADO slowed synchronous bursting upon blockade of anion channel-mediated synaptic inhibition by bicuculline (20 MUM) plus strychnine (1 MUM) and this depression was countered by DPCPX (1 MUM) as tested at 100 MUM ADO. ADO abolished this disinhibited rhythm at >= 500 MUM. Contrary, the single electrical pulse-evoked dorsal root reflex, which was enhanced in bicuculline/strychnine-containing solution, persisted at all ADO doses (5 MUM-2 mM). In control solution, >= 500 MUM ADO depressed this reflex and pulse train evoked bouts of alternating fictive locomotion; this inhibition was reversed by 1 MUM DPCPX. ADO (5 MUM-2 mM) did not depress, but stabilize alternating fictive locomotion evoked by serotonin (10 MUM) plus N-methyl-d-aspartate (4-5 MUM). Addition of DPCPX (1MUM) to control solution did not change either the dorsal root reflex or rhythmic activities indicating lack of endogenous A(1) receptor activity. Our findings show A(1) receptor involvement in ADO depression of the dorsal root reflex, electrically evoked fictive locomotion and spontaneous disinhibited lumbar motor bursting. Contrary, chemically evoked fictive locomotion and the enhanced dorsal root reflex in disinhibited lumbar locomotor networks are resistant to ADO. Because ADO effects in standard solution occurred at doses that are notably higher than those occurring in vivo, we hypothesize that newborn rat locomotor networks are rather insensitive to this neuromodulator. PMID- 22824429 TI - Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. AB - Recently it has become apparent that microglia play a role not only in responding to insults within the central nervous system but also in responding to changes in synaptic activity and potentially modulating synaptic function. This has led to an enormous expansion of interest in how microglia respond to both pathological and nonpathological challenges, with activities that are associated with unique morphological transformations. Examining changes in microglial morphology can provide direct insight into the cells' functional activities, as morphological status is recognized to be tightly coupled with function. Despite these advances in knowledge, many of the image-based morphometric procedures used to investigate changes in microglial morphology have not kept pace. This has created a situation in which morphometric approaches that have been extensively employed in the past can no longer provide accurate information on the complex transformations that microglia can undergo, particularly under non-pathological conditions. This review critically examines the strengths and weaknesses of existing morphometric analysis procedures. This review further examines efforts to improve the utility of existing approaches and discusses new developments, such as digital reconstruction, that yield more accurate and specific information on how microglia remodel themselves. Ultimately, an improved understanding of the strengths and limitations of existing, and emerging, morphometric approaches will greatly facilitate efforts to understand how microglia remodel themselves in response to the full spectrum of challenges that they are known to encounter. PMID- 22824431 TI - Regulation of cholesterol biosynthesis and cancer signaling. AB - Cellular growth is highly dependent on sustained production of lipids. Sterol composition of cellular membranes determines multiple biochemical and biophysical properties of membrane-based processes including vesicle traffic, receptor signaling, and assembly of protein complexes. Lipid biogenesis has become an attractive biochemical target in cancer given the high level of dependency on sterols and lipids in a cancer cell. This review summarized the current knowledge of mechanisms of interaction between the metabolism of sterols and receptor signaling. PMID- 22824430 TI - Cholesterol and prostate cancer. AB - Prostate cancer risk can be modified by environmental factors, however the molecular mechanisms affecting susceptibility to this disease are not well understood. As a result of a series of recently published studies, the steroidal lipid, cholesterol, has emerged as a clinically relevant therapeutic target in prostate cancer. This review summarizes the findings from human studies as well as animal and cell biology models, which suggest that high circulating cholesterol increases risk of aggressive prostate cancer, while cholesterol lowering strategies may confer protective benefit. Relevant molecular processes that have been experimentally tested and might explain these associations are described. We suggest that these promising results now could be applied prospectively to attempt to lower risk of prostate cancer in select populations. PMID- 22824433 TI - Atrial fibrillation monitoring: mathematics meets real life. PMID- 22824432 TI - Post-lanosterol biosynthesis of cholesterol and cancer. AB - Mammalian cells require cholesterol for proliferation. Cholesterol contributes not only to the physicochemical properties of membranes but also to the organization of lipid rafts involved in signal transduction. Inhibition of cholesterol biosynthesis from lanosterol results in the inhibition of cell cycle progression and, in certain cell types, also in the induction of cell differentiation. Cholesterol metabolism, thus, appears to play a relevant role in the decision making between cell proliferation and differentiation. Several regulators of cholesterol metabolism, including certain microRNAs, are also involved in cell cycle regulation. The relevance of these processes in cancer underscores the interest for studying the role of cholesterol in tumorigenesis and exploring the possibility of interfering with the growth of malignant cells by manipulation of cholesterol metabolism. PMID- 22824434 TI - A comprehensive evaluation of rhythm monitoring strategies for the detection of atrial fibrillation recurrence: insights from 647 continuously monitored patients and implications for monitoring after therapeutic interventions. AB - BACKGROUND: Intermittent rhythm monitoring (IRM) to detect atrial fibrillation (AF) recurrence is employed to evaluate the success of therapeutic interventions. In a large population of patients with continuous monitoring (CM), we investigated the sensitivity of various frequencies and durations of IRM strategies on the detection of AF recurrence, the dynamics behind AF recurrence detection, and we describe measures to evaluate temporal AF recurrence. METHODS AND RESULTS: Rhythm histories of 647 patients (mean AF burden, 0.12+/-0.22; median, 0.014; 687 patient-years) with implantable CM devices were reconstructed and analyzed. With the use of computationally intensive simulation, the sensitivity of IRM of various frequencies and durations on the identification of AF recurrence was evaluated. Prolonged-duration IRM was superior to shorter IRM (P<0.0001). However, even with aggressive IRM strategies, AF recurrence was not detected in a great proportion of patients. The temporal AF burden aggregation (AF density) was directly related to IRM sensitivity (P<0.0001). Even at similar AF burdens, patients with high-density AF required higher-frequency or prolonged duration IRM to achieve the same sensitivity as in low-density AF (P<0.0001). Patients with high-density, low-burden AF benefit the most from CM for detection of AF recurrence. CONCLUSIONS: IRM follow-up is significantly inferior to CM. IRM strategies will not identify AF recurrence in a great proportion of patients at risk. Temporal AF characteristics play a significant role in AF recurrence detection with the use of IRM. For the scientific, evidence-based evaluation of AF treatments, CM should be strongly recommended. Prospective studies are required to evaluate whether CM to guide clinical management can also improve patient outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00806689. PMID- 22824436 TI - [Systemic inflammation as a link between chronic obstructive pulmonary disease and its comorbidities]. PMID- 22824437 TI - Keratinocyte expression of inflammatory mediators plays a crucial role in substance P-induced acute and chronic pain. AB - Tibia fracture in rats followed by cast immobilization leads to nociceptive, trophic, vascular and bone-related changes similar to those seen in Complex Regional Pain Syndrome (CRPS). Substance P (SP) mediated neurogenic inflammation may be responsible for some of the signs of CRPS in humans. We therefore hypothesized that SP acting through the SP receptor (NK1) leads to the CRPS-like changes found in the rat model. In the present study, we intradermally injected rats with SP and monitored hindpaw mechanical allodynia, temperature, and thickness as well as tissue levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), and nerve growth factor-beta (NGF) for 72 h. Anti-NGF antibody was utilized to block the effects of SP-induced NGF up-regulation. Fracture rats treated with the selective NK1 receptor antagonist LY303870 prior to cast removal were assessed for BrdU, a DNA synthesis marker, incorporation in skin cells to examine cellular proliferation. Bone microarchitecture was measured using micro computed tomography (MUCT). We observed that: (1) SP intraplantar injection induced mechanical allodynia, warmth and edema as well as the expression of nociceptive mediators in the hindpaw skin of normal rats, (2) LY303870 administered intraperitoneally after fracture attenuated allodynia, hindpaw unweighting, warmth, and edema, as well as cytokine and NGF expression, (3) LY303870 blocked fracture-induced epidermal thickening and BrdU incorporation after fracture, (4) anti-NGF antibody blocked SP-induced allodynia but not warmth or edema, and (5) LY303870 had no effect on bone microarchitecture. Collectively our data indicate that SP acting through NK1 receptors supports the nociceptive and vascular components of CRPS, but not the bone-related changes. PMID- 22824438 TI - Determinants of (sustained) overweight and complaints in children and adolescents in primary care: the DOERAK cohort study design. AB - BACKGROUND: Almost half of the adult Dutch population is currently overweight and the prevalence of overweight children is rising at alarming rates as well. Obese children consult their general practitioner (GP) more often than normal weight children. The Dutch government has assigned a key role to the GP in the prevention of overweight.The DOERAK cohort study aims to clarify differences between overweight and non-overweight children that consult the GP; are there differences in number of consultations and type and course of complaints? Is overweight associated with lower quality of life or might this be influenced by the type of complaint? What is the activity level of overweight children compared to non-overweight children? And is (sustained) overweight of children associated with parameters related to the energy balance equation? METHODS/DESIGN: A total of 2000 overweight (n = 500) and non-overweight children (n = 1500) aged 2 to 18 years who consult their GP, for any type of complaint in the South-West of the Netherlands are included.At baseline, height, weight and waist circumference are measured during consultation. The number of GP consultations over the last twelve months and accompanying diagnoses are acquired from the medical file. Complaints, quality of life and parameters related to the energy balance equation are assessed with an online questionnaire children or parents fill out at home. Additionally, children or parents keep a physical activity diary during the baseline week, which is validated in a subsample (n = 100) with an activity monitor. Parents fill out a questionnaire about demographics, their own activity behaviour and perceptions on dietary habits and activity behaviour, health and weight status of their child. The physical and lifestyle behaviour questions are repeated at 6, 12 and 24 months follow-up. The present study is a prospective observational cohort in a primary care setting. DISCUSSION: The DOERAK cohort study is the first prospective study that investigates a large cohort of overweight and non-overweight children in primary care. The total study population is expected to be recruited by 2013, results will be available in 2015. PMID- 22824439 TI - The digital revolution and adolescent brain evolution. AB - Remarkable advances in technologies that enable the distribution and use of information encoded as digital sequences of 1s or 0s have dramatically changed our way of life. Adolescents, old enough to master the technologies and young enough to welcome their novelty, are at the forefront of this "digital revolution." Underlying the adolescent's eager embracement of these sweeping changes is a neurobiology forged by the fires of evolution to be extremely adept at adaptation. The consequences of the brain's adaptation to the demands and opportunities of the digital age have enormous implications for adolescent health professionals. PMID- 22824440 TI - Reaching youth with out-of-facility HIV and reproductive health services: a systematic review. AB - PURPOSE: Many young people, particularly those who are marginalized and most at risk for HIV and reproductive health-related problems, cannot or will not seek traditional facility-based health services. Policies and programs are being implemented to provide them with these health services in the community. We sought to review the effectiveness of such approaches in increasing HIV and reproductive health service use. METHODS: A systematic literature review was undertaken to identify policies promoting or programs delivering HIV or reproductive health services in the community. We reviewed studies that evaluated uptake of services or commodities. Data from studies meeting inclusion criteria were qualitatively analyzed. RESULTS: Twenty studies met inclusion criteria, including 10 containing comparative data (e.g., before and after study or control study design). The studies generally demonstrated positive impact, although results varied across settings and approaches. The most successful approaches included mail-based chlamydia screening in the Netherlands, condom distribution via street outreach in Louisiana, home-based HIV counseling and testing in Malawi, and promotion of over-the-counter access to emergency contraception in various countries. CONCLUSION: Overall, this review suggests that out-of-facility approaches can be important avenues to reach youth. Continued evaluation is necessary to better understand specific approaches that can successfully deliver health services. PMID- 22824441 TI - Individual and contextual determinants of quality of life in adolescents with congenital heart disease. AB - PURPOSE: An essential goal of health care interventions is to promote quality of life. In line with recent biopsychosocial frameworks emphasizing individual and contextual resources for improving quality of life, the present prospective study aimed at identifying potential determinants of quality of life in a large sample of adolescents with congenital heart disease (CHD). In doing so, the present study focused on parental support, peer support, and sense of coherence (SOC), all representing key psychosocial constructs in adolescence. METHODS: Adolescents with CHD (n at time 1 = 429; 46.6% girls) were assessed twice over a period of 9 months. Cross-lagged analysis from a structural equation modeling approach was used to examine the direction of effects among the study variables, simultaneously controlling for demographic and clinical parameters. RESULTS: Important temporal sequences and developmental pathways were uncovered over time. Perceived health status, SOC, and parental support positively predicted quality of life over time; parental support was also found to positively predict SOC over time. Hence, parental support predicted both directly and indirectly (i.e., through SOC) quality of life over time. Finally, both perceived health status and SOC predicted peer support over time. CONCLUSIONS: The present longitudinal study using a large sample of adolescents with a wide spectrum of congenital heart defects substantially extended our knowledge base on biopsychosocial functioning and quality of life in this population. Both individual and contextual resources need to be taken into account to shed a comprehensive picture of quality of life in adolescents with CHD. PMID- 22824435 TI - Comparison of everolimus-eluting and sirolimus-eluting coronary stents: 1-year outcomes from the Randomized Evaluation of Sirolimus-eluting Versus Everolimus eluting stent Trial (RESET). AB - BACKGROUND: Several recent randomized trials comparing everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) reported similar outcomes. However, only 1 trial was powered for a clinical end point, and no trial was powered for evaluating target-lesion revascularization. METHODS AND RESULTS: Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial is a prospective multicenter randomized open-label trial comparing EES with SES in Japan. The trial was powered for evaluating noninferiority of EES relative to SES in terms of target-lesion revascularization. From February and July 2010, 3197 patients were randomly assigned to receive either EES (1597 patients) or SES (1600 patients). At 1 year, the primary efficacy end point of target-lesion revascularization occurred in 65 patients (4.3%) in the EES group and in 76 patients (5.0%) in the SES group, demonstrating noninferiority of EES to SES (P(noninferiority)<0.0001, and P(superiority)=0.34). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.32% versus 0.38%, P=0.77). An angiographic substudy enrolling 571 patients (EES, 285 patients and SES, 286 patients) demonstrated noninferiority of EES relative to SES regarding the primary angiographic end point of in-segment late loss (0.06+/ 0.37 mm versus 0.02+/-0.46 mm, P(noninferiority)<0.0001, and P(superiority)=0.24) at 278+/-63 days after index stent implantation. CONCLUSIONS: One-year clinical and angiographic outcome after EES implantation was noninferior to and not different from that after SES implantation in a stable coronary artery disease population with relatively less complex coronary anatomy. One-year clinical outcome after both EES and SES use was excellent with a low rate of target-lesion revascularization and a very low rate of stent thrombosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035450. PMID- 22824442 TI - Family influences related to adult substance use and mental health problems: a developmental analysis of child and adolescent predictors. AB - PURPOSE: This study investigated measures of family conflict, family management, and family involvement at ages 10-12, 13-14, and 15-18 years as predictors of adult depression, anxiety, and substance use disorder symptoms classes at age 27. The objective was to assess the relative influence on adult outcomes of each family predictor measured similarly at different points in adolescent development. METHODS: Data were obtained from the Seattle Social Development Project, a theory-driven longitudinal study that began in 1985, with 808 fifth grade students from 18 Seattle public elementary schools. A latent class analysis of adult outcomes was followed by bivariate and multivariate models for each family predictor. Of the original 808 participants, 747 (92% of the original sample) had available data at age 27 on the mental health and substance use latent class indicators. Missing data were handled using full-information maximum likelihood estimation. RESULTS: Four latent classes were derived: a "low disorder symptoms" class, a "licit substance use disorder symptoms" class, a "mental health disorder symptoms" class, and a "comorbid" class. Multivariate results show that family conflict is the strongest and most consistent predictor of the adult mental health and substance use classes. Family management, but not family involvement, was also predictive of the adult outcome classes. CONCLUSIONS: It is important to lessen family conflict and improve family management to prevent later mental health and substance use problems in adulthood. PMID- 22824443 TI - Decomposing the components of friendship and friends' influence on adolescent drinking and smoking. AB - PURPOSE: Friendship networks are an important source of peer influence. However, existing network studies vary in terms of how they operationalize friendship and friend's influence on adolescent substance use. This study uses social network analysis to characterize three types of friendship relations: (1) mutual or reciprocated, (2) directional, and (3) intimate friends. We then examine the relative effects of each friendship type on adolescent drinking and smoking behavior. METHODS: Using a saturated sample from the Add Health data, a nationally representative sample of high school adolescents (N = 2,533 nested in 12 schools), we computed the level of exposure to drinking and smoking of friends using a network exposure model, and their association with individual drinking and smoking using fixed effect models. RESULTS: Results indicated that the influence from mutual or reciprocated type of friendship relations is stronger on adolescent substance use than directional, especially for smoking. Regarding the directionality of directional type of friendship relations, adolescents are equally influenced by both nominating and nominated friends on their drinking and smoking behavior. Results for intimate friends friendship relations indicated that the influence from "best friends" was weaker than the one from non-"best friends," which indicates that the order of friend nomination may not matter as much as nomination reciprocation. CONCLUSIONS: This study demonstrates that considering different features of friendship relationships is important in evaluating friends' influence on adolescent substance use. Related policy implications are discussed. PMID- 22824444 TI - Perceptions of chronicity and recovery among youth in treatment for substance use problems. AB - PURPOSE: To explore how youth contextualize substance use problems and recovery, in general and for themselves, in relation to the commonly accepted chronicity framework. METHODS: Fourteen focus groups were conducted with 118 youth in substance abuse treatment settings (aged 12-24 years; 78.3% male; 66.1% Latino) located throughout diverse areas of Los Angeles County. Transcribed qualitative focus group data were analyzed for major substance use and recovery themes. RESULTS: Most (80%) youth do not accept a chronicity framework that conceptualizes substance use problems as recurring and constituting a lifelong illness. Most (65%) view substance use problems as a function of poor behavioral choices or a developmental/social lifestyle phase. Youth perceptions of recovery tend to parallel this view, as most define recovery to mean having an improved or changed lifestyle that is achieved through making better behavioral choices (67%) and exerting personal control over one's behavior (57%) through willpower, confidence, or discipline. Other recovery themes identified by youth were substance use related (47%), wellness or well-being related (43%), and therapeutic or treatment related (14%). CONCLUSIONS: Findings highlight the importance of considering youth perceptions about substance use chronicity and recovery in making improvements and promoting new developments in clinical and recovery support approaches to better meet the needs of youth with substance use problems. Findings are discussed under a theoretical context of behavior change to provide insights for the treatment and recovery communities. PMID- 22824445 TI - Gender differences in pubertal timing, social competence, and cigarette use: a test of the early maturation hypothesis. AB - PURPOSE: The timing of pubertal maturation has been associated with cigarette use, but the exact mechanisms by which maturation influences cigarette use are unclear. One hypothesis posited to explain this association is the early maturation hypothesis, that boys and girls who mature earlier than their peers have developed physically before their social resources have fully developed, leaving them ill-equipped to deal with challenges that may arise when entering physical maturity. This prospective study examines the relations between pubertal timing, social competence, and cigarette use in a sample of 1,013 boys and girls, followed from 5th through 12th grade. METHODS: Latent growth modeling was used to predict cigarette use across high school years (grades 9-12) from pubertal timing assessed in 5th grade (for girls) and 6th grade (for boys) as mediated by social competence across grades 6-8. RESULTS: Earlier pubertal maturation predicted cigarette use in 9th grade and increased cigarette use across high school. Earlier maturation also predicted lower social competence in 6th grade. For girls, social competence partially mediated the relation between pubertal timing and cigarette use. CONCLUSIONS: The data supported the early maturation hypothesis for both boys and girls, as earlier maturers were more likely to smoke in 9th grade and had lower social competence in 6th grade. However, social competence partially mediated cigarette use for girls only. The mechanisms by which negative outcomes are associated with pubertal maturation appear to differ by gender. PMID- 22824446 TI - Sexually transmitted infections, sexual risk behavior, and intimate partner violence among African American adolescent females with a male sex partner recently released from incarceration. AB - PURPOSE: Social networks directly and indirectly influence sexually transmitted infections (STIs) risk. The objective was to explore associations between sex with a male recently released from incarceration and sexual risk and intimate partner violence (IPV) among African American adolescent females. METHODS: Sociodemographic, psychosocial, and sexual behavior data were collected at baseline, 6, and 12 months from African American females, aged 15-21 years, participating in an HIV/STI prevention trial. Among 653 participants with >=1 follow-up assessments, generalized estimating equations tested associations during follow-up between having a recently released partner and STI acquisition, sexual risk behaviors, and IPV, adjusting for age, treatment assignment, and corresponding baseline measure. RESULTS: Eighty-three (13.6%) participants had a recently released partner at 6 months and 56 (9.3%) at 12 months. Participants with a recently released partner were more likely to have the following: vaginal (adjusted odds ratio [AOR]: 5.48), anal (AOR: 2.43), and oral (AOR: 1.51) sex, a casual partner (AOR: 1.66), sex while high/drunk (AOR: 1.57) or with a high/drunk partner (AOR: 2.27); use condoms inconsistently (AOR: .58); acquire Chlamydia (AOR: 1.80), and experience emotional (AOR: 4.09), physical (AOR: 2.59), or sexual abuse (AOR: 4.10) by a boyfriend. They had a greater number of sex partners, lower partner communication and refusal self-efficacy, were high/drunk during sex more frequently, and used condoms during oral sex less frequently. CONCLUSIONS: A recently released sex partner is associated with sexual risk and IPV among African American adolescent females. Prevention programs should inform adolescents about potential risks associated with recently released partners as well as provide adolescents with skills to establish and maintain healthy sexual relationships. PMID- 22824447 TI - Integrating condom skills into family-centered prevention: efficacy of the Strong African American Families-Teen program. AB - PURPOSE: The Strong African American Families-Teen (SAAF-T) program, a family centered preventive intervention that included an optional condom skills unit, was evaluated to determine whether it prevented unprotected intercourse and increased condom efficacy among rural African American adolescents. Ancillary analyses were conducted to identify factors that predicted youth attendance of the condom skills unit. METHODS: Sixteen-year-old African American youths (N = 502) and their primary caregivers were randomly assigned to SAAF-T (n = 252) or an attention control (n = 250) intervention. SAAF-T families participated in a 5 week family skills training program that included an optional condom skills unit. All families completed in-home pretest, posttest, and long-term follow-up interviews during which adolescents reported on their sexual behavior, condom use, and condom efficacy. Because condom use was addressed only in an optional unit that required caregiver consent, we analyzed efficacy using complier average causal effect analyses. RESULTS: Attendance in both SAAF-T and the attention control intervention averaged 4 of 5 sessions; 70% of SAAF-T youth attended the condom skills unit. Complier average causal effect models indicated that SAAF-T was efficacious in reducing unprotected intercourse and increasing condom efficacy among rural African American high school students. Exploratory analyses indicated that religious caregivers were more likely than nonreligious caregivers to have their youth attend the condom skills unit. CONCLUSIONS: Results suggest that brief condom skills educational modules in the context of a family-centered program are feasible and reduce risk for sexually transmitted infections and unplanned pregnancies. PMID- 22824448 TI - Identifying adolescent females at high risk of pregnancy in a pediatric emergency department. AB - PURPOSE: Emergency departments (EDs) care for adolescent females with unmet reproductive health care needs. Our objective was, among adolescents presenting to a pediatric ED, to estimate pregnancy risk, describe pregnancy intentions, and identify potentially modifiable factors associated with pregnancy risk. METHODS: Using a paper-based questionnaire, we surveyed females aged 15-19 years presenting to our ED, assessing health care access, sexual behaviors, pregnancy intentions, and receptivity to interventions. We calculated the pregnancy risk index (PRI), which estimates pregnancy risk in the subsequent 12 months, by assessing recent sexual activity, contraception at last intercourse, and known contraceptive failure rates. Independent sample t tests and analysis of variance were used to identify risk factors associated with increased PRI. RESULTS: Of 459 females enrolled, 13% were pregnant and 20% reported prior pregnancy. Among 399 nonpregnant females, 238 (60%) had intercourse in the prior 3 months and 73 (31%) used no contraception at last intercourse. Among nonpregnant adolescents, the PRI was 19.5, which equates to 19.5 expected pregnancies per 100 females per year. Factors associated with higher PRI included lacking a primary provider, prior ED visits, wanting a baby now, and reported partner wantedness of pregnancy. Half believed ED doctors should discuss pregnancy prevention, and one-quarter were interested in starting contraception in the ED. CONCLUSIONS: Nearly one-third of adolescent females in a pediatric ED were either pregnant or could be expected to become pregnant within a year. Screening questions can identify adolescents at high risk of pregnancy in the ED setting. These females should be the target for future pregnancy prevention interventions. PMID- 22824449 TI - Premenarchal girls' genital examination experiences. AB - PURPOSE: To explore girls' experiences having an external genital examination during early adolescence. METHODS: Ten premenarchal girls were interviewed about their experiences receiving an external genital examination as part of a larger longitudinal study. Qualitative methods were used for analysis, looking for concepts based on themes and shared beliefs among the girls to create a model of the genital examination experience. RESULTS: Most participants could not remember ever having a genital examination before enrollment in the larger study. The examination was best characterized as "weird," and many aspects of the examination were novel. Overall, genital examinations were not experienced negatively because of moderating factors like having support from mothers during the examination and having examiner preferences toward gender and personal characteristics. With repeated study examinations in the larger study and for those participants who reported their provider performed genital examinations, the examination was viewed as a skill for growing up or routine. CONCLUSIONS: External genital examinations, although a new experience for many girls, can be experienced positively. Providers should address concerns about this important recommended examination and acknowledge that examiner attributes, mothers, and experience of having examinations all influence how genital examinations are experienced. PMID- 22824450 TI - The use of reconsent in a national evaluation of adolescent reproductive health programs. AB - PURPOSE: Reconsent involves asking research participants to reaffirm their consent for study participation when there have been significant changes in the study's procedures, risks, or benefits. We described the reconsent process, identified the reconsent rate, and examined the comparability of youths enrolled via consent and reconsent in a national evaluation of adolescent reproductive health programs. METHODS: Evaluation participants from five abstinence education projects (N = 2,176) and nine projects serving pregnant or parenting adolescents (N = 878) provided either parent or youth consent or reconsent to participate in the national evaluation. Participants completed surveys that included demographic characteristics; sexual intentions, norms and behaviors; and pregnancy history. Multivariate logistic regression was used to examine associations between consent status, demographic characteristics, and risk indicators. RESULTS: The reconsent rates in the abstinence education and pregnant or parenting samples were 45% and 58%, respectively. Participant's age was positively associated with reconsent. Hispanic adolescents (and, for abstinence education, other racial/ethnic minorities) were underrepresented among youth with reconsent. Among abstinence education study participants, risk indicators were not associated with consent status. Among pregnant or parenting teens, those who had experienced repeat pregnancy were less likely than those who had experienced only one pregnancy to have been enrolled via reconsent. CONCLUSIONS: Reconsent can bolster sample size but may introduce bias by missing some racial/ethnic and age-groups. Among high risk adolescents, reconsent may also yield a sample that differs from consented samples on risk characteristics, necessitating statistical adjustments when analyzing data. PMID- 22824451 TI - Parental views of school-located delivery of adolescent vaccines. AB - PURPOSE: School-located immunization has the potential to increase adolescent vaccination rates. This study assessed parents' attitudes toward administration of adolescent vaccines (tetanus, diphtheria, acellular pertussis [Tdap], meningococcal conjugate [MenACWY], human papillomavirus [HPV], and influenza) at school. METHODS: We conducted a mailed survey of parents of sixth graders from July 2009 to September 2009 in three urban/suburban (Aurora, CO) middle schools assessing barriers and facilitators to school vaccination and willingness to consent for vaccines at school. Unadjusted and adjusted analyses examined the association of parent and student characteristics with parent willingness to consent to school-located vaccination. RESULTS: The response rate was 62% (500/806). Parents reported 82% of teens had a regular site of health care, and 17% were uninsured. Overall, 71% of parents would consent for vaccines at school; 72% for Tdap, 71% for MenACWY, 53% for HPV (parents of girls), and 67% for seasonal influenza. Among parents who answered it was important their child receives recommended vaccines, (88%) would consent for influenza vaccine at school, compared with Tdap (76%), MenACWY (74%), and HPV (72%). Multivariable logistic regression analysis demonstrated parents of uninsured teens (odds ratio [OR] 3.77, 95% confidence interval [CI]: 1.40, 12.23), who were unmarried (OR 1.90, 95% CI: 1.14, 3.25), or had a child attending the school with the highest percent eligibility for free/reduced lunch (OR 2.75, 95% CI: 1.36, 5.80) were significantly more willing to consent for vaccines at school. CONCLUSIONS: These data suggest parents are generally supportive of school-located vaccine delivery, particularly for annual influenza vaccination and for uninsured and low-income adolescents. PMID- 22824452 TI - Correlates of sexually transmitted infection prevention knowledge among African American girls. AB - PURPOSE: To identify significant factors that distinguish African American girls who have high sexually transmitted infection (STI) prevention knowledge from those lacking such knowledge. METHODS: We recruited a sample of 715 African American girls from three public health clinics in downtown Atlanta. Using audio computer-assisted self-interviewing (A-CASI) technology, we assessed for age, self-mastery, employment status, attendance at sex education classes, socioeconomic status, and STI prevention knowledge. RESULTS: Slightly more than one-third of the girls did not know that females are more susceptible to STI infections than males; and that having an STI increases the risk of contracting HIV. Almost half of the girls did not know if a man has an STI he will not have noticeable symptoms; and that most people who have AIDS look healthy. Logistic regression findings indicated that being older, having greater self-mastery, and being employed significantly predicted high STI knowledge. CONCLUSIONS: Health educators may especially target African American girls who are younger, unemployed, and experiencing low self-mastery for more tailored STI heath education. PMID- 22824453 TI - Complementary and alternative medicine use among youth with juvenile arthritis: are youth using CAM, but not talking about it? AB - PURPOSE: To examine self-reported use and correlates of complementary and alternative medicine (CAM) in adolescents with juvenile arthritis (JA). METHODS: One hundred thirty-four adolescents with JA completed an online survey of their use of, interest in, and discussions about CAM. The PedsQL 4.0 SF15 assessed quality of life. RESULTS: The majority (72%) of youth reported using >=1 CAM modality. Use did not differ by sex, age, race, or geographic location. The most commonly used CAM modalities were yoga (45%) and meditation, relaxation, or guided imagery (40%). Low psychosocial quality of life was associated with massage and meditation, relaxation, or guided imagery use (p < .05). Only 46% of youth reported discussing CAM with a health care provider. Nonusers were most interested in learning more about massage (79%) and yoga (57%). CONCLUSIONS: Youth with JA reported high use of CAM, but few discussed CAM with health care providers. Findings suggest practitioners should engage adolescents in discussions about CAM. PMID- 22824454 TI - Morphology, ontogeny, and molecular phylogeny of two novel bakuellid-like hypotrichs (Ciliophora: Hypotrichia), with establishment of two new genera. AB - The morphology, ontogeny and molecular phylogeny of Apobakuella fusca gen. n., sp. n. and Parabistichella variabilis gen. n., sp. n., from south China were investigated. Apobakuella fusca, brown colored, demonstrates bakuellid-like infraciliature, and a similar ontogenesis as the genus Bakuella. It is argued, however, that this species represents a novel genus, Apobakuella, which is characterized by two or more marginal rows on the right, several buccal and parabuccal cirri, and lack of frontoterminal and caudal cirri. Phylogenetic analysis based on SSU rRNA gene sequences supports the close relationship of Apobakuella with Neobakuella and Diaxonella within the core Urostylida. By contrast, Parabistichella variabilis has a dominant frontoventral row, few midventral pairs, a long midventral row, and one marginal row on each side. Its morphogenesis exhibits: (1) partial reorganization of the parental adoral membranelles; (2) over six frontoventral-transverse cirri anlagen; (3) intrakinetal development of the midventral row; and (4) very likely, formation of the frontoventral row from the midventral row anlage. Both the morphological characteristics and the SSU rRNA gene sequences suggest that it is incertae sedis among the basal hypotrichs. Further investigation of key taxa with additional molecular markers is required to reveal a better understanding on the phylogeny of Parabistichella. PMID- 22824455 TI - Morphology of three new marine Frontonia species (Ciliophora; Peniculida) with note on the phylogeny of this genus. AB - Members of the ciliate genus Frontonia are common colonizers of periphytic communities in aquatic biotopes. Recent studies indicate that their species diversity is higher than previously supposed. In this study the morphology and infraciliature of three new species, Frontonia sinica spec. nov., F. pusilla spec. nov., and F. elegans spec. nov., isolated from coastal waters of China, were investigated using live observation and silver impregnation methods. Frontonia sinica differs from its congeners by the following combination of characters: ellipsoidal body, about 116 somatic and five or six vestibular kineties, peniculi 1 and 2 four-rowed, peniculus 3 two-rowed, and a single contractile vacuole. Frontonia pusilla has about 72 somatic kineties, four-rowed peniculi 1 and 2, a two-rowed peniculus 3, and two contractile vacuoles. Frontonia elegans has 73 somatic kineties, four-rowed peniculi 1 and 2, a three rowed peniculus 3, and two contractile vacuoles. In the present work, six new small-subunit rRNA gene sequences of six Frontonia species are used to construct the phylogenetic trees. Our phylogenetic analysis supports that the genus Frontonia may be paraphyletic. Meanwhile, no pattern of correlation could be found between the structures of peniculi and the phylogenetic relationships of Frontonia species in the present study. PMID- 22824456 TI - Low level of alcohol drinking among two generations of non-Western immigrants in Oslo: a multi-ethnic comparison. AB - BACKGROUND: Alcohol drinking is a risk factor for harm and disease. A low level of drinking among non-Western immigrants may lead to less alcohol-related harm and disease. The first aim of this study was to describe frequency of drinking in two generations of immigrants in Oslo, contrasting the result to drinking frequency among ethnic Norwegians. The second aim was to study how frequency of drinking among adult immigrants was associated with social interaction with their own countrymen and ethnic Norwegians, acculturation, age, gender, socioeconomic factors and the Muslim faith. METHOD: The Oslo Health Study (HUBRO) was conducted during the period 2000 to 2002 and consisted of three separate surveys: a youth study (15-16-year-olds, a total of 7343 respondents, response rate 88.3%); adult cohorts from 30 to 75 years old (18,770 respondents, response rate 46%); the five largest immigrant groups in Oslo (aged 20-60 years, a total of 3019 respondents, response rate 39.7%). Based on these three surveys, studies of frequency of drinking in the previous year (four categories) were conducted among 15-16-year olds and their parents' generation, 30-60-year-old Iranians, Pakistanis, Turks and ethnic Norwegians. A structural equation model with drinking frequency as outcome was established for the adult immigrants. RESULTS: Adults and youth of ethnic Norwegian background reported more frequent alcohol use than immigrants with backgrounds from Iran, Turkey and Pakistan. Iranians reported a higher drinking frequency than Turks and Pakistanis. In the structural equation model high drinking frequency was associated with high host culture competence and social interaction, while high own culture competence was associated with low drinking frequency. Adult first-generation immigrants with a longer stay in Norway, those of a higher age, and females drank alcohol less frequently, while those with a higher level of education and work participation drank more frequently. Muslim immigrants reported a significantly lower drinking frequency than non-Muslims, although this did not apply to Iranians. CONCLUSIONS: The existence and growth in Western societies of immigrant groups with low-level alcohol consumption contributed to a lower level of consumption at the population level. This may imply reduced drinking and alcohol-related harm and disease even among ethnic Norwegians. PMID- 22824457 TI - Community based study to compare the incidence and health services utilization pyramid for gastrointestinal, respiratory and dermal symptoms. AB - BACKGROUND: Gastrointestinal (GI), respiratory and dermal symptoms are common and cause substantial morbidity, although the information on their exact incidence and comparative burden is limited. The aim of this study was to describe the epidemiology and rate these three major symptom complexes in order to improve our understanding of the health burden imposed by these symptoms. METHODS: We used data from a community based randomised control trial conducted from June 2007 to August 2008 among 277 South Australian families consuming rainwater. Using weekly health diaries, we prospectively collected information on GI (diarrhoea or vomiting), respiratory (sore throat, runny nose or cough) and dermal (rash, generalised itch or dermal infection) symptoms, as well as on relevant GP visits, time off work and/or hospitalisation due to these symptoms. Data were analysed using generalized estimating equations approach taking into account the variable number of weeks of follow-up of each individual and within-family clustering of responses. RESULTS: Over one year, at least one episode of GI symptoms was reported by 54% of participants (95% CI 50%-58%), at least one respiratory episode by 91% (95% CI 88%-93%) and at least one episode of dermal symptoms by 27% (95% CI 24%-30%). The average number of weeks per year during which respiratory symptoms occurred was four times greater than for GI or dermal symptoms (4.9, 1.2 and 1.2 weeks, respectively, p<0.001), with an average number of GP visits per person per year being twice as frequent (0.48, 0.26, 0.19 respectively, p<0.001). However, on a per episode basis, a higher proportion of people saw a GP or were hospitalised for GI symptoms. CONCLUSIONS: This first comparative study of three different symptom complexes showed that although respiratory symptoms are most common, GI symptoms cause a greater per episode burden on healthcare resources. Measuring and comparing the community based burden of these symptom complexes will assist evidence-based allocation of resources. PMID- 22824459 TI - Mitochondrial genome variability within the Candida parapsilosis species complex. AB - Candida parapsilosis species complex includes three closely related species, namely C. parapsilosis (sensu stricto), C. orthopsilosis, and C. metapsilosis. Unlike most other yeast lineages, members of this species complex possess a linear mitochondrial genome. Yet, its circularized mutant form was identified in strains of C. orthopsilosis and C. metapsilosis. To investigate the underlying variability, we performed comparative analyses of the complete mitochondrial DNA sequences in a collection of strains. Our results demonstrate that in contrast to C. parapsilosis and C. metapsilosis, C. orthopsilosis exhibits remarkably high nucleotide diversity whose pattern is consistent with intraspecific genetic exchange. PMID- 22824458 TI - Oxygen glucose deprivation causes mitochondrial dysfunction in cultivated rat hippocampal slices: protective effects of CsA, its immunosuppressive congener [D Ser](8)CsA, the novel non-immunosuppressive cyclosporin derivative Cs9, and the NMDA receptor antagonist MK 801. AB - We have introduced a sensitive method for studying oxygen/glucose deprivation (OGD)-induced mitochondrial alterations in homogenates of organotypic hippocampal slice cultures (slices) by high-resolution respirometry. Using this approach, we tested the neuroprotective potential of the novel non-immunosuppressive cyclosporin (CsA) derivative Cs9 in comparison with CsA, the immunosuppressive CsA analog [D-Ser](8)CsA, and MK 801, a N-methyl-d-aspartate (NMDA) receptor antagonist. OGD/reperfusion reduced the glutamate/malate dependent (and protein related) state 3 respiration to 30% of its value under control conditions. All of the above drugs reversed this effect, with an increase to >88% of the value for control slices not exposed to OGD. We conclude that Cs9, [D-Ser](8)CsA, and MK 801, despite their different modes of action, protect mitochondria from OGD induced damage. PMID- 22824460 TI - Segregation of donor cell mitochondrial DNA in gaur-bovine interspecies somatic cell nuclear transfer embryos, fetuses and an offspring. AB - The fate of foreign mitochondrial DNA (mtDNA) following somatic cell nuclear transfer (SCNT) is still controversial. In this study, we examined the transmission of the heteroplasmic mtDNA of gaur donor cells and recipient bovine oocytes to an offspring and aborted and mummified fetuses at various levels during the development of gaur-bovine interspecies SCNT (iSCNT) embryos. High levels of the donor cell mtDNA were found in various tissue samples but they did not have any beneficial effect to the survival of iSCNT offspring. However, the factors on mtDNA inheritance are unique for each iSCNT experiment and depend on the recipient oocyte and donor cell used, which might play an important role in the efficiency of iSCNT. PMID- 22824461 TI - Neonatal survival interventions in humanitarian emergencies: a survey of current practices and programs. AB - BACKGROUND: Neonatal deaths account for over 40% of all deaths in children younger than five years of age and neonatal mortality rates are highest in areas affected by humanitarian emergencies. Of the ten countries with the highest neonatal mortality rates globally, six are currently or recently affected by a humanitarian emergency. Yet, little is known about newborn care in crisis settings. Understanding current policies and practices for the care of newborns used by humanitarian aid organizations will inform efforts to improve care in these challenging settings. METHODS: Between August 18 and September 25, 2009, 56 respondents that work in humanitarian emergencies completed a web-based survey either in English or French. A snow ball sampling technique was used to identify organizations that provide health services during humanitarian emergencies to gather information on current practices for maternal and newborn care in these settings. Information was collected about continuum-of-care services for maternal, newborn and child health, referral services, training and capacity development, health information systems, policies and guidelines, and organizational priorities. Data were entered into MS Excel and frequencies and percentages were calculated. RESULTS: The majority of responding organizations reported implementing components of neonatal and maternal health interventions. However, multiple barriers exist in providing comprehensive care, including: funding shortages (63.3%), gaps in training (51.0%) and staff shortages and turnover (44.9%). CONCLUSIONS: Neonatal care is provided by most of the responding humanitarian organizations; however, the quality, breadth and consistency of this care are limited. PMID- 22824462 TI - Investigation of slow molecular dynamics using R-CODEX. AB - A solid state NMR experiment is introduced for probing motions on the millisecond time scale, based on dephasing and refocusing (1)H-(13)C or (1)H-(15)N dipolar couplings. The method is related to the previously described Centerband-Only Detection of Exchange or CODEX experiment. The use of an R-type dipolar recoupling sequence takes advantage of the strong (1)H-(13)C or (1)H-(15)N dipolar coupling, while suppressing the effect of (1)H-(1)H homonuclear coupling. This approach paves the way to detect both the correlation time and reorientational angle of the dynamics in fully protonated samples. The performance of this pulse sequence is demonstrated using imidazole methyl sulfonate. PMID- 22824463 TI - Memantine prevents cognitive impairment and reduces Bcl-2 and caspase 8 immunoreactivity in rats injected with amyloid beta1-40. AB - Amyloid-beta peptides (Abeta) can trigger apoptotic cascades in neurons. We found previously that memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors approved for the treatment of moderate to severe Alzheimer's disease, can prevent neurodegeneration induced by intracranial Abeta(1-40) injection. In this study, we tested the hypothesis that memantine prevents Abeta(1-40)-mediated cognitive impairment, neurodegeneration, and apoptosis of hippocampal neurons in rats. In addition, we hypothesized that Abeta(1-40) injection would induce changes in the levels of one or more apoptosis-related proteins, and that these changes would be attenuated by memantine treatment. Female Sprague-Dawley rats were administered memantine (continuous subcutaneous application, 9.6-14.4mg/kg/day; n=8) or vehicle (water; n=8) for 9 days. Two days after treatment initiation, the animals were bilaterally injected with Abeta(1 40) into the CA1/DG region of the hippocampus, subjected to active avoidance testing for 7 days, and sacrificed for immunohistochemical examination of four caspases (3, 6, 8, and 9) and three proteins of the Bcl-2 family (Bcl-2, Bax, and Bad). Injection of Abeta resulted in neurodegeneration, DNA fragmentation, increased Bcl-2 immunostaining, and significantly impaired performance in an active avoidance task, all which were significantly attenuated in rats treated with memantine. No differences in immunoreactivity of caspases 3, 6, 8, and 9 were discovered between groups after 7 days. Additional experiments demonstrated that an increase in caspase 8 immunostaining, observed 3 days after Abeta(1-40) injection, was significantly attenuated in memantine-treated rats. These data suggest that, in rats, memantine can prevent amyloid-triggered expression of apoptosis-related markers and concomitant cognitive deficits. PMID- 22824464 TI - NG, a novel PABA/NO-based oleanolic acid derivative, induces human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway. AB - O(2)-(2,4-dinitro-5-{[2-(12-en-28-beta-D- galactopyranosyl-oleanolate-3-yl) -oxy 2-oxoethyl]amino}phenyl)1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2- diolate (NG), a novel PABA/NO-based derivative of oleanolic acid (OA), has been found to show potent antitumor activity both in vivo and in vitro. In the present study, NG could significantly reduce tumor volume and weight in the H22 solid tumor mouse model. Meanwhile, NG showed selective effects on the HepG2 cells including NO generation, cytotoxic effect and apoptosis, which were prevented by hemoglobin (NO scavenger). Moreover, NG-induced apoptosis of HepG2 cells was characteristic of intracellular reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (Deltapsim) and enhanced Bax-to-Bcl-2 ratio. The release of apoptotic inducing factor (AIF) and cytochrome c (Cyt c) from mitochondria and the activation of caspase-3, 9 were also detected, indicating that NG may induce apoptosis through a mitochondrial-mediated pathway. Simultaneously, NG treatment could lead to the activation of the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK but not ERK1/2. Treatment with SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38) prior to NG was found to reverse NG-induced apoptosis. Moreover, it was found that antioxidant N-acetylcysteine (NAC) blocked the induction of apoptosis and partly reversed the activation of JNK and p38, up regulation of Bax, down-regulation of Bcl-2 and the activation of caspase-3 in NG treated cells. Taking together, these findings suggest that NO can be released from NG, which induces apoptosis through a ROS/MAPK-mediated mitochondrial pathway. PMID- 22824466 TI - A miR-1231 binding site polymorphism in the 3'UTR of IFNAR1 is associated with hepatocellular carcinoma susceptibility. AB - Hepatocellular carcinoma (HCC) is a common liver malignancy worldwide and genetic factors play important roles in the pathogenesis of HCC. Based on in-silico analysis, a case-control study including 420 HCC patients and 420 healthy controls was conducted to investigate the association between HCC susceptibility with a 4-bp insertion/deletion polymorphism (rs17875871) in the 3'UTR of IFNAR1. Computational modeling suggested that rs17875871 was located in seed region of miR-1231 potential target sequence in IFNAR1 3'UTR. Logistic regression analysis showed that the heterozygote and the 4-bp del/del homozygote genotypes confer significantly higher risks of HCC (adjusted OR=1.35, 95% CI=1.01-1.83, P=0.045; OR=1.84, 95% CI=1.18-2.84, P=0.006, respectively). Stratification analysis revealed that this association was more pronounced in HBsAg positive subgroup. Our findings suggested common genetic changes in IFNAR1 may influence HCC risk, likely through miR-1231-mediated regulation, which is possibly involved in the pathogenesis of HBV related HCC. Further replication studies and functional characterization of rs17875871 were needed to fully clarify the underlined molecular mechanism. PMID- 22824465 TI - Diagnostic performance of multiplex cytokine and chemokine assay for tuberculosis. AB - Simultaneous detection of multiple biomarkers might lead to improved diagnostic performance for Mycobacterium tuberculosis infection. In this study, we screened soluble biomarkers that had significant differences in patients with active tuberculosis and healthy controls and evaluated the diagnostic performance of the multiplex cytokine/chemokine assay. Overall, 178 patients with active pulmonary tuberculosis, 156 healthy individuals and 35 patients with bacterial pneumonia or lung cancer were evaluated. Among the 16 soluble biomarkers screened by the microbead-based multiplex assay, five cytokines/chemokines including IFN-gamma, IP-10, MIG, TNF-alpha and IL-2 that showed most significant differences between active pulmonary tuberculosis patients and healthy controls were selected for further analysis. When analyzed individually, both IP-10 and MIG had sensitivity and specificity comparable to IFN-gamma in detection of active TB. Combined detection of IFN-gamma, IP-10 and MIG had significantly improved sensitivity and specificity as compared with individual cytokine and chemokine detection. The responsive levels of IFN-gamma, IP-10, MIG, TNF-alpha and IL-2 were significantly lower in re-treatment pulmonary tuberculosis patients than in new tuberculosis patients. It is concluded that combined IFN-gamma, IP-10, MIG multiplex detection had better diagnostic performance for tuberculosis than the individual cytokine/chemokine assays. The re-treatment pulmonary tuberculosis patients had poor responses to ESAT-6/CFP-10 peptides stimulation. PMID- 22824467 TI - Genetic analysis of an enhancer of the NKX2-5 gene in ventricular septal defects. AB - Congenital heart disease (CHD) is one of the most common birth defects in humans. Mutations in cardiac transcription factor genes, such as GATA4, NKX2-5 and TBX5 genes, have been associated to a small portion of familial and isolated CHD cases. NKX2-5, a highly conserved homeobox gene, is expressed in the developing heart. During embryonic development, NKX2-5 plays pivotal roles in specifying cardiac progenitors, cardiac morphogenesis, cardiomyocyte differentiation and conduction system development. Numerous mutations in NKX2-5 gene have been reported in CHD patients, including atrial septal defect, ventricular septal defect (VSD) and tetrology of Fallot. We have previously identified the sequence variants within the NKX2-5 gene promoter in VSD patients. As several studies have revealed that the NKX2-5 gene is regulated by a complex module involving promoter and multiple independent cardiac enhancers, one of which is located between -3500 bp and -2500 bp upstream to the transcription start site, we hypothesized that the variants within the cardiac enhancer may contribute to CHD. In this study, we genetically analyzed the enhancer of NKX2-5 gene in large cohorts of VSD patients (n=322) and controls (n=336). The results showed that three novel variants, g.1467G>A, g.1487 Ins with a 13 bp insertion and g.1515 Ins with a 6 bp insertion, were identified within the enhancer element in both VSD patients and controls with similar frequencies (P>0.05). Therefore, our data suggested that the enhancer of NKX2-5 gene may not be a contributor to the VSD etiology. Other regulatory elements of the NKX2-5 gene will be further analyzed in CHD patients. PMID- 22824468 TI - In silico analysis of Single Nucleotide Polymorphisms (SNPs) in human BRAF gene. AB - BRAF gene mutations are frequently seen in both inherited and somatic diseases. However, the harmful mutations for BRAF gene have not been predicted in silico. Owing to the importance of BRAF gene in cell division, differentiation and secretion processes, the functional analysis was carried out to explore the possible association between genetic mutations and phenotypic variations. Genomic analysis of BRAF was initiated with SIFT followed by PolyPhen and SNPs&GO servers to retrieve the 85 deleterious non-synonymous SNPs (nsSNPs) from dbSNP. A total of 5 mutations i.e. c.406T>G (S136A), c.1446G>T (R462I), c.1556 A>G (K499E), c.1860 T>A (V600E) and c.2352 C>T (P764L) that are found to exert benign effects on the BRAF protein structure and function were chosen for further analysis. Protein structural analysis with these amino acid variants was performed by using I-Mutant, FOLD-X, HOPE, NetSurfP, Swiss PDB viewer, Chimera and NOMAD-Ref servers to check their solvent accessibility, molecular dynamics and energy minimization calculations. Our in silico analysis suggested that S136A and P764L variants of BRAF could directly or indirectly destabilize the amino acid interactions and hydrogen bond networks thus explain the functional deviations of protein to some extent. Screening for BRAF, S136A and P764Lvariants may be useful for disease molecular diagnosis and also to design the molecular inhibitors of BRAF pathways. PMID- 22824469 TI - Effect of phenolic compounds on protein cross-linking and properties of film from fish myofibrillar protein. AB - The effects of several phenolic ocmpounds (caffeic acid, catechin, ferullic acid and tannic acid) at various concentrations (1, 3 and 5% based on protein) on cross-linking and properties of film from myofibrillar proteins of bigeye snapper (Priacanthus tayenus) were investigated. Among all phenolic compounds used, tannic acid exhibited the highest cross-linking ability on myofibrillar protein as evidenced by higher decrease in free amino groups with coincidentally lower band intensity of myosin heavy chain (MHC). In addition, the extent of protein cross-linking increased with increasing concentration of phenolic compounds. Addition of phenolic compounds could enhance mechanical properties of the resulting films. As phenolic compounds content increased, Young's modulus (E) and tensile strength (TS) of the films increased, while their elongation at break (EAB) decreased (P<0.05), suggesting stronger and stiffer film structure. At the same concentration used, tannic acid rendered the film with higher mechanical properties, compared to others. Phenolic compounds decreased film transparency and affected color of the films differently, depending on types and concentrations used. Films from myofibrillar proteins with and without polyphenol generally had the excellent barrier properties to UV light at the wavelength of 200-800 nm. Therefore, it could potentially be used as inner packaging material for high-fat foods to prevent the lipid oxidation and thus prolonging the shelf life of foods during storage. PMID- 22824470 TI - Encephalopathy or hepatic encephalopathy? PMID- 22824471 TI - Missed nursing care: Magnet versus non-Magnet hospitals. AB - BACKGROUND: The objective of this study was to examine whether the amount, type, and reasons of missed nursing care differ between Magnet and non-Magnet hospitals. METHOD: Data were collected from 124 medical-surgical, intermediate, intensive care, and rehabilitation units in 11 hospitals located in the Midwest and Western regions of the United States. A cross-sectional, descriptive study was conducted. The MISSCARE Survey was utilized to collect data on the level of perceived missed nursing care, and nursing staffing data was collected for each study unit. FINDINGS: Missed nursing care showed significant differences according to Magnet status. Separate analysis showed no staffing-level difference between Magnet and non-Magnet hospitals. CONCLUSIONS: The authors concluded that efficiencies in operations, work environment, and culture characterized by Magnet hospitals should be promoted. PMID- 22824472 TI - A study of a population of Nyssomyia trapidoi (Diptera: Psychodidae) caught on the Pacific coast of Ecuador. AB - BACKGROUND: Cutaneous leishmaniasis is endemic to the Pacific coast of Ecuador, and Nyssomyia trapidoi is considered to be its main vector. Dujardin et al. [1] recorded some differences in body pigmentation and isoenzymatic profiles in sympatric populations of Ny. trapidoi from the Pacific coast of Ecuador and suggested the existence of two cryptic species. METHODS: Entomological collections were performed in November 2008 and March 2011 in the locality of Paraiso Escondido using CDC miniature light traps and human bait. Morphological, isoenzymatical and molecular (sequencing of cytochome b and cytochrome c oxidase 1 of the mitochondrial DNA) analyses, such as detection of Leishmania DNA and phlebovirus RNA in some females, were performed. RESULTS: Neighbor-joining trees from mitochondrial sequences grouped all of Ecuadorian Ny. trapidoi (including the two color variants) in one cluster, except for two specimens which clustered separately in both genes. Isoenzymatic characterization confirmed that the color variants belong to the same population. Additionally, 11.5% of females were found by PCR to contain Endotrypanum monterogeii kinetoplastid DNA. All pools of Ny. trapidoi were negative for phlebovirus RNA. CONCLUSION: Analysis of mitochondrial gene sequences and isoenzymes was unable to support the existence of two sibling species within Ny. trapidoi, which is a probable vector of Endotrypanum monterogeii. PMID- 22824473 TI - Advanced statistical analysis of Raman spectroscopic data for the identification of body fluid traces: semen and blood mixtures. AB - Conventional confirmatory biochemical tests used in the forensic analysis of body fluid traces found at a crime scene are destructive and not universal. Recently, we reported on the application of near-infrared (NIR) Raman microspectroscopy for non-destructive confirmatory identification of pure blood, saliva, semen, vaginal fluid and sweat. Here we expand the method to include dry mixtures of semen and blood. A classification algorithm was developed for differentiating pure body fluids and their mixtures. The classification methodology is based on an effective combination of Support Vector Machine (SVM) regression (data selection) and SVM Discriminant Analysis of preprocessed experimental Raman spectra collected using an automatic mapping of the sample. This extensive cross validation of the obtained results demonstrated that the detection limit of the minor contributor is as low as a few percent. The developed methodology can be further expanded to any binary mixture of complex solutions, including but not limited to mixtures of other body fluids. PMID- 22824474 TI - Flexibility of interval between vaccinations with AS03A-adjuvanted influenza A (H1N1) 2009 vaccine in adults aged 18-60 and >60 years: a randomized trial. AB - BACKGROUND: Flexibility of vaccination schedule and lower antigen content can facilitate pandemic vaccine coverage. We assessed the immune response and safety of AS03-adjuvanted A/California/7/2009 H1N1 pandemic vaccine containing half of the registered adult haemagglutinin (HA) antigen content, administered as a two dose schedule at intervals of 21 days or 6 months in both young and elderly adults. METHODS: In this open-label randomized trial, healthy adults aged 18-60 years (N = 163) and >60 years (N = 143) received AS03A-adjuvanted A/California/7/2009 H1N1 vaccine containing 1.9 MUg HA on Day 0. A second dose was given on Day 21 (n = 177) or Day 182 (n = 106). Haemagglutination-inhibition (HI) antibody responses were analyzed on Days 0, 21, 42, 182, 364 and additionally on Day 203 for subjects vaccinated on Day 182. Solicited and unsolicited adverse events were recorded. RESULTS: The HI antibody response in both age strata 21 days after the first dose met and exceeded all regulatory acceptance criteria although the results suggested a lower response in the older age stratum (geometric mean titres [GMTs] for HI antibodies of 420.5 for subjects aged 18-60 years and 174.4 for those >60 years). A second dose of AS03A adjuvanted A/H1N1/2009 vaccine induced a further increase in antibody titres and the response was similar whether the second dose was administered at 21 days (GMTs of 771.8 for 18-60 years and 400.9 for >60 years) or 6 months (GMTs of 708.3 for 18-60 years and 512.1 for >60 years) following the first dose. Seroprotection rates remained high at 6 months after one dose or two doses while at 12 months rates tended to be higher for the 6 month interval schedule (93.3% for 18-60 years and 80.4% for >60 years) than the 21 day schedule (82.3% for 18 60 years and 50.0% for >60 years). Reactogenicity/safety profiles were similar for both schedules, there was no evidence of an increase in reactogenicity following the second dose. CONCLUSIONS: The results indicate that flexibility in the dosing interval for AS03A adjuvanted vaccine may be possible. Such flexibility could help to reduce the logistic stress on delivery of pandemic vaccination programmes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00975884. PMID- 22824475 TI - A critical assessment of SELDI-TOF-MS for biomarker discovery in serum and tissue of patients with an ovarian mass. AB - BACKGROUND: Less than 25% of patients with a pelvic mass who are presented to a gynecologist will eventually be diagnosed with epithelial ovarian cancer. Since there is no reliable test to differentiate between different ovarian tumors, accurate classification could facilitate adequate referral to a gynecological oncologist, improving survival. The goal of our study was to assess the potential value of a SELDI-TOF-MS based classifier for discriminating between patients with a pelvic mass. METHODS: Our study design included a well-defined patient population, stringent protocols and an independent validation cohort. We compared serum samples of 53 ovarian cancer patients, 18 patients with tumors of low malignant potential, and 57 patients with a benign ovarian tumor on different ProteinChip arrays. In addition, from a subset of 84 patients, tumor tissues were collected and microdissection was used to isolate a pure and homogenous cell population. RESULTS: Diagonal Linear Discriminant Analysis (DLDA) and Support Vector Machine (SVM) classification on serum samples comparing cancer versus benign tumors, yielded models with a classification accuracy of 71-81% (cross validation), and 73-81% on the independent validation set. Cancer and benign tissues could be classified with 95-99% accuracy using cross-validation. Tumors of low malignant potential showed protein expression patterns different from both benign and cancer tissues. Remarkably, none of the peaks differentially expressed in serum samples were found to be differentially expressed in the tissue lysates of those same groups. CONCLUSION: Although SELDI-TOF-MS can produce reliable classification results in serum samples of ovarian cancer patients, it will not be applicable in routine patient care. On the other hand, protein profiling of microdissected tumor tissue may lead to a better understanding of oncogenesis and could still be a source of new serum biomarkers leading to novel methods for differentiating between different histological subtypes. PMID- 22824476 TI - The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. AB - The understanding of the genetic bases of complex diseases such as nonalcoholic fatty liver disease opens new opportunities and challenges. This article explores new tools designed toward moving genomic data into clinical medicine, providing putative answers to more practical questions. PMID- 22824478 TI - Mechanisms of simple hepatic steatosis: not so simple after all. AB - Nonalcoholic fatty liver disease is becoming an epidemic. Fat is typically stored in adipose tissue in the form of triglycerides (TGs). The deposition of TGs in the liver is the result of an imbalance between the amount of energy taken in and the amount used. This balance is maintained by a complex interplay between the dietary intake of nutrients, the hormonal response to the nutrients, and their effect on both the liver and adipose tissue. Disruption of this system is what leads to the development of steatosis and is the focus of this article. PMID- 22824477 TI - The relevance of liver histology to predicting clinically meaningful outcomes in nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease. Nonalcoholic steatohepatitis (NASH), the more severe form of NAFLD, has an increased risk for progression to cirrhosis. The available data suggest increased morbidity and mortality among those patients with advanced histologic severity such as NASH and fibrosis. Despite the lack of a universally accepted histologic definition of NAFLD and inconsistency among pathologists regarding histologic findings essential to the diagnosis of NASH, a few studies have identified specific histologic findings (particularly fibrosis regardless of stage) that are able to predict NAFLD-related mortality as being most important. PMID- 22824479 TI - A myriad of pathways to NASH. AB - Nonalcoholic steatohepatitis (NASH) is defined histopathologically by the presence of macrovesicular steatosis, cellular ballooning, and inflammation. NASH represents a complex multifactorial disease that typically occurs within the context of the metabolic syndrome. NASH lacks homogeneity, and other forms of NASH can present atypically. Less than 50% of patients with NASH respond to pharmacologic treatment, which speaks to this heterogeneity. The authors discuss drugs, disease entities, and nutritional states that can cause or exacerbate underlying NASH indirectly through worsening insulin resistance or directly by interfering with lipid metabolism, promoting oxidative injury, or activating inflammatory pathways. PMID- 22824480 TI - Mechanisms of disease progression in NASH: new paradigms. AB - The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma. PMID- 22824482 TI - Is nonalcoholic fatty liver disease in children the same disease as in adults? AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children, and can present in toddlerhood. There is a differential distribution of NAFLD in children based on race and gender. The gold standard for diagnosis and classification of pediatric NAFLD is liver biopsy although ongoing studies aim to identify and define noninvasive investigations for pediatric NAFLD. Treatments that have been shown to be successful in adult NAFLD, such as insulin sensitizers and Vitamin E, have not been proven to be as definitively successful in children with NAFLD. PMID- 22824483 TI - The cardiovascular link to nonalcoholic fatty liver disease: a critical analysis. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and can progress from simple steatosis to nonalcoholic steatohepatitis and finally to liver cirrhosis. NAFLD is considered to be the hepatic manifestation of the metabolic syndrome because both share common features, which implicates a role of NAFLD in the development and progression of cardiovascular disease (CVD). The diagnosis of NAFLD deserves special attention in clinical practice for cardiovascular risk screening and surveillance strategies to allow for early targeted intervention in selected individuals at risk of future cardiovascular events. PMID- 22824481 TI - Can NASH be diagnosed, graded, and staged noninvasively? AB - Nonalcoholic bland steatosis and nonalcoholic steatohepatitis (NASH) are stages in the spectrum of nonalcoholic fatty liver disease (NAFLD). NASH may progress to end-stage liver disease. Liver biopsy distinguishes between patients with NASH and no NASH and can stage fibrosis. Markers of hepatocyte apoptosis hold promise as noninvasive tests for NASH diagnosis. Several scoring systems that combine routine clinical and laboratory variables and some proprietary panels can assist in predicting fibrosis severity. Noninvasive imaging modalities are reasonably accurate available tools to determine severity of fibrosis in NAFLD, but none of them yet can replace liver biopsy. PMID- 22824485 TI - Management of nonalcoholic steatohepatitis: an evidence-based approach. AB - Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are an increasingly common cause of chronic liver disease in the developed world, with NASH projected to be the leading cause of liver transplantation in the United States by 2020. This review of NASH management addresses current data from the perspective of levels of evidence for therapeutic options in NASH, including lifestyle modification, drug therapies, and bariatric surgery. In particular, behavioral therapies to assist patients in adopting lifestyle changes are highlighted and a research agenda for future NASH management is presented. PMID- 22824484 TI - Psychological and psychiatric aspects of treatment of obesity and nonalcoholic fatty liver disease. AB - Chronic illnesses incur a tremendous cost to American lives in dollars and quality of life. Outcomes in these illnesses are often affected by psychological, behavioral, and pharmacologic issues related to mental illness and psychological symptoms. This article focuses on psychological and psychiatric issues related to the treatment of obesity and nonalcoholic fatty liver disease (NAFLD), including available weight-loss interventions, the complex relationship between psychiatric disorders and obesity, and special considerations regarding use of psychiatric drugs in patients with or at risk for NAFLD and obesity. Recommendations for collaborative care of individuals with comorbid NAFLD and psychological disorders/symptoms are discussed. PMID- 22824486 TI - Preface. Advances and evolving concepts in nonalcoholic fatty liver disease. PMID- 22824487 TI - Prediction of heparin binding sites in bone morphogenetic proteins (BMPs). AB - Heparin is a glycosaminoglycan known to bind bone morphogenetic proteins (BMPs) and the growth and differentiation factors (GDFs) and has strong and variable effects on BMP osteogenic activity. In this paper we report our predictions of the likely heparin binding sites for BMP-2 and 14. The N-terminal sequences upstream of TGF-beta-type cysteine-knot domains in BMP-2, 7 and 14 contain the basic residues arginine and lysine, which are key components of the heparin/HS binding sites, with these residues being highly non-conserved. Importantly, evolutionary conserved surfaces on the beta sheets are required for interactions with receptors and antagonists. Furthermore, BMP-2 has electropositive surfaces on two sides compared to BMP-7 and BMP-14. Molecular docking simulations suggest the presence of high and low affinity binding sites in dimeric BMP-2. Histidines were found to play a role in the interactions of BMP-2 with heparin; however, a pK(a) analysis suggests that histidines are likely not protonated. This is indicative that interactions of BMP-2 with heparin do not require acidic pH. Taken together, non-conserved amino acid residues in the N-terminus and residues protruding from the beta sheet (not overlapping with the receptor binding sites and the dimeric interface) and not C-terminal are found to be important for heparin-BMP interactions. PMID- 22824488 TI - Influence of gravity compensation training on synergistic movement patterns of the upper extremity after stroke, a pilot study. AB - BACKGROUND: The majority of stroke patients have to cope with impaired arm function. Gravity compensation of the arm instantaneously affects abnormal synergistic movement patterns. The goal of the present study is to examine whether gravity compensated training improves unsupported arm function. METHODS: Seven chronic stroke patients received 18 half-hour sessions of gravity compensated reach training, in a period of six weeks. During training a motivating computer game was played. Before and after training arm function was assessed with the Fugl-Meyer assessment and a standardized, unsupported circle drawing task. Synergistic movement patterns were identified based on concurrent changes in shoulder elevation and elbow flexion/extension angles. RESULTS: Median increase of Fugl-Meyer scores was 3 points after training. The training led to significantly increased work area of the hemiparetic arm, as indicated by the normalized circle area. Roundness of the drawn circles and the occurrence of synergistic movement patterns remained similar after the training. CONCLUSIONS: A decreased strength of involuntary coupling might contribute to the increased arm function after training. More research is needed to study working mechanisms involved in post stroke rehabilitation training. The used training setup is simple and affordable and is therefore suitable to use in clinical settings. PMID- 22824489 TI - Clinical findings, orbital imaging, and intraoperative findings in patients with isolated inferior rectus muscle paresis or underaction. AB - PURPOSE: To present the clinical findings, orbital imaging, and intraoperative findings of patients with inferior rectus muscle underaction and to determine whether specific findings can help discern the underlying cause. METHODS: A retrospective observational study was performed on patients presenting with isolated inferior rectus muscle underaction between January 2007 and October 2011. Patient history, ocular motility, fundus torsion, Lancaster red-green plots, and radiographic findings were analyzed. For patients who had surgery, intraoperative findings also were considered. RESULTS: A total of 28 patients with inferior rectus muscle underaction were identified. Of these, 13 (46%) presented with inferior rectus muscle underaction after orbital trauma; 25 (89%) showed no increase in hypertropia >4(Delta) on head tilt to either side. Fundus intorsion was present in all patients. Of 15 patients evaluated by Lancaster red green testing, 12 (80%) showed subjective intorsion. Twenty patients underwent orbital imaging via computed tomography or magnetic resonance imaging, and the results in 8 (40%) revealed obvious changes in the inferior rectus muscle. Nineteen patients underwent surgery; intraoperatively, the muscle appeared grossly normal in 8 patients (42%) and showed posterior muscle slippage in 4 (26%). Less common findings included stretched scar formation, flap tear, missing tissue, extensive muscle adhesions, or inability to identify the muscle. CONCLUSIONS: Clinical findings in patients with inferior rectus muscle underaction are not sufficiently different to identify the cause, and orbital imaging identified a specific abnormality in only 40% of cases. PMID- 22824490 TI - Retinal vessel changes after laser treatment for retinopathy of prematurity. AB - BACKGROUND: The clinical response to retinopathy of prematurity (ROP) treatment is currently assessed subjectively. This study aims to quantify treatment response objectively by assessing changes in digital images of posterior pole retinal vessel width and tortuosity. METHODS: Images of 30 right eyes with type 1 ROP obtained at up to three time points were analyzed: before treatment (T = 0) and 1 (T = 1) and/or 2 weeks (T = 2) after treatment. Width and tortuosity of retinal vessels were analyzed from digital images using computer-assisted image analysis software. RESULTS: Vessel width decreased by 20% (P < 0.004) within the first week and remained stable by the second week after laser treatment. Vessel tortuosity did not significantly change by the first week but decreased 27% (P < 0.01) by second week. CONCLUSIONS: Vessel width appears to decrease dramatic within the first week, whereas the regression of tortuosity follows a slower course. PMID- 22824491 TI - Macular parameters and prematurity: A spectral domain coherence tomography study. AB - PURPOSE: To investigate the association of premature birth with macular parameters measured by spectral domain coherence tomography (SD-OCT). METHODS: The Sydney Adolescent Vascular and Eye Study performed eye examinations in school students across Sydney between 2009 and 2011. Visual acuity, cycloplegic autorefraction, and optical biometry measurements were recorded. Macular parameters were measured with SD-OCT. Questionnaires previously completed by the participants' parents were used to determine perinatal and medical history. Children with retinal disease or a known history of retinopathy of prematurity were excluded from the analysis. RESULTS: Macular measurements from the right eye of 1,672 participants ages 10-19 years were analyzed. The central subfield in those born at <=32 weeks' gestational age was significantly thicker than those born at >=37 weeks' gestational age (266.3 MUm vs 251.7 MUm, P = 0.0007). The average cube thickness and average outer macular ring thickness were smaller in those born at <=32 weeks compared with those born at >=37 weeks (P = 0.03 and 0.02, respectively). Similarly, the cube volume was smaller in the <=32 weeks' group compared with the >=37 weeks' group (P = 0.04). No significant differences were found between the 33-36 weeks' group and the >=37 weeks' group. CONCLUSIONS: In comparison to babies born at term, thicker central maculas and thinner macular outer rings were found in children born <33 weeks gestational age when measured by SD-OCT at ages 10-19 years. PMID- 22824492 TI - Clinical accuracy of the AAPOS pediatric vision screening referral criteria. AB - BACKGROUND: The American Association for Pediatric Ophthalmology and Strabismus (AAPOS) referral criteria for amblyogenic risk factors are consensus criteria that were determined by the best-available data as well as survey results of pediatric ophthalmologists. In 2003 the AAPOS Vision Screening Committee published guidelines to standardize reporting the ability of vision screening devices to detect these factors. We attempted to assess the accuracy of the AAPOS referral criteria. METHODS: Billing records of one pediatric ophthalmologist were reviewed to identify all children who were seen in 2002. Records were excluded if photoscreening had not been performed at the initial visit or if photoscreening results were not available in the record. Of the remaining records, one-half were randomly selected for analysis. Cycloplegic refraction and binocular alignment were evaluated to determine whether the child would have been considered to be at risk for amblyopia on the basis of AAPOS referral critera. The sensitivity and specificity of these factors for detecting amblyopia was then determined. RESULTS: A total of 1,575 records were identified, of which 529 were randomly selected; 7 were excluded for incomplete data. AAPOS referral criteria would have referred 266 patients, of whom 255 had amblyopia and 11 did not; of the 256 patients who would not have been referred, 46 had amblyopia and 210 did not. In this population, the AAPOS referral criteria would have had an 85% sensitivity, 95% specificity, a 5% false-positive rate and a 15% false-negative rate for detecting amblyopia. CONCLUSIONS: Application of the AAPOS referral criteria resulted in underreporting of amblyopia in this study. We propose modifications that may result in increased sensitivity and a lower false-negative rate. PMID- 22824493 TI - Nummular dystrophic calcification of an Ahmed glaucoma valve in a child. AB - We report the case of an otherwise-healthy 4.5-year-old girl with primary congenital glaucoma who had multiple nummular calcium deposits on the dorsal plate of a previously-implanted Ahmed glaucoma valve. The child had received the implant in the right eye at 6 months of age and developed increased intraocular pressure requiring surgical excision of surrounding fibrous encapsulation. Intraoperative inspection revealed that the dorsal plate surface was covered with multiple white nummular lesions; staining and X-ray microanalysis confirmed the lesions to be calcium deposits. Calcium deposits have been documented for various ophthalmic implants, including silicone scleral buckles and intraocular lenses, but to the best of our knowledge they have not previously been described in association with a glaucoma drainage device. PMID- 22824494 TI - Central retinal artery occlusion in Crohn disease. AB - Crohn disease is an inflammatory bowel disease frequently associated with extraintestinal manifestations. Ocular manifestations are uncommon but may cause significant morbidity, including blindness. We report the first case of a 9-year old boy with biopsy-proven Crohn disease who developed a cilioretinal artery sparing central retinal artery occlusion. After 2 months of follow-up, the patient developed optic atrophy with no change in visual acuity. PMID- 22824495 TI - Rectus muscle flap tear as an independent cause of restricted motility. AB - Most published cases of rectus muscle flap tear have been associated with orbital trauma of various degrees of severity. When they accompany an orbital fracture, however, it is difficult to determine whether the flap tear is merely an incidental additional finding or a major contributing cause of the resulting restriction. How to treat the flap itself remains an open question. We report a 24-year-old man with an inferior rectus muscle flap tear caused by direct laceration of the muscle. The major finding was a "reverse leash" vertical restriction. Discarding the flap instead of reattaching it did not prevent a successful result. Our case supports the proposition that rectus muscle flap tear can be a restriction-producing entity. PMID- 22824496 TI - Synthesis, structure and solvatochromic properties of some novel 5-arylazo-6 hydroxy-4-phenyl-3-cyano-2-pyridone dyes. AB - BACKGROUND: A series of some novel arylazo pyridone dyes was synthesized from the corresponding diazonium salt and 6-hydroxy-4-phenyl-3-cyano-2-pyridone using a classical reaction for the synthesis of the azo compounds. RESULTS: The structure of the dyes was confirmed by UV-vis, FT-IR, 1H NMR and 13C NMR spectroscopic techniques and elemental analysis. The solvatochromic behavior of the dyes was evaluated with respect to their visible absorption properties in various solvents. CONCLUSIONS: The azo-hydrazone tautomeric equilibration was found to depend on the substituents as well as on the solvent. The geometry data of the investigated dyes were obtained using DFT quantum-chemical calculations. The obtained calculational results are in very good agreement with the experimental data. PMID- 22824497 TI - Preferences for working in rural clinics among trainee health professionals in Uganda: a discrete choice experiment. AB - BACKGROUND: Health facilities require teams of health workers with complementary skills and responsibilities to efficiently provide quality care. In low-income countries, failure to attract and retain health workers in rural areas reduces population access to health services and undermines facility performance, resulting in poor health outcomes. It is important that governments consider health worker preferences in crafting policies to address attraction and retention in underserved areas. METHODS: We investigated preferences for job characteristics among final year medical, nursing, pharmacy, and laboratory students at select universities in Uganda. Participants were administered a cadre specific discrete choice experiment that elicited preferences for attributes of potential job postings they were likely to pursue after graduation. Job attributes included salary, facility quality, housing, length of commitment, manager support, training tuition, and dual practice opportunities. Mixed logit models were used to estimate stated preferences for these attributes. RESULTS: Data were collected from 246 medical students, 132 nursing students, 50 pharmacy students and 57 laboratory students. For all student-groups, choice of job posting was strongly influenced by salary, facility quality and manager support, relative to other attributes. For medical and laboratory students, tuition support for future training was also important, while pharmacy students valued opportunities for dual practice. CONCLUSIONS: In Uganda, financial and non financial incentives may be effective in attracting health workers to underserved areas. Our findings contribute to mounting evidence that salary is not the only important factor health workers consider when deciding where to work. Better quality facilities and supportive managers were important to all students. Similarities in preferences for these factors suggest that team-based, facility level strategies for attracting health workers may be appropriate. Improving facility quality and training managers to be more supportive of facility staff may be particularly cost-effective, as investments are borne once while benefits accrue to a range of health workers at the facility. PMID- 22824498 TI - Socio-demographic determinants and prevalence of Tuberculosis knowledge in three slum populations of Uganda. AB - BACKGROUND: Knowledge of tuberculosis has been shown to influence health seeking behaviour; and urban slum dwellers are at a higher risk of acquiring tuberculosis than the general population. The study aim was to assess knowledge of tuberculosis and identify the associated socio-demographic determinants, in order to inform tailored interventions for advocacy, communication and social mobilisation in three urban-slum communities of Uganda. METHODS: A cross sectional survey of 1361 adults between April and October 2011. Data was analyzed by descriptive statistics. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) of potential determinants of tuberculosis (TB) knowledge were estimated by multivariable ordinal logistic regression using Stata 11.2 software. RESULTS: We found low knowledge of TB cause (26.7%); symptoms (46.8%), transmission (54.3%), prevention (34%) and free treatment (35%). Knowledge about TB treatment (69.4) and cure (85.1) was relatively high. Independent determinants of poor knowledge of TB in the multivariable analysis included (aOR, 95% CI) lack of formal education (0.56; 0.38 - 0.83, P = 0.004), unemployment (0.67; 0.49 - 0.90, P = 0.010) and never testing for HIV (0.69; 0.51 - 0.92, P < 0.012). Whilst, older age (1.73; 1.30 - 2.29, P < 0.001) and residing in Lira (2.02; 1.50 - 2.72, P < 0.001) were independent determinants of higher knowledge of TB. CONCLUSION: This study revealed deficiencies in the public health knowledge about TB symptoms, diagnosis and treatment among urban-slum dwellers in Uganda. Tuberculosis control programmes in similar settings should consider innovative strategies for TB education, advocacy, communication and social mobilisation to reach the youth, unemployed and less-educated; as well as those who have never tested for HIV. PMID- 22824499 TI - Genetic and phenotypic characterization of the RyhB regulon in Salmonella Typhimurium. AB - Salmonella encodes two homologs of RyhB, a small RNA (sRNA) involved in iron homeostasis. In Salmonella Typhimurium, the expression of both RyhB-1 and RyhB-2 is negatively regulated by the Fur repressor, while stationary phase is the primary signal inducing RyhB-2 expression. To identify the target mRNAs of RyhB-1 and RyhB-2, 9 predicted target genes were analyzed by quantitative RT-PCR to monitor differential transcript levels between wild type and each of three mutants (DeltaryhB-1, DeltaryhB-2 and DeltaryhB-1DeltaryhB-2) under conditions that maximize the expression of both sRNAs. Our results, along with bioinformatic predictions, suggest that the genes acnA, sodB, ftn, STM1273.1n, and acnB are the primary targets of at least one of these sRNAs. To understand the biological roles of the RyhB regulon, the aforementioned deletions were created in either wild type or Deltafur backgrounds and were subjected to various phenotypic assays. The results showed that these sRNAs are singularly or additively involved in the expression of multiple phenotypes, including acid resistance, resistance to hydrogen peroxide, and sensitivity to bactericidal antibiotics. The results support a model whereby RyhB-1 and RyhB-2 have a global regulatory effect on diverse cellular pathways in response to multiple environmental cues via post transcriptional regulation of distinct sets of overlapping targets. PMID- 22824500 TI - Blood selenium concentration in a selected population of children inhabiting industrial regions in Upper Silesia (Poland). AB - PURPOSE: Present study aimed at determining blood selenium concentration (Se-B) in a selected population of children inhabiting industrial regions. METHODS: The studies were conducted on a group of 267 children inhabiting industrial regions in Upper Silesia (Poland). Determination of Se-B was performed using hydride generation atomic absorption technique. RESULTS: In the studied group of children mean Se-B amounted to 76.75+/-12.52MUg/L. Only in 38.20% of studied children the estimated Se-B could be regarded as an optimal. Children with underweight (BMI<15th centile) manifested a significantly lower Se-B than children with BMI within the normal range (BMI 15-85th centile). In the entire study group of children a significant positive linear correlation was disclosed between BMI and Se-B (r=0.16, p<0.05). Regression analysis demonstrated that in the studied subgroup of children (with normal height, body mass and BMI) a higher BMI represented an independent factor of Se-B increase and a more pronounced age an independent factor of Se-B decrease. Moreover, maternal education represented an independent factor of Se-B increase in the studied group of children (with normal height, body mass and BMI). CONCLUSIONS: Se-B in the studied group children from industrial area in Upper Silesia corresponded with the lower range of blood selenium concentrations noted in recent years in other populations. A negative relationship was documented between age and Se-B and a positive relationship between BMI of a child and maternal education on one hand and Se-B of a child on the other. PMID- 22824501 TI - Effects of monocrotophos pesticide on serotonin metabolism during early development in the sea urchin, Hemicentrotus pulcherrimus. AB - Organophosphate pesticides can interfere with the serotonergic nervous system and potentially lead to malformations and behavioral abnormalities during early development in sea urchin. To investigate the mechanism by which monocrotophos (MCP) pesticide disrupts the serotonergic nervous system, we evaluated its effects on serotonin metabolism. Fertilized embryos of sea urchin were incubated with 40% MCP pesticide at nominal concentrations of 0.01, 0.10 and 1.00mg/L, and the effects on tryptophan hydroxylase of Hemicentrotus pulcherrimus (HpTPH), serotonin reuptake transporter (SERT), monoamine oxidase (MAO), and serotonin levels were investigated. The results indicated that MCP pesticide disturbed the baseline pattern of HpTPH and SERT mRNA expression and MAO activity during early development in H. pulcherrimus. When serotonin should be quickly metabolized at 36-hpf stage, HpTPH and SERT expression was decreased and MAO activity was induced by MCP pesticide, leading to the impairment of serotonergic synaptic activity. But when serotonin should be metabolized at low levels during the other six stages, MCP pesticide induced HpTPH and SERT expression, resulting in the improvement of serotonergic synaptic activity. We concluded that this metabolic disturbance is one of the major mechanisms by which MCP pesticides affect the serotonergic nervous system and potentially contribute to various developmental abnormalities. PMID- 22824502 TI - Cadmium effects on early development of chick embryos. AB - The toxic potential of cadmium (Cd) is well-documented for young and adult vertebrates, but it is still poorly understood in the early stages of development. In this study, cadmium effects were investigated on Gallus gallus embryos after injection of CdCl(2) (5MUM and 50MUM) within the egg air chamber, and incubation for 48 and 72h. After exposure, morphological and enzymatic analyses for glucose-6-phosphate dehydrogenase (G6PDH) and glutathione S transferase (GST) were performed. Critical morphological abnormalities occurred after exposure to the highest concentration of cadmium, mainly in the cephalic region, indicating the powerful teratogenic effect of Cd to chick embryos. Cd exposure did not alter enzymatic activities when compared to the control group, but the levels of G6PDH activity were highest in older embryos at stage 19, indicating that antioxidant defenses are not so robust in the earliest embryo stages. PMID- 22824503 TI - Ethylene bisdithiocarbamate pesticides cause cytotoxicity in transformed and normal human colon cells. AB - The effects of the fungicides Maneb, Mancozeb, and Zineb were investigated in transformed colon cells, HT-29, Caco2 and non-transformed cells, CCD-18Co. Significant decreases in viability were observed with Maneb and Mancozeb in HT-29 and CCD-18Co (80-260MUM), and Caco2 cells (40-180MUM). No significant decreases in viability were observed in all cell types up to 800MUM with Zineb. MnCl(2) and ZnCl(2) exposure produced no loss of viability in all cell types up to 400MUM. Light microscopy confirmed viability analysis. Lipid peroxidation was observed with Maneb and Mancozeb in cell types tested (60-200MUM). Caspase 3/7, 8, and 9 activities were observed with Maneb and Mancozeb in cell types tested (40 200MUM). Maneb and Mancozeb treated HT-29 and Caco2 cells demonstrated increases in manganese and zinc concentrations (20-200MUM). The lack of toxicity observed with Zineb, MnCl(2), and ZnCl(2) suggests that both the metal moiety and the organic portion of these fungicides together contribute to toxicity. PMID- 22824505 TI - Structural similarities of fucoidans from brown algae Silvetia babingtonii and Fucus evanescens, determined by tandem MALDI-TOF mass spectrometry. AB - Rapid mass spectrometric investigation of oligosaccharides, obtained by autohydrolysis of fucoidans from brown algae Silvetia babingtonii and Fucus evanescens (Fucales, Phaeophyceae) has shown both similarities and differences in structural features/sulfation pattern of their fragments, obtained in the same conditions. Tandem MALDI-TOF MS of fucooligosaccharides with even DP (degree of polymerization) was close to that observed for fucoidan from F. evanescens. Slight differences in tandem mass spectra of fragments with odd DP indicated, probably, sulfation at C-3 (instead of C-2 in F. evanescens) of some (1->4) linked alpha-L-Fucp residues and/or the presence of short blocks, built up of (1 >3)-linked alpha-L-Fucp residues. PMID- 22824504 TI - Structural characterization and study of immunoenhancing properties of a glucan isolated from a hybrid mushroom of Pleurotus florida and Lentinula edodes. AB - A water soluble glucan isolated from hot aqueous extract of fruit bodies of an edible hybrid mushroom Pfle1r of Pleurotus florida and Lentinula edodes showed macrophages, splenocytes, and thymocytes activation. The glucan consists of terminal, (1->3,6)-linked, and (1->6)-linked beta-D-glucopyranosyl moieties in a molar ratio of nearly 1:1:3. On the basis of acid hydrolysis, methylation, periodate oxidation study, and NMR studies ((1)H, (13)C, DEPT-135, TOCSY, DQF COSY, NOESY, ROESY, HSQC, and HMBC), the structure of the repeating unit of the glucan was established as: [structure: see text]. PMID- 22824506 TI - Novel isolation of water-soluble polysaccharides from the fruiting bodies of Pleurotus ostreatus mushrooms. AB - Novel water-soluble polysaccharides have been isolated from the fruiting bodies of the edible mushroom Pleurotus ostreatus. Three polysaccharide fractions were obtained by ethanol precipitation from cold water, hot water and hot aqueous NaOH extracts. The fractions were purified by size exclusion chromatography showing a unique carbohydrate occurring in each fraction: PC from the cold fraction, PH from the hot fraction and PB from the hot aqueous NaOH fraction. The analysis of the methylated alditol acetates and the NMR studies revealed that all the polysaccharides displayed a linear backbone. PC was formed by alpha-(1->3),(1->6) linked galactopyranosyl residues whereas PH and PB consisted of glucose-linked units. PH was exclusively composed of glucopyranosyl units bound by alpha-(1->4) linkages whereas PB was a beta-linked glucan showing (1->3) and (1->6) glycosidic bonds. The analysis of molecular arrangement by complexation with Congo red showed that only the beta-linked polysaccharide (PB) displayed a triple helix conformation. PMID- 22824507 TI - Simultaneous determination of uronates found in polysaccharides from natural products by HPLC with fluorometric detection. AB - A sensitive high-performance liquid chromatographic (HPLC) method for the determination of uronates isolated from polysaccharides found in natural products such as glycosaminoglycans and alginate is described. Preparation of iduronate, guluronate, and mannuronate as analytical standards for high performance liquid chromatography was achieved by depolymerization of dermatan sulfate and alginate in 2.5 mol L(-1) trifluoroacetic acid at 100 degrees C for 6h. Structures of resulting products (iduronate, guluronate, and mannuronate) were characterized by 600 MHz (1)H NMR. Five uronates (glucuronate, iduronate, mannuronate, guluronate, and galacturonate) were separated on a Dionex CarboPac PA1 column using an isocratic elution with 8 mmol L(-1) acetate buffer (pH 4.84) and were monitored by fluorescence detection using 1.5% 2-cyanoacetamide as a post-column fluorogenic reagent. As little as 50 pmol of each uronate could be detected with excitation at 331 nm and emission at 383 nm. PMID- 22824508 TI - A multiple regression analysis on factors influencing haematopoietic progenitor cell collection for autologous transplantation. AB - Autologous hematopoietic stem cell (HSC) transplantation today is the standard treatment for a wide variety of haematological and oncological diseases. HSC are collected from peripheral blood by leukapheresis (HPC-A) following chemotherapy and/or growth factor-mediated mobilization. The ideal HPC-A collection allows to reach the CD34(+) target dose through a single, tailored leukapheresis. The aim of this paper was to find out which collection parameter might play a key role in obtaining a CD34 dose >4*10(6)/kg with a reduced number of leukapheresis. To address this issue, a multivariate logistic regression was carried out on several operational and laboratory parameters from 943 HPC-A collections performed in 600 hematological and oncological patients. We observed a CD34(+) cells collection efficiency (CE) >50% when patient's pre-apheresis total WBC count was lower than 12.5*10(6)/mL. At the same time, the likelihood of reaching the CD34(+) cells target dose/kg increased from 6 to 3 times when the pre-apheresis WBC count *10(6)/mL t was below 4.3 (OR=6.1; 2.6-14.1) and between 4.3 and 7 (OR=2.8; 1.4 5.7) respectively when compared to a pre-apheresis WBC count >36*10(6)/mL. PMID- 22824509 TI - Estimated prevalence of canine Type 2 Von Willebrand disease in the Deutsch Drahthaar (German Wirehaired Pointer) in Europe. AB - Type 2 Von Willebrand disease (VWD) is a severe coagulopathy occurring in the Deutsch-Drahthaar dog (or German Wirehaired Pointer, DD/GWP). Recently, a causative recessive mutation has been identified, and a DNA test is now available for individual screening. The genotype distribution (clear, carrier, and affected dogs) was investigated in 1855 DD/GWP dogs using data collected by the DD DNA-VWD Databank in several European countries. 1704 (91.8%) DD/GWP dogs were genotypically clear of the VWD mutation, 144 (7.8%) were carriers, and seven (0.4%) were affected. The estimated disease allele frequency was highest in Germany and Sweden (almost 5%), and about 1% in Denmark, Finland and Norway. The Hardy-Weinberg equilibrium was tested in the German sample, and showed no evidence of deviation. PMID- 22824510 TI - Evaluation of N-butylbenzenesulfonamide (NBBS) neurotoxicity in Sprague-Dawley male rats following 27-day oral exposure. AB - N-Butylbenzenesulfonamide (NBBS) is widely used as a plasticizer in polyacetals, polyamides, and polycarbonates and has been found in ground water and effluent from wastewater treatment sites. The compound is lipophilic and distributes rapidly to the brain but also clears rapidly and shows little evidence of accumulation. Limited studies in the literature report neurotoxicity of NBBS in rabbits and rats. Adult Sprague-Dawley male rats (Harlan) received corn oil vehicle or NBBS (100, 200, or 400mg/kg/d) via oral gavage (5 ml/kg bwt) daily/5d/week for 27 d. Deaths were observed in the 400mg/kg/d dose group in the first 5d and dosing was decreased to 300 mg/kg/d. No alterations were observed in gait, locomotor activity, and rearing behavior. No histological lesions were observed in the testis, seminal vesicles, coagulating gland, epididymis, and prostate. In the liver, minimal centrilobular hypertrophy was evident in all rats of the high dose group. Contrary to previous reports, there was no evidence of peripheral nerve lesions or gliosis in the hippocampus or cerebellum. mRNA levels for glial fibrillary acidic acid protein, interferon gamma, CXCR-3, intracellular adhesion molecule-1, and CD11b were not altered in the hippocampus while Iba-1 levels were decreased. These data do not support previous reports of neurotoxicity for NBBS within a 4-week exposure regimen; however, neuropathological injury occurring over an extended period of exposure cannot be ruled out and given the potential for human exposure requires further examination. PMID- 22824511 TI - Changes in the synaptic structure of hippocampal neurons and impairment of spatial memory in a rat model caused by chronic arsenite exposure. AB - Many epidemiological studies and in vitro experiments have found that chronic arsenic exposure may influence memory formation. The goal of this study was to create an animal model of memory impairment induced by chronic arsenite exposure and to study the underlying mechanisms. Sixty male Sprague-Dawley (SD) male rats were randomly divided into a control group, a low-dose sodium arsenite exposure group and a high-dose sodium arsenite exposure group. Sodium arsenite was administered by adding it to drinking water for 3 months. Then, the spatial memory of the rats was examined with Morris water maze and Y maze. The concentration of arsenic in the blood and the brain was determined by an atomic fluorescence absorption spectrometer. The ultra-structure of hippocampal neurons was observed by an electron microscope. Timm staining was used for observing mossy fibers. We found that the concentration of arsenic in the blood and the brain increased in a dose-response manner (P<0.05). The performance of rats in the arsenite exposed group (15 mg/kg) was significantly impaired in the Morris water maze and Y maze tasks than those in the control group (P<0.05). Sodium arsenite exposure resulted in abnormal structural changes in the myelin sheaths of nerve fibers and decreases in the terminals of mossy fibers. Together, chronic sodium arsenite exposure through drinking water results in detrimental changes in the neuronal synapses, which may contribute to the arsenite-induced impairment of spatial memory. PMID- 22824513 TI - Ruthenium polypyridyl squalene derivative: a novel self-assembling lipophilic probe for cellular imaging. AB - Transition metal complexes provide a promising avenue for designing new therapeutic and diagnostic agents. In particular, ruthenium(II) polypyridyl complexes are useful for studying cellular uptake, due to their easy synthesis and unique photophysical properties. Dyes are frequently combined with material substrates to modulate their properties, enhance stability, reduce toxicity, and improve delivery. A novel Ru polypyridyl complex linked to a derivative of the natural lipid squalene (Ru-BIPPBI-hx-SQ) is described. Using the solvent displacement method, Ru-BIPPBI-hx-SQ easily self-assembles into nanosized aggregates in aqueous solution, as characterized by dynamic light scattering. The nanoassemblies exhibit long-lived and intense luminescence. Preliminary biological assessment showed them to be non-toxic; they are efficiently and rapidly transported across the cell membrane without requiring its permeabilization. Ru-labeled nanoassemblies are likely to be significant cellular imaging tools, probing cellular events at very low concentrations. Moreover co nanoassembly, with drug-derivatives based on squalenoylation technology, including gemcitabine and paclitaxel, has given interesting preliminary results. PMID- 22824512 TI - Establishment and characterization of mouse bone marrow-derived mast cell hybridomas. AB - Interleukin (IL)-3-dependent mouse bone marrow-derived mast cells (BMMCs) are an important model for studying the function of mucosal-type mast cells. In the present study, BMMCs were successfully immortalized by cell fusion using a hypoxanthine-aminopterin-thymidine medium-sensitive variant of P815 mouse mastocytoma (P815-6TgR) as a partner cell line. The established mouse mast cell hybridomas (MMCHs) expressed alpha, beta, and gamma subunits of high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) and possessed cytoplasmic granules devoid of or partially filled with electron-dense material. Four independent MMCH clones continuously proliferated without supplemental exogenous IL-3 and showed a degranulation response on stimulation with IgE+antigen. Furthermore, histamine synthesis and release by degranulation were confirmed in MMCH-D5, a MMCH clone that showed the strongest degranulation response. MMCH-D5 exhibited elevated levels of IL-3, IL-4, IL-13, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor (TNF)-alpha, and cyclooxygenase 2, and production of prostaglandin D(2) and leukotriene C(4) in response to IgE-induced stimulation. MMCH clones also expressed Toll-like receptors (TLRs) 1, 2, 4, and 6 and showed elevated levels of TNF-alpha expression in response to stimulation with TLR2 and TLR4 ligands. The MMCHs established using this method should be suitable for studies on FcepsilonRI- and TLR-mediated effector functions of mast cells. PMID- 22824514 TI - Amikacin reverse iontophoresis: optimization of in vitro extraction. AB - The aim of this work was to optimize amikacin reverse iontophoretic extraction across the skin in vitro, for non-invasive drug monitoring. Reverse iontophoresis experiments were performed using vertical diffusion cells. The lower chamber, simulating body fluids, contained amikacin bisulphate and acetaminophen, as marker for electroosmosis, while the upper chamber was filled with the appropriate extraction solution. The effect of concentration of amikacin in the dermal bathing solution and the effect of extraction solution composition and pH were studied. The results show that the extraction of amikacin was independent of pH and always in the anode-to-cathode direction, in agreement with the positive charge of the drug. The presence of amikacin in the bathing solution did not modify acetaminophen extraction at pH 4.0, while the extraction was reduced at pH 8.0. In conclusion, amikacin can be extracted across the skin in vitro by reverse iontophoresis. Owing to the charge of the molecule, extraction takes place at the cathode. Using acetaminophen as neutral marker, it was shown that amikacin can interact with the skin and alter its permselectivity at pH 8.0. PMID- 22824515 TI - Mediastinal neoplasms in patients with Graves disease: a possible link between sustained hyperthyroidism and thymic neoplasia? AB - BACKGROUND: Anterior mediastinal masses are a rare but well documented finding in Graves disease. The vast majority of these lesions represents benign thymic hypertrophy and regress after treatment of the hyperthyroidism. A small percentage of these cases however represent neoplastic/malignant diseases which require further treatment. CASES: 12 year old boy with one year history of refractory Graves disease was found to have an anterior mediastinal mass and underwent curative thyroidectomy for sustained hyperthyroidism. Cervical lymphadenopathy was detected during the procedure and biopsy was obtained. A 23 year old woman who presented with a one month history of hyperthyroid symptoms, was diagnosed with Graves disease and also was found to have an anterior mediastinal mass on imaging. Biopsy of the anterior mediastinal mass was obtained and subsequently the patient underwent robotic thymectomy. Histologic examination and immunophenotyping of the cervical lymph node in a 12 year old boy revealed neoplastic proliferation of T lymphoblasts diagnostic of T lymphoblastic leukemia/lymphoma. Examination of the anterior mediastinal mass biopsy in the 23 year old woman revealed type B1 thymoma which was confirmed after examination of the subsequent robotic thymectomy specimen. CONCLUSION: This is the first reported case of T cell lymphoblastic lymphoma and the third reported case of thymoma associated with sustained hyperthyroidism due to Graves disease. These cases indicate that an anterior mediastinal mass in a patient with active Graves disease may be due to a neoplastic cause, which may require definitive treatment. Caution should be exercised when dismissing a mediastinal mass as benign thymic hyperplasia in patients with active Graves disease. PMID- 22824516 TI - Correlation of anterior segment optical coherence tomography measurements with graft trephine diameter following descemet stripping automated endothelial keratoplasty. AB - BACKGROUND: To assess repeatability of the Zhongshan Assessment Program (ZAP) software measurement of Anterior Segment Optical Coherence Tomography (ASOCT) images and correlate with graft trephine diameter following Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) METHODS: Retrospectively evaluated interventional case series. 121 consecutive eyes undergoing DSAEK over a 26 month period underwent ASOCT imaging 1 month after their surgery. ASOCT images were processed using ZAP software which measured the graft and cornea parameters including anterior and posterior graft arc length and cord length, posterior cornea arc length (PCAL) and anterior chamber width. RESULTS: The graft measurements showed good repeatability on ASOCT using ZAP with high intra class coefficient and small variation in the coefficient of variation. On ASOCT, the mean recipient PCAL was 12.99+/-0.69 mm and the anterior chamber width was 11.16+/-0.57 mm. The mean Graft anterior arc length was 9.69+/-0.66 mm and the mean Graft anterior cord length was 8.92+/-2.94 mm. The mean graft posterior arc length was 9.24+/-0.75 mm and the mean graft posterior cord length was 8.15+/ 0.57 mm. Graft posterior arc length (rho=0.788, p< 0.001) correlated best with intra-operative graft trephine diameter. The mean ratio of posterior graft arc length to PCAL was 0.712 +/- 0.056. CONCLUSIONS: We have validated the repeatability of the ZAP software for DSAEK graft measurements from ASOCT images and shown that the graft arc length parameters calculated from the ASOCT images correlate well with the intra-operative graft trephine diameter. This software may help surgeons determine the optimal DSAEK graft size based on pre-operative ASOCT measurements of the recipient eye. PMID- 22824517 TI - Syntheses, crystal structure and luminescent properties of cadmium complexes based on 2,6-bis(1-phenylbenzimidazol-2-yl)pyridine. AB - Two cadmium complexes, Cd(bpbp)Cl(2) (complex 1) and [Cd(bpbp)(2)](ClO(4))(2) (complex 2), based on 2,6-bis(1-phenylbenzimidazol-2-yl)pyridine (bpbp), were synthesized and characterized by X-ray single crystal structure analyses. For complex 1: crystal system, monoclinic, space group, C2/c, a=27.427(3)A, b=13.4495(15)A, c=14.8381(17)A, beta=106.635(2) degrees , V=5244.4(10)A(3), Z=8. It is a neutral complex. The Cd(II) ion distorted trigonal bipyramidal geometry is five-coordinated by three nitrogen atoms from ligand (bpbp) and two chlorine ions. For complex 2: crystal system, triclinic, space group, P-1, a=13.4791(15)A, b=13.8506(16)A, c=16.5839(19)A, alpha=94.202(2) degrees , beta=106.948(2) degrees , gamma=94.872(2) degrees , V=2935.3(6)A(3), Z=2. It is an ionic complex. The Cd(II) ion octahedral geometry is six-coordinated by six nitrogen atoms from two ligand (bpbp). Both complexes emit blue luminescence with emission peaks at 420 and 430 nm in solid state and with emission peaks at 415 and 425 nm in DMF solution. In complex 1 absorption spectra, there is not only the free ligand absorption peak at 310 nm, but also shows strong Cd-Cl charge transfer peak at 350 nm in DMF solution. PMID- 22824518 TI - The effects of tinnitus and/or hearing loss on the Symptom Checklist-90-Revised test. AB - OBJECTIVE: This study aims to evaluate the psychological attitudes of patients with tinnitus by using The Symptom Checklist-90-Revised and to investigate the relationship between hearing loss and attributed psychological attitudes. MATERIALS AND METHODS: 142 subjects (73 female, 69 male) divided into 4 groups: Group 1 (32 patients with tinnitus and hearing loss-), Group 2 (38 patients with tinnitus), Group 3 (36 patients with hearing loss), Group 4 (36 healthy subjects without tinnitus and hearing loss-control group). The Symptom Checklist-90 Revised (SCL-90-R) test was used to detect the subjects' tendency for psychological problems due to tinnitus and/or hearing loss. RESULTS: Mean values of Somatization (SOM), Obsessive-Compulsive (O-C) and Additional Scale (AS) were higher than cut-off points of 1.00 for Groups 1 and 2 (tinnitus and/or hearing loss). In patients with tinnitus and/or hearing loss, SOM, O-C, Depression (DEP), AS and Global Severity Index (GSI) were significantly higher than patients with hearing loss and control group. By multiple linear regression analysis, tinnitus was the significantly detected confounding factor for increase of SOM, O-C, Interpersonal Sensitivity (I-S), DEP, Hostility (HOS), Paranoid Ideation (PAR), AS and GSI parameters. CONCLUSION: It was concluded that tinnitus could induce some psychological symptoms such as depression; and this is independent of hearing loss. Tinnitus with or without hearing loss is the essential factor for causing psychological problems in patients. Tinnitus duration is not important in the scene of psychological status of the patients. This result shows that, age, gender (male, female), chronic or acute tinnitus experience, and having hearing loss did not cause too much problems in patients. But tinnitus experience in every form (for the present study, intermediate level subjective tinnitus) is significantly important confounding factor for affecting psychological status of the patients. PMID- 22824519 TI - Effectiveness of laryngostroboscopy for monitoring the evolution of vocal nodules after rehabilitator treatment. AB - OBJECTIVE: The aim of this study is to evaluate the effectiveness of the laryngostroboscopy for monitoring the evolution of patients with vocal nodules before and after the logopedic vocal treatment. METHODS: We performed a prospective observational study of 97 dysphonic patients diagnosed of vocal nodules, where we analyzed four stroboscopic parameters (glottal closure, vocal fold vibration, mucosal wave and phase symmetry) by a protocol based on systematic subjective evaluation of the stroboscopic images before and after the rehabilitator vocal treatment; and the results were stratified according to the clinical course. RESULTS: All patients, before the treatment, had some abnormality in at least one of the four analyzed aspects. After the vocal treatment, we found improvement of the four parameters in different degrees. Also, we found a statistically significant relationship between the evolution of each parameter and the clinical course. CONCLUSION: We believe that the laryngostroboscopy, systematized through a protocol, is a useful technique for the diagnosis of structural abnormalities in patients with vocal nodules and is a useful technique for evaluating the results after the rehabilitator treatment, as there is a statistically significant relationship between clinical course and the change in the stroboscopic findings. However it should not be the only technique used for these proposes. PMID- 22824520 TI - Clinical application of a card-type odor identification test to olfactory assessment in Parkinson's disease. AB - OBJECTIVES: Current studies have provided valuable evidence that Parkinson's disease (PD) is closely associated with olfactory loss and that the use of olfactory testing is regarded as one of the potential screening tools for early diagnosis of PD. METHODS: Twenty-six patients with PD, age- and sex-matched 14 patients with other neurological diseases and 10 healthy controls were evaluated the sense of smell by the Open Essence (OE). RESULTS: The motor performance of the patients with PD was assessed using the Hoehn and Yahr scale. The OE scores for patients with PD were significantly lower than those with both the patients with other neurological diseases and controls. There was no significant difference of the OE scores between patients with other neurological diseases and controls. In the PD group, the OE score was not correlated with gender, smoking habit, disease duration, age at examination, or cognitive status. However, the OE scores were significantly correlated with Hoehn and Yahr stages. CONCLUSION: OE was found to be practically self-administered, time-saving, reliable, and inexpensive method for correct diagnosis of olfactory dysfunction associated with PD. PMID- 22824522 TI - Bryophyllum pinnatum inhibits detrusor contractility in porcine bladder strips--a pharmacological study towards a new treatment option of overactive bladder. AB - AIMS: A broad spectrum of synthetic agents is available for the treatment of overactive bladder. Anti-cholinergic drugs show a poor compliance due to side effects. There is an increasing use of plant extracts in medicine. We have therefore investigated the inhibitory effects of leaf press juice from Bryophyllum pinnatum (Lam.) Oken (Kalanchoe pinnata L.) on bladder strips and compared the effects to that of oxybutynin. METHODS: Strips of porcine detrusor were prepared in Krebs solution and contractility was measured in a myograph system chamber aired with O2/CO2 at 37 degrees C. To induce contractions, electrical field stimulation (32 Hz, 40 V) was used for the inhibitory effect measurements, and carbachol (50 MUM) for the relaxant effect measurements. Recordings were obtained in the absence and presence of increasing concentrations of Bryophyllum pinnatum leaf press juice (BPJ, 0.1-10%), and oxybutynin (10-7-10 3 M) as a reference substance. RESULTS: In inhibition experiments, BPJ as well as oxybutynin inhibited electrically induced contractions of porcine detrusor. BPJ at concentrations of 5% inhibited the contraction compared to a time matched control significantly by 74.6+/-10.2% (p<0.001). BPJ as well as oxybutynin relaxed carbachol pre-contracted porcine detrusor strips. The maximum relaxant effect of BPJ compared to a time matched control was 18.7+/-3.7 (p<0.05) at a concentration of 10% BPJ. CONCLUSIONS: Our investigations show that BPJ inhibits contractions induced by electrical field stimulation and relaxes carbachol induced contractions. However, the effect was lower than that of the reference substance oxybutynin. It is important to continue in vitro experiments as well as clinical studies with BPJ that might offer a new treatment option for patients with OAB. PMID- 22824521 TI - Posttraumatic growth, depressive symptoms, posttraumatic stress symptoms, post migration stressors and quality of life in multi-traumatized psychiatric outpatients with a refugee background in Norway. AB - BACKGROUND: Psychiatric outpatients with a refugee background have often been exposed to a variety of potentially traumatizing events, with numerous negative consequences for their mental health and quality of life. However, some patients also report positive personal changes, posttraumatic growth, related to these potentially traumatic events. This study describes posttraumatic growth, posttraumatic stress symptoms, depressive symptoms, post-migration stressors, and their association with quality of life in an outpatient psychiatric population with a refugee background in Norway. METHODS: Fifty five psychiatric outpatients with a refugee background participated in a cross-sectional study using clinical interviews to measure psychopathology (SCID-PTSD, MINI), and four self-report instruments measuring posttraumatic growth, posttraumatic stress symptoms, depressive symptoms, and quality of life (PTGI-SF, IES-R, HSCL-25-depression scale, and WHOQOL-Bref) as well as measures of social integration, social network and employment status. RESULTS: All patients reported some degree of posttraumatic growth, while only 31% reported greater amounts of growth. Eighty percent of the patients had posttraumatic stress symptoms above the cut-off point, and 93% reported clinical levels of depressive symptoms. Quality of life in the four domains of the WHOQOL-Bref levels were low, well below the threshold for the'life satisfaction' standard proposed by Cummins. A hierarchic regression model including depressive symptoms, posttraumatic stress symptoms, posttraumatic growth, and unemployment explained 56% of the total variance found in the psychological health domain of the WHOQOL-Bref scale. Posttraumatic growth made the strongest contribution to the model, greater than posttraumatic stress symptoms or depressive symptoms. Post-migration stressors like unemployment, weak social network and poor social integration were moderately negatively correlated with posttraumatic growth and quality of life, and positively correlated with psychopathological symptoms. Sixty percent of the outpatients were unemployed. CONCLUSIONS: Multi-traumatized refugees in outpatient clinics reported both symptoms of psychopathology and posttraumatic growth after exposure to multiple traumatic events. Symptoms of psychopathology were negatively related to the quality of life, and positively related to post-migration stressors such as unemployment, weak social network and poor social integration. Posttraumatic growth was positively associated with quality of life, and negatively associated with post-migration stressors. Hierarchical regression modeling showed that posttraumatic growth explained more of the variance in quality of life than did posttraumatic stress symptoms, depressive symptoms or unemployment. It may therefore be necessary to address both positive changes and psychopathological symptoms when assessing and treating multi-traumatized outpatients with a refugee background. PMID- 22824524 TI - Treatment outcome of smear-positive pulmonary tuberculosis patients in Tigray Region, Northern Ethiopia. AB - BACKGROUND: Monitoring the outcome of tuberculosis treatment and understanding the specific reasons for unsuccessful treatment outcome are important in evaluating the effectiveness of tuberculosis control program. This study investigated tuberculosis treatment outcomes and predictors for unsuccessful treatment outcome in the Tigray region of Ethiopia. METHODS: Medical records of smear-positive pulmonary tuberculosis (PTB) patients registered from September 2009 to June 2011 in 15 districts of Tigray region, Northern Ethiopia, were reviewed. Additional data were collected using a structured questionnaire administered through house-to-house visits by trained nurses. Tuberculosis treatment outcomes were assessed according to WHO guidelines. The association of unsuccessful treatment outcome with socio-demographic and clinical factors was analyzed using logistic regression model. RESULTS: Out of the 407 PTB patients (221 males and 186 females) aged 15 years and above, 89.2% had successful and 10.8% had unsuccessful treatment outcome. In the final multivariate logistic model, the odds of unsuccessful treatment outcome was higher among patients older than 40 years of age (adj. OR=2.50, 95% CI: 1.12-5.59), family size greater than 5 persons (adj. OR=3.26, 95% CI: 1.43-7.44), unemployed (adj. OR=3.10, 95% CI: 1.33-7.24) and among retreatment cases (adj. OR=2.00, 95% CI: 1.37-2.92) as compared to their respective comparison groups. CONCLUSIONS: Treatment outcome among smear-positive PTB patients was satisfactory in the Tigray region of Ethiopia. Nonetheless, those patients at high risk of an unfavorable treatment outcome should be identified early and given additional follow-up and social support. PMID- 22824523 TI - Force sensor in simulated skin and neural model mimic tactile SAI afferent spiking response to ramp and hold stimuli. AB - BACKGROUND: The next generation of prosthetic limbs will restore sensory feedback to the nervous system by mimicking how skin mechanoreceptors, innervated by afferents, produce trains of action potentials in response to compressive stimuli. Prior work has addressed building sensors within skin substitutes for robotics, modeling skin mechanics and neural dynamics of mechanotransduction, and predicting response timing of action potentials for vibration. The effort here is unique because it accounts for skin elasticity by measuring force within simulated skin, utilizes few free model parameters for parsimony, and separates parameter fitting and model validation. Additionally, the ramp-and-hold, sustained stimuli used in this work capture the essential features of the everyday task of contacting and holding an object. METHODS: This systems integration effort computationally replicates the neural firing behavior for a slowly adapting type I (SAI) afferent in its temporally varying response to both intensity and rate of indentation force by combining a physical force sensor, housed in a skin-like substrate, with a mathematical model of neuronal spiking, the leaky integrate-and-fire. Comparison experiments were then conducted using ramp-and-hold stimuli on both the spiking-sensor model and mouse SAI afferents. The model parameters were iteratively fit against recorded SAI interspike intervals (ISI) before validating the model to assess its performance. RESULTS: Model-predicted spike firing compares favorably with that observed for single SAI afferents. As indentation magnitude increases (1.2, 1.3, to 1.4 mm), mean ISI decreases from 98.81 +/- 24.73, 54.52 +/- 6.94, to 41.11 +/- 6.11 ms. Moreover, as rate of ramp-up increases, ISI during ramp-up decreases from 21.85 +/- 5.33, 19.98 +/- 3.10, to 15.42 +/- 2.41 ms. Considering first spikes, the predicted latencies exhibited a decreasing trend as stimulus rate increased, as is observed in afferent recordings. Finally, the SAI afferent's characteristic response of producing irregular ISIs is shown to be controllable via manipulating the output filtering from the sensor or adding stochastic noise. CONCLUSIONS: This integrated engineering approach extends prior works focused upon neural dynamics and vibration. Future efforts will perfect measures of performance, such as first spike latency and irregular ISIs, and link the generation of characteristic features within trains of action potentials with current pulse waveforms that stimulate single action potentials at the peripheral afferent. PMID- 22824525 TI - DNA methylation: a promising landscape for immune system-related diseases. AB - During hematopoiesis, a unique hematopoietic stem cell (HSC) from the bone marrow gives rise to a subset of mature blood cells that directs all the immune responses. Recent studies have shown that this well-defined, hierarchical process is regulated in part by epigenetic mechanisms. Changes in the DNA methylation profile have a critical role in the division of these stem cells into the myeloid and lymphoid lineages and in the establishment of a specific phenotype and functionality in each terminally differentiated cell type. In this review, we describe how the DNA methylation patterns are modified during hematopoietic differentiation and what their role is in cell plasticity and immune function. An in-depth knowledge of these epigenetic mechanisms will help clarify how cell type specific gene programs are established, and how they can be leveraged in the development of novel strategies for treating immune system-related pathologies. PMID- 22824526 TI - Nucleotide excision repair: new tricks with old bricks. AB - Nucleotide excision repair (NER) is a major DNA repair pathway that ensures that the genome remains functionally intact and is faithfully transmitted to progeny. However, defects in NER lead, in addition to cancer and aging, to developmental abnormalities whose clinical heterogeneity and varying severity cannot be fully explained by the DNA repair deficiencies. Recent work has revealed that proteins in NER play distinct roles, including some that go well beyond DNA repair. NER factors are components of protein complexes known to be involved in nucleosome remodeling, histone ubiquitination, and transcriptional activation of genes involved in nuclear receptor signaling, stem cell reprogramming, and postnatal mammalian growth. Together, these findings add new pieces to the puzzle for understanding NER and the relevance of NER defects in development and disease. PMID- 22824527 TI - Persistence of a bioluminescent Staphylococcus aureus strain on and around degradable and non-degradable surgical meshes in a murine model. AB - Biomaterials are increasingly used for the restoration of human function, but can become infected as a result of peri- or early post-operative bacterial contamination, although biomaterial-associated infections (BAIs) can also initiate at any time from hematogenous spreading of bacteria from an infection elsewhere in the body. Infecting bacteria in BAIs not only seek shelter in their own protective biofilm matrix, but also hide in surrounding tissue. This study compares staphylococcal persistence on and around a degradable and non-degradable surgical mesh through the use of longitudinal bioluminescence imaging in a murine model, including histological evaluation of surrounding tissue after sacrifice. Surgical meshes were first contaminated with bioluminescent Staphylococcus aureus Xen29 and subsequently subcutaneously implanted in mice. Bioluminescent staphylococci persisted on and around non-degradable meshes during the 28-day course of the study, whereas bioluminescence returned to control levels and bacteria disappeared from surrounding tissues once a degradable mesh had fully dissolved. Thus the application of degradable biomaterials yields major advantages with respect to the prevention of BAIs, as dissolution of the implant not only is associated with elimination of the protective biofilm mode of growth of the infecting organisms, but also allows the immune system to clear the surrounding tissue from infecting organisms. PMID- 22824528 TI - Crosslinking strategies facilitate tunable structural properties of fibrin microthreads. AB - A significant challenge in the design of biomimetic scaffolds is combining morphologic, mechanical, and biochemical cues into a single construct to promote tissue regeneration. In this study, we analyzed the effects of different crosslinking conditions on fibrin biopolymer microthreads to create morphologic scaffolds with tunable mechanical properties that are designed for directional cell guidance. Fibrin microthreads were crosslinked using carbodiimides in either acidic or neutral buffer, and the mechanical, structural, and biochemical responses of the microthreads were investigated. Crosslinking in the presence of acidic buffer (EDCa) created microthreads that had significantly higher tensile strengths and moduli than all other microthreads, and failed at lower strains than all other microthreads. Microthreads crosslinked in neutral buffer (EDCn) were also significantly stronger and stiffer than uncrosslinked threads and were comparable to contracting muscle in stiffness. Swelling ratios of crosslinked microthreads were significantly different from each other and uncrosslinked controls, suggesting a difference in the internal organization and compaction of the microthreads. Using an in vitro degradation assay, we observed that EDCn microthreads degraded within 24h, six times slower than uncrosslinked control threads, but EDCa microthreads did not show any significant indication of degradation within the 7-day assay period. Microthreads with higher stiffnesses supported significantly increased attachment of C2C12 cells, as well as increases in cell proliferation without a decrease in cell viability. Taken together, these data demonstrate the ability to create microthreads with tunable mechanical and structural properties that differentially direct cellular functions. Ultimately, we anticipate that we can strategically exploit these properties to promote site specific tissue regeneration. PMID- 22824529 TI - Corn trypsin inhibitor coating attenuates the prothrombotic properties of catheters in vitro and in vivo. AB - Catheters initiate coagulation by activating factor (f) XII, which can lead to catheter thrombosis. Fondaparinux, which only targets activated fX (fXa), is associated with more catheter thrombosis than heparin, which targets fXa and thrombin. To render catheters less thrombogenic and fondaparinux more effective, we examined whether coating catheters with corn trypsin inhibitor (CTI), which blocks fXIIa, attenuates catheter-induced clotting and promotes fondaparinux activity. Compared with unmodified catheters, CTI-coated catheters demonstrated (a) decreased adsorption of fibrinogen and fXII, (b) greater inhibition of fXIIa generated by catheter-induced autoactivation, (c) attenuated fXIIa-mediated activation of fXI and (d) longer plasma clotting times in the absence or presence of fondaparinux. In an accelerated catheter thrombosis model in rabbits, (a) the time to catheter occlusion was longer with CTI-coated catheters than with unmodified catheters and (b) an intravenous dose of fondaparinux that had no effect on the time to occlusion of unmodified catheters extended the time to occlusion of CTI-coated catheters. These findings support the concept that the prothrombotic activity of catheters reflects their capacity to activate fXII and identify CTI immobilization as a novel approach for rendering catheters and other blood-contacting medical devices less thrombogenic. PMID- 22824530 TI - Flt1 peptide-hyaluronate conjugate micelle-like nanoparticles encapsulating genistein for the treatment of ocular neovascularization. AB - Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1). In this work, Flt1 peptide-hyaluronate (HA) conjugates were successfully synthesized and the resulting micelle-like nanoparticles were exploited to encapsulate genistein, an inhibitor of tyrosine specific protein kinases, for the treatment of ocular neovascularization. The mean diameter of genistein-loaded Flt1 peptide-HA conjugate micelles was measured to be 172.0+/-18.7 nm, with a drug-loading efficiency of 40-50%. In vitro release tests of genistein from the genistein-loaded Flt1 peptide-HA conjugate micelles exhibited the controlled release for longer than 24h. In vitro biological activity of genistein/Flt1 peptide-HA micelles was corroborated from the synergistic anti-proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, we could confirm the anti-angiogenic effect of genistein/Flt1 peptide-HA micelles from the statistically significant suppression of corneal neovascularization in silver nitrate cauterized corneas of SD rats. The retinal vascular hyperpermeability was also drastically reduced by the treatment in diabetic retinopathy model rats. PMID- 22824531 TI - Group based diabetes self-management education compared to routine treatment for people with type 2 diabetes mellitus. A systematic review with meta-analysis. AB - BACKGROUND: Diabetes self-management education (DSME) can be delivered in many forms. Group based DSME is widespread due to being a cheaper method and the added advantages of having patient meet and discuss with each other. assess effects of group-based DSME compared to routine treatment on clinical, lifestyle and psychosocial outcomes in type-2 diabetes patients. METHODS: A systematic review with meta-analysis. Computerised bibliographic database were searched up to January 2008 for randomised controlled trials evaluating group-based DSME for adult type-2 diabetics versus routine treatment where the intervention had at least one session and =/>6 months follow-up. At least two reviewers independently extracted data and assessed study quality. RESULTS: In total 21 studies (26 publications, 2833 participants) were included. Of all the participants 4 out of 10 were male, baseline age was 60 years, BMI 31.6, HbA1c 8.23%, diabetes duration 8 years and 82% used medication. For the main clinical outcomes, HbA1c was significantly reduced at 6 months (0.44% points; P=0.0006, 13 studies, 1883 participants), 12 months (0.46% points; P=0.001, 11 studies, 1503 participants) and 2 years (0.87% points; P<0.00001, 3 studies, 397 participants) and fasting blood glucose levels were also significantly reduced at 12 months (1.26 mmol/l; P<0.00001, 5 studies, 690 participants) but not at 6 months. For the main lifestyle outcomes, diabetes knowledge was improved significantly at 6 months (SMD 0.83; P=0.00001, 6 studies, 768 participants), 12 months (SMD 0.85; P<0.00001, 5 studies, 955 participants) and 2 years (SMD 1.59; P=0.03, 2 studies, 355 participants) and self-management skills also improved significantly at 6 months (SMD 0.55; P=0.01, 4 studies, 534 participants). For the main psychosocial outcomes, there were significant improvement for empowerment/self-efficacy (SMD 0.28, P=0.01, 2 studies, 326 participants) after 6 months. For quality of life no conclusion could be drawn due to high heterogeneity. For the secondary outcomes there were significant improvements in patient satisfaction and body weight at 12 months for the intervention group. There were no differences between the groups in mortality rate, body mass index, blood pressure and lipid profile. CONCLUSIONS: Group-based DSME in people with type 2 diabetes results in improvements in clinical, lifestyle and psychosocial outcomes. PMID- 22824532 TI - Liver and pancreatic metastasis of a solitary fibrous tumour. PMID- 22824533 TI - Discussions with adults and youth to inform the development of a community-based tobacco control programme. AB - Project Advancing Cessation of Tobacco in Vulnerable Indian Tobacco Consuming Youth (ACTIVITY) is a community-based group randomized intervention trial focused on disadvantaged youth (aged 10-19 years) residing in 14 low-income communities (slums and resettlement colonies) in Delhi, India. This article discusses the findings of Focus Group Discussions (FGDs) conducted to inform the development and test the appropriateness of Project ACTIVITY's intervention model. The findings of the FGDs facilitated the understanding of factors contributing to increased tobacco uptake and cessation (both smoking and smokeless tobacco) among youth in this setting. Twenty-two FGDs were conducted with youth (10-19 years) and adults in two urban slums in Delhi. Key findings revealed: (i) youth and adults had limited knowledge about long-term health consequences of tobacco use; (ii) socio-environmental determinants and peer pressure were important variables influencing initiation of tobacco use; (iii) lack of motivation, support and sufficient skills hinder tobacco cessation and (iv) active involvement of community, family, religious leaders, local policy makers and health professionals is important in creating and reinforcing tobacco-free norms. The results of these FGDs aided in finalizing the intervention model for Project ACTIVITY and guided its intervention development. PMID- 22824534 TI - Invasive aspergillosis associated with pulmonary hydatid disease. AB - A patient presented with a cavitating lung lesion. Serology and sputum microscopy led to the diagnosis of pulmonary hydatid disease. However, histology of the operative samples revealed aspergillosis in the cavity and surrounding lung tissue. This is the first report of invasive aspergillosis occurring as a consequence of spontaneous hydatid cyst rupture. PMID- 22824535 TI - Automatic epileptic seizure detection in EEGs based on optimized sample entropy and extreme learning machine. AB - Epilepsy is one of the most common neurological disorders - approximately one in every 100 people worldwide are suffering from it. The electroencephalogram (EEG) is the most common source of information used to monitor, diagnose and manage neurological disorders related to epilepsy. Large amounts of data are produced by EEG monitoring devices, and analysis by visual inspection of long recordings of EEG in order to find traces of epilepsy is not routinely possible. Therefore, automated detection of epilepsy has been a goal of many researchers for a long time. This paper presents a novel method for automatic epileptic seizure detection. An optimized sample entropy (O-SampEn) algorithm is proposed and combined with extreme learning machine (ELM) to identify the EEG signals regarding the existence of seizure or not. To the knowledge of the authors, there exists no similar work in the literature. A public dataset was utilized for evaluating the proposed method. Results show that the proposed epilepsy detection approach achieves not only high detection accuracy but also a very fast computation speed, which demonstrates its huge potential for the real-time detection of epileptic seizures. PMID- 22824536 TI - [A survey on the use of fluoroscopy in the treatment of pain: do we perform it correctly?]. AB - OBJECTIVES: Fluoroscopy is technique that is commonly used for procedures in the treatment of pain, but despite its importance in healthcare, many specialists do not know how to use it. We conducted a national survey to evaluate its use. MATERIAL AND METHODS: A questionnaire with 15 questions related to the use of fluoroscopy in the treatment of pain was designed and sent to 105 units that diagnosed and treated pain in Spain, in 2008. RESULTS: A total of 63 (60%) questionnaires with valid responses were received. The majority of specialist (66.6%) had not received specific training on fluoroscopy or pain during their residency. Almost all (90%) of specialists who responded performed procedures that required X-rays in the operating theatre. Just over half (54.7%) performed less than 10 procedures a week, and only 12% performed more than 20 procedures per week. As regards radiation protection, the majority (80%) did not use protective glasses, and only 50% wore leaded gloves. Just under half (47%) were situated less than 0.5 metre from the patient. The majority (76%) did not inform about the radiation, nor was it mentioned in the informed consent (80%). CONCLUSIONS: There is a lack of information on the handling of the fluoroscope in the area of pain treatment, and this usually leads to the adoption of insufficient radiation protection measures. The treatments are usually performed in the operating theatre. More than half the specialists perform less 10 procedures per week with x-rays. The control and follow-up of radiation values is insufficient, as is the information and protection offered to the patient. PMID- 22824537 TI - Multisystemic engagement and nephrology based educational intervention: a randomized controlled trial protocol on the KidneyTteam At Home study. AB - BACKGROUND: Living donor kidney transplantation (LDKT) is the most successful form of renal replacement therapy in terms of wait time and survival rates. However, we observed a significant inequality in the number of LDKT performed between the Dutch and the non-Dutch patients. The objective of this study is to adapt, implement and test an educational home-based intervention to contribute to the reduction of this inequality. Our aim is to establish this through guided communication together with the social network of the patients in an attempt that well-informed decisions regarding renal replacement therapy can be made: Multisystemic Engagement & Nephrology. This manuscript is a detailed description of the Kidney Team At Home-study protocol. METHODS AND DESIGN: All patients (>18 yrs) that are referred to the pre-transplantation outpatient clinic are eligible to participate in the study. Patients will be randomly assigned to either an experimental or a control group. The control group will continue to receive standard care. The experimental group will receive standard care plus a home based educational intervention. The intervention consists of two sessions at the patient's home, an initial session with the patient and a second session for which individuals from their social network are invited to take part. Based on the literature and behavioural change theories we hypothesize that reducing hurdles in knowledge, risk perception, subjective norm, self-efficacy, and communication contribute to well-informed decision making and reducing inequality in accessing LDKT programs. A change in these factors is consequently our primary outcome-measure. Based on power calculations, we aim to include 160 patients over a period of two years. DISCUSSION: If we are able to show that this home-based group educational intervention contributes to 1) achieving well-informed decision regarding treatment and 2) reducing the inequality in LDKT, the quality of life of patients will be improved while healthcare costs are reduced. As the intervention is investigated in a random heterogeneous patient group in daily practice, the transfer to clinical practice in other kidney transplant centers should be relatively easy. TRIAL REGISTRATION: Netherlands Trial Register, NTR2730. PMID- 22824539 TI - The significance of 18F-FDG PET/CT in secondary hemophagocytic lymphohistiocytosis. AB - This study was aimed to investigate the significance of 18F-FDG PET/CT in secondary hemophagocytic lymphohistiocytosis (sHLH) patients. A total of 18 patients received 18F-FDG PET/CT scan at initial diagnosis. All patients (18/18) had at least 3 organs involved, with increased FDG metabolism in different degrees. Fifteen cases (15/18) had definite underlying diseases, including infections (IAHLH), rheumatosis (RAHLH), or malignancy (MAHLH). The SUVmax of patients in MAHLH group was significantly higher than patients in IAHLH group or RAHLH group (P = 0.015, P = 0.045). Furthermore, the SUVmax of patients in IAHLH group was significantly higher than patients of RAHLH group (P = 0.043). Therefore, we concluded that 18F-FDG PET/CT may especially play important role in differential diagnosis of sHLH. PMID- 22824538 TI - Vision-guided ocular growth in a mutant chicken model with diminished visual acuity. AB - Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein beta3 (GNB3), also known as transducin beta3 or Gbeta3. The mutation in GNB3 destabilizes the protein and causes a loss of Gbeta3 from photoreceptors and ON-bipolar cells (Ritchey et al., 2010). FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gbeta3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gbeta3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus. PMID- 22824540 TI - Validation of a commercial TPS based on the VMC(++) Monte Carlo code for electron beams: commissioning and dosimetric comparison with EGSnrc in homogeneous and heterogeneous phantoms. AB - The aim of the present work was the validation of the VMC(++) Monte Carlo (MC) engine implemented in the Oncentra Masterplan (OMTPS) and used to calculate the dose distribution produced by the electron beams (energy 5-12 MeV) generated by the linear accelerator (linac) Primus (Siemens), shaped by a digital variable applicator (DEVA). The BEAMnrc/DOSXYZnrc (EGSnrc package) MC model of the linac head was used as a benchmark. Commissioning results for both MC codes were evaluated by means of 1D Gamma Analysis (2%, 2 mm), calculated with a home-made Matlab (The MathWorks) program, comparing the calculations with the measured profiles. The results of the commissioning of OMTPS were good [average gamma index (gamma) > 97%]; some mismatches were found with large beams (size >= 15 cm). The optimization of the BEAMnrc model required to increase the beam exit window to match the calculated and measured profiles (final average gamma > 98%). Then OMTPS dose distribution maps were compared with DOSXYZnrc with a 2D Gamma Analysis (3%, 3 mm), in 3 virtual water phantoms: (a) with an air step, (b) with an air insert, and (c) with a bone insert. The OMTPD and EGSnrc dose distributions with the air-water step phantom were in very high agreement (gamma ~ 99%), while for heterogeneous phantoms there were differences of about 9% in the air insert and of about 10-15% in the bone region. This is due to the Masterplan implementation of VMC(++) which reports the dose as "dose to water", instead of "dose to medium". PMID- 22824542 TI - Microbleeds in vascular dementia: clinical aspects. AB - Microbleeds are small dot-like lesions which can be appreciated on gradient echo, T2*-weighted magnetic resonance images as hypointensities. They are considered as an expression of small vessel disease on MRI, next to lacunes and white matter hyperintensities (WMH). Microbleeds are relatively common in vascular dementia, with reported prevalences between 35% and 85%. In the context of vascular dementia, microbleeds are mainly thought to result from hypertensive vasculopathy, but the frequent co-occurrence of lobar microbleeds suggests that neurodegenerative pathology and/or cerebral amyloid angiopathy is also of importance. The presence of multiple microbleeds in vascular dementia or in patients with vascular cognitive impairment is related to worse performance on cognitive tests, mainly in psychomotor speed and executive functioning. They may have some predictive value in terms of predicting development of (vascular) dementia, mortality and disability. Data on the occurrence of stroke and post stroke dementia in patients with microbleeds are to date not available. New definitions and diagnostic criteria for vascular dementia and vascular cognitive impairment are needed and should take into account microbleeds. PMID- 22824541 TI - Effects of aging and levodopa on the laryngeal adductor reflex in rats. AB - Dopaminergic neurotransmission plays an essential role in sensorimotor function, and declines with age. Previously, we found the laryngeal adductor reflex (LAR) was increased in excitation by a dopamine receptor antagonist. If this airway protective reflex is similarly affected by aging, it will interfere with volitional control in older adults. The current study tested whether the LAR was affected by aging, and whether such deficits were reversed by levodopa administration in aging rats. We recorded thyroarytenoid (TA) muscle activity at rest and during elicitation of LAR responses by stimulation of the internal branch of the superior laryngeal nerve (iSLN) in 6-, 18- and 30-month-old rats under alpha-chloralose anesthesia. Using paired stimuli at different inter stimulus intervals (ISIs), LAR central conditioning, resting muscle activity, and reflex latency and amplitudes were quantified. Numbers of dopaminergic neurons in the substantia nigra pars compacta (SNpc) were measured using tyrosine hydroxylase staining. We found: (1) increased resting TA muscle activity and LAR amplitude occurred with fewer dopaminergic neurons in the SNpc in 18- and 30 month-old rats; (2) decreases in LAR latency and increases in amplitude correlated with reduced numbers of dopaminergic neurons in the SNpc; (3) test responses were greater at 1000ms ISI in 18-month-old rats compared with 6-month old rats; and (4) levodopa administration further increased response latency but did not alter muscle activity, response amplitude, or central conditioning. In conclusion, increases in laryngeal muscle activity levels and reflex amplitudes accompanied age reductions in dopaminergic neurons but were not reversed with levodopa administration. PMID- 22824543 TI - Alzheimer disease as a vascular disorder: where do mitochondria fit? AB - Although the precise culprit in the etiopathogenesis of Alzheimer disease (AD) is still obscure, defective mitochondria functioning has been proposed to be an upstream event in AD. Mitochondria fulfill a number of essential cellular functions, and it is recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal and vascular homeostasis. Extensive research in postmortem brain tissue from AD subjects, and AD animal and cellular models revealed that mitochondria undergo multiple malfunctions during the course of this disease. The present review summarizes the current views on how mitochondria are implicated in both AD-related neuronal and cerebrovascular degeneration. The understanding of the mitochondrial mechanisms underlying AD pathology is critical to design more effective strategies to halt or delay disease progression. PMID- 22824544 TI - One-step electrochemically co-assembled redox-active [Ru(bpy)2(tatp)]2+-BSA SWCNTs hybrid film for non-redox protein biosensors. AB - A redox-active [Ru(bpy)(2)(tatp)](2+)-BSA-SWCNTs (bpy=2,2'-bipyridine, tatp=1,4,8,9-tetra-aza-triphenylene, BSA=bovine serum albumin, SWCNTs=single walled carbon nanotubes) hybrid film is fabricated on an indium-tin oxide (ITO) electrode via one-step electrochemical co-assembly approach. BSA is inherently dispersive and therefore served as the linking mediator of SWCNTs, which facilitate the redox reactions of [Ru(bpy)(2)(tatp)](2+) employed as a reporter of BSA. The evidences from differential pulse voltammetry, cyclic voltammetry, scanning electron microscope, emission spectroscopy and fluorescence microscope reveal that the [Ru(bpy)(2)(tatp)](2+)-BSA-SWCNTs hybrid can be electrochemically co-assembled on the ITO electrode, showing two pairs of well-defined Ru(II)-based redox waves. Furthermore, the electrochemical co-assembly of the [Ru(bpy)(2)(tatp)](2+)-BSA-SWCNTs hybrid is found to be strongly dependent on the simultaneous presence of BSA and SWCNTs, indicating a good linear response to BSA in the range from 6 to 50mgL(-1). The results from this study provide an electrochemical co-assembly method for the development of non-redox protein biosensors. PMID- 22824545 TI - Microbial stress: from molecules to systems (Belgirate, May 2012). PMID- 22824546 TI - Steady- and transient-state H2S biofiltration using expanded schist as packing material. AB - The performances of three laboratory-scale biofilters (BF1, BF2, BF3) packed with expanded schist for H(2)S removal were studied at different empty bed residence times (EBRT=35, 24 and 16s) in terms of elimination capacity (EC) and removal efficiency (RE). BF1 and BF2 were filled with expanded schist while BF3 was filled with both expanded schist and a nutritional material (UP20; 12% vol). BF1 and BF3 were inoculated with activated sludge, whereas BF2 was not inoculated. A maximum EC of 42 g m(-3) h(-1) was recorded for BF3 at EBRT=35 s demonstrating the ability of schist to treat high H(2)S loading rates, and the ability of UP20 to improve H(2)S removal. Michaelis-Menten and Haldane models were fitted to the experimental elimination capacities while biofilter responses to transient-state conditions in terms of removal efficiency during shock load events were also evaluated for BF1 and BF3. PMID- 22824548 TI - Survived but feeling vulnerable and insecure: a qualitative study of the mental preparation for RTW after breast cancer treatment. AB - BACKGROUND: Improvements in treatment have resulted in an increasing number of cancer survivors potentially being able to return to work after medical treatment. In this paper we focus on the considerations regarding return to work (RTW) of breast cancer absentees in the Belgian context and how these considerations are related to reactions from their social environment. METHODS: A qualitative study was performed to understand the RTW considerations of Belgian breast cancer absentees who had undergone breast cancer surgery in 2006. Twenty two participants (mean age 46) were included and interviewed between May 2008 and August 2009 in their personal environment. An in-depth analysis (Grounded Theory) took place using the Qualitative Analysis Guide of Leuven (Quagol). RESULTS: Before the actual RTW, breast cancer employees try to build an image of the future resumption of work based on medical grounds and their knowledge of the workplace. Four matters are considered prior to RTW: (i) women want to leave the sick role and wish to keep their job; (ii) they consider whether working is worth the effort; (iii) they reflect on their capability; and (iv) they have doubts about being accepted in the workplace after returning. These inner thoughts are both product and input for the interaction with the social environment. The whole process is coloured by uncertainty and vulnerability. CONCLUSION: Our study demonstrated that mental preparation for RTW is not a linear process of improvement. It shows a detailed picture of four types of considerations made by breast cancer survivors before they actually resume work. Vulnerability appears to be an overarching theme during mental preparation. As the social environment plays an important role, people from that environment must become more aware of their influence on decreasing or increasing a woman's vulnerability while preparing for RTW. PMID- 22824547 TI - Error-enhancing robot therapy to induce motor control improvement in childhood onset primary dystonia. AB - BACKGROUND: Robot-generated deviating forces during multijoint reaching movements have been applied to investigate motor control and to tune neuromotor adaptation. Can the application of force to limbs improve motor learning? In this framework, the response to altered dynamic environments of children affected by primary dystonia has never been studied. METHODS: As preliminary pilot study, eleven children with primary dystonia and eleven age-matched healthy control subjects were asked to perform upper limb movements, triangle-reaching (three directions) and circle-writing, using a haptic robot interacting with ad-hoc developed task specific visual interfaces. Three dynamic conditions were provided, null additive external force (A), constant disturbing force (B) and deactivation of the additive external force again (C). The path length for each trial was computed, from the recorded position data and interaction events. RESULTS: The results show that the disturbing force affects significantly the movement outcomes in healthy but not in dystonic subjects, already compromised in the reference condition: the external alteration uncalibrates the healthy sensorimotor system, while the dystonic one is already strongly uncalibrated. The lack of systematic compensation for perturbation effects during B condition is reflected into the absence of after-effects in C condition, which would be the evidence that CNS generates a prediction of the perturbing forces using an internal model of the environment.The most promising finding is that in dystonic population the altered dynamic exposure seems to induce a subsequent improvement, i.e. a beneficial after-effect in terms of optimal path control, compared with the correspondent reference movement outcome. CONCLUSIONS: The short-time error-enhancing training in dystonia could represent an effective approach for motor performance improvement, since the exposure to controlled dynamic alterations induces a refining of the existing but strongly imprecise motor scheme and sensorimotor patterns. PMID- 22824549 TI - Parallel perfusion imaging processing using GPGPU. AB - BACKGROUND AND PURPOSE: The objective of brain perfusion quantification is to generate parametric maps of relevant hemodynamic quantities such as cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) that can be used in diagnosis of acute stroke. These calculations involve deconvolution operations that can be very computationally expensive when using local Arterial Input Functions (AIF). As time is vitally important in the case of acute stroke, reducing the analysis time will reduce the number of brain cells damaged and increase the potential for recovery. METHODS: GPUs originated as graphics generation dedicated co-processors, but modern GPUs have evolved to become a more general processor capable of executing scientific computations. It provides a highly parallel computing environment due to its large number of computing cores and constitutes an affordable high performance computing method. In this paper, we will present the implementation of a deconvolution algorithm for brain perfusion quantification on GPGPU (General Purpose Graphics Processor Units) using the CUDA programming model. We present the serial and parallel implementations of such algorithms and the evaluation of the performance gains using GPUs. RESULTS: Our method has gained a 5.56 and 3.75 speedup for CT and MR images respectively. CONCLUSIONS: It seems that using GPGPU is a desirable approach in perfusion imaging analysis, which does not harm the quality of cerebral hemodynamic maps but delivers results faster than the traditional computation. PMID- 22824551 TI - Assessing methods for measurement of clinical outcomes and quality of care in primary care practices. AB - PURPOSE: To evaluate the appropriateness of potential data sources for the population of performance indicators for primary care (PC) practices. METHODS: This project was a cross sectional study of 7 multidisciplinary primary care teams in Ontario, Canada. Practices were recruited and 5-7 physicians per practice agreed to participate in the study. Patients of participating physicians (20-30) were recruited sequentially as they presented to attend a visit. Data collection included patient, provider and practice surveys, chart abstraction and linkage to administrative data sets. Matched pairs analysis was used to examine the differences in the observed results for each indicator obtained using multiple data sources. RESULTS: Seven teams, 41 physicians, 94 associated staff and 998 patients were recruited. The survey response rate was 81% for patients, 93% for physicians and 83% for associated staff. Chart audits were successfully completed on all but 1 patient and linkage to administrative data was successful for all subjects. There were significant differences noted between the data collection methods for many measures. No single method of data collection was best for all outcomes. For most measures of technical quality of care chart audit was the most accurate method of data collection. Patient surveys were more accurate for immunizations, chronic disease advice/information dispensed, some general health promotion items and possibly for medication use. Administrative data appears useful for indicators including chronic disease diagnosis and osteoporosis/ breast screening. CONCLUSIONS: Multiple data collection methods are required for a comprehensive assessment of performance in primary care practices. The choice of which methods are best for any one particular study or quality improvement initiative requires careful consideration of the biases that each method might introduce into the results. In this study, both patients and providers were willing to participate in and consent to, the collection and linkage of information from multiple sources that would be required for such assessments. PMID- 22824552 TI - The ratio of right ventricular volume to left ventricular volume reflects the impact of pulmonary regurgitation independently of the method of pulmonary regurgitation quantification. AB - BACKGROUND: Previous studies have advocated quantifying pulmonary regurgitation (PR) by using PR volume (PRV) instead of commonly used PR fraction (PRF). However, physicians are not familiar with the use of PRV in clinical practice. The ratio of right ventricle (RV) volume to left ventricle volume (RV/LV) may better reflect the impact of PR on the heart than RV end-diastolic volume (RVEDV) alone. We aimed to compare the impact of PRV and PRF on RV size expressed as either the RV/LV ratio or RVEDV (mL/m(2)). METHODS: Consecutive patients with repaired tetralogy of Fallot were included (n=53). PRV, PRF and ventricular volumes were measured with the use of cardiac magnetic resonance. RESULTS: RVEDV was more closely correlated with PRV when compared with PRF (r=0.686, p<0.0001, and r=0.430, p=0.0014, respectively). On the other hand, both PRV and PRF showed a good correlation with the RV/LV ratio (r=0.691, p<0.0001, and r=0.685, p<0.0001, respectively). Receiver operating characteristic analysis showed that both measures of PR had similar ability to predict severe RV dilatation when the RV/LV ratio-based criterion was used, namely the RV/LV ratio>2.0 [area under the curve (AUC)(PRV)=0.770 vs AUC(PRF)=0.777, p=0.86]. Conversely, with the use of the RVEDV-based criterion (>170mL/m(2)), PRV proved to be superior over PRF (AUC(PRV)=0.770 vs AUC(PRF)=0.656, p=0.0028]. CONCLUSIONS: PRV and PRF have similar significance as measures of PR when the RV/LV ratio is used instead of RVEDV. The RV/LV ratio is a universal marker of RV dilatation independent of the method of PR quantification applied (PRF vs PRV). PMID- 22824550 TI - An observational study of patient versus parental perceptions of health-related quality of life in children and adolescents with a chronic pain condition: who should the clinician believe? AB - BACKGROUND: Previous pediatric studies have observed a cross-informant variance in patient self-reported health-related quality of life (HRQoL) versus parent proxy-reported HRQoL. This study assessed in older children and adolescents with a variety of chronic pain conditions: 1) the consistency and agreement between pediatric patients' self-report and their parents' proxy-report of their child's HRQoL; 2) whether this patient-parent agreement is dependent on additional demographic and clinical factors; and 3) the relationship between pediatric patient HRQoL and parental reported HRQoL. METHODS: The 99 enrolled patients (mean age 13.2 years, 71% female, 81% Caucasian) and an accompanying parent completed the PedsQLTM 4.0 and 36-Item Short-Form Health Survey Version 2 (SF 36v2) at the time of their initial appointment in a pediatric chronic pain medicine clinic. Patients' and parents' total, physical, and psychosocial HRQoL scores were analyzed via an intra-class correlation coefficient, Spearman's correlation coefficient, Wilcoxon signed rank test, and Bland-Altman plot. A multivariable linear regression model was used to evaluate the association between clinical and demographic variables and the difference in patient and proxy scores for the Total Scale Score on the PedsQLTM. RESULTS: With the exception of the psychosocial health domain, there were no statistically significant differences between pediatric patients' self-report and their parents' proxy-report of their child's HRQoL. However, clinically significant patient-parent variation in pediatric HRQoL was observed. Differences in patient parent proxy PedsQLTM Total Scale Score Scores were not significantly associated with patient age, gender, race, intensity and duration of patient's pain, household income, parental marital status, and the parent's own HRQoL on the SF 36v2. No significant relationship existed among patients' self-reported HRQoL (PedsQLTM), parental proxy-reports of the child's HRQoL, and parents' own self reported HRQoL on the SF-36v2. CONCLUSIONS: We observed clinically significant variation between pediatric chronic pain patients' self-reports and their parents' proxy-reports of their child's HRQoL. While whenever possible the pediatric chronic pain patient's own perspective should be directly solicited, equal attention and merit should be given to the parent's proxy-report of HRQoL. To do otherwise will obviate the opportunity to use any discordance as the basis for a therapeutic discussion about the contributing dynamic with in parent-child dyad. PMID- 22824553 TI - Meta-analysis of Prolene Hernia System mesh versus Lichtenstein mesh in open inguinal hernia repair. AB - BACKGROUND: This study was designed to systematically analyse all published randomized clinical trials comparing the Prolene Hernia System (PHS) mesh and Lichtenstein mesh for open inguinal hernia repair. METHOD: A literature search was performed using the Cochrane Colorectal Cancer Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase and Science Citation Index Expanded. Randomized trials comparing the Lichtenstein Mesh repair (LMR) with the Prolene Hernia System were included. Statistical analysis was performed using Review Manager Version 5.1 software. The primary outcome measures were hernia recurrence and chronic pain after operation. Secondary outcome measures included surgical time, peri operative complications, time to return to work, early and long-term postoperative complications. RESULTS: Six randomized clinical trials were identified as suitable, containing 1313 patients. There was no statistical difference between the two types of repair in operation time, time to return to work, incidence of chronic groin pain, hernia recurrence or long-term complications. The PHS group had a higher rate of peri-operative complications, compared to Lichtenstein mesh repair (risk ratio (RR) 0.71, 95% confidence interval 0.55-0.93, P=0.01). CONCLUSION: The use of PHS mesh was associated with an increased risk of peri-operative complications compared to LMR. Both mesh repair techniques have comparable short- and long-term outcomes. PMID- 22824554 TI - Avian metapneumovirus RT-nested-PCR: a novel false positive reducing inactivated control virus with potential applications to other RNA viruses and real time methods. AB - Using reverse genetics, an avian metapneumovirus (AMPV) was modified for use as a positive control for validating all stages of a popular established RT-nested PCR, used in the detection of the two major AMPV subtypes (A and B). Resultant amplicons were of increased size and clearly distinguishable from those arising from unmodified virus, thus allowing false positive bands, due to control virus contamination of test samples, to be identified readily. Absorption of the control virus onto filter paper and subsequent microwave irradiation removed all infectivity while its function as an efficient RT-nested-PCR template was unaffected. Identical amplicons were produced after storage for one year. The modified virus is likely to have application as an internal standard as well as in real time methods. Additions to AMPV of RNA from other RNA viruses, including hazardous examples such HIV and influenza, are likely to yield similar safe RT PCR controls. PMID- 22824555 TI - Can pre-season fitness measures predict time to injury in varsity athletes?: a retrospective case control study. AB - BACKGROUND: The ability to determine athletic performance in varsity athletes using preseason measures has been established. The ability of pre-season performance measures and athlete's exposure to predict the incidence of injuries is unclear. Thus our purpose was to determine the ability of pre-season measures of athletic performance to predict time to injury in varsity athletes. METHODS: Male and female varsity athletes competing in basketball, volleyball and ice hockey participated in this study. The main outcome measures were injury prevalence, time to injury (based on calculated exposure) and pre-season fitness measures as predictors of time to injury. Fitness measures were Apley's range of motion, push-up, curl-ups, vertical jump, modified Illinois agility, and sit-and reach. Cox regression models were used to identify which baseline fitness measures were predictors of time to injury. RESULTS: Seventy-six percent of the athletes reported 1 or more injuries. Mean times to initial injury were significantly different for females and males (40.6% and 66.1% of the total season (p < 0.05), respectively). A significant univariate correlation was observed between push-up performance and time to injury (Pearson's r = 0.332, p < 0.01). No preseason fitness measure impacted the hazard of injury. Regardless of sport, female athletes had significantly shorter time to injury than males (Hazard Ratio = 2.2, p < 0.01). Athletes playing volleyball had significantly shorter time to injury (Hazard Ratio = 4.2, p < 0.01) compared to those playing hockey or basketball. CONCLUSIONS: When accounting for exposure, gender, sport and fitness measures, prediction of time to injury was influenced most heavily by gender and sport. PMID- 22824556 TI - Frontiers in immunology and immune tolerance: new perspectives. PMID- 22824557 TI - Deep brain stimulation surgery for alcohol addiction. AB - BACKGROUND: The consequences of chronic alcohol dependence cause important health and economic burdens worldwide. Relapse rates after standard treatment (medication and psychotherapy) are high. There is evidence from in vivo investigations and from studies in patients that the brain's reward system is critically involved in the development and maintenance of addictive behavior, suggesting that modification of this system could significantly improve the prognosis of addictive patients. Motivated by an accidental observation, we used the nucleus accumbens (NAc), which has a central position in the dopaminergic reward system for deep brain stimulation (DBS) of alcohol addiction. METHODS: We report our first experiences with NAc DBS for alcohol dependence and review the literature addressing the mechanisms leading to addiction. RESULTS: Five patients were treated off-label with bilateral NAc DBS for severe alcohol addiction (average follow-up 38 months). All patients experienced significant and ongoing improvement of craving. Two patients remained completely abstinent for more than 4 years. NAc stimulation was tolerated without permanent side effects. Simultaneous recording of local field potentials from the target area and surface electroencephalography while patients performed neuropsychological tasks gave a hint on the pivotal role of the NAc in processing alcohol-related cues. CONCLUSIONS: To our knowledge, the data presented here reflect the first attempt to treat alcohol-addicted patients with NAc DBS. Electrical NAc stimulation probably counterbalances the effect of drug-related stimuli triggering involuntarily drug-seeking behavior. Meanwhile, two prospective clinical studies using randomized, double-blind, and crossover stimulation protocols for DBS are underway to corroborate these preliminary results. PMID- 22824558 TI - Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. AB - OBJECTIVE: Stimulation of the inferior thalamic peduncle (ITP) is emerging as a promising new therapeutic target in certain psychiatric disorders. The circuitry that includes the nonspecific thalamic system (NSTS), which projects via the ITP to the orbitofrontal cortex (OFC), is involved in the physiopathology of major depression disorder (MDD) and obsessive compulsive disorder (OCD). The safety and efficacy of chronic ITP stimulation in cases of MDD and OCD refractory to medical treatment is presented. MATERIALS AND METHODS: Six patients with OCD and one with MDD were implanted with tetrapolar deep brain stimulation electrodes in the ITP (x = 3.5 mm lateral to the ventricular wall, y = 5 mm behind the anterior commissure, and z = at the intercommissural plane, i.e., anterior commissure posterior commissure [AC-PC] level). The effect of chronic stimulation at 130 Hz, 450 MUs, and 5.0 V on OCD was evaluated before and 3, 6, and 12 months after initiation of electrical stimulation through the Yale-Brown Obsessive Compulsive Scale, Hamilton Depression Rating Scale, and Global Assessment of Function scale. RESULTS: Chronic ITP electrical stimulation in OCD patients decreased the mean Yale-Brown Obsessive Compulsive Scale score to around 51% for the group at the 12 month follow-up, and increased the mean Global Assessment of Function scale score to 68% for a significant improvement (P = 0.026). Three of 6 patients returned to work. The Hamilton Depression Rating Scale score of the only patient with MDD treated to date went from 42 to 6. This condition of the patient, who had been incapacitated for 5 years prior to surgery, has not relapsed for 9 years. Three OCD patients with drug addiction continued to consume drugs in spite of their improvement in OCD. CONCLUSION: Deep brain stimulation in the ITP is safe and may be effective in the treatment of OCD. A multicenter evaluation of the safety and efficacy of ITP in OCD is currently in process. PMID- 22824560 TI - Research on the UK Quality and Outcomes Framework (QOF) and answering wider questions on the effectiveness of pay-for-performance (P4P) in health care. PMID- 22824561 TI - Piloting and validating an innovation to triage patients presenting with cough to community pharmacies in Western Australia. AB - AIM: To develop a tool to assist community pharmacists to triage patients presenting with cough and to validate this against an established cough-specific quality of life (QoL) measure. METHODS: A decision-support tool, the Pharmacy Cough Assessment Tool (PCAT) was developed with reference to published guidelines and a team of clinical experts. The PCAT was validated against the Leicester Cough Questionnaire (LCQ). It was then administered at four community pharmacies in Perth, Western Australia to assess the scope to recruit and follow up participants, and to estimate the proportion of participants who would be advised to consult a general practitioner (GP). The reported outcomes of the consultations with doctors were also recorded. RESULTS: Ninety-nine subjects were recruited over 12 weeks. Thirty-seven participants were advised to consult a GP for further assessment with reference to the PCAT; seven attended their doctor. The LCQ scores of those referred to their GP were significantly lower, indicating a poorer quality of life (adjusted mean and range 13.16 [11.87, 14.46]; non referred 15.82 [14.47, 17.18]; P < 0.001). Scores of this magnitude have previously been shown to identify patients with chronic respiratory conditions. A smaller group of participants also had a poor quality of life based on LCQ scores but were not referred to their GP. Of the seven participants who made an appointment with their GP, most were prescribed treatment or referred for investigation. There was no significant difference in LCQ score based on gender, or decision to consult a GP. CONCLUSIONS: The PCAT identifies patients with cough who might benefit from medical advice and may feasibly be used as an initial screening tool in the community pharmacy setting. PMID- 22824559 TI - A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1. AB - Patients with neurofibromatosis-1 (NF-1) sometime develop neuroendocrine tumors (NET). Although these NETs usually occur in the duodenum or peri-ampullary region, they occasionally grow in the pancreas (PNET). A 62-year-old man with NF 1 had mild liver dysfunction and was admitted to our hospital for further examination. An abdominal contrast-enhanced computed tomography scan demonstrated a 30-mm tumor in the head of the pancreas. The scan showed an invasion of the tumor into the duodenum, and biopsy under an endoscopic ultrasonography indicated that the tumor was a NET. A subtotal stomach-preserving pancreaticoduodenectomy was performed. Macroscopically, the pancreatic tumor was white and elastic hard. Microscopically, tumor cells were composed of ribbons, cords, and solid nests with an acinus-like structure. The tumor was diagnosed as NET G2 according to the WHO classification (2010). The product of the NF-1 gene, i.e., neurofibromin, was weakly positive in the tumor cells, suggesting that the tumor was induced by a mutation in the NF-1 gene. This is the seventh case of PNET arising in NF-1 patients worldwide. PMID- 22824562 TI - Barriers and enablers to managing obesity in general practice: a practical approach for use in implementation activities. AB - BACKGROUND: In 2006, the National Institute of Health and Clinical Excellence (NICE) published guidelines for the prevention and management of overweight and obesity. To tailor the implementation of guidelines, information is needed about the prevailing barriers and enablers, and practical methods for identifying barriers and enablers. AIM: To uncover and describe barriers and enablers to implementing NICE's recommendations on the management of obesity in adults in general practice, using practical qualitative methods. METHODS: A qualitative study involving semistructured interviews with seven general practitioners, seven practice nurses and nine overweight or obese patients, exploring their views and experiences on the implementation of NICE guidelines on obesity. The interviews were undertaken and analysed by a health professional with support of a health service researcher; they were recorded and transcribed verbatim and analysed using a thematic framework approach. The analysis described the reported barriers and enablers. RESULTS: Barriers included: stigma, cost of private sector services, previous patient experience, practitioners not wanting to take responsibility for obesity management, lack of consistency in care, limited practitioner skills, perceived lack of NHS services and constraints imposed by commissioners. Trust between practitioners and patients, practitioners with the skills and confidence to raise the issue of obesity, practice-based procedures and weight management services being available were perceived as enablers to implementation. CONCLUSION: This pragmatic study found that there are many barriers to the implementation of NICE guidance on obesity, involving patients, practitioners and support services for primary care. PMID- 22824563 TI - Accessibility, feasibility and educational impact of a peer review process for general practitioner consultation skills. AB - BACKGROUND: External peer review of consultations has been available to general medical practitioners (GPs) in the west of Scotland for several years. This study aims to assess the feasibility, accessibility and educational impact of consultation peer review for GPs. METHOD: An interview guide was developed and an independent researcher used this to interview a sample of 10 GPs who had submitted consultations for peer review in the previous six months. RESULTS: All GPs interviewed felt that there had been educational impact as a result of consultation peer review, the majority had presented this material as part of their annual appraisal and thought that their appraisal had been enhanced as a result. The process was both acceptable and feasible for the majority of GPs interviewed. CONCLUSION: Consultation peer review appears to be an acceptable and feasible educational activity, resulting in behaviour change. It may be useful as an alternative to multisource feedback and patient questionnaires in provision of evidence of effective communication skills for annual appraisal. PMID- 22824564 TI - Effective recruitment strategies in primary care research: a systematic review. AB - BACKGROUND: Patient recruitment in primary care research is often a protracted and frustrating process, affecting project timeframes, budget and the dissemination of research findings. Yet, clear guidance on patient recruitment strategies in primary care research is limited. This paper addresses this issue through a systematic review. METHOD: Articles were sourced from five academic databases - AustHealth, CINAHL, the Cochrane Methodology Group, EMBASE and PubMed/Medline; grey literature was also sourced from an academic library and the Primary Healthcare Research & Information Service (PHCRIS) website. Two reviewers independently screened the articles using the following criteria: (1) published in English, (2) reported empirical research, (3) focused on interventions designed to increase patient recruitment in primary care settings, and (4) reported patient recruitment in primary care settings. RESULTS: Sixty-six articles met the inclusion criteria. Of these, 23 specifically focused on recruitment strategies and included randomised trials (n = 7), systematic reviews (n = 8) and qualitative studies (n = 8). Of the remaining articles, 30 evaluated recruitment strategies, while 13 addressed the value of recruitment strategies using descriptive statistics and/or qualitative data. Among the 66 articles, primary care chiefly included general practice (n = 30); nursing and allied health services, multiple settings, as well as other community settings (n = 30); and pharmacy (n = 6). Effective recruitment strategies included the involvement of a discipline champion, simple patient eligibility criteria, patient incentives and organisational strategies that reduce practitioner workload. CONCLUSION: The most effective recruitment in primary care research requires practitioner involvement. The active participation of primary care practitioners in both the design and conduct of research helps to identify strategies that are congruent with the context in which patient care is delivered. This is reported to be the optimal recruitment strategy. PMID- 22824565 TI - Targets and prioritization: the case of cancer in the English NHS. AB - From 1999 onwards, patients judged by their general practitioners (GPs) to require urgent access to care for suspected cancer have been referred under the so-called two-week wait rule, or fast track, which guaranteed that they would be seen in a hospital clinic within that period. The two-week wait was introduced in the belief that England's relatively poor cancer outcomes were due, at least in part, to delays in accessing care. This paper assesses the impact of the two week wait against a number of criteria. Although the NHS has largely succeeded in meeting this target, there is little evidence that it has improved outcomes. PMID- 22824566 TI - Adherence to guidelines for drug treatment of asthma in children: potential for improvement in Swedish primary care. AB - BACKGROUND: Adherence to guidelines in general is poor. Because asthma is the most common chronic disease in Swedish children, identifying areas for improvement regarding drug treatment for asthma is crucial. AIM: To explore the utilisation patterns of anti-asthmatic drugs in children with asthma in relation to evidence-based guidelines. METHOD: All children visiting 14 primary healthcare centres in Stockholm, Sweden, who had their first prescription of anti-asthmatic agents dispensed between July 2006 and June 2007 were followed over 24 consecutive months. The children (1033 in total) were divided in two age groups: 0-6 years and 7-16 years. The outcome measurements were: the characteristics of the physicians initiating drug treatment; the extent to which the children were initiated on the drugs recommended in the guidelines; and the amount and frequency of drugs dispensed over time and whether the dosage texts on the prescriptions contained adequate information. RESULTS: In 54% of the older children and 35% of the younger children, only one prescription for anti asthmatic drugs was dispensed during two years of follow-up following the first prescription. In school-aged children, 50% were initiated on inhaled short-acting bronchodilating beta2-agonists (SABA) in monotherapy. Among preschool children, 64% were initiated on SABA and inhaled corticosteroids in combination. In 41% of the prescriptions dispensed, the indication was stated and in 25% the mechanism of action was stated. Drug therapy was initiated by a general practitioner in 42% of the younger children and 72% of the older children. CONCLUSION: There is a need for improvement in adherence to guidelines in important areas. Asthma, especially among children aged 7-16 years, is usually a chronic disease and should, in many cases, be treated with anti-asthmatics counteracting inflammation. However, this was not the case in our study. In addition, the dosage texts written by the physicians did not follow recommendations and may negatively influence patient safety. PMID- 22824567 TI - Glad you brought it up: a patient-centred programme to reduce proton-pump inhibitor prescribing in general medical practice. AB - BACKGROUND: Many patients unnecessarily receive proton-pump inhibitor (PPI) drugs long term with significant financial and safety implications. Educating, empowering and supporting patients to self-manage their symptoms can lead to significant and sustained reductions in PPI prescribing. We aimed to implement a programme to reduce inappropriate PPI prescribing. METHOD: Eligible patients in one general medical practice in rural Scotland were invited for participation between November 2008 and February 2010. Patients attended special nurse advisor clinics, completed dyspepsia questionnaires, received information, formulated self-management plans and were offered flexible support. RESULTS: Of the study population, 437/2883 (15%) were prescribed PPIs. Of these, 166 (38%) were judged eligible for participation. After 12 months, 138/157 (83%) had reduced or stopped their PPIs, while 19/157 (11%) had reverted. The estimated annual net saving in the prescribing budget was ?3180.67. Self-reported understanding of symptom self-management increased from 6/20 (30%) to 18/20 (90%) patients after participation in the programme. CONCLUSION: A patient-centred programme delivered by a specialist nurse significantly reduced PPI prescribing with financial and potential therapeutic benefits. The vast majority of eligible patients were able to 'step down and off' or 'step off' PPI use after 12 months without any complications or deteriorating symptom control. Further research with larger cohorts of practices and patients is needed to develop a feasible, acceptable and effective programme if similar benefits are to be achieved for primary care in general. PMID- 22824568 TI - Recommended care adherence: improved by patient reminder letters but with potential attenuation by the healthcare process complexity. AB - BACKGROUND: American adults receive the recommended care just over half of the time for all recommended services. Many patient reminder strategies have attempted to increase the adherence rates for preventative and chronic disease management. However, there is a lack of data available in relation to adherence rates for symptom-specific recommended services and a lack of data identifying any contributions from the organisational structures to these adherence rates. PURPOSE: To identify the efficacy and differences in patient reminder letter strategies on various categories of recommended services, as well as to analyse the relationship between a novel quantification of a healthcare system's process complexity with adherence rates. DESIGN: Retrospective cohort study analysing pilot data collected from an urban, academic healthcare provider utilising patient reminder letters. PARTICIPANTS: Adults attending one academic medical centre's outpatient practice from 2008 to 2009. INTERVENTION: Two reminder letters sent chronologically if the recommended care was not completed in the appropriate time frame. MAIN MEASURES: Adherence rates of each recommended service at baseline, after first and second reminder letters, and non-adherence rates despite the reminder letter intervention. Process flow complexity was calculated as a composite score combining elements of fastest time to complete routine order, number of different steps in routine order, number of departments involved, and number of sites patients visit. RESULTS: Patient adherence rates increased for all the recommended services after the first reminder letter. Preventative and Chronic Disease Management recommendations demonstrated additional moderate increases after the second reminder letter. Referrals and Radiologogy and Diagnostic Testing (acute, symptom specific) and Labs (acute and nonacute) demonstrated additional minimal adherence rate increases after the second reminder letter. Comparison of the process flow complexity demonstrated an inverse relationship between process complexity and adherence rates, particularly for non-acute orders. CONCLUSIONS: One reminder letter seemed to be sufficient for most recommended care. The complexity of the healthcare process may be an important predictive factor for patient adherence. PMID- 22824569 TI - Development of a prognostic model for predicting spontaneous singleton preterm birth. AB - OBJECTIVE: To develop and validate a prognostic model for prediction of spontaneous preterm birth. STUDY DESIGN: Prospective cohort study using data of the nationwide perinatal registry in The Netherlands. We studied 1,524,058 singleton pregnancies between 1999 and 2007. We developed a multiple logistic regression model to estimate the risk of spontaneous preterm birth based on maternal and pregnancy characteristics. We used bootstrapping techniques to internally validate our model. Discrimination (AUC), accuracy (Brier score) and calibration (calibration graphs and Hosmer-Lemeshow C-statistic) were used to assess the model's predictive performance. Our primary outcome measure was spontaneous preterm birth at <37 completed weeks. RESULTS: Spontaneous preterm birth occurred in 57,796 (3.8%) pregnancies. The final model included 13 variables for predicting preterm birth. The predicted probabilities ranged from 0.01 to 0.71 (IQR 0.02-0.04). The model had an area under the receiver operator characteristic curve (AUC) of 0.63 (95% CI 0.63-0.63), the Brier score was 0.04 (95% CI 0.04-0.04) and the Hosmer Lemeshow C-statistic was significant (p<0.0001). The calibration graph showed overprediction at higher values of predicted probability. The positive predictive value was 26% (95% CI 20-33%) for the 0.4 probability cut-off point. CONCLUSIONS: The model's discrimination was fair and it had modest calibration. Previous preterm birth, drug abuse and vaginal bleeding in the first half of pregnancy were the most important predictors for spontaneous preterm birth. Although not applicable in clinical practice yet, this model is a next step towards early prediction of spontaneous preterm birth that enables caregivers to start preventive therapy in women at higher risk. PMID- 22824570 TI - Laparoscopic surgery for severe ureteric endometriosis. AB - OBJECTIVES: To describe the outcomes of laparoscopic surgery for severe ureteric endometriosis. STUDY DESIGN: Retrospective descriptive study of the clinical and surgical outcomes for patients who underwent laparoscopic surgery for severe ureterohydronephrosis due to endometriosis. The surgery consisted of laparoscopic ureterolysis, ureteric end-to-end anastomosis and ureteral stenting at the Department of Obstetrics and Gynecology, Strasbourg Hospitals, between June 2004 and June 2009. Data were collected from patients' notes and also included telephone interview. Normally distributed data are presented as mean +/- SD, and skewed data as median (range). Categoric variables are reported as absolute values and percentages. Continuous variables are compared using the paired samples t-test. Statistical significance was set at P<0.05. RESULTS: Thirteen patients had severe disease. Two patients had non-functioning kidneys. Left sided lesions were more common (76.9%). All patients had associated deep infiltrative endometriosis (DIE) elsewhere in the pelvis. Laparoscopic treatment was feasible in all cases without the need to convert. Ureterolysis was performed in seven patients (53.8%) and segmental resection with end-to-end anastomosis in six (46.2%) patients. Ureteric wall endometriotic infiltration was present in four cases (30.8%). Median follow up duration was 24 months. All patients had improvement of their pain symptoms. There were no intraoperative complications. Major postoperative complications were seen in three patients (23%). CONCLUSIONS: Ureteric involvement is usually asymptomatic, and therefore in patients with evidence of deep endometriosis it must be excluded by ultrasound or magnetic resonance imaging. Laparoscopic treatment of ureteric endometriosis is feasible. Intrinsic ureteric endometriosis is quite frequent in severe ureterohydronephrosis. Complete excision of the disease is essential to improve pain symptomatology and to prevent recurrence of disease. Long term follow up is required to exclude any stenosis. PMID- 22824573 TI - [Seamless community-health-care cooperation in a cerebral apoplexy: practical use of medicine and welfare inter-regional association critical path]. PMID- 22824571 TI - Risk factors for developmental dysplasia of the hip: a meta-analysis. AB - Early detection and subsequent treatment of developmental dysplasia of the hip (DDH) is thought to improve its prognosis. Frequently reported risk factors for DDH are a positive family history of DDH, female sex and breech presentation, but there is not a lot of systematic knowledge about DDH risk factors. We performed a systematic review and meta-analysis of the available evidence on DDH risk factors. We searched Medline, EMBASE and The Cochrane Library from conception up until October 2011 for primary articles on the subject. All studies reporting on potential risk factors for DDH that allowed construction of a two-by-two table were selected. Language restrictions were not applied. Two reviewers independently selected studies, extracted data and assessed study quality. The association between risk factors and DDH was expressed as a common odds ratio (OR) with a 95% confidence interval (CI). We identified 30 relevant studies reporting on 1,494,387 children; 26 studies were cohort studies and four studies used a case-control design. The risk of DDH was strongly increased in case of breech delivery (OR 5.7, 95% CI 4.4-7.4), female sex (OR 3.8, 95% CI 3.0-4.6) a positive family history of DDH (OR 4.8, 95% CI 2.8-8.2) and clicking hips at clinical examination (OR 8.6, 95% CI 4.5-16.6). This meta-analysis shows that infants born in breech presentation, female infants, infants with a positive family history and clicking hips at clinical examination have an increased risk for DDH. This knowledge can be helpful in the development of screening programs for DDH. PMID- 22824572 TI - The role of CT angiography in military trauma. AB - AIM: To review whole-body computed tomography (CT) angiography as an unmatched way of fully assessing battle-injured patients, and the prevalence of vascular, predominantly arterial, injuries identified. MATERIALS AND METHODS: A retrospective analysis of 144 patients who underwent whole-body CT angiography in March 2011 was made. A vascular radiologist reviewed all images and imaging reports. Data gathered included positive findings from CT, anatomical region injured, mechanism of injury, time to CT, and the number of casualties per incident. RESULTS: One hundred and forty-four patients underwent whole-body CT of which 17% had an occult vascular injury on CT. Twenty of these injuries (56%) were in the lower limbs, excluding extravasation at the site of amputation. Improvised explosive devices (IEDs) accounted for 71% (180 of 253) of battle injuries. The median time from admission to CT was 28 min. An additional 12% longer per patient is taken on average in a multiple casualty incident. Including contrast medium administration, whole-body angiography is completed in less than 2 min (mean 116 s). CONCLUSION: A significant proportion of occult vascular injuries occur in penetrating fragmentation and blast injuries in military trauma. A low threshold for single-pass whole-body CT angiography is therefore justified. PMID- 22824574 TI - [Diagnosis of patients with thoracic outlet syndrome (TOS) using physiological measures of the medial antebrachial cutaneous nerve]. AB - The diagnosis of thoracic outlet syndrome (TOS) remains difficult; therefore, reliable and objective tests are required. We examined the process to diagnose TOS, and assessed the validity of measuring the medial antebrachial cutaneous nerve (MAC), also the ulnar nerve (UN) as a diagnostic tool. Between 2008 and 2011, 86 sides in 73 patients admitted to our hospital for the treatment of TOS were analyzed. In the process for the diagnosis as TOS, the narrow parts of the subclavian artery that was compressed by the anterior scalene muscle were confirmed with a three-dimensional CT angiography. All patients were taken a brachial plexus anesthesiological block to aim at both for diagnosis and treatment of TOS. For the diagnosis of TOS, measurements of latency (LT) and sensory nerve action potential (SNAP) of MAC and UN were analyzed between the TOS side and the non-TOS side and separated into traumatic type or disputed type. In our research, the LT of MAC and UN did not differ much between the TOS side and the non-TOS side; however, the amplitude of SNAP of MAC and UN were lower on the TOS side, especially in traumatic TOS. We concluded that comparison of the amplitude of SNAP of MAC on the injured or non-injured side was comparatively helpful for the diagnosis of TOS. PMID- 22824575 TI - [The Multi-detector-row CT angiography for diagnosis of spinal dural arteriovenous fistula]. AB - PURPOSE: Multi-detector-row CT angiography (MDCTA) is useful for diagnosis of spinal arteriovenous (AV) shunt. So we reported the role and pitfall of MDCTA based on our experience. SUBJECTS: From January 2007 to September 2011, 57 cases used MDCTA in our institution. We investigated 22 case of spinal dural AVF and 5 cases of epidural AVF. METHODS: All cases were performed by Toshiba Aquilion 64. FOV was the whole spine, curved planar reconstruction along the spinal canal, sagittal and axial view obtained by multi-planar reconstruction. RESULTS: MDCTA detected dilated the perimedullary vein in all cases and identified the level of segmental artery matching the result of DSA in 16 cases of spinal dural AVF (73%) and 1 cases of epidural AVF (20%). CONCLUSION: MDCTA is useful for screening, and identifying the shunt point, but care needs to be taken concerning the particular pitfall of MDCTA. PMID- 22824576 TI - [Endovascular trapping using a tandem balloon technique for a spontaneous vertebrovertebral fistula associated with neurofibromatosis type 1]. AB - We report a rare case of a young man who had spontaneous left vertebrovertebral fistula associated with neurofibromatosis Type 1. His complaints were severe pain in the left neck and numbness in the left upper extremity. Cervical MR images showed a large abnormal flow void to the left of the spinal canal. An angiogram demonstrated a fusiform aneurysm and a high flow arteriovenous fistula in the left vertebral artery that drained into the internal vertebral plexus and formed a large venous varix. The occipital artery, the thyrocervical artery and the contralateral vertebral artery were associated with the fistula. The arteriovenous fistula was treated by endovascular coil embolization, using a tandem balloon technique. For this fistula, exhibiting the combination of high flow and multiple associated arteries, the flow control technique during the coil embolization, using tandem balloons in both the subclavian artery and the distal portion of the fistula of the vertebral artery, was safe and feasible for preventing coil migration. PMID- 22824577 TI - [A case of malignant paraganglioma presenting with skull metastases]. AB - A non-functioning paraganglioma is usually benign, however, it may cause distant metastases. There is no histological appearance for the diagnosis of malignancy or absolute criteria for predicting malignant potential. Bony metastases from paraganglioma are known to occur, but, skull metastases are very rare. We report a case of intracranial metastases from a renal paraganglioma. A 61-year-old male presented with temporal headache and exophthalmos on the left side. Seven years prior, he underwent surgery to remove a mass in the right renal hilum, which was diagnosed as renal cell carcinoma at that time. Computed tomography and magnetic resonance imaging showed a ring-like enhanced mass in the left middle fossa, which destroyed the sphenoid bone and the lateral wall of the orbit. Another osteolytic lesion was revealed in the occipital bone. The fragile tumor was totally resected. Histopathological study revealed the Zellballen pattern with extensive coagulation necrosis. No apparent nuclear atypia or mitosis were present. Immunohistochemistry showed reactivity for synaptophysin and chromogranin A in the tumor cells. Review of the surgical specimen of the previously resected renal tumor revealed the same pathological and immunohistochemical findings as those of chief cells in the middle fossa tumor. Thus, this tumor was diagnosed as a malignant paraganglioma metastasized from renal paraganglioma. After six cycle chemotherapy with cyclophosphamide and vincristine, his condition was stable for two years, however, he died four years after the diagnosis of malignancy. PMID- 22824578 TI - [Bilateral abducens nerve palsies in treated cases of subarachnoid hemorrhage]. AB - Isolated abducens nerve palsies associated with the rupture of intracranial aneurysms have rarely been reported. We report two cases of isolated bilateral abducens nerve palsies occurring after subarachnoid hemorrhage due to the rupture of an intracranial aneurysm. Case 1: A 49-year-old woman had bilateral abducens nerve palsies following subarachnoid hemorrhage due to the rupture of the left vertebral artery-posterior inferior cerebellar artery aneurysm. Case 2: A 55-year old man had bilateral abducens nerve palsies following subarachnoid hemorrhage due to dissecting aneurysm of the right vertebral artery. Case 1 and 2 were treated with surgical clipping of the aneurysm and internal occlusion of the parent artery. In both cases, bilateral abducens nerve palsies achieved almost full recovery several months after treatment. It is speculated that the main causes of palsies are compression and stretching of the bilateral abducens nerves by a thick clot in the prepontine cistern. Although most of the abducens palsies may be reversible and have good prognosis, it is important that they are kept in mind as isolated symptoms of subarachnoid hemorrhage. PMID- 22824579 TI - [Granular cell tumor of the neurohypophysis observed with hypoglycemic attack]. AB - Granular cell tumor of the neurohypophysis (GCT) occurs as a solitary, small, nodular tumor and rarely grows to a sufficient size to present symptoms. The authors report a case of a 30-year-old man with GCT presenting with hypoglycemic attack. Hypoglycemic attack could be due to dysfunction of the hypothalamus and one of the important symptoms of GCT. PMID- 22824580 TI - [Surgery for unruptured middle cerebral artery aneurysm]. AB - Although a large number of patients with unruptured middle cerebral artery (MCA) aneurysms (AN) have been treated by surgical clipping in Japan, there has yet been no comprehensive study investigating the surgical risks based on a quantitative evaluation of the extensive existing body of patient records. This systematic review was conducted to determine morbidity of the procedure by performing a meta-analysis of the literature. The authors used a PubMed and J stage search from 2000 to 2011 for studies containing the surgical clipping of the unruptured MCA AN. There were 21 articles, containing a total 1,323 cases of unruptured AN with morbidity specifically located in the MCA. 54 cases indicated significant neurological deficits for a morbidity rate of 4.1% (95% CI; 3.0-5.1). A limited number of studies disclosed an incremental increase in morbidity with the size of the aneurysm. Smaller MCA AN (7+/-3 mm) presented a lower morbidity of 1.48%, whereas giant MCA AN (>25 mm) corresponded with a higher morbidity of 27.8%. Factors consistently associated with high morbidity included incorporated MCA branches, plaque at the neck of the AN, an unclippable configuration, and M1 superior wall AN. Complex aneurysms required a wide array of intracranial bypass procedures, yielding morbidity of 23.4% (95% CI; 20.9-25.9). This is the first systematic review and quantitative meta-analysis of the surgical complications related to unruptured MCA AN. PMID- 22824581 TI - Structure-functional analysis of the Dictyoglomus cell envelope. AB - Several closely related strains of the thermophilic bacterium Dictyoglomus have been isolated from various hot springs on the Philippine archipelago. These strains as well as Dictyoglomus thermophilum H-6-12 were analyzed in view of the structure-functional relationships of the cell envelopes. All envelopes of Dictyoglomus strains show several peculiar features that are apparently either unique for the genus or common for other phylogenetically related Thermotogales. The filamentous cells develop pili at the cell poles, guided by large columnar protein assemblies that traverse the periplasm. Filamentous protein complexes span the periplasmic space at the longitudinal sides of the cell. By the end of the exponential growth phase, Dictyoglomus strains form multicellular aggregates ("rotund bodies") inside a compartment surrounded by a single, continuous outer envelope. The formation of these rotund bodies which are also found in some other deeply branching thermophilic phyla (Thermotoga, Thermus) was studied in detail. The transition between unicellular and multicellular lifestyle can be explained by the partial detachment of a protoplast from the outer envelope during cell division. When the outer envelope is partially detached from the protoplast, mechanical forces generated by protoplast elongation may drive cell rearrangement of daughter cells inside the compartment. During the following rounds of cell division, the overall shape of the compartment changes from spindle-like to globular geometry. Analysis of subcellular fractions of Dictyoglomus cells shows that glucan hydrolases are associated with the compartment. This feature is discussed in view of the multicellular life style of Dictyoglomus. PMID- 22824582 TI - Neoscardovia arbecensis gen. nov., sp. nov., isolated from porcine slurries. AB - Three Gram-positive, anaerobic, pleomorphic strains (PG10(T), PG18 and PG22), were selected among five strains isolated from pig slurries while searching for host specific bifidobacteria to track the source of fecal pollution in water. Analysis of the 16S rRNA gene sequence showed a maximum identity of 94% to various species of the family Bifidobacteriaceae. However, phylogenetic analyses of 16S rRNA and HSP60 gene sequences revealed a closer relationship of these strains to members of the recently described Aeriscardovia, Parascardovia and Scardovia genera, than to other Bifidobacterium species. The names Neoscardovia gen. nov. and Neoscardovia arbecensis sp. nov. are proposed for a new genus and for the first species belonging to this genus, respectively, and for which PG10(T) (CECT 8111(T), DSM 25737(T)) was designated as the type strain. This new species should be placed in the Bifidobacteriaceae family within the class Actinobacteria, with Aeriscardovia aeriphila being the closest relative. The prevailing cellular fatty acids were C(16:0) and C(18:1)omega9c, and the major polar lipids consisted of a variety of glycolipids, diphosphatidyl glycerol, two unidentified phospholipids, and phosphatidyl glycerol. The peptidoglycan structure was A1gammameso-Dpm-direct. The GenBank accession numbers for the 16S rRNA gene and HSP60 gene sequences of strains PG10(T), PG18 and PG22 are JF519691, JF519693, JQ767128 and JQ767130, JQ767131, JQ767133, respectively. PMID- 22824583 TI - Prophylactic or therapeutic administration of Agaricus blazei Murill is effective in treatment of murine visceral leishmaniasis. AB - The present study aimed to investigate the in vitro antileishmanial activity of five fractions obtained from Agaricus blazei water extract (AbM), namely, Fab1, Fab2, Fab3, Fab4, and Fab5; and use the selected leishmanicidal fraction to treat BALB/c mice infected with Leishmania chagasi. A curve dose-titration was performed to obtain the concentration to be test in infected animals. In this context, Fab5 fraction and AbM were used in the doses of 20 and 100 mg/kg/day, respectively, with the product been administered once a day. The effect induced by a chemo-prophylactic regimen, based on the administration Fab5 fraction and AbM 5 days before infection, and maintained for an additional 20 days post infection was compared to a therapeutic regimen, in which the compounds were administered from 0 to 20 days of infection. Control animals were either treated with amphotericin B deoxycholate (AmpB) or received distilled water. All groups were followed up for 10 weeks post-infection, when parasitological and immunological parameters were analyzed. The Fab5 presented the best results of in vitro leishmanicidal activity. In the in vivo experiments, the use of Fab5 or AbM, as compared to control groups, resulted in significant reduced parasite burdens in the liver, spleen, and draining lymph nodes of the infected animals, as compared to control groups. A Type 1 immune response was observed in the Fab5 or AbM treated animals. No significant toxicity was observed. The chemo prophylactic regimen proved to be more effective to induce theses responses. In this context, the data presented in this study showed the potential of the purified Fab5 fraction of AbM as a therapeutic alternative to treat visceral leishmaniasis. In addition, it can be postulated that this fraction can be also employed in a chemo-prophylactic regimen associated or not with other therapeutic products. PMID- 22824584 TI - What is spontaneous pain and who has it? AB - Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain. PERSPECTIVE: Which is more important-stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life. PMID- 22824585 TI - Determination of the mechanical properties of normal and calcified human mitral chordae tendineae. AB - The aim of the present research is to determine the influence of the calcification of human mitral valves on the mechanical properties of their marginal chordae tendineae. The study was performed on marginal chords obtained from thirteen human mitral valves, explanted at surgery, including six non calcified, four moderately calcified and three strongly calcified valves. The mechanical response of the chords from the non-calcified and moderately calcified valves was determined by means of quasi-static tensile tests (the poor condition of the strongly calcified valves prevented them from being mechanically characterised). The material parameters that were obtained and analysed (the Young's modulus, the secant modulus, the proportional limit stress, the ultimate strength, the strain at fracture and the density of energy stored up to maximum load) revealed noticeable differences in mechanical behaviour between the two groups of mitral chordae tendineae. Large scatter was obtained in all cases, nevertheless, considering the mean values, it was observed that the normal chords are between three and seven times stiffer or more resistant than the moderately calcified ones. On the contrary, the results obtained for the strain at fracture showed a rather different picture as, in this case, no significant differences were observed between the two families of chords. A scanning electron microscopy study was conducted in order to find out the relevant features of the calcium deposits present in the calcified chordae tendineae. In addition, the general aspects appreciated in the stress vs. strain curves were correlated with the collagen morphological evidences determined microscopically. Finally, the calcium content present in the three groups of chords was quantitatively determined through atomic absorption spectroscopy; then, the relation between the mechanical properties of normal and moderately calcified chords as a function of its calcium content was obtained. This analysis confirmed the existence of a strong correlation between calcium content and stiffness or resistance whereas the influence on the ductility seems to be negligible. PMID- 22824586 TI - Isolation of a reassortant H13N2 virus from a mallard fecal sample in South Korea. AB - BACKGROUND: Virus subtype H13N2, A/mallard/Kr/SH38-45/2010 (H13N2), was first isolated from a mallard fecal sample in South Korea. RESULTS: Phylogenetic analysis of all eight viral genes revealed that this virus emerged by genetic mixing between Eurasian and North American gene pools, and possibly between wild ducks and gulls. The H13 and N2 surface genes clustered together in a group with Eurasian isolates from gulls and wild birds, respectively. The PB2, PA, NP, M and NS segments belonged to the Eurasian lineage, whereas the PB1 gene clustered in the North American lineage. Furthermore, they showed a bird-dependent pattern in phylogenetic analysis: the M gene was similar to subtype H13 viruses within gulls, whereas other segments were similar to avian influenza viruses of other subtypes from wild ducks. CONCLUSIONS: The data suggests that the novel reassortant H13N2 virus isolated in South Korea might have emerged by genetic reassortment between intercontinental and interspecies transmission in wild birds. PMID- 22824587 TI - Fatal subarachnoid hemorrhage following traumatic rupture of the internal carotid artery. AB - Traumatic subarachnoid hemorrhage (TSAH) is a life-threatening intracranial bleed often associated with violent assault or motor vehicle accidents. The vast majority of TSAH is associated with rupture of the vertebral artery, although rare cases of traumatic aneurysm of the internal carotid artery (ICA) have been reported. A 27-year-old man was found bleeding and unresponsive following a violent altercation in which he received repeated blows to the head and neck. CT scan showed acute SAH, and death ensued within 24 h. Autopsy revealed generalized bruising of the face, a complete midline mandibular fracture, and massive basal SAH resulting from traumatic rupture of the right terminal internal carotid artery at the origin of the middle cerebral artery. Anterior and posterior neck dissection revealed focal hemorrhage associated with the right neural arch of the first cervical vertebra (C1). Autopsy findings were consistent with TSAH resulting from rupture of the ICA following blunt force trauma to the head. The rupture site in TSAH can be difficult to locate, and injury to the ICA may be overlooked if not routinely examined. Dissection of the neck and skull base is required to ensure accurate identification of the site of vascular injury. PMID- 22824588 TI - Urologic complication in laparoscopic radical hysterectomy: meta-analysis of 20 studies. AB - OBJECTIVE: A meta-analysis was done to assess the risk of intraoperative and postoperative urologic complications, and laparoscopic radical hysterectomy (LRH) and lymph node dissection. METHODS: Pubmed, EMBASE and Cochrane library were searched for studies published to December, 2011, supplemented by manual searches of relevant bibliographies from the retrieved articles. Two researchers independently extracted the data. Eligible studies had reported perioperative complications and a sample size of at least 10 patients. RESULTS: The search yielded 19 retrospective studies and one prospective cohort study (intraoperative urologic complication, 18 studies; postoperative urologic complication, 16 studies). When all studies were pooled, the odds ratio (OR) of LRH for the risk of intraoperative urologic complications compared to abdominal radical hysterectomy (ARH) was 1.97 [95% confidence interval (CI) 1.23-3.13] and the OR of LRH for postoperative complication risk compared to ARH was 1.35 [95% CI 0.84 2.16]. In subgroup analysis, obesity and laparoscopic type (laparoscopic assisted vaginal radical hysterectomy) were associated with intraoperative urologic complications. CONCLUSION: Laparoscopic radical hysterectomy is associated with a significant increased risk of intraoperative urologic complications. PMID- 22824589 TI - Performance in anxiety and spatial memory tests following bilateral vestibular loss in the rat and effects of anxiolytic and anxiogenic drugs. AB - Vestibular dysfunction in humans is associated with anxiety and cognitive disorders. However, various animal studies of the effects of vestibular loss have yielded conflicting results, from reduced anxiety to increased anxiety, depending on the particular model of vestibular dysfunction and the anxiety test used. In this study we revisited the question of whether rats with surgical bilateral vestibular deafferentation (BVD) exhibit changes in anxiety-related behaviour by testing them in the open field maze (OFM), elevated plus maze (EPM) and elevated T maze (ETM) in the presence of a non-sedating anxiolytic drug, buspirone, or an anxiogenic drug, FG-7142. We also tested the animals in a spatial T maze (STM) in order to evaluate their cognitive function under the same set of conditions. We found that BVD animals exhibited increased locomotor activity (P<=0.003), reduced supported and unsupported rearing (P<=0.02 and P<=0.000, respectively) and reduced thigmotaxis (P<=0.000) in the OFM, which for the most part the drugs did not modify. By contrast, there were no significant differences between BVD and sham control animals in the EPM and the BVD animals exhibited a marginally longer escape latency in the ETM (P<=0.03), with no change in avoidance latency. In the STM, the BVD animals demonstrated a large and significant decrease in accuracy compared to the sham control animals (P<=0.000), which was not affected by drug treatment. These results have replicated previous findings regarding increased locomotor activity, reduced rearing and thigmotaxis in the OFM, and impaired performance in the STM. However, they failed to replicate some previous results obtained using the EPM and ETM. Overall, they do not support the hypothesis that BVD animals exhibit increased anxiety-like behaviour and suggest that the cognitive deficits may be independent of the emotional effects of vestibular loss. PMID- 22824590 TI - Murine model of repeated exposures to conspecific trained aggressors simulates features of post-traumatic stress disorder. AB - We evaluated repeated exposures of mice to a trained aggressor mouse as a model (adapted from "social stress" models of traumatic stress) for aspects of post traumatic stress disorder (PTSD). Using a "cage-within-cage resident-intruder" protocol, subject C57BL/6J mice were exposed to aggressors for 6 h daily for 5 or 10 days. At one to three random times during each 6-h session, subjects were exposed directly to aggressor for 1 min or 10 bites, whichever came first. Behavioral, physiological, and histological changes associated with aggressor exposure were assessed for up to 6 weeks. During aggressor exposure, subjects displayed less territorial behavior, gained weight, and increased body temperature. One day after the last aggressor exposure, inflammatory cardiac histopathologies were prevalent; after 10 days, only mild myocardial degeneration with fibrosis or fibroplasias was evident, while controls showed almost no cardiac abnormalities at any time. After 4 weeks, the medial prefrontal cortex of control mice showed increased dendritic spine density, but aggressor-exposed mice showed no increase. Behaviors affected by aggressor exposure were evaluated in a partition test wherein the subject mouse is separated from the aggressor by a fenestrated partition that permits sensory cues to pass but prevents direct physical interaction. For up to 4-6 weeks after the last aggressor exposure, subjects showed prolonged grooming, freezing, retarded locomotion and no tail rattling. PTSD and its co-morbidities are often consequent to repeated aggravated "social" assaults (e.g., combat) and manifest socially over time, suggesting the relevance of this repeated aggressor-exposure model to clinical aspects of PTSD. PMID- 22824591 TI - Managing patients with retinal vein occlusions: is there any real step forward? PMID- 22824592 TI - Glaucomatous neurodegeneration: an eye on tumor necrosis factor-alpha. AB - Glaucoma, a neurodegenerative disease, is currently being treated by modulation of one of its primary risk factors, the elevated intraocular pressure. Newer therapies that can provide direct neuroprotection to retinal ganglion cells are being extensively investigated. Tumor necrosis factor-alpha, a cytokine, has been recognized to play an important role in pro and antiapoptotic cellular events. In this paper we review the relevant literature to understand (1) The association of increased expression of tumor necrosis factor-alpha with glaucomatous neurodegeneraion, (2) Modulation of tumor necrosis factor-alpha expression by exposure to various risk factors of glaucoma, (3) Downstream cellular signaling mechanisms following interaction of tumor necrosis factor-alpha with its receptors and (4) Role of tumor necrosis factor-alpha as a possible target for therapeutic intervention in glaucoma. Literature was reviewed using PubMed search engine with relevant key words and a total of 82 English language papers published from 1990 to 2010 are included in this review. PMID- 22824593 TI - Ranibizumab as an adjunct to laser for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To compare the safety, efficacy, and dosing regimen of intravitreal ranibizumab as an adjunct to laser therapy for the treatment of macular edema secondary to branch retinal vein occlusion (BRVO). MATERIALS AND METHODS: Thirty eyes of 30 patients of BRVO of at least 6 weeks duration were randomized into three groups: Group 1 received grid laser treatment alone, Group 2 received a single dose of intravitreal injection of ranibizumab (0.5 mg / 0.05 ml) followed by grid laser treatment on 7 th day following injection, while Group 3 received three loading doses of intravitreal ranibizumab at monthly interval (i.e. 0, 1, & 2 months) + standard laser treatment 7 days after the 1 st injection. Outcome measure noted at 6 months follow-up were the improvement in best-corrected visual acuity (BCVA) and central macular thickness (CMT). RESULTS: At 6 months follow up, there was an average gain of 12 letters (P=0.05), 17.5 letters (P=0.05) and 19 letters (P=0.05) in groups 1, 2, and 3, respectively, with the decrease in CMT being 208.7 MUm (P=0.05), 312.9 MUm (P= 0.05) and 326.8 MUm (P=0.05), respectively, in these groups. Gain in BCVA of more than 3 lines was noted in 1/10 patients in Group 1(10%) as compared to 3/10 (30%) and 4/10 (40%) patients in groups 2 and 3, respectively. CONCLUSION: The gain in BCVA and reduction in CMT were better with combination therapy (single- and triple- dose regimen) compared to grid laser alone. Single dose of intravitreal ranibizumab with grid laser seems to be an effective therapy. PMID- 22824594 TI - Epidemiological and microbiological profile of infective keratitis in Ahmedabad. AB - CONTEXT: Study of patients attending tertiary care ophthalmology institute at Ahmedabad. AIMS: To study the microbiological etiology and epidemiological factors associated with suppurative keratitis. SETTINGS AND DESIGN: A total of 150 corneal scrapings were evaluated from patients presenting with corneal ulcers at a tertiary ophthalmology center, Ahmedabad from July 2007 to June 2008. MATERIALS AND METHODS: Scrapings were subjected to Gram stain, potassium hydroxide preparation and culture for bacterial and fungal pathogens. Socio demographic data and risk factors were recorded. RESULTS: Ninety percent (135/150) people with corneal ulcers had trauma as predisposing factor for keratitis. Trauma due to wooden objects was the leading cause (46/135) followed by vegetable matter and stone injury (23/135). Microbial etiology was established in 59.3% (89/150) of scrapings. Out of 89 positive isolates, 65.1% (58/89) were bacterial while 34.9% (31/89) were fungal. Among the bacterial isolates, 60.3% (35/58) were Gram-positive cocci while 39.7% (23/58) were Gram-negative bacilli. The most common bacterial isolate was Staphylococus aureus (32.7%, 19/58) followed by coagulase-negative Staphylococci (25.8%, 15/58) and Pseudomonas (18.9%, 11/58). Among the 31 fungal pathogens, Aspergillus species was the most common (35.4%11/31), followed by Fusarium species (22.5%, 7/31). CONCLUSION: Trauma with wooden material is the most common predisposing factor for suppurative keratitis. Males were more affected than females. Bacterial ulcers were more common than fungal in areas in and around Ahmedabad. Staphylococcus aureus and Aspergillus were the commonest bacterial and fungal isolates respectively. Geographical variation persists in microbial etiology of suppurative keratitis. PMID- 22824595 TI - Efficacy of preoperative injection versus intraoperative application of mitomycin in recurrent pterygium surgery. AB - PURPOSE: To determine the efficacy of preoperative subconjunctival injection of mitomycin C a day before surgery in the management of recurrent pterygium. MATERIALS AND METHODS: Randomized comparative case series. Fifty eyes with recurrent pterygium were randomly divided into two groups; the mitomycin injection group (25 eyes) and the mitomycin application group (25 eyes). The mitomycin injection group underwent preoperative subconjunctival injection of mitomycin C in low dose (0.1 ml of 0.15 mg/ml) a day before bare sclera pterygium excision surgery. The mitomycin application group underwent bare sclera pterygium excision with topical application of mitomycin C (same concentration). RESULTS: At one year of follow-up, 24 of 25 eyes (96%) in the mitomycin injection group and 23 of 25 (92%) eyes in the mitomycin application group were free of recurrence. The difference was statistically insignificant. As regards postoperative complications, delayed epithelization (more than two weeks) occurred in two eyes (8%) in the mitomycin injection group and in one eye (4%) in the mitomycin application group. Scleral thinning was reported in one eye (4%) in the mitomycin application group which resolved within three weeks after surgery, no other serious postoperative complications were reported. CONCLUSION: Preoperative subconjunctival injection of mitomycin C in low dose (0.1 ml of 0.15 mg/ml) a day before pterygium surgery is a simple and effective modality for management of recurrent pterygium. It has the advantage of low recurrence and complications' rate. PMID- 22824596 TI - Effect of preoperative use of topical prednisolone acetate, ketorolac tromethamine, nepafenac and placebo, on the maintenance of intraoperative mydriasis during cataract surgery: a randomized trial. AB - PURPOSE: To compare the effects of preoperative use of topical anti-inflammatory prednisolone acetate, ketorolac tromethamine, nepafenac and placebo, on the maintenance of intraoperative mydriasis during cataract surgery. DESIGN: Randomized clinical trial. MATERIALS AND METHODS: This single-center, masked, randomized clinical study comprised 140 patients scheduled for cataract surgery. Patients (35 in each group) were randomized to receive placebo, prednisolone acetate, ketorolac tromethamine 0.4% or nepafenac. These eye drops were administered three times daily for the two days prior to surgery. The pupillary diameters were measured by the surgeon using a compass prior to the corneal section and at the end of surgery. The primary outcome was the number of patients with pupil >= 6mm at the end of the surgery; the secondary outcome was the number of patients with pupil >= 6mm at the beginning of the surgery. RESULTS: All the patients achieved pupil >= 6mm at the beginning of the surgery. The number of patients in the prednisolone (29/35), nepafenac (31/35) and ketorolac (30/35) groups with pupil >= 6mm was greater than in the placebo group in the maintenance of intraoperative mydriasis (19/35 - P =0.003). There was no statistical difference among the prednisolone, nepafenac and ketorolac groups in the maintenance of intraoperative mydriasis (P =.791). There were no complications during surgery or related to the preoperative use of the eye drops. CONCLUSION: Preoperative use of ketorolac, prednisolone and nepafenac was effective in maintaining intraoperative mydriasis when compared with placebo. PMID- 22824597 TI - Analysis of photoastigmatic keratectomy with the cross-cylinder ablation. AB - AIM: The aim was to evaluate the safety and efficacy of the "cross-cylinder" technique in the correction of astigmatism. SETTING AND DESIGN: A prospective interventional study from a university eye department was conducted. MATERIAL AND METHODS: The photoastigmatic refractive keratectomy (PARK) using the "cross cylinder" technique was performed in 102 eyes of 84 patients with at least 0.75 D of astigmatism. The study population was divided into two groups: in the first group the preoperative astigmatic power ranged from -0.75 D to -3.00 D (group 1), in the second group it ranged from -3.25 D to -6.00 D (group 2). Group 1 included 82 eyes of 67 patients (29 males and 38 females) with a mean cylinder power of 1.90 +/- 0.63 D, group 2 included 20 eyes of 17 patients (13 males and 4 females) with a mean cylinder power of -4.28 +/- 0.76 D. All eyes were targeted for emmetropia. The results were evaluated using Calossi's vector analysis method. Six-month postoperative outcomes are presented. RESULTS: Six months after PARK the mean sphere for the entire cohort was +0.28 +/- 0.75 D (range +2.5 to -2 D), the mean cylindrical power was +0.33 +/- 0.51 D (range +2.5 to -1.25 D) and the mean spherical equivalent refraction was +0.73 +/- 0.81 D (range +1.75 to -2 D). CONCLUSIONS: The cross-cylinder technique may be safely used with predictable results for the correction of astigmatism. PMID- 22824598 TI - Episcleral plaque brachytherapy using 'BARC I-125 Ocu-Prosta seeds' in the treatment of intraocular tumors: a single-institution experience in India. AB - CONTEXT: To analyze the results of episcleral plaque brachytherapy using indigenous Bhabha Atomic Research Centre (BARC) Iodine-125 Ocu-Prosta seeds for the management of intraocular tumors from a single institute. AIM: To report our initial experience and learning curve on the use of 'BARC I-125 Ocu-Prosta seeds' for the management of intraocular tumors such as choroidal melanomas, retinoblastomas and vasoproliferative tumors (VPT). MATERIALS AND METHODS: We retrospectively reviewed 13 eyes of 13 patients who underwent ophthalmic brachytherapy between May 2008 to March 2012. Nine cases had choroidal melanomas; three had retinoblastomas while one case had VPT. RESULTS: For choroidal melanomas the average apical diameter before brachytherapy was 7.6 mm and average largest basal diameter was 12.1 mm, respectively, which reduced to 4.2 mm and 7.7 mm after the procedure at an average follow-up of 24 months (range 10-43 months). Retinoblastoma and VPT also showed good regression after brachytherapy. CONCLUSION: Plaque radiotherapy using 125 I seeds can be performed under peribulbar anesthesia and provides a viable option for the management of intraocular cancer with minimal invasiveness and surgical complications. Patients in our studies experienced excellent local tumor control. With the availability of indigenous 'BARC I-125 Ocu-Prosta seeds' locally, cost effective ophthalmic brachytherapy can be performed in India. PMID- 22824599 TI - Ophthalmic contributions of Raja Serfoji II (1798-1832). AB - PURPOSE: To investigate and describe the ophthalmic contribution of Raja Serfoji II (1798-1832). MATERIALS AND METHOD: A team of 2 ophthalmologists, director of laboratory services, one archeologist and a photographer visited Sarasvathi Mahal Library, March 2004. Photographs of ophthalmic records were taken and analysed. An interview of the present prince, S Babaji Rajah Bhonsle was taken. Ophthalmologic case sheets of 44 patients, 18 pictures were found. RESULTS: Forty four patient's ophthalmic records were found. Six records were written in Modi script, 38 were written in English and 18 drawings were found. CONCLUSION: In Thanjavur, King Serfoji II carried out methodical ophthalmic practices between 1798 and 1832. Both European and Indian medicines were used. Cataract Surgery was performed. Detailed ophthalmic records were maintained. The only evidence of Serfoji's amazing contribution to medicine lies in 50 charts and manuscripts. PMID- 22824600 TI - Magnetic resonance imaging for the ophthalmologist: a primer. AB - Magnetic resonance imaging (MRI) and computerized tomography (CT) have added a new dimension in the diagnosis and management of ocular and orbital diseases. Although CT is more widely used, MRI is the modality of choice in select conditions and can be complimentary to CT in certain situations. The diagnostic yield is best when the ophthalmologist and radiologist work together. Ophthalmologists should be able to interpret these complex imaging modalities as better clinical correlation is then possible. In this article, we attempt to describe the basic principles of MRI and its interpretation, avoiding confusing technical terms. PMID- 22824601 TI - Managing bevacizumab-induced intraocular inflammation. AB - The outcome of four cases of sterile endophthalmitis that developed after intravitreal injections of bevacizumab has been reported here. All four eyes received 1.25 mg/0.05 ml intravitreal bevacizumab from 0.2-ml aliquots for different etiologies. The inflammation predominantly involved the anterior chamber with mild vitreous reaction. All patients were culture negative and regained preinjection visual acuity and were culture negative following intravitreal antibiotic administration. This report highlights that intravitreal bevacizumab can cause sterile endophthalmitis and this has to be kept in mind, and clinical judgment should be used to differentiate it from infective endophthalmitis. PMID- 22824602 TI - Bilateral acute macular neuroretinopathy in a postpartum, otherwise healthy female: a case report. AB - Acute macular neuroretinopathy (AMN) is a rare, macular disorder which typically affects young women who present with paracentral scotoma in one or both eyes corresponding to red, wedge-shaped parafoveal lesions. A young female presented with the complaints of few black spots (scotomas) in her visual field, which she noticed 1 month after a full-term normal delivery. Fundus examination showed flat, well-demarcated, reddish parafoveal lesions in both eyes, corresponding to the scotoma. Optical coherence tomography (OCT) at the site of lesion showed a well-delineated defect in the reflectivity of outer retinal layer. After 6 months of follow-up, fundus lesions were noted to be fading and repeat OCT revealed the realignment of the defect in the outer retinal reflectivity. PMID- 22824603 TI - Desferrioxamine-related ocular toxicity: a case report. AB - A 29-year-old lady receiving repeated blood transfusions for beta thalassemia since childhood, presented with rapidly deteriorating symptoms of night blindness and peripheral visual field loss. She was recently commenced on high-dose intravenous desferrioxamine for reducing the systemic iron overload. Clinical and investigative findings were consistent with desferrioxamine-related pigmentary retinopathy and optic neuropathy. Recovery was partial following cessation of desferrioxamine. This report highlights the ocular side-effects of desferrioxamine mesylate and the need to be vigilant in patients on high doses of desferrioxamine. PMID- 22824604 TI - Traumatic endophthalmitis presenting as isolated retinal vasculitis and white centered hemorrhages: Case report and review of literature. AB - The article reports a case and review of the literature of endophthalmitis presenting as isolated retinal vasculitis. A 26-year-old male was observed to have white-centered retinal hemorrhages and retinal vasculitis following an occult scleral perforation. At presentation, the visual acuity was 20/60. With clinical suspicion of early endophthalmitis, he underwent wound exploration, scleral tear repair, vitreous biopsy and administration of intravitreal antibiotics. Microbiology evaluation revealed significant presence of methicillin resistant coagulase-negative Staphylococcus epidermidis. Final visual acuity improved to 20/20 at 6 weeks postoperatively. Literature search revealed eight similar cases, all of them due to Staphylococcus species. Retinal vasculitis and white-centered retinal hemorrhages can be a presenting sign of early endophthalmitis, especially with non-fulminant pathogens like S. epidermidis. PMID- 22824605 TI - Nanophthalmos and situs inversus totalis. AB - Nanophthalmos is characterized by short axial length, high hypermetropia, thick sclera and a normal-sized crystalline lens. Situs inversus totalis is the mirror image of the normal morphology of the thoracic and abdominal viscera. To the best of our knowledge this is the first report of a nanophthalmic patient with situs inversus totalis. Therefore, we would like to invite the attention of our colleagues to our case and underline the importance of the systemic examination of the nanophthalmic patients to detect systemic malformations and visceral transpositions. PMID- 22824606 TI - Isolated homonymous hemianopsia due to presumptive cerebral tubercular abscess as the initial manifestation of human immunodeficiency virus infection. AB - We report a case of isolated homonymous hemianopsia due to presumptive cerebral tubercular abscess as the initial manifestation of human immunodeficiency virus (HIV) infection. A 30-year-old man presented to our outpatient department with sudden loss of visibility in his left visual field. He had no other systemic symptoms. Perimetry showed left-sided incongruous homonymous hemianopsia denser above the horizontal meridian. Magnetic resonance imaging revealed irregular well marginated lobulated lesions right temporo-occipital cerebral hemisphere and left high fronto-parietal cerebral hemisphere suggestive of brain tubercular abscess. Serological tests for HIV were reactive, and the patient was started only on anti tubercular drugs with the presumptive diagnosis of cerebral tubercular abscess. Therapeutic response confirmed the diagnosis. Atypical ophthalmic manifestations may be the initial presenting feature in patients with HIV infection. This highlights the need for increased index of suspicion for HIV infection in young patients with atypical ophthalmic manifestations. PMID- 22824607 TI - Spontaneous globe luxation associated with chronic obstructive pulmonary disease. AB - Spontaneous globe luxation is a rarely reported condition which can lead to complications like optic neuropathy. Common causes are thyroid eye disease, shallow orbit and floppy eyelid syndrome. We report a case of spontaneous globe luxation with the onset and severity associated with chronic obstructive pulmonary disease (COPD). To our knowledge, this is the first case of spontaneous globe luxation associated with COPD. PMID- 22824608 TI - Intralesional bleomycin for the treatment of periocular capillary hemangiomas. AB - Periocular infantile capillary hemangiomas do not always respond well to conventional treatment modalities such as systemic or intralesional corticosteroids, radiotherapy or debulking surgery. The authors describe the use of intralesional bleomycin injections (IBIs) to treat potentially amblyogenic lesions in two cases where other modalities have failed. In both cases monthly IBIs successfully cleared the visual axis of the affected eye before the age of 1 year thus preventing permanent sensory deprivation amblyopia. A total of five and nine injections, respectively, were used and no significant side effects were noted. IBI appears to be a useful alternative in the treatment of periocular capillary hemangiomas refractory to more conventional modalities. PMID- 22824609 TI - Candida albicans interface infection after deep anterior lamellar keratoplasty. AB - The clinical features of interface Candida keratitis after deep anterior lamellar keratoplasty (DALK), may imitate rejection or crystalline keratopathy. We report here an 18-year-old woman presented with red eye, 4 months after undergoing DALK. Slit lamp examination revealed keratic precipitates (KPs) and conjunctival injection. She was prescribed corticosteroid treatment for endothelial rejection by another ophthalmologist because of misdiagnosis, but suffered a recurrence of symptoms after reduction of the corticosteroid treatment. At that time, she was referred to our office. The recurrence persisted despite antibiotic and antifungal therapies. Ten days after treatment with interface irrigation with amphotericin, the infiltration and hypopyon were resolved. Topical steroid was added after 3 months of antifungal monotherapy. Irrigant cultures confirmed the presence of Candida albicans. The corneal graft appeared semi-clear with no signs of infection at 17-month follow-up. We recommend a close follow-up and a timely intervention to prevent the need for more invasive treatment such as penetrating keratoplasty. PMID- 22824610 TI - Electrophysiological abnormalities associated with extensive myelinated retinal nerve fibers. AB - An observational case report of electrophysiological abnormalities in a patient with anisomyopic amblyopia as a result of unilateral extensive myelinated retinal nerve fibers (MNFs) is illustrated. The electrophysiological readings revealed an abnormal pattern electroretinogram (PERG) but normal full-field electroretinogram readings in the affected eye. The visual-evoked potential was also undetectable in that eye. Our findings suggest that extensive MNFs can be associated with electrophysiological abnormalities, in particular the PERG, which can aid in diagnosing the cause of impaired vision when associated with amblyopia. PMID- 22824612 TI - Can conventional long case examination be improved? PMID- 22824613 TI - Outcome of in-the-bag implanted square-edge polymethyl methacrylate intraocular lenses with and without posterior capsulotomy in pediatric traumatic cataract. PMID- 22824614 TI - Role of potassium hydroxide preparation in the management of mycotic corneal ulcers. PMID- 22824616 TI - Fractured OzurdexTM implant in the vitreous cavity. PMID- 22824617 TI - Grapevine from the optic nerve head. PMID- 22824618 TI - A comparative study between intravitreal triamcinolone and bevacizumab for macular edema due to central retinal vein occlusion with poor vision. PMID- 22824619 TI - Flare up of choroiditis and choroidal neovasculazation associated with punctate inner choroidopathy during early pregnancy. PMID- 22824620 TI - Sodium arsenite-induced abnormalities in expressions of Caveolin-1, eNOS, IKKbeta, and COX-2 in SV-40 immortalized human uroepithelial cells and in urothelial carcinomas. AB - Arsenic, a known human carcinogen, is found throughout the crust of the earth. Prolonged arsenic exposure is a known cause of urothelial carcinoma (UC) and blackfoot disease (BFD). The aim of this study was to determine the effect of sodium arsenite on Caveolin-1 and downstream signaling molecules (eNOS, IKKbeta and COX-2) expression in human urothelial cells (SV-HUC-1). Immunohistochemical (IHC) staining of Caveolin-1, eNOS, IKKbeta, and COX-2 was also compared between UC patients from endemic and non-endemic areas of BFD in Taiwan. Immunocytochemical staining and Western blotting results revealed increased expression of Caveolin-1, IKKbeta, and COX-2 but decreased eNOS in SV-HUC-1 cells treated with low concentration of arsenite. Additionally, MEK inhibitor (U0126) significantly attenuated arsenite-induced expression of Caveolin-1, IKKbeta and COX-2 while reducing eNOS expression. The IHC staining of UCs revealed that expressions of Caveolin-1, IKKbeta, and COX-2 were significantly higher in patients from endemic areas of BFD compared to patients from non-endemic areas (p=0.011, p=0.002, p=0.0001) whereas eNOS was significantly lower (p=0.0001). The correlation observed between Caveolin-1 and downstream signaling molecule expression may be an important mechanism of arsenic-induced urothelial carcinogenesis. PMID- 22824621 TI - Castleman disease mimicked pancreatic carcinoma: report of two cases. AB - Castleman disease (CD) is an uncommon benign lymphoproliferative disorder, which usually presents as solitary or multiple masses in the mediastinum. Peripancreatic CD was rarely reported. Herein, we report two cases of unicentric peripancreatic CD from our center. A 43-year-old man and a 58-year-old woman were detected to have a pancreatic mass in the routine medical examinations. Both of them were asymptomatic. The computed tomography and ultrasonographic examination revealed a mild enhancing solitary mass at the pancreatic head/neck. No definite preoperative diagnosis was established and Whipple operations were originally planned. The intraoperative frozen section diagnosis of both patients revealed lymphoproliferation. Then the local excisions of mass were performed. Histological examination revealed features of CD of hyaline-vascular type. No recurrence was found during the follow-up period. CD should be included in the differential diagnosis of pancreatic tumors. Local excision is a suitable surgical choice. PMID- 22824622 TI - Chirp excitation of ultrasonic guided waves. AB - Most ultrasonic guided wave methods require tone burst excitations to achieve some degree of mode purity while maintaining temporal resolution. In addition, it is often desirable to acquire data using multiple frequencies, particularly during method development when the best frequency for a specific application is not known. However, this process is inconvenient and time-consuming, particularly if extensive signal averaging at each excitation frequency is required to achieve a satisfactory signal-to-noise ratio. Both acquisition time and data storage requirements may be prohibitive if responses from many narrowband tone burst excitations are measured. Here chirp excitations are utilized to address the need to both test at multiple frequencies and achieve a high signal-to-noise ratio to minimize acquisition time. A broadband chirp is used to acquire data at a wide range of frequencies, and deconvolution is applied to extract multiple narrowband responses. After optimizing the frequency and duration of the desired tone burst excitation, a long-time narrowband chirp is used as the actual excitation, and the desired tone burst response is similarly extracted during post-processing. Results are shown that demonstrate the efficacy of both broadband and narrowband chirp excitations. PMID- 22824623 TI - Microfluidic acoustic trapping force and stiffness measurement using viscous drag effect. AB - It has recently been demonstrated that it was possible to individually trap 70MUm droplets flowing within a 500MUm wide microfluidic channel by a 24MHz single element piezo-composite focused transducer. In order to further develop this non invasive approach as a microfluidic particle manipulation tool of high precision, the trapping force needs to be calibrated to a known force, i.e., viscous drag force arising from the fluid flow in the channel. However, few calibration studies based on fluid viscosity have been carried out with focused acoustic beams for moving objects in microfluidic environments. In this paper, the acoustic trapping force (F(trapping)) and the trap stiffness (or compliance k) are experimentally determined for a streaming droplet in a microfluidic channel. F(trapping) is calibrated to viscous drag force produced from syringe pumps. Chebyshev-windowed chirp coded excitation sequences sweeping the frequency range from 18MHz to 30MHz is utilized to drive the transducer, enabling the beam transmission through the channel/fluid interface for interrogating the droplets inside the channel. The minimum force (F(min,trapping)) required for initially immobilizing drifting droplets is determined as a function of pulse repetition frequency (PRF), duty factor (DTF), and input voltage amplitude (V(in)) to the transducer. At PRF=0.1kHz and DTF=30%, F(min,trapping) is increased from 2.2nN for V(in)=22V(pp) to 3.8nN for V(in)=54V(pp). With a fixed V(in)=54V(pp) and DTF=30%, F(min,trapping) can be varied from 3.8nN at PRF=0.1kHz to 6.7nN at PRF=0.5kHz. These findings indicate that both higher driving voltage and more frequent beam transmission yield stronger traps for holding droplets in motion. The stiffness k can be estimated through linear regression by measuring the trapping force (F(trapping)) corresponding to the displacement (x) of a droplet from the trap center. By plotting F(trapping) - x curves for certain values of V(in) (22/38/54V(pp)) at DTF=10% and PRF=0.1kHz, k is measured to be 0.09, 0.14, and 0.20nN/MUm, respectively. With variable PRF from 0.1 to 0.5kHz at V(in)=54 V(pp), k is increased from 0.20 to 0.42nN/MUm. It is shown that a higher PRF leads to a more compliant trap formation (or a stronger F(trapping)) for a given displacement x. Hence the results suggest that this acoustic trapping method has the potential as a noninvasive manipulation tool for individual moving targets in microfluidics by adjusting the transducer's excitation parameters. PMID- 22824624 TI - Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 [AEZS- 108]. AB - Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS- 108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers. PMID- 22824626 TI - Feline bone marrow-derived mesenchymal stromal cells (MSCs) show similar phenotype and functions with regards to neuronal differentiation as human MSCs. AB - Mesenchymal stromal cells (MSCs) show promise for treatment of a variety of neurological and other disorders. Cat has a high degree of linkage with the human genome and has been used as a model for analysis of neurological disorders such as stroke, Alzheimer's disease and motor disorders. The present study was designed to characterize bone marrow-derived MSCs from cats and to investigate the capacity to generate functional peptidergic neurons. MSCs were expanded with cells from the femurs of cats and then characterized by phenotype and function. Phenotypically, feline and human MSCs shared surface markers, and lacked hematopoietic markers, with similar morphology. As compared to a subset of human MSCs, feline MSCs showed no evidence of the major histocompatibility class II. Since the literature suggested Stro-1 as an indicator of pluripotency, we compared early and late passages feline MSCs and found its expression in >90% of the cells. However, the early passage cells showed two distinct populations of Stro-1-expressing cells. At passage 5, the MSCs were more homogeneous with regards to Stro-1 expression. The passage 5 MSCs differentiated to osteogenic and adipogenic cells, and generated neurons with electrophysiological properties. This correlated with the expression of mature neuronal markers with concomitant decrease in stem cell-associated genes. At day 12 induction, the cells were positive for MAP2, Neuronal Nuclei, tubulin betaIII, Tau and synaptophysin. This correlated with electrophysiological maturity as presented by excitatory postsynaptic potentials (EPSPs). The findings indicate that the cat may constitute a promising biomedical model for evaluation of novel therapies such as stem cell therapy in such neurological disorders as Alzheimer's disease and stroke. PMID- 22824625 TI - Relevance of vitamin D in reproduction. AB - The steroid hormone vitamin D is historically recognized for its relevance to bone health and calcium homeostasis. Recent years have witnessed a shift in focus to non-skeletal benefits of vitamin D; in this latter context, an accruing body of literature attests to a relevance of vitamin D to reproductive physiology. This article reviews the existing data about the diverse and previously underappreciated roles for vitamin D in reproductive health. A large body of available literature suggests that vitamin D deficiency may be detrimental to reproductive biology. However, given that our appreciation of vitamin D's role in reproductive physiology is almost entirely shaped by 'associative' studies and that data based on prospective interventional trials are limited, these concepts remain predominantly conjectural. Exact mechanisms whereby vitamin D may participate in the regulation of reproductive physiology remain far from clear. This review underscores a need for appropriately designed intervention trials to address the existing knowledge gaps and to delineate the specific roles of vitamin D signaling in reproductive biology. PMID- 22824627 TI - Performance of the integrated management of childhood illness algorithm for diagnosis of HIV-1 infection among African infants. AB - OBJECTIVES: Early infant HIV-1 diagnosis and treatment substantially improve survival. Where virologic HIV-1 testing is unavailable, integrated management of childhood illness (IMCI) clinical algorithms may be used for infant HIV-1 screening. We evaluated the performance of the 2008 WHO IMCI HIV algorithm in a cohort of HIV-exposed Kenyan infants. METHODS: From 1999 to 2003, 444 infants had monthly clinical assessments and quarterly virologic HIV-1 testing. Using archived clinical data, IMCI sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using virologic testing as a gold standard. Linear regression and survival analyses were used to determine the effect of age on IMCI performance and timing of diagnosis. RESULTS: Overall IMCI sensitivity, specificity, PPV, and NPV value were 58, 87, 52, and 90%, respectively. Sensitivity (1.4%) and PPV (14%) were lowest at 1 month of age, when 81% of HIV infections already had occurred. Sensitivity increased with age (P < 0.0001), but remained low throughout infancy (range 1.4-35%). Specificity (range 97-100%) was high at each time point and was not associated with age. Fifty-eight percent of HIV-1-infected infants (50 of 86) were eventually diagnosed by IMCI, and use of IMCI was estimated to delay diagnosis in HIV-infected infants by a median of 5.9 months (P < 0.0001). CONCLUSION: IMCI had low sensitivity during the first month of life, when the majority of HIV-1 infections had already occurred and initiation of treatment is most critical. Although sensitivity increased with age, the substantial delay in HIV-1 diagnosis using IMCI limits its utility in early infant HIV-1 diagnosis. PMID- 22824628 TI - Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice. AB - OBJECTIVES: Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. DESIGN: Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. METHODS: NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. RESULTS: NanoART treatments by once-a week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. CONCLUSION: Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people. PMID- 22824629 TI - Chronic immune activation and decreased CD4 cell counts associated with hepatitis C infection in HIV-1 natural viral suppressors. AB - We have established a cohort of natural viral suppressors (NVS) who can suppress HIV-1 replication to less than 400 copies/ml in the absence of therapy (similar to Elite Controllers/Elite Suppressors). Of the 59 patients currently in the NVS cohort, 45.8% have chronic hepatitis C virus (HCV) infection, thereby presenting a unique opportunity to study immune activation and the interaction between HCV and HIV. NVS with chronic HCV infection had elevated levels of immune activation (CD38-positive HLA-DR-positive CD8 cells) compared to NVS without chronic HCV (P = 0.004). The increased levels of immune activation were not associated with sex, HLA B57 status, or injection drug use use. NVS patients with chronic HCV had lower mean CD4 cell counts, CD4 percentage, and CD4/CD8 ratios than NVS without chronic HCV infection (P = 0.038, P = 0.008, and P = 0.048, respectively). The difference in CD4 cell count appeared to occur early in HIV infection with no difference observed in CD4 slopes between groups. Among all NVS, there was a direct correlation between mean CD4 cell count, mean CD4 percentage, and mean CD4/CD8 ratio with percentage of CD38 HLA-DR CD8 cells (P = 0.0018; P = 0.0069; and P = 0.0014, respectively). This study suggests a relationship between HCV infection, immune activation, and CD4 cell counts in the NVS, with chronic HCV infection associated with lower CD4 cell counts and higher levels of immune activation. Further studies are needed to determine if successful HCV treatment lowers immune activation levels and/or increases CD4 cell counts in these patients. PMID- 22824632 TI - Salivary basic proline-rich proteins are elevated in HIV-exposed seronegative men who have sex with men. AB - OBJECTIVE: Innate mucosal factors are associated with protection in HIV-exposed seronegative (HESN) individuals, but studies of MSM have been very limited. We performed proteomic analysis of saliva from a cohort of HESN MSM who have regular unprotected oral receptive intercourse with their HIV-infected partner. METHODS: Saliva samples from HESN (n = 25) and non-exposed male controls (n = 22) were analyzed by 2D-LC mass spectrometry. An overexpressed innate protein factor was further characterized by immunoblot, and compared with CC-chemokine expression, HIV-neutralizing activity, clinical factors, and sexual behavior. RESULTS: Of 337 total proteins, seven were identified as differentially abundant in the HESN group. The five overabundant proteins (Basic salivary proline-rich proteins (bPRP) 2 and 3, Histatin-3, Lysozyme C, and SLPI) have known antimicrobial activity. bPRP2 showed the highest overabundance (>six-fold) in HESN individuals compared with controls (P = 0.009), including multiple isoforms. Salivary bPRP2 correlated with CC-chemokine levels in HESN individuals including RANTES (P = 0.02), MIP-1-alpha (P = 0.01), MIP-1-beta (P = 0.0002), MCP-1 (P = 0.005) and Eotaxin (P = 0.003) but not with frequency of HIV neutralizing activity, oral sexual practices, or viral load of the sexual partner. CONCLUSION: This study identifies salivary bPRP2 as a novel soluble factor elevated in the oral compartment of HIV-exposed MSM. PMID- 22824631 TI - A feasibility analysis of implementing interventions for discordant couples in 14 African countries: implications for epidemic control. AB - We find interventions targeting serodiscordant couples (SDC) may not be feasible in countries where HIV prevalence is less than 5%, because only 3-19/1000 individuals are HIV-positive/negative and in SDC. Interventions may be feasible in countries where prevalence is greater than 10%, because 34-48/1000 individuals are HIV-positive/negative and in SDC. We calculated that 20-27% of all HIV positive individuals, but less than 6% of all HIV-negative individuals, are in SDC. Consequently, targeting HIV-positive partners could significantly reduce transmission, whereas targeting HIV-negative partners may have little impact. PMID- 22824630 TI - Risk factors for chronic kidney disease in a large cohort of HIV-1 infected individuals initiating antiretroviral therapy in routine care. AB - OBJECTIVE: To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART. METHODS: Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes. RESULTS: Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10 099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from -2.18 to -1.37 ml/min per 1.73 m per year; P = 0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30 ml/min per 1.73 m was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60 ml/min per 1.73 m: 3.35 (95% confidence interval (CI) = 1.40-8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type. CONCLUSION: ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI. PMID- 22824636 TI - Strategies for multivariate modeling of moisture content in freeze-dried mannitol containing products by near-infrared spectroscopy. AB - Accurate determination of residual moisture content of a freeze-dried (FD) pharmaceutical product is critical for prediction of its quality. Near-infrared (NIR) spectroscopy is a fast and non-invasive method routinely used for quantification of moisture. However, several physicochemical properties of the FD product may interfere with absorption bands related to the water content. A commonly used stabilizer and bulking agent in FD known for variation in physicochemical properties, is mannitol. To minimize this physicochemical interference, different approaches for multivariate correlation between NIR spectra of a FD product containing mannitol and the corresponding moisture content measured by Karl Fischer (KF) titration have been investigated. A novel method, MIPCR (Main and Interactions of Individual Principal Components Regression), was found to have significantly increased predictive ability of moisture content compared to a traditional PLS approach. The philosophy behind the MIPCR is that the interference from a variety of particle and morphology attributes has interactive effects on the water related absorption bands. The transformation of original wavelength variables to orthogonal scores gives a new set of variables (scores) without covariance structure, and the possibility of inclusion of interaction terms in the further modeling. The residual moisture content of the FD product investigated is in the range from 0.7% to 2.6%. The mean errors of cross validated prediction of models developed in the investigated NIR regions were reduced from a range of 24.1-27.6% for traditional PLS method to 15.7-20.5% for the MIPCR method. Improved model quality by application of MIPCR, without the need for inclusion of a large number of calibration samples, might increase the use of NIR in early phase product development, where availability of calibration samples is often limited. PMID- 22824637 TI - Workshop on physiotherapy for adults with neuromuscular diseases held at the MRC Centre for Neuromuscular Diseases, Queen Square, London, UK on 28th March 2011. PMID- 22824635 TI - Identification of in vivo and in vitro metabolites of triptolide by liquid chromatography-tandem mass spectrometry. AB - Triptolide, a major active constituent of Tripterygium wilfordii Hook F, has multiple pharmacological activities. In this work, a rapid, sensitive and specific liquid chromatography coupled to an ion trap mass spectrometer (MS) with electrospray ionization (ESI) interface has been developed for identification of triptolide and some of its metabolites in rat urine after oral administration of a single dose (0.6 mg/kg) of triptolide to healthy rats, as well as some metabolites in vitro after incubation with rat liver microsome (RLM) and rat intestinal flora, respectively. All samples were separated on a reversed-phase C18 column using a mobile phase of acetonitrile/water (70:30, v/v) and detected by an on-line MS(n) detector. Identification and structural elucidation of the selected metabolites were performed by comparing their full scan MS(n) spectra with those of the parent drug. In this paper we identified ten metabolites in rat urine, four metabolites in RLM incubation solution and one metabolite in rat intestinal flora incubation solution, after drug administration. The metabolic reactions of triptolide that we observed in vivo were hydrolysis reaction, hydroxylation reaction, and the conjugate reaction with sulfate, glucuronide and GSH, respectively. The in vitro metabolic reactions of triptolide observed were hydrolysis and hydroxylation reactions. PMID- 22824633 TI - Hospitalization trends, costs, and risk factors in HIV-infected children on antiretroviral therapy. AB - OBJECTIVE: To assess hospitalization trends in HIV-infected children on antiretroviral therapy (ART) in Thailand, an important indicator of morbidity, ART effectiveness, and health service utilization. DESIGN: Prospective observational cohort METHOD: Children initiating ART in 1999-2009 were followed in 40 public hospitals. Hospitalization rate per 100 person-years were calculated from ART initiation to last follow-up/death. Costs to the healthcare provider were calculated using WHO inpatient estimates for Thailand. Zero-inflated Poisson models were used to examine risk factors for early (<12 months of ART) and late hospitalization (>=12 months) and frequency of admissions. RESULTS: A total of 578 children initiated ART, median follow-up being 64 months [interquartile range (IQR) 43-82]; 211 (37%) children were hospitalized with 451 admissions. Hospitalization rates declined from 63 per 100 person-years at less than 6 months to approximately 10 per 100 person-years after 2 years of ART, and costs fell from $35 per patient-month to under $5, respectively. Age less than 2 years, US Centers of Disease Control and Prevention stage B/C, and stunting at ART initiation were associated with early hospitalization. Among those hospitalized, baseline CD4 cell percentage less than 5%, wasting, initiation on dual therapy, late calendar year, and female sex were associated with higher incidence of early admissions (P <0.02). There were no predictors of late hospitalization, although previous hospitalization in less than 12 months of ART was associated with three times higher incidence of late admissions (P < 0.0001). CONCLUSION: One in three children required hospitalization after ART. Admissions were highest in the first year of therapy and rapidly declined thereafter. Young age, advanced disease stage, and stunting at baseline were predictive of early hospitalization. Treatment initiation before disease progression would likely reduce hospitalization and alleviate demands on healthcare services. PMID- 22824639 TI - Bone health in boys with Duchenne Muscular Dystrophy on long-term daily deflazacort therapy. AB - Quality of life in Duchenne Muscular Dystrophy (DMD) has improved significantly with corticosteroid treatment. However, corticosteroids decrease bone mass and increase vertebral fragility fracture risk. We report on bone health in 39 boys with DMD on long-term deflazacort (0.9 mg/kg/day) therapy. Bone health was defined by lumbar (L(1)-L(4)) bone mineral density (BMD), long-bone and/or symptomatic vertebral fractures. Lumbar BMD was reported as height-adjusted Z scores at initiation of deflazacort (T(0)) and 1-2 year intervals thereafter. Subcapital body fat percentage and ambulatory status were recorded. At T(0), 39 boys, aged 6.6 +/- 1.6 years had height-adjusted BMD Z-score -0.5 +/- 0.8, and 23.5 +/- 5.0% body fat. Height-adjusted Z-scores remained stable with years of deflazacort until loss of ambulation and accrual of body fat. Nine long-bone fractures occurred in eight ambulating boys, two before T(0). Seven vertebral fractures occurred in six non-ambulatory boys after >= 5 years of deflazacort with height-adjusted Z-score -1.8 +/- 0.7, and 47.8 +/- 12% body fat. Bone health in DMD is influenced by disease progression, corticosteroids, BMD Z-scores and fat mass accumulation. Adjustments for short stature must be considered during BMD interpretation. Percent body fat and ambulatory status are useful bone health indicators. Routine use of height adjusted Z-scores is advocated for use in routine clinical practice. PMID- 22824638 TI - Brown-Vialetto-van Laere and Fazio-Londe overlap syndromes: a clinical, biochemical and genetic study. AB - Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17 years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10 years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8 months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease. PMID- 22824640 TI - Yeast as a model system for studying lipid homeostasis and function. AB - Lipids are essential eukaryotic cellular constituents. Lipid metabolism has a strong impact on cell physiology, and despite good progress in this area, many important basic questions remain unanswered concerning the functional diversity of lipid species and on the mechanisms that cells employ to sense and adjust their lipid composition. Combining convenient experimental tractability, a large degree of conservation of metabolic pathways with other eukaryotes and the relative simplicity of its genome, proteome and lipidome, yeast represents the most advantageous model organism for studying lipid homeostasis and function. In this review we will focus on the importance of yeast as a model organism and some of the innovative advantages for the lipid research field. PMID- 22824641 TI - Interaction behaviors at the interface between liquid Al-Si and solid Ti-6Al-4V in ultrasonic-assisted brazing in air. AB - Power ultrasonic vibration (20 kHz, 6 MUm) was applied to assist the interaction between a liquid Al-Si alloy and solid Ti-6Al-4V substrate in air. The interaction behaviors, including breakage of the oxide film on the Ti-6Al-4V surface, chemical dissolution of solid Ti-6Al-4V, and interfacial chemical reactions, were investigated. Experimental results showed that numerous 2-20 MUm diameter-sized pits formed on the Ti-6Al-4V surface. Propagation of ultrasonic waves in the liquid Al-Si alloy resulted in ultrasonic cavitation. When this cavitation occurred at or near the liquid/solid interface, many complex effects were generated at the small zones during the bubble implosion, including micro jets, hot spots, and acoustic streaming. The breakage behavior of oxide films on the solid Ti-6Al-4V substrate, excessive chemical dissolution of solid Ti-6Al-4V into liquid Al-Si, abnormal interfacial chemical reactions at the interface, and phase transformation between the intermetallic compounds could be wholly ascribed to these ultrasonic effects. An effective bond between Al-Si and Ti-6Al-4V can be produced by ultrasonic-assisted brazing in air. PMID- 22824642 TI - HIV-1 CRF01_AE coreceptor usage prediction using kernel methods based logistic model trees. AB - The determination of HIV-1 coreceptor usage plays a major role in HIV treatment. Since Maraviroc has been used in a treatment for patients those exclusively harbor R5-tropic strains, the efficient performance of classifying HIV-1 coreceptor usage can help choose the most advantaged HIV treatment. In general, HIV-1 variants are classified as R5-tropic and X4-tropic or dual/mixed tropic based on their coreceptor usages. The classification of the coreceptor usage has been developed by using the various computational methods or genotypic algorithms based on V3 amino acid sequences. Most genotypic tools have been designed based on a data set of the HIV-1 subtype B that seemed to be reliable only for this subtype. However, the performance of these tools decreases in non-B subtypes. In this study, the support vector machine (SVM) method has been used to classify the HIV-1 coreceptor. To develop an efficient SVM classifier, we present a feature selector using the logistic model tree (LMT) method to select the most relevant positions from the V3 amino acid sequences. Our approach achieves as high as 97.8% accuracy, 97.7% specificity, and 97.9% sensitivity measured by ten-fold cross-validation on 273 sequences. PMID- 22824644 TI - Evaluating cognitive outcome measures for MS clinical trials: what is a clinically meaningful change? AB - Brief cognitive assessments are increasingly emphasized in MS treatment studies and clinical care. While much is known about the reliability of several widely used neuropsychological tests, interpretation of the changes in individual patients is inadequate. The FDA offers guidance on the issue, as related to patient-reported outcomes. Unfortunately, cognitive ability is only weakly correlated with the frequency and severity of self-reported cognitive problems. In this review, we critically examined the psychometrics of neuropsychological testing in MS, emphasizing statistical and anchor-based approaches to interpreting clinically meaningful change. We suggest that there are two paths forward that should be currently pursued. First, to employ co-primary outcomes, including a brief cognitive test and a clinician or observer's impression on a scale of change, where successful treatment would require showing significant improvement in both measures. Secondly, to work toward showing that when reliable brief cognitive tests are employed, increments of statistically-relevant change would correlate with changes in clinically-relevant anchors (such as vocational disability or clinical relapses with cognitive impairment). The latter goal will allow a more parsimonious and scientifically efficient approach of utilizing only the brief cognitive test as a primary outcome. While some progress has been made in this direction, more research is needed. We are of the opinion that data from both the statistical and clinically meaningful approaches will be necessary to develop valid definitions of meaningful change on cognitive outcome measures, and that it would be best to pursue research using tests that already have well established reliability and validity. PMID- 22824643 TI - Brain regions and genes affecting myoclonus in animals. AB - Myoclonus is defined as large-amplitude rhythmic movements. Brain regions underlying myoclonic jerks include brainstem, cerebellum, and cortex. Gamma aminobutyric acid (GABA) appears to be the main neurotransmitter involved in myoclonus, possibly interacting with biogenic amines, opiates, acetylcholine, and glycine. Myoclonic jumping is a specific subtype seen in rodents, comprising rearing and hopping continuously against a wall. Myoclonic jumping can be seen in normal mouse strains, possibly as a result of simply being put inside a cage. Like other types, it is also triggered by changes in GABA, 5HT, and dopamine neurotransmission. Implicated brain regions include hippocampus and dorsal striatum, possibly with respect to D(1) dopamine, NMDA, and delta opioid receptors. There is reason to suspect that myoclonic jumping is underreported due to insufficient observations into mouse cages. PMID- 22824645 TI - [Correlation of optical coherence tomography with retinal histology]. PMID- 22824646 TI - [Design of computerised database for clinical and basic management of uveal melanoma]. AB - PURPOSE: The uveal melanoma is the most common primary intraocular tumour in adults. The objective of this work is to show how a computerised database has been formed with specific applications, for clinical and research use, to an extensive group of patients diagnosed with uveal melanoma. METHOD: For the design of the database a selection of categories, attributes and values was created based on the classifications and parameters given by various authors of articles which have had great relevance in the field of uveal melanoma in recent years. RESULTS: The database has over 250 patient entries with specific information on their clinical history, diagnosis, treatment and progress. It enables us to search any parameter of the entry and make quick and simple statistical studies of them. CONCLUSION: The database models have been transformed into a basic tool for clinical practice, as they are an efficient way of storing, compiling and selective searching of information. When creating a database it is very important to define a common strategy and the use of a standard language. PMID- 22824647 TI - [Automated detection of microaneurysms by using region growing and Fuzzy Artmap neural network]. AB - OBJECTIVE: To assess whether the methodological changes of this new algorithm improves the results of a previously presented strategy. METHODS: We enhance the image and filter out the green channel of the digital color retinography. Multitolerance thresholding was applied to obtain candidate points and make a seed growing region by varying intensities. We took 15 characteristics from each region to train a Fuzzy Artmap neural network using 42 retinal photographs. This network was then applied in the study of 11 good quality retinal photographs included in the diabetic retinopathy early detection screening program, with initial stages of retinopathy, obtained with the Topcon NW200 non-mydriatic retinal camera. RESULTS: Two experienced ophthalmologists detected 52 microaneurysms in 11 images. The algorithm detected 39 microaneurysms and 3,752 more regions, confirming 38 microaneurysm and 135 false positives. The sensitivity is improved compared to the previous algorithm, from 60.53 to 73.08%. False positives have dropped from 41.8 to 12.27 per image. CONCLUSIONS: The new algorithm is better than the previous one, but there is still room for improvement, especially in the initial determination of seeds. PMID- 22824648 TI - [Corneal toxicity due to amantadine]. AB - CASE REPORT: A 64 year-old female with Parkinson disease treated with amantadine for two years who suddenly suffered bilateral corneal oedema. It was initially treated as herpetic endotheliitis without improvement as we lacked information on her chronic treatment. The corneal oedema finally resolved after withdrawing the drug. DISCUSSION: Amantadine hydrochloride may produce endothelial dysfunction. Once the amantadine treatment is stopped, the corneal oedema may be reversible but endothelial density remains low. An ophthalmologist examination should be performed before the initiation of amantadine treatment in order to establish a risk: benefit ratio, especially in those patients with low endothelial density or any endothelial anomaly. PMID- 22824649 TI - [Technique for removing donor sclera by eyeball extrusion]. AB - PURPOSE: To describe a surgery technique for removing donor sclera tissue after corneo-scleral button excision. RESULTS: The extrusion technique is easy to perform. It allows the complete scleral extraction its total clean up to be performed, as well as making easier to isolate the retina and uveal tissue. This technique could have an important role in the anatomical and morphological study of ocular structures. PMID- 22824650 TI - [Neovascular membrane and pregnancy. Treatment with bevacizumab]. AB - CLINICAL CASE: Female in her sixth month of pregnancy, with a history of refractive surgery, who consulted due to a metamorphopsia and decrease in visual acuity in the right eye. A presumed ocular histoplasmosis syndrome (POHS) and a subfoveal choroidal neovascular membrane were observed in the fundoscopy. Two monthly doses of intravitreal bevacizumab were given after the labour, but the third dose was never inyected as the patient became pregnant again. She subsequently had a spontaneous miscarriage. DISCUSSION: Treatment with intravitreal bevacizumab during pregnancy is controversial as it may increase the risk of miscarriage during the first trimester. PMID- 22824651 TI - [The eyesight of Peter Paul Rubens]. PMID- 22824652 TI - [Eye diseases in the works of Pieter Bruegel the Elder (III). Bruegel's syndrome]. PMID- 22824653 TI - Evolutionary history of linked D4Z4 and Beta satellite clusters at the FSHD locus (4q35). AB - We performed a detailed genomic investigation of the chimpanzee locus syntenic to human chromosome 4q35.2, associated to the facioscapulohumeral dystrophy. Two contigs of approximately 150 kb and 200 kb were derived from PTR chromosomes 4q35 and 3p12, respectively: both regions showed a very similar sequence organization, including D4Z4 and Beta satellite linked clusters. Starting from these findings, we derived a hypothetical evolutionary history of human 4q35, 10q26 and 3p12 chromosome regions focusing on the D4Z4-Beta satellite linked organization. The D4Z4 unit showed an open reading frame (DUX4) at both PTR 4q35 and 3p12 regions; furthermore some subregions of the Beta satellite unit showed a high degree of conservation between chimpanzee and humans. In conclusion, this paper provides evidence that at the 4q subtelomere the linkage between D4Z4 and Beta satellite arrays is a feature that appeared late during evolution and is conserved between chimpanzee and humans. PMID- 22824654 TI - Glutathione S-transferase (GST) genes in the red flour beetle, Tribolium castaneum, and comparative analysis with five additional insects. AB - Glutathione S-transferases are important detoxification enzymes involved in insecticide resistance. Sequencing the Tribolium castaneum genome provides an opportunity to investigate the structure, function, and evolution of GSTs on a genome-wide scale. Thirty-six putative cytosolic GSTs and 5 microsomal GSTs have been identified in T. castaneum. Furthermore, 40, 35, 13, 23, and 32 GSTs have been discovered the other insects, Drosophila, Anopheles, Apis, Bombyx, and Acyrthosiphon, respectively. Phylogenetic analyses reveal that insect-specific GSTs, Epsilon and Delta, are the largest species-specific expanded GSTs. In T. castaneum, most GSTs are tandemly arranged in three chromosomes. Particularly, Epsilon GSTs have an inverted long-fragment duplication in the genome. Other four widely distributed classes are highly conserved in all species. Given that GSTs specially expanded in Tribolium castaneum, these genes might help to resist poisonous chemical environments and produce resistance to kinds of different insecticides. PMID- 22824655 TI - Gastrocnemius transcriptome analysis reveals domestication induced gene expression changes between wild and domestic chickens. AB - Artificial selection of chicken for human-preferred traits has manifested great phenotypic differences between wild and domestic chickens. Study on the formation of these phenotypic variations will contribute to comprehensive understanding of the molecular mechanism of animal domestication. We used three kinds of chicken breeds for transcriptome analysis, including the red jungle fowl which was the wild ancestor of chickens, and two other domestic breeds, the chahua chicken and the avian broiler. More than 12,000 genes' expression levels were compared between different chicken breeds, and hundreds of genes displayed differential expression levels compared with wild chicken. Gene ontology analysis showed that differentially expressed genes in domestic chickens tended to be enriched in extracellular matrix, DNA binding and immune system development, etc. Some genes with important biological functions were differentially expressed in the domestic chickens, including titin, myostatin ubiquitin related genes, and transforming growth factor-beta receptor III, indicating possible selection pressures on these genes. PMID- 22824657 TI - The diversity of Staphylococcus aureus among paediatric populations with a high prevalence of HIV infection. PMID- 22824656 TI - Chromatin state and microRNA determine different gene expression dynamics responsive to TNF stimulation. AB - Gene expression is a dynamic process, and what factors influence gene expression changes upon external stimulus have not been clearly understood. We studied gene expression profiles in human umbilical vein endothelial cells (HUVEC) after the Tumor Necrosis Factor (TNF) stimulus, and found that: the promoters of fast response up-regulated genes were enriched with several "active" chromatin markers like H3K27ac and H3K4me3, and also preferentially bound by Pol II and c-Myc; the core-promoter regions of slow-response up-regulated genes were frequently occupied by nucleosomes; down-regulated genes were more intensively regulated by microRNAs. Moreover, the Gene Ontology and motif analysis of the promoter regions revealed that gene clusters with different response behaviors had different functions and were regulated by different sets of transcription factors. Our observations suggested that the different gene expression patterns upon external stimulus were regulated by a combination of multi-layer regulators. PMID- 22824658 TI - Worldwide molecular epidemiology of norovirus infection. AB - Norovirus (NoV) is recognised as one of the emerging viruses causing infection in humans. It is the leading cause of outbreaks of viral gastro-enteritis worldwide. In children, NoV plays an increasing and important role in enteric infection, apart from rotavirus, especially in the post-rotavirus vaccine era. NoV-infected children usually present with typical clinical manifestations of acute viral gastro-enteritis, including vomiting and watery diarrhoea, and paediatric patients are more liable to have dehydration requiring hospitalisation. Other than these symptoms, severe or atypical complications associated with NoV infection include infantile convulsion, necrotising enterocolitis, and, rarely, disseminated disease involving multiple organs. Although most symptoms of NoV infection are self-limiting, recurrent infection is not uncommon in children as well as in the elderly. The rapid evolution and complex genetic diversity of NoV makes for difficulty in identification, classification and surveillance of the virus. Using molecular biological methods, clearer genetic and molecular features of the circulating NoV are now recognised. The emerging GII.4 genotype is currently responsible for 60-90% of outbreaks worldwide. Rapid transmission of NoV from person-to-person makes the infection difficult to control. In addition to personal hygiene such as hand-washing, prevention of NoV will depend largely on the development of an effective vaccine. Given the rapid evolution of the virus, continued molecular epidemiological surveillance is important. PMID- 22824659 TI - Association of indoor air pollution with acute lower respiratory tract infections in children under 5 years of age. AB - BACKGROUND: Indoor air pollution is an important risk factor for acute lower respiratory tract infections (ALRTI) in developing countries. AIM: To determine the relationship of indoor air pollution with ALRTI in children under 5 years of age. METHODS: A prospective, case-control study of risk factors, particularly indoor air pollution, for developing ALRTI in children under 5 years of age was conducted in Udupi District Hospital. The WHO definition of ALRTI was used. Healthy children attending immunisation services were enrolled as controls. Data pertaining to important factors causing indoor air pollution such as cooking fuel other than liquid petroleum gas (LPG) and passive smoking were collected along with potential socio-demographic factors and nutrition in both groups and analysed. RESULTS: A total of 202 children including 101 cases and 101 controls were studied. The proportions of infants (1-12 months) among cases and controls were 62.4% and 71.3%, respectively. Of those with ALRTI, 24.8% had pneumonia, 45.5% had severe pneumonia and 29.7% had very severe disease. Exposure to passive smoking was not associated with ALRTI. Cooking fuel other than LPG was significantly associated with ALRTI (OR 26.3, 95% CI 10.5-65.7). On logistic regression analysis of multiple risk factors, cooking fuel other than LPG emerged as a significant risk factor for developing ALRTI (adjusted OR 4.73, 95% CI 1.67 13.45) along with poor socio-economic status (adjusted OR 3.38, 95% CI 1.63 7.03). Other than LPG, the main fuels used were wood (95%), kerosene and dung and crop residues. CONCLUSION: Indoor air pollution caused by using cooking fuel other than LPG and socio-economic factors are significantly associated with ALRTI. PMID- 22824660 TI - Response to hepatitis A and B vaccination in patients with chronic hepatitis C: 8 year follow-up. AB - BACKGROUND: In patients with chronic hepatitis C (CHC), superinfection with hepatitis A (HAV) or B (HAB) viruses is associated with increased morbidity and mortality. The seroconversion rate of these patients following vaccination is considered to be lower than in healthy subjects. AIM: To evaluate the response to HAV and HBV vaccination in children with CHC. METHODS: Thirty patients with CHC aged from 7.3 to 18 years were compared with 50 healthy age-, gender- and body mass-index-matched controls. Post-vaccination serological evaluation was performed 1 month after the last dose of primary vaccination, 1 month after the booster dose and once a year during follow-up. RESULTS: Twenty-two patients received hepatitis A vaccine and response rate was 95.4%. Thirty patients received hepatitis B vaccine and 80% responded (hepatitis Bs titres >=10 mIU/ml). Thirty-five controls received hepatitis A vaccine and protective anti-HAV antibodies developed in all. All of the controls were vaccinated against hepatitis B virus and 90% responded. After the whole vaccination series, overall seroprotection rates were 86% in patients and 96% in controls. No significant reduction in antibody response was observed in patients or controls during 8 years follow-up. CONCLUSIONS: The rate of seroconversion to the HBV vaccine is lower in patients with CHC than in healthy controls but response to HAV is adequate. PMID- 22824661 TI - Community-onset Staphylococcus aureus bacteraemia in hospitalised African children: high incidence in HIV-infected children and high prevalence of multidrug resistance. AB - BACKGROUND: Invasive bacterial disease causes significant morbidity and mortality in children in developing countries. The burden of invasive disease caused by Staphylococcus aureus and S. aureus antimicrobial resistance patterns in African children in settings with a high prevalence of HIV infection remain ill-defined. AIMS AND OBJECTIVES: To describe the burden of community-onset bacteraemic S. aureus infections in children in an area with a high prevalence of paediatric HIV infection, and to describe the antimicrobial resistance patterns. METHODS: A retrospective record review of children hospitalised at Chris Hani Baragwanath Hospital, Soweto, with S. aureus bacteraemia between January 2005 and December 2006 was conducted. Community-onset S. aureus bloodstream infections were defined as S. aureus cultured from blood obtained within 48 hours of admission. RESULTS: Community-onset S. aureus bacteraemia was identified in 161 children, representing an incidence of 26/100,000, with 63 (39%) isolates identified as methicillin-resistant (10/100,000). The incidence of community-onset S. aureus bacteraemia, both methicillin-susceptible and methicillin-resistant, was inversely related to age and greater in HIV-infected than uninfected children. High rates of antibiotic resistance were observed in MRSA isolates and only resistance to amikacin, fusidic acid and ciprofloxacin was <40%. MRSA isolates were frequently multidrug-resistant. Among HIV-infected children, resistance to trimethoprim-sulfamethoxazole was 100% and to rifampicin was 78%. CONCLUSIONS: This study highlights the burden of S. aureus bacteraemia in a setting with a high prevalence of paediatric HIV infection. The high incidence of S. aureus bacteraemia coupled with a high prevalence of methicillin resistance, particularly in HIV-infected children, needs to be considered in the empirical management of paediatric sepsis in settings such as ours. PMID- 22824662 TI - Thymic involution as a predictor of early-onset neonatal sepsis. AB - BACKGROUND: Diagnosis of early-onset neonatal sepsis (EONS) is often difficult because of vague clinical signs and non-specific laboratory parameters. OBJECTIVE: To assess the statistical validity of thymic size estimation as a diagnostic marker of EONS compared with cord blood interleukin-6 (IL-6) concentrations. SUBJECTS AND METHODS: Thirty-two neonates delivered in hospital and admitted to the neonatal unit with EONS comprised the study group. EONS was diagnosed on the basis of development of clinical signs and symptoms of sepsis within 72 hours of birth in the presence of antenatal risk factors for chorio amnionitis and a positive blood culture. Thirty-two gestational age- and gender matched healthy neonates served as controls. Cord blood IL-6 concentrations were estimated by ELISA. Thymic size was assessed by sonological measurement of thymic dimensions (longitudinal and transverse diameters, thymic volume and thymic index) within 24 hours of birth in the study infants and the controls. Data were analyzed by SPSS 16.0. RESULTS: Thymic size was significantly smaller whereas cord blood IL-6 concentrations were significantly higher (P<0.001) in the sepsis group than in the controls. Sensitivity and specificity of thymic dimensions were comparable to IL-6 concentrations for diagnosing EONS. Significant correlation was noted between reduction in thymic size and a rise in IL-6 concentrations. CONCLUSION: Thymic involution can be used as a reliable diagnostic marker for EONS. PMID- 22824663 TI - Plasmodium vivax malaria admissions and risk of mortality in a tertiary-care children's hospital in North India. AB - BACKGROUND: In 2010, there was an increase in the severity of malaria admissions to Kalawati Saran Children's Hospital, New Delhi and this report describes the morbidity and mortality profile. METHOD: A retrospective chart review of patients admitted with parasitologically confirmed malaria between January and December 2010. RESULTS: There were 156 cases: P. vivax 105 (67.3%), P. falciparum 39 (25%) and mixed infections 12 (7.7%). Thrombocytopenia (platelet count <150*10(9)/L) was present in 90 (85.7%) patients with P. vivax mono-infection. There were 91 (58.3%) patients with severe malaria: P. vivax mono-infection 46 (50.5%), P. falciparum mono-infection 35 (38.5%) and mixed 10 (11%). Severe anaemia and severe thrombocytopenia (platelet count <20*10(9)/L) were detected significantly more often in P. falciparum and P. vivax mono-infection, respectively. Complications including cerebral malaria, acute renal failure, shock, acute respiratory distress syndrome (ARDS) and multiple-organ dysfunction syndrome (MODS) were similar in both groups. The mortality rate of around 20% was similar in severe P. vivax and P. falciparum mono-infection. Risk of mortality in vivax malaria was highest in patients with ARDS followed by MODS and shock. CONCLUSION: Increased morbidity owing to P. vivax malaria was observed and risk of mortality was highest in patients with ARDS and MODS. PMID- 22824664 TI - Caustic soda poisoning in Ghana--an alarming increase. AB - BACKGROUND: In 2010, there was a sudden increase in the number of children admitted to Okomfo Anokye Teaching Hospital, Kumasi with caustic soda poisoning. AIM: To quantify the increase and identify possible causes. METHODS: Detailed review of case-notes of all children admitted with poisoning from January 2009 to June 2010 was undertaken using a standardised proforma. RESULTS: From January to June 2010, there was a six-fold increase in the number of children admitted with caustic soda poisoning compared with January to June 2009 (13 vs 2). Owing to the increase in caustic soda ingestion, there were almost twice the number of cases of chemically-induced poisoning in January-June 2010 (34) as in January-June 2009 (19 cases). In the entire period (January 2009 to June 2010), the majority of admissions for chemical poisoning were children <=3 years of age and 50 of the 72 (69.4%) cases were boys. In six of the 13 cases in the January-June 2010 period, caustic soda was drunk directly from a plastic water bottle. All children with caustic soda poisoning had been given palm oil to drink by their guardians. CONCLUSION: It is suggested that the recent introduction of bottled water is an important element in the increase of caustic soda poisoning. Previously, water was sold in plastic bags. The plastic water bottles are re-used to store caustic soda which children then drink, mistaking it for water. PMID- 22824665 TI - Acute glomerulonephritis in dengue haemorrhagic fever in the absence of shock, sepsis, haemolysis or rhabdomyolysis. AB - Renal damage in dengue haemorrhagic fever (DHF) has been reported in association with shock, haemolysis, rhabdomyolysis and sepsis. This report describes acute glomerulonephritis with DHF without the above-mentioned complications. A 3-year old boy presented with fever, vomiting and oliguria. He had hypertension, deranged renal function and low serum complement (C3), and urine microscopy showed red blood cells and granular casts. The IgM and IgG ELISA (rapid test) for dengue virus were positive. He was managed with maintenance fluids, intravenous furosemide and supportive care. He made an uneventful recovery and was discharged 7 days after admission. PMID- 22824666 TI - Peripheral gangrene in an 18-month-old boy with Plasmodium vivax malaria. AB - An 18-month-old boy presented with a high-grade fever, generalised petechiae and rapidly progressive, blackish discolouration of the fingers of the hands for the past 3 days. At presentation, he was haemodynamically stable. There were gangrenous changes in the index and middle fingers of both hands. Plasmodium vivax was demonstrated in the peripheral blood smear but there was no evidence of disseminated intravascular coagulopathy. The platelet count fell to 10*10(9)/L. Bone marrow aspiration to rule out leukaemia demonstrated schizonts of P. vivax with some atypical lymphocytes. The fingers recovered completely. As far as we are aware, this is the first report of peripheral gangrene associated with P. vivax malaria. PMID- 22824667 TI - Dural sinus thrombosis owing to polycythaemia vera in a 12-year-old girl. AB - Because of the rarity of dural sinus thrombosis in children with polycythaemia vera (PV), the options for diagnosis and treatment remain elusive. A 12-year-old girl was admitted with dural sinus thrombosis associated with PV, diagnosed by magnetic resonance venography. She was managed with interventional endovascular thrombolectomy and venoplasty, phlebotomy, hydroxyurea, low molecular weight heparin, and aspirin followed by warfarin. She made a good recovery without residual neurological deficit. This case highlights the importance of diagnosis and appropriate intervention with multi-modality treatments in patients with PV and thrombosis. PMID- 22824668 TI - Cervical intramedullary conglomerate tuberculomas with tuberculous meningitis- rapid response to medical therapy. AB - Common manifestations of tuberculosis of the central nervous system are tuberculous meningitis and intracranial tuberculomas. Cervical intramedullary tuberculomas are very rare in immunocompetent children. An unusual presentation of tuberculous meningitis with hydrocephalus and conglomerate cervical intramedullary tuberculomas in a 4-year-old boy is reported. PMID- 22824669 TI - Acute transverse myelitis: an unusual complication of typhoid fever. AB - Typhoid fever is associated with a wide spectrum of neurological complications. Acute transverse myelitis is a rare complication with only a few reports in adults and none in children. A 15-year-old boy with typhoid fever is reported who developed acute transverse myelitis in the 3rd week of illness. He was treated with antibiotics and corticosteroids and made a complete recovery. PMID- 22824670 TI - Trimethoprim-sulfamethoxazole treatment for meningitis owing to multidrug resistant Elizabethkingia meningoseptica in an extremely low-birthweight, premature infant. AB - Elizabethkingia meningoseptica is a recognised cause of meningitis in premature neonates and severe infections in immunocompromised adults; multi-drug resistance is a major issue. A premature infant developed sepsis, meningitis and hydrocephalus owing to E. meningoseptica and was treated successfully with trimethoprim-sulfamethoxazole (TMP-SMZ) for 3 weeks. A ventriculoperitoneal shunt was required for hydrocephalus. This is the youngest patient with meningitis caused by E. meningoseptica to have responded to TMP-SMZ. PMID- 22824671 TI - Bilateral giant-sized symmetrical pulmonary hydatid cysts in an 8-year-old girl. AB - An 8-year-old girl presented with a low-grade fever and cough for 4 weeks and minimal physical findings. Chest radiograph demonstrated two giant hydatid cysts occupying two-thirds of each lung and another two cysts in the liver were detected by ultrasonography. The cysts were resected from both lungs and the liver under albendazole cover. She made a complete recovery. PMID- 22824672 TI - A novel leprechaunism mutation, Cys807Arg, in an Arab infant: a rare cause of hypoglycaemia. AB - Leprechaunism is a rare autosomal recessive disorder which is usually fatal in early infancy or childhood. There is a paucity of genetic data on leprechaunism in the Arab population. A 4-month-old boy presented with jaundice, asymptomatic hypoglycaemia and growth retardation with features of leprechaunism. A novel Cys807Arg was identified, which could facilitate antenatal diagnosis for families in the Middle East. PMID- 22824674 TI - Kilogram-scale synthesis of iron oxy-hydroxides with improved arsenic removal capacity: study of Fe(II) oxidation--precipitation parameters. AB - Various iron oxy-hydroxides were synthesized in a continuous flow kilogram-scale production reactor through the precipitation of FeSO(4) and FeCl(2) in the pH range 3-12 under intense oxidative conditions to serve as arsenic adsorbents. The selection of the optimum adsorbent and the corresponding conditions of the synthesis was based not only on its maximum As(III) and As(V) adsorption capacity but also on its potential efficiency to achieve the arsenic health regulation limit in NSF challenge water. As a result, the adsorbent prepared at pH 4, which consists of schwertmannite, was selected because it exhibited the highest adsorption capacity of 13 MUg As(V)/mg, while maintaining a residual arsenic concentration of 10 MUg/L at an equilibrium pH 7. The high surface charge and the activation of an ion-exchange mechanism between SO(4)(2-) adsorbed in the Stern layer and arsenate ions were found to significantly contribute to the increased adsorption capacity. Adsorption capacity values observed in rapid scale column experiments illustrate the improved efficiency of the qualified adsorbent compared to the common commercial arsenic adsorbents. PMID- 22824673 TI - A thymidylate synthase ternary complex-specific antibody, FTS, permits functional monitoring of fluoropyrimidines dosing. AB - 5-Fluorouracil (5FU) and similar fluoropyrimidines induce covalent modification of thymidylate synthase (TS) and inhibit its activity. They are often used to treat solid cancers, but drug resistance and toxicity are drawbacks. Therefore, there is an unmet need for a functional assay to quantify fluorouracil activity in tissues, so as to individually tailor dosing. It is cumbersome to separately quantify unmodified and 5FU-modified TS using currently available commercial anti TS antibodies because they recognize both forms. We report here the first monoclonal antibody (FTS) specific to 5FU-modified TS. By immunoblot assay, the FTS antibody specifically recognizes modified TS in a dose-dependent manner in 5FU-treated cells, in cancer xenograft tissues of 5FU-treated mice, and in the murine tissues. In the same assay, the antibody is nonreactive with unmodified TS in untreated or treated cells and tissues. Speculatively, a high-throughput assay could be enabled by pairing anti-TS antibodies of two specificities, one recognizing only modified TS and another recognizing both forms, to structurally quantify the TS-inhibiting effect of fluorouracil at a cellular or tissue level without requiring prior protein separation. Such a development might aid preclinical analytic studies or make practical the individual tailoring of dosing. PMID- 22824675 TI - Measurement of cyanobacteria using in-vivo fluoroscopy -- effect of cyanobacterial species, pigments, and colonies. AB - The effect of instrument calibration range, algal growth phase, chlorophyll-a and turbidity interference and colony size, on the measurement of phycocyanin by in vivo fluoroscopy (IVF) was investigated. The cyanobacterial species Microcystis aeruginosa PCC 7820, Anabaena circinalis and Planktothricoides raciborskii were used to investigate variation in phycocyanin content in the different cyanobacteria and growth phases. The green alga, Chodatella sp., and Kaolin particles were used as the sources of chlorophyll-a and turbidity respectively to determine how these factors can impact on phycocyanin measurements. Another cyanobacterium, M. aeruginosa PCC 7005, which forms large colonies, was used to investigate the relationships between colony size and phycocyanin concentration measured using IVF. Results showed that chlorophyll-a, turbidity, and the colonial status of the cyanobacteria significantly interfered with the measurement of phycocyanin fluorescence. Models were developed to compensate for the effect of chlorophyll-a, turbidity and colony size on the measurement. The models were successfully used to correct phycocyanin probe data collected from several reservoirs in Taiwan to establish good correlation between measurements made using the phycocyanin probe and microscopic cell counts. PMID- 22824676 TI - What triggers the continuous muscle activity during upright standing? AB - The ankle extensors play a dominant role in controlling the equilibrium during bipedal quiet standing. Their primary role is to resist the gravity toppling torque that pulls the body forward. The purpose of this study was to investigate whether the continuous muscle activity of the anti-gravity muscles during standing is triggered by the joint torque requirement for opposing the gravity toppling torque, rather than by the vertical load on the lower limbs. Healthy adults subjects stood on a force plate. The ankle torque, ankle angle, and electromyograms from the right lower leg muscles were measured. A ground-fixed support device was used to support the subject at his/her knees, without changing the posture from the free standing one. During the supported condition, which eliminates the ankle torque requirement while maintaining both the vertical load on the lower limbs and the natural upright standing posture, the plantarflexor activity was attenuated to the resting level. Also, this attenuated plantarflexor activity was found only in one side when the ipsilateral leg was supported. Our results suggest that the vertical load on the lower limb is not determinant for inducing the continuous muscle activity in the anti-gravity muscles, but that it depends on the required joint torque to oppose the gravity toppling torque. PMID- 22824677 TI - Impact of pre-operative regular physical activity on balance control compensation after vestibular schwannoma surgery. AB - Vestibular compensation after unilateral vestibular deafferentation is modulated by certain individual characteristics, such as pre-operative visual neurosensory preference or vestibular pattern. Physical activity (PA) allows the implementation of new sensorimotor and behavioral strategies leading to an improvement of balance control. This study aimed to evaluate the effect of the level of PA before surgery on balance compensatory mechanisms in patients after vestibular schwannoma (VS) surgery. Thirty patients with VS, 15 considered as regularly physically active and 15 as sedentary participated in this study, including an evaluation of gaze control by videonystagmography and postural control by a sensory organization test. Patients considered as physically active before surgery presented the best pattern of postural compensation, with the classical decrease in postural performances at short term (i.e. eight days) and the increase in postural performances at middle and long terms (i.e. 90 and 180 days, respectively) after surgery. For the sedentary patients, the consequences of surgery were more difficult to manage at short term, even though this did not prevent the ability to compensate well later on. Pre-operative practice of PA promotes the neuroplasticity of neural networks involved in motor learning, which allows to benefit of physical therapy more rapidly and efficiently. PMID- 22824678 TI - Quantification of the postural and technical errors in asymptomatic adults using direct 3D whole body scan measurements of standing posture. AB - Measurement repeatability has important decision-making implications for clinicians and researchers when assessing individuals. The aims of this study were to quantify: (a) the repeatability of direct measurements of standing posture using three dimensional (3D) whole body scanning, and (b) the magnitude of the postural and technical errors involved. Fifty-two asymptomatic adults were scanned twice, 24h apart, using the Vitus Smart 3D whole body scanner. Eleven clinically relevant standing postural measurements were calculated from scan extracted data. The process was repeated with 10 shop mannequins. Systematic error was expressed as absolute changes in means and as standardised effect sizes, with random (within-subject) error expressed as the typical error. Technical error was calculated as the typical error in the measurement of mannequins; total error as the typical error in the measurement of subjects; and postural error as the square root of the difference between the squared total error and the squared technical error. Most standing postural measurements demonstrated good repeatability, with median (95% CI) systematic and random errors of -0.1 degrees (1.1 degrees ) and 2.8 degrees (1.9 degrees ), respectively. However, head and neck postures demonstrated poor repeatability due to large random errors brought about by large postural errors. Overall, most of the error was due to postural error rather than technical error. The relatively small technical errors highlight that this 3D measurement process is generally repeatable, while the relatively large postural errors related to the head and neck suggest that these postures probably lack the precision to be clinically useful using this procedure. PMID- 22824679 TI - Standing body sway in women with and without morning sickness in pregnancy. AB - Morning sickness typically is attributed to hormonal changes in pregnancy. We asked whether morning sickness is associated with changes in standing postural equilibrium, as occurs in research on visually induced motion sickness. Twenty one pregnant women (mean age=30 years, mean height=163cm; mean weight=63kg) were tested during the first trimester. Laboratory-based balance measures were collected, along with perceived postural stability, the presence of morning sickness, and the severity of subjective symptoms. We varied the distance between the feet and the visual task performed during stance. Participants were classified as either experiencing (Sick, n=12) or not experiencing (Well, n=9) morning sickness. Perceived balance stability was lower for Sick than for Well women. The positional variability of sway was reduced for the Sick group, relative to the Well group. Positional variability decreased with wider stance width, and was reduced during performance of a more demanding visual task. Stance width and visual task also influenced the temporal dynamics of sway. Effects of stance width and visual task on postural sway were similar to effects in non pregnant adults, suggesting that sensitive tuning of posture is maintained during the first trimester. The findings suggest that women with morning sickness may attempt to stabilize their bodies by reducing overall body sway. It may be useful to recommend that women adopt wider stance early in pregnancy. PMID- 22824680 TI - Gait speed and gender effects on center of pressure progression during normal walking. AB - The COP progression is the trajectory of the center of foot pressure. Thirty healthy young adults were recruited to participate in this study. All subjects were asked to walk randomly at four different speeds (3km/h, preferred walking speed, 4km/h and 5km/h). A foot pressure measurement system (RS-scan((r)) system) was used to collect the center of pressure (COP) coordinates, COP progression angle and the COP velocity. Four sub-phases of the stance phase were calculated. The initial contact (ICP) and forefoot contact phase (FFCP) corresponded to the loading response. The foot flat phase (FFP) coincided with the mid-stance. The forefoot push-off phase (FFPOP) corresponded to the terminal stance and pre-swing phases. The results of this study indicate that the percentage of time (% time) of COP progression on the ICP, FFCP, FFP and FFPOP were approximately 7.0%, 4.8%, 48.8% and 39.4%, respectively. The COP progression angle was 4.1 (SD=1.6) degrees with an inward curve and the average COP velocity was 31.6cm/s (SD=5.3). The walking speed influenced the % time in the FFP and FFPOP. As the walking speed increased, the % time of COP progression decreased in mid-stance and increased in the terminal and pre-swing stances. Moreover, gender affected the COP progression angle. Men had a significantly larger deviating angle than women during FFCP, FFP and FFPOP. The COP characteristics can offer useful information for clinical rehabilitation in foot functional and structural evaluation. PMID- 22824681 TI - Endoscopic management of trapped fourth ventricle using the posterior fossa route. PMID- 22824682 TI - The endoscopic trans-fourth ventricle aqueductoplasty and stent placement for the treatment of trapped fourth ventricle: long-term results in a series of 18 consecutive patients. AB - BACKGROUND: Different surgical approaches have been described in the past to treat a trapped fourth ventricle (TFV) but, unfortunately, these techniques showed a high rate of dysfunction and complications. During the last 10 years the development of neuroendoscopy has dramatically changed the outcome of these patients. MATERIALS AND METHODS: We conducted a retrospective evaluation of the safety, effectiveness, and long-term outcome of endoscopic aqueductoplasty and stent placement, performed in 18 consecutive patients with symptomatic TFV through a trans-fourth ventricle approach between 1994 and 2010. Thirteen patients underwent endoscopic aqueductoplasty and stent placement and 5 patients underwent aqueductoplasty alone using a tailored suboccipital approach through the foramen of Magendie in prone or sitting position. RESULTS: The mean age of the patients at the time of surgery was 15.2 years. All patients but 3 had a supratentorial ventriculoperitoneal shunt. Fifteen patients presented with slit supratentorial ventricles. At a mean followup of 90.8 months all patients experienced a stable clinical improvement. Only two complications were observed: A transient diplopia due to dysconjugate eye movements in one patient and a transient trochlear palsy in another one. CONCLUSIONS: Our experience and the literature review suggest that endoscopic trans-fourth ventricle aqueductoplasty and stent placement is a minimally invasive, safe, and effective technique for the treatment of TFV and should be strongly recommended, especially in patients with supratentorial slit ventricles. PMID- 22824683 TI - Stent-assisted coil embolization of intracranial aneurysms using Solitaire stent. AB - OBJECTIVE: To report patients with intracranial wide-necked or complex aneurysms who underwent Solitaire stent-assisted coil embolization. MATERIALS AND METHODS: Retrospective analysis of 28 patients with intracranial wide-necked or complex aneurysms. Eighteen of the patients presented with an acute subarachnoid hemorrhage. Thirty-one aneurysms were treated with the support of different applications (n = 32) of the Solitaire AB stents followed by the standard coiling procedure (n = 30). RESULTS: Successful positioning of the remodeling device was obtained in all the cases. One stent required repositioning after full deployment. There were four thromboembolic complications (12.5%) and two hemorrhagic complications (6.25%), which caused three deaths. No permanent procedural morbidity was observed in the surviving patient. Angiographic results included 26 complete occlusions (83.9%), three neck remnants (9.7%) and two incomplete occlusions (6.4%). CONCLUSION: Although the initial technical and clinical results of Solitaire stent-assisted coiling of aneurysms was reported to be encouraging in recent reports, we had encountered higher thromboembolic and hemorrhagic complications in our patients. PMID- 22824684 TI - Impact of Hunt-Hess grade on the glycemic status of aneurysmal subarachnoid hemorrhage patients. AB - OBJECTIVE: This study has explored the impact of Hunt-Hess (H-H) grade of aneurysmal subarachnoid hemorrhage (aSAH) on the glycemic status of such patients during their intensive care unit (ICU) stay and has also analyzed whether H-H grade predicts their outcome independent of their glycemic status. MATERIALS AND METHODS: This was a retrospective case record review of prospectively maintained database of 1090 previously non-diabetic aSAH patients admitted to Thomas Jefferson University Hospital, Philadelphia. H-H grade of SAH, serum and CSF glucose on admission, serum glucose on the day of surgery and 14 days post surgery, as well as the extended Glasgow Outcome Score (GOS-E score) at discharge were noted. After univariate analysis, significant variables (P < 0.05) were entered into a logistic regression model to identify significant associations with admission H-H grade. RESULTS: Although admission serum glucose was significantly higher for H-H grades 4-5 than grades 1-3 (P < 0.001); after postoperative day 4, the difference between the H-H grades got blurred. Admission CSF glucose was also significantly higher for H-H grades 3-4 than for grades 1-3 and 5 (P < 0.001). H-H grades 4-5 were related with higher incidences of both hypoglycemia (serum glucose level < 80 mg/dl) and hyperglycemia (serum glucose level > 200 mg/dl) (P < 0.001) during the 14-day period of ICU stay. Also, the relationship between serum and CSF glucose levels at admission increased with HH grades 1 through 4, but became negative and more tightly bound at H-H grade 5. Admission H-H grades 4-5 contributed to poor outcome compared to lower H-H grades (P < 0.0001). CONCLUSION: Poor admission H-H grades lead to poor immediate glycemic status as well as poor short-term outcome, and it is dependent on serum glucose but independent of CSF glucose in predicting the outcome. PMID- 22824685 TI - Trends in clinical features and early outcome in patients with acute cardioembolic stroke subtype over a 19-year period. AB - OBJECTIVES: To assess changing trends in clinical characteristics and early outcome of patients with acute cardioembolic stroke (ACS) over a 19-year period. MATERIALS AND METHODS: Data of 575 patients with first-ever ACS included in the Sagrat Cor Hospital of Barcelona Stroke Registry were analyzed. Changing trends for 1986-1992, 1993-1998, and 1999-2004 periods were compared. RESULTS: A statistically significant increase (P < 0.001) in the age of patients (74.6 years in 1986-1992 vs. 81.4 years in 1999-2004) and the percentage of patients older than 85 years of age (16% vs. 38.2%) was observed. Patients with hypertension increased from 40.5 to 60.8% (P = 0.001) as were patients with diabetes, chronic bronchitis, and obesity (P = NS). The median length of hospital stay decreased from 18 to 12 days (P = 0.031) and prolonged hospital stay (>12 days) from 18.3 to 13.1 (P = 0.033). In-hospital death rate remained around 20%. CONCLUSIONS: ACS continues to be a severe ischemic stroke subtype with high risk of in-hospital death. The lack of improvement in the early prognosis over a 19-year period may be explained by an increase in the prevalence of major cardiovascular risk factors and progressive aging of the population. PMID- 22824686 TI - Spinal muscular atrophy: clinical spectrum and genetic mutations in Pakistani children. AB - BACKGROUND: In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. MATERIALS AND METHODS: This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. RESULTS: During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. CONCLUSION: SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan. PMID- 22824687 TI - Accuracy of computed tomography angiography in detecting the underlying vascular abnormalities for spontaneous intracerebral hemorrhage: a comparative study and meta-analysis. AB - BACKGROUND: Computed tomography angiography (CTA) is a rapid, non-invasive procedure with a small risk for evaluating patients with various types of strokes. But the effectiveness of CTA in detecting the etiology of spontaneous intracerebral hemorrhage (SICH) has not been well established. AIM: To evaluate the diagnostic value of CTA for detecting underlying vascular abnormalities in patients with SICH. SETTINGS AND DESIGN: This is a comparative study to evaluate the diagnostic accuracy of CTA and digital subtraction angiography (DSA) in SICH. We also did a meta-analysis, combining our results with those of all previous studies to determine a more precise estimate of CTA in detecting the etiology of SICH.. MATERIALS AND METHODS: Between July 2009 and October 2011, CTA and DSA were routinely performed in consecutive young patients (age between 18 and 45 years) with acute non-hypertensive SICH. Imaging data were prospectively stored in the database for analysis. STATISTICAL ANALYSIS: The sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and accuracy were used for evaluating the diagnostic value of CTA for vascular lesion. RESULTS: This study included 92 patients. The sensitivity, specificity, PPV, NPV, and accuracy of CTA for detecting DSA-positive pathologies were 94.6%, 100%, 100%, 96.5%, and 97.8%, respectively. A total of 544 cases were included for meta analysis. The pooled sensitivity, specificity, PPV, NPV, and accuracy of CTA for detecting the etiology in SICH were 95.4%, 98.3%, 96.9%, 97.4%, and 97.2%, respectively. There was no substantial heterogeneity between the studies. CONCLUSIONS: CTA has high PPV and NPV for vascular pathologies. It should be performed as the initial vascular investigation for patients with acute SICH. Future technical advancement of CTA is still needed to eliminate the false negative results. PMID- 22824688 TI - Coexistence of ectopic pituitary adenoma and empty sella in a patient with acromegaly : a case report and review of literature. AB - Ectopic pituitary adenoma with an empty sella is extremely rare. We report an unusual patient with an ectopic growth hormone-secreting pituitary adenoma in the sphenoid sinus with an empty sella. The association is related to a development disorder of the anterior pituitary tissues. Tumor in the sphenoid sinus was completely removed by endoscopic endonasal transsphenoidal approach. During the follow-up, the patient met the criteria for endocrinological cure. PMID- 22824689 TI - Pituitary adenoma presenting with cerebrospinal fluid rhinorrhea as the sole symptom. PMID- 22824690 TI - Pituitary adenoma and concomitant Rathke's cleft cyst: a case report and review of the literature. PMID- 22824691 TI - Growth hormone secreting pituitary adenoma associated with Rathke's cleft cyst. PMID- 22824692 TI - Combined gangliocytoma and non-functioning pituitary adenoma of the pituitary gland. PMID- 22824693 TI - Pituitary apoplexy presenting with pure third ventricular bleed: a neurosurgical image. PMID- 22824694 TI - Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses. AB - Neuronal ceroid lipofuscinosis is a group of progressive neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in neurons and other cell types. This study is a retrospective review of charts of patients with a diagnosis of infantile and late-infantile neuronal ceroid lipofuscinosis seen between January 2009 and December 2011. Of the 16 patients, 5 had infantile type and 11 had late-infantile neuronal ceroid lipofuscinosis. Diagnosis was confirmed by appropriate enzyme assay. Clinical presentation was quite varied. Common presenting features included refractory seizures, developmental delay/regression, and abnormal movements. Visual failure was not common in the present case series, and novel neuroimaging finding in the form of isolated dentate nucleus hyperintensities were noted. During follow-up, all patients had a progressive downhill course and one patient died. Prenatal diagnosis could be offered to one family. This study suggests that infantile and late-infantile neuronal ceroid lipofuscinosis is not uncommon in this region of the country and the phenotype may be different. PMID- 22824695 TI - Surgical treatment in startle epilepsy. AB - This report presents a patient with medically intractable startle epilepsy who was treated with surgery. The ictal onset zone was further localized to a part of the premotor cortex on the basis of intracranial electroencephalography recording and surgical resection of the epileptogenic zone was done. The motor area close to the epileptogenic focus was localized using electrical cortical stimulation and thus preserved. Patient has been seizure-free postoperatively (Engel Class I) during the 18-month follow-up. The patient illustrates that surgery can be an option in patients with medically intractable startle epilepsy with well-defined unilateral epileptogenic zone. PMID- 22824696 TI - Intracranial actinomycosis: varied clinical and radiologic presentations in two cases. AB - Two patients with primary actinomycotic brain infection are presented here. The first case had 2 predisposing factors, cardiac septal defect and chronic mastoiditis, whereas the second patient was a chronic smoker, belonging to a desert region. Both the patients were successfully managed with surgical debridement and prolonged administration of antibiotics. PMID- 22824697 TI - Paraplegia treated with blood transfusion. AB - Extramedullary hematopoiesis is a compensatory response in patients with thalassemia and other chronic anemia and can result in compressive myelopathy, if untreated. Two young adults with history of thalassemia presented with symptoms of spinal cord compression. Presence of extramedullary hematopoiesis was confirmed by magnetic resonance imaging. Both the patients were treated with blood hypertransfusion and showed improvement clinically and radiologically. Although there are various options in the management of such condition, including decompression surgery and radiation treatment, hypertransfusion can be very effective even in severe compression of the spinal cord. Hypertransfusion should be tried as the first line of management in patients with thalassemia presenting with compressive myelopathy to decrease the bulk of extramedullary hematopoietic tissue. PMID- 22824698 TI - Cholesterol granuloma of the sphenoid sinus: an unusual sphenoid sinus lesion. PMID- 22824699 TI - Primary spinal cord glioblastoma multiforme: a report of two cases. PMID- 22824700 TI - Supratentorial intraparenchymal schwannoma mimicking a glial tumor. PMID- 22824701 TI - Subarachnoid hemorrhage after transsphenoidal surgery for pituitary adenoma: a case report and review of literature. PMID- 22824702 TI - Spontaneous arthrodesis of atlanto-axial complex in a case of rheumatoid arthritis. PMID- 22824703 TI - Intraparenchymal pericatheter cyst following ventriculoperitoneal shunt. PMID- 22824704 TI - Idiopathic spinal cord herniation. PMID- 22824705 TI - The eyes in the scanner: latent conjugate eye deviation. PMID- 22824706 TI - Epithelioid hemangioendothelioma of sphenoid bone: a case report of an unusual case. PMID- 22824707 TI - Langerhans cell histiocytosis of the clivus: an unusual cause of a destructive central skull base mass in a child. PMID- 22824708 TI - A cervicothoracic intramedullary ganglioneuroblastoma presenting with acute quadriparesis. PMID- 22824709 TI - High cervical nondysraphic intradural extramedullary lipoma. PMID- 22824710 TI - Intracranial aneurysm revealing a HIV infection and resolving with highly active antiretroviral therapy. PMID- 22824711 TI - Kissing aneurysms of the internal carotid artery treated with surgical clipping. PMID- 22824712 TI - Glioma progression as revealed by diffusion tensor metrics. PMID- 22824713 TI - Usefulness of computed tomographic angiography in the management of extracranial scalp arteriovenous malformation. PMID- 22824714 TI - Pediatric multi vessel intracranial dolichoectasia - a rare occurrence. PMID- 22824715 TI - Multifocal Ewing's sarcoma, presenting radiologically as extradural hematoma. PMID- 22824716 TI - Acute extrapyramidal syndrome and seizures as heralding manifestation of Wilson disease. PMID- 22824717 TI - Giant chondroma of the falx. PMID- 22824718 TI - Anterior cervical osteophytes with multilevel disc prolapse causing progressive dysphagia and quadriparesis. PMID- 22824719 TI - Clinical and polysomnographic characteristics in 20 north Indian patients with narcolepsy: a seven-year experience from a neurology service. PMID- 22824720 TI - Vertex extradural hematoma. PMID- 22824721 TI - A flow cytometry based assay for the enumeration of regulatory T cells in whole blood. AB - The analysis of regulatory T cells (T-reg(s)) is becoming an increasingly important consideration in the development of novel immunotherapeutic strategies. Accurate quantification of T-regs during treatment protocols is crucial, particularly where the therapeutic strategy is targeting T-regs. The TruCOUNTTM method has utility for enumerating different immune cells but has not been used to detect T-regs. We have utilized this technology to develop an assay to enumerate human T-regs in whole blood, based on CD127 expression. The mean number of CD4(+)CD25(+)CD127(lo) T-regs per MUl of whole blood was 48+/-16.9 with a range of 18 - 79 (n=22) and the average percentage was 6.1+/-1.9% (range 2.2 10.4%). The percentages of CD4(+)CD25(+)CD127(lo) T-regs were similar when detected in whole blood or density-gradient separated PBMC, and were comparable to those distinguished using the T-reg marker FoxP3. The assay was robust and reliable for enumeration of the lower frequency T-regs, with CV's for intra-assay repeatability and inter-assay precision of <9% and <35%, respectively. The CV's for the detection of total CD4(+) T lymphocytes using this assay were <2% for intra-assay repeatability and <18% for inter-assay precision, providing further evidence for reproducibility. This assay has a number of advantages over current methods, including small sample volume, the ability to determine absolute cell counts, and no need for hematology cell analyzers. This assay will simplify clinical trial immune monitoring and can be used to provide crucial data on patient T-reg numbers before, during, and after therapeutic interventions. PMID- 22824722 TI - [Organ procurement in France: new challenges]. AB - France has reached a pretty good level of activity, comparable to southern European countries: in 2011, 4945 transplantations (TX) have been performed among them, 2976 (60%) kidney TX, 1164 (24%) liver TX, 398 (8%) heart TX and 312 (6.3%) lung TX. However, the progression has slowed down since 2008 like in many countries. The potential of donors is mainly represented by the donor after brain death (DBD) (90%), living donor (LD) for kidneys transplantation participates for only 10% of the overall kidney TX, and donor after cardiac death (DCD) activity, just started in 2006, for 2.2%. Current challenges to maximize the existing activity of DBD rely upon the implementation of program aimed to monitor deceased organ donation potential, a comprehensive approach of the regional disparities covering the steps of the detection of the potential donor, the rate of organ procurement and the refusal rate to organ donation. The profile of the donors has changed due to substantial epidemiologic shifts and a growing shortage of organs. The resource of expanded criteria donor (ECD) is widely used, mainly defined by a criteria of age. This policy is acceptable and successful under specific allocation scheme based on a donor-recipient matching. Before the TX needs of the population have been adequately met, the opportunities for improvement should be the development of DCD and LD activities, in addition to DBD activity. The extension to the DCD of the 3rd category of Maastricht is currently devised as a possible option for the future. The development of perfusion machine, available for kidney preservation and soon for the other organs is a new technical challenge that might increase the donor pool to previously discarded grafts. This superior and cost-effective method evaluated for ECD kidney preservation has also a potential of resuscitation and prediction of post-transplant outcome. To give a new launch to the TX activity as it was done in 2000, the Agency together with the professionals, has elaborated a "new action plan" for the next few years, which has been acted on April 2012 by the Minister of health. PMID- 22824723 TI - Regression of Benedikt's syndrome after single-stage removal of mesencephalic cavernoma and temporal meningioma: a case report. PMID- 22824724 TI - An automatic medication self-management and monitoring system for independently living patients. AB - This paper describes the development, prototyping, and evaluation of RMAIS (RFID based Medication Adherence Intelligence System). Previous work in this field has resulted in devices that are either costly or too complicated for general (especially elderly) patients to operate. RMAIS provides a practical and economical means for ordinary patients to easily manage their own medications, taking the right dosage of medicine at the prescribed time in a fully automatic way. The system design has the following features: (1) fully automatic operation for easy medication by using the built-in scale for dosage measurement and a motorized rotation plate to deliver the right medicine container in front of a patient, (2) various medication reminder messages for patients, and noncompliance alerts for caregivers (such as doctors, relatives or social workers who take care of the patients), and (3) incremental and economical adoption by pharmacies, patients, and insurance companies. PMID- 22824725 TI - Application of near infrared (NIR) spectroscopy for determining the thickness of articular cartilage. AB - The determination of the characteristics of articular cartilage such as thickness, stiffness and swelling, especially in the form that can facilitate real-time decisions and diagnostics is still a matter for research and development. This paper correlates near infrared spectroscopy with mechanically measured cartilage thickness to establish a fast, non-destructive, repeatable and precise protocol for determining this tissue property. Statistical correlation was conducted between the thickness of bovine cartilage specimens (n=97) and regions of their near infrared spectra. Nine regions were established along the full absorption spectrum of each sample and were correlated with the thickness using partial least squares (PLS) regression multivariate analysis. The coefficient of determination (R2) varied between 53 and 93%, with the most predictive region (R2=93.1%, p<0.0001) for cartilage thickness lying in the region (wavenumber) 5350-8850 cm-1. Our results demonstrate that the thickness of articular cartilage can be measured spectroscopically using NIR light. This protocol is potentially beneficial to clinical practice and surgical procedures in the treatment of joint disease such as osteoarthritis. PMID- 22824726 TI - Snoring sounds variability as a signature of obstructive sleep apnea. AB - Snoring sounds vary significantly within and between snorers. In this study, the variation of snoring sounds and its association with obstructive sleep apnea (OSA) are quantified. Snoring sounds of 42 snorers with different degrees of obstructive sleep apnea and 15 non-OSA snorers were analyzed. The sounds were recorded by a microphone placed over the suprasternal notch of trachea, simultaneously with polysomnography (PSG) data over the entire night. We hypothesize that snoring sounds vary significantly within a subject depending on the level of obstruction, and thus the level of airflow. We also hypothesize that this variability is associated with the severity of OSA. For each individual, we extracted snoring sound segments from the respiratory recordings, and divided them into three classes: non-apneic, hypopneic, and post-apneic using their PSG information. Several features were extracted from the snoring sound segments, and compared using a nonparametric statistical test. The results show significant shift in the median of features among the snoring sound classes (p<0.00001) of an individual. In contrast to hypopneic and post-apneic classes, the characteristics of snoring sounds did not vary significantly over time in non-apneic class. Therefore, we used the total variation norm of each subject to classify the participants as OSA and non-OSA snorers. The results showed 92.9% sensitivity, 100% specificity and 96.4% accuracy. PMID- 22824727 TI - Biomechanical consideration of total hip arthroplasty following failed fixation of femoral intertrochanteric fractures - a finite element analysis. AB - OBJECTIVE: The current study aimed to perform a biomechanical analysis of the effect and distribution of stress and strain values in the femur and its residual screw holes from the implantation of different lengths of total hip prostheses following failed dynamic hip screw (DHS) fixation of AO type A1.1 and A1.3 intertrochanteric fractures. METHODS: Medical image processing, computer-assisted engineering design, and finite element analysis were combined for the analysis and the reliability of the model confirmed by convergence testing and comparison with a physical model. Using finite element analysis, patterns of stress from implantation of total hip prostheses with different stem length were obtained. RESULTS: Stress distribution was concentrated over the third and fourth residual screw holes, especially in the models with shorter stem length. Fracture type (AO type A1.1 or A1.3) did not alter its distribution. In proximal cancellous bone, a stress-shielding effect was seen at the region of the residual fracture fragment, especially in the A1.1 fracture. In the fracture fixed with 2 cable wires, the maximum von Mises stress was in the proximal cable wire. CONCLUSION: The results suggest that an increase in the original stem length equal to the diameter of the femoral isthmus, or a distance between the most distal residual screw hole and the end of the femoral prosthesis, provide improved stress distribution. PMID- 22824728 TI - The impairment of recollection in functional amnesic states. AB - INTRODUCTION: Functional amnesia refers to various forms of amnesia, which have no direct organic brain basis. Psychological stress and trauma were etiologically linked to its development across various cultures. METHODS: We have studied several patients with functional amnesia, employing neuropsychological and neuroimaging methods. Herein we provide a review of the current understanding of the phenomenology, neuropsychology and neurobiology of functional amnesia, which we illustrate by reference to five own case descriptions and other cases presented in the literature. RESULTS: Functional amnesia is mostly of retrograde nature and presents in the form of a memory blockade or repression to recollect episodic-autobiographical events, which may cover the whole past life. Sometimes, the recollection impairment is localized to certain time epochs. In comparison to functional retrograde amnesia, functional isolated anterograde amnesia is much rarer and data on its neurobiology are scant. In patients with functional amnesia with pronounced retrograde episodic-autobiographical memory impairments, we identified changes in brain metabolism, above all reductions in the temporo frontal regions of the right hemisphere. Recently, even subtle structural changes in the white matter of the (right) frontal cortex were described in functional retrograde amnesia by other researchers. CONCLUSIONS: The disruption in recollection in functional amnesia is often accompanied by changes in personality dimensions, pertaining to cognition (self-related processing, theory of mind), autonoetic consciousness and affectivity. This suggests that functional amnesia is a multifaceted condition. We hypothesize that the recollection deficit in functional retrograde amnesia primarily reflects a desynchronization between a frontal lobe system, important for autonoetic consciousness, and a temporo amygdalar system, important for evaluation and emotions. Despite assumptions that functional amnesia can always be reversed, several cases of functional amnesia were found to follow a chronic course, suggesting a need for longitudinal prospective studies to quantify possible global cognitive deterioration over time and its neural underpinnings. PMID- 22824729 TI - Combining multidimensional liquid chromatography and MALDI-TOF-MS for the fingerprint analysis of secreted peptides from the unexplored sea anemone species Phymanthus crucifer. AB - Sea anemones are sources of biologically active proteins and peptides. However, up to date few peptidomic studies of these organisms are known; therefore most species and their peptide diversity remain unexplored. Contrasting to previous venom peptidomic works on sea anemones and other venomous animals, in the present study we combined pH gradient ion-exchange chromatography with gel filtration and reversed-phase chromatography, allowing the separation of the 1-10 kDa polypeptides from the secretion of the unexplored sea anemone Phymanthus crucifer (Cnidaria/Phymanthidae). This multidimensional chromatographic approach followed by MALDI-TOF-MS detection generated a peptide fingerprint comprising 504 different molecular mass values from acidic and basic peptides, being the largest number estimated for a sea anemone exudate. The peptide population within the 2.0 3.5 kDa mass range showed the highest frequency whereas the main biomarkers comprised acidic and basic peptides with molecular masses within 2.5-6.9 kDa, in contrast to the homogeneous group of 4-5 kDa biomarkers found in sea anemones such as B. granulifera and B. cangicum (Cnidaria/Actiniidae). Our study shows that sea anemone peptide fingerprinting can be greatly improved by including pH gradient ion-exchange chromatography into the multidimensional separation approach, complemented by MALDI-TOF-MS detection. This strategy allowed us to find the most abundant and unprecedented diversity of secreted components from a sea anemone exudate, indicating that the search for novel biologically active peptides from these organisms has much greater potential than previously predicted. PMID- 22824731 TI - Identification and dynamic analysis of the purine alkaloids in rat plasma after oral administration of green tea by liquid chromatography hybrid ion trap time-of flight mass spectrometry. AB - A liquid chromatography hybrid ion trap time-of-flight mass spectrometric (LC-IT TOF-MS) method was developed and validated for identification and simultaneous determination of the potential bioactive components from green tea in rat plasma. The plasma samples were extracted by liquid-liquid extraction with ethyl acetate and separated on Shim-pack XR-ODS II column by a gradient elution within a runtime of 8.0 min. The mobile phase consisted of A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) at a flow rate of 0.4 ml/min. Two prototype components and one metabolite were successfully identified as caffeine, theobromine and theophylline according to their retention times, accurate molecule weight, and major fragment ions. Then they were determined with the addition of two internal standards, hypoxanthine and paracetamol. The linear range was 10-10,000 ng/ml for caffeine, 2.0-2000 ng/ml for theobromine and 1.0 1000 ng/ml for theophylline, respectively. Intra-day and inter-day precision were within 6.0% and 10.9%, and accuracy was less than 4.8% and 6.5%, respectively. The validated method was successfully applied to investigate the dynamic change rules of caffeine, theobromine and theophylline in rat plasma after oral administration of caffeine, theobromine and green tea extract. The comparative analysis of the pharmacokinetic parameters indicated that there were obvious differences between green tea extract administration and single substances administration. PMID- 22824730 TI - Development and validation of a RP-HPLC method with fluorescence detection for simultaneous determination of 10-methoxycamptothecin and its metabolite 10 hydroxycamptothecin in rat plasma. AB - Both 10-methoxycamptothecin (MCPT) and 10-hydroxycamptothecin (HCPT) are the natural bioactive derivatives of camptothecin (CPT) isolated from Camptotheca acuminata, and have been confirmed to possess high anti-cancer properties. In the present study, HCPT was identified as the major metabolite of MCPT in rat plasma through HPLC/photodiode array detection (PDA) and LC-MS/MS analysis. A sensitive and reliable RP-HPLC method with fluorescence detection was developed and validated for the simultaneous analysis of MCPT and HCPT in rat plasma. The parental CPT was used as an internal standard (IS). A piecewise linear function was used over lower and higher concentrations, respectively. The calibration curves were linear (r2 > 0.999) over concentrations from 1.25 to 20 ng/mL and 20 to 320 ng/mL for both MCPT and HCPT. The method had an accuracy of 92.24-113.90%, and the intra- and inter-day precision (RSD%) were 10.05% or less for MCPT and HCPT. The stability data showed no significant degradation occurred under the experimental conditions. The mean recoveries at concentrations of 2.5, 40 and 160 ng/mL were 95.09+/-3.94%, 98.67+/-1.40% and 95.65+/-2.15% for MCPT and 84.06+/ 4.39%, 84.85+/-3.10% and 81.03+/-4.44% for HCPT, respectively. The lower limit of quantification (LLOQ) using 0.1 mL of plasma was 1.25 ng/mL for both MCPT and HCPT. This method was successfully applied to the pharmacokinetic study of MCPT and its metabolite HCPT in rat plasma after intravenous administration. PMID- 22824732 TI - Effects of a sublethal pesticide exposure on locomotor behavior: a video-tracking analysis in larval amphibians. AB - Organochlorine pesticides such as endosulfan have been shown to have both lethal and sublethal effects on amphibians. In this context, behavioral endpoints have proved their usefulness in evidencing impacts of such chemicals at environmental concentrations that do not necessarily cause mortality. The recent development of video-tracking technologies now offers the possibility of accurately quantifying locomotor behaviors. However, these techniques have not yet been applied to evaluating the toxicity of pesticides in amphibians. We therefore aimed at determining the potential toxicity of endosulfan on endpoints associated with locomotion after short-term environmental endosulfan exposure in Rana temporaria tadpoles and at using these data as warning systems for survival alterations after a longer exposure. To this end, we analyzed video-tracks of 64 tadpoles (two pesticide treatments: 5 and 50 MUg L(-1), one control and one solvent control) with Ethovision XT 7 software. The highest endosulfan concentration had a significant effect on all four behavioral endpoints. Contaminated tadpoles traveled shorter distances, swam less often, at a lower mean speed, and occupied a less peripherical position than control tadpoles. The lowest endosulfan concentration had similar but lower effects, and did not affect mean speed during swimming. Survival was reduced only after a long-term exposure to endosulfan and was associated with short-term behavioral dysfunctions. These results show that endosulfan strongly affects the behavioral repertory of amphibian tadpoles, but in different ways depending on concentration, thus suggesting that the pesticide has complex modes of action. Given the importance of locomotion and space use in tadpole success in their aquatic environment, these results confirm the toxic action of endosulfan. By highlighting effects before mortality markers, video tracking systems also show their potential as sentinels of sublethal effects of pesticides. PMID- 22824733 TI - Swimming velocity, avoidance behavior and biomarkers in Palaemon serratus exposed to fenitrothion. AB - The aim of this study was to develop two behavioral tests (swimming velocity and avoidance behavior) specific for the common prawn, Palaemon serratus, and to investigate the effects of sublethal concentrations of fenitrothion on behavior and on several biomarkers. In a first bioassay, mortality was investigated in prawns exposed during 96 h to concentrations of fenitrothion ranging from 39 to 40000 ng L(-1). The effects on swimming velocity and biomarkers were determined in prawns exposed to the sub-lethal concentrations of fenitrothion (from 39 to 625 ng L(-1)). A specific newly bioassay was developed to assess the capability of prawns to avoid the toxicant (avoidance test). Finally, in order to determine the effects on biomarkers during the avoidance test, prawns were collected at different times of exposure (30, 60, 90 and 120 min). Results showed that prawns exposed to the sub-lethal concentrations of fenitrothion exhibited a significant inhibition of swimming velocity with a LOEC of 313 ng L(-1). A significant inhibition of both eye AChE (LOEC=78 ng L(-1)) and muscle ChE (LOEC=156 ng L(-1)) activities were also observed. Results from the avoidance test indicated that animals significantly avoided fenitrothion (78 ng L(-1)). However, this capability was not observed in prawns exposed to 156 ng L(-1) fenitrothion. Prawns exposed to fenitrothion showed alterations in enzymes involved in the production of energy (LDH and IDH) possibly in an attempt to cope with additional energetic demands. Impairment of locomotion and avoidance may lead to alterations at the population level. Thus, the present behavioral tests can be useful as ecologically relevant tools for ecological risk assessment. PMID- 22824734 TI - Phytotoxicity of branched cyclohexanes found in the volatile fraction of diesel fuel on germination of selected grass species. AB - During a larger study to screen candidate plant species for phytoremediation of diesel fuel-contaminated soils, it was observed that at relatively low levels of diesel fuel contamination, delayed shoot/root emergence and reduced germination was observed for the majority of plant species investigated. It was theorised that these effects were the result of acute phytotoxicity, caused by the volatile fraction of diesel fuel, with results supporting this theory. This finding was investigated further in the current study. Headspace analysis of diesel fuel showed that between 5% and 10% of diesel fuel consisted of compounds that would volatilise at 20 degrees C, with the most predominant compounds identified being the isomers of xylene (m-, o- and p-), n-alkanes (C9-C12) and alkylbenzenes. There were also low levels of toluene, branched cyclohexanes (methyl-, to butylcyclohexane) and alkenes. Of particular interest were branched cyclohexanes as little work has previously been reported on these compounds. To explain the phytotoxic effect of the volatile fraction of diesel fuel and attribute the effect to a specific compound or group of compounds within diesel fuel, seeds were germinated in petri dishes contaminated with a number of pure branched cyclohexanes. An unusual pattern of germination was apparent, with results varying depending on grass species and the length of cyclohexane branching. Results showed ethyl- and butyl-cyclohexane had a significant effect on the germination rate of selected grass species whereas methyl- and propyl-cyclohexane had little effect. PMID- 22824735 TI - Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. AB - BACKGROUND For a number of reasons, the results of previous meta-analyses may not fully reflect the mental health status of the average woman suffering from polycystic ovary syndrome (PCOS), or the causes of this distress. Our objective was to examine emotional distress and its associated features in women with PCOS. METHODS A comprehensive meta-analysis of comparative studies reporting measures of depression, anxiety or emotional-subscales of quality of life (emoQoL) was performed. PubMed, Embase, PsychInfo and the Cochrane trial register databases were searched up to November 2011 (see Supplementary Data for PUBMED search string). Unpublished data obtained through contact with authors were also included. The standardized mean difference (SMD) of distress scores was calculated. Subgroup analyses and meta-regression analysis of methodological and PCOS-related features were performed. RESULTS Twenty-eight studies (2384 patients and 2705 control women) were included. Higher emotional distress was consistently found for women with PCOS compared with control populations [main outcomes: depression: 26 studies, SMD 0.60 (95% confidence interval (CI) 0.47 0.73), anxiety: 17 studies, SMD of 0.49 (95% CI 0.36-0.63), emoQoL: 8 studies, SMD -0.66 (95% CI -0.92 to -0.41)]. However, heterogeneity was present (I(2) 52 76%). Methodological and clinical aspects only partly explained effect size variation. CONCLUSIONS Women with PCOS exhibit significantly more emotional distress compared with women without PCOS. However, distress scores mostly remain within the normal range. The cause of emotional distress could only partly be explained by methodological or clinical features. Clinicians should be aware of the emotional aspects of PCOS, discuss these with patients and refer for appropriate support where necessary and in accordance with patient preference. PMID- 22824736 TI - Internet highs--seizures after consumption of synthetic cannabinoids purchased online. AB - BACKGROUND: Since 2004, a new wave of synthetic cannabinoids (SCs) known as "Spice drugs" has come under scrutiny because of their suspected link to neurological and psychiatric sequelae. These "herbal incense" or "potpourri blends" have gained popularity as a result of being more potent than natural cannabinoids, are not detected with current screening tests, and are easily modified by manufacturers to bypass legal restrictions. Unfortunately, cases of withdrawal phenomena, nausea, hypertension, and psychosis are now being reported in the medical literature. In addition, after reports in lay media of seizures and coma attributed to the consumption of the drug, anecdotal reports have emerged of similar findings in the medical literature. CASE DESCRIPTION: We report on a 48-year-old man who, after consuming the herbal blend, lost consciousness and suffered several episodes of seizures. Despite a complicated ICU stay, the patient recovered well with no subsequent neurological sequelae. CONCLUSIONS: The authors interpreted the history and findings consistent with the consumption of a large amount of synthetic cannabinoids leading to new-onset seizures and coma. However, at the time of admission, the lack of routine laboratory testing and treatment options delayed the diagnosis and delivery of appropriate therapy. PMID- 22824737 TI - CNS response to a second pro-inflammatory event depends on whether the primary demyelinating lesion is active or resolved. AB - Interleukin-1beta (IL-1beta) is considered to be one of the most important mediators in the pathogenesis of inflammatory diseases, particularly in neurodegenerative diseases such as multiple sclerosis (MS). MS is a chronic inflammatory disease characterized by demyelination and remyelination events, with unpredictable relapsing and remitting episodes that seldom worsen MS lesions. We proposed to study the effect of a unique component of the inflammatory process, IL-1beta, and evaluate its effect in repeated episodes, similar to the relapsing-remitting MS pathology. Using adenoviral vectors, we developed a model of focal demyelination/remyelination triggered by the chronic expression of IL-1beta. The long-term expression of IL-1beta in the striatum produced blood-brain barrier (BBB) breakdown, demyelination, microglial/macrophage activation, and neutrophil infiltration but no overt neuronal degeneration. This demyelinating process was followed by complete remyelination of the area. This simple model allows us to study demyelination and remyelination independently of the autoimmune and adaptive immune components. Re exposure to this cytokine when the first inflammatory response was still unresolved generated a lesion with decreased neuroinflammation, demyelination, axonal injury and glial response. However, a second long-term expression of IL 1beta when the first lesion was resolved could not be differentiated from the first event. In this study, we demonstrated that the response to a second inflammatory stimulus varies depending on whether the initial lesion is still active or has been resolved. Considering that anti-inflammatory treatments have shown little improvement in MS patients, studies about the behavior of specific components of the inflammatory process should be taken into account to develop new therapeutic tools. PMID- 22824738 TI - Toward biotechnological production of adipic acid and precursors from biorenewables. AB - Adipic acid is the most important commercial aliphatic dicarboxylic acid in the chemical industry and is primarily used for the production of nylon-6,6 polyamide. The current adipic acid market volume is about 2.6 million tons/y and the average annual demand growth rate forecast to stay at 3-3.5% worldwide. Hitherto, the industrial production of adipic acid is carried out by petroleum based chemo-catalytic processes from non-renewable fossil fuels. However, in the past years, efforts were made to find alternative routes for adipic acid production from renewable carbon sources by biotechnological processes. Here we review the approaches and the progress made toward bio-based production of adipic acid. PMID- 22824739 TI - Metamorphosis and animal personality: a neglected opportunity. AB - Developmental perspectives represent an underutilized area of animal personality research, in spite of their obvious importance in biology. Animals that undergo metamorphosis are particularly neglected and represent a unique in situ experimental opportunity to study how personality differences are associated with physiological, morphological, or ecological traits over development. PMID- 22824740 TI - Injection of deuterated water into the pulmonary/alveolar circulation; measurement of HDO in exhaled breath and implications to breath analysis. AB - The results of experiments are described in which a known quantity of sterile deuterated water is injected directly into the pulmonary circulation via the right internal jugular vein of several haemodialysis patients and the deuterium to hydrogen ratio, D/H, in the exhaled lung water was measured using the flowing afterglow mass spectrometry technique. The breath D/H abundance was measured in sequential breath exhalations before and after the injection, providing data that are sufficiently detailed to follow the production and loss rate of D/H in the exhaled breath. Thus, in principle, considering isotope dilution the volume of water in the lungs and pulmonary circulation can be derived. However, it is seen that the maximum abundance that the breath D/H reached was much lower than anticipated by considering the likely volume of blood/water in the pulmonary circulation and so it is deduced that either 'leakage' of the injected deuterated water rapidly occurs from the pulmonary to the systemic circulation and/or isotope exchange of deuterium with hydrogen along the bronchial tree efficiently occurs, thus reducing the D/H in the exhaled breath. This latter phenomenon has important implications to breath analysis in which it is often assumed that so called alveolar breath concentrations of metabolites reflect blood/systemic levels. Detailed consideration of the breath D/H abundances when the deuterium is equilibrated amongst the total body water, TBW, of the patients, which occurs about 40 min after injection of the deuterated water, allows the TBW of the patients to be estimated. PMID- 22824741 TI - Beyond RNAi: antiviral defense strategies in Drosophila and mosquito. AB - Virus transmission and spread by arthropods is a major economic and public health concern. The ongoing dissemination of arthropod-borne viruses by blood-feeding insects is an important incentive to study antiviral immunity in these animals. RNA interference is a major mechanism for antiviral defense in insects, including the fruit fly Drosophila melanogaster and several vector mosquitoes. However, recent data suggest that the evolutionary conserved Toll, Imd and Jak-Stat signaling pathways also contribute to antiviral immunity. Moreover, symbionts, such as the intracellular bacterium Wolbachia and the gut microflora, influence the course of virus infection in insects. These results add an additional level of complexity to antiviral immunity, but also provide novel opportunities to control the spread of arboviruses. In this review, we provide an overview of the current knowledge and recent developments in antiviral immunity in Dipteran insects, with a focus on non-RNAi mediated inducible responses. PMID- 22824742 TI - Analysis of gene expression in penicillin G induced persistence of Chlamydia pneumoniae. AB - Chlamydia pneumoniae is responsible for respiratory tract infections and has been associated to chronic diseases such as atherosclerosis. The involvement of C. pneumoniae in chronic diseases may be correlated to its ability to induce persistent forms in which Chlamydiae remain viable but are not cultivable. The aim of our study is to investigate C. pneumoniae specific gene activities associated with the development of Chlamydial persistence in a cell culture system in the presence of penicillin G. Chlamydia-infected HEp 2 cells were incubated with or without penicillin G for up to 72 hours. The relative mRNA expression levels of early and late genes in treated and untreated cell cultures were determined by Real-time RT-PCR. Our results revealed a consistent down regulation of Chlamydial hctA and hctB genes (p=0.012 and p=0.003 respectively) in association with up-regulation of htrA gene (p=0.002) during penicillin G induced persistence suggesting these gene sets as leading candidate for in vivo investigation of the development of persistent Chlamydial infection. In conclusion, the Chlamydial expression pattern of hctA, hctB, and htrA genes may be helpful to identify target molecules to diagnose and treat Chlamydia associated chronic diseases. PMID- 22824743 TI - New insights into the pathogenesis of cutaneous autoimmune disorders. AB - T helper 17 (Th17) cells are characterized by the secretion of IL-17, a proinflammatory cytokine. They represent a newly described T helper subpopulation that is distinct from Th1 and Th2 lineages. Because of their pleiotropic activity on fibroblasts, keratinocytes, endothelial cells, neutrophils and memory T cells, Th17 cells are thought to be crucial in mediating tissue inflammation and autoimmunity. Autoimmune diseases were classically considered as Th1-mediated disorders such as rheumatoid arthritis or mixed Th1/Th2 diseases such as inflammatory bowel diseases, systemic lupus erythematosus, bullous diseases, but new evidence suggests the deep involvement of Th17 cells in their pathogenesis that, potentially, may address a selective therapeutic approach targeting the IL23/Th17 pathway. This review summarizes the current knowledge of the pathogenic contribution of Th17 cells in select cutaneous autoimmune disorders, including lupus erythematosus, scleroderma, dermatomyositis, bullous pemphigoid and pemphigus vulgaris. PMID- 22824744 TI - New insights on the role of T cells in the pathogenesis of celiac disease. AB - Despite intense investigation, the pathogenetic mechanisms leading to villous atrophy in Celiac disease (CD) remain not completely understood. The traditional interpretation is that CD4 cells recognize gliadin and develop an inflammatory reaction by production of Th1 cytokines at the mucosa level inducing CD8 cells to kill mucosal cells by a direct cytotoxic mechanism or by Fas-mediated apoptosis. Recent data, however, have shown that novel CD4 T-cells subpopulations, CD4+ CD25+ Regulatory T cells (Tregs) and Th17 cells also play a role in the ongoing inflammatory process. Both Tregs and Th17 cells are increased in active CD. However, because Tregs have a suppressive activity on inflammation, their role is controversial. In this editorial we discuss these recent findings and the hypothesis formulated to explain the increase of Tregs. To understand the pathogenesis of tissue damage of CD, we have focused on the duodenal micro environment, introducing the new concept of immunological niche that in CD summarizes cellular and cytokine interactions in duodenal mucosa, where a high plasticity of T-cell subsets is present. CD is often complicated by T-cell lymphomas, especially in cases of refractory CD. PMID- 22824745 TI - Immunohistochemical expression and localization of somatostatin receptors in normal prostate, high grade prostatic intraepithelial neoplasia and prostate cancer and its many faces. AB - Data on the immunohistochemical expression and localization of the five somatostatin receptors (SSTRs) have been obtained by our group in separate studies concerning the many faces of prostate cancer (PCa), its precursor high grade prostatic intraepithelial neoplasia (HGPIN) and normal epithelium (Nep). This publication highlights the key findings, with special reference to: normal prostate epithelium; untreated HGPIN and PCa, both clinically and incidentally detected; PCa with NE differentiation; HGPIN and PCa following complete androgen ablation (CAA); and hormone refractory (HR) PCa. Taken together, the data obtained in these investigations demonstrate that SSTR profiling in individual patients with HGPIN and the multifaceted PCa is feasible and is of relevance to better tailor the somatostatin analogue-based treatment. PMID- 22824746 TI - Role of mast cells in innate and adaptive immunity. AB - Mast cells play a central role in inflammatory and immediate allergic reactions and are necessary for allergic reactions. Mast cells play a role in the pathophysiology of autoimmune diseases and appear to be especially important in inflamed tissues, because they infiltrate tissues and produce a variety of cytokines. Mast cells are important for both innate and adaptive immunity in tissues that are in close contact with the environment, i.e. the skin, the airways and the lung, and the lining of the intestine. However, there are still many unsolved issues of mast cell functions, including their regulatory mechanism on cell differentiation in bone marrow; for example, the cytokines and transcription factors necessary for their differentiation and expansion, as well as the molecular mechanism underlying basophil migration from the bloodstream to peripheral tissues such as lymph nodes still need to be clarified. PMID- 22824747 TI - The antioxidant effect of fermented papaya preparation involves iron chelation. AB - Iron-overload is a major clinical problem in various diseases. Under this condition, serum iron which surpasses the binding capacity of transferrin is present as non-transferrin bound iron and cellular unbound Labile Iron Pool (LIP) is increased. LIP participates in the generation of free radicals, including reactive oxygen species (ROS). Increased ROS, with concomitant decrease in anti oxidants, results in oxidative stress and toxicity to the liver, heart and other tissues, causing serious morbidity and eventually mortality. Therapeutic iron chelation reduces the LIP and thereby ameliorates oxidative stress-mediated toxicity. Many food-derived antioxidants have the capacities to scavenge ROS and chelate iron. We have reported that fermented papaya preparation (FPP) has ROS scavenging effect on blood cells in vitro or in vivo (in thalassemic patients and experimental animals). We now investigated FPP's iron chelating effect - its ability to prevent (and revert) LIP accumulation. Liver- and heart-derived cells, and RBCs were exposed to non-transferrin bound iron in the form of ferrous ammonium sulfate and the effect of FPP on their LIP content and ROS generation was measured by flow-cytometry. The results indicate that FPP reduces LIP and ROS, and suggests that its antioxidant mechanism is related, at least in part, to iron chelation. PMID- 22824748 TI - Low frequency of CD8+CD25+FOXP3(BRIGHT) T cells and FOXP3 mRNA expression in the peripheral blood of allergic asthma patients. AB - The aim of this study is to determine whether frequencies of CD8+CD25+ T cells and FoxP3 messenger RNA (mRNA) expression levels in CD8+ T cells isolated from peripheral blood are related to allergic asthma and disease severity. We enrolled 50 patients with allergic asthma (AA) and 25 healthy control subjects (NC) in our study. The frequencies of CD8+CD25+FoxP3 -/+ T cells were assessed with flow cytometry, and mRNA FoxP3 level in CD8+ T cells was determined with real time polymerase chain reaction (RT-PCR). Asthma patients had fewer CD8+CD25+FoxP3bright T cells [SA (median = 3.4%, IQR = 3.1) vs MA (median = 7.5%, IQR = 4.7)] than controls NC [median = 12.1 %, IQR = 8, P < 0.0001] but more CD8+CD25+FoxP3- T cells [SA (median = 96 %, IQR = 3.1) vs MA (median = 92.5%, IQR = 4.7)] than controls NC [median = 87.9%, IQR = 9.2, P < 0.0001]. FoxP3 mRNA level was significantly decreased in CD8+ T cells of severe asthma patients (median = 0.82, IQR = 0.54) than that of patients with mild to moderate asthma and controls [(median = 2.29, IQR = 4.40) vs (median = 2.11, IQR = 3.2)]. The percentage of FoxP3+ T cells was correlated positively with the percentage of forced expiratory volume in 1 second (FEV1) (r = 0.71, p< 0.01) in patients with severe asthma. The proportion of CD8+CD25+FoxP3bright T cells and the level of FOXP3 gene expression in CD8+ T cells are relevant to allergic asthma and disease severity. The manipulation of FoxP3+CD25+CD8+ T cells may prevent chronic allergic inflammation and improve lung function during an acute allergic asthma exacerbation. PMID- 22824749 TI - Serum visfatin is elevated in Chinese women with polycystic ovary syndrome, but might not be a reliable predictor of their glucose intolerance. AB - Both visfatin and polycystic ovary syndrome (PCOS) were previously reported to be in relation to abnormal glucose metabolism (AGM). The hypothesis was investigated in this paper that plasma visfatin level are elevated in Chinese women with PCOS, and could substitute oral glucose tolerance test (OGTT) as a simple predictor for their glucose intolerance. This cross-sectional study enrolled 119 women (91 newly diagnosed PCOS patients and 28 eumenorrheic age- and BMI- matched controls); anthropometric, hormonal, and metabolic parameters including serum visfatin were simultaneously measured in all participants. Plasma visfatin levels were compared between controls and PCOS subjects with various glucose metabolism status diagnosed by OGTT using 75 g of glucose. Pearson correlation coefficients were calculated to determine the correlations between various parameters. Receiver Operating Characteristic (ROC) analysis was performed to examine the diagnostic test performance of visfatin. Plasma visfatin levels were found to be significantly higher in our PCOS population compared to healthy controls (P less than 0.05). An increase in fasting visfatin concentrations with a worsening degree of glucose intolerance among PCOS patients was described. However, the difference did not reach statistical significance. In addition, visfatin was unexpectedly found to correlate with neither age, anthropometric, hormonal nor metabolic parameters. As a predictor for glucose intolerance to distinguish PCOS individuals with normal or abnormal glucose metabolism, visfatin was found to possess low potentially predictive ability according to ROC curve analysis. In conclusion, serum visfatin is significantly elevated in Chinese women with PCOS, but might not be a reliable predictor of their glucose intolerance. PMID- 22824750 TI - Effect of tannin extract against Pseudomonas aeruginosa producing metallo beta lactamase. AB - Carbapenems are the most potent beta-lactam agents with a broad-spectrum activity against Gram-negative and Gram-positive bacteria. They are stable in the presence of penicillinases and cephalosporinases. This study was focused on frequency of metallo beta- lactamase (MBL) among Pesudomonas aeruginosa strains isolated in patients with urinary tract infection, effect of tannin against PA positive strains which produced blaVIM or blaIMP and both of these genes (Species). Detection of MBL was performed by phonotypic and genotypic methods. Tannin extract was tested against P. aeruginosa producing MBL. During the study period, 240 P. aeruginosa isolates were identified. Among them 64 (26.6 percent) isolates were imipenem non-susceptible and confirmed by imipenem/EDTA. Our results revealed that the growth of blaVIM positive P. aeruginosa inhibited at 15 microg/ml concentration. The experiment repeated for blaIMP-positive P. aeruginosa and P. aeruginosa which harbored blaIMP and blaVIM, the results showed 35 microg/ml was the best concentration for inhibition of P. aeruginosa-positive blaIMP and also P. aeruginosa blaIMP and blaVIM. In conclusion, tannin was effective against P. aeruginosa producing blaVIM and blaIMP and both of them so it can be substituted with common antibiotics. The result showed significantly P. aeruginosa-harbored blaIMP was more responsible for imipenem resistance than P. aeruginosa-positive blaVIM. Interestingly, tannin was more effective against MBL P. aeruginosa in comparison with current antibiotics. PMID- 22824751 TI - Palatability, digestibility and emotional pattern in 60 healthy volunteers after ingestion of an iced dessert presented in four different flavours: a subjective evaluation. AB - Several variables lead to changes in human and animal eating behaviour and food choices. A pivotal role is played by food palatability, represented by food, smell, taste, texture, appearance and temperature. The aim of our study is to assess the potential differences in palatability and digestibility of four different flavoured iced desserts, consumed at the end of a standardized meal, and their impact on the emotional status of 60 healthy volunteers. Sixty healthy volunteers, after ENT and psychological assessment, were asked to fill out a Psycho-Emotional Questionnaire (PEQ) to assess their basal emotional pattern before the consumption of an iced dessert at the end of a standard meal, after which they completed an Organoleptic-Sensory Questionnaire (OSQ), a Dynamic Digestibility Questionnaire (DDQ) and again the PEQ. Four different flavors (lemon, tangerine, pineapple and chocolate) were tested on 4 consecutive days on the same subjects. Most of the 60 subjects, by means of OSQ, found taste, aspect, texture and smell of the 4 flavours pleasant, lemon and tangerine were the freshest and lightest. The DDQ identified pineapple and chocolate dessert as those less digestible. By means of PEQ we recorded an improvement in joy, mood and activation, associated with good data of digestibility and palatability after the consumption of all flavors. Our data showed that all flavors improve joy, mood and activation, after their consumption, without statistically significant differences. However, among the tested flavours, lemon and tangerine appear to be the most pleasant and those which facilitate the digestive process. PMID- 22824752 TI - pPKCalpha-mediated effect on in vitro Abeta production in response to gamma secretase inhibitor LY411575 in rat CTXTNA2 astrocytes. AB - Alzheimer's Disease implies memory and cognitive impairment due to beta amyloid accumulation, presence of reactive microglia and astrocytes, loss of synapses, neural network dysfunctions and modifications of neuronal signalling. A key role in such events is played by astrocytes, which actively secrete high levels of beta amyloid protein originating from sequential cleavage of APP by alpha, beta and gamma secretases. Since inhibition of such process could represent an important strategy against the occurrence of Alzheimer's Disease, in this paper the role played by pPKC alpha in the in vitro beta amyloid production in response to gamma secretase inhibitor in rat cortical astrocytes is reported. pPKC alpha increased expression seems to be related to decreased beta amyloid production in parallel to increased astrocytes viability and decreased iNOS expression in the presence of 10 microM LY411575. Thus gamma secretase inhibitor, activating pPKC alpha intracellular pathway could be suggested to prevent or reduce downstream toxic events, representing a useful strategy to counteract Alzheimer's disease. PMID- 22824753 TI - Cyanidin reduces preadipocyte differentiation and relative ChREBP expression. AB - Adipogenesis is a continuous process even in adult adipose tissue for the presence of preadipocytes that, when subjected to appropriate stimuli can proliferate and differentiate. ChREBP, the essential transcription factor for lipogenesis, is expressed in all tissues, but mainly in lipogenic organs. In this study, we focused on ChREBP expression during preadipocytes differentiation. Since it was found that cyanidin-3 reduces body weight in mice even in the presence of a high-fat diet, by decreasing levels of blood glucose and by improving insulin sensitivity, we studied the effect of this substance on adipogenic differentiation. For this purpose we used preadipocytes obtained from subcutaneous and visceral human adipose explant tissue, characterized and stimulated to differentiate in selective media. On cytofluorimetric analysis these cells showed mesenchymal markers (CD29, CD90, CD44), whereas they were negative for hematopoietic markers (CD45, CD10, CD117,CD31). ChREBP expression levels were quantified by immunoelectron-microscopy and western blotting analysis. In this report we show that ChREBP is expressed in preadipocytes (both nuclear and cytoplasmic compartments); the cytoplasmic level of ChREBP increased by 50 percent on day seven of differentiation into mature adipocytes. Cyanidin reduced differentiation by 20 percent (as evaluated by red oil O staining) and the expression of ChREBP. In addition, cyanidin-treated cells showed abnormal morphology, a square shape with irregular size, probably due to the fact that cyanidin may interfere with the extracellular matrix. These findings suggest that dietary cyanidin, may have inhibitory effects on adipogenesis. PMID- 22824754 TI - REV-ERBalpha and the clock gene machinery in mouse peripheral tissues: a possible role as a synchronizing hinge. AB - Rhythmic oscillations of cellular biological processes are driven by translational-transcriptional feedback loops that realize molecular clocks ticking in every single cell, driven by neural and humoral outputs from the suprachiasmatic nuclei of the hypothalamus that are entrained by environmental photon inputs. The nuclear receptor REV-ERBalpha has the capability to reset the molecular oscillators of peripheral tissues. The aim of our study was to evaluate the clock gene machinery function in light/dark cycles (LD) and in constant darkness (DD) exploiting in particular the REV-ERBalpha pattern of expression by using data from two independent experimental settings to reduce procedure related influences. In the LD study C57BL/6 male mice housed on a 12L:12D cycle were sacrificed at 4 h intervals. Liver, kidney, spleen, thymus and testis were harvested and blood was collected. Expression levels of PER1, PER2, CRY1, CRY2, BMAL1, REV-ERBalpha, CLOCK were evaluated by qRT-PCR. In the DD study Balb/c male mice in the third DD cycle as a continuation of the dark phase of the last LD cycle were sacrificed at 4 h intervals. Lung, heart, liver, stomach, kidney, spleen, and testis were harvested and mRNA expression of PER1, PER2, CRY1, CRY2, BMAL1, REV-ERBalpha, CLOCK, was evaluated by qRT-PCR. A statistically significant difference was found for the size of the semi-interquartile range of acrophases of clock gene expression in different organs evaluated in LD and DD conditions (4:38?1:12h versus 1:16?0:10h, p=0.026). A statistically significant difference was found for the acrophases of clock gene expression in different organs evaluated in LD (p=0.01) and in DD (p<0.0001). In LD study only REV-ERBalpha showed concomitant expression in the different peripheral tissues with the phase peaking around 07:03?0.8h. In the DD study all the core clock genes showed concomitant phases in different peripheral mouse tissues and REV-ERB alpha expression peaked around 07:09?0.9h. In conclusion, REV-ERBalpha is the only clock gene that maintains its timing of oscillation in the LD study and in the DD study and its phase of expression remains concomitant in the different mouse peripheral tissues in the presence of LD alternance, or in constant darkness. Oscillation in REV-ERBalpha ligands (heme, carbon monoxide) may affect not only the phase and amplitude of circadian rhythms, but also physiological outputs of the circadian system and REV-ERBalpha may participate in the entrainment of central and peripheral clocks, functioning as a synchronizing hinge of the clock gene machinery. PMID- 22824755 TI - Is there a potential application of a fermented nutraceutical in acute respiratory illnesses? An in-vivo placebo-controlled, cross-over clinical study in different age groups of healthy subjects. AB - The role of oxidants in viral diseases is fairly complex because it includes metabolic regulation both of host metabolism and viral replication. However, a role for reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of virus-induced lung damage is supported by studies and antioxidants can thus be expected to act at many different levels. The aim of the present pilot study was to test an antioxidant nutraceutical approach on some relevant immunological parameters known to be affected in common seasonal respiratory tract infection. The study population consisted of 90 sedentary healthy patients, previously selected as being GSTM1-positive, divided into three groups: A) 20-40 years; B) 41-65 years; B) over 65 years. Each patients was administered a life style and dietary questionnaire. Subjects were supplemented for 6 weeks with either 9g/day (4.5g twice a day sublingually) of a fermented papaya preparation (Osato Research Institute, Gifu, Japan) or placebo. After a further month period of wash out, subjects were treated again in a crossover manner. Parameters checked were as follows: routine blood tests with WBC formula, saliva flow rate and secretary IgA and lysozyme production and redox gene expression of Phase II enzyme and SOD from upper airways cells (from nasal lavage). Salivary secretion rate showed an age-related decline and was significantly increased by FPP supplementation only in the youngest age-group (p less than 0.05). Subjects treated with FPP showed a significantly higher lever of IgA and lisozyme production., irrespective of age group while their baseline production was significantly lower in the oldest age-group as compared to the youngest one (C vs A, p less than 0.05). FPP treatment brought about a significant upregulation of all phase II enzyme and SOD gene expression tested in nasal lavage cells. In conclusion, FPP supplementation during 1 month resulted in higher salivary IgA and increase in phase II and SOD enzyme expression, i.e the most important antioxidant in the respiratory tract. The biological significance of these effects i.e., whether it will help reducing the whole respiratory oxidative stress in the human airway and, hopefully, the incidence and/or severity of URTI remains to be demonstrated in longer clinical trials. PMID- 22824756 TI - Effects of visfatin/PBEF/NAMPT on feeding behaviour and hypothalamic neuromodulators in the rat. AB - Visfatin, also known as pre-B cell colony enhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (NAMPT), is a cytokine that is produced by adipose tissue, skeletal muscle, liver and immune cells. We studied the effects of visfatin/PBEF/NAMPT on feeding behavior, hypothalamic steady state concentrations of aminergic neurotransmitters and hypothalamic mRNA levels of anorexigenic peptides, such as cocaine- and amphetamine-regulated transcript (CART) peptide, corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and orexigenic peptides, such as agouti-related peptide (AgRP) and neuropeptide Y (NPY). Forty eight rats were injected in the arcuate nucleus (ARC) of the hypothalamus with either saline or visfatin/PBEF/NAMPT (3 microg). Food intake was recorded 1, 2 and 24 h following injection, and either dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT) or peptide gene expression were evaluated 2 and 24 h after visfatin/PBEF/NAMPT administration. Compared to vehicle, visfatin/PBEF/NAMPT significantly increased food intake, as evaluated 1, 2 and 24 h post-injection. Visfatin/PBEF/NAMPT treatment led to a significant decrease of DA steady state concentration, CART and CRH mRNA levels. Consequently, visfatin/PBEF/NAMPT could play an orexigenic role in the ARC, and the effect could be mediated by modulation of DA, CART and CRH activity in the hypothalamus. PMID- 22824757 TI - Clock gene expression in mouse kidney and testis: analysis of periodical and dynamical patterns. AB - Molecular clocks drive circadian rhythmicity of cellular functions in peripheral tissues and organs, kidney included, whereas in the testis this clockwork seems constitutively active. We have evaluated the periodicity and the dynamics of expression of the clock genes BMAL1, CLOCK, PER1, PER2, CRY1, CRY2 and REV ERBalpha over 24 h in the kidney and testis using a mouse model. The periodicity was explored by single cosinor, and dynamics were explored by calculation of fractional variations of gene expression related to time intervals. Kidney and testis were harvested at 4-h intervals over a 24-h period from eight-week-old C57BL/6 male mice housed individually on a 12 h light (L)-dark (D) cycle (lights on at 08:00 h; lights off at 20:00 h) and mRNA was extracted and analyzed by Quantitative Real-time Reverse Transcription PCR. A statistically significant difference was evidenced between kidney and testis for the original values of expression level of BMAL1, PER1, PER2 CRY1, CRY2 and REV ERBα. A statistically significant difference was evidenced between kidney and testis for the fractional variation of BMAL1, PER2, CRY1, CRY2 and REV ERBα. A significant 24-h rhythmic component was found for BMAL1, CLOCK, PER1, PER2, CRY1, CRY2 and REV ERBα in the kidney, whereas no core clock gene showed circadian rhythmicity in the testis. Fractional variations provided significant circadian rhythms for BMAL1, PER2, CRY, CRY2 and REV ERBα in the kidney, whereas in the testis the fractional variation calculations showed no circadian rhythmicity, but quantitative comparison showed statistically significant differences in only 16.7 percent of the time points studied. In conclusion, in the kidney the clock gene machinery shows circadian oscillation of mRNA levels and time-related variations in the rate of change of clock gene expression. In the testis the clock genes do not show circadian rhythmicity of expression and the dynamics of variation are not characterized by a periodical pattern, but are quantitatively similar to those observed in the kidney. These data suggest that in the testis the clock gene machinery shows a tissue-specific pattern of function and clock genes may play a different role in the testis with regard to other peripheral tissues, maybe in relation to the presence of developmental and differentiation phenomena. PMID- 22824758 TI - [Severe coronary vasospasm]. AB - A 50-year-old man, with chronic kidney disease and on dialysis, underwent coronary angiography in the context of acute coronary syndrome, which revealed focal lesions (type A) in the proximal left anterior descending and mid circumflex arteries. Ad-hoc angioplasty was performed on both lesions with direct stenting. An immediate drop in arterial blood pressure was observed and the angiogram showed new lesions with reduced flow throughout the coronary tree, progressing to cardiogenic shock and electromechanical dissociation. During cardiopulmonary resuscitation maneuvers, intracoronary verapamil was administered and TIMI 3 flow, sinus rhythm and a rise in blood pressure were obtained. Clinical stability was progressively restored. The patient was discharged medicated with calcium channel blockers and nitrates. During follow-up, he was twice readmitted for unstable angina. Coronary angiography revealed findings that could easily have been interpreted as new obstructive lesions, but these resolved after administration of intracoronary nitrates. PMID- 22824759 TI - [Takotsubo syndrome or acute myocarditis? The role of cardiac magnetic resonance imaging]. AB - Acute myocarditis is often misdiagnosed, and its evolution is not always benign; correct and prompt diagnosis is therefore essential. We report the case of a 62 year-old woman with chest pain after a stressful event and ST-segment elevation on the electrocardiogram, in whom urgent cardiac catheterization showed normal coronary arteries and left ventricular apical ballooning, suggesting takotsubo syndrome. However, cardiac magnetic resonance imaging showed lesions typical of acute myocarditis, thus suggesting this diagnosis. We highlight the diagnostic difficulty in patients with chest pain, elevated troponin and normal coronary arteries, and the key role of cardiac magnetic resonance in differential diagnosis. PMID- 22824760 TI - [Residual platelet activity in patients managed with clopidogrel: clinical implications for the management of patients with acute coronary syndrome]. PMID- 22824761 TI - Synthesis, biological evaluation, and molecular docking studies of 2,5 substituted-1,4-benzoquinone as novel urease inhibitors. AB - A series of 2,5-substituted-1,4-benzoquinone (1-6) were prepared and structurally characterized by elemental analysis, IR spectra, (1)H and (13)C NMR spectra, and single crystal X-ray determination. The urease inhibitory activities of the compounds against H. pylori urease were studied. Among the compounds, 2,5-bis(2 morpholin-4-ylethylamino)-[1,4]benzoquinone (2) shows the most effective activity with IC(50) value of 27.30 +/- 2.17 MUM. Docking simulation was performed to insert compound 2 into the crystal structure of H. pylori urease at the active site to determine the probable binding mode. As a result, compound 2 may be used as a potential urease inhibitor. PMID- 22824762 TI - Fused bicyclic heteroarylpiperazine-substituted L-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group. AB - Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the gamma-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP 4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-pi interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity. PMID- 22824763 TI - Immunoinflammation and functional gastrointestinal disorders. AB - Functional gastrointestinal disorders (FGIDs) are a group of conditions characterized by the dysfunction of the gastrointestinal (GI) tract. Although the specific pathogenesis of FGIDs is unclear, several theories have been proposed to explain the symptoms. Abnormal GI motility and visceral hypersensitivity have always been considered to be the main physiopathologic basis of FGIDs, and FGIDs related to psychomental disorders have also caused a major social concern. In recent years, a growing number of researches have proved that cytokines have a significant influence on GI motility, and the role of cytokines in FGIDs has aroused more and more attention. In this article, we discuss the interaction between immunoinflammation and FGIDs, and make an overview of current studies. PMID- 22824764 TI - Choledochal cysts : a review of literature. AB - Choledochal cysts are cystic dilation of extrahepatic duct, intrahepatic duct, or both that may result in significant morbidity and mortality, unless identified early and managed appropriately. The incidence is common in Asian population compared with western counterpart with more than two third of the cases in Asia being reported from Japan. The traditional anatomic classification system is under debate with more focus on etiopathogenesis and other aspects of choledochal cysts. Even though categorized under the same roof, choledochal cysts vary with respect to their natural course, complications, and management. In this review, with the available literature on choledochal cysts, we discuss different views about the etiopathogenesis along with the natural course, complications, diagnosis, and surgical approach for choledochal cysts, which also explains why the traditional classification is questioned by some authors. PMID- 22824765 TI - Results of short- and long-segment cardioesophageal myotomy for achalasia. AB - BACKGROUND/AIM: We report the results of a short- and long-segment cardiomyotomy for relief of the symptoms of achalasia. PATIENTS AND METHODS: From 1997 to 2009, 41 patients (22 men, 19 women) with achalasia underwent cardiomyotomy. Patients were divided into 2 groups [short-segment group (SSG) and long-segment group (LSG)]. SSG include 22 patients with laparotomy and 8-cm short-segment myotomy and Dor fundoplication. LSG includes 19 patients with thoracotomy and 12-cm long segment myotomy and Belsey partial fundoplication. results: Median follow up was 48 months (range: 12-70 months). Postoperative dysphagia improved in 20 patients in SSG and in 17 patients in LSG (P < 0.001). Slow emptying sensation improved in 19 patients in SSG and in 16 patients in LSG postoperatively (P < 0.001). Heartburn was present in 2 patients in SSG and 3 patients in LSG postoperatively (P = 0.179). Radiologically, barium stasis decreased significantly from 88% to 25% in SSG and from 85% to 30% in LSG. The lower esophageal sphincter (LES) gradient decreased from 32 to 10 mmHg in SSG and from 34 to 14 mmHg in LSG (P < 0.001). CONCLUSIONS: Short-segment cardiomyotomy reduces the LES gradient and relieves obstructive symptoms. PMID- 22824766 TI - Bone density and bone metabolism in patients with inflammatory bowel disease. AB - BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) are at high risk for low bone mineral density (BMD). This study aimed to evaluate BMD in IBD patients and its relationship with bone metabolism in a group of Iranian patients. PATIENTS AND METHODS: A cross-sectional study was conducted on patients with IBD to assess BMD status and serum biochemical factors. After getting the demographic data from 200 patients, they were screened using dual-energy X-ray absorptiometry of the lumbar spine (L2-L4) and femoral neck for BMD status. Serum levels of calcium, phosphate, alkaline phosphatase (ALP), and 25-hydroxyvitamin D (25-OH vitamin D) were measured to assess the bone metabolism status. RESULTS: Two hundred patients with IBD were enrolled in the study. One hundred and eighty three (91.5%) patients were identified as having ulcerative colitis (UC) and 17 (8.5%) as having Crohn's disease (CD). Based on the lumbar and femoral neck bone mass densitometry, 148 (74.4%) patients had low BMD at either lumbar spine or femoral neck. Of these, 100 patients (50.3%) were osteopenic and 48 patients (24.1%) were osteoporotic. A 58.6% and 61% of patients with UC had low BMD in the lumbar and femoral neck, respectively. These results for those with CD were 76.5% and 70.6%, respectively. The mean of femoral neck and lumbar T-scores in patients with UC were -1.14 and -1.38, and in patients with CD were -1.24 and -1.47, respectively (P > 0.05). The mean (+/-SD) levels for calcium (Ca) in UC and CD were in the normal range. The mean (+/-SD) levels of ALP and 25-OH vitamin D in both the groups were in the normal range, and in comparison between groups (UC and CD), no significant differences were observed (P = 0.20 for ALP and P = 0.44 for 25-OH vitamin D). In the assessment of correlation between biochemical markers and BMD, an inverse correlation between lumbar T-score and ALP or 25-OH vitamin D only in patients with UC was observed. CONCLUSIONS: The high prevalence of low BMD in the Iranian population with IBD needs attention. The subclinical vitamin D deficiency may contribute to bone loss in IBD patients, which is more pronounced in patients with UC in this study because of the small population of patients with CD. PMID- 22824767 TI - Right upper quadrant pain with normal hepatobiliary ultrasound: can hepatobiliary scintigraphy define the cause? AB - BACKGROUND/AIM: The objective of this study was to assess the value of hepatobiliary scintigraphy (HS) for the diagnosis of right upper quadrant (RUQ) abdominal pain in patients with normal hepatobiliary ultrasound (HU). This is an observational study with a retrospective analysis of data from March 2008 to August 2010. MATERIALS AND METHODS: We reviewed the HS results of 30 patients, aged 29-69 years (average 45.8 years); 12 male and 18 female patients. Patient selection to perform the HS was RUQ abdominal pain, suspected hepatobiliary disorder, and negative HU. All patients had gone through the standard procedure of HS. RESULTS: Based on predefined interpretation criteria, HS results were divided into 2 patterns: Normal (n=8, 25.8%) and abnormal (n=22, 73%): 18 patients (81.8%) having early gallbladder (GB) and common bile duct visualization, and delayed transit to small bowel (SB), which can be seen only after a fatty meal with normal or abnormal GB ejection fraction (GBEF) pattern characteristic of Oddi's sphincter dyskinesia. The remaining 4 patients (8.18%) had acalculous cholycystitis pattern: Delayed GB visualization with activity appearing in SB before GB. CONCLUSION: HS with fatty meal stimulation and GBEF estimation seems to be a reliable test, which may reveal a biliary cause in more than 70% of patients with RUQ abdominal pain and normal HU. Normal results exclude functional biliary cause. The decision for invasive or noninvasive therapeutic approach may depend on the results of HS. PMID- 22824769 TI - Prevalence of cirrhosis in patients with thrombocytopenia who receive bone marrow biopsy. AB - BACKGROUND/AIM: Thrombocytopenia is a common finding in patients with cirrhosis and may lead to unnecessary referral for bone marrow (BM) biopsy. To date, the prevalence of cirrhosis in patients with thrombocytopenia who receive BM biopsy is largely unknown. MATERIALS AND METHODS: Between fiscal years 2006-2010, 744 patients (>=18 years) who underwent BM biopsies for thrombocytopenia at our hospital were identified retrospectively. 541 patients were excluded who had hematologic malignancies and received chemotherapy. Remaining 203 patients with predominant isolated thrombocytopenia were included in the study. RESULTS: Of 203 patients, 136 (67%) had a normal and 67 (33%) had an abnormal BM examination. Prevalence of cirrhosis in the study population was 35% (95% CI: 28.4-41.9). 51% patients with normal BM were found to have cirrhosis compared to 3% of patients with abnormal BM exam (P < 0.0001). Common causes of cirrhosis were nonalcoholic steatohepatitis (NASH) (47%), followed by alcohol and Hepatitis C virus infection. Idiopathic thrombocytopenia and myelodysplastic syndrome were most frequent causes of thrombocytopenia in patients without cirrhosis. Patients with NASH had higher body mass index (BMI) (33.4 vs. 25.8, P < 0.001) and lower MELD scores (11.1 vs. 16, P = 0.028) when compared to non-NASH patients with cirrhosis. CONCLUSION: Approximately, one third (35%) of patients with cirrhosis induced thrombocytopenia may undergo unwarranted BM biopsies. Clinical diagnosis of cirrhosis is still a challenge for many physicians, particularly with underlying NASH. We propose cirrhosis to be the prime cause of isolated thrombocytopenia. PMID- 22824768 TI - Increased protein carbonylation and decreased antioxidant status in anemic H. pylori infected patients: effect of treatment. AB - BACKGROUND/AIM: Collective evidences suggest the causal association of Helicobacter pylori infection with iron deficiency anemia. Generation of free radicals against this bacterium can lead to turbulence in oxidative-antioxidative system. This study was undertaken to evaluate the marker of oxidative protein injury, protein carbonylation, and total antioxidant status in anemic H. pylori infected patients and to observe the alteration in them after treatment for 1 month with oral ferrous sulfate and anti-H. pylori therapy. Twenty anemic H. pylori-infected patients were randomly divided into 2 groups. The H. pylori infected patients in Group I received both iron supplementation and anti-H pylori therapy, whereas patients in Group II received only the iron supplementation. Fifteen healthy volunteers served as controls. All the study parameters were estimated after 1 month of the treatment. MATERIALS AND METHODS: Protein carbonylation and total antioxidant status were estimated using colorimetric method. Hematologic parameters were evaluated using Sysmex-K-100 automated cell counter. RESULTS: In anemic H. pylori-infected patients, the protein carbonyls (PCOs) were significantly increased, whereas the total antioxidant status, iron, hemoglobin, and ferritin levels were significantly decreased compared with the controls. In Group I, while the PCOs level decreased significantly, there was a significant increase in the total antioxidant status, iron, hemoglobin, and ferritin levels after 1 month. No significant alterations were noted in the levels of PCOs, total antioxidant status, iron, hemoglobin, or ferritin in Group II patients after 1 month of the treatment. CONCLUSIONS: The findings from this study indicate that treatment for both anemia and H. pylori infections is required for lowering the oxidative stress markers, which synergistically bring about an appropriate correction of anemia soon in these patients. PMID- 22824770 TI - Bone marrow cells ameliorate liver fibrosis and express albumin after transplantation in CCl4-induced fibrotic liver. AB - BACKGROUND/AIM: We investigated the effect of bone marrow-derived stem cell (BMSC) transplantation on carbon tetrachloride (CCl 4 )-induced liver fibrosis. PATIENTS AND METHODS: BMSCs of green fluorescent protein (GFP) mice were transplanted into 4-week CCl 4 -treated C57BL/6 mice directly to the liver, and the mice were treated for 4 more weeks with CCl 4 (total, 8 weeks). After sacrificing the animals, quantitative data of percentage fibrosis area and the number of cells expressing albumin was obtained. One-way analysis of variance was applied to calculate the significance of the data. RESULTS: GFP expressing cells clearly indicated migrated BMSCs with strong expression of albumin after 28 days post-transplantation shown by anti-albumin antibody. Double fluorescent immunohistochemistry showed reduced expression of alphaSMA on GFP-positive cells. Four weeks after BMSC transplantation, mice had significantly reduced liver fibrosis as compared with that of mice treated with CCl 4 assessed by Sirius red staining. CONCLUSION: Mice with BMSC transplantation with continuous CCl 4 injection had reduced liver fibrosis and a significantly improved expression of albumin compared with mice treated with CCl 4 alone. These findings strengthen the concept of cellular therapy in liver fibrosis. PMID- 22824771 TI - Immunohistochemical expression of PCNA and CD34 in colorectal adenomas and carcinomas using specified automated cellular image analysis system: a clinicopathologic study. AB - BACKGROUND/AIM: To evaluate the immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and CD34 in colorectal adenomas and carcinomas, and to correlate this expression with different clinicopathologic parameters. MATERIALS AND METHODS: The study was retrospectively designed. A total of 86 tissue samples, including 33 paraffin blocks from patients with colorectal adenomas, 33 paraffin blocks from patients with colorectal adenocarcinomas, and a control group of 20 samples of nontumerous colonic tissue, were included in the study. From each block, 3 sections of 5 MUm thickness were taken, 1 section was stained with hematoxylin and eosin (H and E) and the other 2 sections were stained immunohistochemically for PCNA and CD34. Scoring of the immunohistochemical staining was performed using a specified automated cellular image analysis system (Digimizer). RESULTS: PCNA expression was significantly increased in a sequence of normal mucosa-adenoma-carcinoma. It was significantly higher in adenomas >= 1 cm and those with severe dysplasia, and it showed a significant positive correlation with grade and lymph node involvement in colorectal carcinoma. CD34 showed significantly higher expression in carcinoma than adenoma and in adenoma than in the control group. CD34 expression showed a significant correlation with adenomas carrying severe dysplasia and large-sized adenomas (>=1 cm). It was significantly correlated with tumor grade, lymphovascular invasion, and lymph node involvement in colorectal carcinoma. CONCLUSION: PCNA plays an important role in colorectal neoplastic progression and can be utilized as ancillary marker for the risk of malignant transformation in colorectal adenomas as it correlates with high grade dysplasia and size. Intratumoral quantification of the mean (A and N) of CD34 in colorectal carcinoma reflects the grade of tumors and can predict lymph node involvement and lymphovascular invasion, to make a useful additional prognostic factor. PMID- 22824772 TI - Fatal hepatitis B reactivation treated with entecavir in an isolated anti-HBs positive lymphoma patient: a case report and literature review. AB - Hepatitis B virus (HBV) reactivation is a well-recognized complication that occurs in lymphoma patients who undergo chemotherapy. Only very few cases of HBV reactivation in patients with isolated antibody against hepatitis B surface antigen (anti-HBs) have been reported. We present a case of a 78-year-old woman diagnosed with diffuse large B cell non-Hodgkin's lymphoma who only displayed a positive anti-HBs, as the single possible marker of occult HBV infection, before starting therapy. She was treated with several chemotherapeutic regimens (including rituximab) for disease relapses during 3 years. Forty days after the last cycle of chemotherapy, she presented with jaundice, markedly elevated serum aminotransferase levels, and coagulopathy. HBV serology showed positivity for HBsAg, anti-HBc and anti-HBs. HBV DNA was positive. Antiviral treatment with entecavir was promptly initiated, but the patient died from liver failure. A review of the literature of HBV reactivation in patients with detectable anti-HBs levels is discussed. PMID- 22824773 TI - Giant fungal gastric ulcer in an immunocompetent individual. AB - Candida infection of gastrointestinal tract is frequent in immunocompromised patients and rare in an otherwise healthy person in whom no permissive factor is present. Herein is a case report on 25-year-old woman, 2 months postpartum, with fungal gastric ulcer with invasion leading to fungemia. She developed fever and anemia. Gastric biopsy and blood culture both showed growth of Candida albicans. The patient responded well to parenteral amphotericin B. This supports the hypothesis of invasion of Candida from gastric ulcer into blood. PMID- 22824774 TI - Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene. AB - Mitochondrial DNA depletion syndromes (MDSs) are autosomal recessive diseases characterized by a severe decrease in mitochondrial DNA content leading to dysfunction of the affected organ. Autosomal recessive mutations in MPV17 have been identified in the hepatocerebral form of MDS. We describe the clinical features, biochemical and molecular results of a Saudi infant with a new mutation of MPV17 and compared the features to those of previously reported cases. We stress the importance of such rare cases particularly in countries with high consanguineous marriage rate. PMID- 22824775 TI - A liver lesion with systemic inflammatory manifestations. PMID- 22824776 TI - Sexual medicine: Online risks to health--the problem of counterfeit drugs. PMID- 22824777 TI - Kidney cancer: prognostic and predictive biomarkers for RCC emerge. PMID- 22824779 TI - RNAi-mediated gene knockdown and in vivo diuresis assay in adult female Aedes aegypti mosquitoes. AB - This video protocol demonstrates an effective technique to knockdown a particular gene in an insect and conduct a novel bioassay to measure excretion rate. This method can be used to obtain a better understanding of the process of diuresis in insects and is especially useful in the study of diuresis in blood-feeding arthropods that are able to take up huge amounts of liquid in a single blood meal. This RNAi-mediated gene knockdown combined with an in vivo diuresis assay was developed by the Hansen lab to study the effects of RNAi-mediated knockdown of aquaporin genes on Aedes aegypti mosquito diuresis. The protocol is setup in two parts: the first demonstration illustrates how to construct a simple mosquito injection device and how to prepare and inject dsRNA into the thorax of mosquitoes for RNAi-mediated gene knockdown. The second demonstration illustrates how to determine excretion rates in mosquitoes using an in vivo bioassay. PMID- 22824780 TI - PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting. AB - Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf-PEG-TNF related apoptosis-inducing ligand conjugate (Tf-PEG-TRAIL) for effective cancer therapy. Tf-PEG-TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10 kDa). Eventually, only 10 kDa PEG was linked to Tf and TRAIL because TRAIL (66 kDa) and Tf (81 kDa) were too large to link to 3.4 and 5 kDa PEG. The final conjugate Tf-PEG(10K)-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG(10K)-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG(10K)-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG(10K)-TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf-PEG(10K)-TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf-PEG(10K)-TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf-PEG(10K)-TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG(10K)-TRAIL, respectively. These results suggest that Tf PEG(10K)-TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy. PMID- 22824781 TI - Enhanced delivery of T cells to tumor after chemotherapy using membrane-anchored, apoptosis-targeted peptide. AB - Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1 BAM conjugate on cell membrane was approximately 80 and 40 min in the absence and presence of serum, respectively. ApoPep-1 was resistant to degradation in serum until 2h. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. Accumulation of apoptosis-targeted T cells at other organs such as liver was not detected. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy. PMID- 22824778 TI - Emerging tools for erectile dysfunction: a role for regenerative medicine. AB - Erectile dysfunction (ED) is the most common sexual disorder reported by men to their health-care providers and the most investigated male sexual dysfunction. Currently, the treatment of ED focuses on 'symptomatic relief' of ED and, therefore, tends to provide temporary relief rather than providing a cure or reversing the cause. The identification of a large population of "difficult-to treat" patients has triggered researchers to identify novel treatment approaches, which focus on cure and restoration of the underlying cause of ED. Regenerative medicine has developed extensively in the past few decades and preclinical trials have emphasized the benefit of growth factor therapy, gene transfer, stem cells and tissue engineering for the restoration of erectile function. Development of clinical trials involving immunomodulation in postprostatectomy ED patients and the use of maxi-K channels for gene therapy are illustrative of the advances in the field. However, the search for novel treatment targets and a wealth of preclinical studies represent a dynamic and continuing field of enquiry. PMID- 22824782 TI - Direct cytosolic delivery of cargoes in vivo by a chimera consisting of D- and L arginine residues. AB - The ability of cell-penetrating peptides (CPPs) to deliver a range of membrane impermeable molecules into living cells makes them attractive potential vehicles for therapeutics. However, in vivo, the efficiency of CPP delivery to the cytosol remains unsatisfactory owing to endosomal entrapment and/or systemic toxicity, which severely restrict their bioavailability and efficacy in in vivo applications. In this study, we developed a series of novel chimeras consisting of various numbers of d- and l-arginine residues and investigated their cellular uptake behaviors and systemic toxicities. We demonstrated that the intracellular distribution, uptake efficiency, and systemic toxicity of these oligoarginines were all significantly affected by the number of d-arginine residues in the peptide sequence. We also found that a hybrid peptide, (rR)(3)R(2), possessed low systemic toxicity, high uptake efficiency, and, remarkably, achieved efficient cytosolic delivery not only in cultured cells but also in living tissue cells in mice after intravenous injection, implying that this heterogeneous motif might have promising applications in the delivery of cargoes of small sizes directed to cytosolic targets in vivo. Our studies into the uptake mechanism of (rR)(3)R(2) indicate that its cellular uptake was not affected by pharmacological or physical inhibitors of endocytosis but by the elimination of the membrane potential, suggesting that (rR)(3)R(2) does not enter the cells via endocytosis but rather through direct membrane translocation driven by the membrane potential. The results here might provide useful guidelines for the design and application of CPPs in drug delivery. PMID- 22824783 TI - The effect of mechanical properties of iron oxide nanoparticle-loaded functional nano-carrier on tumor targeting and imaging. AB - To achieve a sufficient targeting efficiency and prolonged half-life in-vivo, the physicochemical parameters including size and surface chemistry of therapeutic and imaging agents should be controlled. In this study, we prepared an iron oxide nanoparticle (IONP)-loaded, functional nano-carrier with different loading contents to modulate the mechanical properties of the system, and compared the characteristics of tumor targeting and imaging in terms of loading contents of IONP. As a functional nano-carrier, chitosan-conjugated, Pluronic-based nano carrier with useful properties such as long blood circulation, good tumor targeting, and easy loading of macromolecules was used. IONPs were efficiently encapsulated into the nano-carrier (high loading efficiency over 95%) and the mechanical properties of the IONP-loaded nano-carrier were controlled by varying the loading amount of IONP. The IONP-loaded nano-carrier with the higher loading content of IONP (40 wt.%) was significantly more rigid (over 2*) than those with lower loading contents of IONP (5 and 15 wt.%). Although the nano-carrier with the higher loading content of IONP showed more enhanced MR contrast effect with higher T(2) relaxivity and higher intracellular uptake in vitro, characteristics of in-vivo tumor targeting and MR cancer imaging were not good compared to that of the nano-carrrier with the lower loading contents of IONP. Since different loading contents did not affect other characteristics of the system (size, surface chemistry, and surface charge), the present result suggests that the mechanical properties (strength/flexibility) of nano-systems are also important factors to be controlled for targeted delivery and imaging. PMID- 22824784 TI - The delivered dose: Applying particokinetics to in vitro investigations of nanoparticle internalization by macrophages. AB - PURPOSE: The aim of this study was to investigate the impact of nanoparticle dosimetry on the interpretation of results from in vitro experiments involving particle-cell interactions. Three different dose metrics were evaluated: 1) The administered dose (particle mass, number or surface area administered per volume media at the onset of an experiment), 2) the delivered dose (particle mass, number or surface area to reach the cell monolayer via diffusion and sedimentation over the duration of an experiment) and 3) the cellular dose (particle mass, number or surface area internalized by the cells during the experiment). The In Vitro Sedimentation and Diffusion and Dosimetry model (ISDD) was used to calculate particle sedimentation and diffusion in cell culture media to predict delivered dose values. These were compared with administered doses and experimentally determined cellular dose values. METHODS: Dosing conditions and predicted delivered dose values were computed in silico using ISDD. In vitro cell association experiments were performed by exposing fluorescently labelled polystyrene beads of 50, 100, 200, 700 and 1000nm diameter to J774A.1 macrophage like cells and determining the internalized particle content (cellular dose) via fluorescence spectroscopy. Experiments were repeated using lipopolysachharide (LPS) to activate and cytochalasin D to inhibit phagocytosis. RESULTS: Only a small fraction (0.03-0.33%) of the administered dose was able to interact with the cells for all particle sizes tested. Measured cellular doses in non-activated J774A.1 cells corresponded well with computed delivered dose values for all particle sizes tested under six different exposure conditions. When cellular doses were averaged and normalized to their corresponding delivered doses, the percentage values of cell-associated particles were: 36 +/- 10%(50 nm), 15 +/- 3%(100 nm), 22 +/- 6%(200 nm), 18 +/- 4%(700 nm), and 42 +/- 19%(1000 nm). Activation of J774A.1 cells with LPS significantly increased the cellular dose (normalized to the delivered dose) in all particle sizes except 50 nm, while cytochalasin D treatment significantly reduced the cellular dose of 100, 200 and 1000 nm particles. CONCLUSIONS: This study demonstrates that dose correction using the ISDD model (i.e. normalization of cellular dose values to the delivered dose) is essential for accurate interpretation of results derived from in vitro particle-cell interaction studies (e.g. particle uptake, cytotoxicity, mechanisms of action, pharmacodynamic studies, etc.). It is of particular relevance to the field of particulate drug delivery systems, because the low density nature of most biomaterials used as drug carriers will result in very low fractions of the administered particle dose reaching the cell monolayer under most commonly used experimental conditions. PMID- 22824786 TI - Encapsulation, solid-phases identification and leaching of toxic metals in cement systems modified by natural biodegradable polymers. AB - Cement mortars loaded with Cr, Pb and Zn were modified by polymeric admixtures [chitosans with low (LMWCH), medium (MMWCH) and high (HMWCH) molecular weight and hydroxypropylchitosan (HPCH)]. The influence of the simultaneous presence of the heavy metal and the polymeric additive on the fresh properties (consistency, water retention and setting time) and on the compressive strength of the mortars was assessed. Leaching patterns as well as properties of the cement mortars were related to the heavy metals-bearing solid phases. Chitosan admixtures lessened the effect of the addition of Cr and Pb on the setting time. In all instances, chitosans improved the compressive strength of the Zn-bearing mortars yielding values as high as 15 N mm(-2). A newly reported Zn phase, dietrichite (ZnAl(2)(SO(4))(4).22H(2)O) was identified under the presence of LMWCH: it was responsible for an improvement by 24% in Zn retention. Lead-bearing silicates, such as plumalsite (Pb(4)Al(2)(SiO(3))(7)), were also identified by XRD confirming that Pb was mainly retained as a part of the silicate network after Ca ion exchange. Also, the presence of polymer induced the appearance and stabilization of some Pb(IV) species. Finally, diverse chromate species were identified and related to the larger leaching values of Cr(VI). PMID- 22824785 TI - SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function. AB - Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML. PMID- 22824787 TI - Could maternal exposure to the antidepressants fluoxetine and St. John's Wort induce long-term reproductive effects on male rats? AB - Based on the limited number of studies that have investigated the adverse effects of maternal treatment with antidepressants on the development of male descendents, this study was carried out in rat in order to evaluate if maternal exposure to fluoxetine (FLX) or St. John's Wort (SJW) could disrupt the development of male offspring. The dams were treated daily, by gavage, with 7.5 mg/kg of FLX or 100 mg/kg SJW during pregnancy and lactation. The reproductive and behavior parameters were analyzed in male pups. Results showed decreases in the weight of the full seminal vesicle and in the number of spermatozoa. Moreover, FLX-exposed pups presented reduced seminiferous epithelium height and diameter of seminiferous tubules. The present study shows that maternal exposure to FLX, but not SJW could interfere on reproductive parameters in adult male rats. PMID- 22824788 TI - Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke. AB - Embryonic stem cells (ESCs) provide a valuable in vitro model for testing toxicity of chemicals and environmental contaminants including cigarette smoke. Mouse ESCs were acutely or chronically exposed to smoke components, cigarette smoke condensate (CSC), or cadmium, an abundant component of CSC, and then evaluated for their self-renewal, apoptosis, DNA damage and telomere function. Acute exposure of ESCs to high dose of CSC or cadmium increased DNA damage and apoptosis. Yet, ESCs exhibited a remarkable capacity to recover following absence of exposure. Chronic exposure of ESCs to low dose of CSC or cadmium resulted in shorter telomeres and DNA damage. Together, acute exposure of ESCs to CSC or cadmium causes immediate cell death and reduces pluripotency, while chronic exposure of ESCs to CSC or cadmium leads to DNA damage and telomere shortening. Notably, a sub-proportion of ESCs during passages is selected to resist to smoke induced oxidative damage to telomeres. PMID- 22824789 TI - Gene expression of the lysophosphatidic acid receptor 1 is a target of transforming growth factor beta. AB - The lysophosphatidic acid (LPA) receptor LPA1/Edg2 is the first identified LPA receptor. Although its wide tissue distribution and biological functions have been well studied, little is known about how LPA1 is transcriptionally regulated. In the current study, we showed that LPA1 is a physiological target of transforming growth factor beta (TGFbeta)-mediated repression. In both normal and neoplastic cells, TGFbeta inhibits LPA1 promoter activity, LPA1 mRNA expression and LPA1-dependent chemotaxis and tumor cell invasion. Knockdown of the TGFbeta intracellular effector Smad3 or Smad4 with lentivirally transduced short hairpin RNA relieved these inhibitory effects of TGFbeta. Interestingly, the LPA1 promoter contains two potential TGFbeta inhibitory elements (TIEs), each consisting of a Smad-binding site and an adjacent E2F4/5 element, structurally similar to the TIE found on the promoter of the well-defined TGFbeta target gene c-myc. Deletion and point mutation analyses indicate that the distal TIE located at 401 bp from the transcription initiation site, is required for TGFbeta repression of the LPA1 promoter. A DNA pull-down assay showed that the -401 TIE was capable of binding Samd3 and E2F4 in TGFbeta-treated cells. TGFbeta-induced binding of the Smad complex to the native -401 TIE sequence of the LPA1 gene promoter was further verified by chromatin immunoprecipitation assays. We therefore identified a novel role of TGFbeta in the control of LPA1 expression and LPA1-coupled biological functions, adding LPA1 to the list of TGFbeta repressed target genes. PMID- 22824790 TI - MEMO1, a new IRS1-interacting protein, induces epithelial-mesenchymal transition in mammary epithelial cells. AB - MEMO1 (mediator of ErbB2-driven cell motility 1) regulates HER2-dependent cell migration. Increased MEMO1 expression is associated with cancer aggressiveness. Here, we found that MEMO1 is also involved in breast carcinogenesis via regulating insulin-like growth factor-I receptor-dependent signaling events. We showed that MEMO1 binds to insulin receptor substrate 1, activates the downstream PI3K/Akt signaling pathway, leads to upregulation of Snail1 and thereby triggers the epithelial-mesenchymal transition (EMT) program. In addition, MEMO1 overexpression is accompanied by growth factor-independent proliferation, anchorage-independent growth in soft agar, and enhanced metastatic potential. Together, these findings suggest that MEMO1 acts as an oncogene and is a potential therapeutic target for cancer treatment. PMID- 22824791 TI - Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway. AB - Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer and is especially implicated in the development and progression of colorectal cancer. The key effector protein of the canonical Wnt pathway is beta-catenin, which functions with T-cell factor/lymphoid enhancer factor to activate expression of Wnt target genes. In this study, we used a new functional screen based on cell survival in the presence of cDNAs encoding proteins that activate the Wnt pathway thus identifying novel Wnt signaling components. Here we identify carboxypeptidase E (|CPE) and its splice variant, DeltaN-CPE, as novel regulators of the Wnt pathway. We show that whereas DeltaN CPE activates the Wnt signal, the full-length CPE (F-CPE) protein is an inhibitor of Wnt/beta-catenin signaling. F-CPE forms a complex with the Wnt3a ligand and the Frizzled receptor. Moreover, F-CPE disrupts disheveled-induced signalosomes that are important for transducing the Wnt signal and reduces beta-catenin protein levels and activity. Taken together, our data indicate that F-CPE and DeltaN-CPE regulate the canonical Wnt signaling pathway negatively and positively, respectively, and demonstrate that this screening approach can be a rapid means for isolation of novel Wnt signaling components. PMID- 22824792 TI - Real-time imaging of the dynamics of death receptors and therapeutics that overcome TRAIL resistance in tumors. AB - Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and its efficacy has been tested in pre-clinical models by delivering it systemically as a purified ligand or via engineered stem cells (SC). However, about 50% of tumor lines are resistant to TRAIL and overcoming TRAIL resistance in aggressive tumors, such as glioblastoma-multiforme (GBM), and understanding the molecular dynamics of TRAIL-based combination therapies are critical to broadly use TRAIL as a therapeutic agent. In this study, we developed death receptor (DR)4/5-reporters that offer an imaging-based platform to identify agents that act in concert with a potent, secretable variant of TRAIL (S-TRAIL) by monitoring changes in DR4/5 expression. Utilizing these reporters, we show a differential regulation of DR4/5 when exposed to a panel of clinically relevant agents. A histone deacetylase inhibitor, MS-275, resulted in upregulation of DR4/5 in all GBM cell lines, and these changes could be followed in real time both in vitro and in vivo in mice bearing tumors and they correlated with increased TRAIL sensitivity. To further assess the dynamics of combinatorial strategies that overcome resistance of tumors to SC released S-TRAIL, we also engineered tumor cells to express live-cell caspase-reporters and SCs to express S-TRAIL. Utilizing DR4/5 and caspase reporters in parallel, we show that MS-275 sensitizes TRAIL-resistant GBM cells to stem cell (SC) delivered S-TRAIL by changing the time-to-death in vitro and in vivo. This study demonstrates the effectiveness of a combination of real-time reporters of TRAIL-induced apoptosis pathway in evaluating the efficacy of SC-TRAIL-based therapeutics and may have implications in targeting a broad range of cancers. PMID- 22824794 TI - DNA damage-induced centrosome amplification occurs via excessive formation of centriolar satellites. AB - Centrosome amplification is a frequent phenomenon in malignancies and may facilitate tumorigenesis by promoting chromosomal instability. On the other hand, a centrosome inactivation checkpoint comprising centrosome amplification leading to elimination of cells by mitotic catastrophe has been described in response to DNA damage by ionizing radiation or cytostatic drugs. So far, the exact nature of DNA damage-induced centrosome amplification, which might be overduplication or fragmentation of existing centrosomes, has been controversial. To solve this controversy, we have established a method to distinguish between these two possibilities using A549 cells expressing photoconvertible CETN2-Dendra2. In response to various DNA-damaging treatments, centrosome amplification but not fragmentation was observed. Moreover, centrosome amplification was preceded by excessive formation of centrin-containing centriolar satellites, which were identified as de novo-generated atypical centrin dots staining positive for centriolar satellite markers but negative or only weakly positive for other established centrosomal markers, and which could be verified as centriolar satellites using immunogold electron microscopy. In line with this notion, disruption of dynein-mediated recruitment of centrosomal proteins via centriolar satellites suppressed centrosome amplification after DNA damage, and excessive formation of centriolar satellites could be inhibited by interference with Chk1, a known mediator of centrosome amplification in response to DNA damage. In conclusion, we provide a model in which a Chk1-mediated DNA damage checkpoint induces excessive formation of centriolar satellites constituting assembly platforms for centrosomal proteins, which subsequently leads to centrosome amplification. PMID- 22824793 TI - Integrin beta5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways. AB - Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell-adhesion receptors that mediate interactions of cells with extracellular matrix. The alphav-beta-family of integrins contributes to tumorigenesis, response to therapy and cancer stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for the development of therapeutic approaches targeting integrins. The study investigated the role of integrin beta5 in breast carcinomas by depleting integrin beta5 using RNA interference and reexpression of integrin beta5. Depletion of integrin beta5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth and tumor angiogenesis, whereas reexpression of integrin beta5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of vascular endothelial growth factor-A in integrin beta5-depleted tumors. Tumor cells deficient in integrin beta5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin beta5 mediates the Src-focal adhesion kinase and MEK-extracellular signal-regulated kinase signaling events that operate independently, and inhibition of these pathways phenocopies integrin beta5 deficiency. Breast carcinoma cells express high levels of integrin beta5, whereas expression of integrin beta3 is limited to stromal compartments and integrin beta6 is lost in metastatic cells. Together, these findings show a critical role for integrin beta5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin beta5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies. PMID- 22824795 TI - The gain of function of p53 cancer mutant in promoting mammary tumorigenesis. AB - Tumor suppressor p53 is critical for suppressing all types of human cancers, including breast cancer. The p53 gene is somatically mutated in over half of all human cancers. The majority of the p53 mutations are missense mutations, leading to the expression of the full-length p53 mutants. Several hotspot mutations, including R175H, are frequently detected in human breast cancer. P53 cancer mutants not only lose tumor suppression activity but, more problematically, also gain new oncogenic activities. Despite correlation of the expression of p53 cancer mutants and the poor prognosis of human breast cancer patients, the roles of p53 cancer mutants in promoting breast cancer remain unclear. We used the humanized p53 cancer mutant knock-in (R175H) mice and mouse mammary tumor virus (MMTV)-Wnt-1 transgenic (mWnt-1) mice to specifically address the gain of function of R175H in promoting breast cancer. Although both R175H/R175HmWnt 1(R175HmWnt-1) and p53(-/-)mWnt-1 mice died from mammary tumor at the same kinetics, which was much earlier than mWnt-1 mice, most of the R175HmWnt-1 mice developed multiple mammary tumors per mouse, whereas p53(-/-)mWnt-1 and mWnt-1 mice mostly developed one tumor per mouse. The multiple mammary tumors arose in the same R175HmWnt-1 mouse exhibited different histological characters. Moreover, R175H gain-of-function mutant expands the mammary epithelial stem cells (MESCs) that give rise to the mammary tumors. As ATM suppresses the expansion of MESCs, the inactivation of ATM by R175H in mammary epithelial cells (MECs) could contribute to the expansion of MESCs in R175HmWnt-1 mice. These findings provide the basis for R175H to promote the initiation of breast cancer by expanding MESCs. PMID- 22824797 TI - MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. AB - The microRNA miR-125b is multi-faceted, with the ability to function as a tumor suppressor or an oncogene, depending on the cellular context. To date, the pro apoptotic role of miR-125b and its underlying mechanisms are unexplored. In this study, both gain- and loss-of-function experiments revealed that miR-125b expression not only induced spontaneous apoptosis in various cell lines derived from the liver, lung and colorectal cancers, but also sensitized cancer cells to diverse apoptotic stimuli, including nutrient starvation and chemotherapeutic treatment. Furthermore, downregulation of miR-125b was a frequent event in hepatocellular carcinoma (HCC) tissues, and the miR-125b level was positively associated with the rate of apoptosis in HCC tissues. Subsequent investigations identified Mcl-1, Bcl-w and interleukin (IL)-6R as direct targets of miR-125b. Restoration of miR-125b expression not only diminished the expression of Mcl-1 and Bcl-w directly but also indirectly reduced the Mcl-1 and Bcl-xL levels by attenuating IL-6/signal transducer and activator of transcription 3 signaling. Consistent with these findings, introduction of miR-125b reduced the mitochondrial membrane potential and promoted the cleavage of pro-caspase-3. These data indicate that miR-125b may promote apoptosis by suppressing the anti apoptotic molecules of the Bcl-2 family and miR-125b downregulation may facilitate tumor development by conferring upon cells the capability to survive under conditions of nutrient deprivation and chemotherapeutic treatment. Our findings highlight the importance of miR-125b in the regulation of apoptosis and suggest miR-125b as an attractive target for anti-cancer therapy. PMID- 22824796 TI - Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. AB - Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5 hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors. PMID- 22824798 TI - Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis. AB - Metastatic breast adenocarcinomas display activation signatures for signaling pathways that trigger cell motility and tissue invasion. Here, we report that the adaptor protein transducer of Cdc42-dependent actin assembly-1 (Toca-1) is expressed in highly invasive breast cancers and regulates their metastatic phenotypes. We show that Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions actively degrading the extracellular matrix (ECM). Toca 1 colocalizes with Cortactin, and we show that this interaction is mediated by the SH3 domain of Toca-1. Stable knockdown (KD) of Toca-1 expression in MDA-MB 231 cells led to a significant defect in epidermal growth factor (EGF)-induced cell migration and invasion. Toca-1 KD cells also showed significant defects in EGF- and Src-induced ECM digestion and formation of invadopodial membrane protrusions. To test the role of Toca-1 in metastasis, we achieved stable Toca-1 KD in both human and rat metastatic breast adenocarcinoma cell lines. Orthotopic tumor xenografting of control and Toca-1 KD cells in natural-killer /B-/T-cell deficient mice revealed a significant defect in spontaneous lung metastases with Toca-1 silencing in vivo. In contrast, no defects in primary tumor growth or lung seeding following tail vein injection of Toca-1 KD cells was observed, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, our results identify Toca-1 as a proinvasive protein in breast adenocarcinoma and a potential therapeutic target to limit tumor metastasis. PMID- 22824801 TI - C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co chaperones CHIP and HOP to determine cellular protein folding/degradation balances. AB - Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-beta in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment. PMID- 22824805 TI - Application of F4TCNQ doped spiro-MeOTAD in high performance solid state dye sensitized solar cells. AB - Amid the investigation of solid-state dye-sensitized solar cells (SDSSCs), it was found that the incorporation of F4TCNQ into the solid hole-transporting materials (HTMs) spiro-MeOTAD forms a spiro-MeOTAD/F4TCNQ (strong electron acceptor) polaron charge-transfer complex. Careful examination indicates that the formation of the polaron charge-transfer complex not only facilitates the conductivity of HTMs but also inhibits the charge recombination across the interface of the heterojunction, i.e. photoanode/HTMs and/or counter electrode/HTMs. As a result, the performance of SDSSCs has been markedly improved by using the organic dye A2 F. At AM1.5 illumination the short circuit current densities J(SC) increase from 8.29 mA cm(-2) (w/o F4TCNQ) to 10.95 mA (w/F4TCNQ), accompanied by a 20% increase of the overall power conversion efficiency, eta, from 4.55% to 5.44%. PMID- 22824799 TI - Tetraspanin CD151 plays a key role in skin squamous cell carcinoma. AB - Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared with other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3 (signal transducers and activators of transcription), a regulator of cell proliferation and apoptosis. CD151 also supports protein kinase C (PKC)alpha-alpha6beta4 integrin association and PKC-dependent beta4 S1424 phosphorylation, while regulating alpha6beta4 distribution. CD151-PKCalpha effects on integrin beta4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including 7,12-dimethylbenz[alpha]anthracene (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting epidermal growth factor receptor, PKC, Jak2/Tyk2 and STAT3. Hence, CD151 'co targeting' may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151/laminin-binding integrin complexes. PMID- 22824800 TI - p53 isoform profiling in glioblastoma and injured brain. AB - The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10 to 70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, some of which can modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry and reverse transcription-PCR. We found that the most consistently expressed isoform in glioblastoma, Delta40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared with tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Delta40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions. PMID- 22824806 TI - The association of adolescent socioeconomic position and adult height: variation across racial/ethnic groups. AB - Numerous studies have demonstrated the association of childhood socioeconomic position and adult height. Many have suggested the use of adult height as a marker of overall childhood well-being. However, few studies have examined the relationship between child/adolescent socioeconomic position and adult height in a racially/ethnically diverse cohort. Using the National Longitudinal Study of Adolescent Health, we examined the association of child/adolescent SEP (maternal education and maternal report of household income) and measured adult height in a diverse cohort of US adolescents/young adults. We found a positive gradient effect of maternal education on height in the overall population and in White and Mixed race males and females; no such gradient existed in Hispanic, Asian, or Black males or females. Only in Mixed race females was household income positively associated with height. These findings emphasize the need to recognize differential effects of socioeconomic status on height in different racial/ethnic and gender subpopulations. PMID- 22824807 TI - Identification of Pold2 as a novel interaction partner of protein inhibitor of activated STAT2. AB - Pold2 is a subunit of the DNA polymerase delta complex, encoding a protein involved in DNA replication and repair. In this study, using a yeast two-hybrid screening technique and the common cDNA fragment of the mouse PIAS2 as a bait, Pold2 was found to interact with PIAS2. A direct interaction between Pold2 and PIAS2 was confirmed by direct yeast two-hybrid. In vivo evidence of Pold2 association with PIAS2 was obtained by co-immunoprecipitation using HEK-293 cells. Subcellular localization studies demonstrated that Pold2 and PIAS2 were partially co-localized in mammalian cells. Collectively, our results suggest that Pold2 interacts under physiological conditions with PIAS2. PMID- 22824808 TI - Solvent-induced intercluster rearrangements and the reversible luminescence responses in sulfide bridged gold(I)-silver(I) clusters. AB - Blue or yellow-green emission is observed from two different crystal types of the same gold(I)-silver(I) molecular cluster [SAu(3)Ag(L1)(3)](BF(4))(2) (L1 = 2 diphenylphosphino-4-methylpyridine) depending on the crystallization conditions; structural data suggest that intermolecular Au...Au interactions account for the luminescence vapochromic responses; a similar observation was made on two other pairs of analogues. PMID- 22824809 TI - Expression of cancer stem cell markers in pancreatic intraepithelial neoplasias and pancreatic ductal adenocarcinomas. AB - Cancer stem cells (CSCs) play pivotal roles in cancer growth, invasion, metastasis and recurrence. Several proteins have been reported as CSC markers for pancreatic ductal adenocarcinoma (PDAC). In the present study, we examined the correlation between pancreatic intraepithelial neoplasias (PanINs) and CSC markers including CD24, CD44, CD133, CXCR4, ESA and nestin using immunohistochemical analysis. Furthermore, we examined the roles and clinical significance of these CSC markers in PDAC. CD24-, CD44-, CXCR4-, ESA- and nestin positive cells were detected in the following tissues, listed in order of increasing percentage: normal ducts < low-grade PanINs < high-grade PanINs < PDACs. CD133 did not increase according to the malignancy grade. In PDAC, cells positive for each of the following CSC markers were detected, listed according to increasing percentage: nestin < CD133 < CD44 < CD24 < CXCR4 < ESA. CXCR4 and ESA expression correlated with well-differentiated PDAC. Venous invasion was positively associated with CD133 and inversely associated with ESA. CSC marker expression levels detected in PDAC cell lines using flow cytometry showed lowest expression of CD133 and highest of CD44, differing from the results obtained using immunohistochemistry. In two PDAC subtypes, adenosquamous carcinoma and anaplastic carcinoma, ESA was expressed more abundantly in adenocarcinoma components, whereas CD44 and nestin showed high expression in anaplastic components. Together, these results suggest that most CSC markers correlate with pancreatic carcinogenesis through the PanIN-to-PDAC sequence. Each CSC marker was related in a different manner with proliferation, differentiation, invasiveness or tissue type of PDAC. PMID- 22824810 TI - Evidence for the existence of dopamine D2-oxytocin receptor heteromers in the ventral and dorsal striatum with facilitatory receptor-receptor interactions. PMID- 22824811 TI - Chronic dim light at night provokes reversible depression-like phenotype: possible role for TNF. AB - The prevalence of major depression has increased in recent decades and women are twice as likely as men to develop the disorder. Recent environmental changes almost certainly have a role in this phenomenon, but a complete set of contributors remains unspecified. Exposure to artificial light at night (LAN) has surged in prevalence during the past 50 years, coinciding with rising rates of depression. Chronic exposure to LAN is linked to increased risk of breast cancer, obesity and mood disorders, although the relationship to mood is not well characterized. In this study, we investigated the effects of chronic exposure to 5 lux LAN on depression-like behaviors in female hamsters. Using this model, we also characterized hippocampal brain-derived neurotrophic factor expression and hippocampal dendritic morphology, and investigated the reversibility of these changes 1, 2 or 4 weeks following elimination of LAN. Furthermore, we explored the mechanism of action, focusing on hippocampal proinflammatory cytokines given their dual role in synaptic plasticity and the pathogenesis of depression. Using reverse transcription-quantitative PCR, we identified a reversible increase in hippocampal tumor necrosis factor (TNF), but not interleukin-1beta, mRNA expression in hamsters exposed to LAN. Direct intracerebroventricular infusion of a dominant-negative inhibitor of soluble TNF, XPro1595, prevented the development of depression-like behavior under LAN, but had no effect on dendritic spine density in the hippocampus. These results indicate a partial role for TNF in the reversible depression-like phenotype observed under chronic dim LAN. Recent environmental changes, such as LAN exposure, may warrant more attention as possible contributors to rising rates of mood disorders. PMID- 22824812 TI - Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. PMID- 22824813 TI - CAMK2A polymorphisms predict working memory performance in humans. PMID- 22824815 TI - An unusual risk factor for intrahepatic cholangiocarcinoma. PMID- 22824814 TI - An integrated fiber-optic microfluidic device for detection of muscular force generation of microscopic nematodes. AB - This paper reports development of an integrated fiber-optic microfluidic device for measuring muscular force of small nematode worms with high sensitivity, high data reliability, and simple device structure. A moving nematode worm squeezed through multiple detection points (DPs) created between a thinned single mode fiber (SMF) cantilever and a sine-wave channel with open troughs. The SMF cantilever was deflected by the normal force imposed by the worm, reducing optical coupling from the SMF to a receiving multimode fiber (MMF). Thus, multiple force data could be obtained for the worm-SMF contacts to verify with each other, improving data reliability. A noise equivalent displacement of the SMF cantilever was 0.28 MUm and a noise equivalent force of the device was 143 nN. We demonstrated the workability of the device to detect muscular normal forces of the parasitic nematodes Oesophagotomum dentatum L3 larvae on the SMF cantilever. Also, we used this technique to measure force responses of levamisole sensitive (SENS) and resistant (LERV) O. dentatum isolates in response to different doses of the anthelmintic drug, levamisole. The results showed that both of the isolates generated a larger muscular normal force when exposed to a higher concentration of levamisole. We also noticed muscular force phenotype differences between the SENS and LERV worms: the SENS muscles were more sensitive to levamisole than the LERV muscles. The ability to quantify the muscular forces of small nematode worms will provide a new approach for screening mutants at single animal resolution. Also, the ability to resolve small differences in muscular forces in different environmental conditions will facilitate phenotyping different isolates of nematodes. Thus, the present technology can potentially benefit and advance the current whole animal assays. PMID- 22824816 TI - Increased number and function of endothelial progenitor cells stimulate angiogenesis by resident liver sinusoidal endothelial cells (SECs) in cirrhosis through paracrine factors. AB - BACKGROUND & AIMS: Recent studies have shown a pathological role of angiogenesis in the progression of chronic liver diseases (CLDs). The present study focused on numbers and angiogenic functions of circulating endothelial progenitor cells (EPCs) in patients with cirrhosis. METHODS: Circulating EPCs were counted by flow cytometry, and correlated with different parameters of liver disease. They were cultured in patients and controls to compare colony-formation, proliferation and tube formation. Interactions of EPCs with hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were examined by indirect and direct co cultures in presence of EPCs and EPC-conditioned medium, respectively. ELISA and inhibition assays were performed to assess the role of EPC-derived angiogenic factors. RESULTS: The number of circulating EPCs was substantially higher in cirrhotic patients compared to controls (p<0.05), and showed good correlation with hepatic disease severity. Functional assays revealed that colonies and proliferation of EPCs were significantly increased in patients compared to controls (p<0.05). Direct and indirect co-cultures of patients' EPCs showed an increase in tube formation by SECs as compared to that observed with control EPCs (p<0.05). There was, however, no tube formation in HSC-EPC co-cultures. Levels of PDGF-BB and VEGF were substantially increased in patients' EPC media and inhibition of these factors by neutralizing antibodies led to a significant reduction in SECs proliferation. CONCLUSIONS: Mobilization and proliferation of EPCs are significantly enhanced in cirrhotic patients in comparison to controls. EPCs may play an important paracrine role in liver angiogenesis by stimulating resident SECs in cirrhosis. PMID- 22824817 TI - Focus. PMID- 22824818 TI - Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy. AB - BACKGROUND & AIMS: Previous studies reported that the combination of three tumor markers for hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP), has the ability to discriminate survival among patients with HCC. In those studies, however, the study population included all patients with various treatment modalities, and tumor markers were measured only before treatment. We investigated the prognostic value of a combination of these tumor markers for HCC, measured before and after treatment, on survival and recurrence in patients treated with hepatectomy. METHODS: A total of 173 patients who underwent hepatectomy for primary, non-recurrent HCC were analyzed. Tumor characteristics, postoperative survival, and recurrence rates were compared according to the number of elevated tumor markers measured before and after treatment. RESULTS: The correlation between the number of elevated tumor markers before treatment and tumor size, rate of portal vein invasion, and tumor differentiation, respectively, was stronger than that between the number of elevated tumor markers after treatment. In contrast, the number of elevated tumor markers after treatment displayed an excellent ability to discriminate post-treatment survival and recurrence rates compared to that before treatment, and was an independent factor associated with survival and recurrence in multivariate analysis. CONCLUSIONS: The combination of tumor markers measured after hepatectomy has a better discriminatory ability for postoperative survival and recurrence in HCC patients treated with hepatectomy in comparison to the combination of tumor markers measured before treatment. PMID- 22824819 TI - Factors related to quality of life in patients with cirrhosis and ascites: relevance of serum sodium concentration and leg edema. AB - BACKGROUND & AIMS: Hyponatremia is common in patients with cirrhosis and ascites and is associated with significant neurological disturbances. However, its potential effect on health-related quality of life (HRQL) in cirrhosis has not been investigated. We aimed at assessing the relationship between serum sodium concentration and other clinical and analytical parameters on HRQL in cirrhosis with ascites. METHODS: A total of 523 patients with cirrhosis and ascites were prospectively investigated. Assessment of HRQL was done with the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire, which is divided into 8 domains, summarized in two components: physical component score (PCS) and mental component score (MCS). Demographic, clinical, and analytical data at baseline were analyzed for their relationship with HRQL. RESULTS: In multivariate analysis, independent predictive factors associated with an impaired PCS were non-alcoholic etiology of cirrhosis, severe ascites, history of previous episodes of hepatic encephalopathy and falls, presence of leg edema, and low serum sodium concentration. With respect to MCS, only two factors were associated with the independent predictive value: low serum sodium concentration and treatment with lactulose or lactitol. In both components, the scores decreased in parallel with the reduction in serum sodium concentration. Variables more commonly associated with the independent predictive value in the individual 8 domains of PCS and MCS were presence of leg edema and serum sodium concentration, 7 and 6 domains, respectively. CONCLUSIONS: Serum sodium concentration and presence of leg edema are major factors of the impaired HRQL in patients with cirrhosis and ascites. PMID- 22824820 TI - Lactobacillus johnsonii La1 without antioxidants does not decrease bacterial translocation in rats with carbon tetrachloride-induced cirrhosis. PMID- 22824821 TI - Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. AB - BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is a widely used treatment for hepatocellular carcinoma. In order to maximize its therapeutic efficacy, doxorubicin-loaded drug-eluting beads have been developed to deliver higher doses of the chemotherapeutic agent and to prolong contact time with the tumor. The purpose of this study was to evaluate the efficacy and safety of drug eluting bead (DC bead(r)) TACE in comparison with conventional TACE (cTACE). METHODS: A total of 129 patients who underwent TACE between August 2008 and February 2011 were enrolled. We compared HCC patients who underwent TACE with DC bead(r) (n=60) to controls who received cTACE (n=69). The primary end points were treatment response and treatment-related adverse events. The secondary end point was time to progression. RESULTS: The treatment response in the DC bead(r) group was significantly higher than that of the cTACE group (p<0.001). The time to progression was significantly better in the DC bead(r) group than in the cTACE group (11.7 and 7.6months, respectively, p=0.018). Subgroup analysis showed that in intermediate-stage HCC, DC bead(r) treatment resulted in a significantly better treatment response and longer time to progression than cTACE (p<0.001 and 0.038, respectively). However, there was no statistically significant difference in liver toxicity between the DC bead(r) and cTACE group (p>0.05). CONCLUSIONS: TACE with DC bead(r) showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in hepatic treatment-related toxicities. DC bead(r) TACE thus appears to be a feasible and promising approach to the treatment of HCC. PMID- 22824822 TI - Recent advances in novel targeted therapies for HER2-positive breast cancer. AB - The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). However, despite this advancement, many tumors develop resistance and novel approaches are needed. Recently, a greater understanding of cellular biology has translated into the development of novel anti-HER2 agents with varying mechanisms of action. The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in HER2-positive metastatic breast cancer (MBC) and in the preoperative setting. Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to improvements in progression-free survival in patients with HER2-positive MBC and higher response rates in the preoperative setting. An alternative approach is the use of novel antibody-drug conjugates such as trastuzumab-emtansine, which recently demonstrated activity in MBC. Neratinib, a pan-HER tyrosine kinase inhibitor, which irreversibly inhibits HER1 and HER2, also has proven activity in MBC. A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90, a molecular chaperone required for the stabilization of cellular proteins. Furthermore, agents are being developed to inhibit the mammalian target of rapamycin, a downstream component of the PTEN/PI3K pathway, which has been implicated in trastuzumab resistance. Finally, there are emerging data indicating that combinations of anti-HER2 agents may circumvent resistance mechanisms and improve patient outcomes. In this review, recent data on these emerging agents and novel combinations for HER2-positive breast cancer are discussed. PMID- 22824823 TI - An antitumor peptide from Musca domestica pupae (MATP) induces apoptosis in HepG2 cells through a JNK-mediated and Akt-mediated NF-kappaB pathway. AB - An antitumor peptide from Musca domestica pupae (MATP) was seen to inhibit proliferation and induce apoptosis in cancer cells in our previous investigation. However, the molecular mechanisms involved in MATP-induced apoptosis are still uncharacterized in the human liver cancer cell line HepG2. The present study was undertaken to elucidate the signaling events in MATP-induced apoptosis of HepG2 cells. In this study, the sustained activation of phosphorylated c-Jun N-terminal kinase (JNK) and the obvious inactivation of phosphorylated Akt(Ser473), which prevented IkappaBalpha from degeneration, were induced by MATP. Simultaneously, the apoptosis induced by MATP was reversed by SP600125 (a JNK inhibitor) whereas it was aggravated by LY294002 (an Akt inhibitor). These results proved that JNK and Akt independently participated in the apoptosis of HepG2 cells, which were treated with MATP. Moreover, the activation of phosphorylated JNK together with the inactivation of phosphorylated Akt(Ser473) restrained nuclear factor-kappaB (NF-kappaB p65) from entering the nucleus. The apoptosis induced by MATP was increased by pyrrolidine dithiocarbamate (NF-kappaB p65 inhibitor) and the restriction of NF-kappaB p65 from entering the nucleus induced the decrease of Bcl-2. Simultaneously, MATP induced the increase of Bax, but this mechanism did not depend on the decrease of NF-kappaB p65 in the nucleus. The release of cytochrome c from the mitochondria, which intensified the expression of caspase-9 and caspase-3, was enhanced by the increase in Bax-to-Bcl-2 expression ratio. The apoptosis of HepG2 cells was induced ultimately by the increase in caspase-3. Taken together, these findings suggest that MATP-induced apoptosis through a JNK mediated and Akt-mediated NF-kappaB pathway. PMID- 22824824 TI - Genomic methylation profiling combined with gene expression microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma taxol resistance. AB - Taxol is a first-line chemoagent used for treatment of nasopharyngeal carcinoma (NPC). A major obstacle to achieving successful treatment is the development of cellular taxol drug resistance. Aberrant DNA methylation has been recognized to be associated with the transcriptional inactivation of genes related to cancer drug resistance development. To identify the mechanism of DNA methylation involved in NPC taxol resistance, we applied a genome-wide DNA methylation microarray assay to reveal methylation alteration in taxol-resistant NPC cell lines (CNE-1/taxol, 5-8F/taxol, HNE-2/taxol) established previously in our laboratory. Combining with gene expression microarray, we identified drug resistance-associated genes in taxol-resistant cell lines. We also investigated the coeffect of taxol and the DNA methyltransferase inhibitor 5-aza-2' deoxycytidine (5-aza-dC) to confirm the involvement of DNA methylation. The methylation profiling revealed differential patterns between the drug-sensitive and -resistant cell lines. As a result, taxol-resistant cell lines were detected to be globally hypermethylated. Forty-eight differentially methylated genes (30 hypermethylated and 18 hypomethylated) were further identified commonly in the three taxol-resistant cell lines. Six of them (DLC1, CHFR, ABCC5, PEG10, ERBB2, and GSTP1) were independently confirmed to contribute to taxol resistance by both methylation-specific PCR and quantitative real-time PCR. Finally, we conclude that DNA methylation is closely correlated with taxol drug resistance in NPC cells. Combined analysis of DNA methylation and gene expression may enable the discovery of new therapeutic targets and prognostic biomarkers of cancers. Furthermore, DNA methylation inhibitors can reverse chemoresistance and prevent the development of acquired drug resistance. PMID- 22824825 TI - Errors in ribosomal sequence datasets generated using PCR-coupled 'panbacterial' pyrosequencing, and the establishment of an improved approach. AB - Universal bacterial primers are often used in PCR-coupled sequencing approaches to investigate environmental and host-associated bacterial communities. Some of these primers can also amplify eukaryotic DNA. This is leading to the submission of datasets to public databases which are erroneously annotated as prokaryotic sequences. The present note sends a message about the risk of submitting incorrectly annotated sequence data and suggests a reliable approach for the sequencing of 16S rRNA genes and identification of bacteria within complex communities. PMID- 22824826 TI - Monitoring changes in the intracellular calcium concentration and synaptic efficacy in the mollusc Aplysia. AB - It has been suggested that changes in intracellular calcium mediate the induction of a number of important forms of synaptic plasticity (e.g., homosynaptic facilitation). These hypotheses can be tested by simultaneously monitoring changes in intracellular calcium and alterations in synaptic efficacy. We demonstrate how this can be accomplished by combining calcium imaging with intracellular recording techniques. Our experiments are conducted in a buccal ganglion of the mollusc Aplysia californica. This preparation has a number of experimentally advantageous features: Ganglia can be easily removed from Aplysia and experiments use adult neurons that make normal synaptic connections and have a normal ion channel distribution. Due to the low metabolic rate of the animal and the relatively low temperatures (14-16 degrees C) that are natural for Aplysia, preparations are stable for long periods of time. To detect changes in intracellular free calcium we will use the cell impermeant version of Calcium Orange which is easily 'loaded' into a neuron via iontophoresis. When this long wavelength fluorescent dye binds to calcium, fluorescence intensity increases. Calcium Orange has fast kinetic properties and, unlike ratiometric dyes (e.g., Fura 2), requires no filter wheel for imaging. It is fairly photo stable and less phototoxic than other dyes (e.g., fluo-3). Like all non-ratiometric dyes, Calcium Orange indicates relative changes in calcium concentration. But, because it is not possible to account for changes in dye concentration due to loading and diffusion, it can not be calibrated to provide absolute calcium concentrations. An upright, fixed stage, compound microscope was used to image neurons with a CCD camera capable of recording around 30 frames per second. In Aplysia this temporal resolution is more than adequate to detect even a single spike induced alteration in the intracellular calcium concentration. Sharp electrodes are simultaneously used to induce and record synaptic transmission in identified pre- and postsynaptic neurons. At the conclusion of each trial, a custom script combines electrophysiology and imaging data. To ensure proper synchronization we use a light pulse from a LED mounted in the camera port of the microscope. Manipulation of presynaptic calcium levels (e.g. via intracellular EGTA injection) allows us to test specific hypotheses, concerning the role of intracellular calcium in mediating various forms of plasticity. PMID- 22824827 TI - Electric field control of magnetism in multiferroic heterostructures. AB - We review the recent developments in the electric field control of magnetism in multiferroic heterostructures, which consist of heterogeneous materials systems where a magnetoelectric coupling is engineered between magnetic and ferroelectric components. The magnetoelectric coupling in these composite systems is interfacial in origin, and can arise from elastic strain, charge, and exchange bias interactions, with different characteristic responses and functionalities. Moreover, charge transport phenomena in multiferroic heterostructures, where both magnetic and ferroelectric order parameters are used to control charge transport, suggest new possibilities to control the conduction paths of the electron spin, with potential for device applications. PMID- 22824828 TI - The impact of county-level radiation oncologist density on prostate cancer mortality in the United States. AB - BACKGROUND: The distribution of radiation oncologists across the United States varies significantly among geographic regions. Accompanying these variations exist geographic variations in prostate cancer mortality. Prostate cancer outcomes have been linked to variations in urologist density, however, the impact of geographic variation in the radiation oncologist workforce and prostate cancer mortality has yet to be investigated. The goal of this study was to determine the effect of increasing radiation oncologist density on regional prostate cancer mortality. METHODS: Using county-level prostate cancer mortality data from the National Cancer Institute and Centers for Disease Control as well as physician workforce and health system data from the Area Resource File a regression model was built for prostate cancer mortality controlling for categorized radiation oncologist density, urologist density, county socioeconomic factors and pre existing health system infrastructure. RESULTS: There was statistically significant reduction in prostate cancer mortality (3.91-5.45% reduction in mortality) in counties with at least 1 radiation oncologist compared with counties lacking radiation oncologists. However, increasing the density of radiation oncologists beyond 1 per 100 000 residents did not yield statistically significant incremental reductions in prostate cancer mortality. CONCLUSION: The presence of at least one radiation oncologist is associated with significant reductions in prostate cancer mortality within that county. However, the incremental benefit of increasing radiation oncologist density exhibits a plateau effect providing marginal benefit. In order to optimize outcomes a geographically aware policy, which addresses the size and distribution of the workforce, must be in place in order prevent geographic disparities in prostate cancer mortality. PMID- 22824829 TI - For human immunodeficiency virus disease, more treatment seems to be better: comment on "Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion". PMID- 22824830 TI - Charge localization increases chemical expansion in cerium-based oxides. AB - In this work, we demonstrate the mechanism by which electronic charge localization increases the chemical expansion coefficient in two model systems, CeO(2-delta) and BaCeO(3-delta). Using Density Functional Theory calculations, we predict that this coefficient is increased by more than 70% when charge is fully localized, consistent with the observation that materials with a smaller degree of charge localization have smaller chemical expansion coefficients. This finding has important consequences for devising materials with smaller chemical expansion coefficients and for the reliability of the widely-used Shannon's ionic radii. PMID- 22824832 TI - Probing excited state electronic communications across diethynyl [2.2]paracyclophane-containing conjugated organometallic polymers. AB - The triplet k(ET) for three organometallic polymers built upon the diethynyl[2.2]paracyclophane was studied to show good excited state electronic communication across the materials. PMID- 22824831 TI - AAV2-mediated gene transfer of VEGF-Trap with potent suppression of primary breast tumor growth and spontaneous pulmonary metastases by long-term expression. AB - Vascular endothelial growth factor (VEGF) is an important signaling protein and a predominant mediator of angiogenesis in tumor growth and metastasis. Therefore, antagonism of the VEGF pathway results in inhibition of abnormal angiogenesis, then suppression of tumor growth and metastasis. VEGF-Trap, a high-affinity soluble decoy receptor, is currently in phase II clinical trails, and has demonstrated more efficacy in different types of solid tumors by intravenous injection every two weeks. In our study, we used recombinant AAV2 as a delivery vehicle to achieve long-lasting expression of VEGF Trap protein in a mouse model for the first time. We report that AAV2-VEGF-Trap can be safely administered and sustained expression in vivo via a single intravenously administration, simultaneously suppressing primary tumor growth and preventing the pulmonary metastases of 4T1 tumors. Decreased microvessel density and increased tumor cell apoptosis were observed in the treatment group. AAV2-VEGF-Trap can obviously decrease not only the concentration of VEGF in sera, but also the concentration of other angiogenic factors, such as aFGF, bFGF, angiopoietin-1 and others. These studies suggest that AAV-mediated long-term expression of VEGF-Trap is a useful and safe tool to block tumor progression and inhibit spontaneous pulmonary metastases. PMID- 22824833 TI - Multifunctional fluorescent-magnetic polyethyleneimine functionalized Fe3O4 mesoporous silica yolk-shell nanocapsules for siRNA delivery. AB - A facile, mild, environmentally friendly and reproducible strategy was used to fabricate the multifunctional fluorescent-magnetic polyethyleneimine functionalized Fe(3)O(4)-mesoporous silica yolk-shell nanocapsules for simultaneous fluorescent tracking and magnetically guided small interfering RNA delivery. PMID- 22824834 TI - The efficacy of transdermal fentanyl for pain relief after endoscopic submucosal dissection: a prospective, randomised controlled trial. AB - OBJECTIVE: Epigastric pain management following endoscopic submucosal dissection is an important consideration. This study aimed to investigate the utility and safety of fentanyl patches for pain relief after the procedure. METHODS: Patients who were scheduled to undergo endoscopic submucosal dissection were prospectively randomised to either a transdermal fentanyl patch group or a placebo control group. An additional pethidine was intravenously administered when pain developed and a numerical rating scale was used to evaluate both pre- and post-procedural pain. RESULTS: One hundred and ten patients were randomly assigned to receive either a 12 mcg/h fentanyl patch or a control patch on the night before the procedure. The fentanyl patch group had significantly lower pain scores immediately following the procedure (mean, 5.17 vs. 4.26, p=0.030). Maximal pain scores during the first 24 h (5.43 vs. 4.46, p=0.038) and pain scores on the day after the procedure (2.98 vs. 1.20, p<0.001) were also lower in the fentanyl patch group. In addition, the fentanyl patch group required a significantly lower dose of pethidine for pain management (24.54 vs. 11.25, p=0.004). CONCLUSIONS: The application of a transdermal fentanyl patch is an effective, convenient, and safe method to control epigastric pain after endoscopic submucosal dissection. PMID- 22824835 TI - Sex differences in coeliac disease risk: a Swedish sibling design study. AB - BACKGROUND: For unknown reasons girls are at an increased risk of coeliac disease compared to boys. However, the observed association might be confounded, since maternal coeliac disease is associated with both an increased risk of the disease in first-degree relatives as well as an increased ratio of girls to boys in offspring. AIMS: We investigate the effect of sex on the risk of coeliac disease before the age of two years using sibling design. METHODS: We identified all singleton children (n=792,401) born between 1987 and 1993 in Sweden using the Swedish Medical Birth Registry. Coeliac disease cases (2264) were identified using the Swedish National Inpatient Registry. We applied both conventional population-based Cox regression models and sibling designs modelling the association in sex discordant siblings. RESULTS: We observed a conclusively increased risk of coeliac disease in girls compared to boys, using both sibling design (hazard ratio 1.67, 95% confidence interval 1.44-1.93) and conventional Cox regression analysis (hazard ratio 1.75, 95% confidence interval 1.61-1.91) that could not be explained by perinatal factors previously associated with the disease. CONCLUSIONS: We confirm that female sex is causally associated with childhood coeliac disease, but the reasons remains unknown. PMID- 22824836 TI - The epidemiology of injury in adventure and extreme sports. AB - The objective of this article is to provide an overview of the current knowledge related to the epidemiology of injury in selected adventure and extreme sports. PubMed and Google Scholar were searched using the terms 'epidemiology', 'injury,' 'adventure sports' and 'extreme sports'. Publications from the past 10 years were largely selected, but commonly referenced or highly regarded older publications were also included. References lists of articles identified in the search strategy were also searched and articles selected that were judged to be relevant. Important aspects of the epidemiology of injury related to adventure and extreme sports are discussed including occurrence of injury, who is affected by injury, where and when injury occurs, injury outcome, risk factors, inciting events, prevention and further research. Given the life-changing impact injury can have in sports (personal, social, financial, psychological, political, and medical), the current paucity of well-designed descriptive and particularly analytical epidemiological studies in some adventure and extreme sports is disturbing. The importance of denominator-based and longitudinal data collection in obtaining an accurate picture of injury risk and severity and as a basis for testing risk factors and evaluating preventive measures is emphasized. PMID- 22824837 TI - The epidemiology of injury in mountaineering, rock and ice climbing. AB - Climbing and mountaineering sports are gaining more and more public interest. This chapter reviews scientific studies on injuries and accidents in climbing and mountaineering sports to evaluate the danger of these sports and their specific injuries and preventive measures. An initial PubMed query was performed using the key words 'rock climbing', 'sport climbing', 'mountaineering', 'alpine injuries' and 'climbing injuries'. More than 500 extracted papers were analyzed which gave information on injury, mortality/fatality, prevention and risk factors. Cross references were also scanned according to the above given criteria. Also the data sources of the UIAA and IFSC Medical Commissions were analyzed. Overall, alpine (traditional) climbing has a higher injury risk than sport climbing, especially indoor climbing. Alpine and ice climbing have more objective dangers which can affect climber safety. Overall injury rates are low, nevertheless fatalities do occur in all climbing disciplines. Altitude-related illnesses/injuries also occur in mountaineering. Most injuries in sport climbing are overstrain injuries of the upper extremity. In alpine climbing, injuries mostly occur through falls which affect the lower extremity. Objective reporting of the injury site and severity varied in most studies according to the injury definition and methodology used. This creates differences in the injury and fatality results and conclusions, which in turn makes inter-study comparisons difficult. In future studies, the UIAA MedCom score for mountain injuries should be used to guarantee inter-study comparability. Evidence in preventive measures is low and further studies must be performed in this field. PMID- 22824838 TI - The epidemiology of injury in hang-gliding and paragliding. AB - Para- and hang-gliding are modern air sports that developed in the 20th century. Performers should possess technical skills and manage certified equipment for successful flight. Injuries may happen during the take-off, flight and landing. PubMed was searched using the search terms 'paragliding' and/or 'hang-gliding'. The reference lists of articles identified in the search strategy were also searched for relevant articles. The most common injuries are fractures, dislocations or sprains in the extremities, followed by spinal and head traumas. Multiple injuries after accidents are common. Collision with electrical wires may cause burn injuries. Fatal outcomes are caused by brain injuries, spinal cord injuries at the cervical level or aorta rupture. Accidents happen because of risk taking behavior, lack of education or use of self-modified equipment. Observational studies have suggested the need for protection of the head, trunk and lower extremities. The measures proposed are often based on conclusions of observational studies and not proven through randomized studies. Better education along with focusing on possible risk factors will probably diminish the risks of hang- and paragliding. Large denominator-based case series, case-control and population-based studies are needed for assessment of the risks of hang- and paragliding. PMID- 22824839 TI - The epidemiology of injury in scuba diving. AB - The epidemiology of injury associated with recreational scuba diving is reviewed. A search of electronic databases and reference lists identified pertinent research. Barotrauma, decompression sickness and drowning-related injuries were the most common morbidities associated with recreational scuba diving. The prevalence of incidents ranged from 7 to 35 injuries per 10,000 divers and from 5 to 152 injuries per 100,000 dives. Recreational scuba diving fatalities account for 0.013% of all-cause mortality aged >= 15 years. Drowning was the most common cause of death. Among treated injuries, recovery was complete in the majority of cases. Dive injuries were associated with diver-specific factors such as insufficient training and preexisting medical conditions. Environmental factors included air temperature and flying after diving. Dive-specific factors included loss of buoyancy control, rapid ascent and repetitive deep diving. The most common event to precede drowning was running out of gas (compressed air). Though diving injuries are relatively rare prospective, longitudinal studies are needed to quantify the effects of known risk factors and, indeed, asymptomatic injuries (e.g. brain lesions). Dive injury health economics data also remains wanting. Meanwhile, health promotion initiatives should continue to reinforce adherence to established safe diving practices such as observing depth/time limits, safety stops and conservative ascent rates. However, there is an obvious lack of evaluated diving safety interventions. PMID- 22824840 TI - The epidemiology of injury among surfers, kite surfers and personal watercraft riders: wind and waves. AB - The objective of this review was to summarize the epidemiological literature for surfboard riding (surfing), kite surfing and personal watercraft (PWC) riding injuries and describe the incidence and nature of these injuries, common risk factors, and strategies for prevention. The databases searched for relevant publications included Medline, ScienceDirect, ProQuest International, PubMed, Academic Search Premier as well as Google Scholar to identify additional, non indexed studies. Overall, there was a lack of good quality descriptive studies for these three sports and many of the studies reviewed involved the use of administrative datasets or case-series designs. Among the few studies to provide incidence estimates, there were inconsistencies in how injury was defined, the inclusion criteria, and the reporting of incidence rates, making comparisons within and between the sports difficult. While the reported incidence rates were generally low, head and lower extremity injuries were common across all three sports. Only two studies reported evidence for postulated risk factors. Bigger waves and surfing over rock or reef sea floor increased the risk of injury among competitive surfers, while older age and having more experience increased the risk of significant injuries among recreational surfers. No evaluations of preventative measures were identified. This review demonstrates the need for well designed epidemiological research, especially studies that focus on the accurate measurement and description of incidence, nature, severity and circumstances of injuries. Once this has occurred, interventions targeted at reducing the incidence of injuries among these sports can be designed, implemented and evaluated. PMID- 22824842 TI - The epidemiology of injury in bungee jumping, BASE jumping, and skydiving. AB - Knowledge regarding epidemiology of injury is of benefit to injury prevention of activities associated with high risk. As relatively 'young' activities, the investigation of injuries and deaths related in extreme sports such as bungee jumping and BASE jumping is relatively sparse. Studies evaluating risk in civilian and military skydiving activities have been reported over the past decades, but technique and equipment has changed. Risk with bungee jumping is only sporadically reported in the literature, most often in connection with eye injuries, but also rare events of serious, life-threatening injuries and even death. BASE is an acronym for Building, Antenna, Span, Earth, which represents the fixed objects from which jumps are made. Estimated risk in BASE jumping for any injury (independent of severity grade) is 0.4-0.5%, which as 5- to 8-fold higher than skydiving. Typically, men outnumber women in a ratio of 10:1 in both injuries and case fatality rates. Age is frequently reported to range from 30 to 40 years. Notably, differences in training and environmental locations exist between recreational skydiving and BASE jumping. As BASE jumps are made from lower altitudes than skydives, jumpers generally fall at lower speeds, have far less aerodynamic control, and may lose flying stability. Yet, typical injuries include a bruised or sprained ankle during landing. Protective gear including helmet and pads may help to prevent such injuries, while more complex knowledge of human factors, environment and training are needed to prevent fatal injuries. PMID- 22824841 TI - The epidemiology of injury in canoeing, kayaking and rafting. AB - The aquatic environment is a complex mix of waterways with varying uses and hazards. It is the intersection of the use of the water and the hazards which provides enjoyment to those who use them as well as risk to a person's health. Canoeing, kayaking and rafting have and continue to be popular recreation sports in aquatic environments. This chapter explores participation in, risks associated with and prevention strategies for keeping canoeists, kayakers and rafters safe and healthy. There is a dearth of good quality descriptive studies exploring these issues, particularly around the risks involved and the effectiveness of proposed prevention strategies. According to Outdoor Foundation, there are 23.9 million people in the USA who undertake paddling activities per annum, with canoeing (10.1 million) being the most popular activity followed by recreational kayaking (6.2 million). There were 141 deaths of canoeists (89) and kayakers (52) identified by the US Coast Guard in their recreational boating statistics data for 2009. The crude rate of death per 100,000 participants for canoeing ranges between 0.72 and 0.92 and for kayaking between 0.37 and 0.41 per annum. Although death is the most severe consequence of a misadventure while paddling, there are a range of other hazards faced such as hitting objects, waterborne diseases, hypothermia from unintended submersion, blisters, muscle strain, cuts and abrasions. There are a range of prevention strategies which have been proposed and provided in this chapter. However, there is very little evidence of their effectiveness. Further research is required in understanding the risk associated with paddling activities, the effectiveness of prevention strategies and how these strategies might be delivered. PMID- 22824843 TI - The epidemiology of extreme hiking injuries in volcanic environments. AB - The objective of this review was to summarize the epidemiological literature for extreme hikers in volcanic environments and describe the incidence, nature and severity of injuries, the factors contributing to the injuries, and strategies for preventing injuries. Due to the relative newness of extreme hiking in volcanic environments, there are only a small handful of studies addressing the topic. Moreover, these studies are primarily focused on extreme hikers in Hawaii Volcanoes National Park. These studies found that the majority of extreme hikers in volcanic environments are inexperienced and unfamiliar with the potential hazards present in volcanic environments. The studies found that upper respiratory irritation resulting from exposure to volcanic gases and dehydration and scrapes, abrasions, lacerations, and thermal burns to the extremities were common injuries. The severity of the injuries ranged from simple on-site treat and-release incidents to more severe incidents and even death. This review reveals a need for well-designed epidemiologic research from volcanic destinations outside of Hawaii that identify the nature and severity of injuries along with the factors contributing to injury incidents. There is also a demonstrated need for studies identifying preventive measures that reduce both the occurrence and severity of extreme hiking incidents in volcanic environments. PMID- 22824844 TI - The epidemiology of injury in skateboarding. AB - The purpose of this report is to review the available literature to provide an epidemiological overview of skateboarding injuries, as well as to suggest possible areas for future research. A literature search was performed with the databases of PubMed, Sport Discus, Google and Google Scholar using the search terms 'skateboard', 'skateboarding', 'injury' and 'injuries', with all articles published in refereed journals in the English language being considered. An ancestry approach was also used. Articles from non-juried journals were also infrequently included to provide anecdotal information on the sport. Comparison of study results was compromised by the diversity of different study populations and variability of injury definitions across studies. The majority of injuries affect young males although conflicting arguments arise over the issues of age and experience in relation to injury severity. Most injuries are acutely suffered, and the most commonly affected body part was the wrist and forearm, with lower leg and ankle injuries also common. The incidence was relatively high but reports on severity differed. Clear conclusions could not be drawn on environmental location and risk factors. Most injuries tend to occur from a loss of balance leading to a fall, in more recent times due to a failed trick. Research on injury prevention is not conclusive although protective equipment and skatepark use are recommended. Further research using more rigorous study designs is required to gain a clearer picture of the incidence and determinants of injury, and to identify risk factors and viable injury countermeasures. PMID- 22824845 TI - The epidemiology of injury in ATV and motocross sports. AB - Off-road motorsports are popular in rural and suburban areas, and allow for racing, recreation, and easy access to backcountry destinations. This chapter will review the incidence and types of injuries sustained in off-road motorsports. We completed a structured review of motocross and all-terrain vehicle (ATV) injuries, assessing for injury rates, risk factors, and mortality figures. Information for this study was obtained from a PubMed search under the terms 'motocross', 'motorcross', 'all-terrain vehicles', 'injury', 'motorcycle', 'ATV'. Abstracts and articles in the English language from 1980 onward were reviewed. Further statistics were obtained from the US Consumer Product Safety Commission publications. Operating vehicles off-road requires coordination, experience, and training. Motocross is an organized sport with national associations governing the competition of highly trained athletes. ATVs are used both recreationally and commercially, typically for farming and ranching. ATV use appears more dangerous that motocross, with a higher mortality rate, disproportionately for children. Both sports continue to have high rates of head, spinal cord, and extremity injury. Future prospective studies in off-road motorsports should evaluate the risk factors for injury and target specific areas for injury prevention. Improved training programs, use and improvement of safety helmets, and for ATV use, limiting access to minors, may improve the overall safety of off-road motorsports. PMID- 22824846 TI - Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells. AB - Despite recent advancements in therapeutic drugs, multiple myeloma remains an incurable disease. Therefore, a more effective treatment is urgently required. In this study, we show that isobavachalcone (IBC), a natural chalcone compound, induces apoptosis- and autophagy-related cell death in myeloma cells. The inhibition of autophagy by knocking down beclin-1 or by using autophagy inhibitors, such as 3-methyladenine, bafilomycin A and chloroquine significantly enhanced IBC-induced cell death, as demonstrated by the increased number of Annexin V-positive cells. Moreover, we demonstrate that the collapse of the mitochondrial membrane potential contributes to chloroquine and IBC-induced cell death, which is accompanied by the activation of caspase-9, and -3, the cleavage of poly (ADP-ribose) polymerase (PARP) and the proteolytic activation of protein kinase Cdelta (PKCdelta). Furthermore, the inhibition of the activation of PKCdelta by rottlerin, an inhibitor of PKCdelta, not only suppressed the activation of PKCdelta, but also the apoptosis induced by the co-treatment of chloroquine and IBC, indicating the involvement of PKCdelta in chloroquine plus IBC-induced cell death. Finally, the combination of chloroquine and IBC had little effect on the viability of normal peripheral blood mononuclear cells. As both chloroquine and IBC have been shown to be relatively specific for cancer cells, the combination of these two agents at non-toxic or sub-toxic concentrations represents an attractive novel regimen for myeloma treatment and warrants further investigation in preclinical and clinical studies. PMID- 22824848 TI - Language network: segregation, laterality and connectivity. PMID- 22824847 TI - Novel monoclonal antibodies specific for CTLD-SSC and sialomucin domains of endosialin, a mural cell marker of tumor vasculature. AB - Endosialin, alternatively named tumor endothelial marker or CD248, was originally discovered as an antigen selectively expressed in tumor blood vessels. Subsequent studies showed that it is confined to stromal fibroblasts and pericytes of tumor vasculature rather than to tumor endothelium. Endosialin levels are upregulated in different tumor types including those derived from the brain, colon and breast. Expression of endosialin is associated with tumor growth, progression and correlates with a pro-proliferative and pro-migratory phenotype. However, the function of endosialin and mechanisms of its regulation are still incompletely understood. To facilitate further study of endosialin in angiogenesis, its interaction with the potential binding partners and other aspects of endosialin function, we generated six new domain-specific anti-endosialin monoclonal antibodies. Two of them recognize the C-type lectin-like domain-Sushi/SCR/CCP and four antibodies are directed to the sialomucin domain. The antibodies are suitable for various immunodetection methods including immunoblotting and immunohistochemistry. They represent important tools for improving our understanding of endosialin regulation, biological role and contribution of its extracellular domains to the tumor phenotype. PMID- 22824849 TI - Pressures to "measure up" in surgery: managing your image and managing your patient. AB - OBJECTIVE: To identify pressures created by surgical culture and social setting and explore mechanisms for how they might impact operative decision-making. BACKGROUND: Surgeons apply judgments within a powerful social context and are constantly socialized and influenced by communicative exchanges. In this study, the authors characterized the nature of the surgical social context, focusing on the interactions between external social influences and the cognitive ability of the surgeon to respond to uncertain, unexpected, or critical moments in operations. METHODS: The authors reviewed the sociological and psychosocial literatures to examine concepts in identity construction, socialization process, and image management literatures and synthesized a conceptual framework allowing for the examination of how social factors and image management might impact surgical performance. RESULTS: The surgeon's professional identity is constructed and negotiated on the basis of the context of surgical culture. Trainees are socialized to display confidence and certainty as part of the "hidden curriculum" and several sociocultural mechanisms regulating "appropriate" surgical behavior exist in this system. In the image management literature, individuals put on a "front" or social performance that is socially acceptable. Several mechanisms for how image management might impact surgical judgment and decision-making were identified through an exploration of the cognitive psychology literature. CONCLUSIONS: Sociopsychological literatures can be linked with decision-making and cognitive capacity theory. When cognitive resources reach their limit during critical and uncertain moments of an operation, the consumption of resources by the pressures of reputation and ego might interfere with the thought processes needed to execute the task at hand. Recognizing the effects of external social pressures may help the surgeon better self-regulate, respond mindfully to these pressures, and prevent surgical error. PMID- 22824850 TI - Surgery for caustic injuries of the upper gastrointestinal tract. AB - BACKGROUND: Surgery is the criterion standard for the treatment of severe burns and of late sequels after ingestion of corrosive agents, but long-term outcome is unknown. METHODS: Patients who underwent surgery between 1987 and 2006, for the treatment of severe caustic burns (group I, n = 268) or of late sequels (group II, n = 79) were included in the study. Survival and functional outcomes were analyzed. Functional success was defined as nutritional autonomy after removal of the jejunostomy and tracheotomy tubes. To compare the observed mortality with the expected mortality in the general population, a standardized mortality ratio (SMR) was used. RESULTS: Overall Kaplan-Meyer survival at 1, 5, 10, and 20 years of patients in group I was 76.4%, 63.6%, 53.9%, and 44.1%, respectively. On multivariate analysis, advanced age (P = 0.0021), extended resection (P = 0.0009), emergency esophagectomy (P = 0.013), and tracheobronchial injuries (P = 0.0011) were independent negative predictors of survival. The SMR of patients in group I was increased to 21.5 when compared to the general French population. Functional success was recorded in 147 (56%) patients in group I. Advanced age (P = 0.012), extended resection (P = 0.012), and emergency tracheotomy (P = 0.02) were independent predictors for failure. After esophageal reconstruction, patients in group II fared better than patients in group I in terms of survival (P = 0.0006) and functional success (P < 0.0001). Still, the SMR of patients in group II increased to 3.67. CONCLUSIONS: The need to perform surgery for caustic injuries has a persistent long-term negative impact on survival and functional outcome. PMID- 22824851 TI - Effects of prolonged pneumoperitoneum on hepatic perfusion during laparoscopy. AB - OBJECTIVE: To assess the influence of prolonged pneumoperitoneum (PP) on liver function and perfusion in a clinically relevant porcine model of laparoscopic abdominal insufflation. BACKGROUND: PP during laparoscopic surgery produces increased intra-abdominal pressure, which potentially influences hepatic function and microcirculatory perfusion. METHODS: Six pigs (49.6 +/- 5.8 kg) underwent laparoscopic intra-abdominal insufflation with 14 mm Hg CO2 gas for 6 hours, followed by a recovery period of 6 hours. Two animals were subjected to 25 mm Hg CO2 gas. Hemodynamic parameters were monitored, and damage parameters in the blood were measured to assess liver injury. Liver total blood flow and function were determined by the indocyanine green (ICG) clearance test. Intraoperative hepatic hemodynamics were measured by simultaneous reflectance spectrophotometry (venous oxygen saturation StO2 and relative tissue hemoglobin concentration rHb) and laser Doppler flowmetry (blood flow and flow velocity). Postmortem liver samples were collected for histological evaluation. RESULTS: A decrease in microvascular perfusion was observed during PP. After 6 hours of PP, ICG clearance increased (P < 0.001), indicating a compensatory improvement of overall liver blood flow resulting in concomitantly improved microcirculatory perfusion (P = 0.024). Minimal parenchymal damage (aspartate aminotransferase) of the liver was seen after 6 hours of PP (P = 0.006), which seemed related to PP pressure. Minor histological damage was observed. CONCLUSIONS: The liver sustains no additional damage due to prolonged PP during laparoscopic surgery. Our findings suggest that prolonged PP does not hamper liver function or cause liver damage after extended laparoscopic procedures. PMID- 22824852 TI - Evaluating time points for measuring recovery after major trauma in adults. AB - OBJECTIVE: To evaluate recovery after major trauma over a 24-month time frame. BACKGROUND: Measuring disability after injury is seen as increasingly important but requires knowledge not only of the measures that should be implemented but also of the critical time points for follow-up. METHODS: Six hundred sixty-two adult major trauma patients from 2 level 1 trauma centers (October 2006 to March 2007) were followed up by telephone at 6-, 12-, 18-, and 24 months after injury. SF-12, Glasgow Outcome Scale-Extended (GOS-E), pain scores, and return to work (RTW) were collected. Multilevel mixed-effects regression models were fitted to analyze change in outcomes over time. RESULTS: Six hundred seventeen (93%) were followed up for at least 1 time point. Functional recovery (GOS-E = 8) [odds ratio (OR) 3.1, 95% CI: 1.9, 5.0] and RTW (OR 2.4, 95% CI: 1.4, 4.0) improved, and physical health (PCS-12) scores were better (mean difference 1.9, 95% CI: 0.9, 2.9), from 6 to 12 months after injury, but changed little from 12 months. Pain scores were unchanged from 6 to 12 months but were higher at 18 months than at 12 months (OR 1.8, 95% CI: 1.2, 2.8). SF-12 mental health (MCS-12) scores decreased until 18 months but improved from 18 to 24 months (mean difference 1.5, 95% CI: 0.2, 2.8). The rate of recovery differed by injury group and age. CONCLUSIONS: Different patterns of recovery were evident for each outcome, and there was a variation in the rate of recovery for some subgroups. The selection of time points for follow-up requires consideration of the outcome measurements of interest and the population being studied. PMID- 22824853 TI - Do micropauses prevent surgeon's fatigue and loss of accuracy associated with prolonged surgery? An experimental prospective study. AB - OBJECTIVE: This prospective experimental study evaluates the effectiveness of micropauses (MPs) to prevent muscular fatigue and its deleterious effect on surgeons during prolonged surgical procedures. BACKGROUND: Operating is a hazard for surgeon's health. Beyond acute injuries and blood-borne infections, back and neck pain is a poorly recognized factor causing chronic ailment in more than half the surgeons surveyed. MP, a 20-second break every 20 minutes, is an accepted strategy used widely in the workplace. METHODS: We designed a crossover experimental study. Sixteen surgeons were tested 3 times: once in a control situation before any surgery (CTL) and twice after a prolonged, reproducible operation (at least 2 hours), 1 of these with formal MP (WMP) the other without (WOMP). Muscular fatigue was tested by holding a 2.5-kg weight as long as possible with a stretched arm. Accuracy was evaluated with a device, measuring the mistakes made when following a predetermined path on a board. Finally, discomfort was measured by visual analog scale. RESULTS: We found a statistically and more importantly clinically significant difference between the CTL and WOMP groups in all 3 tests. MPs prevented completely or almost completely the effects of fatigue associated with surgery [accuracy (No. errors) CTL: 1.1, WOMP: 7.7, WMP: 1.7; fatigue (seconds) CTL: 137, WOMP: 92, WMP: 142]. CONCLUSIONS: Surgical procedures are associated with significant muscular fatigue that can be measured simply and which has a direct effect on comfort and surgical accuracy. More important, this effect is completely or almost completely prevented by MPs. PMID- 22824854 TI - Impact of vancomycin surgical antibiotic prophylaxis on the development of methicillin-sensitive staphylococcus aureus surgical site infections: report from Australian Surveillance Data (VICNISS). AB - OBJECTIVE: To compare risks for developing surgical site infection (SSI) due to Staphylococcus aureus when vancomycin is used for antibiotic prophylaxis with risks when a beta-lactam antibiotic is administered for prophylaxis. BACKGROUND: Vancomycin is often used as surgical antibiotic prophylaxis for major surgery. In nonsurgical populations, there is evidence that vancomycin is less effective for prevention and treatment of methicillin-sensitive Staphylococcus aureus (MSSA) infections. Since 2002, the Victorian Healthcare Associated Surveillance System (VICNISS) has used standardized methods for infection surveillance in Australia, including any prophylactic antibiotic agent administered before surgical procedures. METHODS: Surveillance records were obtained for patients undergoing 4 clean surgical procedures during the period of November 2002 to June 2009. Logistic regression analysis was used to examine risk factors for infection, including age, procedure duration, American Society of Anesthesiologists score, and choice and timing of antibiotic prophylaxis. RESULTS: The data set consisted of 22,549 procedures, including cardiac bypass and hip and knee arthroplasty procedures. Vancomycin prophylaxis was administered in 1610 cases and a beta lactam antibiotic for 20,939 cases. A total of 754 SSIs were recorded. The most frequent pathogens were MSSA, methicillin-resistant Staphylococcus aureus, and Pseudomonas species. The adjusted odds ratio (OR) for an SSI with MSSA was 2.79, where vancomycin prophylaxis was administered (P < 0.001). For methicillin resistant Staphylococcus aureus infection, the adjusted OR for vancomycin was 0.44 (P = 0.05), whereas for Pseudomonas infection, it was 0.96 (P = 0.95). CONCLUSIONS: In a large Australian study population, prophylaxis with vancomycin was found to be associated with an increased risk of SSI due to MSSA when compared with prophylaxis with a beta-lactam antibiotic. Given the potential for poorer surgical outcomes in the setting of indiscriminate prophylactic vancomycin use, measures to improve adherence to guidelines for restricted administration of prophylactic vancomycin are supported. PMID- 22824855 TI - Perioperative fluid administration: historical highlights and implications for practice. AB - Perioperative fluid administration is an important aspect of surgical care but is often poorly understood. Surgeons have historically made a considerable contribution to the evidence base governing current practice. This review provides an overview of the history of perioperative fluid therapy and its relevance to modern practice.Intravenous fluids (IVF) first gained therapeutic importance in the treatment of cholera in the 1830s. From the 1880s, IVF began to be administered perioperatively to compensate for the "injurious" effects of anaesthesia. Clinical improvements were consequently noted, though the adverse effects of saline were observed. The work of Ringer, Hartmann, and others emphasized the importance of the composition of IVF and laid the foundations for the balanced solutions in use today.The intravenous "drip" was introduced by Rudolph Matas in 1924. As the metabolic response to injury was increasingly investigated in the 1940s and 1950s, the cause of post-operative oliguria was debated widely with the most prominent surgeons being Moore and Shires. These differences in opinion, coupled with reports of injured soldiers from the Korean War receiving large IVF infusions and surviving, dictated the surgical practice of liberal IVF administration until very recently.Newer work in fluid therapy has explored the concept of fluid restriction. Shoemaker and colleagues also pioneered the concept of fluid administration to achieve supranormal indices of cardiorespiratory function, which has led to the advent of goal-directed fluid therapy. Alongside the development of balanced solutions, the renewed focus on perioperative fluid therapy has led to IVF administration being guided by physiological principles with a new consideration of the lessons gleaned from history. PMID- 22824856 TI - Extracorporeal life support for pancreatitis-induced acute respiratory distress syndrome. AB - OBJECTIVE: Adult respiratory distress syndrome (ARDS) secondary to acute pancreatitis is associated with a poor prognosis. We hypothesized that extracorporeal life support (ECLS) may be an effective treatment option for the most severe cases of pancreatitis-induced ARDS. METHODS: We reviewed 8 cases of pancreatitis-induced ARDS that were treated with ECLS at our institution. We collected data on demographics, comorbidities, hemodynamic parameters, and ventilatory support used before ECLS. Our outcome measures for this study included survival to discharge, length of ECLS run, days undergoing mechanical ventilation, days in an intensive care unit, total length of hospital stay, adjunct therapies and procedures, and complications. RESULTS: Overall, 5 of the 8 patients (63%) survived to discharge. Seven of the 8 patients underwent venovenous ECLS, and 1 underwent venoarterial ECLS. The overall mean length of ECLS was 9.7 +/- 10.7 days. However, the mean ECLS run length in survivors was 4.3 +/- 1.8 days and the longest ECLS run in a survivor was 7.25 days. Two of the 3 patients who died had very long run lengths (28.8 and 24.7 days, respectively), whereas 1 patient had a short run (2.4 days). Five of the 8 patients (63%), including all of the 3 who died, experienced a bleeding complication of some kind. Two patients required continuous venovenous hemofiltration, 1 of whom died and 1 of whom survived. Six patients underwent tracheostomy on ECLS, 1 patient already had undergone tracheostomy, and 1 patient did not undergo tracheostomy. CONCLUSIONS: ECLS is useful in treating severe pancreatitis-induced ARDS. Pancreatic debridement can be performed during ECLS, using a comprehensive protocol to minimize bleeding complications. PMID- 22824857 TI - Volume-outcome relationships in lower extremity arterial bypass surgery. AB - OBJECTIVE: We sought to investigate whether a volume-outcome relationship exists for lower extremity arterial bypass (LEAB) surgery. METHODS: All LEAB procedures performed in England between 2002 and 2006 were identified from Hospital Episode Statistics data. A Charlson-type risk profile, including operating hospital annual case volume, was identified per patient. Outcome measures of revision bypass, amputation, death and a composite measure were established during the index admission and at 1 year.Quintile analysis and multilevel multivariate modeling were used to identify the existence of a volume-outcome relationship and allow adjustment of results for significant determinants of outcome. RESULTS: A total of 27,660 femoropopliteal bypass and 4161 femorodistal bypass procedures were identified.As volume increased, in-hospital mortality after popliteal bypass decreased from 6.5% to 4.9% (P = 0.0045), with a corresponding odds ratio of 0.980 [95% confidence interval (CI), 0.929-0.992; P = 0.014] for every increase of 50 patients per year. Major amputation decreased from 4.1% to 3.2% (P = 0.006) in high-volume hospitals, with a reduction in risk of 0.955 (95% CI, 0.928-0.983; P = 0.002) at 1 year.For distal bypass, in-hospital mortality decreased from 9.8% to 5.5% (P = 0.004) and 1-year major amputation decreased from 25.4% to 18.2% (P < 0.001), with a corresponding odds ratio of 0.658 (95% CI, 0.517-0.838; P < 0.0001) as the volume increased.An increase in the chance of revision surgery (10.6% vs 8.2%, P < 0.001) was seen with higher volume, with an increased odds ratio of 1.031 (95% CI, 1.005-1.057; P = 0.018). CONCLUSIONS: A positive volume outcome relationship exists for LEAB procedures even after employing multilevel risk adjustment models. There are benefits in terms of mortality and limb salvage both in the short-term and at 1 year postsurgery. PMID- 22824858 TI - Warm, humidified carbon dioxide gas insufflation for laparoscopic appendicectomy in children: a double-blinded randomized controlled trial. AB - OBJECTIVE: To investigate clinical benefits of warm, humidified carbon dioxide (CO(2)) insufflation for acute laparoscopic appendicectomy on postoperative pain and recovery in children (age 8-14 years). BACKGROUND: Conventional CO(2) insufflation leads to desiccation-related peritoneal inflammation and injury, which is preventable with warm, humidified CO2 gas. We hypothesized that reduced peritoneal desiccation would improve patient-centered outcomes in children after laparoscopic appendicectomy. METHOD: A double-blinded, randomized controlled trial was conducted. Intervention group participants received warm (37 degrees C), humidified (98% relative humidity) CO(2) gas insufflation, whereas control participants received standard room temperature (20 degrees C) gas with 0% relative humidity. Perioperative analgesia and anesthesia were standardized. Postoperative opiate usage was converted to morphine equivalent daily dosages (MEDD) for comparison, and pain intensity at rest and on moving was rated by participants using visual analog scales. Postoperative recovery and return to normal activities was assessed using a questionnaire on day 10. RESULTS: Between February 2010 and March 2011, a total of 190 participants were randomized. Both intervention and control groups were matched at baseline. Postoperative MEDD and pain scores were also similar. There were no differences in postoperative recovery parameters. CONCLUSIONS: Warm, humidified CO(2) insufflation for acute laparoscopic appendicectomy has no short-term clinical benefits on postoperative outcomes in pediatric patients (ClinicalTrials.gov trial identifying code: NCT01027455). PMID- 22824859 TI - Slab waveguide photobioreactors for microalgae based biofuel production. AB - Microalgae are a promising feedstock for sustainable biofuel production. At present, however, there are a number of challenges that limit the economic viability of the process. Two of the major challenges are the non-uniform distribution of light in photobioreactors and the inefficiencies associated with traditional biomass processing. To address the latter limitation, a number of studies have demonstrated organisms that directly secrete fuels without requiring organism harvesting. In this paper, we demonstrate a novel optofluidic photobioreactor that can help address the light distribution challenge while being compatible with these chemical secreting organisms. Our approach is based on light delivery to surface bound photosynthetic organisms through the evanescent field of an optically excited slab waveguide. In addition to characterizing organism growth-rates in the system, we also show here, for the first time, that the photon usage efficiency of evanescent field illumination is comparable to the direct illumination used in traditional photobioreactors. We also show that the stackable nature of the slab waveguide approach could yield a 12-fold improvement in the volumetric productivity. PMID- 22824860 TI - Ureteroscopy with laser lithotripsy for urolithiasis in the spinal cord injury population. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: The purpose of this investigation was to review the outcomes and safety of retrograde ureteroscopic laser lithotripsy (URS) for the treatment of urolithiasis in the spinal cord injury (SCI) population. SETTING: Virginia, USA. METHODS: All patients with SCI who underwent URS with holmium:YAG laser lithotripsy for urolithiasis over a 15-year period were identified. Stone size, location and number at presentation were recorded. Information regarding patient characteristics, intra-operative complications, surgical efficacy, stone clearance, peri-operative complications, and follow-up stone events was collected and analyzed. RESULTS: A total of 67 URS procedures were performed on 29 SCI patients during the study period with an average follow-up of 3.4 years. Patients had an average of 2.3 ipsilateral ureteroscopies. The majority (85.1%) used indwelling catheters for long-term bladder management, and complete stone clearance after the first procedure was 34.3%. Of the 44 cases with residual stones >4 mm, 20 (45.5%) were secondary to technical or procedural limitations. The intra-operative complication rate was comparable to non-SCI studies at 1.5%, but peri-operative complications were significantly higher at 29.9% with the majority due to urosepsis. Factors associated with peri-operative complications include chronic obstructive pulmonary disease, motor incomplete injuries and lack of a pre-operative ureteral stent. CONCLUSION: URS in the SCI population is an effective treatment for ureteral or renal stones but may be associated with greater risks and reduced efficacy. PMID- 22824861 TI - Radiosensitization by 2-deoxy-D-glucose and 6-aminonicotinamide involves activation of redox sensitive ASK1-JNK/p38MAPK signaling in head and neck cancer cells. AB - Our previous studies on simultaneous inhibition of glycolysis by 2-deoxy-D glucose (2-DG) and pentose phosphate activity by 6-aminonicotinamide (6-AN) have been shown to induce oxidative stress mediated selective radiosensitization in wide range of human malignant cells. However, the mechanism of radiosensitization induced by this combination (2-DG+6-AN) is not completely understood. Since activation of apoptotic signal regulating kinase (ASK1) and subsequent apoptosis are implicated in oxidative stress response, the role of ASK1 activation in radiosensitization by this combination was investigated in the present study. Our results demonstrated that redox alterations induced by this combination activated ASK1 and subsequent apoptosis during radiosensitization of head and neck carcinoma cells (KB). In addition, mRNA and protein expression of thioredoxin and thioredoxin reductase decreased significantly under similar treatment conditions. Further, the downstream targets such as JNK and p38MAPK were also activated by this combination, and their pharmacological inhibition by SP600125 and SB201291 respectively resulted in suppression of 2-DG+6-AN mediated apoptosis in irradiated KB cells. Interestingly, the activation of ASK1 was mediated by hydrogen peroxide rather than superoxide anions as PEG-catalase but not PEG-SOD suppressed its activation. Our observations clearly suggest that redox alterations by inhibition of glucose metabolism serves as a molecular switch that activate ASK1-JNK/p38MAPK signaling in malignant cells during radiosensitization by 2-DG+6-AN. The present study emphasizes the importance of redox alterations in determining radiosensitivity of tumor cells that may greatly influence the outcome of radiation therapy. PMID- 22824863 TI - NADPH oxidase-mediated upregulation of connexin43 contributes to podocyte injury. AB - The gap junction protein connexin43 (Cx43) was markedly increased in podocytes in a rat model of nephrosis induced by puromycin. However, the mechanisms and roles of the altered Cx43 in podocytes are still unclear. Given that oxidative stress mediates podocyte injury under a variety of pathological situations, we examined the possible involvement of an oxidative stress-related mechanism in the regulation of Cx43. Incubation of podocytes with puromycin led to a time- and concentration-dependent loss of cell viability, which was preceded by an elevation in Cx43 levels. Concomitantly, puromycin also induced NOX4 expression and promoted superoxide (O(2)(.-)) generation. Inhibition of NADPH oxidase with apocynin and diphenyleneiodonium chloride or addition of the superoxide dismutase mimetic tempol completely abrogated, whereas the O(2)(.-) donors menadione and 2,3-dimethoxy-1,4-naphthoquinone reproduced, the effects of puromycin on Cx43 expression and cell injury. Further analysis demonstrated that treatment of podocytes with several structurally different gap-junction inhibitors significantly attenuated the cytotoxicity of puromycin. Our results thus indicate that NADPH oxidase-mediated upregulation of Cx43 contributes to podocyte injury. PMID- 22824864 TI - Pyrroloquinoline quinone stimulates epithelial cell proliferation by activating epidermal growth factor receptor through redox cycling. AB - Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, has been implicated to be an important nutrient in mammals functioning as a potent growth factor. However, the underlying molecular mechanisms have not been elucidated. The present study revealed that PQQ induces the activation (tyrosine autophosphorylation) of epidermal growth factor receptor (EGFR) and its downstream signaling in a ligand-independent manner, leading to increased cellular proliferation in an epithelial cell line A431. PQQ inhibited protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the EGFR signaling by tyrosine dephosphorylation, to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H(2)O(2). PQQ-inducible intracellular ROS production and EGFR activation were significantly suppressed by the pre-treatment with antioxidants. The intracellular redox state regulates the EGFR signaling through the redox-sensitive catalytic cysteine of PTP1B and modulates cell proliferation. Our data suggest that PQQ may stimulate epithelial cell proliferation by activating EGFR by oxidation and subsequent inactivation of PTP1B via its redox cycling. Our results provide novel insight into the mechanisms by which PQQ may function as a growth factor to contribute to mammalian growth. PMID- 22824862 TI - Glutathione (GSH) and the GSH synthesis gene Gclm modulate vascular reactivity in mice. AB - Oxidative stress has been implicated in the development of vascular disease and in the promotion of endothelial dysfunction via the reduction in bioavailable nitric oxide (NO()). Glutathione (GSH) is a tripeptide thiol antioxidant that is utilized by glutathione peroxidase (GPx) to scavenge reactive oxygen species such as hydrogen peroxide and phospholipid hydroperoxides. Relatively frequent single nucleotide polymorphisms (SNPs) within the 5' promoters of the GSH synthesis genes GCLC and GCLM are associated with impaired vasomotor function, as measured by decreased acetylcholine-stimulated coronary artery dilation, and with increased risk of myocardial infarction. Although the influence of genetic knockdown of GPx on vascular function has been investigated in mice, no work to date has been published on the role of genetic knockdown of GSH synthesis genes on vascular reactivity. We therefore investigated the effects of targeted disruption of Gclm in mice and the subsequent depletion of GSH on vascular reactivity, NO() production, aortic nitrotyrosine protein modification, and whole genome transcriptional responses as measured by DNA microarray. Gclm(-/+) and Gclm(-/-) mice had 72 and 12%, respectively, of wild-type (WT) aortic GSH content. Gclm(-/+) mice had a significant impairment in acetylcholine (ACh) induced relaxation in aortic rings as well as increased aortic nitrotyrosine protein modification. Surprisingly, Gclm(-/-) aortas showed enhanced relaxation compared to Gclm(-/+) aortas, as well as increased NO() production. Although aortic rings from Gclm(-/-) mice had enhanced ACh relaxation, they had a significantly increased sensitivity to phenylephrine (PE)-induced contraction. Alternatively, the PE response of Gclm(-/+) aortas was nearly identical to that of their WT littermates. To examine the role of NO() or other potential endothelium-derived factors in differentially regulating vasomotor activity, we incubated aortic rings with the NO() synthase inhibitor L-NAME or physically removed the endothelium before PE treatment. L-NAME treatment and endothelium removal enhanced PE-induced contraction in WT and Gclm(-/+) mice, but this effect was severely diminished in Gclm(-/-) mice, indicating a potentially unique role for GSH in mediating vessel contraction. Whole-genome assessment of aortic mRNA in Gclm(-/-) and WT mice revealed altered expression of genes within the canonical Ca(2+) signaling pathway, which may have a role in mediating these observed functional effects. These findings provide additional evidence that the de novo synthesis of GSH can influence vascular reactivity and provide insights regarding possible mechanisms by which SNPs within GCLM and GCLC influence the risk of developing vascular diseases in humans. PMID- 22824866 TI - Structure of the catalytic sites in Fe/N/C-catalysts for O2-reduction in PEM fuel cells. AB - Fe-based catalytic sites for the reduction of oxygen in acidic medium have been identified by (57)Fe Mossbauer spectroscopy of Fe/N/C catalysts containing 0.03 to 1.55 wt% Fe, which were prepared by impregnation of iron acetate on carbon black followed by heat-treatment in NH(3) at 950 degrees C. Four different Fe species were detected at all iron concentrations: three doublets assigned to molecular FeN(4)-like sites with their ferrous ions in a low (D1), intermediate (D2) or high (D3) spin state, and two other doublets assigned to a single Fe species (D4 and D5) consisting of surface oxidized nitride nanoparticles (Fe(x)N, with x<= 2.1). A fifth Fe-species appears only in those catalysts with Fe contents >=0.27 wt%. It is characterized by a very broad singlet, which has been assigned to incomplete FeN(4)-like sites that quickly dissolve in contact with an acid. Among the five Fe-species identified in these catalysts, only D1 and D3 display catalytic activity for the oxygen reduction reaction (ORR) in the acid medium, with D3 featuring a composite structure with a protonated neighbour basic nitrogen and being by far the most active species, with an estimated turn over frequency for the ORR of 11.4 e(-) per site per s at 0.8 V vs. RHE. Moreover, all D1 sites and between 1/2 and 2/3 of the D3 sites are acid-resistant. A scheme for the mechanism of site formation upon heat-treatment is also proposed. This identification of the ORR-active sites in these catalysts is of crucial importance to design strategies to improve the catalytic activity and stability of these materials. PMID- 22824865 TI - Ceruloplasmin (ferroxidase) oxidizes hydroxylamine probes: deceptive implications for free radical detection. AB - Ceruloplasmin (ferroxidase) is a copper-binding protein known to promote Fe(2+) oxidation in plasma of mammals. In addition to its classical ferroxidase activity, ceruloplasmin is known to catalyze the oxidation of various substrates, such as amines and catechols. Assays based on cyclic hydroxylamine oxidation are used to quantify and detect free radicals in biological samples ex vivo and in vitro. We show here that human ceruloplasmin promotes the oxidation of the cyclic hydroxylamine 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine hydrochloride (CPH) and related probes in Chelex-treated phosphate buffer and rat serum. The reaction is suppressed by the metal chelators DTPA, EDTA, and desferal, whereas heparin and bathocuproine have no effect. Catalase or superoxide dismutase additions do not interfere with the CPH-oxidation yield, demonstrating that oxygen-derived free radicals are not involved in the CPH oxidation mediated by ceruloplasmin. Plasma samples immunodepleted of ceruloplasmin have lower levels of CPH oxidation, which confirms the role of ceruloplasmin (ferroxidase) as a biological oxidizing agent of cyclic hydroxylamines. In conclusion, we show that the ferroxidase activity of ceruloplasmin is a possible biological source of artifacts in the cyclic hydroxylamine-oxidation assay used for reactive oxygen species detection and quantification. PMID- 22824867 TI - Optimized analysis of DNA methylation and gene expression from small, anatomically-defined areas of the brain. AB - Exposure to diet, drugs and early life adversity during sensitive windows of life can lead to lasting changes in gene expression that contribute to the display of physiological and behavioural phenotypes. Such environmental programming is likely to increase the susceptibility to metabolic, cardiovascular and mental diseases. DNA methylation and histone modifications are considered key processes in the mediation of the gene-environment dialogue and appear also to underlay environmental programming. In mammals, DNA methylation typically comprises the covalent addition of a methyl group at the 5-position of cytosine within the context of CpG dinucleotides. CpG methylation occurs in a highly tissue- and cell specific manner making it a challenge to study discrete, small regions of the brain where cellular heterogeneity is high and tissue quantity limited. Moreover, because gene expression and methylation are closely linked events, increased value can be gained by comparing both parameters in the same sample. Here, a step by-step protocol (Figure 1) for the investigation of epigenetic programming in the brain is presented using the 'maternal separation' paradigm of early life adversity for illustrative purposes. The protocol describes the preparation of micropunches from differentially-aged mouse brains from which DNA and RNA can be simultaneously isolated, thus allowing DNA methylation and gene expression analyses in the same sample. PMID- 22824868 TI - Comment on 'Molecular arrangement in water: random but not quite'. AB - Accurate high energy x-ray diffraction data are presented on liquid water measured at room temperature. Sources of both systematic and statistical errors within the experiment are considered and data consistency checks are discussed. It is found that the resulting x-ray pair distribution function is smoothly varying in real space and shows no evidence of small peaks in the 3-5 A region. Our results are in contrast to the recent findings reported in Petkov et al 2012 J. Phys.: Condens. Matter 24 155102. PMID- 22824869 TI - Total synthesis and stereochemical revision of lagunamide A. AB - A revised configurational assignment for the marine metabolite lagunamide A is proposed and validated by total synthesis. PMID- 22824870 TI - Pd-Au bimetallic catalysts: understanding alloy effects from planar models and (supported) nanoparticles. AB - Pd-Au bimetallic catalysts often display enhanced catalytic activities and selectivities compared with Pd-alone catalysts. This enhancement is often caused by two alloy effects, i.e., ensemble and ligand effects. The ensemble effect is a dilution of surface Pd by Au. With increasing surface Au coverage, contiguous Pd ensembles disappear and isolated Pd ensembles form. For certain reactions, for example vinyl acetate synthesis, this effect is responsible for reaction rate enhancement via the formation of highly active surface sites, e.g., isolated Pd pairs. The disappearance of contiguous Pd ensembles also switches off side reactions catalyzed by these sites. This explains the selectivity increase of certain reactions, for example direct H(2)O(2) synthesis. The ligand effects are electronic perturbation of Pd by Au. Via direct charge transfer or by affecting bond lengths, the ligand effects cause the Pd d band to be more filled, moving the d-band center away from the Fermi level. Both changes make Pd more "atomic like" therefore binding reactants and products more weakly. For certain reactions, this eliminates a so-called "self-poisoning" effect and enhances activity/selectivity. PMID- 22824871 TI - Time to stop screening for prostate cancer: comment on "Declines in prostate cancer incidence after changes in screening recommendations". PMID- 22824872 TI - [Is there life after trauma surgery? Way of life in retirement]. AB - The transition from active working life as an emergency surgeon to retirement is accompanied by mixed feelings because the prospect of more free time and a reduced workload is overshadowed by the awareness that an important and satisfying phase in life is coming to an end. Planning well ahead will help to accept a step which will seem abrupt at the given time. Whereas moving to a different location or taking up another emergency surgery task at a reduced level should be considered with care, a social network, especially a large and interesting circle of friends and acquaintances is of considerable importance. If health allows it performing voluntary activities may not only be beneficial for the respective organisations but may also widen one's horizons. Hobbies that often had to be neglected during the period of working life can now be intensively pursued: sports, travelling, photography, gardening, handcraft, the list is long. Those who are lucky enough to have a large family, especially many grandchildren do not need to worry about sufficient tasks and lots of pleasure and diversion in old age. PMID- 22824873 TI - [Is there a life after the trauma surgery? The third period of life]. AB - Professor Probst, for long Secretary General of the German Society of Trauma Surgery and yet responsible for the history of trauma surgery, consultancy work in hospital construction and organisation, author and reviewer, forensic experts. Selected literary themes were post-clinic activities for almost two decades. PMID- 22824874 TI - [Is there life after trauma surgery? Cooperation with the developmental aid worker Karlheinz Bohm]. AB - The editors of the journal The Trauma Surgeon provided the stimulus for the topic "is there life after trauma surgery?": an unusual and original idea given the aging of society. This article describes the friendly attachment with the former actor and current developmental aid worker in Ethiopia, Karlheinz Bohm. During this cooperation five hospitals were founded and a languishing university clinic in the region of Illubarbor near to the Sudanese border could be modernized and raised to be an efficient medical faculty of Ethiopia. The article portrays that training and advanced training were the foremost priority of our actions and was furthermore successful with respect to the cooperation between the Ludwig Maximilians University Munich and the University of Jimma. PMID- 22824875 TI - [Is there life after trauma surgery? Charitable activities after retirement]. AB - Every profession, even that of a doctor of traumatology has to be kept in motion by personal convictions and indignations. It is the only way to give the profession a profile and to get a profile back. This dynamic process also remains at the end of the professional career even when it is no longer the profession and refers"only" to one's own life, as (to be honest) it always was before anyway. So profession is life and life is profession, even afterwards. PMID- 22824876 TI - [Delayed splenic rupture 13 days post-trauma after initially inconspicuous computed tomography examination]. AB - Delayed splenic injuries are rare but nevertheless well known and very dangerous complications after blunt abdominal trauma. The highest incidence is reported between four and eight days after trauma; however some cases with a latent period of weeks have been published. We present a case of delayed splenic rupture 13 days after trauma where most computed tomography (CT) examinations were interpreted as normal and present a review of the pathophysiology of delayed rupture, diagnosis and therapy. PMID- 22824877 TI - Double-helix disruption. PMID- 22824878 TI - Slow science. PMID- 22824880 TI - Binding manners. Interview by Anne Pichon. PMID- 22824886 TI - Interactions with DNA: Into the minor groove. PMID- 22824888 TI - Catalyst-support interactions: Electronic perturbations. PMID- 22824887 TI - Electrochemical sensors: Taking charge of detection. PMID- 22824889 TI - Supramolecular dye aggregates: Nanotube knockout. PMID- 22824890 TI - Protein folding: Turbo-charged crosslinking. PMID- 22824891 TI - The progression of chiral anions from concepts to applications in asymmetric catalysis. AB - Despite the tremendous advances of the past four decades, chemists are far from being able to use chiral catalysts to control the stereoselectivity of any desired reaction. New concepts for the construction and mode of operation of chiral catalysts have the potential to open up previously inaccessible reaction space. The recognition and categorization of distinct approaches seems to play a role in triggering rapid exploration of new territory. This Review both reflects on the origins as well as details a selection of the latest examples of an area that has advanced considerably within the past five years or so: the use of chiral anions in asymmetric catalysis. Defining reactions as involving chiral anions is a difficult task owing to uncertainties over the exact catalytic mechanisms. Nevertheless, we attempt to provide an overview of the breadth of reactions that could reasonably fall under this umbrella. PMID- 22824893 TI - Crystal structures of Lambda-[Ru(phen)2dppz]2+ with oligonucleotides containing TA/TA and AT/AT steps show two intercalation modes. AB - The ruthenium complex [Ru(phen)(2)(dppz)](2+) (where phen is phenanthroline and dppz dipyridophenazine is known as a 'light switch' complex because its luminescence in solution is significantly enhanced in the presence of DNA. This property is poised to serve in diagnostic and therapeutic applications, but its binding mode with DNA needs to be elucidated further. Here, we describe the crystal structures of the Lambda enantiomer bound to two oligonucleotide duplexes. The dppz ligand intercalates symmetrically and perpendicularly from the minor groove of the d(CCGGTACCGG)(2) duplex at the central TA/TA step, but not at the central AT/AT step of d(CCGGATCCGG)(2). In both structures, however, a second ruthenium complex links the duplexes through the combination of a shallower angled intercalation into the C(1)C(2)/G(9)G(10) step at the end of the duplex, and semi-intercalation into the G(3)G(4) step of an adjacent duplex. The TA/TA specificity of the perpendicular intercalation arises from the packing of phenanthroline ligands against the adenosine residue. PMID- 22824892 TI - Crystal structure of Delta-[Ru(bpy)2dppz]2+ bound to mismatched DNA reveals side by-side metalloinsertion and intercalation. AB - DNA mismatches represent a novel target in the development of diagnostics and therapeutics for cancer, because deficiencies in DNA mismatch repair are implicated in cancers, and cells that are repair-deficient show a high frequency of mismatches. Metal complexes with bulky intercalating ligands serve as probes for DNA mismatches. Here, we report the high-resolution (0.92 A) crystal structure of the ruthenium 'light switch' complex Delta-[Ru(bpy)(2)dppz](2+) (bpy = 2,2'-bipyridine and dppz = dipyridophenazine), which is known to show luminescence on binding to duplex DNA, bound to both mismatched and well-matched sites in the oligonucleotide 5'-(dCGGAAATTACCG)(2)-3' (underline denotes AA mismatches). Two crystallographically independent views reveal that the complex binds mismatches through metalloinsertion, ejecting both mispaired adenosines. Additional ruthenium complexes are intercalated at well-matched sites, creating an array of complexes in the minor groove stabilized by stacking interactions between bpy ligands and extruded adenosines. This structure attests to the generality of metalloinsertion and metallointercalation as DNA binding modes. PMID- 22824894 TI - Guided desaturation of unactivated aliphatics. AB - The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal free conditions is outlined. This 'portable desaturase' (Tz(o)Cl) is a bench stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group. PMID- 22824895 TI - Revealing the stereospecific chemistry of the reaction of Cl with aligned CHD3(nu1 = 1). AB - The concept of geometrical constraints and steric hindrance in reactions is implanted deeply in a chemist's 'chemical intuition'. However, until now a true three-dimensional view of these steric effects has not been realized experimentally for any chemical reaction in full. Here we report the complete three-dimensional characterization of the sterics of a benchmark polyatomic reaction by measuring the dependence of the product state-resolved angular distributions on the spatial alignment of the reactive bond in a crossed molecular beam experiment. The results prove the existence of two distinct microscopic reaction mechanisms. Detailed analysis reveals that the origin of the stereodynamics in the HCl(nu = 0) + CD(3)(0(0)) product channel can be captured by a textbook line-of-centres collision model. In contrast, a time-delay pathway, which includes a sharp switch from in-plane to out-of-plane scattering in the forwards direction, appears to be operative in forming the excited HCl(nu = 1) + CD(3)(0(0)) product pair. PMID- 22824896 TI - An ultrasensitive universal detector based on neutralizer displacement. AB - Diagnostic technologies that can provide the simultaneous detection of nucleic acids for gene expression, proteins for host response and small molecules for profiling the human metabolome will have a significant advantage in providing comprehensive patient monitoring. Molecular sensors that report changes in the electrostatics of a sensor's surface on analyte binding have shown unprecedented sensitivity in the detection of charged biomolecules, but do not lend themselves to the detection of small molecules, which do not carry significant charge. Here, we introduce the neutralizer displacement assay that allows charge-based sensing to be applied to any class of molecule irrespective of the analyte charge. The neutralizer displacement assay starts with an aptamer probe bound to a neutralizer. When analyte binding occurs the neutralizer is displaced, which results in a dramatic change in the surface charge for all types of analytes. We have tested the sensitivity, speed and specificity of this system in the detection of a panel of molecules: (deoxy)ribonucleic acid, ribonucleic acid, cocaine, adenosine triphosphate and thrombin. PMID- 22824897 TI - Catalytic asymmetric carbon-carbon bond formation using alkenes as alkylmetal equivalents. AB - Catalytic asymmetric conjugate addition reactions with organometallic reagents are powerful reactions in synthetic chemistry. Procedures that use non-stabilized carbanions have been developed extensively, but these suffer from a number of limitations that prevent their use in many situations. Here, we report that alkylmetal species generated in situ from alkenes can be used in highly enantioselective 1,4-addition initiated by a copper catalyst. Using alkenes as starting materials is desirable because they are readily available and have favourable properties when compared to pre-made organometallics. High levels of enantioselectivity are observed at room temperature in a range of solvents, and the reaction tolerates functional groups that are not compatible with comparable methods-a necessary prerequisite for efficient and protecting-group-free strategies for synthesis. PMID- 22824898 TI - Utilizing redox-chemistry to elucidate the nature of exciton transitions in supramolecular dye nanotubes. AB - Supramolecular assemblies that interact with light have recently garnered much interest as well-defined nanoscale materials for electronic excitation energy collection and transport. However, to control such complex systems it is essential to understand how their various parts interact and whether these interactions result in coherently shared excited states (excitons) or in diffusive energy transport between them. Here, we address this by studying a model system consisting of two concentric cylindrical dye aggregates in a light harvesting nanotube. Through selective chemistry we are able to unambiguously determine the supramolecular origin of the observed excitonic transitions. These results required the development of a new theoretical model of the supramolecular structure of the assembly. Our results demonstrate that the two cylinders of the nanotube have distinct spectral responses and are best described as two separate, weakly coupled excitonic systems. Understanding such interactions is critical to the control of energy transfer on a molecular scale, a goal in various applications ranging from artificial photosynthesis to molecular electronics. PMID- 22824899 TI - Dissecting the mechanisms of a class of chemical glycosylation using primary 13C kinetic isotope effects. AB - Although arguably the most important reaction in glycoscience, chemical glycosylations are among the least well understood of organic chemical reactions, resulting in an unnecessarily high degree of empiricism and a brake on rational development in this critical area. To address this problem, primary (13)C kinetic isotope effects have now been determined for the formation of beta- and alpha manno- and glucopyranosides using a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental and computed values are indicative of associative displacement of the intermediate covalent glycosyl trifluoromethanesulfonates. For the formation of the alpha-mannopyranosides, the experimentally determined KIE differs significantly from that computed for an associative displacement, which is strongly suggestive of a dissociative mechanism that approaches the intermediacy of a glycosyl oxocarbenium ion. The application of analogous experiments to other glycosylation systems should shed further light on their mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity. PMID- 22824900 TI - Spontaneous reduction and C-H borylation of arenes mediated by uranium(III) disproportionation. AB - Transition-metal-arene complexes such as bis(benzene)chromium Cr(eta(6) C(6)H(6))(2) are historically important to d-orbital bonding theory and have modern importance in organic synthesis, catalysis and organic spintronics. In investigations of f-block chemistry, however, arenes are invariably used as solvents rather than ligands. Here, we show that simple uranium complexes UX(3) (X = aryloxide, amide) spontaneously disproportionate, transferring an electron and X-ligand, allowing the resulting UX(2) to bind and reduce arenes, forming inverse sandwich molecules [X(2)U(u-eta(6):eta(6)-arene)UX(2)] and a UX(4) by product. Calculations and kinetic studies suggest a 'cooperative small-molecule activation' mechanism involving spontaneous arene reduction as an X-ligand is transferred. These mild reaction conditions allow functionalized arenes such as arylsilanes to be incorporated. The bulky UX(3) are also inert to reagents such as boranes that would react with the traditional harsh reaction conditions, allowing the development of a new in situ arene C-H bond functionalization methodology converting C-H to C-B bonds. PMID- 22824901 TI - Optically switchable transistor via energy-level phototuning in a bicomponent organic semiconductor. AB - Organic semiconductors are suitable candidates for printable, flexible and large area electronics. Alongside attaining an improved device performance, to confer a multifunctional nature to the employed materials is key for organic-based logic applications. Here we report on the engineering of an electronic structure in a semiconducting film by blending two molecular components, a photochromic diarylethene derivative and a poly(3-hexylthiophene) (P3HT) matrix, to attain phototunable and bistable energy levels for the P3HT's hole transport. As a proof of-concept we exploited this blend as a semiconducting material in organic thin film transistors. The device illumination at defined wavelengths enabled reversible tuning of the diarylethene's electronic states in the blend, which resulted in modulation of the output current. The device photoresponse was found to be in the microsecond range, and thus on a technologically relevant timescale. This modular blending approach allows for the convenient incorporation of various molecular components, which opens up perspectives on multifunctional devices and logic circuits. PMID- 22824903 TI - Life and death with nitrogen. PMID- 22824902 TI - Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization. AB - Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance assisted hydrogen bond to provide an amide surrogate. PMID- 22824904 TI - Molecular detection of cryptic Y-chromosomal material in patients with Turner syndrome. AB - A systematic search for a hidden Y-chromosome mosaicism, in Turner syndrome (TS) patients is justified by the evaluation of the risk of development of germ cell tumors. In this study, we analyzed cryptic Y-chromosome derivatives by polymerase chain reaction (PCR) coupled with fluorescence in situ hybridization (FISH) using Y-specific sequences in patients with TS, and validated this methodology. Unrelated patients with TS (n=32) of Mexican mestizo ethnic origin were diagnosed using cytogenetic analysis. Clinical assessment, endocrine evaluation, karyotyping, FISH and PCR analysis of the Y-chromosomal loci were performed. We found that 9.4% (3 out of 32) patients with TS had Y-chromosome material. Two patients showed Y-chromosome by conventional cytogenetics. One patient had no Y chromosome by initial karyotyping (45, X) but was positive by lymphocyte PCR DNA analysis of the Y-sequence-specific sex-determining region Y (SRY) gene. Our results suggest that the detection of the Y-chromosome material using sensitive methods, such as PCR coupled with FISH, should be carried out in all patients with TS and should not be limited to TS patients with cytogenetically identifiable Y-chromosome and/or virilization. PMID- 22824905 TI - Why do we need accreditation of nuclear medicine departments? PMID- 22824906 TI - Factorial validity of the effort-reward imbalance scale: evidence from multi sample and three-wave follow-up studies. AB - PURPOSE: The present study investigated whether the factor structure of the effort-reward imbalance (ERI) scale (Siegrist et al. Soc Sci Med 58:1483-1499, 2004) remains same across two white-collar samples (i.e., factorial group invariance) and across three measurement times (i.e., factorial time invariance). METHODS: The factorial group invariance was tested using two different samples including 1,301 managers and 758 young white-collar professionals. The factorial time invariance was tested in the latter sample with a four-year three-wave follow-up design. RESULTS: The confirmatory factor analysis performed supported the theoretically based structure of the ERI scale, that is, the scale included two first-order factors of effort and overcommitment and one second-order factor of reward with first-order factors of esteem, career opportunities, and job security. The factorial group invariance of this structure was also supported. In addition, the factor loadings of all factors remained same across three measurements; thus, lending support for the factorial time invariance. CONCLUSION: The ERI scale was found to be a valid tool to measure costs and gains of social exchanges at work as well as individual orientation toward work in these two occupational samples including a longitudinal study design. PMID- 22824908 TI - Downregulation of nucleoporin 88 and 214 induced by oridonin may protect OCIM2 acute erythroleukemia cells from apoptosis through regulation of nucleocytoplasmic transport of NF-kappaB. AB - Oridonin has been utilized for the treatment of various human diseases due to its anti-inflammatory, antibacterial and antitumor effects. However, the precise mechanisms induced by oridonin in human erythroleukemia are yet to be clarified. The present study aimed to elucidate possible oridonin-induced apoptotic mechanisms in OCIM2 cells, as well as the possible mechanisms whereby OCIM2 cells are relatively resistant to oridonin. Results in the present study showed that oridonin significantly inhibited OCIM2 and OCI-AML3 cell proliferation in a dose- and time-dependent manner, while expressing a much higher IC50 in OCIM2, compared to OCI-AML3. These results also indicated that oridonin induced OCIM2 cell apoptosis, associated with p65 and Bax, while activating caspases-9, -6 and -3. However, p65 was only partly translocated into the nucleus, while most of the p65 was retained in the cytoplasm. Moreover, nucleoporin 214 (Nup214) and nucleoporin 88 (Nup88) were downregulated at the transcriptional and protein levels, subsequent to oridonin treatment. Taken together, these data suggest that oridonin has the potential to induce OCIM2 cell-apoptosis, involving NF-kappaB activation, whereas the downregulation of Nup88 and Nup214 may protect OCIM2 through the regulation of the nucleocytoplasmic transport of p65. PMID- 22824909 TI - Homeless veterans who served in Iraq and Afghanistan: gender differences, combat exposure, and comparisons with previous cohorts of homeless veterans. PMID- 22824910 TI - Implementation and evaluation of a depression care model for homebound elderly. AB - Depression affects 14% to 46% of homebound elderly and is costly and disabling. Home health agencies face significant challenges delivering effective depression care. In response, an evidence-based depression care model was developed in a home health agency. Twelve-month program evaluation data demonstrated a 2.99 mean reduction in depression scores (P < .0001) on the Geriatric Depression Scale and confirmed that a clinically effective, operationally feasible, and financially sustainable depression care model can be implemented in home health care. PMID- 22824911 TI - Changes in patient health outcomes from admission to discharge in acute care. AB - Clinical databases comprising data that are available at a national level provide the opportunity to explore the relationships between nursing interventions and patient health outcomes. This research examined baseline and changes in patient health outcomes between admission and discharge using data from 59 157 acute-care hospital-based patient records at 44 hospitals in Canada. Statistically significant improvements in all of the health outcomes were noted, with the exception of pressure ulcers. The standardized indicators offer a mechanism for evaluating the effectiveness and quality of nursing care interventions. PMID- 22824913 TI - The hydrophobic amino acids involved in the interdomain association of phospholipase D1 regulate the shuttling of phospholipase D1 from vesicular organelles into the nucleus. AB - Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidic acid. PLD is localized in most cellular organelles, where it is likely to play different roles in signal transduction. PLD1 is primarily localized in vesicular structures such as endosomes, lysosomes and autophagosomes. However, the factors defining its localization are less clear. In this study, we found that four hydrophobic residues present in the N terminal HKD catalytic motif of PLD1, which is involved in intramolecular association, are responsible for vesicular localization. Site-directed mutagenesis of the residues dramatically disrupted vesicular localization of PLD1. Interestingly, the hydrophobic residues of PLD1 are also involved in the interruption of its nuclear localization. Mutation of the residues increased the association of PLD1 with importin-beta, which is known to mediate nuclear importation, and induced the localization of PLD1 from vesicles into the nucleus. Taken together, these data suggest that the hydrophobic amino acids involved in the interdomain association of PLD1 are required for vesicular localization and disturbance of its nuclear localization. PMID- 22824914 TI - Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism. AB - Although peroxisome proliferator receptor (PPAR)-alpha and PPAR-gamma agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-delta has not been fully investigated. In this study, we examined the effects of the PPAR-delta agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-delta agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemo-attractant protein 1 (MCP-1) and also, PPAR-gamma coactivator (PGC)-1alpha gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-alpha and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-alpha, MCP-1, and PGC-1alpha were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-delta agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1alpha gene expression, and improvement of insulin signaling. PMID- 22824917 TI - Vibrational cooling, heating, and instability in molecular conducting junctions: full counting statistics analysis. AB - We study current-induced vibrational cooling, heating, and instability in a donor acceptor rectifying molecular junction using a full counting statistics approach. In our model, electron-hole pair excitations are coupled to a given molecular vibrational mode which is either harmonic or highly anharmonic. This mode may be further coupled to a dissipative thermal environment. Adopting a master equation approach, we confirm the charge and heat exchange fluctuation theorem in the steady-state limit, for both harmonic and anharmonic models. Using simple analytical expressions, we calculate the charge current and several measures for the mode effective temperature. At low bias, we observe the effect of bias induced cooling of the vibrational mode. At higher bias, the mode effective temperature is higher than the environmental temperature, yet the junction is stable. Beyond that, once the vibrational mode (bias-induced) excitation rate overcomes its relaxation rate, instability occurs. We identify regimes of instability as a function of voltage bias and coupling to an additional phononic thermal bath. Interestingly, we observe a reentrant behavior where an unstable junction can properly behave at a high enough bias. The mechanism for this behavior is discussed. PMID- 22824915 TI - Twenty-five-year atraumatic restorative treatment (ART) approach: a comprehensive overview. AB - BACKGROUND: The atraumatic restorative treatment (ART) approach was born 25 years ago in Tanzania. It has evolved into an essential caries management concept for improving quality and access to oral care globally. RESULTS: Meta-analyses and systematic reviews have indicated that the high effectiveness of ART sealants using high-viscosity glass ionomers in carious lesion development prevention is not different from that of resin fissure sealants. ART using high-viscosity glass ionomer can safely be used to restore single-surface cavities both in primary and in permanent posterior teeth, but its quality in restoring multiple surfaces in primary posterior teeth cavities needs to be improved. Insufficient information is available regarding the quality of ART restorations in multiple surfaces in permanent anterior and posterior teeth. There appears to be no difference in the survival of single-surface high-viscosity glass-ionomer ART restorations and amalgam restorations. DISCUSSION: The use of ART results in smaller cavities and in high acceptance of preventive and restorative care by children. Because local anaesthesia is seldom needed and only hand instruments are used, ART is considered to be a promising approach for treating children suffering from early childhood caries. ART has been implemented in the public oral health services of a number of countries, and clearly, proper implementation requires the availability of sufficient stocks of good high-viscosity glass ionomers and sets of ART instruments right from the start. Textbooks including chapters on ART are available, and the concept is being included in graduate courses at dental schools in a number of countries. Recent development and testing of e-learning modules for distance learning has increasingly facilitated the distribution of ART information amongst professionals, thus enabling more people to benefit from ART. However, this development and further research require adequate funding, which is not always easily obtainable. The next major challenge is the continuation of care to the frail elderly, in which ART may play a part. CONCLUSION: ART, as part of the Basic Package of Oral Care, is an important cornerstone for the development of global oral health and alleviating inequality in oral care. PMID- 22824916 TI - Radiopacity of dental restorative materials. AB - OBJECTIVES: Radiopacity of dental materials enables clinician to radiographically diagnose secondary caries and marginal defects which are usually located on the proximal gingival margin. The aim of this study was to measure the radiopacity of 33 conventional resin composites, 16 flowable resin composites, and 7 glass ionomer cements and to compare the results with the radiopacity values declared by the manufacturers. MATERIALS AND METHODS: From each restorative material, six 2-mm-thick disk-shaped specimens were fabricated and eight 2-mm-thick sections of teeth were made and used as reference. The material samples and tooth sections were digitally radiographed together with the aluminum stepwedge. Gray values were obtained from the radiographic images and radiopacity values were calculated and statistically analyzed. Post hoc Tukey's honestly significant difference test was used to calculate significant differences in radiopacity values between materials and reference dentin and enamel values. RESULTS: The radiopacity values of all 56 restorative materials were above the dentin reference radiopacity value; however, 4 out of 33 conventional composites and 3 out of 16 flowable resin composites had significantly lower radiopacity than enamel (p < 0.05). There were up to 1.53 mm eq Al differences between the measured and the manufacturers' declared radiopacity values of some materials. CONCLUSIONS: Majority of the materials exceed enamel radiopacity and would not hamper radiographic diagnosis of secondary caries. However, manufacturers' data are not always reliable. CLINICAL RELEVANCE: Materials with radiopacity lower than enamel might be misinterpreted as secondary enamel caries on radiographic images, especially when applied as initial increment on the proximal gingival margin. PMID- 22824918 TI - A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients. AB - Colorectal cancer (CRC) represents one of the highest incidences of cancers worldwide. Phosphatidylinositol glycan, class K (PIGK), is a crucial member of the glycosyl-phosphatidylinositol transamidase (GPIT) protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. However, the precise role of PIGK in tumorigenesis remains largely unknown. Recently, we reported low expression of PIGK protein in primary tumors compared to paired normal tissues of colorectal cancer (CRC) patients. To understand the mechanism underlying this phenomenon, we performed sequencing of all 10 exons of the PIGK gene in 45 CRC patients. Corresponding PIGK protein expression was also evaluated in these patients by immunohistochemistry. No mutation was detected in the coding regions, however, we found a single nucleotide polymorphism (C/C->C/G or G/G; rs1048575) in the 3'UTR of the PIGK gene in 67% (30/45) of the patients. Most of the patients (22/26, 85%) with the altered alleles were of Jewish origin. In comparison, 47% (8/17) of the Arabian patients exhibited the altered C/G alleles. We observed a significantly low (p<0.002) expression of PIGK protein in the patients with the altered alleles (C/G or G/G) compared to the ancestral alleles (C/C). Similarly to the CRC patients, we also examined 5 HCC patients and two HCC cell lines (Hep3B and HepG2) for PIGK genotype (SNP-1048575) and corresponding protein expression. We observed altered alleles (C/G or G/G) and corresponding low PIGK protein expression in 4 out of 5 (80%) primary HCC tumors. Among the HCC cell lines, HepG2 line exhibited ancestral C/C alleles, whereas Hep3B showed altered C/G alleles. Similar to the HCC patients, Hep3B line with the altered alleles (C/G) exhibited significantly low (Student's t-test, p<0.002) PIGK protein expression compared to the Hep3B line carrying the ancestral (C/C) alleles. To examine the exogenous PIGK protein expression status, we transiently transfected both HepG2 (C/C alleles) and Hep3B (C/G alleles) cell lines with wt PIGK constructs. We detected exogenously expressed PIGK protein in HepG2 (C/C) cells, but no PIGK expression was detectable in Hep3B (C/G) cells at either mRNA or protein level. Our results demonstrate, for the first time, a link between the SNP 1048575 and low PIGK expression in CRC/HCC patients and also suggest a possible association between altered PIGK expression and disease susceptibility. PMID- 22824919 TI - Hydrophobic salt-modified Nafion for enzyme immobilization and stabilization. AB - Over the last decade, there has been a wealth of application for immobilized and stabilized enzymes including biocatalysis, biosensors, and biofuel cells. In most bioelectrochemical applications, enzymes or organelles are immobilized onto an electrode surface with the use of some type of polymer matrix. This polymer scaffold should keep the enzymes stable and allow for the facile diffusion of molecules and ions in and out of the matrix. Most polymers used for this type of immobilization are based on polyamines or polyalcohols - polymers that mimic the natural environment of the enzymes that they encapsulate and stabilize the enzyme through hydrogen or ionic bonding. Another method for stabilizing enzymes involves the use of micelles, which contain hydrophobic regions that can encapsulate and stabilize enzymes. In particular, the Minteer group has developed a micellar polymer based on commercially available Nafion. Nafion itself is a micellar polymer that allows for the channel-assisted diffusion of protons and other small cations, but the micelles and channels are extremely small and the polymer is very acidic due to sulfonic acid side chains, which is unfavorable for enzyme immobilization. However, when Nafion is mixed with an excess of hydrophobic alkyl ammonium salts such as tetrabutylammonium bromide (TBAB), the quaternary ammonium cations replace the protons and become the counter ions to the sulfonate groups on the polymer side chains (Figure 1). This results in larger micelles and channels within the polymer that allow for the diffusion of large substrates and ions that are necessary for enzymatic function such as nicotinamide adenine dinucleotide (NAD). This modified Nafion polymer has been used to immobilize many different types of enzymes as well as mitochondria for use in biosensors and biofuel cells. This paper describes a novel procedure for making this micellar polymer enzyme immobilization membrane that can stabilize enzymes. The synthesis of the micellar enzyme immobilization membrane, the procedure for immobilizing enzymes within the membrane, and the assays for studying enzymatic specific activity of the immobilized enzyme are detailed below. PMID- 22824920 TI - Gold nanoparticle-based optical microfluidic sensors for analysis of environmental pollutants. AB - Conventional methods of environmental analysis can be significantly improved by the development of portable microscale technologies for direct in-field sensing at remote locations. This report demonstrates the vast potential of gold nanoparticle-based microfluidic sensors for the rapid, in-field, detection of two important classes of environmental contaminants - heavy metals and pesticides. Using gold nanoparticle-based microfluidic sensors linked to a simple digital camera as the detector, detection limits as low as 0.6 MUg L(-1) and 16 MUg L(-1) could be obtained for the heavy metal mercury and the dithiocarbamate pesticide ziram, respectively. These results demonstrate that the attractive optical properties of gold nanoparticle probes combine synergistically with the inherent qualities of microfluidic platforms to offer simple, portable and sensitive sensors for environmental contaminants. PMID- 22824921 TI - The effect of intraoperative infusion of dexmedetomidine on the quality of recovery after major spinal surgery. AB - BACKGROUND: Surgery induces a variety of metabolic, endocrine, and immune changes collectively known as the "stress response," which may often lead to prolonged postoperative convalescence. Anesthetic management may modulate this physiological response, thus affecting the postoperative course. We hypothesized that the intraoperative administration of dexmedetomidine (DEX), a sympatholytic agent, would reduce the stress response and improve the quality of recovery in patients undergoing major surgery. METHODS: We conducted a prospective randomized double-blinded study of 54 patients undergoing multilevel spinal fusion. Anesthesia was maintained using either propofol/fentanyl/dexmedetomidine (PFD) or propofol/fentanyl/placebo-saline (PFS). The quality of recovery (a primary endpoint) was assessed using a 40-item quality of recovery questionnaire and a 9 question Fatigue Severity Scores. The tests were carried out preoperatively on postoperative days (POD) 1, 2, 3, and 30. Blood samples were collected at baseline, in the postanesthesia care unit, and at POD 1 and were analyzed for levels of cortisol, C-reactive proteins (CRP), and cytokines interleukin (IL) 1alpha, IL-1beta, IL-1ra, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor alpha. Data were analyzed using SPSS software (version 18) using a multivariate and mixed model approach to test for the effect of surgery and drug group. Pairwise comparisons were assessed by means of the t test or rank tests after correcting for multiple comparisons. RESULTS: The global 40-item quality of recovery questionnaire scores showed a significant effect of time (F(4,114)=22.63, P<0.001) and drug (F(1,51)=4.368, P=0.042), with average scores decreasing to lower values on POD 1 (163.63+/-2.47) and POD 2 (170.94+/-2.38) compared with baseline (180.56+/-1.588, mean+/-SE, 2-tailed t tests, P<0.001). By POD 3, scores were significantly lower (-13.74 point difference, P=0.005) in the PFS group (169.3+/-3.87) than in the PFD group (183.04+/-2.76). All patients reported significantly higher levels of fatigue postoperatively, but intergroup difference in Fatigue Severity Scores was detected on POD 3 only, with scores in the PFS group higher than in the PFD group (50.0+/-4.0 vs. 36.3+/-4.9, P=0.035). In both groups, plasma cortisol levels were highest in the postanesthesia care unit, whereas CRP levels were elevated on POD 1. DEX significantly reduced the levels of cortisol, but not those of CRP. Levels of cytokines IL-6, IL-8, and IL 10 were significantly higher immediately after surgery and at POD 1. Plasma levels of other cytokines were not affected by surgery. DEX delayed postoperative rise in IL-10 but not in IL-6 or IL-8. CONCLUSIONS: DEX infusion during multilevel spinal fusions moderately improved the quality of recovery and possibly reduced fatigue in the early postoperative period. Moreover, it reduced plasma levels of cortisol and IL-10 in comparison with the control group. Our sample size was not sufficient to detect differences either in the incidence of complications or in clinically relevant outcomes. PMID- 22824922 TI - Report of the 13th annual ISNACC conference at Bhopal, India. PMID- 22824923 TI - A method for estimating zero-flow pressure and intracranial pressure. AB - BACKGROUND: It has been hypothesized that the critical closing pressure of cerebral circulation, or zero-flow pressure (ZFP), can estimate intracranial pressure (ICP). One ZFP estimation method used extrapolation of arterial blood pressure as against blood-flow velocity. The aim of this study was to improve ICP predictions. METHODS: Two revisions have been considered: (1) the linear model used for extrapolation is extended to a nonlinear equation; and (2) the parameters of the model are estimated by an alternative criterion (not least squares). The method is applied to data on transcranial Doppler measurements of blood-flow velocity, arterial blood pressure, and ICP from 104 patients suffering from closed traumatic brain injury, sampled across the United States and England. RESULTS: The revisions lead to qualitative (eg, precluding negative ICP) and quantitative improvements in ICP prediction. While moving from the original to the revised method, the +/-2 SD of the error is reduced from 33 to 24 mm Hg, and the root-mean-squared error is reduced from 11 to 8.2 mm Hg. The distribution of root-mean-squared error is tighter as well; for the revised method the 25th and 75th percentiles are 4.1 and 13.7 mm Hg, respectively, as compared with 5.1 and 18.8 mm Hg for the original method. CONCLUSIONS: Proposed alterations to a procedure for estimating ZFP lead to more accurate and more precise estimates of ICP, thereby offering improved means of estimating it noninvasively. The quality of the estimates is inadequate for many applications, but further work is proposed, which may lead to clinically useful results. PMID- 22824924 TI - Novel GATA6 loss-of-function mutation responsible for familial atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly sustained cardiac arrhythmia, and confers a substantially increased risk of morbidity and mortality. Increasing evidence has indicated that hereditary defects are implicated in AF. However, AF is genetically heterogeneous and the genetic etiology of AF in a significant portion of patients remains unclear. In this study, the entire coding sequence and splice junctions of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, were sequenced in 140 unrelated patients with lone AF. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically-matched healthy individuals used as the controls were genotyped. The functional characteristics of the mutant GATA6 were assessed in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.G469V, was identified in a family with AF inherited in an autosomal dominant pattern. The mutation was absent in the 200 control individuals and the altered amino acid was completely conserved across species. Functional analysis demonstrated that the GATA6 mutation was associated with a significantly decreased transcriptional activity. The findings provide novel insight into the molecular mechanism involved in the pathogenesis of AF, as well as insight into potential therapies for the prevention and treatment of AF. PMID- 22824925 TI - Prevention, detection, and treatment of coinfections: a priority in human immunodeficiency virus-infected persons to reduce viral load and consequent disease progression and transmission : comment on "Effect of early syphilis infection on plasma viral load and CD4 cell count in human immunodeficiency virus infected men". PMID- 22824926 TI - SGEF is overexpressed in prostate cancer and contributes to prostate cancer progression. AB - The purpose of this study was to investigate the potential roles of the SH3 containing guanine nucleotide exchange factor (SGEF) in human prostate cancer. Experimental data showed that SGEF was overexpressed in human prostate cancer cells and specimens. The reduction of SGEF expression through an SGEF-targeting siRNA in androgen-independent C4-2 and C4-2B cells suppressed both anchorage dependent and anchorage-independent growth. In addition, the androgen receptor (AR) antagonist bicalutamide further strengthened this inhibitory effect due to the suppression of the elevated AR transactivation after knockdown of SGEF. Collectively, our results provide the first demonstration that SGEF is a novel promoter of human prostate cancer progression and development. PMID- 22824927 TI - Longitudinal changes in procalcitonin in a heterogeneous group of critically ill patients. AB - OBJECTIVE: The utility of procalcitonin for the diagnosis of infection in the critical care setting has been extensively investigated with conflicting results. Herein, we report procalcitonin values relative to baseline patient characteristics, presence of shock, intensive care unit time course, infectious status, and Gram stain of infecting organism. DESIGN: Prospective, multicenter, observational study of critically ill patients admitted to intensive care unit for >24 hrs. SETTING: Three tertiary care intensive care units. PATIENTS: All consenting patients admitted to three mixed medical-surgical intensive care units. Patients who had elective surgery, overdoses, and who were expected to stay <24 hrs were excluded. INTERVENTIONS: Patients were followed prospectively to ascertain the presence of prevalent (present at admission) or incident (developed during admission) infections and clinical outcomes. Procalcitonin levels were measured daily for 10 days and were analyzed as a function of the underlying patient characteristics, presence of shock, time of infection, and pathogen isolated. MAIN RESULTS: Five hundred ninety-eight patients were enrolled. Medical and surgical infected cohorts had similar baseline procalcitonin values (3.0 [0.7-15.3] vs. 3.7 [0.6-9.8], p=.68) and peak procalcitonin (4.5 [1.0-22.9] vs. 5.0 [0.9-16.0], p=.91). Infected patients were sicker than their noninfected counterparts (Acute Physiology and Chronic Health Evaluation II 22.9 vs. 19.3, p<.001); those with infection at admission had a trend toward higher peak procalcitonin values than did those whose infection developed in the intensive care unit (4.9 vs. 1.4, p=.06). The presence of shock was significantly associated with elevations in procalcitonin in cohorts who were and were not infected (both groups p<.003 on days 1-5). CONCLUSIONS: Procalcitonin dynamics were similar between surgical and medical cohorts. Shock had an association with higher procalcitonin values independent of the presence of infection. Trends in differences in procalcitonin values were seen in patients who had incident vs. prevalent infections. PMID- 22824928 TI - Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation and delirium. AB - OBJECTIVE: To determine whether benzodiazepine and propofol doses are increased at night and whether daytime and nighttime sedative doses are associated with delirium, coma, and delayed liberation from mechanical ventilation. DESIGN: Single-center, prospective cohort study nested within the Awakening and Breathing Controlled randomized trial. SETTING: Saint Thomas Hospital in Nashville, TN, from 2004 to 2006. PATIENTS: Adult patients receiving mechanical ventilation for >12 hrs with continuous recording of hourly sedation dosing. INTERVENTIONS: We measured hourly doses of benzodiazepine and propofol exposure during the daytime (7 AM to 11 PM) and nighttime (11 PM to 7 AM) for 5 days. We quantified nighttime dose increases by subtracting the average hourly daytime dose on the preceding day from subsequent average hourly nighttime dose. We used multivariable logistic regression to determine whether daytime and nighttime dose increases were independently associated with delirium, coma, and delayed liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Among 140 patients, the median Acute Physiology and Chronic Health Evaluation II score was 27 (interquartile range 22-33). Among those receiving the sedatives, benzodiazepine and propofol doses were increased at night on 40% and 41% of patient-days, respectively. Of 485 patient-days, delirium was present on 160 (33%) and coma on 206 (42%). In adjusted models, greater daytime benzodiazepine dose was independently associated with failed spontaneous breathing trial and extubation, and subsequent delirium (p<.02 for all). Nighttime increase in benzodiazepine dose was associated with failed spontaneous breathing trial (p<.01) and delirium (p=.05). Daytime propofol dose was marginally associated with subsequent delirium (p=.06). CONCLUSIONS: Nearly half of mechanically ventilated intensive care unit patients received greater doses of sedation at night, a practice associated with failed spontaneous breathing trials, coma, and delirium. Over the first 5 days in our study, patients spent 75% of their time in coma or delirium, outcomes that may be reduced by efforts to decrease sedative exposure during both daytime and nighttime hours in the intensive care unit. PMID- 22824929 TI - Inhalation versus endovenous sedation in subarachnoid hemorrhage patients: effects on regional cerebral blood flow. AB - OBJECTIVE: Isoflurane is a volatile anesthetic that has a vasodilating effect on cerebral vessels producing a cerebral blood flow increase. Furthermore, it has been shown in animal studies that isoflurane, when used as a preconditioning agent, has neuroprotective properties, inducing tolerance to ischemia. However, it is not routinely used in neurointensive care because of the potential increase in intracranial pressure caused by the rise in cerebral blood flow. Nevertheless, subarachnoid hemorrhage patients who are at risk for vasospasm may benefit from an increase in cerebral blood flow. We measured regional cerebral blood flow during intravenous sedation with propofol and during sedation with isoflurane in patients with severe subarachnoid hemorrhage not having intracranial hypertension. DESIGN: The study is a crossover, open clinical trial (NCT00830843). SETTING: Neurointensive care unit of an academic hospital. PATIENTS: Thirteen patients with severe subarachnoid hemorrhage, (median Fisher scale 4), monitored on clinical indication with intracranial pressure device and a thermal diffusion probe for the assessment of regional cerebral blood flow. An intracranial pressure>18 mm Hg was an exclusion criterion. INTERVENTIONS: Cerebral and hemodynamic variables were assessed at three steps. Step 1: sedation with propofol 3-4 mg/kg/hr; step 2: after 1 hr of propofol discontinuation and isoflurane 0.8%; step 3: after 1 hr of propofol at the same previous infusion rate. Cerebral perfusion pressure and arterial PCO2 were maintained constant. Mean cerebral artery flow velocity and jugular vein oxygen saturation were measured at the end of each step. MEASUREMENTS AND MAIN RESULTS: Regional cerebral blood flow increased significantly during step 2 (39.3+/-29 mL/100 hg/min) compared to step 1 (20.8+/-10.7) and step 3 (24.7+/-8). There was no difference in regional cerebral blood flow comparing step 1 vs. step 3. No significant difference in intracranial pressure, mean cerebral artery transcranial Doppler velocity, PaCO2, cerebral perfusion pressure between the different steps. CONCLUSIONS: Isoflurane increases regional cerebral blood flow in comparison to propofol. Intracranial pressure did not change significantly in the population not affected by intracranial hypertension. PMID- 22824930 TI - Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. AB - OBJECTIVE: This study tested the hypothesis that interruption of the renin angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the prevalence of atrial fibrillation after cardiac surgery. DESIGN: Randomized double-blind placebo controlled study. SETTING: University-affiliated hospitals. PATIENTS: Four hundred forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. INTERVENTIONS: One week to 4 days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5 mg the first 3 days followed by 5 mg/day, with the dose reduced to 2.5 mg/day on the first postoperative day only), or spironolactone (25 mg/day). MEASUREMENTS: The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the prevalence of hypotension, length of hospital stay, stroke, and death. MAIN RESULTS: The prevalence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (p=.95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, p=.006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8+/-8.2 days vs. 5.7+/-3.2 days and 5.8+/-3.4 days, respectively, p=.08 for the comparison of placebo vs. the active treatment groups using log-rank test). Compared with patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4+/-761.5 mins vs. 1091.3+/-3067.3 mins, p=.04). CONCLUSIONS: Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery. PMID- 22824931 TI - Transfusion-related acute lung injury in cardiac surgery patients is characterized by pulmonary inflammation and coagulopathy: a prospective nested case-control study. AB - OBJECTIVE: Transfusion-related acute lung injury is the leading cause of transfusion-related morbidity and mortality. Clinical data on the pathogenesis of transfusion-related acute lung injury are sparse. The objective of the present study was to determine inflammation and coagulation pathways involved in the onset of transfusion-related acute lung injury. DESIGN: Nested case-control study. SETTING: Operating theatre and intensive care department of a tertiary referral hospital. PATIENTS: Elective cardiac surgery patients requiring postsurgery intensive care admission. INTERVENTIONS: None. MEASUREMENTS: Cardiac surgery patients (n=668) were prospectively screened for the onset of transfusion related acute lung injury. Transfusion-related acute lung injury cases (n=16) were randomly assigned to transfused and nontransfused cardiac surgery controls in a 1:2 ratio. Blood samples were taken pre- and postoperatively and at onset of transfusion-related acute lung injury. In addition, at onset of transfusion related acute lung injury, bronchoalveolar lavage fluid was obtained. In plasma and bronchoalveolar lavage fluid, levels of interleukin-6, interleukin-8, elastase-alpha1-antitrypsin complexes, thrombin-antithrombin complexes, plasminogen activator activity, and plasminogen activator inhibitor-1 were determined by means of enzyme-linked immunosorbent assay. MAIN RESULTS: In all patients, cardiac surgery was associated with systemic inflammation, evidenced by an increase in plasma levels of interleukin-6, interleukin-8, and elastase-alpha1 antitrypsin complexes compared with presurgery levels (p<.001). Prior to onset of transfusion-related acute lung injury, systemic interleukin-8 and interleukin-6 levels were higher compared with nontransfused controls (p<.01). In transfusion related acute lung injury cases, bronchoalveolar lavage fluid levels of interleukin-8, interleukin-6, and elastase-alpha1-antitrypsin complexes were elevated compared with control groups (p<.05). Both plasma and bronchoalveolar lavage fluid levels of thrombin-antithrombin complexes were enhanced in transfusion-related acute lung injury cases compared with control groups (p<.01). Bronchoalveolar lavage fluid levels of plasminogen activator activity were decreased due to an increase in plasminogen activator inhibitor-1 levels in transfusion-related acute lung injury cases compared with control groups (p<.01), indicating suppressed fibrinolysis. CONCLUSIONS: Prior to onset of transfusion related acute lung injury, there is systemic inflammation and neutrophil sequestration. Transfusion-related acute lung injury is characterized by both systemic and pulmonary inflammation and activation of neutrophils, as well as enhanced coagulation and suppressed fibrinolysis. PMID- 22824932 TI - Parental decision-making preferences in the pediatric intensive care unit. AB - OBJECTIVE: To assess parental decision-making preferences in the high-stress environment of the pediatric intensive care unit and test whether preferences vary with demographics, complex chronic conditions, prior admissions to the pediatric intensive care unit, and parental positive and negative emotional affect. DESIGN: Institutional Review Board-approved prospective cohort study conducted between December 2009 and April 2010. SETTING: Pediatric intensive care unit at The Children's Hospital of Philadelphia. PARTICIPANTS: Eighty-seven English-speaking parents of 75 children either <18 yrs of age or cognitively incapable of making their own decisions and who were hospitalized in the pediatric intensive care unit for >72 hrs. INTERVENTIONS: Parents were interviewed in person and completed standardized instruments that assessed decision-making preferences and parental affect. MEASUREMENTS AND MAIN RESULTS: The majority of parents in the analytic sample preferred shared decision making with their doctors (40.0%) or making the final decision/mostly making the final decision on their own (41.0%). None of the child and parent characteristics in the analytic sample were found to be significantly associated with the top decision-making preference. Using shared decision making as a reference category, we determined whether positive or negative affect scores were associated with preferring other decision-making options. We found that parents with higher positive affect were less likely to prefer self/mostly self (autonomous decision making). Increased positive affect was also associated with a reduced likelihood of preferring doctor/mostly doctor (delegating the decision), but not to a significant degree. CONCLUSIONS: Most parents in the pediatric intensive care unit prefer their role in decision making to be shared with their doctor or to have significant autonomy in the final decision. A sizeable minority, however, prefer decision-making delegation. Parental emotional affect has an association with decision-making preference. PMID- 22824933 TI - Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: a prospective cohort study. AB - OBJECTIVE: To evaluate the value of continuous electroencephalography in early prognostication in patients treated with hypothermia after cardiac arrest. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit. PATIENTS: Sixty patients admitted to the intensive care unit for therapeutic hypothermia after cardiac arrest. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: In all patients, continuous electroencephalogram and daily somatosensory evoked potentials were recorded during the first 5 days of admission or until intensive care unit discharge. Neurological outcomes were based on each patient's best achieved Cerebral Performance Category score within 6 months. Twenty-seven of 56 patients (48%) achieved good neurological outcome (Cerebral Performance Category score 1-2).At 12 hrs after resuscitation, 43% of the patients with good neurological outcome showed continuous, diffuse slow electroencephalogram rhythms, whereas this was never observed in patients with poor outcome.The sensitivity for predicting poor neurological outcome of low-voltage and isoelectric electroencephalogram patterns 24 hrs after resuscitation was 40% (95% confidence interval 19%-64%) with a 100% specificity (confidence interval 86% 100%), whereas the sensitivity and specificity of absent somatosensory evoked potential responses during the first 24 hrs were 24% (confidence interval 10% 44%) and 100% (confidence interval: 87%-100%), respectively. The negative predictive value for poor outcome of low-voltage and isoelectric electroencephalogram patterns was 68% (confidence interval 50%-81%) compared to 55% (confidence interval 40%-60%) for bilateral somatosensory evoked potential absence, both with a positive predictive value of 100% (confidence interval 63% 100% and 59%-100% respectively). Burst-suppression patterns after 24 hrs were also associated with poor neurological outcome, but not inevitably so. CONCLUSIONS: In patients treated with hypothermia, electroencephalogram monitoring during the first 24 hrs after resuscitation can contribute to the prediction of both good and poor neurological outcome. Continuous patterns within 12 hrs predicted good outcome. Isoelectric or low-voltage electroencephalograms after 24 hrs predicted poor outcome with a sensitivity almost two times larger than bilateral absent somatosensory evoked potential responses. PMID- 22824934 TI - Previous prescription of beta-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis. AB - OBJECTIVES: Results from basic science and narrative reviews suggest a potential role of beta-blockers in patients with sepsis. Although the hypothesis is physiologically appealing, it could be seen as clinically counterintuitive. We sought to assess whether patients previously prescribed chronic beta-blocker therapy had a different mortality rate than those who did not receive treatment. SETTING: Record linkage of administrative databases of Italian patients hospitalized for sepsis during years 2003-2008 were identified and followed up for all-cause mortality at 28 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 9,465 patients aged>=40 yrs who were hospitalized in critical care units for sepsis. Of these, 1,061 patients were on chronic prescription with beta-blockers and 8404 were not previously treated. Despite a higher risk profile, patients previously prescribed with beta-blockers had lower mortality at 28 days (188/1061 [17.7%]) than those previously untreated (1857/8404 [22.1%]) (odds ratio 0.78; 95% confidence interval 0.66-0.93; p=.005 for unadjusted analysis, and odds ratio 0.81; 95% confidence interval 0.68-0.97; p=.025 for adjusted analyses). Sensitivity and pair-matched results confirm the primary findings. CONCLUSIONS: As far as we are aware, this pharmacoepidemiologic assessment is the largest to examine the potential association of previous beta blocker prescription and mortality in patients with sepsis. Chronic prescription of beta-blockers may confer a survival advantage to patients who subsequently develop sepsis with organ dysfunction and who are admitted to an intensive care unit. Prospective randomized clinical trials should formally test this hypothesis. PMID- 22824935 TI - Real-time forecasting of pediatric intensive care unit length of stay using computerized provider orders. AB - OBJECTIVE: To develop a model to produce real-time, updated forecasts of patients' intensive care unit length of stay using naturally generated provider orders. The model was designed to be integrated within a computerized decision support system to improve patient flow management. DESIGN: Retrospective cohort study. SETTING: Twenty-six bed pediatric intensive care unit within an urban, academic children's hospital using a computerized order entry system. PATIENTS: A total of 2,178 consecutive pediatric intensive care unit admissions during a 16 month time period. MEASUREMENTS AND MAIN RESULTS: We obtained unit length of stay measurements, time-stamped provider orders, age, admission source, and readmission status. A joint discrete-time logistic regression model was developed to produce probabilistic length of stay forecasts from continuously updated provider orders. Accuracy was assessed by comparing forecasted expected discharge time with observed discharge time, rank probability scoring, and calibration curves. Cross-validation procedures were conducted. The distribution of length of stay was heavily right-skewed with a mean of 3.5 days (95% confidence interval 0.3-19.1). Provider orders were predictive of length of stay in real-time accurately forecasting discharge within a 12-hr window: 46% for patients within 1 day of discharge, 34% for patients within 2 days of discharge, and 27% for patients within 3 days of discharge. The forecast model incorporating predictive orders demonstrated significant improvements in accuracy compared with forecasts based solely on empirical and temporal information. Seventeen predictive orders were found, grouped by medication, ventilation, laboratory, diet, activity, foreign body, and extracorporeal membrane oxygenation. CONCLUSIONS: Provider orders reflect dynamic changes in patients' conditions, making them useful for real-time length of stay prediction and patient flow management. Patients' length of stay represent a major source of variability in intensive care unit resource utilization and if accurately predicted and communicated, may lead to proactive bed management with more efficient patient flow. PMID- 22824937 TI - Core competency in mechanical ventilation: development of educational objectives using the Delphi technique. AB - OBJECTIVES: We sought to identify and standardize the core clinical knowledge and skills required to care for patients receiving mechanical ventilation. DESIGN: Prospective survey reaching consensus by the Delphi technique. SETTING: North American survey conducted anonymously by electronic e-mail. SUBJECTS: International experts in mechanical ventilation, frontline resident educators, medical education experts, and community intensivists were recruited to participate MEASUREMENTS AND MAIN RESULTS: Fourteen panelists participated (ten content experts, three resident educators, one medical education expert, zero community intensivists). Individual panelists generated a total of 200 educational objectives, of which 109 were duplicates. Of the remaining 91 items, 56 met predefined consensus criteria for inclusion in the final set of educational objectives. The educational objectives spanned a broad range of categories, including respiratory physiology, noninvasive ventilation, lung protective ventilation, weaning, and withholding and withdrawing mechanical ventilation. Agreement among panelists on the items included was high (median proportion supporting item inclusion was 88%, range 70%-100%). CONCLUSIONS: There is a consensus that general resident core competency in mechanical ventilation requires a broad range of knowledge application and skill. These educational objectives may help identify and standardize the educational outcomes related to mechanical ventilation that residents should achieve. PMID- 22824938 TI - Tracheostomy practice in adults with acute respiratory failure. AB - OBJECTIVE: Tracheostomy remains one of the most commonly performed surgical procedures in adults with acute respiratory failure and identifies a patient cohort which is among the most resource-intensive to provide care. The objective of this concise definitive review is the synthesis of current knowledge regarding tracheostomy practice in this context. DATA SOURCE: Peer-reviewed, English language publications pertaining to tracheostomy indications, timing, technique, and management. RESULTS: Contemporary literature concerning tracheostomy use predominately focuses on two aspects: procedure timing and technical considerations. Three recent, large, randomized controlled trials failed to demonstrate an effect of "early" tracheostomy on mortality, infectious complications, intensive care unit, or hospital length of stay. Relative to continued translaryngeal intubation, tracheostomy was associated with less sedation use and earlier mobility. An accumulating body of literature suggests that, relative to conventional surgical methods, percutaneous dilational techniques are advantageous with respect to cost and complication profile. Literature addressing management following tracheostomy placement consists largely of single institution, nonrandomized reports, limiting the ability to formulate specific recommendations regarding this aspect of care. CONCLUSIONS: In patients who otherwise lack indication for surgical airway, clinicians should defer tracheostomy placement for at least 2 wks following the onset of acute respiratory failure to insure need for ongoing ventilatory support. Subpopulations of patients (e.g., those with acute neurological injury or stroke) may benefit from earlier tracheostomy. Percutaneous dilational tracheostomy should be considered the preferred technique for this intervention in the appropriately selected individual. Future investigations should include efforts to optimize post-tracheostomy management and to quantify tracheostomy effects on patient-centric outcomes. PMID- 22824939 TI - Quality improvement and cost savings after implementation of the Leapfrog intensive care unit physician staffing standard at a community teaching hospital. AB - BACKGROUND: Prior studies have shown that implementation of the Leapfrog intensive care unit physician staffing standard of dedicated intensivists providing 24-hr intensive care unit coverage reduces length of stay and in hospital mortality. A theoretical model of the cost-effectiveness of intensive care unit physician staffing patterns has also been published, but no study has examined the actual cost vs. cost savings of such a program. OBJECTIVE: To determine whether improved outcomes in specific quality measures would result in an overall cost savings in patient care DESIGN: Retrospective, 1 yr before-after cohort study SETTING: A 15-bed mixed medical-surgical community intensive care unit PATIENTS: A total of 2,181 patients: 1,113 patients preimplementation and 1,068 patients postimplementation. INTERVENTION: Leapfrog intensive care unit physician staffing standard MEASUREMENTS: Intensive care unit and hospital length of stay, rates for ventilator-associated pneumonia and central venous access device infection, and cost of care. RESULTS: Following institution of the intensive care unit physician staffing, the mean intensive care unit length of stay decreased significantly from 3.5+/-8.9 days to 2.7+/-4.7 days, (p<.002). The frequency of ventilator-associated pneumonia fell from 8.1% to 1.3% (p<.0002) after intervention. Ventilator-associated pneumonia rate per 100 ventilator days decreased from 1.03 to 0.38 (p<.0002). After intervention, the frequency of the central venous access device infection events fell from 9.4% to 1.1% (p<.0002). Central venous access device infection rate per 1000 line days decreased from 8.49 to 1.69. The net savings for the hospital were $744,001. The 1-yr institutional return on investment from intensive care unit physician staffing was 105%. CONCLUSIONS: Implementation of the Leapfrog intensive care unit physician staffing standard significantly reduced intensive care unit length of stay and lowered the prevalence of ventilator-associated pneumonia and central venous access device infection. A cost analysis yielded a 1-yr institutional return on investment of 105%. Our study confirms that implementation of the Leapfrog intensive care unit physician staffing model in the community hospital setting improves quality measures and is economically feasible. PMID- 22824940 TI - Biodegradable PLGA85/15 nanoparticles as a delivery vehicle for Chlamydia trachomatis recombinant MOMP-187 peptide. AB - Development of a Chlamydia trachomatis vaccine has been a formidable task partly because of an ineffective delivery system. Our laboratory has generated a recombinant peptide of C. trachomatis major outer membrane protein (MOMP) (rMOMP 187) and demonstrated that it induced at 20 MUg ml(-1) maximal interleukin (IL)-6 and IL-12p40 Th1 cytokines in mouse J774 macrophages. In a continuous pursuit of a C. trachomatis effective vaccine-delivery system, we encapsulated rMOMP-187 in poly(d,l-lactic-co-glycolic acid) (PLGA, 85:15 PLA/PGA ratio) to serve as a nanovaccine candidate. Physiochemical characterizations were assessed by Fourier transform-infrared spectroscopy, atomic force microscopy, Zetasizer, Zeta potential, transmission electron microcopy and differential scanning calorimetry. The encapsulated rMOMP-187 was small (~200 nm) with an apparently smooth uniform oval structure, thermally stable (54 degrees C), negatively charged ( - 27.00 mV) and exhibited minimal toxicity at concentrations <250 MUg ml (-1) to eukaryotic cells (>95% viable cells) over a 24-72 h period. We achieved a high encapsulation efficiency of rMOMP-187 (~98%) in PLGA, a loading peptide capacity of 2.7% and a slow release of the encapsulated peptide. Stimulation of J774 macrophages with a concentration as low as 1 MUg ml (-1) of encapsulated rMOMP 187 evoked high production levels of the Th1 cytokines IL-6 (874 pg ml(-1)) and IL-12p40 (674 pg ml(-1)) as well as nitric oxide (8 MUM) at 24 h post stimulation, and in a dose-response and time-kinetics manner. Our data indicate the successful encapsulation and characterization of rMOMP-187 in PLGA and, more importantly, that PLGA enhanced the capacity of the peptide to induce Th1 cytokines and NO in vitro. These findings make this nanovaccine an attractive candidate in pursuit of an efficacious vaccine against C. trachomatis. PMID- 22824936 TI - Fluid balance in critically ill children with acute lung injury. AB - OBJECTIVES: In the Fluid and Catheter Treatment Trial (NCT00281268), adults with acute lung injury randomized to a conservative vs. liberal fluid management protocol had increased days alive and free of mechanical ventilator support (ventilator-free days). Recruiting sufficient children with acute lung injury into a pediatric trial is challenging. A Bayesian statistical approach relies on the adult trial for the a priori effect estimate, requiring fewer patients. Preparing for a Bayesian pediatric trial mirroring the Fluid and Catheter Treatment Trial, we aimed to: 1) identify an inverse association between fluid balance and ventilator-free days; and 2) determine if fluid balance over time is more similar to adults in the Fluid and Catheter Treatment Trial liberal or conservative arms. DESIGN: Multicentered retrospective cohort study. SETTING: Five pediatric intensive care units. PATIENTS: Mechanically ventilated children (age>=1 month to <18 yrs) with acute lung injury admitted in 2007-2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fluid intake, output, and net fluid balance were collected on days 1-7 in 168 children with acute lung injury (median age 3 yrs, median PaO2/FIO2 138) and weight-adjusted (mL/kg). Using multivariable linear regression to adjust for age, gender, race, admission day illness severity, PaO2/FIO2, and vasopressor use, increasing cumulative fluid balance (mL/kg) on day 3 was associated with fewer ventilator-free days (p=.02). Adjusted for weight, daily fluid balance on days 1-3 and cumulative fluid balance on days 1-7 were higher in these children compared to adults in the Fluid and Catheter Treatment Trial conservative arm (p<.001, each day) and was similar to adults in the liberal arm. CONCLUSIONS: Increasing fluid balance on day 3 in children with acute lung injury at these centers is independently associated with fewer ventilator-free days. Our findings and the similarity of fluid balance patterns in our cohort to adults in the Fluid and Catheter Treatment Trial liberal arm demonstrate the need to determine whether a conservative fluid management strategy improves clinical outcomes in children with acute lung injury and support a Bayesian trial mirroring the Fluid and Catheter Treatment Trial. PMID- 22824941 TI - Amputations of limbs during the 2005 earthquake in Pakistan: a firsthand experience of the author. AB - PURPOSE: On 8 October 2005 a massive earthquake hit the northern mountainous areas of Pakistan and Kashmir causing 73,338 deaths and leaving over 125,000 severely injured. In a region which was less prepared for such an enormous disaster, mobilising rescue, relief and rehabilitation posed great challenges. The lead author (SMA) established two level 1 orthopaedic trauma and rehabilitation units in existing public hospitals through private philanthropy in the earthquake struck cities of Muzaffarabad in Kashmir and Mansehra in Khyber Pakhtun Khuwa (KPK) Province. The purpose was to combat the major catastrophe and later study the pattern of injuries especially amputations so as to improve the future strategies in similar scenarios. METHODS: This is a retrospective descriptive study of patients suffering from injuries of the limbs due to the earthquake who were managed in these centres with special emphasis on the patients with amputated limbs. The patients were received, worked up, investigated and prepared for definitive surgical procedures, in this case amputations. All patients were provided assistance for the fitting of a prosthesis and rehabilitation by referring them to specialised centres. RESULTS: Of 128,304 patients, 19,700 were managed in the centres established by the lead author over a period of seven months. Of these, 112 patients underwent amputations of upper and lower limbs. CONCLUSIONS: In a massive calamity over a wide geographic area away from big university hospitals, such as the 2005 Pakistan earthquake, the level 1 operating theatre facilities must be established within the area to meet the needs of the patients nearest to their homes and families, and run forever so that patients can have excellent follow-up and can use the same facilities regularly. For example, in this study we managed 112 amputees and placed them in a rehabilitation programme, and transferred these centres to the hospital authorities after five years. PMID- 22824942 TI - Deep-diving dinosaurs. AB - Dysbaric bone necrosis demonstrated in ichthyosaurs may be the result of prolonged deep diving rather than rapid ascent to escape predators. The bone lesions show structural and anatomical similarity to those that may occur in human divers and in the deep diving sperm whale, Physeter macrocephalus. PMID- 22824944 TI - A model of chemotaxis and associative learning in C. elegans. AB - The nematode C. elegans has attracted a great deal of interest from the neuroscience community due to the simplicity of its nervous system, which in the hermaphrodite is composed of just 302 neurons. C. elegans is known to engage in a number of sophisticated behaviours such as chemo- and thermotaxis. Experimental work has shown that these behaviours can be modified by experience and that C. elegans is capable of associative learning. In this paper, we focus on the chemotactic response of C. elegans to sodium chloride mediated by the ASE sensory neurons. We construct a biophysical model of the ASEL and ASER neurons that captures the time course of the ASE responses in response to up- and down-steps in NaCl concentration. We use this model to show that the time course of the ASE responses provide sufficient temporal resolution to successfully drive chemotaxis in C. elegans via steering, pirouettes and control of final turn angle. We show that these different locomotion strategies are individually capable of driving chemotaxis and that by working together they produce the best chemotactic response. We find that there is a separation into upward and downward drives mediated by the left and right ASE neurons. We show that the connectivity from ASEL and ASER must be of opposite polarity and that ASER, and the concomitant ability to sense when the worm is moving down the gradient, is more important for chemotaxis than ASEL, findings that are consistent with existing modelling studies in the literature. Finally, we examine associative learning in the network and show that experimental data can be explained by changes that occur at either the synaptic or sensory neuron level, the choice of which has distinct consequences for network function. PMID- 22824947 TI - Primary hyperparathyroidism is one of the three most frequent endocrine disorders, typically diagnosed in the years following menopause and with advancing age. PMID- 22824945 TI - Review of the invasion of Tetranychus evansi: biology, colonization pathways, potential expansion and prospects for biological control. AB - In the last two decades the subtropical red tomato spider mite, Tetranychus evansi, has expanded its geographical distribution and emerged as a major invasive agricultural pest. The mite is considered to be native to South America. Since its first report from north-eastern Brazil in 1952, it has been reported from different continents. This paper reviews literature on several aspects of the biology of T. evansi related to its status as an invasive species. It addresses taxonomical issues, occurrences, life history traits, host-plant interactions, genetic diversity of geographical isolates and worldwide colonisation pathways. It also presents updated data which allowed the assessment of the actual worldwide distribution of this species, from its discovery to the latest reports. As T. evansi is considered an emerging agricultural pest, we also present data based on modelling of the potential of T. evansi to colonize new geographical areas. In addition, this review presents past and current research on natural enemies of T. evansi potentially useful for its biological control. While summarizing the knowledge on T. evansi, the review emphasizes research possibilities that are worth pursuing, mainly concerning the ability of T. evansi to establish new populations and to detect new promising natural enemies. PMID- 22824948 TI - AME position statement: primary hyperparathyroidism in clinical practice. PMID- 22824949 TI - Half-metallicity of graphene nanoribbons and related systems: a new quantum mechanical El Dorado for nanotechnologies... or a hype for materials scientists? AB - In this work we discuss in some computational and analytical details the issue of half-metallicity in zig-zag graphene nanoribbons and nanoislands of finite width, i.e. the coexistence of metallic nature for electrons with one spin orientation and insulating nature for the electrons of opposite spin, which has been recently predicted from so-called first-principle calculations employing Density Functional Theory. It is mathematically demonstrated and computationally verified that, within the framework of non-relativistic and time-independent quantum mechanics, like the size-extensive spin-contamination to which it relates, half metallicity is nothing else than a methodological artefact, due to a too approximate treatment of electron correlation in the electronic ground state. PMID- 22824950 TI - Computational investigation on the new high energy density material of aluminum enriched 1, 1-diamino-2, 2-dinitroethylene. AB - Aluminum enriched 1, 1-diamino-2, 2-dinitroethylene (Al-FOX-7) crystal, as a new high energy density material (HEDM), was designed and investigated using grand canonical monte carlo (GCMC), NVT+NPT-molecular dynamics (MD) and GGA-PBE-density functional theory (DFT) methods. The results show that, Al atoms break out H-bond of functional group of FOX-7 crystal, and form new Al-H and Al-O bonds. Their atomic content (x) influences the surface electronic states, friction sensitivities and cj detonation properties of Al-FOX-7 crystals. While x is 4 atoms, the crystal has the highest friction sensitivities and cj detonation temperatures, which are about 1.5 times to that of FOX-7 crystal. PMID- 22824952 TI - Characterization of placenta-derived mesenchymal stem cells cultured in autologous human cord blood serum. AB - Human placenta-derived mesenchymal stem cells (P-MSCs) have drawn increasing attention in the field of stem cell research due to their potential in clinical applications as well as their rich and easy to procure cell source. While studies demonstrating the potential of P-MSCs for therapeutic transplantations have been documented, a clinically compliant procedure for P-MSC expansion in vitro has yet to be established. To this end, previous studies have demonstrated that MSCs of bone marrow and cord blood origins cultured in human cord blood serum (hCBS) are comparable to those cultured in fetal bovine serum (FBS), indicating that hCBS may be an alternative to FBS for the development of in vitro cell expansion procedures free of animal components. However, stem cells from origins other than bone marrow or cord blood, particularly from human placental tissues, which have demonstrated a good potential for clinical applications, have not been characterized under similar conditions. In this study, in an attempt to define a clinically compliant protocol for P-MSC expansion in vitro, we examined the effects of human hCBS as a replacement for FBS on cell proliferation capacity, differentiation potential, MSC-specific phenotypic expression and the genetic stability of P-MSCs in cultures. P-MSCs expanded in vitro in autologous hCBS maintained the capacity of self-renewal and expressed surface antigens characteristic of bone marrow-derived mesenchymal stem cells. Under differentiation conditions, the P-MSCs expanded in hCBS developed into adipogenic, osteogenic and neurogenic cell phenotypes. Chromosomal karyotyping and single cell gel electrophoresis analysis demonstrated that P-MSCs cultured in autologous hCBS were genetically stable. These results suggest that autologous hCBS may be used as an alternative to FBS for the in vitro expansion of P-MSCs for clinical applications. PMID- 22824953 TI - Solubilization and bio-conjugation of quantum dots and bacterial toxicity assays by growth curve and plate count. AB - Quantum dots (QDs) are fluorescent semiconductor nanoparticles with size dependent emission spectra that can be excited by a broad choice of wavelengths. QDs have attracted a lot of interest for imaging, diagnostics, and therapy due to their bright, stable fluorescence. QDs can be conjugated to a variety of bio active molecules for binding to bacteria and mammalian cells. QDs are also being widely investigated as cytotoxic agents for targeted killing of bacteria. The emergence of multiply-resistant bacterial strains is rapidly becoming a public health crisis, particularly in the case of Gram negative pathogens. Because of the well-known antimicrobial effect of certain nanomaterials, especially Ag, there are hundreds of studies examining the toxicity of nanoparticles to bacteria. Bacterial studies have been performed with other types of semiconductor nanoparticles as well, especially TiO(2), but also ZnO and others including CuO. Some comparisons of bacterial strains have been performed in these studies, usually comparing a Gram negative strain with a Gram positive. With all of these particles, mechanisms of toxicity are attributed to oxidation: either the photogeneration of reactive oxygen species (ROS) by the particles or the direct release of metal ions that can cause oxidative toxicity. Even with these materials, results of different studies vary greatly. In some studies the Gram positive test strain is reportedly more sensitive than the Gram negative; in others it is the opposite. These studies have been well reviewed. In all nanoparticle studies, particle composition, size, surface chemistry, sample aging/breakdown, and wavelength, power, and duration of light exposure can all dramatically affect the results. In addition, synthesis byproducts and solvents must be considered. High-throughput screening techniques are needed to be able to develop effective new nanomedicine agents. CdTe QDs have anti-microbial effects alone or in combination with antibiotics. In a previous study, we showed that coupling of antibiotics to CdTe can increase toxicity to bacteria but decrease toxicity to mammalian cells, due to decreased production of reactive oxygen species from the conjugates. Although it is unlikely that cadmium-containing compounds will be approved for use in humans, such preparations could be used for disinfection of surfaces or sterilization of water. In this protocol, we give a straightforward approach to solubilizing CdTe QDs with mercaptopropionic acid (MPA). The QDs are ready to use within an hour. We then demonstrate coupling to an antimicrobial agent. The second part of the protocol demonstrates a 96-well bacterial inhibition assay using the conjugated and unconjugated QDs. The optical density is read over many hours, permitting the effects of QD addition and light exposure to be evaluated immediately as well as after a recovery period. We also illustrate a colony count for quantifying bacterial survival. PMID- 22824954 TI - Collagen microsphere production on a chip. AB - We have developed an integrated microfluidic material processing chip and demonstrated the rapid production of collagen microspheres encapsulating cells with high uniformity and cell viability. The chip integrated three material processing steps. Monodisperse microdroplets were generated at a microfluidic T junction between aqueous and mineral oil flows. The flow was heated immediately to 37 degrees C to initiate collagen fiber assembly within a gelation channel. Gelled microspheres were extracted from the mineral oil phase into cell culture media within an extraction chamber. Collagen gelation immediately after microdroplet generation significantly reduced coalescence among microdroplets that led to non-uniform microsphere production. The microfluidic extraction approach led to higher microsphere recovery and cell viability than when a conventional centrifugation extraction approach was employed. These results indicate that chip-based material processing is a promising approach for cell-ECM microenvironment generation for applications such as tissue engineering and stem cell delivery. PMID- 22824955 TI - The chemistry of four-membered aromatics. AB - This article provides an overview on the aromatic systems of four-membered rings. These aromatic four-membered ring systems are rather exotic because of a poor correspondence between the Huckel rule and the structure of four-membered rings. Consequently, such aromatics are generally dications or dianions, to form 2pi or 6pi electron systems respectively. Alternatively, the use of open-shell structures or empty d-orbitals of transition metal atoms could give neutral aromatic four-membered ring systems. This paper summarizes the four-membered aromatic compounds reported to date and describes the various methods for evaluating their aromaticity. PMID- 22824956 TI - Pro-apoptotic role of the MEK/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells. AB - Ursodeoxycholic acid (UDCA) has been regarded as a suppressor of gastrointestinal cancer, but the mechanisms underlying its antitumor effects are not fully understood. Previously, we reported the antitumor effect of UDCA by demonstrating that UDCA induces apoptosis of gastric cancer cells. Bile acids are known to activate the ERK pathway and ERK is a representative oncogenic kinase in cancer cells. Here, we investigated the role of ERK in UDCA-induced gastric cancer cell apoptosis. We found that UDCA enhanced the phosphorylation of ERK1/2 and MEK1/2. The prevention of MEK by the pharmacologic inhibitors PD98059 and U0126, resulted in decreased UDCA-induced apoptosis as shown by the reduction of apoptotic body formation, caspase-8 activity, and caspase-3, -6 and PARP cleavage, indicating that ERK exerts pro-apoptotic activity upon exposure to UDCA. In addition, U0126 reduced UDCA-triggered TNF-related apoptosis-inducing ligand receptor 2 (TRAIL R2/DR5) expression. In gene silencing studies, we observed that RNA interference of ERK2 decreased apoptosis and reduced DR5 overexpression. Lipid raft disrupting agent, methyl-beta-cyclodextrin, blunted the phosphorylation of ERK1/2, indicating that ERK activation is regulated in a lipid raft-dependent manner. On the other hand, tumor-promoting bile acid, deoxycholic acid (DCA), also phosphorylated ERK in SNU601 cells. However, the DCA-triggered ERK pathway exerted anti-apoptotic function in the cells. Suppression of the ERK pathway enhanced DCA-induced apoptosis, and ERK activation was observed to be lipid raft independently controlled. These results indicated that UDCA and DCA may cause differential responses in gastric cancer cells through the ERK signaling molecule. Thus, ERK activation may be a possible mechanism by which UDCA and DCA represent differential activities in gastrointestinal cancer. PMID- 22824957 TI - Nek2C functions as a tumor promoter in human breast tumorigenesis. AB - The serine/threonine kinase Nek2 has been proposed as a requirement for the progression of breast cancer. The aim of this study was to investigate the expression of Nek2C, which is a splice variant of Nek2, and the role it plays in the different stages of breast cancer. We investigated the role of Nek2C in the MCF10 breast cancer cell lines, MCF10A, MCF10AT, MCF10DCIS.com and MCF10CA1a, using RNA interference and plasmid transfection, as well as breast tissue samples of normal breast tissue (NBT), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). We detected the mRNA Nek2C expression levels in the MCF10 cell lines and in human breast samples. Our results revealed that the mRNA expression of Nek2C was significantly upregulated in the MCF10DCIS.com and MCF10CA1a cell lines as well as in human primary breast cancer tissue (DCIS and IDC). As expected, the Nek2C downregulation, using RNA interference, decreased the survival, invasion and migration of MCF10DCIS.com and MCF10CA1a cells. Consistent with these results, the Nek2C upregulation in MCF10A and MCF10AT cells using plasmid transfection increased the survival ability of these cells. Our results also revealed a correlation between Nek2C mRNA expression levels and tumor grade. Taken together, our findings suggest that Nek2C plays a signicficant role in breast cancer development and that Nek2C inhibition may be a useful therapeutic approach to targeting human breast tumors. PMID- 22824958 TI - Electrically controlled polarized photoluminescence of CdSe/ZnS nanorods embedded in a liquid crystal template. AB - A novel homogeneous composite material, consisting of luminescent CdSe/ZnS quantum nanorods, embedded in the nematic liquid crystal 5CB, has been prepared. Liquid crystal cells and free-standing stretched polymer films incorporating this composite material were characterized using polarized micro-photoluminescence and electro-optical measurements under an applied electric field. A liquid crystal induced, macroscopic orientation of the nanorods in a thin layer of the material has been demonstrated. A conventional liquid crystal cell, filled with this composite, exhibits 40% modulation of the nanorod's photoluminescence intensity when subjected to an external electric field. These results indicate that quantum nanorods may have practical applications in photonic devices. PMID- 22824959 TI - Water quality and plankton in the United States nearshore waters of Lake Huron. AB - Our goal in the development of a nearshore monitoring method has been to evaluate and refine an in situ mapping approach to assess the nearshore waters across the Great Lakes. The report here for Lake Huron is part of a broader effort being conducted across all five Great Lakes. We conducted an intensive survey for the United States nearshore of Lake Huron along a continuous shoreline transect (523 km) from Port Huron, Michigan, to Detour Passage. A depth contour of 20 m was towed with a conductivity-temperature depth profiler, fluorometer, transmissometer, and laser optical plankton counter. Multiple cross-contour tows (10-30 m) on the cruise dates were used to characterize the variability across a broader range of the nearshore. The cross-contour tows were comparable with the alongshore contour indicating that the 20-m contour does a good job of representing the nearshore region (10-30 m). Strong correlations were observed between water quality and spatially associated watershed land use. A repeat tow separated by several weeks investigated temporal variability in spatial patterns within a summer season. Strong correlations were observed across each variable for the temporal repeat across broad- and fine-scale spatial dimensions. The survey results for Lake Huron nearshore are briefly compared with a similar nearshore survey in Lake Superior. The biomass concentrations of lower food web components of Lake Huron were notably approximately 54-59 % of those in Lake Superior. The towed instrumentation survey supported the recent view of a change in Lake Huron to an ultra-oligotrophic state, which has been uncharacteristic in recent history. PMID- 22824960 TI - Environmental indicators of biofuel sustainability: what about context? AB - Indicators of the environmental sustainability of biofuel production, distribution, and use should be selected, measured, and interpreted with respect to the context in which they are used. The context of a sustainability assessment includes the purpose, the particular biofuel production and distribution system, policy conditions, stakeholder values, location, temporal influences, spatial scale, baselines, and reference scenarios. We recommend that biofuel sustainability questions be formulated with respect to the context, that appropriate indicators of environmental sustainability be developed or selected from more generic suites, and that decision makers consider context in ascribing meaning to indicators. In addition, considerations such as technical objectives, varying values and perspectives of stakeholder groups, indicator cost, and availability and reliability of data need to be understood and considered. Sustainability indicators for biofuels are most useful if adequate historical data are available, information can be collected at appropriate spatial and temporal scales, organizations are committed to use indicator information in the decision-making process, and indicators can effectively guide behavior toward more sustainable practices. PMID- 22824961 TI - The influence of place attachment and experience use history on perceived depreciative visitor behavior and crowding in an urban national park. AB - Research on recreational place attachment suggests that place identity, or the emotional/symbolic ties people have to places, and place dependence, which describes a functional attachment to a specific place, influence the perception of social and environmental site conditions. Recent research, however, has found that place attachment is not always a predictor of such perceptions. This study investigated the influence of place attachment and experience use history on the perception of depreciative visitor behavior, recreation impacts and crowding in an urban national park. In 2006, 605 on-site visitors to the heavily-used Viennese part of the Danube Floodplains National Park were asked about past experience, place attachment, perceptions of depreciative visitor behavior, crowding, changes in visitor numbers during the past ten years, and recreation impacts on wildlife. Confirmatory factor analysis confirmed the two dimensions of place attachment. Linear regression analyses found that place identity and place dependence were related to some perceived depreciative visitor behaviors and visitor number changes but not to crowding, while experience use history additionally related to perceived crowding. Visitors with higher place attachment and past experience were more sensitive to social and environmental site conditions. Management implications of the findings are discussed. PMID- 22824962 TI - Addressing the growth in intensive care: comment on "Intensive care unit admitting patterns in the Veterans Affairs health care system". PMID- 22824963 TI - Biosynthesis of wine aroma: transcript profiles of hydroxymethylbutenyl diphosphate reductase, geranyl diphosphate synthase, and linalool/nerolidol synthase parallel monoterpenol glycoside accumulation in Gewurztraminer grapes. AB - In developing grapevine (Vitis vinifera L.) berries, precursor volatile organic compounds (PVOCs) are largely stored as glycosides which may be hydrolyzed to release VOCs during fruit ripening, wine making, or aging. VOCs can be further transformed by yeast metabolism. Together, these processes contribute to complexity of wine aromas. Floral and citrus odors of many white wine varietals are attributed to monoterpenes and monoterpene alcohols, while phenolic compounds, norisoprenoids, and other volatiles also play important roles in determining aroma. We present an analysis of PVOCs stored as glycosides in developing Gewurztraminer berries during the growing season. We optimized a method for PVOC analysis suitable for small amounts of Muscat grapevine berries and showed that the amount of PVOCs dramatically increased during and after veraison. Transcript profiling of the same berry samples underscored the involvement of terpenoid pathway genes in the accumulation of PVOCs. The onset of monoterpenol PVOC accumulation in developing grapes was correlated with an increase of transcript abundances of early terpenoid pathway enzymes. Transcripts encoding the methylerythritol phosphate pathway gene 4-hydroxy-3-methylbut-2-enyl diphosphate reductase, as well as geraniol diphosphate synthase, were up regulated preceding and during the increase in monoterpenol PVOCs. Transcripts for linalool/nerolidol synthase increased in later veraison stages. PMID- 22824964 TI - Targeting sources of drought tolerance within an Avena spp. collection through multivariate approaches. AB - In this study, we find and characterize the sources of tolerance to drought amongst an oat (Avena sativa L.) germplasm collection of 174 landraces and cultivars. We used multivariate analysis, non-supervised principal component analyses (PCA) and supervised discriminant function analyses (DFA) to suggest the key mechanism/s responsible for coping with drought stress. Following initial assessment of drought symptoms and area under the drought progress curve, a subset of 14 accessions were selected for further analysis. The collection was assessed for relative water content (RWC), cell membrane stability, stomatal conductance (g (1)), leaf temperature, water use efficiency (WUE), lipid peroxidation, lipoxygenase activity, chlorophyll levels and antioxidant capacity during a drought time course experiment. Without the use of multivariate approaches, it proved difficult to unequivocally link drought tolerance to specific physiological processes in the different resistant oat accessions. These approaches allowed the ranking of many supposed drought tolerance traits in the order of degree of importance within this crop, thereby highlighting those with a causal relationship to drought stress tolerance. Analyses of the loading vectors used to derive the PCA and DFA models indicated that two traits involved in water relations, temperature and RWC together with the area of drought curves, were important indicators of drought tolerance. However, other parameters involved in water use such as g (1) and WUE were less able to discriminate between the accessions. These observations validate our approach which should be seen as representing a cost-effective initial screen that could be subsequently employed to target drought tolerance in segregating populations. PMID- 22824965 TI - Expression of OsBiP4 and OsBiP5 is highly correlated with the endoplasmic reticulum stress response in rice. AB - Binding protein (BiP) is a chaperone protein involved in the folding of secretory proteins in the ER lumen. OsBiP1 is constitutively expressed in various tissues, whereas the expression of OsBiP4 and OsBiP5 (OsBiP4&5) is not detected in any tissue under normal conditions. However, expression of OsBiP4&5 was highly and specifically activated under ER stress conditions induced by DTT treatment, OsBiP1 knockdown, OsBiP1 overexpression, OsIRE1 overexpression, or various exogenous recombinant proteins in transgenic rice. In contrast, OsBiP4&5 did not accumulate in OsIRE1 knockdown transgenic rice even after DTT treatment. When the subcellular localization of OsBiP4&5 was investigated in seed endosperm cells under the ER stress condition, OsBiP4&5 were localized to the ER, but did not participate in ER-derived protein body (PB-I) formation in a different manner to OsBiP1. These results indicate that OsBiP4&5 levels were positively correlated with stress levels in the ER. Taken together, these results suggest that OsBiP4&5 are ER stress-related BiP proteins that are regulated by OsIRE1/OsbZIP50 pathway and that they may have a distinct function from that of OsBiP1 in rice. PMID- 22824967 TI - Swift block-updating EM and pseudo-EM procedures for Bayesian shrinkage analysis of quantitative trait loci. AB - INTRODUCTION: Virtually all existing expectation-maximization (EM) algorithms for quantitative trait locus (QTL) mapping overlook the covariance structure of genetic effects, even though this information can help enhance the robustness of model-based inferences. RESULTS: Here, we propose fast EM and pseudo-EM-based procedures for Bayesian shrinkage analysis of QTLs, designed to accommodate the posterior covariance structure of genetic effects through a block-updating scheme. That is, updating all genetic effects simultaneously through many cycles of iterations. CONCLUSION: Simulation results based on computer-generated and real-world marker data demonstrated the ability of our method to swiftly produce sensible results regarding the phenotype-to-genotype association. Our new method provides a robust and remarkably fast alternative to full Bayesian estimation in high-dimensional models where the computational burden associated with Markov chain Monte Carlo simulation is often unwieldy. The R code used to fit the model to the data is provided in the online supplementary material. PMID- 22824969 TI - p16 promoter hypermethylation is associated with increased breast cancer risk. AB - The current study aimed to investigate the effects of p16 hypermethylation on breast cancer quantitatively through a meta-analysis of available case-control studies (including malignant, benign and normal breast cancer tissues). The PubMed, Web of Science and EBSCO databases were searched from their inceptions to February 1, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of the association between p16 hypermethylation and breast cancer risk. A total of eight studies, including 691 breast cancer cases and 525 control cases, were identified for meta-analysis. Statistically significant ORs of p16 hypermethylation were obtained from the breast cancer and control groups (OR, 6.58; 95% CI, 1.15-37.75; P=0.03). However, no significant associations between the methylation and ER and PR status in breast cancer were detected (OR, 1.24; 95% CI, 0.64-2.41; P=0.52; OR, 1.49; 95% CI, 0.81-2.75; P=0.20, respectively). The meta-analysis indicated that p16 hypermethylation significantly increases breast cancer risk. However, no significant associations between the methylation and ER and PR status in breast cancer were detected. PMID- 22824968 TI - Genetic analysis of phytosterol content in sunflower seeds. AB - Interest in phytosterol contents due to their potential benefits for human health has been largely documented in several crop species. Studies were focused mainly on total sterol content and their concentration or distribution in seed. This study aimed at providing new insight into the genetic control of total and individual sterol contents in sunflower seed through QTL analyses in a RIL population characterized over 2 years showing contrasted rainfall during seed filling. Results indicated that 13 regions on 9 linkage groups were involved in different phytosterol traits. Most of the QTL mapped were stable across years in spite of contrasted growing conditions. Some of them explained up to 30 % of phenotypic variation. Two QTL, located on LG10, near b1, and on LG14, were found to co-localize with QTL for oil content, indicating that likely, a part of the genetic variation for sterol content is only the result of genetic variation for oil content. However, three other QTL, stable over the 2 years, were found on LG1, LG4 and LG7 each associated with a particular class of sterols, suggesting that some enzymes known to be involved in the sterol metabolic pathway may determine the specificity of sterol profiles in sunflower seeds. These results suggest that it may be possible to introduce these traits as criteria in breeding programmes for quality in sunflower. The molecular markers linked to genetic factors controlling phytosterol contents could help selection during breeding programs. PMID- 22824970 TI - Molecular imprinting of protein in Pickering emulsion. AB - A new strategy of molecular imprinting to prepare spherical hydrogels via water in-oil Pickering emulsion polymerization was developed. The imprinted hydrogels exhibited fast adsorption kinetics and significant selectivity for the target protein. PMID- 22824971 TI - Iron-dependent binding of bovine milk alpha-casein with holo-lactoferrin, but not holo-transferrin. AB - Bovine milk alpha-casein has been identified as an iron- and heme-binding protein. However, the physiological role of its iron-binding remains to be elucidated in more detail. alpha-Casein was immobilized on CNBr-activated Sepharose 4B beads, and the alpha-casein agarose beads efficiently bound hemin as well as ferrous ammonium sulfate (Fe(2+)) as compared with control beads. Additionally, alpha-casein-beads bound bovine holo-lactoferrin (Lf), but not holo transferrin. Lf caused the release of Fe(2+) which had bound to the alpha-casein agarose beads beforehand. These results suggest that bovine alpha-casein iron dependently binds holo-bovine Lf more strongly than Fe(2+), and that strong binding between them may play a physiological role in regulating iron homeostasis in the bovine mammary gland. PMID- 22824972 TI - Anaphylaxis after a cat bite. PMID- 22824973 TI - Inhalation of budesonide/formoterol increases diaphragm muscle contractility. AB - BACKGROUND: Although budesonide/formoterol (BUD/FORM) is used clinically as a steroid/beta(2)-agonist single inhaler, it has not yet been clarified whether BUD/FORM has inotropic effects on diaphragm muscles after inhalation. METHODS: We examined the effects of BUD/FORM inhalation, endotoxin injection, and BUD/FORM inhalation plus endotoxin injection on diaphragm contractile properties and nitric oxide (NO) production. After these three treatments, the diaphragm muscle was dissected, and its contractile properties were measured. Histochemistry for the reduced form of nicotinamide adenine dinucleotide phosphate diaphorase was performed for each muscle to assess NO production. RESULTS: The force-frequency curves showed an upward shift 1 h after inhalation (p < 0.05) in the BUD/FORM inhalation only group. The force-frequency curves showed a downward shift 4 h after injection (p < 0.001) in the endotoxin injection groups. In the BUD/FORM inhalation plus endotoxin injection groups, a downward shift in the force frequency curves at 4 h after endotoxin injection was prevented. NO production was inhibited in the BUD/FORM inhalation plus endotoxin injection group compared with that of the endotoxin injection only groups. CONCLUSIONS: BUD/FORM inhalation has an inotropic effect on diaphragm muscle, protects diaphragm muscle deterioration after endotoxin injection, and inhibits NO production. Increments in muscle contractility with BUD/FORM inhalation are induced through a synergistic effect of an anti-inflammatory agent and beta(2)-agonist. PMID- 22824974 TI - Glucocorticoids inhibit MUC5AC production induced by transforming growth factor alpha in human respiratory cells. AB - BACKGROUND: Mucus hypersecretion from airway epithelium is a characteristic feature of severe asthma. Glucocorticoids (GCs) may suppress mucus production and diminish the harmful airway obstruction. We investigated the ability of GCs to suppress mRNA expression and protein synthesis of a gene encoding mucin, MUC5AC, induced by transforming growth factor (TGF)-alpha in human mucoepidermoid carcinoma (NCI-H292) cells and the molecular mechanisms underlying the suppression. METHODS: We determined if GCs such as dexamethasone (DEX), budesonide (BUD), and fluticasone (FP) could suppress MUC5AC production induced by a combination of TGF-alpha and double-strand RNA, polyinosinic-polycytidylic acid (polyI:C). MUC5AC mRNA expression and MUC5AC protein production were evaluated. The signaling pathways activated by TGF-alpha and their inhibition by GCs were tested using a phosphoprotein assay and MUC5AC promoter assay. RESULTS: DEX significantly suppressed the expression of MUC5AC mRNA and MUC5AC protein induced by TGF-alpha. The activation of the MUC5AC promoter by TGF-alpha was significantly inhibited by DEX. DEX did not affect activation of downstream pathways of the EGF receptor or mRNA stability of MUC5AC transcripts. DEX, BUD, and FP suppressed MUC5AC protein expression induced by a combination of TGF-alpha and polyI:C in a dose-dependent manner. CONCLUSIONS: GCs inhibited MUC5AC production induced by TGF-alpha alone or a combination of TGF-alpha and polyI:C; the repression may be mediated at the transcriptional but not post transcriptional level. PMID- 22824975 TI - Analysis of depression in asthmatic patients using the Japanese version of Patient Health Questionnaire-9. AB - BACKGROUND: Previous studies show that depression plays an important role in asthma. However, the association between asthma control and severity, and depression is inconclusive. METHODS: To investigate the association between asthma control and severity, and depression, we assessed differences in asthma control and asthma severity between groups with various grades of depressive state as defined by the PHQ-9 score using data from the Japanese version of Patient Health Questionnaire-9 (J-PHQ-9) and a questionnaire survey including the Asthma Control Test (ACT). RESULTS: The ACT scores in the symptom-screen positive (SP) and major/other depressive disorder (MDD/ODD) group were significantly lower than those in the symptom-screen negative (SN) and non-MDD/ODD groups, respectively. The rate of step1 and of step 3 and 4 in the SP group were significantly lower and higher than those in the SN group, respectively. When the SP group was divided into three, that is minimal, mild, and more than mild (MTM) depressive state subgroups, the ACT scores in the mild and MTM depressive state subgroups were significantly lower than those in the minimal depressive state subgroup. When the MTM subgroup was divided into moderate, moderate-severe and severe depressive state groups, however, there was no significant variation in ACT score and asthma severity among these three depressive state groups. CONCLUSIONS: This study is the first, large-scale investigation of the use of the J-PHQ-9 in asthma patients. Using the J-PHQ-9 and the questionnaire, there was a clear association between asthma control and severity, and depression. As the depression became more severe, the existence of other depression-associated factors unrelated to asthma control and severity might be assumed, although further investigation will be required. PMID- 22824976 TI - Involvement of PU.1 in mast cell/basophil-specific function of the human IL1RL1/ST2 promoter. AB - BACKGROUND: The human IL1RL1/ST2 gene encodes IL33 receptor. Recently, IL33 has been recognized as a key molecule for the development of Th2 response. Although mast cells and basophils are major targets of IL33 and play important roles in IL33-mediated Th2-type immune responses, the expression mechanism of ST2 in mast cells and basophils is largely unknown. In the present study, we analyzed regulation mechanism of the human ST2 promoter in the human mast cell line LAD2 and basophilic cell line KU812. METHODS: Promoter activity was determined by reporter assay with plasmids carrying the wild-type ST2 promoter obtained from human genomic DNA and its mutant. The transcription factor binding to the identified cis-element was identified by an electrophoretic mobility shift assay (EMSA). The effect of candidate transcription factor on ST2 expression was confirmed by analyzing ST2 mRNA level in siRNA-introduced cells. RESULTS: Reporter assay demonstrated that a cis-element of typical Ets-family binding sequence was critical for promoter activity in LAD2 and KU812. An Ets-family transcription factor PU.1 bound to this element in an EMSA. When PU.1 expression was suppressed by siRNA, ST2 mRNA level was significantly reduced in KU812. CONCLUSIONS: These observations indicated that PU.1 positively regulates the ST2 promoter as a transcription factor that directly transactivates the ST2 promoter via Ets-family-related cis-element in mast cells and basophils. PMID- 22824977 TI - Influence of underweight on asthma control. AB - BACKGROUND: Although the association between asthma control and body mass index (BMI) has been thoroughly investigated, most of this work has focused on the influence on asthma incidence or the effect of obesity on asthma control. To date, there have been no published studies on the influence of underweight on asthma control. METHODS: The aim of this study was to investigate the influence of underweight, as defined by the Japan Society for the Study of Obesity (JASSO), on asthma control in Japanese asthmatic patients. Using data from questionnaire surveys administered by the Niigata Asthma Treatment Study Group, we compared asthma control, as measured by the Asthma Control Test (ACT), between a normal weight group (18.5kg/m2 =< BMI < 25kg/m2) and an underweight group (BMI < 18.5kg/m2). RESULTS: Of the asthmatic patients who completed the 2008 and 2010 surveys, 1464 and 1260 cases were classified as being in the normal weight group, and 174 and 155 cases were classified as being in the underweight group. The ACT score (median, [interquartile range]) in the underweight group in 2008 (22, [19 24]) and 2010 (23, [19-25]) was significantly lower than that in the normal group in 2008 (23, [20-25]) and in 2010 (24, [21-25]). CONCLUSIONS: This study is the first, large-scale investigation of the influence of underweight on asthma control, and we have confirmed an adverse influence in a clinical setting. A potential mechanism for this interaction was unknown. Further investigation will be required. PMID- 22824978 TI - Abnormal axon reflex-mediated sweating correlates with high state of anxiety in atopic dermatitis. AB - BACKGROUND: Sweating plays a key role in skin homeostasis, including antimicrobial and moisturizing effects, and regulation of skin surface pH. Impaired axon reflex-mediated (AXR) sweating has been observed in patients with atopic dermatitis (AD). However, the mechanism of such abnormal sudomotor axon reflex remains to be revealed. METHODS: To investigate this mechanism, sudomotor function was analyzed using a quantitative sudomotor axon reflex test (acetylcholine iontophoresis) in patients with AD (n = 26) and healthy volunteers (n = 12). Correlation between sudomotor function and certain background factors, including Spielberger State Trait Anxiety Inventory score, Severity Scoring of Atopic Dermatitis (SCORAD) score, number of circulating eosinophils, and serum concentrations of thymus and activation-regulated chemokine and immunoglobulin E radioimmunosorbent test, was validated. RESULTS: Latency time was significantly prolonged in AD (p = 0.0352), and AXR sweating volume (mg/0-5 min) was significantly lower in AD patients than in healthy controls (p = 0.0441). Direct sweating volume (mg/0-5 min) was comparable in AD patients and healthy controls. A significant correlation between the evaluation results of quantitative sudomotor axon reflex tests and certain background factors was not observed. The latency time in non-lesioned and lesioned areas for AD patients versus continuous anxiety value in the Spielberger State Trait Anxiety Inventory and the AXR versus SCORAD showed significant correlations (p = 0.0424, p = 0.0169, and p = 0.0523, respectively). CONCLUSIONS: Although the number of study subjects was little, abnormal AXR sweating in patients with AD was observed. Correlative analysis suggests possible involvement of continuous anxiety and the immune system in such abnormal sudomotor function. PMID- 22824979 TI - Exhaled nitric oxide (FeNO) as a non-invasive marker of airway inflammation. AB - Nitric oxide (NO), previously very famous for being an environmental pollutant in the field of pulmonary medicine, is now known as the smallest, lightest, and most famed molecule to act as a biological messenger. Furthermore, recent basic researches have revealed the production mechanisms and physiological functions of nitric oxide in the lung, and clinical researches have been clarifying its tight relation to airway inflammation in asthma. On the bases of this knowledge, fractional nitric oxide (FeNO) has now been introduced as one of the most practical tools for the diagnosis and management of bronchial asthma. PMID- 22824980 TI - Impulse oscillometry; therapeutic impacts of transdermal long-acting Beta-2 agonist patch in elderly asthma with inhaled corticosteroid alone. AB - Growing interest had been focused on the involvement of the small airways in asthma, and impulse oscillometry (IOS) has been utilized as pulmonary functions for detecting large and small airways diseases separately. IOS can measure respiratory resistance and reactance at multiple frequencies, not available by spirometry or body plethysmography, is non-invasive techniques and convenient for elderly patients with a low dependency on cooperation during tidal breathing. IOS indices were well correlated with not only predicted FEV1 but also FEF25-75, residual volume/total lung capacity, delta N2 of a single nitrogen washout test which representing air trapping and inhomogeneous ventilation in the distal lung. These parameters and QOL scores were improved by additional transdermal long acting beta-2 agonist patch even in well-controlled elderly asthma treating with inhaled corticosteroids alone. IOS may have a complementary role of spirometry in detecting subtle airways changes in general practice. However, systemic studies are required to investigate the clinical implication of each IOS index. PMID- 22824981 TI - Vibrational energy relaxation of the ND-stretching vibration of NH2D in liquid NH3. AB - The vibrational energy relaxation from the first excited ND-stretching mode of NH(2)D dissolved in liquid NH(3) is studied using molecular dynamics simulations. The rate constants for inter- and intramolecular energy transfer are calculated in the framework of the quantum-classical Landau-Teller theory. At 273 K and an ammonia density of 0.642 g cm(-3) the calculated ND-stretch lifetime of tau = 9.1 ps is in good agreement with the experimental value of 8.6 ps. The main relaxation channel accounting for 52% of the energy transfer involves an intramolecular transition to the first excited state of the umbrella mode. The energy difference between both states is taken up by the near-resonant bending vibrations of the solvent. Less important for the ND-stretch lifetime are both the direct transition to the ground state and intramolecular relaxation via the NH(2)D bending modes contributing 23% each. Our calculations imply that the experimentally observed weak density dependence of tau is caused by detuning the resonance between the ND-stretch-umbrella energy gap and the solvent accepting modes which counteracts the expected linear increase of the relaxation rate with density. PMID- 22824982 TI - Observational study mortality in treated primary aldosteronism: the German Conn's registry. AB - In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04-12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls. PMID- 22824983 TI - Effect of pregnancy on autoregulation of cerebral blood flow in anterior versus posterior cerebrum. AB - Severe preeclampsia and eclampsia are associated with brain edema that forms preferentially in the posterior cerebral cortex possibly because of decreased sympathetic innervation of posterior cerebral arteries and less effective autoregulation during acute hypertension. In the present study, we examined the effect of pregnancy on the effectiveness of cerebral blood flow autoregulation using laser Doppler flowmetry and edema formation by wet:dry weight in acute hypertension induced by phenylephrine infusion in the anterior and posterior cerebrum from nonpregnant (n=8) and late-pregnant (n=6) Sprague-Dawley rats. In addition, we compared the effect of pregnancy on sympathetic innervation by tyrosine hydroxylase staining of posterior and middle cerebral arteries (n=5-6 per group) and endothelial and neuronal NO synthase expression using quantitative PCR (n=3 per group). In nonpregnant animals, there was no difference in autoregulation between the anterior and posterior cerebrum. However, in late pregnant animals, the threshold of cerebral blood flow autoregulation was shifted to lower pressures in the posterior cerebrum, which was associated with increased neuronal NO synthase expression in the posterior cerebral cortex versus anterior. Compared with the nonpregnant state, pregnancy increased the threshold of autoregulation in both brain regions that was related to decreased expression of endothelial NO synthase. Lastly, acute hypertension during pregnancy caused greater edema formation in both brain cortices that was not attributed to changes in sympathetic innervation. These findings suggest that, although pregnancy shifted the cerebral blood flow autoregulatory curve to higher pressures in both the anterior and posterior cortices, it did not protect from edema during acute hypertension. PMID- 22824984 TI - Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase. AB - We investigated whether the quality of myocardial collagen associates with elevated left-sided filling pressures in 38 hypertensive patients with stage C chronic heart failure. Filling pressures were assessed invasively measuring pulmonary capillary wedge pressure. Left ventricular chamber stiffness constant was calculated from the deceleration time of the early mitral filling wave. The fraction of myocardial volume occupied by total collagen tissue and collagen type I fibers was assessed histomorphologically. The degree of collagen cross-linking (CCL), which determines the formation of insoluble stiff collagen, was assessed by colorimetric and enzymatic procedures. The expression of lysyl oxidase (LOX), which regulates CCL, was assessed by Western blot. Compared with patients with normal pulmonary capillary wedge pressure (<=12 mm Hg; n=16), patients with elevated pulmonary capillary wedge pressure (>12 mm Hg; n=22) exhibited increases of left ventricular chamber stiffness constant, fraction of myocardial volume occupied by total collagen tissue, fraction of myocardial volume occupied by collagen type I fibers, CCL, insoluble stiff collagen, and LOX. Pulmonary capillary wedge pressure was correlated with left ventricular chamber stiffness constant (r=0.639; P<0.001), insoluble stiff collagen (r=0.474; P<0.005), CCL (r=0.625; P<0.001), and LOX (r=0.410; P<0.05) in all of the patients but not with fraction of myocardial volume occupied by total collagen tissue or fraction of myocardial volume occupied by collagen type I fibers. In addition, CCL was correlated with insoluble stiff collagen (r=0.612; P<0.005), LOX (r=0.538; P<0.01), left ventricular chamber stiffness constant (r=0.535; P<0.005), peak filling rate (r=-0.343; P<0.05), ejection fraction (r=-0.430; P<0.01), and amino terminal propeptide of brain natriuretic peptide (r=0.421; P<0.05) in all of the patients. These associations were independent of confounding factors. These findings indicate that, in hypertensive patients with stage C heart failure, it is only the quality of collagen (ie, degree of cross-linking) that associates with elevated filling pressures. It is suggested that LOX-mediated excessive CCL facilitates the increase in left ventricular stiffness with the resulting elevation of filling pressures in these patients. PMID- 22824985 TI - Role of yin and yang in diurnal blood pressure variation for cardiovascular disease. PMID- 22824986 TI - Patients with continuous-flow left ventricular assist devices provide insight in human baroreflex physiology. AB - The superior clinical outcome of new continuous-flow left ventricular assist devices (LVADs) challenges the physiological dogma that cardiovascular autonomic homeostasis requires pulsatile blood flow and pressure. We tested the hypothesis that continuous-flow LVADs impair baroreflex control of sympathetic nerve traffic, thus further exacerbating sympathetic excitation. We included 9 male heart failure patients (26-61 years; 18.9-28.3 kg/m(2)) implanted with a continuous-flow LVAD. We recorded ECG, respiration, finger blood pressure, brachial blood pressure, and muscle sympathetic nerve activity. After baseline measurements had been taken, patients underwent autonomic function testing including deep breathing, a Valsalva maneuver, and 15 degrees head-up tilt. Finally, we increased the LVAD speed in 7 patients. Spontaneous sympathetic baroreflex sensitivity was analyzed. Brachial blood pressure was 99+/-4 mm Hg with 14+/-2 mm Hg finger pulse pressure. Muscle sympathetic nerve activity bursts showed a normal morphology, were linked to the cardiac cycle, and were suppressed during blood pressure increases. Mean burst frequency was lower compared with age and body mass index-matched controls in 2 patients, slightly increased in 4 patients, and increased in 2 patients (P=0.11). Muscle sympathetic nerve activity burst latency and the median values of the burst amplitude distribution were similar between groups. Muscle sympathetic nerve activity increased 4+/-1 bursts per minute with head-up tilt (P<0.0003) and decreased 3+/-4 bursts per minute (P<0.031) when LVAD speed was raised. The mean sympathetic baroreflex slope was 3.75+/-0.79%/mm Hg in patients and -3.80+/-0.55%/mm Hg in controls. We conclude that low pulse pressure levels are sufficient to restrain sympathetic nervous system activity through baroreflex mechanisms. PMID- 22824987 TI - Renal resistive index and cardiovascular and renal outcomes in essential hypertension. AB - Increased renal restive index (RI) measured using Doppler ultrasonography has been shown to correlate with the degree of renal impairment in hypertensive patients. We investigated the prognostic role of RI in cardiovascular and renal outcomes. A total of 426 essential hypertensive subjects (mean age, 63 years; 50% female) with no previous cardiovascular disease were included in this study. Renal segmental arterial RI was measured by duplex Doppler ultrasonography. During follow-up (mean, 3.1 years), 57 participants developed the primary composite end points including cardiovascular and renal outcomes. In multivariate Cox regression analysis, RI was an independent predictor of worse outcome in total subjects (hazard ratio, 1.71 for 1 SD increase), as well as in patients with estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m(2) (hazard ratio, 2.11 for 1 SD increase; P<0.01, respectively). When divided into 4 groups based on the respective sex-specific median levels of RI in the eGFR >=60 and eGFR <60 mL/min per 1.73 m(2) groups, the group with eGFR <60 and high RI (male >=0.73, female >=0.72) had a significantly poorer event-free survival rate (chi(2)=126.4; P<0.01), and the adjusted hazard ratio by multivariate Cox regression analysis was 9.58 (95% CI, 3.26-32.89; P<0.01). In conclusion, impairment of renal hemodynamics evaluated by increased RI is associated with an increased risk of primary composite end points, and the combination of high RI and low eGFR is a powerful predictor of these diseases in essential hypertension. In hypertensive patients with chronic kidney disease, RI evaluation may complement predictors of cardiovascular and renal outcomes. PMID- 22824988 TI - Systematic review and meta-analysis on heavy and lightweight polypropylene mesh in Lichtenstein inguinal hernioplasty. AB - BACKGROUND: Recurrence and pain are the two most important outcomes after inguinal hernia surgery. The concept of lightweight or partially absorbable macroporous meshes was developed under the assumption that the observed pain rate could be decreased without increasing the number of recurrences. Few randomized trials were published to analyze their clinical value, and some concern was raised because of an increased risk of recurrence. A systematic review and a meta analysis of RCTs were carried out to determine whether the use of lightweight meshes influenced the pain and recurrence rate after Lichtenstein hernioplasty. METHODS: To assess the value of the lightweight mesh, an extensive literature search was performed. The random-effect meta-analysis model was used to correct for clinical diversity and methodological variations between studies. Recurrence rate, aspects of chronic pain and foreign body feeling at 6-60 months postoperatively were assessed. RESULTS: Eight prospective RCTs of good quality were identified. Analysis demonstrated no significant difference regarding recurrence (OR, 1.11; 95 % CI, 0.57-2.14; p = 0.77). No significant difference was observed concerning severe pain (OR, 0.99; 95 % CI, 0.48-2.02; p = 0.97). Description of any pain resulted in a significant improvement in the lightweight group (OR, 0.65; 95 % CI, 0.50-0.84; p = 0.001). The presence of foreign body feeling was favoring the lightweight group (OR, 0.62; 95 % CI, 0.41-0.94; p = 0.02). CONCLUSIONS: The use of lightweight mesh did not neither increase the recurrence rate nor reduce the incidence of severe pain. A significant reduction in foreign body feeling and overall pain rate in the postoperative period was recorded. Lightweight meshes could be considered as a material of choice in primary inguinal hernioplasty. PMID- 22824989 TI - Mechanical failure of a lightweight polypropylene mesh. AB - We report the case of a 41-year-old male who underwent repair of a recurrent midline abdominal incisional hernia with components separation. The hernia defect was repaired with a 30 cm * 30 cm underlay biological (Strattice) mesh used to partially bridge a small residual gap between the rectus muscles and reinforced with a 30 cm * 30 cm lightweight polypropylene onlay mesh (BARDTM soft mesh). The patient later developed a large persistent seroma that was excised 18 weeks later. On exploration of the previous hernia repair, it was noted that the onlay polypropylene mesh had fractured leaving a 3 cm by 2 cm defect, but the underlying biological mesh was intact preventing a recurrence of the hernia (see Fig. 1). The fractured mesh was repaired with an additional onlay 10 cm * 10 cm polypropylene mesh, the seroma was de-roofed, and the patient was later discharged. This case highlights the early mechanical failure of a lightweight polypropylene mesh; the precise mechanism of failure in this case is unclear and, however, may be related to high intra-abdominal pressures postoperatively. Fig. 1 Photograph showing onlay polypropylene (BARDTM soft mesh) mesh superficial to a biological (Strattice) sublay mesh bridging the recti (on the left and right wound edges). Arrow indicates the 2 cm by 3 cm fracture. PMID- 22824991 TI - The role of nitrogen bridges perturbing the photophysical properties in the porphyrin framework. AB - We have investigated the photophysical properties of vacataporphyrins possessing systematically controlled butadiene linkers on their pi-electron pathways. PMID- 22824990 TI - Pathogenesis of the epigastric hernia. AB - PURPOSE: Epigastric herniation is a rather common condition with a reported prevalence up to 10 %. Only a minority is symptomatic, presumably the reason for the scarce literature on this subject. Epigastric hernias have specific characteristics for which several anatomical theories have been developed. Whether these descriptions of pathological mechanisms still hold with regard to the characteristics of epigastric hernia is the subject of this review. METHODS: A multi-database research was performed to reveal relevant literature by free text word and subject headings 'epigastric hernia', 'linea alba', 'midline' and 'abdominal wall'. Reviewed were studies on anatomical theories describing the pathological mechanism of epigastric herniation, incidence, prevalence and female to-male ratio and possible explanatory factors. RESULTS: Three different theories have been described of which two have not been confirmed by other studies. The attachment of the diaphragm causing extra tension in the epigastric region is the one still standing. Around 1.6-3.6 % of all abdominal hernias and 0.5-5 % of all operated abdominal hernias is an epigastric hernia. Epigastric hernias are 2-3 times more common in men, with a higher incidence in patients from 20 to 50 years. Some cadaver studies show an epigastric hernia rate of 0.5-10 %. These specific features of the epigastric hernias (the large asymptomatic proportion, male predominance, only above umbilical level) are discussed with regard to the general theories. CONCLUSIONS: The epigastric hernia is a very common condition, mostly asymptomatic. Together with general factors for hernia formation, the theory of extra tension in the epigastric region by the diaphragm is the most likely theory of epigastric hernia formation. PMID- 22824993 TI - Continuously-stirred anaerobic digester to convert organic wastes into biogas: system setup and basic operation. AB - Anaerobic digestion (AD) is a bioprocess that is commonly used to convert complex organic wastes into a useful biogas with methane as the energy carrier. Increasingly, AD is being used in industrial, agricultural, and municipal waste(water) treatment applications. The use of AD technology allows plant operators to reduce waste disposal costs and offset energy utility expenses. In addition to treating organic wastes, energy crops are being converted into the energy carrier methane. As the application of AD technology broadens for the treatment of new substrates and co-substrate mixtures, so does the demand for a reliable testing methodology at the pilot- and laboratory-scale. Anaerobic digestion systems have a variety of configurations, including the continuously stirred tank reactor (CSTR), plug flow (PF), and anaerobic sequencing batch reactor (ASBR) configurations. The CSTR is frequently used in research due to its simplicity in design and operation, but also for its advantages in experimentation. Compared to other configurations, the CSTR provides greater uniformity of system parameters, such as temperature, mixing, chemical concentration, and substrate concentration. Ultimately, when designing a full scale reactor, the optimum reactor configuration will depend on the character of a given substrate among many other nontechnical considerations. However, all configurations share fundamental design features and operating parameters that render the CSTR appropriate for most preliminary assessments. If researchers and engineers use an influent stream with relatively high concentrations of solids, then lab-scale bioreactor configurations cannot be fed continuously due to plugging problems of lab-scale pumps with solids or settling of solids in tubing. For that scenario with continuous mixing requirements, lab-scale bioreactors are fed periodically and we refer to such configurations as continuously stirred anaerobic digesters (CSADs). This article presents a general methodology for constructing, inoculating, operating, and monitoring a CSAD system for the purpose of testing the suitability of a given organic substrate for long-term anaerobic digestion. The construction section of this article will cover building the lab-scale reactor system. The inoculation section will explain how to create an anaerobic environment suitable for seeding with an active methanogenic inoculum. The operating section will cover operation, maintenance, and troubleshooting. The monitoring section will introduce testing protocols using standard analyses. The use of these measures is necessary for reliable experimental assessments of substrate suitability for AD. This protocol should provide greater protection against a common mistake made in AD studies, which is to conclude that reactor failure was caused by the substrate in use, when really it was improper user operation. PMID- 22824995 TI - Gold nanoparticle chemiresistors operating in biological fluids. AB - Functionalised gold nanoparticle (Au(NP)) chemiresistors are investigated for direct sensing of small organic molecules in biological fluids. The principle reason that Au(NP) chemiresistors, and many other sensing devices, have limited operation in biological fluids is due to protein and lipid fouling deactivating the sensing mechanism. In order to extend the capability of such chemiresistor sensors to operate directly in biofluids, it is essential to minimise undesirable matrix effects due to protein and lipidic components. Ultrafiltration membranes were investigated as semi-permeable size-selective barriers to prevent large biomolecule interactions with Au(NP) chemiresistors operating in protein-loaded biofluids. All of the ultrafiltration membranes protected the Au(NP) chemiresistors from fouling by the globular biomolecules, with the 10 kDa molecular weight cut-off size being optimum for operation in biofluids. Titrations of toluene in different protein-loaded fluids indicated that small molecule detection was possible. A sensor array consisting of six different thiolate-functionalised Au(NP) chemiresistors protected with a size-selective ultrafiltration membrane successfully identified, and discriminated the spoilage of pasteurised bovine milk. This proof-of-principle study demonstrates the on chip protein separation and small metabolite detection capability, illustrating the potential for this technology in the field of microbial metabolomics. Overall, these results demonstrate that a sensor array can be protected from protein fouling with the use of a membrane, significantly increasing the possible application areas of Au(NP) chemiresistors ranging from the food industry to health services. PMID- 22824994 TI - MRS study of meningeal hemangiopericytoma and edema: a comparison with meningothelial meningioma. AB - Intracranial hemangiopericytomas (HPCs) are rare tumors and their radiological appearance resembles that of meningiomas, especially meningothelial meningiomas. To increase the knowledge on the biochemical composition of this type of tumor for better diagnosis and prognosis, we performed a molecular study using ex vivo high resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) perfomed on HPC and peritumoral edematous tissues. Moreover, to help in the discrimination between HPC and meningothelial meningioma we compared the ex vivo HR-MAS spectra of samples from one patient with HPC and 5 patients affected by meningothelial meningioma. Magnetic resonance imaging (MRI), in vivo localized single voxel 1H-MRS was also performed on the same patients prior to surgery and the in vivo and ex vivo MRS spectra were compared. We observed the presence of OH butyrate, together with glucose in HPC and a low amount of N-acetylaspartate in the edema, that may reflect neuronal alteration responsible for associated epilepsy. Many differences between HPC and meningothelial meningioma were identified. The relative ratios of myo-inositol, glucose and gluthatione with respect to glutamate are higher in HPC compared to meningioma; whereas the relative ratios of creatine, glutamine, alanine, glycine and choline-containing compounds with respect to glutamate are lower in HPC compared to meningioma. These data will be useful to improve the interpretation of in vivo MRS spectra resulting in a more accurate diagnosis of these rare tumors. PMID- 22824996 TI - Molecular mechanisms of a novel beta-thalassaemia mutation due to the duplication of tetranucleotide 'AGCT' at the junction IVS-II/exon 3. AB - We report a new beta-thalassaemia allele detected in a young Italian woman, suffering with mild non-haemolytic anaemia (Hb < 10 g/dL) and not showing Hb variant or Heinz bodies. The allele is characterised by duplication of tetranucleotide 'AG/CT' (+1344/+1347) including the invariant dinucleotide 'AG' of IVS-II acceptor splicing site and the first two nucleotides of codon 105. beta Globin complementary DNA (cDNA) sequencing did not reveal any mutation and qualitative analysis of the reverse transcription PCR reaction showed that only the proximal 3' splice site present in the duplicated gene is used giving race to an anomalous messenger RNA (mRNA) present in trace (1.5 %) because, most probably, rapidly degraded. In the anomalous mRNA, the insertion causes a frameshift and synthesis of an abnormal truncated beta-chain (139 residues), unable to form Hb variant because of the severe conformational changes. The duplication might have arisen from secondary structures generated by quasi palindromic sequence 5'-CCCA(C)AG/CT(CC)TGGG-3'. Restriction fragment length polymorphism analysis for the beta-globin haplotype and familiar segregation analysis indicated that the mutant beta-globin gene was associated with the haplotype V. PMID- 22824997 TI - Frequency and distribution of asymptomatic brain lesions in patients with beta thalassemia intermedia. AB - We aimed to determine the frequency of asymptomatic brain lesions in a group of patients with beta-thalassemia intermedia (beta-TI) and to evaluate correlation of asymptomatic brain lesions with splenectomy, thrombocytosis, blood transfusions, and clinical parameters. Ninety five neurologically intact patients with beta-TI were randomly enrolled in this cross-sectional study. Diffusion weighted imaging brain MRI was performed in every patient to detect cerebral white matter lesions (WML). We found an overall frequency of 15 (15.8 %) for WMLs, 14 (23.7 %) in splenectomized, and 1 (2.8 %) in nonsplenectomized patients. The presence of WML was significantly associated with splenectomy (P = 0.008) and thrombocytosis (P = 0.009). However, after adjustment for splenectomy, thrombocytosis was not significantly associated with the presence of WML (P > 0.05). The number of patients with regular blood transfusions and normal MRI was not significantly higher compared to those with abnormal findings (52.5 % vs. 26.7 %; P = 0.092). In untransfused patients, hydroxyurea (HU) administration was associated with a lower incidence of WML (P < 0.001). Although in univariate analysis either splenectomy or thrombocytosis showed significant correlation with the presence of single or multiple WMLs, thrombocytosis by itself did not significantly contribute in developing asymptomatic brain lesions. The lack of significant correlation between lesions and regular blood transfusions could be related to the treatment with HU in untransfused patients, which increased fetal hemoglobin levels and improved the morphology and the pathological indices of the red blood cells. Larger prospective studies are suggested for the accurate evaluation of the correlation of these factors with developing asymptomatic brain lesions. PMID- 22824999 TI - DNA ploidy may be a prognostic marker in stage I and II serous adenocarcinoma of the endometrium. AB - In patients with serous adenocarcinoma (SAC) of the endometrium, we evaluated the prognostic importance of clinicopathological parameters, DNA ploidy, and immunoexpression of p53, estrogen receptor (ER), progesterone receptor (PR), and Ki-67. In a series of 73 stage I and II SAC, DNA ploidy analysis was performed on hysterectomy specimens using DNA image cytometry. Immunohistochemical analysis of p53, ER, PR, and Ki-67 expression was additionally performed. In the review of the histological slides by three gynecologic pathologists, the presence of a serous component was not agreed upon in 17 (23 %) cases. The remaining 56 cases, consisting of pure SAC or SAC mixed with endometrioid adenocarcinoma, were further analyzed. Tumor recurrence was observed in 14 patients, and 28 patients died during the follow-up period. Patients with diploid (n = 19), aneuploid (n = 29), and tetraploid (n = 8) tumor had 5-year recurrence rates of 10, 38, and 53 %, respectively (p = 0.09). A DNA ploidy parameter, 5c exceeding rate, was found to be a prognostic marker for recurrence (p = 0.03), progression-free survival (p < 0.01), and overall survival (p = 0.02). Immunoexpression of p53, ER, PR, and Ki 67 did not have prognostic value, and the same was true for FIGO stage, lymphovascular invasion, the extent of myometrial invasion, and lymphadenectomy. The histological diagnosis of SAC may be difficult in some cases. Established clinicopathological parameters do not seem to be strong prognosticators in stage I and II disease. A DNA ploidy parameter, 5c exceeding rate, may be a prognostic marker in this patient group and should be further validated in larger series. PMID- 22825000 TI - EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. AB - In non-small cell lung cancer, epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have a major impact upon the level of response to treatment with specific tyrosine kinase inhibitors. This review describes the molecular basis of ALK inhibition, summarizes current data on the effectiveness and safety of ALK inhibition therapy, describes the different testing methodologies with their advantages and disadvantages, provides a suggested testing algorithm and puts forward a proposal for an external quality assessment program in ALK testing. PMID- 22825002 TI - 17beta-estradiol induces an interaction between adenosine monophosphate-activated protein kinase and the insulin signaling pathway in 3T3-L1 adipocytes. AB - Estrogen (17beta-estradiol) has been implicated in maintaining insulin sensitivity. It is thought to act predominantly through genomic pathways and regulate the expression of various genes via binding to estrogen receptors (ERs) alpha and -beta. 17beta-estradiol has been reported to simultaneously stimulate protein kinase B (Akt) and adenosine monophosphate-activated protein kinase (AMPK) in ex vivo skeletal muscle. Since data regarding the interaction between AMPK and the insulin receptor substrate-1 (IRS-1)/Akt pathway are controversial, the correlation between AMPK activation and insulin signaling remains unclear. In this study, we examined whether 17beta-estradiol simultaneously stimulates the activation of AMPK and IRS-1/Akt in 3T3-L1 adipocytes as well as the 17beta estradiol-ER-induced interaction between the AMPK and IRS-1/Akt pathway in 3T3-L1 adipocytes not exposed to insulin. 17beta-estradiol (10-7 M) rapidly activated AMPK and IRS-1/Akt in 3T3-L1 adipocytes, while the ER-alpha/beta non-specific antagonist, ICI 182.780 (10 uM), and the AMPK antagonist compound C (20 uM) reversed the estrogen-induced activation of AMPK and tyrosine (Tyr)-IRS-1/Akt in these cells. Moreover, 17beta-estradiol increased the expression of the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha), adiponectin, uncoupling protein 2 (UCP2) and glucose transporter 4 (GLUT4) genes 24 h after treatment, whereas the ER-alpha/beta non-specific antagonist, ICI 182.780 (10 uM), and the AMPK antagonist compound C (20 uM) reversed the estrogen induced increase in the expression of these genes. These results indicate that 17beta-estradiol activates AMPK through an ER and activates Akt through AMPK activation in 3T3-L1 adipocytes, despite the absence of insulin. Furthermore, 17beta-estradiol regulates the expression of genes related to glucose metabolism through ER-AMPK activation in these cells. PMID- 22825001 TI - Understanding molecular mechanisms in peritoneal dissemination of colorectal cancer : future possibilities for personalised treatment by use of biomarkers. AB - When colorectal cancer (CRC) metastasizes, this is mostly to the liver via the portal circulation. In addition, 10-25 % of CRC patients eventually show metastases in the peritoneum. A selection of these patients is treated with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). However, several clinical needs still exist in which biomarkers could play an important role. Relatively little is known about the biology of peritoneal spread of CRC. The development of peritoneal metastases (PM) involves several steps, including: detachment of malignant cells; anoikis evasion; attachment to and invasion of the peritoneal surface ultimately ending in a colonization phase in which the malignant cells thrive in the newly formed niche. In this paper, we provide an overview of molecules associated with peritoneal dissemination and explore the clinical possibilities of these candidate biomarkers. A literature search was conducted using the PubMed database of the U.S. National Library of Medicine and Medline to identify studies on the biological behaviour of PM of CRC. In a series of over 100 studies on PM published between 1990 and 2010, IGF-1, HIF1alpha, VEGF, EGFR and ITGB1 emerge as the most interesting candidates for possible clinical application. Even though these promising candidate biomarkers have been identified, all of these require extensive further validation prior to clinical application. Yet, the pace of the omics revolution makes that the question is not if, but when biomarkers will be introduced to improve diagnosis and ultimately outcome of patients with PM due to CRC. PMID- 22825004 TI - The effect of gaze direction on three-dimensional face recognition in infant brain activity. AB - In three-dimensional face recognition studies, it is well known that viewing rotating faces enhance face recognition. For infants, our previous study indicated that 8-month-old infants showed recognition of three-dimensional rotating faces with a direct gaze, and they did not learn with an averted gaze. This suggests that gaze direction may affect three-dimensional face recognition in infants. In this experiment, we used near-infrared spectroscopy to measure infants' hemodynamic responses to averted gaze and direct gaze. We hypothesized that infants would show different neural activity for averted and direct gazes. The responses were compared with the baseline activation during the presentation of non-face objects. We found that the concentration of oxyhemoglobin increased in the temporal cortex on both sides only during the presentation of averted gaze compared with that of the baseline period. This is the first study to show that infants' brain activity in three-dimensional face processing is different between averted gaze and direct gaze. PMID- 22825003 TI - Contribution of acid sphingomyelinase in the periaqueductal gray region to morphine-induced analgesia in mice. AB - Opioids are the most widely used drugs for long-term pain management, but their use is limited by the development of antinociceptive tolerance. The present study investigated the role of ceramide production through acid sphingomyelinase (ASM) activation in the periaqueductal gray region, a brain region implicated in opioid analgesia and tolerance. Morphine treatment was found, using immunohistochemistry, to increase ASM expression and intracellular ceramide in the periaqueductal gray 30 min after an acute injection (10 mg/kg). The effects of acute morphine treatment on ASM expression and ceramide generation in the periaqueductal gray region were completely blocked by pretreatment with naloxone and by silencing the ASM gene by plasmid-mediated transfection of ASM shRNA. In chronic morphine pellet-implanted mice, ASM expression and ceramide generation in the periaqueductal gray region were also significantly increased. Functionally, selective silencing of the ASM gene by local ASM shRNA transfection reduced the analgesic response to acute morphine, but the data on the effect of ASM shRNA on the development of antinociceptive tolerance were inconclusive. These data provide evidence that ASM activation and ceramide generation in the periaqueductal gray region play a major role in the antinociceptive mechanism of morphine. PMID- 22825005 TI - Event-related potential correlates of emotional orthographic priming. AB - Event-related potentials were used to explore the underlying mechanisms of masked orthographic priming and to determine whether the emotional valence of a word neighbor prime affects target processing in a lexical decision task. The results showed that the N200 and N400 amplitudes were modified by orthographic priming, which also varied with the emotional valence of the neighbors. These findings provide new evidence that the N400 component is sensitive to orthographic priming and further suggest that the affective content of the neighbor influences target word processing. PMID- 22825007 TI - Evaluation of pesticide residues in farmgate samples of vegetables in Karnataka, India. AB - Fifty Vegetable samples (Beans, Brinjal, Cabbage and Carrot) grown in Kolar district of Karnataka, India were analysed for 20 pesticide residues by gas liquid chromatography equipped with ECD and FTD. Recovery studies were performed at 0.1, 0.5 and 1.0 mg kg(-1) fortification levels of each compound and the recoveries obtained ranged from 73.0% to 96.6% with relative standard deviations lower than 7.5%. The method showed good linearity over the range assessed 0.01 1.0 mg Kg(-1) with correlation coefficient >0.998 and the detection and quantification limits for the pesticides studied varied from 0.0001 to 0.002 mg Kg(-1) and 0.0001-0.001 mg Kg(-1), respectively. All the samples were found to be contaminated, the organo chlorines (97%) dominated followed by organophosphates (83%) and pyrethroids (60%). However, 58% of the samples were found to contain the residues of these insecticides above their respective maximum residue limits (MRL). It is therefore proposed to perform extensive monitoring studies covering all the vegetable crops from different agro-climatic regions of the Karnataka to know the exact status of pesticide contamination. PMID- 22825006 TI - Substance P induces M2-type macrophages after spinal cord injury. AB - The potential benefits or the tissue-damaging effects of inflammatory response after central nervous system injuries have long been disputed. Recent studies have noted that substance P (SP), a neuropeptide, plays an important role in the wound-healing process by recruiting bone marrow stem cells to the injured tissue. In this study, we examined whether SP can enhance recovery from spinal cord injury (SCI) in Sprague-Dawley rats through its known function of stem cell mobilization and/or through the modulation of inflammation. We examined proinflammatory and anti-inflammatory cytokines and markers for macrophage subtypes. SP treatment modulated the SCI microenvironment toward a more anti inflammatory and reparative one by inducing interleukin-10 and M2 macrophages and suppressing inducible nitric oxide synthase and tumor necrosis factor-alpha. This modulation was achieved at 1 day much earlier than SP-stimulated bone marrow stem cells' mobilization. Early intervention of the devastating inflammatory response by SP treatment caused the lesion cavity to become filled with robust axonal outgrowth that overlaid the M2 macrophages at 2 weeks--all of which culminated in tissue sparing and improvement in functional recovery from the SCI. SP is therefore a potential anti-inflammatory modulator for the treatment of injury induced inflammatory central nervous system disorders. PMID- 22825009 TI - More than training. PMID- 22825008 TI - Distribution of metals in the tissues of benthic, Euryglossa orientalis and Cynoglossus arel., and bentho-pelagic, Johnius belangerii., fish from three estuaries, Persian Gulf. AB - Concentrations of Cd, Co, Cu, Ni, Pb, Fe and Zn were determined in the muscle, liver and gills of three commercial benthic and pelagic fish species (Johnius belangerii, Euryglossa orientalis and Cynoglossus arel) from three estuaries in the northwest Persian Gulf. Metals levels varied significantly depending on the tissues, species and locations. Generally, the results showed that liver accumulate higher concentrations of the metals in comparison to muscle and gills, except in few cases. Among the species, E. orientalis showed the highest levels of Co, Cu, Ni and Fe, while the highest concentrations of Pb and Zn were observed in C. arel. J. belangerii accumulated the highest level of Pb element. PMID- 22825010 TI - Biomaterials in the repair of sports injuries. PMID- 22825012 TI - Stretching the boundaries. Interview by Christian Martin. PMID- 22825011 TI - Materials and technology in sport. PMID- 22825018 TI - Cell culture: Soft gels select tumorigenic cells. PMID- 22825019 TI - Organic electronics: Organic thin-film magnetometers. PMID- 22825020 TI - Hydrogels: The catalytic curtsey. PMID- 22825021 TI - Material witness: Two ways to relax. PMID- 22825024 TI - Childhood urticaria. AB - PURPOSE OF REVIEW: The present article reviews childhood urticaria. It provides an update on the current understanding of its pathophysiology and highlights the current practice in the management of this condition. RECENT FINDINGS: Progress has been made in understanding the pathophysiology of urticaria with the elucidation of an autoimmune basis in a significant proportion of children with chronic spontaneous urticaria. H1-antihistamines remain the mainstay of therapy, but there is increasing awareness on the risks of sedating first-generation antihistamines. Omalizumab is increasingly being used off-license in the most refractory cases. SUMMARY: Urticaria is a common disease that affects children and adults. However, paediatric urticaria has specific features and remains poorly understood. Acute spontaneous urticaria is the most common clinical presentation in childhood. It is caused by viral infection in most cases with an identifiable trigger. By contrast, chronic spontaneous urticaria in children may be autoimmune, but more studies are needed to understand the clinical significance of functional autoantibodies in this subgroup of patients. Investigations should always be guided by history. Treatment remains largely symptomatic. H1-antihistamines are the mainstay of therapy but are insufficient to control symptoms in all patients. There is an urgent need for more efficacious therapies. PMID- 22825022 TI - A molecular perspective of water at metal interfaces. AB - Water/solid interfaces are relevant to a broad range of physicochemical phenomena and technological processes such as corrosion, lubrication, heterogeneous catalysis and electrochemistry. Although many fields have contributed to rapid progress in the fundamental knowledge of water at interfaces, detailed molecular level understanding of water/solid interfaces comes mainly from studies on flat metal substrates. These studies have recently shown that a remarkably rich variety of structures form at the interface between water and even seemingly simple flat surfaces. In this Review we discuss the most exciting work in this area, in particular the emerging physical insight and general concepts about how water binds to metal surfaces. We also provide a perspective on outstanding problems, challenges and open questions. PMID- 22825025 TI - Immunoregulation in cutaneous allergy: prevention and control. AB - PURPOSE OF REVIEW: The cutaneous surface is exposed to a myriad of encounters with chemicals, allergens and microbes. Nevertheless, it withstands these environmental assaults without overt inflammation. We will discuss the role of T regulatory cells in a situation where this tissue homeostasis fails - cutaneous allergy, in particular contact hypersensitivity. RECENT FINDINGS: Immune regulation is a complex process that is mediated by many cellular players. T regulatory cells have risen to particular prominence as potent immunosuppressors because their absence results in inflammation including skin allergy. Recent findings revealed that T regulatory cells comprise a heterogeneous group of subpopulations with specialized homing capabilities and suppressor functions. The stability of the T regulatory cell subset in proinflammatory microenvironments is controversially discussed. In addition, it has recently been shown that mechanisms by which T regulatory cells exert their immunosuppressive functions can be adopted by pathogenic effector T cells in certain situations. SUMMARY: In cutaneous allergy, immunoregulatory mechanisms are dysfunctional. The cellular players comprise classical T regulatory cells as well as effector T cells with regulatory activities. Understanding their role in skin homeostasis and the mechanisms by which their regulatory functions are abrogated will yield novel therapeutic targets for the treatment of cutaneous allergies. PMID- 22825026 TI - [(eta2-(Si/Ge)4)Zn(eta2-(Si/Ge)4)](6-)- novel Zintl clusters with mixed Si/Ge tetrahedra bridged by a Zn atom. AB - The solubility of the ternary Zintl phase K(12)Si(17-x)Ge(x) (x = 5), containing mixed group 14 element clusters, was investigated. Novel dimeric tetrahedral Zintl clusters [(eta(2)-E(4))Zn(eta(2)-E(4))](6-) with mixed site occupation (E = Si/Ge) were obtained through reaction with (C(6)H(6))(2)Zn in ammonia solutions and investigated by means of X-ray single crystal diffraction. PMID- 22825027 TI - Changes in the expression of cardiac mitofusin-2 in different stages of diabetes in rats. AB - The aim of this study was to investigate the role of mitofusin-2 (Mfn2) in different stages of diabetes in rats and to analyze the related mechanism(s). A diabetic model in SD rats was induced by a single intraperitoneal injection of 55 mg/kg streptozoticin (STZ). The hearts were isolated from diabetes mellitus (DM) rats at the fourth week (DM4W), eighth week (DM8W) and twelfth week (DM12W) and fasting blood glucose (FBG) levels and the ratio of heart weight to body weight (HW/BW) were measured. Malondialdehyde (MDA) content, superoxide dismutase (SOD) and caspase 3 activities were measured. The expression of Mfn2 of the left anterior myocardium at the mRNA level was detected using RT-PCR. In contrast to the normal group, in the DM4W, DM8W and DM12W groups, there was a significant increase in the FBG levels, but no difference among the DM4W, DM8W and DM12W groups. The HW/BW ratio as well as the MDA content were increased, while SOD activity was reduced. Caspase-3 activity was increased, while the expression of Mfn-2 mRNA levels was reduced. In addition, with the development of diabetic cardiomyopathy, the contents of MDA and caspase 3 were increased, whereas SOD activity and Mfn-2 mRNA levels were further reduced. In conclusion, our results indicated that with the development of diabetes, the expression of cardiac Mfn2 has showed a decrease, which may be associated with the decrease of antioxidant ability and progression of apoptosis. PMID- 22825028 TI - Phenyl-bridged polysilsesquioxane positive and negative resist for electron beam lithography. AB - We present and characterize an organic-inorganic hybrid sol-gel material, phenyl bridged polysilsesquioxane (ph-PSQ), for use as a new high resolution resist for electron beam lithography (EBL). The resist has a unique characteristic as the only positive tone silica-based resist available for EBL. Exploring the processing parameters has revealed that it is possible to switch the behaviour from negative to positive tone by application of a post-exposure bake (PEB). Based on the results from micro-FTIR spectroscopy, a description of the tone switching mechanisms is proposed. The negative tone behaviour is explained by the etch rate difference between silanol groups and cross-linked silica, present in unexposed and in exposed areas of the films, respectively. In the case of positive tone, after a PEB, the etch rate difference between a thermally densified cross-linked silica network and cage-like silica structures allows us to reveal the pattern. Contrast and sensitivity are estimated under different processing conditions, and the significant parameters for line edge roughness minimization are pointed out. Dense patterns down to 25 nm half-pitch and isolated structures down to 30 nm are demonstrated, exploiting the positive tone, and dense patterns down to 60 nm half-pitch are demonstrated in the negative tone. Etching selectivities in fluorinated gases for ph-PSQ nanostructures on silicon substrates are 1-9 for the positive tone and 1-12 for the negative tone. PMID- 22825029 TI - Risk of acute myocardial infarction in patients with total hip or knee replacement: comment on "Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study". PMID- 22825030 TI - Co-treatment with vorinostat synergistically enhances activity of Aurora kinase inhibitor against human breast cancer cells. AB - Aurora kinases (AKs) regulate multiple components of mitotic cell division in eukaryotic cells. Aurora A is frequently amplified or overexpressed in breast cancer cells leading to aberrant chromosome segregation, genomic instability, and activation of oncogenic pathways. In the present studies, we determined the effects of treatment with the pan-AK inhibitor MK-0457 and/or the pan-histone deacetylase inhibitor vorinostat against human breast cancer cells that were either ER-, PR-, and HER2- (MDA-MB-468 and MDA-MB-231) or exhibited Aurora A amplification (BT-474 and MDA-MB-231 cells). Treatment with MK-0457 depleted p AKs levels and their activity, as well as induced G2/M accumulation, DNA endoreduplication, multipolar mitotic spindles, and apoptosis of the breast cancer cells. Similar apoptotic effects were observed with treatment with the Aurora A-specific inhibitor, MLN8237. Treatment with vorinostat induced hsp90 acetylation and inhibited its chaperone association with AKs, leading to depletion of AKs and Survivin. Exposure of the siRNA to AK A also induced apoptosis, which was augmented by co-treatment with MK-0457 and vorinostat. Co treatment with vorinostat enhanced MK-0457-mediated inhibition of the activities of Aurora A and Aurora B, leading to synergistic in vitro activity against human breast cancer cells. Co-treatment with MK-0457 and vorinostat also caused greater tumor growth inhibition and superior survival of mice bearing MDA-MB-231 xenografts. These pre-clinical findings indicate that combined treatment with a pan-AK inhibitor or an Aurora A-specific inhibitor and vorinostat represents a novel therapeutic strategy for the treatment of Aurora A-amplified and/or triple negative breast cancers. PMID- 22825032 TI - Antiangiogenic therapy in the management of brain tumors: a clinical overview. AB - Central to the process of brain tumor development is angiogenesis, which involves a host of molecules and receptors. In recent years, antiangiogenic therapies have been developed and tested for their effectiveness against these tumors. Among them are inhibitors against vascular endothelial growth factor and its receptors, as well as inhibitors targeting the platelet-derived growth factor family, integrins, and histone deacetylase. While many have been shown to be effective with limited toxicity, some tumors are able to adopt escape mechanisms. Further research is needed in the development of effective multi-targeted agents to reduce these effects. PMID- 22825033 TI - Two methods of heterokaryon formation to discover HCV restriction factors. AB - Hepatitis C virus (HCV) is a hepatotropic virus with a host-range restricted to humans and chimpanzees. Although HCV RNA replication has been observed in human non-hepatic and murine cell lines, the efficiency was very low and required long term selection procedures using HCV replicon constructs expressing dominant antibiotic-selectable markers. HCV in vitro research is therefore limited to human hepatoma cell lines permissive for virus entry and completion of the viral life cycle. Due to HCVs narrow species tropism, there is no immunocompetent small animal model available that sustains the complete HCV replication cycle. Inefficient replication of HCV in non-human cells e.g. of mouse origin is likely due to lack of genetic incompatibility of essential host dependency factors and/or expression of restriction factors. We investigated whether HCV propagation is suppressed by dominant restriction factors in either human cell lines derived from non-hepatic tissues or in mouse liver cell lines. To this end, we developed two independent conditional trans-complementation methods relying on somatic cell fusion. In both cases, completion of the viral replication cycle is only possible in the heterokaryons. Consequently, successful trans-complementation, which is determined by measuring de novo production of infectious viral progeny, indicates absence of dominant restrictions. Specifically, subgenomic HCV replicons carrying a luciferase transgene were transfected into highly permissive human hepatoma cells (Huh-7.5 cells). Subsequently, these cells were co-cultured and fused to various human and murine cells expressing HCV structural proteins core, envelope 1 and 2 (E1, E2) and accessory proteins p7 and NS2. Provided that cell fusion was initiated by treatment with polyethylene-glycol (PEG), the culture released infectious viral particles which infected naive cells in a receptor-dependent fashion. To assess the influence of dominant restrictions on the complete viral life cycle including cell entry, RNA translation, replication and virus assembly, we took advantage of a human liver cell line (Huh-7 Lunet N cells) which lacks endogenous expression of CD81, an essential entry factor of HCV. In the absence of ectopically expressed CD81, these cells are essentially refractory to HCV infection. Importantly, when co-cultured and fused with cells that express human CD81 but lack at least another crucial cell entry factor (i.e. SR-BI, CLDN1, OCLN), only the resulting heterokaryons display the complete set of HCV entry factors requisite for infection. Therefore, to analyze if dominant restriction factors suppress completion of the HCV replication cycle, we fused Lunet N cells with various cells from human and mouse origin which fulfill the above mentioned criteria. When co-cultured cells were transfected with a highly fusogenic viral envelope protein mutant of the prototype foamy virus (PFV) and subsequently challenged with infectious HCV particles (HCVcc), de novo production of infectious virus was observed. This indicates that HCV successfully completed its replication cycle in heterokaryons thus ruling out expression of dominant restriction factors in these cell lines. These novel conditional trans complementation methods will be useful to screen a large panel of cell lines and primary cells for expression of HCV-specific dominant restriction factors. PMID- 22825034 TI - Large quantity discrimination by North Island robins (Petroica longipes). AB - While numerosity-representation and enumeration of different numbers of objects and quantity discrimination in particular have been studied in a wide range of species, very little is known about the numerical abilities of animals in the wild. This study examined spontaneous relative quantity judgments (RQJs) by wild North Island robins (Petroica longipes) of New Zealand. In Experiment 1, robins were tested on a range of numerical values of up to 14 versus 16 items, which were sequentially presented and hidden. In Experiment 2, the same numerical contrasts were tested on a different group of subjects but quantities were presented as whole visible sets. Experiment 3 involved whole visible sets that comprised of exceedingly large quantities of up to 56 versus 64 items. While robins shared with other species a ratio-based representation system for representing very large values, they also appeared to have developed an object indexing system with an extended upper limit (well beyond 4) that may be an evolutionary response to ecological challenges faced by scatter-hoarding birds. These results suggest that cognitive mechanism influencing an understanding of physical quantity may be deployed more flexibly in some contexts than previously thought, and are discussed in light of findings across other mammalian and avian species. PMID- 22825035 TI - Habituation and dishabituation during object play in kennel-housed dogs. AB - Domestic dogs are reported to show intense but transient neophilia towards novel objects. Here, we examine habituation and dishabituation to manipulable objects by kennel-housed dogs. Labrador retrievers (N = 16) were repeatedly presented with one toy for successive 30-s periods until interaction ceased. At this point (habituation), a different toy was presented that contrasted with the first in both colour and odour (since the dog's saliva would have accumulated on the first), colour alone, or odour alone. No effect of the type of contrast was detected in the number of presentations to habituation, the difference in duration of interaction between the first presentation of the first toy and the presentation of the second toy (recovery), or the duration of interaction with the second toy (dishabituation). Varying the time interval between successive presentations of the first toy up to habituation between 10 s and 10 min had no effect on the number of presentations to habituation, nor did it alter the extent of dishabituation. Varying the delay from habituation to presentation of the second toy, between 10 s and 15 min, affected neither the recovery nor the dishabituation. Overall, the study indicates that loss of interest in the object during object-orientated play in this species is due to habituation to the overall stimulus properties of the toy rather than to any single sensory modality and is also atypical in its insensitivity to the interval between presentations. PMID- 22825036 TI - Nasolacrimal duct obstruction as a complication of iodine-131 therapy in patients with thyroid cancer. AB - PURPOSE: There are few studies evaluating the effect of radioioine therapy on the lacrimal drainage system. This study reports on symptomatic and asymptomatic nasolacrimal duct obstruction (NLDO) as complications of high-dose radioiodine therapy in these patients. METHODS: Eighty-one cases were randomly selected from a population of radioiodine-treated differentiated thyroid carcinoma patients and were enrolled in a historical cohort study. The patients were categorized into four subgroups on the basis of the received cumulative dose of iodine-131 (I 131). In addition, 17 age-matched and sex-matched individuals were selected as the control group. Using dacryoscintigraphy and a clinical datasheet, the patients and controls were evaluated for partial or complete and symptomatic or asymptomatic NLDO. The data on different subgroups of patients were compared with the data of the control group. RESULTS: Twenty-nine out of 162 exposed eyes (18%) and three out of 34 control eyes (9%) had evidence of NLDO on scintigraphic images. Among patients treated with less than 11.1 GBq of I-131 (subgroup A), six out of 78 eyes (7.7%) had partial or complete NLDO. This was evident in 23 out of 84 eyes (27.4%) among patients treated with 11.1 GBq or more (subgroup B). The frequency of complete NLDO increases significantly when the cumulative dose of radioiodine exceeds 11.1 GBq (2.9% in the control group, 3.8% in subgroup A, and 23.8% in subgroup B; P=0.006). CONCLUSION: NLDO may be considered as a side effect of I-131 therapy, especially with a cumulative dose of 11.1 GBq or more. PMID- 22825038 TI - Potential value of dual-time-point 18F-FDG PET compared with initial single-time point imaging in differentiating malignant from benign pulmonary nodules: a systematic review and meta-analysis. AB - We performed a meta-analysis to assess the potential value of dual-time-point (DTP) imaging as compared with initial single-time-point (STP) scanning with 18F fluorodeoxyglucose (18F-FDG) PET in differentiating malignant from benign single pulmonary nodules. Data on the performance of DTP 18F-FDG PET imaging in assessing lung nodules were extracted from articles of prospective or retrospective original research published between January 2001 and April 2010. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to assess the quality of study methodology. Heterogeneity in the results of the studies was assessed, and summary receiver operating characteristic (SROC) curves were constructed. Eleven studies comprising a total of 788 patients who underwent initial scanning, 778 of whom also underwent DTP imaging, were included in the final analysis. The quality of study methodology was judged to be moderate. Substantial heterogeneity in the results of the studies, with inconsistency (I2) index values above 85%, reflected important differences in study methods and populations, including varying lesion sizes, 18F-FDG avidity, uptake interval for delayed imaging, and threshold for positive result on DTP imaging. SROC curve analysis revealed a statistically nonsignificant trend toward higher sensitivity with DTP imaging, at moderate levels of specificity, when compared with initial STP scanning. The area under the curve (SE) values for DTP and initial STP imaging were 0.839 (0.079) and 0.757 (0.074), respectively. Although the results of our analysis do not support the routine use of DTP imaging with 18F-FDG PET in the differential diagnosis of pulmonary nodules, this technique may provide additional information in selected cases with equivocal results from initial scanning. Further prospective research is required to better define the potential benefits of DTP 18F-FDG PET imaging. PMID- 22825037 TI - I-131 MIBG post-therapy scan is more sensitive than I-123 MIBG pretherapy scan in the evaluation of metastatic neuroblastoma. AB - OBJECTIVE: Iodine-123 metaiodobenzylguanidine (I-123 MIBG) scintigraphy is gradually replacing I-131 MIBG scans in the diagnostic workup of neuroblastoma. High-dose I-131 MIBG, however, is commonly used for subsequent therapy in patients with proven MIBG-avid lesions. The objective of this study was to compare the sensitivities of pretherapy I-123 MIBG and post-therapy I-131 MIBG scans for detecting metastatic lesions of neuroblastoma and determine the suitability of post-therapy scans for detecting new metastases. MATERIALS AND METHODS: Pretherapy I-123 MIBG scans and post-therapy I-131 MIBG scans of 126 patients with neuroblastoma were analyzed retrospectively and the number of detected lesions was compared. RESULTS: In 70 patients (55.6% cases), the pretherapy and post-therapy scans were concordant, showing similar MIBG-avid foci. In the remaining 56 patients (44.4% cases), the post-therapy I-131 MIBG scans revealed additional lesions (i.e. a total of 716 lesions) compared with pretherapy I-123 MIBG scans (only 532 lesions). All lesions detected on pretherapy I-123 MIBG scans were revisualized on the post-therapy I-131 MIBG scans, the latter also revealing 184 new MIBG-avid lesions. CONCLUSION: Post therapy I-131 MIBG scans demonstrate new lesions in almost half of the patients when compared with pretherapy I-123 MIBG scans and therefore are essential to delineate the disease extent. PMID- 22825039 TI - Clinical evaluation of the computed tomography attenuation correction map for myocardial perfusion imaging: the potential for incidental pathology detection. AB - The benefits of hybrid imaging in nuclear medicine have been proven to increase the diagnostic accuracy and sensitivity of many procedures by localizing or characterizing lesions or by correcting emission data to more accurately represent radiopharmaceutical distribution. Single-photon emission computed tomography/computed tomography (SPECT/CT) has a significant role in the diagnosis and follow-up of ischaemic heart disease with attenuation correction data being obtained on an integrated CT scanner. Initially, the CT component of hybrid SPECT/CT systems was what could be described as low specification utilizing fixed output parameters. As technology has progressed, the CT component of newer systems has specifications that are identical to that of stand-alone diagnostic systems. Irrespective of the type of scanner used, the computed tomography attenuation correction (CTAC) for myocardial perfusion imaging produces low quality, limited-range CT images of the chest that include the mediastinum, lung fields and surrounding soft tissues. The diagnostic potential of this data set is unclear; yet, examples exist whereby significant pathology can be identified and investigated further. Despite guidance from a number of professional bodies suggesting that evaluation of the resulting images for every medical exposure be carried out, there is no indication as to whether this should include the evaluation of CTAC images. This review aims to initiate discussion by examining the ethical, legal, financial and practical issues (e.g. CT specification and image quality) surrounding the clinical evaluation of the CTAC for myocardial perfusion imaging images. Reference to discussions that have taken place, and continue to take place, in other modalities, current European and UK legislations, and guidelines and research in the field will be made. PMID- 22825040 TI - Optimized robust plasma sampling for glomerular filtration rate studies. AB - In the presence of abnormal fluid collection (e.g. ascites), the measurement of glomerular filtration rate (GFR) based on a small number (1-4) of plasma samples fails. This study investigated how a few samples will allow adequate characterization of plasma clearance to give a robust and accurate GFR measurement. A total of 68 nine-sample GFR tests (from 45 oncology patients) with abnormal clearance of a glomerular tracer were audited to develop a Monte Carlo model. This was used to generate 20 000 synthetic but clinically realistic clearance curves, which were sampled at the 10 time points suggested by the British Nuclear Medicine Society. All combinations comprising between four and 10 samples were then used to estimate the area under the clearance curve by nonlinear regression. The audited clinical plasma curves were all well represented pragmatically as biexponential curves. The area under the curve can be well estimated using as few as five judiciously timed samples (5, 10, 15, 90 and 180 min). Several seven-sample schedules (e.g. 5, 10, 15, 60, 90, 180 and 240 min) are tolerant to any one sample being discounted without significant loss of accuracy or precision. A research tool has been developed that can be used to estimate the accuracy and precision of any pattern of plasma sampling in the presence of 'third-space' kinetics. This could also be used clinically to estimate the accuracy and precision of GFR calculated from mistimed or incomplete sets of samples. It has been used to identify optimized plasma sampling schedules for GFR measurement. PMID- 22825041 TI - Preoperative 99mTc-sestamibi scintigraphy in patients with primary hyperparathyroidism and concomitant nodular goiter: comparison of SPECT-CT, SPECT, and planar imaging. AB - BACKGROUND: Investigations using a hybrid single photon emission computed tomography/computed tomography (SPECT-CT) scanning technique have been carried out in limited studies and have shown mixed results. However, the assessment of this technique for the detection of parathyroid adenoma in patients with a nodular goiter was performed in only one study with a small sample size. The aim of this prospective study was to assess the role of 99mTc-sestamibi parathyroid SPECT-CT scans for localization of parathyroid adenomas with a concomitant nodular goiter using 99mTc-methoxyisobutyl isonitrile (MIBI) scintigraphy and to compare it with SPECT and planar imaging. METHODS: This study was conducted on 48 patients with primary hyperparathyroidism and nodular goiter, who were candidates for parathyroid surgery and had been referred for parathyroid scintigraphy. The patients underwent an early set of planar 99mTc-MIBI scanning procedures first, followed by SPECT and CT scannings, and finally a delayed set of planar 99mTc MIBI scannings. Sensitivity, specificity, negative and positive predictive values, and accuracy were determined on a per-parathyroid-gland basis for each scanning method, as defined by histology and follow-up. RESULTS: The surgery was successful in 48 out of 50 patients with primary hyperparathyroidism concomitant with thyroid nodularity, and data were completed for 80 sites in 48 patients. The accuracy of SPECT-CT in correctly identifying a parathyroid adenoma was 85.00, versus 75.00% for SPECT (P=0.01, significant). The sensitivity and specificity for SPECT-CT were 77.55 and 96.77%, respectively, versus 67.34 and 87.09%, respectively, for SPECT (P=0.12 and 0.12, not significant). There were nine sites that showed better localization on SPECT-CT scans relative to SPECT images, of which five sites were located in the ectopic regions. CONCLUSION: The results of our study indicate that SPECT-CT is more accurate than sestamibi planar imaging and SPECT for the preoperative identification of parathyroid lesions in patients with primary hyperparathyroidism concomitant with thyroid nodularity. Also, we would recommend the use of SPECT-CT for a workup of all patients with ectopic glands who are scheduled for minimally invasive parathyroid surgery. PMID- 22825042 TI - A dual-signalling electrochemical DNA sensor based on target hybridization induced change in DNA probe flexibility. AB - We report a fully covalent, dual-signalling electrochemical DNA sensor that exploits competitive binding and target hybridization-induced change in probe flexibility for simple and robust detection of target DNA. PMID- 22825046 TI - Network analysis of transcriptional regulation in response to intramuscular interferon-beta-1a multiple sclerosis treatment. PMID- 22825047 TI - Optimizing the safety and practice of ultrasound-guided regional anesthesia: the role of echogenic technology. AB - PURPOSE OF REVIEW: Significant improvements have been made in the quality of ultrasound imaging, and it is now much easier to see nerves. However, the key to safe ultrasound-guided regional anesthesia is to be able to direct the needle to the target. This relies on good needle visibility. We review the recent advances that have been made in this crucial area. RECENT FINDINGS: Echogenic needles can improve shaft and tip visibility independent of experience level, compensate for suboptimal scanning technique, allow steeper insertion angles, reduce technical difficulty, and increase both confidence and satisfaction by anesthesiologists. An echogenic needle encourages holding the probe in one place on the patient, only advancing the needle when it can be seen, hence reducing the likelihood of quality-compromising behaviors. The poor visibility of nonechogenic needles when inserted at steeper angles commonly causes the observer to underestimate the insertion depth of the needle. Significant differences in echogenicity are found when comparing the currently available needles. SUMMARY: Good echogenic needles should increase safety, efficacy, and simplicity, and hopefully further drive the adoption of ultrasound-guided techniques, to the benefit of our patients. PMID- 22825043 TI - Enforced expression of RASAL1 suppresses cell proliferation and the transformation ability of gastric cancer cells. AB - RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and it is an important molecule in the regulation of RAS activation. In the present study, we investigated the role of RASAL1 in gastric carcinogenesis. Decreased expression pattern of RASAL1 in gastric cancer tissues and cell lines was found in protein and RNA levels, although there was no statistically significant relationship between RASAL1 and clinicopathological features. Restored expression of RASAL1 induced by DNA methylation inhibitor 5 aza-2'-deoxycytidine (5'-AZA) and HDAC inhibitor trichostatin A (TSA) implied that RASAL1 expression is regulated by epigenetic mechanisms. The biological role of RASAL1 in gastric carcinogenesis was determined by in vitro tumorigenicity assays. Overexpression of RASAL1 showed suppression of cell proliferation due to cell apoptosis. Subsequently, enforced expression of RASAL1 repressed significantly the gastric cancer cell transformation ability. These findings demonstrated that decreased RASAL1 expression is a characteristic of gastric cancer and regulated by epigenetic mechanisms. RASAL1 may be a functional tumor suppressor involved in gastric cancer. This study provides novel insights into the biological role of RASAL1 in gastric carcinogenesis. PMID- 22825048 TI - Fluid resuscitation in patients with traumatic brain injury: what is a SAFE approach? AB - PURPOSE OF REVIEW: In patients with traumatic brain injury (TBI), dysfunction of the neurovascular unit ('blood-brain barrier') is a common finding, resulting in maldistribution of water and osmoles within the brain. The purpose of the present article is to review the underlying physiology of osmolality and fluid therapy in TBI. RECENT FINDINGS: The findings of the 'Saline versus Albumin Fluid Evaluation' study suggest that infusion of colloidal solutions is associated with adverse outcomes as compared with sole crystalloid infusion in patients suffering from TBI. Comparison of calculated osmolarity and measured in-vitro osmolality suggests that human albumin solutions, Hartmann's solution, and, to a lesser extent, gelatine preparations are hypo-osmolar, and may, therefore, increase brain volume and intracranial pressure. SUMMARY: In the context of the published literature on this topic, it appears that the osmolality of an infusion solution rather than the colloid osmotic pressure per se represents the key determinant in the pathogenesis of cerebral edema formation. PMID- 22825049 TI - Advances in intrathecal drug delivery. AB - PURPOSE OF REVIEW: Intrathecal drug delivery (IDD) continues to gain relevance as a beneficial tool for the treatment of cancer pain, spasticity, and chronic nonmalignant pain. This review includes advances in recommendations for the use of IDD for cancer pain, nonmalignant pain, and spasticity, as well as a new study of cerebrospinal fluid kinetics, updates in logistics, and recent reports of complications. RECENT FINDINGS: Consensus-based guidelines support the use of IDD system (IDDS) in the treatment of cancer-related pain. IDDS with opioids in younger age groups may not be as successful as older patients due to tolerance issues. Research in new technologies to monitor and detect catheter breakage and disconnects is promising. There continues to be a need for more research in outcomes and new therapeutics for IDDS. SUMMARY: IDDS continues to play an important role in the management of severe intractable pain. However, the most important areas in need of advancement, outcome studies and new therapeutics, did not have any significant breakthroughs over the past year. There is some interesting preclinical work on new therapeutics but likely the translation into clinical practice will be challenging. More work is also needed on improving technologies that will result in less catheter breaks and disconnects. PMID- 22825050 TI - Redefining micrometastasis in prostate cancer - a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: Implications in determining local or systemic treatment for biochemical failure after radical prostatectomy. AB - The presence of cells positive for cytokeratins or prostate-specific antigen (PSA) in bone marrow aspirates (BMAs) has been used to indicate the presence of micrometastasis. The aim of this prospective study of prostate cancer patients was to determine the presence of prostate cells in blood and BMAs and to compare them with bone marrow biopsy touch prep samples. The results indicated that there was a satisfactory concordance between circulating prostate cells (CPCs) in blood and disseminated tumor cells (DTCs) in BMAs for all Gleason scores (kappa>0.50). However, neither were concordant with the presence of prostate cells in bone marrow biopsies except for high-grade tumors, Gleason 8 and 9. Phenotypic characteristics of CPCs and DTCs were identical (kappa>0.9) but were different than cells detected in bone marrow biopsies (kappa<0.2). The expression of matrix metalloproteinase-2 (MMP-2) in bone marrow biopsies was positively associated with the Gleason score (trend Chi-squared <0.05) and may explain the differences between the presence of DTCs and the presence of prostate cells in bone marrow biopsies. If the presence of DTCs was used to indicate micrometastatic disease, 20% of patients would be misclassified compared to micrometastasis defined as patients with a positive biopsy. This may have clinical implications for patients with low-grade tumors. PMID- 22825051 TI - Polymer photovoltaic cell embedded with p-type single walled carbon nanotubes fabricated by spray process. AB - In the current study, we fabricated polymer (poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl-C(61) butyric-acid methyl-ester (PCBM) blend) photovoltaic (PV) cells embedded with p-type single walled carbon nanotubes (SWCNTs) with tangled hair morphology. The power conversion efficiency (PCE) rapidly increased with SWCNT concentration of up to 6.83% coverage, and then decreased and saturated with increasing SWCNT concentration; i.e., the PCE peaks at 5.379%. This tendency is mainly associated with hole transport efficiency toward the transparent electrode (indium-tin-oxide (ITO)) via SWCNTs, directly determining the series resistance and shunt resistance of the polymer PV cells embedded with SWCNTs: the PV cell is increasing shunt resistance and decreasing series resistance. PMID- 22825052 TI - Unidirectional peristaltic movement in multisite drug binding pockets of AcrB from molecular dynamics simulations. AB - Tripartite complex AcrB-ToIC, the major efflux system in Escherichia coli, is the principal multidrug transporter in Gram-negative bacteria, which is important in antibiotic drug tolerance. AcrB is a homotrimer that acts as a tripartite complex with the outer membrane channel ToIC and the membrane fusion protein AcrA. Recently, the crystal structures of AcrB bound to the high-molecular-mass drugs rifampicin and erythromycin were reported. Here we performed 20 ns molecular dynamics (MD) simulations of the AcrB-rifampicin-minocycline complex in a lipid bilayer and explicit water. We found that the bound drugs, rifampicin and erythromycin, made a unidirectional peristaltic movement towards the extrusion funnel of ToIC, which was facilitated by the water efflux in the channel of AcrB. With a shift of the Phe-617 loop, rifampicin in the access monomer moved towards the entrance of the distal binding pocket. Minocycline in the binding monomer moved from the distal binding pocket towards the gate of the central funnel. The channel between the entrance and the gate made a concerted opening during the MD simulations, which was helpful for the peristaltic movement. Our results showed that the mutations of Gly616Pro and Gly619Pro prevented the movement of the Phe 617 loop, which indicated the critical role of the flexibility of the Phe-617 loop. In addition, three putative proton translocation channels were proposed based on our results. Our study provided dynamical information and important residues for the peristaltic movement in AcrB, which were critical for substrate uptake and extrusion function. PMID- 22825053 TI - [Tumor management of the spine - no place for soloists]. PMID- 22825054 TI - [Surgical management of thoracolumbar spinal sarcoma]. AB - Primary malignant tumors of the thoracolumbar spine are very rare. The most common entities are chordoma, followed by osteosarcoma, Ewing's sarcoma and chondrosarcoma. Detailed imaging and a sequential biopsy are the most important diagnostic steps. The surgical staging system of Weinstein and Boriani permits a precise analysis of tumor expansion. Therapy under a multimodal concept consists of (neo-) adjuvant therapy and possible radiation. The surgical therapy should be performed as an en bloc excision with sufficient resection borders. The reconstruction of the defects must include methods of vertebral body replacement and long posterior instrumentation. En bloc spondylectomy is a very demanding technique and demands strict indications, close cooperation with adjacent specialties and exact planning of the operation. Only in this manner is the operation possible and offers the only sufficient form of resection. The execution of the en bloc spondylectomy should be left to spine centers with great experience, as they could also guarantee the respective complication management. PMID- 22825055 TI - [Therapy of septic paraplegia]. AB - The frequency of infectious diseases of the spine and associated spinal cord injury are constantly increasing. Affected are multimorbid and elderly patients, mostly after prolonged medical treatment. An acute spinal cord injury due to infection is an emergency. A rapid decision for treatment strategy and if at all possible subtle debridement of the infected tissue with decompression of the spinal cord is paramount. Additionally spinal cord injury necessitates specialized treatment and care of the infection. Spinal cord injured patients in general and these patients in particular are prone to complications and need especially trained nursing personnel. It is therefore recommended that patients with vertebral osteomyelitis associated with spinal cord injury should be transferred to dedicated centres of treatment as soon as possible.Just as in cases of spondylodiscitis without spinal cord injury inconsistent surgical or insufficient antibiotic treatment worsens the prognosis significantly. If it is possible to remit the infection, the prognosis for recovery of motor and sensory function is better than in cases with traumatic spinal cord injury. In many cases at least partial recovery can be observed. PMID- 22825056 TI - A method for the establishment of a cell line with stable expression of the GFP LC3 reporter protein. AB - As the function of autophagy becomes evident in a number of diseases, including cancer and infection, it is crucial to construct macrophage cell lines with stable expression of the microtubule-associated protein light chain 3 (GFP-LC3). In this study, a mouse LC3 open-reading frame was amplified by RT-PCR, and cloned into the pEGFP-C1 plasmid for expression of the GFP-LC3 fusion protein. The recombinant plasmid was transfected into RAW264.7 cells using Lipofectamine 2000 reagent and stably transfected clones were selected by G418 screening. Autophagic puncta formation was observed by fluorescense microscopy. Additionally, we found that starvation treatment induced a significant increase in the number of autophagosomes, while wortmannin treatment significantly repressed the formation of autophagosomes. This study indicated that the RAW264.7 cell line stably expressing GFP-LC3 is available for use in a GFP-LC3 puncta formation assay, and may contribute to basic investigations of autophagic function or drug screening targeted at autophagy. PMID- 22825063 TI - I just feel terrible. PMID- 22825057 TI - TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin. AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis. PMID- 22825064 TI - A different perspective regarding prostate-specific antigen testing. PMID- 22825065 TI - A different perspective regarding prostate-specific antigen testing: in reply. PMID- 22825066 TI - Of sommeliers and wine drinkers. PMID- 22825067 TI - Satisfied to death: a spurious result? PMID- 22825069 TI - Clinician identification of appropriate long-term opioid therapy candidacy. PMID- 22825071 TI - Metropolitan area racial residential segregation, neighborhood racial composition, and breast cancer mortality. AB - PURPOSE: There are significant relationships between racial residential segregation (RRS) and a range of health outcomes, including cancer-related outcomes. This study explores the contribution of metropolitan area RRS, census tract racial composition and breast cancer and all-cause mortality among black and white breast cancer patients. METHODS: This study has three units of analysis: women diagnosed with breast cancer (n = 22,088), census tracts where they lived at diagnosis (n = 1,373), and the metropolitan statistical area (MSA)/micropolitan statistical area (MiSA) where they lived at diagnosis (n = 37). Neighborhood racial composition was measured as the percent of black residents in the census tract. Metropolitan area RRS was measured using the Information Theory Index. Multilevel Cox proportional hazards models examined the association of metropolitan area RRS and census tract racial composition with breast cancer and all-cause mortality. Survival analysis explored and compared the risk of death in women exposed to environments where a higher and lower proportion of residents were black. RESULTS: Breast cancer mortality disparities were largest in racially mixed tracts located in high MSA/MiSA segregation areas (RR = 2.06, 95 % CI 1.70, 2.50). For black but not white women, as MSA/MiSA RRS increased, there was an increased risk for breast cancer mortality (HR = 2.20, 95 % CI 1.09, 4.45). For all-cause mortality, MSA/MiSA segregation was not a significant predictor, but increasing tract percent black was associated with increased risk for white but not black women (HR 1.29, 95 % CI 1.05, 1.58). CONCLUSIONS: Racial residential segregation may influence health for blacks and whites differently. Pathways through which RRS patterns impact health should be further explored. PMID- 22825074 TI - Tetraplegia or paraplegia with brachial diparesis? What is the most appropriate designation for the motor deficit in patients with lower cervical spinal cord injury? AB - The authors seek to clarify the nomenclature used to describe cervical spinal cord injuries, particularly the use of the terms "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia" when applied to patients with lower cervical cord injuries. A review of the origin of the terms and nomenclature used currently to describe the neurological status of patients with SCI in the literature was performed. The terms "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia" have been used very often to describe patients with complete lower cervical SCI despite the fact that the clinical scenario is all the same for most of these patients. Most of these patients have total loss of the motor voluntary movements of their lower trunk and inferior limbs, and partial impairment of movement of their superior limbs, preserving many motor functions of the proximal muscles of their arms (superior limbs). A potentially better descriptive term may be "paraplegia with brachial diparesis". In using the most appropriate terminology, the patients with lower cervical SCI currently referred as presenting with "tetraplegia", "quadriplegia", "quadriparesis", "tetraparesis", "incomplete quadriplegia" or "incomplete tetraplegia", might be better described as having "paraplegia with brachial diparesis". PMID- 22825072 TI - Lifetime risk for cancer death by sex and smoking status: the lifetime risk pooling project. AB - BACKGROUND: Understanding how sex and tobacco exposure may modify lifetime risks for cancer mortality is important for effective communication of risk in targeted public health messages. OBJECTIVE: To determine lifetime risk estimates for cancer death associated with sex and smoking status in the United States. METHODS: A pooled cohort design using ten well-defined epidemiologic cohorts including middle-aged and older individuals was used to estimate the lifetime risk for cancer death at selected index ages, with death from non-cancer causes as the competing risk, by sex and smoking status. RESULTS: There were a total of 11,317 cancer-related deaths. At age 45 years, the lifetime risk of cancer death for male smokers is 27.7 % (95 % CI 24.0-31.4 %) compared to 15.8 % (95 % CI 12.7 18.9 %) for male non-smokers. At age 45 years, the lifetime risk of cancer death for female smokers is 21.7 % (95 % CI 18.8-24.6 %) compared to 13.2 % (95 % CI 11.0-15.4 %) for female non-smokers. Remaining lifetime risk for cancer death declined with age, and men have a greater risk for cancer death compared to women. Adjustment for competing risk of death, particularly representing cardiovascular mortality, yielded a greater change in lifetime risk estimates for men and smokers compared to women and non-smokers. CONCLUSIONS: At the population level, the lifetime risk for cancer death remains significantly higher for smokers compared to non-smokers, regardless of sex. These estimates may provide clinicians with useful information for counseling individual patients and highlight the need for continued public health efforts related to smoking cessation. PMID- 22825075 TI - Expeditious synthesis of saponin P57, an appetite suppressant from Hoodia plants. AB - Pregnane glycoside P57, the appetite suppressant component from Hoodia, was synthesized expeditiously, featuring preparation of the aglycone Hoodigogenin A from digoxin and assembly of the deoxytrisaccharide with glycosyl o alkynylbenzoates as donors. PMID- 22825076 TI - Reentering obstetrics and gynecology. PMID- 22825077 TI - Rh immunoprophylaxis and fetal RHD genotyping: where are we going? PMID- 22825078 TI - Genetic testing in ovarian cancer: getting better, and maybe not just for disease susceptibility anymore. PMID- 22825079 TI - Trends in and effect of private, public, and no insurance on health care coverage for women. PMID- 22825080 TI - Changes in the indications for scheduled births to reduce nonmedically indicated deliveries occurring before 39 weeks of gestation. AB - OBJECTIVE: To estimate the change in indications for scheduled deliveries during the Ohio Perinatal Quality Collaborative's initiative to decrease scheduled deliveries for nonmedical indications before 39 weeks of gestation. METHODS: Documented indications for scheduled deliveries between 36 0/7 and 38 6/7 weeks were categorized as: strong medically accepted reasons for delivery; intermediate acceptability; and unnecessary before 39 weeks. We describe each of these indication categories as a proportion of all deliveries in the participating hospitals between October 2008 and December 2009. RESULTS: The percentage of scheduled deliveries that were unnecessary before 39 weeks or had intermediate indications decreased over time (P=.03). There were 145 fewer with intermediate reasons and 265 fewer that were unnecessary when the first 4 months of the project were compared with the last 4 months. Strong medical indications as a percentage of all deliveries did not change significantly over time (P=.99). CONCLUSION: Our quality collaborative reduced scheduled deliveries of medically unnecessary and intermediate indications for delivery at 36 0/7 and 38 6/7 weeks. However, scheduled deliveries with strong medical indication did not change significantly over time. LEVEL OF EVIDENCE: III. PMID- 22825081 TI - Long-term effect of infection prevention practices and case mix on cesarean surgical site infections. AB - OBJECTIVE: To estimate trends in patient characteristics and obstetric complications in an 8-year cohort of patients undergoing cesarean delivery and to use time series analysis to estimate the effect of infection prevention interventions and secular trends in patient characteristics on postcesarean delivery surgical site infections. METHODS: A multivariable autoregressive integrated moving average model was used to perform time series analysis on a 96 month retrospective cohort of patients who underwent cesarean delivery (January 2003-December 2010) in a U.S. tertiary care hospital. RESULTS: We identified 8,668 women who underwent cesarean delivery. Median age was 26 years (range 12-53 years), 3,093 (35.7%) of patients had body mass indexes (BMIs) of 35 or greater, 2,561 (29.5%) were of white race, and 303 (3.5%) had a surgical site infection. Over the study period, there was a significant increase in the proportion of patients who underwent cesarean delivery who had BMIs of 35 or higher, hypertension or mild preeclampsia, and severe preeclampsia or eclampsia. A nonseasonal autoregressive integrated moving average model with a linear trend and no autocorrelation was identified. In the multivariable autoregressive integrated moving average model of postcesarean surgical site infections, implementation of a policy to administer prophylactic antibiotics within 1 hour before incision, instead of at the time of cord clamp, led to a 48% reduction in cesarean delivery surgical site infections (Delta=-5.4 surgical site infections per 100 cesarean deliveries; P<.001). CONCLUSION: A change in policy to administer prophylactic antibiotics before incision resulted in a significant reduction in postcesarean surgical site infections. LEVEL OF EVIDENCE: III. PMID- 22825082 TI - Maternal preference for cesarean delivery: do women get what they want? AB - OBJECTIVE: To estimate the association between delivery preferences during pregnancy and actual delivery mode. METHODS: This was a prospective cohort study using data from the Norwegian Mother and Child Cohort Study (N=65,959). We analyzed predictors of birth outcome by means of women's preferences for mode or delivery and a range of medical and socioeconomic factors with multivariable logistic regression models. The term "elective" cesarean delivery includes cesarean deliveries planned 8 hours or more before delivery and performed as planned. RESULTS: When asked about delivery preference at 30 weeks of gestation, 5% of the women reported a preference for a cesarean delivery, 84% had a preference for vaginal delivery, and 11% were neutral. Among those with a cesarean delivery preference, 48% subsequently had a cesarean delivery (12% acute and 36% elective), and of those with a vaginal preference 12% delivered by cesarean (8.7% acute and 3.1% elective). When adjusting for maternal characteristics and medical indications, the odds for an acute cesarean delivery among nulliparous women with a cesarean delivery preference was almost two times higher (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.49-2.62) and for elective cesarean delivery the preference was 12 times higher (OR 12.61, 95% CI 9.69-16.42) than for women with a vaginal preference. For multiparous women, the corresponding figures were OR 3.13 (95% CI 1.39-7.05) and OR 10.04 (95% CI 4.59 21.99). When multiparous women with previous cesarean deliveries were excluded, the OR for an elective cesarean delivery was 26 times higher given a cesarean delivery preference compared with a vaginal delivery preference (OR 25.78, 95% CI 7.89-84.28). Based on a small subset of women with planned cesarean delivery on maternal request (n=560), we estimated a predicted probability of 16% for nulliparous women (25% for multiparous women) for such cesarean delivery. CONCLUSION: Pregnant women's expressed preferences for delivery mode were associated with both elective and acute cesarean deliveries. LEVEL OF EVIDENCE: II. PMID- 22825083 TI - Race, ethnicity, and nativity differentials in pregnancy-related mortality in the United States: 1993-2006. AB - OBJECTIVE: To compare trends in and causes of pregnancy-related mortality by race, ethnicity, and nativity from 1993 to 2006. METHODS: We used data from the Pregnancy Mortality Surveillance System. For each race, ethnicity, and nativity group, we calculated pregnancy-related mortality ratios and assessed causes of pregnancy-related death and the time between the end of pregnancy and death. RESULTS: Race, ethnicity, and nativity-related minority women contributed 40.7% of all U.S. live births but 61.8% of the 7,487 pregnancy-related deaths during 1993-2006. Pregnancy-related mortality ratios were 9.1 and 7.5 deaths per 100,000 live births among U.S.- and foreign-born white women, respectively, and slightly higher at 9.6 and 11.6 deaths per 100,000 live births for U.S.- and foreign-born Hispanic women, respectively. Relative to U.S.-born white women, age-standardized pregnancy-related mortality ratios were 5.2 and 3.6 times higher among U.S.- and foreign-born black women, respectively. However, causes and timing of death within 42 days postpartum were similar for U.S.-born white and black women with cardiovascular disease, cardiomyopathy, and other pre-existing medical conditions emerging as chief contributors to mortality. Hypertensive disorders, hemorrhage, and embolism were the most important causes of pregnancy-related death for all other groups of women. CONCLUSION: Except for foreign-born white women, all other race, ethnicity, and nativity groups were at higher risk of dying from pregnancy related causes than U.S.-born white women after adjusting for age differences. Integration of quality-of-care aspects into hospital- and state-based maternal death reviews may help identify race, ethnicity, and nativity-specific factors for pregnancy-related mortality. LEVEL OF EVIDENCE: III. PMID- 22825084 TI - Incidence and risk factors for clinical failure of uterine leiomyoma embolization. AB - OBJECTIVE: To estimate the incidence of clinical failure after uterine leiomyoma embolization and identify possible risk factors. METHODS: One hundred seventy-six consecutive women undergoing uterine leiomyoma embolization were followed prospectively for a median of 48 months (range 12-84 months) to estimate the occurrence of clinical failure, defined as persistence or recurrence of leiomyoma symptoms, and any subsequent invasive treatment. Cumulative failure and reintervention rates were estimated by survival analysis and log-rank tests according to baseline patient characteristics. Multivariable Cox proportional hazards analysis was performed to adjust for confounders. RESULTS: Overall, there were 18 failures at a median of 36 months (range 3-84 months). The cumulative failure rate increased steadily over time, 3% at 1 year, 7% at 3 years, 14% at 5 years, and 18% at 7 years. Of the 18 failures, 11 had reintervention, including six hysterectomies, four myomectomies, and one repeat uterine leiomyoma embolization, at a median of 56 months (range 15-84 months). The cumulative reintervention rate was 0 at 1 year, 3% at 3 years, 7% at 5 years, and 15% at 7 years. Women aged 40 years or younger had a higher failure risk (hazard ratio [HR] 5.89, 95% confidence interval [CI] 2.50-20.02, P=.023) compared with older women. A history of previous myomectomy was also associated with an increased failure risk (HR 3.79, 95% CI 2.07-13.23, P=.037). CONCLUSION: The 7-year cumulative rates of clinical failure and reintervention after uterine leiomyoma embolization were 18% (95% CI 8.2-27.8) and 15% (95% CI 5.2-24.8), respectively. The failure risk was higher for younger patients and for those with a prior myomectomy. LEVEL OF EVIDENCE: III. PMID- 22825085 TI - Decrease in urinary incontinence management costs in women enrolled in a clinical trial of weight loss to treat urinary incontinence. AB - OBJECTIVE: To estimate the effect of a decrease in urinary incontinence (UI) frequency on UI management costs among women enrolled in a clinical trial of a weight loss intervention and to identify factors that predict change in cost. METHODS: This is a secondary cohort analysis of 338 obese and overweight women with 10 or more weekly episodes of UI enrolled in an 18-month randomized clinical trial of a weight loss intervention compared with a structured education program to treat UI. Quantities of resources used for incontinence management, including pads, additional laundry, and dry cleaning, were reported by participants. Direct costs for UI management ("cost") were calculated by multiplying resources used by national resource costs (in 2006 U.S. dollars). Randomized groups were combined to examine the effects of change in incontinence frequency on cost. Possible predictors of change in cost were examined using generalized estimating equations controlling for factors associated with change in cost in univariable analyses. RESULTS: Mean age+/-standard deviation was 53+/-10 years and baseline weight was 97+/-17 kg. Mean weekly UI frequency was 24+/-18 at baseline and decreased by 37% at 6 months and 60% at 18 months' follow-up (both P<.001). At baseline, adjusted mean cost was $7.76+/-$14 per week, with costs increasing significantly with greater incontinence frequency. Mean cost decreased by 54% at 6 months and 81% at 18 months (both P<.001). In multivariable analyses, cost independently decreased by 23% for each decrease of seven UI episodes per week and 21% for each 5 kg of weight lost (P<.001 for both). CONCLUSION: In obese and overweight women enrolled in a clinical trial of weight loss for UI, incontinence management cost decreased by 81% at 18 months ($327 per woman per year) and was strongly and independently associated with decreasing incontinence frequency. LEVEL OF EVIDENCE: II. PMID- 22825086 TI - Robot-assisted laparoscopic myomectomy compared with standard laparoscopic myomectomy. AB - OBJECTIVE: To compare surgical outcomes of laparoscopic myomectomy and robot assisted laparoscopic myomectomy. METHODS: Retrospective cohort study of 115 consecutive laparoscopic myomectomy and 174 consecutive robot-assisted laparoscopic myomectomy performed at Brigham and Women's Hospital over a period of 31 months. Uterine incisions were closed in multiple layers (running barbed suture was used for most cases in the laparoscopic myomectomy group). Surgical outcomes measured included operative time, estimated intraoperative blood loss, length of hospital stay, and perioperative complications. Odds ratios and 95% confidence intervals were calculated from multivariable logistic regression models; adjusted geometric means were estimated from linear regression models on logged outcomes because of skewed distributions. RESULTS: Surgical groups were similar in age, body mass index, and leiomyoma characteristics. Robot-assisted laparoscopic myomectomy had significantly longer operative time than laparoscopic myomectomy (adjusted geometric mean of 195.1 compared with 118.3 minutes, P<.001) and higher estimated blood loss (adjusted geometric mean of 110.0 compared with 85.9 mL, P=.04), but postoperative complications were similar. CONCLUSION: Robot assisted laparoscopic myomectomy and laparoscopic myomectomy have similar operative outcomes in a high-volume surgical practice. Operative time and intraoperative estimated blood loss were significantly greater in the robot assisted laparoscopic myomectomy group, but the level of statistical significance for intraoperative estimated blood loss was marginal and the clinical significance was undetermined. Use of barbed suture in the laparoscopic myomectomy group may account for these differences. LEVEL OF EVIDENCE: II. PMID- 22825087 TI - Recognition and management of nerve entrapment pain after uterosacral ligament suspension. AB - OBJECTIVE: To estimate the incidence, risk factors, and characteristics of neuropathic pain related to nerve entrapment after uterosacral ligament suspension. METHOD: A review of patients who underwent uterosacral ligament suspension from January 2007 to August 2011 was performed. Patients with neuropathic pain attributable to nerve entrapment from uterosacral ligament suspensory suture placement were identified. Factors including surgeon's dominant hand, side of pain, onset of pain, day of suture removal, number of sutures placed and removed, patient age, and body mass index (BMI) were collected. Follow up of patients with neuropathic pain was performed at postoperative visits and by telephone contact. RESULT: Eight (1.6%) of 515 patients had neuropathic pain requiring suture removal from the affected side. The postoperative pain was recognized after discontinuation of intravenous narcotics on postoperative day 1. Patients reported their pain improved after removal of all sutures on the affected side. Patients with neuropathic pain did not differ from those without in regard to age, BMI, and preoperative prolapse stage, or in the number of sutures placed. None of the eight had recurrent pelvic organ prolapse (POP), with a median follow-up of 5 months. CONCLUSION: Eight patients (1.6%) had postoperative neuropathic pain that resolved after all sutures were removed on the affected side. The removal of sutures was not associated with recurrent POP in the short-term. LEVEL OF EVIDENCE: II. PMID- 22825088 TI - Induction of labor in twin compared with singleton pregnancies. AB - OBJECTIVE: To estimate the likelihood of cesarean delivery and length of labor in twin pregnancies undergoing induction of labor as compared with singleton pregnancies. METHODS: This was a retrospective cohort study of 100 patients with twin pregnancy in one maternal-fetal medicine practice undergoing induction of labor from 2005 to 2012. The control group was 100 randomly selected patients in the same practice with a singleton pregnancy undergoing induction of labor over the same time period. The primary outcome was mode of delivery (vaginal or cesarean). RESULTS: The likelihood of cesarean delivery did not differ between the groups (19% in twins compared with 21% in singletons, P=.724) nor did the time from induction to vaginal delivery (median and interquartile time 9.7 [5.5 12.5] hours in twins compared with 10.4 [6.6, 14.1] hours in singletons, P=.255). Results were not different when we looked at nulliparous patients only or multiparous patients only. On adjusted analysis of risk factors for cesarean delivery in patients undergoing induction, twin pregnancy was not independently associated with cesarean delivery. CONCLUSION: Patients with twin pregnancies undergoing induction of labor have a similar risk of cesarean delivery and a similar length of labor as patients with singleton pregnancies undergoing induction of labor. LEVEL OF EVIDENCE: II. PMID- 22825089 TI - Effect of a physical exercise program during pregnancy on uteroplacental and fetal blood flow and fetal growth: a randomized controlled trial. AB - OBJECTIVE: To estimate the effect of supervised physical exercise on maternal physical fitness, fetoplacental blood flow, and fetal growth. METHODS: This was a randomized controlled trial comparing three groups of pregnant women. Groups were as follows: exercise initiated at 13 weeks (group A); exercise initiated at 20 weeks (group B); and a control group (no supervised exercise; group C). The women in groups A and B walked at moderate intensity three times weekly. Physical fitness level was evaluated at weeks 13, 20, and 28. Fetal growth and uteroplacental blood flow were evaluated monthly. Birth weight was registered. Analysis of variance for repeat measures was used for outcomes evaluated throughout pregnancy. Risk ratio was used as a measure of the relative risk of preeclampsia, fetal growth restriction, macrosomia, small-for-gestational-age newborns, and large-for-gestational-age newborns. RESULTS: All the women analyzed completed more than 85% of the program. According to the evaluation conducted at week 28, physical fitness improved, with mean maximal oxygen consumptions (VO2max) of 27.3+/-4.3 (group A), 28+/-3.3 (group B), and 25.5+/-3.8 (group C; P=.03). Mean birth weights were 3,279+/-453 g (group A), 3,285+/-477 g (group B), and 3,378+/-593 g (group C; P=.53), with no difference in the frequency of large for gestational age or small for gestational age. No association was found between the practice of physical activity and the variables investigated (preeclampsia, fetal weight, blood pressure, and pulsatility index of the uterine, umbilical, and middle cerebral arteries). CONCLUSION: Moderate-intensity walking improved the physical fitness level of healthy, pregnant, previously sedentary women without affecting fetoplacental blood flow or fetal growth. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00641550. LEVEL OF EVIDENCE: II. PMID- 22825090 TI - Metabolic syndrome as a risk factor for hypertension after preeclampsia. AB - OBJECTIVE: To identify metabolic and obstetric risk factors associated with hypertension after preeclampsia. METHODS: We analyzed demographic and clinical data from a postpartum screening (blood pressure, microalbuminuria and fasting plasma levels of glucose, insulin, and lipid profile) from 683 primiparous women with a history of preeclampsia. We excluded women with pre-existing hypertension, kidney disease, or diabetes mellitus. In the group of women who were normotensive at postpartum screening, we evaluated the risk of developing chronic hypertension in the years after screening using questionnaires. RESULTS: Hypertension at postpartum screening (n=107, 17% of all cases) was related to obesity (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.2), elevated fasting levels of insulin (OR 1.7, 95% CI 1.0-2.9), low-density lipoprotein (OR 1.6, 95% CI 1.1 2.6), microalbuminuria (OR 2.3, 95%-CI 1.3-4.0), family history of hypertension (OR 1.8, 95% CI 1.1-2.8), and delivery before 34 weeks of gestation (OR 2.5, 95% CI 1.6-4.0). We identified 27 cases of hypertension within 2,095 person-years during a median 6-year follow-up in the group of women normotensive at postpartum screening. The hazard rate for the development of hypertension was 2.9 (95% CI 1.2-7.5) and 8.1 (95% CI 2.8-22.9), respectively, when two and three or more components of the metabolic syndrome were present; 3.7 (95% CI 1.4-10.0) for family history of hypertension; and 4.3 (95% CI 1.6-11.5) for recurrence of a hypertensive disorder in pregnancy. CONCLUSION: Several metabolic and obstetric risk factors related to hypertension postpartum in the short term and predisposed to the subsequent development of chronic hypertension after preeclampsia in initially normotensive women. LEVEL OF EVIDENCE: III. PMID- 22825091 TI - Incidence, risk factors, management, and outcomes of stroke in pregnancy. AB - OBJECTIVE: To estimate the incidence of antenatal stroke in the United Kingdom and to describe risk factors associated with stroke during pregnancy, management, and outcomes. METHODS: A population-based (nationwide) cohort and nested case control study was conducted using the UK Obstetric Surveillance System between October 2007 and March 2010. We investigated the potential factors associated with antenatal stroke using a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Thirty cases of antenatal stroke were reported giving an estimated incidence of 1.5 cases per 100,000 women delivering (95% CI 1.0-2.1). The incidences of nonhemorrhagic and hemorrhagic stroke were 0.9 (95% CI 0.5-1.3) and 0.6 (95% CI 0.3-1.0) per 100,000 women delivering. Factors associated with increased risk of antenatal stroke were history of migraine (adjusted OR 8.5, 95% CI 1.5-62.1), gestational diabetes (adjusted OR 26.8, 95% CI 3.2-infinity), and preeclampsia or eclampsia (adjusted OR 7.7, 95% CI 1.3-55.7). There was wide variation in the use of pharmacologic, surgical, and organized stroke unit care. There were six stroke-related maternal deaths giving a case-fatality rate of 20% of all strokes, 50% of hemorrhagic strokes, and a mortality rate of 0.3 (95% CI 0.1-0.6) per 100,000 women delivering. CONCLUSION: The risk of a stroke during pregnancy is low; however, the poor outcomes in terms of morbidity and mortality and variations in care highlight the importance of such women receiving specialist stroke care. Clinicians should be aware of an association with a history of migraine, gestational diabetes, and preeclampsia or eclampsia. LEVEL OF EVIDENCE: II. PMID- 22825092 TI - Delayed umbilical cord clamping in premature neonates. AB - OBJECTIVE: Delayed umbilical cord clamping is reported to increase neonatal blood volume. We estimated the clinical outcomes in premature neonates who had delayed umbilical cord clamping compared with a similar group who had early umbilical cord clamping. METHODS: This was a before-after investigation comparing early umbilical cord clamping with delayed umbilical cord clamping (45 seconds) in two groups of singleton neonates, very low birth weight (VLBW) (401-1,500 g) and low birth weight (LBW) (greater than 1,500 g but less than 35 weeks gestation). Neonates were excluded from delayed umbilical cord clamping if they needed immediate major resuscitation. Primary outcomes were provision of delivery room resuscitation, hematocrit, red cell transfusions, and the principle Vermont Oxford Network outcomes. RESULTS: In VLBW neonates (77 delayed umbilical cord clamping, birth weight [mean+/-standard deviation] 1,099+/-266 g; 77 early umbilical cord clamping 1,058+/-289 g), delayed umbilical cord clamping was associated with less delivery room resuscitation, higher Apgar scores at 1 minute, and higher hematocrit. Delayed umbilical cord clamping was not associated with significant differences in the overall transfusion rate, peak bilirubin, any of the principle Vermont Oxford Network outcomes, or mortality. In LBW neonates (172 delayed umbilical cord clamping, birth weight [mean+/-standard deviation] 2,159+/-384 g; 172 early umbilical cord clamping 2,203+/-447 g), delayed umbilical cord clamping was associated with higher hematocrit and was not associated with a change in delivery room resuscitation or Apgar scores or with changes in the transfusion rate or peak bilirubin. Regression analysis showed increasing gestational age and birth weight and delayed umbilical cord clamping were the best predictors of higher hematocrit and less delivery room resuscitation. CONCLUSION: Delayed umbilical cord clamping can safely be performed in singleton premature neonates and is associated with a higher hematocrit, less delivery room resuscitation, and no significant changes in neonatal morbidities. LEVEL OF EVIDENCE: II. PMID- 22825093 TI - Diabetes mellitus and sexual function in middle-aged and older women. AB - OBJECTIVE: Diabetes mellitus is an established risk factor for sexual dysfunction in men, but its effect on female sexual function is poorly understood. We examined the relationship of diabetes to sexual function in middle-aged and older women. METHODS: Sexual function was examined in a cross-sectional cohort of ethnically diverse women aged 40-80 years using self-administered questionnaires. Multivariable regression models compared self-reported sexual desire, frequency of sexual activity, overall sexual satisfaction, and specific sexual problems (difficulty with lubrication, arousal, orgasm, or pain) among insulin-treated diabetic, non-insulin-treated diabetic, and nondiabetic women. Additional models assessed relationships between diabetic end-organ complications (heart disease, stroke, renal dysfunction, and peripheral neuropathy) and sexual function. RESULTS: Among the 2,270 participants, mean+/-standard deviation age was 55+/-9.2 years, 1,006 (44.4%) were non-Latina white, 486 (21.4%) had diabetes, and 139 (6.1%) were taking insulin. Compared with 19.3% of nondiabetic women, 34.9% of insulin-treated diabetic women (adjusted odds ratio [OR] 2.04, 95% confidence interval [CI] 1.32-3.15) and 26.0% of non-insulin-treated diabetic women (adjusted OR 1.42, 95% CI 1.03-1.94) reported low overall sexual satisfaction. Among sexually active women, insulin-treated diabetic women were more likely to report problems with lubrication (OR 2.37, 95% CI 1.35-4.16) and orgasm (OR 1.80, 95% CI 1.01-3.20) than nondiabetic women. Among all diabetic women, end-organ complications such as heart disease, stroke, renal dysfunction, and peripheral neuropathy were associated with decreased sexual function in at least one domain. CONCLUSION: Compared with nondiabetic women, diabetic women are more likely to report low overall sexual satisfaction. Insulin-treated diabetic women also appear at higher risk for problems such as difficulty with lubrication and orgasm. Prevention of end-organ complications may be important in preserving sexual activity and function in diabetic women. LEVEL OF EVIDENCE: II. PMID- 22825094 TI - Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. AB - OBJECTIVES: To estimate the effects of self-administered misoprostol compared with placebo before intrauterine device (IUD) insertion in nulliparous women. METHOD: Nulliparous women requesting either the copper T380A or levonorgestrel IUD were randomized to self-administer either 400 MUg of misoprostol or placebo (vaginally or buccally) 3-4 hours before the IUD insertion appointment. The primary outcome was health care provider-perceived ease of insertion recorded on a visual analog scale (anchors: 0 extremely easy, 100 impossible). Patients completed questionnaires addressing pain using a validated visual analog scale (anchors: 0 none, 100 worst imaginable) before insertion, immediately postinsertion, and before clinic discharge. RESULTS: Of the 108 women enrolled in the study, 54 received misoprostol and 54 received placebo. There was no significant difference in perceived ease of insertion between the two groups (25.0 mm [standard error 3.5] compared with 27.4 mm [standard error 3.5], P=.64). Patients who received misoprostol before IUD insertion had significantly higher pain scores before placement (17.1 mm [standard error 3.5] compared with 4.7 mm [standard error 2.0], P=.003). Groups did not differ in perception of pain during IUD insertion (58.4 mm [standard error 3.3] compared with 56.9 mm [standard error 3.0], P=.74). There were two expulsions in the misoprostol group and none in the placebo group. Failed insertions, need for adjuvant pain medication, and need for cervical dilation or ultrasonographic guidance did not differ between the two groups. CONCLUSION: Self-administered misoprostol before IUD insertion does not ease IUD insertion or reduce patient-perceived pain in nulliparous women. These data do not support the routine use of misoprostol before IUD insertion in nulliparous women. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00886834. LEVEL OF EVIDENCE: I. PMID- 22825095 TI - Effect of long-term combined oral contraceptive pill use on endometrial thickness. AB - OBJECTIVE: To estimate whether there is any association of long-term use of combined oral contraceptive pills (OCP) with adverse endometrial growth. METHODS: We reviewed the charts of 137 patients with history of OCP use undergoing endometrial preparation with estrogen for frozen embryo transfer. Endometrial thickness was measured by transvaginal ultrasonography on day 10 after menses and patients were divided into two groups (less than 7 mm and 7 mm or more). RESULTS: Thirty patients had endometrial thickness less than 7 mm and 107 had thickness of 7 mm or more. Mean years of combined OCP use in each group were 9.8+/-4.54 and 5.8+/-4.52, respectively (P<.001). With 10 years of combined OCP use as the threshold, the difference between the two groups (63.35% users in less than 7 mm group compared with 28.04% in the 7 mm or more thickness group) was highly significant (P<.001 by Fisher exact test), with an odds ratio of 4.43 (95% confidence interval 1.89-10.41). Past use of 5 years of OCPs was also associated with a significant (P=.002) difference in endometrial thickness. The mean endometrial thicknesses on cycle day 10 in patients using combined OCP for less than 10 years and 10 years or more were 9.54+/-1.88 mm and 8.48+/-2.33 mm, respectively, with P=.007. The mean endometrial thickness was 9.72+/-1.69 mm in less than 5 years and 8.81+/-2.23 mm in 5 or more years of use, respectively (P=.008). Cycle cancellation rates in the less than 7 mm group and 7 mm or greater endometrial thickness group were 23% and 4%, respectively (P=.002), but there was no difference in the clinical pregnancy rates between the two groups (13% compared with 27%, respectively; P=.15). CONCLUSION: Long-term combined OCP use (5 years or more) can potentially affect optimal endometrial growth, leading to a higher cancellation rate and longer stimulation in frozen embryo transfer cycles. These findings suggest a previously unidentified adverse effect of long term combined OCP use in women who are anticipating future fertility. LEVEL OF EVIDENCE: II. PMID- 22825096 TI - Lessons learned in physician reentry. AB - We describe our early experience with two physicians who successfully completed an obstetrics and gynecology physician reentry program. A 10-step program using an individualized curriculum in a supervised preceptorship is tailored to the candidate's anticipated practice. A reentry curriculum is devised for the candidate based on the advances in the field since they left practice and Accreditation Council for Graduate Medical Education (ACGME) competencies for resident education. The program culminates with an oral boards examination conducted by a panel of obstetrician-gynecologists (ob-gyns). At the completion of the program, the candidate must demonstrate that they are conversant with the field of general obstetrics and gynecology. Both candidates had been part of the medical community, which facilitated their ability to complete the program. One candidate was trained and worked intermittently in obstetrics and gynecology in another country. She used cases from her most recent clinical rotation abroad. The other candidate gathered cases from her future partner and prior colleagues. Both candidates successfully completed the program within 3 months and returned to clinical practice. The first physician practiced as a faculty member for 1 year but had challenges assimilating into a busy resident service while balancing her research duties. We need to enhance opportunities for external reentry candidates to have access to preceptors and their patients. In the future, we will better screen candidates to identify those who are planning to return to active clinical practice. We no longer will accept a case log with cases drawn from other sites. We also will incorporate an assessment of each candidate's surgical skill using surgical simulation. PMID- 22825097 TI - Reentry into clinical practice in obstetrics and gynecology. AB - The American College of Obstetricians and Gynecologists selected "Reentry Into Practice" as the subject for the 2012 Issue of the Year. Physician reentry programs in obstetrics and gynecology are driven by the fact that there is a projected physician shortage, and there are physicians who voluntarily leave clinical practice for a period of time. In planning formal reentry programs, evidence-based practice and highest regard for patient safety must be considered. Our department initiated a reentry fellowship program in 2010. This article describes the process of how we developed our program, the challenges encountered, and the solutions used to overcome these challenges. The formal instruction, evaluation, and documentation of competency are presented. Process improvement has been based on feedback and evaluation from the reentry fellows and from staff and residents. Bringing physicians back into the clinical realm will depend on the success of new programs implementing the guidelines recommended by national regulatory bodies. The guidelines recommend that the programs are accessible, collaborative, comprehensive, ethical, flexible, individualized, innovative, accountable, stable, and responsive. Our reentry program has been successful in helping fellows reestablish clinical practice and is a way to incorporate hands-on competency-based experiences for the reentering obstetrician-gynecologist (ob-gyn). PMID- 22825098 TI - Abnormal fetal-maternal interactions: an evolutionary value? AB - There is clinical and ultrasonographic evidence that "abnormal fetal-maternal interactions" or "fetal-maternal conflicts" may be central to the mechanisms of injury in pregnancy complications such as fetal growth restriction, preeclampsia, fetal death, gestational diabetes, and a subset of patients with preterm parturition. This conceptual framework integrates abnormalities in the placental bed, placental vasculature, and other areas of fetal-maternal interactions with pregnancy complications in light of their possible evolutionary value. PMID- 22825099 TI - What is new in genetics? Best articles from the past year. PMID- 22825100 TI - Bilateral spontaneous adrenal hemorrhage during pregnancy. PMID- 22825101 TI - Endometrial cancer. AB - The epidemiology, prevention, diagnosis, treatment, prognosis, and new International Federation of Gynecology and Obstetrics staging system of endometrial carcinoma are reviewed. Endometrial cancer has increased 21% in incidence since 2008, and the death rate has increased more than 100% over the past two decades. Precursor lesions of complex hyperplasia with atypia are associated with an endometrial carcinoma in more than 40% of cases. Endometrial cancer in white women occurs at twice the incidence as in black women, but, stage for stage, black women have a less favorable prognosis. Preoperative imaging cannot accurately assess lymph node involvement. Gross examination of depth of myometrial invasion does not have the sensitivity, specificity, positive predictive value, or negative predictive value to select women who can have lymphadenectomy safely omitted from the surgical procedure. Although surgical staging remains the most accurate method of determining the extent of disease, the therapeutic value of pelvic lymphadenectomy has not been established. The anatomical extent of lymphadenectomy and the number of lymph nodes removed to establish prognostic and therapeutic benefit are controversial. Research efforts are directed at identifying women with early stage endometrial cancer who only require total hysterectomy and bilateral salpingo-oophorectomy. Minimally invasive surgical techniques have become established as standard therapy for treating women with endometrial cancer. Women with a family history of hereditary nonpolyposis colorectal cancer are at increased risk for endometrial cancer. Conservative treatment to allow for childbearing is possible in select situations. Women with endometrial cancer should be managed by physicians experienced in the complex multimodality treatment of this disease. PMID- 22825102 TI - Performance of an interferon-gamma release assay to diagnose latent tuberculosis infection during pregnancy. PMID- 22825107 TI - Retraction: ACOG Practice Bulletin No. 15: Premenstrual Syndrome (Obstet Gynecol Vol. 95, No. 4) and ACOG Practice Bulletin No. 35: Diagnosis and Treatment of Cervical Carcinomas (Obstet Gynecol 2002;99:855-867). PMID- 22825108 TI - Committee opinion No. 531: improving medication safety. AB - Despite significant national attention, medical errors continue to pervade the U.S. health care system. Medication-related errors consistently rank at the top of all medical errors, which account for thousands of preventable deaths annually in the United States. There are a variety of methods-ranging from broad-based error reduction strategies to the adoption of sophisticated health information technologies-that can assist obstetrician-gynecologists in minimizing the risk of medication errors. Practicing obstetrician-gynecologists should be familiar with these various approaches that, along with efforts directed at assisting the patient in understanding the medical condition for which a medication is prescribed, can improve the safety and efficacy of medication use. PMID- 22825109 TI - Committee opinion No. 532: compounded bioidentical menopausal hormone therapy. AB - Although improvement in long-term health is no longer an indication for menopausal hormone therapy, evidence supporting fewer adverse events in younger women, combined with its high overall effectiveness, has reinforced its usefulness for short-term treatment of menopausal symptoms. Menopausal therapy has been provided not only by commercially available products but also by compounding, or creation of an individualized preparation in response to a health care provider's prescription to create a medication tailored to the specialized needs of an individual patient. The Women's Health Initiative findings, coupled with an increase in the direct-to-consumer marketing and media promotion of compounded bioidentical hormonal preparations as safe and effective alternatives to conventional menopausal hormone therapy, have led to a recent increase in the popularity of compounded bioidentical hormones as well as an increase in questions about the use of these preparations. Not only is evidence lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy, but these claims also pose the additional risks of variable purity and potency and lack efficacy and safety data. The Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists and the Practice Committee of the American Society for Reproductive Medicine provide an overview of the major issues of concern surrounding compounded bioidentical menopausal hormone therapy and provide recommendations for patient counseling. PMID- 22825110 TI - Committee opinion No. 533: lead screening during pregnancy and lactation. AB - Prenatal lead exposure has known adverse effects on maternal health and infant outcomes across a wide range of maternal blood lead levels. Adverse effects of lead exposure are being identified at lower levels of exposure than previously recognized in both children and adults. In 2010, the Centers for Disease Control and Prevention issued the first guidelines regarding the screening and management of pregnant and lactating women who have been exposed to lead. PMID- 22825111 TI - Committee opinion No. 534: well-woman visit. AB - The annual health assessment ("annual examination") is a fundamental part of medical care and is valuable in promoting prevention practices, recognizing risk factors for disease, identifying medical problems, and establishing the clinician patient relationship. The annual health assessment should include screening, evaluation and counseling, and immunizations based on age and risk factors. The interval for specific individual services and the scope of services provided may vary in different ambulatory care settings. The performance of a physical examination is a key part of an annual health assessment visit, and the components of that examination may vary depending on the patient's age, risk factors, and physician preference. The American College of Obstetricians and Gynecologists explains the need for annual assessments and provides guidelines regarding some important elements of the annual examination; specifically, when to perform pelvic examinations in asymptomatic women, including when to start internal pelvic and speculum examinations, and when to initiate formal clinical breast examinations. PMID- 22825112 TI - Committee opinion No. 535: reproductive health care for incarcerated women and adolescent females. AB - Increasing numbers of women and adolescent females are incarcerated each year in the United States and they represent an increasing proportion of inmates in the U.S. correctional system. Incarcerated women and adolescent females often come from disadvantaged environments and have high rates of chronic illness, substance abuse, and undetected health problems. Most of these females are of reproductive age and are at high risk of unintended pregnancy and sexually transmitted infections, including human immunodeficiency virus (HIV). Understanding the needs of incarcerated women and adolescent females can help improve the provision of health care in the correctional system. PMID- 22825113 TI - Patient safety checklist No. 6: documenting shoulder dystocia. PMID- 22825114 TI - Patient safety checklist No. 7: magnesium sulfate before anticipated preterm birth for neuroprotection. PMID- 22825115 TI - The combination of sulfamethoxazole, trimethoprim, and isoniazid or rifampin is bactericidal and prevents the emergence of drug resistance in Mycobacterium tuberculosis. AB - The challenges of developing new drugs to treat tuberculosis (TB) are indicated by the relatively small number of candidates entering clinical trials in the past decade. To overcome these issues, we reexamined two FDA-approved antibacterial drugs, sulfamethoxazole (SMX) and trimethoprim (TMP), for use in TB treatment. SMX and TMP inhibit folic acid biosynthesis and are used in combination to treat infections of the respiratory, urinary, and gastrointestinal tracts. The MICs of SMX and TMP, alone and in combination, were determined for drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistant Mycobacterium tuberculosis strains. While TMP alone was not effective against M. tuberculosis, the combination of TMP and SMX was bacteriostatic against M. tuberculosis. Surprisingly, the combination of SMX and TMP was also active against a subset of MDR M. tuberculosis strains. Treatment of M. tuberculosis with TMP-SMX and a first-line anti-TB drug, either isoniazid or rifampin, was bactericidal, demonstrating that the combination of TMP and SMX with isoniazid or rifampin was not antagonistic. Moreover, the addition of SMX-TMP in combination with either isoniazid or rifampin also prevented the emergence of drug resistance in vitro. In conclusion, this study further illustrates the opportunity to reevaluate the activity of TMP-SMX in vivo to prevent the emergence of drug-resistant M. tuberculosis. PMID- 22825116 TI - Overcoming drug resistance with alginate oligosaccharides able to potentiate the action of selected antibiotics. AB - The uncontrolled, often inappropriate use of antibiotics has resulted in the increasing prevalence of antibiotic-resistant pathogens, with major cost implications for both United States and European health care systems. We describe the utilization of a low-molecular-weight oligosaccharide nanomedicine (OligoG), based on the biopolymer alginate, which is able to perturb multidrug-resistant (MDR) bacteria by modulating biofilm formation and persistence and reducing resistance to antibiotic treatment, as evident using conventional and robotic MIC screening and microscopic analyses of biofilm structure. OligoG increased (up to 512-fold) the efficacy of conventional antibiotics against important MDR pathogens, including Pseudomonas, Acinetobacter, and Burkholderia spp., appearing to be effective with several classes of antibiotic (i.e., macrolides, beta lactams, and tetracyclines). Using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), increasing concentrations (2%, 6%, and 10%) of alginate oligomer were shown to have a direct effect on the quality of the biofilms produced and on the health of the cells within that biofilm. Biofilm growth was visibly weakened in the presence of 10% OligoG, as seen by decreased biomass and increased intercellular spaces, with the bacterial cells themselves becoming distorted and uneven due to apparently damaged cell membranes. This report demonstrates the feasibility of reducing the tolerance of wound biofilms to antibiotics with the use of specific alginate preparations. PMID- 22825117 TI - In vitro and in vivo biological activities of iron chelators and gallium nitrate against Acinetobacter baumannii. AB - We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of Acinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited A. baumannii growth in vitro. Gallium nitrate alone was moderately effective at reducing A. baumannii growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium based therapies shows promise for the control of multidrug-resistant A. baumannii. PMID- 22825118 TI - Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4 kinase beta inhibitors. AB - Type III phosphatidylinositol-4-kinase beta (PI4KIIIbeta) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIbeta inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIbeta in lymphocyte proliferation. Previously proposed functions of PI4KIIIbeta in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIbeta inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C. PMID- 22825119 TI - A potential substrate binding conformation of beta-lactams and insight into the broad spectrum of NDM-1 activity. AB - New Delhi metallo-beta-lactamase 1 (NDM-1) is a key enzyme that the pathogen Klebsiella pneumonia uses to hydrolyze almost all beta-lactam antibiotics. It is currently unclear why NDM-1 has a broad spectrum of activity. Docking of the representatives of the beta-lactam families into the active site of NDM-1 is reported here. All the beta-lactams naturally fit the NDM-1 pocket, implying that NDM-1 can accommodate the substrates without dramatic conformation changes. The docking reveals two major binding modes of the beta-lactams, which we tentatively name the S (substrate) and I (inhibitor) conformers. In the S conformers of all the beta-lactams, the amide oxygen and the carboxylic group conservatively interact with two zinc ions, while the substitutions on the fused rings show dramatic differences in their conformations and positions. Since the bridging hydroxide ion/water in the S conformer is at the position for the nucleophilic attack, the S conformation may simulate the true binding of a substrate to NDM-1. The I conformer either blocks or displaces the bridging hydroxide ion/water, such as in the case of aztreonam, and is thus inhibitory. The docking also suggests that substitutions on the beta-lactam ring are required for beta-lactams to bind in the S conformation, and therefore, small beta-lactams such as clavulanic acid would be inhibitors of NDM-1. Finally, our docking shows that moxalactam uses its tyrosyl-carboxylic group to compete with the S conformer and would thus be a poor substrate of NDM-1. PMID- 22825120 TI - First report of a Pseudomonas aeruginosa isolate coharboring KPC and VIM carbapenemases. PMID- 22825121 TI - Reduced expression of the rplU-rpmA ribosomal protein operon in mexXY-expressing pan-aminoglycoside-resistant mutants of pseudomonas aeruginosa. AB - Pan-aminoglycoside-resistant Pseudomonas aeruginosa mutants expressing the mexXY components of the aminoglycoside-accommodating MexXY-OprM multidrug efflux system but lacking mutations in the mexZ gene encoding a repressor of this efflux system and in the mexXY promoter have been reported (S. Fraud and K. Poole, Antimicrob. Agents Chemother. 55:1068-1074, 2011). Genome sequencing of one of these mutants, K2966, revealed the presence of a mutation within the predicted promoter region of the rplU-rpmA operon encoding ribosomal proteins L21 and L27, consistent with an observed 2-fold decrease in expression of this operon in the mutant relative to wild-type P. aeruginosa PAO1. Moreover, correction of the mutation restored rplU-rpmA expression and, significantly, reversed the elevated mexXY expression and pan-aminoglycoside resistance of the mutant. Reduced rplU-rpmA expression was also observed in a second mexXY-expressing pan-aminoglycoside-resistant mutant, K2968, which, however, lacked a mutation in the rplU-rpmA promoter region. Restoration of rplU-rpmA expression in the K2968 mutant following chromosomal integration of the rplU-rpmA operon derived from wild-type P. aeruginosa failed, however, to reverse the elevated mexXY expression and pan-aminoglycoside resistance of this mutant, although it did so for K2966, suggesting that the mutation impacting rplU-rpmA expression in K2968 also impacts other mexXY-related genes. Increased mexXY expression owing to reduced rplU-rpmA expression in K2966 and K2968 was dependent on PA5471, whose expression was also elevated in these mutants. Thus, mutational disruption of ribosome function, by limiting expression of ribosomal constituents, promotes recruitment of mexXY and does so via PA5471, reminiscent of mexXY induction by ribosome-disrupting antimicrobial agents. Interestingly, reduced rplU-rpmA expression was also observed in a mexXY expressing pan-aminoglycoside-resistant clinical isolate, suggesting that ribosome-perturbing mutations have clinical relevance in the recruitment of the MexXY-OprM aminoglycoside resistance determinant. PMID- 22825122 TI - Effect of reduced vancomycin susceptibility on clinical and economic outcomes in Staphylococcus aureus bacteremia. AB - Reduced vancomycin susceptibility (RVS) may lead to poor clinical outcomes in Staphylococcus aureus bacteremia. The objective of this study was to evaluate the clinical and economic impact of RVS in patients with bacteremia due to S. aureus. A cohort study of patients who were hospitalized from December 2007 to May 2009 with S. aureus bacteremia was conducted within a university health system. Multivariable logistic regression and zero-truncated negative binomial regression models were developed to evaluate the association of RVS with 30-day in-hospital mortality, length of stay, and hospital charges. One hundred thirty-four (34.2%) of a total of 392 patients had bacteremia due to S. aureus with RVS as defined by a vancomycin Etest MIC of >1.0 MUg/ml. Adjusted risk factors for 30-day in hospital mortality included the all patient refined-diagnosis related group (APRDRG) risk-of-mortality score (odds ratio [OR], 7.11; 95% confidence interval [CI], 3.04 to 16.6), neutropenia (OR, 13.4; 95% CI, 2.46 to 73.1), white blood cell count (OR, 1.05; 95% CI, 1.01 to 1.09), immunosuppression (OR, 6.31; 95% CI, 1.74 to 22.9), and intensive care unit location (OR, 3.51; 95% CI, 1.65 to 7.49). In multivariable analyses, RVS was significantly associated with increased mortality in patients with S. aureus bacteremia as a result of methicillin susceptible (OR, 3.90; 95% CI, 1.07 to 14.2) but not methicillin-resistant (OR, 0.53; 95% CI, 0.19 to 1.46) isolates. RVS was associated with greater 30-day in hospital mortality in patients with bacteremia due to methicillin-susceptible S. aureus but not methicillin-resistant S. aureus. Further research is needed to identify optimal treatment strategies to reduce mortality associated with RVS in S. aureus bacteremia. PMID- 22825123 TI - Systematic analysis of pyrazinamide-resistant spontaneous mutants and clinical isolates of Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is a first-line antitubercular drug known for its activity against persistent Mycobacterium tuberculosis bacilli. We set out to systematically determine the PZA susceptibility profiles and mutations in the pyrazinamidase (pncA) gene of a collection of multidrug-resistant tuberculosis (MDR-TB) clinical isolates and PZA-resistant (PZA(r)) spontaneous mutants. The frequency of acquired resistance to PZA was determined to be 10(-5) bacilli in vitro. Selection at a lower concentration of PZA yielded a significantly larger number of spontaneous mutants. The methodical approach employed allowed for determination of the frequency of the PZA(r) phenotype correlated with mutations in the pncA gene, which was 87.5% for the laboratory-selected spontaneous mutants examined in this study. As elucidated by structural analysis, most of the identified mutations were foreseen to affect protein activity through either alteration of an active site residue or destabilization of protein structure, indicating some preferential mutation site rather than random scattering. Twelve percent of the PZA(r) mutants did not have a pncA mutation, strongly indicating the presence of at least one other mechanism(s) of PZA(r). PMID- 22825125 TI - Hydroxyl radicals in ice: insights into local structure and dynamics. AB - The hydroxyl radical and its reactivity within ice environments are crucial to many important atmospheric reactions. The associated molecular mechanisms are largely unknown due to challenges posed by direct experimental measurements and computational studies of this transient species. Here we report insights into the local structure and behaviour of the hydroxyl radical in bulk ice through an extensive study utilizing Car-Parrinello molecular dynamics simulations. Interstitial and in-lattice hydroxyl radicals in hexagonal ice were investigated at primarily 190 K. Our findings, utilizing both HCTH/120 and BLYP functionals, show that OH* can exhibit greater mobility than other ice defects (the trapping energy estimated to be only 0.09 eV). We observe the formation of a two-center three-electron hemibond structure between the hydroxyl radical and an in-lattice water molecule; while controversial, such a structure in ice may be amenable to experimental detection due to its relative stability. Our results show that interstitial water molecules can strongly influence the mobility of the hydroxyl radical in bulk ice through the displacement of the radical to an interstitial location. We also demonstrate that the H-transfer reaction from an interstitial water to the radical is a rare event in ice. Together, these results predict that the radical can be a reactive species in bulk ice, as both interstitial and in lattice OH* can be available for reactions with other species. These microscopic insights should contribute to our understanding of the reactivity of OH* in ice and its implications to atmospheric reactions. PMID- 22825124 TI - Combination of voriconazole and anidulafungin for treatment of triazole-resistant aspergillus fumigatus in an in vitro model of invasive pulmonary aspergillosis. AB - Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of A. fumigatus strains with elevated voriconazole MICs. We used an in vitro model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment. PMID- 22825126 TI - Local delivery of slow-releasing temozolomide microspheres inhibits intracranial xenograft glioma growth. AB - BACKGROUND: Currently, treatment of malignant gliomas with temozolomide in addition to surgical resection and radiotherapy remains the foundation of glioma therapy. In an effort to develop new therapeutic choices to treat malignant gliomas, we have designed slow-releasing microspheres that deliver temozolomide (P-TMZ). The local continuous release of temozolomide at the intracranial tumor site may overcome many obstacles associated with systemic delivery, which will help to further improving the therapeutic effects against malignant gliomas. METHODS: Slow-releasing microspheres containing 10 % temozolomide were prepared, the antitumor efficacy in vitro was evaluated with MTT assay, and the therapeutic efficacy in vivo against gliomas was assessed in human glioma (SGH44) nude mice s.c. and orthotopic xenograft models. RESULTS: A single local injection of P-TMZ led to significant reduction both in s.c. and orthotopic human SHG44 glioma xenografts. P-TMZ, BCNU and TMZ had significant antiglioma effect (P < 0.01), their IC50 value was all less than 10 MUg/ml. Tumor inhibition ratio of P-TMZ, BCNU and TMZ in vivo was higher than empty microspheres P0 (P < 0.01); P-TMZ and BCNU showed higher antitumor efficacy than TMZ (P < 0.05). CONCLUSIONS: Our present results suggest that local delivery of slow-releasing temozolomide microspheres is effective for malignant gliomas. P-TMZ retained good antitumor activity and had better therapeutic effect against glioma both in vitro and in vivo, which provide a new choice for future clinical interstitial chemotherapy. PMID- 22825127 TI - Functional neuroimaging using ultrasonic blood-brain barrier disruption and manganese-enhanced MRI. AB - Although mice are the dominant model system for studying the genetic and molecular underpinnings of neuroscience, functional neuroimaging in mice remains technically challenging. One approach, Activation-Induced Manganese-enhanced MRI (AIM MRI), has been used successfully to map neuronal activity in rodents. In AIM MRI, Mn(2+) acts a calcium analog and accumulates in depolarized neurons. Because Mn(2+) shortens the T1 tissue property, regions of elevated neuronal activity will enhance in MRI. Furthermore, Mn(2+) clears slowly from the activated regions; therefore, stimulation can be performed outside the magnet prior to imaging, enabling greater experimental flexibility. However, because Mn(2+) does not readily cross the blood-brain barrier (BBB), the need to open the BBB has limited the use of AIM MRI, especially in mice. One tool for opening the BBB is ultrasound. Though potentially damaging, if ultrasound is administered in combination with gas-filled microbubbles (i.e., ultrasound contrast agents), the acoustic pressure required for BBB opening is considerably lower. This combination of ultrasound and microbubbles can be used to reliably open the BBB without causing tissue damage. Here, a method is presented for performing AIM MRI by using microbubbles and ultrasound to open the BBB. After an intravenous injection of perflutren microbubbles, an unfocused pulsed ultrasound beam is applied to the shaved mouse head for 3 minutes. For simplicity, we refer to this technique of BBB Opening with Microbubbles and UltraSound as BOMUS. Using BOMUS to open the BBB throughout both cerebral hemispheres, manganese is administered to the whole mouse brain. After experimental stimulation of the lightly sedated mice, AIM MRI is used to map the neuronal response. To demonstrate this approach, herein BOMUS and AIM MRI are used to map unilateral mechanical stimulation of the vibrissae in lightly sedated mice. Because BOMUS can open the BBB throughout both hemispheres, the unstimulated side of the brain is used to control for nonspecific background stimulation. The resultant 3D activation map agrees well with published representations of the vibrissae regions of the barrel field cortex. The ultrasonic opening of the BBB is fast, noninvasive, and reversible; and thus this approach is suitable for high-throughput and/or longitudinal studies in awake mice. PMID- 22825128 TI - Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. AB - The antitumor activity of oleanolic (OA) has attracted attention due to its marked antitumor effects and pharmacological safety. In the present study, the effects of the combination of OA and 5-fluorouracil (5-FU) on Panc-28 human pancreatic cells were studied. The results showed that combined use of OA and 5 FU synergistically potentiated cell death effects on Panc-28 cells, and the pro apoptotic effects were also increased. Further study revealed that the combined treatment could enhance mitochondrial depolarization, lysosomal membrane permeabilization (LMP) and leakage of cathepin D, while the release of cytochrome C did not display significant changes. The expression of apoptosis related proteins was also affected in cells treated with the combination of OA and 5-FU, including activation of caspases-3 and the expression of Bcl-2/Bax, survivin and NF-kappaB. Our results provide evidence that combination of OA and 5-FU may serve as a novel strategy for the treatment of pancreatic cancer. PMID- 22825129 TI - Geometric representation for partial polarization in three dimensions. AB - Recently, we described a geometric construction for determining the eigenvalues of the coherency matrix in three dimensions. We show that this leads directly to a representation of the three-dimensional degree of polarization in terms of a triangular composition plot, in which different polarization measures have simple properties and can be expressed in terms of the matrix invariants. This composition plot is an alternative to the spherical plot recently used to illustrate the degree of polarization in terms of entanglement. PMID- 22825130 TI - Method for improving the resolution and accuracy against birefringence dispersion in distributed polarization cross-talk measurements. AB - We present a novel method for improving the spatial resolution and amplitude accuracy of distributed polarization cross-talk measurements in a polarization maintaining (PM) fiber against its birefringence dispersion. We show that the broadening of measured polarization cross-talk peaks caused by birefringence dispersion can be restored by simply multiplying the measurement data with a compensation function. The birefringence dispersion variable in the function can be obtained by finding the widths of measured cross-talk envelopes at known distances along the fiber. We demonstrate that this method can effectively improve spatial resolution and amplitude accuracy of the space-resolved polarization cross-talk measurements of long PM fibers. PMID- 22825131 TI - Blind image deconvolution with spatially adaptive total variation regularization. AB - A blind deconvolution algorithm with spatially adaptive total variation regularization is introduced. The spatial information in different image regions is incorporated into regularization by using the edge indicator called difference eigenvalue to distinguish edges from flat areas. The proposed algorithm can effectively reduce the noise in flat regions as well as preserve the edge and detailed information. Moreover, it becomes more robust with the change of the regularization parameter. Comparative results on simulated and real degraded images are reported. PMID- 22825132 TI - High-throughput rear-surface drilling of microchannels in glass based on electron dynamics control using femtosecond pulse trains. AB - This study proposes a rear-surface ablation enhancement approach to fabricate high-aspect-ratio microchannels by temporally shaping femtosecond laser pulse trains. In the case study of K9 glass, enhancements of up to a 56 times higher material removal rate and a three times greater maximum drilling depth are obtained by the proposed method, as compared with conventional femtosecond laser drilling at the same processing parameters. The improvements are due to the changes of photon-electron interactions by shaping femtosecond pulse train, which can effectively adjust the photon absorption and localized transient material properties by changing electron dynamics such as free electron densities. PMID- 22825133 TI - Tomographic imaging of a suspending single live cell using optical tweezer combined full-field optical coherence tomography. AB - We propose a label-free depth-resolved tomographic scheme for imaging a single live cell in fluid. This approach utilizes a modified time-domain full-field optical coherence tomography (FF-OCT) system combined with an optical tweezer technique. The optical trap for holding a moving specimen is made by tightly focusing a 1064 nm Q-switching pulsed laser beam with a 1.0 NA microscope objective in the sample arm of the FF-OCT part. By cosharing the probe for both systems, the optical actions of trapping and cellular resolution tomographic imaging could be achieved simultaneously. Feasibility of the combined system is demonstrated by imaging micron-sized polystyrene beads and a living suspension cell in medium. PMID- 22825134 TI - Scattering forces and electromagnetic momentum density in crossed circularly polarized standing waves. AB - We analyze the forces on a small dipolar particle and the electromagnetic momentum density in a configuration consisting in two perpendicular circularly polarized stationary waves. The field distribution shows regions in which the electric and magnetic fields are parallel corresponding to a null Poynting vector. Although the average value of the momentum density, proportional to the Poynting vector, is zero in these regions, there are scattering forces acting on small particles due to light's spin force. The total scattering force suggests a new definition of the average value of the momentum density for free propagating electromagnetic fields. PMID- 22825135 TI - Continuous-wave wavelength conversion for high-power applications using an external cavity diamond Raman laser. AB - We demonstrate continuous-wave (cw) operation of a diamond Raman laser at 1240 nm in an external cavity configuration. The output power increased linearly with pump power with a 49.7% slope efficiency and reached 10.1 W at the maximum available pump power of 31 W. The combination of resonator design with diamond provides a novel approach to power-scalable cw wavelength and beam conversion. PMID- 22825136 TI - Optical rectification effect due to surface plasmon polaritons at normal incidence in a nondiffraction regime. AB - We carried out an experimental and numerical investigation of photoinduced voltage at normal incidence in the nondiffraction regime, which was not predicted to occur by the simple momentum conservation model. We prepared two samples: one having space inversion symmetry and the other without this feature. At normal incidence in the nondiffraction regime, we observed a finite signal only for the asymmetric structure. We found that surface plasmon polaritons (SPPs) are excited by the signal and are attributed to the origin of the voltage. We also evaluated the radiation force of light by using the Maxwell stress tensor and found that pressure of light and not shear force is mainly induced in the structure due to the asymmetric excitation of SPPs. PMID- 22825137 TI - Broadband noncollinear optical parametric amplification without angularly dispersed idler. AB - We report a new scheme for direct generation of broadband angular-dispersion-free mid-IR idler pulses via noncollinear optical parametric amplification when group velocity matched wavelengths cannot be found and the traditional noncollinear geometry fails to increase the phase-matching bandwidth. The scheme does not require any post-amplification idler angular dispersion compensation. We derive and interpret the condition for broadband amplification and absence of idler angular dispersion. A broadband angular-dispersion-free 2.15 MUm idler pulse is generated as an experimental demonstration. We identify the potential of the scheme to generate a broadband 3.5 MUm idler, with a bandwidth supporting a sub two-cycle pulse. PMID- 22825138 TI - Broadband self-pulsating fiber laser based on soliton self-frequency shift and regenerative self-phase modulation. AB - We demonstrate experimentally and numerically the operation of a self-pulsating fiber laser based on the cascaded effects of soliton self-frequency shift and self-phase modulation spectral broadening. The combination of those two effects triggers and sustains the propagation of picosecond pulses in the cavity. At one of the outputs, the laser emits a supercontinuum with spectral width in excess of 150 nm at the repetition rate of 95 kHz. PMID- 22825139 TI - Speckle-metric-optimization-based adaptive optics for laser beam projection and coherent beam combining. AB - Maximization of a projected laser beam's power density at a remotely located extended object (speckle target) can be achieved by using an adaptive optics (AO) technique based on sensing and optimization of the target-return speckle field's statistical characteristics, referred to here as speckle metrics (SM). SM AO was demonstrated in a target-in-the-loop coherent beam combining experiment using a bistatic laser beam projection system composed of a coherent fiber-array transmitter and a power-in-the-bucket receiver. SM sensing utilized a 50 MHz rate dithering of the projected beam that provided a stair-mode approximation of the outgoing combined beam's wavefront tip and tilt with subaperture piston phases. Fiber-integrated phase shifters were used for both the dithering and SM optimization with stochastic parallel gradient descent control. PMID- 22825140 TI - Compact optical function generator. AB - We demonstrate the use of a nonlinear photonic crystal to generate a harmonic comb and an ultrabroad-band acousto-optic modulator for the field amplitudes and phases of the comb to succeed in synthesizing femtosecond and subfemtosecond optical field waveforms. Nonsinusoidal fields of various shapes are synthesized and verified using shaper-assisted linear cross-correlation. The compact all solid-state system could lead to the realization of a portable arbitrary optical waveform synthesizer that is analogous in many aspects to an RF function generator. PMID- 22825141 TI - Giant light extraction enhancement of medical imaging scintillation materials using biologically inspired integrated nanostructures. AB - We have utilized biologically inspired (bio-inspired), moth-eye nanostructures and further improved this biomimetic structure to enhance the scintillator materials external quantum efficiency significantly. As a proof of concept, we have demonstrated very high light output efficiency enhancement for Lu(2)SiO(5):Ce(3+) (LSO:Ce) film in large area, the X-ray mammographic instrument was employed to demonstrate the light output enhancement of the Lu(2)SiO(5):Ce thin film with biologically inspired (bio-inspired) moth-eye-like nanophotonic structures. Our work could be extended to other thin film scintillator materials and is promising to achieve lower patient dose, higher resolution images of human organs and even smaller scale medical imaging. PMID- 22825142 TI - Coherence time measurements using a single detector with variable time resolution. AB - We present a simple technique for measuring coherence times for stationary light fields using a single detector with tunable time resolution. By measuring the equal-time second-order correlation function at varying instrument response functions it is possible to determine the coherence time and also the shape of the temporal decay without the need to record time-resolved data. The technique is demonstrated for pseudothermal light. Possible applications for dynamic light scattering and photon statistics measurements are discussed. PMID- 22825143 TI - Internal Q-switching and self-optical parametric oscillation in a two-dimensional periodically poled Nd:MgO:LiNbO3 laser. AB - We report on an internally Q-switched self-optical parametric oscillator (SOPO) based on a monolithic two-dimensional (2D) periodically poled Nd:MgO:LiNbO(3) (Nd:MgO:PPLN) integrating three device functionalities of a laser gain medium, an electro-optic Bragg Q-switch, and an optical parametric gain medium (OPGM). The quasi-phase-matching conditions required by the Bragg Q-switch and OPGM are both satisfied in the 2D nonlinear photonic crystal (NPC) structure formed in the Nd:MgO:PPLN. A 1525 nm signal with a pulse energy of ~3.3 MUJ (>350 W peak power) was obtained from the SOPO at 8.5 W diode pump power. An off-angle signal at 1612 nm, amplified by a unique gain-enhancement effect in this 2D NPC, was also observed. Tuning of the SOPO in the eye-safe region was demonstrated. PMID- 22825144 TI - Simultaneous passively Q-switched dual-wavelength solid-state laser working at 1065 and 1066 nm. AB - A passively Q-switched dual-wavelength solid-state laser is presented. The two wavelengths are emitted by two different crystals in order to avoid gain competition, and the synchronization between the pulses is obtained by external triggering of the saturable absorber. Sum frequency mixing is demonstrated, proving the interest of this source for terahertz generation in the 0.3-0.4 THz range through difference frequency generation. PMID- 22825145 TI - Generation of linear and nonlinear nonparaxial accelerating beams. AB - We study linear and nonlinear self-accelerating beams propagating along circular trajectories beyond the paraxial approximation. Such nonparaxial accelerating beams are exact solutions of the Helmholtz equation, preserving their shapes during propagation even under nonlinearity. We generate experimentally and observe directly these large-angle bending beams in colloidal suspensions of polystyrene nanoparticles. PMID- 22825146 TI - Electro-optically generating and controlling right- and left-handed circularly polarized multiring modes of light beams. AB - We propose a simple method for generating and controlling right- and left-handed circularly polarized (RHP and LHP) multiring modes of light beams by means of Pockels effect in a single strontium barium niobate (SBN) crystal. The numerical results show that an LHP Laguerre-Gaussian LG(0l) beam, propagating along the optical axis of the crystal, will partly turn into an RHP vortex light field of order l+2. Moreover, a pair of the LHP and RHP components of the output light field is LG-like modes sharing an identically radial index, which is electro optically controllable. The power ratio between these two components depends on the applied electric field and the mode of input beam. PMID- 22825147 TI - Wave propagation in deep-subwavelength mode waveguides. AB - This Letter proposes a dielectric waveguide with deep-subwavelength mode sizes. Results of both frequency domain and time domain analysis show that the effective mode area is below lambda(0)(2)/400 and can even reach lambda(0)(2)/1000 (lambda(0) is the wavelength in vacuum). The effective electrical mode area can be comparable to that of a hybrid plasmonic subwavelength confinement waveguide, with reduced optical absorption. In contrast to slot waveguides, which guide light in low-index materials, the proposed structure guides light in high-index materials. Results obtained in this Letter show that the losses are sensitive to the surface roughness on the tens of nanometers scale. The structure can be used to design ring resonators with a quality factor comparable to that of a diffraction-limited dielectric ring resonator with the same standing wave numbers. The property can be applied in nonlinear effect enhancement or laser design with ultralow threshold. PMID- 22825148 TI - Measurement of two-mode squeezing with photon number resolving multipixel detectors. AB - The measurement of the two-mode squeezed vacuum generated in an optical parametric amplifier (OPA) was performed with photon number resolving multipixel photon counters (MPPCs). Implementation of the MPPCs allows for the observation of noise reduction in a broad dynamic range of the OPA gain, which is inaccessible with standard single photon avalanche photodetectors. PMID- 22825149 TI - Diffractive coherent combining of a 2.5 kW fiber laser array into a 1.9 kW Gaussian beam. AB - Five 500 W fiber amplifiers were coherently combined using a diffractive optical element combiner, generating a 1.93 kW beam whose M(2)=1.1 beam quality exceeded that of the inputs. Combining efficiency near 90% at low powers degraded to 79% at full power owing to thermal expansion of the fiber tip array. PMID- 22825150 TI - Mueller matrices in fluorescence scattering. AB - A reappraisal of the 1929 analysis of luminescence by Soleillet reveals the form of the Mueller matrix for fluorescence scattering whose parameters are directly defined in terms of the now-familiar fluorescence anisotropy parameter. If the scattering analyte is optically active, it is further shown how fluorescence detected circular dichroism and circularly polarized luminescence can be recovered, simultaneously and free of artifacts. PMID- 22825151 TI - Cascaded carbon monoxide laser frequency conversion into the 4.3-4.9 MUm range in a single ZnGeP2 crystal. AB - Collinear cascaded mid-IR frequency conversion in a single nonlinear optical crystal was accomplished. Concurrent collinear generation of the sum frequency of multiline fundamental band carbon monoxide laser radiation as a first frequency conversion cascade resulted in collinear difference frequency generation within the 4.3 to 4.9 MUm spectral range when mixing this sum frequency radiation with the fundamental one as the second cascade in the same ZnGeP(2) nonlinear optical crystal. PMID- 22825152 TI - Optically compensated dual-polarization interferometric fiber-optic gyroscope. AB - We first introduce optical compensation into the field of interferometric fiber optic gyroscopes (IFOGs), using the opposite polarity of the disturbance between two orthogonal polarization states to suppress polarization-fluctuation-induced noise. A dual-polarized IFOG, in which the fast and slow axes of polarization maintaining fiber work simultaneously, is implemented and tested. Interference signals of the two axes are added to achieve optical compensation. Experiments show that the IFOG's sensitivity is effectively enhanced in compensated output: all Allan variance indices are improved, among which bias instability is reduced from 0.335 and 0.227 deg/h(fast and slow axes output, respectively) to 0.061 deg/h. PMID- 22825153 TI - Tailoring the behavior of optical microcavities with high refractive index sol gel coatings. AB - Silica optical resonators with high quality factors, small mode volumes, and high refractive index contrast are desirable in many applications throughout the fundamental and applied sciences. However, these parameters are not easily modified in plain silica devices. In the present work, we theoretically and experimentally demonstrate the use of high refractive index sol-gel coatings to achieve a significant reduction in mode volume of silica toroids while maintaining high quality factors. In addition to tuning the mode volume, the presence of the coating changes both the location and shape of the optical field. PMID- 22825154 TI - Highly sensitive laser-based sensor for nanoparticles in air using a dual-ring mirror setup. AB - One of the most frequently applied techniques to detect nanoparticles in air is analyzing laser light scattering. This technique is very flexible while offering high accuracy and reliability. Yet its functionality highly depends on the sensitivity of the measurement system components. Especially for miniaturized sensor devices with limited space, additional techniques are needed to preserve high intensity of scattered light. In our work we demonstrate a technique using two spherical ring mirrors to identify nanoparticles with diameters below 100 nm in a forward-scattering setup. We succeeded measuring polystyrene particles with diameters of 92 nm with a signal-to-noise-ratio of more than 10. PMID- 22825155 TI - Optimized light-matter interaction and defect hole placement in photonic crystal cavity sensors. AB - Photonic crystal slab cavities were investigated for increased light-matter interaction based on selective placement of sublattice hole sized defect holes inside L3 cavities. A multiple-hole defect (MHD) consisting of three defect holes placed in the regions of highest cavity mode field intensity were demonstrated through finite-difference time-domain simulations and experiments to exhibit the strongest light-matter interaction without introducing significant scattering losses. Compared to an L3 cavity without defect holes, these strategically designed three-hole MHD cavities presented higher quality factor and more than double the resonance wavelength shift upon exposure to a thin oxide and two small chemical molecules. PMID- 22825156 TI - Manipulating stored images with phase imprinting at low light levels. AB - Coherent manipulation of stored images is performed at low light levels based on enhanced cross-Kerr nonlinearity in a four-level N-type electromagnetically induced transparency (EIT) system. Using intensity masks in the signal pulse, quadratic phase shifts with low nonlinear absorption can be efficiently imprinted on the Fraunhofer diffraction patterns already stored in the EIT system. Fast Fourier-transform-based numerical simulations clearly demonstrate that the far field images of the retrieved probe light can be flexibly modulated by applying different signal fields. Our studies could help advance the goals of nonlinear all-optical processing for spatial information coherently stored in EIT systems. PMID- 22825158 TI - Dual-polarization mode-locked Nd:YAG laser. AB - A mode-locked solid-state laser containing a birefringent element is shown to emit synchronously two frequency combs associated to the two polarization eigenstates of the cavity. An analytical model predicts the polarization evolution of the pulse train, which is determined by the adjustable intracavity birefringence. Experiments realized with a Nd:YAG laser passively mode locked by a semiconductor saturable absorber mirror are in perfect agreement with the model. Locking between the two combs arises for particular values of their frequency difference, e.g., half the repetition rate, and the pulse train polarization sequence is then governed by the relative overall phase offset of the two combs. PMID- 22825157 TI - Imaging skins: an imaging modality with ultra-thin form factor. AB - Reduction of the volume and mass of an imaging system would be advantageous in a variety of applications. However, the far-field resolution of any such system is fundamentally limited by aperture size. We present a new imaging modality based on waveguide coupling that is completely confined to a two-dimensional surface. One such imaging skin was shown to have the same resolution as a 0.5 cm diameter lens while maintaining an imaging system depth of a few micrometers. PMID- 22825159 TI - High power single frequency solid state master oscillator power amplifier for gravitational wave detection. AB - High power single frequency, single mode, linearly polarized laser output at the 1 MUm regime is in demand for the interferometric gravitational wave detectors (GWDs). A robust single frequency solid state master oscillator power amplifier (MOPA) is a promising candidate for such applications. We present a single frequency solid state multistage MOPA system delivering 177 W of linearly polarized output power at 1 MUm with 83.5% TEM(00) mode content. PMID- 22825160 TI - Buffer-gas-assisted polarization spectroscopy of 6Li. AB - We report on the demonstration of Doppler-free polarization spectroscopy of the D2 line of (6)Li atoms. Counterintuitively, the presence of an Ar buffer gas, in a certain pressure range, causes a drastic enhancement of the polarization rotation signal. The observed dependence of the signal amplitude on the Ar buffer pressure and the pump laser power is reproduced by calculations based on simple rate equations. We performed stable laser frequency locking using a dispersion signal obtained by polarization spectroscopy for laser cooling of (6)Li atoms. PMID- 22825161 TI - Proton acceleration to 40 MeV using a high intensity, high contrast optical parametric chirped-pulse amplification/Ti:sapphire hybrid laser system. AB - Using a high-contrast (10(10):1) and high-intensity (10(21) W/cm(2)) laser pulse with the duration of 40 fs from an optical parametric chirped-pulse amplification/Ti:sapphire laser, a 40 MeV proton bunch is obtained, which is a record for laser pulse with energy less than 10 J. The efficiency for generation of protons with kinetic energy above 15 MeV is 0.1%. PMID- 22825162 TI - Speckle reduction of endovascular optical coherence tomography using a generalized divergence measure. AB - Endovascular optical coherence tomography (EV-OCT) is an emerging intravascular imaging technique for observing blood vessel walls. Fluctuating speckle noise, especially during rapid pull-back, can severely degrade the visibility of morphological structures. Moreover, the speckle pattern varies in different parts of the image due to beam divergence and is further complicated by interpolation through the coordinate transformation necessary for displaying the rotary scanning images, challenging the use of frequency domain analysis. In this study, a computationally efficient method using a generalized divergence regularization procedure is presented to suppress speckle noise in EV-OCT images. Results show substantial smoothing of the grainy appearance and enhanced visualization of deeper structures as demonstrated in porcine carotid arteries. PMID- 22825163 TI - Coherent artifact in modern pulse measurements. AB - We simulate multishot intensity-and-phase measurements of unstable trains of complex ultrashort pulses using second-harmonic-generation (SHG) frequency resolved optical gating (FROG) and spectral-phase interferometry for direct electric-field reconstruction (SPIDER). Both techniques fail to see the pulse structure. But FROG yields the correct average pulse duration and suggests the instability by exhibiting significant disagreement between measured and retrieved traces. SPIDER retrieves the correct average spectral phase but significantly underestimates the average pulse duration. In short, SPIDER measures only the coherent artifact. An analytical calculation confirms this last fact. PMID- 22825164 TI - Single-fiber diffuse optical time-of-flight spectroscopy. AB - We demonstrate interstitial diffuse optical time-of-fight spectroscopy based on a single fiber for both light delivery and detection. Detector saturation due to the massive short-time reflection is avoided by ultrafast gating of a single photon avalanche diode. We show that the effects of scattering and absorption are separable and that absorption can be assessed independently of scattering. Measurements on calibrated liquid phantoms and subsequent Monte Carlo-based evaluation illustrate that absorption coefficients can be accurately assessed over a wide range of medically relevant optical properties. Our findings pave the way to simplified and less invasive interstitial in vivo spectroscopy. PMID- 22825165 TI - Finite-difference time-domain technique as an efficient tool for calculating the regularized Green function: applications to the local-field problem in quantum optics for inhomogeneous lossy materials. AB - The calculation of the local density of states (LDOS) in lossy materials has long been disputed due to the divergence of the homogeneous Green function with equal space arguments. For arbitrary-shaped lossy structures, such as those of interest in nanoplasmonics, this problem is particularly challenging. A nondivergent LDOS obtained in numerical methods such as the finite-difference time-domain (FDTD) technique, at first sight appears to be wrong. Here we show that FDTD is not only an ideal choice for obtaining the regularized LDOS, but it can address the local field problem for any lossy inhomogeneous material. We exemplify the case of a finite-size photon emitter (e.g., a single quantum dot) embedded within and outside a lossy metal nanoparticle and show excellent agreement with analytical results. PMID- 22825166 TI - Low-loss germanium strip waveguides on silicon for the mid-infrared. AB - Mid-infrared photonics in silicon needs low-loss integrated waveguides. While monocrystalline germanium waveguides on silicon have been proposed, experimental realization has not been reported. Here we demonstrate a germanium strip waveguide on a silicon substrate. It is designed for single mode transmission of light in transverse magnetic (TM) polarization generated from quantum cascade lasers at a wavelength of 5.8 MUm. The propagation losses were measured with the Fabry-Perot resonance method. The lowest achieved propagation loss is 2.5 dB/cm, while the bending loss is measured to be 0.12 dB for a 90 degrees bend with a radius of 115 MUm. PMID- 22825167 TI - Dual-modulation fiber Fabry-Perot interferometer with double reflection for slowly-varying displacements. AB - This Letter describes a dual-amplitude modulation technique incorporated into a double reflection extrinsic-type fiber Fabry-Perot interferometer to measure periodic, nonperiodic as well as quasi-static displacements. The modulation scheme simultaneously maintains the interference signal pair in quadrature and provides a reference signal for displacements inferior to a quarter of the source wavelength. The control and phase demodulation of the interferometer carried out via software enable quasi-real-time measurement and facilitates sensor alignment. The sensor system can be exploited in the low frequency range from 10(-3) to ~500 Hz and has a resolution better than 2.2 nm, targeting applications in geophysics. PMID- 22825168 TI - Generalized optical interferometry for modal analysis in arbitrary degrees of freedom. AB - We generalize the traditional concept of temporal optical interferometry to any degree of freedom of a coherent optical field. By identifying the structure of a unitary optical transformation that we designate the generalized phase operator, we enable optical interferometry to be carried out in any modal basis describing a degree of freedom. The structure of the generalized phase operator is that of a fractional optical transform, thus establishing the connection between fractional transforms, optical interferometry, and modal analysis. PMID- 22825169 TI - Self-referenced spectral interferometry for ultrashort infrared pulse characterization. AB - We demonstrate for the first time (to our knowledge) characterization of ultrashort IR pulses by self-referenced spectral interferometry. Both sub-55-fs pulses from 1.4 MUm to 2 MUm and broadband 2.5-cycle pulses at 1.65 MUm (13 fs FWHM) are characterized. PMID- 22825170 TI - Multiplexing of encrypted data using fractal masks. AB - In this Letter, we present to the best of our knowledge a new all-optical technique for multiple-image encryption and multiplexing, based on fractal encrypting masks. The optical architecture is a joint transform correlator. The multiplexed encrypted data are stored in a photorefractive crystal. The fractal parameters of the key can be easily tuned to lead to a multiplexing operation without cross talk effects. Experimental results that support the potential of the method are presented. PMID- 22825171 TI - 250 W single-crystal fiber Yb:YAG laser. AB - We demonstrate an Yb:YAG single-crystal fiber laser with 251 W output power in continuous-wave and an optical efficiency of 44%. This performance can be explained by the high overlap between pump and signal beams brought by the pump guiding and by the good thermal management provided by the single-crystal fiber geometry. The oscillator performance with a reflectivity of the output coupler as low as 20% also shows high potential for power amplification. PMID- 22825172 TI - Integrated and compact fiber-coupled single-photon system based on nitrogen vacancy centers and gradient-index lenses. AB - A fiber-coupled single-photon system is presented. Gradient-index lenses are utilized for single-photon collection and fiber coupling of a nitrogen-vacancy defect center in a nanodiamond. Integrated filter technology separates excitation and laser light. Therefore, the system is ultracompact with 120 mm(3) in dimension as no bulky free beam optics are used. The commercial availability of all components and their simple assembly allows the implementation of a low-cost single-photon system, possibly approaching single-photon count rates of 500 kcts/s. PMID- 22825173 TI - Continuous wave mirrorless lasing in cholesteric liquid crystals with a pitch gradient across the cell gap. AB - Despite numerous efforts, continuous wave (CW) lasing in dye doped, one dimensional (1D) photonic bandgap cholesteric liquid crystal (CLC) structures has not been previously reported, to our knowledge. Here we report on the observation of lasing in such structures under both coherent (laser) and incoherent (LED) CW light excitation. To achieve this effect, we used a 1D-photonic bandgap structure made of a polymer stabilized CLC with a pitch gradient across the cell thickness. A spectral reflectivity profile of such a CLC structure reveals local minima in the area within a photonic stopband and close to it. The realization of lasing pumped by low power CW light sources opens the possibility of all-organic, compact, tunable CW lasers for display and medical applications. PMID- 22825174 TI - Optical field enhancement in nanoscale slot waveguides of hyperbolic metamaterials. AB - Nanoscale slot waveguides of hyperbolic metamaterials are proposed and demonstrated for achieving large optical field enhancement. The dependence of the enhanced electric field within the air slot on waveguide mode coupling and permittivity tensors of hyperbolic metamaterials is analyzed both numerically and analytically. Optical intensity in the metamaterial slot waveguide can be more than 25 times stronger than that in a conventional silicon slot waveguide, due to tight optical mode confinement enabled by the ultrahigh refractive indices supported in hyperbolic metamaterials. The electric field enhancement effects are also verified with the realistic metal-dielectric multilayer waveguide structure. PMID- 22825175 TI - Efficient distributed control of light-emitting diode array lighting systems. AB - We consider illumination rendering with distributed control of a lighting system with an array of light-emitting diodes (LEDs). As low-cost microprocessors become standard components in LED drivers, distributing the computation of the control signals to individual LED drivers becomes attractive. Common distributed control algorithms require each individual controller to exchange information with all the others and process it. This incurs too large a communication and processing overhead for a low-cost local controller. In this Letter, we propose a distributed control algorithm for achieving global illumination rendering, wherein a controller only needs to communicate within a selected neighborhood. We present design criteria for defining the communication neighborhood and study its impact on rendering performance. PMID- 22825177 TI - Measurement of air refractive index based on surface plasmon resonance and phase detection. AB - A method for refractive index of air measurement is presented based on surface plasmon resonance (SPR) and phase detection using a dual-frequency laser interferometer. Theoretical analyses indicate that the phase-difference variation of the measurement signal versus the reference signal is linear with refractive index of air (RIA) fluctuation, and the calculation formula of RIA is derived. The structure design of the self-adaptive SPR sensor greatly reduces the measurement error resulting from the incident angle shift and improves the sensitivity. The experiments show that measurement uncertainty of 10(-6) order has been achieved when phase detection precision is 0.1 degrees . The phenomenon of sudden phase variation during air pumping and air filling, which is caused by temperature fluctuation, is discussed. PMID- 22825176 TI - Remotely scanned multiphoton temporal focusing by axial grism scanning. AB - A simple technique for remote scanning of the focal plane in temporal focusing multiphoton microscopy is demonstrated both theoretically and experimentally. A new on-axis light propagation optical setup design enables this scanning, which was considered not feasible in previous studies. The focal plane is axially displaced by the movement of a remote optical device, consisting of a double prism grating, and optionally a cylindrical lens. The displacement is linear, and its slope is inversely proportional to the square of the optical system's magnification. PMID- 22825178 TI - Narrowband optical parametric gain in slow mode engineered GaInP photonic crystal waveguides. AB - We predict narrowband parametric amplification in dispersion-tailored photonic crystal waveguides made of gallium indium phosphide. We use a full-vectorial model including the dispersive nature both of the nonlinear response and of the propagation losses. An analytical formula for the gain is also derived. PMID- 22825179 TI - Resolving vibrational wave-packet dynamics of D2(+) using multicolor probe pulses. AB - We demonstrate the generation and real-time observation of the vibrational wave packet of D(2)(+) by using a sub-10-fs extreme UV high-harmonic pump pulse and a three-color probe laser pulse whose wavelength ranges from near-IR to vacuum UV. This multicolor pump-probe scheme can provide us with a powerful experimental tool for investigating a variety of wave packets evolving with a time scale of ~20 fs. PMID- 22825180 TI - Microfiber Fabry-Perot interferometer fabricated by taper-drawing technique and its application as a radio frequency interrogated refractive index sensor. AB - We propose a novel fiber Fabry-Perot interferometer (FPI) that incorporates a length of microfiber as its cavity and two fiber Bragg gratings (FBGs) as reflectors. The microfiber FPI is simply fabricated by flame-heated taper-drawing the central spot of an FBG into a section of microfiber. Ambient refractive index (RI) influences the effective index of microfiber, and thus the free spectrum range of the microfiber FPI, resulting in RI sensing. A dual-wavelength fiber laser based on the microfiber FPI is constructed, enabling radio frequency interrogation with high resolution. RI sensitivity of 911 MHz/RIU is experimentally demonstrated for microfiber FPI with equivalent diameter of 1.455 MUm. Simulation results indicate that the sensitivity can be further enhanced by reducing the diameter of the microfiber. PMID- 22825181 TI - Widely tunable midinfrared difference frequency generation in orientation patterned GaAs pumped with a femtosecond Tm-fiber system. AB - We demonstrate a midinfrared source tunable from 6.7 to 12.7 MUm via difference frequency generation (DFG) in orientation-patterned GaAs, with 1.3 mW average output power. The input pulses are generated via Raman self-frequency shift of a femtosecond Tm-doped-fiber laser system in a fluoride fiber. We numerically model the DFG process and show good agreement between simulations and experiments. We use this numerical model to show an improved design using longer pump pulses. PMID- 22825182 TI - Dispersion-dominated nonlinear fiber-optic channel. AB - We propose to apply a large predispersion (having the same sign as the transmission fiber) to an optical signal before the uncompensated fiber transmission in coherent communication systems. This technique is aimed at simplification of the following digital signal processing of nonlinear impairments. We derive a model describing pulse propagation in the dispersion dominated nonlinear fiber channel. In the limit of very strong initial predispersion, the nonlinear propagation equations for each Fourier mode become local and decoupled. This paves the way for new techniques to manage fiber nonlinearity. PMID- 22825183 TI - Two-dimensional light confinement in cross-index-modulation plasmonic waveguides. AB - We report a numerical study of plasmonic waveguides that localize light in two dimensions at a cross section of 4.2 nm * 2.1 nm with the propagation length of 38 MUm. By varying the geometrical parameters, strong mode confinements (range from lambda(2)/3352 to lambda(2)/2557525) are achieved with controllable propagation distance (44.68-40.988 MUm), and mode size below 1 nm(2) has been demonstrated for the first time. Furthermore, a cross-index-modulation mechanism is proposed to explain the strong field localization behavior, providing guidelines for future waveguide designs. PMID- 22825184 TI - Refraction-based photonic crystal diode. AB - A system composed of air holes in a dielectric host to form two square photonic crystals, with the same orientation and lattice constant but different scatterer radii, making an interface along their body diagonals, is numerically demonstrated to facilitate unidirectional light transmission. Band structure computations are carried out via the plane wave expansion method, whereas finite difference time-domain simulations are carried out to investigate the transient behavior. Unidirectional light transmission is achieved over two adjacent stop bands along the GammaX direction, which are circumvented in the forward direction by scaling down the wave vector and rotating the surface normal. Contrast ratios as high as 0.9 are attained within the lower stop band. PMID- 22825185 TI - Self-homodyne detection of the light orbital angular momentum. AB - A simple optical system for the self-homodyne detection of the orbital angular momentum (OAM) carried by optical beams is introduced. We propose two different schemes based on the use of optical hybrids, which could detect the OAM mode number, even when the input beam might be slightly distorted. A balanced receiver is used to perform a self-homodyne measure of the optical signal from two different locations at the beam wavefront. PMID- 22825186 TI - Optical determination of vacuum Rabi splitting in a semiconductor quantum dot induced by a metal nanoparticle. AB - We propose a theoretical scheme to determine the vacuum Rabi splitting in a single semiconductor quantum dot (SQD) induced by a metal nanoparticle (MNP). Based on cavity quantum electrodynamics, the exciton-plasmon interaction between the SQD and the MNP is considered while a strong pump laser and a weak probe laser are simultaneously presented. By decreasing the distance between them, we can increase the coupling strength. At resonance, thanks to the strong coupling, a vacuum Rabi splitting can be observed clearly in the probe absorption spectrum. The coupling strength can be obtained by measuring the vacuum Rabi splitting. This strong coupling is significant for the investigation of surface-plasmon based quantum information processing. PMID- 22825187 TI - Excitation of a nanowire "molecule" in gold-filled photonic crystal fiber. AB - A pair of gold nanowires, incorporated into a photonic crystal fiber, acts as a plasmonic "molecule." Hybridized modes are excited at specific wavelengths by launching light into the glass core. The formation of bonding and antibonding solutions results in a modal splitting of more than 100 nm, even though the spatial separation between the wires is larger than 3 MUm. The study provides insight into multiwire plasmonic devices with applications as polarizers or filters in near-field optics, nonlinear plasmonics, optical sensing, and telecommunications. PMID- 22825188 TI - Selective edge enhancement in three-dimensional vortex imaging with incoherent light. AB - We demonstrate a new imaging method enabling a selective edge contrast enhancement of three-dimensional amplitude objects with spatially incoherent light. The imaging process is achieved in a spiral modification of Fresnel incoherent correlation holography and uses a vortex impulse response function. The correlation recordings of the object are acquired in a one-way interferometer with the wavefront division carried out by a spatial light modulator. Two different methods based on applying a helical reference wave in the hologram recording and a digital spiral phase modulation in image reconstruction are proposed for edge enhancement of amplitude objects. Results of both isotropic and anisotropic spiral imaging are demonstrated in experiments using an LED as an incoherent source of light. PMID- 22825189 TI - Coherence-multiplexed, label-free biomolecular interaction analysis. AB - This Letter describes an interferometric technique based on the principle of coherence multiplexing for multichannel, label-free biosensing applications. Multiple biosensors can be interrogated simultaneously with a single spectral domain, phase-sensitive interferometer by coding the individual sensograms in coherence-multiplexed channels. The experimental results demonstrate the multiplexed quantitative biomolecular interaction of antibodies binding to antigen-coated functionalized biosensor chip surfaces. The described technique also applies to a variety of other distributed and multiplexed sensing applications besides biosensing. PMID- 22825190 TI - Three-dimensional photoprecipitation of oriented LiNbO3-like crystals in silica based glass with femtosecond laser irradiation. AB - We demonstrate crystals (LiNbO(3)-like) that were space-selectively nucleated and grown in the bulk of silica-based glass by femtosecond laser irradiation at a high repetition rate (typ. 300 kHz). Oriented crystals with their polar axis mostly aligned with or perpendicular to the laser scanning direction have been fabricated by manipulation of the temperature gradient in adjusting the laser parameters. The mechanism for the orientation of femtosecond laser-induced crystallization is briefly discussed. PMID- 22825191 TI - Subfemtosecond synchronization of microwave oscillators with mode-locked Er-fiber lasers. AB - We synchronize an 8.06 GHz microwave signal from a voltage-controlled oscillator with an optical pulse train from a 77.5 MHz mode-locked Er-fiber laser using a fiber-based optical-microwave phase detector. The residual phase noise between the optical pulse train and the synchronized microwave signal is -133 dBc/Hz ( 154 dBc/Hz) at 1 Hz (5 kHz) offset frequency, which results in 838 as integrated rms timing jitter [1 Hz-1 MHz]. The long-term residual phase drift is 847 as (rms) measured over 2 h, which reaches 4*10(-19) fractional frequency instability at 1800 s averaging time. This method has a potential to provide both subfemtosecond-level short-term phase noise and long-term phase stability in microwave extraction from mode-locked fiber lasers. PMID- 22825192 TI - Polarization resolved reflection from ordered vertical silicon nanowire arrays. AB - We measure polarization resolved reflections from ordered vertical silicon nanowire arrays of two different diameters and compare the results to rigorous coupled wave analysis simulations. Ellipsometric analysis based on anisotropic effective-medium approximation is used to fit the experimental data and estimate the diameter and length of the nanowires. In addition, depolarization of light is observed for wavelengths below 400 nm. PMID- 22825193 TI - Optical precursors in coupled-resonator-induced transparency. AB - We experimentally examined the propagation of temporally square modulated optical pulses through a coupled ring resonator. Sharp transient spikes appeared as the square pulses entered the system. The main signal gradually grew up through coupled-resonator-induced transparency (CRIT), with the time constant determined by a second resonator. Transient spikes were attributed to the higher and lower spectral components of the incident pulse, to which the resonators cannot respond; hence, they were interpreted as optical precursors. The experiments, therefore, demonstrated that precursors and the main signal can be observed separately, with amplitudes comparable to that of the incident step in CRIT. PMID- 22825194 TI - Simultaneous multiplane in vivo nonlinear microscopy using spectral encoding. AB - Conventional point-by-point imaging schemes for laser scanning microscopy limit acquisition speeds, particularly when imaging three-dimensional volumes. We report a novel approach that achieves parallelization of multiple fields of view through the use of spectral encoding. By focusing two or more beams of different wavelengths at different positions within a suitable tissue, fluorescence or second/third harmonic generation emissions from these regions can be uniquely separated. We demonstrate that this approach can allow simultaneous in vivo imaging of fluorescence in two planes within the living rodent cortex, and of second harmonic generation in fresh tissue. PMID- 22825195 TI - Light sources generating far fields with tunable flat profiles. AB - Planar, scalar, optical Schell-model, and quasi-homogeneous sources with correlations that are Fourier transforms of multi-Gaussian functions are introduced. It is demonstrated that far fields produced by these families of sources carry interesting characteristics, being flatlike with adjustable steepness of the edge. Beam conditions for such sources are also derived. PMID- 22825196 TI - Tunable protein harmonic diffractive micro-optical elements. AB - Herein, tunable protein harmonic diffractive microlenses (PHDMs) have been constructed by femtosecond laser direct writing from bovine serum albumin. With excellent three-dimensional topography, PHDMs show distinct harmonic diffractive features, such as similarly good imaging performance with smaller thickness than refractive lenses and well controlled minus chromatic dispersion compared with simple diffractive lenses (~5% focal length shift against ~21% of the protein Fresnel zone plate with the same radius under light with wavelength 450-659 nm). Owing to the nature of protein molecules as "building blocks," the focal length of the PHDM can be facilely tuned within seconds by changing the pH value (focal length tunability of up to ~20%). PMID- 22825197 TI - Low-diffraction beaming in plasmonic crystals. AB - We analyze the propagation of electromagnetic modes guided by periodic plasmonic structures. We use full-wave solutions of Maxwell equations to calculate dispersion of these modes and derive analytical description of their optical properties. Finally, we demonstrate that, at a certain frequency range that can be controlled by the geometry, diffraction of these guided states is strongly suppressed, leading to formation of low-diffraction beams. A beaming phenomenon, consistent with earlier experiments, can be used as the foundation for on-chip communication or microscopy. PMID- 22825198 TI - Endogenous contrast blood flow imaging in embryonic hearts using hemoglobin contrast subtraction angiography. AB - The genetic basis of congenital heart disease is yet to be defined, and the interactions between the malformed heart and biomechanical cardiac performance remain poorly understood. Functional optical imaging enables detailed biomechanical phenotyping of cardiac dysfunction in small animal models, which in turn enables specific gene-phenotype relationship. We have developed a new microangiography technique based on flow imaging using endogenous hemoglobin contrast enabling in vivo assessment and biomechanical phenotyping of Xenopus tropicalis embryonic heart. We demonstrated that hemoglobin contrast angiography can be used to quantify physiological response to treatment with well-established cardioactive drugs. PMID- 22825199 TI - Crosstalk-free operation of multielement superconducting nanowire single-photon detector array integrated with single-flux-quantum circuit in a 0.1 W Gifford McMahon cryocooler. AB - We demonstrate the successful operation of a multielement superconducting nanowire single-photon detector (SSPD) array integrated with a single-flux quantum (SFQ) readout circuit in a compact 0.1 W Gifford-McMahon cryocooler. A time-resolved readout technique, where output signals from each element enter the SFQ readout circuit with finite time intervals, revealed crosstalk-free operation of the four-element SSPD array connected with the SFQ readout circuit. The timing jitter and the system detection efficiency were measured to be 50 ps and 11.4%, respectively, which were comparable to the performance of practical single-pixel SSPD systems. PMID- 22825200 TI - Extended propagation-inside-layer expansion method combined with the forward backward method to study the scattering from an object above a rough surface. AB - In this Letter, a fast red rigorous numerical method, based on the method of moments, is developed to calculate the scattering from an object above a rough surface for three-dimensional problems (3D). G. Kubicke has recently developed the extended propagation-inside-layer expansion (E-PILE) method to calculate the scattering from an object above a rough surface for two-dimensional problems. This method allows us to calculate separately and exactly the interactions between the object and the rough surface. The purpose of this paper is to extend the E-PILE method to a 3D problem. In addition, to invert a matrix of large size, the forward-backward (FB) method is applied to calculate the local interactions on the rough surface. PMID- 22825201 TI - Experimental investigation on the competition between wideband stimulated Brillouin scattering and forward stimulated Raman scattering in water. AB - The utilization of a simple focused optical cell to bring to light the competition between wideband stimulated Brillouin scattering (WSBS) and forward stimulated Raman scattering (FSRS) is investigated experimentally. A pulsed, wide bandwidth second-harmonic Nd:YAG laser is used as the pump source. We found that, the competition between WSBS and FSRS is an alternate process, which one dominated depends on the linewidth and energy of the pump laser, focal length, and optical breakdown. PMID- 22825202 TI - Energy efficient nonlinear optics in silicon: are slow-light structures more efficient than nanowires? AB - We compare the energy performance of four-wave mixing in nanowires and slow-light photonic crystals and outline the regimes where each platform exhibits salient advantages and limitations, including analysis of the impact of future fabrication improvement. These results suggest a route towards energy efficient silicon integrated photonics. PMID- 22825203 TI - Sequential single-shot imaging of nanoscale dynamic interactions with a table-top soft x-ray laser. AB - We demonstrate the first real-space recording of nanoscale dynamic interactions using single-shot soft x-ray (SXR) full-field laser microscopy. A sequence of real-space flash images acquired with a table-top SXR laser was used to capture the motion of a rapidly oscillating magnetic nanoprobe. Changes of 30 nm in the oscillation amplitude were detected when the nanoprobe was made to interact with stray fields from a magnetic sample. The table-top visualization of nanoscale dynamics in real space can significantly contribute to the understanding of nanoscale processes and can accelerate the development of new nanodevices. PMID- 22825204 TI - Low-noise chip-based frequency conversion by four-wave-mixing Bragg scattering in SiN(x) waveguides. AB - Low-noise, tunable wavelength-conversion through nondegenerate four-wave mixing Bragg scattering in SiN(x) waveguides is experimentally demonstrated. Finite element method simulations of waveguide dispersion are used with the split-step Fourier method to predict device performance. Two 1550 nm wavelength band pulsed pumps are used to achieve tunable conversion of a 980 nm signal over a range of 5 nm with a peak conversion efficiency of ~5%. The demonstrated Bragg scattering process is suitable for frequency conversion of quantum states of light. PMID- 22825205 TI - Planar optical tweezers using tapered-waveguide junctions. AB - We demonstrate planar optical tweezers using the evanescent field of a silicon nitride tapered-waveguide junction between a singlemode waveguide and a multimode waveguide. Our experiments show that the junction embedded in a fluidic channel holds up to one and two polystyrene particles of sizes of 2.2 MUm and 1 MUm, respectively. The trapped particles are successively substituted by the incoming particles. Our experiments and numerical modeling reveal that the junction particle trapping depends on particle size and number. PMID- 22825206 TI - Spatially resolved measurement of femtosecond laser induced refractive index changes in transparent materials. AB - We present a practical method to determine femtosecond laser induced refractive index changes in transparent materials. Based on an iterative Fourier transform algorithm, this technique spatially resolves the refractive index of complex structures by combining the dimensions of the modified region with the corresponding phase change extracted from far-field intensity measurements. This approach is used to characterize optical waveguides written by a femtosecond laser in borosilicate glass. PMID- 22825207 TI - Distance dependence of the local density of states in the near field of a disordered plasmonic film. AB - We measure the statistical distribution of the photonic local density of states in the near field of a semicontinuous gold film. By varying the distance between the measurement plane and the film, we show that near-field confined modes play a major role in the width of the distribution. Numerical simulations in good agreement with experiments allow us to point out the influence of nonradiative decay channels at short distance. PMID- 22825208 TI - Social comparisons in novel situations: finding inspiration during life transitions. AB - The authors propose that individuals transitioning to a novel environment will prefer upward comparisons, particularly those made with individuals who have experienced a similar transition. Such comparisons help to reduce uncertainty and demonstrate that future success is possible. Study 1 found that individuals facing transitions to unfamiliar situations seek upward comparisons as a result of their uncertainty. Study 2 demonstrated that individuals who perceive themselves to be making a significant life transition are especially motivated by upward comparisons. Study 3 provided evidence that upward comparisons are especially inspiring to individuals making a transition to a novel cultural environment. Study 4 provided experimental evidence that individuals in a novel cultural environment are particularly inspired by upward comparisons with other newcomers. These studies suggest that upward comparisons with individuals who have experienced a similar transition enhance individuals' sense of control over future outcomes and play a key role during adjustment to novel environments. PMID- 22825209 TI - The haves and the have nots. PMID- 22825210 TI - Domino effect. PMID- 22825211 TI - Antitumour potential of catalytic DNA. PMID- 22825218 TI - Differential gene expression in Ulva prolifera under low light and low temperature conditions. AB - The past several years witnessed the increasing global interest in the marine green macroalga Ulva prolifera as it is a key causative species of the massive green tides successively occurring in the Yellow Sea. Accurate localization of the 'seed' source is one of the principal scientific concerns to be solved before it is possible to manage these algal blooms. It has been suggested that somatic cells of Ulva prolifera which settled in cold benthic sediments might serve as one of the major propagule banks. To identify the molecular mechanisms underlying this hypothesis, PCR-based suppression subtractive hybridization was employed to analyze the differential gene expression of Ulva prolifera under low light and low temperature conditions (matching the cold benthic sediments conditions, 6 degrees C, 30 MUmol photons m(-2) s(-1)). 137 ESTs representing 88 unigenes (80 singletons and 8 contigs) were detected as being over-expressed, whereas 109 unigenes (96 singletons and 13 contigs) in 130 ESTs were found to be down regulated in this study. BLASTX analysis revealed that 65 % of the over-expressed and 59 % of the down-regulated genes did not belong to any documented functionally annotated or hypothetical proteins in the public database. However, analysis of the functional defined sequences displayed (1) an obvious sign of senescence, (2) enhancements of the photosynthesis system and the pentose phosphate pathway, (3) slow-down of activities in a wide range of processes including the DNA replication, the transcription, the translation, the glycolysis, the citrate cycle and the pyruvate metabolism in Ulva prolifera cells under low light and low temperature conditions. This work disclosed some basic information of the molecular mechanisms of Ulva prolifera cells under low light and low temperature conditions and provides useful clues for future studies on the "seed" source of the massive green tides. PMID- 22825216 TI - Pushing the limits of targeted therapy in chronic myeloid leukaemia. AB - Tyrosine kinase inhibitor (TKI) therapy targeting the BCR-ABL1 kinase is effective against chronic myeloid leukaemia (CML), but is not curative for most patients. Minimal residual disease (MRD) is thought to reside in TKI-insensitive leukaemia stem cells (LSCs) that are not fully addicted to BCR-ABL1. Recent conceptual advances in both CML biology and therapeutic intervention have increased the potential for the elimination of CML cells, including LSCs, through simultaneous inhibition of BCR-ABL1 and other newly identified, crucial targets. PMID- 22825220 TI - Transforming patient care by LEADing: the tipping point: it's here! PMID- 22825219 TI - APhA House of Delegates: dauntlessly tackling difficult issues facing the profession. PMID- 22825221 TI - Culture trumps strategy: we must encourage the next generation of pharmacists to keep looking over the horizon and not be limited by what they can see today. PMID- 22825217 TI - Kinesins and cancer. AB - Kinesins are a family of molecular motors that travel unidirectionally along microtubule tracks to fulfil their many roles in intracellular transport or cell division. Over the past few years kinesins that are involved in mitosis have emerged as potential targets for cancer drug development. Several compounds that inhibit two mitotic kinesins (EG5 (also known as KIF11) and centromere-associated protein E (CENPE)) have entered Phase I and II clinical trials either as monotherapies or in combination with other drugs. Additional mitotic kinesins are currently being validated as drug targets, raising the possibility that the range of kinesin-based drug targets may expand in the future. PMID- 22825222 TI - The nonpharmacologic basis of therapeutics: to get to the next level in interprofessional patient care, pharmacists need to recognize the social and interpersonal aspects of medical decision making. PMID- 22825223 TI - Report of the 2012 APhA House of Delegates: actions of the legislative body of the American Pharmacist Association. PMID- 22825226 TI - Determining predictors of response to exenatide in type 2 diabetes. AB - OBJECTIVES: To determine predictors of glycemic response to exenatide and to assess change in glycosylated hemoglobin (A1C) and whether a correlation exists between weight loss and glycemic response. DESIGN: Retrospective observational cohort study. SETTING: United States in 2009. PATIENTS: 100 adult patients with type 2 diabetes prescribed exenatide. INTERVENTION: Retrospective chart review of patients to collect demographic data, weight, serum creatinine, diabetes education, and concurrent diabetes medications. MAIN OUTCOME MEASURES: Patients were categorized as responders or nonresponders based on change in A1C. Responders had an A1C decrease of 0.5% or more and nonresponders had an A1C decrease of less than 0.5% from baseline to post-exenatide initiation. Demographic data for each cohort were analyzed. RESULTS: 100 patients met inclusion criteria (61 responders and 39 nonresponders). Responders had a mean A1C decrease of 1.57%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99). CONCLUSION: Our data indicate that patients with a higher baseline A1C are more likely to have a glycemic response to exenatide than patients with a lower baseline A1C. PMID- 22825227 TI - Pharmacy staff characteristics associated with support for pharmacy-based HIV testing. AB - OBJECTIVES: To determine support of in-pharmacy human immunodeficiency virus (HIV) testing among pharmacy staff and the individual-level characteristics associated with in-pharmacy HIV testing support. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: New York City (NYC) from January 2008 to March 2009. PARTICIPANTS: 480 pharmacy staff, including pharmacists, owners/managers, and technicians/clerks. INTERVENTION: 131 pharmacies registered in the Expanded Syringe Access Program (ESAP) completed a survey. MAIN OUTCOME MEASURE: Support of in-pharmacy HIV testing. RESULTS: Support of in-pharmacy HIV testing is high among pharmacy staff (79.4%). Pharmacy staff who supported in pharmacy vaccinations were significantly more likely to support in-pharmacy HIV testing. Pharmacy staff who thought that selling syringes to injection drug users (IDUs) caused the community to be littered with dirty syringes were significantly less likely to support in-pharmacy HIV testing. CONCLUSION: Support for in pharmacy HIV testing was high among our sample of ESAP pharmacy staff actively involved in nonprescription syringe sales. These findings suggest that active ESAP pharmacy staff may be amenable to providing HIV counseling and testing to IDUs and warrants further investigation. PMID- 22825228 TI - Recovering substance-impaired pharmacists' views regarding occupational risks for addiction. AB - OBJECTIVE: To better understand the occupational risks for substance use disorders among pharmacists and possibilities for improved prevention. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: A southeastern state from December 2008 to April 2009. PARTICIPANTS: 32 participants (72.7% men) from the impaired professionals monitoring groups in the geographic regions within the state that had the greatest number of physicians, pharmacists, and allied health professionals currently under monitoring contracts for substance use disorders. INTERVENTION: Guided group discussions regarding substance use among health care providers. MAIN OUTCOME MEASURES: Persistent occupational risks for development of a substance use disorder among pharmacists. RESULTS: Several occupational hazards unique to the pharmacy profession might contribute to the problem of substance use disorders among some members of this population, including increased access to potent drugs of abuse, a stressful/unpleasant working environment, a culture that unofficially condones medication diversion, lack of education related to addiction, and lack of support for individuals seeking treatment. CONCLUSION: These results have important implications for the education of student pharmacists, the continuing education of licensed pharmacists, and the management of pharmacies in which these individuals work. Given the potential occupational risks for substance abuse associated with the pharmacy profession, additional training, monitoring, changes to the work environment, and increased confidential access to treatment may be needed to safeguard pharmacy professionals and the communities they serve. PMID- 22825229 TI - Point-of-care screening to identify cognitive impairment in older adults. AB - OBJECTIVE: To explore associations between results of a rapid screening tool for cognitive impairment and individual patient characteristics in a sample of patients receiving outpatient anticoagulation therapy who were not previously diagnosed with a dementia. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: Pharmacist-managed anticoagulation clinic in Spokane, WA, from June 2006 to March 2007. PARTICIPANTS: 300 community-dwelling patients aged 60 years or older who had at least 6 months of outpatient anticoagulation therapy services. INTERVENTION: Following informed consent, demographic, medical history, medication history, anticoagulation therapy, and cognitive screening data were recorded from participant medical records, and a participant interview was performed using a standardized questionnaire and data collection form. MAIN OUTCOME MEASURES: Cognitive screening status (suggests cognitive impairment versus suggests dementia less likely) was used as an independent variable by which to compare patient demographics, medical history, medication history, and percent of out-of-range International Normalized Ratio (INR) visits. RESULTS: 55 of 300 participants (18.3%) with no previous diagnosis of a cognitive impairment were classified as "suggests cognitive impairment" based on the screening test. Presence or absence of cognitive impairment differed in those needing assistance with taking medications but was not associated with other sample characteristics, including percentage of visits with out-of-range INR value, gender, in-home care needs, age, and number of medical conditions. CONCLUSION: Screening at a convenient health care access point may lead to increased identification of community-dwelling elderly patients with unrecognized and undiagnosed cognitive impairment. Pharmacists are particularly well suited to conduct this screening because of the extended and frequent contact they have with patients in settings such as anticoagulation therapy clinics. PMID- 22825230 TI - Quality-related event learning in community pharmacies: manual versus computerized reporting processes. AB - OBJECTIVE: To determine how staff assessment of key quality-related event (QRE) reporting process characteristics (e.g., ease of use, time to use) and QRE learning (e.g., extent that continuous improvement occurs) differ in community pharmacies in which the QRE reporting process is manual versus computerized. DESIGN: Cross-sectional study. SETTING: Nova Scotia, Canada, in 2010. PARTICIPANTS: 121 questionnaires completed by eligible respondents in pharmacies with a formal QRE reporting process. INTERVENTION: Mail-based survey. MAIN OUTCOME MEASURES: A list of key QRE process characteristics that affect error reporting was identified based on a review of the health care literature and piloted in 2009. The "learning from incidents" construct, as captured by Ashcroft and Parker, was used to assess QRE learning. RESULTS: Regardless of process type, the key strengths of existing QRE reporting systems appear to be that they are cost effective, easy to complete, and involve low risk to operations. However, for almost all reporting and learning characteristics, staff assessments were different between the two pharmacy types (manual versus computerized QRE reporting process), with assessments being higher from staff working in pharmacies with a computerized reporting process. CONCLUSION: A QRE reporting process with a notable computer or automated component may result in more positive staff assessment of various aspects of the reporting process and QRE learning. PMID- 22825232 TI - Pharmaceutical care program for elderly patients with uncontrolled hypertension. AB - OBJECTIVE: To evaluate the effect of a pilot pharmaceutical care program developed for elderly patients with uncontrolled hypertension. METHODS: Nonrandomized single intervention pre/posttest blood pressure study in a community pharmacy in Aracaju, Brazil. This study enrolled elderly patients diagnosed with essential hypertension and uncontrolled blood pressure. Monthly visits were scheduled during a 10-month period. Pharmaceutical interventions were focused on health education and monitoring of drug-related problems. Primary outcomes included target blood pressure control, reduction in blood pressure, pulse pressure, medication adherence, and reduction of anthropometric indices. RESULTS: 35 of 51 patients completed the study. After 10 months of intervention, 57.2% of elderly patients achieved blood pressure control (P = 0.000) and the mean reduction was 26.6 mm Hg (P < 0.0001) for systolic blood pressure, 10.4 mm Hg (P < 0.0001) for diastolic blood pressure, and 15.7 mm Hg (P < 0.0001) for pulse pressure. Medication adherence also improved (P = 0.0000); however, anthropometric indices remained unchanged. CONCLUSION: The pharmaceutical care program improved outcomes by reducing and controlling blood pressure and improving medication adherence among elderly patients with uncontrolled hypertension. PMID- 22825231 TI - Effectiveness of intervention to implement tobacco cessation counseling in community chain pharmacies. AB - OBJECTIVES: To test the feasibility of implementing ask-advise-refer (AAR) tobacco cessation counseling approach in community chain pharmacies serving low socioeconomic areas and to assess the effectiveness of a multimodal intervention on short-term implementation of AAR. DESIGN: Randomized controlled trial. SETTING: South-central Wisconsin from July 2008 through March 2009. PARTICIPANTS: Pharmacists and technicians from 16 community chain pharmacies. INTERVENTION: Training to implement AAR, workflow integration recommendations, tobacco cessation poster to create awareness, and a support visit. MAIN OUTCOME MEASURES: Number of pharmacy patrons asked about tobacco use, number of tobacco users advised to quit, number of tobacco users enrolled in the quit line, and number of quit line cards given. RESULTS: As hypothesized, the multimodal intervention significantly predicted the number of patrons asked to quit (estimate 4.84, incidence rate ratio 127.2, P < 0.001), number of tobacco users advised to quit (2.12, 8.33, P < 0.01), number of tobacco users enrolled in the quit line (2.31, 10.13, P < 0.001), and number of quit line cards given (1.04, 2.82, P < 0.05). CONCLUSION: This trial demonstrates the feasibility of implementing AAR in routine community pharmacy practice. This trial also supports the short-term effectiveness of the multimodal intervention in facilitating AAR in partnership with other public health systems. More research is needed to evaluate the generalizability, effectiveness, and sustainability of AAR, including factors influencing adoption and the impact on cessation. PMID- 22825233 TI - Evaluation of outcomes of a medication therapy management program for patients with diabetes. AB - OBJECTIVE: To measure the impact of an employer-sponsored, pharmacist-provided medication therapy management (MTM) program on clinical outcomes and social and process measures for patients with diabetes with or without associated comorbid conditions. METHODS: Prospective longitudinal study that took place at seven independent pharmacies in Lucas County, OH. A total of 228 patients with diabetes were enrolled. At 6-month intervals, patients were counseled by their pharmacists. Outcome measures included clinical outcomes (glycosylated hemoglobin [A1C], systolic blood pressure (SBP), and diastolic blood pressure [DBP]), social measures (caffeine intake, alcohol consumption, smoking, and exercise), and process measures (visits to ophthalmologist, podiatrist, and dentist). Wilcoxon signed-rank test and percentages were used to report findings. RESULTS: Mean (+/- SD) A1C concentration decreased from 7.08 +/- 1.54% to 6.89 +/- 1.30% at 12 months. Patients with A1C levels greater than 7% at baseline averaged a decrease of 0.5% at 6 months and 0.75% at 12 months. Mean SBP values decreased significantly from baseline to 12 months. A total of 87 patients with a baseline SBP greater than 130 mm Hg experienced a significant change in blood pressure from baseline to 6 months (-7.1 +/- 3.32 mm Hg), and 65 patients experienced a significant change in blood pressure from baseline to 12 months (-11.49 +/- 0.15 mm Hg). A total of 104 patients with a baseline DBP more than 80 mm Hg experienced a significant decrease of 4.44 +/- 1.25 mm Hg at 6 months. Caffeine and alcohol consumption and smoking decreased and exercise increased. In addition, the percentage of patients who visited specialists increased. CONCLUSION: Patients with diabetes experienced improvements in multiple clinical, social, and process measures. PMID- 22825234 TI - Evaluation of pharmacy practice residents' research abstracts and publication rate. AB - OBJECTIVE: To determine the type, scope, and publication rate of pharmacy practice residency projects conducted in a subgroup of the United States. METHODS: Data were collected from the abstract book of the 28th Western States Conference for Pharmacy Residents, Fellows, and Preceptors (May 20-23, 2008). Data on project publication rate, institution affiliation, residency year, research practice setting, research therapeutic area, research hypothesis category, study design, statistical plan, and abstract reporting were extracted independently by two investigators. RESULTS: A total of 446 abstracts were presented at the annual residency meeting, 19 (4.3%) of which were published as full text in PubMed-indexed journals. The majority of the abstracts were presented by residents from California (52%). A total of 390 (87%) and 34 (8%) of the presentations were from postgraduate year (PGY)1 and PGY2 pharmacy residencies, respectively. PGY2 residents were more likely to report results at the time of abstract deadline compared with PGY1 residents (30.8% vs. 10.5%, P = 0.0185). Of the 19 publications found, about 3.6% (14 of 390) were from PGY1 residents compared with 14.7% (5 of 34) from PGY2 residents (P = 0.0126). A significantly higher percentage of abstracts that reported results in the study description resulted in publication compared with those that did not report results (10.2% vs. 3.5%; P = 0.0461). CONCLUSION: Although many residents in the western United States undertake residency projects, few projects result in journal publications. While PGY2 residents appear to be publishing at a higher rate than PGY1 residents, proper resource allocation and research training and collaboration by the residency director may improve overall research type, scope, and publication rate. PMID- 22825235 TI - Efficacy of an over-the-counter intervention follow-up program in community pharmacies. AB - OBJECTIVE: To evaluate whether patient adherence to appropriate self-care advice from a pharmacist or professional year 4 (PY4) advanced pharmacy practice experience (APPE) student provides satisfactory symptom relief. SETTING: Two community pharmacies in the same chain in Massachusetts from mid-December 2009 to June 2010. PRACTICE DESCRIPTION: Pharmacists and PY4 APPE students offered a follow-up phone call to patients who were seeking or had accepted the offer for self-care advice for themselves or others for whom they are primary caregivers. PRACTICE INNOVATION: Patients were provided detailed counseling documented on an over-the-counter (OTC) intervention document, administered a point-of-care survey, offered a follow-up phone call(s), and then administered a follow-up survey. MAIN OUTCOME MEASURES: Patient demographics, point-of-care survey assessing current use and perceived benefit from a pharmacist's consultation, intervention document assessing potential medication-related problems, and follow up telephone survey assessing patient adherence to advice, symptom relief, and satisfaction with the service. RESULTS: Of the 207 patients offered a follow-up phone call, 83 accepted. Of these, 54 completed one call and 9 completed two calls. Of those who completed one phone call and claimed complete adherence to advice provided, 38 (82.6%) experienced great symptom relief. Three patients followed advice only partially and experienced the same level of improvement. More than 75% of patients classified the follow-up as "very helpful," felt that it led to greater symptom improvement, and would like to see this service offered all of the time. CONCLUSION: Pharmacist intervention in OTC therapy is widely accepted and can lead to improved patient outcomes. PMID- 22825236 TI - Improving hepatitis B vaccination rates in the hemodialysis population. PMID- 22825238 TI - Science snippets. APACHE II mortality prediction, health symptoms and disability, and pharmacists and diabetes management teams. PMID- 22825237 TI - Clobazam, ezogabine, and tafluprost. PMID- 22825239 TI - Treatment of infertility in women. AB - OBJECTIVES: To review causes and risk factors associated with infertility, relevant diagnostic procedures, and available pharmacologic and nonpharmacologic treatment options; to identify common dosing, administration, adverse effects, and key counseling points associated with infertility treatments; and to describe the role of the pharmacist in caring for patients with infertility. DATA SOURCES: Available clinical literature identified through searches of Medline and review of major textbooks in reproductive medicine. STUDY SELECTION: Studies were selected primarily to reflect current infertility treatment practices in the United States. The specific criteria evaluated included date of the study; date of publication; study population, including diagnosis, baseline characteristics, and nationality; and number of participants. DATA SYNTHESIS: Treatment of infertility often involves the use of both pharmacologic and nonpharmacologic therapy. This article provides an overview of these pharmacologic treatments and provides two tables that outline the key administration and safety concerns with these products. Nonpharmacologic procedures associated with diagnosis and treatment also are outlined. CONCLUSION: Pharmacists are an excellent resource for patients suffering from infertility. First, pharmacists answer questions about administration and safety of these medications. Second, pharmacists discuss available treatment options and assist with referrals to specialists as needed. Third, pharmacists can provide emotional support for patients who may otherwise suffer in silence. PMID- 22825240 TI - Improving care transitions: optimizing medication reconciliation. AB - OBJECTIVE: To improve understanding of the medication reconciliation process, its effect on patient care and outcomes, and how pharmacists can contribute to improving this process using a standardized framework of service delivery defined in the context of medication therapy management. SUMMARY: Medication reconciliation is an integral part of the care transitions process in which health care professionals collaborate to improve medication safety as the patient transitions between patient care settings or levels of care. In 2005, medication reconciliation came to the forefront of health care when the Joint Commission on Accreditation designated it as a National Patient Safety Goal. Although individual health professionals have different roles in the process, the overall focus of the medication reconciliation process is on global patient safety and improved patient outcomes. CONCLUSION: Medication reconciliation research has been increasing, but more studies are needed on the implementation and adoption of effective medication reconciliation processes, with emphasis on the identification of current best practices for medication reconciliation. The application of the foundational concepts in this publication and future work on the enhancement of the medication reconciliation process will help to improve patient safety and patient care outcomes during care transitions. PMID- 22825241 TI - PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-kappaB activation in THP-1-derived macrophages. AB - Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the protein converting enzyme family, is highly expressed in adult hepatocytes and small intestinal enterocytes. To our knowledge, in this study, we demonstrate for the first time that PCSK9 is upregulated in a dose-dependent manner via oxidized low density lipoprotein (oxLDL) stimulation in THP-1-derived macrophages. PCSK9 small interfering RNA (siRNA) suppresses the oxLDL-induced inflammatory cytokine expression in THP-1-derived macrophages. The exposure of macrophages to oxLDL markedly increased the expression of NF-kappaB protein in the nucleus. However, this effect was significantly attenuated by PCSK9 siRNA. These findings indicate that PCSK9 expression is induced by oxLDL, and that PCSK9 siRNA protects against inflammation via the inhibition of NF-kappaB activation in oxLDL-stimulated THP-1 derived macrophages. Our results suggest that PCSK9 may be used as a therapeutic target for the treatment of atherosclerosis since PCSK9 siRNA suppresses oxLDL induced IkappaB-alpha degradation and NF-kappaB nuclear translocation into THP-1 derived macrophages. PMID- 22825243 TI - Phosphine-catalyzed asymmetric [4+1] annulation of Morita-Baylis-Hillman carbonates with dicyano-2-methylenebut-3-enoates. AB - A novel asymmetric [4+1] annulation of MBH carbonates with dicyano-2-methylenebut 3-enoates has been developed for the first time, providing an efficient and enantioselective synthesis of highly functionalized cyclopentenes bearing one all carbon quaternary stereogenic center. PMID- 22825244 TI - Dual-function triazole-pyridine derivatives as inhibitors of metal-induced amyloid-beta aggregation. AB - Dysregulated metal ions are hypothesized to play a role in the aggregation of the amyloid-beta (Abeta) peptide, leading to Alzheimer's disease (AD) pathology. In addition to direct effects on Abeta aggregation, both Cu and Fe can catalyze the generation of reactive oxygen species (ROS), possibly contributing to significant neuronal toxicity. Therefore, disruption of metal-Abeta interactions has become a viable strategy for AD therapeutic development. Herein, we report a new series of dual-function triazole-pyridine ligands [4-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol 1-yl)ethyl)morpholine (L1), 3-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol (L2), 2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)acetic acid (L3), and 5-(4 (pyridin-2-yl)-1H-1,2,3-triazol-1-yl)pentan-1-amine (L4)] that interact with the Abeta peptide and modulate its aggregation in vitro. Metal chelation and Abeta interaction properties of these molecules were studied by UV-vis, NMR spectroscopy and X-ray crystallography. In addition, turbidity and transmission electron microscopy (TEM) were employed to determine the anti-aggregation properties of L1-L4. All compounds demonstrated an ability to limit metal-induced Abeta aggregation. Overall, our studies suggest the utility of the triazole pyridine framework in the development of chemical reagents toward inhibitors for metal-triggered Abeta aggregation. PMID- 22825245 TI - The partially reversible formation of Li-metal particles on a solid Li electrolyte: applications toward nanobatteries. AB - The feasibility of large-scale implementation of Li-air batteries (LABs) hinges on understanding the thermodynamic and kinetic factors that control charge discharge rates, efficiency and life times. Here, the kinetics of bias-induced reactions is explored locally on the surface of Li-ion conductive glass ceramics, a preferred electrolyte for LABs, using direct current-voltage and strain spectroscopies. Above a critical bias, particle growth kinetics were found to be linear in both the bias and time domains. Partial reversibility was observed for Li particles as evidenced by the presence of anodic peaks following the Li(+) reduction, as well an associated reduction in particle height. The degree of reversibility was highest for the smallest particles formed. These observations thus suggest the possibility of producing nanobatteries with an active anode volume of the order of 0.1 al. PMID- 22825246 TI - What is the clinical relevance of respiratory syncytial virus bronchiolitis?: findings from a multi-center, prospective study. AB - Acute bronchiolitis (AB) is caused primarily by respiratory syncytial virus (RSV). Recent laboratory tools have implicated a variety of other pathogens; however, their clinical relevance has not been clearly defined. The purpose of this study was to determine whether the etiological agents of AB affect its course. A multicenter prospective study was performed in previously healthy children <24 months of age who presented with <4 days duration of AB. Subjects were divided into the following groups: "only RSV," "also RSV," "no RSV," and "no pathogen." The clinical severity score on admission as well as the overall severity of disease was assessed. RSV was the most common cause of AB (77.5 %). "Only RSV" or "also RSV" patients had a higher clinical score on admission compared to those with "no RSV," p < 0.001 and p < 0.02, respectively. "Only RSV" and "also RSV" patients had a higher disease severity score when compared to patients with "no RSV," 5.9 +/- 1.4 vs. 5.1 +/- 1.5, p < 0.001, and 5.6 +/- 1.4 vs. 5.1 +/- 1.5, p < 0.02, respectively. Disease severity did not vary as a function of transfer to the pediatric intensive care unit (PICU) or duration of supplemental oxygen, yet, "only RSV" was associated with a longer length of stay (LOS) than "no RSV," p < 0.02. "Only RSV"-related AB was associated with a more severe initial clinical presentation and a longer LOS. There appears to be little immediate clinical benefit to diagnosing RSV AB to the individual patient, but the application of these diagnostic methods may have significant cost-saving implications and, thus, deserves consideration by medical professionals and health policy analysts. PMID- 22825247 TI - Cell cycle regulation of Rho signaling pathways. AB - The dynamics of the actin cytoskeleton and its regulation by Rho GTPases are essential to maintain cell shape, to allow cell motility and are also critical during cell cycle progression and mitosis. Rho GTPases and their effectors are involved in cell rounding at mitosis onset, in chromosomes alignment and are required for contraction of the actomyosin ring that separates daughter cells at the end of mitosis. Recent studies have revealed how a number of nucleotide exchange factors and GTPase-activating proteins regulate the activity of Rho GTPases during these processes. This review will focus on how the cell cycle machinery, in turn, regulates expression of proteins in the Rho signaling pathways through transcriptional activation, ubiquitylation and proteasomal degradation and modulates their activity through phosphorylation by mitotic kinases. PMID- 22825249 TI - Induced pluripotent stem cells as a tool for gaining new insights into Fanconi anemia. AB - Induced pluripotent stem cells (iPSC) hold significant promise for advancing biomedical research. In the case of monogenic diseases, patient-iPSC and their derivatives contain the disease-causing mutation, suggesting the possibility of recapitulating salient disease features in vitro. Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The etiology of bone marrow failure in FA remains largely unclear, but limited studies on patient bone marrow cells indicate cell intrinsic defects as causative. We examined the feasibility of modeling FA in a system based on hematopoietic differentiation of patient specific iPSC. An informative iPSC-based model is predicated on the ability to derive disease-specific (uncorrected) patient iPSC that contain the disease causing mutation, are pluripotent, maintain a normal karyotype and are capable of hematopoietic differentiation. Careful analysis of hematopoietic differentiation of such iPSC holds the promise of uncovering new insights into bone marrow failure and may enable high-throughput screening with the goal of identifying compounds that ameliorate hematopoietic failure. Ultimately, genetic correction, molecular characterization and successful engraftment of iPSC-derived cells may provide an attractive alternative to current hematopoietic stem cell-targeted gene therapy in some monogenic diseases, including FA. PMID- 22825248 TI - R-loops and genomic instability in Bre1 (RNF20/40)-deficient cells. AB - We have proposed that maintenance of genomic stability may constitute the basis for the tumor-suppressing activity of the Bre1 (RNF20/RNF40) complex. Revisiting the evidence we presented in our recent publication, we discuss the mechanism by which maintenance of genomic stability by the Bre1 complex is achieved through coordination of events during transcription. Among many functions of Bre1, we focus on the two that, when defective, could lead to the formation of R-loops, the RNA:DNA hybrid structures regarded as a major source of genomic instability. Specifically, we discuss the role of Bre1-mediated H2B ubiquitination in the 3' end processing of replication-associated histone mRNA and in heterochromatic gene silencing and show how disturbance of these two functions may result in the specific pattern of chromosomal abnormalities we observe in the Bre1-depleted cells. PMID- 22825250 TI - Alterations of polycomb gene BMI1 in human myeloproliferative neoplasms. PMID- 22825251 TI - DNA excision repair: where do all the dimers go? AB - Exposure of cells to UV light from the sun causes the formation of pyrimidine dimers in DNA that have the potential to lead to mutation and cancer. In humans, pyrimidine dimers are removed from the genome in the form of ~30 nt-long oligomers by concerted dual incisions. Though nearly 50 y of excision repair research has uncovered many details of UV photoproduct damage recognition and removal, the fate of the excised oligonucleotides and, in particular, the ultimate fate of the chemically very stable pyrimidine dimers remain unknown. Physiologically relevant UV doses introduce hundreds of thousands of pyrimidine dimers in diploid human cells, which are excised from the genome within ~24 h. Once removed from the genome, "where do all the dimers go?" In a recent study we addressed this question. Although our study did not determine the fate of the dimer itself, it revealed that the excised ~30-mer is released from the duplex in a tight complex with the transcription/repair factor TFIIH. This finding combined with recent reports that base and oligonucleotide products of the base and double strand break repair pathways also make stable complexes with the cognate repair enzymes, and that these complexes activate the MAP kinase and checkpoint signaling pathways, respectively, raises the possibility that TFIIH-30-mer excision complexes may play a role in signaling reactions in response to UV damage. PMID- 22825253 TI - MALT lymphoma meets stem cells. PMID- 22825252 TI - Reconciling the different roles of Gsk3beta in "naive" and "primed" pluripotent stem cells. AB - Signaling pathways orchestrated by PI3K/Akt, Raf/Mek/Erk and Wnt/beta-catenin are known to play key roles in the self-renewal and differentiation of pluripotent stem cells. The serine/threonine protein kinase Gsk3beta has roles in all three pathways, making its exact function difficult to decipher. Consequently, conflicting reports have implicated Gsk3beta in promoting self-renewal, while others suggest that it performs roles in the activation of differentiation pathways. Different thresholds of Gsk3beta activity also have different biological effects on pluripotent cells, making this situation even more complex. Here, we describe a further level of complexity that is most apparent when comparing "naive" murine and "primed" human pluripotent stem cells. In naive cells, Gsk3beta activity is restrained by PI3K/Akt, but when released from inhibitory signals it antagonizes self-renewal pathways by targeting pluripotency factors such as Myc and Nanog. This situation also applies in primed cells, but, in addition, a separate pool of Gsk3beta is required to suppress canonical Wnt signaling. These observations suggest that different Gsk3beta-protein complexes shift the balance between naive and primed pluripotent cells and identify fundamental differences in their cell signaling. Altogether, these findings have important implications for the mechanisms underpinning the establishment of different pluripotent cell states and for the control of self-renewal and differentiation. PMID- 22825254 TI - Analgesic and anti-inflammatory effects in animal models of an ethanolic extract of Taheebo, the inner bark of Tabebuia avellanedae. AB - Taheebo, the purple inner bark of the Bignoniaceae tree Tabebuia avellanedae Lorentz ex Griseb, which is found in tropical rain forests in northeastern Brazil, has been used as a traditional medicine for various diseases for more than 1,500 years. In the current study, various animal models were used to demonstrate the analgesic and anti-inflammatory properties of its ethanolic extract, thereby investigating its potential as a therapeutic treatment for diseases with pain and inflammation. In the hot plate and writhing tests for the in vivo analgesic effect test of Taheebo, a 200 mg/kg dose of the extract induced a significant anti-nociceptive effect and increased the pain threshold by approximately 30% compared with the control. In vascular permeability and tetradecanoylphorbol acetate (TPA)-, arachidonic acid- and carrageenan-induced paw edema tests for anti-inflammatory effects, treatment with 200 mg/kg Taheebo led to significant anti-inflammatory effects and inhibited inflammation by 30-50% compared with the control. At 100 mg/kg, the extract decreased the levels of pain and inflammation in all tested models, but the degree of inhibition was not statistically significant. The results suggest that the ethanolic extract of the inner bark of Tabebuia avellanedae has the potential to be developed as a therapeutic or supportive drug against diseases with accompanying pain and inflammation, including osteoarthritis. PMID- 22825255 TI - Image quality in low-dose coronary computed tomography angiography with a new high-definition CT scanner. AB - A new generation of high definition computed tomography (HDCT) 64-slice devices complemented by a new iterative image reconstruction algorithm-adaptive statistical iterative reconstruction, offer substantially higher resolution compared to standard definition CT (SDCT) scanners. As high resolution confers higher noise we have compared image quality and radiation dose of coronary computed tomography angiography (CCTA) from HDCT versus SDCT. Consecutive patients (n = 93) underwent HDCT, and were compared to 93 patients who had previously undergone CCTA with SDCT matched for heart rate (HR), HR variability and body mass index (BMI). Tube voltage and current were adapted to the patient's BMI, using identical protocols in both groups. The image quality of all CCTA scans was evaluated by two independent readers in all coronary segments using a 4 point scale (1, excellent image quality; 2, blurring of the vessel wall; 3, image with artefacts but evaluative; 4, non-evaluative). Effective radiation dose was calculated from DLP multiplied by a conversion factor (0.014 mSv/mGy * cm). The mean image quality score from HDCT versus SDCT was comparable (2.02 +/- 0.68 vs. 2.00 +/- 0.76). Mean effective radiation dose did not significantly differ between HDCT (1.7 +/- 0.6 mSv, range 1.0-3.7 mSv) and SDCT (1.9 +/- 0.8 mSv, range 0.8-5.5 mSv; P = n.s.). HDCT scanners allow low-dose 64-slice CCTA scanning with higher resolution than SDCT but maintained image quality and equally low radiation dose. Whether this will translate into higher accuracy of HDCT for CAD detection remains to be evaluated. PMID- 22825256 TI - Is contrast-enhanced cardiac magnetic resonance imaging at 3 T superior to 1.5 T for detection of coronary artery disease? AB - The aim is to compare a compiled clinical routine cardiac magnetic resonance (CMR) imaging protocol performed at both 1.5 and 3 T in patients with suspected coronary artery disease (CAD) undergoing coronary X-ray angiography. CMR including adenosine perfusion and late gadolinium enhancement (LGE) at 1.5 T has been established for noninvasive detection of relevant CAD. However, little is known about the potential advantages of 3 T to detect CAD. Fifty-two evaluable patients (62.3 +/- 10.2 years) were included into the study. All patients were scanned at both 1.5 and 3 T including adenosine stress and rest perfusion, and LGE imaging. CMR images were analyzed by two blinded readers in consensus. X-Ray angiography served as the reference method. A significant CAD was diagnosed by quantitative coronary analysis. Diagnostic accuracy of the combined analysis of perfusion and LGE imaging yielded better values at 1.5 and 3 T than the analysis of perfusion images alone. Specificity and sensitivity at 3 T was superior to 1.5 T in detecting coronary stenoses >=50 % (90 vs. 75 % and 84.4 vs. 75 %) and >=70 % (88 vs. 80 % and 96.3 vs. 88.9 %). This study showed that CMR at 3 T in a routine clinical setting is superior to 1.5 T in detection of significant CAD. 3 T might become the preferred CMR field strength for evaluation of CAD in clinical practice. PMID- 22825257 TI - Use of U-500 insulin in pregnancy is intriguing, but controlled trials are needed. PMID- 22825258 TI - Tattoo pigment lymphadenopathy. PMID- 22825259 TI - Pregestational diabetes with extreme insulin resistance: use of U-500 insulin in pregnancy. AB - BACKGROUND: Increased insulin requirements in pregnancy can hinder attainment of glycemic control in diabetic patients. U-500 insulin is a concentrated form of regular insulin that can be a valuable tool in the treatment of patients with severe insulin resistance. CASE: A 24-year-old woman with pregestational diabetes mellitus experienced increasing insulin requirements during pregnancy, peaking at 650 units daily. The frequent, large-volume injections of standard-concentration insulin were poorly tolerated by the patient and resulted in nonadherence. She subsequently achieved glycemic control on thrice-daily U-500 insulin. CONCLUSION: Pregnancy exacerbates insulin resistance in diabetic patients, and these patients may require high doses of insulin. U-500 insulin is an effective alternative for patients with severe insulin resistance and should be considered for pregnant women with difficulty achieving glycemic control. PMID- 22825260 TI - Tattoo pigment lymphadenopathy mimicking metastasis in vulvar cancer. AB - BACKGROUND: Approximately 24% of American adults have tattoos. Studies of humans and mice demonstrate that tattoo pigment migrates to lymph nodes and can cause lymphadenopathy. CASE: A 32-year-old woman presented with a 6-cm vulvar mass and extensive bilateral inguinofemoral lymphadenopathy. Bilateral small tattoos were noted in the groins. Vulvar biopsy confirmed squamous cell carcinoma, and fine needle aspiration of the lymph nodes showed no evidence of malignancy. The patient underwent a radical hemivulvectomy and bilateral inguinofemoral lymphadenectomy. Both inguinal and femoral nodes were enlarged because of extracellular tattoo pigment and reactive follicular hyperplasia without any evidence of metastasis. CONCLUSION: This case emphasizes the need to consider tattoo pigment as a cause of lymphadenopathy in any patient with a regional tattoo. PMID- 22825261 TI - Clear-cell carcinoma of the abdominal wall after cesarean delivery. AB - BACKGROUND: Clear-cell carcinoma transformed from an abdominal wall scar is extremely rare; there are only 22 cases reported in literature. Here we report a case of a patient with clear-cell carcinoma of the abdominal wall after cesarean delivery and review the relevant literature. CASE: A 49-year-old woman presented with a chief complaint of progressively growing mass of cesarean scar and periodic pain with menstruation for 25 years. Wide surgical resection with clear margins was performed. Clear-cell carcinoma was demonstrated by pathologic examination. The patient underwent six cycles of adjutant chemotherapy postoperatively. The patient remains clinically free of recurrence 8 months after treatment. CONCLUSION: Comprehensive treatment consisting of radical surgery combined with adjuvant therapy should be considered for this uncommon condition. PMID- 22825262 TI - Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy. AB - BACKGROUND: Heterotopic pregnancy describes the relatively rare coexistence of one or more intrauterine gestations and one or more extrauterine (ectopic) gestations. We describe a unique clinical case involving successful treatment of an ovarian heterotopic pregnancy through gestational sac aspiration and injection of hyperosmolar glucose. CASE: A 31-year-old woman presented with an ovarian ectopic pregnancy and a viable intrauterine pregnancy after ovulation induction with oral medications. The ovarian gestational sac was aspirated and then injected transvaginally with a small volume of 50% glucose in water. The ectopic pregnancy resolved, and the intrauterine pregnancy was delivered at term without complication. CONCLUSION: Gestational sac aspiration and injection of hyperosmolar glucose into an ovarian ectopic pregnancy was simple and efficacious without compromising a coexisting intrauterine pregnancy. PMID- 22825263 TI - Necrotizing pancreatitis associated with severe preeclampsia. AB - BACKGROUND: Necrotizing pancreatitis is rare in pregnancy and usually is associated with symptomatic cholelithiasis. We present a case of fatal necrotizing pancreatitis in a patient with severe preeclampsia. CASE: A 25-year old primigravid woman at 35 weeks of gestation presented with decreased fetal movement, pruritus, and malaise. Intrauterine fetal demise was diagnosed in the context of severe thrombocytopenia, hypertension, proteinuria, hemolysis, elevated transaminases, and renal failure. Postpartum, the patient developed metabolic acidosis, hyperglycemia, and hypoxemia followed by cardiopulmonary arrest and death. Autopsy revealed extensive acute pancreatic necrosis, pleural effusions, ascites, and fatty liver without evidence of microthrombi. The cause of death was acute necrotizing pancreatitis resulting from severe preeclampsia. CONCLUSION: Severe preeclampsia may cause widespread end-organ damage and may affect the gastrointestinal system, resulting in fatal necrotizing pancreatitis. PMID- 22825264 TI - Falsely elevated testosterone due to heterophile antibodies. AB - BACKGROUND: Falsely elevated testosterone is a rare phenomenon that may result from heterophile antibodies. Similar to patients with heterophile antibodies for beta-hCG, incorrect management may result in unnecessary testing or therapy. CASE: A previously healthy postmenopausal woman presented with a falsely elevated total testosterone level due to interference consistent with heterophile antibodies, with subsequent normal levels detected by liquid chromatography-mass spectrometry. CONCLUSION: Asymptomatic patients may present with an elevated hormone level due to heterophile antibody interference. Molecular studies for hormone levels can assist greatly when falsely elevated levels are suspected, but these tests are costly and time-intensive. PMID- 22825265 TI - Platinum-based combination chemotherapy for the treatment of advanced-stage squamous cell carcinoma of the vulva. AB - BACKGROUND: Chemoradiation is an alternative to radical vulvectomy with en bloc node dissection for advanced vulvar cancer. We report a case of complete clinical and pathologic response with chemotherapy alone in a patient with advanced vulvar cancer. CASE: A middle-aged woman known to have had human immunodeficiency virus (HIV) for 10 years was newly diagnosed with advanced-stage squamous carcinoma of the vulva. She was treated with a total of nine cycles of platinum-based combination chemotherapy, with complete clinical and pathologic response. She remains in complete clinical remission without evidence of recurrent disease by noninvasive testing in the absence of any further therapy 24 months after her last chemotherapy treatment. CONCLUSION: Platinum-based combination chemotherapy may be used successfully for patients with advanced-stage squamous carcinoma of the vulva. PMID- 22825266 TI - Concealed postpartum hemorrhage treated with transcatheter arterial embolization. AB - BACKGROUND: Postpartum hemorrhage is an obstetric emergency and is a major preventable cause of maternal morbidity and mortality. An arteriovenous fistula is a rare cause of concealed postpartum hemorrhage. CASE: A 20-year-old woman spontaneously delivered at 40 0/7 weeks of gestation. Twelve hours after delivery, she became hemodynamically unstable, developing a large left vaginal hematoma. An angiogram revealed extravasation originating from the right pudendal artery with early filling of a draining vein, consistent with a traumatic arteriovenous fistula. Complete occlusion of the fistula was achieved by embolizing a branch of the right pudendal artery. The postprocedure course was uneventful. CONCLUSION: A vaginal arteriovenous fistula should be considered in cases of concealed postpartum hemorrhage; transcatheter arterial embolization is an effective treatment for these cases. PMID- 22825267 TI - Sacral colpopexy followed by refractory Candida albicans osteomyelitis and discitis requiring extensive spinal surgery. AB - BACKGROUND: Sacral colpopexy is an effective approach to treat vaginal vault prolapse. We report a case of serious Candida albicans infection at the site of sacral mesh attachment. CASE: A 63-year-old woman developed back pain 4 months after sacral colpopexy. Imaging revealed L5 and S1 osteomyelitis and discitis. This was refractory to medical management and surgical debridement with mesh removal and tissue excision in the surgical plane. Cultures demonstrated C albicans. This ultimately required extensive spinal surgery, including two discectomies, L5 corpectomy, partial corpectomies, canal decompression, strut fusion, and posterior screw and rod stabilization and fusion. CONCLUSION: C albicans lumbosacral osteomyelitis and discitis is a rare but serious complication after sacral colpopexy that can result in significant morbidity. PMID- 22825268 TI - Buttock necrosis and paraplegia after bilateral internal iliac artery embolization for postpartum hemorrhage. AB - BACKGROUND: Endovascular embolization has become part of the management of postpartum hemorrhage. CASE: We report a case of bilateral extensive gluteal skin and muscle necrosis with concurrent severe lumbosacral plexopathy after bilateral internal iliac artery embolization for postpartum hemorrhage. The ischemic plexopathy was treated conservatively, with a fair outcome. The complex gluteal wound was treated successfully with debridement and skin grafting. CONCLUSION: Pregnancy is known to increase the pelvic collateral blood vessels, and, hence, such a complication in a healthy pregnant woman is extremely rare. The risk of such a severe complication may be minimized by more selective embolization. PMID- 22825269 TI - Postpartum herpes simplex virus endometritis and disseminated infection in both mother and neonate. AB - BACKGROUND: Herpes simplex virus (HSV) is an unusual cause of postpartum endometritis. We describe a rare case of primary disseminated maternal HSV in the postpartum period associated with endometritis. CASE: A previously healthy patient developed fundal tenderness and postpartum fevers after an uncomplicated vaginal delivery. Despite traditional broad-spectrum antimicrobial therapy, she had persistent fevers and systemic symptoms. Concurrently, her neonate developed fevers and a nonvesicular rash, with viral cultures ultimately returning positive for HSV. The patient developed active pharyngeal and genital herpetic lesions and was diagnosed with HSV endometritis and disseminated HSV. Symptoms and fevers in both the mother and neonate responded to antiviral therapy. CONCLUSION: Herpes simplex virus endometritis should be included in the differential diagnosis for postpartum fevers and fundal tenderness that are unresponsive to broad-spectrum antimicrobial treatment. PMID- 22825270 TI - Bilateral mucinous cystadenomas and massive edema of the ovaries in a virilized adolescent girl. AB - BACKGROUND: Ovarian pathology, including nonfunctional tumors and massive edema of the ovary, has been associated with stromal luteinization and clinical endocrinopathies. CASE: An adolescent girl presented with primary amenorrhea, clitoromegaly, and large abdominopelvic mass. Laboratory evaluation revealed an elevated serum total testosterone level of 241 ng/dL. Magnetic resonance imaging confirmed three cystic adnexal structures, with the largest measuring 16 * 8 * 18 cm. Surgery with pelvic washings, bilateral ovarian cystectomies, unilateral paratubal cystectomy, and bilateral ovarian biopsies were performed. Pathology confirmed bilateral mucinous cystadenomas and massive edema of the ovaries. Postoperatively, the serum total testosterone level normalized. CONCLUSION: Nonfunctional ovarian tumors and massive edema of the ovaries should be considered in the differential diagnosis for a patient presenting with signs of hyperandrogenism. PMID- 22825271 TI - Hyperandrogenism of ovarian etiology: utilizing differential venous sampling for diagnosis. AB - BACKGROUND: We report the diagnosis and management of testosterone hypersecretion in the presence of an adrenal mass and no initially discernible ovarian mass. CASE: A 64-year-old woman with severe hyperandrogenism, including serum testosterone 392 ng/dL, male-pattern baldness, and hirsutism, required bilateral ovarian and adrenal venous sampling to determine the source of the testosterone. Once an ovarian origin was confirmed, total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed for definitive treatment. The adrenal adenoma was left in situ. There was a dramatic decrease in subjective symptomatology and normalization of testosterone postoperatively. CONCLUSION: Preoperative differential venous sampling determined the correct source of testosterone. Subsequent removal of the ovary and steroid cell tumor correctly treated the hyperandrogenism and avoided an unnecessary surgical procedure for the adrenal adenoma. PMID- 22825272 TI - Pregnancy outcome in anti-N-methyl-D-aspartate receptor encephalitis. AB - BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune disorder resulting in neurologic and psychiatric symptoms. Treatment is challenging in pregnancy, because little data exist to guide management. CASE: A 24-year-old woman with a known diagnosis of anti-NMDA receptor encephalitis using intravenous immunoglobulin therapy became pregnant. Her pregnancy was uncomplicated with no relapses. She delivered at 35 4/7 weeks of gestation after having preterm premature rupture of membranes. She had a relapse of symptoms after delivery. CONCLUSION: This patient with anti-NMDA receptor encephalitis had an uneventful pregnancy with overall good outcome; however, she experienced relapse soon after delivery. This disease may mimic other autoimmune diseases, with improvement during pregnancy and risk for relapse postpartum. PMID- 22825273 TI - Uterine clostridial myonecrosis after thermal balloon endometrial ablation. AB - BACKGROUND: We present a case of a patient who had development of uterine clostridial myonecrosis after elective thermal balloon endometrial ablation in the absence of identifiable risk factors. CASE: A 51-year-old woman underwent uneventful thermal balloon endometrial ablation for the treatment of menorrhagia. The next day, she presented with acute inflammatory syndrome, severe intravascular hemolysis, and acute kidney injury. The blood cultures and the high vaginal swab showed moderate growth of Clostridium species. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Her postoperative course was uneventful, and renal function gradually recovered. CONCLUSION: Clostridial myonecrosis after uncomplicated surgery, although rare, should be considered in the differential diagnosis of the acutely septic patient with massive hemolysis, regardless of the presence of patient's risk factors. PMID- 22825274 TI - Successful pregnancy after fertility-sparing local resection and uterine reconstruction for low-grade endometrial stromal sarcoma. AB - BACKGROUND: Fertility-sparing management of endometrial stromal sarcoma has been demonstrated, but reports of pregnancy after such management are rare in our current body of literature. CASE: A 16-year-old nulligravid adolescent girl presented with symptoms of menometrorrhagia and was found to have a 17-cm uterine mass. The patient underwent local resection of the mass with uterine reconstruction. Pathology revealed a low-grade endometrial stromal sarcoma. She was placed on high-dose daily megestrol acetate therapy and remained disease-free for 8 years before achieving pregnancy spontaneously. The patient underwent an uncomplicated pregnancy until 34 weeks of gestation, when she presented in preterm labor and underwent cesarean delivery of a liveborn male neonate, with no evidence of disease recurrence. CONCLUSION: Fertility-sparing management and close follow-up of low-grade endometrial stromal sarcoma may be a viable option for those desiring future fertility. PMID- 22825275 TI - Intact newborn survival after spontaneous umbilical cord vascular rupture before labor. AB - BACKGROUND: Spontaneous umbilical cord vascular rupture is a rare event and historically has led to rapid neonatal demise. This catastrophic event has a small window of opportunity in which intervention may prevent neonatal death. CASE: A 32-year-old multigravid woman's prenatal care was complicated by fetal anomalies, including a two-vessel cord and right pelvic kidney diagnosed during second-trimester ultrasonography. The patient had undergone weekly antenatal testing that was reassuring. She presented to labor and delivery at 36 weeks of gestation with decreased fetal movement and fetal tachycardia and urgently underwent cesarean delivery. On delivery, avulsion of the umbilical cord was noted. The neonate was resuscitated by the neonatal intensive care team and was discharged from the hospital on day of life 14. CONCLUSION: A high clinical suspicion of potential prelabor cord avulsion and rapid intervention can lead to the birth of a live newborn. PMID- 22825276 TI - Electrocautery-associated vascular injury during robotic-assisted surgery. AB - BACKGROUND: The robotic surgical platform is increasingly used in gynecology and, similar to laparoscopy, it has risks of electrocautery-associated injury. CASE: We present three cases of injury caused by failures of the monopolar scissors' insulating sheath while coagulation and cutting currents were set at 35 W. In case 1, an external iliac vein injury required blood transfusion and emergent laparotomy. In case 2, a full-thickness external iliac artery injury was repaired robotically. In case 3, a partial-thickness external iliac artery injury also was repaired robotically. CONCLUSION: Unintended electrosurgical arcs can occur from monopolar instruments. Insulation failure is a common finding in this type of injury. Surgeons should avoid excessive instrument collisions and should change the monopolar scissors' insulating sheath if there are any concerns of a defect in its integrity. PMID- 22825277 TI - Abdominal wall lump after cesarean delivery. AB - BACKGROUND: An abdominal wall desmoid tumor is a rare event, has a strong tendency for local invasion and recurrence, and usually presents as an abdominal lump. CASE: A 35-year-old multiparous woman presented with a painful abdominal lump that had been slowly increasing in size. The pain was not associated with menstruation. Clinical examination, ultrasonography, and abdominal magnetic resonance imaging were performed and suggested a large, sharply defined mass measuring approximately 11 * 7.1 cm in the right anterolateral abdominal wall. There was no family history of familial adenomatous polyposis. The mass was excised and sent for histopathologic examination, which indicated abdominal wall desmoid tumor. CONCLUSION: Abdominal wall desmoid tumors can be diagnostic dilemmas and should be considered in the differential diagnosis for lumps in the abdomen in women. PMID- 22825278 TI - Pregnancy in an intestinal transplant recipient. AB - BACKGROUND: Intestinal transplantation is a relatively new form of therapy for short gut syndrome. Pregnancy after intestinal transplantation is rare. CASE: A 26-year-old small bowel transplant recipient presented for prenatal care. She previously had undergone bariatric surgery and later experienced small bowel necrosis and resection. The resulting short gut syndrome was treated with an isolated small bowel transplant. Medications during this pregnancy included prednisone, esomeprazole, diphenoxylate-atropine, ascorbic acid, tacrolimus, and magnesium supplementation. Throughout her pregnancy, her creatinine level was elevated. Labor was induced at 39 3/7 weeks and resulted in a spontaneous vaginal delivery of a healthy female neonate. Twelve weeks after delivery, the mother was admitted for a rejection reaction that was treated successfully. CONCLUSION: A successful pregnancy in an intestinal transplant recipient resulted in delivery of a healthy term newborn. PMID- 22825279 TI - Perinatal detection of familial adenomatous polyposis. AB - BACKGROUND: Hepatoblastoma is an uncommon fetal neoplasm that may represent an isolated malignancy or a component of a familial cancer or syndromic diagnosis. CASE: A large fetal liver mass was detected on routine ultrasound examination of a 23-year-old woman with thyroid nodules and hypertension. Inferior vena cava compression prompted delivery; postnatal biopsy revealed hepatoblastoma. Maternal thyroid biopsy revealed papillary carcinoma. Neonatal and maternal cytomolecular analysis revealed APC gene disruption at 5q22.2. Pedigree analysis exposed multigenerational colon cancer and thyroid cancer, which in conjunction with genetic testing is consistent with familial adenomatous polyposis. CONCLUSION: This is a novel means of familial adenomatous polyposis diagnosis. Obstetricians and perinatologists should be alert for familial cancer or syndromic diagnoses presenting as fetal neoplasms. PMID- 22825280 TI - Placental abruption remote from term associated with Q Fever infection. AB - BACKGROUND: It has been suggested that Q fever infection in pregnancy is associated with various maternal and neonatal adverse outcomes, including intrauterine growth restriction, stillbirth, preterm delivery, intrauterine fetal death, and oligohydramnios. CASE: We describe the cases of two pregnant women remote from term who presented with premature contractions and fever of unknown origin. During their hospitalizations, they had development of near-complete placental abruption. In both cases, immediate delivery ensued. Fever of unknown origin work-up revealed chronic Q fever infection, and polymerase chain reaction investigation of the placenta demonstrated chronic Q fever placentitis. CONCLUSION: Q fever placentitis may result in placental abruption remote from term. Therefore, in endemic areas, the diagnosis of Q fever requires appropriate surveillance and prenatal care. PMID- 22825281 TI - Neovaginal stenosis presenting as an abdominal mass. AB - BACKGROUND: Neovaginal reconstruction surgeries are associated with long-term complications. One such complication is restenosis. CASE: A 57-year-old woman with cecal neovaginal reconstruction after stenosis from vulvovaginal lichen planus 11 years previously presented with abdominal pain and mass. The mass was from distension of the neovaginal cecum attributable to accumulation of secretions secondary to neovaginal restenosis. This was successfully drained to relieve her symptoms. CONCLUSION: No current guidelines exist on managing or evaluating neovaginas for long-term complications, but annual speculum vaginal examinations may aid in diagnosing complications early. PMID- 22825282 TI - Surrogate decision makers' attitudes towards research decision making for critically ill patients. AB - PURPOSE: To examine the attitudes and preferences of surrogate decision makers (SDMs) regarding their involvement in the consent to research process for ICU patients. METHODS: We presented 136 SDMs of critically ill patients in five ICUs with four hypothetical research scenarios: baseline interventional study of a placebo controlled RCT; study with higher risk of treatment complication; study comparing two accepted treatments; study with shorter enrolment window. For each we asked SDMs if they would want to be involved in the consent to research decision, and to rate the acceptability of their comfort with, and their sense of burden with their involvement. Participants were screened for symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale. RESULTS: For the baseline scenario, most SDMs wished to be involved in research decision making (90 %; 95 % CI 84-95 %); responses varied little across study permutations. The majority considered their involvement to be acceptable (85 %; 95 % CI 77-90 %), whereas, a small minority rated it as being unacceptable (2 %; 95 % CI 1-6 %). Many were comfortable with being involved (50 %; 95 % CI 41-59 %), but the number decreased when risk of harm was higher (34 %; 95 % CI 26-43 %) or enrolment window was shorter (41 %; 95 % CI 33-50 %). A majority (62 %) reported symptoms of anxiety and many (38 %) had symptoms of depression. CONCLUSION: Most of the interviewed SDMs wished to be involved in research decision making for critically ill and incapable loved ones. Variability existed, however, in their desire to be involved when decisions were time-sensitive or perceived risk was greater. PMID- 22825283 TI - Noninvasive ventilation after early extubation in patients recovering from hypoxemic acute respiratory failure: a single-centre feasibility study. AB - PURPOSE: The use of noninvasive ventilation (NIV) to facilitate discontinuation of mechanical ventilation in patients with acute hypoxemic respiratory failure (hypoxemic ARF) has never been explored. This pilot study aims to assess the feasibility of early extubation followed by immediate NIV, compared conventional weaning, in patients with resolving hypoxemic ARF. METHODS: Twenty consecutive hypoxemic patients were randomly assigned to receive either conventional weaning or NIV. The changes in arterial blood gases and respiratory rate were compared between the two groups at 1, 12, 24 and 48 h. Differences in the rate of extubation failure, ICU and hospital mortality, number of invasive-ventilation free-days at day 28, septic complications, number of tracheotomies, days and rates of continuous intravenous sedation, and ICU length of stay were also determined. RESULTS: No patient interrupted the study protocol. Arterial blood gases were similar during invasive mechanical ventilation, 1 h after NIV application following extubation, and after 12, 24 and 48 h. Respiratory rate was higher after 1 h in the NIV group, but no different after 12, 24 and 48 h. The number of invasive-ventilation-free-days at day 28 was 20 +/- 8 (min = 0, max = 25) days in the treatment group and 10 +/- 9 (min = 0, max = 25) days in the control group (p = 0.014). The rate of extubation failure, ICU and hospital mortality, tracheotomies, septic complications, days and rates of continuous sedation, and ICU length of stay were not significantly different between the two groups. CONCLUSIONS: In a highly experienced centre NIV may be used to facilitate discontinuation of mechanical ventilation in selected patients with resolving hypoxemic ARF. PMID- 22825284 TI - High prevalence of intestinal infections and ectoparasites in dogs, Minas Gerais State (southeast Brazil). AB - In the present study, 155 dogs euthanized by the Zoonotic Disease Unit of Uberlandia in Minas Gerais State (Southeast Brazil) were autopsied. Ectoparasites were collected, and the intestinal content of dogs was systematically examined for the presence of helminthic parasites. In total, we isolated 5,155 metazoan parasites of eight species (three intestinal helminth species, five ectoparasite species). The cestode Dipylidium caninum was present in 57 dogs (36.8 %), the nematodes Ancylostoma caninum in 30 (19.4 %) and Toxocara canis in 24 (15.5 %), respectively. Among the ectoparasites, 139 (89.7 %) dogs were infested with Rhipicephalus sanguineus, 115 (74.2 %) with Ctenocephalides felis, 5 (3.2 %) with Tunga penetrans and one specimen (0.7 %) with Amblyomma cajennense, while myiasis was found in one dog (0.7 %). In logistic regression analysis, young age (adjusted odds ratio 5.74; 95 % confidence interval 1.18-27.85) and male sex (3.60; 1.24-10.40) were significantly associated with toxocariasis, and crossbreed dogs (8.20; 1.52-44.31), with dipylidiasis. Male (2.23; 1.12-4.43) and crossbreed dogs (5.17; 1.17-22.83) had also a significant higher number of concomitant parasitoses. Spatial distribution of dogs by neighbourhood identified high-risk areas. Our systematic study shows that dogs in Uberlandia carry a high number of parasites which may cause zoonotic diseases in humans; therefore, further specific evidence-based intervention measures are needed. PMID- 22825285 TI - Genetic variations among Echinococcus granulosus isolates in Egypt using RAPD PCR. AB - Cystic echinococcosis (CE), caused by hydatid cysts, is a widespread and hazardous disease in humans and animals worldwide. The aim of the current study was to investigate the genetic variations among Echinococcus granulosus cyst strains isolated from sheep, camel, pig, and donkey using RAPD-PCR analysis. Seven primers of arbitrary sequences were used in the PCR reactions. The screened primers gave total patterns ranging from 27 to 39 reproducible bands for each isolate. Each population isolate gave its specific pattern. Although distinct polymorphic patterns were obtained among the four isolates, there were several shared bands among them in each primer used. A comparison of the different RAPD PCR patterns showed that primers P1, P3, and OPH 04 yielded band patterns that revealed a high degree of divergence among the four isolates of E. granulosus that allowed easy distinction between them. The remaining primers (P2, P4, P5, and OPH14) amplified DNA fragments that were common to two or more isolates but diversified in the other two or three isolates. The study revealed that the most closely related isolates were of donkey and camel where the similarity coefficent between them ranging from 53 % to 78 %, followed by isolates of pig and sheep (sc = 40 % to 68 %), while the similarity coefficent between isolates of camel and sheep was 33-45 %, between camel and pig was 36 to 57 %, between donkey and pig was 37 to 52 %, and between donkey and sheep was 35 to 54 % which means that they more or distant from each other. In conclusion, hydatid cysts isolated from camel may have the genotypic characters of donkey strain. PMID- 22825286 TI - Diabetes self-management profile short form: a preliminary report. AB - Effective family management of type 1 diabetes in childhood is critical to maintaining optimal glycemic control. The purpose of this study was to provide preliminary evidence for a reduced form of the Diabetes Self-Management Profile (DSMP) using Rasch modeling techniques. The study was a secondary analysis of DSMP data drawn from a previous study on patterns of self-management from 239 preadolescents with type 1 diabetes. Rasch modeling strategies were used to identify the most informative items and then a reduced score composite was correlated with hemoglobin A1c (A1c) and blood glucose monitoring (BGM) frequency. A short form of the DSMP was obtained using seven items that comprised all five subscales of the DSMP. The DSMP Short-Form (DSMP-SF) composite score correlated significantly with child's HbA1c and BGM frequency. The DSMP-SF may be considered a valid and effective screening interview alternative to the longer, original, DSMP, particularly when attempting to identify high-risk patients. PMID- 22825287 TI - Dengue and chikungunya in travelers: recent updates. AB - PURPOSE OF REVIEW: Dengue virus (DENV) and chikungunya virus (CHIKV) cause significant morbidity in many world regions and their epidemiology, pathogenesis, vector issues, and control and prevention continue to fascinate researchers. This review focuses on the progress in these areas in the past 2 years. RECENT FINDINGS: Recent studies have highlighted the features of the epidemiology of DENV and CHIKV in Africa, some places of transmission being detected through travelers as sentinels. Autochthonous transmission of both viruses has been documented in France, raising concern regarding the potential for outbreaks where a competent vector, Aedes albopictus, is present. Some aspects of immune response following DENV and CHIKV infections have been elucidated. New diagnostic techniques for DENV have been explored as well as treatment for CHIKV. Research on Wolbachia as a means of biologic control of mosquito-borne infections including DENV and CHIKV has made significant progress. SUMMARY: These studies further our understanding of the evolving DENV and CHIKV epidemiology and potential transmission in nonendemic regions, and can contribute to the assessment of travelers. The new information on immunological responses to these viruses influences the vaccine development. Risk factors for severe disease and new therapeutic options could improve current treatment. Finally, research on Wolbachia holds promise in these two important vector-borne viral infections. PMID- 22825288 TI - Vaccines for typhoid fever and other salmonelloses. AB - PURPOSE OF REVIEW: This review summarizes the recent advances in vaccination against Salmonella enterica serovar Typhi and highlights the data supporting the development of next generation vaccines to address paratyphoid fever and invasive nontyphoidal Salmonella (iNTS) disease. RECENT FINDINGS: There has been increasing awareness of the disease burden caused by S. Typhi particularly in Africa and greater recognition of S. Paratyphi A's contribution to enteric fever episodes throughout Asia. Groups have been working to improve the existing typhoid vaccines and provide comprehensive data on the feasibility of their implementation in endemic settings. These data have resulted in modifications to the recommendations for typhoid vaccination in traveller markets and endemic settings, and has also led to the development of S. Paratyphi A vaccine components that can be combined with existing typhoid vaccines to generate bivalent formulations against enteric fever. The epidemiology of iNTS serovars as cause of appreciable morbidity and mortality in Africa, and the need for vaccines, has also become more widely appreciated. SUMMARY: Current typhoid vaccines, although moderately effective for short periods of time, cannot be used in all age groups and only target one of the clinically relevant Salmonella serovars. Greater effort must be placed on the development and implementation of improved vaccines for the disease burden resulting from Typhi, Paratyphi A or iNTS infections. PMID- 22825289 TI - Rabies pretravel vaccination. AB - PURPOSE OF REVIEW: This review sought to describe the recent findings on the epidemiology of rabies exposure and rabies cases in travelers and to discuss possible cost-saving measures that could be used to increase pretravel vaccination coverage in travelers. RECENT FINDINGS: On the basis of global data, most cases of rabies in travelers are associated with dog bites, occur in adults who are commonly migrants, and are not necessarily associated with long-term travel. The incidence of injuries to travelers caused by potentially rabid animals is approximately 0.4% per month of stay. Dogs account for 51% of cases, and the remaining animals, notably monkeys, carry a lower risk of rabies transmission. Travel to Southeast Asia, India, and north Africa, young age, and traveling for tourism are risk factors for potential exposure; the duration of travel is not a risk factor. More than 70% of travelers are not immunized prior to departing and do not receive adequate care when injured. SUMMARY: The intradermal vaccination route has been proven economical, safe, and immunogenic in the population of rabies-endemic areas, and this route of administration has been recently used in travelers from developed countries. The immunity provided by the three-dose series is long-lasting and should be considered an investment for future travel. Abbreviated schedules have been tested for last-minute travelers. PMID- 22825290 TI - The public health impact of food-related illness. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on the public health impact of food-related illness in light of recent high-profile outbreaks and advances in the methodology to estimate illness burden. It includes mainly literature from high-income countries, as burden of illness estimations have been focussed in these countries. RECENT FINDINGS: The public health burden of food-related illness is very high, no matter what method is used to measure it. Outbreaks provide only a partial insight because they represent a small proportion of all cases of food-related illness. Recent outbreaks have demonstrated a very wide variety of contaminated food vehicles and illustrated the challenges in investigations when the contaminated foodstuff is an ingredient of many other food items. SUMMARY: Outbreaks will continue to challenge public health responses so that maintaining capacity to respond rapidly is crucial. Technological advances, such as whole genome sequencing, pave the way for identifying food-related illness much more rapidly than at present. There is a need to improve diagnostic yield in clinical laboratories and culturing organisms will remain important. Perhaps one of the greatest challenges, though, is to maintain the interest and support of the public when investigating food-related illness. PMID- 22825291 TI - Genomic transformation of the picoeukaryote Ostreococcus tauri. AB - Common problems hindering rapid progress in Plant Sciences include cellular, tissue and whole organism complexity, and notably the high level of genomic redundancy affecting simple genetics in higher plants. The novel model organism Ostreococcus tauri is the smallest free-living eukaryote known to date, and possesses a greatly reduced genome size and cellular complexity, manifested by the presence of just one of most organelles (mitochondrion, chloroplast, golgi stack) per cell, and a genome containing only ~8000 genes. Furthermore, the combination of unicellularity and easy culture provides a platform amenable to chemical biology approaches. Recently, Ostreococcus has been successfully employed to study basic mechanisms underlying circadian timekeeping. Results from this model organism have impacted not only plant science, but also mammalian biology. This example highlights how rapid experimentation in a simple eukaryote from the green lineage can accelerate research in more complex organisms by generating testable hypotheses using methods technically feasible only in this background of reduced complexity. Knowledge of a genome and the possibility to modify genes are essential tools in any model species. Genomic, Transcriptomic, and Proteomic information for this species is freely available, whereas the previously reported methods to genetically transform Ostreococcus are known to few laboratories worldwide. In this article, the experimental methods to genetically transform this novel model organism with an overexpression construct by means of electroporation are outlined in detail, as well as the method of inclusion of transformed cells in low percentage agarose to allow selection of transformed lines originating from a single transformed cell. Following the successful application of Ostreococcus to circadian research, growing interest in Ostreococcus can be expected from diverse research areas within and outside plant sciences, including biotechnological areas. Researchers from a broad range of biological and medical sciences that work on conserved biochemical pathways may consider pursuing research in Ostreococcus, free from the genomic and organismal complexity of larger model species. PMID- 22825292 TI - [Redefinition of professional roles: if we re-started again from patients?]. AB - Redefining professional roles: should we re-start from patients? The redefinition of nursing competences is a need determined by the progressive changes of the health system and health professions. If on one side the definition of what nurses can or cannot do helps to render more visible the nursing profession, on the other also the WHO agrees that a rigid definition is not realistic. The constantly evolution of technologies and systems reshapes the boundaries between health professions. The actual debate is strikingly centered on professions (what each profession gains or looses, increase or loss of responsibility or power) and only rarely from patients' needs. PMID- 22825293 TI - [Effectiveness of the transparent sterile dressing vs standard to fix the peripheral venous catheter (PVC) on the incidence of phlebitis. A randomized controlled trial]. AB - Effectiveness of the transparent sterile dressing vs standard to fix the peripheral venous catheter (PVC), on the incidence of phlebitis. A randomized controlled trial. INTRODUCTION: The type of dressing could contribute to the incidence of phlebitis, infiltration and accidental removals but the results of the studies are contrasting and samples are limited. AIM: To compare the effectiveness of a transparent polyurethane sterile dressing on the rate of phlebitis associated to peripheral venous catheter (PVC) vs a non sterile sticking plaster in use in current practice (standard dressing). DESIGN: Randomized controlled trial. Participants. 1061 PVCs (703 patients, adults and children) at a research orthopedic hospital in the north of Italy; 540 PVCs allocated to receive the sterile and 521 the standard dressing. RESULTS: 96 PVCs were excluded for phlebitis, 48 (9.6%) in the sterile and 48 (10.1%) in the standard dressing group, RR 0.96 (95%CI 0.697 - 1.335). Accidental removal of the PVCs was more frequent with the sterile dressing (9.6% vs 6.3%) but the number of catheters removed without complications was larger in the standard dressing group (48.9% vs 54.9% P=0.0503). Eighty-five PVCs were replaced for detachment of the dressing (50, 9.2% sterile and 35, 6.7% standard dressing). The cheapest transparent sterile dressing costs 32 cents while the standard 9 cents. CONCLUSIONS: A sticking non sterile plasters is not influential on the rate of phlebitis and ensures an good fix of the PVC compared the transparent sterile dressing to of polyurethane film. PMID- 22825294 TI - [Psychological wellbeing and risk of anxiety/depression in nursing students measured with the General Health Questionnaire-12 ]. AB - Psychological wellbeing and risk of anxiety/depression in nursing students, measured with the General Health Questionnaire-12. Introduction. Psychological wellbeing facilitates the learning performance while emotional problems such as anxiety/depression limit it and may impact on future professional practice. OBJECTIVES: To assess the prevalence of anxiety/depression in nursing students in Rome, at the beginning of the annual course. METHODS: An observational study was conducted administering the 12 items General Health Questionnaire (GHQ-12) to 601 students at the beginning of the annual course. Students were labeled at risk for anxiety and depression with GHQ-12 scores >5. A logistic regression model was used to identify factors associated to anxiety and depression. RESULTS: Thirty four per cent (39% of the females) of the students were at risk for anxiety/depression. The risk was higher for female students (OR=2.9; 95%CI 1.6 5.2; p<0.001), in those unsatisfied with the academic results (OR 2.3; 95%CI 1.4 3.9; p=0.002) and with their general health status (OR=0.4; 95%CI 0.3-0.7; p<=0.001). CONCLUSIONS: The risk for anxiety and depression is high among nursing students, especially for females. A screening since the first year would help to identify subject at risk that could benefit from specific interventions. PMID- 22825295 TI - [Clinical indicators of "ineffective breathing pattern" in children with congenital heart disease]. AB - Clinical indicators of ineffective breathing pattern in children with congenital heart disease. OBJECTIVES: To analyze the accuracy of clinical predictors of nursing diagnosis "Ineffective breathing pattern in children with congenital heart disease". METHOD: 1:1 case-control study with 30 children with congenital heart disease. Fifteen children with the nursing diagnosis "Ineffective breathing pattern" (cases) were compared with other 15 without this diagnosis (controls). A total of 15 clinical indicators were analyzed for their sensibility, specificity, predictive values, likelihood ratios and area under the ROC curve. RESULTS: Four indicators showed an area under the ROC curve > 70%: chest x-ray findings (0.750), adventitious breath sounds (0.737), coughing (0.710) and asymmetric chest expansion (0.702). The indicators of the chest x-ray findings and adventitious breath sounds had a better overall performance for the identification of ineffective breathing pattern. DISCUSSION: These findings suggest that both indicators can be useful for inference of ineffective breathing pattern. Moreover, the presence of the diagnosis was associated with a greater likelihood of the presence of cough, and its absence with an increased probability of the absence of asymmetric chest expansion and percussive sounds. CONCLUSIONS: The comparison among populations with different diseases and carriers of the same nursing diagnosis shows that the predictive ability of clinical indicators can be influenced. PMID- 22825296 TI - [Multicentre, prospective cohort study, to validate the Italian version of the Braden Q scale for the risk of the pressure sores in newborns and up to 8 years old children]. AB - Multicenter prospective cohort study, to validate the Italian version of the Braden Q scale for the risk of pressure sores in newborns and up to 8 years old children. INTRODUCTION: Children admitted to Intensive care Units (ICU), oncology and neurology/neurosurgery wards are at risk of developing pressure sores. AIM: To validate the Italian version of the Braden Q scale for the assessment of the risk of developing pressure sores in children. METHODS: Children from 21 days to 8 years, admitted to intensive and sub intensive units were recruited. Premature babies, children admitted with a pressure sore and with a story of congenital cardiomiopathy were excluded. In this cohort, multicentre and with repeated measurements study, the first assessment was performed after 24 hours from hospital admission, using the Braden Q Scale (Suddaby's version). The pressure sores were assessed with the Skin assessment Tool and staged according to the National Pressure Ulcer Advisory Panel. RESULTS. On the 157 children 524 observation were conducted. The incidence of pressure sores was 17.2%. Only the analysis on specific subgroups of patients showed a good diagnostic accuracy: 71.4% on children 3-8 years; 85.6% in sub intensive wards. CONCLUSIONS: The Braden Q scale may be reliably used and shows a good diagnostic accuracy in children 3-8 years of age admitted to sub-intensive, neurology, oncology and heamatology wards. PMID- 22825297 TI - [Effective transfer of information and responsibilities with handover: a literature review]. AB - Effective transfer of information and responsibilities with handover: a literature review. INTRODUCTION: The simultaneous and interactive transfer of information between health care workers, on patients' conditions is defined handover. The transfer of information implies also the transfer of responsibility and creates the conditions to guarantee patients' safety; however written or verbal handovers are often incomplete, inaccurate and may last longer than feasible for the organization. AIMS: The aim of the review was to identify the strategies to guarantee an effective transmission of clinical information with the handover. METHODS: The literature was searched in Medline and Cinahl including articles published in English and Italian (limits adults <19 years) up to 2011. RESULTS: Over 153 articles retrieved, 44 were analyzed. With the manual search further 11 (articles, chapter of books) were obtained. Several methods for organizing handover and selecting the information to pass over were identified. The preferred method is the bedside handover, although its use influenced by the context. As expected, the choice of the model to be used must rely on a series of local factors, above all the organizational model. Conclusions. Further studies are needed to explore the optimal integration of written and verbal information, to avoid redundancies but guaranteeing, at the same time, the transmission of information essential for care planning and patient's safety. PMID- 22825298 TI - [Listening to and learning from a research made by "children-poets"]. AB - Listeming to and learning from a research made by "children-poets". Cartorime (cartolina/postcard-rhyme) is a "strange" book of poems written by children who encountered suffering, fear, marginalization (children with cancer, hurt by the earthquake, gipsies). Through their words the "children-poets" tell us how hard is the way, but also that everything may become easier if, together, we learn how to enjoy colors, life, and to learn to write, speak and understand the language of poetry. The 27 Cartorime can be sent, flicked through as a book: they take us in a travel where the words become image, shape, drawing, color, taking the hope and courage of inventing life. The Cartorime help to support the projects of the charity Association Zeroconfini. PMID- 22825299 TI - [Manifesto for the strengthening of health care personnel. A collective responsibility to guarantee the right to health]. AB - Manifesto for the strengthening of health care personnel. A collective responsibility to guarantee the right to health. The migration of medical practitioners and nurses causes the loss of human resources compromising the capacity of the health system of developing countries to deliver health care equitably. It is unlikely that migration will stop given the advances in global communication and the scarcity of nursing resources in developed countries. The Manifesto reframes this problem as a collective responsibility and proposes solutions to protect the right of migrating nurses and to start cooperative programs to promote their return to original countries, with enhanced competences and skills. PMID- 22825301 TI - Hypertension: Understanding patients' perceptions could improve therapy. PMID- 22825302 TI - Fatty acid-binding protein 5 promotes cell proliferation and invasion in human intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is a rare primary malignant liver tumor with an extremely poor prognosis. Recently its incidence has increased, however, little attention has been directed to factors related to its molecular carcinogenesis, including oncogenes, tumor suppressor genes and cell cycle related proteins. ICC is generally characterized by strong proliferation, invasion and early metastasis. These biological behaviors of ICC, with respect to the genetic and molecular aspects, remain to be clarified. In this study, we performed a proteomic analysis to identify the proteomic alterations associated with carcinogenesis of ICC. Protein expression profiles of sixteen cases of ICC were compared with those of adjacent non-involved bile duct tissue. Among the 151 protein spots that showed a statistically significant expression difference (P<0.05), there were 50 spots with significantly increased intensity (3-fold increase) and 17 spots with decreased intensity (3-fold decrease) in cancerous tissues. Of these, increased expression of fatty acid-binding protein 5 (FABP5) was further confirmed by western blot analysis and immunohistochemical analysis. Immunohistochemical analysis of FABP5 expression in tumor specimens obtained from 43 patients with mass-forming (MF) type ICC showed a positive correlation of FABP5 immunoreactivity with tumor size (P=0.047), lymph node metastasis (P=0.013), angioinvasion (P=0.032) and staging (P=0.007). In addition, silencing FABP5 with short hairpin RNA (shRNA) suppressed cell proliferation and invasiveness in HuCCT1 cells, and conversely, overexpression of FABP5 in FABP5 negative Hep3B cells increased cell proliferation and invasiveness. Our study shows that FABP5 is significantly overexpressed in ICC combined lymph node metastasis and is involved in cell proliferation and invasion in vitro. Our data suggest that FABP5 may be associated with tumor progression in ICC. PMID- 22825303 TI - Quantification of IFNgamma- and IL17-producing cells after stimulation with citrullinated proteins in healthy subjects and RA patients. AB - Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA) and are currently used as a diagnostic marker. In this study, we wanted to quantify the numbers of T cells that react to a wide range of citrullinated proteins in a wide range of HLA-DR subtypes in order to investigate whether citrullination might create T-cell neo-epitopes and could initiate a universal T-cell response. Therefore, PBMCs from healthy volunteers and RA patients were stimulated with a citrullinated and non-citrullinated cell extract on IFNgamma-ELISpot. We found a significantly higher number of IFNgamma-secreting cells after stimulation with citrullinated proteins compared to non-citrullinated proteins in RA patients (1:14,441 cells vs. 1:32,880 cells) as well as in healthy subjects (1:6,261 reactive cells compared to 1:16,212 cells). Additionally, a higher number of IL17-secreting cells were found after stimulation with citrullinated proteins compared to their non-citrullinated counterparts. Our data indicate that citrulline-dependent T-cell response is not restricted to RA patients but that citrullination as such gives rise to a universal break in tolerance. PMID- 22825304 TI - Rheumatologic diseases and posterior reversible encephalopathy syndrome: two case reports and review of the literature. AB - Rheumatologic diseases have varied clinical presentations, and posterior reversible encephalopathy syndrome (PRES) can be one of their presentations. The exact etiology of PRES is unknown, but endothelial dysfunction and immunosuppressive medications seem to be the likely cause in rheumatologic diseases. Clinical features include headaches, seizures, altered mental status, cortical blindness, vomiting, and focal neurologic deficits. The diagnosis of PRES can be difficult because several neuropsychiatric illnesses are generally prevalent in rheumatologic diseases; however, a high index of suspicion among physicians along with neuroimaging can help in the accurate diagnosis. Treatment guidelines are lacking, but in a few case series, lowering the blood pressure, controlling the seizures, and removing the immunosuppressive drugs have shown good results. There is need for randomized controlled trials addressing the treatment of PRES in rheumatologic diseases. Medline search was done from year 1950 to March 2011 using "posterior reversible encephalopathy" as keyword, and articles relevant to rheumatology were reviewed. We found 48 case reports showing PRES in patients with rheumatologic disease. Most of the patients were female. Age range was from 6 to 59 years. Out of the 48 case reports, 38 patients had systemic lupus erythematosus and most of them had renal disease. Five patients with autoimmune diseases presented with PRES after being started on immunomodulatory drugs. The most frequent symptoms were headache, seizures, and visual changes. PMID- 22825305 TI - Sacrificial template-directed synthesis of mesoporous magnesium oxide architectures with superior performance for organic dye adsorption [corrected]. AB - Mesoporous MgO architectures were successfully synthesized by the direct thermal transformation of the sacrificial oxalate template. The as-prepared mesoporous architectures were characterized by X-ray diffraction (XRD), scanning electronic microscopy (SEM), transmission electron microscopy (TEM), X-ray energy dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FTIR), and nitrogen adsorption-desorption techniques. The MgO architectures showed extraordinary adsorption capacity and rapid adsorption rate for removal of Congo red (CR) from water. The maximum adsorption capacity of the MgO architectures toward CR reached 689.7 mg g-1, much higher than most of the previously reported hierarchical adsorbents. The CR removal process was found to obey the Langmuir adsorption model and its kinetics followed pseudo-second-order rate equation. The superior adsorption performance of the mesoporous MgO architectures could be attributed to the unique mesoporous structure, high specific surface area as well as strong electrostatic interaction. PMID- 22825306 TI - Interleukin-18-induced inflammatory responses in synoviocytes and chondrocytes from osteoarthritic patients. AB - The major pathological changes of osteoarthritis (OA) include cartilage degeneration and synovial inflammation. Previous studies confirmed that interleukin-1 (IL-1) stimulates the secretion of multiple inflammatory factors in synoviocytes and chondrocytes. IL-18 is a member of the IL-1 superfamily. In this study, the pro-inflammatory effects of IL-18 on synoviocytes and chondrocytes in patients with OA were investigated. Knee synovial membrane and cartilage samples were obtained from OA patients, then primary cells were cultured. Synoviocytes and primary chondrocytes at different generations (primary, secondary and tertiary), were stimulated with IL-18, then inflammatory marker levels, including tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2), were measured using reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. IL-1 receptor antagonist (IL-1Ra) was applied to interfere with the IL-18 stimulation of chondrocytes, and then the COX-2 expression in chondrocytes and the PGE2 levels in the medium were measured. The expression of IL-18 receptor alpha (IL-18Ralpha) and IL-18 receptor beta (IL-18Rbeta) in synoviocytes and chondrocytes was assessed, using RT-PCR. Our results showed that IL-18 stimulated the COX-2 and TNF-alpha expressions in primary synoviocytes, while increasing PGE2 and TNF alpha levels in the supernatant (P<0.05) of the culture medium in primary synoviocytes. IL-18 also induced high PGE2 level production in second-generation synoviocytes (P<0.05). Moreover, IL-18 upregulated COX-2 and TNF-alpha mRNA in chondrocytes, while promoting PGE2 and TNF-alpha (P<0.05) secretions in a dose dependent manner. The induced effects were not attenuated by the addition of IL 1Ra (P<0.05). IL-18Ralpha was expressed in the chondrocytes and synoviocytes of 4/8 patients, while IL-18Rbeta was expressed in the chondrocytes of 4/8 patients and in the synoviocytes of 2/8 patients. We conclude that IL-18 induces inflammatory responses in synoviocytes and chondrocytes and that this effect was correlated with, although not entirely dependent on, IL-1beta. PMID- 22825307 TI - Simple and convenient access to alpha,alpha,alpha-trisubstituted amides by double addition of Grignard reagents to acyl cyanohydrins. AB - The double addition of Grignard (alkyl, aryl, alkenyl, alkynyl) reagents to acyl cyanohydrins was performed under unusually smooth conditions with a concomitant O N acyl transfer, providing a very simple and general access to alpha,alpha,alpha trisubstituted amides. PMID- 22825308 TI - A multi-axis MEMS sensor with integrated carbon nanotube-based piezoresistors for nanonewton level force metrology. AB - This paper presents the design and fabrication of a multi-axis microelectromechanical system (MEMS) force sensor with integrated carbon nanotube (CNT)-based piezoresistive sensors. Through the use of proper CNT selection and sensor fabrication techniques, the performance of the CNT-based MEMS force sensor was increased by approximately two orders of magnitude as compared to current CNT based sensor systems. The range and resolution of the force sensor were determined as 84 MUN and 5.6 nN, respectively. The accuracy of the force sensor was measured to be better than 1% over the device's full range. PMID- 22825309 TI - Involvement of phospholipase C-gamma in the pro-survival role of glial cell line derived neurotrophic factor in developing motoneurons in rat spinal cords. AB - The glial cell line-derived neurotrophic factor (GDNF) has been proven to be the most powerful neurotrophic factor in neuronal development. However, it remains uncertain as to which intracellular signaling pathway interacting with GDNF is invovlved in motoneuron (MN) development. In this study, we investigated whether phosphoinositide phospholipase C-gamma (PLC-gamma) is involved in GDNF-promoted MN development. The primary spinal MNs from 12- to 14-day-old embryos of Sprague Dawley rats were cultured and survival was sustained by GDNF. A specific inhibitor of PLC-gamma, 1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione (U73122), was used to block the pro-survival effect of GDNF. Our results showed that MN-like cells appeared at 72 h after initial implantation and were sustained for a period of up to seven days under GDNF treatment. These cultured MNs expressed neuron-specific enolase, SMI-32, 75 kDa low-affinity neurotrophic receptor and choline acetyltransferase. The survival rate of the cultured MNs at 24 h was significantly lower in the GDNF + U73122-treated group (31.87+/-2.17%), compared either with that of the GDNF- (81.38+/-1.13%) or GDNF + DMSO (79.39+/-1.22%)-treated groups. The present data suggest that PLC-gamma may be one of the intracellular signals that play a role in the survival-promoting effects of GDNF in developing spinal MNs. PMID- 22825310 TI - Vacuolar dynamics and replicative aging. PMID- 22825311 TI - Association of shorter leukocyte telomere repeat length with dementia and mortality. AB - BACKGROUND: Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. OBJECTIVE: To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality. DESIGN: We studied available stored leukocyte DNA from a community-based study of aging using realtime polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence. SETTING: A multiethnic community-based study of aging and dementia. PARTICIPANTS: One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia. RESULTS: The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P.001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P=.05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only. CONCLUSION: Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging. PMID- 22825312 TI - Structural landscape of benzoic acid: using experimental crystal structures of fluorobenzoic acids as a probe. AB - Experimental crystal structures of mono and polyfluorinated benzoic acids correspond to high energy computed crystal structures of benzoic acid itself, thereby permitting access to its structural landscape. PMID- 22825313 TI - The impact of tumor microenvironment on cancer treatment and its modulation by direct and indirect antivascular strategies. AB - Tumor cells exploit their microenvironment by growth factors and cytokines such as vascular endothelial growth factor (VEGF) to stimulate abnormal vessel formation that is leaky and tortuous, causing irregular blood flow. The combination of poor perfusion, raised interstitial fluid pressure and areas of vascular collapse leads to hypoxia within tumor. The latter activates factors such as hypoxia inducible factor 1 (HIF-1) that serve to make cancer cells more aggressive and also markedly influences the response of malignant tumors to conventional irradiation and chemotherapy. Accumulating data now suggest that blockade of oncogenic signaling, for example by PI3K/Akt/mTOR inhibitors, might consist a promising strategy since these agents do not only possess antitumor effects but can also alter tumor vasculature and oxygenation to improve the response to radiation and chemotherapy. In many cases, these changes are related to downregulation of HIF-1alpha and VEGF. Here, we review the pathophysiology of tumor microenvironment (TME) and how it adversely affects cancer treatment. The complex interaction of tumor vasculature and radiotherapy is examined together the preclinical evidence supporting a proinvasive/metastatic role for ionising radiation. We will discuss the expanding role of oncogenic signaling, especially PI3K/Akt/mTOR, on tumor angiogenesis. Special emphasis will be paid to the potential of different oncogenic pathways blockade and other indirect antivascular strategies to alter the TME for the benefit of cancer treatment, as an alternative to the classical angiogenetic treatment. PMID- 22825314 TI - Genome-wide analysis of copy number variations reveals that aging processes influence body fat distribution in Korea Associated Resource (KARE) cohorts. AB - Many anthropometric measures, including body mass index (BMI), waist-to-hip ratio (WHR), and subcutaneous fat thickness, are used as indicators of nutritional status, fertility and predictors of future health outcomes. While BMI is currently the best available estimate of body adiposity, WHR and skinfold thickness at various sites (biceps, triceps, suprailiac, and subscapular) are used as indices of body fat distribution. Copy number variation (CNV) is an attractive emerging approach to the study of associations with various diseases. In this study, we investigated the dosage effect of genes in the CNV genome widely associated with fat distribution phenotypes in large cohorts. We used the Affymetrix genome-wide human SNP Array 5.0 data of 8,842 healthy unrelated adults in KARE cohorts and identified CNVs associated with BMI and fat distribution related traits including WHR and subcutaneous skinfold thickness at suprailiac (SUP) and subscapular (SUB) sites. CNV segmentation of each chromosome was performed using Golden Helix SVS 7.0, and single regression analysis was used to identify CNVs associated with each phenotype. We found one CNV for BMI, 287 for WHR, 2,157 for SUP, and 2,102 for SUB at the 5% significance level after Holm Bonferroni correction. Genes included in the CNV were used for the analysis of functional annotations using the Database for Annotation, Visualization and Integrated Discovery (DAVID v6.7b) tool. Functional gene classification analysis identified five significant gene clusters (metallothionein, ATP-binding proteins, ribosomal proteins, kinesin family members, and zinc finger proteins) for SUP, three (keratin-associated proteins, zinc finger proteins, keratins) for SUB, and one (protamines) for WHR. BMI was excluded from this analysis because the entire structure of no gene was identified in the CNV. Based on the analysis of genes enriched in the clusters, the fat distribution traits of KARE cohorts were related to the fat redistribution associated with the aging process. In addition to structural variation, dosage effect analysis of genes based on CNV is useful to gain an understanding of the comprehensive biological phenomena underlying particular phenotypes and/or diseases. PMID- 22825315 TI - Population stratification may bias analysis of PGC-1alpha as a modifier of age at Huntington disease motor onset. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1alpha, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation. PMID- 22825317 TI - Mutations in the sarcosine dehydrogenase gene in patients with sarcosinemia. AB - Sarcosinemia is an autosomal recessive metabolic trait manifested by relatively high concentrations of sarcosine in blood and urine. Sarcosine is a key intermediate in 1-carbon metabolism and under normal circumstances is converted to glycine by the enzyme sarcosine dehydrogenase. We encountered six families from two different descents (French and Arab), each with at least one individual with elevated levels of sarcosine in blood and urine. Using the "candidate gene approach" we sequenced the gene encoding sarcosine dehydrogenase (SARDH), which plays an important role in the conversion of sarcosine to glycine, and found four different mutations (P287L, V71F, R723X, R514X) in three patients. In an additional patient, we found a uniparental disomy in the region of SARDH gene. In two other patients, we did not find any mutations in this gene. We have shown for the first time that mutations in the SARDH gene are associated with sarcosinemia. In addition, our results indicate that other genes are most probably involved in the pathogenesis of this condition. PMID- 22825316 TI - Network medicine: linking disorders. AB - The molecular events underlying many human hereditary disorders remain to be discovered despite the significant advances made in molecular biology and genetics in the past years. Given the complexity of cellular systems and the interplay between different functional modules, it is becoming increasingly evident that profound insights into human disease cannot be derived by analyzing single genetic defects. The generation of different types of disease interaction networks has recently emerged as a unifying approach that holds the promise of shedding some light on common pathological mechanisms by placing the single disorders into a larger context. In this review, I summarize the rationale behind these disease networks and different ways of constructing them. Finally, I highlight some of the first results that have been obtained by systematically analyzing the intertwined relationships between human disorders because they suggest that the current disease classification does not always sufficiently reflect biologically and medically relevant disease relationships. PMID- 22825318 TI - Transdermal delivery of three vitamin C derivatives by Er:YAG and carbon dioxide laser pretreatment. AB - The objective of this study was to investigate the effects of two lasers (Er:YAG and CO2) in enhancing skin permeation of three vitamin C derivatives, L-ascorbic acid 2-phosphate sesquimagnesium salt (MAP-1), magnesium L-ascorbic acid-2 phosphate (MAP-2), and 2-phospho-L-ascorbic acid trisodium salt (SAP). Dorsal skin of 1-week-old pathogen-free pigs was used for this in vitro study. Changes in permeation in laser-treated skin treated by the lasers were examined by confocal scanning electron microscopy. Transdermal flux of vitamin C derivatives was examined with a Franz diffusion cell. Fluxes of MAP-1, MAP-2, and SAP across Er:YAG laser-treated skin were 15-27-fold, 48-123-fold, and 22-56-fold higher, respectively, than their fluxes across intact skin. The fluxes of MAP-1, MAP-2, and SAP across CO2 laser-treated skin were 28-36-fold, 116-156-fold, and 79-102 fold higher, respectively, than their fluxes across intact skin. Optimal fluency for the Er:YAG laser was 3.8 J/cm(2) for MAP-1 and 5 J/cm(2) for MAP-2 and SAP. Optimal fluency for the CO2 laser was 5 W for all three derivatives. In conclusion, optimal fluency for all derivatives was 5 W for the CO2 laser and 3.8 to 5 J/cm(2) for the Er:YAG laser. PMID- 22825319 TI - Biomechanical effect of one session of low-level laser on the bone-titanium implant interface. AB - Low-level laser (LLL) has been used on peri-implant tissues for accelerating bone formation. However, the effect of one session of LLL in the strength of bone implant interface during early healing process remains unclear. The present study aims to evaluate the removal torque of titanium implants irradiated with LLL during surgical preparation of implant bed, in comparison to non-irradiation. Sixty-four Wistar rats were used. Half of the animals were included in LLL group, while the other half remained as control. All animals had the tibia prepared with a 2 mm drill, and a titanium implant (2.2 * 4 mm) was inserted. Animals from LLL group were irradiated with laser (gallium aluminum arsenide), with a wavelength of 808 nm, a measured power output of 50 mW, to emit radiation in collimated beams (0.4 cm(2)), for 1 min and 23 s, and an energy density of 11 J/cm(2). Two applications (22 J/cm(2)) were performed immediately after bed preparation for implant installation. Flaps were sutured, and animals from both groups were sacrificed 7, 15, 30, and 45 days after implant installation, when load necessary for removing implant from bone was evaluated by using a torquimeter. In both groups, torque values tended to increase overtime; and at 30 and 45 days periods, values were statistically higher for LLL group in comparison to control (ANOVA test, p < 0.0001). Thus, it could be suggested that a single session of irradiation with LLL was beneficial to improve bone-implant interface strength, contributing to the osseointegration process. PMID- 22825321 TI - Solution-processed nickel acetate as hole collection layer for polymer solar cells. AB - We report efficient polymer solar cells (PSCs) based on poly(3-hexylthiophene) (P3HT) and indene-C(60) bisadduct (ICBA) with water soluble nickel acetate (NiAc) instead of acidic poly(ethylenedioxythiophene) : poly(styrene sulfonate) (PEDOT : PSS) as hole collection layer (HCL). The NiAc layer after thermal annealing at 150 degrees C for 30 min (alpha-NiAc) shows high transparency with light transmittance better than PEDOT : PSS in the wavelength range of 500-900 nm, high hole mobility of 1.3 * 10(-3) cm(2) V(-1) s(-1) and suitable energy levels for application as HCL. The power conversion efficiency of the PSC based on P3HT/ICBA with the alpha-NiAc anode buffer layer reached 6.08% under the illumination of AM1.5G 100 mW cm(-2), which is among the best efficiencies of the P3HT-based PSCs. This work gives a new option for HCL selection in designing higher efficiency and more stable PSCs. PMID- 22825322 TI - Facilitating drug discovery: an automated high-content inflammation assay in zebrafish. AB - Zebrafish larvae are particularly amenable to whole animal small molecule screens due to their small size and relative ease of manipulation and observation, as well as the fact that compounds can simply be added to the bathing water and are readily absorbed when administered in a <1% DMSO solution. Due to the optical clarity of zebrafish larvae and the availability of transgenic lines expressing fluorescent proteins in leukocytes, zebrafish offer the unique advantage of monitoring an acute inflammatory response in vivo. Consequently, utilizing the zebrafish for high-content small molecule screens aiming at the identification of immune-modulatory compounds with high throughput has been proposed, suggesting inflammation induction scenarios e.g. localized nicks in fin tissue, laser damage directed to the yolk surface of embryos or tailfin amputation. The major drawback of these methods however was the requirement of manual larva manipulation to induce wounding, thus preventing high-throughput screening. Introduction of the chemically induced inflammation (ChIn) assay eliminated these obstacles. Since wounding is inflicted chemically the number of embryos that can be treated simultaneously is virtually unlimited. Temporary treatment of zebrafish larvae with copper sulfate selectively induces cell death in hair cells of the lateral line system and results in rapid granulocyte recruitment to injured neuromasts. The inflammatory response can be followed in real-time by using compound transgenic cldnB::GFP/lysC::DsRED2 zebrafish larvae that express a green fluorescent protein in neuromast cells, as well as a red fluorescent protein labeling granulocytes. In order to devise a screening strategy that would allow both high-content and high-throughput analyses we introduced robotic liquid handling and combined automated microscopy with a custom developed software script. This script enables automated quantification of the inflammatory response by scoring the percent area occupied by red fluorescent leukocytes within an empirically defined area surrounding injured green fluorescent neuromasts. Furthermore, we automated data processing, handling, visualization, and storage all based on custom developed MATLAB and Python scripts. In brief, we introduce an automated HC/HT screen that allows testing of chemical compounds for their effect on initiation, progression or resolution of a granulocytic inflammatory response. This protocol serves a good starting point for more in-depth analyses of drug mechanisms and pathways involved in the orchestration of an innate immune response. In the future, it may help identifying intolerable toxic or off-target effects at earlier phases of drug discovery and thereby reduce procedural risks and costs for drug development. PMID- 22825323 TI - The use of KTP laser in revision stapedectomy. AB - OBJECTIVE: Revision stapes operations have lower success rates than primary surgeries. Success rates have increased since the introduction of the laser. Visible (KTP, argon) and infrared (CO2) spectrum lasers have been used in stapes surgery. A concern has been raised regarding the use of visible lasers in revision stapedectomy because of their properties of tissue penetrance. The objective of our study is to evaluate a series of patients who underwent revision stapedectomy with the use of KTP laser to determine whether there is an increased risk of sensorineural hearing loss associated with the use of this laser. PATIENTS: Patients with otosclerosis requiring revision stapedectomy. INTERVENTION: Revision stapedectomy or stapedotomy were performed using the KTP laser. MAIN OUTCOME MEASURE: The primary outcome evaluated was the incidence of postoperative sensorineural hearing loss. Improvement in air-bone gap was evaluated as a secondary outcome. RESULTS: There were no cases of postoperative sensorineural hearing loss or deafness. Approximately 56.5% of patients achieved closure of the postoperative ABG to within 10 dB; 91.3% of patients achieved a postoperative ABG within 20 dB. The KTP laser was used most commonly to lyse fibrous adhesions. CONCLUSION: Although there is a theoretical risk of penetrance of the KTP laser through the oval window and underlying perilymph with resultant damage to the sense organ-containing endolymph, this theoretical risk did not translate into an increased rate of sensorineural hearing loss in our series. The KTP laser allowed for less traumatic clearing of middle ear adhesions and good hearing results. PMID- 22825324 TI - Clinical efficacy of anti-IgE therapy for eosinophilic otitis media. AB - OBJECTIVE: Eosinophilic otitis media (EOM) is an intractable otitis media characterized by a highly viscous effusion containing eosinophils, and high levels of immunoglobulin (Ig) E are detected in the middle ear effusion (MEE). We carried out a pilot study to determine whether anti-IgE therapy is efficacious in the treatment of EOM. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS AND METHODS: Eight patients with EOM received the anti-IgE agent omalizumab for at least 3 months, in addition to ordinary treatments for EOM. They were evaluated by a questionnaire for ear and respiratory symptoms, clinical scores, surrogate markers in the blood, and hearing acuity before and after the anti-IgE therapy. Nine EOM patients without anti-IgE therapy were included as controls. RESULTS: The ear symptom scores and clinical scores gradually decreased during the therapy. In particular, 5 patients who were treated for more than 1 year showed improvement of their clinical scores with resolution of the MEE. The total serum IgE level was significantly elevated after 3 months of therapy (p < 0.01). Deterioration of the bone conduction hearing levels was more frequently found in the control group than in the omalizumab group. CONCLUSION: This pilot study provides new evidence establishing that long-term anti-IgE therapy improved the clinical ear symptoms of EOM and bone conduction hearing levels were mostly preserved. Therefore, long-term anti-IgE therapy can be effective for EOM to inhibit eosinophilic inflammation in the middle ear. PMID- 22825325 TI - Medical strategies for treatment of castration resistant prostate cancer (CRPC) docetaxel resistant. AB - Current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Cabazitaxel, a new taxane with potential antineoplastic activity, has been approved by Food and Drug Administration (FDA) after docetaxel failure. In a phase III trial, cabazitaxel showed increased overall survival (OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Furthermore, chemotherapy is not the only strategy available: several studies have shown as CRPC remains dependent on androgen receptor function for growth. Abiraterone acetate, an irreversible inhibitor of CYP17, has also been approved by FDA after docetaxel failure. In a phase III trial comparing abiraterone acetate to placebo, abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR 0.65, 95% CI 0.54-0.77; p < 0.0001). This review will discuss current options and the ongoing trials for second-line treatment of CRPC including chemotherapy, hormonal therapies, antiangiogenetic and immune strategies. PMID- 22825326 TI - Protein expression changes during human triple negative breast cancer cell line progression to lymph node metastasis in a xenografted model in nude mice. AB - Triple negative breast cancers (TNBC) lacking hormone receptors and HER-2 amplification are very aggressive tumors. Since relevant differences between primary tumors and metastases could arise during tumor progression as evidenced by phenotypic discordances reported for hormonal receptors or HER-2 expression, in this analysis we studied changes that occurred in our TNBC model IIB-BR-G throughout the development of IIB-BR-G-MTS6 metastasis to the lymph nodes (LN) in nude mice, using an antibody-based protein array to characterize their expression profile. We also analyzed their growth kinetics, migration, invasiveness and cytoskeleton structure in vitro and in vivo. In vitro IIB-BR-G-MTS6 cells grew slower but showed higher anchorage independent growth. In vivo IIB-BR-G-MTS6 tumors grew significantly faster and showed a 100% incidence of LN metastasis after s.c. inoculation, although no metastasis was observed for IIB-BR-G. CCL3, IL1beta, CXCL1, CSF2, CSF3, IGFBP1, IL1alpha, IL6, IL8, CCL20, PLAUR, PlGF and VEGF were strongly upregulated in IIB-BR-G-MTS6 while CCL4, ICAM3, CXCL12, TNFRSF18, FIGF were the most downregulated proteins in the metastatic cell line. IIB-BR-G-MTS6 protein expression profile could reflect a higher NFkappaB activation in these cells. In vitro, IIB-BR-G displayed higher migration but IIB BR-G-MTS6 had more elevated matrigel invasion ability. In agreement with that observation, IIB-BR-G-MTS6 had an upregulated expression of MMP1, MMP9, MMP13, PLAUR and HGF. IIB-BR-G-MTS6 tumors presented also higher local lymphatic invasion than IIB-BR-G but similar lymphatic vessel densities. VEGFC and VEGFA/B expression were higher both in vitro and in vivo for IIB-BR-G-MTS6. IIB-BR-G-MTS6 expressed more vimentin than IB-BR-G cells, which was mainly localized in the cellular extremities and both cell lines are E-cadherin negative. Our results suggest that IIB-BR-G-MTS6 cells have acquired a pronounced epithelial-to mesenchymal transition phenotype. Protein expression changes observed between primary tumor-derived IIB-BR-G and metastatic IIB-BR-G-MTS6 TNBC cells suggest potential targets involved in the control of metastasis. PMID- 22825327 TI - Gadd45a inhibits cell migration and invasion by altering the global RNA expression. AB - Gadd45a, the first well-defined p53 downstream gene, can be induced by multiple DNA-damaging agents, which plays important roles in the control of cell cycle checkpoint, DNA repair process and signaling transduction. Our previous findings suggested that Gadd45a maintains cell-cell adhesion and cell contact inhibition. However, little is known about how Gadd45a participates in the suppression of malignancy in human cancer cells. To examine the functions of Gadd45a in cell invasion and metastasis, we performed the adhesion, wound-healing and transwell assays in Gadd45a (+/+) and Gadd45a (-/-) MEF cell lines. We found the adhesion, migration and invasive abilities were much higher in Gadd45a deficient cells. We furthermore applied high-throughput cDNA microarray analysis and bioinformatics analysis to analyze the mechanisms of Gadd45a gene in invasion and metastasis. Compared with the Gadd45a wild type cells, the Gadd45a deficient cells showed a wide range of transcripts alterations. The altered gene pathways were predicted by the MAS software, which indicated focal adhesion,cell communication,ECM-receptor interaction as the three main pathways. Real-time PCR was employed to validate the differentially expressed genes. Interestingly, we figured out that the deregulations of these genes are caused neither by genomic aberrations nor methylation status. These findings provided a novel insight that Gadd45a may involve in tumor progression by regulating related genes expressions. PMID- 22825328 TI - E2F-1 lacking the transcriptional activity domain induces autophagy. AB - The transcription factor E2F-1 plays a crucial role in the control of cell proliferation. E2F-1 has tumor suppressive properties by inducing apoptosis and autophagy. In this study, E2F-1 and its truncated form (E2Ftr), lacking the transactivation domain (TAD), were compared for their ability to induce autophagy. In Gaussia luciferase-based assays, both E2F-1 and E2Ftr induced the proteolytic cleavage of the autophagic marker LC3. In addition, LC3 and autophagy protein 5 (Atg5) were upregulated by E2F-1 and E2Ftr. Likewise, both E2F proteins induced a punctate pattern of GFP-tagged LC3, indicating autophagosome formation. The presence of double-membrane autophagic vesicles induced by E2F-1 and E2Ftr was confirmed by transmission electron microscopy (TEM). The application of z-VAD fmk, a caspase inhibitor, partially blocked both E2F-1 and E2Ftr-mediated cytotoxicity. Moreover, Atg5 (-/-) cells were more resistant to the E2F-1 or E2Ftr-induced cell killing effect than Atg5 wt cells. The TAD of E2F-1 is not essential for induction of autophagy; apoptosis and autophagy cooperate for an efficient cancer cell killing effect induced by E2F-1 or E2Ftr. E2Ftr-induced autophagy is a promising approach to destroy tumors that are resistant to conventional treatments. PMID- 22825329 TI - Regulation of oncogene-induced cell cycle exit and senescence by chromatin modifiers. AB - Oncogene activation leads to dramatic changes in numerous biological pathways controlling cellular division, and results in the initiation of a transcriptional program that promotes transformation. Conversely, it also triggers an irreversible cell cycle exit called cellular senescence, which allows the organism to counteract the potentially detrimental uncontrolled proliferation of damaged cells. Therefore, a tight transcriptional control is required at the onset of oncogenic signal, coordinating both positive and negative regulation of gene expression. Not surprisingly, numerous chromatin modifiers contribute to the cellular response to oncogenic stress. While these chromatin modifiers were initially thought of as mere mediators of the cellular response to oncogenic stress, recent studies have uncovered a direct and specific regulation of chromatin modifiers by oncogenic signals. We review here the diverse functions of chromatin modifiers in the cellular response to oncogenic stress, and discuss the implications of these findings on the regulation of cell cycle progression and proliferation by activated oncogenes. PMID- 22825330 TI - Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells. AB - Methylthioadenosine phosphorylase (MTAP), a key enzyme in the catabolism of 5' deoxy-5'-methylthioadenosine (MTA), catalyzes the formation of adenine and 5 methylthioribose-1-phosphate. MTAP is expressed in all cells throughout the body, but a significant percentage of human tumors have lost MTAP expression, thereby making MTAP-loss a potential therapeutic target. Here, we have tested an MTAP targeting strategy based on the idea that MTAP-expressing cells can be protected from toxic purine and uracil analogs by addition of MTA, but MTAP-deleted tumor cells cannot. Addition of as little as 10 MUM MTA could entirely protect isogenic MTAP (+) , but not MTAP (-) , HT1080 cells from toxicity caused by the chemotherapy agents 6-thioguanine (6TG) or 5-fluorouracil (5FU). Inhibitor studies showed that MTA protection requires functional MTAP activity. Addition of adenine protected both MTAP (+) and MTAP (-) cells from 6TG and 5FU, consistent with the idea that adenine produced from the MTAP reaction competes with 6TG and 5FU for a rate limiting pool of phosphoribosyl-1-pyrophosphate (PRPP), which is required for the conversion of purine and uracil bases into nucleotides. Extracellular MTA can also protect mouse mesothelioma cells from killing by 6-TG or the drug L-alanosine in an MTAP-dependent manner. In addition, MTA can protect non-transformed MTAP (+) mouse embryo fibroblasts from 6TG toxicity. Taken together, our data suggest that the addition of MTA to anti-purine-based chemotherapy may greatly increase the therapeutic index of this class of drugs if used specifically to treat MTAP (-) tumors. PMID- 22825331 TI - The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. AB - DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of gammaH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients. PMID- 22825334 TI - Cullin-3 protein expression levels correlate with breast cancer progression. AB - Cullin-3 is a component of the Cullin-Ring ubiquitin ligase (CRL) family that plays an important role in mediating protein degradation. Deregulation of Cullin 3 expression has been observed in human cancers; however, a role for Cullin-3 in tumor progression has not been previously recognized. Using the MCF10DCIS.com human breast cancer xenograft model, we show that Cullin-3 is increasingly expressed during progression from comedo ductal carcinoma in situ (DCIS) to invasive carcinomas. Cullin-3 protein is not detected in early lesions but is noticeably increased in DCIS tumors and significantly overexpressed in invasive cancers. In experimental metastasis assays, high expression of Cullin-3 was observed in the lung site. Importantly, Cullin-3 staining is detected in human breast cancer tissues, not in normal breast tissues and its expression level positively correlates with tumor stage. These data suggest that Cullin-3 may play an important role in tumor progression from DCIS to invasive cancer and may serve as a biomarker for the diagnosis of aggressive breast cancer. PMID- 22825332 TI - Autophagic action of new targeting agents in head and neck oncology. AB - The survival rates of patients with squamous cell carcinoma of the head and neck (HNSCC) have not improved significantly despite multi-modality therapy, including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes; for example, in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In HNSCC, the epidermal growth factor receptor antibody cetuximab has shown promising results in combination with radiation. Targeted agents including cetuximab induce stresses to activate prosurvival autophagy. Combining autophagy inhibitors with agents that induce autophagy as a prosurvival response may therefore increase their therapeutic efficacy. Whether autophagy contributes to the prosurvival response or to the antitumor effect of chemotherapeutic drugs is largely unknown. This review will discuss the possible role of autophagy as a novel target for anticancer therapy agents in HNSCC. PMID- 22825333 TI - Differential regulation of p21 (waf1) protein half-life by DNA damage and Nutlin 3 in p53 wild-type tumors and its therapeutic implications. AB - DNA damage induces the canonical p53 pathway including elevation of p21 (waf1) resulting in arrest of cell cycle progression. This can protect cells from subsequent Chk1 inhibition. Some p53 wild-type cancer cells such as HCT116 and U2OS exhibit attenuated p21 (waf1) induction upon DNA damage due to translational inhibition, and are incapable of maintaining arrest upon Chk1 inhibition. The purpose of this study was to determine whether this attenuated p21 (waf1) induction also occurred with the non-DNA damaging agent Nutlin-3 which induces p53 by disrupting binding to its negative regulator MDM2. We find that Nutlin-3 circumvented the attenuated induction of p21 (waf1) protein by increasing its half-life which led to G 1 and G 2 arrest in both cell lines. Interestingly, the p21 (waf1) protein half-life remained short on Nutlin-3 in p53 wild-type MCF10A cells; these cells achieve high p21 (waf1) levels through transcriptional upregulation. Consequently, all three p53 wild-type cells but not p53 mutant MDA-MB-231 cancer cells were protected from subsequent incubation with a combination of DNA damage plus a checkpoint inhibitor. PMID- 22825335 TI - pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma: a tissue-microarray study with clinic-pathological correlations. AB - The EGFR (epidermal growth factor receptor) a member of the family of transmembrane protein kinase receptors known as the erbB family shows a significant correlation with the presence of metastases and poorly differentiated oral cancer. Aim of the present work is to define the key-role of EGFR in oral cancer prognosis. We have analyzed the EGFR expression on 149 cases of oral squamous cell cancers (OSCC) and we have found that it was poorly expressed in normal oral epithelium, but its expression was significantly increased in OSCCs. Moreover, we have recorded that both pEGFR-Tyr 845 and pEGFR-Tyr 1068 were mainly distributed in high histological grading and in advanced stages. Western blotting has confirmed the total absence of EGFR phosphorylation in normal oral epithelium and the higher level of protein phosphorylation in representative cases of OSCCs. The EGF-R amplification was found by fluorescence in situ hybridization (FISH) in 14% of OSCC; interestingly, EGF-R amplification was mainly observed in OSCC with higher histological grading (G2 and G3) and advanced stage (pT4) sub-groups. Kaplan-Meyer survival analysis suggested that patients with positive pEGFR-Tyr 845 tumors had a worse prognosis and were bad responders to chemotherapy. These results confirm the central role of EGF-R activation status as a prognostic biomarker in OSCC. PMID- 22825336 TI - Interferon-gamma enhances radiation-induced cell death via downregulation of Chk1. AB - Interferon-gamma (IFNgamma) is a cytokine with roles in immune responses as well as in tumor control. Interferon is often used in cancer treatment together with other therapies. Here we report a novel approach to enhancement of cancer cell killing by combined treatment of IFNgamma with ionizing radiation. We found that IFNgamma treatment alone in HeLa cells induced phosphorylation of Chk1 in a time- and dose-dependent manner, and resulted in cell arrest. Moreover IFNgamma treatment was correlated with attenuation of Chk1 as the treatment shortened protein half-life of Chk1. As Chk1 is an essential cell cycle regulator for viability after DNA damage, attenuation of Chk1 by IFNgamma pre-treatment in HeLa cells resulted in increased cell death following ionizing radiation about 2-folds than ionizing radiation treatment alone whereas IFNgamma treatment alone had little effect on cell death. X-linked inhibitor of apoptosis-associated factor 1 (XAF1), an IFN-induced gene, seems to partly regulate IFNgamma-induced Chk1 destabilization and radiation sensitivity because transient depletion of XAF1 by siRNA prevented IFNgamma-induced Chk1 attenuation and partly protected cells from IFNgamma-enhanced radiation cell killing. Therefore the results provide a novel rationale to combine IFNgamma pretreatment and DNA-damaging anti-cancer drugs such as ionizing radiation to enhance cancer cell killing. PMID- 22825337 TI - Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3beta in NSCLC cells. AB - mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors has been modest in most cancer types. We have previously demonstrated that the activation of PI3K/Akt and MEK/ERK signaling pathways attenuates the anticancer efficacy of mTORC1 inhibitors. In this study, we report that mTORC1 inhibition also phosphorylates and inactivates GSK3beta, which is a tumor suppressor in lung cancer. Moreover, we show that perifosine, as an Akt inhibitor, decreases rapamycin-induced phosphorylation of GSK3beta and elevated p GSK3beta levels in rapamycin-resistant cell lines. Combination of perifosine with mTORC1 inhibitors showed enhanced anticancer efficacy both in cell cultures and in a xenograft mouse model. In addition, perifosine inhibits the growth of both rapamycin sensitive and resistant A549 cells. However, inhibition of GSK3beta by a selective inhibitor- LiCl, or downregulation of GSK3beta expression by siRNA, reverses the growth inhibitory effects of perifosine on rapamycin resistant cells, suggesting the important role of GSK3beta activation in enhancing mTORC1 inhibitors efficacy by perifosine. Thus, our results provide a potential therapeutic strategy to enhance mTORC1-targeted cancer therapy by using perifosine or targeting GSK3beta. PMID- 22825338 TI - Layered double hydroxides as carriers for quantum dots@silica nanospheres. AB - Quantum dot-hydrotalcite layered nanoplatforms were successfully prepared following a one-pot synthesis. The process is very fast and a priori delamination of hydrotalcite is not a prerequisite for the intercalation of quantum dots. The novel materials were extensively characterized by X-ray diffraction, thermogravimetry, infrared spectroscopy, transmission electron microscopy, true color fluorescence microscopy, photoluminescence, and nitrogen adsorption. The quantum dot-hydrotalcite nanomaterials display extremely high stability in mimicking physiological media such as saline serum (pH 5.5) and PBS (pH 7.2). Yet, quantum dot release from the solid structure is noted. In order to prevent the leaking of quantum dots we have developed a novel strategy which consists of using tailor made double layered hydrotalcites as protecting shells for quantum dots embedded into silica nanospheres without changing either the materials or the optical properties. PMID- 22825339 TI - [The ROCKET AF study]. PMID- 22825340 TI - [The ARISTOTLE study]. PMID- 22825341 TI - [Clinical history: the cornerstone for defining the cause of syncope]. AB - Syncope is a transient loss of consciousness (LOC) due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. However, there are no signs or symptoms specific for LOC due to global cerebral hypoperfusion, and other diseases, commonly defined as non-syncopal LOC, can induce transient LOC with other mechanisms. Moreover, since there are many causes of transient LOC, an adequate method in taking clinical history, which is the cornerstone of diagnosing patients with transient LOC, must be utilized. The first question to be answered is whether the patient had a real LOC, characterized by loss of postural control and unresponsiveness. Therefore, events with similar clinical features, such as falls, drop attack, etc., should be ruled out. Once a LOC is diagnosed, the questions that need an answer are: was LOC with rapid onset and short duration? Did the patient recover spontaneously? If the answers to these questions are positive (therefore, after exclusion of affections such as coma, cardiac arrest, etc.), we are dealing with a transient LOC, which can be an expression of syncope or non-syncopal LOC. From a methodological point of view, we should try to exclude a non-syncopal LOC. Once syncope is diagnosed, we should define the cause. There are some findings in the clinical history that can be considered diagnostic of the cause of syncope. In many other situations, the findings do not permit a definite diagnosis to be made but suggest some causes and, therefore, specific examinations. PMID- 22825342 TI - [New technology for prevention of embolic events in atrial fibrillation: a systematic review on percutaneous endovascular left atrial appendage closure]. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia. The mortality rate of patients with AF is doubled as compared to non-fibrillating controls. The most relevant complication of AF is a major increase in the risk of stroke. The gold standard in reducing cerebrovascular events in AF is warfarin therapy, which is not free from contraindications and limitations. The left atrial appendage (LAA) is the main source of emboli causing stroke in AF. LAA closure is a seducing approach to stroke risk reduction in AF without anticoagulation. Since 1949, heart surgeons have performed LAA closure or amputation in patients with AF. Percutaneous endovascular LAA closure is a new, less invasive, technique to reach the goal. Several devices have been used to perform this intervention, and the results of published trials are encouraging in terms of effectiveness and relative safety of this attractive technique. In this review we examine the published trials and data on percutaneous LAA closure, with particular attention to the risks and benefits of this procedure. PMID- 22825343 TI - [Cardiac arrest management: any news? When the literature does not meet clinical practice]. AB - The percentage of patients transported alive to hospital after an out-of-hospital cardiac arrest has increased in recent years thanks to growing population education. In 2010 the International Liaison Committee on Resuscitation (ILCOR) has published new guidelines for the management of cardiac arrest. These guidelines present several new features, but cardiac compression remains the mainstay of optimal cardiopulmonary resuscitation. Use of atropine and endotracheal drugs are no longer recommended, and early ultrasound evaluation and intraosseous vascular access are new methods now standardized. The best chances of improving patient prognosis are in the period immediately after return of spontaneous circulation (ROSC). It is well known that most patients who experience cardiac arrest without an obvious extra-cardiac cause, show significant underlying coronary artery disease. Hence, the importance of widespread and early use of primary percutaneous coronary intervention. An early percutaneous coronary intervention was found to be crucial not only in increasing survival, but also in improving neurological outcome at discharge. The ILCOR consensus statement suggests that therapeutic hypothermia should be considered as the standard treatment for comatose patients resuscitated from cardiac arrest. This was supported by the evidence that moderate hypothermia is the only treatment for post-ROSC as it is associated with a significant increase in survival. For this reason, it should be started as early as possible, preferably in the pre-hospital setting. Despite the bulk of available literature on the early treatment of cardiac arrest, the studies carried out in Italy indicate that most post-ROSC patients are undertreated or untreated. This results in poor resource utilization with a high social and personal impact that involves both the patients and their families. Teamwork activities addressing the chain of survival become a fundamental tool for the treatment of resuscitated patients. Given the crucial importance of the time elapsing from collapse to cardiopulmonary resuscitation in terms of final prognosis, efforts should be made to promote the "culture of cardiopulmonary resuscitation" not only among health professionals, but also among the general population. PMID- 22825344 TI - [Sudden cardiac death in patients with left ventricular dysfunction from ischemic heart disease: role of the implantable defibrillator. Evidence, guidelines and good clinical judgment]. AB - A number of studies have shown that the implantable cardioverter-defibrillator (ICD) is the most effective therapy for the prevention of sudden cardiac death from ventricular arrhythmias in patients with ischemic heart disease and severe left ventricular dysfunction. However, ejection fraction should not be considered the only parameter for the identification of candidates to ICD; this may lead to a "hyper-simplification" of the choices and to often unnecessary or inappropriate implantations. The purpose of this paper was to review the literature data regarding indications for ICD implantation in primary prevention in patients with severe ischemic left ventricular dysfunction by taking into account different clinical settings, in particular the biological age, the comorbidity profile, the temporal length between the ischemic event and ICD implantation, the possible impact of revascularization in reducing the arrhythmic risk. PMID- 22825345 TI - [Discovering aVR: the unsuspected richness of a lonely lead]. PMID- 22825346 TI - [From the coronary care unit to the intensive cardiac care unit: the evolution of the Cardiovascular Department of a tertiary center]. AB - BACKGROUND: Substantial changes have occurred over time in the diagnoses, procedures and characteristics of patients admitted to coronary care units (CCU). Following the introduction of cardiac surgery activity in our hospital in December 2009, the aim of this study was to evaluate the changes in activity, processes of care and outcomes of patients consecutively admitted to our CCU after the reorganization of the Cardiovascular Department. METHODS: All 1674 consecutive patients admitted to the CCU from January 2009 to December 2010 were enrolled in this retrospective registry. RESULTS: In 2010, the number of patients referred from other hospitals or wards significantly increased (from 17.2% to 28.3%; p<0.001). Significant was also the increase of patients with ST-elevation myocardial infarction (n=190 to n=230, p<0.001), shock (n=20 to n=50, p<0.001), pulmonary edema (n=47 to n=64, p<0.05), cardiac arrest (n=2 to n=8, p<0.05), aortic dissection (n=0 to n=12; p<0.001). Conversely, the number of patients admitted for acute coronary syndromes without ST-segment elevation and GRACE risk score <140 significantly decreased (n=169 to n=52, p<0.001). In parallel, a significant increase in the use of intra-aortic balloon pump (2.0% to 5.6%, p<0.001), continuous hemofiltration (0.3% to 3.1%, p>0.001), non-invasive ventilation (5.6% to 10.5%, p<0.001) and mechanical ventilation (0% to 4.1%, p<0.001) was observed. Intensive care devices were more frequently used in the subgroups affected by shock, acute coronary syndromes without ST-segment elevation and GRACE risk score >200, and heart failure. Interestingly, despite the increase in high-risk clinical conditions the intra-CCU mortality did not change (3.1 vs 2.9%). CONCLUSIONS: Patients admitted to the CCU have high-risk acute clinical conditions. A model based on the sharing of cardiological, cardiac anesthesiological and surgical expertise is effective in increasing admission appropriateness and improving standards of care in a short period of time. PMID- 22825347 TI - [Continuity of care in heart failure: pilot study of the Tuscany region]. AB - BACKGROUND: Heart failure (HF) is one of the leading causes of hospitalization and medical expenditure, especially in elderly patients. Cooperation between specialists and general practitioners may improve outcomes. A 1-year hospital territory disease management program was designed in collaboration with the Tuscany Region and the Ministry of Health involving specialists, general practitioners and nurses to investigate the impact of our model on healthcare organization and hospitalization rates in patients with HF. METHODS: The program used a web-based clinical report form, and monitoring of patients from specialists and nurses was coordinated by the general practitioners. We enrolled 106 patients (78.3% male, mean age 74.6 years), with a mean left ventricular ejection fraction 49% and mean Charlson index 2.2. RESULTS: A statistically significant reduction was observed in the number of hospitalizations and emergency calls compared with the previous year. HF severity did not substantially changed in 69.8% of patients, whereas it improved in 17.0% and worsened in 13.2% (NYHA class). CONCLUSIONS: Our preliminary data suggest that cooperation between hospitals and medical systems in the territory by means of a web-based clinical report may result in better management of healthcare interventions in the territory with subsequent reduction of hospitalizations. An extension of this model is now ongoing for collecting data from different areas, both within and outside Tuscany. PMID- 22825348 TI - [Atrial septal pouch: not always a thrombus. A case report and literature review]. AB - A 69-year-old patient with dilated cardiomyopathy and atrial fibrillation experienced a transient ischemic attack. A septal pouch was diagnosed by transesophageal echocardiography and a mass into the pouch was detected, which was initially defined as thrombotic material. Since the mass did not disappear after a period of effective anticoagulation, a different etiology was suspected and cardiac magnetic resonance showed a lipomatous nature. As far as we know this is the first case of septal pouch lipoma. PMID- 22825349 TI - Inhibition of p38-MAPK alters SRC coactivation and estrogen receptor phosphorylation. AB - The p38 mitogen activated protein kinase pathway (MAPK) is known to promote cell survival, endocrine therapy resistance and hormone independent breast cancer cell proliferation. Therefore, we utilized the novel p38 inhibitor RWJ67657 to investigate the relevance of targeting this pathway in the ER (+) breast cancer cell line MCF-7. Our results show that RWJ67657 inhibits both basal and estrogen stimulated phosphorylation of p38alpha, resulting in decreased activation of the downstream p38alpha targets hsp27 and MAPAPK. Furthermore, inhibition of p38alpha by RWJ67657 blocks clonogenic survival of MCF-7 cells with little effect on non cancerous breast epithelial cells. Even though p38alpha is known to phosphorylate ERalpha at residue within ER's hinge region at Thr311, resulting in increased ERalpha transcriptional activation, our results suggest RWJ67657 inhibits the p38alpha-induced activation of ER by targeting both the AF-1 and AF-2 activation domains within ERalpha. We further show that RWJ67657 decreases the transcriptional activity of the ER coactivators SRC-1, SRC-2 and SRC-3. Taken together, our results strongly suggest that in addition to phosphorylating Thr311 within ERalpha, p38alpha indirectly activates the ER by phosphorylation and stimulation of the known ERalpha coactivators, SRC-1, -2 and-3. Overall, our data underscore the therapeutic potential of targeting the p38 MAPK pathway in the treatment of ER (+) breast cancer. PMID- 22825350 TI - The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4 one triggers cell apoptosis through induction of oxidative stress and upregulation of the p38 MAPK signaling pathway in HL-60 human leukemia cells. AB - The aim of the present study was to discover the signaling pathways associated with 2-(3-hydroxy-5-methoxy-phenyl)-6,7-methylenedioxyquinolin-4-one (YYK1) induced apoptosis in HL-60 human leukemia cells. YYK1 induced cytotoxic effects, cell morphological changes, decreased the cell number and increased reactive oxygen species (ROS) production and loss of mitochondrial membrane potential (DeltaPsim) in HL-60 cells. YYK1-induced apoptosis was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Results from colorimetric assays and western blot analysis indicated that activities of caspase-7/-3, caspase-8 and caspase-9 were increased in YYK1-treated HL-60 cells. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas/CD95, FasL and FADD), intrinsic related proteins (cytochrome c, Apaf-1, AIF and Endo G), the ratio of Bax/Bcl-2 and phosphorylated p38 MAPK were increased in HL-60 cells after YYK1 treatment. Cell apoptosis was significantly reduced after pre-treatment with N-acetylcysteine (NAC; a ROS scavenger) or diphenyleneiodonium chloride (DPI; a NADPH oxidase inhibitor). Blockage of p38 MAPK signaling by SB202190 abolished YYK1-induced Fas/CD95 upregulation and apoptosis in HL-60 cells. We conclude that YYK1 induces both of extrinsic and intrinsic apoptotic pathways via ROS-mediated activation of p38 MAPK signaling in HL-60 human leukemia cells in vitro. PMID- 22825351 TI - Involvement of SlSOS2 in tomato salt tolerance. AB - The Ca(2+)-dependent SOS pathway has emerged as a key mechanism in the homeostasis of Na(+) and K(+) under saline conditions. We recently identified and functionally characterized by complementation studies in yeast and Arabidopsis the gene encoding the calcineurin-interacting protein kinase of the SOS pathway in tomato, SlSOS2.(1) We also show evidences on the biotechnological potential of SlSOS2 conferring salt tolerance to transgenic tomato. The increased salinity tolerance of SlSOS2 overexpressing plants is associated with higher sodium content in stems and leaves. SlSOS2 overexpression upregulates the Na(+)/H(+) exchange at the plasma membrane (SlSOS1) and K(+), Na(+)/H(+) antiport at the endosomal and vacuolar compartments (LeNHX2 and LeNHX4). Therefore, SlSOS2 seems to be involved in tomato salinity tolerance through regulation of Na(+) extrusion from the root, active loading of Na(+) into the xylem and Na(+) and K(+) compartmentalization. PMID- 22825352 TI - HDL- cholesterol: a nut too hard to crack? PMID- 22825353 TI - Increasing the range of drug targets: interacting peptides provide leads for the development of oncoprotein inhibitors. AB - Two limiting aspects are mainly responsible for the sluggish development of new cancer drugs. They concern the chemical properties of potential drug molecules and the structural prerequisites for drug targets. The chemical properties which are being considered desirable for potential drugs are rather restrictive and mainly dictated by the rules of oral availability. Drug target structures are mostly defined as molecules which comprise binding pockets for low molecular weight compounds. These low molecular weight compounds then serve as leads for the derivation of analogs which recognize the same site and which can function as competitive or irreversibly binding inhibitors. The extension of the range of drug targets and the design of suitable lead compounds will be one of the most challenging tasks for drug developers in the future. Such auxiliary drug target structures can be found in the complex networks of interacting proteins which constitute the intracellular signal transduction cascades. The transient assembly of high molecular weight complexes, based on the specific interactions of particular domains, and usually regulated by secondary modifications, propagates extracellular signals through the cytoplasm and into the nucleus. Aberrations in the formation of protein complexes, or in the regulation of their disassembly, often trigger pathological conditions. The interference with interactions of proteins or the interactions of proteins with DNA offer new opportunities for drug discovery and development. Protein complexes which are indispensable for the growth and survival of cancer cells, proteins to which these cells are "addicted," appear most suited for such an approach. Stat3 and Survivin have been used as model proteins. Specific peptide ligands able to recognize and suppress the functions of crucial interaction surfaces of these proteins have been derived and shown to be able to induce cancer cell death. However, further technology development is required to turn such ligands into useful drugs. The technology comprises three steps: (1) the identification of a peptide ligand which specifically interacts with a crucial functional domain of a target protein, (2) the induction of a desired cellular phenotype upon intracellular interaction of the peptide ligand with its target structure and (3) the replacement of the peptide ligand with a functionally equivalent low molecular weight, drug like compound and its optimization through medicinal chemistry. PMID- 22825354 TI - Regulatory insights into the production of UDP-N-acetylglucosamine by Lactobacillus casei. AB - UDP-N-acetylglucosamine (UDP-GlcNAc) is an important sugar nucleotide used as a precursor of cell wall components in bacteria, and as a substrate in the synthesis of oligosaccharides in eukaryotes. In bacteria UDP-GlcNAc is synthesized from the glycolytic intermediate D-fructose-6-phosphate (fructose-6P) by four successive reactions catalyzed by three enzymes: glucosamine-6-phosphate synthase (GlmS), phosphoglucosamine mutase (GlmM) and the bi-functional enzyme glucosamine-1-phosphate acetyltransferase/ N-acetylglucosamine-1-phosphate uridyltransferase (GlmU). We have previously reported a metabolic engineering strategy in Lactobacillus casei directed to increase the intracellular levels of UDP-GlcNAc by homologous overexpression of the genes glmS, glmM and glmU. One of the most remarkable features regarding the production of UDP-GlcNAc in L. casei was to find multiple regulation points on its biosynthetic pathway: (1) regulation by the NagB enzyme, (2) glmS RNA specific degradation through the possible participation of a glmS riboswitch mechanism, (3) regulation of the GlmU activity probably by end product inhibition and (4) transcription of glmU. PMID- 22825355 TI - Effects of curcumin on bleomycin-induced oxidative stress in malignant testicular germ cell tumors. AB - Bleomycin is commonly used in the treatment of testicular cancer. Bleomycin generates oxygen radicals, induces the oxidative cleavage of DNA strands and induces cancer cell apoptosis. Curcumin (diferuloylmethane) is a potent antioxidant and chief component of the spice turmeric. No study investigating the effects of curcumin on intrinsic and bleomycin-induced oxidative stress in testicular germ cell tumors has been reported in the literature. For this reason, the present study aimed to examine the effects of curcumin on oxidative stress produced in wild-type NTera-2 and p53-mutant NCCIT testicular cancer cells incubated with bleomycin and the results were compared with cells treated with H2O2 which directly produces oxidative stress. The protein carbonyl content, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), 8 isoprostane, lipid hydroperoxide (LPO) levels and total antioxidant capacity in the two testicular cancer cell lines were determined. Results showed that bleomycin and H2O2 significantly increased protein carbonyl, TBARS, 8-isoprostane and LPO levels in the NTera-2 and NCCIT cell lines. Bleomycin and H2O2 significantly decreased the antioxidant capacity and GSH levels in NTera-2 cells. Curcumin significantly decreased LPO, 8-isoprostane and protein carbonyl content, and TBARS levels increased in cells treated with bleomycin and H2O2. Curcumin enhanced GSH levels and the antioxidant capacity of NTera-2 cells. In conclusion, curcumin inhibits bleomycin and H2O2-induced oxidative stress in human testicular cancer cells. PMID- 22825356 TI - Loss of HITS (FAM107B) expression in cancers of multiple organs: tissue microarray analysis. AB - Family with sequence similarity 107 (FAM107) proteins consist of two subtypes, FAM107A and FAM107B in mammals, possessing a conserved N-terminal domain of unknown function. Recently we found that FAM107B, an 18 kDa nuclear protein, is expressed in a broad range of tissues and is downregulated in gastrointestinal cancer. Because FAM107B expression is amplified by heat-shock stimulation, we designated it heat shock-inducible tumor small protein (HITS). Although data related to FAM107A as a candidate tumor suppressor have been accumulated, little biological information is available for HITS. In the present study, we examined HITS expression using immunohistochemistry with tissue microarrays and performed detailed statistical analyses. By screening a high-density multiple organ tumor and normal tissue microarray, HITS expression was decreased in tumor tissues of the breast, thyroid, testis and uterine cervix as well as the stomach and colon. Further analysis of tissue microarrays of individual organs showed that loss of HITS expression in cancer tissues was statistically significant and commonly observed in distinct organs in a histological type-specific manner. The HITS expression intensity was inversely correlated with the primary tumor size in breast and thyroid cancers. In addition, effects of tetracycline-inducible HITS expression on tumor growth were investigated in vivo. Forced expression of HITS inhibited tumor xenograft proliferation, compared with the mock-treated tumor xenograft model. These results show that loss of HITS expression is a common phenomenon observed in cancers of distinct organs and involved in tumor development and proliferation. PMID- 22825357 TI - Childhood poverty and young adults' allostatic load: the mediating role of childhood cumulative risk exposure. AB - Childhood poverty is linked to a host of physical and psychological disorders during childhood and later in life. In the study reported here, we showed that the proportion of childhood spent in poverty from birth to age 9 was linked to elevated allostatic load, a marker of chronic physiological stress, in 17-year olds. Furthermore, this prospective longitudinal relationship was mediated by cumulative risk exposure at age 13. The greater the duration of early life spent in poverty, the greater the exposure to cumulative risk. This, in turn, leads to elevated allostatic load. Multiple psychological, biological, and neurological pathways likely account for the social patterning of psychological and physical disease. PMID- 22825358 TI - Comparability effects in probability judgments. AB - Psychological theories of subjective probability judgments assume that accumulated evidence (support) mediates the relation between the description of a to-be-judged event (hypothesis) and the judgment. To scale a probability from the support for a hypothesis, these psychological theories make a strong independence assumption. This assumption is stated in the form of the product rule, in which the support garnered for a particular hypothesis is independent of the support for the alternative hypothesis. In the study reported here, I asked participants to judge the likelihood of a bicyclist winning a simulated race. Results showed that the independence assumption was systematically violated. Observed judgments suggest that when a probability judgment is made, the comparability or similarity of the hypotheses on one dimension increases the weight that judges allocate to differences on the other dimensions. These results speak against the simple scalability-processing assumption of support theory, and they illustrate the need for a theory of judgment processes that describes how the similarity between hypotheses shapes judgment. PMID- 22825359 TI - Photosensitizing properties of biopterin and its photoproducts using 2' deoxyguanosine 5'-monophosphate as an oxidizable target. AB - UV-A radiation (320-400 nm) induces damage to the DNA molecule and its components through photosensitized reactions. Biopterin (Bip) and its photoproducts 6 formylpterin (Fop) and 6-carboxypterin (Cap) accumulate in the skin of human beings suffering from vitiligo, a depigmentation disorder where the protection against UV radiation fails because of the lack of melanin. This study was aimed to evaluate the photosensitizing properties of oxidized pterins present in the skin and to elucidate the mechanisms involved in the photosensitized oxidation of purine nucleotides by pterins in vitro. For this purpose, steady-state and time resolved experiments in acidic (pH 5.0-5.8) aqueous solution were performed using Bip, Fop and Cap as photosensitizers and the nucleotide 2'-deoxyguanosine 5' monophosphate (dGMP) as an oxidizable target. The three pterin derivatives are able to photosensitize dGMP, being Fop the most efficient sensitizer. The reactions proceed through two competing pathways: (1) electron transfer from dGMP to triplet excited-state of pterins (type I mechanism) and (2) reaction of dGMP with (1)O(2) produced by pterins (type II mechanism). Kinetic analysis revealed that the electron transfer pathway is the main mechanism and the interaction of dGMP with the triplet excited-state of pterins and the formation of the corresponding dGMP radicals were demonstrated by laser flash photolysis experiments. The biological implications of the results obtained are also discussed. PMID- 22825360 TI - Nutritional management and growth in children with chronic kidney disease. AB - Despite continuing improvements in our understanding of the causes of poor growth in chronic kidney disease, many unanswered questions remain: why do some patients maintain a good appetite whereas others have profound anorexia at a similar level of renal function? Why do some, but not all, patients respond to increased nutritional intake? Is feed delivery by gastrostomy superior to oral and nasogastric routes? Do children who are no longer in the 'infancy' stage of growth benefit from enteral feeding? Do patients with protein energy wasting benefit from increased nutritional input? How do we prevent obesity, which is becoming so prevalent in the developed world? This review will address these issues. PMID- 22825361 TI - Laparoscopic proximal gastrectomy with a hand-sewn esophago-gastric anastomosis using a knifeless endoscopic linear stapler. AB - Proximal gastrectomy has been applied for selected patients with early upper gastric cancer, because of its potential advantages over total gastrectomy, such as preserving gastric capacity and entailing fewer hormonal and nutritional deficiencies. Esophago-gastric anastomosis is a simple reconstruction method with an excellent postoperative outcome provided that gastroesophageal reflux is properly prevented. Following open surgery, the esophagus is anastomosed to the anterior stomach wall with partial fundoplication to prevent esophageal reflux. We developed a novel laparoscopic hand-sewn method to reproduce the anti-reflux procedure that is used in open surgery. The esophagus is first fixed to the anterior stomach wall with a knifeless endoscopic linear stapler. This fixation contributes to maintaining a stable field for easier hand-sewn anastomosis, and allows us to complete the left side of the fundoplication at the same time. This novel technique was used to successfully perform complete laparoscopic proximal gastrectomy with a hand-sewn esophago-gastric anastomosis in ten patients, without any postoperative complications. No patient had symptoms of gastroesophageal reflux during a median follow-up period of 19.9 months. One patient developed anastomotic stenosis, and this was resolved with endoscopic dilatation. The mean percent body weight loss at 12 months after surgery, in comparison to the preoperative weight, was 10.4 %. Laparoscopic proximal gastrectomy with an esophago-gastric anastomosis using our novel technique would be a feasible choice would be a feasible choice and would show benefit for selected patients with early upper gastric cancer. PMID- 22825362 TI - Method for analysis of different oligosacchiride structures. AB - In this study, an improved, rapid, high yield synthesis of N,N'-4,4'-bis(benzyl-2 boronic acid)-bipyridinium dibromide (o-BBV) is described. The obtained o-BVV is applied in a two-component saccharide sensing system (complex) where it serves as a fluorescence quencher and a saccharide receptor. This system was applied to different natural oligosaccharides isolated from molluscan Rapana venosa (RvH1-a) and arthropodan Carcinus aestuarii (CaeH) hemocyanins (Hcs) and cyclodextrins (CDs). The carbohydrate contents of both Hcs were calculated in our previous work to be 1,6 % and 7 % for CaeH and RvH1-a, respectively. We propose that the difference in fluorescence increase of the native CaeH and RvH1-a when titrating them with the complex is due to the fact that the carbohydrate content of CaeH is lower and the carbohydrate chains are buried in between the structural subunits of the native molecule, while the glycans of the functional unit RvH1-a are exposed on the surface of the molecule leading to a 4-fold fluorescence's intensity change. PMID- 22825363 TI - Capsule endoscopy or angiography in patients with acute overt obscure gastrointestinal bleeding: a prospective randomized study with long-term follow up. AB - OBJECTIVES: Both capsule endoscopy (CE) and angiography have been recommended as first investigation for patients with acute overt obscure gastrointestinal bleeding (OGIB). However, no studies have directly compared the two modalities in patients with overt OGIB. We compared the diagnostic yield and long-term outcomes of patients with overt OGIB randomized to CE or angiogram. METHODS: Consecutive patients presented with acute melena or hematochezia, but nondiagnostic upper and lower endoscopy, were immediately randomized to receive small-bowel CE or angiography. All patients were monitored for rebleeding and anemia for up to 5 years. Primary end point was the diagnostic yield of the assigned investigation. Secondary end points included rebleeding, further transfusion, readmission for bleeding or anemia, and mortality. RESULTS: A total of 60 patients with overt OGIB were randomized. The mean follow-up was 48.5 months. The diagnostic yield of immediate CE was significantly higher than angiography (53.3% vs. 20.0%, P = 0.016). The cumulative risk of rebleeding in the angiography and CE group was 33.3% and 16.7%, respectively (P = 0.10, log-rank test). There was no significant difference in the long-term outcomes between the two groups including further transfusion, hospitalization for rebleeding, and mortality. CONCLUSIONS: In patients with overt OGIB, immediate CE has higher diagnostic yield and comparable long-term outcomes when compared with angiography. PMID- 22825364 TI - Persistent duodenal intraepithelial lymphocytosis despite a long-term strict gluten-free diet in celiac disease. AB - OBJECTIVES: In celiac disease, complete histological normalization of the small intestinal mucosa occurs in only 8-20% of adult patients after commencing a gluten-free diet. Intraepithelial lymphocytosis may persist for years while villous morphology normalizes. Factors contributing to this and the clinical relevance of persistent intraepithelial lymphocytosis were here investigated. METHODS: Altogether 177 adult celiac disease patients adhering to a long-term strict gluten-free diet were enrolled. Co-morbidities, ongoing medications, and consumption of oats and wheat-starch were recorded. Small-bowel morphology and intraepithelial lymphocyte count as well as laboratory parameters of malabsorption were evaluated. Gastrointestinal symptoms and psychological well being were measured by structured questionnaires. RESULTS: In all, 170 (96%) out of the 177 patients evinced normal villous architecture and 7 (4%) villous atrophy. Among patients with normal villous structure, 96 (56%) had persistent intraepithelial lymphocytosis and 74 (44%) completely normal small-intestinal mucosa. Consumption of oats was the only factor contributing to the persistent intraepithelial lymphocytosis. Co-morbidities, Helicobacter pylori gastritis, drugs, or wheat-starch in the diet had no effect. The clinical outcome of the patients with persistent intraepithelial lymphocytosis was good, since no signs of malabsorption, excess malignancies, increase in gastrointestinal symptoms, or impaired quality of life were associated with it when compared to subjects with completely normal mucosa. The only outcome found in this study was a significantly lower, although normal villous height-crypt depth ratio among the patients with persistent intraepithelial lymphocytosis as compared to those with completely normal mucosa. CONCLUSIONS: Despite excellent villous recovery in this study, persistent intraepithelial lymphocytosis was still common among celiac disease patients on a long-term strict gluten-free diet. Consumption of oats was associated with persistent duodenal lymphocytosis and this calls for further investigations. The prognosis of patients with persistent intraepithelial lymphocytosis seems to be good while adhering to a gluten-free diet for a mean of 11 years. PMID- 22825365 TI - A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. AB - OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease. METHODS: In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG. RESULTS: LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection. CONCLUSIONS: LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge. PMID- 22825366 TI - Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. AB - OBJECTIVES: Non-celiac wheat sensitivity (WS) is considered a new clinical entity. An increasing percentage of the general population avoids gluten ingestion. However, the real existence of this condition is debated and specific markers are lacking. Our aim was thus to demonstrate the existence of WS and define its clinical, serologic, and histological markers. METHODS: We reviewed the clinical charts of all subjects with an irritable bowel syndrome (IBS)-like presentation who had been diagnosed with WS using a double-blind placebo controlled (DBPC) challenge in the years 2001-2011. One hundred celiac disease (CD) patients and fifty IBS patients served as controls. RESULTS: Two hundred and seventy-six patients with WS, as diagnosed by DBPC challenge, were included. Two groups showing distinct clinical characteristics were identified: WS alone (group 1) and WS associated with multiple food hypersensitivity (group 2). As a whole group, the WS patients showed a higher frequency of anemia, weight loss, self reported wheat intolerance, coexistent atopy, and food allergy in infancy than the IBS controls. There was also a higher frequency of positive serum assays for IgG/IgA anti-gliadin and cytometric basophil activation in "in vitro" assay. The main histology characteristic of WS patients was eosinophil infiltration of the duodenal and colon mucosa. Patients with WS alone were characterized by clinical features very similar to those found in CD patients. Patients with multiple food sensitivity were characterized by clinical features similar to those found in allergic patients. CONCLUSIONS: Our data confirm the existence of non-celiac WS as a distinct clinical condition. We also suggest the existence of two distinct populations of subjects with WS: one with characteristics more similar to CD and the other with characteristics pointing to food allergy. PMID- 22825367 TI - Extrahepatic portal venous system thrombosis in recurrent acute and chronic alcoholic pancreatitis is caused by local inflammation and not thrombophilia. AB - OBJECTIVES: Extrahepatic portal venous system thrombosis (EPVST) occurs in 13% of patients with either recurrent acute (AP) or chronic (CP) alcoholic pancreatitis. The role of thrombophilia has never been assessed in this entity. METHODS: All consecutive patients with alcoholic AP or CP were included in a prospective study. All patients underwent a computerized tomography (CT) scan of the pancreas to evaluate EPVST as well as thorough testing for thrombophilia (protein C, S, and antithrombin deficiency, factor II, factor V, and JAK2 gene mutations, homocystein, biological antiphospholipid syndrome). RESULTS: A total of 119 patients (male, n=100 (84%); smokers, n=110 (92%)) were included. EPVST was found in 41 patients (35%). The portal, superior mesenteric, or splenic veins were involved in 34%, 24%, and 93% of patients, respectively. Thrombophilia was identified in 18% (n=22), including the biological antiphospholipid syndrome, factor V Leiden mutation, and factor II G20210A gene mutation in 21 (17.6%), 2 (1.6%), and 1 patient (0.8%), respectively. On univariate analysis, the factors associated with EPVST were smoking (RR=1.6 (1.38-1.85), P=0.03), pseudocysts (RR=2.91 (1.29-6.56), P=0.008), a pseudocyst in the pancreatic tail (P=0.03), a high CT severity index for AP (P=0.007), and pancreatic parenchymal necrosis (P=0.02). The presence of hemostatic risk factors was not associated with an increased risk of EPVST. On multivariate analysis, only pseudocysts were associated with EPVST (hazard ratio: 6.402; 95% confidence interval (1.59-26.54), P=0.009). CONCLUSIONS: EPVST is found in 35% of patients with acute/chronic alcoholic pancreatitis. Local inflammation appears to be the major predisposing condition. The presence of some form of thrombophilia does not increase the risk of EPVST and should not be systematically searched for in case of EPVST. PMID- 22825368 TI - Functionalization of nitrogen-doped carbon nanotubes with gallium to form Ga CN(x)-multi-wall carbon nanotube hybrid materials. AB - In an effort to combine group III-V semiconductors with carbon nanotubes, a simple solution-based technique for gallium functionalization of nitrogen-doped multi-wall carbon nanotubes has been developed. With an aqueous solution of a gallium salt (GaI(3)), it was possible to form covalent bonds between the Ga(3+) ion and the nitrogen atoms of the doped carbon nanotubes to form a gallium nitride-carbon nanotube hybrid at room temperature. This functionalization was evaluated by x-ray photoelectron spectroscopy, energy dispersive x-ray spectroscopy, Raman spectroscopy, scanning electron microscopy and transmission electron microscopy. PMID- 22825370 TI - Organic-soluble lacunary {M2(P2W15)2} polyoxometalate sandwiches showing a previously unseen alphabetabetaalpha isomerism. AB - New polyoxometalate 'sandwiches' have been formed where two [P(2)W(15)O(56)](12-) lacunary Dawson clusters encapsulate two transition metal ions to give clusters with the general formula [M(II)(2)(P(2)W(15)O(56))(2)](20-) (where M = Mn, Co, and Ni respectively), [Fe(III)(2)(P(2)W(15)O(56))(2)](18-), and [Cu(II)(4)(P(2)W(15)O(56))(2)](16-). The Mn, Co, and Ni clusters exhibit a hitherto unseen alphabetabetaalpha isomeric geometry and all five compounds are associated with tetrabutylammonium cations which allow for their dissolution in non-aqueous solvent. PMID- 22825369 TI - Pathologic accumulation of alpha-synuclein and Abeta in Parkinson disease patients with dementia. AB - OBJECTIVE: To determine the relative contributions of individual pathologic protein deposits associated with dementia in patients with Parkinson disease (PD). DESIGN: Autopsied patients were analyzed from February 24, 2005, through July 25, 2010, to determine the distribution and severity of individual pathologic protein deposits (alpha-synuclein, Abeta, and tau) using routine protocols for histologic and immunohistochemical analysis and established neuropathologic staging criteria. Clinical data were extracted from an electronic medical record system used for all patients with PD. PATIENTS: Thirty-two consecutive autopsied patients treated at the Washington University Movement Disorders Center who had neuropathologic confirmation of PD and a history of dementia, regardless of the timing of the onset of dementia with respect to motor symptoms. RESULTS: Three pathologic subgroups of dementia associated with PD were identified: (1) predominant synucleinopathy (Braak Lewy body stages 5-6) (12 [38%]), (2) predominant synucleinopathy with Abeta deposition (Braak amyloid stages B-C) but minimal or no cortical tau deposition (19 [59%]), and (3) synucleinopathy and Abeta deposition with at least moderate neocortical tauopathy (Braak tau stages 5-6; 1 [3%]). Kaplan-Meier and Cox regression analyses revealed that patients with synucleinopathy plus Abeta deposition had significantly shorter survival (years from PD onset until death and years from dementia onset until death) than patients with synucleinopathy only. CONCLUSIONS: Dementia associated with PD has 2 major pathologic subgroups: neocortical synucleinopathy and neocortical synucleinopathy with Abeta deposition. Alzheimer disease with neocortical Abeta and tau deposition does not commonly cause dementia with PD. Furthermore, accumulation of Abeta is associated with lower survival rates in PD patients with dementia. Additional studies are needed to prospectively determine the association between alpha-synuclein and Abeta accumulation and the role of Abeta in the development and progression of cognitive impairment in PD. PMID- 22825372 TI - Chemoradiation: Gastro-oesophageal cancer--is CROSSing over so hard to do? PMID- 22825378 TI - Fluorine- and rhenium-containing geldanamycin derivatives as leads for the development of molecular probes for imaging Hsp90. AB - Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone responsible for protein quality control in cells. Hsp90 has been shown to be overexpressed in many human cancers. This has prompted extensive research on Hsp90 inhibitors as novel anticancer agents and, more recently, the development of molecular probes for imaging Hsp90 expression in vivo. This work describes the development of various fluorine-containing and rhenium-containing geldanamycin derivatives as leads for the development of corresponding (18)F-labeled and (99m)Tc-labeled PET and SPECT probes for molecular imaging of Hsp90 expression. All compounds were evaluated in an in vitro ATPase activity assay using Hsp90 isoform Hsp82p. Fluorobenzoylated geldanamycin derivative 5 displayed comparable inhibitory potency like parent compound geldanamycin. PMID- 22825377 TI - Geriatric oncology research to improve clinical care. AB - Cancer incidence increases with advanced age. The Cancer and Aging Research Group, in partnership with the National Institute on Aging and NCI, have summarized the gaps in knowledge in geriatric oncology and made recommendations to close these gaps. One recommendation was that the comprehensive geriatric assessment (CGA) should be incorporated within geriatric oncology research. Information from the CGA can be used to stratify patients into risk categories to better predict their tolerance of cancer treatment, and to follow functional consequences from treatment. Other recommendations were to design trials for older adults with study end points that address the needs of the older and/or vulnerable adult with cancer and to build a better infrastructure to accommodate the needs of older adults to improve their representation in trials. We use a case-based approach to highlight gaps in knowledge regarding the care of older adults with cancer, discuss our current state of knowledge of best practice patterns, and identify opportunities for research in geriatric oncology. More evidence regarding the treatment of older patients with cancer is urgently needed. PMID- 22825379 TI - Human 5-, 12- and 15-lipoxygenase-1 coexist in kidney but show opposite trends and their balance changes in cancer. AB - Lipoxygenases make an impact on every stage of cancer affecting carcinogenesis, metastasis and apoptosis. While there is a rich literature on individual lipoxygenases we lack extensive data on their coexistence and balance in different organs and types of cancer. Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy. One third of patients will relapse and the 5-year survival rate is <10% in cases of metastases. Many drugs are metabolized in the kidneys and might interact with lipoxygenases that are biocatalysts for many endo- and xenobiotics. In the present study, we examined the kidney tissue from healthy individuals and cancer patients by immunohistochemical analysis for the presence of 3 lipoxygenases: 5 LOX, 12S-LOX and 15-LOX-1. Our findings confirmed their coexistence and opposite trends of manifestation in the course of disease with increased 15-LOX-1 and decreased 5- and 12-LOX levels at the onset of cancer reversing with the progressing stage of the disease or the grade of tumor. Unlike other malignancies, there are no biomarkers to individualize RCC management. Modern therapies are using TKI therapy, targeting VEGF and may cause hypertension as a side-effect. 12S-LOX is intertwined with kinases and VEGF and increased secretion of 12S-HETE in urine is known to accompany hypertension. Thus, it may be valuable to probe 12S-LOX activity and monitor its natural metabolite to seek a possible aid in directing the treatment of patients. PMID- 22825375 TI - Cancer treatment according to BRCA1 and BRCA2 mutations. AB - Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise. PMID- 22825380 TI - [Loop diuretics: facts and fallacies]. AB - Refractory edema is a clinical condition which recognises different etiologies and is characterized by decreased or absent diuretic response before the therapeutic goal is reached. Several pharmacokinetic and pharmacodynamic strategies are used in this setting, and further research is needed in order to optimize drug effectiveness. PMID- 22825374 TI - Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy? AB - Personalized medicine for oestrogen receptor-alpha (ERalpha)-positive breast cancer requires predictive biomarkers for broad endocrine resistance as well as biomarkers capable of predicting resistance to a specific agent. In addition, biomarkers could be used to select patients that might benefit from the addition of treatments that do not target ERalpha. However, biomarker identification studies seem to be far from consistent and identified biomarkers seldom face an introduction into clinical practice. Importantly, most of the studies that seek to identify biomarkers have been performed using material from consecutive series of patients treated with tamoxifen (the most commonly prescribed ERalpha antagonist). Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. Another important issue is the lack of differentiation between premenopausal and postmenopausal patients with breast cancer. The hormonal environment of a tumour in patients who are premenopausal is intrinsically distinct from those arising in postmenopausal women. Biomarkers of different biological mechanisms might enable the prediction of either broad endocrine resistance or resistance to a specific agent in each of these patient subtypes. Ultimately, improvements to study design are needed to establish the clinical validity of the most promising biomarkers to predict benefit from endocrine therapy. PMID- 22825381 TI - [A data base of a thoracic and cardiovascular department: information on 1001 patients]. AB - The Authors illustrate the results derived from a data base of a thoracic and cardiovascular Department, comprehensive of 1001 patients (464 M and 537 F, average age 71, minimum age 18 and maximum age 101). The conducted analysis results in several considerations: the cause of patient's hospitalization was not relevant to the direct expertise of the Department in the 27,5% of the cases and the profile of the typical-patient is of an elderly person (73% of the cases over 65 years old), basically overweight or obese (35% of the cases with BMI > 25) and with medium-low cultural level (70% of the cases not over middle school); moreover our patients, although under poly-therapy before hospitalization, were discharged with a number of prescribed medicines even more plentiful. The data base of the Department proved to be a useful tool both to instantaneously monitor the departmental activity and also to rationalize the pharmacological therapies. PMID- 22825382 TI - [Susceptibility rate to tigecycline and antibiotic-resistance among Klebsiella pneumoniae strains isolated in Intensive Care Unit]. AB - Antibiotic resistance in Klebsiella pneumoniae strains is an increasing problem in a lot of hospitals. It is a public health emergency because it relates with high mortality rate among patients in Intensive Care Unit (ICU). From 1/1/2009 to 31/08/2010, in ICU of SS Annunziata Hospital of Taranto, 140 isolated Klebsiella pneumoniae strains were detected. The strain identification and antimicrobial susceptibility testing were performed using a Vitek2 automated system. These isolate showed a low level of susceptibility to levofloxacin (3.4%), ciprofloxacin (6.2%), ceftazidime (2.8%) and piperacillin/tazobactam (8%). We reported also that the 10% and 13.9% of them were susceptible to meropenem and imipenem. An anti-Klebsiella pneumoniae activity in vitro to tigecycline was present in 64.6% of isolates while almost all strains (56/58) tested to colistin were susceptible. In order to our data of worryng high multiclass drug resistance including tygecicline, it needs to apply appropriate measures of surveillance and antibiotic prescription to avoid rapid spread of these mutiresistant strains in other areas. PMID- 22825383 TI - [Genetic and environmental contribution to rheumatoid arthritis: a family study]. AB - We report on the HLA typing of three brothers (A, B, C) with rheumatoid arthritis (RA) and their six sons. This family is interesting for the full concordance for RA between parents. The aim of this study was the discovery of genetic and/or enviromental cofactors determining this absolute concordance. PMID- 22825384 TI - [Diagnosis and treatment of asthma]. AB - Asthma is an inflammatory disease of the airways. It is suggested by characteristic history of recurrent episodes of wheezing, breathlessness, chest tightness, and/or cough especially at night or in early morning. In asthmatic patients spirometry or pulmonary function tests demonstrate airflow obstruction that improves significantly, defined as both a 12% and 200 ml improvement in either FEV1 in response to inhaled bronchodilator. Measurement of airways responsiveness to methacholine in specialized pulmonary function laboratories may help to diagnose asthma. The goals for successful management of asthma are to achieve and maintain control of symptoms and to prevent asthma exacerbations. PMID- 22825385 TI - [Coronary microvascular disease: from experimental models to clinical practice]. AB - Coronary vascular microcirculation plays a major role in the pathogenesis of left ventricular dysfunction as well as in the development of heart failure. Coronary microcirculation includes all the vessels which contribute to provide resistance to coronary flow. It represents the district where coronary circulation blood flow is regulated to ensure that each structural and functional cardiac component receives the proper amount of oxygen and metabolic substrates through the capillary network. Coronary microcirculation is fundamental for myocardial function which largely depends on the ratio between energetic metabolites received from coronary circulation and their utilization by the myocytes. Alterations in coronary microvascular circulation which limit myocardial perfusion can cause repetitive ischemic events leading to left ventricular dysfunction in several ischemic and non ischemic cardiomyopathies as the idiopathic dilated cardiomyopathy. To date, mechanisms underlying microvascular dysfunction are not completely understood and experimental animal models are employed to study alterations which may cause microcirculation impairment. These animals models are unique tools to identify new therapeutic targets, to test new drug therapies for the treatment of left ventricular dysfunction as well as its progression towards overt heart failure. PMID- 22825386 TI - An international survey of tissue banking: a preliminary report. AB - International Atomic Energy Agency is currently carrying out a survey on the tissue banking activities from the tissue banking organisations worldwide. The purpose of the survey is to establish regional and global overview of the current tissue banking activities and practices in order to assist the International Atomic Energy Agency to provide further guidance about the use of radiation technology to sterilise tissues as well as to promote better collaboration between the regional tissue banking associations. The survey is an on-going exercise and the preliminary data is presented here. This exercise is not completed and the authors urge the remaining tissue banks to participate in the survey. PMID- 22825387 TI - Tissue and cell surveillance in Catalonia two and half years after start up. AB - Surveillance was inserted in the current legislation as a tool to guarantee quality in all the processes which make tissues and cells viable for transplantation. In Catalonia, surveillance took off in June 2008 with the creation of the Catalonian Transplant Organization's Surveillance Register. The objective of this Register is to gather relevant events observed at each performance level: donation and retrieval, tissue bank procedures and transplantation. During the first two and a half years of this Register there were 63 notifications: 22 out of 54 were serious adverse events (SAEs) interfering with the process. 32 out of 54 of SAE were detected before allocation. 7 were serious adverse reactions, 3 of them in living donors and 4 of them in recipients. In all cases they recovered without any complications. The other 2 were medical alerts. We conclude that the professional involvement in quality systems established under current law is essential to guarantee quality control in all the processes involved and to ensure the final viability of tissues and cells. PMID- 22825388 TI - Activity and tumor specificity of human heparanase gene core promoter. AB - Heparanase (HPSE) plays a critical role in tumor metastasis and vascularization. In addition, the human HPSE promoter has been cloned and characterized. However, the activity and specificity of the HPSE promoter in tumor cells remains unclear. The core fragment of the HPSE promoter was amplified and cloned into the multiple cloning site of the pEGFP-1 vector. The recombinant plasmid pEGFP-Hp was transfected into human umbilical vein endothelial cells (ECV304) and human hepatoma carcinoma (HepG2), laryngocarcinoma (Hep2) and chronic myelogenous leukemia (K562) cell lines. The vectors pEGFP-1 and pEGFP-N1 were used as negative and positive controls, respectively. The activity and expression of green fluorescent protein (GFP) were analyzed. Results showed that the sequence of the amplified HPSE promoter was in agreement with the GenBank data. The recombinant plasmid pEGFP-Hp was consistent with the expected result. No GFP expression was observed in the transfected cells in the pEGFP-1 group, but a high expression was observed in the pEGFP-N1 group. As regards the pEGFP-Hp group, less fluorescence was revealed in ECV cells with a relatively high fluorescence in tumor cells. The average transfection efficiencies of pEGFP-Hp in the ECV304, HepG2, Hep2 and K562 cell lines were 3.9, 21.3, 10.8 and 6.5%, respectively, while those of pEGFP-Nl were 17.1, 24.0, 14.0 and 11.0%, respectively. The HPSE gene promoter drives the expression of downstream genes in a eukaryotic vector, specifically in tumor cell lines, but its activity is relatively weak. PMID- 22825389 TI - Differential expression of HIF-1 in glioblastoma multiforme and anaplastic astrocytoma. AB - Hypoxia is an important factor mediating tumor progression and therapeutic resistance, in part through proteome changes mediated by the transcription factor hypoxia-inducible factor (HIF)-1. Since glioblastoma multiforme is the epitome of a highly aggressive tumor entity, while lower-grade astrocytomas often show a prolonged clinical course, a profound difference in the extent of hypoxic tissue areas and corresponding magnitude of HIF-1 activity may exist between these entities. In this study, to address this question, serial sections of 11 glioblastomas and 10 anaplastic astrocytomas were immunostained for HIF-1alpha, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX (i.e., hypoxia-related markers), Ki67 (proliferation), phosphorylated ribosomal protein S6 [p-rpS6; mammalian target of rapamycin (mTOR) activity] and CD34 (microvascular endothelium). Digital scans of whole tumor sections were registered to achieve geometric correspondence for subsequent morphometric operations. HIF-1alpha-, GLUT-1- and CA IX-positive staining was found in all 11 glioblastomas, showing a preferential expression in tissue areas adjacent to necroses. A considerable spatial overlap between GLUT-1 and CA IX, and a colocalization of these proteins with areas of enlarged mean diffusion distances were observed. Conversely, 8 of the 10 anaplastic astrocytomas were completely negative for hypoxia-related markers. The glioblastomas also showed significantly greater heterogeneity of intercapillary distances, larger diffusion-limited tissue fractions, significantly higher mTOR activity and a trend for higher proliferation rates. Microregionally, mTOR and proliferation showed a significant spatial overlap with areas of shorter mean diffusion distances. In conclusion, diffusion-limited hypoxia, leading to the expression of hypoxia-related markers is a pivotal element of the glioblastoma phenotype and may be driven by dysregulated growth and proliferation in normoxic subregions. PMID- 22825390 TI - Accessibility of extra-articular pathologies of iliopsoas tendon and bursitis of greater trochanter in hip arthroscopy. AB - PURPOSE: Different pathologies leading to psoas tendon pain and chronic bursitis of the greater trochanter are well known. The purpose of the study was to underline the accessibility of the psoas tendon at lesser trochanter, reproduce the results and measure the distances to anatomical landmarks. METHODS: Twelve hips of six human cadavers underwent hip arthroscopy. The accessibility of the iliopsoas tendon at the lesser trochanter and the bursa at the greater trochanter was documented with the camera. In addition to the usual access portals, alternative ventral ports were analysed concerning accessibility of the lesser trochanter. Afterwards, arthroscopy needles were placed along the extra-articular portals followed by dissection. The distances of the portals in relation to important anatomical landmarks were analysed. RESULTS: The accessibility to the iliopsoas tendon at the lesser trochanter and to the bursa at the greater trochanter throughout the conventional portals was reproducible. Sufficient distances to the important anatomical landmarks could be shown. The mean distance of the distal ventro-lateral and the wide distal ventro-lateral portal to the nervous cutaneous femoris lateralis was 26.8 +/- 5.4 mm and 32.2 +/- 3.9 mm. The mean distance from the more ventral located portals to the nervous arteria and vena femoralis was 28.3 +/- 2.1 mm. CONCLUSION: This is the first study known to us that describes in detail the accessibility of the extra-articular structures underlined by anatomical preparation. In addition, it was demonstrated that a more ventrally located portal had sufficient distance to the important neurovascular structures of the ventral femur and can also be used in addendum if necessary. PMID- 22825391 TI - Destruction of public and governmental experiments of GMO in Europe. AB - The purpose of this article is to compile the destruction of GMO trials from academic or governmental research institutes in Europe, in a factual manner and to highlight their main characteristics. About 80 acts of vandalism against academic or governmental research on GMOs are identified, mainly in 4 countries; namely France, Germany, the United Kingdom and Switzerland. Examples are also provided for Italy and Belgium. The general conclusions that can be drawn from these acts are also discussed. PMID- 22825392 TI - Transcriptomic response of skeletal muscle to lipopolysaccharide in the gilthead seabream (Sparus aurata). AB - The physiological consequences of the activation of the immune system in fish are not well understood. In particular, skeletal muscle, due to its essential role in locomotion and whole-animal energy homeostasis, is a potentially important target of inflammation. In this study, we have evaluated the in vivo effects of lipopolysaccharide (LPS) on the white and red skeletal muscle transcriptome of the gilthead seabream (Sparus aurata) by microarray analysis at 24 and 72 h after injection. In white muscle, the transcriptomic response was characterized by an up-regulation of genes involved in carbohydrate catabolism and protein synthesis at 24 h and a complete reversal of this pattern at 72 h. In red muscle, an up regulation of genes involved in carbohydrate catabolism and protein synthesis was observed only at 72 h after LPS administration. Interestingly, both white and red muscles showed a similar consistent down-regulation of immune genes at 72 h post injection. However, genes involved in muscle contraction showed a general up regulation in response to LPS in both types of muscle. In summary, LPS administration causes muscle type-specific responses regarding the expression of genes involved in carbohydrate and protein metabolism and a common decreased expression of immune genes in skeletal muscle, concomitant with increased expression of genes for contractile elements. Our results evidence a robust and tissue-specific transcriptomic response of the skeletal muscle to an acute inflammatory challenge. PMID- 22825393 TI - Estrogen modulates hepatic gene expression and survival of rainbow trout infected with pathogenic bacteria Yersinia ruckeri. AB - In the aquatic environment, fish are exposed to various stimuli at once and have developed different response mechanisms to deal with these multiple stimuli. The current study assessed the combined impacts of estrogens and bacterial infection on the physiological status of fish. Juvenile rainbow trout were exposed to two different concentrations of 17beta-estradiol (E2) (2 or 20 mg/kg feed) and then infected with three concentrations of Yersinia ruckeri, a bacterial pathogen causing massive losses in wild and farmed salmonid populations. Organism-level endpoints to assess the impact of the single and combined treatments included hepatic vitellogenin transcript expression to evaluate the E2 exposure efficiency and survival rate of pathogen-challenged fish. The two E2 doses increased vitellogenin levels within the physiological range. Infection with Y. ruckeri caused mortality of trout, and this effect was significantly enhanced by a simultaneous exposure to high E2 dose. The hormone reduced survival at intermediate and high (10(4) and 10(6) colony forming units, cfu) bacterial concentrations, but not for a low one (10(2) cfu). Analysis of hepatic gene expression profiles by a salmonid 2 k cDNA microarray chip revealed complex regulations of pathways involved in immune responses, stress responses, and detoxicification pathways. E2 markedly reduced the expression of several genes implicated in xenobiotic metabolism. The results suggest that the interaction between pathogen and E2 interfered with the fish's capability of clearing toxic compounds. The findings of the current study add to our understanding of multiple exposure responses in fish. PMID- 22825394 TI - Identification of two Penelope-like elements with different structures and chromosome localization in kuruma shrimp genome. AB - Penelope, originally found as a key element responsible for the hybrid dysgenesis in Drosophila virilis, has been widely conserved throughout eukaryotic genomes. In other organisms, they are often referred to as Penelope-like elements or PLEs. In this study, we found two types of PLEs, designated MjPLE01 and MjPLE02, from kuruma shrimp, Marsupenaeus japonicus. There was no observed nucleotide similarity between MjPLE01 and 02, and both elements differed from each other in terms of their structure; MjPLE02 has a distinctive endonuclease (EN) domain at the C-terminus while MjPLE01 do not. A phylogenetic tree that includes publicly available PLEs and TERTs showed that MjPLE01 and 02 were closely related to Coprina elements, which have been reported as an EN-deficient PLE, and to Penelope-Poseidon group, which possess an EN domain, respectively. Genomic Southern blot analysis using MjPLE01 as a probe showed several multiple bands that differ among individual shrimps. On the other hand, two major identical bands were observed when MjPLE02 was used. Colony hybridization showed co localization of MjPLE01 and GGTTA repeats, suggesting that MjPLE01 might be prevalent in subtelomeric regions of kuruma shrimp genome. These results suggest that the kuruma shrimp genome has at least two types of PLEs with different domain compositions, phylogenetic positions, and probably chromosomeal localization. Such distinctive types of PLEs in an organism have never been described and hence could be a potential source to understand how multiple PLE types evolved. PMID- 22825395 TI - Callosal disconnection syndrome in a patient with corpus callosum hemorrhage: a diffusion tensor tractography study. PMID- 22825396 TI - A facile method for fabricating TiO2@mesoporous carbon and three-layered nanocomposites. AB - Herein, we report a new and facile method for fabricating TiO(2)@mesoporous carbon hybrid materials. Uniform polydopamine (PDA) layers were coated onto the surface of titanate nanotubes (TNTs) and TiO(2) nanorods (TNDs) through the spontaneous adhesion and self-polymerization of dopamine during the dipping process. Core-shell mesoporous carbon nanotubes with TiO(2) nanorods or nanoparticles encapsulated inside (TiO(2)@MC) were then obtained by transforming PDA layers into carbonaceous ones through calcination in nitrogen at 800 degrees C. The thickness of the mesoporous carbon layers is tens of nanometers and can be controlled by adjusting the coated PDA layers through the self-polymerization reaction time. In addition, three-layered nanocomposites of TiO(2)@MC@MO (MO, metal oxide) can be readily prepared by utilizing PDA layers in TNTs@PDA or TNDs@PDA to adsorb the metal ions, followed by the calcination process. PMID- 22825397 TI - A dodecanuclear Zn cluster sandwiched by polyoxometalate ligands. AB - A dodecazinc silicotungstate K(20)Na(2)[Zn(6)(OH)(7)(H(2)O)(Si(2)W(18)O(66))](2).34H(2)O (1) has been synthesized and characterized by X-ray crystallography, elemental analysis, infrared, UV-vis spectroscopy, cyclic voltammetry, acid-base titration, and DFT calculations. The twelve zinc atoms between the two [Si(2)W(18)O(66)](16-) frameworks make this complex more stable hydrolytically than the heteropolytungstate ligands, [Si(2)W(18)O(66)](16-), themselves. The structurally unique central Zn(12) core is formed by the fusion of two [Zn(6)(OH)(7)(H(2)O)](5+) units through two edge-sharing Zn6 atoms. DFT B3LYP calculations give HOMO-LUMO and (HOMO - 1)-LUMO energy gaps of ~3.65 and 3.91 eV, respectively, as compared to the band gap in ZnO of 3.35 eV. PMID- 22825398 TI - Photoelectron imaging and theoretical calculations of gold-silver hydrides: comparing the characteristics of Au, Ag and H in small clusters. AB - Structures and electronic properties of the mixed metal hydride anions AuAgH(-), Au(2)AgH(-), AuAg(2)H(-) and their neutrals are studied using anionic photoelectron imaging and theoretical calculations. The three isomers of AuAgH(-) are determined to be linear and those of AuAgH are determined to have C(s) symmetry. The structures of Au(2)AgH(-), AuAg(2)H(-) and their corresponding neutrals are determined to be planar with C(s) or C(2v) symmetries. The vertical detachment energies (VDEs) and adiabatic detachment energies (ADEs) of these anions are reported. Similar to the homonuclear Au(m)(-) and Ag(n)(-) clusters, the metal hydride anions with an even number of valence electrons have higher VDEs than those with an odd number. Variation of the VDEs of these metal hydride anions with interchange of Au, Ag and H (for example Au(m)Ag(n)(-)-> Au(m-1)Ag(n+ 1)(-), or Au(m-1)Ag(n)H(-)) will be shown to be characterized by the electronegativities of Au, Ag and H. The results presented in this study provide important insights into the similar and different characteristics of these three elements in small clusters. PMID- 22825399 TI - Diabetes: treating diabetic nephropathy-still an unresolved issue. PMID- 22825400 TI - Obesity: glypican-4: role in insulin signalling. PMID- 22825401 TI - Bone: the growing cost of fractures in Ireland. PMID- 22825403 TI - Double diastereoselection in anti aldol reactions mediated by dicyclohexylchloroborane between an L-erythrulose derivative and chiral aldehydes. AB - Anti aldol reactions of an l-erythrulose derivative with several alpha-chiral aldehydes mediated by dicyclohexylboron chloride are examined. Good yields and stereoselectivities are observed. The results are best explained when the reactions are assumed to occur via boat-like transition states with minimization of 1,3-allylic strain and avoidance of syn pentane interactions. PMID- 22825402 TI - Asymmetry in keratoconus and vision-related quality of life. AB - PURPOSE: To examine the relationship of increased ocular asymmetry over time to vision-related quality of life in keratoconus. METHODS: The subjects were from the Collaborative Longitudinal Evaluation of Keratoconus Study and had complete data on a least 1 scale of the National Eye Institute Visual Function Questionnaire and examination data at baseline and at least 1 follow-up visit. Three measures of disease asymmetry [visual acuity (VA), corneal curvature, and refractive error] and better eye status were assessed. Multilevel models were fit to the data. RESULTS: The analyses were completed using the data from 961 subjects. Six scales on the National Eye Institute Visual Function Questionnaire had adequate variability to the model (distance activity, driving, mental health, near activity, ocular pain, and role difficulties). Refractive error changes were not associated with statistically significant quality-of-life differences. Except for ocular pain, statistically significant, but not clinically meaningful, differences were found for VA changes and corneal curvature changes. For a 0.1 unit logarithm of the minimum angle of resolution of VA change, the quality-of life scales decreased between 0.20 and 0.99 units. For a 1.00-diopter steepening of corneal curvature, these decreases were on the order of 0.20 to 0.59 units. Changes related to asymmetry were small as well; decreases were on the order of 0.20 to 0.38 units. CONCLUSIONS: Increasing ocular asymmetry and decreases in VA and corneal steepening in the better eye were associated with decreasing vision related quality of life, although the magnitudes of the changes were not clinically meaningful. Of these 2 disease status indicators, the vision in the better eye had greater effect on the vision-related quality of life. PMID- 22825404 TI - The North Atlantic Oscillation affects the quality of Cava (Spanish sparkling wine). AB - This study explores the possible effects of the North Atlantic Oscillation (NAO) on the quality of Spanish Cava. We found a significant negative relationship between the mean NAO for the months of March through August of each year between 1970 and 2008 and the probability of obtaining a top quality Cava. The NAO is associated with temperature and rainfall variations in the Cava region, which affect vine physiological processes during grape maturity. The probability of obtaining a top quality Cava was highest when the mean value of the NAO was negative, which causes the mean temperature in the Cava area to decrease, with positive consequences on Cava quality. Although the overall discrimination capacity and explanatory power of the model were low, 80% of clearly favorable years were classified correctly as corresponding to top quality Cava, and 70% of clearly unfavorable years were classified correctly as non top quality Cava. PMID- 22825405 TI - Hop bitter acids inhibit tumorigenicity of hepatocellular carcinoma cells in vitro. AB - Bitter acids (BAs) from the hop plant Humulus lupulus L. exhibit multiple beneficial biological properties with promising effects in cancer therapy and prevention, but information regarding the effects on hepatocellular carcinoma (HCC) is missing. Here, we used two different hop bitter acid extracts enriched for either alpha-acids or beta-acids to obtain insight into whether biological activity varies between these two groups of BAs. At a concentration of 25 ug/ml, only the beta-acid rich started to induce aspartate transaminase (AST) release, and a significant increase was detected with 50 ug/ml of both extracts. Already at lower concentrations both extracts led to a dose-dependent inhibition of proliferation, and migration was suppressed at a concentration as low as 5 ug/ml in HCC cells. The focus on different signaling pathways revealed an inhibition of ERK1/2 phosphorylation, downregulation of AP-1 activity and an alleviation of nuclear factor kappaB (NFkappaB) activity in HepG2 cells incubated with 5 ug/ml of both extracts, whereby the beta-acid rich extract showed more pronounced effects. In conclusion, we identified ERK1/2, AP-1 and NFkappaB, which are important factors in tumor development and progression, as targets of hop BAs. Thus, these data suggest the potential use of BAs as functional nutrients for both prevention and treatment of HCC. PMID- 22825406 TI - Parental needs among children with birth defects: defining a parent-to-parent support network. AB - The objective of this study was to explore how a parent-to-parent support network could impact parents of a child with a structural birth defect by specifically looking at parents' continued needs, aspects influencing their participation in support networks, and their recommendations. Structural birth defects occur in approximately 3 % of all infants, representing a significant public health issue. For many reasons, parents are uniquely qualified to provide support to each other. Data were collected retrospectively through a qualitative approach of focus groups or one-on-one interviews. Thirty one parents of infants registered in the Utah Birth Defect Network participated in the study. Three themes emerged, "current sources and inconsistencies in parent-to-parent-support," "aspects that influence participation in parent-to-parent network," and "recommendations for a parent-to-parent program." Health care providers need to be aware of the services and inform parents about these options. A statewide parent-to-parent network integrated into all hospitals would be a valuable resource to facilitate sharing of issues related to caring for an infant or child with a birth defect. PMID- 22825407 TI - Intravitreal bevacizumab treatment for exudative age-related macular degeneration with good visual acuity. AB - PURPOSE: To investigate the effect of intravitreal bevacizumab on the visual and anatomic outcome of patients with exudative age-related macular degeneration presenting with good visual acuity (VA). METHODS: A file review was performed for all consecutive patients with newly diagnosed exudative age-related macular degeneration and initial VA of >= 20/40 treated in 2005 to 2010 and followed for at least 6 months. Treatment consisted of 3 loading doses of intravitreal bevacizumab every 6 weeks and was repeated when fluid or hemorrhage was present. RESULTS: The cohort included 130 patients (150 eyes). Mean follow-up was 20.2 +/- 13.2 months, and mean number of injections was 11.3 +/- 6.2. At the last examination, VA was stable or improved in 106 eyes (70.7%); 11 eyes (7.3%) lost >= 3 lines. Mean logarithm of the minimum angle of resolution VA measured 0.22 +/ 0.1 (0-0.3) at presentation and 0.22 +/- 0.2 (0-1.3) at the last visit. Corresponding values for central macular thickness were 267 +/- 75 MUm (137-562) and 226 +/- 75 MUm (75-568) (P = 0.14). The most frequent complication (18 eyes, 12%) was corneal epithelial defects. CONCLUSION: Prompt intravitreal bevacizumab treatment for newly diagnosed exudative age-related macular degeneration in patients with good initial best-corrected visual acuity is associated with sustained or improved vision and a good safety profile. Attempts should be made to expedite the access of these patients to treatment, regardless of initial VA. PMID- 22825408 TI - Prevalence and associations of retinal vein occlusions: the Central India Eye and Medical Study. AB - PURPOSE: To determine the prevalence of retinal vein occlusions (RVOs) in rural central India. METHODS: The population-based Central India Eye and Medical Study was performed in rural central India and included 4,711 subjects (30 years and older). Using fundus photographs, we assessed the prevalence of branch retinal vein occlusions and central retinal vein occlusions. RESULTS: An RVO was detected in 38 eyes (0.42 +/- 0.07%; 95% confidence interval: 0.29-0.56) of 35 subjects (0.76 +/- 0.13%; 95% confidence interval: 0.50-1.01). Prevalence of branch retinal vein occlusions was 0.66% +/- 0.12% per subject (95% confidence interval: 0.42%-0.90%) and of central retinal vein occlusions was 0.11% +/- 0.05% per subject (95% confidence interval: 0.01%-0.21%). In binary logistic analysis, presence of RVOs was associated with higher age (P = 0.007), systolic blood pressure (P < 0.001), blood concentration of urea (P = 0.02), and narrower anterior chamber angle (P < 0.03). The RVO prevalence was not significantly (all Ps > 0.10) associated with body mass index; blood concentrations of glucose, cholesterol, high-density lipoproteins, and creatinine; presence of diabetes mellitus, tuberculosis and malaria; nutritional parameters; alcohol consumption; refractive error; and optic disk size. The age-specific prevalence rates of RVOs were 0.18% +/- 0.13%, 0.29% +/- 0.15%, 0.89% +/- 0.34%, 1.07% +/- 0.36%, 2.72% +/ 0.85%, and 3.64% +/- 2.55%, respectively, for decadal age groups. In two (5%) eyes, RVO had caused low vision (visual acuity <20/60 and >=20/400). CONCLUSION: In the rural agrarian low-income population of Central India, RVOs were detected in 0.8% of adults, with branch retinal vein occlusions being approximately seven times more common than central retinal vein occlusions. Main associated factors were higher age, blood pressure, urea blood concentration, and narrow chamber angle. RVOs were no major reason for visual impairment. PMID- 22825409 TI - Dietary sodium intake in heart failure. PMID- 22825410 TI - Periprocedural bridging management of anticoagulation. PMID- 22825411 TI - Medical therapy in peripheral artery disease. PMID- 22825412 TI - Rehospitalization for heart failure: predict or prevent? PMID- 22825413 TI - Imaging findings in a child with Loeys-Dietz syndrome. PMID- 22825414 TI - Pulmonary embolism averted: trapped thrombus in inferior vena cava filters. PMID- 22825416 TI - Letter by christensen et Al regarding article, "new oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation". PMID- 22825417 TI - Unusual site of graft erosion after abdominal sacrocervicopexy. AB - Large fasciomuscular damage of the feminine pelvic floor resulting in pelvic organ prolapse constitutes a challenge for surgical reconstruction.Between 2005 and 2010, ten women aged 47-75 years were treated by abdominoperineal implantation of polypropylene mesh for modified sacral perineocolporectopexy and subsequently followed up. They were suffering from enterocele (9), genital prolapse (8), descending perineum (5), rectal prolapse (4), and rectocele (3). Five women were incontinent (mean Wexner 9) and six had incomplete rectal evacuation. Defecography revealed enterocele III (5) and II (4). Magnetic resonance (MR) diagnosed descending perineum in five patients (mean 3.8 cm).Permanent reconstruction of the pelvic floor and remission of organ prolapse was achieved at 12-months of follow-up in all except one patient. There were two small vaginal mesh erosions and one hematoma within the pelvic floor. Improvement at rectal emptying and anal incontinence (mean Wexner 4) were found.Modified sacral perineocolporectopexy is effective in the treatment of complex pelvic floor anatomical defects and organ prolapse. Improvements in rectal emptying, pelvic feeling of heaviness, and dyspareunia were achieved. The procedure was safe and characterized by good implant tolerance and a low rate of complications. PMID- 22825418 TI - Incidence and risk factors of postoperative stress urinary incontinence following laparoscopic sacrocolpopexy in patients with negative preoperative prolapse reduction stress testing. AB - INTRODUCTION AND HYPOTHESIS: The objectives of this study were to evaluate the incidence of postoperative stress urinary incontinence (SUI) after laparoscopic sacrocolpopexy (LSCP) in women with negative preoperative prolapse reduction stress testing (PPRST) and to identify associated risk factors. METHODS: This was a retrospective cohort study comprising women who consecutively underwent double mesh LSCP without concomitant SUI surgery after a negative PPRST at a tertiary referral center. Negative PPRST was defined by the absence of SUI during cough testing and urodynamic studies with prolapse reduction. RESULTS: Fifty-five patients were assessed in the final analysis. No significant complication was encountered during and after LSCP. Mean follow-up was 25 +/- 11 (range 12-48) months. No patient developed recurrent pelvic organ prolapse (POP) or mesh erosion at last follow-up. Thirty (54.5 %) patients reported the symptom of SUI (subjective SUI) postoperatively, 13 (23.6 %) had a positive cough test (objective SUI) at last visit, and nine (16.4 %) underwent a sling procedure. In univariate analyses, advanced cystocele (stage 3-4) and a history of patient reported SUI before surgery were associated with a higher risk of postoperative subjective and objective SUI after LSCP. Multivariate analyses identified preoperative SUI as the sole independent predictor of subjective SUI [risk ratio (RR = 4.03; 95% confidence interval (CI) = 1.16-14.09), objective SUI, (RR = 4.67; 95% CI = 1.14-19.23), and subsequent anti-SUI surgery after LSCP (RR = 6.17; 95% CI = 1.30-29.41). CONCLUSIONS: SUI is far from uncommon in women after LSCP despite negative PPRST, especially in those with advanced cystocele and a history of SUI preoperatively; after at least 1 year of follow-up, approximately one in six women eventually underwent a sling surgery. These data are useful for counseling patients. PMID- 22825419 TI - FK506-binding protein 51 (FKBP5) gene polymorphism is not associated with glucocorticoid therapy outcome in patients with idiopathic thrombocytopenic purpura. AB - The FKBP5 gene codes for the FK506-binding protein 51 (FKBP5), a co-chaperone of hsp90, which regulates glucocorticoid (GC) receptor sensitivity. The FKBP5 gene single nucleotide polymorphisms (SNP), rs1360780, has been found to modulate GC sensitivity in stress-related psychiatric disorders. The aim of the present study was to examine the effects of rs1360780 on the treatment outcome of patients suffering from idiopathic thrombocytopenic purpura (ITP) administered with GC. The polymorphism of FKBP5, rs1360780, was genotyped in 55 GC-resistant ITP patients, 157 GC-sensitive ITP patients and 110 unrelated healthy individuals using real-time PCR and cycling probe technology with DNA extracted from peripheral blood. No significant differences in FKBP5 rs1360780 genotypes (P=0.51) and alleles (P=0.89) were observed between the GC-resistant ITP patients and the healthy controls. There were no significant differences observed between the GC-sensitive ITP patients and the healthy controls (P=0.40 for genotypes and P=0.62 for T allele), as well as between the GC-sensitive ITP patients and the GC resistant patients (P=0.67 for genotypes and for T allele). The present study demonstrates that the FKBP5 polymorphism may not affect the response of ITP patients to GC treatment. PMID- 22825421 TI - Thromboprophylaxis practices following varicose veins surgery. AB - OBJECTIVE: It is not clear whether patients undergoing varicose veins operations should receive thromboprophylaxis. A nationwide survey was conducted to assess thromboprophylaxis practice patterns in patients undergoing conventional vein surgery or endovenous procedures. METHODS: A questionnaire was e-mailed to all members of the Greek Society of Vascular and Endovascular Surgery (n = 163). RESULTS: In all, 68 members (42%) returned the survey, and 53% reported that they were not performing endovenous procedures. Thromboprophylaxis was used routinely by 52% after conventional surgery and 58% after endovenous procedures. Low molecular-weight heparin was the preferred type of prophylaxis. Risk factors justifying thromboprophylaxis varied considerably among respondents. Postoperative duplex was performed routinely by 48% following stripping and by 76% following endovascular procedures. CONCLUSION: Thromboprophylaxis practices following varicose veins procedures vary among vascular surgeons in Greece. This reflects the uncertainty regarding the exact incidence of thromboembolic events in the existing literature as well as the absence of specific guidelines. PMID- 22825420 TI - CSF hydrothorax: neither migration of peritoneal catheter into the chest nor ascites. Case report and review of the literature. AB - INTRODUCTION: Complications of ventriculoperitoneal (V/P) shunt surgery are generally due to infection, or mechanical or dynamic dysfunction. Thoracic complications like cerebrospinal fluid (CSF) hydrothorax are rarely seen. PATIENT AND METHODS: We present a CSF hydrothorax patient as a rare complication of V/P shunt surgery and review of the literature. The patient was a 7-month-old girl who had V/P shunt surgery for hydrocephalus. Six months after surgery, she was admitted to hospital with the complaint of cough. As the chest X-ray revealed hydrothorax, a chest tube was inserted. Although her shunt tip was in the abdominal cavity in shuntograms, positive beta-2 transferrin in liquid sample and Tc 99m cisternography proved that it was CSF. After we replaced her V/P shunt with a ventriculoatrial shunt, the liquid coming from the chest tube progressively diminished and disappeared, and her chest tube was removed. RESULTS: There are 36 CSF hydrothorax cases, including the present case, in the literature. There is peritoneal catheter migration into the chest in 22 of them (61.1 %). Half of the remaining 14 cases (38.9 %) without catheter migration have also CSF ascites. But, in the other half (seven cases), there is neither catheter migration nor CSF ascites as in the present case. CONCLUSION: CSF hydrothorax following V/P shunt surgery is a very rare complication that may cause serious respiratory distress. It is important to keep in mind that peritoneal catheter migration into the chest may or may not occur. Even ascites may not accompany CSF hydrothorax in a patient without peritoneal catheter migration. PMID- 22825422 TI - Hepatic artery transection reconstructed with splenic artery transposition graft. AB - INTRODUCTION: Hepatic artery transection presents a technical challenge in vascular reconstruction. Formal arterial repair is indicated in patients with underlying liver disease and those undergoing bile duct reconstructions because of a higher risk of complication following hepatic artery injury. This report highlights a novel approach to hepatic artery transection with splenic artery transposition. METHODS: A case of hepatic artery transection repaired with splenic artery transposition is presented with an accompanying literature review. RESULTS: During elective pancreaticoduodenectomy, the common hepatic artery was injured at its origin. The splenic artery was divided and transposed to the hepatic artery, thus restoring arterial flow to the liver and bile duct. CONCLUSION: Various strategies to manage a hepatic artery injury have been described, ranging from ligation to complex vascular reconstruction. In hemodynamically stable patients, arterial transposition using the splenic artery is a feasible method to ensure adequate arterial supply to the liver and biliary tract. PMID- 22825425 TI - Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target? AB - GVHD is a major complication after allo-SCT. In GVHD, some tissues like liver, intestine and skin are infiltrated by donor T cells while others like muscle are not. The mechanism underlying targeted tropism of donor T cells is not fully understood. In the present study, we aim to explore differences in gene expression profile among target versus non-target tissues in a mouse model of GVHD based on chemotherapy conditioning. Expression levels of JAK-signal transducers and activators of transcription (STAT), CXCL1, ICAM1 and STAT3 were increased in the liver and remained unchanged (or decreased) in the muscle and kidney after conditioning. At the start of GVHD the expression levels of CXCL9, ITGb2, SAA3, MARCO, TLR and VCAM1 were significantly higher in the liver or kidney compared with the muscle of GVHD animals. Moreover, biological processes of inflammatory reactions, leukocyte migration, response to bacterium and chemotaxis followed the same pattern. Our data show that both chemotherapy and allogenicity exclusively induce expression of inflammatory genes in target tissues. Moreover, gene expression profile and histopathological findings in the kidney are similar to those observed in the liver of GVHD mice. PMID- 22825423 TI - HACking the centromere chromatin code: insights from human artificial chromosomes. AB - The centromere is a specialized chromosomal region that serves as the assembly site of the kinetochore. At the centromere, CENP-A nucleosomes form part of a chromatin landscape termed centrochromatin. This chromatin environment conveys epigenetic marks regulating kinetochore formation. Recent work sheds light on the intricate relationship between centrochromatin state, the CENP-A assembly pathway and the maintenance of centromere function. Here, we review the emerging picture of how chromatin affects mammalian kinetochore formation. We place particular emphasis on data obtained from Human Artificial Chromosome (HAC) biology and the targeted engineering of centrochromatin using synthetic HACs. We discuss implications of these findings, which indicate that a delicate balance of histone modifications and chromatin state dictates both de novo centromere formation and the maintenance of centromere identity in dividing cell populations. PMID- 22825424 TI - The CENP-A nucleosome: a dynamic structure and role at the centromere. AB - The centromere is a specialized locus that directs the formation of the kinetochore protein complex for correct chromosome segregation. The specific centromere histone H3 variant CENP-A has been described as the epigenetic mark of this chromatin region. Several laboratories have explored its properties, its partners, and its role in centromere formation. Specifically, two types of CENP-A nucleosomes have been described, suggesting there may be more complexity involved in centromere structure than previously thought. Recent work adds to this paradox by questioning the role of CENP-A as a unique centromeric mark and highlighting the assembly of a functional kinetochore in the absence of CENP-A. In this review, we discuss recent literature on the CENP-A nucleosomes and the debate on its role in kinetochore formation and centromere identity. PMID- 22825426 TI - PBSC mobilization in newly diagnosed patients with POEMS syndrome: outcomes and prognostic factors. AB - Autologous PBSC transplantation is a preferred treatment for patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS syndrome). However, data on stem cell mobilization in POEMS syndrome are limited. We retrospectively reviewed outcomes and factors prognostic of mobilization in newly diagnosed patients with POEMS syndrome. A total of 56 patients (41 men and 15 women) were included and the median age was 45 years (range, 24-62). All patients underwent mobilization with CY plus granulocyte CSF (G-CSF) (n=38) or G CSF alone (n=18). The median total number of harvested CD34+ cells was 2.01 * 10(6)/kg (range, 0.18-9.0 * 10(6)/kg). In all, 29 (51.8%) patients failed to yield more than 2 * 10(6)/kg CD34+ cells, and among them, 7 (12.5%) patients yielded <1 * 10(6)/kg CD34+ cells. The overall mobilization-related morbidity was 23.3% and acute renal failure was the most common complication during mobilization. Multivariate analysis showed that hepatomegaly (odds ratio 0.06, 95% confidence interval (CI) 0.01-0.43) and mobilization regimen of G-CSF alone (odds ratio 0.08, 95% CI 0.01-0.70) were independent prognostic factors for successful mobilization in POEMS syndrome. In conclusion, mobilization in newly diagnosed patients with POEMS syndrome is challenging with low yield of CD34+ cells and high morbidity. Induction therapy before mobilization might improve the efficacy and safety of mobilization. PMID- 22825427 TI - Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia. AB - Relapse remains the major cause of treatment failure after hematopoietic cell transplantation (HCT) in acute leukemia, even in patients transplanted in morphologic CR. Various techniques now enable the sensitive quantification of 'minimal' amounts of residual disease (MRD) in patients with acute leukemia in remission. Numerous studies convincingly demonstrate that MRD at the time of transplantation is a powerful, independent predictor of subsequent relapse, with current detection levels of one leukemic cell in 10(5)-10(6) normal cells being prognostically relevant. This recognition provides the rationale to assign patients with detectable MRD (that is, 'MRD(+)' patients) to intensified therapies before, during, or after transplantation, although data supporting these strategies are still sparse. Limited evidence from observational studies suggests that outcomes with autologous HCT are so poor that MRD(+) patients should preferentially be assigned to allogeneic HCT, which can cure a subgroup of these patients, particularly if unmanipulated (T-cell replete) grafts and/or minimized immunosuppression are used to optimize the graft-vs-leukemia effect. Emerging data suggest that additional therapy with non-cross-resistant agents to decrease residual tumor burden before transplantation in MRD(+) patients might be beneficial. Further, other studies hint at immunotherapy (for example, rapid withdrawal of immunosuppression and/or donor lymphocyte infusions) as a means to prevent overt relapse if patients remain, or become, MRD(+) after HCT. Ultimately, controlled clinical studies are needed to define the value of MRD directed therapies, and patients should be encouraged to enter such trials. PMID- 22825428 TI - Diffusion tensor imaging of vascular parkinsonism: structural changes in cerebral white matter and the association with clinical severity. AB - OBJECTIVE: To investigate the white matter (WM) microstructure using diffusion tensor imaging in patients with vascular parkinsonism (VP) and specific fiber tract involvement with respect to clinical severity. DESIGN: Diffusion measures (fractional anisotropy and mean diffusivity) were calculated from diffusion tensor images of patients with VP and control subjects. We performed global-, voxel-, and tract-based analyses to compare WM microstructural properties between groups.We further correlated findings with Unified Parkinson's Disease Rating Scale scores and modified postural instability gait difficulty (PIGD) scores to identify most relevant tract involvement. SETTING: Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. PARTICIPANTS: Twelve patients with VP and 12 age matched healthy controls without VP. RESULTS: In the VP group, the left thalamus, right frontal subcortical WM, and left anterior limb of the internal capsule had a significantly lower regional fractional anisotropy compared with the control group. The bilateral frontal subcortical WM showed a significantly higher regional mean diffusivity. The diffusion metrics in these regions were significantly correlated with the modified PIGD score part III, and the sum of modified PIGD scores parts II and III. Tract-based analysis showed a group difference in mean fractional anisotropy and mean diffusivity for multiple fiber bundles, but only diffusion measures of fiber tracts from the bilateral frontal lobe that pass through the anterior limb of internal capsule and tracts of the genu of the corpus callosum showed significant correlation with these scores. CONCLUSIONS: Disruption of the microstructural organization of frontal lobe WM is associated with the severity of VP. Our findings are in accordance with the frontal lobe disconnection hypothesis for gait problems and reinforce the paradigm that the involvement of fibers related to the prefrontal cortex is crucial for the core features of VP. PMID- 22825429 TI - A new understanding on how heme metabolism occurs in heme oxygenase: water assisted oxo mechanism. AB - Heme metabolism by heme oxygenase (HO) is investigated with quantum mechanical/molecular mechanical (QM/MM) calculations. A mechanism assisted by water is proposed: (1) an iron-oxo species and a water molecule are generated by the heterolytic cleavage of the O-O bond of an iron-hydroperoxo species in a similar way to P450-mediated reactions, (2) a hydrogen atom abstraction by the iron-oxo species from the generated water molecule and the C-O bond formation between the water molecule and the alpha-meso carbon take place simultaneously. The water molecule is hydrogen-bonded to the oxo ligand and to the water cluster in the active site of HO. The water cluster can control the position of the generated water molecule to ensure the regioselective oxidation of heme at the alpha-meso position, at the same time, can facilitate the oxidation by stabilizing a positive charge on the water molecule in the transition state. A key difference between HO and P450 is observed in the structure of the active site; Thr252 in P450 blocks the access of the water molecule to the alpha-meso position, and can thus suppress the undesired heme oxidation for P450. PMID- 22825430 TI - Synthesis and characterization of model silica-gold core-shell nanohybrid systems to demonstrate plasmonic enhancement of fluorescence. AB - In this work, gold-silica plasmonic nanohybrids have been synthesized as model systems which enable tuning of dye fluorescence enhancement/quenching interactions. For each system, a dye-doped silica core is surrounded by a 15 nm spacer region, which in turn is surrounded by gold nanoparticles (GNPs). The GNPs are either covalently conjugated via mercapto silanization to the spacer or encapsulated in a separate external silica shell. The intermediate spacer region can be either dye doped or left undoped to enable quenching and plasmonic enhancement effects respectively. The study indicates that there is a larger enhancement effect when GNPs are encapsulated in the outer shell compared to the system of external conjugation. This is due to the environmental shielding provided by shell encapsulation compared to the exposure of the GNPs to the solvent environment for the externally conjugated system. The fluorescence signal enhancement of the nanohybrid systems was evaluated using a standard HRP-anti-HRP fluorescence based assay platform. PMID- 22825431 TI - Interview with Dominic Wright. PMID- 22825432 TI - [Risk factors in post partum depression]. AB - It is commonly believed that pregnancy is a time of good mental health. However it has been observed, until recently, that many pregnant women, above all in post partum period, manifest depressive symptoms like sadness, social withdrawal and lack of motivation. The consequences are enormous, for mother mental health and for the psychical development of the baby. It becomes therefore necessary to screening and to precociously intervene on these pathological conditions and thanks also to the suitable knowledge of the risk factors for the potential development of depression post partum. PMID- 22825433 TI - [Post partum depression: future perspectives]. AB - AIM: Post partum depression (PPD) is a psychiatric illness approximately affecting 10-20% of women after childbirth. The objective of this work is to update our knowledge of PPD giving particular emphasis to etiopathogenetic hypotheses. METHODS: An accurate search of the literature on this topic was conducted using free dedicated websites such as PubMed. RESULTS: The most recent studies reveal that PPD is a complex disease, whose pathogenesis is not yet clarified, determined by a mix of genetic, biological and environmental factors. Genetic studies have shown a possible involvement of polymorphisms of genes coding for serotonin transporter, 5HT2A and 5HT2C receptors, HMCN1 and METTL13 genes, D2 receptor and GABAA receptor (GABAAR). The involvement of these systems might provide an explanation of the relations among genetic alterations, hormonal fluctuations in the post partum, changes in neurotransmission and mood fluctuations typical of PPD. DISCUSSION: The results obtained so far are not exhaustive. However, there is a substantial evidence showing that patients with PPD may have a high genetic vulnerability, although we have not been able yet to pinpoint a specific biological marker of the disease. Recent research is focusing on the delta subunit of GABAAR and the possible role of selective agonists of this subunit, such as gaboxadol, in the treatment of PPD. PMID- 22825434 TI - [OCD during pregnancy and post partum]. AB - AIM: Obsessive-compulsive disorder (OCD) can occur with specific characteristics during the pregnancy/postpartum period. The presence of OCD in a such delicate period in a woman's life can lead to severe suffering of the patient herself, of her relatives and the newborn. The purpose of this article is to offer a comprehensive review of scientific literature concerning the relationship between OCD and pregnancy/post partum. METHODS: Literature was identified by searching in Medline (Medical Literature Analysis and Retrieval System On-line), using the PubMed search engine. The keywords used were "obsessive-compulsive disorder", "pregnancy", "post partum period", "perinatal period". RESULTS: The last trimester of pregnancy and the post partum period are at increased risk of onset of OCD, especially in susceptible individuals. During pregnancy/post partum, OCD is characterized by typical clinical features: obsessions (in particular aggressive and/or contamination) are more frequent than compulsions (checking and/or washing); further, if untreated, the symptomatology tends to persist and/or recur during any subsequent pregnancies. DISCUSSION: From the literature it appears that the diagnosis of OCD during pregnancy/post partum should be performed as soon as possible, both to ensure the correct patient and family psychoeducation, and timely access to psychopharmacological treatment and/or psychotherapy. PMID- 22825435 TI - [Is the cognitive-behavioural therapy an effective strategy also in the prevention of post partum depression? a critical review]. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of cognitive behavioural therapy (CBT) in the prevention of post partum depression (PPD) in pregnant women at risk. METHODS: PubMed, Medline, PsychInfo, Embase, and the Cochrane Library databases were searched from January 1991 to June 2011 to review studies on the efficacy of CBT in the prevention of PD. RESULTS: The literature analyzed recommends that depression in pregnancy requires an efficient management to provide mother's symptoms relief as well as to prevent PD. While several studies demonstrated the efficacy of CBT in the treatment of PD, only a few controlled studies focused on its efficacy in the prevention of PD in women identified at risk during pregnancy. The efficacy of CBT in preventing PD in pregnant women at risk is supported by only a few studies, presenting some methodological flaws. DISCUSSION: Better designed trials are needed to strongly support the efficacy of such psychotherapeutic preventive strategy in women at risk for PD. PMID- 22825436 TI - [Maternal attachment patterns and personality in post partum depression]. AB - AIMS: This study investigates the prevalence of post partum depression (PPD) in a sample of Roman women, and the role of socio-demographic variables, personality structure and maternal attachment patterns, in order to identify primary and secondary prevention strategies. METHODS: Data were collected in two phases. During the third trimester of pregnancy, a sample of 453 women completed a socio demographic data sheet and the Edinburgh Postnatal Depression Scale (EPDS). Among the patients scoring 12 or more at EPDS, 15 entered the second phase of the study and completed SCID-II and Adult Attachment Interview. PPD diagnosis was confirmed by the SCID-I. The study group was compared with a control group. RESULTS: Among the 453 women who were evaluated, 92 (20.3%) scored >=12 at EPDS, 39 has been enrolled and 15 entered the study. Presence of depressive symptoms was associated with: complications in pregnancy, previous psychiatric disorders, family and marital conflicts. 66.6% of depressed mothers showed more than one diagnosis on Axis II (particularly avoidant/dependent + borderline or histrionic + dependent). The AAI showed a prevalence of insecure (33.3%) and unresolved/disorganized (46.6%) attachment pattern in the clinical group. DISCUSSION AND CONCLUSIONS: Our results suggest that psychological factors such as personality structure and attachment patterns are not only involved in post natal affective disorders, but have a key role in the onset and development of PPD. PMID- 22825437 TI - [Parental care and post partum depression: a case report]. AB - The post partum depression (PPD) is a severe risk factor for the emotional and cognitive development of offspring. The Authors describe the relationship between mother with PPD and her two-year old child. The mother repeats patterns of parental care experienced during her own childhood. PMID- 22825438 TI - [Pharmacotherapy plus psychotherapy in patients with mood disorder and Axis II codiagnosis. A review]. AB - AIM: The main aim of this paper is to review data on the efficacy of combined therapy in patients with mood disorder and axis II codiagnosis. The secondary aim is to assess the impact of personality disorders, psychotherapies, and combination therapy approaches on the treatment outcome. MATERIALS AND METHODS: We searched the Medline database using the following syntax: "major depressive disorder", "bipolar depression", "personality disorder", "comorbidity", "epidemiology", "combined therapy", "sequential therapy". The search included studies published up to february 2011. We divided the selected studies on the basis of the following pharmacotherapy and psychotherapy combination treatment approaches: concurrent treatment, sequential treatment and cross-over treatment. RESULTS: We found six studies about this topic. They show that in patients with unipolar depression combined therapy does not increase significantly the remission rate of the acute phases. However, combined treatment has greater effects on social functioning, interpersonal sensitivity and aggressiveness than pharmacological treatment. The studies indicate also that in patients with either unipolar or bipolar disorder combined therapy is more effective than pharmacological therapy in reducing relapses. DISCUSSION: The available limited data suggest that in patients with mood disorder and axis II codiagnosis pharmacological and psychological combined therapy is useful. In these patients the type of combination approach does not seem to influence the treatment outcome. PMID- 22825439 TI - Development and validation of the Italian version of the 15-item dispositional resilience scale. AB - Studies have shown that psychological hardiness is an important stress resilience resource for individuals. The 15-items Dispositional Resilience Scale (DRS-15) is a short, reliable and valid self-report instrument to measure hardiness that is not available in Italian. The present study was undertaken to create an Italian version of the DRS-15, and evaluate its psychometric properties and validity in the Italian context. An Italian version was produced using multiple independent bilingual translators. This version was administered to a non-clinical sample of adults (N=150), along with measure o psychological well-being (PWB-18) and health. A sub-sample (N = 66) completed the DRS-15 again one month later. Results showed good reliability in terms of internal consistency and test-retest stability. With regard to the subscale, stability was high for all three subscales, whereas two subscales (Commitment and Control) showed marginal internal consistency. DRS-15 total and subscales scores showed a theoretically meaningful pattern of correlations with PWB-18 subscales, supporting the validity of the Italian DRS. Also, multiple regression analysis revealed a correlation between DRS-15 scores and self-rated general health, even after controlling for age and sex. The new Italian DRS-15 provides a valid, reliable and easy to use tool fr assessing stress resilience in clinical and research settings. PMID- 22825440 TI - [Coping styles in schizophrenia: study of clinical and functional variables as determinants of strategies to cope with stress]. AB - AIM: The purpose of this study was to analyze the relation between coping styles, and both clinical and functional variables in a sample of patients with stable schizophrenia. METHODS: Forty-seven consecutive outpatients were enrolled in a cross-sectional study. A clinical assessment was performed and included: the Positive and Negative Syndrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Scale for the Assessment of Unawareness of Mental Disorder (SUMD), the Rosenberg Self-Esteem Scale (RSES), the Quality of Life Scale (QLS) and the questionnaire Short Form Health Survey 36 (SF-36). Coping strategies were assessed with the Coping Inventory for Stressful Situations (CISS), identifying three main coping styles: task-, emotion- and avoidance oriented. Three different multiple regression models with backward elimination were performed in order to discover contributing factors to coping styles. RESULTS: From the results of multiple regression, depressive symptoms and objective quality of life were contributing factors to task-oriented coping style, explaining about 32% of variance. Negative symptoms, subjective quality of life, self-esteem, awareness of symptomatology and attribution of symptoms to illness resulted to be contributing factors to emotion-oriented coping strategies, explaining about 60% of variance. DISCUSSION: These results suggested the role of some clinical and functional variables as contributing factors to coping styles. In this context, supportive and rehabilitative interventions and cognitive-behavioral therapy focused to manage psychotic symptoms and to decrease distress could help patients to employ more adaptive coping strategies and improve their outcomes. PMID- 22825441 TI - [Dissociative phenomena in a sample of outpatients]. AB - AIM: The study describes the frequency and the quality of dissociative phenomena and their relationship with axis I disorders and the psychopathological severity in outpatients. METHODS: The sample (N=383) was subjected to MINI diagnostic interview and self-assessment scales DES and SCL-90. The data were analysed using SPSS. RESULTS: The 11,0% of subjects has a score >=20 on DES. The 5,2% has no dissociative symptoms. The absorption images is the most frequent dissociative phenomenon, the less common is the dissociation amnesia. A relationship between dissociative phenomena and conditions unemployment, marital separation and single parties and an inverse relationship with age founded. Dissociative phenomena are more frequent in participants who have been diagnosed at least one axis I disorder and their severity is positively correlated with the number of diagnosed diseases and scores to the General Symptomatic Index. DISCUSSION: Our results point towards the existence of three types of dissociative experiences. The first type, represented by the factor absorption/imaginative involvement, is expressed along a continuum from normal to pathological; a second type, represented by the factor depersonalization/derealization, occurs in a significantly more intense and specific among subjects with axis I disorders; the latest manifestation dissociative, described by the dissociation amnesia, seems to have a predominantly typological feature that qualifies it as an experience not commonly distributed in the general population. The identifying of dissociative symptoms is necessary for the psychopathologic evaluation and to improve the effectiveness of treatment programs. PMID- 22825442 TI - Defecation 2: Internal anorectal resistance is a critical factor in defecatory disorders. AB - BACKGROUND: The aim of this study was to test our hypothesis that the reason why imaging is of little assistance in diagnosing "constipation" causes may be related to the high sensitivity of internal anorectal flow resistance in defecation to small changes in geometry. We applied a mathematical model to describe the effects on flow mechanics of observed changes in the shape of the rectum and anus during defecation. METHODS: Three groups of patients were studied with video proctograms. Group 1 comprised 4 patients with normal defecation studied with video proctography or magnetic resonance imaging (MRI). Group 2 comprised 8 patients with fecal incontinence, studied by video X-ray electromyography. Group 3 comprised 8 patients with constipation evaluated by video MRI. RESULTS: Three muscle vectors open the anorectal angle prior to defecation, causing the anorectal luminal diameter to increase to approximately twice its resting size. These vectors are forwards (anterior wall), backwards and downwards (posterior wall). Resistance to passage of a fecal bolus through the anorectum is determined by viscous friction against the anorectal wall and by the energy required to deform the bolus as it flows. The observed changes in anorectal geometry serve to reduce both the viscous friction in the anus and the deformation of the bolus, which reduces the force required to facilitate its passage through the anus. For example, if the effective diameter of the anus is doubled during defecation, the frictional resistance is reduced by a factor of 8. CONCLUSIONS: The sensitivity of flow resistance to geometry explains why MRI or computed tomography (CT) scans taken during defecation are not often helpful in diagnosing causation. Small changes in geometry can have a disproportionate affect on flow resistance. Combining accurate directional measurements during dynamic MRI or CT scans taken during defecation with observations of bolus deformation, and if possible, simultaneous anorectal manometry, may provide clinically helpful insights on patients with anorectal evacuation disorders. PMID- 22825443 TI - Coagulases as determinants of protective immune responses against Staphylococcus aureus. AB - During infection, Staphylococcus aureus secretes two coagulases (Coa and von Willebrand factor binding protein [vWbp]), which, following an association with host prothrombin and fibrinogen, form fibrin clots and enable the establishment of staphylococcal disease. Within the genomes of different S. aureus isolates, coagulase gene sequences are variable, and this has been exploited for a classification of types. We show here that antibodies directed against the variable prothrombin binding portion of coagulases confer type-specific immunity through the neutralization of S. aureus clotting activity and protection from staphylococcal disease in mice. By combining variable portions of coagulases from North American isolates into hybrid Coa and vWbp proteins, a subunit vaccine that provided protection against challenge with different coagulase-type S. aureus strains in mice was derived. PMID- 22825444 TI - Prc contributes to Escherichia coli evasion of classical complement-mediated serum killing. AB - Escherichia coli is a common Gram-negative organism that causes bacteremia. Prc, a bacterial periplasmic protease, and its homologues are known to be involved in the pathogenesis of Gram-negative bacterial infections. The present study examined the role of Prc in E. coli bacteremia and characterized the ability of the prc mutant of the pathogenic E. coli strain RS218 to cause bacteremia and survive in human serum. The prc mutant of RS218 exhibited a decreased ability to cause a high level of bacteremia and was more sensitive to serum killing than strain RS218. This sensitivity was due to the mutant's decreased ability to avoid the activation of the antibody-dependent and -independent classical complement cascades as well as its decreased resistance to killing mediated by the membrane attack complex, the end product of complement system activation. The demonstration of Prc in the evasion of classical complement-mediated serum killing of pathogenic E. coli makes this factor a potential target for the development of therapeutic and preventive measures against E. coli bacteremia. PMID- 22825445 TI - The amino acid sequence of Neisseria lactamica PorB surface-exposed loops influences Toll-like receptor 2-dependent cell activation. AB - Toll-like receptors (TLRs) play a major role in host mucosal and systemic defense mechanisms by recognizing a diverse array of conserved pathogen-associated molecular patterns (PAMPs). TLR2, with TLR1 and TLR6, recognizes structurally diverse bacterial products such as lipidated factors (lipoproteins and peptidoglycans) and nonlipidated proteins, i.e., bacterial porins. PorB is a pan neisserial porin expressed regardless of organisms' pathogenicity. However, commensal Neisseria lactamica organisms and purified N. lactamica PorB (published elsewhere as Nlac PorB) induce TLR2-dependent proinflammatory responses of lower magnitude than N. meningitidis organisms and N. meningitidis PorB (published elsewhere as Nme PorB). Both PorB types bind to TLR2 in vitro but with different apparent specificities. The structural and molecular details of PorB-TLR2 interaction are only beginning to be unraveled and may be due to electrostatic attraction. PorB molecules have significant strain-specific sequence variability within surface-exposed regions (loops) putatively involved in TLR2 interaction. By constructing chimeric recombinant PorB loop mutants in which surface-exposed loop residues have been switched between N. lactamica PorB and N. meningitidis PorB, we identified residues in loop 5 and loop 7 that influence TLR2-dependent cell activation using HEK cells and BEAS-2B cells. These loops are not uniquely responsible for PorB interaction with TLR2, but NF-kappaB and MAP kinases signaling downstream of TLR2 recognition are likely influenced by a hypothetical "TLR2-binding signature" within the sequence of PorB surface-exposed loops. Consistent with the effect of purified PorB in vitro, a chimeric N. meningitidis strain expressing N. lactamica PorB induces lower levels of interleukin 8 (IL-8) secretion than wild-type N. meningitidis, suggesting a role for PorB in induction of host cell activation by whole bacteria. PMID- 22825446 TI - Stressor-induced increase in microbicidal activity of splenic macrophages is dependent upon peroxynitrite production. AB - Exposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1alpha (IL-1alpha) and IL-1beta, and increased reactivity of splenic CD11b(+) macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to kill Escherichia coli both in vitro and in vivo, through a Toll-like receptor 4 dependent mechanism. The present study tested the hypothesis that stressor enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation with E. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing of E. coli demonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing. PMID- 22825447 TI - Intracellular trafficking of Clostridium perfringens iota-toxin b. AB - Clostridium perfringens iota-toxin is composed of an enzymatic component (Ia) and a binding component (Ib). Ib binds to a cell surface receptor, undergoes oligomerization in lipid rafts, and binds Ia. The resulting complex is then endocytosed. Here, we show the intracellular trafficking of iota-toxin. After the binding of the Ib monomer with cells at 4 degrees C, oligomers of Ib formed at 37 degrees C and later disappeared. Immunofluorescence staining of Ib revealed that the internalized Ib was transported to early endosomes. Some Ib was returned to the plasma membrane through recycling endosomes, whereas the rest was transported to late endosomes and lysosomes for degradation. Degraded Ib was delivered to the plasma membrane by an increase in the intracellular Ca(2+) concentration caused by Ib. Bafilomycin A1, an endosomal acidification inhibitor, caused the accumulation of Ib in endosomes, and both nocodazole and colchicine, microtubule disrupting agents, restricted Ib's movement in the cytosol. These results indicated that an internalized Ia and Ib complex was delivered to early endosomes and that subsequent delivery of Ia to the cytoplasm occurs mainly in early endosomes. Ib was either sent back to the plasma membranes through recycling endosomes or transported to late endosomes and lysosomes for degradation. Degraded Ib was transported to plasma membranes. PMID- 22825448 TI - Evaluation of the trimeric autotransporter Ata as a vaccine candidate against Acinetobacter baumannii infections. AB - Acinetobacter baumannii is a multidrug-resistant (MDR) nosocomial pathogen for which immunotherapeutic alternatives are needed. We previously identified a surface autotransporter of A. baumannii, Ata, that bound to various extracellular matrix/basal membrane proteins and was required for full virulence, biofilm formation, and the adhesion of A. baumannii to collagen type IV. We show here that Ata binding to collagen type IV was inhibited by antibodies to Ata. In addition, in the presence of complement and polymorphonuclear cells (PMNs), antibodies to Ata were highly opsonic against A. baumannii ATCC 17978 and showed low to moderate killing activity against four heterologous A. baumannii strains, whereas in the absence of PMNs, antibody to Ata efficiently promoted complement dependent bactericidal killing of all of the tested A. baumannii isolates. Using a pneumonia model of infection in both immunocompetent and immunocompromised mice, we found that, compared to normal rabbit sera, antisera to Ata significantly reduced the levels of A. baumannii ATCC 17978 and two MDR strains in the lungs of infected mice. The ability of Ata to engender anti-adhesive, bactericidal, opsonophagocytic, and protective antibodies validates its potential use as an antigenic target against MDR A. baumannii infections. PMID- 22825449 TI - Increased chain length promotes pneumococcal adherence and colonization. AB - Streptococcus pneumoniae is a mucosal pathogen that grows in chains of variable lengths. Short-chain forms are less likely to activate complement, and as a consequence they evade opsonophagocytic clearance more effectively during invasive disease. When grown in human nasal airway surface fluid, pneumococci exhibited both short- and long-chain forms. Here, we determined whether longer chains provide an advantage during colonization when the organism is attached to the epithelial surface. Chain-forming mutants and the parental strain grown under conditions to promote chain formation showed increased adherence to human epithelial cells (A549 cells) in vitro. Additionally, adherence to A549 cells selected for longer chains within the wild-type strain. In vivo in a murine model of colonization, chain-forming mutants outcompeted the parental strain. Together, our results demonstrate that morphological heterogeneity in the pneumococcus may promote colonization of the upper respiratory tract by enhancing the ability of the organism to bind to the epithelial surface. PMID- 22825452 TI - Protein A-specific monoclonal antibodies and prevention of Staphylococcus aureus disease in mice. AB - Staphylococcus aureus is a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin resistant S. aureus [MRSA]) has prompted research into staphylococcal vaccines and preventive measures. The envelope of S. aureus is decorated with staphylococcal protein A (SpA), which captures the Fcgamma portion of immunoglobulins to prevent opsonophagocytosis and associates with the Fab portion of V(H)3-type B cell receptors to trigger B cell superantigen activity. Nontoxigenic protein A (SpA(KKAA)), when used as an immunogen in mice, stimulates humoral immune responses that neutralize the Fcgamma and the V(H)3(+) Fab binding activities of SpA and provide protection from staphylococcal abscess formation in mice. Here, we isolated monoclonal antibodies (MAbs) against SpA(KKAA) that, by binding to the triple-helical bundle fold of its immunoglobulin binding domains (IgBDs), neutralize the Fcgamma and Fab binding activities of SpA. SpA(KKAA) MAbs promoted opsonophagocytic killing of MRSA in mouse and human blood, provided protection from abscess formation, and stimulated pathogen-specific immune responses in a mouse model of staphylococcal disease. Thus, SpA(KKAA) MAbs may be useful for the prevention and therapy of staphylococcal disease in humans. PMID- 22825451 TI - The WalKR system controls major staphylococcal virulence genes and is involved in triggering the host inflammatory response. AB - The WalKR two-component system is essential for the viability of Staphylococcus aureus, playing a central role in controlling cell wall metabolism. We produced a constitutively active form of WalR in S. aureus through a phosphomimetic amino acid replacement (WalR(c), D55E). The strain displayed significantly increased biofilm formation and alpha-hemolytic activity. Transcriptome analysis was used to determine the full extent of the WalKR regulon, revealing positive regulation of major virulence genes involved in host matrix interactions (efb, emp, fnbA, and fnbB), cytolysis (hlgACB, hla, and hlb), and innate immune defense evasion (scn, chp, and sbi), through activation of the SaeSR two-component system. The impact on pathogenesis of varying cell envelope dynamics was studied using a murine infection model, showing that strains producing constitutively active WalR(c) are strongly diminished in their virulence due to early triggering of the host inflammatory response associated with higher levels of released peptidoglycan fragments. Indeed, neutrophil recruitment and proinflammatory cytokine production were significantly increased when the constitutively active walR(c) allele was expressed, leading to enhanced bacterial clearance. Taken together, our results indicate that WalKR play an important role in virulence and eliciting the host inflammatory response by controlling autolytic activity. PMID- 22825453 TI - OxyR activation in Porphyromonas gingivalis in response to a hemin-limited environment. AB - Porphyromonas gingivalis is a Gram-negative obligately anaerobic bacterium associated with several forms of periodontal disease, most closely with chronic periodontitis. Previous studies demonstrated that OxyR plays an important role in the aerotolerance of P. gingivalis by upregulating the expression of oxidative stress genes. Increases in oxygen tension and in H(2)O(2) both induce activation of OxyR. It is also known that P. gingivalis requires hemin as an iron source for its growth. In this study, we found that a hemin-limited growth environment significantly enhanced OxyR activity in P. gingivalis. As a result, expression of sod, dps, and ahpC was also upregulated. Using a chromatin immunoprecipitation quantitative PCR (qPCR) analysis, DNA binding of activated OxyR to the promoter of the sod gene was enhanced in P. gingivalis grown under hemin-limited conditions compared to excess-hemin conditions. Cellular tolerance of H(2)O(2) was also enhanced when hemin was limited in the growth medium of P. gingivalis. Our work supports a model in which hemin serves as a signal for the regulation of OxyR activity and indicates that P. gingivalis coordinately regulates expression of oxidative-stress-related genes by this hemin concentration-dependent pathway. PMID- 22825450 TI - Innate immune gene polymorphisms in tuberculosis. AB - Tuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and "case control" association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB. PMID- 22825454 TI - A smoking-associated 7-gene signature for lung cancer diagnosis and prognosis. AB - Smoking is responsible for 90% of lung cancer cases. There is currently no clinically available gene test for early detection of lung cancer in smokers, or an effective patient selection strategy for adjuvant chemotherapy in lung cancer treatment. In this study, concurrent coexpression with multiple signaling pathways was modeled among a set of genes associated with smoking and lung cancer survival. This approach identified and validated a 7-gene signature for lung cancer diagnosis and prognosis in smokers using patient transcriptional profiles (n=847). The smoking-associated gene coexpression networks in lung adenocarcinoma tumors (n=442) were highly significant in terms of biological relevance (network precision = 0.91, FDR<0.01) when evaluated with numerous databases containing multi-level molecular associations. The gene coexpression network in smoking lung adenocarcinoma patients was confirmed in qRT-PCR assays of the identified biomarkers and involved signaling pathway genes in human lung adenocarcinoma cells (H23) treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Furthermore, the western blotting results of p53, phospho-p53, Rb and EGFR in NNK treated H23 and transformed normal human lung epithelial cells (BEAS-2B) support their functional involvement in smoking-induced lung cancer carcinogenesis and progression. PMID- 22825455 TI - The gut microbiota, environment and diseases of modern society. AB - The human gut microbiota is a complex community that provides important metabolic functions to the host. Consequently, alterations in the gut microbiota have been associated with the pathogenesis of several human diseases associated with a disturbance in metabolism, particularly those that have been increasing in incidence over the last several decades including obesity, diabetes and atherosclerosis. In this review, we explore how advances in deep DNA sequencing technology have provided us a greater understanding of the factors that influence that composition of the gut microbiota and its possible links to the pathogenesis of these diseases. PMID- 22825456 TI - Hemoglobin level at initiation of darbepoetin alfa: impact on need for transfusion and associated costs in chemotherapy-induced anemia treatment in Europe. AB - PURPOSE: Erythropoiesis-stimulating agents can reduce red blood cell transfusion rates in patients developing anemia while receiving chemotherapy. We investigated potential cost savings from reduced transfusion rates in patients starting darbepoetin alfa (DA) at higher versus lower hemoglobin (Hb) levels. METHODS: Two systematic literature reviews were performed: transfusion outcomes in patients receiving DA stratified by baseline Hb level and costs of transfusion in Europe. Potential cost savings were calculated by multiplying the difference in transfusion rates between Hb levels by the midpoint of transfusion costs. RESULTS: Despite differences in baseline characteristics, treatment duration and analysis technique, the clinical studies (n = 8) showed that fewer transfusions were required when DA was initiated at higher versus lower Hb levels. The economic studies (n = 9) showed that 1 unit of transfusion ranged from 130 to 537 (2010-adjusted values). Cost savings from initiating DA at higher versus lower Hb levels were 503-2,226 (2 units transfused) and 880 3,895 (3.5 units) per ten patients. CONCLUSIONS: Transfusion incidence increases with DA initiation at lower Hb levels. Potential cost savings depend on the number of units transfused and cost items included. DA initiation according to guidelines can reduce transfusions and potentially reduce transfusion-associated costs. PMID- 22825457 TI - Symptom burden in head and neck cancer: impact upon oral energy and protein intake. AB - PURPOSE: This study explored relationships between oral symptom burden (xerostomia, thick secretions, and mucosal sensitivity), energy and protein intake, and weight change over time among head and neck cancer (HNC) patients who have completed concurrent chemoradiation (CCR). METHODS: Symptom burden was assessed utilizing the Vanderbilt Head and Neck Symptom Survey version 2.0. Weight change was measured from diagnosis to treatment completion, and to the early, mid, and late recovery stage. Energy and protein intake were determined utilizing 24-h diet recalls. RESULTS: Forty-three adult patients treated for HNC enrolled in the study. Mean percentage weight loss from diagnosis to treatment completion was 7.91 +/- 4.06 %. Within the mid-recovery stage significant inverse relationships were found between oral protein intake and xerostomia and mucosal sensitivity (r = -0.818, p = 0.012; r = -0.726, p = 0.032, respectively). After controlling for weight change, significant inverse relationships were found within the mid-recovery stage between oral energy intake and xerostomia and mucosal sensitivity (r = -0.740, p = 0.046; r = -0.751, p = 0.043, respectively). Significant, inverse relationships were also found between oral protein intake and xerostomia and mucosal sensitivity (r = -0.835, p = 0.019; r = -0.726, p = 0.033, respectively). CONCLUSIONS: Xerostomia and mucosal sensitivity were significantly related to oral energy and protein intake post-CCR in mid-recovery. Weight loss was greatest from diagnosis to treatment completion and continued through the mid-recovery stage. Assessment of oral symptom burden (xerostomia and mucosal sensitivity) and its impact on oral intake and weight post-CCR should be conducted routinely in good patient care. PMID- 22825458 TI - Biomarkers for bladder cancer aggressiveness. AB - PURPOSE OF REVIEW: Bladder cancer is associated with high recurrence and mortality rates. Development of accurate surveillance tests to evaluate disease aggressiveness and for prognosis of disease recurrence and progression is a major clinical need. At the molecular level bladder cancer displays a vast heterogeneity as reflected by the presence of multiple potential biomarkers associated with various disease phenotypes. The scope of this review is to briefly summarize the latest findings on biomarkers potentially beneficial in disease stratification based on aggressiveness and prognosis. RECENT FINDINGS: Multiple potential biomarkers for bladder cancer have been identified corresponding to chromosome, DNA, and epigenetic alterations, as well as changes in RNA, miRNAs, and protein expression levels and modifications. We summarize some of the main biomarker findings reported in the past year that are considered to be potentially correlated to disease aggressiveness. A comparison to existing latest evidence from the classical US Food and Drug Administration-approved bladder cancer detection markers is made. SUMMARY: Potential biomarkers detected noninvasively in urine specimens, as well as in excised tissue specimens following initial treatment, are briefly reported. The prognostic information provided may be significant, as multiple markers by now have been found to correlate with disease outcome. However, the studies presented were in general either too small, and/or the performance of the single biomarkers was moderate. The information presently available suggests that single biomarkers may be insufficient for effective monitoring and patient management. A concerted effort to establish panels of biomarkers based on the ample existing knowledge, and validate them in proper clinical trials is urgently needed. PMID- 22825459 TI - Bulbar urethroplasty: transecting vs. nontransecting techniques. AB - PURPOSE OF REVIEW: To transect or not to transect the bulbar urethra in nontraumatic urethral strictures still remains an issue that is open to debate. Herewith, we evaluate and compare the results of these two different options in the treatment of bulbar urethral strictures. RECENT FINDINGS: In 404 patients, bulbar urethroplasty using transecting techniques (end-to-end anastomosis and augmented anastomotic repair) provided a success rate ranging from 90 to 98.6%. In 522 patients, bulbar urethroplasty using nontransecting techniques (nontransecting anastomotic urethroplasty and simple oral grafting techniques) provided approximately the same success rate, ranging from 81.8 to 100%. SUMMARY: Future studies, including more homogenous series of patients and subjective evaluation of urinary and sexual complications after repair, are necessary to surely establish the gold standard of treatment for nontraumatic strictures located in the proximal bulbar urethra. PMID- 22825460 TI - Predictive factors for recurrence progression and cancer specific survival in high-risk bladder cancer. AB - PURPOSE OF REVIEW: Despite standard treatment with transurethral resection (TUR) and adjuvant Bacillus Calmette-Guerin (BCG), a large percentage of high-risk bladder cancer (HRBC) recur, and some progress. On the basis of review of the current guidelines and literature, we have developed actualized clinical and molecular prognostic factors of recurrence, progression and cancer specific survival (CSS) in patients with HRBC. RECENT FINDINGS: A Medline search was conducted to identify the current literature updating the most important clinic and pathological predictive factors published in the last years. Also, there have been reviewed the new molecular markers that can assess prognosis and BCG response. SUMMARY: Despite different methodological bias, as short follow-up, a small number of patients and a different definition of prognostic factors, increased evidence supports sex, age, grade, stage, multifocality, history of previous recurrences, carcinoma in situ in the prostatic urethra and early recurrence as prognostic factors for recurrence, progression and CSS in nonmuscle invasive bladder cancer. Also lymphovascular invasion in TUR and new molecular markers (galectin-3, profilin-1, and combination of markers) are increasingly useful in predicting prognosis and BCG response. Moreover, there is enough evidence to consider the implementation of new specific risk tables for patients treated with BCG. In cases with poor prognostic factors after TUR in HRBC early cystectomy should be considered. PMID- 22825461 TI - Pathological possibilities and pitfalls in detecting aggressive bladder cancer. AB - PURPOSE OF REVIEW: The prognosis of patients with high-risk bladder cancer is generally poor. In addition to advanced stage and high-grade tumors, several histopathological subtypes of invasive bladder cancer have been identified as being more aggressive than conventional forms. However, modalities for early detection of such aggressive neoplasms are limited. This review examines the pathological features of aggressive bladder cancer and critically reviews the performance of selected methodologies that are commonly used to detect such lesions. RECENT FINDINGS: Strategies including bladder tumor antigen assay, NMP22, ImmunoCyt, and UroVysion hold promise for the early detection of aggressive urothelial carcinomas of the bladder. However, such approaches are currently limited by their sensitivity and potential for false-positive results, and are unlikely to substitute cystoscopy. SUMMARY: Molecular-based detection techniques represent potentially attractive strategies for noninvasive detection of aggressive bladder cancer using urine as the specimen source. Identification of new markers and development of novel platforms may improve detection in the future. PMID- 22825462 TI - "Yo no sabia..."-immigrant women's use of national health systems for reproductive and abortion care. AB - Half of pregnancies worldwide are unintended; half of these end in abortion. Immigrant women encounter more obstacles to reproductive healthcare than non immigrant women, and access to national healthcare is a particularly important factor in abortion access. Spain's government recently liberalized abortion laws, including abortion services in the national health system available to immigrants. Evidence suggests that immigrant women in Spain experience difficulties navigating the health system-the impact of the changed abortion laws on immigrant's women's access to care is not yet clear. Through a literature review and analysis, this paper examines the experiences of immigrant women with national health systems, and their use of such systems for reproductive and abortion care, in order to explore what could be expected in Spain as the national health system expands to include abortion care, and to illuminate immigrant women's experiences with using national health systems for reproductive healthcare more broadly. PMID- 22825463 TI - Trends in recreational computer use among Latino children in California. AB - In this study we examine differential trends in recreational computer use among Latino and white children in California. We analyzed data from the children's sample (age 4-11) of the 2001 and 2009 California Health Interview Survey. Multivariate analysis was used to estimate the impact of language spoken at home, income and parental education, on recreational computer use. Latino children had substantially lower recreational computer use in 2001, compared to whites, but by 2009 the gap had almost disappeared. Among Latinos, compared to families where English is spoken exclusively, recreational computer use was substantially lower in families where Spanish is spoken exclusively. Parental education and income were significantly associated with recreational computer use, but only among Latinos, and the association with parental education changed from 2001 to 2009, explaining some of the difference in trend between Latino and white children. PMID- 22825464 TI - Tuberculosis in indigenous communities of Antioquia, Colombia: epidemiology and beliefs. AB - Morbidity and mortality caused by tuberculosis are increased in most of the Latin American indigenous communities. Factors that could explain this situation are poverty and limited health services access due to social conflicts and geographical isolation. We determined the frequency of tuberculosis in Colombian indigenous communities and described their knowledge related to transmission and control. We developed a descriptive study and health survey. Interviews were performed to find ancestral knowledge about tuberculosis. Sputum samples from patients with respiratory symptoms were analyzed. 10 indigenous communities were studied, which tuberculosis incidence was 291/100,000. Communities believe that tuberculosis is a body and spirit disease, which transmission is by direct contact or by witchcraft. Tuberculosis incidence in the studied communities was ninefold higher than that of the general population from Antioquia Department. Knowledge exchange could facilitate the community empowerment and implementation of educational activities which might improve the control of the disease. PMID- 22825465 TI - Intensified case-finding for latent tuberculosis infection among the Baltimore City Hispanic population. AB - Foreign-born immigrants are at high risk for latent TB infection (LTBI). In conjunction with the Baltimore City Health Department (BCHD), student volunteers conducted intensified LTBI case-finding (ICF) using tuberculin skin testing (TST) in the Hispanic community from 2006-2010. We sought to determine the yield of ICF and estimate the LTBI prevalence. Retrospective cross-sectional study. Among 478 individuals screened, 164 (34.3 %) had a positive TST, 227 (47.5 %) had a negative TST, and 87 (18.2 %) did not return. Among those who completed screening, the prevalence of LTBI was 164/391 (41.9, 95 % CI 0.37-0.47). ICF referrals accounted for 4.4 % of all LTBI referrals to BCHD and for 41 % of referrals among Hispanics. We found a high rate of undiagnosed LTBI within the Hispanic community. This student-run ICF program accounted for almost half of all LTBI cases among Hispanics. Community resources are needed to target this high risk population. PMID- 22825466 TI - Formation of higher-order structures of chiral poly(ethynylpyridine)s depending on size, temperature, and saccharide recognition. AB - Amphiphilic 2,6-pyridylene ethynylene "meta-ethynylpyridine" polymers having chiral oligo(oxyethylene) side chains were developed as hosts for saccharide recognition. The polymers were prepared via a Sonogashira reaction and fractionated by gel permeation chromatography (GPC). They showed circular dichroism (CD) activity due to their higher-order chiral helical structures, and their CD and UV-vis spectra changed depending on not only saccharide recognition but also molecular size, temperature, and metal cation recognition. PMID- 22825467 TI - Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c Jun in leukemia cells. AB - Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex induced BIM and apoptosis were decreased in cells harboring dominant-negative c Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about -2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment. PMID- 22825468 TI - Alpha-synuclein: from secretion to dysfunction and death. AB - The aggregation, deposition, and dysfunction of alpha-synuclein (aSyn) are common events in neurodegenerative disorders known as synucleinopathies. These include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A growing body of knowledge on the biology of aSyn is emerging and enabling novel hypotheses to be tested. In particular, the hypothesis that aSyn is secreted from neurons, thus contributing to the spreading of pathology not only in the brain but also in other organs, is gaining momentum. Nevertheless, the precise mechanism(s) of secretion, as well as the consequences of extracellular aSyn species for neighboring cells are still unclear. Here, we review the current literature and integrate existing data in order to propose possible mechanisms of secretion, cell dysfunction, and death. Ultimately, the complete understanding of these processes might open novel avenues for the development of new therapeutic strategies. PMID- 22825469 TI - Copy number aberrations of BCL2 and CDKN2A/B identified by array-CGH in thymic epithelial tumors. AB - The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment. PMID- 22825470 TI - Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity. AB - Cancer stem cells (CSCs) represent a population of cancer cells that possess unique self-renewal and differentiation characteristics required for tumorigenesis and are resistant to chemotherapy-induced apoptosis. Lung CSCs can be enriched by several markers including drug-resistant side population (SP), CD133(pos) and ALDH(high). Using human non-small cell lung adenocarcinoma cell lines and patient-derived primary tumor cells, we demonstrate that SP cells represent a subpopulation distinct from other cancer stem/progenitor cell (CS/PC) populations marked by CD133(pos) or ALDH(high). The non-CS/PCs and CS/PCs of each subpopulation are interconvertible. Epithelial-mesenchymal transition (EMT) promotes the formation of CD133(pos) and ALDH(high) CS/PC subpopulations while suppressing the SP CS/PC subpopulation. Rac1 GTPase activity is significantly increased in cells that have undergone EMT, and targeting Rac1 is effective in inhibiting the dynamic conversion of non-CS/PCs to CS/PCs, as well as the CS/PC activity. These results imply that various subpopulations of CS/PCs and non CS/PCs may achieve a stochastic equilibrium in a defined microenvironment, and eliminating multiple subpopulations of CS/PCs and effectively blocking non-CS/PC to CS/PC transition, by an approach such as targeting Rac1, can be a more effective therapy. PMID- 22825471 TI - Synergistic effects of nelfinavir and bortezomib on proteotoxic death of NSCLC and multiple myeloma cells. AB - Exploiting protein homeostasis is a new therapeutic approach in cancer. Nelfinavir (NFV) is an HIV protease inhibitor that induces endoplasmic reticulum (ER) stress in cancer cells. Under conditions of ER stress, misfolded proteins are transported from the ER back to the cytosol for subsequent degradation by the ubiquitin-proteasome system. Bortezomib (BZ) is a proteasome inhibitor and interferes with degradation of misfolded proteins. Here, we show that NFV and BZ enhance proteotoxicity in non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells. The combination synergistically inhibited cell proliferation and induced cell death. Activating transcription factor (ATF)3 and CCAAT-enhancer binding protein homologous protein (CHOP), markers of ER stress, were rapidly increased, and their siRNA-mediated knockdown inhibited cell death. Knockdown of double-stranded RNA activated protein kinase-like ER kinase, a signal transducer in ER stress, significantly decreased apoptosis. Pretreatment with the protein synthesis inhibitor, cycloheximide, decreased levels of ubiquitinated proteins, ATF3, CHOP, and the overall total cell death, suggesting that inhibition of protein synthesis increases cell survival by relieving proteotoxic stress. The NFV/BZ combination inhibited the growth of NSCLC xenografts, which correlated with the induction of markers of ER stress and apoptosis. Collectively, these data show that NFV and BZ enhance proteotoxicity in NSCLC and MM cells, and suggest that this combination could tip the precarious balance of protein homeostasis in cancer cells for therapeutic gain. PMID- 22825472 TI - Skeletal muscle damage and impaired regeneration due to LPL-mediated lipotoxicity. AB - According to the concept of lipotoxicity, ectopic accumulation of lipids in non adipose tissue induces pathological changes. The most prominent effects are seen in fatty liver disease, lipid cardiomyopathy, non-insulin-dependent diabetes mellitus, insulin resistance and skeletal muscle myopathy. We used the MCK(m) hLPL mouse distinguished by skeletal and cardiac muscle-specific human lipoprotein lipase (hLPL) overexpression to investigate effects of lipid overload in skeletal muscle. We were intrigued to find that ectopic lipid accumulation induced proteasomal activity, apoptosis and skeletal muscle damage. In line with these findings we observed reduced Musculus gastrocnemius and Musculus quadriceps mass in transgenic animals, accompanied by severely impaired physical endurance. We suggest that muscle loss was aggravated by impaired muscle regeneration as evidenced by reduced cross-sectional area of regenerating myofibers after cardiotoxin-induced injury in MCK(m)-hLPL mice. Similarly, an almost complete loss of myogenic potential was observed in C2C12 murine myoblasts upon overexpression of LPL. Our findings directly link lipid overload to muscle damage, impaired regeneration and loss of performance. These findings support the concept of lipotoxicity and are a further step to explain pathological effects seen in muscle of obese patients, patients with the metabolic syndrome and patients with cancer-associated cachexia. PMID- 22825474 TI - Technology: when two halves are better than one whole. PMID- 22825473 TI - Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. AB - The retinitis pigmentosa GTPase regulator (RPGR) and nephrocystin-4 (NPHP4) comprise two key partners of the assembly complex of the RPGR-interacting protein 1 (RPGRIP1). Mutations in RPGR and NPHP4 are linked to severe multisystemic diseases with strong retinal involvement of photoreceptor neurons, whereas those in RPGRIP1 cause the fulminant photoreceptor dystrophy, Leber congenital amaurosis (LCA). Further, mutations in Rpgrip1 and Nphp4 suppress the elaboration of the outer segment compartment of photoreceptor neurons by elusive mechanisms, the understanding of which has critical implications in uncovering the pathogenesis of syndromic retinal dystrophies. Here we show RPGRIP1 localizes to the photoreceptor connecting cilium (CC) distally to the centriole/basal body marker, centrin-2 and the ciliary marker, acetylated-alpha-tubulin. NPHP4 abuts proximally RPGRIP1, RPGR and the serologically defined colon cancer antigen-8 (SDCCAG8), a protein thought to partake in the RPGRIP1 interactome and implicated also in retinal-renal ciliopathies. Ultrastructurally, RPGRIP1 localizes exclusively throughout the photoreceptor CC and Rpgrip1(nmf247) photoreceptors present shorter cilia with a ruffled membrane. Strikingly, Rpgrip1(nmf247) mice without RPGRIP1 expression lack NPHP4 and RPGR in photoreceptor cilia, whereas the SDCCAG8 and acetylated-alpha-tubulin ciliary localizations are strongly decreased, even though the NPHP4 and SDCCAG8 expression levels are unaffected and those of acetylated-alpha-tubulin and gamma-tubulin are upregulated. Further, RPGRIP1 loss in photoreceptors shifts the subcellular partitioning of SDCCAG8 and NPHP4 to the membrane fraction associated to the endoplasmic reticulum. Conversely, the ciliary localization of these proteins is unaffected in glomeruli or tubular kidney cells of Rpgrip1(nmf247), but NPHP4 is downregulated developmentally and selectively in kidney cortex. Hence, RPGRIP1 presents cell type-dependent pathological effects crucial to the ciliary targeting and subcellular partitioning of NPHP4, RPGR and SDCCAG8, and acetylation of ciliary alpha-tubulin or its ciliary targeting, selectively in photoreceptors, but not kidney cells, and these pathological effects underlie photoreceptor degeneration and LCA. PMID- 22825475 TI - Genomics: personal genome project. PMID- 22825476 TI - Investigation of proNT/NMN secretion from small cell lung carcinoma cells using a mouse xenograft model. AB - Proneurotensin/neuromedin N (proNT/NMN), the precursor of neurotensin (NT) and neuromedin N (NMN), is produced by cancer tissues derived from the pancreas and colon. NT stimulates tumor growth and proliferation through its receptors; however, little is known about the precursor molecule in cancer tissues. We previously demonstrated that proNT/NMN is secreted from small cell lung carcinoma (SCLC) cell lines in serum-free conditioned medium, but not from non-small cell lung carcinoma (NSCLC) cell lines. It was suggested that this precursor may serve as a tumor marker for SCLC. In this study, we established in vivo xenograft models to evaluate the possibility of proNT/NMN as a specific tumor marker. SBC3 cells, derived from human SCLC, were inoculated into mice, and the proNT/NMN levels in plasma and tumor tissues were detected using specific antibodies. In contrast to control mouse plasma, the proNT/NMN levels in tumor-bearing mice increased as the tumors grew, and the elevated plasma proNT/NMN levels were decreased by tumor resection. Moreover, proNT/NMN was expressed in SBC3 tumors, suggesting that proNT/NMN was secreted into blood from the tumor, and this secretion may be specific to SCLC. PMID- 22825477 TI - A comparison of patient and surgeon preoperative expectations of spinal surgery. AB - STUDY DESIGN: Cross-sectional study of agreement between patients' and surgeons' expectations of the outcome of spinal surgery. OBJECTIVE: Patients' satisfaction after spinal surgery depends, in part, on whether their expectations of surgery are fulfilled. Whether the patient always fully understands the key messages conveyed by the surgeon, to formulate realistic expectations, is not known. This study evaluates the level of agreement in expectations declared preoperatively by the patient and the surgeon. SUMMARY OF BACKGROUND DATA: Previous studies have investigated the importance of realistic expectations for the patients' satisfaction with surgical treatments, but there is still a need for a more detailed analysis in the field of spinal surgery. METHODS: The study included 225 German-speaking patients (92 men and 133 women; mean +/- SD [range] age, 62 +/- 15 [15-90] yr) and their treating spinal surgeons (N = 7). Following the preoperative informed consent consultation, the patient and the surgeon independently completed a questionnaire about baseline neurological status and realistic expectations regarding various patient-orientated outcomes (axial pain (back/neck), radiating pain (leg/arm), pain medication usage, sensory and motor function, and the ability to work, do household activities, and play sports). Concordance was given by percent agreement and kappa coefficients. RESULTS: Agreement between the patient and the surgeon about the existence of spine related neurological deficits occurred in 75% (sensory) and 61% (motor) cases. The patient but not the surgeon reported a sensory deficit in 20% cases and motor deficit in 35% cases; for 4% to 5% cases, the physician reported such a deficit that the patient was seemingly unaware of. The patients consistently had higher expectations than the surgeons, especially for back or neck pain and function (work, household activities, and sports); weighted kappa values for agreement were low, ranging from 0.097 to 0.222. CONCLUSION: The findings demonstrate wide discrepancies between the patient and the surgeon regarding the expected result of surgery. They highlight the need for clearer explanations of the association between the spinal problem and neurological deficits and the improvement that can be expected in pain and function after surgery. Systematic, routine evaluation of outcomes should assist in deriving the information necessary to document the improvement achieved and to formulate realistic expectations of surgery. PMID- 22825478 TI - Complications after 147 consecutive vertebral column resections for severe pediatric spinal deformity: a multicenter analysis. AB - STUDY DESIGN: Retrospective multicenter review. OBJECTIVE: Determine the definition, indications, results, and outcomes, focusing on complications of vertebral column resection (VCR) for severe pediatric spinal deformity. SUMMARY OF BACKGROUND DATA: The strict definition of the VCR procedure, indications, results, outcomes, and the numerous, potentially serious complications are unknown or controversial, and a large multicenter review has never been performed. METHODS: A total of 147 patients treated by 7 pediatric spinal deformity surgeons were reviewed-seventy-four females and 73 males, with an average age of 13.7 years, an average of 1.6 (range, 1-5) vertebrae resected, and an average follow-up of 17 months (range, 0.5-64 mo). The strict definition of VCR used was a "3-column circumferential vertebral osteotomy creating a segmental defect with sufficient instability to require provisional instrumentation." RESULTS: Indications for a VCR were divided into 5 diagnostic categories: kyphoscoliosis (n = 52), severe scoliosis (n = 37), congenital deformity (n = 28), global kyphosis (n = 17), and angular kyphosis (n = 13). Eighty-four primary and 63 revision patients with 174 operative procedures, 127 posterior-only (17 staged), and 20 patients combined anterior-posterior (10 staged) were reviewed. Average preoperative upright, flexibility, and postoperative Cobb measures (% correction or average kyphosis decrease) were kyphoscoliosis: 91 degrees , 65 degrees , 44 degrees (51% coronal), 104 degrees , 81 degrees , and 47 degrees (decrease, 57 degrees sagittal); severe scoliosis: 104 degrees , 78 degrees , and 33 degrees (67%); congenital deformity: 47 degrees , 38 degrees , 22 degrees (46% coronal), 56 degrees , 48 degrees , and 32 degrees (decrease, 24 degrees sagittal); global kyphosis: 101 degrees , 79 degrees , and 47 degrees (decrease, 54 degrees ); and angular kyphosis: 88 degrees , 90 degrees , and 38 degrees (decrease, 50 degrees ), respectively. Operative time averaged 545 minutes (range, 204-1355 min) and estimated blood loss averaged 1610 mL (range, 50-8244 mL) for an average 65% blood volume loss (range, 6%-316%). Eighty-six patients (59%) developed a complication, 39 patients (27%) having an intraoperative neurological event (spinal cord monitoring change or failed wake-up test); however, no patient had complete permanent paraplegia. CONCLUSION: A total of 147 consecutive pediatric VCRs performed by 7 surgeons demonstrated excellent radiographical correction. However, these complex reconstructions were associated with a 59% complication rate, thus emphasizing the challenging nature of these patients and procedures. PMID- 22825479 TI - The effect of glucosamine sulfate on the proliferative potential and glycosaminoglycan synthesis of nucleus pulposus intervertebral disc cells. AB - STUDY DESIGN: On the basis of the similarities in the structure of cartilage and intervertebral disc and on the property of glucosamine of being the building block for the construction of proteoglycan aggregates, we investigated the compound's role in the proliferation of nucleus pulposus cells under iso- and hyperosmotic conditions, the putative activation of signaling cascades, and the induction of glycosaminoglycan production. OBJECTIVE: We examined the mode of action of glucosamine in nucleus pulposus cells. SUMMARY OF BACKGROUND DATA: Glucosamine that naturally occurs in cartilage tissues has been widely used for treating osteoarthritis, but its role in nucleus pulposus cells is largely unknown. METHODS: The effect of glucosamine sulfate on the viability and proliferation of nucleus pulposus cells was assessed by the microculture tetrazolium test (MTT) assay, direct cell counting, and tritiated thymidine incorporation. Changes in the expression and phosphorylation profile of selected proteins were estimated by Western analysis. Glycosaminoglycan production was measured using the Blyscan assay. RESULTS: We showed that glucosamine sulfate up to 1 mM did not influence the viability, proliferation rate, or novel DNA synthesis of nucleus pulposus cells in the presence or absence of elevated osmolality but induced the transient phosphorylation of p38 mitogen-activated protein kinase. The highest concentration used (10 mM) negatively affected cellular proliferation and resulted in deactivation of extracellular signal regulated kinases and c-Jun N-terminal kinases. Interestingly, these effects resulted from an additional hyperosmotic stress provoked by glucosamine alone. Finally, we found that a long-term incubation with glucosamine leads to an increase in the glycosaminoglycan content of nucleus pulposus cells. CONCLUSION: Glucosamine sulfate was not found to reverse the high osmolality-mediated delay of proliferation in nucleus pulposus cells needed for the maintenance of the tissue's homeostasis. In addition, glycosaminoglycan synthesis stimulated by glucosamine provides a possible promising clinical role for treating disc degenerative disorders. PMID- 22825480 TI - Anomalous vertebral arteries in the extra- and intraosseous regions of the craniovertebral junction visualized by 3-dimensional computed tomographic angiography: analysis of 100 consecutive surgical cases and review of the literature. AB - STUDY DESIGN: Consecutive case series and literature review. OBJECTIVE: To describe the utility of 3-dimensional computed tomographic angiography (3D CTA) for evaluating vertebral artery (VA) anomalies before surgery. SUMMARY OF BACKGROUND DATA: Recent advances in instrumentation surgery at the craniovertebral junction (CVJ) enable us to perform rigid internal fixation. However, the risk of VA injury as a complication of the surgery has become a major problem. Thus, the importance of preoperative evaluation of the VA course has been emphasized. METHODS: Cases of 100 consecutive patients who underwent CVJ instrumentation surgery since July 1998 were analyzed. Occipitocervical/thoracic or C1-C2 posterior fusion was performed for atlantoaxial subluxation (AAS) in 59 patients and cervical fixation including C2 was required for middle-to-lower cervical lesions in 41 patients. Twenty-seven patients with AAS had a congenital skeletal anomaly (CSA) at the CVJ including os odontoideum and occipitalization of C1 (AAS-CSA[+] group). Anomalous VAs at the extra- and intraosseous regions were evaluated by 3D CTA. RESULTS: No neurovascular injury occurred during surgery. Abnormal courses of the VA at the extraosseous region were detected in 10 cases: 2 had fenestration and 8 had a persistent first intersegmental artery. All 10 cases were in the AAS-CSA(+) group. A high-riding VA was detected in 31 cases. Fourteen out of the 31 cases were in the AAS-CSA(+) group, indicating 51.9% of the AAS-CSA(+) group had high-riding VA. In the AAS-CSA(+) group, a C1 C2 transarticular screw and C2 pedicle screw were actually inserted in 58% and 31% of the planned insertions, respectively. CONCLUSION: The present findings suggest that the frequency of an abnormal VA at the extra- and intraosseous regions is increased when patients have AAS and CSA at the CVJ. Using preoperative 3D CTA, we can precisely identify anomalous VAs and thereby reduce the risk of their intraoperative injury. PMID- 22825481 TI - The importance of susceptibility-weighted imaging in familial cerebral cavernous malformation. PMID- 22825482 TI - Ballistic charge transport through bio-molecules in a dissipative environment. AB - The question whether dissipative bio-molecular systems can support efficient coherent (phase-conserving) charge transport is raised again following recent experiments on electron-energy transfer in bio-molecules. In this work we formulate conditions under which the current due to coherent ballistic resonant charge transport through DNA molecular junctions can be measured in spite of coupling to the dissipative environment. PMID- 22825484 TI - Association of family structure to later criminality: a population-based follow up study of adolescent psychiatric inpatients in Northern Finland. AB - The influence of family structure on criminality in adolescents is well acknowledged in population based studies of delinquents, but not regarding adolescent psychiatric inpatients. The association of family structure to criminality was examined among 508 adolescents receiving psychiatric inpatient treatment between 2001 and 2006. Family structure and DSM-IV based psychiatric diagnoses were based on the K-SADS-PL-interview and criminality on criminal records provided by the Finnish Legal Register Centre. After adjusting for socio demographic, clinical and family factors, the adolescents from single parent families, child welfare placements and those not living with their biological parents showed an increased risk of committing crimes at an earlier age than adolescents from two parent families. Lack of a safe and stable family environment has important implications for adolescents with severe mental disorder. When these adolescents are discharged from hospital, special attention should be focused on organizing stable and long term psychosocial support which compensates for the lack of stable family environment and seeks to prevent future adversities. PMID- 22825483 TI - Quantitative vertebral morphometry based on parametric modeling of vertebral bodies in 3D. AB - Quantitative vertebral morphometry (QVM) was performed by parametric modeling of vertebral bodies in three dimensions (3D). INTRODUCTION: Identification of vertebral fractures in two dimensions is a challenging task due to the projective nature of radiographic images and variability in the vertebral shape. By generating detailed 3D anatomical images, computed tomography (CT) enables accurate measurement of vertebral deformations and fractures. METHODS: A detailed 3D representation of the vertebral body shape is obtained by automatically aligning a parametric 3D model to vertebral bodies in CT images. The parameters of the 3D model describe clinically meaningful morphometric vertebral body features, and QVM in 3D is performed by comparing the parameters to their statistical values. Thresholds and parameters that best discriminate between normal and fractured vertebral bodies are determined by applying statistical classification analysis. RESULTS: The proposed QVM in 3D was applied to 454 normal and 228 fractured vertebral bodies, yielding classification sensitivity of 92.5% at 7.5% specificity, with corresponding accuracy of 92.5% and precision of 86.1%. The 3D shape parameters that provided the best separation between normal and fractured vertebral bodies were the vertebral body height and the inclination and concavity of both vertebral endplates. CONCLUSION: The described QVM in 3D is able to efficiently and objectively discriminate between normal and fractured vertebral bodies and identify morphological cases (wedge, (bi)concavity, or crush) and grades (1, 2, or 3) of vertebral body fractures. It may be therefore valuable for diagnosing and predicting vertebral fractures in patients who are at risk of osteoporosis. PMID- 22825485 TI - Trichosanthin inhibits DNA methyltransferase and restores methylation-silenced gene expression in human cervical cancer cells. AB - Epigenetic silencing of tumor suppressor genes is a well-established oncogenic process and the reactivation of tumor suppressor genes that have been silenced by promoter methylation is an attractive molecular target for cancer therapy. In this study, we investigated the demethylation activity of trichosanthin (TCS, the main bioactive component isolated from a Chinese medicinal herb) and its possible mechanism of action in cervical cancer cell lines. HeLa human cervical adenocarcinoma and CaSki human cervical squamous carcinoma cells were treated with various concentrations (0, 20, 40 and 80 ug/ml) of TCS for 48 h and the mRNA and protein expression levels of the tumor suppressor genes adenomatous polyposis coli (APC) and tumor suppressor in lung cancer 1 (TSLC1) were detected using reverse transcription (RT)-PCR and western blotting, respectively. We analyzed the methylation status of APC and TSLC1 using methylation-specific PCR (MSP). The expression levels and enzyme activity of DNA methyltransferase 1 (DNMT1) were also examined. The mRNA and protein expression levels of APC and TSLC1 were increased following treatment with various concentrations (0, 20, 40 and 80 ug/ml) of TCS for 48 h. The expression of the APC gene increased 2.55+/-0.29-, 3.44+/-0.31- and 4.36+/-0.14-fold, respectively. The expression of the TSLC1 gene increased 2.28+/-0.15-, 4.23+/-0.88- and 6.09+/-0.23-fold, respectively. MSP detection showed that TCS induced demethylation in HeLa and CaSki cells and that this demethylation activity was accompanied by the decreased expression of DNMT1 and reduced DNMT1 enzyme activity. Our experimental results demonstrate for the first time that TCS is capable of restoring the expression of methylation silenced tumor suppressor genes and is potentially useful as a demethylation agent for the clinical treatment of human cervical cancer. PMID- 22825487 TI - Growth and optical properties of silver nanostructures obtained on connected anodic aluminum oxide templates. AB - Ag nanostructures are grown by AC electrodeposition on anodic alumina oxide (AAO) connected membranes acting as templates. Depending on the thickness of the template and on the voltage applied during the growth process, different Ag nanostructures with different optical properties are obtained. When AAO membranes about 1 MUm thick are used, the Ag nanostructures consist in Ag nanorods, at the bottom of the pores, and Ag nanotubes departing from the nanorods and filling the pores almost for the whole length. When AAO membranes about 3 MUm thick are used, the nanostructures are Ag spheroids, at the bottom of the pores, and Ag nanowires that do not reach the upper part of the alumina pores. The samples are characterized by angle resolved x-ray photoelectron spectroscopy, scanning electron microscopy and UV-vis and Raman spectroscopies. A simple NaOH etching procedure, followed by sonication in ethanol, allows one to obtain an exposed ordered array of Ag nanorods, suitable for surface-enhanced Raman spectroscopy, while in the other case (3 MUm thick AAO membranes) the sample can be used in localized surface plasmon resonance sensing. PMID- 22825486 TI - Hyperpolarization-activated current (I(h)) in vestibular calyx terminals: characterization and role in shaping postsynaptic events. AB - Calyx afferent terminals engulf the basolateral region of type I vestibular hair cells, and synaptic transmission across the vestibular type I hair cell/calyx is not well understood. Calyces express several ionic conductances, which may shape postsynaptic potentials. These include previously described tetrodotoxin sensitive inward Na(+) currents, voltage-dependent outward K(+) currents and a K(Ca) current. Here, we characterize an inwardly rectifying conductance in gerbil semicircular canal calyx terminals (postnatal days 3-45), sensitive to voltage and to cyclic nucleotides. Using whole-cell patch clamp, we recorded from isolated calyx terminals still attached to their type I hair cells. A slowly activating, noninactivating current (I(h)) was seen with hyperpolarizing voltage steps negative to the resting potential. External Cs(+) (1-5 mM) and ZD7288 (100 MUM) blocked the inward current by 97 and 83 %, respectively, confirming that I(h) was carried by hyperpolarization-activated, cyclic nucleotide gated channels. Mean half-activation voltage of I(h) was -123 mV, which shifted to -114 mV in the presence of cAMP. Activation of I(h) was well described with a third order exponential fit to the current (mean time constant of activation, tau, was 190 ms at -139 mV). Activation speeded up significantly (tau=136 and 127 ms, respectively) when intracellular cAMP and cGMP were present, suggesting that in vivo I(h) could be subject to efferent modulation via cyclic nucleotide-dependent mechanisms. In current clamp, hyperpolarizing current steps produced a time dependent depolarizing sag followed by either a rebound afterdepolarization or an action potential. Spontaneous excitatory postsynaptic potentials (EPSPs) became larger and wider when I(h) was blocked with ZD7288. In a three-dimensional mathematical model of the calyx terminal based on Hodgkin-Huxley type ionic conductances, removal of I(h) similarly increased the EPSP, whereas cAMP slightly decreased simulated EPSP size and width. PMID- 22825488 TI - Mapping protein-specific micro-environments in live cells by fluorescence lifetime imaging of a hybrid genetic-chemical molecular rotor tag. AB - The micro-viscosity and molecular crowding experienced by specific proteins can regulate their dynamics and function within live cells. Taking advantage of the emerging TMP-tag technology, we present the design, synthesis and application of a hybrid genetic-chemical molecular rotor probe whose fluorescence lifetime can report protein-specific micro-environments in live cells. PMID- 22825489 TI - Kinetico-mechanistic studies of cyclometalating C-H bond activation reactions on Pd(II) and Rh(II) centres: the importance of non-innocent acidic solvents in the process. AB - The activation of C-H bonds in homogeneous systems has been the subject of study for many years due to its involvement in important industrial catalytic processes. A large number of reviews on the different areas involved have appeared, but those dealing with kinetic studies, including activation parameters, are rather scarce due to the severe difficulties in interpreting experimental data. In this perspective, the information available from kinetico mechanistic studies of cyclometalation reactions on Pd(II) and Rh(II) centres via C-H bond activation is considered. Experimental results from studies performed on complexes of these metal centres indicate that the historically accepted electrophilic substitution classification is not a satisfactory mechanistic term for the process occurring during the reaction. A definite acid-assisted phenomenon is evident for all the processes studied, which contradicts the expected need for a proton abstractor in the reaction. This is even more surprising when considering the expected hydrolysis of M-C bonds in such acidic media, indicating that metalation prevails under these conditions. Only the presence of coordinated acid molecules in solvolytic carboxylic acid media can explain the observations. The fine tuning between the proton abstraction capacity of a coordinated RCO(2)H molecule and its Lewis basicity results in a unique reactivity trend. DFT calculations carried out for these acid-assisted processes fully agree with the experimental trends observed. PMID- 22825490 TI - A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. AB - The isolation of circulating tumor cells (CTCs) from the blood of patients afflicted with solid malignant tumors becomes increasingly important as it may serve as a 'liquid biopsy' with the potential of monitoring the course of the cancer disease and its response to cancer therapy, with subsequent molecular characterization. For this purpose, we functionalized a structured medical Seldinger guidewire (FSMW), normally used to obtain safe access to blood vessels and other organ cavities, with a chimeric monoclonal antibody directed to the cell surface expressed epithelial cell surface adhesion molecule (EpCAM). This medical device was optimized in vitro and its biocompatibility was tested according to the regulations for medical devices and found to be safe with no noteworthy side effects. Suitability, specificity and sensitivity of the FSMW to catch and enrich CTCs in vivo from circulating peripheral blood were tested in 24 breast cancer or non-small cell lung cancer (NSCLC) patients and in 29 healthy volunteers. For this, the FSMW was inserted through a standard venous cannula into the cubital veins of healthy volunteers or cancer patients for the duration of 30 min. After removal, CTCs were identified by immuno-cytochemical staining of EpCAM and/or cytokeratins and staining of their nuclei and counted. The FSMW successfully enriched EpCAM-positive CTCs from 22 of the 24 patients, with a median of 5.5 (0-50) CTCs in breast cancer (n=12) and 16 (2-515) CTCs in NSCLC (n=12). CTCs could be isolated across all tumor stages, including early stage cancer, in which distant metastases were not yet diagnosed, while no CTCs could be detected in healthy volunteers. In this observatory study, no adverse effects were noted. Evidently, the FSMW has the potential to become an important device to enrich CTCs in vivo for monitoring the course of the cancer disease and the efficacy of anticancer treatment. PMID- 22825491 TI - New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo Guidelines. AB - BACKGROUND: The Tokyo Guidelines for the management of acute cholangitis and cholecystitis were published in 2007 (TG07) and have been widely cited in the world literature. Because of new information that has been published since 2007, we organized the Tokyo Guidelines Revision Committee to conduct a multicenter analysis to develop the updated Tokyo Guidelines (TG13). METHODS/MATERIALS: We retrospectively analyzed 1,432 biliary disease cases where acute cholangitis was suspected. The cases were collected from multiple tertiary care centers in Japan. The 'gold standard' for acute cholangitis in this study was that one of the three following conditions was present: (1) purulent bile was observed; (2) clinical remission following bile duct drainage; or (3) remission was achieved by antibacterial therapy alone, in patients in whom the only site of infection was the biliary tree. Comparisons were made for the validity of each diagnostic criterion among TG13, TG07 and Charcot's triad. RESULTS: The major changes in diagnostic criteria of TG07 were re-arrangement of the diagnostic items and exclusion of abdominal pain from the diagnostic list. The sensitivity improved from 82.8 % (TG07) to 91.8 % (TG13). While the specificity was similar to TG07, the false positive rate in cases of acute cholecystitis was reduced from 15.5 to 5.9 %. The sensitivity of Charcot's triad was only 26.4 % but the specificity was 95.6 %. However, the false positive rate in cases of acute cholecystitis was 11.9 % and not negligible. As for severity grading, Grade II (moderate) acute cholangitis is defined as being associated with any two of the significant prognostic factors which were derived from evidence presented recently in the literature. The factors chosen allow severity assessment to be performed soon after diagnosis of acute cholangitis. CONCLUSION: TG13 present a new standard for the diagnosis, severity grading, and management of acute cholangitis. PMID- 22825492 TI - Prognostic factors of acute cholangitis in cases managed using the Tokyo Guidelines. AB - BACKGROUND/PURPOSE: In 2007, the Tokyo Guidelines (TG07) working group established diagnostic criteria for assessment of the severity of acute cholangitis. This study aimed to analyze outcomes and identify predictors of mortality in patients with acute cholangitis managed according to the TG07. METHODS: In this study, 215 consecutive cases of acute cholangitis were reviewed. Risk factors associated with mortality or refractory cholangitis, which is defined on the basis of prolonged hospitalization (>28 days) or disease resulting in fatality, were examined using multivariate logistic regression analysis. RESULTS: There were 52, 133, and 30 cases of mild, moderate, and severe cholangitis, respectively. The overall mortality rate was 4.2 % (9/215). Mortality rates in patients with mild, moderate, and severe cholangitis were 0, 2.3, and 20.0 %, respectively (moderate vs. severe, p = 0.001). Multivariate analysis showed that serum albumin levels <=2.8 g/dl and PT-INR >1.5 were significant predictors of mortality. There were 57 patients (26.5 %) with refractory cholangitis. Multivariate analysis showed that serum albumin level <=2.8 g/dl, PT-INR >1.5, etiology and inpatient status were significant predictors of refractory cholangitis. CONCLUSIONS: The TG07 severity assessment criteria for acute cholangitis were significantly predictive of mortality. Hypoalbuminemia is an important risk factor in addition to organ dysfunction. PMID- 22825493 TI - Changes in kinematic variables at various muscle lengths of human elbow flexors following eccentric exercise. AB - Exercise-induced muscle damage causes a disproportionally larger drop in maximal force when measured at short versus optimal or long muscle lengths, resulting in a shift of the length (angle)-force relationship towards longer lengths. However, little attention has been given to the potential effect of this shift on the rate of force development (RFD) and isotonic function at different muscle lengths. This study examined RFD at various elbow angles and kinematic variables at two different ranges of elbow flexion, so as to include mainly the ascending (S condition) or the descending limb (L condition) of the angle-force curve, following eccentric exercise. Seven male volunteers performed an eccentric exercise protocol with the elbow flexors, which caused significant changes in indicators of muscle damage (P < 0.05-0.001). Optimum angle for force generation was significantly shifted towards longer elbow flexors lengths post exercise (P < 0.05-0.01). RFD was significantly decreased at all the angles tested but no differences were revealed between angles (P < 0.05-0.001). The kinematic variables measured were also significantly impaired following eccentric damage (P < 0.05-0.001). Maximal isotonic force showed a greater impairment in the S condition, however no significant differences between the S and L condition were found in maximal angular velocity (MAV) and time, angle and isotonic force needed to achieve MAV. These results suggest that impairment of RFD following muscle damage is not muscle-length dependent and the rightward shift of the angle-force curve is not the determinant of the decline in either RFD or the isotonic performance at the different ranges of the elbow flexion movement. PMID- 22825494 TI - Acetate-producing bifidobacteria protect the host from enteropathogenic infection via carbohydrate transporters. AB - The human gut harbors a large and diverse community of commensal bacteria. Among them, Bifidobacterium is known to exhibit various probiotic effects including protection of hosts from infectious diseases. We recently discovered that genes encoding an ATP-binding-cassette-type carbohydrate transporter present in certain bifidobacteria contribute to protecting gnotobiotic mice from death induced by enterohemorrhagic Escherichia coli O157:H7. We elucidated the molecular mechanism on lethal infection in mice associated with several bifidobacterial strains by a multi-omics approach combining genomics, transcriptomics and metabolomics. The combined data clearly show that acetate produced by protective bifidobacteria acts in vivo to promote defense functions of the host epithelial cells and thereby protects the host from lethal infection. As demonstrated here, our multi omics approach provides a powerful strategy for evaluation of host-microbial interactions in the complex gut ecosystem. PMID- 22825495 TI - Is bile acid a determinant of the gut microbiota on a high-fat diet? AB - Recently, we discovered that bile acid, a main component of bile, is a host factor that regulates the composition of the cecal microbiota in rats. Because bile secretion increases on a high-fat diet and bile acids generally have strong antimicrobial activity, we speculated that bile acids would be a determinant of the gut microbiota in response to a high-fat diet. The observed changes in the rat cecal microbiota triggered by cholic acid (the most abundant bile acid in human biliary bile) administration resemble those found in animals fed high-fat diets. Here, we discuss the rationale for this hypothesis by evaluating reported diet-induced gut microbiota alterations based on the postulate that bile acids worked as an underlying determinant. The identification of host factors determining the gut microbiota greatly contributes to understanding the causal relationships between changes in the gut microbiota and disease development, which remain to be elucidated. PMID- 22825496 TI - Ready...aim...fire into the lumen: a new role for enterocyte microvilli in gut host defense. AB - Recent studies from our laboratory revealed that enterocyte brush border microvilli release small vesicles laden with host defense machinery into the intestinal lumen. In this addendum, we introduce a multi-faceted model for the function of these lumenal vesicles in the gut; we also consider some of the important unanswered questions that must be addressed in order to develop our understanding of this novel aspect of innate intestinal immunity. PMID- 22825497 TI - Micronutrient supplemented probiotic yogurt for HIV-infected adults taking HAART in London, Canada. AB - The Human Immunodeficiency Virus has devastating effects worldwide. The burden is less pronounced, but still present in Canada where approximately 64,000 men and women are HIV positive. The virus and the life-saving antiretroviral therapies often contribute to diarrhea and other gastrointestinal disturbances. Certain probiotic organisms, such as Lactobacillus rhamnosus GR-1, have been shown to alleviate diarrhea as well as delay the decline of CD4 lymphocytes in some subjects. In addition, micronutrient formulae have been used extensively among HIV positive persons as a cost-effective method for improving quality of life and immune function. The objective of the present study was to combine probiotics and micronutrients into an affordable and highly palatable nutritional supplement and assess outcomes in 21 HIV-positive participants receiving highly active antiretroviral therapy in London, Ontario, Canada. The design was a randomized, double blind, three-period, cross-over controlled trial with three different formulations of supplemented yogurt; micronutrient and probiotic (A), micronutrient alone (B) and probiotic alone (C). The period of intake for each of the types was 30 days with a 14 day wash-out period between the intervention types. The mean increase in CD4 was greatest with B (41 cells/uL, SD 221). Supplement A showed a mean change of +19 cells/uL (SD 142) and supplement C a mean change of - 7 cells/uL (SD 154). All yogurt types caused an increase in subjective energy and ability to perform daily activity scores. According to the safety measures taken to assess the tolerance of the yogurt, there were no adverse events and the yogurt was well-tolerated. These preliminary findings suggest that micronutrient supplemented probiotic yogurt may support immune function among people living with HIV. PMID- 22825498 TI - Collateral effects of antibiotics on mammalian gut microbiomes. AB - Antibiotics are an essential component of the modern lifestyle. They improve our lives by treating disease, preventing disease, and in the case of agricultural animals by improving feed efficiency. However, antibiotic usage is not without collateral effects. The development and spread of antibiotic resistance is the most notorious concern associated with antibiotic use. New technologies have enabled the study of how the microbiota responds to the antibiotic disturbance, including how the community recovers after the antibiotic is removed. One common theme in studies of antibiotic effects is a rapid increase in Escherichia coli followed by a gradual decline. Increases in E. coli are also associated with systemic host stresses, and may be an indicator of ecosystem disturbances of the intestinal microbiota. Moreover, recent studies have shown additional effects mediated by antibiotics on the gut microbiota, such as the stimulation of gene transfer among gut bacteria and the reduction of immune responses in peripheral organs. Querying the microbiota after antibiotic treatment has led to intriguing hypotheses regarding predicting or mitigating unfavorable treatment outcomes. Here we explore the varied effects of antibiotics on human and animal microbiotas. PMID- 22825501 TI - Palonosetron: an evidence-based choice in prevention of nausea and vomiting induced by moderately emetogenic chemotherapy. AB - AIMS AND BACKGROUND: In 2003, the second-generation, 5-HT(3) receptor antagonist (5-HT(3) RA) palonosetron was approved by the FDA for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy. We reviewed the current knowledge on the role of palonosetron against acute and delayed emesis in patients with solid tumors undergoing single-day moderately emetogenic chemotherapy regimens. METHODS: A literature review in PubMed was performed to update currently available preclinical and clinical evidence on palonosetron, prioritizing randomized clinical trials. RESULTS: The distinct pharmacology of palonosetron provides a rationale behind the improved efficacy observed with the drug in prevention of delayed symptoms. This may be explained by allosteric binding properties and by palonosetron-triggered receptor internalization, which result in prolonged inhibition of the 5-HT(3) receptor function. Very recent pharmacology experiments have also suggested that palonosetron would be able to differentially inhibit 5-HT(3)/neurokinin 1 (NK-1) receptor signaling cross-talk. In two recent meta-analyses, palonosetron was shown to be more effective than other available 5-HT(3) RAs in preventing acute and delayed nausea and vomiting for both HEC and MEC. Recent findings also suggest that a single-day regimen of palonosetron plus dexamethasone (both drugs administered intravenously) may provide a reasonable therapeutic alternative to reduce the total dexamethasone dose administered in patients undergoing moderately emetogenic chemotherapy. CONCLUSIONS: On the basis of accumulating data, the evidence-based international guidelines devised from the major organizations have been recently updated to recommend the use of palonosetron plus 3-day dexamethasone for the optimal prevention of nausea and vomiting due to moderately emetogenic chemotherapy. There is still a need to investigate the efficacy of palonosetron in combination with an NK-1 receptor antagonist and dexamethasone in well-designed randomized trials. PMID- 22825503 TI - Estimating all cancers incidence with the MIAMOD model: a new method to include multiple tumors. AB - AIMS AND BACKGROUND: The MIAMOD method has been widely applied to derive regional and national cancer burden estimates. The method is based on a back-calculation approach using cancer-specific mortality and relative survival to derive expected incident and prevalent cases. Multiple tumors occurring in the same site for the same person (for example colon-colon) can be estimated just once. This has little effect on cancer-specific estimates, whereas it limits all cancers-combined estimates, where only cancer cases, rather than cancer diagnoses, can be accounted for by the method. The aim of this article is to present a specific strategy of application of the MIAMOD method to all cancers sites, which better approximates an estimate of 'cancer diagnoses'. METHODS: The strategy consists of breaking down the estimation process in separate applications to the most frequent cancer sites and to a 'remainder-site', given by all malignant sites except the previous ones. The separate estimates are then summed up to derive the overall quantities for all cancers combined. Cancer-specific mortality in the years 1985-2004 in the Tuscany cancer registry area (about 1,200,000 inhabitants) and relative survival data in the same area and periods (end of follow-up, 31 December 2006) were used to produce the estimates, which were then tested using observed incidence data in the same area and period. RESULTS: The standard application of the MIAMOD method underestimates all cancer incidence for both sexes. The mean relative difference between observed and expected incident cases is -14.8% for males and -17.2% for females. With the alternative method, the same mean relative difference drops to -8.2% for males and -6.1% for females. CONCLUSIONS: The study provides a strategy to reduce a structural limit of the MIAMOD method in estimating the total burden of cancer disease. PMID- 22825502 TI - A case-control study of the risk of cutaneous melanoma associated with three selenium exposure indicators. AB - AIMS AND BACKGROUND: A direct association between exposure to the metalloid selenium and risk of cutaneous melanoma has been suggested by some observational and experimental cohort studies, whereas other studies have yielded inconsistent results. Since some of the inconsistencies may be due to exposure misclassification arising from the use of exposure indicators that do not adequately reflect body tissue selenium content or the levels of the biologically relevant species of this metalloid, we examined this issue using multiple indicators of exposure. METHODS: We analyzed the relation of selenium exposure with risk of cutaneous melanoma using two different biomarkers, plasma and toenail selenium concentration, and estimated dietary selenium intake in a population-based case-control series (54 cases, 56 controls) from an Italian community. RESULTS: In unmatched and matched logistic regression models as well as nonparametric generalized additive models, higher plasma selenium levels were strongly associated with excess disease risk. In contrast, toenail and dietary selenium exhibited little relation with melanoma risk. The pattern of correlation among indicators of exposure differed by disease status, with dietary intake associated with plasma selenium levels in patients but not in controls. CONCLUSIONS: Our data showed that different selenium exposure indicators can yield different inferences about melanoma risk. Although the series was small, our results are consistent with a positive association between circulating levels of selenium and melanoma risk. Further investigation of the exposure classification performance of various selenium biomarkers and of metabolic patterns of the metalloid and of its speciation are needed to help elucidate the relation between selenium exposure and human health. PMID- 22825504 TI - Capecitabine in elderly patients with metastatic breast cancer. AB - AIMS AND BACKGROUND: Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. MATERIALS AND METHODS: Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. RESULTS: Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. CONCLUSIONS: Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy. PMID- 22825505 TI - Electrochemotherapy for the treatment of recurrent head and neck cancers: preliminary results. AB - AIMS AND BACKGROUND: Electrochemotherapy is a tumor ablation modality providing delivery into the cell interior of impermeant or poorly permeant chemotherapeutic drugs such as cisplatin and bleomycin. A locally applied electrical field enhances the membrane permeability allowing intracellular accumulation of the chemotherapeutic agent. The aim of the study was to evaluate the effectiveness of ECT for the treatment of a group of patients affected by recurrent of extended primary head and neck cancer and not suitable for standard therapeutic options. METHODS AND STUDY DESIGN: From April 2009 to January 2011, we treated with electrochemotherapy a total of 15 patients with head and neck cancers, 13 with squamous cell carcinoma, 1 with basaloid carcinoma and 1 with Merkel cell carcinoma. Electrical pulses were delivered to 33 lesions (3 primaries, 30 recurrences) after an intravenous bolus injection of a dose of 15,000 IU/m2 of bleomycin. In 3 cases, the lesion treated was a pathologic lymph node. RESULTS: Of the 31 lesions assessable for the study, 19 (61.5%) showed a complete response, 10 (32.5%) a partial response, 1 (3%) stable disease and 1 (3%) progression of the disease. The objective response 2 months after the procedure was 94%. All the lesions that underwent complete regression were less than 3 cm in their maximum diameter. The 2 assessable cases of pathologic lymph nodes showed a partial or no response. After a follow-up of 2 to 20 months, 29% of the patients were alive and free of disease, 50% were alive with disease, 14% died for disease and 7% died for other causes. CONCLUSIONS: Our study confirms the effectiveness of electrochemotherapy in the treatment or local control of recurrent or extended primary head and neck cancer in patients not suitable for standard therapeutic options. PMID- 22825506 TI - Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer. AB - AIMS AND BACKGROUND: The incidence and development of cancer are closely related to dysfunction of immune function. The immune system cannot identify and remove malignant and mutant cells, which cause tumor cells to escape from surveillance and clearance of the immune system. Immunobiological cancer therapy plays an important role in strengthening body immunological surveillance function and killing remaining tumor cells in the body. We investigated the role of DC/CIK (dendritic cell/cytokine-induced killer cells) immunobiological cancer therapy in maintenance therapy of advanced non-small cell lung cancer. METHODS: When 60 cases of non-small cell lung cancer patients in stage IIIb and IV reached stable disease after treatment with 4 cycles of a two-drug regimen with platinum, they were randomly divided into two groups. One group was treated with DC/CIK immunobiological cancer therapy, and the other was taken as a control group. Finally, cancer progression time and toxicity reaction of the two groups were evaluated. RESULTS: DC/CIK treatment prolongs progression-free survival (3.20 months [95% CI, 2.94-3.50] vs 2.56 months [95% CI, 2.39-2.73]; P <0.05). In the treatment group, the proportion of NK cells, T-cell subgroups CD3+, CD4+ and CD8+ had a significant change before and after treatment. Liver and kidney function and blood tests of the treatment group were within the normal range before and after treatment. In the treatment group, 1 case suffered from chest distress, 3 cases suffered from acratia, and 4 cases suffered from pyrexia. CONCLUSIONS: DC/CIK treatment had potential benefit for patients with advanced non-small cell lung cancer compared with the control group and had no obvious side effects. DC/CIK treatment is a safe and effective method for maintenance therapy of advanced non-small cell lung cancer. PMID- 22825507 TI - Axillary lymph node dissection in patients with breast cancer and sentinel lymph node micrometastasis or isolated tumor cells: is it necessary? AB - AIMS AND BACKGROUND: Sentinel lymph node biopsy is the standard method for axillary lymph node staging in patients with early stage breast cancer. The aim of the study was to evaluate the necessity of axillary lymph node dissection in patients with breast cancer and sentinel lymph node micrometastasis or isolated tumor cells. METHODS: Sentinel lymph node biopsy was performed in 136 patients for breast cancer staging: 16 of them (11.7%) were found to have micrometastasis or isolated tumor cells and underwent axillary lymph node dissection. Micrometastases were considered when tumor invasion was <= 2 mm and >0.2 mm in diameter and isolated tumor cells when detected alone or in clusters of <0.2 mm in diameter. The dissection of the three axillary lymph node levels of Berg was performed in all cases. RESULTS: Two patients (12.5%) presented isolated tumor cells and 14 (87.5%) micrometastasis in the sentinel lymph node. Among them, 25% presented nonsentinel axillary lymph node tumor invasion, whereas 75% had no further nodal involvement. CONCLUSIONS: Results suggest that micrometastasis or isolated tumor cells of the sentinel lymph node represent the only site of cancer involvement of the axilla, especially in patients with early breast tumors, and that axillary lymph node dissection may be unnecessary in these cases and represent an overtreatment. PMID- 22825508 TI - Long-term side effects and cosmetic outcome in a pool of breast cancer patients treated with intraoperative radiotherapy with electrons as sole treatment. AB - AIMS: To evaluate late toxicity and cosmetic outcome after intraoperative radiotherapy using electrons (ELIOT) as sole treatment modality in early breast cancer patients. METHODS: A total of 119 patients selected randomly among 1200 cases was analyzed. Late toxicities were documented using the LENT-SOMA scoring system, cosmesis was evaluated with the Harvard scale, and a numeric rating scale was used to assess symptoms. RESULTS: After a median follow-up of 71 months, grade II fibrosis was observed in 38 patients (31.9%) and grade III fibrosis in 7 patients (5.9%). Postoperative complications (12.6%) did not correlate with late toxicity. Physicians and patients scored cosmesis as excellent or good in 84% and 77.3% of the cases, respectively. Patient satisfaction was higher than 90%. CONCLUSIONS: In the study, ELIOT gives low and acceptable long-term toxicity. A longer follow-up and a larger number of patients are needed to confirm these promising results. PMID- 22825509 TI - Use of volumetric modulated arc radiotherapy in patients with early stage glottic cancer. AB - AIMS AND BACKGROUND: We compared conformal, intensity-modulated radiotherapy (IMRT) and intensity-modulated arc therapy (IMAT) in early stage glottic cancer in terms of dosimetric features as target coverage, dose to the organs at risk and total treatment time. METHODS AND MATERIALS: Five consecutive T1 glottic squamous cell carcinoma patients were selected for the study. Three-dimensional conformal radiotherapy (3D-CRT), 3-field or 5-field intensity-modulated radiotherapy (3F-IMRT and 5F-IMRT), or IMAT, which was in 2 different forms--a regular IMAT (R-IMAT) and an alternative IMAT (A-IMAT) with an unirradiated section, was planned for each patient. The prescribed dose was 63 Gy in 28 fractions. The minimum dose for 95% of the clinical target volume (D95), maximum dose point at clinical target volume (Dmax), total monitor units, left and right carotid artery doses (V35 and V50 - percentage of volume receiving 35 Gy and 50 Gy), and total treatment time were calculated for each plan. RESULTS: Median D95 values in the 5 plans studied with each technique ranged between 63 and 63.3 Gy (P = NS). Median Dmax values for each technique ranged between 65.4 and 70.8 Gy. The number of hot spots with IMRT and IMAT was significantly higher than with 3D CRT plans. Conformal radiotherapy plans median V35 (93.6%) and V50 (76.6-83.3%) values for carotid arteries were significantly higher than with IMRT and IMAT (2.9%-11.4% and 0.0%). Average treatment times for 3D-CRT, 3F-IMRT, 5F-IMRT, R IMAT and A-IMAT techniques were calculated as 64, 119, 147, 39 and 32 seconds, respectively. CONCLUSIONS: IMAT has significantly decreased the treatment time compared to IMRT and 3D-CRT with acceptable homogeneous clinical target volume coverage and low carotid dose. PMID- 22825510 TI - High-dose 3D-CRT in the radical and postoperative setting for prostate cancer. Analysis of survival and late rectal and urinary toxicity. AB - PURPOSE: The aim of the study was to retrospectively compare outcome and complications of prostate cancer patients treated with a curative and postoperative intent using a pretreatment defined NCCN classification. MATERIAL AND METHODS: A total of 103 patients was treated curatively (RAD) and 94 postoperatively (POST-OP). The mean age was higher in the RAD group (72.6 years; range, 56.4-85.1) than in the POST-OP group (65.4 years; range, 43.9-77) (P <0.0001). According to the NCCN prognostic classification, 13 (12%) patients were at low risk, 48 (47%) at intermediate risk and 42 (41%) at high risk in the RAD group. In the POST-OP group, 13 (14%) patients were low risk, 37 (40%) at intermediate risk and 44 (46%) at high risk. Hormone therapy was used in 98 patients (95%) in the RAD group and 45 patients (47.8%) in the POST-OP group. Patients were treated with three-dimensional conformal radiotherapy. The prescription dose was 80 Gy in 2-Gy fractions in the RAD group and 70 Gy in 2-Gy fractions in the POST-OP. RESULTS: No biochemical, clinical relapse was found in low-risk patients in the RAD group and 1 relapse was found in the POST-OP group. The largest number of relapses occurred (39%) and (33%) in intermediate-high risk in RAD and POST-OP groups, respectively. In the cause-specific survival analysis, no significant differences were found in the high-risk group between RAD and POST OP groups (P = 0.9). In the analysis of 5-year biochemical relapse-free survival, no significant differences were found in the high-risk group between RAD and POST OP groups (P = 0.1020). CONCLUSIONS: Radiotherapy in the RAD low-risk group was an excellent treatment. RAD and POST-OP radiotherapy were well tolerated with very low toxicity. The cause-specific survival at 5 years was 95% and 97% for the two treatment groups, RAD and POST-OP, respectively (logrank test, P = 0.2908). PMID- 22825511 TI - Gastrointestinal stromal tumors: prognostic factors and therapeutic implications. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the digestive tract. They have recently been recognized as a separate nosological entity and the literature on these stromal tumors has rapidly expanded. MATERIALS AND METHODS: The surgical records of 50 patients with primary GISTs treated at the Digestive Surgery Department of the Catholic University of Rome from January 1993 to December 2010 were reviewed and the prognostic factors were analyzed. RESULTS: Surgery was performed in all patients with curative intent. The median age at presentation was 66.5 years (range, 28 81). Adjuvant therapy was administered in 26 (52%) cases. Median follow-up was 71 months (range, 5-208). There was an 8% recurrence rate. The actuarial 5-year overall and disease-free survival rates were 66.3% and 57.2%, respectively. High mitotic rate (P <0.001), tumor size greater than 10 cm (P = 0.007) and tumor rupture (P = 0.05) were the only prognostically significant negative factors for overall survival in multivariate analysis. CONCLUSIONS: The present study confirmed the important role of aggressive surgical management of GISTs to offer these patients the most appropriate treatment for long-term survival. PMID- 22825512 TI - Increased diagnostic yield of small bowel tumors with PillCam: the role of capsule endoscopy in the diagnosis and treatment of gastrointestinal stromal tumors (GISTs). Italian single-center experience. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare tumors, accounting for 1-3% of all gastrointestinal malignancies; they are, however, the most common gastric and small bowel mesenchymal tumors. The length and relative inaccessibility of the small bowel have long constrained the diagnosis of GISTs mainly presenting with chronic or intermittent bleeding as the sole clinical manifestation. AIM: To report on the prevalence of small bowel GISTs in a prospectively recorded series of patients undergoing capsule endoscopy (CE). PATIENTS AND METHODS: Between 2001 and 2007 five hundred patients were referred to our endoscopy unit for small bowel evaluation with capsule endoscopy. We retrospectively evaluated all charts. The main indications for CE were obscure occult or obscure-overt bleeding. Two hundred eighty-nine patients underwent CE for either obscure-occult or obscure-overt bleeding and 211 for other indications. Patient outcome and care processes were measured by follow-up telephone interviews and chart review. Statistical computations were performed using Fisher's exact test and Student's t-test. RESULTS: CE identified a small bowel tumor in 20 patients (4.0%) and 9 tumors turned out to be GISTs (45.0%). Traditional endoscopic and radiological imaging failed to detect the GIST in all these cases. In one case a small bowel GIST was diagnosed by angiography and CE proved false negative. Overall, CE was able to diagnose a small bowel GIST in 9 out of 10 cases. All patients underwent surgical treatment and showed normalized hemoglobin levels at follow-up. The main limitation of this study is the small number of cases. CONCLUSIONS: CE is an effective and sensitive diagnostic device compared with conventional radiology and plays an important role in the algorithm for the diagnostic work-up of suspected small bowel tumors. PMID- 22825513 TI - Association of thymidylate synthase and hypoxia inducible factor-1alpha DNA polymorphisms with pancreatic cancer. AB - BACKGROUND: Thymidylate synthase and hypoxia inducible factor-1alpha play a central role in the control of tumor progression. In the present study, we investigated the effect of three DNA polymorphisms within the thymidylate synthase gene and two within hypoxia inducible factor-1alpha on the prognosis of pancreatic cancer. PATIENTS AND METHODS: A retrospective study was performed in 59 patients diagnosed with invasive ductal adenocarcinoma of the pancreas and 159 healthy volunteers. The studied DNA polymorphisms were a variable tandem repeat of 28 bp (rs45445694), a G/C single nucleotide polymorphism (rs34743033), and a deletion of 6 bp (ins1494del 6bp; rs34489327) within the thymidylate synthase gene and C1772T and G1790A single nucleotide polymorphisms within hypoxia inducible factor-1alpha (rs11549465 and rs11549467, respectively) . Variable tandem repeats were determined by specific polymerase chain reaction, whereas thymidylate synthase single nucleotide polymorphism G/C, ins1494del 6pb, and hypoxia inducible factor-1alpha polymorphisms were identified by polymerase chain reaction and RFLP. Thymidylate synthase and hypoxia inducible factor-1alpha genotype distributions in patients and healthy volunteers were determined. The impact of the polymorphisms on clinico-pathological variables, including survival, was also studied. RESULTS: The frequency of carriers of the variant del6bp allele was significantly higher among patients (70.0% vs 51.0% of healthy donors, P = 0.02); 42% of male patients were homozygous 2R/2R vs 13.6% of females (P = 0.03), but differences regarding gender were not observed among healthy volunteers. Concerning hypoxia inducible factor-1alpha C1772T and G1790A single nucleotide polymorphisms, the rates of variant T/T and A/A homozygous genotypes were significantly elevated among patients (18.6% vs 5.3%, P = 0.001, and 5.1% vs none, P = 0.021 respectively). CONCLUSIONS: In our study, the variant del14946bp allele within the thymidylate synthase gene, and TT and AA genotypes of C1772T and G1790A hypoxia inducible factor-1alpha single nucleotide polymorphisms were associated with the development of pancreatic cancer. The 2R/2R genotype of variable tandem repeat thymidylate synthase polymorphism might be a risk factor for pancreatic cancer in males. PMID- 22825514 TI - Downregulating PRL-3 inhibit migration and invasion of lung cancer cell via RhoA and mDia1. AB - AIMS AND BACKGROUND: The overexpression of phosphatase of regenerating liver-3 (PRL-3) affects the migration and invasion of epithelial cells. Little is known about the substrates or pathways that PRL-3 interacts with. METHODS: We studied the action and the mechanism of PRL-3 in migration and invasion of lung cancer. We detected the expression of PRL-3 in lung cancer cell lines and normal human bronchial epithelial cell. RESULTS: We found that PRL-3 expression was high in lung cancer cells. Knockdown of PRL-3 by siRNA inhibited cell migration and invasion and reorganizated the cytoskeleton. Furthermore, blocking PRL-3 decreased RhoA activity and mDia1 expression. Blocking RhoA or mDia1 showed the similar changes of cytoskeleton and suppression of migration and invasion as inhibiting PRL-3 expression. Blocking RhoA inhibited the expression of mDia1. CONCLUSIONS: These data indicate that downregulating PRL-3 inhibit cell migration and invasion by inactivating RhoA to downregulate mDia1 to reorganizate cytoskeleton of lung cancer cells. PMID- 22825515 TI - Temperament and character traits associated with health-related quality of life in cancer patients. AB - BACKGROUND: There is an increase in the attention to factors influencing the quality of life of cancer patients. The aim of the present study was to evaluate temperament and character traits related to health-related quality of life (HRQoL) in patients with cancer. METHODS: Two hundred and three inpatients from three Italian oncology departments filled in the Temperament Character Inventory (TCI-140) based on Cloninger's personality model, the SF-36 questionnaire assessing HRQoL, and the Hospital Anxiety and Depression Scale (HADS). Eighty percent of patients were undergoing chemotherapy. RESULTS: Lower levels of harm avoidance and higher levels of self-directedness were significantly correlated with a better HRQoL. Regression analysis controlling for psychopathology (anxiety and depression symptoms) showed that the influence of temperament and character traits on quality of life seemed to add little to the influence of psychopathology. CONCLUSIONS: The present study demonstrates the existence of some relations between HRQoL and temperament and character traits assessed using the TCI-140 questionnaire. However, among the psychological factors, psychopathology seems to retain more influence on HRQoL of cancer patients. PMID- 22825516 TI - Hope Herth Index (HHI): a validation study in Italian patients with solid and hematological malignancies on active cancer treatment. AB - AIMS AND BACKGROUND: Although hope is a widely used term, the experience of hope in patients with chronic or even life-threatening diseases is often disregarded due to the scarcity of carefully designed and validated assessment tools. The aim of this study was to validate the Hope Herth Index (HHI) questionnaire in the Italian population of patients with solid or hematological malignancies during active cancer treatment. METHODS: After the translation procedures, the psychometric properties of the Italian version of HHI were evaluated in 266 patients with non-advanced cancer cared for in four different settings. Summative scores ranged from 12-48, with a higher score denoting greater hope. Confirmative factorial analysis was performed to assess dimensionality. The test-retest reliability was assessed by means of the Lin concordance coefficient (two weeks' interval, 80 patients). Concurrent validity was assessed through the following questionnaires: Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp), Edmonton Symptom Assessment Scale (ESAS), and System Belief Inventory (SBI-15R). RESULTS: A total of 266 patients were enrolled. Confirmative factor analysis did not confirm the original three-factor solution, whereas a one-factor solution did perform well. Cronbach's alpha was 0.84 and the test-retest reliability was 0.64 (95% CI 0.51; 0.76). Large convergence was found with spiritual well-being as measured by the FACIT-Sp (0.69) and with anxiety-depression as measured by the HADS (inverse correlation: -0.51). Physical symptoms and religiousness were only slightly correlated, as expected. CONCLUSIONS: The Italian version of HHI is a valid and reliable assessment tool - useful to initiate conversation with someone who is troubled but finds it difficult to talk - in patients with either solid or hematological malignancies on active cancer treatment during the non-advanced stages of the disease. PMID- 22825517 TI - "Do elderly cancer patients have different care needs compared with younger ones?". PMID- 22825518 TI - Sunitinib and everolimus in pancreatic neuroendocrine tumors. PMID- 22825519 TI - Hypofractionation in current clinical practice: a flash forward to the near future of radiation oncology? PMID- 22825520 TI - Predictive value of maspin and Ki-67 expression in transurethral resection specimens in patients with T1 bladder cancer. AB - AIMS AND BACKGROUND: To evaluate the clinical significance of maspin and Ki-67 expression in patients with newly diagnosed T1 bladder cancer. METHODS AND STUDY DESIGN: Maspin and Ki-67 expression was investigated by immunohistochemistry from paraffin-embedded tissues of 68 patients undergoing transurethral resection for bladder cancer. Clinicopathological data were retrospectively reviewed from available charts and pathological reports. Maspin and Ki-67 expression levels were classified according to the staining percentage. Cases in which at least 5% of the tumor cells stained for maspin were scored as positive. Ki-67 labeling index was considered to be positive when samples demonstrated >10% reactivity. RESULTS: Maspin expression was found as an independent predictor of recurrence and progression (P <0.05). Patients with negative maspin expression were 2.191 times more likely to relapse than patients with positive maspin expression. Patients with negative maspin expression were 4.345 times more likely to progress than patients with positive maspin expression. Furthermore, the maspin-negative group was found to have shorter recurrence and progression-free survival (P <0.05). No significant association was found between maspin subcellular localization pattern and recurrence-free, progression-free or overall survival (P >0.05). There was no correlation between Ki-67 expression and tumor recurrence, progression or tumor-related death (P >0.05). Chi-square tests showed a significant relationship between Ki-67 expression and tumor size and tumor grade (P <0.05). CONCLUSIONS: Our findings suggested that the evaluation of maspin expression in stage T1 bladder tumors is a useful prognostic marker for predicting the tumor behavior. PMID- 22825521 TI - Temozolomide combined with radiotherapy in the treatment of recurrent cranial meningioma previously treated with multiple surgical resections and two sessions of radiosurgery: a case report and literature review. AB - Meningioma is a common primary brain tumor in adults. The treatment approach depends on its grade, size and symptoms. The case reported here was a repeatedly recurring transitional meningioma, previously treated with several surgical procedures and two sessions of cranial radiosurgery. At the time of last relapse, temozolomide was administered alone and combined with external beam radiation therapy. At the last follow-up after 38 months, the disease was stable. In conclusion, in this case of plurirecurrent meningioma, treatment with temozolomide alone and in combination with radiotherapy was feasible and associated with limited morbidity, providing clinical benefit and long local disease control. We discuss the case comparing our approach with other experiences reported in the literature. PMID- 22825522 TI - Treatment of osteonecrosis of the jaw (ONJ) by medical ozone gas insufflation. A case report. AB - Osteonecrosis of the jaw (ONJ) is an adverse event reported in patients receiving cancer treatment, especially bisphosphonates and denosumab. A patient with multiple myeloma who underwent up to 22 intravenous zoledronic acid infusions without previous dental examination developed a devastating ONJ lesion in the right horizontal mandibular ramus. He was treated with local ozone gas applications every third day by means of a special bell to avoid O(3) diffusion. Azithromycin 500 mg/day was administered for 10 days prior to the O(3) applications. O(3) therapy resulted in sequestration of the necrotic bone after a median of 15 applications, following which surgery was necessary to remove it. Interestingly, removal was possible without the resection of the healthy mandible edge because of the presence of the bone sequestrum. Medical O(3) gas administration was effective and safe in a patient treated with bisphosphonates who developed a >2.5 cm ONJ lesion. Future research is needed to demonstrate the efficacy and tolerability of such treatment in a larger number of patients. PMID- 22825524 TI - Thyroid-like metastases to the scalp from a papillary renal cell carcinoma: a case report. AB - The skin can host metastatic tumors originating from different organs. We report a case of metastatic renal cell carcinoma to the scalp in a 73-year-old man with features very similar to those of thyroid papillary carcinoma. The histogenesis in relation to its structure is discussed. PMID- 22825523 TI - A case of small cell carcinoma of the prostate and review of the literature. AB - AIM AND BACKGROUND: Small cell carcinoma of the prostate (SCCP) is a relatively rare entity, an aggressive tumor with a tendency to metastasize early. There is no standard chemotherapy regimen for SCCP. We report the case of a 67-year-old man with an initial diagnosis of prostate adenocarcinoma with bone metastases who subsequently developed a small cell carcinoma of the prostate with liver metastases. METHODS AND STUDY DESIGN: A review of this case and of the current literature was done with a view to highlighting the ideal approach to such an unusual tumor. RESULTS AND CONCLUSION: The patient was treated with carboplatin and etoposide and after 3 cycles achieved a good response. Unfortunately he developed massive pulmonary embolism which impeded the continuation of treatment and caused his death. By reviewing the literature we found there is no standard of care and new targeted therapies have failed to prove any benefit so far. It is mandatory to persevere in planning trials and exploring new drugs to improve the outcome of patients with SCCP. It might also be worth creating a register for SCCP where data can be collected to coordinate the management of these patients and to establish better connections among cancer centers. PMID- 22825525 TI - Sarcomatoid carcinoma of the stomach with osteoclast-like giant cells. AB - Carcinomas with osteoclast-like giant cells (OGCs) are a rare type of malignant tumor that is histologically characterized by the presence of multinucleated giant cells that resemble osteoclasts mixed with poorly differentiated adenocarcinoma cells. In this study, we report the clinicopathological and immunohistochemical features of a gastric sarcomatoid carcinoma with OGCs in a 37 year-old male. An abdominal CT scan demonstrated a large mass, measuring 15 cm * 10 cm, in the lesser curvature of the stomach. Microscopic examination revealed that the tumor was composed of sarcomatoid and carcinomatous elements with infiltrating OGCs. Immunohistochemical analysis showed that the sarcomatoid and carcinomatous elements were both variably positive for CK7 and EMA. The sarcomatoid components were also vimentin and SMA positive. This is the first report of a gastric sarcomatoid carcinoma with OGCs. The present tumor has progressed rapidly with extensive perigastric involvement and multiple intrahepatic metastases. PMID- 22825526 TI - LDOC1 gene expression in two patients with head and neck squamous cell carcinomas and Parkinson's disease. AB - INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. Risk factors for this cancer include tobacco and alcohol use, ultraviolet light exposure, and viral infection. Parkinson's disease is one of the most common neurodegenerative disorders, with a prevalence of 3% in persons over the age of 65 years. Apoptosis is a programmed cell death machinery pivotal for normal development, the establishment of highly organized neuronal circuitry, and the elimination of cancer cells. It has been suggested that increased expression of proapoptotic genes is associated with head tumors. One of these genes is the leucine zipper, down-regulated in cancer 1 (LDOC1) gene. CASE REPORT: We report two interesting cases of a 79-year-old man and a 98-year-old woman, both with Parkinson's disease and well-differentiated multiple HNSCC, in whom we evaluated the possible differential expression of LDOC1. RESULTS: We found that LDOC1 gene expression was increased in both patients compared with three male and three female controls. Conclusions. These findings suggest that apoptosis may play a pathogenetic role in HNSCC. PMID- 22825527 TI - Jejunal obstruction caused by metastasis from an undiagnosed breast cancer: a case report. AB - Solitary metastasis from breast carcinoma to the gastrointestinal tract is an uncommon finding. We describe a female patient with a solitary jejunal metastasis from an undiagnosed breast cancer who presented to the emergency department with a bowel obstruction. Abdominal surgery was performed, revealing a jejunal stenosis from a metastatic lobular carcinoma. The primary tumor in the left breast was subsequently diagnosed and surgically removed. PMID- 22825528 TI - Implementation of a standardized pathway for the treatment of cardiac arrest patients using therapeutic hypothermia: "CODE ICE". AB - Out-of-hospital cardiac arrest is common and is associated with high mortality. The majority of in-hospital deaths from resuscitated victims of cardiac arrest are due to neurologic injury. Therapeutic hypothermia (TH) is now recommended for the management of comatose survivors of cardiac arrest. The rapid triage and standardized treatment of cardiac arrest patients can be challenging, and implementation of a TH program requires a multidisciplinary team approach. In 2010, we revised our institution's TH protocol, creating a "CODE ICE" pathway to improve the timely and coordinated care of cardiac arrest patients. As part of CODE ICE, we implemented comprehensive care pathways including measures such as a burst paging system and computerized physician support tools. "STEMI on ICE" integrates TH with our regional ST-elevation myocardial infarction network. Retrospective data were collected on 150 consecutive comatose cardiac arrest victims treated with TH (n = 82 pre-CODE ICE and n = 68 post-CODE ICE) from 2007 to 2011. After implementation of CODE ICE, the mean time to initiation of TH decreased from 306 +/- 165 minutes to 196 +/- 144 minutes (P < 0.001), and the time to target temperature decreased from 532 +/- 214 minutes to 392 +/- 215 minutes (P < 0.001). There was no significant change in survival or neurologic outcome at hospital discharge. Through the implementation of CODE ICE, we were able to reduce the time to initiation of TH and time to reach target temperature. Additional studies are needed to determine the effect of CODE ICE and similar pathways on clinical outcomes after cardiac arrest. PMID- 22825529 TI - Utility of coronary artery calcium scoring in the evaluation of patients with chest pain. AB - Although coronary artery calcium (CAC) scoring has an established role in risk stratifying asymptomatic patients at intermediate risk of coronary heart disease (CHD), its utility in the evaluation of patients with chest pain is uncertain. We conducted a literature review of articles investigating the utility of: (1) CAC scoring in elective patients with indeterminate chest pain symptoms, (2) CAC as a "gatekeeper" in the triage of patients presenting to the emergency department (ED) with chest pain, and (3) the cost-effectiveness of the use of CAC scoring in the ED. We also evaluated the predictive accuracy of the absence of CAC in a pooled analysis of applicable studies. Only studies evaluating patients classified as low or intermediate risk were included. Low to intermediate risk was established by Framingham risk scores, Thrombolysis in Myocardial Infarction scores, Diamond-Forrester classification, or by the absence of typical angina symptoms, ischemic electrocardiogram, positive cardiac biomarkers, or a prior history of CHD. In our pooled analysis, the presence of any CAC resulted in a high sensitivity (range 70%-100%) for predicting the presence of obstructive coronary disease among symptomatic patients subsequently referred for coronary angiography. More importantly, a CAC score of 0 in low- and intermediate-risk ED populations with chest pain had a high negative predictive value (99.4%) for CHD events over an average follow-up of 21 months. CAC scoring also seems cost effective in this population. Although further research is needed, carefully selected ED patients with a normal electrocardiogram, normal cardiac biomarkers, and CAC = 0 may be considered for early discharge without further testing. PMID- 22825530 TI - Updating an institutional chest pain algorithm: incorporating new evidence on emerging pharmacotherapy. AB - Clinical treatment pathways are useful to ensure that evidence-based medicine is consistently applied in hospital systems and have been shown to improve patient outcomes. Such pathways need to be regularly updated and revised by incorporating new evidence from clinical trials to ensure optimal clinical care. In 2011, we published the Columbia University Medical Center/New York Presbyterian Hospital - Clinical Pathways for Acute Coronary Syndromes and Chest Pain. This algorithm includes primary percutaneous coronary intervention for all patients with ST segment elevation myocardial infarction and an early invasive approach for patients with non-ST-segment elevation myocardial infarction. Since our last chest pain algorithm update, the novel antiplatelet agent ticagrelor has been introduced in the United States, resulting in an important revision of our acute coronary syndrome clinical pathways. Herein, we present our updated chest pain algorithm and provide rationale for the changes that we have made to our protocol. PMID- 22825531 TI - Implementing a state-based stroke quality improvement collaborative: the Massachusetts experience. AB - BACKGROUND: The Stroke Collaborative Reaching for Excellence is a voluntary stroke quality improvement (QI) collaborative led by a partnership between the Massachusetts Department of Public Health and the American Heart Association/American Stroke Association. Since 2005, the collaborative has assisted Massachusetts Primary Stroke Service hospitals in improving the quality of acute stroke care based on national clinical guidelines. We provide a general overview for states seeking to establish a public-private partnership to promote hospital stroke QI. METHODS: Based on the Institute for Healthcare Improvement's Collaborative model, the program enrolled hospitals, trained staff in data collection, and provided expertise on clinical QI. To assess the success of the model at engaging hospitals, rates of change in participation and case entry were calculated with descriptive statistics. RESULTS: From 2005 to 2010, 58 of 70 (83%) Primary Stroke Service hospitals participated in the collaborative, accounting for over 85% of the statewide annual stroke discharges. On average, 74% of hospital representatives attended learning sessions, 55% participated in data quality conference calls, and 54% attended regional meetings. Over 39,000 cases were entered into the registry from 2007 to 2010, with a 15% increase from 2007 (mean, 171 +/- 136; n = 9425) to 2010 (mean, 197 +/- 143; n = 10,809). CONCLUSION: Consistent participation and case entry confirm that a voluntary state-based hospital QI collaborative is feasible and sustainable. This occurred in the absence of continued hospital funding. Further research is needed to identify the relationship between program participation and improved patient care and the generalizability of the model. PMID- 22825533 TI - State of the art: emergency department observation units. AB - Hospitals and emergency departments face the challenges of escalating healthcare costs, mismatched resource utilization, concern over avoidable admissions, and hospital and emergency department overcrowding. One approach that has been used by hospitals to address these issues is the use of emergency department observation units. Research in this setting has increased in recent years, leading to a better understanding of the role of these units and their unique benefits. These benefits have been proven for health systems as a whole and for several acute conditions including chest pain, asthma, syncope, transient ischemic attack, atrial fibrillation, heart failure, abdominal pain, and more. Benefits include a decrease in diagnostic uncertainty, lower cost and resource utilization, improved patient satisfaction, and clinical outcomes that are comparable to admitted patients. As more hospitals begin to use observation units, there is a need for further education and research in how to optimize the use of emergency department observation units. The purpose of this article is to provide a general overview of observation units, including advancements and research in this field. PMID- 22825532 TI - Design and implementation of a stand-alone chest pain evaluation center within an academic emergency department. AB - Chest pain is a common presenting symptom for emergency department (ED) patients; however, a thorough cardiac evaluation can be difficult to complete within the ED setting. Implementation of a stand-alone unit for the evaluation of chest pain may improve care for patients with chest pain. We designed a protocol for identifying patients without an acute coronary syndrome and with low-to intermediate likelihood of obstructive coronary artery disease (CAD). These patients were monitored in a stand-alone chest pain evaluation center (CPEC) staffed with a small group of providers and tested for CAD, if necessary. In the first 6 weeks of operation, 181 patients were evaluated in the CPEC. The prevalence of CAD risk factors was low. Of the 181 patients, 159 (88%) were discharged home and 22 (12%) required admission to the hospital for further care. We compared the number of chest pain evaluations and admissions for first 6 weeks of operation to the same 6-week period from the 2 previous years. Whereas ED chest pain evaluations increased 66% over the 2-year time frame, the proportion admitted to the hospital decreased from 53% to 42% (P < 0.0001). In conclusion, evidence-based evaluation of chest pain in patients without acute coronary syndrome and with low-to-intermediate likelihood of obstructive CAD can result in the significant majority of patients being discharged from the ED. Creation of a stand-alone CPEC in an academic hospital was associated with a significant reduction in hospital admissions. PMID- 22825534 TI - 2012 Oman Heart Association simplified guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. AB - Although current practice guidelines provide an evidence-based approach to the management of acute coronary syndromes, application of the evidence by individual physicians has been suboptimal. This gap between comprehensive guidelines and actual practice stimulated Oman Heart Association to issue a simplified series for the management of the common cardiac abnormalities to be applied by the entire cardiac caregivers all over the country. This simplified approach for the management of non-ST-elevation acute coronary syndrome provides a practical and systematic means to implement evidence-based medicine into clinical practice. PMID- 22825535 TI - Prognostic importance of electrocardiographic abnormalities in patients with acute noncardiac conditions. AB - The electrocardiogram's (ECG) ability to aid in the diagnosis and risk stratification of patients with acute coronary syndromes is well established. We sought to investigate the prognostic significance of ECG abnormalities in patients with noncardiac conditions in the emergency department. Patients presenting to the emergency department who were evaluated for possible acute coronary syndrome were consecutively enrolled and an initial ECG was obtained (n = 1024). Only patients with noncardiac diagnoses were reviewed in this analysis (n=493) and 30-month follow-up was obtained. Sinus tachycardia, atrial fibrillation/flutter, ST depression, and left bundle branch block were associated with increased 30-month mortality. After controlling for history of coronary artery disease, age, sex, diabetes mellitus, hypertension, and renal insufficiency, sinus tachycardia and ST-segment depression >=1 mm were independent predictors of 30-month mortality with a hazard ratio of 2.33 (95% confidence interval, 1.36-4.00; P = 0.002) and 2.49 (95% confidence interval, 1.10-5.67; P = 0.029), respectively. In conclusion, ST-segment depression and sinus tachycardia in patients presenting to the hospital with noncardiac conditions are independently associated with increased 30-month mortality. PMID- 22825536 TI - Impact of chronic kidney disease on long-term clinical outcomes after percutaneous coronary intervention with drug-eluting or bare-metal stents. AB - Chronic kidney disease (CKD) is associated with adverse outcomes after coronary bare-metal stent (BMS) and drug-eluting stent (DES) implantation, but it is unclear which stent type is associated with lower risk for morbidity and mortality in this population. Uniform treatment standards during coronary stent implantation and a median follow-up period of 2.8 years characterize the FReIburg STent (FRIST) registry, designed as a long-term outcome evaluation of a single tertiary referral cardiovascular center. CKD, defined as creatinine clearance <60 mL/min, was present at baseline in 180 (12%) of 1502 consecutive patients undergoing coronary stent intervention. Patients received first-generation DES (n = 117) or BMS (n = 63). Kaplan-Meier and multivariate Cox model analyses were applied to compare survival rates and adjust for existing clinical, procedural, and angiographic differences between the patients. The primary end point was mortality (cardiac and noncardiac death) and secondary end points were recurrent myocardial infarction, stent thrombosis, target vessel revascularization, sepsis, and major bleeding. Patients with a glomerular filtration rate <60 mL/min had a higher mortality rate (28.3% vs. 10.1%, P < 0.001) than patients with a good renal function. In patients with CKD, there was no difference in mortality rates in the BMS vs. the DES group (hazard ratio, 0.971; 95% confidence interval, 0.48 1.954). In summary, patients with CKD have significantly higher rates of death, but there appears to be no difference in long-term clinical outcomes of first generation DES compared with BMS implantation during primary percutaneous coronary intervention. PMID- 22825537 TI - Society of chest pain centers: building better value into health care. AB - With initiation of VBP, acute care hospitals are rewarded based on how closely clinical guidelines and practices are followed and how well hospitals enhance patients' experiences. Thus, the VBP program requires reengineering of acute care processes. Patient-centered care must remain the focus of a rigorous curriculum of goals and metrics for acute care hospitals. PMID- 22825538 TI - Intracomplex general acid/base catalyzed cleavage of RNA phosphodiester bonds: the leaving group effect. AB - The general acid/base catalyzed cleavage of a number of alkyl esters of uridine 3'- (and -5'-)phosphate has been studied by utilizing a cleaving agent, in which the catalytic moiety (a substituted 1,3,5-triazine) is tethered to an anchoring Zn(II):cyclen moiety. Around pH 7, formation of a strong ternary complex between uracil, Zn(II) and cyclen brings the general acid/base catalyst close to the scissile phosphodiester linkage, resulting in rate acceleration of 1-2 orders of magnitude with the uridine-3'-phosphodiesters. Curiously, no acceleration was observed with their 5'-counterparts. A beta(lg) value of -0.7 has been determined for the general acid/base catalyzed cleavage, consistent with a proton transfer to the leaving group in the rate-limiting step. PMID- 22825539 TI - IBD: Risk of ulcerative colitis is increased for 20 years in women who stop smoking. PMID- 22825540 TI - IBS: Distinct neuro-immune patterns defined in IBS subtypes. PMID- 22825541 TI - Upregulation of miR-20a and miR-106b is involved in the acquisition of malignancy of pediatric brainstem gliomas. AB - Brainstem glioma (BSG) is an entity which commonly occurs in pediatric patients and carries a dismal prognosis. However, the category of adult BSG has displayed considerably benign biological behavior, thus providing a unique perspective to comparatively understand the malignant features of pediatric BSG. microRNAs (miRNAs) have been associated with cancer development and progression. To identify miRNAs specifically involved in the acquisition of malignant progression of pediatric BSG, we analyzed the miRNA expression profiles in orthotopic models which could simulate the BSG heterogeneity by microarrays. Our research revealed that miR-20a and miR-106b (known to be closely related) were the two most robust upregulated miRNAs in pediatric BSG compared to adult subtype. Furthermore, the two types of human BSG tissue were utilized to verify the microarray data by qRT PCR and in situ hybridization. The results indicated good consistency with that of the microarray method. In conclusion, our studies provide evidence that miR 20a and miR-106b may serve as putative causative involvement of malignant progression of pediatric BSG, thereby serving as likely novel targets for constraining the rapid fatal course of pediatric BSG. PMID- 22825543 TI - Cancer diagnoses after living kidney donation: linking U.S. Registry data and administrative claims. AB - BACKGROUND: Mortality records identify cancer as the leading cause of death among living kidney donors, but information on the burden of cancer outside death records is limited in this population. METHODS: We examined a database wherein U.S. Organ Procurement and Transplantation Network identifiers for 4,650 living kidney donors in 1987 to 2007 were linked to administrative data of a U.S. private health insurer (2000-2007 claims) to identify postdonation cancer diagnoses. Skin cancer and non-skin cancer diagnoses were ascertained from International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes on billing claims. Donors were also matched one-to-one with general insurance beneficiaries by sex and age when benefits began. Diagnosis rates within observation windows were compared as rate ratios. RESULTS: The median time from donation to the end of plan insurance enrollment was 7.7 years, with a median observation period of 2.1 years. Skin cancer rates were similar among prior living donors in the observation period and nondonor controls (rate ratio, 0.91; 95% confidence interval [CI], 0.59-1.40). In contrast, the rate of total non-skin cancers was significantly less common among donors than among controls (rate ratio, 0.74; 95% CI, 0.55-0.99), although reduced relative risk was limited to donors captured earlier in relation to donation. Several cases of cancer diagnosis (uterine, melanoma, "other") were identified within the first year after donation. Prostate cancer diagnosis was significantly more common among living donors compared with controls (rate ratio, 3.80; 95% CI, 1.42-10.2). CONCLUSIONS: Continued study of cancer after kidney donation is warranted to ensure that evaluation, selection, and long-term follow-up support overall good health of the donor. PMID- 22825544 TI - Use of diagnostic tests in adolescents with essential hypertension. AB - OBJECTIVE: To describe the use of diagnostic tests in adolescents with essential hypertension. DESIGN: Longitudinal analysis of administrative claims data. SETTING: Michigan Medicaid program during 2003 to 2008. PARTICIPANTS: Adolescents with 3 or more years of Medicaid eligibility (>= 11 months/y) who had a diagnosis of essential hypertension and 1 or more antihypertensive medication pharmacy claims. MAIN OUTCOME MEASURES: We examined adolescents' echocardiogram use and compared it with electrocardiogram (EKG) and renal ultrasonography use. We examined timing of the 3 diagnostic tests in relation to the first pharmacy claim. We examined patient demographics and presence of obesity-related comorbidities. RESULTS: During 2003 to 2008, there were 951 adolescents with essential hypertension who had antihypertensive pharmacy claims; 24% (226) had echocardiograms; 22% (207) had renal ultrasonography; and 50% (478) had EKGs. Males (odds ratio [OR], 1.53; 95% CI, 1.06-2.21), younger adolescents (OR, 1.69; 95% CI, 1.17-2.44), those who had EKGs (OR, 5.79; 95% CI, 4.02-8.36), and those who had renal ultrasonography (OR, 2.22; 95% CI, 1.54-3.20) were more likely to obtain echocardiograms compared with females, older adolescents, and adolescents who did not have EKGs or renal ultrasonography. CONCLUSIONS: Guideline recommended diagnostic tests-echocardiograms and renal ultrasonography-were equally poorly used by adolescents with essential hypertension. Sex and age differences exist in the use of echocardiograms by adolescents with essential hypertension. The decision and choice of diagnostic tests to evaluate adolescents with essential hypertension warrant further study to understand the underlying rationale for those decisions and to determine treatment effectiveness. PMID- 22825546 TI - The A to G polymorphism at -1082 of the interleukin-10 gene is rare in the Han Chinese population. AB - Interleukin-10 (IL-10) is a multifunctional anti-inflammatory cytokine involved in various physiological and pathophysiological processes including cardiovascular disease. It has been reported that 50-75% of the variation in IL 10 production is genetically controlled. In the present study, the IL-10 -1082A/G (rs1800896) polymorphism was detected in 174 coronary artery disease (CAD) patients confirmed by selective coronary angiography and 176 age and gender matched controls from the Jiangsu area (East China). The majority of the subjects (93.14%) carried the AA wild-type genotype, whereas only 0.29% carried the GG genotype. Our results suggest that IL-10 -1082A/G is rare and unlikely to be a significant contributory to disease susceptibility in the Han Chinese population. PMID- 22825545 TI - Rifampicin alters the expression of reference genes used to normalize real-time quantitative RT-PCR data. AB - Suitable reference genes for correct quantification of reverse transcription PCR (qRT-PCR) have to be constantly expressed in all samples under investigation. Thus, it is mandatory to determine expression stability of control genes before normalization. We aimed to establish optimum inducing concentrations for the prototypical enzyme and drug transporter inducer rifampicin in LS180 cells and concurrently assessed reference gene stability under rifampicin treatment. LS180 cells were treated with increasing concentrations of rifampicin (up to 200 MUM), and expression of eight different reference genes and some target genes (CYP3A4, ABCB1, and ABCC1) was quantified using real-time qRT-PCR. To check whether the results can be generalized, HepG2 cells were also investigated. We demonstrated that higher concentrations of rifampicin (>50 MUM) change the expression of reference genes and thus may complicate and adulterate normalization of qRT-PCR data. The results stress the need for proper validation of potential reference genes in respective cells, tissues, and particular experimental conditions. Programs like geNorm and NormFinder alone do not warrant an adequate choice of the most suitable reference gene. Scrutiny of the reference gene expression and plausibility of the data remain necessary and protect from erroneous quantification and misinterpretation of qRT-PCR data. PMID- 22825547 TI - Epstein-Barr virus and methotrexate-related CNS lymphoma in a patient with rheumatoid arthritis. AB - Patients with rheumatoid arthritis (RA), especially those treated with methotrexate (MTX), might have an increased risk of lymphoproliferative disorders that are associated with Epstein-Barr virus (EBV). We describe a case of EBV associated central nervous system (CNS) lymphoma (diffuse large B-cell lymphoma) in a patient with RA on a short course of MTX treatment. The neoplastic cells express the B-cell surface markers (CD20, Pax-5 and CD30), and EBV-encoded RNA was demonstrated by in situ hybridization. The patient's lymphoma did not recur for the 8-year follow-up period after the tumor resection and cessation of MTX. MTX may promote EBV-positive CNS lymphoma in RA patient due to its immunosuppressive properties as well as reactivating latent EBV infection. PMID- 22825549 TI - Acute liver failure in Japan: definition, classification, and prediction of the outcome. AB - Acute liver failure is a clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to severe impairment of liver function caused by massive or submassive liver necrosis. Viral hepatitis is the most important and frequent cause of acute liver failure in Japan. The diagnostic criteria for fulminant hepatitis, including that caused by viral infections, autoimmune hepatitis, and drug allergy induced-liver damage, were first established in 1981. Considering the discrepancies between the definition of fulminant hepatitis in Japan and the definitions of acute liver failure in the United States and Europe, the Intractable Hepato-Biliary Disease Study Group established the diagnostic criteria for "acute liver failure" for Japan in 2011, and performed a nationwide survey of patients seen in 2010 to clarify the demographic and clinical features and outcomes of these patients. According to the survey, the survival rates of patients receiving medical treatment alone were low, especially in those with hepatic encephalopathy, despite artificial liver support, consisting of plasma exchange and hemodiafiltration, being provided to almost all patients in Japan. Thus, liver transplantation is inevitable to rescue most patients with hepatic encephalopathy. The indications for liver transplantation had, until recently, been determined according to the guideline published by the Acute Liver Failure Study Group in 1996. Recently, however, the Intractable Hepato-Biliary Disease Study Group established a scoring system to predict the outcomes of acute liver failure patients. Algorithms for outcome prediction have also been developed based on data-mining analyses. These novel guidelines need further evaluation to determine their usefulness. PMID- 22825550 TI - The efficacy of nocturnal administration of branched-chain amino acid granules to improve quality of life in patients with cirrhosis. AB - BACKGROUND: Nocturnal administration of branched-chain amino acid (BCAA) granules improves serum albumin levels in patients with cirrhosis. However, it is unclear whether or not this administration method can improve the patients' quality of life (QOL). In this study, we aimed to investigate the efficacy of BCAA granules, given nocturnally, in improving QOL in these patients. METHODS: We performed a multicenter, randomized controlled trial examining the comparative effects of BCAA granules given orally for 3 months with daytime or nocturnal administration in patients with compensated cirrhosis. Health-related QOL was measured by a Japanese version of the questionnaire on subjective and objective symptoms, and the Short Form-8 (SF-8) questionnaire. RESULTS: Twenty-one patients received BCAA granules three times a day (one sachet after each meal: the daytime group), and 16 patients received the granules twice a day (one sachet after breakfast, and two sachets before bedtime: the nocturnal group). Baseline characteristics did not differ between the groups (whole cohort: Child-Pugh grade A/B, 21/16; mean age, 68.2 years). There was no significant difference in any of the subjects revealed by the questionnaire regarding subjective or objective symptoms, or by the SF-8 between the daytime group and the nocturnal group after 3 months of treatment. The daytime group showed a significant effect on general health, vitality, social functioning, mental health, and role emotional as revealed on the SF-8. Conversely, the nocturnal group exhibited a significant decrease in the occurrence of muscle cramps in the legs (P = 0.014) and significantly improved Fisher's ratio after 3 months (P = 0.04). CONCLUSIONS: Nocturnal administration of BCAA granules in patients with cirrhosis reduced the occurrence of muscle cramps in the leg but did not improve the patients' QOL. PMID- 22825551 TI - Increased admission serum estradiol level is correlated with high mortality in patients with severe acute pancreatitis. AB - BACKGROUND: Sexual dimorphism in critical diseases has been documented. Severe acute pancreatitis is a disease with high mortality. We hypothesized that admission sex hormone levels may be used as an early predictor of outcome in these patients. METHODS: A prospective cohort of patients with severe acute pancreatitis admitted to the intensive care unit for at least 48 h were enrolled (n = 62). Serum levels of estradiol, progesterone, and testosterone were determined on admission. The association of sex hormone levels and various disease severity scoring systems with patient outcome was analyzed. RESULTS: There was no difference in overall mortality between the sexes. However, estradiol was significantly elevated in nonsurvivors (39 vs. 206 pg/mL, p < 0.001). The estradiol level was the best single-variable predictor of mortality (area under the curve 0.97), followed by the sequential organ failure assessment score, the multiple organ dysfunction score, and the acute physiology and chronic health care evaluation II (APACHE II) score. A serum estradiol level of 102 pg/mL was both sensitive and specific to predict mortality. There were no differences between survivors and non-survivors in terms of age, body mass index, or progesterone and testosterone levels. CONCLUSIONS: Admission serum estradiol level is a good marker of disease severity and predictor of death in patients with severe acute pancreatitis. PMID- 22825552 TI - [Mesenchymal stem cells and rheumatism. State of the art]. AB - Mesenchymal stem cells (MSC) are multipotent. They are able to regenerate tissue damage and, in parallel, inhibit inflammation and fibrosis. As they are non immunogenic, MSCs can be safely transplanted using autologous and allogeneic procedures: an option for refractory connective tissue diseases and osteoarthritis. PMID- 22825553 TI - Crystal structure of ISG54 reveals a novel RNA binding structure and potential functional mechanisms. AB - Interferon-stimulated gene 56 (ISG56) family members play important roles in blocking viral replication and regulating cellular functions, however, their underlying molecular mechanisms are largely unclear. Here, we present the crystal structure of ISG54, an ISG56 family protein with a novel RNA-binding structure. The structure shows that ISG54 monomers have 9 tetratricopeptide repeat-like motifs and associate to form domain-swapped dimers. The C-terminal part folds into a super-helical structure and has an extensively positively-charged nucleotide-binding channel on its inner surface. EMSA results show that ISG54 binds specifically to some RNAs, such as adenylate uridylate (AU)-rich RNAs, with or without 5' triphosphorylation. Mutagenesis and functional studies show that this RNA-binding ability is important to its antiviral activity. Our results suggest a new mechanism underlying the antiviral activity of this interferon inducible gene 56 family member. PMID- 22825555 TI - Re: interdisciplinary critique of sipuleucel-T as immunotherapy in castration resistant prostate cancer. PMID- 22825556 TI - Re: interdisciplinary critique of sipuleucel-T as immunotherapy in castration resistant prostate cancer. PMID- 22825554 TI - The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. AB - During developmental and tumor angiogenesis, semaphorins regulate blood vessel navigation by signaling through plexin receptors that inhibit the R-Ras subfamily of small GTPases. R-Ras is mainly expressed in vascular cells, where it induces adhesion to the extracellular matrix (ECM) through unknown mechanisms. We identify the Ras and Rab5 interacting protein RIN2 as a key effector that in endothelial cells interacts with and mediates the pro-adhesive and -angiogenic activity of R-Ras. Both R-Ras-GTP and RIN2 localize at nascent ECM adhesion sites associated with lamellipodia. Upon binding, GTP-loaded R-Ras converts RIN2 from a Rab5 guanine nucleotide exchange factor (GEF) to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand bound/active beta1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active beta1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1. PMID- 22825560 TI - Fourteenth biannual report of the Cochrane Haematological Malignancies Group- focus on autologous stem cell transplantation in hematological malignancies. PMID- 22825561 TI - Defect engineering: reduction effect of hydrogen atom impurities in HfO2-based resistive-switching memory devices. AB - In this study, we propose a new and effective methodology for improving the resistive-switching performance of memory devices by high-pressure hydrogen annealing under ambient conditions. The reduction effect results in the uniform creation of oxygen vacancies that in turn enable forming-free operation and afford uniform switching characteristics. In addition, H(+) and mobile hydroxyl (OH(-)) ions are generated, and these induce fast switching operation due to the higher mobility compared to oxygen ions. Defect engineering, specifically, the introduction of hydrogen atom impurities, improves the device performance for metal-oxide-based resistive-switching random access memory devices. PMID- 22825562 TI - Au(I)-catalyzed and iodine-mediated cyclization of enynylpyrazoles to provide pyrazolo[1,5-a]pyridines. AB - Pyrazolo[1,5-a]pyridines and 6-iodopyrazolo[1,5-a]pyridines were synthesized by gold-catalyzed and iodine-mediated cyclization of enynylpyrazoles in good to excellent yields, respectively. The iodinated adducts were further converted to 6 arylpyrazolo[1,5-a]pyridines via Suzuki-Miyaura coupling reaction and 6 cyanopyrazolo[1,5-a]pyridine by Ullmann condensation reaction. One of the cyclization adducts, 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine, was converted to a p38 kinase inhibitor, 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5 a]pyridine, in two steps. PMID- 22825563 TI - Ruthenium amino carboxylate complexes as asymmetric hydrogen transfer catalysts. AB - The synthesis and characterization of optically active amino carboxylate complexes of formula [(eta(6)-arene)Ru(Aa)Cl] (arene = C(6)H(6), C(6)Me(6), Aa = amino carboxylate) as well as those of the related trimers [{(eta(6) arene)Ru(Aa)}(3)][BF(4)](3) are reported. Trimerization takes place with chiral self-recognition: only diastereomers equally configured at the metal, R(Ru)R(Ru)R(Ru) or S(Ru)S(Ru)S(Ru), are detected. The crystal structures of the complexes [(eta(6)-C(6)H(6))Ru(Pip)Cl] and [{(eta(6) C(6)Me(6))Ru(Pro)}(3)][BF(4)](3) have been determined by X-ray diffraction methods. Both types of complexes catalyse the hydrogen transfer reaction from 2 propanol to ketones with moderate enantioselectivity (up to 68% ee). The enantiodifferentiation achieved can be accounted for by assuming that Noyori's bifunctional mechanism is operating. PMID- 22825565 TI - The sedation dispute: what is next? PMID- 22825566 TI - Comparison of video laryngoscopes with direct laryngoscopy for tracheal intubation: some clarification needed. PMID- 22825567 TI - Family practice enhancements for patients with severe mental illness. AB - Individuals with severe mental health disorders experience difficulty maneuvering the complexity encountered in primary care (PC). This study describes the impact of three components of primary care practice enhancements on: changes in missed appointments, changes in health outcomes, number of ER visits and hospitalization days, and perceptions of integrated care. Missed PC appointments: baseline to post practice enhancement changed from 42 to 11, statistically significant (p < .01). Changes in health outcomes: SF-12 scores had no significant change nor did ER utilization and hospitalization; however, outcomes are low-base rate and assessment period was short. Integration of care: liaison was most helpful in accessing and navigating PC, educating and reconciling medication lists. Behavioral health staff voiced relief regarding access and felt better informed. Strategies focusing on increasing communication, staff education, and reducing barriers to access and receipt of PC may improve integration and continuity of care. PMID- 22825568 TI - Measuring the later stages of the recovery journey: insights gained from clubhouse members. AB - The Recovery Assessment Scale (RAS) is a frequently used measure of recovery from mental illness but has previously been shown to poorly differentiate between more recovered consumers. This research aimed to: (1) identify components of later recovery stages; (2) ascertain the extent to which these are measured in the RAS; and (3) suggest modifications to improve the ability of the RAS to differentiate between more recovered consumers. Clubhouse members who scored high on the RAS participated in focus groups in which they discussed areas of recovery most recently or yet to be achieved. Constant comparative analysis of data indicated that later stages of recovery are characterized by: (a) accepting your illness and gaining control over symptoms (b) self love and optimism, (c) doing things for and experiencing pleasure, (d) contributing through meaningful activity, (e) having a diversity of friendships, (f) being needed and valued by others and (g) coming to terms with family relationships. Results suggest the RAS would be improved by addition of items, particularly in functional and social recovery domains. PMID- 22825569 TI - Hypertension in children and adolescents: more questions than answers. PMID- 22825570 TI - Serum interleukin-15 levels in cancer patients with cachexia. AB - Interleukin-15 (IL-15) has important anabolic effects on muscle protein metabolism through a decrease in the ATP-ubiquitin-dependent proteolytic pathway. The role of IL-15 in human cancer cachexia is unknown. The aim of this study was to assess the relationship between interleukin-15 (IL-15) in cancer patients with cachexia at diagnosis of malignancy and 8 weeks later. An observational study of 21 cancer patients (with and without cachexia) and 8 healthy subjects was conducted. Body composition was measured by leg-to-leg impedance. Serum IL-15 levels were assessed at baseline and after 4 and 8 weeks. Baseline IL-15 values were similar in cancer patients and in healthy subjects. Cancer patients with lower baseline levels of IL-15 (<2 pg/ml) had significantly higher fat mass (%) along the study. Eighteen patients completed the study: five patients showed an increase of 3.7 kg at the end of the study (5.4% of body weight) and showed a mean increase of IL-15 of 1.32 pg/ml (121%) at 4 weeks and 2.32 pg/ml (197%) at 8 weeks, as compared with mean decrease of -4.1 kg (-5.3%) and -0.09 pg/ml (-2.5%) and 0.6 pg/ml (40.8%) in the 13 patients who lost weight (P=0.001 and P=0.022, respectively). Changes of IL-15 at 4 and 8 weeks were directly associated with changes in body weight, body mass index (BMI), fat-free mass and muscle mass (P<0.05), and indirectly associated with percentage of weight loss (P<0.05). In summary, although the results indicate that IL-15 does not have a role in cancer cachexia pathogenesis, the association during evolution between serum IL-15 and changes in weight and muscle mass suggests a possible role of IL-15 as a marker of the body composition response in cancer patients who are losing weight at the time of diagnosis. PMID- 22825571 TI - Chromosomes without a 30-nm chromatin fiber. AB - How is a long strand of genomic DNA packaged into a mitotic chromosome or nucleus? The nucleosome fiber (beads-on-a-string), in which DNA is wrapped around core histones, has long been assumed to be folded into a 30-nm chromatin fiber, and a further helically folded larger fiber. However, when frozen hydrated human mitotic cells were observed using cryoelectron microscopy, no higher-order structures that included 30-nm chromatin fibers were found. To investigate the bulk structure of mitotic chromosomes further, we performed small-angle X-ray scattering (SAXS), which can detect periodic structures in noncrystalline materials in solution. The results were striking: no structural feature larger than 11 nm was detected, even at a chromosome-diameter scale (~1 MUm). We also found a similar scattering pattern in interphase nuclei of HeLa cells in the range up to ~275 nm. Our findings suggest a common structural feature in interphase and mitotic chromatins: compact and irregular folding of nucleosome fibers occurs without a 30-nm chromatin structure. PMID- 22825572 TI - The enhanced antitumor effects of biodegradable cationic heparin polyethyleneimine nanogels delivering HSulf-1 gene combined with cisplatin on ovarian cancer. AB - HSulf-1 (heparan sulfate 6-O-endosulfatase 1), a commonly downregulated gene in the majority of ovarian cancer cell lines, has been identified to play an important role in regulating tumorigenesis. Our previous studies demonstrated that HSulf-1 could inhibit angiogenesis and tumorigenesis in vivo. The employment of polymeric nanoparticles to deliver functional gene holds much promise as an effective therapeutic strategy against ovarian cancer. To develop more effective therapy, in this study, we investigated the antitumor effect of heparin polyethyleneimine (HPEI) nanogels delivering HSulf-1 combined with cisplatin (DDP) on ovarian cancer. Expression of HSulf-1 in vitro and in vivo was determined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis. A SKOV3 intraperitoneal ovarian carcinomatosis model in nude mice was established to assess the antitumor efficacy. Mice were treated with NS, pEP/HPEI complexes, pHSulf-1/HPEI complexes, DDP or pHSulf-1/HPEI plus DDP, respectively. Intraperitoneal tumors were weighed. Antiangiogenic effect in vivo was evaluated by CD31 immunostaining and alginate-encapsulate tumor cell assay. Detection of the proliferative cells and apoptotic cells in tumor tissues were performed by Ki-67 staining and TUNEL assay. Stable expression of HSulf-1 was detected in the pHSulf-1/HPEI and pHSulf-1/HPEI plus DDP groups. The combination of pHSulf-1/HPEI complexes with DDP exhibited enhanced antitumor activity, compared with the monotherapy of HSulf-1 or DDP alone (P<0.01). the combination therapy exerted significant antitumor activity through enhanced antiangiogenesis, induction of apoptosis and suppression of cell proliferation. Collectively, these observations provide evidence that HPEI nanogels delivering HSulf-1 combined with DDP may have a promising application in the therapy of human ovarian cancer. PMID- 22825574 TI - New dibenzofuran/spirobifluorene hybrids as thermally stable host materials for efficient phosphorescent organic light-emitting diodes with low efficiency roll off. AB - A new class of host materials DBFSF (DBFSF2 and DBFSF4) is facilely synthesized through a Suzuki coupling reaction between dibenzofuran and spirobifluorene. Their thermal, electrochemical, electronic absorption and photoluminescent properties are fully investigated. High glass transition temperatures (T(g)) of 115 degrees C and 124 degrees C are observed for DBFSF2 and DBFSF4, respectively, due to the introduction of bulky spirobifluorene groups. As expected, the DBFSF4 with a twisted-linkage exhibits higher triplet energy than DBFSF2 and can be used in blue and green phosphorescent OLEDs. Electrophosphorescent devices with DBFSF2 and DBFSF4 as hosts were fabricated. Besides the good current efficiencies of 22.2 cd A(-1) for blue and 64.4 cd A(-1) for green, low efficiency roll-off has also been achieved for both devices. PMID- 22825573 TI - Validity testing of the stopwatch urine stream interruption test in radical prostatectomy patients. AB - OBJECTIVE: To assess convergent validity of the stopwatch urine stream interruption test (UST). Specific aims were to describe relationships among stopwatch UST scores and 4 common clinical indices of pelvic floor muscle strength: 24-hour urine leakage, confidence in performing pelvic muscle exercise, 24-hour pad count, and daily pelvic muscle exercise count. DESIGN: Secondary analysis; instrumentation study. METHODS: The final sample consisted of baseline stopwatch UST scores and measurements of comparison variables from 47 participants in a randomized clinical trial of 3 approaches to pelvic floor training for patients with urinary incontinence following radical prostatectomy. The sample size provided 80% power to detect correlations of moderate strength or higher. The stopwatch UST was conducted in an examination room at the study site by trained study personnel (MP, ADC, JP, SM). Measurements of comparison variables were obtained from 3 instruments: 24-hour pad test, Broome pelvic muscle self-efficacy scale, and 3-day bladder diary. Relationships among study variables were evaluated with Pearson correlation coefficients. RESULTS: Stopwatch UST scores were moderately correlated with 24-hour urine leakage on the 24-hour pad test (r = 0.35, P < .05), the most robust comparison measure. Correlations between stopwatch UST scores and all other comparison measures were in the appropriate direction, although weak, and did not reach statistical significance. CONCLUSION: Findings suggest that the stopwatch UST may be a valid index of pelvic floor muscle strength in men following radical prostatectomy. With further testing, the stopwatch UST could become a valuable clinical tool for assessing pelvic floor muscle strength in radical prostatectomy patients with urinary incontinence. PMID- 22825577 TI - Management of poor postictal suppression during electroconvulsive therapy with propofol anesthesia: a report of two cases. AB - There is increasing evidence that a greater degree of postictal suppression (the abruptness and magnitude of the EEG voltage drop at the end of the seizure) may be associated with better clinical response to electroconvulsive therapy. Retrospective studies have shown better postictal suppression when propofol is used for induction rather than the more commonly used methohexital. We report two patients in whom poor postictal suppression was rectified by switching from methohexital to propofol. The clinical significance of this improvement in postictal suppression is unclear, and prospective studies will be needed to clarify any clinical benefits. PMID- 22825578 TI - The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque. AB - RATIONALE: The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects. OBJECTIVES: Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. RESULTS: PQCA attenuated a scopolamine induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies. CONCLUSIONS: These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease. PMID- 22825579 TI - Residual dopamine receptor desensitization following either high- or low-dose sub chronic prior exposure to the atypical anti-psychotic drug olanzapine. AB - RATIONALE: Anti-psychotic drugs are antagonists of dopamine D2 receptors and repeated administration may lead to the development of dopamine receptor supersensitivity. OBJECTIVES: The objective of this study is to investigate the effects of sub-chronic olanzapine treatments upon the induction of dopamine receptor supersensitivity. METHODS: Rats were administered ten daily low or high doses of the atypical anti-psychotic drug olanzapine (0.01 or 1.0 mg/kg). After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on five successive days. Five days after the apomorphine sensitization protocol, in separate experiments, either a conditioning test or an apomorphine sensitization test was conducted. RESULTS: During the anti-psychotic treatment the high dose of olanzapine induced profound locomotion suppression, whereas the low dose had no effect upon locomotion. The apomorphine treatments given to the vehicle control group generated locomotor sensitization. This sensitization effect was attenuated by the same degree for both the low or high dose prior olanzapine treatments. Also, the low and high-dose olanzapine pre-treatments diminished subsequent apomorphine-conditioned and apomorphine-sensitized locomotor responses. CONCLUSIONS: The equivalent attenuation of the apomorphine sensitization produced by both olanzapine doses indicates that this effect was unrelated to the direct effects of olanzapine upon locomotion. Furthermore, the persistence of the desensitization effects well after the termination of the olanzapine treatments is indicative of a residual desensitization of the dopamine system. These findings are of importance when considering the use of atypical anti-psychotic drugs in the treatment of psychoses and other disorders in which overactivity of the dopamine system is considered a contributory factor. PMID- 22825580 TI - Post-extinction fluoxetine treatment prevents stress-induced reemergence of extinguished fear. AB - RATIONALE: The post-extinction exposure of rats to a sub-conditioning procedure (SCP; i.e., retraining with a shock intensity that is too weak to induce by itself significant fear conditioning) has been reported to provoke the reemergence of extinguished fear. This phenomenon can be prevented by chronic fluoxetine treatment. OBJECTIVES: We sought to examine another potential inducer of fear reemergence, acute stress, in rats and determine whether fluoxetine prevents this phenomenon. METHODS: Because in previous studies fluoxetine was administered before extinction, we first analyzed its effect on the SCP associated reemergence of auditory-cued conditioned fear in rats injected after extinction to avoid any interaction between fluoxetine and extinction learning. Next, we used the same protocol but replaced the SCP with acute stress. RESULTS: We found that the SCP and acute stress, which were carried out 3 weeks after fear extinction, similarly provoked the reemergence of extinguished fear in rats injected with vehicle during the 3-week period. In contrast, the animals treated with fluoxetine during this period behaved similarly to those not exposed to an inducer of fear reemergence. CONCLUSIONS: Our data establish acute stress as an inducer of fear reemergence. The results provide further support for the hypothesis that fluoxetine interfered with mechanisms that reactivated extinguished fear, even when administered after fear extinction. PMID- 22825581 TI - Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. AB - PURPOSE: EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor-resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. EXPERIMENTAL DESIGN: pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC(50) concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. RESULTS: Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. CONCLUSIONS: These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy. PMID- 22825582 TI - The impact of non-drug-related toxicities on the estimation of the maximum tolerated dose in phase I trials. AB - The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non-drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs-the "3+3" dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials. PMID- 22825583 TI - New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. AB - Malignant pleural mesothelioma (MPM) is a highly lethal cancer with limited therapeutic options. Recent work has focused on the frequent somatic inactivation of two tumor suppressor genes in MPM-NF2 (Neurofibromatosis type 2) and the recently identified BAP1 (BRCA associated protein 1). In addition, germline mutations in BAP1 have been identified that define a new familial cancer syndrome, which includes MPM, ocular melanoma, and other cancers. These recent advances may allow screening of high-risk individuals and the development of new therapies that target key pathways in MPM. PMID- 22825584 TI - Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer. AB - PURPOSE: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient derived colorectal cancer (CRC) models. EXPERIMENTAL DESIGN: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis. RESULTS: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance. CONCLUSIONS: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients. PMID- 22825585 TI - CpG island methylator phenotype-positive tumors in the absence of MLH1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis. AB - PURPOSE: Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. EXPERIMENTAL DESIGN: Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival. RESULTS: CIMP(+) was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors. No BRAF V600E mutation was detected. Among the CIMP(+) tumors, 15 (55.6%) were CIMP(+)/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP(+)/MLH1-U tumors had the worst OS and TTR. CONCLUSIONS: Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP(+)/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development. PMID- 22825586 TI - Prevention and treatment of type 1 diabetes mellitus by the manipulation of invariant natural killer T cells. AB - Invariant natural killer T (iNKT) cells are CD1d-restricted T cells with regulatory functions. iNKT cells are numerically and functionally deficient in experimental models of type 1 diabetes mellitus (T1DM). Moreover, various experimental strategies correcting the defect of or stimulating iNKT cells prevent T1DM. Here, we review the data on the role of iNKT cells in the development of T1DM and discuss indications, obstacles and prospects of the use of iNKT cell manipulations in the prevention and treatment of human T1DM. PMID- 22825587 TI - Serum cytokeratin 18 as a biomarker for gastric cancer. AB - Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleaved CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator. PMID- 22825589 TI - Sex-specific differences in effect size estimates at established complex trait loci. AB - BACKGROUND: Genetic differences between men and women may contribute to sex differences in prevalence and progression of many common complex diseases. Using the WTCCC GWAS, we analysed whether there are sex-specific differences in effect size estimates at 142 established loci for seven complex diseases: rheumatoid arthritis, type 1 diabetes (T1D), Crohn's disease, type 2 diabetes (T2D), hypertension, coronary artery disease and bipolar disorder. METHODS: For each Single nucleotide polymorphism (SNP), we calculated the per-allele odds ratio for each sex and the relative odds ratios (RORs; the effect size is higher in men with ROR greater than one). RORs were then meta-analysed across loci within each disease and across diseases. RESULTS: For each disease, summary RORs were not different from one, but there was between-SNP heterogeneity in the RORs for T1D and T2D. Four loci in T1D, three in Crohn's disease and three in T2D showed differences in the genetic effect between men and women (P<0.05). We probed these differences in additional independent replication samples for T1D and T2D. The differences remained for the T1D loci CTSH, 17q21 and 20p13 and the T2D locus BCL11A, when WTCCC data and replication data were meta-analysed. Only CTSH showed different genetic effect between men and women in the replication data alone. CONCLUSION: Our results exclude the presence of large and frequent differences in the effect size estimates between men and women for the established loci in the seven common diseases explored. Documenting small differences in genetic effects between men and women requires large studies and systematic evaluation. PMID- 22825590 TI - Are behavioural risk factors to be blamed for the conversion from optimal blood pressure to hypertensive status in Black South Africans? A 5-year prospective study. AB - BACKGROUND: Longitudinal cohort studies in sub-Saharan Africa are urgently needed to understand cardiovascular disease development. We, therefore, explored health behaviours and conventional risk factors of African individuals with optimal blood pressure (BP) (<= 120/80 mm Hg), and their 5-year prediction for the development of hypertension. METHODS: The Prospective Urban Rural Epidemiology study in the North West Province, South Africa, started in 2005 and included African volunteers (n = 1994; aged > 30 years) from a sample of 6000 randomly selected households in rural and urban areas. RESULTS: At baseline, 48% of the participants were hypertensive (>= 140/90 mmHg). Those with optimal BP (n = 478) were followed at a success rate of 70% for 5 years (213 normotensive, 68 hypertensive, 57 deceased). Africans that became hypertensive smoked more than the normotensive individuals (68.2% vs 49.8%), and they also had a greater waist circumference [ratio of geometric means of 0.94 cm (95% CI: 0.86-0.99)] and greater amount of gamma-glutamyltransferase [0.74 U/l (95% CI: 0.62-0.88)] at baseline. The 5-year change in BP was independently explained by baseline gamma glutamyltransferase [R(2) = 0.23, beta = 0.13 U/l (95% CI: 0.01-0.19)]. Alcohol intake also predicted central systolic BP and carotid cross-sectional wall area (CSWA) at follow-up. Waist circumference was another predictor of BP changes [beta = 0.18 cm (95% CI: 0.05-0.24)] and CSWA. HIV infection was inversely associated with increased BP. CONCLUSIONS: During the 5 years, 24% of Africans with optimal BP developed hypertension. The surge in hypertension in Africa is largely explained by modifiable risk factors. Public health strategies should focus aggressively on lifestyle to prevent a catastrophic burden on the national health system. PMID- 22825591 TI - Innate interferons inhibit allergen and microbial specific T(H)2 responses. AB - Several studies provided evidence of innate interferons (IFNs) regulating T(H)2 cytokine production using purified CD4(+) memory cells and T(H)2 polarisation via interleukin-4 (IL-4). Vitally, none of these previous studies examined IFN attenuation of T(H)2 responses to allergen or antigen. This study therefore sought to investigate the abrogation of specific allergen- and antigen-stimulated T(H)2 response in peripheral blood mononuclear cells (PBMC) derived from 12 sensitised individuals by IFN-beta and IFN-lambda. PBMC were cultured in the presence of house dust mite (HDM) allergen, rhinovirus (RV), influenza vaccine and tetanus toxoid (TT)+/-either IFN-beta or IFN-lambda for 3 and 5 days. IFN gamma, IL-5 and IL-13 protein levels were measured by ELISA. Quantitative PCR (qPCR) was used to investigate induction of genes involved in control of T(H)2 cytokines. No alteration in T(H)1 IFN-gamma allergen/antigen response was observed with addition of IFN-beta or IFN-lambda. Consistent abrogation of T(H)2 response to HDM and influenza was observed with IFN-beta at both time points; attenuation was observed by day 5 with RV and TT. IFN-lambda had no consistent effect on T(H)2 production except in the presence of RV (multiplicity of infection=5); a decrease in IL-5 alone was observed in the presence of trivalent inactivated influenza vaccine. GATA binding protein 3 (GATA3) and suppressors of cytokine signalling3 mRNA were differentially regulated in HDM and influenza stimulated cultures+/-IFN-beta. We concluded that IFN-beta produced a strong and consistent abrogation of T(H)2 cytokine production in the presence of a range of allergen and antigen stimulants. PMID- 22825592 TI - It's NOT FAIR! Or is it? The promise and the tyranny of evidence-based performance assessment. AB - Evidence-based medicine (EBM), by its ability to decrease irrational variations in health care, was expected to improve healthcare quality and outcomes. The utility of EBM principles evolved from individual clinical decision-making to wider foundational clinical practice guideline applications, cost containment measures, and clinical quality performance measures. At this evolutionary juncture one can ask the following questions. Given the time-limited exigencies of daily clinical practice, is it tenable for clinicians to follow guidelines? Whose or what interests are served by applying performance assessments? Does such application improve medical care quality? What happens when the best interests of vested parties conflict? Mindful of the constellation of socially and clinically relevant variables influencing health outcomes, is it fair to apply evidence based performance assessment tools to judge the merits of clinical decision making? Finally, is it fair and just to incentivize clinicians in ways that might sway clinical judgment? To address these questions, we consider various clinical applications of performance assessment strategies, examining what performance measures purport to measure, how they are measured and whether such applications demonstrably improve quality. With attention to the merits and frailties associated with such applications, we devise and defend criteria that distinguish between justice-sustaining and justice-threatening performance-based clinical protocols. PMID- 22825594 TI - Skeletal muscle alpha-actin diseases (actinopathies): pathology and mechanisms. AB - Mutations in the skeletal muscle alpha-actin gene (ACTA1) cause a range of congenital myopathies characterised by muscle weakness and specific skeletal muscle structural lesions. Actin accumulations, nemaline and intranuclear bodies, fibre-type disproportion, cores, caps, dystrophic features and zebra bodies have all been seen in biopsies from patients with ACTA1 disease, with patients frequently presenting with multiple pathologies. Therefore increasingly it is considered that these entities may represent a continuum of structural abnormalities arising due to ACTA1 mutations. Recently an ACTA1 mutation has also been associated with a hypertonic clinical presentation with nemaline bodies. Whilst multiple genes are known to cause many of the pathologies associated with ACTA1 mutations, to date actin aggregates, intranuclear rods and zebra bodies have solely been attributed to ACTA1 mutations. Approximately 200 different ACTA1 mutations have been identified, with 90 % resulting in dominant disease and 10 % resulting in recessive disease. Despite extensive research into normal actin function and the functional consequences of ACTA1 mutations in cell culture, animal models and patient tissue, the mechanisms underlying muscle weakness and the formation of structural lesions remains largely unknown. Whilst precise mechanisms are being grappled with, headway is being made in terms of developing therapeutics for ACTA1 disease, with gene therapy (specifically reducing the proportion of mutant skeletal muscle alpha-actin protein) and pharmacological agents showing promising results in animal models and patient muscle. The use of small molecules to sensitise the contractile apparatus to Ca(2+) is a promising therapeutic for patients with various neuromuscular disorders, including ACTA1 disease. PMID- 22825595 TI - Mapping the synthesis of low nuclearity polyoxometalates from octamolybdates to Mn-Anderson clusters. AB - A comprehensive study of the isomer-independent synthesis of TRIS ((HOCH(2))(3)CNH(2)) Mn-Anderson compounds from Na(2)MoO(4).2H(2)O, via the corresponding octamolybdate species, is presented. Three octamolybdate salts of [Mo(8)O(26)](4-) in the beta-isomer form, with tetramethylammonium (TMA), tetraethylammonium (TEA) and tetrapropylammonium (TPA) as the counter cation, were synthesised from the sodium molybdate starting material. Fine white powdery products for the three compounds were obtained, which were fully characterised by elemental analysis, TGA, solution and solid state Raman, IR and ESI-MS, revealing a set ratio of Na and organic cations for each of the three compounds; (TMA)(2)Na(2)[Mo(8)O(26)] (1), (TEA)(3)Na(1)[Mo(8)O(26)] (2) and (TPA)(2)Na(2)[Mo(8)O(26)] (3), and the analyses also confirmed that the three compounds all consisted of the octamolybdate in the beta-isomeric form. ESI-MS analyses of 1, 2 and 3 show similar fragmentation for these beta-isomers compared to the previously reported study for the alpha-isomer ((TBA)(4)[alpha Mo(8)O(26)]) (A) in the synthesis of ((TBA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)]) (B), and compounds 1, 2 and 3 were successfully used to synthesise equivalent TRIS Mn-Anderson compounds: (TMA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (4), (TEA)(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (5) and (TPA)(2)Na(1)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (6), as well as Na(3)[MnMo(6)O(18)((OCH(2))(3)CNH(2))(2)] (7). This is the first example where symmetric organically-grafted Mn-Anderson compounds have been synthesised in DMF from anything but the {Mo(8)O(26)} alpha-isomer. PMID- 22825596 TI - The right medicine for World Drug Day. PMID- 22825597 TI - Novel lymphoblastoid cell lines from primary neoplasms of the upper aero digestive tract. PMID- 22825593 TI - Brain dendritic cells: biology and pathology. AB - Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. In their quiescent and mature form, the presentation of self-antigens by DC leads to tolerance; whereas, antigen presentation by mature DC, after stimulation by pathogen-associated molecular patterns, leads to the onset of antigen-specific immunity. DC have been found in many of the major organs in mammals (e.g. skin, heart, lungs, intestines and spleen); while the brain has long been considered devoid of DC in the absence of neuroinflammation. Consequently, microglia, the resident immune cell of the brain, have been charged with many functional attributes commonly ascribed to DC. Recent evidence has challenged the notion that DC are either absent or minimal players in brain immune surveillance. This review will discuss the recent literature examining DC involvement within both the young and aged steady-state brain. We will also examine DC contributions during various forms of neuroinflammation resulting from neurodegenerative autoimmune disease, injury, and CNS infections. This review also touches upon DC trafficking between the central nervous system and peripheral immune compartments during viral infections, the new molecular technologies that could be employed to enhance our current understanding of brain DC ontogeny, and some potential therapeutic uses of DC within the CNS. PMID- 22825598 TI - Monitoring of substance abuse in India--initiatives & experiences. PMID- 22825588 TI - Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. AB - BACKGROUND: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. METHODS: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174374 deaths or major non-fatal vascular outcomes recorded among 1085949 people in 121 prospective studies. RESULTS: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. CONCLUSION: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. PMID- 22825599 TI - Role of the RT-PCR method in ante-mortem & post-mortem rabies diagnosis. PMID- 22825600 TI - Stem cells in the light of evolution. AB - All organisms depend on stem cells for their survival. As a result, stem cells may be a prerequisite for the evolution of specific characteristics in organisms that include regeneration, multicellularity and coloniality. Stem cells have attracted the attention of biologists and medical scientists for a long time. These provide materials for regenerative medicine. We review in this paper, the link between modern stem cell research and early studies in ancient organisms. It also outlines details on stem cells in the light of evolution with an emphasis on their regeneration potential, coloniality and multicellularity. The information provided might be of use to molecular biologists, medical scientists and developmental biologists who are engaged in integrated research involving the stem cells. PMID- 22825601 TI - Establishment & characterization of lymphoblastoid cell lines from patients with multiple primary neoplasms in the upper aero-digestive tract & healthy individuals. AB - BACKGROUND & OBJECTIVES: A major drawback for genetic studies as well as long term genotype-phenotype correlation studies in cancer is lack of representative human cell lines providing a continuous source of basic biomolecules and a system to carry out various experimental investigations. This can be overcome to some extent by establishing lymphoblastoid cell lines (LCLs) by infecting peripheral blood lymphocytes with Epstein Barr virus (EBV) which is known to immortalize human resting B cells in vitro giving rise to actively proliferating B lymphoblastoid cell lines. The present study involves preparation and characterization of LCLs generated from patients with multiple primary neoplasms (MPN) of upper aero-digestive tract (UADT). METHODS: Thirty seven LCLs were established from UADT MPN patients and healthy age, sex and habit matched controls using EBV crude stock. Characterization was done with respect to expression of CD-19 (Pan B-cell marker), CD3 (T cell specific marker), CD56 (NK cell specific marker), cell morphology, ploidy analysis, genotype and gene expression comparison with the parent lymphocytes. RESULTS: LCLs showed rosette morphology with doubling time of approximately 24 h. Ploidy analysis showed diploid DNA content which was maintained for at least 30 population doublings. When compared with parent lymphocytes there appeared no change at genetic and gene expression level. INTERPRETATION & CONCLUSIONS: Our results show that lymphoblastoid cell lines are a good surrogate of isolated lymphocytes bearing their close resemblance at genetic and phenotypic level to parent lymphocytes and are a valuable resource for understanding genotype-phenotype interactions. PMID- 22825602 TI - Changing pattern of substance abuse in patients attending a de-addiction centre in north India (1978-2008). AB - BACKGROUND & OBJECTIVES: The patterns of abused psychoactive substances change over time, and it is important to document such changes. The present retrospective study was carried out to document these changes in patients registered in a de-addiction centre in north India over three decades. METHODS: Case notes of all patients registered in the centre from September 1978 till December 31, 2008 were reviewed. Comparisons were made among three decades (1978 1988, 1989-1998, and 1999-2008). RESULTS: The number of registered subjects increased eight-fold over the decades, and age of the subjects presenting for the treatment decreased. The percentages of subjects presenting for the treatment with opioid dependence were 36.8 per cent (n=204), 42.9 per cent (n=809) and 53.2 per cent (n=2219), respectively for the three decades (P<0.001). The proportion of subjects using natural opioids decreased over the three decades (47.4, 26.5 and 18.3%; P<0.001), with a concomitant emergence and/or increase of newer and prescription opioids such as buprenorphine, codeine and dextropropoxyphene. Dependence on tobacco and sedative-hypnotics also increased, and inhalant abuse was reported especially in the third decade. Polysubstance dependence increased significantly over the decades (P<0.001). INTERPRETATION & CONCLUSIONS: Our results showed major shifts in the patterns of substance abuse in clinic attending patients in north India over the three decades from 1978 till 2008. These have important implications for all the stakeholders concerned with combating the challenge of psychoactive substance abuse in our society. PMID- 22825603 TI - Role of reverse transcriptase polymerase chain reaction for the diagnosis of human rabies. AB - BACKGROUND & OBJECTIVES: Traditionally, rabies diagnosis is made by demonstration of rabies viral antigen by direct immunofluorescence (DIF) and mouse inoculation test (MIT). The present study was carried out to evaluate the role of reverse transcriptase-polymerase chain reaction (RT-PCR) in comparison with these conventional techniques for the diagnosis of rabies. METHODS: Skin biopsies, corneal impression smears and saliva sample were collected ante-mortem and brain tissue and CSF were collected post-mortem from ten clinically suspected rabies patients. DIF, Seller staining, MIT and RT-PCR were performed on the patients' samples for the diagnosis of rabies. The ability of RT-PCR to detect rabies virus earlier as compared to other assays was tested both for reference virus as well as clinical isolates. RESULTS: All samples taken ante-mortem were negative for DIF test. Six of 10 post-mortem brain tissues of the clinically suspected patients were positive both by RT-PCR and MIT, of these six, five were positive by DIF test and four were positive by Seller stain. RT-PCR could detect the rabies virus earlier as compared to DIF, both from clinical isolates and fixed rabies virus. INTERPRETATION & CONCLUSIONS: The present results showed 100 per cent sensitivity and specificity of RT-PCR as compared to 83.3 per cent of DIF and 66.7 per cent of Sellers stain for diagnosis of rabies. RT-PCR also detected rabies viral infection earlier as compared to conventional tests and can also be used on ante-mortem samples. Thus, the present study shows the usefulness of RT PCR as an alternative to MIT for the confirmation of rabies diagnosis. PMID- 22825604 TI - Expression of androgen receptor in breast cancer & its correlation with other steroid receptors & growth factors. AB - BACKGROUND & OBJECTIVES: Breast cancer is the second most common malignancy in Indian women. Among the members of the steroid receptor superfamily the role of estrogen and progesterone receptors (ER and PR) is well established in breast cancer in predicting the prognosis and management of therapy, however, little is known about the clinical significance of androgen receptor (AR) in breast carcinogenesis. The present study was aimed to evaluate the expression of AR in breast cancer and to elucidate its clinical significance by correlating it with clinicopathological parameters, other steroid receptors (ER and PR) and growth factors receptors (EGFR and CD105). METHODS: Expression of AR, ER, PR, epidermal growth factor receptor (EGFR) and endoglin (CD105) was studied in 100 cases of breast cancer by immunohistochemistry (IHC). Risk ratio (RR) along with 95% confidence interval (CI) was estimated to assess the strength of association between the markers and clinicopathological characteristics. Categorical principal component analysis (CATPCA) was applied to obtain new sets of linearly combined expression, for their further evaluation with clinicopathological characteristics (n=100). RESULTS: In 31 cases presenting with locally advanced breast cancer (LABC), the expression of AR, ER, PR, EGFR and CD105 was associated with response to neoadjuvant chemotherapy (NACT). The results indicated the association of AR+ (P=0.001) and AR+/EGFR- (P=0.001) with the therapeutic response to NACT in LABC patients. The AR expression exhibited maximum sensitivity, specificity and likelihood ratio of positive and negative test. The present results showed the benefit of adding AR, EGFR and CD105 to the existing panel of markers to be able to predict response to therapy. INTERPRETATION & CONCLUSIONS: More studies on the expression profiles of AR+, AR+/CD105+ and AR+/EGFR- in larger set of breast cancer patients may possibly help in confirming their predictive role for therapeutic response in LABC patients. PMID- 22825605 TI - A novel autologous stem cell procedure for the treatment of aplastic anaemia using reprogrammed mature adult cells: a pilot study. AB - BACKGROUND & OBJECTIVES: Aplastic anaemia is a life threatening rare bone marrow failure disorder. The underlying haematopoietic cellular deficit leads to haemorrhage, infection and severe anaemia. The treatment of choice for this haematological condition is allogeneic bone marrow transplantation from fully matched HLA sibling. Though this procedure is curative in the majority of young patients with aplastic anaemia, extending this benefit to older patients or those lacking a family donor remains a major challenge. Herein, the safety and efficacy of infusing autologous retrodifferentiated haematopoietic stem cells (RHSC) into four patients with aplastic anaemia without the use of any pre- or post conditioning regimen including immunosuppression is described. METHODS: Un mobilized, mononuclear cells were harvested from four patients with acquired aplastic anaemia by aphaeresis. Mononuclear cells of patients were cultured with purified monoclonal antibody against the monomorphic regions of the beta chain of MHC class II antigens (Clone CR3/43) for 3 h, to obtain autologous RHSC. Autologous RHSC were washed and infused into the four patients without the use of any pre- or post-conditioning regimen. Thereafter, the efficacy (engraftment) of autologous RHSC was assessed in these patients. RESULTS: Following single infusion of the autologous RHSC, two of the four patients with aplastic anaemia become transfusion independent for more than seven years. Karyotyping and G banding analysis prior and post-procedure in all patients remained the same. INTERPRETATION & CONCLUSIONS: The findings of this pilot study demonstrated the functional utility of reprogrammed fully differentiated adult cells into pluripotent stem cells with extensive repopulation potentials in a human setting and without any pre- or post-conditioning regimen, including immunosuppression. This autologous approach of stem cell creation may broaden the curative potentials of stem cell therapy to a wider population of patients with aplastic anaemia, including many patients suffering from other haematological and non haematological disorders. PMID- 22825606 TI - Prevalence of dental fluorosis & dental caries in association with high levels of drinking water fluoride content in a district of Gujarat, India. AB - BACKGROUND & OBJECTIVES: Endemic fluorosis resulting from high fluoride concentration in groundwater is a major public health problem in India. This study was carried out to measure and compare the prevalence of dental fluorosis and dental caries in the population residing in high and normal level of fluoride in their drinking water in Vadodara district, Gujarat, India. METHODS: A cross sectional study was conducted in Vadodara district, six of the 261 villages with high fluoride level and five of 1490 with normal fluoride level in drinking water were selected. The data collection was made by house-to-house visits twice during the study period. RESULTS: The dental fluorosis prevalence in high fluoride area was 59.31 per cent while in normal fluoride area it was 39.21 per cent. The prevalence of dental caries in high fluoride area was 39.53 per cent and in normal fluoride area was 48.21 per cent with CI 6.16 to 11.18. Dental fluorosis prevalence was more among males as compared to females. Highest prevalence of dental fluorosis was seen in 12-24 yr age group. INTERPRETATION & CONCLUSIONS: The risk of dental fluorosis was higher in the areas showing more fluoride content in drinking water and to a lesser degree of dental caries in the same area. High fluoride content is a risk factor for dental fluorosis and problem of dental fluorosis increased with passage of time suggesting that the fluoride content in the water has perhaps increased over time. Longitudinal studies should be conducted to confirm the findings. PMID- 22825607 TI - Analysis of calpain-3 protein in muscle biopsies of different muscular dystrophies from India. AB - BACKGROUND & OBJECTIVES: Calpain-3, a Ca [2]+ -dependent protease has been implicated in the pathology of neuromuscular disorders (NMDs). The current study aimed to analyze calpain-3 expression in cases diagnosed as muscular dystrophy from the Indian population. METHODS: Calpain-3 Western blot analysis in muscle biopsies of immunohistochemically confirmed cases of Duchenne muscular dystrophy (DMD) (n=10), dysferlinopathy (n=30) and sarcoglycanopathy (n=8) was carried out. Calpain-3 Western blotting was also used in a blinded study to identify cases of calpain-3 deficiency in 28 NMD patients with potential muscular dystrophy. RESULTS: Calpain-3 appeared as a full length 94 kDa band with an autolytic product (~60 kDa) on Western blots with antibody NCL-CALP-12A2 (Ab-2). Eight of the 10 DMD samples showed absence of 94 kDa band but presence of 60 kDa band while one case of sarcoglycanopathy showed absence of both. Twenty one of the 30 dysferlinopathy samples showed both bands while six showed only the 60 kDa band and three showed absence of both. In the blinded study, five NMD cases with potential muscular dystrophy that showed complete absence of both bands in retrospect exhibited clinical features of limb girdle muscular dystrophy 2A (LGMD2A). INTERPRETATION & CONCLUSIONS: While the study revealed a consistent pattern of calpain-3 in DMD, one sarcoglycanopathy and three dysferlinopathy samples exhibited secondary reduction in calpain-3. It was recognized that both calpain-3 bands should be considered to confirm calpain deficiency. Further, western blot offers an economical and fast preliminary screening method for LGMD2A especially in cases of complete absence of calpain-3 prior to conclusive diagnosis by genetic testing. PMID- 22825609 TI - Absolute lymphocyte count as a surrogate marker for CD4 counts after six months of HAART initiation in a resource-limited setting in India. AB - BACKGROUND & OBJECTIVES: Owing to the ever-expanding access to HAART (highly active anti-retroviral therapy) in resource-limited settings, there is a need to evaluate alternate markers like absolute lymphocyte count (ALC) as a surrogate for CD4 counts. This study was done to assess the usefulness of ALC as a surrogate marker for CD4 counts in monitoring HIV-infected patients after HAART initiation. METHODS: In this study, 108 HIV-positive adult patients of both sexes fulfilling the inclusion criteria were included. CD4 and ALC were recorded at baseline. After initiation on HAART, these patients were followed up at three month intervals. RESULTS: ALC and CD4 counts were positively correlated (Spearman correlation coefficient= 0.553). After six months of HAART, the sensitivity of an ALC increase as a marker for CD4 count increase at six months was 82 per cent, specificity was 100 per cent, PPV was 100 per cent and NPV was 31 per cent. Area under the corresponding ROC curve for CD4 increase of >100 cells/MUl was 0. 825 +/- 0.053. INTERPRETATION & CONCLUSIONS: ALC may be a useful surrogate marker in predicting an increase in CD4 counts as a response to HAART, but of questionable value in predicting a decrease in CD4 counts. PMID- 22825608 TI - A human corneal endothelium equivalent constructed with acellular porcine corneal matrix. AB - BACKGROUND & OBJECTIVES: Artificial corneal endothelium equivalents can not only be used as in vitro model for biomedical research including toxicological screening of drugs and investigation of pathological corneal endothelium conditions, but also as potential sources of grafts for corneal keratoplasty. This study was aimed to demonstrate the feasibility of constructing human corneal endothelium equivalents using human corneal endothelial cells and acellular porcine corneal matrix. METHODS: Porcine corneas were decellularized with sodium dodecyl sulphate (SDS) solution. Human corneal endothelial cells B4G12 were cultured with leaching liquid extracted from the acellular porcine corneal matrix, and then cell proliferative ability was evaluated by MTT assay. B4G12 cells were transplanted to a rat corneal endothelial deficiency model to analyze their in vivo bio-safety and pump function, and then seeded and cultured on acellular porcine corneal matrix for two wk. Corneal endothelium equivalents were analyzed using HE staining, trypan blue and alizarin red S co-staining, immunofluorescence and corneal swelling assay. RESULTS: The leaching liquid from acellular porcine corneal matrix had little influence on the proliferation ability of B4G12 cells. Animal transplantation of B4G12 cells showed that these cells had similar function to the native cells without causing a detectable immunological reaction and neoplasm in vivo. These formed a monolayer covering the surface of the acellular porcine corneal matrix. Trypan blue and alizarin red S co-staining showed that B4G12 cells were alive after two wk in organ culture and cell boundaries were clearly delineated. Proper localizations of ZO-1 and Na+/K+ ATPase were detected by immunofluorescence assay. Functional experiments were conducted to show that the Na+/K+ ATPase inhibitor ouabain could block the ionic-pumping function of this protein, leading to persistent swelling of 51.7 per cent as compared to the control. INTERPRETATION & CONCLUSIONS: Our findings showed that B4G12 cells served as a good model for native corneal endothelial cells in vivo. Corneal endothelium equivalents had properties similar to those of native corneal endothelium and could serve as a good model for in vitro study of human corneal endothelium. PMID- 22825610 TI - Evaluation of an immunochromatographic test for discrimination between Mycobacterium tuberculosis complex & non tuberculous mycobacteria in clinical isolates from extra-pulmonary tuberculosis. AB - BACKGROUND & OBJECTIVES: Accurate diagnosis of tuberculosis (TB) is crucial to facilitate early treatment of the patients, and to reduce its spread. Clinical presentation of Mycobacterium tuberculosis complex (MTBC) and non tuberculous mycobacteria (NTM) may or may not be the same, but the treatment regimen is always different for both the infections. Differentiation between MTBC and NTM by routine laboratory methods is time consuming and cumbersome. This study was aimed to evaluate an immunochromatographic test (ICT), based on mouse monoclonal anti MPT64, for simple and rapid discrimination between MTBC and NTM in clinical isolates from extra-pulmonary tuberculosis cases. METHODS: A total of 800 clinical samples were collected from patients suspected to have extra-pulmonary tuberculosis. Preliminary diagnosis has been done by direct Ziehl-Neelsen (ZN) staining followed by culture in BACTEC system. A total of 150 clinical isolates, which were found positive in BD 460 TB system during September 2009 to September 2010 were selected for the screening by ICT test. p-nitro-alpha-acetylamino- beta hydroxy propiophenone (NAP) test was performed for differentiation of MTBC and NTM. M. tuberculosis complex was further confirmed by IS6110 PCR of BACTEC culture positive isolates, this served as the reference method for MTBC identification and comparative evaluation of the ICT kit. RESULTS: Of the 150 BACTEC culture positive isolates tested by ICT kit, 101 (67.3%) were found positive for MTBC and remaining 49 (32.7%) were considered as NTM. These results were further confirmed by IS6110 PCR that served as the reference method for detection of MTBC. H 37 Rv reference strain was taken as a control for ICT test and IS6110 PCR. The reference strain showed the presence of MPT64 antigen band in the ICT test. Similar bands were formed in 101 of 102 MTBC isolates tested, proving 99.1 per cent sensitivity and no bands were detected in 48 (100%) NTM isolates tested, proving 100 per cent specificity of the ICT kit. INTERPRETATION & CONCLUSIONS: Our findings show that ICT test can be used on direct culture positive specimens. It does not require any special equipment, is simple and less time consuming. It can easily discriminate between MTBC and NTM and thus can help in appropriate management of tuberculosis. PMID- 22825611 TI - A ten year analysis of multi-drug resistant blood stream infections caused by Escherichia coli & Klebsiella pneumoniae in a tertiary care hospital. AB - BACKGROUND & OBJECTIVES: Extensive use of antibiotics has added to the escalation of antibiotic resistance. This study was undertaken to evaluate the association, if any between antibiotic use and resistance in a hospital setting, and also detect the predominant mechanism of antibiotic resistance in Escherichia coli and Klebsiella pneumoniae over a period of 10 years. METHODS: In a retrospective study of 10 years, a total of 77,618 blood culture samples from 2000 to 2009 from indoor patients were screened and those yielding E. coli and K. pneumoniae were included in the study. Antibiotic susceptibility records as well as the percentage of ESBL producers were noted. A total of 423 isolates of 2009 were also screened for AmpC and carbapenemase production. Antibiotic consumption data of 10 years were analysed. RESULTS: ESBL producing E. coli increased from 40 per cent in 2002 to 61 per cent in 2009, similarly there was a significant (P<0.05) rise in resistance to cefotaxime (75 to 97%), piperacillin-tazobactum (55- 84%) and carbapenem (2.4-52%) in K. pneumoniae. A significant (P<0.05) association was observed between resistance and consumption of carbapenem and piperacillin and tazobactum consumption in K. pneumonia. INTERPRETATION & CONCLUSIONS: Our study demonstrated a rise in consumption and resistance to broad spectrum antimicrobial agents and also established an association between consumption and resistance to these antibiotics. Over a period of 10 years, the emergence of pan-resistance in K. pneumoniae could be due to the production of carbapenemases whereas ESBL production was the common mechanism of resistance in E. coli. This study warrants a directed effort towards continued surveillance and antibiotic stewardship to minimize selection pressure and spread. PMID- 22825612 TI - Antibacterial & antitoxic effects of the cardiovascular drug lacidipine in an animal model. AB - BACKGROUND & OBJECTIVES: Vibrio cholerae produces acute infection by liberating potent enterotoxin, called cholera toxin in human intestine. Cardiovascular drug lacidipine possessing powerful in vitro action against V. cholerae was tested to determine its possible activity against a toxigenic V. cholerae strain in an established animal model. METHODS: In the rabbit intestine four loops were constructed, 3 of which were injected with over night grown V. cholerae 569B culture. Of these, two loops were simultaneously given graded doses (100, 200 MUg) of lacidipine, one was left as such for a positive control. The first loop received sterile medium (negative control). After 18 h, contents of all the loops were examined for accumulation of fluid and number of viable cells. RESULTS: Lacidipine when administrated with live V. cholerae 569B, caused a reduction in the number of viable bacteria along with amount of fluid in the loops. The amount of fluid and number of viable cells were much reduced in the loop that had 200 MUg of lacidipine than the loop that received 100 MUg of the drug. INTERPRETATION & CONCLUSIONS: Lacidipine has distinct inhibitory action against V. cholerae 569B with respect to both viability and production of cholera toxin in the rabbit ileum. Structural modifications of this compound may possibly lead to procurement of new potent antimicrobial drugs. PMID- 22825613 TI - A multiplex PCR assay for the simultaneous identification of virulent & avirulent Bacillus anthracis targeting genes of plasmids & chromosomal DNA. PMID- 22825614 TI - Analysis of humoral responses to proteins encoded by region of difference 1 of Mycobacterium tuberculosis in sarcoidosis in a high tuberculosis prevalence country. PMID- 22825615 TI - Pore size distribution and capacitance in microporous carbons. AB - Modelling shows that the pore size distribution of microporous carbons determined by NLDFT only hides relatively small variations of the surface-related capacitance C/S between 0.7 and 1.3 nm. This suggests again that C/S in TEABF(4) AN is 0.09 +/- 0.01 F m(-2) for our typical carbons, including carbide-based samples. PMID- 22825616 TI - Outcomes of medical malpractice litigation against US physicians. PMID- 22825617 TI - The role of P2Y(14) and other P2Y receptors in degranulation of human LAD2 mast cells. AB - Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y(14) receptor (P2Y(14)R) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2Y(1)R, P2Y(12)R, and P2Y(13)R, were similar, and P2Y(11)R and P2Y(4)R were highly expressed at 5.8- and 3.8-fold of P2Y(1)R, respectively. Least expressed P2Y(2)R was 40-fold lower than P2Y(1)R, and P2Y(6)R and P2Y(14)R were <=50 % of P2Y(1)R. None of the native P2YR agonists alone induced beta-hexosaminidase (beta-Hex) release, but some nucleotides significantly enhanced beta-Hex release induced by C3a or antigen, with a rank efficacy order of ATP > UDPG >= ADP >> UDP, UTP. Although P2Y(11)R and P2Y(4)R are highly expressed, they did not seem to play a major role in degranulation as neither P2Y(4)R agonist UTP nor P2Y(11)R agonists ATPgammaS and NF546 had a substantial effect. P2Y(1)R-selective agonist MRS2365 enhanced degranulation, but ~1,000-fold weaker compared to its P2Y(1)R potency, and the effect of P2Y(6)R agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2Y(14)R, MRS2690, enhanced C3a-induced beta-Hex release, which was inhibited by a P2Y(14)R antagonist, specific P2Y(14)R siRNA and pertussis toxin, suggesting a role of P2Y(14)R activation in promoting human mast cell degranulation. PMID- 22825618 TI - Solid-state synthesis of poly(3',4'-dimethoxy-2,2':5',2"- terthiophene): comparison with poly(terthiophene) and poly(3',4'-ethylenedioxy-2,2':5',2"- terthiophene). AB - A new terthiophene monomer: 3',4'-dimethoxy-2,2':5',2"-terthiophene (TMT) was synthesized and characterized by 1H-NMR, 13C-NMR and FTIR. The solid-state oxidative polymerizations of TMT were performed in various ratios of oxidant (FeCl3) to monomer (TMT). The resulting polymers were characterized by 1H-NMR, FTIR, UV-vis-NIR, GPC, X-ray diffraction, CV, as well as TGA and conductivity measurements. The structure and properties of poly (TMT) were compared with those of polyterthiophene [poly(TT)] and poly (3',4'-ethylenedioxy-2,2':5',2" terthiophene) [poly(TET)] prepared under the same polymerization conditions. After comparative analysis with poly(TT) and poly(TET), the effects of the dimethoxy substituent and FeCl3 on the structural and physicochemical properties of the poly(TMT)s were discussed in depth. The comparison suggested that the dimethoxy-substituted polymer did not display higher crystallinity, thermal stability, conductivity and electrochemical activity than ethylenedioxy substituted one. The results also showed that the effect of FeCl3 on poly(TMT) was similar that seen with the poly(TT), in which the oxidation degree, electrochemical activity and conductivity increased steadily with increasing [FeCl3/[TT] ratio. Furthermore, the poly(TMT) and poly(TT) are mostly made up of dimers with a small amount of higher molecular weight components. PMID- 22825619 TI - Synthesis, characterization, antibacterial and antifungal evaluation of novel monosaccharide esters. AB - A novel series of 3-(2-furyl)acrylate monosaccharide esters Ia-f and menthyloxycarbonyl monosaccharide esters IIa-f were designed and synthesized. The chemical structures of the target compounds were confirmed by IR, 1H- and 13C-NMR and ESI-MS, and the target compounds were investigated for their in vitro antibacterial and antifungal activities. The antibacterial screening results showed that the 3-(2-furyl)acrylate monosaccharide ester derivatives Ia-f were either inactive or only weakly active against the three Gram-positive bacterial strains tested, whereas the menthyloxycarbonyl monosaccharide ester derivatives IIa-f exhibited higher levels of activity, with compound IIe being especially potent. The results of the antifungal screening revealed that compounds Ib, Ie, IIb and IIc displayed potent in vitro activities, whereas If and IIf showed promising activities against all of the microorganisms tested, with If exhibiting levels of activity deserving of further investigation. PMID- 22825620 TI - Ultrasound-promoted one-pot, three-component synthesis of spiro[indoline-3,1' pyrazolo[1,2-b]phthalazine] derivatives. AB - A series of 3'-aminospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazine]-2,5',10' trione derivatives have been synthesized by a one-pot three-component reaction of isatin, malononitrile or ethyl cyanoacetate and phthalhydrazide catalyzed by piperidine under ultrasound irradiation. For comparison the reactions were carried out under both conventional and ultrasonic conditions. In general, improvement in rates and yields were observed when the reactions were carried out under sonication compared with classical conditions. PMID- 22825621 TI - Buddleja officinalis Maximowicz extract inhibits lipid accumulation on adipocyte differentiation in 3T3-L1 cells and high-fat mice. AB - Obesity is a global health problem. It is also known to be a risk factor for the development of metabolic disorders, type 2 diabetes, systemic hypertension, cardiovascular disease, dyslipidemia, and atherosclerosis. In this study, we elucidated that Buddleja officinalis Maximowicz extract significantly inhibited lipid accumulation during 3T3-L1 adipocyte differentiation. Furthermore, Buddleja officinalis Maximowicz extract reduced the body weight gain induced through feeding a high-fat diet to C57BL/6 mice. The treatment of Buddleja officinalis Maximowicz extract significantly reduced the adipose tissue weight to 2.7/100 g of body weight in high-fat mice. When their adipose tissue morphology was investigated for histochemical staining, the distribution of cell size in the high-fat diet groups was hypertrophied compared with those from Buddleja officinalis Maximowicz extract-treated mice. In addition, in Buddleja officinalis Maximowicz extract-treated mice, a significant reduction of serum triglyceride and T-cholesterol was observed at to 21% and 17%, respectively. The discovery of bioactive compounds from diet or dietary supplementation is one of possible ways to control obesity and to prevent or reduce the risks of various obesity-related diseases. These results support that Buddleja officinalis Maximowicz extract is expected to create the therapeutic interest with respect to the treatment of obesity. PMID- 22825622 TI - Supercritical synthesis of biodiesel. AB - The synthesis of biodiesel fuel from lipids (vegetable oils and animal fats) has gained in importance as a possible source of renewable non-fossil energy in an attempt to reduce our dependence on petroleum-based fuels. The catalytic processes commonly used for the production of biodiesel fuel present a series of limitations and drawbacks, among them the high energy consumption required for complex purification operations and undesirable side reactions. Supercritical fluid (SCF) technologies offer an interesting alternative to conventional processes for preparing biodiesel. This review highlights the advances, advantages, drawbacks and new tendencies involved in the use of supercritical fluids (SCFs) for biodiesel synthesis. PMID- 22825623 TI - Bioactivity-guided isolation of ethyl-p-methoxycinnamate, an anti-inflammatory constituent, from Kaempferia galanga L. extracts. AB - This study evaluated the anti-inflammatory effect of Kaempferia galanga (KG) using an activity-guided approach. KG rhizomes were serially extracted with petroleum ether, chloroform, methanol and water. These extracts (2 g/kg each) were tested for their ability to inhibit carrageenan-induced rat paw edema. The chloroform extract was found to exert the highest inhibition (42.9%) compared to control (p < 0.001), hence it was further fractionated by washing serially with hexane, hexane-chloroform (1:1) and chloroform. The chloroform fraction (1 g/kg) showed the highest inhibitory effect (51.9%, (p < 0.001), on carrageenan-induced edema. This chloroform fraction was further fractionated with hexane-chloroform (1:3) and chloroform, and of the two fractions, the hexane-chloroform sub fraction was the most effective in inhibiting edema (53.7%, p < 0.001). GC-MS analysis of the active sub-fraction identified ethyl-p-methoxycinnamate (EPMC) as the major component, which was re-crystallized. EPMC dose-dependently inhibited carrageenan-induced edema with an MIC of 100 mg/kg. Moreover, in an in vitro study, EPMC non-selectively inhibited the activities of cyclooxygenases 1 and 2, with IC50 values of 1.12 uM and 0.83 uM respectively. These results validate the anti-inflammatory activity of KG which may be exerted by the inhibition of cyclooxygenases 1 and 2. EPMC isolated from this plant may be the active anti inflammatory agent. PMID- 22825624 TI - Differentiation of bone marrow-derived mesenchymal stem cells into chondrocytes using chondrocyte extract. AB - Reprogramming cells using cell extracts is an effective method for harvesting cells of interest. The aim of this study was to investigate the chondrogenic transdifferentiation potential of swine bone marrow-derived mesenchymal stem cells (BM-MSCs) by culturing with chondrocyte extract, using monolayer and micromass culture. Chondrogenic-specific markers were detected via reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. After 7 days of induction in monolayer culture, BM-MSCs reversibly permeabilized with streptolysin O (SLO), a bacterial exotoxin that is capable of forming large pores in the plasma membrane of mammalian cells, and expressed chondrocyte-specific genes such as type II collagen (COL II) and aggrecan. A positive protein expression of COL II was also observed. However, BM-MSCs treated without SLO did not express the related genes and proteins. The transition of reprogrammed BM MSCs was lost 14 days later. By using micromass culture, reprogrammed BM-MSCs were able to maintain the change until the 14th day. In summary, permeabilized BM MSCs were transiently transdifferentiated into chondrocytes by co-culturing with the chondrocyte extract. Moreover, a high-density culture method was able to increase the time in which the phenotypic change was maintained. PMID- 22825625 TI - PI3Kgamma activation is required for LPS-induced reactive oxygen species generation in respiratory epithelial cells. AB - OBJECTIVE: In this study, we investigated the molecular basis of reactive oxygen species (ROS) generation induced by lipopolysaccharide (LPS) in A549 cells--an alveolar epithelial cell line. EXPERIMENTAL DESIGN: A549 cells or normal human bronchial epithelial (NHBE) cells were stimulated with LPS. ROS generation was measured in A549 cells or NHBE cells pre-treated with a selective inhibitor of phosphatidylinositol 3-kinase gamma (PI3Kgamma), AS 605240, PI3Kgamma siRNA, or a ROS scavenger, pyridoxamine (PM). RESULTS: Treatment of A549 cells or NHBE cells with LPS caused a significant increase in intracellular ROS generation. Pretreatment with the PI3Kgamma inhibitor, AS 605240 decreased the LPS-induced increase of ROS generation, phosphorylation of Akt, and production of phosphatidyl 3,4,5-trisphosphate in A549 cells. In addition, interference with siRNA for PI3Kgamma significantly reduced LPS-induced ROS generation in A549 cells. Treatment of A549 cells with LPS or hydrogen peroxide increased the nuclear factor-kappaB (NF-kappaB) in the nucleus, accompanying an increase in phosphorylation of inhibitory kappaB-alpha, degradation of the protein, and reduction of cytosolic NF-kappaB. Pretreatment with AS 605240 reduced these LPS induced changes. In addition, pretreatment with PM or N-acetyl cysteine resulted in inhibition of nuclear NF-kappaB activation. CONCLUSION: These results suggest that PI3Kgamma plays a key role in LPS-induced ROS generation in alveolar epithelial cells, thereby activating NF-kappaB. PMID- 22825627 TI - Increased synovial expression of IL-27 by IL-17 in rheumatoid arthritis. AB - OBJECTIVES AND DESIGN: Interleukin (IL) 17 plays an important role in synovial inflammation and bone destruction in rheumatoid arthritis (RA), while IL-27 exerts a regulatory role in T cell-mediated immune responses. Our aim was to study the influence of IL-17 on IL-27 production in RA. MATERIALS AND METHODS: Following injection of IL-17 in the knee joint of CIA mice, synovium was examined for IL-17 and IL-27 expression by western blot, real-time PCR, and immunohistochemistry. IL-17 and IL-27 levels were measured by ELISA in mouse bone marrow-derived dendritic cells (BM-DCs) and in synovial fluid (SF) macrophages from RA patients. RESULTS: IL-17 exacerbated disease progression in CIA mice. Histological analysis showed increased pannus formation associated with cartilage and bone erosion following injection with IL-17. The expression of IL-27 was increased in CIA mice. The expression of IL-17 and IL-27 was increased more in IL 17-injected CIA mice than in control mice. The majority of cells expressing IL-27 were co-localized with synovial macrophages. Increased expression of IL-27 by application of recombinant IL-17 was confirmed in CIA BM-DCs and in SF macrophages from RA patients. CONCLUSION: IL-17 enhanced expression of IL-27 in synovial macrophages from RA patients and CIA mice, indicating an interaction between IL-17 and IL-27 as an autoregulatory mechanism. PMID- 22825626 TI - Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats. AB - OBJECTIVE: To assess effects of postconditioning with the vagal stimulation (VS) on the local and systematic inflammatory responses to acute myocardial ischemia reperfusion injury (IRI). METHODS: Sixty male Sprague-Dawley rats were randomly allocated into three groups: sham group, ischemia reperfusion group (IR group), and postconditioning with the VS group (POVS group). Serum levels of inflammatory cytokines during reperfusion and myocardial levels of inflammatory cytokines in both ischemic and non-ischemic regions at the end of the experiment were assayed. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining. RESULTS: The infarct size was significantly reduced in the POVS group compared to the IR group. Serum levels of TNF-alpha at 30, 60, and 120 min of reperfusion and serum levels of HMGB-1, ICAM-1, IL-1, and IL-6 at 120 min of reperfusion were significantly lower in the POVS group than in the IR group. Myocardial levels of TNF-alpha, HMGB-1, ICAM-1, IL-1, and IL-6 in both ischemic and non-ischemic regions were also significantly reduced in the POVS group compared with the IR group. CONCLUSIONS: Postconditioning with the VS can significantly attenuate the local and systemic inflammatory responses to myocardial IRI, and provide an obvious cardioprotection. PMID- 22825629 TI - The BHLH transcription factor DEC1 plays an important role in the epithelial mesenchymal transition of pancreatic cancer. AB - DEC1 (BHLHE40/Stra13/Sharp2) is a basic helix-loop-helix (bHLH) transcription factor that is involved in the regulation of apoptosis and cell proliferation and the response to hypoxia. Epithelial-mesenchymal transition (EMT) is an important step leading to invasion and migration of various tumor cells, and TGF-beta treatment has been shown to induce cancer cells to undergo EMT. However, the significance of DEC1 in TGF-beta-induced EMT remains unknown. We examined the role of DEC1 in EMT of PANC-1 cells, a human pancreatic cancer cell line. As a result, we found that DEC1 was upregulated by TGF-beta in PANC-1 cells, and regulated the expression and the levels of nuclear, cytoplasmic or membrane localization of EMT-related factors, including phosphorylated Smad3 (pSmad3), snail, claudin-4 and N-cadherin. In the presence of TGF-beta, DEC1 knockdown by siRNA inhibited morphological changes during EMT processes, while TGF-beta induced PANC-1 cells to taken on a spindle-shaped morphology. Furthermore, a combination treatment of DEC1 expression with TGF-beta was closely linked to the migration and invasion of PANC-1 cells. Immunohistochemically, DEC1 and pSmad3 were detected within pancreatic cancer tissues, whereas claudin-4 expression was weaker in the cancer tissues compared with the adjacent non-cancer pancreatic tissues. These findings suggest that DEC1 plays an important role in the regulation of these EMT-related factors in pancreatic cancer. PMID- 22825631 TI - Oblique paraspinal approach for thoracic disc herniations using tubular retractor with robotic holder: a technical note. AB - INTRODUCTION: Symptomatic thoracic disc herniations (TDHs) are uncommon and can be surgically treated. Although transthoracic decompression is considered the gold standard, it is associated with significant comorbidities. In particular, approach via a posterior laminectomy has been associated with poor results. Several strategies have been developed for the resection of TDHs without manipulating the spinal cord. We describe a minimally invasive technique by using 3-D navigation and tubular retractors with the aid of a robotic holder via an oblique paraspinal approach. MATERIALS AND METHODS: The 20-mm working tube via an oblique trajectory through the fascia provides a good surgical field for thoracic discectomy through a microscope. We present our first five patients with TDHs operated using this minimally invasive approach. RESULTS: Neurological symptoms were improved postoperatively, and there were no surgical complications. There was no instability or recurrence during the follow-up period. CONCLUSION: The oblique paraspinal approach may offer an alternative surgical option for treating TDHs. PMID- 22825630 TI - Gait impairment in cervical spondylotic myelopathy: comparison with age- and gender-matched healthy controls. AB - INTRODUCTION: Gait impairment is a primary symptom of cervical spondylotic myelopathy (CSM); however, little is known about specific kinetic and kinematic gait parameters. The objectives of the study were: (1) to compare gait patterns of people with untreated CSM to those of age- and gender-matched healthy controls; (2) to examine the effect of gait speed on kinematic and kinetic parameters. MATERIALS AND METHODS: Sixteen patients with CSM were recruited consecutively from a neurosurgery clinic, and 16 healthy controls, matched to age (+/- 5 years) and gender, were recruited for comparison. Patients and controls underwent three-dimensional gait analysis using a Vicon((r)) motion analysis system, at self-selected speed over a 10-m track. Controls were also assessed at the speed of their CSM match. RESULTS: At self-selected speed, the CSM group walked significantly more slowly, with shorter stride lengths and longer double support duration. They showed significant decreases in several kinematic and kinetic parameters, including sagittal range of motion at the hip and knee, ankle plantarflexion, anteroposterior ground reaction force (GRF) at toe-off, power absorption at the knee in loading response and terminal stance, and power generation at the ankle. At matched speed, the CSM group showed significant decreases in knee flexion during swing, total sagittal knee range of motion, peak ankle plantarflexion and anteroposterior GRF. CONCLUSION AND IMPLICATIONS: The findings suggested that people with CSM have significant gait abnormalities that have not been previously reported. In particular, there are key differences in the motor strategies used in the terminal stance phase of gait that cannot be explained by speed alone. PMID- 22825632 TI - Rheumatoid vertical and subaxial subluxation can be prevented by atlantoaxial posterior screw fixation. AB - PURPOSE: Literature has described a risk for subsequent vertical subluxation (VS) and subaxial subluxation (SAS) following atlantoaxial subluxation in rheumatoid patients; however, the interaction of each subluxation and the radiographic findings for atlantoaxial fixation has not been described. The purpose of this study was to evaluate the effects of two different posterior atlantoaxial screw fixation on the development of subluxation in patients with rheumatoid atlantoaxial subluxation. METHODS: Between 1996 and 2006, rheumatoid patients treated with transarticular fixation and posterior wiring (TA) or C1 lateral mass C2 pedicle screw fixations (SR) in the Nagoya Spine Group hospitals, a multicenter cooperative study group, were included in this study. VS, SAS, craniocervical sagittal alignment, and range of motion (ROM) at the atlantoaxial adjacent segments were investigated to determine whether posterior atlantoaxial screw fixation is a prophylactic or a risk factor for the development of VS and SAS. RESULTS: The mean follow-up was 7.2 years (4-12). No statistically significant difference was observed among the patients treated with either of the procedure during the follow-up period. Of 34 patients who underwent posterior atlantoaxial screw fixation, SAS was observed in 26.5 % during the follow-up period; however, VS was not observed. Postoperative C2-7 angle, and Oc-C1 and C2 3 ROM were significantly different between patients with and without postoperative SAS. The incidence of SAS was 38.9 % for TA and 12.5 % for SR; statistically significant differences were observed in the postoperative C1-2 and C2-7 angles, and C2-3 ROM. CONCLUSIONS: Atlantoaxial posterior screw fixation may be an appropriate prophylactic intervention for VS and SAS if the atlantoaxial joint develops bony fusion following physiological alignment. Compared to TA, SR provided optimal atlantoaxial angle and prevented lower adjacent segment degeneration, thereby reducing SAS. PMID- 22825634 TI - Estimation of the measurement uncertainty in quantitative determination of ketamine and norketamine in urine using a one-point calibration method. AB - An approach was proposed for the estimation of measurement uncertainty for analytical methods based on one-point calibration. The proposed approach is similar to the popular multiple-point calibration approach. However, the standard deviation of calibration was estimated externally. The approach was applied to the estimation of measurement uncertainty for the quantitative determination of ketamine (K) and norketamine (NK) at a 100 ng/mL threshold concentration in urine. In addition to uncertainty due to calibration, sample analysis was the other major source of uncertainty. To include the variation due to matrix effect and temporal effect in sample analysis, different blank urines were spiked with K and NK and analyzed at equal time intervals within and between batches. The expanded uncertainties (k = 2) were estimated to be 10 and 8 ng/mL for K and NK, respectively. PMID- 22825635 TI - Inhibition of arabidopsis hypocotyl elongation by jasmonates is enhanced under red light in phytochrome B dependent manner. AB - Jasmonates are phytohormones derived from oxygenated fatty acids that regulate a broad range of plant defense and developmental processes. In Arabidopsis, hypocotyl elongation under various light conditions was suppressed by exogenously supplied methyl jasmonate (MeJA). Moreover, this suppression by MeJA was particularly effective under red light condition. Mutant analyses suggested that SCF(COI1)-mediated proteolysis was involved in this function. However, MeJA action still remained in the coi1 mutant, and (+)-7-iso-JA-L-Ile, a well-known active form of jasmonate, had a weaker effect than MeJA under the red light condition, suggesting that unknown signaling pathway are present in MeJA-mediated inhibition of hypocotyl elongation. EMS mutant screening identified two MeJA insensitive hypocotyl elongation mutants, jasmonate resistance long hypocotyl 1 (jal1) and jal36, which had mutations in the phytochrome B (PHYB) gene. These analyses suggested that inhibition of hypocotyl elongation by jasmonates is enhanced under red light in phyB dependent manner. PMID- 22825637 TI - Tetrabromobisphenol A: tissue distribution in fish, and seasonal variation in water and sediment of Lake Chaohu, China. AB - Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardants (BFRs). It has been detected in various environment media and has been approved to be high toxic to aquatic organisms. However, the exposure levels of TBBPA in the main watersheds in China have not been investigated sufficiently. In this study TBBPA concentrations in water, sediment and tissues of four fish species from Lake Chaohu were determined. Spatial and temporal distribution patterns of TBBPA in water and sediment, and the relationship among TBBPA concentrations in fish tissues and fish size were analyzed. The results showed that the maximum TBBPA concentration in sediment was 518 ng/g in March 2008. It is almost the highest value than those ever reported anywhere in the world. In lake water, TBBPA level reached the maximum value of 4.87 MUg/L in July. Tissue distributions of TBBPA in four fish species were similar, and the mean concentrations in the fish were in the range of 28.5-39.4 ng/g, much higher than those reported in Japan, Europe, and the United States. The maximum concentrations of TBBPA were found in kidneys where TBBPA concentration was positively correlated with fish size of Cyprinus carpio. Results demonstrated a widespread distribution of TBBPA in Lake Chaohu. The source was mainly inflow rivers near the cities. The distribution coefficient among water, fish, and sediment was 1:28:117. This indicated that sediment was the main repository for TBBPA within Lake Chaohu. Furthermore, TBBPA may pose a potential ecological risk in the lake during summer. PMID- 22825638 TI - The legacy of persistent organic pollutants in Azerbaijan: an assessment of past use and current contamination. AB - Azerbaijan has a history of production and heavy use of organochlorine pesticides (OCPs) with use focused in the main agricultural lowland region centred on the Kur River. Using a number of data sources, including archived reports from several government ministries, we attempt to construct production and use inventories for dichlorodiphenyltrichloroethane (DDT) and HCHs and compare these to scientific estimates of production and use of these chemicals in the 1960s to the 1980s. Notable discrepancies are evident particularly for DDT, with Azeri government records indicating much higher use (147-fold) than that estimated by the international scientific community. Soil and river sediment data from the 1980s and 2000s are also presented. While it is recognised that analytical uncertainties remain high for these older data (generated by GC-ECD), there is some evidence to show a decline in concentrations for some OCPs over this period. Extremely high concentrations of OCPs are evident for soils sampled in the vicinity of obsolete pesticide storage sites (found in numerous locations around the agricultural lowlands) and these levels may pose a health risk to wildlife and humans. River sediment data indicate high levels of both OCPs and polychlorinated biphenyls (PCBs), particularly downstream of the confluence of the two main rivers, the Kur and Araz. Particle-bound annual fluxes from the Kur River into the Caspian Sea are estimated for PCBs and OCPs and these are likely to influence levels observed in local coastal sediments, with agreement between river sediment data generated in the early 2000s and coastal marine sediment data generated from separate studies. We recommend that monitoring efforts should focus on soils in agricultural areas and around pesticide storage and production facilities as these soils will continue to provide a source of POPs to the regional environment. PMID- 22825639 TI - Influence of algal bloom degradation on nutrient release at the sediment-water interface in Lake Taihu, China. AB - Algal bloom could drastically influence the nutrient cycling in lakes. To understand how the internal nutrient release responds to algal bloom decay, water and sediment columns were sampled at 22 sites from four distinct regions of China's eutrophic Lake Taihu and incubated in the laboratory to examine the influence of massive algal bloom decay on nutrient release from sediment. The column experiment involved three treatments: (1) water and sediment (WS); (2) water and algal bloom (WA); and (3) water, sediment, and algal bloom (WSA). Concentrations of dissolved oxygen (DO), total nitrogen (TN), total phosphorus (TP), ammonium (NH (4) (+) -N), and orthophosphate (PO (4) (3-) -P) were recorded during incubation. The decay of algal material caused a more rapid decrease in DO than in the algae-free controls and led to significant increases in NH (4) (+) -N and PO (4) (3-) -P in the water. The presence of algae during the incubation had a regionally variable effect on sediment nutrient profiles. In the absence of decaying algae (treatment WS), sediment nutrient concentrations decreased during the incubation. In the presence of blooms (WSA), sediments from the river mouth released P to the overlying water, while sediments from other regions absorbed surplus P from the water. This experiment showed that large-scale algal decay will dramatically affect nutrient cycling at the sediment-water interface and would potentially transfer the function of sediment as "container" or "supplier" in Taihu, although oxygen exchange with atmosphere in lake water was stronger than in columns. The magnitude of the effect depends on the physical-chemical character of the sediments. PMID- 22825641 TI - Extracorporeal shock-wave therapy reduces progression of knee osteoarthritis in rabbits by reducing nitric oxide level and chondrocyte apoptosis. AB - INTRODUCTION: The goal for treating osteoarthritis (OA) is finding ways to decrease joint pain and dysfunction and prevent and slow the cartilage degeneration. Extracorporeal shock-wave therapy (ESWT) has been found to improve motor dysfunction and ameliorate pain with OA in animals. However, few studies have found that it can prevent and slow joint degeneration in vivo. The aim of study was to investigate the effect of ESWT on OA in rabbit. MATERIALS AND METHODS: A total of 30 male New Zealand white rabbits were divided into 3 groups: control, OA induced by anterior cruciate ligament transaction (ACLT), and ALCT plus ESWT. The animals were killed at 4 and 8 weeks. Nitric oxide (NO) level was measured in the synovial cavity of knee joints, and cartilage sections were graded macroscopically by a Mankin scoring system. Chondrocyte apoptosis was investigated by flow cytometry and the expression of active caspase 3 by indirect immunohistochemistry. RESULTS: ESWT significantly reduced the NO level in the synovial cavity of knee joints (P < 0.05) and chondrocyte apoptosis (P < 0.05) of rabbits with OA. ESWT treatment significantly decreased the severity of cartilage lesions at both times as compared to rabbits with OA alone (P < 0.05). CONCLUSION: ESWT reduced the progression of OA in rabbits. This effect may be related to decreased level of NO and is likely mediated by reduced chondrocyte apoptosis. ESWT may be a useful treatment for knee OA. PMID- 22825640 TI - HCH contamination from former pesticide production in Brazil--a challenge for the Stockholm Convention implementation. AB - Hexachlorocyclohexane (HCH) isomers (alpha-, beta- and gamma- HCH [lindane]) were recently added to the list of persistent organic pollutants regulated by the Stockholm Convention, and therefore, the legacy of HCH and lindane production has become an issue of global relevance. The production of lindane with the much larger quantities of associated waste isomers has generated large waste deposits and contaminated sites. This article presents an overview of HCH-polluted sites in Brazil as a basis for further activities related to the Stockholm Convention. The locations of HCH stockpiles and contaminated sites in Brazil arising from production and formulation have been compiled and mapped. This shows that the measures taken over the past 25 years have not resulted in remediation of the HCH pollution. An exposure risk study has been summarised for one major site and is included to demonstrate the contemporary relevance of the contamination. Major site remediation efforts are planned at one site but people live close to several other sites, and there is an urgent need of further assessments and remediation to ensure the protection of human health and the environment. The Stockholm Convention requires a systematic approach and should be adopted for the assessment of all sites and appropriate isolation/remediation measures should be facilitated. The appropriate planning of these activities for the production site in Rio de Janeiro could be a positive contribution for Rio+20 highlighting that green economy and sustainable production also include the appropriate management of legacies of historic production of an industrial sector (here the organochlorine industry). PMID- 22825642 TI - Overexpression of hexokinase-2 in giant cell tumor of bone is associated with false positive in bone tumor on FDG-PET/CT. AB - INTRODUCTION: The aim of the current study was to evaluate the usefulness of maximum standardized uptake value (SUV(max)) in 2-deoxy-2-F(18)-fluoro-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) for preoperative differential diagnosis between benign and malignant bone tumors. MATERIALS AND METHODS: Seventy-nine patients with bone tumors were examined by FDG-PET prior to histopathological diagnosis. The SUV(max) was calculated and compared between benign and malignant lesions, and among different histopathological subgroups, to identify false-positive histological subtypes. RESULTS: There was a statistically significant difference in the SUV(max) of benign (3.7 +/- 3.3; n = 17) and malignant (5.3 +/- 3.3; n = 62) bone tumors. However, receiver operating characteristic curve analysis revealed the poor accuracy of this distinction. The cut-off value was determined to be 2.6, while the value of sensitivity and specificity was calculated to be 74.2 and 64.7 %, respectively. Giant cell tumor of bone (9.0 +/- 2.0; n = 5) displayed a higher SUV(max) than osteosarcoma (4.2 +/- 2.3; n = 18). Immunohistochemical analysis demonstrated that markers of these cancers, hexokinase-2 (HK-2) and glucose transporter type 1 (GLUT-1), supported our findings. CONCLUSION: The poor accuracy of SUV(max) in 18F-FDG-PET/CT in distinguishing malignant from benign bone tumors was confirmed; some benign bone tumors showed high FDG uptake. Giant cell tumor of bone was a major false-positive histopathological subtype of bone tumors, showing high FDG accumulation. HK-2 contributed significantly to FDG uptake, whereas GLUT-1 appeared to play no role in FDG uptake in giant cell tumor of bone. PMID- 22825643 TI - Low incidence of reinfection with the hepatitis C virus following treatment in active drug users in Amsterdam. AB - BACKGROUND: More than two-thirds of hepatitis C virus (HCV) infections are associated with injecting drug use. Despite the wide availability of standard treatment with pegylated interferon and ribavirin, active drug users (DU) have limited access to HCV treatment. Physicians may be reluctant to prescribe treatment because of the presumed high risk of reinfection. However, data on reinfection in treated DU remain scarce. METHODS: Active DU with chronic HCV infection were treated in a multidisciplinary setting. After achieving a sustained virologic response, patients were tested at 6-12-monthly intervals for HCV RNA. To distinguish between relapse and reinfection, sequence and phylogenetic analyses were performed on the NS5B region of the HCV genome. The incidence of reinfection was calculated using person-time techniques. RESULTS: From April 2005 to March 2010, 69 active DU treated for HCV had sufficient follow up, median 2.5 years (interquartile range, 1.6-3.7). Sustained virologic response was achieved in 42 patients (61%). During follow-up, 41 patients remained HCV RNA negative; of these, two patients died. During treatment, five out of 41 injected drugs, which increased to 11 out of 41 after the end of treatment. One case of reinfection was observed, followed by spontaneous clearance of the virus. The overall incidence was 0.76/100 person-years (95% confidence interval 0.04-3.73). For only those individuals reporting injecting drug use, the incidence was 3.42/100 person-years (95% confidence interval 0.17-16.90). CONCLUSION: We report a low incidence of HCV reinfection following treatment in DU participating in a multidisciplinary programme. Active drug use, including injecting, should not preclude access to treatment for HCV. PMID- 22825644 TI - Gastropericardial fistula: a potential role for conservative treatment. AB - Gastropericardial fistulae are rare entities associated with considerable mortality and morbidity. Most commonly seen secondary to surgery and trauma, they also occur because of peptic ulcer disease. Surgical correction remains the definitive treatment and conservative management is normally associated with poor outcomes. We present the case of a woman with multiple comorbidities who presented with a pneumopericardium secondary to a benign peptic ulcer-related gastropericardial fistula. This case shows that early nasojejunal feeding in patients not fit for a surgical intervention can be associated with a good outcome. We therefore propose that in cases where surgery is not feasible, conservative management with antibiotics and nasojejunal feeding remains a viable alternative. PMID- 22825645 TI - Evaluation of four time-saving methods of reading capsule endoscopy videos. AB - OBJECTIVE: Review of wireless capsule endoscopy recordings is time consuming. The aim of this study was to evaluate four time-saving methods offered with Rapid Software. METHODS: A total of 100 wireless capsule endoscopy videos with abnormal findings were evaluated using five different ways of viewing: (a) manual mode at a speed of 10 frames per second (fps), (b) manual mode at a speed of 20 fps, (c) manual mode with a simultaneous display of two images at a speed of 20 fps, (d) automatic mode at a speed of 10 fps, and (e) quickview mode at a speed of 3 fps. Then, we calculated the concordance of abnormal findings between each one of the four time-saving methods using method A. RESULTS: The mean reading time with time saving methods was significantly shorter than with method A (method A: 59.8 min, method B: 30 min, method C: 30.2 min, method D: 32.2 min, method E: 16.3 min). The agreement in finding abnormal lesions between method A and the four evaluated methods was excellent and almost perfect (kappa>0.8), except for quickview in recognizing polyps. Diagnostic miss rate was 1% for method D, 2% for B and C, and 12% for E. No tumors and cases of celiac or Crohn's disease were lost by all four methods. CONCLUSION: We conclude that manual mode/20 fps, the simultaneous projection of two images/20 fps, and automatic mode/10 fps have minimal diagnostic miss rates and can safely replace slower modes in clinical practice. The quickview mode is a safe diagnostic tool only when larger or diffuse lesions are suspected, such as Crohn's or celiac disease. PMID- 22825646 TI - HCV coinfection possibly promotes left ventricular dysfunction development: analysis of brain natriuretic peptide serum levels in HCV/HIV-coinfected and HIV monoinfected patients. AB - OBJECTIVE: Hepatitis C virus (HCV) has been already linked to possible myocarditis and cardiomyopathy development. The brain natriuretic peptide (BNP) is a sensitive biomarker of left ventricular dysfunction. The present study aimed to evaluate the potential risk of cardiac injury in HIV-infected and HCV/HIV coinfected patients with or without antiretroviral (ARV) therapy by comparing BNP serum levels in the groups studied. METHODS: Eighty HIV-infected patients (65 men, 15 women, mean age 40 years; 29 with HCV coinfection, 48 on combined ARV therapy) were included in the cross-sectional study. BNP serum levels were evaluated by enzyme-linked immunosorbent assay. The BNP cut-off level for possible heart failure was 42 fmol/l as in an immunocompetent population. RESULTS: Seventy-eight (97.5%) patients studied had a BNP concentration above 42 fmol/l; seven patients (8.7%) had a concentration above 168 fmol/l associated with a worse outcome. There was no difference in the mean BNP serum levels in ARV treated and untreated patients. However, the mean BNP serum level was significantly higher in HCV/HIV-coinfected patients in comparison with HIV monoinfected patients (160.0 +/- 130.9 vs. 81.9 +/- 37.2 fmol/l; P<0.0001). There was no relationship between BNP serum levels and HIV viral load, CD4 cell count, sex, age, and abacavir or protease inhibitors use. CONCLUSION: A significant association was found between HCV coinfection and BNP serum level in HIV-infected patients. HCV coinfection possibly enhances the risk of left ventricular dysfunction development in this vulnerable population. PMID- 22825648 TI - Biofilms in dermatology. AB - Biofilms are diverse communities of microorganisms embedded within a self produced matrix of extracellular polymeric substance which are firmly attached to biotic or abiotic surfaces. Approximately 80% of all human infections are associated with biofilms and evidence for their role in an ever-growing number of cutaneous disorders is constantly unfolding. Biofilms present a difficult challenge to clinicians due to their persistent nature, inability to be cultured with standard techniques, and resistance to conventional antimicrobial therapy. Although limited treatment options are presently available, better understanding of the molecular biology of biofilms and their pathogenicity will likely lead to the development of novel anti-biofilm agents for clinical use. PMID- 22825649 TI - A look at epidermal barrier function in atopic dermatitis: physiologic lipid replacement and the role of ceramides. AB - This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of clinically quiescent skin of patients with AD. PMID- 22825647 TI - Comparative efficacy of pegylated interferons alpha-2a and 2b in the treatment of HBeAg-negative chronic hepatitis B infection. AB - INTRODUCTION: Interferons, pegylated interferons (PegIFN), and oral antivirals are used in the treatment of chronic hepatitis B (CHB) virus infection. The number of studies comparing the efficacy of PegIFNs in the treatment of HBe antigen-negative CHB is rather limited. In this trial, the efficacy of two PegIFN products used in the treatment of CHB is compared. METHODS: Study data were obtained from 16 tertiary healthcare service centers located in various areas of Turkey. Data of patients who were consecutively treated with PegIFN alpha-2a or alpha-2b for CHB were recorded retrospectively. Hepatitis B virus DNA and liver enzymes were analyzed at the beginning of the treatment and during weeks 12, 24, 48, and 72. A P-value less than 0.05 was considered to be significant. RESULTS: A total of 155 patients were enrolled in this trial. Two cases were excluded because of insufficient data. Among the remaining 153 patients, 81 (53%) patients were in the PegIFN alpha-2a group and 72 (47%) patients were in the alpha-2b group. Treatment success was found to be 17.2% for the PegIFN alpha-2a group and 18.0% for the PegIFN alpha-2b group (P>0.05). In terms of efficacy (weeks 24, 48, and 72), there were no significant differences between the groups (P>0.05). CONCLUSION: According to our results, for HBe antigen-negative CHB cases, the response rate during the sixth month after the treatment with PegIFN was determined to be ~17%. No difference was found between the efficacy rates of the two PegIFN products used in the treatment of HBe antigen-negative CHB. PMID- 22825651 TI - Expression of VIP and its receptors in the testis of the spotted ray Torpedo marmorata (Risso 1880). AB - The aim of this work was to study, by immunoprecipitation, in situ hybridization and immunohistochemistry, and the expression of the vasoactive intestinal peptide (VIP) and of its receptors (VPAC(1)R and VPAC(2)R) in the testis of a nonmammalian vertebrate, the cartilaginous fish Torpedo marmorata. We demonstrated that, differently from mammals, VIP and VPAC(2)R were widely distributed in the testicular cells while the VPAC(1)R had a limited distribution. In details, we showed that VIP and VPAC(2)R were present in mitotic and differentiating germ cells as well as in the cells involved in the steroidogenesis, i.e., Leydig, Sertoli cells, and prespermatogonia and spermatogonia. The possibility that VIP is involved in the spermatogenesis and particularly in the steroidogenesis of T. marmorata is discussed. PMID- 22825652 TI - Solid-pseudopapillary neoplasms of the pancreas: clinical and pathological features of 33 cases. AB - PURPOSE: Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, with a low potential for malignancy. The clinical and pathological features of 33 SPNs were reviewed. METHODS: This study conducted a retrospective analysis of 33 patients who underwent surgery for a pathologically confirmed SPN from 2000 to 2011. RESULTS: Thirty of the 33 patients (91 %) were female, and the median age at diagnosis was 29.2 years (range 12-59). The most common symptom was abdominal discomfort with dull pain (58 %). Others included asymptomatic lesions that were only detected incidentally during imaging (21 %), a palpable abdominal mass (15 %) and indigestion (6 %). All 33 patients underwent surgery with a curative intent and 3 (9 %) underwent laparoscopic surgery. The mean diameter of the tumors was 4.9 cm (range 2-15 cm), and they occurred in the head (9, 27 %), neck (5, 15 %), body or tail (19, 58 %) of the pancreas. One patient had lymph node metastases, one patient had portal venous invasion and 8 patients had perineural invasion. The patient follow-up ranged from 4 to 118 months, and 32 patients were alive and well without recurrence. One patient relapsed 10 months after distal pancreatectomy with splenectomy and underwent a second surgery via laparotomy. Unfortunately, the patient died of multiple organ failure 12 days after the second surgery. CONCLUSION: SPNs are rare neoplasms with malignant potential but excellent prognosis. Adequate surgical resection, including laparoscopic surgery, may therefore be performed safely and is associated with a long-term survival, even in invasive cases. PMID- 22825653 TI - Association of extrahepatic bile duct duplication with pancreaticobiliary maljunction and congenital biliary dilatation in children: a case report and literature review. AB - We herein report a case of cystic-type congenital biliary dilatation (CBD) in whom an extremely rare anomalous duplication of the common bile duct and pancreaticobiliary maljunction were diagnosed intraoperatively by meticulous surgical manipulations via conventional open surgery. By performing a dissection at the outer epicholedochal layer of the cyst, a thin cord-like structure shown to be the distal part of the common bile duct was identified. A further exploration revealed that the most distal (extra- and intrapancreatic) part of the common bile duct was duplicated, and each branch of the duct was connected to the main and accessory pancreatic ducts. The experience with our case and a literature review showed that extrahepatic bile duct duplication is generally associated with pancreaticobiliary maljunction and CBD. We conclude that an extremely careful exploration with delicate and meticulous surgical manipulation is essential to identify these morphological anomalies and prevent intraoperative and postoperative complications of CBD, such as pancreatic duct injury or pancreatitis. PMID- 22825655 TI - Antitumor effects of the novel quinazolinone MJ-33: inhibition of metastasis through the MAPK, AKT, NF-kappaB and AP-1 signaling pathways in DU145 human prostate cancer cells. AB - Quinazolinone compounds have been shown to have antitumor activity in many human cancer cell lines. In the present study, we investigated the anti-metastatic activity of MJ-33 (2-(3-ethoxyphenyl)-6-pyrrolidinylquinazolinone), a novel quinazolinone derivate, and the signaling pathway of MJ-33 in human prostate cells. MJ-33 exhibited a growth inhibitory effect on DU145, LNCaP and PC-3 cells by MTT assay. DU145 cells showed greater sensitivity to the growth inhibition of MJ-33 than that of LNCaP and PC-3 cells. MJ-33 also had an inhibitory effect on the invasion, migration and adhesion of DU145 cells using Boyden chamber transwell assays, wound-healing and adhesion assay. In addition, MJ-33 inhibited cell metastasis through the reduction of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (u PA) enzyme activities and protein levels by gelatin zymography assay and western blot analysis, respectively. MJ-33 reduced the protein levels of p-JNK, p-p38, p ERK, p-AKT and nuclear NF-kappaB (p65), c-fos and c-Jun protein levels by western blotting. Using electrophoretic mobility-shift assay (EMSA), we demonstrated that MJ-33 blocked the activation of transcription factor AP-1 (activator protein-1) and NF-kappaB, which led to the inhibition of MMP-2 and MMP-9 expression. Collectively, our data showed that MJ-33 decreased protein levels of MAPKs (mitogen-activated protein kinases), AKT, AP-1 and NF-kappaB, resulting in the inhibition of matrix metalloproteinases. Downregulation of MMP-2 and MMP-9 reduces the invasion, migration and adhesion activities of DU145 cells. MJ-33 may be a promising agent against prostate cancer metastasis. PMID- 22825654 TI - Effects of a proton pump inhibitor on the physiological accumulation of fluoro-2 deoxy-D-glucose (FDG) in FDG-positron emission tomography. AB - PURPOSES: The physiological accumulation of fluoro-2-deoxy-D-glucose (FDG) is common in medical examinations of the digestive tract conducted using FDG positron emission tomography (PET). The aim of this study was to determine the effects of a proton pump inhibitor (PPI) on the physiological FDG accumulation in the digestive tract. METHODS: A total of 130 patients examined from July 2007 to October 2008 were included in the final analysis. A PPI was administered orally prior to FDG-PET in 65 patients. The remaining 65 patients underwent FDG-PET without administration of the PPI. The assessments used visual and quantitative evaluations. RESULTS: Visual evaluation showed that physiological FDG accumulation in the stomach was significantly reduced (p = 0.037) in the PPI group compared with the control group. The quantitative evaluation also revealed a significant reduction in the maximum standardized uptake values (SUV(max)) in the stomach in the PPI group compared with the control group (p < 0.0001). Physiological FDG accumulation in the colon showed a decreasing trend on visual evaluation in the PPI group compared with the control group, and the quantitative evaluation found a significant reduction in the physiological FDG accumulation in the colon in the PPI group (p = 0.045). CONCLUSIONS: The oral administration of a PPI was effective for reducing the physiological accumulation of the FDG in the alimentary tract. However, based on the error associated with SUV(max) measurement, a quantitative evaluation should therefore be combined with the visual evaluation. PMID- 22825656 TI - Copper(II) complexes as turn on fluorescent sensors for nitric oxide. AB - Two copper(II) complexes, 1 and 2, of two tridentate N-donor ligands, L(1) and L(2) [L(1) = dansyl derivative of bis-[3-(dimethylamino)-propyl]amine; L(2) = dansyl derivative of dipropylenetriamine] were synthesized and characterized. The quenched fluorescence intensity of complexes 1 and 2, in degassed methanol or aqueous (buffered at pH 7.2) solution, was found to reappear on exposure to nitric oxide. This is attributed to the reduction of paramagnetic Cu(II) center by nitric oxide to diamagnetic Cu(I). PMID- 22825657 TI - Antifungal drugs. PMID- 22825658 TI - Association between sleep duration and overweight: the importance of parenting. AB - OBJECTIVE: Sleep duration has been related to overweight in children, but determinants of sleep duration are unclear. The aims were to investigate the association between sleep duration and childhood overweight adjusted for family characteristics and unhealthy behaviours, to explore determinants of sleep duration and to determine with sleep competing activities. METHOD: A cross sectional study was carried out in 2006 among 4072 children aged 4-13 years in the city of Zwolle, The Netherlands. In these children, data were available on measured height, weight and waist circumference, and from a parental questionnaire, on socio-demographic characteristics, child's sleep duration, nutrition, physical activity and sedentary behaviour. Associations were studied in 2011 using logistic and linear regression analyses, adjusted for potential confounders. RESULTS: Short sleep duration was associated with overweight for 4-8 year-old boys (odds ratio (OR):3.10; 95% confidence interval (CI):1.15-8.40), 9 13-year-old boys (OR:4.96; 95% CI:1.35-18.16) and 9-13-year-old girls (OR:4.86; 95% CI:1.59-14.88). Among 4-8-year-old girls no statistically significant association was found. Determinants for short sleep duration were viewing television during a meal, permission to have candy without asking, not being active with their caregiver and a late bedtime. For all children, short sleep duration was strongly associated with more television viewing and computer use. CONCLUSIONS: Association between sleep duration and overweight is not explained by socio-demographic variables, drinking sugared drinks and eating snacks. Parents have a key role in stimulating optimal sleep duration. Improving parenting skills and knowledge to offer children more structure, and possibly with that, increase sleeping hours, may be promising in prevention of overweight. PMID- 22825659 TI - Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention? AB - OBJECTIVE: We investigated to what extent changes in metabolic rate and composition of weight loss explained the less-than-expected weight loss in obese men and women during a diet-plus-exercise intervention. DESIGN: In all, 16 obese men and women (41 +/- 9 years; body mass index (BMI) 39 +/- 6 kg m(-2)) were investigated in energy balance before, after and twice during a 12-week very-low energy diet(565-650 kcal per day) plus exercise (aerobic plus resistance training) intervention. The relative energy deficit (EDef) from baseline requirements was severe (74%-87%). Body composition was measured by deuterium dilution and dual energy X-ray absorptiometry, and resting metabolic rate (RMR) was measured by indirect calorimetry. Fat mass (FM) and fat-free mass (FFM) were converted into energy equivalents using constants 9.45 kcal per g FM and 1.13 kcal per g FFM. Predicted weight loss was calculated from the EDef using the '7700 kcal kg(-1) rule'. RESULTS: Changes in weight (-18.6 +/- 5.0 kg), FM (-15.5 +/- 4.3 kg) and FFM (-3.1 +/- 1.9 kg) did not differ between genders. Measured weight loss was on average 67% of the predicted value, but ranged from 39% to 94%. Relative EDef was correlated with the decrease in RMR (R=0.70, P<0.01), and the decrease in RMR correlated with the difference between actual and expected weight loss (R=0.51, P<0.01). Changes in metabolic rate explained on average 67% of the less-than-expected weight loss, and variability in the proportion of weight lost as FM accounted for a further 5%. On average, after adjustment for changes in metabolic rate and body composition of weight lost, actual weight loss reached 90% of the predicted values. CONCLUSION: Although weight loss was 33% lower than predicted at baseline from standard energy equivalents, the majority of this differential was explained by physiological variables. Although lower than-expected weight loss is often attributed to incomplete adherence to prescribed interventions, the influence of baseline calculation errors and metabolic downregulation should not be discounted. PMID- 22825663 TI - Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. AB - Stem cell transplantation has been used to improve neural function in intracerebral hemorrhage (ICH). However, reports on bone marrow-derived mesenchymal stem cell (MSC) transplantation in ICH are limited. We aimed to explore the therapeutic effect and related mechanisms by transplantation of MSCs in rats with ICH. An experimental rat ICH model was established by intrastriatal administration of collagenase. The rats were randomly divided to receive either rat MSCs or PBS solution intravenously. In addition, behavioral tests using the modified neurological severity score (mNSS) were performed following ICH. Immunohistochemistry was performed to detect the Brdu-labeled MSCs and the protein expression of caspase 2, NF200 and GFAP in neural tissues. Western blotting and ELISA were performed to measure the protein expression of Akt and bcl-2 or the protein content of G-CSF and BDNF. The MSC-transplanted group demonstrated better neural function on the mNSS test following ICH compared with the control group (P<0.05). The MSC-transplanted group also showed reduced hemorrhage volume at 24 and 72 h following ICH. In the perihematomal regions of rat brain with ICH, a substantial number of Brdu-labeled MSCs were observed, and a high protein expression of caspase 3, NF200 and GFAP was found in the MSC transplanted group. The protein content of Akt, Bcl-2, G-CSF and BDNF were all elevated by MSC transplantation. Intravenously transplanted MSCs are capable of improving functional recovery and restoring neurological deficits in experimental ICH. The mechanisms are associated with enhanced survival and differentiation of neural cells, and increased expression of anti-apoptotic proteins and trophic factors. PMID- 22825661 TI - Balanced ubiquitination determines cellular responsiveness to extracellular stimuli. AB - Signal strength evoked by ligand stimulation is crucial for cellular responses such as fate decision, cell survival/death, secretion, and migration. For example, morphogens are secreted signaling molecules that form concentration gradients within tissues and induce distinct cell fates in a signal strength dependent manner. In addition to extracellular ligand abundance, the sensitivity of signal-receiving cells to ligands also influences signal strength. Cell sensitivity to ligands is controlled at various levels: receptor presentation at the cell surface, positive/negative regulation of signal transduction, and target gene activation/repression. While the regulation of signal transduction and gene transcription is well studied, receptor presentation is still not fully understood. Recently, it was reported that cellular sensitivity to the Wingless (Wg)/Wnt morphogen is regulated by balanced ubiquitination and deubiquitination of its receptor Frizzled (Fz). In this review, we review how ubiquitination regulates receptor presentation at the cell surface for the detection of extracellular signal strength. PMID- 22825660 TI - The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. AB - The mammalian genome is transcribed in a developmentally regulated manner, generating RNA strands ranging from long to short non-coding RNA (ncRNAs). NcRNAs generated by intergenic sequences and protein-coding loci, represent up to 98 % of the human transcriptome. Non-coding transcripts comprise short ncRNAs such as microRNAs, piwi-interacting RNAs, small nucleolar RNAs and long intergenic RNAs, most of which exercise a strictly controlled negative regulation of expression of protein-coding genes. In humans, the DLK1-DIO3 genomic region, located on human chromosome 14 (14q32) contains the paternally expressed imprinted genes DLK1, RTL1, and DIO3 and the maternally expressed imprinted genes MEG3 (Gtl2), MEG8 (RIAN), and antisense RTL1 (asRTL1). This region hosts, in addition to two long intergenic RNAs, the MEG3 and MEG8, one of the largest microRNA clusters in the genome, with 53 miRNAs in the forward strand and one (mir-1247) in the reverse strand. Many of these miRNAs are differentially expressed in several pathologic processes and various cancers. A better understanding of the pathophysiologic importance of the DLK1-DIO3 domain-containing microRNA cluster may contribute to innovative therapeutic strategies in a range of diseases. Here we present an in depth review of this vital genomic region, and examine the role the microRNAs of this region may play in controlling tissue homeostasis and in the pathogenesis of some human diseases, mostly cancer, when aberrantly expressed. The potential clinical implications of this data are also discussed. PMID- 22825664 TI - Genetics: FAN1 mutations result in defective DNA damage repair and karyomegalic interstitial nephritis. PMID- 22825669 TI - Assessment of kidney function: Estimating GFR in children. AB - In a new study, Schwartz and colleagues have investigated the best way to estimate glomerular filtration rate (GFR) in children. Having already improved GFR estimation with the use of creatinine-based equations, the investigators now propose a more precise method for cystatin C measurement. The precision of a GFR equation will strongly depend on the analytical precision of the biological variables included. PMID- 22825665 TI - Intensive home haemodialysis: benefits and barriers. AB - Accumulating evidence of the benefits of intensive home haemodialysis has led to increased international interest in this modality as a viable option for renal replacement therapy. Until the late 1970s, haemodialysis was primarily performed at home; however, the development of in-centre and satellite dialysis units and the advent of peritoneal dialysis led to decreased numbers of patients being managed by home haemodialysis. Over the past decade, a move towards once again providing and supporting haemodialysis at home has emerged, due to a desire to offer a more convenient form of dialysis for the patient in a more cost-effective manner. This shift has generated clinical evidence indicating benefits both from receiving haemodialysis at home, and from the option to provide intensive dialysis treatment in this setting. With the development of new home haemodialysis programs, specific patient-related, physician-related and cost related barriers to their introduction have been encountered, including patient fear of self-cannulation and lack of expert medical knowledge in the area. This Review discusses the benefits and barriers associated with intensive home haemodialysis. PMID- 22825672 TI - Risk factors: Hyperfiltration--a risk factor for renal function decline. PMID- 22825670 TI - Anticoagulants in atrial fibrillation patients with chronic kidney disease. AB - Atrial fibrillation is an important cause of preventable, disabling stroke and is particularly frequent in patients with chronic kidney disease (CKD). Stage 3 CKD is an independent risk factor for stroke in patients with atrial fibrillation. Warfarin anticoagulation is efficacious for stroke prevention in atrial fibrillation patients with stage 3 CKD, but recent observational studies have challenged its value for patients with end-stage renal disease and atrial fibrillation. Novel oral anticoagulants such as dabigatran, apixaban and rivaroxaban are at least as efficacious as warfarin with reduced risks of intracranial haemorrhage. However, all these agents undergo renal clearance to varying degrees, and hence dosing, efficacy, and safety require special consideration in patients with CKD. Overall, the novel oral anticoagulants have performed well in randomized trials of patients with stage 3 CKD, with similar efficacy and safety profiles as for patients without CKD, albeit requiring dosing modifications. The required period of discontinuation of novel oral anticoagulants before elective surgery is longer for patients with CKD owing to their reduced renal clearance. Although much remains to be learned about the optimal use of these new agents in patients with CKD, they are attractive anticoagulation options that are likely to replace warfarin in coming years. PMID- 22825673 TI - Lupus nephritis: Implications of the new ACR lupus nephritis guidelines. AB - The American College of Rheumatology recently published guidelines for the screening, treatment, and management of lupus nephritis. How will or should these guidelines impact our current daily practice? PMID- 22825674 TI - Studies on the metabolism of five model drugs by fungi colonizing cadavers using LC-ESI-MS/MS and GC-MS analysis. AB - It is well-known that cadavers may be colonized by microorganisms, but there is limited information if or to what extent these microbes are capable of metabolizing drugs or poisons, changing the concentrations and metabolic pattern of such compounds in postmortem samples. The aim of the present study was to develop a fungal biotransformation system as an in vitro model to investigate potential postmortem metabolism by fungi. Five model drugs (amitriptyline, metoprolol, mirtazapine, promethazine, and zolpidem) were each incubated with five model fungi known to colonize cadavers (Absidia repens, Aspergillus repens, Aspergillus terreus, Gliocladium viride, and Mortierella polycephala) and with Cunninghamella elegans (positive control). Incubations were performed in Sabouraud medium at 25 degrees C for 5 days. After centrifugation, a part of the supernatants was analyzed by liquid chromatography-tandem mass spectrometry with product ion scanning. Another part was analyzed by full scan gas chromatography mass spectrometry after extraction and derivatization. All model drugs were metabolized by the control fungus resulting in two (metoprolol) to ten (amitriptyline) metabolites. Of the model fungi, only Abs. repens and M. polycephala metabolized the model drugs: amitriptyline was metabolized to six and five, metoprolol to two and two, mirtazapine to five and three, promethazine to six and nine, and zolpidem to three and four metabolites, respectively. The main metabolic reactions were demethylation, oxidation, and hydroxylation. The presented in vitro model is applicable to studying drug metabolism by fungi colonizing cadavers. PMID- 22825675 TI - Isolation and structural elucidation of a new sildenafil analogue from a functional coffee. AB - A sildenafil analogue was detected in a functional coffee sample labelled to have male sexual performance enhancement effects. This analogue was isolated and purified by flash chromatography and preparative high-performance liquid chromatography. Its structure was elucidated using high-resolution mass spectrometry; electrospray ionization-tandem mass spectrometry; and nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and infrared spectroscopy. Compared with sildenafil, instead of an N-methylpiperazinyl moiety, ring opening of the piperazine ring with the loss of a carbon atom resulted in a substituted benzenesulfonamide. The chemical name of this analogue is N-[2 (dimethylamino)ethyl]-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide. It is named descarbonsildenafil because it has one less carbon atom when compared with sildenafil. PMID- 22825676 TI - Removal of sulfonamide antibiotics upon conventional activated sludge and advanced membrane bioreactor treatment. AB - This work reports the removal efficiencies of nine sulfonamides (SAs) and one of their acetylated metabolites during conventional activated sludge (CAS) and membrane bioreactor (MBR) treatments. Two different types of membranes were studied, hollow-fiber membranes and flat-sheet membranes, in two separate pilot plants operating in parallel to a full-scale CAS treatment. A total of 48 water samples and 16 sewage sludge samples were analyzed by liquid chromatography tandem mass spectrometry. We obtained 100% elimination in the MBR effluents for three SAs (sulfadiazine, sulfadimethoxine, and sulfamethoxypyridazine) and the metabolite. For the rest of the SAs, the removal efficiencies during CAS and MBR treatments were similar and usually below 55%. Sulfamethizole was the most recalcitrant SA, exhibiting negative removal efficiencies in all the treatments investigated. The concentrations of SAs in the different sewage sludge types were also calculated and ranged from 0.01 to 11 ng g(-1). Furthermore, adsorption and biodegradation of SAs in activated sludge were investigated in two sets of batch reactors, which were spiked at high and low concentration (1,000 and 50 ng mL( 1), respectively). All SAs followed a similar trend and, with the exception of sulfathiazole, were not fully eliminated after 25 days of treatment. PMID- 22825677 TI - Thermally annealed gold nanoparticles for surface-assisted laser desorption ionisation-mass spectrometry of low molecular weight analytes. AB - Metal nanomaterials have an emerging role in surface-assisted laser desorption ionisation-mass spectrometry (SALDI-MS) providing a useful tool to overcome some limitations intrinsically related to the use of conventional organic matrices in matrix-assisted LDI-MS. In this contribution, the possibility to use a stainless steel-supported gold nanoparticle (AuNP) film as a versatile platform for SALDI MS was assessed. A sacrificial anode electrosynthetic route was chosen in order to obtain morphologically controlled core-shell AuNPs; the colloidal AuNPs were, thereafter, drop cast onto a stainless-steel sample plate and the resulting AuNP film was thermally annealed in order to improve its effectiveness as LDI-MS promoter. Spectroscopic characterization of the nanostructured film by X-ray photoelectron spectroscopy was crucial for understanding how annealing induced changes in the surface chemistry and influenced the performance of AuNPs as desorption/ionisation promoter. In particular, it was demonstrated that the post deposition treatments were essential to enhance the AuNP core/analyte interaction, thus resulting in SALDI-MS spectra of significantly improved quality. The AuNP films were applied to the detection of three different classes of low molecular weight (LMW) analytes, i.e. amino acids, peptides and LMW polymers, in order to demonstrate the versatility of this nanostructured material. PMID- 22825678 TI - Multiplexed protein detection using an affinity aptamer amplification assay. AB - Affinity probe capillary electrophoresis (APCE) is potentially one of the most versatile technologies for protein diagnostics, offering an excellent balance between robustness, analysis speed and sensitivity. Combining the immunosensing and separating strength of capillary electrophoresis with the signal enhancement power of nucleic acid amplification, aptamers can further push the analytical limits of APCE to offer ultrasensitive, multiplexed detection of protein biomarkers, even when differences in electrophoretic mobility between the different aptamer-target complexes are limited. It is demonstrated how, through careful selection of experimental parameters, simultaneous detection of picomolar levels of three target proteins can be achieved even with aptamers that were initially selected under very different conditions and further taking into account that the aptamers need to be modified to allow successful PCR amplification. Aptamer-enhanced APCE offers limits of detection that are orders of magnitude lower than those that can be achieved through traditional capillary electrophoresis-based immunosensing. With recent developments in aptamer selection that for the first time realise the promise of aptamers as easily accessible, high affinity recognition molecules, it can therefore be envisioned that aptamer-enhanced APCE on parallel microfluidic platforms can be the basis for a truly high-throughput multiplexed proteomics platform, rivalling genetic screening for the first time. PMID- 22825679 TI - Quantitative mass spectrometry in proteomics. PMID- 22825680 TI - A new diterpenoid from the leaves of Clerodendron trichotomum. AB - A new diterpenoid was isolated from the leaves of Clerodendron trichotomumThunb. (Verbenaceae) along with one each of a known diterpenoid, phenylethanoid glycoside, and sterol and two known flavonoids. Their chemical structures were characterized on the basis of spectroscopic data and X-ray analysis. In addition, their antioxidant activities were evaluated using four different analyses. PMID- 22825681 TI - Pollen Typhae total flavone improves insulin-induced glucose uptake through the beta-arrestin-2-mediated signaling in C2C12 myotubes. AB - Defects in insulin-stimulated glucose uptake in skeletal muscle result from the dysfunction of insulin signaling including the phosphatidylinositol-3 kinase (PI3K) pathway and a novel beta-arrestin-2-mediated signaling, which leads to insulin resistance (IR). Pollen Typhae, a Chinese herb, has been used for thousands of years in traditional Chinese medicine, and has the potential to inhibit the development of IR. We have previously reported that Pollen Typhae total flavone (PTF), the extract from Pollen Typhae, ameliorates high-glucose- and high-insulin-induced impairment of glucose uptake in 3T3-L1 adipocytes, but the mechanisms remain unclear. The objective of this study was to investigate the effects of PTF on glucose uptake, and to explore the underlying mechanisms in C2C12 myotubes. PTF improved insulin-stimulated glucose uptake in a dose- and time-dependent manner in C2C12 myotubes, and prevented palmitate-induced IR. Furthermore, PTF enhanced the basal gene expression of Src and Akt2, elevated the protein expression of beta-arrestin-2, Src and Akt, increased the phosphorylation of insulin receptor-beta at Tyr1150/1151 and Akt at Thr308/Ser473 in an insulin dependent manner, but had no effects on the protein expression of PI3K-p85 or the activity of PI3K. Inhibition of Src but not PI3K restrained PTF-induced phosphorylation of Akt and glucose uptake. Our findings indicate that PTF improves insulin-induced glucose uptake via the beta-arrestin-2-mediated signaling in C2C12 myotubes. PMID- 22825682 TI - Abstracts from the 2011 Joint Annual Meeting of the American Association for Cancer Education, the European Association for Cancer Education and the Cancer Patient Education Network. Buffalo, New York, USA. September 8-10, 2011. PMID- 22825683 TI - Determination of the consequences of VHL mutations on VHL transcripts in renal cell carcinoma. AB - Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumour suppressor gene are common in sporadic conventional (clear cell) renal cell carcinoma (ccRCC). The effects on VHL expression are unknown but increased understanding may be relevant clinically, either in terms of prognosis or in therapy selection. We have examined the expression of VHL mutant RNA in 84 ccRCC tumours previously screened for mutations in genomic DNA, 56 of which contained 52 unique mutations or polymorphisms. Based on the predicted change to the primary amino acid sequence, 24 of the mutations were missense, 11 resulted in frameshifts with premature truncation, 9 resulted in immediate truncation at the site of the mutation and 2 were frameshifts which extended the reading frame beyond the normal stop codon. Nine tumours had intronic variants, including substitution of invariant residues at splice sites, deletion of nucleotides spanning the exon intron junction, an intronic variant of unknown function and the polymorphism c.463+43A>G. Four variants were identified which were present in genomic DNA but not in mRNA. Three of these, all encoding apparent missense changes to the primary amino acid sequence, were located close to the ends of exons, reduced the strength of the splice site and function as null rather than missense variants. One nonsense variant was not detectable in mRNA but all other mutations resulting in premature truncation codons (PTCs) were, suggesting truncating VHL mutations may potentially generate truncated VHL protein. An intronic variant, c.341-11T>A, previously regarded as of unknown function, is associated with an increased level of skipping of exon 2 and may, therefore, reduce production of pVHL. Our data show that the biological consequences of VHL mutations are not necessarily predictable from the sequence change of the mutation and that for the majority of VHL mutations, the potential for the generation of mutant protein exists. PMID- 22825684 TI - Assessment of gemcitabine, cisplatin and methylprednisolone (GEM-P) combination treatment for non-Hodgkin T cell lymphoma. AB - T cell lymphoma is rare with few dedicated studies and no consensus regarding optimal treatment. We undertook a retrospective hospital review to assess the efficacy of gemcitabine, cisplatin and methylprednisolone (GEM-P) combination therapy. Twenty-nine patients were followed up for a median duration of 28 months. Twenty-three patients received standard GEM-P. Due to hearing impairment, 3 patients had cisplatin substituted with carboplatin and 1 with oxaliplatin. In 2 cases, rituximab was added to GEM-P in view of the presence of EBV + B cell clones. Overall response rate (RR) [complete response (CR) + partial response (PR)] was 73 % (95 % CI range 54-86 %). 11/29 (38 %) achieved CR and 10/29 (35 %) had PR. In first-line treatment, 4/10 patients achieved CR and 4/10 had PR relating to a RR of 80 %. CR was seen in 4/9 (45 %), 2/8 (25) and 1/2 (50 %) patients treated in the second, third and fifth-sixth line respectively. Thus, GEM-P was found to be effective as first-line or salvage therapy in T cell lymphoma. PMID- 22825685 TI - Microwave-assisted synthesis of BiOBr/graphene nanocomposites and their enhanced photocatalytic activity. AB - BiOBr/graphene nanocomposites were synthesized by a green single-step microwave strategy and characterized by X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. The photocatalytic activity of the as-prepared BiOBr nanoplates and BiOBr/graphene nanocomposites for the photodegeneration of organic dyes in aqueous solution under visible light irradiation was investigated. The results show that BiOBr/graphene nanocomposites have a higher photocatalytic activity than bare BiOBr nanoplates. PMID- 22825686 TI - Pressure overload-induced cardiac remodeling and dysfunction in the absence of interleukin 6 in mice. AB - Congestive heart failure is associated with increased expression of pro inflammatory cytokines, and the levels of these cytokines correlate with heart failure severity and prognosis. Chronic interleukin 6 (IL-6) stimulation leads to left ventricular (LV) hypertrophy and dysfunction, and deletion of IL-6 reduces LV hypertrophy after angiotensin II infusion. In this study, we tested the hypothesis that IL-6 deletion has favorable effects on pressure-overloaded hearts. We performed transverse aortic constriction on IL-6-deleted (IL6KO) mice and C57BL/6J mice (CON) to induce pressure overload. Pressure overload was associated with similar LV hypertrophy, dilation, and dysfunction in CON and IL6KO mice. Re-activation of the fetal gene program was also similar in pressure overloaded CON and IL6KO mice. There were no differences between CON and IL6KO mice in LV fibrosis or expression of extracellular matrix proteins after pressure overload. In addition, no group differences in apoptosis or autophagy were seen. These data indicate that IL-6 deletion does not block LV remodeling and dysfunction induced by pressure overload. Attenuated content of IL-11 appears to be a compensatory mechanism for IL-6 deletion in pressure-overloaded hearts. We infer from these data that limiting availability of IL-6 alone is not sufficient to attenuate LV remodeling and dysfunction in failing hearts. PMID- 22825687 TI - The suppression of TRIM21 and the accumulation of IFN-alpha play crucial roles in the pathogenesis of osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head (ONFH), the pathogenesis of which remains unclear, has been observed in autoimmune disease patients treated with corticosteroids. Recently, it has been shown that anti-tripartite motif containing 21 (TRIM21) autoantibodies, which are often present in patients with systemic lupus erythematosis and Sjogren's syndrome, inhibit the E3 ligase activity of TRIM21. TRIM21 negatively regulates nuclear factor-kappaB (NF-kappaB) and interferon regulatory factors (IRFs) 3 and 7, three downstream transcription factors, via toll-like receptor 4 signaling. The aim of this study was to clarify the role of TRIM21 in the pathogenesis of ONFH using an animal model. Male Wistar rats were injected with lipopolysaccharide (LPS) twice and with methylprednisolone (MPSL) or saline three times. N-acetyl cysteine (NAC) was administered either concurrently with MPSL or once daily for the 3 days following the last MPSL injection. The incidence of ONFH in the MPSL group was 23.5%. Co treatment of NAC and MPSL increased the incidence of ONFH to 55.6%. MPSL treatment decreased the activity of NF-kappaB in the liver and significantly increased the activity of both IRF3 and IRF7. No significant differences were observed in the activity of any of these three transcription factors between the MPSL and the co-treatment groups. In the femoral head, co-treatment with NAC and MPSL significantly decreased the expression of TRIM21 at 3 h and significantly increased the expression of interferon (IFN)-alpha at 24 h when compared with the MPSL group. IFN-alpha is known to induce cell death. These findings suggest that the suppression of TRIM21 in the femoral head causes an accumulation of IFN alpha, which in turn leads to the development of ONFH. In conclusion, the suppression of TRIM21 resulting from altered NF-kappaB and IRF homeostasis accelerates the ONFH in rats treated with corticosteroids following LPS administration. PMID- 22825688 TI - Drugs for urinary tract infections. PMID- 22825689 TI - What comes after metformin for type 2 diabetes. PMID- 22825690 TI - Pertuzumab (Perjecta) for HER2-positive metastatic breast cancer. PMID- 22825691 TI - Phase II study of paclitaxel in combination with carboplatin for patients with recurrent or persistent uterine sarcoma. AB - OBJECTIVE: To evaluate the efficacy and toxicity of combined paclitaxel and carboplatin treatment for persistent or recurrent uterine sarcoma. METHODS: Paclitaxel was administrated at 175 mg/m2 intravenously over 3 h plus carboplatin at AUC 5 intravenously over 30 min every 3-week cycle in patients with recurrent or progressive uterine sarcoma, who were unsuitable candidates for curative treatment with either surgery or radiotherapy. The Simon's two-stage optimal design was chosen for defining the total number of patients required for the phase II study. A total of 13 patients were entered in the study at the first stage of trial. A median of four cycles were administrated per patient, with a range of one to nine cycles. Prior to the study, 4 (30.8%) of the 13 patients had received radiotherapy or chemotherapy. The response was measured by evaluation of the size of the mass by CT scan. RESULTS: The overall response rate was 15.4% (2/13), with two patients exhibiting partial responses. There was 1 (7.7%) case of stable disease and 9 (69.2%) cases of progression disease. The median progression free survival was 2.23 months (95% confidence interval 1.94-3.67). Peripheral neuropathy and hematologic toxicity, including anemia and neutropenia, were the most frequent adverse events. One patient died from treatment-related toxicities. CONCLUSIONS: Paclitaxel in combination with carboplatin demonstrated acceptable levels of toxicity, but it was not active in the treatment of recurrent or progressive uterine sarcoma. This regimen might have limited role for advanced uterine sarcomas. PMID- 22825692 TI - Association between polymorphisms in DNA repair genes (XRCC1 and XRCC7) and risk of preeclampsia. AB - PURPOSE: Although the exact genes involved in preeclampsia (PE) are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. XRCC1 (MIM: 194360) and XRCC7 (MIM: 600899) play a crucial role in the DNA repair pathways. Functional polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) and XRCC7 (G6721T) may be risk factors for PE. In the present study, the association between the genetic polymorphisms of XRCC1 and XRCC7 and risk of PE is investigated. METHODS: The present case-control study was performed on 151 preeclapmtic patients, and a total of 344 normal pregnant women, as a control group. Control women had no history of pregnancies with PE. RESULTS: Neither polymorphism of Arg194Trp XRCC1 nor polymorphism of G6721T XRCC7 associated with the risk of PE. The Gln/Gln genotype of Arg399Gln XRCC1 polymorphism increased the risk of PE (OR=2.39, 95 % CI: 1.38-4.14, P=0.002). Statistical analysis revealed that the haplotype "194Arg-399Gln" showed higher frequency among PE patients compared to the controls (OR=1.65, 95% CI: 1.23-2.19, P=0.001). CONCLUSIONS: The present results suggest that the 399Gln allele of the XRCC1 is significant risk factor for PE development. PMID- 22825693 TI - Endometriosis in menopause: a single institution experience. AB - PURPOSE: This study aims to present the clinical characteristics of a series of postmenopausal women with endometriosis and to evaluate the preferential location, extension and histopathological features of the lesions. METHODS: We retrospectively examined the clinical records of 72 postmenopausal women with endometriosis who underwent surgery between January 1998 and December 2010. RESULTS: The median age of patients at the time of surgery was 58.5 years. Eleven patients (15.3%) had previous history of endometriosis and five patients had previously undergone surgery for this reason. Only two patients included in the study were using hormone replacement therapy at the time of surgery. The most frequent location of endometriotic lesions was the ovary and among patients with endometriomas, 35% (20/57) had different grades of metaplasia, hyperplasia, atypia and endometrioid carcinoma arising in endometriosis. The proportions of epithelium, stroma and hemorrhage in endometriotic lesions were higher in patients with concomitant endometrial or ovarian cancer. CONCLUSIONS: Endometriosis should be considered in the differential diagnosis of postmenopausal cystic lesions of the ovary. The administration of exogenous estrogen is not a prerequisite for the presence of endometriosis in postmenopausal women, and histological signs of functionally active lesions were also observed in the absence of exogenous hormone intake. PMID- 22825694 TI - Osteosarcoma in a pregnant woman: case report. PMID- 22825695 TI - Higher dN/dS ratios in the HCV core gene, but not in the E1/HVR1 gene, are associated with human immunodeficiency virus-associated immunosuppression. AB - Coinfection with HCV and HIV is prevalent among former commercial blood donors in some rural areas in China. Genetic variability of the HCV core and E1/HVR1 was investigated in 23 patients chronically infected with HCV-1b, with or without concomitant HIV infection. Genetic variability in the core sequence was higher under HIV-associated immunocompromised conditions. Both the Shannon entropy values at each nucleotide position and the dN/dS values at each codon were statistically higher in HIV/HCV-coinfected patients with lower CD4+ T cell counts (p-values were <0.0001 and equal to 0.0372, respectively). The more significant difference of dN/dS value occurred in a specific subregion of the core gene that is enriched in CTL/Th epitopes (p = 0.0083). The dN/dS values of full-length core antigen were found to be negatively correlated with the S/CO ratio of plasma anti HCV antibodies. By contrast, no significant difference in genetic diversity/complexity and dN/dS values in the E1/HVR1 region was found between those two groups. These results suggest that the dN/dS ratio in the core gene, but not in the E1/HVR1 gene, is influenced more by host CD4+ T cell-mediated cellular immunity. PMID- 22825696 TI - Tracing the genetic history of porcine reproductive and respiratory syndrome viruses derived from the complete ORF 5-7 sequences: a Bayesian coalescent approach. AB - To trace the genetic history of porcine reproductive and respiratory syndrome virus (PRRSV), we determined the complete sequences of ORFs 5 to 7 of four PRRSV isolates. These sequences were analyzed together with published sequences from 146 isolates from various parts of the world using a Bayesian coalescent approach as well as Bayesian inference and maximum-likelihood methods. All of the European type (EU-type) viruses were classified into one of two groups or unclassified (4 isolates), while all North American-type (NA-type) viruses belonged to one of three major groups or were unclassified (5 isolates). Within each genotype, no apparent periodic and/or geographic influence on the evolution of PRRSVs was observed. The evolutionary rate of PRRSV isolates was estimated to be 1.55 * 10( 3) substitutions/site/year, and the time of the most recent common ancestor (TMRCA) was 491.2 years ago. Here, the TMRCA for the EU- and NA-type viruses was 58.7 and 62.6 years ago, respectively. A Bayesian skyline plot revealed that the viruses evolved at an almost constant population size until the late 1970s, when they experienced a population expansion that continued until the late 1980s. The population size then remained constant again until the early 2000s, when a rapid, sharp decline in the effective number of infections occurred. PMID- 22825697 TI - Quantitative comparison of the RNA bacteriophage Qbeta infection cycle in rich and minimal media. AB - As bacteriophages are dependent on the host for multiplication, their infection cycle is expected to be influenced by the host's physiological state. To elucidate how and which steps of the bacteriophage infection cycle are influenced by changes in the physiological state of the host, we quantitatively compared the infection cycle of lytic RNA bacteriophage Qbeta in Escherichia coli cultured in rich and minimal media. The adsorption rate constants in both media were almost the same. A difference of 15 min in the latent period and an approximately twofold increase in the rate of phage release were observed, although approximately 10(5) molecules of coat proteins, equivalent to approximately 600 1000 phage particles, accumulated in an infected cell prior to burst. Addition of Mg(2+) to minimal medium markedly affected the Qbeta infection cycle, and these results suggest that Mg(2+) is required for the stages of the infectious cycle after adsorption. PMID- 22825698 TI - Full-length genome analysis of vesicular stomatitis New Jersey virus strains representing the phylogenetic and geographic diversity of the virus. PMID- 22825699 TI - Accurate dispensing of volatile reagents on demand for chemical reactions in EWOD chips. AB - Digital microfluidic chips provide a new platform for manipulating chemicals for multi-step chemical synthesis or assays at the microscale. The organic solvents and reagents needed for these applications are often volatile, sensitive to contamination, and wetting, i.e. have contact angles of <90 degrees even on the highly hydrophobic surfaces (e.g., Teflon(r) or Cytop(r)) typically used on digital microfluidic chips. Furthermore, often the applications dictate that the processes are performed in a gas environment, not allowing the use of a filler liquid (e.g., oil). These properties pose challenges for delivering controlled volumes of liquid to the chip. An automated, simple, accurate and reliable method of delivering reagents from sealed, off-chip reservoirs is presented here. This platform overcomes the issues of evaporative losses of volatile solvents, cross contamination, and flooding of the chip by combining a syringe pump, a simple on chip liquid detector and a robust interface design. The impedance-based liquid detection requires only minimal added hardware to provide a feedback signal to ensure accurate volumes of volatile solvents are introduced to the chip, independent of time delays between dispensing operations. On-demand dispensing of multiple droplets of acetonitrile, a frequently used but difficult to handle solvent due to its wetting properties and volatility, was demonstrated and used to synthesize the positron emission tomography (PET) probe [(18)F]FDG reliably. PMID- 22825700 TI - Association between manganese superoxide dismutase gene polymorphism and breast cancer risk: a meta-analysis of 17,842 subjects. AB - The aim of this meta-analysis was to explore the association between the manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk, and to investigate the interaction of this gene polymorphism with known risk factors for breast cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) for breast cancer risk associated with co-dominant models [valine/alanine (Val/Ala) vs. Val/Val, Ala/Ala vs. Val/Val], a dominant model (Val/Ala + Ala/Ala vs. Val/Val) and a recessive model (Ala/Ala vs. Val/Ala + Val/Val) were statistically estimated. This meta-analysis included 8,102 breast cancer cases and 9,740 controls from 14 published case-control studies. The data revealed no significant association between the MnSOD polymorphism and the risk of developing breast cancer. However, upon subgroup analyses, the risk was significantly increased in premenopausal women with the dominant model of the MnSOD gene polymorphism (OR, 1.15; 95% CI, 1.01-1.31). Statistically significant increased risks were also identified in women with the MnSOD genotypes containing the Ala allele who had a tobacco smoking history (OR, 1.17; 95% CI, 1.02-1.34), a higher body mass index (OR, 1.26; 95% CI, 1.02-1.56) or who used oral contraceptives (OR, 1.98; 95% CI, 1.34-2.93). By contrast, there was no significant association between breast cancer risk and alcohol consumption and ethnicity. This meta analysis demonstrated no statistically significant association between the MnSOD gene polymorphism and breast cancer susceptibility, except in premenopausal women with certain unhealthy lifestyle habbits. PMID- 22825701 TI - Investigation of formally zerovalent Triphos iron complexes. AB - The reduction of Triphos [PhP(CH(2)CH(2)PPh(2))(2)] iron halide complexes has been explored, yielding formally zerovalent (kappa(3)-Triphos)Fe(kappa(2) Triphos) and (kappa(3)-Triphos)Fe(kappa(2)-Bpy). Electrochemical analysis, coupled with the metrical parameters of (kappa(3)-Triphos)Fe(kappa(2)-Bpy), reveal an electronic structure consistent with a pi-radical monoanion bipyridine chelate that is antiferromagnetically coupled to a low spin, Fe(I) metal center. PMID- 22825703 TI - Multiple sclerosis: TNF receptor 1 gene variant could explain failure of TNF blocking drugs in multiple sclerosis. PMID- 22825704 TI - Infectious disease: Pathogenesis of cerebral malaria-a step forward. PMID- 22825702 TI - The benefits of exercise training in multiple sclerosis. AB - Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and neurodegeneration within the CNS. This damage of CNS structures leads to deficits of body functions, which, in turn, affect patient activities, such as walking, and participation. The pathogenesis and resulting consequences of MS have been described as concepts within the International Classification of Functioning, Disability and Health (ICF) model- an international standard to describe and measure health and disability. Evidence suggests that exercise training in people with MS has the potential to target and improve many of the components outlined in the ICF model. Although the body of research examining the effects of exercise training on depression, cognition and participatory outcomes is not sufficiently developed, some preliminary evidence is promising. Exercise training is proposed to affect inflammation, neurodegeneration, and CNS structures, but current evidence is limited. In this Review, we discuss evidence from clinical trials that suggests beneficial effects of exercise training on muscle strength, aerobic capacity and walking performance, and on fatigue, gait, balance and quality of life. Issues with current studies and areas of future research are highlighted. PMID- 22825707 TI - Stroke: Misery perfusion in cerebrovascular disease--is it important? PMID- 22825711 TI - Application of a proteomic approach to identify proteins associated with primary graft non-function after liver transplantation. AB - Primary graft non-function (PNF) is a rare, life-threatening complication of liver transplantation. Increasing use of extended criteria donor pools and high risk recipients seem to influence the incidence of PNF. Primary failure is associated with high patient morbidity and inferior graft survival. The only available treatment for PNF is emergency hepatic retransplantation, which is also correlated with significant morbidity and mortality. Therefore, researchers are working to identify risk factors of diagnostic value to prevent PNF. The current study attempted to explore liver proteomic patterns in patients with PNF. Using two-dimensional gel electrophoresis and liquid chromatography-mass spectrometry (LC-MS), we compared liver protein homogenates from 3 patients with PNF to those obtained from 6 healthy liver samples to identify potential new biomarkers of PNF. Our comparisons revealed 21 proteins with differential expression (13 upregulated and 8 downregulated). Most of these proteins are involved in energy metabolism, lipid metabolism, peptide cleavage, cell differentiation, and apoptosis. Although none of these proteins appeared more than once in separate analyses, this preliminary study shows that two-dimensional gel electrophoresis and LC-MS may allow identification of characteristic proteins to be used as biomarkers of a life-threatening complication of liver transplantation. Larger scale analyses could improve patient care by finding suitable prognostic and therapeutic options. These data represent the first global proteomic approach to study PNF. PMID- 22825712 TI - Selecting speed-dependent pathways for a programmable nanoscale texture by wet interfaces. AB - The realization of well-defined and ordered structures on the nanoscale is a main issue in nanoscience and nanotechnology, biotechnology and other related fields like plastic or organic electronics. Among the bottom-up approaches, to date, self-assembly (equilibrium aggregates) received a major attention. In spite of this, far from equilibrium conditions allow for the generation of a wider landscape of organized systems depending on the set of control parameters employed. Under an adaptation vision of the structures, here we report some case studies showing how it is possible to programme and control the nanoscale features of ordered super- or supra-aggregates at wet interfaces by modulating the dynamic parameters. In particular, speed is foreseen as a threshold factor for changing the aggregation mechanism along with the shape and degree of order of the structures as well as, within a specific aggregation path, their size and defectivity. PMID- 22825710 TI - Central mechanisms of pain revealed through functional and structural MRI. AB - MR-based brain imaging technologies provide a suite of functional and structural metrics that can be used to test hypotheses about the CNS mechanisms underlying pain perception and chronification, from a cellular level to a systems level. Two types of functional MRI discussed in this review provide insight into pain mechanisms: stimulus-evoked fMRI and task-free ("resting state") fMRI. The former can assess how the brain responds to noxious or non-noxious stimuli normally or in a chronic pain state as a window into understanding pain, hyperalgesia and allodynia. The latter can assess functional connectivity reflecting synchronous ultra-slow frequency oscillation between brain areas. This provides insight into how brain areas work together as networks to produce pain and how these networks may be modified due to chronic pain. Perfusion MR (e.g., arterial spin labeling) can also provide task-free information pertaining to ongoing brain activity that may reflect spontaneous (ongoing) chronic pain. Structural MR techniques can be used to delineate gray and white matter abnormalities and markers of neuroinflammation associated with chronic pains. Functional and structural MRI findings point to brain and peripheral nerve abnormalities in patients with chronic pain, some of which are pre-existing and others that develop with prolonged pain (and related neuroinflammation) over time. Recent studies indicate that some structural brain abnormalities associated with chronic pain are reversible following effective pain treatment. These data together with findings from studies of individual differences suggest that some chronic pains arise from a combination of pre-existing vulnerabilities and sustained abnormal input. PMID- 22825713 TI - The N-terminal half of the connexin protein contains the core elements of the pore and voltage gates. AB - Connexins form channels with large aqueous pores that mediate fluxes of inorganic ions and biological signaling molecules. Studies aimed at identifying the connexin pore now include a crystal structure that provides details of putative pore-lining residues that need to be verified using independent biophysical approaches. Here we extended our initial cysteine-scanning studies of the TM1/E1 region of Cx46 hemichannels to include TM2 and TM3 transmembrane segments. No evidence of reactivity was observed in either TM2 or TM3 probed with small or large thiol-modifying reagents. Several identified pore residues in E1 of Cx46 have been verified in different Cx isoforms. Use of variety of thiol reagents indicates that the connexin hemichannel pore is large and flexible enough, at least in the extracellular part of the pore funnel, to accommodate uncommonly large side chains. We also find that that gating characteristics are largely determined by the same domains that constitute the pore. These data indicate that biophysical and structural studies are converging towards a view that the N terminal half of the Cx protein contains the principal components of the pore and gating elements, with NT, TM1 and E1 forming the pore funnel. PMID- 22825715 TI - The noncanonical functions of Cx43 in the heart. AB - There is abundant evidence showing that connexins form gap junctions. Yet this does not exclude the possibility that connexins can exert other functions, separate from that of gap junction (or even a permeable hemichannel) formation. Here, we focus on these noncanonical functions of connexin43 (Cx43), particularly in the heart. We describe two specific examples: the importance of Cx43 on intercellular adhesion, and the role of Cx43 in the function of the sodium channel. We propose that these two functions of Cx43 have important repercussions on the propagation of electrical activity in the heart, irrespective of the presence of permeable gap junction channels. Overall, the gap junction independent functions of Cx43 in cardiac electrophysiology emerge as an exciting area of future research. PMID- 22825714 TI - Degradation of endocytosed gap junctions by autophagosomal and endo-/lysosomal pathways: a perspective. AB - Gap junctions (GJs) are composed of tens to many thousands of double-membrane spanning GJ channels that cluster together to form densely packed channel arrays (termed GJ plaques) in apposing plasma membranes of neighboring cells. In addition to providing direct intercellular communication (GJIC, their hallmark function), GJs, based on their characteristic double-membrane-spanning configuration, likely also significantly contribute to physical cell-to-cell adhesion. Clearly, modulation (up-/down-regulation) of GJIC and of physical cell to-cell adhesion is as vitally important as the basic ability of GJ formation itself. Others and we have previously described that GJs can be removed from the plasma membrane via the internalization of entire GJ plaques (or portions thereof) in a cellular process that resembles clathrin-mediated endocytosis. GJ endocytosis results in the formation of double-membrane vesicles [termed annular gap junctions (AGJs) or connexosomes] in the cytoplasm of one of the coupled cells. Four recent independent studies, consistent with earlier ultrastructural analyses, demonstrate the degradation of endocytosed AGJ vesicles via autophagy. However, in TPA-treated cells others report degradation of AGJs via the endo /lysosomal degradation pathway. Here we summarize evidence that supports the concept that autophagy serves as the cellular default pathway for the degradation of internalized GJs. Furthermore, we highlight and discuss structural criteria that seem required for an alternate degradation via the endo-/lysosomal pathway. PMID- 22825716 TI - Design and implementation of a microelectrode assembly for use on noncontact in situ electroporation of adherent cells. AB - In situ electroporation of adherent cells provides significant advantages with respect to electroporation systems for suspension cells, such as causing minimal stress to cultured cells and simplifying and saving several steps within the process. In this study, a new electrode assembly design is shown and applied to in situ electroporate adherent cell lines growing in standard multiwell plates. We designed an interdigitated array of electrodes patterned on copper with printed circuit board technology and covered with nickel/gold. Small interelectrode distances were used to achieve effective electroporation with low voltages. Epoxy-based microseparators were constructed to avoid direct contact with the cells and to create more uniform electric fields. The device was successful in the electropermeabilization of two different adherent cell lines, C2C12 and HEK 293, as assessed by the intracellular delivery of the fluorescent dextran FD20S. Additionally, as a collateral effect, we observed cell electrofusion in HEK 293 cells, thus making this device also useful for performing cell fusion. In summary, we show the effectiveness of this minimally invasive device for electroporation of adherent cells cultured in standard multiwell plates. The cheap technologies used in the fabrication process of the electrode assembly indicate potential use as a low-cost, disposable device. PMID- 22825718 TI - Genomic CGH-assessed structural DNA alterations in rectal carcinoma as related to local recurrence following primary operation for cure. AB - Several factors determine overall outcome and possible local recurrence after curative surgery for rectal carcinoma. Surgical performance is usually believed to be the most pertinent factor, followed by adjuvant oncological treatment and tumor histopathology. However, chromosomal instability is common in colorectal cancer and tumor clones are assumed to differ in aggressiveness and potential of causing local recurrence. The aim of this study was, therefore, to evaluate if genetic alterations in primary rectal carcinoma are predictive of local recurrences. A large clinical database with linked bio-bank allowed for careful matching of two patient groups (R0) resected for rectal carcinoma. One group had developed early, isolated local recurrences and the other group seemed cured after 93 months follow-up. DNA from the primary tumors was analysed with array CGH (comparative genomic hybridization) including 55,000 genomic probes. DNA from all primary tumors in both groups displayed previously reported and well recognised DNA aberrations in colorectal carcinoma. Significant copy number gains were confirmed in the 4q31.1-31.22 region in DNA from tumors with subsequent local recurrence. Twenty-two affected genes in this region code for products with high relevance in tumor biology (p53 regulation, cell cycle activity, transcription). DNA from rectal carcinoma displayed well-known aberrations as described for colon carcinoma with no obvious prediction of local rectal recurrence. Gains in the 4q31.1-31.22 DNA region are highly potential for local recurrence despite R0 resection to be confirmed in larger patient materials. PMID- 22825717 TI - Shedding of phosphatidylserine from developing erythroid cells involves microtubule depolymerization and affects membrane lipid composition. AB - Phosphatidylserine (PS), which is normally localized in the cytoplasmic leaflet of the membrane, flip-flops to the external leaflet during aging of, or trauma to, cells. A fraction of this PS undergoes shedding into the extracellular milieu. PS externalization and shedding change during maturation of erythroid cells and affect the functioning, senescence and elimination of mature RBCs. Several lines of evidence suggest dependence of PS shedding on intracellular Ca concentration as well as on interaction between plasma membrane phospholipids and microtubules (MTs), the key components of the cytoskeleton. We investigated the effect of Ca flux and MT assembly on the distribution of PS across, and shedding from, the membranes of erythroid precursors. Cultured human and murine erythroid precursors were treated with the Ca ionophore A23187, the MT assembly enhancer paclitaxel (Taxol) or the inhibitor colchicine. PS externalization and shedding were measured by flow cytometry and the cholesterol/phospholipids in RBC membranes and supernatants, by 1H-NMR. We found that treatment with Taxol or colchicine resulted in a marked increase in PS externalization, while shedding was increased by colchicine but inhibited by Taxol. These results indicate that PS externalization is mediated by Ca flux, and PS shedding by both Ca flux and MT assembly. The cholesterol/phospholipid ratio in the membrane is modified by PS shedding; we now show that it was increased by colchicine and A23187, while taxol had no effect. In summary, the results indicate that the Ca flux and MT depolymerization of erythroid precursors mediate their PS externalization and shedding, which in turn changes their membrane composition. PMID- 22825719 TI - Adipose-derived mesenchymal stem cells: biology and potential applications. AB - Adipose tissue is derived from the mesoderm during embryonic development and is present in every mammalian species, located throughout the body. Adipose tissue serves as an endocrine organ, functioning to maintain energy metabolism through the storage of lipids. While two types of adipose tissue exist (brown and white), white adipose yields the commonly studied adipose-derived stem cells (ASCs). Adipose-derived stem cells provide a promising future in the field of tissue engineering and regenerative medicine. Due to their wide availability and ability to differentiate into other tissue types of the mesoderm-including bone, cartilage, muscle, and adipose-ASCs may serve a wide variety of applications. Adipose stem cells have been utilized in studies addressing osteoarthritis, diabetes mellitus, heart disease, and soft tissue regeneration and reconstruction after mastectomy and facial repair. Various delivery systems and scaffolds to incorporate adipose stem cells have also been established. Adipose stem cells have been studied in vitro and in vivo. Much information in vitro has been obtained on adipose stem cell potency and biology as a function of donor gender, body mass index, and anatomical location. Further in vitro studies have examined the various cell populations within the heterogeneous population within the stromal vascular fraction (SVF) from which ASCs are obtained. While many animal models are used to investigate adipose tissue, preclinical in vivo experiments are most widely conducted in the mouse model. Common analyses of animal studies utilizing ASCs include pre-labeling cells and immunostaining cells. PMID- 22825721 TI - Controlling magnetic communication through aromatic bridges by variation in torsion angle. AB - A series of heteroaromatic bridging ligands are employed in the synthesis of a family of paramagnetic, heterometallic ring dimers. The extent of spin propagation between the rings via the organic conduit is investigated through micro-SQUID magnetometry and EPR spectroscopy from which conclusions over the mechanism of spin-communication are drawn. PMID- 22825720 TI - Prospective isolation and characterization of human bone marrow-derived MSCs. AB - There is an increasing interest in adult stem cells, especially mesenchymal stem/stromal cells (MSCs), in hematology and regenerative medicine because of the simplicity of isolation and ex vivo expansion of these cells. Conventionally, MSCs are functionally isolated from tissue based on their capacity to adhere to the surface of culture flasks. This isolation procedure is hampered by the unpredictable influence of secreted molecules and interactions with co-cultured hematopoietic and other unrelated cells, as well as by the arbitrarily selected removal time of non-adherent cells prior to the expansion of MSCs. Finally, functionally isolated cells do not provide biological information about the starting population. To circumvent these limitations, several strategies have been developed to facilitate the prospective isolation of MSCs based on the selective expression or absence of surface markers. The isolation and ex vivo expansion of these cells require an adequate quality control of the source and product. Here we summarize the most frequently used markers and introduce new targets for antibody-based isolation and characterization of bone marrow-derived MSCs. PMID- 22825723 TI - [Influence of carbon fiber foot orthoses on plantar pressure distribution in cycling]. AB - BACKGROUND: Several equipment interventions like optimizing seat position or optimizing shoe/insole/pedal interface are suggested to reduce overuse injury in cycling. Data analyzing clinical or biomechanical effects of those interventions is sparse. Foot orthoses out of carbon fiber are one possibility to alter the interface between foot and pedal. The aim of this study was therefore to analyze plantar pressure distribution in carbon fiber foot orthoses in comparison to standard insoles of commercially available cycling shoes. MATERIALS AND METHODS: 11 painfree triathletes (Age: 29+/-9, 1.77+/-0.04 m, 68+/-5 kg) were tested on a cycle ergometer at 60 and 90 rotations per minute (rpm) at workloads of 200 and 300 Watts. Subjects wore in randomized order a cycling shoe with its standard insole (control condition CO) or the shoe with carbon fiber foot orthoses (Condition CA). Mean peak pressure out of 30 movement cycles were extracted for the total foot and specific foot regions (rear, mid, fore foot (medial, central, lateral) and toe region). Three-factor ANOVAs (factor foot orthoses, rpm, workload) for repeated measures (alpha = 0.05) were used to analyze the main question of a foot orthoses effect on peak in-shoe plantar pressure. RESULTS: Peak pressures in the total foot were in a range of 70-75 kPa for 200 Watts (W) (300 W: 85-110 kPa). The carbon fiber foot orthoses reduced peak pressures by 4,1% compared to the standard insole (p = 0,10). In the foot regions rear (-16,6 %, p < 0.001), mid (-20,0 %, p < 0.001) and fore foot (-5.9 %, p < 0.03) CA reduced peak pressure compared to CO. In the toe region, peak pressure was higher in CA (+16,2 %) compared to CO (p < 0,001). The lateral fore foot showed higher peak pressures in CA (+34 %) and CO (+59 %) compared to medial and central fore foot. CONCLUSION: Carbon fiber can serve as a suitable material for foot orthoses manufacturing in cycling. Plantar pressures do not increase due to the stiffness of the carbon. Individual customization may have the potential to reduce peak pressure in certain foot areas. PMID- 22825724 TI - Identification of a novel population in high-grade oligodendroglial tumors not deleted on 1p/19q using array CGH. AB - Oligodendroglial tumors (ODTs) are primary tumors of the central nervous system that show recurrent codeletion of whole chromosome arms 1p and 19q. Non-1p/19q deleted high-grade ODTs can present other genetic aberrations, CDKN2A deletion (9p21.3), EGFR amplification (7p11.2) and/or chromosome 10 loss, which are associated with a poor prognosis. The identification of these abnormalities allowed drafting a histo-molecular classification. The aim of this study was to precisely identify, using array CGH, the genomic hallmarks of these tumors, particularly those that are not deleted on 1p/19q. We studied 14 formalin-fixed paraffin-embedded high-grade ODTs using pangenomic oligonucleotide array CGH with an average resolution of 22.3 kb. The 1p/19q codeletion was found in five anaplastic oligodendrogliomas. The three genomic aberrations carrying a poor prognosis were found, most often associated, in five out of nine tumors not deleted on 1p/19q. In addition, four recurrent copy number alterations, involving genes that participate to cell growth and cycle, were found to be strongly associated in five tumors not deleted on 1p/19q: gain or amplification at 1q32.1 (MDM4, PIK3C2B genes), 12q14.1 (CDK4 gene), 12q14.3-q15 (MDM2 gene) and homozygous deletion at 22q13.1 (APOBEC3B gene). MDM2, MDM4, CDK4 and PIK3C2B are known for potentially being amplified or overexpressed in high-grade gliomas. However, the involvement of APOBEC3B, coding for mRNA edition enzyme, is described here for the first time. Our results show a strong association between these four alterations. Therefore, this can open a perspective for a novel subgroup in high-grade ODTs not deleted on 1p/19q. PMID- 22825725 TI - Allergic fungal otomastoiditis: a case report. AB - Allergic mucin is described as thick, peanut butter-like mucus impacted in the paranasal sinuses of patients with allergic fungal rhinosinusitis. The presence of allergic mucin in the middle ear has never been reported. We encountered a 65 year-old female with allergic mucin found impacted in her left middle ear and mastoid cavity during revised tympanoplasty surgery at our institute. Bilateral endoscopic sinus surgery performed 3 months later showed no evidence of fungal infection or allergic mucin in her paranasal sinuses. We report the case herein and propose the term allergic fungal otomastoiditis for this disease entity. PMID- 22825726 TI - [Zn(phen)(O,N,O)(H2O)] and [Zn(phen)(O,N)(H2O)] with O,N,O is 2,6-dipicolinate and N,O is L-threoninate: synthesis, characterization, and biomedical properties. AB - Two ternary Zn(II) complexes, with 1,10-phenanthroline (phen) as the main ligand and a carboxylate-containing ligand [dipicolinate (dipico) or L-threoninate (L Thr)] as the subsidiary ligand, were prepared and characterized by elemental analysis, Fourier transform IR, UV, and fluorescence spectroscopy, X-ray diffraction, molar conductivity, and electrospray ionization mass spectrometry. X ray structure analysis shows that both [Zn(phen)(dipico)(H(2)O)].H(2)O (1) and [Zn(phen)(L-Thr)(H(2)O)Cl].2H(2)O (2) have octahedral geometry about the Zn(II) atom. Both complexes can inhibit topoisomerase I, and have better anticancer activity than cisplatin against nasopharyngeal cancer cell lines, HK1 and HONE-1, with concentrations causing 50 % inhibition of cell proliferation (IC(50)) in the low micromolar range. Complex 2 has the highest therapeutic index for HK1. Both Zn(II) complexes can induce cell death by apoptosis. Changing the subsidiary ligand in the Zn(II) complexes affects the UV-fluorescence spectral properties of the coordinated phen ligand, the binding affinity for some DNA sequences, nucleobase sequence-selective binding, the phase at which cell cycle progression was arrested for treated cancer cells, and their therapeutic index. PMID- 22825727 TI - Spondyloarthritis: CASPAR criteria in early psoriatic arthritis. PMID- 22825733 TI - Osteoarthritis: OA chondrocytes made senescent by genomic DNA damage. PMID- 22825734 TI - Experimental arthritis: synovial remodelling and vascularization by Dickkopf-1 in osteoarthritis. PMID- 22825731 TI - Clinical features of polymyalgia rheumatica and giant cell arteritis. AB - Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are inflammatory diseases that typically affect white individuals >50 years. Women are affected ~2 3 times more often than men. PMR and GCA occur together more frequently than expected by chance. The main symptoms of PMR are pain and stiffness in the shoulders, and often in the neck and pelvic girdle. Imaging studies reveal inflammation of joints and bursae of the affected areas. GCA is a large-vessel and medium-vessel arteritis predominantly involving the branches of the aortic arch. The typical clinical manifestations of GCA are new headache, jaw claudication and visual loss. PMR and GCA usually remit within 6 months to 2 years from disease onset. Some patients, however, have a relapsing course and might require long-standing treatment. Diagnosis of PMR and GCA is based on clinical features and elevated levels of inflammatory markers. Temporal artery biopsy remains the gold standard to support the diagnosis of GCA; imaging studies are useful to delineate large-vessel involvement in GCA. Glucocorticoids remain the cornerstone of treatment of both PMR and GCA, but patients with GCA require higher doses. Synthetic immunosuppressive drugs also have a role in disease management, whereas the role of biologic agents is currently unclear. PMID- 22825735 TI - Autoimmunity: disordered NETs implicated in pathogenesis of MPO-ANCA-associated vasculitis. PMID- 22825736 TI - The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo. AB - AZD7762, a novel checkpoint kinase 1 (Chk 1)inhibitor, has been proven to sensitize various tumor cells to DNA damage. However, whether or not AZD7762 sensitizes breast cancer cells to radiation has not been defined. In the present study, we aimed to demonstrate for the first time, that AZD7762 not only promotes radiation-induced apoptosis and mitotic catastrophe of p53 mutant T47D breast cancer cells in vitro, but also delays their xenograft growth in response to radiation in vivo. Our mechanistic study showed that AZD7762 treatment resulted in the abrogation of radiation-induced G2/M arrest and the inhibition of radiation damage repair as demonstrated by increased radiation-induced gammaH2AX expression and decreased RAD51 protein expression. These results suggest that AZD7762 may effectively abrogate radiation-induced G2/M arrest and inhibit radiation damage repair in conferring radiosensitivity on p53 mutant T47D breast cancer cells, by promoting radiation-induced apoptosis and mitotic catastrophe. The clinical application of AZD7762, as an adjuvant in the radiotherapy of breast cancers, should be further explored. PMID- 22825740 TI - Hydrodynamic trapping of Tetrahymena thermophila for the long-term monitoring of cell behaviors. AB - Microfluidic trapping technology has been widely applied for single-cell observation in order to reveal characteristic cell behaviors. However, this strategy has yet to be tested for monitoring highly motile cells, which are often biologically important. In this paper, we seek the conditions that enable effective and long-term trapping of a prominent model ciliate Tetrahymena thermophila within a hydrodynamic microfluidic device. Although motility and flexibility of T. thermophila make it difficult to avoid escaping from the trap, we show that tuning some key parameters in the hydrodynamic circuit was effective to achieve approximately 40 h cell retention, which is long enough to monitor cell behaviors over several generations. Here, we demonstrate the real-time observation of cell division and phagocytic digestion, revealing interesting phenomena such as a wide distribution in doubling time in a poor synthetic medium and heterogeneous time courses in digestion processes. Our results present a strategy for trapping highly motile ciliate cells in order to study the dynamic behaviors of single cells. PMID- 22825739 TI - Relationship between apolipoprotein E4 genotype and white matter integrity in HIV positive young adults in South Africa. AB - HIV-associated dementia (HAD) is a serious neuropsychiatric disorder affecting people with AIDS. Host genotype may affect the pathogenesis of HIV in the central nervous system (CNS). One gene relevant to the individual variation in acquiring HAD may be Apolipoprotein E (ApoE). We aimed to investigate the relationship of ApoE genotype to neuropsychological function and white matter integrity of the corpus callosum in a region of interest a priori analysis of HIV-positive subjects with clade C HIV. Forty-five subjects underwent ApoE genotyping, neuropsychological testing, and diffusion tensor imaging (DTI). Subjects (n = 24) with at least one epsilon4 allele when compared to subjects with no epsilon4 allele (n = 19) had significantly decreased immediate and delayed recall on the Hopkins Verbal Learning test (p = 0.05) and significantly decreased fractional anisotrophy in the corpus callosum (p = 0.007). These data indicate that the epsilon4 allelic variant of ApoE is associated with memory impairment and white matter damage of the corpus callosum in HIV-positive subjects. PMID- 22825738 TI - TLR-4-dependent and -independent mechanisms of fetal brain injury in the setting of preterm birth. AB - In this study, we sought to assess how essential activation of toll-like receptor 4 (TLR-4) is to fetal brain injury from intrauterine inflammation. Both wild-type and TLR-4 mutant fetal central nervous system cells were exposed to inflammation using lipopolysaccharide in vivo or in vitro. Inflammation could not induce neuronal injury in the absence of glial cells, in either wild-type or TLR-4 mutant neurons. However, injured neurons could induce injury in other neurons regardless of TLR-4 competency. Our results indicate that initiation of neuronal injury is a TLR-4-dependent event, while propagation is a TLR-4-independent event. PMID- 22825741 TI - Accelerated C-N bond formation in dropcast thin films on ambient surfaces. AB - The aza-Michael addition and the Mannich condensation occur in thin films deposited on ambient surfaces. The reagents for both C-N bond formation reactions were transferred onto the surface by drop-casting using a micropipette. The surface reactions were found to be much more efficient than the corresponding bulk solution-phase reactions performed on the same scale in the same acetonitrile solvent. The increase in rate of product formation in the thin film is attributed to solvent evaporation in the open air which results in reagent concentration and produces rate acceleration similar to that seen in evaporating droplets in desorption electrospray ionization. This thin film procedure has potential for the rapid synthesis of reaction products on a small scale, as well as allowing rapid derivatization of analytes to produce forms that are easily ionized by electrospray ionization. Analysis of the derivatized sample directly from the reaction surface through the use of desorption electrospray ionization is also demonstrated. PMID- 22825742 TI - Hexuronic acid stereochemistry determination in chondroitin sulfate glycosaminoglycan oligosaccharides by electron detachment dissociation. AB - Electron detachment dissociation (EDD) has previously provided stereo-specific product ions that allow for the assignment of the acidic C-5stereochemistry in heparan sulfate glycosaminoglycans (GAGs), but application of the same methodology to an epimer pair in the chondroitin sulfate glycoform class does not provide the same result. A series of experiments have been conducted in which glycosaminoglycan precursor ions are independently activated by electron detachment dissociation (EDD), electron induced dissociation (EID), and negative electron transfer dissociation (NETD) to assign the stereochemistry in chondroitin sulfate (CS) epimers and investigate the mechanisms for product ion formation during EDD in CS glycoforms. This approach allows for the assignment of electronic excitation products formed by EID and detachment products to radical pathways in NETD, both of which occur simultaneously during EDD. The uronic acid stereochemistry in electron detachment spectra produces intensity differences when assigned glycosidic and cross-ring cleavages are compared. The variations in the intensities of the doubly deprotonated (0,2)X(3) and Y(3) ions have been shown to be indicative of CS-A/DS composition during the CID of binary mixtures. These ions can provide insight into the uronic acid composition of binary mixtures in EDD, but the relative abundances, although reproducible, are low compared with those in a CID spectrum acquired on an ion trap. The application of principal component analysis (PCA) presents a multivariate approach to determining the uronic acid stereochemistry spectra of these GAGs by taking advantage of the reproducible peak distributions produced by electron detachment. PMID- 22825743 TI - Tandem mass spectrometry of heparan sulfate negative ions: sulfate loss patterns and chemical modification methods for improvement of product ion profiles. AB - Heparan sulfate (HS) is a polysaccharide modified with sulfation, acetylation, and epimerization that enable its binding with protein ligands and regulation of important biological processes. Tandem mass spectrometry has been employed to sequence linear biomolecules e.g., proteins and peptides. However, its application in structural characterization of HS is limited due to the neutral loss of sulfate (SO(3)) during collisional induced dissociation (CID). In this report, we studied the dissociation patterns of HS disaccharides and demonstrate that the N-sulfate (N-S) bond is especially facile during CID. We identified factors that influence the propensities of such losses from precursor ions and proposed a Free Proton Index (FPI) to help select ions that are able to produce meaningful backbone dissociations. We then investigated the thermodynamics and kinetics of SO(3) loss from sulfates that are protonated, deprotonated, and metal adducted using density functional theory computations. The calculations showed that sulfate loss from a protonated site was much more facile than that from a deprotonated or metal-adducted site. Further, the loss of SO(3) from N-sulfate was energetically favored by 3-8 kcal/mol in transition states relative to O sulfates, making it more prone to this process by a substantial factor. In order to reduce the FPI, representing the number of labile sulfates in HS native chains and oligosaccharides, we developed a series of chemical modifications to selectively replace the N-sulfates of the glucosamine with deuterated acetyl group. These modifications effectively reduced the sulfate density on the HS oligosaccharides and generated considerably more backbone dissociation using on line LC/tandem MS. PMID- 22825744 TI - Evaluation of nanoporous gold with controlled surface structures for laser desorption ionization (LDI) analysis: surface area versus LDI signal intensity. AB - The structural effect of a nanoporous gold (NPG) surface on the signal intensities of laser desorption ionization-mass spectrometry (LDI-MS) were investigated using NPG surfaces with controlled structures. The relationship between surface area and LDI efficiency was compared and evaluated. Comparisons between bare flat gold and NPG surfaces show that nanostructures increased LDI efficiency. We also found that the LDI signal decreased with increasing depth of nanoporous layers, thus increasing the surface area. This result agrees with a previous report (Shin J. A. et al., J. Am. Soc. Mass Spectrom. 2010, 21, 989) in which the LDI efficiency of small molecules decreased for ZnO wires with longer lengths. This observation was explained by the penetration and deposition of samples into locations inaccessible to photons because of structural screening. The LDI-MS analysis of oils with NPG surfaces (but without matrix) showed the same trend whereby the NPG with about a 200 nm depth of porous area showed the highest sensitivity. This study clearly shows that the active surface area for solution chemistry can differ from LDI-MS and that NPGs can function as a substrate for LDI oil analysis. PMID- 22825745 TI - Alterations of MEN1 and E-cadherin/beta-catenin complex in sporadic pulmonary carcinoids. AB - Pulmonary carcinoids, distinct in typical and atypical, represent 2-5% of all primary lung tumors. The aim of this study was to investigate the molecular alterations correlated with the development of this form of neoplasms. A collection of 38 paraffin-embedded apparently sporadic carcinoids was investigated, through a combined study, for protein expression/localization of menin, p53, beta-catenin and E-cadherin and for mutational analysis of the MEN1, TP53 and CTNNB1 genes. Menin was expressed in 71% of cases, with a prevalent cytoplasmic (c) localization, beta-catenin was expressed in 68.4% of cases, of which 36.8% with a membranous (m) and 31.6% with a cytoplasmic localization. Membranous E-cadherin immunoreactivity was detected in 84.2% cases, nuclear p53 expression in 5.3% of cases. Positive correlation was found between c-menin and c beta-catenin expression (rho=0.439, P=0.008). In addition, m-beta-catenin showed a positive correlation with both c-beta-catenin and E-cadherin expression (rho=0.380, P=0.022 and rho=0.360, P=0.040, respectively). With regard to the E cadherin/beta-catenin complex, we found also a significant positive correlation between c-menin and 'disarrayed' beta-catenin expression (rho=0.481, P=0.007). MEN1 gene variants were characterized in 34% of cases. c-menin was more highly expressed in tumors with MEN1 variants, compared to tumors without MEN1 variants (P=0.023). Three nucleotide variants of TP53 were also detected. This study confirms the involvement of the MEN1 gene in the development of sporadic pulmonary carcinoids, demonstrates the accumulation of menin in the cytoplasm, and indicates that the disarrayed pattern of the complex significantly correlates with c-menin accumulation. PMID- 22825746 TI - NSCT-based multimodal medical image fusion using pulse-coupled neural network and modified spatial frequency. AB - In this article, a novel multimodal medical image fusion (MIF) method based on non-subsampled contourlet transform (NSCT) and pulse-coupled neural network (PCNN) is presented. The proposed MIF scheme exploits the advantages of both the NSCT and the PCNN to obtain better fusion results. The source medical images are first decomposed by NSCT. The low-frequency subbands (LFSs) are fused using the 'max selection' rule. For fusing the high-frequency subbands (HFSs), a PCNN model is utilized. Modified spatial frequency in NSCT domain is input to motivate the PCNN, and coefficients in NSCT domain with large firing times are selected as coefficients of the fused image. Finally, inverse NSCT (INSCT) is applied to get the fused image. Subjective as well as objective analysis of the results and comparisons with state-of-the-art MIF techniques show the effectiveness of the proposed scheme in fusing multimodal medical images. PMID- 22825747 TI - Efficacy and safety of endoscopic laser lithotripsy for urinary stone treatment in children. AB - We reviewed our 6 years of experience with endoscopic holmium: yttrium aluminum garnet (YAG) laser lithotripsy for treatment of urinary stones in different locations in 111 children. A retrospective review was performed on endoscopic holmium: YAG laser lithotripsy procedures performed to treat stones in children between March 2006 and March 2012. In total, 120 laser lithotripsy procedures were performed to treat 131 stones in 111 children (80 males and 31 females; age range, 11 months to 16 years; median age, 6 years). Stones were located in the kidney in 48 cases (36.7 %), ureter in 52 (39.7 %), bladder in 21 (16.0 %), and urethra in 10 (7.6 %). Stone size ranged from 4 to 30 mm (mean, 12.8 mm), and anesthesia duration was 10-170 min (mean, 56 min). Forty-four ureters required balloon dilation, and 61 double J stents were inserted. Follow-up ranged from 3 to 75 months (mean, 35 months). Complete stone clearance was achieved at the end of the procedure in 102 (91.9 %) patients (age < 7 years, 93.3 % vs. age >= 7 years, 90.2 %; p > 0.05). The success rate was 81.3 % for kidney stones (<10 mm, 90.9 % vs. >= 10 mm, 78.4 %; p > 0.05) and 100 % for the ureter, bladder, and urethral stones. Overall success rate with extracorporeal shockwave lithotripsy was 100 %. No major complications were encountered during or after the procedures. These results confirm the effectiveness and safety of holmium laser lithotripsy for treating all urinary stone locations in children of all ages. PMID- 22825748 TI - In vitro proliferation and differentiation of adipose-derived stem cells isolated using anti-CD105 magnetic beads. AB - The present study aimed to investigate the feasibility of isolating adipose derived stem cells (ADSCs) by selecting cells that express the surface receptor CD105. Surface antigen expression of the unsorted cells was undertaken using FACS analysis. Primary adipose-derived cells were isolated. The second passage cells were incubated with anti-CD105 magnetic beads, and separated using a magnetic separator. Cell growth and colony formation was determined by counting and Giemsa staining, respectively. Cells also underwent histological immunohistochemical, and RT-PCR analyses to determine their chondrogenic, adipogenic and osteogenic potential. Increased cell proliferation and colony formation was observed in CD105-positive (CD105+) as compared to the CD105-negative (CD105-) cells (P<0.001). Following induction, the expression of type II collagen and the number of calcium deposits and lipid droplets in the CD105+ ADCs were markedly higher than in the CD105- ADCs. Furthermore, increased alkaline phosphatase (AKP), leptin and PPARgamma2 mRNA expression was detected in the CD105+ ADCs (P<0.01). Isolation of CD105+ ADSCs by MACS was feasible. Thus, CD105 can be used as a relatively specific marker for the selection of ADSCs. Although the chondrogenic, adipogenic and osteogenic potential of these cells is suggestive of their potential for use in tissue engineering treatments, further in vivo studies are necessary. PMID- 22825749 TI - Retinol assessment among women and children in sahelian mobile pastoralists. AB - Micronutrient deficiencies are widespread in developing countries, particularly in remote communities such as mobile pastoralists. The nutritional and vitamin A status of this population is not well-documented in Chad. This study assessed serum retinol levels among women and children under five-year-old in nomadic and semi-nomadic pastoralist and rural-settled communities, who are similarly exposed to risk factors such as gastrointestinal parasitic infection, anaemia and emaciation. The novel method of portable fluorometry was used for the first time to measure beta-carotene and retinol levels in a pastoral nomadic area. Moderate level blood retinol deficiency (<0.7 MUmol/L) was observed in 5% (CI 1-11) of nomadic, 29% (CI 13-45) of semi-nomadic and 22% (CI 8-35) of sedentary women. In children, 1% (CI 0.1-4), 17% (CI 9-25) and 28% (CI 18-39), respectively, had moderate level blood retinol deficiency. In nomadic communities, women and children had blood retinol levels close to normal. Deficiency of retinol was strongly linked with lifestyle (nomadic, semi-nomadic and settled) among women and lifestyle and age among children. The results support an ecological linkage between human retinol levels and livestock milk retinol. This study shows the feasibility of portable retinol and beta-carotene measurement in human blood as well as human and animal milk under remote field conditions, but the approach requires further validation. PMID- 22825750 TI - Fatty acid-RGD peptide amphiphile micelles as potential paclitaxel delivery carriers to alpha(v)beta3 integrin overexpressing tumors. AB - PURPOSE: To design and synthesize fatty acid-RGD peptide amphiphiles with ADA linker for their potential delivery of hydrophobic drugs like paclitaxel targeted to alpha(v)beta(3) integrin overexpressing tumors. METHODS: Four amphiphiles - C16 or C18 fatty acid-RGD peptide and ADA linker were designed and synthesized. CMC, size and zeta potential of the amphiphiles were determined. FITC loaded micelles uptake into A2058 melanoma cells was investigated at 4 degrees C and 37 degrees C using confocal microscopy. Paclitaxel was loaded into micelles, their encapsulation efficiency and cytotoxicity of micelles was evaluated. The stability of the micelles was determined using FRET method. RESULTS: Mass, (1)H NMR and HPLC analysis confirmed the formation of amphiphiles and their purity. Among the amphiphiles, C18-(ADA)(2)-RGD amphiphile exhibited lowest CMC (9.00 +/- 1.73 MUM) and its micelles had suitable size (194.63 +/- 44.86 nm) and zeta potential (0.27 +/- 1.96 mV) for targeting. The cellular uptake of the micelles was temperature dependent and the micelles were stable. The IC50 of paclitaxel loaded in micelles decreased 50% in alpha(v)beta(3) integrin overexpressing cells and showed a 4 fold increase in normal cells when compared to free paclitaxel. CONCLUSION: Amphiphiles of fatty acids-ADA-RGD were synthesized. These amphiphiles formed stable micelles and were effective as targeted delivery carriers to alpha(v)beta(3) integrin overexpressing tumors. PMID- 22825751 TI - The role of recombinant epidermal growth factor and serotonin in the stimulation of tumor growth in a SCCHN xenograft model. AB - One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0 phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0 arresting cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit 562 cells were injected into NMRI-Foxn1nu mice. Treatment was performed with 15 ug murine or human EGF, or 200 ug serotonin. The control mice were treated with Lactated Ringer's solution (5 mice/group). Tumor size was measured on days 4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN tumors. PMID- 22825752 TI - MicroRNA-9 suppresses uveal melanoma cell migration and invasion through the NF kappaB1 pathway. AB - The aggressive course of uveal melanoma is believed to reflect its unusually invasive and metastatic nature, which is associated with the nuclear factor kappaB (NF-kappaB) pathway. MicroRNAs (miRNAs) have been implicated in the regulation of various biological and pathological processes in cancer, however, the special role of miR-9 in uveal melanoma metastasis is largely unknown. In the present study, we showed that miR-9 is significantly reduced in highly invasive uveal melanoma cell lines, and suppressed migration and invasion of highly invasive cells. Furthermore, miR-9 negatively modulated NF-kappaB1 expression by direct targeting at its 3'-UTRs. Additionally, downstream targets of NF-kappaB1, such as MMP-2, MMP-9 and VEGFA, were regulated by miR-9 in the same pattern as NF kappaB1. Therefore, miR-9 suppresses uveal melanoma cell migration and invasion partly through downregulation of the NF-kappaB1 signaling pathway. PMID- 22825753 TI - Isolation of head and neck squamous carcinoma cancer stem-like cells in a syngeneic mouse model and analysis of hypoxia effect. AB - The incidence of oral tumors is increasing around the world and despite recent advances in early detection and diagnosis, current treatments are still unsatisfactory. Recent data suggest that tumor persistence and recurrence could be due to the presence of a rare cell population called cancer stem cells (CSCs), which are generally spared by traditional treatments. Therefore, identification and characterization of CSCs are extremely important to develop novel and effective treatment strategies for cancer. The aim of this study was to identify and isolate CSCs in an established murine head and neck squamous cell carcinoma (HNSCC) cell line and to investigate the influence of hypoxic conditions on the isolated cell popul-ation. Using the expression of the aldehyde dehydrogenase 1 (ALDH1) enzymatic activity, which is now recognized as a CSC marker in various tumors, we isolated a cell population expressing high levels of ALDH1 (ALDH1high) representing 1+/-0.6% in the murine SCC-VII cell line. These cells were injected subcutaneously in syngeneic animals to evaluate their tumorigenic properties. For the lowest injected cell dose (250 injected cells), tumor occurrence and median tumor size were higher in ALDH1high injected mice than in ALDH1low injected mice. Following an in vivo passage and culture in serum-free medium, the percentage of ALDH1high cells increased by 3-fold in SCC-VII CSCs (oral spheres) compared to the SCC-VII cell line. This percentage was further increased when oral spheres were cultured under hypoxic conditions. In conclusion, this study reports for the first time the isolation of HNSCC CSCs in a syngeneic mouse model and the use of hypoxia as a method to further enrich the ALDH1high cell population. PMID- 22825754 TI - Predicting longitudinal trajectories of health probabilities with random-effects multinomial logit regression. AB - Researchers often encounter longitudinal health data characterized with three or more ordinal or nominal categories. Random-effects multinomial logit models are generally applied to account for potential lack of independence inherent in such clustered data. When parameter estimates are used to describe longitudinal processes, however, random effects, both between and within individuals, need to be retransformed for correctly predicting outcome probabilities. This study attempts to go beyond existing work by developing a retransformation method that derives longitudinal growth trajectories of unbiased health probabilities. We estimated variances of the predicted probabilities by using the delta method. Additionally, we transformed the covariates' regression coefficients on the multinomial logit function, not substantively meaningful, to the conditional effects on the predicted probabilities. The empirical illustration uses the longitudinal data from the Asset and Health Dynamics among the Oldest Old. Our analysis compared three sets of the predicted probabilities of three health states at six time points, obtained from, respectively, the retransformation method, the best linear unbiased prediction, and the fixed-effects approach. The results demonstrate that neglect of retransforming random errors in the random effects multinomial logit model results in severely biased longitudinal trajectories of health probabilities as well as overestimated effects of covariates on the probabilities. PMID- 22825755 TI - [Superficial venous thrombosis. A review]. AB - This review summarizes the epidemiology, clinical aspects, diagnosis and new therapeutic options of the superficial venous thrombosis. An important new finding is, that the thrombophlebitis is actually a thrombosis, which occurs in an intra- or epifascial vein. It can be associated with deep venous thrombosis or pulmonary embolism, thus carrying considerable risk. Other underlying diseases such as underlying tumors or infections as well as acquired or inherited disorders of coagulation must be considered. New placebo-controlled studies show a clear benefit for low molecular weight heparin or the pentasaccharide fondaparinux. In addition to the medical treatment, compression is recommended for superficial venous thrombosis in varicose veins, but not in normal veins. PMID- 22825756 TI - [Pityriasis rubra pilaris]. AB - Pityriasis rubra pilaris is an inflammatory papulosquamous skin disease of unknown etiology. Incidence rates vary between 1:5,000-1:50,000. Six subtypes are differentiated on clinical background. The juvenile circumscribed subtype has best prognosis. Generalized disease impairs quality of life of patients. It is associated with various complications and comorbidities. Treatment of pityriasis rubra pilaris is challenging. Retinoids are first line drugs. In recalcitrant cases, tumor necrosis factor-alpha inhibitors have been used successfully. PMID- 22825757 TI - Role of the p38 MAPK signaling pathway in mediating interleukin-28A-induced migration of UMUC-3 cells. AB - Although interleukin-28A (IL-28A) is believed to have an antiviral effect, its role in tumor migration requires further examination. The present study was intended to verify the effect of IL-28A on the migration of UMUC-3 bladder cancer cells. IL-28A and its receptor IL-28AR1 mRNA were detected in UMUC-3 cells. Although exogenous IL-28A showed no effect on cell proliferation, a wound-healing migration assay showed that the migration of UMUC-3 cells was induced by IL-28A. Furthermore, treatment of the cells with IL-28A significantly promoted MMP-9 expression via binding activities of NF-kappaB and AP-1. IL-28A also induced the activation of p38 MAPK and Jak2-Stat2 signaling. Using the p38 MAPK inhibitor SB203580 and the dominant-negative plasmid DN-p38, we found evidence that the inhibition of p38 MAPK signaling suppressed the effects of IL-28A including wound healing migration and MMP-9 expression by activation of NF-kappaB and AP-1 binding in UMUC-3 cells. However, Jak-2 inhibition by AG490 did not affect IL-28A induced migration of UMUC-3 cells. Collectively, we suggest for the first time that the p38 MAPK pathway mediates IL-28A-induced cell migration through MMP-9 expression by activating NF-kappaB and AP-1 binding motifs. PMID- 22825758 TI - [Current trends of fetal echocardiography]. PMID- 22825759 TI - [Speckle tracking--a new ultrasound tool for the assessment of fetal myocardial function]. AB - Speckle tracking is a new ultrasound tool to assess 2D ventricular global and segmental myocardial velocity and deformation (strain, strain rate). Multiple factors such as fetal motion, high heart rates, low blood pressure, small size of the heart, physiological cardiac translation, filling and maturational changes of myocardium, polyhydramnion, maternal obesity and aortic pulsation can degrade the image quality and result in artifacts and measurement errors which may have an impact on the final analysis. Therefore deformation indices such as strain and strain rate offer a quantitative technique for the estimation of global and segmental myocardial function and contractility. At present longitudinal peak systolic strain is the most commonly applied deformation parameter used to analyse segmental and global myocardial contractility in adults. When obtained using Doppler methods, these measurements are angle dependent, whereas speckle tracking techniques overcome the limitations of Doppler echocardiography which is a particular advantage in foetal echocardiography. Nevertheless, the time and training necessary to acquire high-quality video clips limit the implementation of speckle tracking into clinical routine. It is not yet clear whether this new technique will identify subclinical myocardial impairment earlier than with current techniques or allow for better discrimination between healthy fetuses and fetuses with congenital heart disease. The clinical use of speckle tracking will have to be demonstrated in larger groups of complicated pregnancies. PMID- 22825760 TI - [Disorders of laterality and heterotaxy in the foetus]. AB - Disorders of laterality and heterotaxy syndromes are rare diseases with an incidence of 1-1.5/10,000 live births. They are associated with numerous viscerocardiac anomalies and malformations. In particular, heterotaxy syndromes are associated with complex cardiac and extracardiac malformations that have an important impact on the prenatal and postnatal course. A prenatal differentiation between the 2 main variants of heterotaxy--left and right isomerism--is possible by assessment of cardiac rhythm, anomalies of caval veins and descending aorta and concomittant cardiac and extracardiac anomalies. An exact diagnosis is mandatory for adequate counselling of the parents and planning of postnatal care. Left isomerism has a high intrauterine mortality, caused by early atrioventricular block with subsequent cardiac failure and hydrops. In contrast, right isomerism has a high postnatal mortality due to the more complex type of cardiac defects and splenic disorders. The type of associated cardiac and extracardiac anomalies determines the postnatal morbidity and mortality. Polysplenia and asplenia may be associated with immunological disorders, that cannot be ruled out in the prenatal period, and further complicate the postnatal course. PMID- 22825761 TI - [Neurological and psychomotor development of foetuses and children with congenital heart disease--causes and prevalence of disorders and long-term prognosis]. AB - Children with severe congenital heart defects (CHD) requiring open heart surgery in the first year of life are at high risk for developing neurological and psychomotor abnormalities. Depending on the type and severity of the CHD, between 15 and over 50% of these children have deficits, which are usually confined to distinct domains of development, although formal intelligence tends to be normal. Children with mild CHD, who comprise the majority of congenital heart defects, have a far better developmental prognosis than those with complex CHD. This review concentrates on the impact of severe CHD on the developing brain of the foetus and infant. It also provides a summary of recent clinical and neuroimaging studies, and an overview of the long-term neurological prognosis. Advanced neuroimaging modalities indicate that, related to altered cerebral blood flow and oxygenation, foetuses with severe CHD show delayed third trimester brain maturation and increased vulnerability for hypoxic injury. Morphological and neurological abnormalities are present before surgery, commonly affecting the white matter. In the long-term, impaired neurological and developmental outcomes are related to the combination of prenatal, perinatal and additional perioperative risk factors. Therefore, new therapeutic approaches aim to optimise the intra- and perinatal management of foetuses and newborns with congenital heart defects. Identification and avoidance of risk factors, early neurodevelopmental assessment and therapy may optimise the long-term outcome in this high-risk population. PMID- 22825762 TI - [Late preterms: the influence of foetal gender on neonatal outcome]. AB - BACKGROUND: The group of the so-called late preterms (infants born at 34 0/7-36 6/7 weeks gestational age) has been underestimated with respect to their neonatal outcome. Among infants born before the 29th week of pregnancy, a gender-specific difference in favour of females regarding morbidity became evident. The aim of this study is to investigate whether these findings are transferable to the group of late preterms. METHODS: The neonatal outcome of 528 consecutive singletons, born at 34 0/7-36 6/7 weeks gestational age and requiring intensive care, was examined. RESULTS: Neonatal complications have been particularly analysed with regard to gender-specific differences. Boys (n=292) were significantly more frequently affected by sepsis (3.8 vs. 0.9%; p=0,0314, x2-test). Girls had significantly longer stays in the neonatal intensive care unit (median 12 (Q1:8; Q3:17) vs. 11 (6;16) days; p=0.0149, t-test). In a multiple logistic regression model, male gender and premature rupture of membranes were borderline significant with respect to the occurrence of sepsis - boys had a 4.4-fold risk (OR=0.228 [95% CI: 0.050-1.041]; p=0.0564) and premature rupture of membranes had a 3.5 fold risk (OR=3.462 [0.938-12.779]; p=0.0623). Strong cause variables for the length of stay in the neonatal intensive care unit were birth weight, gestational age and premature rupture of membranes after adjustment. CONCLUSION: The influence of foetal gender on the neonatal outcome in the late preterm group (34 0/7-36 6/7 gestational age) has been relativised. PMID- 22825763 TI - [Acute foeto-foetal transfusion syndrome--case report and review of the literature]. AB - The perinatal morbidity and mortality risk in monochorionic twin pregnancies are 3-5-fold increased compared to those of dichorionic twin pregnancies. Partially, this is due to the higher rate of preterm delivery but also to the twin-to-twin transfusion syndrome (TTTS). Caused by unidirectional blood flow via placental anastomoses, the TTTS leads to weight differences of more than 20% between monochorial twins. The blood donor often shows oligohydramnios, whereas the recipient shows polyhydramnios. Lewi et al. demonstrated, in a study with 202 monochorionic twin pregnancies, a 9% rate of severe TTTS. The mortality of this complication is about 90% when untreated. In contrast to the chronic TTTS, little is known about the acute intrapartal one, which is characterised by anaemia and hypovolaemia of the donor and polyglobulia of the recipient without significant weight differences between the two. In most cases, anaemia occurred after normal delivery of the first twin. Still, there are no means or signs for early detection. We describe the case of a 30-year-old primigravida with a monochorionic diamniotic twin pregnancy. During pregnancy, no evidence of TTTS could be detected. At 37 + 1 weeks gestation labour was induced with prostaglandin-containing gel. Both foetuses showed cephalic presentation. The CTG of the first twin showed a conspicuous heart rate. After labour the first twin presented with anaemia and hypovolaemic shock, the APGAR was 2/7/8. The infant's haemoglobin was 13.7 g/dL. After delivery, the second twin with APGAR 10/10/10 showed a haemoglobin of 19.6 g/dL, which is in the upper normal range. Their birth weights differed by merely 10.4%. Acute TTTS is frequently characterised by anaemia and hypovolaemia of the second twin. In our case of a monochorionic twin delivery with acute TTTS the donor was born first. Early diagnosis and neonatal intervention is essential for reducing postnatal morbidity and mortality. PMID- 22825764 TI - Prevalence of scoliosis in cystic fibrosis. AB - BACKGROUND: The prevalence of idiopathic scoliosis in the general pediatric population is reported to be between 0.5% and 3.2%. Previous studies have reported an increased prevalence of scoliosis in children with cystic fibrosis (CF). HYPOTHESIS: The prevalence of scoliosis in CF children is greater than in the normal population. METHODS: Chest X-rays of 319 patients attending the Royal Brompton CF Centre were reviewed. The Cobb angle of any spinal lateral curvature was measured. Scoliosis was defined as a Cobb angle of more than 10 degrees . RESULTS: Median age of the whole group of patients was 10.9 years (range 1.1-18 years), 53% were females. Seven patients (2.2%) had radiological signs of scoliosis, their mean age was 14.5 +/- 2.3 years (range: 11.5-18 years), 5 were females. Age at onset of scoliosis was between 5 and 10 years for three patients and over 10 years for the others. All the curves were thoracic and with right convexity: apices between T7 and T9 for the single curves (n = 5) and between T4 and T5 (n = 2) for the double curves. CONCLUSION: CF patients showed a similar prevalence of scoliosis as in the normal population (2.2% vs. 0.5-3.2%). There was the same gender (female) and side (right-sided) predilection as in normal population. PMID- 22825765 TI - The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells. AB - Luteolin has been shown to have a strong anticancer effect on various cancer models via programmed cell death (apoptosis). However, the fundamental mechanisms of these effects are still unclear. In the present study, we examined the question of whether or not luteolin can inhibit proliferation of pancreatic carcinoma cells, via apoptosis. We used three human pancreatic carcinoma cell lines, PANC-1, CoLo-357 and BxPC-3 in our study. In luteolin-treated pancreatic carcinoma cells, typical features of apoptosis were observed. Luteolin increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptotic protein Bcl-2, with a concomitant increase in the levels of caspase-3 and cleaved PARP after treatment for 24 h. Luteolin inhibited HUVEC proliferation and vessel growth in CAM in vivo. In addition, the concentration of VEGF in the conditioned medium from human pancreatic carcinoma cells was downregulated by luteolin. Pancreatic carcinoma cells, pretreated with luteolin, could decrease the capillary-like structure formation by HUVEC, which was analyzed by a co-culture system. The abatement of VEGF secretion was related to the inhibition of VEGF mRNA expression, which may be regulated by inhibiting the transcription activity of nuclear transcription factor NF-kappaB. PMID- 22825767 TI - Effects of botulinum toxin A on fracture healing in rats: an experimental study. AB - INTRODUCTION: Fracture healing is a complex process influenced by intrinsic and extrinsic factors. The aim of the present study was to evaluate the effects of botulinum toxin (BTX) A on fracture healing. MATERIALS AND METHODS: Following the induction of bilateral standard closed femoral fractures and relative fixation in 18 Wistar albino rats, 8 IU of BTX A were injected into the right femoral region. After 28 days, all of the rats were sacrificed, the diameter of the callus was measured, and fracture healing was assessed by biomechanical and histopathologic evaluation. RESULTS: While an increase in biomechanical and histopathologic healing was noted on the side injected with BTX A, a decrease in callus diameter was observed. CONCLUSION: Botulinum toxin A administration increases the healing power in a relatively fixated fracture and decreases the callus diameter, just as if rigid fixation had been performed. The beneficial effect of BTX A on fracture healing might be associated with increased fixation rigidity. PMID- 22825766 TI - Radioprotective effects produced by the condensation of plasmid DNA with avidin and biotinylated gold nanoparticles. AB - The treatment of aqueous solutions of plasmid DNA with the protein avidin results in significant changes in physical, chemical, and biochemical properties. These effects include increased light scattering, formation of micron-sized particles containing both DNA and protein, and plasmid protection against thermal denaturation, radical attack, and nuclease digestion. All of these changes are consistent with condensation of the plasmid by avidin. Avidin can be displaced from the plasmid at higher ionic strengths. Avidin is not displaced from the plasmid by an excess of a tetra-arginine ligand, nor by the presence of biotin. Therefore, this system offers the opportunity to reversibly bind biotin-labeled species to a condensed DNA-protein complex. An example application is the use of biotinylated gold nanoparticles. This system offers the ability to examine in better detail the chemical mechanisms involved in important radiobiological effects. Examples include protein modulation of radiation damage to DNA, and radiosensitization by gold nanoparticles. PMID- 22825768 TI - MicroRNAs: key gene regulators with versatile functions. PMID- 22825769 TI - Abdominoperineal resection for squamous cell anal carcinoma: survival and risk factors for recurrence. AB - BACKGROUND: Despite the results of combined chemoradiation therapy for anal canal squamous cell carcinoma (SCC), up to 30 % of patients will undergo abdominoperineal resection (APR). The aim of this study was to evaluate oncologic outcomes, survival, and recurrence, following APR for anal canal SCC performed in a single center over a 13-year period. METHODS: All patients who underwent APR for anal canal SCC between 1996 and 2009 were retrospectively included. Demographic data, details on treatments, pathological report, and follow-up were noted. Survival curves were plotted using the Kaplan-Meier method and potential prognostic factors were evaluated using Cox proportional hazards models. RESULTS: A total of 105 patients (77 women) were included. Indications for APR included tumor persistence (n = 42; 40 %), recurrence (n = 55; 52.4 %), or a contraindication to radiotherapy (n = 8; 7.6 %). Median follow-up was 33.3 months (range, 1.5-174.3 months). Overall survival and disease-free survival were, respectively, 61 and 48 % at 5 years. In multivariate analysis, tumor stage (T3 or T4), positive margin on pathologic examination and existence of distant metastases at the time of the surgery were associated with a poor prognosis. The indication for APR (persistent vs recurrent disease), gender, concurrent HIV infection, or performance of a VRAM flap did not influence OS or DFS. Overall recurrence rate was 42.6 % (n = 43 of 101). The type of recurrence did not exert a significant effect on survival (p = .4571). CONCLUSION: This study describes the largest single series of APR for anal carcinoma. Major prognostic factors for survival and recurrence were T status and involved margin. The 5-year overall survival was 60 %. PMID- 22825770 TI - Circulating endothelial cell (CEC) as a diagnostic and prognostic marker in malignant pleural mesothelioma (MPM). AB - BACKGROUND: The purpose of this study was to investigate the diagnostic and prognostic value of circulating endothelial cell (CEC), a potential surrogate of tumor angiogenesis, in malignant pleural mesothelioma (MPM). METHODS: We prospectively evaluated CEC count in 4.0 mL of peripheral blood sampled from patients with a suspicion of MPM. An automated system was used to capture CECs with an anti-CD146 antibody. RESULTS: Of 109 eligible patients, 30 were finally diagnosed with non-malignant diseases, and 79 were with MPM. CEC count was significantly higher in MPM patients than in NM patients (mean CEC count, 120.3 and 39.9, respectively; P = 0.001), and a receiver operating characteristic (ROC) curve analysis showed that CEC provided a significant diagnostic performance in discrimination between MPM and nonmalignant diseases with an area under curve (AUC-ROC) of 0.700 (95 % confidence interval [95 % CI], 0.595-0.806; P = 0.001). Among MPM patients, CEC count was positively correlated with intratumoral microvessel density (MVD), a measurement of tumor angiogenesis (Spearman correlation coefficiency [r] = 0.444; P = 0.001). Higher CEC count (>50) was significantly associated with a poor prognosis (median overall survival, 11.4 months [95 % CI, 7.6-15.2] for higher CEC count patients versus 20.1 months [95 % CI, 16.0-24.2] for lower CEC count patients; P = 0.028). A multivariate analysis showed that higher CEC count was a significant and independent factor to predict a poor prognosis (hazard ratio [HR], 2.24, [95 % CI, 1.24-4.43]; P = 0.009). CONCLUSIONS: CEC, as a surrogate of tumor angiogenesis, was a promising marker in diagnosis and prediction of prognosis in MPM. PMID- 22825771 TI - Palliative surgical outcomes: are we looking through a keyhole? PMID- 22825772 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for persistent and recurrent advanced ovarian carcinoma: a multicenter, prospective study of 246 patients. AB - BACKGROUND: Epithelial ovarian carcinoma is the main cause of death from gynaecological cancers in the western world. The initial response rate to the frontline therapy is high. However, the prognosis of persistent and recurrent disease remains poor. During the two past decades, a new therapeutic approach to peritoneal carcinomatosis has been developed, combining maximal cytoreductive effort with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A retrospective, multicentric study of 246 patients with recurrent or persistent ovarian cancer, treated by cytoreductive surgery and HIPEC in two French centers between 1991 and 2008, was performed. RESULTS: An optimal cytoreductive surgery was possible in 92.2 % of patients. Mortality and morbidity rates were 0.37 % and 11.6 %, respectively. The overall median survival was 48.9 months. There was no significant difference in overall survival in patients with persistent or recurrent disease. In multivariate analysis, performance status was a significant prognostic factor in patients with extensive peritoneal carcinomatosis (peritoneal cancer index >10). CONCLUSIONS: Salvage therapy combining optimal cytoreductive surgery and HIPEC is feasible and may achieve long-term survival in highly selected patients with recurrent ovarian carcinoma, including those with platinum resistant disease, with acceptable morbidity. PMID- 22825773 TI - Preoperative localization strategies for primary hyperparathyroidism: an economic analysis. AB - BACKGROUND: Strategies for localizing parathyroid pathology preoperatively vary in cost and accuracy. Our purpose was to compute and compare comprehensive costs associated with common localization strategies. METHODS: A decision-analytic model was developed to evaluate comprehensive, short-term costs of parathyroid localization strategies for patients with primary hyperparathyroidism. Eight strategies were compared. Probabilities of accurate localization were extracted from the literature, and costs associated with each strategy were based on 2011 Medicare reimbursement schedules. Differential cost considerations included outpatient versus inpatient surgeries, operative time, and costs of imaging. Sensitivity analyses were performed to determine effects of variability in key model parameters upon model results. RESULTS: Ultrasound (US) followed by 4D-CT was the least expensive strategy ($5,901), followed by US alone ($6,028), and 4D CT alone ($6,110). Strategies including sestamibi (SM) were more expensive, with associated expenditures of up to $6,329 for contemporaneous US and SM. Four gland, bilateral neck exploration (BNE) was the most expensive strategy ($6,824). Differences in cost were dependent upon differences in the sensitivity of each strategy for detecting single-gland disease, which determined the proportion of patients able to undergo outpatient minimally invasive parathyroidectomy. In sensitivity analysis, US alone was preferred over US followed by 4D-CT only when both the sensitivity of US alone for detecting an adenoma was >= 94 %, and the sensitivity of 4D-CT following negative US was <= 39 %. 4D-CT alone was the least costly strategy when US sensitivity was <= 31 %. CONCLUSIONS: Among commonly used strategies for preoperative localization of parathyroid pathology, US followed by selective 4D-CT is the least expensive. PMID- 22825774 TI - Short-term outcomes after combined colon and liver resection for synchronous colon cancer liver metastases: a population study. AB - INTRODUCTION: The timing of surgical resection for stage IV colon cancer with liver metastasis and the safety of simultaneous colon and liver resection remains controversial. The purpose of our study was to evaluate short-term outcomes after combined colon and liver resection (CCLR) versus colon resection (CR) or liver resection alone (LR) using a population database. METHODS: The National Inpatient Sample was used to select patients who had surgery for colon cancer from 2002 to 2006. We evaluated for in-hospital morbidity, mortality, and prolonged length of stay (PLOS). Our analysis was done using design-weighted unadjusted analysis and logistic regression. RESULTS: We identified 361,096 patients during our study period (CCLR 3,625; CR 322,286; LR 35,185). CCLR was not associated with an increased risk of complications (odds ratio (OR) 1.12; 95% confidence interval (CI) 0.94-1.33; P=0.21) or PLOS (OR 1.19; 95% CI 0.99-1.4; P=0.06) compared with CR. In-hospital mortality occurred in 3.5% of patients who underwent CCLR and was not significantly associated with mortality compared with CR alone (OR 1.17; 95% CI 0.79-1.74; P=0.43). Liver lobectomy with CR was associated with a PLOS and a trend toward increased morbidity and mortality. Significant predictors of complications, mortality, and PLOS included: age>70 years, male gender, nonprivate health insurance, and Elixhauser score>1. CONCLUSIONS: CCLR with limited liver resection can be performed with similar morbidity and mortality to colectomy alone. For patients who require hepatic lobectomy, however, strong consideration should be given to a staged approach. PMID- 22825775 TI - Primary tumor thickness as a prognostic factor in Merkel cell carcinoma: the next big thing? PMID- 22825776 TI - MRI of radiographically occult ischial apophyseal avulsions. AB - BACKGROUND: Acute avulsions of unossified ischial apophyses in children may go undetected on radiography. Therapy includes rest and rehabilitation; however, substantial displacement may require surgery. OBJECTIVE: Our purpose is to illustrate the utility of MRI in the detection of these radiographically occult injuries in skeletally immature children. MATERIALS AND METHODS: This retrospective study of more than 5 years included children with ischial avulsions who were evaluated with both radiography and MRI within 3 weeks of acute injury. Initially, radiographs were reviewed to identify those children with unossified ischial apophyses. Subsequently, their MRI examinations were assessed for physeal disruption, bone/soft tissue edema, periosteal/perichondrial elevation and disruption. Initial and follow-up radiographs (if available) were reviewed. Patient age, symptoms and offending activity were determined from clinical records. RESULTS: Five children met inclusion criteria. All initial radiographs were normal. MRI showed: edema (n = 5), periosteal elevation (n = 4), periosteal/perichondrial disruption (n = 4), >5.5 mm displacement (n = 0). Follow up radiographs in two children (2 and 2.5 months from MRI) showed osseous ischial irregularity. The apophyses remained unossified. CONCLUSIONS: Acute unossified ischial apophyseal avulsions in children may be radiographically undetected. In the setting of correlative clinical symptoms, MRI can be used to identify these injuries and to help direct appropriate therapy. PMID- 22825777 TI - Cervical spine anomalies in Menkes disease: a radiologic finding potentially confused with child abuse. AB - BACKGROUND: Menkes disease is an X-linked recessive disorder of copper transport caused by mutations in ATP7A, a copper-transporting ATPase. Certain radiologic findings reported in this condition overlap with those caused by child abuse. However, cervical spine defects simulating cervical spine fracture, a known result of nonaccidental pediatric trauma, have not been reported previously in this illness. OBJECTIVE: To assess the frequency of cervical spine anomalies in Menkes disease after discovery of an apparent C2 posterior arch defect in a child participating in a clinical trial. MATERIALS AND METHODS: We examined cervical spine radiographs obtained in 35 children with Menkes disease enrolled in a clinical trial at the National Institutes of Health Clinical Center. RESULTS: Four of the 35 children with Menkes disease had apparent C2 posterior arch defects consistent with spondylolysis or incomplete/delayed ossification. CONCLUSION: Defects in C2 were found in 11% of infants and young children with Menkes disease. Discovery of cervical spine defects expands the spectrum of radiologic findings associated with this condition. As with other skeletal abnormalities, this feature simulates nonaccidental trauma. In the context of Menkes disease, suspicions of child abuse should be considered cautiously and tempered by these findings to avoid unwarranted accusations. PMID- 22825778 TI - A HYSCORE investigation of bimetallic titanium-vanadium microporous catalysts: elucidating the nature of the active sites. AB - Vanadium and titanium bimetallic AlPO-5 molecular sieves have been synthesized and characterized by means of Electron Spin Echo detected EPR and Hyperfine Sublevel Correlation (HYSCORE) spectroscopy. Direct evidence for framework substitution of redox-active Ti ions and VO(2+) units at Al sites is provided through the detection of large (31)P hyperfine couplings. PMID- 22825779 TI - A fast and simple method for probing the interaction of peptides and proteins with lipids and membrane-mimetics using GB1 fusion proteins and NMR spectroscopy. AB - The expression of peptides and proteins as fusions to the B1 domain of streptococcal protein G (GB1) is very popular since GB1 often improves the solubility of the target protein and because the first purification step using IgG affinity chromatography is simple and efficient. However, the following protease digest is not always complete or can result in a digest of the target protein. In addition, a further purification step such as RP-HPLC has to be used to get rid of the GB1 tag and undigested fusion protein. Because the protease digest and the following purification step are not only time-consuming but generally also expensive, we tested if GB1 fusion proteins can directly be used for NMR interaction studies using lipids or membrane-mimetics. Based on NMR binding studies using only the GB1 part, this fusion tag does not significantly interact with different membrane-mimetics such as micelles, bicelles, or liposomes. Thus spectral changes observed using GB1-fusion proteins indicate lipid- and membrane interactions of the target protein. The method was initially established to probe membrane interactions of a large number of mutants of the FATC domain of the ser/thr kinase TOR. To demonstrate the usefulness of the approach, we show NMR binding data for the wild type protein and a leucine to alanine mutant. PMID- 22825780 TI - Preimplantation processing of ex vivo-derived vascular biomaterials: effects on peripheral cell adhesion. AB - The use of ex vivo-derived scaffolds as vascular conduits has shown to be a clinically valid approach to repair or bypass occluded vessels. Implantation of allogeneic tissue grafts requires careful processing to lower immunogenicity and prevent bacterial infection. However, the mechanical/chemical treatments used to prepare biological scaffolds can result in significant alterations to the native structure and surface chemistry, which can affect in vivo performance. Of particular importance for vascular grafts are binding interactions between the implanted biomaterial and host cells from the circulation and adjacent vasculature. Here we present a comparison of four strategies used to decellularize allogeneic human umbilical vein (HUV) scaffolds: ethanol/acetone, sodium chloride, sodium dodecyl sulfate (SDS), or Triton X-100. Scanning electron microscopy revealed that all four techniques achieved removal of native cells from both the lumenal and ablumenal surfaces of HUV grafts. Platelets and promyelocytic HL-60 cells showed preferential binding on the more loosely structured ablumenal surface, although low surface coverage was observed overall by peripheral blood cells. Vascular endothelial cell adhesion was highest on HUV decellularized using ethanol/acetone, and significantly higher than on SDS processed grafts (p = 0.016). Primary cells showed high viability on the lumenal surface regardless of decellularization technique (over 95% in all cases). These results demonstrate the critical effects of various chemical processing strategies on the adhesive properties of ex vivo-derived vascular grafts. Careful application-specific consideration is warranted when selecting a processing strategy that minimizes innate responses (e.g. thrombosis, inflammation) that are often deleterious to graft survival. PMID- 22825781 TI - [Acute tubulointerstitial nephritis as hyperergic reaction of the kidneys]. AB - Acute tubulointerstitial nephritis was formerly only observed during the early phase of infections. With the emergence of antibiotics this disease became a rarity. In contrast the importance of drug-associated acute tubulointerstitial nephritis grew in importance and is now the most common form and expression of a hyperergic reaction of the kidneys. Acute tubulointerstitial nephritis occurs as a third form in cases of systemic autoimmune diseases, e.g., in idiopathic tubulointerstitial nephritis or within the scope of Sjogrens syndrome with distal tubular acidosis. The common symptoms of the drug-induced form are fever, side pain, microhematuria or macrohematuria and a mostly sharp increase in creatinine levels but to a greatly differing extent. Histologically, there is interstitial edema and interstitial lymphocyte-rich infiltration with tubulitis. The symptoms can be subclinical or even non-existent. In most case remission occurs, sometimes only partial remission or transformation to chronic interstitial nephritis. Risk factors are for example delayed diagnosis, recurrent episodes and the accompanying use of analgesics. The more acute and intense the clinical symptoms are, the earlier the diagnosis and therefore the better the prognosis. A temporary steroid treatment can promote regression. PMID- 22825782 TI - [Is non-oral hormonal contraception really free of risks? Comment on the case report by Spinner et al]. PMID- 22825783 TI - Cryopreservation of human skeletal muscle impairs mitochondrial function. AB - Previous studies have investigated if cryopreservation is a viable approach for functional mitochondrial analysis. Different tissues have been studied, and conflicting results have been published. The aim of the present study was to investigate if mitochondria in human skeletal muscle maintain functionality after long term cryopreservation (1 year). Skeletal muscle samples were preserved in dimethyl sulfoxide (DMSO) for later analysis. Human skeletal muscle fibres were thawed and permeabilised with saponin, and mitochondrial respiration was measured by high-resolution respirometry. The capacity of oxidative phosphorylation was significantly (P < 0.05) reduced in cryopreserved human skeletal muscle samples. Cryopreservation impaired respiration with substrates linked to Complex I more than for Complex II (P < 0.05). Addition of cytochrome c revealed an increase in respiration indicating cytochrome c loss from the mitochondria. The results from this study demonstrate that normal mitochondrial functionality is not maintained in cryopreserved human skeletal muscle samples. PMID- 22825784 TI - A study to evaluate the action of lipocryolysis. AB - Since ancient times human beings have been conceiving methods that could help reduce the accumulation of undesired fat tissue in their own bodies. Lipocryolysis has already been recognized as an therapy for localized fat reduction by means of a combination of regulated and controlled vacuum and heat extraction therapy. This study was designed to quantify the claimed reduction of local adiposities. For this purpose, 16 treatments were analysed. The data suggested that lipocryolysis is effective for localized reduction of adiposities and that the reduction obtained are measurable. PMID- 22825785 TI - Development of a vitrification-based cryopreservation protocol for the storage of saltcedar (Tamarix boveana Bunge). AB - We cryopreserved in vitro shoot tips of saltcedar (Tamarix boveana Bunge) using the vitrification technique. The success of the cryopreservation protocol was strongly affected by preculture, loading duration, dehydration duration in plant vitrification solution 2 (PVS2), and medium composition during post-warming regrowth. The highest explant regrowth (50 percent) occurred when the following conditions were employed: preculture in 0.4 M glycerol; treatment with a loading solution (LS) consisting of 2 M glycerol + 0.4 M sucrose in culture medium for 40 min at room temperature; and dehydration in PVS2 at 0 degree C for 45 min before rapid immersion in liquid nitrogen (LN). Rewarming was performed in a water-bath at 40 degree C for 2 min. Explants were then immersed in unloading solution for 10 min before plating on recovery medium supplemented with 0.01 mg per liter thidiazuron (TDZ). TDZ was progressively eliminated from the medium over a period of 6 weeks. Plantlets were transferred to a double-layer medium to enhance rooting. This protocol was successfully applied to three individuals of T. boveana harvested from the wild. PMID- 22825786 TI - High-efficiency encapsulation-vitrification protocols for cryopreservation of embryogenic calli of the oriental medicinal plant Anemarrhena asphodeloides Bunge. AB - Embryogenic calli from in vitro grown tillers of Anemarrhena asphodeloides Bunge were successfully cryopreserved by the encapsulation-vitrification technique. Excised embryogenic calli were precultured for 4 days in liquid MS medium supplemented with 2 mg per liter kinetin (KIN), 0.1 mg per liter alpha naphthalene acetic acid (NAA) and 0.75 M sucrose, then encapsulated in calcium alginate beads and loaded with a mixture of 2 M glycerol + 0.4 M sucrose for 60 min at 25 +/- 1 degree C. Calli were then dehydrated with the PVS2 solution for 80 min at 0 degree C. After changing the solution with fresh PVS2, calli were directly immersed in liquid nitrogen (LN). After rapid rewarming in a water-bath at 35 degree C for 5 min, calli were washed three times with liquid MS medium supplemented with 2 mg L-1 KIN, 0.1 mg per liter NAA and 1.2 M sucrose, then transferred on solid MS medium supplemented with 2 mg per liter KIN, 0.1 mg per liter NAA, 3 % (w/v) sucrose and 0.75 % (w/v) agar. Cryopreserved cultures were kept in the dark for 5 days prior to exposure to a 14h light/10h dark photoperiod with a light intensity of 36 MUmol per square meter per sec provided by white cool fluorescent tubes at 25 +/- 1 degree C. Survival of cryopreserved embryogenic calli reached 80 percent, including after storage for c. 1 year. No significant difference was observed in the morphological development of plants coming from control and cryopreserved embryogenic calli. This encapsulation vitrification method appears promising for the cryopreservation of A. asphodeloides Bunge germplasm. PMID- 22825787 TI - Amidic and acetonic cryoprotectants improve cryopreservation of volvocine green algae. AB - A number of volvocalean green algae species were subjected to a two-step cryopreservation protocol with various cryoprotectants. Potential cryoprotectants were methanol (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N methylformamide, and hydroxyacetone (HA). We confirmed prior reports that MeOH was effective for cryopreserving Chlamydomonas, but did not work well for larger volvocaleans such as Volvox. In contrast, DMF and HA were effective for both unicellular and multicellular representatives. When we used a cold-inducible transposon to probe Southern blots of Volvox DNA samples taken before and after storage for one month in LN, we could detect no differences, indicating that the genome had remained relatively stable and that the transposon had not been induced by the cryopreservation procedure. We believe these methods will facilitate long-term storage of several volvocine algal species, including Volvox strains harboring transposon-induced mutations of developmental interest. PMID- 22825788 TI - Caseinate protects stallion sperm during semen cooling and freezing. AB - Extenders with a defined composition containing only components with clearly protective effects on sperm during storage would be an advantage. The aims of the present work were to assess whether caseinate, improves cooled and frozen equine semen quality. Semen from six stallions were suspended with four different cooling extenders C1) Kenney extender; C2) 0.6 % caseinate; C3) 2.7 % caseinate ; and C4) C1 + 2.1 % caseinate, and frozen extenders: F1) INRA 82 extender; F2) 1.35 % caseinate; and F3) 2.7 % caseinate. Although there was no significant difference between the motility rate among the cooled (C1:45.0, C2:36.7, C3:38.3 and C4:48.3) and frozen extenders (F1:16.9, F2:21.1 and F3:18.6), significant higher values of sperm velocity variables were observed with the 1.35 % caseinate extender compared to the control (VSL: 40.8 x 18.9 and VAP: 46.8 x 25.0 um/s), respectively. Caseinate seemed to be responsible for sperm protection during preservation and showed to be as efficient as milk. PMID- 22825789 TI - Narrowing oF the critical hydration window for cryopreservation of Salix caprea seeds following ageing and a reduction in vigour. AB - We investigated the effects of desiccation, rehydration and cryopreservation on the viability of seeds of a wild mountain species and seven clones of Salix caprea L. Seeds responded differently to all treatments depending on clone, seed initial moisture content (MC) and seed vigour. Fresh seeds of two randomly selected clones tolerated desiccation to MC 8.5-9.6 % FW (0.09-0.11 g water per g dry mass. g/gdw) without any noticeable loss in viability and were successfully cryopreserved at MCs ranging from 8.5 to 23.4 % (0.09-0.30 g/gdw). Storage at 5 degree C for approximately 10 weeks significantly reduced the viability of seed lots of a wild species and of three S. caprea clones, whilst viability of seeds of four other clones remained unaffected. Since all clones tested were genetically derived from one tree, this variation is unlikely to be of maternal origin. Most probably paternal x environmental factors have influenced seed behavior during desiccation and storage. As viability decreased due to partial ageing, seeds became more susceptible to desiccation stress. When seeds of three clones were cryopreserved, the hydration window for survival was wider for highly vigorous seeds (c. 0.05-0.28 g/gdw) than for seeds with intermediate vigour (c. 0.10-0.24 g/gdw) and low vigour (c. 0.20-0.37 g/gdw). Rehydration to MC above 0.15 g/gdw improved germination of low vigour seeds, both in controls and after cryopreservation. In contrast, cryopreservation of high vigour seeds rehydrated to MCs above 0.11 g/gdw resulted in a sharp decrease in normal seedling production. Whilst no effect of cryogenic temperature on germination and normal seedling production was observed when seeds of seven clones were cryopreserved within their hydration windows, the results indicate the need to account for seed lot vigour when designing cryopreservation protocols. PMID- 22825790 TI - Measurement of membrane hydraulic conductivity of bovine carotid artery endothelial cells using a perfusion microscope. AB - The osmotic properties of bovine carotid artery endothelial cells (BCAECs) associated with cryobiology were investigated using a perfusion microscope. These properties include the hydraulic conductivity (Lp) and its activation energy (ELp). The response of isolated cells was observed when the extracellular concentration increased from 0.15 M to 0.5 M NaCl at three different temperatures. The transient volumes of the cell were calculated from the measurements of the projected areas with an assumption of a spherical cell. The hydraulic conductivity (Lp) and the osmotically inactive volume (Vb) of BCAECs were simultaneously determined using nonlinear regression to fit the change of cell volume estimated by water transport equations to measured cell volumes. The Lp values were 0.26 +/- 0.08, 0.12 +/- 0.02, and 0.06 +/- 0.02 m/atm/min (mean +/- SD) at 23, 11 and 4 degree C, respectively, yielding the activation energy of Lp of 47.6 kJ/mol according to the Arrhenius relationship. PMID- 22825791 TI - Desiccation sensitivity and cryopreservation of excised embryonic axes of Citrus suhuiensis cv. limau madu, Citrumelo [Citrus paradisi macf. * Poncirus trifoliata (l.) raf.] and Fortunella polyandra. AB - Excised embryonic axes from seeds of three taxa, namely, Citrus suhuiensis cv. limau madu, Citrumelo (Citrus paradisi x Poncirus trifoliate) and Fortunella polyandra, were desiccated in a laminar airflow, over silica gel, and ultra rapidly. Desiccation sensitivity (WC50) was estimated for each taxon using the quantal response model. High desiccation tolerance (WC50 = 0.11 g water per g dry mass. g/gdw) was observed for limau madu embryonic axes desiccated in a laminar airflow and ultra-rapidly (WC50 =0.10 g/gdw). Desiccation tolerance was substantially lower (WC50 = 0.19 g/gdw) for silica gel dehydration. Similarly, high desiccation tolerance (WC50 = 0.15 g/gdw) was associated with F. polyandra embryonic axes when desiccated in a laminar airflow, while a lower desiccation tolerance (WC50 = 0.17 g/gdw) was observed with silica gel dehydration. Ultra rapid desiccation led to the highest desiccation tolerance (WC50 = 0.14 g/gdw). The dehydration rate, however, had no influence on desiccation tolerance (WC50 ~ 0.14 g/gdw) for Citrumelo embryonic axes. After each desiccation period, embryonic axes were directly immersed in liquid nitrogen (LN) followed by rapid rewarming. Normal seedling recovery of 80 to 83% for excised embryonic axes of limau madu was observed for laminar airflow and ultra-rapid dehydration, but for silica gel dehydration, 57% recovery was obtained. Similarly, for Citrumelo, high recoveries of 100% and 97% were obtained from axes desiccated in a laminar airflow and using ultra-rapid dehydration, respectively, whereas a lower value was associated with silica gel dehydration (80%). For F. polyandra, 50% recovery was obtained both for laminar airflow and ultra-rapid dehydration, while much lower recovery (43%) was associated with silica gel dehydration. Regardless of the drying method employed, axis survival percentages following exposure to LN were commensurate with the desiccation sensitivity pattern. PMID- 22825793 TI - Evaluation of potentially toxic metals pollution in the sediments of the Kor river, southwest Iran. AB - This study is carried out to evaluate potentially toxic metal concentrations (As, Cd, Cr, Cu, Hg, Mo, Ni, Pb, and Zn) together with their spatial distribution, degree of pollution, and potential ecological risk in Kor river sediments (southwest Iran) using sediment quality guidelines, geoaccumulation index (I geo), Hakanson potential ecological risk index (RI), and standard methods of statistical analysis. The study area stretches some 140 km from the Drodzan Dam to Bakhtegan Lake, a stretch of river where different industrial and domestic activities (e.g., petrochemical complex, oil refinery, industrial meat processing complex, Marvdasht city sewage) and ecological value overlap with each other. Calculated geoaccumulation index indicate that 50 % of the stations are moderately to very extremely polluted. The potential ecological risk for nine investigated metals in Kor river is Hg (948) > Mo (51.9) > Ni (37.8) > Cd (29.8) > As (22) > Cu (16.6) > Pb (13.3) > Zn (3.3) > Cr (1). Results show that sediments in parts of Kor river sediments are heavily affected by effluents discharged from industrial plants and other parts are affected by agriculture and urban runoff from nearby lands. These phenomena may cause a risk of secondary water pollution under sediment disturbance and/or changes in the physical chemical characteristics of the aquatic system. PMID- 22825794 TI - The interaction between acquired mitochondrial disease and neurodegeneration. PMID- 22825795 TI - Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation. AB - Mutations in the NKX2.1 gene, which is essential for the development, differentiation and organization of the basal ganglia, cause benign hereditary chorea (BHC) characterized by childhood-onset non-progressive chorea. We herein report the clinical features of six patients from a single family with a novel intronic mutation and present the dopaminergic neuronal imaging by using positron emission tomography (PET) imaging to assess the integrity of the striatal dopaminergic system using [(11)C]-CFT for the presynaptic dopamine transporter function and [(11)C]-raclopride for the postsynaptic D2 receptor function. The patients showed mild generalized chorea without either congenital hypothyroidism or a history of pulmonary infection and some of the patients had goiter. Genetic analyses of NKX2.1 gene showed a novel heterozygous c.464-9C>A mutation that created a new acceptor splice site resulting in the production of an aberrant transcript with a 7-bp insertion identical to a intronic sequence of genomic DNA. Oral levodopa failed to improve the involuntary movement, while haloperidol, a dopamine D2 receptor blocking agent, exacerbated the choric movement in a single patient. The dopaminergic PET studies in the two patients revealed decreased raclopride binding in the striatum, while the CFT binding was not altered. The impairment of D2 receptor function in the basal ganglia may result in exacerbation of the chorea induced by haloperidol. The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation. PMID- 22825796 TI - Pressure dependent aerosol formation from the cyclohexene gas-phase ozonolysis in the presence and absence of sulfur dioxide: a new perspective on the stabilisation of the initial clusters. AB - The ozonolysis of cyclohexene is studied with respect to the pressure dependent formation of stable gas-phase products and secondary organic aerosol (SOA) as well as the influence of the presence of SO(2). In addition the rate coefficient for the initial reaction cyclohexene + O(3) was determined at 295 K. The observed increase in CO and ethene yields at low pressures and the absence of ketene in the product spectrum confirm previously proposed reaction pathways forming these decomposition products. An enhanced ethene formation at pressures below 300 mbar coincides with drastically decreased aerosol yields pointing to a high influence on SOA formation of chemical activation driven dynamics in the vinylhydroperoxide channel. The static reactor experiments at 450 mbar in the presence of SO(2) in the present study showed a similar sensitivity of additional particle formation to H(2)SO(4) number densities as found in near-atmospheric flow reactor experiments [Sipilaet al., Science, 2010, 327, 1243], a surprising result with regard to the very different experimental approaches. At low pressures (around 40 mbar) no significant new particle formation is observed even at high H(2)SO(4) concentrations. These findings indicate that the collisional stabilisation of initial clusters is an important aspect for SOA formation processes involving sulfuric acid and organic compounds. The results may have implications for geo engineering strategies based on stratospheric sulfur injection, but caution is mandatory when room temperature laboratory results are extrapolated to stratospheric conditions. PMID- 22825797 TI - A computational model of fibroblast growth factor-2 binding to endothelial cells under fluid flow. AB - Fibroblast growth factor-2 (FGF2) is an angiogenic growth factor that binds to cell surface receptors (FGFR) and heparan sulfate proteoglycans (HSPG), as well as HSPG in the basement membrane. FGF2 plays a critical role in angiogenesis, yet clinical FGF2 trials demonstrated limited success perhaps due to inadequate understanding of FGF2 binding in physiological conditions. We developed a computational model of FGF2 binding to isolated (HSPG or FGFR) or combined (HSPG and FGFR) binding sites under physiological fluid flow and predicted the effects of FGF2 concentration, binding site density, fluid flow rate, and delivery mode (continuous vs. bolus) on FGF2 complex formation. The isolated binding site models showed increased binding with FGF2 and binding site density. However, in the triad model, increasing FGF2 concentration decreased triads (FGF2-HSPG-FGFR) and increased FGF2-HSPG complexes. Fluid flow decreased time to equilibrium and dissociation in isolated binding site models, yet flow effect in the triad model depended on binding site density. Similarly, FGF2 capture and complex stability in bolus delivery depended on bolus size, flow rate, association and dissociation rate constants, as well as binding site density. This model shows the integrated effects of FGF2 binding stoichiometry, fluid flow, and delivery mode, and enhances our understanding of FGF2 complex formation under physiological conditions. PMID- 22825798 TI - A thrombus susceptibility comparison of two pulsatile Penn State 50 cc left ventricular assist device designs. AB - Left ventricular assist devices (LVADs) have proven successful as bridge to transplant devices for patients awaiting donor organs. While survival rates continue to increase, destination therapy remains hindered by thrombus formation within the device. Research has shown that thrombosis is correlated to the fluid dynamics within the device and may be a result of sustained shear rates below 500 s(-1) on the polyurethane blood sac used in the Penn State pulsatile LVAD. Particle image velocimetry is used to compare flow within two 50 cc LVAD designs to assess fluid patterns and quantify wall shear rates in regions known from in vivo studies to be susceptible to thrombus formation. The two designs differ in their front face geometry. The V-1 model has an outward-facing "dome" whereas the face of the V-2 model is flat. A thrombus susceptibility metric, which uses measured wall shear rates and exposure times, was applied to objectively compare pump designs over the entire cardiac cycle. For each design, there are regions where wall shear rates remained below 500 s(-1) for the entire cardiac cycle resulting in high thrombus susceptibility potential. Results of this study indicate that the V-2 device had an overall lower propensity for thrombus formation in the current region of interest. PMID- 22825800 TI - The ghosts of departed quantities: approaches to dealing with observations below the limit of quantitation. AB - A common but not necessarily logical requirement in drug development is that a 'limit of quantitation' be set for chemical assays and that observations that fall below the limit should not be treated as real data but should be labelled as below the limit and set aside for special treatment. We examine five of seven approaches to analysing such data considered by Beal in 2001, concentrating in particular on two: one that treats the data as a truncated sample and another that treats them as a censored sample. In fact, using a pattern-mixture framework, one can show that the former consists of using the conditional distribution of the 'acceptable values' and the latter adds the information from the marginal mixing distribution. We illustrate these approaches with a real example, concentrating in particular on the two likelihood-based methods, provide various formulae that may be used to compare these and other approaches, check these formulae using simulations and make some recommendations as to which approach one should use. PMID- 22825799 TI - Floating lipid bilayers: models for physics and biology. AB - Progress in the determination of structure and fluctuation spectrum of a floating bilayer system, as well as potential applications for biological studies, is reviewed. The system described here was first introduced by Charitat et al. (Eur Phys J B 8:583-593, 1999) and consists of a planar bilayer floating at 2-3 nm away from an adsorbed one on a solid surface in contact with bulk water. This model has been widely used for surface scattering studies using both neutrons and synchrotron radiation and its use in studies of relevance for physics and biology research areas will be described, together with the progress towards the production of complex biomimetic samples for use with scattering techniques. PMID- 22825801 TI - Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment. AB - Human diseases produced by pathogenic actinomycetes are increasing because they may be present as opportunistic infections. Some of these microbes cause systemic infections associated with immunosuppressive conditions, such as chemotherapy for cancer, immunosuppressive therapy for transplant, autoimmune conditions, and AIDS; while others usually cause localized infection in immunocompetent individuals. Other factors related to this increase in incidence are: antibiotic resistance, not well defined taxonomy, and a delay in isolation and identification of the offending microbe. Examples of these infections are systemic disease and brain abscesses produced by Nocardia asteroides or the located disease by Nocardia brasiliensis, named actinomycetoma. During the Pathogenic Actinomycetes Symposium of the 16th International Symposium on Biology of Actinomycetes (ISBA), held in Puerto Vallarta, Mexico, several authors presented recent research on the mechanisms by which N. brasiliensis modulates the immune system to survive in the host and advances in medical treatment of human actinomycetoma. Antibiotics and antimicrobials that are effective against severe actinomycetoma infections with an excellent therapeutic outcome and experimental studies of drugs that show promising bacterial inhibition in vivo and in vitro were presented. Here we demonstrate a systemic strong acquired immune response in humans and experimental mice at the same time of a local dominance of anti inflammatory cytokines environment. The pathogenic mechanisms of some actinomycetes include generation of an immunosuppressive micro environment to evade the protective immune response. This information will be helpful in understanding pathogenesis and to design new drugs for treatment of actinomycetoma. PMID- 22825802 TI - Retinal pigment epithelium tear through the fovea with maintained visual acuity of 20/20. PMID- 22825803 TI - Application of split-green fluorescent protein for topology mapping membrane proteins in Escherichia coli. AB - A topology map of a membrane protein defines the location of transmembrane helices and the orientation of soluble domains relative to the membrane. In the absence of a high-resolution structure, a topology map is an essential guide for studying structure-function relationships. Although these maps can be predicted directly from amino acid sequence, the predictions are more accurate if combined with experimental data, which are usually obtained by fusing a reporter protein to the C-terminus of the protein. However, as reporter proteins are large, they cannot be used to report on the cytoplasmic/periplasmic location of the N terminus of a protein. Here, we show that the bimolecular split-green fluorescent protein complementation system can overcome this limitation and can be used to determine the location of both the N- and C-termini of inner membrane proteins in Escherichia coli. PMID- 22825804 TI - Effects of locally administered insulin on bone formation in non-diabetic rats. AB - The possibility to control bone formation would be favorable in many areas of medicine, where bone defects is still a major challenge. Insulin has been suggested to exert both systemic and local anabolic effects in bone tissues. This raised the question whether locally administrated insulin could provide new therapeutic strategies for patients with local bone defects and impaired bone healing. The aim of this study was to evaluate bone formation in non-diabetic rats when local insulin is administered. This study differs from previous reports in two aspects: the use of non-diabetic animals and locally administered insulin. Twenty-four implants were inserted into 12 rats-one insulin-coated and one control-in each tibia for four weeks. Interferometry and histomorphometry were used to evaluate the surface topography and bone formation, respectively. Results demonstrated no significant changes in surface topography after insulin immobilization. Histomorphometry revealed significantly more bone around the insulin-coated implants (BA) (p = 0.005) and a similar amount of bone at the implant surface (BIC) (p = 0.117) compared with the controls. It was concluded that locally administered insulin from a titanium implant surface has the potential to increase bone formation not only in diabetic subjects but also in non-diabetic subjects. PMID- 22825805 TI - Non-severe nocturnal hypoglycemic events: experience and impacts on patient functioning and well-being. AB - PURPOSE: Non-severe nocturnal hypoglycemic events (NSNHEs) are hypoglycemic events that occur during sleep but do not require medical assistance from another individual. This study was conducted to better understand the NSNHEs as patients actually experience them in their daily life, and how they impacted functioning and well-being. METHODS: Nine focus groups were held in four countries with diabetics (Type 1 and Type 2) who had experienced an NSNHE within the previous month: France (2 groups); Germany (2 groups); United Kingdom (2 groups); and United States (3 groups). These groups were audio-taped, translated to English where applicable, and analyzed thematically. RESULTS: Seventy-eight people with diabetes participated in the focus groups: 41 (53 %) were female and 37 (47 %) were male; 24 (31 %) had Type 1 diabetes, and 54 (69 %) had Type 2 diabetes. Participant reports were grouped into several major themes: next day effects, symptoms, sleep impacts, social impacts, corrective action, practical management, feelings about NSNHEs, and work impacts. CONCLUSIONS: People with both Type 1 and Type 2 diabetes experience NSNHEs. The range of impact on these patients is wide, from very mild to severe with a majority of participants experiencing strong impacts that limit their daily functioning. This finding suggests that NSNHEs are more impactful than previously believed. PMID- 22825806 TI - Intensive care unit admitting patterns in the Veterans Affairs health care system. AB - BACKGROUND: Critical care resource use accounts for almost 1% of US gross domestic product and varies widely among hospitals. However, we know little about the initial decision to admit a patient to the intensive care unit (ICU). METHODS: To describe hospital ICU admitting patterns for medical patients after accounting for severity of illness on admission, we performed a retrospective cohort study of the first nonsurgical admission of 289,310 patients admitted from the emergency department or the outpatient clinic to 118 Veterans Affairs acute care hospitals between July 1, 2009, and June 30, 2010. Severity (30-day predicted mortality rate) was measured using a modified Veterans Affairs ICU score based on laboratory data and comorbidities around admission. The main outcome measure was direct admission to an ICU. RESULTS: Of the 31,555 patients (10.9%) directly admitted to the ICU, 53.2% had 30-day predicted mortality at admission of 2% or less. The rate of ICU admission for this low-risk group varied from 1.2% to 38.9%. For high-risk patients (predicted mortality >30%), ICU admission rates also varied widely. For a 1-SD increase in predicted mortality, the adjusted odds of ICU admission varied substantially across hospitals (odds ratio = 0.85-2.22). As a result, 66.1% of hospitals were in different quartiles of ICU use for low- vs high-risk patients (weighted kappa = 0.50). CONCLUSIONS: The proportion of low- and high-risk patients admitted to the ICU, variation in ICU admitting patterns among hospitals, and the sensitivity of hospital rankings to patient risk all likely reflect a lack of consensus about which patients most benefit from ICU admission. PMID- 22825807 TI - Access to care after Massachusetts' health care reform: a safety net hospital patient survey. AB - BACKGROUND: Massachusetts' health care reform substantially decreased the percentage of uninsured residents. However, less is known about how reform affected access to care, especially according to insurance type. OBJECTIVE: To assess access to care in Massachusetts after implementation of health care reform, based on insurance status and type. DESIGN AND PARTICIPANTS: We surveyed a convenience sample of 431 patients presenting to the Emergency Department of Massachusetts' second largest safety net hospital between July 25, 2009 and March 20, 2010. MAIN MEASURES: Demographic and clinical characteristics, insurance coverage, measures of access to care and cost-related barriers to care. KEY RESULTS: Patients with Commonwealth Care and Medicaid, the two forms of insurance most often newly-acquired under the reform, reported similar or higher utilization of and access to outpatient visits and rates of having a usual source of care, compared with the privately insured. Compared with the privately insured, a significantly higher proportion of patients with Medicaid or Commonwealth Care Type 1 (minimal cost sharing) reported delaying or not getting dental care (42.2 % vs. 27.1 %) or medication (30.0 % vs. 7.0 %) due to cost; those with Medicaid also experienced cost-related barriers to seeing a specialist (14.6 % vs. 3.5 %) or getting recommended tests (15.6 % vs. 5.9 %). Those with Commonwealth Care Types 2 and 3 (greater cost sharing) reported significantly more cost-related barriers to obtaining care than the privately insured (45.0 % vs. 16.0 %), to seeing a primary care doctor (25.0 % vs. 6.0 %) or dental provider (58.3 % vs. 27.1 %), and to obtaining medication (20.8 % vs. 7.0 %). No differences in cost-related barriers to preventive care were found between the privately and publicly insured. CONCLUSIONS: Access to care improved less than access to insurance following Massachusetts' health care reform. Many newly insured residents obtained Medicaid or state subsidized private insurance; cost related barriers to access were worse for these patients than for the privately insured. PMID- 22825808 TI - Air-breathing behavior and physiological responses to hypoxia and air exposure in the air-breathing loricariid fish, Pterygoplichthys anisitsi. AB - Hypoxic water and episodic air exposure are potentially life-threatening conditions that fish in tropical regions can face during the dry season. This study investigated the air-breathing behavior, oxygen consumption, and respiratory responses of the air-breathing (AB) armored catfish Pterygoplichthys anisitsi. The hematological parameters and oxygen-binding characteristics of whole blood and stripped hemoglobin and the intermediate metabolism of selected tissue in normoxia, different hypoxic conditions, and after air exposure were also examined. In normoxia, this species exhibited high activity at night and AB behavior (2-5 AB h(-1)). The exposure to acute severe hypoxia elicited the AB behavior (4 AB h(-1)) during the day. Under progressive hypoxia without access to the water surface, the fish were oxyregulators with a critical O2 tension, calculated as the inspired water O2 pressure, as 47 +/- 2 mmHg. At water O2 tensions lower than 40 mmHg, the fish exhibited continuous apnea behavior. The blood exhibited high capacity for transporting O2, having a cathodic hemoglobin component with a high Hb-O2 affinity. Under severe hypoxia, the fish used anaerobic metabolism to maintain metabolic rate. Air exposure revealed physiological and biochemical traits similar to those observed under normoxic conditions. PMID- 22825809 TI - Pre- and post-pandemic prevalence of antibodies to the 2009 pandemic influenza A (H1N1) virus in Austrian adults. AB - Antibody prevalence to the 2009 pandemic influenza A (H1N1) virus was determined in a sample of the Austrian population to assess the post-pandemic seropositivity rate, the infection attack rate, and the proportion of subclinical infections during the 2009/2010 influenza pandemic in Austrian adults. A total of 480 sera from individuals aged between 18 and 57 years from all nine federal states of Austria were collected between April and June 2010. Information on demographic characteristics, vaccination history, and history of suspected or verified influenza virus infection was ascertained. Antibodies were determined using a commercial ELISA and compared with 80 age-matched adult sera collected before the pandemic began. The overall seropositivity rate was 28% and was highest among young adults aged 18-29 years, followed by adults aged 50-57 years. Among seropositive unvaccinated individuals, infection was asymptomatic in more than 80%. Extrapolation to the overall Austrian adult population indicates that more than 1.3 million persons aged 18-57 years became infected in 2009. Compared with the pre-pandemic seropositivity rate, the infection rate was highest among young adults but low in those aged 30-57 years. Among 69 individuals previously vaccinated with the 2009 pandemic influenza A (H1N1) virus, 71% had specific antibodies. The study demonstrates that infection rates based on surveillance of clinical cases considerably underestimated the infection attack rate during the 2009 H1N1 pandemic in Austria and that vaccination against this virus elicited long-lasting seropositivity in more than 70% of adults. PMID- 22825810 TI - Prevalence of abnormal anal cytology in women infected with HIV. AB - Anal cancer is a rare disease. Nevertheless, it may be a reason for concern among groups in which its incidence is increasing: those who engage in anoreceptive intercourse, promiscuous persons, and those with sexually transmitted infections (HPV and HIV). The aim of this study was to evaluate the prevalence of abnormal anal cytology in women infected with HIV seen at Hospital de Clinicas de Porto Alegre, Brazil. A cross-sectional design was used. Anal smear screening was offered to all women infected with HIV seen at the hospital's outpatient sexually transmitted infections clinic from March 2006 to March 2008. A total of 184 patients were thus enrolled. Only patients who gave written consent were included in the study. The prevalence of abnormal anal cytology was 14.1% (26 patients). Twenty-two patients presented atypical squamous cells of undetermined significance, and four exhibited low-grade intraepithelial neoplasia. Initially, abnormal anal cytology was significantly associated with age, number of pregnancies, smoking, abnormal cervical cytology, CD4+ < 200 cells/mm3 and hepatitis C co-infection. After adjustment, only CD4+ < 200 cells/mm3 and smoking were found to increase the risk of altered anal cytology. The anal Pap method described is simple and can be used for screening in cohorts of HIV-positive women who are at risk of developing anal carcinoma, mainly those with CD4+ counts <200 cells/mm3 and smokers. PMID- 22825811 TI - Case report: management and HBV sequencing in a patient co-infected with HBV and HIV failing tenofovir. AB - Nucleos(t)ide analogs such as tenofovir, lamivudine, or emtricitabine are active against both HBV and HIV. Tenofovir confers potent and durable HBV-DNA suppression but the best strategy in case of resistance of HBV to tenofovir remains unknown. A case of a 22-year-old patient with co-infection with HBV and HIV transmitted perinatally is reported. After prolonged and intermittent treatment of HIV with lamivudine and tenofovir, HBV became resistant to lamivudine. Subsequently, clinical resistance to tenofovir occurred, manifesting as HBV-DNA breakthrough. The non-compliance was reasonable excluded and HIV-RNA remained constantly suppressed. Entecavir (1 mg daily) was added and the combination therapy resulted in a rapid and continuous suppression of HBV-DNA for over 12 months. The treatment was well-tolerated and safe. No known mutations, such as rtA181T/V associated with rtN236T or A194T that are associated with reduced susceptibility or resistance to tenofovir were detected. However, a unique and complex HBV substitution pattern was found: with a development of rtR192PR mutation at the time of virological failure. Adding entecavir to failing therapy with tenofovir and emtricitabine was feasible, well-tolerated and resulted in virological success. The rtR192PR, which is located in the B domain near the rtA194T, occurring in a context of a very complex substitutions patterns, might be associated with resistance to tenofovir. PMID- 22825812 TI - Human immunodeficiency virus enhances hepatitis C virus replication by differential regulation of IFN and TGF family genes. AB - HIV co-infection significantly impacts the natural history of hepatitis C virus (HCV) by increasing plasma HCV viral load, accelerating liver disease progression, and reducing rates of HCV clearance. Cytokines play an important role in regulating hepatic inflammation and fibrogenesis during chronic HCV infection, yet the impact of HIV on cytokine expression is unknown. In this study, an HCV continuous infection cell culture system was modified to permit co infection with HIV to test the hypothesis that virus-induced disregulation of immune-response genes, particularly interferons and TGF-beta, may create a permissive environment for the initial establishment of HIV/HCV co-infection in the host. CCR5-expressing Huh-7.5 hepatoma cells were transduced with human CD4 antigen to allow HIV infection in vitro. Co-infection of CD4+ Huh-7.5 cells with HIV and HCV or co-culture of HIV-infected CD4+ Huh-7.5 cells and HCV-infected Huh 7.5 cells increased the level of HCV RNA compared to HCV mono-infection. Quantitative gene expression analysis revealed HIV-induced up regulation of most tested IFN family genes when compared to HCV or co-infection. HCV infection induced up regulation of many TGF family genes that were subsequently down regulated in the presence of HIV or HIV/HCV. Interestingly, co-infection resulted in down regulation of several IFN genes and significant up regulation of TGF-beta genes leading to an overall enhancement of HCV replication. These data suggest that HIV infection may influence HCV replication in vitro by increasing levels of HCV RNA, possibly through the differential regulation of endogenous IFN and TGF family genes. PMID- 22825813 TI - Toll-like receptor 3 polymorphism and its association with hepatitis B virus infection in Saudi Arabian patients. AB - Hepatitis B virus (HBV) is the major causative agent of chronic liver complications including cirrhosis and hepatocellular carcinoma (HCC). Individuals infected with HBV show a wide spectrum of disease manifestations ranging from asymptomatic carriers to HCC. TLR3 is part of the innate immune system that recognizes double-stranded RNA (dsRNA) and provides early immune response to exogenous antigens. The genetic polymorphisms such as single nucleotide polymorphisms (SNPs) in the TLR3 could be considered as factors for the susceptibility to viral pathogens including HBV. Due to lack of knowledge on the role of TLR3 polymorphisms in HBV infection, this study investigated the distribution of nine SNPs in the TLR3 gene and its association with Saudi Arabian patients infected with HBV. A total of 707 patients and 600 uninfected controls were examined for different parameters including the nine SNPs (rs5743311, rs5743312, rs1879026, rs5743313, rs5743314, rs5743315, rs111611328, rs78726532 and a newly identified SNP located at position 184322913 of chr4). The association analysis confirmed that only one SNP, rs1879026 (G/T), showed a significant difference (P = 0.0480; OR = 0.809, 95% CI = 0.655-0.999) in the distribution between HBV carriers and uninfected controls. While, the rest of the SNPs showed no significant association with regards to HBV infection or in the progression to cirrhosis of the liver and HCC. Furthermore, haplotype analysis revealed that one haplotype GCGA (rs1879026, rs5743313, rs5743314, and rs5743315, respectively), was associated significantly with HBV infection in this population. These findings indicate that genetic variations in the TLR3 gene could affect the outcome of HBV infection among Saudis. PMID- 22825814 TI - Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection. AB - The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre-S1 84 (P = 0.042), pre-S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log-rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre-S1 and pre-S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection. PMID- 22825815 TI - The prevalence and long term outcome of occult hepatitis B virus infections in community based populations. AB - Features of occult hepatitis B infection in community-based populations have yet to be described. In this study we documented: (1) the prevalence and demographics, (2) associated serology and viral loads, and (3) clinical outcomes of occult hepatitis B infection in community-based populations. Hepatitis B surface antigen (HBsAg)-negative sera collected from three Northern Canadian communities (HBsAg prevalences: 11-12%) in 1983-1985 were tested for HBV-DNA by nested stage polymerase chain reaction. Of 706 HBsAg negative sera, 9 (1.3%) were HBV-DNA positive. The median age of occult hepatitis B infected patients at the time of sampling was 9.8 years (range 3.1-50.4 years) and six (67%) were female. Two (22%) individuals were anti-HBs positive (in the absence of prior vaccination). Viral loads were undetectable in all but two samples (2.40 and 2.86 log10 IU/ml). Only one of the five (20%) patients who were assessed clinically, remained HBV-DNA positive at 25-30 year follow-up. There was no clinical, biochemical or radiologic evidence of chronic hepatitis, cirrhosis or hepatocellular carcinoma in these individuals or on review of the charts from the remaining four infected patients. The results of this study suggest that in community-based populations: (1) occult hepatitis B infection is not as common as HBsAg positive infection, (2) the majority of infected subjects are young females, (3) a minority are anti-HBs positive, (4) viral loads are either undetectable or low, and (5) in the absence of concurrent liver disease, occult hepatitis B infection does not appear to be associated with long term adverse clinical outcomes. PMID- 22825817 TI - Development of quantitative RT-PCR assays for detection of three classes of HHV 6B gene transcripts. AB - The monitoring of active human herpesvirus 6 (HHV-6) B infection is important for distinguishing between the reactivation and latent state of the virus. The aim of this present study is to develop a quantitative reverse transcription polymerase chain reaction (RT-PCR) assay for diagnosis of active viral infection. Primers and probes for in house quantitative RT-PCR methods were designed to detect the three kinetic classes of HHV-6B mRNAs (U90, U12, U100). Stored PBMCs samples collected from 10 patients with exanthem subitum (primary HHV-6B infection) and 15 hematopoietic stem cell transplant recipients with HHV-6B reactivation were used to evaluate reliability for testing clinical samples. Excellent linearity was obtained with high correlation efficiency between the diluted RNA (1-100 ng/reaction) and C(t) value of each gene transcript. The U90 and U12 gene transcripts were detected in all of the peripheral blood mononuclear cells (PBMCs) samples collected in acute period of primary HHV-6B infection. Only one convalescent PBMCs sample was positive for the U90 gene transcript. Additionally, the reliability of HHV-6B quantitative RT-PCRs for diagnosis of viral reactivation in hematopoietic transplant recipients was evaluated. Relative to virus culture, U90 quantitative RT-PCR demonstrated the highest assay sensitivity, specificity, positive predictive value, and negative predictive value. Thus, this method could be a rapid and lower cost alternative to virus culture, which is difficult to perform generally, for identifying active HHV-6B infection. PMID- 22825818 TI - Recombination and natural selection in hepatitis E virus genotypes. AB - To gain new insights into the evolutionary processes that created the genetic diversity of the hepatitis E virus (HEV), the Recombination Detection Program (RDP) and SimPlot program were employed to detect recombination events in the genome, then the fixed-effects likelihood (FEL) method was used to detect natural selection effects on viral proteins. Recombination analysis provided strong evidence for both intergenotype and intragenotype recombination events in the sequences analyzed. Recombination events were found to be distributed non randomly, with the highest frequency in the X domain and the helicase. Strain DQ450072 was identified as intergenotype-recombinant. Natural selection analysis revealed that codons under both negative selection and positive selection were distributed non-randomly. ORF1 and ORF2 have experienced strong purifying selection across genotypes. Furthermore, potentially important sites were also found under positive selection in the N-terminal end of ORF2 and the C-terminal end of ORF3. No significant difference was found among the selective pressures on different genotypes. PMID- 22825816 TI - Hepatitis C viremia and genotype distribution among a sample of nonmedical prescription drug users exposed to HCV in rural Appalachia. AB - Research has demonstrated that hepatitis C (HCV) genotype distribution varies geographically and demographically. This exploratory study examines HCV viremia, viral concentration, and genotype distribution among anti-HCV positive, rural Appalachian nonmedical prescription drug users. The study population was randomly selected from a pool of 200 anti-HCV positive participants in a longitudinal study. Those randomly chosen were representative of the overall pool in terms of demographics, drug use, and other risk behaviors. Participants were tested serologically for HCV RNA, viral concentration, and genotype, and interview administered questionnaires examined behavioral and demographic characteristics. Of the 81 participants, 69% tested RNA positive, 59% of which had viral loads exceeding 800,000 IU/ml. Approximately 66% of the RNA positive sample had genotype 1a; types 2b (16%) and 3a (13%) were less common. RNA positive participants were not significantly different than RNA negative participants demographically or behaviorally. Likewise, with the exception of education, genotype 1 participants were not significantly different than those with genotype 2 or 3. The prevalence of active HCV infection highlights a need for prevention and treatment in this population. However, the predominance of genotype 1 may present challenges due to its association with decreased responsiveness to drug treatment, although the novel class of direct-acting antivirals such as telaprevir and boceprevir offer new hope in this regard. The prevalence of genotype 1 may also foreshadow heightened burden of hepatocellular carcinoma and elevated healthcare expenditures. More research is needed to characterize HCV infection and genotype in this population. PMID- 22825819 TI - Seroprevalence of neutralizing antibodies to human adenovirus type 5 in healthy adults in China. AB - Human adenoviruses have been used to develop candidate HIV vaccine vectors, but a major obstacle to the use of vectors derived from Ad5 and other common serotypes is the high prevalence of neutralizing antibodies (NAbs) in humans. Prior studies have reported a prevalence of Ad5 between 60% and 70% in Europe and US, and up to 98% in surveyed African and Asian (Thai) tropical countries. However, few studies have reported on the Ad5 prevalence in Chinese populations. In this study, a total of 1,250 healthy adult serum samples from six administratively separate regions of China were screened by high-throughput luciferase-based virus neutralization assays. Results showed that overall 72% of healthy adults were Ad5 seropositive, and 46.4% with baseline Ad5 NAb titers of >200 in China. Comprehensive analysis by geographical region and age showed that the seroprevalence of Ad5 in southern China such as Guangxi was higher than that in other regions. Geographical differences and climate were considered as the major factors affecting the titer levels of Ad5 in healthy adults. In addition, no apparent gender and ethnic difference was found in any group classified according to region, age, or NAb titer. The present study may provide useful insights for the future development of Ad5-based vaccines and gene therapy. PMID- 22825820 TI - Longitudinal observation of Epstein-Barr virus antibodies in athletes during a competitive season. AB - Epstein-Barr virus (EBV) serology continues to be the first diagnostic test when infectious mononucleosis is suspected. Due to possible mild immunosuppression in competitive athletes, EBV reactivation determined by increases in salivary viral load have been identified as one possible cause in recurrent respiratory infections. The long-term variation in EBV antibody levels in athletes compared to a control group remains unclear. The purpose of the study was to investigate the time course of changes in concentration of EBV antibodies in athletes with special emphasis on antibodies against early antigens (EAs) and avidity determination. During a competition season of approximately 12 months, the serological status of 15 biathletes (age 27 +/- 3 years, 7 female, 8 male, international to Olympic level) was compared with 11 controls (age 23 +/- 1 years; 1 female 10 male) at multiple time points. In addition, 43 healthy swimmers (age 22 +/- 4 years, 18 female, 25 male, national to international level) were tested to validate the results with only two time points interspersed by approximately 6 months of intensive physical exercise. Analysis of quantitative antibody intensity bands revealed stable values during a competition season. In particular, IgG-antibodies against EAs may persist and were found in 15% of past infections in swimmers exhibiting fluctuations in concentration after 6 months. These results provide evidence that positive Anti-EA-IgG may persist in healthy athletes and thus, should not be used to diagnose EBV reactivations or to identify a compromised immune function. PMID- 22825821 TI - Analysis of the codon 72 polymorphism of TP53 and human papillomavirus infection in Iranian patients with prostate cancer. AB - The TP53 gene is one of the most important tumor suppressor genes controlling DNA transcription and cell regulation. Common polymorphisms in p53 gene may play a role in some cancers. Some studies have reported an association between human papillomavirus (HPV) infections and prostate cancer. The aim of this study was to investigate whether the TP53 codon 72 polymorphism and HPV infection are responsible for susceptibility to prostate cancer in Iranian men. The prostate biopsies were taken during surgery from 68 Iranian prostatic cancer patients, and 85 patients with benign prostate hyperplasia. For genotyping of the p53 polymorphism at codon 72, PCRRFLP methods were used and the PCR products were digested with BstU1. An attempt was also made to detect HPV DNA in benign prostate hyperplasia and prostate cancer specimens. Among cancer cases, the distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes were 26.5%, 45.4%, and 19.1%, respectively. Among patients with benign prostate hyperplasia, the distribution of Arg/Arg, Arg/Pro, and Pro/Pro genotypes were 27%, 53%, and 20%, respectively. The allele frequencies did not differ significantly between prostate cancer and benign prostate hyperplasia samples. Human papillomavirus was detected only in three patients (4.4%; P = 0.71). The results from this study suggest that the TP53 codon 72 polymorphism and HPV infection do not confer susceptibility to prostate cancer in the Iranian population. Larger population based studies are needed to clarify the relation between prostate carcinoma and p53 polymorphism and HPV infection. PMID- 22825822 TI - Oral health profile in patients infected with HTLV-1: clinical findings, proviral load, and molecular analysis from HTLV-1 in saliva. AB - Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been implicated in several disorders, including periodontal disease. The proviral load is an important biological marker for understanding HTLV-1 pathogenesis and elucidating whether or not the virus is related to the clinical manifestation of the disease. This study describes the oral health profile of HTLV-1 carriers and HAM/TSP patients in order to investigate the association between the proviral load in saliva and the severity of the periodontal disease and to examine virus intra-host variations from peripheral blood mononuclear cells and saliva cells. It is a cross-sectional analytical study of 90 individuals carried out from November 2006 to May 2008. Of the patients, 60 were HTLV-1 positive and 30 were negative. Individuals from the HTLV-1 positive and negative groups had similar mean age and social-economic status. Data were analyzed using two available statistical software packages, STATA 8.0 and SPSS 11.0 to conduct frequency analysis. Differences of P < 0.05 were considered statistically significant. HTLV-1 patients had poorer oral health status when compared to seronegative individuals. A weak positive correlation between blood and saliva proviral loads was observed. The mean values of proviral load in blood and saliva in patients with HAM/TSP was greater than those in HTLV 1 carriers. The HTLV-1 molecular analysis from PBMC and saliva specimens suggests that HTLV-1 in saliva is due to lymphocyte infiltration from peripheral blood. A direct relationship between the proviral load in saliva and oral manifestations was observed. PMID- 22825823 TI - Molecular and epidemiological features of gastroenteritis outbreaks involving genogroup I norovirus in Victoria, Australia, 2002-2010. AB - GI noroviruses are relatively rare and systematic studies of the molecular epidemiology of GI norovirus outbreaks are lacking. The current study examined the molecular virology of GI norovirus outbreaks in Victoria, Australia (2002 2010). Of 1,617 norovirus outbreaks identified, 69 (4.3%) were associated with GI norovirus alone, 1,540 (95.2%) with GII norovirus alone and 8 (0.5%) with GI + GII. Some differences between GI and GII outbreak epidemiology were found. GI outbreaks peaked in the 2-month period November/December whereas GII outbreaks peaked in the 2-month period September/October and GI norovirus outbreaks were significantly more common in non-healthcare settings (37.7%) than GII outbreaks (9.5%). ORF 1/ORF 2 genotypes found in the 69 outbreaks involving GI norovirus alone were: GI.2/GI.2, 7 outbreaks; GI.2/GI.6, 18 outbreaks; GI.3b/GI.3, 14 outbreaks; GI.4/GI.4, 21 outbreaks; GI.8/GI.8, one outbreak; GI.d/GI.3, four outbreaks; and GI.e/GI.13, one outbreak. The current study appears to be the first to have identified the recombinant form, GI.2/GI.6. Whereas GI.2/GI.6 and GI.3b/GI.3 outbreaks occurred with equal frequency in both healthcare and non healthcare settings, GI.4/GI.4 occurred predominantly in healthcare settings. GI ORF 1/ORF 2 genotypes found in the eight outbreaks involving GI + GII norovirus were GI.2/GI.6, GI.3b/GI.3, and GI.4/GI.4, indicating GI genotypes in GI + GII outbreaks were similar to those found in outbreaks involving GI alone. Apparent differences in the evolution of different GI genotypes were noted. GI.2/GI.2, GI.2/GI.6, and GI.4/GI.4 strains tended to undergo periodic shifts in nucleotide sequence whereas various GI.3b/GI.3 strains tended to circulate simultaneously. PMID- 22825824 TI - Molecular epidemiology of norovirus gastroenteritis outbreaks in New Zealand from 2002-2009. AB - Noroviruses are the most common cause of acute non-bacterial gastroenteritis outbreaks worldwide, including New Zealand. New Zealand has a population of 4.4 million, which allows for centralized outbreak surveillance and a Norovirus Reference Laboratory, which facilitates efficient diagnosis, surveillance, and tracking of norovirus outbreaks. Norovirus outbreak strains are identified, sequenced, and compared with international reference strains. Between January 2002 and December 2009, 1,206 laboratory-confirmed norovirus outbreaks were recorded. The predominant outbreak settings were healthcare institutions for the elderly and acute care patients. Other outbreak settings included catering establishments, cruise ships, homes, community events, school camps, child related settings, and consumption of contaminated shellfish. Of the 1,206 outbreaks, 105 (8.7%) were caused by norovirus genogroup I (GI) strains, 1,085 (89.9%) were caused by genogroup II (GII) strains, and both GI and GII strains were detected in 9 (0.8%) outbreaks. The genogroup was not identified in 7 (0.6%) outbreaks. A range of norovirus genotypes, including GI genotypes 1-6, GII genotypes 2-8, and GII.12, were associated with these outbreaks. The predominant genotype was GII.4, which was identified in 825 (68.4%) outbreaks. Norovirus GII.4 variant strains, including 2002 (Farmington Hills), 2004 (Hunter), 2006a (Laurens, Yerseke), 2006b (Minerva), and 2010 (New Orleans) implicated in overseas outbreaks also occurred in New Zealand, providing evidence of global spread. PMID- 22825825 TI - Dynamics of urinary polyomavirus shedding in healthy adult women. AB - The hypothesis was examined that physiologic variation of estrogen concentrations during the menstrual cycle can provoke BK virus (BKV) excretion. BKV and JCV viral loads were determined in urine specimens obtained almost daily from 20 healthy, non-pregnant women over 2 months. Asymptomatic urinary shedding of BKV was observed in 123 (12.0%) of 1,021 specimens from 11 (55%) study subjects. Two subjects excreted JCV in their urine, with one subject excreting detectable JCV in all urine specimens. Analysis of 36 complete menstrual cycles revealed no difference in the prevalence of BKV excretion between pre-ovulatory and post ovulatory phases of the menstrual cycle. The unexpected day-to-day variability in BKV excretion suggests that as yet unidentified factors may contribute to the periodic shedding of BKV by healthy women. PMID- 22825826 TI - Investigation of polyomaviruses replication in pediatric patients with nephropathy receiving rituximab. AB - Rituximab is a chimeric monoclonal antibody reacting with the CD20 antigen on B cells. It has been proposed as treatment for the idiopathic nephrotic syndrome, recurrent idiopathic nephropathy, and focal segmental glomerulosclerosis refractory to steroids. Rituximab influences T-cell immunity and may predispose the patients to opportunistic infections, such as progressive multifocal leukoencephalopathy caused by the polyomavirus JC (JCV). The risk of latent viruses infections/reactivations in pediatric patients receiving monoclonal antibodies is not well known yet. In this longitudinal 6-month study, the effects of rituximab on JCV and BK virus (BKV) replication have been investigated. Blood, serum, and urine samples have been collected monthly from 11 pediatric patients (mean age: 11 years) with the idiopathic nephrotic syndrome and recurrent idiopathic nephropathy, under rituximab therapy. JCV and BKV real-time PCRs and sequencing of the viral protein 1 and the non-coding control region have been conducted. The same investigations have been undertaken on samples collected from eight pediatric patients (controls, mean age: 6 years), with idiopathic nephrotic syndrome or focal segmental glomerulosclerosis, treated with conventional chemotherapy. JCV was detected in the urine of one patient (9%), and one control (12.5%); BKV was found in the urine of 7/11 patients (63.6%) and 2/8 controls (25%) and in blood samples from four patients. No significant difference was found in the mean viral loads and in the viral molecular characterizations between the two groups. The polyomaviruses replication was not associated with rituximab therapy in children. PMID- 22825827 TI - Use of MMP-8 and MMP-9 to assess disease severity in children with viral lower respiratory tract infections. AB - Matrix metalloproteinases (MMPs) play an important role in respiratory inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. It was hypothesized that MMP-8 and MMP-9 may function as biological markers to assess disease severity in viral lower respiratory tract infections in children. MMP-8 and MMP-9 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) and granulocytes obtained in both the acute and recovery phase from 153 children with mild, moderate, and severe viral lower respiratory tract infections were determined using real-time PCR. In addition, MMP-8 and MMP-9 concentrations in blood and nasopharyngeal specimens were determined during acute mild, moderate, and severe infection, and after recovery using ELISA. Furthermore, PBMCs and neutrophils obtained from healthy volunteers were stimulated with RSV, LPS (TLR4 agonist), and Pam3Cys (TLR2 agonist) in vitro. Disease severity of viral lower respiratory tract infections in children is associated with increased expression levels of the MMP-8 and MMP-9 genes in both PBMCs and granulocytes. On the contrary, in vitro experiments showed that MMP-8 and MMP-9 mRNA and protein expression in PBMCs and granulocytes is not induced by stimulation with RSV, the most frequent detected virus in young children with viral lower respiratory tract infections. These data indicate that expression levels of the MMP-8 and MMP-9 genes in both PBMCs and neutrophils are associated with viral lower respiratory tract infections disease severity. These observations justify future validation in independent prospective study cohorts of the usefulness of MMP-8 and MMP-9 as potential markers for disease severity in viral respiratory infections. PMID- 22825828 TI - Diversity in the VP7 encoding genes of rotavirus strains isolated from adolescent and adult cases of acute gastroenteritis. AB - A study was conducted to examine the diversity in the VP7 genes of rotavirus strains circulating in adolescent and adult cases of acute gastroenteritis during two different time periods, 1993-1996 and 2004-2007. The multiplex RT-PCR carried out on 131 rotavirus positive fecal specimens detected 65 (49.6%) single and 48 (36.6%) mixed infections of VP7 genotypes that included 43G1 (38.1%), 37G2 (32.7%), 8G3 (7.1%), 15G4 (13.3%), and 10G9 (8.8%) specificities. Sequencing and phylogenetic analysis of the VP7 gene amplicons revealed the presence of G1-IA (4.7%), G1-IB (69.8%), and G1-IC (25.5%) lineages within the G1 strains, G2-IIb1 (70.3%) and G2-IIb2 (29.7%) lineages within G2 strains, G3-3S1 (12.5%) and G3-3S4 (87.5%) lineages within G3 strains, G4-Ia (6.7%) and G4-Ib (93.3%) lineages within G4 strains, and G9-III lineage within G9 strains. The variability within VP7 genotypes was evident by 1.4-8.0% and 1.3-3.9% amino acid divergence respectively from the prototype strains and between the groups of strains at the two time points. This is the first report describing the phylogenetic analysis of VP7 genes of rotaviruses from adolescent and adult cases of acute gastroenteritis in India. Since adults infected with rotavirus could act as a source of infection and affect the epidemiology of rotaviruses in children, genetic analysis of the rotavirus strains circulating in adults is required. The intragenotypic diversity within VP7 genes demonstrated by the present study highlights the need for constant surveillance of rotavirus infections to understand better the evolution and transmission of group A rotaviruses in the community. PMID- 22825829 TI - Molecular epidemiology of rotavirus and norovirus in Ile-Ife, Nigeria: high prevalence of G12P[8] rotavirus strains and detection of a rare norovirus genotype. AB - Rotavirus (RV) and norovirus (NoV) are considered the most common causes of viral gastroenteritis in children. In this study, the prevalence of RV and NoV infection in 55 children with diarrhea from the rural community Akinlalu in Southwestern Nigeria was investigated using real-time PCR assays. The RV and NoV strains were genotyped by PCR and/or sequencing. RV and NoV infections occurred with a prevalence of 34.5% and 25.5% respectively, with predominance in children <1 year. Most infections occurred during the dry season with increasing prevalence of RV as the dry season progressed (October-January). Infections with RV VP6 subgroup (SG) II were more prevalent (27.3%) than SGI (7.3%). Similarly, NoV genogroup II infections were more common (23.6%) than genogroup I (1.8%). Five children out of 55 (9.1%) were co-infected with both RV and NoV. Notably, G12P[8] was the predominant RV strain (36.8%, n = 7), observed for the first time in Nigeria. The VP7 gene of the G12 strains clustered within lineage III, sharing high nucleotide identity with each other (>99%) indicating introduction in Nigeria from a single donor. Furthermore, a putative novel genotype within genogroup I NoV was detected, which till date has only been reported once in humans. To conclude, a high prevalence of the emerging G12P[8] RV strain was observed for the first time in Nigeria, as well as a putative novel NoV genotype in humans. These results provide new information which can be important for future vaccine evaluations and possible introduction in Nigeria. PMID- 22825830 TI - Isolation of saffold virus type 2 in green monkey kidney cells. AB - Saffold viruses (SAFV) have been discovered recently and they are classified into Theilovirus species in genus Cardiovirus in the Picornaviridae family. SAFV, especially those belonging to the genotype 2, have been difficult to propagate in laboratory cell lines. This study describes the successful isolation of an efficiently growing SAFV-2 strain directly from a stool specimen by standard virological methods. The availability of SAFV isolates that can be propagated to high titers is crucial to the future studies on pathogenesis and epidemiology of these novel human viruses. PMID- 22825831 TI - A diagnostic polymerase chain reaction assay for Zika virus. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus. Infection results in a dengue like illness with fever, headache, malaise, and a maculopapular rash. Nearly all cases are mild and self-limiting but in 2007, a large outbreak of ZIKV was reported from the island of Yap (in Micronesia, northwest of Indonesia). Singapore is already endemic for dengue, and its impact on public health and economic burden is significant. Other dengue-like infections (e.g., Chikungunya virus) are present. Yet only 10% of reported dengue cases have laboratory confirmation. The identification and control of other dengue-like, mosquito transmitted infections is thus important for the health of Singapore's population, as well as its economy. Given that ZIKV shares the same Aedes mosquito vector with both dengue and Chikungunya, it is possible that this virus is present in Singapore and causing some of the mild dengue-like illness. A specific and sensitive one-step, reverse transcription polymerase chain reaction (RT-PCR) with an internal control (IC) was designed and tested on 88 archived samples of dengue-negative, Chikungunya-negative sera from patients presenting to our hospital with a dengue-like illness, to determine the presence of ZIKV in Singapore. The assay was specific for detection of ZIKV and displayed a lower limit of detection (LoD) of 140 copies viral RNA/reaction when tested on synthetic RNA standards prepared using pooled negative patient plasma. Of the 88 samples tested, none were positive for ZIKV RNA, however, the vast majority of these were from patients admitted to hospital and further study may be warranted in community-based environments. PMID- 22825832 TI - Usefulness of impulse oscillometry and fractional exhaled nitric oxide in children with Eosinophilic bronchitis. AB - BACKGROUND: Eosinophilic bronchitis (EB) is a common cause of chronic cough. Although EB shares many immunopathologic features with asthma, it does not show airway hyperresponsiveness or reversible airway obstruction by spirometry. OBJECTIVE: Compared to healthy children without pulmonary disease, we hypothesized that EB patients would demonstrate abnormal pulmonary function and inflammation with impulse oscillometry (IOS) and fractional exhaled nitric oxide (FeNO), which are more sensitive tests of these parameters than spirometry. METHODS: A total of 232 children with asthma, 109 with EB, and 115 control subjects were enrolled. We compared pulmonary function parameters and FeNO levels among the three groups. Additionally, we designated a screening cutoff value of FeNO combined with IOS parameters to distinguish EB from the control group, and identify which children with EB have more asthmatic characteristics. RESULTS: By IOS, the bronchodilator response of the EB and asthma groups increased significantly compared to controls for both reactance at 5 Hz (Delta X5) and reactance area (Delta AX) (P < 0.0001). Cutoff values to distinguish EB from controls were a Delta X5 of -20% (sensitivity, 77.5%; specificity, 49.6%), and Delta AX of -30% (sensitivity, 75.0%; specificity, 46.0%), when the FeNO is 20 ppb. CONCLUSIONS: Reversible airway obstruction in IOS and elevated FeNO levels can be detected in children with EB. This would support that EB in children shows airway characteristics similar to those of asthma, and that a continuum exists between asthma and EB. PMID- 22825833 TI - Genome-based cryptic gene discovery and functional identification of NRPS siderophore peptide in Streptomyces peucetius. AB - Identification of secondary metabolites produced by cryptic gene in bacteria may be difficult, but in the case of nonribosomal peptide (NRP)-type secondary metabolites, this study can be facilitated by bioinformatic analysis of the biosynthetic gene cluster and tandem mass spectrometry analysis. To illustrate this concept, we used mass spectrometry-guided bioinformatic analysis of genomic sequences to identify an NRP-type secondary metabolite from Streptomyces peucetius ATCC 27952. Five putative NRPS biosynthetic gene clusters were identified in the S. peucetius genome by DNA sequence analysis. Of these, the sp970 gene cluster encoded a complete NRPS domain structure, viz., C-A-T-C-A-T-E C-A-T-C-A-T-C domains. Tandem mass spectrometry revealed that the functional siderophore peptide produced by this cluster had a molecular weight of 644.4 Da. Further analysis demonstrated that the siderophore peptide has a cyclic structure and an amino acid composition of AchfOrn-Arg-hOrn-hfOrn. The discovery of functional cryptic genes by analysis of the secretome, especially of NRP-type secondary metabolites, using mass spectrometry together with genome mining may contribute significantly to the development of pharmaceuticals such as hybrid antibiotics. PMID- 22825834 TI - Expression, renaturation and biological activity of recombinant conotoxin GeXIVAWT. AB - Conotoxins are a diverse array of small peptides mostly with multiple disulfide bridges. These peptides become an increasing significant source of neuro pharmacological probes and drugs as a result of the high selectivity for ion channels and receptors. Conotoxin GeXIVAWT (CTX-GeXIVAWT) is a 28-amino acid peptide containing five cysteines isolated from the venom of Conus generalis. Here, we present a simple and fast strategy of producing disulfide-rich conotoxins via recombinant expression. The codes of novel conotoxin gene GeXIVAWT were optimized and generated two pairs of primers by chemical synthesis for construction of expression vector. Recombinant expression vector pET22b(+) GeXIVAWT fused with pelB leader and His-tag was successfully expressed as an insoluble body in Escherichia coli BL21(DE3) cells. Recombinant conotoxin GeXIVAWT (rCTX-GeXIVAWT) was obtained by dissolving the insoluble bodies and purifying with a Ni-NTA affinity column, which was further purified using reverse phase high-performance liquid chromatography and identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The rCTX-GeXIVAWT renatured in vitro could inhibited the growth of Sf9 cell with biological activity assay. This expression system may prove valuable for future structure function studies of conotoxins. PMID- 22825835 TI - Two-stage meta-analysis of survival data from individual participants using percentile ratios. AB - Methods for individual participant data meta-analysis of survival outcomes commonly focus on the hazard ratio as a measure of treatment effect. Recently, Siannis et al. (2010, Statistics in Medicine 29:3030-3045) proposed the use of percentile ratios as an alternative to hazard ratios. We describe a novel two stage method for the meta-analysis of percentile ratios that avoids distributional assumptions at the study level. PMID- 22825836 TI - A 10-year follow-up study on long-term clinical outcomes of lumbar microendoscopic discectomy. AB - OBJECT: The aim of this study was to determine the 10-year clinical outcomes of microendoscopic discectomy (MED), a surgical procedure for the treatment of lumbar disc herniation (LDH). METHODS: A total of 151 patients with LDH were treated with MED and followed postoperatively for up to 10 years. The modified MacNab criteria were used to examine the clinical outcomes. In a subset of patients (n = 107), the disc-height ratio was measured radiographically according to the Mochida's method. RESULTS: Based on the modified MacNab criteria, 120 (79%) patients were rated as excellent, 20 (12.9%) as good, 7 (4.6%) as fair, and 5 (3.5%) as poor. Only 5 patients (3.5%) required additional surgery due to a recurrence of herniation. Other complications included intraoperative dural lacerations (5 patients) and spondylodiscitis (3 patients). Mochida's method showed an average disc-height ratio of 76.25%. Approximately 67% of the patients were able to maintain their primary occupations. CONCLUSION: The 10-year follow up study showed that the long-term clinical outcomes of MED are satisfactory and better than those of the traditional discectomy procedure. The MED procedure is both feasible and efficacious for the treatment of LDH. PMID- 22825837 TI - Prone positioning for successful gamma knife radiosurgical treatment of far anterior skull base lesions: a technical note. AB - BACKGROUND: Gamma Knife targeting is geometrically limited by the physical dimensions of the head, helmet, headframe, and the radiation target position. All four aspects need to be considered for accurate treatment planning. Within the available space, delivery of the treatment isodose is based on the target position, which must be brought into the center of the collimator. In cases of anatomically challenging target positions in far eccentric locations of the head, careful treatment planning needs to be performed that does not exceed the limits of the system. CLINICAL PRESENTATION: We describe a case of a challenging far anterior ethmoid sinus hemangiopericytoma in an 80-year-old woman. TECHNIQUE: The tumor was treated successfully by positioning the patient prone on a Model C Gamma unit. The physical restrictions of the Gamma Knife surgical system and the rationale for improved anterior targeting using the prone position are discussed. CONCLUSION: A thoughtful approach to positioning in challenging anterior lesions extends the targeting capabilities of certain Gamma units. PMID- 22825838 TI - Melanoma cell-derived factors stimulate hyaluronan synthesis in dermal fibroblasts by upregulating HAS2 through PDGFR-PI3K-AKT and p38 signaling. AB - In many cancers hyaluronan content is increased, either by tumor cells or the surrounding stromal cells and this increased hyaluronan content correlates with unfavorable clinical prognosis. In the present work, we studied the effects of melanoma cell (aggressive melanoma cell line C8161)-derived factors on fibroblast hyaluronan synthesis, intracellular signaling, MMP expression and invasion. Treatment of the fibroblast cultures with melanoma cell conditioned medium (CM) caused accumulation of hyaluronan in the culture medium and formation of thick pericellular hyaluronan coat and hyaluronan cables. The expression of Has2 was increased approximately 20-fold by the C8161 melanoma cell CM, while Has1 and Has3 were increased twofold. Knock-down of Has2 expression with siRNA showed that Has2 was responsible for the increased hyaluronan synthesis induced by the melanoma cell CM. To find out the signaling routes, which led to Has2 upregulation, the phosphorylation profiles of 46 kinases were screened with phosphokinase array kit. Melanoma cell CM treatment strongly induced a rapid phosphorylation of p38, JNK, AKT, CREB, HSP27, STAT3 and cJUN. Treatment of the fibroblasts with specific inhibitors of PI3K, AKT and p38 reduced the melanoma cell CM-induced hyaluronan secretion, while the inhibitor of PDGFR totally blocked it. In addition, siRNA for PDGFRalpha/beta inhibited Has2 upregulation in melanoma cell CM-treated fibroblasts. In parallel with the increased hyaluronan synthesis the melanoma cell CM-treated fibroblasts showed spindle shape, numerous long cell protrusions, enhanced MMP expression and increased invasion into collagen-Cultrex matrix. siRNA blocking of Has2 or PDGFRalpha/beta expression reversed the stimulatory effect of melanoma cell CM on fibroblast invasion. PDGF secreted by melanoma cells thus mediated fibroblasts activation, with HAS2 upregulation as a major factor in the fibroblast response. This effect on stromal matrix is suggested to favor tumor growth. PMID- 22825840 TI - Consistent quasistatic and acoustic elasticity determination of poly-L-lactide based rapid-prototyped tissue engineering scaffolds. AB - This paper is concerned with reliable and physically sound elasticity determination of rapid-prototyped tissue engineering scaffolds made of poly-L lactide (PLLA), with and without small portions of tricalcium phosphate (TCP) inclusions. At the level of overall scaffolds, that is, that of several millimeters, multiple uniaxial loading-unloading (quasistatic) tests were performed, giving access to the scaffolds' Young's moduli, through stress-strain characteristics during unloading. In addition, acoustic tests with 0.05 MHz frequency delivered an independent access to elastic properties, in terms of the normal components of the scaffolds' stiffness tensors. The latter strongly correlate, in a linear fashion, with the Young's moduli from the unloading tests, revealing porosity independence of Poisson's ratio. The magnitude of the latter is in full agreement with literature data on polymers. Both of these facts underline that both ultrasound tests and quasistatic unloading tests reliably provide the elastic properties of tissue engineering scaffolds. PMID- 22825839 TI - Accelerated proliferation of hepatocytes in rats with iron overload after partial hepatectomy. AB - Although iron overload is implicated in hepatocarcinogenesis, the precise mechanism was not known yet. In the present study, we investigated the effect of iron overload upon the induction of hepatocyte proliferation after 70% partial hepatectomy (PH) in rats fed with rat chow with 3% carbonyl iron for 3 months. In normal-diet rats, the increase in Ki-67 labeling index (LI) commenced at 24 h post-PH and the LIs of proliferating cell nuclear antigen (PCNA) incorporated 5 bromo-2'-deoxyuridine (BrdU) and phospho-histone H3 reached maximum values at 36 and 48 h after PH, respectively. In iron-overload rats, the above parameters occurred 12 h earlier compared to that of normal-diet rats, shortening the G0-G1 transition. Interestingly, nuclear staining for metallothionein (MT), which is essential for hepatocyte proliferation, was noted even at 0 h in iron-overload rats, while MT expression occurred at 6 h in the normal rats. Moreover, nuclear factor kappa B (NF-kappaB) expression, which is an essential early event leading to liver regeneration, was detected in Kupffer cells at 0 h in iron-overload rats. These results may indicate that overloaded iron, maybe through the induction of MT and NF-kappaB, may keep liver as a state ready to regenerate in response to PH, by bypassing signal transduction cascades involved in the initiation of liver regeneration. PMID- 22825841 TI - Dynamics of the lipid content and biomass of Calanus finmarchicus (copepodite V) in a Norwegian Fjord. AB - Calanus finmarchicus is the dominant zooplankton species in the North Atlantic. This zooplankton is also of interest for commercial harvesting due to its high abundance and biochemical contents. In the present study, copepodite stage V of C. finmarchicus was sampled at different depths from January to June in 2009, 2010 and 2011 in the Trondheimsfjord (63 degrees 29'N 10 degrees 18'E). The fatty acid composition was analyzed in individual copepods and in the seston. It was found that the fatty acid profile of copepods was related to the fatty acid profile of potential food sources. This study indicates that the onset of vertical migration of stage V, which was observed in May, has a strong link to the production of phytoplankton and lipid accumulation in C. finmarchicus. The content of 14:0 and 16:0 fatty acids in the specimens did not increase from February to May in surface waters. This suggests that these fatty acids in the diet were used as precursors for the biosynthesis of 20:1n-9 and 22:1n-11 fatty acids and fatty alcohols. A potential harvesting season of C. finmarchicus could be when the species is abundant in surface waters; the content of n-3 fatty acids will vary throughout this season. The peak abundance of C. finmarchicus in the spring varied substantially between the years studied. PMID- 22825842 TI - Sex chromosomes and associated rDNA form a heterochromatic network in the polytene nuclei of Bactrocera oleae (Diptera: Tephritidae). AB - The olive fruit fly, Bactrocera oleae, has a diploid set of 2n = 12 chromosomes including a pair of sex chromosomes, XX in females and XY in males, but polytene nuclei show only five polytene chromosomes, obviously formed by five autosome pairs. Here we examined the fate of the sex chromosomes in the polytene complements of this species using fluorescence in situ hybridization (FISH) with the X and Y chromosome-derived probes, prepared by laser microdissection of the respective chromosomes from mitotic metaphases. Specificity of the probes was verified by FISH in preparations of mitotic chromosomes. In polytene nuclei, both probes hybridized strongly to a granular heterochromatic network, indicating thus underreplication of the sex chromosomes. The X chromosome probe (in both female and male nuclei) highlighted most of the granular mass, whereas the Y chromosome probe (in male nuclei) identified a small compact body of this heterochromatic network. Additional hybridization signals of the X probe were observed in the centromeric region of polytene chromosome II and in the telomeres of six polytene arms. We also examined distribution of the major ribosomal DNA (rDNA) using FISH with an 18S rDNA probe in both mitotic and polytene chromosome complements of B. oleae. In mitotic metaphases, the probe hybridized exclusively to the sex chromosomes. The probe signals localized a discrete rDNA site at the end of the short arm of the X chromosome, whereas they appeared dispersed over the entire dot-like Y chromosome. In polytene nuclei, the rDNA was found associated with the heterochromatic network representing the sex chromosomes. Only in nuclei with preserved nucleolar structure, the probe signals were scattered in the restricted area of the nucleolus. Thus, our study clearly shows that the granular heterochromatic network of polytene nuclei in B. oleae is formed by the underreplicated sex chromosomes and associated rDNA. PMID- 22825843 TI - Mitochondrial haplotypes reveal olive fly (Bactrocera oleae) population substructure in the Mediterranean. AB - The olive fly (Bactrocera oleae) is the most important olive tree (Olea europaea) pest. In the Mediterranean basin, where 98 % of its main hosts are concentrated, it causes major agricultural losses, due to its negative effect on production and quality of both olive and olive oil. Previous phylogeographic analyses have established that Mediterranean olive fly populations are distinct from other Old World populations, but did not agree on the specific population substructure within this region. In order to achieve a higher resolution of the diversity of olive fly populations, particularly in Central and Western Mediterranean (home to 70 % of the world production), we comparatively analyzed a set of samples from Portugal in the context of published mitochondrial sequences across the species' worldwide range. Strong evidence of population substructure was found in the Central and Western Mediterranean area, with two clearly separate phylogenetic branches. Together with previously published data, our results strongly support the existence of at least three distinct Mediterranean populations of the olive fly, raise the possibility of additional regional substructure and suggest specific avenues for future research. This knowledge can be instrumental in the development of better management and control strategies for a major pest of Mediterranean agriculture. PMID- 22825845 TI - Classic kaposi sarcoma with pulmonary involvement mimicking endobronchial tuberculosis in a child. AB - Kaposi' sarcoma (KS) is a low-grade vascular neoplasm and classic KS, a subtype of KS, is extremely rare in children. Childhood pulmonary involvement in classic KS has not been reported in the literature. We describe an HIV-seronegative pediatric case with a fulminant course of classic KS with pulmonary involvement mimicking endobronchial tuberculosis. PMID- 22825844 TI - Current statin usage for patients with acute coronary syndrome undergoing percutaneous coronary intervention: multicenter survey in Korea. AB - BACKGROUND: Although high-dose statin therapy has been reported to improve outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), patterns of statin usage for such patients have not been reported in real-world clinical practice. HYPOTHESIS: Some clinical factors would affect the pattern of statin usage in patients with ACS. METHODS: In the multicenter prospective registry, 3362 patients with ACS who underwent PCI were analyzed. High-dose statin treatment was defined as atorvastatin >=40 mg or rosuvastatin >=20 mg per day. The patterns of statin usage were investigated for 30 days after the index PCI. RESULTS: High-dose statins were administered prior to PCI to 13.7% and 19.6% of patients with unstable angina/non-ST-elevated myocardial infarction (UA/NSTEMI) and ST-elevated myocardial infarction (STEMI), respectively (P < 0.001). After PCI, 476 (14.2%) patients were maintained on high dose statins, and 550 (16.4%) patients received no statins. Independent factors associated with high-dose statin usage after PCI were STEMI (odds ratio [OR]: 1.704, 95% confidence interval [CI]: 1.321-2.197, P < 0.001), high total cholesterol level (OR: 1.445, 95% CI: 1.136-1.837, P = 0.003), and current smoker (OR: 1.556, 95% CI: 1.206-2.008, P < 0.011). The absence of hypercholesterolemia was an independent factor determining the nonuse of statins (OR: 0.229, 95% CI: 0.148-0.353, P < 0.001). CONCLUSIONS: In real-world clinical practice, high-dose statin treatment is being underused despite extensive evidence for patients with ACS undergoing PCI, particularly in UA/NSTEMI. Efforts are needed to ensure that clinical practice complies with evidence-based guidelines. PMID- 22825846 TI - Kallikrein-related peptidase-7 regulates caspase-14 maturation during keratinocyte terminal differentiation by generating an intermediate form. AB - The maturation and activation mechanisms of caspases are generally well understood, except for those of caspase-14, which is activated at the onset of keratinocyte terminal differentiation. We investigated the possible involvement of epidermal proteases expressed in the late stage of differentiation, and found that the chymotrypsin-like serine protease kallikrein-related peptidase-7 (KLK7) cleaved procaspase-14 at Tyr(178), generating an intermediate form that consists of a large (20 kDa) and a small subunit (8 kDa). We prepared an antibody directed to this cleavage site (h14Y178 Ab), and confirmed that it recognized a 20-kDa band formed when procaspase-14 was incubated with chymotrypsin or KLK7. We then constructed a constitutively active form of the intermediate, revC14-Y178. The substrate specificity of revC14-Y178 was completely different from that of caspase-14, showing broad specificity for various caspase substrates except WEHD 7-amino-4-trifluoromethylcoumarin (AFC), the preferred substrate of active, mature caspase-14. K(m) values for VEID-AFC, DEVD-AFC, LEVD-AFC, and LEHD-AFC were 0.172, 0.261, 0.504, and 0.847 MUM, respectively. We confirmed that the mature form of caspase-14 was generated when procaspase-14 was incubated with KLK7 or revC14-Y178. Expression of constitutively active KLK7 in cultured keratinocytes resulted in generation of both the intermediate form and the mature form of caspase-14. Immunohistochemical analysis demonstrated that the intermediate form was localized at the granular layer. Our results indicate that regulation of procaspase-14 maturation during terminal differentiation is a unique two-step process involving KLK7 and an activation intermediate of caspase 14. PMID- 22825847 TI - Degradomics reveals that cleavage specificity profiles of caspase-2 and effector caspases are alike. AB - Caspase-2 is considered an initiator caspase because its long prodomain contains a CARD domain that allows its recruitment and activation in several complexes by homotypic death domain-fold interactions. Because little is known about the function and specificity of caspase-2 and its physiological substrates, we compared the cleavage specificity profile of recombinant human caspase-2 with those of caspase-3 and -7 by analyzing cell lysates using N-terminal COmbined FRActional DIagonal Chromatography (COFRADIC). Substrate analysis of the 68 cleavage sites identified in 61 proteins revealed that the protease specificities of human caspases-2, -3, and -7 largely overlap, revealing the DEVD?G consensus cleavage sequence. We confirmed that Asp(563) in eukaryotic translation initiation factor 4B (eIF4B) is a cleavage site preferred by caspase-2 not only in COFRADIC setup but also upon co-expression in HEK 293T cells. These results demonstrate that activated human caspase-2 shares remarkably overlapping protease specificity with the prototype apoptotic executioner caspases-3 and -7, suggesting that caspase-2 could function as a proapoptotic caspase once released from the activating complex. PMID- 22825848 TI - The AT-rich DNA-binding protein SATB2 promotes expression and physical association of human (G)gamma- and (A)gamma-globin genes. AB - Matrix attachment region (MAR)-binding protein (MARBP) has profound influence on gene transcriptional control by tethering genes to the nuclear scaffold. MARBP SATB2 is recently known as a versatile regulator functioning in the differentiation of multiple cell types including embryonic stem cells, osteoblasts and immunocytes. Roles of SATB2 in erythroid cells and its working mechanism in orchestrating target gene expression are largely unexplored. We show here that SATB2 is expressed in erythroid cells and activates gamma-globin genes by binding to MARs in their promoters and recruiting histone acetylase PCAF. Further analysis in higher-order chromatin structure shows that SATB2 affects physical proximity of human (G)gamma- and (A)gamma-globin promoters via self association. We also found that SATB2 interacts with SATB1, which specifically activates epsilon-globin gene expression. Our results establish SATB2 as a novel gamma-globin gene regulator and provide a glimpse of the differential and cooperative roles of SATB family proteins in modulating clustered genes transcription and mediating higher-order chromatin structures. PMID- 22825849 TI - The H3K4me3 histone demethylase Fbxl10 is a regulator of chemokine expression, cellular morphology, and the metabolome of fibroblasts. AB - Fbxl10 (Jhdm1b/Kdm2b) is a conserved and ubiquitously expressed member of the JHDM (JmjC domain-containing histone demethylase) family. Fbxl10 was implicated in the demethylation of H3K4me3 or H3K36me2 thereby removing active chromatin marks and inhibiting gene transcription. Apart from the JmjC domain, Fbxl10 consists of a CxxC domain, a PHD domain, and an Fbox domain. By purifying the JmjC and the PHD domain of Fbxl10 and using different approaches we were able to characterize the properties of these domains in vitro. Our results suggest that Fbxl10 is rather a H3K4me3 than a H3K36me2 histone demethylase. The PHD domain exerts a dual function in binding H3K4me3 and H3K36me2 and exhibiting E3 ubiquitin ligase activity. We generated mouse embryonic fibroblasts stably overexpressing Fbxl10. These cells reveal an increase in cell size but no changes in proliferation, mitosis, or apoptosis. Using a microarray approach we were able to identify potentially new target genes for Fbxl10 including chemokines, the noncoding RNA Xist, and proteins involved in metabolic processes. Additionally, we found that Fbxl10 is recruited to the promoters of Ccl7, Xist, Crabp2, and RipK3. Promoter occupancy by Fbxl10 was accompanied by reduced levels of H3K4me3 but unchanged levels of H3K36me2. Furthermore, knockdown of Fbxl10 using small interfering RNA approaches showed inverse regulation of Fbxl10 target genes. In summary, our data reveal a regulatory role of Fbxl10 in cell morphology, chemokine expression, and the metabolic control of fibroblasts. PMID- 22825850 TI - DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation. AB - Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a nucleocytoplasmic shuttling protein that is a key player in the p53-triggered DNA damage response, acting as a cofactor for p53 in response to DNA damage. hnRNP K is a substrate of the ubiquitin E3 ligase MDM2 and, upon DNA damage, is de-ubiquitylated. In sharp contrast with the role and consequences of the other post-translational modifications, nothing is known about the role of SUMO conjugation to hnRNP K in p53 transcriptional co-activation. In the present work, we show that hnRNP K is modified by SUMO in lysine 422 within its KH3 domain, and sumoylation is regulated by the E3 ligase Pc2/CBX4. Most interestingly, DNA damage stimulates hnRNP K sumoylation through Pc2 E3 activity, and this modification is required for p53 transcriptional activation. Abrogation of hnRNP K sumoylation leads to an aberrant regulation of the p53 target gene p21. Our findings link the DNA damage induced Pc2 activation to the p53 transcriptional co-activation through hnRNP K sumoylation. PMID- 22825851 TI - Sizzled is unique among secreted frizzled-related proteins for its ability to specifically inhibit bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases. AB - BMP-1/tolloid-like proteinases (BTPs) are major enzymes involved in extracellular matrix assembly and activation of bioactive molecules, both growth factors and anti-angiogenic molecules. Although the control of BTP activity by several enhancing molecules is well established, the possibility that regulation also occurs through endogenous inhibitors is still debated. Secreted frizzled-related proteins (sFRPs) have been studied as possible candidates, with highly contradictory results, after the demonstration that sizzled, a sFRP found in Xenopus and zebrafish, was a potent inhibitor of Xenopus and zebrafish tolloid like proteases. In this study, we demonstrate that mammalian sFRP-1, -2, and -4 do not modify human BMP-1 activity on several of its known substrates including procollagen I, procollagen III, pN-collagen V, and prolysyl oxidase. In contrast, Xenopus sizzled appears as a tight binding inhibitor of human BMP-1, with a K(i) of 1.5 +/- 0.5 nM, and is shown to strongly inhibit other human tolloid isoforms mTLD and mTLL-1. Because sizzled is the most potent inhibitor of human tolloid like proteinases known to date, we have studied its mechanism of action in detail and shown that the frizzled domain of sizzled is both necessary and sufficient for inhibitory activity and that it acts directly on the catalytic domain of BMP 1. Residues in sizzled required for inhibition include Asp-92, which is shared by sFRP-1 and -2, and also Phe-94, Ser-43, and Glu-44, which are specific to sizzled, thereby providing a rational basis for the absence of inhibitory activity of human sFRPs. PMID- 22825852 TI - Generation of N-acylphosphatidylethanolamine by members of the phospholipase A/acyltransferase (PLA/AT) family. AB - Bioactive N-acylethanolamines (NAEs), including N-palmitoylethanolamine, N oleoylethanolamine, and N-arachidonoylethanolamine (anandamide), are formed from membrane glycerophospholipids in animal tissues. The pathway is initiated by N acylation of phosphatidylethanolamine to form N-acylphosphatidylethanolamine (NAPE). Despite the physiological importance of this reaction, the enzyme responsible, N-acyltransferase, remains molecularly uncharacterized. We recently demonstrated that all five members of the HRAS-like suppressor tumor family are phospholipid-metabolizing enzymes with N-acyltransferase activity and are renamed HRASLS1-5 as phospholipase A/acyltransferase (PLA/AT)-1-5. However, it was poorly understood whether these proteins were involved in the formation of NAPE in living cells. In the present studies, we first show that COS-7 cells transiently expressing recombinant PLA/AT-1, -2, -4, or -5, and HEK293 cells stably expressing PLA/AT-2 generated significant amounts of [(14)C]NAPE and [(14)C]NAE when cells were metabolically labeled with [(14)C]ethanolamine. Second, as analyzed by liquid chromatography-tandem mass spectrometry, the stable expression of PLA/AT-2 in cells remarkably increased endogenous levels of NAPEs and NAEs with various N-acyl species. Third, when NAPE-hydrolyzing phospholipase D was additionally expressed in PLA/AT-2-expressing cells, accumulating NAPE was efficiently converted to NAE. We also found that PLA/AT-2 was partly responsible for NAPE formation in HeLa cells that endogenously express PLA/AT-2. These results suggest that PLA/AT family proteins may produce NAPEs serving as precursors of bioactive NAEs in vivo. PMID- 22825853 TI - Biochemical and structural study of the atypical acyltransferase domain from the mycobacterial polyketide synthase Pks13. AB - Pks13 is a type I polyketide synthase involved in the final biosynthesis step of mycolic acids, virulence factors, and essential components of the Mycobacterium tuberculosis envelope. Here, we report the biochemical and structural characterization of a 52-kDa fragment containing the acyltransferase domain of Pks13. This fragment retains the ability to load atypical extender units, unusually long chain acyl-CoA with a predilection for carboxylated substrates. High resolution crystal structures were determined for the apo, palmitoylated, and carboxypalmitoylated forms. Structural conservation with type I polyketide synthases and related fatty-acid synthases also extends to the interdomain connections. Subtle changes could be identified both in the active site and in the upstream and downstream linkers in line with the organization displayed by this singular polyketide synthase. More importantly, the crystallographic analysis illustrated for the first time how a long saturated chain can fit in the core structure of an acyltransferase domain through a dedicated channel. The structures also revealed the unexpected binding of a 12-mer peptide that might provide insight into domain-domain interaction. PMID- 22825854 TI - Adverse subpopulation regression for multivariate outcomes with high-dimensional predictors. AB - Biomedical studies have a common interest in assessing relationships between multiple related health outcomes and high-dimensional predictors. For example, in reproductive epidemiology, one may collect pregnancy outcomes such as length of gestation and birth weight and predictors such as single nucleotide polymorphisms in multiple candidate genes and environmental exposures. In such settings, there is a need for simple yet flexible methods for selecting true predictors of adverse health responses from a high-dimensional set of candidate predictors. To address this problem, one may either consider linear regression models for the continuous outcomes or convert these outcomes into binary indicators of adverse responses using predefined cutoffs. The former strategy has the disadvantage of often leading to a poorly fitting model that does not predict risk well, whereas the latter approach can be very sensitive to the cutoff choice. As a simple yet flexible alternative, we propose a method for adverse subpopulation regression, which relies on a two-component latent class model, with the dominant component corresponding to (presumed) healthy individuals and the risk of falling in the minority component characterized via a logistic regression. The logistic regression model is designed to accommodate high-dimensional predictors, as occur in studies with a large number of gene by environment interactions, through the use of a flexible nonparametric multiple shrinkage approach. The Gibbs sampler is developed for posterior computation. We evaluate the methods with the use of simulation studies and apply these to a genetic epidemiology study of pregnancy outcomes. PMID- 22825855 TI - KIT proto-oncogene exon 8 deletions at codon 419 are highly frequent in acute myeloid leukaemia with inv(16) in Indian population. AB - The KIT gene is a receptor tyrosine kinase class III expressed by early hematopoietic progenitor cells and plays a significant role in hematopoietic stem cell proliferation, differentiation and survival which is considered to be a remarkable feature in the course of growth of acute myeloid leukaemia (AML). Owing to insufficient study of mutations in the KIT gene, the diagnosis and rate of recurrence of these mutations with divergent subtypes in AML cases in India is of concern. In order to find out the frequency of mutations of KIT gene exon 8 in 109 AML cases, we have performed polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by DNA sequencing and have identified 24 mutations in exon 8 in 13 cases, including deletions at codon 418 (n = 3), 419 (n = 11) and 420 (n = 5) as well as point mutations at codon 417 (n = 1) and 421 (n = 4). In eleven AML cases, exon 8 deletion and point mutations involved the loss at codon Asp419 immoderately conserved cross species placed in the receptor extracellular domain. Frequency elevation of the KIT proto-oncogene exon 8 deletion and point mutations in AML cases allude a crucial function for this region of the receptor extracellular domain. Thus, we report the incidence of acquired mutations in exon 8, with consistent loss at codon Asp419, in 10.09 % of AML cases in a selected Indian population. PMID- 22825857 TI - Sclerotherapy in an undetected pregnancy - a catastrophe? AB - According to the guidelines and the manufacturer's information, pregnancy is a contraindication for sclerotherapy with Polidocanol. However, in some cases sclerotherapy has been conducted in a period when the pregnancy is not known by the patient. When pregnancy is diagnosed, patients and gynecologists often ask the phlebologist if there is an indication for the interruption of pregnancy. Up to now, there is only rare information on sclerotherapy, polidocanol and pregnancy. Current knowledge is summed up in this article together with case reports. The existing case reports and mainly retrospective case series on intended or accidentally conducted sclerotherapy with common sclerosants and doses show no increased risk for the mother and the unborn child. However, in view of the limited literature data available and the high probability for spontaneous regression of varicose veins postpartum, sclerotherapy should be avoided in pregnancy, if possible. Conservative measures during pregnancy or an elimination of varicose veins before pregnancy should be preferred. In single cases e.g. painful genitoanal varices, the use of sclerotherapy can be helpful even during pregnancy. Thereby, a very thorough clarification of the mother with a final written consent and an implementation according to the guidelines are especially important. According to the current data, there is no reason for an interruption after a sclerotherapy that has been conducted during undetected pregnancy. PMID- 22825856 TI - Quorum sensing: how bacteria can coordinate activity and synchronize their response to external signals? AB - Quorum sensing is used by a large variety of bacteria to regulate gene expression in a cell-density-dependent manner. Bacteria can synchronize population behavior using small molecules called autoinducers that are produced by cognate synthases and recognized by specific receptors. Quorum sensing plays critical roles in regulating diverse cellular functions in bacteria, including bioluminescence, virulence gene expression, biofilm formation, and antibiotic resistance. The best studied autoinducers are acyl homoserine lactone (AHL) molecules, which are the primary quorum sensing signals used by Gram-negative bacteria. In this review we focus on the AHL-dependent quorum sensing system and highlight recent progress on structural and mechanistic studies of AHL synthases and the corresponding receptors. Crystal structures of LuxI-type AHL synthases provide insights into acyl-substrate specificity, but the current knowledge is still greatly limited. Structural studies of AHL receptors have facilitated a more thorough understanding of signal perception and established the molecular framework for the development of quorum sensing inhibitors. PMID- 22825858 TI - Drug-eluting stents and drug-coated balloons in peripheral artery disease. AB - Restenosis remains a major problem after angioplasty in peripheral artery disease despite stenting. It occurs in 30 - 50% / year depending on lesion localization and characteristics. One main reason for restenosis is neointimal hyperplasia, which can be suppressed by the topical administration of antiproliferative drugs. In percutaneous coronary intervention the concept of "local drug delivery" has been used for almost a decade with great success. In recent years, drug-eluting stents and drug coated balloons have also been increasingly used in the treatment of peripheral arterial disease as a consequence of positive results of clinical trails. The following article is an overview of the currently available data of completed trials, ongoing and planned studies. Evidence suggests that "drug coating technology" is reliable, safe and efficient in reducing the target lesion revascularization and binary restenosis rate significantly. With regard to limb salvage and mortality in critical limb ischemia, there is no benefit shown in current published studies. PMID- 22825859 TI - Popliteal entrapment syndrome and age. AB - On the occasion of diagnosing a popliteal entrapment syndrome in a 59-year old man with no cardiovascular risk factors, who developed acute ischemic leg pain during long distance running, we give an overview on this entity with emphasis on patients' age. The different types of the popliteal artery compression syndrome are summarized. The diagnostic and therapeutic approaches are discussed. The most important clinical sign of a popliteal entrapment syndrome is the lack of atherosclerotic risk factors in patients with limited walking distance. Not only in young athletes but also in patients more than 50 years old the popliteal entrapment syndrome has to be taken into account. PMID- 22825860 TI - Endovascular abdominal aneurysm repair: trends in Germany. AB - BACKGROUND: As a minimally invasive technique endovascular aneurysm repair (EVAR) reduces the risk of mortality and should be the preferred technique used in older patients. We analysed trends in endovascular and open surgical procedures in patients hospitalized for abdominal aortic aneurysm (AAA) in Germany. PATIENTS AND METHODS: We used national statistics (DRG statistics) published by the Federal Office of Statistics in Germany to calculate the incidence of patients hospitalised with ruptured (rAAA) and elective (eAAA) AAA. In addition, annual procedure rates of endovascular (EVAR) procedures were calculated. RESULTS: Incidence rates of eAAA per 100,000 males (females) showed a small increase from 2006 to 2007 but remained almost unchanged with 74.8 (8.8) in 2007 and 74.5 (9.8) in 2009. Incidence rates of rAAA per 100 000 males remained unchanged but showed a decreasing trend in females. The rate of people treated by EVAR increased form 2006 to 2009: in males from 24.0 % to 40.3 % and in females from 17.3 % to 31.0 %. In younger males (55 - 60 years) the increase in those who received EVAR was smaller (from 22.1 % to 33.9 %) than in older males (85 - 90 years) (from 20.4 to 41.6 %). Despite a clear increase in the use of EVAR from 2006 to 2009 there is only a small trend in reduction of the death rates which is more pronounced in rAAA. CONCLUSIONS: There has been a relevant increase in EVAR procedures for the treatment of AAA in Germany in recent years. Parallel to this increase of EVAR, aneurysm-related in-hospital deaths seem be declining slightly. A causal relationship between these trends remains to be proven. PMID- 22825861 TI - Ventilatory threshold is related to walking tolerance in patients with intermittent claudication. AB - BACKGROUND: This study assessed the relationship between lower limb hemodynamics and metabolic parameters with walking tolerance in patients with intermittent claudication (IC). PATIENTS AND METHODS: Resting ankle-brachial index (ABI), baseline blood flow (BF), BF response to reactive hyperemia (BFRH), oxygen uptake (VO2), initial claudication distance (ICD) and total walking distance (TWD) were measured in 28 IC patients. Pearson and Spearman correlations were calculated. RESULTS: ABI, baseline BF and BF response to RH did not correlate with ICD or TWD. VO2 at first ventilatory threshold and VO2peak were significantly and positively correlated with ICD (r = 0.41 and 0.54, respectively) and TWD (r = 0.65 and 0.71, respectively). CONCLUSIONS: VO2peak and VO2 at first ventilatory threshold, but not ABI, baseline BF and BFHR were associated with walking tolerance in IC patients. These results suggest that VO2 at first ventilatory threshold may be useful to evaluate walking tolerance and improvements in IC patients. PMID- 22825863 TI - Endovascular treatment for the spontaneous rupture of a non-aneurysmal subdiaphragmatic aorta. AB - The case of a patient who underwent an endovascular aortic repair for a spontaneous rupture of a non-aneurysmal subdiaphragmatic aorta without trauma, infection, or inflammation is reported. The patient is a 51-year-old male diagnosed with subdiaphragmatic aortic rupture and was in a state of hemorrhagic shock upon admission to the hospital. Intraoperative aortography revealed the abdominal aortic rupture site located above the celiac artery. A coated thoracic stent graft was used. Completion angiography showed a total exclusion with no endoleaks. After six months of follow-up, computed tomographic scans confirmed the absence of endoleaks or graft displacements. PMID- 22825862 TI - Perioperative use of aspirin for patients undergoing carotid endarterectomy. AB - BACKGROUND: This study was initiated to evaluate the cardiovascular benefit of perioperative use of acetylsalicylic acid (ASA) in patients undergoing carotid surgery. PATIENTS AND METHODS: A prospective two-arm comparative study was conducted and focused on cardiac, neurological and bleeding complications for patients with high-grade (> 80 %) asymptomatic or symptomatic (> 60 %), internal carotid artery stenosis based on NASCET criteria who were treated by surgery. Between March 2008 and November 2010, 540 patients underwent carotid endarterectomy in two European vascular centers. In particular, 267 consecutive patients (49.4 %) had taken perioperative ASA in one center; in 273 consecutive patients in the other center ASA administration was stopped 5 days preoperatively. RESULTS: The overall complication rate was lower in the ASA group (5.2 % versus 17.6 %), p < 0.001, 95 %CI [2.1;7.2], OR 3.8. In detail, the myocardial event rate was lower in the ASA arm: 0.7 versus 4.4 %; p = 0.012, OR 6.1 (95 %CI [1.4;27.45]. Concerning stroke, ASA patients benefit from oral antiaggregation as well: 1.5 vs. 5.5 %; p = 0.036), OR 4.5, 95 %CI[1.3;11.7], respectively. The bleeding complications were similar in both subgroups, 8 for the ASA group (3.0 %) and 10 (3.7 %) for the non-ASA group, p = 0.66. Multivariate logistic regression analysis showed significant benefit of the ASA treatment in patients with hypertension, diabetes mellitus and hypercholesterolemia, p < 0.001. Additionally, female patients of the ASA group also had significantly less overall (p = 0.10, OR5.3), cardiac (p = 0.021, OR 3.6) and neurologic (p = 0.042, OR 6.7) complications. Bleeding risk was not higher in female patients receiving ASA (p = 0.25). CONCLUSIONS: Perioperative use of ASA for patients undergoing carotid endarterectomy is associated with a lower risk of cardiac and neurological events without significant increase of postoperative bleeding necessitating revision. PMID- 22825864 TI - Bailout directional atherectomy for side branch salvage following subintimal recanalization of infragenicular arteries. AB - A 64-year old diabetic male presenting with critical limb ischemia was treated with percutaneous angioplasty for occlusion of the infragenicular popliteal artery and crural vessels. Directional atherectomy was uncommonly used in the false lumen created by following subintimal angioplasty of the infrapopliteal vessels for re-access into the true lumen. The positive clinical and angiographic results indicate that atherectomy can be considered a useful tool for rescue interventions to reopen large side branches unintentionally occluded during subintimal angioplasty. PMID- 22825865 TI - The chimney graft technique for preserving renal arteries in stent-graft sealing zones. AB - Patients with juxtarenal aneurysms require complex surgical open repair, which is associated with increased mortality and morbidity. An alternative procedure that can be used is the "chimney graft" technique. Three cases of abdominal aortic aneurysms were successfully treated in our department with this technique. One type-Ia endoleak occurred which was successfully treated with coiling and biological glue infusion. All of the chimney grafts have remained patent for the period of observation. The "chimney" technique has good results as a bail out procedure in complex EVAR or in well planned difficult cases. Long-term data is necessary to determine the efficacy of this technique. PMID- 22825866 TI - Management of extensive venous thrombosis following cardiac surgery in a patient with Behcet's disease. AB - Behcet's disease is a multisystemic vasculitis of unknown etiology, which is characterized by recurrent urogenital ulceration, cutaneous eruptions, ocular manifestations, arthritis and vasculitis, and its diagnosis is based on clinical criteria. Herein, we report a case of a patient with Behcet's disease, who was successfully managed with anticoagulant and anti-inflammatory therapy for disseminated venous thrombosis leading to pleural effusion, Budd-Chiari syndrome and central nervous system involvement following coronary artery bypass grafting surgery. PMID- 22825867 TI - [Angiology and vascular surgery -- an attempt for establishing a joint definition]. PMID- 22825868 TI - Phosphorylation of claudin-2 on serine 208 promotes membrane retention and reduces trafficking to lysosomes. AB - Claudins are critical components of epithelial and endothelial tight junction seals, but their post-transcriptional regulation remains poorly understood. Several studies have implicated phosphorylation in control of claudin localisation and/or function, but these have focused on single sites or pathways with differing results, so that it has been difficult to draw general functional conclusions. In this study, we used mass spectrometry (MS) analysis of purified claudin-2 from MDCK II cells and found that the cytoplasmic tail is multiply phosphorylated on serines, a threonine and tyrosines. Phos-tag SDS PAGE revealed that one site, S208, is heavily constitutively phosphorylated in MDCK II cells and in mouse kidney; this site was targeted for further study. Mutational analysis revealed that the phosphomimetic mutant of claudin-2, S208E, was preferentially localised to the plasma membrane while claudin-2 S208A, which could not be phosphorylated at this site, both immunolocalized and co fractionated with lysosomal markers. Mutations at sites that were previously reported to interfere with plasma membrane targeting of claudin-2 reduced phosphorylation at S208, suggesting that membrane localisation is required for phosphorylation; however phosphorylation at S208 did not affect binding to ZO-1 or ZO-2 Administration of forskolin or PGE2 resulted in dephosphorylation at S208 and transient small increases in transepithelial electrical resistance (TER). Together these data are consistent with phosphorylation at S208 playing a major role in the retention of claudin-2 at the plasma membrane. PMID- 22825869 TI - The N-terminal TOG domain of Arabidopsis MOR1 modulates affinity for microtubule polymers. AB - Microtubule-associated proteins of the highly conserved XMAP215/Dis1 family promote both microtubule growth and shrinkage, and move with the dynamic microtubule ends. The plant homologue, MOR1, is predicted to form a long linear molecule with five N-terminal TOG domains. Within the first (TOG1) domain, the mor1-1 leucine to phenylalanine (L174F) substitution causes temperature-dependent disorganization of microtubule arrays and reduces microtubule growth and shrinkage rates. By expressing the two N-terminal TOG domains (TOG12) of MOR1, both in planta for analysis in living cells and in bacteria for in vitro microtubule-binding and polymerization assays, we determined that the N-terminal domain of MOR1 is crucial for microtubule polymer binding. Tagging TOG12 at the N terminus interfered with its ability to bind microtubules when stably expressed in Arabidopsis or when transiently overexpressed in leek epidermal cells, and impeded polymerase activity in vitro. In contrast, TOG12 tagged at the C-terminus interacted with microtubules in vivo, rescued the temperature-sensitive mor1-1 phenotype, and promoted microtubule polymerization in vitro. TOG12 constructs containing the L174F mor1-1 point mutation caused microtubule disruption when transiently overexpressed in leek epidermis and increased the affinity of TOG12 for microtubules in vitro. This suggests that the mor1-1 mutant protein makes microtubules less dynamic by binding the microtubule lattice too strongly to support rapid plus-end tracking. We conclude from our results that a balanced microtubule affinity in the N-terminal TOG domain is crucial for the polymerase activity of MOR1. PMID- 22825871 TI - The Bro1-domain-containing protein Myopic/HDPTP coordinates with Rab4 to regulate cell adhesion and migration. AB - Protein tyrosine phosphatases (PTPs) are a group of tightly regulated enzymes that coordinate with protein tyrosine kinases to control protein phosphorylation during various cellular processes. Using genetic analysis in Drosophila non transmembrane PTPs, we identified one role that Myopic (Mop), the Drosophila homolog of the human His domain phosphotyrosine phosphatase (HDPTP), plays in cell adhesion. Depletion of Mop results in aberrant integrin distribution and border cell dissociation during Drosophila oogenesis. Interestingly, Mop phosphatase activity is not required for its role in maintaining border cell cluster integrity. We further identified Rab4 GTPase as a Mop interactor in a yeast two-hybrid screen. Expression of the Rab4 dominant-negative mutant leads to border cell dissociation and suppression of Mop-induced wing-blade adhesion defects, suggesting a critical role of Rab4 in Mop-mediated signaling. In mammals, it has been shown that Rab4-dependent recycling of integrins is necessary for cell adhesion and migration. We found that human HDPTP regulates the spatial distribution of Rab4 and integrin trafficking. Depletion of HDPTP resulted in actin reorganization and increased cell motility. Together, our findings suggest an evolutionarily conserved function of HDPTP-Rab4 in the regulation of endocytic trafficking, cell adhesion and migration. PMID- 22825872 TI - Mph1 kinetochore localization is crucial and upstream in the hierarchy of spindle assembly checkpoint protein recruitment to kinetochores. AB - The spindle assembly checkpoint (SAC) blocks entry into anaphase until all chromosomes have stably attached to the mitotic spindle through their kinetochores. The checkpoint signal originates from unattached kinetochores, where there is an enrichment of SAC proteins. Whether the enrichment of all SAC proteins is crucial for SAC signaling is unclear. Here, we provide evidence that, in fission yeast, recruitment of the kinase Mph1 is of vital importance for a stable SAC arrest. An Mph1 mutant that eliminates kinetochore enrichment abolishes SAC signaling, whereas forced recruitment of this mutant to kinetochores restores SAC signaling. In bub3Delta cells, the SAC is functional when only Mph1 and the Aurora kinase Ark1, but no other SAC proteins, are enriched at kinetochores. We analyzed the network of dependencies for SAC protein localization to kinetochores and identify a three-layered hierarchy with Ark1 and Mph1 on top, Bub1 and Bub3 in the middle, and Mad3 as well as the Mad1-Mad2 complex at the lower end of the hierarchy. If Mph1 is artificially recruited to kinetochores, Ark1 becomes dispensable for SAC activity. Our results highlight the crucial role of Mph1 at kinetochores and suggest that the Mad1-Mad2 complex does not necessarily need to be enriched at kinetochores for functional SAC signaling. PMID- 22825870 TI - Role of Scd5, a protein phosphatase-1 targeting protein, in phosphoregulation of Sla1 during endocytosis. AB - Phosphorylation regulates assembly and disassembly of proteins during endocytosis. In yeast, Prk1 and Ark1 phosphorylate factors after vesicle internalization leading to coat disassembly. Scd5, a protein phosphatase-1 (PP1) targeting subunit, is proposed to regulate dephosphorylation of Prk1/Ark1 substrates to promote new rounds of endocytosis. In this study we analyzed scd5 PP1Delta2, a mutation causing impaired PP1 binding. scd5-PP1Delta2 caused hyperphosphorylation of several Prk1 endocytic targets. Live-cell imaging of 15 endocytic components in scd5-PP1Delta2 revealed that most factors arriving before the invagination/actin phase of endocytosis had delayed lifetimes. Severely affected were early factors and Sla2 (Hip1R homolog), whose lifetime was extended nearly fourfold. In contrast, the lifetime of Sla1, a Prk1 target, was extended less than twofold, but its cortical recruitment was significantly reduced. Delayed Sla2 dynamics caused by scd5-PP1Delta2 were suppressed by SLA1 overexpression. This was dependent on the LxxQxTG repeats (SR) of Sla1, which are phosphorylated by Prk1 and bind Pan1, another Prk1 target, in the dephosphorylated state. Without the SR, Sla1DeltaSR was still recruited to the cell surface, but was less concentrated in cortical patches than Pan1. sla1DeltaSR severely impaired endocytic progression, but this was partially suppressed by overexpression of LAS17, suggesting that without the SR region the SH3 region of Sla1 causes constitutive negative regulation of Las17 (WASp). These results demonstrate that Scd5/PP1 is important for recycling Prk1 targets to initiate new rounds of endocytosis and provide new mechanistic information on the role of the Sla1 SR domain in regulating progression to the invagination/actin phase of endocytosis. PMID- 22825873 TI - Proper positioning of the cleavage furrow requires alpha-actinin to regulate the specification of different populations of microtubules. AB - Proper positioning of the cleavage furrow is essential for successful cell division. The mitotic spindle, which consists of dynamic astral microtubules and stable equatorial microtubules is responsible for this process. However, little is known about how microtubules are regulated in a time- and region-dependent manner. Here, we show that alpha-actinin-regulated cortical actin filament integrity is crucial to specify different populations of microtubules during cell division in mammalian cells. Depletion of alpha-actinin caused aberrant recruitment of centralspindlin, but not aurora B or PRC1, to the tips of astral microtubules, leading to a stable association of astral microtubules with the cortex and induction of ectopic furrowing. Depletion of alpha-actinin also caused impaired assembly of midzone microtubules, leading to a failure of relocation of aurora B to midzone. Our findings unveil an unexpected yet crucial role for an actin crosslinking protein in the regulation of the localization of the microtubule-associated cytokinetic regulator. PMID- 22825874 TI - Wnt5a signaling controls cytokinesis by correctly positioning ESCRT-III at the midbody. AB - Wnts activate at least two signaling pathways, the beta-catenin-dependent and independent pathways. Although the beta-catenin-dependent pathway is known to contribute to G1-S transition, involvement of the beta-catenin-independent pathway in cell cycle regulation remains unclear. Here, we show that Wnt5a signaling, which activates the beta-catenin-independent pathway, is required for cytokinesis. Dishevelled 2 (Dvl2), a mediator of Wnt signaling pathways, was localized to the midbody during cytokinesis. Beside the localization of Dvl2, Fz2, a Wnt receptor, was detected in the midbody with the endosomal sorting complex required for transport III (ESCRT-III) subunit, CHMP4B. Depletion of Wnt5a, its receptors, and Dvl increased multinucleation. The phenotype observed in Wnt5a-depleted cells was rescued by the addition of purified Wnt5a but not Wnt3a, which is a ligand for the beta-catenin-dependent pathway. Moreover, depletion of Wnt5a signaling caused loss of stabilized microtubules and mislocalization of CHMP4B at the midbody, which affected abscission. Inhibition of the stabilization of microtubules at the midbody led to the mislocalization of CHMP4B, while depletion of CHMP4B did not affect the stabilization of microtubules, suggesting that the correct localization of CHMP4B depends on microtubules. Fz2 was localized to the midbody in a Rab11-dependent manner, probably along stabilized microtubules. Fz2 formed a complex with CHMP4B upon Wnt5a stimulation and was required for proper localization of CHMP4B at the midbody, while CHMP4B was not necessary for the localization of Fz2. These results suggest that Wnt5a signaling positions ESCRT-III in the midbody properly for abscission by stabilizing midbody microtubules. PMID- 22825876 TI - Biochemical and genetic analyses of childhood attention deficit/hyperactivity disorder. AB - Attention deficit/hyperactivity disorder (ADHD) in children is a neurobehavioral disorder characterized by inattention, hyperactivity, and/or impulsivity. The biochemical abnormalities and genetic factors play significant roles in the etiology of ADHD. These symptoms affect the behavior performance and social relationships of children in school and at home. Recently, many studies about biochemical abnormalities in ADHD have been published. Several research groups have also suggested the genetic contribution to ADHD, and attempted to identify susceptibility and candidate genes for this disorder through the genetic linkage and association studies. To date, these studies have reported substantial evidence implicating several genes (dopaminergic: DRD4, DAT1, DRD5, COMT; noradrenergic: DBH, ADRA2A; serotonergic: 5-HTT, HTR1B, HTR2A; cholinergic: CHRNA4, and central nervous system development pathway: SNAP25, BDNF) in the etiology of ADHD. Understanding the biochemistry and genetics of ADHD will allow us to provide a useful addition with other treatment procedures for ADHD. PMID- 22825875 TI - Genetic identification of intracellular trafficking regulators involved in Notch dependent binary cell fate acquisition following asymmetric cell division. AB - Notch signalling is involved in numerous cellular processes during development and throughout adult life. Although ligands and receptors are largely expressed in the whole organism, activation of Notch receptors only takes place in a subset of cells and/or tissues and is accurately regulated in time and space. Previous studies have demonstrated that endocytosis and recycling of both ligands and/or receptors are essential for this regulation. However, the precise endocytic routes, compartments and regulators involved in the spatiotemporal regulation are largely unknown. In order to identify intracellular trafficking regulators of Notch signalling, we have undertaken a tissue-specific dsRNA genetic screen of candidates potentially involved in endocytosis and recycling within the endolysosomal pathway. dsRNA against 418 genes was induced in the Drosophila melanogaster sensory organ lineage in which Notch signalling regulates binary cell fate acquisition. Gain or loss of Notch signalling phenotypes were observed in adult sensory organs for 113 of them. Furthermore, 26 genes were found to regulate the steady state localisation of Notch, Sanpodo, a Notch co-factor, and/or Delta in the pupal lineage. In particular, we identified 20 genes with previously unknown function in D. melanogaster intracellular trafficking. Among them, we identified CG2747 and we show that it regulates the localisation of clathrin adaptor AP-1 complex, a negative regulator of Notch signalling. Together, our results further demonstrate the essential function of intracellular trafficking in regulating Notch-signalling-dependent binary cell fate acquisition and constitute an additional step toward the elucidation of the routes followed by Notch receptor and ligands during signalling. PMID- 22825877 TI - Abductor pollicis longus tendon division with swan neck thumb deformity. AB - Swan neck thumb deformity can be caused by osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, tendon transfers and paralytic diseases. Abductor pollicis longus is one of the major stabilizing tendon of the carpometacarpal joint of thumb. To the best of our knowledge, swan neck thumb deformity owing to division of abductor pollicis longus tendon is rare. In this article, we describe a case of isolated division of abductor pollicis longus tendon presenting with swan-neck deformity of thumb and discuss the mechanism, management and outcome. The patient was treated by repair of the divided tendon using palmaris longus tendon graft. At approximately 107 weeks following treatment, the patient was having full range of thumb movement and the deformity completely disappeared. We also describe the unusual mechanism whereby an isolated division of abductor pollicis longus tendon results in swan neck thumb deformity. Level of clinical evidence IV. PMID- 22825878 TI - Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study. AB - Increased use of non-invasive forms of respiratory support such as CPAP and HFNC in premature infants has generated a need for further investigation of the pulmonary effects of such therapies. In a series of in vitro tests, we measured delivered proximal airway pressures from a HFNC system while varying both the cannula flow and the ratio of nasal prong to simulated nares diameters. Neonatal and infant sized nasal prongs (3.0 and 3.7 mm O.D.) were inserted into seven sizes of simulated nares (range: 3-7 mm I.D. from anatomical measurements in 1-3 kg infants) for nasal prong-to-nares ratios ranging from 0.43 to 1.06. The nares were connected to an active test lung set at: TV 10 ml, 60 breaths/min, Ti 0.35 sec, compliance 1.6 ml/cm H2O and airway resistance 70 cm H2O/(L/sec), simulating a 1-3 kg infant with moderately affected lungs. A Fisher & Paykel Healthcare HFNC system with integrated pressure relief valve was set to flow rates of 1-6 L/min while cannula and airway pressures and cannula and mouth leak flows were measured during simulated mouth open, partially closed and fully closed conditions. Airway pressure progressively increased with both increasing HFNC flow rate and nasal prong-to-nares ratio. At 6 L/min HFNC flow with mouth open, airway pressures remained <1.7 cm H2O for all ratios; and <10 cm H2O with mouth closed for ratios <0.9. For ratios >0.9 and 50% mouth leak, airway pressures rapidly increased to 18 cm H2O at 2 L/min HFNC flow followed by a pressure relief valve limited increase to 24 cm H2O at 6 L/min. Safe and effective use of HFNC requires careful selection of an appropriate nasal prong-to-nares ratio even with an integrated pressure relief valve. PMID- 22825880 TI - Acute effect of Aloe vera gel extract on experimental models of pain. AB - The present study was performed to explore the effect of aqueous extract of Aloe vera on behavioural parameters of pain. Pain assessment was performed by the tail flick and formalin tests. A. vera (100 mg/kg, per oral (p.o.)) produced an insignificant decrease in the pain response in the tail-flick and formalin tests. Moreover, A. vera (200 and 400 mg/kg, p.o.) did not have significant effect on the tail-flick test. However, A. vera (200 and 400 mg/kg, p.o.) significantly decreased the second phase of the formalin-induced pain. Thus, these findings suggest that A. vera exerts its effect by a peripheral mechanism of action rather than central. PMID- 22825879 TI - Effect of chelerythrine against endotoxic shock in mice and its modulation of inflammatory mediators in peritoneal macrophages through the modulation of mitogen-activated protein kinase (MAPK) pathway. AB - A quaternary benzo [c] alkaloid chelerythrine (CHE), which is a traditional herbal prescription, has been used for the treatment of various inflammatory diseases. To gain insight into the anti-inflammatory effect and molecular mechanisms underlying the anti-inflammatory activity of CHE, we used experimentally induced mice endotoxic shock moled and lipopolysaccharide (LPS) induced murine peritoneal macrophages to examine the anti-inflammatory function of CHE. CHE displayed significant anti-inflammatory effects in experimentally induced mice endotoxic shock model in vivo through inhibition of LPS-induced tumor necrosis factor-alpha (TNF-alpha) level and nitric oxide (NO) production in serum. Additionally, our data suggest that CHE treatment inhibits LPS-induced TNF alpha level and NO production in LPS-induced murine peritoneal macrophages through selective inhibition of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation. Moreover, the effects of CHE on NO and cytokine TNF-alpha production can possibly be explained by the role of p38 MAPK and ERK1/2 in the regulation of inflammatory mediators expression. PMID- 22825881 TI - Event-weighted proportional hazards modelling for recurrent gap time data. AB - The analysis of gap times in recurrent events requires an adjustment to standard marginal models. One can perform this adjustment with a modified within-cluster resampling technique; however, this method is computationally intensive. In this paper, we describe a simple adjustment to the standard Cox proportional hazards model analysis that mimics the intent of within-cluster resampling and results in similar parameter estimates. This method essentially weights the partial likelihood contributions by the inverse of the number of gap times observed within the individual while assuming a working independence correlation matrix. We provide an example involving recurrent mammary tumours in female rats to illustrate the methods considered in this paper. PMID- 22825883 TI - Roles of transcriptional network during the formation of lymphatic vessels. AB - The lymphatic vascular system, also known as the second vascular system in vertebrates, plays crucial roles in various physiological and pathological processes. It participates in the maintenance of normal tissue fluid balance, trafficking of the immune cells and absorption of fatty acids in the gut. Furthermore, lymphatic system is associated with the pathogenesis of a number of diseases, including lymphedema, inflammatory diseases and tumour metastasis. Lymphatic vessels are comprised of lymphatic endothelial cells (LECs), which are differentiated from blood vascular endothelial cells. This review highlights recent advances in our understanding of the transcriptional control of LEC fate determination and reflects on efforts to understand the roles of transcriptional networks during this discrete developmental process. PMID- 22825884 TI - Assessment of environmental cockroach allergen exposure. AB - In the past, cockroach allergen exposure assessment mainly focused on settled dust in homes in low-income urban cities in the United States. That choice was not wrong; without measureable levels of cockroach allergen, it is difficult to show associations with any home characteristics, much less with health outcomes (e.g., allergy, asthma). However, recent studies in other suburban areas, schools, and other countries have elucidated the importance of cockroach allergen in these environments too. In addition, characterizing the underlying factors that give rise to cockroach allergen exposure (or protect against it) can lead to more targeted public health interventions. This review discusses different approaches to sampling indoor environments, interprets recent asthma and allergy studies, compares cockroach allergen levels from past studies with those of recent studies, and describes strategies for decreasing exposures. PMID- 22825885 TI - Pushing the frontiers in polyoxometalate and metal oxide cluster science. PMID- 22825882 TI - The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. AB - Recent evidence suggests that an altered mammalian (mechanistic) target of rapamycin (mTOR) signaling pathway and its pharmacological modulation might be implicated in several neurological diseases including epileptogenesis. mTOR is a molecular sensor, which regulates protein synthesis, enhancing mRNA translation of genes involved in the regulation of cell proliferation and survival, working as part of two distinct multimeric complexes known as mTORC1 and mTORC2. mTOR is an evolutionarily highly conserved serine/threonine kinase belonging to the phosphoinositide 3-kinase-related kinase family and represents one of the most recently studied pathways in relation to epilepsy and epileptogenesis, due to its suggested pivotal role in many aspects of cellular proliferation and growth also including neurodegeneration, neurogenesis, and synaptic plasticity. In this review, we report the cellular and molecular features of mTOR and related pathways, analyze their function in the brain including all current related evidence of their role, and finally, discuss the possible involvement of mTOR signaling in epileptogenesis and epilepsy, giving further consideration to future developments in this area. PMID- 22825886 TI - Toxic effects of PCB126 and TCDD on shortnose sturgeon and Atlantic sturgeon. AB - Exposure to chemical contaminants is often invoked to explain recruitment failures to populations of sturgeon worldwide, but there is little empirical evidence to support the idea that young sturgeon are sensitive at environmentally relevant concentrations. The authors used shortnose sturgeon (Acipenser brevirostum) and Atlantic sturgeon (Acipenser oxyrinchus) as models to investigate the sensitivities of sturgeon to early-life-stage toxicities from embryonic exposures to graded doses of polychlorinated biphenyl 126 (PCB126) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Survival to hatching of shortnose sturgeon decreased with increasing dose, although the duration of the embryonic period was not significantly altered by exposure in either species. Morphometric features of larvae of both species were affected by dose, including shortening of the body, reduction in head size, reduction in quantity of yolk reserves, and reduction in eye size. Eye development in both species was delayed with increasing dose for both chemicals. The persistence of larvae in a food-free environment decreased inversely with dose in both species, with sharp declines occurring at PCB126 and TCDD doses of >=1 ppb and >=0.1 ppb, respectively. Dose responsive early-life-stage toxicities reported here are among the more sensitive found in fish and occurred at burdens similar to those found in situ in a sympatric bottom-dwelling bony fish in the Hudson River Estuary. The present study is among the first demonstrating the sensitivity of any sturgeon to the hallmark early-life-stage toxicities induced by aryl hydrocarbon receptor agonists. PMID- 22825887 TI - Probing the electronic structure, chemical bonding, and excitation spectra of [CuE](+/0/-) (E = 14 group element) diatomics employing DFT and ab initio methods. AB - The electronic structure, chemical bonding, and excitation spectra of neutral, cationic, and anionic diatomic molecules of Cu and 14 group elements formulated as [CuE](+/0/-) (E = C, Si, Ge, Sn, Pb) were investigated by density functional theory (DFT) and time-dependent (TD)-DFT methods. The electronic and bonding properties of the diatomics analyzed by natural bond orbital (NBO) analysis approch revealed a clear picture of the chemical bonding in these species. The spatial organization of the bonding between Cu and E atoms in the [CuE](+/0/-) (E = Si, Ge, Sn, Pb) molecules can easily be recognized by the cut-plane electron localization function representations. Particular emphasis was given on the absorption spectra of the [CuE](+/0/-) which were simulated using the results of TD-DFT calculations employing the hybrid Coulomb-attenuating CAM-B3LYP functional. The absorption bands have thoroughly been analyzed and assignments of the contributing principal electronic transitions associated to individual excitations have been made. PMID- 22825888 TI - Optic disc topographic analysis in diabetic patients. AB - The aim of our study was to evaluate the optic disc (OD) topographic parameters by using Heidelberg Retina Tomograph II (HRT II) in patients with type 2 diabetes mellitus (DM). The study group consisted of 78 patients with type 2 DM (patient group) and age-sex matched 50 healthy subjects (control group). All patients and controls underwent a detailed ophthalmological examination, automated perimetry, central corneal thickness (CCT) measurement and OD topography by using HRT II. Glycosylated haemoglobin (HbA1c) levels of the diabetic patients were also noted. Age, gender, intraocular pressure and CCT measurements were similar in patients with diabetes and control group. Mean retinal nerve fiber layer thickness (MRNFLT) and retinal nerve fiber layer cross-sectional area (RNFLcsA) parameters were found significantly lower in diabetic patients compared to those of the controls (p = 0.030, p = 0.038). In the patient group, MRNFLT value was found significantly lower in patients with DM duration >=120 months (p = 0.020) and HbA1c level >=7 % (p = 0.029). Rim volume, MRNFLT and RNFLcsA values were significantly lower in proliferative diabetic retinopathy group (p = 0.004, p = 0.003, p = 0.001 respectively) and laser treated patients (p = 0.003, p = 0.002, p = 0.004 respectively). In conclusion, poor metabolic control of diabetes, severe DR and received laser therapies cause RNFL damage. Heidelberg Retina Tomograph may help us to detect and follow-up the changes in optic disc and RNFL in diabetic patients. PMID- 22825889 TI - The relation between superior phacoemulsification incision and steep axis on astigmatic outcomes. AB - To evaluate the relation between superior phacoemulsification incision and different steep axis on astigmatism outcomes. This prospective, randomized study comprised three groups each with 24 eyes with age-related cataracts and underwent 3.0 mm superior clear corneal incision (CCI). The three groups of the patients were divided by the location of the steep axis. The steep axis was between 0 and 30 degrees in group 1, 31-60 degrees in group 2, 61-90 degrees in group 3. The degree was accepted as the distance from the steep axis to the distal aspect of the wound. Outcome measures were including the changes in mean total astigmatism, surgically-induced astigmatism (SIA), axis deviation, uncorrected visual acuity (UCVA), and best corrected visual acuity (BCVA). Astigmatism was measured by manuel keratometry readings before surgery and day-1, week-1, week-2, week-4 and week-8 postoperatively. The surgically-induced astigmatism was calculated by the vector analysis using the Holladay-Cravy-Koch method. The magnitude of mean total astigmatism was lowest in group 1 and highest in group 3 at 8th week. Surgically induced astigmatism was 0.52 diopter (D), 0.88 D, 1.03 D in group 1, group 2, and group 3 respectively. The change in SIA was significant in group 1 (P < 0.05). The change in the astigmatic axis deviation was highest in group 1 (31.5 +/- 31.3, P < 0.05). The mean UCVA and BCVA were not significant pre and postoperatively between groups (P > 0.05). Axis deviation and SIA were stable after the week-1 and week-2 examinations respectively. Cataract surgery with CCI on or near the steep axis is resulted in decreased SIA and increased axis deviation. PMID- 22825890 TI - Resonance assignments of Ca2+-bound human S100A11. AB - The S100 family belongs to the EF-hand calcium-binding proteins regulating a wide range of important cellular processes via protein-protein interactions. Most S100 proteins adopt a conformation of non-covalent homodimer for their functions. Calcium binding to the EF-hand motifs of S100 proteins is essential for triggering the structural changes, promoting exposure of hydrophobic regions necessary for target protein interactions. S100A11 is a protein found in diverse tissues and possesses multiple functions upon binding to different target proteins. RAGE is a multiligand receptor binding to S100A11 and the interactions at molecular level have not been reported. However, the three-dimensional structure of human S100A11 containing 105 amino acids is still not available for further interaction studies. To determine the solution structure, for the first time we report the (1)H, (15)N and (13)C resonance assignments and protein secondary structure prediction of human S100A11 dimer in complex with calcium using a variety of triple resonance NMR experiments and the chemical shift index (CSI) method, respectively. PMID- 22825891 TI - Cardiology journal: first impact factor = 1.309. PMID- 22825892 TI - To inhale or to nebulize: treating the pulmonary vascular bed post-operatively in children with congenital heart disease. PMID- 22825893 TI - "Benign" early repolarization versus malignant early abnormalities: clinical electrocardiographic distinction and genetic basis. AB - In the great majority of cases the ECG pattern of early repolarization (ERP) is a benign phenomenon observed predominantly in teenagers, young adults, male athletes and the black race. The universally accepted criterion for its diagnosis is the presence, in at least two adjoining leads, of >= 1 mm or 0.1 mV ST segment elevation. In benign ERP reciprocal ST segment changes are possible only in lead aVR. In contrast, reciprocal ST segment changes can be observed in several leads in idiopathic ventricular fibrillation (IVF) and acute coronary syndrome. In benign ERP the ST segment and T wave patterns have a relative temporal stability. IVF is an entity with low prevalence, possibly familiar, and characterized by the occurrence of VF events in a young person. More frequently this occurs in male subjects without structural heart disease and with otherwise with normal ECG even using high right accessory leads and/or after ajmaline injection. Several clinical entities cause ST segment elevation include asthenic habitus, acute pericarditis, ST segment elevation myocardial infarction, Brugada syndrome, congenital short QT syndrome, and idiopathic VF. In these circumstances clinical and ECG data are most important for differential diagnosis. In IVF the modifications could be dramatic and predominantly at night during vagotonic predominance when J waves > 2 mm in amplitude. The ST/T abnormalities are dynamic, inconstant, and reversed with isoproterenol. Convex upward J waves, with horizontal/descending ST segments or "lambda-wave" ST shape are suggestive of IVF with early repolarization abnormalities. Premature ventricular contractions with very short coupling and "R on T" phenomenon are characteristics with two pattern: When originate from right ventricular outflow tract left bundle branch block morphology and from peripheral Purkinje network, left bundle branch block pattern. The inherited-familial forms are not frequent in IVF; however mutations were identified in the genes KCNJ8, DPP6, SCN5A, SCN3B, CACNA1C, CACNB2, and CACNA2D1. The management of IVF has class I indication for ICD implantation. Ablation therapy is considered additional to ICD implantation in those patients with repetitive ventricular arrhythmia. Quinidine is a highly efficient drug that prevents recurrence. PMID- 22825894 TI - Left main disease management strategy: indications and revascularization methods in particular groups of subjects. AB - Surgical revascularization with coronary artery by-pass grafting is still recommended in vast majority of patients with unprotected left main disease. The aim of the paper was to analyze optimal treatment of left main disease in selected groups of patients, on the basis of current guidelines and information gained from literature data. We focused on data in relation to treatment of elderly patients, diabetics and those hemodynamically unstable. Additionally we discussed the issue of anti-platelet therapy and informed consent. As far as efficacy of treatment is concerned, not only method of revascularization but also general condition of the patient, the factors influencing peri-operative risk and optimal pharmacotherapy should be taken into account. Therefore establishment of the heart team is crucial when choosing the most suitable method of invasive treatment of left main disease. PMID- 22825895 TI - Increased mean platelet volume associated with extent of slow coronary flow. AB - BACKGROUND: Slow coronary flow (SCF) is characterized by delayed opacification of epicardial coronary vessels. SCF can cause ischemia and sudden cardiac death. We investigated the association between presence and extent of SCF, and cardiovascular risk factors and hematologic indices. METHODS: In this study, 2467 patients who received coronary angiography for suspected or known ischemic heart disease were retrospectively evaluated between April 2009 and November 2010. Following the application of exclusion criteria, our study population consisted of 57 SCF patients (experimental group) and 90 patients with age- and gender matched subjects who proved to have normal coronary angiograms (control group). Baseline hematologic indices were measured by the automated complete blood count (CBC) analysis. The groups were evaluated for cardiovascular risk factors and medications. Patients were categorized based on the angiographic findings of vessels with or without SCF. Moreover, patients with SCF were divided into subgroups relative to the extent of SCF. RESULTS: Among the 147 patients (mean age 52.7 +/- 10.0, 53.7% male), mean platelet volume (MPV) ranged from 6.5 fL to 11.7 fL (median 7.9 fL, mean 8.1 +/- 0.8 fL). Diabetes (OR = 3.64, 95% CI 1.15 10.43, p = 0.03), hypercholesterolemia (OR = 4.94, 95% CI 1.99-12.21, p = 0.001), smoking (OR = 3.54, 95% CI 1.43-8.72, p = 0.006), hemoglobin (OR = 1.69, 95% CI 1.22-2.36, p = 0.002), and MPV (OR = 2.52, 95% CI 1.43-4.44, p = 0.001) were found to be the independent correlates of SCF presence. Only MPV (OR = 2.13, 95% CI 1.05-4.33, p = 0.03) was identified as an independent correlate of extent of SCF. CONCLUSIONS: Elevated baseline MPV value was found to be an independent predictor of the presence and extent of SCF. PMID- 22825896 TI - The evaluation of doxorubicin-induced cardiotoxicity: comparison of Doppler and tissue Doppler-derived myocardial performance index. AB - BACKGROUND: Doxorubicin is a chemotherapeutic agent used in a wide spectrum of cancers. However, cardiotoxic effects have limited its clinical use. The early detection of doxorubicin-induced cardiotoxicity is crucial. The purpose of our study was to assess values of Doppler and tissue Doppler imaging (TDI)-derived myocardial performance index (MPI) in adult cancer patients receiving doxorubicin treatment. METHODS: A total of 45 patients underwent echocardiographic examinations before any doxorubicin had been administered and then after doxorubicin. Doppler and TDI-derived MPI of left ventricular (LV) were determined in the evaluation of cardiotoxicity. Additionally, TDI-derived MPI of right ventricular (RV) was determined. RESULTS: All patients underwent control echocardiographic examination after mean 5 +/- 1.7 months. The LV MPI obtained by both Doppler and TDI were increased after doxorubicin treatment (0.56 +/- 0.11, 0.61 +/- 0.10, p = 0,005 vs 0.51 +/- 0.09, 0.59 +/- 0.09, p = 0.001, respectively). There was no correlation between Doppler-derived MPI and cumulative doxorubicin dose (coefficient of correlation 0.11, p = 0.6). TDI derived MPI was correlated with cumulative doxorubicin dose (coefficient of correlation 0.35, p = 0.015), but this correlation is weak (r = 0.38). The study population was divided into two groups according to doxorubicin dose (below and above 300 mg level). There was a moderate correlation between TDI-derived MPI and less than 300 mg of doxorubicin dose (coefficient of correlation 0.51, p = 0.028). However, Doppler-derived MPI was not correlated with less than 300 mg of doxorubicin dose (coefficient of correlation 0.38, p = 0.123). Also, there was no significant change in the TDI-derived RV-MPI (0.49 +/- 0.14, 0.50 +/- 0.12, p = 0.56). CONCLUSIONS: TDI-derived MPI is a useful parameter and an early indicator compared with Doppler-derived MPI in the detection of cardiotoxicity during the early stages. Also, doxorubicin administration does not affect RV function. PMID- 22825897 TI - Fever in myocardial infarction: is it still common, is it still predictive? AB - BACKGROUND: Before introduction of reperfusion therapy, fever was frequently observed in patients with acute myocardial infarction (AMI). Little is known about this symptom during the widespread use of primary percutaneous coronary intervention (pPCI). The aim of this study was to assess, whether body temperature is a predictor of impaired left ventricular systolic function in patients with AMI. METHODS: Our cohort included 171 patients (48 women) aged 57 (51-67) years, admitted due to the first AMI with ST elevation treated with successful pPCI. Standard body temperature measurements were performed twice a day. Left ventricular function was assessed by echocardiography using the wall motion score index (WMSI) and ejection fraction (EF). The following inflammatory response markers were determined on admission: C-reactive protein, fibrinogen and white blood cell count. RESULTS: Within 48 h of observation the median (1(st); 3(rd) quartiles) peak body temperature was 37.0 degrees C (36.7-37.2 degrees C). A temperature above 37.5 degrees C was observed only in 17 (10%) patients. There was no significant correlation between peak body temperature and any of the determined inflammatory response markers. WMSI was assessed at 1.3 (1.1-1.6), whereas EF at 56% (49-62%). There was no significant correlation between the left ventricular function and peak body temperature or determined markers of inflammation. CONCLUSIONS: In the era of pPCI and aggressive antiplatelet treatment, fever is not a common symptom associated with uncomplicated AMI and thus not correlated with left ventricular function and markers of inflammation. PMID- 22825898 TI - Evaluation of left ventricular systolic asynchrony in patients with subclinical hypothyroidism. AB - BACKGROUND: The heart was very sensitive to fluctuating thyroid hormone levels. To assess intra-left ventricular (LV) systolic asynchrony in patients with subclinical thyroid dysfunction. METHODS: Fifty patients with subclinical hypothyroidism and 40 controls were included. A diagnosis of subclinical hypothyroidism was reached with increased TSH and normal free T4. All subjects were evaluated by echocardiography. Evaluation of intra-LV systolic asynchrony was performed by tissue synchronization imaging (TSI), and four TSI parameters of systolic asynchrony were calculated. LV asynchrony was defined by these parameters. RESULTS: All of the groups were similar in terms of demographic findings and conventional and Doppler echocardiograpic parameters except peak systolic velocity and early diastolic velocity. LV systolic asynchrony parameters of TSI including; standard deviation of Ts of the 12 LV segments (Ts-SD-12), maximal difference in Ts between any 2 of the 12 LV segments (Ts-12), standard deviation of TS of the 6 basal LV segments (Ts-SD-6), maximal difference in Ts between any of the 6 basal LV segments (Ts-6) were significantly lengthened in patients with subclinical hypothyroidism than controls (p <0.001, p < 0.001, p < 0.001 and p < 0.001, respectively). The prevalence of LV asynchrony was significantly higher in patients with subclinical hypothyroidism than control. CONCLUSIONS: Patients with subclinical hypothyroidism present evidence of LV asynchrony by TSI. LV systolic asynchrony could be a warning sign of the early stage in cardiac systolic dysfunction in subclinical hypothyroid patients. PMID- 22825899 TI - Oxidative stress and severity of coronary artery disease in young smokers with acute myocardial infarction. AB - BACKGROUND: Cigarette smoking increases the oxidative stress mediated vascular dysfunction in young adults. We aimed to investigate the relation between the oxidative stress indices and coronary artery disease (CAD) severity in young patients presenting with acute myocardial infarction (AMI). METHODS: Young patients (aged < 35 years) who were admitted consecutively to our hospital with a diagnosis of AMI were included in the study. Age matched healthy subjects were selected as controls. Oxidative stress indices including lipid hydroperoxide (LOOH), total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), paraoxonase (PON) and arylesterase (ARE) activities were measured in serum. CAD severity was assessed by calculating the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery Study) score. We analyzed the association between the oxidative indices and CAD severity. RESULTS: Forty two young patients were admitted to the hospital with AMI (age 32.4 +/- 2.6 years; 39 males, 3 females). Current and heavy smoking was commonly observed among the patients (79%). All patients underwent emergency coronary angiography. Twenty-eight healthy subjects were selected as controls. Patients had significantly higher OSI and TOS levels (median, interquartile range) [0.44 (0.26-1.75) vs 0.25 (0.22-0.30), p < 0.001 and 6.0 (4.4-20.8) vs 4.1 (3.7-4.6), p < 0.001], respectively, and lower TAS and LOOH levels [1.6 +/- 0.1 vs 1.7 +/- 0.1, p = 0.02 and 3.0 +/- 0.8 vs 3.6 +/- 0.4, p = 0.001], respectively, compared to the control group. CAD severity correlated positively with OSI (r = 0.508, p = 0.001) and TOS levels (r = 0.471, p = 0.002). Subjects with an intermediate to high SYNTAX score (>= 22) demonstrated significantly higher OSI (median, interquartile range) [0.40 (0.34-1.75) vs 0.34 (0.26-0.68), p = 0.01] and TOS [6.9 (4.4-20.8) vs 5.8 (4.5-11.4), p = 0.01] levels compared to subjects with low SYNTAX score. CONCLUSIONS: Oxidative stress is an important contributor to CAD severity among young smokers. Elevated OSI and TOS levels reflect disease severity and vascular damage related to heavy smoking in early onset CAD. PMID- 22825900 TI - Comparison of inhaled nitric oxide and aerosolized iloprost in pulmonary hypertension in children with congenital heart surgery. AB - BACKGROUND: Pulmonary arterial hypertension is of importance in congenital cardiac surgery as being a significant cause of morbidity and mortality. Although therapy options are limited, inhaled nitric oxide (NO) is used as a standard therapy. The present study aimed to compare inhaled NO and aerosolized iloprost in children with secondary pulmonary hypertension who underwent congenital cardiac surgery. METHODS: Sixteen children included in the study were randomized into either inhaled NO or aerosolized iloprost group. For both groups, the observation period terminated at 72 h after cardiopulmonary bypass. RESULTS: There was no significant difference between the groups in terms of mean age, weight, cross clamp time, pump time, and extubation time. No significant change was observed in the arterial tension and central venous pressure of both groups before the operation, 30 min after the pump, 45 min after the pump, and after extubation, whereas an increase was observed in the heart rate and cardiac output, and a decrease was observed in the pulmonary artery pressure. The mean values at the above-mentioned time points showed no difference between the groups. No serious adverse event and mortality was detected. CONCLUSIONS: Both inhaled NO and aerosolized iloprost were found to be effective and comparable in the management of pulmonary hypertension. PMID- 22825901 TI - Management of elderly patients with troponin positive chest pain in a district general hospital. AB - BACKGROUND: The number of elderly patients that present with an acute coronary syndrome (ACS) is increasing, reflecting the growing number of people in the general population in this age group. The various guidelines do not generally specify a management strategy in this elderly group and the management is often at the discretion of the treating physician. We conducted an audit within our Cardiology Department to compare our practice of management of ACS in the elderly population based on the European Society of Cardiology guidelines. METHODS: We conducted a retrospective analysis of the management of patients aged 80 and above that were admitted with troponin positive chest pain from 1(st) January to 31(st) December 2010. Patient information was primarily obtained from our computer data base system that includes blood results, ECHOs, diagnostic angiograms, discharge and clinic letters. If the information was inadequate we obtained patient files or contacted the relevant general practitioner. RESULTS: Octo-nonagenarians represented just over a third (35%) of all patients that were admitted with a troponin positive event during the study period. We noted a 10% mortality rate observed in our study population over a 12 month period. Atrial fibrillation was an incidental finding in 22% of patients. Nearly half of these patients (49%) were managed by the cardiologists. 68% of these patients underwent diagnostic coronary angiography, of which 32% went on to have percutaneous coronary intervention and 7% underwent surgical intervention. Majority (80%) of patients that underwent angioplasty had more than 1 stent and 74% of patients required more than one coronary vessel to be stented. The length of stay in hospital was double for patients who were under the care of the general medical teams rather than the cardiology team. This group also had a higher number of other comorbidities such as dementia, malignancy, a history of gastro intestinal bleeds and chronic renal impairment. CONCLUSIONS: Octo and nonagenarians represent a significant proportion of our ACS patients. They have high mortality, greater number of comorbidities, diseased coronary vessels and if intervention was undertaken required more than one stent. Therefore, octo-nonagenarians represent a very complex group of patients. Guidelines and risk stratification are of limited value in this group as clinical trial data is currently lacking. Quality of life and risk to benefit assessments are of paramount importance in this group. PMID- 22825902 TI - Traditional risk factors and coronary artery calcium in young adults. AB - BACKGROUND AND METHODS: 362 symptomatic subjects of 45 years of age or younger were selected from a large database of around 4100 persons who underwent coronary artery calcium (CAC) scoring by means of a 64-multidetector computed tomography (MDCT). Amongst them, a group with the CAC > 0 Agatston units (n = 65) and a group with no detectable calcium (CAC = 0, n = 297) were compared in terms of risk factors presence. Risk factors considered were gender, body mass index, smoking habits, blood pressure level, blood lipids, presence of diabetes mellitus, family history of cardiovascular disease, and physical activity. RESULTS: The vast majority of subjects with a positive CAC were males (54, 83.1%) compared to those with a negative CAC (147, 49.5%, p < 0.001, chi2). More frequent results of CAC < 0 were observed in obese subjects (38.5% vs. 24.2%, p < 0.05), among smokers (41.5% vs. 27.6%, p < 0.05). Presence of arterial hypertension coexisted with a more frequent CAC > 0 (76.9% vs. 60.6%, p < 0.05). Also, the frequency of a positive CAC was significantly higher in patients with diabetes mellitus (10.8%), compared to those without diabetes mellitus (4.0%, p < 0.05). Effects of high lipids, family history, and physical activity were not observed. Accumulation of at least 4 risk factors was associated with more frequent positive CAC (26.0 vs. 15.9%, p < 0.05). Multivariate regression analysis showed that only male gender and presence of diabetes mellitus were independent predictors of a positive CAC in younger subjects (F = 5.06, p < 0.001, multiple R = 0.321). CONCLUSIONS: Traditional risk factors, apart from gender and diabetes mellitus, do not seem to allow for distinguishing young persons with a premature coronary atherosclerosis. Therefore, CAC scoring might be considered justified in symptomatic young men with diabetes mellitus. PMID- 22825903 TI - Congenital absence of the pericardium: a rare cause of right ventricular dilatation and levoposition of the heart. AB - Congenital absence of the pericardium is a rare cardiac defect with variable clinical presentations and is usually discovered incidentally. The pathology may lead to serious complications such as incarceration of cardiac tissue, myocardial ischemia, aortic dissection or valvular insufficiency. Diagnosis is not difficult so long as some tips are remembered. We present the cases of two patients with congenital absence of left pericardium. PMID- 22825904 TI - Difficult dual stage transcutaneous lead extraction complicated by fracture of both leads. AB - Extraction of two long-implanted (11 year-old) active leads due to local infection was complicated by the fracture of both leads with a metal sheath. The presence of a temporary pacing lead, inserted due to pacemaker dependence, made extraction even more difficult. The fixation of both proximal extracted lead endings in the occluded subclavian vein was much stronger than the connection of the tips of the leads with the RAA and RVA endocardium. The disintegration of both leads caused by drawing upon the distal ending added additional technical complications to the final procedure. The presented case underscores the necessity of having a full set of tools to hand even during what appears to be a routine lead extraction procedure. The importance of proper lead implantation on its extraction (in what may be the distant future) is discussed. PMID- 22825905 TI - Characteristics of systolic and diastolic potentials recorded in the left interventricular septum in verapamil-sensitive left ventricular tachycardia. AB - We studied the electrophysiological characteristics of systolic (SP) and diastolic (DP) potentials recorded during sinus rhythm (SR) in the left interventricular septum of a 27 year-old woman presenting with verapamil sensitive idiopathic left ventricular tachycardia (VT). During SR, and during VT, SP was activated from ventricular base-to-apex, and DP from apex-to-base. SP and DP were both detected at the site of successful ablation during SR, whereas during VT, DP was detected away from the earliest activation site. Thus, SP apparently reflected a critical component of the reentrant circuit, while DP reflected the activation of a bystander pathway. PMID- 22825906 TI - Epicardial fat necrosis: an uncommon etiology of chest pain. AB - Epicardial fat necrosis (EFN) is a rare cause of severe chest pain. We present a case of EFN successfully treated conservatively. With the advent of computed tomography and magnetic resonance imaging, the diagnosis can be made more precisely, avoiding the need for surgical intervention. We review the clinical characteristics, pathogenesis and treatment options of EFN. PMID- 22825907 TI - 'Idiopathic' acute myocardial infarction in a young patient with noncompaction cardiomyopathy. AB - Isolated left ventricular noncompaction (LVNC) is a rare hereditary cardiomyopathy characterized by prominent intraventricular trabeculations separated by deep intertrabecular recessus. While cardiac ischemia due to microvascular dysfunction is common in these patients, ST-segment elevation myocardial infarction (STEMI) is rare and usually seen as a consequence of coincidental coronary artery disease. We report the case of a 20 year-old male patient admitted to our emergency department with a complaint of squeezing chest pain who was subsequently diagnosed with STEMI according to electrocardiographic findings, although an emergent coronary angiogram demonstrated normal coronary arteries. Echocardiography revealed isolated LVNC, and the diagnosis was confirmed via magnetic resonance imaging. Repeat coronary catheterization with acetylcholine infusion and coronary flow reserve measurement failed to demonstrate vasospasm or microvascular dysfunction. As no apparent cause was found, this case was designated 'idiopathic' myocardial infarction. Coronary thromboembolism due to stagnation of blood in the left ventricular cavity remained as the most probable mechanism underlying myocardial infarction. PMID- 22825908 TI - QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. AB - Vorinostat is a histone deacetylase inhibitor used in the treatment of recurrent or persistent cases of cutaneous T-cell lymphoma (CTCL). A retrospective review of 116 patients from phase I and II clinical trials who had a baseline and at least one subsequent ECG revealed that four patients had Grade 2 and one patient had Grade 3 QTc interval prolongation; however, a MEDLINE search found no reported cases of torsades de pointes (TdP) in patients treated with vorinostat. We describe the case of a 49 year-old male with a history of CTCL actively undergoing treatment with vorinostat. During day 1 of hospitalization, he developed a pulseless polymorphic ventricular tachycardia requiring resuscitation. He was found to have a QTc of 826 ms. Following correction of potassium and magnesium, QTc gradually decreased and no further ventricular arrhythmia was noted. Other factors implicated in this case included concurrent sertraline and doxepin therapy (both drugs have been associated with the development of TdP in overdose). The mechanism of development of TdP in this patient is postulated to be related to vorinostat use in combination with hypokalemia and concomitant treatment with medications associated with QTc prolongation. This case highlights the importance of post-market surveillance. PMID- 22825909 TI - Ablation of a left lateral accessory pathway in a patient with dextroposition of the heart. PMID- 22825910 TI - Unusual cause of right heart compression. PMID- 22825911 TI - Termination of pacemaker-mediated tachycardia by a critically timed atrial extrasystole. PMID- 22825912 TI - Nebulized hyaluronan ameliorates lung inflammation in cystic fibrosis mice. AB - RATIONALE: Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. STUDY DESIGN/METHODS: F508del homozygous mice (Cftr(F508del) ) and transgenic mice overexpressing the ENaC channel beta-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 ug/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARgamma) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. RESULTS: Nebulized HA reduced TNFalpha expression (P < 0.005); TNFalpha, MIP-2, and MPO protein levels (P < 0.05); MPO activity (P < 0.05); and CD68+ cells counts (P < 0.005) in lung tissues of Cftr(F508del) and Scnn1b-Tg mice, compared with saline treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARgamma protein in both IB3-1 and CFBE41o cells (P < 0.05). CONCLUSIONS: Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy. PMID- 22825913 TI - Investigation of allelic heterogeneity of the CCK-A receptor gene in paranoid schizophrenia. AB - The cholecystokinin type A receptor (CCKAR) gene has been found to be associated with positive symptoms in patients with schizophrenia but the results reported to date are inconsistent. Considering the involvement of allelic heterogeneity in poor replication of the CCKAR finding, we genotyped five single nucleotide polymorphisms (SNPs) located in the 5' putative regulatory region of the CCKAR gene in a Chinese case-control sample and then applied the 5-SNP haplotype analysis to extract allelic heterogeneity information. The results showed that three individual haplotypes were strongly associated with increased risk of schizophrenia (corrected P = 2.9 * 10(-4), P = 2.5 * 10(-5), and P = 1.4 * 10( 5), respectively) and their combination gave an odds ratio (OR) of 6.12 with 95% CI 3.67-10.21 (P = 6.7 * 10(-15)). The haplotypes were also associated with some clinical symptoms including hallucination, suspiciousness, and hostility. Our work provided further evidence in support of the CCKAR hypothesis of schizophrenia and also suggested that haplotype-based association analysis may be a powerful approach for identification of allelic heterogeneity of a disease underlying gene, which is very likely to be attributable to poor replication of an initial finding due to the reduction of sample power and the complexity of genetic architectures. PMID- 22825916 TI - Con: early extubation in the operating room following cardiac surgery. AB - Ultra-fast-track anesthesia for cardiac surgery introduces risks to the patient that may be mitigated by transferring the patient to the intensive care unit with a secure airway. These risks include poorly controlled pain leading to catecholamine surges that result in arrhythmias, strain on fresh suture lines, and potentially myocardial ischemia. On the converse side, the patients frequently require titration of potent narcotic pain medicine that can lead to hypoxemia and hypercarbia in the immediate postoperative stage causing myocardial dysfunction. Finally, the economic benefit of ultra-fast-track anesthesia is questionable and until there is a complete cost analysis that includes operating room time, cost of ultra-fast-track medications, and compares the cost of reintubation and delayed surgical operation, it is difficult to weigh in on the cost benefit advocated in the literature. PMID- 22825915 TI - IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy. AB - Reliable prognostic biomarkers of grade II gliomas remain unclear. This study aimed to examine the role of mutations of isocitrate dehydrogenase (IDH1/2), 1p/19q co-deletion, and clinicopathological factors in patients with grade II glioma who were primarily treated with radiotherapy or chemoradiotherapy after surgery. Seventy-two consecutive patients, including 49 cases of diffuse astrocytomas (DA), 4 oligodendrogliomas (OL) and 19 oligoastrocytomas (OA), who underwent treatment from 1991 to 2010 at a single institution were examined. The overall survival (OS) of the DA patients (8.3 years) was significantly shorter than that of the OL and OA patients (11.7 years). IDH1/2 mutations were found in 46.9% of the DA patients and 82.6% of the OL and OA patients. The progression free survival (PFS) and OS of the patients with IDH1/2 mutations (8.4 and 16.3 years) were significantly longer than those of the patients without IDH1/2 mutations (3.3 and 4.5 years). Among the patients with IDH1/2 mutations, those who were initially treated with chemoradiotherapy including nimustine hydrochloride (ACNU), had significantly longer PFS than those treated with radiotherapy alone, whereas no significant difference in PFS was observed between the chemoradiotherapy and radiotherapy groups in the patients without IDH1/2 mutations. Oligodendroglial tumors, age <40 years, initial Karnofsky performance status (KPS) >=80, and IDH1/2 mutations were favorable prognostic factors regarding PFS and OS. IDH1/2 mutation was a predictive factor of response to chemoradiotherapy in grade II gliomas. Patients with IDH1/2 mutations may benefit more from chemoraiotherapy than those without IDH1/2 mutations. PMID- 22825914 TI - In vivo infection by a neuroinvasive neurovirulent dengue virus. AB - Although neurological manifestations associated with dengue infections have been reported in endemic countries, the viral or host characteristics determining the infection or alteration of nervous function have not been described. In order to investigate neurobiological conditions related to central nervous system dengue virus (DENV) infection, we established a mouse model of neuroinfection. A DENV-4 isolate was first adapted to neuroblastoma cells, later inoculated in suckling mice brain, and finally, this D4MB-6 viral variant was inoculated intraperitoneally in Balb/c mice at different postnatal days (pnd). Virus-induced fatal encephalitis in 2 and 7 pnd mice but infected at 14 and 21 pnd mice survived. The younger mice presented encephalitis at the sixth day postinfection with limb paralysis and postural instability concomitant with efficient viral replication in brain. In this mice model, we found activated microglial cells positive to viral antigen. Neurons, oligodendrocytes, and endothelial cells were also infected by the D4MB-6 virus in neonatal mice, which showed generalized and local plasma leakage with blood-brain barrier (BBB) severe damage. These results suggest that there was a viral fitness change which led to neuroinfection only in immune or neurological immature mice. Infection of neurons, endothelial, and microglial cells may be related to detrimental function or architecture found in susceptible mice. This experimental neuroinfection model could help to have a better understanding of neurological manifestations occurring during severe cases of dengue infection. PMID- 22825917 TI - Characterizing the intrinsic bioremediation potential of 1,4-dioxane and trichloroethene using innovative environmental diagnostic tools. AB - An intrinsic biodegradation study involving the design and implementation of innovative environmental diagnostic tools was conducted to evaluate whether monitored natural attenuation (MNA) could be considered as part of the remedial strategy to treat an aerobic aquifer contaminated with 1,4-dioxane and trichloroethene (TCE). In this study, advanced molecular biological and stable isotopic tools were applied to confirm in situ intrinsic biodegradation of 1,4 dioxane and TCE. Analyses of Bio-Trap(r) samplers and groundwater samples collected from monitoring wells verified the abundance of bacteria and enzymes capable of aerobically degrading TCE and 1,4-dioxane. Furthermore, phospholipid fatty acid analysis with stable isotope probes (PLFA-SIP) of the microbial community validated the ability for microbial degradation of TCE and 1,4-dioxane. Compound specific isotope analysis (CSIA) of groundwater samples for TCE resulted in delta(13)C values that indicated likely biodegradation of TCE in three of the four monitoring wells sampled. Results of the MNA evaluation showed that enzymes capable of aerobically degrading TCE and 1,4-dioxane were present, abundant, and active in the aquifer. Taken together, these results provide direct evidence of the occurrence of TCE and 1,4-dioxane biodegradation at the study site, supporting the selection of MNA as part of the final remedy at some point in the future. PMID- 22825918 TI - Drug-coated balloons for coronary and peripheral interventional procedures. AB - Paclitaxel-coated balloon (PCB) angioplasty reduces neointimal proliferation, restenosis, and clinical need for target lesion revascularization (TLR). PCB was superior for coronary restenosis in bare-metal and drug-eluting stents compared with uncoated balloon angioplasty and was noninferior compared with paclitaxel eluting stents. PCB angioplasty should be considered for treatment of coronary in stent restenosis. For de novo lesions, PCB plus endothelial progenitor cell capturing stents reduced restenosis and TLR in early reports. Among patients with de novo lesions and diabetes, the combination of PCB plus bare-metal stent revealed similar results in lesions compared with paclitaxel-eluting stents. The early results for PCB in small vessels are also very encouraging. Dual antiplatelet therapy duration may be shorter with PCB angioplasty compared with drug-eluting stents. Nevertheless, the risk for thrombotic vessel occlusion is minimized. Considering peripheral arterial disease, PCB angioplasty for femoropopliteal lesions was superior to uncoated balloon angioplasty. Registries indicate PCB to also be effective in lesions below the knee. Since there is no certain class effect, efficacy and safety have to be demonstrated for different types of PCB for coronary and peripheral interventions. PMID- 22825920 TI - Endocardial pacing: the wave of the future? AB - Cardiac resynchronization therapy (CRT) is a proven treatment for heart failure and requires the implantation of a left ventricular (LV) lead, usually placed in a tributary of the coronary sinus. Encouraged by the fact that approximately 30 % of the patients receiving CRT do not benefit from this therapy, LV endocardial pacing has been proposed as an alternative to traditional LV transvenous epicardial pacing. Endocardial LV pacing has a number of potential advantages over conventional LV epicardial pacing, including a more physiological endocardial-to-epicardial transmural activation sequence, a faster ventricular activation, a larger choice of stimulation sites and a potential superior hemodynamic performance. On the other hand, cardiologists will have to deal with new implant techniques' (transseptal), higher risk of thromboembolic events, and challenging extraction procedures of infected material. The future of endocardial stimulation will depend on the results of randomized studies adequately powered to assess the feasibility, the safety and the effectiveness of this new pacing strategy. PMID- 22825919 TI - A primer on arrhythmias in patients with hypertrophic cardiomyopathy. AB - Patients with hypertrophic cardiomyopathy are at risk of atrial and ventricular arrhythmias, yet treatment options for these patients are made almost solely by extrapolation from patients with other diseases. Heart block may be seen spontaneously but is especially prevalent following septal reduction strategies. Atrial fibrillation is the most common arrhythmia in patients with hypertrophic cardiomyopathy. The onset of atrial fibrillation often represents a turning point clinically for patients, marked by substantial functional deterioration and morbidity. Sudden cardiac death is the most common cause of death in the young patient, but still contributes to mortality in older patients. Major risk factors for sudden cardiac death include resuscitated sudden cardiac death, marked hypertrophy, syncope, and family history of sudden cardiac death due to hypertrophic cardiomyopathy. Minor risk factors for sudden cardiac death include nonsustained ventricular tachycardia, and hypotensive response to exercise. Emerging possible risk factors include atrial fibrillation, myocardial ischemia, left ventricular outflow tract obstruction, genetic mutations, left ventricular apical aneurysms, myocardial fibrosis, and end stage disease. PMID- 22825921 TI - Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects. AB - Diabetes is associated with microcirculatory dysfunction and heart failure and changes in insulin and IGF1 levels. Whether human cardiac microvascular endothelial cells (HMVEC-Cs) are sensitive to insulin and/or IGF1 is not known. We studied the role of insulin receptors (IRs) and IGF1 receptors (IGF1Rs) in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF1 in HMVEC Cs and human umbilical vein endothelial cells (HUVECs). IR and IGF1R gene expression was studied using real-time RT-PCR. Receptor protein expression and phosphorylation were determined by western blot and ELISA. Metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate inflammatory responses. According to gene expression and protein in HMVEC-Cs and HUVECs, IGF1R is more abundant than IR. Immunoprecipitation with anti-IGF1R antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF1 hybrid receptors in HMVEC-Cs. IGF1 at a concentration of 10(-8) mol/l significantly stimulated phosphorylation of both IGF1R and IR in HMVEC-Cs. In HUVECs IGF1 10( 8) mol/l phosphorylated IGF1R. IGF1 stimulated DNA synthesis at 10(-8) mol/l and glucose accumulation at 10(-7) mol/l in HMVEC-Cs. TNF-alpha dramatically increased E-selectin expression, but no inflammatory or anti-inflammatory effects of insulin, IGF1 or high glucose were seen. We conclude that HMVEC-Cs express more IGF1Rs than IRs, and mainly react to IGF1 due to the predominance of IGF1Rs and insulin/IGF1 hybrid receptors. TNF-alpha has a pronounced pro-inflammatory effect in HMVEC-Cs, which is not counteracted by insulin or IGF1. PMID- 22825922 TI - Iodothyronine deiodinase structure and function: from ascidians to humans. AB - Iodothyronine deiodinases are important mediators of thyroid hormone (TH) action. They are present in tissues throughout the body where they catalyse 3,5,3' triiodothyronine (T(3)) production and degradation via, respectively, outer and inner ring deiodination. Three different types of iodothyronine deiodinases (D1, D2 and D3) have been identified in vertebrates from fish to mammals. They share several common characteristics, including a selenocysteine residue in their catalytic centre, but show also some type-specific differences. These specific characteristics seem very well conserved for D2 and D3, while D1 shows more evolutionary diversity related to its Km, 6-n-propyl-2-thiouracil sensitivity and dependence on dithiothreitol as a cofactor in vitro. The three deiodinase types have an impact on systemic T(3) levels and they all contribute directly or indirectly to intracellular T(3) availability in different tissues. The relative contribution of each of them, however, varies amongst species, developmental stages and tissues. This is especially true for amphibians, where the impact of D1 may be minimal. D2 and D3 expression and activity respond to thyroid status in an opposite and conserved way, while the response of D1 is variable, especially in fish. Recently, a number of deiodinases have been cloned from lower chordates. Both urochordates and cephalochordates possess selenodeiodinases, although they cannot be classified in one of the three vertebrate types. In addition, the cephalochordate amphioxus also expresses a non-selenodeiodinase. Finally, deiodinase-like sequences have been identified in the genome of non-deuterostome organisms, suggesting that deiodination of externally derived THs may even be functionally relevant in a wide variety of invertebrates. PMID- 22825923 TI - Cylindrospermopsin determination in water by LC-MS/MS: optimization and validation of the method and application to real samples. AB - A new method for determining dissolved cylindrospermopsin (CYN) in waters using solid-phase extraction (SPE) with graphitized carbon cartridges and quantification by liquid chromatography coupled with tandem mass spectrometry is described and discussed. The method has been suitably validated: the linear range covered is from 0.900 to 125 ug CYN/L. Limits of detection and quantification were 0.5 and 0.9 ug CYN/L, respectively, and allow CYN determination at concentrations below the guideline proposed of 1 ug CYN/L in natural waters. The method exhibits mean recoveries from 83 to 95%, and intermediate precision (relative standard deviation (%)) values from 5 to 12%, ensuring adequacy against the Association of Official Analytical Chemists guidelines. The method is robust against the following three influential factors considered in the cleanup stage: the batch of the graphitized carbon cartridges, the flow rate of the water sample through the cartridge, and the final redissolved water volume after SPE treatment. The method has been successfully applied to detection and quantification of CYN in water samples from aquaria of a toxicological in vivo laboratory experiment. PMID- 22825924 TI - Fetal evaluation of the modified-myocardial performance index in pregnancies complicated by diabetes. AB - OBJECTIVE: To evaluate the fetal cardiac function by modified myocardial performance index (Mod-MPI) in pregnant diabetic patients. METHODS: Modified myocardial performance index was measured in fetuses of patients with diabetes (DM) between 30 and 40 weeks of gestation. The isovolumetric contraction time, isovolumetric relaxation time and ejection time were measured. Mod-MPI was calculated as (isovolumetric contraction time + isovolumetric relaxation time)/ejection time. Results were analyzed by using one-way analysis of variance (post hoc Bonferroni correction), Chi-square and Student's test. RESULTS: Modified myocardial performance index values of fetuses from DM mothers were significantly higher than controls (0.43 vs 0.37, P < 0.0001), and it was not different between gestational versus pregestational DM (0.42 vs 0.45, P = 0.18). Mod-MPI was also higher in the presence of polyhydramnios (0.49 vs 0.41, P < 0.0001), insulin use (0.46 vs 0.40, P < 0.05), and large for gestational age fetuses (0.49 vs 0.40, P < 0.0001). There were no significant differences in Mod MPI between newborns with versus without neonatal complications such as hypoglycemia or polycythemia. CONCLUSIONS: In fetuses of DM mothers, evaluation of the Mod-MPI identifies those with worse maternal disease and large fetal size. PMID- 22825925 TI - Intermittent and extended-infusion beta-lactam utilization in cystic fibrosis. PMID- 22825927 TI - Keep hope alive. PMID- 22825926 TI - A parent-mediated intervention to increase responsive parental behaviors and child communication in children with ASD: a randomized clinical trial. AB - Longitudinal research has demonstrated that responsive parental behaviors reliably predict subsequent language gains in children with autism spectrum disorder. To investigate the underlying causal mechanisms, we conducted a randomized clinical trial of an experimental intervention (Focused Playtime Intervention, FPI) that aims to enhance responsive parental communication (N = 70). Results showed a significant treatment effect of FPI on responsive parental behaviors. Findings also revealed a conditional effect of FPI on children's expressive language outcomes at 12-month follow up, suggesting that children with baseline language skills below 12 months (n = 24) are most likely to benefit from FPI. Parents of children with more advanced language skills may require intervention strategies that go beyond FPI's focus on responsive communication. PMID- 22825928 TI - Postponing the proposed changes in DSM 5 for autistic spectrum disorder until new scientific evidence adequately supports them. PMID- 22825929 TI - A systematic review of psychosocial interventions for adults with autism spectrum disorders. AB - Individuals with autism spectrum disorders (ASD) spend the majority of their lives as adults, and psychosocial interventions show promise for improving outcomes in this population. This research conducted a systematic review of all peer-review studies evaluating psychosocial interventions for adults with ASD. A total of 1,217 studies were reviewed, only 13 met inclusion criteria. The majority of studies were single case studies or non-randomized controlled trials, and most focused on applied behavior analysis or social cognition training. Effects of psychosocial treatment in adults with ASD were largely positive ranging from d = 0.14-3.59, although the quantity and quality of studies is limited. There is substantial need for the rigorous development and evaluation of psychosocial treatments for adults with ASD. PMID- 22825930 TI - The influence of flankers on race categorization of faces. AB - Context affects multiple cognitive and perceptual processes. In the present study, we asked how the context of a set of faces would affect the perception of a target face's race in two distinct tasks. In Experiments 1 and 2, participants categorized target faces according to perceived racial category (Black or White). In Experiment 1, the target face was presented alone or with Black or White flanker faces. The orientation of flanker faces was also manipulated to investigate how face inversion effect would interact with the influences of flanker faces on the target face. The results showed that participants were more likely to categorize the target face as White when it was surrounded by inverted White faces (an assimilation effect). Experiment 2 further examined how different aspects of the visual context would affect the perception of the target face by manipulating flanker faces' shape and pigmentation, as well as their orientation. The results showed that flanker faces' shape and pigmentation affected the perception of the target face differently. While shape elicited a contrast effect, pigmentation appeared to be assimilative. These novel findings suggest that the perceived race of a face is modulated by the appearance of other faces and their distinct shape and pigmentation properties. However, the contrast and assimilation effects elicited by flanker faces' shape and pigmentation may be specific to race categorization, since the same stimuli used in a delayed matching task (Experiment 3) revealed that flanker pigmentation induced a contrast effect on the perception of target pigmentation. PMID- 22825931 TI - Sustained attention, attentional selectivity, and attentional capacity across the lifespan. AB - Changes in sustained attention, attentional selectivity, and attentional capacity were examined in a sample of 113 participants between the ages of 12 and 75. To measure sustained attention, we employed the sustained-attention-to-response task (Robertson, Manly, Andrade, Baddeley, & Yiend, Neuropsychologia 35:747-58, 1997), a short continuous-performance test designed to capture fluctuations in sustained attention. To measure attentional selectivity and capacity, we employed a paradigm based on the theory of visual attention (Bundesen, Psychological Review 97:523-547, 1990), which enabled the estimation of parameters related to attentional selection, perceptual threshold, visual short-term memory capacity, and processing capacity. We found evidence of age-related decline in each of the measured variables, but the declines varied markedly in terms of magnitude and lifespan trajectory. Variables relating to attentional capacity showed declines of very large effect sizes, while variables relating to attentional selectivity and sustained attention showed declines of medium to large effect sizes, suggesting that attentional control is relatively preserved in older adults. The variables relating to sustained attention followed a U-shaped, curvilinear trend, and the variables relating to attentional selectivity and capacity showed linear decline from early adulthood, providing further support for the differentiation of attentional functions. PMID- 22825933 TI - Informed decision making about prostate cancer testing in predominantly immigrant black men: a randomized controlled trial. AB - BACKGROUND: Decision support interventions have been developed to help men clarify their values and make informed decisions about prostate cancer testing, but they seldom target high-risk black and immigrant men. PURPOSE: This study evaluated the efficacy of a decision support intervention focused on prostate cancer testing in a sample of predominantly immigrant black men. METHODS: Black men (N = 490) were randomized to tailored telephone education about prostate cancer testing or a control condition. RESULTS: Post-intervention, the intervention group had significantly greater knowledge, lower decision conflict, and greater likelihood of talking with their physician about prostate cancer testing than the control group. There were no significant intervention effects on prostate specific antigen testing, congruence between testing intention and behavior, or anxiety. CONCLUSIONS: A tailored telephone decision support intervention can promote informed decision making about prostate cancer testing in black and predominantly immigrant men without increasing testing or anxiety. PMID- 22825934 TI - Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders. AB - Copy-number variants (CNVs) collectively represent an important cause of neurodevelopmental disorders such as developmental delay (DD)/intellectual disability (ID), autism, and epilepsy. In contrast to DD/ID, for which the application of microarray techniques enables detection of pathogenic CNVs in -10 20% of patients, there are only few studies of the role of CNVs in epilepsy and genetic etiology in the vast majority of cases remains unknown. We have applied whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) to a cohort of 102 patients with various types of epilepsy with or without additional neurodevelopmental abnormalities. Chromosomal microarray analysis revealed 24 non-polymorphic CNVs in 23 patients, among which 10 CNVs are known to be clinically relevant. Two rare deletions in 2q24.1q24.3, including KCNJ3 and 9q21.13 are novel pathogenic genetic loci and 12 CNVs are of unknown clinical significance. Our results further support the notion that rare CNVs can cause different types of epilepsy, emphasize the efficiency of detecting novel candidate genes by whole-genome array CGH, and suggest that the clinical application of array CGH should be extended to patients with unexplained epilepsies. PMID- 22825935 TI - [New values for impact factor (IF)]. PMID- 22825936 TI - Combined hypotensive treatment with >= 3 hypotensive drugs in patients with recurrent atrial fibrillation and arterial hypertension ensures more effective arrhythmia control than using less drugs. AB - BACKGROUND: Combined arterial hypertension (AH) therapy ensures the effectiveness of treatment and improves haemodynamic parameters of cardiac function. AIM: The evaluation of therapeutic regimens in the prevention of recurrence of atrial fibrillation (AF) episodes in hypertensive patients with paroxysmal/persistent forms of AF. METHODS: Prospective observation included patients (n = 164), without and with AH, grade I and II, with paroxysmal (51.3%) or persistent (48.7%) recurrent form of arrhythmia. Mean duration of AF was 4.0 years, (Q1:2; Q3:7). The anti-arrhythmic drugs were ineffective in prevention of AF episodes or non tolerated and were not used. In all patients precise control of blood pressure (BP) was implemented: patients were treated with beta-blockers: 100%; ACE-I: 65%, spironolactone: 47%, thiazide diuretics: 34%, loop-diuretics: 7%, calcium antagonists: 26.5% and alpha-blockers: 14.5%. Evaluation of symptomatic and confirmed AF episodes was performed every 3 months during 1-year follow-up. RESULTS: AH, grade I and II, was diagnosed in 115, 75%, of patients; (74% men, mean age 65.5 +/- 9.7 years). Persistent form of arrhythmia was more frequent in patients with AH: 83% in comparison with patients without AH: 67% (p < 0.05). BP values were similar in normotensive and hypertensive patients after completing the study: 123 +/- 9/79 +/- 4 vs. 124 +/- 10/80 +/- 0.5 mm Hg. One hypotensive drug was used in 6 patients, 2 drugs in 38 patients, 3 in 37, 4 in 27, 5 in 7. Patients treated with . 3 drugs had more AF episodes in 3 months prior to evaluation: 4.7 +/- 0.8 vs. 2.9 +/- 0.4, p = 0.0444. But during 1-year follow-up, observed in 3-months periods, they had significant reduction in every 3-months period, p = 0.0001. Patients treated with 1.2 drugs had significant reduction after 3 months: p = 0.0029, 6 months: p = 0.04 and 12 months: p = 0.0012, but not after 9 months. CONCLUSIONS: AH promotes more advanced AF forms occurrence. Combined hypotensive therapy with minimum 3 drugs, including RAA inhibitors, may be effective in terms of BP control and reduction of arrhythmia episodes. PMID- 22825937 TI - [Atrial fibrillation and hypertension]. PMID- 22825938 TI - The independent relationship between systemic inflammation and fragmented QRS complexes in patients with stable angina pectoris. AB - BACKGROUND: QRS complex fragmentations can frequently be seen on routine ECG with narrow or wide QRS complex. Fragmented QRS complexes (fQRS) are defined as various RSR' patterns (>= 1 R' or notching of S wave or R wave) in two contiguous leads corresponding to a major coronary artery territory. In previous studies, fQRS has been associated with increased morbidity and mortality, sudden cardiac death and recurrent cardiovascular events. The causative relationship between fQRS and cardiac fibrosis has been shown, but it has not been extensively studied whether there are different mechanisms for the development of fQRS AIM: To interrogate the relationship between systemic inflammation and the presence of fQRS in patients with stable angina pectoris. METHODS: A total of 353 eligible patients who underwent coronary angiography with a suspicion of coronary artery disease (CAD) at our institution between April 2010 and December 2010 were enrolled consecutively. All patients had angina pectoris or angina equivalent symptoms with either a positive treadmill test or myocardial perfusion study. Patients with recent acute coronary syndrome either with or without ST-segment elevation, significant organic valve disease, and patients having any QRS morphology with QRS duration >= 120 ms, as well as patients with permanent pacemakers, were excluded from the study. RESULTS: Patients with fQRS had older age (p = 0.01), higher C-reactive protein (CRP) (p < 0.001), longer QRS time (p < 0.001) and more severe CAD (p < 0.001) compared to patients with non-fragmented QRS. When we performed multiple logistic regression analysis, we found that the fragmentations in QRS complexes were positively related with increased CRP (OR: 3.8, 95% CI 1.573.9.278, p = 0.003), and QRS duration (OR: 1.1, 95% CI 1.008.1.101, p = 0.019) and negatively related with left ventricular ejection fraction [%] (OR: 1.0, 95% CI 0.914.0.992, p = 0.020). CONCLUSIONS: In our study, we found that fQRS was independently related with increased CRP and QRS duration as well as left ventricular systolic dysfunction. Fragmented QRS, which may come about as an end effect of inflammation at cellular level, can represent increased cardiac risk by different causative mechanisms in patients with stable CAD. In addition, fragmentations on ECG may be useful for identifying patients who should be investigated and treated for their increased inflammatory status and possible chronic infections. PMID- 22825939 TI - [Is CRP a harbinger of changes in the QRS complex or just a statistical relationship?]. PMID- 22825940 TI - Platelet activation and microvascular injury in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Dual antiplatelet therapy reduces the risk of thrombotic complications after primary percutaneous coronary intervention (PCI). AIM: To assess whether inhibition of platelet function attenuates microvascular damage in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 83 STEMI patients treated with primary PCI. Platelet aggregation was measured on admission (ADM) and 4 days later (D4) by light transmission aggregometry after stimulation with 0.5 mM of arachidonic acid and after stimulation with 5 and 20 MUM of adenosine diphosphate (ADP) on treatment with dual antiplatelet therapy with aspirin and clopidogrel. Platelet-neutrophil aggregate (PNA) and platelet-monocyte aggregate (PMA) were analysed by flow cytometry. Contrast-enhanced magnetic resonance imaging was performed 2-4 days after STEMI to detect the area of perfusion defect at rest and to determine the size of microvascular obstruction. Microvascular obstruction was expressed as a percentage of infarct area. RESULTS: Perfusion defect at rest was found in 56 (67.5%) patients whereas microvascular obstruction in 63 (75.9%) patients. Patients with perfusion defect at rest had on admission a significantly higher level of both PMA (7.0 vs. 4.5%, p = 0.004) and PNA (4.1 vs. 2.2%, p = 0.016), however there were no significant differences at D4. Platelet aggregation after stimulation with 5 MUM of ADP on ADM was correlated (r = 0.37, p = 0.004) with microvascular obstruction area. Moreover, the higher the concentration of PMA(ADM) (r = 0.31, p = 0.016), PNA(ADM) (r = 0.34, p = 0.006) and PM(AD4) (r = 0.35, p = 0.005) the larger the size of microvascular obstruction. Infarct size (beta = 0.43, 95% CI 0.19 to 0.67, p < 0.0001), TIMI < 3 after PCI (beta = -0.27, 95% CI -1.90 to -0.11, p = 0.015) and PMA(D4) (beta = 0.21, 95% CI 0.13 to 1.86, p = 0.032) independently influenced the size of microvascular obstruction (R2 = 0.60, p < 0.0001). CONCLUSIONS: Excessive platelet activation during reperfusion in STEMI patients despite dual antiplatelet therapy is associated with greater microvascular impairment. PMID- 22825941 TI - [High platelet reactivity during reperfusion - a new risk factor of no reflow?]. PMID- 22825942 TI - Do overweight patients have a better five years prognosis after an acute myocardial infarction treated with coronary intervention? AB - BACKGROUND: Obesity and overweight alone may confer a survival benefit after myocardial infarction, independent of age, medical care or therapy. AIM: To evaluate the impact of body mass index (BMI) on long-term mortality in ST-segment elevation acute myocardial infarction (STEMI) patients treated by primary angioplasty (PCI). METHODS: We prospectively studied a homogenous group of 131 patients who had suffered STEMI, and subsequently exhibited a TIMI 3 flow after primary PCI. The patients (41 women, 90 men, mean age 58.3 +/- 10.8 years) were analysed in two groups: Group 1 - 30 (23%) patients with BMI < 25 kg/m(2) and Group 2 - 101 (77%) patients with BMI >= 25 kg/m(2). RESULTS: Altogether, 19 (14.5%) patients died during the five-year follow-up period - nine out of 30 (30%) were patients with BMI < 25 kg/m(2), and ten out of 101 (10%) were patients with BMI >= 25 kg/m(2) (p < 0.001). Individuals with BMI >= 25 kg/m(2) had lower five-year mortality, and this was independent of other potentially confounding variables. Area under the receiver-operating characteristic (ROC) curves for death with respect to weight on ROC analysis was significantly different than for a random model (p < 0.05). There were no significant differences in 30-day mortality and one-year mortality (p = 0.6517 and p = 0.3573, respectively). CONCLUSIONS: Patients after primary angioplasty for STEMI with BMI < 25 kg/m(2) and patients with BMI >= 25 kg/m(2) have no difference in 30-day or one-year mortality, but individuals with BMI >= 25 kg/m(2) have a better five year prognosis, and this is independent of other potentially confounding variables. PMID- 22825943 TI - [To gain weight, or not: new cardiology question?]. PMID- 22825944 TI - Regional differences in determining cardiovascular diseases as the cause of death in Poland: time for change. AB - BACKGROUND: Data regarding deaths in many countries is a reliable source of information on population health status, due to the legal obligation to register the fact of a death and its cause. Such data is widely used to analyse regional health differences, changes in health over time, and to pursue and monitor the effects of health policies. Therefore, it is extremely important that the data is reliable and comparable across the country. AIM: To analyse death rates from cardiovascular diseases in 2007-2009 among residents of large Polish cities, where medical universities are located, in order to assess the magnitude of differences in mortality in those populations. METHODS: The information on deaths was collected from a routine death registration system run by the Central Statistical Office. We analysed mortality by accessing individual death records of the residents of the following cities: Bialystok, Bydgoszcz, Gdansk, Katowice, Krakow, Lublin, Lodz, Poznan, Szczecin, Warsaw and Wroclaw. The following causes of death were taken into account: diseases of the circulatory system in total (ICD-10: I00-I99); ischaemic heart disease (I20-I25) including myocardial infarction (I21-I22); pulmonary heart disease and other heart diseases (I26-I51) including cardiac arrest (I46); heart failure (I50); complications and ill defined descriptions of heart disease (I51); cerebrovascular diseases (I60-I69); and atherosclerosis (I70). The death rates were age-standardised by the direct method, taking as a standard the so-called 'European age structure'. RESULTS: Comparison of mortality rates in the studied cities revealed substantial and unjustified differences in the values of the rates for individual groups of diseases. The death rate from myocardial infarction in Katowice was nearly three times higher than those in Wroclaw and Krakow (74.8/100,000 against 25.2 and 25.7/100,000). Mortality rates from pulmonary heart disease and other heart diseases in Warsaw, Lodz, Bydgoszcz, and Szczecin were in the range of 12 19/100,000, while in the other cities it was lower than 1/100,000 residents. The death rates from atherosclerosis in Wroclaw and Krakow were several (6-9) times higher than in Bialystok, Katowice, Warsaw and Szczecin. CONCLUSIONS: As one of the main reasons that may be responsible for such substantial regional differences in death rates, the authors assume that different criteria are used to determine the causes of death, perhaps resulting from insufficient training of health professionals in this field. Therefore actions to develop and implement uniform rules for determining causes of death, appropriate training of doctors responsible for completing death certificates, and adequate education in this area during medical studies must be urgently undertaken. PMID- 22825945 TI - [Are we confident about the causes of death in Poland?]. PMID- 22825946 TI - Vascular response and mechanical integrity of the new biodegradable polymer coated sirolimus-eluting PROLIM stent implanted in porcine coronary arteries. AB - BACKGROUND: Although durable polymer coated drug-eluting stents (DES) are standard care in percutaneous coronary interventions, new stent platforms employing biodegradable polymer based drug delivery are increasingly being used in clinical practice. AIM: To evaluate the short- (28 days) and medium-term (90 days) vascular effects of the new biodegradable polymer coated sirolimus-eluting stent - the PROLIM stent. METHODS: The objectives of the study were evaluated using standard angiographic and histological methods. In addition, the mechanical integrity of tested stents was assessed using Faxitron imaging. A total of 12 PROLIM stents, 11 biodegradable polymer only coated stents (BPCS), and 12 bare metal stents (BMS) were implanted in the coronary arteries of 16 female non atheroslerotic domestic swine using an overstretch of 1.1:1.0. RESULTS: At 28 days, neointimal proliferation was significantly lower in the PROLIM and BMS stents compared to the BPCS stents (p <= 0.05). Interestingly, despite thin neointima found at this time in the PROLIM group, there was a further significant decrease in neointimal formation between 28 and 90 days (p = 0.04). Although a statistically bigger neointima was found in BPCS stents at 28 days compared to the PROLIM and BMS stents, there was a 50% decrease in the neointimal area at 90 days follow-up (p = 0.02) which reached the level seen in other groups. The endothelialisation was completed in all tested stents after 28 days. There was a significant increase of fibrin depositions in the PROLIM treated arteries at 28 days which were resorbed nearly completely at 90 days follow-up. At 28 days, the inflammatory response was found to be numerically higher in the BPCS stents (p = NS) compared to other tested groups. On the contrary, at 90 days follow-up when the degradation process of the polymer had been completed, the inflammatory reaction decreased substantially to the level seen in the PROLIM and BMS stents. Faxitron analysis of the stented arteries revealed no major abnormalities except for isolated strut fractures observed in the mid portions of two BMS stents and one BPCS stent. CONCLUSIONS: The PROLIM - a biodegradable polymer coated sirolimus-eluting stent - demonstrates very good short-term and medium-term angiographic and histological results. The lack of 'catch-up phenomenon', fast endothelialisation process, and minimal inflammatory reaction may contribute to favourable clinical outcomes using PROLIM stents. PMID- 22825947 TI - [Biodegradable polymers are an alternative to traditional drug-eluting stents]. PMID- 22825948 TI - The impact of a previous history of ischaemic episodes on the occurrence of left ventricular free wall rupture in the setting of myocardial infarction. AB - BACKGROUND: Ischaemic episodes preceding myocardial infarction (MI) are one of the defence mechanisms protecting the body from the consequences of sudden ischaemia. Left ventricular free wall rupture (LVFWR) is a rare complication of MI but leading, in a majority of patients, to sudden cardiac death. AIM: To assess the impact of a previous history of ischaemic episodes (IEs) on the occurrence of LVFWR in patients with acute MI (AMI) managed by percutaneous coronary intervention (PCI). METHODS: The study population consisted of 270 patients who had died during hospitalisation for AMI. All the patients were managed by PCI. The study group (the LVFWR group) consisted of 49 patients who developed LVFWR during hospitalisation and the control group (the non-LVFWR group) consisted of the remaining 221 patients who had died from causes other than LVFWR. In all the patients with LVFWR the rupture was confirmed by autopsy. The data on AMI was obtained from history or medical records. The data on IEs was obtained on the basis of the symptoms that were reported by the patients in the past that directly preceded the most recent AMI or on the basis of medical records. RESULTS: Compared to the non-LVFWR group the LVFWR group was characterised by an older age (70.3 +/- 3.4 vs. 65.2 +/- 9.9 years, p < 0.001) and a higher percentage of females (75.0% vs. 60.2%, p < 0.001). The LVFWR group was also characterised by a higher percentage of IEs in the past (61.2% vs. 40.2%, p = 0.003), a lower percentage of patients with a history of MI (14.2% vs. 33.4%, p = 0.004), a higher percentage of patients with multivessel coronary artery disease (77.5% vs. 61.5%, p = 0.03), a longer interval from the onset of symptoms to PCI (9.0 +/- 5.5 vs. 4.5 +/- 3.2 h, p < 0.001) and a lower percentage of patients with IEs in the past but without an MI (6.1% vs. 23.9%, p < 0.001). Our study showed that independent risk factors for LVFWR in the setting of AMI were: older age (OR 1.1, 95% CI 1.02-1.19), male sex (OR 0.2, 95% CI 0.07-0.52) and a longer interval between the onset of symptoms and PCI (OR 1.25, 95% CI 1.07 1.47). CONCLUSIONS: A previous history of IEs in patients without a previous history of AMI was a protective factor against the development of LVFWR in the setting of AMI. PMID- 22825949 TI - Socioeconomic factors and the risk of metabolic syndrome in the adult Polish population: the WOBASZ study. AB - BACKGROUND: Metabolic syndrome (MetS) increases the risk of cardiovascular disease and its development is determined by certain socioeconomic and lifestyle factors. AIM: To investigate the impact of socioeconomic and lifestyle factors on the risk of MetS and the underlying contributing factors in the Polish population aged 20-74 years. METHODS: Between 2003 and 2005, as part of the National Multicentre Health Survey (WOBASZ, Wieloosrodkowe Badanie Stanu Zdrowia Ludnosci), a random sample of Polish residents aged 20 to 74 years was investigated. Data on sociodemographic and anthropometric parameters, blood pressure, lipid and glucose levels and medical history were collected. MetS was defined according to the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) and by the International Diabetes Federation (IDF) in 2005. Data necessary to evaluate MetS and the socioeconomic characteristics were obtained for 5940 men and 6627 women. RESULTS: MetS was identified in 26.0% of men and 23.9% of women according to the AHA/NHLBI definition, and in 30.7% of men and 26.8% of women according to the IDF definition. In both genders older age, higher body mass index and current smoking increased the risk of developing MetS, whereas higher physical activity and good self-rated health decreased the risk. Moreover, women with higher education and in the higher quartile of alcohol intake were associated with a lower risk of having MetS. Household per-capita income did not affect the risk of having MetS in either gender. CONCLUSIONS: A relatively high percentage of individuals with MetS was observed in the Polish population aged 20 to 74 years. In both sexes, the risk of MetS and its contributing factors was significantly associated with age and the following lifestyle factors: body mass index, smoking, self-rated health and, additionally for women, higher education and alcohol intake. PMID- 22825950 TI - [Social factors: fashion or an important direction of research?]. PMID- 22825951 TI - [Right ventricular and tricuspid insufficiency following two ventricular pacemaker implantation]. AB - A case of a 76-year-old woman with a right ventricular failure and severe tricuspid insufficiency following permanent pacemaker implantation is presented. PMID- 22825952 TI - [Massive infiltration of the right vetricular wall caused by large B-cell lymphoma]. AB - We presented a case of symptomatic secondary cardiac B-cell lymphoma localised in the free wall of the right ventricle (RV). It was detected during transthoracic echocardiography and confirmed by nuclear magnetic resonance imaging. The RV free wall motion abnormalities, decreased dimensions of RV and small pericardial effusion were found. The tumour dimensions declined after the first cycle of chemiotherapy with antracyclins. PMID- 22825953 TI - [Obstructive sleep apnea and cardio-vascular damage]. PMID- 22825954 TI - [Dynamic ECG changes after thromboendarterectomy in a patient with chronic thromboembolic pulmonary hypertension and C protein deficiency]. AB - A case of a 44-year-old-man with chronic thromboembolic pulmonary hypertension (PH) and C-protein deficiency, with a history of previous acute pulmonary embolism is presented. The ECG showed negative T waves in leads: II, III, aVF and V(1)-V(6). The follow-up echocardiography revealed severe PH with the right ventricular systolic pressure (RVSP) - 95-100 mm Hg, markedly enlarged right ventricular end-diastolic diameter (RVEDD), and decreased left ventricular end diastolic diameter (LVEDD). The patient was in NYHA III/IV class. He was referred for pulmonary thromboendarterectomy. Three months after thromboendarterectomy echocardiography showed marked reduction of RVEDD, increased LVEDD, RVSP - 50-55 mm Hg. The 3 months follow-up ECG showed normalisation to positive T waves. The patient was in NYHA class I and he stayed on the anticoagulation therapy. PMID- 22825955 TI - [Why perform EKG after pulmonary embolism?]. PMID- 22825956 TI - [Myocardial viability imaging in ischaemic heart disease, part 1: current role of echocardiography and CMR. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 22825957 TI - [Cardioverter-defibrillator in the treatment of arrhythmia induced by trastuzumab used in the adjuvant setting in a patient with positive human epidermal growth factor receptor type-2 breast cancer]. AB - A case of a 36-year old woman with HER2-positive early breast cancer treated with adjuvant trastuzumab left ventricle dysfunction and cardiac arrest in ventricular fibrillation mechanism is presented. After having been successfully resuscitated, trastuzumab therapy was withheld, pharmacotherapy (beta-blocker, ACE-I) implemented and ICD was implanted. Echocardiography performed 6 months later, revealed normal systolic function of the left ventricle. The patient died despite further oncologic treatment due to progression of the disease. The authors discuss the approach to this dramatic but lone cardiac side effect of trastuzumab treatment. PMID- 22825958 TI - [ICD in cardiac dysfunction induced by trastuzumab - one of the most important problems in cardiac oncology]. PMID- 22825960 TI - [Stented stent is not the same]. PMID- 22825959 TI - [Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial]. PMID- 22825961 TI - [Stress cardiomyopathy - is it always benign?]. PMID- 22825962 TI - [Report on the XVI Scientific and Training Symposium of Working Group of Cardiac Rehabilitation and Exercise Physiology of the Polish Cardiac Society]. PMID- 22825963 TI - Fatigue in ankylosing spondylitis: causes, consequences and self-management. AB - OBJECTIVES: To explore the perceived causes, consequences and management of fatigue in ankylosing spondylitis (AS). METHODS: In this single-cohort qualitative study, ten participants completed a seven-day diary and participated in a semi-structured interview exploring possible causes, consequences and self management of fatigue. Interviews were recorded, transcribed and analysed using 'framework' analysis. Ethical approval was obtained. RESULTS: Three themes emerged: patterns and causes, consequences and management of fatigue. While patients' descriptions of fatigue were similar, the patterns and perceived causes of fatigue varied between individuals. Fatigue impacted on social life, relationships and work. Two approaches to fatigue management were observed: help and support from others and self-management, with four participants having sought medical help for fatigue. CONCLUSIONS: The study suggested that fatigue has a negative impact on quality of life in people with AS. Future practice should include a comprehensive fatigue assessment and the development of treatment programmes directed at enhancing self-management techniques. PMID- 22825965 TI - Biomarkers of exposure and effect in a lacertid lizard (Podarcis bocagei Seoane) exposed to chlorpyrifos. AB - In Europe, reptiles have been recently included in environmental risk-assessment processes for registration of plant-protection products. However, data on toxicity effects of most compounds are lacking. Chlorpyrifos is the most commonly used organophosphorus insecticide worldwide. In the present study, the authors exposed a lacertid lizard, Podarcis bocagei, to sublethal concentrations of chlorpyrifos. Individuals were exposed through spiked food for a period of 20 d (low dose 0.12 mg/kg/d, high dose 1.57 mg/kg/d). After exposure, various biomarkers of exposure and effect were evaluated, including the activities of glutathione S-transferase and enzymes involved in the glutathione redox cycle, glutathione concentrations, activities of esterases, liver and testes histopathologies, as well as locomotory and predatory behavior. The results indicate that sublethal, subchronic exposure to chlorpyrifos can affect P. bocagei in a dose-dependent manner. Adverse effects occurred at both the subindividual and individual levels, including inhibition of carboxylesterases and cholinesterases (ChEs), liver histopathological changes, and altered predatory behaviors. Animals exposed to chlorpyrifos took more time to capture and subdue prey items. The results suggest a link between effects at subindividual levels of organization with those observed at the whole individual level after exposure to environmentally realistic dosages of chlorpyrifos. PMID- 22825966 TI - Storage stability studies for tributyltin determination in human urine samples using headspace solid-phase microextraction and gas chromatography mass spectrometry. AB - A headspace solid-phase micro-extraction (HS-SPME) method was employed in order to study the effect of storage conditions of human urine samples spiked with tributyltin (TBT) using gas chromatography and mass spectrometry. To render the analyte more volatile, the derivatization (ethylation) was made in situ by sodium tetraethylborate (NaBEt(4) ), which was added directly to dilute unpreserved urine samples and in buffers of similar acidity. The stability of TBT in human urine matrix was compared with the stability of TBT in buffer solutions of similar pH value. Critical parameters of storage conditions such as temperature and time, which affect the stability of TBT in this kind of matrix, were examined extensively. The tests showed that the stability of TBT remains practically satisfactory for a maximum of 2 days of storage either at +4 or 20 degrees C. Greater variations were observed in the concentration of TBT in human urine samples at +4 degrees C and lower ones at -20 degrees C over a month's storage. The freeze-thaw cycles have negative effect on the stability and should be kept to a minimum. The results from spiked urine samples are also discussed in comparison to those acquired from buffer solutions of equal TBT concentration. PMID- 22825964 TI - Management of acute renal dysfunction in sepsis. AB - Acute kidney injury (AKI) often complicates sepsis, leading to greater complexity and a worsening prognosis. Advances in the clinical management of sepsis may have secondary benefits with respect to renal outcomes. In critically ill patients, this disorder typically produces multiple organ dysfunction. Among the several disorders encountered in sepsis, AKI is one of the most important because it is a life-threatening condition, increases the complexity and cost of care, and is an independent risk factor for mortality. The potential interventions in sepsis related AKI consist of effective prevention/protection strategies for the kidney in patients at risk, early recognition and attenuation of renal damage, pathophysiology-driven pharmacologic support, efficient extracorporeal blood purification therapy, and strategies that promote recovery of renal function. Existing and hybrid extracorporeal therapies are being investigated not only as means to replace lost kidney function, but also to modulate the immune response to sepsis. PMID- 22825967 TI - Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles. AB - We examined whether there is a correlation among early embryo cleavage, speed of cleavage, and implantation potential for in-vitro fertilization (IVF) treatment and intracytoplasmic sperm injection (ICSI). This retrospective study examined 112 cycles of IVF and 82 cycles of ICSI in patients less than 40 years of age. Early cleavage was defined as embryonic mitosis occurring 25-27 h after insemination. These day-3 embryos were then grouped according to cleavage speed (rapid, normal, and slow) and morphological quality (good or poor). A larger proportion of early-cleavage embryos developed normally compared to non-early cleavage embryos (IVF: 69.1 % vs. 47.1 %, respectively; ICSI: 63.0 % vs. 45.6 %, respectively). The early-cleavage embryos also produced more good quality embryos than the non-early-cleavage embryos (IVF: 80.2 % vs. 56.4 %, respectively; ICSI: 73.4 % vs. 59.4 %). The implantation rate was significantly higher with early cleavage embryos in both IVF (42.9 % vs. 19.7 %) and ICSI (48.1 % vs. 24 %). These results indicate that early-cleavage embryos have a higher rate of normal development and develop into better quality embryos on day 3, resulting in more and higher quality embryos to choose from for day-3 embryo transfer. Thus, early cleavage may be a useful criterion when selecting embryos for IVF or ICSI. PMID- 22825969 TI - Self-perceived need for interpreter among immigrants in Denmark. AB - AIM: Starting in June 2011, immigrants who have lived for more than 7 years in Denmark have to pay a user-fee for interpreters in GP consultations and when hospitalised. We do not know yet how many immigrants will be affected by this amendment to the Danish Health Act and which socioeconomic factors characterise the immigrants who might be affected. To shed light on this, we investigated self perceived need for interpreter (SNI) in GP consultations among participants from the largest non-Western immigrant groups in Denmark, the association between socioeconomic factors and SNI, and the characteristics of the immigrants potentially affected by the act amendment. METHODS: Survey data on 2866 immigrants from former Yugoslavia, Iraq, Iran, Lebanon, Pakistan, Somalia, and Turkey, linked to registry information on socioeconomic factors were examined. We compared unadjusted proportions of SNI by country of birth. Logistic regression analyses were performed to investigate associations between SNI and socioeconomic factors. RESULTS: Overall, 20% of immigrants living longer than 3 years in Denmark and 15% after 7 years reported a need for interpretation in their encounters with GPs. Of the latter group, the majority were outside the labour force (72.3%) and reported poor health (56%). Sex, age, length of stay, education, employment and household income were important factors for SNI. CONCLUSIONS: The amendment to the Health Act will primarily affect immigrants with modest household income, poor health and who are outside the labour force, thereby contributing and creating ethnic and social inequalities in access to health care in Denmark. PMID- 22825968 TI - Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. AB - PURPOSE: To detect expression of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) in oocytes, and their receptor type 2 receptor for BMPs (BMPR2) in cumulus cells in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF), and determine if BMPR2, BMP15, and GDF9 expression correlate with hyperandrogenism in FF of PCOS patients. METHODS: Prospective case-control study. Eighteen MII-oocytes and their respective cumulus cells were obtained from 18 patients with PCOS, and 48 MII-oocytes and cumulus cells (CCs) from 35 controls, both subjected to controlled ovarian hyperstimulation (COH), and follicular fluid (FF) was collected from small (10-14 mm) and large (>18 mm) follicles. RNeasy Micro Kit (Qiagen) was used for RNA extraction and gene expression was quantified in each oocyte individually and in microdissected cumulus cells from cumulus-oocyte complexes retrieved from preovulatory follicles using qRT-PCR. Chemiluminescence and RIA assays were used for hormone assays. RESULTS: BMP15 and GDF9 expression per oocyte was higher among women with PCOS than the control group. A positive correlation was found between BMPR2 transcripts and hyperandrogenism in FF of PCOS patients. Progesterone values in FF were lower in the PCOS group. CONCLUSION: We inferred that BMP15 and GDF9 transcript levels increase in mature PCOS oocytes after COH, and might inhibit the progesterone secretion by follicular cells in PCOS follicles, preventing premature luteinization in cumulus cells. BMPR2 expression in PCOS cumulus cells might be regulated by androgens. PMID- 22825970 TI - Acute myeloid leukemia in clinical practice: a retrospective population-based cohort study in Miyazaki Prefecture, Japan. AB - We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients >=65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients >=75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age <=64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients <=64 years, 33.8 %; 65-74 years, 21.6 %; >=75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data. PMID- 22825971 TI - Effects of study time and meaningfulness on environmental context-dependent recognition. AB - In two experiments, we examined whether the size of place-context-dependent recognition decreased with study time and with the meaningfulness of the to-be remembered materials. A group of 80 undergraduates intentionally studied a list of words in a short (1.5 s per item) or a long (4.0 s per item) study-time condition (Exp. 1). Another 40 undergraduates studied lists consisting of words and nonwords in the long-study-time condition (Exp. 2). After a short retention interval, recognition for the targets was tested in the same or in a different context. Context was manipulated by means of the combination of place, subsidiary task, and experimenter. Significant context-dependent recognition discrimination was found for words in the short-study-time condition (Exp. 1), but not in the long-study-time condition (Exps. 1 and 2). Significant effects were found as well for nonwords, even in the long-study-time condition (Exp. 2). These results are explained well by an outshining account: that is, by principles of outshining and encoding specificity. PMID- 22825972 TI - The association of TGF-beta1 codon 10 polymorphism with suicide behavior. AB - Many risk factors have been identified for suicide behavior and although a role for cytokines has been suggested in specific psychiatric conditions and suicide behavior, this role is not well-defined. Since some polymorphisms can alter the expression of cytokines, in this study we attempted to assess the role of TGF beta1 codon 10 (T/C) polymorphisms (rs1982073) in suicide behavior. A total of 145 individuals with suicide behavior as well as 200 control participants (without any history of suicide behavior) were included in the study. TGF-beta1 codon 10 polymorphism was determined using allele-specific oligonucleotide polymerase chain reaction. Our results demonstrated that the TGF-beta1 codon 10 T/T genotype was significantly more prevalent in individuals with suicide behavior (41.7%), in comparison with the controls (27%). The findings of this study demonstrated an association between TGF-beta1 (codon 10) T/C polymorphisms and suicide behavior. PMID- 22825973 TI - [Diagnostic accuracy of an automatic blood pressure device for ankle brachial index determination in ischemic stroke patients]. AB - INTRODUCTION: Ankle brachial index (ABI) is not widespread in clinical practice because the need for specific equipment and training. Doing it without these requirements, quicker and with a cheaper method would facilitate their routine use. AIMS: To evaluate sensitivity and specificity of an automatic blood pressure device detecting ABI < 0.90, when technique is performed by nurses. To evaluate agreement between two techniques for the ABI determination. PATIENTS AND METHODS. Diagnostic accuracy study in 30 ischemic stroke patients. For each patient, three measurements were performed with the automatic device, and one with the reference method. RESULTS: The automatic blood pressure device performance detecting ABI < 0.90 was acceptable for each of the three measurements (sensitivity: 78%, 87% and 100%; specificity: 95%, 100% and 100%; positive predictive value: 87%, 100% and 100%; negative predictive value: 91%, 96% y 100%; accuracy: 90%, 97% y 100%). The intraclass correlation coefficients for intra-observer, inter-observer and inter method variability showed acceptable levels, with results of 0.64, 0.83 and 0.75, respectively. In the Bland Altman test only inter-method comparison had less than 5% of its values out of range. CONCLUSIONS: Sensitivity and specificity of an automatic blood pressure device detecting ABI < 0.90 shows acceptable levels when technique is performed by nurses. This suggests its potential as screening tool in transient ischemic attack/ischemic stroke patients. PMID- 22825974 TI - [Dichotic listening in Spanish-speaking children: validation of a set of dichotic lists of Spanish words and syllables]. AB - INTRODUCTION: Dichotic listening test can estimate hemispheric dominance for language. AIM: To study the usefulness of a new set of dichotic pairs of Spanish stimuli in middle childhood. SUBJECTS AND METHODS: The stratified control group comprised 40 healthy, right-handed children, aged 3.5- 7.5 years, of both sexes, with average ability at speaking Spanish. The clinical sample comprised 12 children with right spastic hemi-paretic cerebral palsy, average general intelligence and sentence repetition index over -2z. Each listening series is composed of 20 age-appropriate dichotic pairs: one syllable, word, or number; or trains of two or three syllables or numbers. Voice onset time, duration and stress of stimuli were balanced. Hemispheric dominance index (HDI) for language was calculated using a formula with the scores of stimuli from right or left ears. Statistical analysis evaluated the age-related accuracy and discriminant power of each HDI. RESULTS: In the non-forced attention paradigm, the range of HDI is 0-200. Values of HDI >= 112 indicate left hemisphere dominance for language, whereas values of HDI <= 88 indicate right hemisphere dominance. All 40 typical subjects showed left HDI for language, without influence of age and sex. In contrast, ten out of twelve (83%) right hemiparetic children had right HDI. CONCLUSIONS: The results show that this new set of dichotic pairs is useful in the initial assessment of cerebral dominance for language and valid for use in Spanish speaking children aged 3.5 years or more. PMID- 22825975 TI - [Evaluation of the quality of life of patients with a Chiari type I malformation. A pilot study in a cohort of 67 patients]. AB - INTRODUCTION: The Chiari type I malformation (CM-I) is a low prevalence disorder whose manifestations vary highly, depending on the associated malformative complex. The people with a CM-I can suffer anxiety, depression symptoms and an un defined loss of quality of life. The main purpose of this study is to establish the impact of CM-I on quality of life, as well as the presence of anxiety and depression in these patients. PATIENTS AND METHODS: Prospective study of a cohort of 67 patients suffering from CM-I who undergo an evaluation by means of the SIP scale (Sickness Impact Profile), STAI (State-Trait Anxiety Inventory) and BDI (Beck's Depression Inventory) of their quality of life and of the presence of anxiety and depressive symptoms respectively. For every patient the degree of cerebellar tonsillar ectopia and the presence of syringomyelia and/or hydrocephalus were registered. RESULTS: The impact of the CM-I on the quality of life was none for 6 patients (9%), mild for 36 (53.7%), moderate for 17 (25.4%) and severe for 8 (11.9%). The most affected area of activity was work. A total of 86.6% of the patients presented a moderate or high anxiety level. In 25.4% of the patients moderate or severe depressive symptoms were also acknowledged. CONCLUSIONS: The great majority of patients with a CM-I consider that their disorder implies a loss of their quality of life which, in many cases, is associated with high anxiety and depressive symptoms. PMID- 22825976 TI - [Lampreys as an animal model in regeneration studies after spinal cord injury]. AB - Spinal cord injuries are an important sanitary and economical problem for the society. In mammals, including humans, a traumatic injury to the spinal cord leads to a loss of motor and sensorial function, which is irreversible due to the low regenerative ability of the central nervous system. In contrast to mammals, functional recovery occurs spontaneously after a complete spinal cord transection in lampreys. Functional recovery occurs because in these animals about 50% of the reticulospinal axons regenerate after injury and also because of the occurrence of processes of reorganization and plasticity of the spinal circuits. In this review, we first analyze the characteristics and regeneration ability of lampreys as compared to mammals. Then, we compile the knowledge about the process of recovery after a spinal cord injury acquired in studies using the lampreys as animal model and finally we provide some general perspectives about the molecular processes implicated in regeneration that can be investigated in a very advantageous way in this animal model and which knowledge could allow to develop new therapies for patients suffering spinal cord injury. PMID- 22825977 TI - [Deficiency, disability, neurology and literature]. AB - INTRODUCTION: Literature has always been attracted to neurological pathologies and the numerous works published on the subject are proof of this. Likewise, a number of physicians have been fiction writers and have drawn on their scientific knowledge to help develop their stories. AIMS: The study addresses the appearance of neurological pathologies in a sample of literary works and examines the description of the disease, its treatment, the patient's view and the relationship between healthcare professionals and the socio-familial milieu. DEVELOPMENT: We review some of the greatest literary works of all times that deal with neurological pathologies, such as Don Quixote, Julius Caesar, David Copperfield, The Idiot or Miau, and many of them are seen to offer a very faithful portrayal of the disease. Similarly, we have also reviewed works that provide a personal account of life with neurological diseases and the ensuing disability written either by the patients themselves or by their relatives, examples being The Diving Bell and the Butterfly, My Left Foot or One Chance in a Thousand. CONCLUSIONS: Literature has helped to offer a realistic vision of neurologically-based pathologies and the healthcare professionals who work with them; there are many examples that portray the experiences of the patients themselves and the importance of support from the family is a feature that is constantly underlined. PMID- 22825979 TI - [Intravenous fibrinolysis in a 14-year-old male with cerebral infarction due to dissection of the internal carotid artery]. PMID- 22825980 TI - [Autoimmune hepatitis in a patient with multiple sclerosis under treatment with glatiramer acetate]. PMID- 22825981 TI - [Highly refractory epilepsy in a poorly defined sample. Reply]. PMID- 22825982 TI - High-efficiency cascade CdS/CdSe quantum dot-sensitized solar cells based on hierarchical tetrapod-like ZnO nanoparticles. AB - Quantum dot-sensitized solar cells (QDSCs) constructed using cascade CdS/CdSe sensitizers and the novel tetrapod-like ZnO nanoparticles have been fabricated. The cascade co-sensitized QDSCs manifested good electron transfer dynamics and overall power conversion efficiency, compared to single CdS- or CdSe-sensitized cells. The preliminary CdS layer is not only energetically favorable to electron transfer but behaves as a passivation layer to diminish the formation of interfacial defects during CdSe synthesis. On the other hand, the anisotropic tetrapod-like ZnO nanoparticles, with a high electron diffusion coefficient, can afford a better carrier transport than traditional ZnO nanoparticles. The resultant solar cell yielded an excellent performance with a solar power conversion efficiency of 4.24% under simulated one sun (AM1.5G, 100 mW cm(-2)) illumination. PMID- 22825983 TI - Confidence in ASD occluder devices is eroding. PMID- 22825984 TI - Left main coronary intervention: are we moving too quickly without the appropriate evidence base? PMID- 22825985 TI - Rotational atherectomy for heavily calcified unprotected left main disease: proceed with caution. PMID- 22825986 TI - Unprotected left main disease: surgery, stents, or both? PMID- 22825987 TI - Transradial cardiac catheterization: the "unfreeze-change" theory. PMID- 22825988 TI - Left and right find common ground, or east meets west, via Turkey. PMID- 22825989 TI - Right or left radial access: to each their own. PMID- 22825990 TI - Sheathless in the USA. PMID- 22825991 TI - Vascular surgeons and carotid revascularization: what's theirs is theirs, and what's ours is theirs. PMID- 22825993 TI - Heavy hitting: concussions and the courts. PMID- 22825992 TI - Treatment of co-occurring posttraumatic stress disorder and substance use disorders. AB - There is a significant need for advanced understanding of treatment of co occurring posttraumatic stress disorder (PTSD) and substance use disorders (SUD). Approximately half of individuals seeking SUD treatment meet criteria for current PTSD, and individuals with co-occurring PTSD-SUD tend to have poorer treatment outcomes compared with those without such comorbidity. However, there is not sufficient empirical evidence to determine a best course of treatment for these individuals. This paper provides a review of the literature relevant to the treatment of co-occurring PTSD-SUD. To date, treatment studies have focused primarily on non-exposure-based psychosocial treatments, exposure-based psychosocial treatments, and medication trials. The most promising outcome data thus far are for psychosocial treatments that incorporate an exposure therapy component; however, further research is needed, particularly as related to how best to implement these approaches in real-world treatment settings. PMID- 22825994 TI - India's "rural doctor" proposal stirs criticism. PMID- 22825997 TI - Medical training and care under the rainbow umbrella. PMID- 22825998 TI - Defining diagnostic tissue in the era of personalized medicine. PMID- 22825995 TI - Plasma bicarbonate and risk of type 2 diabetes mellitus. AB - BACKGROUND: Several biomarkers of metabolic acidosis, including lower plasma bicarbonate and higher anion gap, have been associated with greater insulin resistance in cross-sectional studies. We sought to examine whether lower plasma bicarbonate is associated with the development of type 2 diabetes mellitus in a prospective study. METHODS: We conducted a prospective, nested case-control study within the Nurses' Health Study. Plasma bicarbonate was measured in 630 women who did not have type 2 diabetes mellitus at the time of blood draw in 1989-1990 but developed type 2 diabetes mellitus during 10 years of follow-up. Controls were matched according to age, ethnic background, fasting status and date of blood draw. We used logistic regression to calculate odds ratios (ORs) for diabetes by category of baseline plasma bicarbonate. RESULTS: After adjustment for matching factors, body mass index, plasma creatinine level and history of hypertension, women with plasma bicarbonate above the median level had lower odds of diabetes (OR 0.76, 95% confidence interval [CI] 0.60-0.96) compared with women below the median level. Those in the second (OR 0.92, 95% CI 0.67-1.25), third (OR 0.70, 95% CI 0.51-0.97) and fourth (OR 0.75, 95% CI 0.54-1.05) quartiles of plasma bicarbonate had lower odds of diabetes compared with those in the lowest quartile (p for trend = 0.04). Further adjustment for C-reactive protein did not alter these findings. INTERPRETATION: Higher plasma bicarbonate levels were associated with lower odds of incident type 2 diabetes mellitus among women in the Nurses' Health Study. Further studies are needed to confirm this finding in different populations and to elucidate the mechanism for this relation. PMID- 22825999 TI - Gottron papules: a pathognomonic sign of dermatomyositis. PMID- 22826000 TI - A woman with community-acquired Clostridium difficile infection. PMID- 22826001 TI - From outlier to trendsetter. PMID- 22826002 TI - Increased risk of bladder cancer following diagnosis with bladder pain syndrome/interstitial cystitis. AB - AIMS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent disorder that may contribute to bladder cancer (BC). This cohort study set out to investigate the association between IC/BPS and BC by using a population-based dataset. METHODS: The data for this study were sourced from the Taiwan National Health Insurance program. The case cohort comprised 7,562 patients with IC/BPS, and 22,686 randomly selected subjects were used as a comparison cohort. A Cox proportional hazards regression model (stratified by age group, geographic location, urbanization level, and the index year) was constructed to estimate the risk of subsequent BC following a diagnosis of IC/BPS. We also ran the analysis utilizing an alternative comparison cohort composed of patients with urinary incontinence (UI). RESULTS: In the study sample of 30,248 patients, 96 patients (0.32%) received a diagnosis of BC during the 3-year follow-up period; 48 (0.63% of patients with IC/BPS) were from the study cohort; and 48 (0.21% of patients without IC/BPS) were from the comparison cohort. The incidence rate of BC was 2.12 (95% CI: 1.58-2.78) per 1,000 person-years in patients with IC/BPS and 0.70 (95% CI: 0.52-0.92) per 1,000 person-years in comparison patients. Cox proportional analysis revealed that the adjusted HR for BC during the 3-year follow-up period for patients with IC/BPS was 2.95 (95% CI: 1.97-4.41) that of comparison subjects. When performing the analysis with the alternative UI comparison cohort, the adjusted HR for BC was 1.96 (95% CI: 1.14-3.39). CONCLUSIONS: This investigation detected a novel association between BC and prior IC/BPS. PMID- 22826003 TI - Polyethylenimine functionalized magnetic nanoparticles as a potential non-viral vector for gene delivery. AB - Polyethylenimine (PEI) functionalized magnetic nanoparticles were synthesized as a potential non-viral vector for gene delivery. The nanoparticles could provide the magnetic-targeting, and the cationic polymer PEI could condense DNA and avoid in vitro barriers. The magnetic nanoparticles were characterized by Fourier transform infrared spectroscopy, X-ray powder diffraction, dynamic light scattering measurements, transmission electron microscopy, vibrating sample magnetometer and atomic force microscopy. Agarose gel electrophoresis was used to asses DNA binding and perform a DNase I protection assay. The Alamar blue assay was used to evaluate negative effects on the metabolic activity of cells incubated with PEI modified magnetic nanoparticles and their complexes with DNA both in the presence or absence of an external magnetic field. Flow cytometry and fluorescent microscopy were also performed to investigate the transfection efficiency of the DNA-loaded magnetic nanoparticles in A549 and B16-F10 tumor cells with (+M) or without (-M) the magnetic field. The in vitro transfection efficiency of magnetic nanoparticles was improved obviously in a permanent magnetic field. Therefore, the magnetic nanoparticles show considerable potential as nanocarriers for gene delivery. PMID- 22826004 TI - Transplantation of nano-bioglass/gelatin scaffold in a non-autogenous setting for bone regeneration in a rabbit ulna. AB - Bioactive glass has been investigated for variety of tissue engineering applications. In this study, fabrication, in vitro and in vivo evaluation of bioactive glass nanocomposite scaffold were investigated. The nanocomposite scaffolds with compositions based on gelatin and bioactive glass nanoparticles were prepared. The apatite formation at the surface of the nanocomposite samples confirmed by Fourier transform infrared spectroscopy, scanning electron microscopy and X-ray powder diffraction analyses. The in vitro characteristics of bioactive glass scaffold as well as the in vivo bone formation capacity of the bioactive glass scaffold in rabbit ulnar model were investigated. The bioactive glass scaffold showed no cytotoxicity effects in vitro. The nanocomposite scaffold made from gelatin and bioactive glass nanoparticles could be deliberated as an extremely bioactive and prospective bone tissue engineering implant. Bioactive glass scaffolds were capable of guiding bone formation in a rabbit ulnar critical-sized-defect model. Radiographic evaluation indicated that successful bridging of the critical-sized defect on the sides both next to and away from the radius took place using bioactive glass scaffolds. X-ray analysis also proposed that bioactive glass scaffolds supported normal bone formation via intramembranous formation. PMID- 22826005 TI - The integrative biology of reproductive functioning in nonhuman primates. AB - At the 34th annual meeting of the American Society of Primatologists in 2011, the society organized an interdisciplinary symposium entitled, "Reproductive Function & Dysfunction in Nonhuman Primates." The articles in this special section, excluding this introduction, represent the findings presented by four of the five speakers in that symposium. The data presented highlight the myriad factors that contribute to primate reproductive function and dysfunction, including hormones, genes, maternal variance, environmental factors, social relationships, and strategic interactions. Collectively, these articles emphasize the integrative nature of primate reproductive function, and highlight the importance of the nonhuman primate as a model for human reproductive function and dysfunction in humans. PMID- 22826006 TI - Measuring cohabitation and family structure in the United States: assessing the impact of new data from the Current Population Survey. AB - In 2007, the Current Population Survey (CPS) introduced a measure that identifies all cohabiting partners in a household, regardless of whether they describe themselves as "unmarried partners" in the relationship to householder question. The CPS now also links children to their biological, step-, and adoptive parents. Using these new variables, we analyze the prevalence of cohabitation as well as the demographic and socioeconomic characteristics of different-sex cohabiting couples during the years 2007-2009. Estimates of cohabitation produced using only unmarried partnerships miss 18 % of all cohabiting unions and 12 % of children residing with cohabiting parents. Although differences between unmarried partners and most newly identified cohabitors are small, newly identified cohabitors are older, on average, and are less likely to be raising shared biological or adopted children. These new measures also allow us to identify a small number of young, disadvantaged couples who primarily reside in households of other family members, most commonly with parents. We conclude with an examination of the complex living arrangements and poverty status of American children, demonstrating the broader value of these new measures for research on American family and household structure. PMID- 22826007 TI - Maternal and paternal family history of type 2 diabetes differently influence lipid parameters in young nondiabetic Japanese women. AB - OBJECTIVES: We assessed the association of family history of type 2 diabetes (T2D) with parameters used for health checkups in young Japanese women. METHODS: The subjects were 497 nondiabetic women aged 19-39 years. Among them, the mothers of 34 subjects and fathers of 50 had T2D (MD group and PD group, respectively). The subjects were assessed for levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). RESULTS: TC and LDL-C level showed a tendency to increase in the MD group compared with subjects without family history of T2D. LDL-C/HDL-C ratio >=2.14 was found in 32.4 and 18.0 % of subjects in the MD and PD groups, respectively. When adjusted for differences in age, body mass index, smoking status, and drinking habits, the MD group was found to have a higher risk of abnormal TC and LDL-C levels than the PD group. LDL-C/HDL-C ratio was independently associated with maternal family history but not with paternal family history (odds ratio 3.44 [99 % confidence interval 1.11-10.6] and 1.21 [0.38-3.89], respectively). There was no association between TG/HDL-C ratio and family history type of T2D. CONCLUSIONS: Maternal family history of T2D had a more pronounced effect on the lipid parameters generally evaluated during health checkups than did paternal family history of T2D. Therefore, we recommend systematic screening for early detection and appropriate healthcare guidance for Japanese women, particularly those with maternal family history of T2D. PMID- 22826008 TI - Control of cell adhesion and neurite outgrowth by patterned gold nanoparticles with tunable attractive or repulsive surface properties. AB - Guiding of neuronal cells on surfaces is required for the investigation of fundamental aspects of neurobiology, for tissue engineering, and for numerous bioelectronic applications. A modular method to establish nanostructured chemical templates for local deposition of gold nanoparticles is presented. A process comprising nanoimprint lithography, silanization, lift-off, and gold nanoparticle immobilization is used to fabricate the particle patterns. The chemical composition of the surface can be modified by in situ adsorption of cell-binding ligands to locally addressed particles. The versatility of this approach is demonstrated by inverting the binding affinity between rat cortical neurons and nanopatterned surfaces via wet-chemical means and thereby reversing the pattern of guided neurons. PMID- 22826009 TI - Violence against women in South Africa: policy position and recommendations. AB - Violence against women (VAW) in South Africa remains rampant, irrespective of human rights- focused laws passed by the government. This article reflects on the position of two acts: the Domestic Violence Act No 116 of 1998 and Criminal Law (Sexual Offense and Related Matters) Act No 32 of 2007. Both are framed to protect women against all forms of violence. The article discusses the prisms of the two laws, an account of the position taken or interpreted by the reviewed literature regarding the acts, and the findings and recommendations regarding the infrastructure and supports needed to appropriately implement the two acts. PMID- 22826010 TI - Conformity in diversity? Isotopic investigations of infant feeding practices in two iron age populations from Southern Oland, Sweden. AB - This article presents the results of a study of infant diet at two Iron Age sites on the island of Oland, Sweden. The cemetery at Bjarby contained a large number of subadults who had survived the earliest years of life, whereas most individuals at Triberga had died by 6 months of age. To investigate whether differences in infant feeding could explain the different mortality rates, the carbon, nitrogen, and sulfur stable isotope ratios of bone and tooth dentin collagen from the two sites were analyzed. Twenty-two samples from Triberga and 102 from Bjarby yielded data that could be included in the carbon and nitrogen analysis. Twelve samples from Triberga and 42 from Bjarby were included in the sulfur analysis. The results for carbon (delta(13) C: Triberga X = -18.8, s.d. = 1.1; Bjarby X = -19.8, s.d. = 0.4), nitrogen (delta(15) N: Triberga X = 12.9, s.d. = 1.5; Bjarby X = 13.4, s.d. = 1.4), and sulfur (delta(34) S: Triberga X = 8.1, s.d. = 1.1; Bjarby X = 5.8, s.d. = 1.3) suggest that diet was broadly similar at both sites and based on terrestrial resources. At Bjarby, females and high-status individuals consumed higher-trophic level protein than other males from early childhood onward. There was some indication that the contribution of marine resources to the diet may also have differed between the sexes at Triberga. No consistent differences in breast milk intake were observed between the two sites, but there was substantial variation at each. This variation may reflect an influence of gender and social status on infant feeding decisions. PMID- 22826011 TI - How should unmatched orthopaedic surgery applicants proceed? AB - BACKGROUND: Obtaining an orthopaedic surgery residency is competitive. Advisors must understand what factors may help unmatched candidates reapply successfully. QUESTIONS/PURPOSES: We determined (1) the attitude of leaders of orthopaedic surgery residency programs toward interviewing unmatched students; (2) whether a surgical internship or a research year is preferred in considering reapplicants; (3) the importance of United States Medical Licensing Examination (USMLE) scores, recommendations, and Alpha Omega Alpha (AOA) membership; and (4) whether academic and nonacademic programs evaluate reapplicants differently. METHODS: We sent an anonymous 19-question survey to 151 Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic surgery residency programs in five waves, 1 week apart (December 5, 2009-January 5, 2010). Investigators were blinded to the respondents' identities. RESULTS: Ninety-one of the 151 programs (60%) responded. Sixty-eight of the 91 programs (75%) stated they rarely accept unmatched applicants. Sixty-eight programs (75%) agreed an unmatched applicant should do a surgery internship for 1 year. Of the 36 programs that recommended a research year, 32 were academic programs. Academic programs were more likely than nonacademic programs to view as important new recommendations (85% versus 67%), minimum scores of 220 on Step I (67% versus 49%) and Step II (64% versus 36%), and AOA membership (85% versus 67%). CONCLUSIONS: By completing a surgical internship, unmatched students may increase their chances of matching. Students considering academic programs should ensure their academic record meets certain benchmarks and may consider a research year but risk limiting their acceptance to academic programs. PMID- 22826012 TI - What are the risks accompanying the reduced wear benefit of low-clearance hip resurfacing? AB - BACKGROUND: Clearance is an important determinant of metal-metal bearing function. Tribologic theory and laboratory evidence suggest low clearance (LC) reduces wear but with a potential to increase friction and clinical reports show LC resurfacings have high implant failure rates. Thus, the role of LC is unclear. QUESTIONS/PURPOSES: We asked: is in vivo wear as reflected by cobalt (Co) and chromium (Cr) levels reduced in LC bearings, and if so, is this benefit offset by increased friction as assessed by implant-bone interface changes? METHODS: We retrospectively reviewed 26 patients with LC resurfacings. We assessed Co and Cr levels in blood and urine, hip function, and radiographic adverse features. These data were compared with those from 26 patients with a similar resurfacing but with conventional clearance (CC) from a previous study. Minimum followup was 4.0 years (mean, 4.1 years; range, 4.0-4.7 years). RESULTS: Co and Cr ion comparisons showed three phases: in the first 2 months, there was no difference between the cohorts; at 2 to 24 months, the CC group showed higher levels; and subsequently, levels in the two groups converged. A mean Oxford hip score of 13 and step activity of 1.9 million cycles per year in the LC group were similar to those of the CC group. Cup radiolucencies were seen in three patients in the LC group and none in the CC group. CONCLUSIONS: Lower Co and Cr levels suggest lower wear in the LC resurfacings in the intermediate term, but the presence of radiolucencies raises the concern that higher bearing friction is affecting implant fixation. A larger clearance than the theoretically predicted ideal may be required to allow for minor manufacturing imperfections, component deformation, and progressive changes in the in vivo lubricant. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22826013 TI - Surgeon volume is associated with cost and variation in surgical treatment of proximal humeral fractures. AB - BACKGROUND: The issue of rising costs will likely dominate the healthcare debate in the forthcoming years. QUESTIONS/PURPOSES: We assessed factors including surgeon volume that were associated with lower hospital costs and variations in surgical treatment for proximal humeral fractures. METHODS: We used national databases for 2001 to 2008 to extract information on 25,731 patients undergoing surgery for proximal humeral fractures. We calculated hospital cost by converting hospital charges based on the hospital accounting reports collected by the Centers for Medicare & Medicaid Services. RESULTS: In a multivariate linear regression analysis, higher surgeon volume, open reduction and internal fixation (versus hemiarthroplasty), and lower burden of comorbidities were associated with lower hospital cost. Higher surgeon volume was linearly associated with lower hospital costs such that, on average, adjusting for all other factors, a surgeon performing 20 shoulder arthroplasties per year saves a hospital approximately US $1800 per surgery. Factors associated with higher utilization of hemiarthroplasty included high surgeon volume (odds ratio [OR] = 1.46; 95% CI = 1.43, 1.97; as compared with low surgeon volume) and earlier years of our study period (OR = 0.61; 95% CI = 0.56, 0.66; for hemiarthroplasty in 2007-2008 versus 2001-2002). CONCLUSIONS: Higher surgeon volume was associated with lower hospital costs for proximal humeral fractures. Therefore, policies on minimum volume requirements by hospitals may result in substantial cost savings. There is provider-based practice variation in the surgical treatment of proximal humeral fractures and evidence-based guidelines in this area are needed. LEVEL OF EVIDENCE: Level III, economic analysis. See Instructions for Authors for a complete description of levels of evidence. PMID- 22826014 TI - Oligo[poly(ethylene glycol)fumarate] hydrogel enhances osteochondral repair in porcine femoral condyle defects. AB - BACKGROUND: Management of osteochondritis dissecans remains a challenge. Use of oligo[poly(ethylene glycol)fumarate] (OPF) hydrogel scaffold alone has been reported in osteochondral defect repair in small animal models. However, preclinical evaluation of usage of this scaffold alone as a treatment strategy is limited. QUESTIONS/PURPOSES: We therefore (1) determined in vitro pore size and mechanical stiffness of freeze-dried and rehydrated freeze-dried OPF hydrogels, respectively; (2) assessed in vivo gross defect filling percentage and histologic findings in defects implanted with rehydrated freeze-dried hydrogels for 2 and 4 months in a porcine model; (3) analyzed highly magnified histologic sections for different types of cartilage repair tissues, subchondral bone, and scaffold; and (4) assessed neotissue filling percentage, cartilage phenotype, and Wakitani scores. METHODS: We measured pore size of freeze-dried OPF hydrogel scaffolds and mechanical stiffness of fresh and rehydrated forms. Twenty-four osteochondral defects from 12 eight-month-old micropigs were equally divided into scaffold and control (no scaffold) groups. Gross and histologic examination, one-way ANOVA, and one-way Mann-Whitney U test were performed at 2 and 4 months postoperatively. RESULTS: Pore sizes ranged from 20 to 433 MUm in diameter. Rehydrated freeze dried scaffolds had mechanical stiffness of 1 MPa. The scaffold itself increased percentage of neotissue filling at both 2 and 4 months to 58% and 54%, respectively, with hyaline cartilage making up 39% of neotissue at 4 months. CONCLUSIONS: Rehydrated freeze-dried OPF hydrogel can enhance formation of hyaline-fibrocartilaginous mixed repair tissue of osteochondral defects in a porcine model. CLINICAL RELEVANCE: Rehydrated freeze-dried OPF hydrogel alone implanted into cartilage defects is insufficient to generate a homogeneously hyaline cartilage repair tissue, but its spacer effect can be enhanced by other tissue-regenerating mediators. PMID- 22826016 TI - Aggressive early debridement for treatment of acutely infected cemented total hip arthroplasty. AB - BACKGROUND: Up to 2% of THAs are complicated by infection, leading to dissatisfied patients with poor function and major social and economic consequences. The challenges are control of infection, restoration of full function, and prevention of recurrence. Irrigation and debridement with or without exchange of modular components remains an attractive alternative to two stage reimplantation in acutely infected THAs but with variable results from previous studies. QUESTIONS/PURPOSES: We therefore determined the rate at which aggressive early debridement with exchange of modular components controlled acutely infected cemented THAs. METHODS: We retrospectively studied all 26 patients presenting with acutely infected cemented THAs (16 primaries, 10 revisions) occurring within 6 weeks of the index operation or of hematogenous spread from a confirmed source of infection elsewhere between 1999 and 2006. Microbiology confirmed bacterial colonization in all patients, with 18 early postoperative infections and eight acute hematogenous infections. Patients underwent aggressive debridement with open complete synovectomy, exchange of all mobile parts, debridement of all aspects of the joint, irrigation with antiseptic solutions, and pulsatile lavage. Minimum followup was 5 years (mean, 6.6 years; range, 5-11 years). RESULTS: Eight patients had multiple washouts with control of infection in four at latest followup. Five patients underwent two-stage revisions and one patient was placed on long-term antibiotic suppression. Twenty patients returned to their expected functional level with no radiographic evidence of prosthetic failure. At minimum 5-year followup, we had a 77% infection control rate. CONCLUSIONS: Our data confirm current literature and suggest there may be a role for aggressive early debridement in controlling acute postoperative and hematogenous infections after cemented THA. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22826015 TI - Alumina-on-alumina THA performed in patients younger than 30 years: a 10-year minimum followup study. AB - BACKGROUND: THA in patients younger than 30 years presents challenges because of uncertainties regarding the long-term survivorship of prostheses. Alumina-on alumina bearings, which exhibit little long-term wear, may be a reasonable option but the long-term survivorship is unknown. QUESTIONS/PURPOSES: We determined (1) the survival rate of alumina-on-alumina bearings in patients younger than 30 years after a 10-year followup, (2) the incidence of audible hip clicking and squeaking, (3) radiographic evidence of osteolysis, and (4) the effects on pregnancy, childbirth, and career choice. METHODS: We retrospectively reviewed 62 patients who had 75 THAs with alumina-on-alumina bearings followed more than 10 years (average, 11.5; range, 10-13.5 years). Mean patient age at the time of surgery was 24 years (range, 18-30 years). All operations were performed using the same cementless implant at a single center. We determined survival, presence of osteolysis, and function (Harris hip score, WOMAC). RESULTS: The 10-year survival rate of alumina-on-alumina bearings in THAs, with revision for any reason as the end point, was 98.9%. Audible hip clicking and squeaking were identified in 10 hips and two hips, respectively. No osteolysis was detected. None of the 11 patients who became pregnant had been affected by their THA during pregnancy or childbirth. Seven of the 14 patients who were unemployed at the time of index surgery stated that their THA affected their job choice. CONCLUSIONS: We found a high 10-year survival of cementless alumina-on-alumina bearings in THAs in patients younger than 30 years. Lifetime events such as job choice, pregnancy, and childbirth should be considered when choosing THA for patients younger than 30 years. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22826017 TI - Arteriotomy closure device safety after percutaneous coronary intervention in the direct thrombin inhibitor era: a comparative study. AB - OBJECTIVES: To investigate the safety and risk of vascular complications of arteriotomy closure devices (ACD) with the direct thrombin inhibitor bivalirudin in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: ACDs and manual compression have been shown to have a similar risk of complications in the setting of PCI with heparin +/- glycoprotein (GP) IIb/IIIa inhibitor usage. In many centers bivalirudin is becoming the most frequent type of anticoagulation used during PCI. We sought to determine the risk of vascular complications using Angio-Seal, Perclose, and manual compression for groin hemostasis using predominantly bivalirudin. METHODS: Our institution's interventional database retrospectively identified 14,354 consecutive patients undergoing PCI from 2000 to 2008. Patients were grouped by the adjunctive anticoagulation used (bivalirudin vs. heparin + GP IIb/IIIa inhibitors) as well as ACD employed. The incidence of complications was evaluated using multivariable analysis to account for baseline differences between groups. RESULTS: Patients undergoing PCI with adjunctive bivalirudin had significantly fewer complications overall, regardless of closure method (2.9% vs. 8.7%, P < 0.001). The Perclose group had significantly fewer complications than the Angio-Seal and manual compression groups (3.9% vs. 5.6% vs. 9.0%, P < 0.001) respectively; the Angio-Seal group had significantly fewer complications than manual compression. Multivariable analysis also identified age >= 65, female gender, BMI <= 26, and operator as independent predictors of complications. CONCLUSIONS: The use of adjunctive bivalirudin during PCI was associated with fewer vascular complications. In addition, the Perclose and Angio-Seal devices had significantly fewer complications than manual compression and women >= 65 are at highest risk. PMID- 22826018 TI - An algorithm for the calculation of three-dimensional collagen fiber orientation in ligaments using angle-sensitive MRI. AB - A method based on angle-sensitive magnetic resonance imaging for determining unknown orientations of collagen fibers in ligaments is presented. Collagen fibers were stepwise rotated around two independent axes within a 3T magnetic resonance tomograph (from 0 degrees to 180 degrees , step size=10 degrees ). Analyzing the magnetic resonance signal intensity of each voxel as a function of the rotation angle, directions were calculated by means of a computational algorithm. The accuracy of the algorithm was validated using 1000 random test directions, revealing an average deviation of 4.4 degrees (median+/-standard deviation: 2.7 degrees +/-9 degrees ). Subsequently, the presented method was applied to three specimens of the human iliotibial tract mounted in different directions in a rotatable plastic box. Polarized light microscopy was used to verify parallel alignment of the collagen fibers in the three specimens. The calculated directions were compared with the directions of the specimens. Analyzing each voxel separately, average deviations (median+/-standard deviation) in the three specimens were: 11.2 degrees (3.6 degrees +/-20.4 degrees ), 12 degrees (5 degrees +/-24.1 degrees ), and 20.4 degrees (8.7 degrees +/-27 degrees ). If the magnetic resonance signal intensity of each voxel was averaged with the intensity of immediately neighboring voxels, average deviations (median+/-standard deviation) were 8.5 degrees (3.6 degrees +/-17.4 degrees ), 6.2 degrees (0 degrees +/-18 degrees ), and 9.2 degrees (5 degrees +/-19.2 degrees ). The presented method has the potential to be applied in situ to anatomical structures like cartilage, ligaments, tendons and fascia. PMID- 22826019 TI - A pilot evaluation of appetite-awareness training in the treatment of childhood overweight and obesity: a preliminary investigation. AB - OBJECTIVE: The aim of this study was to conduct a preliminary evaluation of Children's Appetite Awareness Training (CAAT), a treatment for childhood obesity which encourages overweight children to eat in response to internal appetite cues. METHOD: Overweight children (ages 6-12 years old) were randomized to either the CAAT treatment group (N = 23), to receive 1-h treatment sessions over 6 weeks, or a wait-list group (N = 24). Weight and height of children and parents in both groups were assessed at pre- and post-treatment (or equivalent time for wait-list control) and at a 6-month follow-up for those in the CAAT group. RESULTS: The intervention had a significant, short-term effect on the BMI of children who participated. Although at 6-month follow-up, children's BMI has not increased significantly, the difference between pretreatment and follow-up BMI was no longer significant. DISCUSSION: These results are encouraging for the use of CAAT with overweight children. Long-term effectiveness could be enhanced through increasing the duration of the program, adding booster sessions and increased involvement of parents. PMID- 22826020 TI - The first reported cases of human cryptosporidiosis caused by Cryptosporidium hominis in Slovak Republic. AB - Cryptosporidiosis belongs to the important parasitic infections with zoonotic potential and the occurrence in European countries is rare. The first cases of cryptosporidiosis caused by Cryptosporidium hominis detected in the Slovak republic were described here. Collection of examined humans consisted of five family members. Faecal specimens were examined by formalin sedimentation, by the Sheather's sugar flotation and by immunochromatography and visualised by the Ziehl-Neelsen acid fast stain. A fragment of the Cryptosporidium small subunit ribosomal RNA gene was amplified by nested polymerase chain reaction and species was determined by restriction fragment length polymorphism analysis with the endonucleases SspI and VspI. C. hominis was found in faeces of two immunocompetent siblings (a 7-year-old boy and a 2-year-old girl). The symptoms occurred only in the boy as gastrointestinal disorders lasting 5 days, and manifested by abdominal pain, an elevated body temperature (37.2 degrees C), mild diarrhoea, accompanied by lassitude, depression and anorexia. Ultrasonic scan revealed enlarged spleen and mezenteric lymph nodes. Microscopic examination of the stool sample revealed numerous Cryptosporidium oocysts. The DNA typing identified C. hominis subtype IbA10G2. Cryptosporidium was also detected in the boy's sister without any complications and symptoms. Their father, mother and grandmother were parasitologically negative. The source of infection remained unknown. Human cases in present study reflect necessity of systematic attention on intestinal parasites diagnostic inclusive of cryptosporidia. PMID- 22826021 TI - An influence of ethanol and temperature on products formation by different preparations of Zymomonas mobilis extracellular levansucrase. AB - The ethanol and temperature effects on the ratio between Zymomonas mobilis 113S extracellular levansucrase activities were studied using fermentation broth supernatant, "levan-levansucrase" sediment precipitated by ethanol and highly purified enzyme. The fructooligosaccharide (FOS) production at different temperatures in the presence of ethanol was investigated. An ethanol increases FOS biosynthesis activity part of levansucrase. Especially, this effect was pronounced at lower temperatures (35-40 degrees C) and using purified levansucrase. The inverse relationship between temperature and ratio synthetic activity/total activity of levansucrase was found. The FOS composition containing mostly 1-kestose, 6-kestose, and neokestose obtained in the presence of different ethanol concentrations was found relative constant, while the changes in the sucrose concentration and temperature gave slight changes in the ratio between 1 kestose and 6-kestose. PMID- 22826022 TI - Inverted V sign in hydromyelia with Chiari type 1 malformation. PMID- 22826023 TI - Ataxia-telangiectasia or neurologic Wilson's disease: when strong family history becomes a diagnostic bias. PMID- 22826024 TI - Tuning the doping type and level of graphene with different gold configurations. AB - Au nanoparticles and films are deposited onto clean graphene surfaces to study the doping effect of different Au configurations. Micro-Raman spectra show that both the doping type and level of graphene can be tuned by fine control of the Au deposition. The morphological structures of Au on graphene are imaged by transmission electron microscopy, which indicate a size-dependent electrical characteristic: isolated Au nanoparticles produce n-type doping of graphene, while continuous Au films produce p-type doping. Accordingly, graphene field effect transistors are fabricated, with the in situ measurements suggesting the tunable conductivity type and level by contacting with different Au configurations. For interpreting the experimental observations, the first principles approach is used to simulate the interaction within graphene-Au systems. The results suggest that, different doping properties of Au-graphene systems are induced by the chemical interactions between graphene and the different Au configurations (isolated nanoparticle and continuous film). PMID- 22826025 TI - Salivary concentration of progesterone and cortisol significantly differs across individuals after correcting for blood hormone values. AB - Between-individual variation of salivary progesterone (P4) and cortisol levels does not always closely reflect blood hormone concentrations. This may be partly a function of individual differences in salivary hormone excretion. We tested whether time of day at sampling and ethnicity contributed to individual variation in salivary hormones after adjusting for blood hormone levels. Forty-three Caucasian and 15 Japanese women (18-34 years) collected four sets of matched dried blood spot (DBS) and saliva specimens across a menstrual cycle (N = 232 specimen sets). Linear fixed-effects (LFE) models were used to estimate the effects of diurnal variation and ethnicity on salivary P4 and cortisol while adjusting for DBS levels. For each hormone, women with exclusively positive or negative residuals (unexplained variance) from the LFE models were categorized as high- or low-saliva-to-DBS hormone ratio (SDR; high or low salivary secretors), respectively. We found that salivary P4 (P < 0.05) was significantly higher in early morning compared to the afternoon, after controlling for DBS levels, ethnicity, and BMI. After further adjusting for this diurnal effect, significant individual variation in salivary P4 and cortisol remained: sixteen and nine women, respectively were categorized as low or high salivary secretors for both hormones (P < 0.001), suggesting systematic individual-specific variation of salivary hormonal concentration. We conclude that when saliva is used to quantify P4 or cortisol levels, time of day at sampling should be controlled. Even with this adjustment, salivary P4 and cortisol do not closely mirror between- individual variation of serum P4 and cortisol in a substantial proportion of individuals. PMID- 22826026 TI - Animal lectins: potential antitumor therapeutic targets in apoptosis. AB - Lectins, a group of carbohydrate-binding proteins ubiquitously distributed into plants and animals, are well-known to have astonishing numerous links to human cancers. In this review, we present a brief outline of the representative animal lectins such as galectins, C-type lectins, and annexins by targeting programmed cell death (or apoptosis) pathways, and also summarize these representative lectins as possible anti-cancer drug targets. Taken together, these inspiring findings would provide a comprehensive perspective for further elucidating the multifaceted roles of animal lectins in apoptosis pathways of cancer, which, in turn, may ultimately help us to exploit lectins for their therapeutic purposes in future drug discovery. PMID- 22826027 TI - A global measure to assess switching antipsychotic medications in the treatment of schizophrenia. AB - OBJECTIVES: It is common practice to switch antipsychotic medications in the treatment of patients with schizophrenia to enhance clinical efficacy and/or reduce drug-related side effects. The conventional Clinical Global Impression (CGI) of severity scale is a well-understood measure to track switching effects but does not differentiate between the severity of clinical symptoms and the impact of side effects.. METHODS: We developed a CGI-switch instrument that contains distinct global severity scales for clinical efficacy, safety and/or tolerability, and a third unified (integrated) CGI severity score to assess these interrelated assessments. An integrated Clinical Global Impression of Change was also created to assess global clinical change relative to the initiation of treatment. RESULTS: Interrater reliability conducted as part of a rater-training program for a clinical study (Novartis protocol CIL0522D; clinitrials.gov identifier: CT01207414) revealed high interrater agreement (Cronbach's alpha = 0.945). Data were collected from 1066 CGI assessments during the course of the trial. CGI raters easily grasped the utility of the instrument. The distinction made between efficacy and safety/tolerability facilitated serial tracking of each condition during the course of treatment. CONCLUSION: The modified CGI-switch instrument is a simple, reliable, and practical metric to assess the benefits, if any of switching antipsychotic medications in patients with schizophrenia. PMID- 22826028 TI - Brown rice and its component, gamma-oryzanol, attenuate the preference for high fat diet by decreasing hypothalamic endoplasmic reticulum stress in mice. AB - Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, gamma oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD. PMID- 22826030 TI - A transition model for quality-of-life data with non-ignorable non-monotone missing data. AB - In this paper, we consider a full likelihood method to analyze continuous longitudinal responses with non-ignorable non-monotone missing data. We consider a transition probability model for the missingness mechanism. A first-order Markov dependence structure is assumed for both the missingness mechanism and observed data. This process fits the natural data structure in the longitudinal framework. Our main interest is in estimating the parameters of the marginal model and evaluating the missing-at-random assumption in the Effects of Public Information Study, a cancer-related study recently conducted at the University of Pennsylvania. We also present a simulation study to assess the performance of the model. PMID- 22826029 TI - Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCbeta activation in diabetes. AB - To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A-dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho-c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)beta2 in endothelial cells (EC-PKCbeta2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCbeta isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho-c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC PKCbeta2Tg mice exhibited decreased GLP-1R expression and increased phospho-c Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCbeta2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4-protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCbeta activation and the increased degradation of GLP-1R in the glomerular endothelial cells. PMID- 22826031 TI - Variation in antibiotic prescriptions: is area deprivation an explanation? Analysis of 1.2 million children in Germany. AB - PURPOSE: Inadequate use of antibiotics can lead to problems such as resistance. Overuse is especially a problem for children, since they are more affected by acute (often virus-caused) infections. While the problem has been addressed internationally over the past several years, regional variations in prescriptions are striking. Therefore, the present study aims to analyze regional variations in antibiotic prescription on a district level in Germany and tries to identify reasons for those variations through adding possible influencing factors to the analysis on individual and district levels. METHODS: We analyzed 1.2 million children insured in a German health insurance fund. Antibiotic prescriptions were quantified in 2010 and reasons for prescriptions were analyzed in multilevel regressions based on the district of residence, regional deprivation, and age and sex of the child. RESULTS: Thirty-six percent of all children aged 0-17 years received an antibiotic prescription in 2010. In the south, prevalences are generally lower, and also to the very north. The highest prevalences are found in the close-to-border districts in the west, as well as in a band throughout the middle of Germany, in rather low population density areas. Regional variation in the prevalence range from 19 to 53 % between districts. Regional deprivation can explain part of this variation. CONCLUSIONS: Including area deprivation measures helped identify an influence of especially regional income and occupational deprivation on antibiotic prescriptions for children. Regional analysis such as this can help identify specific regions and groups of persons to address information programs on the risks of preventable antibiotic consumption and alternative treatment methods. PMID- 22826032 TI - Bioequivalence requirements in the European Union: critical discussion. AB - The aim of the present paper is to summarize the revised European Union (EU) Guideline on the Investigation of Bioequivalence and to discuss critically with respect to previous European requirements and present US Food and Drug Administration guidelines its more relevant novelties such as the following: in order to facilitate the development of generic medicinal products, the EU guideline includes the eligibility for Biopharmaceutics Classification System (BCS)-based biowaivers not only for BCS class I drugs but also for class III drugs with tighter requirements for dissolution and excipient composition. The permeability criterion of BCS classification has been substituted with human absorbability, as per the Biopharmaceutical Drug Disposition Classification System. The widening of the acceptance range for C (max) is possible only for highly variable reference products with an additional clinical justification. This scaled widening is carried out with a proportionality constant of 0.760 which is more conservative than the FDA approach and maintains the consumer risk at a 5% level when the intra-subject CV is close to 30%, due to the smooth transition between the scaled and the constant criteria. The guideline allows for the possibility of two-stage designs to obtain the necessary information on formulation differences and variability from interim analyses as a part of the pivotal bioequivalence study, instead of undertaking pilot studies. The guideline also specifies that the statistical analyses should be performed considering all factors as fixed, which has implications in the case of replicate designs. PMID- 22826033 TI - Guidelines for the quality control of population pharmacokinetic-pharmacodynamic analyses: an industry perspective. AB - Quality population modeling and simulation analyses and reports are something every modeler desires. However, little attention in the literature has been paid to what constitutes quality regarding population analyses. Very rarely do published manuscripts contain any statement about quality assurance of the modeling results contained therein. The purpose of this manuscript is to present guidelines for the quality assurance of population analyses, particularly with regards to the use of NONMEM from an industrial perspective. Quality guidelines are developed for the NONMEM installation itself, NONMEM data sets, control streams, output listings, output data files and resultant post-processing, reporting of results, and the review processes. These guidelines were developed to be thorough yet practical, though are not meant to be completely comprehensive. It is our desire to ensure that what is reported accurately reflects the collected data, the modeling process, and model outputs for a modeling project. PMID- 22826035 TI - Rationalizing structure and target relationships between current drugs. AB - A recent analysis of structure and target relationships between current drugs and bioactive compounds has revealed that only a small fraction of drugs that are active against the same or overlapping targets are involved in substructure relationships and/or share the same topology. By contrast, structurally related drugs displayed a tendency to preferentially act against different targets. For bioactive compounds, opposite trends were observed. These surprising findings arising from the global analysis have now been examined in detail by analyzing structure and target relationships between drugs at the level of individual targets and individual drugs and by comparing the results of local (target- or drug-based) and global relationship analysis. On the basis of target-based analysis, on average, only 14% of drugs active against a given target form well defined structural relationships. In addition, drug-based analysis revealed that on average 72% of all structurally related drugs have no or at most 20% target overlap. Taken together, the results of our current analysis at the level of single targets and drugs rationalize their unexpected structure and target relationships in a consistent manner. These findings also have implications for ligand binding characteristics of popular drug targets and for frequently observed polypharmacological drug behavior. PMID- 22826034 TI - Drug repurposing: far beyond new targets for old drugs. AB - Repurposing drugs requires finding novel therapeutic indications compared to the ones for which they were already approved. This is an increasingly utilized strategy for finding novel medicines, one that capitalizes on previous investments while derisking clinical activities. This approach is of interest primarily because we continue to face significant gaps in the drug-target interactions matrix and to accumulate safety and efficacy data during clinical studies. Collecting and making publicly available as much data as possible on the target profile of drugs offer opportunities for drug repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs. PMID- 22826036 TI - Protein-directed synthesis of NIR-emitting, tunable HgS quantum dots and their applications in metal-ion sensing. AB - The development of luminescent mercury sulfide quantum dots (HgS QDs) through the bio-mineralization process has remained unexplored. Herein, a simple, two-step route for the synthesis of HgS quantum dots in bovine serum albumin (BSA) is reported. The QDs are characterized by UV-vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, luminescence, Raman spectroscopy, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), circular dichroism (CD), energy dispersive X-ray analysis (EDX), and picosecond-resolved optical spectroscopy. Formation of various sizes of QDs is observed by modifying the conditions suitably. The QDs also show tunable luminescence over the 680-800 nm spectral regions, with a quantum yield of 4-5%. The as-prepared QDs can serve as selective sensor materials for Hg(II) and Cu(II), based on selective luminescence quenching. The quenching mechanism is found to be based on Dexter energy transfer and photoinduced electron transfer for Hg(II) and Cu(II), respectively. The simple synthesis route of protein-capped HgS QDs would provide additional impetus to explore applications for these materials. PMID- 22826037 TI - Brief communication: prenatal and early postnatal stress exposure influences long bone length in adult rat offspring. AB - Stress during the prenatal and early postnatal periods (perinatal stress, PS) is known to impact offspring cognitive, behavioral, and physical development, but effects on skeletal growth are not clear. Our objective was to analyze effects of variable, mild, daily PS exposure on adult offspring long bone length. Twelve pregnant rat dams were randomly assigned to receive variable stress from gestational days 14-21 (Prenatal group), postpartum days 2-9 (Postnatal), both periods (Pre-Post), or no stress (Control). Differences in adult offspring tibia and femur length were analyzed among treatment groups. Mean tibia length differed among groups for males (P = 0.016) and females (P = 0.009), and differences for femur length approached significance for males (P = 0.051). Long bone length was shorter among PS-exposed offspring, especially those exposed to postnatal stress (Postnatal and Pre-Post groups). Results persisted when controlling for nose-tail length. These differences might reflect early stunting that is maintained in adulthood, or delayed growth among PS-exposed offspring. This study suggests that PS results in shorter long bones in adulthood, independently of effects on overall body size. Stunting and growth retardation are major global health burdens. Our study adds to a growing body of evidence suggesting that PS is a risk factor for poor linear growth. PMID- 22826038 TI - Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice. AB - Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi-Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9-months-old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC. PMID- 22826039 TI - Zinc inhibits high glucose-induced apoptosis in peritoneal mesothelial cells. AB - Zinc (Zn) plays an important role in influencing many types of apoptosis. However, its function in apoptosis in peritoneal mesothelial cells (PMCs) remains unknown. Here, we studied the effects of Zn on high glucose (HG)-induced apoptosis in rat PMCs (RPMCs) and examined the underlying molecular mechanisms. We found that Zn supplementation inhibited HG-induced RPMC apoptosis significantly, by attenuating reactive oxygen species (ROS) production, inhibiting HG-induced sFasR and sFasL over-expression, caspase-8 and caspase-3 activation, and inhibiting release of cytochrome c from mitochondria to the cytosol. Further analysis revealed that Zn supplementation facilitated cell survival through activation of the phosphatidylinositol 3-kinase/Akt signaling pathway and MAPK/ERK pathways. These results indicate that Zn can inhibit apoptosis in HG-induced RPMCs by several independent mechanisms, including an indirect antioxidative effect and probably by inhibition of caspase-8 and caspase 3 activation. PMID- 22826040 TI - Pot-bellied pig neoplasia: a retrospective case series (2004-2011). AB - The current report summarizes the incidence and variety of neoplasms in pot bellied pigs as documented by the pathology group at the University of Tennessee, College of Veterinary Medicine (UTCVM) between 2004 and 2011. Sixty-three pot bellied pig cases (53 necropsies and 10 surgical biopsies) were identified from the UTCVM case database. Of these, 22 cases from 21 patients (34.9%) were given a diagnosis of neoplasia, including 10 females, 3 spayed females, 2 males, and 7 neutered males. The mean age of affected animals was 11.3 years. The incidence of neoplasia among the necropsy cases was 28% (15/53), and in the surgical biopsy material, the incidence was 70% (7/10). Reproductive and gastrointestinal tissues were most commonly affected, and malignancies were frequently identified, with hepatic and intestinal carcinomas predominating. Multiple neoplasms were often identified in patients submitted for necropsy, and in 4 out of 11 of the necropsy cases, at least 1 of the neoplasms was a malignancy. Six necropsy cases revealed metastatic spread. PMID- 22826041 TI - Host range of Canine minute virus in cell culture. AB - Canine minute virus (CnMV) is a member of the Bocavirus genus, together with Bovine parvovirus (BPV), which emerged as a new pathogen of dogs in 1967. The genus Bocavirus gained more recognition after the recent identification of Human bocavirus in pooled specimens from the respiratory tract of children. The cell culture host range of CnMV appears to be restricted to the Walter Reed canine cell (WRCC) line, although there is a report that indicates susceptibility of the Madin-Darby canine kidney (MDCK) cell line. In order to study the susceptibility of different cell lines to CnMV, the replication in cell cultures of canine, bovine, and human origin and the interaction of the virus with freshly isolated canine peripheral blood mononuclear cells were evaluated. The in vitro host range was unexpectedly wide. As shown by indirect fluorescent antibody and polymerase chain reaction assays, CnMV replicates efficiently in the A72 and MDCK canine cell lines. Bovine and human cell lines support the replication of CnMV less efficiently. In contrast, canine mononuclear blood cells are permissive to replication of CnMV in vitro. The present study revealed the ability of CnMV to replicate in continuous cell lines of different origin and, partially, in canine mononuclear cells. PMID- 22826042 TI - Characterization of extraintestinal pathogenic Escherichia coli isolated from captive wild felids with bacteremia. AB - Diseases caused by extraintestinal pathogenic Escherichia coli (ExPEC) in wild felids are rarely reported. Although urinary tract infections are infrequently reported in domestic cats, such infections when present are commonly caused by ExPEC. The present work characterized ExPEC strains isolated from 2 adult felines, a snow leopard (Panthera uncia) and a black leopard (Panthera pardus melas), that died from secondary bacteremia associated with urinary tract infections. Isolates from both animals were classified into the B2 phylogenetic group and expressed virulence genotypes that allowed them to cause severe disease. In addition, strains from the black leopard showed multidrug resistance. PMID- 22826043 TI - Assessment of airway hyperresponsiveness: comparison of spirometry and body plethysmography. AB - While methacholine (MCH) testing is commonly used in the clinical diagnosis of asthma, the detection of airway narrowing often relies on either spirometry or body plethysmography, however comparative studies are rare. In this study we performed MCH testing in 37 patients with variable shortness of breath at work and in 37 patients with no history of airway disease. The inclusion criteria were: no acute respiratory infection within 6 weeks, no severe diseases, normal baseline specific airway resistance (sR(aw)), normal baseline forced expiratory volume in 1 s (FEV(1)), Tiffeneau index >70%, no previous treatment with steroids within 14 days and no short acting bronchodilators within 24 h. Cumulative doses of 0.003, 0.014, 0.059, 0.239 and 0.959 mg MCH were inhaled by a dosimeter method. A FEV(1) decrease of >=20% from baseline and a 100% increase of sR(aw) to >=2.0 kPa/s was defined as end-of-test-criterion. Provocation doses were calculated by interpolation. Performance of lung function parameters was compared using receiver-operating-characteristic (ROC) analysis. ROC analysis resulted in an area under the ROC curve (AUC) of 0.74 for FEV(1) vs. 0.82 for sR(aw). The corresponding Youden Indices (J) were 0.46 for FEV(1) and 0.57 for sR(aw). The Youden Index of sR(aw) was higher and sensitivity and specificity (73%/84%) were rather well-balanced, in contrast to FEV(1) (54%/92%). In conclusion, in cumulative MCH challenges sR(aw) was found to be the overall most useful parameter for the detection of bronchial hyperresponsiveness. Body plethysmography yielded a balanced sensitivity-specificity ratio with higher sensitivity than spirometry, but comparable specificity. PMID- 22826044 TI - Hospital management of patients with exacerbation of severe chronic obstructive pulmonary disease. AB - The article assesses the originally developed criteria of clinical stability and treatment protocol in the hospital management and discharge procedures of patients with exacerbations of severe chronic obstructive pulmonary disease (COPD). The study included 34 patients (26 males, 8 females), aged 58-80 years, hospitalized due to exacerbation of severe (23 patients) and very severe (11 patients) COPD. On admission, the mean FEV1 was 0.78 +/- 0.22 L (31.7% +/- 8.2% of predicted), FVC 2.52 +/- 0.87 L (77.9% +/- 9.8% of predicted) and FEV1/FVC 33.17% +/- 10.84%. Before hospitalization, 10 out of the 34 patients were diagnosed with chronic respiratory failure. All patients were treated according the same treatment protocol which included the developed criteria of clinical stability. Meeting all these criteria in a 24-h observation period was the basis to slash the dose of systemic glucocorticosteroids by half. The maintenance of the stability criteria through the subsequent 24 h allowed discharging a patient from the hospital. Every patient was supplied with a detailed plan of out-of hospital treatment. The results show that the mean duration of hospitalization was 6.4 +/- 4.8 days. Only one patient required readmission within 4 weeks after discharge. Two patients died; one during the hospitalization time and the other after discharge. In the latter case, death was not directly related to the COPD exacerbation. In conclusion, the protocol of treatment and the criteria of stability used for patients with COPD exacerbation enabled to optimize the hospitalization time. A shortening of hospitalization was not associated with increased risk of readmission within 4 weeks after discharge. PMID- 22826045 TI - Pulmonary rehabilitation in patients referred for lung transplantation. AB - Effectiveness of pulmonary rehabilitation in patients with chronic obstructive lung diseases, cystic fibrosis, and interstitial lung disease is well documented but little is known about the results of pulmonary rehabilitation in patients referred for lung transplantation. The purpose of this study is to prospectively examine the efficacy of Nordic walking, a low cost, accessible, and proven beneficial form of physical exercise, as a form of pulmonary rehabilitation in patients referred for lung transplantation. Twenty-two male patients referred for lung transplantation at the Department of Lung Diseases and Tuberculosis in Zabrze, Poland, were invited to take part in the study. The rehabilitation program, which was conducted for 12 weeks, was based on Nordic walking exercise training with ski poles. Lung function tests (FVC, FEV1), mobility (6 min walking test (6MWT)), rating of dyspnea (Oxygen Cost Index, MRC and Baseline Dyspnea Index), and quality of life assessments (SF-36) were performed before and after the completion of the exercise program. No adverse events were observed after completing the pulmonary rehabilitation program in patients referred for lung transplantation. After 12 weeks of pulmonary rehabilitation with Nordic walking we observed a significant increase in the mean distance walked in the 6MWT (310.2 m vs. 372.1 m, p < 0.05). The results of lung function tests also showed improvement in FVC. There were no significant differences in the perception of dyspnea before and after completing the rehabilitation program. General health and quality of life questionnaire (SF-36) showed improvement in the domain of social functioning (p < 0.05). In conclusion, pulmonary rehabilitation with a Nordic walking program is a safe and feasible physical activity in end-stage lung disease patients referred for lung transplantation and results in improvements in patients' mobility and quality of life. PMID- 22826046 TI - Effects of nasal insufflation on arterial gas exchange and breathing pattern in patients with chronic obstructive pulmonary disease and hypercapnic respiratory failure. AB - High flow nasal insufflations (NI) can improve gas exchange and alleviate dyspnea in patients with acute respiratory failure. In the present study we investigated the effects of high flow nasal insufflations in COPD patients with chronic hypercapnic respiratory failure (HRF). Seventeen patients with severe COPD and HRF were recruited. We delivered a mixture of 20 L/min room air and 2 L/min O(2) through a nasal cannula either into both nostrils (NI) or into one nostril (Partial NI). Respiratory pattern and PaCO(2) responses under NI were compared with low flow oxygen of 2 L/min. High flow nasal insufflations led to a systematic reduction in respiratory rate from 19.8 +/- 4.2 at baseline to 18.0 +/ 4.7 during NI (p < 0.008) and 18.1 +/- 5.2 breaths/min during Partial NI (P < 0.03). The mean group inspiratory duty cycle (T(I)/T(T)) and mean group PaCO(2) remained constant between all experimental conditions. Individual responses to NI were heterogeneous: six patients demonstrated marked reductions in respiratory rate (>20% fall from baseline), another group (n = 6) demonstrated no change in respiratory rate but marked reductions in arterial carbon dioxide of more than 8 mmHg. In conclusion, high flow (20 L/min) nasal insufflations of warm and humidified air during wakefulness for 45 min reduced respiratory rate without deterioration of hypercapnia. Our data indicate that high flow NI improved efficiency of breathing and may be used as an adjunct to low flow oxygen for preventing hypercapnic respiratory failure in severely ill COPD patients. PMID- 22826047 TI - Exposure to traffic-related air pollutants as a risk of airway obstruction. AB - Dynamic increases in the number of vehicles, particularly in large urban areas, cause a visible decline in the average speed of cars. Street networks are not able to efficiently handle generated traffic, which could result in increasing levels of air pollutant emissions and consequently in a greater incidence of people suffering from respiratory diseases. This study presents the effects of investigations on the influence of traffic-related air pollutants on inhabitants of two Polish cities living in the proximity of busy roads. As a control group rural area residents were taken. In 2005-2006 and 2008-2009 respiratory function tests were conducted on a group of 3,506 people (including residents of non-urban areas). The investigation has shown that people living near busy urban roads had a significant increase in the risk of bronchi obstruction. PMID- 22826048 TI - Occupational immediate-type allergic asthma due to potassium tetrachloroplatinate in production of cytotoxic drugs. AB - Allergic immediate-type reactions by halogenated compounds of platinum (Pt) (platinum salts) have been described in workers in precious metal refineries and catalyst productions. In both industries there are exposures to many different Pt compounds. It is believed that the most important allergens are those compounds with the highest number of halide ligands. It is unknown whether sensitizations to compounds with a lower number of halide ligands represent co-sensitizations or are due to cross-reactivity. We report a worker engaged in the production of cytotoxic drugs with occupational asthma and exposure to only one Pt salt with four halide ligands. The 22-year-old worker developed work-related sneezing, runny nose, and variable dyspnea about a year after he had started to work in the cytotoxic drugs production with exposure to potassium tetrachloroplatinate(II) (K(2)PtCl(4)). He was immediately removed from his workplace and admitted for a medical opinion about 6 months afterwards. Spirometry was normal, but asthma was corroborated by a positive response to methacholine. The results of skin prick testing could not be interpreted due to urticaria factitia. Challenge with K(2)PtCl(4) by a dosimeter method yielded a clear immediate-type reaction with an increase of exhaled nitric oxide from 32 to 156 ppb after 24 h indicating an increased airway inflammation. Pt salts with four halide ligands like K(2)PtCl(4) may cause an allergic immediate-type reaction and occupational asthma. Workers in the production of Pt-containing cytotoxic drugs with exposure to these substances should be included in medical surveillance programs for the prevention of occupational asthma caused by Pt salts. PMID- 22826049 TI - Comparison of different non-invasive methods for detection of allergic asthma. AB - Non-invasive methods to assess inflammation of lower airways are induced sputum (IS), exhaled nitric oxide (eNO), and exhaled breath condensate (EBC). Here we focused on the assessment of airway inflammation with a panel of non-invasive methods in health care workers (HCWs) with suspected latex allergy with and without current allergic respiratory symptoms about 10 years after the latex ban in German health care facilities. Seventy-seven non-smoking subjects were examined by skin prick test and specific IgE measurements, eNO, IS, and EBC. Sensitivity, specificity, and positive and negative predicted values for relevant biomarkers were calculated using current asthma symptoms as the gold standard. Twenty-nine subjects (38%) reported ongoing asthmatic symptoms (AS). In these subjects the EBC concentrations of nitrogen oxides (NO(x); p=0.027) and leukotriene B(4) (p=0.025) were significantly higher than in subjects without AS. In addition, in the subjects with AS the numbers of eosinophils (p=0.015) and the concentrations of IL-5 (p= 0.021) in IS samples were significantly higher than in the subjects without AS. A good correlation between several inflammatory markers in IS was detected. The maximum Youden Index was reached for IS total eosinophils >=3.5.10(4) with a test efficiency of 0.72. In conclusion, non-invasive inflammatory monitoring with EBC and IS may assist the diagnosis of allergic asthma. Self-reported current asthmatic symptoms were reflected by eosinophilic inflammation and the best parameter to support the asthma diagnosis is a total number of eosinophils >=3.5.10(4) in IS. PMID- 22826050 TI - Deep nasal inspirations increase the cough threshold in children with mild asthma. AB - Asthma is a chronic inflammatory disease characterized by bronchospasms accompanied with frequent coughing, the pathogenesis of which is not clear. In healthy adults deep inspirations (DIs) provide a protective effect against bronchoconstriction triggered by methacholine inhalation, which correlates with the number of accompanying cough efforts. The aim was to study the effect of deep nasal inspirations representing the voluntary equivalent of the sniff-like aspiration reflex on the capsaicin-induced cough in children with mild asthma. The cough reflex sensitivity to capsaicin was determined using a compressed air driven nebulizer in 21 children (8 girls and 13 boys of median age 13.3 year) suffering from mild asthma (FEV(1)~80%). The effect of five previous DIs through the nose was examined on the elicitability of two and five or more cough efforts (C2, C5). Under control conditions, the concentration of 20.86 (14.58-29.8) MUmol/l of capsaicin provoked two cough efforts (C2). After five DIs similar reaction required significantly higher concentrations of capsaicin: 29.02 (18.88 44.6) MUmol/l; P=0.016. Five or more cough efforts (C5) were not significantly changed after previous DIs 161.49 (77.31-337.33) MUmol/l and without DIs 141.52 (68.77-291); P=0.54. A series of five deep inspirations decreases the cough reflex sensitivity to evoke two efforts (C2) in children with mild asthma. The inhibitory effect of similar DIs disappeared after repeated applications of increasing doses of capsaicin, aiming to evoke five or more cough efforts, suggesting a reflex character of protective effect of DIs. PMID- 22826051 TI - Reproducibility of sensitivity to capsaicin assessed by single breath inhalation methodology. AB - The hallmark of sensory hyperreactivity is an enhanced capsaicin induced cough reflex. The cough reflex can be modified by activation of nociceptive (capsaicin sensitive) nerve terminals. The aim of our study was to assess the influence of exposure to CO(2) concentrations up to 2.0 vol% on capsaicin induced cough reflex on four different occasions. Sixteen healthy volunteers were exposed to CO(2) concentrations of 0.5, 1.0, and 2.0 vol% for 4 h and to clean air in a repeated measures cross-over design. After exposure the capsaicin induced cough reflex was assessed by the single breath dose-response method according to ERS 2007 guidelines. After blank solutions, capsaicin doses (n=12, range 0.49 to 1000 MUM) were administrated from a nebulizer combined with a provocation system (Masterscope, software APS version 5.02). Doses were doubled every minute and the concentration causing five or more coughs (C5) was fixed as the end point. The inter-individual C5 capsaicin responsiveness reflected a representative range (0.95-1000 MUM). On an intra-individual basis, a good reproducibility could be demonstrated for four tests within 3 weeks. There was no influence of CO(2) challenge on the cough reflex. The first capsaicin test demonstrated a lower C5 threshold independent of the CO(2) concentration applied. In conclusion, assessing the capsaicin cough reflex by single breath inhalation is reliable. However, the at cough sensitivity might be overestimated at the first test occasion. Exposure to CO(2) in concentrations of up to 2.0 vol% has no effect on sensory reactivity. PMID- 22826052 TI - Occupational non-immediate type allergic asthma due to ammonium persulfate. AB - While numerous cases of immediate-type occupational asthma due to persulfates with positive skin prick test reactions to ammonium persulfate are well documented, few non-immediate type reactions have been described in the literature. We report the case of an atopic worker who developed work-related asthmatic symptoms shortly after he began his job in persulfate production. The diagnosis of asthma was corroborated by methacholine testing. The patient showed a positive patch test reaction to ammonium persulfate, while skin prick test was negative. He presented an isolated late symptomatic airway obstruction after a cumulative dose of 0.6 mg ammonium persulfate administered by a dosimeter method. An immunologic mechanism was demonstrated by a significant increase in exhaled nitric oxide and the number of eosinophils in induced sputum. These findings suggest that isolated late bronchial reactions to persulfates are mediated by eosinophilic inflammatory responses. PMID- 22826053 TI - Bronchial allergen challenges: doubling or quadrupling dose steps? AB - Inhalation challenges with allergens are considered the gold standard for the diagnosis of occupational asthma. However, no standardized methods are available. One open question is the degree of dose augmentation in the stepwise challenge protocols. Recently, it was recommended to increase the allergen concentrations by no more than doubling between dosing steps for safety reasons. We analyzed retrospectively our dosimeter allergen challenges performed with quadrupling dose steps during the last 10 years. Allergens were inhaled by an APSpro dosimeter and a DeVilbiss 646 nebulizer. The test was terminated after a fall of FEV(1) of at least 20%. Seventeen tests in 13 subjects were considered positive. The mean FEV(1) decreases 10 and 20-30 min after the last allergen dose were 26.7 +/- 6.4 and 26.2 +/- 6.5%baseline, respectively. Terminal dose response slopes did not differ between doubling (Cockcroft and Davis, J Allergy Clin Immunol, 122:1034 1035, 2008) and quadrupling doses, nor were there any differences concerning the maximal responses. The results suggest that quadrupling dose steps may be an acceptable alternative, without serious increase in risk of severe asthmatic reactions. We assume that by shortening the test duration, physicians might choose lower starting doses and thus make allergen inhalation challenges safer. PMID- 22826054 TI - Evaluation of laryngopharyngeal reflux in pediatric patients with asthma using a new technique of pharyngeal pH-monitoring. AB - There is a debate about the association between asthma and gastroesophageal and/or laryngopharyngeal reflux (LPR). Pharyngeal pH-monitoring is a new technique that allows a physician to assess whether reflux passes the upper esophageal sphincter barrier. The aim of the study was to assess the prevalence of LPR in children with difficult-to-treat asthma. The present study was an open, prospective one. A total of 21 subjects of the mean age 12.7 years were enrolled in the study. All children were asked to fill out a Reflux Symptoms Index questionnaire and a 24-h pharyngeal pH monitoring was performed, using the Dx-pH Measurement System. The LPR was diagnosed in 13 (61.9%) children. There was a positive correlation between LPR diagnosis and the degree of asthma control. The LPR was more frequent in children treated with a higher than lower doses of fluticasone (p = 0.019, OR = 17.3) and in those using montelukast compared with non-users (p = 0.008, OR = 19.0). The mean Reflux Symptoms Index score was almost twice greater in children with LPR than in those without it (13.2 vs. 6.8, respectively, p = 0.003). We conclude that the prevalence of laryngopharyngeal reflux in children with difficult-to-treat asthma is substantial. PMID- 22826055 TI - Latent airway hyperresponsiveness: a phenomenon bordering bronchial asthma definition. AB - The basic features of bronchial asthma are dyspnea with wheezing and objectively confirmed obstructive respiratory disorder reversible after inhalation of bronchodilators. In stable intermittent bronchial asthma, these features are not present; therefore confirmation of asthma consists of the presence of bronchial hyperresponsiveness (BHR). In the present study, there were 902 bronchoprovocation tests performed for the verification of BHR. A significant criterium for BHR is a decrease of FEV(1) of 20% from the baseline level. Every test either positive or negative was finished with inhalation of four doses of salbutamol through a spacer. We obtained 675 bronchoprovocation tests negative and 227 positive. Among the 675 subjects with a negative test there were 49 subjects who after inhalation of salbutamol had an increase in FEV(1) of >=20% above baseline. The bronchodilatatory response of these 49 subjects, makes one think about the so-called latent bronchospasm present already at baseline, limiting further constriction during bronchoprovocation tests. The detection of such latent bronchospasm in BHR increases the number of patients with an objectively confirmed bronchial asthma from 25.0% to 30.5%. Our results suggest that bronchodilation test be performed in all patients with suspected bronchial asthma to allow detecting latent bronchospasm as an initial stage of the disease. PMID- 22826056 TI - Impact of daytime sleepiness on rehabilitation outcome in the elderly. AB - Daytime sleepiness (DS) is associated with poor health, impaired physical functioning, as well as somatic and psychiatric morbidity. The impact of DS on functional outcome in the elderly is unknown. We investigated whether observed daytime sleepiness in geriatric patients with moderate to severe functional impairment was associated with functional clinical outcomes. We addressed the issue by determining the impact of observed daytime sleepiness, by means of the Essener Questionnaire of Age and Sleepiness (EQAS), on improvement in functional status - measured by the Barthel ADL Index - among disabled geriatric in patients. We included 129 patients, 28 (22%) were male and 101 (78%) were female. Sleepiness according to EQAS scale was absent in 27 (21%) patients, mild in 71 (55%) patients and moderate to severe in 31 (24%) patients. The three patient groups did not differ in the Barthel ADL Index (BI) on admission or co-morbid conditions. Geriatric treatment was comparable across groups. Improvement in the BI of at least 1 standard deviation (SD) occurred in 23/27 (85%) of subjects without sleepiness, in 53/71 (75%) of subjects with mild to moderate sleepiness and in 15/31 (44%) of subject with severe sleepiness (p < 0.01). BI increased at least 2 SD in 20/27 (74%), 38/71 (54%) and 11/31 (35%) individuals, respectively (p < 0.02). We conclude that the daytime sleepiness predicts a poorer functional recovery rate in older patients during geriatric in-hospital rehabilitation. Furthermore, we found a significant association and a dose response relationship between severity of daytime sleepiness and improvement in Barthel ADL Index. PMID- 22826057 TI - Pulmonary physiotherapy in patients with bronchial asthma. AB - In the present study we investigated the effectiveness of a 3-month breathing exercise program in patients with mild-to-moderate asthma, as assessed from spirometric indices. The study group consisted of 28 asthma patients (mean age of 43 years). The physiotherapy program consisted of 45-min exercise sessions, performed twice a week for 3 months. We measured the flow-volume indices (FEV(1), FVC, PEF, MEF(50)) before and after the exercise sessions at the beginning and end of the physiotherapy program. In addition, the patients measured their personal best peak expiratory flow (PEF). We found no significant changes in spirometric indices before and after an exercise session either at the beginning or end of the physiotherapy program, although there was a tendency for lower values after the exercise sessions at both beginning and end of the physiotherapy program. There was a significant decrease in PEF after an exercise session at the beginning of the physiotherapy program; this decrease lost significance after completion of the physiotherapy program. However, PEF values were greater both before and after the exercise sessions at the end of the physiotherapy program compared with the corresponding sessions before the program. We conclude that the breathing exercise program employed in the study failed to appreciably improve lung function in asthmatic patients. However, there was no asthma exacerbations observed during the conduction of breathing exercise program, which underscores the need for pulmonary rehabilitation in asthma treatment. PMID- 22826058 TI - Hypoxemia during bilevel positive airway pressure treatment in patients with obstructive sleep apnea syndrome and chronic respiratory insufficiency. AB - In patients with obstructive sleep apnea (OSA) syndrome and chronic respiratory insufficiency one of the options of treatment is bilevel positive airway pressure (BPAP) during sleep. The aim of the study was to find out what are the factors influencing the early results of BPAP treatment in such OSA patients. The study was carried out in 55 adult obese patients (mean body mass index 45 +/- 7 kg/m(2)), severe OSA syndrome (mean apnea/hypopnea index 62 +/- 19), and chronic respiratory insufficiency (mean PaCO(2) 54 +/- 5.7 torr) who underwent polysomnography during BPAP treatment. In 31 patients (56%) the mean SaO(2) during sleep was <88% despite the optimal BPAP and oxygen titration: 83 +/- 4% during NREM and 81 +/- 7% during REM sleep vs. 91 +/- 2% and 90 +/- 3%, respectively, in the remaining 24 patients (p < 0.001). The patients with advanced hypoxemia during sleep and BPAP treatment had lower forced vital capacity (2.2 +/- 0.9 vs. 2.7 +/- 0.8 l, p < 0.05), lower diurnal PaO(2) (49 +/- 8 vs. 54 +/- 7 torr), higher diurnal PaCO(2) (57 +/- 5 vs. 52 +/- 5 torr, p < 0.01), and higher PaCO(2) during sleep (75 +/- 13 vs. 59.5 +/- 7.5 torr). In conclusion, in obese patients with severe OSA syndrome and chronic alveolar hypoventilation there is a risk of sleep hypoxemia during BPAP treatment, despite optimal pressure titration. PMID- 22826059 TI - Validation of the Essener Questionnaire of Age and Sleepiness in the elderly using pupillometry. AB - In the elderly population, daytime sleepiness (DS) is a burden that affects quality of life, cognitive and physical functioning as well as health status and morbidity. The measurement of DS in older subjects continues to be a challenge, as there are only few elderly-specific assessment tools available. Therefore, we compared the newly developed Essener Questionnaire of Age and Sleepiness (EQAS) with pupillography, a physiological measure of sleepiness. The aim was to identify EQAS cut-off values for increased daytime sleepiness. For the validation study, we determined EQAS scores and the pupillary unrest index (PUI) of the pupillographic sleepiness test (PST) in 88 geriatric in-patients. We also collected data on age, gender, co-morbidities, and geriatric assessment in these subjects. Of all included patients 37 (42%) completed the PST. Fourteen (16%) subjects refused to participate and 37 (42%) subjects could not complete 11 min required for a valid PUI. Subjects with complete and incomplete pupillometry did not differ in basic assessment parameters of health status or cognitive functioning. EQAS scores correlated significantly with PUI values (r = 0.70; p < 0.001) demonstrating a dose-response relationship. Based on ROC analysis, an EQAS score above 3 was optimal to distinguished sleepy from non-sleepy participants with sensitivity of 67%, specificity of 93% and positive and negative predictive values of 75% and 90%, respectively. In conclusion, the high negative and positive predictive values of the EQAS indicate that this instrument is a useful and valid assessment tool for daytime sleepiness in the elderly. The easy administration of this observational instrument favors its adoption in geriatric medicine. PMID- 22826060 TI - Lung function at age 18-25 years: a comparison of different reference value systems. AB - The anthropometrical data of the Caucasian population have significantly changed within the last five decades. The European Community for Coal and Steel (ECCS) assumes a plateau phase and recommends the entry of 25 years old for calculation of reference values in this age range. The question arises if the commonly used reference recommendations for lung function of the ECCS can still be accepted. In the present study standardized spirometric lung function tests were performed by pneumotachography, recording lung volumes and flows (MasterScreen Pneumo, CareFusion, Hochberg) in asymptomatic nonsmoking subjects (202 females, 201 males), aged between 18 and 26, according to the ATS/ERS criteria. The results were compared with the reference recommendations of ECCS, SAPALDIA, LuftiBus, and Bochum (only males). All absolute lung function values showed a correlation (p< 0.05) with height. With respect to FVC and FEV(1), SAPALDIA and Bochum reference values were comparable and close to a 100 (range 97.6-101.4) %pred, whereas both ECCS and LuftiBus showed higher values (range 103.6-109.9%pred). The FEV(1)/FVC ratio was close to a 100 (range 97.6-101.7) %pred in all reference systems, whereas flows showed a wide variability between the reference systems (77.1 114.6%pred), single flows (e.g., 96.9-114.2%pred for MEF(50)) and males/females (males: 93.6-114.6%pred; females: 77.1-107.9%pred). We conclude that SAPALDIA reference values for FVC and FEV(1) should be used, as they better represent lung function in the age group. ECCS and LuftiBus reference values are appreciably (4 10%) lower. Differences between reference systems were less important for the FEV(1)/FVC ratio and lung flows. PMID- 22826061 TI - Pulmonary function impairment in patients undergoing allogeneic hematopoietic cell transplantation. AB - Deterioration of pulmonary function can be the sole symptom of early stages of pulmonary complications following allogeneic hematopoietic cells transplantation (alloHCT). The aim of the study was to evaluate the prevalence and types of pulmonary function abnormalities in allogenic cells recipients. Twenty three (5 children and 18 adults) allogeneic hematopoietic cells recipients who underwent pulmonary function assessment before and 6-12 months after alloHCT were included in the study. Forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), total lung capacity (TLC), and lung diffusion capacity for carbon dioxide (D(L)CO) were determined. Values <80% of predicted were considered abnormal. We found significant reductions of FVC, D(L)CO, and TLC after alloHCT. The most important reduction was noted in D(L)CO (pre-alloHCT of 85%+/-15% vs. post- alloHCT of 60% +/- 21%, p< 0.05). Six patients (26%) presented with lung function impairment before alloHCT: obstructive lung disease (4%), restrictive lung disease (13%), and decreased D(L)CO (17%). In 19 patients (83%) pulmonary function abnormalities were demonstrated after alloHCT. The most common disturbance was a D(L)CO decrease that occurred in 16 patients (70%). In conclusion, frequency of pulmonary function abnormalities in patients after alloHCT is high. A diffusion capacity decrease and restrictive pattern of ventilation insufficiency develop in the majority of patients after alloHCT. It would be reasonable to include pulmonary function testing to standard periodic examination in patients qualified for, and after, alloHCT procedure. PMID- 22826062 TI - Lung impairment in scleroderma. AB - Scleroderma typically manifests as fibrosis of the skin, but may also involve other organs, particularly the lungs. Interstitial lung disease and functional abnormalities are observed in the majority of patients. The aim of this study was to evaluate radiological changes in the lungs and their correlation with functional disorders in scleroderma patients. The study was conducted in 37 scleroderma patients (F/M-31/6). High resolution computed tomography (HRCT), Warrick score system and spirometry, body plethysmography, and lung diffusion examinations (DLco) were performed. The HRCT showed septal and subpleural lines in 70%, ground-glass opacities in 51%, and honeycomb lungs in 30% of the cases. The DLco values were decreased in 92% of the patients. Total lung capacity (TLC) showed a restrictive pattern in 24% of the patients, and only in 11% of them obstruction predominated. The Warrick score correlated inversely with both DLco (r=0.36; p>0.05). Interstitial lung disease often coexists with scleroderma and is accompanied by functional lung abnormalities. PMID- 22826063 TI - Severity of nocturnal cardiac arrhythmias correlates with intensity of sleep apnea in men. AB - Various cardiac arrhythmias frequently occur in patients with sleep apnea, but complex analysis of the relationship between their severity and the probable arrhythmogenic risk factors is conflicting. The question is what cardiovascular risk factors and how strongly they are associated with the severity of cardiac arrhythmias in sleep apnea. Adult males (33 with and 16 without sleep apnea), matched for cardiovascular co-morbidity were studied by polysomnography with simultaneous ECG monitoring. Arrhythmia severity was evaluated for each subject by a special 7-degree scoring system. Laboratory, clinical, echocardiographic, carotid ultrasonographic, ambulatory blood pressure, and baroreflex sensitivity values were also assessed. Moderate sleep apnea patients had benign, but more exaggerated cardiac arrhythmias than control subjects (2.53 +/- 2.49 vs. 1.13 +/- 1.64 degrees of cumulative severity, p < 0.05). We confirmed strong correlations between the arrhythmia severity and known arrhythmogenic risk factors (left ventricular ejection fraction and dimensions, right ventricular diameter, baroreflex sensitivity, carotid intima-media thickness, age, previous myocardial infarction, and also apnea-hypopnea index). In multivariate modelling only the apnea-hypopnea index indicating the sleep apnea intensity remained highly significantly correlated with the cumulative arrhythmia severity (beta = 0.548, p < 0.005). In conclusion, sleep apnea modifying cardiovascular risk factors and structures or functions provoked various nocturnal arrhythmias. The proposed scoring system allowed a complex analysis of the contribution of various triggers to arrhythmogenesis and confirmed the apnea-hypopnea index as an independent risk for nocturnal cardiac arrhythmia severity in sleep apnea. PMID- 22826065 TI - Costs of smoking-attributable productivity losses in Poland. AB - In Poland smoking poses a severe socioeconomic problem. Not only does tobacco consumption cause an increase in direct medical costs due to the necessity for treatment of smoking-attributable diseases, but it also generates indirect costs due to productivity losses. The aim of this paper was to estimate the annual productivity loss due to smoking in Poland from the societal perspective and to compare the obtained results with the equivalent research in other selected countries (Germany, Sweden, and USA). The assessment was performed by the use of the human capital approach, considering loss of productivity until achieving the retirement age and gross income. Four distinct components of indirect costs of nicotine consumption were included: costs of premature mortality, costs of acquired disability, as well as costs of absenteeism and presenteeism caused by smokers. The costs of smoking-attributable productivity loss within a year amount to more than 15 billion PLN (1 Euro approx. 4 PLN) which is about 402 PLN per capita and 1418 PLN per smoker. This represents about 2.6% of Polish annual Gross Domestic Product (GDP), which is more than in Germany, Sweden, or the USA. This amount clearly shows the enormous socioeconomic burden and suggests the need for taking measures to reduce it. PMID- 22826064 TI - beta2-adrenergic receptor gene polymorphism and response to bronchodilating treatment evaluated by spirometry. AB - beta2-adrenergic receptors re abundantly expressed in airways, which explains the role of beta2 agonists, the strongest bronchodilators, in treatment of bronchial constriction. There may be a relation between beta2ADR gene polymorphism and the response to treatment with beta2 agonists. In the present study we attempted to study these relationship in vivo, estimating spirometric values before and after the use of salbutamol in reference to variant of beta2ADR gene polymorphisms. The study involved 148 healthy male volunteers. After the examination of the gene polymorphism of the beta2-adrenergic receptor (beta2-ADR) at nucleotide positions 46 and 79 (g.46 and g.79) we performed spirometry testing in all subjects. The pulmonary function was checked twice a day; before and 15 min after the administration of salbutamol. All subjects had normal basic values of spirometry. The use of salbutamol significantly increased spirometric values in all groups determined by beta2ADR gene polymorphisms. Analysis of the spirometric values in individual groups showed a significant increase only in peak expiratory flow (g.46AA and g.79CC). The results of this study give an insight into a possibly important mechanism of the response to treatment with beta2-agonists. PMID- 22826066 TI - Cigarette smoking among students and the influence of legal regulations on passive smoking. AB - Research suggests that reducing the degree of nicotine addiction in the population cannot be achieved only by prevention programs. Legislative measures are necessary to be taken by the state. The aim of this study was to assess the degree of tobacco abuse in three groups of students. It also assesses the influence of ban on smoking in public places on passive contact of students with tobacco. A customized survey made up of open and closed questions was conducted among 102 students of electrical faculty, 109 medical students, and 71 students of animal husbandry faculty. The results showed that significantly more women from the electrical faculty smoked. Among the students of animal husbandry, men smoke significantly more cigarettes than women. Women studying animal husbandry start smoking significantly earlier (by about 2 years) than women from other faculties. They are also significantly less likely to smoke cigarettes at school and at home. According to the study, the Polish law to ban smoking in public places, in force since the 15th of November 2010, did not make students quit smoking, although the rate of smoking students decreased. Students did not observe restrictions on smoking in their environment. The study indicates a positive influence of the anti-nicotine legislation on passive smoking, just after 3 months from its introduction. PMID- 22826067 TI - Medical students' aptitude toward smoking in Warsaw, Strasbourg and Teheran. AB - Cigarette smoking is a leading cause of preventable death in the world. Medical students play a role in smoking prevention especially as future physicians, but also as role models in society. Their approach, although influenced by medical education, is based on cultural and socio-economic background. The aim of this study was to analyze smoking habits, prevalence and attitudes towards smoking cessation in medical students from three different countries: Poland, France and Iran. A questionnaire on tobacco smoking was distributed among medical students from three Medical Universities: in Warsaw, Strasbourg and Teheran. The study population consisted of 1,036 students: 499 from Poland, 367 from France and 170 from Iran. The percentage of smokers among medical students was 14% in Warsaw, 14.4% in Strasbourg and 3.5% in Teheran. The prevalence of ex-smokers was 13.6%, 18%, and 1.2% respectively. The use of nicotine replacement therapy or pharmacological aid in smoking cessation was 9% in Warsaw, 7% in Strasbourg, and none in Teheran. In Strasbourg students willing to choose surgical specialization were more likely to be smoking with OR 2.6 (95% CI 1.4-5.0). Never-smokers were more likely than actual smokers to discourage their friends and family from smoking. In Warsaw OR was 3.8 (95% CI 2.0-7.2), in Strasbourg 6.2 (2.6-14.4) and 7.2 (1.0-82.6) in Teheran. In conclusion, similarities in smoking prevalence and attitudes between medical students in Warsaw and Strasbourg were observed, while in Teheran the percentage of smokers reported was much lower. Pharmacological aid or nicotine replacement therapy in smoking cessation was rarely used among medical students. PMID- 22826068 TI - Epidemiology of pertussis in an urban region of Poland: time for a booster for adolescents and adults. AB - Since the last decades, an increase of reported incidence of pertussis has been observed in many countries, including Poland, despite high vaccination coverage among infants and children. Before the vaccinations era, pertussis was a major cause of morbidity and mortality among infants and young children. Currently, pertussis is increasingly reported in adolescents and adults. The objective of this paper was to present the epidemiology of pertussis in Mazovian region in Poland in years 2005-2009. In this report we analyzed retrospectively the epidemiological data collected by the Sanitary Station in Warsaw, Poland. A total of 1,455 cases of pertussis were reported in the Mazovian region of Poland in the years 2005-2009. The incidence of pertussis ranged from 2.4/100,000 (2006) to 7.9/100,000 (2008). The incidence was the highest in two groups: infants (>1 year of age; from 13.3/100,000 in 2005 to 32.7/100,000 in 2007) and teenagers (age of 10-14 years; from 11.8/100,000 in 2006 to 68.5/100,000 in 2008). The highest proportion of cases was also reported in the 10-14 years age-group (from 26.4% in 2009 to 46.0% in 2008). The number of hospitalizations due to pertussis ranged from 137 (2005) to 46 (2006), while the percentage of cases requiring hospitalization ranged from 37% (2005) to 25% (2007 and 2008). Three hundred ninety two (27%) cases of pertussis were reported among patients with negative or not confirmed history of pertussis vaccination. We conclude that there is an urgent need for booster vaccination against pertussis in adolescents and adults in Poland. PMID- 22826069 TI - Rhinitis as a cause of respiratory disorders during pregnancy. AB - Rhinitis is a common disease of women during pregnancy. It can start in almost any gestational week and disappears after delivery. The main symptoms are sneezing, nasal congestion or running nose. The diagnosis is usually based on history, physical examination, blood tests, and exclusion of the other more common types of rhinitis. The etiology remains to be clarified. The rhinitis may be caused by numerous substances and hormones secreted during pregnancy (PGH, VIP, estrogen, progesterone). They lead to changes in the nasal mucosa in the form of increased activity of serous-mucous glands and increase of their vasculature. The best treatment is using saline irrigations, exercise, and mechanical alar dilators. The nasal decongestants provide only temporary relief. The aim of this study was to evaluate the prevalence of pregnancy rhinitis. The study was conducted on 117 pregnant women in the province of the West Pomerania in 2009-2010. The information was obtained from interviews, questionnaires, and data contained in pregnancy records. About 39% of pregnant women suffered from pregnancy rhinitis. Most such ailments were found during 13th and 21st week of gestation. Doctors should pay more attention to symptoms which result from pregnancy rhinitis, which are reported by their patients. The quality of prenatal care understood as an education of pregnant women as far as pregnancy rhinitis is concerned, is much insufficient. Pregnancy rhinitis significantly affects quality of life of pregnant women and, as a result, it may affect fetal development. PMID- 22826070 TI - Subglottic and tracheal stenosis due to Wegener's granulomatosis. AB - Wegener's granulomatosis (WG) is characterized histologically by necrotizing granulomatous angitis that most commonly involves the upper, lower respiratory tract and kidneys, but may affect any organ system. Otolaryngological manifestations are frequent and diverse but subglottic stenosis and tracheal stenosis are less common. The aim of the study was to assess the clinical features and the response to treatment in WG patients with subglottic or tracheal stenosis. The disease activity at the time of examination was scored in 55 patients with WG (29 females, 26 males) according to clinical, serological, radiological and bronchoscopic findings: subglottic and tracheal stenosis were observed in 9% and 5% of WG patients, respectively. CT scans of the larynx and trachea showed mucosal thickening extended 3-4 cm below the vocal cords in three and the thyroid cartilage in one patient. The degree of narrowing of the axial luminal diameter ranged 50-90%. Mechanical dilation of the stenosis and long acting local corticosteroids may be of therapeutic benefit, along with conventional immunosuppressive treatment. PMID- 22826071 TI - Pulmonary aspergillosis: therapeutic management and prognostic factors from 16 years of monocenter experience. AB - Twenty three patients of the University Hospital Bonn were reviewed following surgical procedures for pulmonary aspergilloma, including the choice of antifungal therapy, diagnostic findings, decision-making in treatment, and treatment outcomes of the past 16 years. We used pathological records to identify aspergilloma patients. A review of patients' records and follow-up phone calls to patients, families, or general practitioners were done. Data collected from 1995 to 2011 included patients with aspergilloma (n = 15), multiple aspergillomas (n = 2) and chronic necrotizing pulmonary aspergillosis (n = 6). Classification and diagnosis were based on pathological records. The decision to use systemic antimycotic therapy was based on perioperative findings suspecting parenchymal involvement of the fungal infection. Seventeen patients received systemic antimycotic chemotherapy. Compared with the use of Amphotericin B, newer drugs such as voriconazol, caspofungin, or posaconazol showed no better result in the morbidity and mortality of the patients. Postoperative complications requiring extended therapy and/or prolonged ICU stay (>48 h) were seen in 12 (52.2%) patients. During follow-up there were ten deaths; one death (4.4%) from aspergillus-associated sepsis, nine deaths from patients' underlying diseases (n = 4 within <3 months, n = 6 within >3 months of follow-up). In conclusion, in our cohort, immunocompromised patients with no documented preexisting lung-cavities were most likely to develop pulmonary aspergilloma. Postoperative morbidity (52.2%) was high, but related mainly to patient co-morbidity; postoperative mortality was reasonably low. Patients showing classical symptoms or immunocompromised patients should be considered for surgery. Encapsulated Aspergilloma without invasion of surrounding parenchyma requires no antifungal chemotherapy. PMID- 22826072 TI - Influence of rapid influenza test on clinical management of children younger than five with febrile respiratory tract infections. AB - Children are an important vector for spreading influenza and they are at increased risk for complications. The appropriate diagnosis of influenza may help start early antiviral treatment and may optimize the use of antibiotics and additional laboratory tests. The objective of this study was to describe the influence of rapid influenza detection test (RIDT) on clinical management of children with acute febrile respiratory tract infections. The method consisted of a prospective, open, cohort study conducted in three primary care clinics in Warsaw, Poland, during the epidemic influenza seasons of 2009/2010 and 2010/2011. A total number of 256 children of the age 0-5 years with symptoms of febrile respiratory tract infection were enrolled into the study. A 115 of them were tested with RIDT (BD Directigen EZ FluA + B) and another 141 children, who were not tested, constituted a control group. We found that RIDT gave positive results in 35 (30%) out of the 115 tested children. Antibiotics, additional blood tests and urinalysis were administered more often in the control group compared with the rapid test group (16% vs. 7%; 14% vs. 5%, and 47% vs. 32%, respectively). Chest radiograms were made only in six cases of children from the control group. We conclude that in children with symptoms of acute febrile respiratory tract infection, the rapid influenza detection test provides a rational use of antivirals, reduces an inappropriate use of antibiotics, and decreases a number of additional tests conducted. PMID- 22826073 TI - Influenza immunization rates in children and teenagers in Polish cities: conclusions from the 2009/2010 season. AB - The aim of this study was to determine influenza vaccine coverage among children aged 0-18 years in inner city practices in Poland in the 2009/2010 season and factors that might have influenced low vaccination coverage. A retrospective review of 11,735 vaccination charts of children aged 0-18 from seven randomly selected general practices in the capital city of Warsaw and one large practice in the city of Wroclaw was performed. We calculated the numbers of children who were vaccinated in the 2009/2010 season and analyzed the age distribution of vaccinated children. We also reviewed the vaccination history in patients who were vaccinated against influenza including: previous influenza vaccinations, modification (widening) of standard immunization scheme, and a proportion of children who completed the recommended two-dose schedule of vaccination. In the calculations, 95% confidence intervals were used. Out of the total of 11,735 children surveyed, 362 (3.1%, CI: 2.8-3.4%) were vaccinated against influenza in the 2009/2010 season. For 115 of these 362 (31.8%, CI: 27.0-36.6%) children it was their first vaccination against influenza. The mean age of a vaccinated child was 6.0 +/- 4.3 years. Children aged 2-5 were most commonly vaccinated (153/362, 42.3%, CI: 37.2-47.4%), while infants (aged 6-12 months) were vaccinated rarely (15/362, 4.4%, CI: 2.2-6.2%). In the group of children younger than 8 years (86/362 children) who were vaccinated for the first time in their life only 29/86 (33.7%, CI: 23.7-43.7%) completed the recommended two-dose schedule. In conclusion, the importance of vaccinating children against influenza is hugely understated in Poland. General physicians should actively recommend annual influenza immunization of children. Recommendations of National Immunization Program concerning influenza vaccine should be clearer, simpler, and easier to implement. PMID- 22826074 TI - Pharmacotherapy for sarcoidosis: an example of an off-label procedure. AB - Sarcoidosis is a granulomatous multiorgan diseases with an unknown etiology, with the predominant lung involvement. Immunosuppressive agents such as corticosteroids, methotrexate, azathioprinum, ciclosporinum A, chlorambucil, cyclophosphamide, hydroxychlorochinum, indomethacin, pentoxyfillinum, thalidomide, leflunomidum, and adalimumab, or infliximab have been used in its treatment. It should be emphasized that the Summary of Products Characteristics (SPC) of these drugs does not specifically recommend their use in the therapy for sarcoidosis. That makes the application of the drugs in sarcoidosis an off-label use, which is not formally accepted by the authorities but is supported by medical bibliography or recommendations given by scientific bodies. Thus the off label drugs raise legal, but also ethical and medical problems. The dosing regimen and the required duration of therapy for sarcoidosis are missing. In effect the therapy usually follows the recommendations from the American and European Respiratory Societies (ATS/ERS), based on the long-term medical research. The American Food and Drug Administration recognizes the existence of the off-label use. European legislations do not precisely specify the rules for the admissibility of the off-label use. The doctrine of law assumes that the off label use constitutes a medical experiment. Therefore, the commencement of therapy with such drugs requires patients' informed consent, which must be kept along with other medical records. Insufficient knowledge of the legal regulations may result in civil and professional liability of a physician supervising the therapy of a sarcoidosis patient, especially in case of adverse effects. PMID- 22826075 TI - Invasive pneumococcal bacteremia in a 9-year-old boy caused by serotype 1: course, treatment and costs. AB - Streptococcus pneumoniae is a leading cause of bacteremia, sepsis, meningitis, pneumonia, sinusitis, and acute otitis media in young children. Some serotypes are associated with particular disease syndromes, such as complicated pneumonias in children, or with higher rates of hospitalization in children and are consistently responsible for outbreaks in certain populations. In this report we describe a case of a nine-year-old boy who developed an abscess of pleura and invasive pneumococcal bacteremia. The boy was admitted to the hospital with abdominal pain and vomiting, accompanied by mild cough and fever. Chest X-ray revealed lower left lobe consolidation with pleural inflammation and chest CT showed extensive interstitial-alveolar changes in the left lung with atelectasis and pleural effusion causing a reduction in lung volume up to the fourth rib. From the 6(th) day of hospitalization on, suction drainage and intrapleural administration of alteplase were continued for 5 days. Intravenous antibiotics were administered for subsequent 32 days. The course of disease was complicated with labial herpes and acute adenoviral gastroenteritis. The costs of diagnosis (11.7%), pharmacotherapy (55.2%), hospitalization (30.7%) and additional procedures (2.4%) were about 4,444, while the cost of treatment from the perspective of the National Health Fund was only 1,508. The costs of treating the boy with sepsis caused by S. pneumoniae serotype 1 were thus about three times higher than those from the perspective of providers of the National Health Fund. Administration of a new pneumococcal conjugated vaccine containing serotype 1 (PHiD-CV10 or PCV13) could have prevented invasive pneumococcal disease in the described patient. PMID- 22826076 TI - Nosocomial rotovirus gastroenetrocolitis in children hospitalized primarily due to respiratory infections. AB - Rotaviruses are the leading cause of community-acquired and nosocomial gastroenterocolitis in children. There is little data concerning the epidemiology of nosocomial rotavirus gastroenterocolitis (NRVG) in Central European countries. The aim of our study was to analyze the epidemiology of NRVG in a pediatric hospital in Warsaw, Poland, where the majority of children was admitted due to respiratory tract infections. Retrospective chart analysis of 49,697 patients aged 0-18 hospitalized during 2006-2009 was performed. NRVG was defined as acute gastroeneterocolitis (>3 loose stools in 24 h or vomiting), confirmed with A rapid immunochromatographic test, if symptoms developed >48 h after admission. In total, 469 cases of NRVG were diagnosed. The cumulative attack rate of NRVG for the hospital was calculated as 0.97% (CI 0.86-1.02), the cumulative incidence density was 2.07/1000 bed-days (CI 2.01-2.13). The majority of NRVG were diagnosed at the General Pediatrics Ward (206 cases, 44%) and Allergology and Pulmonology Ward (122 cases, 26%), where the mean duration of hospital stay was longer than 5 days (9.9 +/- 1.0 and 6.1 +/- 0.8 days, respectively). Primary causes of hospitalization of the children with nosocomial rotavirus gastroenterocolitis were respiratory tract infections (including pneumonia, bronchitis, and otitis media) present in 287 cases (61.2%). The nosocomial rotavirus infection was mostly diagnosed among patients aged 6 months - 2 years (201 cases, 42.8%), less common were infections among infants younger than 6 months (133 cases, 28.3%) and children aged 2-6 (115 cases, 24.5%). The mean age of a child with NRVG was 16.2 +/- 10.2. In conclusion, rotavirus gastroenteritis is the most important nosocomial infection in children hospitalized due to respiratory tract infections and can prolong their hospital stay. PMID- 22826077 TI - Mental health of Polish students and the occurrence of respiratory tract infections. AB - The aim of the paper was to examine the association between the psychological status and the occurrence of respiratory tract infections which constitute the most common group of disorders in the student population. The study comprised 500 Polish students aged 19-21. Two psychological scales were utilized: the Goldberg GHQ-12 scale to examine the general psychological status and the CES-D scale to evaluate the symptoms of depression. In addition a pro-health questionnaire in the examined group of students was performed. We found an increased stress level in 51% of students and the symptoms of depression in 22%. An association between distress and the occurrence of respiratory tract infections was found, based on statistical analyses. The highest stress level and related high distress index were observed in the students suffering from lower respiratory tract infections (7.1 scale value). This group self-evaluated their health status as poor, based on the pro-health questionnaire. In the same group of students, lack of sleep (5.4), lack of regular eating habits (4.2) and lack of physical activity (3.9) were also observed. The study shows that the Polish student population is exposed to increased stress level, which, in turn, increases the occurrence of respiratory tract infections. PMID- 22826078 TI - Atherosclerotic factors in PR3 pulmonary vasculitis. AB - Autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis are connected with higher risk of atherosclerosis and cardiovascular complications and mortality. This results from inflammatory damage to the vessel wall by vasculitis. The aim of the present study was to evaluate whether patients with Wegener's granulomatosis (WG) and pulmonary involvement have an increased prevalence of atherosclerotic disease as characterized traditional risk factors. Twenty one patients with WG in remission and 15 control subject were entered to the study. Traditional risk factor for cardiovascular disease such as hyperglycemia, hypertension, smoking, obesity, and dyslipidemia were assessed. Both systolic and diastolic blood pressure were higher in WG patients (p<0.025). Total cholesterol, LDL and TG levels were markedly elevated in 18 of the 21 in pulmonary WG patients. Compared with controls, plasma levels of hsCRP were raised in WG patients; 3.68 (0.79-9.75) mg/l vs. 0.14 (0.12-0.59) mg/l (p<0.01). We conclude that non-pharmacological and pharmacological treatments of traditional risk factors are crucial to prevent cardiovascular disease in WG patients and thus should be part of therapy to control WG activity and damage caused by it. PMID- 22826079 TI - Vagal heart rate control in patients with atrial fibrillation: impact of tonic activation of peripheral chemosensory function in heart failure. AB - Heart failure (HF) and atrial fibrillation (AF), emerging as two epidemics of the twenty-first century, are commonly associated with each other. Both have been mechanistically linked to changes in cardiac vagal control. The importance of peripheral chemosensors, located in the carotid body, has not been elucidated so far. We therefore investigated whether tonic activation of excitatory chemoreceptor afferents contributes to the altered vagal control in HF patients with a history of AF. In 18 patients (72 +/-9 year, 7 male) with sinus rhythm and a history of AF (n=9, without any evidence of structural heart disease, AF group; n=9 with structural heart disease and clinical presentation of HF, AFHF group) we investigated the impact of chemosensory deactivation (by breathing 100% oxygen) on heart rate, blood pressure, cardiac output, total peripheral resistance, oxygen saturation and breathing rate. Ten healthy individuals served as a control group. In addition, we performed a deep breathing test demonstrating an impaired heart rate variation in patients with and without HF as compared with controls (expiration/inspiration difference: 23.9+/-6.9 vs. 6.9+/-6.1 bpm, and 23.9+/-6.9 vs. 7.8+/-4.8 bpm; p<0.05). In both control and AF groups, heart rate decreased during chemoreceptor deactivation (control: -4.8+/-3.4%; AF: -5.1+/-3.0%; p<0.05), whereas heart rate did not change in AFHF patients. This resulted in impaired cardiac chemoreflex sensitivity in AFHF patients (1.9+/-1.6 vs. 0.5+/ 1.2 ms/mmHg; p<0.05). In conclusion, our data suggest that tonic activation of excitatory chemoreceptor afferents contributes to a low vagal tone in heart failure patients with a history of AF (Clinical Trials NCT01262508). PMID- 22826080 TI - Pulmonary arterial hypertension in patients with sarcoidosis: the Pulsar single center experience. AB - Sarcoidosis is a systemic granulomatous disease with unknown etiology. Lungs and lymph nodes are commonly affected. Also, cases of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are described. However, the exact prevalence of PAH in patients with sarcoidosis is unclear. A 111 patients with proven sarcoidosis were recruited from January 2010 to October 2010. All patients were studied prospectively by transthoracic echocardiography (TTE) for the presence of PH. In assumed PH, a right heart catheterization (RHC) followed if there were no other reasons for PH. In 23 of the 111 patients (21%) PH was assumed in TTE. Three patients presented with severe mitral insufficiency III degrees and IV degrees , in eight patients PH was supposed to be caused by chronic heart failure or relevant diastolic dysfunction > II degrees , two patients declined undergoing RHC. Of the ten patients investigated with RHC, four showed a precapillary pulmonary arterial hypertension and in one patient a postcapillary hypertension was diagnosed. All four patients with precapillary PH had a radiologic stage III and IV. In three of the four patients a significantly reduced transfer factor for carbon monoxide (TLCO) <50% was found. All patients with precapillary PH had a chronic course of sarcoidosis lasting >=13 years. This is the first study which prospectively investigated a large cohort of patients with sarcoidosis for the prevalence of PH and PAH. The prevalence of precapillary PH was found to be at least 3.6% (4/111) and therefore exceeds the prevalence of PAH in the normal population by far. A chronic and progressive lung involvement due to sarcoidosis seems to be the most evident risk factor for developing a sarcoidosis PH. PMID- 22826081 TI - Cutaneous changes: an initial manifestation of pulmonary Wegener's granulomatosis. AB - Cutaneous vasculitis can occur as an isolated dermatologic disorder or as manifestation of a potentially life-threatening systemic vasculitis such as Wegener's granulomatosis (WG). The aim of the study was to characterize cutaneous lesions in 66 WG patients (30 female, 36 male) and to assess the viability of skin biopsy the diagnosis of WG. Skin involvement was observed in 21 (32%) WG patients; in 14 (21%) patients as an initial manifestation and in other seven during the diagnosis establishment. Cutaneous lesions included palpable purpura(n=10), subcutaneous nodules(=4), hemorrhagic bullae (n=3), ulcers (n=2), pustules (n=1), pyoderma gangrenosum (n =1). The patient with pulmonary WG can present initially with cutaneous symptoms and positive PR3-ANCA serologic test results. Leukocytoclastic vasculitis (LCV) was the predominant histopathologic pattern. PMID- 22826082 TI - Posturography in differential diagnosis of normal pressure hydrocephalus and brain atrophy. AB - Differentiation between normal pressure hydrocephalus (NPH) and brain atrophy is difficult in clinical practice. The purpose of this paper was to apply two advanced statistical, pattern recognition methods: discriminant analysis (DA) and k-nearest neighbour (K-NN) for the classification of NPH and atrophy patients to approach computer aided differential diagnosis. The classification is based on a few measures of the center of foot pressure (COP) movements (radius, area, and length). The posturography method gives a measure of current postural stability by a quantitative evaluation of postural sways. Measurements have been performed in the standing upright position in two conditions: with eyes open (EO) and closed (EC). The study comprises 18 patients (mean age 64 +/-13 years) diagnosed as normal pressure hydrocephalus and qualifying for shunt implantation. The patients were evaluated by static posturography twice: before and after surgery. The NPH patients were compared with 36 atrophy patients (mean age 64+/-13 years) and 47 healthy persons (mean age 60 +/-7 years). There were two basic dissimilarities in the NPH patients before surgery in comparison with the other groups: very large sways and their independence from vision. Over 90% of the NPH cases both before and after surgery were correctly classified. There also were over 90% of correctly classified patients if we compared the before surgery NPH and atrophy patients. Further posturographic measurements and data collection are needed to verify these results. PMID- 22826083 TI - Psychological background of pro-health behavior. AB - In this study, psychological conditions of pro-health lifestyle behavior have been analyzed. A first research group consisted of 88 healthy people (44 males, 44 females) aged 19-39. Psychological analysis showed a positive correlation between the internal locus of control and adherence to healthy diets; a correlation extending to the knowledge about healthy food. Social exclusion appeared to reduce the possibility of reaping new knowledge about healthy diets and was negatively correlated with the tendency of using healthy diet or dietary supplements. A second group consisted of 70 women aged 20-65. The subjects in this group were oriented towards using a diet which reduces body mass; pro-health both physical and psychological objectives other than body mass reduction were secondary in this study. General self-esteem and physical self-esteem were found to be positively correlated with the involvement in physical activities and satisfaction from dietary intervention. These outcomes were negatively correlated with body mass. The study shows that the efficiency of prevention is related to the locus of control, self-efficacy expectation, faith in the result, and self esteem. The information about the interconnections among these variables may be useful in building preventive behavioral programs. PMID- 22826084 TI - Cardiovascular effects of the valsalva maneuver during static arm exercise in elite power lifting athletes. AB - The objective of the study was to investigate whether a blood pressure increase during static exercises might affect the left ventricular function and whether a possible pressure overload might decrease cardio-respiratory adaptation to aerobic exercise in power lifting athletes. Nine resistance-trained athletes and ten age-matched untrained men participated in high intensity isometric exercise performed during the Valsalva maneuver and in an incremental arm cranking test. All subjects underwent echocardiographic evaluation. The combine effect of exercise and increased intrathoracic pressure due to the Valsalva maneuver was a significant increase in systolic blood pressure in the athletes compared with controls. Echocardiography demonstrated significant differences in left ventricular mass and left ventricular mass index; both being higher in the athletes than in controls. The intraventricular septum diameter and left ventricular posterior wall thickness were significantly greater and the myocardial performance index was lower in the athletes compared with controls, indicating a better left ventricular function in the athletes. A cumulative effect of mechanical compression of peripheral blood vessels by contracting muscles and intrathoracic pressure increase during the Valsalva maneuver did not compromise myocardial contractility and cardiorespiratory adaptation to incremental arm exercise in power lifting athletes. PMID- 22826085 TI - Computer games and fine motor skills. AB - The study seeks to determine the influence of computer games on fine motor skills in young adults, an area of incomplete understanding and verification. We hypothesized that computer gaming could have a positive influence on basic motor skills, such as precision, aiming, speed, dexterity, or tremor. We examined 30 habitual game users (F/M - 3/27; age range 20-25 years) of the highly interactive game Counter Strike, in which players impersonate soldiers on a battlefield, and 30 age- and gender-matched subjects who declared never to play games. Selected tests from the Vienna Test System were used to assess fine motor skills and tremor. The results demonstrate that the game users scored appreciably better than the control subjects in all tests employed. In particular, the players did significantly better in the precision of arm-hand movements, as expressed by a lower time of errors, 1.6 +/- 0.6 vs. 2.8 +/- 0.6 s, a lower error rate, 13.6 +/- 0.3 vs. 20.4 +/- 2.2, and a shorter total time of performing a task, 14.6 +/- 2.9 vs. 32.1 +/- 4.5 s in non-players, respectively; p < 0.001 all. The findings demonstrate a positive influence of computer games on psychomotor functioning. We submit that playing computer games may be a useful training tool to increase fine motor skills and movement coordination. PMID- 22826086 TI - Toward the clarification of ideas: medical futility, persistent/obstinate therapy and extra/ordinary means. AB - Despite reluctance of a part of medical society to accept the moral and/or legal permission to euthanasia, there is seemingly a common agreement on the need to resolve the problem of excessive therapy. Several ethical concepts are used to justify decisions to withhold/withdraw such treatment. Three of them are of particular value. The ordinary-extraordinary means distinction has a long tradition deeply-rooted in the Catholic medical ethics. During the last decades the concept of futile (or pointless) treatment has reached popularity within bioethical discourse. Also, slightly less common in use, the term 'obstinate therapy' and the relative concept seems to provide interesting insights into ethical debate. What is however to be emphasized is the ambiguity of meanings attached to these terms/concepts which prompt many bioethicists to reject these terms in favor of other concepts. In the present study a PubMed literature database review is done in order to recognize and then to classify the different ways of interpretation of the three concepts related to withholding/withdrawing excessive treatment. Retrieved interpretations of these concepts are evaluated in the light of an integrated model of moral justification. The undertaken analyses permit reaching the conclusion that the concepts which are the subject matter of this article can be properly defined and used only within the context of the so called holistic ethics and as an example of such i.e., a holistic approach to bioethics, the life's programs approach to bioethics is given. PMID- 22826087 TI - Psychological attachment in patients with spondylosis of cervical and lumbar spine. AB - Persons with spondylosis of the cervical spine have a low sense of security, difficulties in relationships with their mothers, difficulties in contact with their own body and in coping with dysphoric affect. The question arises: Are those problems the result of the current medical condition, or one of its causes? In order to find the answer one should look closer at the period of an individual's life when a sense of security and a pattern of emotional relationships are formed, and a sense of own body and defence attitudes are developed. The earliest period of life in which these processes occur is the initial relationship between the child and mother; the period of attachment and object relation. If the attachment style in the group studied does not deviate significantly from the control group, it ought to be assumed that the present problems are situational. The problems would then a result of a chronic difficult (stressful) situation which is spondylosis of cervical or lumbar spine. In an attempt to answer the above question, preliminary studies in a 90-person group were conducted. The group included 30 patients with spondylosis of the cervical spine, 30 patients with spondylosis of the lumbar spine, and 30 control persons without spondylosis. PMID- 22826088 TI - Fear and anger among adolescents and the behavior of their mothers. AB - The aim of the present study was to show differences between adolescents from complete and incomplete families concerning their perception of parents' behavior, their fear, and expressed and unexpressed anger. The research included 126 girls and boys. The methodology consisted of standard scientifically verified and validated psychometric tools to assess the feelings and behavior outlined above. The major finding was that in the adolescents from incomplete families the acceptant and inconsequent behavior significantly increased the level of fear they felt which was associated with the expression of anger. Both reactions - fear and anger seem to be strictly connected with the adolescents' gender. PMID- 22826089 TI - Psychosomatic disorders among adopted people. AB - Adoption is connected with a number of traumatic experiences, of which the experience of being abandoned by biological parents is of major significance. The fact of being abandoned usually involves a stay at a hospital and later on in various forms of family or institutionalized foster care, until the child is finally placed in an adoptive family. An important research question, both on theoretical and empirical grounds, concerns the psychosomatic dependencies between adoption and children's psycho-physical development. The article presents an attempted synthesis of the theoretical findings and the results of the conducted empirical research. Considerations, apart from its cognitive aim, also have a practical end, i.e. to indicate problems in adopted children's development which should be of special importance for adoptive parents. PMID- 22826090 TI - Market surveillance of in vitro diagnostics by the BfArM until end 2010: safety of IVD for therapeutic drug monitoring. AB - The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD for therapeutic drug monitoring (TDM) between begin 1999 until end of 2010 were analysed. A total of 2,851 notifications were received, of which 65 were related to IVD for TDM included in this study (54 tests vs. 11 analysers). Reports were received from manufacturers (58), CAs (5 cases) and users (2 cases). Most frequently IVD used for TDM of toxicologically relevant substances, antibiotics, antiepileptics and immunosuppressives were affected. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 50 cases (76.9%), 40 (74.1%) of which were tests and 10 (90.9%) analysers. In 11 cases (16.9%, all tests), the root cause remained unclear and in 4 cases (6.2%, 3 tests, 1 analyser) a product failure was excluded. Product failures in tests were most commonly material defects (12 cases), interferences (7 cases) and manufacturing errors (7 cases), whereas in the analyser group software errors (5 cases) were most common. Corrective actions were performed in 56 cases (86.2%); 46 (85.2%) in tests, and 10 (90.9%) in analysers. In the group of tests these were predominantly (multiple entries) customer information (46 cases, mandatory in case of a recall), recall (29 cases), modifications in production or quality management (29 cases) and modifications of the instructions for use (9 cases). However, in the analyser group corrective actions were typically customer information (10 cases), recall (5 cases) and software-update (4 cases). The obtained data demonstrate that there are differences in the type of product failures between analysers and tests, which are followed by different corrective actions depending on the root causes of product failure accordingly. The results and the experience since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety even though further optimisation is possible. PMID- 22826091 TI - Market surveillance of in vitro diagnostics by the BfArM until end 2010: how safe are products for tumor diagnostics? AB - The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD (tests, calibrators, kits, and control materials, except laboratory analyzers) for tumor diagnostics received by the BfArM between begin 1999 until end of 2010 were analyzed. All notifications were analyzed in respect to the type of product, the source of notification, the underlying product defects and the corrective actions performed. In the observation period, a total of 2,851 notifications were received of which 84 were related to IVD for tumor diagnostics included in this study (clinical chemistry - 63, histology - 6, molecular biology - 3, rapid tests - 12). Reports were received from manufacturers (68 cases), CA (8 cases), users (4 cases) and other sources (4 cases). In the group of IVD based on clinical chemistry means, the affected products were mostly those for the measurement of prostate specific antigen (PSA, 14 cases), human chorion gonadotropine (13 cases), carcino embryonic antigen (6 cases), CA 19-9 (6 cases), alpha(1) fetoprotein (6 cases) and CA 125 (5 cases), whereas in test strips 9 out of the 12 notifications were related to PSA. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 66 cases (78.6%). In 10 cases (11.9%) the root cause remained unclear and in 6 cases and 2 cases (7.1% and 2.4%) a product failure was excluded or a user error was the underlying cause. Most common root causes of product failures were material defects (24 cases) and manufacturing errors (15 cases). Corrective actions were performed by the manufacturers in 64 cases (76.2%) and were predominantly (multiple entries possible) customer information (62 cases, mandatory in case of a recall), recalls (45 cases), modifications in production or quality management (45 cases) and design changes (14 cases). The obtained results suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety and provides valuable information on product specific problems serving for improvement of product safety. PMID- 22826092 TI - Point source modeling of matched case-control data with multiple disease subtypes. AB - In this paper, we propose nonlinear distance-odds models investigating elevated odds around point sources of exposure, under a matched case-control design where there are subtypes within cases. We consider models analogous to the polychotomous logit models and adjacent-category logit models for categorical outcomes and extend them to the nonlinear distance-odds context. We consider multiple point sources as well as covariate adjustments. We evaluate maximum likelihood, profile likelihood, iteratively reweighted least squares, and a hierarchical Bayesian approach using Markov chain Monte Carlo techniques under these distance-odds models. We compare these methods using an extensive simulation study and show that with multiple parameters and a nonlinear model, Bayesian methods have advantages in terms of estimation stability, precision, and interpretation. We illustrate the methods by analyzing Medicaid claims data corresponding to the pediatric asthma population in Detroit, Michigan, from 2004 to 2006. PMID- 22826093 TI - Evaluation of three approaches for real-time monitoring of roller compaction with near-infrared spectroscopy. AB - Three different approaches have been evaluated for monitoring ribbon density through real-time near-infrared spectroscopy measurements. The roll compactor was operated to produce microcrystalline cellulose (MCC) ribbons of varying densities. The first approach used the slope of the spectra which showed a variation through the ribbon that could be attributed to density. A second qualitative approach was also developed with a principal component analysis (PCA) model with spectra taken in-line during the production of ribbons in an ideal roll pressure range. The PCA (i.e., real-time) density scans show that the model was able to qualitatively capture the density responses resulting from variation in process parameters. The third approach involved multivariate partial least squares (PLS) calibration models developed at wavelength regions of 1,120-1,310 and 1,305-2,205 nm. Also, various PLS models were developed using three reference methods: caliper, pycnometer, and in-line laser. The third approach shows a quantitative difference between the model-predicted and the measured densities. Models developed at high-wavelength region showed highest accuracy compared with models at low-wavelength region. All the PLS models showed a high accuracy along the spectra collected throughout the production of the ribbons. The three methods showed applicability to process control monitoring by describing the changes in density during in-line sampling. PMID- 22826094 TI - Brief communication: the human humerus from the Broken Hill Mine, Kabwe, Zambia. AB - The distal half of a right human humerus (E.898), recovered ex situ in 1925 by Hrdlicka at the Broken Hill Mine, Kabwe, Zambia, has figured prominently in assessments of Middle Pleistocene Homo postcranial variation and of the phylogenetic polarity and functional anatomy of Pleistocene Homo upper limb morphology. Reassessment of distal humeral features that distinguish modern human and some archaic Homo humeri, especially relative olecranon breadth and medial and lateral pillar thicknesses, confirm previous studies placing it morphologically close to recent humans, as well as possibly to Early Pleistocene Homo. However, it completely lacks stratigraphic context, and there is faunal and archeological evidence for human activity at Broken Hill from the Middle Pleistocene to the Holocene. Given its uncertain geological age and modern human morphology, the Broken Hill E.898 humerus should not be used in analyses of Pleistocene humans until it is securely dated. PMID- 22826095 TI - Superior functionality by design: selective ozone sensing realized by rationally constructed high-index ZnO surfaces. AB - A new technique is reported for the transformation of smooth nonpolar ZnO nanowire surfaces to zigzagged high-index polar surfaces using polycrystalline ZnO thin films deposited by atomic layer deposition (ALD). The c-axis-oriented ZnO nanowires with smooth nonpolar surfaces are fabricated using vapor deposition method and subsequently coated by ALD with a ZnO particulate thin film. The synthesized ZnO-ZnO core-shell nanostructures are annealed at 800 degrees C to transform the smooth ZnO nanowires to zigzagged nanowires with high-index polar surfaces. Ozone sensing response is compared for all three types of fabricated nanowire morphologies, namely nanowires with smooth surfaces, ZnO-ZnO core-shell nanowires, and zigzagged ZnO nanowires to determine the role of crystallographic surface planes on gas response. While the smooth and core-shell nanowires are largely non-responsive to varying O(3) concentrations in the experiments, zigzagged nanowires show a significantly higher sensitivity (ppb level) owing to inherent defect-rich high-index polar surfaces. PMID- 22826096 TI - Risk-assessment models for predicting venous thromboembolism among hospitalized non-surgical patients: a systematic review. AB - Venous thromboembolism (VTE) prophylaxis is suboptimal in American hospitals despite long-standing evidence-based recommendations. Data from observational studies indicate a lower uptake of effective prophylaxis in patients hospitalized with medical versus surgical conditions. Reluctance to use prophylaxis in medical patients has been attributed to difficulty in identifying at-risk patients and balancing risks of bleeding against occurrence of VTE. Several risk-assessment models (RAMs) have been proposed to assist physicians in identifying non-surgical patients who need prophylaxis. We conducted a systematic review of published RAMs, based on objective criteria, to determine whether any RAM is validated sufficiently to be employed in clinical practice. We identified 11 RAMs, six derived from primary data and five based on expert opinion. The number, types, and strength of association of VTE risk predictors were highly variable. The variability in methods and outcome measurement precluded pooled estimates of these different models. Published RAMs for VTE lack generalizability and adequate validation. As electronic health records become more ubiquitous, validated dynamic RAMs are needed to assess VTE risk at the point-of-care in real time. PMID- 22826097 TI - Effect of early syphilis infection on plasma viral load and CD4 cell count in human immunodeficiency virus-infected men: results from the FHDH-ANRS CO4 cohort. AB - BACKGROUND: Concomitant syphilis and human immunodeficiency virus (HIV) infection is increasingly frequent in industrialized countries. METHODS: From a large hospital cohort of HIV-infected patients followed up in the Paris area between 1998 and 2006, we examined the effect of early syphilis on plasma HIV-1 RNA levels and CD4 cell counts. We compared 282 HIV-1-infected men diagnosed as having incident primary or secondary syphilis with 1233 syphilis-free men matched for age (+/-5 years), sexual orientation, participating center, length of follow up (+/-6 months), and immunologic and virologic status before the date of syphilis diagnosis (index date). Increase in viral load (VL) (plasma HIV-1 RNA) of at least 0.5 log or a rise to greater than 500 copies/mL in patients with previously controlled VL during the 6 months after the index date was analyzed, as were CD4 cell count variations and CD4 slope after the index date. RESULTS: During the 6 months after the index date, VL increase was observed in 77 men with syphilis (27.3%) and in 205 syphilis-free men (16.6%) (adjusted odds ratio [aOR], 1.87; 95% CI, 1.40-2.49). Even in men with a VL of less than 500 copies/mL undergoing antiretroviral therapy, syphilis was associated with a higher risk of VL increase (aOR, 1.52; 95% CI, 1.02-2.26). The CD4 cell count decreased significantly (mean, -28/MUL) compared with the syphilis-free group during the syphilis episode (P = .001) but returned to previous levels thereafter. CONCLUSIONS: In HIV-infected men, syphilis was associated with a slight and transient decrease in the CD4 cell count and with an increase in VL, which implies that syphilis may increase the risk of HIV transmission, even in patients receiving antiretroviral therapy and with a VL of less than 500 copies/mL. PMID- 22826099 TI - Isolation and molecular characterisation of alkaline protease producing Bacillus thuringiensis. AB - Proteases are of particular interest because of their action on insoluble keratin substrates and generally on a broad range of protein substrates. Proteases are one of the most important groups of industrial enzymes used in detergent, protein, brewing, meat, photographic, leather, dairy, pharmaceutical and food industry. In the present study, the organism isolated from the protein rich soil sample was identified by biochemical and molecular characterisation as Bacillus thuringiensis and further optimum conditions for alkaline protease synthesis were determined. The growth conditions for B. thuringiensis was optimised by inoculating into yeast extract casein medium at different pH and incubating at different temperatures. The maximum protease production occurred at pH 8 and at 37 degrees C. B. thuringiensis showed proteolytic activity at various culture conditions. Optimum conditions for the protease activity were found to be 47 degrees C and pH 8. In the later stage, the blood removing action of crude and partially purified protease was found to be effective within 25 min in the presence of commercial detergents indicating the possible use of this enzyme in detergent industry. Enzyme also showed good activity against hair substrate keratin and can be used for dehairing. PMID- 22826100 TI - One-dimensional migration of olfactory ensheathing cells on synthetic materials: experimental and numerical characterization. AB - Olfactory ensheathing cells (OECs) are of great interest for regenerative purposes since they are believed to aid axonal growth. With the view set on the strategies to achieve reconnection between neuronal structures, it is of great importance to characterize the behaviour of these cells on long thread-like structures that may efficiently guide cell spread in a targeted way. Here, rat OECs were studied on polycaprolactone (PCL) long monofilaments, on long bars and on discs. PCL turns out to be an excellent substrate for OECs. The cells cover long distances along the monofilaments and colonize completely these structures. With the help of a one-dimensional (1D) analytical model, a migration coefficient, a net proliferation rate constant and the fraction of all cells which undergo migration were obtained. The separate effect of the three phenomena summarized by these parameters on the colonization patterns of the 1D path was qualitatively discussed. Other features of interest were also determined, such as the speed of the advance front of colonization and the order of the kinetics of net cell proliferation. Characterizing migration by means of these quantities may be useful for comparing and predicting features of the colonization process (such as times, patterns, advance fronts and proportion of motile cells) of different cell-substrate combinations. PMID- 22826098 TI - A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity. AB - The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease. PMID- 22826101 TI - Silicone breast implant materials. AB - This opinion article has been written on request because of the recent public controversy over silicone breast implants produced by a now-defunct company, Poly Implant Prosthese (PIP) in France. More than 300,000 PIP devices have been implanted. The purposes of my article are to (1.) provide a general overview of silicone breast implant materials, (2.) to describe the general safety of these materials as reported to date, and (3.) to summarise current publicly available information about these aspects of the PIP prostheses. The materials covered are the silicone rubber from which the implant shells are made and the silicone gel used to fill the shell. The materials safety issues are biocompatibility (especially of the gel) and biodurability of the shell. The literature reviewed indicates that biocompatibility is not an issue with other current generation implants. However, biodurability is. A rough estimate of implant shell rupture rate is ~10+% at 10 years. Information is still emerging about the PIP implants. Initial regulatory disclosures suggest the PIP implants may have both biocompatibility and biodurability problems. They also suggest that PIP implants may have been produced using silicone materials not certified as medical grade. Governmental health and regulatory agencies are just now in the process of deciding what actions should be taken to protect patients. PMID- 22826102 TI - Pacing postconditioning: impact of pacing algorithm, gender, and diabetes on its myocardial protective effects. AB - Pacing postconditioning (PPC) induces cardioprotection. The aim of this study was to determine the optimal pacing algorithm and possible influence of gender and diabetes on PPC. Unprotected regional ischemia for 30 min served as negative control and classical PPC (ten cycles of 30 s left ventricular pacing alternated with 30 s right atrial pacing) as positive control. Area at risk and infarct size were determined by blue dye and triphenyltetrazolium chloride staining. For achieving protection, the minimal number of PPC cycles was seven and the minimal duration of a PPC protocol was 200 s. The protective effect of PPC was comparable in male and female hearts, but no protection could be induced by PPC in diabetic hearts. PPC can provide myocardial protection when using at least seven cycles of ventricular pacing. PPC protection is independent of gender, but sensitive to experimental diabetes. PMID- 22826103 TI - Multiple tests of cost-effectiveness angles. AB - Cost-effectiveness angles are an attractive measure of performance when comparing effects and costs of health-care therapies because they have a clear interpretation and are well suited for statistical inference. In clinical trials, a common setup is the comparison of multiple new therapies with a single control. If cost-effectiveness angles are calculated for each comparison, multiplicity issues should be taken into account when quantifying uncertainty of the point estimates. Therefore, this paper proposes a parametric test for multiple cost effectiveness angles that guarantees strong family-wise error rate control. The idea is to replace the test of m cost-effectiveness angles as a union intersection test of 3m linear hypotheses. Considering the correlation structure of the individual test statistics for the linear hypotheses leads to a maximum type test for the intersection hypothesis. Inverting these test decisions then gives simultaneous CIs of cost-effectiveness angles with the appropriate coverage probabilities. PMID- 22826104 TI - Extraanatomic reconstruction for isolated thoracic aorta coarctation in an adult patient. AB - A 42-year-old male patient with no medical history except hypertension presented with intermittent chest pain radiating to the left shoulder. From coronary computed tomography, a coarctation of proximal descending thoracic aorta was found demonstrating near aortic occlusion. From various available surgical options for this condition, we chose extraanatomic bypass from the left subclavian artery to the descending aorta. PMID- 22826105 TI - Ectopic overexpression of porcine DGAT1 increases intramuscular fat content in mouse skeletal muscle. AB - The microsomal enzyme 1, 2-acyl CoA: diacylglyceroltransferase-1 (DGAT1) plays an important role in triglyceride storage in adipose tissue and expresses in skeletal muscle as well. The primary goal of the present study was to investigate the effect of porcine DGAT1 on intramuscular fat (IMF) content of transgenic mice produced by pronuclear microinjection with muscle specific promoter of porcine muscle creatine kinase (MCK). In normal chow-fed diet, 4 month-old male transgenic mice expressed more DGAT1, ACC1, UCP1, and FABP4 mRNAs and proteins in skeletal muscle than control mice by real-time PCR and western blot. No significant changes were detected for ACC2, CD36, ADRP, PPAR gamma and LPL. Triacylglycerol assay and soleus muscle sections showed overexpression of porcine DGAT1 in skeletal muscle increased intramyocellular triglyceride and percent of the total cell surface covered by lipid droplets. Thus, upregulation of porcine DGAT1 in skeletal muscle increases IMF content. The present study may further serve to develop transgenic pigs with higher IMF content and improved meat quality. PMID- 22826107 TI - Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study. AB - BACKGROUND: Limited evidence suggests that the risk of acute myocardial infarction (AMI) may be increased shortly after total hip replacement (THR) and total knee replacement (TKR) surgery. However, risk of AMI in these patients has not been compared against matched controls who have not undergone surgery. The objective of this study was to evaluate the timing of AMI in patients undergoing THR or TKR surgery compared with matched controls. METHODS: Retrospective, nationwide cohort study within the Danish national registries. All patients who underwent a primary THR or TKR (n = 95,227) surgery from January 1, 1998, through December 31, 2007, were selected and matched to 3 controls (no THR or TKR) by age, sex, and geographic region. All study participants were followed up for AMI, and disease- and medication history-adjusted hazard ratios (HRs) were calculated. RESULTS: During the first 2 postoperative weeks, the risk of AMI was substantially increased in THR patients compared with controls (adjusted HR, 25.5; 95% CI, 17.1-37.9). The risk remained elevated for 2 to 6 weeks after surgery (adjusted HR, 5.05; 95% CI, 3.58-7.13) and then decreased to baseline levels. For TKR patients, AMI risk was also increased during the first 2 weeks (adjusted HR, 30.9; 95% CI, 11.1-85.5) but did not differ from controls after the first 2 weeks. The absolute 6-week risk of AMI was 0.51% in THR patients and 0.21% in TKR patients. CONCLUSIONS: Risk of AMI is substantially increased in the first 2 weeks after THR (25-fold) and TKR (31-fold) surgery compared with controls. Risk assessment of AMI should be considered during the first 6 weeks after THR surgery and during the first 2 weeks after TKR surgery. PMID- 22826106 TI - Production of mouse pups from germline transmission-failed knockout chimeras. AB - Occasionally, chimeras do not transmit the gene of interest to pups in gene disruption experiments. However, the risk of failure could be reduced if we could identify embryonic stem (ES)-derived germ cells in the testis. Here, we report the production of pups from three lines of infertile chimeric male mice and the establishment of knockout lines by combining green fluorescent protein-tagged ES cells with intracytoplasmic sperm injection. PMID- 22826108 TI - Age-dependent effects of hippocampal neurogenesis suppression on spatial learning. AB - Reducing hippocampal neurogenesis sometimes, but not always, disrupts hippocampus dependent learning and memory. Here, we tested whether animal age, which regulates rate of hippocampal neurogenesis, is a factor that influences whether deficits in spatial learning are observed after reduction of neurogenesis. We found that suppressing the generation of new hippocampal neurons via treatment with temozolomide, an antiproliferation agent, impaired learning the location of a hidden platform in the water maze in juvenile mice (1-2 months old) but not in adult mice (2-3 months old) or middle-aged mice (11-12 months old). These findings suggest that during juvenility, suppression of neurogenesis may alter hippocampal development, whereas during adulthood and aging, pre-existing neurons may compensate for the lack of new hippocampal neurons. PMID- 22826109 TI - Human mesenchymal stem cells increase anti-oxidant defences in cells derived from patients with Friedreich's ataxia. AB - Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder which is, at present, incurable. Oxidative damage and inhibition of mitochondrial function are key determinants of cellular damage in FRDA, since there is greater sensitivity to oxidative stress in cells with frataxin deficiency. In addition, frataxin-deficient cells have an impaired ability to recruit antioxidant defences against endogenous oxidative stress. We have recently shown that factors derived from bone marrow-derived mesenchymal stem cells (MSCs) increase hydrogen peroxide scavenging enzymes and offer protection against hydrogen peroxide-mediated injury in cells derived from patients with FRDA. Here we extend these studies and have performed a series of experiments showing that expression of superoxide dismutase (1 and 2) enzymes is reduced in FRDA cells but can be restored by treatment with conditioned medium from human MSCs. Furthermore, we have demonstrated that exposure to factors secreted by MSCs increases resistance to nitric oxide-induced oxidative stress in FRDA fibroblasts through, at least in part, restoring the expression of the superoxide dismuting enzymes and via modulation of PI(3) kinase/Akt pathways. These findings suggest that MSCs secrete factors that improve the cellular homeostasis of cells derived from FRDA patients and provide suitable support for their enhanced survival. This study further suggests the potential therapeutic use of MSCs in patients with FRDA. PMID- 22826110 TI - Comparison of methods for imputing ordinal data using multivariate normal imputation: a case study of non-linear effects in a large cohort study. AB - BACKGROUND: Multiple imputation is becoming increasingly popular for handling missing data, with Markov chain Monte Carlo assuming multivariate normality (MVN) a commonly used approach. Imputing categorical variables (which are clearly non normal) using MVN imputation is challenging, and several approaches have been suggested. However, it remains unclear which approach should be preferred. METHODS: We explore methods for imputing ordinal variables using MVN imputation, including imputing as a continuous variable and as a set of indicators, and various methods for assigning imputed values to the possible categories (rounding), for estimating a non-linear association between an ordinal exposure and binary outcome. We introduce a new approach where we impute as continuous and assign imputed values into categories based on the mean indicators imputed in a separate round of imputation. We compare these approaches in a simple setting where we make 50% of data in an ordinal exposure missing completely at random, within an otherwise complete real dataset. RESULTS: Methods that impute the ordinal exposure as continuous distorted the non-linear exposure-outcome association by biasing the relationship towards linearity irrespective of the rounding method. In contrast, imputing using indicators preserved the non-linear association but not the marginal distribution of the ordinal variable. CONCLUSIONS: Imputing ordinal variables as continuous can bias the estimation of the exposure-outcome association in the presence of non-linear relationships. Further work is needed to develop optimal methods for handling ordinal (and nominal) variables when using MVN imputation. PMID- 22826111 TI - Longitudinal patterns of autonomic nervous system responding to emotion evocation among children with conduct problems and/or depression. AB - Conduct disorder (CD) and depression co-occur at far greater levels than chance, despite largely separate diagnostic criteria. One potential shared mechanism of this comorbidity is emotion dysregulation, which characterizes both internalizing and externalizing disorders. Previous research demonstrates that respiratory sinus arrhythmia (RSA)-a peripheral biomarker of emotion regulation-is attenuated among children with CD, and among children with depression. However, few studies have examined biomarkers of emotion regulation as a function of heterotypic comorbidity. We evaluated longitudinal patterns of RSA and RSA reactivity to emotion evocation across three annual assessments among 207 children diagnosed at ages 8-12 years with CD (n = 30), depression (n = 28), comorbid CD and depression (n = 80), or no psychiatric condition (n = 69). Using continuous symptom counts as predictors, Depression * CD interactions were observed for both Time 1 resting RSA and Time 1 RSA reactivity. CD, depression, and their interaction were all associated with low resting RSA at Time 1. In addition, concurrently elevated CD and depression scores predicted the greatest RSA reactivity to emotion evocation. Psychopathology scores were unrelated to developmental changes in RSA and RSA reactivity over time. PMID- 22826112 TI - Traditional Chinese medicine and immune regulation. AB - Traditional Chinese medicines (TCMs) have a long history in Asian countries and are traditionally used to prevent and treat a variety of diseases. The rising interest in TCMs in recent years is reflected in both the increase in their market demand as well as scientific research. Previous studies show that TCMs perform dual roles on immunological regulation: immunological activation and immunological suppression. This review highlights studies focusing on the immunomodulatory effects of TCMs, describing their stimulatory effect on immune cells, immune organs, cytokine production, tumorigenesis, as well as their inhibitory function on inflammation, allergy, autoimmune disease, and graft rejection. Components of both innate and adaptive immunity may be modulated by specific TCMs. TCMs may also have antitumor effects and may play a role in regulating apoptosis. Immunomodulatory effects of TCMs may lead to new medications to treat allergic and autoimmune diseases. More high quality studies are needed to achieve scientific validity to these potential treatments. Evidence presented in this review reveals the role of TCMs in immune regulation and proposes a promising future for them in immunomodulatory therapies. PMID- 22826113 TI - The long-term marriage between autoimmunity and internal medicine: a homage to Manuel Carlos Dias. AB - Our understanding of autoimmune diseases results from the perfect combination of basic and clinical scientific research, and the figure that is closest to the proposed autoimmunology specialist is certainly the internist. The role of B cells in rheumatoid arthritis, the immunological mechanisms to fibrosis or to tissue specific damage, the classification of Bechet's syndrome, the clinical outcomes of antiphospholid syndrome, and new biomarkers for vascular complications in systemic sclerosis constitute, among others, are ideal examples of this combination. For these reason, this issue includes comprehensive reviews in all these areas and is dedicated to Dr. Manuel Carlos Dias and his career in the perfectioning and teaching of the clinical skills necessary to manage autoimmune disease. We are convinced that these discussions are likely of interest to basic scientists and clinicians alike for the proposed translational applications. PMID- 22826114 TI - Ross procedure for everyone. AB - Aortic valve replacement using a pulmonary homograft is a complex procedure which provides very good functional results in most patients. Negligible valve-related morbidity, freedom from anticoagulation, and the ability to accommodate growth make it a valid therapeutic modality in infants and children. Due to the excellent quality of life which it provides, the procedure is increasingly being performed in adults. However, it has become apparent that pulmonary homograft insufficiency may be a relatively common problem. Dilatation of the pulmonary autograft is the most common complication after a Ross procedure affecting nearly one-third of patients. It was suggested that dilatation of the pulmonary autograft occurs because of a geometric mismatch between the aortic and pulmonary roots. Despite there been no morphological or physiological data, the authors believed that spatial geometry may influence the dilatation of the neo-aortic root. Herein, I analyse the actual literature stressing long-term results and predictive factors for neo-aorta failure following the Ross procedure. According to my previous morphological investigations I made a proposition of how the Ross procedure may be modified in order to include it for everyone as an aortic valve substitute. PMID- 22826115 TI - Outbreaks of foot-and-mouth disease in Peninsular Malaysia from 2001 to 2007. AB - This is a retrospective study of the outbreaks of foot-and-mouth disease (FMD) in Peninsular Malaysia between 2001 and May 2007. In total, 270 outbreaks of FMD were recorded. Serotype O virus (89.95 %) and serotype A (7.7 %) had caused the outbreaks. Significant differences on the occurrence of FMD were found between the years (t = 5.73, P = 0.000, df = 11), months (t = 4.7, P = 0.000, df = 11), monsoon season (t = 2.63, P = 0.025, df = 10) and states (t = 4.84, P = 0.001, df = 10). A peak of outbreaks observed in 2003 could be due to increased animal movement and the other peak in 2006 could be due to a compromised FMD control activities due to activities on the eradication of highly pathogenic avian influenza. Cattle (86 % of outbreaks) suffered the most. However, no difference in disease occurrence between species was observed. The populations of cattle (r = 0.672, P = 0.023) and sheep (r = 0.678, P = 0.022) were significantly correlated with occurrence of FMD. Movement of animals (66 % of outbreaks) was the main source for outbreaks. A combination of control measures were implemented during outbreaks. In conclusion, the findings of this study show that FMD is endemic in Peninsular Malaysia, and information gained could be used to improve the existing control strategy. PMID- 22826116 TI - Village chickens management in Wolaita zone of southern Ethiopia. AB - Little effort has been made to improve village chickens housing, feeding, and health care. Due to this, the amount of output obtained is usually low. The aim of this study was to elicit farmers' knowledge on the routine husbandry practices of village chickens. One hundred nineteen farmers were one-on-one interviewed in the highland and lowland areas of Wolaita zone (southern Ethiopia) to generate the dataset used in this analysis. We found that all the respondents supplemented the scavenging chickens with locally available feed resources. However, the amount of supplementary feeds provided hardly meets the nutritional requirement of the flock. As a result, farmers were forced to practice a sort of preferential feeding mainly based on laying performance and the scavenging ability of different classes of the family flock. Moreover, there is a wide difference in the amount and type of feed available among seasons. This variation has forced farmers to resort on strategic supplementation to overcome the adverse effect of inherent feed (grain) scarcity on chickens' performance especially during wet season. Feed loss should be kept at a minimum by using feeding troughs, and a fraction of money obtained from selling of the chickens and eggs needs to be set aside to purchase feed. The risk of disease was higher during main rain season (June to September). Besides providing sanitary condition and feed supplementation, capacitating the veterinary service and validating the efficacy of ethno-veterinary practices through objective studies is required to improve the health status of village chickens. Majority of the farmers use rudimentary types of in-house built shelters to protect their chickens from adverse effects of bad weather, predation, and theft. This indicates the importance of constructing proper types of shelters from locally (freely) available or inexpensive materials. The existing tradition of responsibility sharing among family members while doing the routine husbandry practices needs to be strengthened to maximize the efficient use of family's labor force. This improvement plan needs to be mainly implemented through adoption of the existing best traditional practices and through the rational use of cheap and readily available local resources. PMID- 22826117 TI - Long-term monitoring of dioxins and furans near a municipal solid waste incinerator: human health risks. AB - Since 1996, a wide surveillance programme has been developed to get overall information on the impact of a municipal solid waste incinerator (MSWI) in Tarragona (Catalonia, Spain). The concentrations of polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) have been periodically measured in soil and vegetation samples collected at locations in the incinerator surroundings. Furthermore, air PCDD/F levels have been also monitored by using active and passive sampling devices, generating a huge amount of information regarding the environmental status of the zone. In the last survey (2009-2010), mean PCDD/F levels in vegetation, soil and air were 0.06 ng I-TEQ kg(-1), 0.58 ng I-TEQ kg( 1) and 10.5 fg WHO-TEQ m(-3), respectively. Both soil and herbage showed a notable reduction in the PCDD/F concentrations in comparison with the baseline study, with this decrease only being significant for soils. In contrast, PCDD/F values in air remained similar during the whole assessment period. Human exposure to PCDD/Fs was evaluated under different scenarios, and the associated non carcinogenic and carcinogenic risks were assessed. The hazard quotient was below unity in all cases, while cancer risks were under 10(-6), which is lower than the maximum recommended guidelines. The current results clearly show that the MSWI of Tarragona does not produce additional health risks for the population living nearby. PMID- 22826118 TI - Karen Vousden: getting the big picture on p53. Interview by Caitlin Sedwick. PMID- 22826119 TI - Autophagy regulation through Atg9 traffic. AB - Rapid membrane expansion is the key to autophagosome formation during nutrient starvation. In this issue, Yamamoto et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201202061) now provide a mechanism for vesicle mediated initiation of autophagosome biogenesis. They show that Atg9 vesicles, produced de novo during starvation, are ~30-60 nm in size and contain ~30 molecules of Atg9. These vesicles assemble to form an autophagosome, and subsequently, the Atg9 embedded in the outer membrane is recycled to avoid degradation. PMID- 22826120 TI - Mechanistic insights into the regulation of metabolic enzymes by acetylation. AB - The activity of metabolic enzymes is controlled by three principle levels: the amount of enzyme, the catalytic activity, and the accessibility of substrates. Reversible lysine acetylation is emerging as a major regulatory mechanism in metabolism that is involved in all three levels of controlling metabolic enzymes and is altered frequently in human diseases. Acetylation rivals other common posttranslational modifications in cell regulation not only in the number of substrates it modifies, but also the variety of regulatory mechanisms it facilitates. PMID- 22826121 TI - A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis. AB - In yeasts and worms, KASH (Klarsicht/ANC-1/Syne/homology) domain and SUN (Sad 1/UNC-84) domain nuclear envelope (NE) proteins play a crucial role in meiotic chromosome movement and homologue pairing. However, although the vertebrate SUN domain protein SUN1 is involved in these processes, its partner has remained identified. Based on subcellular localization screening in mouse spermatocytes, we identified a novel germ cell-specific protein, KASH5, that localized exclusively at telomeres from the leptotene to diplotene stages in both spermatocytes and oocytes. KASH5 possesses hitherto unknown KASH-related sequences that directly interacted with SUN1 and mediated telomere localization. Thus, KASH5 is a mammalian meiosis-specific KASH domain protein. We show that meiotic chromosome movement depended on microtubules and that KASH5 interacted with the microtubule-associated dynein-dynactin complex. These results suggest that KASH5 connects the telomere-associated SUN1 protein to the cytoplasmic force generating mechanism involved in meiotic chromosome movement. Our study strongly suggests that the meiotic homologue-pairing mechanism mediated by the SUN-KASH NE bridge is highly conserved among eukaryotes. PMID- 22826122 TI - K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc. AB - KRAS, BRAF, and PI3KCA are the most frequently mutated oncogenes in human colon cancer. To explore their effects on morphogenesis, we used the colon cancer derived cell line Caco-2. When seeded in extracellular matrix, individual cells proliferate and generate hollow, polarized cysts. The expression of oncogenic phosphatidylinositol 3-kinase (PI3KCA H1047R) in Caco-2 has no effect, but K-Ras V12 or B-Raf V600E disrupts polarity and tight junctions and promotes hyperproliferation, resulting in large, filled structures. Inhibition of mitogen activated protein/extracellular signal-regulated kinase (ERK) kinase blocks the disruption of morphology, as well as the increased levels of c-myc protein induced by K-Ras V12 and B-Raf V600E. Apical polarity is already established after the first cell division (two-cell stage) in Caco-2 three-dimensional cultures. This is disrupted by expression of K-Ras V12 or B-Raf V600E but can be rescued by ribonucleic acid interference-mediated depletion of c-myc. We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation. PMID- 22826123 TI - Atg9 vesicles are an important membrane source during early steps of autophagosome formation. AB - During the process of autophagy, cytoplasmic materials are sequestered by double membrane structures, the autophagosomes, and then transported to a lytic compartment to be degraded. One of the most fundamental questions about autophagy involves the origin of the autophagosomal membranes. In this study, we focus on the intracellular dynamics of Atg9, a multispanning membrane protein essential for autophagosome formation in yeast. We found that the vast majority of Atg9 existed on cytoplasmic mobile vesicles (designated Atg9 vesicles) that were derived from the Golgi apparatus in a process involving Atg23 and Atg27. We also found that only a few Atg9 vesicles were required for a single round of autophagosome formation. During starvation, several Atg9 vesicles assembled individually into the preautophagosomal structure, and eventually, they are incorporated into the autophagosomal outer membrane. Our findings provide conclusive linkage between the cytoplasmic Atg9 vesicles and autophagosomal membranes and offer new insight into the requirement for Atg9 vesicles at the early step of autophagosome formation. PMID- 22826124 TI - Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. AB - BACKGROUND: There is interest in whether a short course of combination antiretroviral therapy (cART) at the time of human immunodeficiency virus (HIV) seroconversion could induce long-term immunologic control after its interruption. We aimed to determine the time of virologic rebound after interruption of treatment initiated close to HIV seroconversion and to identify potential cases of posttreatment controllers (PTCs) in the CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe) Collaboration. METHODS: Prospective cohort study nested within the CASCADE database of routinely collected data about patients with HIV with well-estimated date of HIV seroconversion from Europe, Canada, and Australia in the post-cART era. Participants were individuals who interrupted successful cART initiated within 3 months of HIV seroconversion. The main outcome was loss of PTC status, defined as the earlier date of virologic rebound (first of 2 consecutive measurements showing HIV RNA levels >50 copies/mL) or reinitiation of any ART after cART interruption. RESULTS: Median time to loss of PTC status in 259 eligible individuals was 1.7 months. Eleven patients did not experience virologic rebound by 24 months after treatment interruption. CONCLUSION: Most patients experience virologic rebound soon after cART interruption; however, although PTCs are rare, the results of this study confirm their existence. PMID- 22826125 TI - Intrarenal oxygenation by blood oxygenation level-dependent MRI in contrast nephropathy model: effect of the viscosity and dose. AB - PURPOSE: To compare the effects of osmolality versus viscosity of radio-contrast media on intra-renal oxygenation as determined by blood oxygenation level dependent (BOLD) MRI in a model of contrast induced nephropathy (CIN). MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were divided into five groups. Nitric oxide synthase inhibitor L-NAME (10 mg/kg), cyclooxygenase inhibitor indomethacin (10 mg/kg), or saline, and radio-contrast iodixanol (high viscosity, 784 or 1600 mg I/kg) or iothalamate (high osmolality, 1600 mg I/kg) were administered. BOLD MRI images were acquired on Siemens 3 Tesla (T) scanner using a multiple gradient recalled echo sequence at baseline, following L-NAME (or saline), indomethacin (or saline), and radio-contrast agents. R2* (=1/T2*) was used as the BOLD MRI parameter in renal medulla and cortex. Mixed-effects models with first order auto-regressive variance-covariance models were used to analyze the data. RESULTS: The magnitude of change in medullary R2* (MR2*) with same dose of iodine was larger with iodixanol compared with iothalalmate both in pretreated groups (303% versus 225.6%, < 0.01) and the control group (191.6% versus -1.8%, P < 0.01). The MR2* change in high dose iodixanol was approximately twice compared with the low dose (303% versus 133%, P < 0.01). CONCLUSION: The viscosity of radio-contrast seems to play a more significant role than osmolality in terms of renal oxygenation changes as evaluated by BOLD MRI. Additionally, iodixanol induced a dose-dependent increase in renal medullary hypoxia. PMID- 22826126 TI - Synthesis and interaction of bovine serum albumin with p-hydroxybenzoic acid derivatives. AB - Three novel p-hydroxybenzoic acid derivatives (HSOP, HSOX, HSCP) were synthesized from p-hydroxybenzoic acid and sulfonamides (sulfamonomethoxine sodium, sulfamethoxazole and sulfachloropyridazine sodium) and characterized by elemental analysis, HNMR and MS. Interactions between derivatives and bovine serum albumin (BSA) were studied by fluorescence quenching spectra, UV-vis absorption spectra and time-resolved fluorescence spectra. Based on fluorescence quenching calculation and Forster's non-radioactive energy transfer theory, the values of the binding constants, basic thermodynamic parameters and binding distances were obtained. Experimental results indicated that the three derivatives had a strong ability to quench fluorescence from BSA and that the binding reactions of the derivatives with BSA were a static quenching process. Thermodynamic parameters showed that binding reactions were spontaneous and exothermic and hydrogen bond and van der Waals force were predominant intermolecular forces between the derivatives and BSA. Synchronous fluorescence spectra suggested that HSOX and HSCP had little effect on the microenvironment and conformation of BSA in the binding reactions but the microenvironments around tyrosine residues were disturbed and polarity around tyrosine residues increased in the presence of HSOP. PMID- 22826127 TI - The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity. AB - The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID- 22826128 TI - New perspectives concerning feedback influences on cardiorespiratory control during rhythmic exercise and on exercise performance. AB - The cardioaccelerator and ventilatory responses to rhythmic exercise in the human are commonly viewed as being mediated predominantly via feedforward 'central command' mechanisms, with contributions from locomotor muscle afferents to the sympathetically mediated pressor response. We have assessed the relative contributions of three types of feedback afferents on the cardiorespiratory response to voluntary, rhythmic exercise by inhibiting their normal 'tonic' activity in healthy animals and humans and in chronic heart failure. Transient inhibition of the carotid chemoreceptors during moderate intensity exercise reduced muscle sympathetic nerve activity (MSNA) and increased limb vascular conductance and blood flow; and reducing the normal level of respiratory muscle work during heavier intensity exercise increased limb vascular conductance and blood flow. These cardiorespiratory effects were prevented via ganglionic blockade and were enhanced in chronic heart failure and in hypoxia. Blockade of MU opioid sensitive locomotor muscle afferents, with preservation of central motor output via intrathecal fentanyl: (a) reduced the mean arterial blood pressure (MAP), heart rate and ventilatory responses to all steady state exercise intensities; and (b) during sustained high intensity exercise, reduced O(2) transport, increased central motor output and end-exercise muscle fatigue and reduced endurance performance. We propose that these three afferent reflexes - probably acting in concert with feedforward central command - contribute significantly to preserving O(2) transport to locomotor and to respiratory muscles during exercise. Locomotor muscle afferents also appear to provide feedback concerning the metabolic state of the muscle to influence central motor output, thereby limiting peripheral fatigue development. PMID- 22826129 TI - Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs. AB - The alveolo-capillary barrier is effectively impermeable to large solutes such as proteins. A hallmark of acute lung injury/acute respiratory distress syndrome is the accumulation of protein-rich oedema fluid in the distal airspaces. Excess protein must be cleared from the alveolar space for recovery; however, the mechanisms of protein clearance remain incompletely understood. In intact rabbit lungs 29.8 +/- 2.2% of the radio-labelled alveolar albumin was transported to the vascular compartment at 37 degrees C within 120 min, as assessed by real-time measurement of 125I-albumin clearance from the alveolar space. At 4 degrees C or 22 degrees C significantly lower albumin clearance (3.7 +/- 0.4 or 16.2 +/- 1.1%, respectively) was observed. Deposition of a 1000-fold molar excess of unlabelled albumin into the alveolar space or inhibition of cytoskeletal rearrangement or clathrin-dependent endocytosis largely inhibited the transport of 125I-albumin to the vasculature, while administration of unlabelled albumin to the vascular space had no effect on albumin clearance. Furthermore, albumin uptake capacity was measured as about 0.37 mg ml-1 in cultured rat lung epithelial monolayers, further highlighting the (patho)physiological relevance of active alveolar epithelial protein transport. Moreover, gene silencing and pharmacological inhibition of the multi-ligand receptor megalin resulted in significantly decreased albumin binding and uptake in monolayers of primary alveolar type II and type I-like and cultured lung epithelial cells. Our data indicate that clearance of albumin from the distal air spaces is facilitated by an active, high capacity, megalin-mediated transport process across the alveolar epithelium. Further understanding of this mechanism is of clinical importance, since an inability to clear excess protein from the alveolar space is associated with poor outcome in patients with acute lung injury/acute respiratory distress syndrome. PMID- 22826130 TI - Control of neuronal excitability by NMDA-type glutamate receptors in early developing binaural auditory neurons. AB - Precise control of neuronal excitability in the auditory brainstem is fundamental for processing timing cues used for sound localization and signal discrimination in complex acoustic environments. In mature nucleus laminaris (NL), the first nucleus responsible for binaural processing in chickens, neuronal excitability is governed primarily by voltage-activated potassium conductances (K(VA)). High levels of K(VA) expression in NL neurons result in one or two initial action potentials (APs) in response to high-frequency synaptic activity or sustained depolarization. Here we show that during a period of synaptogenesis and circuit refinement, before hearing onset, K(VA) conductances are relatively small, in particular low-voltage-activated K(+) conductances (K(LVA)). In spite of this, neuronal output is filtered and repetitive synaptic activity generates only one or two initial APs during a train of stimuli. During this early developmental time period, synaptic NMDA-type glutamate receptors (NMDA-Rs) contain primarily the GluN2B subunit. We show that the slow decay kinetics of GluN2B-containing NMDA-Rs allows synaptic responses to summate, filtering the output of NL neurons before intrinsic properties are fully developed. Weaker Mg(2+) blockade of NMDA Rs and ambient glutamate early in development generate a tonic NMDA-R-mediated current that sets the membrane potential at more depolarized values. Small KLVA conductances, localized in dendrites, prevent excessive depolarization caused by tonic activation of NMDA-Rs. Thus, before intrinsic properties are fully developed, NMDA-Rs control the output of NL neurons during evoked synaptic transmission. PMID- 22826131 TI - Equal sensitivity of Cav1.2 and Cav1.3 channels to the opposing modulations of PKA and PKG in mouse chromaffin cells. AB - Mouse chromaffin cells (MCCs) express high densities of L-type Ca2+ channels (LTCCs), which control pacemaking activity and catecholamine secretion proportionally to their density of expression. In vivo phosphorylation of LTCCs by cAMP-PKA and cGMP-PKG, regulate LTCC gating in two opposing ways: the cAMP-PKA pathway potentiates while the cGMP-PKG cascade inhibits LTCCs. Despite this, no attempts have been made to answer three key questions related to the two Cav1 isoforms expressed in MCCs (Cav1.2 and Cav1.3): (i) how much are the two Cav1 channels basally modulated by PKA and PKG?, (ii) to what extent can Cav1.2 and Cav1.3 be further regulated by PKA or PKG activation?, and (iii) are the effects of both kinases cumulative when simultaneously active? Here, by comparing the size of L-type currents of wild-type (WT; Cav1.2+Cav1.3) and Cav1.3-/- KO (Cav1.2) MCCs, we provide new evidence that both PKA and PKG pathways affect Cav1.2 and Cav1.3 to the same extent either under basal conditions or induced stimulation. Inhibition of PKA by H89 (5 MUM) reduced the L-type current in WT and KO MCCs by~60%,while inhibition of PKG by KT 5823 (1 MUM) increased by~40% the same current in both cell types. Given that Cav1.2 and Cav1.3 carry the same quantity of Ca2+ currents, this suggests equal sensitivity of Cav1.2 and Cav1.3 to the two basal modulatory pathways. Maximal stimulation of cAMP-PKA by forskolin (100 MUM) and activation of cGMP-PKG by pCPT-cGMP (1mM) uncovered a~25% increase of L-type currents in the first case and~65% inhibition in the second case in both WT and KO MCCs, suggesting equal sensitivity of Cav1.2 and Cav1.3 during maximal PKA or PKG stimulation. The effects of PKA and PKG were cumulative and most evident when one pathway was activated and the other was inhibited. The two extreme combinations(PKA activation-PKG inhibition vs. PKG activation-PKA inhibition) varied the size of L-type currents by one order of magnitude (from 180% to 18% of control size). Taken together our data suggest that: (i) Cav1.2 and Cav1.3 are equally sensitive to PKA and PKG action under both basal conditions and maximal stimulation, and (ii) PKA and PKG act independently on both Cav1.2 and Cav1.3, producing cumulative effects when opposingly activated. These extreme Cav1 channel modulations may occur either during high-frequency sympathetic stimulation to sustain prolonged catecholamine release (maximal L type current) or following activation of the NO-cGMP-PKG signalling pathway (minimal L-type current) to limit the steady release of catecholamines. PMID- 22826132 TI - Endocannabinoid-dependent plasticity at spinal nociceptor synapses. AB - Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB)1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long term depression (LTD)of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB(1) receptor-deficient mice (CB(1) (-/- ) mice and sns-CB(1)(-/-) mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB1 receptor antagonist AM251 and mimicked by pharmacological activation of CB1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB(1) receptors in CB(1)(-/ ) and sns-CB(1)(-/-) mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hither to unknown function of CB1 receptors in primary nociceptors. Both findings may have important implications for our understanding of endogenous pain control mechanisms and of analgesia evoked by cannabinoid receptor agonists. PMID- 22826133 TI - Long-term facilitation of ventilation following acute continuous hypoxia in awake humans during sustained hypercapnia. AB - In awake humans, long-term facilitation of ventilation (vLTF) following acute intermittent hypoxia (AIH) is only expressed if CO2 is maintained above normocapnic levels. vLTF has not been reported following acute continuous hypoxia (ACH) and it is not known whether this might be unmasked by elevated CO2. Twelve healthy participants completed three trials. In all trials end-tidal pressure of CO2 was elevated 4-5 mmHg above normocapnic levels. During Trial 1 (AIH) participants were exposed to eight 4 min episodes of hypoxia. During Trial 2 (ACH) participants were exposed to continuous hypoxia for 32 min. In Trial 3 (Control) participants were exposed to euoxia throughout. To assess the contribution of the carotid body (CB) in observed ventilatory responses, CB afferent discharge before and after each trial was transiently inhibited with hyperoxia. Minute ventilation ( V E) increased following all trials, but was significantly greater in Trials 1 and 2 when compared with Trial 3 (Trial 1: 4.96 +/- 0.87, Trial 2: 5.07 +/- 0.7, Trial 3: 2.55 +/- 0.98 l min-1, P < 0.05). Hyperoxia attenuated VE to a similar extent in baseline and recovery in all trials (Trial 1: 3.0 +/- 0.57 vs. 3.27 +/- 0.68, Trial 2: 1.97 +/- 0.62 vs. 2.56 +/- 0.62, Trial 3: 2.23 +/- 0.49 vs. 2.15 +/- 0.55 l min-1, P > 0.05). Data are means +/- SEM. In awake humans with elevated CO2, ACH evokes a sustained increase in ventilation that is comparable to that evoked by AIH. However, a gradual positive drift in ventilation in response to elevated CO2 accounts for approximately half of this apparent vLTF. Additionally, our data support the view that the CB is not directly involved in maintaining vLTF. PMID- 22826134 TI - Short-term repeatability of resting myocardial blood flow measurements using rubidium-82 PET imaging. AB - BACKGROUND: Rubidium-82 ((82)Rb) PET imaging has been proposed for routine myocardial blood flow (MBF) quantification. However, few studies have investigated the test-retest repeatability of this method. The aim of this study was to optimize same-day repeatability of rest MBF imaging with a highly automated analysis program (FlowQuant) using image-derived input functions and dual spillover corrections (SOC). METHODS: Test-retest repeatability of resting left-ventricle (LV) MBF was measured in patients (n = 27) with suspected coronary artery disease (CAD) and healthy volunteers (n = 9). The effects of scan-time, reconstruction, and quantification methods were assessed with correlation and Bland-Altman repeatability coefficients. RESULTS: Factors affecting rest MBF included gender, suspected CAD, and SOC (P < .001). Significant test-retest correlations were found using all analysis methods tested (r > 0.79). The best repeatability coefficient for same-day MBF was 0.20 mL/minute/g using a 6-minute scan-time, iterative reconstruction, SOC, resting rate-pressure-product (RPP) adjustment, and left atrium input function. This protocol was significantly less variable than standard protocols using filtered back-projection reconstruction, longer scan-time, no SOC, or LV input function. CONCLUSION: Absolute MBF can be measured with good repeatability using FlowQuant analysis of (82)Rb PET scans with a 6-minute scan time, iterative reconstruction, dual SOC, RPP-adjustment, and an image-derived input function in the left atrium cavity. PMID- 22826136 TI - Development and initial testing of a measure of public and self-stigma in the military. AB - OBJECTIVE: This research developed and tested the Military Stigma Scale (MSS), a 26-item scale, designed to measure public and self-stigma, two theorized core components of mental health stigma. METHOD: The sample comprised 1,038 active duty soldiers recruited from a large Army installation. Soldiers' mean age was 26.7 (standard deviation = 5.9) years, and 93.6% were male. The sample was randomly split into a scale development group (n = 520) and a confirmatory group (n = 518). RESULTS: Factor analysis conducted with the scale development group resulted in the adoption of two factors, named public and self-stigma, accounting for 52.1% of the variance. Confirmatory factor analysis conducted with the confirmatory group indicated good fit for the two-factor model. Both factors were components of a higher order stigma factor. The public and self-stigma scales for the exploratory and confirmatory groups demonstrated good internal consistency (alpha = .94 and .89; alpha = .95 and .87, respectively). Demographic differences in stigma were consistent with theory and previous empirical research: Soldiers who had seen a mental health provider scored lower in self-stigma than those who had not. CONCLUSIONS: The MSS comprises two internally consistent dimensions that appear to capture the constructs of public and self-stigma. The overall results indicate that public and self-stigma are dimensions of stigma that are relevant to active duty soldiers and suggest the need to assess these dimensions in future military stigma research. PMID- 22826135 TI - A 3D interconnected microchannel network formed in gelatin by sacrificial shellac microfibers. PMID- 22826137 TI - Dobutamine-induced high cardiac index did not prevent vasospasm in subarachnoid hemorrhage patients: a randomized controlled pilot study. AB - BACKGROUND: Prevention of vasospasm is a challenging issue in subarachnoid hemorrhage (SAH) patients and the objective is to compare high dobutamine-induced cardiac index (CI) and high norepinephrine-induced hypertension for the prevention of vasospasm in SAH patients. METHODS: Single center, single blind, controlled randomized study. Patients hospitalized in intensive care unit (ICU) for a moderate to severe SAH (WFNS grade >=2) were randomized to receive dobutamine to reach a 25 % increase in cardiac index or norepinephrine to reach a mean arterial pressure >=100 mmHg. Norepinephrine could be used in the dobutamine group to maintain a cerebral pressure perfusion >=60 mmHg. Primary endpoint was the incidence of angiographic vasospasm in the first 14 days in the ICU setting, which was upheld by a cerebral arteriography. Secondary endpoints were the incidence of delayed ischemic deficits, duration of mechanical ventilation, and ICU length of stay (LOS). RESULTS: During the 3-year study, 41 patients were randomized. Six patients were excluded--3 because of consent withdrawal and 3 who did not receive the assigned treatment. Respectively, 17 and 18 patients in the dobutamine and the norepinephrine group were kept in analysis. Five (28 %) patients in the dobutamine group and 5 (27 %) patients in the norepinephrine group developed vasospasm in ICU (p = 1). Seven (41 %) patients presented a delayed ischemic deficit in the dobutamine group and 9 (50 %) in the norepinephrine group (p = 0.24). Duration of mechanical ventilation was 8 [0.5 11.5] days in the dobutamine group and 19 [2.7-23] days in the norepinephrine group (p = 0.01). ICU LOS was 11 [6-15] days in the dobutamine group and 21 [9 28] days in the norepinephrine group (p = 0.01). CONCLUSION: As compared to norepinephrine-induced hypertension, dobutamine-induced high CI did not reduce the rate of vasospasm in SAH patients. Dobutamine may reduce durations of mechanical ventilation and ICU LOS. PMID- 22826138 TI - The pattern and pace of hyperacute hemorrhage expansion. AB - BACKGROUND: Intracerebral hemorrhage (ICH) expansion is common during the first 24 h after onset, but the pattern and pace of hyperacute hemorrhage growth have not been described because serial imaging is typically performed over the course of hours and days, not minutes. The purpose of this study is to elucidate the spatial and temporal characteristics of hyperacute hemorrhage expansion within minutes of ICH onset. METHODS: An 86-year-old man with probable cerebral amyloid angiopathy developed an ICH while in the MRI scanner. Hyperacute hemorrhage growth was captured at three time points over a 14-min interval of MRI data acquisition and at fourth time point with CT 22 h later. MRI and CT datasets were spatially coregistered, and three-dimensional models of ICH expansion were generated. RESULTS: Longitudinal analysis revealed that the spatial pattern of ICH growth was asymmetric at each time point. Maximal expansion occurred along the anterior-posterior plane during the first 4 min but along the superior inferior plane during the next 10 min. The temporal pace of ICH expansion was also non-uniform, as growth along the anterior-posterior plane outpaced medial lateral growth during the first 4 min (2.8 vs. 2.5 cm), but medial-lateral growth outpaced anterior-posterior growth over the next 10 min (1.0 vs. 0.2 cm). CONCLUSIONS: We provide evidence for asymmetric, non-uniform expansion of a hyperacute hemorrhage. These serial imaging observations suggest that hemorrhage expansion may be caused by local cascades of secondary vessel rupture as opposed to ongoing bleeding from a single ruptured vessel. PMID- 22826139 TI - Analysis of multi-stage treatments for recurrent diseases. AB - Patients with a non-curable disease such as many types of cancer usually go through the process of initial treatment, a various number of disease recurrences and salvage treatments, and eventually death. The analysis of the effects of initial and salvage treatments on overall survival is not trivial. One may try to use disease recurrences and salvage treatments as time-dependent covariates in a Cox proportional hazards model. However, because disease recurrence is an intermediate outcome between initial treatment and final survival, the interpretation of such an estimation result is awkward. It does not estimate the causal effects of treatments on overall survival. Nevertheless, such causal effect estimates are critical for treatment decision making. Our approach to address this issue is that, at any treatment stage, for each patient, we compute a potential survival time if he or she would receive the optimal subsequent treatments, and use this potential survival time to do comparison between current stage treatment groups. This potential survival time is assumed to follow an accelerated failure time model at each treatment stage and calculated by backward induction, starting from the last stage of treatment. By doing that, the effects on survival of different treatments at each stage can be consistently estimated and fairly compared. Under suitable conditions, these estimated effects have a causal interpretation. We evaluated the proposed model and estimation method by simulation studies and illustrated using the motivating, real data set that describes initial and salvage treatments for patients with soft tissue sarcoma. PMID- 22826140 TI - Cost of attempted suicide: a retrospective study of extent and associated factors. AB - QUESTIONS UNDER STUDY: Suicidal behaviour is a major source of burden of disease. While most studies focus on cost associated with completed suicides, data on costs of, non-lethal, suicide attempts are lacking. The aim of this study was to assess direct annual cost of suicide attempts in Basel in 2003 from a health services perspective. METHODS: Retrospective cost-of-illness-study of the Basel cohort of the 2003 WHO/EURO-Multicentre Study on Parasuicide. We extracted cost information from the two major hospitals involved in treatment of these patients. We determined overall cost, compared cost medians and identified variables associated with higher cost by means of logistic regression. RESULTS: For 2003, treatment of suicide attempters in Basel's main hospitals amounted to 3,373,025 Swiss Francs (CHF), mainly attributable to psychiatric care. Mean and median cost per case were 19,165 CHF and 6,108 CHF, respectively. Based on these findings, the extrapolated direct medical costs for medical treatment of suicide attempts in Switzerland per year amount to 191 million CHF. Parameters associated with high costs were age above 65 (p<0.01), using a hard method (p<0.05), receiving intensive care (p<.05), and lethal intention (p<0.05). The ICD-10 diagnostic category F3 was associated with significantly higher costs than F1 (p<0.05) and F4 (p<0.05). CONCLUSIONS: Attempted suicide produces substantial direct medical costs, which are only a part of the financial burden. Prevention targeting mood disorders, the elderly and the use of hard methods may be most cost-effective. Further research should aim at identifying additional indirect costs and the cost effectiveness of prevention measures. PMID- 22826141 TI - Fibrillary glomerulonephritis complicated by membranous nephropathy in a patient with tuberculosis. AB - Fibrillary glomerulonephritis (FGN) is a morphologically defined entity characterized by glomerular accumulations of non-branching, randomly arranged fibrils; these differ from amyloid fibrils by their larger size and lack of reactivity with Congo red and other amyloid-specific dyes. FGN is a rare disease and may mimic membranous nephropathy under routine light microscopy and immunohistochemistry. However, electron microscopy shows the fibrillary nature of these glomerular deposits. We report a rare case of membranous nephropathy complicated by fibrillary deposits in a 60-year-old man with a history of bone tuberculosis. PMID- 22826142 TI - Recurrence of fibrillary glomerulonephritis in a renal transplant recipient. AB - Fibrillary glomerulonephritis (FGN) is a rare glomerular deposition disease and a rare cause of nephrotic syndrome. The patients usually present with renal insufficiency, nephrotic range proteinuria and microscopic hematuria. The electron microscopy study is the only means of diagnosis. The clinical course of the disease is generally unpredictive and the patients inevitably progress to ESRD. Here, we describe a case of FGN, which presented with nephrotic syndrome and impaired renal function. Renal biopsy showed that 26 out of 30 glomeruli were completely sclerosed. Remaining showed mesangial expansion and double contour consistent with a membranoproliferative pattern, with 70 % interstitial fibrosis and tubular atrophy. Immunofluorescence revealed C3 (2+) diffuse mesangial deposits. Electron microscopic showed subendothelial dense deposits with organized tubular structures. During follow-up, the patient underwent renal transplantation from a living unrelated kidney donor. Later on, as the renal allograft function showed deterioration, renal biopsy was performed and showed recurrence of FGN in the renal allograft. PMID- 22826143 TI - Short- and long-term efficacy of levamisole in children with steroid-sensitive nephrotic syndrome. AB - PURPOSE: In this study, we aimed to evaluate short- and long-term effects of levamisole therapy in steroid-sensitive nephrotic syndrome (SSNS) in children. METHODS: The study consisted of 29 SSNS patients who had been treated with levamisole for 12 months. Laboratory values and clinical data were analyzed for three separate periods for each patient: 1 year prior to the initiation of levamisole therapy (Pre-Lev), during 1 year of levamisole therapy (During-Lev), and the year following cessation of levamisole therapy (End-Lev). RESULTS: The level of proteinuria fell from median 135.0 (24.0-633.0) mg/h/m(2) Pre-Lev to median 4.4 (2.4-654.0) mg/h/m(2) During-Lev and median 4.8 (2.2-105.0) mg/h/m(2) End-Lev (p = 0.0001, for each). Median relapse frequency fell from 4.0 (3.0-8.0) relapses/patient per year Pre-Lev to 0.0 (0.0-2.0) During-Lev (p = 0.0001) with 23/29 patients having no relapse and 0.0 (0.0-1.0) End-Lev (p = 0.0001) with 18/29 patients without relapse. During-Lev, all children had marked diminution in annual steroid burden from a median of 5582.0 (2137.0-17340.0) mg/m(2) per year Pre-Lev to 2166.0 (840.0-9325.0) mg/m(2) per year (p = 0.0001). End-Lev, the annual steroid burden also continued to fall, to 0.0 (0.0-5386.0) mg/m(2) per year (p = 0.0001). The age and duration of NS were significantly higher in the children with relapses than in the children with sustained remission (p = 0.009 and p = 0.014, respectively). The side effects that are expected during levamisole therapy did not occur in our patients. CONCLUSION: Thus, our study showed that levamisole is a safe and effective steroid-sparing agent, with long lasting effect even 12 months after withdrawal. PMID- 22826144 TI - Pulmonary hemorrhage complicating Goodpasture's disease in the course of pulmonary tuberculosis. AB - A 72-year-old man with ESRD on hemodialysis was referred to the hospital because of hemoptysis. A chest radiograph showed diffuse infiltration in the right lung field. Laboratory data showed hematuria and proteinuria. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgG along the glomerular basement membrane (GBM). However, circulating IgG anti-GBM antibodies were not detected. Because the findings of renal biopsy suggested Goodpasture's disease, the patient was treated with plasmapheresis and pulse steroid therapy, which resulted in a rapid resolution of his pulmonary symptoms and chest radiograph abnormalities. However, sputum culture on admission yielded Mycobacterium tuberculosis 3 weeks later. Therefore, immuosuppressive agents were discontinued and antituberculous agents were administered. There was no relapse of pulmonary hemorrhage during the next 1-year period of follow-up, but the patient did not regain renal function and remained on hemodialysis. PMID- 22826145 TI - Catheter-related infections in chronic hemodialysis: a clinical and economic perspective. AB - PURPOSE: Central venous catheters emerged as a major risk factor for infectious complications in hemodialysis (HD) patients. We aimed to assess the incidence of bacteremia in catheter-dependent HD patients and to characterize its clinical and economic impact. METHODS: We retrospectively collected clinical data and healthcare costs from 15 months for 75 admitted catheter-dependent HD patients, to document the type of bacteremia (complicated or not), pathogen and inflammation. RESULTS: Bacteremia (97 % with Staphylococcus aureus, 33 % methicillin-resistant) was present in 51 % patients, with an overall infections incidence of 5.79 per 1,000 catheter-days. Metastatic complications occurred in 21 % of bacteremic patients and were associated with higher mortality (38 vs. 4 %; p = 0.001). Although, in patients starting dialysis on catheter (41 %) as compared to those using catheter as bridge angioaccess, inflammation (higher C reactive protein; p = 0.006) and anemia (lower Hb; p = 0.008) were more pronounced, bacteremia occurred in a lower proportion (32 vs. 64 %, p = 0.007). The total medical costs were 47 % higher in patients with complicated bacteremia than in those without bacteremia (p = 0.008) and 45 % higher in patients starting HD on catheter than in those using catheter as bridge angioaccess (p = 0.002). CONCLUSIONS: Despite the limitations resulting from retrospective cross-sectional single-center design, our study suggests that patients already on HD who required catheters as bridge angioaccess were more prone to bacteremia. This highlights the importance of close angioaccess monitoring to avoid unnecessary catheter usage. A similar increase in costs when initiating dialysis on catheter as in case of complicated bacteremia strongly supports the initial placement of a native arteriovenous fistula. PMID- 22826146 TI - Renal sarcoidosis with normal serum vitamin D and refractory hypercalcemia. AB - INTRODUCTION: Sarcoidosis is a multi-system disorder characterized by non caseating epithelioid granulomas in multiple organs. Renal involvement may usually occur as granulomatous interstitial nephritis, but renal failure is uncommon. We report a case of renal-limited sarcoidosis diagnosed by renal biopsy, associated with abnormal calcium metabolism. CASE PRESENTATION: A 30-year old Caucasian male presented with unexplained renal function impairment and hypercalcemia. The patient did not have any history of kidney disease, cough, skin rash, dysuria, hematuria or any other symptoms. Physical examination was unremarkable. Serum creatinine was 2.2 mg/dl and serum calcium was 11.5 mg/dl. Serum intact parathyroid hormone level (12 pg/mL) was decreased. Serum angiotensin-converting enzyme (ACE), 1,25-dihydroxyvitamin D (1,alpha-25 vit D) and pre-proparathyroid hormone (PTHrP) levels and urinary calcium excretion were all in normal range. The renal biopsy showed severe interstitial nephritis with non-caseating granuloma. The patient was treated with prednisone with starting dose of 1 mg/kg. After 2 months of prednisone therapy, serum creatinine decreased. However, because of continued of hypercalcemia unresponsive to low calcium diet and prednisone, chloroquine was prescribed. Six months after the onset, the patient's serum creatinine is stable at 1.30 mg/dl, serum calcium is 10.8 mg/dl, and serum ACE and 1,alpha-25 vit D levels are in normal range. He does not have any signs of extra-renal relapse. CONCLUSION: The mechanisms of abnormal calcium metabolism in this patient with renal-limited sarcoidosis are unclear. PMID- 22826147 TI - Proteinuria in the elderly: evaluation and management. AB - While aging is accompanied by many age-related changes in renal physiology and function, proteinuria should not be considered to be a part of "normal aging". There are many age-prevalent illnesses that predispose one to developing proteinuria and early recognition, and treatment may help retard disease progression or offer an early cure. The presence of proteinuria warrants further evaluation and follow-up if one has any hope of avoiding its progression and delaying the initiation of treatment. This review article will discuss the anatomy and physiology of the aging kidney, the pathophysiology and etiology of proteinuria during later life, methods to evaluate proteinuria, and ways to monitor and manage this problem. PMID- 22826148 TI - CD146 gene expression in clear cell renal cell carcinoma: a potential marker for prediction of early recurrence after nephrectomy. AB - OBJECTIVES: To investigate whether CD146 gene expression could provide useful information to predict early recurrence after nephrectomy. METHODS: This study included 84 patients with clear cell renal cell carcinoma (cRCC), and 44 subjects without tumor were used as controls. Quantitative RT-PCR was used to measure the CD146 gene expression. RESULTS: The mean value of CD146 expression in patients with metastatic cRCC (0.0438+/-0.0024) was significantly higher than in those with localized cRCC (0.0374+/-0.0012, P=0.018) or in controls (0.0344+/-0.0010, P=0.001). Of patients with localized cRCC, those with recurrence had a significantly higher CD146 expression than those without recurrence (P=0.029). The univariate analysis showed that CD146 was associated with early recurrence. The recurrence-free survival curve indicated that patients with a high CD146 expression had a significantly higher recurrence rate than those with a low CD146 expression (P=0.018). CONCLUSIONS: CD146 gene expression can be useful for predicting early recurrence and stratifying the patients into risk groups for possible adjuvant treatment. PMID- 22826149 TI - Declines in prostate cancer incidence after changes in screening recommendations. PMID- 22826150 TI - Accuracy and precision of vessel area assessment: manual versus automatic lumen delineation based on full-width at half-maximum. AB - PURPOSE: To evaluate the accuracy and precision of manual and automatic blood vessel diameter measurements, a quantitative comparison was conducted, using both phantom and clinical 3D magnetic resonance angiography (MRA) data. Since diameters are often manually measured, which likely is influenced by operator dependency, automatic lumen delineation, based on the full-width at half-maximum (FWHM), could improve these measurements. MATERIALS AND METHODS: Manual and automatic diameter assessments were compared, using MRA data from a vascular phantom (geometry obtained with MUCT) and clinical MRA data. The diameters were manually assessed by 15 MRA experts, using both caliper and contour tools. To translate the experimental results to clinical practice, the precision obtained using phantom data was compared to the precision obtained with clinical data. RESULTS: A diameter error <10% was obtained with resolutions above 2, 3, and 5 pixels/diameter for the automatic FWHM, contour, and caliper methods, respectively. Using phantom data, precision of the manual methods was low (error >20%), even at high resolutions, while precision for the automatic method was high (error <3%) when using more than 2 pixels/diameter. A similar trend was found with clinical data. CONCLUSION: The results obtained clearly demonstrate improvement in the accuracy and precision of vessel diameter measurements with use of the automatic FWHM-based method. PMID- 22826151 TI - Phosphorylation of CRMP2 is involved in proper bifurcation of the apical dendrite of hippocampal CA1 pyramidal neurons. AB - The neural circuit in the hippocampus is important for higher brain functions. Dendrites of CA1 pyramidal neurons mainly receive input from the axons of CA3 pyramidal neurons in this neural circuit. A CA1 pyramidal neuron has a single apical dendrite and multiple basal dendrites. In wild-type mice, most of CA1 pyramidal neurons extend a single trunk, or alternatively, the apical dendrite bifurcates into two daughter trunks at the stratum radiatum layer. We previously reported the proximal bifurcation phenotype in Sema3A-/-, p35-/-, and CRMP4-/- mice. Cdk5/p35 phosphorylates CRMP2 at Ser522, and inhibition of this phosphorylation suppressed Sema3A-induced growth cone collapse. In this study, we analyzed the bifurcation points of the apical dendrites of hippocampal CA1 pyramidal neurons in CRMP2KI/KI mice in which the Cdk5/p35-phosphorylation site Ser522 was mutated into an Ala residue. The proximal bifurcation phenotype was not observed in CRMP2KI/KI mice; however, severe proximal bifurcation of apical dendrites was found in CRMP2KI/KI;CRMP4-/- mice. Cultured hippocampal neurons from CRMP2KI/KI and CRMP2KI/KI;CRMP4-/- embryos showed an increased number of dendritic branching points compared to those from wild-type embryos. Sema3A increased the number of branching points and the total length of dendrites in wild-type hippocampal neurons, but these effects of Sema3A for dendrites were not observed in CRMP2KI/KI and CRMP2KI/KI;CRMP4-/-hippocampal neurons. Binding of CRMP2 to tubulin increased in both CRMP2KI/KI and CRMP2KI/KI:CRMP4-/- brain lysates. These results suggest that CRMP2 and CRMP4 synergistically regulate dendritic development, and CRMP2 phosphorylation is critical for proper bifurcation of apical dendrite of CA1 pyramidal neurons. PMID- 22826152 TI - In vitro and in vivo inhibitory activities of four Indian medicinal plant extracts and their major components on rat aldose reductase and generation of advanced glycation endproducts. AB - The polyol enzyme aldose reductase (AR) and advanced glycation endproducts (AGEs) play an important role in diabetic complications such as cataracts. The purpose of this study was to investigate four standardized plant extracts used for the treatment of diabetes and related diseases, and their principal components for AR inhibitory activity and to find out their influence in diabetic complications. Thus, Boswellia serrata Triana & Planch. (Burseraceae), Lagerstroemia speciosa (L.) Pers. (Lythraceae), Ocimum gratissimum (L.) (Lamiaceae) and Syzygium cumin (L.) Skeels. (Myrthaceae) and their respective major constituents, boswellic acid, corosolic acid, ursolic acid and ellagic acid, were studied for their inhibitory activity against rat lens AR, rat kidney AR, human recombinant AR and generation of AGEs. In addition, in vivo inhibition of lens galactitol accumulation by the major constituents of the plants in galactose-fed rat has been studied. The results revealed that all the tested extracts and their active ingredients possess significant AR inhibitory actions in both in vitro and in vivo assays with urosolic acid showing the most potent effect. Furthermore, the study indicates the potential of the studied plants and their major constituents as possible protective agents against long-term diabetic complications. PMID- 22826154 TI - Complete nucleotide sequence of an Argentinean isolate of sweet potato virus G. AB - Sweet potato virus G belongs to the largest plant virus genus Potyvirus. This virus was detected for the first time in Argentina and then sequenced using the method of next-generation pyrosequencing. The complete genome was found to be 10,798 nucleotides excluding the poly-A tail with a predicted genome organization typical for a member of the genus Potyvirus. This is the first report of the complete genomic sequence of a SPVG isolated from South America. PMID- 22826153 TI - Vocal-motor and auditory connectivity of the midbrain periaqueductal gray in a teleost fish. AB - The midbrain periaqueductal gray (PAG) plays a central role in the descending control of vocalization across vertebrates. The PAG has also been implicated in auditory-vocal integration, although its precise role in such integration remains largely unexplored. Courtship and territorial interactions in plainfin midshipman fish depend on vocal communication, and the PAG is a central component of the midshipman vocal-motor system. We made focal neurobiotin injections into the midshipman PAG to both map its auditory-vocal circuitry and allow evolutionary comparisons with tetrapod vertebrates. These injections revealed an extensive bidirectional pattern of connectivity between the PAG and known sites in both the descending vocal-motor and the ascending auditory systems, including portions of the telencephalon, dorsal thalamus, hypothalamus, posterior tuberculum, midbrain, and hindbrain. Injections in the medial PAG produced dense label within hindbrain auditory nuclei, whereas those confined to the lateral PAG preferentially labeled hypothalamic and midbrain auditory areas. Thus, the teleost PAG may have functional subdivisions playing different roles in vocal-auditory integration. Together the results confirm several pathways previously identified by injections into known auditory or vocal areas and provide strong support for the hypothesis that the teleost PAG is centrally involved in auditory-vocal integration. PMID- 22826156 TI - Simulating from marginal structural models with time-dependent confounding. AB - We discuss why it is not always obvious how to simulate longitudinal data from a general marginal structural model (MSM) for a survival outcome while ensuring that the data exhibit complications due to time-dependent confounding. On the basis of the relation between a directed acyclic graph and an MSM, we suggest a data-generating process that satisfies both these requirements, the general validity of which we prove. Our approach is instructive regarding the interpretation of MSMs and useful in that it allows one to examine the finite sample performance of methods that claim to adjust for time-dependent confounding. We apply our methodology to design a simulation study that emulates typical longitudinal studies such as the Swiss HIV Cohort Study so that competing methods of adjusting for time-dependent covariates can be compared. PMID- 22826155 TI - Delay in virus accumulation and low virus transmission from transgenic rice plants expressing Rice tungro spherical virus RNA. AB - Rice tungro, a devastating viral disease of rice in South and Southeast Asia, is caused by the joint infection of a DNA virus, Rice tungro bacilliform virus (RTBV) and an RNA virus Rice tungro spherical virus (RTSV). RTBV and RTSV are transmitted exclusively by the insect vector Green leafhopper (GLH). RTSV is necessary for the transmission of RTBV. To obtain transgenic resistance against RTSV, indica rice plants were transformed using DNA constructs designed to express an untranslatable sense or anti-sense RTSV RNA. Progeny of primary transformants showing low copies of the integrated transgenes and accumulating the corresponding transcripts at low levels were challenged with viruliferous GLH. Three out of four transgenic plant lines expressing untranslatable RTSV RNA in the sense orientation and two out of the four lines expressing an RTSV gene in the anti-sense orientation showed delayed buildup of RTSV RNA over time. Transmission of RTBV from the above lines was reduced significantly. PMID- 22826157 TI - Reliable and valid assessment of competence in endoscopic ultrasonography and fine-needle aspiration for mediastinal staging of non-small cell lung cancer. AB - BACKGROUND AND STUDY AIMS: Fine-needle aspiration (FNA) guided by endoscopic ultrasonography (EUS) is important in mediastinal staging of non-small cell lung cancer (NSCLC). Training standards and implementation strategies of this technique are currently under discussion. The aim of this study was to explore the reliability and validity of a newly developed EUS Assessment Tool (EUSAT) designed to measure competence in EUS - FNA for mediastinal staging of NSCLC. PATIENTS AND METHODS: A total of 30 patients with proven or suspected NSCLC underwent EUS - FNA for mediastinal staging by three trainees and three experienced physicians. Their performances were assessed prospectively by three experts in EUS under direct observation and again 2 months later in a blinded fashion using digital video-recordings. Based on the assessments, intra-rater reliability, inter-rater reliability, and construct validity were explored. RESULTS: The intra-rater reliability was good (Cronbach's alpha = 0.80), but comparison of results based on direct observations and blinded video-recordings indicated a significant bias favoring consultants (P = 0.022). Inter-rater reliability was very good (Cronbach's alpha = 0.93). However, one rater assessing five procedures or two raters each assessing four procedures were necessary to secure a generalizability coefficient of 0.80. The assessment tool demonstrated construct validity by discriminating between trainees and experienced physicians (P = 0.034). CONCLUSIONS: Competency in mediastinal staging of NSCLC using EUS and EUS - FNA can be assessed in a reliable and valid way using the EUSAT assessment tool. Measuring and defining competency and training requirements could improve EUS quality and benefit patient care. PMID- 22826158 TI - Fully covered self-expanding metal stents for refractory pancreatic duct strictures in chronic pancreatitis. AB - Fully covered self-expanding metal stents (FC-SEMSs), which can be removed from the bile duct, have recently been used in the main pancreatic duct (MPD) in chronic pancreatitis. The aim of this study was to investigate the feasibility, safety, and efficacy of FC-SEMSs in painful chronic pancreatitis with refractory pancreatic strictures. The primary endpoints were technical success and procedure related morbidity. Secondary endpoints were pain relief at the end of follow-up and resolution of the dominant pancreatic stricture at endoscopic retrograde pancreatography. Over 5 months, 10 patients with painful chronic pancreatitis and refractory dominant pancreatic duct strictures were treated with FC-SEMSs. All FC SEMSs were successfully released and removed, although two stents were embedded in the MPD at their distal end and treated endoscopically without complications. Mild abdominal pain was noted in three patients after stent release. During treatment, pain relief was achieved in nine patients, but one continued to take morphine, because of addiction. Cholestasis developed in two patients and was treated endoscopically; no patient developed acute pancreatitis or pancreatic sepsis. After stent removal, the diameter of the narrowest MPD stricture had increased significantly from 3.5 mm to 5.8 mm. Patients were followed up for a mean of 19.8 months: two patients who continued drinking alcohol presented with mild acute pancreatitis; one patient developed further chronic pancreatic pain; and one had a transient pain episode. At the end of the study, nine patients no longer had chronic pain and no patients had required surgery. Endoscopic treatment of refractory MPD stricture in chronic pancreatitis by placement of an FC-SEMS appears feasible, safe, and potentially effective. PMID- 22826159 TI - Accelerated 3D MERGE carotid imaging using compressed sensing with a hidden Markov tree model. AB - PURPOSE: To determine the potential for accelerated 3D carotid magnetic resonance imaging (MRI) using wavelet based compressed sensing (CS) with a hidden Markov tree (HMT) model. MATERIALS AND METHODS: We retrospectively applied HMT model based CS and conventional CS to 3D carotid MRI data with 0.7 mm isotropic resolution from six subjects with known carotid stenosis (12 carotids). We applied a wavelet-tree model learned from a training database of carotid images to improve CS reconstruction. Quantitative endpoints such as lumen area, wall area, mean and maximum wall thickness, plaque calcification, and necrotic core area were measured and compared using Bland-Altman analysis along with image quality. RESULTS: Rate-4.5 acceleration with HMT model-based CS provided image quality comparable to that of rate-3 acceleration with conventional CS and fully sampled reference reconstructions. Morphological measurements made on rate-4.5 HMT model-based CS reconstructions were in good agreement with measurements made on fully sampled reference images. There was no significant bias or correlation between mean and difference of measurements when comparing rate 4.5 HMT model based CS with fully sampled reference images. CONCLUSION: HMT model-based CS can potentially be used to accelerate clinical carotid MRI by a factor of 4.5 without impacting diagnostic quality or quantitative endpoints. PMID- 22826160 TI - Having a well-trained workforce is necessary for a healthy economy, productive citizens, and strong families. PMID- 22826162 TI - Career development during childhood and adolescence. AB - Identity development is central to the career development of children and adolescents. This article reviews the literature pertaining to identity development as being composed of career exploration, commitment, and reconsideration and offers some implications for career interventions. PMID- 22826163 TI - Teenage employment and career readiness. AB - Most American youth hold a job at some point during adolescence, but should they work? This article presents a broad overview of teenage employment in the United States. It begins by describing which teenagers work and for how long and then focuses attention on the consequences (both good and bad) of paid work in adolescence. It then presents recent nationally representative data from the Monitoring the Future Study suggesting that limited hours of paid work do not crowd out developmentally appropriate after-school activities. A review of the literature also supports the idea that employment for limited hours in good jobs can promote career readiness and positive development. The article concludes with a discussion of the implications of youth work for practitioners and policymakers who are delivering career-related programming. PMID- 22826164 TI - What schools are doing around career development: implications for policy and practice. AB - This article describes the role that schools are playing in supporting career development for young people. It examines the history of career-related programming in schools, including school-to-work programs, career and technical education, the college and career readiness movement, and current school reform initiatives. This understanding of schools' history, roles, opportunities, and constraints can help practitioners and policymakers think about how to build a system that supports youth development. PMID- 22826165 TI - Support for career development in youth: program models and evaluations. AB - This article examines four influential programs-Citizen Schools, After School Matters, career academies, and Job Corps-to demonstrate the diversity of approaches to career programming for youth. It compares the specific program models and draws from the evaluation literature to discuss strengths and weaknesses of each. The article highlights three key lessons derived from the models that have implications for career development initiatives more generally: (1) career programming can and should be designed for youth across a broad age range, (2) career programming does not have to come at the expense of academic training or preparation for college, and (3) program effectiveness depends on intentional design and high-quality implementation. PMID- 22826167 TI - Development in youth enterprises. AB - Business enterprises run by youth can create jobs and teach the principles of free enterprise but also convey skills that can be used by employees in large companies, as well as political activists and entrepreneurs. Research is needed to test the efficacy of this approach and identify its key components. PMID- 22826166 TI - Marketable job skills for high school students: what we learned from an evaluation of After School Matters. AB - This article summarizes findings from an experimental evaluation of After School Matters (ASM), a paid, apprenticeship-based, after-school program in Chicago for high school students. Analysis of quantitative data from a mock job interview revealed that ASM participants did not demonstrate more marketable job skills than youth in the control group. Qualitative data suggested that the nature of interpersonal interactions and the degree of professional orientation in apprenticeships contributed to variation in marketable job skills across apprenticeships. The article considers the perspective of human resource professionals who participated in the evaluation and describes an interviewing skills curriculum developed in response to the evaluation findings. PMID- 22826168 TI - Building business-community partnerships to support youth development. AB - A confluence of social, economic, and demographic trends has left a generation of young Americans facing an uncertain future in the workforce. If we are to improve their prospects and prepare them for rewarding careers, disparate stakeholders employers, educators, youth advocates, and others-must work in common purpose. This article suggests ways to build community partnerships, with a special focus on engaging private employers in the effort. PMID- 22826169 TI - Supporting vocationally oriented learning in the high school years: rationale, tasks, challenges. AB - This article highlights the limitations of our current educational system in terms of vocational learning and highlights the role that vocational learning can play in supporting youth development and improving youth outcomes. It discusses the role that nonschool settings can play in supporting vocational learning and suggests strategies to improve our in-school and out-of-school systems to build a more coherent whole that promotes youth development across various settings. PMID- 22826170 TI - Next steps for research and practice in career programming. AB - The articles in this volume of New Directions for Youth Development highlight the broad research base relevant to career programming from which policy and practice can draw. This concluding article integrates these findings to highlight next steps for research and practice related to career programming. PMID- 22826171 TI - COX-2 in the neurodegenerative process of Parkinson's disease. AB - The enzyme cyclooxygenase-2 (COX-2), responsible for the first committed step in the synthesis of several important mediators which are involved in both initiation and resolution of inflammation, and the subsequent generation of prostaglandins (PGs) upon activation has been shown to participate in the neurodegenerative processes of a variety of diseases. This review looks particular at the role of COX-2 in the pathogenesis of Parkinson's disease, involving the generation of PGs and the role of the two different parts of the cyclooxygenase-cyclooxygenase and peroxidase activity. PMID- 22826172 TI - Peritoneal washing cytologic analysis of ovarian serous tumors of low malignant potential to detect peritoneal implants and predict clinical outcome. AB - BACKGROUND: Patients with ovarian serous tumors of low malignant potential (OSLMP) who have peritoneal implants, especially invasive implants, are at an increased risk of developing tumor recurrence. To the best of the authors' knowledge, the ability of peritoneal washing (PW) cytology to detect the presence and type of peritoneal implants has not been adequately investigated, and its prognostic significance is unknown. METHODS: Records and PW specimens of 101 patients diagnosed with and treated for OSLMP between 1996 and 2010 at The University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patients' staging biopsy findings were compared with the results of the authors' review of the PWs. Follow-up data were also analyzed. RESULTS: Of the 96 patients for whom staging biopsy results were available, 26 (27%) had peritoneal implants (17 noninvasive and 9 invasive), 19 (20%) had endosalpingiosis, and 51 (53%) had negative findings. The PW specimens of 18 of the 26 patients (69%) with peritoneal implants were positive for serous neoplasm, and a correlation was found between cytologic and histologic findings (P < .0001). The sensitivity, specificity, positive predictive value, and negative predictive value were 69%, 84%, 62%, and 88%, respectively. Four of 101 patients had disease recurrence; 3 of these patients had invasive implants and 1 patient had noninvasive implants. None of the patients who had negative staging biopsy findings or endosalpingiosis but did have PW specimens that were positive for serous neoplasm developed disease recurrence. CONCLUSIONS: PW cytology detects the presence of peritoneal implants with moderate accuracy. However, long-term studies are needed to determine whether positive PW cytologic findings are an independent predictor of tumor recurrence. PMID- 22826173 TI - A conditional likelihood approach for regression analysis using biomarkers measured with batch-specific error. AB - Measurement error is common in epidemiological and biomedical studies. When biomarkers are measured in batches or groups, measurement error is potentially correlated within each batch or group. In regression analysis, most existing methods are not applicable in the presence of batch-specific measurement error in predictors. We propose a robust conditional likelihood approach to account for batch-specific error in predictors when batch effect is additive and the predominant source of error, which requires no assumptions on the distribution of measurement error. Although a regression model with batch as a categorical covariable yields the same parameter estimates as the proposed conditional likelihood approach for linear regression, this result does not hold in general for all generalized linear models, in particular, logistic regression. Our simulation studies show that the conditional likelihood approach achieves better finite sample performance than the regression calibration approach or a naive approach without adjustment for measurement error. In the case of logistic regression, our proposed approach is shown to also outperform the regression approach with batch as a categorical covariate. In addition, we also examine a 'hybrid' approach combining the conditional likelihood method and the regression calibration method, which is shown in simulations to achieve good performance in the presence of both batch-specific and measurement-specific errors. We illustrate our method by using data from a colorectal adenoma study. PMID- 22826175 TI - CT fractional flow reserve: the next level in non-invasive cardiac imaging. AB - The haemodynamic effect of a coronary artery stenosis is a better predictor of prognosis than anatomical lumen obstruction. Until recently, no individual non invasive test could provide both accurate coronary anatomy and lesion-specific myocardial ischaemia. However, computer tomography (CT) fractional flow reserve, which can be calculated from a standard CT coronary angiogram, was recently demonstrated to accurately detect and rule out the haemodynamic significance of individual coronary artery stenoses. PMID- 22826176 TI - Folate-conjugated thermo-responsive micelles for tumor targeting. AB - Folate-conjugated and thermo-responsive poly((N-isopropylacrylamide)-co- acrylamide-co-(octadecyl acrylate)-co-(folate-(polyethylene glycol)-(acrylic acid))) (P(NIPA-co-AAm-co-ODA-co-FPA)) micelles with mean diameter of about 60 nm and lower critical solution temperature (LCST) of about 39 degrees C were synthesized by free radical random copolymerization. Single-factor tests of acrylamide and octadecyl acrylate were carried out to modulate micelles' LCST and diameter, respectively. LCST, diameter, and morphology of micelles were determined by UV-vis spectrophotometer, laser particle size analyzer, and transmittance electron microscope (TEM), respectively. Fluorescein was then used as a model drug to investigate the drug loading content of micelles. Micelles with maximum amount of octadecyl acrylate (180 mg) were found to yield drug loading content of 10.48%. Near infrared dye No.10 was chosen as the tracer to monitor micelles in vivo. The targeting behaviors of micelles in folate receptor positive Bel-7402 tumor bearing nude mice were assessed by a self-constructed near infrared imaging system. Results showed satisfactory targeting capability of the thermo-responsive micelles toward Bel-7402 tumors, and targeting accumulation could last for more than 96 h, enabling P(NIPA-co-AAm-co-ODA-co-FPA) micelles to function as a diagnostic reagent as well as a targeted tumor therapy. PMID- 22826177 TI - MR assessment of regional myocardial mechanics. AB - Regional myocardial function can be measured by several MR techniques including tissue tagging, phase velocity mapping, and more recently, displacement encoding with stimulated echoes (DENSE) and strain encoding (SENC). Each of these techniques was developed separately and has undergone significant change since its original implementation. As a result, in the current literature, the common features and the differences between the techniques and what they measure are often unclear and confusing. This review article delivers an extensively referenced introductory text which clarifies the current methodology from the starting point of the Bloch equations. By doing this in a consistent way for each method, the similarities and differences between them are highlighted. In addition, their capabilities and limitations are discussed, together with their relative advantages and disadvantages. While the focus is on sequence design and development, the principal parameters measured by each technique are also summarized, together with brief results, with the reader being directed to the extensive literature on data processing and clinical applications for more detail. PMID- 22826174 TI - Morphological and neurochemical comparisons between pulvinar and V1 projections to V2. AB - The flow of visual information is clear at the earliest stages: the retina provides the driving (main signature) activity for the lateral geniculate nucleus (LGN), which in turn drives the primary visual cortex (V1). These driving pathways can be distinguished anatomically from other modulatory pathways that innervate LGN and V1. The path of visual information after V1, however, is less clear. There are two primary feedforward projections to the secondary visual cortex (V2), one from the lateral/inferior pulvinar and the other from V1. Because both lateral/inferior pulvinar and V2 cannot be driven visually following V1 removal, either or both of these inputs to V2 could be drivers. Retinogeniculate and geniculocortical projections are privileged over modulatory projections by their layer of termination, their bouton size, and the presence of vesicular glutamate transporter 2 (Vglut2) or parvalbumin (PV). It has been suggested that such properties might also distinguish drivers from modulators in extrastriate cortex. We tested this hypothesis by comparing lateral pulvinar to V2 and V1 to V2 projections with LGN to V1 projections. We found that V1 and lateral pulvinar projections to V2 are similar in that they target the same layers and lack PV. Projections from pulvinar to V2, however, bear a greater similarity to projections from LGN to V1 because of their larger boutons (measured at the same location in V2) and positive staining for Vglut2. These data lend support to the hypothesis that the pulvinar could act as a driver for V2. PMID- 22826178 TI - Phytochemical characterisation of green beans (Phaseolus vulgaris L.) by using high-performance liquid chromatography coupled with time-of-flight mass spectrometry. AB - INTRODUCTION: Although green beans (Phaseolus vulgaris L.) constitute a major agro-industrial crop worldwide and involve many bean varieties, the phytochemical composition and how this fluctuates among varieties is not well known. OBJECTIVE: The purpose of this work was to conduct a comprehensive characterisation of the phytochemical compounds found in three varieties of green bean. METHODOLOGY: Hydromethanol extracts from green beans were analysed by high-performance liquid chromatography (HPLC) coupled with electrospray time-of-flight mass spectrometry (ESI-TOF-MS) in order to characterise phytochemical compounds from different varieties of P. vulgaris L. The compounds were characterised based on interpreting their mass spectrum provided by the TOF-MS as well as by comparison with information from the literature (some compounds have been described previously in Fabaceae). RESULTS: In this work, 72 phytochemical compounds were tentatively characterised by HPLC-ESI-TOF-MS. These compounds were classified as, 10 phenolic acids, 59 flavonoids, two lignans and an iridoid. Notably, out of the 72 compounds, 54 are new and their isomers have been characterised for the first time in green beans. CONCLUSION: The phytochemical composition of three different varieties of P. vulgaris L have been characterised using HPLC-ESI-TOF-MS. A total of 72 phytochemical compounds were characterised, 54 being reported in green beans for the first time. Among these were the main flavonoids detected. These results highlight the influence that variety can exert on the quality of phytochemicals. Given that new phytochemical compounds have been characterised, this study offers a useful approach for improving and updating the food composition tables. PMID- 22826179 TI - Profile likelihood-based confidence interval of the intraclass correlation for binary outcome data sampled from clusters. AB - The intraclass correlation in binary outcome data sampled from clusters is an important and versatile measure in many biological and biomedical investigations. Properties of the different estimators of the intraclass correlation based on the parametric, semi-parametric, and nonparametric approaches have been studied extensively, mainly in terms of bias and efficiency [see, for example, Ridout et al., Biometrics 1999, 55:137-148; Paul et al., Journal of Statistical Computation and Simulation 2003, 73:507-523; and Lee, Statistical Modelling 2004, 4: 113 126], but little attention has been paid to extending these results to the problem of the confidence intervals. In this article, we generalize the results of the four point estimators by constructing asymptotic confidence intervals obtaining closed-form asymptotic and sandwich variance expressions of those four point estimators. It appears from simulation results that the asymptotic confidence intervals based on these four estimators have serious under-coverage. To remedy this, we introduce the Fisher's z-transformation approach on the intraclass correlation coefficient, the profile likelihood approach based on the beta-binomial model, and the hybrid profile variance approach based on the quadratic estimating equation for constructing the confidence intervals of the intraclass correlation for binary outcome data. As assessed by Monte Carlo simulations, these confidence interval approaches show significant improvement in the coverage probabilities. Moreover, the profile likelihood approach performs quite well by providing coverage levels close to nominal over a wide range of parameter combinations. We provide applications to biological data to illustrate the methods. PMID- 22826180 TI - Serous epithelium, serious interpretations. PMID- 22826181 TI - Acute pain management in an unusual case of psoriasis. PMID- 22826182 TI - Case reports: iatrogenic bronchial rupture following the use of endotracheal tube introducers. AB - PURPOSE: Endotracheal tube introducers are often used in difficult tracheal intubations, but they are rarely deemed responsible for airway injuries. There have been only a few reports of severe complications, such as pharyngeal perforation, mainstem bronchus bleeding, perforation of the tracheal mucosa, and tracheal abrasion associated with hemopneumothorax. Using a computed tomography (CT) scan, we illustrate two cases of non-severe airway injuries related to endotracheal tube introducers. CLINICAL FEATURES: We present two cases of distal bronchial lacerations caused by introducers. The first occurrence was caused by a Muallem ET Tube Stylet (METTS) in a patient who underwent surgery for a total thyroidectomy and presented hemoptysis at suction after tracheal intubation. The second occurrence was caused by an Eschmann(r) Tracheal Tube Introducer (gum elastic bougie) in a patient whose trachea was intubated before a radiofrequency ablation of a single lung metastasis. There was evidence of blood on the tip of the bougie after withdrawal. In both cases, a CT scan showed a post-traumatic bronchial laceration with an acquired bronchial ectasia surrounded by ground glass opacity due to alveolar hemorrhage. The patients had no other clinical complications, and bronchial lesions resolved spontaneously at control CT scan. CONCLUSION: These two cases show that airway damage related to endotracheal tube introducers may not be exceptional. It is not unusual to have some blood on an airway management device, and the rate and severity of these lesions are unknown. However, damage to the airway can be avoided by adapting preventive techniques during tracheal intubation. PMID- 22826183 TI - In vitro characterizations of mesoporous hydroxyapatite as a controlled release delivery device for VEGF in orthopedic applications. AB - Following bone implant surgery, prolonged ischemic conditions at the implant site often result in postsurgical complications like failure of osseointegration at the bone-implant interface which can lead to implant failure. Thus, restoration of the vascular supply is paramount to the proper development of the bone. High surface area mesostructured materials have been shown to be attractive candidates for bone regeneration to enhance cell adhesion and cell proliferation. This study uses hydroxyapatite, a naturally occurring mineral in the bone, fabricated to a range of suitable pore sizes, infused with vascular endothelial growth factor (VEGF), to be progressively released to stimulate revascularization. In this study, several characterizations including nitrogen adsorption analysis, Fourier transformed infrared spectroscopy, X-ray diffraction, field emission scanning electron microscope, and transmission electron microscope were used to evaluate the synthesized mesoporous hydroxyapatite (MHA). The results showed that MHA can gradually release VEGF for enhancing revascularization, which is beneficial for orthopedic applications. PMID- 22826184 TI - MR angiography of carotid artery aneurysms in a porcine model at 3 Tesla: comparison of two different macrocyclic gadolinium chelates and of dynamic and conventional techniques. AB - PURPOSE: To evaluate the differences in image quality of two macrocyclic gadolinium-based contrast agents, gadobutrol and gadoterate meglumine, using time resolved, contrast-enhanced MR angiography (CE-MRA) in a porcine carotid artery aneurysm model and to compare image quality between dynamic and conventional, single acquisition CE-MRA. MATERIALS AND METHODS: Bilateral carotid aneurysms were created surgically in this Institutional Animal Care and Use Committee approved study. Dynamic CE-MRA studies optimized for high temporal resolution were performed at 3 Tesla. Scans using equivalently dosed (on a per mmol basis) gadobutrol and gadoterate meglumine were compared qualitatively and quantitatively in terms of contrast-to-noise ratio (CNR). Higher spatial resolution dynamic and conventional CE-MRA were also compared. RESULTS: N = 16 aneurysms were assessed. Qualitative evaluation of dynamic CE-MRA scans demonstrated a preference for gadobutrol over gadoterate meglumine. Significantly higher aneurysm CNR was found with gadobutrol (133 +/- 44) versus gadoterate meglumine, the latter at both equivalent and double injection rates (94 +/- 35 and 102 +/- 38). In a blinded assessment, conventional CE-MRA was preferred qualitatively when compared with dynamic CE-MRA. However, dynamic CE-MRA was generally capable of providing diagnostic image quality. CONCLUSION: Gadobutrol is preferred to gadoterate meglumine for high temporal resolution dynamic CE-MRA, a fact with important clinical implications for low dose CE-MRA protocols in patients at risk for nephrogenic systemic fibrosis. Conventional high resolution CE-MRA provides superior image quality when compared with dynamic CE-MRA. PMID- 22826185 TI - A comparison of least squares and conditional maximum likelihood estimators under volume endpoint censoring in tumor growth experiments. AB - Measurements in tumor growth experiments are stopped once the tumor volume exceeds a preset threshold: a mechanism we term volume endpoint censoring. We argue that this type of censoring is informative. Further, least squares (LS) parameter estimates are shown to suffer a bias in a general parametric model for tumor growth with an independent and identically distributed measurement error, both theoretically and in simulation experiments. In a linear growth model, the magnitude of bias in the LS growth rate estimate increases with the growth rate and the standard deviation of measurement error. We propose a conditional maximum likelihood estimation procedure, which is shown both theoretically and in simulation experiments to yield approximately unbiased parameter estimates in linear and quadratic growth models. Both LS and maximum likelihood estimators have similar variance characteristics. In simulation studies, these properties appear to extend to the case of moderately dependent measurement error. The methodology is illustrated by application to a tumor growth study for an ovarian cancer cell line. PMID- 22826186 TI - [Ophthalmological findings in paediatric and adolescent multiple sclerosis]. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system of unknown aetiology. The onset of MS in childhood poses diagnostic and therapeutic challenges. Differential diagnoses include acute disseminated encephalomyelitis and neurometabolic leukoencephalopathies. In this article the ophthalmological findings of paediatric and adolescent MS patients are described and discussed in the light of earlier studies. METHODS: In a retrospective study we evaluated the ophthalmological and neuro-ophthalmological findings of 44 paediatric/adolescent MS patients (aged 8-18 years). RESULTS: In 18/44 patients optic neuritis was found. Abnormalities of ocular motility were seen in 9/44 patients, 5/44 had abduction limitation, 3/44 internuclear ophthalmoplegia and 1/44 horizontal gaze palsy. Furthermore, 13/44 children showed nystagmus, mostly gaze-induced nystagmus. Uveitis was present in 4/44 patients. CONCLUSIONS: The ophthalmological and neuroophthalmological findings may lead to the diagnosis of MS. Children presenting with these symptoms should be examined by a paediatric neurologist. PMID- 22826187 TI - [Research funding in German ophthalmology]. AB - Since 2004 applications for research funding in ophthalmology have been evaluated together with those from neurosurgery, neuropathology, psychiatry, psychotherapy, psychosomatics, otolaryngology and neurology by a joint review board of the German Research Council (DFG). Facing a decreasing number of applications--in contrast to the need and importance of widespread ocular diseases--the working group "young academics" of the Deutsche Ophthalmologische Gesellschaft (DOG) assessed the perception of funding programmes and grants available. Young ophthalmologists think that they have poor prospects to receive funding by a DFG proposal. In comparison, specialist funding quotas show a stable development within the neurosciences over the last years. The sum of requested funding has a strong correlation with the total amount actually paid. By clarifying the number of funded proposals, the better transparency and communication for the existing programmes should improve the cooperativeness, the funding rate and number of applications in future. This inventory explicitly includes a motivational guidance for young researchers to take the initiative to do more proposals. PMID- 22826188 TI - [Faden operations - indications beyond esotropia and surgical results]. AB - BACKGROUND: Faden operations is a well-known surgical option for the treatment of esotropia. To the best of our knowledge there are only a few reports available dealing with this particular topic. PATIENTS AND METHOD: Retrospective series of patients in whom between 2000 and 2011 a faden operation was performed under all indications except esotropia. 23 patients (9 Graves' disease, 9 third nerve palsy, 3 sixth nerve palsy, 1 muscle dystrophy, 2 orbital trauma) were included. RESULTS: 5 out of 7 horizontally disturbed patients were operated unilaterally and the remaining 2 bilaterally. The field of binocular single vision increased from 15-70 degrees preoperatively by 10-25 degrees (unilateral) and 20-35 degrees (bilateral) to 30-80 degrees postoperatively. Out of the 16 vertically disturbed patients only one was operated on superior and inferior rectus simultaneously and all the other on only one muscle. The field of binocular single vision increased from 5-55 degrees preoperatively by 5-45 degrees to 10 80 degrees postoperatively. There were no complications so far and none of the patients worsened with the surgery. CONCLUSION: A faden operation might help to increase the field of binocular single vision in cases of restrictive squint like Graves' disease or in paralytic strabismus. PMID- 22826189 TI - Formamide-based RNA isolation at above zero temperatures from high starch cassava tubers. AB - INTRODUCTION: Cassava (Manihot esculenta) tubers are a main source of carbohydrate for a large percentage of people in the tropics. However, obtaining RNA from such high starch tubers proves problematic because gelation occurs during standard isolation procedures. In preliminary studies, formamide was used to homogenise tubers at room temperature and no gelation was observed. OBJECTIVES: To develop a simple, reproducible formamide-based procedure for RNA isolation from high starch tissues without the initial use of liquid nitrogen or lyophilisation. A second objective was to determine the impact of storage of formamide homogenates at 4 degrees C on RNA integrity. METHODOLOGY: Tubers were homogenised in 100% formamide at room temperature and stored for 1, 4 or 7 days at 4 degrees C. Homogenates were centrifuged at 14000 * g for 10 min and RNA recovered from the supernatants by isopropanol precipitation followed by dissolution in guanidinium buffer. Protein was removed by standard phenol chloroform-isoamyl alcohol extraction and RNA recovered by isopropanol precipitation. For immediate RNA isolation, formamide homogenates can be processed without incubation at 4 degrees C. RESULTS: In formamide homogenates a non-gelatinous white pellet was observed which was identified as starch by Lugol's staining. Intact RNA was observed by agarose gel electrophoresis. The RNA was successfully used in downstream RT-PCR reactions. CONCLUSION: Formamide maintained the integrity of the RNA during tissue processing at 25 +/- 2 degrees C and storage at 4 degrees C. This room temperature formamide-based RNA isolation procedure met the criteria of simplicity, low-cost, reproducibility and addressed gelation problems associated with high starch tissues. PMID- 22826190 TI - Glucocorticoid-related changes in body mass index among children and adolescents with rheumatic diseases. AB - OBJECTIVE: To examine the temporal and dose-related effects of glucocorticoids (GCs) on body mass index (BMI) in children with rheumatic diseases. METHODS: Children initiating GCs for a rheumatic disease (n = 130) were assessed every 3 months for 18 months. BMI, weight, and height Z score trajectories were described according to GC starting dosage in prednisone equivalents: high (>=1.0 mg/kg/day), low (<0.2 mg/kg/day to a maximum of 7.5 mg/day), and moderate (between high and low) dosage. The impact of GC dosing, underlying diagnosis, pubertal status, physical activity, and disease activity on BMI Z scores and on percent body fat was assessed with longitudinal mixed-effects growth curve models. RESULTS: The GC starting dose was high in 59% and moderate in 39% of patients. The peak BMI Z score was +1.29 at 4 months with high-dose GCs and +0.69 at 4.2 months with moderate-dose GCs (P < 0.001). Overall, 50% (95% confidence interval 41-59%) of the children returned to within +0.25 SD of their baseline BMI Z score. Oral GC dose over the preceding 3 months was the most significant determinant of BMI Z score and percent body fat. The proportion of days in receipt of GCs, disease activity, and a diagnosis of systemic-onset juvenile idiopathic arthritis were also associated with BMI Z scores. The correlation between changes in BMI and changes in percent body fat was 0.09. CONCLUSION: In children with rheumatic diseases starting moderate and high doses of GCs, BMI Z scores peaked at 4 months, and only half returned to within +0.25 SD of their baseline BMI Z score after 18 months. PMID- 22826192 TI - Development of a mechanically tuneable 3D scaffold for vascular reconstruction. AB - Material compliance has been shown to be a predictor of vascular graft patency and as such is a critical parameter when designing new materials. Although ex vivo derived materials have been clinically successful in a number of applications their mechanical properties are a direct function of the original vessel and are not easily controllable. These investigations describe an approach to modulate the mechanical properties of an ex vivo derived scaffold by machining variable (discrete) wall thicknesses to control compliance. Human umbilical arteries (HUAs) were machine lathed directly from the umbilical cord at wall thicknesses of 250, 500, 750, and 1000 MUm then decellularized using 1% sodium dodecyl sulfate. Compliance over physiological pressures, increased from 3.08 +/- 1.84% to 11.47 +/- 4.11% as direct function of each discrete vessel diameter. Radial stress strain analysis revealed primary and secondary failure points attributed to the discrete layers within the anisotropic scaffold. Maximum strength and suture retention were shown to increase with increasing wall thickness, by contrast stress failure decreased with increasing thickness due to increasing proportions of the mechanically weaker amorphous Wharton's jelly. Reseeded smooth muscle cells were shown to adhere, proliferate, and migrate from the scaffold surface showing the potential of the HUA as a mechanically "tunable" material with applications as an acellular implant or as a tissue engineered construct. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A:3189 3196, 2012. PMID- 22826191 TI - Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer. AB - Endometrial cancer is primarily a hormonally mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.75-1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR = 1.01, 95% CI = 0.88-1.16), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer. PMID- 22826193 TI - MR proton spectroscopy for myocardial lipid deposition quantification: a quantitative comparison between 1.5T and 3T. AB - PURPOSE: To evaluate 3T magnetic resonance spectroscopy (MRS)-derived myocardial fat-signal fractions in comparison with those from 1.5T MRS. MATERIALS AND METHODS: We conducted phantom, ex vivo and in vivo myocardial specimen evaluations at both 1.5T and 3T using (1)H-MRS. A phantom with nine fat-water emulsions was constructed to assess the accuracy of the spectroscopy measurements. Ex vivo spectroscopy data were acquired in 70 segments from 21 autopsy heart slices. In vivo spectroscopy data were acquired in the interventricular septum from 22 human volunteers. RESULTS: Phantom experiments demonstrated that 1.5T and 3T measurements were highly correlated with the reference values (r = 0.78, P < 0.05). The ex vivo and in vivo experiments demonstrated an increase in signal-to-noise ratio (SNR) of 45 +/- 73% and 76 +/- 72% at 3T compared to 1.5T (P < 0.05). The mean fat-signal fraction was similar at 3T and 1.5T (1.11 +/- 1.18 vs. 1.00 +/- 1.09, respectively, P = NS) in ex vivo studies but were significantly different in the in vivo studies (2.47 +/- 1.46 vs. 1.56 +/- 1.34, P < 0.05). The fat-signal fractions from 3T and 1.5T correlated fairly well in all experiments. CONCLUSION: 3T MRS has significantly greater SNR and could potentially be more accurate as compared to 1.5T for quantification of myocardial fat fraction in in vivo studies. PMID- 22826194 TI - Statistical models for longitudinal zero-inflated count data with applications to the substance abuse field. AB - This study fills in the current knowledge gaps in statistical analysis of longitudinal zero-inflated count data by providing a comprehensive review and comparison of the hurdle and zero-inflated Poisson models in terms of the conceptual framework, computational advantage, and performance under different real data situations. The design of simulations represents the special features of a well-known longitudinal study of alcoholism so that the results can be generalizable to the substance abuse field. When the hurdle model is more natural under the conceptual framework of the data, the zero-inflated Poisson model tends to produce inaccurate estimates. Model performance improves with larger sample sizes, lower proportions of missing data, and lower correlations between covariates. The simulation also shows that the computational strength of the hurdle model disappears when random effects are included. PMID- 22826195 TI - Foot-related health care use in patients with rheumatoid arthritis in an outpatient secondary care center for rheumatology and rehabilitation in The Netherlands: a cohort study with a maximum of fifteen years of followup. AB - OBJECTIVE: To describe foot-related health care use over time in a cohort of rheumatoid arthritis (RA) patients in an outpatient secondary care center for rheumatology and rehabilitation in The Netherlands. METHODS: A total of 1,087 patients with recent-onset RA from 1995 to September 2010 were included in the study. All foot-related visits to the podiatrist, rehabilitation physician, orthopedic surgeon, and the multidisciplinary foot-care clinic were registered and described. Logistic regression techniques for longitudinal data were used to analyze the course of foot-related health care use. RESULTS: A total of 32.9% of patients visited a podiatrist in secondary care during the course of their disease. For most patients, a visit to the podiatrist took place during the first year after diagnosis. This was followed by a significant decrease in visits in the ensuing years. Nine percent of patients visited the rehabilitation physician with foot symptoms, with peak prevalences between year 10 and 11 and during year 14 of followup. The orthopedic surgeon was visited by 5.3% of patients with foot symptoms, with a significant increase in visits over time. The multidisciplinary foot-care clinic was visited by 7.5% of patients. This was significantly associated with visits to the rehabilitation physician. CONCLUSION: In an outpatient secondary care center in The Netherlands, RA patients with foot symptoms visited the podiatrist in an early stage of the disease. When foot symptoms worsened, patients visited the rehabilitation physician, who subsequently referred patients to the multidisciplinary foot-care clinic for therapeutic footwear. The orthopedic surgeon was the final step in the management of foot symptoms. PMID- 22826196 TI - Acute and chronic exposure of chick embryo to ethanol alters brain neurosteroid levels. AB - Neurosteroids are modulators of neuronal function that may play important role in brain maturation. The aim of the present investigation was to study the effect of prenatal exposure to acute and chronic ethanol on brain progesterone, estradiol, and testosterone concentration on 10th and 15th days following egg incubation. Eggs were exposed to ethanol at 10 % in chronic treatment and 70 % in acute treatment. Progesterone, estradiol, and testosterone were assayed by radioimmunoassay method. It was shown that brain progesterone level was significantly decreased (P < 0.05) in chronic ethanol group on embryonic day 10, but it was significantly decreased (P < 0.05) in acute and chronic groups on embryonic day 15. Brain estradiol level was significantly increased (P < 0.05) in chronic ethanol group on embryonic day 10, and it was decreased (P < 0.05) in acute and chronic groups of ethanol on embryonic day 15. Brain testosterone was significantly increased (P < 0.05) in acute and chronic ethanol-exposed groups on embryonic days 10 and 15. Our observations suggest that ethanol may modulate neurosteroid synthesis in the brain. PMID- 22826197 TI - Bioactive TiO2 fiber films prepared by electrospinning method. AB - Electrospining method was used to prepare bioactive TiO(2) fibers films in this study. The acetic acid/ethanol/tetrabutyl titanate/polyvinylpyrrolidone (PVP) solvent system was used as precursor for the electrospining. The TiO(2) fiber structures (including its fiber diameter, morphology, and phase composition) could be controlled by changing feeding rate, PVP concentration and sinter temperature. The fiber films were subjected to simulated body fluid soaking experiments and MG63 cells culture experiments to study their bioactivity. According to the X-ray diffraction and MTT assay results, the fiber containing with anatase showed better apatite formation ability than that without anatase at the early stage, while cell proliferated on anatase-rutile TiO(2) fiber was better than that on other samples (p < 0.05).Some string beads in the fiber were beneficial for apatite formation, while the cell proliferated best on the fiber film without string beads (p < 0.05). The fiber with a diameter of 200 nm had the best apatite formation ability and osteoblast compatibility (p < 0.05). The results showed that the TiO(2) fiber film structure had great influence on its bioactivity. It indicated that the electronspining method is an effective way to prepare bioactive titania fiber films, and it is possible to control the structure of the films in the spinning process to optimize the bioactivity of TiO(2) fiber. PMID- 22826198 TI - Extension of the intravoxel incoherent motion model to non-gaussian diffusion in head and neck cancer. AB - PURPOSE: To extend the intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) model to restricted diffusion and to simultaneously quantify the perfusion and restricted diffusion parameters in neck nodal metastases. MATERIALS AND METHODS: The non-gaussian (NG)-IVIM model was developed and tested on diffusion-weighted MRI data collected on a 1.5-Tesla MRI scanner from eight patients with head and neck cancer. Voxel-wise parameter quantification was performed by using a noise-rectified least-square fitting method. The NG-IVIM, IVIM, Kurtosis, and ADC (apparent diffusion coefficient) models were used for comparison. For each voxel, within the metastatic node, the optimal model was determined using the Bayesian Information Criterion. The voxel percentage preferred by each model was calculated and the optimal model map was generated. Monte Carlo simulations were performed to evaluate the accuracy and precision dependency of the new model. RESULTS: For the eight neck nodes, the range of voxel percentage preferred by the NG-IVIM model was 2.3-79.3%. The optimal modal maps showed heterogeneities within the tumors. The Monte Carlo simulations demonstrated that the accuracy and precision of the NG-IVIM model improved by increasing signal-to-noise ratio and b value. CONCLUSION: The NG-IVIM model characterizes perfusion and restricted diffusion simultaneously in neck nodal metastases. PMID- 22826199 TI - Optimal design of multi-arm multi-stage trials. AB - In drug development, there is often uncertainty about the most promising among a set of different treatments. Multi-arm multi-stage (MAMS) trials provide large gains in efficiency over separate randomised trials of each treatment. They allow a shared control group, dropping of ineffective treatments before the end of the trial and stopping the trial early if sufficient evidence of a treatment being superior to control is found. In this paper, we discuss optimal design of MAMS trials. An optimal design has the required type I error rate and power but minimises the expected sample size at some set of treatment effects. Finding an optimal design requires searching over stopping boundaries and sample size, potentially a large number of parameters. We propose a method that combines quick evaluation of specific designs and an efficient stochastic search to find the optimal design parameters. We compare various potential designs motivated by the design of a phase II MAMS trial. We also consider allocating more patients to the control group, as has been carried out in real MAMS studies. We show that the optimal allocation to the control group, although greater than a 1:1 ratio, is smaller than previously advocated and that the gain in efficiency is generally small. PMID- 22826201 TI - [No liability when the patient does not understand the medical patient information]. PMID- 22826203 TI - Health care providers' perspectives of an intervention designed to improve colorectal cancer screening rates in family medicine residency clinics : a qualitative study. AB - The purpose of this study was to obtain feedback from family medicine residents and clinic nurses regarding a colorectal cancer screening (CRCS) intervention. Focus groups were used to ask participants three questions about their perceptions of the intervention and subsequent patient screening behaviors. Content analysis and constant comparison were used to yield two meaningful themes from the participant responses: patient-specific issues and study design issues. Patient-specific issues included: lack of education and fear, finances and insurance coverage, and compliance. Study design issues included: lack of time, a need for reminders to discuss CRCS with patients, quality of the nurse's role, and a need for better clinical staff education and awareness. Results show ways to significantly improve future implementation of the CRCS intervention. Ultimately, future use of clinic-based CRCS interventions could be vastly improved by utilizing strategies to promote teamwork and increase the sense of mutual ownership among clinic staff. PMID- 22826204 TI - Synthesis, characterizations, and biocompatibility of block poly(ester-urethane)s based on biodegradable poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3/4HB) and poly(epsilon-caprolactone). AB - A type of block poly(ester-urethane)s (abbreviated as PUBC) based on bacterial copolyester poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P3/4HB) and biodegradable poly(epsilon-caprolactone) (PCL) was synthesized by melting polymerization using 1,6-hexamethylene diisocyanate (HDI) as the coupling agent, with different 3HB, 4HB and PCL contents and segment lengths. Stannous octanoate (Sn(Oct)(2)) was used as catalyst. The chemical structure, molecular weight and thermal property were characterized by (1)H NMR, FTIR GPC, DSC and TGA. DSC analysis revealed that the PUBC polyurethanes exhibit amorphous to semi crystalline (20.9% crystallinity degree) with T(g) range from -39.7 to -21.5 degrees C. The hydrophilicity was investigated by static contact angle of deionized water and CH(2)I(2). The obtained PUBCs are hydrophobic (water contact angle 73.7-90.2 degrees ). Platelet adhesion study and plasma recalcification time revealed that the block polyurethanes possess hemastasis ability. CCK-8 assay illuminated that the no cytotoxic polyurethanes maintain rat aortic smooth muscle cells (RaSMCs) good viability. It was found that the 4HB content in the materials is an important factor to affect the sustainable cell viability. PMID- 22826205 TI - Use of psychotropic drugs, systemic antihistamines and medications for cough in 6 year-old children: a survey in the Bas-Rhin Region, France. AB - PURPOSE: The use of drugs in France is among the highest in developed countries. Among them, psychotropic medication in children has always been a matter of concern. Furthermore, on the basis of concerns about safety and efficacy, international authorities have either advised against the use of cough and cold medication or considered such an action. This survey aims to assess the prevalence of use of psychotropic drugs, antihistamines and medications for cough as well as parents' knowledge about the drugs used in 2009. METHODS: The study is based on a representative sample of 6-year-old children who were in kindergarten in 2009. School physicians asked their parents to answer a standardized questionnaire. Data were collected about the child, his or her family, and the consumption of psychotropic drugs, antihistamines, and medications for cough in the past 12 months. The Anatomical Therapeutic Chemical (ATC) classification system was used to classify the drugs used. RESULTS: The data from 5707 children were analyzed. The proportion of children who consumed at least one psychotropic drug was 0.68% (ATC code N). Antihistamines for systemic use were by far the most frequently consumed drugs (ATC code R06), with a prevalence of 17.54%. The great majority of antihistamines for systemic use were meant to treat cough, not insomnia or agitation. CONCLUSION: The use of psychotropic drugs was low in 2009 in the French region of Bas-Rhin. The promotion of alternatives to antihistamines for systemic use to treat cough should nevertheless be strengthened. PMID- 22826206 TI - Respiratory function at age 8-9 after extremely low birthweight or preterm birth in Victoria in 1997. AB - To determine if respiratory function at 8 years of age in extremely low birth weight (ELBW; birth weight <1,000 g) or extremely preterm (EPT, <28 weeks' gestation) children born in 1997 remains worse than normal birth weight (NBW; birth weight, >2,499 g) and term (37-42 weeks) controls, particularly in those ELBW/EPT children who had bronchopulmonary dysplasia (BPD). This was a cohort study of 201 consecutive ELBW/EPT survivors born in the state of Victoria during 1997, and 199 contemporaneous randomly selected NBW/term controls. Respiratory function was measured at 8 years of age according to standard guidelines, and compared with previous cohorts born in 1991-1992. Respiratory function data were available for almost 75% of both cohorts. ELBW/EPT subjects had substantial reductions in airflow compared with controls (e.g., mean difference in forced expiratory volume in 1 sec [FEV1 ] -0.91 SD, 95% confidence interval [CI] -1.19 to -0.63 SD, and in maximum expiratory flow between 25% and 75% of vital capacity [FEF25-75% ] -0.96 SD, 95% CI -1.22 to -0.71). These differences were similar to those observed between ELBW/EPT and controls subjects born in 1991-1992. Within the ELBW/EPT cohort, children who had BPD in the newborn period had significant reductions in both the FEV1 (-0.76 SD) and FEF25-75% (-0.58 SD) compared with those who did not have BPD, which were not statistically significant from those in the 1991-92 cohort. ELBW/EPT children born in 1997 still have significantly abnormal lung function compared with NBW/term controls, but results were similar to an earlier era when survival rates were lower. Pediatr Pulmonol. 2013; 48:449 455. (c) 2012 Wiley Periodicals, Inc. PMID- 22826207 TI - Behavior of primary human osteoblasts on trimmed and sandblasted Ti6Al4V surfaces functionalized with integrin alphavbeta3-selective cyclic RGD peptides. AB - It is well known that functionalization of surfaces with cell adhesive peptides mimicking the integrin binding motif of extracellular matrix proteins is a feasible approach to improve osseointegration of implant materials. Also, modification of the surface properties of the material (e.g., roughness) strongly influences cell behavior. However, these two approaches are rarely studied together. This study addressed the hypothesis that the combination of peptide functionalization and surface roughness will have an enhancing effect on the adhesion process of osteoblasts. To test this hypothesis, a series of alphavbeta3 selective cyclic RGD peptides were prepared and immobilized on trimmed (S(a) = 0.74 MUm, smooth) and sandblasted (S(a) = 3.24 MUm, rough) Ti6Al4V disks. Effects of these surface modifications were evaluated with respect to integrin alphavbeta3-mediated adhesive capacity, cell morphology, and spreading of primary human osteoblasts. After 3 h of incubation, osteoblasts adhered more strongly on sandblasted than on trimmed noncoated Ti6Al4V surfaces. Their attachment efficiency was further enhanced in the presence of RGD peptides. However, peptide functionalization had a relatively stronger impact on osteoblast attachment on trimmed surfaces compared with sandblasted surfaces. Cell morphology after 3 h of culture was exclusively altered by surface topography. RGD coating was critical for osteoblast spreading on both trimmed and sandblasted materials after 1 h of incubation but it showed almost negligible effects after 3 h. The results of this study provide evidence that the alliance of RGD coating and surface topography on Ti6Al4V positively influences osteoblast adhesion and spreading, especially at very early adhesion times. PMID- 22826208 TI - Individual and family characteristics associated with BRCA1/2 genetic testing in high-risk families. AB - BACKGROUND: Little is known about family members' interrelated decisions to seek genetic testing for breast cancer susceptibility. METHODS: The specific aims of this cross-sectional, descriptive, cohort study were (i) to examine whether individual and family characteristics have a direct effect on women's decisions to use genetic testing for hereditary susceptibility to breast cancer and (ii) to explore whether family characteristics moderate the relationships between individual characteristics and the decision to use genetic testing. Participants were women (>18 years old) who (i) received genetic testing for hereditary breast cancer and who agreed to invite one of their female relatives into the study and (ii) female relatives who had NOT obtained genetic testing and were identified by pedigree analysis as having >10% chances of hereditary susceptibility to breast cancer. RESULTS: The final sample consisted of 168 English-speaking, family dyads who completed self-administered, mailed surveys with validated instruments. Multivariate conditional logistic regression analyses showed that the proposed model explained 62% of the variance in genetic testing. The factors most significantly associated with genetic testing were having a personal history of cancer; perceiving genetic testing to have more benefits than barriers; having greater family hardiness; and perceiving fewer negative consequences associated with a breast cancer diagnosis. No significant interaction effects were observed. CONCLUSIONS: Findings suggest that both individual and family characteristics are associated with the decision to obtain genetic testing for hereditary breast cancer; hence, there is a need for interventions that foster a supportive family environment for patients and their high-risk relatives. PMID- 22826209 TI - Osseointegration assessment of chairside argon-based nonthermal plasma-treated Ca P coated dental implants. AB - This study investigated the effect of an Argon-based nonthermal plasma (NTP) surface treatment-operated chairside at atmospheric pressure conditions applied immediately prior to dental implant placement in a canine model. Surfaces investigated comprised: Calcium-Phosphate (CaP) and CaP + NTP (CaP-Plasma). Surface energy was characterized by the Owens-Wendt-Rabel-Kaelble method and chemistry by X-ray photoelectron spectroscopy (XPS). Six adult beagles dogs received 2 plateau-root form implants (n = 1 each surface) in each radii, providing implants that remained 1 and 3 weeks in vivo. Histometric parameters assessed were bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Statistical analysis was performed by Kruskall-Wallis (95% level of significance) and Dunn's post-hoc test. The XPS analysis showed peaks of Ca, C, O, and P for the CaP and CaP-Plasma surfaces. Both surfaces presented carbon primarily as hydrocarbon (C-C, C-H) with lower levels of oxidized carbon forms. The CaP surface presented atomic percent values of 38, 42, 11, and 7 for C, O, Ca, and P, respectively, and the CaP-Plasma presented increases in O, Ca, and P atomic percent levels at 53, 12, and 13, respectively, in addition to a decrease in C content at 18 atomic percent. At 1 week no difference was found in histometric parameters between groups. At 3 weeks significantly higher BIC and BAFO were observed for CaP-Plasma treated surfaces. Surface elemental chemistry was modified by the Ar-based NTP. Ar-based NTP improved bone formation around plateau-root form implants at 3 weeks compared with CaP treatment alone. PMID- 22826210 TI - Cognitive influences as mediators of family and peer support for pediatric cancer survivors' physical activity. AB - OBJECTIVE: The objective of this study was to determine the extent to which self efficacy mediates the relations between social support and childhood cancer survivors' physical activity (PA). METHODS: A structured telephone survey was conducted with 105 childhood cancer survivors aged 8-16 years. Participants completed measures assessing their PA as well as proposed predictors of PA including various demographic, medical, cognitive, and social influences. Multiple mediation analyses were utilized to evaluate the relations between social support, cognitive influences, and survivor PA. RESULTS: Cognitive influences, including perceived benefits, barriers, and self-efficacy for PA, partially mediated the influence of family and peer support on survivor PA. Self efficacy emerged as a significant unique mediator, indicating that higher levels of family and peer support are associated with higher levels of survivor PA via increases in survivor self-efficacy. CONCLUSIONS: Social support has both direct and indirect influences on survivor PA. Indirectly, social support influences PA via survivor self-efficacy. Interventions should target family and peer support as well as self-efficacy to increase survivor PA. PMID- 22826212 TI - Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept. AB - BACKGROUND: Understanding of cardiac outflow tract (OFT) remodeling is essential to explain repositioning of the aorta and pulmonary orifice. In wild type embryos (E9.5-14.5), second heart field contribution (SHF) to the OFT was studied using expression patterns of Islet 1, Nkx2.5, MLC-2a, WT-1, and 3D-reconstructions. Abnormal remodeling was studied in VEGF120/120 embryos. RESULTS: In wild type, Islet 1 and Nkx2.5 positive myocardial precursors formed an asymmetric elongated column almost exclusively at the pulmonary side of the OFT up to the pulmonary orifice. In VEGF120/120 embryos, the Nkx2.5-positive mesenchymal population was disorganized with a short extension along the pulmonary OFT. CONCLUSIONS: We postulate that normally the pulmonary trunk and orifice are pushed in a higher and more frontal position relative to the aortic orifice by asymmetric addition of SHF-myocardium. Deficient or disorganized right ventricular OFT expansion might explain cardiac malformations with abnormal position of the great arteries, such as double outlet right ventricle. PMID- 22826213 TI - Disc-electrospun cellulose acetate butyrate nanofibers show enhanced cellular growth performances. AB - Cellulose acetate butyrate nanofibers were prepared separately by two electrospinning techniques; a needleless electrospinning using a disc as spinneret and a rotary drum as collector and a conventional needle electrospinning using a rotary drum as collector. Compared to the needle electrospun nanofibers, the disc-electrospun nanofibers were coarser with a wider diameter distribution. Both fibers had a similar surface morphology and they showed no difference in chemical components, but the disc-electrospun nanofibers were slightly higher in crystallinity. The productivity of disc electrospinning was 150 times larger than that of needle electrospinning. The disc-electrospun nanofiber mats were found to have a three dimensional fibrous structure with an average pore size of 9.1 MUm, while the needle-electrospun nanofibers looked more like a two-dimensional sheet with a much smaller average pore size (3.2 MUm). Fibroblasts and Schwann cells were cultured on the fibrous matrices to assess the biocompatibility. The disc-electrospun nanofiber webs showed enhanced cellular growth for both fibroblasts and Schwann cells, especially in a long culture period. PMID- 22826211 TI - Laser microfabricated poly(glycerol sebacate) scaffolds for heart valve tissue engineering. AB - Microfabricated poly(glycerol sebacate) (PGS) scaffolds may be applicable to tissue engineering heart valve leaflets by virtue of their controllable microstructure, stiffness, and elasticity. In this study, PGS scaffolds were computationally designed and microfabricated by laser ablation to match the anisotropy and peak tangent moduli of native bovine aortic heart valve leaflets. Finite element simulations predicted PGS curing conditions, scaffold pore shape, and strut width capable of matching the scaffold effective stiffnesses to the leaflet peak tangent moduli. On the basis of simulation predicted effective stiffnesses of 1.041 and 0.208 MPa for the scaffold preferred (PD) and orthogonal, cross-preferred (XD) material directions, scaffolds with diamond shaped pores were microfabricated by laser ablation of PGS cured 12 h at 160 degrees C. Effective stiffnesses measured for the scaffold PD (0.83 +/- 0.13 MPa) and XD (0.21 +/- 0.03 MPa) were similar to both predicted values and peak tangent moduli measured for bovine aortic valve leaflets in the circumferential (1.00 +/- 0.16 MPa) and radial (0.26 +/- 0.03 MPa) directions. Scaffolds cultivated with fibroblasts for 3 weeks accumulated collagen (736 +/- 193 MUg/g wet weight) and DNA (17 +/- 4 MUg/g wet weight). This study provides a basis for the computational design of biomimetic microfabricated PGS scaffolds for tissue engineered heart valves. PMID- 22826214 TI - Effects of retinoic acid and Gbx1 on feather-bud formation and epidermal transdifferentiation in chick embryonic cultured dorsal skin. AB - BACKGROUND: Retinoic acid, an active metabolite of retinol, is known to regulate cell proliferation, differentiation, and morphogenesis during normal development of many tissues. Using chick embryonic tarsometatarsal skin, we showed previously that the expression of Gbx1, a divergent homeobox gene, is increased in the epidermis through interaction with retinol-pretreated dermal fibroblasts followed by epidermal transdifferentiation to mucous epithelium. This present study was performed to elucidate the effects of retinoic acid and Gbx1 on feather-bud formation and epidermal transdifferentiation. RESULTS: We showed that Gbx1 was expressed in the chick embryonic dorsal epidermis as early as at placode stage (Hamburger and Hamilton stage 31) and increased in amount during feather-bud formation. Treatment with 1 MUM retinoic acid for 24 hr inhibited feather-bud formation and induced the transdifferentiation of the epidermis to a mucosal epithelium with a concomitant increase in Gbx1 mRNA expression in the epithelium. Furthermore, transient transfection of the epidermis with Gbx1 cDNA by electroporation induced elongation of the feather bud, but did not result in transdifferentiation. CONCLUSIONS: These results indicate that Gbx1 was involved in the feather-bud formation and was one of target genes of retinoic acid and that other signals in addition to Gbx1 were required for epidermal mucous transdifferentiation. PMID- 22826215 TI - Hydrophobic gating of mechanosensitive channel of large conductance evidenced by single-subunit resolution. AB - Mechanosensitive (MS) ion channels are membrane proteins that detect and respond to membrane tension in all branches of life. In bacteria, MS channels prevent cells from lysing upon sudden hypoosmotic shock by opening and releasing solutes and water. Despite the importance of MS channels and ongoing efforts to explain their functioning, the molecular mechanism of MS channel gating remains elusive and controversial. Here we report a method that allows single-subunit resolution for manipulating and monitoring "mechanosensitive channel of large conductance" from Escherichia coli. We gradually changed the hydrophobicity of the pore constriction in this homopentameric protein by modifying a critical pore residue one subunit at a time. Our experimental results suggest that both channel opening and closing are initiated by the transmembrane 1 helix of a single subunit and that the participation of each of the five identical subunits in the structural transitions between the closed and open states is asymmetrical. Such a minimal change in the pore environment seems ideal for a fast and energy-efficient response to changes in the membrane tension. PMID- 22826216 TI - Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. AB - Toll-like receptors (TLRs) are critical components of innate immunity and function as rapid pathogen sensors. TLR4 is expressed on CD4(+) T cells as well, the functional significance of which is unclear. In this study, we analyzed the function of TLR4 in T cells but did not find a role in promoting T helper (Th) cell polarization. Instead, TLR4 ligation enhanced both CD4(+) T-cell proliferation and survival in vitro. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that the loss of TLR4 solely in CD4(+) T cells almost completely abrogated disease symptoms, mainly through blunted Th17 and, to a lesser degree, Th1 responses. Moreover, Tlr4(-/-) gammadelta T cells were defective in IL-17 and IFN-gamma production following EAE induction. This study supports an important role of this innate receptor in the direct regulation of T-cell activation and survival during autoimmune inflammation. PMID- 22826217 TI - Twelve-month-old infants recognize that speech can communicate unobservable intentions. AB - Much of our knowledge is acquired not from direct experience but through the speech of others. Speech allows rapid and efficient transfer of information that is otherwise not directly observable. Do infants recognize that speech, even if unfamiliar, can communicate about an important aspect of the world that cannot be directly observed: a person's intentions? Twelve-month-olds saw a person (the Communicator) attempt but fail to achieve a target action (stacking a ring on a funnel). The Communicator subsequently directed either speech or a nonspeech vocalization to another person (the Recipient) who had not observed the attempts. The Recipient either successfully stacked the ring (Intended outcome), attempted but failed to stack the ring (Observable outcome), or performed a different stacking action (Related outcome). Infants recognized that speech could communicate about unobservable intentions, looking longer at Observable and Related outcomes than the Intended outcome when the Communicator used speech. However, when the Communicator used nonspeech, infants looked equally at the three outcomes. Thus, for 12-month-olds, speech can transfer information about unobservable aspects of the world such as internal mental states, which provides preverbal infants with a tool for acquiring information beyond their immediate experience. PMID- 22826218 TI - The cell wall is a real drag. PMID- 22826219 TI - Platelets harness the immune response to drive liver cancer. PMID- 22826220 TI - Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite. AB - Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite--the deadliest of those that cause malaria--is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum. PMID- 22826221 TI - Liver X receptor beta protects dopaminergic neurons in a mouse model of Parkinson disease. AB - Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor beta (LXRbeta) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical layering during development and survival of dopaminergic neurons throughout life. In the present study we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of LXRbeta as a target for prevention or treatment of PD. The dopaminergic neurons of the substantia nigra of LXRbeta(-/-) mice were much more severely affected by MPTP than were those of their WT littermates. In addition, the number of activated microglia and GFAP-positive astrocytes was higher in the substantia nigra of LXRbeta(-/-) mice than in WT littermates. Administration of the LXR agonist GW3965 to MPTP-treated WT mice protected against loss of dopaminergic neurons and of dopaminergic fibers projecting to the striatum, and resulted in fewer activated microglia and astroglia. Surprisingly, LXRbeta was not expressed in the neurons of the substantia nigra but in the microglia and astroglia. We conclude that LXR agonists may have beneficial effects in treatment of PD by modulating the cytotoxic functions of microglia. PMID- 22826222 TI - Volcanic ash layers illuminate the resilience of Neanderthals and early modern humans to natural hazards. AB - Marked changes in human dispersal and development during the Middle to Upper Paleolithic transition have been attributed to massive volcanic eruption and/or severe climatic deterioration. We test this concept using records of volcanic ash layers of the Campanian Ignimbrite eruption dated to ca. 40,000 y ago (40 ka B.P.). The distribution of the Campanian Ignimbrite has been enhanced by the discovery of cryptotephra deposits (volcanic ash layers that are not visible to the naked eye) in archaeological cave sequences. They enable us to synchronize archaeological and paleoclimatic records through the period of transition from Neanderthal to the earliest anatomically modern human populations in Europe. Our results confirm that the combined effects of a major volcanic eruption and severe climatic cooling failed to have lasting impacts on Neanderthals or early modern humans in Europe. We infer that modern humans proved a greater competitive threat to indigenous populations than natural disasters. PMID- 22826223 TI - Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise. AB - Voluntary exercise is known to have an antidepressant effect. However, the underlying mechanism for this antidepressant action of exercise remains unclear, and little progress has been made in identifying genes that are directly involved. We have identified macrophage migration inhibitory factor (MIF) by analyzing existing mRNA microarray data and confirmed the augmented expression of selected genes under two experimental conditions: voluntary exercise and electroconvulsive seizure. A proinflammatory cytokine, MIF is expressed in the central nervous system and involved in innate and adaptive immune responses. A recent study reported that MIF is involved in antidepressant-induced hippocampal neurogenesis, but the mechanism remains elusive. In our data, tryptophan hydroxylase 2 (Tph2) and brain-derived neurotrophic factor (Bdnf) expression were induced after MIF treatment in vitro, as well as during both exercise and electroconvulsive seizure in vivo. This increment of Tph2 was accompanied by increases in the levels of total serotonin in vitro. Moreover, the MIF receptor CD74 and the ERK1/2 pathway mediate the MIF-induced Tph2 and Bdnf gene expression as well as serotonin content. Experiments in Mif(-/-) mice revealed depression like behaviors and a blunted antidepressant effect of exercise, as reflected by changes in Tph2 and Bdnf expression in the forced swim test. In addition, administration of recombinant MIF protein produced antidepressant-like behavior in rats in the forced swim test. Taken together, these results suggest a role of MIF in mediating the antidepressant action of exercise, probably by enhancing serotonin neurotransmission and neurotrophic factor-induced neurogenesis in the brain. PMID- 22826224 TI - Variation in neural development as a result of exposure to institutionalization early in childhood. AB - We used structural MRI and EEG to examine brain structure and function in typically developing children in Romania (n = 20), children exposed to institutional rearing (n = 29), and children previously exposed to institutional rearing but then randomized to a high-quality foster care intervention (n = 25). In so doing, we provide a unique evaluation of whether placement in an improved environment mitigates the effects of institutional rearing on neural structure, using data from the only existing randomized controlled trial of foster care for institutionalized children. Children enrolled in the Bucharest Early Intervention Project underwent a T1-weighted MRI protocol. Children with histories of institutional rearing had significantly smaller cortical gray matter volume than never-institutionalized children. Cortical white matter was no different for children placed in foster care than never-institutionalized children but was significantly smaller for children not randomized to foster care. We were also able to explain previously reported reductions in EEG alpha-power among institutionally reared children compared with children raised in families using these MRI data. As hypothesized, the association between institutionalization and EEG alpha-power was partially mediated by cortical white matter volume for children not randomized to foster care. The increase in white matter among children randomized to an improved rearing environment relative to children who remained in institutional care suggests the potential for developmental "catch up" in white matter growth, even following extreme environmental deprivation. PMID- 22826225 TI - Amino acid starvation induces reactivation of silenced transgenes and latent HIV 1 provirus via down-regulation of histone deacetylase 4 (HDAC4). AB - The epigenetic silencing of exogenous transcriptional units integrated into the genome represents a critical problem both for long-term gene therapy efficacy and for the eradication of latent viral infections. We report here that limitation of essential amino acids, such as methionine and cysteine, causes selective up regulation of exogenous transgene expression in mammalian cells. Prolonged amino acid deprivation led to significant and reversible increase in the expression levels of stably integrated transgenes transcribed by means of viral or human promoters in HeLa cells. This phenomenon was mediated by epigenetic chromatin modifications, because histone deacetylase (HDAC) inhibitors reproduced starvation-induced transgene up-regulation, and transcriptome analysis, ChIP, and pharmacological and RNAi approaches revealed that a specific class II HDAC, namely HDAC4, plays a critical role in maintaining the silencing of exogenous transgenes. This mechanism was also operational in cells chronically infected with HIV-1, the etiological agent of AIDS, in a latency state. Indeed, both amino acid starvation and pharmacological inhibition of HDAC4 promoted reactivation of HIV-1 transcription and reverse transcriptase activity production in HDAC4(+) ACH 2 T-lymphocytic cells but not in HDAC4(-) U1 promonocytic cells. Thus, amino acid deprivation leads to transcriptional derepression of silenced transgenes, including integrated plasmids and retroviruses, by a process involving inactivation or down-regulation of HDAC4. These findings suggest that selective targeting of HDAC4 might represent a unique strategy for modulating the expression of therapeutic viral vectors, as well as that of integrated HIV-1 proviruses in latent reservoirs without significant cytotoxicity. PMID- 22826226 TI - Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. AB - Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients. PMID- 22826227 TI - Factors associated with the diversification of the gut microbial communities within chimpanzees from Gombe National Park. AB - The gastrointestinal tract harbors large and diverse populations of bacteria that vary among individuals and within individuals over time. Numerous internal and external factors can influence the contents of these microbial communities, including diet, geography, physiology, and the extent of contact among hosts. To investigate the contributions of such factors to the variation and changes in gut microbial communities, we analyzed the distal gut microbiota of individual chimpanzees from two communities in Gombe National Park, Tanzania. These samples, which were derived from 35 chimpanzees, many of whom have been monitored for multiple years, provide an unusually comprehensive longitudinal depth for individuals of known genetic relationships. Although the composition of the great ape microbiota has been shown to codiversify with host species, indicating that host genetics and phylogeny have played a major role in its differentiation over evolutionary timescales, the geneaological relationships of individual chimpanzees did not coincide with the similarity in their gut microbial communities. However, the inhabitants from adjacent chimpanzee communities could be distinguished based on the contents of their gut microbiota. Despite the broad similarity of community members, as would be expected from shared diet or interactions, long-term immigrants to a community often harbored the most distinctive gut microbiota, suggesting that individuals retain hallmarks of their previous gut microbial communities for extended periods. This pattern was reinforced in several chimpanzees sampled over long temporal scales, in which the major constituents of the gut microbiota were maintained for nearly a decade. PMID- 22826228 TI - HLA-B may be more protective against HIV-1 than HLA-A because it resists negative regulatory factor (Nef) mediated down-regulation. AB - Human leukocyte antigen HLA-B alleles have better protective activity against HIV 1 than HLA-A alleles, possibly due to differences in HLA-restricted HIV-1 specific CD8+ cytotoxic T lymphocyte (CTL) function, but the mechanism is unknown. HIV-1 negative regulatory factor (Nef) mediates down-regulation of surface expression of class I HLA (HLA-I) and may therefore impair immune recognition by CTL. Because of sequence differences in the cytoplasmic domains, HLA-A and -B are down-regulated by Nef but HLA-C and -E are not affected. However, the latter are expressed at low levels and are not of major importance in the CTL responses to HIV-1. Here, we compared the role of the cytoplasmic domains of HLA-A and -B in Nef-mediated escape from CTL. We found HLA-B cytoplasmic domains were more resistant to Nef-mediated down-regulation than HLA A cytoplasmic domains and demonstrated that these differences affect CTL recognition of virus-infected cells in vitro. We propose that the relative resistance to Nef-mediated down-regulation by the cytoplasmic domains of HLA-B compared with HLA-A contributes to the better control of HIV-1 infection associated with HLA-B-restricted CTLs. PMID- 22826229 TI - Enzymatic resistance to the lipopeptide surfactin as identified through imaging mass spectrometry of bacterial competition. AB - Many species of bacteria secrete natural products that inhibit the growth or development of competing species. In turn, competitors may develop or acquire resistance to antagonistic molecules. Few studies have investigated the interplay of these countervailing forces in direct competition between two species. We have used an imaging mass spectrometry (IMS) approach to track metabolites exchanged between Bacillus subtilis and Streptomyces sp. Mg1 cultured together. Surfactin is a cyclic lipopeptide produced by B. subtilis that inhibits the formation of aerial hyphae by streptomycetes. IMS analysis exposed an addition of 18 mass units to surfactin in the agar proximal to Streptomyces sp. Mg1 but not other streptomycetes tested. The spatially resolved change in the mass of surfactin indicated hydrolysis of the molecule. We observed that the aerial growth of Streptomyces sp. Mg1 was resistant to inhibition by surfactin, which suggests that hydrolysis was a mechanism of resistance. To identify possible enzymes from Streptomyces sp. Mg1 with surfactin hydrolase activity, we isolated secreted proteins and identified candidates by mass spectrometry. We purified one candidate enzyme that hydrolyzed surfactin in vitro. We tested the role of this enzyme in surfactin resistance by deleting the corresponding gene from the S. Mg1 genome. We observed that aerial growth by the DeltasfhA mutant strain was now sensitive to surfactin. Our results identify an enzyme that hydrolyzes surfactin and confers resistance to aerial growth inhibition, which demonstrates the effective use of an IMS approach to track natural product modifications during interspecies competition. PMID- 22826230 TI - X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex specific manner. AB - Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of "bivalent" genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utx-null ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx-null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males that were smaller in size and had reduced lifespan. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a midgestation lethality, UTX-null male and female ES cells gave rise to all three germ layers in teratoma assays, though sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx-null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development. PMID- 22826231 TI - Talin couples the actomyosin cortex to the plasma membrane during rear retraction and cytokinesis. AB - Contraction of the cortical actin cytoskeleton underlies both rear retraction in directed cell migration and cytokinesis. Here, we show that talin, a central component of focal adhesions, has a major role in these processes. We found that Dictyostelium talin A colocalized with myosin II in the rear of migrating cells and the cleavage furrow. During directed cell migration, talin A-null cells displayed a long thin tail devoid of actin filaments, whereas additional depletion of SibA, a transmembrane adhesion molecule that binds to talin A, reverted this phenotype, suggesting a requirement of the link between actomyosin and SibA by talin A for rear retraction. Disruptions of talin A also resulted in detachment of the actomyosin contractile ring from the cell membrane and concomitant regression of the cleavage furrow under certain conditions. The C terminal actin-binding domain (ABD) of talin A exhibited a localization pattern identical to that of full-length talin A. The N-terminal FERM domain was found to bind phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] in vitro. In vivo, however, PtdIns(4,5)P2, which is known to activate talin, is believed to be enriched in the rear of migrating cells and the cleavage furrow in Dictyostelium. From these results, we propose that talin A activated by PtdIns(4,5)P2 in the cell posterior or cleavage furrow links actomyosin cytoskeleton to adhesion molecules or other membrane proteins, and that the force is transmitted through these links to retract the tail during cell migration or to cause efficient ingression of the equator during cytokinesis. PMID- 22826232 TI - IL-7 receptor alpha blockade, an off-switch for autoreactive T cells. PMID- 22826233 TI - Effective inhibition of cytomegalovirus infection by external guide sequences in mice. AB - Ribonuclease P complexed with external guide sequence (EGS) bound to mRNA represents a unique nucleic acid-based gene interference approach for modulation of gene expression. Compared with other strategies, such as RNA interference, the EGS-based technology is unique because a custom-designed EGS molecule can hybridize with any mRNA and recruit intracellular ribonuclease P for specific degradation of the target mRNA. It has not been reported whether the EGS-based technology can modulate gene expression in mice. In this study, a functional EGS was constructed to target the mRNA encoding the protease (mPR) of murine cytomegalovirus (MCMV), which is essential for viral replication. Furthermore, a unique attenuated strain of Salmonella was generated for gene delivery of EGS in cultured cells and in mice. Efficient expression of EGS was observed in cultured cells treated with the generated Salmonella vector carrying constructs with the EGS expression cassette. Moreover, a significant reduction in mPR expression and viral growth was found in MCMV-infected cells treated with Salmonella carrying the construct with the functional EGS sequence. When MCMV-infected mice were orally treated with Salmonella carrying EGS expression cassettes, viral gene expression and growth in various organs of these animals were reduced and animal survival improved. Our study suggests that EGS RNAs, when expressed following Salmonella-mediated gene transfer, effectively inhibit viral gene expression and infection in mice. Furthermore, these results demonstrate the feasibility of developing Salmonella-mediated delivery of EGS as a unique approach for treatment that reduces viral diseases in vivo. PMID- 22826235 TI - Topological soft matter: Kagome lattices with a twist. PMID- 22826234 TI - Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1. AB - The ubiquitous EBV causes infectious mononucleosis and is associated with several types of cancers. The EBV genome encodes an early gene product, BARF1, which contributes to pathogenesis, potentially through growth-altering and immune modulating activities, but the mechanisms for such activities are poorly understood. We have determined the crystal structure of BARF1 in complex with human macrophage-colony stimulating factor (M-CSF), a hematopoietic cytokine with pleiotropic functions in development and immune response. BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding of BARF1 to M-CSF dramatically reduces but does not completely abolish M CSF binding and signaling through its cognate receptor FMS. A three-pronged down regulation mechanism is proposed to explain the biological effect of BARF1 on M CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis. PMID- 22826236 TI - Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors. AB - Unique insights for the reprograming of cell lineages have come from embryonic development in the ascidian Ciona, which is dependent upon the transcription factors Ci-ets1/2 and Ci-mesp to generate cardiac progenitors. We tested the idea that mammalian v-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and mesoderm posterior (MESP) homolog may be used to convert human dermal fibroblasts into cardiac progenitors. Here we show that murine ETS2 has a critical role in directing cardiac progenitors during cardiopoiesis in embryonic stem cells. We then use lentivirus-mediated forced expression of human ETS2 to convert normal human dermal fibroblasts into replicative cells expressing the cardiac mesoderm marker KDR(+). However, although neither ETS2 nor the purported cardiac master regulator MESP1 can by themselves generate cardiac progenitors de novo from fibroblasts, forced coexpression of ETS2 and MESP1 or cell treatment with purified proteins reprograms fibroblasts into cardiac progenitors, as shown by the de novo appearance of core cardiac transcription factors, Ca(2+) transients, and sarcomeres. Our data indicate that ETS2 and MESP1 play important roles in a genetic network that governs cardiopoiesis. PMID- 22826237 TI - Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. AB - Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB. PMID- 22826238 TI - The SHORT-ROOT protein acts as a mobile, dose-dependent signal in patterning the ground tissue. AB - A key question in developmental biology is how cellular patterns are created and maintained. During the formation of the Arabidopsis root, the endodermis, middle cortex (MC), and cortex are produced by periclinal cell divisions that occur at different positions and at different times in root development. The endodermis and cortex arise continuously from the periclinal divisions of cells that surround the quiescent center (QC) at the tip of the root. The MC arises between days 7 and 14 from periclinal divisions of the endodermis. The divisions that produce the middle cortex begin in the basal region of the root meristem away from the QC and then spread apically and circumferentially around the root. Although the transcription factor SHORT-ROOT (SHR) is required for both of these divisions, the mechanism that determines where and when SHR acts to promote cell division along the longitudinal axis of the root is unknown; SHR is present along the entire length of the root tip, but only promotes periclinal divisions at specific sites. Here we show that the abundance of the SHR protein changes dynamically as the root develops, and that the pattern of cell division within the endodermis is sensitive to the dose of this protein: high levels of SHR prevent the formation of the MC, whereas intermediate levels of SHR promote MC formation. These results provide a mechanism for the longitudinal patterning of the endodermis, and represent the first example in plants of a mobile transcription factor whose function (activator or repressor) depends upon concentration. PMID- 22826239 TI - Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase. AB - The extent of convergent molecular evolution is largely unknown, yet is critical to understanding the genetics of adaptation. Target site insensitivity to cardenolides is a prime candidate for studying molecular convergence because herbivores in six orders of insects have specialized on these plant poisons, which gain their toxicity by blocking an essential transmembrane carrier, the sodium pump (Na,K-ATPase). We investigated gene sequences of the Na,K-ATPase alpha-subunit in 18 insects feeding on cardenolide-containing plants (spanning 15 genera and four orders) to screen for amino acid substitutions that might lower sensitivity to cardenolides. The replacement N122H that was previously shown to confer resistance in the monarch butterfly (Danaus plexippus) and Chrysochus leaf beetles was found in four additional species, Oncopeltus fasciatus and Lygaeus kalmii (Heteroptera, Lygaeidae), Labidomera clivicollis (Coleoptera, Chrysomelidae), and Liriomyza asclepiadis (Diptera, Agromyzidae). Thus, across 300 Myr of insect divergence, specialization on cardenolide-containing plants resulted in molecular convergence for an adaptation likely involved in coevolution. Our screen revealed a number of other substitutions connected to cardenolide binding in mammals. We confirmed that some of the particular substitutions provide resistance to cardenolides by introducing five distinct constructs of the Drosophila melanogaster gene into susceptible eucaryotic cells under an ouabain selection regime. These functional assays demonstrate that combined substitutions of Q(111) and N(122) are synergistic, with greater than twofold higher resistance than either substitution alone and >12-fold resistance over the wild type. Thus, even across deep phylogenetic branches, evolutionary degrees of freedom seem to be limited by physiological constraints, such that the same molecular substitutions confer adaptation. PMID- 22826240 TI - Subunit sharing among high- and low-fidelity DNA polymerases. PMID- 22826241 TI - Multiple B-vitamin depletion in large areas of the coastal ocean. AB - B vitamins are some of the most commonly required biochemical cofactors in living systems. Therefore, cellular metabolism of marine vitamin-requiring (auxotrophic) phytoplankton and bacteria would likely be significantly compromised if B vitamins (thiamin B(1), riboflavin B(2), pyridoxine B(6), biotin B(7), and cobalamin B(12)) were unavailable. However, the factors controlling the synthesis, ambient concentrations, and uptake of these key organic compounds in the marine environment are still not well understood. Here, we report vertical distributions of five B vitamins (and the amino acid methionine) measured simultaneously along a latitudinal gradient through the contrasting oceanographic regimes of the southern California-Baja California coast in the Northeast Pacific margin. Although vitamin concentrations ranged from below the detection limits of our technique to 30 pM for B(2) and B(12) and to ~500 pM for B(1), B(6), and B(7), each vitamin showed a different geographical and depth distribution. Vitamin concentrations were independent of each other and of inorganic nutrient levels, enriched primarily in the upper mesopelagic zone (depth of 100-300 m), and associated with water mass origin. Moreover, vitamin levels were below our detection limits (ranging from <=0.18 pM for B(12) to <=0.81 pM for B(1)) in extensive areas (100s of kilometers) of the coastal ocean, and thus may exert important constraints on the taxonomic composition of phytoplankton communities, and potentially also on rates of primary production and carbon sequestration. PMID- 22826242 TI - Immunoglobulin isotype influences affinity and specificity. PMID- 22826243 TI - Visual discrimination performance, memory, and medial temporal lobe function. AB - We evaluated recent proposals that structures in the medial temporal lobe (MTL)- in particular, perirhinal cortex--support not just memory but certain kinds of perceptual abilities as well. Specifically, it has been suggested that the perirhinal cortex supports the perceptual abilities needed to accomplish visual discrimination performance when the stimuli have complex features and overlapping elements. However, the tasks that have been studied are quite challenging. Stimulus features must be held in working memory while attention shifts among the several parts of the display. When working memory capacity is exceeded, performance must depend on retrieval from long-term memory. Five patients with limited hippocampal lesions and one patient with large MTL lesions were asked to identify the unique object among twin pairs of objects that had a high degree of feature overlap and perceptual similarity. The patient groups performed similarly to controls when there were few objects and features in the displays, but exhibited abrupt declines in performance when the displays contained more objects and more features. Notably, the impairment was observed in memory-impaired patients with hippocampal lesions, not only in association with large MTL lesions that included perirhinal cortex. The pattern of performance suggested that patients encountered difficulty because working memory capacity was exceeded in the more difficult conditions such that performance needed to depend at least in part on long-term memory. Furthermore, when the burden on working memory was removed entirely, the patient with large MTL lesions performed as well as controls. Accordingly, we suggest that deficits on difficult discrimination tasks reported for patients with MTL lesions are due to impaired memory rather than impaired perception. PMID- 22826244 TI - Genetic data suggest a natural prehuman origin of open habitats in northern Madagascar and question the deforestation narrative in this region. AB - The impact of climate change and anthropogenic deforestation on biodiversity is of growing concern worldwide. Disentangling how past anthropogenic and natural factors contributed to current biome distribution is thus a crucial issue to understand their complex interactions on wider time scales and to improve predictions and conservation strategies. This is particularly important in biodiversity hotspots, such as Madagascar, dominated by large open habitats whose origins are increasingly debated. Although a dominant narrative argues that Madagascar was originally entirely covered by woodlands, which were destroyed by humans, a number of recent studies have suggested that past climatic fluctuations played a major role in shaping current biome distributions well before humans arrived. Here, we address the question of the origin of open habitats in the Daraina region in northern Madagascar, using a multiproxy approach combining population genetics modeling and remote-sensing analyses. We show that (i) contrary to most regions of Madagascar, the forest cover in Daraina remained remarkably stable over the past 60 y, and (ii) the golden-crowned sifaka (Propithecus tattersalli), a forest-dwelling lemur, underwent a strong population contraction before the arrival of the first humans, hence excluding an anthropogenic cause. Prehuman Holocene droughts may have led to a significant increase of grasslands and a reduction in the species' habitat. This contradicts the prevailing narrative that land cover changes are necessarily anthropogenic in Madagascar but does not preclude the later role played by humans in other regions in which recent lemur bottlenecks have been observed. PMID- 22826245 TI - Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder. AB - The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1(-/-) astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course. PMID- 22826246 TI - Crystal structure of LpxK, the 4'-kinase of lipid A biosynthesis and atypical P loop kinase functioning at the membrane interface. AB - In Gram-negative bacteria, the hydrophobic anchor of the outer membrane lipopolysaccharide is lipid A, a saccharolipid that plays key roles in both viability and pathogenicity of these organisms. The tetraacyldisaccharide 4' kinase (LpxK) of the diverse P-loop-containing nucleoside triphosphate hydrolase superfamily catalyzes the sixth step in the biosynthetic pathway of lipid A, and is the only known P-loop kinase to act upon a lipid substrate at the membrane. Here, we report the crystal structures of apo- and ADP/Mg(2+)-bound forms of Aquifex aeolicus LpxK to a resolution of 1.9 A and 2.2 A, respectively. LpxK consists of two alpha/beta/alpha sandwich domains connected by a two-stranded beta-sheet linker. The N-terminal domain, which has most structural homology to other family members, is responsible for catalysis at the P-loop and positioning of the disaccharide-1-phosphate substrate for phosphoryl transfer on the inner membrane. The smaller C-terminal domain, a substructure unique to LpxK, helps bind the nucleotide substrate and Mg(2+) cation using a 25 degrees hinge motion about its base. Activity was severely reduced in alanine point mutants of conserved residues D138 and D139, which are not directly involved in ADP or Mg(2+) binding in our structures, indicating possible roles in phosphoryl acceptor positioning or catalysis. Combined structural and kinetic studies have led to an increased understanding of the enzymatic mechanism of LpxK and provided the framework for structure-based antimicrobial design. PMID- 22826247 TI - A systems science perspective and transdisciplinary models for food and nutrition security. AB - We argue that food and nutrition security is driven by complex underlying systems and that both research and policy in this area would benefit from a systems approach. We present a framework for such an approach, examine key underlying systems, and identify transdisciplinary modeling tools that may prove especially useful. PMID- 22826250 TI - Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of effector function. AB - After primary infection, human cytomegalovirus (HCMV) persists as a life-long latent infection, with host immunosuppression often resulting in clinical reactivation. During lytic infection, major changes in the expression of secreted cellular proteins (the secretome) occur that have profound effects on host-cell interactions, particularly at the level of the host immune response. In contrast, little is known about changes in the secretome that accompany latent infection, yet this is likely to be of major importance for the life-long carriage of this persistent human pathogen in the face of constant immunosurveillance. We have analyzed the secretome of cells carrying latent HCMV and have identified changes in several secreted cellular proteins known to be involved in regulation of the immune response and chemoattraction. Here, we show that a latency-associated increase in CC chemokine ligand (CCL)8 results in the recruitment of cluster of differentiation (CD)4(+) T cells to supernatants from latently infected CD34(+) cells but that these latent supernatants, also rich in immunosuppressive factors, inhibit cytokine secretion and cytotoxicity of HCMV-specific T-helper (Th)1 CD4(+) T cells. These results identify a strategy by which sites of latent HCMV can firstly recruit CD4(+) T cells and then inhibit their antiviral effector functions, thereby aiding the maintenance of latent infection in the face of the host immune response. PMID- 22826252 TI - Paths of convergence for agriculture, health, and wealth. AB - This special feature calls for forward thinking around paths of convergence for agriculture, health, and wealth. Such convergence aims for a richer integration of smallholder farmers into national and global agricultural and food systems, health systems, value chains, and markets. The articles identify analytical innovation, where disciplines intersect, and cross-sectoral action where single, linear, and siloed approaches have traditionally dominated. The issues addressed are framed by three main themes: (i) lessons related to agricultural and food market growth since the 1960s; (ii) experiences related to the integration of smallholder agriculture into national and global business agendas; and (iii) insights into convergence-building institutional design and policy, including a review of complexity science methods that can inform such processes. In this introductory article, we first discuss the perspectives generated for more impactful policy and action when these three themes converge. We then push thematic boundaries to elaborate a roadmap for a broader, solution-oriented, and transdisciplinary approach to science, policies, and actions. As the global urban population crosses the 50% mark, both smallholder and nonsmallholder agriculture are keys in forging rural-urban links, where both farm and nonfarm activities contribute to sustainable nutrition security. The roadmaps would harness the power of business to reduce hunger and poverty for millions of families, contribute to a better alignment between human biology and modern lifestyles, and stem the spread of noncommunicable chronic diseases. PMID- 22826253 TI - Green revolution: impacts, limits, and the path ahead. AB - A detailed retrospective of the Green Revolution, its achievement and limits in terms of agricultural productivity improvement, and its broader impact at social, environmental, and economic levels is provided. Lessons learned and the strategic insights are reviewed as the world is preparing a "redux" version of the Green Revolution with more integrative environmental and social impact combined with agricultural and economic development. Core policy directions for Green Revolution 2.0 that enhance the spread and sustainable adoption of productivity enhancing technologies are specified. PMID- 22826254 TI - Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change. AB - Polar bears (PBs) are superbly adapted to the extreme Arctic environment and have become emblematic of the threat to biodiversity from global climate change. Their divergence from the lower-latitude brown bear provides a textbook example of rapid evolution of distinct phenotypes. However, limited mitochondrial and nuclear DNA evidence conflicts in the timing of PB origin as well as placement of the species within versus sister to the brown bear lineage. We gathered extensive genomic sequence data from contemporary polar, brown, and American black bear samples, in addition to a 130,000- to 110,000-y old PB, to examine this problem from a genome-wide perspective. Nuclear DNA markers reflect a species tree consistent with expectation, showing polar and brown bears to be sister species. However, for the enigmatic brown bears native to Alaska's Alexander Archipelago, we estimate that not only their mitochondrial genome, but also 5-10% of their nuclear genome, is most closely related to PBs, indicating ancient admixture between the two species. Explicit admixture analyses are consistent with ancient splits among PBs, brown bears and black bears that were later followed by occasional admixture. We also provide paleodemographic estimates that suggest bear evolution has tracked key climate events, and that PB in particular experienced a prolonged and dramatic decline in its effective population size during the last ca. 500,000 years. We demonstrate that brown bears and PBs have had sufficiently independent evolutionary histories over the last 4-5 million years to leave imprints in the PB nuclear genome that likely are associated with ecological adaptation to the Arctic environment. PMID- 22826255 TI - Archaeal virus with exceptional virion architecture and the largest single stranded DNA genome. AB - Known viruses build their particles using a restricted number of redundant structural solutions. Here, we describe the Aeropyrum coil-shaped virus (ACV), of the hyperthermophilic archaeon Aeropyrum pernix, with a virion architecture not previously observed in the viral world. The nonenveloped, hollow, cylindrical virion is formed from a coiling fiber, which consists of two intertwining halves of a single circular nucleoprotein. The virus ACV is also exceptional for its genomic properties. It is the only virus with a single-stranded (ss) DNA genome among the known hyperthermophilic archaeal viruses. Moreover, the size of its circular genome, 24,893 nt, is double that of the largest known ssDNA genome, suggesting an efficient solution for keeping ssDNA intact at 90-95 degrees C, the optimal temperature range of A. pernix growth. The genome content of ACV is in line with its unique morphology and confirms that ACV is not closely related to any known virus. PMID- 22826256 TI - Discovery, taxonomic distribution, and phenotypic characterization of a gene required for 3-methylhopanoid production. AB - Hopanoids methylated at the C-3 position are a subset of bacterial triterpenoids that are readily preserved in modern and ancient sediments and in petroleum. The production of 3-methylhopanoids by extant aerobic methanotrophs and their common occurrence in modern and fossil methane seep communities, in conjunction with carbon isotope analysis, has led to their use as biomarker proxies for aerobic methanotrophy. In addition, these lipids are also produced by aerobic acetic acid bacteria and, lacking carbon isotope analysis, are more generally used as indicators for aerobiosis in ancient ecosystems. However, recent genetic studies have brought into question our current understanding of the taxonomic diversity of methylhopanoid-producing bacteria and have highlighted that a proper interpretation of methylhopanes in the rock record requires a deeper understanding of their cellular function. In this study, we identified and deleted a gene, hpnR, required for methylation of hopanoids at the C-3 position in the obligate methanotroph Methylococcus capsulatus strain Bath. Bioinformatics analysis revealed that the taxonomic distribution of HpnR extends beyond methanotrophic and acetic acid bacteria. Phenotypic analysis of the M. capsulatus hpnR deletion mutant demonstrated a potential physiological role for 3 methylhopanoids; they appear to be required for the maintenance of intracytoplasmic membranes and cell survival in late stationary phase. Therefore, 3-methylhopanoids may prove more useful as proxies for specific environmental conditions encountered during stationary phase rather than a particular bacterial group. PMID- 22826257 TI - Developed and developing world responsibilities for historical climate change and CO2 mitigation. AB - At the United Nations Framework Convention on Climate Change Conference in Cancun, in November 2010, the Heads of State reached an agreement on the aim of limiting the global temperature rise to 2 degrees C relative to preindustrial levels. They recognized that long-term future warming is primarily constrained by cumulative anthropogenic greenhouse gas emissions, that deep cuts in global emissions are required, and that action based on equity must be taken to meet this objective. However, negotiations on emission reduction among countries are increasingly fraught with difficulty, partly because of arguments about the responsibility for the ongoing temperature rise. Simulations with two earth system models (NCAR/CESM and BNU-ESM) demonstrate that developed countries had contributed about 60-80%, developing countries about 20-40%, to the global temperature rise, upper ocean warming, and sea-ice reduction by 2005. Enacting pledges made at Cancun with continuation to 2100 leads to a reduction in global temperature rise relative to business as usual with a 1/3-2/3 (CESM 33-67%, BNU ESM 35-65%) contribution from developed and developing countries, respectively. To prevent a temperature rise by 2 degrees C or more in 2100, it is necessary to fill the gap with more ambitious mitigation efforts. PMID- 22826258 TI - A quantitative quasispecies theory-based model of virus escape mutation under immune selection. AB - Viral infections involve a complex interplay of the immune response and escape mutation of the virus quasispecies inside a single host. Although fundamental aspects of such a balance of mutation and selection pressure have been established by the quasispecies theory decades ago, its implications have largely remained qualitative. Here, we present a quantitative approach to model the virus evolution under cytotoxic T-lymphocyte immune response. The virus quasispecies dynamics are explicitly represented by mutations in the combined sequence space of a set of epitopes within the viral genome. We stochastically simulated the growth of a viral population originating from a single wild-type founder virus and its recognition and clearance by the immune response, as well as the expansion of its genetic diversity. Applied to the immune escape of a simian immunodeficiency virus epitope, model predictions were quantitatively comparable to the experimental data. Within the model parameter space, we found two qualitatively different regimes of infectious disease pathogenesis, each representing alternative fates of the immune response: It can clear the infection in finite time or eventually be overwhelmed by viral growth and escape mutation. The latter regime exhibits the characteristic disease progression pattern of human immunodeficiency virus, while the former is bounded by maximum mutation rates that can be suppressed by the immune response. Our results demonstrate that, by explicitly representing epitope mutations and thus providing a genotype phenotype map, the quasispecies theory can form the basis of a detailed sequence specific model of real-world viral pathogens evolving under immune selection. PMID- 22826259 TI - Double electron-electron resonance shows cytochrome P450cam undergoes a conformational change in solution upon binding substrate. AB - Although cytochrome P450cam from Pseudomonas putida, the archetype for all heme monooxygenases, has long been known to have a closed active site, recent reports show that the enzyme can also be crystallized in at least two clusters of open conformations. This suggests that the enzyme may undergo significant conformational changes during substrate binding and catalytic turnover. However, these conformations were observed in the crystalline state, and information is needed about the conformations that are populated in solution. In this study, double electron-electron resonance experiments were performed to observe substrate-induced changes in distance as measured by the dipolar coupling between spin labels introduced onto the surface of the enzyme on opposite sides of the substrate access channel. The double electron-electron resonance data show a decrease of 0.8 nm in the distance between spin labels placed at S48C and S190C upon binding the substrate camphor. A rotamer distribution model based on the crystal structures adequately describes the observed distance distributions. These results demonstrate conclusively that, in the physiologically relevant solution state, the substrate-free enzyme exists in the open P450cam-O conformation and that camphor binding results in conversion to the closed P450cam C form. This approach should be useful for investigating many other P450s, including mammalian forms, in which the role of conformational change is of central importance but not well understood. PMID- 22826260 TI - Binding and biomimetic cleavage of the RNA poly(U) by synthetic polyimidazoles. AB - Four polyimidazoles were used in the binding and cleavage studies with poly(U). The two polydisperse polyvinylimidazoles were previously described by others, while the other two new polymers of polyethyleneimines were prepared by cationic polymerization of oxazolines. The latter had imidazole units attached to each nitrogen of the polymers. They were characterized by gel permeation chromatography and had very low polydispersities. When they were partially protonated they bound to the poly(U) and catalyzed its cleavage by a process analogous to that used by the enzyme ribonuclease A. The kinetics of the cleavage were followed by an assay we had previously described using phosphodiesterase I from Crotalus venom after the cleavage processes. Cleavage of poly(U) with Zn(2+) was also examined, with and without the polymers. A scheme is described in which these cleavages could be made sequence selective with various RNAs, particularly with important targets, such as viral RNAs. PMID- 22826261 TI - Calculation of thermodynamic hydricities and the design of hydride donors for CO2 reduction. AB - We have developed a correlation between experimental and density functional theory-derived results of the hydride-donating power, or "hydricity", of various ruthenium, rhenium, and organic hydride donors. This approach utilizes the correlation between experimental hydricity values and their corresponding calculated free-energy differences between the hydride donors and their conjugate acceptors in acetonitrile, and leads to an extrapolated value of the absolute free energy of the hydride ion without the necessity to calculate it directly. We then use this correlation to predict, from density functional theory-calculated data, hydricity values of ruthenium and rhenium complexes that incorporate the pbnHH ligand-pbnHH = 1,5-dihydro-2-(2-pyridyl)-benzo[b]-1,5-naphthyridine-to model the function of NADPH. These visible light-generated, photocatalytic complexes produced by disproportionation of a protonated-photoreduced dimer of a metal-pbn complex may be valuable for use in reducing CO(2) to fuels such as methanol. The excited-state lifetime of photoexcited [Ru(bpy)(2)(pbnHH)](2+) is found to be about 70 ns, and this excited state can be reductively quenched by triethylamine or 1,4-diazabicyclo[2.2.2]octane to produce the one-electron reduced [Ru(bpy)(2)(pbnHH)](+) species with half-life exceeding 50 MUs, thus opening the door to new opportunities for hydride-transfer reactions leading to CO(2) reduction by producing a species with much increased hydricity. PMID- 22826262 TI - Chemically reduced graphene contains inherent metallic impurities present in parent natural and synthetic graphite. AB - Graphene-related materials are in the forefront of nanomaterial research. One of the most common ways to prepare graphenes is to oxidize graphite (natural or synthetic) to graphite oxide and exfoliate it to graphene oxide with consequent chemical reduction to chemically reduced graphene. Here, we show that both natural and synthetic graphite contain a large amount of metallic impurities that persist in the samples of graphite oxide after the oxidative treatment, and chemically reduced graphene after the chemical reduction. We demonstrate that, despite a substantial elimination during the oxidative treatment of graphite samples, a significant amount of impurities associated to the chemically reduced graphene materials still remain and alter their electrochemical properties dramatically. We propose a method for the purification of graphenes based on thermal treatment at 1,000 degrees C in chlorine atmosphere to reduce the effect of such impurities on the electrochemical properties. Our findings have important implications on the whole field of graphene research. PMID- 22826263 TI - A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy. AB - We report the development of an all-fiber-optic scanning endomicroscope capable of high-resolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized double-clad fiber, a compact rapid two dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of bench-top SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth. PMID- 22826264 TI - Surface energetics of freely suspended fluid molecular monolayer and multilayer smectic liquid crystal films. AB - A study of the surface energetics of the thinnest substrate-free liquid films, fluid molecular monolayer and multilayer smectic liquid crystal films suspended in air, is reported. In films having monolayer and multilayer domains, the monolayer areas contract, contrary to predictions from the van der Waals disjoining pressure of thin uniform slabs. This discrepancy is accounted for by modeling the environmental asymmetry of the surface layers in multilayer films, leading to the possibility that preferential end-for-end polar ordering of the rod shaped molecules can reduce the surface energy of multilayers relative to that of the monolayer, which is inherently symmetric. PMID- 22826266 TI - Calorimetric, FTIR and 1H NMR measurements in combination with DFT calculations for monitoring solid-state changes of dynamics of sibutramine hydrochloride. AB - Two forms of sibutramine hydrochloride, monohydrate and anhydrous, have been investigated by calorimetric methods, Fourier transform infrared (FTIR) absorption and (1) H nuclear magnetic resonance (NMR) measurements as well as by density functional theory (DFT) of vibrational frequencies and infrared intensities, calculations of steric hindrances and Monte Carlo simulations. The results of FTIR spectra combined with DFT calculations permitted identification of the bands corresponding to the dynamics and vibrations of water molecules. NMR study and Monte Carlo simulations revealed the occurrence of reorientation jumps of the methyl groups in sibutramine cation and also revealed that the reorientation of isopropyl group is possible only in sibutramine monohydrate hydrochloride. The hydration of sibutramine hydrochloride causes a change in the conformation of sibutramine cation. PMID- 22826265 TI - Counteracting chemical chaperone effects on the single-molecule alpha-synuclein structural landscape. AB - Protein structure and function depend on a close interplay between intrinsic folding energy landscapes and the chemistry of the protein environment. Osmolytes are small-molecule compounds that can act as chemical chaperones by altering the environment in a cellular context. Despite their importance, detailed studies on the role of these chemical chaperones in modulating structure and dimensions of intrinsically disordered proteins have been limited. Here, we used single molecule Forster resonance energy transfer to test the counteraction hypothesis of counterbalancing effects between the protecting osmolyte trimethylamine-N oxide (TMAO) and denaturing osmolyte urea for the case of alpha-synuclein, a Parkinson's disease-linked protein whose monomer exhibits significant disorder. The single-molecule experiments, which avoid complications from protein aggregation, do not exhibit clear solvent-induced cooperative protein transitions for these osmolytes, unlike results from previous studies on globular proteins. Our data demonstrate the ability of TMAO and urea to shift alpha-synuclein structures towards either more compact or expanded average dimensions. Strikingly, the experiments directly reveal that a 21 [urea][TMAO] ratio has a net neutral effect on the protein's dimensions, a result that holds regardless of the absolute osmolyte concentrations. Our findings shed light on a surprisingly simple aspect of the interplay between urea and TMAO on alpha-synuclein in the context of intrinsically disordered proteins, with potential implications for the biological roles of such chemical chaperones. The results also highlight the strengths of single-molecule experiments in directly probing the chemical physics of protein structure and disorder in more chemically complex environments. PMID- 22826267 TI - Microarray-based identification of Pitx3 targets during Xenopus embryogenesis. AB - BACKGROUND: Unexpected phenotypes resulting from morpholino-mediated translational knockdown of Pitx3 in Xenopus laevis required further investigation regarding the genetic networks in which the gene might play a role. Microarray analysis was, therefore, used to assess global transcriptional changes downstream of Pitx3. RESULTS: From the large data set generated, selected candidate genes were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. CONCLUSIONS: We have identified four genes as likely direct targets of Pitx3 action: Pax6, beta Crystallin-b1 (Crybb1), Hes7.1, and Hes4. Four others show equivocal promise worthy of consideration: Vent2, and Ripply2 (aka Ledgerline or Stripy), eFGF and RXRalpha. We also describe the expression pattern of additional and novel genes that are Pitx3-sensitive but that are unlikely to be direct targets. PMID- 22826268 TI - CNVD: text mining-based copy number variation in disease database. AB - Copy number variation (CNV) is a kind of chromosomal structural reorganization that has been detected, in this decade, mainly by high-throughput biological technology. Researchers have found that CNVs are ubiquitous in many species and accumulating evidence indicates that CNVs are closely related with complex diseases. The investigation of chromosomal structural alterations has begun to reveal some important clues to the pathologic causes of diseases and to the disease process. However, many of the published studies have focused on a single disease and, so far, the experimental results have not been systematically collected or organized. Manual text mining from 6301 published papers was used to build the Copy Number Variation in Disease database (CNVD). CNVD contains CNV information for 792 diseases in 22 species from diverse types of experiments, thus, ensuring high confidence and comprehensive representation of the relationship between the CNVs and the diseases. In addition, multiple query modes and visualized results are provided in the CNVD database. With its user-friendly interface and the integrated CNV information for different diseases, CNVD will offer a truly comprehensive platform for disease research based on chromosomal structural variations. The CNVD interface is accessible at http://bioinfo.hrbmu.edu.cn/CNVD. PMID- 22826269 TI - Juvenile polyposis syndrome presenting with familial gastric cancer and massive gastric polyposis. PMID- 22826270 TI - Family history of cancer in patients with gastric cancer. PMID- 22826272 TI - Concordance and discordance in tumor genomic profiling. PMID- 22826271 TI - Six cycles of doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. AB - PURPOSE: The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity. PATIENTS AND METHODS: Between 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS). RESULTS: A total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P=.77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P=.44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS. CONCLUSION: For women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome. PMID- 22826273 TI - Improving survival trends in primary myelofibrosis: an international study. AB - PURPOSE: Despite the lack of major improvements in the treatment of primary myelofibrosis (PMF), there are recent indications that the survival of patients might have increased over the years. This study was aimed at ascertaining whether survival prolongation has actually occurred in PMF. PATIENTS AND METHODS: A total of 802 patients diagnosed with PMF in four European countries were compared for the presentation of features and survival according to the diagnostic periods 1980 to 1995 (n = 434) and 1996 to 2007 (n = 368); relative survival was estimated for the two groups. RESULTS: Patients diagnosed between 1996 and 2007 more often had constitutional symptoms (31% v 23%) but a lower incidence of marked anemia (31% v 39%), leukocytosis greater than 25 * 10(9)/L (9% v 13%), and blood blasts (27% v 33%); risk distribution was comparable between the two groups. Median survival was 4.6 years (95% CI, 4.0 to 5.1) for patients from 1980 to 1995 and 6.5 years (95% CI, 5.5 to 7.4) for patients from 1996 to 2007 (P < .001). The latter group of patients showed improved relative survival, especially for women, patients younger than age 65 years, and patients with low or intermediate-1-risk disease. Rates of PMF-attributable mortality at 5 and 10 years were significantly lower in the second period; this reduction in disease specific mortality occurred across all patient subgroups, except in intermediate 2-risk or high-risk patients. CONCLUSION: Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations. PMID- 22826275 TI - Before we throw out progression-free survival as a valid end point... PMID- 22826274 TI - Influence of chemotherapy on EGFR mutation status among patients with non-small cell lung cancer. AB - PURPOSE: EGFR mutation is a predictor of epidermal growth factor receptor tyrosine kinase inhibitor treatment response in patients with non-small-cell lung cancer (NSCLC). However, it remains unclear whether chemotherapy affects EGFR mutation status in NSCLC. We investigated the influence of chemotherapy on EGFR mutations in plasma and tumor tissues from patients with NSCLC. PATIENTS AND METHODS: Samples were derived from three cohorts: one, 264 patients with advanced NSCLC who received first-line chemotherapy with matched pre- and postchemotherapy blood samples; two, 63 patients with stages IIb to IIIb disease with pre- and post-neoadjuvant chemotherapy tumor tissues; and three, 79 patients with advanced NSCLC who underwent palliative surgery. EGFR mutation status was determined and analyzed to reveal potential impact of chemotherapy. RESULTS: In the first cohort, EGFR mutations were detected in 34.5% of the prechemotherapy plasma samples (91 of 264) but in only 23.1% of the postchemotherapy plasma samples (61 of 264). The decrease in EGFR mutation rate was statistically significant (P < .001). Patients whose EGFR mutations switched from positive to negative after chemotherapy had a better partial response (PR) than patients with a reverse change (P = .037). A similar decrease in EGFR mutation rate was observed in tissues after neoadjuvant chemotherapy in the second cohort (34.9% [22 of 63] v 19.0% [12 of 63]; P = .013). In the third cohort, 38.0% of the tumors (30 of 79) showed an intratumor heterogeneity of EGFR mutation, whereas 62.0% (49 of 79) were homogeneous, either with EGFR mutation or no mutation. CONCLUSION: Our results suggest that chemotherapy may reduce EGFR mutation frequency in patients with NSCLC, likely the result of a preferential response of subclones with EGFR mutations in tumors with heterogeneous tumor cell populations. PMID- 22826276 TI - Validation of a nomogram for predicting risk of local recurrence for ductal carcinoma in situ. PMID- 22826277 TI - Is family history associated with improved survival in patients with gastric cancer? PMID- 22826279 TI - Design of testis cancer trials: who knows best? PMID- 22826278 TI - Full facial edema: a novel presentation of subcutaneous panniculitis-like T-cell lymphoma. PMID- 22826280 TI - Primary intracranial germ cell tumor originating from septum pellucidum that mimics central neurocytoma. PMID- 22826281 TI - Risk of colorectal cancer after detection and removal of adenomas at colonoscopy: population-based case-control study. AB - PURPOSE: Empirical evidence for recommendations of surveillance intervals after detection and removal of adenomas at colonoscopy is still sparse and mostly based on observations of adenoma recurrence. We aimed to assess risk of colorectal cancer (CRC) according to time since polypectomy and factors that might be relevant for risk stratification. METHODS: In a population-based case-control study conducted in Germany, detailed history and results of previous large-bowel endoscopies were obtained by interview and from medical records. Risk of CRC among participants with detection of at least one adenoma at a preceding colonoscopy compared with participants without previous large-bowel endoscopy was assessed according to time since polypectomy among 2,582 cases with CRC and 1,798 matched controls. RESULTS: Adjusted odds ratios (95% CIs) of CRC for participants with polypectomy less than 3, 3 to 5, and 6 to 10 years ago (using participants without previous endoscopy as reference group) were 0.2 (0.2 to 0.3), 0.4 (0.3 to 0.6), and 0.9 (0.5 to 1.5), respectively. Strong, significant risk reduction within 5 years was consistently seen for women and men, younger and older participants, patients with and without high-risk polyps (three or more polyps, at least one polyp >= 1 cm, at least one polyp with villous components), and those with and without polypectomy in the right colon. With adjusted odds ratios of 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.5) and 0.4 (0.2 to 0.8) for patients with polypectomy less than 3, 3 to 5, and 6 to 10 years ago, risk reduction was particularly strong for left-sided CRC. CONCLUSION: Extension of surveillance intervals to 5 years should be considered, even after detection and removal of high-risk polyps. PMID- 22826282 TI - What a difference a letter can make. PMID- 22826283 TI - Cerebral air embolism caused by chemoradiotherapy for esophageal cancer. PMID- 22826285 TI - Successful target attainment of telavancin at elevated MICs: fact or fiction? PMID- 22826289 TI - A novel gene cassette potentially conferring resistance to aminoglycosides. PMID- 22826287 TI - Clonal complex 258, the most frequently found multilocus sequence type complex in KPC-2-producing Klebsiella pneumoniae isolated in Brazilian hospitals. PMID- 22826290 TI - Hyperventilation in anticipatory music performance anxiety. AB - OBJECTIVES AND METHODS: Self-report studies have shown an association between music performance anxiety (MPA) and hyperventilation complaints. However, hyperventilation was never assessed physiologically in MPA. This study investigated the self-reported affective experience, self-reported physiological symptoms, and cardiorespiratory variables including partial pressure of end-tidal CO(2) (Petco(2)), which is an indicator for hyperventilation, in 67 music students before a private and a public performance. The response coherence between these response domains was also investigated. RESULTS: From the private to the public session, the intensity of all self-report variables increased (all p values < .001). As predicted, the higher the musician's usual MPA level, the larger were these increases (p values < .10). With the exception of Petco(2), the main cardiorespiratory variables also increased from the private to the public session (p values < .05). These increases were not modulated by the usual MPA level (p values > .10). Petco(2) showed a unique response pattern reflected by an MPA-by-session interaction (p < .01): it increased from the private to the public session for musicians with low MPA levels and decreased for musicians with high MPA levels. Self-reported physiological symptoms were related to the self reported affective experience (p values < .05) rather than to physiological measures (p values > .17). CONCLUSIONS: These findings show for the first time how respiration is stimulated before a public performance in music students with different MPA levels. The hypothesis of a hyperventilation tendency in high performance-anxious musicians is supported. The response coherence between physiological symptoms and physiological activation is weak. PMID- 22826291 TI - Electrophysiologic evidence for multilevel deficits in emotional face processing in patients with bulimia nervosa. AB - BACKGROUND: Empirical evidence suggests substantial deficits regarding emotion recognition in bulimia nervosa (BN). The aim of the current study was to investigate electrophysiologic evidence for deficits in emotional face processing in patients with BN. METHODS: Event-related potentials were recorded from 13 women with BN and 13 matched healthy controls while viewing neutral, happy, fearful, and angry facial expressions. Participants' recognition performance for emotional faces was tested in a subsequent categorization task. In addition, the degree of alexithymia, depression, and anxiety were assessed via questionnaires. RESULTS: Categorization of emotional faces was hampered in BN (p = .01). Amplitudes of event-related potentials differed during emotional face processing: face-specific N170 amplitudes were less pronounced for angry faces in patients with BN (mean [M] [standard deviation {SD}] = 1.46 [0.56] uV versus M [SD] = 1.23 [0.61] uV, p = .02). In contrast, P3 amplitudes were more pronounced in patients with BN as compared with controls (M [SD] = 2.64 [0.46] uV versus M [SD] = 1.25 [0.39] uV, p = .04), independent of emotional expression. CONCLUSIONS: The study provides novel electrophysiologic data showing that emotional faces are processed differently in patients with BN as compared with healthy controls. We suggest that deficits in early automatic emotion classification in BN are followed by an increased allocation of attentional resources to compensate for those deficits. These findings might contribute to a better understanding of the impaired social functioning in BN. PMID- 22826292 TI - Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future. AB - Compared with younger people, older people are much more variable in their organ function, and these large individual differences contribute to the complexity of geriatric medicine. What determines this variability? Is it due to the accumulation of different life experiences, or because of the variation in the genes we are born with, or an interaction of both? This paper reviews key findings from ageing twin cohorts probing these questions. Twin studies are the perfect natural experiment to dissect out genes and life experiences. We discuss the paradox that ageing is strongly determined by heritable factors (an influence that often gets stronger with time), yet longevity and lifespan seem not to be so heritable. We then focus on the intriguing question of why DNA sequence-identical twins might age differently. Animal studies are increasingly showing that epigenetic modifications occurring in early development and adulthood, might be key to ageing phenomena but this is difficult to investigate longitudinally in human populations, due to ethical problems of intervention and long lifespan. We propose that identical twin studies using new and existing cohorts may be useful human models in which to investigate the interaction between the environment and genetics, mediated by epigenetic modifications. PMID- 22826293 TI - Neighbourhoods matter too: the association between neighbourhood socioeconomic position, population density and breast, prostate and lung cancer incidence in Denmark between 2004 and 2008. AB - BACKGROUND: Previous studies have shown that cancer incidence is related to a number of individual factors, including socioeconomic status. The aim of this study was to refine the current knowledge about indicators associated with cancer incidence by evaluating the influence of neighbourhood characteristics on breast, prostate and lung cancer incidence in Denmark. METHODS: All women aged 30-83 years were followed for breast cancer between 2004 and 2008, men between 50 and 83 years were followed for prostate cancer and both sexes between ages 50 and 83 were followed for lung cancer. Registry data obtained from Statistics Denmark included age, sex, availability of breast cancer screening, marital status, education, disposable income and occupational socioeconomic status on the individual level and population density and neighbourhood socioeconomic status (the proportion of unemployed) on the parish level. Frailty modelling with individuals on the first level and parishes on the second level was conducted. RESULTS: A significantly lower HR of breast cancer was found in areas with low population density (HR=0.93; CI 0.88 to 0.99), while neighbourhood unemployment had no effect. Inhabitants of lower unemployment areas had a higher risk of prostate cancer (HR=1.14; CI 1.08 to 1.21) compared with those in higher unemployment areas, whereas population density had no effect. Risk of lung cancer was lower in areas with lowest population density (HR=0.80; CI 0.74 to 0.85) and lowest in areas with lowest unemployment (HR=0.88; CI 0.84 to 0.92). CONCLUSIONS: In addition to individual-level factors, characteristics on the neighbourhood level also have an influence on breast, prostate and lung cancer incidence. PMID- 22826294 TI - The psychosocial pathway to mental well-being at the local level: investigating the effects of perceived relative position in a deprived area context. AB - BACKGROUND: The study investigated whether perceived relative position was associated with mental well-being for people living in deprived areas, as a contribution to debates about income inequality, relative deprivation and health. METHODS: A survey of 4615 residents of deprived areas of Glasgow measured mental well-being using the WEMWBS scale. Perceived relative position was assessed locally and across wider society in relation to housing, neighbourhood and standard of living. Personal and dwelling characteristics were controlled for. RESULTS: Mental well-being was found to be positively associated with: perceived relative quality (RR 4.1, 95% CI 2.4 to 6.8) and status (RR 7.1, 95% CI 4.5 to 11.1) of the home; perceived internal reputation of the neighbourhood (RR 4.9, 95% CI 2.9 to 8.2), though not external reputation; and perceived relative standard of living (RR 5.2, 95% CI 3.2 to 8.4). Furthermore, respondents who thought they lived in an area where some people had higher incomes than others also reported higher mental well-being (RR 4.5, 95% CI 2.2 to 9.1), controlling for the effects of their own income. CONCLUSION: Studies of inequality and health could give more consideration to the importance of the residential domain of housing and neighbourhood to mental well-being outcomes, via the psychosocial pathway. The local spatial scale may be more important to issues of relative deprivation than previously thought, as people make local as well as broader comparisons. The ability to make upward comparisons of income within deprived areas may be beneficial to residents rather than detrimental, possibly as an indicator of area progress and 'normality'. PMID- 22826295 TI - Balancing community mobilisation and measurement needs in the evaluation of targeted interventions for HIV prevention. PMID- 22826296 TI - Asian dust storm events are associated with an acute increase in stroke hospitalisation. AB - OBJECTIVE: Asian dust storms (ADS) are long-ranged meteorological phenomena, which are suggested to be associated with several health problems. This study aimed to investigate the risk of stroke hospitalisation following ADS events by conducting a population-based study. STUDY DESIGN AND SETTING: The authors identified 810 947 hospitalisations with an admission diagnosis of stroke during the time period between 2000 and 2009 in Taiwan. The ARIMA method (Auto Regressive Integrated Moving Average) was used to examine the associations between ADS episodes and the daily number of stroke hospitalisations. RESULTS: There were 46 separate ADS episodes which resulted in a total of 135 ADS days between 2000 and 2009. The Kruskal-Wallis test revealed that there was a significant difference in the mean number of daily stroke admissions among ADS days (239.6), post-ADS days (249.2) and non-ADS days (219.7) (p<0.001). After adjusting for the time-trend effect, ambient temperature, season, SO(2) and CO, the authors found post-ADS days 1 and 2 to have a significantly higher number of stroke admission than non-ADS days. Post-ADS days 1 and 2 had significantly higher numbers of ischaemic but not haemorrhagic stroke admissions. CONCLUSION: The authors conclude that ADS events are associated with an acute increase in stroke admission rates. PMID- 22826297 TI - Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. AB - Two to three years after infection, a fraction of HIV-1-infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti-HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4 induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti-HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti-HIV-1 serologic breadth and potency should not be limited to single epitopes. PMID- 22826298 TI - Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. AB - The intestinal microbiota contributes to the development of the immune system, and conversely, the immune system influences the composition of the microbiota. Toll-like receptors (TLRs) in the gut recognize bacterial ligands. Although TLR signaling represents a major arm of the innate immune system, the extent to which TLRs influence the composition of the intestinal microbiota remains unclear. We performed deep 16S ribosomal RNA sequencing to characterize the complex bacterial populations inhabiting the ileum and cecum of TLR- and MyD88-deficient mice. The microbiota of MyD88- and TLR-deficient mouse colonies differed markedly, with each colony harboring distinct and distinguishable bacterial populations in the small and large intestine. Comparison of MyD88-, TLR2-, TLR4-, TLR5-, and TLR9 deficient mice and their respective wild-type (WT) littermates demonstrated that the impact of TLR deficiency on the composition of the intestinal microbiota is minimal under homeostatic conditions and after recovery from antibiotic treatment. Thus, differences between TLR-deficient mouse colonies reflected long term divergence of the microbiota after extended husbandry in isolation from each other. Long-term breeding of isolated mouse colonies results in changes of the intestinal microbiota that are communicated to offspring by maternal transmission, which account for marked compositional differences between WT and mutant mouse strains. PMID- 22826300 TI - A gas that ignites a bright spark. PMID- 22826301 TI - Potentiating exercise training with resveratrol. PMID- 22826299 TI - Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor. AB - When a cell undergoes apoptosis, phosphatidylserine (PS) is exposed on the outer leaflet of the plasma membrane. PS acts as an "eat-me" signal to direct phagocytes expressing PS receptors to engulf the apoptotic cell. We recently reported that the immunoreceptor CD300a, which is expressed on myeloid cells, is a PS receptor. We show that CD300a does not facilitate macrophage phagocytosis of apoptotic cells. Instead, CD300a delivers an inhibitory signal in mast cells to suppress production of LPS-induced inflammatory cytokines and chemokines. After cecal ligation and puncture (CLP), when a large number of cells undergo apoptosis in the peritoneal cavity, CD300a-deficient peritoneal mast cells produced more chemoattractant and recruited more neutrophils than did wild-type (WT) mast cells. As a result, CD300a-deficient mice showed increased neutrophil recruitment and improved bacterial clearance in the peritoneal cavity, and survived longer than WT mice. Antibody blockade of CD300a-PS interactions improved bacterial clearance and extended survival of WT mice subjected to CLP. These results indicated that CD300a is a nonphagocytic PS receptor that regulates mast cell inflammatory responses to microbial infections. PMID- 22826302 TI - Beyond a one-track mind: understanding blood flow to the brain in humans. PMID- 22826303 TI - Comment on the paper by Gibala, Little, Macdonald and Hawley entitled physiological adaptations to low-volume, high-intensity interval training in health and disease. PMID- 22826305 TI - LupusQoL-FR is valid to assess quality of life in patients with systemic lupus erythematosus. AB - OBJECTIVE: To cross-culturally adapt the LupusQoL into French, to test its measurement properties and to further investigate its domain structure. METHODS: The cultural adaptation process according to guidelines and pre-testing resulted in the LupusQoL-FR. SLE patients completed the LupusQoL-FR at baseline, 15 days, 3 months and 6 months. Validity was studied through content and construct validity (factorial and Rasch analysis for structural validity, Spearman's correlation and Mann-Whitney tests for external validity). Cronbach's alpha and intra-class correlation coefficients were computed for reliability. The standardized response mean was computed to evaluate responsiveness. RESULTS: In all, 182 patients, age 39.6 (10.6) years, mostly outpatients [mean SELENA-SLEDAI 2.6 (3.5)] were recruited. Factor analysis with eight imposed factors was very close to the original LupusQoL. A screeplot with parallel analysis showed that LupusQoL domains could be aggregated in two physical and mental scales. Both eight- and two-factor structures showed a good Rasch fit, internal consistency (Cronbach's alpha: 0.85-0.95), and test-retest reliability (intra-class correlation coefficient 0.79-0.95). External convergent (correlation with SF-36, r=0.59-0.78) and divergent validity (according to SELENA-SLEDAI) were also satisfactory. CONCLUSION: The LupusQoL-FR is valid to assess quality of life in SLE patients. A two-factor structure of physical and mental aggregated scales is a valid alternative to the original eight-domain structure. PMID- 22826306 TI - Comment on: arthropathy with infiltrate IgG4-positive plasma cells in synovium. PMID- 22826307 TI - Posttranslational modifications of proteins in type 1 diabetes: the next step in finding the cure? AB - The overall role of modification of beta-cell antigens in type 1 diabetes has not been elucidated and was the focus of a recent workshop on posttranslational modification of proteins in type 1 diabetes. The prevailing opinion of the workshop attendees was that novel insights into the mechanism of loss of immune tolerance might be gained and that novel diagnostic and therapeutic approaches could be developed for type 1 diabetes if protein modifications were shown to play a critical role in the disease. PMID- 22826308 TI - Modulating mitochondrial fission to lower diabetic oxidative stress. PMID- 22826309 TI - Sweet and low: measuring brain glucose during hypoglycemia. PMID- 22826311 TI - The challenging search for diabetic nephropathy genes. PMID- 22826310 TI - More news about NUCB2/nesfatin-1: a new factor in the hypothalamic control of glucose homeostasis? PMID- 22826312 TI - Identifying biomarkers of subclinical diabetes. PMID- 22826316 TI - The protein tyrosine phosphatase SHP-1 regulates phagolysosome biogenesis. AB - The process of phagocytosis and phagosome maturation involves the recruitment of effector proteins that participate in phagosome formation and in the acidification and/or fusion with various endocytic vesicles. In the current study, we investigated the role of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) in phagolysosome biogenesis. To this end, we used immortalized bone marrow macrophages derived from SHP-1-deficient motheaten mice and their wild-type littermates. We found that SHP-1 is recruited early and remains present on phagosomes for up to 4 h postphagocytosis. Using confocal immunofluorescence microscopy and Western blot analyses on purified phagosome extracts, we observed an impaired recruitment of lysosomal-associated membrane protein 1 in SHP-1-deficient macrophages. Moreover, Western blot analyses revealed that whereas the 51-kDa procathepsin D is recruited to phagosomes, it is not processed into the 46-kDa cathepsin D in the absence of SHP-1, suggesting a defect in acidification. Using the lysosomotropic agent LysoTracker as an indicator of phagosomal pH, we obtained evidence that in the absence of SHP-1, phagosome acidification was impaired. Taken together, these results are consistent with a role for SHP-1 in the regulation of signaling or membrane fusion events involved in phagolysosome biogenesis. PMID- 22826313 TI - What do magnetic resonance-based measurements of Pi->ATP flux tell us about skeletal muscle metabolism? AB - Magnetic resonance spectroscopy (MRS) methods offer a potentially valuable window into cellular metabolism. Measurement of flux between inorganic phosphate (Pi) and ATP using (31)P MRS magnetization transfer has been used in resting muscle to assess what is claimed to be mitochondrial ATP synthesis and has been particularly popular in the study of insulin effects and insulin resistance. However, the measured Pi->ATP flux in resting skeletal muscle is far higher than the true rate of oxidative ATP synthesis, being dominated by a glycolytically mediated Pi<->ATP exchange reaction that is unrelated to mitochondrial function. Furthermore, even if measured accurately, the ATP production rate in resting muscle has no simple relationship to mitochondrial capacity as measured either ex vivo or in vivo. We summarize the published measurements of Pi->ATP flux, concentrating on work relevant to diabetes and insulin, relate it to current understanding of the physiology of mitochondrial ATP synthesis and glycolytic Pi< >ATP exchange, and discuss some possible implications of recently reported correlations between Pi->ATP flux and other physiological measures. PMID- 22826317 TI - Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanoma. AB - CD73 is a cell surface enzyme that suppresses T cell-mediated immune responses by producing extracellular adenosine. Growing evidence suggests that targeting CD73 in cancer may be useful for an effective therapeutic outcome. In this study, we demonstrate that administration of a specific CD73 inhibitor, adenosine 5' (alpha,beta-methylene)diphosphate (APCP), to melanoma-bearing mice induced a significant tumor regression by promoting the release of Th1- and Th17-associated cytokines in the tumor microenvironment. CD8+ T cells were increased in melanoma tissue of APCP-treated mice. Accordingly, in nude mice APCP failed to reduce tumor growth. Importantly, we observed that after APCP administration, the presence of B cells in the melanoma tissue was greater than that observed in control mice. This was associated with production of IgG2b within the melanoma. Depletion of CD20+ B cells partially blocked the anti-tumor effect of APCP and significantly reduced the production of IgG2b induced by APCP, implying a critical role for B cells in the anti-tumor activity of APCP. Our results also suggest that APCP could influence B cell activity to produce IgG through IL-17A, which significantly increased in the tumor tissue of APCP-treated mice. In support of this, we found that in melanoma-bearing mice receiving anti-IL-17A mAb, the anti-tumor effect of APCP was ablated. This correlated with a reduced capacity of APCP-treated mice to mount an effective immune response against melanoma, as neutralization of this cytokine significantly affected both the CD8+ T cell- and B cell-mediated responses. In conclusion, we demonstrate that both T cells and B cells play a pivotal role in the APCP-induced anti-tumor immune response. PMID- 22826318 TI - CD8 T cells are essential for recovery from a respiratory vaccinia virus infection. AB - The precise immune components required for protection against a respiratory Orthopoxvirus infection, such as human smallpox or monkeypox, remain to be fully identified. In this study, we used the virulent Western Reserve strain of vaccinia virus (VACV-WR) to model a primary respiratory Orthopoxvirus infection. Naive mice infected with VACV-WR mounted an early CD8 T cell response directed against dominant and subdominant VACV-WR Ags, followed by a CD4 T cell and Ig response. In contrast to other VACV-WR infection models that highlight the critical requirement for CD4 T cells and Ig, we found that only mice deficient in CD8 T cells presented with severe cachexia, pulmonary inflammation, viral dissemination, and 100% mortality. Depletion of CD8 T cells at specified times throughout infection highlighted that they perform their critical function between days 4 and 6 postinfection and that their protective requirement is critically dictated by initial viral load and virulence. Finally, the ability of adoptively transferred naive CD8 T cells to protect RAG-/- mice against a lethal VACV-WR infection demonstrated that they are both necessary and sufficient in protecting against a primary VACV-WR infection of the respiratory tract. PMID- 22826319 TI - A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice. AB - Malignant B cells responding to external stimuli are likely to gain a growth advantage in vivo. These cells may therefore maintain surface CD19 expression to amplify transmembrane signals and promote their expansion and survival. To determine whether CD19 expression influences this process, EMU-Myc transgenic (c Myc(Tg)) mice that develop aggressive and lethal B cell lymphomas were made CD19 deficient (c-Myc(Tg)CD19-/-). Compared with c-Myc(Tg) and c-Myc(Tg)CD19+/- littermates, the median life span of c-Myc(Tg)CD19-/- mice was prolonged by 81 83% (p < 0.0001). c-Myc(Tg)CD19-/- mice also lived 42% longer than c-Myc(Tg) littermates following lymphoma detection (p < 0.01). Tumor cells in c-Myc(Tg) and c-Myc(Tg)CD19-/- mice were B lineage derived, had a similar phenotype with a large blastlike appearance, invaded multiple lymphoid tissues, and were lethal when adoptively transferred into normal recipient mice. Importantly, reduced lymphomagenesis in c-Myc(Tg)CD19-/- mice was not due to reductions in early B cell numbers prior to disease onset. In mechanistic studies, constitutive c-Myc expression enhanced CD19 expression and phosphorylation on active sites. Reciprocally, CD19 expression in c-Myc(Tg) B cells enhanced c-Myc phosphorylation at regulatory sites, sustained higher c-Myc protein levels, and maintained a balance of cyclin D2 expression over that of cyclin D3. These findings define a new and novel c-Myc:CD19 regulatory loop that positively influences B cell transformation and lymphoma progression. PMID- 22826321 TI - Decoding the regulation of mast cell exocytosis by networks of Rab GTPases. AB - Exocytosis is a key event in mast cell functions. By this process, mast cells release inflammatory mediators, contained in secretory granules (SGs), which play important roles in immunity and wound healing but also provoke allergic and inflammatory responses. The mechanisms underlying mast cell exocytosis remained poorly understood. An essential step toward deciphering the mechanisms behind exocytosis is the identification of the cellular components that regulate this process. Because Rab GTPases regulate specific trafficking pathways, we screened 44 Rabs for their functional impacts on exocytosis triggered by the FcepsilonRI or combination of Ca 2+ ionophore and phorbol ester. Because exocytosis involves the continuous reorganization of the actin cytoskeleton, we also repeated our screen in the presence of cytochalasin D that inhibits actin polymerization. In this paper, we report on the identification of 30 Rabs as regulators of mast cell exocytosis, the involvement of 26 of which has heretofore not been recognized. Unexpectedly, these Rabs regulated exocytosis in a stimulus-dependent fashion, unless the actin skeleton was disrupted. Functional clustering of the identified Rabs suggested their classification as Rabs involved in SGs biogenesis or Rabs that control late steps of exocytosis. The latter could be further divided into Rabs that localize to the SGs and Rabs that regulate transport from the endocytic recycling compartment. Taken together, these findings unveil the Rab networks that control mast cell exocytosis and provide novel insights into their mechanisms of action. PMID- 22826320 TI - Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. AB - Dendritic cells (DCs) are potent inducers of T cell immunity, and autologous DC vaccination holds promise for the treatment of cancers and chronic infectious diseases. In practice, however, therapeutic vaccines of this type have had mixed success. In this article, we show that brief exposure to inhibitors of mechanistic target of rapamycin (mTOR) in DCs during the period that they are responding to TLR agonists makes them particularly potent activators of naive CD8+ T cells and able to enhance control of B16 melanoma in a therapeutic autologous vaccination model in the mouse. The improved performance of DCs in which mTOR has been inhibited is correlated with an extended life span after activation and prolonged, increased expression of costimulatory molecules. Therapeutic autologous vaccination with DCs treated with TLR agonists plus the mTOR inhibitor rapamycin results in improved generation of Ag-specific CD8+ T cells in vivo and improved antitumor immunity compared with that observed with DCs treated with TLR agonists alone. These findings define mTOR as a molecular target for augmenting DC survival and activation, and document a novel pharmacologic approach for enhancing the efficacy of therapeutic autologous DC vaccination. PMID- 22826322 TI - Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-beta1 signaling. AB - Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin induced pulmonary fibrosis was significantly reduced in Chit1-/- mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-beta1 to augment fibroblast TGF-beta receptors 1 and 2 expression and TGF-beta-induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-beta1 effects by increasing receptor expression and canonical and noncanonical TGF-beta1 signaling. PMID- 22826323 TI - Activation-induced cytidine deaminase-initiated off-target DNA breaks are detected and resolved during S phase. AB - Activation-induced cytidine deaminase (AID) initiates DNA double-strand breaks (DSBs) in the IgH gene (Igh) to stimulate isotype class switch recombination (CSR), and widespread breaks in non-Igh (off-target) loci throughout the genome. Because the DSBs that initiate class switching occur during the G1 phase of the cell cycle, and are repaired via end joining, CSR is considered a predominantly G1 reaction. By contrast, AID-induced non-Igh DSBs are repaired by homologous recombination. Although little is known about the connection between the cell cycle and either induction or resolution of AID-mediated non-Igh DSBs, their repair by homologous recombination implicates post-G1 phases. Coordination of DNA breakage and repair during the cell cycle is critical to promote normal class switching and prevent genomic instability. To understand how AID-mediated events are regulated through the cell cycle, we have investigated G1-to-S control in AID dependent genome-wide DSBs. We find that AID-mediated off-target DSBs, like those induced in the Igh locus, are generated during G1. These data suggest that AID mediated DSBs can evade G1/S checkpoint activation and persist beyond G1, becoming resolved during S phase. Interestingly, DSB resolution during S phase can promote not only non-Igh break repair, but also Ig CSR. Our results reveal novel cell cycle dynamics in response to AID-initiated DSBs, and suggest that the regulation of the repair of these DSBs through the cell cycle may ensure proper class switching while preventing AID-induced genomic instability. PMID- 22826324 TI - Recombinatorial biases and convergent recombination determine interindividual TCRbeta sharing in murine thymocytes. AB - Overlap of TCR repertoires among individuals provides the molecular basis for public T cell responses. By deep-sequencing the TCRbeta repertoires of CD4+CD8+ thymocytes from three individual mice, we observed that a substantial degree of TCRbeta overlap, comprising ~10-15% of all unique amino acid sequences and ~5-10% of all unique nucleotide sequences across any two individuals, is already present at this early stage of T cell development. The majority of TCRbeta sharing between individual thymocyte repertoires could be attributed to the process of convergent recombination, with additional contributions likely arising from recombinatorial biases; the role of selection during intrathymic development was negligible. These results indicate that the process of TCR gene recombination is the major determinant of clonotype sharing between individuals. PMID- 22826325 TI - Successful limb-sparing treatment strategy for diabetic foot osteomyelitis. AB - BACKGROUND: Diabetic foot osteomyelitis is common and causes substantial morbidity, including major amputations, yet the optimal treatment approach is unclear. We evaluated an approach to limb salvage that combines early surgical debridement or limited amputation with antimicrobial therapy. METHODS: We conducted a retrospective cohort study of patients treated between May 1, 2005, and May 31, 2007. The primary end point was cure, defined as not requiring further treatment for osteomyelitis of the affected limb. The secondary end point was limb salvage, defined as not requiring a below-the-knee amputation or a more proximal amputation. RESULTS: Fifty patients with diabetic foot osteomyelitis met the study criteria. Initial surgical management included local amputation in 43 patients (86%) and debridement without amputation in seven (14%). Most infections (n = 30; 60%) were polymicrobial, and Staphylococcus aureus was the most common pathogen (n = 23; 46%). Parenteral antibiotics were used in 45 patients (90%). Patients who had pathologic evidence of osteomyelitis at the surgical margin received therapy for a median of 43 days (interquartile range [IQR], 36-56 days), whereas those without evidence of residual osteomyelitis received therapy for a median of 19 days (IQR, 13-40 days). Overall, 32 patients (64%) were considered cured after a median follow-up of 26 months (IQR, 12-38 months). Fifteen of 18 patients (83%) who failed initial therapy were treated again with limb-sparing surgery. Limb salvage was achieved in 47 patients (94%), with only three patients (6%) requiring below-the-knee amputation. CONCLUSIONS: In patients with diabetic foot osteomyelitis, surgical debridement or limited amputation plus antimicrobial therapy is effective at achieving clinical cure and limb salvage. PMID- 22826326 TI - Reliability of a new supination resistance measurement device and validation of the manual supination resistance test. AB - BACKGROUND: Kinematic observations are inconsistent in predicting lower-extremity injury risk, and research suggests that kinetic variables may be more important in this regard. Before kinetics can be prospectively investigated, we need reliable ways of measuring them clinically. A measurement instrument was manufactured that closely mirrors a manual test used to clinically estimate supination resistance force. The reliability of the instrument and the validity of the clinical test were investigated. METHODS: The left feet of 26 healthy individuals (17 men and 9 women; mean +/- SD age, 25.9 +/- 9.2 years; mean +/- SD weight, 77.7 +/- 13.3 kg) were assessed. Foot Posture Index (FPI-6), manual supination resistance, and machine supination resistance were measured. Intrarater and interrater reliability of all of the measurements were calculated. Correlations of the supination resistance measured by the device with FPI-6, the manual supination resistance test, and body weight were investigated. RESULTS: Interrater reliability of all of the measurements was generally poor. The supination resistance machine correlated highly with the manual supination test for the rater experienced with its use. Supination resistance measurements correlated poorly with the FPI-6 and weakly with body weight. CONCLUSIONS: The supination resistance machine was shown to have sufficient limits of agreement for the study, but improvements need to be made for more meaningful research going forward. In this study, the force required to supinate a foot was independent of its posture, and approximately 12% of it was explained by body weight. Further work is required with a much larger sample size to build regression models that sufficiently predict supination resistance force and that will be of clinical use. The manual supination test is a valid clinical test for clinicians experienced in its use. PMID- 22826327 TI - Intrarater and interrater reliability of first metatarsophalangeal joint dorsiflexion: goniometry versus visual estimation. AB - BACKGROUND: Visual estimation (VE) and goniometric measurement (GM) are commonly used to assess first metatarsophalangeal joint dorsiflexion. The purposes of this study were to determine the intrarater and interrater reliability of VE and GM and to establish whether reliability was influenced by the experience of the examiner. METHODS: Ten experienced and ten inexperienced examiners evaluated three real-size photographs of a first metatarsophalangeal joint positioned in various degrees of dorsiflexion on two separate occasions. RESULTS: Experienced examiners demonstrated excellent intrarater and interrater reliability for GM (intraclass correlation coefficient [ICC], >0.953; standard error of measurement [SEM], 1.8 degrees -2.5 degrees ) compared with inexperienced examiners, who showed fair-to-good intrarater and interrater reliability (ICC, 0.322-0.597; SEM, 2.0 degrees -3.0 degrees ). For VE, inexperienced examiners demonstrated fair-to good interrater and excellent intra-rater reliability (ICC, 0.666-0.808), which was higher compared with experienced examiners (ICC, 0.167-0.672). The SEM (2.8 degrees -4.4 degrees ) was less varied than that of experienced examiners (SEM, 3.8 degrees -6.4 degrees ) for VE, but neither group's SEMs were clinically acceptable. CONCLUSIONS: Although minimal differences between intrarater and interrater reliability of GM and VE are noted, this study suggests that GM is more reliable than VE is when used by experienced examiners. These findings support the continued use of GM for first metatarsophalangeal joint dorsiflexion assessment. PMID- 22826328 TI - Inhibition of matrix metalloproteinase 9 expression in rat dermal fibroblasts using small interfering RNA. AB - BACKGROUND: Matrix metalloproteinases (MMPs) degrade extracellular matrix components. Increased MMP-9 content in diabetic skin contributes to skin vulnerability and refractory foot ulcers. To identify ways to decrease MMP-9 levels in skin, inhibition of MMP-9 expression in dermal fibroblasts using small interfering RNA was investigated in vitro. METHODS: A full-thickness wound was created on the midback of streptozotocin-induced diabetic rats; skin biopsies were performed 3 days later. Skin MMP-9 expression was observed by immunohistochemical analysis. Dermal fibroblasts from 1-day-old normal Sprague Dawley rats cultured with high glucose and homocysteine concentrations were transfected with small interfering RNA complexes. Cells were collected 30, 48, and 72 hours after transfection, and reverse transcription-polymerase chain reaction, Western blot analysis, and gelatin zymography for MMP-9 were performed. RESULTS: Expression of MMP-9 was increased in diabetic rat skin, especially around wounds. After 30-, 48-, and 72-hour transfection with each MMP-9-specific small interfering RNA, reverse transcription-polymerase chain reaction showed markedly decreased MMP-9 messenger RNA expression, protein abundance, and activity. Of four MMP-9 small interfering RNAs, one sequence had a stable high inhibition rate (>70% at 30 and 48 hours after transfection). CONCLUSIONS: Expression of MMP-9 was increased in diabetic rat skin, especially around wounds, and was markedly inhibited after MMP-9 small interfering RNA transfection in vitro (P < .05). These findings may provide new treatments for diabetic skin wounds. PMID- 22826329 TI - Optimization of an infected shoe model for the evaluation of an ultraviolet shoe sanitizer device. AB - BACKGROUND: Onychomycosis and tinea pedis (athlete's foot) are infections of the nails and skin caused by pathogenic fungi collectively known as dermatophytes. These infections are difficult to treat, and patients often relapse; it is thought that a patient's footwear becomes infected with these fungal organisms and, thus, is an important reservoir for reinfection. Therefore, it is important to find an effective means for killing the dermatophytes that may have colonized the inner surface of the shoes of patients with superficial fungal infections. In this study, we developed an in vitro model for culturing dermatophytes in footwear and used this model to evaluate the effectiveness of a commercial ultraviolet shoe sanitizer in eradicating the fungal elements residing in shoes. METHODS: Leather and athletic shoes (24 pairs) were inoculated with either Trichophyton rubrum or Trichophyton mentagrophytes (10(7) colony-forming units/mL) strains and were placed at 35 degrees C for 4 to 5 days. Next, we compared the ability of swabbing versus scraping to collect microorganisms from infected shoes. Following the optimized method, shoes were infected and were irradiated with one to three cycles of radiation. The inner surfaces of the shoes were swabbed or scraped, and the specimens were cultured for dermatophyte colony forming units. RESULTS: Leather and canvas shoes were infected to the same extent. Moreover, scraping with a scalpel was overall more effective than was swabbing with a cotton-tipped applicator in recovering viable fungal elements. Irradiation of shoes with one, two, or three cycles resulted in reduction of fungal colonization to the same extent. CONCLUSIONS: The developed infected shoe model is useful for assessing the effectiveness of ultraviolet shoe sanitizers. Also, ultraviolet treatment of shoes with a commercial ultraviolet C sanitizing device was effective in reducing the fungal burden in shoes. These findings have implications regarding breaking foot infection cycles. PMID- 22826330 TI - Relationship between student academic and clinical performance in podiatric medical education at Des Moines University. AB - BACKGROUND: This study was performed to determine whether a relationship exists regarding academic achievement between years 1 and 2 of podiatric medical education at Des Moines University. Furthermore, this study evaluates the relationship between academic performance in the first 2 years and clinical performance in year 3. METHODS: The academic records of four classes (2007-2010, N = 164) were examined for grade point averages and clinical performance scores using pairwise Pearson product moment correlations. RESULTS: Significant high correlations existed in academic performance scores between year 1 and year 2 for individual classes and pooled data. Significant low to moderate correlations were found between academic performance and clinical performance scores for individual classes and pooled data. CONCLUSIONS: These results help define the relationship between student academic and clinical performance for podiatric medicine students at Des Moines University and suggest that nonacademic characteristics may play a pivotal role in clinical abilities. These characteristics need to be further identified and developed in the academic curriculum. There may be attributes identified that also benefit the admissions process. PMID- 22826331 TI - A cross-disciplinary approach to understanding flatfoot. AB - As form follows function, pedal anatomy is embedded in a history of evolution. This literature review seeks to further the understanding of physiologic and pathologic flatfoot through cross-disciplinary research of expired and extant members of the Homininae subfamily. Archaeological, anthropological, paleontological, and ontogenetic evidence presents multiple biomechanical similarities and anatomical parallels between flatfooted hominins and humans. Recognizing an evolutionary pattern in flatfoot pathologic disorders enhances anticipation and effective treatment. PMID- 22826332 TI - Surgical reconstruction of severe forefoot derangement in a patient with traumatically acquired contralateral limb-length discrepancy: a case report. AB - Limb-length discrepancy is a very common condition. A severe debilitating forefoot deformity resulting from a post-traumatic limb length discrepancy is quite rare. This case study discusses the surgical reconstruction of a forefoot deformity of a 64-year-old male following a post-traumatic limb-length discrepancy from a motor vehicle accident that caused compensatory biomechanical changes in the unaffected lower extremity. These changes resulted in a severe hallux abducto valgus deformity with subluxated metatarsophalangeal joints of the second and third digits, leaving the patient with a severe symptomatic forefoot deformity that closely mimics the radiographic appearance of a rheumatoid forefoot. The forefoot deformity was corrected using the Mckeever and Hoffman procedures with Kirschner-wire fixation. Seven months following the corrective procedures, the patient was able to obtain an asymptomatic plantigrade foot and can now wear regular footwear. PMID- 22826333 TI - Double crush syndrome in the lower extremity: a case report. AB - Upton and McComas first described double crush syndrome in 1973. The theory behind double crush syndrome postulated that a proximal lesion in a nerve would make that same nerve more vulnerable to additional distal lesions. Many of the studies investigating the possibility of the double crush syndrome involve lesions in the upper extremity with very few articles written specifically about double crush syndrome in the lower extremity. We present the case of a 33-year old massage therapist who uses her feet to provide therapy to clients who presented to our clinic with symptoms consistent with tarsal tunnel syndrome. Her failure to progress in a satisfactory manner after a variety of therapies made us search for additional etiologies for her foot pain. In cases where tarsal tunnel persists after surgical therapy, the treating physician should search for more proximal lesions along the course of the nerve. PMID- 22826334 TI - Surgical treatment of a young patient with bilaterally destroyed first metatarsophalangeal joints suffering from gout. AB - The authors present an unusual case of untreated gout leading to major bony destructions in both metatarsophalangeal joints, leading to joints of enormous dimensions. If untreated, gout can cause disabling destructions with direct influence on both private and working life, even in young patients. In potentially noncompliant patients, simple surgical procedures and postoperative regimes are valuable treatment options resulting in acceptable clinical results. PMID- 22826335 TI - Osteochondritis dissecans of the tarsal navicular bone: a case report. AB - Osteochondritis dissecans most often affects the convex articular surfaces of the knee, the elbow, and the ankle joints; other sites of manifestation are very rare. Here we report a case of osteochondritis dissecans of the talonavicular joint affecting the concave part of the tarsal navicular bone in a 22-year-old woman, which was successfully treated by surgery, leading to complete recovery. Early diagnosis and surgery in stages of undamaged cartilage may help to prevent disease progression and the development of disabling osteoarthritis in the physiologically heavily loaded talo-navicular joint. PMID- 22826336 TI - A blueprint for an office-based emergencies course. AB - We describe the development and implementation of an office-based emergencies course for podiatric medical students. The program included a didactic session along with clinical skills stations incorporating task trainers, high-fidelity simulators, and a standardized patient. We tailored the course to the level of the junior podiatric medical student. The primary goal of this program was to provide a review on how to handle selected office-based medical emergencies. This course focused on complications of common chronic medical conditions, such as asthma, chronic obstructive pulmonary disease, diabetes, and hypertension, along with other unexpected emergencies, such as altered mental status, seizure, and syncope. In developing such a course, it is important to keep in mind the level of the learner and resources such as faculty availability and the facilities available for teaching. PMID- 22826338 TI - The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. AB - The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. Nowadays, it is generally accepted that recurring mood disorders are brain diseases resulting from the combination, to various degrees, of genetic and other biological as well as environmental factors, evolving through the lifespan. All areas of neuroscience, from genes to behaviour, molecules to mind, and experimental to clinical, are actively engaged in attempts at elucidating the pathophysiology of depression and the mechanisms underlying the efficacy of antidepressant treatments. This first of two special issues of Philosophical Transactions B seeks to provide an overview of current developments in the field, with an emphasis on cellular and molecular mechanisms, and how their unravelling opens new perspectives for future research. PMID- 22826337 TI - Genetic diversity as a marker for timing infection in HIV-infected patients: evaluation of a 6-month window and comparison with BED. AB - BACKGROUND: It has been reported that the increase in human immunodeficiency virus (HIV) sequence diversity in drug resistance surveillance specimens may be used to classify the duration of HIV infection as <1 or >1 year. We describe a mixed base classifier (MBC) optimized to categorize the duration of subtype B infections as <6 or >6 months on the basis of sequences for drug resistance surveillance specimens and compared MBC findings with those of serologic methods. METHODS: The behavior of the MBC was examined across a range of thresholds for calling mixed bases. MBC performance was then evaluated using either complete pol sequences or sites reflecting evolutionary pressures (HLA selection sites, sites that increased in entropy over the course of infection, and codon positions). RESULTS: The MBC performance was optimal when secondary peaks on the sequencing chromatogram accounted for at least 15% of the area of primary peaks. A cutoff of <0.45% mixed bases in the pol region best identified recent infections (sensitivity = 82.7%, specificity = 78.8%), with improvement achieved by analyzing only sites that increased in entropy. CONCLUSIONS: In an extended data set of 1354 specimens classified by BED, the optimized MBC performed significantly better than a simple MBC (agreement, 68.98% vs 67.13%). If further validated, the MBC may prove beneficial for detecting recent infection and estimating the incidence of HIV infection. PMID- 22826339 TI - Probing the diversity of serotonin neurons. AB - The serotonin (5-HT) system is generally considered as a single modulatory system, with broad and diffuse projections. However, accumulating evidence points to the existence of distinct cell groups in the raphe. Here, we review prior evidence for raphe cell heterogeneity, considering different properties of 5-HT neurons, from metabolism to anatomy, and neurochemistry to physiology. We then summarize more recent data in mice and zebrafish that support a genetic diversity of 5-HT neurons, based on differential transcription factor requirements for the acquisition of the 5-HT identity. In both species, PET1 plays a major role in the acquisition and maintenance of 5-HT identity in the hindbrain, although some 5-HT neurons do not require PET1 for their differentiation, indicating the existence of several transcriptional routes to become serotoninergic. In mice, both PET1 dependent and -independent 5-HT neurons are located in the raphe, but have distinct anatomical features, such as the morphology of axon terminals and projection patterns. In zebrafish, all raphe neurons express pet1, but Pet1 independent 5-HT cell groups are present in the forebrain. Overall, these observations support the view that there are a number of distinct 5-HT subsystems, including within the raphe nuclei, with unique genetic programming and functions. PMID- 22826340 TI - Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. AB - Using in situ hybridization, we describe, for the first time, the profiles of expression of serotonin receptors (Htr/5-HTR) along the dorsal-ventral axis of mouse hippocampus. cRNA probes for most Htrs, excluding Htr6, were used. All hippocampal subregions and the entorhinal cortex cells providing input into the hippocampus were examined. The study shows that some, but not all, Htrs are expressed in the cells of the hippocampal circuitry. At both the subfield and the cell type levels, a somewhat overlapping pattern is observed. Four serotonin receptors, Htr1a, Htr2a, Htr2c and Htr7, display an expression pattern that changes along the dorsal-ventral axis of the hippocampus. Given the proposed functional differentiation of the hippocampus along its long axis, with the dorsal pole more involved in cognitive functions and the ventral pole more involved in mood and anxiety, our results suggest that serotonin receptors enriched in the ventral pole probably contribute to mood- and anxiety-related behaviours. PMID- 22826341 TI - Transcriptional regulation of the 5-HT1A receptor: implications for mental illness. AB - The serotonin-1A (5-HT(1A)) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre- and post-synaptic 5-HT(1A) receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre- versus post-synaptic 5-HT(1A) receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress induced expression of the 5-HT(1A) receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT(1A) autoreceptor expression in animal models and humans. Its association with altered 5-HT(1A) expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene * environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT(1A) heteroreceptors, and rs6295-induced upregulation of 5 HT(1A) autoreceptors. Targeted therapeutics to inhibit 5-HT(1A) autoreceptor expression and induce 5-HT(1A) heteroreceptor expression may ameliorate treatment of anxiety and major depression. PMID- 22826342 TI - Effects of the antidepressant fluoxetine on the subcellular localization of 5 HT1A receptors and SERT. AB - Serotonin (5-HT) 5-HT(1A) autoreceptors (5-HT(1A)autoR) and the plasmalemmal 5-HT transporter (SERT) are key elements in the regulation of central 5-HT function and its responsiveness to antidepressant drugs. Previous immuno-electron microscopic studies in rats have demonstrated an internalization of 5-HT(1A)autoR upon acute administration of the selective agonist 8-OH-DPAT or the selective serotonin reuptake inhibitor antidepressant fluoxetine. Interestingly, it was subsequently shown in cats as well as in humans that this internalization is detectable by positron emission tomography (PET) imaging with the 5-HT(1A) radioligand [(18)F]MPPF. Further immunocytochemical studies also revealed that, after chronic fluoxetine treatment, the 5-HT(1A)autoR, although present in normal density on the plasma membrane of 5-HT cell bodies and dendrites, do not internalize when challenged with 8-OH-DPAT. Resensitization requires several weeks after discontinuation of the chronic fluoxetine treatment. In contrast, the SERT internalizes in both the cell bodies and axon terminals of 5-HT neurons after chronic but not acute fluoxetine treatment. Moreover, the total amount of SERT immunoreactivity is then reduced, suggesting that SERT is not only internalized, but also degraded in the course of the treatment. Ongoing and future investigations prompted by these finding are briefly outlined by way of conclusion. PMID- 22826343 TI - Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. AB - Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour. PMID- 22826344 TI - The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. AB - A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from clinical observations that drugs enhancing extracellular levels of 5-HT (5 HT(Ext)) have antidepressant effects in many patients. However, whether such drugs indeed correct a primary deficit remains unresolved. Still, a number of anomalies in putative biomarkers of central 5-HT function have been repeatedly reported in depression patients over the past 40 years, collectively indicating that 5-HT deficiency could be present in depression, particularly in severely ill and/or suicidal patients. This body of literature on putative 5-HT biomarker anomalies and depression has recently been corroborated by data demonstrating that such anomalies indeed occur consequent to severely reduced 5-HT(Ext) levels in a mouse model of naturalistic 5-HT deficiency, the tryptophan hydroxylase 2 His(439) knockin (Tph2KI) mouse. In this review, we will critically assess the evidence for 5-HT deficiency in depression and the possible role of polymorphisms in the Tph2 gene as a causal factor in 5-HT deficiency, the latter investigated from a clinical as well as preclinical angle. PMID- 22826345 TI - Selective deletion of forebrain glycogen synthase kinase 3beta reveals a central role in serotonin-sensitive anxiety and social behaviour. AB - Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3beta (GSK3beta). Furthermore, GSK3beta inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3beta activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3beta mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3beta in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2beta expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3beta mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3beta being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum. PMID- 22826346 TI - A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. AB - Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine. PMID- 22826347 TI - Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression. AB - The monoamine hypothesis of depression has dominated our understanding of both the pathophysiology of depression and the action of pharmacological treatments for the last decades, and it has led to the production of several generations of antidepressant agents. However, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic-pituitary adrenal (HPA) axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Moreover, new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviours in animal models. In a transgenic mouse model of depression, in which a downregulation of glucocorticoid receptors (GR) causes a deficit in the HPA axis feedback control, besides alterations in monoamine neurotransmission and neuroplasticity, we found modifications in the expression of many proteins involved in epigenetic regulation, as well as clock genes, in the hippocampus and the frontal cortex, that might be central in the genesis of depressive-like behaviours. PMID- 22826349 TI - A retrospective study of S-1 monotherapy as second-line treatment for patients with advanced biliary tract cancer. AB - OBJECTIVE: Gemcitabine has been widely used, and cisplatin plus gemcitabine is considered as standard first-line chemotherapy for patients with advanced biliary tract cancer. However, no standard therapy was established following the progression to gemcitabine-containing first-line therapy. As S-1 monotherapy as second-line chemotherapy is still not well known in a practical setting this study aimed to clarify its efficacy and safety. METHODS: We retrospectively reviewed 55 consecutive patients who received S-1 monotherapy as second-line chemotherapy after failure of a gemcitabine-containing regimen at our institution from September 2007 to March 2011. The inclusion criteria were preserved organ function and an Eastern Cooperative Oncology Group performance status of 0-2 and without massive ascites or pleural effusion. S-1 was administered orally twice a day at a dose of 40 mg/m(2) for 28 days, followed by 14 days of rest. RESULTS: Fifty-one patients were selected for this analysis. The overall response rate was 4.0% and the disease control rate was 38.0%. The median survival time was 6.0 months and the median progression-free survival was 2.3 months. Adverse events were generally mild, and treatment-related death did not occur. In the subgroup analysis, overall survival was significantly shorter in the patients with peritoneal dissemination and those who had shown no response to the first-line chemotherapy (P= 0.033 and 0.023, respectively). CONCLUSIONS: S-1 monotherapy as the second-line chemotherapy for patients with gemcitabine-refractory advanced biliary tract cancer is also feasible in a practical setting and its efficacy is almost the same as in the previous prospective study. PMID- 22826348 TI - Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone-serotonin-NGFI-A signalling cascade. AB - Variations in parental care direct phenotypic development across many species. Variations in maternal pup licking/grooming (LG) in the rat regulate the development of individual differences in hypothalamic-pituitary-adrenal responses to stress. The adult offspring of mothers that show an increased frequency of pup LG have increased hippocampal glucocorticoid receptor (GR) expression and more modest pituitary-adrenal responses to stress. This parental effect is mediated by the epigenetic programming of a GR exon 1 promoter (exon 1(7)) through the binding of the transcription factor nerve growth factor-inducible factor A (NGFI A). In this paper, we report that: (i) the association of NGFI-A with the exon 1(7) GR promoter is dynamically regulated by mother-pup interactions; (ii) this effect is mimicked by artificial tactile stimulation comparable to that provided by pup LG; (iii) that serotonin (5-HT) induces an NGFI-A-dependent increase in GR transcription in hippocampal neurons and NGFI-A overexpression is sufficient for this effect; and (iv) that thyroid hormones and 5-HT are key mediators of the effects of pup LG and tactile stimulation on NGFI-A binding to the exon 1(7) GR promoter in hippocampus. These findings suggest that pup LG directly activates 5 HT systems to initiate intracellular signalling pathways in the hippocampus that regulate GR transcription. PMID- 22826350 TI - A case of acute exacerbation of idiopathic pulmonary fibrosis after proton beam therapy for non-small cell lung cancer. AB - There have been no reports describing acute exacerbations of idiopathic pulmonary fibrosis after particle radiotherapy for non-small cell lung cancer. The present study describes the case of a 76-year-old Japanese man with squamous cell carcinoma of the lung that relapsed in the left upper lobe 1 year after right upper lobectomy. He had been treated with oral prednisolone 20 mg/day every 2 days for idiopathic pulmonary fibrosis, and the relapsed lung cancer was treated by proton beam therapy, which was expected to cause the least adverse effects on the idiopathic pulmonary fibrosis. Fifteen days after the initiation of proton beam therapy, the idiopathic pulmonary fibrosis exacerbated, centered on the left upper lobe, for which intensive steroid therapy was given. About 3 months later, the acute exacerbation of idiopathic pulmonary fibrosis had improved, and the relapsed lung cancer became undetectable. Clinicians should be aware that an acute exacerbation of idiopathic pulmonary fibrosis may occur even in proton beam therapy, although proton beam therapy appears to be an effective treatment option for patients with idiopathic pulmonary fibrosis. PMID- 22826351 TI - Referral-free health care and delay in diagnosis for lung cancer patients. AB - OBJECTIVE: Lung cancer is not only one of the most prevalent cancers but is also a lethal disease with a very low 5-year survival rate. Delay in diagnosis further reduces the chance of early treatment and worsens patients' survival. The purpose of this study was to understand the delay in the diagnosis of lung cancer under the healthcare system in Taiwan, and to identify the factors associated with it. METHODS: A total of 840 patients diagnosed with lung cancer who had completed or were undergoing cancer treatments were recruited from a medical center in central Taiwan from July 2007 to January 2011. Structured questionnaires were administered regarding demographic characteristics, factors associated with their time to diagnosis and the length of delay in days. RESULTS: Mean age was 62.68 years with 52.16 days to diagnosis on average. Number of hospital visits before confirmation of diagnosis differed significantly with the level of healthcare institution initially visited (P < 0.001). Compared with patients who had three or more hospital visits, patients who only visited two and one hospital(s) had a significant 34.91-day (95% confidence interval: 16.29-53.53) and 42.25-day (95% confidence interval: 20.76-63.76) reduction in their time to diagnosis (P < 0.001). CONCLUSIONS: As the number of hospital visits increased, the delay in diagnosis also increased. It is vital to shorten the time to diagnosis for lung cancer patients by limiting the number of medical visits and educating the public to restrict excessive use of medical resources and strengthen their trust in medical professionals. PMID- 22826352 TI - Emerging methods for preparing iPS cells. AB - In 1998, human embryonic stem cells were first generated and were expected to contribute greatly to regenerative medicine. However, when medical treatments were performed using human embryonic stem cells, there were problems, such as transplant rejection, as well as bioethical issues. Induced pluripotent stem cells were generated from mouse and human fibroblasts in 2006 and 2007 by introducing four transcription factors (Oct3/4, Sox2, c-Myc and Klf4). This process was defined as direct reprogramming, and induced pluripotent stem cells were better tolerated. Although induced pluripotent stem cells have contributed greatly to biomedical research and regenerative medicine, high tumorigenic potential is still a critical problem due to the introduction of the oncogene c Myc and reprogramming with a virus vector. To address this, we reprogrammed somatic cells by transfection with microribonucleic acids to avoid using virus vectors for genomic integration into the host genome. We found that it was possible to reprogram mouse and human cells to pluripotency by direct transfection of three mature microribonucleic acids (mir-200c, -302s and -369s) with increased expression levels in embryonic stem cells and induced pluripotent stem cells. The microribonucleic acid-induced pluripotent stem cells have a reduced risk of mutations and tumorigenesis. Our laboratory also introduced four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) into cancer cells, generating induced pluripotent cancer cells that exhibited strikingly less malignant features, suggesting the possibility of a novel type of cancer therapy. However, the gene transduction method is not yet safe for clinical applications, due to a genomic integration that may cause tumor formation. We are currently investigating the reprogramming method using microribonucleic acids in cancer cells to develop a very safe, highly efficient and highly complete reprogramming for clinical applications. PMID- 22826353 TI - Measurements of the neutron dose and energy spectrum on the International Space Station during expeditions ISS-16 to ISS-21. AB - As part of the international Matroshka-R and Radi-N experiments, bubble detectors have been used on board the ISS in order to characterise the neutron dose and the energy spectrum of neutrons. Experiments using bubble dosemeters inside a tissue equivalent phantom were performed during the ISS-16, ISS-18 and ISS-19 expeditions. During the ISS-20 and ISS-21 missions, the bubble dosemeters were supplemented by a bubble-detector spectrometer, a set of six detectors that was used to determine the neutron energy spectrum at various locations inside the ISS. The temperature-compensated spectrometer set used is the first to be developed specifically for space applications and its development is described in this paper. Results of the dose measurements indicate that the dose received at two different depths inside the phantom is not significantly different, suggesting that bubble detectors worn by a person provide an accurate reading of the dose received inside the body. The energy spectra measured using the spectrometer are in good agreement with previous measurements and do not show a strong dependence on the precise location inside the station. To aid the understanding of the bubble-detector response to charged particles in the space environment, calculations have been performed using a Monte-Carlo code, together with data collected on the ISS. These calculations indicate that charged particles contribute <2% to the bubble count on the ISS, and can therefore be considered as negligible for bubble-detector measurements in space. PMID- 22826354 TI - Monte Carlo mitochondrial dosimetry and microdosimetry of 131I. AB - A mitochondrion is an organelle found in most eukaryotic cells, which produces most of the energy needed by a living cell. It has been shown that ionising radiation causes mitochondrial damage leading to apoptosis or cell death. The aim of this work was to calculate, by Monte Carlo simulation, the specific energy (z) into the mitochondria, due to Auger electrons, conversion electrons and beta emission from (131)I, where the radionuclide was carried by a vector to the cell surface and the surrounding environment. A concentric spherical geometry represents a cell and its nucleus. Three different volumes were used to represent the mitochondria; they were placed in random positions within the cytoplasm. The z produced by a single event is due to low-energy electrons (76 %) and beta particles (24 %) and the mitochondria receive a total mean z two orders of magnitude higher than that of the cell nucleus. PMID- 22826355 TI - Investigation of the activity level and radiological impacts of naturally occurring radionuclides in blast furnace slag. AB - The activity level and possible radiological impacts of naturally occurring radionuclides on the health of workers and members of the public, as a result of utilisation of blast furnace slag (BFS) samples as a substitute for aggregate in road construction were investigated by using a gamma-ray spectrometer and potential exposure scenarios given in Radiation Protection 122. The mean activity concentrations of the (226)Ra, (232)Th and (40)K in BFS samples were found to be 152.4, 54.9 and 183.1 Bq kg(-1), respectively. These values are compared with typical values measured in BFS samples from the European Union countries, which are 270, 70 and 240 Bq kg(-1) for (226)Ra, (232)Th and (40)K, respectively. The values of radium equivalent activity index calculated for BFS samples were within the recommended safety limits. The highest total annual effective doses evaluated as 0.9 and 0.4 mSv y(-1) for members of the public and workers, respectively, were lower than the annual limit of 1 mSv y(-1). PMID- 22826356 TI - Radon monitoring in groundwater samples from some areas of northern Rajasthan, India, using a RAD7 detector. AB - Radon monitoring has been increasingly conducted worldwide because of the hazardous effects of radon on the health of human beings. In the present research, groundwater samples were taken from hand pumps at different areas of the districts of SriGanganagar, Hanumangarh, Sikar and Churu in northern Rajasthan. RAD7, an electronic radon detector (Durridge co., USA), was used to estimate the radon concentration in groundwater used for drinking. Radon concentration in the groundwater ranged from 0.5 +/- 0.3 Bq l(-1) (Chimanpura) to 85.7+/-4.9 Bq l(-1)(Khandela) with an average value of 9.03+/-1.03 Bq l(-1). In 89 % of the samples, radon concentration is well below the allowed maximum contamination level (MCL) of radon concentration in water of 11 Bq l(-1), proposed by US Environmental Protection Agency (USEPA). Only in 11 % of the samples, the recorded values were found to be higher than MCL proposed by USEPA and only in 5 % of the samples, the recorded values were found to be higher than the values between 4 and 40 Bq l(-1) suggested for radon concentration in water for human consumption by the United Nations Scientific Committee on the effect of Atomic Radiation (UNSCEAR). The annual effective dose in stomach and lungs per person was also evaluated in this research. The estimated total annual effective dose of adults ranged from 1.34 to 229.68 uSv y(-1). The total annual effective dose from three locations of the studied area was found to be greater than the safe limit (0.1 mSv y(-1)) recommended by World Health Organization and EU Council. PMID- 22826357 TI - The plasma concentration of HDL-associated apoM is influenced by LDL receptor mediated clearance of apoB-containing particles. AB - ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 +/- 0.13 uM, P = 0.003, and 1.23 +/- 0.10 uM, P = 0.02, respectively) as compared with noncarriers (0.93 +/- 0.04 uM). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 +/- 5% versus 90 +/- 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = 0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles. PMID- 22826359 TI - Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials. AB - BACKGROUND AND PURPOSE: In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta analysis of published randomized trials. METHODS: Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow up of >=14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported. RESULTS: Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days-3 months; OR, 0.93; 95% CI, 0.87-0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91-1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97-1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74-0.91). CONCLUSIONS: The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: http//www.clinicaltrials.gov. Unique identifier: NCT00059306. PMID- 22826360 TI - High dosing of alpha-tocopherol inhibits rat liver regeneration by modifying signal transducer and activator of transcription protein expression and its correlation with cell redox state and retinoid metabolism. AB - Lipid peroxidation (LP) promoted by partial hepatectomy (PH) is qualitatively distinct among subcellular fractions and temporally transient, probably being a necessary physiological event for rat liver regeneration. In fact, alpha tocopherol (vitamin E [VE]) exerts adverse effects, partially inhibiting PH induced rat liver regeneration and inducing decreased cyclin D1 expression. The phosphorylation of signal transducer and activator of transcription (STAT) factors 1 and 3 are involved in DNA synthesis and cyclin D1 expression after PH, which is stimulated by production of retinoic acid (RA). Hence, this study was aimed at addressing these events, and its association with cell redox state and oxidative stress, probably underlying VE effects on rat liver regeneration. PH enhanced activation of STAT proteins, mainly as activated STAT-3, significantly change the cytoplasmic pool for STATs. The latter was associated to a more reduced cytoplasmic redox state and increased alcohol dehydrogenase (ADH) mediated retinol oxidation to RA. Whereas alpha-tocopherol promoted minor changes in the parameters tested when administered to sham (control)-animals, pretreatment with VE blocked the PH-induced increase of reactive oxygen species (ROS), altering the pattern of STAT protein activation, blunting RA formation by decreased ADH activity, inducing higher liver caspase-3 activity and increasing tumor necrosis factor-alpha concentrations, while levels of interleukin-6 were decreased; altogether coinciding with disturbed PH-promoted changes on the liver redox state. In conclusion, altered activation and translocation of STAT-1 and -3 proteins and inhibited retinoid metabolism seem to be involved in the VE-induced inhibition of rat liver regeneration. Data suggest that a PH-induced increase of ROS could participate in the activation of STAT factors, retinoid metabolism and changes in the cell redox state during proliferation of liver cells. PMID- 22826361 TI - Paradoxical expression of AHCYL1 affecting ovarian carcinogenesis between chickens and women. AB - We investigated S-adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) gene expression in human epithelial ovarian cancer (EOC) using the chicken, which is the most relevant animal model. Ovarian cancer was detected in 10 of 136 laying hens (7.4%). Results of the present study indicated that AHCYL1 mRNA and protein are most abundant in the glandular epithelium of adenocarcinoma of cancerous, but not normal, ovaries of hens. In addition, bisulfite sequencing to examine methylation patterns in the promoter region of the AHCYL1 gene revealed that 30 38% of the three CpG sites were demethylated in ovarian cancer cells as compared with normal ovarian cells. Furthermore, in human ovarian cancer cells such as OVCAR-3, AHCYL1 protein was predominantly in the nucleus and had a similar expression pattern to that in chicken ovarian cancer cells. Thereafter, we examined the prognostic value of AHCYL1 expression in patients with EOC using multivariate linear logistic regression and Cox's proportional hazard analyses. In 109 human patients with EOC, 14 (12.8%), 41 (37.6%) and 54 (49.6%) patients showed weak, moderate and strong expression of AHCYL1 protein, respectively. However, intermediate or high expression of AHCYL1 protein was a favorable factor for overall responses (adjusted odds ratio, 7.23; 95% confidence interval [CI], 1.36-38.39), and for progression-free survival (adjusted hazard ratio, 0.20; 95% CI, 0.07-0.55). From these results, we conclude that AHCYL1 expression is associated with ovarian carcinogenesis as an oncogene in chickens, whereas it plays the role of tumor suppressor in human EOC, suggesting a paradoxical function of AHCYL1 in ovarian carcinogenesis. PMID- 22826363 TI - Morphological analysis in context versus isolation: use of a dynamic assessment task with school-age children. AB - PURPOSE: The current study investigated the ability of typically developing children in Grades 3 and 5 to use morphological analysis to determine the meanings of derived words with and without context clues. Also of interest was the relation between children's reading practices and their performance in determining the meanings of derived words. METHOD: Children provided definitions for 20 low-frequency derived words that were presented to them in isolation and in context. Responses were scored on a scale of 0 to 5 based on the children's performance on the Dynamic Assessment of Morphological Analysis--Modified (DATMA M), which was created by the authors. RESULTS: Results indicated a large variability in the children's performance on the DATMA-M. Children in Grade 5 achieved significantly higher scores as compared to children in Grade 3. Overall, children performed better in the context condition than the isolation condition. Significant correlations were found for reading frequency and DATMA-M scores. There was no significant difference in performance between the isolation and context conditions after controlling for reading frequency. CONCLUSION: The findings of this study emphasize the need for continued research to enable speech language pathologists to use assessments such as the DATMA-M to obtain insights into the morphological analytical skills of school-age children. PMID- 22826364 TI - Vocabulary use across genres: implications for students with complex communication needs. AB - PURPOSE: This study examined the vocabulary words and multiword sequences used by 124 typically developing kindergarten and 1st-grade students when they wrote about self-selected topics. The study extends previous research by examining the vocabulary used in different genres. METHOD: A total of 457 writing samples were analyzed. The samples were classified according to 9 genres and were analyzed using the Child Language Analysis ( MacWhinney, 2006) software program. RESULTS: The authors found that 140 words represented 70% of the vocabulary produced. The most common genre types were narrative recounts and opinions. The patterns of frequency for words and multiword sequences varied across genres. The degree of variation was greater for particular vocabulary words. For instance, the word going was used predominantly in 1 genre. In contrast, the word mom was used in every genre except 3. The structure words tended to be used with high frequency across genres. CONCLUSION: The word lists generated can be used to inform vocabulary selection, organization, and instruction for students with complex communication needs who are beginning writers. PMID- 22826365 TI - Social, emotional, and behavioral functioning of secondary school students with low academic and language performance: perspectives from students, teachers, and parents. AB - PURPOSE: Adolescence is a time of transition when young people with language difficulties are at increased risk of experiencing social, emotional, and behavioral difficulties (SEBD). Most studies of social, emotional, and behavioral functioning (SEBF) in individuals with language difficulties focus on children with a clinical diagnosis of language impairment. This study explores SEBF in a nonclinical group of 12-year-old students with low educational and language performance from their own perspectives and those of their parents and teachers. METHOD: The Strengths and Difficulties Questionnaire ( Goodman, 1997) was given to 352 mainstream secondary school students who were underperforming academically and had poor language performance. Two hundred and twenty-five of their parents and 230 of their teachers also completed the questionnaire. RESULTS: Students with low educational attainment and poor language showed significantly greater SEBD than a normative sample as reported by themselves, their parents, and their teachers. Significant differences were found across informants, with students identifying more overall difficulties than parents or teachers. CONCLUSION: Secondary school students with low academic and language performance are more vulnerable to experiencing SEBD compared to typically developing peers. The extent of their difficulties varied depending on the informant, emphasizing the importance of gaining views from multiple perspectives. PMID- 22826366 TI - Differentiating children with and without language impairment based on grammaticality. AB - PURPOSE: This study compared the diagnostic accuracy of a general grammaticality measure (i.e., percentage grammatical utterance; PGU) to 2 less comprehensive measures of grammaticality--a measure that excluded utterances without a subject and/or main verb (i.e., percentage sentence point; PSP) and a measure that looked only at verb tense errors (i.e., percentage verb tense usage; PVT)--in differentiating children with and without language impairment. METHOD: Two groups of 3-year-olds, 17 with language impairment and 17 with typical language, participated in a picture description task. PGU, PSP, and PVT were computed. Receiver operating characteristic curve analyses were conducted to determine the best cutoff value for each measure. RESULTS: All 3 measures demonstrated a sensitivity of 100%. PGU showed a specificity of 88%, and both PSP and PVT showed a specificity of 82%. In addition, PGU showed a larger positive likelihood ratio than the other 2 measures. CONCLUSION: PGU, PSP, and PVT were all sensitive to language impairment. However, PGU was less likely than PSP and PVT to misclassify children with typical language. The resultant diagnostic accuracy makes PGU an appropriate measure to use to screen for language impairment. PMID- 22826367 TI - Longitudinal patterns of behavioral, emotional, and social difficulties and self concepts in adolescents with a history of specific language impairment. AB - PURPOSE: This study explored the prevalence and stability of behavioral difficulties and self-concepts between the ages of 8 and 17 years in a sample of children with a history of specific language impairment (SLI). We investigated whether earlier behavioral, emotional, and social difficulties (BESD); self concepts; and language and literacy abilities predicted behavioral difficulties and self-concepts at 16/17 years. METHOD: In this prospective longitudinal study, 65 students were followed up with teacher behavior ratings and individual assessments of language, literacy, and self-concepts at 8, 10, 12, 16, and 17 years. RESULTS: The students had consistently higher levels than norms of 5 domains of BESD, which had different trajectories over time, and poorer scholastic competence, whose trajectory also varied over time. Earlier language ability did not predict later behavioral difficulties or self-concepts, but the prediction of academic self-concept at 16 by literacy at 10 years approached significance. CONCLUSIONS: The importance of distinguishing domains of behavioral difficulties and self-concept is demonstrated. Language, when measured at 8 or 10 years of age, was not a predictor of behavior or self-concepts at 16 years, or of self-concepts at 17 years. The study stresses the importance of practitioners addressing academic abilities and different social-behavioral domains in delivering support for adolescents with SLI. PMID- 22826368 TI - Training secondary school teachers in instructional language modification techniques to support adolescents with language impairment: a randomized controlled trial. AB - PURPOSE: This study evaluated the efficacy of a collaborative intervention where a speech-language pathologist (SLP) trained mainstream secondary school teachers to make modifications to their oral and written instructional language. The trained teachers' uptake of techniques in their whole-class teaching practices and the impact this had on the language abilities of students with language impairment (LI) were evaluated. METHOD: Two secondary schools were randomly assigned to either a trained or a control condition. A cohort of 13 teachers (7 trained and 6 control) and 43 Year 8 students with LI (21 trained and 22 control) were tested at pre, post, and follow-up times-teachers by structured interview and students by standardized spoken and written language assessments. RESULTS: Significantly increased use of the language modification techniques by the trained teachers was observed when compared to the control group of untrained teachers, with this increased use maintained over time. Results from the trained group of students showed a significant improvement in written expression and listening comprehension relative to the control group of students. CONCLUSION: This randomized controlled trial is one of the first investigations to evaluate a collaborative intervention that links changes in mainstream secondary teachers' instructional language practices with improvements in the language abilities of adolescents with LI. PMID- 22826370 TI - Progress in understanding adolescent language disorders. AB - PURPOSE: This prologue introduces a clinical forum on adolescent language disorders, a topic that has long been of interest to school-based speech-language pathologists/therapists. METHOD: A rationale for the clinical forum is provided, and the content is contrasted with a previous forum on the same topic that was published nearly 20 years ago. Implications and directions for future research and practice in adolescent language disorders are discussed. CONCLUSIONS: Considerable progress has occurred in our understanding of the nature, assessment, and treatment of language and communication disorders in adolescents and young adults. Yet we continue to need to build the evidence base on the most effective and efficient ways of enhancing the spoken and written language skills of young people with language and communication disorders in academic, social, emotional, and vocational domains. PMID- 22826369 TI - Postschool educational and employment experiences of young people with specific language impairment. AB - PURPOSE: This study examined the postschool educational and employment experiences of young people with and without specific language impairment (SLI). METHOD: Nineteen-year-olds with (n = 50) and without (n = 50) SLI were interviewed on their education and employment experiences since finishing compulsory secondary education. RESULTS: On average, young people with SLI were less successful than their peers without SLI, but they did attain some achievements. Young people with SLI obtained ~2, mostly vocational qualifications in the first few years post school. Young people continuing in education at 19 years were most commonly in lower level educational placements than their typically developing (TD) peers. Performance IQ and language/literacy skills were the strongest predictors of educational experience level at this age. Young people with SLI truant less and report feeling more supported than TD peers. In terms of employment, similar proportions of young people with and without SLI had jobs. A larger proportion of young people with SLI, however, were not in education, employment, or training at 19 years of age. CONCLUSION: In the immediate postschool years, young people with SLI fare less well in education and employment than their TD peers. PMID- 22826371 TI - Oral language competence, young speakers, and the law. AB - PURPOSE: This paper highlights the forensic implications of language impairment in 2 key (and overlapping) groups of young people: identified victims of maltreatment (abuse and/or neglect) and young offenders. METHOD: Two lines of research pertaining to oral language competence and young people's interface with the law are considered: 1 regarding investigative interviewing with children as victims or witnesses in the context of serious allegations of sexual abuse, and the other pertaining to adolescent offenders as suspects, witnesses, or victims. The linguistic demands that forensic interviewing places on these young people are also considered. Literature concerning the impact of early maltreatment on early language acquisition is briefly reviewed, as is the role of theory of mind in relation to the requirements of investigative interviewing of children and adolescents. IMPLICATIONS: High-risk young people (i.e., those who are subject to child protection orders because of suspected or confirmed maltreatment, and those who are engaged with the youth justice system) face an elevated risk for suboptimal language development but may need to draw on their language skills in high-stakes forensic interviews. Implications for early intervention policy and practice are identified, and the need for greater speech-language pathology advocacy and engagement in forensic interviewing research is emphasized. PMID- 22826372 TI - Developmental communication impairments in adults: outcomes and life experiences of adults and their parents. AB - PURPOSE: This study identifies the outcomes and documents the longitudinal life experiences of adults who attended a specialist residential school for children with pervasive and complex developmental communication impairments. METHOD: Semistructured interviews were carried out with 26 adult ex-pupils who had attended the school and the parents of 15 of the ex-pupils. RESULTS: Seven key themes were identified from the data, including (a) lack of appropriate support and the impact of this in early childhood, (b) advantages and disadvantages of specialist educational provision compared to mainstream and other provision, (c) changing impact of developmental communication impairments over time, (d) challenging transition away from specialist educational provision, (e) absence of appropriate support for adults with developmental communication impairments, (f) persisting impact of developmental communication impairments on social and emotional functioning in adult life, and (g) differences in perspective between the adult ex-pupils and their parents. CONCLUSION: Across the adult ex-pupils and their parents, the perceived reported benefits of early intervention, parental support, specialist educational provision, and guidance at times of transitions should inform current service provision for this vulnerable group of individuals and their families. PMID- 22826374 TI - Survival following surgery with or without adjuvant chemotherapy for stage I-IIIA non-small cell lung cancer: an east asian population-based study. AB - BACKGROUND: Asian ethnicity is associated with a distinct molecular etiology, treatment response, and survival outcome among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I-IIIA NSCLC. METHODS: This study recruited patients aged >=18 years with histologically proven stage IA-IIIA NSCLC registered in the Taiwan Cancer Registry database in January 2004 to December 2007. Platinum-containing adjuvant chemotherapy had to be started within 90 days of the primary surgery. Kaplan-Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time. RESULTS: This study included 2,231 patients with stage IA-IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group for both stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival outcome of stage II (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.39-0.94; p = .024) and IIIA (HR, 0.71; 95% CI, 0.52-0.96; p = .029) patients. Among these patients, those who received adjuvant chemotherapy had a superior overall survival outcome for both genders, for the subgroup of patients aged >=70 years, and for those with adenocarcinoma. CONCLUSION: Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC. PMID- 22826375 TI - SMS for disease control in developing countries: a systematic review of mobile health applications. AB - Mobile phones provide a low cost method of addressing certain health system needs in developing countries. We examined SMS-supported interventions for prevention, surveillance, management and treatment compliance of communicable and non communicable diseases in developing countries. We searched both peer-reviewed and grey literature reporting the use of SMS messages for disease prevention, surveillance, self-management and compliance in developing countries. A total of 98 applications fulfilled the inclusion criteria (33 prevention, 19 surveillance, 29 disease management and 17 patient compliance applications). In 31 projects, the SMS applications were evaluated. The majority of applications focused on HIV/AIDS and were located in India, South Africa and Kenya. Most used bulk (push) messaging. In general, they were well accepted by the population. The review provides further evidence that mobile phones are an appropriate and promising tool for disease control interventions in developing countries. PMID- 22826373 TI - Management of unusual histological types of breast cancer. AB - There is increased understanding of the heterogeneity of breast tumors, with greater emphasis now being placed on histological and molecular profiles and, in particular, their implications for prognosis and therapy. This review addresses breast cancers of unusual histological subtype with an approximate incidence <=1%. Given the rarity of these tumors, the literature contains primarily case reports, small series, and population-based studies. Data are heterogeneous and almost entirely retrospective, frequently gathered over long time periods, in the context of changing pathological techniques and reporting. In addition, our understanding of the disease biology and therapeutic context has also evolved significantly over this time. There is often limited information about the specific therapies used and the rationale for choosing such an approach. Meaningful comparisons of treatment modalities are not feasible and it is not possible to define management guidelines. Instead, this review correlates the available information to give an impression of how each subgroup behaves-of the favored surgical technique, responses to therapy, and prognosis-as well as the emerging molecular data, highlighting new research areas for potential target in clinical trials. Each tumor subtype described represents a small but real cohort of patients with breast cancer, and although inferences may be made from this review, we are mindful of the paucity of data. The management of each patient must be considered in the context of their unique clinical presentation and correlated with the evidence-based principles that apply to more common breast cancer histologies. PMID- 22826376 TI - Satisfaction with telemedicine for teaching listening and spoken language to children with hearing loss. AB - Auditory-Verbal Therapy (AVT) is an effective early intervention for children with hearing loss. The Hear and Say Centre in Brisbane offers AVT sessions to families soon after diagnosis, and about 20% of the families in Queensland participate via PC-based videoconferencing (Skype). Parent and therapist satisfaction with the telemedicine sessions was examined by questionnaire. All families had been enrolled in the telemedicine AVT programme for at least six months. Their average distance from the Hear and Say Centre was 600 km. Questionnaires were completed by 13 of the 17 parents and all five therapists. Parents and therapists generally expressed high satisfaction in the majority of the sections of the questionnaire, e.g. most rated the audio and video quality as good or excellent. All parents felt comfortable or as comfortable as face-to-face when discussing matters with the therapist online, and were satisfied or as satisfied as face-to-face with their level and their child's level of interaction/rapport with the therapist. All therapists were satisfied or very satisfied with the telemedicine AVT programme. The results demonstrate the potential of telemedicine service delivery for teaching listening and spoken language to children with hearing loss in rural and remote areas of Australia. PMID- 22826377 TI - The epsilon4 allele of the APOE gene is associated with more severe peripheral neuropathy in type 2 diabetic patients. AB - We examined the association between the epsilon4 allele of the apolipoprotein E gene and severity of peripheral neuropathy in 234 patients with type 2 diabetes mellitus (T2DM). Based on the Neuropathy Disability Score (NDS), patients were divided into group A (NDS <= 6: mild or no neuropathy) and group B (NDS > 6: severe neuropathy). In each group, patients were further divided into epsilon4 carriers and non-epsilon4 carriers. In multivariate analysis, a more than 5-fold increased risk of severe neuropathy was associated with epsilon4 carrier status (adjusted odds ratio [aOR]: 5.26, 95% confidence interval [CI]: 2.24-12.31, P = .0001). The other significant risk factors for severe neuropathy included male gender (aOR: 2.08, 95% CI: 1.05-4.14, P = .036), diabetes duration (aOR: 1.05, 95% CI: 1.00-1.09, P = .039), and hemoglobin A1c (aOR: 1.32, 95% CI: 1.05-1.66, P = .020). In conclusion, the epsilon4 carrier status appears to be associated with severe peripheral neuropathy in T2DM. PMID- 22826378 TI - Schizophrenia and retinitis pigmentosa: are there mechanisms which blind insanity? PMID- 22826379 TI - Identification of putative candidate genes for juvenile wood density in Pinus radiata. AB - Wood formation is a complex developmental process driven by the annual activity of the vascular cambium. Conifers usually produce juvenile wood at young ages followed by mature wood for the rest of their lifetime. Juvenile wood exhibits poorer wood quality (i.e., lower density) compared with mature wood and can account for up to 50% of short-rotation harvested logs, thus representing a major challenge for commercial forestry globally. Wood density is an important quality trait for many timber-related products. Understanding the molecular mechanisms involved in the regulation of juvenile wood density is critical for the improvement of juvenile wood quality via marker-aided selection. A previous study has identified several candidate genes affecting mature wood density in Picea sitchensis (Bong.) Carr.; however, genes associated with juvenile wood density in conifers remain poorly characterized. Here, cDNA microarrays containing 3320 xylem unigenes were used to investigate genes differentially transcribed in juvenile wood with high (HD) and low density (LD) in Pinus radiata D.Don. In total, 814 xylem unigenes with differential transcription were identified in at least one of two microarray experiments and 73 genes (45 for HD, 28 for LD) were identified in both experiments, thus representing putative candidate genes for juvenile wood density. Interestingly, cellulose synthases (PrCesA3, PrCesA11) and sucrose synthase (SuSy), which are involved in secondary cell wall formation, had stronger transcription in juvenile wood with HD, while genes functioning in primary wall formation (pectin synthesis, cell expansion and other modifications) were more transcribed in LD wood. Cell wall genes encoding monolignol biosynthesis enzymes, arabinogalactan proteins, actins and tubulins were differentially transcribed in either HD or LD juvenile wood; however, the latter had exclusively greater transcription of genes involved in monolignol polymerization (laccase and peroxidase). The identified candidate genes also included many non-cell-wall genes (transcription factors, environmental responsive genes, hormone signalling, etc.) and genes with unknown functions, suggesting complex gene pathways in the regulation of juvenile wood density. Interestingly, 19 out of 73 candidate genes for wood density were among the 108 candidate genes previously identified for microfibril angle, and 16 genes appeared to influence both traits in a synergistic manner for wood stiffness. PMID- 22826380 TI - How fast do European conifers overgrow wounds inflicted by rockfall? AB - The capacity of trees to recover from mechanical disturbance is of crucial importance for tree survival but has been primarily investigated in saplings using artificially induced wounds. In this study, mature Larix decidua Mill., Picea abies (L.) Karst. and Abies alba Mill. trees growing on alpine slopes that were wounded by naturally occurring rockfall were analyzed to determine their efficiency in overgrowing wounds. In total 43 L. decidua, P. abies and A. alba trees were sampled. First, 106 samples from 27 L. decidua and P. abies trees were analyzed to reconstruct yearly and overall overgrowth rates. Cross sections were taken at the maximum extension of the injury and overgrowth rates were determined on a yearly basis. Results clearly showed that L. decidua overgrew wounds more efficiently than P. abies with an average overgrowth rate of 19 degrees and 11.8 degrees per year, respectively. The higher on the stem the injury was located, the faster the wound was closed. Young and small trees overgrew wounds more efficiently than older or thicker trees. In contrast, no correlation was observed between injury size or increment before/after wounding and wound closure. Second, cross sections from 16 L. decidua, P. abies and A. alba (54 injuries) were used to assess closure rates at different heights around the injury. Overgrowth was generally smallest at the height of the maximum lateral extension of the injury and increased at the upper and lower end of the injury. The efficiency with which L. decidua closes wounds inflicted by rockfall makes this species highly adapted to sites with this type of mechanical disturbance. PMID- 22826381 TI - Ecophysiological responses of a young blue gum (Eucalyptus globulus) plantation to weed control. AB - Early weed control may improve the growth of forest plantations by influencing soil water and nutrient availability. To understand eucalypt growth responses to weed control, we examined the temporal responses of leaf gas-exchange, leaf nitrogen concentration (N) and water status of 7-month-old Eucalyptus globulus L. trees in a paired-plot field trial. In addition, we monitored the growth, leaf N and water status of the competing vegetation in the weed treatment. By the end of the 11-month experiment, complete weed control (WF treatment) of largely woody competitors increased the basal diameter of E. globulus by 14%. As indicated by pre-dawn water potentials of > - 0.05 MPa, interspecies competition for water resources was minimal at this site. In contrast, competition for N appeared to be the major factor limiting growth. Estimations of total plot leaf N (g m(-2) ground) showed that competing vegetation accounted for up to 70% of the total leaf N at the start of the trial. This value fell to 15% by the end of the trial. Despite increased leaf N(area) in WF trees 5 months after imposition of weed control, the photosynthetic capacity (A(1500)) of E. globulus was unaffected by treatment suggesting that the growth gains from weed control were largely unrelated to changes in leaf-level photosynthesis. Increased nutrient availability brought about by weed control enabled trees to increase investment into leaf-area production. Estimates of whole-tree carbon budget based on direct measurements of dark respiration and A(1500) allowed us to clearly demonstrate the importance of leaf area driving greater productivity following early weed control in a nutrient-limited site. PMID- 22826382 TI - Written disclosure treatment for posttraumatic stress disorder in substance use disorder inpatients. AB - Comprehensive exposure-based approaches to treating posttraumatic stress disorder (PTSD) are effective, but they are time intensive and not widely used because of factors such as client noncompliance and fears of iatrogenic effects. Exposure by writing disclosure (WD), modeled after Pennebaker's brief stress-reduction procedure, may circumvent these obstacles. WD treatment reduces PTSD symptoms in trauma victims but has rarely been tested in diagnosed PTSD participants and never in substance use disorder (SUD) populations-despite high comorbidity rates. The authors applied a standard Pennebaker WD treatment for 45 SUD inpatients screened for full or subsyndromal PTSD in an uncontrolled study. Results suggested potential strong cost-effectiveness: Posttreatment outcome measures showed significant symptom reductions, which remained stable at 3-month follow up. With converging evidence from future controlled studies, WD strategies may emerge as effective and easily implemented treatment options for PTSD in SUD treatment settings. PMID- 22826383 TI - Peer review: is the process broken? PMID- 22826384 TI - Use of a simulation laboratory to train radiology residents in the management of acute radiologic emergencies. AB - OBJECTIVE: Simulation laboratories use realistic clinical scenarios to train physicians in a controlled environment, especially in potentially life threatening complications that require prompt management. The objective of our study was to develop a comprehensive program using the simulation laboratory to train radiology residents in the management of acute radiologic emergencies. MATERIALS AND METHODS: All radiology residents attended a dedicated simulation laboratory course lasting 3 hours, divided over two sessions. Training included basic patient management skills, management of a tension pneumothorax, massive hemorrhage, and contrast agent reactions. Participants were presented with 20 multiple-choice questions before and after the course. Pre- and posttest results were analyzed, and the McNemar test was used to compare correct responses by individual question. RESULTS: Twenty-six radiology residents attended the class. The average pre- and posttest scores and the average difference between the scores for all residents were 13.8, 17.1, and 3.3, respectively (p < 0.0001). Incorrect answers on the pretest examination that were subsequently answered correctly concerned administration of epinephrine for severe reactions, management of a tension pneumothorax, oxygen therapy, ECG placement, cardiopulmonary resuscitation technique, and where to stand during a code situation. Persistent incorrect answers concerned vasovagal reactions and emergency telephone numbers at an off-site imaging center. CONCLUSION: Simulation laboratories can be used to teach crisis management and crisis resource management for radiology residents and should be part of the education toolbox. Defined objectives lead to a comprehensive course dealing with the management of acute radiologic emergencies. Such programs can improve the role of radiologists as members of the health care team. PMID- 22826385 TI - Whole-body diffusion-weighted MRI: tips, tricks, and pitfalls. AB - OBJECTIVE: We examine the clinical impetus for whole-body diffusion-weighted MRI and discuss how to implement the technique with clinical MRI systems. We include practical tips and tricks to optimize image quality and reduce artifacts. The interpretative pitfalls are enumerated, and potential challenges are highlighted. CONCLUSION: Whole-body diffusion-weighted MRI can be used for tumor staging and assessment of treatment response. Meticulous technique and knowledge of potential interpretive pitfalls will help to avoid mistakes and establish this modality in radiologic practice. PMID- 22826386 TI - Translational optical imaging. AB - OBJECTIVE: Optical imaging is experiencing significant technologic advances. Simultaneously, an array of specific optical imaging agents has brought new capabilities to biomedical research and is edging toward clinical use. We review progress in the translation of macroscopic optical imaging-including fluorescence guided surgery and endoscopy, intravascular fluorescence imaging, diffuse fluorescence and optical tomography, and multispectral optoacoustics (photoacoustics)-for applications ranging from tumor resection and assessment of atherosclerotic plaques to dermatologic and breast examinations. CONCLUSION: Optical imaging could play a major role in the move from imaging of structure and morphology to the visualization of the individual biologic processes underlying disease and could, therefore, contribute to more accurate diagnostics and improved treatment efficacy. PMID- 22826387 TI - MR/PET: a new challenge in hybrid imaging. AB - OBJECTIVE: This article provides a short overview of hybrid imaging and the potential advantages of combined MR/PET. We will address some of the challenges that had to be met before MR/PET could become clinically available as well as further scientific work that has to be done to increase the potential benefit of this emerging hybrid modality. CONCLUSION: Hybrid imaging, the combination of two imaging modalities into one, promises the compensation of specific deficits of the modalities involved. PET/CT has gained wide acceptance for oncologic imaging in recent years; however, MRI has certain advantages that could make combined MR/PET more tempting in various clinical applications. The development of new clinical whole-body MR/PET systems offers new insights in metabolic and functional processes in oncology as well as cardiovascular and neurologic diseases. PMID- 22826389 TI - Microbubbles as ultrasound contrast agents for molecular imaging: preparation and application. AB - OBJECTIVE: The purpose of this review is to describe trends in microbubble application in molecular imaging. CONCLUSION: Microbubbles are used for contrast ultrasound imaging as blood-pool agents in cardiology and radiology. Their promise as targeted agents for molecular imaging is now being recognized. Microbubbles can be functionalized with ligand molecules that bind to molecular markers of disease. Potential clinical applications of molecular imaging with microbubble-based ultrasound contrast agents are in the monitoring of the biomarker status of vascular endothelium, visualizing tumor vasculature, and imaging inflammation and ischemia-reperfusion injury zones and thrombi. PMID- 22826390 TI - Pancreatic imaging mimics: part 1, imaging mimics of pancreatic adenocarcinoma. AB - OBJECTIVE: The purpose of this article is to describe the imaging features of diseases that may closely simulate pancreatic adenocarcinoma, either radiologically or pathologically. CONCLUSION: Neoplastic and inflammatory diseases that can closely simulate pancreatic adenocarcinoma include neuroendocrine tumor, metastasis to the pancreas, lymphoma, groove pancreatitis, autoimmune pancreatitis, and focal chronic pancreatitis. Atypical imaging findings that should suggest diagnoses other than adenocarcinoma include the absence of significant duct dilatation, incidental detection, hypervascularity, large size (> 5 cm), IV tumor thrombus, and intralesional ducts or cysts. PMID- 22826391 TI - Pancreatic imaging mimics: part 2, pancreatic neuroendocrine tumors and their mimics. AB - OBJECTIVE: This pictorial essay reviews the imaging appearance of pancreatic neuroendocrine tumors, as well as a number of mimics on CT. CONCLUSION: Pancreatic neuroendocrine tumors have a distinct appearance, typically characterized by a well-defined hypervascular mass best visualized on arterial phase images. However, a number of other lesions can mimic the CT appearance of pancreatic neuroendocrine tumors, including pancreatic metastases, acinar cell carcinoma, pancreatoblastoma, solitary fibrous tumor, pancreatic hamartoma, serous adenoma, intrapancreatic splenules, exophytic gastrointestinal stromal tumors, and peripancreatic paragangliomas. PMID- 22826392 TI - Imaging of granulomatous fibrosing mediastinitis. AB - OBJECTIVE: The purpose of this article is to review and illustrate the pathogenesis, natural history, imaging features, and treatment of granulomatous fibrosing mediastinitis. CONCLUSION: Granulomatous fibrosing mediastinitis is an infiltrative disorder characterized by encasement of the mediastinal viscera; in most cases in the United States, it represents an idiosyncratic immune response to histoplasma. Familiarity with the various imaging features of fibrosing mediastinitis is important for prompt and accurate diagnosis as well as for planning and guiding surgical and less-invasive treatments. PMID- 22826388 TI - Molecular imaging of prostate cancer: PET radiotracers. AB - OBJECTIVE: Recent advances in the fundamental understanding of the complex biology of prostate cancer have provided an increasing number of potential targets for imaging and treatment. The imaging evaluation of prostate cancer needs to be tailored to the various phases of this remarkably heterogeneous disease. CONCLUSION: In this article, I review the current state of affairs on a range of PET radiotracers for potential use in the imaging evaluation of men with prostate cancer. PMID- 22826393 TI - Aborted myocardial infarction: evaluation of changes in area at risk, late gadolinium enhancement, and perfusion over time and comparison with overt myocardial infarction. AB - OBJECTIVE: The objective of our study was to analyze comprehensive MRI findings of aborted myocardial infarction (MI) in terms of the area at risk, late enhancement, and perfusion on initial and follow-up studies compared with overt MI. SUBJECTS AND METHODS: Eleven cases of aborted MI and 18 cases of overt MI were included in this study. We evaluated the location and signal pattern of infarction on both T2-weighted imaging and delayed enhancement MRI. For quantitative analysis, we calculated the size and contrast ratio of the myocardial signal abnormality compared with remote myocardium on T2-weighted imaging and delayed enhancement MRI. We also evaluated the regional systolic function on cine MRI and the perfusion abnormality on first-pass perfusion MRI. Six months after initial imaging, MRI was repeated to see changes in enhancement pattern and functional indexes. RESULTS: T2-weighted images of all patients showed homogeneous high signal intensity (SI) along the vascular territory of the culprit lesion. MRI of patients with aborted MI showed no (n = 5) or minimal (n = 6) delayed enhancement. Compared with overt MI cases, aborted MI cases also were significantly smaller (p = 0.001) and showed significantly lower SI (p = 0.002) of the enhancing region on delayed enhancement MRI. On follow-up delayed enhancement MRI, the enhancing region was smaller in most cases. All aborted MI cases except one showed hypokinesia and a perfusion defect at the corresponding vascular territory on the initial MRI, but these abnormal findings had normalized on follow-up MRI. CONCLUSION: The characteristic MRI findings of aborted MI are the absence of or minimal enhancement on delayed enhancement MRI compared with overt MI. On follow-up MRI of aborted MI cases, the area at risk, minimal enhancement, and perfusion defect had normalized. PMID- 22826394 TI - Normal range of emphysema and air trapping on CT in young men. AB - OBJECTIVE: The purpose of our study was to assess the normal range of CT measures of emphysema and air trapping in young men with normal lung function. MATERIALS AND METHODS: A cohort of 70 young men with high-normal spirometry and body plethysmography underwent paired inspiratory and expiratory CT. Visual and quantitative scores of emphysema and air trapping were obtained. On CT, emphysema was defined as the 15th percentile of the attenuation curve (Perc(15)), and as the percentage of inspiratory voxels below -950 (IN(-950)) and below -960 (IN( 960)) HU. On CT, air trapping was defined as the expiratory-to-inspiratory ratio of mean lung density (EI-ratio(MLD)), and the percentage of voxels below -856 HU in expiration (EXP(-856)). Means, medians, and upper limits of normal (ULN) are presented for the total population and for smokers and nonsmokers separately. RESULTS: The mean age (+/- SD) of the subjects was 36.1 +/- 9.3 years. Smoking history was limited (range, 0-11 pack-years). Spirometry was high normal, ranging from 113% to 160% of predicted for vital capacity (VC), and from 104% to 140% of predicted for forced expiratory volume in 1 second (FEV(1)). The ULN was 2.73% for IN(-950), 0.87% for IN(-960), -936 HU for Perc(15), 89.0% for EI-ratio(MLD), and 17.2% for EXP(-856).Visual CT scores showed minimal emphysema in eight (11%), > 5 lobules of air trapping in five (7%), and segmental air trapping in three (4%) subjects. CT measures were similar for never- and ever-smokers. CONCLUSION: We report the normal range of CT values for young male subjects with normal lung function, which is important to define pulmonary disease. PMID- 22826395 TI - Role of contrast-enhanced sonography in differentiation of subtypes of hepatocellular adenoma: correlation with MRI findings. AB - OBJECTIVE: Hepatocellular adenomas (HCAs) are divided into three subtypes according to genotype and phenotype. The two main subgroups are hepatocyte nuclear factor 1alpha (HNF1alpha)-inactivated HCA and inflammatory HCA. Specific imaging features of these subgroups of adenoma have been delineated with MRI. The aim of this study was to document the contrast-enhanced sonographic (CEUS) features specific for adenoma subtypes and to correlate them with MRI findings. MATERIALS AND METHODS: We retrospectively analyzed data on 38 patients with HCA confirmed at pathologic examination in all cases. All cases were classified with MRI. RESULTS: HNF1alpha-inactivated HCA (n = 16) was found to have a homogeneous hyperechoic aspect at baseline gray-scale sonography, isovascularity or moderate hypervascularity with mixed filling in the arterial phase, and isoechogenicity in the portal and late portal venous phases. Homogeneous hyperechogenicity during B mode sonography was the most specific pattern (sensitivity, 88%; specificity, 91%) and correlated with diffuse fat repartition observed on MR images obtained with chemical-shift sequences. In inflammatory HCA (n = 17) the association of arterial hypervascularity with centripetal filling, linear vascularities, peripheral rim of sustained enhancement, and central washout in the late venous phase was specific (sensitivity, 64%; specificity, 100%). Discrepancy between delayed washout during CEUS and sustained enhancement during MRI could be related to differences between gadolinium and microbubbles in diffusing in the interstitial spaces. In the five other HCA cases (four unclassified, one beta catenin activated) CEUS showed characteristics of benign hepatocellular tumors with no specific features. CONCLUSION: HNF1alpha-inactivated HCA and inflammatory HCA had characteristic CEUS patterns. Delayed washout, an unusual finding in benign hepatic lesions, is of particular interest and was a characteristic of inflammatory HCA subtype. PMID- 22826396 TI - Enhancement patterns of hepatocellular carcinoma after transarterial chemoembolization using drug-eluting beads on arterial phase CT images: a pilot retrospective study. AB - OBJECTIVE: The purpose of this article is to assess CT enhancement patterns of hepatocellular carcinoma (HCC) within 1 month after transarterial chemoembolization (TACE) using drug-eluting beads and to determine whether enhancement patterns may be useful for predicting local tumor progression. MATERIALS AND METHODS: Forty-one patients with 50 HCCs underwent CT within 1 month after TACE with drug-eluting beads. Two blinded readers independently reviewed the arterial phase images and classified enhancement patterns as follows: no enhancement, peripheral ring enhancement, and peripheral nodulelike enhancement. Enhancement patterns were correlated with time to tumor progression of enhancing tissue by log-rank test. RESULTS: In the group with no enhancement, 92.3% (24/26) had not progressed and 7.7% (2/26) showed progression; for peripheral ring enhancement, 83.3% (10/12) had not progressed and 16.7% (2/12) showed progression; and for peripheral nodulelike enhancement, 16.7% (2/12) had not progressed and 83.3% (10/12) showed progression. The time to progression of enhancing tissue was significantly different between the group with no enhancement plus peripheral ring enhancement and the group with peripheral nodulelike enhancement (p < 0.001). CONCLUSION: Analysis of enhancement patterns at the arterial phase of the first follow-up CT after TACE with drug-eluting beads is helpful for predicting progression of treated HCC. PMID- 22826397 TI - The incremental value of contrast-enhanced MRI in the detection of biopsy-proven local recurrence of prostate cancer after radical prostatectomy: effect of reader experience. AB - OBJECTIVE: The purpose of this study is to retrospectively assess the incremental value of contrast-enhanced MRI (CE-MRI) to T2-weighted MRI in the detection of postsurgical local recurrence of prostate cancer by readers of different experience levels, using biopsy as the reference standard. MATERIALS AND METHODS: Fifty-two men with biochemical recurrence after prostatectomy underwent 1.5-T endorectal MRI with multiphase contrast-enhanced imaging and had biopsy within 3 months of MRI. Two radiologists (reader 1 had 1 year and reader 2 had 6 years of experience) independently reviewed each MRI study and classified the likelihood of recurrent cancer on a 5-point scale. Areas under receiver operating characteristic curves (A(z)) were calculated to assess readers' diagnostic performance with T2-weighted MRI alone and combined with CE-MRI. Interobserver agreement was assessed using Cohen kappa statistics. RESULTS: Thirty-three patients (63%) had biopsy-proven local recurrence of prostate cancer. With the addition of CE-MRI to T2-weighted imaging, the A(z) for cancer detection increased significantly for reader 1 (0.77 vs 0.85; p = 0.0435) but not for reader 2 (0.86 vs 0.88; p = 0.7294). The use of CE-MRI improved interobserver agreement from fair (kappa = 0.39) to moderate (kappa = 0.58). CONCLUSION: CE-MRI increased interobserver agreement and offered incremental value to T2-weighted MRI in the detection of locally recurrent prostate cancer for the relatively inexperienced reader. PMID- 22826398 TI - Atypical metastases from prostate cancer: 10-year experience at a single institution. AB - OBJECTIVE: The purpose of the study was to retrospectively review the frequency, sites, and patterns of atypical metastases from prostate cancer and to determine whether any correlation exists between the atypical sites and biochemical or histologic variables. MATERIALS AND METHODS: All available imaging studies of 620 consecutive patients with biopsy-proven prostate carcinoma seen at our institute between 1999 and 2009 were reviewed. Eighty-two patients (mean age, 72 years; age range, 58-87 years) with atypical sites of metastases were identified. Patients were separated into groups on the basis of the presence or absence of concurrent osseous metastasis and high or low Gleason grade, and metastatic patterns were compared using the Fisher exact test. The maximum prostate-specific antigen (PSA) level for each patient was recorded and correlated with metastatic pattern using the Mann-Whitney test. RESULTS: The most frequent sites of atypical metastases were the lungs and pleura (40%, 33/82), liver (37%, 30/82), supradiaphragmatic lymph nodes (34%, 28/82), and adrenal glands (15%, 12/82). Supradiaphragmatic lymphadenopathy was more common in patients with osseous metastases (45%, 25/56) than in patients without concurrent osseous involvement (12%, 3/26; p < 0.05). There was no significant correlation between the other atypical metastatic sites and osseous metastases. Abdominal visceral metastasis occurred more frequently in patients with a high Gleason grade (25/43, 58%) than in patients with a low Gleason grade (9/29, 31%; p < 0.05). There was no significant correlation between metastatic pattern and PSA level. CONCLUSION: The lungs and pleura, liver, supradiaphragmatic lymph nodes, and adrenal glands are the most common extranodal metastatic sites of prostate cancer. Supradiaphragmatic lymphadenopathy was strongly associated with concurrent osseous metastases. PMID- 22826399 TI - Comparison of CT-based methodologies for detection of growth of solid renal masses on active surveillance. AB - OBJECTIVE: The purpose of this study is to retrospectively compare 1D, 2D, and 3D measurements on CT for detection of growth of solid renal masses on active surveillance. MATERIALS AND METHODS: Forty solid renal masses measuring at least 1 cm in patients who underwent two CT studies at least 3 months apart were included. Two radiologists independently assessed the studies for interval growth using gestalt visual assessment and 1D, 2D, and 3D measurements. Prospective reports were also evaluated for indications of growth. The summation-of-areas technique was used to calculate volumes of lesions, which served as reference standard in determination of growth. Logistic regression analysis for correlated data was used to compare accuracy of methodologies for detection of lesion growth. Interreader agreement was assessed using kappa coefficients and intraclass correlation coefficients. RESULTS: The accuracy of gestalt visual, 1D, 2D, and 3D assessments for detection of interval growth was 72.5%, 70.0%, 82.5%, and 85% for reader 1 and 77.5%, 70.0%, 90.0%, and 95.0% for reader 2. These differences were significant or nearly significant (p = 0.003-0.054) for the greater accuracy of 2D or 3D measurements than for 1D measurements for reader 1 as well as the greater accuracy of 2D measurements than 1D measurements and 3D measurements than gestalt visual assessment or 1D measurements for reader 2. The accuracy of prospective reports for detection of growth was 65.0%. Reader agreement was fair for gestalt visual assessment (kappa = 0.31) and nearly perfect for 1D, 2D, and 3D measurements (intraclass correlation coefficient = 0.97-0.99). CONCLUSION: Our results show that 2D or 3D measurements may be preferable to 1D measurements on CT in assessment for growth of solid renal masses on active surveillance. PMID- 22826401 TI - Intraobserver and interobserver variability of renal volume measurements in polycystic kidney disease using a semiautomated MR segmentation algorithm. AB - OBJECTIVE: Total renal volume and changes in kidney volume are markers of disease progression in autosomal-dominant polycystic kidney disease (ADPKD) but are not used in clinical practice in part because of the complexity of manual measurements. This study aims to assess the intra- and interobserver reproducibility of a semiautomated renal volumetric algorithm using fluid sensitive MRI pulse sequences. SUBJECTS AND METHODS: Renal volumes of 17 patients with ADPKD were segmented from high-resolution coronal HASTE and true fast imaging with steady-state precession (FISP) MR acquisitions. Measurements performed independently by four readers were repeated, typically after 7 days. Intraobserver agreement indexes were calculated for total kidney volume for each patient. Interobserver agreement indexes were obtained for the six paired combinations of readers as well as for two readers after rigorous formalized training. Pearson and concordance correlation coefficients, coefficients of variation (CVs), and 95% limits of agreement were determined. RESULTS: The HASTE and true FISP sequences performed similarly with a median intraobserver agreement of greater than 98.1% and a CV of less than 2.4% across all readers. The median interobserver agreement was greater than 95.2% and the CV was less than 7.1%, across all reader pairs. Reader training further lowered interobserver CV. The mean total kidney volume was 1420 mL (range, 331-3782 mL) for HASTE imaging and 1445 mL (range, 301-3714 mL) for true FISP imaging, with mean image processing times per patient of 43 and 28 minutes, respectively. CONCLUSION: This semiautomated MR volumetric algorithm provided excellent intraobserver and very good interobserver reproducibility using fluid-sensitive pulse sequences that emphasize cyst conspicuity. PMID- 22826400 TI - Renal cell carcinoma: value of multiphase MDCT with multiplanar reformations in the detection of pseudocapsule. AB - OBJECTIVE: The purpose of this study was to assess the diagnostic performance of four-phase (unenhanced, arterial, portal, and nephrographic-excretory) MDCT with multiplanar reformations in the detection of pseudocapsule of renal cell carcinoma (RCC). MATERIALS AND METHODS: In a retrospective study of 29 histologically proven RCCs in 29 patients (17 men, 12 women; mean age, 59 years), examinations were performed with a 16-MDCT scanner. The protocol included unenhanced and three-phase (arterial, portal, and nephrographic-excretory) contrast-enhanced CT. The data were analyzed by two reviewers blinded to the histopathologic results. Any discrepancy was resolved by consensus. The presence of a regular, high- or low-attenuation halo surrounding a renal neoplasm was considered to represent renal pseudocapsule. The accuracy of MDCT in the detection of pseudocapsule with the histopathologic results as the standard of reference was evaluated. Unenhanced transverse images and multiplanar reformations in the transverse, coronal, and sagittal planes of each contrast enhanced phase were separately analyzed. The chi-square two-way test was used to compare each CT phase and multiplanar reformation with histologic results. RESULTS: The mean diameter of RCCs on CT scans was 5.6 cm (range, 2.8-15 cm), in accordance with the pathologic result. MDCT enabled detection of renal pseudocapsule in 20 of 29 RCCs with 83% sensitivity, 80% specificity, 95% positive predictive value, 50% negative predictive value, and 83% overall accuracy. Imaging in the portal and nephrographic phases with coronal and sagittal reformations proved more accurate in the detection of pseudocapsule (p < 0.05). CONCLUSION: Multiphase MDCT with multiplanar reformations had satisfactory results in the detection of renal pseudocapsule in RCC. PMID- 22826402 TI - Autopsy as a quality control measure for radiology, and vice versa. AB - OBJECTIVE: Radiologic studies are anatomic studies lacking the natural full color, 3D, and microscopic-level examination of autopsies, suggesting that autopsies might be able to serve as quality control for radiology. MATERIALS AND METHODS: Cases in which complete or near-complete autopsies were performed at a university hospital in 2008 were reviewed, and antemortem radiologic diagnoses were compared with corresponding autopsy findings. Discrepancies between antemortem radiologic diagnoses and autopsy findings were categorized. RESULTS: For 729 of the 828 diagnoses reviewed in the study, the pathologic condition in question was thought to be present at the time that a radiologic study of the relevant anatomic region was performed. Of these 729 radiologic diagnoses, 201 (27.6%) were determined to be discrepant from the corresponding autopsy diagnoses (i.e., autopsy deemed correct), but many of these radiologic discrepancies were not of clinical significance. The radiologic error rate considers only the clinically relevant discrepancies categorized as "missed diagnosis" or "misinterpretation"; it was calculated to be 3.3%. Interestingly, 32 autopsy discrepancies (i.e., radiology deemed correct) were also identified in the study. CONCLUSION: The results of this study suggest that even in 2008 patients sometimes died with undiagnosed or misdiagnosed diseases. Radiologic diagnoses discrepant from autopsy findings were consistently identified in this study and show that autopsies can help radiologists sharpen their skills in interpreting radiologic studies and can perhaps serve as quality control for radiology. The results also suggest that radiology can serve as quality control for autopsy. PMID- 22826403 TI - Improved image quality in dual-energy abdominal CT: comparison of iterative reconstruction in image space and filtered back projection reconstruction. AB - OBJECTIVE: The purpose of this study is to investigate whether an iterative reconstruction in image space (IRIS) algorithm improves the image quality of dual energy CT abdominal examinations performed during the hepatic arterial phase. MATERIALS AND METHODS: Seventy patients with suspected liver masses underwent contrast-enhanced multiphase abdominal examination and were enrolled in the study. A dual-energy CT protocol was performed in the hepatic arterial phase (parameters: tube A, 140 kV and 90 mA; tube B, 80 kV and 382 mA; automatic tube current modulation on; and collimation, 14 * 1.2 mm). The reconstructions were performed with filtered back projection (FBP) and IRIS algorithms at a slice thickness of 3 mm and kernels of B30 and I30. The image noise was measured on the liver, aorta, and subcutaneous fat on the FBP and IRIS fusion images (m = 0.3) at the same position. The image noise and diagnostic acceptability of all images were scored by two radiologists. RESULTS: The image noise using the IRIS algorithm was lower than that using the standard FBP algorithm on the liver, aorta, and subcutaneous fat, respectively. The signal-to-noise ratio and contrast to-noise ratio of images reconstructed with the IRIS algorithm also were significantly higher than for those reconstructed with the FBP algorithm. The diagnostic acceptability score using the IRIS algorithm was higher than that using the FBP algorithm at the same dose level (1.20 +/- 0.40 vs 1.37 +/- 0.57; p < 0.05). CONCLUSION: Compared with standard FBP reconstruction, an IRIS algorithm enables significant reduction of image noise and improvement of image quality and has the potential to decrease radiation exposure during contrast-enhanced dual energy CT abdominal examination. PMID- 22826404 TI - Spectrum of high-resolution MRI findings in diabetic neuropathy. AB - OBJECTIVE: Diabetes is the most common cause of neuropathy. Focal diabetic neuropathy, although less common than entrapment neuropathy, clinically mimics entrapment neuropathy. This article depicts the spectrum of MR abnormalities in diabetic subjects- from abnormal T2 hyperintensity and fascicular enlargement in the acute and subacute stages to atrophic-appearing fascicles with intraepineurial fat deposition in the chronic stage-on high-resolution high-field (3-T) MRI. CONCLUSION: A spectrum of imaging abnormalities is observed in diabetic neuropathy. It is important for radiologists to understand the pathophysiology and recognize high-resolution MR appearances of these lesions and of related entities in the differential diagnosis for appropriate diagnosis and patient treatment. PMID- 22826405 TI - Musculoskeletal injuries related to yoga: imaging observations. AB - OBJECTIVE: The purpose of this article is to describe the imaging appearances of musculoskeletal injuries related to yoga. We performed an automated search in the database of a large tertiary care center and conducted a retrospective analysis of the imaging findings in 38 patients over a 9-year period. CONCLUSION: The most frequently encountered musculoskeletal injuries were tendinous lesions, including tears of the supraspinatus, Achilles, and peroneus brevis tendons and fibrocartilaginous tears involving the medial meniscus, acetabular labrum, glenoid labrum, and lumbar disk with extrusion. PMID- 22826406 TI - Performing fluoroscopically guided interlaminar lumbar epidural injections. AB - OBJECTIVE: The purpose of this video article is to provide a step-by-step guide for performing fluoroscopically guided interlaminar lumbar epidural injections, emphasizing the anatomy of the epidural space, anatomic landmarks to aid in needle placement, techniques, and ways of minimizing potential complications. CONCLUSION: Low back pain and radiculopathy afflict millions of people each year with enormous socioeconomic ramifications and individual disability. This condition has a prevalence of at least 13% and is the second most common symptom related cause for office visits in the United States. Epidural injections have become the most commonly performed intervention in the management of chronic low back pain in the United States. PMID- 22826407 TI - Imaging findings in tick-borne encephalitis with differential diagnostic considerations. AB - OBJECTIVE: The purpose of this article is to provide a practical review of the spectrum of imaging findings in patients with tick-borne encephalitis (TBE) and to address possible differential diagnoses. CONCLUSION: Imaging findings in TBE resemble those of other infections, such as meningoencephalitis. However, a predilection for the thalami, basal ganglia, cerebellum, and anterior horns of the spinal cord suggests the possibility of TBE. PMID- 22826408 TI - Fracture mimics on temporal bone CT: a guide for the radiologist. AB - OBJECTIVE: The objective of this article is to discuss and illustrate commonly visualized fissures and sutures in the temporal bone. This topic is important because a thorough knowledge of normal anatomy is necessary to avoid misinterpretation as fractures. CONCLUSION: Small normal anatomic fissures are now routinely visualized with the increasing use of MDCT in trauma patients. An awareness of these structures is required by radiologists interpreting studies with fine temporal bone slices to prevent erroneous interpretation. PMID- 22826409 TI - Dynamic pulmonary CT of children. AB - OBJECTIVE: Wide-detector CT allows simultaneous imaging of the entire airway and lungs in small children. Images acquired in multiple phases by continuous scanning during respiration are viewed dynamically, allowing more complete airway and pulmonary evaluation than possible with static protocols. The purpose of this study was to evaluate whether low-dose techniques can be applied to dynamic pulmonary CT of small children. MATERIALS AND METHODS: The study included 24 infants and small children with persistent respiratory difficulty who underwent dynamic pulmonary CT (11 with IV contrast administration, 13 without contrast administration). No significant difference in patient age was present in the two groups. Continuous-mode wide-detector scans were obtained at 350-millisecond gantry rotation for a total of 1.4 seconds at 80 kVp. Some contrast-enhanced studies for simultaneous vascular and airway evaluation were performed at slightly greater tube current. The effective dose for each patient was calculated, and the Student t test was performed to compare effective dose measurements. RESULTS: All studies were of diagnostic quality, frequently yielding critical information not available with other diagnostic tests. The mean effective dose for all patients was 1.7 (SD, 1.1) mSv. In the group who received contrast material, the mean effective dose was greater (1.9 [SD, 1.4] mSv) than in the group who did not receive contrast material (1.5 [SD, 0.7] mSv), but the difference was not significant (p = 0.4). CONCLUSION: Wide-detector dynamic CT is ideal for evaluation of the airway and lungs in infants and small children with persistent respiratory distress. Effective doses are low, typically less than 2 mSv. PMID- 22826410 TI - Uterine artery embolization of large fibroids: comparative study of procedure with and without pretreatment gonadotropin-releasing hormone agonists. AB - OBJECTIVE: The purpose of this study was to evaluate the safety of pretreatment with gonadotropin-releasing hormone (GnRH) agonists before uterine artery embolization (UAE) of large fibroids. MATERIALS AND METHODS: The cases of 40 patients with large fibroids (>= 10 cm) were retrospectively analyzed. Among the 40 patients, 28 (control group) underwent UAE without pretreatment with GnRH agonists, and 12 (GnRH group) received GnRH agonists 1-5 times before UAE. MRI was used to assess necrosis of large fibroids and their volumes in both groups within 3 months after UAE. RESULTS: Complete necrosis of large fibroids after UAE was achieved in 39 of 40 patients (97.5%). Only one patient, who was in the control group, had incomplete necrosis of the predominant fibroid. When GnRH agonists were administered before UAE, the mean volume reduction rate of fibroids was 36.3%. The final mean volume reduction rates of the predominant fibroids and the uterus after UAE in the GnRH group were 56.5% (range, 38-79%) and 50.8% (range, 35-72%), significantly higher than the volume reduction rates of 35.1% (range, 7-65%) and 34.9% (range, 16-54%) in the control group (p < 0.001). Grade D complications were not seen in the GnRH group but occurred in four patients in the control group. CONCLUSION: Pretreatment with GnRH agonists before UAE of large fibroids was safe for patients with large fibroids and did not prevent performance of UAE. PMID- 22826411 TI - Follow-up of radiologically totally implanted central venous access ports of the upper arm: long-term complications in 127,750 catheter-days. AB - OBJECTIVE: The purpose of this article is to retrospectively evaluate radiologically totally implanted central venous access ports (VAPs) of the upper arm in terms of safety, technical feasibility, and device-related complications. MATERIALS AND METHODS: Five hundred seven consecutive patients (mean [+/- SD] age, 59.2 +/- 11.4 years) who received a totally implanted central VAP between January 2005 and July 2010 were included. The insertion procedure was performed in an interventional radiology suite using the Seldinger technique. Neither antibiotic prophylaxis nor long-term anticoagulation was administered. RESULTS: In 507 patients, a total of 523 devices were implanted. Of these 523 procedures, 512 complete datasets were available during follow-up. The primary technical success rate was 99.04%. All procedures were completed without major complications. During follow-up and with a total number of 127,750 days of totally implanted central VAP implantation (248 +/- 279 days/patient; range, 1 1687 days/patient), 50 devices had to be revised because of complications (9.8%). Complications occurred at a mean of 114 +/- 183 days (range, 1-1113 days) after placement. Early complications were noted in 21 of 512 cases (4.1%), and late complications were noted in 29 of 512 cases (5.7%). Complications were as follows: local infections, 4.9% (25/512); systemic infections, 0.4% (2/512); venous thrombosis, 1.6% (8/512); paralysis of the median nerve, 0.6% (3/512); skin dehiscence at the port site, 0.2% (1/512); and mechanical problems including catheter line displacement, port hub rotation, and catheter fracture, 2.1% (11/512). CONCLUSION: Radiologic placement of a totally implanted central VAP is a safe procedure with a low rate of both early and late device-related complications. The method is effective for delivery of chemotherapy, parenteral nutrition, and frequent IV medication. PMID- 22826412 TI - Extrahepatic soft tissue mimicking applicator-tract implantation after percutaneous radiofrequency ablation of hepatic malignancy. AB - OBJECTIVE: The purpose of our study was to identify extrahepatic soft tissue mimicking applicator-tract implantation after percutaneous radiofrequency ablation of hepatic malignancy on triple-phase dynamic CT. MATERIALS AND METHODS: A database was reviewed for 131 patients who underwent percutaneous radiofrequency ablation for treatment of a hepatic tumor over a 3-year period. Patients who developed extrahepatic soft tissue adjacent to the previous ablation zone mimicking applicator-tract implantation were identified. The clinical features of patients, characteristics of extrahepatic soft tissue on CT, soft tissue changes on follow-up CT, and histopathologic results were evaluated. RESULTS: Extrahepatic soft tissue developed in five patients (3.8%) at 2-8 months after percutaneous radiofrequency ablation. Extrahepatic soft tissue showed progressive enhancement during the delayed phase of dynamic CT. Four lesions were completely resolved without any treatment. However, one lesion was enlarged and xanthogranulomatous inflammation was diagnosed by percutaneous biopsy. Univariate analysis showed that an index tumor with a subcapsular location and a prior biopsy had high odds ratios. CONCLUSION: The possibility of a benign inflammatory lesion should be considered when extrahepatic soft tissue showing radiologic findings similar to applicator-tract implantation develops after radiofrequency ablation of a hepatic tumor. PMID- 22826413 TI - Triple receptor-negative breast cancer: imaging and clinical characteristics. AB - OBJECTIVE: The objective of our study was to retrospectively evaluate the imaging findings of patients with breast cancer negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) so-called "triple receptor-negative cancer"-and to compare the mammographic findings and clinical characteristics of triple receptor-negative cancer with non triple receptor-negative cancers (i.e., ER-positive, PR-positive, or HER2 positive or two of the three markers positive). CONCLUSION: Triple receptor negative cancer was most commonly an irregular noncalcified mass with ill-defined or spiculated margins on mammography and a hypoechoic or complex mass with an irregular shape and noncircumscribed margins on ultrasound. Most triple receptor negative cancers were discovered on physical examination. Compared with non triple receptor-negative cancers, triple receptor-negative cancers were found in younger women and were a higher pathologic grade. PMID- 22826415 TI - Linear breast calcifications. PMID- 22826414 TI - Preoperative needle biopsy of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasound in patients with breast cancer. AB - OBJECTIVE: The purpose of this study was to assess whether sentinel lymph nodes (SLNs) that undergo targeted needle biopsy after identification by contrast enhanced ultrasound (CEUS) using intradermally injected microbubbles results in more node-positive breast cancer patients being diagnosed preoperatively. Furthermore, we sought to determine whether the addition of CEUS to gray-scale sonography of the axilla reduces the number of patients having axillary lymph node (ALN) dissection as a second procedure. SUBJECTS AND METHODS: Intradermal microbubble injection was performed in 136 breast cancer patients who had no abnormal ALNs on routine gray-scale axillary sonography. When an enhancing ALN was visualized, percutaneous sonography-guided fine-needle aspiration cytology or core needle biopsy was performed. Depending on the biopsy results, patients underwent SLN biopsy or ALN dissection. If the putative SLN biopsy was positive or a biopsy tract was seen in the excised SLN, the procedure was defined as successful. RESULTS: SLNs were identified and biopsied in 126 of the 136 cases (93%). Seventeen patients had positive sonography-guided biopsy results (13%) and were treated with immediate ALN dissection. In seven patients, the biopsied node was the only positive node. The remaining 109 patients underwent SLN biopsy. In nine cases (8%), a positive lymph node was identified. Four of these false negative cases had only micrometastases. CONCLUSION: SLNs can be identified and biopsied using CEUS to increase the accuracy of preoperative axillary staging. If the needle biopsy result is negative, conventional SLN biopsy is indicated. PMID- 22826416 TI - Peer review in clinical radiology practice. PMID- 22826417 TI - PET/CT and renal pathology: a blind spot for radiologists? Part 1, primary pathology. AB - OBJECTIVE: PET/CT with (18)F-FDG shows metabolically active disease and is widely used for the diagnosis and follow-up of patients with cancer. Nonmetabolically active renal pathology may be missed without close attention to the CT portion of the study, whereas metabolically active pathology may be missed on PET because of physiologic tracer excretion in the kidneys. This article illustrates primary lesions of the kidney on FDG PET/CT with emphasis on key anatomic features and the appearance of tracer uptake. CONCLUSION: Close attention to both the FDG PET and CT portions of the study is essential to interpret renal pathology correctly on FDG PET/CT examinations. PMID- 22826418 TI - PET/CT and renal pathology: a blind spot for radiologists? Part 2--lymphoma, leukemia, and metastatic disease. AB - OBJECTIVE: PET/CT with (18)F-FDG is a powerful tool to evaluate patients with hematologic malignancy or to assess the burden of metastatic disease from solid tumors. Metabolically active renal pathology associated with lymphoma, leukemia, or metastatic disease can be missed without close attention to both the PET and CT portions of the study because of physiologic FDG excretion in the kidneys. This article illustrates the appearance of tracer uptake and the key anatomic features of lymphoma, leukemia, and metastatic disease involving the kidney on FDG PET/CT. CONCLUSION: Close attention to both the FDG PET and CT portions of an FDG PET/CT study is essential to evaluate the kidneys in oncology patients. PMID- 22826419 TI - Evaluation of the aortic root with MRI and MDCT angiography: spectrum of disease findings. AB - OBJECTIVE: This article reviews the spectrum of disease processes that may involve the aortic root with particular emphasis on the role of cardiovascular MRI and MDCT angiography in their assessment. Key MRI and MDCT imaging findings are discussed and illustrated. CONCLUSION: Radiologists should be aware of the spectrum of disease processes that may involve the aortic root and their appearances at MRI and MDCT angiography. PMID- 22826420 TI - Complications of biliary and gastrointestinal stents: MDCT of the cancer patient. AB - OBJECTIVE: The goal of this article is to discuss and show the common complications of biliary and gastrointestinal stents as depicted by MDCT in cancer patients. Major complications include stent misplacement or displacement, bleeding, obstruction, perforation, stent fracture or collapse, and infection. This topic encompasses several relevant issues, including interpretative difficulties, therapeutic decisions, and potential malpractice concerns. CONCLUSION: Awareness and methodical assessment of stents could allow detection of stenting complications, potentially sparing the patient from associated morbidity and mortality. PMID- 22826421 TI - Clinical correlation of a new practical MRI method for assessing cervical spinal canal compression. AB - OBJECTIVE: The purpose of this study was to evaluate interobserver agreement and whether or not a new MRI grading system correlates with symptoms and neurologic signs for assessing spinal canal compression. MATERIALS AND METHODS: One hundred patients (52 men and 48 women; mean age, 50 years) underwent MRI of the cervical spine at our institution and were evaluated by two musculoskeletal radiologists. The presence and grade of cervical canal stenosis at the maximal narrowing point was assessed according to the new grading system suggested by Kang et al. (Kang system). The results correlated with the clinical manifestations and neurologic examination. Statistical analysis was performed using kappa statistics, categoric regression analysis, and nonparametric correlation analysis (Spearman correlation). RESULTS: Interobserver agreement in the grading of spinal stenosis between the two readers was almost perfect (kappa = 0.925). Most of the patients with grade 0 cervical canal stenosis showed no neurologic manifestation, and patients with grades 2 and 3 cervical canal stenosis had positive neurologic manifestations. The correlation coefficient (R) of reader 1 between MRI grade (0, 1, 2, and 3) and neurologic manifestations (positive or negative) was 0.846. The R of reader 2 was 0.808. In the younger age group (< 50 years old), the R of reader 1 was 0.834 and the R of reader 2 was 0.745. In the older age group (>= 50 years old), the R of reader 1 was 0.839 and the R of reader 2 was 0.839. CONCLUSION: The interobserver agreement of the Kang system was almost perfect and was higher than in the study by Kang et al. Grade 0 cervical canal stenosis represents negative neurologic manifestations and grades 2 and 3 cervical canal stenosis represent positive neurologic manifestations. The Kang system and clinical manifestations are significantly correlated, especially in the older age group (>= 50 years). PMID- 22826422 TI - Scapholunate advanced collapse and scaphoid nonunion advanced collapse: MDCT arthrography features. AB - OBJECTIVE: The aim of this article is to present the imaging features of scapholunate advanced collapse (SLAC) and scaphoid nonunion advanced collapse (SNAC) on MDCT arthrography. CONCLUSION: MDCT arthrography is an excellent tool for patients with clinically suspected SLAC or SNAC wrist because it allows identification of the spectrum of findings for diagnosis and proper classification, which directly impact management. PMID- 22826423 TI - Synovial sarcoma: imaging features of common and uncommon primary sites, metastatic patterns, and treatment response. AB - OBJECTIVE: The purpose of this review is to describe the imaging features, common and uncommon sites, metastatic pattern, and treatment response of synovial sarcoma. CONCLUSION: Synovial sarcoma primarily occurs in young adults, most commonly in the lower extremities; presents as a large, noninfiltrative, well circumscribed mass adjacent to joints, often with punctuate calcifications; and may exhibit a triple signal pattern on T2-weighted images. Small synovial sarcomas can mimic benign lesions. This tumor has a propensity for late local recurrence and metastasis, most commonly to lung. PMID- 22826424 TI - Differentiation of branchial cleft cysts and malignant cystic adenopathy of pharyngeal origin. AB - OBJECTIVE: There is an increasing incidence of head and neck cancers that present as neck masses in a nonsmoking nondrinking population. These masses can be confused with benign cystic neck masses. The purpose of this study was to determine imaging criteria to differentiate benign lateral neck cysts from malignant cystic adenopathy. MATERIALS AND METHODS: A retrospective analysis of patients who underwent contrast-enhanced neck CT between July 2003 and July 2011 was performed. Patients were diagnosed with either a branchial cleft cyst or pharyngeal squamous cell cancer. Each examination was reviewed by a neuroradiologist, and, for each cyst or cystic lymph node, the anatomic level in the neck, dimensions, wall thickness, septations, homogeneity, extracapsular spread, calcifications, and fat stranding were recorded. Data analysis was performed using Student t tests and chi-square tests. RESULTS: Twenty-one patients with branchial cleft cysts and 29 patients with squamous cell carcinoma met the inclusion criteria. Significant differences between the groups were found with regard to size, homogeneity, and extracapsular spread. Branchial cleft cysts were found to be larger on the long axis (p < 0.001), short axis (p < 0.001), and height (p < 0.001). They were less likely to have extracapsular spread (p = 0.044) or septations (p = 0.059) and more likely to be homogeneous (p < 0.001). CONCLUSION: Misdiagnosis of malignant cysts in the neck may lead to delay in diagnosis, a violated neck, tumor spillage, and spread. Differences in radiographic criteria can guide clinical decision making in the patient with a neck mass. However, fine-needle aspiration may be necessary to confirm the diagnosis. PMID- 22826425 TI - Complex genitourinary abnormalities on fetal MRI: imaging findings and approach to diagnosis. AB - OBJECTIVE: The objective of this article is to present the fetal MRI patterns of complex genitourinary abnormalities including epispadias-exstrophy complex, cloacal malformation, urogenital sinus anomaly, posterior urethral valves, and other causes that result in lower urinary tract dilatation without oligohydramnios. Relevant embryology will be reviewed, and practical points will be provided that can aid in interpretation. CONCLUSION: Complex genitourinary abnormalities have recognizable imaging findings on fetal MRI. Imaging findings may be subtle; a high index of suspicion and a systematic checklist are useful for accurate diagnosis. Familiarity with fetal MRI patterns of complex genitourinary abnormalities is crucial for making more precise diagnoses that will likely impact pregnancy management, counseling, and postnatal treatment. PMID- 22826426 TI - Comparison of different methods of calculating CT radiation effective dose in children. AB - OBJECTIVE: CT radiation dose is a subject of intense interest and concern, especially in children. Effective dose, a summation of whole-body exposure weighted by specific organ sensitivities, is most often used to compute and compare radiation dose; however, there is little standardization, and there are numerous different methods of calculating effective dose. This study compares five such methods in a group of children undergoing routine chest CT and explores their advantages and pitfalls. MATERIALS AND METHODS: Patient data from 120 pediatric chest CT examinations were retrospectively used to calculate effective dose: two scanner dose-length product (DLP) methods using published sets of conversion factors by Shrimpton and Deak, the imaging performance and assessment of CT (ImPact) calculator method, the Alessio online calculator, and the Huda method. RESULTS: The Huda method mean effective dose (4.4 +/- 2.2 mSv) and Alessio online calculator (5.2 +/- 2.8 mSv) yielded higher mean numbers for effective dose than both DLP calculations (Shrimpton, 3.65 +/- 1.8 mSv, and Deak, 3.2 +/- 1.5 mSv) as well as the ImPact calculator effective dose (3.4 +/- 1.7 mSv). Mean differences ranged from 10.2% +/- 10.1% lower to 28% +/- 37.3% higher than the Shrimpton method (used as the standard for comparison). Differences were more marked at 120 kVp than at 80 or 100 kVp and varied at different ages. Concordance coefficients relative to the Shrimpton DLP method were Deak DLP, 0.907; Alessio online calculator, 0.735; ImPact calculator, 0.926; and Huda, 0.777. CONCLUSION: Different methods of computing effective dose for pediatric CT produce varying results. The method used must be clearly described to allay confusion about documenting and communicating dose for archiving as well as comparative research purposes. PMID- 22826427 TI - High-risk breast lesions at imaging-guided needle biopsy: usefulness of MRI for treatment decision. AB - OBJECTIVE: The purpose of this study is to evaluate the role of MRI for characterization of high-risk breast lesions diagnosed at imaging-guided needle biopsy. MATERIALS AND METHODS: In this retrospective analysis of 220 patients, 227 high-risk lesions (94 papillomas, 64 radial sclerosing lesions, 46 lobular neoplasias, and 23 atypical ductal hyperplasias) found at 11-gauge vacuum assisted or 14-gauge needle biopsy were studied with dynamic MRI (time resolution, 84 or 88 seconds; gadopentetate dimeglumine or gadobenate dimeglumine, 0.1 mmol/kg). When lesions showed contrast enhancement on subtracted images, they were considered suspicious for malignancy. The reference standard was histopathologic examination after surgical excision in 190 of 227 (84%) lesions and negative follow-up (>= 24 months) in 37 of 227 (16%) lesions. Predictive values and likelihood ratios were calculated. RESULTS: Of 227 lesions, 155 (68%) were contrast enhancing and 72 (32%) were not. Of 155 contrast enhancing lesions, 28 (18%) were upgraded to malignancy after surgical excision (nine papillomas, one radial sclerosing lesion, 11 lobular neoplasias, and seven atypical ductal hyperplasias); there were 11 invasive carcinomas and 17 ductal carcinomas in situ, four of the latter being G3. Of 72 non-contrast-enhancing lesions, two (3%) were upgraded to malignancy after surgical excision (one radial sclerosing lesion and one lobular neoplasia), both of which were G1 ductal carcinoma in situ. Cancer probability was significantly higher for contrast enhancing (18%) than for non-contrast-enhancing (3%) lesions (p = 0.001) and for nonmasslike (43%) than for masslike (14%) lesions (p = 0.005). The positive predictive value was 18% (28/155; 95% CI, 13-24%), the negative predictive value was 97% (70/72; 95% CI, 94-99%), the positive likelihood ratio was 1.448 (95% CI, 1.172-1.788), and the negative likelihood ratio was 0.188 (95% CI, 0.152-0.232). CONCLUSION: The absence of enhancement at dynamic MRI allowed reliable exclusion of invasive cancers among high-risk lesions diagnosed at needle biopsy. PMID- 22826428 TI - Radiology residents taking call. PMID- 22826429 TI - Save CAD marks for billing purposes? PMID- 22826430 TI - Tree-in-bud calcified opacities: extending the spectrum of tomographic manifestations of nonthrombotic pulmonary embolism. PMID- 22826431 TI - Plagiarism: reason? PMID- 22826432 TI - Sp1 facilitates DNA double-strand break repair through a nontranscriptional mechanism. AB - Sp1 is a ubiquitously expressed transcription factor that is phosphorylated by ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation and H(2)O(2). Here, we show by indirect immunofluorescence that Sp1 phosphorylated on serine 101 (pSp1) localizes to ionizing radiation-induced foci with phosphorylated histone variant gammaH2Ax and members of the MRN (Mre11, Rad50, and Nbs1) complex. More precise analysis of occupancy of DNA double-strand breaks (DSBs) by chromatin immunoprecipitation (ChIP) shows that Sp1, like Nbs1, resides within 200 bp of DSBs. Using laser microirradiation of cells, we demonstrate that pSp1 is present at DNA DSBs by 7.5 min after induction of damage and remains at the break site for at least 8 h. Depletion of Sp1 inhibits repair of site specific DNA breaks, and the N-terminal 182-amino-acid peptide, which contains targets of ATM kinase but lacks the zinc finger DNA binding domain, is phosphorylated, localizes to DSBs, and rescues the repair defect resulting from Sp1 depletion. Together, these data demonstrate that Sp1 is rapidly recruited to the region immediately adjacent to sites of DNA DSBs and is required for DSB repair, through a mechanism independent of its sequence-directed transcriptional effects. PMID- 22826434 TI - The Myc 3' Wnt-responsive element regulates homeostasis and regeneration in the mouse intestinal tract. AB - The Wnt/beta-catenin signaling pathway controls cellular proliferation in the intestines. In response to Wnt, beta-catenin transits into the nucleus and associates with members of the T-cell factor (TCF) family of transcription factors. beta-Catenin/TCF complexes bind Wnt responsive DNA elements (WREs) to activate target gene expression. The c-MYC proto-oncogene (MYC) is a direct target of beta-catenin/TCF complexes. We recently identified the MYC 3' WRE, which maps 1.4-kb downstream from the MYC transcription stop site. To investigate the role of the Myc 3' WRE in the intestines, we generated a mouse model with a germ line deletion of this element. The intestinal architecture was largely preserved in knockout mice; however, removal of the Myc 3' WRE compromised the crypt microenvironment. In comparison to wild-type intestines, knockout intestines contained an increased number of proliferative cells and a reduced number of differentiated cells comprising both absorptive and secretory lineages. Using a model of colitis, we found that knockout colons repaired more rapidly during the recovery period of the protocol. These results indicate that regulation of MYC expression through the Myc 3' WRE contributes to intestinal homeostasis. Furthermore, our study implicates MYC as an important regulator of intestinal regeneration following injury. PMID- 22826433 TI - Role of SUMOylation in full antiestrogenicity. AB - The selective estrogen receptor downregulator (SERD) fulvestrant can be used as second-line treatment for patients relapsing after treatment with tamoxifen, a selective estrogen receptor modulator (SERM). Unlike tamoxifen, SERDs are devoid of partial agonist activity. While the full antiestrogenicity of SERDs may result in part from their capacity to downregulate levels of estrogen receptor alpha (ERalpha) through proteasome-mediated degradation, SERDs are also fully antiestrogenic in the absence of increased receptor turnover in HepG2 cells. Here we report that SERDs induce the rapid and strong SUMOylation of ERalpha in ERalpha-positive and -negative cell lines, including HepG2 cells. Four sites of SUMOylation were identified by mass spectrometry analysis. In derivatives of the SERD ICI164,384, SUMOylation was dependent on the length of the side chain and correlated with full antiestrogenicity. Preventing SUMOylation by the overexpression of a SUMO-specific protease (SENP) deSUMOylase partially derepressed transcription in the presence of full antiestrogens in HepG2 cells without a corresponding increase in activity in the presence of agonists or of the SERM tamoxifen. Mutations increasing transcriptional activity in the presence of full antiestrogens reduced SUMOylation levels and suppressed stimulation by SENP1. Our results indicate that ERalpha SUMOylation contributes to full antiestrogenicity in the absence of accelerated receptor turnover. PMID- 22826435 TI - Transthyretin blocks retinol uptake and cell signaling by the holo-retinol binding protein receptor STRA6. AB - Vitamin A is secreted from cellular stores and circulates in blood bound to retinol-binding protein (RBP). In turn, holo-RBP associates in plasma with transthyretin (TTR) to form a ternary RBP-retinol-TTR complex. It is believed that binding to TTR prevents the loss of RBP by filtration in the kidney. At target cells, holo-RBP is recognized by STRA6, a plasma membrane protein that serves a dual role: it mediates uptake of retinol from extracellular RBP into cells, and it functions as a cytokine receptor that, upon binding holo-RBP, triggers a JAK/STAT signaling cascade. We previously showed that STRA6-mediated signaling underlies the ability of RBP to induce insulin resistance. However, the role that TTR, the binding partner of holo-RBP in blood, plays in STRA6-mediated activities remained unknown. Here we show that TTR blocks the ability of holo-RBP to associate with STRA6 and thereby effectively suppresses both STRA6-mediated retinol uptake and STRA6-initiated cell signaling. Consequently, TTR protects mice from RBP-induced insulin resistance, reflected by reduced phosphorylation of insulin receptor and glucose tolerance tests. The data indicate that STRA6 functions only under circumstances where the plasma RBP level exceeds that of TTR and demonstrate that, in addition to preventing the loss of RBP, TTR plays a central role in regulating holo-RBP/STRA6 signaling. PMID- 22826436 TI - Foxm1 mediates cross talk between Kras/mitogen-activated protein kinase and canonical Wnt pathways during development of respiratory epithelium. AB - While Kras/mitogen-activated protein kinase (MAPK) and canonical Wnt/beta-catenin are critical for lung morphogenesis, mechanisms integrating these important signaling pathways during lung development are unknown. Herein, we demonstrate that the Foxm1 transcription factor is a key downstream target of activated Kras(G12D). Deletion of Foxm1 from respiratory epithelial cells during lung formation prevented structural abnormalities caused by activated Kras(G12D). Kras/Foxm1 signaling inhibited the activity of canonical Wnt signaling in the developing lung in vivo. Foxm1 decreased T-cell factor (TCF) transcriptional activity induced by activated beta-catenin in vitro. Depletion of Foxm1 by short interfering RNA (siRNA) increased nuclear localization of beta-catenin, increased expression of beta-catenin target genes, and decreased mRNA and protein levels of the beta-catenin inhibitor Axin2. Axin2 mRNA was reduced in distal lung epithelium of Foxm1-deficient mice. Foxm1 directly bound to and increased transcriptional activity of the Axin2 promoter region. Foxm1 is required for Kras signaling in distal lung epithelium and provides a mechanism integrating Kras and canonical Wnt/beta-catenin signaling during lung development. PMID- 22826437 TI - Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants. AB - Noonan syndrome (NS) is a relatively common autosomal dominant disorder characterized by congenital heart defects, short stature, and facial dysmorphia. NS is caused by germ line mutations in several components of the RAS-RAF-MEK extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway, including both kinase-activating and kinase-impaired alleles of RAF1 (~3 to 5%), which encodes a serine-threonine kinase for MEK1/2. To investigate how kinase-impaired RAF1 mutants cause NS, we generated knock-in mice expressing Raf1(D486N). Raf1(D486N/+) (here D486N/+) female mice exhibited a mild growth defect. Male and female D486N/D486N mice developed concentric cardiac hypertrophy and incompletely penetrant, but severe, growth defects. Remarkably, Mek/Erk activation was enhanced in Raf1(D486N)-expressing cells compared with controls. RAF1(D486N), as well as other kinase-impaired RAF1 mutants, showed increased heterodimerization with BRAF, which was necessary and sufficient to promote increased MEK/ERK activation. Furthermore, kinase-activating RAF1 mutants also required heterodimerization to enhance MEK/ERK activation. Our results suggest that an increased heterodimerization ability is the common pathogenic mechanism for NS-associated RAF1 mutations. PMID- 22826438 TI - Epigenetic control of cell cycle-dependent histone gene expression is a principal component of the abbreviated pluripotent cell cycle. AB - Self-renewal of human pluripotent embryonic stem cells proceeds via an abbreviated cell cycle with a shortened G(1) phase. We examined which genes are modulated in this abbreviated period and the epigenetic mechanisms that control their expression. Accelerated upregulation of genes encoding histone proteins that support DNA replication is the most prominent gene regulatory program at the G(1)/S-phase transition in pluripotent cells. Expedited expression of histone genes is mediated by a unique chromatin architecture reflected by major nuclease hypersensitive sites, atypical distribution of epigenetic histone marks, and a region devoid of histone octamers. We observed remarkable differences in chromatin structure--hypersensitivity and histone protein modifications--between human embryonic stem (hES) and normal diploid cells. Cell cycle-dependent transcription factor binding permits dynamic three-dimensional interactions between transcript initiating and processing factors at 5' and 3' regions of the gene. Thus, progression through the abbreviated G(1) phase involves cell cycle stage-specific chromatin-remodeling events and rapid assembly of subnuclear microenvironments that activate histone gene transcription to promote nucleosomal packaging of newly replicated DNA during stem cell renewal. PMID- 22826439 TI - The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein. AB - Dishevelled (Dvl) is a key component in the canonical Wnt signaling pathway and becomes hyperphosphorylated upon Wnt stimulation. Dvl is required for LRP6 phosphorylation, which is essential for subsequent steps of signal transduction, such as Axin recruitment and cytosolic beta-catenin stabilization. Here, we identify the HECT-containing Nedd4-like ubiquitin E3 ligase ITCH as a new Dvl binding protein. ITCH ubiquitinates the phosphorylated form of Dvl and promotes its degradation via the proteasome pathway, thereby inhibiting canonical Wnt signaling. Knockdown of ITCH by RNA interference increased the stability of phosphorylated Dvl and upregulated Wnt reporter gene activity as well as endogenous Wnt target gene expression induced by Wnt stimulation. In addition, we found that both the PPXY motif and the DEP domain of Dvl are critical for its interaction with ITCH, as mutation in the PPXY motif (Dvl2-Y568F) or deletion of the DEP domain led to reduced affinity for ITCH. Consistently, overexpression of ITCH inhibited wild-type Dvl2-induced, but not Dvl2-Y568F mutant-induced, Wnt reporter activity. Moreover, the Y568F mutant, but not wild-type Dvl2, can reverse the ITCH-mediated inhibition of Wnt-induced reporter activity. Collectively, these results indicate that ITCH plays a negative regulatory role in modulating canonical Wnt signaling by targeting the phosphorylated form of Dvl. PMID- 22826440 TI - Discovery of O-GlcNAc-6-phosphate modified proteins in large-scale phosphoproteomics data. AB - Phosphorylated O-GlcNAc is a novel post-translational modification that has so far only been found on the neuronal protein AP180 from the rat (Graham et al., J. Proteome Res. 2011, 10, 2725-2733). Upon collision induced dissociation, the modification generates a highly mass deficient fragment ion (m/z 284.0530) that can be used as a reporter for the identification of phosphorylated O-GlcNAc. Using a publically available mouse brain phosphoproteome data set, we employed our recently developed Oscore software to re-evaluate high resolution/high accuracy tandem mass spectra and discovered the modification on 23 peptides corresponding to 11 mouse proteins. The systematic analysis of 220 candidate phosphoGlcNAc tandem mass spectra as well as a synthetic standard enabled the dissection of the major phosphoGlcNAc fragmentation pathways, suggesting that the modification is O-GlcNAc-6-phosphate. We find that the classical O-GlcNAc modification often exists on the same peptides indicating that O-GlcNAc-6 phosphate may biosynthetically arise in two steps involving the O-GlcNAc transferase and a currently unknown kinase. Many of the identified proteins are involved in synaptic transmission and for Ca(2+)/calmodulin kinase IV, the O GlcNAc-6-phosphate modification was found in the vicinity of two autophosphorylation sites required for full activation of the kinase suggesting a potential regulatory role for O-GlcNAc-6-phosphate. By re-analyzing mass spectrometric data from human embryonic and induced pluripotent stem cells, our study also identified Zinc finger protein 462 (ZNF462) as the first human O GlcNAc-6-phosphate modified protein. Collectively, the data suggests that O GlcNAc-6-phosphate is a general post-translation modification of mammalian proteins with a variety of possible cellular functions. PMID- 22826441 TI - Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. AB - Despite of the progress in identifying many Lys acetylation (Kac) proteins, Kac substrates for Kac-regulatory enzymes remain largely unknown, presenting a major knowledge gap in Kac biology. Here we identified and quantified 4623 Kac sites in 1800 Kac proteins in SIRT1(+/+) and SIRT1(-/-) MEF cells, representing the first study to reveal an enzyme-regulated Kac subproteome and the largest Lys acetylome reported to date from a single study. Four hundred eighty-five Kac sites were enhanced by more than 100% after SIRT1 knockout. Our results indicate that SIRT1 regulates the Kac states of diverse cellular pathways. Interestingly, we found that a number of acetyltransferases and major acetyltransferase complexes are targeted by SIRT1. Moreover, we showed that the activities of the acetyltransferases are regulated by SIRT1-mediated deacetylation. Taken together, our results reveal the Lys acetylome in response to SIRT1, provide new insights into mechanisms of SIRT1 function, and offer biomarker candidates for the clinical evaluation of SIRT1-activator compounds. PMID- 22826442 TI - Thrombosis in myeloproliferative neoplasms with JAK2V617F mutation. AB - Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders and are characterized by advanced proliferation and survival advantage. These abnormalities are considered to derive from the point mutation in exon 14 of the Janus kinase 2 genes (JAK2 V617F). The thrombosis rate and the high prevalence of JAK2V617F in patients with MPN suggest that there is an association between the 2 in MPN. Apart from the mutation, other variables are documented to cause endothelial dysfunction and involve in thrombotic tendency. Endothelial progenitor cells differentiated from hematopoietic stem cell in patients with JAK2V617F MPN play an indispensable role in initiating and modulating neoangiogenesis. Although a risk-oriented therapeutic approach has been applied to MPN treatments, the further study on pathogenesis of MPN may provide more novel preventions and therapies for MPN. PMID- 22826443 TI - The effects of vitamin D deficiency on atrial fibrillation. AB - BACKGROUND: Vitamin D deficiency is associated with cardiovascular disease such as coronary artery disease, heart failure, and hypertension. Vitamin D deficiency activates the renin-angiotensin-aldosterone system, which affects the cardiovascular system. For this reason, it could be suggested that there is a relationship between vitamin D deficiency and atrial fibrillation (AF). In our study, we compared 25-hydroxyvitamin D (25-OHD) levels between nonvalvular AF, valvular AF, and control groups in sinus rhythm. METHOD: A total of 102 patients with nonvalvular chronic AF without any other cardiovascular disease (mean age 62.51 +/- 5.88; group I) and 96 patients with AF, which is associated with mitral valve disease (mean age 61.51 +/- 5; group II) were included in our study. Of all, 100 age-matched healthy people with sinus rhythm were accepted as control groups (mean age 61.35 +/- 5.44). Routine biochemical parameters, 25-OHD and parathormone levels were performed. RESULTS: Baseline characteristics of the study groups were comparable. Group I patients had a lower vitamin D level than group II and the control group (6.51 +/- 4.89, 9.24 +/- 7.39, and 11.18 +/- 6.98 ng/mL, P < .001, respectively). In groups I and II, the patients' left atrium diameter and systolic pulmonary artery pressure are higher than the control group. CONCLUSION: As a result, our study revealed a relationship between vitamin D deficiency and nonvalvular AF. PMID- 22826444 TI - Relevance of immobility and importance of risk assessment management for medically ill patients. AB - Recent or continued immobility is a significant risk factor for venous thromboembolism (VTE) in acutely ill medical patients. Patients may benefit from thromboprophylaxis; however, its optimal duration remains unclear. The Extended Clinical Prophylaxis in Acutely Ill Medical Patients (EXCLAIM) study was the first trial to systematically investigate how the degree of immobilization relates to the risk of developing VTE. EXCLAIM offers insights into the duration of VTE risk associated with reduced mobility and helps identify which patients would benefit most from extended-duration thromboprophylaxis. Further recent studies suggest that extended-duration thromboprophylaxis may be in order in certain high-risk patients to protect the patients from the risk of VTE events occurring, particularly in the posthospitalization period. Baseline d-dimer data and level of mobility could be included in risk assessment. Physicians are recommended to consider the use of extended-duration thromboprophylaxis based on individual risk assessment management (RAM) and balance of benefit and harm. PMID- 22826445 TI - Murine monoclonal antibody to platelet factor 4/heparin complexes as a potential reference standard for platelet activation assays in heparin-induced thrombocytopenia. AB - Quality control of the platelet activation assays to diagnose heparin-induced thrombocytopenia (HIT), (14)C-serotonin release assay (SRA) and platelet aggregation test (PAT) has yet to be established due to lack of reference standards and the difficulty of obtaining significant amounts of HIT antibodies from patients with HIT. We prepared a murine monoclonal antibody to human platelet factor 4 (hPF4)/heparin complexes (HIT-MoAb) and investigated the platelet activating action of HIT-MoAb by using SRA and PAT. The HIT-MoAb activated human platelets at low heparin concentration and the platelet activations were inhibited at high heparin concentration in both SRA and PAT. The HIT-MoAb produced a concentration-dependent effect. Moreover, the platelet activation at low heparin concentration was inhibited by anti-FcgammaRIIa antibody. These results indicated that HIT-MoAb has characteristics similar to human HIT antibodies regarding heparin-dependent platelet activation. Therefore, it is suggested that HIT-MoAb has the potential to be a positive control or reference standard in platelet activation assays. PMID- 22826446 TI - Effect of mean platelet volume on thrombus formation in patients with cancer. PMID- 22826447 TI - Global call for free academic movement for international dialogue. PMID- 22826448 TI - ATLANTIC DIP: closing the loop: a change in clinical practice can improve outcomes for women with pregestational diabetes. AB - OBJECTIVE: Prospective evaluation of pregnancy outcomes in women with pregestational diabetes over 6 years. RESEARCH DESIGN AND METHODS: The ATLANTIC Diabetes in Pregnancy group provides care for women with diabetes throughout pregnancy. In 2007, the group identified that women were poorly prepared for pregnancy and outcomes were suboptimal. A change in practice occurred, offering women specialist-led, hub-and-spoke evidence-based care. We now compare outcomes from 2005 to 2007 with those from 2008 to 2010. RESULTS: There was an increase in the numbers attending preconception care (28-52%, P = 0.01). Glycemic control before and throughout pregnancy improved. There was an overall increase in live births (74-92%, P < 0.001) and decrease in perinatal mortality rate (6.2-0.65%, P < 0.001). There was a decrease in large-for-gestational-age babies in mothers with type 1 diabetes mellitus (30-26%, P = 0.02). Elective caesarean section rates increased, while emergency section rates decreased. CONCLUSIONS: Changing the process of clinical care delivery can improve outcomes in women with pregestational diabetes. PMID- 22826450 TI - No relation between cystic fibrosis-related diabetes and type 1 diabetes autoimmunity. PMID- 22826451 TI - Glucose-6-phosphate dehydrogenase deficiency and type 2 diabetes. PMID- 22826452 TI - The diagnosis of neonatal diabetes in a mother at 25 years of age. PMID- 22826453 TI - Sitagliptin-associated angioedema. PMID- 22826454 TI - Low prevalence of diabetic retinopathy in a Chinese population. PMID- 22826455 TI - Assessment of emotional struggles in type 2 diabetes: patient perspectives. PMID- 22826456 TI - Vertical evolution and horizontal transfer of CR1 non-LTR retrotransposons and Tc1/mariner DNA transposons in Lepidoptera species. AB - Horizontal transfer (HT) is a complex phenomenon usually used as an explanation of phylogenetic inconsistence, which cannot be interpreted in terms of vertical evolution. Most examples of HT of eukaryotic genes involve transposable elements. An intriguing feature of HT is that its frequency differs among transposable elements classes. Although HT is well known for DNA transposons and long terminal repeat (LTR) retrotransposons, non-LTR retrotransposons rarely undergo HT, and their phylogenies are largely congruent to those of their hosts. Previously, we described HT of CR1-like non-LTR retrotransposons between butterflies (Maculinea) and moths (Bombyx), which occurred less than 5 million years ago (Novikova O, Sliwinska E, Fet V, Settele J, Blinov A, Woyciechowski M. 2007. CR1 clade of non LTR retrotransposons from Maculinea butterflies (Lepidoptera: Lycaenidae): evidence for recent horizontal transmission. BMC Evol Biol. 7:93). In this study, we continued to explore the diversity of CR1 non-LTR retrotransposons among lepidopterans providing additional evidences to support HT hypothesis. We also hypothesized that DNA transposons could be involved in HT of non-LTR retrotransposons. Thus, we performed analysis of one of the groups of DNA transposons, mariner-like DNA elements, as potential vectors for HT of non-LTR retrotransposons. Our results demonstrate multiple HTs between Maculinea and Bombyx genera. Although we did not find strong evidence for our hypothesis of the involvement of DNA transposons in HT of non-LTR retrotransposons, we demonstrated that recurrent and/or simultaneous flow of TEs took place between distantly related moths and butterflies. PMID- 22826458 TI - PredAlgo: a new subcellular localization prediction tool dedicated to green algae. AB - The unicellular green alga Chlamydomonas reinhardtii is a prime model for deciphering processes occurring in the intracellular compartments of the photosynthetic cell. Organelle-specific proteomic studies have started to delineate its various subproteomes, but sequence-based prediction software is necessary to assign proteins subcellular localizations at whole genome scale. Unfortunately, existing tools are oriented toward land plants and tend to mispredict the localization of nuclear-encoded algal proteins, predicting many chloroplast proteins as mitochondrion targeted. We thus developed a new tool called PredAlgo that predicts intracellular localization of those proteins to one of three intracellular compartments in green algae: the mitochondrion, the chloroplast, and the secretory pathway. At its core, a neural network, trained using carefully curated sets of C. reinhardtii proteins, divides the N-terminal sequence into overlapping 19-residue windows and scores the probability that they belong to a cleavable targeting sequence for one of the aforementioned organelles. A targeting prediction is then deduced for the protein, and a likely cleavage site is predicted based on the shape of the scoring function along the N terminal sequence. When assessed on an independent benchmarking set of C. reinhardtii sequences, PredAlgo showed a highly improved discrimination capacity between chloroplast- and mitochondrion-localized proteins. Its predictions matched well the results of chloroplast proteomics studies. When tested on other green algae, it gave good results with Chlorophyceae and Trebouxiophyceae but tended to underpredict mitochondrial proteins in Prasinophyceae. Approximately 18% of the nuclear-encoded C. reinhardtii proteome was predicted to be targeted to the chloroplast and 15% to the mitochondrion. PMID- 22826457 TI - Evolution of HLA-DRB genes. AB - The HLA region shows diversity concerning the number and content of DRB genes present per haplotype. Similar observations are made for the equivalent regions in other primate species. To elucidate the evolutionary history of the various HLA-DRB genes, a large panel of intron sequences obtained from humans, chimpanzees, rhesus macaques, and common marmosets has been subjected to phylogenetic analyses. Special attention was paid to the presence and absence of particular transposable elements and/or to their segments. The sharing of different parts of the same long interspersed nuclear element-2 (LINE2, L2) and various Alu insertions by the species studied demonstrates that one precursor gene must have been duplicated several times before the Old World monkey (OWM) and hominid (HOM) divergence. At least four ancestral DRB gene families appear to have been present before the radiation of OWM and HOM, and one of these even predates the speciation of Old and New World primates. Two of these families represent the pseudogenes DRB6/DRB2 and DRB7, which have been locked in the genomes of various primate species over long evolutionary time spans. Furthermore, all phylogenies of different intron segments show consistently that, apart from the pseudogenes, only DRB5 genes are shared by OWM and HOM, and they demonstrate the common history of certain DRB genes/lineages of humans and chimpanzees. In contrast, the evolutionary history of some other DRB loci is difficult to decipher, thus illustrating the complex history of the evolution of DRB genes due to a combination of mutations and recombination-like events. The selected approach allowed us to shed light on the ancestral DRB gene pool in primates and on the evolutionary relationship of the various HLA-DRB genes. PMID- 22826460 TI - Purifying selection modulates the estimates of population differentiation and confounds genome-wide comparisons across single-nucleotide polymorphisms. AB - An improved understanding of the biological and numerical properties of measures of population differentiation across loci is becoming increasingly more important because of their growing use in analyzing genome-wide polymorphism data for detecting population structures, inferring the rates of migration, and identifying local adaptations. In a genome-wide analysis, we discovered that the estimates of population differentiation (e.g., F(ST), theta, and Jost's D) calculated for human single-nucleotide polymorphisms (SNPs) are strongly and positively correlated to the position-specific evolutionary rates measured from multispecies alignments. That is, genomic positions (loci) experiencing higher purifying selection (lower evolutionary rates) produce lower values for the degree of population differentiation than those evolving with faster rates. We show that this pattern is completely mediated by the negative effects of purifying selection on the minor allele frequency (MAF) at individual loci. Our results suggest that inferences and methods relying on the comparison of population differentiation estimates (F(ST), theta, and Jost's D) based on SNPs across genomic positions should be restricted to loci with similar MAFs and/or the rates of evolution in genome scale surveys. PMID- 22826461 TI - Patterns of molecular evolution of an avian neo-sex chromosome. AB - Newer parts of sex chromosomes, neo-sex chromosomes, offer unique possibilities for studying gene degeneration and sequence evolution in response to loss of recombination and population size decrease. We have recently described a neo-sex chromosome system in Sylvioidea passerines that has resulted from a fusion between the first half (10 Mb) of chromosome 4a and the ancestral sex chromosomes. In this study, we report the results of molecular analyses of neo-Z and neo-W gametologs and intronic parts of neo-Z and autosomal genes on the second half of chromosome 4a in three species within different Sylvioidea lineages (Acrocephalidea, Timaliidae, and Alaudidae). In line with hypotheses of neo-sex chromosome evolution, we observe 1) lower genetic diversity of neo-Z genes compared with autosomal genes, 2) moderate synonymous and weak nonsynonymous sequence divergence between neo-Z and neo-W gametologs, and 3) lower GC content on neo-W than neo-Z gametologs. Phylogenetic reconstruction of eight neo-Z and neo-W gametologs suggests that recombination continued after the split of Alaudidae from the rest of the Sylvioidea lineages (i.e., after ~42.2 Ma) and with some exceptions also after the split of Acrocephalidea and Timaliidae (i.e., after ~39.4 Ma). The Sylvioidea neo-sex chromosome shares classical evolutionary features with the ancestral sex chromosomes but, as expected from its more recent origin, shows weaker divergence between gametologs. PMID- 22826462 TI - Evolution of cyclin B3 shows an abrupt three-fold size increase, due to the extension of a single exon in placental mammals, allowing for new protein-protein interactions. AB - Cyclin B3 evolution has the unique peculiarity of an abrupt 3-fold increase of the protein size in the mammalian lineage due to the extension of a single exon. We have analyzed the evolution of the gene to define the modalities of this event and the possible consequences on the function of the protein. Database searches can trace the appearance of the gene to the origin of metazoans. Most introns were already present in early metazoans, and the intron-exon structure as well as the protein size were fairly conserved in invertebrates and nonmammalian vertebrates. Although intron gains are considered as rare events, we identified two cases, one at the prochordate-chordate transition and one in murids, resulting from different mechanisms. At the emergence of mammals, the gene was relocated from chromosome 6 of platypus to the X chromosome in marsupials, but the exon extension occurred only in placental mammals. A repetitive structure of 18 amino acids, of uncertain origin, is detectable in the 3,000-nt mammalian exon encoded sequence, suggesting an extension by multiple internal duplications, some of which are still detectable in the primate lineage. Structure prediction programs suggest that the repetitive structure has no associated three dimensional structure but rather a tendency for disorder. Splice variant isoforms were detected in several mammalian species but without conserved pattern, notably excluding the constant coexistence of premammalian-like transcripts, without the extension. The yeast two-hybrid method revealed that, in human, the extension allowed new interactions with ten unrelated proteins, most of them with specific three-dimensional structures involved in protein-protein interactions, and some highly expressed in testis, as is cyclin B3. The interactions with activator of cAMP-responsive element modulator in testis (ACT), germ cell-less homolog 1, and chromosome 1 open reading frame 14 remain to be verified in vivo since they may not be expressed at the same stages of spermatogenesis as cyclin B3. PMID- 22826459 TI - Gene expression levels are correlated with synonymous codon usage, amino acid composition, and gene architecture in the red flour beetle, Tribolium castaneum. AB - Gene expression levels correlate with multiple aspects of gene sequence and gene structure in phylogenetically diverse taxa, suggesting an important role of gene expression levels in the evolution of protein-coding genes. Here we present results of a genome-wide study of the influence of gene expression on synonymous codon usage, amino acid composition, and gene structure in the red flour beetle, Tribolium castaneum. Consistent with the action of translational selection, we find that synonymous codon usage bias increases with gene expression. However, the correspondence between tRNA gene copy number and optimal codons is weak. At the amino acid level, translational selection is suggested by the positive correlation between tRNA gene numbers and amino acid usage, which is stronger for highly expressed genes. In addition, there is a clear trend for increased use of metabolically cheaper, less complex amino acids as gene expression increases. tRNA gene numbers also correlate negatively with amino acid size/complexity (S/C) score indicating the coupling between translational selection and selection to minimize the use of large/complex amino acids. Interestingly, the analysis of 10 additional genomes suggests that the correlation between tRNA gene numbers and amino acid S/C score is widespread and might be explained by selection against negative consequences of protein misfolding. At the level of gene structure, three major trends are detected: 1) complete coding region length increases across low and intermediate expression levels but decreases in highly expressed genes; 2) the average intron size shows the opposite trend, first decreasing with expression, followed by a slight increase in highly expressed genes; and 3) intron density remains nearly constant across all expression levels. These changes in gene architecture are only in partial agreement with selection favoring reduced cost of biosynthesis. PMID- 22826463 TI - Absolute oral bioavailability and metabolic turnover of beta-sitosterol in healthy subjects. AB - The metabolic turnover, absolute oral bioavailability, clearance, and volume of distribution for beta-sitosterol were measured in healthy subjects. [(14)C]beta Sitosterol was used as an isotopic tracer to distinguish pulse doses from dietary sources and was administered by both oral and intravenous routes. The administered doses of [(14)C]beta-sitosterol were in the region of 3 to 4 MUg, sufficiently low as not to perturb the kinetics of beta-sitosterol derived from the diet. Because the plasma concentrations of [(14)C]beta-sitosterol arising from such low doses were anticipated to be very low, the ultrasensitive isotope ratio analytical method of accelerator mass spectrometry was used. The limit of quantification for [(14)C]beta-sitosterol was approximately 0.1 pg/ml, the oral absolute bioavailability was just 0.41%, clearance was 85 ml/h, volume of distribution was 46 L, and the turnover was 5.8 mg/day. Given the steady-state concentrations of beta-sitosterol (2.83 MUg/ml), then the dietary load was calculated to be approximately 1400 mg/day. PMID- 22826464 TI - Vasohibin-2 expressed in human serous ovarian adenocarcinoma accelerates tumor growth by promoting angiogenesis. AB - Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (-/-) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis. PMID- 22826465 TI - The ghrelin axis--does it have an appetite for cancer progression? AB - Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHSR), is a peptide hormone with diverse physiological roles. Ghrelin regulates GH release, appetite and feeding, gut motility, and energy balance and also has roles in the cardiovascular, immune, and reproductive systems. Ghrelin and the GHSR are expressed in a wide range of normal and tumor tissues, and a fluorescein-labeled, truncated form of ghrelin is showing promise as a biomarker for prostate cancer. Plasma ghrelin levels are generally inversely related to body mass index and are unlikely to be useful as a biomarker for cancer, but may be useful as a marker for cancer cachexia. Some single nucleotide polymorphisms in the ghrelin and GHSR genes have shown associations with cancer risk; however, larger studies are required. Ghrelin regulates processes associated with cancer, including cell proliferation, apoptosis, cell migration, cell invasion, inflammation, and angiogenesis; however, the role of ghrelin in cancer is currently unclear. Ghrelin has predominantly antiinflammatory effects and may play a role in protecting against cancer-related inflammation. Ghrelin and its analogs show promise as treatments for cancer-related cachexia. Further studies using in vivo models are required to determine whether ghrelin has a role in cancer progression. PMID- 22826466 TI - Targeting the IKKbeta/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer. AB - Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFalpha, VEGF, IKKbeta, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKbeta/mTOR/VEGF signaling pathway is activated by TNFalpha in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer. PMID- 22826468 TI - Drug efflux transporters and multidrug resistance in acute leukemia: therapeutic impact and novel approaches to mediation. AB - Multidrug resistance (MDR), which is mediated by multiple drug efflux ATP-binding cassette (ABC) transporters, is a critical issue in the treatment of acute leukemia, with permeability glycoprotein (P-gp), multidrug resistance-associated protein 1, and breast cancer resistance protein (i.e., ABCG2) consistently being shown to be key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise as a result of specific gene expression profiles and that drug-induced overexpression of P-gp and other MDR proteins can result in acquired resistance, with multiple ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs used to treat acute leukemia. Furthermore, numerous anticancer drugs, including agents commonly used for the treatment of acute leukemia (e.g., doxorubicin, vincristine, mitoxantrone, and methotrexate), have been shown to be P-gp substrates or to be susceptible to efflux mediated by other MDR proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR protein expression and responses to therapy or survival rates in acute leukemia. Here we review the importance of MDR in cancer, with a focus on acute leukemia, and we highlight the need for rapid accurate assessment of MDR status for optimal treatment selection. We also address the latest research on overcoming MDR, from inhibition of P-gp and other MDR proteins through various approaches (including direct antagonism and gene silencing) to the design of novel agents or novel delivery systems for existing therapeutic agents, to evade cellular efflux. PMID- 22826469 TI - How we do it: effective stabilization of the apical delivery sheath during transapical aortic valve implantation. AB - A technique is described by which an effective stabilisation of the apical introducer sheath is achieved by a pneumatic holding arm, during transapical aortic valve implantation procedure. PMID- 22826467 TI - Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined HDAC and methyltransferase inhibitors in chemoresistant cancers. AB - Metastatic solid tumors are aggressive and mostly drug resistant, leading to few treatment options and poor prognosis as seen with clear cell renal cell carcinoma (ccRCC) and triple-negative breast cancer (TNBC). Therefore, the identification of new therapeutic regimes for the treatment of metastatic disease is desirable. ccRCC and TNBC cell lines were treated with the HDAC inhibitor romidepsin and the methyltransferase inhibitor decitabine, two epigenetic modifying drugs approved by the U.S. Food and Drug Administration for the treatment of various hematologic malignancies. Cell proliferation analysis, flow cytometry, quantitative PCR, and immunoblotting techniques were used to evaluate the antitumor synergy of this drug combination and identify the reexpression of epigenetically silenced tumor suppressor genes. Combinatorial treatment of metastatic TNBC and stage IV ccRCC cell lines with romidepsin/decitabine leads to synergistic inhibition of cell growth and induction of apoptosis above levels of individual drug treatments alone. Synergistic reexpression of the tumor suppressor gene secreted frizzled related protein one (sFRP1) was observed in combinatorial drug-treated groups. Silencing sFRP1 (short hairpin RNA) before combinatorial drug treatment showed that sFRP1 mediates the growth inhibitory and apoptotic activity of combined romidepsin/decitabine. Furthermore, addition of recombinant sFRP1 to ccRCC or TNBC cells inhibits cell growth in a dose-dependent manner through the induction of apoptosis, identifying that epigenetic silencing of sFRP1 contributes to renal and breast cancer cell survival. Combinatorial treatment with romidepsin and decitabine in drug resistant tumors is a promising treatment strategy. Moreover, recombinant sFRP1 may be a novel therapeutic strategy for cancers with suppressed sFRP1 expression. PMID- 22826470 TI - Is partial decalcification of posterior mitral annular bed logical in all mitral valve replacement procedures? PMID- 22826471 TI - Cancer/testis antigen expression as a predictor for epidermal growth factor receptor mutation and prognosis in lung adenocarcinoma. AB - OBJECTIVES: Immune therapy targeting cancer/testis (CT) antigens improve the survival in several types of solid tumours. The expression of CT antigens is related to poor survival in non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutation is the best predictive factor for the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. The aim of this study was to elucidate the correlation between the expression of CT antigens and clinicopathological factors, including the EGFR mutation, and to analyse the prognosis in lung adenocarcinoma. METHODS: Data were collected from a total of 281 lung adenocarcinoma patients who underwent surgery. Among them, 125 cases, whose specimens were too small to extract sufficient DNA and/or RNA, and 2 cases with the coexistence of another histological lung cancer were excluded. A total of 154 patients were reviewed. The expression of CT antigens (melanoma-associated antigen gene [MAGE]-A4 and KK-LC-1) and the EGFR-activating mutation (L858R point mutation in exon 21 and inframe deletion in exon 19) was evaluated by using polymerase chain reaction amplification. RESULTS: The expression of MAGE-A4 and KK-LC-1 was detected in 14 (9%) and 54 patients (35%) with adenocarcinoma. The EGFR-activating mutation was found in 64 patients (42%). Univariate and multivariate analyses demonstrated that tumours expressing at least one CT antigen were associated with no EGFR mutation (odds ratio = 0.3; 95% confidence interval, 0.14-0.71; P < 0.01). A survival analysis was performed in 135 patients who underwent complete resection and the 5-year overall survival rate was 71.1% in those with any expression of CT antigens and 83.2% in those without expression of the genes (P < 0.04). CONCLUSION: Two different therapeutic targets, EGFR activating mutation and CT antigen, have a negative relationship with each other. PMID- 22826472 TI - Reply to Colli and Romero-Ferrer. PMID- 22826473 TI - Nurse practitioners replacing young doctors: it works, but does it make sense? PMID- 22826474 TI - Outcomes after lobectomy using thoracoscopy vs thoracotomy: a comparative effectiveness analysis utilizing the Nationwide Inpatient Sample database. AB - OBJECTIVES: We examined the Nationwide Inpatient Sample (NIS) database to compare short-term postoperative outcomes following open and thoracoscopic lobectomy. Thoracoscopic (video-assisted thoracic surgery) lobectomy has been demonstrated to be associated with fewer postoperative complications compared with open thoracotomy lobectomy in several large case series. However, as no randomized trial has been performed, there are many who question this. METHODS: We examined the NIS database for all patients undergoing lobectomy as their principal procedure either via thoracoscopic or open thoracotomy from 2007 to 08. We compared the postoperative outcomes of these two groups of patients after propensity matching these groups based on several preoperative variables. RESULTS: Over a 2-year-period, 68 350 patients underwent a lobectomy by either thoracoscopy [n = 10 554 (15%)] or thoracotomy [n = 57 796(85%)]. Thirty-two percent of thoracoscopic lobectomies (n = 3421) were performed in either rural or non-teaching urban centres. Although in propensity-matched cohorts there was no difference in operative mortality, thoracoscopic lobectomy was associated with a lower incidence of postoperative complications [n = 4146 (40.8%) vs n = 13 913 (45.1%), P < 0.001] and shorter length of stay (5.0 vs 7.0 days; P < 0.001) compared with open lobectomy. Specifically, the incidences of supraventricular arrhythmias, myocardial infarction, pulmonary embolism and empyema were lower. CONCLUSIONS: This large national database study demonstrates that thoracoscopic lobectomy is associated with fewer in-hospital postoperative complications compared with open lobectomy. Thoracoscopic lobectomy appears to be applicable to the wider general thoracic surgical community. PMID- 22826475 TI - Repair of tetralogy of Fallot: the right ventricle and the two villains. PMID- 22826476 TI - Thyroid antibodies and risk of preterm delivery: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Observational studies suggest possible associations between thyroid antibodies and risk of preterm delivery. However, whether thyroid antibodies are risk factors of preterm labor remains controversial. Our goal was to evaluate the associations between thyroid antibodies and risk of preterm delivery by conducting a meta-analysis of prospective cohort studies. METHODS: PubMed, Embase, and Wangfang databases were searched through January 2012 to identify studies that met pre-stated inclusion criteria. Data were extracted using standardized forms. Either a fixed- or a random-effects model was used to calculate the overall combined relative ratio (RR) with its corresponding 95% confidence interval (95% CI) to evaluate the relationship between thyroid antibodies and preterm delivery risk. Subgroup analyses were mainly performed by type of thyroid antibodies including thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab). RESULTS: Eleven prospective cohort studies involving 35 467 participants were included. The combined RR of preterm delivery for pregnant women with thyroid antibodies compared with the reference group was 1.41 (95% CI 1.08-1.84, P=0.011). Subgroup analysis yielded the combined RR of preterm delivery for pregnant women with TPO-Ab compared with the reference group was 1.69 (95% CI 1.19-2.41, P=0.003), whereas pregnant women with positive TG-Ab had no obvious risk of preterm delivery compared with the reference group (RR=0.88, 95% CI 0.60-1.29, P=0.513). Sensitivity analysis restricted to studies excluding women with thyroid dysfunction yielded similar results. Meta-regression analysis suggested that the status of exclusion or inclusion of women with thyroid dysfunction was the major source of heterogeneity in this meta-analysis. No evidence of publication bias was observed. CONCLUSIONS: Current evidence suggests that the presence of TPO-Ab in pregnant women significantly increases the risk of preterm delivery. PMID- 22826477 TI - Cytokine responses to novel antigens in a peri-urban population in Brazil exposed to Leishmania infantum chagasi. AB - Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-gamma (IFN-gamma) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-alpha (TNF-alpha) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen-driven IFN-gamma, TNF alpha, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN gamma, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-gamma:IL-10 and TNF-alpha:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36-71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates. PMID- 22826478 TI - High household economic burden caused by hospitalization of patients with severe dengue fever cases in Can Tho province, Vietnam. AB - During 2006-2007, a cohort of 144 confirmed dengue cases in Can Tho Province, Vietnam were compared with a matching set of 144 households that had no dengue cases. Approximately 6-9 months after sickness, there were no significant differences in terms of knowledge of the etiology of dengue, mosquito breeding habitats, and prevention measures in respondents from both sets of households. There was also no difference in the abundance of Aedes aegypti (Linn.) adults but the average numbers of late instar and pupal Ae. aegypti per household were greater in the negative control houses. Thus, the risk seemed to be no higher in case households, although it is conceivable that changes may have occurred in either group over the intervening period. The average cost for a dengue patient was 2,798,000 Vietnamese Dong (VND) (US$167.77), 2,154,000 VND for direct costs, and 644,000 VND for indirect costs. There was a 22% difference in cost for those with and without health insurance. In terms of impact on family economies, 47.2% had to borrow money for treatment, and after 6 months, 71.7% had not begun or had only managed part repayments. Approximately 72.9% indicated that the cost of supporting a dengue patient had impacted on the family economy, with the loss averaging 36% of the annual income in the lowest economic quartile. PMID- 22826479 TI - Detection of persistent west nile virus RNA in experimentally and naturally infected avian hosts. AB - To determine whether West Nile virus (WNV) persistent infection in avian hosts may potentially serve as an overwintering mechanism, House Sparrows and House Finches, experimentally and naturally infected with several strains of WNV, and two naturally infected Western Scrub-Jays were held in mosquito-proof outdoor aviaries from 2007-March 2008. Overall, 94% (n = 36) of House Sparrows, 100% (n = 14) of House Finches and 2 Western Scrub-Jays remained WNV antibody positive. When combined by species, 37% of the House Sparrows, 50% of the House Finches, and 2 Western Scrub-Jays were WNV RNA positive at necropsy, up to 36 weeks post infection. Infectious WNV was not detected. Our study supports the hypothesis that some avian hosts support the long-term persistence of WNV RNA, but it remains unresolved whether these infections relapse to restart an avian-arthropod transmission cycle and thereby serve as an overwintering mechanism for WNV. PMID- 22826480 TI - Prevalence and diversity of Bartonella spp. in bats in Peru. AB - Bartonella infections were investigated in bats in the Amazon part of Peru. A total of 112 bats belonging to 19 species were surveyed. Bartonella bacteria were cultured from 24.1% of the bats (27/112). Infection rates ranged from 0% to 100% per bat species. Phylogenetic analyses of gltA of the Bartonella isolates revealed 21 genetic variants clustering into 13 divergent phylogroups. Some Bartonella strains were shared by bats of multiple species, and bats of some species were infected with multiple Bartonella strains, showing no evident specific Bartonella sp.-bat relationships. Rarely found in other bat species, the Bartonella strains of phylogroups I and III discovered from the common vampire bats (Desmodus rotundus) were more specific to the host bat species, suggesting some level of host specificity. PMID- 22826481 TI - Community-based rapid oral human immunodeficiency virus testing for tuberculosis patients in Lima, Peru. AB - Among tuberculosis patients, timely diagnosis of human immunodeficiency virus (HIV) co-infection and early antiretroviral treatment are crucial, but are hampered by a myriad of individual and structural barriers. Community-based models to provide counseling and rapid HIV testing are few but offer promise. During November 2009-April 2010, community health workers offered and performed HIV counseling and testing by using the OraQuick Rapid HIV-1/2 Antibody Test to new tuberculosis cases in 22 Ministry of Health establishments and their household contacts (n = 130) in Lima, Peru. Refusal of HIV testing or study participation was low (4.7%). Intervention strengths included community-based approach with participant preference for testing site, use of a rapid, non invasive test, and accompaniment to facilitate HIV care and family disclosure. We will expand the intervention under programmatic auspices for rapid community based testing for new tuberculosis cases in high incidence establishments. Other potential target populations include contacts of HIV-positive persons and pregnant women. PMID- 22826482 TI - The association of beliefs about heredity with preventive and interpersonal behaviors in communities affected by podoconiosis in rural Ethiopia. AB - Little is known about how beliefs about heredity as a cause of health conditions might influence preventive and interpersonal behaviors among those individuals with low genetic and health literacy. We explored causal beliefs about podoconiosis, a neglected tropical disease (NTD) endemic in Ethiopia. Podoconiosis clusters in families but can be prevented if individuals at genetically high risk wear shoes consistently. Adults (N = 242) from four rural Ethiopian communities participated in qualitative assessments of beliefs about the causes of podoconiosis. Heredity was commonly mentioned, with heredity being perceived as (1) the sole cause of podoconiosis, (2) not a causal factor, or (3) one of multiple causes. These beliefs influenced the perceived controllability of podoconiosis and in turn, whether individuals endorsed preventive and interpersonal stigmatizing behaviors. Culturally informed education programs that increase the perceived controllability of stigmatized hereditary health conditions like podoconiosis have promise for increasing preventive behaviors and reducing interpersonal stigma. PMID- 22826483 TI - Phylogenetic analysis of dengue virus types 1 and 4 circulating in Puerto Rico and Key West, Florida, during 2010 epidemics. AB - We describe sequences of six strains of dengue virus (DENV): three DENV-1 isolates and two DENV-4 isolates from Puerto Rico, and a DENV-1 strain from Key West, Florida, obtained from blood donors during 2010 epidemics. Phylogenetic analysis revealed that the Puerto Rico DENV-1 strains constitute a new lineage within genotype V different from those that circulated in Puerto Rico during the past two decades. The newer Puerto Rico DENV-1 strains associated with strains from the Caribbean and South America. The DENV-1 strain from Key West, Florida clustered with a strain isolated from mosquito pools collected in that area and with a number of strains from Nicaragua and Mexico circulating during 2006-2009. The Puerto Rico DENV-4 isolates of genotype II associated with strains that have circulated on the island throughout the 1980s and 1990s and with strains from the Caribbean region and Central America. Introduction and circulation of novel DENV lineages in dengue-endemic regions have the potential to increase the severity of dengue cases. PMID- 22826484 TI - Artesunate for severe acute Plasmodium falciparum infection in a patient with myasthenia gravis. AB - We report a case of severe malaria in a patient with underlying myasthenia gravis who was successfully treated with artesunate. The outcome was favorable. Artesunate seems to be a good option for patients with underlying myasthenia gravis disease because they benefit from a better toxicity profile than quinine. PMID- 22826485 TI - Benznidazole shortage makes chagas disease a neglected tropical disease in developed countries: data from Spain. AB - Chagas disease is a neglected tropical disease endemic in Latin America. The first-line treatment option is benznidazole, but stocks are expected to run out in the coming months. Spain would need around 5 million benznidazole tablets. This drug shortage could make Chagas disease a neglected tropical disease also in developed countries. PMID- 22826486 TI - Sentinel surveillance for zoonotic parasites in companion animals in indigenous communities of Saskatchewan. AB - Indigenous communities may have increased risk of exposure to zoonotic parasites, including Echinococcus granulosus, Toxocara canis, Toxoplasma gondii, Diphyllobothrium spp., and Giardia duodenalis, for which dogs may serve as sentinels for or sources of human infection. Canid fecal samples were collected from dogs and the environment in five indigenous communities across Saskatchewan and Alberta (N = 58, 62, 43, 66, and 25). Parasites in individual fecal samples were quantified using fecal flotation and a commercial immunofluorescent antibody test for Giardia and Cryptosporidium. Overall, the prevalence of canine intestinal parasitic infection was 20-71%, which is 5-16 times higher in indigenous communities than a nearby urban center in Saskatchewan. The overall prevalences of T. canis, Diphyllobothrium, and taeniid eggs in dog feces were, respectively, 11.8%, 4.9%, and 1.2% in our study compared with 0-0.2% in urban dogs. Giardia cysts present in 21% of samples were identified as zoonotic genotype Assemblage A. PMID- 22826487 TI - Boiling as household water treatment in Cambodia: a longitudinal study of boiling practice and microbiological effectiveness. AB - This paper focuses on the consistency of use and microbiological effectiveness of boiling as it is practiced in one study site in peri-urban Cambodia. We followed 60 randomly selected households in Kandal Province over 6 months to collect longitudinal data on water boiling practices and effectiveness in reducing Escherichia coli in household drinking water. Despite > 90% of households reporting that they used boiling as a means of drinking water treatment, an average of only 31% of households had boiled water on hand at follow-up visits, suggesting that actual use may be lower than self-reported use. We collected 369 matched untreated and boiled water samples. Mean reduction of E. coli was 98.5%; 162 samples (44%) of boiled samples were free of E. coli (< 1 colony-forming unit [cfu]/100 mL), and 270 samples (73%) had < 10 cfu/100 mL. Storing boiled water in a covered container was associated with safer product water than storage in an uncovered container. PMID- 22826488 TI - Comparison of performance of serum and plasma in panbio dengue and Japanese encephalitis virus enzyme-linked immunosorbent assays. AB - We examined the comparative performance of serum and plasma (in dipotassium EDTA) in Panbio Dengue enzyme-linked immunosorbent assays (ELISAs) for detection of non structural protein 1 (NS1), IgM, and IgG, and a dengue/Japanese encephalitis virus (JEV) combination IgM ELISA in a prospective series of 201 patients with suspected dengue in Laos. Paired comparisons of medians from serum and plasma samples were not significantly different for Dengue IgM, and NS1 which had the highest number of discordant pairs (both 2%; P = 0.13 and P = 0.25, respectively). Comparison of qualitative final diagnostic interpretations for serum and plasma samples were not significantly different: only 1.5% (3 of 201 for Dengue/JEV IgM and Dengue IgG) and 2.0% (4 of 201; IgM and NS1) showed discordant pairs. These results demonstrate that plasma containing EDTA is suitable for use in these ELISAs. PMID- 22826489 TI - Molecular identification of a case of Paragonimus pseudoheterotremus infection in Thailand. AB - Paragonimiasis is an important food-borne parasitic zoonosis caused by infection with lung flukes of the genus Paragonimus. In Southeast Asia, Paragonimus heterotremus is the only proven causative pathogen. Recently, a new Paragonimus species, P. pseudoheterotremus, was found in Thailand. This species is genetically similar to P. heterotremus and is considered as a sister species. However, infectivity or pathogenicity of P. pseudoheterotremus to humans remains unclear. We report the first confirmed human pulmonary paragonimiasis case caused by P. pseudoheterotremus infection. After polymerase chain reaction/sequencing of the DNA extracted from Paragonimus eggs in the sputum of the patient, partial internal transcribed spacer 2 and cytochrome c oxidase subunit 1 sequences were approximately identical (98-100%) with those of P. pseudoheterotremus. For P. heterotremus, the partial internal transcribed spacer 2 sequence was approximately identical (99-100%), but the partial mitochondrial cytochrome c oxidase subunit 1 sequence showed a similarity of 90-95%. PMID- 22826490 TI - First report of orchitis in man caused by Brucella abortus biovar 1 in Ecuador. AB - We present a 44-year-old man from a rural community in northern Ecuador who worked on a cattle farm where he was involved with primary veterinary care, including assistance during births (or calving) and placenta retention and artificial insemination, with minimal precautions. In September of 2009, quite abruptly, he developed asthenia and hypersomnia without any apparent cause or symptoms like fever, chills, or night sweats. On November 14, 2009, he suffered from pain and edema in the right testicle that coincided with pain in the abdomen. Clinical, serological, and bacteriological investigations confirmed the first case of unilateral orchitis in man in Ecuador caused by Brucella abortus biovar 1. Because brucellosis is a neglected disease, special attention should be given to it in the training of medical and veterinary students. PMID- 22826491 TI - Community sleeping pattern and anopheline biting in southeastern Iran: a country earmarked for malaria elimination. AB - An important variable in determining the vectorial capacity of malaria mosquito species is the degree of mosquito-human contact. This parameter can be affected by community sleeping behavior and the host-feeding habits of vectors. A cross sectional study of 775 randomly selected inhabitants, including 385 Baluchi residents and 390 Afghani refugees, was conducted in a malarious area in Sabaz District, Sistan-Baluchestan Province, southeastern Iran. In addition, monitoring of human landing periodicity of main malaria vectors was carried out during an entire transmission season. Afghanis and Baluchis showed diversity in sleeping behavior. Most (79.6%) respondents were familiar with symptoms of malaria and also aware of an association between mosquitoes and malaria. Despite this familiarity, 94.6% of Afghan refugees, 74.8% of Baluch residents, and 87.2% of study participants did not use self-protection preventive measures. Overall, only 8.8% of participants reported using bed nets regularly. Surveyed persons used bed nets mainly during second quarter of night. Three major species of malaria vectors (Anopheles culicifacies, An. fluviatilis, and An. stephensi) started biting by sunset and continued throughout the night. The results of present study indicated that synchronization of encounters between inhabitants and mosquito vectors was caused by poor self-protection and sleeping behavior of inhabitants. In addition, diversity in culture and behavior of the two communities may cause the prevalence of malaria to be different between them. Therefore, promoting awareness of self-protection against mosquito bites could promote community participation in malaria elimination program in this malaria-endemic region. PMID- 22826492 TI - Plasmodium vivax pre-erythrocytic-stage antigen discovery: exploiting naturally acquired humoral responses. AB - The development of pre-erythrocytic Plasmodium vivax vaccines is hindered by the lack of in vitro culture systems or experimental rodent models. To help bypass these roadblocks, we exploited the fact that naturally exposed Fy- individuals who lack the Duffy blood antigen (Fy) receptor are less likely to develop blood stage infections; therefore, they preferentially develop immune responses to pre erythrocytic-stage parasites, whereas Fy+ individuals experience both liver- and blood-stage infections and develop immune responses to both pre-erythrocytic and erythrocytic parasites. We screened 60 endemic sera from P. vivax-exposed Fy+ or Fy- donors against a protein microarray containing 91 P. vivax proteins with P. falciparum orthologs that were up-regulated in sporozoites. Antibodies against 10 P. vivax antigens were identified in sera from P. vivax-exposed individuals but not unexposed controls. This technology has promising implications in the discovery of potential vaccine candidates against P. vivax malaria. PMID- 22826494 TI - No association of phenotypic ABO blood group and malaria during pregnancy. AB - In a few small studies an association between blood group O and placental malaria has been described. The relationship between blood group and malaria in pregnancy (Plasmodium vivax and Plasmodium falciparum) was analyzed in 1,468 women from three longitudinal cohort studies in which weekly malaria screening was done systematically during pregnancy. One-third of women (447 of 1,468) had at least one malaria infection in pregnancy. The ABO blood group phenotype was not associated with the species of infection, frequency of malaria attacks, symptoms of malaria, hematocrit, or parasitemia during pregnancy. PMID- 22826493 TI - Predictors of Plasmodium falciparum malaria incidence in Chano Mille, South Ethiopia: a longitudinal study. AB - We assessed potential effects of local meteorological and environmental conditions, indoor residual spraying with insecticides, insecticide-treated nets (ITNs) use at individual and community levels, and individual factors on Plasmodium falciparum malaria incidence in a village in south Ethiopia. A cohort of 8,121 people was followed for 101 weeks with active and passive surveillance. Among 317 microscopically confirmed P. falciparum malaria episodes, 29.3% occurred among temporary residents. The incidence density was 3.6/10,000 person weeks of observation. We observed higher malaria incidence among males, children 5-14 years of age, ITNs non-users, the poor, and people who lived closer to vector breeding places. Rainfall increased and indoor residual spraying with Deltamethrin reduced falciparum incidence. Although ITNs prevented falciparum malaria for the users, we did not find that free mass ITNs distribution reduced falciparum malaria on a village level. PMID- 22826495 TI - Epidemiology of ehrlichiosis and anaplasmosis among American Indians in the United States, 2000-2007. AB - Ehrlichiosis and anaplasmosis infections among American Indians (AIs) have never been specifically examined, despite high rates of other tick-borne rickettsial diseases among AIs. The epidemiology of ehrlichiosis and anaplasmosis among AIs was analyzed using the National Electronic Telecommunications System for Surveillance (NETSS), Case Report Forms (CRFs), and Indian Health Service (IHS) inpatient and outpatient visits. The 2000-2007 average annual ehrlichiosis and anaplasmosis incidence among AIs reported to NETSS was almost 4-fold lower (4.0/1,000,000) than that using IHS data (14.9). American Indian cases reported from CRFs had a higher proportion of hospitalization (44%) compared with IHS (10%). American Indian incidence of ehrlichiosis and anaplasmosis was higher and showed a different age and geographical distribution than other races. These results highlight the need to improve collaboration between the ehrlichiosis and anaplasmosis surveillance systems for AIs so as to develop interventions that target the unique epidemiology and mitigate the burden of disease among this high risk population. PMID- 22826496 TI - Profile of Trypanosoma cruzi reactivity in a population at high risk for endemic pemphigus foliaceus (Fogo selvagem). AB - Fogo selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Chagas disease was identified in a Brazilian Amerindian population of high risk for FS. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. The profile of anti-Dsg1 antibodies showed positive results in 15 of 40 FS sera and in 33 of 150 sera from healthy individuals from endemic FS sites, and no cross-reactivity between Chagas disease and FS was observed. PMID- 22826497 TI - Genetic characterization of atypical Mansonella (Mansonella) ozzardi microfilariae in human blood samples from northeastern Peru. AB - DNA sequence comparisons are useful for characterizing proposed new parasite species or strains. Microfilariae with an atypical arrangement of nuclei behind the cephalic space have been recently described in human blood samples from the Amazon region of Peru. Three blood specimens containing atypical microfilariae were genetically characterized using three DNA markers (5S ribosomal DNA, 12S ribosomal DNA, and cytochrome oxidase I). All atypical microfilariae were clustered into the Mansonella group and indistinguishable from M. ozzardi based on these DNA markers. PMID- 22826498 TI - Maternal anemia at first antenatal visit: prevalence and risk factors in a malaria-endemic area in Benin. AB - The risk factors for maternal anemia (hemoglobin level less than 110 g/L) were studied in human immunodeficiency virus-negative pregnant women in Benin at the time of first antenatal visit and prior to any prevention. Data for the first 1,005 pregnant women included in a multicentre randomized controlled trial were analyzed. Anemia was common (68.3%), and malaria and helminth infestations were prevalent in 15.2% and 11.1% of the women. A total of 33.3%, 31.3% and 3.6% of the women were iron, folic acid and vitamin B12 deficient, respectively. These parasitic infections and nutrient deficiencies were associated with a high risk of anemia. Twenty-one percent, 15%, 12%, 11% and 7% of anemia were attributable to malnutrition, malaria, iron, folic acid deficiencies, and helminth infestations, respectively. Most anemia was caused by factors that could be prevented by available tools, stressing the need to reinforce their implementation and to evaluate their effectiveness throughout the course of the pregnancy. PMID- 22826499 TI - Fatal co-infection--melioidosis and leptospirosis. AB - Co-infection of melioidosis and leptospirosis is uncommon. We report here four such cases, confirmed by blood culture for melioidosis and blood polymerase-chain reaction for leptospirosis, which occurred among rescuers involved in a search and rescue operation for a young man who was suspected to have drowned in Lubuk Yu, a recreational forest in Pahang, Malaysia. Despite treatment, three of the patients died from the co-infection. PMID- 22826501 TI - Age bias in physicians' recommendations for physical activity: a behavioral model of healthcare utilization for adults with arthritis. AB - OBJECTIVE: To examine whether age bias exists in physicians' recommendations for physical activity among individuals with arthritis. METHODS: A cross-sectional sample with 33,071 U.S. adults, 45 years or older with physician-diagnosed arthritis was obtained from 2007 Behavioral Risk Factor Surveillance System Survey. We used logistic regression to examine physicians' recommendations for physical activity as a function of age controlling for gender, race, education, marital status, employment, income, health insurance, personal physician, emotional support, body mass index, activity limitations, health status, and comorbidities. RESULTS: Majority of individuals were females (65%), White (85%), had annual household income < $50,000 (67%), and with comorbidities (86%). Respondents were approximately equal across age groups: middle-aged group (53%) and older group (47%). About 36% were obese and 44% had activity limitations, and 44% did not receive any physicians' recommendations for physical activity. Results from logistic regression indicated older adults (>= 65 years old) were less likely (OR = 0.87; 95% CI, 0.82-0.92) to receive physicians' recommendations for physical activity compared with the middle-aged group (45-64 years old). CONCLUSIONS: This study indicates that although the benefits associated with the physical activity is well recognized, there is age bias in physicians' recommendations for physical activity. PMID- 22826502 TI - How much does prior myocardial infarction increase risk of sudden cardiac death in the young? PMID- 22826500 TI - A NAC transcription factor and SNI1 cooperatively suppress basal pathogen resistance in Arabidopsis thaliana. AB - Transcriptional repression of pathogen defense-related genes is essential for plant growth and development. Several proteins are known to be involved in the transcriptional regulation of plant defense responses. However, mechanisms by which expression of defense-related genes are regulated by repressor proteins are poorly characterized. Here, we describe the in planta function of CBNAC, a calmodulin-regulated NAC transcriptional repressor in Arabidopsis. A T-DNA insertional mutant (cbnac1) displayed enhanced resistance to a virulent strain of the bacterial pathogen Pseudomonas syringae DC3000 (PstDC3000), whereas resistance was reduced in transgenic CBNAC overexpression lines. The observed changes in disease resistance were correlated with alterations in pathogenesis related protein 1 (PR1) gene expression. CBNAC bound directly to the PR1 promoter. SNI1 (suppressor of nonexpressor of PR genes1, inducible 1) was identified as a CBNAC-binding protein. Basal resistance to PstDC3000 and derepression of PR1 expression was greater in the cbnac1 sni1 double mutant than in either cbnac1 or sni1 mutants. SNI1 enhanced binding of CBNAC to its cognate PR1 promoter element. CBNAC and SNI1 are hypothesized to work as repressor proteins in the cooperative suppression of plant basal defense. PMID- 22826503 TI - Simulation in the pediatric emergency department. AB - Simulation provides a means to educate, monitor, evaluate, and potentially document the competency of emergency physicians. The evolution of high-fidelity simulators has led to a surge of enhanced medical applications that fit nicely into the core of emergency medicine training. Simulation can facilitate training in resuscitation, procedures, CRM, and mass casualty management. Although improved outcomes from simulation are not well established, there is a general consensus regarding the added value over current training. And finally, simulation provides the ability to construct training to match the current educational efforts related to individual physicians or system-level improvements in communication and patient safety. PMID- 22826505 TI - Tobacco control policy in the UK: blueprint for the rest of Europe? AB - INTRODUCTION: With male smoking prevalence at ~30% in 1998, the UK implemented stricter tobacco control policies, including a comprehensive cessation treatment programme. We evaluate their effect. METHODS: Data for the UK (excluding Northern Ireland) are applied to 'SimSmoke', a simulation model used to examine the effect of tobacco control policies over time on smoking initiation and cessation. Upon validating the model against smoking prevalence, the model is used to distinguish the effect of policies implemented between 1998 and 2009 on smoking prevalence. Using standard attribution methods, the model estimates lives saved as a result of policies. RESULTS: The model predicts smoking prevalence accurately between 1998 and 2009. A relative reduction of 23% in smoking rates over that period is attributed to tobacco control policies, mainly tax increases, smoke-free air laws, advertising restrictions and cessation treatment programmes. The model estimates that 210 000 deaths will be averted by the year 2040, as a consequence of policies implemented between 1998 and 2010. CONCLUSIONS: The results document the UK's success in reducing smoking prevalence and prolonging lives, thereby providing an example for other European nations. When Framework Convention for Tobacco Control- (FCTC) consistent policies are also implemented, the model projects that smoking prevalence will fall by another 28% with an additional 168,000 deaths averted by 2040. PMID- 22826507 TI - Coded statutory data sets for evaluation of public health law. AB - BACKGROUND AND OBJECTIVES: The evaluation of public health law requires reliable accounts of underlying statutes and regulations. States often enact public health related statutes with nonuniform provisions, and variation in the structure of state legal codes can foster inaccuracy in evaluating the impact of specific categories of law. The optimal format for empirical analysis is a machine readable 50-state coded data set. This study provides a comprehensive assessment of these resources and related materials with a focus on statutory data sets. RESEARCH DESIGN: An exhaustive literature search was followed by a "pearling" or "snowball" approach to assure the most complete inventory of this very diverse and diffuse information. We also interviewed three leading investigators to identify barriers to wider use and availability of coded legal data sets. RESULTS: We identified relatively few accessible coded statutory data sets, and others that are not available for use outside the group or individual that compiled them. The Robert Wood Johnson Foundation-funded Public Health Law Research Program has made funding available for the development and dissemination of additional data sets, as well as extensive guidance regarding their use in the evaluation of public health law. Investigators reported serious obstacles to these activities in the past. CONCLUSIONS: Compilation of coded statutory data sets requires a focused investment of resources that has only recently become available. Funders should require grantees to make their work accessible to other investigators so as to assure development of public health law research and evaluation. PMID- 22826506 TI - Day length and weather effects on children's physical activity and participation in play, sports, and active travel. AB - BACKGROUND: Children in primary school are more physically active in the spring/summer. Little is known about the relative contributions of day length and weather, however, or about the underlying behavioral mediators. METHODS: 325 British children aged 8 to 11 wore accelerometers as an objective measure of physical activity, measured in terms of mean activity counts. Children simultaneously completed diaries in which we identified episodes of out-of-home play, structured sports, and active travel. Our main exposure measures were day length, temperature, rainfall, cloud cover, and wind speed. RESULTS: Overall physical activity was higher on long days (>= 14 hours daylight), but there was no difference between short (< 9.5 hours) and medium days (10.2-12.6 hours). The effect of long day length was largest between 5 PM and 8 PM, and persisted after adjusting for rainfall, cloud cover, and wind. Up to half this effect was explained by a greater duration and intensity of out-of-home play on long days; structured sports and active travel were less affected by day length. CONCLUSIONS: At least above a certain threshold, longer afternoon/evening daylight may have a causal role in increasing child physical activity. This strengthens the public health arguments for daylight saving measures such as those recently under consideration in Britain. PMID- 22826508 TI - Orientation field estimation for latent fingerprint enhancement. AB - Identifying latent fingerprints is of vital importance for law enforcement agencies to apprehend criminals and terrorists. Compared to live-scan and inked fingerprints, the image quality of latent fingerprints is much lower, with complex image background, unclear ridge structure, and even overlapping patterns. A robust orientation field estimation algorithm is indispensable for enhancing and recognizing poor quality latents. However, conventional orientation field estimation algorithms, which can satisfactorily process most live-scan and inked fingerprints, do not provide acceptable results for most latents. We believe that a major limitation of conventional algorithms is that they do not utilize prior knowledge of the ridge structure in fingerprints. Inspired by spelling correction techniques in natural language processing, we propose a novel fingerprint orientation field estimation algorithm based on prior knowledge of fingerprint structure. We represent prior knowledge of fingerprints using a dictionary of reference orientation patches. which is constructed using a set of true orientation fields, and the compatibility constraint between neighboring orientation patches. Orientation field estimation for latents is posed as an energy minimization problem, which is solved by loopy belief propagation. Experimental results on the challenging NIST SD27 latent fingerprint database and an overlapped latent fingerprint database demonstrate the advantages of the proposed orientation field estimation algorithm over conventional algorithms. PMID- 22826509 TI - A functional methylome map of ulcerative colitis. AB - The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n = 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n = 185). The EWAS identified 61 disease-associated loci harboring differential DNAm in cis of a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factor CFI, the serine protease inhibitor SPINK4, and the adhesion molecule THY1 (also known as CD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation. PMID- 22826510 TI - A fine scale phenotype-genotype virulence map of a bacterial pathogen. AB - A large fraction of the genes from sequenced organisms are of unknown function. This limits biological insight, and for pathogenic microorganisms hampers the development of new approaches to battle infections. There is thus a great need for novel strategies that link genotypes to phenotypes for microorganisms. We describe a high-throughput strategy based on the method Tn-seq that can be applied to any genetically manipulatable microorganism. By screening 17 in vitro and two in vivo (carriage and infection) conditions for the pathogen Streptococcus pneumoniae, we create a resource consisting of >1800 interactions that is rich in new genotype-phenotype relationships. We describe genes that are involved in differential carbon source utilization in the host, as well as genes that are involved both in virulence and in resistance against specific in vitro stresses, thereby revealing selection pressures that the pathogen experiences in vivo. We reveal the secondary response to an antibiotic, including a dual role efflux pump also involved in resistance to pH stress. Through genetic-interaction mapping and gene-expression analysis we define the mechanism of attenuation and the regulatory relationship between a two-component system and a core biosynthetic pathway specific to microorganisms. Thus, we have generated a resource that provides detailed insight into the biology and virulence of S. pneumoniae and provided a road map for similar discovery in other microorganisms. PMID- 22826511 TI - Do firstborn children have an increased risk of ADHD? AB - OBJECTIVE: Although previous reports have found no birth-order influence on ADHD risk, the authors hypothesize that being the firstborn is a risk factor for developing ADHD. METHOD: They selected all of the currently treated ADHD outpatients (n = 748) from our database. Families with adopted sons, nonnuclear families, and families with only one child and with sons (affected or unaffected) younger than 6 or older than 18 years were excluded. A total of 181 families with 213 ADHD sons met the inclusion criteria. We used all siblings without a clinical diagnosis of ADHD and who had no contact with our service as our unaffected controls (n = 173). RESULTS: The bivariate analysis showed that ADHD was associated with birth order and that firstborn children had nearly twice the ADHD risk of children with other birth orders. CONCLUSION: birth order can be an ADHD risk factor in clinical samples. PMID- 22826512 TI - "Ecological" and highly demanding executive tasks detect real-life deficits in high-functioning adult ADHD patients. AB - OBJECTIVE: Many adult ADHD patients with a convincing history of real-life executive deficits perform entirely within normal limits or with minimally impaired performance in classical executive tests. The authors assessed a group of high cognitive functioning adult ADHD participants on "ecological" and "highly demanding" executive tasks. METHOD: A total of 117 adult ADHD participants were classified as showing either a high-functioning (Hi-ADHD) or a low-functioning (Lo-ADHD) neuropsychological profile based on standard assessment. Their performance was compared with healthy controls (n = 21) on an ecological task of executive function (the hotel task) and computerized tasks of high cognitive demand. RESULTS: Lo-ADHD significantly differed from controls on multiple standard neuropsychological variables as well as on the experimental tasks. Hi ADHD and healthy controls did not differ significantly on any of the standard neuropsychological variables, but a significant difference was found between the groups on measures of the experimental tasks. CONCLUSION: Real-life executive dysfunction of patients with ADHD who perform within normal range on standard assessment can be detected with the use of more ecological and highly demanding tasks. PMID- 22826513 TI - Dietary antioxidants and the aetiology of pancreatic cancer: a cohort study using data from food diaries and biomarkers. AB - OBJECTIVE: To investigate whether the dietary antioxidants vitamins C and E, selenium and zinc decrease the risk of developing pancreatic cancer, for the first time using 7-day food diaries, the most accurate dietary methodology in prospective work. DESIGN: 23,658 participants, aged 40-74 years, recruited into the EPIC-Norfolk Study completed 7-day food diaries which recorded foods, brands and portion sizes. Nutrient intakes were calculated in those later diagnosed with pancreatic cancer and in 3970 controls, using a computer program with information on 11,000 foods. Vitamin C was measured in serum samples. The HRs of developing pancreatic cancer were estimated across quartiles of intake and thresholds of the lowest quartile (Q1) against a summation of the three highest (Q2-4). RESULTS: Within 10 years, 49 participants (55% men), developed pancreatic cancer. Those eating a combination of the highest three quartiles of all of vitamins C and E and selenium had a decreased risk (HR=0.33, 95% CI 0.13 to 0.84, p<0.05). There were threshold effects (Q2-4 vs Q1) for selenium (HR=0.49, 95% CI 0.26 to 0.93, p<0.05) and vitamin E (HR=0.57, 95% CI 0.29 to 1.09, p<0.10). The HRs of quartiles for antioxidants, apart from zinc, were <1, but not statistically significant. For vitamin C, there was an inverse association with serum measurements (HR trend=0.67, 95% CI 0.49 to 0.91, p=0.01), but the threshold effect from diaries was not significant (HR=0.68, 95% CI 0.37 to 1.26). CONCLUSION: The results support measuring antioxidants in studies investigating the aetiology of pancreatic cancer. If the association is causal, 1 in 12 cancers might be prevented by avoiding the lowest intakes. PMID- 22826514 TI - Childhood medulloblastoma: the paradigm shift in molecular stratification and treatment profile. AB - Medulloblastoma is the most common malignant brain tumor of childhood, accounting for nearly 25% to 30% of primary central nervous system tumors in children younger than 18 years of age. Risk stratification into low and high risk categories has been based on age of clinical presentation, extent of postsurgical residual tumor, and disease dissemination. The World Health Organization (WHO) in 2007 recognized 5 histological subtypes as classic, anaplastic, large cell, desmoplastic/nodular, and medulloblastoma with extensive nodularity. Recent work with gene expression profiling along with histological classification has generated a novel combined histopathological and molecular stratification scheme into 4 subgroups (Wnt, Shh, group 3, and group 4). This could now help to identify patients who might benefit from dose escalation and de-escalation of therapy. Restratification brings optimism in treating these patients as scholars now have the ability to profile a more targeted therapy approach. This review discusses the literature regarding this new research endeavor. PMID- 22826515 TI - Filicide-suicide involving children with disabilities. AB - Filicide-suicide, or murder of a child by a parent followed by suicide, has an unknown incidence in both the general and disabled population. As there is no national database, the authors examined known associated factors and newspaper reports to characterize filicide-suicide victims and perpetrators involving children with disabilities. A newspaper search was conducted using LexisNexis and NewsBank: Access World News databases through the University of California, Irvine Library's Web site. Age, gender of child and parent, method used, and diagnoses of parent and child were recorded. Twenty-two news articles were found describing a total of 26 disabled children as victims of filicide-suicide between 1982 and 2010. Eighty-one percent of children killed were male, and 54% were autistic. Thirty percent of perpetrators had a reported mental illness. Male children or children with autism may be at risk for filicide-suicide, but accurate record keeping is needed to determine the incidence and risk factors and aid in its prevention in the disabled population. PMID- 22826516 TI - Informing policy and programme decisions for scaling up the PMTCT and paediatric HIV response through joint technical missions. AB - In 2005, due to slow global progress in the scale-up of prevention of mother-to child transmission (PMTCT) and paediatric HIV programmes, the Inter-agency Task Team (IATT) on the Prevention of HIV infection among Pregnant Women, Mothers, and their Children initiated joint technical missions (JTMs) to countries of high HIV disease burden. The JTMs were intended to galvanize country actions for a more comprehensive response to PMTCT and paediatric HIV by bringing national and global stakeholders together to review national policies and programmes and develop country-specific recommendations for accelerating scale-up. Between 2005 and 2010, the IATT conducted JTMs in 18 low- and middle-income countries. In 2007, to assess the role played by the missions, a review in the first eight countries (Burkina Faso, Cameroon, Cote d'Ivoire, India, Malawi, Rwanda, Tanzania and Zambia) that hosted JTMs was undertaken. Country progress was assessed through desk review and key informant interviews. For each country, documents reviewed included JTM reports, baseline data for PMTCT and paediatric HIV care and treatment, and 2004 to 2007 trend data on key PMTCT and paediatric HIV indicators. Drawing upon the findings, this paper posits that JTMs contributed to national scale-up of PMTCT and paediatric HIV programmes through strengthening governance and co-ordination mechanisms for the programmes, promoting enabling policy environments, and supporting the development of national scale-up plans, which have been critical for leveraging additional financial resources for scale up. Although the impact of the JTMs could be enhanced through greater follow-up and continued targeted assistance in technical areas such as infant and young child feeding, community-based programming and supply chain management, findings indicate that the JTMs are a useful mechanism for informing policy and programme decisions necessary for scaling up PMTCT and paediatric HIV responses. Moreover, by bringing stakeholders together around unified action plans, the JTMs created a platform for common action-a key tenet of the 'Three Ones' principles for effective HIV/AIDS responses. PMID- 22826517 TI - Actor interfaces and practices of power in a community health worker programme: a South African study of unintended policy outcomes. AB - This paper makes a contribution to a much-neglected aspect of policy analysis: the practice of power in implementation. Practices of power are at the heart of every policy process, yet are rarely explicitly explored in the health policy literature. This paper provides a detailed study of micro-practices of power by those at the frontline of service delivery in the implementation of a national community health worker policy in one rural South African sub-district. The paper is based on a small-scale qualitative study which collected data through observations, interviews and focus group discussions with health services and facility managers, community health workers and community members. Practices of power were analysed using VeneKlasen and Miller's categorization of multiple dimensions of power, as power over, power with, power to and power within. Furthermore, the concept of 'actor interface analysis' allowed exploration of different actors' experience, interests and their specific location in the landscape of local health system governance. The study revealed that almost all policy actors exercised some form of power, from authoritative power, derived from hierarchy and budget control, to the discretionary power of those working at lower levels to withhold labour or organize in-service training. Each of these practices of power had their rationale in different actors' efforts to make the intervention 'fit' their understandings of local reality. While each had a limited impact on policy outcomes, their cumulative effect produced a significant thinning down of the policy's intent. However, discretionary power was not always used to undermine policy. One manager's use of discretionary power in fact led to a partial reconstruction of the original policy intent. The paper concludes that understanding and being responsive to the complexity of local realities, interests and contexts and the multi-layered practices of power may allow managers to adopt more appropriate management strategies. PMID- 22826518 TI - Remimazolam: new beginnings or just a me-too? PMID- 22826519 TI - New horizons in sedative hypnotic drug development: fast, clean, and soft. PMID- 22826520 TI - Recirculatory pharmacokinetic modeling: what goes around, comes around. PMID- 22826521 TI - Tranexamic acid for routine use in off-pump coronary artery bypass surgery: evidence base "fait accompli" or more research needed? PMID- 22826522 TI - Chronic postsurgical pain: are we closer to understanding the puzzle? PMID- 22826523 TI - Research into new drugs in anesthesia: then & now. PMID- 22826524 TI - Departmental and institutional strategies for reducing fraud in clinical research. PMID- 22826525 TI - An unusual cause of anesthesia circuit blockade by SODASORB PRE-PAK. PMID- 22826526 TI - Separation of components of methylprednisolone acetate solution for safe intrathecal administration. PMID- 22826527 TI - Large randomized trials to overcome barriers to patient safety. PMID- 22826528 TI - Stylet-assisted tracheal intubation through an ILMA in a patient with an anterior larynx. PMID- 22826529 TI - Abstracts of the 2012 Annual Meeting of the Society for Technology in Anesthesia (STA). January 18-21, 2012. PMID- 22826530 TI - Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine. AB - BACKGROUND: Dexmedetomidine, an alpha(2)-receptor agonist, prolongs analgesia when used in neuraxial and IV blocks. We evaluated the effect of dexmedetomidine added to ropivacaine for tibial nerve block on the duration of the sensory blockade. METHODS: For this prospective, randomized, controlled, double-blind, crossover trial, 14 healthy volunteers were allocated to 2 groups. All volunteers received an ultrasound-guided tibial nerve block 4 to 5 cm proximally to the medial malleolus. In group R, 10 mL of 0.5% ropivacaine was injected for the block; in group RD, 10 mL of a solution containing 0.5% ropivacaine with 1 MUg/kg of dexmedetomidine was administered. After the injection, monitoring of vital signs, evaluation of onset and resolution of sensory block, and level of sedation (Observer's Assessment of Alertness/Sedation scale) were performed. Three weeks later, the same procedure was repeated, but the study subjects were allocated to the other group in a crossover fashion. The primary end point was the duration of sensory blockade. The time and carryover effects were also evaluated. Secondary outcomes were the onset time and the presence of adverse effects such as hypotension, bradycardia, hypoxia, and sedation. RESULTS: Sensory blocks lasted longer in group RD than in group R (21.5 vs 16.2 hours; mean pairwise difference 5.3 hours [95% confidence interval: 3.9-6.7 hours]; P < 0.0001). Onset times were similar between groups. The mean systolic and diastolic blood pressure levels were stable throughout the study period in group R. In group RD, a noticeable decrease in systolic and diastolic blood pressure was observed between 60 and 480 minutes (P < 0.05); 2 volunteers experienced a 30% decrease in systolic blood pressure when compared with the baseline value as compared with none in group R. Heart rate was similar between groups except at 60 minutes (P < 0.01). CONCLUSION: Dexmedetomidine added to ropivacaine for tibial nerve block prolongs the duration of sensory blockade with similar onset time. However, patients should be monitored for potential adverse effects such as hypotension, bradycardia, and sedation. PMID- 22826531 TI - Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. AB - BACKGROUND: Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6). METHODS: This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations. RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti inflammatory effect; the meta-analysis showed a mean preoperative-postoperative IL-6 concentration difference (95% confidence interval) of -71 (-101 to -41) pg/mL. CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen. PMID- 22826532 TI - Multiple perpetrator sexual assault: how does it differ from assault by a single perpetrator? AB - Research that attempts to identify characteristic features of multiple perpetrator sexual assault (MPSA) is limited. This study compared demographic and assault related characteristics of 135 cases of MPSA with 139 cases of single perpetrator sexual assault (SPSA) reported to the Haven sexual assault referral centre, Camberwell, London, over a 4-year period, and aimed to identify any unique features of MPSA victims, perpetrators and assault type. Victims of MPSA were younger, less likely to be White, more likely to report previous self-harm and more likely to sustain injuries than victims of SPSA. Multiple perpetrators were younger, less likely to be White and more likely to be strangers to the victim than single perpetrators. The nature of the assault was different in single and multiple perpetrator cases; in MPSA, there were more completed rapes and more multiple rapes, and perpetrators were more likely to meet the victim in an outside location before carrying out the assault in a place of residence that was not the victim's. These findings add to a scant but growing evidence base. PMID- 22826533 TI - Genetic variability in the endocannabinoid system and 12-week clinical response to citalopram treatment: the role of the CNR1, CNR2 and FAAH genes. AB - First line treatment of major depression is based on selective serotonin re uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment. PMID- 22826534 TI - Meta-analysis and inadequate responders to intervention: a reply. PMID- 22826535 TI - Meta-analysis and inadequate responders to intervention: a response. PMID- 22826536 TI - A comparison of the performance of samplers for respirable dust in workplaces and laboratory analysis for respirable quartz. AB - The divergent sampling techniques for respirable dust and the analyses for crystalline silica are an important area of interest and discussion among industrial occupational hygienists in Europe. The variety of equipment for air sampling, methods and instrumentation can cause differences between results for the analysis of respirable crystalline silica (RCS). In this study, a Workplace Atmosphere Multi-sampler (WAM), developed by Adhesia, was used to compare respirable dust samplers in the workplace. This rotating device enables the comparison of 12 samplers in a workplace in each run. Seven laboratories participated in the comparison, using six different respirable dust samplers [British Cast Iron Research Association (BCIRA) to the Higgins Dewell (HD) design, Dorr Oliver, Casella SIMPEDS, SKC HD with a polycarbonate filter and polyvinylchloride filter, and the CIP10-R). Each laboratory analysed samples supplied by the samplers and reported the total respirable dust concentration and the RCS concentration. The techniques used were X-ray diffraction direct-on filter, X-ray diffraction with deposition, infrared direct-on-filter, and infrared with potassium bromide (KBr) discs. The experiments were carried out in four different industries (enamel, sand extraction, foundry and brickworks). Generally, the SKC conductive black plastic sampler is oversampled (y = 1.52x + 0.008) and the CIP10 is undersampled (y = 0.74x + 0.068) when compared with the median air concentration. A pair-wise comparison of the different industries using t-tests indicated significant differences (P < 0.05) between the SKC conductive plastic samplers and the other samplers. The same series of statistical calculations were performed for the results obtained for RCS (quartz) and showed significant differences for the CIP10 techniques and the SKC conductive plastic cyclone analyses when using a polyvinylchloride filter. PMID- 22826537 TI - Overreliance on a single study: there is no real evidence that applying quality criteria to exposure in asbestos epidemiology affects the estimated risk. AB - A critical need exists for reliable risk management policies and practices that can effectively mitigate asbestos-related health threats, and such policies and practices need to be based on sound science that adequately distinguishes hazardous situations from those that are not. Toward that end, the disparate means by which study quality has been addressed in recent meta-analyses used to establish potency factors (K ( L ) and K ( M ) values) for asbestos cancer risks were compared by conducting additional sensitivity analyses. Results suggest that, other than placing undue emphasis on the influence of the K ( L ) and K ( M ) values reported from a single study, there appears to be little to no evidence of a systematic effect of study quality on K ( L ) or K ( M ) values; none of the findings warrant excluding studies from current or future meta-analyses. Thus, we argue that it is better to include as much of the available data as possible in these analyses while formally addressing uncertainty as part of the analysis itself, rather than sequentially excluding studies based on one type of limitation or another. Throwing out data without clearly proving some type of bias is never a good idea because it will limit both the power to test various hypotheses and the confidence that can be placed in any findings that are derived from the resulting, truncated data set. We also believe that it is better to identify the factors that contribute to variation between studies included in a meta-analysis and, by adjusting for such factors as part of a model, showing that the disparate values from individual studies can be reconciled. If such factors are biologically reasonable (based on other evidence) and, if such a model can be shown to fit the data from all studies in the meta analysis, the model is likely to be predictive of the parameters being evaluated and can then be applied to new (unstudied) environments. PMID- 22826538 TI - Development of off-gas emission kinetics for stored wood pellets. AB - A lumped three-reaction kinetic model for off-gas emissions of stored wood pellets in sealed containers has been developed accounting for the formation of CO and CO(2) and the depletion of O(2). Off-gas emission data at different conditions were used to extract kinetic model parameters by numerically fitting the proposed model equations. The fitted kinetic model parameters for different cases showed consistency with one another. With properly estimated model parameters, the current kinetic model can be used to predict off-gas emissions, oxygen depletion, and the buildup of toxic air pollutants in wood pellet storage containers/vessels. PMID- 22826539 TI - High cardiovascular risk in severely obese young children and adolescents. AB - OBJECTIVE: To assess the prevalence of cardiovascular risk factors in severely obese children and adolescents. METHODS: A nationwide prospective surveillance study was carried out from July 2005 to July 2007 where paediatricians were asked to report all new cases of severe obesity in 2-18-year-old children to the Dutch Paediatric Surveillance Unit. Severe obesity is defined by gender and age dependent cut-off points for body mass index based on Dutch National Growth Studies corresponding to the adult cut-off point of 35 kg/m(2). Paediatricians were asked to complete a questionnaire for every severely obese child regarding socio-demographic characteristics and cardiovascular risk factors (blood pressure, fasting blood glucose and lipids). RESULTS: In 2005, 2006 and 2007, 94%, 87% and 87%, respectively, of paediatricians in the Netherlands responded to the monthly request from the Dutch Paediatric Surveillance Unit and 500 children with newly diagnosed severe obesity were reported. 72.6% (n=363) of paediatricians responded to a subsequent questionnaire. Cardiovascular risk factor data were available in 255/307 (83%) children who were correctly classified as severely obese. 67% had at least one cardiovascular risk factor (56% hypertension, 14% high blood glucose, 0.7% type 2 diabetes and up to 54% low HDL-cholesterol). Remarkably, 62% of severely obese children aged <=12 years already had one or more cardiovascular risk factors. CONCLUSION: A high number (2/3) of severely obese children have cardiovascular risk factors. Internationally accepted criteria for defining severe obesity and guidelines for early detection and treatment of severe obesity and comorbidity are urgently needed. PMID- 22826540 TI - GeneTalk: an expert exchange platform for assessing rare sequence variants in personal genomes. AB - SUMMARY: Next-generation sequencing has become a powerful tool in personalized medicine. Exomes or even whole genomes of patients suffering from rare diseases are screened for sequence variants. After filtering out common polymorphisms, the assessment and interpretation of detected personal variants in the clinical context is an often time-consuming effort. We have developed GeneTalk, a web based platform that serves as an expert exchange network for the assessment of personal and potentially disease-relevant sequence variants. GeneTalk assists a clinical geneticist who is searching for information about specific sequence variants and connects this user to other users with expertise for the same sequence variant. AVAILABILITY: GeneTalk is available at www.gene-talk.de. Users can login without registering in a demo account. CONTACT: peter.krawitz@gene talk.de. PMID- 22826541 TI - RILogo: visualizing RNA-RNA interactions. AB - SUMMARY: With the increasing amount of newly discovered non-coding RNAs, the interactions between RNA molecules become an increasingly important aspect for characterizing their functionality. Many computational tools have been developed to predict the formation of duplexes between two RNAs, either based on single sequences or alignments of homologous sequences. Here, we present RILogo, a program to visualize inter- and intramolecular base pairing between two RNA molecules. The input for RILogo is a pair of structure-annotated sequences or alignments. In the latter case, RILogo displays the alignments in the form of sequence logos, including the mutual information of base paired columns. We also introduce two novel mutual information based measures that weigh the covariance information by the evolutionary distances of the aligned sequences. We show that the new measures have an increased accuracy compared with previous mutual information measures. AVAILABILITY AND IMPLEMENTATION: RILogo is freely available as a stand-alone program and is accessible via a web server at http://rth.dk/resources/rilogo. CONTACT: pmenzel@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22826542 TI - A prescription for the Epley maneuver: www.youtube.com? AB - OBJECTIVES: Video-sharing Web sites are being used for information about common conditions including dizziness. The Epley maneuver (EM) is a simple and effective treatment for benign paroxysmal positional vertigo (BPPV) of the posterior canal. However, the maneuver is underused in routine care. In this study, we aimed to describe and analyze the available information about the EM on youtube.com. METHODS: A YouTube search was performed on August 31, 2011, for videos that demonstrated the entire EM. Detailed data were abstracted from each video and corresponding Web site. Videos were rated on the accuracy of the maneuver by 2 authors, with differences resolved by adjudication. Comments posted by viewers were assessed for themes regarding video use. RESULTS: Of the 3,319 videos identified, 33 demonstrated the EM. The total number of hits for all videos was 2,755,607. The video with the most hits (802,471) was produced by the American Academy of Neurology. Five of the videos accounted for 85% of all the hits. The maneuver demonstration was rated as accurate in 64% (21) of the videos. Themes derived from the 424 posted comments included patients self-treating with the maneuver after reviewing the videos, and providers using the videos as a prescribed treatment or for educational purposes. CONCLUSION: Accurate video demonstration of the Epley maneuver is available and widely viewed on YouTube. Video-sharing media may be an important way to disseminate effective interventions such as the EM. The impact of video Web sites on outcomes and costs of care is not known and warrants future study. PMID- 22826543 TI - Career mentorship for young neurologists in Europe. PMID- 22826544 TI - Massive and exclusive pontocerebellar damage in mitochondrial disease and NUBPL mutations. PMID- 22826545 TI - Recurrent stroke on imaging and presumed paradoxical embolism: a cross-sectional analysis. PMID- 22826546 TI - Solitary sclerosis: Progressive myelopathy from solitary demyelinating lesion. PMID- 22826547 TI - Clinical Reasoning: a 54-year-old man with unilateral weakness and vascular risk factors. PMID- 22826548 TI - Journal Club: a randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. PMID- 22826549 TI - Teaching NeuroImages: isolated hypoglossal nerve palsy due to internal carotid artery dissection. PMID- 22826550 TI - Marginal additive hazards model for case-cohort studies with multiple disease outcomes: an application to the Atherosclerosis Risk in Communities (ARIC) study. AB - In the case-cohort studies conducted within the Atherosclerosis Risk in Communities (ARIC) study, it is of interest to assess and compare the effect of high-sensitivity C-reactive protein (hs-CRP) on the increased risks of incident coronary heart disease and incident ischemic stroke. Empirical cumulative hazards functions for different levels of hs-CRP reveal an additive structure for the risks for each disease outcome. Additionally, we are interested in estimating the difference in the risk for the different hs-CRP groups. Motivated by this, we consider fitting marginal additive hazards regression models for case-cohort studies with multiple disease outcomes. We consider a weighted estimating equations approach for the estimation of model parameters. The asymptotic properties of the proposed estimators are derived and their finite-sample properties are assessed via simulation studies. The proposed method is applied to analyze the ARIC Study. PMID- 22826551 TI - Fundus autofluorescence and spectral-domain optical coherence tomography findings suggesting tissue remodelling in retinal pigment epithelium tear. AB - AIM: To study tissue remodelling and wound healing after retinal pigment epithelium (RPE) tears due to age-related macular degeneration. METHODS: Retrospective longitudinal study of 36 eyes (33 patients) with RPE tears. Imaging was performed using fundus autofluorescence (FAF) (lambda=488 nm) and spectral domain optical coherence tomography (SD-OCT). Presence of intraretinal hyper reflective dots in SD-OCT, which correlated with hyperfluorescent dots in FAF, indicating RPE migration was studied. Morphology of subretinal mass and RPE layer integrity in the RPE denuded area over time were examined. RESULTS: 7 of 36 eyes (19.4%) showed patchy or hazy hyperfluorescent areas in FAF, and the majority of eyes (83.3%) showed hyper-reflective dots, which possibly represent intraretinal RPE migration and hard exudates. Homogenous subretinal mass was encountered in about half of all cases. In one case (2.8%), the RPE layer proliferated and covered the defect. CONCLUSIONS: SD-OCT and FAF showed a considerable amount of RPE proliferation, migration and repopulation. Intraretinal RPE migration did not form a functional RPE layer. A small defect might be repaired by cell proliferation. But this RPE proliferation is not sufficient to cover large defects. PMID- 22826552 TI - Long term visual outcomes, graft survival and complications of deep anterior lamellar keratoplasty in patients with herpes simplex related corneal scarring. AB - AIMS: To report long term visual outcomes, complications and graft survival of patients undergoing deep anterior lamellar keratoplasty (DALK) to treat corneal scarring secondary to herpes simplex virus (HSV) keratitis. METHODS: Retrospective, non-comparative case series. 18 patients who underwent DALK for HSV keratitis related corneal scarring between January 2004 and February 2007 were included. DALK was performed by Anwar's big bubble technique. Data collected for analysis included preoperative characteristics, intraoperative complications and postoperative acuity, complications and subsequent operations. RESULTS: Mean best corrected distance visual acuity (LogMAR) improved from 1.51 +/- 0.90 preoperatively to 0.82 +/- 0.85 at the last follow-up (p=0.05). 27% of patients with more than 4 years follow-up had a best corrected distance visual acuity of 6/12 or better and 64% were 6/24 or better. Six patients (33%) experienced a recurrence of HSV keratitis and 9 (50%) experienced an episode of graft rejection. There were five cases (28%) of graft failure, four of whom had had a previous episode of graft rejection. Logistic regression did not find an association with graft rejection, HSV recurrence, any other observed postoperative host corneal vascularisation and any postoperative complication. The majority of patients underwent a second operation with 50% requiring cataract surgery. CONCLUSIONS: DALK for the treatment of HSV related corneal scarring is associated with a high percentage of postoperative complications. DALK in this context is also associated with a large percentage of secondary operations. Patients should be aware of this when giving informed consent for DALK to treat HSV related corneal scars. PMID- 22826553 TI - Occupational hepatitis C seroconversions in a Brazilian hospital. AB - BACKGROUND: There are six known cases of occupational human immunodeficiency virus (HIV) seroconversion in Brazil. However, there are neither published cases of occupational hepatitis C virus (HCV) seroconversion nor systematic studies of blood and body fluid exposures (BBFE) that could estimate the risk of HCV or HIV occupational seroconversion in Brazil. AIMS: To describe the outcomes of BBFEs in a Brazilian hospital over 12 years and 2 months. METHODS: Statistical analysis of a computerized database of exposure events recorded on printed forms. Incidence rates (IR) were calculated as the number of BBFE per 100 full-time equivalent worker-years. RESULTS: There were 1457 BBFE, 87% being percutaneous and 561 (38%) recurring in health care workers (HCWs) who reported having previous exposures. The highest IRs occurred in laboratory technicians (9.7), medical students (9.5), cleaning staff (9.5) and nursing aids (9.2). The IR in temporary employees was 13.0. Two HCWs, a nursing aid and a surgeon, seroconverted to hepatitis C after HCV exposures involving 13 G catheter needles. The risk of acquiring a HCV infection was 2 in 38 percutaneous HCV exposures, i.e. 5% (95% CI: 0.89-16.3). There were no seroconversions to HIV despite 80 percutaneous HIV exposures. CONCLUSIONS: HCV has a higher potential for occupational transmission than HIV. Measures to reduce the risks of BBFE and occupational transmission of blood-borne viral infections should be improved in Brazil. PMID- 22826554 TI - Low fitness is associated with exercise abnormalities among asymptomatic firefighters. AB - BACKGROUND: Low cardiorespiratory fitness (CRF) has been repeatedly linked to cardiovascular morbidity and mortality, while higher CRF levels are protective. This relationship is likely to be highly relevant in firefighters, who have increased risk of cardiovascular disease (CVD) mortality during strenuous emergencies, which can require prolonged periods of near-maximal heart rates (HR) and high workloads. Abnormalities during maximal stress testing could mark future CVD risk during strenuous duties. AIMS: To determine if low CRF among asymptomatic firefighters is associated with higher risk of electrocardiographic (ECG) and autonomic abnormalities during maximal exercise stress testing and recovery. METHODS: Male career firefighters completed a maximal stress test exercising to volitional exhaustion (mean maximal age-predicted HR achieved 98%, standard deviation (SD) = 6.5). CRF was measured as maximal metabolic equivalents (METS) achieved. Abnormal exercise tests included the following: abnormal HR recovery; chronotropic insufficiency; exaggerated blood pressure response; and ECG abnormalities. The relationship of CRF to stress testing abnormalities was analysed using peak METS categories and peak METS as a continuous variable after adjusting for age, body mass index (BMI) and metabolic syndrome (MetSyn). RESULTS: There were 1149 study participants. CRF was inversely associated with the risk of both ECG and autonomic exercise testing abnormalities before and after adjustment for age, BMI and MetSyn. CONCLUSIONS: Firefighters with lower CRF are significantly more prone to exhibit abnormal stress test parameters, which may indicate higher future risk of cardiovascular events. As such, firefighters with low CRF (<= 12 METS) should receive cardiovascular risk reduction, including efforts to improve their CRF. PMID- 22826555 TI - An outbreak of occupational asthma due to chromium and cobalt. AB - BACKGROUND: Five metal turners employed by an aerospace manufacturer presented to the Birmingham Chest Clinic occupational lung disease unit. Four cases of occupational asthma (OA) due to chromium salt (3) and cobalt (1) were diagnosed by serial peak-expiratory flow measurements and specific inhalation challenge testing. AIMS: To measure the extent of the outbreak and to provide epidemiological data to ascertain the aetiology. METHODS: Participants answered a detailed, self-administered questionnaire, designed to detect occupational lung disease. Urine chromium and cobalt excretion, spirometry and exhaled nitric oxide measurements were taken. Those with possible, probable or definite non-OA or OA, after questionnaire, were invited to undertake two-hourly peak flow measurements and received specialist follow-up. RESULTS: A total of 62 workers (95% of workforce) participated. Sixty-one per cent of employees were working in higher metalworking fluid (MWF) exposure areas. Ninety per cent of workers had urinary chromium excretion indicating occupational exposure. Sixty-six per cent of workers reported active respiratory symptoms, although there were no significant differences between exposure groups. Two further workers with probable OA were identified and had significantly higher urinary chromium and cobalt concentration than asymptomatic controls. Eighteen cases of occupational rhinitis (OR) were identified, with significantly raised urinary chromium concentration compared with asymptomatic controls. CONCLUSIONS: Chromium salt and cobalt can be responsible for OA and OR in workers exposed to MWF aerosols. Onset of symptoms in those with positive specific challenges followed change in MWF brand. Workers with OA had increased urinary concentrations of chromium and cobalt, and those with OR had increased urinary concentrations of chromium. PMID- 22826556 TI - Renal biomarkers and prognosis in acute pulmonary embolism. PMID- 22826557 TI - Putting the microscope on stent thrombosis. PMID- 22826558 TI - Cardiovascular disease mortality in the Americas: current trends and disparities. AB - OBJECTIVE: To describe the current situation and trends in mortality due to cardiovascular disease (CVD) in the Americas and explore their association with economic indicators. DESIGN AND SETTING: This time series study analysed mortality data from 21 countries in the region of the Americas from 2000 to the latest available year. MAIN OUTCOMES MEASURES: Age-adjusted death rates, annual variation in death rates. Regression analysis was used to estimate the annual variation and the association between age-adjusted rates and country income. RESULTS: Currently, CVD comprised 33.7% of all deaths in the Americas. Rates were higher in Guyana (292/100 000), Trinidad and Tobago (289/100 000) and Venezuela (246/100 000), and lower in Canada (108/100 000), Puerto Rico (121/100 000) and Chile (125/100 000). Male rates were higher than female rates in all countries. The trend analysis showed that CVD death rates in the Americas declined -19% overall (-20% among women and -18% among men). Most countries had a significant annual decline, except Guatemala, Guyana, Suriname, Paraguay and Panama. The largest annual declines were observed in Canada (-4.8%), the USA (-3.9%) and Puerto Rico (-3.6%). Minor declines were in Mexico (-0.8%) and Cuba (-1.1%). Compared with high-income countries the difference between the median of death rates in lower middle-income countries was 56.7% higher and between upper middle income countries was 20.6% higher. CONCLUSIONS: CVD death rates have been decreasing in most countries in the Americas. Considerable disparities still remain in the current rates and trends. PMID- 22826559 TI - Combined use of optical coherence tomography and intravascular ultrasound imaging in patients undergoing coronary interventions for stent thrombosis. AB - OBJECTIVE: This prospective study sought to assess the diagnostic value of optical coherence tomography (OCT) compared with intravascular ultrasound (IVUS) in patients presenting with stent thrombosis (ST). DESIGN AND SETTING: Although the role of IVUS in this setting has been described, the potential diagnostic value of OCT in patients suffering ST remains poorly defined. Catheterization Laboratory, University Hospital. PATIENTS AND INTERVENTIONS: Fifteen consecutive patients with ST undergoing rescue coronary interventions under combined IVUS/OCT imaging guidance were analysed. MEAN OUTCOME MEASURES: Analysis and comparison of OCT and IVUS findings before and after interventions. RESULTS: Before intervention, OCT visualised the responsible thrombus in all patients (thrombus area 4.7+/-2.5 mm(2), stent obstruction 82+/-14%). Minimal stent area was 4.7+/ 2.1 mm(2) leading to severe stent underexpansion (expansion 60+/-21%). Although red or mixed thrombus (14 patients) induced partial strut shadowing (total length 12.3+/-6 mm), malapposition (six patients), inflow-outflow disease (five patients), uncovered struts (nine patients) and associated in-stent restenosis (five patients, four showing neoatherogenesis) was clearly recognised. IVUS disclosed similar findings but achieved poorer visualisation of thrombus-lumen interface and strut malapposition, and failed to recognise uncovered struts and associated neoatherosclerosis. After interventions, OCT demonstrated a reduced thrombus burden (2.4+/-1.6 mm(2)) and stent obstruction (24+/-14%) with improvements in stent area (6.8+/-2.9 mm(2)) and expansion (75+/-21%) (all p<0.05). IVUS and OCT findings proved to be complementary. CONCLUSIONS: OCT provides unique insights on the underlying substrate of ST and may be used to optimise results in these challenging interventions. In this setting, OCT and IVUS have complementary diagnostic values. PMID- 22826560 TI - Intraoperative 2D and 3D transoesophageal echocardiographic predictors of aortic regurgitation after transcatheter aortic valve implantation. AB - BACKGROUND: Post-procedural aortic regurgitation (AR) has been described in a large number of patients receiving transcatheter aortic valve implantation (TAVI). OBJECTIVE: The aim of this study was to examine the intraoperative 2 dimensional (2D) and 3-dimensional (3D) echocardiographic features of the aortic valve associated with significant post-procedural paravalvular AR. METHODS: A total of 135 patients (81+/-7 years) with severe symptomatic aortic stenosis, who underwent TAVI, were imaged with comprehensive 2D and 3D transoesophageal echocardiography before the procedure and peri-procedure. Various baseline and peri-procedural echocardiographic characteristics were tested to predict paravalvular AR post-TAVI: calcifications at the aortic valve commissures and leaflets, 'aortic annulus eccentricity index', 'area cover index', overlap between aortic prosthesis and anterior mitral leaflet. Post-procedural paravalvular AR>=2 was considered significant. RESULTS: Successful TAVI was achieved in all patients. The incidence of paravalvular AR>=2 immediately after the procedure was 21% (28 patients). Commissural calcifications and, particularly, the calcification of the commissure between the right coronary and non-coronary cusps was significantly more frequent in presence of paravalvular AR; the area cover index pre-TAVI was significantly lower among patients with AR (11.1+/-11.8% vs 20.8+/-12.5%, p=0.0004). Multivariate analysis revealed that calcification of the commissure between the right coronary and non-coronary cusps (OR=2.66, 95% CI 1.39 to 5.12, p=0.001), and the area cover index pre-TAVI (OR=0.95, 95% CI 0.91 to 0.99, p=0.006) were the only independent predictors of significant paravalvular AR after TAVI. CONCLUSIONS: Intraoperative 2D and 3D transoesophageal echocardiography identified calcification of the commissure between the right coronary and non-coronary cusps and the area cover index as independent predictors of significant paravalvular AR following TAVI. PMID- 22826561 TI - Percutaneous cardiac support devices for cardiogenic shock: current indications and recommendations. PMID- 22826562 TI - Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy. AB - The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of <= 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor. PMID- 22826563 TI - SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. AB - Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation. PMID- 22826564 TI - Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks. AB - As pediatric Hodgkin lymphoma (HL) survival rates approach > 95%, treatment decisions are increasingly based on minimizing late effects. Using a model-based approach, we explored whether the addition of radiotherapy contributes to improved overall long-term survival. We developed a state-transition model to simulate the lifetime HL clinical course, and we compared 2 treatment strategies: chemotherapy alone (CT) and chemoradiotherapy (CRT). Data on HL relapse, late recurrence, and excess second cancer and cardiac late-effects mortality were estimated from the published literature and databases. Outcomes included conditional life expectancy, cause-specific mortality, and proportion alive at age 50. For a hypothetical cohort of HL patients (diagnosis age 15), conditional life expectancy was 57.2 years with CT compared with 56.4 years with CRT. Estimated lifetime HL mortality risk was 3.6% with CT versus 2.2% with CRT. In contrast, combined risk of excess late-effects mortality was lower for CT (1.8% vs 7.4% with CRT). Among those alive at age 50, only 9.2% of those initially treated with CT were at risk for radiation-related late effects (100% for CRT). Initial treatment with CT may be associated with longer average per-person life expectancy. These results support the need for careful consideration of the risk benefit profile of radiation as frontline therapy in pediatric patients. PMID- 22826566 TI - Risk factors for in-hospital mortality among children with tuberculosis: the 25 year experience in Peru. AB - OBJECTIVE: We examined factors associated with in-hospital death among children with tuberculosis (TB). We hypothesized that a negative response to tuberculin skin testing (TST) would predict decreased survival. METHODS: This retrospective cohort comprised 2392 children ages 0 to 14 years hospitalized with TB at a Peruvian referral hospital over the 25-year study period. Detailed chart abstraction captured clinical history including TB contacts, physical examination findings, diagnostic data, treatment regimen, and hospitalization outcome. We used Cox proportional hazards regression analyses to determine risk factors for mortality. RESULTS: Of 2392 children, 2 (0.1%) were known to be HIV-positive, 5 (0.2%) had documented multidrug-resistant TB, and 266 (11%) died. The median time from hospitalization to death was 16 days (interquartile range: 4-44 days). Reaction of <5 mm induration on TST predicted death in a multivariable analysis (hazard ratio [HR]: 3.01; 95% confidence interval [CI]: 2.15-4.21; P < .0001). Younger age, period of admission, alteration of mental status (HR: 3.25; 95% CI: 2.48-4.27; P < .0001), respiratory distress (HR: 1.40; 95% CI: 1.07-1.83; P = .01), peripheral edema (HR: 1.97; 95% CI: 1.42-2.73; P < .0001), and hemoptysis (HR: 0.57; 95% CI: 0.32-1.00; P = .05) were associated with mortality. Treatment regimens that contained rifampicin (HR: 0.47; 95% CI: 0.33-0.68; P < .0001) were associated with improved survival. CONCLUSIONS: Negative reaction to TST is highly predictive of death among children with active TB. In children with clinical and radiographic findings suggestive of TB, a negative TST should not preclude or delay anti-TB therapy. PMID- 22826567 TI - The HEADS-ED: a rapid mental health screening tool for pediatric patients in the emergency department. AB - BACKGROUND AND OBJECTIVE: The American Academy of Pediatrics called for action for improved screening of mental health issues in the emergency department (ED). We developed the rapid screening tool home, education, activities/peers, drugs/alcohol, suicidality, emotions/behavior, discharge resources (HEADS-ED), which is a modification of "HEADS," a mnemonic widely used to obtain a psychosocial history in adolescents. The reliability and validity of the tool and its potential for use as a screening measure are presented. METHODS: ED patients presenting with mental health concerns from March 1 to May 30, 2011 were included. Crisis intervention workers completed the HEADS-ED and the Child and Adolescent Needs and Strengths-Mental Health tool (CANS MH) and patients completed the Children's Depression Inventory (CDI). Interrater reliability was assessed by using a second HEADS-ED rater for 20% of the sample. RESULTS: A total of 313 patients were included, mean age was 14.3 (SD 2.63), and there were 182 females (58.1%). Interrater reliability was 0.785 (P < .001). Correlations were computed for each HEADS-ED category and items from the CANS MH and the CDI. Correlations ranged from r = 0.17, P < .05 to r = 0.89, P < .000. The HEADS-ED also predicted psychiatric consult and admission to inpatient psychiatry (sensitivity of 82% and a specificity of 87%; area under the receiver operator characteristic curve of 0.82, P < .01). CONCLUSIONS: The results provide evidence to support the psychometric properties of the HEADS-ED. The study shows promising results for use in ED decision-making for pediatric patients with mental health concerns. PMID- 22826565 TI - Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. AB - The interactions between the bone marrow (BM) microenvironment and acute myeloid leukemia (AML) is known to promote survival of AML cells. In this study, we used reverse phase-protein array (RPPA) technology to measure changes in multiple proteins induced by stroma in leukemic cells. We then investigated the potential of an mTOR kinase inhibitor, PP242, to disrupt leukemia/stroma interactions, and examined the effects of PP242 in vivo using a mouse model. Using RPPA, we confirmed that multiple survival signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), were up-regulated in primary AML cells cocultured with stroma. PP242 effectively induced apoptosis in primary samples cultured with or without stroma. Mechanistically, PP242 attenuated the activities of mTORC1 and mTORC2, sequentially inhibited phosphorylated AKT, S6K, and 4EBP1, and concurrently suppressed chemokine receptor CXCR4 expression in primary leukemic cells and in stromal cells cultured alone or cocultured with leukemic cells. In the in vivo leukemia mouse model, PP242 inhibited mTOR signaling in leukemic cells and demonstrated a greater antileukemia effect than rapamycin. Our findings indicate that disrupting mTOR/AKT signaling with a selective mTOR kinase inhibitor can effectively target leukemic cells within the BM microenvironment. PMID- 22826568 TI - Early growth of infantile hemangiomas: what parents' photographs tell us. AB - BACKGROUND AND OBJECTIVES: Infantile hemangiomas (IH) are recognized as growing rapidly during the first months of life, but details of early growth before 3 months of age have not been well-characterized. Our goal was to study early IH growth by using parental photographs of infant children with facial IHs to better understand early hemangioma growth, with the aim of improving guidance for physicians and parents of infants with high-risk IH. METHODS: Serial images of 30 infants showing IH at intervals of 1 to 2 weeks up to 6 months were analyzed for characteristics of color, thickness, and distortion of anatomic landmarks. The presence or absence of an IH precursor at birth was noted. Mean scores per age interval were compiled. Results were analyzed by using signed rank test. An assessment of "optimal time for referral" was made. RESULTS: IH growth was nonlinear; most rapid growth occurred between 5.5 and 7.5 weeks of age. The mean "optimal age for referral" was 4 weeks of age. Hemangioma precursors were present at birth in 65% of patients. CONCLUSIONS: The most rapid hemangioma growth occurs before 8 weeks of age, much earlier than previously appreciated. Specialty evaluation and initiation of treatment, however, typically occur after the age of most rapid growth. Our findings suggest a need for a paradigm shift in the timing of referral and initiation of treatment of high-risk IH so that therapy can be initiated before or early in the course of most rapid growth, rather than after it is already completed. PMID- 22826569 TI - Food insecurity and obesogenic maternal infant feeding styles and practices in low-income families. AB - OBJECTIVES: We explored the relationship between household food insecurity and maternal feeding styles, infant feeding practices, and perceptions and attitudes about infant weight in low-income mothers. METHODS: Mothers participating in the Special Supplemental Food Program for Women, Infants, and Children with infants aged between 2 weeks and 6 months were interviewed. By using regression analyses, the following relationships were examined between food insecurity and: (1) controlling feeding styles (restrictive and pressuring); (2) infant feeding practices, including breastfeeding, juice consumption, and adding cereal to the bottle; and (3) perceptions and attitudes about infant weight. Path analysis was used to determine if perceptions and attitudes about infant weight mediated the relationships between food insecurity and controlling feeding styles. RESULTS: The sample included 201 mother-infant pairs, with 35% reporting household food insecurity. Food-insecure mothers were more likely to exhibit restrictive (B [SE]: 0.18 [0.08]; 95% confidence interval [CI]: 0.02-0.34) and pressuring (B [SE]: 0.11 [0.06]; 95% CI: 0.001-0.22) feeding styles compared with food-secure mothers. No associations were found with feeding practices. Concern for their infant becoming overweight in the future was associated with food insecurity (adjusted odds ratio: 2.11 [95% CI: 1.02-4.38]). This concern mediated the relationship between food insecurity and both restrictive (P = .009) and pressuring (P = .01) feeding styles. CONCLUSIONS: Increased concern about future overweight and controlling feeding styles represent potential mechanisms by which food insecurity could be related to obesity. Obesity prevention should aim to decrease food insecurity and to reduce controlling feeding styles in families who remain food insecure. PMID- 22826570 TI - The experience of families with children with trisomy 13 and 18 in social networks. AB - BACKGROUND: Children with trisomy 13 and trisomy 18 (T13-18) have low survival rates and survivors have significant disabilities. For these reasons, interventions are generally not recommended by providers. After a diagnosis, parents may turn to support groups for additional information. METHODS: We surveyed parents of children with T13-18 who belong to support groups to describe their experiences and perspectives. RESULTS: A total of 503 invitations to participate were sent and 332 questionnaires were completed (87% response rate based on site visits, 67% on invitations sent) by parents about 272 children. Parents reported being told that their child was incompatible with life (87%), would live a life of suffering (57%), would be a vegetable (50%), or would ruin their family (23%). They were also told by some providers that their child might have a short meaningful life (60%), however. Thirty percent of parents requested "full" intervention as a plan of treatment. Seventy-nine of these children with full T13-18 are still living, with a median age of 4 years. Half reported that taking care of a disabled child is/was harder than they expected. Despite their severe disabilities, 97% of parents described their child as a happy child. Parents reported these children enriched their family and their couple irrespective of the length of their lives. CONCLUSIONS: Parents who engage with parental support groups may discover an alternative positive description about children with T13-18. Disagreements about interventions may be the result of different interpretations between families and providers about the experiences of disabled children and their quality of life. PMID- 22826571 TI - Overly aggressive new guidelines for lipid screening in children: evidence of a broken process. PMID- 22826572 TI - The prevalence and course of idiopathic toe-walking in 5-year-old children. AB - BACKGROUND: Children walking on their toes instead of with a typical gait, without evidence of an underlying medical condition, are defined as idiopathic toe-walkers. The prevalence of idiopathic toe-walking is unknown. METHODS: A cross-sectional prevalence study of 5.5-year-old children (n = 1436) living in Blekinge County, Sweden, was performed at the regular 5.5-year visit to the local child welfare center. Children were assessed for a history of toe-walking or whether they still walked on their toes. Additionally, all 5.5-year-old children (n = 35) admitted to the clinic for children with special needs in the county were assessed. RESULTS: Of the 1436 children in the cohort (750 boys, 686 girls), 30 children (2.1%, 20 boys and 10 girls) still walked on their toes at age 5.5 years and were considered as active toe-walkers. Forty children (2.8%, 22 boys and 18 girls) had previously walked on their toes but had stopped before the 5.5 year visit and were considered as inactive toe-walkers. At age 5.5 years, the total prevalence of toe-walking was 70 (4.9%) of 1436. For children with a neuropsychiatric diagnosis or developmental delay, the total prevalence for active or inactive toe-walking was 7 (41.2%) of 17. CONCLUSIONS: This study establishes the prevalence and- early spontaneous course of idiopathic toe walking in 5.5-year-old children. At this age, more than half of the children have spontaneously ceased to walk on their toes. The study confirms earlier findings that toe-walking has a high prevalence among children with a cognitive disorder. PMID- 22826573 TI - Guidelines for lipid screening in children and adolescents: bringing evidence to the debate. PMID- 22826574 TI - Pediatric versus adult drug trials for conditions with high pediatric disease burden. AB - BACKGROUND AND OBJECTIVE: Optimal treatment decisions in children require sufficient evidence on the safety and efficacy of pharmaceuticals in pediatric patients. However, there is concern that not enough trials are conducted in children and that pediatric trials differ from those performed in adults. Our objective was to measure the prevalence of pediatric studies among clinical drug trials and compare trial characteristics and quality indicators between pediatric and adult drug trials. METHODS: For conditions representing a high burden of pediatric disease, we identified all drug trials registered in ClinicalTrials.gov with start dates between 2006 and 2011 and tracked the resulting publications. We measured the proportion of pediatric trials and subjects for each condition and compared pediatric and adult trial characteristics and quality indicators. RESULTS: For the conditions selected, 59.9% of the disease burden was attributable to children, but only 12.0% (292/2440) of trials were pediatric (P < .001). Among pediatric trials, 58.6% were conducted without industry funding compared with 35.0% of adult trials (P < .001). Fewer pediatric compared with adult randomized trials examined safety outcomes (10.1% vs 16.9%, P = .008). Pediatric randomized trials were slightly more likely to be appropriately registered before study start (46.9% vs 39.3%, P = .04) and had a modestly higher probability of publication in the examined time frame (32.8% vs 23.2%, P = .04). CONCLUSIONS: There is substantial discrepancy between pediatric burden of disease and the amount of clinical trial research devoted to pediatric populations. This may be related in part to trial funding, with pediatric trials relying primarily on government and nonprofit organizations. PMID- 22826575 TI - Prevalence and correlates of low fundamental movement skill competency in children. AB - OBJECTIVE: To describe the demographic and health-related characteristics of school-aged children with low competency in fundamental movement skills (FMS). METHODS: Cross-sectional representative school-based survey of Australian elementary and high school students (n = 6917) conducted in 2010. Trained field staff measured students' height, weight, and assessed FMS and cardiorespiratory endurance (fitness). Information on students' demographics and physical activity was collected by questionnaire. RESULTS: Overall, the prevalence of students with low motor skill competency was high. Girls with low socioeconomic status (SES) were twice as likely to be less competent in locomotor skills compared with high SES peers. Among boys, there was a strong association between low competency in FMS and the likelihood of being from non-English-speaking cultural backgrounds. There was a clear and consistent association between low competency in FMS and inadequate cardiorespiratory fitness. For boys, there was a clear association between low competency in object-control skills and not meeting physical activity recommendations. Conversely, the odds of being inactive were double among girls who had low competency in locomotor skills. CONCLUSIONS: Low competency in FMS is strongly associated with lower cardiorespiratory fitness and physical activity levels in children and adolescents. The characteristics of students with competency in FMS differ by gender and skills types and show that interventions need to target girls from low SES backgrounds and boys from non-English-speaking cultural backgrounds. The high prevalence of low competency in FMS among Grade 4 students indicates that FMS interventions need to start during the preschool and early school years. PMID- 22826576 TI - Misclassification of newborns due to systematic error in plotting birth weight percentile values. AB - OBJECTIVES: Higher than expected small for gestational age (SGA) rates and lower than expected large for gestational age (LGA) rates have been observed. A possible explanation is a leftward shift of percentile curves for birth weight due to a systematic error in plotting birth weight values in charts (ie, plotting weekly mean birth weight data at the beginning of the weeks). Our objectives were to assess how common this plotting error is and to analyze the effect of this error on SGA and LGA classification based on data from the German perinatal survey. METHODS: First, a systematic literature search for birth weight charts was performed, and the charts were analyzed for the plotting error. Second, percentile values (10th, 50th, and 90th) for 25 to 42 completed weeks of gestation were calculated from the data of 1181200 male singleton newborns (German perinatal survey, 1995-2000). Birth weight percentile curves were calculated with and without the plotting error, and the resulting SGA and LGA rates were analyzed. RESULTS: Fourteen of the 16 identified publications contained the systematic error in plotting. Using our calculated percentile curves, a leftward shift caused by the plotting error led to an SGA rate of 12.5% and an LGA rate of 7.7%; ~5% of newborns were misclassified. CONCLUSIONS: Percentile charts should be examined for the described systematic error and, if necessary, corrected. PMID- 22826578 TI - Global Health. Paying the poor. PMID- 22826577 TI - Living with spina bifida: a historical perspective. PMID- 22826579 TI - Tensions between drug use policies and infection control. PMID- 22826580 TI - Monkey business: reflections on testosterone. PMID- 22826581 TI - A passion for accuracy. PMID- 22826582 TI - Local government must take up fight against obesity after government fails to do so, says expert. PMID- 22826583 TI - Pertussis cases rise 10-fold among older children and adults in England and Wales. PMID- 22826584 TI - Vaccination for voluntary and private sector workers should be free. PMID- 22826585 TI - Management of difficult and severe eczema in childhood. PMID- 22826586 TI - Approve bevacizumab for use in eye disease in cash strapped times. PMID- 22826587 TI - Sale of baby milk is an expensive monopoly in Greece. PMID- 22826588 TI - Twitter in emergencies. Follow our roadmap. PMID- 22826589 TI - Classifying mental and neurological conditions together: authors' reply to letters. PMID- 22826590 TI - Natural family planning is effective and culturally acceptable. PMID- 22826591 TI - Antenatal checks should look for heart disease in at risk women. PMID- 22826592 TI - Time to open up the finances of medical journals. PMID- 22826593 TI - Income from reprints creates a conflict of interests. PMID- 22826594 TI - Not useful in modern healthcare. PMID- 22826595 TI - But is community care any cheaper? PMID- 22826596 TI - Let's be clear about capitalism. PMID- 22826597 TI - QFracture is better than FRAX tool in assessing risk of hip fracture. PMID- 22826598 TI - The reliable clinical examination. PMID- 22826599 TI - Gene therapy to be authorised for first time in EU. PMID- 22826600 TI - Several US states resist expansion of healthcare coverage to poor people. PMID- 22826601 TI - US women without health insurance are more likely to have late stage cervical cancer. PMID- 22826602 TI - Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. AB - Patients with small fibre neuropathy typically manifest pain in distal extremities and severe autonomic dysfunction. However, occasionally patients present with minimal autonomic symptoms. The basis for this phenotypic difference is not understood. Sodium channel Na(v)1.7, encoded by the SCN9A gene, is preferentially expressed in the peripheral nervous system within sensory dorsal root ganglion and sympathetic ganglion neurons and their small diameter peripheral axons. We recently reported missense substitutions in SCN9A that encode functional Na(v)1.7 variants in 28% of patients with biopsy-confirmed small fibre neuropathy. Two patients with biopsy-confirmed small fibre neuropathy manifested minimal autonomic dysfunction unlike the other six patients in this series, and both of these patients carry the Na(v)1.7/R185H variant, presenting the opportunity to compare variants associated with extreme ends of a spectrum from minimal to severe autonomic dysfunction. Herein, we show by voltage-clamp that R185H variant channels enhance resurgent currents within dorsal root ganglion neurons and show by current-clamp that R185H renders dorsal root ganglion neurons hyperexcitable. We also show that in contrast, R185H variant channels do not produce detectable changes when studied by voltage-clamp within sympathetic neurons of the superior cervical ganglion, and have no effect on the excitability of these cells. As a comparator, we studied the Na(v)1.7 variant I739V, identified in three patients with small fibre neuropathy characterized by severe autonomic dysfunction as well as neuropathic pain, and show that this variant impairs channel slow inactivation within both dorsal root ganglion and superior cervical ganglion neurons, and renders dorsal root ganglion neurons hyperexcitable and superior cervical ganglion neurons hypoexcitable. Thus, we show that R185H, from patients with minimal autonomic dysfunction, does not produce detectable changes in the properties of sympathetic ganglion neurons, while I739V, from patients with severe autonomic dysfunction, has a profound effect on excitability of sympathetic ganglion neurons. PMID- 22826603 TI - Comparative molecular field analysis to derive pharmacophore maps for disposition parameters of intravenous anaesthetic agents. AB - BACKGROUND: The present study examines the molecular basis of the disposition kinetics for i.v. hypnotic agents using comparative molecular field analysis (CoMFA). METHODS: The systemic clearance (Cl(s) litre min(-1)) and apparent volume of distribution at steady state (Vd(ss) litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition. Molecular alignment was achieved by field-fit minimization with the lead structure for all models eltanolone. The resulting pharmacophore maps were also compared with the pharmacophores for cardiovascular depression (expressed in terms of the drug concentration in 50% patients, associated with a 20% decrease in mean arterial pressure during infusion anaesthesia in the absence of other adjuvant drugs or noxious stimulation), which were taken from the literature. RESULTS: The CoMFA model for Cl was based on two latent variables, explained 95.2% of the variance in observed activities, and showed good intrinsic predictability (cross-validated q(2) 0.663). The model for Vd(ss) was also based on two latent variables: r(2) 0.986 and q(2) 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions (r= 0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cl(s) 1.9:1; Vd(ss) 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 (P<0.05) and 0.407 (ns) for Cl(s) (for electrostatic and steric models) and 0.225 and -0.448 for Vd(ss) (both ns). CONCLUSIONS: Comparison of CoMFA models for drug disposition show only small elements of commonality, suggesting different molecular features may be responsible are two properties. There was better similarity for both disposition pharmacophores with the pharmacophores for cardiovascular depression. PMID- 22826604 TI - Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway. AB - Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of beta-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes. PMID- 22826605 TI - PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis. AB - The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease. PMID- 22826606 TI - Changing the tumor microenvironment: new strategies for immunotherapy. AB - Solid tumors are composed of malignant cells surrounded by a tumor-conditioned stroma that contains extracellular matrix and a variety of nonmalignant populations, including myeloid cells, lymphocytes, fibroblasts, and endothelial cells. These stromal elements form a local immunoregulatory network that must be overcome to achieve eradication of established tumors by immunotherapy. On March 21-22, 2012, a symposium was held in Pamplona, Spain, to share the recent advances regarding the molecules and cells that create and sustain this immune hostile tumor microenvironment. Excellent targets for immunotherapeutic intervention were identified, and a number of therapeutic strategies under translation from mouse to human were presented. PMID- 22826608 TI - Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are important mediators of reflux-induced cell signalling in esophageal cells. AB - Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-kappaB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett's esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF kappaB activity. DCA-induced DNA damage was independent of NF-kappaB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF kappaB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-kappaB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-kappaB activity (and possibly acid and DCA-induced NF-kappaB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-kappaB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-kappaB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus. PMID- 22826610 TI - Making the Patient-Consumer in Margaret Thatcher's Britain. PMID- 22826609 TI - Mapping the human cortical surface by combining quantitative T(1) with retinotopy. AB - We combined quantitative relaxation rate (R1= 1/T1) mapping-to measure local myelination-with fMRI-based retinotopy. Gray-white and pial surfaces were reconstructed and used to sample R1 at different cortical depths. Like myelination, R1 decreased from deeper to superficial layers. R1 decreased passing from V1 and MT, to immediately surrounding areas, then to the angular gyrus. High R1 was correlated across the cortex with convex local curvature so the data was first "de-curved". By overlaying R1 and retinotopic maps, we found that many visual area borders were associated with significant R1 increases including V1, V3A, MT, V6, V6A, V8/VO1, FST, and VIP. Surprisingly, retinotopic MT occupied only the posterior portion of an oval-shaped lateral occipital R1 maximum. R1 maps were reproducible within individuals and comparable between subjects without intensity normalization, enabling multi-center studies of development, aging, and disease progression, and structure/function mapping in other modalities. PMID- 22826611 TI - Evolution of continent ileostomy. AB - Continent ileostomy can be defined as a surgical procedure that facilitates planned intermittent evacuation of a bowel reservoir through an ileostomy. It was devised by Nils Kock in 1969. Subsequently, continent ileostomy (or Kock pouch) became a viable alternative in the management of patients who had traditionally required an end ileostomy. Kock pouch appeared to provide substantial physical and psychosocial benefits over a conventional ileostomy. The procedure became popular until ileal pouch anal anastomosis (IPAA) was introduced in 1980. Despite its benefits, continent ileostomy had many short term complications including intubation problems, ileus, anastomotic leaks, peritonitis and valve problems. Operative mortalities have also been reported in the literature. Most of these problems have been eliminated with increasing experience; however, valve-related problems remain as an "Achilles' heel" of the technique. Many modifications have been introduced to prevent this problem. Some patients have had their pouch removed because of complications mainly related to valve dysfunction. Although revision rates can be high, most of the patients who retain their reservoirs are satisfied with regard to their health status and quality of life. Today, this procedure is still appropriate for selected patients for whom pouch surgery is not possible or for patients who have failed IPAA. Both the patient and their physician must be highly motivated to accept the risk of failure and the subsequent need for revisional operations. PMID- 22826612 TI - Natural history of Barrett's esophagus. AB - The natural history of Barrett's esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett's epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett's to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett's is a subject of ongoing research, including the Barrett's Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett's and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE. PMID- 22826613 TI - Multicausality in fatty liver disease: is there a rationale to distinguish between alcoholic and non-alcoholic origin? AB - Apart from alcohol, there are other factors that may induce complications, which resemble alcohol-related liver disorders. In particular, obesity has been brought into focus as a risk factor for fatty liver disease. The term "non-alcoholic" fatty liver disease is commonly used to distinguish between obesity-related and alcohol-related hepatic steatosis. This review uses the epidemiological perspective to critically assess whether it is necessary and useful to differentiate between alcoholic and "non-alcoholic" fatty liver disease. The MEDLINE database was searched using the PubMed search engine, and a review of reference lists from original research and review articles was conducted. The concept to distinguish between alcoholic and "non-alcoholic" fatty liver disease is mainly based on specific pathomechanisms. This concept has, however, several limitations including the common overlap between alcohol misuse and obesity related metabolic disorders and the non-consideration of additional causal factors. Both entities share similar histopathological patterns. Studies demonstrating differences in clinical presentation and outcome are often biased by selection. Risk factor reduction is the main principle of prevention and treatment of both disease forms. In conclusion, alcoholic and "non-alcoholic" fatty liver diseases are one and the same disease caused by different risk factors. A shift from artificial categories to a more general approach to fatty liver disease as a multicausal disorder may optimize preventive strategies and help clinicians more effectively treat patients at the individual level. PMID- 22826614 TI - Significance of regenerating islet-derived type IV gene expression in gastroenterological cancers. AB - The regenerating islet-derived members (Reg), a group of small secretory proteins, which are involved in cell proliferation or differentiation in digestive organs, are upregulated in several gastrointestinal cancers, functioning as trophic or antiapoptotic factors. Regenerating islet-derived type IV (RegIV), a member of the Reg gene family, has been reported to be overexpressed in gastroenterological cancers. RegIV overexpression in tumor cells has been associated with carcinogenesis, cell growth, survival and resistance to apoptosis. Cancer tissue expressing RegIV is generally associated with more malignant characteristics than that without such expression, and RegIV is considered a novel prognostic factor as well as diagnostic marker in some gastroenterological cancers. We previously investigated the expression levels of RegIV mRNA of 202 surgical colorectal cancer specimens with quantitative real time reverse-transcriptase polymerase chain reaction and reported that a higher level of RegIV gene expression was a significant independent predictor of colorectal cancer. The biologic functions of RegIV protein in cancer tissue, associated with carcinogenesis, anti-apoptosis and invasiveness, are being elucidated by molecular investigations using transfection techniques or neutralizing antibodies of RegIV, and the feasibility of antibody therapy targeting RegIV is being assessed. These studies may lead to novel therapeutic strategies for gastroenterological cancers expressing RegIV. This review article summarizes the current information related to biological functions as well as clinical importance of RegIV gene to clarify the significance of RegIV expression in gastroenterological cancers. PMID- 22826615 TI - Hepato-biliary profile of potential candidate liver progenitor cells from healthy rat liver. AB - AIM: To evaluate the presence of progenitor cells in healthy adult rat liver displaying the equivalent advanced hepatogenic profile as that obtained in human. METHODS: Rat fibroblastic-like liver derived cells (rFLDC) were obtained from collagenase-isolated liver cell suspensions and characterized and their phenotype profile determined using flow cytometry, immunocytochemistry, reverse transcription polymerase chain reaction and functional assays. RESULTS: rFLDC exhibit fibroblastoid morphology, express mesenchymal (CD73, CD90, vimentin, alpha-smooth muscle actin), hepatocyte (UGT1A1, CK8) and biliary (CK19) markers. Moreover, these cells are able to store glycogen, and have glucose 6 phosphatase activity, but not UGT1A1 activity. Under the hepatogenic differentiation protocol, rFLDC display an up-regulation of hepatocyte markers expression (albumin, tryptophan 2,3-dioxygenase, G6Pase) correlated to a down-regulation of the expression of the biliary marker CK19. CONCLUSION: Advanced hepatic features observed in human liver progenitor cells could not be demonstrated in rFLDC. However, we demonstrated the presence of an original rodent hepato-biliary cell type. PMID- 22826616 TI - Edaravone inhibits apoptosis caused by ischemia/reperfusion injury in a porcine hepatectomy model. AB - AIM: To investigate the effect of E3-methyl-1-phenyl-2-pyrazolin-5-one (Edr) on hepatic ischemia-reperfusion (I/R) injury and liver regeneration in a porcine hepatectomy model. METHODS: One hour ischemia was induced by occluding the vessels and the bile duct of the right and median lobes. A 40% left hepatectomy was performed after reperfusion. Six animals received Edr (3 mg/kg per hour) intravenously and six control animals received saline just before reperfusion. Remnant liver volume, hemodynamics, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase and lactic acid, were compared between the groups. The expression of transforming growth factor-beta (TGF-beta1) and toll-like receptor (TRL) mRNA in hepatic tissues was examined using reverse transcription polymerase chain reaction. Apoptosis was demonstrated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. RESULTS: Serum AST (P = 0.029), and toll like receptor 4 level (P = 0.043) were significantly lower after 3 h in animals receiving Edr. In addition, TUNEL staining in Edr-treated pigs showed significantly fewer hepatocytes undergoing apoptosis compared with control pigs. After 1 mo, all factors were non significantly different between the two groups. CONCLUSION: Edr is considered to reduce hepatic injury in the early stage of I/R injury in a porcine model. PMID- 22826617 TI - Polo-like kinase 1, a new therapeutic target in hepatocellular carcinoma. AB - AIM: To investigate the role of polo-like kinase 1 (PLK1) as a therapeutic target for hepatocellular carcinoma (HCC). METHODS: PLK1 gene expression was evaluated in HCC tissue and HCC cell lines. Gene knockdown with short-interfering RNA (siRNA) was used to study PLK1 gene and protein expression using real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, and cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2(4-sulfophenyl)-2H-tetrazolium (MTS) and bromodeoxyuridine (BrdU) assays. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and caspase-inhibition assay. Huh-7 cells were transplanted into nude mice and co-cultured with PLK1 siRNA or control siRNA, and tumor progression was compared with controls. RESULTS: RT-PCR showed that PLK1 was overexpressed 12-fold in tumor samples compared with controls, and also was overexpressed in Huh-7 cells. siRNA against PLK1 showed a reduction in PLK1 gene and protein expression of up to 96% in Huh-7 cells, and a reduction in cell proliferation by 68% and 92% in MTS and BrdU cell proliferation assays, respectively. There was a 3-fold increase in apoptosis events, and TUNEL staining and caspase-3 assays suggested that this was caspase-independent. The pan-caspase inhibitor Z-VAD-FMK was unable to rescue the apoptotic cells. Immnofluorescence co-localized endonuclease-G to fragmented chromosomes, implicating it in apoptosis. Huh-7 cells transplanted subcutaneously into nude mice showed tumor regression in siPLK1-treated mice, but not in controls. CONCLUSION: Knockdown of PLK1 overexpression in HCC was shown to be a potential therapeutic target, leading to apoptosis through the endonuclease-G pathway. PMID- 22826618 TI - Zinc finger protein A20 protects rats against chronic liver allograft dysfunction. AB - AIM: To investigate the effect of zinc finger protein A20 on chronic liver allograft dysfunction in rats. METHODS: Allogeneic liver transplantation from DA rats to Lewis rats was performed. Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.) mediated gene transfer administered intravenously every 10 d starting from POD 10. The recipient rats were injected with physiological saline, rAdEasy-A20 (1 * 10(9) pfu/30 g weight) or rAdEasy (1 * 10(9) pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10. Liver tissue samples were harvested on POD 30 and POD 60. RESULTS: Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis. A20 overexpression ameliorated the effects on liver function, attenuated liver allograft fibrosis and prolonged the survival of the recipient rats. Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF) beta1, interleukin-1beta, caspase-8, CD40, CD40L, intercellular adhesion molecule 1, vascular cell adhesion molecule-1 and E-selectin. A20 treatment suppressed liver cell apoptosis and inhibited nuclear factor-kappaB activation of Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF-beta1 in HSCs. CONCLUSION: A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs, LSECs and HSCs. PMID- 22826619 TI - Quality audit of colonoscopy reports amongst patients screened or surveilled for colorectal neoplasia. AB - AIM: To complete a quality audit using recently published criteria from the Quality Assurance Task Group of the National Colorectal Cancer Roundtable. METHODS: Consecutive colonoscopy reports of patients at average/high risk screening, or with a prior colorectal neoplasia (CRN) by endoscopists who perform 11 000 procedures yearly, using a commercial computerized endoscopic report generator. A separate institutional database providing pathological results. Required documentation included patient demographics, history, procedure indications, technical descriptions, colonoscopy findings, interventions, unplanned events, follow-up plans, and pathology results. Reports abstraction employed a standardized glossary with 10% independent data validation. Sample size calculations determined the number of reports needed. RESULTS: Two hundreds and fifty patients (63.2 +/- 10.5 years, female: 42.8%, average risk: 38.5%, personal/family history of CRN: 43.3%/20.2%) were scoped in June 2009 by 8 gastroenterologists and 3 surgeons (mean practice: 17.1 +/- 8.5 years). Procedural indication and informed consent were always documented. 14% provided a previous colonoscopy date (past polyp removal information in 25%, but insufficient in most to determine surveillance intervals appropriateness). Most procedural indicators were recorded (exam date: 98.4%, medications: 99.2%, difficulty level: 98.8%, prep quality: 99.6%). All reports noted extent of visualization (cecum: 94.4%, with landmarks noted in 78.8% - photodocumentation: 67.2%). No procedural times were recorded. One hundred and eleven had polyps (44.4%) with anatomic location noted in 99.1%, size in 65.8%, morphology in 62.2%; removal was by cold biopsy in 25.2% (cold snare: 18%, snare cautery: 31.5%, unrecorded: 20.7%), 84.7% were retrieved. Adenomas were noted in 24.8% (advanced adenomas: 7.6%, cancer: 0.4%) in this population with varying previous colonic investigations. CONCLUSION: This audit reveals lacking reported items, justifying additional research to optimize quality of reporting. PMID- 22826620 TI - Natural orifice transluminal endoscopic surgery vs laparoscopic ovariectomy: complications and inflammatory response. AB - AIM: To compare natural orifice transluminal endoscopic surgery (NOTES) vs standard laparoscopic ovariectomy in mini pigs with respect to technical aspects, complications and parameters of systemic inflammatory response. METHODS: This was a randomized, experimental, survival study. Ten female mini pigs underwent NOTES transgastric ovariectomy (NOTES group) and ten female mini pigs underwent laparoscopic ovariectomy (LAP group). A "percutaneous endoscopic gastrostomy" approach with guidewire and sphincterotome was used for gastrotomy creation. The ovary was resected using standard biopsy forceps and a snare. The access site was closed using a "KING" closure with a single endoloop and several clips. In the laparoscopic group, a three-port laparoscopy and an ovariectomy were performed with the use of standard laparoscopic devices. C-reactive protein (CRP), white blood count and interleukin (IL)-6 plasma levels were used as indicators of systemic inflammatory response. All animals were euthanized 28 d after surgery. RESULTS: All animals survived without complications. The mean procedure time was 41.3 min +/- 17.6 min (NOTES group) and 25.7 min +/- 5.25 min (LAP group, P < 0.02). Postmortem examinations demonstrated that 50% and 70% of animals were free of any complications in the NOTES and LAP groups, respectively. The remaining animals developed minor complications (adhesions) in a comparable frequency between the two groups. In the NOTES group, one animal developed a small intramural gastric abscess close to the gastrotomy site. A minor serous exudate that was present in 50% and 40% of the animals in the NOTES and laparoscopy groups, respectively, was not considered a complication. In both groups CRP levels increased significantly on the 2nd and 7th postoperative days (POD) and returned to normal after 28 d. On POD 2, an increase of CRP level was significantly higher in the NOTES group compared to the LAP group. Values of IL-6 did not differ from baseline values in either of the groups postoperatively. Interestingly, the platelet count decreased significantly on POD 2, but returned close to baseline values on POD 7 and PODs 28-30. CONCLUSION: Both NOTES and laparoscopic ovariectomies had a similar frequency of minor complications. However, the NOTES technique produced an increased systemic inflammatory response on POD 2. PMID- 22826621 TI - Inhibitory effects of carbon dioxide insufflation on pneumoperitoneum and bowel distension after percutaneous endoscopic gastrostomy. AB - AIM: To evaluate the inhibitory effects of carbon dioxide (CO(2)) insufflation on pneumoperitoneum and bowel distension after percutaneous endoscopic gastrostomy (PEG). METHODS: A total of 73 consecutive patients who were undergoing PEG were enrolled in our study. After eliminating 13 patients who fitted our exclusion criteria, 60 patients were randomly assigned to either CO(2) (30 patients) or air insufflation (30 patients) groups. PEG was performed by pull-through technique after three-point fixation of the gastric wall to the abdominal wall using a gastropexy device. Arterial blood gas analysis was performed immediately before and after the procedure. Abdominal X-ray was performed at 10 min and at 24 h after PEG to assess the extent of bowel distension. Abdominal computed tomography was performed at 24 h after the procedure to detect the presence of pneumoperitoneum. The outcomes of PEG for 7 d post-procedure were also investigated. RESULTS: Among 30 patients each for the air and the CO(2) groups, PEG could not be conducted in 2 patients of the CO(2) group, thus they were excluded. Analyses of the remaining 58 patients showed that the patients' backgrounds were not significantly different between the two groups. The elevation values of arterial partial pressure of CO(2) in the air group and the CO(2) group were 2.67 mmHg and 3.32 mmHg, respectively (P = 0.408). The evaluation of bowel distension on abdominal X ray revealed a significant decrease of small bowel distension in the CO(2) group compared to the air group (P < 0.001) at 10 min and 24 h after PEG, whereas there was no significant difference in large bowel distension between the two groups. Pneumoperitoneum was observed only in the air group but not in the CO(2) group (P = 0.003). There were no obvious differences in the laboratory data and clinical outcomes after PEG between the two groups. CONCLUSION: There was no adverse event associated with CO(2) insufflation. CO(2) insufflation is considered to be safer and more comfortable for PEG patients because of the lower incidence of pneumoperitoneum and less distension of the small bowel. PMID- 22826622 TI - Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability. AB - AIM: To investigate endoscopic and clinicopathologic characteristics of early gastric cancer (EGC) according to microsatellite instability phenotype. METHODS: Data were retrospectively collected from a single tertiary referral center. Of 981 EGC patients surgically treated between December 2003 and October 2007, 73 consecutive EGC patients with two or more microsatellite instability (MSI) mutation [high MSI (MSI-H)] and 146 consecutive EGC patients with one or no MSI mutation (non-MSI-H) were selected. The endoscopic and clinicopathologic features were compared between the MSI-H and non-MSI-H EGC groups. RESULTS: In terms of endoscopic characteristics, MSI-H EGCs more frequently presented with elevated pattern (OR 4.38, 95% CI: 2.40-8.01, P < 0.001), moderate-to-severe atrophy in the surrounding mucosa (OR 1.91, 95% CI: 1.05-3.47, P = 0.033), antral location (OR 3.99, 95% CI: 2.12-7.52, P < 0.001) and synchronous lesions, compared to non MSI-H EGCs (OR 2.65, 95% CI: 1.16-6.07, P = 0.021). Other significant clinicopathologic characteristics of MSI-H EGC included predominance of female sex (OR 2.77, 95% CI: 1.53-4.99, P < 0.001), older age (> 70 years) (OR 3.30, 95% CI: 1.57-6.92, P = 0.002), better histologic differentiation (OR 2.35, 95% CI: 1.27-4.34, P = 0.007), intestinal type by Lauren classification (OR 2.34, 95% CI: 1.15-4.76, P = 0.019), absence of a signet ring cell component (OR 2.44, 95% CI: 1.02-5.86, P = 0.046), presence of mucinous component (OR 5.06, 95% CI: 1.27 20.17, P = 0.022), moderate-to-severe lymphoid stromal reaction (OR 3.95, 95% CI: 1.59-9.80, P = 0.003), and co-existing underlying adenoma (OR 2.66, 95% CI: 1.43 4.95, P = 0.002). CONCLUSION: MSI-H EGC is associated with unique endoscopic and clinicopathologic characteristics including frequent presentation in protruded type, co-existing underlying adenoma, and synchronous lesions. PMID- 22826623 TI - Weekend and nighttime effect on the prognosis of peptic ulcer bleeding. AB - AIM: To evaluate whether weekend or nighttime admission affects prognosis of peptic ulcer bleeding despite early endoscopy. METHODS: Retrospective data collection from four referral centers, all of which had a formal out-of-hours emergency endoscopy service, even at weekends. A total of 388 patients with bleeding peptic ulcers who were admitted via the emergency room between January 2007 and December 2009 were enrolled. Analyzed parameters included time from patients' arrival until endoscopy, mortality, rebleeding, need for surgery and length of hospital stay. RESULTS: The weekday and weekend admission groups comprised 326 and 62 patients, respectively. There were no significant differences in baseline characteristics between the two groups, except for younger age in the weekend group. Most patients (97%) had undergone early endoscopy, which resulted in a low mortality rate regardless of point of presentation (1.8% overall vs 1.6% on the weekend). The only outcome that was worse in the weekend group was a higher rate of rebleeding (12% vs 21%, P = 0.030). However, multivariate analysis revealed nighttime admission and a high Rockall score (>= 6) as significant independent risk factors for rebleeding, rather than weekend admission. CONCLUSION: Early endoscopy for peptic ulcer bleeding can prevent the weekend effect, and nighttime admission was identified as a novel risk factor for rebleeding, namely the nighttime effect. PMID- 22826624 TI - Microbial profile and antibiotic sensitivity pattern in bile cultures from endoscopic retrograde cholangiography patients. AB - AIM: To identify the frequency of bacterial growth, the most commonly grown bacteria and their antibiotic susceptibility, and risk factors for bacterial colonization in bile collected from patients with different biliary diseases. METHODS: This prospective study was conducted between April 2010 and August 2011. Patients with various biliary disorders were included. Bile was aspirated by placing a single-use, 5F, standard sphincterotome catheter into the bile duct before the injection of contrast agent during endoscopic retrograde cholangiopancreaticography (ERCP). Bile specimens were transported to the microbiology laboratory in blood culture bottles within an anaerobic transport system. Bacteria were cultured and identified according to the standard protocol used in our clinical microbiology laboratory. The susceptibilities of the organisms recovered were identified using antimicrobial disks, chosen according to the initial gram stain of the positive cultures. RESULTS: Ninety-one patients (27% male, mean age 53.7 +/- 17.5 years, range: 17-86 years) were included in the study. The main indication for ERCP was benign biliary disease in 79 patients and malignant disease in 12 patients. The bile culture was positive for bacterial growth in 46 out of 91 (50.5%) patients. The most frequently encountered organisms were Gram-negative bacteria including Escherichia coli (28.2%), Pseudomonas (17.3%) and Stenotrophomonas maltophilia (15.2%). There were no significant differences between patients with malignant and benign disease (58% vs 49%, P = 0.474), patients with acute cholangitis and without acute cholangitis (52.9% vs 50%, P = 0.827), patients who were empirically administered antibiotics before intervention and not administered (51.4% vs 60.7%, P = 0.384), with regard to the bacteriobilia. We observed a large covering spectrum or low resistance to meropenem, amikacin and imipenem. CONCLUSION: We did not find a significant risk factor for bacteriobilia in patients with biliary obstruction. A bile sample for microbiological analysis may become a valuable diagnostic tool as it leads to more accurate selection of antibiotics for the treatment of cholangitis. PMID- 22826625 TI - Gender preference and implications for screening colonoscopy: impact of endoscopy nurses. AB - AIM: To assess the gender preferences, specifically the gender of the nursing staff (endoscopy assistants) and the impact on acceptance for screening colonoscopy (SC). METHODS: Patients or relatives attending the clinics or health care workers working in a tertiary center were invited to participate in this questionnaire study. The questionnaire enquired on the general demographics (1) age, gender, ethnicity, education level, and employment status, previous history of colonoscopy, family or personal history of colonic pathologies, personal and family history of any cancers; (2) subjects were asked if they would go for an SC if they had appropriate indications (age over 50 years, family history of colorectal cancer (CRC), fecal occult blood positive, anemia especially iron deficiency anemia, bleeding per rectum with or without loss of appetite, weight loss and abdominal pain) with and without symptoms attributable to CRC; and (3) preferences for the gender of the endoscopists and assistants and whether they would still undergo SC even if their preferences were not met. RESULTS: Eighty four point seven percent (470/550) completed questionnaire were analysed. More female subjects expressed gender preferences for the endoscopists [overall 70%; female (67.7%) and male (2.3%)] compared to male subjects [overall 62.8%; male (56%) and female (6.8%), P = 0.102]. Similarly, more female subjects expressed gender preferences for the assistants [overall 74.5%; female (73.4%) and male (1.1%)] compared to male subjects [overall 58%, male (49.3%) and female (8.7%), P < 0.001]. Overall, a third would decline an SC, despite having appropriate indications, if their preferences were not met. On univariate analysis, male gender, non-Malay ethnicity (Chinese and others) and previous colonoscopy experience were more likely to undergo an SC, even if their preferences were not met (all P < 0.05). Gender and previous experience [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.00-2.82, P < 0.05] with colonoscopy (OR 4.70, 95% CI 1.41-15.66, P < 0.05) remained significant on multivariate analysis. CONCLUSION: Genders preference for the endoscopy nurses/assistants is more common than for the endoscopist among women and has implications for the success of a screening colonoscopy program. PMID- 22826626 TI - Sedation-associated hiccups in adults undergoing gastrointestinal endoscopy and colonoscopy. AB - AIM: To investigate whether the incidence of hiccups in patients undergoing esophagogastroduodenoscopy (EGD) or same-day bidirectional endoscopy (EGD and colonoscopy; BDE) with sedation is different from those without sedation in terms of quantity, duration and typical onset time. METHODS: Consecutive patients scheduled for elective EGD or same-day BDE at the gastrointestinal endoscopy unit or the health examination center were allocated to two groups: EGD without sedation (Group A) and BDE with sedation (Group B). The use of sedation was based on the patients' request. Anesthesiologists participated in this study by administrating sedative drugs as usual. A single experienced gastroenterologist performed both the EGD and the colonoscopic examinations for all the patients. The incidence, duration and onset time of hiccups were measured in both groups. In addition, the association between clinical variables and hiccups were analyzed. RESULTS: A total of 435 patients were enrolled in the study. The incidences of hiccups in the patients with and without sedation were significantly different (20.5% and 5.1%, respectively). The use of sedation for patients undergoing endoscopy was still significantly associated with an increased risk of hiccups (adjusted odds ratio: 8.79, P < 0.001) after adjustment. The incidence of hiccups in males under sedation was high (67.4%). The sedated patients who received 2 mg midazolam developed hiccups more frequently compared to those receiving 1 mg midazolam (P = 0.0028). The patients with the diagnosis of gastroesophageal reflux disease (GERD) were prone to develop hiccups (P = 0.018). CONCLUSION: Male patients undergoing EGD or BDE with sedation are significantly more likely to suffer from hiccups compared to those without sedation. Midazolam was significantly associated with an increased risk of hiccups. Furthermore, patients with GERD are prone to develop hiccups. PMID- 22826627 TI - Factors predicting survival in patients with proximal gastric carcinoma involving the esophagus. AB - AIM: To investigate the clinicopathologic features which predict surgical overall survival in patients with proximal gastric carcinoma involving the esophagus (PGCE). METHODS: Electronic pathology database established in the Department of Pathology of the Nanjing Drum Tower Hospital was searched for consecutive resection cases of proximal gastric carcinoma over the period from May 2004 through July 2009. Each retrieved pathology report was reviewed and the cases with tumors crossing the gastroesophageal junction line were selected as PGCE. Each tumor was re-staged, following the guidelines on esophageal adenocarcinoma, according to the 7th edition of the American Joint Commission on Cancer Staging Manual. All histology slides were studied along with the pathology report for a retrospective analysis of 13 clinicopathologic features, i.e., age, gender, Helicobacter pylori (H. pylori) infection, surgical modality, Siewert type, tumor Bormann's type, size, differentiation, histology type, surgical margin, lymphovascular and perineural invasion, and pathologic stage in relation to survival after surgical resection. Prognostic factors for overall survival were assessed with uni- and multi-variate analyses. RESULTS: Patients' mean age was 65 years (range: 47-90 years). The male: female ratio was 3.3. The 1-, 3- and 5-year overall survival rates were 87%, 61% and 32%, respectively. By univariate analysis, age, male gender, H. pylori, tumor Bormann's type, size, histology type, surgical modality, positive surgical margin, lymphovascular invasion, and pT stage were not predictive for overall survival; in contrast, perineural invasion (P = 0.003), poor differentiation (P = 0.0003), > 15 total lymph nodes retrieved (P = 0.008), positive lymph nodes (P = 0.001), and distant metastasis (P = 0.005) predicted poor post-operative overall survival. Celiac axis nodal metastasis was associated with significantly worse overall survival (P = 0.007). By multivariate analysis, >= 16 positive nodes (P = 0.018), lymph node ratio > 0.2 (P = 0.003), and overall pathologic stage (P = 0.002) were independent predictors for poor overall survival after resection. CONCLUSION: Patients with PGCE showed worse overall survival in elderly, high nodal burden and advanced pathologic stage. This cancer may be more accurately staged as gastric, than esophageal, cancer. PMID- 22826628 TI - Impact of lymphatic and/or blood vessel invasion in stage II gastric cancer. AB - AIM: To determine the prognostic value of lymphatic and/or blood vessel invasion (LBVI) in patients with stage II gastric cancer. METHODS: From January 2001 to December 2006, 487 patients with histologically confirmed primary gastric adenocarcinoma were diagnosed with stage II gastric cancer according to the new 7th edition American Joint Committee on Cancer stage classification at the Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Shanghai Cancer Center. All patients underwent curative gastrectomy with standard lymph node (LN) dissection. Fifty-one patients who died in the postoperative period, due to various complications or other conditions, were excluded. Clinicopathological findings and clinical outcomes were analyzed. Patients were subdivided into four groups according to the status of LBVI and LN metastases. These four patient groups were characterized with regard to age, sex, tumor site, pT category, tumor grading and surgical procedure (subtotal resection vs total resection), and compared for 5-year overall survival by univariate and multivariate analysis. RESULTS: The study was composed of 320 men and 116 women aged 58.9 +/- 11.5 years (range: 23-88 years). The 5-year overall survival rates were 50.7% and the median survival time was 62 mo. Stage IIa cancer was observed in 334 patients, including 268 T3N0, 63 T2N1, and three T1N2, and stage IIb was observed in 102 patients, including 49 patients T3N1, 51 T2N2, one T1N3, and one T4aN0. The incidence of LBVI was 28.0% in stage II gastric cancer with 19.0% (51/269) and 42.5% (71/167) in LN-negative and LN-positive patients, respectively. In 218 patients (50.0%), there was neither a histopathologically detectable LBVI nor LN metastases (LBVI(-)/LN(-), group I); in 51 patients (11.7%), LBVI with no evidence of LN metastases was detected (LBVI(+)/LN(-), group II). In 167 patients (38.3%), LN metastases were found. Among those patients, LBVI was not determined in 96 patients (22.0%) (LBVI(-)/LN(+), group III), and was determined in 71 patients (16.3%) (LBVI(+)/LN(+), group IV). Correlation analysis showed that N category and the number of positive LNs were significantly associated with the presence of LBVI (P < 0.001). The overall 5 year survival was significantly longer in LN-negative patients compared with LN positive patients (56.1% vs 42.3%, P = 0.015). There was a significant difference in the overall 5-year survival between LBVI-positive and LBVI-negative tumors (39.6% vs 54.8%, P = 0.006). Overall 5-year survival rates in each group were 58.8% (I), 45.8% (II), 45.7% (III) and 36.9% (IV), and there was a significant difference in overall survival between the four groups (P = 0.009). Multivariate analysis in stage II gastric cancer patients revealed that LBVI independently affected patient prognosis in LN-negative patients (P = 0.018) but not in LN positive patients (P = 0.508). CONCLUSION: In LN-negative stage II gastric cancer patients, LBVI is an additional independent prognostic marker, and may provide useful information to identify patients with poorer prognosis. PMID- 22826629 TI - Effect of interferon-gamma and tumor necrosis factor-alpha on hepatitis B virus following lamivudine treatment. AB - AIM: To evaluate anti-hepatitis B virus (HBV) activity and cytotoxicity of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) following lamivudine treatment of HepG2.2.15 cells. METHODS: HepG2.2.15 cells were treated with 2 MUmol/L lamivudine for 16 d (lamivudine group), cultured for 10 d, followed by 5 ng/mL TNF-alpha and 1000 U/mL IFN-gamma for 6 d (cytokine group), or treated with 2 MUmol/L lamivudine for 10 d followed by 5 ng/mL TNF alpha and 1000 U/mL IFN-gamma for 6 d (sequential group), or cultured without additions for 16 d (control group). Intracellular DNA was extracted from 3 * 10(5) HepG2.2.15 cells from each group. The extracted DNA was further purified with mung bean nuclease to remove HBV relaxed circular DNA that may have remained. Both HBV covalently closed circular DNA (cccDNA) and HBV DNA were examined with real-time polymerase chain reaction. The titers of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were quantified with enzyme-linked immunosorbent assay. Cell viability was measured with the cell counting kit-8 assay. RESULTS: Compared to lamivudine alone (22.63% +/- 0.12%), both sequential (51.50% +/- 0.17%, P = 0.034) and cytokine treatment (49.66% +/- 0.06%, P = 0.041) showed a stronger inhibition of HBV cccDNA; the difference between the sequential and cytokine groups was not statistically significant (51.50% +/- 0.17% vs 49.66% +/- 0.06%, P = 0.88). The sequential group showed less inhibition of HBV DNA replication than the lamivudine group (67.47% +/- 0.02% vs 82.48% +/- 0.05%, P = 0.014); the difference between the sequential and cytokine groups was not statistically significant (67.47% +/- 0.02% vs 57.45% +/- 0.07%, P = 0.071). The levels of HBsAg and HBeAg were significantly decreased in the sequential treatment group compared to the other groups [HBsAg: 3.48 +/- 0.04 (control), 3.09 +/- 0.08 (lamivudine), 2.55 +/- 0.13 (cytokine), 2.32 +/- 0.08 (sequential), P = 0.042 for each between-group comparison; HBeAg: 3.48 +/- 0.01 (control), 3.08 +/- 0.08 (lamivudine), 2.57 +/- 0.15 (cytokine), 2.34 +/- 0.12 (sequential), P = 0.048 for each between-group comparison]. Cell viability in the cytokine group was reduced to 58.03% +/- 8.03% compared with control cells (58.03% +/- 8.03% vs 100%, P = 0.000). Lamivudine pretreatment significantly reduced IFN-gamma + TNF-alpha-mediated toxicity of HepG2.2.15 cells [85.82% +/- 5.43% (sequential) vs 58.03% +/- 8.03% (cytokine), P = 0.002]. CONCLUSION: Sequential treatment overcame the lower ability of lamivudine alone to inhibit cccDNA and precluded the aggressive cytotoxicity involving IFN-gamma and TNF alpha by decreasing the viral load. PMID- 22826630 TI - Difficulty in differentiating two cases of sigmoid stenosis by diverticulitis from cancer. AB - The incidence of colonic diverticulosis with or without diverticulitis has increased in the Japanese population due to the modernization of food and aging. The rate of diverticulitis in colon diverticulosis ranges from 8.1% to 9.6%. However, few cases of stenosis due to diverticulitis have been reported. These reports suggest that the differentiation between sigmoid diverticulitis and colon cancer is difficult. This report describes two cases of colon stenosis due to diverticulitis that were difficult to differentiate from colon cancer. Case 1 was a 70-year-old woman with narrowed stools for 1 month who underwent colonofiberscopy (CFS). CFS revealed a diverticulum and circumferential stenosis in the sigmoid colon. Barium enema revealed a marked, hourglass-shaped, 2-cm circumferential stenosis in the sigmoid colon. Fluorodeoxyglucose (FDG)-positron emission tomography computed tomography (CT) revealed an increased FDG uptake at the affected portion of the sigmoid colon. Sigmoid colon cancer was suspected, and laparoscopic sigmoidectomy was performed. Pathological examination demonstrated active inflammation with no evidence of malignancy. Case 2 was a 50 year-old man who presented to a nearby clinic with reduced stool output despite the urge to defecate. CFS detected severe stenosis in the sigmoid colon approximately 25 cm from the dentate line. Contrast-enhanced abdominal CT revealed multiple diverticula, wall thickening, and swelling of the lymph nodes around the peritoneal aorta and the inferior mesenteric artery. A partial sigmoidectomy was performed. Pathological examination of the resected specimen revealed no changes in the mucosal epithelial surface, but a marked infiltration of inflammatory cells was observed. PMID- 22826631 TI - Global health and service learning: lessons learned at US medical schools. AB - BACKGROUND: Interest in global health is rapidly increasing amongst US medical students. Many students aspire to incorporate global health into their future careers, while others seek international opportunities to better prepare themselves for domestic practice. US medical schools have begun responding to this burgeoning interest with varying intensity and through a number of different strategies. CONCLUSIONS: Three important themes involved include: increasing the academic rigor of programming, fostering sustainable site partnerships, and encouraging mentorship and reflection for the students involved. Finally, the growing practice of service learning might also play a helpful role in integrating these themes into expanding global health programs. PMID- 22826632 TI - Space Radiation and Bone Loss. AB - Exposure to ionizing radiation may negatively impact skeletal integrity during extended spaceflight missions to the moon, Mars, or near-Earth asteroids. However, our understanding of the effects of radiation on bone is limited when compared to the effects of weightlessness. In addition to microgravity, astronauts will be exposed to space radiation from solar and cosmic sources. Historically, radiation exposure has been shown to damage both osteoblast precursors and local vasculature within the irradiated volume. The resulting suppression of bone formation and a general state of low bone-turnover is thought to be the primary contributor to bone loss and eventual fracture. Recent investigations using mouse models have identified a rapid, but transient, increase in osteoclast activity immediately after irradiation with both spaceflight and clinically-relevant radiation qualities and doses. Together with a chronic suppression of bone formation after radiation exposure, this acute skeletal damage may contribute to long-term deterioration of bone quality, potentially increasing fracture risk. Direct evidence for the damaging effects of radiation on human bone are primarily demonstrated by the increased incidence of fractures at sites that absorb high doses of radiation during cancer therapy: exposures are considerably higher than what could be expected during spaceflight. However, both the rapidity of bone damage and the chronic nature of the changes appear similar between exposure scenarios. This review will outline our current knowledge of space and clinical exploration exposure to ionizing radiation on skeletal health. PMID- 22826633 TI - Emerging options for the management of scorpion stings. AB - Scorpion stings are common in many tropical countries. Although most scorpion stings cause only localized pain without life-threatening envenoming, about one third of stings cause systemic envenoming which can result in death. Children are particularly sensitive to scorpion envenoming. The severity of scorpion stings is related to the presence of neurotoxins in the venom that cause a sudden release of neurotransmitters from the autonomic nervous system, predominantly sympathetic. There is also a strong inflammatory response that worsens symptoms, including those of a respiratory nature. Several vital functions may be directly affected, including the cardiovascular, respiratory, and neuromuscular systems. Hypertension is constant at the beginning of systemic envenoming and sometimes has a severe cardiac and respiratory impact. Although controversial, immunotherapy is the only etiological treatment. Administered early, it prevents many complications and improves the outcome. New antivenoms are highly purified immunoglobulin fragments, the efficacy and safety of which are excellent. As a consequence, adverse reactions to antivenoms are now very rare and usually mild, which should limit any reluctance regarding their routine use. Symptomatic treatment is still necessary to support immunotherapy, especially in cases of delayed arrival at hospital. A combination of both approaches should be considered, based on local resources and constraints. PMID- 22826634 TI - State of health economic evaluation research in Saudi Arabia: a review. AB - BACKGROUND: If evaluation of economic evidence is to be used increasingly in Saudi Arabia, a review of the published literature would be useful to inform policy decision-makers of the current state of research and plan future research agendas. The purpose of this paper is to provide a critical review of the state of health economic evaluation research within the Saudi context with regard to the number, characteristics, and quality of published articles. METHODS: A literature search was conducted on May 8, 2011 to identify health economic articles pertaining to Saudi Arabia in the PubMed, Embase, and EconLit databases, using the following terms alone or in combination: "cost*", "economics", "health economics", "cost-effectiveness", "cost-benefit", "cost minimization", "cost utility analysis", and "Saudi". Reference lists of the articles identified were also searched for further articles. The tables of contents of the Saudi Pharmaceutical Journal and the Saudi Medical Journal were reviewed for the previous 5 years. RESULTS: The search identified 535 citations. Based on a reading of abstracts and titles, 477 papers were excluded. Upon reviewing the full text of the remaining 58 papers, 43 were excluded. Fifteen papers were included. Ten were categorized as full economic evaluations and five as partial economic evaluations. These articles were published between 1997 and 2010. The majority of the studies identified did not clearly state the perspective of their evaluation. There are many concerns about the methods used to collect outcome and costs data. Only one study used some sort of sensitivity analysis to assess the effects of uncertainty on the robustness of its conclusions. CONCLUSION: This review highlights major flaws in the design, analysis, and reporting of the identified economic analyses. Such deficiencies mean that the local economic evidence available to decision-makers is not very useful. Thus, building research capability in health economics is warranted. PMID- 22826635 TI - Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. AB - The prevalence of obesity and diabetes continues to rise in the US. Glucagon-like peptide-1 receptor agonist (GLP-1RA) is an effective treatment option for type 2 diabetes mellitus (T2DM) that promotes weight loss. Common and effective treatment options added to metformin therapy (basal insulin, sulfonylureas, and pioglitazone) contribute to weight gain, which makes the addition of GLP-1RAs advantageous. Exenatide was the first agent in this class and has recently been approved for use in combination with insulin glargine by the US Food and Drug Administration and the European Medicines Agency. Until recently, there was a lack of data examining basal insulin combined with these agents. The main purpose of this article is to review the prospective interventional data on the safety and efficacy of GLP-1RAs (exenatide, liraglutide, albiglutide, lixisenatide) combined with basal insulin therapy in nonpregnant adults with T2DM. Databases searched were PubMed, Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews (inception to January 2012). Abstracts presented at relevant diabetes and endocrine meetings from 2009 to 2011 were also reviewed, as were reference lists of identified publications. A total of five studies met the criteria and were included in the review. Data from these studies demonstrated that this combination therapy offers advantages for the treatment of diabetes, such as additional lowering of A1c without major risk for hypoglycemia, lower basal insulin requirements, decreased postprandial glucose levels (with or without fasting plasma glucose decreases), and weight loss, or at the very least, less weight gain. However, the gastrointestinal side effects and high cost of these agents may limit their use. This review demonstrates that adding a GLP-1RA to an existing basal insulin regimen is a reasonable treatment strategy in nonpregnant adult patients with T2DM. PMID- 22826636 TI - Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. AB - A novel hypothesis of obesity is suggested by consideration of diet-related inflammation and evolutionary medicine. The obese homeostatically guard their elevated weight. In rodent models of high-fat diet-induced obesity, leptin resistance is seen initially at vagal afferents, blunting the actions of satiety mediators, then centrally, with gastrointestinal bacterial-triggered SOCS3 signaling implicated. In humans, dietary fat and fructose elevate systemic lipopolysaccharide, while dietary glucose also strongly activates SOCS3 signaling. Crucially however, in humans, low-carbohydrate diets spontaneously decrease weight in a way that low-fat diets do not. Furthermore, nutrition transition patterns and the health of those still eating diverse ancestral diets with abundant food suggest that neither glycemic index, altered fat, nor carbohydrate intake can be intrinsic causes of obesity, and that human energy homeostasis functions well without Westernized foods containing flours, sugar, and refined fats. Due to being made up of cells, virtually all "ancestral foods" have markedly lower carbohydrate densities than flour- and sugar-containing foods, a property quite independent of glycemic index. Thus the "forgotten organ" of the gastrointestinal microbiota is a prime candidate to be influenced by evolutionarily unprecedented postprandial luminal carbohydrate concentrations. The present hypothesis suggests that in parallel with the bacterial effects of sugars on dental and periodontal health, acellular flours, sugars, and processed foods produce an inflammatory microbiota via the upper gastrointestinal tract, with fat able to effect a "double hit" by increasing systemic absorption of lipopolysaccharide. This model is consistent with a broad spectrum of reported dietary phenomena. A diet of grain-free whole foods with carbohydrate from cellular tubers, leaves, and fruits may produce a gastrointestinal microbiota consistent with our evolutionary condition, potentially explaining the exceptional macronutrient-independent metabolic health of non-Westernized populations, and the apparent efficacy of the modern "Paleolithic" diet on satiety and metabolism. PMID- 22826637 TI - Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. AB - BACKGROUND: Insulin degludec (IDeg) is a neutral, ultralong-acting new generation basal insulin analog developed by NovoNordisk currently in Phase III clinical development. IDeg offers a duration of action of more than 42 hours in adults, much longer than current basal insulin formulations. OBJECTIVE: The aim of this review is to assess the efficacy and safety data of IDeg in the treatment of type 1 and type 2 diabetes mellitus. METHODS: Relevant English language articles from 2010 to 2012 were identified through MEDLINE, PubMed, EMBASE, Scopus, BIOSIS, and Google Scholar. Online conference proceedings of the 71st ADA Scientific Sessions and the 47th EASD Annual Meeting were reviewed. Studies were compared in terms of their study designs, primary and secondary efficacy parameters, and tolerability data. RESULTS: There are a total of nine published trials investigating the clinical efficacy and safety of IDeg in over 3000 subjects with type 1 and 2 diabetes. Only three trials were published in full. All were open-label, randomized multicenter trials with durations of 16 to 52 weeks. IDeg and coformulations of IDeg with insulin aspart (IAsp) were compared to insulin glargine (IGlar), detemir, and biphasic IAsp 30 (BIAsp 30). CONCLUSION: Based upon the available evidence, there appear to be no reported differences between IDeg and IGlar, detemir, or BIAsp 30 in the reduction of the primary efficacy end points of HbA(1c) and mean fasting plasma glucose (FPG) concentrations. Only flexible dosing of IDeg provided a significant reduction in FPG compared to IGlar. IDeg demonstrated a significant reduction in nocturnal hypoglycemia in type 1 diabetes. In type 2 diabetes, IDeg reduced the incidence of hypoglycemia by 18% and 58% compared to IGlar and BIAsp 30, respectively. PMID- 22826638 TI - Right Diet: a television series to combat obesity among adolescents in Kuwait. AB - BACKGROUND: Adolescent obesity is a growing public health problem in Kuwait. Reducing obesity can lower the risk of several chronic diseases. Fourteen obese adolescent boys volunteered to participate in a 6-month multidimensional television series on weight loss. METHODS: The adolescent boys were recruited through advertisements in schools. The program included counseling sessions, nutritional education, exercise, family support, peer group involvement, and incentives designed to motivate participants. RESULTS: The mean age of the boys was 15.6 +/- 0.8 years. On average, subjects lost 10.6 +/- 8.9 kg in weight and gained 3.3 +/- 1.6 cm in height during the study period. The difference in mean body mass index at baseline and at 6 months following intervention was significant (P < 0.001) at 36.8 +/- 4.6 and 32.0 +/- 5.4, kg/m(2) respectively. Participants ranked counseling as the most important component of the program, followed by family support and type of program. CONCLUSION: This type of television series could be used as a model for future public health programs to prevent and control obesity among adolescents. PMID- 22826639 TI - Lactose intolerance: diagnosis, genetic, and clinical factors. AB - Most people are born with the ability to digest lactose, the major carbohydrate in milk and the main source of nutrition until weaning. Approximately 75% of the world's population loses this ability at some point, while others can digest lactose into adulthood. This review discusses the lactase-persistence alleles that have arisen in different populations around the world, diagnosis of lactose intolerance, and its symptomatology and management. PMID- 22826640 TI - Age-dependent safety analysis of propofol-based deep sedation for ERCP and EUS procedures at an endoscopy training center in a developing country. AB - INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography (EUS) procedures in elderly patients are on the rise, and they play an important role in the diagnosis and management of various gastrointestinal diseases. The use of deep sedation in these patients has been established as a safe and effective technique in Western countries; however, it is uncertain if the situation holds true among Asians. The present study aimed to evaluate the age-dependent safety analysis and clinical efficacy of propofol based deep sedation (PBDS) for ERCP and EUS procedures in adult patients at a World Gastroenterology Organization (WGO) Endoscopy Training Center in Thailand. METHODS: We undertook a retrospective review of anesthesia or sedation service records of patients who underwent ERCP and EUS procedures. All procedures were performed by staff endoscopists, and all sedations were administered by anesthesia personnel in the endoscopy room. RESULTS: PBDS was provided for 491 ERCP and EUS procedures. Of these, 252 patients (mean age, 45.1 + 11.1 years, range 17-65 years) were in the <65 age group, 209 patients (mean age, 71.7 + 4.3 years, range 65-80 years) were in the 65-80 year-old group, and 30 patients (mean age, 84.6 + 4.2 years, range 81-97 years) were in the >80 age group. Common indications for the procedures were pancreatic tumor, cholelithiasis, and gastric tumor. Fentanyl, propofol, and midazolam were the most common sedative drugs used in all three groups. The mean doses of propofol and midazolam in the very old patients were relatively lower than in the other groups. The combination of propofol, midazolam, and fentanyl, as well as propofol and fentanyl, were frequently used in all patients. Sedation-related adverse events and procedure related complications were not statistically significantly different among the three groups. Hypotension was the most common complication. CONCLUSION: In the setting of the WGO Endoscopy Training Center in a developing country, PBDS for ERCP and EUS procedures in elderly patients by trained anesthesia personnel with appropriate monitoring is relatively safe and effective. Although adverse cardiovascular events, including hypotension, in this aged group is common, all adverse events were usually transient, mild, and easily treated, with no sequelae. PMID- 22826641 TI - Intensive interdisciplinary outpatient pain management program for chronic back pain: a pilot study. AB - BACKGROUND: Chronic back pain is relatively resistant to unimodal therapy regimes. The aim of this study was to introduce and evaluate the short-term outcome of a three-week intensive multidisciplinary outpatient program for patients with back pain and sciatica, measured according to decrease of functional impairment and pain. METHODS: The program was designed for patients suffering from chronic back pain to provide intensive interdisciplinary therapy in an outpatient setting, consisting of interventional injection techniques, medication, exercise therapy, back education, ergotherapy, traction, massage therapy, medical training, transcutaneous electrical nerve stimulation, aquatraining, and relaxation. RESULTS: Based on Oswestry Disability Index (ODI) and Numeric Rating Scale (NRS) scores, a significant improvement in pain intensity and functionality of 66.83% NRS and an ODI of 33.33% were achieved by our pain program within 3 weeks. CONCLUSION: This paper describes the organization and short-term outcome of an intensive multidisciplinary program for chronic back pain on an outpatient basis provided by our orthopedic department, with clinically significant results. PMID- 22826643 TI - Awareness among nurses about reporting of adverse drug reactions in Sweden. AB - BACKGROUND: The purpose of this study was to investigate awareness among nurses regarding their new role as reporters of adverse drug reactions in Sweden and factors that may influence reporting by nurses. METHODS: In 2007, all nurses were included in the adverse drug reaction reporting scheme in Sweden. A questionnaire was sent to 753 randomly selected nurses in September 2010. RESULTS: Of the 453 (60%) responding nurses, 265 (58%) were aware that nurses were included in the reporting of adverse drug reactions. Sixty-one nurses (14%) stated that they had reported an adverse drug reaction. Fifteen percent (n = 70) of the respondents had received training about reporting of adverse drug reactions. Almost one third of these (n = 21, 30%) had reported an adverse drug reaction on at least one occasion. Among nurses without training, a smaller proportion (n = 40, 11%, P < 0.05) had reported an adverse drug reaction on at least one occasion. The two factors considered most important by nurses for reporting were the severity of the adverse drug reaction and if the reaction was to a newly approved drug. A majority of the nurses (n = 397, 88%) were interested in a training course in pharmacology as part of their ongoing professional development. One third (32%) of all nurses stated that one reason for not reporting a suspected adverse drug reaction was that the physician responsible did not regard the reaction necessary to report. CONCLUSION: We found that more than half of the study population of nurses in Sweden were aware of their new role as reporters of adverse drug reactions, but few of the responding nurses had reported an adverse drug reaction. Given that training seems to be associated with high reporting frequency, we suggest more training in pharmacovigilance for nurses. PMID- 22826642 TI - Fluoroscopic cervical epidural injections in chronic axial or disc-related neck pain without disc herniation, facet joint pain, or radiculitis. AB - BACKGROUND: While chronic neck pain is a common problem in the adult population, with a typical 12-month prevalence of 30%-50%, there is a lack of consensus regarding its causes and treatment. Despite limited evidence, cervical epidural injections are one of the commonly performed nonsurgical interventions in the management of chronic neck pain. METHODS: A randomized, double-blind, active, controlled trial was conducted to evaluate the effectiveness of cervical interlaminar epidural injections of local anesthetic with or without steroids for the management of chronic neck pain with or without upper extremity pain in patients without disc herniation, radiculitis, or facet joint pain. RESULTS: One hundred and twenty patients without disc herniation or radiculitis and negative for facet joint pain by means of controlled diagnostic medial branch blocks were randomly assigned to one of two treatment groups, ie, injection of local anesthetic only (group 1) or local anesthetic mixed with nonparticulate betamethasone (group 2). The primary outcome of significant pain relief and improvement in functional status (>=50%) was demonstrated in 72% of group 1 and 68% of group 2. The overall average number of procedures per year was 3.6 in both groups with an average total relief per year of 37-39 weeks in the successful group over a period of 52 weeks. CONCLUSION: Cervical interlaminar epidural injections of local anesthetic with or without steroids may be effective in patients with chronic function-limiting discogenic or axial pain. PMID- 22826644 TI - Costs and outcomes associated with clopidogrel discontinuation in Medicare beneficiaries with acute coronary syndrome in the coverage gap. AB - BACKGROUND: Current guidelines for acute coronary syndrome recommend clopidogrel for an optimal period of 12 months in order to reduce the risk of reinfarction and mortality. Premature clopidogrel discontinuation has been associated with higher rates of rehospitalization, coronary stent thrombosis, and mortality. No data exist regarding the effect of the Medicare Part D coverage gap on medical costs and outcomes in Medicare beneficiaries who discontinue their clopidogrel upon entering the coverage gap. METHODS: Beneficiaries with a Medicare Advantage plan in 2009 who had a diagnosis of acute coronary syndrome were taking clopidogrel 75 mg daily, and reached the gap in the same year representing the study sample. From this cohort, those who filled at least two prescriptions for clopidogrel (continued) versus those that did not (discontinued) while in the gap were compared with regard to outcomes related to acute coronary syndrome and expenditure 30 days after the last prescription was filled and during any time while in the gap. Descriptive and multivariate analyses were used to compare these differences. RESULTS: A total of 1365 beneficiaries with acute coronary syndrome met the inclusion criteria, of which 705 beneficiaries entered into the coverage gap, wherein 103 (14.6%) and 602 (85.4%) of beneficiaries discontinued and continued clopidogrel, respectively. Compared with those who continued clopidogrel during the gap, beneficiaries who discontinued clopidogrel showed a higher trend in the number of hospitalizations related to acute coronary syndrome and emergency room visits, albeit not statistically significant. Those who discontinued clopidogrel showed a higher mean adjusted cost per member per month in hospitalizations ($3604) related to acute coronary syndrome and outpatient visits ($1144) related to acute coronary syndrome and total medical costs ($5614), albeit not statistically significant. CONCLUSION: Medicare beneficiaries who face large out-of-pocket costs for clopidogrel while in the coverage gap and discontinue therapy may experience adverse events related to acute coronary syndrome. PMID- 22826645 TI - Hepatocellular carcinoma: cost-effectiveness of screening. A systematic review. AB - Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. HCC is a potential target for cancer surveillance (or screening) as it occurs in well defined, at-risk populations. Curative therapy is possible only for small tumors and screening strategy has been recommended by the US, Italian, and other international liver societies and is practiced widely, but its benefits are not clearly established. The objective of this study was to review the available evidence with respect to the cost-effectiveness of key technologies in the prevention HCC. The literature search was conducted with the support of PubMed. Firstly we selected articles by reading the abstracts. Secondly, we read the articles and the revision was further restricted, with the following as inclusion criteria: (1) full economic evaluation of HCC screening programs; (2) comparison between HCC techniques; (3) outcome measures expressed in terms of quality adjusted life years (QALY); (4) full text availability. The initial review of the literature yielded 346 articles. Of those, 288 were excluded at the first stage. Of those excluded, 108 did not meet the target, 106 did not present the cost analysis, 33 did not analyze the treatment of the disease, and in 41 the abstract was not available. Of the 58 included in the first step, seven examined the cost effectiveness of different HCC screening techniques, seven investigated the cost effectiveness of HCC screening versus no screening, and one looked at the cost effectiveness of timing for HCC surveillance and monitoring, while 43 were about HBV vaccination and screening. We included only the seven articles examining the cost-effectiveness of different HCC screening techniques. In general, incidence is the key parameter which determines the cost-effectiveness of HCC screening. Discrepancies in the results exist when determining the type of technology to be used. Ultrasound (US) alone or in association with alpha fetoprotein (AFP) technology is likely to be the most cost effective and the use of computed tomography (CT) gives controversial results. PMID- 22826647 TI - World-class journal - perfect venue for your best work. PMID- 22826646 TI - Clostridium difficile outbreaks: prevention and treatment strategies. AB - The incidence and severity of Clostridium difficile infection (CDI) have increased dramatically over the past decade. Its treatment, however, has largely remained the same with the exception of oral vancomycin use as a first-line agent in severe disease. From 1999 to 2004, 20,642 deaths were attributed to CDI in the United States, almost 7 times the rate of all other intestinal infections combined. Worldwide, several major CDI outbreaks have occurred, and many of these were associated with the NAP1 strain. This 'epidemic' strain has contributed to the rising incidence and mortality of CDI. The purpose of this article is to review the current management, treatment, infection control, and prevention strategies that are needed to combat this increasingly morbid disease. PMID- 22826648 TI - Transcatheter interventions for multiple lesions in adults with congenital heart disease. AB - Recent advances in diagnosis, surgery and interventional management have significantly changed the quality of life of patients with congenital heart disease. Historically, congenital heart disease patients with multiple cardiac lesions have been referred for surgery; however, with the advent of newer technologies and expertise, transcatheter treatment has evolved as an alternative option. A series of patients who underwent interventional procedures for multiple congenital heart disease lesions with excellent procedural and medium-term outcomes is reported. PMID- 22826649 TI - Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin. AB - BACKGROUND: Coronary artery disease (CAD) occurs at an earlier age in South Asians compared with other ethnic groups. Infection and inflammation show a positive association with the disease. OBJECTIVE: To investigate the association of infection and inflammatory markers with premature CAD in the Indian Atherosclerosis Research Study population. METHODS: Antibody titres for Chlamydia pneumoniae, cytomegalovirus (CMV), Helicobacter pylori, herpes simplex virus and levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and secretory phospholipase A2, were measured in 866 individuals (433 CAD patients and matched controls). All individuals were followed-up for recurrent cardiac events for four years. ANOVA was used to study the association of infection and inflammation with CAD. RESULTS: The present study found that the odds of CAD occurrence was 2.42 (95% CI 1.26 to 4.64; P<0.008), with all four infections and increased in the presence of hsCRP (OR 4.67 [95% CI 1.43 to 15.25]); P=0.011). Only anti-CMV antibody levels were a significant risk factor for CAD occurrence (OR 2.23 [95% CI 1.20 to 4.15]; P=0.011) and recurrent cardiac events (OR 1.94 [95% CI 0.85 to 4.45]; P=0.015). Mean values of the inflammatory biomarkers IL-6 (P=0.035), fibrinogen (P=0.014), hsCRP (P=0.010) and secretory phospholipase A2 (P=0.002) increased with CMV antibody levels. Incorporating hsCRP and IL-6 in the risk prediction models significantly increased the OR to 2.56 (95% CI 1.16 to 5.63; P=0.019) with a c statistic of 0.826. CONCLUSIONS: Pathogen burden, especially CMV infection in combination with inflammatory markers, is a significant predictor of CAD risk in the young Indian population. PMID- 22826650 TI - Use of cardiac computed tomography in the management of symptomatic coronary aneurysm: A case study and literature review. AB - Coronary artery aneurysms are rare malformations caused by atherosclerosis, connective tissue disease or vasculitides, and are usually discovered incidentally with invasive coronary angiography. A case involving a 58-year-old male presenting with an acute coronary syndrome who was found on invasive angiogram to have a giant aneurysm of the left anterior descending coronary artery is described. The incidence, pathophysiology and management of giant aneurysms in the context of an acute coronary syndrome are reviewed. PMID- 22826651 TI - Hypovolemia-induced severe coronary spasm leading to acute myocardial infarction. AB - Acute ST-elevation myocardial infarction (STEMI) is a well recognized manifestation of severe coronary artery spasm. Although there are many recognized triggers, hypovolemia has not been previously described. The present report describes a case of acute STEMI that occurred four days following major colonic surgery in a severely dehydrated patient. Coronary angiography revealed underfilled coronary arteries with severe multifocal spasm, which largely resolved with aggressive fluid repletion and intracoronary nitrate. PMID- 22826652 TI - Metastatic atrial sarcoma extending from the lung into the left atrium via a pulmonary vein. AB - Lung tumours are the leading metastatic cancers that spread to the heart through direct invasion, and rarely extend into the chambers of the left side of the heart via pulmonary veins. A case of primary lung sarcoma involving a patient who presented with dyspnea and fatigue is reported. This sarcoma extended from the lung into the left atrium via (a/the) pulmonary vein. Chemotherapy and radiotherapy were recommended. Surgery was not considered due to high risk and the advanced stage of the tumour. PMID- 22826653 TI - Ventricular fibrillation during coronary angiography in a patient with left dominant coronary artery ectasia. AB - The presence of coronary ectasias in otherwise normal epicardial coronary arteries are an infrequent angiographic finding. Coronary ectasia is not a benign condition and has been associated with a high risk of coronary events. In the present case, a patient with left dominant coronary artery ectasia who developed ventricular fibrillation during coronary angiography is described. This event was unexpected, and has not been previously reported. PMID- 22826654 TI - Progressive left ventricular noncompaction and systolic dysfunction. AB - Left ventricular noncompaction is a condition characterized by prominent ventricular trabeculations, often accompanied by systolic dysfunction. The present case involves an adult with a small ventricular septal defect, initially exhibiting mild systolic dysfunction and slightly prominent left ventricular trabeculations progressing over 13 years to severe dilated cardiomyopathy and overt noncompaction. The present case strongly suggests a correlation between the extent of noncompaction and the degree of systolic dysfunction. The initial presence of a small ventricular septal defect and mild trabeculations highlights the genetic determinants of non-compaction and the importance of closely following patients with mild noncompaction due to the possibility of progression. More sensitive diagnostic criteria are needed to avoid overlooking mild cases, which may show prominent trabeculations without reaching a requisite ratio of compacted to noncompacted tissue. PMID- 22826655 TI - Mature and immature microRNA ratios in cultured rat cardiomyocytes during anoxia reoxygenation. AB - BACKGROUND: The critical role of microRNAs (miRNAs) in the global control of gene expression in the heart has recently been postulated; however, the mechanisms of miRNA regulation in cardiac pathology are not clear. OBJECTIVE: To evaluate the levels of miR-1, miR-208a and miR-29a expressed in neonatal rat cardiomyocytes during anoxia-reoxygenation (AR). METHODS: Reverse transcription coupled with real-time polymerase chain reaction was used to evaluate the level of mature and immature miRNAs in cardiomyocyte culture during AR. RESULTS: THE INITIAL LEVELS OF THE MATURE AND IMMATURE MIRNAS WERE DIFFERENT: mature - miR-1 7.46+/-4.440, miR-208a 0.02+/-0.015 and miR-29a 5.60+/-2.060; immature - miR-1 0.02+/-0.007, miR-208a 0.05+/-0.029 and miR-29a 0.01+/-0.008. The most prominent changes were observed for immature miRNAs during AR, with immature miR-1 and miR-29a expressed at significantly higher levels during remote reoxygenation (AR [0.5 h/24 h]) compared with control, while the level of expressed immature miR-208a was significantly decreased during acute reoxygenation (AR [0.5 h /1 h]) and returned to control levels during remote reoxygenation (AR [0.5h /24 h]). Also, the ratios of mature to immature miRNAs were significantly increased during acute reoxygenation for miR-1 and miR-208a, returning to control levels during remote reoxygenation, while for miR-29a, this ratio had the progressive tendency to decrease under AR. CONCLUSION: The discordance between the estimated levels of mature and immature miRNA during AR supports the hypothesis that transcriptional and post-transcriptional regulatory mechanisms at the miRNA level play a role in the response of cardiomyocytes to AR, and could be a contributing factor in the differential resistance of cardiomyocytes to AR. PMID- 22826656 TI - From The Editor's Desk. PMID- 22826657 TI - Crossroads: Presented June 5, 2002 as the Graduation Address to the Class of 2002 of the Ochsner Clinic Foundation's Graduate Medical Education Program. PMID- 22826658 TI - Annual ochsner graduate medical education house staff graduation speakers. PMID- 22826660 TI - Patient registries: a new gold standard for "real world" research. AB - Physicians in community-based practice rarely have the time, nor the inclination, to participate in formal, controlled clinical research. While few would question the importance of statistically valid clinical trials focused on establishing the safety and efficacy of new pharmaceuticals and medical devices, most busy practitioners recognize that formal clinical research can't be approached casually. Beyond the operational infrastructure typically required to execute medical research, the imposition of fundamentally experimental research is such that it is not easily accommodated in day-to-day medical practice. Indeed, the often artificial nature of controlled clinical research is, in many ways, incompatible with actual practice conditions. However, the characteristics and, more importantly, the outcomes of "real world" medical practice are becoming of increasing scientific and practical importance. Underscored by recent post approval drug recalls, the "real world" practice environment can be an invaluable source of information on the actual effectiveness of treatment regimens, drugs, and devices. Inasmuch as clinical trials tend to exclude noncompliant patients and those with comorbid conditions, a new paradigm is appropriate for capturing the outcomes of actual practice. While not without statistical and analytical limitation, the brand of "naturalistic" research undertaken in observational patient registries is becoming rapidly accepted by both the scientific and practitioner communities. PMID- 22826661 TI - Liver transplantation for hepatocellular carcinoma: the ochsner experience. AB - Liver transplantation is now advocated for patients with early stage hepatocellular carcinoma (HCC) not amenable to surgical resection. In this article we review our experience with liver transplantation as treatment for patients with HCC and end-stage liver disease. Between April 1998 and May 2002, 36 patients with a diagnosis of HCC underwent liver transplantation at Ochsner Clinic Foundation. A retrospective analysis was performed examining pretransplant staging of disease, pathologic staging, disease recurrence, and patient survival. Cumulative 1- and 3-year patient survival rates are 80% and 61%, respectively. To date, none of our patients has developed evidence of recurrent cancer. Our data support liver transplantation as the treatment of choice for patients with unresectable early stage HCC. PMID- 22826659 TI - Hypertension research program at ochsner: a program in translational research. PMID- 22826662 TI - Adult congenital heart disease. AB - One million people over the age of 20 suffer from congenital heart disease in the United States. These adult patients can slip through the cracks of our medical system; many are too old to be cared for in most pediatric institutions by pediatric cardiologists and, unfortunately, most adult cardiologists are not trained in congenital heart disease. Therefore, it is important to identify the common lesions in adult congenital heart disease and how they should be managed. Acyanotic congenital heart disease in the adult population primarily involves left-to-right shunts, such as atrial septal defect, patent ductus arteriosus, and obstructive lesions such as aortic coarctation of the aorta. The most common form of cyanotic congenital heart disease in adults is tetralogy of Fallot. Other complex conditions seen in adults include univentricular hearts, Ebstein's anomaly of the tricuspid valve, and corrected transposition of the great vessels. Most patients with congenital heart disease will need to undergo surgery, catheterization, or catheterization intervention. Results are excellent in the adult population. Long-term follow-up is needed for any adult congenital heart patient receiving care in institutions that are well organized and well equipped, as we learn more about the natural and unnatural history of these conditions. PMID- 22826663 TI - Overview of lower respiratory tract infections: diagnosis and treatment. AB - Because the diagnosis and treatment of community-acquired pneumonia (CAP) continue to present decision-making challenges, a number of professional organizations have developed treatment guidelines to provide parameters for diagnosis and treatment. The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) both recently updated their guidelines for the treatment of CAP to take into account the changes that have occurred in antimicrobial susceptibility and the availability of newer antimicrobial agents. Both the IDSA and ATS guidelines stratify treatment according to where the patient is treated, but the ATS guidelines further characterize patients according to the presence or absence of cardiopulmonary disease or other modifying factors. For outpatients with CAP, doxycycline, a macrolide, or a newer fluoroquinolone with enhanced activity against Streptococcus pneumoniae are the IDSA-preferred agents for empiric treatment. The ATS recommends monotherapy with a macrolide or doxycycline in patients without modifying factors, or combination therapy with a beta-lactam plus a macrolide, or monotherapy with an antipneumococcal fluoroquinolone in patients with modifying factors. For empiric therapy of CAP in hospitalized patients, the IDSA recommendations are as follows: an extended-spectrum cephalosporin plus a macrolide, a beta-lactam/beta-lactamase inhibitor plus a macrolide, or a fluoroquinolone with extended activity against S. pneumoniae. For hospitalized patients without modifying factors, the ATS recommends monotherapy with azithromycin or an antipneumococcal fluoroquinolone. For hospitalized patients with modifying factors, combination therapy with a beta lactam plus a macrolide, doxycycline, or monotherapy with a respiratory fluoroquinolone are recommended. Given the increasing resistance of S. pneumoniae to macrolides and doxycycline, a respiratory fluoroquinolone may represent the best choice of therapy. PMID- 22826664 TI - The preliminary capsule endoscopy experience at ochsner clinic foundation. AB - Diagnostic capabilities for the small bowel have made a giant leap forward this year with the release and availability of the M2A Video Capsule by Given Imaging, Ltd. (Yoqneam, Israel). This technology is most applicable to the patient with unexplained gastrointestinal bleeding. The patient swallows the capsule, which can take continuous digital images of the gastrointestinal tract for the life of the self-contained battery. In April 2002, Ochsner Clinic Foundation began making this available to patients and referring physicians. Our experience with the first 19 cases is described. PMID- 22826665 TI - A report on vaccine availability and administration protocols as of august 2002. AB - The development of vaccines has contributed to the great increase in human survival and longevity over the past 200 years. While some developments have been restricted due to interactions, side effects, or eradication, the 17 commonly recommended vaccines form a safe an effective arsenal held against infectious agents. Primary vaccination is a key component of the fight against infectious disease, as well as vaccination of immigrants and travelers. High-risk groups have some special considerations. While vaccine supply and production problems have, and in some cases continue to pose difficulties, following the recommended guidelines will help to ensure the safety and health of the population. PMID- 22826667 TI - Curtis tyrone, MD. PMID- 22826666 TI - Alcohol and liver disease. PMID- 22826668 TI - Scanning the literature. PMID- 22826669 TI - Case studies. PMID- 22826670 TI - 2002 alton ochsner award relating smoking and health. PMID- 22826672 TI - Ongoing clinical protocols. PMID- 22826674 TI - Case study answers. PMID- 22826675 TI - From the editors desk. PMID- 22826673 TI - Recent publications by ochsner authors. PMID- 22826676 TI - The New ACGME Resident Duty Hours: Big Changes, Bigger Challenges. PMID- 22826677 TI - The code of medical ethics of the american medical association. PMID- 22826678 TI - Telemedicine and the pediatric tertiary care center: presented as the 2002 melinda j. Pouncey memorial lecture. PMID- 22826679 TI - Pain management - the challenge. AB - Chronic pain is a significant public health problem in the United States. While the understanding that pain is an important biological signal has always been appreciated by health care professionals, management of pain has now come under significant scrutiny following its recognition as the fifth vital sign. Since the measurement of pain is not objective, the answers to questions regarding how to best manage the problem are not always self-evident. Multiple modalities, including interventional procedures and noninvasive techniques, are available for the treatment of pain. Acute pain is usually self-limiting when a reversible element can be identified. If acute pain is undertreated, it may become chronic in nature with the attendant problems of prolonged pain. Chronic pain creates psychological and social problems that are difficult and frustrating for both patient and physician. A multimodal therapeutic program in which the patient is an active participant can satisfactorily manage most pain problems. The use of opioids is considered legitimate medical therapy for chronic nonmalignant pain. If the need for opioid therapy is felt to be indicated, the physician should adhere to recommended guidelines as published by state licensing boards and professional organizations. Successful pain management is a rewarding experience for health care professionals. PMID- 22826680 TI - The principles of mohs micrographic surgery for cutaneous neoplasia. AB - Skin cancer is the most common form of cancer, and although its most common forms are rarely life threatening, the morbidity of this disease is substantial, especially in the southern regions of the United States. Mohs micrographic surgery (MMS) is a precise form of microscopically controlled excisional surgery created in the US but currently practiced worldwide and used to treat various cutaneous carcinomas. The history, technique, indications, and recurrence rates of MMS are discussed to allow the practicing physician to understand the specific instances when patients will best benefit from this procedure. PMID- 22826681 TI - Benzocaine induced methemoglobinemia: a potentially fatal complication of transesophageal echocardiography. AB - Transesophageal echocardiography (TEE) is a relatively safe procedure with complications including bleeding, esophageal perforation, and respiratory failure being rare. One of our patients recently developed severe cyanosis despite pulse oximetry of 85% following TEE. This directs our attention to a rare, easily treatable, but potentially fatal complication of this procedure. PMID- 22826682 TI - Cystic fibrosis: more questions than answers. PMID- 22826683 TI - Ochsner case studies. PMID- 22826684 TI - Dean Holland Echols, MD: The Sixth Founder. PMID- 22826685 TI - Scanning the literature. PMID- 22826687 TI - Ochsner cancer institute studies vitamin e and selenium as prostate cancer prevention agents. PMID- 22826686 TI - Scanning the literature. PMID- 22826689 TI - Ongoing protocols at ochsner. PMID- 22826690 TI - Ionizing Radiation and Bone Loss: Space Exploration and Clinical Therapy Applications. AB - Damage to normal, nontumor bone tissue following therapeutic irradiation increases the risk of fracture among cancer patients. For example, women treated for various pelvic tumors have been shown to have a greater than 65% increased incidence of hip fracture by 5 years postradiotherapy. Another practical situation in which exposure to ionizing radiation may negatively impact skeletal integrity is during extended spaceflight missions. There is a limited understanding of how spaceflight-relevant doses and types of radiation can influence astronaut bone health, particularly when combined with the significant effects of mechanical unloading experienced in microgravity. Historically, negative effects on osteoblasts have been studied. Radiation exposure has been shown to damage osteoblast precursors. Damage to local vasculature has been observed, ranging from decreased lumen diameter to complete ablation within the irradiated volume, causing a state of hypoxia. These effects result in suppression of bone formation and a general state of low bone turnover. More recently, however, we have demonstrated in pre-clinical mouse models, a very rapid but transient increase in osteoclast activity after exposure to spaceflight and clinically relevant radiation doses. Combined with long-term suppression of bone formation, this skeletal damage may cause long-term deficits. This review will present a broad set of literature outlining our current set knowledge of both clinical therapy and space exploration exposure to ionizing radiation. Additionally, we will discuss prevention of the initial osteoclast-mediated bone loss, the need to promote normal bone turnover and long-term quality of bone tissue, and our hypothesized molecular mechanisms. PMID- 22826691 TI - Reliability and validity of the valued activity inventory for adults with cancer. AB - The authors assessed the psychometric properties of the Valued Activity Inventory for Adults With Cancer (VAI-AC), a self-report instrument that measures activity limitations. Participants included 50 older adults undergoing chemotherapy who completed the VAI-AC and measures of physical and mental function, symptom intensity, and mood 3 days before and the day of chemotherapy. Test-retest reliability was assessed by determining the average number of items for which the importance of an activity was rated consistently and by calculating the intraclass correlation coefficient (ICC) for the first and second VAI-AC scores. Convergent validity was assessed by correlating the VAI-AC scores with the other measures. Participants consistently rated the importance of 90% of the items. The 72-hour test-retest reliability ICC was 0.67. Participants with fewer activity limitations indicated better physical function (r = 0.58, p < .001), better mental function (r = 0.55, p < .001), lower symptom intensity (r = -0.57, p < .001), and fewer depressive symptoms (r = -0.68, p < .001). The VAI-AC demonstrated evidence of test-retest reliability and convergent validity in this convenience sample of older adults undergoing chemotherapy for cancer. PMID- 22826692 TI - An evidence-based review of apixaban and its potential in the prevention of stroke in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is a common cardiac arrhythmia, especially in the elderly population. It is associated with cardioembolic complications, particularly strokes, resulting in severe functional deficit or death. AF patients are first stratified into low, intermediate, and high risk for thromboembolic events using the CHADS(2) and CHA(2)DS(2)-VASc score systems. Depending on their risks, patients are treated with either therapeutic anticoagulation with warfarin or acetylsalicylic acid for stroke prevention. Although warfarin is the recommended therapy, it is underutilized clinically due to concern for narrow therapeutic window, drug-to-drug and drug-to-food interactions, and hemorrhagic complications. Newer anticoagulant agents such as dabigatran (a direct thrombin inhibitor) and rivaroxaban (a direct factor Xa inhibitor) have already been approved by US Food and Drug Administration for stroke prevention in patients with nonvalvular atrial fibrillation. Apixaban is the newest oral direct factor Xa inhibitor and it has been extensively studied in the AVERROES and ARISTOTLE trials. Apixaban demonstrated reduced incidence of primary outcome of stroke and bleeding events when compared with warfarin. Apixaban is currently being reviewed by the Food and Drug Administration as a stroke prophylactic agent. In addition, there are several other indirect factor Xa inhibitors and vitamin K antagonists under study presently. Results from these studies will provide us with information about possible alternatives to warfarin. PMID- 22826693 TI - Dietary factors and fluctuating levels of melatonin. AB - Melatonin is secreted principally by the pineal gland and mainly at nighttime. The primary physiological function is to convey information of the daily cycle of light and darkness to the body. In addition, it may have other health-related functions. Melatonin is synthesized from tryptophan, an essential dietary amino acid. It has been demonstrated that some nutritional factors, such as intake of vegetables, caffeine, and some vitamins and minerals, could modify melatonin production but with less intensity than light, the most dominant synchronizer of melatonin production. This review will focus on the nutritional factors apart from the intake of tryptophan that affect melatonin levels in humans. Overall, foods containing melatonin or promoting the synthesis of it by impacting the availability of tryptophan, as well those containing vitamins and minerals which are needed as co-factors and activators in the synthesis of melatonin, may modulate the levels of melatonin. Even so, the influence of daytime diet on the synthesis of nocturnal melatonin is limited, however, the influence of the diet seems to be more obvious on the daytime levels. PMID- 22826694 TI - Disability in people affected by leprosy: the role of impairment, activity, social participation, stigma and discrimination. AB - BACKGROUND: Leprosy-related disability is a challenge to public health, and social and rehabilitation services in endemic countries. Disability is more than a mere physical dysfunction, and includes activity limitations, stigma, discrimination, and social participation restrictions. We assessed the extent of disability and its determinants among persons with leprosy-related disabilities after release from multi drug treatment. METHODS: We conducted a survey on disability among persons affected by leprosy in Indonesia, using a Rapid Disability Appraisal toolkit based on the International Classification of Functioning, Disability and Health. The toolkit included the Screening of Activity Limitation and Safety Awareness (SALSA) scale, Participation Scale, Jacoby Stigma Scale (anticipated stigma), Explanatory Model Interview Catalogue (EMIC) stigma scale and Discrimination assessment. Community members were interviewed using a community version of the stigma scale. Multivariate linear regression was done to identify factors associated with social participation. RESULTS: Overall 1,358 persons with leprosy-related disability (PLD) and 931 community members were included. Seventy-seven percent of PLD had physical impairments. Impairment status deteriorated significantly after release from treatment (from 59% to 77%). Around 60% of people reported activity limitations and participation restrictions and 36% anticipated stigma. As for participation restrictions and stigma, shame, problems related to marriage and difficulties in employment were the most frequently reported problems. Major determinants of participation were severity of impairment and level of education, activity and stigma. Reported severity of community stigma correlated with severity of participation restrictions in the same districts. DISCUSSION: The majority of respondents reported problems in all components of disability. The reported physical impairment after release from treatment justifies ongoing monitoring to facilitate early prevention. Stigma was a major determinant of social participation, and therefore disability. Stigma reduction activities and socio economic rehabilitation are urgently needed in addition to strategies to reduce the development of further physical impairment after release from treatment. PMID- 22826695 TI - Putting plasticity in its place. PMID- 22826696 TI - Systematic, balancing gradients in neuron density and number across the primate isocortex. AB - The cellular and areal organization of the cerebral cortex impacts how it processes and integrates information. How that organization emerges and how best to characterize it has been debated for over a century. Here we demonstrate and describe in the isocortices of seven primate species a pronounced anterior-to posterior gradient in the density of neurons and in the number of neurons under a unit area of the cortical surface. Our findings assert that the cellular architecture of the primate isocortex is neither arranged uniformly nor into discrete patches with an arbitrary spatial arrangement. Rather, it exhibits striking systematic variation. We conjecture that these gradients, which establish the basic landscape that richer areal and cellular structure is built upon, result from developmental patterns of cortical neurogenesis which are conserved across species. Moreover, we propose a functional consequence: that the gradient in neurons per unit of cortical area fosters the integration and dimensional reduction of information along its ascent through sensory areas and toward frontal cortex. PMID- 22826697 TI - Near-death experiences between science and prejudice. AB - Science exists to refute dogmas; nevertheless, dogmas may be introduced when undemonstrated scientific axioms lead us to reject facts incompatible with them. Several studies have proposed psychobiological interpretations of near-death experiences (NDEs), claiming that NDEs are a mere byproduct of brain functions gone awry; however, relevant facts incompatible with the ruling physicalist and reductionist stance have been often neglected. The awkward transcendent look of NDEs has deep epistemological implications, which call for: (a) keeping a rigorously neutral position, neither accepting nor refusing anything a priori; and (b) distinguishing facts from speculations and fallacies. Most available psychobiological interpretations remain so far speculations to be demonstrated, while brain disorders and/or drug administration in critical patients yield a well-known delirium in intensive care and anesthesia, the phenomenology of which is different from NDEs. Facts can be only true or false, never paranormal. In this sense, they cannot be refused a priori even when they appear implausible with respect to our current knowledge: any other stance implies the risk of turning knowledge into dogma and the adopted paradigm into a sort of theology. PMID- 22826699 TI - Enhancement of Closed-State Inactivation by Neutralization of S4 Arginines in Domain IV of a Sodium Channel. PMID- 22826698 TI - Reprogramming movements: extraction of motor intentions from cortical ensemble activity when movement goals change. AB - The ability to inhibit unwanted movements and change motor plans is essential for behaviors of advanced organisms. The neural mechanisms by which the primate motor system rejects undesired actions have received much attention during the last decade, but it is not well understood how this neural function could be utilized to improve the efficiency of brain-machine interfaces (BMIs). Here we employed linear discriminant analysis (LDA) and a Wiener filter to extract motor plan transitions from the activity of ensembles of sensorimotor cortex neurons. Two rhesus monkeys, chronically implanted with multielectrode arrays in primary motor (M1) and primary sensory (S1) cortices, were overtrained to produce reaching movements with a joystick toward visual targets upon their presentation. Then, the behavioral task was modified to include a distracting target that flashed for 50, 150, or 250 ms (25% of trials each) followed by the true target that appeared at a different screen location. In the remaining 25% of trials, the initial target stayed on the screen and was the target to be approached. M1 and S1 neuronal activity represented both the true and distracting targets, even for the shortest duration of the distracting event. This dual representation persisted both when the monkey initiated movements toward the distracting target and then made corrections and when they moved directly toward the second, true target. The Wiener filter effectively decoded the location of the true target, whereas the LDA classifier extracted the location of both targets from ensembles of 50-250 neurons. Based on these results, we suggest developing real-time BMIs that inhibit unwanted movements represented by brain activity while enacting the desired motor outcome concomitantly. PMID- 22826700 TI - Primary stroke center concept: strengths and limitations. PMID- 22826701 TI - A non-adhesive solid-gel electrode for a non-invasive brain-machine interface. AB - A non-invasive brain-machine interface (BMI) or brain-computer interface is a technology for helping individuals with disabilities and utilizes neurophysiological signals from the brain to control external machines or computers without requiring surgery. However, when applying electroencephalography (EEG) methodology, users must place EEG electrodes on the scalp each time, and the development of easy-to-use electrodes for clinical use is required. In this study, we developed a conductive non-adhesive solid-gel electrode for practical non-invasive BMIs. We performed basic material testing, including examining the volume resistivity, viscoelasticity, and moisture retention properties of the solid-gel. Then, we compared the performance of the solid-gel, a conventional paste, and an in-house metal-pin-based electrode using impedance measurements and P300-BMI testing. The solid-gel was observed to be conductive (volume resistivity 13.2 Omegacm) and soft (complex modulus 105.4 kPa), and it remained wet for a prolonged period (>10 h) in a dry environment. Impedance measurements revealed that the impedance of the solid-gel-based and conventional paste-based electrodes was superior to that of the pin-based electrode. The EEG measurement suggested that the signals obtained with the solid gel electrode were comparable to those with the conventional paste-based electrode. Moreover, the P300-BMI study suggested that systems using the solid gel or pin-based electrodes were effective. One of the advantages of the solid gel is that it does not require cleaning after use, whereas the conventional paste adheres to the hair, which requires washing. Furthermore, the solid-gel electrode was not painful compared with a metal-pin electrode. Taken together, the results suggest that the solid-gel electrode worked well for practical BMIs and could be useful for bedridden patients such as those with amyotrophic lateral sclerosis. PMID- 22826702 TI - A changing landscape in castration-resistant prostate cancer treatment. AB - Prostate cancer (PC) is the leading cause of cancer and the second leading cause of cancer-death among men in the Western world. About 10-20% of men with PC present with metastatic disease at diagnosis, while 20-30% of patients diagnosed with localized disease will eventually develop metastases. Although most respond to initial androgen-deprivation therapy (ADT), progression to castration resistant PC (CRPC) is universal. In 2004 the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have now led to an unprecedented number of new drug approvals within the past years, providing many new treatment options for patients with metastatic CRPC. Four new drugs have received U.S. Food and Drug Administration (FDA)-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. The data supporting the approval of each of these agents are described in this review, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. PMID- 22826703 TI - Using transgenic reporters to visualize bone and cartilage signaling during development in vivo. AB - Green fluorescent protein was first used as a marker of protein expression in vivo 18 years ago, heralding the beginning of what became known as the Green Revolution. Since then, there has been an explosion in the number of transgenic lines in existence, and these transgenic tools are now being applied to skeletal research. Advances in transgenesis are also leading to increasing use of new model organisms for studying skeletogenesis. Such new models include the small teleosts zebrafish and medaka, which due to their optical translucency offer imaging possibilities in the live animals. In this review, we will introduce a number of recent advances in genetic engineering and transgenesis and the new genetic tools that are currently being developed. We will provide examples of how zebrafish and medaka transgenic lines are helping us to understand the behavior of skeletal cells in vivo. Finally, we will discuss future prospects for the application of transgenic technology to skeletal research. PMID- 22826704 TI - Global Biodiversity of Aquatic Ammonia-Oxidizing Archaea is Partitioned by Habitat. AB - Archaea play an important role in nitrification and are, thus, inextricably linked to the global carbon and nitrogen cycles. Since the initial discovery of an ammonia monooxygenase alpha-subunit (amoA) gene associated with an archaeal metagenomic fragment, archaeal amoA sequences have been detected in a wide variety of nitrifying environments. Recent sequencing efforts have revealed extensive diversity of archaeal amoA sequences within different habitats. In this study, we have examined over 8000 amoA sequences from the literature and public databases in an effort to understand the ecological factors influencing the distribution and diversity of ammonia-oxidizing archaea (AOA), with a particular focus on sequences from aquatic habitats. This broad survey provides strong statistical support for the hypothesis that different environments contain distinct clusters of AOA amoA sequences, as surprisingly few sequences are found in more than one habitat type. Within aquatic environments, salinity, depth in the water column, and temperature were significantly correlated with the distribution of sequence types. These findings support the existence of multiple distinct aquatic AOA populations in the environment and suggest some possible selective pressures driving the partitioning of AOA amoA diversity. PMID- 22826705 TI - Viscosity dictates metabolic activity of Vibrio ruber. AB - Little is known about metabolic activity of bacteria, when viscosity of their environment changes. In this work, bacterial metabolic activity in media with viscosity ranging from 0.8 to 29.4 mPas was studied. Viscosities up to 2.4 mPas did not affect metabolic activity of Vibrio ruber. On the other hand, at 29.4 mPas respiration rate and total dehydrogenase activity increased 8 and 4-fold, respectively. The activity of glucose-6-phosphate dehydrogenase (GPD) increased up to 13-fold at higher viscosities. However, intensified metabolic activity did not result in faster growth rate. Increased viscosity delayed the onset as well as the duration of biosynthesis of prodigiosin. As an adaptation to viscous environment V. ruber increased metabolic flux through the pentose phosphate pathway and reduced synthesis of a secondary metabolite. In addition, V. ruber was able to modify the viscosity of its environment. PMID- 22826706 TI - Stimulation of autotrophic denitrification by intrusions of the bosporus plume into the anoxic black sea. AB - Autotrophic denitrification was measured in the southwestern coastal Black Sea, where the Bosporus Plume injects oxidized chemical species (especially O(2) and [Formula: see text]) into the oxic, suboxic, and anoxic layers. Prominent oxygen intrusions caused an overlap of [Formula: see text] and sulfide at the same station where autotrophic denitrification activity was detected with incubation experiments. Several bacteria that have been proposed to oxidize sulfide in other low oxygen environments were found in the Black Sea including SUP05, Sulfurimonas, Arcobacter, and BS-GSO2. Comparison of TRFLP profiles from this mixing zone station and the Western Gyre (a station not affected by the Bosporus Plume) indicate the greatest relative abundance of Sulfurimonas and Arcobacter at the appropriate depths at the mixing zone station. The autotrophic gammaproteobacterium BS-GSO2 correlated with ammonium fluxes rather than with sulfide fluxes and the maximum in SUP05 peak height was shallower than the depths where autotrophic denitrification was detected. Notably, anammox activity was not detected at the mixing zone station, though low levels of DNA from the anammox bacteria CandidatusScalindua were present. These results provide evidence for a modified ecosystem with different N(2) production pathways in the southwest coastal region compared to that found in the rest of the Black Sea. Moreover, the same Sulfurimonas phylotype (BS139) was previously detected on >30 MUm particles in the suboxic zone of the Western Gyre along with DNA of potential sulfate reducers, so it is possible that particle-attached autotrophic denitrification may be an overlooked N(2) production pathway in the central Black Sea as well. PMID- 22826707 TI - Pairing experimentation and computational modeling to understand the role of tissue inducer cells in the development of lymphoid organs. AB - The use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insights into the role of tissue inducer cells and associated signaling pathways in the formation and function of lymphoid organs. Despite advances in experimental technologies, the molecular and cellular process orchestrating the formation of a complex three-dimensional tissue is difficult to dissect using current approaches. Therefore, a robust set of simulation tools have been developed to model the processes involved in lymphoid tissue development. Specifically, the role of different tissue inducer cell populations in the dynamic formation of Peyer's patches has been examined. Utilizing approaches from systems engineering, an unbiased model of lymphoid tissue inducer cell function has been developed that permits the development of emerging behaviors that are statistically not different from that observed in vivo. These results provide the confidence to utilize statistical methods to explore how the simulator predicts cellular behavior and outcomes under different physiological conditions. Such methods, known as sensitivity analysis techniques, can provide insight into when a component part of the system (such as a particular cell type, adhesion molecule, or chemokine) begins to have an influence on observed behavior, and quantifies the effect a component part has on the end result: the formation of lymphoid tissue. Through use of such a principled approach in the design, calibration, and analysis of a computer simulation, a robust in silico tool can be developed which can both further the understanding of a biological system being explored, and act as a tool for the generation of hypotheses which can be tested utilizing experimental approaches. PMID- 22826709 TI - Detrimental effects of rat mesenchymal stromal cell pre-treatment in a model of acute kidney rejection. AB - Mesenchymal stromal cells (MSC) have shown immunomodulatory and tissue repair potential including partial tolerance induction by pre-treatment of donor specific cells in a rat heart transplantation model. Very recently, we could show that autologous MSC attenuated ischemia reperfusion injury in a highly mismatched donor-recipient rat kidney transplant model. Therefore, we investigated donor specific MSC pre-treatment in this rat kidney transplantation model to study whether graft function could be improved, or if tolerance could be induced. Donor and recipient-type MSC or phosphate buffered saline (PBS) as a control was injected i.v. 4 days before kidney transplantation. Mycophenolate mofetil immunosuppression (20mg/kg body weight) was applied for 7 days. Kidney grafts and spleens were harvested between days 8 and 10 and analyzed by quantitative RT-PCR and immunohistology. In addition, creatinine levels in the blood were measured and serum was screened for the presence of donor-specific antibodies. Surprisingly, application of both donor- and recipient-specific MSC resulted in enhanced humoral immune responses verified by intragraft B cell infiltration and complement factor C4d deposits. Moreover, signs of inflammation and rejection were generally enhanced in both MSC-treated groups relative to PBS control group. Additionally, pre-treatment with donor-specific MSC significantly enhanced the level of donor-specific antibody formation when compared with PBS- or recipient MSC-treated groups. Pre-treatment with both MSC types resulted in a higher degree of kidney cortex tissue damage and elevated creatinine levels at the time point of rejection. Thus, MSC pre-sensitization in this model impairs the allograft outcome. Our data from this pre-clinical kidney transplantation model indicate that pre-operative MSC administration may not be optimal in kidney transplantation and caution must be exerted before moving forward with clinical studies in order to avoid adverse effects. PMID- 22826708 TI - Tolerogenic therapies in transplantation. AB - Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials. PMID- 22826710 TI - Erythromycin treatment hinders the induction of oral tolerance to fed ovalbumin. AB - The mucosal immune system is constantly exposed to antigen, whether it be food antigen, commensal bacteria, or harmful antigen. It is essential that the mucosal immune system can distinguish between harmful and non-harmful antigens, and initiate an active immune response to clear the harmful antigens, while initiating a suppressive immune response (tolerance) to non-harmful antigens. Oral tolerance is an immunologic hyporesponsiveness to an orally administered antigen and is important in preventing unnecessary gastrointestinal tract inflammation, which can result in a number of autoimmune and hypersensitivity diseases. Probiotics (beneficial intestinal bacteria), T regulatory cells, and dendritic cells (DCs) are all essential for generating tolerance. Antibiotics are commonly prescribed to fight infections and often necessary for maintaining health, but they can disrupt the normal intestinal probiotic populations. There is increasing epidemiologic evidence that suggests that antibiotic usage correlates with the development of atopic or irritable bowel disorders, which often result due to a breakdown in immune tolerance. This study investigated the effect of the antibiotic erythromycin on oral tolerance induction to ovalbumin. The results demonstrated that antibiotic treatment prior to exposure to fed antigen prevents tolerance to that antigen, which may be associated with a reduction in intestinal Lactobacillus populations. Furthermore, antibiotic treatment resulted in a significant decrease in the tolerogenic CD11c(+)/CD11b(+)/CD8alpha(-) mesenteric lymph node DCs independent of tolerizing treatment. These results provide evidence that antibiotic treatment, potentially through its effects on tolerogenic DCs and intestinal microflora, may contribute to autoimmune and atopic disorders via a breakdown in tolerance and support prior epidemiologic studies correlating increased antibiotic usage with the development of these disorders. PMID- 22826712 TI - Pathogenesis of autoimmunity in common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) presents in up to 25% of patients with autoimmune (AI) manifestations. Given the frequency and early onset in some patients with CVID, AI dysregulation seems to be an integral part of the immunodeficiency. Antibody-mediated AI cytopenias, most often affecting erythrocytes and platelets make up over 50% of these patients. This seems to be distinct from mainly cell-mediated organ-specific autoimmunity. Some patients present like patients with AI lymphoproliferative syndrome. Interestingly, in the majority of patients with AI cytopenias the immunological examination reveals a dysregulated B and T cell homeostasis. These phenotypic changes are associated with altered signaling through the antigen receptor which may well be a potential risk factor for disturbed immune tolerance as has been seen in STIM1 deficiency. In addition, elevated B cell-activating factor serum levels in CVID patients may contribute to survival of autoreactive B cells. Of all genetic defects associated with CVID certain alterations in TACI, CD19, and CD81 deficiency have most often been associated with AI manifestations. In conclusion, autoimmunity in CVID offers opportunities to gain insights into general mechanisms of human autoimmunity. PMID- 22826711 TI - Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. AB - Wiskott-Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1-10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was(-/-) mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients. PMID- 22826713 TI - Expression of XCR1 Characterizes the Batf3-Dependent Lineage of Dendritic Cells Capable of Antigen Cross-Presentation. AB - Cross-presentation of antigen by dendritic cells (DCs) to CD8(+) T cells is a fundamentally important mechanism in the defense against pathogens and tumors. Due to the lack of an appropriate lineage marker, cross-presenting DCs in the mouse are provisionally classified as "Batf3-IRF-8-Id2-dependent DCs" or as "CD8(+) DCs" in the spleen, and as "CD103(+)CD11b(-) DCs" in the periphery. We have now generated a mAb to XCR1, a chemokine receptor which is specifically expressed on CD8(+) DCs and a subpopulation of double negative DCs in the spleen. Using this antibody, we have determined that only XCR1(+)CD8(+) (around 80% of CD8(+) DCs) and their probable precursors, XCR1(+)CD8(-) DCs, efficiently take up cellular material and excel in antigen cross-presentation. In lymph nodes (LNs) and peripheral tissues, XCR1(+) DCs largely, but not fully, correspond to CD103(+)CD11b(-) DCs. Most importantly, we demonstrate that XCR1(+) DCs in the spleen, LNs, and peripheral tissues are dependent on the growth factor Flt3 ligand and are selectively absent in Batf3-deficient animals. These results provide evidence that expression of XCR1 throughout the body defines the Batf3 dependent lineage of DCs with a special capacity to cross-present antigen. XCR1 thus emerges as the first surface marker characterizing a DC lineage in the mouse and potentially also in the human. PMID- 22826715 TI - Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources. AB - Shikimic acid properties and its available analytical techniques are discussed. Plants having the highest content of shikimic acid are shown. The existing isolation methods are analyzed and the most optimal approaches to extracting this acid from natural sources (plants and microorganisms) are considered. PMID- 22826714 TI - Evolution of the land plant exocyst complexes. AB - Exocyst is an evolutionarily conserved vesicle tethering complex functioning especially in the last stage of exocytosis. Homologs of its eight canonical subunits - Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84 - were found also in higher plants and confirmed to form complexes in vivo, and to participate in cell growth including polarized expansion of pollen tubes and root hairs. Here we present results of a phylogenetic study of land plant exocyst subunits encoded by a selection of completely sequenced genomes representing a variety of plant, mostly angiosperm, lineages. According to their evolution histories, plant exocyst subunits can be divided into several groups. The core subunits Sec6, Sec8, and Sec10, together with Sec3 and Sec5, underwent few, if any fixed duplications in the tracheophytes (though they did amplify in the moss Physcomitrella patens), while others form larger families, with the number of paralogs ranging typically from two to eight per genome (Sec15, Exo84) to several dozens per genome (Exo70). Most of the diversity, which can be in some cases traced down to the origins of land plants, can be attributed to the peripheral subunits Exo84 and, in particular, Exo70. As predicted previously, early land plants (including possibly also the Rhyniophytes) encoded three ancestral Exo70 paralogs which further diversified in the course of land plant evolution. Our results imply that plants do not have a single "Exocyst complex" - instead, they appear to possess a diversity of exocyst variants unparalleled among other organisms studied so far. This feature might perhaps be directly related to the demands of building and maintenance of the complicated and spatially diverse structures of the endomembranes and cell surfaces in multicellular land plants. PMID- 22826716 TI - Follicular pityriasis rosea. A case report and a new classification of clinical variants of the disease. AB - BACKGROUND: Atypical forms of pityriasis rosea are often noticed in Indian children. MAIN OBSERVATIONS: We describe a 9-year-old male child with predominant follicular eruptions on trunk consistent with a clinical diagnosis of pityriasis rosea. CONCLUSION: Follicular pityriasis rosea is an extremely rare presentation of the disease. We propose a new classification of clinical variants of pityriasis rosea. PMID- 22826717 TI - Multiple aplasia cutis congenita lesions located along Blaschko's lines in a patient with tetralogy of Fallot-A. AB - BACKGROUND: Aplasia cutis congenita (ACC) is a congenital absence of skin, and a single alopecic lesion on the scalp is the most common form. MAIN OBSERVATION: We present a case of ACC with tetralogy of Fallot-A. Differetial diagnosis included Adams-Oliver syndrome and nevus psiloliparus. Interestingly, our patient showed multiple ACC lesions, which were located along Blaschko's lines. CONCLUSIONS: As far as we know, our case is the third case of ACC with tetralogy of Fallot-A. Also, this is the first case of ACC associated with Blaschko's lines. PMID- 22826718 TI - Oculodentodigital Syndrome with Syndactyly Type III in a Pakistani consanguineous family. AB - BACKGROUND: Oculodentodigital syndrome (ODD; OMIM #164200) is a rare autosomal dominant disorder with pleiotropic effects. It is caused by mutation in gap junction protein alpha 1 (GJA1) gene which encodes connexion 43. ODD is characterised by symptoms i.e. craniofacial, neurologic, limb, ocular abnormalities, syndactyly type III of the hands, phalangeal abnormalities, diffuse skeletal dysplasia, enamel dysplasia, and hypotrichosis. OBJECTIVES: To study the Molecular Genetics of Oculodentodigital syndrome. PATIENTS/MATERIALS AND METHODS: Our current study includes a Pakistani family affected with ODD. Clinical evaluation revealed that this family shows typical form of ODD with Syndactyly type III. Mutations in GJA1 have been reported in ODD and also in syndactyly type III. In this study we sequenced the coding exons of GJA1 gene in affected and normal individuals of the family for mutation detection. RESULTS: Direct sequencing of the affected individuals showed a mutation at the nucleotide position 389 T>C. This mutation changed the codon 130 from Isoleucine to Threonine. Normal family members did not show this mutation. CONCLUSION: Our study showed no gross neurological upset with I130T mutation in GJA1 gene. This may present novel phenotypic outcome with the I130T. The study will help in better understanding of pathophysiology of oculodentodigital syndrome and type III syndactyly. PMID- 22826719 TI - Hailey-Hailey disease treated with methotrexate. AB - BACKGROUND: Hailey-Hailey disease (HHD) is a chronic, recurrent blistering disorder characterized clinically by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. MAIN OBSERVATIONS: We report a long standing case of HHD initially unresponsive to cyclosporin, multiple topical and systemic steroids. Good response was achieved with methotrexate 7,5 mg weekly for 16 week, intramuscularly, and topical steroids as needed. CONCLUSION: In conclusion, we suggest that methotrexate could be considered a therapeutic option for the treatment of HHD and in particular as a maintaining therapy to control the disease flares. PMID- 22826720 TI - Efficacy of 5% imiquimod cream in a patient with classic Kaposi sarcoma. AB - BACKGROUND: The classic Kaposi sarcoma is most common in the Mediterranean population over 50 years of age and presents with reddish-brown papules and nodules particularly on the lower limbs. Treatment depends on the clinical presentation and extension of lesions. Imiquimod is as an immune response modifier with antiangiogenic activity. MAIN OBSERVATIONS: We present a 74-year old man with classic Kaposi sarcoma who had multiple, small, violaceous papules and nodules on the trunk and extremities with a history of 14 years. He complained particularly from plantar hyperkeratotic painful nodules. Treatment with imiquimod 5% cream under occlusion resulted with almost complete regression within 12 weeks. No local or systemic side effects were observed. CONCLUSIONS: Topical imiquimod was a safe and effective therapy in our patient with classic Kaposi sarcoma. PMID- 22826721 TI - Photoletter to the editor: Blue nevus with satellitosis mimicking melanoma. Contribution of dermoscopy and reflectance confocal microscopy. AB - Blue nevus is an acquired benign melanocytic nevus that can undergo malignant transformation. We report a 70-year-old man who presented with a recently enlarged long-term blue nodule on his scalp. He reported onset of new satellitosis around the lesion. Although clinically thought to be a malignant melanoma, histopathological, dermoscopic and reflectance confocal-microscopy examinations did not confirm this diagnosis. PMID- 22826722 TI - Photoletter to the editor: Dermoscopy of atypical lichen sclerosus involving the tongue. AB - Involvement of tongue during the course of lichen sclerosus is extremely rare, with only five - to our knowledge - described cases in the English literature. We present clinical and dermoscopic findings of a female patient who concomitantly developed genital, skin and oral lesions of lichen sclerosus. Tongue involvement consisted of a linear atrophic whitish plaque, strikingly mimicking "en coupe de sabre" scleroderma. Dermoscopic examination revealed a well demarcated, linear, dense, white, homogenous area, with papillae projections hardly seen in the affected area. Dermoscopy of lesions located on the trunk revealed whitish plaques with comedo-like openings in the center and an erythematous halo at the periphery. Since clinical differentiation of oral LS and other oral diseases appearing as white atrophic plaques is almost impossible without using histology, we believe that dermoscopy might represent an additional tool, contributing to the final diagnosis, and thus avoiding an ablative procedure at this site sensitive localization. PMID- 22826724 TI - Photoletter to the editor: Dermoscopy in clinically atypical psoriasis. AB - Diagnosis of psoriasis is usually established clinically, based on the characteristic morphology and distribution of lesions. However, cases of psoriasis with atypical presentation do exist. In this manuscript we report and highlight the significant role of dermoscopy in the diagnosis of three clinically atypical and heterogeneous cases of psoriasis. PMID- 22826723 TI - Photoletter to the editor: Dermoscopy of granuloma faciale. AB - Granuloma faciale (GF) is a rare benign inflammatory dermatosis that usually develops as a solitary brownish-red plaque on the face. It clinically mimics and is often misinterpreted as, sarcoidosis, lupus erythematosus, lupus vulgaris, lymphoma or basal cell carcinoma.Dermoscopy, which is valuable for evaluation and differentiation between malignant and benign skin tumors, allows better visualization of dermal vascular structures and color variations. In this context, it might serve as an adjuvant diagnostic tool in the differentiation of inflammatory disorders, too. In the current manuscript, we present the dermoscopic features observed in a lesion of GF and discuss them in correlation with the underlying histopathological alterations. PMID- 22826725 TI - Photoletter to the editor: The Friar Tuck sign in trichotillomania. AB - Trichotillomania (TTM) is an impulse-control disorder, in which patients chronically pull hair from the scalp and/or other sites. We herein report a 8 year-old male patient who developed TTM in the classical tonsure pattern ("Friar Tuck" sign). The diagnosis was confirmed by trichoscopy, which showed decreased hair density, broken hairs with different shaft lengths, black dots, signs of hemorrhage, and an absence of exclamation mark hairs. PMID- 22826726 TI - Duodenal perforation in a 12-month old child with severe malaria. AB - Peptic ulcer disease (PUD) in children remains rare and difficult to diagnose before the onset of complications. We report on a case of a 12-month child with perforated duodenal ulcer, association with malaria. The severity of the febrile presentation and the positive laboratory confirmation of malaria delayed the diagnosis of PUD. Surgical intervention was successful and without significant sequelae. An awareness of the possibility, and a lower threshold for considering PUD in children may help prevent complications. PMID- 22826727 TI - A community survey of the pattern and determinants of household sources of energy for cooking in rural and urban south western, Nigeria. AB - INTRODUCTION: The use of solid fuels for cooking is associated with indoor pollution and lung diseases. The objective of the study was to determine the pattern and determinants of household sources of energy for cooking in rural and urban South Western, Nigeria. METHODS: We conducted a cross sectional study of households in urban (Ado-Ekiti) and rural (Ido-Ekiti) local council areas from April to July 2010. Female respondents in the households were interviewed by trained interviewers using a semi-structured questionnaire. RESULTS: A total of 670 households participated in the study. Majority of rural dwellers used single source of energy for cooking (55.6%) and urban dwellers used multiple source of energy (57.8%). Solid fuel use (SFU) was higher in rural (29.6%) than in urban areas (21.7%). Kerosene was the most common primary source of energy for cooking in both urban and rural areas (59.0% vs.66.6%) followed by gas (17.8%) and charcoal (6.6%) in the urban areas, and firewood (21.6%) and charcoal (7.1%) in the rural areas. The use of solid fuel was strongly associated with lack of ownership of dwellings and larger household size in urban areas, and lower level of education and lower level of wealth in the rural areas. Kerosene was associated with higher level of husband education and modern housing in urban areas and younger age and indoor cooking in rural areas. Gas was associated with high income and modern housing in the urban areas and high level of wealth in rural areas. Electricity was associated with high level of education, availability of electricity and old age in urban and rural areas respectively. CONCLUSION: The use of solid fuel is high in rural areas, there is a need to reduce poverty and improve the use of cleaner source of cooking energy particularly in rural areas and improve lung health. PMID- 22826728 TI - Congenital orbital teratoma: a case report and challenges of its management in a resource limited setting. AB - We report a case of congenital immature teratoma of the orbit in a female neonate who presented on the second day of life. She was successfully managed by modified exenteration. The patient was lost to follow-up intermittently over a 24-month period without recurrence of the tumour. However the patient could not be traced again after 24 months of follow up. This happened despite concerted efforts to educate the parents. The possible implications of this and other social factors, in a challenging and resource limited setting, on the prognosis of the disease and cosmetic outcome are considered. PMID- 22826729 TI - Incidence and correlates of low birth weight at a referral hospital in Northwest Ethiopia. AB - BACKGROUND: Weight at birth is a good indicator of the newborn's chances for survival, growth, long-term health and psychosocial development. Low birth weight (LBW) babies are significantly at risk of death, contributing to the high perinatal morbidity and mortality in developing countries. Hence, this study aims to assess the incidence and associated factors of low birth weight (LBW) in Gondar University Hospital deliveries. METHODS: A cross-sectional study, conducted on 305 live births from May 1- July 30, 2010. Information on independent variables was collected from the mothers just before discharge using a structured interview questionnaire. Neonatal weight was measured using standard beam balance. Both interviews and weight measurements were done by two trained midwives. Gestational age was determined by last normal menstrual period and/or ultrasound examinations. RESULTS: The mean and standard deviations of the birth weights were 2976 +/- 476 grams. Incidence of LBW (birth weight <2500 grams) was 17.1% (95%CI 13.3%, 21.6%). LBW was associated with first delivery (AOR=2.85), lack of antenatal care follow up (AOR= 5.68) or infrequent visits and being HIV positive (AOR=3.22). More female newborns were with low birth weight than males though the difference was not significant after controlling for potential confounders in the multivariate analysis. CONCLUSION: There is a high incidence of LBW. Efforts should to enhance national antenatal care utilization in general, and particularly in Gondar, should be encouraged as its absence is closely associated with LBW. PMID- 22826730 TI - Primary B cell lymphoma of the tongue: a case report. AB - Malignant lymphoma of the oral cavity is rare and of the tongue even rarer. Location of oral lymphomas is more frequent in masticatory mucosa than in movable mucosa; the lingual and buccal mucosa is rarely involved; whereas the gingival vestibule and Waldeyer's ring seem to be the most frequent site of occurrence. We describe a 78 year old male who presented with a mass lesion primarily involving the base of tongue and was diagnosed as diffuse large B cell lymphoma. The patient was treated with CHOP chemotherapy and radiotherapy. The lesion was completely disappeared). He has currently remained disease free for 16 months. Although oral lymphoma of tongue is very uncommon, it should always be considered in differential diagnosis of various benign and malignant lesions in this region. A proper clinical evaluation, histopathologic as well as immunohistochemical evaluation of biopsy specimen may aid in the diagnosis and thus, help in proper management. PMID- 22826731 TI - Prevalence and risk factors for zoonotic helminth infection among humans and animals - Jos, Nigeria, 2005-2009. AB - BACKGROUND: Zoonotic infections are among the most common on earth and are responsible for over 60% of human infectious diseases, some of which are caused by helminth parasites. Infection may result from ingestion of infective stage of worms with food, contaminated soil; skin penetration or direct animal contact. This study estimates the prevalence of zoonotic helminth infections (ZHI) among animals and humans in Jos and identifies associated risk factors METHODS: We reviewed laboratory records from five hospitals, one veterinary clinic and meat inspection record at abattoir in Jos from 2005-2009. Prevalence was defined as the observed frequency of cases of zoonotic helminth in the sampled population within the study period. Odd ratio analysis was used to identify factors associated with ZHI. RESULTS: Of 6689 humans tested, 524 (7.8%) were positive. Observed ZHI are: Ascaris species (4.5%), Taeniasis-Cysticercosis (1.5%), Schistosoma species (1.1%), Strongyloidosis (0.09%). Among animals, 3520 (18.1%) of 19508 tested/observed were positive; including Fasciola species (12.7%), Taeniasis-Cysticercosis (5.0%), Strongyloidosis (0.4%), Ascaris species (0.04%). The risk of infection was higher among humans aged 6-19 (OR: 3.2; 95% CI: 2.0 5.2) and 20-60 (OR: 2.3; 95% CI: 1.7-3.9). Peri-urban dwellers are at higher risk (OR: 1.5; 95% CI: 1.3-1.9); and so are farmers. CONCLUSION: The prevalence of zoonotic helminth infection is high among humans and animals in Jos. Risk of infection are higher among human age 6-60, peri-urban dwellers and farmers. This calls for the formulation of workable collaboration between human and veterinary medical disciplines for better control of zoonotic helminth infections. PMID- 22826732 TI - Giant cystic lymphangioma of the mesentery: varied clinical presentation of 3 cases. AB - Giant cystic lymphangioma is an uncommon mesenteric tumor which is usually reported in children. In this paper, we describe 3 cases, that was admitted in our department, two with abdominal distension, pain, and an abdominopelvic mass; the other present an acute abdomen. Preoperative studies including abdominal ultrasonography and computed tomography failed to determine the cause of the pain for the female patients. The laparotomy found a giant cystic tumor of the small bowel mesentery. The histological study showed a tumor that was diagnosed as a cystic lymphangioma. Based on those three cases a review of the literature is suggested. PMID- 22826733 TI - Health insurance education strategies for increasing the insured among older population - a quasi experimental study in rural Kenya. AB - INTRODUCTION: The older population in most developing countries are uninsured and lack access to health services. This study assessed the extent to which a multi strategy health insurance education intervention would increase the number of insured among the older population in rural Kenya. METHODS: The quasi experimental study prospectively followed 1,104 unpaired older persons (60 years or more) in a 10-month health insurance education and enrollment intervention. The adjusted odds ratios computed at 95% confidence interval using a binary logistic regression tested the association between being insured and the multi strategies. RESULTS: At baseline, the lack of adequate knowledge on health insurance (52.9%) and high premiums (38.1%) were the main reasons for being uninsured. The insured older persons increased three-fold (from 7.7% to 23.8%) in the experimental site but remained almost unchanged (from 4.0% to 4.6%) in the control. The computed adjusted odds ratio for variables with significance (p < 0.05) show that the older people who obtained health insurance education through the chief's public meeting, an adult daughter, an adult son, a relative sister/brother, an agent of the National Hospital Insurance Fund, and a health insurance beneficiary were 2.6, 4.2, 2.8, 2.3, 2.5 and 2.5 times respectively more likely to be insured. Access to health insurance education using a combination of 1-3 strategies and >3 strategies predisposed the older people 14.3 times and 52.2 times respectively to being insured. CONCLUSION: Health insurance education through multiple strategies and their intensity and frequency were pivotal in increasing being insured among the older population in rural Kenya. PMID- 22826734 TI - Histopathologic characteristics and short-term outcomes of colorectal cancer in young Tunisian patients: one center's experience. AB - INTRODUCTION: Colorectal carcinoma (CRC) is generally a disease of persons older than 40 years. Concerning younger patients, controversies still exist regarding features and prognosis of CRC. We performed this study to characterise CRC in young patients (<= 40 years) as well as to evaluate short-term outcome in comparison with older patients (>40 years) with CRC. METHODS: Clinical and histopathological parameters of 40 patients aged 40 years or less were compared with 240 patients aged more than 40 years. RESULTS: In young patients, the minority suffered from hereditary cancer syndromes (0.4%). Furthermore, up to 87% of young patients denied any cancers in their families. Compared with older patients, young patients had more mucinous adenocarcinomas (32.5% vs. 11.5%; p=0.02), more venous invasion (p=0.021), more perineural invasion (p=0.028). For grading (p=0.42), lymphatic invasion (p=0.17) and tumor sites (p=0.46), no significant differences between young and older patients were found. Young patients had less post operative morbidity (p=0.039), less post operative mortality (0.029). Young and older patients had the same overall 1-year survival rates (p=0.24), and the same cancer-related 1-year survival rates (p=0.1). CONCLUSION: Tunisian patients present with colorectal cancer at a more advanced stage of the disease at younger ages compared to developed countries. The early detection of CRC followed by a sufficient oncologic treatment is crucial regardless of age. It is mandatory for all patients with suspicious symptoms to undergo early adequate diagnoses. PMID- 22826735 TI - To avoid operating on pseudo tumoral pulmonary infarctions mimicking lung cancer. AB - Pulmonary infarction usually appears as a hump-shaped triangular opacity with its base applied to a pleural surface. In some cases, pulmonary infarctions may appear as a pseudo tumoral opacity mimicking lung cancer. Thoracotomy could be prevented by repeating CT scan in properly selected patients. PMID- 22826736 TI - Cerebellar ganglioglioma. AB - The cerebellar location of ganglioglioma (GG) is exceptional. We report one case of a 27-year-old man who underwent an intracranial hypertension syndrome and a static cerebellar syndrome. Brain magnetic resonance images revealed a cyst image in the vermis. Histological study after surgical removal, revealed a ganglioglioma tumor. Through this case and literature review, the authors discuss some epidemiological, histological, clinical, radiological and management features of this very rare tumor. PMID- 22826737 TI - Cancer in Angola, resources and strategy for its control. AB - BACKGROUND: Cancer is an increasingly important health problem in Africa. The number of cancer cases in this region could double, ranging between 700 000 and 1 600 000 new cases in 2030. The mortality rate is higher than 80% and is explained, mainly, by a lack of early detection, diagnostics and treatment resources. In Angola, about 7,000 patients die of cancer every year. METHODS: Data were derived from open-ended interviews conducted in 2010-11 with health authorities, clinicians, nurses and Administration of Hospitals. According Angola epidemiological data, results of interviews and international published advocacy for cancer control we develop a potential strategy for its control. The objectives are to identify existing resources for cancer control and describe the needs thereto, in order to establish an oncological program to guide the development of Angola cancer control strategies. RESULTS: Malaria remains the leading cause of illness and death in Angola, and other communicable diseases remain a public health problem. However, 9 000 new cases of cancer are diagnosed each year.The most common types of cancer are: cancer of the cervix, breast, prostate, esophagus, stomach and head and neck, as well as cancers with infectious origin, such as Kaposi's sarcoma and liver and bladder cancer. The foundation for developing national cancer control strategies includes: oncological data; investment and training; identifying and removing barriers; guidance and protection of the patient. Angolan National Cancer Centre, Sagrada Esperanca Clinic and Girassol Clinic are now developing a cancer program. CONCLUSION: Improving the economic situation of Angola creates conditions for an increase in life expectancy which in itself is associated with an increased risk of oncological diseases. On the other hand, infectious diseases, associated with the risk of malignant tumors, are endemic. Thus, an increase in patients with malignant disease is expected. A plan is therefore necessary to organize the response to this old but less visible nosologic situation. PMID- 22826738 TI - Sociodemographic factors and delay in the diagnosis of cervical cancer in Morocco. AB - BACKGROUND: In Morocco, cervical cancer is the second most common cancer in women. The cases of cervical cancer are diagnosed at a late stage: 43.7% presented at stage II of diagnosis (FIGO) and 38.1% in advanced stage (stage III and IV). The main objective of this study is to investigate factors associated to late the diagnosis of cervical cancer in Morocco as measured by the stage at diagnosis and delays between first symptoms and diagnosis of cancer. METHODS: Cross-sectional studies, conducted from June-2008 to June-2010 at two main oncological centers. Two-hundred cases were recruited. Stages I & II were identified as "early-stage". The dates of first-symptoms, first-consultation and first-diagnosis were used to define "Patient", "Medical" and "Total" delays. RESULTS: Elevated risks for late stage was observed for women unmarried (OR=5.0; 95%CI: 1.43-16.66); living > 100 km from center of diagnosis (OR=4.51; 95%CI: 1.35-15.11); without a familial history of cancer (OR=14.28; 95%CI: 2.22-100) and whose was the first symptom not bleeding (OR=25; 95%CI: 1.62-300). Frequency of housewives was significantly higher for women with a "patient-delay" >= 1 month. Frequency of patients who had symptoms of "bleeding" was significantly higher for women with a "patient-delay" <1 month. Frequency of patients from urban area was significantly higher for women with a "Medical-delay" < 1 month. Elevated risks for a long "Total-delay" was observed for women aged < 50 years (OR=2.44; 95%CI: 1.24-4.76); illiterate (OR = 3.85; 95%CI: 1.45-10.00) and from rural-area (OR=2.56; 95%CI: 1.25-5.26). CONCLUSION: Our results may represent an important tool in guiding the actions for an early diagnosis of cervical cancer. PMID- 22826739 TI - Africa has unique and urgent barriers to cleft care: lessons from practitioners at the Pan-African Congress on Cleft Lip and Palate. AB - BACKGROUND: The goals of this study were to delineate the protocols employed for managing patients with cleft lip and palate deformities, delineate the challenges facing practitioners and patients, and to determine the patient and physician barriers to cleft care delivery in the region. METHODS: Survey questionnaires were administered to practitioners attending the second Pan-African Congress on Cleft Lip and Palate (PACCLIP), which took place in Ibadan, Nigeria, West Africa from February 4-7, 2007. The conference included 225 participants, representing 17 African countries RESULTS: Protocols for repair of cleft lip and palate deformities were varied, with Millard's and von Langenbeck's techniques being the preferred approach for the management of cleft lip and palate deformities, respectively. A large proportion of providers have limited access to core cleft care supporting teams, especially speech language pathologists, orthodontists, and audiologists. Several challenging barriers to cleft care were also identified at both the institutional and individual levels and are reported. CONCLUSION: Geographic separation in Africa presents a similar challenge due to isolationism as it does to surgeons in Europe. Specific to Africa are the increased barriers to care, and economic and financial hardship at various levels. A focus on funding, team building, infrastructural support, and patient education appear to be crucial in improving the care and lives of children with facial clefts in Africa. PMID- 22826740 TI - [Tuberculous pericarditis at the University Hospital of Bobo-Dioulasso, Burkina Faso]. PMID- 22826741 TI - [Intussusception in adults: report of 17 cases]. PMID- 22826742 TI - Junctional ectopic tachycardia following repair of congenital heart defects experience in multimodal management from a West African Centre. AB - BACKGROUND: Postoperative junctional ectopic tachycardia (JET) is a rare and transient phenomenon occurring after repair of congenital heart defects. Report on this arrhythmia in the subregion is rare. We set out to determine the incidence of this arrhythmia and review the treatment and outcomes of treatment in our centre. METHODS: Retrospective search of the records of all patients aged 18 years and below admitted into the intensive care unit (ICU) following repair or palliation of a congenital heart defect over 5 years, from January 1, 2006 to December 31, 2010. A review of clinical notes, operative records, anaesthetic charts, cardiopulmonary bypass (CPB) records, nursing observation charts, electrocardiograms (ECGs) and out-patient follow-up records was undertaken. RESULTS: 510 children under 18 years were enlisted. 7 cases of postoperative JET were recorded, (1.37%). 184 (36.1%) of these were performed under CPB. All JET cases were from cases done under CPB, 3.8%. Median age was 3 years and median weight 11.3 kg. No patient was febrile at diagnosis. 4 patients had amiodarone administration, 5 had magnesium sulphate infusion, 2 patients had direct current shock (DCS) whilst 3 patients had all three therapeutic modalities. All patients had control of the arrhythmia with conversion to sinus rhythm and no recurrence. CONCLUSION: We report a JET incidence of 1.37% among children undergoing CPB for repair of congenital heart defects. We demonstrate the therapeutic effectiveness of amiodarone, magnesium sulphate infusions and DCS alone or in combination in the management of JET on various substrates with good outcome. PMID- 22826743 TI - Gastrointestinal stromal tumour of the rectum: a report of two cases. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract in adults, although rectal localisation of these tumours is very rare. We report here two cases of rectal stromal tumours in a 77 year-old woman and a 65-year-old man, confirmed by histology and immunohistochemistry. Surgery for rectal GIST patients is the standard treatment and adjuvant imatinib, a tyrosine kinase inhibitor, is indicated for GISTs with a high risk of malignancy, as well as in the case of metastatic or unresectable tumours. PMID- 22826744 TI - Primary retroperitoneal malignant melanoma. AB - We report a case of an extremely rare primary malignant melanoma presenting in the retroperitomeum, indurcing a diagnostic and management problem. PMID- 22826745 TI - Estimating the cost to rural ambulating HIV/AIDS patients on highly active antiretroviral therapy (HAART) in rural Ghana: a pilot study. AB - BACKGROUND: Subsidized antiretroviral therapy programs obviously lowers the cost of antiretroviral drugs but other major costs are still incurred, which makes the overall cost of accessing and consuming antiretroviral treatment very high and sometimes catastrophic. The objective of this study was to estimate the total cost to rural ambulating HIV/AIDS patients on highly active antiretroviral therapy in a rural area of the middle belt of Ghana. METHODS: This was a convenient cross-sectional study of people diagnosed with HIV/AIDS receiving outpatient care and carried out from September to October 2009 involving 80 HIV/AIDS patients on HAART. Data was derived from patients' medical records on health care utilization and a completed pre tested questionnaire used to obtain the cost of transportation and estimates of individual earned income from which the labor productivity loses (opportunity cost) for days not worked as a result of attending the antiretroviral clinic were derived. RESULTS: The median total, indirect and direct annual costs to rural ambulating HIV/AIDS patients on HAART were estimated to be $US71.18 (115.16 Ghana cedis), $US2.740 (3.92 Ghana cedis) and $US53.04 (75.00 Ghana cedis) respectively. CONCLUSION: Although the cost of antiretroviral drugs has been subsidized by government from $360 to $41.38 per annum, HIV/AIDS patients on HAART spend double of this subsidized amount out of their pocket seeking health care. We recommend that agencies associated with HIV/AIDS activities, supplements government's effort by helping to get antiretroviral closer to the door step of patients so as to reduce this huge financial burden which constitutes more than 100% of their median annual earned income. PMID- 22826747 TI - Analgesic neuropeptide W suppresses seizures in the brain revealed by rational repositioning and peptide engineering. AB - Anticonvulsant neuropeptides play an important role in controlling neuronal excitability that leads to pain or seizures. Based on overlapping inhibitory mechanisms, many anticonvulsant compounds have been found to exhibit both analgesic and antiepileptic activities. An analgesic neuropeptide W (NPW) targets recently deorphanized G-protein coupled receptors. Here, we tested the hypothesis that the analgesic activity of NPW may lead to the discovery of its antiepileptic properties. Indeed, direct administration of NPW into the brain potently reduced seizures in mice. To confirm this discovery, we rationally designed, synthesized, and characterized NPW analogues that exhibited anticonvulsant activities following systemic administration. Our results suggest that the combination of neuropeptide repositioning and engineering NPW analogues that penetrate the blood brain barrier could provide new drug leads, not only for the treatment of epilepsy and pain but also for studying effects of this peptide on regulating feeding and energy metabolism coupled to leptin levels in the brain. PMID- 22826746 TI - The chemical nature of mercury in human brain following poisoning or environmental exposure. AB - Methylmercury is among the most potentially toxic species to which human populations are exposed, both at high levels through poisonings and at lower levels through consumption of fish and other seafood. However, the molecular mechanisms of methylmercury toxicity in humans remain poorly understood. We used synchrotron X-ray absorption spectroscopy (XAS) to study mercury chemical forms in human brain tissue. Individuals poisoned with high levels of methylmercury species showed elevated cortical selenium with significant proportions of nanoparticulate mercuric selenide plus some inorganic mercury and methylmercury bound to organic sulfur. Individuals with a lifetime of high fish consumption showed much lower levels of mercuric selenide and methylmercury cysteineate. Mercury exposure did not perturb organic selenium levels. These results elucidate a key detoxification pathway in the central nervous system and provide new insights into the appropriate methods for biological monitoring. PMID- 22826748 TI - Irritable Bowel Syndrome in Iran: SEPAHAN Systematic Review No. 1. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Due to its high prevalence and absence of curative therapy, IBS has the potential to create tremendous burden on the health care system. Herein, we systematically reviewed the published literature to investigate the epidemiology of IBS in Iran. METHODS: Studies that were reviewed in this article were primarily identified through four online bibliographic databases including PubMed, Google Scholar, Iran Medex, and Scientific Information Database. Manual search of reference lists was carried out to identify any additional studies such as relevant abstracts and also recent review articles which may have been missed. Potentially related studies were retrieved and the selection criteria were applied. Eligible articles were reviewed. RESULTS: From 4176 studies identified, 18 eligible studies were included. It was reported that in Iran, the prevalence of IBS was in the range of 1.1% to 25% and was more common in women. In addition, the difference in frequency of different age groups was minimal. There was a minimal difference in IBS prevalence within different age groups. CONCLUSIONS: In Iran, the incidence of IBS was in the wide range. Since there are not enough population-based studies, researchers should focus on developing well-designed population-based studies to determine the epidemiology of IBS in Iran. Moreover, cohort studies should be conducted in order to investigate the natural history of IBS. Investigating the etiology of IBS and attempt to organize health promotion programs are highly suggested. PMID- 22826749 TI - Gastroesophageal Reflux Disease in Iran: SEPAHAN Systematic Review No. 2. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most prevalent disorders affecting gastrointestinal tract with a wide range of frequency around the world. In this study, we aimed to review all of the published studies about GERD's prevalence in Iran systematically. METHODS: We searched bibliographic databases including PubMed and Google Scholar and local databases (Scientific Information Database and Iran Medex) to achieve all relevant articles to our subject and included them based on predefined inclusion criteria. RESULTS: Twenty two articles were included in the study to estimate the prevalence of GERD in Iran. Based on these articles, the prevalence of GERD in Iran was within the range of 1.9 to 52%. CONCLUSIONS: Due to the differences between studies, such as characteristics of the sampled population and the diagnostic criteria, the reported prevalence of GERD was remarkably different in the reviewed studies. Nonetheless, because of the high prevalence of GERD in Iran, conducting large scale epidemiological studies should be considered to determine factors associated with the prevalence of GERD to prevent and control it. PMID- 22826750 TI - Seroprevalence of hepatitis a in patients with chronic hepatitis C in isfahan province. AB - OBJECTIVES: Patients with Hepatitis C Virus infection are at high risk of getting hepatitis A virus. Hepatitis A virus is an important widespread virus that usually causes more severe medical consequences in patients with chronic liver disease. The purpose of this study was to evaluate prevalence of Hepatitis A Virus antibody in patients with chronic HCV in Isfahan province, Iran. METHODS: A cross-sectional study was carried out on 117 patients with chronic hepatitis C virus from spring 2010 to spring 2011. Subject's characteristics such as age, gender, education, genotype of HCV infection and history of intravenous drug use were collected by questionnaire and studied. Statistical analysis was done by SPSS software (version 19.0. 2010, SPSS) using Chi-square test, Fisher Exact tests and Cochran-Armitage trend test. RESULTS: The mean age of the subjects was 33.18 +/- 10.97 years. The seroprevalence of HAV was 94.9% in patients with chronic HCV. The prevalence of anti-HAV increased nearly as age increased. But, there was no statistically significant difference in HAV positive rate according to the age groups (P = 0.242) and other patient's characteristics. CONCLUSIONS: According to the high HAV immunity in our study and less severe form of HAV infection, vaccination was not required in these patients. However, hepatitis A vaccination program should be performed in HAV seronegative patients with HCV to produce an adequate immune response. PMID- 22826751 TI - Mental health of Medical Students in Different Levels of Training. AB - OBJECTIVES: Medical education and training can directly contribute to the development of psychological distress in medical students. This can lead to catastrophic consequences such as impaired academic performance, impaired competency, medical errors and attrition from medical school. This study aimed to assess the prevalence of psychological morbidity among Iranian medical students. METHODS: This was a cross-sectional study. Samples of medical students in different levels of training (basic science, clinical clerkship, internship, and residency stage) were entered into the study. The 12-item General Health Questionnaire (GHQ-12) was used to measure psychological morbidity. Both univariate and multivariate analyses were used to report on findings. RESULTS: In all, 220 medical students were invited to take part in the study. Of these, 192 students agreed to fill in the questionnaire. The mean age of respondents was 25.4 (SD = 5.2) and 53% were female. Overall 49.5% of the students scored above the threshold on the GHQ-12 (score > 3.5). The results obtained from logistic regression analysis indicated that female gender and level of training were the most significant contributing factors to increased psychological distress [OR for female gender = 2.99; OR for the basic science group = 6.73]. CONCLUSIONS: Psychological distress appears to be common in medical students and significantly varies by gender and level of training. The psychological well-being of medical students needs to be more carefully addressed, and closer attention to eliminating the risk factors is critical to prevent consequent adverse outcomes. PMID- 22826752 TI - Seroprevalence and Risk Factors of Hepatitis C Virus among Juveniles in Correctional Center in Isfahan, Iran. AB - OBJECTIVES: Juveniles in custody are affected by blood borne viruses due to high rates of risk behaviors. Therefore, they have a disproportionate burden of infectious diseases, such as hepatitis C virus (HCV) infection. The purpose of the present study was to determine prevalence and associated characteristics of hepatitis C infection in inmates of a correctional center in Isfahan, Iran. METHODS: We conducted a cross-sectional study of HCV infection in 160 youths, who were admitted to correctional center in Isfahan during 2008-2009. Subjects were asked questions regarding behaviors that might put them at high risk for acquiring HCV and blood was drawn for this test. Sera were analyzed for HCV Ab and RIBA test was performed on antibody-positive HCV. We used Chi-square test and logistic regression model to analyze data and P < 0.05 was considered statistically significant. RESULTS: A total of 160 young prisoners (147 boys and 13 girls) were studied. The mean age of the inmates was 16.59 +/- 1.24 year. A history of intravenous drug addiction was reported in 3.8% of them. HCV infection was detected in 7 (4.4%) subjects. This study revealed that history of IDU was the main risk factor for HCV (OR, 134.44; 95% confidence interval [CI], 7.29 2481.03). CONCLUSIONS: To prevent HCV transmission, proper drug prevention educations should be performed in young age prisoners. PMID- 22826753 TI - Prevalence of anti HCV infection in patients with Beta-thalassemia in isfahan iran. AB - OBJECTIVES: Hepatitis C virus (HCV) is the major cause of post-transfusion hepatitis infection (PTH). Patients with thalassemia major are at high risk of hepatitis C due to the blood transfusion from donors infected by HCV. The aim of this study was to detect the prevalence of anti-HCV antibodies and risk factors in multitransfused thalassemic patients in Isfahan-Iran to establish more preventive strategies. METHODS: This study was conducted to assess the patients with beta-thalassemia in Isfahan hospitals during 1996-2011 for HCV infection. A structured interview questionnaire was developed by the trained researcher to collect the demographic and risk factors. Statistical analysis was done by Chi square test, Mann-Withney and multiple logistic regressions using SPSS software, version 15. RESULTS: 466 patients with major thalassemia participated in this study. The mean age of patients was 17.46 +/- 8.3. Two hundred and seventy (58.3%) and 193 (41.7%) of participants were male and female, respectively. The prevalence of HCV was estimated 8% among thalassemia patients. History of surgery, history of dental procedure, number of units transfused per month, number of transfusion per month and duration of transfusion had significant association with HCV seropositivity in univariate analysis. There were no statistical significant risk factors for HCV seropositivity in multiple logistic regression models. CONCLUSIONS: Our findings revealed that blood transfusion was the main risk factors for HCV infection among beta-thalassemic patients. Therefore, more blood donor screening programs and effective screening techniques are needed to prevent transmission of HCV infection among beta-thalassemic patients. PMID- 22826754 TI - Effect of Consuming Zinc-fortified Bread on Serum Zinc and Iron Status of Zinc deficient Women: A Double Blind, Randomized Clinical Trial. AB - After iron deficiency, zinc deficiency is the major micronutrient deficiency in developing countries, and staple food fortification is an effective strategy to prevent and improve it among at-risk-populations. No action has been taken to reduce zinc deficiency via flour fortification so far in Iran, and little is known about the influence of zinc fortification of flour on serum zinc and the iron status, and also about the optimum and effective amount of zinc compound that is used in food fortification. The objective of this study is to evaluate the influence of consuming zinc-fortified breads on the zinc and iron status in the blood serum. In this study, three types of bread were prepared from non fortified and fortified flours, with 50 and 100 ppm elemental zinc in the form of sulfate. Eighty zinc-deficient women aged 19 to 49 years were randomly assigned to three groups; The volunteers received, daily, (1) a non-fortified bread, (2) a high-zinc bread, and (3) a low-zinc bread for one month. Serum zinc and iron were measured by Atomic Absorption before and after the study. Results showed a significant increase in serum zinc and iron levels in all groups (p < 0.001) except in the control (p > 0.05). Absorption of zinc and iron in the group that consumed high-zinc bread was significantly greater than that in the group that received low-zinc bread (p < 0.01). It was concluded that fortification of flour with 50-100 ppm zinc was an effective way to achieve adequate zinc intake and absorption in zinc-deficient people. It also appeared that consuming zinc fortified bread improved iron absorption. PMID- 22826755 TI - Hepatitis C among Intravenous Drug Users in Isfahan, Iran: a Study of Seroprevalence and Risk Factors. AB - OBJECTIVES: Hepatitis C virus (HCV) is one of the major public health problems worldwide which is transmitted through contact with infected blood or blood products. One of the most prevalent modes of HCV transmission is injecting drug with unclean needles or syringes. Therefore intravenous drug users (IVDUs) are the most important group who should be considered. The aim of this study was to evaluate seroprevalence and risk factors of hepatitis C virus in IVDUs population. METHODS: The cross-sectional study was carried out on intravenous drug users who attended health and social care Drop-in centers during November 2008 to February 2009 in Isfahan province, Iran. Data was gathered using interviewer-administered questionnaire including demographic characteristics and main risk factors for HCV infection. 5ml venous blood sample was obtained from each subject. The HCV-Ab test was performed on all blood samples by ELISA. The data was analyzed using descriptive statistical methods and multiple logistic regressions by SPSS software, version 15. RESULTS: The mean age of participants was 31.77 +/- 8.51. 503 (94.7%) were men and 28 (5.3%) were women. HCV seroprevalence was 47.1% (95% CI: 42.9, 51.3). The multiple logistic regressions demonstrated that history of tattooing (OR 1.72, 95% CI 1.02-2.90), history of imprisonment (OR 2.49, 95% CI 1.40-4.42) and sharing needles/syringes (OR 2.76, 95% CI 1.54-4.95) are significant predictors of risk of HCV in IVDU population. CONCLUSIONS: In conclusion, according to the high prevalence of HCV infection among IVDUs and high adds of HCV infection from tattooing, sharing of needles/syringes and imprisonment, effective harm reduction programs should be expanded among IVDUs to prevent new HCV infections. PMID- 22826756 TI - The Efficiency of Mental Health Integration in Primary Health Care: a Ten-year Study. AB - OBJECTIVES: This study was conducted on the estimation of the efficiency of mental health program in primary health care in Chaharmahal and Bakhtyari province, situated in center of the Islamic Republic of Iran, from 1999 to 2009. METHODS: One of the important objectives of mental health program is screening of mental health disorders and follow up. According to the prescription of mental health program, General Practitioners (GPs) were appointed to screen under covered individuals, treat patients and also follow-up the patients with mental health disorders who needs referring to psychiatric clinics. Diagnostic criteria of mental disorders were based on American Psychiatry Association (DSM IV1994). Patients were categorized in four groups as follows: 1 - Severe mental disorders, such as major depression, schizophrenia, bipolar disorders, etc., 2 - Mild mental disorders, such as neurosis, anxiety, etc., 3 - Convulsive disorders and 4 - Behavioral disorders. The convulsive disorders and their types were diagnosed by physical examination and electroencephalography. In order to screen mental retardation, intelligence scale (IQ) score < 70 was considered as mental retardation. During the 10 years (1999 to 2009) of conducting program, all new diagnosed cases were confirmed by psychiatrists. All data was recorded in health files by trained GPs and they were assessed and justified by psychiatrists. RESULTS: During 10 years after conducting and stabilizing integrated mental health in primary health care, 13514 patients overall were newly detected and followed. Ten years incidence of total psychiatric disorders was estimated in about 15.9 per 1000 populations. CONCLUSIONS: Integrated mental health care offers the opportunity to increase access and develop efficiency of the mental health cares. PMID- 22826757 TI - Seroprevalence of Hepatitis C Infection among Laboratory Health Care Workers in Isfahan, Iran. AB - OBJECTIVES: Clinical laboratory health care workers can become infected through their occupation with blood-borne pathogens by percutanous injuries and mucocutaneous blood contacts such as cuts, needle sticks, splashes to mucous membranes or other body injuries. The purpose of this study was to determine the seroprevalence of, Hepatitis C virus (HCV), and some of the risk factors in medical laboratory health care workers. METHODS: Through a descriptive cross sectional study, 203 participants employed in the clinical laboratories of the city of Isfahan, composed of medical laboratory technologists, technicians and cleaning staff were studied. Participant data were obtained through a self reporting questionnaire and the level of anti-HCV antibody was measured by enzyme linked immunosorbent assay (ELISA). Chi-square test was used to determine risk factors associated with infection. RESULTS: The mean age of the individuals (n = 203) was 35.8 +/- 9.54 years. There were 115 women (56.7%) and 88 men (43.3%). All of the subjects were negative for HCV Ab. CONCLUSIONS: Hepatitis C infection is infrequent in laboratory health care workers in Isfahan province. PMID- 22826758 TI - Comparison of the preventive analgesic effect of rectal ketamine and rectal acetaminophen after pediatric tonsillectomy. AB - OBJECTIVES: There is a little data about rectal administration of Ketamine as a postoperative analgesic, so we compared the efficacy of rectal ketamine with rectal acetaminophen, which is applied routinely for analgesia after painful surgeries like tonsillectomy. METHODS: In this single-blinded comparative trial, we enrolled 70 children undergoing elective tonsillectomy, and divided them randomly in two groups. Patients received rectal ketamine (2 mg / kg) or rectal acetaminophen (20 mg / kg) at the end of surgery. The children's Hospital of Eastern Ontario Pain scale was used to estimate pain in children. Also the vital signs, Wilson sedation scale, and side effects in each group were noted and compared for 24 hours. RESULTS: The ketamine group had a lower pain score at 15 minutes and 60 minutes after surgery in Recovery (6.4 +/- 0.8, 7.4 +/- 1 vs. 7.1 +/- 1.2, 7.8 +/- 1.2 in the acetaminophen group, P < 0.05) and one hour and two hours in the ward (7.2 +/- 0.7, 7 +/- 0.5 vs. 7.9 +/- 1.2, 7.5 +/- 1.2 in the acetaminophen group, P < 0.05), with no significant differences till 24 hours. Dreams and hallucinations were not reported in the ketamine group. Systolic blood pressure was seen to be higher in the ketamine group (104.4 +/- 7.9 vs. 99.8 +/- 7.7 in the acetaminophen group) and nystagmus was reported only in the ketamine group (14.2%). Other side effects were equivalent in both the groups. CONCLUSIONS: With low complications, rectal ketamine has analgesic effects, especially in the first hours after surgery in comparison with acetaminophen, and it can be an alternative analgesic with easy administration in children after tonsillectomy. PMID- 22826759 TI - Hepatitis C Virus and Associated Risk Factors among Prison Inmates with History of Drug Injection in Isfahan, Iran. AB - OBJECTIVES: Hepatitis C virus (HCV) infection is a major public health problem worldwide with serious complications. According to the importance of intravenous drug use (IDU) as the main risk factor for HCV infection and transmission and prison as the main source of risky behaviors, this study conducted to define HCV infection and related risk factors in prison inmates with history of IDU in Isfahan province, Iran. METHODS: This is a cross -sectional study which the prison inmates with IDU history in voluntary basis were enrolled. A validated questionnaire was asked and blood sample was obtained from each subject for the presence of HCV antibody. Odds ratio and logistic regression were used for data analysis and P-value < 0.05 considered significant. RESULTS: I943 inmates with history of IDU participated in the study. The overall prevalence of HCV antibody was 41.6%. The main independent risk factors were number of injection in the month [OR: 1.006 (1.002- 1.011)], Length of drug addiction [OR: 1.05 (1.004 1.098)], multiple incarceration [OR: 1.15 (1.05-1.23)] and use of needle/syringe share inside prison [OR: 4.19 (2.22-7.9)]. In our study, marriage was a protective factor for HCV infection [OR: 0.34 (0.18-0.64)] as well. CONCLUSIONS: According to relatively high prevalence of HCV infection and associated risk factors which observed in this study it is important to primary prevention in prisons through syringe/needle exchange and counsel with imprisoned IDUs. PMID- 22826760 TI - Preventive Therapy of Experimental Colitis with Selected iron Chelators and Anti oxidants. AB - OBJECTIVES: Iron chelators, such as maltol and kojic acid, have antioxidant and anti-inflammatory properties. They may have beneficial effects on inflammatory bowel disease (IBD) because iron can develop and aggravate inflammation in IBD. In the present study, the effect of selected iron chelators and anti-oxidants were evaluated on a model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: Colitis was induced with instillation of 75 mg/kg TNBS in 0.25 ml ethanol 50% via the anus in fasted male Wistar rats. The animals were assigned randomly to 12 groups (n = 6) and treated once daily, started 2 hours before colitis induction, with normal saline (5 ml/kg), maltol (70, 140, 280 mg/kg), kojic acid (75, 150, 300 mg/kg), vitamin E (400 mg/kg), deferiprone (L1) (150 mg/kg) and prednisolone (4 mg/kg) orally and deferoxamine (50 mg/kg) intraperitoneally for 5 days. In the sixth day, rats were scarified and colon tissues were assessed macroscopically and pathologically. RESULTS: Maltol (280 mg/kg) was able to reduce colon weight / length ratio, ulcer index and total colitis index similar to prednisolone, deferoxamine and deferiprone as positive controls. However, kojic acid and vitamin E could not significantly alleviate macroscopic and/or pathologic features of inflammation in comparison to normal saline. CONCLUSIONS: Maltol with the highest test dose was capable to protect against experimentally induced colitis. Kojic acid and vitamin E were not effective in this animal model of colon inflammation. More detailed studies are warranted to explore the mechanisms involved in anti-colitic property of maltol and to explain ineffectiveness of kojic acid and vitamin E. PMID- 22826761 TI - Identification of Patients with Hepatitis C Virus Infection in Persons with Background of Intravenous Drug Use: The First Community Announcement-based Study From Iran. AB - OBJECTIVES: Injection drug use plays the most important role in transmission of hepatitis C. In Iran, surveys have been conducted on various high risk groups but this is the first announcement based study for hepatitis C virus HCV prevalence among cases with history of intravenous drug using (IVDU) in the country. METHODS: The announcement-based detection and follow-up of patients with anti-HCV positive project in volunteers with history of intravenous drug using was conducted in Isfahan province. At the first step, six focus groups were conducted and 2 pilot studies were carried out in two cities to design the main study. Comprehensive community announcement was done in all of public places and for physicians. The volunteers were invited to Isfahan reference laboratories and the serum samples were sent to Infectious Diseases Research Center Laboratory in standard conditions and HCV-Ab was tested by ELISA method. RESULTS: In this study, 1,747 individuals that are estimated 50% of all expected intravenous drug users in the community were presented themselves. The most important reasons of success in recruiting volunteers in this study were the perfect propaganda, appropriate cooperation of lab staffs, continuous evaluation and good cooperation in Isfahan province administrations. HCV-Ab was detected in 34% of them and the HCV-Ab positives were sent for further follow-up procedures including confirmatory test, education, and treatment. CONCLUSIONS: In spite of some limitations to select real cases, this study was considered as a successful experience. Compared to the surveys in Iran on HCV prevalence in intravenous drug users, the results of this study, which was based on volunteers by announcement seems to be noteworthy. PMID- 22826762 TI - Certain hospital waste management practices in isfahan, iran. AB - OBJECTIVES: Infected hospital wastes are among hazardous wastes, and special treatment methods are needed for their disposal. Having information about present status of medical waste management systems is of great importance in finding weak, and for future planning. Such studies have not been done for most of the hospitals in Iran. METHODS: This paper reports the results of a study on the present status of medical waste management in Isfahan hospitals. A ten page researcher made questionnaire was used to collect data in terms of collection, transportation, segregation, treatment and disposal. For assessment of autoclaves, standard tests including TST (Time, Steam, and Temperature) strip test and spore tests were used. Samples were made of stack gases of incinerators. Quantity and composition of hospital wastes in Isfahan were also measured manually. RESULTS: Of all wastes in selected hospitals, 40% were infected wastes (1.59 kg/day/bed), which is 15 to 20% higher than World Health Organization (WHO) standards. TST and Spore test results were negative in all samples. Stack gases analysis showed high concentration of CO in some samples. Besides, the combustion efficiency in some samples is less than 99.5%, which is the standard criterion in Iran. CONCLUSIONS: This study may create awareness regarding the magnitude of the problem of waste management in hospitals of Isfahan and may stimulate interests for systematic control efforts for hospital waste disposal. Hospital waste management cannot succeed without documented plans, certain equipment, defined staff trainings, and periodic evaluations. PMID- 22826763 TI - Dyspepsia in Iran: SEPAHAN Systematic Review No. 3. AB - BACKGROUND: Dyspepsia is an upper gastrointestinal tract syndrome presenting epigastric pain and discomfort, fullness sensation, early satiety, nausea, vomiting, and belching. The prevalence of dyspepsia has been reported to be high all over the world. In this study, we reviewed studies reporting the prevalence of dyspepsia in Iran and discussed the probable risk factors of dyspepsia to shed light on future research on this topic. METHODS: The four electronic databases of PubMed, Google Scholar, IranMedex, and Scientific Information Database were searched. The keywords for the electronic search were "dyspepsia" and "Iran". A manual search of the reference lists of the selected articles was also carried out. Two reviewers reviewed and identified articles independently and selected relevant studies based on our inclusion and exclusion criteria. RESULTS: Nine articles reporting the prevalence of dyspepsia in Iran were included. The reported prevalence ranged from 2.2% to 29.9%. The majority of studies have reported the prevalence of dyspepsia to be higher in women. CONCLUSION: Dyspepsia seems to be highly prevalent in Iran. Considering the wide range of data reported in different studies, conducting further population-based studies is necessary to investigate the epidemiology and risk factors of dyspepsia among Iranians. PMID- 22826764 TI - Effects of Common Anti-epileptic Drugs on the Serum Levels of Homocysteine and Folic Acid. AB - OBJECTIVES: Elevated total plasma homocysteine has been established as an independent risk factor for CVD. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with CAD. Interference with folate and homocysteine metabolism by some drugs, may lead to increased plasma homocysteine levels. The object of the study was to examine the effect of AEDs on the serum concentrations of folic acid. METHODS: A total of 22, older than 18-year-old, epileptic patients, admitted in the Neurology Clinic, who were treated with AED at least for one year were selected. Twenty-two sex- and age-range-matched controls were enrolled in the study. Concentrations of total homocysteine and folic acid in the serum were measured in a fasted status. Demographic and medicine information was collected via a questionnaire. Data were analyzed by spss(16) software. RESULTS: Mean of serum Hcy concentration in the patients was significantly higher compared to that in the controls (p = 0.04). Serum folic acid had a nonsignificant negative correlation with the dose of drug used (p = 0.2). Serum homocysteine was not significantly correlated with the dose and duration of drug consumption (p values were 0.4, 0.24, respectively). Serum homocysteine was not significantly correlated with the kind of drug (p = 0.4), but folic acid concentration was significantly lower in the monotherapy group than in the poly therapy group (p = 0.02). CONCLUSIONS: Homocysteine (Hcy) was not different between the epileptic and nonepileptic groups, although the means of the serum folic acid were similar. Possible mechanisms by which AEDs could cause hyper-homocysteinemia might be through the dysfunction of homocysteine metabolism, the acceleration of vitamin metabolism, and the interference in the metabolism of folic acid coenzymes. PMID- 22826765 TI - Health Promoting Behaviors in a Population-based Sample of Middle-aged Women and its Relevant Factors in Yazd, Iran. AB - OBJECTIVES: This study is carried out with the aim of describing the pattern of health-promoting behaviors (HPBs) among middle-aged women and its relevant factors in Iran as a Muslim developing country. METHODS: In a cross-sectional study, 483 middle-aged women were selected using cluster random sampling from Yazd city in Central Iran. An adjusted Persian version of Health Promoting Lifestyle Profile II was used for measuring HPBs. The demographic data were collected too. RESULTS: The average score of middle-aged women HPBs was 2.73 +/- 0.36 (2.69 +/- 2.76, %95). Spiritual growth and physical activity had the highest and the lowest score in HPBs' dimensions, respectively. HPBs had a positive significant correlation with age (p=0.02) and education level (p=0.001) and a negative significant correlation with number of children (p=0.005). HPBs had a higher level in retired women than employees and housewives. CONCLUSIONS: In spite of a desirable level of HPBs in spiritual growth and interpersonal relationship dimensions among this group, their level of HPBs in physical activity and health responsibility dimensions was undesirable. It means that the feature of health among Iranian middle-aged women in a Muslim developing country is different from the industrialized developed and also the non-Muslim countries; hence, they need a different intervention programs. PMID- 22826766 TI - Preoperative Topical Diclofenac and Ketorolac in Prevention of Pain and Discomfort Following Photorefractive Keratectomy: A Randomized Double-masked Placebo-controlled Clinical Trial. AB - OBJECTIVES: To compare the efficacy of a single dose of topical diclofenac 0.1% and ketorolac 0.5%, with placebo and with each other in the prevention of post PRK pain and discomfort. METHODS: In this randomized double-masked trial, adults undergoing bilateral PRK surgery were assigned to two arms. The first arm received a single dose diclofenac 0.1%, randomly in either the right, or left eye, and artificial tear (as the placebo) in the other eye. The second arm received ketorolac 0.5%, by the same pattern. The primary outcome of this study was ocular[1] pain assessed by visual analogue scale (VAS), and,[2] discomfort including itching, foreign body sensation, tearing and photophobia which were questioned in 4 degrees. RESULTS: In the final analysis, 47 and 36 subjects remained in the diclofenac and ketorolac treated arms, respectively. In both arms, on the first and second post-operation days, VAS scores were significantly lower in the pretreated eye. Moreover, on the first post-operation day, the intensity of all ocular discomfort items was statistically lower in the pretreated eyes; whereas, on the second day, such a difference was only observed for foreign body sensation and itching in the diclofenac treated arm and for photophobia in ketorolac treated arm. Comparison of the two arms (diclofenac pretreated eyes vs. ketorolac pretreated eyes) on both first and second post operation days showed no significant difference neither in the VAS scores nor the ocular discomfort items. CONCLUSIONS: Either diclofenac or ketorolac instilled at a dose of one drop 30 minutes in advance of the operation would be equally beneficial in the short-term prevention of post-PRK pain and discomfort. PMID- 22826767 TI - Bloating in Iran: SEPAHAN Systematic Review No. 4. AB - OBJECTIVES: Bloating is a common and bothersome gastrointestinal symptom. Despite its high prevalence, associated costs, and effects on the quality of life, very few studies have reported the epidemiology of bloating in Iran. Through this systematic review, findings and limitations of the current research will be discussed. METHODS: In March 2012, we searched PubMed, Google Scholar, Scientific Information Database, IranMedex, and Magiran to find articles for inclusion in the study. Two of the authors screened the articles on the basis of titles and abstracts. The full manuscripts of these publications were then evaluated according to the predefined criteria. RESULTS: Fifteen articles were included in the study, and data regarding the prevalence of bloating were extracted. The studies depict a prevalence of 1.5% to 8.8% for bloating in the Iranian population. Two studies reported the prevalence of functional bloating to be 1.5% and 10% according to the Rome III and Rome II criteria, respectively. Female to male ratio remains >=1 for most of the studies criteria. CONCLUSIONS: In Iran, data on the prevalence of bloating are limited, and have mostly been gathered from a highly selective population. The results of the present study advocate the necessity to perform further studies on the general population, which may help health policy makers in the allocation of the appropriate resources. PMID- 22826768 TI - Constipation in Iran: SEPAHAN Systematic Review No. 5. AB - BACKGROUND: Constipation is physically and mentally troublesome for many patients and has adverse effects on their quality of life. The aim of the present study was to systematically review previous studies on the epidemiology of constipation in Iran. METHODS: Bibliographic databases including PubMed, Google Scholar, and Iranian databases including Scientific Information Database, Iran Medex, and Magiran were searched to select studies that reported the prevalence of constipation in Iran. RESULTS: Overall, 10 articles met the inclusion criteria of the current study. The prevalence of constipation in Iran ranged from 1.4-37%, and the prevalence of functional constipation was reported to be 2.4-11.2%. Gender, age, socioeconomic status and educational level seem to have major effects on this condition. CONCLUSION: The prevalence of constipation is high in Iran. There are very few data available regarding the natural history, quality of life and risk factors of constipation in our country. Conducting population-based studies is necessary to explore different epidemiological aspects of constipation in Iran. PMID- 22826769 TI - Edentulism and Tooth Loss in Iran: SEPAHAN Systematic Review No. 6. AB - OBJECTIVES: Tooth loss appears to have an important role in the loss of mastication and esthetics. The aim of this systematic review was to investigate the prevalence of tooth loss and edentulism in the Iranian population. METHODS: Studies reviewed in this article were primarily identified via search of the online bibliographic databases including PubMed and Iranian Biomedical Journals, by using "tooth loss", "edentulism", "epidemiology", and "Iran" as keywords. Studies potentially related to this topic were retrieved and the selection criteria applied. From the chosen studies the eligible articles were reviewed. RESULTS: Of the studies identified after conducting the search, 10 eligible studies were extracted. The prevalence of tooth loss ranges between 0.3% in 3 to 5-year-old children to 70.7% in adults over 65. There is a lack of well-designed epidemiological studies on edentulism and tooth loss in Iran. The prevalence of tooth loss is high and it increases by aging. CONCLUSIONS: It seems that the prevalence of tooth loss is high among adults in Iran. It is highly suggested that population-based studies should be established to investigate the epidemiology and risk factors of tooth loss in Iran. The results of such studies will be useful in the adoption of appropriate preventive strategies. PMID- 22826770 TI - Surveillance system for hepatitis C infection: A practical approach. AB - Hepatitis C virus (HCV) infection is a serious public health concern throughout the world. Despite its public health prominence, however, how surveillance systems for hepatitis C should be designed is still a challenging issue especially in developing countries such as Iran. Establishing a surveillance system needs an ongoing process of case investigation, data collection, analysis of data and also dissemination of data to public health professionals and health care providers.This review article tries to provide the best recommendations for planning and implantation a surveillance system for HCV infection. PMID- 22826771 TI - Diagnostic value of serologic tests in celiac screening. AB - OBJECTIVES: Celiac disease is one of the malabsorption syndromes leads to growth and development retardation in children. There is no test lonely can definitely diagnose celiac; however, the collection of clinical findings, serologic tests, intestinal biopsy, and response to treatment may diagnose it. Although diagnostic value is variable in different studies, they are used a non-invasive and appropriate screening methods today. This study aimed to evaluate diagnostic value of celiac serologic tests in children less than 15-year-old. METHODS: During two years, this study conducted on children referred to Al-Zahra hospital (Isfahan, Iran). All the children who had duodenal biopsy tests were evaluated in terms of serologic tests and clinical symptoms due to suspected celiac. The results were analyzed through descriptive statistics, chi-square and Fisher's exact tests using SPSS software. RESULTS: 15.8 percent of children were under 2 years, 37.3 percent between age range of 2 to 12 years and 10.5 percent were above 12 years. 8.1 percent of children with negative anti-endomysial antibody (EMA) suffered from celiac; while 20.0 percent of children with positive EMA suffered from celiac. 15.4 percent of children with negative anti-gliadin antibody (AGA) had celiac; while 11.6 percent of those with positive AGA suffered from it. 11.1 percent of those with negative tissue transglutaminase antibody (tTG) and 37.5 percent with positive tTG suffered from celiac. CONCLUSIONS: According to our study results, there is no correlation between gastrointestinal symptoms such as vomiting diarrhea, anorexia, bulimia, and failure to thrive (FFT) with celiac. TTG was the best screening test method to diagnose celiac disease and other tests such as AGA and EMA do not have high diagnostic value. PMID- 22826772 TI - Mental disorder prevention and physical activity in Iranian elderly. AB - OBJECTIVES: Mental disorders such as depression, anxiety and dementia are common in elderly. However, physical activity is suggested to be effective in preventing such aging-related disorders. The aim of this study was to investigate the role of physical activity on mental health in later life. METHODS: Four hundred elderly people were randomly divided into the intervention and control groups. The intervention consisted of exercise twice a week for two months. Mental health status before, just after, and three months after the study was assessed with the 28-item General Health Questionnaire (GHQ-28). RESULTS: The mean of the GHQ-28 total scale decreased in the case group and this change remained significant after three months (before: 8 +/- 5.5, after three months: 5.6 +/- 4.6, p < .001). GHQ subscales including somatization, anxiety, social dysfunction, and depression decreased significantly in the case group just after and three months after the intervention. CONCLUSIONS: Physical activity significantly prevents mental disorder in older adults. Although it has effects on anxiety, social dysfunction, and depression, the greatest influence is on improving the somatization symptoms. PMID- 22826773 TI - High risky behaviors among intravenous drug users in Isfahan, Iran: A study for hepatitis C harm reduction programs. AB - OBJECTIVES: Intravenous drug users (IVDUs) who share needles/syringes and practice sexual behaviors, are the most important group in the transmission of blood-borne infection diseases such as hepatitis C virus (HCV). Therefore identification of prevalent high-risky behaviors among IVDUs to detect the most route of transmission among them is essential to develop harm reduction programs among IVDUs and decrease HCV transmission from them to community. METHODS: The cross-sectional study was carried out on 1510 intravenous drug users from November 2008 to February 2009 in Isfahan province, Iran. After obtaining consent form from participants, information was collected by interviewer-administered validated questionnaire. The data was analyzed with descriptive statistical methods by SPSS software, version 15. RESULTS: 1510 IVDUs participated in the study with the mean age 32.16 +/- 8.26. 66.4% of participants had a history of illegal sexual activity. Among male IVDUs who had illegal sexual contact, 40.6% reported having homosexual contact and 36.2% of them have used condom in their contact. Also 57.7% had sexual contact with female sex workers. 83.5% of IVDUs reported having multiple sexual partners, and 30.9% had IVDUs sexual partners. The mean number of injection and duration of injection among IVDUs were 75.12 +/- 95.51 times per month and 12.34 +/- 7.53 years respectively. 36.9% of subjects have reported sharing needles/syringes. CONCLUSIONS: According to the high prevalence of unprotected sexual contacts and unsafe injection among IVDUs, effectiveness interventions and harm reduction programs are necessary to prevent spread of blood-borne infection diseases particularly HCV. With reduction of risky behaviors and consequently decrease of spread of HCV, these programs benefit both drug users and society. PMID- 22826774 TI - Burnout: interpreting the perception of Iranian primary rural health care providers from working and organizational conditions. AB - OBJECTIVES: Health care providers in the rural centers offer the primary health services in the form of proficiencies and professions to the most required target population in the health system. These services are provided in certain condition and population with a verity of limitations. This study aimed to describe and interpret the experiences of the employees from their own working condition in the rural health centers. METHODS: The present study conducted in a qualitative research approach and content analysis method through individual and group interviews with 26 employed primary health care providers (including 7 family physicians, 7 midwives, and 12 health workers) in the rural health centers in Isfahan in 2009. Sampling was done using purposive sampling method. The data were analyzed using qualitative content analysis as constant comparative basis. RESULTS: During the content analysis process, six themes were obtained; "instability and frequent changes", "involved in laws and regulations", "pressure and stress due to unbalanced workload and manpower", "helplessness in performing the tasks and duties", "sense of identity threat and low self-concept", and "deprivation of professional development". The mentioned themes indicate a main and more important theme called "burnout". CONCLUSIONS: Health services providers in the rural health centers are working in stressful and challenging work conditions and are suffered from deprivation of something for which are responsible to the community. PMID- 22826775 TI - Hepatitis C virus infection in patients with hemophilia in Isfahan, Iran. AB - OBJECTIVES: Patients with hereditary bleeding disorders are at risk of viral infection such as hepatitis C due to frequent transfusion of blood and blood products. This study aimed to determine the prevalence of hepatitis C and associated risk factors in hemophilic patients in Isfahan, the second big province in Iran. METHODS: In a descriptive study, patients with hemophilia in Isfahan province were enrolled. A questionnaire, including demographic and risk factors of hepatitis C was completed through a structured interview with closed questions by a trained interviewer for each patient and HCV-Ab test results were extracted from patient records. RESULTS: In this study, 232 of 350 patients with hemophilia A and B (66%) were positive for hepatitis C. Based on Multivariate Logistic Regression model, no independent risk factor was found. CONCLUSIONS: Prevalence of hepatitis C in patients with haemophilia A and B in Isfahan is high. Since no independent risk factor for hepatitis C disease was found in this high risk group, it can be concluded that multitransfusion is the only predictor for hepatitis C. PMID- 22826776 TI - Health-State Utilities in Liver Cirrhosis: A Cross-sectional Study. AB - OBJECTIVES: Liver cirrhosis can change many aspects of life of the patients and their family and effects society. We aimed to study the utility of cirrhosis from the point of view of the patients, their family, and their care takers to find appropriate interventions, and training and counselling programmes to support patients. METHODS: In this cross-sectional study with a goal-based sampling method, 66 individuals constructed of 30 decompensated patients with cirrhosis, 21 of the patients family members, and 15 care takers were included. The data were collected through face to face interview and completing of questionnaire consisted of demographic information (age, gender, marital status, and income), the duration of illness, and assessment of utility of cirrhosis using techniques of time trade, standard gamble, rating scale, and the willingness to pay. RESULTS: 52% of participants were men and 48% women which consisted of 58 married, 4 single, and 4 divorced or widowed with the mean duration of having cirrhosis of 3.7 +/- 1.4 years. The mean scores of utility of the three groups in all preference-based measures had significant differences (P < 0.05). Different techniques of patient utility in this research from the highest to the lowest were standard gamble (0.55), willingness to pay (0.54), rating scale (0.25), and rating scale (0.05), respectively. CONCLUSIONS: The results of the currents study suggested that the cirrhosis status has had the most negative effect on patients, and that patients had a lower utility rate than their family members and caretakers. PMID- 22826777 TI - Collision tumor in form of primary adenocarcinoma and neuroendocrine carcinoma of the duodenum. AB - Collision tumor is a rare phenomenon characterized by coexistence of completely distinct and independent tumors at the same body location. Collision tumors have been reported in different sites. However, they are extremely uncommon in the duodenum. We report the case of a 52-year old man with a collision tumor in the third portion of the duodenum with two distinct tumors of primary adenocarcinoma and neuroendocrine carcinoma, and both tumors coexisting within a single metastatic lymph node. Immunohistochemistry studies were performed to conclude that this was a case of collision cancer. To the best of our knowledge, this is the first collision tumor case reported to date at this location, and the first report of lymph node with a collision metastasis from a collision tumor. Such tumor is very rare and may thus provide diagnostic challenges. This report also provides a review of other cases on duodenal collision tumors. PMID- 22826778 TI - A case report of an extremely rare and aggressive tumor: primary malignant pericardial mesothelioma. AB - Primary pericardial malignant mesothelioma (PMPM) is extremely rare with an incidence less than 0.0022%. It comprises 0.7% of all mesothelioma cases. To date, approximately 350 cases of pericardial mesothelioma have been reported in the literature. Its typical presentation is insidious, with nonspecific signs and symptoms, and usually results in constrictive pericarditis, cardiac tamponade and congestive heart failure either by a serous effusion or by direct tumorous constriction of the heart. With the exception of several case reports, the outcome is uniformly fatal, and patients typically die within six months of diagnosis. Here we report a 72-year-old Cauca -sian male with persistent pericardial and pleural effusion. He was diagnosed with PMPM after pericardectomy. He had only one cycle of chemotherapy with cisplatin and pemetrexed. He developed acute kidney injury as result of chemotherapy. He died 1 month after diagnosis and 6 months after the first symptoms. PMID- 22826779 TI - Granular cell tumour of the urinary bladder. AB - With only 16 cases reported in the literature, the mostly benign granular cell tumour of the urinary bladder is exceptionally rare. We present the case of a 68 year old patient with one of these lesions demonstrating our histological findings including several immunohistochemical stainings used to differentiate between other more common entities. PMID- 22826780 TI - A case of a giant pseudoangiomatous stromal hyperplasia of the breast: magnetic resonance imaging findings. AB - Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a benign myofibroblastic process. We present the case of a 17-year-old girl who underwent diagnostic work-up due to an enlargement of her left breast. She was submitted to ultrasounds and magnetic resonance imaging (MRI) which depicted a 14 cm lesion in her left breast. The patient was later operated and histology revealed PASH. Although PASH may range from 0.6-12 cm, a few lesions over 12 cm have been described, the largest being 20 cm. Large series present mammographic and ultrasonographic features of PASH in the literature, but little has been reported on the MR characteristics of PASH up to today. Signal on the T1-weighted image (T1WI) and T2-weighted image (T2WI) may vary. Curves generated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies are mainly type I or less frequently type II. There are no reports about diffusion-weighted imaging and corresponding apparent diffusion coefficient (ADC) values for PASH in the literature. ADC values in our case lie within the range of values reported for other benign breast lesions. The presence of slit-like spaces within the lesion on MR imaging along with DCE-MRI type I curve and ADC values consistent with a benign lesion may favour the diagnosis of PASH. Tissue biopsy is necessary, however for the final diagnosis. This case report will further contribute to the understanding of MR imaging features of PASH, especially in cases where mammography is not indicated. PMID- 22826781 TI - Rare Cancers Europe: joining forces to tackle a common problem. PMID- 22826782 TI - The use of radiotherapy in the management of follicular cystitis refractory to conservative and surgical management. AB - Follicular cysitis is a proliferative benign lesion which can act locally malignant. Conservative management is best; however, when this fails, surgical resection is necessary up to and including cystectomy in extreme refractory cases. We present a clinical review and our results using radiation in this disease in a woman facing cystectomy. PMID- 22826783 TI - Ovarian small cell carcinoma complicated by carcinomatous meningitis. AB - Meningeal metastasis is rare in the clinical course of ovarian carcinoma and its prognosis is extremely poor. We experienced a case of carcinomatous meningitis from metastatic ovarian small cell carcinoma. A 33-year-old woman with atypical genital bleeding, was diagnosed with a right ovarian tumor and referred to our department. She underwent a total abdominal hysterectomy, bilateral salpingo oophorectomy, omentectomy, and lymphadenectomy. It was an optimal debulking surgery. She was diagnosed with ovarian carcinoma classified as Stage IIIc according to the Federation Internationale de Gynecologie et d'Obstetrique classification system. Histological findings showed small cell carcinoma of the pulmonary type. The tumor was bilateral with paraaortic lymph node involvement. The patient was treated with irinotecan and cisplatin (CPT-P therapy). After 4 courses of CPT-P therapy, multiple liver metastases and Virchow's lymph node metastases were found. She was treated with amrubicin as a second-line chemotherapy, but the treatment was ineffective. Five months after surgery, the patient complained of severe headache and nausea. Lumbar puncture was performed and cytology was positive. Magnetic resonance brain imaging indicated meningeal thickening. The patient was diagnosed with meningeal metastasis and received 19 Gy whole cranial irradiation. In spite of these treatments, her disease progressed rapidly and she was often drowsy. She died of aspiration pneumonia 6 months after surgery. PMID- 22826784 TI - Cystic pancreatic lymphangioma. AB - Lymphangioma of the pancreas is a rare benign tumor of lymphatic origin. Retroperitoneal lymphangiomas account for 1% of all lymphangiomas. Herein, we report a case of cystic pancreatic lymphangioma diagnosed in 34 year-old female patient who was hospitalized for a slight pain in the epigastrium and vomiting. Radiological imaging revealed a large multiloculated cystic abdominal mass with enhancing septations involving the upper retroperitoneum. During the laparoscopic surgery, a well circumscribed polycystic tumor was completely excised preserving the pancreatic duct. The patient made a complete recovery and is disease-free 12 months postoperatively. PMID- 22826785 TI - Nephrogenic adenoma of the ureter. AB - Nephrogenic adenoma (NA) is an uncommon benign lesion of the urothelial tract. The diagnostic features that are useful in the recognition of this benign entity are: the characteristic mixture of various architectural patterns, associated stromal edema and inflammation, hyaline sheath around tubules, and lack of mitotic activity. Although NA appears with hematuria or obstruction, frequently found incidentally in endoscopy or imaging modalities. PMID- 22826786 TI - A case of primary clear cell hepatocellular carcinoma in a non-cirrhotic liver: an immunohistochemical and ultrastructural study. AB - The clear cell variant of hepatocellular carcinoma is a rare entity, occurring at a frequency of less than 10% of hepatocellular carcinoma, with a female prevalence and usually associated with hepatitis C and cirrhosis. We reported a case of primary clear cell hepatocellular carcinoma occurring in a non-cirrhotic liver without history of hepatitis. Our examination included gross pathology, histopathology, immunohistochemistry, special stains, and electron microscopy evaluation. The tumor was composed of sheets of medium-to-large cells with foamy and reticulated cytoplasm and small-to-medium sized nuclei with variably prominent nucleoli. Oil red O stain showed abundant intracellular lipid. Periodic Acid-Schiff stain confirmed the presence of abundant glycogen deposition. Immunohistochemically the tumor cells were positive for Hep Par1, negative for epithelial membrane antigen, steroidogenic factor-1, HMB45, melan A, CK7 and CK20. Electron microscopy study was performed, which was first done in a clear cell hepatocellular carcinoma occurring in a non-cirrhotic liver without elevation of liver function tests. Ultrastructural evaluation of the clear cells showed scarce cellular organelles, cytoplasmic lipid vacuoles and swollen mitochondria. PMID- 22826788 TI - Metastatic melanoma and vemurafenib: novel approaches. AB - Metastatic melanoma (MM) presents a treatment challenge to oncologists worldwide. Dacarbazine is the first line chemotherapy treatment for MM, though the overall response rates are very poor. Recently, the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation was found to play a main role in MM. This mutation is present in 40-60% of melanoma patients. Vemurafenib is a BRAF kinase inhibitor that showed impressive results in phase I-III trials and was thus recently approved for the treatment of MM. This paper will briefly focus on vemurafenib in the treatment of MM and highlight concerns. PMID- 22826787 TI - Intramedullary pilomyxoid astrocytoma with intracerebral metastasis exhibiting oligoden-droglioma-like features. AB - Intramedullary glioma are rare and their biological behaviour can differ from their cerebral counterparts. Pilomyxoid astrocytoma (PMA, WHO grade II), predominantly occur in the hypothalamic/chiasmatic region of infants and children. The few reported cases of pediatric intramedullary PMA displayed a particularly aggressive behavior. Here, we report a diagnostically challenging case of a five year old female patient presenting with intramedullary glioma and local tumor recurrence three years later. Twelve years after the initial manifestation, a second tumor was found intracerebrally. We performed a comprehensive histological, molecular pathological and imaging analysis of the tumors from both localizations. The results revealed a metastasizing PMA with unique histological and genetic features. Our study indicates that PMA comprise a heterogeneous group including aggressive subtypes which may not be compatible with the current classification according to WHO grade II. Furthermore, the case emphasizes the increasing relevance of molecular pathological markers complementing classic histo-logical diagnosis. PMID- 22826789 TI - Neurological manifestation of colonic adenocarcinoma. AB - Paraneoplastic neurologic disorders are extremely rare in cancer patients and are most commonly associated with certain tumors, such as ovarian cancer, small cell lung cancer, and breast cancer. We report here a paraneoplastic neurological syndrome in a 53-year-old man with colonic adenocarcinoma with a solitary liver metastasis. His paraneoplastic syndrome was successfully treated by methylprednisolone and primary oncologic therapies including neoadjuvant chemotherapy and definitive surgery. This is also the first documented case of simultaneous manifestation of a sensory neuropathy and limbic encephalitis with colon cancer. PMID- 22826790 TI - Unexpectedly durable palliation of metastatic olfactory neuroblastoma using anti angiogenic therapy with Bevacizumab. AB - Olfactory neuroblastomas (ONBs) are rare malignant tumors that arise from olfactory epithelium and typically present with symptoms attributable to locally invasive disease. Kadish radiographic staging and Hyams' histopathologic grading are prognostic. Overall survival rates, averaging 60-70% at 5 years, remain limited by high rates of delayed loco-regional and distant progression. At initial presentation, the available evidence supports the use of multimodality therapy, historically surgery and radiation, to improve disease-free and overall survival. At recurrence/progression, the available evidence supports the use of therapy to improve disease control and symptoms (palliation), but patient heterogeneity dictates individualization of modalities. Although the ideal use of chemotherapy as a modality remains undefined, the available evidence supports it use, historically platinum-based, for palliation. However, recent insights into the molecular-genetic aberrations of ONBs, coupled with the emergence chemotherapeutic agents capable of targeting such aberrations, suggest an expanded role. The authors report a case of a 60 years-old man, heavily pre treated for metastatic ONB, presenting with profound central-nerve-system and head-and-neck symptoms. He experienced unexpectedly durable palliation with Bevacizumab anti-angiogenic therapy. Additionally, he experienced localized palliation with an Ommaya reservoir. The authors review the literature regarding historical and emerging therapies for ONB to emphasize the needs for individualization and translational-clinical studies. PMID- 22826791 TI - Malignant epithelioid hemangioendothelioma of the liver successfully treated with Sorafenib. AB - Hepatic epithelioid hemangioendothelioma (HEH) is a rare disease of unknown etiology for which a standard systemic treatment has not been established. The common expression of vascular endothelial growth factor (VEGF) and its receptor in HEH provide a rationale for the reported use of antiangiogenic drugs, including bevacizumab, lenalidomide and thalidomide. We report a case of a young male patient with HEH who was treated with sorafenib for almost 2 years. Sorafenib was used instead of other VEGF inhibitors due to its convenient oral route, its dual antiangiogenic and antiproliferative activity, and its favorable safety profile. Sorafenib therapy resulted in durable stabilization with progressive calcification of liver tumors and minor but stable response of lung lesions. PMID- 22826792 TI - Romiplostim as early treatment of immune thrombocytopenia with severe immunodeficiency. AB - Immunosuppressive agents are the standard therapeutic approach for immune thrombocy-topenia (ITP). Their prolonged use may increase the risk of infectious complications, particularly when the patient is already at higher infectious risk. In this setting, the use of drugs with a mechanism of action alternative to immunosuppression, like thrombopoietin receptor agonists (TRAs), may find particular indication. We report the unique case of a patient with severe immunodeficiency and ITP, who experienced a serious infectious complication while on steroids treatment, and who was successfully treated with Romiplostim second line. The present experience supports the effectiveness and safety of TRAs as early treatment of ITP patients with drug-induced immunodeficiency or with active infections. PMID- 22826793 TI - Non-secretory immunoglobulin E myeloma associated with immunoglobulin G monoclonal gammopathy of undetermined significance. AB - A 68-year old woman came to our hospital with a severe case of anemia. Serum immunoelectropheresis identified a monoclonal immunoglobulin (Ig) G and kappa protein. The serum IgE level was within the nomal range and the amounts of remaining immunogloblins were low. On bone marrow aspirate, plasma cells made up 55.5% of nucleated cells and the plasma cells showed positive readings for IgE kappa and IgG by immunohistochemistry. Serum immunofixation did not reveal the IgE monoclonal band. She was diagnosed as having non-secretory IgE myeloma with IgG monoclonal gammopathy of undetermined significance. The nature of this rare myeloma will be discussed. PMID- 22826794 TI - Transient ischemic attacks as the first presentation of JAK2-V617F positive chronic myeloproliferative neoplasm. AB - Several studies have shown that thrombotic events may underlie a latent or subclinical myeloproliferative neoplasm (MPN) and precede its definite diagnosis by 1-2 years. An early diagnosis of patients with MPN, especially those with thrombotic events in the latent MPN phase, would be beneficial for their management, preventing further morbidity and improving their quality of life. For the majority of these cases, the location of thrombosis is mainly in the splanchnic major veins, while ischemic stroke and cerebral venous thrombosis are rarely observed. In this report, we present a female patient with transient ischemic attacks who suffered from a latent MPN, on the basis of a positive testing for the JAK2-V617F mutation. PMID- 22826795 TI - Thrombotic microangiopathy associated with bortezomib treatment in a patient with relapsed multiple myeloma. AB - Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) describe microvascular occlusive disorders characterized by thrombocytopenia due to increased platelet aggregation and fragmentation hemolysis. We report here what to our knowledge is the second case of TTP/HUS associated with bortezomib treatment. PMID- 22826796 TI - A case of cutaneous large B-cell lymphoma of the legs appearing as chronic venous ulceration. AB - We report here a case of a woman with a cutaneous large B-cell lymphoma of the legs. She had a plaque lesion, superficially ulcerated and necrotized with tumorous borders situated on the posterior side of the right leg and two red or bluish-red nodular lesions. A skin biopsy from both nodular and plaque lesion showed a diffuse infiltrate of atypical large B cells CD20(+) and CD79a(+), spanning epidermis, dermis and subcutaneous tissue. A therapeutic approach containing anti-CD20 monoclonal antibody (rituximab) was suggested. PMID- 22826797 TI - Adrenal extramedullary hematopoiesis associated with beta-thalassemia major. AB - The presence of apparently normal hematopoietic tissue outside of bone marrow cavity is defined as extramedullary hematopoiesis (EMH). EMH is a rare complication in thalassemia major (TM) and adrenal gland as well. This report describes a case of adrenal EMH in a 26-year-old man with beta-TM. He has been transfused with regular blood transfusion since 9 months. During the routine physical examination he was incidentally found to have a hypoechoic mass at his abdominal ultrasonography. Abdominal computed tomography scan revealed a right well-defined suprarenal mass 7.7*7.3*5.8 cm in size. The diagnosis of EMH was confirmed with ultrasonographic-guided fine needle biopsy. Treatment options which include intensified regular blood transfusion and hydroxyurea have been started. PMID- 22826798 TI - Hematological profile of sickle cell disease from South Gujarat, India. AB - The aim of this study was to determine hematological profile of sickle cell disease (SCD) from Surat, South Gujarat, India. This prospective cross-sectional study was conducted in the Department of Pediatrics and Sickle Cell Anemia Laboratory, Faculty of Pathology, Government Medical College, Surat, India, between July 2009 and December 2010. Patients included in this study were in their steady state for a long period of time without any symptoms related to SCD or other diseases which could affect the hematological parameters. Venous blood of all patients was collected in ethylenediaminetetraacetic acid and hematological indices were measured. Thirty-three subjects homozygous in all were studied for their hematological parameters for sickle cell anemia. Moderate to severe anemia, low mean cell volume and high foetal hemoglobin dominate the hematological profile of SCD children. PMID- 22826799 TI - Genotype-phenotype correlation of beta-thalassemia spectrum of mutations in an Indian population. AB - Coexistence of thalassemia, hemoglobinopathies and malaria has interested geneticists over many decades. The present study represents such a population from the eastern Indian state of Orissa. Children and their siblings (n=38) were genotyped for beta-thalassemia mutations and genotype-phenotype correlation was determined. The major genotype was IVS 1.5 mutation: 26% homozygous (n=10) and 37% (n=14) double heterozygous with other mutations or hemoglobinopathies. Sickle hemoglobin was the major associated hemoglobinopathy (n=12, 32%). Other mutations found were Cd 8/9, HbE and Cd 41/42. The study population did not contain any IVS 1.1 mutations which is the second major Indo-Asian genotype. Genotype-phenotype correlation revealed that genotypes of IVS 1.5, Cd 8/9 Cd 41/42 alone or in association, exhibit severe, moderate and mild severity of thalassemia, respectively. Identification of the mutation at an early age as a part of new born screening and early intervention may help reduce the thalassemia-related morbidity. PMID- 22826800 TI - The pharmacokinetics of Hemiscorpius lepturus scorpion venom and Razi antivenom following intramuscular administration in rat. AB - Hemiscorpius lepturus (H. lepturus) is one of the most dangerous scorpions in Iran. Intramuscular administration (IM) of available Razi antivenom to H. lepturus venom is used by many of Iranian clinicians. The purpose of the current study was to investigate the efficiency of IM route for treatment of envenomed patients by H. lepturus. We compared the pharmacokinetics parameters of venom and antivenom via subcutaneous (SC) and IM administration, respectively. The blood samples were taken at various predetermined time intervals, i.e., 10, 40, 60, 180, 210, 360 and 400min following 5MUg (131)I-labeled venom and 5, 10, 40, 120 and 360min following 0.2ml of (131)I-labeled antivenom administration. The radio iodination was carried out using the chloramin-T method. The results showed that pharmacokinetic parameters of the venom were T(elimination half-life) = 103.25min; Vd/F (apparent volume of distribution) = 14.9ml/kg; Cl/F (total blood clearance) = 0.04ml/kg/min; mean resident residual time (MRT) = 244.3min, and for the antivenom T(1/2) = 628.59min, Vd = 666.66ml/kg, Cl = 0.13ml/kg/min and MRT = 1292min. A comparison of pharmacokinetic profiles indicated that the intramuscular administration was helpful in the referral less than 2hr to clinical centers but not those exceeding 3hr. Overall, the data showed that immunotherapy against H. lepturus stings was likely to be more effective through intravenous administration. PMID- 22826801 TI - A novel solid-state thermal rectifier based on reduced graphene oxide. AB - Recently, manipulating heat transport by phononic devices has received significant attention, in which phonon--a heat pulse through lattice, is used to carry energy. In addition to heat control, the thermal devices might also have broad applications in the renewable energy engineering, such as thermoelectric energy harvesting. Elementary phononic devices such as diode, transistor and logic devices have been theoretically proposed. In this work, we experimentally create a macroscopic scale thermal rectifier based on reduced graphene oxide. Obvious thermal rectification ratio up to 1.21 under 12 K temperature bias has been observed. Moreover, this ratio can be enhanced further by increasing the asymmetric ratio. Collectively, our results raise the exciting prospect that the realization of macroscopic phononic device with large-area graphene based materials is technologically feasible, which may open up important applications in thermal circuits and thermal management. PMID- 22826802 TI - Counting in the dark: non-intrusive laser scanning for population counting and identifying roosting bats. AB - Population surveys and species recognition for roosting bats are either based on capture, sight or optical-mechanical count methods. However, these methods are intrusive, are tedious and, at best, provide only statistical estimations. Here, we demonstrated the successful use of a terrestrial Light Detection and Ranging (LIDAR) laser scanner for remotely identifying and determining the exact population of roosting bats in caves. LIDAR accurately captured the 3D features of the roosting bats and their spatial distribution patterns in minimal light. The high-resolution model of the cave enabled an exact count of the visibly differentiated Hipposideros larvatus and their roosting pattern within the 3D topology of the cave. We anticipate that the development of LIDAR will open up new research possibilities by allowing researchers to study roosting behaviour within the topographical context of a cave's internal surface, thus facilitating rigorous quantitative characterisations of cave roosting behaviour. PMID- 22826803 TI - Global dispersion of bacterial cells on Asian dust. AB - The atmospheric dispersion of bacteria over long distances is an important facet of microbial ecology. Certain groups of dispersed bacteria can adapt to their new location and affect established ecosystems. Aeolian dust particles are known to be carriers of microbes but further research is needed to expand our understanding of this field of microbiology. Here we showed the potential of aeolian dust to global migration of bacterial cells. We demonstrated the presence of microbial cells on dust particles directly by bio-imaging. Bacterial abundance on dust particles declined from 10(5) to less than 10(3) cells/m3 as the dust event subsided. Taxonomically diverse bacteria were identified by 16S rRNA gene sequencing and some of these bacteria retained growth potential. Our results confirm that bacteria can attach to aeolian dust particles and they have the potential to migrate globally during dust events and thus can contribute to the diversity of downwind ecosystems. PMID- 22826804 TI - Surgical neurology international stereotactic: inaugural editorial. PMID- 22826805 TI - Stereotactic radiosurgery for movement disorders. AB - Initially designed for the treatment of functional brain targets, stereotactic radiosurgery (SRS) has achieved an important role in the management of a wide range of neurosurgical pathologies. The interest in the application of the technique for the treatment of pain, and psychiatric and movement disorders has returned in the beginning of the 1990s, stimulated by the advances in neuroimaging, computerized dosimetry, treatment planning software systems, and the outstanding results of radiosurgery in other brain diseases. Since SRS is a neuroimaging-guided procedure, without the possibility of neurophysiological confirmation of the target, deep brain stimulation (DBS) and radiofrequency procedures are considered the best treatment options for movement-related disorders. Therefore, SRS is an option for patients who are not suitable for an open neurosurgical procedure. SRS thalamotomy provided results in tremor control, comparable to radiofrequency and DBS. The occurrence of unpredictable larger lesions than expected with permanent neurological deficits is a limitation of the procedure. Improvements in SRS technique with dose reduction, use of a single isocenter, and smaller collimators were made to reduce the incidence of this serious complication. Pallidotomies performed with radiosurgery did not achieve the same good results. Even though the development of DBS has supplanted lesioning as the first alternative in movement disorder surgery; SRS might still be the only treatment option for selected patients. PMID- 22826806 TI - Radiation mechanisms of pain control in classical trigeminal neuralgia. AB - Classical trigeminal neuralgia is a chronic pain condition that was clinically recognized centuries ago. Nevertheless, the pathological mechanism(s) involved in the development of classical trigeminal neuralgia is still largely based on the theory of peripheral versus central nervous system origin. Limitations of both hypotheses are discussed. Evidence of radiation effects in the electrical conduction of peripheral nerves is reviewed. Results of experimental studies using modern and current radiosurgery techniques and doses are also brought to discussion in an attempt to elucidate the radiation mechanisms involved in the conduction block of excessive sensory information triggering pain attacks. Clinical features and prognostic factors associated with pain control, recurrence, and facial numbness in patients submitted to surgical procedures for classical trigeminal neuralgia are discussed in the context of the features related to the pathogenesis of this condition. Studies focusing on the electrophysiology properties of partially demyelinated trigeminal nerves submitted to radiosurgery are vital to truly advance our current knowledge in the field. PMID- 22826808 TI - Trends and importance of radiosurgery for the development of functional neurosurgery. AB - Functional neurosurgery includes surgery conducted to ablate, augment, or modulate targets that lead to improvement in neurological function or behavior. Surgical approaches for this purpose include destructive lesioning with different mechanical or biologic agents or energy sources, non-destructive electrical modulation, and cellular or chemical augmentation. Our purpose was to review the role of stereotactic radiosurgery used for functional indications and to discuss future applications and potential techniques. Imaging and neurophysiological research will enable surgeons to consider new targets and circuits that may be clinically important. Radiosurgery is one minimal access approach to those targets. PMID- 22826807 TI - Novel applications of deep brain stimulation. AB - The success of deep brain stimulation (DBS) surgery in treating medically refractory symptoms of some movement disorders has inspired further investigation into a wide variety of other treatment-resistant conditions. These range from disorders of gait, mood, and memory to problems as diverse as obesity, consciousness, and addiction. We review the emerging indications, rationale, and outcomes for some of the most promising new applications of DBS in the treatment of postural instability associated with Parkinson's disease, depression, obsessive-compulsive disorder, obesity, substance abuse, epilepsy, Alzheimer's type dementia, and traumatic brain injury. These studies reveal some of the excitement in a field at the edge of a rapidly expanding frontier. Much work still remains to be done on basic mechanism of DBS, optimal target and patient selection, and long-term durability of this technology in treating new indications. PMID- 22826809 TI - Strategies for the return of behavioral surgery. AB - BACKGROUND: Behavioral surgery (BS) is resurging because of unmet clinical need, advances in basic sciences, neuroimaging, neurostimulation, and stereotaxy. However, there is a danger that BS will fall unless acceptable strategies are adopted by BS providers. METHODS: A critical review of conditions leading to rise of psychosurgery (PS) and concerns resulting in its fall was conducted to learn lessons and safeguard BS of the future. RESULTS: PS rose and spread in 1960 like wildfire without adequate preclinical and clinical studies. Hundreds of patients had PS without adequate preoperative diagnosis or assessment, proper consent, and non-objective reporting of outcome. Furthermore, there was public opposition against PS because of its potential abuse to control violent behavior and dissidents. Advances in neurostimulation, neuroimaging, and stereotaxy, and emergence of treatment-resistant mental disorders led to increased interest in BS. Several recent studies have shown BS to be safe and effective. However, concerns related to strength of evidence, safety, efficacy, consent, and objectivity of studies have been raised. Unless clinical and regulatory governance structures are adopted in each jurisdiction, BS will face the same fate as that of PS in the past. CONCLUSION: THE FUTURE OF BS AS A SAFE AND EFFECTIVE THERAPY IS DEPENDENT UPON ADOPTING CLEAR MORAL ETHICAL AND GOVERNANCE STANDARDS ON THE FOLLOWING LINES: Patients must have failed adequate therapies; must be assessed by psychiatrist-led multidisciplinary teams; patients' abilities to give consent and diagnosis must be verified by independent authorities designated for this purpose by the state; and the independent authority must also decide whether the teams were adequately trained to perform BS. PMID- 22826810 TI - The amygdala as a target for behavior surgery. AB - The amygdala was a popular target during the era of psychosurgery, specifically for the treatment of intractable aggression. This mesiotemporal structure was thought to primarily mediate fear and anger. However, recent evidence suggests that the amygdala is part of a complex network that mediates the formation of a larger repertoire of positive and negative emotions. Dysfunctions within the network or the amygdala itself can lead to various mental illnesses. In those cases, deep brain stimulation (DBS) applied focally may treat the symptoms. This review presents data supporting the potential therapeutic role of DBS of the amygdala in the treatment of anxiety disorders, addiction, and mood disorders. The success of DBS for psychiatric conditions will likely depend on our ability to precisely determine the optimal target for a specific case. PMID- 22826811 TI - Vagus nerve stimulation for epilepsy: A review of the peripheral mechanisms. AB - Vagus nerve stimulation (VNS) is a unique epilepsy treatment in that a peripheral intervention is used to treat a disease that is entirely related to pathological events occurring within the brain. To understand how stimulation of the vagus nerve can be used to stop seizures, an understanding of the peripheral anatomy and physiology of the vagus nerve is essential. The peripheral aspects of the vagus nerve are discussed in this review, with an explanation of which fibers and branches are involved in producing these antiepileptic effects, along with speculation about the potential for improving the therapy. PMID- 22826812 TI - Pitfalls in precision stereotactic surgery. AB - Precision is the ultimate aim of stereotactic technique. Demands on stereotactic precision reach a pinnacle in stereotactic functional neurosurgery. Pitfalls are best avoided by possessing in-depth knowledge of the techniques employed and the equipment used. The engineering principles of arc-centered stereotactic frames maximize surgical precision at the target, irrespective of the surgical trajectory, and provide the greatest degree of surgical precision in current clinical practice. Stereotactic magnetic resonance imaging (MRI) provides a method of visualizing intracranial structures and fiducial markers on the same image without introducing significant errors during an image fusion process. Although image distortion may potentially limit the utility of stereotactic MRI, near-complete distortion correction can be reliably achieved with modern machines. Precision is dependent on minimizing errors at every step of the stereotactic procedure. These steps are considered in turn and include frame application, image acquisition, image manipulation, surgical planning of target and trajectory, patient positioning and the surgical procedure itself. Audit is essential to monitor and improve performance in clinical practice. The level of stereotactic precision is best analyzed by routine postoperative stereotactic MRI. This allows the stereotactic and anatomical location of the intervention to be compared with the anatomy and coordinates of the intended target, avoiding significant image fusion errors. PMID- 22826813 TI - Hypofractionated stereotactic radiotherapy for large arteriovenous malformations. AB - Cerebral arteriovenous malformations (AVMs) are abnormal connections between the arteries and veins, with possible serious consequences of intracranial hemorrhage. The curative treatment for AVMs includes microsurgery and radiosurgery, sometimes with embolization as an adjunct. However, controversies exist with the treatment options available for large to giant AVMs. Hypofractionated stereotactic radiotherapy (HSRT) is one treatment option for such difficult lesions. We aim to review recent literature, looking at the treatment outcome of HSRT in terms of AVM obliteration rate and complications. The rate of AVM obliteration utilizing HSRT as a primary treatment was comparable with that of stereotactic radiosurgery (SRS). For those not totally obliterated, HSRT makes them smaller and turns some lesions manageable by single-dose SRS or microsurgery. Higher doses per fraction seemed to exhibit better response. However, patients receiving higher total dose may be at risk for higher rates of complications. Fractionated regimens of 7 Gy * 4 and 6-6.5 Gy * 5 may be accepted compromises between obliteration and complication. Embolization may not be beneficial prior to HSRT in terms of obliteration rate or the volume reduction. Future work should aim on a prospectively designed study for larger patient groups and long-term follow-up results. PMID- 22826814 TI - Image guidance for brain metastases resection. AB - The primary goal in removing a metastatic brain tumor is to maximize surgical resection while minimizing the risk of neurological injury. Intraoperative image guidance is frequently used in the resection of both primary and metastatic brain tumors. Stereotactic volumetric techniques allow for smaller craniotomies, facilitate lesion localization, and help neurosurgeons avoid eloquent structures. In turn, this leads to decreased patient morbidity and shorter hospitalizations. Image guidance is not without shortcomings, however, perhaps the most significant of which is inaccuracy of tumor resection associated with intraoperative brain shifts. The goal of this review is to expound on the uses of image guidance and discuss avoidance of technical pitfalls in the resection of cerebral metastatic lesions. PMID- 22826817 TI - Integration of surgery and radiosurgery. PMID- 22826818 TI - Importance of intraoperative magnetic resonance imaging for pediatric brain tumor surgery. AB - BACKGROUND: High-field intraoperative MRI (IoMRI) is gaining increasing recognition as an invaluable tool in pediatric brain tumor surgery where the extent of tumor resection is a major prognostic factor. We report the initial experience of a dedicated pediatric 3-T intraoperative MRI (IoMRI) unit with integrated neuronavigation in the management of pediatric brain tumors. METHODS: Seventy-three children (mean age 9.5 years; range 0.2-19 years) underwent IoMRI between October 2009 and January 2012, during 79 brain tumor resections using a 3 T MR scanner located adjacent to the neurosurgical operating theater that is equipped with neuronavigation facility. IoMRI was performed either to assess the extent of tumor resection after surgical impression of complete/intended tumor resection or to update neuronavigation. The surgical aims, IoMRI findings, extent of tumor resection, and follow-up data were reviewed. RESULTS: Complete resection was intended in 47/79 (59%) operations. IoMRI confirmed complete resection in 27/47 (57%). IoMRI findings led to further resection in 12/47 (26%). In 7/47 (15%), IoMRI was equivocal for residual tumor and no evidence of residual tumor was found on re-inspection. In 32/79 (41%) operations, the surgical aim was partial tumor resection. In this subset, surgical resection was extended following IoMRI in 13/32 (41%) operations. None of the patients required early second look procedure for residual disease. CONCLUSIONS: At our institution, IoMRI has led to increased rate of tumor resection and a change in surgical strategy with further tumor resection in 32% of patients. While interpreting IoMRI, it is important to be aware of the known pitfalls. PMID- 22826815 TI - Radiosurgery for high-grade glioma. AB - BACKGROUND: For patients with newly diagnosed high-grade gliomas (HGG), the current standard-of-care treatment involves surgical resection, followed by concomitant temozolomide (TMZ) and external beam radiation therapy (XRT), and subsequent TMZ chemotherapy. For patients with recurrent HGG, there is no standard of care. Stereotactic radiosurgery (SRS) is used to deliver focused, relatively large doses of radiation to a small, precisely defined target. Treatment is usually delivered in a single fraction, but may be delivered in up to five fractions. The role of SRS in the management of patients with HGG is not well established. METHODS: The PubMed database was searched with combinations of relevant MESH headings and limits. Case reports and/or small case series were excluded. Attention was focused on overall median survival as an objective measure, and data were examined separately for newly diagnosed and recurrent HGG. RESULTS: With respect to newly diagnosed HGG, there is strong evidence that addition of an SRS boost prior to standard XRT provides no survival benefit. However, recent retrospective evidence suggests a possible survival benefit when SRS is performed after XRT. With respect to recurrent HGG, there is suggestion that SRS may confer a survival benefit but with potentially higher complication rates. Newer studies are investigating the combination of SRS with targeted molecular agents. Controlled prospective clinical trials using advanced imaging techniques are necessary for a complete assessment. CONCLUSIONS: SRS has the potential to provide a survival benefit for patients with HGG. Further research is clearly warranted to define its role in the management of newly diagnosed and recurrent HGG. PMID- 22826816 TI - Deep brain stimulation of the globus pallidus internus and Gilles de la Tourette syndrome: Toward multiple networks modulation. AB - BACKGROUND: Gilles de la Tourette's syndrome (GTS) is a complex neuropsychiatric disorder characterized by disabling motor and vocal tics. The pathophysiology of GTS remains poorly understood. Conventional treatment consists in pharmacological and behavioral treatment. For patients suffering severe adverse effects or not responding to pharmacological treatment, deep brain stimulation (DBS) presents an alternative treatment. However, the optimal target choice in DBS for GTS remains a divisive issue. METHODS: A PubMed search from 1999 to 2012 was conducted. Thirty-three research articles reporting on DBS in patients with GTS were selected and analyzed. RESULTS: Eighty-eight patients with Tourette's syndrome were treated since 1999 with DBS. The majority of patients received thalamic stimulation. Significantly fewer patients were treated with globus pallidus internus stimulation. Occasionally, the anterior limb of the internal capsule and the nucleus accumbens were implanted. The subthalamic nucleus was selected once. All targets were reported with positive results, but of variable extent. Only 14 patients exhibited level 1 evidence. CONCLUSION: In light of the wide spectrum of associated behavioral co-morbidities in GTS, multiple networks modulation may result in the most efficacious treatment strategy. The optimal locations for DBS within the cortico-basal ganglia-thalamocortical circuits remain to be established. However, at the current stage, comparison between targets should be done with great caution. Significant disparity between number of patients treated per target, methodological variability, and quality of reporting renders a meaningful comparison between targets difficult. Randomized controlled trials with larger cohorts and standardization of procedures are urgently needed. PMID- 22826819 TI - Application of image guidance in pituitary surgery. AB - BACKGROUND: Surgical treatment of pituitary pathologies has evolved along the years, adding safety and decreasing morbidity related to the procedure. Advances in the field of radiology, coupled with stereotactic technology and computer modeling, have culminated in the contemporary and widespread use of image guidance systems, as we know them today. Image guidance navigation has become a frequently used technology that provides continuous three-dimensional information for the accurate performance of neurosurgical procedures. We present a discussion about the application of image guidance in pituitary surgeries. METHODS: Major indications for image guidance neuronavigation application in pituitary surgery are presented and demonstrated with illustrative cases. Limitations of this technology are also presented. RESULTS: Patients presenting a history of previous transsphenoidal surgeries, anatomical variances of the sphenoid sinus, tumors with a close relation to the internal carotid arteries, and extrasellar tumors are the most important indications for image guidance in pituitary surgeries. The high cost of the equipment, increased time of surgery due to setup time, and registration and the need of specific training for the operating room personnel could be pointed as limitations of this technology. CONCLUSION: Intraoperative image guidance systems provide real-time images, increasing surgical accuracy and enabling safe, minimally invasive interventions. However, the use of intraoperative navigation is not a replacement for surgical experience and a systematic knowledge of regional anatomy. It must be recognized as a tool by which the neurosurgeon can reduce the risk associated with surgical approach and treatment of pituitary pathologies. PMID- 22826820 TI - Comprehensive review of stereotactic radiosurgery for medically and surgically refractory pituitary adenomas. AB - Despite advances in surgical techniques and medical therapies, a significant proportion of pituitary adenomas remain endocrinologically active, demonstrate persistent radiographic disease, or recur when followed for long periods of time. While surgical intervention remains the first-line therapy, stereotactic radiosurgery is increasingly recognized as a viable treatment option for these often challenging tumors. In this review, we comprehensively review the literature to evaluate both endocrinologic and radiographic outcomes of radiosurgical management of pituitary adenomas. The literature clearly supports the use of radiosurgery, with endocrinologic remission rates and time to remission varying by tumor type [prolactinoma: 20-30%, growth hormone secreting adenomas: ~50%, adrenocorticotrophic hormone (ACTH)-secreting adenomas: 40-65%] and radiographic control rates almost universally greater than 90% with long-term follow-up. We stratify the outcomes by tumor type, review the importance of prognostic factors (particularly, pre-treatment endocrinologic function and tumor size), and discuss the complications of treatment (with special attention to endocrinopathy and visual complications). We conclude that the literature supports the use of radiosurgery for treatment-refractory pituitary adenomas, providing the patient with a minimally invasive, safe, and effective treatment option for an otherwise resistant tumor. As such, we provide literature-based treatment considerations, including radiosurgical dose, endocrinologic, radiographic, and medical considerations for each adenoma type. PMID- 22826822 TI - Optical quantification of cellular mass, volume, and density of circulating tumor cells identified in an ovarian cancer patient. AB - Clinical studies have demonstrated that circulating tumor cells (CTCs) are present in the blood of cancer patients with known metastatic disease across the major types of epithelial malignancies. Recent studies have shown that the concentration of CTCs in the blood is prognostic of overall survival in breast, prostate, colorectal, and non-small cell lung cancer. This study characterizes CTCs identified using the high-definition (HD)-CTC assay in an ovarian cancer patient with stage IIIC disease. We characterized the physical properties of 31 HD-CTCs and 50 normal leukocytes from a single blood draw taken just prior to the initial debulking surgery. We utilized a non-interferometric quantitative phase microscopy technique using brightfield imagery to measure cellular dry mass. Next we used a quantitative differential interference contrast microscopy technique to measure cellular volume. These techniques were combined to determine cellular dry mass density. We found that HD-CTCs were more massive than leukocytes: 33.6 +/- 3.2 pg (HD-CTC) compared to 18.7 +/- 0.6 pg (leukocytes), p < 0.001; had greater volumes: 518.3 +/- 24.5 fL (HD-CTC) compared to 230.9 +/- 78.5 fL (leukocyte), p < 0.001; and possessed a decreased dry mass density with respect to leukocytes: 0.065 +/- 0.006 pg/fL (HD-CTC) compared to 0.085 +/- 0.004 pg/fL (leukocyte), p < 0.006. Quantification of HD-CTC dry mass content and volume provide key insights into the fluid dynamics of cancer, and may provide the rationale for strategies to isolate, monitor or target CTCs based on their physical properties. The parameters reported here can also be incorporated into blood cell flow models to better understand metastasis. PMID- 22826823 TI - Characterization of catechol 2,3-dioxygenase from Planococcus sp. strain S5 induced by high phenol concentration. AB - This study aimed at characterization of a new catechol 2,3-dioxygenase isolated from a Gram-positive bacterium able to utilize phenol as the sole carbon and energy source. Planococcus sp. strain S5 grown on 1 or 2 mM phenol showed activity of both a catechol 1,2- and catechol 2,3-dioxygenase while at a higher concentrations of phenol only catechol 2,3-dioxygenase activity was observed. The enzyme was optimally active at 60 degrees C and pH 8.0. Kinetic studies showed that the K(m) and V(max) of the enzyme were 42.70 uM and 329.96 mU, respectively. The catechol 2,3-dioxygenase showed the following relative meta-cleavage activities for various catechols tested: catechol (100%), 3-methylcatechol (13.67%), 4-methylcatechol (106.33%) and 4-chlorocatechol (203.80%). The high reactivity of this enzyme towards 4-chlorocatechol is different from that observed for other catechol 2,3-dioxygenases. Nucleotide sequencing and homology search revealed that the gene encoding the S5 catechol 2,3-dioxygenase shared the greatest homology with the known genes encoding isoenzymes from Gram-negative Pseudomonas strains. PMID- 22826824 TI - An improved method for RNA isolation from plants using commercial extraction kits. AB - Isolation of RNA from plants rich in secondary metabolites using commercial kits often results in contaminated preparations which are not suitable for downstream applications. Although many specific protocols appropriate for plants with a high content of phenolics, anthocyanins and polysaccharides have been developed, these are often expensive, time consuming and not applicable to different types of tissues. This study presents a simple and efficient modification of RNA extraction from different types of tissues using two commercial reagent kits. By simple improvement, we routinely obtained high-quality RNA of the following plants: the blackcurrant bush, black chokeberry bush, pear tree, apricot tree, apple tree, hardy kiwi, tangerine tree, highbush blueberry and cranberry plant. PMID- 22826825 TI - Addendum: Transdermal estrogen (Med Lett Drugs Ther 2012;54:41). PMID- 22826826 TI - David A. Winter, Ph.D., P.Eng. PMID- 22826821 TI - Embolization and radiosurgery for arteriovenous malformations. AB - The treatment of arteriovenous malformations (AVMs) requires a multidisciplinary management including microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). This article reviews the recent advancements in the multimodality treatment of patients with AVMs using endovascular neurosurgery and SRS. We describe the natural history of AVMs and the role of endovascular and radiosurgical treatment as well as their interplay in the management of these complex vascular lesions. Also, we present some representative cases treated at our institution. PMID- 22826827 TI - Interlaboratory workshop on anti-HPA-1a alloantibody quantification with the mAb specific immobilization of platelet antigen technique. PMID- 22826830 TI - Rheumatoid arthritis. Linking ACPA to bone loss in rheumatoid arthritis. PMID- 22826828 TI - Re: Correlation of size and type of modic types 1 and 2 lesions with clinical symptoms: a descriptive study in a subgroup of patients with chronic low back pain on the basis of a university hospital patient sample. PMID- 22826829 TI - Therapy. Tissue engineering: harnessing stem cells in cartilage repair. PMID- 22826831 TI - Abnormal semen parameters in bipolar men treated with valproate. PMID- 22826832 TI - A combined index of structure and function for staging glaucomatous damage. AB - OBJECTIVES: To present and evaluate a new combined index of structure and function (CSFI) for staging and detecting glaucomatous damage. METHODS: Observational study including 333 glaucomatous eyes (295 with perimetric glaucoma and 38 with preperimetric glaucoma) and 330 eyes of healthy subjects.All the eyes were tested with standard automated perimetry and spectral domain optical coherence tomography within 6 months. Estimates of the number of retinal ganglion cells (RGCs) were obtained from standard automated perimetry and spectral domain optical coherence tomography and a weighted averaging scheme was used to obtain a final estimate of the number of RGCs for each eye. The CSFI was calculated as the percent loss of RGCs obtained by subtracting estimated from expected RGC numbers. The performance of the CSFI for discriminating glaucoma from normal eyes and the different stages of disease was evaluated by receiver operating characteristic curves. RESULTS: The mean CSFI, representing the mean estimated percent loss of RGCs, was 41% and 17% in theperimetric and preperimetric groups, respectively(P.001). They were both significantly higher than the mean CSFI in the healthy group (P.001). The CSFI had larger receiver operating characteristic curve areas than isolated indexes of structure and function for detecting perimetric and preperimetric glaucoma and differentiating among early, moderate, and advanced stages of visual field loss. CONCLUSION: An index combining structure and function performed better than isolated structural and functional measures for detection of perimetric and preperimetric glaucoma as well as for discriminating different stages of the disease. PMID- 22826833 TI - Plan launched to find HIV cure. PMID- 22826834 TI - Cambodia unravels cause of mystery illness. PMID- 22826835 TI - Brazilian fitness programme registers health benefits. PMID- 22826836 TI - Motion and rest: Galen on exercise and health. PMID- 22826837 TI - Bibliography. Renal pathophysiology. Current world literature. PMID- 22826838 TI - SOMAscanTM used to investigate protein expression in non-small-cell lung cancer. PMID- 22826839 TI - Two-layered polymeric membrane prevents hematocrit issues in dried blood spot analysis. PMID- 22826840 TI - Grinding procedure influence on LC-MS/MS determination of ethyl glucuronide concentrations in hair. PMID- 22826841 TI - New ELISA bulks up detection ability of steroid screening methods. PMID- 22826842 TI - New strategic outsourcing program from Metabolon. PMID- 22826843 TI - [Internal quality control for antimicrobial susceptibility test: an experience feedback]. AB - Internal quality control (IQC) position in antimicrobial susceptibility testing must be evaluated attentively before using. Ours S. aureus ATCC 25923 use during year 2011 has given precious information that can be useful for other laboratories. First, IQC should never be used before checking that all the realisation process steps are controlled. It will then appear that reagents are the most susceptible to give false results. That's what happens in 2.74% of antimicrobial susceptibility test. IQC is then useful to limit their clinical's impact. However, IQC use also shows that quality improvement will be difficult without industrial producer's involvement. PMID- 22826844 TI - [Sign of the times]. PMID- 22826845 TI - Maternal exposure to magnetic fields from high-voltage power lines and the risk of birth defects. AB - The issue of adverse human health effects due to exposure to electromagnetic fields is still unclear, and congenital anomalies are among the outcomes that have been inconsistently associated with such exposure. We conducted a population based, case-control study to examine the risk of congenital anomalies associated with maternal exposure to magnetic fields (MF) from high-voltage power lines during pregnancy in a community in northern Italy. We identified 228 cases of congenital malformations diagnosed in live births, stillbirths, and induced abortions among women living in the municipality of Reggio Emilia during the period 1998-2006, and a reference group of healthy newborns was matched for year of birth, maternal age, and hospital of birth. We identified maternal residence during early pregnancy and used Geographic Information System to determine whether the residences were within geocoded corridors with MF >=0.1 MUT near high voltage power lines, then calculated the relative risk (RR) of congenital anomalies associated with maternal exposure. One case and 5 control mothers were classified as exposed, and the RR associated with MF >=0.1 MUT was 0.2 (95% CI: 0.0-2.0) after adjusting for maternal education. While small or moderate effects may have gone undetected due to low statistical power, the results of this study overall do not provide support for major effects of a teratogenic risk due to exposure to MF during early pregnancy. PMID- 22826846 TI - [Acute myeloblastic leukemia and pregnancy]. PMID- 22826847 TI - [Pernicious anemia revealed by hematemesis]. PMID- 22826848 TI - [IRIDA: what's new]. PMID- 22826849 TI - [Thrombocytopenia induced by digoxin overdose]. PMID- 22826850 TI - Place of genotyping and phenotype in addition tp the assay of serum alpha - 1 antitrypsin. PMID- 22826851 TI - Pericytes and the blood-brain barrier: recent advances and implications for the delivery of CNS therapy. AB - "Once the regulation of brain endothelial transcytosis is understood at the molecular level, it should be possible to exploit these mechanisms as targets for facilitated CNS drug delivery". PMID- 22826852 TI - Therapeutic delivery using gene-delivery methods. AB - "With the introduction of the sophisticated tools of molecular biology, gene therapy has evolved as a new therapeutic option for different malignancies". PMID- 22826853 TI - Delivery of therapeutic RNA molecules to cancer cells by bacteria. AB - Delivery of RNA-based therapeutics, for example RNA interference (RNAi) effectors, to target cells is one of the major obstacles for the development of RNA-based therapies. Since it has been known for a long time that bacteria can mediate tumor shrinkage, it was obvious to use nonpathogenic bacteria to produce and deliver therapeutic RNA molecules into target cells to induce RNAi. During the last years, two bacteria-based concepts were developed for this strategy, transkingdom RNAi (tkRNAi) and bacteria-mediated RNAi (bmRNAi). The first concept, tkRNAi, delivers RNAi effectors into target cells by invasive bacteria, which themselves produce therapeutic shRNAs. The bmRNAi technology utilizes invasive bacteria conveying RNAi effector-encoding DNA constructs that will act as a matrix for transcription of these sequences in the target cell by the host cell's transcription machinery. PMID- 22826854 TI - Recent advances in fetal gene therapy. AB - Over the first decade of this new millennium gene therapy has demonstrated clear clinical benefits in several diseases for which conventional medicine offers no treatment. Clinical trials of gene therapy for single gene disorders have recruited predominantly young patients since older subjects may have suffered irrevocablepathological changes or may not be available because the disease is lethal relatively early in life. The concept of fetal gene therapy is an extension of this principle in that diseases in which irreversible changes occur at or beforebirth can be prevented by gene supplementation or repair in the fetus or associated maternal tissues. This article ccnsiders the enthusiasm and skepticism held for fetal gene therapy and its potential for clinical application. It coversa spectrum of candidate diseases for fetal gene therapy including Pompe disease, Gaucher disease, thalassemia, congenital protein C deficiency and cystic fibrosis. It outlines successful and not-so-successful examples of fetal gene therapy in animal models. Finally the application and potential of fetal gene transfer as a fundamental research tool for developmental biology and generation of somatic transgenic animals is surveyed. PMID- 22826855 TI - Nucleic acid delivery using magnetic nanoparticles: the Magnetofection technology. AB - In recent years, gene therapy has received considerable interest as a potential method for the treatment of numerous inherited and acquired diseases. However, successes have so far been hampered by several limitations, including safety issues of viral-based nucleic acid vectors and poor in vivo efficiency of nonviral vectors. Magnetofection has been introduced as a novel and powerful tool to deliver genetic material into cells. This technology is defined as the delivery of nucleic acids, either 'naked' or packaged (as complexes with lipids or polymers, and viruses) using magnetic nanoparticles under the guidance of an external magnetic field. This article first discusses the principles of the Magnetofection technology and its benefits as compared with standard transfection methods. A number of relevant examples of its use, both in vitro and in vivo, will then be highlighted. Future trends in the development of new magnetic nanoparticle formulations will also be outlined. PMID- 22826856 TI - Perinatal gene delivery to the CNS. AB - The relative inaccessibility of the brain compared with other major organs, the highly regulated transfer of molecules across the blood-brain barrier and the limited capacity of neurons to regenerate, make efficient gene delivery to the CNS both challenging and imperative. Perinatal gene delivery to the CNS represents a powerful tool for the investigation of genes in development and disease. However, it may also hold immense therapeutic value for neonatal lethal neurodegenerative diseases for which no treatment is available. This article will focus on the use of perinatal gene delivery as a research tool and the potential it has to develop into a realistic therapy that can be translated to the clinic. PMID- 22826858 TI - Is confidential peer review in jeopardy? PMID- 22826859 TI - Leapfrog releases hospital safety scores. PMID- 22826860 TI - Measuring safety culture--can it be done? PMID- 22826861 TI - NQF endorses chronic conditions measures. PMID- 22826862 TI - New survey tools for patient safety COPs. PMID- 22826863 TI - Amino acid prodrugs for oral delivery: challenges and opportunities. PMID- 22826864 TI - Why is understanding lung characteristics becoming increasingly important in the design of inhalers? PMID- 22826865 TI - Optimizing the adeno-associated viral vector system: a brief summary. AB - rAAV vectors have emerged as one of the leading gene transfer systems in preclinical and clinical applications. Promising intrinsic features of this vector system are nonpathogenicity, high stability and low immunogenicity. Application of the vector system has been improved by simplifying the production procedure and by expanding the vector platform using alternative serotypes and vectors with artificial capsids (mosaic, hybrid or specifically engineered). The current limitations of the vector system are addressed based on the increasing knowledge on the virus-host interaction by further optimizing the capsid as well as the vector genome. PMID- 22826857 TI - Advances in polymeric and inorganic vectors for nonviral nucleic acid delivery. AB - Nonviral systems for nucleic acid delivery offer a host of potential advantages compared with viruses, including reduced toxicity and immunogenicity, increased ease of production and less stringent vector size limitations, but remain far less efficient than their viral counterparts. In this article we review recent advances in the delivery of nucleic acids using polymeric and inorganic vectors. We discuss the wide range of materials being designed and evaluated for these purposes while considering the physical requirements and barriers to entry that these agents face and reviewing recent novel approaches towards improving delivery with respect to each of these barriers. Furthermore, we provide a brief overview of past and ongoing nonviral gene therapy clinical trials. We conclude with a discussion of multifunctional nucleic acid carriers and future directions. PMID- 22826866 TI - Screening of siRNA nanoparticles for delivery to airway epithelial cells using high-content analysis. AB - AIMS: Delivery of siRNA to the lungs via inhalation offers a unique opportunity to develop a new treatment paradigm for a range of respiratory conditions. However, progress has been greatly hindered by safety and delivery issues. This study developed a high-throughput method for screening novel nanotechnologies for pulmonary siRNA delivery. METHODOLOGY: Following physicochemical analysis, the ability of PEI-PEG-siRNA nanoparticles to facilitate siRNA delivery was determined using high-content analysis (HCA) in Calu-3 cells. Results obtained from HCA were validated using confocal microscopy. Finally, cytotoxicity of the PEI-PEG-siRNA particles was analyzed by HCA using the Cellomics multiparameter cytotoxicity assay. CONCLUSION: PEI-PEG-siRNA nanoparticles facilitated increased siRNA uptake and luciferase knockdown in Calu-3 cells compared with PEI-siRNA. PMID- 22826867 TI - Self-assembling peptides and their potential applications in biomedicine. AB - For many years, peptides have been known to self-assemble to form nano- and micro scale structures. Their nature of assembly and assembled morphology has since been investigated as this area of research has important implications for the development of both drug delivery and tissue regeneration. In this article, we explore the process of peptide self-assembly in vivo, and experiments that exploit the structures formed. Particular focus is directed towards diphenylalanine, the simplest self-assembling peptide, which generally forms tube like structures on assembly. In addition, different peptides that may assemble into a range of other morphologies are highlighted and potential applications in regenerative medicine and drug delivery discussed. PMID- 22826868 TI - Subunit vaccines of the future: the need for safe, customized and optimized particulate delivery systems. AB - A major challenge for current vaccine development is the fact that many new subunit vaccines based on highly purified recombinant proteins are poorly immunogenic and mobilize insufficient immune responses for protective immunity. Adjuvants are therefore needed in vaccine formulations to enhance, direct and maintain the immune response to vaccine antigens. Few adjuvants are currently approved for human use that mainly induce humoral immunity, and there is therefore an unmet medical need for development of effective and safe adjuvants that in addition can stimulate cellular or mucosal immunity, or combinations thereof, depending on the requirements for protection against the specific disease. Vaccine delivery systems are important components of adjuvants that allow proper delivery of antigens to antigen-presenting cells. Moreover, they often possess intrinsic immunopotentiating activity and/or can be customized towards a given immunological profile by the appropriate combination with immunopotentiating compounds. This article reviews the current status of human tailored vaccine delivery with special focus on how to design safe particulate vaccine delivery systems with respect to composition, physicochemical properties, antigen association and choice of administration route, in order to better customize vaccine formulations towards specific diseases in the future. PMID- 22826869 TI - Biopharmaceutical challenges of therapeutics in space: formulation and packaging considerations. PMID- 22826870 TI - Delivery of the vitamin E compound tocotrienol to cancer cells. AB - Tocotrienol, a member of the vitamin E family of compounds, is currently receiving increased attention owing to its highly promising anticancer effects. However, its potential in cancer therapy is limited by its poor bioavailability and its inability to specifically reach tumors at therapeutic concentrations after intravenous administration. In order to address these problems, various delivery strategies have been proposed, such as the inclusion of tocotrienol in gamma-cyclodextrins, prodrugs and emulsions, and entrapment in lipid nanoparticles and vesicles. Among these approaches, we have demonstrated that the entrapment of tocotrienol within vesicles bearing transferrin, whose receptors are overexpressed on numerous cancer cells, significantly improved the uptake by cancer cells overexpressing transferrin receptors. Consequently, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles led to tumor regression and even complete tumor suppression in some cases in a murine tumor model, as well as improvement of animal survival. Transferrin-bearing vesicles are therefore highly promising for the delivery of tocotrienol to cancer cells in vitro and in vivo, and should be further investigated to optimize the anticancer therapeutic effect of tocotrienol. PMID- 22826871 TI - Case study: to-BBB's G-Technology, getting the best from drug-delivery research with industry-academia partnerships. AB - To-BBB aims to develop efficacious treatments for patients with devastating neurological conditions based on to-BBB's proprietary G-Technology that safely enhances the delivery of drugs across the blood-brain barrier. Through strategic research collaborations, a small company such as to-BBB is able to deliver the high-quality research necessary to develop these novel treatments. PMID- 22826872 TI - From RNA interference technology to effective therapy: how far have we come and how far to go? AB - Over a decade has passed since the first description of RNAi in animals--the fundamental endogenous process by which small dsRNAs mediate sequence-specific gene silencing. This discovery has radically transformed our understanding of gene regulation and function and spawned a whole new biotechnology industry focused on developing RNAi-based therapeutic approaches to a variety of human diseases that have otherwise proved challenging to conventional therapies. While RNAi technologies hold great promise as a powerful medical tool, successful delivery of RNAi agents and effective measurement of their uptake are major challenges in translating RNAi therapies to the clinic. Exciting developments in the field have also been tempered by safety concerns surrounding the immunogenic potential of this gene silencing technology and the potential side effects associated with exploiting a crucial biological pathway for therapeutic benefit. This article examines the progress of RNAi therapeutics including advances in delivery and safety, and recent findings from several Phase I-III clinical trials. The emergence of a novel application of RNAi in enhancing the delivery of low-molecular weight drugs to neuronal tissues will also be presented to provide an outlook on the future of RNAi technologies. PMID- 22826873 TI - Biodegradable polyoxalate and copolyoxalate particles for drug-delivery applications. AB - Polyoxalate and copolyoxalate were developed in the 1970s and have been used for biomedical applications such as suture coating purposes, owing to their biocompatibility and biodegradability. They are known to degrade into diols and oxalic acid, which are considered biocompatible. One of the advantages of oxalate based polymer is the ease of control of physicochemical properties, such as biodegradability, crystallinity and mechanical strength. The composition and hydrophobicity of diols greatly influenced their hydrolytic stability and mechanical properties. Oxalate-based polymers have faster hydrolytic-degradation kinetics than the commercial biodegradable polymers, poly(lactide-co-glycolide) and poly(caprolactone). Recently, our group has developed fully biodegradable polymer drug carriers based on oxalate-based polymers that are composed of various diols. The hydrophobicity of the oxalate-based polymers allowed them to be formulated into nano- or micro-particles, which are suitable for targeting macrophages in inflammatory diseases. The nano- or micro-particles exhibited excellent cytotoxicity profiles and fast drug-release kinetics, suggesting great potential as drug-delivery systems for the treatment of acute inflammatory diseases. In this article, we discuss the synthesis and physicochemical properties of oxalate-based polymers which can be used as a drug-delivery vehicle for the treatment of inflammatory diseases. PMID- 22826874 TI - Structural investigation and intracellular trafficking of a novel multicomposite cationic solid lipid nanoparticle platform as a pDNA carrier. AB - BACKGROUND: The ability to efficiently cross cellular barriers and accomplish high-level transgene expression is a critical challenge to broad application of nonviral vectors, such as cationic solid lipid nanoparticles (SLN). AIMS: This study aims to design and characterize in vitro multicomposite SLN as a novel platform for pDNA delivery. RESULTS/DISCUSSION: The distribution of each component (stearic acid, stearylamine, phosphatidylcholine, cholesterol, protamine and Pluronic F68) in the SLN matrix was studied by electron spectroscopy for chemical analysis and NMR in order to establish its influence on SLN cytotoxicity and transfection efficiency. Multicomposite SLN mediated the expression of enhanced green fluorescent protein in a way comparable with the positive control, but inducing a lower cytotoxicity. Moreover, the carrier exhibited the ability to enter the nucleoli, probably as a result of the synergic action of the nuclear localization signal of protamine and the flexibility of the lipid matrix owing to the phosphatidylcholine. CONCLUSION: The multicomposite SLN showed good transfection efficiency and negligible cytotoxicity, both crucial factors for an efficient gene-delivery system. Considering the fact that nucleoli have emerged in recent years as important targets in many fields, this novel carrier could have significant future therapy involvements whenever there is a requirement to overcome subcellular barriers. However, further work needs to be carried out in order to fully characterize the formulation, to elucidate where alternative colloidal structures might exist and play a role in obtaining the results presented. PMID- 22826875 TI - A GENS-based approach to cardiovascular pharmacology: impact on metabolism, pharmacokinetics and pharmacodynamics. AB - Pharmacological outcomes depend on many factors, with many of them being sexually dimorphic. Thus, physiological gender/sex (GENS) differences can influence pharmacokinetics, pharmacodynamics and, thus, bioavailability and resulting in efficacy of treatment, meaning GENS differences should be an important consideration in therapeutics. In particular, drug response can change according to different hormonal environments. Therefore, GENS-specific differences have a particular clinical relevance in terms of drug delivery, especially for those substances with a narrow therapeutic margin. Since adverse effects are more frequent among women, safety is a key issue. Overall, the status of women, from a pharmacological point of view, is often different and less studied than that of men and deserves particular attention. Further studies focused on women's responses to drugs are necessary in order to make optimal pharmacotherapeutic decisions. PMID- 22826876 TI - Nanostructured self assembled lipid materials for drug delivery and tissue engineering. AB - Every living organism comprises of lipids as basic building blocks in addition to other components. Utilizing these lipids for pharmaceutical and biomedical applications can overcome biocompatibility and biodegradability issues. A well known example is liposomes (lipids arranged in lamellar structures), but other than that there are additional unique mesophasic structures of lipids formed as a result of lipid polymorphisms, which include cubic-, hexagonal- or sponge-phase structures. These structures provide the advantages of stability and production feasibility compared with liposomes. Cubosomes, which exist in a cubic structure, have improved stability, bioadhesivity and biocompatibility. Hexagonal phases or hexosomes exhibit hexagonal arrangements and can encapsulate different drugs with high stability. Lipids also forms tube-like structures known as tubules and ribbons that are also utilized in different biomedical applications, especially in tissue engineering. Immune stimulating complexes are nanocage-like structures formed as a result of interactions of lipid, antigen and Quillaja saponin. These lipidic mesophasic structures have been utilized for gene, vaccine and drug delivery. This article addresses lipid self-assembled supramolecular nanostructures, including cubosomes, hexosomes, tubules, ribbons, cochleates, lipoplexes and immune stimulating complexes and their biomedical applications. PMID- 22826877 TI - Addressing the problem of noncompliance with inhalers by design: the 'patient friendly' approach. PMID- 22826878 TI - Next-Generation Protein Therapeutics Summit conference report. AB - The 2011 Next-Generation Protein Therapeutics Summit integrated five promising strategic approaches to designing and realizing the next generations of protein and biologic drugs. The conference sessions focused on non-antibody and antibody therapeutics, innovations in improving the physicochemical properties of these drugs, routes of administration, methodologies for reducing unwanted immunogenic reactions, and novel drugs from non-natural amino acids. PMID- 22826879 TI - Upconversion nanoparticles for potential cancer theranostics. AB - Lanthanide-doped upconversion nanoparticles have recently attracted significant interest in the field of biomedicine. In the past 2 years, our group has been studying the applications of upconversion nanoparticles in biomedical imaging and drug delivery, as well as imaging-guided novel cancer therapies. PMID- 22826880 TI - Accurate delivery of chemicals and intense light on infected areas only for targeted therapy inside the body. AB - Bacteria and virus deactivation is performed inside and on the skin of the body using the novel device described in this paper. This device delivers on the infected spot only the needed amount of drug and light necessary for therapy, while the excess is siphoned out, thus eliminating the deleterious affects that maybe caused by intravenous injection. A charged coupled device provides means for visual monitoring of the therapeutic reaction and an LED or laser diode supplies the intense light for the photochemical deactivation. The spectra and kinetics of the photochemical reaction that generate the reactive species, such as 1O2 and OH radicals that are responsible for pathogen deactivation, are presented. Topical therapy experiments on New Zealand rabbits are described. PMID- 22826881 TI - Nano-organized shells and their application in controlled release. AB - AIM: The release characteristics of hollow-shell drug-delivery carriers are strongly dependent on the properties of the capsule shell, in particular its thickness and porous structure. The aim of this investigation was to conduct a detailed study of the relationship between capsule processing parameters, the resulting shell characteristics and subsequent release of an encapsulated liquid. METHODS: Hollow spherical polymer capsules of constant outer diameter were prepared using electrohydrodynamic processing and the shell thickness of the capsules varied between 100-150 nm. For each type of capsule, the size and structure of channels present in the shell were extensively studied using electron microscopy. To investigate the effect upon the release characteristics the capsules were loaded with a water-soluble dye of molecular weight approximately 961 and release profiles determined using ultraviolet spectroscopy. RESULTS: The channel diameter was found to be similar for all shell thicknesses ( 5 nm). The majority of the channels were radially aligned and through the full thickness of the shell. It was found that the rate of release decreased with increasing shell thickness and it became increasingly linear with respect to time; modeling confirmed that the release was diffusion dominated. CONCLUSIONS: The results of the study show that by controlling the structural characteristics of the shell of the hollow drug-carrier particles at the nanoscale through their forming methodology, the release profile can in turn be tailored according to the application requirements. PMID- 22826882 TI - Theoretical study of bone cancer therapy by plasmonic nanoparticles. AB - BACKGROUND: Progress made by the scientific community in the understanding of cell receptors and metabolic pathways has led to discovery of chemical and protein agents which act as delivery vectors to specific tissues. Conjugating these agents to noble-metal nanoparticles allows for subsequent accumulation on or within targeted cells. Utilizing the unique light absorption properties of these nanoparticles then allows for photothermal heating of the particles and surrounding tissue. DISCUSSION: The heat equations are solved for the case of gold nanoparticles in biological hard tissues, such as bone, for applications to two future cancer therapies: nanophotothermolysis and nanophotohyperthermia. CONCLUSIONS: A survey of recent research in bone-targeting bioconjugates and simulations of nanoparticle thermal fields shows promise for these therapies in the near future. PMID- 22826883 TI - Curcumin sensitizes chemotherapeutic drugs via modulation of PKC, telomerase, NF kappaB and HDAC in breast cancer. AB - BACKGROUND: Several tumor markers are overexpressed in breast cancer. Chemotherapy in breast cancer fails due to resistance to chemotherapeutic drugs. A phytochemical such as curcumin can be used in a therapeutic modality as it elicits anti-tumor effects. METHODS: Action of curcumin on the expression of several tumor markers, such as protein kinase C, telomerase, NF-kappaB and histone deacetylase in MCF-7 (ER positive), MDA-MB-231 (ER negative), MCF- 12F (control) and also in mice mammary tumors were investigated. RESULTS: Curcumin downregulated the expression of tumor markers both in vitro and in vivo and sensitized tumor cells to the chemotherapeutic drugs cyclophosphamide and paclitaxel. DISCUSSION: Curcumin may be of considerable value in synergistic therapy of cancer such that the drug dose level could be minimized reducing the associated toxicity. PMID- 22826884 TI - Novel dry powder inhaler particle-dispersion systems. AB - Dry powder inhalers are a diverse family of devices that have emerged as a rapidly growing segment of the respiratory therapeutics area. The forces that these devices must impart into dry powder formulations for effective dispersion performance and reproducibility of delivery are relatively large, and multiple mechanisms have been developed in attempts to improve the efficiency of these systems. In this review, we address the reasons for the proliferation of dry powder inhalers, beginning with an abbreviated introduction on the basic inter particulate forces that need to be disrupted to achieve successful powder dispersion and effective lung delivery. From this background, we survey the diversity of inhaler designs, starting from marketed devices, before introducing some of the novel device designs under development, both patient driven (passive) and device driven (active), as we attempt to link the themes of the device design features to the present understanding of the dynamics governing powder dispersion. Finally, we conclude by providing some assessment on the future of the wide range of device designs and mechanisms that have evolved by considering technical, regulatory and market forces. PMID- 22826885 TI - Pulmonary delivery of inhalable nanoparticles: dry powder inhalers. AB - Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers. PMID- 22826886 TI - Non-invasive radiofrequency ablation of malignancies mediated by quantum dots, gold nanoparticles and carbon nanotubes. AB - Various types of nanoparticles efficiently heat in radiofrequency fields, which can potentially be used to produce cancer cell cytotoxicity within minutes. Multifunctional and targeted nanoparticles have demonstrated effective cancer control in vivo without significant toxicity associated with radiofrequency field exposure. Importantly, animals treated systemically with targeted nanoparticles smaller than 50 nm demonstrate tumor necrosis after radiofrequency field exposure without acute or chronic toxicity to normal tissues. Likewise, the future holds great promise for multifunctional imaging as well as multimodality therapy with chemotherapeutic molecules and ionizing radiation sensitizing agents attached to nanoparticle constructs. However, the appropriate balance of safety and efficacy for diagnosis, therapy, and therapeutic monitoring with these nanoparticles remains to be fully elucidated. PMID- 22826887 TI - Trans-scleral delivery of macromolecules. AB - Non-invasive drug delivery to the posterior segment of the eye represents an important unmet medical need, and trans-scleral delivery could be an interesting solution. This review analyses the possibility of trans-scleral drug delivery for high molecular weight compounds, such as proteins and genetic material, which currently represent the most innovative and efficacious molecules for the treatment of many diseases of the posterior segment of the eye. The paper reviews all the barriers, both static and dynamic, involved in trans-scleral administration of drugs, trying to elucidate the role of each of them in the specific case of macromolecules. Delivery systems to sustain drug release and enhancing strategies to improve trans-scleral penetration are also described. Finally, the review approaches the use of computational models as a screening tool to evaluate the feasibility of trans-scleral administration for macromolecules. PMID- 22826888 TI - Delivery of antigens used for vaccination: recent advances and challenges. AB - Pasteur's principle 'isolate, inactivate, inject' was the starting point for the successful development of many vaccines, but now, new ways for antigen discovery and vaccine administration present a challenge. Whereas vaccines against polio, measles and influenza are common for many parts of the world, the development of thermostable vaccines not being injected would ease vaccine distribution in developing countries. This review summarizes the general principles of vaccination and looks at common and novel vaccination targets. It also gives a rationale for using other routes than parenteral administration, such as mucosal or transdermal vaccination, and focuses on novel vaccination vehicles, as well as their formulation and stability aspects. Additionally, the review looks at novel application devices for the administration of vaccines. PMID- 22826889 TI - Analysing the relationship between urban livelihoods and water infrastructure in three settlements in Cusco, Peru. AB - This paper explores the role played by water infrastructure in urban livelihoods. It is based on a study of three settlements in Cusco, Peru, and shows that different modes of organising infrastructure co-exist within the same city, despite national policy prescriptions for urban water provision. Further, unequal access of households to these services exists within the same settlements and amplifies household vulnerability which, in turn, feeds back to undermine local, autonomous governance of water. This paper draws on the work of van Vliet et al. and Marvin and Graham to develop a framework that considers infrastructure organisation alongside household livelihoods in order to analyse the features of governance and vulnerability that affect urban livelihoods by privileging some groups and bypassing others. PMID- 22826891 TI - City, region, and in between: New York City's water supply and the insights of regional history. AB - Urban historians have greatly expanded their geographical purview in recent years, incorporating suburbs and hinterlands into their analysis of social and environmental change. Urban environmental historians and suburban historians have played a critical role in the regionalization of urban history over the last decade. This case study of the development of New York City's water supply reveals the benefits of taking a regional approach to urban history. From the New York Public Library to Central Park's Great Lawn to neighborhood parks, the New York City landscape bears the traces of the continuous development of the city's water network. Expansion of the water system in rural hinterlands enabled municipal officials to put urban reservoirs to new uses, creating some of the city's most beloved public spaces. The rehabilitation of urban infrastructure underscores the intimate linkages between rural development and the urban built environment. PMID- 22826892 TI - From the "Phoenix of Legends" to the "Ultimate Monument" of the times: stadia, spectators, and urban development in postwar Paris. AB - This article analyzes the renovation and construction of the Parc des Princes and the Stade de France in post-Second World War Paris. The history of the two stadia testifies to a shift in the envisioned role of stadia in the Parisian basin between the late 1960s and the end of the twentieth century and stands as evidence for the emergence of new urban planning actors. Both stadia were also critiqued as symbols of broader problems with Parisian urbanization, notably as manifestations of anti-democratic planning processes. At the same time, the Parc and the Stade also reflected an emerging consensus over the role of spectator sport in society, accompanied by attempts to re-envision mass sporting spectatorship as a more democratic and familial practice. This article thus situates the two stadia within the history of Parisian urbanization and within broader global urbanizing processes. PMID- 22826894 TI - Upholding indigenous freedoms of religion and medicine: Peyotists at the 1906 1908 Oklahoma Constitutional Convention and First Legislature. PMID- 22826895 TI - Fat Christians and fit elites: negotiating class and status in Evangelical Christian weight-loss culture. AB - As American culture has become increasingly concerned about fatness, the fat body and weight loss have become salient symbols for other social tensions. This article uses the case of evangelical Christian weight-loss culture to argue that class is one of those tensions. Drawing on ethnographic work in a Christian weight-loss program as well as on recent theories of class, I argue that certain recurring concerns in Christians' weight-loss discourse, notably concerns about fat Christian leaders and appearing healthy, reflect tensions about class-based aspirations and class-based denigrations evangelicals face in negotiating their position in American society. PMID- 22826896 TI - San Francisco's Pioneer Mother Monument: maternalism, racial order, and the politics of memorialization, 1907-1915. AB - The 1907-1915 campaign to create San Francisco's Pioneer Mother Monument provides both a case study of conservative uses of maternalism and a window into the political mutability of maternalist rhetoric. Ella Sterling Mighels, a pioneer descendant, utilized the monument campaign to promote white women's moral influence over middle-class men, to argue against Asian immigration and labor unrest, and to inculcate old-fashioned moral values among urban children. Although some of Mighels's contemporaries cited pioneer mothers as proof of women's fitness for suffrage, Mighels herself used the pioneer mother to argue against suffrage. The final statue, created by the sculptor Charles Grafly, failed to encapsulate Mighels's multivalent political message and to express her ideals about gender, race, class, and morality. PMID- 22826897 TI - Sexual minorities, human rights and public health strategies in Africa. AB - Remarkable progress has been made towards the recognition of sexual minority rights in Africa. At the same time, a marked increase in attacks, rhetorical abuse, and restrictive legislation against sexual minorities or 'homosexuality' makes activism for sexual rights a risky endeavour in many African countries. Campaigns for sexual rights and 'coming out' are frequently perceived as a form of Western cultural imperialism, leading to an exportation of Western gay identities and provoking a patriotic defensiveness. Cultures of quiet acceptance of same-sex relationships or secretive bisexuality are meanwhile also problematic given the high rate of HIV prevalence on much of the continent. This article examines specific initiatives that are using subtle, somewhat covert means to negotiate a path between rights activism and secretive bisexuality. It argues that strategies primarily focused on health concerns that simultaneously yet discreetly promote sexual rights are having some success in challenging prevalent homophobic or 'silencing' cultures and discourses. PMID- 22826898 TI - Proceedings of 2011 Perfusion Downunder Winter Meeting. August 6-8, 2011, Hayman Island, Queensland, Australia. PMID- 22826899 TI - Proceedings of the 63rd International Symposium on Crop Protection, May 24, 2011. Gent, Belgium. PMID- 22826900 TI - Cancer Cell Line Encyclopedia launched by Novartis and Broad Institute. PMID- 22826901 TI - Investment fund established to combat cancer drug 'development gap'. PMID- 22826902 TI - New allergic disease regulator identified by researchers. PMID- 22826903 TI - Using electronic health records to improve quality and efficiency: the experiences of leading hospitals. AB - An examination of nine hospitals that recently implemented a comprehensive electronic health record (EHR) system finds that clinical and administrative leaders built EHR adoption into their strategic plans to integrate inpatient and outpatient care and provide a continuum of coordinated services. Successful implementation depended on: strong leadership, full involvement of clinical staff in design and implementation, mandatory staff training, and strict adherence to timeline and budget. The EHR systems facilitate patient safety and quality improvement through: use of checklists, alerts, and predictive tools; embedded clinical guidelines that promote standardized, evidence-based practices; electronic prescribing and test-ordering that reduces errors and redundancy; and discrete data fields that foster use of performance dashboards and compliance reports. Faster, more accurate communication and streamlined processes have led to improved patient flow, fewer duplicative tests, faster responses to patient inquiries, redeployment of transcription and claims staff, more complete capture of charges, and federal incentive payments. PMID- 22826904 TI - Who pays for health care when workers are uninsured? AB - Employer-sponsored insurance coverage forms the backbone of the U.S. health insurance system, yet there are crucial weaknesses that have contributed to a growing number of uninsured Americans. Ultimately, the lack of employer-based coverage generates public costs in the form of taxpayer bills to fund public insurance or uncompensated care programs for care that would otherwise be paid for through insurance. This report quantifies those costs, using data from the Medical Expenditure Panel Surveys to estimate public program spending and uncompensated care costs for uninsured workers and their dependents. In 2004, uninsured and publicly insured workers and their dependents accounted for $45 billion in public costs. This includes $33 billion associated with public program insurance costs and $12 billion in uncompensated care costs. Public costs associated with uninsured and publicly insured workers and their dependents were 45 percent greater in 2004 than in 1999. All costs are reported in 2004 dollars. PMID- 22826905 TI - The widening health care gap between high- and low-wage workers. AB - Rising health care costs affect everyone, but pose a particular problem for low wage workers and their families. Few of these workers are eligible for public insurance programs or can afford to purchase private insurance, and they are less likely than high-wage workers to work for companies offering health coverage. Using data from the Medical Expenditure Panel Survey, this report finds that, between 1996 and 2003, low-wage workers were more likely than high-wage workers to be uninsured and to spend a proportionally higher share of family income on out-of-pocket health costs. They were less likely to have a usual source of care, less likely to have received preventive services, used fewer health care services overall, and were less likely to use the latest generation of medical technologies (e.g., prescription drugs approved within the prior 20 years). They were also more likely to report worse general and mental health than high-wage workers. PMID- 22826906 TI - [Retrospective study of direct composite restorations according to the USPHS criteria]. AB - The purpose of this retrospective study was to evaluate and describe the occurrence of different deficiencies of composite restorations in molar and premolar teeth. Further aim was to investigate possible correlations between occurring malformations and the localization or size of the restorations. 240 class II composite restorations (in 85 patients) were involved in the study. Control examinations were carried out five years after restorations, according to the United States Public Health Services' criteria. Namely, anatomic form, marginal integrity, marginal stain, color stability, surface smoothness, and the presence of secondary caries or fractures of the restorations. The associations between variables were calculated by bivariate analyses using either Pearson chi square or Fisher tests. P < 0.05 was considered significant. In 0.8% of the fillings, secondary caries and in 0.4% of the cases, fracture was found as a failure. The frequency of adjacent deficiencies were found as follows: color instability, 12.5%; marginal stain, 20.8%; anatomic deformity, 15.0%; failure of marginal integrity, 8.8%; and surface roughness, 2.5%. Color instability was significantly more frequent in premolar teeth, than in molars (P = 0.031). Color instability (P = 0.015), marginal stain (P < 0.001) and anatomic form malformation (P = 0.002) occurred more frequently in MOD restorations than in MO/OD fillings. Our results suggest that class II restorations are correct both functionally and esthetically in 98.8% of the cases, even after a 5-year-period. PMID- 22826907 TI - [A clinical study of dental surgery in anticoagulated patients]. AB - It is a worldwide trend that oral surgeons do not stop patients' anticoagulant therapy, but they leave the INR in the therapeutic range (INR: 2.0-3.0). The reason is that stopping drugs carries a higher risk of embolism, and thrombosis. The purpose of the present study is to reproduce these international guidelines in a Hungarian setting. On the day of surgery a lab test is performed immediately before the operation. These tests include coagulation data. A control (INR < 1.89) and an experimental group (INR: 2.0-3.0) were formed. Clinical complications, especially bleeding and thromboembolic complications were monitored. Based on the data and types of surgery no significant differences were found between the two groups. In conclusion it can be stated that it would be advisable to implement international guidelines and recommendations because there is a higher risk for anticoagulated patients if their therapy is stopped as if their INR is left in the therapeutic range. Of course appropriate wound care and bleeding control are necessary. PMID- 22826908 TI - [Clinical, microbiological and immunological findings in peri-implantitis patients with bar-retained lower removable partial dentures, compared to a healthy control group (12-month-follow-up)]. AB - Cause, treatment strategies and prognosis of peri-implantitis is not well understood. The aim of this study was to followup clinical, microbiological and immunological findings in individuals wearing bar-retained lower partial dentures with and without peri-implantitis, pre and post treatment. From the Tuebingen Implant Registry recall program 16 peri-implantitis patients were compared to 16 healthy individuals in a prospective, unblinded study. Peri-implantitis was treated with a single anti-inflammatory therapy according to the CIST protocol while the controls received professional implant cleaning. The following findings were recorded at four time points before treatment (T1) and 30, 90, 360 days post treatment (T2-T4): sulcular fluid flow rate, probing depth, plaque and bleeding index, implant stability (Periotest); sulcular concentrations of interleukin-1 beta, plasminogen activator inhibitor 2, prostaglandin E2, and the sum score of five periodonto-pathogenic bacteria species by PCR (Hain Microldent test). Statistically significant differences between healthy and diseased implants were found for probing depth, bleeding on probing, bacterial load, and implant stability. For the first three, a significant decrease in severity was observed after treatment, but reached initial pre-treatment values within one year. No changes could be observed in the individuals without peri-implantitis. The results of the present study confirm marked differences in peri-implant findings between healthy and diseased sites. They demonstrate that a single anti inflammatory intervention can initially--but not sustained--reduce probing depth, bleeding on probing, and the total bacterial load as evident from PCR diagnostics. Further immunological diagnostic measures do not seem to provide more information in the patients investigated. PMID- 22826909 TI - [Full dental rehabilitation of a patient with implantable cardioverter defibrillator]. AB - During dental rehabilitation of a patient with ICD, an upper telescope retained overdenture with acrylic baseplate and lower cantilever bridges were constructed. In the consultation following the anamnesis and the clinical examination, the cardiologist did not believe antibiotic profilaxis to be necessary, adding that it is advisable to avoid the use of ultrasonic depurator and electrocauter. Nowadays after saving the life the improving of patient's better quality of life is an important aspect. The risk of ICD-implantation is minimal however, not negligible, the patient can pursue a way of life free of limitation. According to the latest trends, the number of ICD-implantations will increase exponentially in the near future, due to the aging of the population, the simplification and safeness of implantation and the increase of patients who can be treated with the device. In case of arritmia or putative dysfunction, the latest ICD-s are able to send emergency alert to the arritmia centre with the help of an outer transmitter. Probably the system will completely change the follow-up of patients with ICD within the next few years, clinical researches of its efficiency are going on at present. PMID- 22826910 TI - [A follow-up report of an uncomplicated crown fracture case starting from first aid to the final definitive rehabilitation based on the experience]. AB - Ten years ago a female child, who suffered an accident on her upper central incisors arrived in the dentistry-clinic. She was diagnosed with an uncomplicated crown fracture, whose follow-up story from first-aid to the final definitive rehabilitation with anterior press ceramic veneer will be shown. This publication analyses all the various kinds of possible therapies and connections with the uncomplicated crown fracture-type dental injuries according to the age of the patients and deduces how and why the adequate therapy and follow-up were choosen in this case. PMID- 22826911 TI - [Dentists' workforce in Hungary and international migration]. AB - In Hungary, cross-national migration in dental care was performed rather by patients from abroad instead of the domestic dentists' migration for working abroad. Actually, this tacitly realized and so-called dental tourism experienced two basic changes. The National Medical Tourism Ltd. arranged the First Conference for Development of Dental Tourism on 21 April 2011. Hungary's prime minister addressed the meeting and finally signed an agreement with the organizing Ltd. about governmental financial support for development of dental tourism. On the other hand, Germany and Austria deleted all restrictions against the free cross-national workforce migration since 1 May this year. For understanding and prognosis of dentists' future migration, it is inevitable to collect and analyse relevant data of the previous years. This study is presenting data obtained from January 1, 2006 to December 31, 2010. According to the net outcome, the dentists' human resource system was balanced down to the end of 2010. However, this state is unsure even for the near future, thus preventing the deficit of dentists all necessary measures must be taken to keep up the present level of the domestic dentral service. PMID- 22826912 TI - [The elderly and the use of the use of recreational drugs: an underestimated problem]. PMID- 22826913 TI - [Alcohol consumption among persons aged 55+ in The Netherlands]. AB - In The Netherlands no detailed information about alcohol consumption among older persons (55 years and older) is available. Therefore we investigated the prevalence and determinants of alcohol consumption with data from the Longitudinal Aging Study Amsterdam. The results show that 13.4% of persons of 55 years and older are heavy drinkers (male >3 glasses per day, female >2 glasses per day). Most heavy drinkers are younger than 75 years of age, and in this age group more female (22.2%) than male (14.8%) are heavy drinkers. 13% of all participants frequently drinks 6 or more glasses in a short period of time (binge drinking). In the age group of 55-65 years alcohol consumption has considerably increased over a period of ten years. This increase is stronger among females than among males. When people grow older alcohol consumption decreases, which seems associated with a decline in physical or psychological health and/or cognitive decline. Heavy and binge drinking is associated with younger age, higher education and income, and may be strongly related to their social lifes. PMID- 22826914 TI - [Alcohol consumption and depressive symptoms among older adults: results of the Longitudinal Aging Study Amsterdam]. AB - The aim of this research is to investigate the often assumed relation between alcohol use and depressive symptoms among older men and women. For this study, a subsample of 2119 participants of the Longitudinal Aging Study Amsterdam, aged 65 to 85 years at baseline, was followed over time and visited in their homes in 1992, 1995, 1998 and 2002. Depressive symptoms are assessed with the Centre for Epidemiologic Studies Depression Scale (CES-D). Alcohol use is measured with questions about the frequency and quantities of alcohol use. A relation between depressive symptoms and alcohol use could not be demonstraded in a population based sample of older drinkers. Only older heavily drinking men with higher levels of depressive symptoms, higher levels of anxiety, and more chronic diseases at baseline significantly reduced the number of glasses consumed per week from 26 to 14 in the ten years of follow-up. Heavily drinking women do not reduce the level of alcohol intake during follow-up. Public prevention strategies are needed to make older heavy drinking women and men who are still in relatively good health aware of the potential risks of excessive alcohol use. PMID- 22826915 TI - [Benzodiazepin addiction: a silent addiction among older people]. AB - Benzodiazepines are frequently prescribed for a longer period of time for anxiety disorders and insomnia in spite of the many guidelines to prescribe these drugs only short-term. These guidelines are based on the risk-benefit balance between long-term effectiveness and side effects like addiction, anterograde amnesia, and increased risk on falling (resulting in hip fractures), traffic accidents and even mortality. Also low-dose benzodiazepine use can lead to benzodiazepine dependence. Although initially most attention has been paid to the physical withdrawal syndrome, psychological aspects of benzodiazepine dependence have received more and more attention in the past decades. Recently, a relationship between the brain-reward system, involved in addiction, and benzodiazepine use, was demonstrated. When long-term benzodiazepine use is recognised as problematic by both physician and patient, different treatment modalities are available to support patients in achieving abstinence. One of every four patients is able to stop by themselves with the aid of a minimal intervention providing psychoeducation and encouragement. Two out of three long-term uses are able to stop their usage with the aid of systematic tapering protocols guided by a physician or psychologist. In case of an underlying insomnia or anxiety disorder, cognitive-behavioural therapy should be added to the tapering protocol. In contrast to the general opinion, advanced old age has no negative impact on the treatment response. PMID- 22826916 TI - [Old and a pint! The practice of a 65-year-old alcoholic]. AB - Alcohol abuse and addiction in The Netherlands among the older adults aged 65 and over has increased in the last decade. Outreaching care is important as most of the elderly do not receive the care they need. We discuss the detoxification and group therapy of an elderly alcoholic. Issues that will be discussed are potential risks and choices that need to be made. PMID- 22826917 TI - [The variation in getting older is understanding and influencing, that is our motivation. A review of the research of the geriatric department of the UMC St. Radboud]. PMID- 22826918 TI - Living with diabetes: what patients are saying. AB - The purpose of this study was to explore the thoughts and feelings of patients with diabetes. The study analyzed the responses to an open-ended question, which was the last item (Question 43) on a diabetes survey that was mailed to 2,615 persons, 534 (22%) with diabetes in eastern North Carolina. Content analysis of the data revealed the following themes: coping/prayer, support, effects of diabetes, metaphors, controlling comorbidities, and appreciation/thankfulness. PMID- 22826919 TI - Selfhelp Community Services: innovations help older men and women maintain independence in a changing world. PMID- 22826920 TI - Home care in Spain. PMID- 22826921 TI - Honoring the patient and the family: when the family refuses DNR. PMID- 22826922 TI - Disabled adults in adult care facilities facing disasters in New York City: an aggregate assessment. AB - Disabled adults who reside in adult care facilities (ACFs) are an at-risk population in the event of an emergency or disaster. This aggregate requires housing in congregate residential settings due to frailty, function, and/or cognitive impairments. All senior residents need long-term assistance to maintain maximum independence, including 24-hr on-site monitoring, case management, and personal care services such as eating, toileting, transferring, bathing, and dressing. Twenty-five percent of this special population of older adults has psychiatric disabilities and nonmental health comorbidities (Caron et al, 2008). Through a literature search, the challenges and risks of this aggregate in the event of a naturally occurring or manmade emergency, including epidemiological and environmental risks, are identified. Evidence-based literature reveals that the foundation of an effective emergency response and recovery is planning and preparation. Lessons learned from past disasters in the United States have brought attention to the needs of disabled and chronically ill older adults. Developing partnerships, improving communication systems, identifying emergency shelters for disabled adults, and empowering ACF residents and staff through education are recommended with the universal goal of reducing injury, preventing or controlling illness, and saving lives. An innovative educational program utilizing Hybrid Modality is outlined in this article including planning, coalition building, and the use of mapping systems as tools and strategies to improve outcomes. Resources such as local, state, and federal agencies; consumer groups; and trade associations are referenced for accessibility. PMID- 22826923 TI - What you need to know about reverse mortgages. PMID- 22826924 TI - NYC Department for the Aging Annual Plan Summary, Part 1: April 1, 2012-March 31, 2013. PMID- 22826925 TI - Elsie Shemin Roth. Interview by Marian Brickner. PMID- 22826926 TI - [The research on time-frequency detection method of respiratory component in ballistocardiogram signal]. AB - Based on the fact that the respiratory component modulates the cardiac cycle component in the ballistocardiogram (BCG) signal, we propose a method that detects respiratory with time-frequency analysis for the sitting ballistocardiography system. Firstly, we demodulated the BCG signal by using the variable frequency complex demodulation (VFCDM) to obtain the output for different center frequency of interest. Then we calculated the instantaneous frequencies and the instantaneous amplitudes by the time-frequency representation. We reconstructed the time-domain waveform of respiratory at last. In order to verify the feasibility and accuracy of this method, we applied wavelet transform and nasal thermistor signal to compare qualitatively and quantitatively. The simulation results showed that the proposed method could detect the respiratory rate from BCG signal more accurately, which provided meaningful attempt for monitoring the multiple physiological parameters synchronously and unconsciously. PMID- 22826927 TI - [Development of an adaptive pneumatic tourniquet]. AB - A new adaptive pneumatic tourniquet was developed for limb operation and first aid. The crucial hardware circuits of the adaptive pneumatic tourniquet were designed based on the microprocessor C8051F340 and blood pressure module CSN602, software was programmed and an experiment was carried out for verifying the system. Results showed that the prototype could measure accurately systolic blood pressure, heart rate and other relative parameters and the designed device could adjust tourniquet cuff's pressure through inflation and deflation according to systolic blood pressure and limb circumference. This designed system integrated the advantages of the adaptive pneumatic tourniquet, and could be used for controlling life-threatening extremity hemorrhage operation and maintaining a bloodless opeation field. PMID- 22826928 TI - [Haptic tracking control for minimally invasive robotic surgery]. AB - Haptic feedback plays a significant role in minimally invasive robotic surgery (MIRS). A major deficiency of the current MIRS is the lack of haptic perception for the surgeon, including the commercially available robot da Vinci surgical system. In this paper, a dynamics model of a haptic robot is established based on Newton-Euler method. Because it took some period of time in exact dynamics solution, we used a digital PID arithmetic dependent on robot dynamics to ensure real-time bilateral control, and it could improve tracking precision and real time control efficiency. To prove the proposed method, an experimental system in which two Novint Falcon haptic devices acting as master-slave system has been developed. Simulations and experiments showed proposed methods could give instrument force feedbacks to operator, and bilateral control strategy is an effective method to master-slave MIRS. The proposed methods could be used to tele robotic system. PMID- 22826929 TI - [QRS complex detection using empirical mode decomposition and windowing technique]. AB - A QRS complex detection algorithm based on empirical mode decomposition (EMD) and adaptive windowing technique is proposed in this paper. In this algorithm we mainly used Hilbert-Huang transform to propose EMD method suitable for QRS complex detection, with which the 30th signal in sddb database and the 208th signal in mit-db database could be processed, and then obtained R wave detection results. At the same time, Q and S points' detection technique was analyzed with adaptive windowing technique. The detection results, through proceeding R wave detection on part data of MIT/BIT arrhythmia database, showed that the proposed algorithm in this paper had a very good detection effect, and that its average correct detection rate of R wave reached 99.62%, its average sensitivity of QRS complex was 98.91%, and the corresponding average specificity was 99.35%. PMID- 22826930 TI - [The effects of multi-mode audio frequency pulse modulating laser together with electrical stimulation on blood pressure and hemorrheology of the spontaneously hypertensive rats]. AB - In order to explore new ways in restraining the ascending blood pressure, this paper reports a research on the effects of multi-mode audio frequency pulse modulating laser irradiation with electrical stimulation on the hemorrheology and blood pressure of the spontaneously hypertensive rats (SHR). Forty male SHR were randomly divided into four groups: Group A (control), Group B (treated with electrical stimulation on stomach 36 point (ST-36)), Group C (treated with low level pulse laser irradiation on Erjian acupuncture point), Group D (low level laser irradiation together with electrical stimulation on Erjian acupuncture point and ST-36). Laser irradiation lasted for 45 min/ day, while electrical stimulation lasted for 30 min/day. After 10 days' treatment, we compared the hemorrheology and blood pressure of the rats in the four groups. The results were that values of hemorrheology in group A and group C were obviously improved compared with those in the other two groups. Meanwhile, the blood pressures in the three treated groups (B, C, and D) were lower than in the control group after the treatment, and the value of the rats in group A was the lowest. In conclusion, the treatment the laser irradiation combined with electrodes stimulation on spontaneously hypertensive rats brought better results of hemorrheology and blood pressure in the tested rats. PMID- 22826931 TI - [Linear features analysis of human body balance regulation under passive movement]. AB - In order to find the linear region of adjustment process about human body balance under the passive movement, and provide the basis for the unified evaluation criteria of passive balance test, an equipment was built with pulsed excitation source and wave detector of gravity's center. The pulsed excitation source was a multi-dimensional motion platform with high accuracy. The wave detector was a force platform. Human body and force platform were treated as a whole object, and the dynamic model of the object was built using the method of system identification. The balance ability was evaluated by setting time. In the pulse excitement range from 2mm to 20 mm with 2mm increments, balance ability of 5 students was evaluated and analyzed respectively. Results showed that response curve of human balance regulation was a typical second order linear system characteristic, and in a large enough linear region, the evaluating result had good consistency. PMID- 22826932 TI - [An electronic medical record information system of DICOM-RT module-based in radiation therapy]. AB - Electronic medical records (EMR) is the clinical diagnosis, guiding intervention and digital medical service record of outpatient, hospital patients (or care object) in medical institution. And it is the complete, detailed clinical information resource which has produced and recorded in all previous medical treatments. Radiotherapy electronic medical records contain texts, images and graphics, therefore the information is more complicated. This paper proposes an EMR information system based on DICOM-RT standard, through the use of seven objects of DICOM-RT to achieve the information exchange and sharing between different systems, equipments, convenient radiotherapy treatment data management, improve the efficiency of radiation treatment. PMID- 22826933 TI - [Analysis of young male anthropometric parameters for design of driving and operations in cars]. AB - Fitting formulas of typical parameters were obtained through analysis of anthropometric parameters of armored car driver and operators. These formulas could be a basis for design of product and equipment of cars, cumulating and updating of basic data of similar sample and edition of relative standards. 76 anthropometric static parameters and 11 functional parameters were chosen, and 1 243 soldiers with armored forces were chosen to be tested. The correlation and fitting formulas of body height, sitting height and other parameters were measured and obtained. We also contrasted measured data with data from GJB1835 1993. The present analysis showed that the correlation between sizes of body length and body height and sitting height was significant. Sizes of body length and enclose size and width direction were all increased compared to those in the 1980s. The present results were consistent with other researchers' current research results. The measured data could be an important basis for the data of young male anthropometric parameters and edition of relative standards and design of specific equipment. PMID- 22826934 TI - [Manual handling of defective channels in siemens somatom Sensation 16 CT]. AB - The present paper introduces the components and operating principle of Sensation 16 CT date measuring system (DMS), analyzes the fixed position of modules and channels in array detector modules (ADM), the Checkup table, Tuneup table and IRS table in ICS Syngo Service. The author also puts forward a solution of manual handling of defective channels. PMID- 22826935 TI - [An analysis on biomedical effects of bipolar electric pulses at different central frequency]. AB - Adopting the cell model of multilayer spherical symmetry and the circuit analysis, the present paper gives the calculated results of the voltages on each of several parts of malignant Tonsillar B-cells and Jurkat T lymphocytes when the first-order Gaussian pulses at different central frequency apposed on them. The relationship between the central frequency and the transmembrane voltages of plasma membrane is also given. The optimum frequency causing electroporation in nuclear envelope is given as well. The paper discusses the reasons of electroporation in membrane and DNA degradation in nuclear. The work provides a reference for usage of transient bipolar electric pulses in cancer treatment. PMID- 22826936 TI - [Changes of carotid wave intensity in patients with different blood pressure and its clinical significance]. AB - Wave intensity (WI) is a new technique in Echocardiography. We can understand the haemodynamics about interaction between the left ventricle and peripheral arteries by WI. The indexes of WI mainly included W1, W2 and NA. W1 can reflect the contractility of left ventricule. W2 can reflect the ability of cardiac actively to stop the blood flow. NA can reflect the resistance of peripheral artery. The subjects included three groups that they were patients with uncured primary hypertension (HP1), cured primary hypertension (HP2) and normal controls (NC). Carotid WI examination was performed and analyzed. The results showed that the WI contributed to understand the changes of hamodanymic caused by interaction between peripheral artery resistance and relevant left ventricular systolic function and it was more sensitive than routine echocardiography. The W1 and NA help to assess the curative effect and follow-up of primary hypertension. PMID- 22826937 TI - [The influence of energy on X-ray voxel Monte Carlo algorithm based on kilovoltage cone beam computed tomography images for dose calculation]. AB - This paper is to investigate how the different energy impact the accuracy of X ray Voxel Monte Carlo (XVMC) algorithm when it is applied for dose calculation in Kilovoltage cone beam CT(kv-CBCT) images. The CIRS model 062 was used to calibrate the CT numbers-relative electron density table of CT and CBCT images. CT and CBCT scans were performed when simulation model of human head-and-neck placed in same position to simulate locally advanced nasopharyngeal carcinoma. 6MV and 15MV photon were selected in Monaco TPS to design intensity-modulated radiotherapy (IMRT) plans. XVMC algorithm was selected for dose calculation then the calculation results were compared and the impact of energy on the calculation accuracy was analyzed. The comparison results of dose volume histograms (DVHs), dose received by targets, organs at risk, conform index and uniform index of targets indicate a high agreement between CT based and CBCT based plans. More evaluation indicators show higher accuracy when 15MV photon was selected for dose calculation. gamma index analysis with the criterion of 2mm/2% and threshold of 10% was used for comparison of dose distribution. The average pass rate of each plane was 99.3% +/- 0.47% on the base of 6MV and 99.4% +/- 0.44% on the base of 15MV. CBCT images after calibration has high accuracy of dose calculation and has higher accuracy when 15MV photon was selected. PMID- 22826938 TI - [The anxiety level of the patients who will have ultrasound-guided puncture biopsy: a survey study]. AB - In order to fully understand the anxiety level of the patients who will have ultrasound-guided puncture biopsy, and the survey results will guide the future clinical care to reduce the anxiety score of the patients, and to im-prove the satisfaction of them, which reflects the quality of care, we used Zung Self rating Anxiety Scale (SAS) to investigate outpatients who will have ultrasound guided puncture biopsy in a upper first-class hospital by convenience sampling way. The results showed that the SAS standard score of the patients was higher than the Chinese normal population's, and there is significant difference between the patients and the normal population's score (t = 47.12, P < 0.001). So for reducing the patients' anxiety level we should give health education and care intervention to the patients before the operation. This reflects the Patient centered Culture and Excellent-quality Care in China. PMID- 22826939 TI - [Denoising of medical CT image based on sparse decomposition]. AB - Noises are inevitably introduced to medical CT images because of various factors in the medical image processes. Noises in medical images will greatly degrade the quality of images and bring difficulties to clinical diagnosis. Therefore, it is necessary for medical CT images to be denoised. In the present paper, the sparse decomposition of images is used to denoise medical CT images. A new block-based sparse decomposition of images denoising method is proposed. Experimental results showed that block-based sparse decomposition of images denoising had a certain function. With the same number of atoms, the computing speed of the image constructed by the new algorithm was improved by about 15 times, compared with the whole image sparse decomposition denoising. PMID- 22826940 TI - [Experimental study on animal with automatic drug injection based on predictive control for vascular interventional therapy]. AB - This paper focuses on the animal experiment of automatic drug delivery based on predictive control for vascular interventional therapy. Improvement of drug delivery system based on predictive control used in simulated experiments was put forward after the presence of time varying parameters and the characteristics of individual differences of animal had been studied. The adaptability of time varying parameters and fault tolerance of the system were also enhanced. Different injection methods were tested on animals. It is proved that higher target blood concentration can be reached while injecting during diastolic than that while injecting during systolic or injecting at a constant speed within the whole cardiac cycle. The results also showed that the improved drug injection system based on predictive control which synchronizes with the cardiac cycle could be applied to clinical trials. PMID- 22826941 TI - [Biomechanical research on different pairs of lumbar laminectomy with finite element analysis]. AB - The finite element model of the intact lumbar spine (L1-L5) was set up to study the biomechanical changes of three different pairs of the lumbar laminectomy. The three-dimensional finite elements model of L1-L5 vertebrae structure was constructed by the combination of self-compiled software and Hyper Mesh. The finite element model was compared with the experimental data in vitro. The finite element model was modified of stenosis at L3-L4 and L4-L5 with the same boundary conditions and physical loads to study the motion and loading in the annulus changes at the surgical site as a result of surgical alteration. The study suggested that the removal of posterior lumbar spinal elements for the treatment of stenosis at L3-L4 and L4-L5 produced a graded increase in motion at the surgical site, with the greatest changes occurring in flexion-extension and axial rotation and that during lateral bending the amount of resection was only slightly affected. The data showed that for flexion-extension and axial rotation the increases in motion were correlated to the extent of posterior element removal. It is necessary to retain the greatest degree of posterior lumbar structures in thorough decompression, which can further reduce the postoperative intervertebral disc, facet degeneration. PMID- 22826942 TI - [Studies on the mechanical properties of thermoplastic polymer resin materials for medical outside fixation]. AB - Temperature scanning tests and uniaxial tensile tests at room temperature under different strain rates for three kinds of existing low-temperature outside fixed thermoplastic medical polymer resin materials (A, B and C) were conducted on dynamic mechanical analyzer and micro material testing machine to contrast their mechanical properties. It is shown that the glass transition temperatures of these three materials are all around 65 degrees C, but material C has the widest range of shaping temperature. Stress-strain responses of the three materials are rate-dependent and material C shows better plasticity. PMID- 22826943 TI - [Study on preparation and physicochemical properties of surface modified sintered bone]. AB - The aim of this study is to investigate a new method for preparing a biomimetic bone material-surface modified sintered bovine cancellous bone, and to improve its bioactivity as a tissue engineering bone. The prepared sintered bovine cancellous bones with the same size were randomly divided into two groups, immersing in 1 and 1. 5 times simulated body fluid (SBF), respectively. The three time periods of soak time were 7, 14, and 21 days. After sintered bone was dried, the surface morphology of sintered bone and surface mineralization composition were observed under scanning electron microscopy (SEM). By comparing the effect of surface modification of sintered bone materials, we chose the most ideal material and studied its pore size, the rate of the porosity, the compress and bend intensity. And then the material and the sintered bone material without surface modification were compared. The study indicated that sintered bone material immersed in SBF (1.5 times) for 14 days showed the best effect of surface modification, retaining the original physico-chemical properties of sintered bone. PMID- 22826944 TI - [Quantification of residues DNA in animal-derived biological scaffold materials]. AB - Quantification of residual DNA in animal-derived biological scaffold materials is one of technical specifications for evaluating decellularization process and immunotoxicity risk. Up to now, there have been no standard methods available for quantification of residues DNA in animal-derived biological scaffold materials. In this study, a three-step method, including proteinase K digestion, DNA purification and determination of DNA using fluorescence assay, was designed for residual DNA quantification. A parallel recovery experiment of standard DNA using the same protocol to test article determination was used for adjusting final results of residuul DNA amount. DNA purification based on magnetic beads enabled the experiments to get high accuracy and repeatability. The validation experiment showed that the three-step method had high sensitivity up to 6.25ng of DNA per sample with good linearity (recovery curve R2 > 0.99) in the concentration range of 3. 125-100ng, and 25-400ng per sample. This method is useful for determining micro or trace amount DNA remained in the biomaterials. PMID- 22826945 TI - [Research on Tat peptide-polyethylene glycol modified gelatin-siloxane nanoparticles across the blood-brain barrier]. AB - Gelatin-siloxane nanoparticles (GS NPs) have been considered to be good gene carrier candidate in vitro, since they have several advantages such as low toxicity, easy preparation and surface modification. In this study, the Tat-PEG GS NPs were synthesized by the gelatin-siloxane, surface-modified with the polyethylene glycol (H2 N-PEG-COOH) and Tat peptide (KYGRRRQRRKKRGC) and thus constructed a delivery system which can cross BBB (Blood-brain barrier). The morphology, diameter, and zeta potential of Tat-PEG-GS NPs carrier system were characterized with transmission electron microscopy (TEM) and Nano-ZS zetasizer dynamic light scattering Detector. The organ distribution and dynamic evolution localized in the brain parenchyma of Tat-PEG-GS NPs in vivo was investigated with Cri in vivo imaging system and TEM. The obtained Tat-PEG-GS NPs were approximately spherical in shape with average particle size of 150-200 nm and zeta potentials of (32.27 +/- 2.47) mV. In vivo imaging results showed that the accumulation of Tat-PEG-GS NPs was higher in the brain than the accumulation of PEG-GS NPs, but the accumulation of Tat-PEG-GS NPs was lower in the liver than the accumulation of PEG-GS NPs. These differences are statistically significant. The nanocomplex could cross the BBB and reach the neural tissues tested with TEM. The Tat-PEG-GS NPs could cross the BBB and escape the arrest of the reticuloendothelial system (RES), and it would be potential nano-carrier systems for central delivery. PMID- 22826946 TI - [Preparation of alpha-tricalcium phosphate/HA whisker/carboxymethyl chitosan gelatin composite porous bone cement]. AB - In order to investigate the effects of HA whisker and carboxymethyl chitosan gelatin(CMC-Gel) on the mechanical properties of porous calcium phosphate cement, a series of alpha-tricalcium phosphate (alpha-TCP), HA whisker and L-sodium glutamate porogen with different mass fractions were mixed, and setting liquid was added to them to prepare alpha-TCP/HA whisker composite porous bone cement. Then, the cement was immersed in a series of CMC-Gel solutions which had different weight ratios of CMC to Gel to prepare alpha-TCP/HA whisker/CMC-Gel composite porous bone cement. The compressive strengths and microstructure of cement were characterized by mechanical testing machine and SEM. The results showed that when the mass fraction of HA whisker is 4%, the compressive strength of alpha-TCP/HA whisker composite porous bone cement reaches 2.57MPa, which is 1.81 times that of alpha-TCP bone cement. When the weight ratio of CMC to Gel is 50:50, the compressive strength of alpha-TCP/HA whisker/CMC-Gel composite porous bone cement is 3. 34MPa, which is 2.35 times that of alpha-TCP bone cement, and the toughness of the composite cement is greatly improved as well. PMID- 22826947 TI - [Radioiodine labeled L-tyrosine SPECT scintigraphy in E. coli focus infection of mouse]. AB - The aim of this study was to assess the role of 131 I-L-tyrosine for diagnosing E. coli infection and differentiating the infection from the inflammary lesion in mice. The L-tyrosine was labeled with 125 I by N-bromosuccinimide. The binding rates of 125 I-L-tyrosine with E. coli were tested by culturing E. coli with 125 I-L-tyrosine in poor nitrogen yeast medium and in rich nitrogen LB medium separately. The bio-distribution of 125 I-L-tyrosine and the 131 I-L-tyrosine SPECT scintigraphy in E. coli infection of mice were studied separately. The results revealed that the label rate of 125 I-L-tyrosine was more than 99%. The percentage of 125 I-L-tyrosine binding with E. coli was 2.78% in yeast medium, and was 0.85% in LB medium. The distribution peak of 125 I-L-tyrosine in E. coli focal infection of mice was in the range between 45 and 60 min. The infection/normal muscle ratio was 2.46 after 60 minutes. The SPECT scintigraphy demonstrated an accumulation of the 131 I-L-tyrosine in the E. coli focal infection during the 45-60 minutes. The infection/normal muscle ratio of the 131 I-L-tyrosine radioactivity was 2.51 in infectious mouse. However, the SPECT scintigraphy also demonstrated an accumulation of the 131 I-L-tyrosine in the inflammatory lesion during the 45-60 minutes. The lesion/normal muscle ratio of the 131 I-L-tyrosine radioactivity was 2.29 in inflammatory mouse at 60 mins. Thus, the 131 I-L-tyrosine SPECT scintigraphy could diagnose the E. coli infection, but it can not be used for differentiating the bacteria infection and the inflammatory lesion in mice. Our study revealed that the 131 I-L-tyrosine would play a potential role in diagnosing the inflammatory lesion in human beings. PMID- 22826948 TI - [Low frequence pulsed electromagnetic fields induce chondrocyte-like cells differentiation of rat bone marrow-derived mesenchymal stem cells in vitro]. AB - Mesenchymal stem cells (MSCs) are multipotent stem cells that differentiate into a variety of cell types. Low frequency pulsed electromagnetic fields (LFPEMFs) therapy can causes biochemical changes at the cellular level to accelerate tissue repair in mammals. So, we tested the hypothesis that LFPEMFs can promote chondrogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) in vitro. The rBMSCs were isolated by adherence method and the third generation of the rBMSCs were randomly divided into LFPEMFs groups, chondrocyte induced group and control group. LFPEMFs groups with complete medium were exposed to 50Hz, 1mT PEMFs for 30 min every day, lasting for 10, 15 and 20 d, respectively. Chondrocyte-induced group were treated with chondrogenic media, while control groups were only cultured with complete medium. The mRNA expressions of type II-collagen (Col II) and aggrecan were determined by Real time fluorescent quantitation PCR. The protein expression of Col II and aggrecan were detected with toluidine blue stain or immunocytochemical stain, respectively. The result showed that the mRNA and protein expression level of Col II and aggrecan were significantly higher in the LFPEMFs group or chondrocyte induced group, compared to the control group. It suggest that LFPEMFs could contribute to rBMSCs to differentiate into chondrogenic differentiation in vitro. PMID- 22826949 TI - [Expression of Myc-R9-EGFP fusion protein and validation of its transduction activity]. AB - To construct, express, purify and identify the Myc-R9-EGFP fusion protein and validate its transduction activity in the cultured porcine embryo fibroblasts. cDNA of pig c-Myc gene was amplified by RT-PCR with specific primers of 9 arginine (R9) from the primordial genital ridges and inserted into prokaryotic expression vector pET-28a-EGFP. After DNA sequencing confirmation, the recombinant plasmid was then transformed into BL21 (Escherichia coli) strain. After IPTG induction, the target fusion protein was efficiently induced to express, successfully purified by Novagen His-Bind kit, identified by SDS-PAGE and Western blotting. Finally, its high transduction activity in the porcine embryo fibroblasts was validated. The purified Myc-R9-EGFP fusion protein and the validation of its transduction activity in fibroblasts have provided an experimental foundation for further studies on the biological characterization of Myc protein, and soundly facilitated the further study of establishing pig induced pluripotent stem cells by recombinant protein. PMID- 22826950 TI - [Effect of Jumonji domain-containing protein-3 on the proliferation and migration of lung cancer cell line]. AB - For investigating the effect of Jumonji domain-containing protein-3 (JMJD3) on the behavior of lung cancer cell line, A549 proliferation was measured with EDU staining and flow cytometer after JMJD3 expression plasmid and pcDNA3. 1 transfection at 48h. The migration ability of A549 was tested at the same time. The expression of p21 mRNA was measured with RT-PCR. The results showed that JMJD3 transfection increased the EDU positive cells ratio (JMJD3: 40.75% +/- 2.07%, control: 20.97% +/- 1.5%, P < 0.001). G1 phase cell ration also increased after JMJD3 transfection (JMJD3:47. 80% +/- 1.85%, control: 54.60% +/- 0.95%, P = 0.005). The mRNA expression of p21 decreased in JMJD3 group (JMJD3: 35. 89% +/- 3.71%, control: 91.78% +/- 3.74%, P < 0.001). The distances of migration were (0.47 +/- 0.27) cm and (0.96 +/- 0.40) cm after 24h and 48h with JMJD3 tranfection, compared to (0.57 +/- 0.22)cm and (1.08 +/- 0.33)cm in control, respectively (P > 0.05). JMJD3 promoted the proliferation of A549 and decreased the G1 cell numbers, decreased the p21 mRNA, but had no effect on A549 migration. PMID- 22826951 TI - [Expression of reconstructed BCR-ABL-pIRES-SEA plasmids in the skeletal muscles of BALB/c mice]. AB - This paper is aimed to investigate the transcription and expression of BCR-ABL pIRES-SEA fusion gene vaccines in vivo in mice. The reconstructed plasmids (BCR ABL-pIRES-SEA) which were developed previously in our laboratory were injected into the skeletal muscles of BALB/c mice at 14d intervals for three cycles. The transcription and expression of BCR-ABL and staphylococcal enterotoxin A (SEA) in injection site were detected using RT-PCR and immunohistological methods. The BCR ABL/SEA mRNA and protein could be identified in the injection site of BCR-ABL pIRES-SEA vaccinated mice. The reconstructed BCR-ABL-pIRES-SEA plasmids can effectively express gene production in the skeletal muscles of mice and have the common features of DNA vaccine. PMID- 22826952 TI - [Effect of monoamine oxidase inhibitor on the differentiation of malignant glioma cell]. AB - To investigate the effect of monoamine oxidase inhibitor tranylcypromine (TCP) on the differentiation of human U251 glioma cells, we treated U251 cells with TCP and/or 100 nmol/L histone deacetylase inhibitor trychostatin A (TSA). The differentiation of U251 cells was observed with inverted microscopy. The cell proliferation and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Apoptosis was observed by Hoechst 33258 staining. The levels of differentiation-related genes were assessed by real-time PCR and Western blotting. TCP-induced differentiation was characterized by typical morphological changes, inhibition of cellular proliferation, accumulation of cells in the G1 phase of the cell cycle, decreased expression of the pluripotency transcription factors Oct4 and Sox2, and increased expression of glial fibrillary acid protein (GFAP). The combination of TCP and TSA treatment also triggered an over-expression of GFAP. These findings suggest that TCP may induce differentiation of U251 glioma cells, and the differentiation process may be promoted by histone deacetylase inhibitor TSA. PMID- 22826953 TI - [Prokaryotic expression, purification, and identification of recombinant human IL 11 protein]. AB - A DNA fragment encoding recombinant human interleukin 11 (hrIL-11) was obtained by PCR from previously constructed pET24a-hrIL-11 plasmid. Then pET21a-hrIL-11 expression vector was constructed routinely and transformed into BL-21(DE3). By the induction of Isopropyl-1-thio-beta-D-galactoside (IPTG), hrIL-11 protein was highly expressed at about 20% of the total bacterial proteins and was identified by Western blot. After purification with Ni-NTA affinity chromatography and refolding with renaturation buffer, the purity of the target hrIL-11 protein reached 95% and its biology activity was 1 x 10(6) IU/mg, determined by stimulating the proliferation of T1165, which facilitates further researches into effects of IL-11 on platelet proliferation and other function. PMID- 22826954 TI - [Accurate 3D free-form registration between fan-beam CT and cone-beam CT]. AB - Because the X-ray scatters, the CT numbers in cone-beam CT cannot exactly correspond to the electron densities. This, therefore, results in registration error when the intensity-based registration algorithm is used to register planning fan-beam CT and cone-beam CT. In order to reduce the registration error, we have developed an accurate gradient-based registration algorithm. The gradient based deformable registration problem is described as a minimization of energy functional. Through the calculus of variations and Gauss-Seidel finite difference method, we derived the iterative formula of the deformable registration. The algorithm was implemented by GPU through OpenCL framework, with which the registration time was greatly reduced. Our experimental results showed that the proposed gradient-based registration algorithm could register more accurately the clinical cone-beam CT and fan-beam CT images compared with the intensity-based algorithm. The GPU-accelerated algorithm meets the real-time requirement in the online adaptive radiotherapy. PMID- 22826955 TI - [Surface-enhanced Raman spectroscopic analysis of uric acid]. AB - Based on Ag nanoparticles as the surface-enhanced Raman spectroscopy (SERS) active nanostructure, the SERS of uric acid was presented in the paper. The absorption spectroscopies of uric acid and the mixture of silver colloids and uric acid were measured. The possible enhancing mechanism of the uric acid on silver colloid was speculated. The characteristic SERS bands of uric acid were tentatively assigned. The influence of absorption time and different ion on the SERS of uric acid were also discussed. The SERS spectral intensity changes linearly with the uric acid concentration, which indicated that the SERS might provide a new kind of direct and fast detecting method for the detection of uric acid. The detection limit of uric acid in silver sol is found to be 1 mg/L. PMID- 22826956 TI - [Study on femoral 3D reconstruction and computer aid low-temperature deposition manufacturing]. AB - Serious femoral damages are a common human bone disease. Rebuilding the femur and studying its mechanical properties are a continuous medical research topic, but traditional femoral prosthesis often cause some problems such as prosthesis loosening. In this work, we selected a healthy male, took his femur scanning by CT, and rebuilt high-precision femur prototypes by Mimics10.0 software, then chose the material having good biocompatibility and biodegradable, utilizing low temperature deposition manufacturing (LDM) technology for the femoral manufacturing. This approach, fabricating the femur via LDM technology, laid a foundation for the later research on the femoral implantation in the human body. PMID- 22826957 TI - [Fast gamma index calculation method in dose distribution comparison]. AB - As a method of dosimetric verification in radiotherapy, gamma index has been widely used for evaluating dose distribution in research and clinical cases. However, for three-dimensional dose distributions, gamma index calculation is very time consuming for the computers. In this paper, based on a pre-sorting technique, we implement a parallel computing algorithm of gamma index on graphic processing unit (GPU). Dose comparisons are performed for seven cases to test our new implementation. It was shown that the GPU-based gamma index calculations achieved a speedup of ten-folds in comparison with corresponding CPU implementation without losing accuracy. The result showed that utilizing GPU parallel computing to speed up gamma index calculations could be reliable and efficient in the implementation. PMID- 22826958 TI - [Fabrication of three-dimensional microwell patterns and their integration with C17. 2 neural stem cells]. AB - UV photolithography and hydrofluoric acid wet etching were used to produce silicon master molds and polydimethylsiloxane (PMDS)-based soft lithography was adopted to fabricate three-dimensional poly(lactic-co-glycolic acid) (PLGA) and PDMS microwell patterns with high aspect ratio and channel connection. Nine microwell patterns were thus obtained with different structural dimensions. Patterns were treated with oxygen plasma etching and polylysine coating to enhance hydrophilicity and cell compatibility for subsequent culture of C17. 2 neural stem cells. With proliferation during the culture, C17. 2 cells gradually distributed within the microwells, showing an obviously three-dimensional (3-D) growth behavior. The presence of channel structures greatly favored the 3-D growth of C17. 2 neural stem cells on the microwell patterns. Multi-layered scanning with confocal microscopy and 3-D rendering after carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) staining showed that most C17. 2 cells grew within a range of 30 to 90 microm from the microwell bottom. Immunofluorescence staining indicated that C17. 2 cells within 3-D microwell patterns were uniformly nestin-positive on day 2 after cell plating. It could well be concluded that the microwell patterns thus fabricated were suitable for the 3-D culture and subsequent differentiation of C17. 2 neural stem cells. And the cells can be maintained with uniform stemness properties while cultured in these microwell patterns. PMID- 22826959 TI - [Construction and application of a noval gene-target therapy system in hepatocellular carcinoma]. AB - This paper is aimed to explore the efficiency of a noval gene-target therapy system in hepatocellular carcinoma (HCC) treatment in vitro, by using survivin gene as the target. A new fusion promoter (AV) driving pcDNA3. 1 (-)AV plasmid, which contained the cytomegalovirus (CMV) enhancer and alpha-fetoprotein (AFP) promoter, was constructed by molecular biologic method. The eukaryotic expression plasmid pcDNA3. 1(-)AVGFP and pcDNA3. 1 (-)AVsiRNA-survivin were constructed by cloning and inserting the green fluorescent protein (GFP) and siRNA-survivin sequence into pcDNA3. 1(-) AV plasmid separately. Then these two plasmids were transfected into HepG2, SMMC-7721 and Hela cells by using nanoparticles of calcium phosphate. The transfection efficiencies were detected by GFP. Reversed transcript polymerase chain reaction (RT-PCR) and western-blot were used to evaluate the knockdown efficiency of siRNA-survivin. The growth curves and cell death of HepG2 cells transfected with or without pcDNA3. 1(-)AVsiRNA-survivin were detected by MTT assay and flow cytometry assay, respectively. The results showed that after transfected with pcDNA3. 1(-)AVGFP vector, only HepG2 cells displayed strong GFP signaling, whereas, no GFP was found in Hela cells, suggesting that AV promoter can specifically drive downstream of gene expression in HCC cells. Furthermore, the mRNA and protein expression levels of survivin in HepG2 cells, but not in Hela and SMMC-7721 cells, were significantly silenced after pcDNA3. 1(-)AVsiRNA-survivin transfection. Finally, compared with the control cells, HepG2 cells, which were transfected with pcDNA3. 1(-) AVsiRNA survivin plasmid, presented 68.8% cell death, including 38.68% apoptosis and 30.12% necrosis, and significant cell growth inhibition (P < 0.05). These findings indicated that this noval gene-target therapy system could specifically target HCC cells with high efficiency, providing a new gene therapy strategy for HCC. PMID- 22826960 TI - [Advances in sensor node and wireless communication technology of body sensor network]. AB - With the development of the wireless communication technology, implantable biosensor technology, and embedded system technology, Body Sensor Network (BSN) as one branch of wireless sensor networks and important part of the Internet of things has caught more attention of researchers and enterprises. This paper offers the basic concept of the BSN and analyses the related research. We focus on sensor node and wireless communication technology from perspectives of technology challenges, research advance and development trend in the paper. Besides, we also present a relative overview of domestic and overseas projects for the BSN. PMID- 22826961 TI - [The research progress in brain vigilance detection]. AB - Vigilance is the body level of awareness for objective things. It has been used in security, medical and other fields since people used it as an objective indicator. Therefore automatical vigilance detection has become a major issue needed to be resolved as soon as possible. The methods of vigilance detection at home and abroad in recent years was analyzed in this paper, which will benefit the research and the people dedicated in vigilance detection. PMID- 22826962 TI - [Research progress of Wnt signaling pathway in the epidermal repair]. AB - Wnt signaling pathway is a complex protein interaction network, and its function can most commonly or often be seen in embryonic development and cancer treatments, and meanwhile it is also involved in normal physiological processes in adult animals. Recently, with the rapid development of skin tissue engineering, there have been more and more researches on signal pathway in skin wound healing. At present, it is known that Wnt signaling pathway plays a vital role in the epidermal stem cells, epidermal growth factors, hair follicle development and other important factors related to the epidermal repair. The systemic research on Wnt signaling pathway has important clinical significance in the demonstration and functional process of the skin tissue. In this paper, we review the research development of the Wnt signaling pathway in the epidermal repair process. PMID- 22826963 TI - [Research progress of the anti-tumor effect of sonodynamic and photodynamic therapy]. AB - Cancer, as a serious threat to human health, is one of the major killers. The treatment of cancer has attracted more and more attention. Currently, the means of treating cancer is also increasing, but there is no emergence of a fully satisfactory treatment. A combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT), named sono-photodynamic therapy (S-PDT), is a new composite cancer therapy. Because the therapy can significantly improve the tumor curing effect, it has good application prospects in cancer prevention and treatment. The present article reviewed the progress of the anti-tumor mechanisms and influencing factors of S-PDT. PMID- 22826964 TI - [Clinical application of recombinant human thyroid-stimulating hormone in management of differentiated thyroid carcinoma]. AB - Traditionally, during the follow-up and in order to receive 131 I therapy, patients with differentiated thyroid carcinoma (DTC) have to withdraw from using thyroid hormone. The hypothyroidism induced by hormone withdrawal can negatively affect the quality-of-life (QOL) of DTC patients. Without the hormone withdrawal, recombinant human thyroid-stimulating hormone-aided management of DTC patients can effectively obviate the consequences of hypothyroidism. This review will focus on the clinical application of recombinant human thyroid-stimulating hormone (rhTSH) in the management of DTC patients. PMID- 22826965 TI - [Current status and progress of tracheal substitute]. AB - According to the numerous experimental studies but limited clinical applications, the tracheal replacement is still far to be applied maturely. This should be attribute to the poor biocompatibility of the substitute and insufficient vascularization, even with added prosthetic migration and dislocation, epithelial ischemia and necrosis, as well as local infections, and so on. Here we present a review in the attempts to summarize the progress and prospective advances in tracheal substitute. PMID- 22826966 TI - [Future reproductive ability in post-treatment Asherman's syndrome patients]. AB - BACKGROUND: Hysteroscopy is the best approach for the management of Asherman syndrome with reproductive purposes, since it allows a quick diagnosis and treatment of partial or total uterine adhesions. However, there are a few studies on the reproductive outcome in patients with Asherman's syndrome. OBJECTIVE: Evaluate the results of adherenciolisis hysteroscopy in women with Asherman's syndrome. PATIENTS AND METHODS: We performed a cohort study of thirty-nine patients diagnosed with Asherman's syndrome and who underwent surgical hysteroscopic adherenciolisis by bipolar energy through the period from 2006 to June 2011. RESULTS: Thirty-nine cases were reviewed. All patients restored their menstrual cycle in the course of the first three months after surgery. The pregnancy rate after hysteroscopic treatment was 71.7% (28/39), with a son living at home in 28.2% of the cases (11/39). There was no statistical difference to achieve term pregnancy based on a cut-off point at 35 years of age. A history of menstrual pattern before hysteroscopy was associated with perinatal success. All pregnancies were achieved spontaneously within the first year after the procedure. CONCLUSIONS: Spontaneous pregnancy is possible after hysteroscopic adherenciolisis in Asherman's Syndrome. It confirms the viability of using bipolar energy to restore the size and shape of the uterine cavity with minimal endometrial damage and with an exclusive reproductive purpose. PMID- 22826967 TI - [Conservative treatment of endometrial cancer as a way to preserve fertility. Five-year experience at Instituto Nacional de Perinatilogia Isidro Espinoza de los Reyes]. AB - BACKGROUND: Progestins have been used in the treatment of advanced and metastatic endometrial cancer since the early 1960s. There is evidence that progestins can be used in fertility-preserving treatments in young women diagnosed with well differentiated clinical stage 1A(EC1A) endometrioid type endometrial carcinoma. OBJECTIVE: Describe a fertility preservation treatment in women with primary infertility and EC1A endometrioid type endometrial carcinoma. PATIENTS AND METHODS: A historical cohort study. We analyzed 6 cases of women under 35 years assisted at the Oncology and Reproductive Medicine Department of the Instituto Nacional de Perinatologia of Mexico who met our inclusion criteria. Five women were treated with 500 mg medroxyprogesterone acetate (MPA) every other day; one woman was treated with 40 mg/day megestrol acetate (MGA). The treatment was continued to a maximum period of 11 months, provided that women gave good response to the treatment. The change in endometrial histology was assessed at four and six months of treatment. The primary endpoint was pathological complete response (CR). RESULTS: Follow-up time averaged 31 months; 66.6% of women responded to the initial hormone treatment; the remaining 33.4% responded to a second period of progesterone with histology in endometrial biopsy negative for cancer. Average response time was 6.8 months. Two patients had recurrence at an average of 19.5 months. Endometrial routine was performed with a disease-free interval of 15 to 24 months during which assisted reproductive technologies (ART) could be applied. Two patients achieved full-term pregnancy thanks to ART. The remaining patients did not continue with ART on their own initiative. CONCLUSIONS: In young women diagnosed with well-differentiated endometrioid EC1A carcinoma, the fertility-preserving treatment with progestin may be proposed together with strict selection and close monitoring of the patient. PMID- 22826968 TI - [Use of simulators for the training of resident physicians]. AB - BACKGROUND: Laparoscopy has had a notable evolution in the last years, being nowadays one of the most common practices in our medical centers. It is indispensable that every surgical specialist develop the necessary skill level to perform this kind of surgery. The ideal way to initiate will be by pelvitrainers that could be virtual or with direct vision. OBJECTIVE: To evaluate the effect of structured practices in pelvitrainers after 3 days of constant training. MATERIAL AND METHODS: We studied 15 residents without previous laparoscopy experience, there were announced 6 exercises that were performed for 3 daily hours in 3 consecutive days with a LAPA-PRO(MR) pelvitrainer, the time was taken in every exercise during the first and final day. RESULTS: A statistical descriptive and graphical analysis was realized. All exercises presented a significant difference between the times before and after the training. A difference was verified between both averages, no matter the exercise type, which means that the constant training in pelvitrainers offers a major skill acquisition. CONCLUSIONS: The pelvitrainer is a viable tool for the development of laparoscopic skills across the accomplishment of structured practices in medical students without a previous surgical experience. PMID- 22826969 TI - [Robotics in gynecology. Background, feasibility and applicability]. AB - BACKGROUND: Robotic surgery is a technology that emerged from the fusion and improvement of laparoscopy, robotics and telepresence. All these three technologies underwent a long experimentation process in which several applications and innovations were tested until the only system approved for use in humans was developed: the Da Vinci system by Intuitive Surgical Inc. Gynecology, being one of the pioneer branches of Medicine involved in the development of laparoscopy, is one of the fields with the greatest possibilities for robotics, which offers great diversity of applications in hysterectomies, myomectomies, endometriosis, and in the fields of urogynecology and, most importantly, oncology. There are no publications in Mexico with a proper description of the clinical experience with gynecologic robotic surgery, though a great amount of clinical experience has been accumulated in institutions that already have such equipment. A serious evaluation of the cost-benefit ratio is required because of the high cost of this technology. OBJECTIVE: Evaluate and analyze the accumulated experience on this technology of foreign institutions in order to assess the benefits, cost and effectiveness of robotic surgery. CONCLUSION: The key to the optimal use of robotic technology is to diminish costs and speed the learning curve, and this implies the entry of other systems into the market as well as institutions with a high volume of patients and determined to invest in a highly trained and skilled surgical team. In order to recommend its implementation in our country an assessment of the efficiency and advantages of robotic technology considering institutional needs is mandatory. PMID- 22826970 TI - [Anti-Ro/SSA antibodies in congenital heart block]. AB - Describe a case of a female patient having anti-Ro/SSA antibodies without any other risk factor or collagen disease. In her first pregnancy a congenital heart block and hydrops in the fetus were diagnosed, and these caused stillbirth. In a second pregnancy an in utero treatment resulted in the succesful delivery of a normal child. PMID- 22826971 TI - [Possible association of gynecological cancer and rheumatoid arthritis]. AB - BACKGROUND: The association between rheumatoid arthritis and cancer is controversial. Previous studies have shown a correlation between rheumatoid arthritis and the development of lymphoma. OBJECTIVE: Describe a case of rheumatoid arthritis and associated breast cancer plus the identification of the clinical features of a set of cases in which arthritis and cancer go along. MATERIAL AND METHOD: This is a retrospective clinical series study. A database of Hospital General ISSSTECALI of Mexicali, Mexico, containing information on patients suffering from both rheumatoid arthritis and cancer until 2012 was checked. The medical files confirmed the diagnoses. The data available included age, date of arthritis diagnosis, date of cancer diagnosis, related conditions, results of serological tests, type of cancer, treatments used and follow-up information. RESULTS: Fifteen cases of women suffering from both rheumatoid arthritis and cancer were identified on the database of the Hospital General ISSSTECALI in Mexicali. The case described here is the number four on that list. The average age was 54 years and the average time between arthritis and cancer diagnoses was four years. Ten patients were administered methotrexate. Nine patients (60%) suffered from breast cancer and six more from cervical cancer. Three patients suffered from cervical dysplasia. CONCLUSIONS: These cases emphasize the need of strict follow-up on patients suffering from inflammatory rheumatoid condition. If cancer follows chronic inflammation, immunosuppression, or it is pure coincidence, is still a matter of debate. PMID- 22826973 TI - [Plasmoblastic lymphoma initially recognized as ovarian tumor]. AB - Plasmablastic lymphoma is an uncommon B-cell lymphoma representing <3% of all non Hodgkin lymphoma associated with human immunodeficiency virus infection. It displays a distinctive affinity for extranodal presentation in the oral cavity. The case of a plasmablastic lymphoma present in the ovary, cervix and soft thigh tissues of a 27-year-old woman with human immunodeficiency infection is reported. PMID- 22826972 TI - [Diagnosis of isolated fetal aberrant right subclavian artery]. AB - A case of a fetal isolated aberrant right subclavian artery (ARSA) diagnosis and discuss its clinical implications and the methodology used to assess the fetal right subclavian artery by transabdominal ultrasound in normal cases and those with ARSA is reported. CLINICAL CASE: A 35-year-old pregnant woman in her twentieth week of pregnancy was evaluated at our Fetal Medicine Unit. An isolated ARSA was detected by a transabdominal ultrasound scan of the fetus. The visualization of this anomaly was achieved through an axial view of the fetal thorax, at the level of the three vessels and trachea scanning plane. It was observed that the origin of ARSA from the aortic arch was close to the ductus arteriosus and it followed a retrotracheal course towards the right arm. The described methodology used to assess the right subclavian artery could be useful for prenatal diagnosis in cases of ARSA. Based on this protocol, further studies could be performed to evaluate the utility of ARSA as a sonographic marker for chromosomal abnormality and congenital heart disease. After the diagnosis of an isolated ARSA, the performance of a fetal karyotype test is still debatable. PMID- 22826975 TI - [Overestimation of induced abortion in Colombia and other Latin American countries]. PMID- 22826974 TI - [Critical assessment of the new resources for normal delivery in obstetric practice. 1957]. PMID- 22826976 TI - [Overestimation of induced abortion in Colombia and other Latin American countries]. PMID- 22826977 TI - [Overestimation of induced abortion in Colombia and other Latin American countries]. PMID- 22826978 TI - [Common immunophenotypic features of submandibular salivary glands and thymus in rats]. AB - INTRODUCTION: Submandibular salivary gland is a part of the neuro-immune endocrine system. It contains biological factors which regulate a number of functions in the body including the modulation of thymus function. OBJECTIVE: The aim of the study was to investigate immunophenotypic characteristics of submandibular salivary glands of rats during ontogenesis, using the panels of monoclonal antibodies and to compare with the phenotypic characteristics of epithelial components of the thymus. METHODS: Submandibular salivary glands and thymus were obtained from 1, 30 and 60 days old male AO (Albino, Oxford) rats. Streptavidin-biotin peroxidase method was used for staining. RESULTS: Immunohistochemical analysis of rat submandibular salivary glands showed phenotypic heterogeneity of particular components of this gland during the postnatal development. We demonstrated that rat submandibular salivary glands share common antigens with rat thymic epithelial cells, but the observed phenotypic similarity between the individual regions was considered much more significant. Our data showed that the phenotypic similarity between duct epithelial cells and subcapsular epithelial cells and most medullary cells, whereas cortical epithelial cells are phenotypically similar to acinar cells. CONCLUSION: This immunohistological study showed phenotypic complexity of the submandibular salivary gland and similarity to the thymus that opens new perspectives in studying phenotypic similarities between this gland and lymphatic organs. PMID- 22826979 TI - [Evaluation of psycho-motor development in children with West syndrome]. AB - INTRODUCTION: West Syndrome (WS) is age-related epileptic encephalopathy characterised by a triad of symptoms: specific seizure type, pathognomonic electroencephalographic (EEG) pattern--hypsarrhythmia and delay and/or regression in psychomotor development (PMD). Aetiologically, it occurs in three forms: symptomatic, cryptogenic and idiopathic. OBJECTIVE: Estimation of PMD in children with WS according to aetiology. METHODS: The observed group consisted of 65 children. Age range was between 6 and 30 months. The patients were divided into three groups according to aetiology. All patients underwent psychological examination with Brunet-Lesine test, as well as PMD evaluation based on achieved developmental milestones for the corresponding age. RESULTS: Statistically significant better values in the Human Developmental Index (HDI) had patients with idiopathic compared to otherforms of WS, at testing after 12 months (93.0 +/ 8.1 vs. 46.8 +/- 6.1 vs. 45.6 +/- 3.8), as well as after 24 months (93.9 +/- 7.7 vs. 51.9 +/- 5.5 vs. 50.9 +/- 4.4). The best values of HDI after 24 months had patients with improvement in PMD with the average of 66.2 +/- 4.4, which was statistically significant compared to those with unchanged PMD (41.5 +/- 5.3) and with further regression in PMD (28.3 +/- 4.4). Significant correlation was obtained between PMD after 12 and 24 months (r = 0.477), as well as a considerable improvement in HDI from the 12th to 24th month (49.4 +/- 4.0 vs. 53.7 +/- 3.9). CONCLUSION: The patients with idiopathic WS accomplished the best PMD. Improvement in PMD after 12 and 24 months of treatment was associated with improved HDI. Improvement in PMD was observed in all patients after 2 years of follow-up. PMID- 22826980 TI - [Evaluation of neurophysiological parameters and good metabolic control in patients with type 1 diabetes mellitus]. AB - INTRODUCTION: Numerous authors have indicated the beneficial effect of glycoregulation on micro- and macro-angiopathic complications. OBJECTIVE: The aim of the study was to examine whether intensive treatment with maintaining blood glucose concentrations close to normal range could improve electrophysiological parameters. METHODS: The study involved 81 patients with type 1 diabetes mellitus type 1 randomly assigned to intensive insulin therapy. The patients were followed for a period of 3 months by metabolic and electrophysiological control. The metabolic control included daily measurement of concentration of blood glucose and HbA1c and lipid status, while the neurophysiological control included nerve conduction velocity (NCV) of median, peroneal, tibial and sural nerve and latency of F wave. RESULTS: In the beginning of our study blood glucose was 9.10 +/- 3.69 mmol/l and HbA1c 8.12 +/- 1.20%. After 3 months of administered intensive insulin therapy, blood glucose was 7.88 +/- 2.79 mmol/l and HbA1c 6.63 +/- 1.33. After 3 months NCV improved in the tibial, median and sural nerve (p < 0.05) and latency of F wave. CONCLUSION: We found a significant association between the metabolic control and NCV findings which suggests that good metabolic control influences the improvement of neurophysiological parameters in patients with type 1 diabetes mellitus. PMID- 22826981 TI - [Detection of laboratory biomarkes in haematological and pulmonology patients at high risk for aspergillosis]. AB - INTRODUCTION: During the past decades a dramatic increase in the incidence of invasive fungal diseases, especially invasive aspergillosis has been observed. Undiagnosed and diagnosed late invasive aspergillosis is followed by lethality of up to 90%. Detection of early laboratory biomarkers (galactomannan and anti Aspergillus antibodies) contributes to early diagnosis and is used for screening, as well as for monitoring therapy of aspergillosis. OBJECTIVE: The aim was to evaluate usefulness of "non-culture" methods (galactomannan and anti-Aspergillus antibodies IgA, IgM and IgG) for early diagnosis of aspergillosis in high-risk patients. METHODS: Prospective two-year study involved 262 high-risk patients for aspergillosis. In pulmonology and haematology patients (adults and children) blood samples were tested on galactomannan and anti-Aspergillus antibodies. RESULTS: Early laboratory biomarkers were statistically significantly higher in pulmonology patients (p = 0.00033). However, in haematological patients galactomannan was a more frequently positive finding, while in pulmonology patients it was the finding of anti-Aspergillus antibodies. It is interesting that, despite the possible immunosuppression, in about 1/3 of haematological patients anti-Aspergillus antibodies were confirmed. CONCLUSION: Early diagnosis and treatment of aspergillosis represent both clinical and laboratory problem. Nowadays, the application of new "non-culture" methods is of particular importance for the outcome of aspergillosis. Clinical features, laboratory findings of biomarkers and their correct interpretation significantly increase the possibility of timely implementation of appropriate therapy. In this regard, the new organization of reference laboratory for medical mycology has significantly improved the outcome of aspergillosis in high-risk patients in our country. However, further investigations, implementation of European standards and introduction of new diagnostic methods are necessary in this field. PMID- 22826982 TI - [Comparison of haemostatic efficacy for endoscopic injection therapy of epinephrine and combination therapy of epinephrine and hemoclips for bleeding peptic ulcers]. AB - INTRODUCTION: Endoscopic injection therapy of epinephrine is safe and effective in the treatment of bleeding peptic ulcer, but with high risk of rebleeding. The combination therapy of epinephrine and hemoclips could lead to a reduction of rebleeding and a potential reduction in mortality. OBJECTIVE: To investigate the efficacy and safety of epinephrine injection therapy and combination therapy with epinephrine and hemoclips in treating bleeding peptic ulcers. METHODS: A prospective randomized study included 58 patients with bleeding gastric or duodenal ulcer. In 30 patients endoscopic injection therapy with diluted epinephrine was applied (group I), while in 28 patients combination therapy of epinephrine and hemoclips was applied (group II). RESULTS; Initial haemostasis was achieved in most patients treated with epinephrine injection therapy (93.3%) and patients treated with combination therapy of epinephrine and hemoclips (96.4%). After initial haemostasis was achieved rebleeding was significantly more frequent in the patients treated with epinephrine (28.5%) than in the patients treated with combination therapy (3.7%, p < 0.05). Two patients treated with epinephrine injection therapy were subjected to surgical intervention, whereas no patient treated with combination therapy needed surgery. Lethal ending occurred in one patient treated with epinephrine and in one patient treated with combination therapy. The difference between the two groups of patients in need for surgical intervention and mortality was not statistically significant. CONCLUSION: Combination therapy with epinephrine and hemoclips is more efficient than epinephrine alone in the treatment of bleeding peptic ulcers. PMID- 22826983 TI - [Evaluation of the efficacy and toxicity of protocol cisplatin, 5-fluorouracil, leucovorin compared to protocol fluorouracil, doxorubicin and mitomycin C in locally advanced and metastatic gastric cancer]. AB - INTRODUCTION: Still there is no consensus on the choice of the most efficient and the least toxic chemotherapy regimen in the treatment of advanced gastric cancer. Nowadays few therapy protocols are available for treating this disease. OBJECTIVE: Study was conducted to compare the efficacy and toxicity of FAM (flurouracil, doxorubicin, mitomycin C) with CDDP and FU/FA (cisplatin, 5 fluorouracil, leucovorin) protocols in patients with locally advanced and metastatic gastric cancer. METHODS: This randomized study involved a group of 50 patients with locally advanced or metastatic gastric cancer, who had not previously undergone chemotherapy treatment. Progression free survival, overall survival and drug toxicity were evaluated. For statistical analysis chi squaretest, Kaplan-Meier curve and the log rank test were used. RESULTS: The overall response rate was 20% in the group treated with FAM and 24% in the group treated with CDDP, FU/FA (4% of patients from each group had complete response), but without significant statistical difference. Median survival was 10.9 months in the FAM group and 11.8 months in CDDP, FU/FA group, with no statistically significant difference. Non-haematological and haematological toxicities of CDDP, FU/FA were considerably less frequent than of FAM, and there was no treatment related deaths in any of the groups. CONCLUSION: Both investigated regimens demonstrated moderate efficacy. The study shows in favour of justified application of both protocols, while in regard to toxicity CDDP and FU/FA can be recommended as preferable treatment for locally advanced and metastatic gastric cancer. New strategies should be considered for better efficacy in the treatment of advanced gastric cancer. New strategies are necessary with the goal to achieve a better therapeutic effect. PMID- 22826984 TI - [Chronic kidney disease during a 12-year period at tertiary health institution]. AB - INTRODUCTION: Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in paediatric population. OBJECTIVE: The aim of the study was analysis of aetiology, staging and associated complications of CKD at the time of diagnosis. METHODS: Data of 97 patients (56 boys) of average age 7.8 +/- 5.8 years, referred for the first time to the Institute for Mother and Child Healthcare "Dr Vukan Cupic", Belgrade in the period 1998-2009, due to CKD, stage 2-5, were analysed. In each patient illness history was obtained, and physical examination, laboratory, X-ray and other investigations were performed according to the indications. CKD was classified according to the glomerular filtration rate into four grades: 2--mild (60-90 ml/min/1.73 m2); 3--moderate (30-60 ml/min/1.73 m2); 4--advanced (15-30 ml/ min/1.73 m2); and 5--terminal (< 15 ml/min/1.73 m2). RESULTS: The most frequent causes of CKD were congenital anomalies of the kidney and urinary tract (43.3%), followed by glomerular diseases (17.5%), hereditary kidney diseases (16.5%), metabolic diseases (7.2%) and other causes (15.5%). Mild CKD was found in 29.8%, moderate in 28.9%, advanced in 22.7%, and terminal in 18.6% children. Among patients with CKD stage 4 and 5, 75% of patients presented with acute renal failure, while 25% had earlier detected CKD (stage 1), but were not under regular follow-up. Associated complications included metabolic acidosis (63%), anaemia (60%), hypertension (42.3%), short stature (25.8%), renal osteodystrophy (13.4%) and cardiovascular diseases (7.2%). CONCLUSION: Congenital anomalies of the kidney and urinary tract are the leading cause of CKD in paediatric population. A significant proportion (41.3%) of patients had advanced and terminal CKD. In most patients CKD was diagnosed late and with associated complications. PMID- 22826985 TI - In vivo susceptibility of ESBL producing Escherichia coli to ceftriaxone in children with acute pyelonephritis. AB - INTRODUCTION: The choice of empiric therapy of acute pyelonephritis (APN) in children should be based on the knowledge of Escherichia coli (E. coli) as the most common uropathogen and its antibiotic sensitivities considering that nowadays ESBL-producing [ESBL (+)] E. coli is on the rise worldwide. OBJECTIVE: To examine in vivo susceptibility of ESBL (+) E. coli to ceftriaxone (CTX), and to evaluate the options for empiric therapy for APN in children. METHODS: Retrospective study of CTX empiric therapy of APN in children treated at the University Children's Hospital in Belgrade from January 2005 to December 2009. ESBL phenotypic confirmatory test with ceftazidime, CTX and cefotaxime was performed for all urine isolates by disc diffusion method on Mueller-Hinton agar plates. In vivo sensitivity of CTX documented by clinical response to empiric CTX therapy was compared between two groups of children: group I with ESBL (+) E. coli and group II with ESBL (-) E. coli APN. RESULTS: Group I with ESBL (+) APN consisted of 94 patients and group II of 120 patients with ESBL (-) APN, respectively. All patients received CTX as empiric therapy at a mean dose of 66.9 mg during 7.2 +/- 2.6 days of therapy. Clinical effect of CTX was similar in patients with ESBL (+) compared to those with ESBL (-) APN. CONCLUSIONS: In vitro resistance of ESBL E. coli to CTX determined by standard methods is not sufficiently predictive for its in vivo sensitivity. Therefore CTX may be used as empiric therapy for acute pyelonephritis in children. PMID- 22826987 TI - Results of application of external fixation with different types of fixators. AB - INTRODUCTION: Extra-focal or external fixation is the method of fracture fixation through the healthy part of the bone using pins or wires. OBJECTIVE: The aim was to determine which external splints (Ortofix, Mitkovic, Charnley and Ilizarov) had the best biomechanical properties in primary stabilization of spiral, transverse and commutative bone fractures. METHODS: To determine the investigation methodology of biomechanical characteristics of the external fixator we used mathematical and computer simulator (software), juvidur physical model and clinical examination. RESULTS: Values of advancing fragments in millimetres obtained by the study of mathematical and computer simulator (software): Charnley--0.080 mm, Mitkovic M 20--0.785 mm, Ilizarov--2.245 mm and Ortofix--1.400 mm. In testing thejuvidur model the following values were obtained: the external fixator Mitkovic M20--1.380 mm, Ortofix--1.470 mm, Ilizarov--2.410 mm, and Charnley--2.510 mm. Clinical research of biomechanical characteristics of the effect of vertical force yielded the following results: Mitkovic M20--0.89 mm, Ortofix--0.14 mm, Charnley--0.80 mm and Ilizarov--1.23 mm. CONCLUSION: When determining the total number of the stability test splints under the effect of vertical force (compression) and force effect in antero-posterior, later-lateral plane of cross, spiral and comminuted long bone fractures, the best unified biomechanical stability was shown bythe following external fixators: firstly, Mitkovic M20 (0.93mm), secondly, Charnley fixator (1.14 mm), thirdly, Ortofix (1.22 mm), and fourthly, Ilizarov (1.60 mm). PMID- 22826986 TI - [Possibilities of fast track surgery principles in the treatment of congenital urological anomalies]. AB - INTRODUCTION: Urogenital congenital anomalies are among the most common congenital anomalies and very frequent pathology in paediatric urology. Health care systems strive to shorten the duration and reduce the costs of hospitalization, while maintaining treatment effectiveness. OBJECTIVE: To evaluate the duration of hospital stay of surgically treated patients with congenital urogenital anomalies and estimate the possibility of using fast track surgery principles in paediatric urology in the local settings of a developing country. METHODS: Retrospective non-randomized study included 552 patients who had been surgically treated at the Urology Department of the University Children's Hospital, during 2010. In line with their congenital anomalies, all patients were classified in one of four groups: I--upper urinary tract anomalies (252 patients); II--genital anomalies (164 patients); III--testicular anomalies (76 patients) and IV--associated anomalies (60 patients). We analyzed the total duration of stay as well as pre- and post-operative stay in the hospital. RESULTS: The average duration of hospitalization was 4.7 +/- 4.0 days. Patients with testicular anomalies stayed for the shortest period (2.3 +/- 1.9 days) (p < 0.01) and patients with associated anomalies stayed in the hospital the longest (6.5 +/- 4.7 days) (p < 0.01). CONCLUSION: Modern methods of surgical treatment allow reduction of hospitalization, financial savings to the healthcare system and greater comfort for patients. Our results showed that this is also possible to apply in our environment. PMID- 22826988 TI - [Outpatient utilization of non-steroidal anti-inflammatory drugs in three largest municipalities in South Backa district]. AB - INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of musculoskeletal system diseases (MSD) and are associated with numerous adverse effects. OBJECTIVE: To determine the amount and structure of outpatient consumption of NSAIDs and its correlation with musculoskeletal system diseases in three municipalities in South Backa district with different levels of health care. To examine whether the cost of drugs and the level of health care influence the choice of drugs. METHODS: Data on the quarterly consumption of NSAIDs have been collected from all pharmacies in Novi Sad, Vrbas and Backa Palanka. Data are presented by the number of defined daily dosage (DDD) per 1000 inhabitants. Cost (in RSD)/DDD was also calculated. The drug utilization 90% (DU90%) methodology was used. Data on the incidence of MSD from the three municipalities were obtained from the Institute of Public Health of Vojvodina and were presented as the number of patients/1000 inhabitants. RESULTS: The highest total outpatient consumption of NSAIDs was recorded in Backa Palanka, a municipality with the highest prevalence of MSD. The lowest NSAIDs consumption and the lowest number of patients were observed in Vrbas. Diclofenac was NSAID with the highest consummation in all three municipalities, while ibuprofen, meloxicam and nimesulide were dispensed in much smaller amounts. The cheapest NSAIDs were found to be piroxicam and naproxen, diclofenac was the third in terms of price/DDD, while ibuprofen was the sixth. CONCLUSION: In order to improve prescription practice and the profile of drug usage in the population, it is important to educate health care professionals, and to inform general population about the risks of inappropriate drug use. PMID- 22826989 TI - [Adjustment disorders in hospital treated adolescents: a follow-up study]. AB - INTRODUCTION: Adjustment disorders represent a frequent diagnostic entity especially among adolescents. They involve a wide spectrum of various emotional and behaviour problems. OBJECTIVE: The aim was to investigate characteristics of diagnostic category known as adjustment disorders among hospital treated adolescents for the first time at the Clinical Department for Children and Adolescents of the Institute of Mental Health in Belgrade, during five consecutive years, as well as to investigate the outcome of the disorder in follow-up period. METHODS: We conducted a retrospective investigation of the first time hospital treated adolescents from Belgrade with discharge diagnosis of adjustment disorders during 2000-2004. The follow up was conducted 5-10 years after a first discharge from the hospital. RESULTS: During the investigated period 75 adolescents from Belgrade were hospitalized for the first time with diagnosis adjustment disorder. From the studied patients the main sample was formed that included 24 (32%) males and 51 (68%) females. After 5-10 years a follow-up of 52 patients was conducted (sample at follow-up) which included 16 (30.77%) males and 36 (69.23%) females. Of the main sample, 70% of the patients were under follow-up. After the first hospitalization 58% of adolescents continued with further psychiatric treatment, either as rehospitalized or out-of hospital patients. CONCLUSION: Our findings showed that 38% of adolescents under follow-up for 5-10 years after the first discharge from hospital with the diagnosis adjustment disorders had multiple hospitalizations. The outcome of the disorder among these patients was the worst, because three-quarters of the patients were rediagnosed in the follow-up period with a new psychiatric disorder, often from psychotic spectrum. PMID- 22826990 TI - The clinical significance of antibody determination to cyclic citrullinated peptides in systemic sclerosis. AB - INTRODUCTION: Anti-citrullinated peptides antibodies (ACPA) are present in 80% of sera of rheumatoid arthritis (RA) patients with high specificity for diagnosis and prediction for the development of early erosive arthritis. A few studies have reported a low frequency ACPA in systemic sclerosis (SSc) patients with the presence of arthritis. OBJECTIVE: The aim of our study was to determine the frequency of ACPA in systemic sclerosis (SSc) patients, their correlation with clinical manifestations and radiographic features. METHODS: The study included 82 patients with SSc, mean age 54.4 years, 59 with the limited (ISSc) and 23 with the diffuse (dSSc) form of the disease. The control group included 28 healthy age and sex matched subjects. ACPA and rheumatoid factor (RF) were determined in all SSc patients and healthy subjects in whom standard radiography of hands and wrists was also done. RESULTS: The presence of ACPA was detected in 11 (13.4%) of SSc patients. Their level was not increased in any of the controls. Positive RF was found in 15.9% of SSc patients. Arthritis was present in 17.1%, as well as marginal bone erosions. There was a statistically significant association between positive ACPA and arthritis (p < 0.0001) and positive ACPA and marginal bone erosions (p = 0.0002). CONCLUSION: The research confirmed the correlation between ACPA with clinical signs of arthritis and radiographic damage of hand joints. ACPA is a useful diagnostic marker in the identification of SSc patients with arthritis and anatomic bone damage enabling the use of adequate therapy in order to prevent joint damage and poor quality of life. PMID- 22826991 TI - [Mitochondrial myopathy, encephalopathy, lactate acidosis with stroke-like episodes syndrome (MELAS): a case report]. AB - INTRODUCTION: Mitochondrial encephalopathy, lactacidosis and stroke-like episodes (MELAS) represent a multisystemic dysfunction due to various mutations in mitochondrial DNA. Here we report a patient with genetically confirmed MELAS. CASE OUTLINE: A patient is presented whose clinical features involved short stature, easy tendency to fatigue, recurrent seizures, progressive cognitive decline, myopathy, sensorineural deafness, diabetes mellitus as well as stroke like episodes. The major clinical feature of migraine type headache was not present. Neuroimaging studies revealed signs of ischemic infarctions localized in the posterior regions of the brain cortex. Electron microscopy of the skeletal muscle biopsy showed subsarcolemmal accumulation of a large number of mitochondria with paracristal inclusions in the skeletal muscle cells. The diagnosis of MELAS was definitively confirmed by the detection of a specific point mutation A to G at nucleotide position 3243 of mitochondrial DNA. CONCLUSION: When a relatively young patient without common risk factors for ischemic stroke presents with signs of occipitally localized brain infarctions accompanied with multisystemic dysfunction, MELAS syndrome, it is necessary to conduct investigations in order to diagnose the disease. PMID- 22826992 TI - [Congenital interruption of the inferior vena cava: a case report]. AB - INTRODUCTION: Congenital interruption of the inferior vena cava is a rare entity. It can be associated with other organ and system malformations, especially the cardiovascular system. Usually, patients are asymptomatic and the anomaly is therefore diagnosed incidentally. In some cases it can be of clinical importance. CASE OUTLINE: A 22-year-old female was diagnosed during evaluation of cardiac symptoms. Clinical examination showed normal findings. CT angiography and cavography were used to establish the diagnosis of inferior vena cava interruption. Since there was no need for surgical intervention the patient was discharged in good condition. During a five year follow-up no significant health problems were noted with patient leading normal life. CONCLUSION: Diagnostic tools used to establish the diagnosis of inferior vena cava interruption are ultrasonography, as well as CT and MR angiography and phlebography. Mediastinal masses found on chest roentgenogram must raise suspicion of inferior vena cava interruption. Although the anomaly is rare, physicians should be aware of the infrahepatic interruption of the IVC, especially because it can present at any age. PMID- 22826993 TI - A rare case of benign omentum teratoma. AB - INTRODUCTION: Mature teratomas (benign cystic teratomas or dermoid cysts) are among the most common ovarian tumours; however, teratomas of the omentum and mesentery are extremely rare. Teratoma in the intraperitoneal cavity is uncommon and atypical, and it is even more uncommon in adulthood. CASE OUTLINE: An 82-year old female was admitted to our department with clinical signs of abdominal tumour. The ultrasound scan and preoperative laboratory tests were done. Explorative laparotomy revealed tumour with torsion on its pedicle at the greater omentum. After removal of the mass and the incision a tooth and hair were found, characteristics of teratoma. CONCLUSION: The excision was very effective and also definitive treatment for this case. The patient recovered well and was discharged 3 days later. The patient probably carried the tumour all her life asymptomatically until admission. PMID- 22826994 TI - [Metastatic brain tumour in pregnancy: a case report]. AB - INTRODUCTION: Malignant tumours of the central nervous system in pregnancy are rare and are most frequently diagnosed in the second part of pregnancy. Of all malignant tumours which may occur in pregnancy, intracranial tumours bear the highest risk of maternal and foetal morbidity and mortality. CASE OUTLINE: A 29 year-old primipara was admitted to our hospital as an emergency in the twenty ninth week of pregnancy due to headache, right eye sight disorders (double vision), nausea and vomiting. The patient had a total thyroidectomy and a dissection of lymph glands of the neck at the age of seven years due to papillary carcinoma of the thyroid glands. The clinical and sonographic test revealed regular foetal growth and morphology. The MRI showed expansive changes in the brain parenchyma corresponding to metastatic lesion with the subtentorial herniation of the uncus of the hippocampus by compressive effect onto the right cerebral peduncle of the mesencephalon. Emergent neurosurgical intervention was indicated. Having in mind the age at pregnancy, it was decided to perform a caesarean operation. Alive female child was born weighing 1,370 grams. The post operative procedure was normal. The patient was transferred to the neurosurgery department on the first post-operative day, where she underwent emergent surgery. Immunohistochemistry confirmed the metastatic tumour originating from the primary papillary adenocarcinoma of the thyroid gland. CONCLUSION: Neurosurgical diseases in pregnancy simultaneously jeopardize two lives and represent both medical and ethical problem. Upon confirming the presence of intracranial malignancy in pregnancy, further procedure is very individual and it implies cooperation of gynaecologists, neurologists, neurosurgeons, oncologists, anaesthesiologists and neonatologists. PMID- 22826995 TI - [The role of cytokines in orthodontic tooth movement]. AB - One of the most important breakthroughs in the understanding of bone biology was the identification of the role of cytokines in bone remodelling including the alveolar bone exposed to the effect of mechanical forces during orthodontic treatment. Since bone remodelling is associated, in its early phase, with inflammation of the surrounding tissue, the hypothesis has been suggested on the role of proinflammatory cytokines in the process of bone remodelling, primarily IL-1beta, IL-6 and TNFalpha. These cytokines function as response mediators in the acute phase of inflammation, as well as in the processes of metabolism, and stimulation of resorption and inhibition of bone formation. Mostly uninvestigated, the dynamics of concurrent changes of these three cytokines during the early phase of orthodontic teeth movement in children and adults was the subject of our investigation presented in this article on the current knowledge on the role of cytokines in this process. PMID- 22826996 TI - [Total hip arthroplasty]. AB - Total hip arthroplasty is most common reconstructive hip procedure in adults. In this surgery we replace some parts of the upper femur and acetabulum with biocompatible materials. The main goal of this surgery is to eliminate pain and regain full extent of joint motion, maintaining hip stability. Surgical technique, biomaterials, design of the prosthesis and fixation techniques have evolved with time adjusting to each other. After total hip arthroplasty patients' quality of life should be improved. There are many various postoperative complications. Some of them are fatal, and some are minor, which may become manifested years after surgery. Each next surgical procedure following previous hip surgery is associated with considerably lower chances to be successful. Therefore, in primary total hip arthroplasty, preoperative evaluation and preparation of patients are essential. Every orthopaedic surgeon needs to improve already adopted surgical skills applying them with precision and without compromise, with the main goal to achieve long-term durability of the selected implant. The number of total hip arthroplasties will also increase in future, and newer and higher quality materials will be used. PMID- 22826997 TI - [Autogynephilia]. AB - Gender identity disorder is a sexual disorder characterized by strong identification with the opposite gender, followed by unpleasant feeling dueto the birth given gender. Longstanding clinical experience with transgender population has brought new knowledge and better understanding of gender identity and gender identity disorders. Initial knowledge referred to sexual orientation of gender dysphoric persons such as homosexual, heterosexual, bisexual and asexual.The contemporary literature dealing with transgenderism and transsexualism brings out the concept of autogynephilia (from Greek "love oneself as a woman") which is the subject of numerous controversies among the experts in this field as well as in the transgender community. The concept of autogynephilia gained importance in Blanchard's work and his attempts to improve diagnostic categories of gender identity disorders and implement efficient strategies in the management of adult male patients. The main topic of this paper refers to the evolution of the autogynephilia concept, which most prominent authors within the field elaborate as a type of male paraphillic tendency of a person to be sexually by the idea of a phantasy or an image of oneself as a woman, naming these persons "nonhomosexual transsexuals" or "autogynephilic transsexuals". PMID- 22826998 TI - [Dr. Atanasije Puljo: pioneer of Serbian dentistry]. AB - This paper describes the life and work of Dr. Atanasije Puljo (1878-1944). He was a volunteer in the Balkan wars, an active participant in the First World War; he was the first who noted the importance of team-work of a dentist and a surgeon in the care of jaw and facial injuries. He established primacy in this field, as he came up with this brilliant idea three years before other colleagues. His method of treatment of the upper jaw neglected fractures, called the Balkan method, was recognized worldwide. Dr. Puljo is the pioneer of dental radiology in Serbia, founder of the Odontology Clinic of the Medical Faculty and main supporter of the establishment of the School of Dentistry. Merits of Dr. Atanasije Puljo, medical practitioner with a broad knowledge in different fields, remain within the academic institution that was founded by this pioneer of dentistry in Serbia. PMID- 22826999 TI - All that glitters... PMID- 22827000 TI - Vernakalant. Too dangerous in atrial fibrillation. AB - The usual aim of treatment for patients with symptomatic paroxysmal or recent onset atrial fibrillation, including after cardiac surgery, is to slow the heart rate. Electrical and drug (amiodarone) cardioversion are other options. Vernakalant, an antiarrhythmic drug, has been authorised in the European Union for rapid reduction of recent-onset atrial fibrillation. It is only available in an injectable form. Vernakalant has not been compared in clinical trials with treatments slowing the heart rate, or with electrical cardioversion. The only available comparison with another antiarrhythmic agent is a clinical pharmacology study versus amiodarone, a slow-acting drug, based on the rate of cardioversion at 90 minutes in 240 patients. As expected, given the brief observation period, the rate was significantly higher with vernakalant (51.7% versus 5.2%). During clinical evaluation, 6 deaths occurred in the vernakalant groups versus none in the other groups (placebo or amiodarone). The main adverse effects of vernakalant are cardiac arrhythmias (ventricular arrhythmia, torsades de pointes, bradycardia) and severe hypotension. Altered taste, sneezing, paraesthesia, nausea and pruritus were frequent, and respiratory and neuropsychological effects were also reported. A trial in atrial flutter was interrupted when cases of cardiogenic shock occurred. Interactions are to be expected with drugs that prolong the QT interval, and also with drugs that lower the heart rate or the blood potassium concentration. In practice, it is better to continue to use amiodarone for drug cardioversion and to avoid using vernakalant. PMID- 22827002 TI - INN common stems: -azepam,-azam,-azolam. PMID- 22827001 TI - Sunitinib and pancreatic neuroendocrine tumours. More assessment needed. AB - There is no standard first-line cytotoxic chemotherapy for patients with metastatic or inoperable well-differentiated pancreatic neuroendocrine tumours. All available regimens have significant toxicity. Sunitinib, a tyrosine kinase inhibitor, has been authorised for oral administration in this situation. Sunitinib has not been compared with cytotoxic regimens. Clinical evaluation is based on a double-blind randomised placebo-controlled trial that was halted prematurely after 171 patients had been treated for a median of about 10 months. During the trial, there were 9 deaths in the sunitinib group versus 21 deaths in the placebo group. The median progression-free survival time was statistically significantly longer with sunitinib than with placebo (11.4 versus 5.5 months), but the results are undermined by methodological issues. Adverse events classified as serious by the investigators (neutropenia, hypertension, palmoplantar erythrodysaesthesia, etc.) occurred in about 13% of patients in the sunitinib group versus 7% of patients in the placebo group. Two patients treated with sunitinib died of heart failure. More assessment of sunitinib is needed. The only available trial, a placebo-controlled study, failed to show whether the benefits outweigh the risks. PMID- 22827003 TI - Drug-induced colour vision disorders. AB - Acquired colour vision disorders may be caused by ocular, neurological or metabolic disorders, but they can also be drug-induced. In some cases, these disorders may precede or reveal the onset of severe and sometimes irreversible eye damage. The drugs implicated mainly include: phosphodiesterase type 5 inhibitors such as sildenafil; digoxin; anti-infectives including interferon alfa; ethambutol; metronidazole; and some antimalarials. PMID- 22827004 TI - Towards better reporting of adverse drug reactions. AB - Effective local initiatives for improving the collection of reports on adverse drug reactions. PMID- 22827005 TI - Warts: frequent spontaneous clearance. AB - Common and plantar warts are frequent and benign but can be a source of discomfort. In a randomised trial, 49% of patients with common warts were cured with cryotherapy after 13 weeks, compared to 15% of patients who used vaseline containing salicylic acid and 8% of patients who received no treatment. Similar cure rates were obtained in the subgroup of patients with plantar warts. In another randomised trial, about 14% of patients with plantar warts were cured with cryotherapy or topical salicylic acid at 12 weeks, and overall 32% of patients were cured at 6 months. Adverse effects (none serious) were more frequent with cryotherapy in one trial but not in the other trial. PMID- 22827006 TI - Migraine attacks: paracetamol first. AB - About half of all patients with acute migraine obtain substantial relief after 2 hours with a single oral dose of paracetamol 1000 mg. PMID- 22827007 TI - Anterior cruciate ligament rupture: no routine surgery. AB - A 2-year trial suggests that well-conducted rehabilitation is as effective as immediate surgery, and that surgery can be avoided in about 50% of cases, These results resolve questions left unanswered by 2 other, lower-quality trials. PMID- 22827008 TI - 2011 drug packaging review: too many dangers and too many patients overlooked. AB - Every year, Prescrire's analysis of drug packaging confirms the importance of taking packaging into account in assessing a drug's harm-benefit balance. Safe, tried and true options are available, yet the quality of most of the drug packaging Prescrire examined in 2011 left much to be desired. Few of the packaging items examined help prevent medication errors and many actually increase the risks: misleading and confusing labelling, dosing devices that create a risk of overdose, bottles without a child-proof cap, and inadequate or dangerous patient information leaflets. Umbrella brands continue to expand and are a potential source of medication errors. Some patients are at greater risk: the patient leaflets for NSAIDs endanger pregnant women and their unborn babies; children are insufficiently protected by paediatric packaging and are at risk due to the lack of child-proof caps on too many bottles. The raft of regulatory measures taken by the French drug regulatory agency (Afssaps) in the aftermath of the Mediator disaster overlooked the importance of packaging. Until drug regulatory agencies tackle the vast issue of drug packaging, it is up to healthcare professionals to protect patients from harm. PMID- 22827009 TI - Drug packaging: improvements needed to protect children. PMID- 22827010 TI - Rebuilding regulation after the Mediator disaster: drug regulatory agencies must tackle the issue of packaging. PMID- 22827011 TI - Going the distance. The endurance athlete's guide to managing diabetes. PMID- 22827012 TI - Celiac disease. When gluten becomes an enemy. PMID- 22827013 TI - Perfecting insulin. The challenges of making this lifesaver work like a pancreas. PMID- 22827014 TI - Profit ability. Elizabeth Profit aims to take a swing at pro tennis. PMID- 22827015 TI - Anatomy of a test strip. Each tiny bit of plastic contains big technology. PMID- 22827016 TI - Diabetes chic. Forget boring black medical bags. Designers of diabetes supply cases make staying healthy look good. PMID- 22827017 TI - The making of an Ironman. Cliff Scherb takes diabetes in stride. PMID- 22827018 TI - Baked with love (not gluten). A guide to baking without wheat, rye, and barley for people with celiac disease or gluten intolerance. PMID- 22827019 TI - Deaths: leading causes for 2008. AB - OBJECTIVES: This report presents final 2008 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements the Division of Vital Statistics' annual report of final mortality statistics. METHODS: Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2008. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. RESULTS: in 2008, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Cerebrovascular diseases; Accidents (unintentional injuries); Alzheimer's disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for approximately 76 percent of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2008 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. PMID- 22827020 TI - [Reversible lupininin inhibitors of cholinesterases of mammalian blood and of optical ganglia of individuals of the commander squid Berryteuthis magister from different zones of species areal]. AB - Arylsulfoesters and carbonic lupinin esters are studied for the first time as reversible inhibitors of mammalian blood cholinesterases. Studied in detail is sensitivity of cholinesterases to mono- and bislupinin inhibitors in Commander squid individuals from different habitation zones. PMID- 22827021 TI - [Peculiarities of structural organization of hemoglobin of Chironomus plumosus L. (Diptera: Chironomidae)]. AB - In Ch. plumosus and Ch. riparius there were revealed various structural hemoglobin variants including monomers, dimers, trimers, tetramers, hexamers, and octamers. The multitude of the protein organization ways seems to be based on diversity of the monomers with the approximately equal molecular weight from 12 to 16 kDa in Ch. plumosus and from 11.8 to 15.2 kDa in C. riparus. In PAGE with 8 M urea, the hemoglobins were aggregated into high molecular complexes with mol. weights about 260 and 180 kDa in Ch. plumosus and about 523 and 174 kDa in C. riparus. PMID- 22827022 TI - [Activity of digestive enzymes of thick-billed murre (Uria lomvia) and common murre (U. aalga) invaded by cestodes]. AB - Activities of digestive enzymes (proteases, carbohydrases, acid and alkaline phosphatases) are determined in intestinal mucosa of the thick-billed and common murres Comparative analysis of the obtained results is performed for non-infected and for birds infested by cestodes. It has been established that at invasion by cestode Alcataenia armillaris (Cestoda: Tetrabothriidae), activities of carbohydrase and alkaline phosphatase in intestinal mucosa of the thick-billed murre decreases. Parasitizing of cestodes Tetrabothrius jaegerskieldi (Cestoda: Tetrabothriidae) in intestine of the common murre induces a decrease of saccharase activity. There is studied kinetics of desorption of enzymes from digestive-transport surfaces of the bird intestine. Peculiarities of firmness of enzyme fixation are established on the surface of intestinal mucosa of invaded murres. According to the obtained data, a decrease of the carbohydrase activities in intestine of infested murres is likely to be due to absorption of a part of enzymes hydrolyzing carbohydrates on the surface of cestodes. PMID- 22827023 TI - [Balance hypothesis of action of socially significant volatile chemosignals on reactivity of chromosome machinery of the bone marrow dividing cells in the house mouse Mus domesticus L]. AB - Volatile chemosignals released by female CBA laboratory mice have been shown to produce action of different direction, depending on conditions of performance of experiment, on chromosome machinery of bone marrow cells in syngenic adult males. Thus, chemosignals secreted into environment by isolated adult females decrease frequency of mitotic disturbances in bone marrow dividing cells in male recipients as compared with spontaneous level in control animals. At the same time, 2,5-dimethylpyrazine - pheronome released only by high density caged females - increases frequency of mitotic disturbances. Preliminary 24-h-long action of chemosignals of isolated females decreases effect of the subsequent action of 2,5-dimethylpyrazine, although the level of disturbances exceeds that in control animals. The simultaneous action of used chemosignals neutralizes completely the 2,5-dimethylpyrazine action, the frequency of mitotic disturbances being not different from that after chemosignals of isolated females. The hypothesis is put forward about dependence of the revealed cytogenetic effects in male recipients on zoosocial conditions of maintenance of female donors of chemocommunication signals. PMID- 22827024 TI - [Temperature dependence of monoamine-induced pulmonary respiration of mollusc Lymnaea stagnalis]. AB - Pulmonary respiration of molluscs (spontaneous and mediated by intracavital injection of monoamines) was studied at different environmental temperatures (5, 15, and 25 degrees C). It was established that monoamines (dopamine, serotonin, adrenalin) did not enlarge the temperature diapason, in which the respiratory behavior was realized. Microelectrode studies of spontaneous electrical activity of neurons from the respiratory network of Lymnaea stagnalis (RPeD1, VD4, cells of the Vi cluster) have shown that the respiratory program, both spontaneous and the monoamine-induced, is terminated in hypothermia. The indicated effects are suggested to be due to temperature dependence of the chemical, predominantly peptidergical, transmission of signal between neurons of the central pattern generator of respiratory pattern in Lymnaea. PMID- 22827025 TI - [Morpho-functional changes in small intestine epithelium of frog Rana temporaria during hibernation]. AB - Structure and function of small intestinal epithelium were studied in overwintering frogs Rana temporaria at various stages of hibernation. In the process of testing of absorption of arginine vasotocin (AVT) in experiments in vitro it is established that at the period of hibernation there is preserved the capability of the epithelium for absorption of this nonapeptide without hydrolysis. However, as compared with October-December, in January-February and later, a decrease of the AVT absorption takes place, which is the most pronounced in March-April. Changes in epithelial structures appear by the middle of winter and are progressing by spring. In April-May, as compared with the beginning of hibernation, the height of enterocytes, the length of microvilli, and the number of microvilli decrease by 33 %, 40 %, and 57 %, respectively. The absence of features of destruction indicates an adaptive character of the observed changes. Dynamics of the studied parameters indicates morphological plasticity of the small intestine epithelium of R. temporaria at the period of hibernation. PMID- 22827026 TI - [Effect of selank on the main carboxypeptidases in the rat nervous tissue]. AB - Effect of single selank administration on activity of carboxypeptidase H and of phenylmethylsulfonylfluoride-inhibited carboxypeptidase - enzymes detaching arginine and lysine from C-terminus of molecules-precursors of biologically active peptides was studied. The preparation has been shown to cause long, preserved for 24 h changes of activities of these carboxypeptidases. It is suggested that the change in activity of the studied enzymes can be one of mechanisms of regulation of level of neuropeptides at action of selank. PMID- 22827027 TI - [Effect of change in activity level of catecholaminergic systems on motor, respiratory, and cardiac activities in rat embryos]. AB - Parameters of motor, respiratory and cardiac activities were studied in rat embryos (E17-20) after changes in activity level of catecholaminergic systems. To produce conditions for excessive level of catecholamines, the animal were administered individually with preparation of L-DOPA at doses of 25, 50 and 100 mg/kg. Also studied was action of L-DOPA after blockade of D1-(antagonist - SCH 23390, 0.1 mg/kg), D2-(antagonist - sulpiride, 50 mg/kg) dopaminic, and beta2 (antagonist - propranolol, 1 mg/kg) adrenergic receptors. It was found out in E17 18 that the DOPA administration regardless of dose, while in E19-20 dose dependently produces continuous generalized activity. Between E18 and E19, ontogenetically new is the appearance in 92 % of embryos of stereotypical head movements (circular movements, lateral and dorso-ventral flexions) following in the nearsecond rhythm. Injection of DOPA to rat embryos increased 2-6 times the number of respiratory movements by the gasping type in E17-20 and decreased the amount of episodes of continuous rhythmical respiration in E19-20. No significant heart rate changes were observed after introduction of DOPA to E17-20. There was noted a tendency for a weak acceleration of the heart rate. The changes in activities of the motor and respiratory systems due to a rise of catecholamine level are not connected with activation of the dopamine system, as they are not reduced by blockade of dopamine receptors. PMID- 22827028 TI - [Calcium-binding proteins and metabolic activity in thalamotelencephalic parts of the turtle visual system]. AB - Distribution of three calcium-binding proteins (CaBPr) calbindin (CB), calretinin (CR) and parvalbumin (PV) in parallel with metabolic activity (cytochrome oxidase, CO) was studied in telencephalic projection zones of the tecto- and thalamofugal visual pathways in experiments on the Horsfield's terrapin Testudo horsfieldi and the pond turtle Emys orbicularis. It was shown that the nucleus rotundus (Rot) and dorsal lateral geniculate nucleus (GLd) terminal fields in both zones (dorsolateral region of the anterior ventricular ridge, Advrdl and dorsolateral cortex, Cxdl, respectively) were CB-immunoreactive (-ir) in the both studied turtle species. The highest density of CB-ir terminals and the focus of rotundal projections in the Advrdl core coincided precisely. The GLd terminal field in Cxdl also was CR-ir. The PV contribution to innervation of both projectional zones was much lower, especially to innervation of Cxdl from GLd. In spite of similar CB-ir innervation, the projectional field of the tectofugal pathway of Advrdl had the much higher CO activity than of that of the thalamofugal pathway in Cxdl. The neurons immunoreactive to all three CaBPr types were distributed in Cxdl in different ratios in each of layers. In the visual Advrdl area the overwhelming majority were PV-ir neurons, whereas CB-ir neurons were absent. The conclusion is made that in spite of the CB- or CB/CR immunoreactivity predominates over the PV-immunoreactivity in both thalamotelencephalic pathways of the visual system, the tectofugal (rotundo Advrdl) pathway having the higher metabolic activity. PMID- 22827029 TI - [Comparative aspects of structural organization of astrocytes of the first layer of the human and rat cerebral cortex]. AB - Importance of study of astrocytes for fundamental biology and medicine is due their key role in formation of the brain barrier system. On taking into consideration the controversial data on structure of the mammalian neocortex superficial layers, of great actuality are the comparative studies of the structural and cytochemical organization of astrocytes in human and in the laboratory animals used in the experimental studies connected with modeling of brain diseases and traumas. The goal of the present work was to study structural organization of astrocytes in the human and rat neocortical layer I. The work was on the autopsy and experimental material from Wistar rats. Astrocytes were revealed immunocytochemically by using antibodies to GFAP, vimentin and nestin. The preparations were examined with aid of light and confocal laser microscopy. No significant difference in the sizes of perinuclear areas were established between the rat and human astrocytes. In the majority of cortex regions, the specter of proteins forming intermediate filaments in these cells was identical. However, there were essential differences revealed in organization of the superficial glial bordering lamina (SGBL). The human SGBL is formed by interlacing of thin processes in the layer I processes, whereas the rat SGBL is represented by specialized astrocytes spread along the cortical surface and connected with the wide-blade processes. The human layer I astrocytes have translaminar processes passing via several cortical layers, whereas in rats such processes are located within the limits of one layer. The revealed differences in the astrocyte structural organization should be taken into account when interpreting results of experimental studies carried out on rats and extrapolating these results to human. PMID- 22827030 TI - [Effect of hypoxia and indometacin of activities of digestive enzymes in rats at various stages of postnatal ontogenesis]. PMID- 22827032 TI - [Structural changes in hippocampus fascia dentate in rats after action of hypoxia at the perinatal period of development]. PMID- 22827031 TI - [Change of characher of motor, respiratory and cardiac activities in rat embryos at stimulation of release of endogenous catecholamines]. PMID- 22827033 TI - [Correlative formation of functions as one of mechanisms of functional evolution (by an example of maturation of stereognosis and speech function in child ontogenesis)]. AB - A possibility of correlative formation in ontogenesis of central mechanisms of stereognosis and speech function is considered in the paper by example of comparison of changes in spatial organization of interregional interaction of various cortex areas in children of three ages (5-6, 7-8 and 9-10 years) and in adult examinees during their performances of stereognostical, verbal-mnestical and motor manual activity (tepping-test). With age dynamics of children there is observed a significant increase of the degree of similarity of the spatial structure of EEG interrelations characteristic of periods of performance of stereognostical test with patterns of changes of the EEG distant connections revealed at performance of speech tasks. In turn, the similarity of patterns of interregional EEG relations characteristic of stereognostical tasks with the patterns revealed at the periods of performance of the tepping-test is not increased with age. On the whole, the obtained data allow believing that with increase of children's age there rises the degree of topological similarity of the spatial structure of systemic interactions of the cortex zones, on which there are "supported" processes of realization of stereognostical and speech functions. Progressing increase with children's age of the degree of similarity of distributive organization of neurophysiological mechanisms of central provision of the speech and stereognosis functions can indicate in favor of concept of correlative formation of these higher psychical functions in postnatal ontogenesis. The obtained results show that the correlative interfunctional interactions promoting progressive development of cognitive functions in the child ontogenesis can be realized through long fiber associated and commissural pathways composing the morphofunctional longitudinal-transversal "skeleton" ofneocortex in the close interaction with thalamo-cortical integrative systems. PMID- 22827034 TI - [Cellular composition and regulatory function of fetal liver stroma]. AB - Hematopoietic differentiation and formation of hepatic tissue both take place in mammalian liver during its prenatal development. Hematopoietic and hepatic stem cells self-renew, proliferate and differentiate within specific microenvironment that is organized by stromal elements. Stroma of developing liver consists of different cell populations such as mesenchymal stromal cells, Ito cells, portal fibroblasts and myofibroblasts, vascular endothelial and smooth muscle cells, cells undergoing epithelial-to-mesenchymal transition. In this review, their phenotypical and functional properties, possible derivation and role in the regulation of hematopoiesis and hepatogenesis are discussed. PMID- 22827035 TI - [Laser microdissection for biology and medicine]. AB - For routine extraction of DNA, RNA, proteins and metabolites, small tissue pieces are placed into lysing solution. These tissue pieces in general contain different cell types. For this reason, lysate contains components of different cell types, which complicates the interpretation of molecular analysis results. The laser microdissection allows overcoming this trouble. The laser microdissection is a method to procure tissue samples contained defined cell subpopulations, individual cells and even subsellular components under direct microscopic visualization. Collected samples can be undergone to different downstream molecular assays: DNA analysis, RNA transcript profiling, cDNA library generation and gene expression analysis, proteomic analysis and metabolite profiling. The laser microdissection has wide applications in oncology (research and routine), cellular and molecular biology, biochemistry and forensics. This paper reviews the principles of different laser microdissection instruments, examples of laser microdissection application and problems of sample preparation for laser microdissection. PMID- 22827036 TI - [SRY and SOX9: the main genetic factors of mammalian sex determination]. AB - More than 20 years have passed since the discovery of the gene SRY (Sry in mice genome) which turn on the process of mammalian sex determination. Factor SRY is the key trigger of this process by means of initiation the autosomal gene SOX9 expression. SOX9 transcript is the master regulator of Sertoli cell differentiation and the male type of gonad development. In this review the features of SRYand SOX9 expression, intracellular transport and the targets of SRY and SOX9 transcripts, the male and female signal pathways interaction and the mechanisms of initial gonadal sex differentiation are discussed. The evolutionary aspects of the role of SRY and SOX9 are also compared which implies the differentiation of the testes in males is conserved in vertebrates and SOX9 shows highly conserved as the master factor in this process. PMID- 22827037 TI - [The estimation of similarity in characteristics of the post-mitotic daughter L 929 cells during their migration along the substrate]. AB - Using time-lapse microscopy, spreading of the post-mitotic daughter cells has been studied. The work was performed on non-synchronized cells of established L 929 cell line. The study was aimed to characterize the morphology of the cells as they move along the substrate and to determine whether the area of the migrating cells changes nonrandom. Two new parameters have been proposed for comparison of cell morphology: the identity indicator (II) and the synchronism indicator (SI). Time-dependent changes in the area in pairs of cells were measured to calculate these parameters. The first indicator shows the degree of coincidence between the absolute values of the area in the pair of the cells, whereas the second indicator shows synchronism of the changes in the cell areas and does not depend on their absolute values. The lower are the indicators, the higher is the similarity in the time-dependent changes in the areas of cell pairs studied. The indicators were shown to be approximately 1.5-fold lower for the pairs of the post-mitotic daughter cells than those for any other pair of the cells. The results indicate a nonrandom pattern of change in the morphology of the cells during their movement along the substrate. PMID- 22827038 TI - [The reorganization of the actin cytoskeleton of nuclear erythrocytes and leukocytes in fish, frogs and birds during cell migration]. AB - Changes in the spatial organization of actin filaments of nuclear erythrocytes and leukocytes during their migration in fish, frogs and birds have been studied by the method of confocal laser scanning microscopy. It has been shown that, during movement of cells, the reorganization of cytoskeleton microfilaments in erythrocytes is similar to that in leukocytes. During migration, red blood cells of amphibious and birds form pseudopodia filled with bunches in parallel laid actin filaments. Erythrocytes in fish do not form pseudopodia. Similar to leukocytes change in the structure of the actin cytoskeleton in nuclear erythrocytes determines the ability of red blood cells to reactions of migration and phagocytosis. PMID- 22827039 TI - [Large-scale fragmentation of dna and the death of tumor cells by the action of the binary system ascorbic acid-metallocomplexes of cobalt in vitro]. AB - High-molecular-weight DNA fragments are the markers of the early stage of apoptosis induced in eukaryotic cells by cytotoxins of different nature. The dynamics of the development of large-scale DNA fragmentation in K-562 leukemia cells by the action of the antitumor drug, the binary system ascorbic acid- cobalt phthalocyanine within 48 h of incubation, which correspond to two periods of the doubling of cell number in growing control cultures, have been studied. It was shown that, within the first hours of incubation, hydrogen peroxide generated by the system induces the formation of DNA fragments from 2200 to 50 kbp long. Later on the cell death accompanied by a decrease in the content of fragmented DNA is observed. Within 24 h of incubation, part of fragmented DNA remains unrepaired; after 48 h of incubation, a delay or a slowed down proliferation of K 562 cells, which differ from control cells also by a high level of death and a higher content of high-molecular-weight DNA fragments, is observed. PMID- 22827040 TI - [Morphological and functional abnormalities in neuromuscular junctions of Drosophila melanogaster induced by the expression of human APP gene]. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the loss of neurocortical and hippocampal synapses that precedes amyloidosis and neurodegeneration and closely correlates with memory impairment. Mutations in the amyloid precursor protein (APP) cause familial AD and result in the increased production of amyloid-beta-protein (Abeta). To gain insights into synaptic effects of APP, we expressed APP, mutant form APP-Swedish and BACE in the motor neurons of fly larvae. We have shown that targeted expression of APP (APP Swedish) in Drosophila larval motor neurons causes significant morphological and functional changes in neuromuscular junctions (NMJs): a dramatic increase in the number of synaptic buttons and changes in exocytosis as revealed by incorporation of the styryl dye FM4-64. Analysis of the number and distribution of mitochondria showed that motor neurons overexpressing APP (APP-Swedish) had a significant reduction of functional mitochondria in the presynaptic terminal. Significant synaptic abnormalities were observed for APP (APP-Swedish) and human beta secretase (BACE) resulting in secretion of amyloid beta protein (Abeta). We suggest that APP participates in regulation of synaptic functions and its elevated expression leads to synaptic pathology independently from neurotoxic effects of Abeta. PMID- 22827041 TI - [Isolation and proteomic analysis of exosomes secreted by human cancer cells in vitro]. AB - Exosomes are 20-100 nm membrane vesicles of endocytic origin secreted by most cell types in vitro and in vivo. Since exosomes contain both RNA (mRNA and microRNA) and proteins, which can be transferred to another cell, and be functional in that new environment, these vesicles may be involved in the communication between cells. The secretion of exosomes by tumor cells and their implication in the transport and propagation of infectious cargo suggest their participation in pathological situations. Our purpose here is to describe methods for the production, purification, and proteomic characterization of exosomes derived from human cancer cells in vitro. Based on exosomes' unique lipidic composition, we have developed the new approach to increase production of exosomes by cells in vitro. Secondly, we have developed quality control by laser correlation spectroscopy for exosomal assays based on the amount of MHC class I and CD63 molecules on their surface. At last, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was used after 2D electrophoresis for the proteomic analysis of exosomes derived from cancer cell lines. This study describes the protein composition of brain tumor cell-derived exosomes in more detail. PMID- 22827042 TI - [Telomere length in the population of long-lived persons of North-West region of Russia]. AB - Interdisciplinary study of telomere length, polymorphism of genes of renin angiotensin (ACE) and serotonin (5HTR2A and 5HTTPR) systems in population of aged and old inhabitants of the North-West of Russia was conducted, in their relations to data from clinical and geriatric anamnesis, and psychological functioning. Regular link between telomere length and respondent's age was demonstrated in subgroups of old respondents and long-livers, by method of factor analysis. PMID- 22827043 TI - [Research on the emission spectrum of NO molecule's gamma-band system by corona discharge]. AB - The optical emission spectrum of the gamma-band system of NO molecule, A2 sigma+ -> X2 pi(r), has been analyzed and calculated based on the energy structure of NO molecule' doublet states. By employing the theory of diatomic molecular Spectra, some key parameters of equations for the radiative transition intensity were evaluated theoretically, including the potentials of the doublet states of NO molecule's upper and lower energy levels, the electronic transition moments calculated by using r-centroid approximation method, and the Einstein coefficient of different vibrational and rotational levels. The simulated spectrum of the gamma-band system was calculated as a function of different vibrational and rotational temperature. Compared to the theoretical spectroscopy, the measured results were achieved from corona discharge experiments of NO and N2. The vibrational and rotational temperatures were determined approximately by fitting the measured spectral intensities with the calculated ones. PMID- 22827044 TI - [Diagnosis of electron energy and comparative effects of OH, O or O3 on NO oxidation in pulsed corona discharge]. AB - The spectrum of excited N2 molecules and ions was measured by optical emission spectroscopy in pulsed corona discharge with a wire-to-plate reactor. The ratio of emission intensities emitted by the excited molecules and ions of N2 was compared with numerical simulation to determine average electron energies and electric field distributions. Within 2 cm distance from wire electrode in horizontal and vertical directions, electric field and average electron energies appear to be in the ranges of 11.05 19.6 MV x m(-1) and 10.10-13.92 eV respectively; as the distance increases, average electron energies and electric field show a similar trend: first decrease and then increase. Chemically active species, such as OH, O and O3, can be generated through the energetic electron collisions with H2O and O2 directly or indirectly. For the NO oxidation, there is no coexistence of NO and O3, whereas there is a coexistence of NO and OH. NO is oxidized by O3 or O more efficiently than by OH radical. PMID- 22827045 TI - [The influence of laser plasma effects on the characteristics of thin film damage]. AB - Optical components with higher surface quality and higher damage threshold requirement are necessary in high-energy/power laser system, which strongly depends on the performance of optical thin films. The damage morphologies on the surface of the HfO2/SiO2 anti-reflection film, caused by focused laser pulses, were investigated in the present paper. The studies revealed that the shock wave formed with the expansion of laser plasma, and its velocity and pressure decease rapidly with the radius. The spectrum of laser plasma, recorded by EEP2000 spectrometer, shows that the wavelength of laser plasma radiation is shorter than incident laser, which will increase the probability of multi-photon absorption; the photon energy in deep ultraviolet region, higher than the band gap of HfO2, can be absorbed directly. The ionization effect of laser plasma can easily induce film damage. The combination of shock wave and ionization effect determines the damage morphology of films. In the case of laser pulse focused on the film surface, the radiation and shock wave effects are the highest, not only the film is removed, but also the quartz substrate is broken-down. When the focus point is away from the film surface to a certain distance, the radiation of laser plasma and shock wave decrease rapidly, as a result, no damage can be found except that the thin-film can be peeled away from the substrate. PMID- 22827046 TI - [Transient emission spectra from OH, CH and C2 free radicals in the combustion reaction of n-decane]. AB - Using an intensified spectroscopic detector CCD and a heated shock tube, transient emission spectra of n-decane in the combustion reaction were measured in a spectral range of 200-850 nm. Experiments were conducted at temperatures of 1100-1600 K, a pressure of 2.0 atm, an initial fuel mole fraction of 1.0% and an equivalence ratio of 1.0. Results show that the main emission bands are attributed to OH, CH and C2 radicals produced during the combustion process of n decane. Emission intensities of the three radicals reached their maximums only after 5 micros from the onset of their ignitions. After about 30 micros had passed, the band of OH radical was still observed, but the bands of CH and C2 radicals almost disappeared. Time histories of spectral emission intensities represent the time histories of concentrations of the three radicals during the process of combustion The emission peak ratio of OH (306.4 nm)/CH(431.4 nm) is approximately 27/100 in the combustion of n-decane, which is much greater than the corresponding ratio of about 7/100 in the combustion of n-heptane. This result reveals that the two fuels have different reaction mechanisms. High resolution characteristic spectra of CH and C2 were also acquired in the present experiment, the spectra show the rotational structures of the bands clearly. Current results are valuable for understanding the property and validating the mechanism of n-decane combustion reaction PMID- 22827047 TI - [Terahertz time-domain spectroscopy of alpha endosulfan persistent organic pollutant]. AB - Frequency-dependent absorption coefficient spectrum and refractive index spectrum of alpha endosulfan, a kind of persistent organic pollutants, are presented in the terahertz frequency region by terahertz (THz) time-domain spectroscopy (TDS). The spectral features in the THz region have a number of unique characteristic absorption peaks. The result demonstrates that THz-TDS is a promising method to identify materials. Then we adopted density functional calculation method to analyze theoretic absorption coefficients of single alpha endosulfan molecule within 0.2-2 THz. The results show that absorption peaks at 1.68, 1.91 THz in theoretical calculation correspond to 1.7, 1.88 THz in the experiment. Finally, vibrational modes and approximate assignments were discussed, showing that these matched peaks are caused by intramolecular vibrational modes of alpha endosulfan. Others might be related to intermolecular vibrational modes or combined vibrational modes. PMID- 22827048 TI - [THz spectroscopic investigation of energetic ion salt]. AB - In order to further explore the terahertz spectrum characteristics of energetic ion salts on the basis of the research on traditional nitro energetic materials, and extend applicable scope of terahertz wave technology in the study of safety testing field, experimental measurement and theoretical analysis of THz spectrum for new energetic ion salts (5-ATN and BMDATHBT) were introduced. The absorption coefficient of the samples was measured in the region of 0.5-2.0 THz by time domain spectroscopy and by Fourier transform infrared spectroscopy in the 2.0-8.0 THz region. Using the density functional theory methods, the vibration characteristics were simulated by Gaussian 03 and Materials Studio 4.3. The simulated spectrum of samples is in agreement with the experimental data. The result showed that ion salts have the typical absorption peaks that have close relation with the tribal structure, and the interaction between particles and the single skeleton vibrations of individual ion are the main reason for energetic ion salt to form absorption peak in terahertz band, which provides references for detecting high nitrogen compounds by terahertz technique. PMID- 22827049 TI - [Studies on signal-to-noise ratio standard for THz time-domain spectroscope]. AB - Terahertz time-domain spectroscopy (THz-TDS) is an important part of THz technology, but its low scan speed always becomes the bottleneck In this article signals of TDS system under different scan speed were compared. The signal quality was getting worse while scan speed was increasing, and the time constant of lock-in amplifier plays an important role in the process. The main noise was found introduced from the circuit according to the experiment results. PMID- 22827050 TI - [Qualitative and quantitative detections of pyrethroid pesticides by terahertz time-domain spectroscopy]. AB - Pyrethroids pesticides are broad-spectrum insecticides which were used to control variety of pests, and were mainly used to hygienic insecticides and agricultural pest control. The room-temperature terahertz spectra of b-cypermethrin, 1 cyhalothrin and deltamethrin were investigated by terahertz time-domain spectroscopy (THz-TDS) technology. The three pyrethroids pesticides were easily discriminated according to the absorption spectra within 0.2-2.2 THz. We employed SLR and PLS method to perform the quantitative analysis of the mixture of deltamethrin in polyethylene. The PLS method provides better result than SLR method. The detection limit of deltamethrin content in the mixture can be down to 2.0%, and the maximum value of absolute error was 0.8%. The root mean square error was 0.55%. This result proved that the THz-TDS technique is quite potential for pesticide molecular discrimination and content determination. PMID- 22827051 TI - [Four styles of spectral line shape function and their transformation relation]. AB - Four styles of spectral line shape function and their transformation relation were investigated theoretically. The photon number and energy distribution as functions of frequency and wavelength resulting from Doppler broadening were investigated, and the maximum intensity and FWHM (full width at half maximum intensity) were obtained. The results show that the photon number distribution as function of frequency is almost the same as the energy distribution as function of frequency, while the photon number distribution as function of wavelength is almost the same as the energy distribution as function of wavelength. The method has been presented by analyzing the Doppler spectral line shape function, with which the ratio of density between two spectral lines can be obtained according to the ratio of maximum value of two spectral lines. PMID- 22827052 TI - [FTIR spectra investigation of rat sensitive tissues exposure to ELF-EMF]. AB - Nonthermal effects of extremely low frequency electromagnetic fields (ELF-EMF) are related to changes in the microstructure of biological tissues after exposure to electromagnetic radiation. Fourier transform infrared spectroscopy (FTIR) analysis method can effectively study the mechanisms of biological effects of electromagnetic radiation. The present paper studies the characteristics of sensitive tissues of rat after ELF-EMF exposure. FTIR analysis of sensitive tissues of control group and experimental group showed that 50 Hz, 0.75 mT ELF EMF exposure for 20 days can affect molecular level of the rat testis, blood and brain. Experimental results show that regular changes in absorption peak positions and intensity in the spectra of sensitive tissue may be caused by exposure to ELF-EMF, therefore, Fourier transform infrared spectroscopy is an effective means to study mechanism of biological effects of electromagnetic fields. PMID- 22827053 TI - [Physiological differences between HPS/PHI over-expressing transgenic and wild type geraniums under formaldehyde stress revealed by FTIR analysis]. AB - In the present study, FTIR was used to analyze changes in chemical component contents and spectra characters of 3-hexulose-6-phosphate synthase/6-phosphate-3 hexuloisomerase (HPS/PHI) over-expressing transgenic and wild-type (WT) geraniums under formaldehyde (HCHO) stress to examine if FTIR could be a new method for identification of phenotypic differences between the transgenic plants with a photosynthetic HCHO-assimilation pathway and the WT plants. The WT and transgenic geranium plants were treated with 4 mmol x L(-1) HCHO for 0, 1, 2, 3 and 4 days, respectively. The comparison of FTIR spectral characteristics at different time points between the transgenic and WT plants indicated that the contents of carbohydrate, proteins and aliphatic compounds were significantly higher than those in the WT plants after 4 days of HCHO-treatment. This may be due to installation of the photosynthetic HCHO-assimilation pathway in the transgenic geranium, which enhanced its ability to metabolize and assimilate HCHO, thus allowed more HCHO to be fixed to 6-phosphate fructose, and then entered assimilation pathways for synthesis of a variety of intracellular components. The results suggest that FTIR can be a new method to identify the phenotypic differences between transgenic plants with a photosynthetic HCHO-assimilation pathway and WT plants. PMID- 22827054 TI - [Phase correction technology research and improvement based on single-sided interferograms in FTIR]. AB - In the Fourier transform infrared spectrometers the interferograms are usually sampled by the means of the single-side beyond zero path difference and the interferograms are asymmetric. These phase-corrected technologies are researched and improved in the present paper. In the Mertz method which requires apodization to be higher, the interferograms are apodized by these asymmetric windows so that the width of the main lobe increases and spectral resolution reduced. In order to solve these problems, a method which combines the Mertz and Forman methods is presented in the paper. In the method a double-side interferogram is constructed by the mirrored processing of the single-side interferogram beyond zero path difference, followed by the symmetric apodization, fast Fourier transform (FFT) to rebuild spectrum. And in the method high resolution phase spectrum is computed by the symmetrization of double-side interfergram to improve the phase-correction accuracy. In the experiment, these asymmetric window functions have the lower resolution compared with these symmetric window functions. And the spectrum which is acquired by the improved phase corrected method is compared with the spectra which are acquired by the Mertz and Forman methods, and the improved method has less error than Mertz, less computation than Forman, and the spectral resolution achieved 2 cm(-1). PMID- 22827055 TI - [Recognition of corn seeds based on pattern recognition and near infrared spectroscopy technology]. AB - Pattern recognition technology and data mining methods have become a hot topic in chemometrics. Near infrared (NIR) spectroscopic analysis has been widely used in spectrum signal processing and modeling since it has advantages of quickness, simplicity and nondestructiveness. Based on five different methods of pattern recognition, namely the locally linear embedding (LLE), wavelet transform (WT), principal component analysis (PCA), partial least squares (PLS) and support vector machine (SVM), the pattern recognition system for corn seeds was proposed using NIR technology, and applied to classification of 108 hybrid samples and 178 female samples for corn seeds. Firstly, we get rid of noise or reduce the dimension using LLE, WT, PCA, PLS, and then use SVM to identify two-class samples. In the meantime, 1-norm SVM is the method of direct classification and identification. Experimental results of three different spectral regions show that the performances of three methods: PCA+SVM, LLE+SVM, PLS+SVM are superior to WT+SVM and 1-norm SVM methods, and obtain a high classification accuracy, which indicates the feasibility and effectiveness of the proposed methods. Moreover, this investigation provides the theoretical support and practical method for recognition of corn seeds utilizing near infrared spectral data. PMID- 22827056 TI - [Research on detection of oil in water based on near-infrared scattering method]. AB - The harm assessment and responsibility of marine mineral oil pollution require the content of mineral oil to be obtained by real-time online monitoring. In the present paper, the method of online monitoring of the oil content in water is presented, a creative technology based on optical scattering theory was proposed. Firstly the particle distribution of oil drops was scanned by Marvin laser particle meter, then with the help of the scattering signal, the crude, diesel of different concentrations from 0 to 30 mg x L(-1) was measured in experiment, the linearity is more than 0.99. This paper presents a feasible setup for the online monitoring of the content of mineral oil. PMID- 22827057 TI - [FTIR spectroscopic study of broad bean diseased leaves]. AB - In the present paper, broad bean rust, fusarium rhizome rot, broad bean zonate spot, yellow leaf curl virus and normal leaves were studied using Fourier transform infrared spectroscopy combined with chemometrics. The results show that the spectra of samples were similar, only with minor differences in absorption intensity of several peaks. Second derivative analyses show that the significant difference of all samples was in the range of 1200-700 cm(-1). The data in the range of 1 200-700 cm(-1) were selected to evaluate correlation coefficients, hierarchical cluster analysis (HCA) and principal component analysis (PCA). Results showed that the correlation coefficients are larger than 0.928 not only between the healthy leaves, but also between the same diseased leaves. The values between healthy and diseased leaves, and among diseased leaves, are all declined. HCA and PCA yielded about 73.3% and 82.2% accuracy, respectively. This study demonstrated that FTIR techniques might be used to detect crop diseases. PMID- 22827058 TI - [Prediction of chlorophyll content of leaves of oil camelliae after being infected with anthracnose based on Vis/NIR spectroscopy]. AB - The prediction model of chlorophyll content of leaves in canopies of oil camelliae under disease was explored and built by analyzing the Vis/NIR spectroscopy characteristics of oil camelliae canopies after being injected with anthracnose. Through field survey of disease index (DI), chlorophyll content and spectral data of leaves in canopies surviving different severity of disease were acquired. The first order differential of spectral data combined with moving average filter was pretreated. The prediction model of BP neural network of chlorophyll content was built by extracting sensitive wave band from spectral resample data. The results showed that with the disease being aggravated, reflection peaks and valleys of spectra of oil camelliae canopies in visible light region vanished gradually, steep red edges from red light to near infrared leveled little by little, and reflectivity of healthy oil camelliae was far larger than that of ill ones. The sensitive wave band of absorption and reflection of chlorophyll lay in the region of 84-512, 533-565, 586-606 and 672 724 nm. The correlation coefficient r and RMSE between predictive values calculated from BP neural network using sensitive wave band as input variables and observed values was 0.9921 and 0.0458 respectively. It was therefore feasible to utilize Vis/NIR spectroscopy technology to forecast the chlorophyll content of oil camelliae after being infected with anthracnose. PMID- 22827059 TI - [Study on online detection modeling parameters of jujube internal quality of southern Xinjiang with near infrared spectrometric techniques]. AB - To establish the on-line near infrared spectral correction model for the jujube quality of Southern Xinjiang, the main influence factors of online testing results were analyzed, and the corresponding parameters were studied. First of all, the collecting conditions of different jujube were set, such as measurement condition, spectral region, and the parameters of the apparatus. With near infrared spectrometer and self-designed jujube batch collecting attachment, the quality spectrum of jujube was obtained, and combining spectral preprocessing and detection precision, condition parameters were selected. Secondly, through PLS spectrum correction with different modeling parameters and two-dimensional correlation spectroscopy analysis, Brix characteristic spectral parameters were selected. The results showed that with sugar degree central wavelength 9116, 9 418 and 10,500 cm(-1), acquisition resolution 16 cm(-1), and scan number 8, the sugar degree relative error was 8%-10%, the size of single grain jujube spectra was reduced to 1/10 of the original, and the time was reduced to 3 seconds. It was concluded that with the experimental parameters, the spectra were compressed, a primary online correction model was established, and the jujube quality online detection with near infrared spectroscopy was basically realized. PMID- 22827060 TI - [Study on the detection and pattern classification of pesticide residual on vegetable surface by using visible/near-infrared spectroscopy]. AB - A nondestructive testing based on visible/near-infrared reflectance spectroscopy was put forward for the common high pesticide residues of green plants in the wavelength range from 600 to 1100 nm. Firstly, spectral features were extracted by wavelet transform from original spectral data. Secondly, the principal component analysis (PCA) was done in the further analysis of spectral characteristics. Thirdly, the two PCs were applied as inputs of artificial neural network, and a multi-neuron perceptron neural network was established. Finally, It was proved that the type of pesticide residues was effectively identified and showed by classification results. In short, the study provides a new approach to the detection of pesticide residues in vegetables and fruits. PMID- 22827062 TI - [FTIR study on the reduction of 1-benzyl-3-hydroxypyrrolidine-2,5-dione]. AB - The title compound was synthesized by reducing (S)-1-benzyl-3-hydroxypyrrolidine 2, 5-dione with sodium borohydride-iodin. The raw material, intermediate, and the end product were characterized by IR spectra and the mechanism of reduction of imide by sodium borohydride-iodin was also studied by IR spectra. According to the IR spectra, it was concluded that the product was (S)-1-bezyl-3 hydroxypyrrolidine. The mechanism of the reduction is that borane, formed in situ by reacting sodium borohydride with iodine, partly was conjugated to carbonyl to form four-member-ring intermediate and partly conjugated to nitrogen. (S)-1 benzyl-3-hydroxypyrrolidine/BH3 complex was gained when the reduction finished. The title compound was obtained by removing borane from the complex in methanol. PMID- 22827061 TI - [Research on the application of mid-infrared based quantification of water in oil used by marine-borne machines]. AB - A method that could be used to quantify the concentration of water in oil for marine-borne machine is discussed in the present paper. Water molecule has distinct absorption bands in mid-infrared section in 3773-3509 cm(-1), so it could be applied to the quantification of water in oil. An experimental sample cell was designed to accomplish the experiment for the convenience of sample preparation and mount in measurement, and it was designed to suit for FTIR spectrometer. The authors chose to prepare the sample oil by blending different amount of water into oil through titration. The spectra of oil with different water concentration were acquired and their integrals were calculated. The analysis of experimental result shows that the functional relationship between the integral of spectrum in 3773-3509 cm(-1) and the percentage of water content in oil is a quadratic curve. The relative error between the fitted curve and experimental data is at the level of 0.01%. The research work in this paper presents the possibility of quantification of water content in oil through mid infrared and gives us an idea to design a kind of new sensor based on mid infrared LED and PIN for measure and to warn people who monitor the abnormal variation of water content in different kind of oil used in marine-borne mechanical system. PMID- 22827063 TI - [A method of temperature measurement for hot forging with surface oxide based on infrared spectroscopy]. AB - High temperature large forging is covered with a thick oxide during forging. It leads to a big measurement data error. In this paper, a method of measuring temperature based on infrared spectroscopy is presented. It can effectively eliminate the influence of surface oxide on the measurement of temperature. The method can measure the surface temperature and emissivity of the oxide directly using the infrared spectrum. The infrared spectrum is radiated from surface oxide of forging. Then it can derive the real temperature of hot forging covered with the oxide using the heat exchange equation. In order to greatly restrain interference spectroscopy through included in the received infrared radiation spectrum, three interference filter system was proposed, and a group of optimal gap parameter values using spectral simulation were obtained. The precision of temperature measurement was improved. The experimental results show that the method can accurately measure the surface temperature of high temperature forging covered with oxide. It meets the requirements of measurement accuracy, and the temperature measurement method is feasible according to the experiment result. PMID- 22827064 TI - [A novel online process monitoring method based on near infrared spectroscopy and its application to the column chromatographic separation for traditional Chinese medicine]. AB - Near infrared spectroscopy (NIRS) is a process analysis and monitoring tool with many advantages, while it needs to set up quantitative or discriminative calibration models in advance, and needs to adjust these models when the process conditions are varied, which makes it difficult for ordinary user to take its full advantage of it. To tackle this problem, this paper presented a novel, simple and model-free methodology for online process monitoring based on two reciprocal viewpoints of measuring the variability of spectroscopy-both the similarity and dissimilarity of process spectrum, i.e., the adaptive moving window standard deviation function(AMWSW) and similarity function(S). The methodology was validated by a column chromatography process of traditional Chinese medicine using near infrared spectroscopy. The online trend curves of AMWSW and S obtained by proposed method were validated by a comparison with the content variation curves of multiple indicative components analyzed by high performance liquid chromatography (HPLC), and these trend curves demonstrated their potential for real-time process status monitoring, accurately determining the beginning point, the peak point, the end point of the elution, and the phase change from water solution to ethanol solution. The proposed methodology can also be used to other process analysis techniques, such as ultraviolet/visible, infrared, Raman, fluorescence, chromatograph and mass spectrum. PMID- 22827065 TI - [Mid-infrared distributed-feedback quantum cascade laser-based photoacoustic detection of trace methane gas]. AB - There have been considerable interests in methane detection based on infrared absorption spectroscopy for industrial and environment monitoring. The authors report on the realization of photoacoustic detection of methane (CH4) using mid infrared distributed-feedback quantum cascade laser (DFB-QCL). The absorption line at 1316.83 cm(-1) was selected for CH4 detection, which can be reached by the self-manufactured DFB-QCL source operating in pulsed mode near 7.6 microm at room-temperature. The CH4 gas is filled to a Helmholtz resonant photoacoustic cell, which was equipped with a commercial electret microphone. The DFB-QCL was operated at 234 Hz with an 80 mW optical peak power. A detection limit of 189 parts per billion in volume was derived when the signal-to-noise ratio equaled 1. PMID- 22827066 TI - [Characterization of soil calcium carbonate using mid-infrared photoacoustic spectroscopy]. AB - The mid-infrared photoacoustic spectra of CaCO3 was determined and characterized, and multi-calibration methods of principal component regression (PCA), partial least squares regression (PLSR), and GRNN artificial neural network were applied to quantitative analysis of soil carbonate. The results showed that abundant absorptions were found in the mid-infrared photoacoustic spectra of CaCO3, especially the very strong band at the wavenumber of 1450 cm(-1), in which there was few interferences, and could be used as spectral indicator of soil carbonate; the calibration results were good or excellent with the three chemometric methods, in which PLSR and GRNN modeling were excellent with a R2 more than 0.9, and PCA modeling was good with a R2 of 0.847; the validation results showed that PLSR and PCA modeling were excellent with higher R2 values ( > 0.9), and GRNN was also very satisfied with a R2 of 0. 882. Totally, PLSR modeling was the best with RPD values more than 3.0, indicating its strong potential in the prediction of soil carbonate. PMID- 22827068 TI - [Resolution of overlapping Raman signals based on an adaptiveI immune algorithm]. AB - Raman spectroscopy can be used in situ real-time measurement because it's rapid, and it is helpful to real-time online monitoring of process control. With the complexity of the environment and the characteristics of Raman signal, it is hard to avoid some overlapping spectrum peaks. Based on the advantage of immune algorithm, an immune algorithm (IA) was applied to the overlapping Raman signals of aromatics. With extraction of each single Raman spectrum peak signal from the mixture signals for resolution, Results show that the method is effective to identify the overlapped Raman signal for its fast resolution and accurate quantitative determination with the relative error less than 1%. For the overlapping Raman signals with fluorescence background disturbance, we proposed an adaptive immune algorithm, which is combined with independent component analysis. It can effectively resolve the fluorescence background signal, and it provides a new way for Raman spectra analysis of complex samples. PMID- 22827067 TI - [Study of ice VII structure influenced by high pressure using Raman spectrum]. AB - Raman spectra of ice VII phase were obtained at room temperature when the pressure was from 2.5 to 23 GPa. The experimental results indicate that the oxygen atoms distance do-o of ice decreased with pressure increasing,which results in that hydrogen bond is shortened, O--H bond is lengthened,force constant is reduced, and Raman spectra are red shifted. The orientation order of proton (hydrogen atom) is first increased and then decreased with varying the pressure, which leads to the Raman intensity increasing and then decreasing, and Raman linewidth is decreased and then increased, and the linewidth is the least when the pressure is 13 GPa. PMID- 22827069 TI - [Rapid detection of 6-benzylaminopurine residues in sprout beans by surface enhanced raman spectroscopy]. AB - New method for rapid and quantitative analysis of 6-benzylaminopurine (6-BA) residues in sprout beans was studied by using FAST-SPE and portable surface enhanced Raman spectroscopy (SERS). With homemade sprout bean samples as blank control, 6-BA solutions extracted from inserted-treatment samples showed typical characteristic Raman peaks at 1002 cm(-1) tested by SERS, and normalized 1002 cm( 1) intensities had a good linear relationship with gradient concentrations of 6 BA insert-standard solutions. The high concentration linear range was 0.5-14 microg x mL(-1), and the low one was 0. 1-2 microg x mL(-1). The quantitative detection limit was down to 0.02 mg x kg(-1) that was below the maximum allowable residues (MAL) of 0. 2 mg kg(-1) in related National Standard. The recoveries were 82.3%-95.1% and the RSD was below 5%. This method with portable equipment and simple pre-treatment showed good reproducibility, short test time-consuming and easy operating, and thus it would provide efficient and sensitive solutions for large-scale on-site and rapid detections. PMID- 22827070 TI - [Research on the mineral phase and component of non-crystalline and nano crystalline corrosion products on bronzes unearthed from Shang Tomb in Xingan]. AB - The patinas on bronzes in Shang Tomb of Xingan were powdery, pale green, which were more like "bronze disease", but the mineral composition of patinas was not paratacamite or atacamite. Micro X-ray diffraction (XRD) and high performance transmission electroscope (HTEM) showed that the patinas were mainly composed of non-crystalline and nano-crystalline SnO2, and the size of nano-crystalline particle was in the range of 4-5.7 nm; Moreover, the energy-dispersive X-ray spectrometry showed that element tin is the primary ingredient of the sample, as well as little copper, silicon, lead and iron were detected. By studying the crystal lattice stripe image of the nanometer SnO2, it was deduced that the chemical formula of nano-crystalline SnO2 did not include other elements; The Raman spectrum of the sample showed that there were not any characteristic peaks of SnO2, the spectrum was more like non-crystalline SnO2, and the weak and broad peak of 973 cm(-1) indicated that the sample may contain silicate grains, It was inferred that little of copper, silicon, lead and iron should exist in the form of non-crystalline silicate particles. PMID- 22827071 TI - [An SVM real-time method by utilizing curvelet transform in nonlinear laser induced fluorescence of oil recognition]. AB - This paper presents a real-time nonlinear laser fluorescence recognition method. First, the feature vectors consisting of transform coefficients were obtained by utilizing the three layers curvelet transform to decompose the pre-processing fluorescence spectrum of the heavy oil, diesel, crude oil and other types of common oils in various angles and different scales. Then the feature vectors were regarded as the parameters and sent into the support vector machines (SVM) for training. Finally, the trained SVM was used for spectral classification of the oil slicks. Results from the trial suggest that it didn't rely on a large number of samples, so that the number of support vectors was significantly reduced and the operation time was shortened for real-time running. Compared with traditional methods, the proposed method proves to be more efficient, faster and more reliable and has real-time capabilities. PMID- 22827072 TI - [Fluorescent labeling of latent fingerprints with PAMAM capped ZnS QDs]. AB - Stable PAMAM (polyamidoamine) capped ZnS (zinc sulfide) QDs (quantum dots) were prepared and characterized with UV-Vis spectrum and PL(photoluminescence) emission spectrum on the base of coordination of Zn2+ ions with PAMAM dendrimers. The results show that Zn2+ ions coordinated with N atoms of PAMAM ligand and the saturated coordinating time is about 6 h; PAMAM capped ZnS QDs emitted strong blue light under the irradiation of UV light at the wavelength of 365 nm, and the PL emission peak is at about 500 nm. Finally, the prepared PAMAM capped ZnS QDs were applied in the fluorescent labeling of latent fingerprints on tinfoils; Latent fingerprints emitting strong blue light and were successfully detected with good resolving rate. PMID- 22827073 TI - [A novel method for extracting leaf-level solar-induced fluorescence of typical crops under Cu stress]. AB - The leaf-level solar-induced fluorescence changes when the typical crops are under Cu stress, which can be considered as a sensitive indicator to estimate the stress level. In the present study, wheat (Triticum aestivum L.), pea (Pisum sativum L.) and Chinese cabbage (Brassica campestris L.) were selected and cultured with copper solutions or copper polluted soil with different Cu stress. The apparent reflectance of leaves was measured by an ASD Fieldspec spectrometer and an integrating sphere. As the apparent reflectance was seldom affected by the fluorescence emission at 580-650 and 800-1000 nm, so the apparent solar-induced fluorescence can be separated from the apparent reflectance based on PROSPECT model. The re-absorption effect of chlorophyll was corrected by three methods, called GM (Gitelson et al.'s model), AM (Agati et al.'s model) and LM (Lagorio et al.'s model). After the re-absorption correction, the solar-induced fluorescence under different Cu stress was obtained, and a positive relationship was found between the height of far RED fluorescence (FRF) and the copper contents in leaves. PMID- 22827074 TI - [Monitoring the chlorophyll fluorescence parameter Fv/Fm in compact corn based on different hyperspectral vegetation indices]. AB - In order to further assess the feasibility of monitoring the chlorophyll fluorescence parameter Fv/Fm in compact corn by hyperspectral remote sensing data, in the present study, hyperspectral vegetation indices from in-situ remote sensing measurements were utilized to monitor the chlorophyll fluorescence parameter Fv/Fm measured in the compact corn experiment. The relationships were analyzed between hyperspectral vegetation indices and Fv/Fm, and the monitoring models were established for Fv/Fm in the whole growth stages of compact corn. The results indicated that Fv/Fm was significantly correlated to the hyperspectral vegetation indices. Among them, structure-sensitive pigment index (SIPI) was the most sensitive remote sensing variable for monitoring Fv/Fm with correlation coefficient (r) of 0.88. The monitoring model of Fv/Fm was established on the base of SIPI, and the determination coefficients (r2) and the root mean square errors (RMSE) were 0.8126 and 0.082 respectively. The overall results suggest that hyperspectral vegetation indices can be potential indicators to monitor Fv/Fm during growth stages of compact corn. PMID- 22827075 TI - [Chlorophyll fluorescence spectrum analysis of greenhouse cucumber disease and insect damage]. AB - The present paper is based on chlorophyll fluorescence spectrum analysis. The wavelength 685 nm was determined as the primary characteristic point for the analysis of healthy or disease and insect damaged leaf by spectrum configuration. Dimensionality reduction of the spectrum was achieved by combining simple intercorrelation bands selection and principal component analysis (PCA). The principal component factor was reduced from 10 to 5 while the spectrum information was kept reaching 99.999%. By comparing and analysing three modeling methods, namely the partial least square regression (PLSR), BP neural network (BP) and least square support vector machine regression (LSSVMR), regarding correlation coefficient of true value and predicted value as evaluation criterion, eventually, LSSVMR was confirmed as the appropriate method for modeling of greenhouse cucumber disease and insect damage chlorophyll fluorescence spectrum analysis. PMID- 22827076 TI - [Research on retrieving thermospheric O/N2 from FUV remote sensing]. AB - Magnetic storms usually cause significant departures of thermospheric O and N2 from their normal values. To study the effects on thermospheric neutral species caused by magnetic storms, a method to retrieve thermospheric O/N2 based on the data obtained from global ultraviolet imager on board TIMED is presented. With the help of AURIC, the normalizations of observing angles and SZAs were preformed to the measurements and a relationship between 135.6/LBHs and O/N2 was established. Finally, applying the proposed method to retrieve O/N2 during a magnetic period (29, September - 4, October, 2002), it was shown that magnetic storms could induce significant O/N2 depletion, extending from the polar regions towards the equator. PMID- 22827077 TI - [A novel technology for water quality testing based on UV spectral analysis]. AB - Water pollution control and prevention require that the water quality testing is of real time, online and portability. The presejt paper provides a water detecting system based on UV-visible spectra. The R2 of the linear regression is greater than 0.99 between absorbance and COD of the samples. Single measurement is within 1 s. At the same time, two methods were presented for direct comparison and normalization of the spectra and their corresponding indicator parameters. By a large number of experiments with standard solution of the potassium hydrogen phthalate and water samples, we found that these methods can be used to classify samples, find suitable mathematical model of the test water from the database, to improve the universal ability of the UV water testing technology, and get other water quality indices. PMID- 22827078 TI - [Research on the DNA condensation properties by ultraviolet spectrum]. AB - In order to explore the property and mechanism of DNA condensation, the authors studies the effect of different concentrations of spermine(SPM), spermidine (SPD) and hexamminecobalt(III) chloride on the ultraviolet (UV) absorption value of calf thymus DNA by UV spectrophotometer from the macro. The results showed that SPD and SPM interaction with the DNA had the similar characteristics in UV spectrum. The UV absorption value of calf thymus DNA at 260 nm appeared increased decreased-increased with the increasing the concentration of SPD and SPM. The value of hexamminecobalt(III) chloride system showed decreased and then increased, suggesting that SPM, SPD and hexamminecobalt(III) chloride could make DNA condense, but in different ways. Relatively, hexamminecobalt(III) chloride was more sensitive than SPD and SPM. The result of UV spectral analysis coincided with recent single-molecule experimental results. PMID- 22827079 TI - [Vegetation stress spectra and their relations with the contents of metal elements within the plant leaves in metal mines in Heilongjiang]. AB - In this paper, Duobao Mt. and Tong Mt. were taken as examples. The spectra of the crown or leaf of the vegetation were collected. Fourteen metal elements in the rock, soil (A, B, C) and vegetation (root, trunk, leaf), and biological chemical parameters were measured. It was indicated that different metal elements were selected and enriched in different vegetation. The red edge position (REP) and the absorbing depth are related to biological chemical parameters. A multivariable regression equation was built between the absorption depths and the contents of metal elements. The relative coefficients between the absorbing depths and chemical elements, including Co, Cu, N, Mo, Ag, Sb, W, Pb and As, are greater than 0.75. Thus, it is important to analyze and measure the contents of metal elements by hyper-spectral remote sensing of vegetation stress spectrum. PMID- 22827080 TI - [Simultaneous detection of phenol and anionic surfactant in water based on continuous spectrum]. AB - Phenol and anionic surfactant are important indices for water-quality. Based on improvement and optimization of standard methods (spectrophotometry) for the two indices, we integrated the respective two color-extractants into a composited reagent. Using a self-developed microspectrometer with a design of splitting behind and collection of continuous spectrum signal (340-770 nm) in real time, a compound detection system was constructed. This system could simultaneously detect phenol and anionic surfactant in water without chemical and spectral interferences, leading to great decreases in reagent amount and detection time. The detection limits for phenol and anionic surfactant are 0. 003 and 0.016 mg x L(-1), respectively. This method was applied to water-quality monitoring of real samples in comparison with standard methods, and the results indicated that its reproducibility (relative standard deviation, n=5) and accuracy (relative error to results by standard methods) were less than 5%, contenting with the related standard. PMID- 22827081 TI - [Study on the spectrophotometric determination of hydroxyl free radical from low power trench-type ultrasound]. AB - Under the condition of different pH (7-11) and different ethanol volume fraction (45% to 85%), the ultraviolet-visible absorption spectra of malachite green were studied in neutral and alkaline ethanol solution, the maximum absorption wavelength at 620 nm was found, and the matching degree of standard curve was better established. In low power trench-type ultrasound apparatus, the absorption of the malachite green solution was measured under ultrasound and non-ultrasound, respectively. the difference values of the ultraviolet absorption of the malachite green solution under low power trench-type ultrasound were measured results of the hydroxyl free radical oxidation degrading malachite green, therefore hydroxyl free radical from low power trench-type ultrasound was determined indirectly. Then the contents of hydroxyl free radical in four conditions were measured. The detection limit of the method of 8.4 x 10(-6) mmol x L(-1) and the relative standard deviation of the method of 9.4 x 10(-5) - 3.7 x 10(-4) mmol x L(-1) were determined, a higher testing precision and good reproducibility were confirmed. It can be applied for fast detection of neutral and alkaline ethanol solution system in the case of very low concentration of hydroxyl free radicals. Since malachite green is heat sensitive, so compared to measuring temperature, the method possessed better functions for thermal effects of ultrasound. PMID- 22827082 TI - [Contrastive study on dynamic spectrum extraction method]. AB - Dynamic spectrum method extracts the absorbance of the artery pulse blood with some wavelengths. The method can reduce some influence such as measurement condition, individual difference and spectrum overlap. It is a new way for noninvasive blood components detection However, how to choose a dynamic spectrum extraction method is one of the key links for the weak ingredient spectrum signal. Now there are two methods to extract the dynamic spectral signal frequency domain analysis and single-trial estimation in time domain In the present research, comparison analysis and research on the two methods were carrued out completely. Theoretical analysis and experimental results show that the two methods extract the dynamic spectrum from different angles. But they are the same in essence--the basic principle of dynamic spectrum, the signal statistical and average properties. With the pulse wave of relative stable period and amplitude, high precision dynamic spectrum can be obtained by the two methods. With the unstable pulse wave due to the influence of finger shake and contact-pressure change, the dynamic spectrum extracted by single-trial estimation is more accurate than the one by frequecy domain analysis. PMID- 22827083 TI - [In situ temperature measurement by absorption spectroscopy based on time division multiplexing technology]. AB - Tunable diode laser absorption spectroscopy (TDLAS) technology is a kind of high sensitivity, high selectivity of non contacting gas in situ measurement technique. In the present paper, in situ gas temperature measurement of an open environment was achieved by means of direct scanning multiple characteristic lines of H2O and combined with least-squares algorithm. Through the use of HITRAN spectral database, the boundary effect on the gas temperature and concentration measurements was discussed in detail, and results showed that the combination of scanning multiple characteristic lines and least-squares algorithm can effectively reduce the boundary effect on the gas temperature measurements under the open environment. Experiments using time division multiplexing technology to simultaneously scan 7444.36, 7185.60, 7182.95 and 7447.48 cm(-1), the four characteristic H2O lines, the gas temperature of tubular furnace in the range of 573-973 K was measured under different conditions. The maximum temperature difference between absorption spectrum measurement and thermocouple signal was less than 52.4 K, and the maximum relative error of temperature measurement was 6.8%. PMID- 22827084 TI - [Theoretical analysis of the residual amplitude modulation of frequency modulation strong absorption spectroscopy]. AB - The application of frequency modulation (FM) spectroscopy technology in the trace gas detection is greatly restricted by the residual amplitude modulation (RAM) which induced by the birefringence of the electro-optic modulator (EOM) and the misaligned linear polarization direction of laser to the EOM. Based on the interaction between the laser field and crystal, a line-shape expression of the FM spectroscopy with RAM is obtained. The angle between the polarization direction of input light and the principle axis of EOM, theta, the phase difference between the two principle axes of electro-optic crystal, delta phi, and the modulation index FM, beta, are the major factors to influence the lineshape. The larger theta and larger delta phi are, the stronger distortion of the lineshape is. Meanwhile a DC offset exists in the FM dispersion spectroscopy which is influenced by theta and delta phi. Finally a servo control of theta and delta phi is suggested to reduce the RAM. These phenomenon and the analysis of the lineshape provide a necessary technical support for the fiber components based FM spectroscopy. PMID- 22827085 TI - [High transmission and low group velocity of a photonic crystal coupled-cavity waveguide]. AB - A two-dimensional photonic crystal coupled-cavity waveguide was designed and optimized by combining photonic crystal wavguide and cavity, transmission spectra of the waveguide were calculated by using FDTD method, and the transmittance and the group velocity were obtained through the transmission spectra. The calculation results show that a group velocity of upsilon(g) = c/130 and corresponding transmission of 20.1% can be obtained at wavelength 1.551 microm, and a group velocity of upsilon(g) = c/50 and transmission of 29.2% was obtained at wavelength 1.502 microm. The slow light in the waveguide was also analyzed by using photonic bandstructure calculated by plane-wave-expansion (PWE) method. The results of the photonic crystal waveguide with high transmission and low group velocity will have potential application in optical storage, optical delay and photonic integration. PMID- 22827086 TI - [Polarization-sensitive characteristics of the transmission spectra in photonic crystal with nematic liquid crystal defects]. AB - The polarization-sensitive characteristics in the transmission spectra of TiO2/SiO2 optical multilayer films of one-dimensional photonic crystal (1D PC) with nematic liquid crystal defects were investigated in the present paper. The transmission spectra measurements and simulated results show that the polarization-sensitive feature was obvious when natural light was normal incident onto the parallelly aligned nematic liquid crystal. There were peaks of the extraordinary light (TE mode) with center wavelengths 1831 and 1800 nm and the ordinary light (TM mode) with center wavelengths 1452 and 1418 nm in the photonic forbidden band, respectively. With applied voltage increasing, the peaks of the extraordinary light was blue-shifted, and coincided with the peaks of O light gradually. Their tunable ranges were about 31 and 34 nm, respectively. For the random nematic liquid crystal, polarization sensitivity was not observed. Meanwhile, an individual extraordinary light peak with center wavelength 1801 nm and an individual ordinary light peak with center wavelength 1391 nm were obtained in the photonic forbidden band, respectively. The peaks were also found blue-shifted with applied voltage increasing, and their tunable ranges were about 64 and 15 nm, respectively. The polarization insensitive photonic crystal with nematic liquid crystal defects can be achieved by random liquid crystal molecules, which make the effective refractive index of the extraordinary light equal to that of the ordinary light. PMID- 22827087 TI - [Study on predicting protein content of wheat seeds by using wheat leaves SPAD value]. AB - The present paper is to study and build the rapid nondestructive prediction technique of wheat grain quality in the pre-harvest period, The analysis of SPAD value aimed at five different periods from the first leaf to the 4th leaf to obtain SPAD values with the sampling period and the changes of leaf using 31 kinds of wheat materials, near infrared spectroscopy was used for the determination of protein of the grain And the leaf SPAD values and maturity correlation of grain protein content were established. It was found that decreasing rate of the top leaf SPAD and grain protein content showed significant negative correlation y = -3.2109x + 14.286, linear regression equation is y = 3.2109x + 14.286, and correlation coefficient is r = -0.8490. With significant analysis, we assume that there is a very significant linear correlation between decreasing rate of the top leaf SPAD value and grain protein content. So we can use decreasing rate of the top leaf SPAD values to predict the protein content of grain PMID- 22827088 TI - [Research on the carbon content of coal by LIBS]. AB - A method is introduced about quantitative analysis of carbon in coal by LIBS (laser-induced breakdown spectroscopy) in the present paper, and it introduces data optimization technology and method based on spectral data integration, normalization and data screening processing to overcome the poor quality of precision in the analysis because of laser source energy fluctuation, self absorption, sample surface roughness etc. It is showed that the standard deviation (SD) is less than 1.6% using the method to analyze C element content in coal, and this method also can be used for other element analysis for coal. PMID- 22827089 TI - [Study of cortex phellodendri chinensis decoction experiment based on the spectral imaging technology]. AB - The purpose of decoction traditional Chinese medicine is to make full exhalation of medicinal materials active ingredients, thus it has the maximum effect of traditional Chinese medicine to treat disease. In order to detect the dissolution change of medicinal materials active ingredients in decoction process, this paper applys spectral imaging technology, with Chinese traditional medicine cortex phellodendri as an example, discussing its fluorescence intensity at different time in decoction process. And the analysis results reflect edgewise the dissolution rule of cortex phellodendri active ingredients. PMID- 22827090 TI - [Estimated nitrogen nutrition index based on the hyperspectral for wheat of drip irrigation under mulch]. AB - The accurate wheat management needs a reasonable nitrogen application, and it is one of the key measures for real-time and quantitatively monitoring of nitrogen status to gain the higher yield of wheat. In the present study, two field experiments were conducted with different nitrogen stress and wheat cultivars, the relationship was analyzed between spectral parameters and the partial factor productivity from applied N (PFPn), and the estimating model was established for PFP, in the growth stages of wheat. The result indicated that there was a highly significant correlation between the PFP, and GreenNDVI at jointing, the correlation coefficient (r) was 0.6404, the estimating model of PFPn was established, and the root mean square errors (RMSE) was 0.4597. The result indicated that the PFPn can be effectively estimated by using spectral parameters. PMID- 22827091 TI - [Hyperspectral estimation models of chlorophyll content in apple leaves]. AB - The present study chose the apple orchard of Shandong Agricultural University as the study area to explore the method of apple leaf chlorophyll content estimation by hyperspectral analysis technology. Through analyzing the characteristics of apple leaves' hyperspectral curve, transforming the original spectral into first derivative, red edge position and leaf chlorophyll index (LCI) respectively, and making the correlation analysis and regression analysis of these variables with the chlorophyll content to establish the estimation models and test to select the high fitting precision models. Results showed that the fitting precision of the estimation model with variable of LCI and the estimation model with variable of the first derivative in the band of 521 and 523 nm was the highest. The coefficients of determination R2 were 0.845 and 0.839, the root mean square errors RMSE were 2.961 and 2.719, and the relative errors RE% were 4.71% and 4.70%, respectively. Therefore LCI and the first derivative are the important index for apple leaf chlorophyll content estimation. The models have positive significance to guide the production of apple cultivation. PMID- 22827092 TI - [Research on the method of copper converting process determination based on emission spectrum analysis]. AB - A method of copper converting process determination based on PbO/PbS emission spectrum analysis was described. According to the known emission spectrum of gas molecules, the existence of PbO and PbS was confirmed in the measured spectrum. Through the field experiment it was determined that the main emission spectrum of the slag stage was from PbS, and the main emission spectrum of the copper stage was from PbO. The relative changes in PbO/PbS emission spectrum provide the method of copper converting process determination. Through using the relative intensity in PbO/PbS emission spectrum the copper smelting process can be divided into two different stages, i.e., the slag stage (S phase) and the copper stage (B phase). In a complete copper smelting cycle, a receiving telescope of appropriate view angle aiming at the converter flame, after noise filtering on the PbO/PbS emission spectrum, the process determination agrees with the actual production. Both the theory and experiment prove that the method of copper converting process determination based on emission spectrum analysis is feasible. PMID- 22827093 TI - [Analytical figures of merit of Hildebrand grid and ultrasonic nebulizations in inductively coupled plasma atomic emission]. AB - Hildebrand grid nebulizer is a kind of improved Babington nebulizer, which can nebulize solutions with high total dissolved solids. And the ultrasonic nebulizer (USN) possesses advantage of high nebulization efficiency and fine droplets. In the present paper, the detection limits, matrix effects, ICP robustness and memory effects of Hildebrand grid and ultrasonic nebulizers for ICP-AES were studied. The results show that the detection limits using USN are improved by a factor of 6-23 in comparison to Hildebrand grid nebulizer for Cu, Pb, Zn, Cr, Cd and Ni. With the USN the matrix effects were heavier, and the degree of intensity enhancement and lowering depends on the element line, the composition and concentrations of matrices. Moreover, matrix effects induced by Ca and Mg are more significant than those caused by Na and Mg, and intensities of ionic lines are affected more easily than those of atomic lines. At the same time, with the USN ICP has less robustness. In addition, memory effect of the USN is also heavier than that of Hildebrand grid nebulizer. PMID- 22827094 TI - [Determination of trace element contents in Urtica laetevirens Maxim. reaped in different months by ICP-MS]. AB - The contents of twenty kinds of trace elements, Al, Ba, Ca, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S and Zn, were determined by ICP-MS with microwave digestion in Urtica laetevirens Maxim. The recovery (n=7) is 95.4%-101.2%, and the RSD (n=7) is 1.2%-5.3%. The contents of K, P, S, Ca and Na in the samples were abundant while Fe, Mg, Mn and Zn were less abundant. The contents of Al, Cr and Pb which were harmful to human were kept at low level. The contents of trace elements in Urtica laetevirens Maxim. also showed obvious seasonal dynamics. This result provides some theoretical basis for the study of internal relations between trace elements in Urtica laetevirens Maxim. and its efficacy. It's also useful for better development and utilization of the resource. PMID- 22827095 TI - [Determining of the content of determination of elements of Pedicularis from different places by ICP-MS after micriware-assisted digestion]. AB - The content of elements in Pedicularis was determined by ICP-MS aftermicriware assisted digestion. Recovery and RSD of the method is 95%-102% and 1.24%-2.18% respectively, and the method is rapid and precise. There is different Element content in Pedicularis from different places. There are some relations between altitude and content in different places. The result of Pedicularis can provide theoretical basis for medicine research. PMID- 22827096 TI - [Determination of gold and silver in twenty plants from the copper mining area by inductively coupled plasma-mass spectrometry]. AB - The preconcentration and determination of gold and silver in twenty plants from the copper mining area by ICP-MS was described. The plant samples were decomposed by dry-ashing and aqua regia. 107Ag, 109Ag and 197Au were chosen as determining isotopes and 103Rh and 203Tl were chosen as internal standards. The conditions of sample digestion were elected and the interferences on instrument measurement were eliminated through the experiments. The detection limits of method were 0.048 and 1.06 ng x g(-1) for Au and Ag. The precisions (n=5) were between 0.85% and 9.05% RSD, and the recoveries were between 93.6%-101.6% (Au, Ag). The method is sensitive quick,simple and has been applied to the analysis of gold and silver in plants from the copper mining area. Under the given analytical conditions, the results showed that the contents of the Au and Ag varied in these diferent plants, the ranging between 0.181-0.99 ng x g(-1) for Au and 280-2150 ng x g(-1) for Ag respectively. The geochemical anomalies on Ag were discovered in Pteris, Dicranopteris pedata and Bolbitis heteroclita, which can be regarded as prospecting effective indicator plants. PMID- 22827097 TI - [Determination of heavy metals in dominant plant species in Vanadium/Titanium mine area by microwave digestion-ICP-AES]. AB - Ten kinds of dominant plants in Vanadium/Titanium mine area were collected, the contents of heavy metals including Pb, Zn, Cu, Cr, Cd and Ti of which aboveground and underground parts were determined by ICP-AES using microwave digestion, respectively. All samples of the plants were digested with HNO3-H2O2 system. The relative standard deviation was less than 5% for all the elements, and the recoveries were 92.90%-103.85% by adding standard recovery experiment. This method was simple, sensitive and precise and can perform simultaneous multi elements determination compared with conventional method of the plants determination, which could satisfy the sample examination request and provide scientific rationale for determining inorganic elements of plants. PMID- 22827098 TI - [Indirect determination of iodine with methyl isobutyl ketone (MIBK) extraction by atomic fluorescence spectrometer]. AB - In this paper, a new method was developed for indirect determination of iodine with methyl isobutyl ketone (MIBK) extraction by atomic fluorescence spectrometer (AFS). Based upon the complex, which can be extacted perfectly by MIBK, formed between I- and Hg2+ in 0.1 mol x L(-1) of nitric acid, indirectly measuring the iodine in organic phase becomes possible. The effects of extraction conditions and other influence factors were investigated. Under the optimized experimental conditions, the results showed that the linearity between its absorbance and the concentration of iodine was 0-12 microg x L(-1), the detection limit is 0.14 microg x L(-1), and the relative standard deviation is 3.3%. The method has been applied to the determination of iodine in eggs, and the recoveries are in the range of 101.8%-110.4%. PMID- 22827099 TI - [Preconcentration of ultra-trace germanium in water samples with nano-sized TiO2 colloid and determination by HGAFS with colloid sampling]. AB - A novel method for preconcentration of ultra-trace germanium and determination by hydride generation atomic fluorescence spectrometry (HGAFS) was presented in this work. When the pH values of solution were 6.0-8.0, the adsorption efficiency of nano-sized TiO2 colloid for germanium was 97.0%-99.0% in a short time. Nano-sized TiO2 colloid was used to concentrate the ultra-trace germanium in water sample due to its high absorption capacity. After centrifugation, the supernatant fluid was removed. The sediment which contained the concentrated Ge(IV) was inverted to colloid by adding HCl of certain concentration. Ge(IV) in colloid was directly determined by HGAFS. The proposed method possesses low detection limit (3sigma) (0.060 microg x L(-1)) and good precision (the relative standard deviation (RSD) is 2.0%, n=6). The method is was also quite simple and time saving (without any filtration and desorption process). Satisfactory results were obtained when applying this method to the determination of ultra-trace germanium in water samples. PMID- 22827100 TI - [Determination of selenium in plant samples by hydride generation atomic fluorescence spectrometry]. AB - A method was developed by hydride generation atomic fluorescence spectrometry (HG AFS)for the determination of selenium in plant samples. Effects of reagent and pre-reduction method on the fluorescence intensity of selenium were studied. The influence of coexisting foreign ions on the determination of selenium was also investigated. Under the optimized digestive and experimental conditions, the linear regression equation was I = 139.98c + 27.71 for Se. The linear range, the correlation coefficient,and the detection limit of Se was 0-10 ng x mL(-1), 1.0000, and 1.45 ng x g(-1) respectively. The recovery of Se (98.9%-101%, mean=100%) was determined through the use of standard reference material. The relative standard deviation for nine replicate analyses was 0.73% for Se content in shrub leaves. This method was verified by analyzing the national reference material (GSV-1)and the found value was in good agreement with the certified value. The proposed method that was successfully used for the determination of Se in plant samples has the advantages of simple operation, low cost, and high efficiency. PMID- 22827101 TI - [Preparation of sub-standard samples and XRF analytical method of powder non metallic minerals]. AB - In order to solve the problem that standard samples of non-metallic minerals are not satisfactory in practical work by X-ray fluorescence spectrometer (XRF) analysis with pressed powder pellet, a method was studied how to make sub standard samples according to standard samples of non-metallic minerals and to determine how they can adapt to analysis of mineral powder samples, taking the K feldspar ore in Ebian-Wudu, Sichuan as an example. Based on the characteristic analysis of K-feldspar ore and the standard samples by X-ray diffraction (XRD) and chemical methods, combined with the principle of the same or similar between the sub-standard samples and unknown samples, the experiment developed the method of preparation of sub-standard samples: both of the two samples above mentioned should have the same kind of minerals and the similar chemical components, adapt mineral processing, and benefit making working curve. Under the optimum experimental conditions, a method for determination of SiO2, Al2O3, Fe2O3, TiO2, CaO, MgO, K2O and Na2O of K-feldspar ore by XRF was established. Thedetermination results are in good agreement with classical chemical methods, which indicates that this method was accurate. PMID- 22827102 TI - [Research on the application of improved M-P neural network to the determination of lead and zinc ore element contents by energy disperse X-ray fluorescence analysis]. AB - Because of different constraints (such as different kinds of measurable elements, characteristic X-ray energy, changes in matrix composition, etc.), usually it's not easy to get accurate information of elements, resulting in mistakes in later data analysis of energy disperse X-ray fluorescence measurement. The method is based on McCulloch-Pitts neural network (M-P neural network), according to matrix effect, to establish a new neural network model for quantitative forecasting of Zn by taking the data of X-ray fluorescence measurements of Cu, Fe, Pb, etc in lead-zinc mine in western Tianshan as the training sample. The relative error between predicted value and measured value is less than 5%. This method can be more accurate and rapid for X-ray fluorescence; it provides a new approach to correcting information of X-ray fluorescence. PMID- 22827103 TI - [EDXRF study on the chemical composition and raw material recipe of Jindezhen porcelains in the five dynasties]. AB - Early crafts of porcelain making in Jindezhen were an important issue in ceramic history of China. The chemical composition of white porcelain and celadon samples excavated from Xianghu Kiln in the five dynasties was analyzed using energy dispersive X-ray fluorescence (EDXRF). Raw material recipes of the samples were discussed. The results showed that white porcelain bodies of Xianghu Kiln in the Five Dynasties were made from porcelain stone, while celadon bodies were made from porcelain stone and Zijin clay. Glaze ash and glaze stone were both used in the formula of white porcelain and celadon glaze, and the amount of glaze ash in the celadon was higher than that in the white porcelain samples. PMID- 22827104 TI - [Biomimetic mineralization of rod-like cellulose nano-whiskers and spectrum analysis]. AB - Cellulose nano-whiskers/nano-hydroxyapatite composite was prepared with biomimetic mineralization using rod-like cellulose nano-whiskers as template. The cellulose nano-whiskers and cellulose nano-whiskers/nano-hydroxyapatite composite were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and scanning electron microscope-energy dispersive analysis of X-rays (SEM EDXA). Variation and distribution of carbon, oxygen, calcium, and phosphorus in the composites were studied. The morphologies and growth mechanism of nano hydroxyapatite were analyzed. The results showed that nano-hydroxyapatite was formed on the surface of cellulose nano-whiskers; the carbon-oxygen ratio of cellulose nano-whiskers and cellulose nano-whiskers/nano-hydroxyapatite composite was 1.81 and 1.54, respectively; the calcium-phosphorus ratio of the composite was 1.70. The nucleation of nano-hydroxyapatite was around the hydroxyl groups of cellulose nano-whiskers. It is suggested that there is coordination between the hydroxyl groups of cellulose nano-whiskers and calcium ions of nano hydroxyapatite. The nano-hydroxyapatite can distribute in the matrix of cellulose nano-whiskers. From the atomic force microscope (AFM) images, we can see that the diameter of the spherical nano-hydroxyapatite particles was about 20 nm. PMID- 22827105 TI - [Study of the calibration model of different pathlength spectra in near infrared noninvasive biochemical sensing]. AB - The spectral subtraction approach with different flow blood volume in near infrared noninvasive biochemical sensing can eliminate human tissue background interference, but at the same time the pathlength of subtracted spectrum is unknown. Thus, the model will be insufficiently effective if established directly with pathlength-unknown spectra, which is a big problem for subtracted blood volume spectrometry. In the present paper, a simulated experiment was designed to simulate this issue. The orthogonal signal correction method was proposed to eliminate the influence brought by pathlength. Compared with the PLS model before and after orthogonal signal correction, the root mean square error of cross validation (RMSECV) was from 90.17 mg x dL(-1) down to 31.62 mg x dL(-1), and the correlation coefficient was improved from 0.9787 to 0.9968. The experimental results show that using the orthogonal signal correction method can effectively restrain the interference information of path-length, and improve the prediction precision of calibration model. The conclusion in this paper sets the stage for the practical application of the spectral subtraction approach with different flow blood volume. PMID- 22827106 TI - [The melioration on spectra response heterogeneity of hadamard transform spectral imager]. AB - Hadamard transform optics has been developed in the past decades. It has been used in distinguishing targets, detecting feeble signals and so on. Hadamard transform spectral imager (HTSI), based on digital micro-mirror device, is a new dispersion spectral imager. HTSI has been developed in our laboratory. The spectral heterogeneity of encoded image captured by HTSI has been researched according to spectrum calibration in this paper. Relative and absolute spectrum emittance calibration algorithms have been proposed first time on HTSI to meliorate the spectrum heterogeneity. It aims at the problem that the accuracy of recovered spectrum is depressed by the heterogeneity noise and disorder encoding spectrum in spectral image. Simulation and experiment result have demonstrated that the meliorated spectral curve is close to the standard spectrum, and the variance of the recovered spectrum ranges from 2.4% to 4.2% with regard to the spectral image of 7 waves. This is fully satisfied for the requirement of laboratory and projects. PMID- 22827107 TI - [Temperature compensation for portable Vis/NIR spectrometer measurement of apple fruit soluble solids contents]. AB - Visible (Vis)/near infrared (NIR) spectroscopy has been used successfully to measure soluble solids content (SSC) in fruit. However, for practical implementation, the NIR technique needs to be able to compensate for fruit temperature fluctuations, as it was observed that the sample temperature affects the NIR spectrum. A portable Vis/NIR spectrometer was used to collect diffused transmittance spectra of apples at different temperatures (0-30 degrees C). The spectral data of apple at 20 degrees C was used to develop a norm partial least squares (PLS) model. Slope/bias technique was found to well suits to control the accuracy of the calibration model for SSC concerning temperature fluctuations. The correctional PLS models were used to predict the SSC of apple at 0, 10 and 30 degrees C, respectively. The correctional method was found to perform well with Q values of 0.810, 0.822 and 0.802, respectively. When no precautions are taken, the Q value on the SSC may be as small as 0.525-0.680. The results obtained highlight the potential of portable Vis/NIR instruments for assessing internal quality of fruits on site under varying weather conditions. PMID- 22827108 TI - [A soft discretization method of celestial spectrum characteristic line based on fuzzy C-means clustering]. AB - Discretization of continuous numerical attribute is one of the important research works in the preprocessing of celestial spectrum data. For characteristic line of celestial spectrum, a soft discretization algorithm is presented by using improved fuzzy C-means clustering. Firstly, candidate fuzzy clustering centers of characteristic line are chosen by using density values of sample data, so that its anti-noise ability is improved. Secondly, parameters in the fuzzy clustering are dynamically adjusted by taking compatibility of decision table as criteria, so that optimal discretization effect of the characteristic line is achieved. In the end, experimental results effectively validate that the algorithm has higher correct recognition rate of the algorithm by using three SDSS celestial spectrum data sets of high-redshift quasars, late-type star and quasars. PMID- 22827109 TI - [Duties of TB patients or suspected patients and their close relations]. AB - The effective laws impose the duty upon TB patients or persons suspected to have TB as well as their close relations to undergo compulsory sanitary, epidemiological and examinations. Furthermore, treatment is also mandatory and in case of infecting patients hospitalization, isolation and treatment. Duty does not denote enforcement required in certain particularly dangerous infectious diseases. Poland operates a system of mandatory TB vaccination applicable, today, only to infants. Persons suspected of TB have the obligation to provide necessary information helping in diagnosing the disease or helping to find the source of infection and transmission of the disease. TB patients are under obligation to discontinue performing their work in case it may prevent the disease from spreading onto other persons. PMID- 22827110 TI - [Changes in food preferences in pregnant women]. AB - INTRODUCTION: Pregnant women frequently show significant changes in their eating habits. The aim of the study was to evaluate the pleasure derived from the consumption of selected food groups in women during the first and second trimester of pregnancy. MATERIAL AND METHODS: The studied group included 64 healthy women, aged 23-38. 32 women were in the first trimester of pregnancy and 32 women in the second trimester. The food preference interviews were conducted by the presentation of colourful photographs showing selected food groups. Then each participant answered the following question: "How much pleasure do you take from this food?". The results were recorded on a linear analogue scale. The women evaluated the pleasure they derived from food before pregnancy and in the first or second trimester of pregnancy. RESULTS: The women in the first trimester of pregnancy, showed a lower preference for eggs, sweets, pasta, red meat, fast food, salty snacks, spicy food, and seafood as compared to their preferences before the pregnancy. The women in the second trimester declared a significantly higher preference for chicken soup, fruit and sour food, and rated the taste of beef and pork, spicy food and salty snacks as less pleasurable than before the pregnancy. CONCLUSIONS: The first trimester of pregnancy is a period of decreased pleasure derived from food, whereas the perception of food in the second trimester is characterized by a general hedonic dimension similar to that from before the pregnancy. Both in the first and the second trimester of pregnancy women show a lower preference for beef and pork, spicy food and salty snacks. PMID- 22827111 TI - [Thromboembolic venous disease as a first sign of neoplastic disease--a case report]. AB - Venous thromboembolism is a one of the most common complications of cancer, which contributes to mortality in cancer patients. The prognosis of cancer patients with thrombosis is significantly worse. Venous thromboembolism can be the first manifestation of occult cancer. Incidence of subsequent cancer diagnosis after thrombotic event reaches 25% and is highest within the first 6 months. Risk of cancer diagnosis is significantly higher in patients with idiopathic thrombosis compared with those with secondary thrombosis. We present case of 67-year-old man with recurrent vein thromboembolism and pulmonary embolism, who was subsequently diagnosed with disseminated adenocarcinoma, most likely of the lung. PMID- 22827112 TI - [Hyponatremic hypervolemia in heart failure--the hot spot for vasopressin receptor antagonists?]. AB - Dilutional hyponatremia is the most common electrolyte disorder occurring in heart failure (HF). The relation between hyponatremia and increased morbidity and mortality is widely evidenced. Treatment of this condition is circumscribed by strict correlation of electrolyte and water balance, though. Neurohormonal activation in HF is the effect of compensatory mechanisms due to insufficient effective blood volume. One of the factors is increased serum argininovasopressin (AVP) concentration. The principal effects of this action are free water retention via V2 receptor and vasoconstriction by V(1A) receptor. Stimulation of V(1A) receptor also contributes to heart muscle remodeling. Diuretics are still the basic treatment of hypervolemia. At the same time they have a very unfavorable side effect in the form of exacerbating hyponatremia. The new direction of investigations occurred after noticing the spectacular aquaretic effect of antagonizing AVP receptors. The effect is new group of drugs- vasopressin receptor antagonists called the vaptans. Unlike the diuretics, they cause free water excretion without electrolyte loss. The registration includes in hospital treatment of states of hyponatremia (conivaptan, tolvaptan, mozavaptan), the two other (lixivaptan, satavaptan) are undergoing research. Apart from improving clinical status, there is still no evidence of improving the patients' survival. Further research in this field is necessary to demonstrate whether there is prognosis amelioration in short-term and long-term patients' observation. PMID- 22827113 TI - [Prostate cancer dependance upon cholesterol, statins and diet]. AB - The aim of the work is to analyze the influence of higher cholesterol and LDL level on risk of prostate cancer. The work is based on the available literature in that field. The metabolism of cholesterol is mainly regulated by the statins, which may thus inhibit prostate cancer growth. Keeping the appropriate body mass and level of cholesterol by proper diet and physical exercises may be the prophylaxis of prostate cancer. PMID- 22827114 TI - [Factors influencing the variable response to treatment with oral anticoagulants]. AB - During therapy with oral anticoagulants, which are the main drugs used for treatment and prevention of thromboembolic diseases, there is significant variability in individual doses required to achieve the therapeutic effect. Oral anticoagulant therapy requires regular monitoring of INR, which should be within the range of 2-3. Currently there is no reliable test predicting which patient will require an extremely high or low dose of these drugs. The variability of responses to oral anticoagulants is regulated by demographic factors such as age, sex, body mass; environmental factors and genetic factors. The personal factors include medication, diet, coexisting systemic diseases. Among genetic factors the most important are polymorphisms of two genes which take part in metabolism of vitamin K and oral anticoagulants. These are: a gene encoding CYP2C9, an enzyme which is involved in hepatic metabolism ofcoumarin derivatives and vitamin K epoxide reductase complex subunit 1 (VOKRC1), the target enzyme of action of oral anticoagulants. Less important are mutations in genes encoding other subunits of cytochrome P450, vitamin K dependent clotting factors, calumenin, gamma-glutamyl carboxylase, apolipoprotein E and microsomal epoxide hydrolase. All these factors can affect both the pharmacokinetics and pharmacodynamics of coumarin derivatives. Considering the main genetic and environmental factors we can predict the dose of oral anticoagulants required in about two-thirds of cases. PMID- 22827115 TI - [Treatment of premature ejaculation]. AB - Premature ejaculation is the most common sexual dysfunction in men. Its prevalence rate in Europe and in United States is estimated to be between 20% and 30%. The diagnosis of premature ejaculation is based on three main criteria: increased intravaginal ejaculatory latency time (IELT), lack of control over ejaculation and interpersonal psychological disturbances. Premature ejaculation is classified as lifelong (primary) or acquired (secondary) and might be facilitated by chronic prostatitis, diabetes mellitus, hyperthyroidism, obesity. The exact etiology of the disease remains unclear, although 5-HT (5 hydroxytryptamine) receptors are known to have a significant role. The use of SSRIs (selective serotonine reuptake inhibitors) is old and efficient form of therapy for premature ejaculation. Other drugs like tramadol, clomipramine, local anaesthetics and PDE-5 (phosphodiesterase 5) inhibitors also have some efficacy in the treatment of premature ejaculation. To minimize adverse effects the "on demand" therapy is preferred to the daily treatment. Simple questionnaires for patients are used to assess treatment effects. PMID- 22827116 TI - [Hypospadias--a psychological view. Psychosocial and psychosexual implications]. AB - This theoretical research paper refers to the psychological consequences ofhypospadias, a male congenital deficiency of the urethra. Hypospadias is defined as an abnormal opening of the urethra on the underside of the penis and is a frequently found malformation with an incidence of 1 per 300 males. This malformation affects one of the most personal parts of the male anatomy and its psychological repercussions are undeniable. The vast majority of studies concerning this condition are found in the medical domain: surgical and pediatric urology and endocrynology. The difficulty in finding data about psychological implications of hypospadias, along with the lack of opportunities for discussing it was an objective to contribute a modest advancement in the field of psychology. Because of the fact that hypospadias is a psychological condition as well as a physical one, this theoretical paper discusses the influenceses of the condition on the patient's psychosocial (in the view of E. H. Erikson's theory) and psychosexual development (relation to the object theory of O. F. Kernberg). PMID- 22827117 TI - [Application of laser therapy in the physiotherapy of patients with multiple sclerosis]. AB - Multiple sclerosis is a chronic disease of the nervous system, which main manifestations are disseminated demyelinated the changes in the central nervous system. The pathogenesis of this disease is still not known, the curative treatment is not possible. In connection with the alleged autoimmune genesis of MS patients are administered immunomodulatory drugs. Patients with multiple sclerosis suffer from a number of symptoms associated with this disease. The aim of this article is to present the main clinical symptoms characteristic of MS and to present biological effects of low-energy lasers used in the treatment of multiple sclerosis. PMID- 22827118 TI - Life-history correlates of extinction risk and recovery potential. AB - Extinction risk is inversely associated with maximum per capita population growth rate (r(max)). However, this parameter is not known for most threatened species, underscoring the value in identifying correlates of r(max) that, in the absence of demographic data, would indirectly allow one to identify species and populations at elevated risk of extinction and their associated recovery potential. We undertook a comparative life-history analysis of 199 species from three taxonomic classes: Chondrichthyes (e.g., sharks; n = 82), Actinopterygii (teleost or bony fishes; n = 47), and Mammalia (n = 70, including 16 marine species). Median r(max) was highest for (and similar between) terrestrial mammals (0.71) and teleosts (0.43), significantly lower among chondrichthyans (0.26), and lower still in marine mammals (0.07). Age at maturity was the primary (and negative) correlate of r(max). In contrast, although body size was negatively correlated with r(max) in chondrichthyans and mammals, evidence of an association in teleosts was equivocal, and fecundity was not related to r(max) in fishes, despite recurring assertions to the contrary. Our analyses suggest that age at maturity can serve as a universal predictor of extinction risk in fishes and mammals when r(max) itself is unknown. Moreover, in contrast to what is generally expected, the recovery potential of teleost fishes does not differ from that of terrestrial mammals. Our findings are supportive of the application of extinction risk criteria that are based on generation time and that are independent of taxonomic affinity. PMID- 22827119 TI - Transcending scale dependence in identifying habitat with resource selection functions. AB - Multi-scale resource selection modeling is used to identify factors that limit species distributions across scales of space and time. This multi-scale nature of habitat suitability complicates the translation of inferences to single, spatial depictions of habitat required for conservation of species. We estimated resource selection functions (RSFs) across three scales for a threatened ungulate, woodland caribou (Rangifer tarandus caribou), with two objectives: (1) to infer the relative effects of two forms of anthropogenic disturbance (forestry and linear features) on woodland caribou distributions at multiple scales and (2) to estimate scale-integrated resource selection functions (SRSFs) that synthesize results across scales for management-oriented habitat suitability mapping. We found a previously undocumented scale-specific switch in woodland caribou response to two forms of anthropogenic disturbance. Caribou avoided forestry cut blocks at broad scales according to first- and second-order RSFs and avoided linear features at fine scales according to third-order RSFs, corroborating predictions developed according to predator-mediated effects of each disturbance type. Additionally, a single SRSF validated as well as each of three single-scale RSFs when estimating habitat suitability across three different spatial scales of prediction. We demonstrate that a single SRSF can be applied to predict relative habitat suitability at both local and landscape scales in support of critical habitat identification and species recovery. PMID- 22827120 TI - Landscape-level influences of terrestrial snake occupancy within the southeastern United States. AB - Habitat loss and degradation are thought to be the primary drivers of species extirpations, but for many species we have little information regarding specific habitats that influence occupancy. Snakes are of conservation concern throughout North America, but effective management and conservation are hindered by a lack of basic natural history information and the small number of large-scale studies designed to assess general population trends. To address this information gap, we compiled detection/nondetection data for 13 large terrestrial species from 449 traps located across the southeastern United States, and we characterized the land cover surrounding each trap at multiple spatial scales (250-, 500-, and 1000 m buffers). We used occupancy modeling, while accounting for heterogeneity in detection probability, to identify habitat variables that were influential in determining the presence of a particular species. We evaluated 12 competing models for each species, representing various hypotheses pertaining to important habitat features for terrestrial snakes. Overall, considerable interspecific variation existed in important habitat variables and relevant spatial scales. For example, kingsnakes (Lampropeltis getula) were negatively associated with evergreen forests, whereas Louisiana pinesnake (Pituophis ruthveni) occupancy increased with increasing coverage of this forest type. Some species were positively associated with grassland and scrub/shrub (e.g., Slowinski's cornsnake, Elaphe slowinskii) whereas others, (e.g., copperhead, Agkistrodon contortrix, and eastern diamond-backed rattlesnake, Crotalus adamanteus) were positively associated with forested habitats. Although the species that we studied may persist in varied landscapes other than those we identified as important, our data were collected in relatively undeveloped areas. Thus, our findings may be relevant when generating conservation plans or restoration goals. Maintaining or restoring landscapes that are most consistent with the ancestral habitat preferences of terrestrial snake assemblages will require a diverse habitat matrix over large spatial scales. PMID- 22827121 TI - Assessing the status and trend of bat populations across broad geographic regions with dynamic distribution models. AB - Bats face unprecedented threats from habitat loss, climate change, disease, and wind power development, and populations of many species are in decline. A better ability to quantify bat population status and trend is urgently needed in order to develop effective conservation strategies. We used a Bayesian autoregressive approach to develop dynamic distribution models for Myotis lucifugus, the little brown bat, across a large portion of northwestern USA, using a four-year detection history matrix obtained from a regional monitoring program. This widespread and abundant species has experienced precipitous local population declines in northeastern USA resulting from the novel disease white-nose syndrome, and is facing likely range-wide declines. Our models were temporally dynamic and accounted for imperfect detection. Drawing on species-energy theory, we included measures of net primary productivity (NPP) and forest cover in models, predicting that M. lucifugus occurrence probabilities would covary positively along those gradients. Despite its common status, M. lucifugus was only detected during -50% of the surveys in occupied sample units. The overall naive estimate for the proportion of the study region occupied by the species was 0.69, but after accounting for imperfect detection, this increased to -0.90. Our models provide evidence of an association between NPP and forest cover and M. lucifugus distribution, with implications for the projected effects of accelerated climate change in the region, which include net aridification as snowpack and stream flows decline. Annual turnover, the probability that an occupied sample unit was a newly occupied one, was estimated to be low (-0.04 0.14), resulting in flat trend estimated with relatively high precision (SD = 0.04). We mapped the variation in predicted occurrence probabilities and corresponding prediction uncertainty along the productivity gradient. Our results provide a much needed baseline against which future anticipated declines in M. lucifugus occurrence can be measured. The dynamic distribution modeling approach has broad applicability to regional bat monitoring efforts now underway in several countries and we suggest ways to improve and expand our grid-based monitoring program to gain robust insights into bat population status and trend across large portions of North America. PMID- 22827122 TI - Allowable levels of take for the trade in Nearctic songbirds. AB - The take of Nearctic songbirds for the caged-bird trade is an important cultural and economic activity in Mexico, but its sustainability has been questioned. We relied on the theta-logistic population model to explore options for setting allowable levels of take for 11 species of passerines that were subject to legal take in Mexico in 2010. Because estimates of population size necessary for making periodic adjustments to levels of take are not routinely available, we examined the conditions under which a constant level of take might contribute to population depletion (i.e., a population below its level of maximum net productivity). The chance of depleting a population is highest when levels of take are based on population sizes that happen to be much lower or higher than the level of maximum net productivity, when environmental variation is relatively high and serially correlated, and when the interval between estimation of population size is relatively long (> or = 5 years). To estimate demographic rates of songbirds involved in the Mexican trade we relied on published information and allometric relationships to develop probability distributions for key rates, and then sampled from those distributions to characterize the uncertainty in potential levels of take. Estimates of the intrinsic rate of growth (r) were highly variable, but median estimates were consistent with those expected for relatively short-lived, highly fecund species. Allowing for the possibility of nonlinear density dependence generally resulted in allowable levels of take that were lower than would have been the case under an assumption of linearity. Levels of take authorized by the Mexican government in 2010 for the 11 species we examined were small in comparison to relatively conservative allowable levels of take (i.e., those intended to achieve 50% of maximum sustainable yield). However, the actual levels of take in Mexico are unknown and almost certainly exceed the authorized take. Also, the take of Nearctic songbirds in other Latin American and Caribbean countries ultimately must be considered in assessing population-level impacts. PMID- 22827123 TI - Weather effects on avian breeding performance and implications of climate change. AB - The influence of recent climate change on the world's biota has manifested broadly, resulting in latitudinal range shifts, advancing dates of arrival of migrants and onset of breeding, and altered community relationships. Climate change elevates conservation concerns worldwide because it will likely exacerbate a broad range of identified threats to animal populations. In the past few decades, grassland birds have declined faster than other North American avifauna, largely due to habitat threats such as the intensification of agriculture. We examine the effects of local climatic variations on the breeding performance of a bird endemic to the shortgrass prairie, the Lark Bunting (Calamospiza melanocorys) and discuss the implications of our findings relative to future climate predictions. Clutch size, nest survival, and productivity all positively covaried with seasonal precipitation; yet relatively intense daily precipitation events temporarily depressed daily survival of nests. Nest survival was positively related to average temperatures during the breeding season. Declining summer precipitation may reduce the likelihood that Lark Buntings can maintain stable breeding populations in eastern Colorado although average temperature increases of up to 3 degrees C (within the range of this study) may ameliorate declines in survival expected with drier conditions. Historic climate variability in the Great Plains selects for a degree of vagility and opportunism rather than strong site fidelity and specific adaptation to local environments. These traits may lead to northerly shifts in distribution if climatic and habitat conditions become less favorable in the drying southern regions of the Great Plains. Distributional shifts in Lark Buntings could be constrained by future changes in land use, agricultural practices, or vegetative communities that result in further loss of shortgrass prairie habitats. PMID- 22827124 TI - Flows, droughts, and aliens: factors affecting the fish assemblage in a Sierra Nevada, California, stream. AB - The fishes of Martis Creek, in the Sierra Nevada of California (USA), were sampled at four sites annually over 30 years, 1979-2008. This long-term data set was used to examine (1) the persistence and stability of the Martis Creek fish assemblage in the face of environmental stochasticity; (2) whether native and alien fishes responded differently to a natural hydrologic regime (e.g., timing and magnitude of high and low flows); and (3) the importance of various hydrologic and physical habitat variables in explaining the abundances of native and alien fish species through time. Our results showed that fish assemblages were persistent at all sample sites, but individual species exhibited marked interannual variability in density, biomass, and relative abundance. The density and biomass of native fishes generally declined over the period of study, whereas most alien species showed no significant long-term trends. Only alien rainbow trout increased in both density and biomass at all sites over time. Redundancy analysis identified three hydrologic variables (annual 7-day minimum discharge, maximum winter discharge, and number of distinct winter floods) and two habitat variables (percentage of pool habitat and percentage of gravel substrate) that each explained a significant portion of the annual variation in fish assemblage structure. For alien taxa, their proportional contribution to the total fish assemblage was inversely related to mean annual streamflow, one-day maximum discharge in both winter and spring, and the frequency of springtime floods. Results of this study highlight the need for continuous annual monitoring of streams with highly variable flow regimes to evaluate shifts in fish community structure. Apparent successes or failures in stream management may appear differently depending on the time series of available data. PMID- 22827125 TI - Using the functional response of a consumer to predict biotic resistance to invasive prey. AB - Predators sometimes provide biotic resistance against invasions by nonnative prey. Understanding and predicting the strength of biotic resistance remains a key challenge in invasion biology. A predator's functional response to nonnative prey may predict whether a predator can provide biotic resistance against nonnative prey at different prey densities. Surprisingly, functional responses have not been used to make quantitative predictions about biotic resistance. We parameterized the functional response of signal crayfish (Pacifastacus leniusculus) to invasive New Zealand mud snails (Potamopyrgus antipodarum; NZMS) and used this functional response and a simple model of NZMS population growth to predict the probability of biotic resistance at different predator and prey densities. Signal crayfish were effective predators of NZMS, consuming more than 900 NZMS per predator in a 12-h period, and Bayesian model fitting indicated their consumption rate followed a type 3 functional response to NZMS density. Based on this functional response and associated parameter uncertainty, we predict that NZMS will be able to invade new systems at low crayfish densities (< 0.2 crayfish/m2) regardless of NZMS density. At intermediate to high crayfish densities (> 0.2 crayfish/m2), we predict that low densities of NZMS will be able to establish in new communities; however, once NZMS reach a threshold density of 2000 NZMS/m2, predation by crayfish will drive negative NZMS population growth. Further, at very high densities, NZMS overwhelm predation by crayfish and invade. Thus, interacting thresholds of propagule pressure and predator densities define the probability of biotic resistance. Quantifying the shape and uncertainty of predator functional responses to nonnative prey may help predict the outcomes of invasions. PMID- 22827126 TI - Temporal scales and patterns of invertebrate biodiversity dynamics in boreal lakes recovering from acidification. AB - Despite international policy implementation to reduce atmospheric acid deposition and restore natural resources from cultural acidification, evidence of ecological recovery is equivocal. Failure to meet recovery goals means that acidification still threatens biodiversity in many areas of the world. Managers thus need information to manage biodiversity, especially its components that are sensitive to stress (acid-sensitive taxa). We analyzed 20-year time series (1988-2007) of water quality and littoral invertebrates in acidified and circum-neutral lakes across Sweden to evaluate regional biodiversity dynamics and the extent to which changes in water quality affect these dynamics. We used multivariate time series modeling to (1) test how individual species groups within invertebrate communities track changes in the abiotic environment and (2) reveal congruencies of taxon contributions to species group change across lakes. Chemical recovery in the lakes was equivocal, and increases of pH and alkalinity were observed in subsets of acidified and circum-neutral lakes. Time series analyses revealed two different patterns of species groups for invertebrate communities across lakes; the first species group showed monotonic change over time, while the second group showed fluctuating temporal patterns. These independent species groups correlated distinctly with different sets of environmental variables. Recovery of pH and alkalinity status was associated with species group patterns only in a few lakes, highlighting an overall weak recovery of invertebrate species. The sets of species, including acid-sensitive taxa, composing these species groups differed markedly across lakes, highlighting context-specific responses of invertebrates to environmental variation. These results are encouraging because disparate local scale dynamics maintain the diversity of sensitive invertebrate species on a regional scale, despite persisting acidification problems. Our study can inform and help refine current acidification-related policy focused on sensitive biodiversity elements. PMID- 22827127 TI - Watershed land use effects on lake water quality in Denmark. AB - Mitigating nutrient losses from anthropogenic nonpoint sources is today of particular importance for improving the water quality of numerous freshwater lakes worldwide. Several empirical relationships between land use and in-lake water quality variables have been developed, but they are often weak, which can in part be attributed to lack of detailed information about land use activities or point sources. We examined a comprehensive data set comprising land use data, point-source information, and in-lake water quality for 414 Danish lakes. By excluding point-source-influenced lakes (n = 210), the strength in relationship (R2) between in-lake total nitrogen (TN) and total phosphorus (TP) concentrations and the proportion of agricultural land use in the watershed increased markedly, from 10-12% to 39-42% for deep lakes and from 10-12% to 21-23% for shallow lakes, with the highest increase for TN. Relationships between TP and agricultural land use were even stronger for lakes with rivers in their watershed (55%) compared to lakes without (28%), indicating that rivers mediate a stronger linkage between landscape activity and lake water quality by providing a "delivery" mechanism for excess nutrients in the watershed. When examining the effect of different near freshwater land zones in contrast to the entire watershed, relationships generally improved with size of zone (25, 50, 100, 200, and 400 m from the edge of lake and streams) but were by far strongest using the entire watershed. The proportion of agricultural land use in the entire watershed was best in explaining lake water quality, both relative to estimated nutrient surplus at agricultural field level and near-lake land use, which somewhat contrasts typical strategies of management policies that mainly target agricultural nutrient applications and implementation of near-water buffer zones. This study suggests that transport mechanisms within the whole catchment are important for the nutrient export to lakes. Hence, the whole watershed should be considered when managing nutrient loadings to lakes, and future policies should ideally target measures that reduce the proportion of cultivated land in the watershed to successfully improve lake water quality. PMID- 22827128 TI - Expert variability provides perspective on the strengths and weaknesses of citizen-driven intertidal monitoring program. AB - Citizen scientist programs are a means to efficiently conduct large-scale surveys of ecosystems or managed species, provided that concerns over the quality and use of data generated by nonexperts can be addressed. This study presents actions taken in a citizen science program to assure data quality and demonstrates the validity of citizen-generated data. In this case the accuracy of data collected by secondary school students as citizens in a program that quantitatively sampled benthic rocky intertidal communities at 13 sites on Maui, Molokai, Oahu, and Hawai'i island during the years 2004-2007 was evaluated. In 2007, two independent research teams collected data simultaneously with students at five sites on eight sampling dates. Comparisons of Shannon diversity and Bray-Curtis similarity values computed and simulated from student and researcher collected data revealed that nonexpert students accurately collect community-level data within the range of the variation that occurs between researchers. Students were, however, likely to misidentify cryptic and rare species. These findings have direct implications for the conservation goals of the monitoring program as the assessment reveals that students are likely to misidentify early alien introductions but are able to monitor the abundances of native and introduced species once they become established. The validity assessment designed for this investigation is unique in that it directly compares consistent errors made by citizens in data collection to expert variability to identify usage limitations and can be a guide for future studies that involve the efforts of trained volunteers. PMID- 22827129 TI - Interaction networks in coastal soft-sediments highlight the potential for change in ecological resilience. AB - Recent studies emphasize the role of indirect relationships and feedback loops in maintaining ecosystem resilience. Environmental changes that impact on the organisms involved in these processes have the potential to initiate threshold responses and fundamentally shift the interactions within an ecosystem. However, empirical studies are hindered by the difficulty of designing appropriate manipulative experiments to capture this complexity. Here we employ structural equation modeling to define and test the architecture of ecosystem interaction networks. Using survey data from 19 estuaries we investigate the interactions between biological (abundance of large bioturbating macrofauna, microphytobenthos, and detrital matter) and physical (sediment grain size) processes. We assess the potential for abrupt changes in the architecture of the network and the strength of interactions to occur across environmental gradients. Our analysis identified a potential threshold in the relationship between sediment mud content and benthic chlorophyll a, at -12 microg/g, using quantile regression. Below this threshold, the interaction network involved different variables and fewer feedbacks than above. This approach has potential to improve our empirical understanding of thresholds in ecological systems and our ability to design manipulative experiments that test how and when a threshold will be passed. It can also be used to indicate to resource managers that a particular system has the potential to exhibit threshold responses to environmental change, emphasizing precautionary management and facilitating a better understanding of how persistent multiple stressors threaten the resilience and long-term use of natural ecosystems. PMID- 22827130 TI - Suppressing antagonistic bioengineering feedbacks doubles restoration success. AB - In a seagrass restoration project, we explored the potential for enhancing the restoration process by excluding antagonistic engineering interactions (i.e., biomechanical warfare) between two ecosystem engineers: the bioturbating lugworm Arenicola marina and the sediment-stabilizing seagrass Zostera noltii Hornem. Applying a shell layer underneath half of our seagrass transplants successfully reduced adult lugworm density by over 80% and reduced lugworm-induced microtopography (a proxy for lugworm disturbance) at the wave-sheltered site. At the wave-exposed site adult lugworm densities and microtopography were already lower than at the sheltered site but were further reduced in the shell-treated units. Excluding lugworms and their bioengineering effects corresponded well with a strongly enhanced seagrass growth at the wave-sheltered site, which was absent at the exposed site. Enhanced seagrass growth in the present study was fully assigned to the removal of lugworms' negative engineering effects and not to any (indirect) evolving effects such as an altered biogeochemistry or sediment stabilizing effects by the shell layer. The context-dependency implies that seagrass establishment at the exposed site is not constrained by negative ecosystem-engineering interactions only, but also by overriding physical stresses causing poor growth conditions. Present findings underline that, in addition to recent emphasis on considering positive (facilitating) interactions in ecological theory and practice, it is equally important to consider negative engineering interactions between ecosystem-engineering species. Removal of such negative interactions between ecosystem-engineering species can give a head start to the target species at the initial establishment phase, when positive engineering feedbacks by the target species on itself are still lacking. Though our study was carried out in a marine environment with variable levels of wave disturbance, similar principles may be expected to apply to other ecosystems that are inhabited by ecosystem engineers. PMID- 22827131 TI - Marine reserves reduce risk of climate-driven phase shift by reinstating size- and habitat-specific trophic interactions. AB - Spatial closures in the marine environment are widely accepted as effective conservation and fisheries management tools. Given increasing human-derived stressors acting on marine ecosystems, the need for such effective action is urgently clear. Here we explore mechanisms underlying the utility of marine reserves to reinstate trophic dynamics and to increase resilience of kelp beds against climate-driven phase shift to sea urchin barrens on the rapidly warming Tasmanian east coast. Tethering and tagging experiments were used to examine size and shelter-specific survival of the range-extending sea urchin Centrostephanus rodgersii (Diadematidae) translocated to reefs inside and outside no-take Tasmanian marine reserves. Results show that survival rates of C. rodgersii exposed on flat reef substratum by tethering were approximately seven times (small urchins 10.1 times; large urchins 6.1 times) lower on protected reef within marine reserve boundaries (high abundance of large predatory-capable lobsters) compared to fished reef (large predatory lobsters absent). When able to seek crevice shelter, tag-resighting models estimated that mortality rates of C. rodgersii were lower overall but remained 3.3 times (small urchins 2.1 times; large urchins 6.4 times) higher in the presence of large lobsters inside marine reserves, with higher survival of small urchins owing to greater access to crevices relative to large urchins. Indeed, shelter was 6.3 times and 3.1 times more important to survival of small and large urchins, respectively, on reserved relative to fished reef. Experimental results corroborate with surveys throughout the range extension region, showing greater occurrence of overgrazing on high relief rocky habitats where shelter for C. rodgersii is readily available. This shows that ecosystem impacts mediated by range extension of such habitat modifying organisms will be heterogeneous in space, and that marine systems with a more natural complement of large and thus functional predators, as achievable within no-take reserves, will minimize local risk of phase shifts by reinstating size and habitat-specific predator-prey dynamics eroded by fishing. Importantly, our findings also highlight the crucial need to account for the influence of size dynamics and habitat complexity on rates of key predator-prey interactions when managing expectations of ecosystem-level responses within marine reserve boundaries. PMID- 22827132 TI - Forest conservation delivers highly variable coral reef conservation outcomes. AB - Coral reefs are threatened by human activities on both the land (e.g., deforestation) and the sea (e.g., overfishing). Most conservation planning for coral reefs focuses on removing threats in the sea, neglecting management actions on the land. A more integrated approach to coral reef conservation, inclusive of land-sea connections, requires an understanding of how and where terrestrial conservation actions influence reefs. We address this by developing a land-sea planning approach to inform fine-scale spatial management decisions and test it in Fiji. Our aim is to determine where the protection of forest can deliver the greatest return on investment for coral reef ecosystems. To assess the benefits of conservation to coral reefs, we estimate their relative condition as influenced by watershed-based pollution and fishing. We calculate the cost effectiveness of protecting forest and find that investments deliver rapidly diminishing returns for improvements to relative reef condition. For example, protecting 2% of forest in one area is almost 500 times more beneficial than protecting 2% in another area, making prioritization essential. For the scenarios evaluated, relative coral reef condition could be improved by 8-58% if all remnant forest in Fiji were protected rather than deforested. Finally, we determine the priority of each coral reef for implementing a marine protected area when all remnant forest is protected for conservation. The general results will support decisions made by the Fiji Protected Area Committee as they establish a national protected area network that aims to protect 20% of the land and 30% of the inshore waters by 2020. Although challenges remain, we can inform conservation decisions around the globe by tackling the complex issues relevant to integrated land-sea planning. PMID- 22827133 TI - Open and closed seascapes: where does habitat patchiness create populations with high fractions of self-recruitment? AB - Which populations are replenished primarily by immigrants (open) and which by local production (closed) remains an important question for management with implications for response to exploitation, protection, and disturbance. However, we lack methods for predicting population openness. Here, we develop a model for openness and show that considering habitat isolation explains the existence of surprisingly closed populations in high-dispersal species, including many marine organisms. Relatively closed populations are expected when patch spacing is more than twice the standard deviation of a species'. dispersal kernel. In addition, natural scales of habitat patchiness on coral reefs are sufficient to create both largely open and largely closed populations. Contrary to some previous interpretations, largely closed marine populations do not require mean dispersal distances that are unusually short, even for species with relatively long pelagic larval durations. We predict that habitat patchiness has strong control over population openness for many marine and terrestrial species with a highly dispersive life stage and relatively sedentary adults. This information can be used to make initial predictions about where populations will be more or less resilient to local exploitation and disturbance. PMID- 22827134 TI - Concentrating anthropogenic disturbance to balance ecological and economic values: applications to forest management. AB - To maintain healthy ecosystems, natural-disturbance-based management aims to minimize differences between unmanaged and managed landscapes. Two related approaches may help accomplish this goal, either applied together or in isolation: (1) concentrating anthropogenic disturbance through zoning (with protected areas and intensive management); and (2) emulating natural disturbances. The purpose of this paper is to examine the effects of these two approaches, applied both in isolation and in combination, on the structure of the forest landscape. To do so, we use a spatially explicit landscape simulation model on a large fire-dominated landscape in eastern Canada. Specifically, we examine the effects of (1) increasing the maximum size of logged stands (cutblocks) to better emulate the full range of fire sizes in a fire-dominated landscape, (2) increasing protected areas, and (3) adding aggregated or dispersed intensive wood production areas to the landscape in addition to protected areas (triad management). We focus on maximizing the amount and minimizing the fragmentation of old-growth forest and on reducing road construction. Increasing maximum cutblock size and adding protected areas led to reduced road construction, while the latter also resulted in less fragmentation and more old growth. Although protected areas led to reduced harvest volume, the addition of an intensive production zone (triad management) counterbalanced this loss and resulted in more old growth than equivalent scenarios with protected areas but no intensive production zone. However, we found no differences between aggregated and dispersed intensive wood production. Our results imply that differences between unmanaged and managed landscapes can be reduced by concentrating logging efforts through a combination of protected areas and intensive wood production, and by creating some larger cutblocks. We conclude that the forest industry and regulators should therefore seek to increase protected areas through triad management and consider increasing maximum cutblock size. These results add to a growing body of literature indicating that intensive management on a small part of the landscape may be better than less intensive management spread out over a much larger part of the landscape, whether this is in the context of forestry, agriculture, or urban development. PMID- 22827135 TI - Comparing modern and presettlement forest dynamics of a subboreal wilderness: does spruce budworm enhance fire risk? AB - Insect disturbance is often thought to increase fire risk through enhanced fuel loadings, particularly in coniferous forest ecosystems. Yet insect disturbances also affect successional pathways and landscape structure that interact with fire disturbances (and vice-versa) over longer time scales. We applied a landscape succession and disturbance model (LANDIS-II) to evaluate the relative strength of interactions between spruce budworm (Choristoneura fumiferana) outbreaks and fire disturbances in the Boundary Waters Canoe Area (BWCA) in northern Minnesota (USA). Disturbance interactions were evaluated for two different scenarios: presettlement forests and fire regimes vs. contemporary forests and fire regimes. Forest composition under the contemporary scenario trended toward mixtures of deciduous species (primarily Betula papyrifera and Populus spp.) and shade tolerant conifers (Picea mariana, Abies balsamea, Thuja occidentalis), with disturbances dominated by a combination of budworm defoliation and high-severity fires. The presettlement scenario retained comparatively more "big pines" (i.e., Pinus strobus, P. resinosa) and tamarack (L. laricina), and experienced less budworm disturbance and a comparatively less-severe fire regime. Spruce budworm disturbance decreased area burned and fire severity under both scenarios when averaged across the entire 300-year simulations. Contrary to past research, area burned and fire severity during outbreak decades were each similar to that observed in non-outbreak decades. Our analyses suggest budworm disturbances within forests of the BWCA have a comparatively weak effect on long-term forest composition due to a combination of characteristics. These include strict host specificity, fine-scaled patchiness created by defoliation damage, and advance regeneration of its primary host, balsam fir (A. balsamea) that allows its host to persist despite repeated disturbances. Understanding the nature of the three way interaction between budworm, fire, and composition has important ramifications for both fire mitigation strategies and ecosystem restoration initiatives. We conclude that budworm disturbance can partially mitigate long term future fire risk by periodically reducing live ladder fuel within the mixed forest types of the BWCA but will do little to reverse the compositional trends caused in part by reduced fire rotations. PMID- 22827136 TI - Carbon stocks across a chronosequence of thinned and unmanaged red pine (Pinus resinosa) stands. AB - Forests function as a major global C sink, and forest management strategies that maximize C stocks offer one possible means of mitigating the impacts of increasing anthropogenic CO2 emissions. We studied the effects of thinning, a common management technique in many forest types, on age-related trends in C stocks using a chronosequence of thinned and unmanaged red pine (Pinus resinosa) stands ranging from 9 to 306 years old. Live tree C stocks increased with age to a maximum near the middle of the chronosequence in unmanaged stands, and increased across the entire chronosequence in thinned stands. C in live understory vegetation and C in the mineral soil each declined rapidly with age in young stands but changed relatively little in middle-aged to older stands regardless of management. Forest floor C stocks increased with age in unmanaged stands, but forest floor C decreased with age after the onset of thinning around age 40 in thinned stands. Deadwood C was highly variable, but decreased with age in thinned stands. Total ecosystem C increased with stand age until approaching an asymptote around age 150. The increase in total ecosystem C was paralleled by an age-related increase in total aboveground C, but relatively little change in total belowground C. Thinning had surprisingly little impact on total ecosystem C stocks, but it did modestly alter age-related trends in total ecosystem C allocation between aboveground and belowground pools. In addition to characterizing the subtle differences in C dynamics between thinned and unmanaged stands, these results suggest that C accrual in red pine stands continues well beyond the 60-100 year management rotations typical for this system. Management plans that incorporate longer rotations and thinning in some stands could play an important role in maximizing C stocks in red pine forests while meeting other objectives including timber extraction, biodiversity conservation, restoration, and fuel reduction goals. PMID- 22827137 TI - High richness and dense seeding enhance grassland restoration establishment but have little effect on drought response. AB - Restorations commonly utilize seed addition to formerly arable lands where the development of native plant communities is severely dispersal limited. However, variation in seed addition practices may profoundly affect restoration outcomes. Theory and observations predict that species-rich seed mixtures and seeding at high densities should enhance native plant community establishment, minimize exotic species cover, and may promote resistance and resilience to, and recovery from, environmental perturbations. We studied the post-seeding establishment of native plant communities in large grassland restoration plots, which were sown at two densities crossed with two levels of species richness on formerly arable land in Nebraska, USA, and their responses to drought. To evaluate drought resistance, recovery, and resilience of restored plant communities, we erected rainfall manipulation structures and tracked the response of seeded species cover and total plant biomass during experimental drought relative to controls and in the post-drought growing season. High seed richness and high-density seeding treatments resulted in greater richness and cover of native, seeded species per 0.5 m2 compared to low-richness and low-density treatments. Cover differences in response to seed mixture richness were driven by native forbs. Richness and cover of exotic species were lowest in high-richness and high-density treatments. We found little evidence of differential drought resistance, recovery, and resilience among seeding treatments. Increases in exotic species across years were restricted to drought subplots, and were not affected by seeding treatments. Grassland restoration was generally enhanced and exotic cover reduced both by the use of high-richness seed mixtures and high-density seeding. Given the lack of restoration treatment effects on the resistance, recovery, or resilience of seeded species exposed to drought, and the increases in exotic species following drought, other forms of active management may be needed to produce restored plant communities that are robust to climate change. PMID- 22827138 TI - Long-term population dynamics of seeded plants in invaded grasslands. AB - In recent decades, dozens of studies have involved attempts to introduce native and desirable nonnative plant species into grasslands dominated by invasive weeds. The newly introduced plants have proved capable of establishing, but because they are rarely monitored for more than four years, it is unknown if they have a high likelihood of persisting and suppressing invaders for the long-term. Beyond invaded grasslands, this lack of long-term monitoring is a general problem plaguing efforts to reintroduce a range of taxa into a range of ecosystems. We introduced species from seed and then periodically measured plant abundances for nine years at one site and 15 years at a second site. To our knowledge, our 15 year data are the longest to date from a seeding experiment in invaded, never cultivated grassland. At one site, three seeded grasses maintained high densities for three or more years, but then all or nearly all individuals died. At the second site, one grass performed similarly, but two other grasses proliferated and at least one greatly suppressed the dominant invader (Centaurea maculosa). In one study, our point estimate suggests that the seeded grass Thinopyrum intermedium reduced C. maculosa biomass by 93% 15 years after seeding. In some cases, data from three and fewer years after seeding falsely suggested that seeded species were capable of persisting within the invaded grassland. In other cases, data from as late as nine years after seeding falsely suggested seeded populations would not become large enough to suppress the invader. These results show that seeded species sometimes persist and suppress invaders for long periods, but short-term data cannot predict if, when, or where this will occur. Because short-term data are not predictive of long-term seeded species performances, additional long-term data are needed to identify effective practices, traits, and species for revegetating invaded grasslands. PMID- 22827139 TI - Canopy and leaf composition drive patterns of nutrient release from pruning residues in a coffee agroforest. AB - In a coffee agroforest, the crop is cultivated under the shade of fruit-bearing and nitrogen (N)-fixing trees. These trees are periodically pruned to promote flowering and fruiting as well as to make nutrients stored in tree biomass available to plants. We investigated the effect of canopy composition and substrate quality on decomposition rates and patterns of nutrient release from pruning residues in a coffee agroforest located in Costa Rica's Central Valley. Initial phosphorus (P) release was enhanced under a canopy composed solely of N fixing, Erythrina poeppigiana compared to a mixed canopy of Erythrina and Musa acuminata (banana). Both initial and final N release were similar under the two canopy types. However, after five months of decomposition, a higher proportion of initial N had been released under the single canopy. Although patterns of decomposition and nutrient release were not predicted by initial substrate quality, mass loss in leaf mixtures rates were well predicted by mean mass loss of their component species. This study identifies specific pruning regimes that may regulate N and P release during crucial growth periods, and it suggests that strategic pruning can enhance nutrient availability. For example, during the onset of rapid fruit growth, a two-species mixture may release more P than a three-species mixture. However, by the time of the harvest, the two- and three species mixtures have released roughly the same amount of N and P. These nutrients do not always follow the same pattern, as N release can be maximized in single-species substrates, while P release is often facilitated in species mixtures. Our study indicates the importance of management practices in mediating patterns of nutrient release. Future research should investigate how canopy composition and farm management can also mediate on-farm nutrient losses. PMID- 22827140 TI - Evaluating greenhouse gas emissions inventories for agricultural burning using satellite observations of active fires. AB - Fires in agricultural ecosystems emit greenhouse gases and aerosols that influence climate on multiple spatial and temporal scales. Annex 1 countries of the United Nations Framework Convention on Climate Change (UNFCCC), many of which ratified the Kyoto Protocol, are required to report emissions of CH4 and N2O from these fires annually. In this study, we evaluated several aspects of this reporting system, including the optimality of the crops targeted by the UNFCCC globally and within Annex 1 countries, and the consistency of emissions inventories among different countries. We also evaluated the success of individual countries in capturing interannual variability and long-term trends in agricultural fire activity. In our approach, we combined global high-resolution maps of crop harvest area and production, derived from satellite maps and ground based census data, with Terra and Aqua Moderate Resolution Imaging Spectroradiometer (MODIS) measurements of active fires. At a global scale, we found that adding ground nuts (e.g., peanuts), cocoa, cotton and oil palm, and removing potato, oats, rye, and pulse other from the list of 14 crops targeted by the UNFCCC increased the percentage of active fires covered by the reporting system by 9%. Optimization led to a different recommended list for Annex 1 countries, requiring the addition of sunflower, cotton, rapeseed, and alfalfa and the removal of beans, sugarcane, pulse others, and tuber-root others. Extending emissions reporting to all Annex 1 countries (from the current set of 19 countries) would increase the efficacy of the reporting system from 6% to 15%, and further including several non-Annex 1 countries (Argentina, Brazil, China, India, Indonesia, Thailand, Kazakhstan, Mexico, and Nigeria) would capture over 55% of active fires in croplands worldwide. Analyses of interannual trends from the United States and Australia showed the importance of both intensity of fire use and crop production in controlling year-to-year variations in agricultural fire emissions. Remote sensing provides an effective means for evaluating some aspects of the current UNFCCC emissions reporting system; and, if combined with census data, field experiments and expert opinion, has the potential to improve the robustness of the next generation inventory system. PMID- 22827141 TI - Projected vegetation changes for the American Southwest: combined dynamic modeling and bioclimatic-envelope approach. AB - This study focuses on potential impacts of 21st century climate change on vegetation in the Southwest United States, based on debiased and interpolated climate projections from 17 global climate models used in the Fourth Assessment Report of the Intergovernmental Panel on Climate Change. Among these models a warming trend is universal, but projected changes in precipitation vary in sign and magnitude. Two independent methods are applied: a dynamic global vegetation model to assess changes in plant functional types and bioclimatic envelope modeling to assess changes in individual tree and shrub species and biodiversity. The former approach investigates broad responses of plant functional types to climate change, while considering competition, disturbances, and carbon fertilization, while the latter approach focuses on the response of individual plant species, and net biodiversity, to climate change. The dynamic model simulates a region-wide reduction in vegetation cover during the 21st century, with a partial replacement of evergreen trees with grasses in the mountains of Colorado and Utah, except at the highest elevations, where tree cover increases. Across southern Arizona, central New Mexico, and eastern Colorado, grass cover declines, in some cases abruptly. Due to the prevalent warming trend among all 17 climate models, vegetation cover declines in the 21st century, with the greatest vegetation losses associated with models that project a drying trend. The inclusion of the carbon fertilization effect largely ameliorates the projected vegetation loss. Based on bioclimatic envelope modeling for the 21st century, the number of tree and shrub species that are expected to experience robust declines in range likely outweighs the number of species that are expected to expand in range. Dramatic shifts in plant species richness are projected, with declines in the high-elevation evergreen forests, increases in the eastern New Mexico prairies, and a northward shift of the Sonoran Desert biodiversity maximum. PMID- 22827142 TI - Estimating population impacts via dynamic occupancy analysis of Before-After Control-Impact studies. AB - Estimating environmental impacts on populations is one of the main goals of wildlife monitoring programs, which are often conducted in conjunction with management actions or following natural disturbances. In this study we investigate the statistical power of dynamic occupancy models to detect changes in local survival and colonization from detection-nondetection data, while accounting for imperfect detection probability, in a Before-After Control-Impact (BACI) framework. We simulated impacts on local survival and/or detection probabilities, and asked questions related to: (1) costs and benefits of different analysis models, (2) confounding changes in detection with changes in local survival, (3) sampling design trade-offs, and (4) species with low vs. high rates of turnover. Estimating seasonal effects on local survival and colonization, as opposed to estimating Before-After effects, had little effect on the power to detect changes in local survival. Estimating a parameter that accounted for pretreatment differences in local survival between Control and Impact sites decreased power by 50%, but it was critical to include when such differences existed. When the experimental treatment had a negative impact on species detectability but analysis assumed constant detection, the Type I error rates were dramatically inflated (0.20 0.33). In general, there was low power (< 0.5) to detect a 50% decrease in local survival for all combinations of sites (N = 50 vs. 100), seasons sampled (8 vs. 12), and visits per site per season (4 vs. 6). Unbalanced designs performed worse than balanced designs, with the exception of the case of treatments being implemented in different seasons at different sites. Adding more control sites improved the ability to detect changes in local survival. Surveying more seasons after impact resulted in modest power gains, but at least three seasons before impact were required to successfully implement BACI occupancy studies. Turnover rates had a low impact on power. Occupancy studies conducted in a BACI design offer the opportunity to detect environmental impacts on wildlife populations without the costs of intensive studies. However, given the low power to detect small changes (20%) in local survival, these studies should be used when researchers are confident that major treatment impacts will occur or very large sample sizes are obtainable. PMID- 22827143 TI - An endowed chair in physician assistant studies. PMID- 22827144 TI - Evidence-based medicine: its roots and its fruits revisited. PMID- 22827145 TI - Attitudes toward interprofessional education: comparing physician assistant and other health care professions students. AB - PURPOSE: Since the release of the 1988 World Health Organization report on the need for interprofessional education (IPE) programs, various forms of IPE curricula have been implemented within institutions of higher education. The purpose of this paper is to describe results of a study using the Readiness for Interprofessional Learning Scale (RIPLS) to compare physician assistant (PA) students with other health professions students. METHODS: The RIPLS survey was completed by 158 health professions graduate students, including 71 PA students, at a small northeastern university in the fall of 2010. Students were enrolled in either counseling psychology, occupational therapy, physical therapy, or PA studies. Students completed the RIPLS survey, demographic questions, and a question regarding experience with the health care environment. RESULTS: PA students scored significantly lower on three of the four subscales of the RIPLS survey, as well as lower in total score. Females of all health professions scored significantly higher on the RIPLS total score and on the Teamwork and Collaboration subscale than did males. Students with prior exposure to the health care system as a patient or as an immediate family member of a patient scored significantly higher on the Negative Professional Identity subscale than did students without such exposure. CONCLUSIONS: Results indicate that PA students may value interprofessional collaboration less than other health professions students. Also, there may be gender and experiential differences in readiness for interprofessional learning. These findings may affect the design of IPE experiences and support integration of interprofessional experiences into PA education. PMID- 22827146 TI - Benchmarking the scholarly productivity of physician assistant educators: an update. AB - PURPOSE: Success in scholarship has long challenged physician assistant (PA) educators, most of whom enter academia with little experience in research or writing. Since most PA programs grant a professional graduate degree, and expectations for PA faculty typically focus on teaching and service rather than research, it is reasonable for promotion and tenure decisions to be based on comparisons from within the PA education realm. Providing such benchmarks is the focus of this report. Predictors of successful publication and trends over time are also explored briefly. METHODS: De-identified data from the 2010 Faculty Survey were obtained from the Physician Assistant Education Association (PAEA), including basic demographics, faculty rank and program role, degree, and number of peer-reviewed publications. PAEA distributed the online survey in March 2010 to all faculty associated with member programs. The response rate was 35%, N = 425. SPSS version 19 was used for data analysis. RESULTS: Respondents were 58.1% female. The mean number of publications reported by respondents over their entire career was 4.2, and over the last 3 years was 1.7. The respective median numbers of publications were one and zero. Logistic regression analysis identified three significant predictors of publication success: number of years in PA education, previous publications, and highest degree attained. CONCLUSIONS: This study seeks to provide rational benchmarks for PA program faculty seeking promotion or tenure. Previous publications and highest degree attained are key factors predicting successful publication. There is a continuing need for faculty development activities to help PA educators publish successfully. PMID- 22827147 TI - The relationship between faculty characteristics and the implementation of cultural competency training in physician assistant education. AB - PURPOSE: Cultural competency training has been present in academic medicine for many years, but interest resurfaced when the Institute of Medicine released a report on health care disparity and called for curricular improvement in medical education to eliminate this disparity. Unfortunately, many limitations in the implementation and assessment of the training have emerged, and it has been demonstrated that cultural competency training has not been uniform across medical education or physician assistant education. METHODS: A national online survey of faculty members at 141 accredited PA programs was conducted. The study addressed the relationship of specific faculty characteristics with the implementation of cultural elements in cultural competency training in the didactic phase of PA programs. RESULTS: Results of the study demonstrated that disability was excluded most frequently in the implementation process. In addition, a significant relationship between a lack of previous cultural competency training by faculty members and the implementation of less cultural elements was demonstrated. CONCLUSION: These findings support the need for a standardized definition of culture and greater emphasis on cultural competency training for faculty. PMID- 22827148 TI - Physician assistant student exposure to the long-term care setting by working with a consultant pharmacist. AB - PURPOSE: Physician assistant (PA) students need exposure to a wide range of clinical settings including long-term care (LTC); however, finding consistent educational LTC opportunities is difficult. This article describes a unique, replicable, educational opportunity for PA students to get exposure to the LTC setting by working with a consultant pharmacist. METHODS: Pairs of students spent 4 hours with the pharmacist, reviewing and copresenting two to three patient charts. Students completed a questionnaire that asked them to describe what they had learned. RESULTS: Students indicated they had an increased appreciation of having strong knowledge of medication prescribing and monitoring and avoiding polypharmacy, as well as disease prevention, the importance of interprofessional care, and preventing medication errors. CONCLUSION: Although LTC settings vary, consultant pharmacists may provide a reliable gateway to the LTC setting for PA students. Gains in skills were not directly measured; however, students reported an increased appreciation for aspects of geriatric care related to all six of the competencies outlined in Competencies for the Physician Assistant Profession. PMID- 22827149 TI - Information literacy needs in graduate-level health sciences education. AB - PURPOSE: To determine whether incorporating information literacy education through workshops led by library faculty improves students' information literacy skills. METHODS: A series of information literacy initiatives were incorporated into the curriculum of a physician assistant program. Initiatives included two library workshops, class instruction, and a research paper. Assessment included subjective and objective measures of students' information literacy skills and research competencies. RESULTS: Students' ratings of their skills were significantly higher on the postmeasure (t37 = 2.85, P = .007). The objective measures of these skills revealed an increase from 25% to 65% of the class scoring above 70% correct. Class assignments also revealed an improvement from 10% of the class citing and referencing material correctly at the beginning of the initiative to 80% at the end of the initiative. CONCLUSION: Engaging academic library faculty and providing students with guided instruction has a significant positive effect on objective as well as subjective measures of students' skills. PMID- 22827150 TI - Challenges and innovations in bioethics instruction for physician assistant programs. AB - Ethics spans all of the medical specialties and is constantly evolving as new medical technologies develop. As PAs become involved in Institutional Ethics Committees (IEC) and related settings, ethics instruction becomes an increasingly important component of their education. Students need the tools to face ethical dilemmas in order to provide the best possible care to their patients across the life span. Furthermore, PAs have a clear role and responsibility in end-of-life and palliative care. Ethics education can be most effective when incorporated into both the preclinical and clinical phases of instruction. There are many ways in which this can be accomplished so that future PAs are equipped with the necessary tools, skills, and information. PMID- 22827151 TI - The elusive role of the physician assistant program medical director. PMID- 22827152 TI - The art of medicine in poetry and prose: the work of Donald Hall. PMID- 22827153 TI - Factoring leadership into the admissions process. PMID- 22827154 TI - The use of videoconferencing for clinical site evaluations. PMID- 22827155 TI - Spontaneous and posed emotional facial expressions following severe traumatic brain injury. AB - AIM: The current study aimed to test the intensity of spontaneous emotional expressions and the accuracy of posed emotional expressions in patients with severe traumatic brain injury (TBI). METHOD: Twenty-three participants with TBI and 27 matched control participants were asked to relate personal angry, happy, and sad events (spontaneous expressivity) and to pose angry, happy, and sad expressions in response to a photo or word cue (posed expressivity). Their emotional facial expressions were coded via judges' ratings. RESULTS: Participants with TBI had less intense sad expressions when relating a sad event than did control participants. No group difference emerged in the happy and angry events, the latter possibly due to differentially low interrater reliability for anger ratings. Participants with TBI were impaired in their ability to pose sad emotions. CONCLUSIONS: These preliminary findings suggest that patients with TBI are impaired at expressing sad expressions either spontaneously or deliberately. This may reflect difficulties in the initiation or suppression of facial expression as well as an impaired semantic knowledge of the facial configuration of sad expression. PMID- 22827157 TI - Laser photocoagulation in intermediate uveitis associated with retinoschisis. AB - PURPOSE: To describe cases of pars planitis associated with retinoschisis, in which laser photocoagulation was carried out. METHODS: Retrospective review. RESULTS: Three pars planitis cases were associated with retinoschisis and underwent laser photocoagulation. All cases were idiopathic. Retinoschisis was located in the inferior retinal quadrants in all cases and all of them were in bullous formation. None of the cases developed retinal detachment. CONCLUSION: As well as posterior vitreous detachment, or peripheral retinal tears, retinoschisis may accompany pars planitis. Laser photocoagulation of the pars plana is effective in these cases both as a treatment and to prevent sight-threatening complications like retinal detachment. PMID- 22827158 TI - Fluorescein analogues as photoremovable protecting groups absorbing at ~520 nm. AB - A new photoremovable protecting group, (6-hydroxy-3-oxo-3H-xanthen-9-yl)methyl (1), with a molar absorption coefficient epsilon of ~4 * 10(4) m(-1) cm(-1) at ~520 nm for the release of carboxylates or phosphates is reported. Three derivatives of 1 (diethyl phosphate, acetate, and bromide) were isolated as complexes with DDQ and shown to release the ligands with quantum yields <=2.4% in aqueous solution. PMID- 22827159 TI - Development of a CrN/Cu nanocomposite coating on titanium-modified stainless steel for antibacterial activity against Pseudomonas aeruginosa. AB - A relatively simple method was developed to fabricate CrN/Cu nanocomposite coatings using pulsed DC magnetron sputtering for application in antibacterial activity. These nanocomposite coatings were applied on titanium (Ti)-modified stainless steel substrata (D-9 alloy) and the antibacterial activity of these coating with respect to the Gram-negative bacterium Pseudomonas aeruginosa was investigated qualitatively and quantitatively. Scanning electron microscopy, epifluorescence microscope analyses, and total viable counts confirmed that inclusion of copper in the CrN/Cu nanocomposite coatings provided antibacterial activity against P. aeruginosa. The quantitative examination of the bacterial activity of P. aeruginosa was estimated by the survival ratio as calculated from the number of viable cells which formed colonies on nutrient agar plates. PMID- 22827160 TI - Concentration of trichloroethylene in breast milk and household water from Nogales, Arizona. AB - The United States Environmental Protection Agency has identified quantification of trichloroethylene (TCE), an industrial solvent, in breast milk as a high priority need for risk assessment. Water and milk samples were collected from 20 households by a lactation consultant in Nogales, Arizona. Separate water samples (including tap, bottled, and vending machine) were collected for all household uses: drinking, bathing, cooking, and laundry. A risk factor questionnaire was administered. Liquid-liquid extraction with diethyl ether was followed by GC-MS for TCE quantification in water. Breast milk underwent homogenization, lipid hydrolysis, and centrifugation prior to extraction. The limit of detection was 1.5 ng/mL. TCE was detected in 7 of 20 mothers' breast milk samples. The maximum concentration was 6 ng/mL. TCE concentration in breast milk was significantly correlated with the concentration in water used for bathing (rho = 0.59, p = 0.008). Detection of TCE in breast milk was more likely if the infant had a body mass index <14 (RR = 5.2, p = 0.02). Based on average breast milk consumption, TCE intake for 5% of the infants may exceed the proposed U.S. EPA Reference Dose. Results of this exploratory study warrant more in depth studies to understand risk of TCE exposures from breast milk intake. PMID- 22827161 TI - Shape and size of highly concentrated micelles in CTAB/NaSal solutions by Small Angle Neutron Scattering (SANS). AB - Highly concentrated micelles in CTAB/NaSal solutions with a fixed salt/surfactant ratio of 0.6 have been studied using Small Angle Neutron Scattering (SANS) as a function of temperature and concentration. A worm-like chain model analysis of the SANS data using a combination of a cylindrical form factors for the polydisperse micellar length, circular cross-sectional radius with Gaussian polydispersity, and the structure factor based on a random phase approximation (RPA) suggests that these micelle solutions have a worm-like micellar structure that is independent of the concentration and temperature. The size of the micelle decreases monotonically with increasing temperature and increases with concentration. These observations indicate that large micelles are formed at low temperature and begin to break up to form smaller micelles with increasing temperature. PMID- 22827162 TI - In vivo encapsulation of nucleic acids using an engineered nonviral protein capsid. AB - In Nature, protein capsids function as molecular containers for a wide variety of molecular cargoes. Such containers have great potential for applications in nanotechnology, which often require encapsulation of non-native guest molecules. Charge complementarity represents a potentially powerful strategy for engineering novel encapsulation systems. In an effort to explore the generality of this approach, we engineered a nonviral, 60-subunit capsid, lumazine synthase from Aquifex aeolicus (AaLS), to act as a container for nucleic acid. Four mutations were introduced per subunit to increase the positive charge at the inner surface of the capsid. Characterization of the mutant (AaLS-pos) revealed that the positive charges lead to the uptake of cellular RNA during production and assembly of the capsid in vivo. Surprisingly, AaLS-pos capsids were found to be enriched with RNA molecules approximately 200-350 bases in length, suggesting that this simple charge complementarity approach to RNA encapsulation leads to both high affinity and a degree of selectivity. The ability to control loading of RNA by tuning the charge at the inner surface of a protein capsid could illuminate aspects of genome recognition by viruses and pave the way for the development of improved RNA delivery systems. PMID- 22827163 TI - The Triform algorithm: improved sensitivity and specificity in ChIP-Seq peak finding. AB - BACKGROUND: Chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) is the most frequently used method to identify the binding sites of transcription factors. Active binding sites can be seen as peaks in enrichment profiles when the sequencing reads are mapped to a reference genome. However, the profiles are normally noisy, making it challenging to identify all significantly enriched regions in a reliable way and with an acceptable false discovery rate. RESULTS: We present the Triform algorithm, an improved approach to automatic peak finding in ChIP-Seq enrichment profiles for transcription factors. The method uses model-free statistics to identify peak-like distributions of sequencing reads, taking advantage of improved peak definition in combination with known characteristics of ChIP-Seq data. CONCLUSIONS: Triform outperforms several existing methods in the identification of representative peak profiles in curated benchmark data sets. We also show that Triform in many cases is able to identify peaks that are more consistent with biological function, compared with other methods. Finally, we show that Triform can be used to generate novel information on transcription factor binding in repeat regions, which represents a particular challenge in many ChIP-Seq experiments. The Triform algorithm has been implemented in R, and is available via http://tare.medisin.ntnu.no/triform. PMID- 22827164 TI - The content of high-intensity sweeteners in different categories of foods available on the Polish market. AB - The objective of this study was to measure the concentrations of nine high intensity sweeteners (acesulfame-K, aspartame, alitame, cyclamate, dulcin, neohesperidin DC, neotame, saccharin and sucralose) in different categories of food available on the Polish market. Over 170 samples of different brands of beverages, yoghurts, fruit preparations, vegetable preserves and fish products were analysed using an analytical procedure based on SPE and LC/MS. The results indicated that foodstuffs under the study generally comply with European Union legislation in terms of sweetener content. However, a few cases of food product mislabelling were detected, i.e. the use of cyclamate for non-approved applications. PMID- 22827166 TI - Morphology and identification of first instars of the European and Mediterranean blowflies of forensic importance. Part I: Chrysomyinae. AB - Light microscopy photographs, line illustrations and scanning electron micrographs are provided for first instars of Chrysomya albiceps (Wiedemann), Chrysomya megacephala (Fabricius) and Protophormia terraenovae (Robineau Desvoidy) (all: Diptera: Calliphoridae). The following morphological structures are documented: pseudocephalon; antennal complex; maxillary palpus; facial mask; thoracic and abdominal spinulation; spiracular field; posterior spiracles, and cephaloskeleton. New diagnostic features of the cephaloskeleton and the spinulation of abdominal segments are described. Verification of earlier descriptions revealed major discrepancies among published data. The present results allow for the clarification, correction and, especially, complementation of existing information provided by numerous authors. Finally, an identification key for first-instar larvae of European and Mediterranean Chrysomyinae of forensic importance is presented. PMID- 22827167 TI - Breast size increment during pregnancy and breastfeeding in mothers with polycystic ovary syndrome: a follow-up study of a randomised controlled trial on metformin versus placebo. AB - OBJECTIVE: To study the significance of breast size increment in pregnancy, and the impact of metformin during pregnancy on breastfeeding in women with polycystic ovary syndrome (PCOS). DESIGN: A follow-up study of a randomised controlled trial (the PregMet study). SETTING: Eleven secondary care centres. POPULATION: Women with PCOS during pregnancy and postpartum. METHODS: Women with PCOS were randomised to treatment with metformin or placebo from the first trimester to delivery. Questionnaires were sent to 240 participants 1 year postpartum: 186 responded. MAIN OUTCOME MEASURES: Pre-pregnancy and late pregnancy brassiere size and breastfeeding patterns were registered, and androgen levels were measured in the mothers. RESULTS: No difference in breast size increment and breastfeeding were found between the placebo and metformin groups. Breast size increment correlated positively with the duration of both exclusive and partial breastfeeding, whereas body mass index (BMI) correlated negatively with the duration of partial breastfeeding. Dehydroepiandrostenedione-sulphate (DHEAS), testosterone and free testosterone index (FTI) in pregnancy did not correlate with breast size increment or duration of breastfeeding. Women with no change in breast size were more obese, had higher blood pressure, serum triglycerides and fasting insulin levels, and had a shorter duration of breastfeeding compared with those with breast size increment. CONCLUSIONS: Metformin and androgens had no impact on breastfeeding. Women with PCOS who had no breast size increment in pregnancy seem to be more metabolically disturbed and less able to breastfeed. PMID- 22827168 TI - 'Candidatus Halomonas phosphatis', a novel polyphosphate-accumulating organism in full-scale enhanced biological phosphorus removal plants. AB - Microautoradiography combined with fluorescence in situ hybridization (MAR-FISH) was used to screen for potential polyphosphate-accumulating organisms (PAOs) in full-scale enhanced biological phosphorus removal (EBPR) plants. Clone library analyses and application of MAR-FISH using newly designed probes revealed that small rods related to uncultured Halomonas within the gammaproteobacterial family Halomonadaceae were actively involved in uptake of orthophosphate. Although deeply branched in the Gammaproteobacteria, they were not targeted by the gammaproteobacterial probe (GAM42a). A part of them were also not targeted with the general bacterial probes (EUBmix). They could take up short-chain fatty acids (e.g. acetate and propionate) and ethanol under both anaerobic and aerobic conditions. Polyhydroxyalkanoate storage was observed under anaerobic conditions. There was no indication of a denitrifying capability. A survey of the occurrence of these Halomonas-PAOs in 23 full-scale EBPR plants revealed that they made up 0.5-5.7% of all bacteria in the plants, and were often in higher abundance than the well-described PAOs 'Candidatus Accumulibacter phosphatis'. This indicates a potentially important role for these uncultured Halomonas bacteria in the EBPR process in full-scale plants and we propose to name them 'Candidatus Halomonas phosphatis'. PMID- 22827169 TI - 'Cosmeceuticals'. Of men, science and laws.... AB - Through the hybrid term 'Cosmeceuticals', the present paper aims at reviewing some scientific and legal sources of ambiguities or uncertainties that, in many regulatory cases, added confusions to the respective roles of drugs and cosmetics. The origins of such questions, likely arose from new anti-ageing claims from the cosmetic industry in the late 80s which faced a rather old regulatory backdrop. Based on the analysis of some legal statements and scientific facts from a 2012 vision, this review tentatively aims at re-defining the respective roles of these two branches that both fill the two vital needs of humans, 'being' and 'well-being'. PMID- 22827170 TI - The impact of an electronic nursing documentation system on efficiency of documentation by caregivers in a residential aged care facility. AB - AIMS AND OBJECTIVES: To examine the effect of the introduction of an electronic nursing documentation system on the efficiency of documentation in a residential aged care facility. BACKGROUND: Modern technology has the potential to free caregivers in residential aged care facilities from their burden of paper documentation and allow them more time to care for residents. To date, there is inadequate evidence to verify this assumption. DESIGN: Longitudinal cohort study with work sampling method for data collection. METHODS: This study was conducted between 2009-2011; two months before and 3, 6, 12 and 23 months after implementation of an electronic documentation system. A work classification tool was used by an observer to record documentation activities being performed on paper or on a computer by the caregivers. RESULTS: When compared with the proportion of time caregivers spent on documentation in the preimplementation period, personal carers' proportion reduced at three months after implementation. The proportion increased from six months and then dropped at 23 months. Recreational activity officers' proportion increased at three months after implementation. It stabilised at six months and increased again at 12 months. At 23 months, the proportion returned to the preimplementation level. Less than half of the caregivers' time on documentation after implementation was associated with computer-related tasks. CONCLUSIONS: Introduction of an electronic documentation system may not necessarily lead to efficiency in documentation for the caregivers. Charting some information items on paper and others on a computer may hinder realization of documentation efficiency. RELEVANCE TO CLINICAL PRACTICE: To optimise the efficiency benefit of electronic documentation in a residential aged care facility, it is not only necessary to automate all nursing forms but also to ensure that the system is aligned with caregivers' documentation practice. Continuous education and mentor support is essential to ensure caregivers' effective usage of the electronic system. PMID- 22827171 TI - Evaluating perceived benefits of ecoregional assessments. AB - The outcomes of systematic conservation planning (process of assessing, implementing, and managing conservation areas) are rarely reported or measured formally. A lack of consistent or rigorous evaluation in conservation planning has fueled debate about the extent to which conservation assessment (identification, design, and prioritization of potential conservation areas) ultimately influences actions on the ground. We interviewed staff members of a nongovernmental organization, who were involved in 5 ecoregional assessments across North and South America and the Asia-Pacific region. We conducted 17 semistructured interviews with open and closed questions about the perceived purpose, outputs, and outcomes of the ecoregional assessments in which respondents were involved. Using qualitative data collected from those interviews, we investigated the types and frequency of benefits perceived to have emerged from the ecoregional assessments and explored factors that might facilitate or constrain the flow of benefits. Some benefits reflected the intended purpose of ecoregional assessments. Other benefits included improvements in social interactions, attitudes, and institutional knowledge. Our results suggest the latter types of benefits enable ultimate benefits of assessments, such as guiding investments by institutional partners. Our results also showed a clear divergence between the respondents' expectations and perceived outcomes of implementation of conservation actions arising from ecoregional assessments. Our findings suggest the need for both a broader perspective on the contribution of assessments to planning goals and further evaluation of conservation assessments. PMID- 22827173 TI - Carbohydrate mimics and lectins: a source of new drugs and therapeutic opportunities. AB - Mimics of oligosaccharides capable of interfering with lectin activity are currently being pursued by a number of groups in an effort to produce tools for glycobiology and to design antagonists of medically relevant lectins. The field is reviewed in this chapter. After a brief overview of the state of the art, examples from our and others' studies on the dendritic cell receptor DC-SIGN are illustrated. PMID- 22827174 TI - A short overview on the medicinal chemistry of (-)-shikimic acid. AB - Shikimic acid, a natural compound is a key intermediate in the biosynthesis of amino acids. Consequently, this derivative is widely present in many plants and has interesting biological properties. But besides the pharmacological relevance of shikimic acid itself, it is also an intermediate in the synthesis of many drugs, being the most relevant the antiviral agent oseltamivir (TamifluTM). Here we present a short overview on recent natural, biotechnological and synthetical sources of shikimic acid, togheter with pharmacological applications of this compound and a selection of derivatives, including oseltamivir (TamifluTM). PMID- 22827175 TI - Recent progress on fucosyltransferase inhibitors. AB - Fucosyltransferases (FucTs) are enzymes that transfer L-fucose from GDP-fucose to a glycoside or a peptide. They have important roles in a variety of diseases including cancer and autoimmune disorders, viral and bacterial infections and inflammatory processes, and thus they represent important drug targets for the development of agents for the treatment of such disorders. This review highlights recent developments regarding carbohydrate mimics as inhibitors of FucTs. The most recent and relevant synthetic strategies are described. PMID- 22827176 TI - Mycalamides, pederin and psymberin as natural carbohydrates and potential antitumor agents: past and future perspectives. AB - The mycalamide class of potent antiviral and antitumor natural compounds originally isolated from marine sponges in 1988 is a new interdisciplinary approach to molecular recognition. We review new synthetic approaches to this new family of natural products with remarkable biological activity. Some biological evaluation data are compiled and compared to other structurally similar molecular targets. PMID- 22827177 TI - Carbohydrate based potential chemotherapeutic agents: recent developments and their scope in future drug discovery. AB - In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases. PMID- 22827178 TI - Diels-Alder cycloaddition in the synthesis of 1-azafagomine, analogs, and derivatives as glycosidase inhibitors. AB - This comprehensive review deals with the synthesis of 1-azafagomine, analogs, and derivatives having the Diels-Alder cycloaddition as the key step. Most of the compounds referred are racemic or have been resolved by lipase transesterification. There are two asymmetric cycloadditions leading to 1 azafagomine or to an analog. In one case both enantiomers of 1-azafagomine were prepared together with a pair of derivatives. The study comprises glycosidase inhibition studies of the target compounds to a set of glycosidic enzymes, and evidenced molecular features that enhance or diminish their activity as glycosidase inhibitors. PMID- 22827179 TI - Advances in the synthesis of calystegines and related products and their biochemical properties. AB - The revision of the structures and properties of Calystegines shows that they can be regarded as carbohydrate mimics, with related biological activities and peculiar characteristics. Not only they can be isolated from food plants, but they can be obtained from a variety of monosaccharide derivatives and of non carbohydrate products. Although several synthetic calystegine analogs have been reported as glycosidase inhibitors, new, more potent and effective inhibitors are required. PMID- 22827180 TI - Spirocyclic nucleosides in medicinal chemistry: an overview. AB - This review describes some spiro- and pseudospironucleoside derivatives as well as their biological and pharmacological applications. PMID- 22827181 TI - Development of aminoglycoside antibiotics by carbohydrate chemistry. AB - With the development of glycomics, more and more carbohydrate mimetics were used to investigate the interactions between carbohydrate-proteins, especially in physiological and pathological processes, molecular recognition, signal transduction, cell communication, cell differentiation and developmental events. Recently, because of the drug-resistance of microorganisms and the development of antibiotics, the interactions between carbohydrate mimetics and RNAs are becoming hot issue. Aminoglycosides, one family of important antibiotics, can bind with 30S subunits of rRNA to prevent the normal translations of proteins, inhibit the proteins involving in the drug-resistance. In this review, the latest advances in development and applications of aminoglycosides are summarized and the detailed descriptions on the SAR study (Structure-activity relationship) of aminoglycoside derivatives are discussed. PMID- 22827182 TI - Comparison of two dosage regimens of the substrate for the [13C]methacetin breath test. AB - The [(13)C]methacetin breath test ([(13)C]MBT)--a valuable non-invasive tool dedicated to the assessment of the liver metabolic capacity--still needs standardisation. The aim of this study was to check whether currently used dosage regimens of [(13)C]methacetin provide concordant [(13)C]MBT results in subjects with an atypical body constitution. Healthy volunteers: low body mass<55 kg (eight women), and high body mass>95 kg (eight large body frame men) were recruited. They underwent [(13)C]MBT on separate days, taking in random order [(13)C]methacetin: a fixed 75 mg dose (FX75), or a 1 mg kg(-1) body mass-adjusted dose (BMAD). Samples of expiratory air for (13)CO(2) measurement were collected over 3 h. The maximum momentary (13)C elimination in breath air occurred earlier and was higher following BMAD than with FX75 in the low body mass females (T (max) 14.6 +/- 1.0 min vs. 22.1 +/- 2.4 min, p = 0.019; D (max) 41.9 +/- 2.9 % dose h(-1) vs. 36.6 +/- 3.6 % dose h(-1), p = 0.071). In the high body mass men, T (max) remained unchanged, whereas D (max) was slightly higher with BMAD compared to FX75 (21.5 +/- 3.2 min vs. 23.0 +/- 3.0 min; 38.5 +/- 2.9 % dose h( 1) vs. 32.3 +/- 2.5 % dose h(-1)). It is concluded that in subjects with a body constitution outside the general population average, the dosage of the substrate may affect some results of the [(13)C]MBT. The dosage-related differences appear, however, to be insignificant if the result of the [(13)C]MBT is reported as a cumulative (13)C recovery in breath air. PMID- 22827183 TI - The management of ocular allergy. AB - There is a broad spectrum of ocular allergy. In the mild forms it is no more than an inconvenience, but severe forms such as eczematous kerato-conjunctivitis can be sight-threatening. However, with proper understanding of the diseases and constructive management, most patients can be satisfactorily controlled. PMID- 22827184 TI - Chronic allergic conjunctivitis. AB - Chronic allergic conjunctivitis (CAC) or perennial allergic conjunctivitis (PAC) is the most frequent form of allergy of the conjunctiva that is encountered in Northern Europe, particularly in city areas. Itching, redness of the mucosa, swelling of the lids and tearing are the main symptoms. Seasonal factors and associated rhinitis are often noted. Symptoms may respond to antiallergic drugs. In contrast, there are generally no specific signs of the disease on slitlamp examination. Most of the time the mucosal aspect (papillary, follicular or atrophic type) is common to other forms of conjunctival allergy. Non-specific factors may predispose to the appearance of CAC, such as an intolerance to a contact lens, a local infection, or a trauma of the eye. Astigmatism, heterophoria and photosensitization may also be triggering agents for the appearance of symptoms of an authentic CAC in an atopic patient. The close association between allergic and non-specific factors may explain the possibility of unilateral forms of CAC and, most of all, the frequent association of CAC to other forms of chronic conjunctivitis. The diagnosis relies on good clinical evaluation of both symptoms and signs. Serum IgE levels are elevated in no more than 30% of cases while tear levels of IgE are more often pathological (over 50% of cases); skin-testing remains the best method for confirming the diagnosis. In most cases it indicates an allergy to house dust and/or mites. Elimination of the offending allergen is the first treatment in CAC. Antiallergic drugs are also effective, such as antihistamines and mast cell stabilizers, nedocromil sodium being very efficient in this respect. In cases where this kind of treatment cannot be pursued indefinitely, specific desensitization to house dust or mites is effective and induces a prompt resolution of symptoms, whereas signs will persist a long time. All non-specific factors associated with the allergy should also be carefully considered and treated, although results are better in pure rather than associated clinical forms of CAC. PMID- 22827185 TI - Vernal Keratoconjunctivitis (VKC). AB - Vernal keratoconjunctivitis (VKC) is an allergic ocular disease in children and young adults. It is linked to atopy but it is characterized by typical inflammatory changes of ocular tissues. The conjunctiva often shows hyperplasia, with infiltration of lymphocytes and eosinophils; also mast cells, confined to the substantia propria in normal subjects, invade the epithelium in VKC. Both mucosal (MC(T)) and connective tissue (MC(TC)) types of mast cell can be found in the conjunctival tissues of VKC patients, whereas MC(TC) predominate in the normal eye. Much of the damage caused to the surface of the eye in VKC appears to be due to cytotoxic factors released from the invading eosinophils. Ongoing studies of cell/mediator interactions involved in the inflammatory process are contributing to the understanding of VKC and other allergic eye diseases also providing the rationale for effective treatment which may be found by blocking the immunological inflammatory network at specific points. Therapeutic studies with nedocromil sodium have shown encouraging results. For example, a six-week placebo comparison in Italy found nedocromil sodium eye drops to be efficacious in reducing hyperaemia, eye itching and inflammatory cells present in tears. Similarly, a four-week trial in Egypt showed this drug superior to sodium cromoglycate using the same q.i.d. regimen. PMID- 22827186 TI - Treatment of ragweed pollen seasonal allergic conjunctivitis (SAC) with b.i.d. nedocromil sodium 2% ophthalmic solution. AB - An eight-week multicenter double-masked placebo-controlled group comparison was carried out in 86 patients (age 13-60 years) to determine efficacy and safety of b.i.d. nedocromil sodium 2% ophthalmic solution in ragweed SAC. Treatment was timed to coincide with the predicted ragweed pollen season, taking the two to three weeks of peak pollen counts as the period for analysis. Clinical efficacy was measured from group mean symptom scores (0-4 scale of severity) recorded by the patients on daily diary cards, and the results of clinic examinations made before and after a one-week baseline and following one, three, five and eight weeks of treatment. During the peak pollen season, use of nedocromil sodium reduced all symptoms, with statistically significant differences from placebo, for itching, tearing/watering, overall eye condition and the total symptom summary score (itching+tearing+burning). Clinical assessments of nedocromil sodium showed significant relief of tearing, conjunctival injection and edema. Overall opinions also demonstrated significant benefit with nedocromil sodium, 61% of patients rating active treatment at least moderately effective compared with 36% for placebo (clinicians' opinions were respectively 46% vs 21%). Nedocromil sodium 2% ophthalmic solution b.i.d. caused no major side-effects and was more effective than placebo in relieving major symptoms of SAC. PMID- 22827187 TI - Studies comparing the efficacy of nedocromil sodium eye drops with sodium cromoglycate and placebo in seasonal allergic conjunctivitis. AB - Two multicentre, double-blind, placebo controlled group comparative studies were carried out in Finland, during the birch pollen seasons of 1987 and 1989, to compare the efficacy and tolerability of 2% nedocromil sodium eye drops (twice daily) with either 2% sodium cromoglycate eye drops (four times daily) and/or placebo, in patients with seasonal allergic conjunctivitis. Study 1 compared nedocromil sodium (64 patients) with placebo (62 patients) and showed that the opinions of treatment efficacy of both patients and clinicians were significantly in favour of nedocromil sodium (p = 0.003, patients; p = 0.006, clinicians). In addition, the placebo group used significantly more topical (p<0.05) and oral (p<0.01) concomitant antihistamine therapy. Diary card scores and clinical assessments showed trends for active treatment. Study 2 compared nedocromil sodium (60 patients) with sodium cromoglycate (61) and placebo (64). Symptomatology was low, in general, but patient diary card scores showed significant control of itching by both active treatments. Clinical assessments also showed some improvement with both active treatments, reaching statistical significance for grittiness and photophobia. Overall opinions demonstrated a high placebo effect. At the end of the trial, full or moderate control of symptoms was reported by 80% of patients (73% clinicians) receiving nedocromil sodium, 75% of patients (74% clinicians) receiving sodium cromoglycate and 73% of patients (69% clinicians) receiving placebo. Taken as a whole, these results suggest that twice daily nedocromil sodium eye drops are as efficacious as four times daily sodium cromoglycate eye drops in controlling seasonal allergic conjunctivitis. PMID- 22827188 TI - Nedocromil sodium 2% ophthalmic solution (Tilavist(TM)) A new topical treatment for ocular allergic inflammation. AB - Nedocromil sodium, a non-toxic pyranoquinoline dicarboxylate, was developed as a novel topical treatment for allergic inflammatory lung diseases. With a broader pharmacological potential than the chromone compound sodium cromoglycate, nedocromil sodium has more potent antiinflammatory effects whilst maintaining a good safety profile due to rapid excretion, unmetabolized. Having the ability to stabilize both mucosal (MC(T)) and connective tissue (MC(TC)) mast cells and directly to inhibit activated cells such as eosinophils, which are involved in continuing allergic inflammation in the eye as well as in the airways, nedocromil sodium appears ideally suited to the treatment of allergic conjunctivitis. Preliminary therapeutic trials have confirmed efficacy and the lack of side effects of the 2% eye drop formulation of nedocromil sodium, and its comparative potency which permits twice-daily administration for seasonal ocular symptoms, with the safe option of increasing to four times daily use for more severe, chronic allergic inflammatory conditions. With many patients already symptomatic at the start of trial treatment, nedocromil sodium eye drops have also proved to have a rapid onset of action providing relief of symptoms in 24 hours in the majority of cases, and often within one hour of the first dose. PMID- 22827189 TI - Nedocromil sodium and astemizole, alone or combined, for treatment of seasonal allergic conjunctivitis (SAC). AB - SAC is caused by allergen interaction with IgE antibody on conjunctival mast cells, leading to local release of vasoactive inflammatory mediators such as histamine. Nedocromil sodium both stabilizes mast cells and has antiinflammatory activity against other cells involved in allergic inflammation. Astemizole is a second generation orally-active H(1)-receptor antagonist with reduced CNS effects such as drowsiness. This multicentre, double blind, double dummy trial compared efficacy and safety of qid 2% nedocromil sodium eye drops with once daily 10 mg oral astemizole, placebo, and combined active treatments for a four-week period. SAC patients (n=207, aged 6-70 years) recorded their symptoms each day on diary cards. Signs and symptoms were also evaluated by clinicians after one, two and four weeks and overall opinions were recorded at the end of treatment. Nedocromil sodium eye drops and astemizole, alone or combined, significantly reduced ocular symptoms compared to placebo (for diary card total symptom score and patients' opinion). Clinicians' opinion showed significantly decreased symptoms with nedocromil sodium, alone or combined, but not with astemizole alone. All treatments were well tolerated, with drowsiness the most frequent side effect observed in patients treated with astemizole. These results demonstrate the effectiveness of nedocromil sodium eye drops in the treatment of SAC. PMID- 22827190 TI - Round-table discussion and questions. PMID- 22827191 TI - Visualization of retinal vasculitis in Eales' disease. AB - Between 1970 and 1991 the authors examined 466 patients with Eales' disease. The mean age at diagnosis was 30, ranging between 14 and 55 years. The mean follow-up period was 43.5 months. At the initial examination, 356 cases were bilateral and 110 cases were unilateral (822 eyes). Vitreous hemorrhage was present in 257 of the 822 eyes. In the remaining 565 eyes, the major retinal lesions were retinal neovascularization (40.7%), vascular sheathing (20.7%), vascular sheathing and retinal hemorrhages (10.6%), retinitis proliferans (9.4%), disc neovascularization (9.0%), branch vein occlusion (3.2%), tractional retinal detachment (2.4%), central vein occlusion (1.8%), central vascular sheathing (1.1%), obliterated vessels (1.1%). Forty-nine out of the 110 initially unilateral cases eventually developed bilateral involvement after a mean period of 42 months. The percentage of eyes with a vision of 0.1 and better rose from 68.1% in the initial examination to 77.9% in the final examination. Fluorescein angiograms of the affected eyes show dye leakage with retinal staining, microaneurysms, capillary non-perfusion and neovascularization. Fundus changes are characteristic of Eales' disease. Unilateral cases should be closely followed because of the risk of involvement of the other eye. Fluorescein angiography is a requirement for early identification of vascular changes and for proper follow-up in Eales' disease. PMID- 22827192 TI - Photocoagulation in Eales' disease. AB - Between 1970 and 1991 the authors examined 466 cases with Eales' disease. 359 eyes of 295 of these 466 cases received photocoagulation treatment. The mean age was 30.4, ranging between 14 and 55 years. Ten eyes with persistent vitreous hemorrhage underwent pars plana vitrectomy before photocoagulation. 210 eyes were treated with xenon arc, 135 with argon laser, 12 with krypton laser and two with yellow dye laser. Hypoxic areas and retinal neovascularizations were closed completely in 298 eyes. In 21 eyes with elevated neovascularizations intruding into the vitreous cavity feeder vessel photocoagulation was used. 24 eyes with disc neovascularization were treated with panretinal photocoagulation. 12 eyes with branch vein occlusion and four eyes with central vein occlusion received photocoagulation treatment to areas of non-perfusion and retinal neovascularization. At a mean follow-up of 43 months, seven new retinal neovascularizations and three new disc neovascularizations developed in eyes which previously had received photocoagulation for retinal neovascularization and hypoxia. Nine out of 21 eyes with elevated neovascularizations developed vitreous hemorrhage. Disc neovascularization resolved completely in 13 out of 24 eyes, it partially regressed in eight eyes and did not respond to treatment in three eyes. The visual acuities were improved in 12.3%, maintained in 77.4% and deteriorated in 10.3% of the eyes after treatment. Periodic follow-up and early photocoagulation treatment is useful in stabilizing the retinal lesions and in maintaining functional levels of vision in Eales' disease. PMID- 22827193 TI - Diagnostic and therapeutic dilemmas in ocular toxoplasmosis. AB - Ocular toxoplasmosis, a leading cause of visual handicaps in young people, represents a late manifestation of congenital infection in the majority of cases. Ocular involvement in acquired toxoplasmosis has been repeatedly reported and shows that toxoplasmic retinitis may develop in the wake of acquired infection. The diagnosis of ocular toxoplasmosis is mainly clinical since serologic tests are positive for a considerable percentage of the general population and are not indicative for ocular involvement. The demonstration of local synthesis of toxoplasma antibodies in the eye by intraocular fluid analysis is a valuable diagnostic tool. The application of the polymerase chain reaction, in which the parasite's DNA is detected, may be expected to change the diagnostic repertoire drastically in the future. The need for appropriate therapy for patients with ocular toxoplasmosis is a matter of continued debate: the majority of the medications used for treatment have potentially serious side effects and the efficacy of treatments has not been clarified in previous studies. Recently, a prospective multicenter study to evaluate the efficacy of current therapeutic strategies for ocular toxoplasmosis was performed in The Netherlands and included 106 patients with active ocular toxoplasmosis. The principal conclusion of this study is that only drug therapy with pyrimethamine had any perceptible influence on any aspect of ocular toxoplasmosis, but this effect may not be worth the risk of side effects except in fovea threatening lesions. PMID- 22827194 TI - The effect of topical indomethacin on subjective symptoms in chronic corneal edema. AB - The authors conducted a masked randomized study of 15 patients to evaluate the effect of administration of topical indomethacin 1% suspension on complaints in chronic corneal edema. Patients who complained of photophobia, pain, itching, burning sensation, foreign body sensation and tearing, were treated with topical indomethacin 1% or placebo and followed for eight weeks. The severity of the complaints was rated and the scores were evaluated (Wilcoxon matched-pairs test). Of the eight patients treated with indomethacin, seven (87%), had symptomatic improvement and the severity of the total score of their complaints was significantly decreased. Of the seven patients treated with placebo, no symptomatic improvement was observed and severity of the complaints remained unchanged. However, when the placebo-treated patients subsequently received indomethacin drops, the complaints were significantly decreased. This study suggests that topical administration of indomethacin 1% may reduce ocular complaints in patients with chronic corneal edema. PMID- 22827195 TI - Sympathetic ophthalmia as a complication of argon laser trabeculoplasty. AB - The results of argon laser trabeculoplasty (ALT) in a series of 254 eyes are presented with a follow-up of over five years. ALT was effective in lowering the IOP in most cases of primary open angle glaucoma (56.3%). Several complications were observed. These included anterior uveitis, hemorrhage, formation of peripheral anterior synechiae, elevation of IOP. The most serious complication observed was presumed sympathetic ophthalmia in an aphakic eye with uveitic glaucoma 12 months after ALT. PMID- 22827196 TI - Immunopathology of ocular onchocerciasis 3. Th-2 helper T cells in the conjunctiva. AB - Ocular onchocerciasis is the second most common infectious cause of blindness in the world. Th-2 helper T (Th-2) cells are thought to play a critical role in immediate hypersensitivity against allergens and extra-cellular parasitic infections. Th-2 cells secrete a high amount of IL-4, regulate IgE production, and recruit eosinophils and mast cells. Conjunctival biopsies from ten African patients with ocular onchocerciasis were evaluated for the presence of II-2, IL 4, mast cells and major basic protein (MBP), a marker for eosinophils. IL-4 mRNA was detected in seven of ten conjunctival specimens using in situ hybridization, yet IL-4 was detected in only one specimen using immunohistochemical staining. In contrast, IL-2 mRNA was detected in three of ten conjunctival specimens and IL-2 was detected in two specimens. There were greater numbers of mast cells and the presence of MBP in specimens with IL-4 mRNA. Furthermore, the three biopsies containing both IL-2 and IL-4 mRNA had greater numbers of CD4+cell infiltration and the patient with IL-4 protein in his conjunctiva also had the highest IgE in his aqueous humor. These findings suggest that Th-2 cells and their lymphokines are important for the localized host responsiveness to ocular onchocerciasis. PMID- 22827197 TI - Effects of topical FK506 on experimental allergic conjunctivitis. AB - In vitro studies of FK506 demonstrated that the agent inhibited the T-cell receptormediated signal transduction that results in the transcription of interleukin 2. Recent in vitro studies have demonstrated an identical spectrum of activities of FK506 on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from basophils and mast cells. The effects of topical FK506 on allergic conjunctivitis were therefore studied in the rat. Passive anaphylaxis was induced in Wistar rats by injecting anti-ovalbumin IgE at the conjunctiva followed by intravenous injection of antigen (ovalbumin) and Evans blue. Topical FK506 (0.03-0.1%) significantly suppressed the passive anaphylaxis in the rat conjunctiva when given at 15 and five minutes, or six, four and two hours before the antigen challenge. The efficacy was more intense than that of 0.1% betamethasone or 2% disodium cromoglycate. These data thus suggest that topical FK506 might be beneficial for the therapy of severe allergic diseases in the eye. PMID- 22827198 TI - Topical diclofenac sodium, dexamethasone and placebo compared in a model of immunogenic uveitis in rabbits. AB - Unacceptable side effects involved in topical steroid usage for uveitis have prompted the search for alternative antiinflammatory drugs for the treatment of ocular inflammation. Cyclooxygenase inhibitors have been widely used for systemic inflammatory conditions over the last two decades and are therefore natural candidates to be studied for uveitis therapy. Previous studies of cyclooxygenase inhibitors in uveitis models yielded inconclusive and sometimes contradicting results. The authors compared the clinical effect of topical dexamethasone, diclofenac and placebo in an immunogenic uveitis model produced in ovalbumin immunized NZW rabbits challenged with ovalbumin in the vitreous. Nine clinical parameters of inflammation were compared employing a double blind placebo controlled protocol. Three groups of 16 eyes each, were assigned for each preparation and were followed for nine days with biomicroscopic examinations. Diclofenac was superior or equal to dexamethasone for iris hyperemia (p=0.059) and conjunctival injection (p=0.02), equal for corneal haziness and AC fibrin, yet inferior for corneal endothelial debris, iris fibrin and AC cells and flare (p<0.05). Placebo was inferior (p<0.05) to the other groups for the above mentioned parameters excluding fibrin precipitation on the iris that was greater in diclofenac treated eyes. While some clinical criteria of inflammation responded better to steroids than to diclofenac, the results of this study show that others responded better or equal to diclofenac. The authors hypothesize that although diclofenac reduces prostaglandin levels it may induce high levels of leukotrienes that maintain cellular exudation. PMID- 22827199 TI - The use of doxycycline and tetracycline in ocular rosacea. AB - The authors compared the effects of doxycycline and tetracycline hydrochloride on subjective symptoms in ocular rosacea. Twenty-four patients with symptomatic ocular rosacea were prospectively treated with doxycycline 100 mg/day (group 1, n=16) or tetracycline hydrochloride 1g/day (group 2, n=8). The dosages of each drug were gradually tapered and discontinued according to symptomatic response. Patients were followed from six weeks to three years. In group 1, 15 patients (94%) had symptomatic improvement (12 patients were asymptomatic and three symptomatically improved), and two patients (13%) had gastrointestinal tract (GIT) complications followed by discontinuation of medication. In group 2, seven of the eight patients (87%) were asymptomatic and one patient (13%) had symptomatic improvement; three patients discontinued the use of tetracycline as a result of GIT complaints. This study indicates that both tetracycline hydrochloride and doxycycline can control the symptoms of ocular rosacea. PMID- 22827200 TI - Polymerase chain reaction for diagnosis of herpetic intraocular inflammation. AB - The authors present a polymerase chain reaction method for rapid and direct diagnosis of herpetic intraocular infections using small volume samples of intraocular fluid from 29 patients with various intraocular inflammatory diseases and 24 controls with senile cataract. Of six patients with early acute retinal necrosis from whom aqueous humor was tested, four were found to be positive for the presence of varicella-zoster (VZV) DNA while the other two were positive for the presence of herpes simplex virus (HSV) DNA. One of the patients with HSV DNA had been tested at an extremely early stage, at which time the aqueous humor viral antibody ratio did not predict a specific viral infection. Among four patients with acute retinal necrosis in relatively late stages following treatment with acyclovir from whom vitreous was obtained and tested, only one was found to have the presence of any viral DNA (VZV). On the other hand, the vitreous viral antibody ratio was found to be predictive of VZV infection in all four cases. VZV DNA was also detected in aqueous humor samples from four patients with suspected herpes zoster anterior uveitis, while HSV DNA was found in the aqueous humor of one patient with nonspecific keratouveitis. Neither human cytomegalovirus DNA nor human herpesvirus-6 DNA was detected in any sample included in this study. Finally, Epstein-Barr virus DNA was detected in the aqueous humor of the majority of patients studied and identified in cataract patients as well, suggesting either low specificity of the authors' assay for this virus or ubiquity of this virus in human eyes. In summary, the PCR method proved to be a very useful tool in establishing an etiological diagnosis in patients in the early stages of acute retinal necrosis, and in patients with anterior uveitis due to suspected HSV or VZV infection. PMID- 22827201 TI - Immunohistochemical study on IRBP-induced EAU. AB - We studied the pathogenesis of IRBP-induced experimental autoimmune uveoretinitis (EAU) by immunohistochemical detection of various immune cells using specific monoclonal antibodies to their surface markers and adhesion molecules. The following results were obtained: (1) During each stage of EAU, CD4 positive T cells predominated over CD8 positive T cells in the retina and the uvea. (2) One day prior to the clinical onset of disease, la positive cells began to appear in the ciliary body. (3) LFA-1 and ICAM-1 were expressed on intraocularly infiltrating cells. (4) ICAM-1 was also expressed on endothelial cells of uveal and retinal vessels. In addition, ICAM-1 was expressed on ciliary body epithelium and retinal pigment epithelium, a finding which may be associated with the breakdown of the blood-ocular barrier. In conclusion, the expression of LFA-1 and ICAM-1 in EAU demonstrates that adhesion molecules, such as these, play an important role in inflammatory ocular disease in vivo. PMID- 22827202 TI - Chronic uveitis in Gaucher's disease. AB - Thirty patients with Gaucher's disease have been examined in the authors' clinic; 29 of them suffered from the adult form and one had the juvenile type of the disease. The authors found intraocular abnormalities in four patients: three suffered from uveitis and in one, multiple vitreous opacities were observed. Two of the three patients had bilateral uveitis, while in one the uveitis was confined to the right eye only. In two of the three patients the manifestations of Gaucher's disease were present before the onset of uveitis. In one of the three, however, bilateral uveitis with spontaneous hyphema in the left eye was the presenting symptom. The diagnosis of Gaucher's disease in this case was arrived at during the work-up investigations for the etiology of the ocular manifestations. Initially the ocular symptoms in these three patients manifested as acute anterior uveitis, becoming chronic and involving also the posterior segments at a later stage. PMID- 22827203 TI - Postoperative fibrinoid reaction in extracapsular surgery with intraocular lens implantation in diabetic retinopathy patients. AB - IOL implantation in diabetic retinopathy patients is still controversial. To ascertain the frequency of inflammatory complications in diabetic patients and the influence of such surgery on the evolution and treatment of diabetic retinopathy, the authors have reviewed 198 consecutive diabetic eyes (120 operated patients) with extracapsular cataract extraction and posterior chamber intraocular lens implantation. The mean follow-up period was 26 months with a range from 19 to 36 months. Postoperative visual acuity was 0.45. The incidence of inflammatory reaction with fibrinoid component was 3.03% vs 2.5% in a matched control group. Intensive topical corticosteroid treatment was effective in controlling the inflammatory reaction in all cases within one to three days. The diabetic retinopathy did not show an increase in progression after IOL implantation but in one case with severe postoperative inflammatory reaction. Photocoagulation postoperatively was indicated in all cases, being effective in all but the case in which retinopathy got worse; this case required vitrectomy with endophotocoagulation because of vitreous haziness. Visual acuity improved following cataract surgery regardless of the incidence of inflammation or the type of diabetic retinopathy. PMID- 22827204 TI - Topical and systemic Ofloxacin (Tarivid) in the treatment of Gentamycin-resistant Pseudomonas corneal abscess. AB - The authors present a case of fulminant, devastating Pseudomonas corneal abscess associated with hypopion and extensive stromal infiltrates. In spite of massive intravenous, sub-conjunctival and topical Cefazolin and Gentamycin administration, there was a continuously worsening course with early formation of descematocele and a threat to the integrity of the eye. Based on previous reports in the literature on the efficacy of I.V and topical Ofloxacin (Tarivid) treatment of Gentamycin-resistant Pseudomonas keratitis in vitro and in vivo, intravenous 200 mgx2/day Ofloxacin as well as hourly topical Ofloxacin 0.3% was administered. Dramatic and significant improvement was gradually observed with complete resolution of the corneal infiltrates and scarring of the descematocele as well as healing of the epithelial defects within 14 days. No local side effects were observed. The authors recommend topical and systemic Ofloxacin treatment in Gentamycin-resistant Pseudomonas corneal ulcers. PMID- 22827205 TI - The role of cytokines in angiogenesis. AB - Using the corneal model of neovascularization developed in their laboratory, the authors investigated the angiogenic potential of interleukin-1 (IL-1alpha and beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNFalpha), transforming growth factor beta (TGFbeta), granulocyte macrophage colony stimulating factor (GM-CSF), and interferon (IFN(gamma) and IFN(gamma)). Various concentrations of the tested cytokine were sequestered into Elvax-40 and implanted at 2.5 mm from the limbus within the corneal stroma of the rabbit eye. Three distinct groups of cytokines could be observed according to their angiogenic potential in this system. IL-1alpha was by far the most potent stimulator of neovascularization, inducing this process at concentrations as low as one nanogram per implant. TGFbeta, TNFalpha and GM-CSF induced significant neovascularization only at concentrations of 500 nanograms per implant. IL-2, IL 6, IL-8, IFNalpha and IFN(gamma) did not induce any significant neovascularization at the concentration tested (0.5 MUg to 10 MUg per implant). PMID- 22827206 TI - Influence of interferons corneal angiogenesis induced by basic fibroblast growth factor and lipopolysaccharide. AB - A controlled and reproducible angiogenic stimulus was induced in the rabbit cornea by Elvax-40 implants sequestering either 500 ng of lipopolysaccharide (LPS) or 500 ng of basic fibroblast growth factor (bFGF). The effect of IFNalpha and IFN(beta) on angiogenesis was studied by inserting implants sequestering 500 ng of these cytokines (approximately 10(4) Units/implant) adjacent to the LPS or bFGF implants. Interferon-alpha or gamma did not inhibit the bFGF-induced angiogenesis, and in most of these experiments an enhancing effect was observed. This enhancement was not statistically significant. The LPS induced angiogenesis, however, was slightly inhibited in the presence of either interferon-alpha or gamma but these differences were not statistically significant with p=0.1 only. Both cytokines were non angiogenic and there was no detectable difference between them regarding their effect on the angiogenic process induced by either bFGF or LPS. PMID- 22827207 TI - PGE(2) and leucocyte levels in aqueous humor after lens extraction and intraocular lens implantation. AB - In order to study the inflammatory response after cataract surgery and intraocular lens implantation the leukocyte (WBC) and prostaglandin E(2) (PGE(2)) levels in aqueous humor were measured in rabbit eyes at different time points (1, 3, 7, 14 and 28 days) postoperatively. In the first group lenses were implanted in the anterior chamber of the eye, without lens extraction, while in the second group the lens was removed and the IOL was placed in the capsular bag. A third group of animals was injected with 10 ng endotoxin into the vitreous in order to induce an inflammation of the uvea. In the endotoxin group high levels of WBC and PGE(2) were observed at 24 h postoperatively, followed by a decrease over time. In the intraocular lens groups WBC and PGE(2) were detected at all time points, and at higher levels compared to the endotoxin group. The WBC was high at day 1 and 3, declined over time, and then increased at day 28 postoperatively. The PGE(2) level was highest at day 3 in rabbits with anterior chamber lenses, while it peaked at day 7 in the animals with IOLs implanted in the capsular bag. In animals with the extracapsular lens extraction without an implanted IOL, the levels of WBC and PGE(2) decreased over time, and were statistically lower after one week compared with animals with an IOL placed in the capsular bag. The results demonstrate that the inflammatory response after cataract surgery persists for at least one month, probably due to surgical trauma and foreign body reactions. PGE(2) and WBC could be used to study postoperative trauma and biocompatibility of different IOL materials and designs. PMID- 22827208 TI - The role of cyclosporin eye drops in ocular inflammatory diseases. AB - Fifty-nine patients were treated with cyclosporin A (CsA) eye drops for various diseases. Most patients with severe vernal keratoconjunctivitis responded well to the treatment. Treatment had little or no effect on anterior uveitis (acute and chronic) or on the fate of high-risk corneal grafts. The response of patients suffering from peripheral corneal melting, ocular pemphigoid or Stevens-Johnson syndrome was variable. Among these, some patients responded well to the treatment with CsA drops while others had no detectable clinical benefit. The large differences in the observed treatment responses may be interpreted to indicate that a different pathological mechanism may take place within a group of patients with similar diagnoses and clinical manifestations. PMID- 22827209 TI - Lacrimal defects in adult and senile rheumatoid arthritis. AB - Rheumatoid arthritis presents with different clinical manifestations according to the age of onset. The authors have studied the involvement of the lacrimal function in two different cohorts of patients, 70 adult-onset (onset of the disease between 15 and 60 years of age) and 30 old-onset (60-79 years), as compared to two groups of normal controls of the same age. Schirmer I, Break-Up Time (BUT), and Bengal rose were tested. Senile rheumatoid arthritis (SRA) not only did not show more severe lacrimal changes when compared to adult rheumatoid arthritis (ARA) of the same duration, but failed to show statistical differences in tear secretion when compared to a healthy population of the same age. ARA patients showed a significant tear deficiency when compared to a healthy population of the same age. Within this cohort of patients, 'long-lasting' ARA showed more severe changes when compared to 'short-lasting' ARA. These results would suggest that the involvement of the lacrimal system is more important when rheumatoid arthritis develops in adult rather than in old age, being a function of the duration rather than of the severity of the disease. PMID- 22827210 TI - IOL implantation following cataract extraction in children with uveitis Surgery and immediate follow-up. AB - The surgical technique and immediate results following posterior chamber IOL implantation after cataract extraction in eight children suffering from chronic uveitis are described. In all cases, improvement of the visual acuity and a better control of the intraocular inflammatory processes could be achieved after surgery. In three of the eight eyes a multifocal IOL was implanted, while five eyes received a monofocal lens. Long-term follow-up of these cases will enable us to evaluate the feasibility of IOL implantation as a routine procedure in children suffering from chronic uveitis and complicated cataract in one eye. PMID- 22827211 TI - Ocular involvement in toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) or Lyell's syndrome is an acute life-threatening disease often triggered by an adverse drug reaction and/or infection. It is characterized by an extensive epidermal loss and severe mucosal involvement. Its pathophysiology is unresolved, but several studies support the hypothesis of an immune mediation. The authors review the ocular involvement of ten drug-induced TEN cases observed in the last four years (eight females and two males; mean age=47). An epidermal loss ranging from 24 to 95% of body surface area was associated with ocular (10/10), oral (9/10), genital (6/10) and anal (4/10) involvement. Ocular findings in the acute phase were: bilateral mucopurulent conjunctivitis (9/10), with inflammatory membranes (3/10), punctate epithelial keratitis (6/10) and corneal ulcers (3/10). Skin palpebral detachment occurred in seven cases, all with extensive and severe systemic disease. In the chronic phase of the disease the authors observed keratoconjunctivitis sicca (4/7), symblepharon (3/7), entropion with trichiasis (2/7) and corneal neovascularization (2/7). HLA B44 (B12) was observed in four of eight studied patients. In conclusion, ocular involvement is frequent in TEN patients and, in those who survive, it significantly contributes to the morbidity of the disease. PMID- 22827212 TI - HLA and idiopathic uveitis. AB - Idiopathic uveitis is the most common form of chronic uveitis seen in our area. Characteristically it is a heterogeneous entity in its clinical severity, evolution and therapeutic response, and immune mechanisms are thought to be involved. The phenotype frequencies of HLA antigens were studied in 62 patients with idiopathic uveitis and compared with their frequencies in northern Portugal. The authors also included two groups with a well known immunogenetic background Behcet's syndrome (BS: n=20) and ankylosing spondylitis (AS: n=18) which are, respectively, the most severe and the most frequent of the rheumatic forms in the area. An increased frequency of HLA B5(B51) in Behcet uveitis (55%; RR=8) was confirmed in the authors' population. They also found in idiopathic uveitis an increased risk for HLA B27 (RR=14). HLA B27 positive idiopathic uveitis was predominantly unilateral (80%) and anterior (97%), whereas B27 negative forms showed a higher prevalence of severe panuveitis. In conclusion, the authors confirmed in their population the association of HLA B27 with uveitis, and HLA B51 with Behcet uveitis. In this last entity an intermediate frequency between northern Europe and the Mediterranean area was observed. PMID- 22827213 TI - Discontinued drugs in 2011: cardiovascular drugs. AB - This perspective is part of an annual series of papers discussing drugs dropped from development in the previous year. Specifically, this paper focuses on the 19 cardiovascular drugs discontinued in 2011 after reaching preclinical or Phase I - III clinical trials. Information for this perspective is mainly derived from a search of Pharmaprojects. PMID- 22827216 TI - Sex steroid hormone effects in normal and pathologic conditions in lung physiology. AB - Progesterone and estradiol participate in the regulation of many pulmonary functions, for example progesterone mediates the fall of alveolar carbon dioxide tension observed in the luteal phase of the menstrual cycle and during pregnancy in humans, when progesterone levels are high. The treatment with estradiol diminishes vasoconstriction and hypoxia. Progesterone and estradiol in addition to participating in non-pathological functions such as vasodilation and lung maturation, also have influence on pathologies as asthma, cystic diseases and cancer. Therefore this review will provide an overview of the action and effects of these hormones in lung, their mechanism of action through their intracellular receptors and their influence over asthma, cystic lung diseases and cancer. PMID- 22827217 TI - Role of estradiol and progesterone in HIV susceptibility and disease progression. AB - The Acquired Immunodeficiency Syndrome (AIDS) constitutes the main infectious cause of death in adults worldwide. Epidemiological data suggest the existence of differences in viral load and CD4(+) T lymphocytes cell counts related to gender. Women have more favorable clinical and viro-immunological patterns than men in early infection, although once established the infection these patterns are reversed. Increasing evidence shows that estradiol (E) and progesterone (P) participate in the regulation of several infections, such as that produced by human immunodeficiency virus (HIV). Several functions of these hormones involve the interaction with their intracellular receptors (ER and PR, respectively). During infection, E and P not only exert their action upon the immune system, but also directly act on the virus. Effects of E and P depend on their concentration or the phase of HIV infection but in general terms, they could exert a protective role against HIV infection. PMID- 22827214 TI - Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells. AB - We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single dose radiation. To understand the role of miRNA in regulation of radiation induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by microarray. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17 92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity. PMID- 22827218 TI - Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy. AB - Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases. PMID- 22827219 TI - Morphological and functional features of the sex steroid-responsive posterodorsal medial amygdala of adult rats. AB - The rat posterodorsal medial amygdala (MePD) expresses receptors for gonadal hormones and integrates sex steroid-sensitive subcortical networks. Male-female differences are found in the morphology, connectivity, and local neuropil structure of MePD. For example, dendritic spine density is sexually-dimorphic and changes with the estrous cycle and following gonadal hormones manipulations. Due to its connectivity, the MePD may affect emotionally-loaded social behaviors, according to a former Newman's seminal proposition. Unilateral fiber-sparing ibotenic acid damage of the MePD does not impair male sexual behavior. However, microinjecting glutamate and histamine into the right MePD facilitates ejaculation. Further, MePD-lesioned rats are not different from normal rats in anxiety-like behavior as evaluated by the elevated plus maze test or innate fear test induced by a live cat. In another study, an adapted model for inducing aggressive behavior in rats by a brief period of restraint prior to the resident intruder paradigm was used to study Fos-immunoreactivity in the MePD. Following stressful stimulation (restraint) or the restraint and fight condition, but not after aggression alone, Fos-immunoreactivity was detected in the MePD. Microinjecting the inhibitory neuropeptide somatostatin into the right MePD notably reduces fighting behavior without affecting locomotion. Overall, these data indicate that sex steroids and local neurochemical stimulatory/inhibitory transmitters modulate the MePD and reinforce the idea that this area is a node for modulating social behavior neural networks. PMID- 22827220 TI - Sex steroids regulation of appetitive behavior. AB - Appetite is the desire to satisfy the need to consume food, felt as hunger. It is regulated by the balance of food intake and energy expenditure via signals between the brain, the digestive tract and the adipose tissue. Males and females vary in terms of eating behavior as well as the way the body fat is stored. Energy balance and body fat distribution are part of the sexual dimorphism in many mammalian species including human beings. These sex dissimilarities could be related to the different sex steroid hormone profile in each sex. Gonadal steroid hormones play an important role in the regulation of food intake and energy homeostasis. Human epidemiological and experimental animal studies have shown that estradiol has a key role in the control of food intake and energy balance. Estradiol has long been known to inhibit feeding in animals. There are important changes in food intake patterns during the estrous cycle, with a reduction of food intake around the time of ovulation, when estradiol presents its highest levels. Men have less total fat and more central fat distribution which carries a much greater risk for metabolic disorders while women have more total fat and more gluteal/femoral subcutaneous fat distribution. Men and postmenopausal women accumulate more fat in the intraabdominal depot. This review is focused on the mechanism by which sex steroids affect feeding behavior and fat distribution. PMID- 22827221 TI - Analysis of paralytic shellfish toxins and their metabolites in shellfish from the North Yellow Sea of China. AB - Samples of toxic scallop (Patinopecten yessoensis) and clam (Saxidomus purpuratus) collected on the northern coast of China from 2008 to 2009 were analysed. High-performance liquid chromatography with post-column oxidation and fluorescence detection was used to determine the profile of the main paralytic shellfish poisoning (PSP) toxins in these samples and their total toxicity. Hydrophilic interaction liquid ion chromatography with mass spectrometric detection confirmed the toxin profile and detected several metabolites in the shellfish. Results show that C1/2 toxins were the most dominant toxins in the scallop and clam samples. However, GTX1/4 and GTX2/3 were also present. M1 was the predominant metabolite in all the samples, but M3 and M5 were also identified, along with three previously unreported presumed metabolites, M6, M8 and M10. The results indicate that the biotransformation of toxins was species specific. It was concluded that the reductive enzyme in clams is more active than in scallops and that an enzyme in scallops is more apt to catalyse hydrolysis of both the sulfonate moiety at the N-sulfocabamoyl of C toxins and the 11 hydroxysulfate of C and GTX toxins to produce metabolites. This is the first report of new metabolites of PSP toxins in scallops and clams collected in China. PMID- 22827222 TI - Current advances in vehicles for brain gene delivery. AB - Gene therapy is a novel and promising treatment strategy for brain diseases. Yet, its development is largely obscured by various in vivo transport hurdles, especially the special BBB structure of brain. Developing an ingenious delivery vehicle can provide a great solution. Conventional vehicles for brain gene delivery are viral and non-viral vectors. With inherent superiority of gene transfection, researches on viral vectors are mainly focused on problems of brain cell targeting and global brain delivery. Non-viral vectors are more studied for better brain cell entrance either directly delivered to brain or systemically delivered to the body. Novel vehicles are cell vehicles (genetically engineered or nanoparticle- carrying cells) and exosomes. They exhibit distinct and unique features compared to viral and non-viral vectors. This review gives a summarization of current advances in these four kinds of brain gene vehicles. The merits and demerits of them are also pointed out respectively. We are hoping to give a clue to the future development direction of vehicles for brain gene delivery. PMID- 22827223 TI - New insights in the gene electrotransfer process: evidence for the involvement of the plasmid DNA topology. AB - Electropermeabilization is a non-viral method that can be used to transfer plasmid DNA (pDNA) into cells and tissues. According the applications and considered tissues, this safe method can be less efficient than the viral approaches. Biophysical mechanisms of gene electrotransfer are not entirely known. Contrary to small molecules that have direct and fast access to the cytoplasm, pDNA is electrophoretically pushed towards the permeabilized membrane where it forms a complex before being transferred into the cytoplasm. In order to understand the biophysical mechanisms of gene electrotransfer and in this way to improve it, we investigated the dependence of the topology of pDNA i.e. linear versus supercoiled on both pDNA/membrane interaction and gene expression. Our results revealed that: i) even if pDNA/membrane interactions are only slightly affected by the topology of pDNA, ii) gene transfer and expression are strongly influenced by it. Indeed, the linearization of pDNA leads to a decrease in the transfection level. PMID- 22827224 TI - mRNA as a versatile tool for exogenous protein expression. AB - Several viral and non-viral vectors have been developed for exogenous protein expression in specific cells. Conventionally, this purpose is achieved through the use of recombinant DNA. But mainly due to the risks associated with permanent genetic alteration of cells, safety and ethical concerns have been raised for the use of DNA-based vectors in human clinical therapy. In the last years, synthetic messenger RNA has emerged as powerful tool to deliver genetic information. RNA vectors exhibit several advantages compared to DNA and are particularly interesting for applications that require transient gene expression. RNA stability and translation efficiency can be increased by cis-acting structural elements in the RNA such as the 5'-cap, the poly(A)-tail, untranslated regions and the sequence of the coding region. Here we review recent developments in the optimization of messenger RNA as vector for modulation of protein expression emphasizing on stability, transfection and immunogenicity. In addition, we summarize current pre-clinical and clinical studies using RNA-based vectors for immunotherapy, T cell, stem cell as well as gene therapy. PMID- 22827225 TI - The third international symposium on ocular inflammation. PMID- 22827226 TI - Aqueous and serum beta(2)-microglobulin levels in patients with senile cataracts, and cataracts associated with uveitis or atopy. AB - beta(2)-Microglobulin (beta(2) M) has been reported to be elevated in patients with a variety of neoplasms and inflammatory disorders, and is believed to be a sensitive although nonspecific marker for lymphocyte activation and/or proliferation. In order to investigate the role of inflammation in the pathogenesis of various types of cataract, the authors measured beta(2)M concentrations in the aqueous humor and serum of patients with senile cataracts (82 eyes), cataracts secondary to uveitis (16 eyes) and cataracts associated with atopic dermatitis (eight eyes). In addition, measurements were made in six patients with rhegmatogenous retinal detachment (RRD) and three patients with central retinal artery occlusion (CRAO) for comparison. The average aqueous beta(2)M was increased in eyes with uveitic cataracts (678 MUg/1) and RRD (533 MUg/1), when compared to eyes with senile cataracts (265 MUg/1), atopic cataracts (309 MUg/1) and CRAO (122 MUg/1). However, comparison of beta(2)M to albumin aqueous-to-serum ratios (protein coefficient analysis) revealed that the aqueous beta(2)M elevation was specific in only uveitic cataracts, with the elevation in RRD being most likely due to breakdown of the bloodocular barrier. Higher aqueous beta(2)M concentrations were also found in cataracts with a posterior subcapsular cataract component, although this was related to a higher percentage of uveitic cataracts in this group. There was no statistically significant difference found in association with a past medical history of diabetes mellitus, hypertension or heart disease. These results are discussed in the context of the pathogenesis of cataract and the role of beta(2)M in inflammatory processes of the eye. PMID- 22827227 TI - Immunohistochemical and cytokine analysis of eyes from rats with adjuvant arthritis. AB - Adjuvant induced arthritis in the rat is an animal model of juvenile chronic arthritis (JCA). An anterior uveitis may also develop in this model which closely resembles that seen in association with JCA in the human. Female Lewis rats (150-225 g) were injected intradermally with either Freund's complete adjuvant (FCA, n=5) or Freund's incomplete adjuvant (FIA, n=5). Eyes were examined by slit lamp biomicroscopy every two days, and the animals sacrificed 21 days post immunisation. Aqueous humour and serum interleukin-6 (IL-6) levels were determined using the B(9) bioassay, and serial tissue sections of the globes were stained with a variety of monoclonal antibodies. In the FCA group, arthritis was detected in two rats, but no rats from either group developed clinical uveitis. Immunohistochemical analysis revealed greater numbers of macrophages and MHC class II+ve cells in the irises and ciliary bodies of FCA treated rats than were seen in the FIA group. No other cellular infiltrate was detected. Serum IL 6 levels were greater in the FCA group (range 6-122 U/ml, median 42) than the FIA group (range 2-27, median 3) (p=0.018), the highest values seen in the two rats which developed arthritis (100, 122 U/ml). In the aqueous of both groups, IL-6 levels were <5 U/ml, and albumin levels were not significantly different (FCA median=2.0 mg/ml, FIA median=1.8). The authors" results suggest that in the adjuvant induced arthritis model, infiltration with macrophages and MHC class II+ve cells occurs in the absence of clinical uveitis. PMID- 22827228 TI - The role of eosinophil cationic protein (ECP) and histamine in vernal keratoconjunctivitis. AB - OBJECTIVES: (1) to measure levels of tear eosinophil cationic protein (ECP) in patients with vernal keratoconjunctivitis (VKC); (2) to verify any correlation between ECP and the severity of the disease; (3) to verify the effect of different topical therapies on the levels of tear ECP; (4) to investigate the activity of histamine degrading enzymes in tears and plasma of VKC patients. METHODS: ECP was measured by RIA in tears from 23 VKC patients before and after therapy, and from seven controls. Tear cytology, ocular signs and symptoms were also evaluated before and after treatment. Histamine was measured by ELISA in both plasma and tears from 19 VKC patients and six age-matched controls, in both acid-treated (no enzyme activity) and untreated (enzyme activity) samples. RESULTS: (1) tear ECP levels were significantly higher in VKC patients than in healthy controls; (2) tear ECP levels showed a significant correlation to signs (p <0.005) and symptoms (p <0.001) of the disease; (3) tear ECP was reduced by both 2% cyclosporine and 0.1% dexamethasone; (4) tear and plasma histaminase activity, measured by the ratio of histamine in treated to untreated samples, were significantly lower in VKC patients compared to controls (p <0.0001 and p <0.001, respectively). CONCLUSIONS: Tear ECP levels reflect the clinical status of VKC patients. The measurement of ECP may prove to be a useful objective tool in evaluating allergic conjunctivitis and the effectiveness of specific treatments. Moreover, VKC patients show a significantly impaired histaminase capability, at both the local and systemic level. This dysfunction may exacerbate the effects of local histamine release in the course of the disease. PMID- 22827229 TI - Transforming growth factor beta2 levels in aqueous humor during corneal transplantation and cataract surgery. AB - Transforming growth factor-beta (TGF-beta) is a molecule with an extremely wide range of biological activities. In aqueous humor (AH) TGF-beta is one of the factors involved in immunosuppression, and contributes to the immunological privilege of the anterior chamber of the eye. It may well be that ocular diseases, like corneal inflammation, disturb this immunological privilege by altering the cytokine equilibrium in AH. We compared the amounts of active, total, and the ratio active/total TGF-beta in AH of patients with severe corneal disease leading to corneal transplantation with those values in patients with cataract. IL-6 levels in AH were determined too since raised levels may indicate intraocular inflammation. The aqueous humor samples were collected from patients with cataract undergoing cataract surgery and patients with corneal disease undergoing corneal transplantation. TGF-beta(2) levels and IL-6 levels in AH were measured with a capture ELISA. TGF-beta(2) in AH was mainly present as a latent complex. Eyes with corneal disease prior to corneal transplantation did not differ from eyes with cataract in the level of active, total, or the ratio active/total TGF-beta(2) in AH. None of the eyes showed significant IL-6 levels. In both corneal disease and cataract the amounts of IL-6 and TGF-beta(2) in AH thus suggest the presence of a normal immunological balance. This may have a positive influence on corneal graft survival. However, we observed raised levels of active TGF-beta(2) in age-group 61-80 years, which might be related to the onset of cataract development. PMID- 22827230 TI - Nedocromil sodium and sodium cromoglycate inhibit plasma extravasation in the guinea-pig conjunctiva. AB - Nedocromil sodium (NS) and sodium cromoglycate (CS) (both applied locally into the conjunctival sac) reduced in a dose dependent manner plasma extravasation induced by topical bradykinin and by topical substance P (SP), NS being approximately ten times more potent than CS. Plasma extravasation induced by SP was unaffected by the histamine H(1) receptor antagonist, pyrilamine, which completely blocked the plasma extravasation induced by histamine. NS and CS reduced the plasma extravasation caused by the mechanical stimulation of the conjunctiva, a response that was not affected by the tachykinin NK(1) antagonist CP-(99.994). NS or CS did not affect the contraction of strips of the guinea-pig trachea in vitro caused by SP in the presence of the tachykinin NK(2) receptor antagonist SR-(48968). NS, more potently than CS, reduces the plasma extravasation caused by various inflammatory stimuli in the guinea-pig conjunctiva, without inhibiting tachykinin NK(1) receptors, but probably by acting at the level of the venular endothelium. However, an inhibitory action of NS and CS on neural transmission of sensory nerves cannot be excluded. PMID- 22827231 TI - Tuberculosis presenting with sudden loss of vision. AB - A 22-year old woman presented with unilateral painless sudden loss of vision due to a solitary choroidal granuloma with exudative neurosensory retinal detachment. Her medical history was negative. Her systemic examination was unremarkable except for a positive tuberculin skin test and mildly enlarged cervical lymph nodes, the biopsy of which confirmed the diagnosis of tuberculosis. Fundus fluorescein angiography showed the choroidal lesion with multiple small hyperfluorescent spots and central pigment epithelial detachment. Choroidal tuberculoma resolved completely, with full recovery of vision following antituberculous treatment. To the best of the authors" knowledge, this is the first report of a tuberculoma of the choroid leading to the diagnosis and treatment of tuberculous lymphadenitis. PMID- 22827232 TI - Involvement of cell adhesion molecules in the pathogenesis of experimental autoimmune uveoretinitis. AB - Cell adhesion molecules (CAMs) are cell surface proteins that are important for the interaction between cells and the extracellular matrix. These CAMs are critical for the migration of leukocytes to areas of inflammation. In addition, CAMs are involved in the interaction of lymphocytes and antigen presenting cells, and play an integral role in lymphocyte stimulation. Experimental autoimmune uveoretinitis (EAU) is an experimental model of posterior uveitis in humans. Recent studies show that CAM expression is upregulated in eyes with EAU. Furthermore, studies have now demonstrated that antibodies against certain CAMs can inhibit EAU. This paper reviews the role of CAMs in EAU. PMID- 22827233 TI - News from the international ocular inflammation society: 4th isaac cesar michaelson medal and prize. PMID- 22827234 TI - Shifts in comparative advantages for maize, oat and wheat cropping under climate change in Europe. AB - Climate change is anticipated to affect European agriculture, including the risk of emerging or re-emerging feed and food hazards. Indirectly, climate change may influence such hazards (e.g. the occurrence of mycotoxins) due to geographic shifts in the distribution of major cereal cropping systems and the consequences this may have for crop rotations. This paper analyses the impact of climate on cropping shares of maize, oat and wheat on a 50-km square grid across Europe (45 65 degrees N) and provides model-based estimates of the changes in cropping shares in response to changes in temperature and precipitation as projected for the time period around 2040 by two regional climate models (RCM) with a moderate and a strong climate change signal, respectively. The projected cropping shares are based on the output from the two RCMs and on algorithms derived for the relation between meteorological data and observed cropping shares of maize, oat and wheat. The observed cropping shares show a south-to-north gradient, where maize had its maximum at 45-55 degrees N, oat had its maximum at 55-65 degrees N, and wheat was more evenly distributed along the latitudes in Europe. Under the projected climate changes, there was a general increase in maize cropping shares, whereas for oat no areas showed distinct increases. For wheat, the projected changes indicated a tendency towards higher cropping shares in the northern parts and lower cropping shares in the southern parts of the study area. The present modelling approach represents a simplification of factors determining the distribution of cereal crops, and also some uncertainties in the data basis were apparent. A promising way of future model improvement could be through a systematic analysis and inclusion of other variables, such as key soil properties and socio-economic conditions, influencing the comparative advantages of specific crops. PMID- 22827235 TI - The effects of a positive health priming intervention on somatic complaints. AB - Somatic complaints are common and form a major burden. Previous studies suggested that such complaints might be increased by 'illness-related memory', for example due to worries about health. In this ambulatory study we tested whether we could decrease somatic complaints through enhancing the activation of health-related memory by a 'positive health'-priming intervention. Forty-three students were randomly assigned to the 'positive health'-group or a control group. Using online measures, participants reported negative affect (NA) and somatic complaints for a period of six days, while each morning performing the priming task. The intervention caused a decrease in somatic complaints but only for participants with low trait NA or low somatosensory amplification. These findings seem to suggest that priming or other interventions directed at activating positive health memory might reduce health complaints, but only in certain subgroups. PMID- 22827236 TI - Vaccines for hantaviruses: progress and issues. PMID- 22827237 TI - The dynamic and changing epidemiology of meningococcal disease at the country based level: the experience in Turkey. PMID- 22827239 TI - MenACWY-TT vaccine for active immunization against invasive meningococcal disease. AB - Meningococcal disease remains a significant global cause of morbidity and mortality despite the availability of polysaccharide and conjugate vaccines. The implementation of monovalent meningococcal serogroup C vaccine in developed countries has significantly decreased the incidence of meningococcal disease, while the recent introduction of monovalent serogroup A conjugate vaccine in the African meningitis belt aims to reduce the incidence of high endemic disease in this area. Three quadrivalent meningococcal vaccines have already been licensed; a polysaccharide (MenACWY-PS) and two conjugated (MenACWY-DT and MenACWY-CRM) vaccines. An investigational MenACWY-TT vaccine is described in this article. Clinical trials in infants older than 9 months of age, toddlers, children, adolescents and adults have indicated that this vaccine is well tolerated and immunogenic. The inclusion of a spacer molecule coupled with the polysaccharide (for serogroups A and C) and tetanus toxoid as the carrier protein aims to elicit robust immune responses. The tolerability of this vaccine is comparable to that of polysaccharide quadrivalent vaccines and monovalent meningococcal serogroup C vaccines. More importantly, the immunogenicity, antibody persistence and induction of immune memory aim to provide protection to a wide range of susceptible subjects. PMID- 22827240 TI - Solid vaccine protection against SIV in rhesus monkeys provides proof-of-concept for further evaluation of a novel HIV vaccine approach in humans. AB - Protection against acquisition of fully heterologous, neutralization-resistant SIV was achieved in rhesus monkeys with adenovirus/poxvirus vector-based vaccines. Protection against acquisition of infection required the inclusion of envelope antigens and correlated with the induction of binding antibodies against the Env protein. The vaccines also facilitate virological control in vaccinated animals that became infected, correlating with multiple humoral and cell-mediated immune responses, especially against the Gag protein. These results are discussed in the context of human trials, particularly the Thai RV144 efficacy trial. PMID- 22827241 TI - Dynamic modeling for pandemic influenza. AB - It is now widely agreed upon that most infectious diseases require a dynamic approach to validly analyze infectious disease control. Given the size of the spread and the potential impact, pandemic influenza certainly presents an area where dynamic modeling is much needed. In this article, a dynamic model used for pandemic influenza is analyzed. The future challenge is to couple such complex dynamic models to economic information to inform decision-makers on the relative cost-effectiveness of interventions. PMID- 22827242 TI - Cationic liposomal vaccine adjuvants in animal challenge models: overview and current clinical status. AB - Cationic liposome formulations can function as efficient vaccine adjuvants. However, due to the highly diverse nature of lipids, cationic liposomes have different physical-chemical characteristics that influence their adjuvant mechanisms and their relevance for use in different vaccines. These characteristics can be further manipulated by incorporation of additional lipids or stabilizers, and inclusion of carefully selected immunostimulators is a feasible strategy when tailoring cationic liposomal adjuvants for specific disease targets. Thus, cationic liposomes present a plasticity, which makes them promising adjuvants for future vaccines. This versatility has also led to a vast amount of literature on different experimental liposomal formulations in combination with a wide range of immunostimulators. Here, we have compiled information about the animal challenge models and administration routes that have been used to study vaccine adjuvants based on cationic liposomes and provide an overview of the applicability, progress and clinical status of cationic liposomal vaccine adjuvants. PMID- 22827243 TI - Considerations for setting the specifications of vaccines. AB - The specifications of vaccines are determined by the particular product and its method of manufacture, which raise issues unique to the vaccine in question. However, the general principles are shared, including the need to have sufficient active material to immunize a very high proportion of recipients, an acceptable level of safety, which may require specific testing or may come from the production process, and an acceptable low level of contamination with unwanted materials, which may include infectious agents or materials used in production. These principles apply to the earliest smallpox vaccines and the most recent recombinant vaccines, such as those against HPV. Manufacturing development includes more precise definitions of the product through improved tests and tighter control of the process parameters. Good manufacturing practice plays a major role, which is likely to increase in importance in assuring product quality almost independent of end-product specifications. PMID- 22827244 TI - Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production. AB - In the 20th century, three influenza pandemics killed approximately 100 million people. The traditional method of influenza vaccine manufacturing is based on using chicken eggs. However, the necessity of the availability of millions of fertile eggs in the event of a pandemic has led research to focus on the development of cell culture-derived vaccines, which offer shorter lead-in times and greater flexibility of production. So far, the cell substrates being evaluated and in use include Vero, Madin-Darby canine kidney, PER.C6 and insect cells. However, Vero cells are the most widely accepted among others. This review introduces briefly the concepts of advanced cell culture-derived influenza vaccine production and highlights the advantages of these vaccines in terms of efficiency, speed and immunogenicity based on the clinical data obtained from different studies. PMID- 22827245 TI - Mucosal immunity and nasal influenza vaccination. AB - Influenza remains a threat to public health, with immunization being a suitable method of infection prevention and control. Our understanding of the immunological regulations at the mucosa, antigen processing and presentation, and B-cell activation has improved, enabling research and targeted induction of immune responses at the site of antigen delivery. Nasal influenza immunization has distinct features compared with intramuscular vaccines, providing protection at the pathogen's entry site, higher levels of mucosal antibodies, cross protection and needle-free application. This review summarizes our knowledge about mucosal immunity and the experience from clinical trials on the impact and safety of nasal influenza vaccination. PMID- 22827246 TI - Risks associated with the use of live-attenuated vaccine poliovirus strains and the strategies for control and eradication of paralytic poliomyelitis. AB - The Global Polio Eradication Initiative was launched in 1988 with the aim to eliminate paralytic poliomyelitis. Two effective vaccines are available: inactivated polio vaccine (IPV) and oral polio vaccine (OPV). Since 1964, OPV has been used instead of IPV in most countries due to several economic and biological advantages. However, in rare cases, the live-attenuated Sabin strains of OPV revert to neurovirulence and cause vaccine-associated paralytic poliomyelitis in vaccinees or lead to emergence of vaccine-derived poliovirus strains. Attenuating mutations and recombination events have been associated with the reversion of vaccine strains to neurovirulence. The substitution of OPV with an improved new generation IPV and the availability of new specific drugs against polioviruses are considered as future strategies for outbreak control and the eradication of paralytic poliomyelitis worldwide. PMID- 22827248 TI - Public willingness to pay for recovering and downlisting threatened and endangered marine species. AB - Nonmarket valuation research has produced economic value estimates for a variety of threatened, endangered, and rare species around the world. Although over 40 value estimates exist, it is often difficult to compare values from different studies due to variations in study design, implementation, and modeling specifications. We conducted a stated-preference choice experiment to estimate the value of recovering or downlisting 8 threatened and endangered marine species in the United States: loggerhead sea turtle (Caretta caretta), leatherback sea turtle (Dermochelys coriacea), North Atlantic right whale (Eubalaena glacialis), North Pacific right whale (Eubalaena japonica), upper Willamette River Chinook salmon (Oncorhynchus tshawytscha), Puget Sound Chinook salmon (Oncorhynchus tshawytscha), Hawaiian monk seals (Monachus schauinslandi), and smalltooth sawfish (Pristis pectinata). In May 2009, we surveyed a random sample of U.S. households. We collected data from 8476 households and estimated willingness to pay for recovering and downlisting the 8 species from these data. Respondents were willing to pay for recovering and downlisting threatened and endangered marine taxa. Willingness-to-pay values ranged from $40/household for recovering Puget Sound Chinook salmon to $73/household for recovering the North Pacific right whale. Statistical comparisons among willingness-to-pay values suggest that some taxa are more economically valuable than others, which suggests that the U.S. public's willingness to pay for recovery may vary by species. PMID- 22827249 TI - Editorial: ion fluxes and cancer. PMID- 22827250 TI - Update in pharmacological management of coronary no-reflow phenomenon. AB - The no-reflow phenomenon (NRP) is defined as the lack of adequate myocardial tissue perfusion despite a patent epicardial coronary artery. The incidence of NRP varies between 2-5% of elective percutaneous coronary interventions (PCI) and 30% in primary PCI. Clinically, it is an independent predictor of myocardial infarction, in-hospital mortality, and long-term mortality. It may be categorized in interventional (after PCI, especially in saphenous venous grafts) or reperfusion NRP (after re-opening of a totally occluded coronary artery, usually during primary PCI or thrombolysis). There are many physiopathological factors implicated: distal microembolization, interstitial and intracellular edema, coronary spasm and capillary plugging. Although reperfusion and no reflow is a field of intense research, no single mechanical or pharmacological therapy has demonstrated a clear efficacy against NRP, probably due to its multifactorial nature. Once established, the treatment of NRP is based on vasodilators like adenosine, verapamil, nitroprusside or nicorandil. However, the efficacy of these measures is poor, so every effort should be made to prevent the apparition of NRP. The objective of this report is to provide an update of the pharmacological armamentarium available for the prevention and treatment of NRP, and suggest a systematic approach of the management of NRP according to the different possible clinical scenarios. PMID- 22827252 TI - Analysis of high dimensional data using pre-defined set and subset information, with applications to genomic data. AB - BACKGROUND: Based on available biological information, genomic data can often be partitioned into pre-defined sets (e.g. pathways) and subsets within sets. Biologists are often interested in determining whether some pre-defined sets of variables (e.g. genes) are differentially expressed under varying experimental conditions. Several procedures are available in the literature for making such determinations, however, they do not take into account information regarding the subsets within each set. Secondly, variables (e.g. genes) belonging to a set or a subset are potentially correlated, yet such information is often ignored and univariate methods are used. This may result in loss of power and/or inflated false positive rate. RESULTS: We introduce a multiple testing-based methodology which makes use of available information regarding biologically relevant subsets within each pre-defined set of variables while exploiting the underlying dependence structure among the variables. Using this methodology, a biologist may not only determine whether a set of variables are differentially expressed between two experimental conditions, but may also test whether specific subsets within a significant set are also significant. CONCLUSIONS: The proposed methodology; (a) is easy to implement, (b) does not require inverting potentially singular covariance matrices, and (c) controls the family wise error rate (FWER) at the desired nominal level, (d) is robust to the underlying distribution and covariance structures. Although for simplicity of exposition, the methodology is described for microarray gene expression data, it is also applicable to any high dimensional data, such as the mRNA seq data, CpG methylation data etc. PMID- 22827251 TI - On the role of endothelial TRPC3 channels in endothelial dysfunction and cardiovascular disease. AB - In endothelium, calcium (Ca(2+)) influx through plasma membrane Ca(2+)-permeable channels plays a fundamental role in several physiological functions and in the pathogenesis of cardiovascular disease. Current knowledge on the influence of Ca(2+) influx in signaling events associated to endothelial dysfunction has grown significantly over recent years, particularly after identification of members of the Transient Receptor Potential Canonical (TRPC) family of channel forming proteins as prominent mediators of Ca(2+) entry in endothelial cells. Among TRPC members TRPC3 has been at the center of many of these physiopathological processes. Progress in elucidating the mechanism/s underlying regulation of endothelial TRPC3 and characterization of signaling events downstream TRPC3 activation are of most importance to fully appreciate the role of this peculiar cation channel in cardiovascular disease and its potential use as a therapeutic target. In this updated review we focus on TRPC3 channels, revising and discussing current knowledge on channel expression and regulation in endothelium and the roles of TRPC3 in cardiovascular disease in relation to endothelial dysfunction. PMID- 22827253 TI - Factors influencing the adoption of home telecare by elderly or chronically ill people: a national survey. AB - AIMS AND OBJECTIVES: The primary aim is to provide insight into client characteristics and characteristics of home telecare contacts, which may influence the adoption of home telecare. Secondary aim is to examine the applicability of four perceived attributes in Rogers' diffusion of innovations theory, which may influence the adoption: relative advantage, compatibility, complexity and observability. BACKGROUND: Western countries face strongly increasing healthcare demands. At the same time, a growing nursing shortage exists. The use of home telecare may be instrumental in improving independence and safety and can provide support to older and chronically ill people, but a precondition for its uptake is that clients consider it as a useful and helpful technological tool. DESIGN: A survey conducted among clients of seven home care organisations in the Netherlands connected to a home telecare system. METHODS: In 2007, a postal questionnaire was distributed to 468 older or chronically ill clients: 254 responded (54%). The data were analysed by regression techniques, employing a theoretical model. RESULTS: This study showed that clients' perceived attributes - relative advantage, compatibility, complexity and observability - have a significant effect on adoption of home telecare explaining 61% of the variance. The chance of adoption is higher when a client already receives long term personal and/or nursing care, he/she lives alone and when there are fixed daily contacts via the home telecare system. The perception of possible benefits can still be enhanced. CONCLUSIONS: The concept of perceived attributes, derived from Rogers' diffusion of innovation theory, has been useful to explain clients' adoption of home telecare. RELEVANCE TO CLINICAL PRACTICE: Home care organisations can best focus on clients already in care and people living alone, in offering home telecare. Nurses, who aim to enhance the client's adoption of home telecare, have to take into account clients' perceived attributes of such new technology. PMID- 22827255 TI - Branched polymeric media: boron-chelating resins from hyperbranched polyethylenimine. AB - Extraction of boron from aqueous solutions using selective resins is important in a variety of applications including desalination, ultrapure water production, and nuclear power generation. Today's commercial boron-selective resins are exclusively prepared by functionalization of styrene-divinylbenzene (STY-DVB) beads with N-methylglucamine to produce resins with boron-chelating groups. However, such boron-selective resins have a limited binding capacity with a maximum free base content of 0.7 eq/L, which corresponds to a sorption capacity of 1.16 +/- 0.03 mMol/g in aqueous solutions with equilibrium boron concentration of ~70 mM. In this article, we describe the synthesis and characterization of a new resin that can selectively extract boron from aqueous solutions. We show that branched polyethylenimine (PEI) beads obtained from an inverse suspension process can be reacted with glucono-1,5-D-lactone to afford a resin consisting of spherical beads with high density of boron-chelating groups. This resin has a sorption capacity of 1.93 +/- 0.04 mMol/g in aqueous solution with equilibrium boron concentration of ~70 mM, which is 66% percent larger than that of standard commercial STY-DVB resins. Our new boron-selective resin also shows excellent regeneration efficiency using a standard acid wash with a 1.0 M HCl solution followed by neutralization with a 0.1 M NaOH solution. PMID- 22827256 TI - Natural killer (NK)/T-cell lymphoma mimicking granulomatosis with polyangiitis (Wegener's). PMID- 22827257 TI - Directional and path-finding motion of polymer hydrogels driven by liquid mixing. AB - The spreading of a miscible liquid with a low surface tension on a water surface generates the directional motion of submerged polymer hydrogels, which could be attributed to convective flows resulting from the gradient of surface tension along the surface (Marangoni effect). The direction and velocity of this motion can be well controlled by altering the driving conditions. Furthermore, a spherical hydrogel can smartly find the path to walk through a microfluidic maze when liquid mixing occurs near the maze exit. This convenient chemical driving approach to transporting submerged objects in a desired way may be useful in microfluidics, micromechanics, and other applications. PMID- 22827258 TI - Fatally flawed? A review and ethical analysis of lethal congenital malformations. AB - Prenatally diagnosed abnormalities that are associated with death in the newborn period are often referred to as 'lethal malformations'. Yet, for many of the commonly described lethal malformations long-term survival is possible if supportive interventions are provided. In this paper we analyse and review fetal or congenital lethal abnormalities. The designation 'lethal' overlaps with the concept of 'medical futility'. The term is used for a heterogenous group of conditions, and hinders clear communication and counselling. We argue that the term should be avoided, and propose in its place a set of key questions that should be addressed by counselling. PMID- 22827259 TI - Human skin equivalents are an excellent tool to study the effect of moisturizers on the water distribution in the stratum corneum. AB - In this study, the mode of action of moisturizers on the level of water in the stratum corneum was studied using cryo-scanning electron microscopy. As model for dry skin, we used human skin equivalents (HSEs) generated at 93% or 60% relative humidity (RH). During the generation of the HSEs, the moisturizers were applied during a period of maximal 2 weeks. In HSEs generated under normal culture conditions (93% RH), application of 10% glycerol or 5% urea formulations resulted in increased water levels. Whereas the 5% urea formulations resulted mainly in the formation of intercellular water domains, after 10% glycerol both swelling of corneocytes and formation of intercellular water domains were noticed. A reduction in RH to 60% during treatment reduced the stratum corneum water levels drastically. Treatment with the non-occlusive lipophilic moisturizer isopropyl isostearate resulted in increased water level in the central part of the stratum corneum compared with the untreated control. Our results show that HSEs can be used as a model to study the water distribution. PMID- 22827261 TI - Phlebotominae of epidemiological importance in cutaneous leishmaniasis in northwestern Argentina: risk maps and ecological niche models. AB - In Argentina, 58.2% out of the 8126 Cutaneous Leishmaniasis (CL) incident cases accumulated from 1954 to 2006 were reported in the provinces of Salta and Jujuy. The aim of this study was to develop an exploratory risk map and a potential distribution map of the vector, in order to offer recommendations for CL prevention. A total of 12 079 Phlebotominae (Diptera: Psychodidae) belonging to the species Lutzomyia neivai (Pinto), Lu. migonei (Franca), Lu. cortelezzii (Brethes), Lu. shannoni (Dyar), Lu. quinquefer (Dyar) and Brumptomyia spp. (Franca & Parrot) were captured. Potential distribution models were created for two species, Lu. neivai (incriminated vector of Leishmania braziliensis) and Lu. migonei, associated with domestic animals in Argentina and that in turn could be involved as a link between zoonotic transmission cycles and anthropozoonotic. The Maximum Entropy Modeling System (MaxEnt) was used. The Jackknife test was performed, and the 'rainfall of the driest month' was the variable that best generalized the models. Accuracy was evaluated by the area under the curve (AUC) and validated by the Cohen's kappa index. This approximation provides a new analytical resource of high potential for the prevention of the disease, in order to allocate resources properly and to develop the most suitable strategies for action. PMID- 22827264 TI - Metagenomic analysis of hadopelagic microbial assemblages thriving at the deepest part of Mediterranean Sea, Matapan-Vavilov Deep. AB - The marine pelagic zone situated > 200 m below the sea level (bls) is the largest marine subsystem, comprising more than two-thirds of the oceanic volume. At the same time, it is one of the least explored ecosystems on Earth. Few large-scale environmental genomics studies have been undertaken to examine the phylogenetic diversity and functional gene repertoire of planktonic microbes present in mesopelagic and bathypelagic environments. Here, we present the description of the deep-sea microbial community thriving at > 4900 m depth in Matapan-Vavilov Deep (MVD). This canyon is the deepest site of Mediterranean Sea, with a deepest point located at approximately 5270 m, 56 km SW of city Pylos (Greece) in the Ionian Sea (36 degrees 34.00N, 21 degrees 07.44E). Comparative analysis of whole metagenomic data revealed that unlike other deep-sea metagenomes, the prokaryotic diversity in MVD was extremely poor. The decline in the dark primary production rates, measured at 4908 m depth, was coincident with overwhelming dominance of copiotrophic Alteromonas macleodii'deep-ecotype' AltDE at the expense of other prokaryotes including those potentially involved in both autotrophic and anaplerotic CO(2) fixation. We also demonstrate the occurrence in deep-sea metagenomes of several clustered regularly interspaced short palindromic repeats systems. PMID- 22827262 TI - Detection and kinetic characterization of a highly reactive heme-thiolate peroxygenase compound I. AB - The extracellular heme-thiolate peroxygenase from Agrocybe aegerita (AaeAPO) has been shown to hydroxylate alkanes and numerous other substrates using hydrogen peroxide as the terminal oxidant. We describe the kinetics of formation and decomposition of AaeAPO compound I upon its reaction with mCPBA. The UV-vis spectral features of AaeAPO-I (361, 694 nm) are similar to those of chloroperoxidase-I and the recently described cytochrome P450-I. The second-order rate constant for AaeAPO-I formation was 1.0 (+/-0.4) * 10(7) M(-1) s(-1) at pH 5.0, 4 degrees C. The relatively slow decomposition rate, 1.4 (+/-0.03) s(-1), allowed the measurement of its reactivity toward a panel of substrates. The observed rate constants, k2', spanned 5 orders of magnitude and correlated linearly with bond dissociation enthalpies (BDEs) of strong C-H bond substrates with a log k2' vs BDE slope of ~0.4. However, the hydroxylation rate was insensitive to a C-H BDE below 90 kcal/mol, similar to the behavior of the tert butoxyl radical. The shape and slope of the Bronsted-Evans-Polanyi plot indicate a symmetrical transition state for the stronger C-H bonds and suggest entropy control of the rate in an early transition state for weaker C-H bonds. The AaeAPO II Fe(IV)O-H BDE was estimated to be ~103 kcal/mol. All results support the formation of a highly reactive AaeAPO oxoiron(IV) porphyrin radical cation intermediate that is the active oxygen species in these hydroxylation reactions. PMID- 22827265 TI - Silver migration from silver-modified activated carbon applied as a water filtration medium in classic cartridges of jug filter systems. AB - A comprehensive study was undertaken in order to examine the possible adverse effect of jug filter systems (JFSs) on the quality of filtered water taking into account the released amounts of silver (Ag) into the filtered test water. Nine brands of JFSs (A-I) were investigated according to BS 8427:2004 using a validated ICP/MS method. Essential modification of BS 8427:2004 within the domain of the composite sample preparation was proposed and applied during the tests. The established grand mean concentrations of released Ag from A-H classic cartridges (containing Ag-modified activated carbon and ion exchange resins) and I classic cartridge (containing non-modified activated carbon and ion exchange resin) installed in corresponding JFSs were in the range of 2.6-13.1 ug l-1 and lower than 0.014 ug l-1, respectively. These values were applied for the estimation of the daily intakes of Ag connected with the consumption of water filtered using JFSs (ranging from < 0.0004 to 0.374 ug kg-1 day-1). After taking into account the grand mean concentrations of Ag established during the whole cycle of exploitation for nine JFSs and on the basis of available toxicological data for this element, no long-term risk for human health with respect to appearance of argyria (a condition caused by improper exposure to the Ag or Ag compounds) could be expected (the Hazard Quotient indices estimated as ratios of the daily intakes to the reference dose of Ag were equal or lower than 0.075). Ag modified activated carbon is not included in the positive list of the authorised substances of the European Commission Regulation (EU) No. 10/2011. Additionally, this material has not been approved by European Food Safety Authority (EFSA). A part of water filtered by JFSs can be directly consumed as drinking water and additionally the remaining water can be applied for the preparation of food products (drinks, soups, etc.). In both cases the quality of water has to fulfil the requirements listed in Directive 98/83/EC (Regulation (EC) No. 178/2002 defines the quality of water intentionally incorporated into the food after the point of compliance as defined in Article 6 of Directive 98/83/EC). However, it should be underlined that point-of-use water treatment units (including JFSs) are not regulated under Directive 98/83/EC and additionally the parametric value for Ag is not included in this document. Therefore, a provisional migration limit for Ag leached from JFSs at the level of 25 ug l-1 was proposed. This value for Ag would limit intake to less than 13% of the human No Observed Adverse Effect Level (NOAEL) (0.39 mg person-1 day-1), using an assumption that each day 2 L of filtered water is consumed containing this metal at the provisional migration limit. All the JFSs tested meet this requirement. PMID- 22827266 TI - Conflation of values and science: response to Noss et al. PMID- 22827267 TI - Hax-1 is rapidly degraded by the proteasome dependent on its PEST sequence. AB - BACKGROUND: HS-1-associated protein X-1 (Hax-1), is a multifunctional protein that has sequence homology to Bcl-2 family members. HAX-1 knockout animals reveal that it plays an essential protective role in the central nervous system against various stresses. Homozygous mutations in the HAX-1 gene are associated with autosomal recessive forms of severe congenital neutropenia along with neurological symptoms. The protein level of Hax-1 has been shown to be regulated by cellular protease cleavage or by transcriptional suppression upon stimulation. RESULTS: Here, we report a novel post-translational mechanism for regulation of Hax-1 levels in mammalian cells. We identified that PEST sequence, a sequence rich in proline, glutamic acid, serine and threonine, is responsible for its poly ubiquitination and rapid degradation. Hax-1 is conjugated by K48-linked ubiquitin chains and undergoes a fast turnover by the proteasome system. A deletion mutant of Hax-1 that lacks the PEST sequence is more resistant to the proteasomal degradation and exerts more protective effects against apoptotic stimuli than wild type Hax-1. CONCLUSION: Our data indicate that Hax-1 is a short-lived protein and that its PEST sequence dependent fast degradation by the proteasome may contribute to the rapid cellular responses upon different stimulations. PMID- 22827268 TI - Ultraviolet-tunable laser induced phototransformations of matrix isolated isoeugenol and eugenol. AB - In situ photochemical transformations of monomers of 2-methoxy-4-(prop-1 enyl)phenol (isoeugenol) and 2-methoxy-4-(prop-2-enyl)phenol (eugenol) isolated in low temperature matrices were induced by tunable UV laser light, and the progress of the reactions was followed by FTIR spectroscopy. Conformer-selective E <-> Z geometrical isomerizations could be successfully induced by irradiation at different wavelengths from the 310-298 nm range in the isoeugenol molecule, contains an asymmetrically substituted exocyclic C?C bond. Photolysis of both studied compounds was also observed, with H-atom shift from the OH group and formation of two types of long-chain conjugated ketenes. The photoproduced ketenes were found to undergo subsequent photodecarbonylation. Interpretation of the observed photoprocesses was supported by quantum chemical calculations undertaken at different levels of theory (DFT, MP2, QCISD). PMID- 22827269 TI - Characterization of Arabidopsis calcium-dependent protein kinases: activated or not by calcium? AB - CDPKs (calcium-dependent protein kinases), which contain both calmodulin-like calcium binding and serine/threonine protein kinase domains, are only present in plants and some protozoans. Upon activation by a stimulus, they transduce the signal through phosphorylation cascades to induce downstream responses, including transcriptional regulation. To understand the functional specificities of CDPKs, 14 Arabidopsis CPKs (CDPKs in plants) representative of the three main subgroups were characterized at the biochemical level, using HA (haemagglutinin)-tagged CPKs expressed in planta. Most of them were partially or mainly associated with membranes, in agreement with acylation predictions. Importantly, CPKs displayed highly variable calcium-dependences for their kinase activities: seven CPKs from subgroups 1 and 2 were clearly sensitive to calcium with different intensities, whereas six CPKs from subgroup 3 exhibited low or no calcium sensitivity to two generic substrates. Interestingly, this apparent calcium-independence correlated with significant alterations in the predicted EF-hands of these kinases, although they all bound calcium. The noticeable exception, CPK25, was calcium-independent owing to the absence of functional EF-hands. Taken together, the results of the present study suggest that calcium binding differentially affects CDPK isoforms that may be activated by distinct molecular mechanisms. PMID- 22827270 TI - Autophagy and Its Comprehensive Impact on ALS. AB - Autophagy is a degradative modality that involves intracellular elimination of proteins and organelles by lysosomes. It is a conservative process and plays a crucial role in cell growth and development, and keeping cellular homeostasis especially under stress-induced situations. Recently, increasing evidence suggests that autophagic alternations may contribute to amyotrophic lateral sclerosis (ALS) as one of initial factors. LC3-II and p62 are found increased in spinal cord of both ALS patients and experimental models, indicating overwhelming autophagic level. But the aggregation of ALS-associated proteins, including SOD1 and TDP-43 suggest possible insufficiency of autophagy induction. Besides, augment autophagic level through genetic pathway or rapamycin leads to paradoxical results in different neurodegenerative diseases models. So, it remains controversial about autophagic effects on ALS progress. In this review, we will depict a comprehensive role that autophagy plays in ALS and focus on the influence of impaired autophagic flux and excessive autophagic vacuoles (AVs) that may aggregate ALS development. And we will discuss the potential therapeutic targets through modulating autophagic level to treat this disease. PMID- 22827271 TI - Intraocular inflammation in transgenic mice expressing a foreign antigen in their lens a preliminary report. AB - Lens-induced uveitis can be elicited in experimental animals by immunization with lens antigens, followed by puncture of the lens capsule. The animal disease, that serves as a model for the human disease (also known as phacoanaphylactic endophthalmitis), has been shown to be mediated by antibodies against the lens antigens. Here the authors report on a new disease model for lens-induced uveitis which is cell-mediated. This experimental disease is induced in transgenic (Tg) mice that express hen egg lysozyme (HEL) in their lens. Eyes of these mice show disrupted lens, but no inflammation. On the other hand, severe inflammation develops in eyes of these Tg mice following intraperitoneal injection of lymphocytes from syngeneic wildtype donors sensitized against HEL. Furthermore, the recipient mice exhibit intense cellular immunity but no antibodies against HEL. PMID- 22827272 TI - Production of IL-8 and the other cytokines by T cell clones established from the ocular fluid of patients with Behcet's disease. AB - Behcet's disease is a systemic inflammatory disease immunologically characterized by the infiltration of CD(4)(+)T cells and polymorphonuclear cells in the affected tissues, including the eye. Despite extensive studies, neither the etiology nor the pathogenic mechanism of Behcet's disease has been clarified. Production of cytokines by T cell clones (TCC) from the ocular fluid (18 CD(3)(+)CD(4)(+)CD8 clones and 4 CD(3)(+)CD(4)(-)CD8(+) clones) and peripheral blood mononuclear cells (PBMC) (16 CD(3)(+)CD(4)(+)CD8(-) clones) of two patients with uveitis associated with Behcet's disease was investigated to understand better the immunopathology of the disease. The level of IL-8 spontaneously produced by TCC from the ocular fluid (mean: 659 pg/ml) or PBMC (536 pg/ml) of the patients was significantly higher (p<0.005, and p<0.05, respectively) than that by TCC (18 CD(3)(+)CD(4)(+)(-)CD8(+) clones) and 4 CD(3)(+)CD(4)(-)CD8(+) clones) from PBMC of healthy donors (241 pg/ml). As for the other cytokines, IL Ialpha, IL-2, IL-6, IL-10, and TNF-alpha were produced at low but detectable amounts by the majority of TCC from the ocular fluid of patients with Behcet's disease; IL-3, IFN-Y, and GM-CSF were produced by some of TCC at low amounts; and IL-4 was not produced by any TCC tested. IL-8 production by TCC from the ocular fluid was further up-regulated upon stimulatation with PHA, but was suppressed by FK506 and hydrocortisone, though not by diclofenac sodium. Colchicine rather increased IL-8 production by these TCC. These results suggest that T cells in both the affected tissues and PBMC play an important role in the pathogenesis of uveitis associated with Behcet's disease through IL-8 and probably the other cytokines. PMID- 22827273 TI - Recurrence risk factors in patients with the Vogt-Koyanagi-Harada syndrome in Japan. AB - The Vogt-Koyanagi-Harada (VKH) syndrome is a form of recurrent uveitis with often a poor long-term visual acuity. The risk factors for recurrence of the VKH syndrome were investigated statistically by using a multiple logistic regression model. The clinical data of 87 patients were used for the statistical analysis. Among them, 58 patients (66.8%) had no recurrences, while 29 patients (33.3%) had recurrences. By multiple logistic regression analysis, dysacousia (p<0.01), cutaneous manifestations (p<0. 05), prodromal symptoms (p<0. 05), onset to treatment interval (days) (p<0. 05) and retinal detachment (p<0. 01) were significantly and independently associated with the recurrence. The Relapse Score was constructed by using a logistic model as follows: Relapse Score=+1. 459X (Dysacousia) + 1. 458x (Cutaneous manifestations) +0. 032x (Onset to treatment interval) -1. 637x (Prodromal symptoms) -1. 773x (Retinal detachment)+1. 247. It is supposed that the Relapse Score might be helpful for predicting the clinical course and modifying the dose or duration of systemic steroid therapy of the patients with the VKH syndrome. PMID- 22827274 TI - Alternative routes of immunization for the induction of experimental autoimmune uveoretinitis (EAU) in rodents: a comparison. AB - Experimental autoimmune uveoretinitis (EAU) in rodents is a widely used model of ocular autoimmunity. EAU has traditionally been elicited by injecting the uveitogenic protein in complete Freund's adjuvant (CFA) into the footpad(s) (FP). Because this route of immunization causes severe arthritis and inflammation, it is being banned by many institutions and investigators are switching to the subcutaneous (SC) route. However, there are no studies that systematically compare the outcome of these two immunization routes using defined clinical, histopathological and immunological criteria. We therefore undertook to compare the FP and SC routes of immunization in the Lewis rat and in the B 10. A mouse models of EAU. Animals were immunized with interphotoreceptor retinoid-binding protein (IRBP) or the retinal soluble antigen (S-Ag) in CFA, either by the traditional FP route or by the SC route. The parameters studied were kinetics and severity of EAU by clinical observation and by histopathology, respectively, as well as immunological responses by delayed-type hypersensitivity (DTH), serum antibody titers and lymphocyte proliferation to the uveitogen. In mice immunized with graded doses of IRBP, development of disease induced by the FP and SC methods had essentially identical kinetics. However, the SC method resulted in a somewhat higher incidence and severity of disease as well as higher DTH at the lower antigen doses. Antibody titers tended to be higher with FP immunization. In rats immunized with S-Ag, kinetics and severity of disease, DTH, proliferative responses of draining lymph node cells to the immunizing antigen, and serum antibody titers induced by FP and SC methods were similar. In rats immunized with IRBP, SC immunization resulted in somewhat higher responses across the board than FP. We conclude that at higher doses of antigen disease scores and immunological responses in animals immunized SC are comparable to those of FP-immunized animals. At limiting doses of antigen, however, the SC route appears to result in more severe disease than the traditional FP method. PMID- 22827275 TI - Adhesion molecule expression on circulating lymphocytes and monocytes in patients with isolated idiopathic retinal vasculitis. AB - Idiopathic retinal vasculitis (RV) is a disease of unknown aetiology in which immune responses are involved in the pathogenesis of disease. T cells are thought to be important in this disease and there is evidence of peripheral T cell activation in a significant proportion of patients. The authors examined the expression of the leukocyte adhesion molecules (LeuCAMs) CD11a and CD18 on the peripheral T cells and monocytes of 11 patients with active idiopathic retinal vasculitis compared with 11 age, sex and race matched controls. Although the percentage of T cells expressing HLA DR was increased in the patient group the percentage of cells expressing CD11a and CD18 and the density, expressed as mean fluorescence intensity (MFI) were no different in the two groups. The expression of CD11a and CD18 on peripheral blood monocytes was also not found to be different between patients and controls. Adhesion between leukocytes and endothelial cells is essential for emigration of leukocytes and their accumulation in disease. Our findings suggest that any upregulation of leukocyte adhesion molecules occurring as part of this process is taking place in response to locally produced cytokines. PMID- 22827276 TI - Immunosuppression in Behcet's disease Clinical management and long-term visual outcome. AB - The authors review the visual prognosis of 44 patients with Behcet's disease referred to the Ophthalmology and Rheumatology Departments (Hospital S. Joao-one of the two major referral centers in Northern Portugal), due to ocular complaints or for routine examination, in the last ten years. All fulfilled the clinical criteria for diagnosis of Behcet's disease. Twenty-six were male and 18 female, with mean age 37 years (range 23-66). The mean evolution time since the first clinical manifestations was ten years (range 1-21). Aphthous stomatitis (100%) and genital ulcers (77.3%) were the initial manifestations preceding eye involvement. HLA-B(51)(5) was present in 27 of 36 typed patients (75%). Ocular manifestations were present in 33 patients (75%)-22 patients with panuveitis, eight with hypopyon, four with chronic anterior uveitis and three with episcleritis. Mean age of onset of ocular complications was 32 years (range 20 54). Retinal vaso-occlusive vasculitis was diagnosed in 26 patients (22 with panuveitis and four with posterior uveitis). To prevent ocular relapses, all needed immunosuppression with corticosteroids (drops, depo or systemic), combined with cyclosporine A (CsA) (5 mg/kg/day) in 13 patients and with chlorambucil or cyclophosphamide in six patients, when sight threatening uveitis had previously been refractory to treatment with systemic steroids. The 13 patients under CsA were observed for a period ranging from eight months to five years. Lowdose CsA was found to abrogate the intraocular inflammation, was well tolerated and had no major adverse effects. Regardless of the type of treatment, 21% (14/66) of the eyes lost useful vision five to ten years after initial diagnosis. PMID- 22827277 TI - Effect of extended wear disposable contact lenses on tear LTC4 in giant papillary conjunctivitis. AB - Disposable contact lenses have been proposed as an alternative treatment of giant papillary conjunctivitis (GPC), a common contact lens complication associated with increased tear inflammatory mediators, especially LTC(4). In this study, tear LTC(4) was determined by ELISA in tears from eight patients, fitted with disposable contact lenses for the treatment of manifest GPC. An initial decrease in tear LTC(4) in the first ten days of disposable contact lens wear was later followed by increased LTC(4) in six of eight patients (75%) at the end of the first month of disposable contact lens wear. The results of this study indicate that extended wear disposable contact lenses might have a limited place in GPC treatment, since they do not prevent pathogenic inflammatory mediator response in the long term. PMID- 22827278 TI - Suppression of experimental allergic conjunctivitis in guinea pigs by oral administration of antigen. AB - Feeding antigen can induce an immunological unresponsiveness termed oral tolerance. The authors examined the effect of the oral administration of two antigens, ovalbumin (OVA) and cedar pollen extract (CPE) on experimental allergic conjunctivitis in guinea pigs quantitatively. After the primary active immunization with either OVA or CPE, guinea pigs were given each antigen orally everyday. After five antigen injections, conjunctivitis was elicited by the instillation of the antigen eye drops. The early phase of allergic reaction was evaluated by measuring the leakage of Evans blue injected intravenously. The later inflammation was evaluated by the number of infiltrating leukocytes. Oral administration of both OVA and CPE significantly reduced conjunctival exudation. Cellular infiltration was also markedly diminished in the OVA-fed group. Serum levels of anti-OVA IgE and anti-CPE IgE antibodies were suppressed by feeding of each antigen, and there was a positive correlation between the IgE level and the amount of dye leakage. This result suggests that the conjunctivitis was suppressed because of the inhibition of antigen-specific IgE production. PMID- 22827279 TI - An unusual case of melanoma-associated retinopathy. AB - Paraneoplastic syndromes pose some of the most baffling clinical presentations encountered in medicine. Brain degenerations with accompanying dementia, peripheral neuritis and the Eaton-Lambert myasthenia gravis syndrome comprise a few examples of the clinical conditions which manifest as remote expressions of cancer. The uncontrolled expression of key proteins by cancers is thought responsible for inciting autoimmune reactions which affect the corresponding component within the host. Paraneoplastic retinopathies have been reported to occur in association with a variety of different types of cancer. Indications of retinal hypersensitivity manifest in these patients through the production of autoantibodies reactive with specific retinal cells or antigens. This form of vision loss is suspected to develop in ways similar to that proposed for other paraneoplasias, as a form of ocular hypersensitivity induced by the cancer's aberrant expression of specific retinal proteins. The subject of this report had a history of vision abnormalities linked with the surgical removal of a melanoma. The authors sought evidence of retinal hypersensitivity through a series of immunologic assays described by others to reveal a recognizable pattern of autoantibody reactions characteristic of patients with melanoma associated retinopathy, the MAR syndrome. Although autoantibodies were present, the authors were unable to identify any single retinal antigen or cell type which might represent the target of the patient's ostensibly autoimmune reactions. PMID- 22827280 TI - Characteristics of immunotolerance induced by intratesticular injection of S antigen. AB - Experimental autoimmune uveoretinitis (EAU) induced by immunization of male Lewis rats with bovine S-antigen (S-Ag) is prevented by injection of S-Ag into the testis prior to immunization. This protection of animals is due to the induction of systemic immunotolerance or immunosuppression, which the authors designate orchidic tolerance. In this paper they first present a brief review of several features of orchidic tolerance reported previously and features uncovered more recently, and then propose a possible sequence of events that is initiated by antigen challenge in the testis and results in the proliferation of specific subclasses of lymphocytes with immunosuppressive activity and prevention of the onset of EAU. PMID- 22827281 TI - Ocular immune privilege in the immunosuppressive intraocular microenvironment. AB - Immune privilege exists in the normal eye (anterior chamber, vitreous cavity, subretinal space): when foreign tissue/cellular grafts are placed in the eye, rejection is largely, if not completely, avoided. The ineffectiveness of the immune response in this circumstance results from eye-dependent alterations in (a) the induction of systemic immunity to graft antigens, and (b) the expression of cell-mediated immunity within the eye. Recent evidence indicates that eye derived factors, present in the intraocular microenvironment, modify the afferent and efferent limbs of the immune response. Studies of aqueous humor as a prototype of the intraocular microenvironment have demonstrated that this fluid profoundly inhibits antigen-driven T cell activation such that proliferation and lymphokine production are curtailed. Moreover, aqueous humor modifies the functional properties of conventional antigen presenting cells (APC) such that exogenous antigens are processed uniquely. When antigen-pulsed APC exposed to aqueous humor are injected intravenously, they induce Anterior Chamber Associated Immune Deviation (ACAID). Several factors in aqueous humor have been implicated as immunosuppressants: transforming growth factorbeta, alpha-melanocyte stimulating hormone, vasoactive intestinal peptide, calcitonin gene related peptide, and hydrocortisone (because Cortisol binding globulin is virtually absent). In certain experimentally-induced ocular disorders, resident ocular cells fail to secrete immunosuppressive factors constitutively, and this may explain why immune privilege is also lost. PMID- 22827283 TI - Intermittent traction stretch promotes the osteoblastic differentiation of bone mesenchymal stem cells by the ERK1/2-activated Cbfa1 pathway. AB - Mechanical stress plays a crucial role in bone formation and absorption. We investigated the osteoblastic differentiation of bone mesenchymal stem cells (BMSCs) affected by intermittent traction stretch at different time points and explored the mechanism of osteoblastic differentiation under this special mechanical stimulation. The BMSCs and C3H10T1/2 cells were subjected to 10% elongation for 1-7 days using a Flexcell Strain Unit, and then the mRNA levels of osteoblastic genes and the expression of core-binding factor a1 (Cbfa1) were examined. Furthermore, we focused specifically on the role of the extracellular signal-regulated kinases 1/2 (ERK1/2) and Cbfa1 in the osteogenesis of BMSCs stimulated by the stretch. The results of these experiments showed that the stretch induces a time-dependent increase in the expression of osteoblastic genes. The synthesis of osteoblastic genes was downregulated after the knockdown of Cbfa1 expression by short-interfering RNA. Furthermore, the stress-induced increase in the expression of Cbfa1 mRNA and osteoblastic genes was inhibited by U0126, an ERK1/2 inhibitor. These results indicate that long periods of intermittent traction stretch promote osteoblastic differentiation of BMSCs through the ERK1/2-activated Cbfa1 signaling pathway. PMID- 22827284 TI - Palladium-catalyzed annulation of allenes with indole-2-carboxylic acid derivatives: synthesis of indolo[2,3-c]pyrane-1-ones via Ar-I reactivity or C-H functionalization. AB - Two methodologies, one involving Ar-I reactivity and the other through C-H functionalization, for the formation of indolo[2,3-c]pyrane-1-ones via the corresponding allenes, are presented. A highly efficient approach to indolo[2,3 c]pyrane-1-one derivatives through the Pd-catalyzed regioselective annulation of allenes with 3-iodo-1-alkylindole-2-carboxylic acids is described. This method is fairly general for a wide range of allenes affording the respective indolo[2,3 c]pyrane-1-ones in good to excellent yields. In addition, a Pd(II)-catalyzed oxidative coupling of indole-2-caboxylic acid derivatives with allenes via direct C-H functionalization to afford the corresponding indolo[2,3-c]pyrane-1-ones in moderate to good yields has been developed. PMID- 22827285 TI - Targeted polymersome delivery of siRNA induces cell death of breast cancer cells dependent upon Orai3 protein expression. AB - Polymersomes, polymeric vesicles that self-assemble in aqueous solutions from block copolymers, have been avidly investigated in recent years as potential drug delivery agents. Past work has highlighted peptide-functionalized polymersomes as a highly promising targeted delivery system. However, few reports have investigated the ability of polymersomes to operate as gene delivery agents. In this study, we report on the encapsulation and delivery of siRNA inside of peptide-functionalized polymersomes composed of poly(1,2-butadiene)-b poly(ethylene oxide). In particular, PR_b peptide-functionalized polymer vesicles are shown to be a promising system for siRNA delivery. PR_b is a fibronectin mimetic peptide targeting specifically the alpha(5)beta(1) integrin. The Orai3 gene was targeted for siRNA knockdown, and PR_b-functionalized polymer vesicles encapsulating siRNA were found to specifically decrease cell viability of T47D breast cancer cells to a certain extent, while preserving viability of noncancerous MCF10A breast cells. siRNA delivery by PR_b-functionalized polymer vesicles was compared to that of a current commercial siRNA transfection agent, and produced less dramatic decreases in cancer cell viability, but compared favorably in regards to the relative toxicity of the delivery systems. Finally, delivery and vesicle release of a fluorescent encapsulate by PR_b-functionalized polymer vesicles was visualized by confocal microscopy, and colocalization with cellular endosomes and lysosomes was assessed by organelle staining. Polymersomes were observed to primarily release their encapsulate in the early endosomal intracellular compartments, and data may suggest some escape to the cytosol. These results represent a promising first generation model system for targeted delivery of siRNA. PMID- 22827286 TI - Arginase-1 expression in granulomas of tuberculosis patients. AB - Mycobacterium tuberculosis (Mtb) is an intracellular pathogen able to survive and multiply within macrophages. Several mechanisms allow this bacterium to escape macrophage microbicidal activity. Mtb may interfere with the ability of mouse macrophages to produce antibactericidal nitric oxide, by inducing the expression of arginase 1 (Arg1). It remains unclear whether this pathway has a role in humans infected with Mtb. In this study, we investigated the expression of Arg1 in granulomas of human lung tissues from patients with tuberculosis. We show that Arg1 is expressed not only in granuloma-associated macrophages, but also in type II pneumocytes. PMID- 22827288 TI - The effects of direct renin inhibitor, aliskiren, on arterial hypertension, chronic kidney disease and cardiovascular disease: optimal pharmacotherapy. AB - The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD. PMID- 22827287 TI - Dosage effects of X and Y chromosomes on language and social functioning in children with supernumerary sex chromosome aneuploidies: implications for idiopathic language impairment and autism spectrum disorders. AB - BACKGROUND: Supernumerary sex chromosome aneuploidies (X/Y-aneuploidies), the presence of extra X and/or Y chromosomes, are associated with heightened rates of language impairments and social difficulties. However, no single study has examined different language domains and social functioning in the same sample of children with tri-, tetra-, and pentasomy X/Y-aneuploidy. The current research sought to fill this gap in the literature and to examine dosage effects of X and Y chromosomes on language and social functioning. METHODS: Participants included 110 youth with X/Y-aneuploidies (32 female) and 52 with typical development (25 female) matched on age (mean ~12 years; range 4-22) and maternal education. Participants completed the Wechsler intelligence scales, and parents completed the children's communication checklist-2 and the social responsiveness scale to assess language skills and autistic traits, respectively. RESULTS: Both supernumerary X and Y chromosomes were related to depressed structural and pragmatic language skills and increased autistic traits. The addition of a Y chromosome had a disproportionately greater impact on pragmatic language; the addition of one or more X chromosomes had a disproportionately greater impact on structural language. CONCLUSIONS: Given that we link extra X chromosomes with structural language impairments and an extra Y chromosome with pragmatic language impairments, X/Y-aneuploidies may provide clues to genetic mechanisms contributing to idiopathic language impairment and autism spectrum disorders. PMID- 22827289 TI - Mechanisms of incretin effects on plasma lipids and implications for the cardiovascular system. AB - Dyslipidemia is a prominent feature of type 2 diabetes and insulin resistance that contributes to increased atherosclerosis and cardiovascular disease (CVD) risks under these conditions. Incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) have recently been developed and are approved for clinical use for treatment of type 2 diabetes. Besides improved glycemic control, other benefits are being increasingly appreciated, one of which is improved plasma lipid profile. This review aims to summarize the evidence and potential mechanism of such agents in humans in modulating fasting and postprandial lipoprotein metabolism. PMID- 22827290 TI - Cardiac protection via metabolic modulation: an emerging role for incretin-based therapies? AB - Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease. PMID- 22827291 TI - Incretin pharmacology: a review of the incretin effect and current incretin-based therapies. AB - Given the demonstrated importance of the incretin effect on the prandial insulin response, augmentation of the incretin effect in people with type 2 diabetes is an important pharmacological approach to glycemic management. In recent years, the use of incretin-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, has increased dramatically due to their demonstrated efficacy, low risk of hypoglycemia when used as monotherapy, and reasonable tolerability. Given their effects on glycemic parameters and the likelihood of aiding in weight loss, GLP-1 receptor agonists provide a unique treatment option for people with type 2 diabetes. Increased clinical experience and study of incretin-based therapies will help answer questions about safety issues that have arisen from post marketing reports. The potential benefit of incretin-based therapies in the treatment of people with type 2 diabetes and cardiovascular disease is currently an active area of inquiry. While the potential benefits of incretin-based therapies in the arena of cardiovascular risk reduction are promising, results from ongoing outcomes-based studies will help determine the role of these agents in this setting. PMID- 22827292 TI - Glucagon like Peptide-1 and atherosclerosis. AB - Patients with type 2 diabetes mellitus are at high risk for developing cardiovascular diseases. Traditional medicines for type 2 diabetes, such as sulfonylureas, pioglitazone, and insulin have glucose lowering effects; however, they also increase the frequency of hypoglycemia and/or body weight and thus may cancel out the benefits of glucose lowering on the development of atherosclerosis. In contrast, the recently developed glucagon like peptide-1 based therapy using glucagon-like peptide-1 receptor agonists or dipeptidyl peptidase-4 inhibitors has numerous beneficial effects in the management of hyperglycemia with less risk of hypoglycemia and weight gain. Glucagon-like peptide-1-based therapy also lowers blood pressure and blood lipids and thus may prevent progression of atherosclerosis. Furthermore, glucagonlike peptide-1 receptors are abundantly expressed in vascular cells such as endothelial cells, monocyte/macrophages and smooth muscle cells. Recent studies suggest that the anti-inflammatory and vasodilatory properties of glucagon-like peptide-1 signaling on endothelial cells, its anti-inflammatory effect on macrophages and anti-proliferative effects on smooth muscle cells may halt atherosclerosis. Although large clinical trials are required to confirm these beneficial effects, glucagon-like peptide-1-based therapy could provide both glucose lowering and protection against cardiovascular diseases in patients with type 2 diabetes. PMID- 22827293 TI - Editorial: beyond glycemic control: incretins and cardiovascular protection in diabetes. PMID- 22827294 TI - Incretins and preservation of endothelial function. AB - The endothelium is critical for multiple processes occurring on both sides of the vascular wall including regulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It is frequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelial dysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia, hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by synthetic glucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or by hyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improve endothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduit arteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitric oxide production. Additional studies are necessary to confirm improvement of endothelial function after prolonged treatment with incretin based medications as well as the cardiovascular benefit of these agents. PMID- 22827295 TI - Delivering laboratory results by text message and e-mail: a survey of factors associated with conceptual acceptability among STD clinic attendees. AB - OBJECTIVE: This study examines factors associated with the acceptability of receiving sexually transmitted disease (STD) laboratory results by text message and e-mail among clinic attendees. SUBJECTS AND METHODS: An anonymous self administered survey was conducted with a convenience sample of STD clinic attendees in South Carolina and Mississippi in 2009-2010. In total, 2,719 individuals with a median age of 26 years (interquartile range, 21-32 years) completed the survey. RESULTS: More than 70% had Internet access at home, and 80% reported using text messaging daily. Participants preferred receiving laboratory results by text message compared with e-mail (50.2% versus 42.3%; p<0.001). Acceptability of receiving laboratory results by text message was higher with younger age (adjusted odds ratio [aOR] 1.13; 95% confidence interval [CI] 1.10 1.26), daily use of text messaging (aOR 1.30; 95% CI 1.14-1.49), and reporting cell phone and text message as the preferred choice of regular communication with the clinic (aOR 2.31; 95% CI 1.50-3.58) and was significantly lower in female subjects (aOR 0.89; 95% CI 0.81-0.98) and those with college-level education (aOR 0.88; 95% CI 0.77-0.99). CONCLUSIONS: A majority of STD clinic attendees have access to cell phones and Internet. The acceptability of receiving STD laboratory results electronically may facilitate test result delivery to patients and expedite treatment of infected individuals. PMID- 22827296 TI - In vitro and in vivo assessment of the effect of Laurus novocanariensis oil and essential oil in human skin. AB - Laurus novocanariensis is an endemic plant from the Madeira Island forest that derives a fatty oil, with a strong spicy odour, from its berries that has been used for centuries in traditional medicine to treat skin ailments. This work aimed to investigate the effect of the application of both the oil and its essential oil on normal skin, to assess their safety and potential benefits. Diffusion studies with Franz cells using human epidermal membranes were conducted. The steady-state fluxes of two model molecules through untreated skin were compared with those obtained after a 2-h pre-treatment with either the oil or the essential oil. Additionally, eleven volunteers participated in the in vivo study that was conducted on the forearm and involved daily application of the oil for 5 days. Measurements were performed every day in the treated site with bioengineering methods that measure erythema, irritation and loss of barrier function. Slightly higher steady-state fluxes were observed for both the lipophilic and the hydrophilic molecule when the epidermal membranes were pre treated. Nevertheless, such differences had no statistical significance, which seems to confirm that neither the oil nor the essential oil impaired the epidermal barrier. Results collected with the Chromameter, the Laser Doppler Flowmeter and the visual scoring are in agreement with those established in the in vitro study. They indicate that the repeated application of the oil did not cause erythema, because the results observed in the first day of the study were maintained throughout the week. Application of the oil did not affect the skin barrier function, because the transepidermal water loss remained constant throughout the study. The stratum corneum hydration was slightly reduced on days 4 and 5. This work shows that both the oil and the essential oil were well tolerated by the skin and did not cause significant barrier impairment or irritation. PMID- 22827297 TI - Salusins, newly identified regulators of hemodynamics and mitogenesis, increase in polycystic ovarian syndrome. AB - In the current study, we aimed to investigate whether serum salusin alpha and beta levels are different in PCOS subjects. Fifty women with PCOS and 50 healthy, age- and body mass index matched controls were included to the prospective cross sectional study. All subjects underwent venous blood drawing on the early follicular phase after an overnight fasting. Serum salusin alpha and beta levels were measured with EIA, and ELISA respectively. The relationships between serum salusin levels and anthropometric and metabolic parameters were also assessed. Plasma salusin alpha and beta levels were higher in women with PCOS compared to control group. Serum salusin alpha level correlated positively with salusin beta and fasting serum insulin levels. The serum salusin beta levels were correlated positively with HOMA-IR, TG, LDL-C, LH, FSH, and total testosterone levels. Our results indicate that salusins, newly identified regulators of hemodynamics and mitogenesis, are increased within the serum of women with PCOS. PMID- 22827298 TI - Heterodivalent linked macrocyclic beta-sheets with enhanced activity against Abeta aggregation: two sites are better than one. AB - This paper reports a series of heterodivalent linked macrocyclic beta-sheets 6 that are not only far more active against amyloid-beta (Abeta) aggregation than their monovalent components 1a and 1b but also are dramatically more active than their homodivalent counterparts 4 and 5. The macrocyclic beta-sheet components 1a and 1b comprise pentapeptides derived from the N- and C-terminal regions of Abeta and molecular template and turn units that enforce a beta-sheet structure and block aggregation. Thioflavin T fluorescence assays show that heterodivalent linked macrocyclic beta-sheets 6 delay Abeta(1-40) aggregation 6-8-fold at equimolar concentrations and substantially delay aggregation at substoichiometric concentrations, while homodivalent linked macrocyclic beta-sheets 4 and 5 and monovalent macrocyclic beta-sheets 1a and 1b only exhibit more modest effects at equimolar or greater concentrations. A model to explain these observations is proposed, in which the inhibitors bind to and stabilize the early beta-structured Abeta oligomers and thus delay aggregation. In this model, heterodivalent linked macrocyclic beta-sheets 6 bind to the beta-structured oligomers more strongly, because N-terminal-derived component 1a can bind to the N-terminal-based core of the beta-structured oligomers, while the C-terminal-derived component 1b can achieve additional interactions with the C-terminal region of Abeta. The enhanced activity of the heterodivalent compounds suggests that polyvalent inhibitors that can target multiple regions of amyloidogenic peptides and proteins are better than those that only target a single region. PMID- 22827299 TI - Bacteriophage therapy: practicability and clinical need meet in the multidrug resistance era. PMID- 22827300 TI - Microbial diversity in the cystic fibrosis airways: where is thy sting? PMID- 22827301 TI - Salmonella cross-protective vaccines: fast-forward to the next generation of food safety. PMID- 22827304 TI - Innate barriers to viral infection. AB - Innate immunity represents the foremost barrier to viral infection. In order to infect a cell efficiently, viruses need to evade innate immune effectors such as interferons and inflammatory cytokines. Pattern recognition receptors can detect viral components or pathogen-associated molecular patterns. These receptors then elicit innate immune responses that result in the generation of type I interferons and proinflammatory cytokines. Organized by the Society for General Microbiology, one session of this conference focused on the current state-of-the art knowledge on innate barriers to infection of different RNA and DNA viruses. Experts working on innate immunity in the context of viral infection provided insight into different aspects of innate immune recognition and also discussed areas for future research. Here, we provide an overview of the session on innate barriers to infection. PMID- 22827305 TI - Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. AB - Existing drugs have limited efficacy against the rising threat of drug-resistant TB, have significant side effects, and must be given in combinations of four to six drugs for at least 6 months for drug-sensitive TB and up to 24 months for drug-resistant TB. The long treatment duration has led to increased patient noncompliance with therapy. This, in turn, drives the development of additional drug resistance in a spiral that has resulted in some forms of TB being currently untreatable by existing drugs. New antitubercular drugs in development, particularly those with mechanisms of action that are different from existing first- and second-line TB drugs, are anticipated to be effective against both drug-sensitive and drug-resistant TB. SQ109 is a new TB drug candidate with a novel mechanism of action that was safe and well tolerated in Phase I and early Phase II clinical trials. We describe herein the identification, development and characterization of SQ109 as a promising new antitubercular drug. PMID- 22827307 TI - Acting antisense: plasmid- and chromosome-encoded sRNAs from Gram-positive bacteria. AB - sRNAs that act by base pairing were first discovered in plasmids, phages and transposons, where they control replication, maintenance and transposition. Since 2001, however, computational searches were applied that led to the discovery of a plethora of sRNAs in bacterial chromosomes. Whereas the majority of these chromsome-encoded sRNAs have been investigated in Escherichia coli, Salmonella and other Gram-negative bacteria, only a few well-studied examples are known from Gram-positive bacteria. Here, the author summarizes our current knowledge on plasmid- and chromosome-encoded sRNAs from Gram-positive species, thereby focusing on regulatory mechanisms used by these RNAs and their biological role in complex networks. Furthermore, regulatory factors that control the expression of these RNAs will be discussed and differences between sRNAs from Gram-positive and Gram-negative bacteria highlighted. The main emphasis of this review is on sRNAs that act by base pairing (i.e., by an antisense mechanism). Thereby, both plasmid encoded and chromosome-encoded sRNAs will be considered. PMID- 22827306 TI - Optimizing the balance between host and environmental survival skills: lessons learned from Listeria monocytogenes. AB - Environmental pathogens - organisms that survive in the outside environment but maintain the capacity to cause disease in mammals - navigate the challenges of life in habitats that range from water and soil to the cytosol of host cells. The bacterium Listeria monocytogenes has served for decades as a model organism for studies of host-pathogen interactions and for fundamental paradigms of cell biology. This ubiquitous saprophyte has recently become a model for understanding how an environmental bacterium switches to life within human cells. This review describes how L. monocytogenes balances life in disparate environments with the help of a critical virulence regulator known as PrfA. Understanding L. monocytogenes survival strategies is important for gaining insight into how environmental microbes become pathogens. PMID- 22827309 TI - Enterobacter cloacae complex: clinical impact and emerging antibiotic resistance. AB - Species of the Enterobacter cloacae complex are widely encountered in nature, but they can act as pathogens. The biochemical and molecular studies on E. cloacae have shown genomic heterogeneity, comprising six species: Enterobacter cloacae, Enterobacter asburiae, Enterobacter hormaechei, Enterobacter kobei, Enterobacter ludwigii and Enterobacter nimipressuralis, E. cloacae and E. hormaechei are the most frequently isolated in human clinical specimens. Phenotypic identification of all species belonging to this taxon is usually difficult and not always reliable; therefore, molecular methods are often used. Although the E. cloacae complex strains are among the most common Enterobacter spp. causing nosocomial bloodstream infections in the last decade, little is known about their virulence associated properties. By contrast, much has been published on the antibiotic resistance features of these microorganisms. In fact, they are capable of overproducing AmpC beta-lactamases by derepression of a chromosomal gene or by the acquisition of a transferable ampC gene on plasmids conferring the antibiotic resistance. Many other resistance determinants that are able to render ineffective almost all antibiotic families have been recently acquired. Most studies on antimicrobial susceptibility are focused on E. cloacae, E. hormaechei and E. asburiae; these studies reported small variations between the species, and the only significant differences had no discriminating features. PMID- 22827308 TI - Evolutionary and genomic insights into meningococcal biology. AB - Epidemic disease caused by Neisseria meningitidis, the meningococcus, has been recognized for two centuries, but remains incompletely controlled and understood. There have been dramatic reductions in serogroup A and C meningococcal disease following the introduction of protein-polysaccharide conjugate vaccines, but there is currently no comprehensive vaccine against serogroup B meningococci. Genetic analyses of meningococcal populations have provided many insights into the biology, evolution and pathogenesis of this important pathogen. The meningococcus, and its close relative the gonococcus, are the only pathogenic members of the genus Neisseria, and the invasive propensity of meningococci varies widely, with approximately a dozen 'hyperinvasive lineages' responsible for most disease. Despite this, attempts to identify a 'pathogenome', a subset of genes associated with the invasive phenotypes, have failed; however, genome-wide studies of representative meningococcal isolates using high-throughput sequencing are beginning to provide details on the relationship of invasive phenotype and genotype in this fascinating organism and how this relationship has evolved. PMID- 22827310 TI - Nosocomial Gram-positive antimicrobial susceptibility pattern at a referral teaching hospital in Tehran, Iran. AB - AIMS: The aim of the study was to evaluate epidemiology and susceptibility patterns of nosocomial Gram-positive infections in a referral teaching hospital. METHODS: Over a 1 year period, Gram-positive microorganisms isolated from specimens of hospitalized patients with documented nosocomial infection underwent antimicrobial susceptibility testing using the disk diffusion test. In addition, possible risk factors for developing multidrug-resistant bacteria were evaluated. RESULTS: During the study period, a total of 137 nosocomial infections were detected. Staphylococcus aureus was the most frequently isolated microorganism (56.2%), followed by Enterococcus spp. (21.9%) and Staphylococcus epidermidis (15.3%). All S. aureus strains were sensitive to vancomycin, teicoplanin, linezolid and chloramphenicol. More than 50% of enterococci strains were resistant to vancomycin and teicoplanin. Possible risk factors for multidrug resistance among isolated pathogens were history of antibiotic use and intubation of patient for mechanical ventilation. CONCLUSION: This study showed high rates of antimicrobial resistance among nosocomial Gram-positive pathogens, complicating antibiotic therapy and its outcomes. PMID- 22827312 TI - Physiological adaptation along environmental gradients and replicated hybrid zone structure in swordtails (Teleostei: Xiphophorus). AB - Local adaptation is often invoked to explain hybrid zone structure, but empirical evidence of this is generally rare. Hybrid zones between two poeciliid fishes, Xiphophorus birchmanni and X. malinche, occur in multiple tributaries with independent replication of upstream-to-downstream gradients in morphology and allele frequencies. Ecological niche modelling revealed that temperature is a central predictive factor in the spatial distribution of pure parental species and their hybrids and explains spatial and temporal variation in the frequency of neutral genetic markers in hybrid populations. Among populations of parentals and hybrids, both thermal tolerance and heat-shock protein expression vary strongly, indicating that spatial and temporal structure is likely driven by adaptation to local thermal environments. Therefore, hybrid zone structure is strongly influenced by interspecific differences in physiological mechanisms for coping with the thermal environment. PMID- 22827313 TI - What's gotten under Alec's skin? A response to Roddie McKenzie. PMID- 22827314 TI - Liquid chromatography-tandem mass spectrometry method for the determination of anthelmintics in alfalfa plants. AB - A simple and inexpensive liquid chromatography-tandem mass spectrometric method for the determination of anthelmintics in alfalfa plants (Medicago sativa L.) was developed and validated. Anthelmintics in plant leaves and stems (green chops) were extracted with methanol/acetonitrile (7:3, v/v) followed by a concentration and clean-up step using solid-phase extraction (Strata-X, 500 mg, 6 ml cartridge). After drying with nitrogen gas, the adsorbed analytes were eluted with methanol/acetonitrile (50:50, v/v) mixture followed by 100% acetonitrile. Chromatographic separation was achieved on an Atlantis T-3 (2.1 * 100 mm * 3 um) analytical column with a Phenomenex guard cartridge (C8, 4 * 3 mm) attached to a Waters triple quadrupole mass spectrometer operated in positive electrospray ionisation mode with selected reaction monitoring. Samples were analysed using gradient elution at a flow rate of 0.35 ml min-1. The mobile phase consisted of a 10 mM ammonium formate solution in (A) water/acetonitrile (90:10, v/v) and (B) methanol/acetonitrile (50:50, v/v). The method was validated for levamisole, fenbendazole, fenbendazole sulphoxide and fenbendazole sulphone at 10, 20 and 40 ug kg-1 and for eprinomectin at 20, 40 and 80 ug kg-1. Limits of quantification (LOQ) were 10 ug kg-1 for all analytes except eprinomectin, which had an LOQ of 20 ug kg-1. The overall mean recovery in green plants was between 74.2% and 81.4% with repeatabilities ranging from 2.2% to 19.1% and reproducibilities in the range 3.8-8.7%. The validated method was applied to plant samples in a study on the behaviour of anthelmintic drugs in a soil, plant and water system. PMID- 22827315 TI - Solidarity in contemporary bioethics--towards a new approach. AB - This paper, which is based on an extensive analysis of the literature, gives a brief overview of the main ways in which solidarity has been employed in bioethical writings in the last two decades. As the vagueness of the term has been one of the main targets of critique, we propose a new approach to defining solidarity, identifying it primarily as a practice enacted at the interpersonal, communal, and contractual/legal levels. Our three-tier model of solidarity can also help to explain the way in which crises of solidarity can occur, notably when formal solidaristic arrangements continue to exist despite 'lower tiers' of solidarity practices at inter-personal and communal levels having 'broken away'. We hope that this contribution to the growing debate on the potential for the value of solidarity to help tackle issues in bioethics and beyond, will stimulate further discussion involving both conceptual and empirically informed perspectives. PMID- 22827316 TI - A dialectic of cooperation and competition: solidarity and universal health care provision. AB - The concept of solidarity has achieved relatively little attention from philosophers, in spite of its signal importance in a variety of social movements over the past 150 years. This means that there is a certain amount of preliminary philosophical work concerning the concept itself that must be undertaken before one can ask about its potential use in arguments concerning the provision of health care. In this paper, I begin with this work through a survey of some of the most prominent bioethical, political philosophical and intellectual historical literature concerned with the project of determining a philosophically specific and historically perspicacious meaning of the term 'solidarity'. This provides a conceptual foundation for a sketch of a four-tiered picture of social competition and cooperation within the nation-state. Corresponding to this picture is a four-tiered account of health care provision. These two models, taken together, provide a framework for articulating the conclusion that, while there are myriad examples of solidarity in claiming health care for some, or even many, the concept does not provide a basis for claiming health care for all. PMID- 22827317 TI - Family solidarity and informal care: the case of care for people with dementia. AB - According to Bayertz the core meaning of solidarity is the perception of mutual obligations between the members of a community. This definition leaves open the various ways solidarity is perceived by individuals in different communities and how it manifests itself in a particular community. This paper explores solidarity as manifested in the context of families in respect of caregiving for a family member who has become dependent because of disease or illness. Though family caregiving is based on the same perception of mutual obligation as the solidarity that supports welfare arrangements in society, the manifestation of solidarity in families is different. Solidarity that underpins welfare arrangements is based on a perception of mutual obligation towards an anonymous dependent other and is enforced by the government. Solidarity in families is directed towards a concrete other and is based on free choice, albeit often accompanied by a strong sense of personal duty. In this paper we try to distinguish between solidarity as a sociological concept and as a moral concept. An important moral element of solidarity, as expressed in families, is the need for recognition of family caregivers, not only of their concrete practical efforts, but also of their own identity as caregivers and as individuals. We illustrate this argument by referring to examples in the Nuffield Council on Bioethics report Dementia: ethical issues, about the experiences of family caregivers in dementia care and the importance for them of recognition of their role. PMID- 22827318 TI - Solidarity, children and research. AB - While research on children is supported by many professional guidelines, international declarations and domestic legislation, when it is undertaken on children with no possibility of direct benefit it rests on shaky moral foundations. A number of authors have suggested that research enrolment is in the child's best interests, or that they have a moral duty or societal obligation to participate. However, these arguments are unpersuasive. Rather, I will propose in this paper that research participation by children seems most reasonable when considered as an act of solidarity; a form of identification with, and provision of practical assistance to, those who are less well off. This is an articulation of the view that many children, and their parents, seem to take seriously the suffering of others, and wish to assist in advancing other children's wellbeing. Perhaps, by fostering an environment in which children are encouraged to take solidarity seriously, participation in research which holds out substantial hope of benefit to those less well off would come to be perceived as a behavioural norm rather than an exceptional practice. PMID- 22827319 TI - Altruism or solidarity? The motives for organ donation and two proposals. AB - Proposals for increasing organ donation are often rejected as incompatible with altruistic motivation on the part of donors. This paper questions, on conceptual grounds, whether most organ donors really are altruistic. If we distinguish between altruism and solidarity--a more restricted form of other-concern, limited to members of a particular group--then most organ donors exhibit solidarity, rather than altruism. If organ donation really must be altruistic, then we have reasons to worry about the motives of existing donors. However, I argue that altruism is not necessary, because organ donation supplies important goods, whatever the motivation, and we can reject certain dubious motivations, such as financial profit, without insisting on altruism. Once solidaristic donation is accepted, certain reforms for increasing donation rates seem permissible. This paper considers two proposals. Firstly, it has been suggested that registered donors should receive priority for transplants. While this proposal appears based on a solidaristic norm of reciprocity, it is argued that such a scheme would be undesirable, since non-donors may contribute to society in other ways. The second proposal is that donors should be able to direct their organs towards recipients that they feel solidarity with. This is often held to be inconsistent with altruistic motivation, but most donation is not entirely undirected in the first place (for instance, donor organs usually go to co-nationals). While allowing directed donation would create a number of practical problems, such as preventing discrimination, there appears to be no reason in principle to reject it. PMID- 22827320 TI - Global solidarity, migration and global health inequity. AB - The grounds for global solidarity have been theorized and conceptualized in recent years, and many have argued that we need a global concept of solidarity. But the question remains: what can motivate efforts of the international community and nation-states? Our focus is the grounding of solidarity with respect to global inequities in health. We explore what considerations could motivate acts of global solidarity in the specific context of health migration, and sketch briefly what form this kind of solidarity could take. First, we argue that the only plausible conceptualization of persons highlights their interdependence. We draw upon a conception of persons as 'ecological subjects' and from there illustrate what such a conception implies with the example of nurses migrating from low and middle-income countries to more affluent ones. Next, we address potential critics who might counter any such understanding of current international politics with a reference to real-politik and the insights of realist international political theory. We argue that national governments- while not always or even often motivated by moral reasons alone--may nevertheless be motivated to acts of global solidarity by prudential arguments. Solidarity then need not be, as many argue, a function of charitable inclination, or emergent from an acknowledgment of injustice suffered, but may in fact serve national and transnational interests. We conclude on a positive note: global solidarity may be conceptualized to helpfully address global health inequity, to the extent that personal and transnational interdependence are enough to motivate national governments into action. PMID- 22827321 TI - Solidarity for global health. PMID- 22827323 TI - Coronary artery dilation among patients with paediatric-onset systemic lupus erythematosus. AB - OBJECTIVES: This study aimed to evaluate increased coronary artery dimensions in patients with paediatric-onset systemic lupus erythematosus (SLE) in comparison with healthy controls, and to identify risk factors associated with increased coronary artery dimensions in the SLE patients. METHODS: As part of a longitudinal cohort study of coronary artery disease (CAD) in paediatric-onset SLE, 83 children with SLE and 36 healthy controls were enrolled for a cross sectional analysis. Their coronary artery diameters were measured by echocardiography while their body mass index (BMI), blood pressure, and other cardiovascular factors were recorded. The age at diagnosis, serum uric acid (UA) and creatinine levels, and other lupus-related factors were further evaluated in SLE patients. Data were analysed using linear regression. RESULTS: Mean body surface area (BSA)-adjusted dimensions of the left coronary artery (LCA) and right coronary artery (RCA) were significantly larger in SLE patients than in controls (both p < 0.001). The age at diagnosis, BMI, and serum UA and creatinine levels were associated with LCA and RCA diameters. There were no correlations between the coronary artery diameters and blood pressure, SLE duration, SLE Disease Activity Index (SLEDAI), C-reactive protein (CRP), C3, C4, anti-double stranded-DNA (anti-dsDNA), or lipid profile. In multivariate analysis, serum UA level, age at diagnosis, and BMI were consistently associated with coronary artery dimensions (p < 0.001, p = 0.008, and p = 0.006 for LCA; p = 0.020, 0.013, and 0.008 for RCA). CONCLUSIONS: Increased coronary artery diameters were found in children with SLE and were associated with higher serum UA levels. The pathogenic mechanisms warrant further investigation. PMID- 22827324 TI - An optical microscopy study on the phase structure of poly(L-lactide acid)/poly(propylene carbonate) blends. AB - The dependence of phase structure of PLLA/PPC blends on the blend ratio, the heat treatment temperature and time was investigated by optical microscopy. It is found that, at lower PPC content, e.g., less than 30%, the PLLA crystalline spherulites fill the whole space with the PPC dispersed in the amorphous region of PLLA. No evident phase separation has been observed under optical microscope. When the content of PPC reaches 40%, phase separation takes place. The phase separation of the PLLA/PPC blend happens prior to the crystallization of PLLA. Therefore, the heat-treatment temperature and time are the two most important factors that control the phase structure of the blend. At low heat-treatment temperatures, e.g., lower than 190 degrees C, the PPC and the amorphous PLLA part compose a continuous phase with the crystalline PLLA domains dispersed in it. When the sample was heat-treated at 200 degrees C for 5 min, a bicontinuous phase structure was observed. With further increase of the heat-treatment temperature, the crystalline PLLA composes the continuous phase with PPC domains randomly dispersed in it. Similar phase reversal phenomenon has also been observed by heat-treating the samples at 200 degrees C for different times. It is further confirmed that the crystallization of PLLA in the blends is influenced by the different phase structures. For example, the crystallinity of PLLA in the blend increases with increasing heat-treatment temperature. PMID- 22827322 TI - Galectin-3 binds Neisseria meningitidis and increases interaction with phagocytic cells. AB - Galectin-3 is expressed and secreted by immune cells and has been implicated in multiple aspects of the inflammatory response. It is a glycan binding protein which can exert its functions within cells or exogenously by binding cell surface ligands, acting as a molecular bridge or activating signalling pathways. In addition, this lectin has been shown to bind to microorganisms. In this study we investigated the interaction between galectin-3 and Neisseria meningitidis, an important extracellular human pathogen, which is a leading cause of septicaemia and meningitis. Immunohistochemical analysis indicated that galectin-3 is expressed during meningococcal disease and colocalizes with bacterial colonies in infected tissues from patients. We show that galectin-3 binds to N. meningitidis and we demonstrate that this interaction requiresfull-length, intact lipopolysaccharide molecules. We found that neither exogenous nor endogenous galectin-3 contributes to phagocytosis of N. meningitidis; instead exogenous galectin-3 increases adhesion to monocytes and macrophages but not epithelial cells. Finally we used galectin-3 deficient (Gal-3(-/-) ) mice to evaluate the contribution of galectin-3 to meningococcal bacteraemia. We found that Gal-3(-/-) mice had significantly lower levels of bacteraemia compared with wild-type mice after challenge with live bacteria, indicating that galectin-3 confers an advantage to N. meningitidis during systemic infection. PMID- 22827325 TI - Changes in size of deforested patches in the Brazilian Amazon. AB - Different deforestation agents, such as small farmers and large agricultural businesses, create different spatial patterns of deforestation. We analyzed the proportion of deforestation associated with different-sized clearings in the Brazilian Amazon from 2002 through 2009. We used annual deforestation maps to determine total area deforested and the size distribution of deforested patches per year. The size distribution of deforested areas changed over time in a consistent, directional manner. Large clearings (>1000 ha) comprised progressively smaller amounts of total annual deforestation. The number of smaller clearings (6.25-50.00 ha) remained unchanged over time. Small clearings accounted for 73% of all deforestation in 2009, up from 30% in 2002, whereas the proportion of deforestation attributable to large clearings decreased from 13% to 3% between 2002 and 2009. Large clearings were concentrated in Mato Grosso, but also occurred in eastern Para and in Rondonia. In 2002 large clearings accounted for 17%, 15%, and 10% of all deforestation in Mato Grosso, Para, and Rondonia, respectively. Even in these states, where there is a highly developed agricultural business dominated by soybean production and cattle ranching, the proportional contribution of large clearings to total deforestation declined. By 2009 large clearings accounted for 2.5%, 3.5%, and 1% of all deforestation in Mato Grosso, Para, and Rondonia, respectively. These changes in deforestation patch size are coincident with the implementation of new conservation policies by the Brazilian government, which suggests that these policies are not effectively reducing the number of small clearings in primary forest, whether these are caused by large landholders or smallholders, but have been more effective at reducing the frequency of larger clearings. PMID- 22827326 TI - Structure analysis and comparative characterization of the cytochrome c' and flavocytochrome c from thermophilic purple photosynthetic bacterium Thermochromatium tepidum. AB - The thermodynamic and spectroscopic properties of two soluble electron transport proteins, cytochrome (Cyt) c' and flavocytochrome c, isolated from thermophilic purple sulfur bacterium Thermochromatium (Tch.) tepidum were examined and compared with those of the corresponding proteins from a closely related mesophilic bacterium Allochromatium (Alc.) vinosum. These proteins share sequence identities of 82% for the cytochromes c' and 86% for the flavocytochromes c. Crystal structures of the two proteins have been determined at high resolutions. Differential scanning calorimetry and denaturing experiments show that both proteins from Tch. tepidum are thermally and structurally much more stable than their mesophilic counterparts. The denaturation temperature of Tch. tepidum Cyt c' was 22 degrees C higher than that of Alc. vinosum Cyt c', and the midpoints of denaturation using guanidine hydrochloride were 2.0 and 1.2 M for the Tch. tepidum and Alc. vinosum flavocytochromes c, respectively. The enhanced stabilities can be interpreted on the basis of the structural and sequence information obtained in this study: increased number of hydrogen bonds formed between main chain nitrogen and oxygen atoms, more compact structures and reduced number of glycine residues. Many residues with large side chains in Alc. vinosum Cyt c' are substituted by alanines in Tch. tepidum Cyt c'. Both proteins from Tch. tepidum exhibit high structural similarities to their counterparts from Alc. vinosum, and the different residues between the corresponding proteins are mainly located on the surface and exposed to the solvent. Water molecules are found in the heme vicinity of Tch. tepidum Cyt c' and form hydrogen bonds with the heme ligand and C-terminal charged residues. Similar bound waters are also found in the vicinity of one heme group in the diheme subunit of Tch. tepidum flavocytochrome c. Electron density map of the Tch. tepidum flavocytochrome c clearly revealed the presence of disulfur atoms positioned between two cysteine residues at the active site near the FAD prosthetic group. The result strongly suggests that flavocytochrome c is involved in the sulfide oxidation in vivo. Detailed discussion is given on the relationships between the crystal structures and the spectroscopic properties observed for these proteins. PMID- 22827327 TI - Assessing regional hydrology and water quality implications of large-scale biofuel feedstock production in the Upper Mississippi River Basin. AB - A recent U.S. Department of Energy study estimated that more than one billion tons of biofuel feedstock could be produced by 2030 in the United States from increased corn yield, and changes in agricultural and forest residue management and land uses. To understand the implications of such increased production on water resources and stream quality at regional and local scales, we have applied a watershed model for the Upper Mississippi River Basin, where most of the current and future crop/residue-based biofuel production is expected. The model simulates changes in water quality (soil erosion, nitrogen and phosphorus loadings in streams) and resources (soil-water content, evapotranspiration, and runoff) under projected biofuel production versus the 2006 baseline year and a business-as-usual scenario. The basin average results suggest that the projected feedstock production could change the rate of evapotranspiration in the UMRB by approximately +2%, soil-water content by about -2%, and discharge to streams by 5% from the baseline scenario. However, unlike the impacts on regional water availability, the projected feedstock production has a mixed effect on water quality, resulting in 12% and 45% increases in annual suspended sediment and total phosphorus loadings, respectively, but a 3% decrease in total nitrogen loading. These differences in water quantity and quality are statistically significant (p < 0.05). The basin responses are further analyzed at monthly time steps and finer spatial scales to evaluate underlying physical processes, which would be essential for future optimization of environmentally sustainable biofuel productions. PMID- 22827328 TI - Differential expression of HLA-A and B-alleles on uveal melanoma as determined by immuno-histology. AB - HLA molecules play an important role in the presentation of antigens to the immune system, including tumor-specific antigens. Uveal melanomas vary in the level of expression of monomorphic HLA molecules. However, since the HLA system is polymorphic and since antigen-presentation may be linked to the expression of specific HLA alleles, the authors wondered whether allelic differences in expression existed on uveal melanomas. In order to test this, tissue sections from 23 uveal melanomas were stained in an indirect immunoperoxidase technique with monoclonal antibodies against monomorphic and polymorphic determinants of HLA molecules. All uveal melanomas showed a high level of expression of the monomorphic determinants of HLA-Class I. The polymorphic HLA-Class I molecules A2, A3, Bw4 and Bw6 varied in expression, with a higher expression of HLA-A than of HLA-B. A low level of expression of both beta2-microglobulin and HLA-B locus products was associated with a large tumor diameter. Expression of HLA-Class II molecules was low (0 to 35%). The observation that expression of the HLA-A allelic products was higher than of the HLA-B subtypes may have implications for the search of tumorspecific peptides for immunotherapeutic use: it may be worthwile to select peptides that specifically bind to HLA-A and not to HLA-B. PMID- 22827329 TI - Systemic cyclosporin treatment for high-risk corneal transplantation. AB - The success rate for uncomplicated penetrating keratoplasty is very high. However, in high risk patients there is a significantly increased risk for immunologic graft failure and the success rate is relatively poor. Oral cyclosporin A treatment has dramatically decreased the rejection rate in solid organ transplantation. Its oral use in ophthalmology has so far been relatively limited and topical use restricted by poor penetration of the drug into ocular tissues. The favorable results of oral cyclosporin treatment to prevent corneal graft failure in high-risk patients is demonstrated in this study. High-risk corneal transplant patients were selected from the general population scheduled to undergo corneal transplantation. Twenty-two of 277 patients who were operated during a four-year period were regarded as high-risk keratoplasty patients. Systemic cyclosporin A treatment (5mg/kg/day) was given prophylactically to 14 of these patients who were considered to be at high-risk for keratoplasty rejection (CsA group). In addition the patients received a low dose of corticosteroids. Eight similar patients receiving high dose corticosteroids served as a control group (control group). In the CsA group graft survival was 78.6% compared with 37.5% in the control group at 1.5 years. The grafts of patients receiving CsA had a significantly better survival rate (p.o5) than those in control at one and 1.5 years. On the follow-up to four years graft survival in patients treated with CsA was, however, decreasing to 35.7%. The low graft survival in both high-risk groups is in great contrast to graft survival in all patients operated during the same period (93.1%). Systemic cyclosporin treatment when received at the time of the operation is effective in reducing failure from irreversible rejection in high-risk keratoplasty, but for maximal effect, a six-month period of treatment is too short. Subjective side effects were frequent but still acceptable. Blood tests did not reveal any pathological hepatic or renal laboratory values caused by system CsA administration. Careful and frequent follow-ups of the patients are however needed. PMID- 22827330 TI - Association of Propionibacterium acnes endophthalmitis with HLA-DQw5. AB - BACKGROUND: An HLA-DQ1 association has been suspected in patients who develop Propionibacterium acnes endophthalmitis following cataract surgery. New techniques exist which may help to define this association. MATERIALS AND METHODS: Patients with culture-proven P. acnes endophthalmitis following cataract surgery were HLA-typed with new sera able to detect fine specificities in the HLA DQ1 region and compared to a large number of racially-matched controls. Sequence specific oligonucleotide typing with probes and primers designed to amplify and define the HLA-DQ1 region was then performed. P. acnes patients were compared to HLA-DQ1-matched controls who had undergone cataract surgery but had no evidence of chronic post-operative inflammation. RESULTS: Thirteen of 15 P. acnes patients (87%) were serologically defined as carrying a split of DQw1 (DQw5 or DQ26). HLA DQw5 was increased to a statistically significant degree (p < 0.014) with an odds ratio of 3.72 (95% confidence interval 1.34 to 10.31). Sequence-specific oligonucleotide typing confirmed the DQw5 predominance: Seventy-three percent of P. acnes patients had DQB1 (*)0501 or DQB1 (*)0503 vs. 33% of DQw1-matched cataract patients without inflammation (not significant). CONCLUSION: HLA-DQ2w5 is associated with the development of P. acnes endophthalmitis following cataract surgery. The molecular mechanism of this association is unknown. PMID- 22827331 TI - The detection of herpesviral DNA in aqueous fluid samples from patients with Fuchs' heterochromic cyclitis. AB - Members of the herpesvirus family have been found in association with a variety of intraocular inflammatory conditions. The aetiology and pathogenic mechanisms underlying the specific uveitis entity Fuchs' heterochromic cyclitis (FHC) have yet to be determined. This study investigates the presence of specific herpesviral DNA in samples of aqueous fluid from patients with FHC. Aqueous humour was obtained from 40 patients undergoing cataract surgery, 20 patients with a clinical diagnosis of FHC and 20 patients with senile cataract who acted as controls. Each sample was tested for the presence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV) and varicella-zoster virus (VZV) DNA after initial amplification with virus specific primers using the polymerase chain reaction (PCR). Herpesviral DNA could not be detected in any of the aqueous samples from the FHC patients. Although a viral aetiology is unlikely, this study cannot exclude the possibility that a virus may be the initiating factor in the development of FHC or that virus may be sequestered in different ocular tissues. Control patients also showed no significant carriage of herpesvirus in their aqueous humour implying that detection of any herpesviral DNA in aqueous samples may be clinically relevant. PMID- 22827332 TI - Human conjunctival mast cell responses in vitro to various secretagogues. AB - Human conjunctiva was enzymatically digested into monodispersed cell preparations using collagenase and hyaluronidase. The preparations were enriched for mast cells using Percoll gradient centrifugation prior to challenge with various secretagogues. Mast cell percentage (9.7 +/- 2.9%) and viability (96 +/- 3%) were determined using toluidine blue staining and vital dye exclusion, respectively. The mast cell enriched preparations were challenged with calcium ionophore A(23187') compound 48/80, concanavalin A, anti-IgE, morphine and substance P. Mediator release was quantified by radioimmunoassay. The calcium ionophore A(23187), compound 48/80, concanavalin A and anti-IgE stimulated histamine release from the conjunctival mast cell preparations, with EC(30) values of 0.028, 62.5, 24.4 and 1.9 epsilong/ml, respectively. Morphine but not substance P challenge induced significant but low levels of histamine release. Tryptase, sulfidopeptide leukotriene, and prostaglandin D(2) levels in cell supernatants were also increased following stimulation. The profile of mediator release observed with these cells compared to that reported from human lung and human skin mast cells suggest that human conjunctival mast cells may have unique biological responses. PMID- 22827333 TI - Keratoconjunctivitis sicca, autoimmune diseases and adenovirus type 8 infection. AB - In epidemic keratoconjunctivitis caused by adenovirus type 8 (Ad8), 21 patients were followed between 1.5-18 months. Thirty-three percent of the patients developed classical corneal subepithelial opacities. In considering comorbidity possibly influencing the outcome of the disease it was found that: (1) two patients with keratoconjunctivitis sicca did not develop subepithelial opacities, (2) 6/9 patients showing little propensity for developing subepithelial opacities were found to have a variety of manifest diseases of autoimmune nature, and, (3) dense opacities developed in five subjectively healthy persons. These findings suggest that susceptibility to stromal keratitis in Ad8 infections might at least in part be determined by the condition of the host immune status. PMID- 22827334 TI - Immunosuppressive properties of tissues of the ocular anterior segment. AB - To determine whether explants of various tissues comprising the anterior segment of individual normal eyes can display immunosuppressive properties in vitro, explants of iris/ciliary body, cornea, cornea-limbus, sclera and conjunctiva were prepared from single eyes of BALB/c mice and tested for their capacity to suppress alloantigen-driven T cell activation in vitro. Cultured explants of iris and ciliary body, and of cornea, but not sclera or conjunctiva, suppressed T cell activation in vitro. Similarly, the supernatants of cultured iris/ciliary body and cornea explants displayed immunosuppressive properties. Prostaglandins appeared to make a minor contribution to the inhibition observed. The authors conclude that certain tissues within the anterior segment of the eye (iris, ciliary body, cornea) contain cells that secrete immunosuppressive factors, whereas other tissues (conjunctiva, sclera) lack this feature. The secretions of the former tissues undoubtedly contribute to the immunosuppressive features of the microenvironment in the anterior segment of the eye, and help to account for the existence of immune privilege. PMID- 22827335 TI - Clinical pathologic findings of Propionibacterium acnes endophthalmitis. AB - The autors presented two typical cases of patients who were infected with Propionibacterium acnes (P. acnes) after intraocular lens implantation. The patients were treated successfully by the removal of the intraocular lens and the residual lens capsule, and the administration of intravitreal vacomycin. The histopathology illustrated numerous prokaryote bacilli surrounding the lens material without inflammatory reaction. The thickened bacterial cell wall structure may relate to the resistance of P. acnes killing and degradation by the host neutrophils and macrophages. Complete removal of the lens material which may sequester the bacterial growth in the eye is important to eradicate P. acnes endophthalmitis. PMID- 22827336 TI - CalpB modulates border cell migration in Drosophila egg chambers. AB - BACKGROUND: Calpains are calcium regulated intracellular cysteine proteases implicated in a variety of physiological functions and pathological conditions. The Drosophila melanogaster genome contains only two genes, CalpA and CalpB coding for canonical, active calpain enzymes. The movement of the border cells in Drosophila egg chambers is a well characterized model of the eukaryotic cell migration. Using this genetically pliable model we can investigate the physiological role of calpains in cell motility. RESULTS: We demonstrate at the whole organism level that CalpB is implicated in cell migration, while the structurally related CalpA paralog can not fulfill the same function. The downregulation of the CalpB gene by mutations or RNA interference results in a delayed migration of the border cells in Drosophila egg chambers. This phenotype is significantly enhanced when the focal adhesion complex genes encoding for alpha-PS2 integrin ( if), beta-PS integrin (mys) and talin (rhea) are silenced. The reduction of CalpB activity diminishes the release of integrins from the rear end of the border cells. The delayed migration and the reduced integrin release phenotypes can be suppressed by expressing wild-type talin-head in the border cells but not talin-head(R367A), a mutant form which is not able to bind beta-PS integrin. CalpB can cleave talin in vitro, and the two proteins coimmunoprecipitate from Drosophila extracts. CONCLUSIONS: The physiological function of CalpB in border cell motility has been demonstrated in vivo. The genetic interaction between the CalpB and the if, mys, as well as rhea genes, the involvement of active talin head-domains in the process, and the fact that CalpB and talin interact with each other collectively suggest that the limited proteolytic cleavage of talin is one of the possible mechanisms through which CalpB regulates cell migration. PMID- 22827337 TI - RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. AB - The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161). Furthermore, we find that RSK-dependent SOS1 phosphorylation creates 14-3-3-binding sites. We show that mutating Ser(1134) and Ser(1161) disrupts 14-3-3 binding and modestly increases and extends MAPK activation. Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation. PMID- 22827338 TI - Diastereodivergent hydroxyfluorination of cyclic and acyclic allylic amines: synthesis of 4-deoxy-4-fluorophytosphingosines. AB - A diastereodivergent hydroxyfluorination protocol enabling the direct conversion of some conformationally biased allylic amines to the corresponding diastereoisomeric amino fluorohydrins has been developed. Sequential treatment of a conformationally biased allylic amine with 2 equiv of HBF(4).OEt(2) followed by m-CPBA promotes epoxidation of the olefin on the face proximal to the amino group under hydrogen-bonded direction from the in situ formed ammonium ion. Regioselective and stereospecific epoxide ring-opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety) then occurs in situ to give the corresponding amino fluorohydrin. Alternatively, an analogous reaction using 20 equiv of HBF(4).OEt(2) results in preferential epoxidation of the opposite face of the olefin, which is followed by regioselective and stereospecific epoxide ring opening by transfer of fluoride from a BF(4)(-) ion (an S(N)2-type process at the carbon atom distal to the ammonium moiety). The synthetic utility of this methodology is demonstrated via its application to a synthesis of 4-deoxy-4 fluoro-L-xylo-phytosphingosine and 4-deoxy-4-fluoro-L-lyxo-phytosphingosine, each in five steps from Garner's aldehyde. PMID- 22827339 TI - Lateral dimension-dependent antibacterial activity of graphene oxide sheets. AB - Graphene oxide (GO) is a promising precursor to produce graphene-family nanomaterials for various applications. Their potential health and environmental impacts need a good understanding of their cellular interactions. Many factors may influence their biological interactions with cells, and the lateral dimension of GO sheets is one of the most relevant material properties. In this study, a model bacterium, Escherichia coli ( E. coli ), was used to evaluate the antibacterial activity of well-dispersed GO sheets, whose lateral size differs by more than 100 times. Our results show that the antibacterial activity of GO sheets toward E. coli cells is lateral size dependent. Larger GO sheets show stronger antibacterial activity than do smaller ones, and they have different time- and concentration-dependent antibacterial activities. Large GO sheets lead to most cell loss after 1 h incubation, and their concentration strongly influences antibacterial activity at relative low concentration (<10 MUg/mL). In contrast, when incubating with small GO sheets up to 4 h, the inactivation rate of E. coli cells continues increasing. The increase of small GO sheet concentration also results in persistent increases in their antibacterial activity. In this study, GO sheets with different lateral sizes are all well dispersed, and their oxidation capacity toward glutathione is similar, consistent with X-ray photoelectron spectroscopy and ultraviolet-visible absorption spectroscopy results. This suggests the lateral size-dependent antibacterial activity of GO sheets is caused by neither their aggregation states, nor oxidation capacity. Atomic force microscope analysis of GO sheets and cells shows that GO sheets interact strongly with cells. Large GO sheets more easily cover cells, and cells cannot proliferate once fully covered, resulting in the cell viability loss observed in the followed colony counting test. In contrast, small GO sheets adhere to the bacterial surfaces, which cannot effectively isolate cells from environment. This study highlights the importance of tailoring the lateral dimension of GO sheets to optimize the application potential with minimal risks for environmental health and safety. PMID- 22827341 TI - Commensurate solid-solid phase transitions in self-assembled monolayers of alkylthiolates lying on metal surfaces. AB - A temperature-induced commensurate solid-solid phase transition in self-assembled monolayers (SAMs) of alkylthiolates lying on Pt(111) is predicted from molecular dynamics simulations based on ab initio potential energy surfaces. As the system cools down from room temperature to low enough temperature, SAMs of alkylthiolates with more than ~12 carbon atoms undergo an abrupt change of orientation from a nearly upright to a tilted configuration. As the initial hexagonal arrangement of the sulfur headgroups is kept fixed during the simulations, the phase transition is entirely governed by chain-chain interactions. Similar commensurate phase transitions are predicted for hexagonally arranged SAMs with lattice spacings of the order of 4.7-4.9 A, which, among others, excludes the well-known cases of densely packed SAMs of alkylthiolates on Au(111) and Ag(111). These findings could be relevant for the design of novel electronic or optical devices controllable by temperature. PMID- 22827340 TI - Chronic and intermittent exposure to alcohol vapors: a new model of alcohol induced osteopenia in the rat. AB - BACKGROUND: Different models are used to study the effects of chronic alcohol consumption on bone tissue in the rat. However, the current models take several months to show indices of osteopenia as observed in chronic drinkers. Numerous studies have supported that chronic and intermittent exposure to ethanol vapors has predictive validity as a model of alcohol dependence in humans. However, this model has never been applied to bone research to study its effects on the parameters that define osteopenia. This was the goal of this study in the rat. METHODS: Male Wistar rats were exposed to ethanol vapor inhalation (n = 6) or air (controls, n = 6). Animals were exposed to chronic (11 weeks) and intermittent (14 hours a day) ethanol vapor reaching stable blood alcohol levels (BALs; 150 to 250 mg/dl) at the end of the third week of inhalation. After the sacrifice, right and left femur and tibia were dissected free of fat and connective tissue and bone mineral density (BMD) was assessed by dual X-ray absorptiometry. The microarchitecture of the femur was studied using microcomputed tomography. RESULTS: The BMD of the left and right femurs and the left tibia was lower in the ethanol group compared with the control group. The bone volume fraction (BV/TV) and the bone surface density (BS/TV) were lower in the ethanol group compared with control animals. The trabecular number (Tb.N) was lower in the ethanol group while the trabecular spacing was higher. CONCLUSIONS: The decrease in the BMD, BV/TV, and Tb.N is in the same range as what is observed in human drinkers and what is reported with other animal alcohol models (Lieber-DeCarli liquid diet, ethanol in the tap water). Therefore, this model could be useful to study the effects of chronic alcohol consumption in the bone research field and has the advantage of controlling easily targeted BALs. PMID- 22827342 TI - Seventeenth International Congress on Animal Reproduction (ICAR 2012), Vancouver, Canada. Foreword. PMID- 22827343 TI - An amazing 10 years: the discovery of egg and sperm in the 17th century. AB - The scientific identification of the key components of sexual reproduction - eggs and sperm - took place during an amazing decade of discovery in the 1660s and 1670s. The names of many of the people involved are now forgotten, and yet their work, and the difficulties they faced and the conflicts they endured, resonate strongly to the present day. Despite this period of innovation, the respective roles of egg and sperm remained unclear for another 170 years. Why did this take so long? And what did people think before these discoveries? By tracing the contours of this major milestone in human knowledge, we can also gain insight into our current knowledge, and the boundaries we may be unwittingly trapped by. PMID- 22827344 TI - The Simmet lecture: new horizons on an old landscape--oxidative stress, DNA damage and apoptosis in the male germ line. AB - Our ability to diagnose and treat male infertility is gradually improving in concert with advances in our understanding of the molecular mechanisms underpinning defective sperm function. In this context, one of the factors to emerge as a major causative agent in male infertility is oxidative stress. Spermatozoa are particularly susceptible to such stress because they are exceptionally rich in vulnerable substrates such as polyunsaturated fatty acids, proteins and DNA. The lack of sperm cytoplasm also provides these cells with little capacity to protect themselves from oxidative attack or to effect any repair, should damage occur. Similarly, sperm chromatin is in a quasi-crystalline state and has very little capacity to respond to any DNA damage induced by oxidative attack. When the latter does occur, it appears to be initiated by reactive oxygen species (ROS) generated by the sperm mitochondria. These free radicals attack the lipids present in the sperm mitochondria generating electrophilic aldehydes, which bind to components of the mitochondrial electron transport chain stimulating yet more ROS production. The oxidative stress created via this self-propagating mechanism initiates an apoptotic cascade as a result of which the spermatozoa loose their capacity for fertilization and suffer damage to their DNA. Phosphatidylserine externalization is a late event in sperm apoptosis and may facilitate the silent phagocytosis of moribund cells in the female reproductive tract, that is, the phagocytosis of senescent spermatozoa without the accompanying generation of an inflammatory response. Encouragingly, the involvement of oxidative stress in the aetiology of male infertility has opened up new opportunities for therapeutic interventions involving the judicious administration of nucleophiles and other forms of antioxidants. PMID- 22827345 TI - Effects of exposure to environmental chemicals during pregnancy on the development of the male and female reproductive axes. AB - There is a large body of literature describing effects of environmental chemicals (ECs), many of them anthropogenic with endocrine-disrupting properties, on development in rodent laboratory species, some of which lead to impaired reproduction and adverse health. This literature joins extensive human epidemiological data and opportunistic wildlife findings on health effects of ECs. In contrast, the effect of endocrine disruption on foetal development and reproductive performance in domestic species is less extensively documented. This applies both to domestic farm and to companion species even though the former is critical to food production and the latter share our homes and many aspects of the modern developed human lifestyle. In domestic species, the nature of chemicals exposure in utero and their consequences for animal health and production are poorly understood. A complication in our understanding is that the pace of development, ontogeny and efficiency of foetal and maternal hepatic and placental activity differs between domestic species. In many ways, this reflects the difficulties in understanding human exposure and consequences of that exposure for the foetus and subsequent adult from epidemiological and largely rodent-based data. It is important that domestic species are included in research into endocrine disruption because of their (i) wide variety of exposure to such chemicals, (ii) greater similarity of many developmental processes to the human, (iii) economic importance and (iv) close similarities to developed world human lifestyle in companion species. PMID- 22827346 TI - Effects of maternal diet and exposure to bisphenol A on sexually dimorphic responses in conceptuses and offspring. AB - Whereas sexual differentiation is considered as the onset of differentiation of the male or female gonads, mounting evidence indicates that sex differences in developmental programming are established as early as the zygotic stage. Genetic and epigenetic differences between the sexes might govern how each responds to shifts in their early environment, including in the uterus or culture dish, as in the case of in vitro cultured pre-implantational embryos. Even if no differences are evident between the sexes at birth, divergent conceptus responses to surrounding changes, such as maternal diet and exposure to endocrine disrupting compounds (EDC), such as bisphenol A (BPA), might predispose one sex over the other to later adult-onset diseases, otherwise termed developmental origin of health and disease (DOHaD). Overall, males subjected to less than optimal in utero conditions tend to be at greater risk for various diseases, including neurobehavioural disorders. As the placenta is the primary nutrient acquisition and communication organ between the dam and foetus, its ability to adapt rapidly to environmental shifts might buffer the conceptus against environmental insults. The placenta of one sex over the other might possess greater ability to respond to environmental fluctuations. In utero environmental changes, including maternal nutrient excess or reduction or exposure to the EDC, BPA, might govern sex dependent behavioural alterations. In sum, this review examines the evidence to date that male and female zygotes and conceptuses diverge in their responses to shifting environmental conditions and whether these contrasting sexually dimorphic responses underpin later DOHaD outcomes, namely neurobehavioural changes. PMID- 22827347 TI - Effects of maternal environment during gestation on ovarian folliculogenesis and consequences for fertility in bovine offspring. AB - Mammals such as cattle, swine, sheep and humans are born with a highly variable number of ovarian follicles and oocytes in the ovaries that dwindle during ageing and are never replenished. This variation in the ovarian reserve is reflected in the numbers of antral follicles in the ovaries at all ages after birth. As numbers of follicles in ovaries are determined during gestation, the role of maternal nutrition and health during gestation (at time of ovarian development in their foetuses) has been investigated as factors that may impact oogonia proliferation and thus follicle numbers post-natally. These studies have found that both nutrition and health impact numbers of follicles in their offspring. The idea that numbers of follicles and oocytes in ovaries impact fertility is a long-held belief in reproductive biology. This has recently been tested in cattle, and it has been shown that cows with a relatively high number of antral follicles in ovaries have higher pregnancy rates, shorter calving to conception intervals and fewer artificial inseminations during the breeding season compared with cows with a lower number of follicles, and similarly, heifers with many follicles had higher pregnancy rates than those with fewer follicles. Studies summarized in this review highlight the importance of the maternal environment during gestation in determining the size of the ovarian reserve in their offspring and also the contribution of the ovarian reserve to subsequent fertility in cattle. PMID- 22827348 TI - Exploiting multimedia in reproductive science education: research findings. AB - Education in reproductive science is operating from an outdated paradigm of teaching and learning. Traditionally, reproductive education follows the pattern where students read a textbook, listen to instructor presentations, re-read the textbook and class notes and then complete a test. This paradigm is inefficient, costly and has not incorporated the potential that technology can offer with respect to increases in student learning. Further, teachers of reproductive science (and all of science for that matter) have little training in the use of documented methods of instructional design and cognitive psychology. Thus, most of us have learned to teach by repeating the approaches our mentors used (both good and bad). The technology now exists to explain complex topics using multimedia presentations in which digital animation and three-dimensional anatomical reconstructions greatly reduce time required for delivery while at the same time improving student understanding. With funding from the Small Business Innovation Research program through the U.S. Department of Education, we have developed and tested a multimedia approach to teaching complex concepts in reproductive physiology. The results of five separate experiments involving 1058 university students and 122 patients in an OB/GYN clinic indicate that students and patients learned as much or more in less time when viewing the multimedia presentations when compared to traditional teaching methodologies. PMID- 22827349 TI - Ethics, politics and protests: using contentious issues in reproductive sciences as educational opportunities. AB - Contentious issues and polarized viewpoints can be utilized in the classroom and beyond to create a reflective dialogue among students and citizens. This dialogue leads to both a greater understanding, as well as an enhanced appreciation of alternative viewpoints. Exploring and discussing the scientific, ethical, moral, political, legal and societal aspects of contentious issues of human reproduction provides ideal subject matter for developing critical thinking skills in the field of reproductive science. PMID- 22827350 TI - Reproductive science in the global village. AB - Livestock production contributes not only to national economies, but also to sustainability and profitability of agriculture, as well as to the fabric of local societies. Efficient and viable animal production systems are dependent upon the effective management of animal reproduction. Similar arguments can be made in support of the importance of reproduction for companion and performance animals, whereas its key role in preserving endangered species is indisputable. Despite such considerations, the widespread dissemination of current and credible information regarding animal reproduction faces challenges, not only in the developing world, but also in developed countries, where animal reproduction education is apparently in decline. This review will examine these issues, as well as various ways in which animal reproduction education and knowledge transfer is currently being pursued throughout the world. It will conclude with suggested avenues and opportunities for improvement. PMID- 22827351 TI - Domestic animal models for biomedical research. AB - Experimental animals in biomedical research provide insights into disease mechanisms and models for determining the efficacy and safety of new therapies and for discovery of corresponding biomarkers. Although mouse and rat models are most widely used, observations in these species cannot always be faithfully extrapolated to human patients. Thus, a number of domestic species are additionally used in specific disease areas. This review summarizes the most important applications of domestic animal models and emphasizes the new possibilities genetic tailoring of disease models, specifically in pigs, provides. PMID- 22827352 TI - Livestock induced pluripotent stem cells. AB - Chimeric animals generated from livestock-induced pluripotent stem cells (iPSCs) have opened the door of opportunity to genetically manipulate species for the production of biomedical models, improving traits of agricultural importance and potentially providing a system to test novel iPSC therapies. The potential of pluripotent stem cells in livestock has long been recognized, with many attempts being chronicled to isolate, culture and characterize pluripotent cells from embryos. However, in most cases, livestock stem cells derived from embryonic sources have failed to reach a pluripotent state marked by the inability to form chimeric animals. The in-depth understanding of core pluripotency factors and the realization of how these factors can be harnessed to reprogram adult cells into an induced pluripotent state has changed the paradigm of livestock stem cells. In this review, we will examine the advancements in iPSC technology in mammalian and avian livestock species. PMID- 22827353 TI - Global food systems: feeding the world. PMID- 22827354 TI - Twenty years of embryonic stem cell research in farm animals. AB - Notable distinctions between an embryonic stem cell (ESC) and somatic cell are that an ESC can maintain an undifferentiated state indefinitely, self-renew, and is pluripotent, meaning that the ESC can potentially generate cells representing all the three primordial germ layers and contribute to the terminally differentiated cells of a conceptus. These attributes make the ESC an ideal source for genome editing for both agricultural and biomedical applications. Although, ESC lines have been successfully established from rodents and primates, authentic ungulate stem cell lines on the contrary are still not available. Outstanding issues including but not limited to differences in pluripotency characteristics among the existing ESC lines, pre-implantation embryo development, pluripotency pathways, and culture conditions plague our efforts to establish authentic ESC lines from farm animals. In this review, we highlight some of these issues and discuss how the recent derivation of induced pluripotent stem cells (iPSCs) might augur the establishment of robust authentic ESC lines from farm animals. PMID- 22827355 TI - Pluripotency network in porcine embryos and derived cell lines. AB - Huge amounts of work have been dedicated to the establishment of embryonic stem cell lines from farm animal species since the successful isolation of embryonic stem cells from the mouse and from the human. However, no conclusive results have been obtained so far, and validated lines have yet to be established in domestic animals. Many limiting factors have been suggested and need to be studied further to isolate truly pluripotent cell lines from livestock. In this review, we will discuss the difficulties in deriving and maintaining embryonic stem cell lines from farm animal embryos and how can this lack of success be explained. We will summarize results obtained in our laboratory regarding derivation of pluripotent cells in the pigs. Problems related to the identification of standard methods for derivation, maintenance and characterization of cell lines will also be examined. We will focus our attention on the need for appropriate stemness-related marker molecules that can be used to reliably investigate pluripotency in domestic species. Finally, we will review data presently available on functional key pluripotency-maintaining pathways in farm animals. PMID- 22827356 TI - Induced pluripotent stem cells from pigs and other ungulate species: an alternative to embryonic stem cells? AB - Robust embryonic stem cell (ESC) lines from livestock species have been difficult to derive and maintain, and unlike mouse ESC, have not contributed to our ability to understand directed differentiation in vitro. Nor have such cells yet provided a simpler means than pronuclear injection to manipulate the genomes of agriculturally important species, such as cattle, sheep and pigs. Induced pluripotent stem cells (iPSC) generated by reprogramming somatic cells, such as fibroblasts, with a set of stemness genes, most usually but not exclusively POU5F1, SOX2, KLF4 and c-MYC, offer an alternative to ESC in these regards, as they exhibit a pluripotent phenotype resembling that of ESC, yet are readily generated in the laboratory. Accordingly, such cells, in association with cloning technologies, may be useful for introducing complex genetic changes into livestock, although this potential has yet to be demonstrated. Porcine iPSC may be especially valuable because the pig is a prime biomedical model for tissue transplantation. In general, iPSC from livestock, like those from humans, are of the epiblast type and depend upon FGF2 and activin/nodal signalling systems to maintain their pluripotency and growth. Recent experiments, in which newly reprogrammed porcine and bovine cells were selected on a LIF-based medium in presence of specific protein kinase inhibitors, have allowed iPSC cells of the naive type, resembling the more amenable blastocyst-derived mouse ESC and iPSC to be isolated. However, hurdles still remain if such cells are to achieve their biotechnological promise. PMID- 22827357 TI - Recent advances in stem and germ cell research: implications for the derivation of pig pluripotent cells. AB - Pluripotent stem cells have the unique capacity to contribute to all the tissues of an adult animal after transfer into a host embryo. How pluripotency is acquired during early development and how it is maintained in stem cells have attracted the interest of many scientists for over three decades. Much progress in our understanding of how stem cells arise in culture and the signals required for homoeostasis has enabled the derivation of pluripotent cells in multiple species. Here, we discuss recent developments in stem cell biology that will impact the generation of pluripotent cells from different embryonic origins and will contribute to increase our capacity for generating transgenic animals. PMID- 22827358 TI - Developmental and epigenetic anomalies in cloned cattle. AB - Many of the developmental anomalies observed in cloned animals are related to foetal and placental overgrowth, a phenomenon known as the 'large offspring syndrome' (LOS) in ruminants. It has been hypothesized that the epigenetic control of imprinted genes, that is, genes that are expressed in a parental specific manner, is at the root of LOS. Our recent research has focused on understanding epigenetic alterations to imprinted genes that are associated with assisted reproductive technologies (ART), such as early embryo in vitro culture (IVC) and somatic cell nuclear transfer (SCNT) in cattle. We have sought and identified single nucleotide polymorphisms in Bos indicus DNA useful for the analysis of parental-specific alleles and their respective transcripts in tissues from hybrid embryos derived by crossing Bos indicus and Bos taurus cattle. By analysing differentially methylated regions (DMRs) of imprinted genes SNRPN, H19 and the IGF2R in cattle, we demonstrated that there is a generalized hypomethylation of the imprinted allele and the biallelic expression of embryos produced by SCNT when compared to the methylation patterns observed in vivo (artificially inseminated). Together, these results indicate that imprinting marks are erased during the reprogramming of the somatic cell nucleus during early development, indicating that such epigenetic anomalies may play a key role in mortality and morbidity of cloned animals. PMID- 22827359 TI - Lessons learned from cloning dogs. AB - The aim of this article is to review dog cloning research and to suggest its applications based on a discussion about the normality of cloned dogs. Somatic cell nuclear transfer was successfully used for production of viable cloned puppies despite limited understanding of in vitro dog embryo production. Cloned dogs have similar growth characteristics to those born from natural fertilization, with no evidence of serious adverse effects. The offspring of cloned dogs also have similar growth performance and health to those of naturally bred puppies. Therefore, cloning in domestic dogs can be applied as an assisted reproductive technique to conserve endangered species, to treat sterile canids or aged dogs, to improve reproductive performance of valuable individuals and to generate disease model animals. PMID- 22827360 TI - Advancing pig cloning technologies towards application in regenerative medicine. AB - Regenerative medicine is expected to make a significant contribution by development of novel therapeutic treatments for intractable diseases and for improving the quality of life of patients. Many advances in regenerative medicine, including basic and translational research, have been developed and tested in experimental animals; pigs have played an important role in various aspects of this work. The value of pigs as a model species is being enhanced by the generation of specially designed animals through cloning and genetic modifications, enabling more sophisticated research to be performed and thus accelerating the clinical application of regenerative medicine. This article reviews the significant aspects of the creation and application of cloned and genetically modified pigs in regenerative medicine research and considers the possible future directions of the technology. We also discuss the importance of reproductive biology as an interface between basic science and clinical medicine. PMID- 22827361 TI - Agency perspectives on food safety for the products of animal biotechnology. AB - Animal biotechnology represents one subset of tools among a larger set of technologies for potential use to meet increasing world demands for food. Assisted reproductive technologies (ART) such as artificial insemination and embryo transfer continue to make positive contributions in food animal production. The US Food and Drug Administration (FDA) performed a comprehensive risk assessment to identify potential food consumption or animal health risks associated with animal cloning, an emerging ART. At that time, FDA concluded that animal cloning posed no unique risks either to animal health or to food consumption, and food from animal clones and their sexually reproduced offspring required no additional federal regulation beyond that applicable to conventionally bred animals of the species examined. At this time, no new information has arisen that would necessitate a change in FDA's conclusions on food from animal clones or their sexually reproduced offspring. Use of recombinant DNA technologies to produce genetically engineered (GE) animals represents another emerging technology with potential to impact food animal production. In its regulation of GE animals, FDA follows a cumulative, risk-based approach to address scientific questions related to the GE animals. FDA evaluates data and information on the safety, effectiveness and stability of the GE event. FDA carries out its review at several levels (e.g. molecular biology, animal safety, food safety, environmental safety and claim validation). GE animal sponsors provide data to address risk questions for each level. This manuscript discusses FDA's role in evaluation of animal cloning and GE animals. PMID- 22827362 TI - Manipulation of follicle development to ensure optimal oocyte quality and conception rates in cattle. AB - Over the last several decades, a number of therapies have been developed that manipulate ovarian follicle growth to improve oocyte quality and conception rates in cattle. Various strategies have been proposed to improve the responses to reproductive biotechnologies following timed artificial insemination (TAI), superovulation (SOV) or ovum pickup (OPU) programmes. During TAI protocols, final follicular growth and size of the ovulatory follicle are key factors that may significantly influence oocyte quality, ovulation, the uterine environment and consequently pregnancy outcomes. Progesterone concentrations during SOV protocols influence follicular growth, oocyte quality and embryo quality; therefore, several adjustments to SOV protocols have been proposed depending on the animal category and breed. In addition, the success of in vitro embryo production is directly related to the number and quality of cumulus oocyte complexes harvested by OPU. Control of follicle development has a significant impact on the OPU outcome. This article discusses a number of key points related to the manipulation of ovarian follicular growth to maximize oocyte quality and improve conception rates following TAI and embryo transfer of in vivo- and in vitro derived embryos in cattle. PMID- 22827363 TI - The role of progesterone in oocyte acquisition of developmental competence. AB - It is generally accepted that progesterone (P4) is a key regulator of reproductive function in mammals. In cattle, the primary focus of P4's actions has been uterine receptivity and maintenance of pregnancy. Studies in mammalian laboratory species and ovarian derived cell lines also highlight their role in ovarian function. Extensive research in non-mammalian species has elucidated a critical role for P4 and both its nuclear and membrane-bound receptors in oocyte maturation and ovulation. Until recently, such a role in mammalian oocytes has been disputed. However, as oestrous synchronization regimes are constantly tweaked and revised to maximize pregnancy rates to artificial insemination in cattle, the importance of P4 priming of the dominant ingfollicle is once again tak centre stage. Sequencing of the bovine genome and the development of multiple transcriptomic data mining tools have facilitated an explosion in global transcriptome profiling of immature and matured oocytes and their surrounding cumulus cells. Many of the differentially regulated genes and their associated preferentially populated pathways appear to be P4 regulated in other tissues. Therefore, attention is once again turning to a potential role for P4 in ovulatory follicle development and oocyte maturation in cattle. The current review summarizes the most recent findings in these areas. PMID- 22827364 TI - Factors affecting oocyte and embryo transcriptomes. AB - The most important factor affecting the oocyte and early embryo transcriptome is the legacy from the follicular environment prior to meiotic resumption. Up to the 8-cell stage, the oocyte responds to maternal instructions stored before resumption of the meiotic division. Recent evidence suggests that properly prepared or programmed oocytes (in vivo) can achieve close to 100% blastocyst rates in standard in vitro conditions/media. Therefore, the optimal oocyte requires perfect follicular timing and differentiation, but the intra-oocyte mechanisms involved in such preparation are not completely understood. In addition, the influence of maternal mRNA storage and degradation, as well as the length of the poly A tail that influences the general pattern of the oocyte/early embryo transcriptome, is an important factor. Several hypotheses have been put forth to explain the depletion of the maternal store, including the potential role of microRNA (miRNA) in this process. The activation of the embryonic genome could be dependent on, or associated with, the process of maternal mRNA degradation, but obviously other functions are being activated at this critical time point. This review will focus on the period from full-size oocytes to the eight-cell stage and will summarize the impact of the important factors, that is, follicle, maternal RNA storage and embryonic genome activation, on the transcriptome. PMID- 22827365 TI - Role of the oviduct in early embryo development. AB - This review highlights the role of the oviduct in early embryo development, which has to fulfil many aligned and well-tuned tasks during early embryogenesis. The oviductal lining is subjected to dynamic changes to timely accomplish gamete transport, fertilization and embryo development and to deliver a competent and healthy conceptus to the endometrium which can implant and develop to term. Although knowledge about the role of the oviduct is limited, we know that embryos are very sensitive to the environment in which they develop. The success of in vitro embryo production techniques demonstrates that it is possible to bypass the oviduct during early development and, to a certain extent, replicate the conditions in vitro. However, comparative studies show that embryos developed in vivo are superior to their in vitro produced counterparts, underlining our relatively poor knowledge of the biology of the oviduct. Oviduct activity is orchestrated by various factors, depending on cyclic dynamics, which crucially affect the success of tubal transfer and/or (re-)collection of embryos in embryo transfer studies. This paper reviews data which demonstrate that in vivo culture of embryos in the bovine oviduct is a useful tool for the assessment of embryos developed under various conditions (e.g. superovulation vs single ovulation, lactating dairy cows vs non-lactating cows). It is concluded that more work in the field of early embryo development within the oviduct would contribute to improved ART protocols leading to healthy pregnancies and offspring. PMID- 22827366 TI - What sperm can teach us about energy production. AB - Mammalian sperm have evolved under strict selection pressures that have resulted in a highly polarized and efficient design. A critical component of that design is the compartmentalization of specific metabolic pathways to specific regions of the cell. Although the restricted localization of mitochondria to the midpiece is the best known example of this design, the organization of the enzymes of glycolysis along the fibrous sheath is the primary focus of this review. Evolution of variants of these metabolic enzymes has allowed them to function when tethered, enabling localized energy production that is essential for sperm motility. We close by exploring how this design might be mimicked to provide an energy-producing platform technology for applications in nanobiotechnology. PMID- 22827367 TI - The effects of increased testicular temperature on testis-specific isoform of Na+/K+ -ATPase in sperm and its role in spermatogenesis and sperm function. AB - Impaired testicular thermoregulation is commonly implicated in abnormal spermatogenesis and impaired sperm function in animals and humans, with outcomes ranging from subclinical infertility to sterility. Bovine testes must be maintained 4-5 degrees C below body-core temperature for normal spermatogenesis. The effects of elevated testicular temperature have been extensively studied in cattle using a scrotal insulation model, which results in abnormal spermatogenesis and impaired sperm morphology and function. Using this model and proteomic approaches, we compared normal and abnormal sperm (from the same bulls) to elucidate the molecular basis of impaired function. We identified a cohort of sperm functional proteins differentially expressed between normal vs abnormal sperm, including a testis-specific isoform of Na(+) /K(+) -ATPase. In addition to its role as a sodium pump regulating sperm motility, Na(+) /K(+) -ATPase is also involved as a signalling molecule during sperm capacitation. In conclusion, because of its involvement in regulation of sperm function, this protein has potential as a fertility marker. Furthermore, comparing normal vs abnormal sperm (induced by scrotal insulation) is a useful model for identifying proteins regulating sperm function. PMID- 22827368 TI - The emerging pathophysiology of age-related testicular degeneration with a focus on the stallion and an update on potential therapies. AB - Studies in laboratory rodents are shedding light on the pathophysiology of testicular ageing and now suggest a complicated basis for age-related declines in testicular function. A highly significant contributor to infertility may involve failure of specific and complex testicular microenvironments (niches) comprised of a variety of cellular and molecular components. Our laboratory has applied testis tissue xenografting to the study of testicular ageing in the stallion. Using this technique, we have confirmed that the disease is tissue autologous. As would be expected from a tissue autologous disease, hormonal and non-hormonal therapies designed to drive the function of the diseased testis are ineffective. However, we have some evidence that contact with young, normal testicular tissue may improve the condition of aged, degenerate testes. Perhaps, paracrine factors from young testicular cells may partially restore a young microenvironment and allow for the maintenance of testicular function. These findings form the basis for future studies designed to determine whether cells, genes or proteins from a normal testis can aid the function of a degenerate testis. PMID- 22827369 TI - Biological characteristics of fish germ cells and their application to developmental biotechnology. AB - We have revealed several unique characteristics of germ cell development using rainbow trout, including the fact that spermatogonia transplanted into the peritoneal cavity of newly hatched embryos migrate toward recipient gonads, that spermatogonia transplanted into female recipients start oogenesis and produce functional eggs and that diploid germ cells transplanted into triploid trout can complete gametogenesis. By combining these unique features of fish germ cells, we established allogeneic and xenogeneic transplantation systems for spermatogonia in several fish species. Spermatogonia isolated from the mature testes of vasa green fluorescent protein (Gfp) transgenic rainbow trout were transplanted into the peritoneal cavity of triploid masu salmon newly hatched embryos. These spermatogonia migrated toward recipient salmon genital ridges with extending pseudopodia and were subsequently incorporated into them. We further confirmed that the donor-derived spermatogonia resumed gametogenesis and produced sperm and eggs in male and female salmon recipients, respectively. By inseminating the resulting eggs and sperm, we obtained only rainbow trout offspring in the F1 generation, suggesting that the triploid salmon recipients produced functional gametes derived only from donor trout. We further confirmed that this intra peritoneal transplantation of germ cells is applicable to several marine fishes, which could be of benefit in the production of bluefin tuna that has a large broodstock (>100 kg) and is difficult to maintain in captivity. Gamete production of bluefin tuna could be more easily achieved by generating a surrogate species, such as mackerel, that can produce tuna gametes. PMID- 22827370 TI - Directional freezing of reproductive cells and organs. AB - Directional freezing is based on a simple thermodynamic principle where ice crystals are precisely controlled through the sample by regulating the velocity of the sample movement through the predetermined temperature gradient. Directional freezing permits a precise and uniform cooling rate in both small and large volume samples. Directional freezing was used for slow and rapid freezing, as well as for vitrification of oocytes and embryos using the minimum drop size technique. Sperm samples from a wide range of domestic and wild animals were successfully cryopreserved using the directional freezing method. The method enabled, for the first time, successful freezing of a whole ovary and freeze drying of mammalian cells followed by thawing and transplantation and rehydration, respectively. PMID- 22827371 TI - Controlled stress improves oocyte performance--cell preconditioning in assisted reproduction. AB - A recently emerged concept utilizing a controlled environmental impact as a treatment for cells and tissues aims to improve neither the in vitro conditions nor the procedures, but the cell itself. Hydrostatic pressure stress emerged as the most controllable and most effective stressor, proving the principle that controlled stress improves cell performance in in vitro procedures, whereas further studies using different stressors (osmotic, oxidative or mechanic stresses) supported the principle. The present summary reviews studies of various stress treatments to treat oocytes of three species (murine, porcine, human) before vitrification, in vitro maturation, enucleation and somatic cell nuclear transfer. Eventually, cleavage and blastocyst rates and--in cases when hydrostatic pressure was used--blastocyst cell number and birth rates as well were significantly improved compared to untreated controls. PMID- 22827372 TI - Seminal plasma and its effect on ruminant spermatozoa during processing. AB - Seminal plasma can both inhibit and stimulate sperm function, making its use as a supportive medium somewhat contradictory. These effects are directed by the multifunctional action of numerous inorganic and organic components, but it is the direct association of seminal plasma proteins with the sperm membrane that is thought to exert the most significant response. In vitro handling of spermatozoa in preparation for artificial insemination may involve washing, dilution, cooling, freezing, re-warming and sex-sorting. These processes can alter proteins of the sperm surface and reduce seminal plasma in the sperm environment. This, among other factors, may destabilize the sperm membrane and reduce the fertilizable lifespan of spermatozoa. Such handling-induced damage may be prevented or reversed through supplementation of seminal plasma, but the effectiveness of this technique differs with species, and the source and subsequent treatment of both spermatozoa and seminal plasma. Seminal plasma appears to act as a protective medium during in vitro processing of ram spermatozoa, but this does not appear to be the case for bull spermatozoa. The reasons for this divergent effect will be discussed with particular emphasis on the influence of the major proteins of ruminant seminal plasma, known as BSP proteins. The biochemical and biophysical properties of these proteins are well documented, and this information has provided greater insight into the signalling pathways of capacitation and the protective action of extender components. PMID- 22827373 TI - Effects of surgical sterilization on canine and feline health and on society. AB - Surgical sterilization of dogs and cats is a well-accepted measure for population control in some countries, but is considered unethical as an elective surgery in other countries. This is a review of what is known regarding positive and negative effects of gonadectomy surgery on individual animals and on societal management of unowned dog and cat populations. PMID- 22827374 TI - Progress in development of immunocontraceptive vaccines for permanent non surgical sterilization of cats and dogs. AB - Each year, millions of cats and dogs are euthanized worldwide. There are insufficient resources to control shelter animals in developed countries, as well as feral cat and wild dog population levels, with current surgical sterilization techniques. Thus, population control of these animals will likely depend on the development of new non-surgical methods for cat and dog sterilization. One promising area of research is the development of contraceptive vaccines, or immunocontraceptives. In this article, previous approaches aimed at developing contraceptive vaccines will be reviewed, with a focus on those most related to sterilization of cats and dogs. There are a number of steps in reproduction that have been, or could be, targeted by the immune system, and the advantages and obstacles for inducing immunity to each of these will be discussed. Our current understanding of how these vaccines cause sterility, and our current ability to dissect these mechanisms in cats and dogs, also will be discussed. PMID- 22827376 TI - Gonadotropin-releasing hormone targeting for gonadotroph ablation: an approach to non-surgical sterilization. AB - Surgical sterilization is the mainstay of dog and cat population control, but its use is still often limited by the costs and effort involved, especially in developing countries. An ideal non-surgical sterilant that is safe, effective, permanent, administered as a single injection and capable of being manufactured inexpensively could have a significant impact on the world-wide dog and cat overpopulation problem. One approach towards developing such an agent is the targeting of pituitary gonadotrophic cells with cytotoxic agents using gonadotropin-releasing hormone (GnRH). GnRH is a peptide that binds to high affinity receptors selectively expressed on gonadotrophs and some types of cancers. Both small molecules and proteins have been conjugated to GnRH analogues to generate targeted cytotoxic and imaging agents. Although most of these efforts have focused on development of human cancer therapeutics, available reproductive studies in rats and dogs suggest that current compounds do not have sufficient therapeutic windows for complete gonadotroph ablation, in part owing to poor stability of peptide targeting sequences. The only reported longer-term study of gonadotroph ablation in dogs reported suppression of serum testosterone for 8 months, but endocrine function then recovered, raising important questions about the mechanism of reproductive suppression and its recovery. Although studies to date suggest that this is a potentially attractive approach to non-surgical sterilization, ideal agents are yet to be developed, and important mechanistic questions remain to be answered. PMID- 22827375 TI - Targeted gene silencing to induce permanent sterility. AB - A non-surgical method to induce sterility would be a useful tool to control feral populations of animals. Our laboratories have experience with approaches aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A combination/modification of these methods may provide a useful framework for the design of approaches that can be used to sterilize cats and dogs. For this approach to succeed, it has to meet several conditions: it needs to target a gene essential for fertility. It must involve a method that can selectively silence the gene of interest. It also needs to deliver the silencing agent via a minimally invasive method. Finally, the silencing effect needs to be sustained for many years, so that expansion of the targeted population can be effectively prevented. In this article, we discuss this subject and provide a succinct account of our previous experience with: (i) molecular reagents able to disrupt reproductive cyclicity when delivered to regions of the brain involved in the control of reproduction and (ii) molecular reagents able to ameliorate neuronal disease when delivered systemically using a novel approach of gene therapy. PMID- 22827377 TI - Breeding or assisted reproduction? Relevance of the horse model applied to the conservation of endangered equids. AB - Many wild equids are at present endangered in the wild. Concurrently, increased mechanization has pushed back the numbers of some old native horse breeds to levels that are no longer compatible with survival of the breed. Strong concerns arose in the last decade to preserve animal biodiversity, including that of rare horse breeds. Genome Resource Banking refers to the cryostorage of genetic material and is an approach for ex situ conservation, which should be applied in combination with in situ conservation programmes. In this review, we propose that, owing to the great reproductive similarity among the different members of the genus Equus, the domestic horse can be used to optimize cryopreservation and embryo production protocols for future application in wild equids. We will give this hypothesis a scientific underpinning by listing successful applications of epididymal sperm freezing, embryo freezing, intracytoplasmic sperm injection, oocyte vitrification and somatic cell nuclear transfer in domestic horses. Some ART fertilization methods may be performed with semen of very low quality or with oocytes obtained after the death of the mare. PMID- 22827378 TI - Genetic selection and conservation of genetic diversity*. AB - For 100s of years, livestock producers have employed various types of selection to alter livestock populations. Current selection strategies are little different, except our technologies for selection have become more powerful. Genetic resources at the breed level have been in and out of favour over time. These resources are the raw materials used to manipulate populations, and therefore, they are critical to the past and future success of the livestock sector. With increasing ability to rapidly change genetic composition of livestock populations, the conservation of these genetic resources becomes more critical. Globally, awareness of the need to steward genetic resources has increased. A growing number of countries have embarked on large scale conservation efforts by using in situ, ex situ (gene banking), or both approaches. Gene banking efforts have substantially increased and data suggest that gene banks are successfully capturing genetic diversity for research or industry use. It is also noteworthy that both industry and the research community are utilizing gene bank holdings. As pressures grow to meet consumer demands and potential changes in production systems, the linkage between selection goals and genetic conservation will increase as a mechanism to facilitate continued livestock sector development. PMID- 22827379 TI - Selective breeding in fish and conservation of genetic resources for aquaculture. AB - To satisfy increasing demands for fish as food, progress must occur towards greater aquaculture productivity whilst retaining the wild and farmed genetic resources that underpin global fish production. We review the main selection methods that have been developed for genetic improvement in aquaculture, and discuss their virtues and shortcomings. Examples of the application of mass, cohort, within family, and combined between-family and within-family selection are given. In addition, we review the manner in which fish genetic resources can be lost at the intra-specific, species and ecosystem levels and discuss options to best prevent this. We illustrate that fundamental principles of genetic management are common in the implementation of both selective breeding and conservation programmes, and should be emphasized in capacity development efforts. We highlight the value of applied genetics approaches for increasing aquaculture productivity and the conservation of fish genetic resources. PMID- 22827380 TI - How developments in cryobiology, reproductive technologies and conservation genomics could shape gene banking strategies for (farm) animals. AB - Many local breeds are currently at risk because of replacement by a limited number of specialized commercial breeds. Concurrently, for many breeds, allelic diversity within breeds declines because of inbreeding. Gene banking of germplasm may serve to secure the breeds and the alleles for any future use, for instance to recover a lost breed, to address new breeding goals, to support breeding schemes in small populations to minimize inbreeding, and for conservation genetics and genomics research. Developments in cryobiology and reproductive technology have generated several possibilities for preserving germplasm in farm animals. Furthermore, in some mammalian and bird species, gene banking of material is difficult or impossible, requiring development of new alternative methods or improvement of existing methods. Depending on the species, there are interesting possibilities or research developments in the use of epididymal spermatozoa, oocytes and embryos, ovarian and testicular tissue, primordial germ cells, and somatic cells for the conservation of genetic diversity in farm- and other animal species. Rapid developments in genomics research also provide new opportunities to optimize conservation and sampling strategies and to characterize genome-wide genetic variation. With regard to gene banks for farm animals, collaboration between European countries is being developed through a number of organizations, aimed at sharing knowledge and expertise between national programmes. It would be useful to explore further collaboration between countries, within the framework of a European gene banking strategy that should minimize costs of conservation and maximize opportunities for exploitation and sustainable use of genetic diversity. PMID- 22827381 TI - Nutritional influences on folliculogenesis. AB - Folliculogenesis is an intricate process that involves the proliferation and differentiation of both somatic and germ cells. This process depends on complex interactions between systemic factors such as both pituitary gonadotrophins and metabolic hormones and/or local factors produced by the ovarian somatic and germ cells, such as the IGF system and TGF-beta superfamily members. In domestic ruminants, follicular development begins during foetal life with formation of primordial follicles from the association of germ cells and pre-granulosa cells. After follicular formation, folliculogenesis begins with a primordial follicle progressing into more developed stages (i.e. primary, secondary, pre-antral and antral) in a continuous, progressive process to either ovulation or, as in most cases, to atresia. Even early stages of follicular formation and subsequent development are influenced by both internal (e.g. genotype) and/or external environmental (e.g. nutrition and season) factors. Among these external factors, nutrition is one of the most important affecting reproductive function, and this is the focus of this review, because other reviews in this issue discuss other environmental factors. A number of studies have now shown that nutrition can have both positive and negative effects on follicular growth, oestrous activity, oocyte quality, blastocyst development and pregnancy outcome. Therefore, understanding the intricate processes involved during folliculogenesis and the ways in which factors, such as nutrition, affect them is leading to new opportunities to improve pregnancy rates by influencing follicle development and oocyte quality. This review will focus on follicular development from foetal to adult stages and the influences that nutrition has during some of these developmental stages. PMID- 22827382 TI - Follicle selection in the avian ovary. AB - Follicle development in the highly efficient laying hen is characterized by a well-organized follicular hierarchy. This is not the case in other chickens such as the broiler breeder hen that has excessive follicle development and lower reproductive efficiency. Although management practices can optimize egg production in less productive breeds of chickens, the factors that contribute to this difference are not known. Interactions between the oocyte and surrounding somatic cells are believed to be involved in promoting follicle selection. Anti Mullerian hormone (AMH) has been shown to have a role in regulating rate of follicle development in mammals. In hens, the expression of AMH is restricted to the growing population of follicles and, similar to mammals, is markedly decreased at around the time of follicle selection. The oocyte factors, growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), have been identified in the hen, and their expression pattern has been characterized. Anti-Mullerian hormone expression in hens is decreased by a protein factor from the oocyte (not GDF9) and is also decreased by vitamin D. Associated with the decrease in AMH expression by vitamin D, follicle-stimulating hormone receptor mRNA is increased. These data suggest that information about AMH regulation may enhance our understanding of follicle selection, particularly in birds with aberrant follicle development. PMID- 22827383 TI - The critical roles of progesterone receptor (PGR) in ovulation, oocyte developmental competence and oviductal transport in mammalian reproduction. AB - Progesterone is critical for successful ovulation in the ovary and for the multi faceted role of the oviduct in mammalian reproduction. Its effects are mediated by progesterone receptor (PGR), which is highly expressed in the ovary, specifically granulosa cells of preovulatory follicles in response to the luteinizing hormone (LH) surge that occurs just prior to ovulation, and in the oviduct, predominantly luminal epithelial cells but also muscle cells. This review will summarize research which shows that progesterone, via the actions of PGR, plays a key role in the functions of these cells and in the important periovulatory events of oocyte release, acquisition of oocyte developmental competence and oviductal transport of the newly formed embryo. PGR is a nuclear receptor that regulates the expression of many downstream target genes. However, although much is known about its expression characteristics in ovarian and oviductal cells, there is still much to unravel about the mechanisms by which PGR exerts its control over these important reproductive processes, particularly in the oviduct. PMID- 22827384 TI - Life or death decisions in the corpus luteum. AB - The corpus luteum (CL) is an ephemeral endocrine organ. During its lifespan, it undergoes a period of extremely rapid growth that involves hypertrophy, proliferation and differentiation of the steroidogenic cells, as well as extensive angiogenesis. The growth phase is followed by a period in which remodelling of the tissue ceases, but it engages in unparalleled production of steroids, resulting in extraordinarily high metabolic activity within the tissue. It is during this stage that a critical juncture occurs. In the non-fertile cycle, uterine release of prostaglandin (PG)F(2alpha) initiates a cascade of events that result in rapid loss of steroidogenesis and destruction of the luteal tissue. Alternatively, if a viable embryo is present, signals are produced that result in rescue of the CL. This review article summarizes the major concepts related to the fate of the CL, with particular focus on recent insights into the mechanisms associated with the ability of PGF(2alpha) to bring about complete luteolysis. It has become clear that the achievement of luteolysis depends on repeated exposure to PGF(2alpha) and involves coordinated actions of heterogeneous cell types within the CL. Together, these components of the process bring about not only the loss in progesterone production, but also the rapid demise of the structure itself. PMID- 22827385 TI - Mechanisms linking metabolic status and disease with reproductive outcome in the dairy cow. AB - Culling for infertility remains the main reason for disposal of dairy cows, limiting productive lifespan. In extreme cases, ovulation is inhibited, preventing the possibility of conception. More often cows do conceive, but fail to remain pregnant owing to intrinsic problems in the embryo and/or to a poor quality reproductive tract environment. Both aspects have a genetic component and are also influenced by management practices affecting nutrition and health. The relative importance of these factors varies among heifers, first-lactation and older cows. A common theme, however, is that an internal signalling system exists which reduces fertility when the cow is in an unsuitable metabolic state to sustain a pregnancy. This may be directly related to nutrient shortage caused by inadequate feed intake, or because available nutrients are being prioritized towards growth or milk production, away from reproduction. Evidence is presented for the involvement of the somatotrophic axis (GH, IGF1, insulin, IGFBP2) and leptin as key metabolic signalling molecules. Another emerging theme is the interaction between metabolism and disease that affects the fertility. Common examples include (i) calf diseases causing inadequate heifer growth and increased age at first calving; (ii) poor peripartum energy status reducing the capacity of the uterus to involute and mount an effective immune response, thereby increasing the likelihood of endometritis; and (iii) development of mastitis after conception, a contributory factor to both early and late embryo mortality. Finally, recent evidence suggests that times of metabolic stress cause mitochondrial damage that also contributes to a reduction in longevity. PMID- 22827386 TI - Reproduction in farm animals in an era of rapid genetic change: will genetic change outpace our knowledge of physiology? AB - Compared with other domestic species, genetic nucleus selection has gradually increased both prolificacy and productivity of the breeding sow and the post natal growth performance of commercial progeny. However, increasing variation in litter birth weight and foetal development may be indirect consequences of interactions among multiple genes controlling prolificacy and prenatal development. Phenotypic plasticity in the litter phenotype also results from effects of sow metabolic state on the developing embryo. New genomic tools may provide the opportunity to better balance the selection of genes controlling the component traits affecting the size and quality of litters born, particularly in multiparous sows. PMID- 22827387 TI - Should weaning be the start of the reproductive cycle in hyper-prolific sows? A physiological view. AB - Normally, sows are in anoestrus during lactation and start their new cycle at the day of weaning. Modern hybrid primiparous sows that suckle large numbers of piglets may lose substantial amounts of body reserves during lactation. This compromises follicle development during lactation. As modern sows have short weaning-to-oestrus intervals, these compromised follicles are recruited for ovulation directly after weaning, resulting in lower ovulation rates and lower embryo survival. Postponing or skipping first oestrus after weaning in primiparous sows may help to limit the negative consequences of lactation on subsequent reproduction. Multiparous sows may have very high litter sizes, especially after long lactations as applied in organic sows. These high litter sizes compromise piglet birthweight and survival and subsequent performance. Inducing lactation oestrus in multiparous sows may help to limit litter size and improve piglet survival and performance. This study discusses physiological and reproductive effects of extending the start of a new pregnancy after lactation in primiparous sows and induction of lactation oestrus in multiparous sows. We thereby challenge the view that weaning is an ideal start for the reproductive cycle in modern sows. PMID- 22827388 TI - Environmental pollutants and diseases of sexual development in humans and wildlife in South Africa: harbingers of impact on overall health? AB - This study deals with disorders of sexual development in humans, wildlife and animals in an urban nature reserve (RNR) and a currently DDT-sprayed malarial area. High levels of oestrogenic chemical residues in water, sediment and tissue; skewed sex ratios; reduced biodiversity; gonadal malformations in sharptooth catfish and freshwater snails; intersex in catfish; and impaired spermatogenesis in catfish and striped mouse are of serious concern in the RNR. Persistent eggshell thinning in African darter eggs, intersex in male Mozambican tilapia, follicular atresia in females and impaired spermatogenesis in males following laboratory exposure of parent fish to environmentally relevant DDT and DDE concentrations, and abnormalities in freshwater snails were found in the DDT sprayed area. Human studies related to DDT exposure indicated impaired semen quality, a weak association with sperm chromatin defects and higher risks for external urogenital birth defects in those who were born to mothers whose houses were sprayed and those who were homemakers (stay at home mother) instead of being employed. These findings indicate that diseases of sexual development occurred in both human and wildlife populations exposed to environmental endocrine disruptor chemicals in South Africa. The chemical mixtures, possibly related to disorders of sexual differentiation (DSD), were very different between the two. However, DSD occurred concurrently in the malarial area, possibly indicating that humans and wildlife shared exposures. Moreover, it emphasizes the importance of suspecting disease in the other when disease is found in either human or wildlife populations. PMID- 22827389 TI - Environmental endocrine disruptors in farm animal reproduction: research and reality. AB - In this review, possible comparative advantages of studying endocrine disruption in farm animals vs laboratory rodents are discussed. First, using farm animals, the generality of findings in laboratory rodents are challenged. Farm animals may in certain aspects be better models for humans than laboratory rodents, and sometimes there might be methodological advantages in using farm animals. Second, there are several in vitro studies based on cell-culture systems from sows and cows where the effects of chemicals on sex steroid secretion can be measured and maturation and fertilization of oocytes may be assessed. These in vitro systems are powerful tools for dissecting the mechanisms of action for endocrine disrupting chemicals. Third, in a set of recent in vivo studies using sheep, goats and pigs, in which very different exposure regimens to endocrine-disrupting chemicals have been used, a full panel of reproductive parameters pertinent to farm animals were assessed. Clinically, it is suggested that endocrine disruption in farm animals should be considered when impaired reproduction could be linked to change in source of feed or pasture. Finally, epigenetic and toxicogenomic approaches can be particularly rewarding in elucidating endocrine disruption in future farm animal studies. PMID- 22827391 TI - Sperm interaction with the female reproductive tract. AB - Sperm transit in the female tract is a critical event for the success of fertilization. From their deposition in the vagina to final migration in the oviduct, sperm pass through the different compartments of the genital tract in which they encounter different environments. The cervix and the uterotubal junction (UTJ) are two barriers with different relative importance according to the species. The protein composition, the degree of glycosylation and the hydration of the cervical mucus change during the oestrous cycle. Several sperm surface proteins are associated with their migration through the cervical mucus and the UTJ. Data regarding the interaction of sperm with secretions of the epithelial tissue lining the different compartments of the female genital tract during the sperm transit are reviewed, with a particular emphasis on the migration of sperm through the cervix. PMID- 22827392 TI - Enhancing insemination performance in pigs through controlled release of encapsulated spermatozoa. AB - Encapsulation of boar semen is a novel technique that allows insemination to be performed as a single intervention without the need to dilute the semen. The research reviewed in this paper shows that spermatozoa encapsulated in alginate are able to achieve the same fertility as two or three inseminations per oestrus using standard techniques and unencapsulated cells. The use of encapsulated spermatozoa is currently limited by the need for longer semen processing time and wastage of disposable material (catheters, plastic bottles, etc.). In this review, the advantages, the drawbacks and the future possibilities for artificial insemination with encapsulated spermatozoa in the sow are discussed, with the aim of applying this promising new methodology for the optimization of sow reproductive performance. PMID- 22827393 TI - Impact of metal nanoparticles on germ cell viability and functionality. AB - Metal nanoparticles play an increasing role in consumer products, biomedical applications and in the work environment. Therefore, the effects of nanomaterials need to be properly understood. This applies especially to their potential reproductive toxicology (nanoreprotoxicity), because any shortcomings in this regard would be reflected into the next generation. This review is an attempt to summarize the current knowledge regarding the effects of nanoparticles on reproductive outcomes. A comprehensive collection of significant experimental nanoreprotoxicity data is presented, which highlight how the toxic effect of nanoparticles can be influenced, not only by the particles' chemical composition, but also by particle size, surface modification, charge and to a considerable extent on the experimental set-up. The period around conception is characterized by considerable cytological and molecular restructuring and is therefore particularly sensitive to disturbances. Nanoparticles are able to penetrate through biological barriers into reproductive tissue and at least can have an impact on sperm vitality and function as well as embryo development. Particularly, further investigations are urgently needed on the repetitively shown effect of the ubiquitously used titanium dioxide nanoparticles on the development of the nervous system. It is recommended that future research focuses more on the exact mechanism behind the observed effects, because such information would facilitate the production of nanoparticles with increased biocompatibility. PMID- 22827390 TI - Epigenetic mechanisms in the actions of endocrine-disrupting chemicals: gonadal effects and role in female reproduction. AB - There is a heightened interest and concern among scientists, clinicians and regulatory agencies as well as the general public, regarding the effects of environmental endocrine-disrupting chemicals (EDCs). In this review, we identify the main epigenetic mechanisms and describe key ovarian processes that are vulnerable to the epigenetic actions of EDCs. We also provide an overview of the human epidemiological evidence documenting the detrimental effects of several common environmental EDCs on female reproduction. We then focus on experimental evidence demonstrating the epigenetic effects of these EDCs in the ovary and female reproductive system, with an emphasis on methoxychlor, an organochlorine pesticide. We conclude the review by describing several critical issues in studying epigenetic effects of EDCs in the ovary, including transgenerational epigenetic effects. PMID- 22827394 TI - Seminal plasma components in camelids and comparisons with other species. AB - Camelid semen is characterized by a highly viscous, low-volume ejaculate with a low concentration of spermatozoa that exhibit low progressive motility. The viscous seminal plasma is currently the major impediment to the development of assisted reproductive technologies (ARTs) in camelids. To advance ARTs such as sperm cryopreservation and artificial insemination in camelids, it is necessary to identify the cause of the viscosity and gain an understanding of the role of seminal plasma components on sperm function and fertility. Numerous compounds and proteins have been identified as mediators of sperm function and predictors of fertility in other livestock species, and understanding the importance of specific proteins has progressed the success of ARTs in these species. Current knowledge on the components of camelid seminal plasma is outlined, together with the implications of these components for the development of ARTs in camelids. The cause of semen viscosity, as well as proteins that are present in camelid seminal plasma, is described for the first time. Seminal plasma components are compared with those of other species to hypothesize their role in sperm function and fertility. PMID- 22827395 TI - T-cell tolerance to the developing equine conceptus. AB - One of the most intriguing and dramatic examples of immunological tolerance is displayed by the mammalian foetal-placental unit, which thrives as a semi allograft in the mother's uterus during pregnancy. The success of the so-called foetal allograft stands in stark contrast to the failure of most tissue and organ grafts to survive without genetic matching of donor and recipient or drastic immunosuppression of the recipient's immune system. Experiments conducted over the past 60 years have revealed multiple mechanisms that enable the conceptus to avoid immunological detection or destruction. Many of these mechanisms are directed towards evading immune-mediated damage by maternal T lymphocytes, and they can be grouped into three classes: (i) downregulation of major histocompatibility complex (MHC) gene expression in placental trophoblast cells; (ii) local and systemic alterations in maternal immune reactivity; and (iii) innate defence mechanisms of the trophoblast cells that comprise the barrier between foetal and maternal tissues. The redundancy in these protective mechanisms helps ensure the transmission of life from generation to generation and provides a rich field of study of ways in which functional immunological tolerance can be manifest. The variation in placental forms and function among mammalian species present opportunities to discover and understand novel tolerogenic mechanisms that may have broad application in biology, medicine and animal husbandry. This review focuses on the evidence obtained from studies of pregnancy in the mare that support the case for selective T-cell tolerance to the mammalian conceptus. PMID- 22827396 TI - Modulation of maternal immune system during pregnancy in the cow. AB - There is a molecular crosstalk between the trophoblast and maternal immune cells of bovine endometrium. The uterine cells are able to secrete cytokine/chemokines to either induce a suppressive environment for establishment of the pregnancy or to recruit immune cells to the endometrium to fight infections. Despite morphological differences between women and cows, mechanisms for immune tolerance during pregnancy seem to be conserved. Mechanisms for uterine immunesuppression in the cow include: reduced expression of major histocompatability proteins by the trophoblast; recruitment of macrophages to the pregnant endometrium; and modulation of immune-related genes in response to the presence of the conceptus. Recently, an eGFP transgenic cloned embryo model developed by our group showed that there is modulation of foetal proteins expressed at the site of syncytium formation, suggesting that foetal cell can regulate not only by the secretion of specific factors such as interferon-tau, but also by regulating their own protein expression to avoid excessive maternal recognition by the local immune system. Furthermore, foetal DNA can be detected in the maternal circulation; this may reflect the occurrence of an invasion of trophoblast cells and/or their fragment beyond the uterine basement membrane in the cow. In fact, the newly description of exosome release by the trophoblast cell suggests that could be a new fashion of maternal-foetal communication at the placental barrier. Additionally, recent global transcriptome studies on bovine endometrium suggested that the immune system is aware, from an immunological point of view, of the presence of the foetus in the cow during early pregnancy. PMID- 22827397 TI - An overview of molecular and cellular mechanisms associated with porcine pregnancy success or failure. AB - Prenatal mortality remains one of the major constraints for the commercial pig industry in North America. Twenty to thirty per cent of the conceptuses are lost early in gestation and an additional 10-15% is lost by mid-to-late gestation. Research over the last two decades has provided critical insights into how uterine capacity, placental efficiency, genetics, environment, nutrition and immune mechanisms impact successful conceptus growth; however, the exact cause and effect relationship in the context of foetal loss has yet to be determined. Similar to other mammalian species such as the human, mouse, rat, and primates, immune cell enrichment occurs at the porcine maternal-foetal interface during the window of conceptus attachment. However, unlike other species, immune cells are solely recruited by conceptus-derived signals. As pigs have epitheliochorial placentae where maternal and foetal tissue layers are separate, it provides an ideal model to study immune cell interactions with foetal trophoblasts. Our research is focused on the immune-angiogenesis axis during porcine pregnancy. It is well established that immune cells are recruited to the maternal-foetal interface, but their pregnancy specific functions and how the local milieu affects angiogenesis and inflammation at the site of foetal arrest remain unknown. Through a better understanding of how immune cells modulate crosstalk between the conceptus and the mother, it might be possible to therapeutically target immune cells and/or their products to reduce foetal loss. In this review, we provide evidence from the literature and from our own work into the immunological factors associated with porcine foetal loss. PMID- 22827398 TI - Immunity and inflammation in the uterus. AB - Microbes often infect the uterus and particularly the endometrium of animals. Infections are most commonly associated with natural service, pregnancy and the post-partum period, leading to inflammation with the elaboration of cytokines, chemokines and prostaglandins. Clinical diseases such as metritis, endometritis and abortion are important causes of infertility. The adaptive immune response to infection has been characterized previously, so the present review aims to highlight the emerging role for innate immunity in the endometrium. The detection of microbes and the innate immune response depends on the detection of pathogen associated molecular patterns by pattern recognition receptors. The main families of pattern recognition receptors are Toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and C-type lectin receptors. These receptors are most often expressed by hematopoietic cells, but the epithelial and stromal cells of the endometrium also possess functional receptors. For example, endometrial cells express TLR4 for recognition of the lipopolysaccharide endotoxin of Gram-negative bacteria, leading to secretion of IL-6, IL-8 and prostaglandin E(2) . It is likely that the epithelial and stromal cells provide a first line of defence in the endometrium to alert hematopoietic cells to the presence of microbes within the uterus. PMID- 22827400 TI - Surface decontamination and quality enhancement in meat steaks using plant extracts as natural biopreservatives. AB - Nine plant extracts were evaluated as biopreservatives to decontaminate and maintain the quality of meat steaks. Most of the extracts exhibited a remarkable antibacterial activity against antibiotic resistant strains from Salmonella Typhimurium and Staphylococcus aureus. The pomegranate peel extract (PPE), cinnamon bark extract (CBE), and lemon grass leaves extract (LGE) were the most effective as bactericides, with minimal inhibitory concentrations (MIC) of 250, 350, and 550 MUg/mL, respectively. The most effective treatments, for decontaminating meat steak surfaces, were the application of combined PPE, CBE, and LGE at their MIC values and the treatment with double MIC from PPE; these treatments resulted in complete bacterial inhibitions during the first 2 days of storage period for 7 days. The sensory evaluation of treated steaks revealed that these two treatments had the highest panelist overall scores. The highest scores, for individual attributes, were observed in the treated steaks with double MIC from PPE. Application of plant extracts could be impressively recommended for comprehensive meat decontamination and quality attributes enhancement. PMID- 22827401 TI - 'He did what? Well, that wasn't handed over!' Communicating risk in mental health. AB - Mental health inpatient units are dynamic, complex environments that provide care for patients with heterogeneous ages, diagnoses and levels of acuity. These environments commonly expose clinicians and patients to many potential risks. Despite extensive research into risk assessment, prediction and management, no study has investigated how risk information is communicated at handover in acute mental health settings. Given the pivotal role handover plays in informing risk management, this evidence gap is significant. This paper reports on a study that investigated the practices of communicating risk at handover in an Australian acute mental health inpatient unit. The aim of this research was to identify the frequency and type of risk information communicated between nursing shifts, and the methods by which this communication was performed. A secondary aim was to identify effective and ineffective risk communication practices. This study involved an observational design method using a 14-item Clinical Audit Tool derived from handover principles outlined by World Health Organization. Five hundred occasions of patient handover were observed. Few risk information items were observed to be communicated in any method. Risk communication practice was inconsistent, and a key recommendation from the study is the use of standardized handover tools that ensures risk information is adequately reported. PMID- 22827402 TI - Comparison of low-light nonmydriatic digital imaging with 35-mm ETDRS seven standard field stereo color fundus photographs and clinical examination. AB - PURPOSE: To compare agreement between diagnosis of clinical level of diabetic retinopathy (DR) and diabetic macular edema (DME) derived from nonmydriatic fundus images using a digital camera back optimized for low-flash image capture (MegaVision) compared with standard seven-field Early Treatment Diabetic Retinopathy Study (ETDRS) photographs and dilated clinical examination. Subject comfort and image acquisition time were also evaluated. SUBJECTS AND METHODS: In total, 126 eyes from 67 subjects with diabetes underwent Joslin Vision Network nonmydriatic retinal imaging. ETDRS photographs were obtained after pupillary dilation, and fundus examination was performed by a retina specialist. RESULTS: There was near-perfect agreement between MegaVision and ETDRS photographs (kappa=0.81, 95% confidence interval [CI] 0.73-0.89) for clinical DR severity levels. Substantial agreement was observed with clinical examination (kappa=0.71, 95% CI 0.62-0.80). For DME severity level there was near-perfect agreement with ETDRS photographs (kappa=0.92, 95% CI 0.87-0.98) and moderate agreement with clinical examination (kappa=0.58, 95% CI 0.46-0.71). The wider MegaVision 45 degrees field led to identification of nonproliferative changes in areas not imaged by the 30 degrees field of ETDRS photos. Field area unique to ETDRS photographs identified proliferative changes not visualized with MegaVision. Mean MegaVision acquisition time was 9:52 min. After imaging, 60% of subjects preferred the MegaVision lower flash settings. CONCLUSIONS: When evaluated using a rigorous protocol, images captured using a low-light digital camera compared favorably with ETDRS photography and clinical examination for grading level of DR and DME. Furthermore, these data suggest the importance of more extensive peripheral images and suggest that utilization of wide-field retinal imaging may further improve accuracy of DR assessment. PMID- 22827404 TI - Latent transforming growth factor-beta binding protein 2 negatively regulates coalescence of oxytalan fibers induced by stretching stress. AB - Oxytalan fibers are extracellular matrix components consisting of pure microfibrils. However, the mechanism whereby oxytalan fibers develop is not fully understood. We have previously reported that in human periodontal ligament (PDL) fibroblasts subjected to stretching stress, bundles of oxytalan fibers coalesce under the control of fibulin-5. Latent transforming growth factor-beta binding protein 2 (LTBP-2) is known to bind to fibulin-5. The purpose of this study was to clarify the role of LTBP-2 in the coalescence of oxytalan fibers. We subjected PDL fibroblasts to stretching in order to examine the effects of LTBP-2 on the coalescence of oxytalan fibers in cell/matrix layers. Interaction of LTBP-2 with fibulin-5 was examined by immunoprecipitation assay, and changes in LTBP-2 deposition upon stretching were investigated by Western blotting and immunofluorescence assays. We used small interfering RNA against LTBP-2 in PDL cell culture and examined the appearance of oxytalan fibers on the basis of immunofluorescence. Stretching induced coalescence of oxytalan fibers, but did not affect LTBP-2 expression. The amount of extracellularly deposited LTBP-2 was decreased by about 70% as a result of stretching, compared with the control. LTBP 2 interacted with fibulin-5 on the fibers, and stretching decreased the amount of the LTBP-2 interacted with fibulin-5 by about 60%. Oxytalan fiber coalescence did not occur when LTBP-2 was suppressed by about 95%, whereas it occurred when LTBP 2 was suppressed by about 40%, fibulin-5 being colocalized with oxytalan fibers. These results suggest that LTBP-2, in response to tension stress, may negatively control the function of fibulin-5, thereby modulating the mechanism of oxytalan fiber coalescence. PMID- 22827403 TI - Association of serum amyloid A with subclinical atherosclerosis in women with gestational diabetes. AB - The aim of our study was to evaluate serum amyloid A (SAA), an acute phase reactant, and carotid intima-media thickness (CIMT) as a valid predictor of atherosclerosis in women with gestational diabetes mellitus (GDM). Serum samples from 39 pregnant women with GDM and 25 healthy pregnant women were collected for the analysis of SAA. CIMT was measured in both groups to evaluate future atherosclerotic heart disease risk. The SAA level was measured with ELISA. The mean arterial blood pressure (MABP), CIMT and SAA levels were significantly higher in women with GDM compared with healthy pregnant controls (p = 0.033, p = 0.001 and p = 0.004, respectively). There were significant correlations between SAA and age, BMI, MABP, 50-g oral glucose tolerance test (OGTT), and A1c (p = 0.048, p = 0.037, p = 0.035, p = 0.042 and p = 0.048, respectively) and between CIMT and BMI, MABP, and 50-g OGTT, (p = 0.001, p = 0.004 and p < 0.001, respectively) in correlation analysis. Furthermore, there was a correlation between SAA and CIMT (p = 0.048). Increased SAA and CIMT values in GDM compared with healthy controls might indicate an increased risk of subclinical atherosclerosis and future atherosclerotic heart disease and the importance of inflammation in this process. These changes were associated with obesity, hypertension and glucose intolerance-related factors (BMI, MABP, and 50-g OGTT), which may be relevant to GDM pathophysiology. PMID- 22827405 TI - Gonadal function in male patients with ankylosing spondylitis. AB - OBJECTIVE: To assess reproductive function in male ankylosing spondylitis (AS) patients in comparison to healthy controls. METHODS: Twenty AS patients were compared to 24 healthy male subjects with regard to demographic data, urological examination, testicular ultrasound (US), semen analysis, anti-sperm antibodies, and hormone profile. Exclusion criteria were present use of sulfasalazine or methotrexate, and ever use of biological/cytotoxic agents. Disease activity of AS was evaluated by clinical and laboratory assessments. RESULTS: Demographic data were similar in AS and controls (p = 0.175). Varicocele was found significantly more frequently in AS patients than in controls (40% vs. 8%, p = 0.027). Semen analysis revealed no significant differences in sperm quality between AS patients and controls (p > 0.05). By contrast, the median of normal sperm forms was significantly lower in AS patients with vs. those without varicocele [13.5 (range 2-27) vs. 22 (range 10-32.5)%, p = 0.049] whereas no difference in sperm morphology was observed comparing AS patients and controls without varicocele (p = 0.670). Comparison of AS patients with and without varicocele showed that anti sperm antibodies, hormones, inflammatory markers, and disease activity scores did not contribute to the impaired sperm morphology observed in AS patients with varicocele. CONCLUSIONS: An increased frequency of varicocele was found in AS patients associated with sperm abnormalities but independent of therapy, anti sperm antibodies, hormonal alterations, or disease parameters. Investigation for varicocele should be routine in AS patients with fertility problems. PMID- 22827406 TI - Reflections-On leaving the JNE editorship. PMID- 22827407 TI - Podcast and unfolding case study to promote active learning. PMID- 22827408 TI - Pedometer-determined physical activity and body composition in Chinese working adults. AB - PURPOSE: Overweight and obesity are prevalent public health problems in many developed and developing regions. Despite extensive documentation on the health benefits of physical activities, little is known about the level of physical activity in the Hong Kong Chinese population. Working adults, in particular, deserve primary attention because they account for the largest proportion of Hong Kong society. The purposes of this study were to investigate pedometer-determined physical activity and examine the associations between physical activity and body composition variables among Chinese working adults in Hong Kong. DESIGN: This study adopted a descriptive cross-sectional design. METHODS: A quota sample of 913 working adults from nine major occupational categories was recruited. Demographic characteristics and body composition parameters (weight, height, and waist and hip circumferences) were assessed. Body mass index and waist-to-hip ratio were then calculated. Physical activity was measured in terms of daily walking steps using a pedometer over 1 week. Participants were then categorized as "inactive,""somewhat active," or "regularly active." Descriptive and inferential statistics (analysis of variance, t test, and chi(2) test) were used appropriately. FINDINGS: Of the 913 participants, 893 returned complete step count records. The completion rate was 97.8%. Participants on average walked 8,661 steps per day, suggesting a "somewhat active" populace. Significant differences were found between the group "regularly active" and "inactive" in most of the body composition parameters. However, a significant weak correlation was found between physical activity and body mass index (r= 0.12, p= .001). Such findings deserve further investigation. CONCLUSIONS: The Chinese working adults in Hong Kong were found to be somewhat active in physical activity. CLINICAL RELEVANCE: Findings pose implications for healthcare professionals who are responsible for health promotion in the Asian community setting. Leisure-type physical activity, such as walking, can be incorporated into daily routines. PMID- 22827409 TI - Influence of hyperbaric oxygen therapy on peri-implant bone healing in rats with alloxan-induced diabetes. AB - AIM: The influence of hyperbaric oxygen therapy (HBOT) on peri-implant bone healing in rats with alloxan-induced type-1 diabetes was studied. MATERIALS AND METHODS: Forty-eight male rats were randomly divided into six groups: (1) healthy rats (HR) that received no HBOT; (2) HR that underwent 10 sessions of HBOT before implant installation; (3) HR that underwent 10 sessions of HBOT after implant installation; (4) rats with induced diabetes (DR) without HBOT; (5) DR that underwent 10 sessions of HBOT before implant installation; (6) DR that underwent 10 sessions of HBOT after implant installation. A screw-shaped titanium implant was inserted into the femur. The animals were killed 28 days after implantation. The percentage of bone-to-implant contact (BIC) within the implant threads was evaluated. RESULTS: Lower BIC was observed in DR (35.35 +/- 18.04) compared with the HR (69.07 +/- 09.01) (p = 0.001). However, with HBOT, either before or after implantation, BIC was increased in DR. HBOT before implantation was p = 0.03; HBOT after implantation was p = 0.08. This increase reversed the negative effect of diabetes; therefore, the differences between DR and HR were not significant with HBOT (p >= 0.21). CONCLUSION: HBOT, either before or after implantation, increased the BIC in DR to the level of HR. PMID- 22827411 TI - The Diagnosis of Intraocular Inflammation and Cytomegalovirus Retinitis in HIV Infected Patients by Laser Flare Photometry Laser Flare Photometry in HIV Infected Patients. AB - PURPOSE: To assess the sensitivity and specificity of the Kowa Laser Flare Photometer in screening for intraocular inflammation and cytomegalovirus retinitis in HIV-infected patients. PATIENTS AND METHODS: Using the Kowa Flare Cell 1000, 142 HIV-infected patients were evaluated for aqueous flare. RESULTS: Patients with posterior segment disease had higher flare values (p<0.0001). A specificity of 93% and a sensitivity of 75% was found (cutoff value of 8 photon counts/msec). For a cutoff value of 5 photon counts/msec a specificity of 59% and a sensitivity of 91% was found. Patients with cytomegalovirus retinitis had higher flare values (p<0.0001). A specificity of 86% and a sensitivity of 75% was found for the cutoff value of 8 photon counts/msec and respectively of 53% and 91% for a cutoff value of 5 photon counts/msec. Assuming a 30% prevalence of cytomegalovirus retinitis in the HIV-infected population, positive predictive values of 70% (cutoff value of 8 photon counts/msec) and 45% (cutoff value of 5 photon counts/msec) were estimated. CONCLUSIONS: The clinical use of laser flare photometry may assist in the diagnosis of intraocular inflammation in HIV infected patients. The authors recommend screening of HIV-infected patients by laser flare photometry, and, if high flare values are detected, they recommend that such patients have a full eye examination and be considered at risk of having more extensive disease. This technique does not replace a full ophthalmological examination if there are predisposing visual complaints. PMID- 22827410 TI - Identification of oxidized amino acid residues in the vicinity of the Mn(4)CaO(5) cluster of Photosystem II: implications for the identification of oxygen channels within the Photosystem. AB - As a light-driven water-plastoquinone oxidoreductase, Photosystem II produces molecular oxygen as an enzymatic product. Additionally, under a variety of stress conditions, reactive oxygen species are produced at or near the active site for oxygen evolution. In this study, Fourier-transform ion cyclotron resonance mass spectrometry was used to identify oxidized amino acid residues located in several core Photosystem II proteins (D1, D2, CP43, and CP47) isolated from spinach Photosystem II membranes. While the majority of these oxidized residues (81%) are located on the oxygenated solvent-exposed surface of the complex, several residues on the CP43 protein ((354)E, (355)T, (356)M, and (357)R) which are in close proximity (<15 A) to the Mn(4)CaO(5) active site are also modified. These residues appear to be associated with putative oxygen/reactive oxygen species exit channel(s) in the photosystem. These results are discussed within the context of a number of computational studies which have identified putative oxygen channels within the photosystem. PMID- 22827412 TI - Antineutrophil cytoplasmic antibodies in chronic idiopathic intraocular inflammatory disease. AB - Antineutrophil cytoplasmic antibodies (ANCA) are found in the sera of patients with Wegener's granulomatosis and other systemic necrotising vasculitides. Antibody levels correlate closely with disease activity so that follow-up of ANCA titres might be helpful in guiding therapy. The authors assessed in a cohort of patients with chronic ocular inflammatory disease ANCA titres prospectively over a two-year period, by an indirect immunofluorescent technique. They found that sera from 10/64 patients (15.6%) stained positive for c-ANCA antibodies, and none stained for p-ANCA. Six c-ANCA positive patients had one or more clinical relapses (range one to three) during this study period. Each relapse correlated with a rise in ANCA titre. The remaining four patients who were found to have persistently low titres of c-ANCA had no clinical relapses. The authors conclude that although c-ANCA is only present in a small proportion of patients with idiopathic chronic intraocular inflammatory disease, the ANCA titre may be used to monitor disease activity in this group of patients. Further study to assess the potential of c-ANCA titres in predicting disease relapse is indicated, which in the future may minimise the side effects of currently used immunosuppressive therapies. PMID- 22827413 TI - Calprotectin is raised in endogenous posterior uveitis. AB - Calprotectin, the L1 leucocyte protein, is found in large quantities in the cytosol of granulocytes and monocytes. Plasma calprotectin levels are increased in infections, malignant tumours, vascular insults and various other pathogenic conditions. The authors have investigated plasma calprotectin and ANCA levels in 27 patients with endogenous posterior uveitis (EPU) and six healthy volunteers. Compared to the control values, the mean levels of plasma calprotectin were raised in patients with active uveitis (p<0.005 (ANOVA)). Raised serum ANCA titres, which are also associated with neutrophil activation, were also detected in some patients with EPU but the level of ANCA did not correlate with that of calprotectin. The authors suggest that measurement of plasma calprotectin may be a sensitive indicator of disease activity in patients with endogenous posterior uveitis. PMID- 22827414 TI - Analysis of herpes virus group (DNA) from cerebrospinal fluid in vogt-koyanagi harada disease. AB - In order to detect herpes virus group DNA including that of the Epstein-Barr virus (EBV) in patients with Vogt-Koyanagi-Harada disease (VKH), the authors employed the polymerase chain reaction (PCR) procedure using DNA from cerebrospinal fluid (CSF) obtained from patients with VKH. Method. Seven CSF samples were obtained from six definite, active VKH cases and DNA was isolated. DNA fragments containing parts of herpes simplex virus (HSV), herpes zoster virus (VZV), cytomegalo virus (CMV), EBV and human herpes virus type 6 (HHV-6) sequences were amplified by PCR. Results. No DNA fragment corresponding to the DNA sequence of the herpes virus group was detected. Conclusion. Our results suggest that the herpes virus group does not have a close association with the cause of VKH. PMID- 22827415 TI - Usage of TCR Vgamma2(+) T Lymphocytes in Experimental Autoimmune Uveoretinitis. AB - Experimental autoimmune uveoretinitis (EAU) is a T cell mediated autoimmune disease that serves as a model of human intraocular inflammatory disease (uveitis). It is initiated in susceptible animals by immunization with retinal antigens, such as interphotoreceptor retinoid binding protein (IRBP) and S Antigen (SAg) or by adoptive transfer of ocular Ag-specific uveitogenic T cells. Previous studies of T cell receptor (TCR) usage by uveitogenic T cells have implicated Vbeta8(+) -expressing T cells in the pathogenesis of EAU. Here, the authors have analyzed the TCR Vgamma repertoire in the retinas of Lewis rats with and without EAU as well as the repertoire of several SAg- or IRBP-specific T cell lines. They detected Vgamma2 transcripts in all four pathogenic lines and in the retinas of Lewis rats with EAU but not in the two non-pathogenic lines nor in the retinas of naive rats. Vgamma7 transcripts were detected in RNAs obtained from the retina, regardless of whether the rat had EAU or not. However, the authors could not detect Vgamma4, Vgamma5 or Vgamma6 TCR transcripts in any of the samples analyzed. Taken together, their data suggests a correlation between recruitment of Vgamma2(+) T cells and EAU pathogenesis. PMID- 22827416 TI - Treatment of CMV retinopathy in patients with AIDS. AB - Cytomegalovirus (CMV) retinitis, the most common intraocular infection in patients with AIDS, appears to be increasing in frequency as these patients live longer. Untreated, CMV retinitis progresses throughout the entire retina resulting in blindness. Ganciclovir and foscarnet, as intravenous formulations, are the only two drugs currently approved by the FDA for the treatment of CMV retinitis. In the Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial (FGCRT), both drugs were shown to be equally effective in controlling the retinitis. As these drugs have different toxic profiles, and different infusion times, the choice of initial therapy will depend on coexisting medical factors, concurrent medications and patient's lifestyle. Additionally, the FGCRT showed that ganciclovir was associated with a 50% greater mortality rate than with foscarnet. More recently, oral ganciclovir was recently approved for maintenance therapy. Local therapy for CMV retinitis has been used as intravitreal injections of either ganciclovir or foscarnet, or investigationally as a sustained release implant of ganciclovir. While it has been shown that local therapy is effective in controlling the retinitis, the contralateral eye and extraocular sites remain unprotected from CMV disease, which invariably is a systemic disease. Finally, clinical trials are underway to determine the effectiveness and toxicities of cidofovir, a nucleotide analogue (given intravenously or intravitreally) and a neutralizing monoclonal anti-CMV antibody used as adjunctive therapy to prolong the time to relapse. PMID- 22827417 TI - Phlyctenular keratoconjunctivitis a potentially blinding disorder. AB - Phlyctenular keratoconjunctivitis, a delayed hypersensitivity reaction to foreign proteins (i.e., bacterial products), occurs more often in children and young adults sensitized to Staphylococcus aureus inhabiting the lid margins. Clinical manifestations occur on the conjunctiva and/or the cornea. Management strategies used to treat a 14-year-old girl with a long history of keratoconjunctivitis with severe corneal involvement and secondary lacrimal gland enlargement included a complete ocular examination, blood workups, cultures, vigorous lid hygiene, topical antibiotics and steroids, and systemic doxycycline. Phlyctenular keratoconjunctivitis was diagnosed, and Streptoccocus viridans was found colonizing the lid margins and fornices. Subsequent treatment quieted the active inflammation and the secondary lacrimal gland enlargement. However, the residual corneal scarring permanently compromised visual acuity. This patient demonstrates the potentially blinding consequences of untreated phlyctenular keratoconjunctivitis. Moreover, Streptoccocus viridans is not frequently associated with this disorder. To our knowledge hypertrophy of the lacrimal gland, as a secondary complication of this disorder, has not been reported previously. PMID- 22827418 TI - Limitations of SCID-Hu mouse model for antiretinal autoantibody responses. AB - The transfer of human peripheral blood mononuclear cells (PBMC) to mice with severe combined immune deficiency (SCID) allows the investigation of immune function. The authors investigated the potential of SCID mice to produce anti retinal antibodies from PBMC derived from retinal vasculitis patients, and in vivo primed with retinal antigen on days 2 and 22 following transfer. Using Western blotting they could not detect any anti-retinal humoral response in sera from reconstituted animals. Human CD(4)(+) or CD8(+) T cells in spleen or lymph nodes from reconstituted animals were not detected by histological examination. Similarly, no ocular pathology was apparent. The possible mechanisms involved in the lack of an anti-retinal specific antibody response in reconstituted SCID mice are discussed. PMID- 22827419 TI - American Uveitis Society Meeting October 30, 1995 Marriott Marquis Hotel, Atlanta, GA, USA. AB - 1 Retinal vascular occlusion and scleroderma. Tessler H, Flores-Guevara J, Goldstein D, Chicago, IL, USA. 2 MHC Class II antigen expression in ciliary body in spontaneous and experimental uveitis. Kalsow C, Zhavoronkova M, Dwyer A, Rochester, NY & Scottsville, NY, USA. 3 IL-10 in the vitreous of patients with intraocular lymphoma. Whitcup S, Solomon D, Nussenblatt R, Chan C-C, Bethesda, MD, USA 4 Iris juvenile xanthogranuloma studied by immunohistochemistry. Shields J, Shields C, Eagle R, DePotter P, Collins M, Philadelphia, PA, USA. 5 Outcomes analysis in with JRA-associated uveitis. Dana M-R, Merayo-Lloves J, Foster C, Boston MA, USA. 6 Persistent glaucoma secondary to periocular steroids. Akduman L, Conway M, Burchfield J, Kolker A, Black D, DelPriore L, Kaplan H, St. Louis, MO, USA 7 The use of itraconazole in ocular histoplasmosis Callanan D, Fish G, Dallas, TX, USA 8 Succesful treatment of macular hole secondary to sympathetic ophthalmia. Cano J, Diaz M, Navea A, Ruiz C, Castilla M. Barcelona, Spain. 9 HLA-DR2+ intermediate uveitis. Pulido J, Tang W, Han D, Mieler W. Milwaukee, WI, USA. 10 Vein occlusion in AIDS misdiagnosed as CMV retinitis. Park K, Marx J, Rao N. Los Angeles, CA, USA. 11 HIV-associated foveal hemorrhage. Crews K, Zimmerman P, Lohner S. Salt Lake City, UT, USA. 12 Cytomegalovirus papillitis in patients with AIDS. Patel S, Rutzen A, Marx J, Thach A, Chong L, Rao N, Los Angeles, CA, USA. 13 Recurrence rate of CMV retinitis following the ganciclovir implant and pars plans vitrectomy and silicone oil. Marx J, Thach A, Rao N, Chong L. Los Angeles, CA, USA. PMID- 22827420 TI - Minutes of the International Council Meeting of the International Ocular Inflammation Society (IOIS). PMID- 22827421 TI - The AJRH: 20 years on. PMID- 22827422 TI - The 2012 National Strategic Framework for Rural Health: part of the solution? PMID- 22827423 TI - Making a difference: an appreciation of the career of Professor John Humphreys. PMID- 22827424 TI - Experience of overseas-trained health professionals in rural and remote areas of destination countries: a literature review. AB - This study aimed to review and synthesise existing literature that investigated the experience of overseas-trained health professionals (OTHPs) in rural and remote areas of destination countries. A systematic literature review was conducted using electronic databases and manual search of studies published from January 2004 to February 2011. Data were analysed from the final 17 original report articles that met the inclusion criteria. The reviewed research studies were conducted in Australia, Canada, New Zealand, the UK and the USA. Overseas trained medical practitioners were the most frequently researched (n = 14); two studies involved nurses and one study included several health professionals. Three main themes emerged from the review and these were: (i) expectations; (ii) cultural diversity; and (iii) orientation and integration to rural and remote health work environment. The OTHPs were expected to possess the appropriate professional and cultural skills while they themselves expected recognition of their previous experiences and adequate organisational orientation and support. A welcoming and accepting community coupled with a relaxed rural lifestyle and the joy of continued patient care resulted in successful integration and contributed to increased staff retention rates. Recognition of expectations and cultural diversity by all parties and comprehensive orientation with sufficient organisational support are important elements in the integration of OTHPs and subsequent delivery of quality health care to people living in rural and remote areas. PMID- 22827425 TI - Theory in rural health. AB - OBJECTIVE: This paper offers theories to explain persistent rural health challenges and describes their application to rural health and research. METHODS: Review of theories from several disciplines. FINDINGS: Key issues in rural health are poorer health status and access to health care, staff shortages, relationship based health provision and the role of health services in community sustainability. These could be fruitfully addressed by applying theory and findings around social determinants of health, economic sociology, the role of culture and capitals approaches to measuring assets. In particular, the concept of rural health might be a barrier to progressing knowledge; and relational approaches, common in geography, offer a more useful conceptual framework for studying health and place. CONCLUSIONS: To move beyond its current stage, rural health needs to look to other disciplines' theories and ideas; particularly, it needs a more contemporary understanding of what place means so that health status and service provision can be improved by more thoughtful research. PMID- 22827426 TI - 'We don't have anyone with dementia here': a case for better intersectoral collaboration for remote Indigenous clients with dementia. AB - OBJECTIVE: This paper reports on findings related to intersectoral collaboration stemming from an evaluation of a dementia awareness resource for use in remote Aboriginal communities*. The resource includes a DVD in English and three (3) Aboriginal languages of the Northern Territory. DESIGN: A qualitative evaluation was conducted in four Northern Territory Aboriginal communities/organisations where the resource had been implemented by external dementia educators. The method included five focus groups with Indigenous aged care workers, community members and aged care service users (n = 26), individual interviews with health care professionals and service coordinators (n = 5), and observation. Data were analysed thematically. RESULTS: Specific findings relating to intersectoral collaboration as a key enabling factor of effective dementia awareness and care are discussed in this paper. In addition to context variables such as understaffing and under-resourcing, there might be a lack of knowledge or interest on the part of some health practitioners concerning clients with dementia within remote communities. CONCLUSION: Dementia awareness in remote communities needs to be tackled from a 'whole system' perspective and not be the exclusive domain of the aged care services. Strategies that increase the critical mass of informed caregivers as well as health professionals will contribute to better services. PMID- 22827427 TI - Electronic records suggest suboptimal management of chronic kidney disease in general practice. AB - OBJECTIVE: To examine electronic records of GP management of chronic kidney disease. DESIGN: Cross-sectional study. SETTING: Thirteen general practices. PARTICIPANTS: Fifteen thousand four hundred and fiftteen active patients aged 50 years and over. MAIN OUTCOME MEASURE: Recorded estimated glomerular filtration rate (eGFR) and diabetes, and rate of prescribing of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARBs). RESULTS: Six thousand and fifty-nine (39%) patients had hypertension and 1859 (12%), diabetes. Two thousand six hundred and eighty-nine (17%) patients were recorded with eGFR < 60 mL min(-1) (1.73 m(2) )(-1) , while 3344 (22%) did not have an eGFR result recorded. Hypertension, diabetes and eGFR <60 mL min(-1) (1.73 m(2) )(-1 ) were shown to be significantly related to prescribing of ACE/ARBs; however, 31% of known diabetics and 23% of diabetics with an eGFR < 60 mL min(-1) (1.73 m(2) )(-1 ) are not recorded as receiving ACE or ARB therapy. Forty-two per cent of patients with eGFR < 60 mL min(-1) (1.73 m(2) )(-1) , are also not recorded as receiving ACE or ARB therapy. There was a 23% variation in the rates of prescribing of ACE/ARBs by practice for patients with diabetes and eGFR < 60 mL min(-1) (1.73 m(2) )(-1) . CONCLUSION: The overall recording of eGFR and the recorded prescribing of ACE or ARB therapy in known diabetics and patients with eGFR < 60 mL min(-1) (1.73 m(2) )(-1) appear suboptimal. Also, the variations in prescribing between practices require further investigation. PMID- 22827428 TI - How prepared are rural and remote health care practitioners to provide evidence based management for people with chronic lung disease? AB - OBJECTIVE: To investigate the existing experience, training, confidence and knowledge of rural/remote health care practitioners in providing management for people with chronic obstructive pulmonary disease (COPD). DESIGN: Descriptive cross-sectional, observational survey design using a written anonymous questionnaire. This study formed part of a larger project evaluating the impact of breathe easy walk easy (BEWE), an interactive education and training program for rural and remote health care practitioners. SETTING: Rural (n = 1, New South Wales) and remote (n = 1, Northern Territory) Australian health care services. PARTICIPANTS: Health care practitioners who registered to attend the BEWE training program (n = 31). MAIN OUTCOME MEASURES: Participant attitudes, objective knowledge and self-rated experience, training and confidence related to providing components of management for people with COPD. RESULTS: Participants were from a variety of professional backgrounds (medical, nursing, allied health) but were predominantly nurses (n = 13) or physiotherapists (n = 9). Most participants reported that they had minimal or no experience or training in providing components of management for people with COPD. Confidence was also commonly rated by participants as low. Mean knowledge score (number of correct answers out of 19) was 8.5 (SD = 4.5). Questions relating to disease pathophysiology and diagnosis had higher correct response rates than those relating more specifically to pulmonary rehabilitation. CONCLUSION: The results of this study indicate that some rural and remote health care practitioners have low levels of experience, knowledge and confidence related to providing components of management for people with COPD and that education and training with an emphasis on pulmonary rehabilitation would be beneficial. PMID- 22827429 TI - Food for thought: enabling and constraining factors for effective rural eating disorder service delivery. AB - OBJECTIVE: This study examined the effectiveness of an assessment and referral model of eating disorder service delivery in the Northern Rivers of New South Wales and its potential as a model for rural service delivery. DESIGN: A qualitative evaluative research design used brief and extended semistructured interviews with clients, and surveys and semistructured extended interviews with service providers who either referred clients to the service or to whom clients were referred. SETTING: A sole practitioner service based in a small non government women's health service in rural New South Wales. PARTICIPANTS: Clients of the service, all but one of whom was woman; service providers including general practitioners, private practice psychologists and social workers, dietitians, mental health service workers. MAJOR OUTCOME MEASURES: Participant identified enabling and constraining factors which contributed to the effectiveness of the service model. RESULTS: Whilst all service providers and most clients found the assessment process to be beneficial, they identified a number of constraining factors in the referral part of the service which undermined the effectiveness of the model of service delivery, especially for those with more complex or severe presentations. CONCLUSIONS: For a rural ED service to be effective, a number of enabling factors must be present including the capacity to provide: treatment services as well as assessment; a multidisciplinary team approach to assessment and treatment; and expert consultation and training to generalist practitioners, counsellors, hospital wards and other service providers. PMID- 22827430 TI - Helping and hindering: perceptions of enablers and barriers to collaboration within a rural South Australian mental health network. AB - OBJECTIVE: To evaluate clinicians' perceptions of what helps and hinders the delivery of mental health care across a service network in a rural setting. DESIGN: Qualitative, semistructured interviews were conducted with 10 individuals who work in one rural mental health care service network. SETTING: A regional centre in rural South Australia involving representatives of the mental health team, general practice, hospital, community health and nongovernment organisations. RESULTS: Clinicians' perceptions of barriers and enablers to working within their mental health care network were explored. Participants showed a strong shared commitment to effective mental health care delivery and a good understanding of the services that each offers. Interview data suggested that working relationships between local services could be perceived as stronger when a personal or historical element is recognisable. Similarly, the notion of familiarity and community involvement were perceived as facilitators in this network. A perceived barrier for participants was the failure to attract staff with mental health experience, leading to dependence upon the dedication and commitment of existing service providers. CONCLUSIONS: Collaboration is especially necessary in rural areas, where access to health care services is known to be difficult. The informality of relationships between service providers was shown to be the main facilitator in the network. This is both a strength as it promotes the communication between services and service providers that is essential for successful collaboration, yet is also a threat to the sustainability of the network based on the difficulties of staff recruitment and retention to rural settings. PMID- 22827431 TI - Prevalence of hypertension and pre-hypertension in rural women: a report from the villages of West Bengal, a state in the eastern part of India. AB - OBJECTIVE: To find out the prevalence of hypertension, pre-hypertension and tachycardia among the women in rural areas of West Bengal, identify co-factors associated with the prevalence and contribute to the body of evidence for future health programs to identify at-risk groups. DESIGN: A population-based cross sectional study was conducted. SETTING: The study was conducted in remote villages. PARTICIPANTS: 1186 women participants, aged 18 years or more were included. MAIN OUTCOME MEASURES: They were interviewed using standard structured questionnaire. Blood pressure and tachycardia was monitored using digital sphygmomanometer. For each participant, we made two blood pressure measurements with an interval of 48 hours. Data was analysed statistically using SPSS software. RESULTS: Overall prevalence of hypertension in the study subjects was 24.7% and that of pre-hypertension and tachycardia was 40.8% and 6.4%, respectively. Both hypertension and pre-hypertension were seen to increase with age. Other identified significant factors were use of biomass fuel for cooking, absence of separate kitchen, higher body mass index (BMI), education and average family income. CONCLUSION: This study suggests quite high prevalence of hypertension as well as pre-hypertension among the women of rural areas. The findings are significant from the women health perspectives. Early detection of pre-hypertensive and hypertensive subjects will help to formulate intervention strategies to allay the spread of cardiovascular diseases. PMID- 22827432 TI - The readability of patient handouts from an inner regional hospital emergency department. PMID- 22827433 TI - Measuring what matters in delivering services to remote-dwelling Indigenous mothers and infants in the Northern Territory, Australia. AB - PROBLEM: In the Northern Territory, 64% of Indigenous births are to remote dwelling mothers. Delivering high-quality health care in remote areas is challenging, but service improvements, informed by participative action research, are under way. Evaluation of these initiatives requires appropriate indicators. Few of the many existing maternal and infant health indicators are specifically framed for the remote context or exemplify an Indigenous consumer perspective. We aimed to identify an indicator framework with appropriate indicators to demonstrate improvements in health outcomes, determinants of health and health system performance for remote-dwelling mothers and infants from pregnancy to first birthday. DESIGN: We reviewed existing indicators; invited input from experts; investigated existing administrative data collections and examined findings from a record audit, ethnographic work and the evaluation of the Darwin Midwifery Group Practice. SETTING: Northern Territory. PROCESS: About 660 potentially relevant indicators were identified. We adapted the Aboriginal and Torres Strait Islander Health Performance Framework and populated the resulting framework with chosen indicators. We chose the indicators best able to monitor the impact of changes to remote service delivery by eliminating duplicated or irrelevant indicators using expert opinion, triangulating data and identifying key issues for remote maternal and infant health service improvements. LESSONS LEARNT: We propose 31 indicators to monitor service delivery to remote-dwelling Indigenous mothers and infants. Our inclusive indicator framework covers the period from pregnancy to the first year of life and includes existing indicators, but also introduces novel ones. We also attempt to highlight an Indigenous consumer. PMID- 22827434 TI - Equal health is 20 steps away. PMID- 22827435 TI - One month is sufficient for urinary iodine to return to its baseline value after the use of water-soluble iodinated contrast agents in post-thyroidectomy patients requiring radioiodine therapy. AB - BACKGROUND: There is a concern regarding the use of iodinated contrast agents (ICA) for chest and neck computed tomography (CT) to localize metastatases in patients with differentiated thyroid cancer (DTC). This is because the iodine in ICA can compete with (131)I and interfere with subsequent whole scans or radioactive iodine treatment. The required period for patients to eliminate the excess iodine is not clear. Therefore, knowing the period for iodine levels to return to baseline after the injection of ICA would permit a more reliable indication of CT for DTC patients. The most widely used marker to assess the plasmatic iodine pool is the urinary iodine (UI) concentration, which can be collected over a period of 24 hours (24U) or as a single-spot urinary sample (sU). As 24U collections are more difficult to perform, sU samples are preferable. It has not been established, however, if the measurement of iodine in sU is accurate for situations of excess iodine. METHODS: We evaluated 25 patients with DTC who received ICA to perform chest or neck CT. They collected 24U and sU urinary samples before the CT scan and 1 week and 1, 2, and 3 months after the test. UI was quantified by a semiautomated colorimetric method. RESULTS: Baseline median UI levels were 21.8 MUg/dL for 24U and 26 MUg/dL for sU. One week after ICA, UI median levels were very high for all patients, 800 MUg/dL. One month after ICA, however, UI median levels returned to baseline in all patients, 19.0 MUg/dL for 24U and 20 MUg/dL for sU. Although the values of median UI obtained from sU and 24U samples were signicantly different, we observed a significant correlation between samples collected in 24U and sU in all evaluated periods. CONCLUSION: One month is required for UI to return to its baseline value after the use of ICA and for patients (after total thyroidectomy and radioiodine therapy) to eliminate the excess of iodine. In addition, sU samples, although not statistically similar to 24U values, can be used as a good marker to evaluate patients suspected of contamination with iodine. PMID- 22827436 TI - In vitro regulatory effect of epididymal serpin CRES on protease activity of proprotein convertase PC4/PCSK4. AB - PC4 or PCSK4 belongs to the 9-member superfamily of mammalian subtilases collectively called Proprotein Convertases or Proprotein Convertase Subtilisin/Kexins that convert inactive precursor proteins into their active mature forms by endoproteolytic cleavage. PC4-activity plays a crucial role in mammalian fertilization via activation of sperm surface proteins. PC4 knockout mice exhibit severely impaired male fertility due to premature sperm acrosome reaction. Regulation of sperm-PC4 activity during its storage and transport through epididymis is an important determinant for ultimate egg-binding and fertilizing capacities of sperms. Herein we show that epididymal serpin CRES (cystatin related epididymal spermatogenic) recombinant protein inhibits PC4 activity in vitro in a differential manner when measured against the fluorogenic substrate Boc- RVRR-MCA depending on its oligomeric state. Thus while CRES-dimer exhibits K(i) ~8 MUM, the corresponding monomer showed K(i) > 100 MUM. Both forms also blocked PC4-mediated processing of human proIGF-2 in human placenta tropoblast cell line with dimer being more efficient. Using specific inhibitors and substrates, we also demonstrated the presence of PC4-like activity and CRES protein in varying levels in the fluids of various epididymal compartments. Our observations suggest a potential function of CRES as a regulator of PC4 in sperm egg interaction and fertilization. PMID- 22827437 TI - The PP2A-Abeta gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRalpha/beta. AB - Protein phosphatase-2A (PP-2A) is a major serine/threonine phosphatase abundantly expressed in eukaryotes. PP-2A is a heterotrimer that contains a 65 kD scaffold A subunit, a 36 kD catalytic C subunit, and a regulatory B subunit of variable isoforms ranging from 54-130 kDs. The scaffold subunits, PP2A-Aalpha/beta, act as platforms for both the C and B subunits to bind, and thus are key structural components for PP-2A activity. Mutations in both genes encoding PP2A-Aalpha and PP2A-Abeta lead to carcinogenesis and likely other human diseases. Our previous work showed that the gene coding for PP2A-Aalpha is positively regulated by multiple transcription factors including Ets-1, CREB, and AP-2alpha but negatively regulated by SP-1/SP-3. In the present study, we have functionally dissected the promoter of the mouse PP2A-Abeta gene. Our results demonstrate that three major cis-elements, including the binding sites for Ets-1, SP1/SP3, and RXRalpha/beta, are present in the proximal promoter of the mouse PP2A-Abeta gene. Gel mobility shifting assays reveal that Ets-1, SP1/SP3, and RXRalpha/beta all bind to PP2A-Abeta gene promoter. In vitro mutagenesis and reporter gene activity assays demonstrate that while Ets-1 displays negative regulation, SP1/SP3 and RXRalpha/beta positively regulate the promoter of the PP2A-Abeta gene. Co expression of the cDNAs encoding Ets-1, SP1/SP3, or RXRalpha/beta and the luciferase reporter gene driven by PP2A-Abeta promoter further confirm their control over the PP2A-Abeta promoter. Finally, ChIP assays demonstrate that Ets 1, SP1/SP3, and RXRalpha/beta can all bind to the PP2A-Abeta gene promoter. Together, our results reveal that multiple transcription factors regulate the PP2A-Abeta gene. Moreover, our results provide important information explaining why PP2A-Aalpha and PP2A-Abeta display distinct expression levels. PMID- 22827438 TI - The tumor suppressor p53 regulates c-Maf and Prox-1 to control lens differentiation. AB - The tumor suppressor p53 plays a key role in regulating apoptosis and cell cycle progression. In addition, p53 is implicated in control of cell differentiation in muscle, the circulatory system, ocular lens and various carcinoma tissues. However, the mechanisms by which p53 controls cell differentiation are not fully understood. Here we present evidence that p53 directly regulates c-Maf and Prox1, two important transcription factors controlling differentiation in the ocular lens. First, human and murine c-Maf and Prox1 gene promoters contain authentic p53 DNA binding sites. Second, p53 directly binds to the p53 binding sites found in the promoter regions. Third, exogenous p53 induces dose-dependent expression of the luciferase report gene driven by both c-Maf and Prox1 promoters, and p53 binds to both promoters in the ChIP assays. Fourth, in the in vitro differentiation model, knockdown of p53 significantly inhibits lens differentiation which is associated with downregulated expression of c-Maf and Prox1. Finally, in p53 knockout mice, the expression of c-Maf and Prox1 are significantly altered. Together, our results reveal that p53 regulates lens differentiation through modulation of two important transcription factors, c-Maf and Prox1, and through them p53 thus controls expression of various differentiation-related downstream crystallin genes. PMID- 22827440 TI - Securing the demographic and genetic future of tuatara through assisted colonization. AB - Climate change poses a particular threat to species with fragmented distributions and little or no capacity to migrate. Assisted colonization, moving species into regions where they have not previously occurred, aims to establish populations where they are expected to survive as climatic envelopes shift. However, adaptation to the source environment may affect whether species successfully establish in new regions. Assisted colonization has spurred debate among conservation biologists and ecologists over whether the potential benefits to the threatened species outweigh the potential disruption to recipient communities. In our opinion, the debate has been distracted by controversial examples, rather than cases where assisted colonization may be a viable strategy. We present a strategic plan for the assisted migration of tuatara (Sphenodon punctatus), an endemic New Zealand reptile. The plan includes use of extant populations as reference points for comparisons with assisted-colonization populations with respect to demography, phenotypic plasticity, and phenology; optimization of genetic variation; research to fill knowledge gaps; consideration of host and recipient communities; and inclusion of stakeholders in the planning stage. When strategically planned and monitored, assisted colonization could meet conservation and research goals and ultimately result in the establishment of long-term sustainable populations capable of persisting during rapid changes in climate. PMID- 22827439 TI - Photonic gene circuits by optically addressable siRNA-Au nanoantennas. AB - The precise perturbation of gene circuits and the direct observation of signaling pathways in living cells are essential for both fundamental biology and translational medicine. Current optogenetic technology offers a new paradigm of optical control for cells; however, this technology relies on permanent genomic modifications with light-responsive genes, thus limiting dynamic reconfiguration of gene circuits. Here, we report precise control of perturbation and reconfiguration of gene circuits in living cells by optically addressable siRNA Au nanoantennas. The siRNA-Au nanoantennas fulfill dual functions as selectively addressable optical receivers and biomolecular emitters of small interfering RNA (siRNA). Using siRNA-Au nanoantennas as optical inputs to existing circuit connections, photonic gene circuits are constructed in living cells. We show that photonic gene circuits are modular, enabling subcircuits to be combined on demand. Photonic gene circuits open new avenues for engineering functional gene circuits useful for fundamental bioscience, bioengineering, and medical applications. PMID- 22827441 TI - Development of the nervous system in Phoronopsis harmeri (Lophotrochozoa, Phoronida) reveals both deuterostome- and trochozoan-like features. AB - BACKGROUND: Inferences concerning the evolution of invertebrate nervous systems are often hampered by the lack of a solid data base for little known but phylogenetically crucial taxa. In order to contribute to the discussion concerning the ancestral neural pattern of the Lophotrochozoa (a major clade that includes a number of phyla that exhibit a ciliated larva in their life cycle), we investigated neurogenesis in Phoronopsis harmeri, a member of the poorly studied Phoronida, by using antibody staining against serotonin and FMRFamide in combination with confocal microscopy and 3D reconstruction software. RESULTS: The larva of Phoronopsis harmeri exhibits a highly complex nervous system, including an apical organ that consists of four different neural cell types, such as numerous serotonin-like immunoreactive flask-shaped cells. In addition, serotonin and FMRFamide-like immunoreactive bi- or multipolar perikarya that give rise to a tentacular neurite bundle which innervates the postoral ciliated band are found. The preoral ciliated band is innervated by marginal serotonin-like as well as FMRFamide-like immunoreactive neurite bundles. The telotroch is innervated by two neurite bundles. The oral field is the most densely innervated area and contains ventral and ventro-lateral neurite bundles as well as several groups of perikarya. The digestive system is innervated by both serotonin- and FMRFamide like immunoreactive neurites and perikarya. Importantly, older larvae of P. harmeri show a paired ventral neurite bundle with serial commissures and perikarya. CONCLUSIONS: Serotonin-like flask-shaped cells such as the ones described herein for Phoronopsis harmeri are found in the majority of lophotrochozoan larvae and therefore most likely belong to the ground pattern of the last common lophotrochozoan ancestor. The finding of a transitory paired ventral neurite bundle with serially repeated commissures that disappears during metamorphosis suggests that such a structure was part of the "ur-phoronid" nervous system, but was lost in the adult stage, probably due to its acquired sessile benthic lifestyle. PMID- 22827442 TI - Comparison of the class and individual characteristics of Turkish 7.65 mm Browning/.32 Automatic caliber self-loading pistols with consecutive serial numbers. AB - Firearms identification is based on the fundamental principle that it is impossible to manufacture two identical items at the microscopic level. As firearm manufacturing technologies and quality assurance are improving, it is necessary to continually challenge this principle. In this study, two different makes of 7.65 mm Browning/.32 Automatic caliber self-loading pistols of Turkish manufacture were selected and examined. Ten pistols with consecutive serial numbers were examined and each fired 10 times. The fired cartridge cases were recovered for comparison purposes. It was found that for each make of pistol, the individual characteristics within the firing pin impression, ejector, and breech face marks of all 10 pistols were found to be significantly different. PMID- 22827443 TI - Treatment of mild traumatic brain injury with an erythropoietin-mimetic peptide. AB - Mild traumatic brain injury (mTBI) results in an estimated 75-90% of the 1.7 million TBI-related emergency room visits each year. Post-concussion symptoms, which can include impaired memory problems, may persist for prolonged periods of time in a fraction of these cases. The purpose of this study was to determine if an erythropoietin-mimetic peptide, pyroglutamate helix B surface peptide (pHBSP), would improve neurological outcomes following mTBI. Sixty-four rats were randomly assigned to pHBSP or control (inactive peptide) 30 MUg/kg IP every 12 h for 3 days, starting at either 1 hour (early treatment) or 24 h (delayed treatment), after mTBI (cortical impact injury 3 m/sec, 2.5 mm deformation). Treatment with pHBSP resulted in significantly improved performance on the Morris water maze task. Rats that received pHBSP required 22.3+/-1.3 sec to find the platform, compared to 26.3+/-1.3 sec in control rats (p=0.022). The rats that received pHBSP also traveled a significantly shorter distance to get to the platform, 5.0+/-0.3 meters, compared to 6.1+/-0.3 meters in control rats (p=0.019). Motor tasks were only transiently impaired in this mTBI model, and no treatment effect on motor performance was observed with pHBSP. Despite the minimal tissue injury with this mTBI model, there was significant activation of inflammatory cells identified by labeling with CD68, which was reduced in the pHBSP-treated animals. The results suggest that pHBSP may improve cognitive function following mTBI. PMID- 22827444 TI - Multidomain protein solves the folding problem by multifunnel combined landscape: theoretical investigation of a Y-family DNA polymerase. AB - Approximately three-fourths of eukaryotic proteins are composed of multiple independently folded domains. However, much of our understanding is based on single domain proteins or isolated domains whose studies directly lead to well known energy landscape theory in which proteins fold by navigating through a funneled energy landscape toward native structure ensembles. The degrees of freedom for proteins with multiple domains are many orders of magnitude larger than that for single domain proteins. Now, the question arises: How do the multidomain proteins solve the "protein folding problem"? Here, we specifically address this issue by exploring the structure folding relationship of Sulfolobus solfataricus DNA polymerase IV (DPO4), a prototype Y-family DNA polymerase which contains a polymerase core consisting of a palm (P domain), a finger (F domain), and a thumb domain (T domain) in addition to a little finger domain (LF domain). The theoretical results are in good agreement with the experimental data and lead to several theoretical predictions. Finally, we propose that for rapid folding into well-defined conformations which carry out the biological functions, four domain DPO4 employs a divide-and-conquer strategy, that is, combining multiple individual folding funnels into a single funnel (domains fold independently and then coalesce). In this way, the degrees of freedom for multidomain proteins are polynomial rather than exponential, and the conformational search process can be reduced effectively from a large to a smaller time scale. PMID- 22827445 TI - Electrophoretic deposition of the thiophene-based copolymer and its composites with C60. AB - Electrophoretic deposition is a useful and efficient technique to deposit conjugated polymers, if suitable suspension of the target polymer is obtained. Unfortunately, neither general theory nor universal procedure for the preparation of a suspension suitable for electrophoretic deposition has seemed to be established yet. Thus, accumulation of individual knowledge is still important in this area. Here, the preparation of suspensions of a thiophene-based polymer poly(3-octylthiophene-2,5-diyl-co-3-decyloxythiophene-2,5-diyl) (POT-co-DOT) and their application to the electrophoretic deposition have been reported. The suspensions of POT-co-DOT with various good/poor solvents ratios were easily obtained by mixing a toluene solution of the polymer and acetonitrile. The composition of the dispersion medium significantly affects the surface morphology of the film prepared by the electrophoretic deposition in the suspension. Composite films consisting of POT-co-DOT and C(60) have also been successfully prepared by electrophoretic deposition. Because the optical absorption peak at 333 nm in C(60) showed neither significant broadening nor a red shift, C(60) molecules were expected to be well-dispersed in the composite films. A photovoltaic device with a composite film prepared from a POT-co-DOT/C(60) = 2:1 suspension showed 10 times larger short-circuit current density and 5 times larger power conversion efficiency than a device with pure POT-co-DOT, although further work is required to improve the device performance. PMID- 22827446 TI - Population growth rate responses of Ceriodaphnia dubia to ternary mixtures of specific acting chemicals: pharmacological versus ecotoxicological modes of action. AB - When considering joint toxic apical effects at higher levels of biological organization, such as the growth of populations, the so-called pharmacological mode of action that relies on toxicological mechanistic effects on molecular target sites may not be relevant. Such effects on population growth rate will depend on the extent to which juvenile and adult survival rates and production rates (juvenile developmental rates and reproduction) are affected by toxic exposure and also by the sensitivity of population growth rates to life-history changes. In such cases, the ecotoxicological mode of action, defined as the crucial life-history trait processes and/or xenobiotic-life-history trait interactions underlying a toxicological effect on population growth rate, should be considered. Life-table response experiments with the crustacean Ceriodaphnia dubia exposed to single and ternary mixtures of nine compounds were conducted to test the hypothesis that joint effects on population growth rates could be predicted from the mixture constituent ecotoxicological mode of action. Joint effects of mixtures containing pharmacologically dissimilar compounds (cadmium, lambda-cyhalothrin, and chlorpyrifos) that differentially affected life-history traits contributing to population growth rates were accurately predicted by the independent-action concept. Conversely, the concentration-addition concept accurately predicted joint effects of two different mixtures: one containing pharmacologically similar acting pyrethroids that also affected similarly life history traits, the other one that included pharmacologically dissimilar compounds (3,4-dichloroaniline, sodium bromide, and fenoxycarb) acting mainly on reproduction rates. These results indicate that when assessing combined effects on population growth rate responses, selection of mixture toxicity conceptual models based on the ecotoxicological mode of action of mixture constituents provided more accurate predictions than those based on the pharmacological mode of action. PMID- 22827447 TI - US health policy related to hookah tobacco smoking. AB - OBJECTIVES: Although US cigarette smoking is decreasing, hookah tobacco smoking (HTS) is an emerging trend associated with substantial toxicant exposure. We assessed how a representative sample of US tobacco control policies may apply to HTS. METHODS: We examined municipal, county, and state legal texts applying to the 100 largest US cities. We developed a summary policy variable that distinguished among cities on the basis of how current tobacco control policies may apply to HTS and used multinomial logistic regression to determine associations between community-level sociodemographic variables and the policy outcome variable. RESULTS: Although 73 of the 100 largest US cities have laws that disallow cigarette smoking in bars, 69 of these cities have exemptions that allow HTS; 4 of the 69 have passed legislation specifically exempting HTS, and 65 may permit HTS via generic tobacco retail establishment exemptions. Cities in which HTS may be exempted had denser populations than cities without clean air legislation. CONCLUSIONS: Although three fourths of the largest US cities disallow cigarette smoking in bars, nearly 90% of these cities may permit HTS via exemptions. Closing this gap in clean air regulation may significantly reduce exposure to HTS. PMID- 22827448 TI - Ammonium-directed olefinic epoxidation: kinetic and mechanistic insights. AB - The ammonium-directed olefinic epoxidations of a range of differentially N substituted cyclic allylic and homoallylic amines (derived from cyclopentene, cyclohexene, and cycloheptene) have been investigated, and the reaction kinetics have been analyzed. The results of these studies suggest that both the ring size and the identity of the substituents on nitrogen are important in determining both the overall rate and the stereochemical outcome of the epoxidation reaction. In general, secondary amines or tertiary amines with nonsterically demanding substituents on nitrogen are superior to tertiary amines with sterically demanding substituents on nitrogen in their ability to promote the oxidation reaction. Furthermore, in all cases examined, the ability of the (in situ formed) ammonium substituent to direct the stereochemical course of the epoxidation reaction is either comparable or superior to that of the analogous hydroxyl substituent. Much slower rates of ring-opening of the intermediate epoxides are observed in cyclopentene-derived and cycloheptene-derived allylic amines as compared with their cyclohexene-derived allylic and homoallylic amine counterparts, allowing for isolation of these intermediates in both of the former cases. PMID- 22827450 TI - Detergent-free incorporation of a seven-transmembrane receptor protein into nanosized bilayer Lipodisq particles for functional and biophysical studies. AB - SMA-Lipodisq nanoparticles, with one bacteriorhodopsin (bR) per 12 nm particle on average (protein/lipid molar ratio, 1:172), were prepared without the use of detergents. Using pulsed and continuous wave nitroxide spin label electron paramagnetic resonance, the structural and dynamic integrity of bR was retained when compared with data for bR obtained in the native membrane and in detergents and then with crystal data. This indicates the potential of Lipodisq nanoparticles as a useful membrane mimetic. PMID- 22827449 TI - Cardiovascular disease is associated with high-fat-diet-induced liver damage and up-regulation of the hepatic expression of hypoxia-inducible factor 1alpha in a rat model. AB - CVD (cardiovascular disease) is associated with abnormal liver enzymes, and NAFLD (non-alcoholic fatty liver disease) is independently associated with cardiovascular risk. To gain insights into the molecular events underlying the association between liver enzymes and CVD, we developed an HFD (high-fat diet) induced NAFLD in the SHR (spontaneously hypertensive rat) and its control WKY (Wistar-Kyoto) rat strain. We hypothesized that hepatic induction of Hif1a (hypoxia-inducible factor 1alpha) might be the link between CVD and liver injury. Male SHRs (n=13) and WKY rats (n=14) at 16 weeks of age were divided into two experimental groups: standard chow diet and HFD (10 weeks). HFD-fed rats, irrespective of the strain, developed NAFLD; however, only HFD-SHRs had focus of lobular inflammation and high levels of hepatic TNFalpha (tumour necrosis factor alpha). SHRs had significantly higher liver weight and ALT (alanine aminotransferase) levels, irrespective of NAFLD. Liver abundance of Hif1a mRNA and Hif1alpha protein were overexpressed in SHRs (P<0.04) and were significantly correlated with ALT levels (R=0.50, P<0.006). This effect was not reverted by a direct acting splanchnic vasodilator (hydralazine). Angiogenesis may be induced by the HFD, but the disease model showed significantly higher hepatic Vegf (vascular endothelial growth factor) levels (P<0.025) even in absence of dietary insult. Hif1a mRNA overexpression was not observed in other tissues. Liver mRNA of Nr1d1 (nuclear receptor subfamily 1, group D, member 1; P<0.04), Ppara [Ppar (peroxisome-proliferator-activated receptor) alpha; P<0.05], Pparg (Ppargamma; P<0.001) and Sirt1 (Sirtuin 1; P<0.001) were significantly upregulated in SHRs, irrespective of NAFLD. Sirt1 and Hif1a mRNAs were significantly correlated (R=0.71, P<0.00002). In conclusion, CVD is associated with Hif1a-related liver damage, hepatomegaly and reprogramming of liver metabolism, probably to compensate metabolic demands. PMID- 22827451 TI - Association of liver stiffness with hepatic expression of pharmacokinetically important genes in alcoholic liver disease. AB - BACKGROUND: Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease (ALD) is normally owing to hepatic end-stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness (LS) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. METHODS: We quantified mRNA expression levels of various cytochrome P-450 isoenzymes (CYPs) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography (Fibroscan) were obtained. RESULTS: Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4, CYP2E1, and solute carrier organic anion transporter 1B1 (SLCO1B1) were negatively correlated with increasing LS. CYPs and drug transporters tended to be up-regulated in alcoholics without advanced fibrosis (LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD. However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1, SLC22A2, and SLCO1B1 were significantly lower. CONCLUSIONS: In conclusion, CYPs and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy. PMID- 22827452 TI - Inhibitory effect of adenovirus-mediated siRNA-targeting BMPR-IB on UHMWPE induced bone destruction in the murine air pouch model. AB - OBJECTIVE: Adenovirus expressing small interfering RNA (siRNA)-targeting BMPR-IB was locally administered into the air pouch of mice to improve bone resorption induced by ultra-high molecular weight polyethylene (UHMWPE) particles. METHOD: Air pouches were established on the back of BALB/c mice, followed by the surgical introduction of a section of calvaria from a syngeneic mouse donor. The bone implanted pouches were stimulated with the UHMWPE suspension. UHMWPE-containing mice were divided into three study groups to receive injections of adenovirus expressing BMPR-IB siRNA (BMPR-IB group), adenovirus expressing missense siRNA, and virus-free culture medium (control group) into the pouches, respectively. The tissues were harvested at 14 days after the treatment for molecular and histological analyses. RESULTS: Adenovirus-mediated BMPR-IB siRNA treatment significantly improved UHMWPE particle-induced bone resorption, reduced TRAP and RANK gene and protein expression levels, and diminished the number of TRAP positive cells. Furthermore, the BMPR-IB siRNA inhibited osteoclast differentiation by targeting osteoblast for the induction of osteoprotegerin formation and downregulation of receptor for activation of nuclear factor-kappaB ligand production. CONCLUSIONS: This study suggested that loss of bone morphogenetic protein signaling by BMPR-IB siRNA directs osteoblasts to decrease bone destruction in part by downregulating osteoclastogenesis through the receptor for activation of nuclear factor-kappaB ligand-osteoprotegerin pathway. Local administration of adenovirus expressing siRNA-targeting BMPR-IB may be a feasible and effective therapeutic candidate to treat or prevent wear debris associated osteolysis. PMID- 22827453 TI - Integrating an evidence-based intervention into clinical practice: 'transitional relationship model'. AB - The transitional relationship model (TRM) facilitates the discharge process by providing peer support and hospital staff involvement until a therapeutic relationship has been established with a community care provider. A quasi experimental, action-oriented research design was employed in which psychiatric wards at six hospital sites implemented the model in three waves. Helpful strategies were identified by each wave of wards for consideration by subsequent wards. Using an ethnographic approach, qualitative data were examined to uncover experiences and perceptions of TRM implementation and to help identify key issues that were supporting or hampering implementation. Specific strategies that facilitate the implementation of TRM include: (1) the use of educational modules for on-ward hospital staff training and peer training; (2) presence of on-site champions; and (3) supportive documentation systems. Issues identified as barriers to implementation included: (1) feeling drowned, swamped and overwhelmed; (2) death by process; (3) team dynamics; and (4) changes in champions. Staged large-scale implementation of the TRM allowed for iterative improvements to the model leading to positive outcomes. This study highlights the need to address work environment issues, particularly interprofessional teams. PMID- 22827454 TI - Production of staphylococcal enterotoxin R by Staphylococcus aureus strains. AB - Staphylococcal enterotoxin D and R (SED, SER) production was determined in 24 S. aureus strains harboring sed gene. Seven of them were not able to produce SED as evidenced by enzyme-linked immunosorbent assay and Western blotting. Sequencing revealed that all these strains harbor a variant of sed gene. Expression of SER was detectable in 22 out of 24 isolates, with variance in productivity ranging from ~40 to 450 ng/mL. Out of the seven isolates not able to produce SED, three produced high amounts of SER (249-396 ng/mL), two produced less than 200 ng/mL of SER, and two were found to express no detectable amount of SER. Three of those were assigned to spa type t1677 with two being of agr type III and one of agr type I. One strain was t084, agr type II, one t603, agr type II, one 2920, agr type III, one t2920, agr type III, and one t5160, agr type I. Because conventional screening procedures involve only the detection of classical enterotoxins in food, the isolates not able to produce SED presented in this study could pose a threat to human health due to SER production. PMID- 22827455 TI - Controlled assembly and plasmonic properties of asymmetric core-satellite nanoassemblies. AB - The assembly of noble metal nanoparticles offers an appealing means to control and enhance the plasmonic properties of nanostructures. However, making nanoassemblies with easily modifiable gap distances with high efficiency has been challenging. Here, we report a novel strategy to assemble gold nanoparticles (AuNPs) into Janus-type asymmetric core-satellite nanostructures. Markedly different desorption efficiency between large and small AuNPs in ethanol allows us to prepare the asymmetric core-satellite nanoassemblies in a dispersed colloidal state with near 100% purity. The resulting nanoassemblies have well defined structures in which a core AuNP (51 nm) is covered by an average of 13 +/ 3 satellite AuNPs (13 nm) with part of the core surfaces left unoccupied. Strong surface plasmon coupling is observed from these nanoassemblies as a result of the close proximity between the core and the satellites, which appears significantly red-shifted from the surface plasmon resonance frequencies of the constituting nanoparticles. The dependence of the surface plasmon coupling on a gap distance of less than 3 nm is systematically investigated by varying the length of the alkanedithiol linkers. The asymmetric core-satellite nanoassemblies also serve as an excellent surface-enhanced Raman scattering substrate with an enhancement factor of ~10(6). Finally, we demonstrate that the presented assembly method is extendible to the preparation of compositionally heterogeneous core-satellite nanoassemblies. PMID- 22827456 TI - Decreased serum melatonin levels in rats with experimental autoimmune uveitis/pinealitis and in patients with uveitis. AB - The authors measured serum levels of the pineal hormone melatonin to investigate the possibility of pineal dysfunction in both rats with experimental autoimmune uveitis/pinealitis (EAU/EAP) and uveitis patients. The serum melatonin concentrations of EAU/EAP rats were measured by radioimmunoassay over a 24-hour (h) period, and in uveitis patients at night (0200 h). Melatonin concentrations were assayed in six patients with Behcet's disease, four with Vogt-Koyanagi Harada (VKH) disease, three with sarcoidosis, three with Kirisawa-type uveitis, and one with tubulointerstitial nephritis and uveitis syndrome. Nocturnal serum melatonin levels were significantly lower in Lewis rats with EAU/EAP (2200 h: 33.6+/-20.4 pg/ml, 0200 h: 43.2+/-13.9 pg/ml) than in the controls (2200 h: 117.5+/-25.3 pg/ml, 0200 h: 132.4+/-20.2 pg/ml) (p>0.01, at 2200 h and 0200 h). Melatonin levels were significantly lower in VKH disease (20.7+/-10.5 pg/ml) (p>0.01) and Behcet's disease (42.1+/-42.5 pg/ml) (p>0.05) than in the controls (79.4+/-36.7 pg/ml). These results suggest that there is a decrease in pineal gland function due to pinealitis in EAU/EAP rats. The markedly decreased nocturnal serum melatonin levels may also be related to the presence of retinal uveitogenic antigens in uveitis patients. PMID- 22827457 TI - The eyes of transforming growth factor-sZ1 (TGF-sZ1) transgenic mice Morphology and the development of endotoxin-induced uveitis. AB - Transforming growth factor-beta (TGFsZ) is a potent regulator of cellular growth and immune function. The authors studied ocular histology and endotoxin-induced uveitis in a TGF-sZ(1) transgenic (Tg) murine model. TGF-sZ(1) Tg mice were generated by micro injecting a gene constructed by fusing the mouse albumin enhancer/promoter and porcine TGF-sZ(1) cDNA. The eyes of Tg mice from two to 14 weeks of age were studied histologically. Tg mice, two to five weeks of age exhibited mild fragmentation of the lens fibers and retinal edema. No pathology was found from six to ten weeks of age, however, a progressive increased frequency of cataract was observed from 11 to 14 weeks of age. Plasma TGF-sZ(1) levels were much higher in Tg mice than age-matched wild type control littermates (wt). Endotoxin-induced uveitis (EIU) in six-to eight-week-old Tg and wt mice was induced by footpad injection of lipopolysaccharide (LPS). Mice were euthanized 24 hr after LPS injection, the eyes were collected for histology and serum assayed for IL-6 and TGF-sZ(1). There was a decrease in the mean numbers of infiltrating cells in Tg mice compared to wt mice. Serum IL-6 and TGF-sZ(1) were much higher in Tg mice. The authors concluded that expression of the TGF-sZ(1) transgene in the eyes may have effect on lens growth. Overexpression of TGF-sZ(1) results in little or no effect on the development of EIU. PMID- 22827458 TI - Etiology and clinical features of anterior uveitis in southern croatia (dalmatia). AB - Patients with endogenous uveitis represent 6.5+ of patients in University Hospital Split, which serves most of South Croatia. Within a four-year period 208 patients were treated for endogenous uveitis. Results of clinical-laboratory examinations and treatment of 112 subjects suffering from anterior uveitis are presented and compared. Acute anterior uveitis (AAU) was the commonest form of uveal inflammation. It was present in 49+ of all uveitis cases and in 91.1+ of all anterior uveitis cases (AU). 67.6+ of the subjects with AAU had and 32.4+ did not have the HLA B(27) antigen. The inflammatory pattern in B(27)(+) patients was typical of B(27)(+) AAU. Patients with B(27)(+) AAU exhibited the same inflammatory pattern as those with B(7)(+) AAU. B(27)(+) AAU patients had significantly more systemic/rheumatic diseases (p>0.05), while patients with B(27)(-) AAU had significantly more infectious diseases (p>0.05). Forty percent of the patients with chronic anterior uveitis suffered from juvenile rheumatoid arthritis. The authors observed the rise in peripheral blood IgG, IgA, IgM, CD(2)(+), CD(4)(+) and B cells during the acute phase of AAU. Normalization of B cells (CD(20)(+)) was observed in early remission of anterior uveitis, about eight weeks after the onset of the disease. PMID- 22827459 TI - Independent Associations of the HLA-B27 Antigen and the Complement Haplotype SC21 in Chronic Anterior Uveitis. AB - There is evidence of an association between major histocompatibility complex (MHC) genes and acute anterior uveitis; here the authors report the frequency of class I and class III MHC phenotypes in 32 Mexican mestizo patients with chronic anterior uveitis and compared them to those present in 100 ethnically matched healthy controls. Results showed in patients statistically significant increased frequencies of HLA-B(27) antigen (pC=0.02, OR=6.33, 95+ CI:1.63-26.47) and the complotype SC(21) (pC=0.04, OR=4.5, 95+ CI:1.40-14.67); the authors found a decreased frequency of HLA-B(35) (p=0.006, OR=0.10, 95+ CI: 0.00-0.65) as compared to normal controls. None of the individuals bearing the SC(21) complotype were positive for HLA-B(27), suggesting independent roles of the class I and class III antigens in the genetic susceptibility to chronic anterior uveitis. PMID- 22827460 TI - Recent developments in the treatment of posterior uveitis. AB - Uveitis is an intraocular inflammation that can be caused by infection, autoimmune disease, trauma or malignancy. It is a serious cause of visual handicap and therapy is targeted at: removal of possible infectious agents, the immunological processes that lead to or sustain the inflammation and finally to prevent or treat the destructive effects of the inflammation on the delicate ocular structures. In this review the latest developments concerning the treatment of posterior uveitis are illuminated, e. g., new approaches concerning the treatment of infectious uveitis including the therapy of herpes virus (VZV, HSV and CMV), bacterial and toxoplasma infections of the eye. Several new ways to influence the immune response and inflammation are described including the use of interferons, modulation of cytokines, soft steroids, other new immunosuppressive drugs and treatment of autoimmune uveitis by oral tolerization. An overview is given to illustrate new ways to administer drugs into eyes, such as intravitreal devices. Finally new developments in the field of the treatment of the various complications of uveitis (cystoid macular edema) are described. PMID- 22827461 TI - Rifabutin induced vitritis in AIDS patients. AB - The authors report three patients with the acquired immunodeficiency syndrome (AIDS) who developed uveitis while prophylactically taking rifabutin (300 mg/kg or more), clarithromycin and fluconazole. The uveitis presented unilaterally, but became bilateral within seven days in each patient. Inflammation was more severe in the vitreous than in the anterior chamber. Examination of the vitreous and blood from one patient with microbiological smears, bacterial and fungal culture and the polymerase chain reaction (PCR) to herpesviruses did not reveal an infectious etiology. Discontinuation or decreasing the dose of rifabutin to 300 mg/day and treatment with topical steroids and cycloplegics resulted in resolution of the uveitis within two weeks. Our findings support the observation that prophylactic doses of rifabutin, combined with clarithromycin, fluconazole or other agents which can increase rifabutin levels, can induce uveitis in patients with AIDS. It is important to recognize that a severe vitritis which can obscure visualization of the retina can be solely attributed to rifabutin in patients with AIDS. Therapy requires lowering the dose of rifabutin and the use of topical corticosteroids and cycloplegics. PMID- 22827463 TI - On the ATP-dependent activation of the radical enzyme (R)-2-hydroxyisocaproyl-CoA dehydratase. AB - Members of the 2-hydroxyacyl-CoA dehydratase enzyme family catalyze the beta,alpha-dehydration of various CoA-esters in the fermentation of amino acids by clostridia. Abstraction of the nonacidic beta-proton of the 2-hydroxyacyl-CoA compounds is achieved by the reductive generation of ketyl radicals on the substrate, which is initiated by the transfer of an electron at low redox potentials. The highly energetic electron needed on the dehydratase is donated by a [4Fe-4S] cluster containing ATPase, termed activator. We investigated the activator of the 2-hydroxyisocaproyl-CoA dehydratase from Clostridium difficile. The activator is a homodimeric protein structurally related to acetate and sugar kinases, Hsc70 and actin, and has a [4Fe-4S] cluster bound in the dimer interface. The crystal structures of the Mg-ADP, Mg-ADPNP, and nucleotide-free states of the reduced activator have been solved at 1.6-3.0 A resolution, allowing us to define the position of Mg(2+) and water molecules in the vicinity of the nucleotides and the [4Fe-4S] cluster. The structures reveal redox- and nucleotide dependent changes agreeing with the modulation of the reduction potential of the [4Fe-4S] cluster by conformational changes. We also investigated the propensity of the activator to form a complex with its cognate dehydratase in the presence of Mg-ADP and Mg-ADPNP and together with the structural data present a refined mechanistic scheme for the ATP-dependent electron transfer between activator and dehydratase. PMID- 22827462 TI - Adaptive evolution of Toll-like receptor 5 in domesticated mammals. AB - BACKGROUND: Previous studies have proposed that mammalian toll like receptors (TLRs) have evolved under diversifying selection due to their role in pathogen detection. To determine if this is the case, we examined the extent of adaptive evolution in the TLR5 gene in both individual species and defined clades of the mammalia. RESULTS: In support of previous studies, we find evidence of adaptive evolution of mammalian TLR5. However, we also show that TLR5 genes of domestic livestock have a concentration of single nucleotide polymorphisms suggesting a specific signature of adaptation. Using codon models of evolution we have identified a concentration of rapidly evolving codons within the TLR5 extracellular domain a site of interaction between host and the bacterial surface protein flagellin. CONCLUSIONS: The results suggest that interactions between pathogen and host may be driving adaptive change in TLR5 by competition between species. In support of this, we have identified single nucleotide polymorphisms (SNP) in sheep and cattle TLR5 genes that are co-localised and co-incident with the predicted adaptive codons suggesting that adaptation in this region of the TLR5 gene is on-going in domestic species. PMID- 22827464 TI - Photochemical control of RNA structure by disrupting pi-stacking. AB - Photolabile nucleotides that disrupt nucleic acid structure are useful mechanistic probes and can be used as tools for regulating biochemical processes. Previous probes can be limited by the need to incorporate multiple modified nucleotides into oligonucleotides and in kinetic studies by the rate-limiting step in the conversion to the native nucleotide. Photolysis of aryl sulfide 1 produces high yields of 5-methyluridine, and product formation is complete in less than a microsecond. Aryl sulfide 1 prevents RNA hairpin formation and complete folding of the preQ(1) class I riboswitch. Proper folding is achieved in each instance upon photolysis at 350 nm. Aryl sulfide 1 is a novel tool for modulating RNA structure, and formation of 5-methyluridine within a radical cage suggests that it will be useful in kinetic studies. PMID- 22827465 TI - Adherence to the Mediterranean diet and serum uric acid: the ATTICA study. AB - OBJECTIVE: The present study aimed to explore potential associations between adherence to a Mediterranean diet and serum uric acid (UA) levels. METHODS: The sample consisted of 2380 men and women free of cardiovascular or renal disease who participated in the ATTICA study. Dietary intake was assessed using a food frequency questionnaire (FFQ) and adherence to the Mediterranean diet was evaluated with the MedDietScore. Serum UA was measured and hyperuricaemia was defined as UA concentration > 7.0 mg/dL in men or > 6.0 mg/dL in women. RESULTS: MedDietScore was inversely associated with UA levels (b-coefficient per quartile of the score = -0.07 +/- 0.03, p = 0.02) independently of sex, presence of overweight, hypertension, or abnormal glucose metabolism, and alcohol or coffee intake. Those at the fourth quartile of MedDietScore had a 70% lower likelihood of having hyperuricaemia [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.11 0.82] compared to those at the first quartile, after adjustment for several confounders. According to stratified analyses by sex, body mass index (BMI) status, hypertension, abnormal glucose, alcohol and coffee intake, the inverse association between serum UA and MedDietScore remained significant in women (b coefficient = -0.194 +/- 0.055, p < 0.001), overweight subjects (b-coefficient = 0.103 +/- 0.047, p = 0.02), in those with normal glucose metabolism (b coefficient = -0.074 +/- 0.037, p = 0.04), and in those abstaining from alcohol (b-coefficient = -0.212 +/- 0.073, p = 0.004) and coffee (b-coefficient = -0.221 +/- 0.096, p = 0.02). CONCLUSION: Adherence to the Mediterranean diet is associated with lower serum UA levels and lower likelihood of hyperuricaemia. These findings support a potential role of this dietary pattern in the prevention and treatment of hyperuricaemia and gout. PMID- 22827466 TI - Perceptions of healthy eating and physical activity in an ethnically diverse sample of young children and their parents: the DEAL prevention of obesity study. AB - BACKGROUND: Ethnicity is a consistent correlate of obesity; however, little is known about the perceptions and beliefs that may influence engagement with obesity prevention programmes among ethnic minority children. Barriers to (and facilitators of) healthy lifestyles were examined in the qualitative arm of the London (UK) DiEt and Active Living (DEAL) study. METHODS: Children aged 8-13 years and their parents, from diverse ethnic groups, were recruited through schools and through places of worship. Thirteen focus group sessions were held with 70 children (n = 39 girls) and eight focus groups and five interviews with 43 parents (n = 34 mothers). RESULTS: Across ethnic groups, dislike of school meals, lack of knowledge of physical activity guidelines for children and negativity towards physical education at school among girls, potentially hindered healthy living. Issues relating to families' wider neighbourhoods (e.g. fast food outlets; lack of safety) illustrated child and parental concerns that environments could thwart intentions for healthy eating and activity. By contrast, there was general awareness of key dietary messages and an emphasis on dietary variety and balance. For ethnic minorities, places of worship were key focal points for social support. Discourse around the retention of traditional practices, family roles and responsibilities, and religion highlighted both potential facilitators (e.g. the importance of family meals) and barriers (reliance on convenience stores for traditional foods). Socio-economic circumstances intersected with key themes, within and between ethnic groups. CONCLUSIONS: Several barriers to (and facilitators of) healthy lifestyles were common across ethnic groups. Diversity of cultural frameworks not only were more nuanced, but also shaped lifestyles for minority children. PMID- 22827467 TI - GABA(A) receptor regulation after experimental traumatic brain injury. AB - The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) is responsible for most fast synaptic inhibition in the adult brain. The GABA(A)R protein is composed of multiple subunits that determine the distribution, properties, and dynamics of the receptor. Several studies have shown that the Janus kinase/signal transducer and activator of transcription (JaK/STAT) and early growth response 3 (Egr3) signaling pathways can alter GABA(A)R subunit expression after status epilepticus (SE). In this study we investigated changes in these pathways after experimental TBI in the rat using a lateral fluid percussion injury (FPI) model. Our results demonstrated changes in the expression of several GABA(A)R subunit levels after injury, including GABA(A)R alpha1 and alpha4 subunits. This change appears to be transcriptional, and there is an associated increase in the phosphorylation of STAT3, and an increase in the expression of Egr3 and inducible cAMP element repressor (ICER) after FPI. These findings suggest that the activation of the JaK/STAT and Egr3 pathways after TBI may regulate injury related changes in GABA(A)R subunit expression. PMID- 22827468 TI - Aspirin and recurrent venous thromboembolism in patients with symptomatic atherosclerosis: retrospective cohort study. PMID- 22827469 TI - Environmental perchlorate and thiocyanate exposures and infant serum thyroid function. AB - BACKGROUND: Breastfed infants rely on maternal iodine for thyroid hormone production required for neurodevelopment. Dietary iodine among women of childbearing age in the United States may be insufficient. Perchlorate (competitive inhibitor of the sodium/iodide symporter [NIS]) exposure is ubiquitous. Thiocyanate, from cigarettes and diet, is a weaker NIS inhibitor. Environmental perchlorate and thiocyanate exposures could decrease breast milk iodine by competitively inhibiting NIS in lactating breasts (thus impairing infants' iodine availability), and/or infants' thyroidal NIS to directly decrease infant thyroid function. The current study assessed the relationships between environmental perchlorate and thiocyanate exposures and infant serum thyroid function. METHODS: Iodine, perchlorate, and thiocyanate in breast milk, maternal and infant urine, and infant serum thyroid function tests were cross-sectionally measured in Boston-area women and their 1-3 month-old breastfed infants. Univariate and multivariable analyses assessed relationships between iodine, perchlorate, thiocyanate, thyroid-stimulating hormone (TSH), and free thyroxine (FT4) levels. RESULTS: In 64 mothers and infants, median (range) iodine levels were 45.6 MUg/L (4.3-1080) in breast milk, 101.9 MUg/L (27-570) in maternal urine, and 197.5 MUg/L (40-785) in infant urine. Median perchlorate concentrations were 4.4 MUg/L (0.5-29.5) in breast milk, 3.1 MUg/L (0.2-22.4) in maternal urine, and 4.7 MUg/L (0.3-25.3) in infant urine. There were no correlations between infant TSH or FT4 and iodine, perchlorate, and thiocyanate levels in breast milk, maternal urine, and infant urine. In multivariable analyses, perchlorate and thiocyanate levels in breast milk, maternal urine, and infant urine were not significant predictors of infant TSH or FT4. CONCLUSIONS: Boston-area mothers and their breastfed infants are generally iodine sufficient. Although environmental perchlorate and thiocyanate are ubiquitous, these results do not support the concern that maternal and infant environmental perchlorate and thiocyanate exposures affect infant thyroid function. PMID- 22827470 TI - Thumbs down for HIV: domain level rearrangements do occur in the NNRTI-bound HIV 1 reverse transcriptase. AB - One of the principal targets in human immunodeficiency virus type 1 (HIV-1) therapy is the reverse transcriptase (RT) enzyme. Non-nucleoside RT inhibitors (NNRTIs) are a class of highly specific drugs which bind to a pocket approximately 10 A from the polymerase active site, inhibiting the enzyme allosterically. It is widely believed that NNRTIs function as "molecular wedges", disrupting the region between thumb and palm subdomains of the p66 subunit and locking the thumb in a wide-open conformation. Crystal structure data suggest that the binding of NNRTIs forces RT into a wide-open conformation in which the separation between the thumb and fingers subdomains is much higher than in the apo structure. Using ensemble molecular dynamics simulations (aggregate sampling ~600 ns), we have captured RT bound to the NNRTI efavirenz in a closed conformation similar to that of the apo enzyme, suggesting the constraint of thumb motion is not as complete as previously believed. Rather, our investigation confirms that a conformational distribution across open and closed states must exist in the drug-bound enzyme and that allosteric modulation is effected via the alteration of the kinetic landscape of conformational transitions upon drug binding. A more detailed understanding of the mechanism of NNRTI inhibition and the effect of binding upon domain motion could aid the design of more effective inhibitors and help identify novel allosteric sites. PMID- 22827471 TI - Death following injection sclerotherapy due to phenol toxicity. AB - Prolapse rectum (PR) or protrusion of the rectum beyond the anus occurs frequently in populations at both extremes of age. In the pediatric population, in developed countries, the commonest cause for PR is thought to be cystic fibrosis (CF). Treatment options for CF include conservative management, surgical resection and fixation, suturing, and injection sclerotherapy (IS). The last is considered an attractive treatment option because it is minimally invasive. In this case report, the authors present the details about a 2-year-old female child, with PR and CF, who died after IS, using phenol as the sclerotherapeutic agent. Autopsy findings and toxicology tests performed to establish phenol toxicity are documented. The available literature is reviewed. This case report underscores the risks of using phenol for IS and emphasizes the point that the procedure is not innocuous and an adverse outcome including fatality is a possibility. PMID- 22827473 TI - CPMV-DOX delivers. AB - The plant virus, Cowpea mosaic virus (CPMV), is developed as a carrier of the chemotherapeutic drug doxorubicin (DOX). CPMV-DOX conjugate, in which eighty DOX molecules are covalently bound to external surface carboxylates of the viral nanoparticle (VNP), shows greater cytotoxicity than free DOX toward HeLa cells when administered at low dosage. At higher concentrations, CPMV-DOX cytotoxicity is time-delayed. The CPMV conjugate is targeted to the endolysosomal compartment of the cells, in which the proteinaceous drug carrier is degraded and the drug released. This study is the first demonstrating the utility of CPMV as a drug delivery vehicle. PMID- 22827474 TI - Cardiac troponin I in racing standardbreds. AB - BACKGROUND: Upper reference limits for cTnI have not been established for healthy Standardbred racehorses. OBJECTIVES: To establish cTnI upper reference limits for Standardbred racehorses and determine if increases in plasma cTnI concentration can be detected in 1-2 hours after a race. ANIMALS: Samples were obtained from 586 apparently healthy Standardbreds aged 2-14 years before racing and from the winners of 144 races 1-2 hours after the end of the race. METHODS: Prospective, observational study; convenience sampling; assay validation; and reference limits determinations were performed according to ASCVP guidelines. Plasma cardiac troponin I concentrations before racing were determined, potential outliers identified, and the 95th and 99th percentile upper reference limits calculated using nonparametric methods. The correlation between cTnI concentration and age, differences in median cTnI concentrations by subgroups and differences between cTnI concentrations before and after racing in winning horses were determined. RESULTS: The 95th and 99 th percentile upper reference limits for all horses excluding outliers were < 0.04 ng/mL and 0.06 ng/mL. There were no significant differences in cTnI concentrations based on age (P = .06), sex (P = .35), gait (P = .55), or race classification (P = .65) and a weak correlation of cTnI with age (rho = 0.09, P = .03). There were no significant differences between cTnI concentrations before and after racing in winning horses (P = .70). CONCLUSIONS AND CLINICAL IMPORTANCE: Because of lack of standardization across cTnI assays, the reference limits apply only to the Stratus CS immunoassay. Future studies looking at the effects of high intensity, short duration exercise on cTnI should consider sampling more than 2 hours after racing or using an ultrasensitive assay. PMID- 22827475 TI - Web-conferenced simulation sessions: a satisfaction survey of clinical simulation encounters via remote supervision. AB - PURPOSE: A critical barrier to expanding simulation-based instruction in medicine is the availability of clinical instructors. Allowing instructors to remotely observe and debrief simulation sessions may make simulation-based instruction more convenient, thus expanding the pool of instructors available. This study compared the impact of simulation sessions facilitated by in-person (IP) faculty versus those supervised remotely using Web-conferencing software (WebEx((r)), Cisco [ www.webex.com/ ]). SUBJECTS AND METHODS: A convenience sample of preclinical medical students volunteered to "care for" patients in a simulation laboratory. Students received either standard IP or Web-conferenced (WC) instruction. WC sessions were facilitated by off-site instructors. A satisfaction survey (5-point Likert scale, where 1=strongly disagree and 5=strongly agree) was completed immediately following the sessions. RESULTS: Forty-four surveys were analyzed (WC n=25, IP n=19). In response to the question "Was the communication between faculty and students a barrier to understanding the case?," the average student responses were 2.8 (95% confidence interval [CI] 2.4-3.2) for WC and 4.5 (95% CI 4.0-5.0) for IP (p<0.0001). In response to the question "Would you participate again in such a session?," the average student responses were 4.2 (95% CI 4.0-4.5) for WC and 4.9 (95% CI 4.6-5.2) for IP (p=0.0003). Both groups agreed that they acquired new skills (4.2 for WC, 4.5 for IP; p=0.39) and new knowledge (4.6 for WC, 4.7 for IP; p=0.41). CONCLUSIONS: Telecommunication can successfully enhance access to simulation-based instruction. In this study, a Web interface downgraded the quality of student-faculty communication. Future investigation is needed to better understand the impact of such an effect on the learning process and to reduce barriers that impede implementation of technology facilitated supervision. PMID- 22827476 TI - Biodiversity of freshwater diatom communities during 1000 years of metal mining, land use, and climate change in central Sweden. AB - We subjected a unique set of high-quality paleoecological data to statistical modeling to examine if the biological richness and evenness of freshwater diatom communities in the Falun area, a historical copper (Cu) mining region in central Sweden, was negatively influenced by 1000 years of metal exposure. Contrary to ecotoxicological predictions, we found no negative relation between biodiversity and the sedimentary concentrations of eight metals. Strikingly, our analysis listed metals (Co, Fe, Cu, Zn, Cd, Pb) or the fractional land cover of cultivated crops, meadow, and herbs indicating land disturbance as potentially promoting biodiversity. However, correlation between metal- and land-cover trends prevented concluding which of these two covariate types positively affected biodiversity. Because historical aqueous metal concentrations--inferred from solid-water partitioning--approached experimental toxicity thresholds for freshwater algae, positive effects of metal mining on biodiversity are unlikely. Instead, the positive relationship between biodiversity and historical land-cover change can be explained by the increasing proportion of opportunistic species when anthropogenic disturbance intensifies. Our analysis illustrates that focusing on the direct toxic effects of metals alone may yield inaccurate environmental assessments on time scales relevant for biodiversity conservation. PMID- 22827477 TI - Intraoperative spectral-domain optical coherence tomography in coats' disease. AB - The authors describe the spectral-domain optical coherence tomography findings in three patients undergoing examinations under anesthesia for treatment of Coats' disease. Patients were treated using a multifaceted approach of intravitreal bevacizumab and indirect diode laser vascular ablation. A handheld, portable spectral-domain optical coherence tomography system was used as a novel and critical intraoperative tool in differentiating Coats' disease from diffuse retinoblastoma and other simulating conditions and to monitor reductions in subretinal and intraretinal exudation during the course of treatment. PMID- 22827478 TI - Does rapid maxillary expansion induce adverse effects in growing subjects? AB - OBJECTIVE: To assess the scientific evidence that rapid maxillary expansion (RME) causes Adverse Effects on the midpalatal suture, vertical dimension, dental and periodontal structures in growing subjects. MATERIALS AND METHODS: Electronic databases were searched for articles dated through December 2011. The quality of the studies was ranked on a 13-point scale in which 1 was the low end of the scale and 13 was the high end. RESULTS: Thirty relevant articles were identified. The amount of midpalatal suture opening ranged from 1.6 to 4.3 mm in the anterior region and from 1.2 to 4.4 mm in the posterior region. At the end of the active phase, RME resulted in slight inferior movement of the maxilla (SN-PNS +0.9 mm; SN-ANS +1.6 mm), increased tipping of anchored teeth from 3.4 degrees to 9.2 degrees and bending of the alveolar bone from 5.1 degrees to 11.3 degrees . In the long term, RME did not modify the facial growth patterns, and no significant changes on dentoalveolar structures were observed. Of the 30 studies, 2 were medium-high quality, 8 were medium quality, and 20 were low quality. CONCLUSIONS: RME always opened the midpalatal suture in growing subjects. The vertical changes were small and transitory. In the long-term evaluation, an uprighting of anchored teeth was observed and periodontal structures were not compromised. PMID- 22827472 TI - Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. AB - The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-beta neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARgamma (peroxisome-proliferator-activated receptor gamma) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic brain injury. PMID- 22827480 TI - Ethanol-induced memory impairment in a discriminative avoidance task is state dependent. AB - BACKGROUND: A considerable amount of experimental evidence has demonstrated ethanol (EtOH) induced amnestic effects following EtOH administration during pretraining in a variety of tasks both in humans and in laboratory animals. Although the phenomenon of state-dependency is known to play a critical role in memory deficits induced by both pharmacological and nonpharmacological pretraining perturbations, the involvement of this phenomenon in EtOH-induced anterograde amnesia has been overlooked. This study aimed to investigate the role of state-dependency in EtOH-induced amnestic effects and its interactions with the well-known anxiolysis and locomotor alterations. METHODS: Mice were treated with 1.2 or 2.4 g/kg EtOH before training and/or before testing in the plus-maze discriminative avoidance task, an animal model that concomitantly evaluates learning, memory, anxiety-like behavior, and general activity. RESULTS: Whereas both doses of EtOH induced anxiolysis, the 1.2 g/kg dose enhanced locomotion while the 2.4 g/kg dose decreased it. In addition, the administration of 1.2 g/kg of this drug during pretraining caused memory impairment, which was counteracted by the pretest administration of the same dose, revealing the participation of the state-dependency. Conversely, the administration of 2.4 g/kg EtOH led to amnestic effects irrespective of the time of the administration (pretraining and/or pretest), eliminating the influence of state-dependency. CONCLUSIONS: Our data demonstrate that EtOH-induced memory deficits are critically related to state-dependency, which can also be affected by the dose range. These results indicate the possible participation of EtOH-induced modifications in anxiety and motor activity levels in relation to state-dependent memory deficits. PMID- 22827479 TI - A prospective randomized split-mouth study on pain experience during chairside archwire manipulation in self-ligating and conventional brackets. AB - OBJECTIVE: To investigate patient discomfort during archwire engagement and disengagement in patients treated with self-ligating and conventional brackets using a split-mouth design. MATERIALS AND METHODS: Eighteen consecutive patients (15 female, 3 male; age: 22.2 +/- 6.4 years) who requested treatment with fixed orthodontic appliances were randomly assigned for bonding with SmartClip self ligating brackets on one side of the dentition and conventional standard edgewise brackets on the other. During the course of treatment, patients rated the discomfort experienced during every archwire engagement and disengagement using a numeric rating scale. Results were evaluated for round and rectangular nickel titanium and rectangular stainless steel, titanium molybdenum, and Elgiloy archwires. Patients also rated their overall experience retrospectively for both bracket systems. RESULTS: Regardless of archwire type, disengagement was rated as being significantly more painful on the SmartClip side (P = .027). For rigid, rectangular archwires, engagement and disengagement were rated as being significantly more painful on the SmartClip side (P = .031; P = .004). Retrospective ratings favored conventional brackets beyond ratings recorded during treatment. CONCLUSION: Engagement and disengagement of rigid rectangular archwires caused more pain with SmartClip self-ligating brackets than with conventional ones. Careful archwire manipulation and patience during full alignment are essential for limiting chairside pain. Low pain levels will help ensure treatment satisfaction and compliance. PMID- 22827481 TI - An asymmetric organocatalytic Povarov reaction with 2-hydroxystyrenes. AB - An organocatalytic asymmetric three-component Povarov reaction involving 2 hydroxystyrenes has been established to provide an efficient method to access structurally diverse cis-disubstituted tetrahydroquinolines in high stereoselectivities of up to >99:1 dr and 97% ee. This protocol also provides an easy access to tetrahydroquinolines with chiral quaternary stereocenters upon using alpha-alkyl 2-hydroxystyrenes as substrates. The theoretical studies revealed that the Povarov reaction proceeded through a sequential vinylogous Mannich reaction and an intramolecular Friedel-Crafts reaction, wherein the phosphoric acid acted as bifunctional catalyst to activate 2-hydroxystyrene and aldimine simultaneously. PMID- 22827482 TI - Morphological and molecular characterization of Paramecium (Viridoparamecium nov. subgen.) chlorelligerum Kahl (Ciliophora). AB - We redescribe Paramecium chlorelligerum, a forgotten species, which Kahl (Tierwelt Dtl., 1935, 30:651) briefly but precisely described in the addendum to his ciliate monographs as a Paramecium with symbiotic green algae. The redescription is based on classical morphological methods and the analysis of the small subunit (SSU) rDNA. Morphologically, P. chlorelligerum differs from P. (C.) bursaria, the second green species in the genus, by having a special swimming shape, the length of the caudal cilia, the size of the micronucleus, the size of the symbiotic algae, the contractile vacuoles (with collecting vesicles vs. collecting canals), and the number of excretory pores/contractile vacuole (1 vs. 2-3). The molecular investigations show that P. chlorelligerum forms a distinct branch distant from the P. (Chloroparamecium) bursaria clade. Thus, we classify P. chlorelligerum in a new subgenus: Paramecium (Viridoparamecium) chlorelligerum. The symbiotic alga belongs to the little-known genus Meyerella, as yet recorded only from the plankton of a North American lake. PMID- 22827483 TI - High-throughput sequence analysis of small RNAs in grapevine (Vitis vinifera L.) affected by grapevine leafroll disease. AB - Grapevine leafroll disease (GLRD) is one of the most economically important virus diseases of grapevine (Vitis spp.) worldwide. In this study, we used high throughput sequencing of cDNA libraries made from small RNAs (sRNAs) to compare profiles of sRNA populations recovered from own-rooted Merlot grapevines with and without GLRD symptoms. The data revealed the presence of sRNAs specific to Grapevine leafroll-associated virus 3, Hop stunt viroid (HpSVd), Grapevine yellow speckle viroid 1 (GYSVd-1) and Grapevine yellow speckle viroid 2 (GYSVd-2) in symptomatic grapevines and sRNAs specific only to HpSVd, GYSVd-1 and GYSVd-2 in nonsymptomatic grapevines. In addition to 135 previously identified conserved microRNAs in grapevine (Vvi-miRs), we identified 10 novel and several candidate Vvi-miRs in both symptomatic and nonsymptomatic grapevine leaves based on the cloning of miRNA star sequences. Quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) of selected conserved Vvi-miRs indicated that individual members of an miRNA family are differentially expressed in symptomatic and nonsymptomatic leaves. The high-resolution mapping of sRNAs specific to an ampelovirus and three viroids in mixed infections, the identification of novel Vvi-miRs and the modulation of certain conserved Vvi-miRs offers resources for the further elucidation of compatible host-pathogen interactions and for the provision of ecologically relevant information to better understand host-pathogen environment interactions in a perennial fruit crop. PMID- 22827484 TI - Noticeable decreased expression of tenascin-X in calcific aortic valves. AB - Calcification of aortic valves results in valvular aortic stenosis and is becoming a common valvular condition in elderly populations. An understanding of the molecular mechanisms of this valve lesion is important for revealing potential biomarkers associated with the development and progression of this disease. In order to identify proteins that are differentially expressed in calcific aortic valves (CAVs) compared with those in adjacent normal valvular tissues, comprehensive analysis of differentially expressed proteins in the tissues was done by a quantitative proteomic approach with isobaric tag for absolute and relative quantitation labeling followed by nanoliquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. The proteomic analysis revealed 105 proteins differentially expressed in CAVs in contrast to adjacent normal valvular tissues with high confidence. Significantly increased expression (>=1.3-fold) was found in 34 proteins, whereas decreased expression (<0.77-fold) was found in 39 proteins in CAVs. Among them, alpha-2-HS-glycoprotein showed the greatest increase in expression (6.54-fold) and tenascin-X showed the greatest decrease in expression (0.37-fold). Numerous extracellular matrix proteins such as collagens were identified as proteins with significantly decreased expression. Panther pathway analysis showed that some of the identified proteins were linked to blood coagulation and integrin signaling pathways. Cluster analysis of the 105 proteins differentially expressed in CAVs based on the expression pattern revealed that tenascin-X was clustered with proteins controlling collagen structure and function, especially collagen fibrillogenesis, such as decorin and fibromodulin. We confirmed decreased levels of these proteins in CAVs by Western blot analyses. These results indicated that massive destruction of the extracellular matrix occurs in CAVs. PMID- 22827485 TI - Structure and ligand-based design of P-glycoprotein inhibitors: a historical perspective. AB - Computer-assisted drug design (CADD) is a valuable approach for the discovery of new chemical entities in the field of cancer therapy. There is a pressing need to design and develop new, selective, and safe drugs for the treatment of multidrug resistance (MDR) cancer forms, specifically active against P-glycoprotein (P-gp). Recently, a crystallographic structure for mouse P-gp was obtained. However, for decades the design of new P-gp inhibitors employed mainly ligand-based approaches (SAR, QSAR, 3D-QSAR and pharmacophore studies), and structure-based studies used P-gp homology models. However, some of those results are still the pillars used as a starting point for the design of potential P-gp inhibitors. Here, pharmacophore mapping, (Q)SAR, 3D-QSAR and homology modeling, for the discovery of P-gp inhibitors are reviewed. The importance of these methods for understanding mechanisms of drug resistance at a molecular level, and design P-gp inhibitors drug candidates are discussed. The examples mentioned in the review could provide insights into the wide range of possibilities of using CADD methodologies for the discovery of efficient P-gp inhibitors. PMID- 22827486 TI - Large magnetoresistance through a single molecule due to a spin-split hybridized orbital. AB - Using organic materials in spintronic devices raises a lot of expectation for future applications due to their flexibility, low cost, long spin lifetime, and easy functionalization. However, the interfacial hybridization and spin polarization between the organic layer and the ferromagnetic electrodes still has to be understood at the molecular scale. Coupling state-of-the-art spin-polarized scanning tunneling spectroscopy and spin-resolved ab initio calculations, we give the first experimental evidence of the spin splitting of a molecular orbital on a single non magnetic C(60) molecule in contact with a magnetic material, namely, the Cr(001) surface. This hybridized molecular state is responsible for an inversion of sign of the tunneling magnetoresistance depending on energy. This result opens the way to spin filtering through molecular orbitals. PMID- 22827487 TI - Recent developments in statistical methods for detecting genetic loci affecting phenotypic variability. AB - A number of recent works have introduced statistical methods for detecting genetic loci that affect phenotypic variability, which we refer to as variability controlling quantitative trait loci (vQTL). These are genetic variants whose allelic state predicts how much phenotype values will vary about their expected means. Such loci are of great potential interest in both human and non-human genetic studies, one reason being that a detected vQTL could represent a previously undetected interaction with other genes or environmental factors. The simultaneous publication of these new methods in different journals has in many cases precluded opportunity for comparison. We survey some of these methods, the respective trade-offs they imply, and the connections between them. The methods fall into three main groups: classical non-parametric, fully parametric, and semi parametric two-stage approximations. Choosing between alternatives involves balancing the need for robustness, flexibility, and speed. For each method, we identify important assumptions and limitations, including those of practical importance, such as their scope for including covariates and random effects. We show in simulations that both parametric methods and their semi-parametric approximations can give elevated false positive rates when they ignore mean variance relationships intrinsic to the data generation process. We conclude that choice of method depends on the trait distribution, the need to include non genetic covariates, and the population size and structure, coupled with a critical evaluation of how these fit with the assumptions of the statistical model. PMID- 22827488 TI - The golden pathway to thiolate-stabilized nanoparticles: following the formation of gold(I) thiolate from gold(III) chloride. AB - Pathways for the formation of gold thiolate complexes from gold(III) chloride precursors AuCl(4)(-) and AuCl(3) are examined. This work demonstrates that two distinct reaction pathways are possible; which pathway is accessible in a given reaction may depend on factors such as the residue group R on the incoming thiol. Density functional theory calculations using the BP86 functional and a polarized triple-zeta basis set show that the pathway resulting in gold(III) reduction is favored for R = methyl. A two-to-one ratio of thiol or thiolate to gold can reduce Au(III) to Au(I), and a three-to-one ratio can lead to polymeric Au(SR) species, which was first suggested by Schaaff et al. J. Phys. Chem. B, 1997, 101, 7885 and later confirmed by Goulet and Lennox J. Am. Chem. Soc., 2010, 132, 9582. Most transition states in the pathways examined here have reasonable barrier heights around 0.3 eV; we find two barrier heights that differ substantially from this which suggest the potential for kinetic control in the first step of thiolate-protected gold nanoparticle growth. PMID- 22827489 TI - Impaired verbal fluency under topiramate--evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy. AB - BACKGROUND AND PURPOSE: Treatment with topiramate (TPM) is known to negatively affect executive functions and verbal fluency in particular. However, judgments of cognitive side effects under TPM rarely consider clinical conditions and possible effects of epilepsy, treatment, and drug load. METHODS: This retrospective cross-sectional study in large cohorts of patients with epilepsy evaluated the impact of TPM mono- and polytherapy on verbal fluency. To isolate TPM-induced effects from those of epilepsy and antiepileptic medication in general, verbal fluency under TPM (N = 421) was compared to the performance of a matched sample of patients with an antiepileptic medication other than TPM (N = 351), untreated patients (N = 108), and healthy controls (N = 100). RESULTS: Impaired verbal fluency performance was seen in 77% of the patients treated with TPM. Compared to healthy controls, verbal fluency in untreated patients was reduced by 22%, under monotherapy without TPM by 31% and under TPM monotherapy by 45%. With and without TPM, verbal fluency performance linearly decreased with each additional drug in polytherapy. On each level, performance under TPM was 21 28% worse than in the respective condition without TPM. Unimpaired performance under TPM was primarily associated with lower dose, higher education, and a later onset of epilepsy. CONCLUSIONS: The majority of patients under TPM shows reduced verbal fluency. However, when taking the cumulative negative effects of epilepsy, and the concomitant drug regimen into account, TPM is associated with a 21-28% poorer performance as compared with other drugs. Additionally, the data indicate an impact of dose and reserve capacity on the occurrence of impairments. PMID- 22827490 TI - Phase III studies on novel oral anticoagulants for stroke prevention in atrial fibrillation: a look beyond the excellent results. AB - In this overview we address the three phase III studies that compared new oral anticoagulants (dabigatran, rivaroxaban and apixaban) with warfarin in the setting of stroke prevention in atrial fibrillation. Strengths and weaknesses of the studies were examined in detail through indirect comparison. We analyze and comment the inclusion and exclusion criteria, the characteristics of randomized patients, the primary efficacy and safety end points and side effects. All new oral anticoagulants resulted in being non-inferior to vitamin K antagonists in reducing stroke or systemic embolism in patients with atrial fibrillation. Dabigatran 150 mg and apixaban were superior to vitamin K antagonists. Importantly, new oral anticoagulants significantly reduced hemorrhagic stroke in all three studies. Major differences among new oral anticoagulants include the way they are eliminated and side effects. Both dabigatran and apixaban were tested in low- to moderate-risk patients (mean CHADS2 [Congestive heart failure, Hypertension, Age, Diabetes, Stroke] score = 2.1-2.2) whereas rivaroxaban was tested in high-risk patients (mean CHADS2 score = 3.48) and at variance with dabigatran and apixaban was administered once daily. Apixaban significantly reduced mortality from any cause. The choice of a new oral anticoagulant should take into account these and other differences between the new drugs. PMID- 22827491 TI - Characterization and antimicrobial resistance of Listeria monocytogenes isolated from retail beef meat in Poland. AB - Four hundred seventeen retail beef meat samples purchased in the eastern part of Poland during October 2009 to January 2011 were tested for the presence of Listeria monocytogenes. It was found that 81 (19.4%) of them were positive for this microorganism as identified by the culture and polymerase chain reaction (PCR) methods. Molecular serotyping performed by PCR revealed that the majority of the isolates (50 strains; 61.7%) were of 1/2a serotype. Furthermore, 26 (32.1%) L. monocytogenes strains were classified as 1/2c serotype, and only five strains belonged to serotypes 1/2b or 4b (four and one isolates, respectively). All the isolates were positive for the inlA, inlC, inlJ, and lmo2672 sequences, whereas two L. monocytogenes (both of 4b serotype) had another virulence marker gene--llsX. The results of the antimicrobial resistance revealed that the strains were sensitive to most of the antimicrobials used in the study except oxacillin (62.7% resistant strains). Several isolates (17.3%) were also resistant to ceftriaxone. Our results indicate that L. monocytogenes identified in raw beef meat possessed virulence markers that make them potentially pathogenic for humans. Therefore, this kind of food may create a public health concern. PMID- 22827492 TI - Curved polycyclic aromatic molecules that are pi-isoelectronic to hexabenzocoronene. AB - Reported here are two types of curved pi-molecules that are pi-isoelectronic to planar hexabenzocoronene (HBC) but are forced out of planarity either by an embedded seven-membered ring or by atom crowding at the fjord region. Embedding a heptagon in HBC leads to a novel saddle-shaped molecule 1, whose pi-backbone is slightly less curved than the previously reported [7]circulene in terms of the average Gauss curvature, but surprisingly much more rigid than [7]circulene. Overcrowded fjord regions in novel derivatives of hexabenzoperylene (HBP) 2a,b lead to both chiral twisted and antifolded conformers. The successful synthesis of 1 and 2a,b is related to introducing alkoxyl groups to unprecedented positions of hexaphenylbenzenes. It is found that the red twisted isomer of 2b isomerizes at elevated temperature to the yellow anti-folded conformer. This finding along with the study on the thermodynamics and kinetics of the thermal isomerization has improved the early understandings on the conformation of HBP. In the crystals, 1 lacks pi-pi interactions between neighboring molecules, while twisted 2a exhibits both face-to-face and edge-to-face pi-pi interactions. Twisted-2b is found to function as a p-type semiconductor in thin film transistors, but the thin films of 1 appear insulating presumably due to lacking pi-pi interactions. By exploring three different types of curvatures in 1 and the two isomers of 2b, this study has revealed that the curvature of pi-face plays a role in determining the frontier molecular orbital energy levels and pi-pi interactions and thus needs to be considered when one designs new organic semiconductors. PMID- 22827493 TI - Influence of the cosolute environment on IgG solution structure analyzed by small angle X-ray scattering. AB - Small-angle X-ray scattering experiments of two monoclonal antibodies (mAbs) were performed as a function of Hofmeister salt type and concentration including 100 mM Na(2)SO(4), 100-600 mM of NaSCN, or 100-600 mM arginine chloride at pH 6.0 to yield information on the effects of cosolutes on mAb solution conformation and flexibility. Minimal selected ensemble (MSE) procedures used to reconstruct the SAXS form factors revealed that both IgG1 mAbs exist in a conformational equilibrium with two subpopulations that vary in overall shape and size. The "closed" mAb conformation is characterized by a maximum dimension of ~155 A and shorter distances between Fab-Fab and Fab-FC domains. The "open" mAb conformation has a maximum dimension of ~175 A and an increase in the interdomain distances with concomitant increases in overall mAb flexibility. Analysis of the distribution of shapes and sizes of mAb structures within the conformational equilibrium indicates that they remain essentially unchanged under conditions with a broad range of chaotropic and kosmotropic salts including 100-600 mM NaSCN and 100 mM Na(2)SO(4). Analysis of the conformations within each MSE population under various conditions reveals a striking similarity between many of the MSE structures, IgG crystal structures, and single-molecule imaging studies; MSE analysis of mAb form factors also identified an overall relaxation of the mAb structure unique to solution conditions containing arginine chloride, characterized by an increased maximum dimension and a shift toward the population of the "open" mAb conformation. Our results provide the first comprehensive characterization of mAb conformational diversity in solution and are of direct relevance to understanding the effects of solution conditions on protein structural dynamics and stability. PMID- 22827494 TI - Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature. AB - BACKGROUND: Prophylactic central neck dissection (CND) has been proposed in the treatment of patients affected by papillary thyroid carcinoma (PTC) with clinically negative neck lymph nodes. The procedure allows pathologic staging of lymph nodes of the central compartment and treatment of the micrometastases. Nevertheless, the morbidity that its routine use adds to the total thyroidectomy must be taken into account. The aim of this study was to characterize the morbidity that CND adds to the total thyroidectomy. METHODS: This was a retrospective study of 1087 patients with PTC and clinically negative neck lymph nodes. Patients were divided into three study groups: Group A, total thyroidectomy; Group B, total thyroidectomy and ipsilateral CND; Group C, total thyroidectomy and bilateral CND. Primary endpoints of the study were evaluated by comparing the rates of transient and permanent recurrent laryngeal nerve (RLN) injury and hypoparathyroidism in the three study groups. RESULTS: Analysis of data showed no significant differences in the rate of transient (Group A: 3.6%, Group B: 3.9%, and Group C: 5.5%; p=0.404) and permanent (Group A: 1%, Group B: 0.5%, and Group C: 2.3%; p=0.099) RLN injury between the three study groups. Both ipsilateral CND and bilateral CND were associated with a higher rate of transient hypoparathyroidism (Group: A 27.7%, Group B: 36.1%, and Group C: 51.9%; p=0.014; odds ratio [OR]: 1.477; 95% confidence interval [CI]: 1.091-2.001; p<0.001; OR: 2.827; 95% CI: 2.065-3.870, respectively). Bilateral CND had a higher rate of permanent hypoparathyroidism (Group A: 6.3%, Group B: 7%, and Group C: 16.2%; p<0.001; OR: 2.860; 95% CI: 1.725-4.743). CONCLUSIONS: The increased rates of transient and permanent hypoparathyroidism in our series suggest a critical review of indications for the routine use of prophylactic CND for PTC. Prophylactic CND ipsilateral to the tumor associated with total thyroidectomy may represent an effective strategy for reducing the rate of permanent hypoparathyroidism. Concomitant completion contralateral paratracheal lymph node neck dissection should be performed in presence of lymph node metastasis on intraoperative frozen-section pathology. This approach limits the use of bilateral CND to patients with intraoperative pathological findings of lymph node metastases. PMID- 22827495 TI - Fewer and older patients with rheumatoid arthritis need total knee replacement. AB - OBJECTIVES: Recent studies have suggested a decreased need for orthopaedic surgery in patients with rheumatoid arthritis (RA). We analysed trends in total knee replacement (TKR) in RA using TKR in osteoarthritis (OA) as a point of reference. METHODS: Data on TKRs from the Finnish Arthroplasty Register and population data from Statistics Finland were used to analyse the trends in TKRs among patients aged >= 40 years with primary osteoarthritis (OA) or RA in Finland for the period from 1980 to 2010. RESULTS: During 1980-2010, the overall incidence of TKRs increased 20-fold from 14.2 to 305.3 operations per 10(5) person-years. After peaking in 1992, the annual incidence of TKRs for RA decreased gradually from 19.6 to 10.8 per 10(5) [incidence rate ratio (IRR) 0.97, p < 0.001]. The decrease was more pronounced in women and the older (>= 60 years) age group. The mean age at the time of TKR among patients with RA increased over time, converging with that of patients with OA. CONCLUSION: There is a clear decrease in the annual incidence of TKRs in RA, while among OA patients the incidence is increasing steadily. Furthermore, patients with RA seem to receive their TKRs at an older age. Both of these findings suggest improving long-term outcome in RA. PMID- 22827496 TI - Observation of charge transport in single titanium dioxide nanotubes by micro photoluminescence imaging and spectroscopy. AB - We present the first report of photoluminescence spectra and images of single TiO(2) (anatase) nanotubes. In previous work using ensembles of conventional TiO(2) nanoparticles, we interpreted the broad photoluminescence (PL) spectrum to be a superposition of hole trap emission, peaking in the green, and broad red PL arising from electron traps. PL spectra of individual nanotubes in inert environment show a similar broad emission, with peaks at around 560-610 nm. The PL from single nanotubes differs from the more blue-shifted PL of ordered nanotube films. The intensity of PL is found to be larger for single nanotubes than for ordered arrays, as a result of competition from transport in the contiguous samples and from introduction of additional trap states when the nanotubes are dispersed. PL images of single nanotubes show the emission to be concentrated in the area of excitation, but the peaks in the red and green components of the PL are not spatially coincident. Remote PL, occurring away from the excitation point, is observed in the green (~510 nm), showing the possible contribution of charge transport to the observed PL. While the PL from ensembles of TiO(2) nanotubes is fairly insensitive to contacting media, exposure of single nanotubes to air and ethanol changes the shape and intensity of the PL spectrum. Our results point to a very different trap state distribution in TiO(2) nanotubes compared to that of conventional TiO(2) nanoparticles, which we attribute to differences in exposed crystal facets. In addition, separation of nanotubes introduces additional photoluminescent trap states and changes the character of the emission from excitonic in the array to trap-mediated in single nanotubes. PMID- 22827497 TI - Evaluation of the CEL-100 videolaryngoscope(TM) for double-lumen tracheal tube insertion after failure using the Macintosh laryngoscope. AB - We prospectively evaluated the CEL-100 videolaryngoscope(TM) for insertion of double-lumen tracheal tubes in 48 consecutive patients who had been found to have an unanticipated Cormack and Lehane grade 3 (n=43) and grade 4 (n=5) laryngeal view and in whom two attempts at tracheal intubation using the Macintosh laryngoscope had failed. When the CEL-100 was subsequently employed, the glottic view improved in 45 (94%) patients. The view improved by one grade in 15 (31%) patients and by two grades in 30 (63%) patients, compared with the Macintosh blade (p<0.001). Double-lumen tracheal tube insertion was successful when using the CEL-100 in 43 out of 48 patients (90%; 95% CI 81-98%). This occurred on the first attempt in 27 (56%) patients, 14 (29%) on the second and two (4%) on the third. We conclude that the CEL-100 videolaryngoscope is an effective device in this context, and we therefore propose that this device can be used in circumstances when double-lumen tube insertion proves difficult. PMID- 22827499 TI - DGT-induced copper flux predicts bioaccumulation and toxicity to bivalves in sediments with varying properties. AB - Many regulatory frameworks for sediment quality assessment include consideration of contaminant bioavailability. However, the "snap-shots" of metal bioavailability provided by analyses of porewaters or acid-volatile sulfide simultaneously extractable metal (AVS-SEM) relationships do not always contribute sufficient information. The use of inappropriate or inadequate information for assessing metal bioavailability in sediments may result in incorrect assessment decisions. The technique of diffusive gradients in thin films (DGT) enables the in situ measurement of metal concentrations in waters and fluxes from sediment porewaters. We utilized the DGT technique to interpret the bioavailability of copper to the benthic bivalve Tellina deltoidalis in sediments of varying properties contaminated with copper-based antifouling paint particles. For a concentration series of copper-paint contaminated sandy, silty-sand, and silty sediment types, DGT-probes were used to measure copper fluxes to the overlying water, at the sediment-water interface, and in deeper sediments. The overlying water copper concentrations and DGT-Cu fluxes were shown to provide excellent exposure concentration-response relationships in relation to lethal effects occurring to the copper-sensitive benthic bivalve, T. deltoidalis. The study demonstrates the strength of the DGT technique, which we expect will become frequently used for assessing metal bioavailability in sediments. PMID- 22827500 TI - Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic. AB - Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone. Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches with varying biological activity, especially when scaleup synthesis was attempted. Since the MTX is conjugated through an ester linkage, there were concerns that biological inconsistency could also result from serum esterase activity and differential bioavailability of the targeted conjugate. In order to resolve these problems, we undertook a novel approach to synthesize a polyvalent G5-MTX(n) conjugate through click chemistry, attaching the MTX to the dendrimer through an esterase-stable amide linkage. Surface plasmon resonance binding studies show that a G5-MTX(10) conjugate synthesized in this manner binds to the FA receptor (FR) through polyvalent interaction showing 4300-fold higher affinity than free MTX. The conjugate inhibits dihydrofolate reductase, and induces cytotoxicity in FR-expressing KB cells through FR-specific cellular internalization. Thus, the polyvalent MTX on the dendrimer serves the dual role as a targeting molecule as well as a chemotherapeutic drug. The newly synthesized G5-MTX(n) conjugate may serve as a FR-targeted chemotherapeutic with potential for cancer therapy. PMID- 22827501 TI - Duodenal endoscopic findings and histopathologic confirmation of intestinal lymphangiectasia in dogs. AB - BACKGROUND: The diagnosis of intestinal lymphangiectasia (IL) has been associated with characteristic duodenal mucosal changes. However, the sensitivity and specificity of the endoscopic duodenal mucosal appearance for the diagnosis of IL are not reported. HYPOTHESIS/OBJECTIVES: To evaluate the utility of endoscopic images of the duodenum for diagnosis of IL. Endoscopic appearance of the duodenal mucosal might predict histopathologic diagnosis of IL with a high degree of sensitivity and specificity. ANIMALS: 51 dogs that underwent upper gastrointestinal (GI) endoscopy and endoscopic biopsies. METHODS: Retrospective review of images acquired during endoscopy. Dogs were included if adequate biopsies were obtained during upper GI endoscopy and digital images were saved during the procedure. Images were assessed for the presence and severity of IL. Using histopathology as the gold standard, the sensitivity and specificity of endoscopy for diagnosing IL were calculated. RESULTS: Intestinal lymphangiectasia (IL) was diagnosed in 25/51 dogs. Gross endoscopic appearance of the duodenal mucosa had a sensitivity and specificity (95% confidence interval) of 68% (46%, 84%) and 42% (24%, 63%), respectively for diagnosis of IL. Endoscopic images in cases with lymphopenia, hypocholesterolemia, and hypoalbuminemia had a sensitivity of 80%. CONCLUSIONS AND CLINICAL IMPORTANCE: Endoscopic duodenal mucosa appearance alone lacks specificity and has only a moderate sensitivity for diagnosis of IL. Evaluation of biomarkers associated with PLE improved the sensitivity; however, poor specificity for diagnosis of IL supports the need for histopathologic confirmation. PMID- 22827502 TI - Posttreatment low-risk drinking as a predictor of future drinking and problem outcomes among individuals with alcohol use disorders. AB - BACKGROUND: Treatment for alcohol disorders has traditionally been abstinence oriented, but evaluating the merits of a low-risk drinking outcome as part of a primary treatment endpoint is a timely issue given new pertinent regulatory guidelines. This study explores a posttreatment low-risk drinking outcome as a predictor of future drinking and problem severity outcomes among individuals with alcohol use disorders in a large private, not for profit, integrated care health plan. METHODS: Study participants include adults with alcohol use disorders at 6 months (N = 995) from 2 large randomized studies. Logistic regression models were used to explore the relationship between past 30-day drinker status at 6 months posttreatment (abstinent [66%], low-risk drinking [14%] defined as nonabstinence and no days of 5+ drinking, and heavy drinking [20%] defined as 1 or more days of 5+ drinking) and 12-month outcomes, including drinking status and Addiction Severity Index measures of medical, psychiatric, family/social, and employment severity, controlling for baseline covariates. RESULTS: Compared to heavy drinkers, abstinent individuals and low-risk drinkers at 6 months were more likely to be abstinent or low-risk drinkers at 12 months (adj. ORs = 16.7 and 3.4, respectively; p < 0.0001); though, the benefit of abstinence was much greater than that of low-risk drinking. Compared to heavy drinkers, abstinent and low-risk drinkers were similarly associated with lower 12-month psychiatric severity (adj. ORs = 1.8 and 2.2, respectively, p < 0.01) and family/social problem severity (adj. OR = 2.2; p < 0.01). While abstinent individuals had lower 12-month employment severity than heavy drinkers (adj. OR = 1.9; p < 0.01), low risk drinkers did not differ from heavy drinkers. The drinking groups did not differ on 12-month medical problem severity. CONCLUSIONS: Compared to heavy drinkers, low-risk drinkers did as well as abstinent individuals for many of the outcomes important to health and addiction policy. Thus, an endpoint that allows low-risk drinking may be tenable for individuals undergoing alcohol specialty treatment. PMID- 22827503 TI - Syntheses of (-)-cryptocaryolone and (-)-cryptocaryolone diacetate via a diastereoselective oxy-Michael addition and oxocarbenium allylation. AB - The total syntheses of both (-)-cryptocaryolone and (-)-cryptocaryolone diacetate is presented herein. The usage of a diastereoselective oxy-Michael addition/benzylidene acetal formation coupled with a selective axial oxocarbenium allylation allowed for the preparation of the alpha-C-glycoside moiety present in the bicyclic bridged structure. In addition, the syn-1,3-diol of the linear portion was installed via a Wacker oxidation followed by a subsequent directed reduction of the appropriate homoallylic alcohol precursor. PMID- 22827504 TI - Genetic analysis of NR4A2 gene in a large population of Han Chinese patients with Parkinson's disease. AB - BACKGROUND: NR4A2 gene is a transcription factor crucial for differentiation and survival of midbrain dopamine (DA) neurons, and several variants have been eported to be associated with Parkinson's disease (PD) in the Caucasian population. METHODS: To determine whether there is any association of NR4A2 mutation or variation with PD in the Han Chinese population, we performed a genetic analysis of all the exons and exon-intron boundaries in 689 PD patients and 672 controls from mainland China using direct sequencing analysis. RESULTS: We identified four novel variants and two previously reported variants. Two novel variants (exon 2 c.-20 C>G and exon 3 c.711 C>A) were only found in PD. The others (exon 2 c.-35 A>G; exon 8 c.1615 G>A; intron 4 IVS4-16 G>T; and intron 6 IVS6 + 18 insG) were found in both PD and controls at different frequencies. CONCLUSIONS: Collectively, our results suggest that NR4A2 may be a susceptibility gene for PD in the Chinese population. PMID- 22827505 TI - Depressive symptoms and use of perspective taking within a communicative context. AB - OBJECTIVE: The ability to take the perspective of one's conversational partner is essential for successful communication. We assessed whether individuals who report high levels of depressive symptoms have more difficulty with navigating this interpersonal task. METHOD: Undergraduate students participated in a computerised communication task that, on some trials, required perspective taking (N=125). RESULTS: When participants were grouped according to their self-reported depressive symptoms, the "dysphoric group" (BDI >= 16, n=37) showed more errors than a "non-dysphoric group" (BDI <= 10, n=56) on trials requiring participants to use the perspective of the speaker, but not on control trials where perspective taking was not required. The dysphoric group demonstrated slower response times overall. CONCLUSIONS: Individuals with moderate to high levels of depressive symptoms are more challenged by using a speaker's perspective to interpret statements. PMID- 22827506 TI - Evaluation of North American isolates of Soybean mosaic virus for gain of virulence on Rsv-genotype soybeans with special emphasis on resistance-breaking determinants on Rsv4. AB - Resistance to Soybean mosaic virus (SMV) in soybean is conferred by three dominant genes: Rsv1, Rsv3 and Rsv4. Over the years, scientists in the USA have utilized a set of standard pathotypes, SMV-G1 to SMV-G7, to study interaction with Rsv-genotype soybeans. However, these pathotypes were isolated from a collection of imported soybean germplasm over 30 years ago. In this study, 35 SMV field isolates collected in recent years from 11 states were evaluated for gain of virulence on soybean genotypes containing individual Rsv genes. All isolates were avirulent on L78-379 (Rsv1), whereas 19 were virulent on L29 (Rsv3). On PI88788 (Rsv4), 14 of 15 isolates tested were virulent; however, only one was capable of systemically infecting all of the inoculated V94-5152 (Rsv4). Nevertheless, virulent variants from 11 other field isolates were rapidly selected on initial inoculation onto V94-5152 (Rsv4). The P3 cistrons of the original isolates and their variants on Rsv4-genotype soybeans were sequenced. Analysis showed that virulence on PI88788 (Rsv4) was not associated, in general, with selection of any new amino acid, whereas Q1033K and G1054R substitutions were consistently selected on V94-5152 (Rsv4). The role of Q1033K and G1054R substitutions, individually or in combination, in virulence on V94-5152 (Rsv4) was confirmed on reconstruction in the P3 cistron of avirulent SMV-N, followed by biolistic inoculation. Collectively, our data demonstrate that SMV has evolved virulence towards Rsv3 and Rsv4, but not Rsv1, in the USA. Furthermore, they confirm that SMV virulence determinants on V94-5152 (Rsv4) reside on P3. PMID- 22827507 TI - Ramadan fasting in diabetes patients on insulin pump therapy augmented by continuous glucose monitoring: an observational real-life study. AB - BACKGROUND AND AIMS: Hypoglycemia during the daytime of Ramadan fasting is the most feared complication of diabetes. Insulin pump therapy has been proposed as the ideal "theoretical" method for insulin delivery. We report a prospective observational, single-center study of insulin-treated patients using insulin pump therapy during Ramadan 2011. PATIENTS AND METHODS: Twenty-one patients (10 males and 11 females) were selected; median age was 26 years. They adjusted their insulin as per their usual practices. Outcome measures obtained before and during Ramadan included body weight, glycosylated hemoglobin, blood glucose, total insulin dose differences, overriding tendency, suspension time during fasting, and number of hypoglycemic episodes. RESULTS: The patients fasted for a median of 29 days. The observed changes during Ramadan were overall not significant quantitatively, but some trends were noted. The total insulin administered during Ramadan was not different from that in the pre-Ramadan period, but there was a redistribution of insulin over a 24-h period in relation to the changes in the daily lifestyle and eating patterns. Basal insulin was decreased during the daytime by 5-20% from before Ramadan and increased during the nighttime. The mean change in the overall amount of basal insulin was not significant. A larger than usual amount of insulin bolus was given at the meals Iftar, Fowala, and Suhur; the change in the total amount of bolus insulin as a percentage change from total insulin was also not significant. No major hypoglycemic episodes were reported. Minor hypoglcemic episodes were equally distributed between daytime and nighttime and were managed by either basal insulin adjustment or suspension from the pump. CONCLUSIONS: This study confirms the advantages provided by insulin pump use in patients with diabetes were enhanced by the use of continuous glucose monitoring. We provided more evidence-based advice on how best to adjust the insulin pump during fasting. PMID- 22827508 TI - Mobile telemonitoring for arrhythmias in outpatients in the Republic of Georgia: a brief report of a pilot study. AB - As the very first trial of mobile telemedicine in the Republic of Georgia, in June-December 2010 we investigated 35 outpatients with different types of arrhythmia (male/female ratio=16/19; 12-80 years old), among them 5 patients with concomitant epilepsy. The control group comprised 7 clinically healthy sportsmen (soccer players, all men; 15-17 years old), during a 30-min velo ergometer stress test. A three-lead electrocardiogram (ECG) loop recorder (Vitaphone BT 3300; Vitasystems GmbH, Mannheim, Germany) was used in automatic mode, using special LRMA software (MDT, Lazne Bohdanec, Czech Republic) and a Nokia (Espoo, Finland) model 6730 Symbian phone. Automatically recorded arrhythmia events were transmitted from the loop recorder by Bluetooth((r)) (Bluetooth SIG, Inc., Kirkland, WA) to a phone and then by 3G (through our partner mobile operator, MagtiCom Ltd. [Tbilsi, Georgia]) to the Vitasystems server in Germany and were available to Georgian physicians via e-mail/Internet. Arrhythmias were recorded/monitored during 7-68 h of observation. The number of automatically recorded ECG events varied between 3 and 170 per observation, or 0.4-10.7 hourly. Cases of sinus brady- and tachyarrhythmia, sinus node weakness syndrome, atrial fibrillation, supraventricular tachycardia, supraventricular premature complexes, and ventricular premature complexes were correctly recognized by automatic recognition software and recorded. In 3 patients and 1 sportsman previously unspecified (despite multiple investigations), arrhythmias were recorded: paroxysmal tachycardia (n=1), sinus node weakness syndrome (n=1), and ventricular premature complexes (n=2). In 3 cases (all women) light insomnia and nervousness were reported. In 2 patients with neurosis (both elderly men, 1 with epilepsy) we had to stop investigation prematurely because of anxiety/agitation. Mobile telecardiology represents feasible methodology to monitor arrhythmias in outpatients in Georgia, promoting earlier discharge of non-life-threatening cases, improving patients' comfort of life, and increasing their mobility with enhanced safety. Mobile telehealth might also represent significant cost-saving for insurance companies (this is an ongoing study). Finally, in remote areas mobile telemonitoring of patients will improve quality of care by timely provision of a second opinion in cases when local expertise is not sufficient. PMID- 22827509 TI - Acute behavioral effects of nicotine in male and female HINT1 knockout mice. AB - Human genetic association and brain expression studies, and mouse behavioral and molecular studies implicate a role for the histidine triad nucleotide-binding protein 1 (HINT1) in schizophrenia, bipolar disorder, depression and anxiety. The high comorbidity between smoking and psychiatric disorders, schizophrenia in particular, is well established. Associations with schizophrenia and HINT1 are also sex specific, with effects more predominant in males; however, it is unknown if sex differences associated with the gene extend to other phenotypes. Thus, in this study, using a battery of behavioral tests, we elucidated the role of HINT1 in acute nicotine-mediated behaviors using male and female HINT1 wild-type (+/+) and knockout (-/-) mice. The results show that male HINT1 -/- mice were less sensitive to acute nicotine-induced antinociception in the tail-flick, but not hot-plate test. At low nicotine doses, male and female HINT1 -/- mice were less sensitive to nicotine-induced hypomotility, although the effect was more pronounced in females. Baseline differences in locomotor activity observed in male HINT1 +/+ and -/- mice were absent in females. Nicotine did not produce an anxiolytic effect in male HINT1 -/- mice, but rather an anxiogenic response. Diazepam also failed to induce an anxiolytic response in these mice, suggesting a general anxiety phenotype not specific to nicotine. Differences in anxiety-like behavior were not observed in female mice. These results further support a role for HINT1 in nicotine-mediated behaviors and suggest that alterations in the gene may have differential effects on phenotype in males and females. PMID- 22827511 TI - Discussion of "overweight and obese boys reduce food intake in response to a glucose drink but fail to increase intake in response to exercise of short duration". PMID- 22827512 TI - Postexercise cooling interventions and the effects on exercise-induced heat stress in a temperate environment. AB - The aim of this study was to examine the effects of cool water immersion (20 degrees C; CWI) while wearing a cooling jacket (Cryovest;V) and a passive control (PAS) as recovery methods on physiological and thermoregulatory responses between 2 exercise bouts in temperate conditions. Nine well-trained male cyclists performed 2 successive bouts of 45 min of endurance cycling exercise in a temperate environment (20 degrees C) separated by 25 min of the respective recovery interventions. Capillary blood samples were obtained to measure lactate (La-), sodium (Na+), bicarbonate (HCO3-) concentrations and pH, whilst body mass loss (BML), core temperature (T(core)), skin temperature (T(skin)), heart rate (HR), oxygen uptake , and minute ventilation were measured before (Pre), immediately after the first exercise bout (Ex1), the recovery (R), and after the second exercise bout (Ex2). V and CWI both resulted in a reduction of T(skin) at R (-2.1 +/- 0.01 degrees C and -11.6 +/- 0.01 degrees C, respectively, p < 0.01). Despite no difference in final values post-Ex2 (p > 0.05), V attenuated the rise in HR, minute ventilation, and oxygen uptake from Ex1 to Ex2, while T(core) and T(skin) were significantly lower following the second session (p < 0.05). Further, CWI was also beneficial in lowering T(core), T(skin), and BML, while a rise in Na+ was observed following Ex2 (p < 0.05). Overall results indicate that cooling interventions (V and CWI) following exercise in a temperate environment provide a reduction in thermal strain during ensuing exercise bouts. PMID- 22827513 TI - The radical cationic repair pathway of cyclobutane pyrimidine dimer: the effect of sugar-phosphate backbone. AB - Radical cationic repair process of cis-syn thymine dimer has been investigated when (1) sugar-phosphate backbones were substituted by hydrogen atoms, (2) phosphate group was substituted by two hydrogen atoms each on a sugar ring and (3) sugar-phosphate backbone was taken into account. The effect of the interactions between N1 and N1' lone pairs and the C6-C6' antibonding orbital are the most important evidences for the cleavage of the C6-C6' bond in the first step of radical cationic repair mechanism in the absence of the sugar-phosphate backbone. The impact of the N1 and N1' lone pairs on the C6-C6' bond cleavage decreases and the energy barrier of the cleavage of that bond significantly increases in the presence of the deoxynucleoside sugars and the sugar-phosphate backbone. PMID- 22827514 TI - Structural and electrical characterization of Bi2Se3 nanostructures grown by metal-organic chemical vapor deposition. AB - We characterize nanostructures of Bi(2)Se(3) that are grown via metal-organic chemical vapor deposition using the precursors diethyl selenium and trimethyl bismuth. By adjusting growth parameters, we obtain either single-crystalline ribbons up to 10 MUm long or thin micrometer-sized platelets. Four-terminal resistance measurements yield a sample resistivity of 4 mOmega.cm. We observe weak antilocalization and extract a phase coherence length l(phi) = 178 nm and spin-orbit length l(so) = 93 nm at T = 0.29 K. Our results are consistent with previous measurements on exfoliated samples and samples grown via physical vapor deposition. PMID- 22827515 TI - Adaptive acid tolerance response of Vibrio parahaemolyticus as affected by acid adaptation conditions, growth phase, and bacterial strains. AB - Vibrio parahaemolyticus strain 690 was isolated from gastroenteritis patients. Its thermal and ethanol stress responses have been reported in our previous studies. In this study, we further investigated the effects of various acid adaptation conditions including pH (5.0-6.0) and time (30-90 min) on the acid tolerance in different growth phases of V. parahaemolyticus 690. Additionally, the adaptive acid tolerance among different V. parahaemolyticus strains was compared. Results indicated that the acid tolerance of V. parahaemolyticus 690 was significantly increased after acid adaptation at pH 5.5 and 6.0 for 30-90 min. Among the various acid adaptation conditions examined, V. parahaemolyticus 690 acid-adapted at pH 5.5 for 90 min exhibited the highest acid tolerance. The acid adaptation also influenced the acid tolerance of V. parahaemolyticus 690 in different growth phases with late-exponential phase demonstrating the greatest acid tolerance response (ATR) than other phases. Additionally, the results also showed that the induction of adaptive ATR varied with different strains of V. parahaemolyticus. An increase in acid tolerance of V. parahaemolyticus was observed after prior acid adaptation in five strains (556, 690, BCRC 13023, BCRC 13025, and BCRC 12864), but not in strains 405 and BCRC 12863. PMID- 22827516 TI - Discovery of a potential anti-ischemic stroke agent: 3-pentylbenzo[c]thiophen 1(3H)-one. AB - The development of novel antithrombotic agents with strong free radical scavenging activity is of great significance for the treatment of ischemic stroke. In the present study, 3-alkyl/arylalkyl-substituted benzo[c]thiophen 1(3H)-ones (5a-h) were designed and synthesized. The most active compound 5d significantly inhibited the adenosine diphosphate (ADP) induced and arachidonic acid (AA) induced in vitro platelet aggregation, superior to clinically used antiplatelet drug aspirin (ASP) and anti-ischemic stroke drugs 3-n-butylphthalide (NBP) and edaravone (Eda). More importantly, in comparison with both NBP and Eda, 5d exhibited stronger antithrombotic and free radical scavenging activities and better or comparable neuroprotective effects against ischemia/reperfusion (I/R) in rats by ameliorating neurobehavioral function, reducing infarct size and brain water content, attenuating cerebral damage, and normalizing the levels of oxidative enzymes. Overall, our findings may provide an alternative strategy for the design of novel anti-ischemic stroke agents more potent than drugs like NBP and Eda. PMID- 22827517 TI - Editorial: chemical biology Down Under. PMID- 22827518 TI - Microbial biodiscovery: back to the future. AB - Microbial metabolites are remarkable versatile as potent and selective drug lead candidates, and as in situ molecular probes, capable of interrogating key signalling, transport and developmental pathways. Microbial biodiscovery as a drug discovery paradigm has served science and society extremely well, and with appropriate modernisation and reinvestment is well placed to continue to do so into the future. Advances across many disciplines have revealed an untapped silent microbial secondary metabolism, which promises access to unprecedented bioactive chemical space. This renewed capacity can be further enhanced by recognition of the critical importance of widening the search parameters from narrow single bioassay/indication directed programs, to target both active and (seemingly) inactive metabolites, as well as new and known compounds, and a diversity of non-enzymatic chemical transformation products (all too often dismissed as artefacts). Many of the technical and commercial challenges that confronted microbial biodiscovery late last century have been resolved. The need is great and the time is right to re-plumb microbial biodiscovery back into the drug discovery pipeline. PMID- 22827519 TI - Towards isozyme-selective HDAC inhibitors for interrogating disease. AB - Histone deacetylase (HDAC) enzymes have emerged as promising targets for the treatment of a wide range of human diseases, including cancers, inflammatory and metabolic disorders, immunological, cardiovascular, and infectious diseases. At present, such applications are limited by the lack of selective inhibitors available for each of the eighteen HDAC enzymes, with most currently available HDAC inhibitors having broad-spectrum activity against multiple HDAC enzymes. Such broad-spectrum activity maybe useful in treating some diseases like cancers, but can be detrimental due to cytotoxic side effects that accompany prolonged treatment of chronic diseased states. Here we summarize progress towards the design and discovery of HDAC inhibitors that are selective for some of the eleven zinc-containing classical HDAC enzymes, and identify opportunities to use such isozyme-selective inhibitors as chemical probes for interrogating the biological roles of individual HDAC enzymes in diseases. PMID- 22827520 TI - Drug-likeness and increased hydrophobicity of commercially available compound libraries for drug screening. AB - Most drug discovery programs today originate by selection of 'hit' molecules resulting from assays against large compound screening libraries. The chemical space in which these hits reside has implications for its biological activity in vivo and likelihood of progression to a drug candidate. We have created a database of commercially available screening compounds and natural products in order to analyse the drug- and lead-likeness of commercial screening compounds and compare them with i) orally administered drugs, ii) non-orally administered drugs, and iii) compounds with significant biological activity but unspecified or not yet determined route of administration from the public databases DrugBank and ChEMBL. The data set contained 15.5 million entries from 102 vendors, which resulted in just over 8 million unique chemical structures. We review these data for current drug/lead-likeness, then utilise substructure-based filters for promiscuity and unwanted groups, and finally compare chemical properties for structures within the different sub-sets. While the majority of the commercial compounds satisfy various drug-likeness rules, they show a larger molecular weight and higher hydrophobicity compared to orally available drugs, with generally higher aromaticity and lower solubility. This 'right shift' of chemical properties has also been found in the majority of the compounds with significant biological activity in ChEMBL, reflecting a common trend in current drug discovery, towards larger, more hydrophobic compounds and fewer drug-like compounds. In particular, successful drugs were found to possess much lower median logD values than those found for compound collections. In addition, commercial compounds show a quite narrow distribution in molecular weight, with a median absolute deviation of only 78 Da around a median of 387 Da. For high throughput screening a highly stringent combination of several lead-likeness and substructure filters against unwanted groups could be applied, resulting in 2 million lead-like structures. For fragment based screening approaches the rule of three (Ro3) would select around 400,000 structures. PMID- 22827521 TI - Cysteine-rich mini-proteins in human biology. AB - Understanding the relationship between structure and function underpins both biochemistry and chemical biology, and has enabled the discovery of numerous agricultural and therapeutic agents. Small cysteine-rich proteins, which form a unique set of protein frameworks and folds, are found in all living organisms and often play crucial roles as hormones, growth factors, ion channel modulators and enzyme inhibitors in various biological pathways. Here we review secreted human cysteine-rich mini-proteins, classify them into broad families and briefly describe their structure and function. To systematically investigate this protein sub-class we designed a step-wise high throughput algorithm that is able to isolate the mature and active forms of human secreted cysteine-rich proteins (up to 200 amino acids in length) and extract their cysteine scaffolds. We limited our search to frameworks that contain an even number of cysteine residues (< 20), all of which are engaged in intra-molecular disulfide bonds. We found 53 different cysteine-rich frameworks spread over 378 secreted cysteine-rich mini proteins. Restricting our search to those that contain >5% cysteine residues led to the identification of 22 cysteine-rich frameworks representing 21 protein families. Analysis of their molecular targets showed that these mini-proteins are frequently ligands for G protein- and enzyme-coupled receptors, transporters, extracellular enzyme inhibitors, and antimicrobial peptides. It is clear that these human secreted mini-proteins possess a wide diversity of frameworks and folds, some of which are conserved across the phylogenetic spectrum. Further study of these proteins will undoubtedly lead to insights into unresolved questions of basic biology, and the development of system-specific human therapeutics. PMID- 22827522 TI - Discovery and applications of disulfide-rich cyclic peptides. AB - Cyclic peptides typically have much higher stability and improved biopharmaceutical properties over their linear counterparts. Our work focuses on the discovery of naturally occurring disulfide-rich cyclic peptides and their applications in drug design. These peptides provide a design basis for re engineering natural acyclic peptides to improve their biopharmaceutical properties by chemically linking their termini. Here we describe examples of the discovery of the cyclotide family of peptides, their chemical re-engineering to introduce desired pharmaceutical activities, studies of their biopharmaceutical properties and applications of cyclization technologies to naturally occurring toxins, including conotoxins and scorpion toxins. In the case of the conotoxin Vc1.1, we produced an orally active peptide with potential for the treatment of neuropathic pain by cyclising the native peptide. In the case of the scorpion toxin chlorotoxin, a cyclised derivative had improved biopharmaceutical properties as a tumour imaging agent over the naturally occurring linear chlorotoxin. Ongoing chemical and structural studies of these classes of disulfide-rich peptides promise to increase their value for use in dissecting biological processes in plants and mammals while also providing leads to new classes of biopharmaceuticals. PMID- 22827523 TI - Therapeutic potential of cone snail venom peptides (conopeptides). AB - Cone snails have evolved many 1000s of small, structurally stable venom peptides (conopeptides) for prey capture and defense. Whilst < 0.1% have been pharmacologically characterised, those with known function typically target membrane proteins of therapeutic importance, including ion channels, transporters and GPCRs. Several conopeptides reduce pain in animals models, with one in clinical development (chi-conopeptide analogue Xen2174) and one marketed (omega- conotoxin MVIIA or Prialt) for the treatment of severe pain. In addition to their therapeutic potential, conopeptides have been valuable probes for studying the role of a number of key membrane proteins in normal and disease physiology. PMID- 22827524 TI - Computational modelling of linear motif-mediated protein interactions. AB - Chemical information can be used to inform biology through being employed to develop bioinformatic tools. One area where bioinformatic tools are valuable is the study of linear motif-mediated protein interactions. Linear motifs are short sequences found mostly in disordered regions of proteins that function in cellular signaling and regulation, by binding to protein interaction domains or by being the target of post-translational modifications. Linear motifs pose difficulty not only to experimental study, but also computational methods; they are difficult to identify due to their small size; and their binding specificity is affected by several factors acting in concert. We discuss the different ways linear motifs can be represented computationally, and how computational approaches can integrate the different specificity-determining factors. We illustrate these issues on our own work focusing on the use of three-dimensional structural information in predicting protein phosphorylation sites, and the integration of diverse types of data in predicting nuclear localization. Computational approaches will play an increasing role in the future, allowing new relationships and system-wide understanding to be unearthed from the large datasets becoming available through high-throughput studies. PMID- 22827525 TI - Lipoamino acids as major components of absorption promoters in drug delivery. AB - Many biologically active compounds are unsuitable for development as drugs due to their poor bioavailability. For hydrophilic compounds, modifications to increase lipophilicity can increase passive diffusion or increase uptake into the lymphatic system. Alternatively, improved bioavailability of hydrophilic drug candidates may be achieved by formulation with absorption promoters such as surfactants, penetration enhancers, or ion pairing agents. This approach to enhancing bioavailability also has the potential to widen the range of compound categories that can be used as chemical probes to study biological systems in cells and in vivo where membrane permeability would otherwise be a significant limitation. Lipidic amino acids, which combine the structural properties of lipids with those of alpha-amino acids, represent a relatively unexplored class of agents that can improve drug adsorption. This review discusses the potential of absorption promoters possessing lipoamino acids for improving drug bioavailability. PMID- 22827526 TI - Advances in peptide-based human papillomavirus therapeutic vaccines. AB - Cervical cancer is the second leading cause of cancer in women worldwide. Human papillomavirus (HPV) is responsible for all cases of cervical cancer. Commercial prophylactic HPV vaccines are now available, but unfortunately these vaccines have no therapeutic effect against established HPV infections. In order to accelerate the control of cervical cancer and treat established HPV infections, it is necessary to develop therapeutic vaccines to eradicate HPV by generating cell-mediated immunity against HPV infected cells. Two HPV-encoded early proteins, the E6 and E7 oncoproteins, are the preferred targets because they are consistently expressed in virtually all cervical cancer cells and are necessary for the induction and maintenance of HPV-associated disease. A variety of vaccine strategies have been employed targeting immune responses to these proteins. Peptide-based vaccines are a promising strategy for the development of therapeutic HPV vaccines because of their safety, stability, and ease of production. This review summarizes the prospects of peptide-based vaccines for the treatment of established HPV infections. We address the challenges that scientists currently face for developing peptide-based vaccines and explore feasible strategies for improving the potency of the induced immune response with the aim of treating established HPV infections. PMID- 22827527 TI - Selective up-regulation of JunD transcript and protein expression in vasopressinergic supraoptic nucleus neurones in water-deprived rats. AB - The magnocellular neurones (MCN) of the supraoptic nucleus (SON) undergo reversible changes during dehydration. We hypothesise that alterations in steady state transcript levels might be partially responsible for this plasticity. In turn, regulation of transcript abundance might be mediated by transcription factors. We have previously used microarrays to identify changes in the expression of mRNAs encoding transcription factors in response to water deprivation. We observed down-regulation of 11 and up-regulation of 31 transcription factor transcripts, including members of the activator protein-1 gene family, namely c-fos, c-jun, fosl1 and junD. Because JunD expression and regulation within the SON has not been previously described, we have used in situ hybridisation and the quantitative reverse transcriptase-polymerase chain reaction to confirm the array results, demonstrating a significant increase in JunD mRNA levels following 24 and 72 h of water deprivation. Western blot and immunohistochemistry revealed a significant increase in JunD protein expression following dehydration. Double-staining fluorescence immunohistochemistry with a neurone-specific marker (NeuN) demonstrated that JunD staining is predominantly neuronal. Additionally, JunD immunoreactivity is observed primarily in vasopressin-containing neurones with markedly less staining seen in oxytocin containing MCNs. Furthermore, JunD is highly co-expressed with c-Fos in MCNs of the SON following dehydration. These results suggest that JunD plays a role in the regulation of gene expression within MCNs of the SON in association with other Fos and Jun family members. PMID- 22827529 TI - Ozone gas effectively kills laboratory strains of Trichophyton rubrum and Trichophyton mentagrophytes using an in vitro test system. AB - BACKGROUND: Ozone gas possesses antimicrobial potential against many microorganisms, however limited data exist on its effect on the keratinophilic dermatophyte fungi Trichophyton rubrum and Trichophyton mentagrophytes; two organisms commonly isolated as the etiological agent in onychomycosis and tinea pedis patients. OBJECTIVE/METHODS: We utilized a commercial ozone gas generation device for testing the fungicidal effects of ozone on ATCC strains of Trichophyton rubrum and Trichophyton mentagrophytes. RESULTS: We demonstrated that ozone gas is effective in killing > 99% of viable fungi present in various experimental systems. CONCLUSION: This work represents a proof of principle regarding ozone gas and its fungicidal effect on dermatophyte fungi. From these findings, further ozone gas studies will be conducted to develop a novel adjunct therapy for use in parallel with current antifungal medications and/or devices to better treat onychomycosis and tinea pedis patients in the short and long term. PMID- 22827528 TI - Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice. AB - BACKGROUND: Graves'-like disease, reflected by thyrotropin receptor (TSHR) antibodies and hyperthyroidism in some mouse strains, can be induced by immunization with adenovirus-expressing DNA for the human TSHR or its A-subunit. The conventional approach involves two or three adenovirus injections at 3-week intervals and euthanasia 10 weeks after the first injection. To investigate TSHR antibody persistence in mice with differing degrees of self-tolerance to the TSHR A-subunit, we studied the effect of delaying euthanasia until 20 weeks after the initial immunization. METHODS: Wild-type (WT) mice and transgenic (tg) mice expressing low intrathyroidal levels of the human TSHR A-subunit were immunized with A-subunit-adenovirus on two occasions; a second group of mice was immunized on three occasions. Sera obtained 4, 10, and 20 weeks (euthanasia) after the initial immunization were tested for thyrotropin (TSH) binding inhibition (TBI), antibody binding to TSHR A-subunit protein-coated enzyme-linked immunosorbent assay (ELISA) plates, and thyroid stimulating antibody activity (TSAb; cyclic adenosine monophosphate [cAMP] generation). Serum thyroxine (T4) and thyroid histology were studied at euthanasia. RESULTS: THE majority of WT mice retained high TSHR antibody levels measured by TBI or ELISA at euthanasia but only about 50% were TSAb positive. Low-expressor tgs exhibited self-tolerance, with fewer mice positive by TBI or ELISA and antibody levels were lower than in WT littermates. In WT mice, antibody persistence was similar after two or three immunizations; for tgs, only mice immunized three times had detectable TSAb at 20 weeks. Unlike our previous observations of hyperthyroidism in WT mice examined 4 or 10 weeks after immunization, all mice were euthyroid at 20 weeks. CONCLUSIONS: Our findings for induced TSHR antibodies in mice, similar to data for human thyroid autoantibodies, indicate that the parameters that contribute to the concentration of the antibody and thereby play a critical role in long-term persistence of TSHR antibodies are the degree of self-tolerance to the TSHR and chronic stimulation. PMID- 22827530 TI - The prevalence and clinical characteristics of systemic lupus erythematosus with infectious brain lesions in China. AB - OBJECTIVE: Infectious brain lesions (IBLs) are life-threatening in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the prevalence of IBL in SLE patients and the clinical characteristics of SLE patients with IBL. METHODS: Medical charts of 15 consecutive SLE patients with IBL admitted to Peking Union Medical College Hospital (PUMCH) from January 1995 to October 2010 were reviewed systematically. A total of 150 cases were randomly selected as controls from 4115 SLE inpatients without IBL in PUMCH during the same period. RESULTS: The prevalence of IBL in SLE patients was 0.4%. Significant differences were observed between SLE patients with and without IBL in the following manifestations (p < 0.05): arthritis/musculoskeletal involvement (66.7% vs. 32.0%), C-reactive protein (CRP) elevation (84.6% vs. 28.0%), anti-dsDNA antibody positivity (13.3% vs. 42.9%), and elevated SLE Disease Activity Index (SLEDAI) score (> 5) (13.3% vs. 71.3%). Fever was the most common manifestation (80%), followed by headache and focal neurological signs (73.3%). Twelve patients presented with infections in other sites, including pulmonary infection (66.7%) and meningitis (40.0%). Enhanced cranial magnetic resonance imaging (MRI) revealed point-enhancing or ring-enhancing lesions in all patients evaluated (12/12, 100%). Mycobacterium tuberculosis was the most common pathogen (10 cases, 66.7%). After administration of antibiotics targeting the pathogens, 11 patients (73.3%) recovered. CONCLUSIONS: IBL is not common in SLE patients. In stable SLE patients with fever, focal neurological signs, and CRP elevation, IBL should be suspected. Enhanced cranial MRI and a thorough check-up should be performed in a timely manner. It is very important to identify the pathogens and initiate treatment as early as possible. PMID- 22827532 TI - Progenitor cell homing in the postischemic myocardium: just an unmotivated pitstop in the microcirculation? AB - OBJECTIVE: We developed a model for direct assessment of BMC sequestration in the postischemic murine myocardium after direct antegrade intracoronary injection. METHODS: Modified syngeneic heterotopic heart transplantation was used as a basic model for global myocardial I/R injury in a total of n = 29 animals. IVM was employed to analyze the right ventricular subepicardial coronary microcirculation and for tracking fluorescently labeled BMCs. RESULTS: IVM allowed monitoring all segments of the coronary microcirculation including feeding arterioles, nutritive capillaries, and postcapillary venules. WI and generalized atherosclerosis induced profound reperfusion failure, particularly in nutritive myocardial capillaries. BMCs were found to exclusively sequester in myocardial capillaries, but not in coronary arterioles or postcapillary venules. The sequestration of BMCs in coronary capillaries occurred independent of WI, generalized atherosclerosis, or adhesion molecule function. CONCLUSIONS: This is the first study allowing direct assessment of BMC homing to the postischemic myocardium. Heterotopic heart transplantation and IVM are proper means to study the myocardial sequestration of BMCs after direct antegrade intracoronary injection in vivo. We show for the first time that intracoronarily injected BMCs sequester exclusively in nutritive myocardial capillaries. PMID- 22827533 TI - Abiological self-assembly via coordination: formation of 2D metallacycles and 3D metallacages with well-defined shapes and sizes and their chemistry. PMID- 22827531 TI - Glycan-targeted virus-like nanoparticles for photodynamic therapy. AB - Virus-like particles (VLPs) have proven to be versatile platforms for chemical and genetic functionalization for a variety of purposes in biomedicine, catalysis, and materials science. We describe here the simultaneous modification of the bacteriophage Qbeta VLP with a metalloporphyrin derivative for photodynamic therapy and a glycan ligand for specific targeting of cells bearing the CD22 receptor. This application benefits from the presence of the targeting function and the delivery of a high local concentration of singlet oxygen generating payload. PMID- 22827534 TI - Antibacterial activities of liposomal linolenic acids against antibiotic resistant Helicobacter pylori. AB - Helicobacter pylori (H. pylori) infection with its vast prevalence is responsible for various gastric diseases including gastritis, peptic ulcers, and gastric malignancy. While effective, current treatment regimens are challenged by a fast declining eradication rate due to the increasing emergence of H. pylori strains resistant to existing antibiotics. Therefore, there is an urgent need to develop novel antibacterial strategies against H. pylori. In this study, we developed a liposomal nanoformulation of linolenic acid (LipoLLA) and evaluated its bactericidal activity against resistant strains of H. pylori. Using a laboratory strain of H. pylori, we found that LipoLLA was effective in killing both spiral and coccoid forms of the bacteria via disrupting bacterial membranes. Using a metronidazole-resistant strain of H. pylori and seven clinically isolated strains, we further demonstrated that LipoLLA eradicated all strains of the bacteria regardless of their antibiotic resistance status. Furthermore, under our experimental conditions, the bacteria did not develop drug resistance when cultured with LipoLLA at various sub-bactericidal concentrations, whereas they rapidly acquired resistance to both metronidazole and free linolenic acid (LLA). Our findings suggest that LipoLLA is a promising antibacterial nanotherapeutic to treat antibiotic-resistant H. pylori infection. PMID- 22827535 TI - Twenty-five years of bicycle helmet promotion for children in Skaraborg District, Sweden. AB - The purpose of this study is to describe some of the results of a long-term bicycle helmet campaign for children in Skaraborg District, Sweden. The hospital discharge data for bicycle-related injuries occurring in children under the age of 15 were reviewed, to assess changes in patterns for head and other body injuries. The study shows that head injuries to children as a result of bicycle injuries were reduced between 94 and 99% in the study areas. The tremendous gains in safety for children who ride bicycles in Skaraborg District were the result of not only national policy changes that occurred in the latter half of this study period but also the result of local collaborations based on the Safe Communities model, which were organised during the first part of the study period. PMID- 22827536 TI - Highly efficient enzyme-functionalized porous zirconia microtubes for bacteria filtration. AB - In contrast to polymer membranes, ceramic membranes offer considerable advantages for safe drinking water provision due to their excellent chemical, thermal, and mechanical endurance. In this study, porous ceramic microtubes made of yttria stabilized zirconia (YSZ) are presented, which are conditioned for bacteria filtration by immobilizing lysozyme as an antibacterial enzyme. In accordance with determined membrane pore sizes of the nonfunctionalized microtube of <=200 nm, log reduction values (LRV) of nearly 3 (i.e., bacterial retention of 99.9%) were obtained for bacterial retention studies using gram-positive model bacterium Micrococcus luteus. Immobilization studies of lysozyme on the membrane surface reveal an up to six times higher lysozyme loading for the covalent immobilization route as compared to unspecific immobilization. Antibacterial activity of lysozyme-functionalized microtubes was assessed by qualitative agar plate test using Micrococcus luteus as substrate showing that both the unspecific and the covalent lysozyme immobilization enhance the microtubes' antibacterial properties. Quantification of the enzyme activity at flow conditions by photometric assays reveals that the enzyme activities of lysozyme-functionalized microtubes depend strongly on applied flow rates. Intracapillary feeding of bacteria solution and higher flow rates lead to reduced enzyme activities. In consideration of different applied flow rates in the range of 0.2-0.5 mL/min, the total lysozyme activity increases by a factor of 2 for the covalent immobilization route as compared to the unspecific binding. Lysozyme leaching experiments at flow conditions for 1 h show a significant higher amount of washed out lysozyme (factor 1.7-3.4) for the unspecific immobilization route when compared to the covalent route where the initial level of antibacterial effectiveness could be achieved by reimmobilization with lysozyme. The presented platform is highly promising for sustainable bacteria filtration. PMID- 22827537 TI - Congenital adrenal hyperplasia associated with mutation in an 11beta-hydroxylase like gene in a cat. PMID- 22827538 TI - Effects of sugammadex and rocuronium mast cell number and degranulation in rat liver. AB - We investigated the effect of rocuronium- and sugammadex-induced mast cell increase and degranulation in rat portal triads. Forty-two rats, in six groups, received either rocuronium 1 mg.kg(-1); sugammadex 15 mg.kg(-1); sugammadex 100 mg.kg(-1); rocuronium 1 mg.kg(-1) and 5 min later, sugammadex 15 mg.kg(-1); rocuronium 1 mg.kg(-1) and 5 min later, sugammadex 100 mg.kg(-1); or isotonic saline. Total mast cell numbers were significantly higher with rocuronium only, than in all other groups (p<0.003), although in all active groups, the number was greater than the control. Total mast cell number was significantly higher with rocuronium and low-dose sugammadex compared with low-dose sugammadex only. The number of tryptase-positive mast cells with rocuronium only was significantly higher than in all other groups (p<0.003). Tryptase-positive mast cell numbers in both groups receiving both rocuronium and sugammadex were significantly higher compared with both groups receiving sugammadex only. Rocuronium increased mast cell numbers, and degranulation was mitigated by sugammadex. These results suggest that sugammadex may be beneficial in treatment of rocuronium-induced anaphylaxis. PMID- 22827539 TI - Coordinated dynamic gene expression changes in the central nucleus of the amygdala during alcohol withdrawal. AB - BACKGROUND: Chronic alcohol use causes widespread changes in the cellular biology of the amygdala's central nucleus (CeA), a GABAergic center that integrates autonomic physiology with the emotional aspects of motivation and learning. While alcohol-induced neurochemical changes play a role in dependence and drinking behavior, little is known about the CeA's dynamic changes during withdrawal, a period of emotional and physiologic disturbance. METHODS: We used a qRT-PCR platform to measure 139 transcripts in 92 rat CeA samples from control (N = 33), chronically alcohol exposed (N = 26), and withdrawn rats (t = 4, 8, 18, 32, and 48 hours; N = 5, 10, 7, 6, 5). This focused transcript set allowed us to identify significant dynamic expression patterns during the first 48 hours of withdrawal and propose potential regulatory mechanisms. RESULTS: Chronic alcohol exposure causes a limited number of small magnitude expression changes. In contrast, withdrawal results in a greater number of large changes within 4 hours of removal of the alcohol diet. Sixty-five of the 139 measured transcripts (47%) showed differential regulation during withdrawal. Over the 48-hour period, dynamic changes in the expression of gamma-aminobutyric acid type A (GABA(A) ), ionotropic glutamate and neuropeptide system-related G-protein-coupled receptor subunits, and the Ras/Raf signaling pathway were seen as well as downstream transcription factors (TFs) and epigenetic regulators. Four temporally correlated gene clusters were identified with shared functional roles including NMDA receptors, MAPKKK and chemokine signaling cascades, and mediators of long-term potentiation, among others. Cluster promoter regions shared overrepresented binding sites for multiple TFs including Cebp, Usf-1, Smad3, Ap-2, and c-Ets, suggesting a potential regulatory role. CONCLUSIONS: During alcohol withdrawal, the CeA experiences rapid changes in mRNA expression of these functionally related transcripts that were not predicted by measurement during chronic exposure. This study provides new insight into dynamic expression changes during alcohol withdrawal and suggests novel regulatory relationships that potentially impact the aspects of emotional modulation. PMID- 22827541 TI - Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study. PMID- 22827542 TI - Degradation of aromatic compounds through the beta-ketoadipate pathway is required for pathogenicity of the tomato wilt pathogen Fusarium oxysporum f. sp. lycopersici. AB - Plant roots react to pathogen attack by the activation of general and systemic resistance, including the lignification of cell walls and increased release of phenolic compounds in root exudate. Some fungi have the capacity to degrade lignin using ligninolytic extracellular peroxidases and laccases. Aromatic lignin breakdown products are further catabolized via the beta-ketoadipate pathway. In this study, we investigated the role of 3-carboxy-cis,cis-muconate lactonizing enzyme (CMLE), an enzyme of the beta-ketoadipate pathway, in the pathogenicity of Fusarium oxysporum f. sp. lycopersici towards its host, tomato. As expected, the cmle deletion mutant cannot catabolize phenolic compounds known to be degraded via the beta-ketoadipate pathway. In addition, the mutant is impaired in root invasion and is nonpathogenic, even though it shows normal superficial root colonization. We hypothesize that the beta-ketoadipate pathway in plant pathogenic, soil-borne fungi is necessary to degrade phenolic compounds in root exudate and/or inside roots in order to establish disease. PMID- 22827540 TI - Reassessment of the function of somatolactin alpha in lipid metabolism using medaka mutant and transgenic strains. AB - BACKGROUND: Somatolactin alpha (SLa) is a fish-specific peptide hormone secreted from the pituitary. In medaka, SLa functions to darken the skin color and lack of SLa makes it pale. Transcription of SLa is enhanced or suppressed when fish are kept in dark or bright conditions, respectively, indicating SLa's important role in background acclimation of the skin color. Bizarrely, however, the lack of SLa seems to cause the additional defect of increased triglycerides in organs, which could not be rescued (decreased) by its overexpression. RESULTS: To assess this enigmatic result, we investigated genetic (the SLa, Slc45a2, r, and Y genes) and nongenetic (age, fasting, water temperature, and background color) effects on hepatic triglycerides. These experiments found that percent hepatic triglycerides quickly change in response to external/internal environments. Effects of SLa seemed to be much less obvious, although it may increase the proportion of hepatic triglycerides at least during certain breeding conditions or under certain genetic backgrounds. CONCLUSIONS: The present results do not exclude the possibility that SLa takes part in lipid metabolism or other physiological processes. However, we suggest that skin-color regulation is the only definite role of SLa so far demonstrated in this species. PMID- 22827543 TI - The antidepressant effect of Cynanchum auriculatum in mice. AB - CONTEXT: Antidepressant effects of various plants are generally attributed to their anti-inflammation and antioxidant activities. Cynanchum auriculatum Royle ex Wight (Asclepiadaceae) is a traditional medicinal plant in China and India used for immunological regulation, anti-inflammation, and antioxidant purposes. However knowledge about its antidepressant activity has been poorly investigated. OBJECTIVE: To investigate the antidepressant activities of the total glycosides of C. auriculatum (TGC) and its CHCl3/MeOH (10:1) fractions (TGC-D and TGC-E) in mice. MATERIALS AND METHODS: TGC, TGC-D and TGC-E (20, 40 and 80 mg/kg) were intragastrically administered to mice twice a day for 5 days. The tail suspension test, forced swimming test, and locomotor activity test in mice were used to evaluate the effect of C. auriculatum. The inhibition of [3H]-serotonin reuptake in rat brain synaptosomes was detected to investigate their mechanism. RESULTS: TGC, TGC-D and TGC-E (80 mg/kg) decreased the immobility time by 61.7, 64.5, and 61.9% in tail suspension test. TGC (80 mg/kg), TGC-D (80 mg/kg) and TGC-E (20 mg/kg) decreased the immobility time by 32.6, 47.3, and 48.7% in forced swimming test. TGC (80 mg/kg) and TGC-E (20 and 40 mg/kg) decreased the crossing distances by 28.8, 29.5, and 36.2% in locomotor activity test. TGC, TGC-D and TGC-E (10 mg/L) inhibited serotonin reuptake by 7.4, 4.5, and 71.1% in rat brain synaptosomes, and IC50 value of TGC-E was 5.2 mg/L. DISCUSSION AND CONCLUSION: TGC, TGC-D and TGC-E have potential antidepressant activities. The antidepressive effect of TGC-E maybe attributed partly by the inhibiting effect on serotonin reuptake. PMID- 22827544 TI - Asymmetric syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R) hopromine. AB - The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(alpha-methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-(alpha-methyl-p-methoxybenzyl)amide to alpha,beta unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R)-hopromine. The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (-)-(R,R)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4'R,4''S)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (-)-(R,R)-hopromine. PMID- 22827545 TI - Identifying novel adenosine receptor ligands by simultaneous proteochemometric modeling of rat and human bioactivity data. AB - The four subtypes of adenosine receptors form relevant drug targets in the treatment of, e.g., diabetes and Parkinson's disease. In the present study, we aimed at finding novel small molecule ligands for these receptors using virtual screening approaches based on proteochemometric (PCM) modeling. We combined bioactivity data from all human and rat receptors in order to widen available chemical space. After training and validating a proteochemometric model on this combined data set (Q(2) of 0.73, RMSE of 0.61), we virtually screened a vendor database of 100910 compounds. Of 54 compounds purchased, six novel high affinity adenosine receptor ligands were confirmed experimentally, one of which displayed an affinity of 7 nM on the human adenosine A(1) receptor. We conclude that the combination of rat and human data performs better than human data only. Furthermore, we conclude that proteochemometric modeling is an efficient method to quickly screen for novel bioactive compounds. PMID- 22827547 TI - Gold-catalyzed hydrosilyloxylation driving tandem aldol and Mannich reactions. AB - The chemoselective formation of an enolate from alkyne in the presence of a carbonyl and imine group was realized, which constructed a variety of structural motifs under exceedingly mild reaction conditions in a tandem process. Reaction driving tandem hydrosilyloxylation/aldol reactions was achieved through the formation of enol silyl ethers catalytically generated in situ from readily available alkynes. These reactions were expanded to obtain beta-amino enol silyl ethers in good yields via the tandem hydrosilyloxylation/isomerization/Mannich reaction. PMID- 22827548 TI - A review of the role of lymphoma markers and occupational and environmental exposures. AB - Immune deficiency and altered immunity are among the best characterized and strongest known risk factors of non-Hodgkin lymphomas (NHL). For instance, chronic inflammation or certain disturbances in the immune system are associated with an increased lymphoma risk. Occupational and environmental factors (i.e., dioxin) as well as lifestyle factors (i.e., obesity) may contribute to these risk factors. The precise role of these factors in the etiology of NHL, however, is still not entirely clear. Although the existing epidemiologic studies have not revealed consistent patterns of perturbations of the immune system by these factors, the findings might suggest an adverse impact on both the humoral and cell-mediated immune system. PMID- 22827549 TI - Thermal inactivation of acid-adapted Escherichia coli O157:H7 in dairy compost. AB - It is well documented that stress-adapted microorganisms can develop cross resistance to other unrelated stress. This study was designed to evaluate the thermal resistance of acid-adapted Escherichia coli O157:H7 in both fresh and finished dairy composts. A three-strain mixture of E. coli O157:H7, either acid adapted or non-adapted (control), was inoculated into dairy compost to a final concentration of approximately 10(7) CFU/g. The inoculated compost was kept in an environmental chamber which was programmed to raise temperature from room to target temperatures (50 degrees C, 55 degrees C, and 60 degrees C) in 2 days, simulating the early phase of composting. In fresh dairy compost with 2 days of come-up time, acid-adapted and control E. coli O157:H7 survived for 19 and 17 days at 50 degrees C, respectively, and 6 and 4 days for both types of culture at 55 degrees C and 60 degrees C, respectively. Overall, pathogen survival was non significant (p>0.05) between control and acid-adapted cultures at all tested temperatures. In finished compost, the same trend in pathogen survival between control and acid-adapted cultures was observed at 55 degrees C. However, the duration of survival for both cultures was short in comparison to that in fresh compost. In fresh compost with short come-up time (15 min), acid-adaptation provided E. coli O157:H7 some cross-protection to heat at 55 degrees C up to 30 min of exposure. The effect of heating medium on thermal resistance of acid adapted E. coli O157:H7 revealed that in saline, acid-adapted E. coli O157:H7 was inactivated slower (p<0.05) with 0.5 and 1 h of heat exposure at 55 degrees C as compared to control culture. Our results revealed that cross-protection against heat in E. coli O157:H7 due to acid-adaptation was demonstrated in saline but lost in fresh dairy compost with 2 days of come-up time during composting. Additionally, the type of compost and heating medium can influence the rate of pathogen inactivation at composting temperatures. PMID- 22827550 TI - Low-level laser therapy ameliorates CCl4-induced liver cirrhosis in rats. AB - This study investigated the effects of low-level laser therapy (LLLT) in the liver function, structure and inflammation in a experimental model of carbon tetrachloride (CCl(4))-induced liver cirrhosis. Wistar rats were divided into Control, LLLT, CCl(4) and CCl(4) +LLLT groups. CCl(4) groups received CCl(4) (0.4 g kg(-1); i.p.), three times a week, for 12 weeks. A 830 nm LLLT was performed with a continuous wave, 35 mW, 2.5 J cm(-2) per point, applied to four points of the liver (right and left upper and lower extremities, in the four lobes of the liver) for 2 weeks. Liver structure and inflammation (cirrhotic areas, collagen deposition, inflammation, density of Kupffer and hepatic stellate cells) and function (aspartate aminotransferase, alkaline phosphatase, gamma glutamyltransferase, lactate dehydrogenase, total proteins and globulins) were evaluated. LLLT significantly reduced CCl(4)-increased aspartate aminotransferase (P < 0.001), alkaline phosphatase (P < 0.001), gamma-glutamyl transferase (P < 0.001) and lactate dehydrogenase (P < 0.01) activity, as well as total proteins (P < 0.05) and globulins (P < 0.01). LLLT also reduced the number of cirrhotic areas, the collagen accumulation and the hepatic inflammatory infiltrate. Of note, LLLT reduced CCl(4)-increased number of Kupffer cells (P < 0.05) and hepatic stellate cells (P < 0.05). We conclude that LLLT presents beneficial effects on liver function and structure in an experimental model of CCl(4) induced cirrhosis. PMID- 22827551 TI - pH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy. AB - The main objective of this study was aimed at tumor microenvironment-responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 MUg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model. PMID- 22827553 TI - Comparative genomic analysis of bovine, environmental, and human strains of Pseudomonas aeruginosa. AB - Genomic analyses on versatility of the ubiquitous opportunistic pathogen Pseudomonas aeruginosa have been focusing on clinical strains from humans but much less on animal and environmental strains. Here, we aimed to compare genomic patterns of bovine, environmental, and human strains of P. aeruginosa. A collection of 71 strains, equally representing bovine (non-clinical), environmental (aquatic), and human (clinical) isolates from all main subregions of Hungary was genotyped by PCR microarray. Results were interpreted in comparison with internationally established human clinical and environmental clones, based on single nucleotide polymorphisms, on di- and multiallelic loci (fliC and fpvA) of the conserved core genome, and on genetic markers for the flexible accessory genome. As a result, a total of 33 clones were identified, with one bovine, 10 environmental, and five human clones regarded as new ones. In spite of general clonal diversity, bovine and human clones seemed to be habitat related. Bovine strains were characterized by significant overrepresentation of type III FpvA pyoverdine receptor, while the environmental and human strains showed the dominance of type I FpvA. Genotypes of non-clinical bovine strains of P. aeruginosa differed from those of human clinical strains, supporting the hypothesis about specific groups of strains colonizing specific habitats. PMID- 22827552 TI - Risk of malignancy in thyroid incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography: a systematic review. AB - BACKGROUND: The expanding use of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) has led to the identification of increasing numbers of patients with an incidentaloma in the thyroid gland. We aimed to review the proportion of incidental thyroid cancers found by (18)F-FDG PET or PET/computed tomography imaging. METHODS: Studies evaluating thyroid carcinomas discovered incidentally in patients or healthy volunteers by (18)F-FDG PET were systematically searched in the PubMed database from 2000 to 2011. The main exclusion criteria were known thyroid disease, lack of assigned diagnoses, investigation of diffuse uptake only, or investigation of patients with head and neck cancer, or cancer in the upper part of the thorax. RESULTS: Twenty-two studies met our criteria comprising a total of 125,754 subjects. Of these, 1994 (1.6%) had unexpected focal hypermetabolic activity, while 999 of 48,644 individuals (2.1%) had an unexpected diffuse hypermetabolic activity in the thyroid gland. A diagnosis was assigned in 1051 of the 1994 patients with a focal uptake, 366 of whom (34.8%) had thyroid malignancy. Likewise, a diagnosis was assigned in 168 of 999 patients with a diffuse uptake, 7 of whom (4.4%) had thyroid malignancy. In the eight studies reporting individual maximum standardized uptake values (SUV(max)), the mean SUV(max) was 4.8 (standard deviation [SD] 3.1) and 6.9 (SD 4.7) in benign and malignant lesions, respectively (p<0.001). CONCLUSIONS: Incidentally found thyroid nodules, using (18)F-FDG PET, are at high risk of harboring malignancy if uptake is focal. SUV are significantly higher in malignant than in benign nodules. The pronounced inhomogeneity and other shortcomings of the studies are discussed. PMID- 22827554 TI - Vagal afferents mediate early satiation and prevent flavour avoidance learning in response to intraperitoneally infused exendin-4. AB - Glucagon-like peptide-1 receptor (GLP-1R) agonists such as exendin-4 (Ex-4) affect eating and metabolism and are potential candidates for treating obesity and type II diabetes. In the present study, we tested whether vagal afferents mediate the eating-inhibitory and avoidance-inducing effects of Ex-4. Subdiaphragmatic vagal deafferentation (SDA) blunted the short-term (< 1 h) but not long-term eating-inhibitory effect of i.p.-infused Ex-4 (0.1 MUg/kg) in rats. A dose of 1 MUg/kg Ex-4 reduced 0.5, 1, 2 and 4 h cumulative food intake in SDA and sham-operated rats to a similar extent. Paradoxically, SDA but not sham rats developed a conditioned flavour avoidance (CFA) after i.p. Ex-4 (0.1 MUg/kg). SDA completely blunted the induction of c-Fos expression by Ex-4 in the hypothalamic paraventricular nucleus. Ex-4, however, increased the number of c-Fos expressing cells, independent of intact vagal afferents, in the nucleus accumbens and in the central nucleus of the amygdala, the lateral external parabrachial nucleus, the caudal ventrolateral medulla and the dorsal vagal complex. These data suggest that intact vagal afferents are only necessary for the full expression of the early satiating effect of Ex-4 but not for later eating-inhibitory actions, when circulating Ex-4 might reach the brain via the circulation. Our data also dissociate the satiating and avoidance-inducing effects of the low Ex-4 dose tested under our conditions and suggest that vagal afferent signalling may protect against the development of CFA. Taken together, these findings reveal a complex role of vagal afferents in mediating the effects of GLP-1R activation on ingestive behaviour. PMID- 22827555 TI - Self-reported cognitive impairment after breast cancer treatment in young women from the ELIPPSE40 cohort: the long-term impact of chemotherapy. AB - Cognitive impairment (CI) is common after cancer treatments, but little is known about the long-term evolution of CI, especially in premenopausal women. Since September 2005, all consecutive women included in the French National Health Insurance Fund registry with a diagnosis of primary breast cancer, aged 18-40 years and living in South Eastern France, were asked to participate in a cohort study, including telephone interviews, medical data, and prescription refills of psychotropic drugs and adjuvant endocrine therapy. At each interview, CI is defined as self-report of frequent memory loss and attention deficits. As of February 2010, 222 women with available medical data had taken part in the 10-, 16-, and 28-month telephone interviews, with CI being reported by 37.4%, 36.5%, and 42.3% of participants, respectively. Tranquilizers' dispensation was associated with CI self-report at all three interviews; chemotherapy was reported only at the 28-month interview. At 28 months, besides chemotherapy and tranquilizer's dispensation, having a low educational level and not being a native French woman were also independently associated with CI. Reports of CI were common in young women and primarily related to psycho-social vulnerabilities and cancer treatment. As they affect quality of life, long-term CI complaints deserve greater consideration. PMID- 22827556 TI - A clinical, neurolinguistic, and radiological study of a Chinese follow-up case with primary progressive aphasia. AB - Primary progressive aphasia (PPA) is a progressive neurodegenerative disorder characterized by the deterioration of language functions. The Han language bears some unique features from the Latin languages; however, the features of PPA in the Han language-speaking population are not well understood. In this study, we performed a 3-year follow-up on a Han language-speaking PPA patient with corresponding changes in magnetic resonance imaging (MRI). During the early stage, linguistic analysis revealed several symptoms including difficulty with auditory comprehension, right-left disorientation, reading disorders, and agraphia, specifically the execution of serial oral instructions. This Chinese PPA patient presented with a reading disorder, but his word comprehension ability remained intact. There are two different possible modalities of incorrect writing in this case. The patient also presented with noun-verb double dissociation. The early-stage MRI showed atrophy of the left frontal lobe, which was most severe in the inferior frontal gyrus. Three years later, the patient was found to have progressive atrophy in the parietal, frontal, and temporal lobes, among which the frontal lobe remained the most severely affected region. The brain imaging of the Chinese-speaking PPA patient showed changes similar to those of a Latin language speaking PPA patient. The prominent change was asymmetrical atrophy in the frontal and temporal lobes. This is the first report of noun-verb double dissociation existing in a Chinese-language speaking PPA patient. The dissociation may be related to an impaired function of the inferior frontal gyrus, which is likely associated with verb-naming in Chinese-speaking people. Several unique features were observed in this case, including impairment in writing ability. PMID- 22827557 TI - A highly sensitive and specific qPCR assay for quantification of the biomarker SOX11 in mantle cell lymphoma. AB - OBJECTIVES: Mantle cell lymphoma (MCL) is one of the most heterogeneous lymphoid neoplasms with a variable course of disease. Although t(11;14)(q13;q32) is the hallmark of MCL resulting in cyclin D1 (CCND1) overexpression in 90% of patients, this is difficult to validate by immunohistochemistry. We hypothesised that SOX11 could be a robust molecular biomarker for MCL. METHODS: We have developed very sensitive and specific RT-qPCR assay employing a poly-A specific RT primer to circumvent contamination from gDNA caused by the intron-less nature of SOX11. RESULTS: We found a significant difference between the expression levels of SOX11 in patients with MCL at diagnosis (n = 21) and in healthy donors (n = 18) (blood: P < 0.0001; marrow: P = 0.0001). SOX11 expression of very low levels close to the assay sensitivity was detected in only 2 of 18 healthy donors, while low levels of CCND1 expression was observed in all blood and 12 of 13 marrow samples within the defined detection limit of Cq = 40. In spiking experiments of the GRANTA-519 MCL cell line into mononuclear cells from normal donor, the sensitivity of the SOX11 assay was found to be 2 * 10(-4) , while the sensitivity of the CCND1 assay was estimated to 2 * 10(-3) because of the normal background expression. In longitudinal sampling from patients with MCL the minimal residual disease (MRD) values based on the SOX11 expression mirrored the clinical disease development. CONCLUSION: This SOX11 RT-qPCR assay could be a useful tool for MRD monitoring in patients with MCL. PMID- 22827558 TI - Redox properties of structural Fe in clay minerals. 2. Electrochemical and spectroscopic characterization of electron transfer irreversibility in ferruginous smectite, SWa-1. AB - Structural Fe in clay minerals is an important, albeit poorly characterized, redox-active phase found in many natural and engineered environments. This work develops an experimental approach to directly assess the redox properties of a natural Fe-bearing smectite (ferruginous smectite, SWa-1, 12.6 wt % Fe) with mediated electrochemical reduction (MER) and oxidation (MEO). By utilizing a suite of one-electron-transfer mediating compounds to facilitate electron transfer between structural Fe in SWa-1 and a working electrode, we show that the Fe2+/Fe3+ couple in SWa-1 is redox-active over a large range of potentials (from E(H) = -0.63 V to +0.61 V vs SHE). Electrochemical and spectroscopic analyses of SWa-1 samples that were subject to reduction and re-oxidation cycling revealed both reversible and irreversible structural Fe rearrangements that altered the observed apparent standard reduction potential (E(H)(o)) of structural Fe. E(H)(o)-values vary by as much as 0.56 V between SWa-1 samples with different redox histories. The wide range of E(H)-values over which SWa-1 is redox-active and redox history-dependent E(H)(o)-values underscore the importance of Fe bearing clay minerals as redox-active phases in a wide range of redox regimes. PMID- 22827559 TI - Cigarette smoke exposure greatly increases alcohol consumption in adolescent C57BL/6 mice. AB - BACKGROUND: Alcohol and tobacco are often used together, and alcoholism is much more common among smokers compared with nonsmokers. Studies in humans suggest that nicotine (an active ingredient in cigarette smoke) can increase the consumption of alcohol. Research on rats and mice demonstrated mixed results; some studies report that nicotine increases alcohol consumption, while others show a decrease in drinking. Because cigarette smoke includes many other chemicals, these also may play a significant role in alcohol consumption. For example, 2 of these other constituents, monoamine oxidase inhibitors and acetaldehyde, increase alcohol tolerance and/or alcohol consumption in rodents. This study was designed to investigate how cigarette smoke from tobacco may modify self-administration of alcohol in adolescent C57BL/6 mice, a critical time when adolescent humans begin abusing drugs. METHODS: C57BL/6 male mice (4 to 5 weeks old) were acclimated for 3 weeks to consume a 10% (w/v) alcohol solution during a 2-hour daily access in the dark. Subsequently, half the animals were exposed to cigarette smoke for 6 h/d for 16 days. The remaining animals (control) were placed in a smoke-free adjacent chamber. Immediately following the 6-hour period in the chambers, the control and smoke-exposed mice were given access to the 10% alcohol solution for 2 hours. RESULTS: Animals exposed to cigarette smoke for 6 h/d consumed approximately 3- to 5-fold more alcohol than the mice in the control group throughout the 16-day study. The mice in the smoke group had a blood alcohol concentration that was nearly 4-fold that of the control mice. CONCLUSIONS: Cigarette smoke increases alcohol consumption several fold higher than reported studies using nicotine treatment alone in adolescent rodents. Thus, this model should be useful to determine the roles of other bioactive components in cigarette smoke that may be important in the high co-abuse of smoking and alcohol consumption. PMID- 22827560 TI - Early first-trimester crown-rump length measurements in male and female singleton fetuses in IVF pregnancies. AB - OBJECTIVES: The generally higher birth-weight of male newborns compared to female newborns is attributed mainly to intrauterine exposure to testosterone. We aimed to determine if crown-rump length (CRL) differs between male and female fetuses early in the first trimester. METHODS: A retrospective cohort study of 333 women with nondiabetic singleton IVF pregnancies attending a single university affiliated tertiary medical center in 2000-2007 who underwent CRL measurement before 50 days of pregnancy (date of measurement minus oocyte retrieval date plus 14 days). Data on pregnancy outcome, including fetal sex, were collected by routine follow-up telephone interview and combined with the delivery data. RESULTS: There were 169 female and 164 male fetuses according to the reported fetal sex at delivery. Most of the CRL measurements (68.7%) were performed at an actual gestational age of 43-45 days. On linear regression analysis, male fetal sex was a significant (p = 0.011) predictor of larger CRL: CRL (mm) = -23.851 + GA (days) * 0.621 + 0.334 * Sex (F = 1, M = 2), R(2) = 0.512, p <0.001. A general linear model, adjusted for gestational age (40-50 days), revealed that mean CRL was significantly higher in male than in female fetuses (4.58 +/- 0.09 mm, [95% CI: 4.3-4.7] vs 4.24 +/- 0.09 mm [4.0-4.4]; p < 0.001). CONCLUSIONS: Male fetuses are larger than female fetuses in the early first trimester. Given that gonadal differentiation has not yet occurred, still unidentified nonhormonal factors are apparently responsible for this difference. PMID- 22827561 TI - Birth outcomes of cases with left-sided obstructive defects of the heart in the function of maternal socio-demographic factors: a population-based case-control study. AB - OBJECTIVE: To evaluate the birth outcomes and maternal variables of cases with different types of left-sided obstructive defects (LSOD) of the heart. METHODS: Live-born infants were selected from the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, and 302 cases with LSOD, 469 matched controls and 38,151 all controls without any defect, and 20,750 malformed controls with other isolated defects were compared. The diagnosis of LSOD was based on autopsy report or the documents of surgical intervention. RESULTS: Four types of LSOD were differentiated: 56 cases with valvular aortic stenosis (VAS), 76 cases with hypoplastic left heart syndrome (HLHS), 113 cases with coarctation of the aorta (COA) and 57 cases with other congenital abnormalities of aorta (OCA). Cases with LSOD had male excess (64.6%) with a higher rate of preterm birth (14.2 vs. 6.6%) and low birthweight (15.6 vs. 4.3%) compared to matched controls. The high rate of preterm birth was particularly characteristic for HLHS (17.1%) while intrauterine fetal growth restriction was found in cases OCA (22.8%) and COA (13.3%). The mothers of cases with LSOD had higher birth order and lower socio-economic status than controls without any defect. CONCLUSIONS: The general pattern of birth outcomes and maternal variables were similar in the types of LSOD cases, but the higher rate of preterm birth and low birthweight indicated some association with their adverse fetal development. PMID- 22827562 TI - Comparative analysis of cesarean delivery rates over a 10-year period in a single Institution using 10-class classification. AB - OBJECTIVE: To evaluate the variables associated with changes in cesarean delivery (CD) rates in a University Hospital with standardized and unchanged protocols of care. METHODS: Retrospective analysis of consecutive deliveries between two triennia 10 years apart. The Robson classification of CD was used, and the analysis focused on factors affecting Robson's classes 1 and 2 combined (term singleton cephalic nulliparae) and class 5 (previous CD). RESULTS: A total of 8237 deliveries occurred in the 1st period, and 8420 in the 2nd. CD increased from 12.5 to 18% (p < 0.001). Robson's classes 1 and 2 combined contributed more than other classes to CD rates (32 vs 36%; p < 0.001). At multivariate analysis, BMI (Odds ratio [OR]: 1.08; 95% CI: 1.06-1.1) and maternal age (OR: 1.06; 95% CI: 1.05-1.08) were independently related to CD. In Robson class 5, the rate of CD increased from 34 to 46%, p < 0.001, mostly due to an increase in elective CD (39 vs 67.5%; p < 0.001). At multivariate analysis, BMI (OR: 1.06 95% CI: 1.02-1.1) and more than one previous CD (OR: 18.7; 95% CI: 9.6-36.4) were independently related to CD. CONCLUSIONS: BMI and maternal age are independent factors associated to the increasing rate of CD in nulliparae with spontaneous or induced labor at term. In women with previous CD, BMI and more than one previous CD are factors associated with the increasing rate of CD. PMID- 22827563 TI - Proteomic analysis of midtrimester amniotic fluid to identify novel biomarkers for preterm delivery. AB - OBJECTIVE: The aim of this study was to identify possible biomarkers for preterm delivery by analyzing midtrimester amniotic fluid. METHODS: Thirty-two amniotic fluid samples were studied; 16 patients had a spontaneous preterm delivery and 16 patients delivered at term. The proteomic technique consisted of surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) using different types of solid chromatographic chips (Q10, CM10 and IMAC30). RESULTS: Mass spectrometry tracings were obtained from the amniotic fluids of both patients who delivered preterm and patients who delivered at term. Seven potential markers were identified to be differentially expressed in patients who delivered preterm. CONCLUSIONS: Proteomic analysis of amniotic fluid obtained in the midtrimester reveals the presence of a set of proteins in patients at risk for preterm delivery. PMID- 22827564 TI - Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. AB - We conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg( 1) infused over 15 min followed by a 16 mg.kg(-1) .h(-1) infusion until chest closure with a 2 mg.kg(-1) load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined. PMID- 22827566 TI - Toward cold chemistry with magnetically decelerated supersonic beams. PMID- 22827565 TI - Structural elucidation and quantification of phenolic conjugates present in human urine after tea intake. AB - In dietary polyphenol exposure studies, annotation and identification of urinary metabolites present at low (micromolar) concentrations are major obstacles. To determine the biological activity of specific components, it is necessary to have the correct structures and the quantification of the polyphenol-derived conjugates present in the human body. We present a procedure for identification and quantification of metabolites and conjugates excreted in human urine after single bolus intake of black or green tea. A combination of a solid-phase extraction (SPE) preparation step and two high pressure liquid chromatography (HPLC)-based analytical platforms was used, namely, accurate mass fragmentation (HPLC-FTMS(n)) and mass-guided SPE-trapping of selected compounds for nuclear magnetic resonance spectroscopy (NMR) measurements (HPLC-TOFMS-SPE-NMR). HPLC FTMS(n) analysis led to the annotation of 138 urinary metabolites, including 48 valerolactone and valeric acid conjugates. By combining the results from MS(n) fragmentation with the one-dimensional (1D)-(1)H NMR spectra of HPLC-TOFMS-SPE trapped compounds, we elucidated the structures of 36 phenolic conjugates, including the glucuronides of 3',4'-di- and 3',4',5'-trihydroxyphenyl-gamma valerolactone, three urolithin glucuronides, and indole-3-acetic acid glucuronide. We also obtained 26 h-quantitative excretion profiles for specific valerolactone conjugates. The combination of the HPLC-FTMS(n) and HPLC-TOFMS-SPE NMR platforms results in the efficient identification and quantification of less abundant phenolic conjugates down to nanomoles of trapped amounts of metabolite corresponding to micromolar metabolite concentrations in urine. PMID- 22827567 TI - Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. AB - OBJECTIVE: To evaluate perinatal outcome after sildenafil citrate (SC) administration at the onset of pregnancy in a rat pre-eclampsia model. DESIGN: In vivo animal experimental study. SETTING: Fundacion IVI-Instituto Universitario IVI, Valencia, Spain. SAMPLE: Control and pre-eclampsia-induced pregnant Wistar rats exposed to chronic SC administration. METHODS: We evaluated the use of SC, which was tested as a potential therapeutic tool to maintain vasodilatation in complicated pregnancies. We have demonstrated previously that SC shows a hypotensive selective effect in normal rat pregnancies when compared with nonpregnant animals. MAIN OUTCOME MEASURES: Maternal blood pressure, weight and mortality during pre- and postnatal development, maternal blood cellularity and haemodynamic changes with maternal and fetal Doppler quantitative indices. RESULTS: SC restores normal values of blood pressure, cell count and proteinuria for maternal syndrome. In offspring, SC improves weight gain and increases survival rates without fetotoxic effects. According to the haemodynamic results, SC has a significant effect on the resistance index in the uterine artery in pre eclamptic animals, as it restores normal values to correlate with an increase in fetal perfusion through the ductus venosus. CONCLUSIONS: These results suggest that SC administration during pregnancy may have a potential benefit for the treatment of hypertension during pregnancy by reversing the maternal effects of pre-eclampsia and by improving uteroplacental and fetal perfusion. PMID- 22827568 TI - Evaluation of bacterial resistance to essential oils and antibiotics after exposure to oregano and cinnamon essential oils. AB - Essential oils (EOs) are excellent antimicrobial agents sometimes used in active food packaging. This work studies the susceptibility of 48 clinical isolates and 12 reference strains of Gram-negative bacilli to oregano essential oil, cinnamon essential oil, and combinations of both. Furthermore, the tendency of the clinical isolates to develop resistance to these EOs and to different antibiotics after sequential oregano or cinnamon exposure was studied. For this purpose, antibiotic susceptibility (through disk diffusion assays and minimum inhibitory concentration [MIC] determination) and oregano and cinnamon susceptibility (through MIC and minimum bactericidal concentration [MBC] determination) were compared after 50 passages in the presence or absence of subinhibitory concentrations of oregano and cinnamon essential oils. The results showed that all strains were susceptible to both EOs and their combination independently of the antibiotic resistance profile. In addition, neither synergistic nor antagonistic effects were observed between oregano and cinnamon essential oils at the concentrations tested. After the sequential exposure to both EOs, only Serratia marcescens, Morganella morganii, and Proteus mirabilis treated with oregano changed their antibiotic resistance profile and/or increased their resistance to this EO. However, the changes in antibiotic and oregano resistance were not related. PMID- 22827569 TI - Pediatric cardiology fellowship--more outpatient activity needed. PMID- 22827570 TI - Cardiac transplant coronary allograft vasculopathy in children: Achilles' heel. PMID- 22827571 TI - Helios expression in FoxP3(+) T regulatory cells. AB - Recent work debates the suitability of Helios, an Ikarios family transcription factor, as a marker of thymic-derived natural T regulatory cells. However, Helios expression could be of particular importance in cancer. We and others reported that the majority of peripheral and tumour-infiltrating FoxP3(+) Tregs expresses Helios. Additionally, recent observations indicate that FoxP3(+)Helios(+) Tregs possess more suppressive characteristics, as compared to FoxP3(+)Helios(-) Tregs. PMID- 22827572 TI - Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). AB - Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. Through screening and lead optimization using the human PERK crystal structure, we discovered compound 38 (GSK2606414), an orally available, potent, and selective PERK inhibitor. Compound 38 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice. PMID- 22827573 TI - Induction of anoikis by sodium arsenite in rat hepatoma FGC4 cells: comparison with cadmium chloride and implications for assessment of regulation of heat shock protein 70. AB - CONTEXT: Arsenic, a toxic metalloid with major health concerns, elicits upregulation of heat shock protein 70 (HSP70) in rat hepatoma FGC4 cells, together with evidence of detachment of viable cells from the growth substratum. OBJECTIVE: To determine if this cell detachment was linked to anoikis, and the impact of this on measurement of HSP70 expression. MATERIALS AND METHODS: FGC4 cells were exposed to sodium arsenite, and detached and attached cells were taken for assessment of cell viability, activation of procaspase-3, and expression of HSP70. RESULTS: Exposure to sodium arsenite led to loss of viable cells from the substratum, associated with apoptosis in detached, but not attached, cells. Upregulation of HSP70 of a similar magnitude was demonstrated in both cell populations. Exposure of cells to cadmium chloride, a toxic metal, also of major environmental concern and believed to act by an oxidative stress mechanism, produced very little release of viable cells from the culture substratum, was not associated with apoptosis, but did elicit a modest upregulation of HSP70 in both cell populations. DISCUSSION: Exposure of FGC4 cells to sodium arsenite elicits anoikis, a form of anchorage-dependent apoptosis, and assessment of the level of HSP70 upregulation in such cells should take account of the detached cell population. Further, the data suggest that this phenomenon is selective to sodium arsenite, rather than to another toxic element that shares a similar mechanism of toxicity. PMID- 22827574 TI - Sodium caprate transiently opens claudin-5-containing barriers at tight junctions of epithelial and endothelial cells. AB - Claudin-5 is a tight junction (TJ) protein which limits the diffusion of small hydrophilic molecules. Thus, it represents a potential pharmacological target to improve drug delivery to the tissues protected by claudin-5-dependent barriers. Sodium caprate is known as an absorption enhancer which opens the paracellular space acting on TJ proteins and actin cytoskeleton. Its action on claudin-5 is not understood so far. Epithelial and endothelial systems were used to evaluate the effect of caprate on claudin-5 in TJ-free cells and on claudin-5 fully integrated in TJ. To this aim, confocal microscopy on live and fixed cells and isolated mouse brain capillaries, Western blotting and permeability assays were employed. Caprate reversibly reduced claudin-5 trans-interactions in TJ-free human embryonic kidney-293 cells expressing claudin-5-YFP. It decreased the membranous claudin-5 and the F-actin content in Madin-Darby canine kidney-II cells expressing Flag-claudin-5, thereby increasing the permeability to the small molecule lucifer yellow. Interestingly, zonula occludens protein 1 (ZO-1), which links transmembranous TJ proteins to the actin cytoskeleton, was not affected by caprate treatment. Similarly, endogenous claudin-5 in the membrane of brain endothelia was displaced together with F-actin, whereas ZO-1 remained unaffected. Caprate transiently opens the paracellular space, reducing the intercellular claudin-5/claudin-5 interactions and the polymerized actin at the perijunctional region of endothelial and epithelial cells. In conclusion, the study further elucidates the cellular effects of caprate at the tight junctions. PMID- 22827575 TI - Diastereoselective addition of arylzinc reagents to sugar aldehydes. AB - The diastereoselective arylation of sugar-derived aldehydes is described. The arylating reagents are generated in situ by a boron-to-zinc exchange reaction of arylboronic acids with Et(2)Zn to generate arylethylzinc reagents. The exquisite reactivity of the arylzinc reagents allowed for an efficient and mild arylation, delivering the corresponding products in diastereoisomeric ratios of up to >20:1. The utility of the methodology is highlighted with an efficient formal synthesis of (+)-7-epi-goniofufurone, a member of the styryllactone family of natural products. PMID- 22827576 TI - Social identity, attribution, and emotion: comparisons of Americans, Korean Americans, and Koreans. AB - The social identity of another person, in addition to the social identity of self, can be an important factor affecting the types of attribution judgments and emotions that individuals indicate for the other person. In April 2007, the perpetrator of the shooting incident on the Virginia Tech University campus was identified as a person who emigrated to the USA from Korea at a young age. The current study compared non-Korean Americans, Korean Americans, Koreans in the USA, and Koreans in Korea in terms of their attributions and emotions concerning the perpetrator and the shooting incident. Participants were asked to indicate (1) the extent to which they attributed the cause of the incident to either American society or the perpetrator, (2) their emotions (e.g., upset), and (3) the extent to which they categorized the perpetrator as an American, a Korean American, or a Korean. The results indicated that non-Korean Americans were most likely to attribute the cause of the incident to the perpetrator as opposed to American society. Non-Korean Americans, Korean Americans, and Koreans in the United States had more negative emotions (e.g., unhappy, sad, and upset) about the incident than Koreans in Korea did. The results also indicated that individuals differed in their attributions and emotions depending on how they categorized the perpetrator. For example, categorizing the perpetrator as being a Korean was positively related to Americans' tendency to hold the perpetrator responsible, while categorizing the perpetrator as being an American was negatively related to the tendency to hold the perpetrator responsible among Koreans in Korea. The findings may imply that social identity theory, intergroup emotion theory, and cultural orientations (e.g., individualism and collectivism) can provide insights into people's reactions to a tragic incident. PMID- 22827577 TI - Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. AB - SIGNIFICANCE: The NADPH oxidase 2 (NOX2) is known to play a major role in innate immunity for several decades. Phagocytic cells provide host defense by ingesting microbes and destroy them by different mechanisms, including the generation of reactive oxygen species (ROS) by NOX2, a process known as oxidative burst. The phagocytic pathway of dendritic cells (DCs), highly adapted to antigen processing, has been shown to display remarkable differences compared to other phagocytes. Contrary to macrophages and neutrophils, the main function of DC phagosomes is antigen presentation rather than pathogen killing or clearance of cell debris. RECENT ADVANCES: In the last few years, it became clear that NOX2 is also involved in the establishment of adaptive immunity. Several studies support the idea of a relationship between antigen presentation and the level of antigen degradation, the latter one being regulated by the pH and ROS within phagosomes. CRITICAL ISSUES: The regulation of phagosomal pH exerted by NOX2, and thereby of the efficacy of antigen cross-presentation in DCs, represents a clear illustration of how NOX2 can influence CD8(+) T lymphocyte responses. In this review, we want to put emphasis on the relationship between ROS generation and antigen processing and presentation, since there is growing evidence that the low levels of ROS generated by DCs play an important role in these processes. FUTURE DIRECTIONS: In the next years, it will be interesting to unravel possible mechanisms involved and to find other possible connections between NOX family members and adaptive immune responses. PMID- 22827578 TI - Deep transcranial magnetic stimulation for treatment-resistant bipolar depression: a case report of acute and maintenance efficacy. AB - Deep Transcranial Magnetic Stimulation (dTMS) is currently being evaluated as a possible treatment for several neuropsychiatric disorders and has been demonstrated as a safe and effective procedure. This case presents a patient with bipolar depression that has been treated with 20 daily consecutive dTMS sessions and with one dTMS session every 2 weeks for the following 3 months. Depressive symptoms improved rapidly and response was maintained during the next 6 months; cognitive performances also improved. This report suggests that add-on dTMS may help overcoming drug-resistance in bipolar depression and protect from subsequent bipolar episodes of any polarity. PMID- 22827579 TI - The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. AB - BACKGROUND: Distant metastases at presentation are rare in well-differentiated thyroid cancer (WDTC). The objective of this study was to report outcomes for patients presenting with distant metastases managed by thyroidectomy and radioactive iodine (RAI) therapy. METHODS: Fifty-two patients with distant metastases from thyroid cancer diagnosed before thyroid surgery (n=32) or on a postoperative RAI scan after thyroid surgery (n=20) were identified from a database of patients with WDTC treated between 1985 and 2005. The median age was 58 years (range 12-83 years), with a male-to-female ratio of 3:2. Forty-seven patients (90%) had total thyroidectomy and two (4%) had thyroid lobectomy, and three patients (6%) were found to be unresectable. Distant metastases were classified into pulmonary and extrapulmonary. Overall survival (OS), disease specific survival (DSS), and locoregional recurrence-free survival were calculated by the Kaplan-Meier method. Factors predictive of the outcome were determined by univariate and multivariate analyses. RESULTS: Thirty-nine patients (75%) were diagnosed with pulmonary metastases alone and 13 (25%) with extrapulmonary metastases. The sites of extrapulmonary metastases were bone in nine, mediastinum in one, pyriform sinus in one and skin in one, and one patient had synchronous lung, bone, and intracerebral metastases. After thyroid surgery, 47 patients (90%) were treated with RAI alone, and 2 patients had external beam radiation in addition to RAI. With a median follow-up after surgery of 78.5 months, the 5-year OS and DSS were 65% and 68%, respectively. Twenty-nine patients (56%) died during follow-up, of whom 24 (46%) died of thyroid cancer. Six patients (12%) developed recurrent disease in the lateral neck, and three patients (6%) developed recurrence in the thyroid bed. Over 45 years, follicular pathology and extrapulmonary metastases were predictive of lower 5-year DSS (56% vs. 100%, p<0.001; 50% vs. 70%, p=0.004; and 46% vs. 75%, p=0.013, respectively). CONCLUSION: Approximately half of patients with WDTC presenting with distant metastases die of disease within 5 years of initial diagnosis despite thyroid surgery and RAI. Age over 45 years, extrapulmonary metastases, and follicular pathology were significant predictors of the poor outcome. PMID- 22827581 TI - Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. AB - Fulvestrant is effective in postmenopausal women with estrogen receptor-positive advanced breast cancer (ABC). So far, no published data exist on fulvestrant combined with chemotherapy. We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate (CM) to fulvestrant in two cohorts (A and B) of heavily pre-treated estrogen receptor-positive advanced ABC patients. From October 2006 to September 2009, 33 postmenopausal patients received fulvestrant 250 mg via i.m. injection q28 days. In A, 20 patients added metronomic cyclophosphamide (50 mg p.o. daily) and methotrexate (2.5 mg p.o. twice daily on day 1 and day 4 weekly) after disease progression, continuing fulvestrant at the same dose. In B, 13 patients started fulvestrant plus metronomic CM upfront. Thirty-two patients were evaluable for response. Clinical benefit (partial response + stable disease >24 months) for A + B was 56% (95% CI 38-74%). The addition of metronomic CM did not determine relevant toxicities. Treatment with fulvestrant plus metronomic CM was effective in advanced ABC and was minimally toxic providing long-term disease control in a high proportion of patients. The prolonged clinical benefit, often desirable in such patients, supports this regimen as an additional and useful therapeutic tool. PMID- 22827582 TI - Iodine-sensitized degradation of 2,4,6-trichlorophenol under visible light. AB - Molecular iodine has been studied, for the first time, as a sensitizer for the degradation of 2,4,6-trichlorophenol (TCP) in aqueous solution under visible light (lambda >= 450 nm). TCP was degraded in the presence of commercial I(2), but the reaction rate decreased significantly after 2 h. When a solution of NaI and H(2)O(2) was used as an iodine source with phosphotungstic acid (PW) as a catalyst, TCP degradation was not only fast but also followed zero-order kinetics. Importantly, the I(2) concentration remained unchanged with time, indicative of I(2) recycling as a kind of photocatalyst. During TCP degradation, 2,6-dichloro-1,4-benzoquinone was produced as the main intermediate (76%), which slowly degraded in the irradiated solution. For every equivalent of TCP consumed at the 2 h time point, approximately 1.7 equivalents of chloride ions were produced. Further study of the effect of variables including the type of polyoxometalates (POM) and the initial concentration of each component revealed that the rate of TCP degradation under visible light was determined by the rate of I(2) production in the dark. The optimum pH and apparent activation energy for TCP disappearance were 4.5 and 42.8 kJ/mol, respectively. It is proposed that TCP degradation is initiated by iodine radicals produced from I(2) photolysis, followed by I(2) regeneration through a POM-catalyzed oxidation of I(3)(-) by H(2)O(2). PMID- 22827583 TI - Understanding men's aggression in bars: development of the Beliefs and Attitudes toward Male Alcohol-Related Aggression (BAMARA) inventory. AB - BACKGROUND: While several qualitative studies suggest that beliefs and attitudes are important in explaining men's alcohol-related aggression, no quantitative instrument measuring men's beliefs and attitudes about male alcohol-related aggression has been developed. The purpose of this study was to develop and test a theoretically based multidimensional inventory measuring Beliefs and Attitudes toward Male Alcohol-Related Aggression (BAMARA) consisting of 9 dimensions: (i) expected negative consequences; (ii) expected positive consequences; (iii) personal approval; (iv) perceived male peer approval; (v) perceived female peer approval; (vi) perceived normality; (vii) relaxed norms when drinking; (viii) alcohol as an excuse; and (ix) male honor/protection of masculinity. METHODS: A random sample of 1,343 young adult male college and university students participated in an online survey. Item analyses using confirmatory factor analytic (CFA) and item-response theory (IRT) procedures were conducted to select a refined pool of items promoting high internal consistency and discriminant validity of the 9 scales. We evaluated the criterion validity of the 9 scales, the BAMARA total score (BAMARA-Total), and a short form of the inventory (BAMARA SF) in terms of their association with experiences of barroom aggression and other theoretically linked constructs. RESULTS: CFA and IRT analyses resulted in a 53-item inventory consisting of the 9 scales with adequate model fit and good internal consistency indices. Criterion validity was demonstrated, with the BAMARA scales correlating well with reports of actual experiences of aggression in bars. BAMARA-Total and BAMARA-SF were found to be significantly associated with barroom aggression controlling for a number of important control variables. CONCLUSIONS: This new instrument is expected to have many important applications in the male aggression literature, with the full BAMARA being employed for the assessment of specific beliefs and attitudes and the BAMARA-SF used as a general attitudinal measure. PMID- 22827584 TI - Flavin-catalyzed insertion of oxygen into rhenium-methyl bonds. AB - Flavins and related molecules catalyze organic Baeyer-Villiger reactions. Combined experimental and DFT studies indicate that these molecules also catalyze the insertion of oxygen into metal-carbon bonds through a Baeyer-Villiger-like transition state. PMID- 22827585 TI - Impact of Helicobacter pylori on the clinical course of recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis is one of the most common lesions of oral mucosa. Helicobacter pylori is suggested as one of the etiological agents of recurrent aphthous stomatitis. Here, we conduct a study for evaluating the impact of H. pylori eradication on clinical course of recurrent aphthous stomatitis. METHODS: Forty-six patients with minor aphthous lesions were enrolled. The number of RAS lesions at last 6 months and vitamin B(12) levels were recorded. All patients were detected for H. pylori with endoscopic biopsy. H. pylori was positive in 30 patients and negative in 16 patients. H. pylori-positive 30 patients received eradication therapy. Three months after therapy, patients were re-evaluated with urea breath test; 18 patients were negative (eradicated), and the remainders (12 patients) were positive (non-eradicated) for H. pylori. 6 months after eradication, vitamin B(12) levels and number of aphthous lesions at 6 months were recorded. RESULTS: Vitamin B(12) levels were significantly increased in H. pylori-eradicated group (P = 0.001), whereas no significant change was found in non-eradicated group (P = 0.638). Mean number of aphthous lesions (per 6 months) of H. pylori-eradicated group was significantly decreased after eradication (P = 0.0001); in the non-eradicated group, no significant change was found (P = 0.677). In Hp-positive group, number of RAS lesions and vitamin B(12) levels were negatively correlated when evaluated both before and after eradication. CONCLUSIONS: This study provides evidence to support the beneficial effect of H. pylori eradication in patients with recurrent aphthous stomatitis. The underlying mechanism might be the increase in vitamin B(12) levels after eradication. PMID- 22827587 TI - Pleiotropic effects of the mioC mutation on the physiology of Pseudomonas aeruginosa PAO1. AB - Flavodoxin (Fld) is a bacterial electron-transfer protein that possesses flavin mononucleotide as a prosthetic group. In the genomes of the Pseudomonas species, the mioC gene is the sole gene, annotated Fld, but its function remains unclear. In this study, phenotype microarray analysis was performed using the wild-type and mioC mutant of pathogenic Pseudomonas aeruginosa PAO1. Our results showed that the mioC mutant is very resistant to oxidative stress. Different antibiotics and metals worked differently on the sensitivity of the mutant. Other pleiotropic effects of mutation in the mioC gene, such as biofilm formation, aggregation ability, motility and colony morphology, were observed under iron stress conditions. Most of the phenotypic and physiological changes could be recovered in the wild type by complementation. Mutation of the mioC gene also influenced the production of pigments. The mioC mutant and mioC over-expressed complementation cells, over-produced pyocyanin and pyoverdine, respectively. Various secreted chemicals were also changed in the mutant, which was confirmed by (1) H NMR analysis. Interestingly, physiological alterations of the mutant strain were restored by the cell-free supernatant of the wild type. The present study demonstrates that the mioC gene plays an important role in the physiology of P. aeruginosa and might be considered as a suitable drug target candidate in pathogenic P. aeruginosa. PMID- 22827586 TI - Genome-wide analysis of zygotic linkage disequilibrium and its components in crossbred cattle. AB - BACKGROUND: Linkage disequilibrium (LD) between genes at linked or independent loci can occur at gametic and zygotic levels known asgametic LD and zygotic LD, respectively. Gametic LD is well known for its roles in fine-scale mapping of quantitative trait loci, genomic selection and evolutionary inference. The less well studied is the zygotic LD and its components that can be also estimated directly from the unphased SNPs. RESULTS: This study was set up to investigate the genome-wide extent and patterns of zygotic LD and its components in a crossbred cattle population using the genomic data from the Illumina BovineSNP50 beadchip. The animal population arose from repeated crossbreeding of multiple breeds and selection for growth and cow reproduction. The study showed that similar genomic structures in gametic and zygotic LD were observed, with zygotic LD decaying faster than gametic LD over marker distance. The trigenic and quadrigenic disequilibria were generally two- to three-fold smaller than the usual digenic disequilibria (gametic or composite LD). There was less power of testing for these high-order genic disequilibria than for the digenic disequilibria. The power estimates decreased with the marker distance between markers though the decay trend is more obvious for the digenic disequilibria than for high-order disequilibria. CONCLUSIONS: This study is the first major genome wide survey of all non-allelic associations between pairs of SNPs in a cattle population. Such analysis allows us to assess the relative importance of gametic LD vs. all other non-allelic genic LDs regardless of whether or not the population is in HWE. The observed predominance of digenic LD (gametic or composite LD) coupled with insignificant high-order trigenic and quadrigenic disequilibria supports the current intensive focus on the use of high-density SNP markers for genome-wide association studies and genomic selection activities in the cattle population. PMID- 22827589 TI - Electrospray ionization-ion mobility spectrometry identified monoclonal antibodies that bind exclusively to either the monomeric or a dimeric form of prostate specific antigen. AB - Macroion mobility spectrometry was used to distinguish between a monoclonal antibody (clone M612165) that bound exclusively to monomeric prostate specific antigen and a different monoclonal antibody (clone M612166) that bound exclusively to a dimeric form of the antigen that only comprised 6.8% of the total protein. In the presence of excess antigen, the mobility spectrum of M612165 was replaced by a composite spectrum that represented a mixture of antibodies that included either one or two equivalents of the protein antigen. In similar circumstances, the mobility spectrum of M612166 was replaced by a composite spectrum that represented a mixture of antibodies that included either two or four equivalents of the protein antigen. When exposed to either of the two antibodies, the mobility spectrum of the prostate specific antigen showed a concomitant decrease in the monomeric antigen in one case and in the dimeric antigen in the other case. While sensitive kinetic exclusion assays demonstrated large differences in the antigen binding behavior of the two antibodies, these functional studies alone were insufficient to reveal the likely structural origins of the observed differences. Macroion mobility measurements were shown to be a useful and informative complement to functional studies in understanding complex macromolecular interactions. PMID- 22827590 TI - Increased population density of neurosurgeons associated with decreased risk of death from motor vehicle accidents in the United States. AB - OBJECT: Motor vehicle accidents (MVAs) are a leading cause of death and disability in young people. Given that a major cause of death from MVAs is traumatic brain injury, and neurosurgeons hold special expertise in this area relative to other members of a trauma team, the authors hypothesized that neurosurgeon population density would be related to reduced mortality from MVAs across US counties. METHODS: The Area Resource File (2009-2010), a national health resource information database, was retrospectively analyzed. The primary outcome variable was the 3-year (2004-2006) average in MVA deaths per million population for each county. The primary independent variable was the density of neurosurgeons per million population in the year 2006. Multiple regression analysis was performed, adjusting for population density of general practitioners, urbanicity of the county, and socioeconomic status of the county. RESULTS: The median number of annual MVA deaths per million population, in the 3141 counties analyzed, was 226 (interquartile range [IQR] 151-323). The median number of neurosurgeons per million population was 0 (IQR 0-0), while the median number of general practitioners per million population was 274 (IQR 175-410). Using an unadjusted analysis, each increase of 1 neurosurgeon per million population was associated with 1.90 fewer MVA deaths per million population (p < 0.001). On multivariate adjusted analysis, each increase of 1 neurosurgeon per million population was associated with 1.01 fewer MVA deaths per million population (p < 0.001), with a respective decrease in MVA deaths of 0.03 per million population for an increase in 1 general practitioner (p = 0.007). Rural location, persistent poverty, and low educational level were all associated with significant increases in the rate of MVA deaths. CONCLUSIONS: A higher population density of neurosurgeons is associated with a significant reduction in deaths from MVAs, a major cause of death nationally. This suggests that the availability of local neurosurgeons is an important factor in the overall likelihood of survival from an MVA, and therefore indicates the importance of promoting neurosurgical education and practice throughout the country. PMID- 22827591 TI - Editorial: neurosurgical presence. PMID- 22827592 TI - Azide quenching of singlet oxygen in suspensions of microenvironments of neutral and surface charged liposomes and micelles. AB - The azide anion is often used as a physical quencher of singlet oxygen, the important active intermediate in photosensitized oxidation. An observed effect of azide on the rate of a reaction is considered an indication to the involvement of singlet oxygen. In most biological photosensitizations, the light-absorbing sensitizer is located in a membrane or in an intracellular organelle, whereas azide is water soluble. The quenching it causes relies on a physical encounter with singlet oxygen during the latter's short lifetime. This can happen either if azide penetrates into the membrane's lipid phase or if singlet oxygen is intercepted when diffusing in the aqueous phase. We demonstrate in this article the difference, in liposomes' suspension, between the effect of azide when using a water-soluble and membrane-bound chemical targets of singlet oxygen, whereas this difference does not exist when micelles are used. We explain the difference on the population of sensitizer and target in the liposome vs micelle. We also show the effect that exists on azide quenching of singlet oxygen by electrically charged lipids in liposomes. This is a result of the accumulation or dilution of azide in the debye layer near the membranes' surface, due to the surface Gouy Chapman potential. PMID- 22827594 TI - Paracetamol intoxications: a retrospective population-based study in Iceland. AB - OBJECTIVE: Paracetamol is the most common cause of acute liver failure (ALF) in many countries. Much data on paracetamol toxicity originate from liver transplant centers and tertiary referral institutions. The authors analyzed the population based annual incidence of paracetamol overdoses and ALF, and described the risk factors for hepatotoxicity. METHODS: A search was undertaken for the diagnosis of paracetamol overdoses in the diagnoses registry of the National University Hospital of Iceland from 2004 to 2009 serving a population of 219,249 inhabitants. Relevant information was collected from medical records. RESULTS: A total of 1913 drug-related poisoning episodes were identified and reviewed, 352 (18%) involved paracetamol overdoses. The annual incidence of paracetamol overdoses declined from 30.0 (2004) to 16.0/100,000 per year (2009) (p < 0.05). The female/male ratio was 3.0 and the largest age group was 16-25 years. After the initial examination, 26% were discharged home. Hospitalized index visits were 182 with accidental overdoses constituting 16 (9%) with no gender difference. Compared with intentional overdose the accidental group had higher aminotransferases (p < 0.005). ALF occurred in 3.8% (7/182) of the index visits and the incidence was 0.7/100,000 per year. In the intentional group, 1.2% (2/163) developed ALF versus 25% (4/16) of the accidental group (p = 0.001). Only one patient died from ALF and none underwent liver transplantation. CONCLUSION: The annual incidence of paracetamol overdoses was high in this population-based study but declined. Young females with intentional overdose accounted for most of the cases, whereas accidental overdoses were more common in older patients. The occurrence of ALF was low and mostly associated with accidental overdose. PMID- 22827595 TI - Prognostic impact of lymphadenectomy in uterine serous cancer. AB - OBJECTIVE: To estimate the survival impact of lymphadenectomy in women diagnosed with uterine serous cancer. DESIGN: Women with a diagnosis of uterine serous cancer were identified from the Surveillance, Epidemiology and End Results Program (SEER) from 1988 to 2007. Only surgically treated women were included. SETTING: The Surveillance, Epidemiology and End Results Program database provided data from 17 registries. POPULATION: The study population comprised 4178 women. METHODS: Statistical analyses using Student's t-test, Kaplan-Meier survival methods and Cox proportional hazards regression were performed. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Three thousand, one hundred and ninety-four (67.7%) women underwent lymphadenectomy. Older women (>=65 years) and Caucasian women (relative to Asian) were less likely to have lymphadenectomy (P < 0.001). The prevalence of nodal metastasis in women having lymphadenectomy was 32%. Of the 1997 women who had disease grossly confined to the uterus and underwent lymphadenectomy, 387 (19%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival; women who underwent lymphadenectomy were 41% (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.54-0.64; P < 0.001) less likely to die than women who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared with women with 1-10 nodes removed, those with more extensive lymphadenectomy (>10 nodes removed) were 26% (HR, 0.74; 95% CI, 0.67-0.83; P < 0.001) less likely to die. The impact of the extent of lymphadenectomy on survival was significant in both node-negative and node-positive women. CONCLUSION: Age and race influenced the prevalence of lymphadenectomy in our cohort. This study suggests that the extent of lymphadenectomy is associated with significant improvement in survival of women with uterine serous cancer. PMID- 22827596 TI - Genetic determinants of athletic performance. AB - An extraordinary revolution in medical research has taken place over the past decade, enabled by the completion of the first human genome sequence in 2001. The Human Genome Project (HGP) has resulted in the 6 billion letter reference human genome sequence and the ultra-high throughput technologies used by medical researchers to identify correlations between positions within the human genome (genotypes) and diseases or traits (phenotypes). Just as every human disease has a genetic component, so too does every human trait. The vast majority of these diseases and traits also have an environmental component that works in conjunction with the body's hardwiring to produce the resultant phenotype- termed "complex genetic traits". A derivative of the HGP has been a deeper understanding not only of diseases but of normal human variability across the population, including aspects of athleticism. The technologies also now exist for consumers to cheaply gain access to variations in the genetic code that are correlated to traits that confer aspects of longevity, memory performance, athleticism and a multitude of others there-through gaining insight into propensities. Communication of propensity to a phenotype such as athletic performance is fraught with technical, legal (e.g., patents), social and ethical issues. That being said, the information is available, has benefit in some cases, and will be utilized in the future. Given that the "genie is out of the bottle" with respect to our ability to deliver this genetic information to individuals, over the past decade our team has worked diligently to craft the appropriate testing and communication paradigms for complex traits. Here we discuss several of the major risks and benefits of this type of testing for athletic performance. It is important to understand the limitations of genetic information in determining the vast majority of traits. PMID- 22827593 TI - Quantitation of DNA adducts by stable isotope dilution mass spectrometry. AB - Exposure to endogenous and exogenous chemicals can lead to the formation of structurally modified DNA bases (DNA adducts). If not repaired, these nucleobase lesions can cause polymerase errors during DNA replication, leading to heritable mutations and potentially contributing to the development of cancer. Because of their critical role in cancer initiation, DNA adducts represent mechanism-based biomarkers of carcinogen exposure, and their quantitation is particularly useful for cancer risk assessment. DNA adducts are also valuable in mechanistic studies linking tumorigenic effects of environmental and industrial carcinogens to specific electrophilic species generated from their metabolism. While multiple experimental methodologies have been developed for DNA adduct analysis in biological samples, including immunoassay, HPLC, and 32P-postlabeling, isotope dilution high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) generally has superior selectivity, sensitivity, accuracy, and reproducibility. As typical DNA adduct concentrations in biological samples are between 0.01-10 adducts per 108 normal nucleotides, ultrasensitive HPLC-ESI-MS/MS methodologies are required for their analysis. Recent developments in analytical separations and biological mass spectrometry, especially nanoflow HPLC, nanospray ionization MS, chip-MS, and high resolution MS, have pushed the limits of analytical HPLC-ESI-MS/MS methodologies for DNA adducts, allowing researchers to accurately measure their concentrations in biological samples from patients treated with DNA alkylating drugs and in populations exposed to carcinogens from urban air, drinking water, cooked food, alcohol, and cigarette smoke. PMID- 22827597 TI - Predictive genomics DNA profiling for athletic performance. AB - Genes control biological processes such as muscle, cartilage and bone formation, muscle energy production and metabolism (mitochondriogenesis, lactic acid removal), blood and tissue oxygenation (erythropoiesis, angiogenesis, vasodilatation), all essential in sport and athletic performance. DNA sequence variations in such genes confer genetic advantages that can be exploited, or genetic 'barriers' that could be overcome to achieve optimal athletic performance. Predictive Genomic DNA Profiling for athletic performance reveals genetic variations that may be associated with better suitability for endurance, strength and speed sports, vulnerability to sports-related injuries and individualized nutritional requirements. Knowledge of genetic 'suitability' in respect to endurance capacity or strength and speed would lead to appropriate sport and athletic activity selection. Knowledge of genetic advantages and barriers would 'direct' an individualized training program, nutritional plan and nutritional supplementation to achieving optimal performance, overcoming 'barriers' that results from intense exercise and pressure under competition with minimum waste of time and energy and avoidance of health risks (hypertension, cardiovascular disease, inflammation, and musculoskeletal injuries) related to exercise, training and competition. Predictive Genomics DNA profiling for Athletics and Sports performance is developing into a tool for athletic activity and sport selection and for the formulation of individualized and personalized training and nutritional programs to optimize health and performance for the athlete. Human DNA sequences are patentable in some countries, while in others DNA testing methodologies [unless proprietary], are non patentable. On the other hand, gene and variant selection, genotype interpretation and the risk and suitability assigning algorithms based on the specific Genomic variants used are amenable to patent protection. PMID- 22827598 TI - Performance of two new, automated chemiluminescence assay panels for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome. AB - INTRODUCTION: Anticardiolipin (aCL) and anti-beta2-glycoprotein I (abeta2GPI) antibodies are two of the three laboratory criteria for antiphospholipid syndrome (APS). All assays for antiphospholipid antibodies (aPL), coagulation assays as well as ELISAs, show methodological shortcomings, which makes the search for better assays everlasting. The purpose of this study was to investigate the diagnostic performance of two new, fully automated systems (Zenit RA and HemosIL Acustar) applying chemiluminescent technology for aPL detection. METHODS: The study cohort consisted of a patient population presenting with thrombosis. In such patient population, the demonstration of aPL determines whether a patient has APS or not with implications for treatment. One hundred and twenty-four patients with thrombotic complications, of whom 26 were patients with definite APS, were integrated in this study. Besides, aPL titres were compared to the Sapporo standards. RESULTS: Results of both systems agreed well with ELISA and mutually. Analysis of the discrepant results between Zenit and Acustar finally led to one misclassification as APS. CONCLUSION: Diagnostic performances of both Zenit RA and HemosIL Acustar were comparable with odds ratios lower limits of CI of 5 for abeta2 GPI IgG for Zenit and Acustar and 6 and 5 for aCl IgG on Zenit and Acustar, respectively. However, even with these new automated systems, titres differed largely between systems, especially for abeta2 GPI IgG. PMID- 22827599 TI - Mesenchymal stromal cells as universal donor cells. AB - Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage for which use of autologous cells have been preferred to avoid immune rejection. Recently, however, rodent as well as human mesenchymal stromal cells (MSCs) have been reported to be uniquely immune tolerant, both in in vitro as well as in vivo transplant models. In this editorial, we briefly summarize the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "Universal Donor Cells." PMID- 22827600 TI - Daphnetin methylation stabilizes the activity of phosphoribulokinase in wheat during cold acclimation. AB - The methylation of daphnetin (7,8-dihydroxycoumarin) to its 8-methyl derivative is catalyzed by a wheat (Triticum aestivum L.) O-methyltransferase (TaOMT1). This enzyme is regulated by cold and photosystem II excitation pressure (plastid redox state). Here, we investigated the biological significance of this methylation and its potential role in modulating the activity of kinases in wheat. To identify the potential kinases that may interact with daphnetin in wheat, the soluble protein extract from aerial parts of cold-acclimated wheat was purified by DEAE cellulose separation and affinity chromatography on a daphnetin derivative (7,8 dihydroxy-4-coumarin acetic acid)-EAH sepharose column. Mass spectrometric analysis indicated that wheat phosphoribulokinase (TaPRK) is the major kinase that binds to daphnetin. This TaPRK plays an important role in regulating the flow of carbon through the Calvin cycle, by catalyzing the final step in the regeneration of ribulose 1,5-bisphosphate from ribulose-5-phosphate (Ru5P) and ATP. The activities of TaPRK, endogenous or recombinant, are inhibited by daphnetin in a specific and dose-dependent manner, but not by its monomethyl derivative (7-methyl, 8-hydroxycoumarin). Furthermore, HPLC-MS analysis of wheat extracts reveals that 7,8-dimethoxycoumarin is more abundant than its monomethyl derivative. The results also show that cold acclimation does not alter the level of TaPRK mRNA or its enzyme activity, and thus ensures the stable generation of ribulose 1,5-biphosphate. PMID- 22827602 TI - Thyroidectomy decreases snoring and sleep apnea symptoms. AB - BACKGROUND: Patients with goiter often complain of compressive symptoms, which may contribute to symptoms of obstructive sleep apnea (OSA). However, the impact of thyroid enlargement on these symptoms is not clear. Therefore, we sought to evaluate whether symptoms of sleep apnea resolved after thyroidectomy by using a validated questionnaire. METHODS: The Berlin Questionnaire, a validated sleep apnea assessment tool, was provided to patients at a single academic institution before and after thyroidectomy. Patients who admitted to symptoms of snoring were asked to complete the questionnaire before and 8 weeks after surgery to assess for improvement in symptoms. The questionnaire uses 3 categories of questions to determine risk of sleep apnea. Two symptom categories must be positive for a patient to be considered high risk for sleep apnea. RESULTS: Forty-five patients completed both pre- and postoperative questionnaires. The average age of patients completing the questionnaire was 53+/-2 years, and 78% of patients were female. Average body mass index was 33.3+/-1.4 kg/m(2). Based on their preoperative questionnaire score, 71% of patients were considered to be high risk for OSA, and this decreased to 51% after surgery (p=0.002). Overall scores significantly improved after surgery (mean 2.0 vs. 1.6, p<0.0001). Specifically, patients noted a significant decrease in snoring frequency after surgery (p=0.002), as well as a significant decrease in whether or not their snoring bothered others (p=0.004). The frequency of nodding off during the day also significantly decreased after surgery (p=0.02). Among patients with >=25% improvement compared with those with <25% improvement in scores, the only significant difference found was a higher preoperative thyrotropin among patients with <25% improvement (p=0.03). No significant difference was found between age, gender, presence of compressive symptoms, gland weight at resection, presence of thyroiditis, or the largest dimension of the gland at resection. CONCLUSIONS: Thyroid surgery appears to significantly improve symptoms of OSA in patients who screened positive for symptoms before surgery. Evaluation of patients with OSA should include evaluation of thyroid disease, as symptoms of sleep apnea may improve with thyroidectomy. PMID- 22827601 TI - The role of individual carbohydrate-binding sites in the function of the potent anti-HIV lectin griffithsin. AB - Griffithsin (GRFT) is a lectin that has been shown to inhibit HIV infection by binding to high mannose glycan structures on the surface of gp120, and it is among the most potent HIV entry inhibitors reported so far. However, important biochemical details on the antiviral mechanism of GRFT action remain unexplored. In order to understand the role of the three individual carbohydrate-binding sites (CBS) in GRFT, mutations were made at each site (D30A, D70A, and D112A), and the resulting mutants were investigated. NMR studies revealed that each GRFT variant was folded but showed significant peak movement on the carbohydrate binding face of the protein. The wild-type and each point mutant protein appeared as tight dimers with a K(d) below 4.2 MUM. Mutation of any individual CBS on GRFT reduced binding of the protein to mannose, and ELISA assays revealed a partial loss of ability of each GRFT point mutant to bind gp120, with a near-complete loss of binding by the triple mutant D30A/D70A/D112A GRFT. A more quantitative surface plasmon resonance (SPR) examination showed a rather small loss of binding to gp120 for the individual GRFT point mutants (K(D): 123 to 245 pM range versus 73 pM for wild-type GRFT), but dramatic loss of the triple mutant to bind gp120 derived from R5 and X4 strains (K(D) > 12 nM). In contrast to the 2- to 3-fold loss of binding to gp120, the single CBS point mutants of GRFT were significantly less able to inhibit viral infection, exhibiting a 26- to 1900-fold loss of potency, while the triple mutant was at least 875-fold less effective against HIV 1 infection. The disparity between HIV-1 gp120 binding ability and HIV inhibitory potency for these GRFT variants indicates that gp120 binding and virus neutralization do not necessarily correlate, and suggests a mechanism that is not based on simple gp120 binding. PMID- 22827603 TI - Social representation of events in world history: crosscultural consensus or Western discourse? How Turkish students view events in world history. AB - The perceptions of historical events are considered to be an important cultural, political, and social psychological variable. Earlier studies have shown a crosscultural consensus on historical events that are considered to be important. It has been indicated that a strong Western-Christian European template dominates the view of which events are considered to be important events in history, by many samples across the world. It was the aim of this study to test this finding with a Turkish sample, which would represent some unique characteristics in that it is Muslim, comes from an Empire background, and has undergone a recent nation building process. College students (n = 372) responded to a questionnaire that was utilized in seven other countries. It was shown that Turkish students were not Eurocentric as expected by the literature: They were highly sociocentric; they gave importance to events related to Turkish history. They were similar to their European counterparts in that war and violence were given primary importance when selecting events as important in history. However, they did not behave as predicted by earlier literature: They did not see Western European events as having a primary importance in history but gave at least equal importance to events that originated from Ottoman Empire roots. The results were discussed in terms of the unique cultural and historical variables that contribute to the identity and social psychological attributions of Turkish students. Further research should focus on not only which events are considered as important historical events but also the reasons behind these. PMID- 22827604 TI - Spirastrellolide B: construction of the C(26)-C(40) northern hemisphere and a related [5,5,7]-bis-spiroketal analogue. AB - Differential synthetic access to an advanced C26-C40 northern hemisphere fragment of spirastrellolide B and to a related [5,5,7]-bis-spiroketal analogue from a common intermediate has been achieved. Central to this venture is the regiocontrolled functionalization of a C(31-32) alkyne, exploiting different transition metal catalysts (cf. Pt(II) and Au(I)). PMID- 22827605 TI - Redox properties of structural Fe in clay minerals. 1. Electrochemical quantification of electron-donating and -accepting capacities of smectites. AB - Clay minerals often contain redox-active structural iron that participates in electron transfer reactions with environmental pollutants, bacteria, and biological nutrients. Measuring the redox properties of structural Fe in clay minerals using electrochemical approaches, however, has proven to be difficult due to a lack of reactivity between clay minerals and electrodes. Here, we overcome this limitation by using one-electron-transfer mediating compounds to facilitate electron transfer between structural Fe in clay minerals and a vitreous carbon working electrode in an electrochemical cell. Using this approach, the electron-accepting and -donating capacities (Q(EAC) and Q(EDC)) were quantified at applied potentials (E(H)) of -0.60 V and +0.61 V (vs SHE), respectively, for four natural Fe-bearing smectites (i.e., SWa-1, SWy-2, NAu-1, and NAu-2) having different total Fe contents (Fe(total) = 2.3 to 21.2 wt % Fe) and varied initial Fe(2+)/Fe(total) states. For every SWa-1 and SWy-2 sample, all the structural Fe was redox-active over the tested E(H) range, demonstrating reliable quantification of Fe content and redox state. Yet for NAu-1 and NAu-2, a significant fraction of the structural Fe was redox-inactive, which was attributed to Fe-rich smectites requiring more extreme E(H)-values to achieve complete Fe reduction and/or oxidation. The Q(EAC) and Q(EDC) values provided here can be used as benchmarks in future studies examining the extent of reduction and oxidation of Fe-bearing smectites. PMID- 22827606 TI - Electrocardiographic diagnosis of biventricular pacing in patients with nonapical right ventricular leads. AB - BACKGROUND: Assessment of left ventricular (LV) capture is of paramount importance in patients with biventricular (BiV) pacing. Our goal was to identify electrocardiographic features that differentiate between BiV and right ventricular (RV)-only pacing in patients with nonapical RV leads. METHODS: The study enrolled 300 consecutive patients with BiV devices and nonapical RV leads, and obtained from them 558 electrocardiograms with either BiV pacing (n = 300) or RV-only pacing (n = 258). RV pacing served as a surrogate for loss of LV capture. Electrocardiograms from the first 150 patients were used to identify BiV-specific features, and to construct an algorithm to differentiate between BiV and RV-only pacing. Electrocardiograms from the second 150 patients were used to validate the algorithm. RESULTS: The following electrocardiographic features typical of BiV pacing were identified: QS in lead V6 (specificity = 98.7%, sensitivity = 54.7%), dominant R in lead V1 (specificity = 100%, sensitivity = 23.3%), q in lead V6 (specificity = 96%, sensitivity = 22.7%), and a QRS < 160 ms (specificity = 100%, sensitivity = 66.0%). The algorithm based on those features was found to have an overall diagnostic accuracy of 95.0%, a specificity of 96.0%, and a sensitivity of 93.5%. CONCLUSIONS: The study identified QRS features that were very specific for BiV pacing in patients with nonapical RV leads. Sequential arrangement of those features resulted in an algorithm that was very accurate for differentiating between BiV pacing and loss of LV capture. PMID- 22827607 TI - Differential regulation of CXCL5 by FGF2 in osteoblastic and endothelial niche cells supports hematopoietic stem cell migration. AB - Stem cell maintenance requires a specific microenvironment. Hematopoietic stem cells (HSCs) are mainly maintained by the endosteal osteoblast (OB) niche, which provides a quiescent HSC microenvironment, and the vascular niche, which regulates the proliferation, differentiation, and mobilization of HSCs. The systemic administration of FGF2 failed to induce normal hematopoiesis in bone marrow (BM) by reducing SDF-1, an important factor for hematopoiesis. Interestingly, SDF-1 levels were decreased in the OBs, but increased in vascular endothelial C166 cells when FGF2 was administered. We hypothesized that FGF2 induces changes in HSC migration from BM; therefore, we investigated FGF2-induced factors of HSC migration by a microarray chip. We searched the genes that were decreased in primary OBs, but increased in C166 cells upon FGF2 treatment. We confirmed selected genes that function in the extracellular region and identified the CXCR2-related chemokine candidate LIX/Cxcl5. A chemotaxis assay showed that CXCL5 induced the migration of HSCs (CD34(-/low)LSK). Our data suggest that the differential regulation of the chemokine CXCL5 between OBs and endothelial cells upon FGF2 treatment is involved in HSC mobilization from the OB niche or BM to peripheral blood. PMID- 22827608 TI - Identification and confirmation of differentially expressed fucosylated glycoproteins in the serum of ovarian cancer patients using a lectin array and LC MS/MS. AB - In order to discover potential glycoprotein biomarkers in ovarian cancer, we applied a lectin array and Exactag labeling based quantitative glycoproteomics approach. A lectin array strategy was used to detect overall lectin-specific glycosylation changes in serum proteins from patients with ovarian cancer and those with benign conditions. Lectins, which showed significant differential response for fucosylation, were used to extract glycoproteins that had been labeled using isobaric chemical tags. The glycoproteins were then identified and quantified by LC-MS/MS, and five glycoproteins were found to be differentially expressed in the serum of ovarian cancer patients compared to benign diseases. The differentially expressed glycoproteins were further confirmed by lectin-ELISA and ELISA assay. Corticosteroid-binding globulin (CBG), serum amyloid p component (SAP), complement factor B (CFAB), and histidine-rich glycoprotein (HRG) were identified as potential markers for differentiating ovarian cancer from benign diseases or healthy controls. A combination of CBG and HRG (AUC = 0.825) showed comparable performance to CA125 (AUC = 0.829) in differentiating early stage ovarian cancer from healthy controls. The combination of CBG, SAP, and CA125 showed improved performance for distinguishing stage III ovarian cancer from benign diseases compared to CA125 alone. The ability of CBG, SAP, HRG, and CFAB to differentiate the serum of ovarian cancer patients from that of controls was tested using an independent set of samples. Our findings suggest that glycoprotein modifications may be a means to identify novel diagnostic markers for detection of ovarian cancer. PMID- 22827610 TI - Nutritional assessments for ordinary medical care in patients with chronic liver disease. AB - AIM: In patients with chronic liver disease who are at risk of malnutrition, simple and useful assessments for nutritional status should be established for ordinary medical care. The prognostic nutritional index (PNI) and controlling nutritional status (CONUT) are simple assessments constructed of only two or three laboratory data. We aimed to describe the potential of PNI and CONUT as a nutritional assessment tool in patients with chronic liver disease. METHODS: We enrolled 165 patients, aged 18-85 years, with chronic liver disease. These patients were nutritionally assessed by PNI or CONUT, demonstrating the association with the severity of chronic liver disease or anthropometric values. RESULTS: The value of PNI or CONUT was significantly associated with the severity of chronic liver disease (P < 0.001, respectively). In addition, the value of CONUT was significantly associated with all the anthropometric values such as body mass index (BMI, P < 0.05), mid-arm circumference (AC, P < 0.001), mid-arm muscle circumference (AMC, P < 0.001), and triceps skinfold thickness (TSF, P < 0.001), whereas the value of PNI was significantly associated with the values of AC (P < 0.01), AMC (P < 0.05) and TSF (P < 0.05). Approximately 80% of cirrhotic patients were assessed by PNI or CONUT to have obvious malnutrition. CONCLUSION: PNI and CONUT are potential tools for nutritional assessment in patients with chronic liver disease, especially for ordinary medical care, because of their simplicity. PMID- 22827609 TI - Identification of sulfoglycolipid bioactivities and characteristic fatty acids of marine macroalgae. AB - The fatty acid compositions of 21 species of marine macroalgae, including 5 species of Chlorophyta (green algae), 13 of Rhodophyta (red algae), and 3 of Heterokontophyta (brown algae), were collected from northeastern Taiwan to survey their functional lipids. The lipid contents of green algae ranged from 15.36 to 20.15 mg/g, dry basis (db), and were characterized by a high content of C18:2 and C18:3, red algae (18.57-28.34 mg/g db) were high in C20:4 and C20:5, and brown algae (13.11-19.56 mg/g db) were high in C18:4, C20:4, and C:20:5. All algal lipids contained fatty acids of odd-number carbons, C17:0, and C17:1. Red algae had relatively higher levels of polyunsaturated fatty acids (PUFAs) and were richer in eicosapentaenoic acid (EPA) than green and brown algae. A red alga, Porphyra crispata , was extracted with ethanol and separated on a hydrophobic column (Diaion HP-20 column) to obtain sulfoglycolipids (sulfoquinovosyldiacylglycerols, SQDGs). The main fatty acids in SQDGs were palmitic acid (C16:0), 33.3%; EPA (C20:5), 30.0%; arachidonic acid (C20:4), 12.7%; oleic acid (C18:1), 7.52%; and stearic acid (C18:0), 6.83%. The n-3/n-6 ratio was 1.9, whereas the authentic standard, spinach SQDG, did not contain n-3 fatty acids. Sulfoglycolipids inhibited the growth of human hepatocellular carcinoma cell line (HepG2). The IC50 was 126 MUg/mL, which is lower than that of the spinach SQDG (255 MUg/mL). PMID- 22827611 TI - The domain Archaea in human mucosal surfaces. AB - Archaea present distinct features from bacteria and eukaryotes, and thus constitute one of the branches of the phylogenetic tree of life. Members of this domain colonize distinct niches in the human body, arranged in complex communities, especially in the intestines and the oral cavity. The diversity of archaea within these niches is limited to a few phylotypes, constituted in particular by methane-producing archaeal organisms. Although they are possibly symbionts, methanogens may play a role in the establishment of mucosal diseases by favouring the growth of certain bacterial groups. PMID- 22827612 TI - A novel approach: transumbilical endoscopic exploration and biopsy for patients with unknown ascites. AB - BACKGROUND: The main surgical methods used for the diagnosis of unknown ascites are laparotomy, laparoscopic exploration, and natural orifice translumenal endoscopic surgery (NOTES). This article introduces a novel method: transumbilical endoscopic exploration and biopsy. PATIENTS AND METHODS: From September 2009 to January 2012, 11 patients with unknown ascites were scheduled for transumbilical endoscopic exploration and biopsy at the First Affiliated Hospital of Harbin Medical University, Harbin, China. After the patient underwent general anesthesia and artificial pneumoperitoneum, a 1.0-cm trocar was placed at the umbilical region. After initial observation of the whole peritoneal cavity with a laparoscope, a sterile endoscope (gastroscope) was put through the trocar. The surgeon regulated the depth of insertion of the endoscope and the direction of the trocar, while the endoscopic physician was in charge of turning the camera lens of the endoscope, controlling the biopsy forceps, irrigation, and suction. After exploration, four to six pieces of tissues were obtained for biopsy. RESULTS: These patients were diagnosed by endoscopic exploration and pathological examination: 3 cases were tuberculous peritonitis, 2 cases were malignant peritoneal mesotheliomas, 2 cases were peritoneal carcinomatosis, 1 case was a small intestinal tumor, 2 cases were advanced ovarian cancer, and 1 case was cirrhosis. CONCLUSION: Transumbilical endoscopic exploration and biopsy is an easy, practical, and effective method for the diagnosis of unknown ascites. PMID- 22827613 TI - Use of catechol as selective redox mediator in scanning electrochemical microscopy investigations. AB - The use of catechols, and more specifically of dopamine, as a specific redox mediator for scanning electrochemical microscopy (SECM) investigations was evaluated in the challenging situation of an ultrathin layer deposited on a conductive substrate (carbon materials). Experiments show that dopamine is a well adapted redox system for SECM in feedback mode and in unbiased conditions. Used as a redox mediator, catechol permits the investigations of modified surfaces without an electrical connection of the sample thanks to fast charge transfer kinetics but with a surface selectivity that does not exist in classical outer sphere redox mediators. The interest of catechol in SECM as a sensitive redox mediator is exemplified by monitoring several modification steps of an ultrathin (<1 nm) hierarchically porous organic monolayer deposited on carbon substrates. For quantitative analysis, the SECM approach curves using dopamine could simply be characterized with an irreversible electron transfer kinetics model in a large range of pH. PMID- 22827614 TI - Protective effects of alpha-tocopherol against oxidative stress related to nephrotoxicity by monosodium glutamate in rats. AB - CONTEXT: Chronic oral intake of high doses of monosodium glutamate (MSG) could be harmful to tissues and organs. Oxidative stress enhances membrane damage by lipid peroxidation and alterations of antioxidant enzymes, which affects the functional activity of organs. Antioxidant vitamins have the capacity to regulate the oxidative stress related functional and pathological processes. OBJECTIVE: In this study, the protective role of alpha-tocopherol against MSG-induced nephrotoxicity was analyzed. MATERIALS AND METHODS: MSG (4 g/kg) was given orally to female wistar rats for a period of 180 days. Renal function parameters (urea, uric acid, and creatinine), lipid peroxidation markers (malondialdehyde and conjugated dienes), antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, and reduced glutathione), and histopathology were investigated. All tests were done in rats treated with MSG and at two different doses of alpha-tocopherol (100 and 200 mg/kg). RESULTS: Oral exposure of MSG significantly increased renal function markers, lipid peroxidation byproducts, and altered antioxidant system. Moreover, the kidney showed congested glomeruli, tubular swelling, capillary congestion and microhemorrhages in stromal areas of the tubules. Co-administration of MSG and alpha-tocopherol (200 mg/kg) significantly reduced the oxidative damage compared with MSG-treated group and also restored the normal renal function. DISCUSSION: The results indicated that oxidative stress was involved in MSG-induced functional and pathological changes in the kidney. alpha-tocopherol modulates the functional disorder and maintains the normal architecture of renal tissue by reducing oxidative stress. CONCLUSION: The alpha-tocopherol may be a potent protective agent in combating MSG-induced renal toxicity. PMID- 22827615 TI - Stabilization and structural alteration of the G-quadruplex DNA made from the human telomeric repeat mediated by Troger's base based novel benzimidazole derivatives. AB - Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3'-overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Troger's base skeleton with the G quadruplex DNA (G4DNA). These Troger's base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV-vis titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA. PMID- 22827616 TI - Structure-dependent demetalation kinetics of chlorophyll a analogs under acidic conditions. AB - Demetalation of chlorophyll (Chl) a and its analogs is an important reaction in oxygenic photosynthetic organisms, which produces the primary electron acceptors in photosystem II reaction centers and is crucial in the Chl degradation. From these viewpoints, demetalation reactions of four Chl a analogs, 3,8-divinyl-Chl a (DV-Chl a), 3-devinyl-3-ethyl-Chl a (mesoChl a), 13(2)-demethoxycarbonyl-Chl a (pyroChl a) and protochlorophyll a (PChl a), were kinetically analyzed under weakly acidic conditions, and were compared with that of Chl a. DV-Chl a exhibited slower demetalation kinetics than did Chl a, whereas demetalation of mesoChl a was faster than that of Chl a. The difference in demetalation kinetics of the three chlorophyllous pigments originates from the electron-withdrawing ability of the vinyl group as the peripheral substituent compared with the ethyl group. Removal of the electron-withdrawing and homoconjugating 13(2) methoxycarbonyl group in Chl a (Chl a -> pyroChl a) accelerated demetalation kinetics by two-fold. PChl a possessing the porphyrin-type skeleton exhibited slower demetalation kinetics than Chl a. The structure-dependent demetalation properties of Chl a analogs will be useful for understanding in vivo Chl demetalation reactions in oxygenic photosynthetic organisms. PMID- 22827617 TI - Better safe than sorry. PMID- 22827619 TI - Excessive TV watching in patients with frontotemporal dementia. AB - The "environmental dependency syndrome" refers to a loss of personal autonomy such that a person's environment almost entirely controls their actions. The goal of this study is to learn if patients with frontotemporal degeneration (FTD) exhibit prolonged TV watching, a behavior which may be a symptom of environmental dependency. We recruited 40 patients with FTD and 48 patients with Alzheimer's disease (AD), and asked these participants' caregivers about TV watching behaviors including total viewing time and channel/show preference, along with other behaviors indicative of environmental dependency. Compared to AD patients, FTD patients watched TV for a longer time. In addition, the patients who watched more TV showed more signs of environmental dependency. Increased TV watching may be a sign of environmental dependency, however further research is needed to explore other hypotheses. PMID- 22827618 TI - Genomic and transcriptomic insights into the thermo-regulated biosynthesis of validamycin in Streptomyces hygroscopicus 5008. AB - BACKGROUND: Streptomyces hygroscopicus 5008 has been used for the production of the antifungal validamycin/jinggangmycin for more than 40 years. A high yield of validamycin is achieved by culturing the strain at 37 degrees C, rather than at 30 degrees C for normal growth and sporulation. The mechanism(s) of its thermo regulated biosynthesis was largely unknown. RESULTS: The 10,383,684-bp genome of strain 5008 was completely sequenced and composed of a linear chromosome, a 164.57-kb linear plasmid, and a 73.28-kb circular plasmid. Compared with other Streptomyces genomes, the chromosome of strain 5008 has a smaller core region and shorter terminal inverted repeats, encodes more alpha/beta hydrolases, major facilitator superfamily transporters, and Mg2+/Mn2+-dependent regulatory phosphatases. Transcriptomic analysis revealed that the expression of 7.5% of coding sequences was increased at 37 degrees C, including biosynthetic genes for validamycin and other three secondary metabolites. At 37 degrees C, a glutamate dehydrogenase was transcriptionally up-regulated, and further proved its involvement in validamycin production by gene replacement. Moreover, efficient synthesis and utilization of intracellular glutamate were noticed in strain 5008 at 37 degrees C, revealing glutamate as the nitrogen source for validamycin biosynthesis. Furthermore, a SARP-family regulatory gene with enhanced transcription at 37 degrees C was identified and confirmed to be positively involved in the thermo-regulation of validamycin production by gene inactivation and transcriptional analysis. CONCLUSIONS: Strain 5008 seemed to have evolved with specific genomic components to facilitate the thermo-regulated validamycin biosynthesis. The data obtained here will facilitate future studies for validamycin yield improvement and industrial bioprocess optimization. PMID- 22827621 TI - Coeliotomy-assisted intrauterine insemination in dogs: a study of 238 inseminations. AB - OBJECTIVE: (1) To report whelping rates and litter sizes following coeliotomy assisted intrauterine inseminations (CAII) performed commercially and (2) to identify factors that may influence these outcomes. DESIGN: Retrospective single cohort observational study. PROCEDURE: All oestrous cycles in bitches that presented to the study hospital for CAII between 1 January 2005 and 31 December 2010 were included. One insemination was performed per oestrus. Whelping and litter size following CAII were recorded. Potential determinants of these outcomes were assessed. RESULTS: Of 238 inseminations performed, 174 (73.1%) resulted in whelping. The known litter size ranged from 1 to 16 pups (mean +/- SD 6.12 +/- 3.12 pups). From univariable analyses, progressive motility percentage was the only variable significantly associated with odds of whelping (P = 0.020); bitch parity and weight were associated with litter size when adjusted for each other (P = 0.035 and 0.003, respectively). Inseminations performed with >200 * 10(6) progressively motile sperm were more likely to result in whelping relative to inseminations with >100-200 * 10(6) progressively motile sperm (odds ratio 3.61, 95% confidence interval 0.84-15.5, P = 0.084), and, in a separate model, relative to >75-125 * 10(6) progressively motile sperm (odds ratio 6.09, 95% confidence interval 1.41-26.36, P = 0.016). CONCLUSION: Whelping rates and litter sizes were similar to other case studies and the experimental reports of CAII. Progressive motility percentage affects the odds of whelping, and litter size is affected by both the weight and parity of the bitch. Importantly, these findings provide some evidence that whelping rates with CAII are not maximised unless more than 200 * 10(6) progressively motile sperm are inseminated. PMID- 22827623 TI - Resolution of life-threatening dysphagia caused by caudal occipital malformation syndrome following foramen magnum decompressive surgery. AB - A Cavalier King Charles Spaniel was presented with acute onset, life-threatening dysphagia suspected to be secondary to medulla oblongata compression caused by caudal occipital malformation syndrome. The patient required urgent tracheostomy tube placement to remain stable and was subsequently cured of the presenting neurological deficits by foramen magnum decompressive surgery. Neurogenic dysphagia is a relatively common presenting sign in human Chiari malformation syndromes, but has not been described as a major clinical sign in veterinary patients. Caudal occipital malformation syndrome should be included in the differential diagnosis list for susceptible breeds presenting with dysphagia. Early recognition favours expeditious surgical intervention and a positive outcome in human patients, and this may also be the case in veterinary patients. PMID- 22827622 TI - Flow cytometric detection of alpha-1-acid glycoprotein on feline circulating leucocytes. AB - OBJECTIVE: To assess whether alpha-1-acid glycoprotein (AGP) can be detected on the membrane of feline circulating leucocytes. DESIGN: The presence of AGP on circulating leucocytes was investigated in both clinically healthy cats and cats with different diseases. A group of feline coronavirus (FCoV)-positive cats, comprising cats with feline infectious peritonitis (FIP) and cats not affected by FIP but seropositive for FCoV, were included in this study because the serum concentration of AGP increases during FCoV infection. PROCEDURE: Flow cytometry (using an anti-feline AGP antibody), serum protein electrophoresis, routine haematology and measurement of the serum AGP concentration were performed using blood samples from 32 healthy cats (19 FCoV-seropositive), 13 cats with FIP and 12 with other diseases (6 FCoV-seropositive). The proportion of cats with AGP positive leucocytes in the different groups (e.g. controls vs sick; FIP vs other diseases, etc.) or in cats with different intensities of inflammatory response was compared using a Chi-square test. RESULTS: AGP-positive leucocytes were found in 23% of cats. Compared with controls, the proportion of patients with positive granulocytes and monocytes was higher among sick cats (especially cats with diseases other than FIP) and cats with high serum AGP concentration, but not in cats with leucocytosis or that were FCoV-seropositive. CONCLUSION: AGP-positive leucocytes can be found in feline blood, especially during inflammation. Conversely, no association between AGP-positive leucocytes and FIP was found. Further studies are needed to elucidate the mechanism responsible for this finding and its diagnostic role in cats with inflammation. PMID- 22827624 TI - Comparative approach to understanding traumatic injury in the immature, postnatal brain of domestic animals. AB - Traumatic brain injury (TBI) is a frequent occurrence in veterinary medicine, but the mechanisms leading to brain damage after a head impact are incompletely understood, particularly in the postnatal immature and still developing nervous system. This paper reviews neurotrauma studies, largely in paediatric humans and experimental animal models, in order to outline the pathophysiological and biomechanical events likely to be operative in head trauma involving domestic animal species in the postnatal period, as there is almost no other information available in the veterinary literature. Predicting the outcome of TBI is particularly difficult at this developmental time, in large part because recovery is influenced by the stage of brain maturation and neuroplasticity. An important part of the clinical management of TBI is the differentiation of primary brain damage, which occurs at the moment of head impact and is largely refractory to treatment, from the cascade of secondary events, which evolve over time and are potentially preventable and amenable to therapeutic intervention. An understanding of the causes and consequences of secondary brain damage such as hypoxia-ischaemia, brain swelling, elevated intracranial pressure, and infection is critical to limiting the resulting brain injury. PMID- 22827625 TI - Effect on the breech and tail characteristics of Merino lambs of varying the duration of application of occlusive plastic clips as an alternative to mulesing. AB - OBJECTIVE: The objective of the study was to determine the minimum duration of clip application required to increase the size of the perineal and tail bare areas and reduce breech wrinkle, dag or urine stain scores of Merino lambs. METHOD: The study was conducted on a single farm in western New South Wales using 491 unmulesed lambs of a plain body type (9-14 weeks of age; mean (+/-SD) bodyweight 26.9 +/- 5.0 kg; 82% wrinkle score 1 or 2) randomly allocated into 10 groups. Groups 1-9 included 39-46 lambs treated with the clips, which were removed at 1-7, 10 or 14 days, respectively, after application. Group 10 comprised 53 lambs that were unclipped, unmulesed controls. Visual scores, bare area measurements and bodyweights were assessed before and at 28 and 60 days following clip application. RESULTS: Clips increased the size of the perineal and tail bare areas if left on the lambs for a minimum of 4-6 days. The increases in the size of the perineal and tail bare areas were similar to the results of previous studies. This indicates that the clips performed as expected, despite the current study being conducted on lambs with a plain body type. CONCLUSION: When used as an alternative to mulesing, clips should remain on lambs for a minimum of 4-6 days to effectively increase the size of the perineal and tail bare areas. Further research is required to determine the degree of protection against flystrike provided by the clip method. PMID- 22827626 TI - Effects of intra-articular sodium pentosan polysulfate and glucosamine on the cytology, total protein concentration and viscosity of synovial fluid in horses. AB - OBJECTIVE: Evaluate synovial fluid cytology, total protein concentration and viscosity after intra-articular administration of combined pentosan polysulfate and glucosamine in horses. DESIGN: Ten adult Standardbred horses had each carpal joint (n = 20) randomly assigned to one of two treatments: control (5 mL saline) or treated (pentosan polysulfate and glucosamine). All horses received an intra articular injection every 7 days for 3 weeks and synovial fluid samples were collected on days 1 (baseline), 2, 3, 7, 8, 9, 14, 15, 16 and 21. Synovial fluid variables measured included total protein concentration, total nucleated cell count, red blood cell count, the neutrophil, lymphocyte, mononuclear cell and eosinophil percentages, and viscosity. RESULTS: Following injection, the total nucleated cell count increased in the synovial fluid samples from both groups. Values were significantly higher in treated joints on days 2, 3, 15 and 16. Red blood cell counts were low and no differences were seen between treated and control joints. Total protein concentrations and neutrophil percentages increased in both groups after injection, but decreased towards normal ranges within 7 days. Total protein concentration was significantly higher in treated joints on days 1, 3, 8, 9 and 15. Percentages of neutrophils were higher in treated joints on day 2, but significantly lower on days 8 and 15. Viscosity was significantly higher in treated joints on day 2 only. CONCLUSIONS: Intra-articular administration of combined pentosan polysulfate and glucosamine causes a mild inflammatory synovitis that is not substantially different to that elicited by injection of a similar volume of saline and so we conclude that these drugs are safe to use in the horse. PMID- 22827627 TI - Kunjin flaviviral encephalomyelitis in an Arabian gelding in New South Wales, Australia. AB - Flaviviruses, including Kunjin virus, are arboviruses that cause encephalomyelitis in humans and horses. This case report describes an Arabian gelding exhibiting neurological signs of flavivirus encephalomyelitis, the diagnostic investigation and confirmation of an unreported case of Kunjin virus equine encephalomyelitis in Australia. PMID- 22827628 TI - Effect of diet on serum 25-hydroxyvitamin D concentration in the short-beaked echidna (Tachyglossus aculeatus). AB - BACKGROUND: Elevated concentrations of 25-hydroxyvitamin D (25(OH)-D) were diagnosed in captive short-beaked echidnas (Tachyglossus aculeatus) from three different zoological facilities within Australia. RESULTS: The mean serum 25(OH) D concentration in the wild echidnas was 24.7 nmol/L and was significantly higher in captive echidnas from all three facilities: Facility 1, mean 335.5 nmol/L (P < 0.001); Facility 2, mean 187.2 nmol/L (P = 0.003); Facility 3, mean 194 nmol/L (P = 0.005). Animals did not appear to have clinical manifestations of vitamin D toxicosis. The increased serum 25(OH)-D concentration was attributed to excessive dietary intake and a reduction in the amount of vitamin D(3) in the diet of echidnas from Facility 1 resulted in a marked decrease in the serum 25(OH)-D concentrations (mean 33 nmol/L). The reduction in serum 25(OH)-D concentration was statistically significant (P = 0.002) and the resulting concentrations were similar to those of wild echidnas (P = 0.212). CONCLUSION: It is not known what effect an elevated serum 25(OH)-D concentration has on echidnas. PMID- 22827629 TI - Antibiotic prescribing habits of vets in Australia. PMID- 22827631 TI - Self-organization of bent rod molecules into hexagonally ordered vesicular columns. AB - Bent-shaped rigid-core molecules with flexible chiral dendrons grafted to the outer side of the bend were synthesized and characterized by circular dichroism, differential scanning calorimetry, X-ray scatterings, and transmission electron microscopy in solution and the solid state. The bent aromatic rods based on hepta and nonaphenylene with nitrile groups at both ends self-assemble into well ordered hollow tubular structures in aqueous solution, while the bent rod based on heptaphenylene without nitrile groups showed no apparent aggregations in aqueous solution. In the solid state, the rigid-flexible molecules based on heptaphenylene rod without the nitrile group self-assemble into a 2D oblique columnar structure with the columnar cross-section containing two interlocked molecules. Remarkably, the rigid flexible molecules based on hepta-, nona-, and undecaphenylene with nitrile groups self-assemble into a hexagonal columnar structure with weak 3D order. A model of vesicular channel structure is proposed based on small- and wide-angle X-ray diffraction on oriented fibers, density measurement, reconstruction and simulation of electron density maps, and molecular dynamics simulation. In contrast to the hollow tubular structure found in solution, in the solid both the outside and the interior of the columns are filled by the pendant aliphatic coils. Filling of the interior of these vesicular channels is made possible by some bent rod molecules turning their obtuse apex inward. One in 7, 2 in 8, and 4 in 10 molecules are thus inverted in a column slice in compounds with hepta-, nona-, and undecaphenylene cores, respectively. These are new examples of vesicular double-segregated columnar structures recently discovered in some dendrons. PMID- 22827632 TI - Medical students and sun prevention: knowledge and behaviours in France. AB - BACKGROUND: High sun exposure is a major risk factor of skin cancer, and physicians are first-line players in a sun-risk prevention campaign. OBJECTIVES: To survey medical students at the end of their general medical education about their knowledge and behaviours concerning natural and artificial sun risk and its prevention. METHODS: A 32-question survey was e-mailed to fifth or sixth year medical school students or first-year resident, attending residency-exam preparatory courses in Paris. RESULTS: Among 1,374 students, 570 (41.7%) completed the questionnaires. General aspects of sun-protection measures were known to >75% but responses to specific questions, mainly the impact of environmental conditions on sun risk, were frequently erroneous. Although most students declared using sunscreen and avoiding peak hours, 39% never or exceptionally (<1/year) performed skin self-examination. Fewer than one-third wore long sleeves or cap/hat in the sun, and tanning beds were used by 13.5%, but their regulations remained unknown by 30-68%. CONCLUSION: The sixth year of medical school signals the end of non-specialized training. Students' results and practices were almost comparable to those of the French general population. Medical schools might not be providing adequate sun-protection education programmes, perhaps diminishing the ability of future doctors to educate patients. PMID- 22827630 TI - Mapping serum albumin adducts of the food-borne carcinogen 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine by data-dependent tandem mass spectrometry. AB - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic aromatic amine that is formed during the cooking of meats. PhIP is a potential human carcinogen: it undergoes metabolic activation to form electrophilic metabolites that bind to DNA and proteins, including serum albumin (SA). The structures of PhIP-SA adducts formed in vivo are unknown and require elucidation before PhIP protein adducts can be implemented as biomarkers in human studies. We previously examined the reaction of genotoxic N-oxidized metabolites of PhIP with human SA in vitro and identified covalent adducts formed at cysteine34 (Cys34); however, other adduction products were thought to occur. We have now identified adducts of PhIP formed at multiple sites of SA reacted with isotopic mixtures of electrophilic metabolites of PhIP and 2-amino-1-methyl-6-[2H5]-phenylimidazo[4,5 b]pyridine ([2H5]-PhIP). The metabolites used for study were 2-nitro-1-methyl-6 phenylimidazo[4,5-b]pyridine (NO2-PhIP), 2-hydroxyamino-1-methyl-6 phenylimidazo[4,5-b]pyridine (HONH-PhIP), or N-acetyloxy-2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (N-acetoxy-PhIP). Following proteolytic digestion, PhIP-adducted peptides were separated by ultra performance liquid chromatography and characterized by ion trap mass spectrometry, employing isotopic data dependent scanning. Analysis of the tryptic or tryptic/chymotryptic digests of SA modified with NO2-PhIP revealed that adduction occurred at Cys34, Lys195, Lys199, Lys351, Lys541, Tyr138, Tyr150, Tyr401, and Tyr411, whereas the only site of HONH PhIP adduction was detected at Cys34. N-Acetoxy-PhIP, a penultimate metabolite of PhIP that reacts with DNA to form covalent adducts, did not appear to form stable adducts with SA; instead, PhIP and 2-amino-1-methyl-6-(5-hydroxy) phenylimidazo[4,5-b]pyridine, an aqueous reaction product of the proposed nitrenium ion of PhIP, were recovered during the proteolysis of N-acetoxy-PhIP modified SA. Some of these SA adduction products of PhIP may be implemented in molecular epidemiology studies to assess the role of well-done cooked meat, PhIP, and the risk of cancer. PMID- 22827633 TI - Lymphatic flow obstruction by tumor demonstrated using real-time fluorescence navigation. PMID- 22827634 TI - Multilocus sequence types of environmental Campylobacter jejuni isolates and their similarities to those of human, poultry and bovine C. jejuni isolates. AB - In this study, we investigated the multilocus sequence type (MLST) diversity and population genetics of Campylobacter jejuni isolates collected from the natural waters (n = 57), wild birds (n = 37) and zoo animals (n = 19) in southern Finland, the Helsinki area and the Helsinki Zoo, respectively. On average, we found C. jejuni in 20%, 10.4% or 11.5% of the samples collected from natural waters, wild birds and zoo animals, respectively. High ST diversity was detected in all three sources and 41.2% of the STs were novel, but the multi-host adapted ST-45 was the most common ST detected. The MLST data, supplemented with C. jejuni isolates from domestically acquired human infections (n = 454), poultry (n = 208) and bovines (n = 120), were utilized in a population structure study. The results indicate four groups of strains with varying ecological associations, demonstrating presence of genetically distinct lineages within each of the studied sources. We discovered that the greatest ST overlap occurs between human isolates and isolates from natural waters and poultry, which suggests that the latter two are the most important sources of C. jejuni among domestically acquired infections in Finland. PMID- 22827635 TI - The prognosis of anaplastic astrocytoma with radiologic necrosis mimicking glioblastoma. AB - Anaplastic astrocytoma (AA) sometimes shows a rapid poor course like glioblastoma. In this study, we investigated the prognosis of AA with radiologic necrosis which is the representative radiologic finding of glioblastoma. From 1995 to 2010, we operated on 26 patients who were confirmed to have AA. The male:female ratio was 13:13, and the median age was 47.23 years. The mean follow up period was 3 years. We analyzed the prognostic significance of radiologic necrosis with age, sex, KPS, tumour location, radiologic findings, extent of removal and radiation therapy oncology group recursive partitioning analysis (RTOG-RPA) classification. The median progression-free survival (PFS) was 0.5 (+/ 0.17) years and the median overall survival (OS) was 1.6 (+/- 0.40) years. In univariate analysis, the clinical variables of younger age (p = 0.030) and RTOG RPA class III (p = 0.043) correlated with longer PFS, and KPS (p = 0.038), radiologic necrosis (p = 0.013) and the extent of removal (p = 0.041) correlated with OS. The median OS was 1.0 (+/- 0.21) year in AA with radiologic necrosis compared to AA without radiologic necrosis, which showed 2.1 (+/- 0.29) years median OS. On multivariate analysis, there was no statistically significant prognostic factor. However, Cox's regression model revealed that gross total removal was associated with a longer OS (hazard ratio = 0.136; 95% CI, 0.018 to 1.046; p = 0.055) compared to partial removal or biopsy. Gross total resection was associated with good prognosis, and AA with radiologic necrosis had poor prognosis like glioblastoma. PMID- 22827636 TI - Acculturation and celiac disease risk in second-generation immigrants: a nationwide cohort study in Sweden. AB - OBJECTIVES: The burden of celiac disease (CD) is increasingly recognized as a global problem. However, whether this situation depends on genetics or environmental factors is uncertain. The authors examined these aspects in Sweden, a country in which the risk of CD is generally considered to be high. If environmental factors are relevant, CD risk in second-generation immigrant children should be related to maternal length of stay in Sweden before delivery. MATERIAL AND METHODS: Linking the Swedish Medical Birth Registry to other national registries, the authors investigated all singleton children (n = 792,401) born in Sweden between 1987 and 1993. They studied the risk of CD in children before age 6 as a function of the mother's geographical region of birth and length of stay in Sweden before delivery using Cox regression models. RESULTS: In children whose mothers immigrated to Sweden from a country outside of Europe, a maternal length of stay in Sweden of more than 5 years increased the hazard ratio (HR) of CD (1.73, 95% confidence interval (CI) 1.06-2.81). The authors observed a similar result among children born to mothers from a Nordic country outside of Sweden (HR 1.57, 95% CI 0.89-2.75), but a non-conclusive protective effect was observed in second-generation immigrant children from a non Nordic European country (HR 0.65, 95% CI 0.39-1.09). CONCLUSIONS: The risk of CD among second-generation immigrants seems to be conditioned by maternal length of stay in Sweden before delivery, suggesting that environmental factors contribute to the variation in CD risk observed across populations. PMID- 22827637 TI - Recent patents and developments in glaucoma biomarkers. AB - Glaucoma is an eye condition mainly developed from an excessive intraocular pressure. The condition tends to be inherited and may not show up until later in life. The increased pressure, can damage the optic nerve, provoking loss of vision. Without treatment, glaucoma can cause blindness within a few years; consequently glaucoma has to be diagnosed before long-term visual loss occurs. If it is diagnosed and treated early, the disease can be controlled. Usually, the patient does not notice any early symptoms or pain from this increased pressure, so the early diagnosis is problematic. Over half of the patients with glaucoma are unaware they have this blinding disease and by the time they are diagnosed, they already have irreversibly lost approximately 30-50% of their retinal ganglion cells. Glaucoma diagnosis is currently based on specific signs of the disease, characteristic optic nerve head changes and visual field loss. Thus, improved methods for early diagnosis of glaucoma are needed. Molecular genetics are valuable for the understanding the pathophysiology and cure of glaucoma, but still are not widely used for its diagnosis. Genetic studies on glaucoma have revealed many genes and chromosomal loci associated to glaucoma. Consequently, a better understanding of the molecular mechanisms underlying glaucoma is required to obtain early diagnosis and avoid potential disease progression. In this article, we revise the patents and the corresponding literature on the latest developments and approaches in glaucoma diagnosis, using mainly molecular genetics. PMID- 22827638 TI - The hypothalamic-neurohypophyseal system: current and future treatment of vasopressin and oxytocyn related disorders. AB - The hypothalamus and posterior pituitary form a complex neurohumoral system playing a key role in maintaining body fluid homeostasis and reproductive function. We review the pathophysiology mechanisms of posterior pituitary hormones and their implications, beyond water balance and delivery, in social functioning, pair bonding and affiliative behavior. Actual and future treatments for neurohypophysis related disorders are also discussed, particularly focusing on the development of new therapeutic compounds and patents. PMID- 22827639 TI - Role of thrombin activatable fibrinolysis inhibitor in endocrine and cardiovascular disorders: an update. AB - Thrombin activatable fibrinolysis inhibitor (TAFI) is a zymogene that potently inhibits fibrinolysis through the removal of the carboxy-terminal lysine and arginine residues from partially degraded fibrin polymers. In addition, TAFI has a suppressor effect on conversion of inactive plasminogen to plasmin. Since impaired fibrinolysis is a very well established risk factor for cardiovascular morbidity and mortality, understanding the role of TAFI in cardiovascular disorders, insulin resistance, diabetes and other endocrine problems may hold promise for improving management of these diseases. This paper includes a review of current evidence on TAFI pathway and its alteration in endocrine and cardiovascular disorders and relevant patents. PMID- 22827640 TI - Drug resistance-related microRNAs in esophageal cancer. AB - INTRODUCTION: Drug resistance has been the main obstacle in cancer therapy. A number of drug resistance-related molecules are under investigation but no one agent has already been used in clinical practice. The research on drug resistance related microRNAs (miRNAs) may eventually lead to improved clinical strategies and outcomes for patients with esophageal cancer (EC). AREAS COVERED: This review summarizes the recent advances in drug resistance-related miRNAs in EC, and also analyzes the clinical and therapeutic applications they provide. The authors envisage future developments in the molecular mechanisms of these miRNAs and their potential applications to cancer treatment. EXPERT OPINION: Drug resistance related miRNAs can be used as a useful therapeutic tool for EC. More investigations should be performed to promote the success of therapeutic-clinical use of miRNAs in cancer. PMID- 22827641 TI - Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy 131I whole-body scans. AB - BACKGROUND: While radioiodine (RAI) therapy remains the most effective treatment modality for RAI-avid distant metastatic follicular cell-derived thyroid cancer, the therapeutic utility of empiric RAI therapy in patients with structurally identifiable distant metastases that demonstrate RAI avidity only on the post therapy scan (negative diagnostic whole-body scan [DxWBS]) remains uncertain. METHODS: We report a retrospective assessment of the structural response to RAI therapy in 27 patients (median age 54 years, 59% male) with metastatic thyroid cancer (45% classical papillary thyroid cancer, 21% poorly differentiated, 15% tall-cell variant, 15% follicular variant, and 4% Hurthle cell carcinoma) with structurally identifiable distant metastases (86% pulmonary metastases) in whom a properly conducted DxWBS was negative, and the post-therapy scan showed RAI-avid metastatic lesions at the time of RAI remnant ablation. RESULTS: In response to the initial RAI ablation, none of the selected patients demonstrated structural disease regression, and no patient was rendered free of disease. However, 12 patients (44%) demonstrated stable lesions on serial structural imaging after an RAI ablation. Structural disease progression was seen in the remaining 56% (15/27), a median of 6 months after ablation. Unfortunately, additional RAI therapies given to 12/15 patients with progressive disease and 5/12 patients with stable lesions failed to cause structural disease regression, cure, or conversion from progressive to stable disease in any patient. All of the disease-specific deaths (7/27) were in patients who had structural disease progression (n=15) in response to RAI ablation. None of the patients with persistent but stable lesions on structural imaging (n=12) have died of thyroid cancer over a median follow-up period of 3.7 years. CONCLUSIONS: While 44% of patients with the DxWBS negative/post-therapy scan-positive macroscopic distant metastasis will have stable cross-sectional imaging after RAI remnant ablation, the other 56% will demonstrate structural disease progression that cannot be effectively treated with repeated empiric RAI activities. Furthermore, the high disease-specific mortality rate seen within the first few years of remnant ablation in this small subset of patients with persistent progressive disease despite a positive post therapy RAI scan argues that treatments other than repeated empiric RAI dosing be strongly considered. PMID- 22827692 TI - Lifetime productivity losses associated with obesity status in early adulthood: a population-based study of Swedish men. AB - BACKGROUND: Obesity is a well-known risk factor for sick leave, disability pension and premature death. Obesity is therefore presumably related to increased productivity losses. OBJECTIVE: The aim of this study was to estimate the lifetime productivity losses to society associated with obesity status. METHODS: This study was based on a 38-year follow-up of a nationwide cohort of 45 920 Swedish men performing mandatory military conscription tests at age 18.7 +/- 0.5 years. Body mass index (BMI) based on measured height and weight at the time of military conscription tests was used to define underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)) and obesity (>=30.0 kg/m(2)). Data on sick leave, disability pension and premature death were retrieved from national registers. The calculations were adjusted for socioeconomic index, smoking and muscular strength. RESULTS: Using the human capital approach, the lifetime productivity losses were calculated as 55.6 (95% CI 50.7, 62.0) * ?1000 and 55.6 (95% CI 50.9, 61.4) * ?1000 for underweight and normal weight, respectively, and 72.6 (95% CI 66.3, 80.7) * ?1000 and 95.4 (95% CI 89.0, 102.9) * ?1000 for overweight and obesity, respectively. If using the friction cost method instead, the estimated productivity losses were reduced by about 80%. CONCLUSION: Obesity is associated with almost twice as high productivity losses to society as for normal weight over a lifetime. These costs are important to include in health economic analyses of obesity intervention programmes in order to ensure an effective allocation of resources from a societal perspective. PMID- 22827693 TI - Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. AB - BACKGROUND: The intestinal microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD). Faecal microbiota transplantation (FMT) has been used for the management of IBD as well as infectious diarrhoea. AIM: To undertake a systematic review of FMT in patients with IBD. METHODS: The systematic review followed Cochrane and PRISMA recommendations. Nine electronic databases were searched in addition to hand searching and contacting experts. Inclusion criteria were reports (RCT, nonrandomised trials, case series and case reports) of FMT in patients with IBD. RESULTS: Of the 5320 articles identified, 17 fulfilled the inclusion criteria, none of which were controlled trials. There were nine case series/case reports of patients receiving FMT for management of their IBD, and eight where FMT was for the treatment of infectious diarrhoea in IBD. These 17 articles reported on 41 patients with IBD (27 UC, 12 Crohn's, 2 unclassified) with a follow-up period of between 2 weeks and 13 years. Where reported, FMT was administered via colonoscopy/enema (26/33) or via enteral tube (7/33). In patients treated for their IBD, the majority experienced a reduction of symptoms (19/25), cessation of IBD medications (13/17) and disease remission (15/24). There was resolution of C. difficile infection in all those treated for such (15/15). CONCLUSIONS: Whilst the available evidence is limited and weak, it suggests that faecal microbiota transplantation has the potential to be an effective and safe treatment for IBD, at least when standard treatments have failed. Well-designed randomised controlled trials are required to investigate these findings. PMID- 22827694 TI - Risk of hernia occurrence where division of an indirect inguinal sac without ligation is undertaken. AB - We sought to ascertain the risk of inguinal hernia occurrence when division of the processus vaginalis is undertaken without ligation, in the context of laparoscopic Fowler-Stephens orchidopexy. A cohort of patients with intra abdominal testes subjected to a two-stage Fowler-Stephens procedure was reviewed. Analysis of a 68-month period between November 2005 and August 2011 was performed. A comprehensive search of the literature was undertaken, and these data were compared with previously published studies of patients undergoing orchidopexy or herniotomy where the peritoneal defect was not closed. The procedure was undertaken as previously described, with a conventional first stage using a three-port technique. No attempt was made to approximate the peritoneal margins of the processus vaginalis/hernia or close the internal ring at the second stage. In our own experience 17 patients with undescended testes (2 with bilateral cases) underwent laparoscopically assisted, gubernaculum-sparing, Fowler-Stephens orchidopexy. Median age at first operation was 1.86 years (range, 1-9 years). All 17 patients had successful surgery with all 19 testes palpable within the scrotum at postoperative assessment at 3 and 6 months. No direct, indirect, or incisional hernias were noted at a mean follow-up of 2.7 years (standard deviation 1.71). Our experience and reports in the literature do support simple division of the indirect hernia sac as a tenable alternative to ligation. The result of this limited review would support a prospective randomized trial comparing ligation with simple division of hernia sacs. PMID- 22827695 TI - Comparative study of C^N and N^C type cyclometalated ruthenium complexes with a NAD+/NADH function. AB - Cyclometalated ruthenium complexes having C(^)N and N(^)C type coordinating ligands with NAD(+)/NADH function have been synthesized and characterized by spectroscopic methods. The variation of the coordinating position of sigma donating carbon atom leads to a drastic change in their properties. Both the complex Ru(phbn)(phen)(2)]PF(6) ([1]PF(6)) and [Ru(pad)(phen)(2)]PF(6) ([2]PF(6)) reduced to Ru(phbnHH)(phen)(2)]PF(6) ([1HH]PF(6)) and [Ru(padHH)(phen)(2)]PF(6) ([2HH]PF(6)) by chemical and electrochemical methods. Complex [1]PF(6) photochemically reduced to [1HH]PF(6) in the presence of the sacrificial agent triethylamine (TEA) upon irradiation of visible light (lambda >= 420 nm), whereas photochemical reduction of [2]PF(6) was not successful. Both experimental results and theoretical calculations reveal that upon protonation the energy level of the pi* orbital of either of the ligands phbn or pad is drastically stabilized compared to the nonprotonated forms. In the protonated complex [Ru(padH)(phen)(2)](PF(6))(2) {[2H](PF(6))(2)}, the Ru-C bond exists in a tautomeric equilibrium with Ru?C coordination and behaves as a remote N heterocyclic carbene (rNHC) compex; on the contrary, this behavior could not be observed in protonated complex [Ru(phbnH)(phen)(2)](PF(6))(2) {[1H](PF(6))(2)}. PMID- 22827697 TI - Black tea polyphenols reverse epithelial-to-mesenchymal transition and suppress cancer invasion and proteases in human oral cancer cells. AB - Epithelial-to-mesenchymal transition (EMT) in cancer cells is considered to be a prerequisite for acquiring invasive/migratory phenotype and subsequent metastasis. This study provides molecular evidence associated with the antimetastatic effect of black tea polyphenol extracts (BTE), which contain polyphenols including gallic acid, gallocatechin, catechin, epigallocatechin-3 gallate, epicatechin-3-gallate, and theaflavin 3,3'-digallate, in an an oral squamous cell culture system by showing a nearly complete inhibition on the invasion (p < 0.001) of SCC-4 cells via reduced activities of MMP-2 (p < 0.001) and u-PA (p < 0.001). Immunoblot was performed to find that BTE could induce up regulation of epithelial markers such as E-cadherin and inhibit mesenchymal markers such as snail-1 and vimentin. BTE inhibited p-FAK and p-paxillin, indicating the anti-EMT effect of BTE in oral squamous cell carcinoma. BTE was evidenced by its inhibition of the tumor growth of SCC-4 cells via cancer cell xenografted nude mice mode. These results suggested that BTE could reduce invasion by reversing EMT in human oral cancer cells. PMID- 22827696 TI - Antifungal therapy in European hospitals: data from the ESAC point-prevalence surveys 2008 and 2009. AB - The study aimed to identify targets for quality improvement in antifungal use in European hospitals and determine the variability of such prescribing. Hospitals that participated in the European Surveillance of Antimicrobial Consumption Point Prevalence Surveys (ESAC-PPS) were included. The WHO Anatomical Therapeutic Chemical (ATC) classification for 'antimycotics for systemic use' (J02) 2009 version was used. Demographic data and information about indications and diagnoses were collected in 2008 and 2009. From 99,053 patients, 29,324 (29.6%) received antimicrobials. Antifungals represented 1529 of 40,878 (3.7%) antimicrobials. Antifungals were mainly (54.2%) administered orally. Hospital acquired infections represented 44.5% of indications for antifungals followed by medical prophylaxis at 31.2%. The site of infection was not defined in 36.0% of cases but the most commonly targeted sites were respiratory (19.2%) and gastrointestinal (18.8%). The most used antifungal was fluconazole (60.5%) followed by caspofungin (10.5%). Antifungal-antibacterial combinations were frequently used (77.5%). The predominance of fluconazole use in participating hospitals could result in an increase in prevalence of inherently resistant fungi, increasing the need for newer antifungals. Although acknowledging that antifungal prophylaxis in the immunocompromised host needs further exploration, repetitive surveys using ESAC-PPS methodology may help to monitor the effects of interventions set to regulate antifungal use. PMID- 22827698 TI - Lengthened G1 phase indicates differentiation status in human embryonic stem cells. AB - The cell cycle in pluripotent stem cells is notable for the brevity of the G1 phase, permitting rapid proliferation and reducing the duration of differentiation signal sensitivity associated with the G1 phase. Changes in the length of G1 phase are understood to accompany the differentiation of human embryonic stem cells (hESCs), but the timing and extent of such changes are poorly defined. Understanding the early steps governing the differentiation of hESCs will facilitate better control over differentiation for regenerative medicine and drug discovery applications. Here we report the first use of real time cell cycle reporters in hESCs. We coexpressed the chromatin-decorating H2B GFP fusion protein and the fluorescence ubiquitination cell cycle indicator (FUCCI)-G1 fusion protein, a G1 phase-specific reporter, in hESCs to measure the cell cycle status in live cells. We found that FUCCI-G1 expression is weakly detected in undifferentiated hESCs, but rapidly increases upon differentiation. hESCs in the G1 phase display a reduction in undifferentiated colony-initiating cell function, underscoring the relationship between G1 phase residence and differentiation. Importantly, we demonstrate inter- and intracolony variation in response to chemicals that induce differentiation, implying extensive cell-cell variation in the threshold necessary to alter the G1 phase length. Finally, gain of differentiation markers appears to be coincident with G1 phase lengthening, with distinct G1 phase profiles associated with different markers of early hESC differentiation. Our data demonstrate the tight coupling of cell cycle changes to hESC differentiation, and highlight the cell cycle reporter system and assays we have implemented as a novel avenue for investigating pluripotency and differentiation. PMID- 22827699 TI - Poly(ethylene glycol) vesicles: self-assembled site for luminescence generation. AB - Fluorescence in poly(ethylene glycol) (PEGs 400-12000) solutions is reported here for the first time. PEG solutions form a vesicular organization with the hydrophilic groups attached at both ends which arrange themselves beyond a particular concentration and offer electron-dense regions at the center of the vesicle. These vesicles provide an inherent site for fluorescence generation in PEG solutions. Fluorescence emission was observed at ~380 nm with an excitation wavelength of 300 nm. PEG of molecular weight 6000 was found to show maximum emission intensity at a particular concentration. The formation of PEG vesicles (~1 nm size) was confirmed by dynamic light scattering (DLS) and confocal laser microscopy. On addition of metal ions the polymeric vesicle breaks up to monomeric PEG, and hence, the fluorescence intensity decreases with a red shift. Fluorescence lifetime measurements indicate the nature of complexation of the metals with PEG. Since PEGs are used as one of the phases in aqueous biphasic systems (ABS) of liquid-liquid extractions, the nature of the fluorescence emission spectrum of the PEG phase after extraction was studied. Metal extraction in the PEG-rich phase of an ABS leads to quenching of fluorescence in PEG. PMID- 22827700 TI - Antihyperglycemic, antihyperlipidemic, and renoprotective effects of Chlorella pyrenoidosa in diabetic rats exposed to cadmium. AB - OBJECTIVE: The objective of the present study is to evaluate the antihyperlipidemic effect of Chlorella pyrenoidosa in diabetic rats exposed to cadmium (Cd). MATERIALS AND METHODS: Group 1 and 2 rats were treated as control and C. pyrenoidosa control. Group 3 and 4 rats were given single injection of streptozotocin (40 mg/kg b.w; i.p) followed by Cd (0.6 mg/kg b.w; s.c) for 5 days per week for a total period of 90 days. In addition, group 4 rats alone were treated with C. pyrenoidosa throughout the study period of 90 days. Assessments of plasma glucose, insulin, lipid profile and renal function markers were performed in control and experimental rats along with histological examination of kidney tissues. RESULTS: Diabetic rats exposed to Cd showed increased levels of plasma glucose and decreased levels of plasma insulin accompanied by the significantly elevated levels of tissue lipids viz., total cholesterol, triglyceride, free fatty acid, and phospholipids compared with control rats. Alterations in lipoproteins (low density lipoprotein-C, very low density lipoprotein-C, and high density lipoprotein-C) levels were also observed. DISCUSSION: Elevated levels of urinary albumin, creatinine, and blood urea nitrogen confirmed the onset of renal dysfunction in unsupplemented diabetic rats exposed to Cd. CONCLUSION: C. pyrenoidosa (100 mg/kg body weight) supplemented diabetic nephropathic rats showed near normal biochemical profile and well preserved renal histology that substantiate the antihyperglycemic, antihyperlipidemic, and renoprotective effects of C. pyrenoidosa in diabetic rats exposed to Cd. PMID- 22827701 TI - Impaired emotion processing from vocal and facial cues in frontotemporal dementia compared to right hemisphere stroke. AB - To advance our understanding about the emotional and cognitive deficits of patients with frontotemporal dementia with behavioral variant (bvFTD), the current study examined comprehension and expression of emotions from prosodic and facial cues in a 66-year-old woman. The patient diagnosed with bvFTD is compared to six patients with acute right hemisphere stroke. Recognition of emotion from prosodic cues was assessed using an identification task in four conditions with decreasing verbal demands (neutral sentences, language-like pseudo sentences, monosyllables, and asyllabic vowel sounds). Repetition of utterances with emotional connotations and self-generated conversations were analyzed to measure relative changes in mean fundamental frequency (f0), f0 variance, speech rate, and intensity along with the facial musculature pattern. The patient showed a marked deficit in identifying emotions in all four prosody conditions; and she did not show much variation in modulating mean f0, f0 variance, speech rate and intensity for all emotion categories when compared to neutral utterances. In addition, this patient demonstrated little to no facial expressions during emotionally provoking tasks, but demonstrated no difficulty recognizing emotions from facial expressions or verbal scenarios. Results show that the patient seems to have selective impairment in recognition of emotions from prosody and expression of emotions using both prosodic and facial features. Impaired processing of emotional prosody and facial expressions could be important for detecting bvFTD with greater right hemisphere atrophy. PMID- 22827702 TI - Stereoselective synthesis and antiviral activity of methyl-substituted cycloSal pronucleotides. AB - Methyl-substituted cycloSal-pronucleotides of d4TMP were synthesized with high diastereoselectivities in satisfying chemical yields. The individual diastereomers were tested against HIV-1 and HIV-2 infected wild-type CEM/0 and HIV-2 infected thymidine kinase deficient CEM cells. All diastereomers tested showed significant antiviral activity in CEM/0 and strong activity in CEM/TK(-) cell cultures. The antiviral activities were strongly dependent on the chirality at the phosphate group and the position of the methyl-group(s) in the cycloSal moiety. In CEM/TK(-) cell cultures the difference in antiviral potency was found to be 7- to 20-fold. The stability of each diastereomer was studied in aqueous phosphate buffer and in CEM/0 cell extracts. Large differences in the half-lives were found. A comparison of the relative lipophilicity of the methyl-substituted cycloSal triesters was performed based on the retention times obtained by reversed phase HPLC. The results obtained clearly confirm the importance of a diastereoselective synthesis of cycloSal-pronucleotides. PMID- 22827703 TI - Short read sequence typing (SRST): multi-locus sequence types from short reads. AB - BACKGROUND: Multi-locus sequence typing (MLST) has become the gold standard for population analyses of bacterial pathogens. This method focuses on the sequences of a small number of loci (usually seven) to divide the population and is simple, robust and facilitates comparison of results between laboratories and over time. Over the last decade, researchers and population health specialists have invested substantial effort in building up public MLST databases for nearly 100 different bacterial species, and these databases contain a wealth of important information linked to MLST sequence types such as time and place of isolation, host or niche, serotype and even clinical or drug resistance profiles. Recent advances in sequencing technology mean it is increasingly feasible to perform bacterial population analysis at the whole genome level. This offers massive gains in resolving power and genetic profiling compared to MLST, and will eventually replace MLST for bacterial typing and population analysis. However given the wealth of data currently available in MLST databases, it is crucial to maintain backwards compatibility with MLST schemes so that new genome analyses can be understood in their proper historical context. RESULTS: We present a software tool, SRST, for quick and accurate retrieval of sequence types from short read sets, using inputs easily downloaded from public databases. SRST uses read mapping and an allele assignment score incorporating sequence coverage and variability, to determine the most likely allele at each MLST locus. Analysis of over 3,500 loci in more than 500 publicly accessible Illumina read sets showed SRST to be highly accurate at allele assignment. SRST output is compatible with common analysis tools such as eBURST, Clonal Frame or PhyloViz, allowing easy comparison between novel genome data and MLST data. Alignment, fastq and pileup files can also be generated for novel alleles. CONCLUSIONS: SRST is a novel software tool for accurate assignment of sequence types using short read data. Several uses for the tool are demonstrated, including quality control for high throughput sequencing projects, plasmid MLST and analysis of genomic data during outbreak investigation. SRST is open-source, requires Python, BWA and SamTools, and is available from http://srst.sourceforge.net. PMID- 22827704 TI - Primary prevention of Type 2 diabetes in South Asians--challenges and the way forward. AB - Preventing diabetes is of enormous value, particularly for the South Asian countries, which have a huge healthcare burden from the onslaught of the disease. Type 2 diabetes has been proved to be preventable using lifestyle changes, even in South Asians despite their heightened risk profile. Strategies to improve awareness about diabetes and translation of preventive measures by innovative, culturally specific programmes have to be implemented at national levels. Integrated involvement of the government, community, media, healthcare and education services, and financial support from national and international organizations, are required. South Asian countries have initiated national programmes for diabetes prevention and management. It is also encouraging to note that joint ventures between developed countries such as the USA, UK and other European countries and centres of excellence in South Asia have been initiated to develop large-scale, community-oriented, pragmatic intervention strategies. PMID- 22827707 TI - Hydrogen-bonding effects on the formation and lifetimes of charge-separated states in molecular triads. AB - Photoinduced electron transfer in two molecular triads comprised of a triarylamine donor, a d(6) metal diimine photosensitizer, and a 9,10 anthraquinone acceptor was investigated with particular focus on the influence of hydrogen-bonding solvents on the electron transfer kinetics. Photoexcitation of the ruthenium(II) and osmium(II) sensitizers of these triads leads to charge separated states containing an oxidized triarylamine unit and a reduced anthraquinone moiety. The kinetics for formation of these charge-separated states were explored by using femtosecond transient absorption spectroscopy. Strong hydrogen bond donors such as hexafluoroisopropanol or trifluoroethanol cause a thermodynamic and kinetic stabilization of these charge-separated states that is attributed to hydrogen bonding between alcoholic solvent and reduced anthraquinone. In the ruthenium triad this effect leads to a lengthening of the lifetime of the charge-separated state from ~750 ns in dichloromethane to ~3000 ns in hexafluoroisopropanol while in the osmium triad the respective lifetime increases from ~50 to ~2000 ns between the same two solvents. In both triads the lifetime of the charge-separated state correlates with the hydrogen bond donor strength of the solvent but not with the solvent dielectric constant. These findings are relevant in the greater context of solar energy conversion in which one is interested in storing light energy in charge-separated states that are as long-lived as possible. Furthermore they are relevant for understanding proton coupled electron transfer (PCET) reactivity of electronically excited states at a fundamental level because changes in hydrogen-bonding strength accompanying changes in redox states may be regarded as an attenuated form of PCET. PMID- 22827706 TI - The prevalence of urinary incontinence in pregnancy among a multi-ethnic population resident in Norway. AB - OBJECTIVES: To investigate prevalence of urinary incontinence (UI) in a multi ethnic population of pregnant women, and to analyse for possible associations of the known risk factors for UI in such a population. DESIGN: Population-based cross-sectional study. SETTING: All pregnant women in three administrative city districts attending the Child Health Clinics. POPULATION AND SAMPLE: Out of 823 women identified in the [corrected] first trimester, 772 (94%) [corrected] agreed to participate in the study at 28 weeks of gestation. Inclusion criteria were: healthy women at 20 weeks of gestation or less and able to communicate in Norwegian, Arabic, English, Sorani, Somali, Tamil, Turkish, Urdu or Vietnamese. METHODS: Differences between ethnic groups were tested by simple descriptive statistics. Associations were estimated by logistic regression analysis and presented as crude (cOR) and adjusted (aOR) odds ratios. MAIN OUTCOME MEASURES: Prevalence of UI as ascertained using the International Consultation on Incontinence Questionnaire-urinary incontinence-short form. RESULTS: Prevalence rates of UI at 28 weeks of gestation were 26% for women of African origin, 36% for women of Middle Eastern origin, 40% for women of East Asian origin, 43% for women of South Asian origin and 45% for women of European/North American origin. The difference was significant between women of African and European/North American origins (P = 0.011) and between women of African and South Asian origins (P = 0.035). Age (aOR 1.05; 95% CI 1.01-1.09) and parity (aOR 2.34; 95% CI 1.66 3.28) were positively associated with the prevalence of UI in pregnancy. Women of African origin had significantly reduced odds for UI (aOR 0.42; 95% CI 0.20 0.87). East Asian and African women reported the highest perceived impact of UI in pregnancy. CONCLUSIONS: A high prevalence of UI was found in a multi-ethnic pregnant population. PMID- 22827705 TI - Liver protein targets of hepatotoxic 4-bromophenol metabolites. AB - The hepatotoxicity of bromobenzene (BB) is directly related to the covalent binding of both initially formed epoxide and secondary quinone metabolites to at least 45 different liver proteins. 4-Bromophenol (4BP) is a significant BB metabolite and a precursor to reactive quinone metabolites; yet, when administered exogenously, it has negligible hepatotoxicity as compared to BB. The protein adducts of 4BP were thus labeled as nontoxic [Monks, T. J., Hinson, J. A., and Gillette, J. R. (1982) Life Sci. 30, 841-848]. To help identify which BB derived adducts might be related to its cytotoxicity, we sought to identify the supposedly nontoxic adducts of 4BP and eliminate them from the BB target protein list. Administration of [(14)C]-4BP to phenobarbital-induced rats resulted in covalent binding of 0.25, 0.33, and 0.42 nmol equiv 4BP/mg protein in the mitochondrial, microsomal, and cytosolic fractions, respectively. These values may be compared to published values of 3-6 nmol/mg protein from a comparable dose of [(14)C]-BB. After subcellular fractionation and 2D electrophoresis, 47 radioactive spots on 2D gels of the mitochondrial, microsomal, and cytosolic fractions were excised, digested, and analyzed by LC-MS/MS. Twenty-nine of these spots contained apparently single proteins, of which 14 were nonredundant. Nine of the 14 are known BB targets. Incubating freshly isolated rat hepatocytes with 4BP (0.1-0.5 mM) produced time- and concentration-dependent increases in lactate dehydrogenase release and changes in cellular morphology. LC-MS/MS analysis of the cell culture medium revealed rapid and extensive sulfation and glucuronidation of 4BP as well as formation of a quinone-derived glutathione conjugate. Studies with 7-hydroxycoumarin, (-)-borneol, or D-(+)-galactosamine showed that inhibiting the glucuronidation/sulfation of 4BP increased the formation of a GSH-bromoquinone adduct, increased covalent binding of 4BP to hepatocyte proteins, and potentiated its cytotoxicity. Taken together, our data demonstrate that protein adduction by 4BP metabolites can be toxicologically consequential and provide a mechanistic explanation for the failure of exogenously administered 4BP to cause hepatotoxicity. Thus, the probable reason for the low toxicity of 4BP in vivo is that rapid conjugation limits its oxidation and covalent binding and thus its toxicity. PMID- 22827709 TI - High charge mobility in a tetrathiafulvalene-based microporous metal-organic framework. AB - The tetratopic ligand tetrathiafulvalene-tetrabenzoate (H4TTFTB) is used to synthesize Zn2(TTFTB), a new metal-organic framework that contains columnar stacks of tetrathiafulvalene and benzoate-lined infinite one-dimensional channels. The new MOF remains porous upon desolvation and exhibits charge mobility commensurate with some of the best organic semiconductors, confirmed by flash-photolysis-time-resolved microwave conductivity measurements. Zn2(TTFTB) represents the first example of a permanently porous MOF with high charge mobility and may inspire further exploration of the electronic properties of these materials. PMID- 22827708 TI - [Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist. AB - BACKGROUND AND PURPOSE: Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and MU opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ MU opioid receptor agonist. EXPERIMENTAL APPROACH: The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [(35)S] GTPgammaS binding, [(35)S]-GTPgammaS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. KEY RESULTS: From calcium mobilization studies [Dmt(1)]N/OFQ(1 13)-NH(2) was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt(1)]N/OFQ(1-13)-NH(2) was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [(35)S]-GTPgammaS binding studies, at rat spinal cord receptors in [(35)S]-GTPgammaS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt(1) ]N/OFQ(1-13)-NH(2) was able to elicit robust and long-lasting antinociceptive effects. CONCLUSIONS AND IMPLICATIONS: Collectively, these results demonstrate that [Dmt(1)]N/OFQ(1-13)-NH(2) behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics. PMID- 22827710 TI - Differences between objective efficacy and perceived efficacy in patients with palmar hyperhidrosis treated with either botulinum toxin or endoscopic thoracic sympathectomy. AB - BACKGROUND: Moderate to severe palmar hyperhidrosis can disturb people's work and social and emotional lives. Botulinum toxin and sympathectomy are currently considered the most effective treatment options but few studies have analysed the concordance between efficacy and patient satisfaction in comparisons of these two types of treatments. OBJECTIVE: To assess the relation between efficacy and the satisfaction of patients with palmar hyperhidrosis treated with either botulinum toxin or endoscopic thoracic sympathectomy. MATERIAL AND METHODS: This retrospective, observational study included all patients treated with either botulinum toxin or endoscopic thoracic sympathectomy in a single reference hospital in 2005-2010. Information was obtained from computerized medical records and a telephone survey about patients' educational and socio-economic level, awareness of treatment options, pre- and post-treatment severity of palmar hyperhidrosis, satisfaction and associated side effects. Predictors of efficacy and patient satisfaction with each treatment were analysed with ordinal and multinomial logistic regression models. RESULTS: Patients who underwent sympathectomy had more severe palmar hyperhidrosis but efficacy and patient satisfaction were greater compared with patients given botulinum toxin. The severity of the compensatory palmar hyperhidrosis was predictive of less satisfaction after sympathectomy. In the group treated with botulinum toxin, low socio-economic status, lack of information about treatment options, fewer sessions and a shorter anhidrotic effect were associated with less satisfaction. CONCLUSION: In studies of expectations regarding the outcome of palmar hyperhidrosis treatment, doctors should consider the factors that determine patient satisfaction in relation to the treatment options. PMID- 22827711 TI - Associations between anti-microbial resistance phenotypes, anti-microbial resistance genotypes and virulence genes of Escherichia coli isolates from Pakistan and China. AB - The objective of this study was to determine the association between phenotypic resistance, genotypic resistance and virulence genes of Escherichia coli isolates in Jiangsu province, China and Punjab province Pakistan. A total of 62 E. coli isolates were characterized for phenotypic resistance, genotypic resistance and virulence factor genes. The anti-microbial resistance phenotype and genotypes in relation to virulence factor genes were assessed by statistical analysis. Of 20 tested virulence genes, twelve were found and eight were not found in any isolates. sitA and TspE4C2 were the most prevalent virulence genes. Of the 13 anti-microbial agents tested, resistance to ampicillin, sulphonamide and tetracycline was the most frequent. All isolates were multiresistant, and 74% were resistant to trimethoprim and sulphamethaxazole. Phenotypically, tetracycline-, cefotaxime- and trimethoprim-resistant isolates had increased virulence factors as compared with susceptible isolates. Genotypically, resistant genes Tem, ctx-M, Tet, Sul 1, dhfr1, Cat2 and flo-R showed the association with the virulence genes. Almost all classes of anti-microbial-resistant genes have a high association with virulence. Resistant isolates have more virulent genes than the susceptible isolates. PMID- 22827712 TI - Patients with genetic cancer undergoing surveillance at a specialized clinic rate the quality of their care better than patients at non-specialized clinics. AB - OBJECTIVES: To compare ratings of quality of care between patients with genetic cancer who receive specialized care with patients who receive non-specialized care while controlling for socio-demographic and clinical variables; MATERIAL AND METHODS: All patients in a national cohort of adult patients diagnosed with familial adenomatous polyposis (FAP) who had undergone prophylactic colorectal surgery were assessed (n = 276, response rate 76%). Quality of care was measured with the Quality of Care from the Patient Perspective (QPP). Univariate and multivariate logistic regression analyses were performed; RESULTS: Patients receiving specialized care were significantly more likely to report the quality of care as better in all three QPP dimensions investigated than those receiving non-specialized care; CONCLUSIONS: In order to promote and maintain good quality of care for surgically treated patients with FAP, and to minimize the risk of cancer, specialized care, including continuity and easy access of health care professionals, should be provided. PMID- 22827714 TI - Therapeutic potential of natural products in Parkinson's disease. AB - The central objective in treating patients with Parkinson's disease (PD) is two fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents. PMID- 22827713 TI - An experimental study on in situ transfection of the interleukin-1 receptor antagonist (IL-1ra) gene into the rat cornea. AB - OBJECTIVE: To investigate the efficiency of the transfection of PEGFP-IL-1ra plasmid via cation polymer mediation (poly-ethylenimine, PEI) by injection into the corneal stroma. METHODS: Plasmid PEGFP-hIL-1ra recombinants were constructed and transferred into corneal endothelial cells via cation polymer mediation. Plasmid PEGFP-hIL-1ra recombinants and/or PEI-in-vivo were injected into the corneal stroma of Wistar rats. Corneas were harvested at different time points (days 3, 6, 14 and 21) after injection. The expression of IL-1ra after transfection was studied by fluorescence microscopy, transmission electron microscopy, real time polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Plasmid PEGFP-hIL-1ra recombinants were constructed successfully. After injection of pEGFP-hIL-1ra plasmid into the cornea, IL-1ra mRNA expression was detected in the corneal stroma and reached a peak on day 6. IL-1ra-GFP granules could be observed in every layer of the cornea in the PEGFP-hIL-1ra recombinant group by transmission electron microscopy, but not in the negative control (PEI-in-vivo) group. P63 immunocytochemical staining in the corneal epithelium was positive in both groups. There was no impairment in the ultrastructure of cells in both groups. CONCLUSIONS: By direct injection of PEGFP-hIL-1ra into the corneal stroma and mediation by the cation polymer, the IL 1ra gene could be transferred and expressed in corneal tissue efficiently. This may be a novel technique for gene transfection to the cornea in situ. PMID- 22827715 TI - Systems drug discovery: a quantitative, objective approach for safer drug development. AB - We are currently witnessing a dramatic change in the pharmaceutical industry as many companies are downscaling their efforts to discover new drug candidates and are instead turning toward collaboration with academic partners. This trend has been dubbed open innovation. The reason for this change of policy stems from the realization that, in spite of massive investments in their drug development programs in the past 30 years, the number of new drugs reaching the market has remained stable over the same period. We review past and present drug discovery strategies and present a novel more holistic approach that we term Systems Drug Discovery. This approach aims at quantifying the physiological state of organ slice cultures using high content imaging and metabolomics. The characterization in a quantitative manner of healthy, diseased, and drug-treated tissues will allow defining a multiparametric space, within which tissues are healthy. This in turn will allow an objective assessment of the impact of candidate drugs on cells. This quantitative approach should help guide the development of new drugs reducing failure rates in clinical phase. PMID- 22827716 TI - Riedel's thyroiditis with increased IgG4 plasma cells: evidence for an underlying IgG4-related sclerosing disease? AB - BACKGROUND: Riedel's thyroiditis (RT) is a very rare chronic fibrosing disorder of unknown etiology that is often associated with multifocal fibrosclerosis (MFS). Immunoglobulin (Ig) G4-related sclerosing disease (IgG4-RSD), a new clinico-pathological entity also associated with MFS, is characterized by IgG4+ plasma cell infiltration and fibrosis in one or more organs. Although the association of RT and IgG4-RSD has been suggested, it has seldom been studied or reported. We report a classical case of RT with serological (IgG4 levels) and immunohistochemical (IgG and IgG4) assessment, in search of an underlying IgG4 RSD. PATIENT: The patient was a 57-year-old woman who underwent a subtotal thyroidectomy for a long-standing goiter with a rapidly enlarging isthmic nodule. RESULTS: Histopathological examination of the surgical specimen revealed all of the morphological features of RT and IgG4-RSD, including partial fibrosis of the thyroid gland with destruction of the thyroid follicular architecture; obliterative phlebitis; and a mixed infiltrate composed of lymphocytes, eosinophils, and plasma cells. The fibro-inflammatory process extended beyond the thyroid capsule into the surrounding tissues. Immunohistochemical examination revealed approximately 70 IgG4+ plasma cells per high power field (HPF) with an IgG4/IgG ratio of 35%. Although serum levels of IgG4 were normal (20 mg/dL), total IgG levels were slightly elevated (1370 mg/dL). There was no evidence of involvement of other organs at the time of RT diagnosis. CONCLUSIONS: The morphological similarities between RT and IgG4-RSD suggest that these entities are closely related. Therefore, RT with increased IgG4+ plasma cells, with or without elevated IgG4 serum levels, may represent the first clinical manifestation of an underlying IgG4-RSD. However, due to the rarity of both conditions and the limited specificity and sensitivity of both IgG4 serum levels and IgG/IgG4 immunohistochemistry in the diagnosis of IgG4-RSD, further studies are needed to verify this hypothesis. PMID- 22827717 TI - Production benefits learning: the production effect endures and improves memory for text. AB - The production effect is the superior retention of material read aloud relative to material read silently during an encoding episode. Thus far it has been explored using isolated words tested almost immediately. The goal of this study was to assess the efficacy of production as a study strategy, addressing: (a) whether the production benefit endures beyond a short session, (b) whether production can boost memory for more complex material, and (c) whether production transfers to educationally relevant tests. In Experiment 1 a 1-week retention interval was included, and a production effect was observed. In Experiment 2 a production effect was observed for both word pairs and sentence stimuli. In Experiment 3 educationally relevant essays were read and tested with a fill-in the-blanks test: Memory was superior for questions that probed information that had been read aloud relative to information that had been read silently. We conclude that the production benefit is enduring and generalises to text and different test formats, indicating that production constitutes a worthwhile study strategy. PMID- 22827718 TI - Meta-analysis: sequential therapy for Helicobacter pylori eradication in children. AB - BACKGROUND: Problems with the standard triple treatment recommended for Helicobacter pylori eradication therapy include unsatisfactory (less than 80%) eradication rates among children. AIM: To assess the evidence for sequential therapy compared with triple therapy on H. pylori eradication rates in children. METHODS: The Cochrane Library, MEDLINE and EMBASE databases were searched in May 2012, with no language restrictions, as were abstracts from major gastroenterology conferences, for randomised controlled trials (RCTs) comparing sequential therapy with standard triple therapy for H. pylori eradication. Additional references were obtained from reviewed articles. Authors were contacted for extra information. Dichotomous data were pooled to obtain the relative risk (RR) of the eradication rate, with a 95% CI. RESULTS: Ten RCTs involving a total of 857 children aged 3-18 years met the inclusion criteria. Of the 409 patients in the sequential therapy group, 318 (78%, 95% CI 73-82) experienced eradication compared with 314 of the 444 patients (71%, 95% CI 66-75) in the standard triple therapy group (RR 1.14, 95% CI 1.06-1.23, number needed to treat 15; fixed-effects model). Sequential therapy was superior to 7-day standard triple therapy, but was not significantly better than 10-day or 14-day triple therapy. There were no significant differences between groups in the risk of adverse effects. CONCLUSIONS: The pooled evidence suggests that 10-day sequential therapy compared with standard triple therapy may be considered as an option for increasing the eradication rates in children; however, it is still less than desired. PMID- 22827719 TI - Screening fecal enterococci from Greek healthy infants for susceptibility to antimicrobial agents. AB - Enterococci are among the first lactic acid bacteria to colonize the neonatal gastrointestinal tract, but they are also characterized as significant nosocomial pathogens. The aim of this study was to investigate the incidence of antibiotic resistance in enterococci isolated from neonates' gut microbiota as well as the presence of genetic determinants encoding for certain antibiotic resistance traits. A total of 263 fecal samples derived from 97 infants were collected on day 4, 30, and 90 after delivery. Enterococcus faecalis was the most frequently identified species (54.6%) followed by E. faecium, while E. casseliflavus/E. flavescens and E. gallinarum were also traced. The isolates were examined for their resistance to 12 antibiotics. Rifampicin resistance was the highest observed (53.2%), followed by resistance to tetracycline (42.0%), erythromycin (35.7%), and vancomycin (11.2%). Multiresistant strains were highly prevalent. Only intrinsic vancomycin resistance (vanC1 and vanC2/C3) was traced. The ermB gene was detected in 49 out of 96 erythromycin-resistant isolates, while tet genes were detected in 51 out of 113 tetracycline-resistant strains, with tet(L) being the most frequently observed. In conclusion, antibiotic-resistant enterococci are already established in the fecal microbiota of healthy neonates, from the first days of an infant's life. PMID- 22827720 TI - Bistable dynamic coordination polymer showing reversible structural and functional transformations. AB - A bistable dynamic coordination polymer [Ni(pca)(bdc)(0.5)(H(2)O)(2)] having a two-dimensional (2D) zigzag sheet structure is synthesized solvothermally. Topological analysis revealed that the frameworks have an hcb type of uninodal net. The compound exhibits guest specific reversible structural transformations accompanying reversible changes in physical properties driven by inherent flexibility and transformability. PMID- 22827721 TI - What are the main running-related musculoskeletal injuries? A Systematic Review. AB - BACKGROUND: Musculoskeletal injuries occur frequently in runners and despite many studies about running injuries conducted over the past decades it is not clear in the literature what are the main running-related musculoskeletal injuries (RRMIs). OBJECTIVE: The aim of this study is to systematically review studies on the incidence and prevalence of the main specific RRMIs. METHODS: An electronic database search was conducted using EMBASE (1947 to October 2011), MEDLINE (1966 to October 2011), SPORTDiscus(1975 to October 2011), the Latin American and Caribbean Center on Health Sciences Information (LILACS) [1982 to October 2011] and the Scientific Electronic Library Online (SciELO) [1998 to October 2011] with no limits of date or language of publication. Articles that described the incidence or prevalence rates of RRMIs were considered eligible. Studies that reported only the type of injury, anatomical region or incomplete data that precluded interpretation of the incidence or prevalence rates of RRMIs were excluded. We extracted data regarding bibliometric characteristics, study design, description of the population of runners, RRMI definition, how the data of RRMIs were collected and the name of each RRMI with their rates of incidence or prevalence. Separate analysis for ultra-marathoners was performed. Among 2924 potentially eligible titles, eight studies (pooled n = 3500 runners) were considered eligible for the review. In general, the articles had moderate risk of bias and only one fulfilled less than half of the quality criteria established. RESULTS: A total of 28 RRMIs were found and the main general RRMIs were medial tibial stress syndrome (incidence ranging from 13.6% to 20.0%; prevalence of 9.5%), Achilles tendinopathy (incidence ranging from 9.1% to 10.9%; prevalence ranging from 6.2% to 9.5%) and plantar fasciitis (incidence ranging from 4.5% to 10.0%; prevalence ranging from 5.2% to 17.5%). The main ultra-marathon RRMIs were Achilles tendinopathy (prevalence ranging from 2.0% to 18.5%) and patellofemoral syndrome (prevalence ranging from 7.4% to 15.6%). CONCLUSION: This systematic review provides evidence that medial tibia stress syndrome, Achilles tendinopathy and plantar fasciitis were the main general RRMIs, while Achilles tendinopathy and patellofemoral syndrome were the most common RRMIs for runners who participated in ultra-marathon races. PMID- 22827722 TI - Tracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infection. AB - Hepatitis B e-antigen (HBeAg)-negative chronic HBV infection is highly prevalent in several parts of the world, including India, with the clinical spectrum ranging from inactive carrier (IC) state to chronic 'e-negative' hepatitis B (CHB) and culminating in advanced liver disease such as cirrhosis (LC). The present study has for the first time investigated the natural diversity of HBV belonging to genotype D in treatment-naive Indian patients representing the above phases of HBeAg-negative infection to identify candidate mutations associated with each disease state. Studies of full-length HBV/D sequences revealed that the progressive accumulation and persistence of mutations in basal core promoter, negative regulatory element, Pre-core region, the B- and T-cell epitopes of X protein as well as deletions in the PreS region contribute significantly to disease progression from IC through CHB to LC. In addition, the development of CHB was associated with a significant increase in viral variants characterized by mutations in enhancer II, preS1 promoter, T-cell epitope of core and B-cell epitope region of PreS1. While few of the mutations were previously reported in the context of HBV genotypes B and C, others had not been documented before. Our results thus highlight a distinct pattern of mutation in HBV/D that may help in predicting clinical outcomes of HBeAg-negative infection and have implications for better clinical management of the patients. PMID- 22827723 TI - Lipophilic caffeic acid derivatives protect cells against H2O2-Induced DNA damage by chelating intracellular labile iron. AB - Naturally occurring cinnamic acid derivatives are ubiquitously distributed in the plant kingdom, and it has been proposed that their consumption contributes to the maintenance of human health. However, the molecular mechanisms underlying their health keeping effects remain unknown. In the present investigation, we evaluated the capacity of several cinnamic acid derivatives (trans-cinnamic, p-coumaric, caffeic and ferulic acids, as well as caffeic acid-methyl and -propyl esters) to protect cells from oxidative stress-induced DNA damage. It was observed that effective protection was based on the ability of each compound to (i) reach the intracellular space and (ii) chelate intracellular "labile" iron. These results support the notion that numerous lipophilic iron chelating compounds, present abundantly in plant-derived diet components, may protect cells in conditions of oxidative stress and in this way be important contributors toward maintenance of human health. PMID- 22827724 TI - Separation of americium from curium by oxidation and ion exchange. AB - Nuclear energy has the potential to be a clean alternative to fossil fuels, but in order for it to play a major role in the US, many questions about the back end of the fuel cycle must be addressed. One of these questions is the difficult separation of americium from curium. Here, we report the oxidation of Am in two systems, perchloric acid and nitric acid and the affect of changing the acid has on the oxidation. K(d) values were observed and a direct separation factor was calculated and was seen to be as high as 20 for four metal(IV) pillared phosphate phosphonate inorganic organic hybrid ion exchange materials. These ion exchangers are characterized by very low selectivity for cations with low charge but extremely high uptake of ions of high charge. PMID- 22827726 TI - Practical approaches to supporting young women with intellectual disabilities and high support needs with their menstruation. AB - Menstrual myths may influence decisions about menstrual and fertility management for women with intellectual disabilities and high support needs. We identify six myths (related to menstruation, menstrual management, communication, sexual feelings, menstrual difficulties, and surgical elimination) and the evidence that dispels these myths. We provide reflexive questions for practitioners to help them critically reflect on their own approaches to menstrual management. We encourage those supporting women with disabilities to consider the reflective questions we have provided and to strive to support informed decision-making about menstruation and the related areas of fertility and sexual feelings. PMID- 22827727 TI - I deeply respect the support for human rights. PMID- 22827728 TI - The use of perineal massage in the second stage of labor and follow-up of postpartum perineal outcomes. AB - Because perineal trauma causes both short- and long-term problems after labor, the high rate of episiotomies and spontaneous lacerations is an important women's health problem in Turkey. Our aim in this study was to investigate whether perineal massage during labor decreased perineal trauma and trauma-related problems. The study included 396 pregnant women who were giving birth for the first time, between March 2007 and February 2009, in Turkey. It can be concluded that perineal massage decreases the amount of suture material required for episiotomy and thereby the size of the episiotomy and the rate of episiotomies and lacerations. PMID- 22827729 TI - Safe motherhood practices among women of urban slums in bangladesh. AB - In this article we examine the prevalence and factors associated with the utilization of safe motherhood practices among slum-dwelling women of Bangladesh using the 2006 Bangladesh Urban Health Survey data. Overall, the utilization of maternal health care services was very low. The binary logistic regression analyses yielded significantly increased skilled services utilization for women with higher education levels, nonworking women, non-Muslims, women undergoing their first pregnancy, women who had lived in the slum longer, and amongst the rich. Awareness should be created through information, education, and communication programs, and services should be provided with minimum cost to promote safe motherhood practices among the urban poor in Bangladesh. PMID- 22827730 TI - Sex and gender traps and springboards: a focus group study among gender researchers in medicine and health sciences. AB - We explored the difficulties that gender researchers encounter in their research and the strategies they use for solving these problems. Sixteen Swedish researchers, all women, took part in focus group discussions; the data were analyzed using qualitative content analysis. The problems reported fell into four main categories: the ambiguity of the concepts of sex and gender; traps associated with dichotomization; difficulties with communication; and issues around publication. Categories of suggested problem-solving strategies were adaptation, pragmatism, addressing the complexities, and definition of terms. Here the specific views of gender researchers in medicine and health sciences "medical insiders"-bring new challenges into focus. PMID- 22827731 TI - Construction of negative images of menstruation in Indian TV commercials. AB - Menstruation is a perfectly normal physiological process; however, it is problematized in TV commercials. In the current study, a thematic analysis of 50 Indian TV commercials was conducted to identify the latent themes. Social captivity, restrictions, professional inefficiency, and physical and mental discomfort emerged as major themes after the analysis. The knowledge that manufacturers use such themes for image building and creating a conducive buying environment may prevent the reinforcement of menstrual taboos in Indian society. It can also guide the manufacturers in ideating and creating positive and healthier ways of advertising female hygiene products. PMID- 22827732 TI - Collagen scaffolds incorporating select therapeutic agents to facilitate a reparative response in a standardized hemiresection defect in the rat spinal cord. AB - A multifaceted therapeutic approach involving biomaterial scaffolds, neurotrophic factors, exogenous cells, and antagonists to axon growth inhibitors may ultimately prove necessary for the treatment of defects resulting from spinal cord injury (SCI). The objective of this study was to begin to lay the groundwork for such strategies by implanting type I collagen scaffolds alone and incorporating individually a soluble Nogo receptor, chondroitinase ABC (ChABC), and mesenchymal stem cells (MSCs) into a standardized 3-mm-long hemiresection defect in the rat spinal cord. Statistically significant improvement in hindlimb motor function between the first and fourth weeks post-SCI was recorded for the scaffold-alone group and for the ChABC and MSC groups, but not the control group. Four weeks post-SCI, the scaffolds appeared intact with open pores, which were infiltrated with host cells. Of note is that in some cases, a few growth associated protein 43 (GAP-43)-positive axons were seen reaching the center of the scaffold in the scaffold-alone and ChABC groups, but not in control animals. Angiogenic cells were prevalent in the scaffolds; however, the number of both macrophages and angiogenic cells in the scaffolds was significantly less than in the control lesion at 4 weeks. The results lay the foundation for future dose response studies and to further investigate a range of therapeutic agents to enhance the regenerative response in SCI. PMID- 22827733 TI - A systematic review on fluoridated food in caries prevention. AB - OBJECTIVE: This paper aims to provide a systematic review of the caries prevention effect of fluoridated food, excluding water. The main aim of this review was to evaluate the presence of scientific evidence relating to the effects of fluoride intake via food on the occurrence of carious lesions. The outcome was defined as a clinical outcome, so only papers evaluating a decrease in caries indices were included. MATERIALS AND METHODS: Relevant databases (Medline(r), Embase(r), The Cochrane Library) were searched. The date range was set from 01.01.1966 to 03.31.2011. One hundred and thirty-nine reports were identified and assessed. Only three papers fulfilled the inclusion criteria and were discussed in detail. RESULTS: No paper related to the use of fluoridated salt in caries prevention fulfilled the inclusion criteria. The use of milk as a vehicle for providing additional fluoride in a dental public health programme was evaluated in two papers. The consumption of fluoridated milk was an effective measure to prevent caries in the primary teeth. The use of fluoridated sugar demonstrated a reduction in caries increment in the permanent dentition in one paper. CONCLUSIONS: Literature on the effectiveness of fluoridation in foods in caries prevention is scant and almost all the studies have been conducted in children. There is low evidence that the use of milk fluoridation is effective in reducing the caries increment. PMID- 22827735 TI - The onset, recurrence and associated obstetric risk factors for urinary incontinence in the first 18 months after a first birth: an Australian nulliparous cohort study. AB - OBJECTIVE: To investigate the contribution of obstetric risk factors to persistent urinary incontinence (UI) between 4 and 18 months postpartum. DESIGN: Prospective pregnancy cohort. SETTING: Six metropolitan public hospitals in Victoria, Australia. SAMPLE: A total of 1507 nulliparous women recruited to the Maternal Health Study in early pregnancy (<=24 weeks of gestation). METHODS: Data from hospital records and self-administered questionnaires/telephone interviews at <=24 and 30-32 weeks of gestation and at 3, 6, 9, 12 and 18 months postpartum analysed using logistic regression. MAIN OUTCOME MEASURES: Persistent UI 4-18 months postpartum in women continent before pregnancy. RESULTS: Of the women who were continent before pregnancy, 44% reported UI 4-18 months postpartum, and 25% reported persistent UI (symptoms at multiple follow ups). Compared with spontaneous vaginal birth, women who had a caesarean before labour (adjusted odds ratio [aOR] 0.4, 95% confidence interval [95% CI] 0.2-0.9), in first-stage labour (aOR 0.4, 95% CI 0.2-0.6) or in second-stage labour (aOR 0.4, 95% CI 0.2-1.0) were less likely to report persistent UI 4-18 months postpartum. Prolonged second stage labour in women who had an operative vaginal birth was associated with increased likelihood of UI (aOR 2.5, 95% CI 1.3-4.6). Compared with women who were continent in pregnancy, women reporting UI in pregnancy had a seven-fold increase in odds of persistent UI (aOR 7.4, 95% CI 5.1-10.7). CONCLUSIONS: Persistent UI is common after childbirth and is more likely following prolonged labour in combination with operative vaginal birth. The majority of women reporting persistent UI at 4-18 months postpartum also experienced symptoms in pregnancy. PMID- 22827734 TI - DNA repair and crossing over favor similar chromosome regions as discovered in radiation hybrid of Triticum. AB - BACKGROUND: The uneven distribution of recombination across the length of chromosomes results in inaccurate estimates of genetic to physical distances. In wheat (Triticum aestivum L.) chromosome 3B, it has been estimated that 90% of the cross over events occur in distal sub-telomeric regions representing 40% of the chromosome. Radiation hybrid (RH) mapping which does not rely on recombination is a strategy to map genomes and has been widely employed in animal species and more recently in some plants. RH maps have been proposed to provide i) higher and ii) more uniform resolution than genetic maps, and iii) to be independent of the distribution patterns observed for meiotic recombination. An in vivo RH panel was generated for mapping chromosome 3B of wheat in an attempt to provide a complete scaffold for this ~1 Gb segment of the genome and compare the resolution to previous genetic maps. RESULTS: A high density RH map with 541 marker loci anchored to chromosome 3B spanning a total distance of 1871.9 cR was generated. Detailed comparisons with a genetic map of similar quality confirmed that i) the overall resolution of the RH map was 10.5 fold higher and ii) six fold more uniform. A significant interaction (r = 0.879 at p = 0.01) was observed between the DNA repair mechanism and the distribution of crossing-over events. This observation could be explained by accepting the possibility that the DNA repair mechanism in somatic cells is affected by the chromatin state in a way similar to the effect that chromatin state has on recombination frequencies in gametic cells. CONCLUSIONS: The RH data presented here support for the first time in vivo the hypothesis of non-casual interaction between recombination hot-spots and DNA repair. Further, two major hypotheses are presented on how chromatin compactness could affect the DNA repair mechanism. Since the initial RH application 37 years ago, we were able to show for the first time that the iii) third hypothesis of RH mapping might not be entirely correct. PMID- 22827736 TI - Safety and efficacy of healthy volunteer stem cell mobilization with filgrastim G CSF and mobilized stem cell apheresis: results of a prospective longitudinal 5 year follow-up study. AB - BACKGROUND AND OBJECTIVES: G-CSF-mobilized peripheral blood stem cells have long replaced marrow as the major source for allogeneic transplants. Conclusive evidence questioning the long-term safety of G-CSF for donors has not been provided, but the cumulative number of followed donors remains insufficient to rule out rare adverse events. A long-term active follow-up study of G-CSF mobilized healthy volunteer donors was therefore performed. PATIENTS AND METHODS: Two hundred and three successive donors were evaluated pre-apheresis, subjected to G-CSF-mobilization/apheresis, and actively followed for 5 years by the same physicians and laboratories. Follow-up laboratory work included standard biochemical/haematological tests and T-cell phenotyping. RESULTS: Donor epidemiology was typical for reported stem cell donor cohorts. Acute adverse effects of G-CSF and apheresis were mild and transient, consistent with the previous reports. Mean circulating CD34(+) cells after nine doses of G-CSF were 124 per MUl. Other biochemical/haematological parameters were also altered, consistent with G-CSF treatment. Spleen enlargement was modest. At first follow up, all clinical and laboratory parameters had normalized. Leucocyte/lymphocyte counts and CD4/CD8 ratios were the same as during premobilization work-up and remained unchanged throughout. A single severe but likely unrelated adverse event, a case of papillary thyroid carcinoma, was reported. CONCLUSION: The studies add an observation time of almost 500 donor years to the growing body of evidence of the long-term safety of G-CSF for allogeneic donor stem cell mobilization. PMID- 22827737 TI - Detection of airborne influenza a virus in experimentally infected pigs with maternally derived antibodies. AB - This study assessed whether recently weaned piglets with maternally derived antibodies were able to generate infectious influenza aerosols. Three groups of piglets were assembled based on the vaccination status of the dam. Sows were either non-vaccinated (CTRL) or vaccinated with the same (VAC-HOM) strain or a different (VAC-HET) strain to the one used for challenge. Piglets acquired the maternally derived antibodies by directly suckling colostrum from their respective dams. At weaning, pigs were challenged with influenza virus by direct contact with an infected pig (seeder pig) and clinical signs evaluated. Air samples, collected using a liquid cyclonic air collector, and individual nasal swabs were collected daily for 10 days from each group and tested by matrix real time reverse transcriptase polymerase chain reaction (RRT-PCR) assay. Virus isolation and titration were attempted for air samples on Madin-Darby canine kidney cells. All individual pigs from both VAC-HET and CTRL groups tested positive during the study but only one pig in the VAC-HOM group was positive by nasal swab RRT-PCR. Influenza virus could not be detected or isolated from air samples from the VAC-HOM group. Influenza A virus was isolated from 3.2% and 6.4% air samples from both the VAC-HET and CTRL groups, respectively. Positive RRT-PCR air samples were only detected in VAC-HET and CTRL groups on day 7 post-exposure. Overall, this study provides evidence that recently weaned pigs with maternally derived immunity without obvious clinical signs of influenza infection can generate influenza infectious aerosols which is relevant to the transmission and the ecology of influenza virus in pigs. PMID- 22827738 TI - Increasing the band gap of iron pyrite by alloying with oxygen. AB - Systematic density functional theory studies and model analyses have been used to show that the band gap of iron pyrite (FeS(2)) can be increased from ~1.0 to 1.2 1.3 eV by replacing ~10% of the sulfur atoms with oxygen atoms (i.e., ~10% O(S) impurities). O(S) formation is exothermic, and the oxygen atoms tend to avoid O-O dimerization, which favors the structural stability of homogeneous FeS(2-x)O(x) alloys and frustrates phase separation into FeS(2) and iron oxides. With an ideal band gap, absence of O(S)-induced gap states, high optical absorptivity, and low electron effective mass, FeS(2-x)O(x) alloys are promising for the development of pyrite-based heterojunction solar cells that feature large photovoltages and high device efficiencies. PMID- 22827739 TI - Association of distinct IL-31 polymorphisms with pruritus and severity of atopic dermatitis. PMID- 22827740 TI - In vitro fertilization treatment influences glucose tolerance in multiple pregnancy. PMID- 22827741 TI - Radiation exposure in patients with inflammatory bowel disease--primum non nocere? AB - BACKGROUND: Patients with Inflammatory Bowel disease (IBD) are frequently exposed to diagnostic medical radiation for the diagnosis and evaluation of their disease. Despite increasing awareness of the potentially serious downstream effects, few studies have quantified radiation exposure in IBD patients. METHODS: We conducted a retrospective review of 280 consecutive patients attending IBD clinics at our hospital. All incidences of diagnostic medical radiation from initial diagnosis until 30 June 2010 inclusive were recorded. The radiation dose for each procedure was obtained from standardized tables and the effective dose for each procedure calculated by multiplying this value by the number of procedures during the study period. The sum of doses received was the cumulative effective dose. RESULTS: The mean and median cumulative effective radiation doses were 10.17 mSv and 4.12 mSv respectively. Crohn's disease patients had significantly higher cumulative effective radiation exposure than UC patients (p < 0.001) with exposure exceeding 10 mSv in 58.3%, 25 mSv in 18.1% and 50 mSv in 6.3%, respectively. Smoking status, disease duration, and previous surgery were significant predictors for increased radiation exposure even after adjusting for other predictors. 47 small bowel magnetic resonance (MR) studies were undertaken as an alternative to ionising radiation in the last 3 years. CONCLUSIONS: Patients with IBD, particularly those with Crohn's disease, are exposed to significant amounts of diagnostic medical radiation in their lifetime. Clinicians must remain vigilant to the risk of cumulative radiation when evaluating these patients and consider non-ionizing alternatives such as intestinal ultrasound and MR imaging where clinically appropriate. PMID- 22827742 TI - Binding kinetics and mechanism of action: toward the discovery and development of better and best in class drugs. AB - Binding kinetics (BK), an often overlooked key aspect of the broader concept of drug mechanism of action (MOA), is increasingly recognized as a springboard from pharmacokinetics (PK) to pharmacodynamics, and as a critical differentiator and predictor for drug efficacy and safety. Just as greater attention to PK issues has helped reduce the attrition of drugs tested in clinical trials, the emerging paradigm shift from primarily affinity/potency-emphasized to a more holistic BK perceptive and MOA-informed approach is expected to further enhance the success of drug discovery and development. This perspective attempts to envision what this new approach looks like when proper emphasis is placed on BK and MOA in designing better and best in class drugs. PMID- 22827743 TI - In vivo rat PK profiling in drug discovery: new challenges. AB - The importance of evaluating drug metabolism and pharmacokinetic (DMPK) properties very early in the drug discovery process in order to reduce attrition during development is now well recognised. In this paper we illustrate an approach for PK screening that provides a range of parameters that would not be available from conventional PK profiling. In combination with an assessment of physicochemical and in vitro properties, the in vivo PK protocol described provides better mechanistic understanding of the PK behaviour of a compound or class of compounds. The higher level of interpretation and use of in vitro and in vivo data better describe the disposition properties and give an estimation of the biophase concentration of the drug, providing a clear guidance for the design of higher quality molecules. Moreover, the collection of a broader set of in vivo and in vitro PK data improves the predictability of the DMPK science and it can allow an integrated safety risk assessment. PMID- 22827744 TI - In silico fragment-based drug design. AB - IMPORTANCE OF THE FIELD: In silico fragment-based drug design (FBDD) is a relatively new approach inspired by the success of the biophysical fragment-based drug discovery field. Here, we review the progress made by this approach in the last decade and showcase how it complements and expands the capabilities of biophysical FBDD and structure-based drug design to generate diverse, efficient drug candidates. AREAS COVERED IN THIS REVIEW: Advancements in several areas of research that have enabled the development of in silico FBDD and some applications in drug discovery projects are reviewed. WHAT THE READER WILL GAIN: The reader is introduced to various computational methods that are used for in silico FBDD, the fragment library composition for this technique, special applications used to identify binding sites on the surface of proteins and how to assess the druggability of these sites. In addition, the reader will gain insight into the proper application of this approach from examples of successful programs. TAKE HOME MESSAGE: In silico FBDD captures a much larger chemical space than high-throughput screening and biophysical FBDD increasing the probability of developing more diverse, patentable and efficient molecules that can become oral drugs. The application of in silico FBDD holds great promise for historically challenging targets such as protein-protein interactions. Future advances in force fields, scoring functions and automated methods for determining synthetic accessibility will all aid in delivering more successes with in silico FBDD. PMID- 22827745 TI - Immunogenicity of therapeutics: a matter of efficacy and safety. AB - IMPORTANCE OF THE FIELD: The unwanted immunogenicity of therapeutic proteins is a major concern regarding patient safety. Furthermore, pharmacokinetic, pharmacodynamic and clinical efficacy can be seriously affected by the immunogenicity of therapeutic proteins. Authorities have fully recognized this issue and demand appropriate and well-characterized assays to detect anti-drug antibodies (ADAs). AREAS COVERED IN THIS REVIEW: We provide an overview of the immunogenicity topic in general, the regulatory background and insight into underlying immunological mechanisms and the limited ability to predict clinical immunogenicity a priori. Furthermore, we comment on the analytical testing approach and the status-quo of appropriate method validation. WHAT THE READER WILL GAIN: The review provides insight regarding the analytical approach that is expected by regulatory authorities overseeing immunogenicity testing requirements. Additionally, the factors influencing immunogenicity are summarized and key references regarding immunogenicity testing approaches and method validation are discussed. TAKE HOME MESSAGE: The unwanted immunogenicity of protein therapeutics is of major concern because of its potential to affect patient safety and drug efficacy. Analytical testing is sophisticated and requires more than one assay. Because immunogenicity in humans is hardly predictable, assay development has to start in a timely fashion and for clinical studies immunogenicity assay validation is mandatory prior to analyzing patient serum samples. Regarding ADAs, the question remains as to when such antibodies are regarded of clinical relevance and what levels are, if at all, acceptable. In summary, the detection of ADAs should raise the awareness of the physician concerning patient safety and of the sponsor/manufacture concerning the immunogenic potential of the drug product. PMID- 22827746 TI - Advances in microfluidics for drug discovery. AB - IMPORTANCE OF THE FIELD: Microfluidics is considered as an enabling technology for the development of unconventional and innovative methods in the drug discovery process. The concept of micrometer-sized reaction systems in the form of continuous flow reactors, microdroplets or microchambers is intriguing, and the versatility of the technology perfectly fits with the requirements of drug synthesis, drug screening and drug testing. AREAS COVERED IN THIS REVIEW: In this review article, we introduce key microfluidic approaches to the drug discovery process, highlighting the latest and promising achievements in this field, mainly from the years 2007 - 2010. WHAT THE READER WILL GAIN: Despite high expectations of microfluidic approaches to several stages of the drug discovery process, up to now microfluidic technology has not been able to significantly replace conventional drug discovery platforms. Our aim is to identify bottlenecks that have impeded the transfer of microfluidics into routine platforms for drug discovery and show some recent solutions to overcome these hurdles. TAKE HOME MESSAGE: Although most microfluidic approaches are still applied only for proof of-concept studies, thanks to creative microfluidic research in the past years unprecedented novel capabilities of microdevices could be demonstrated, and general applicable, robust and reliable microfluidic platforms seem to be within reach. PMID- 22827747 TI - Affinity-based screening techniques: their impact and benefit to increase the number of high quality leads. AB - IMPORTANCE OF THE FIELD: The generation of new chemical leads as a starting point for drug development is a critical step in pharmaceutical drug discovery. High throughput screening and the attached processes have rapidly evolved over the past few years to become one of the main sources for new leads by testing large compound libraries for activity against a target of interest in biochemical in vitro tests using the recombinant protein or cell-based assays. Very recently, the traditional functional assay read-out technologies are being complemented by biophysical methods which directly measure the physical interaction (affinity) between a low molecular weight compound and a target protein. These technologies are receiving increasing attention and application for affinity screening and increasingly complement and augment the more classical activity screens. Today, such biophysical techniques are applied in hit identification as well as later stages such as hit validation, optimization and lead optimization phase. AREAS COVERED IN THIS REVIEW: This review focuses on the principle and application of selected affinity-based screening technologies, especially those which increasingly have been used in different phases of the lead finding process over the past few years. Furthermore, we highlight how throughput, robustness and information content of the discussed methods guide and determine their impact in lead finding and how to make the best use of them. WHAT THE READER WILL GAIN: The reader will gain an insight into the very broad spectrum of biophysical affinity screening methods and its high potential to support the generation of new leads. As a consequence, the reader will be able to judge which affinity method is of advantage at a certain lead discovery phase. TAKE HOME MESSAGE: Biophysical methods are very powerful tools to identify new hits and/or validate/optimize a hit to a lead. Those technologies often offer novel ways of screening complementing available classical screening technologies. An integrated, holistic approach using the combination of functional read-out technologies with different biophysical methods enables a project team to efficiently promote and progress the most promising chemotypes. PMID- 22827748 TI - Advances in targeted therapeutic agents. AB - IMPORTANCE OF THE FIELD: The number of disease-associated protein targets has significantly increased over the past decade due to advances in molecular and cellular biology technologies, human genetic mapping efforts and information gathered from the human genome project. The identification of gene products that appear to be involved in supporting the underlying cause of disease has offered the biopharmaceutical industry an opportunity to develop compounds that can specifically target these molecules to improve therapeutic responses and lower the risk of unwanted side effects that are commonly seen in traditional small chemical-based medicines. AREAS COVERED IN THIS REVIEW: An overview of targeted drug therapies is presented in this review. We include a review of the various classes of targeted therapeutic agents, the types of disease-associated molecules being targeted by these agents and the challenges currently being encountered for the successful development of these various platforms for the treatment of disease. WHAT THE READER WILL GAIN: An understanding of the current targeted therapy landscape, the discovery and selection of disease-specific gene products that are being targeted, and an overview of targeted therapies in preclinical and clinical studies. A description of the various targeted therapeutic platforms, target selection criteria and examples of each are discussed in order to provide the reader with the current status of the field and emerging areas of targeted therapy discovery and development. TAKE HOME MESSAGE: Novel medications are in demand for the treatment of serious medical conditions including cancer, autoimmune, infectious and metabolic diseases. Targeted therapies offer a way to develop very specific treatments for serious medical conditions while concomitantly resulting in little to no off-target toxicity. Targeted therapies provide an opportunity to develop personalized medicines with superior treatment modalities for the patient and a better quality of life. PMID- 22827749 TI - Fatality after cardiac arrest in thyrotoxic periodic paralysis due to profound hypokalemia resulting from intravenous glucose administration and inadequate potassium replacement. AB - BACKGROUND: Thyrotoxic periodic paralysis (TPP) is a variant of periodic paralysis (PP) that occurs in patients with underlying mutations in genes for cation channels, if they develop thyrotoxicosis. It is disabling, and fatalities sometimes occur. Here, we present a patient with TPP who developed hypokalemic paralysis that was probably aggravated by the administration of a carbohydrate, probably contributing to, if not causing, a fatal outcome. SUMMARY: A 30-year-old Chinese patient received (131)I treatment for Graves' disease (GD) in our hospital. Three days later in the middle of the night, he developed aggravating paralytic symptoms after a heavy evening meal. The next morning, he was seen in a small clinic and was treated with 1250 mL 5% glucose containing 25 mL 10% potassium chloride (KCl). By early afternoon, he had not improved and was transferred to a city hospital, arriving with grade I muscle strength and severed facial and bulbar paralysis that was shortly followed by cardiac arrest with failure of resuscitation. Shortly before he died, his serum K(+) was 1.15 mEq/L (normal=3.5-5). CONCLUSIONS: We postulate that severe hypokalemia developed in our patient in part in response to the high intravenous glucose load that he received. We advocate caution against using intravenous glucose solutions for potassium administration in patients with TPP and recommend a review of guidelines suggesting this form of treatment. In rural settings with limited resources, we favor oral potassium, not to exceed 100 mEq per day, and transfer to a modern medical facility in settings where muscle weakness is developing in patients with TPP. PMID- 22827750 TI - Serotype distribution of invasive Streptococcus pneumoniae in Canada during the introduction of the 13-valent pneumococcal conjugate vaccine, 2010. AB - A baseline serotype distribution was established by age and region for 2058 invasive Streptococcus pneumoniae isolates collected during the implementation period of the 13-valent pneumococcal conjugate vaccine (PCV13) program in many parts of Canada in 2010. Serotypes 19A, 7F, and 3 were the most prevalent in all age groups, accounting for 57% in <2 year olds, 62% in 2-4 year olds, 45% in 5-14 year olds, 44% in 15-49 year olds, 41% in 50-64 year olds, and 36% in >=65 year olds. Serotype 19A was most predominant in Western and Central Canada representing 15% and 22%, respectively, of the isolates from those regions, whereas 7F was most common in Eastern Canada with 20% of the isolates. Other prevalent serotypes include 15A, 23B, 12F, 22F, and 6C. PCV13 serotypes represented 65% of the pneumococci isolated from <2 year olds, 71% of 2-4 year olds, 61% of 5-14 year olds, 60% of 15-49 year olds, 53% of 50-64 year olds, and 49% of the >=65 year olds. Continued monitoring of invasive pneumococcal serotypes in Canada is important to identify epidemiological trends and assess the impact of the newly introduced PCV13 vaccine on public health. PMID- 22827751 TI - The effect of maternal fasting during Ramadan on preterm delivery: a prospective cohort study. AB - OBJECTIVE: To determine the effect of fasting during the month of Ramadan on the rate of preterm delivery (PTD). DESIGN: A prospective cohort study of women with singleton pregnancies who elected to fast and matched controls. SETTING: Four medical centres in Beirut, Lebanon. POPULATION: Women presenting for prenatal care (20-34 weeks of gestation) during the month of Ramadan, September 2008. METHODS: Data were collected prospectively. The frequency of PTD was evaluated in relation to the duration of fasting and the stage of gestation at the time of fasting. MAIN OUTCOME MEASURES: The primary endpoint was the percentage of pregnant women who had PTD, defined as delivery before 37 completed weeks of gestation. RESULTS: A total of 468 women were approached, of whom 402 were included in the study. There were no differences in smoking history and employment. There was no difference in the proportion of women who had PTD at <37 weeks (10.4% versus 10.4%) or PTD at <32 weeks (1.5% versus 0.5%) in the Ramadan fasted group and the controls, respectively. The PTD rate was also similar in those who fasted before or during the third trimester. The mean birthweight was lower (3094 +/- 467 g versus 3202 +/- 473 g, P = 0.024) and the rate of ketosis and ketonuria was higher in the Ramadan-fasted women. On multivariate stepwise logistic regression analysis, fasting was not associated with an increased risk of PTD (odds ratio 0.72; 95% confidence interval 0.34-1.54; P = 0.397). The only factor that had a significant effect on the PTD rate was body mass index (odds ratio 0.43; 95% confidence interval 0.20-0.93; P = 0.033). CONCLUSIONS: Fasting during the month of Ramadan does not seem to increase the baseline risk of preterm delivery in pregnant women regardless of the gestational age during which this practice is observed. PMID- 22827752 TI - Innovative topical formulations for treatment of dermatitis. AB - The treatment of dermatitis with conventional dosage forms (ointment, cream, lotion etc.) has many concerns due to side effects especially in long-term therapy. Recent studies focused on strategies to optimize the potency of formulation while minimizing side effects. Several attempts have been made to increase the safety of treatment, including special vehicles (nanoparticle, liposome, patch etc.), combined therapy and new synthesized agents. This review provides major innovations and advances of new approaches for dermatitis treatment based on the published articles and patent applications. PMID- 22827753 TI - Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part I: cytokines in atopic dermatitis. AB - Atopic dermatitis is a chronic allergic inflammatory disease of the skin. Its pathophysiology involves an orchestrated sequence of allergic provocation by IgE mediated and non-IgE-mediated Th2 responses to allergens. Allergen sensitization precedes the immunopathogenesis. Th2 cytokines such as IL-4 and IL-5 play a key role in both the sensitization and effector phases of allergic skin inflammation. Recently, the roles of new cytokines including IL-16, IL-17, IL-21, IL-22, IL-23, IL-27, IL-31, IL-33, IL-35 and thymus stromal lymphopoietin (TSLP), and Th2 polarization in the immunopathogenesis of skin inflammation and physically injured skin have been described, in addition to roles for IL-4, IL- 5, IL-9, IL 13, IFN-gamma and TGF-beta. Sensitization occurs via the skin for aeroallergen including house dust mites and superantigens and through the gastrointestinal tract for food allergens. Alternatively, food allergens can be sensitized through skin. Atopic dermatitis is described under the structure of sensitization phase and effector phase in this review. Especially, the clinically effective applications of cytokines in AD and relevant patents are updated in this review. PMID- 22827754 TI - Atopic dermatitis and cytokines: the immunoregulatory and therapeutic implications of cytokines in atopic dermatitis--part II: negative regulation and cytokine therapy in atopic dermatitis. AB - Atopic dermatitis is an immunologic disease that results in allergic inflammations of the skin. Cytokines are involved in the negative regulation of immunopathogenesis of atopic dermatitis. Negative immune regulation is also achieved by immune cells in addition to cytokines which are subsequently regulated by a counter-regulatory mechanism. Allergen tolerance is an important aspect of the treatment of atopic dermatitis. Recently, the IL-27, IL-21, and IL 10 cytokines were found to be important components of the counter regulatory mechanism that terminates immune response, and protects the host from excessive immune responses. IL-10 and TGF-beta are well-known to be involved in the immune tolerance. IL-10 and IFN-gamma are promising cytokines with respect to the prevention of allergen sensitization and the induction of allergen-specific tolerance. In particular, IFN-gamma has unique tolerogenic effects with respect to pre-sensitized allergens, especially in atopic dermatitis. In this review, the role of cytokines in the immune tolerance and relevant patents are reviewed, and therapeutic strategies are presented based on the immunologic architecture of AD. PMID- 22827755 TI - Anti-irritants agents for the treatment of irritant contact dermatitis: clinical and patent perspective. AB - This overview defines whether anti-irritant agents, in fact, inhibit, prevent or treat irritant contact dermatitis (ICD) in man. We performed a literature search using PubMed, EMBASE, and Scopus via the library at University of California San Francisco, and a hand search of relevant text books to investigate chemicals that can be considered anti-irritants in either prevention or treatment. Emphasis was placed on data that included quantitative and qualitative results and that followed evidence-based dermatological guidelines. Related patents were summarized. Conflicting observations summarized here suggest well controlled, but often arduous, field type studies are required for confirmation. PMID- 22827756 TI - Blackfly vectors of zoonotic onchocerciasis in Japan. AB - Studies of blackfly vectors of Onchocerca dewittei japonica Uni, Bain & Takaoka (Spirurida: Onchocercidae), a parasite of wild boar implicated in the aetiology of zoonotic onchocerciasis in Japan, and six other zoonotic Onchocerca species of this country are reviewed. Molecular identification of infective larvae found in wild-caught female blackflies showed that Simulium bidentatum (Shiraki) (Diptera: Simuliidae) is a natural vector of O. dewittei japonica, and also Onchocerca sp. sensu Fukuda et al., another parasite of wild boar. Inoculation experiments demonstrated that Simulium arakawae Matsumura and four other Simulium species are putative vectors. Similarly, S. arakawae, S. bidentatum and Simulium oitanum (Shiraki) are putative vectors of Onchocerca eberhardi Uni & Bain and Onchocerca skrjabini Rukhlyadev, parasites of sika deer. Morphometric studies of infective larvae indicated that Onchocerca lienalis Stiles, a bovine species, is transmitted by S. arakawae, Simulium daisense (Takahasi) and Simulium kyushuense Takaoka, and that Onchocerca sp. sensu Takaoka & Bain, another bovine species, is transmitted by S. arakawae, S. bidentatum, S. daisense and S. oitanum. Prosimulium sp. (Diptera: Simuliidae) and Simulium japonicum Matsumura are suspected vectors of Onchocerca suzukii Yagi, Bain & Shoho and O. skrjabini [Twinnia japonensis Rubtsov (Diptera: Simuliidae) may also transmit the latter], parasites of Japanese serow, following detection of the parasites' DNA genes in wild-caught blackflies. PMID- 22827757 TI - Saccharomyces cerevisiae strains and the reduction of Aspergillus parasiticus growth and aflatoxin B1 production at different interacting environmental conditions, in vitro. AB - The effect of Saccharomyces cerevisiae RC008 and RC016, previously selected based on their aflatoxin B(1) binding ability and beneficial properties, against Aspergillus parasiticus under different interacting environmental conditions was evaluated. Studies concerning the lag phase, growth rate and aflatoxin B(1) production were carried out in vitro under different regimes of a (w) (0.95 and 0.99), pH (4 and 6), temperature (25 and 37 degrees C), and oxygen availability (normal and reduced). Both yeast strains showed great antagonistic activity at pH 4, decreasing growth rate compared with the control. The RC008 strain showed the greatest inhibitory activity at all assayed conditions. A. parasiticus produced large amounts of AFB(1) in vitro. A significant decrease of AFB(1) levels in comparison with the control were observed with yeast interaction. Differences between control and treatment values ranged from 130 to 5400 ng ml(-1). S. cerevisiae RC008 and RC016 could be considered as effective agents in reducing growth and AFB(1) production at different interacting environmental conditions, related to that found in stored feedstuff. The importance of the present work lies in the search for live strains with both probiotic and biocontrol properties able to prolong the safe storage of feedstuff and exert beneficial properties after animal consumption and which could be included in a novel product for animal feed. PMID- 22827758 TI - Comparison of HER2 immunohistochemical results using a monoclonal antibody (SV2 61gamma) and a polyclonal antibody (for Dako HercepTest) in advanced gastric cancer. AB - We compared a monoclonal antibody (SV2-61gamma) and a polyclonal antibody (Dako HercepTest) in immunohistochemical assessments of human epidermal growth factor receptor 2 (HER2) expression in 73 samples of advanced gastric cancer. Results were scored as 0 to 3+, and equivocal or discordant (SV2-61gamma/Dako HercepTest = 0/2+, 0/3+, 1+/3+ or 2+/3+) cases were subjected to fluorescence in situ hybridization (FISH) analysis. The frequencies of HER2 scores of 2+ or 3+ were 15.1% (11/73) using SV2-61gamma and 38.4% (28/73) using Dako HercepTest. All of the equivocal or discordant cases with a HER2 score of 3+ using Dako HercepTest exhibited amplification of the HER2 gene regardless of the HER2 score determined with SV2-61gamma. The results of the HER2 tests differed according to the antibodies used for immunohistochemistry that preceded FISH analysis, being 15.1% (11/73) using SV2-61gamma and 23.3% (17/73) using Dako HercepTest. Thus, therapeutic decisions might be markedly influenced by the selection of antibody used in the HER2 test. PMID- 22827759 TI - High frequency of t(14;18) in Hodgkin's lymphoma associated with follicular lymphoma. AB - t(14;18) is a common cytogenetic abnormality in B-cell lymphoma, especially in follicular lymphoma (FL), but is rarely seen in Hodgkin's lymphoma (HL). However, due to the small number of cases, the incidence of t(14;18) in HL associated with FL remains unclear. In this study, we applied chromogenic in situ hybridization and fluorescence in situ hybridization for t(14;18) on paraffin-embedded tissue from four HL associated with FL cases and 11 HL cases without a history of FL for comparison. t(14;18) was present in all of the three successfully-tested HL associated with FL cases and one case without a history of FL. The frequency of t(14;18) was significantly high in HL associated with FL (p = 0.013). All Hodgkin's and Reed-Sternberg (HRS) cells having t(14;18) showed immunoreactivity for BCL2 and were negatively stained for nuclear factor-kappaB (NF-kappaB), even in Epstein-Barr virus (EBV)-infected cases. However, HRS cells without t(14;18) showed BCL2 and NF-kappaB immunoreactivity in 33% and 57% of cases, respectively. There was an inverse correlation between t(14;18) and NF-kappaB. In conclusion, we assume the incidence of t(14;18) in HL associated with FL is higher than previously believed and BCL2 expression derived from t(14;18) may play a role in the pathogenesis of HL associated with FL. PMID- 22827760 TI - Desmoplastic reaction in biopsy specimens of early colorectal cancer: a Japanese prospective multicenter study. AB - We previously reported that detection of desmoplastic reaction (DR) in pretreatment biopsy specimens was useful for predicting the depth of submucosal invasion (SM depth) in nonpedunculated early colorectal cancers (ECRCs) in a retrospective study. Here, we performed a prospective multicenter study for verification of our previous findings. Subjects were diagnosed with ECRC by endoscopy, and with adenocarcinoma from the biopsy specimens. Eleven institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum participated in this collaborative study. A total of 112 patients with ECRC were enrolled. For nonpedunculated ECRCs, presence of DR was significantly correlated with SM depth. The sensitivity and specificity of detection of DR for prediction of pSM2 (tumor invasion >=1000 um) in nonpedunculated ECRCs were 68.6% and 92.0%, respectively. Evaluation of DR in pretreatment biopsy specimens may be useful for the clinicopathological diagnosis of colorectal carcinoma with massive invasion into the submucosal layer. PMID- 22827761 TI - Infantile adenomyoma subclinically excreted into the patient's diaper. AB - Adenomyoma is a rare condition of the gastrointestinal tract, consisting of glandular structures lined by columnar or cuboidal epithelium and surrounded by smooth muscle bundles. The vast majority of adenomyomas of gastrointestinal tract have been reported to be located at the propyloric segment of the stomach and their localization in the bowel of infantile patients is considered rare. A review of the literature showed that 13 cases of infantile adenomyoma in the bowel have been reported. In the previous cases, intussusception was the most common complication of adenomyoma in the bowel and all cases underwent laparotomy. Here we describe an extremely rare case of infantile adenomyoma subclinically eliminated in the diaper. In addition, we performed immunohistochemical analysis to speculate on the origin of the adenomyoma. PMID- 22827762 TI - Mixed angiosarcoma, clear cell adenocarcinoma and mature teratoma elements in an ovarian tumor: a case report and literature review. AB - Malignant transformation of a mature teratoma in the ovary is a rare event, with an approximate rate of only 1-2%. Here, we report an ovarian tumor with a unique combination of epithelial and non-epithelial malignant components, including mature teratoma elements. A 59 year-old postmenopusal woman underwent total hysterectomy and bilateral salpingo-oophorectomy to remove a huge solid mass of the right ovary. The ovarian tumor was 16 * 12 * 4.5 cm in dimensions, composed of red-brown and greyish-white tissue with several cystic areas. Microscopically, atypical cells immunopositive for both CD31 and CD34 formed irregular ectatic vascular patterns with a high MIB-1 labeling index in red-brown areas. In contrast, tubule-cystic and papillary structures were lined by HNF-1beta immunopositive atypical cuboidal and hobnail cells with clear cytoplasm in greyish-white areas. In addition, normal-looking epithelial and stromal components, including mature squamous, cuboidal and ciliated epithelial cells, and adipose tissues, were observed in red-brown areas, suggesting an ovarian tumor combining angiosarcoma, clear cell adenocarcinoma, and mature teratoma features. We could demonstrate identical X-chromosome inactivation patterns among all three components by human androgen receptor gene (HUMARA) assays, pointing to complex inter-relationships regarding their pathogenesis. These observations suggest that a malignant tumor composed of two characteristic phenotypes arose in mature teratoma. PMID- 22827763 TI - Pulmonary hypoplasia on preterm infant associated with diffuse chorioamniotic hemosiderosis caused by intrauterine hemorrhage due to massive subchorial hematoma: report of a neonatal autopsy case. AB - A male infant born prematurely at 31 weeks of gestation weighed 789 g and had mildly brown-colored oral/tracheal aspirates at delivery. The amniotic fluid was also discolored, and its index was below 5. The patient died of hypoxemic respiratory and cardiac failure 2 hours after birth. The maternal profiles showed placenta previa and intrauterine growth restriction (IUGR) at 22 weeks of gestation, and revealed recurrent episodes of antenatal and substantial vaginal bleeding and oligohydramnios, indicating chronic abruption-oligohydramnios sequence. The thickened placenta, weighing 275 g, grossly displayed unevenness and diffuse opacity with green to brown discoloration in the chorioamniotic surface, and revealed chronic massive subchorial hematomas (Breus' mole) with old peripheral blood clot, circumvallation, and infarction. Microscopically, diffuse Berlin-blue staining-positive hemosiderin deposits were readily encountered in the chorioamniotic layers of the chorionic plate, consistent with diffuse chorioamniotic hemosiderosis (DCH) due to Breus' mole, accompanied by diffuse amniotic necrosis. At autopsy, an external examination showed several surface anomalies and marked pulmonary hypoplasia, 0.006 (less 0.012) of lung:body weight ratio. Since Breus' mole has a close relationship with intrauterine hemorrhage, resulting in DCH, IUGR, and/or pulmonary hypoplasia of the newborn, the present features might be typical. PMID- 22827764 TI - Primitive myxoid mesenchymal tumor of infancy: report of two cases and review of the literature. AB - Primitive myxoid mesenchymal tumor of infancy is a recently recognized soft tissue tumor with only a few cases reported. Here, we reported another two cases of the lesion, a 5-month-old boy presenting with a soft tissue mass in the neck region that recurred 2 months later and a 3-day-old girl with a congenital superficial dorsal lumbar mass that extended to the spinal canal 1 month later. They shared similar histological patterns, such as unusual diffuse myxoid background, delicate vascular network, small cystic spaces, low to moderate cellularity, and primitive mesenchymal tumor cells. Immunohistochemically, the tumor cells showed positive for vimentin, CD99, CD117 and nestin, negative for myoid, lipoblastic, histiocytic, and neural markers. In conclusion, primitive myxoid mesenchymal tumor of infancy is a distinctive entity with its own clinical pathological features. Expression of CD99, CD117 and nestin may be consistent with the primitive nature of the tumor and may serve as ancillary markers for differential diagnosis from the other infantile tumors. PMID- 22827765 TI - An adult case of midgut volvulus in familial visceral myopathy. AB - We report an adult case of midgut volvulus in familial visceral myopathy (FVM) that had affected family members over three generations. The patient was a Japanese woman in her fifties, who had chronic intestinal pseudo-obstruction (CIPO) since the age of about 40 years and had been treated chronically with conservative therapies. Her abdominal symptoms suddenly worsened and surgery became necessary. Surgery revealed a midgut volvulus secondary to intestinal malrotation and the twisted intestine was resected. Histology revealed diffuse damage of myocytes confined to the muscularis propria throughout the resected intestine. The myocytes were irregulary arranged, contained cytoplasmic inclusions, and had mild and focal vacuolar changes. The mucsularis propria showed hypertrophy with delicate interstitial fibrosis. A diagnosis of FVM was made on the basis of this characteristic myopathy. Intestinal malrotation is known to be a complication of CIPO in children, but is rare in adults. Although midgut volvulus appears to be extremely rare, it can occur after a relatively stable chronic phase in adult CIPO patients, who should be monitored carefully to assess the risk of such complications. PMID- 22827766 TI - Malignant diffuse-type tenosynovial giant cell tumor of the buttock. AB - Malignant diffuse-type tenosynovial giant cell tumor (D-TSGCT) is an unusual sarcoma. We report a case of malignant D-TSGCT located in the left buttock. A 58 year old woman noticed a small mass at her left buttock 3 months previously. The mass tended to enlarge rapidly, and became 6 cm in diameter. Tumor resection was performed. Grossly, the tumor showed a solid growth pattern and whitish appearance with hemorrhage and necrosis. Microscopically, the tumor was composed of a proliferation of short spindle and oval mononucleated cells with numerous osteoclast-like multinucleated giant cells, which occasionally showed coagulative necrosis. In addition, tumor cells had high mitotic activity and atypical mitoses. Immunohistochemically, the mononucleated cells were positive for CD163 and focally positive for CD68 (clone KP-1 and PG-M1), CD4, smooth muscle actin and S100 protein. Osteoclast-like multinucleated giant cells were positive for CD68 (clone KP-1 and PG-M1) and CD4. Pulmonary metastases were found 6 months after the operation. These findings indicate that this lesion is consistent with malignant D-TSGCT. PMID- 22827767 TI - Clinicopathologic features and molecular analysis of enterovirus 71 infection: report of an autopsy case from the epidemic of hand, foot and mouth disease in China. AB - A 15-month boy with fatal hand, foot, and mouth disease (HFMD) exhibited atypical symptoms and progressed rapidly to death. An autopsy was performed the next day and tissue sections were stained for histopathological examination. His intestinal samples were tested for enterovirus 71 (EV71), and the whole-genome sequence of EV71 was analyzed. An autopsy revealed that the central nervous system, lungs, and gut displayed severe meningitis and brainstem encephalitis, remarkable pulmonary congestion, edema, moderate inflammatory infiltration, and hemorrhage as well as intestinal mucosal congestion, epithelial necrosis, thinning intestinal wall, and submucosal lymphoid follicular hyperplasia. The heart showed myocardial interstitial congestion, myocardial edema, and some inflammatory infiltrates. There were no significant alterations in the architecture of other organs. EV71 antigen and apoptotic cells were detected in brain, lung and intestine by immunohistochemical staining and TUNEL (TdT-mediated dUTP nick-end labeling) respectively. Intestinal contents and intestinal autopsy samples of this case were positive for EV71, and the EV71 strain was classified as subgenogroup C4. In China, the severe forms of HFMD were mostly caused by EV71 subgenogroup C4 infection. Severe intestinal damages may relate to EV71 subgenogroup C4 infection. Thus, children with severe EV71 HFMD may have serious pathological changes in their central nervous system, lungs, and gut. Physicians should pay special attention to infants with atypical symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment. PMID- 22827768 TI - Kikuchi Fujimoto disease (histiocytic necrotizing lymphadenitis) following Hodgkin lymphoma. PMID- 22827769 TI - Coinfection of Aspergillus and Cryptococcus in post-tuberculosis pulmonary cavity. PMID- 22827770 TI - Survey on breastfeeding among Chinese female physicians and nurses. AB - The present study investigated knowledge of and beliefs about breastfeeding among Chinese female physicians and nurses and their breastfeeding practices. This study documented knowledge, attitudes and practices of breastfeeding among Chinese medical staff. A total of 367 female physicians and nurses completed a self-administered, anonymous questionnaire; 96.2% indicated that breastfeeding was natural, but 29.2% thought it difficult. Only 18.5% of the participants questioned breastfeeding women on feeding status, and 12.8% gave breastfeeding advice when asked. After graduation from school, 79.3% of the participants stated that they did not receive training in breastfeeding. In personal practice, 69.2% initiated breastfeeding; 19.1% were still breastfeeding at 4 months, and only three nurses continued breastfeeding for more than 1 year. In conclusion, breastfeeding-related knowledge is surprisingly poor, and attitudes are less positive. The exclusive breastfeeding rate was found to be low among Chinese female physicians and nurses. The findings highlight the need to re-educate medical staff on breastfeeding, and imply the need for Baby-Friendly Hospital Initiative implementation/training. PMID- 22827771 TI - Pressurized liquid extraction and HPLC quantification of folic acid in fortified wheat flours. AB - A pressurized liquid extraction (PLE) method using phosphate buffer as solvent was applied for folic acid (FA) extraction from fortified wheat flours and was compared to a standard solid-liquid extraction (SLE) method. Extracted FA was quantified by reverse phase high-performance liquid chromatography (RP-HPLC) hyphenated with a phenyl column and an absorption photometric detector (lambda = 280 nm). Detection and quantification limits were 0.12 and 0.4 ng, respectively, corresponding to 0.06 and 0.2 MUg g(-1) of analyzed wheat flour. Equivalent FA contents were found by both extraction methods, but a single PLE allowed a total recovery of FA content, whereas at least three successive SLEs were needed to achieve a total recovery of FA. The obtained results indicated that PLE is a rapid and efficient technique for FA extraction from fortified wheat flour. PMID- 22827772 TI - How accurate can genetic predictions be? AB - BACKGROUND: Pre-symptomatic prediction of disease and drug response based on genetic testing is a critical component of personalized medicine. Previous work has demonstrated that the predictive capacity of genetic testing is constrained by the heritability and prevalence of the tested trait, although these constraints have only been approximated under the assumption of a normally distributed genetic risk distribution. RESULTS: Here, we mathematically derive the absolute limits that these factors impose on test accuracy in the absence of any distributional assumptions on risk. We present these limits in terms of the best-case receiver-operating characteristic (ROC) curve, consisting of the best case test sensitivities and specificities, and the AUC (area under the curve) measure of accuracy. We apply our method to genetic prediction of type 2 diabetes and breast cancer, and we additionally show the best possible accuracy that can be obtained from integrated predictors, which can incorporate non-genetic features. CONCLUSION: Knowledge of such limits is valuable in understanding the implications of genetic testing even before additional associations are identified. PMID- 22827773 TI - Hydration energies of aromatic ions in the gas phase. AB - The hydration energies of aromatic ions, measured by using energy-resolved collision-induced dissociation measurements, are reported. The hydration energies of protonated acetophenone, aniline, anisole, benzene, benzonitrile, phenol, and toluene are 0.67 +/- 0.04, 0.62 +/- 0.04, 0.86 +/- 0.04, 0.46 +/- 0.06, 0.84 +/- 0.04, 0.75 +/- 0.07, and 0.42 +/- 0.04 eV, respectively. The measured values are in good agreement with those predicted by using coupled cluster theory, provided the proper geometries of the ions and sufficient basis set were used. PMID- 22827774 TI - Porphyrin shell microbubbles with intrinsic ultrasound and photoacoustic properties. AB - Porphyrin-phospholipid conjugates were used to create photonic microbubbles (MBs) having a porphyrin shell ("porshe"), and their acoustic and photoacoustic properties were investigated. The inclusion of porphyrin-lipid in the MB shell increased the yield, improved the serum stability, and generated a narrow volumetric size distribution with a peak size of 2.7 +/- 0.2 MUm. Using an acoustic model, we calculated the porshe stiffness to be 3-5 times greater than that of commercial lipid MBs. Porshe MBs were found to be intrinsically suitable for both ultrasound and photoacoustic imaging with a resonance frequency of 9-10 MHz. The distinctive properties of porshe MBs make them potentially advantageous for a broad range of biomedical imaging and therapeutic applications. PMID- 22827775 TI - Antidepressant-like effect of bis-eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system. AB - Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist), SCH23390 (15 MUg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function. PMID- 22827776 TI - Evaluation of a self-adhering flowable composite in terms of micro-shear bond strength and microleakage. AB - PURPOSE: The objective of this study was to evaluate dentin bond strength and microleakage of a self-adhering flowable resin with or without adhesive resin. MATERIALS AND METHODS: Dentin pieces were randomly assigned to three groups (n = 10): Group OR (Optibond+Revolution Formula 2 Flow); Group VF (Vertise Flow); and Group OVF (Optibond+Vertise Flow). Then specimens were stressed in shear at a cross-head speed of 1 mm/min until the bond failed. Moreover, microleakage was determined by restoring Class V cavities. A statistical analyses was carried out using Mann-Whitney U and Kruskal-Wallis tests (p < 0.05). RESULTS: Group OVF specimens produced the highest mean shear bond strength. In addition, the results showed that the marginal seal in group VF was similar to that in group OR. CONCLUSION: Self-adhering flowable composite resin combined with adhesive resin provided stronger dentin bond strength and a better marginal seal than when it was used individually. VF is a useful material with an acceptable bond strength and marginal seal. PMID- 22827777 TI - Alkaline phosphatase-responsive anodic electrochemiluminescence of CdSe nanoparticles. AB - Alkaline phosphatase (ALP) catalyzes the hydrolysis and transphosphorylation of a wide variety of phosphoric acid monoesters and plays an important role in clinical diagnosis. In this work, an ALP-responsive anodic electrochemiluminescence (ECL) system based on coreaction of CdSe nanoparticles (NPs) and triethylamine has been designed for facile detection of ALP. The substrate of ALP, i.e., phenyl phosphate salt, shows no effect on the ECL emission whereas its catalytic product of phenol may induce ECL inhibition. For the buffer containing phenyl phosphate, the ECL emission is found to decline in the presence of ALP with different incubation time. The mechanism investigations indicate that the deposition of the electropolymerized phenol products may compete with the electrophoretic-driven adsorption of CdSe NPs on glassy carbon electrode and induce the ECL inhibition, which can be demonstrated by scanning electron microscopy, energy dispersive spectrometry, and anodic stripping voltammetry. Therefore, an inhibition type strategy has been developed to sensitively detect ALP ranging from 0.5 to 6.4 nM (activity ca. 2-25 U/L), with a detection limit of 0.5 nM. The potential interference from the common proteins is negligible. The recovery of ALP in diluted serum samples ranges from 91 to 114%, implicating its potential applications in the complex biological matrixes. PMID- 22827779 TI - Soy intake and metabolic health: beyond isoflavones. PMID- 22827780 TI - Effects of soy on metabolic biomarkers of cardiovascular disease in elderly women with metabolic syndrome. AB - BACKGROUND: This study ascertained the effects of soy, in the forms of textured soy protein (TSP) and soy nuts, on lipid profiles, apolipoproteins, inflammatory and prothrombotic markers, and blood pressure in elderly women diagnosed with metabolic syndrome (MetS). METHODS: This was a 12-week parallel, randomized, controlled trial conducted in rural health centers of Babol, Iran. Participants were 75 women, ages 60-70 years, who were diagnosed with MetS. Subjects were randomized to one of the following 3 groups: i) soy nut (35 g/d), ii) TSP (35 g/d), and iii) control. Blood biochemical markers measured at baseline and at the end of the study included: triglycerides (TG), cholesterol, HDL-C, LDL-C, VLDL-C, ApoB100, ApoAI, C-reactive protein (CRP), and fibrinogen. RESULTS: Soy nuts significantly improved LDL-C, VLDL-C, and ApoB100levels (P < 0.05), while fewer, significant improvements were observed in these variables in the TSP group compared to mean changes from baseline (P < 0.001). Similar results were found for ApoAI in the treatment groups (P < 0.01). Serum total cholesterol (TC) decreased significantly in the treatment groups compared with the control group (P < 0.005). Differences from the control group in terms of TG, HDL-C, fibrinogen, CRP, and blood pressure were not significant. CONCLUSION: Both forms of soy improved lipid profiles. The group that consumed soy nuts had greater improvement than the TSP group. Therefore, moderate daily intake of soy may be a safe, inexpensive, and practical method to improve the risk of cardiovascular disease (CVD) and reduce the need for medical treatment. IRCT ID: IRCT 138804212130N1. PMID- 22827781 TI - Isolated vertigo and possibility of brain ischemia. AB - BACKGROUND: In cases of isolated vertigo, physicians are unable to definitely distinguish between central or peripheral vertigo by history and physical examination. Some central causes of isolated vertigo such as cerebellar stroke can be life-threatening and require intervention. Brain infarction can be detected shortly after the onset of clinical symptoms by using diffusion-weighted MRI (DWI). We have conducted this study to perform DWI on isolated vertigo patients with a higher probability of brain infarction. METHODS: We enrolled 55 consecutive patients with isolated vertigo who had at least one cardiovascular risk factor. A questionnaire that consisted of cardiovascular risk factors was completed and DWI performed for each patient. We analyzed the association of cardiovascular risk factors with infarction as identified by DWI. RESULTS: Using DWI, 5 (9.1%) patients had an acute ischemic stroke. Among cardiovascular risk factors, analysis showed a significant relationship between diabetes mellitus (DM) and infarction. CONCLUSION: Isolated vertigo may occur due to the occlusion of a small artery in the area of brain circulated by the posterior inferior cerebellar artery. According to our results, DWI may be used in diabetic patients with isolated vertigo to locate a probable infarction. PMID- 22827778 TI - The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial Mesenchymal transition of cancer. AB - Epithelial to Mesenchymal transition (EMT) in cancer, a process permitting cancer cells to become mobile and metastatic, has a signaling hardwire forged from development. Multiple signaling pathways that regulate carcinogenesis enabling characteristics in neoplastic cells such as proliferation, resistance to apoptosis and angiogenesis are also the main players in EMT. These pathways, as almost all cellular processes, are in their turn regulated by ubiquitination and the Ubiquitin-Proteasome System (UPS). Ubiquitination is the covalent link of target proteins with the small protein ubiquitin and serves as a signal to target protein degradation by the proteasome or to other outcomes such as endocytosis, degradation by the lysosome or specification of cellular localization. This paper reviews signal transduction pathways regulating EMT and being regulated by ubiquitination. PMID- 22827782 TI - Effects of low dose zinc supplementation on biochemical markers in non-alcoholic cirrhosis: a randomized clinical trial. AB - BACKGROUND: The present study aimed to evaluate the effects of low dose zinc (Zn) supplementation on biochemical markers and underlying disease status in non alcoholic cirrhotic patients. METHODS: We enrolled 60 cirrhotic patients in a double-blind, placebo-controlled, randomized clinical trial. All patients in the interventional group (n = 30) received long-term, low dose Zn supplementation (50 mg elemental Zn sulfate daily). The control group (n = 30) received placebo (starch). Child-Pugh scores and biochemical markers were assessed for both interventional and control groups at the first day and the end of the 90th day of the interventional period. A per-protocol analysis was performed after excluding all participants who did not receive or complete the randomized intervention. The mean differences of quantitative variables between and within groups were evaluated by independent samples t-test and paired-samples t-test, respectively. SPSS version 13.00 was used for statistical analysis. RESULTS: In the initial evaluation, 16 (53.30%) patients from the interventional group had a Child-Pugh score of 5-8 and 14 (46. 70%) had a score of 9-12. In the control group 18 (60.00%) had a Child-Pugh score of 5-8 and 12 (40.00%) scored 9-12. After three months the mean Child-Pugh score in the interventional group showed a significant improvement (from 6.56 +/- 0.21 to 5.72 +/- 0.22, P = 0.001) whereas in the control group despite no significant decline, the mean Child-Pugh score increased slightly (from 6.25 +/- 0.27 to 6.67 +/- 0.31, P = 0.14). Zn supplementation significantly decreased copper (Cu; P = 0.01) and creatinine (Cr; P < 0.0001) levels. CONCLUSION: In this study, we determined that low dose Zn supplementation could prevent deterioration of clinical status of cirrhosis and prevent excess Cu accumulation in non-alcoholic cirrhotic patients. Zn supplementation produces metabolic effects and trends towards improvements in liver function, hepatic encephalopathy, and nutritional status. Registration ID in IRCT: IRCT201106122017N4. PMID- 22827783 TI - Long-term continuous methimazole or radioiodine treatment for hyperthyroidism. AB - BACKGROUND: There is no general agreement as to which treatment is best for hyperthyroidism. The objective of this study is to investigate the effectiveness of continuous methimazole (MMI) treatment and to compare the results of neuropsychological testing in patients receiving long-term continuous MMI to those on replacement thyroxine following radioiodine-induced (RAI) hypothyroidism. METHODS: We enrolled 239 patients with diffuse toxic goiter who had recurrences of hyperthyroidism. Of these, 104 patients were randomized into two groups, MMI and treatment with thyroxine following RAI hypothyroidism. The remaining 135 patients voluntarily enrolled into either of the two groups. From all patients, 59 MMI-treated patients and 73 patients in the RAI group completed follow up. Thyroid function tests, serum lipids and lipoproteins, echocardiography, bone mineral density (BMD) and seven neuropsychology tests were performed at the final visit. RESULTS: In the RAI group compared to the MMI treated group during a mean of 14 years follow up, there were more incidences of elevated TSH [> 5 mU/L; adjusted relative risk (RR) 1.23; 95% confidence interval (CI) 1.04-1.47), increased triglycerides (> 150 mg/dL; RR 2.20; 95% CI 1.34 3.62), HDL-C (< 40 mg/dL; RR 3.46; 95% CI 1.40 - 8.53), and early diastolic annular velocity (< 12.2 cm; RR 3.91; 95% CI 1.42-10.74), in addition to a decreased early diastolic to annular velocity ratio (< 6.7; RR 7.14; 95% CI 1.38 34.48). The MMI group scored better in neuropsychology tests that included mood, direction, logical memory, repeated numbers, and intelligence quotient (IQ). CONCLUSION: Long-term MMI treatment was superior to RAI therapy in patients with diffuse toxic goiter when mood, cognition, cardiac function and occurrence of thyroid dysfunction were compared. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT 201009224794N1. PMID- 22827784 TI - Pediatric-onset Behcet disease in Bahrain: report of nine cases and literature review. AB - BACKGROUND: This report studies the clinical features of Behcet disease (BD) in children and compares our results with other international studies. METHODS: We retrospectively reviewed patient data that included the clinical picture, HLA typing, and treatment in BD cases. RESULTS: This study reviewed data from a total of nine children with BD. Median age at presentation was seven years, with a male to female ratio of 2:1. There was one patient who had Down's syndrome. Oral ulcers were present in all children, while genital ulcers were present in only 66% of cases. Skin manifestation was seen in 88% and uveitis in 55%. There was evidence of gastrointestinal (55%), neurological (55%), and musculoskeletal manifestations (77%). HLA B5 was positive in 66% of cases and 55% had positive family histories. Apart from gastrointestinal symptoms, our results were comparable with other studies. CONCLUSION: Awareness of BD symptoms in the pediatric age group is crucial for early diagnosis and treatment. The coexistence of BD and Down's syndrome needs further genetic study, which may link these two major disorders. PMID- 22827785 TI - Robot-assisted thyroidectomy: early experience. AB - BACKGROUND: The numbers of thyroid surgeries have been increasing recently. Robot assisted thyroidectomy allows for a better cosmetic outcome in comparison with conventional open thyroidectomy. METHODS: We performed two robot-assisted endoscopic thyroidectomies by a gasless unilateral axillo-breast approach using the da Vinci surgical robot system. RESULTS: We performed right thyroid lobectomies in both patients. The pathologic reports were: micropapillary carcinoma without extracapsular invasion in patient 1 and a benign cyst in patient 2. The operation times were 165 minutes in patient 1 and 110 minutes in patient 2. No postoperative complications occurred. CONCLUSION: Regarding our early experience, robotic thyroidectomy using the gasless axillo-breast approach is a safe, feasible, and cosmetically good procedure. PMID- 22827786 TI - Review of 17 cases of neurobrucellosis: clinical manifestations, diagnosis, and management. AB - BACKGROUND: Neurobrucellosis (NB) is a rare, but important complication of brucellosis. The clinical features vary greatly and, in general, tend to be chronic. Many laboratory procedures are usually employed in the diagnosis of NB. Even though the culture method is the gold standard, growth rate is low and time consuming. Thus the rate of sequelae and mortality increase in case of a delay in treatment. Therefore it is necessary to perform serological tests in both serum and cerebrospinal fluid (CSF) in suspected patients. In this study we aim to evaluate clinical features, diagnosis, and treatment of patients with NB. METHODS: We enrolled 17 patients diagnosed with NB. Clinical features, cultures, serological tests, additional laboratory findings, and CSF analyses were recorded for all patients. RESULTS: There were 14 female and 3 male patients. Ten patients presented with neuropsychiatric symptoms and signs (aphasia, diplopia, hemiparesis, facial paralysis, tremor, ataxia, depression, personality disorder, and hallucinations). Serum standard agglutination test (SAT) was negative in 4 (23.5%) patients and serum Coombs' test was negative in 2 (11.7%). CSF SAT was negative in 4 (23.5%) patients and CSF Coombs was negative in 3 (17.6%) patients. B. melitensis grew in the blood of 6 (35.2%) patients and in the CSF of 3 (17.6%). Treatment protocol for 11 patients consisted of ceftriaxone, rifampicin, and doxycyline for a period of four weeks, followed by rifampicin and doxycyline for an additional four weeks. The remaining patients were given different treatment combinations. One patient died, mild sequelae was present in another patient and the remaining patients recovered without any sequelae. CONCLUSION: NB should be considered in the differential diagnosis of neurological and psychiatric cases that are encountered in endemic areas for brucellosis. In order to prevent overlooking this diagnosis, Coombs' test should be performed in both CSF and serum. PMID- 22827787 TI - Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. AB - BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis seen clinically. Current treatments for OA are limited to decreasing associated pain, maintaining or improving joint function, and minimizing disability. However, these treatments have no effect on the regeneration of hyaline cartilage. Since mesenchymal stem cells (MSCs) have been described as promising cell sources for cartilage repair, the present study was designed to examine whether intra articular injection of scaffold-free adipose-derived stem cells (ASCs) obtained from subcutaneous adipose tissue could restore the matrix of arthritic knee joints in mature animals. METHODS: OA was induced in adult white New Zealand rabbits by unilateral anterior cruciate ligament transection (ACLT); the contralateral knee was considered the sham-operated group. At 12 weeks following surgery, the ASCs treated group was injected intra-articularly with a single dose of 1 * 10(6) cells suspended in 1 mL of medium. The control group received 1 mL of medium without cells and the sham-operated group received no treatment. All rabbits were sacrificed at 16 and 20 weeks after surgery. OA progression was evaluated radiologically, grossly, and histologically using hematoxylin and eosin, Safranin-O, and toluidine blue staining. RESULTS: At 12 weeks after surgery all knees subjected to ACLT showed radiological signs of OA. The findings showed significant differences in the quality of cartilage between ASCs-injected group compared to control group, particularly at 20 weeks after surgery. CONCLUSION: This study suggests that ASCs obtained from subcutaneous adipose tissue could be a viable approach for treating OA. PMID- 22827788 TI - Nasopharyngeal carrier rate of Streptococcus pneumoniae in children: serotype distribution and antimicrobial resistance. AB - BACKGROUND: This study aimed to define the nasopharyngeal carrier rates, serotype distribution, and antimicrobial resistance patterns of Streptococcus pneumoniae in healthy children less than ten years-old in Tehran. METHODS: This was a cross sectional study conducted from November 2008 until January 2009. Nasopharyngeal specimens were collected by trained investigators from 1300 healthy children recruited from 20 randomly selected day care centers and 50 elementary schools in Tehran and inoculated into blood agar. Positive cultures that grew alpha hemolytic colonies were gram-stained and serotypes of the isolates identified by the Quellung reaction. All isolated pneumococci were tested for sensitivity to different antibiotics by the disc diffusion method. RESULTS: The carrier rate for Streptococcus pneumoniae was 44.1%. Serotypes 19, 6, 14, 17, 20, 23, and 21 were most common, found in decreasing order from 11.9% to 6.1%. Only 38.56% of isolates belonged to strains covered by the heptavalent pneumococcal vaccine. Most (69.4%) were resistant to one or more antimicrobial agents: tetracycline (69.85%), clarithromycin (57.2%), azithromycin (54.9%), co-trimoxazole (11.8%), penicillin (9.2%), and vancomycin (1.5%). All isolates were sensitive to rifampin and meropenem. CONCLUSION: This study has revealed the nasopharyngeal carrier rate, serotype distribution and antibiotic sensitivities of Streptococcus pneumoniae strains in children from Tehran. Our findings may have implications on the type and efficacy of pneumococcal conjugate vaccines that should be used for prevention of pneumococcal invasive disease in Iranian children. PMID- 22827789 TI - Impact of modified radical mastectomy on health-related quality of life in women with early stage breast cancer. AB - BACKGROUND: Systematic reviews favor a better body image and sexual activity in patients who have undergone conservative breast surgery (BCS) compared to modified radical mastectomy (MRM). In those patients with the same survival, MRM remains the surgical choice among both surgeons and patients in Iran as well as in many other countries. This cross-sectional study focuses on health-related quality of life in early stage breast cancer patients following BCS and MRM. METHODS: From all post-op patients who referred to the Motahari Clinic, Shiraz, Iran, we used a convenient sampling method to select 160 MRM patients and 127 who underwent BCS. Translated copies of the EORTC QLQ-C30 (version 3) and the EORTC QLQ-BR23 questionnaires, in addition to a third questionnaire which was customized and prepared for this study, were completed by the patients under our supervision RESULTS: The two groups were compared by a multivariate method (Hotelling's trace test) after controlling for variables with unequal values such as disease stage, hormonal and radiotherapy treatments, and patients' role in the choice of surgery. We noted a significant difference (P < 0.001) attributed to a significantly better BI in the BCS group (average: 78.49 +/- 23.14) compared to the MRM group (average: 60.71 +/- 23.14). DISCUSSION: We concluded that in terms of body image, BCS has a better impact on health-related quality of life. PMID- 22827790 TI - Confounding variables in epidemiologic studies: basics and beyond. AB - This article discusses the importance, definition, and types of confounders in epidemiology. Methods to identify and address confounding are discussed, as well as their strengths and limitations. The article also describes the difference among confounders, mediators, and effect modifiers. PMID- 22827791 TI - Rib plasmacytoma and IgA multiple myeloma with hyperviscosity syndrome. AB - Solitary bone plasmacytoma (SPB) can progress to generalized myeloma if not treated early. The elderly population is increasing and delays in diagnosis of plasma cell malignancies are frequent among them. Hyperglobulinemia of multiple myeloma (MM) plays a role in hyperviscosity syndrome (HVS). A 65-year-old woman with hypertension and diabetes mellitus was admitted due to loss of appetite, muscle weakness, breathlessness and discrete expectoration, without fever. Chest X-ray showed an abnormal shadow projection on the right lung field, while computed tomography (CT) revealed an osteolytic mass at the sixth rib. There were more than 50% of plasma cells in the bone marrow samples and high IgA levels according to serum electrophoresis. Rib plasmacytoma and overt IgA-producing myeloma with HVS were diagnosed, but treatment was unsuccessful. Case studies may enhance the awareness about this ominous condition, which may develop unnoticed, particularly in elderly patients with renal insufficiency, and can pose difficulties with diagnosis in primary care settings. PMID- 22827792 TI - Endobronchial metastases of fibrosarcoma and non-Hodgkin's lymphoma. AB - Endobronchial metastases of extrapulmonary malignant tumors are rarely encountered. Herein, we have reported two cases of endobronchial metastases from nonpulmonary tumors. The first case was a 32-year-old female patient who underwent surgery for a sclerosing epitheloid fibrosarcoma in her left thigh in 2007. Metastatic bilateral parenchymal nodules in her lungs were seen on thorax CT. Bronchoscopy revealed a mass plugging, particularly in the openings of the anterior and lateral basal segments of the left lower lung lobe. Pathological examination of the biopsies was interpreted as fibrosarcoma metastasis. The second case was a 49-year-old male patient who complained of cough, weight loss, excessive sweating, and fatigue. A 7 * 8 cm, irregular limited soft tissue density in the right middle lobe of the lung that showed air bronchogram and cystic regions was detected on thorax CT. Bronchoscopy was performed. Pathological examination of the bronchoscopic materials taken from the mass that had obstructed the entrance of the middle lobe revealed a large B cell diffuse lymphoma. PMID- 22827793 TI - Photoclinic. PMID- 22827794 TI - First international conference on school health: October 19-20, 2011, Shiraz, Iran. PMID- 22827795 TI - Developing a framework for understanding and enabling open source drug discovery. AB - Open source drug discovery is increasingly being sought as a solution for managing product development complexities. Three drivers encouraging the use of the open source strategy include: upstream knowledge-based complexities associated with complementary assets, technological complexities given the scale of research and interdependencies between disciplines and downstream commercialization complexities. While literature currently discusses the need for open source strategies and their outcomes, we have reached a critical stage for a framework to cohesively understand how the drivers affect the open source models chosen as well as the governance strategies to ensure a successful outcome both in terms of knowledge access and product development. In this paper, an initial framework is designed with a focus on the type of participant as impacting the motivation to participate in an open source initiative, the objective of any open source strategy as impacting the structural model adopted and the structure of knowledge produced as impacting its management. It is anticipated that this framework should then provide an opportunity to develop governance rules for open source drug discovery initiatives. PMID- 22827796 TI - Discovery and design of carbohydrate-based therapeutics. AB - IMPORTANCE OF THE FIELD: Till now, the importance of carbohydrates has been underscored, if compared with the two other major classes of biopolymers such as oligonucleotides and proteins. Recent advances in glycobiology and glycochemistry have imparted a strong interest in the study of this enormous family of biomolecules. Carbohydrates have been shown to be implicated in recognition processes, such as cell-cell adhesion, cell-extracellular matrix adhesion and cell-intruder recognition phenomena. In addition, carbohydrates are recognized as differentiation markers and as antigenic determinants. Due to their relevant biological role, carbohydrates are promising candidates for drug design and disease treatment. However, the growing number of human disorders known as congenital disorders of glycosylation that are being identified as resulting from abnormalities in glycan structures and protein glycosylation strongly indicates that a fast development of glycobiology, glycochemistry and glycomedicine is highly desirable. AREAS COVERED IN THIS REVIEW: The topics give an overview of different approaches that have been used to date for the design of carbohydrate based therapeutics; this includes the use of native synthetic carbohydrates, the use of carbohydrate mimics designed on the basis of their native counterpart, the use of carbohydrates as scaffolds and finally the design of glyco-fused therapeutics, one of the most recent approaches. The review covers mainly literature that has appeared since 2000, except for a few papers cited for historical reasons. WHAT THE READER WILL GAIN: The reader will gain an overview of the current strategies applied to the design of carbohydrate-based therapeutics; in particular, the advantages/disadvantages of different approaches are highlighted. The topic is presented in a general, basic manner and will hopefully be a useful resource for all readers who are not familiar with it. In addition, in order to stress the potentialities of carbohydrates, several examples of carbohydrate-based marketed therapeutics are given. TAKE HOME MESSAGE: Carbohydrates are a rich class of natural compounds, possessing an intriguing and still not fully understood biological role. This richness offers several strategies for the design of carbohydrate-based therapeutics. PMID- 22827797 TI - Discovery and characterization of beta-1,6-glucan inhibitors. AB - IMPORTANCE OF THE FIELD: The increasing number of patient populations at high risk of opportunistic infections has highlighted the need for the improvement in antifungal treatments. Due to the limited number of currently available antifungal drugs and the concerns for possible prevalence of resistant strains, drugs with a new mechanism of action are most desirable. AREAS COVERED IN THIS REVIEW: Although the cell wall is considered to be one of the ideal targets for antifungal drugs, insufficient information on the enzymes involved in its construction has restricted the discovery of new inhibitors. This review introduces the recent discovery of the inhibitors of beta-1,6-glucan, one of the essential components of the yeast cell wall. WHAT THE READER WILL GAIN: The readers will gain the strategy to obtain the beta-1,6-glucan synthesis inhibitors, their mechanisms of actions, and antifungal activities in vitro as well as in vivo. TAKE HOME MESSAGE: The beta-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum. Additionally, they can be useful tools in the study on beta-1,6-glucan synthesis and the virulence of Candida species. PMID- 22827798 TI - Advances in quantitative structure-activity relationship models of antimalarials. AB - IMPORTANCE OF THE FIELD: Malaria still remains one of the deadliest infectious diseases having a tremendous morbidity and mortality impact in the developing world. Computational tools such as quantitative structure-activity relationship (QSAR) studies help medicinal chemists to understand the consistent relationship between antimalarial activity and molecular properties, and design new potent and selective ligands that may act on different classes of antimalarial drug targets so that these compounds may eventually be synthesized and assayed. AREA COVERED IN THIS REVIEW: In the present review, we focus on the current knowledge of QSARs and pharmacophore models of different classes of antimalarial drugs. In this context, we also review the reported docking studies of antimalarial compounds acting on different targets to explore the interaction pattern at the molecular level. WHAT THE READER WILL GAIN: The reader will gain an overview of advances of QSAR and related theoretical models of antimalarial drug compounds. TAKE HOME MESSAGE: This review infers that most of the reported QSAR models are analog based QSARs with a limited applicability domain, but QSAR models based on diverse chemical structures acting on a particular target have been reported in very few cases. PMID- 22827799 TI - The antibiotic resistome. AB - IMPORTANCE OF THE FIELD: Antibiotics are essential for the treatment of bacterial infections and are among our most important drugs. Resistance has emerged to all classes of antibiotics in clinical use. Antibiotic resistance has, proven inevitable and very often it emerges rapidly after the introduction of a drug into the clinic. There is, therefore, a great interest in understanding the origins, scope and evolution of antibiotic resistance. AREAS COVERED IN THIS REVIEW: The review discusses the concept of the antibiotic resistome, which is the collection of all genes that directly or indirectly contribute to antibiotic resistance. WHAT THE READER WILL GAIN: The review seeks to assemble current knowledge of the resistome concept as a means of understanding the totality of resistance and not just resistance in pathogenic bacteria. TAKE HOME MESSAGE: The concept of the antibiotic resistome provides a framework for the study and understanding of how resistance emerges and evolves. Furthermore, the study of the resistome reveals strategies that can be applied in new antibiotic discoveries. PMID- 22827800 TI - De novo design: balancing novelty and confined chemical space. AB - IMPORTANCE OF THE FIELD: De novo drug design serves as a tool for the discovery of new ligands for macromolecular targets as well as optimization of known ligands. Recently developed tools aim to address the multi-objective nature of drug design in an unprecedented manner. AREAS COVERED IN THIS REVIEW: This article discusses recent advances in de novo drug design programs and accessory programs used to evaluate compounds post-generation. WHAT THE READER WILL GAIN: The reader is introduced to the challenges inherent in de novo drug design and will become familiar with current trends in de novo design. Furthermore, the reader will be better prepared to assess the value of a tool, and be equipped to design more elegant tools in the future. TAKE HOME MESSAGE: De novo drug design can assist in the efficient discovery of new compounds with a high affinity for a given target. The inclusion of existing chemoinformatic methods with current structure-based de novo design tools provides a means of enhancing the therapeutic value of these generated compounds. PMID- 22827802 TI - Role of the small RNA RyhB in the Fur regulon in mediating the capsular polysaccharide biosynthesis and iron acquisition systems in Klebsiella pneumoniae. AB - BACKGROUND: The capsular polysaccharide (CPS) and iron acquisition systems are important determinants of Klebsiella pneumoniae infections, and we have previously reported that the ferric uptake repressor (Fur) can play dual role in iron acquisition and CPS biosynthesis. In many bacteria, Fur negatively controls the transcription of the small non-coding RNA RyhB to modulate cellular functions and virulence. However, in K. pneumoniae, the role played by RyhB in the Fur regulon has not been characterised. This study investigated Fur regulation of ryhB transcription and the functional role of RyhB in K. pneumoniae. RESULTS: Deletion of fur from K. pneumoniae increased the transcription of ryhB; the electric mobility shift assay and the Fur-titration assay revealed that Fur could bind to the promoter region of ryhB, suggesting that Fur directly represses ryhB transcription. Additionally, in a Deltafur strain with elevated CPS production, deletion of ryhB obviously reduced CPS production. The following promoter reporter assay and quantitative real-time PCR of cps genes verified that RyhB activated orf1 and orf16 transcription to elevate CPS production. However, deletion of ryhB did not affect the mRNA levels of rcsA, rmpA, or rmpA2. These results imply that Fur represses the transcription of ryhB to mediate the biosynthesis of CPS, which is independent of RcsA, RmpA, and RmpA2. In addition, the Deltafur strain's high level of serum resistance was attenuated by the deletion of ryhB, indicating that RyhB plays a positive role in protecting the bacterium from serum killing. Finally, deletion of ryhB in Deltafur reduced the expression of several genes corresponding to 3 iron acquisition systems in K. pneumoniae, and resulted in reduced siderophore production. CONCLUSIONS: The regulation and functional role of RyhB in K. pneumoniae is characterized in this study. RyhB participates in Fur regulon to modulate the bacterial CPS biosynthesis and iron acquisition systems in K. pneumoniae. PMID- 22827804 TI - Electrochemical biofilm control: mechanism of action. AB - Although it has been previously demonstrated that an electrical current can be used to control biofilm growth on metal surfaces, the literature results are conflicting and there is no accepted mechanism of action. One of the suggested mechanisms is the production of hydrogen peroxide (H(2)O(2)) on metal surfaces. However, there are literature studies in which H(2)O(2) could not be detected in the bulk solution. This is most likely because H(2)O(2) was produced at a low concentration near the surface and could not be detected in the bulk solution. The goals of this research were (1) to develop a well-controlled system to explain the mechanism of action of the bioelectrochemical effect on 316L stainless steel (SS) surfaces and (2) to test whether the produced H(2)O(2) can reduce cell growth on metal surfaces. It was found that H(2)O(2) was produced near 316L SS surfaces when a negative potential was applied. The H(2)O(2) concentration increased towards the surface, while the dissolved oxygen decreased when the SS surface was polarized to -600 mV(Ag/AgCl). When polarized and non polarized surfaces with identical Pseudomonas aeruginosa PAO1 biofilms were continuously fed with air-saturated growth medium, the polarized surfaces showed minimal biofilm growth while there was significant biofilm growth on the non polarized surfaces. Although there was no detectable H(2)O(2) in the bulk solution, it was found that the surface concentration of H(2)O(2) was able to prevent biofilm growth. PMID- 22827803 TI - Is single reading with computer-aided detection (CAD) as good as double reading in mammography screening? A systematic review. AB - BACKGROUND: In accordance with European guidelines, mammography screening comprises independent readings by two breast radiologists (double reading). CAD (computer-aided detection) has been suggested to complement or replace one of the two readers (single reading + CAD).The aim of this systematic review is to address the following question: Is the reading of mammographic x-ray images by a single breast radiologist together with CAD at least as accurate as double reading? METHODS: The electronic literature search included the databases Pub Med, EMBASE and The Cochrane Library. Two independent reviewers assessed abstracts and full-text articles. RESULTS: 1049 abstracts were identified, of which 996 were excluded with reference to inclusion and exclusion criteria; 53 full-text articles were assessed for eligibility. Finally, four articles were included in the qualitative analysis, and one in a GRADE synthesis. CONCLUSIONS: The scientific evidence is insufficient to determine whether the accuracy of single reading + CAD is at least equivalent to that obtained in standard practice, i.e. double reading where two breast radiologists independently read the mammographic images. PMID- 22827805 TI - Worker lead poisoning during renovation of a historic hotel reveals limitations of the OSHA lead in construction standard. PMID- 22827806 TI - Methotrexate for treatment of lichen planus: old drug, new indication. AB - Treatment of generalized lichen planus is often disappointing and is associated with relapses. Though reports have suggested a beneficial role of various immunosuppressive and immunomodulatory agents, most of these reports are retrospective series or anecdotes. Oral methotrexate has been found to be useful in recent studies. In this study, we prospectively evaluated the role of low-dose oral methotrexate (15 mg/week in adults or 0.25 mg/kg/week for children) in generalized lichen planus. Mean improvement in 24 evaluated patients (two of them were of paediatric age group) at the end of 14 weeks of treatment was 79%. By the end of 24 weeks treatment, 14 of 24 (58%) patients had complete remission of their disease. Side effects were observed in 12 of 24 (50%) patients. Most of these adverse effects were mild; only one requiring treatment discontinuation due to significantly deranged liver function test. During post-treatment follow-up of 3 months, none had relapse of lichen planus. Overall, low- dose methotrexate is effective and reasonably safe option in treatment of eruptive lichen planus, provided haematological and biochemical parameters are regularly monitored. PMID- 22827807 TI - Cropping practices modulate the impact of glyphosate on arbuscular mycorrhizal fungi and rhizosphere bacteria in agroecosystems of the semiarid prairie. AB - A growing body of evidence obtained from studies performed under controlled conditions suggests that glyphosate use can modify microbial community assemblages. However, few studies have examined the influence of glyphosate in agroecosystems. We examined 4 wheat-based production systems typical of the Canadian prairie over 2 years to answer the following question: Does preseeding of glyphosate impact soil rhizosphere microorganisms? If so, do cropping practices influence this impact? Glyphosate caused a shift in the species dominating the arbuscular mycorrhizal fungal community in the rhizosphere, possibly through the modification of host plant physiology. Glyphosate stimulated rhizobacterial growth while having no influence on saprotrophic fungi, suggesting a greater abundance of glyphosate-tolerant 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in bacteria than in fungi. Glyphosate stimulated rhizosphere bacteria in pea but not in urea-fertilized durum wheat, which is consistent with inhibition of EPSPS tolerance to residual glyphosate through high ammonium levels. Mitigation of the effects of glyphosate on rhizosphere bacteria through tillage suggests a reduction in residual glyphosate activity through increased adsorption to soil binding sites upon soil mixing. The influence of glyphosate on Gram-negative bacteria was mitigated under drought conditions in 2007. Our experiment suggests that interactions between soil fertility, tillage, and cropping practices shape the influence of glyphosate use on rhizosphere microorganisms. PMID- 22827808 TI - The metabolic syndrome predicts cardiovascular events: results of a 13-year follow-up in initially healthy 58-year-old men. AB - BACKGROUND: The metabolic syndrome is a global health problem and is associated with subsequent development of cardiovascular disease (CVD). However, data are scarce concerning prospective association of the syndrome and CVD in populations free of diabetes and previous CVD that also is free of all cardiovascular drugs. The aim of this study was to assess the risk of cardiovascular events due to the metabolic syndrome in a population-based cohort of initially healthy, low-risk, and medication-free 58-year-old Swedish men during 13-years of follow-up. METHODS: From a total population sample of 1728 subjects, a stratified and randomly selected group of 391 subjects was included. The metabolic syndrome was defined according to the National Cholesterol Education Program. Cardiovascular events and cause of death were investigated by contact with the Centre of Epidemiology at the National Board of Health and Welfare. RESULTS: The metabolic syndrome increased the risk of cardiovascular events with a hazard ratio of 2.1 [95% confidence interval (CI) 1.3-3.4], P=0.003. When adjusted for the factors of leisure-time physical activity, smoking habits, alcohol intake, and low-density lipoprotein cholesterol (LDL-C), the hazard ratio was 2.0 (95% CI 1.1-3.4), P=0.016. CONCLUSION: In a 13-year follow-up in initially healthy men, the metabolic syndrome increases the risk of cardiovascular events by two-fold. This risk was maintained also after adjustment for lifestyle factors. PMID- 22827810 TI - Assessment of the ochratoxin A production ability of Aspergillus tubingensis. AB - Aspergillus tubingensis is a black Aspergillus frequently isolated from different agricultural products, including grapes. Conflicting results have been published in recent years about its ability to produce ochratoxin A (OTA), a potent nephrotoxic and carcinogenic mycotoxin. This study re-examined six A. tubingensis strains deposited in international culture collections for OTA production. OTA could not be detected in any A. tubingensis extract using HPLC coupled with a fluorescence detector (FLD), whereas it was easily detected in ochratoxigenic A. niger extracts used as positive control. The same outcome was obtained using LC MS. The presence of other metabolites with retention times similar to the OTA signal in the A. tubingensis extracts or background noise of the growth media may be reasons for the misinterpretation of the chromatograms obtained by HPLC-FLD. PMID- 22827809 TI - Blow fly Lucilia sericata nuclease digests DNA associated with wound slough/eschar and with Pseudomonas aeruginosa biofilm. AB - In chronic wounds, it may be clinically important to remove extracellular bacterial and patient DNA as its presence may impede wound healing and promote bacterial survival in biofilm, in which extracellular DNA forms part of the biofilm architecture. As medicinal maggots, larvae of Lucilia sericata Meigen (Diptera: Calliphoridae) have been shown to efficiently debride wounds it became of interest to investigate their excretions/secretions (ES) for the presence of a deoxyribonuclease (DNAse) activity. Excretions/secretions products were shown to contain a DNAse, with magnesium, sodium and calcium metal ion dependency, and a native molecular mass following affinity purification of approximately 45 kDa. The affinity purified DNAse degraded genomic bacterial DNA per se, DNA from the slough/eschar of a venous leg ulcer, and extracellular bacterial DNA in biofilms pre-formed from a clinical isolate of Pseudomonas aeruginosa. The latter finding highlights an important attribute of the DNAse, given the frequency of P. aeruginosa infection in non-healing wounds and the fact that P. aeruginosa virulence factors can be toxic to maggots. Maggot DNAse is thus a competent enzyme derived from a rational source, with the potential to assist in clinical wound debridement by removing extracellular DNA from tissue and biofilm, and promoting tissue viability, while liberating proteinaceous slough/eschar for debridement by the suite of proteinases secreted by L. sericata. PMID- 22827811 TI - Is intrapartum fever associated with ST-waveform changes of the fetal electrocardiogram? A retrospective cohort study. AB - OBJECTIVE: To investigate the association between maternal intrapartum fever and ST-waveform changes of the fetal electrocardiogram. DESIGN: Retrospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: We studied 142 women with fever (>=38.0 degrees C) during labour and 141 women with normal temperature who had been included in two previous studies. In both groups, we counted the number and type of ST-events and classified them as significant (intervention needed) or not significant, based on STAN((r)) clinical guidelines. MAIN OUTCOME MEASURES: Number and type of ST-events. RESULTS: Both univariable and multivariable regression analysis showed no association between the presence of maternal intrapartum fever and the number or type of ST-events. CONCLUSIONS: Maternal intrapartum fever is not associated with ST-segment changes of the fetal electrocardiogram. Interpretation of ST-changes in labouring women with fever should therefore not differ from other situations. PMID- 22827813 TI - Health behaviours and outcomes associated with fly-in fly-out and shift workers in Western Australia. AB - AIMS: To examine the association of health behaviours and outcomes with employment type in the West Australian adult population. METHODS: Cross-sectional study of employed adults aged 16 years and over using self-reported information collected in the WA Health and Wellbeing Surveillance System between 2008 and 2010. A total of 380 fly-in fly-out (FIFO) workers, 913 shift workers and 10 613 workers of other employment types were identified. RESULTS: FIFO workers exhibited similar health behaviours to shift workers but had a different sociodemographic profile. Compared with other employment types, FIFO workers were significantly more likely to be current smokers, drink alcohol at risky levels, and be overweight or obese, after adjusting for age, sex and survey sampling strategies. They were less likely to report current mental health problems. CONCLUSIONS: Self-reported health behaviours of FIFO workers differ from other employment types. FIFO workers are expected to increase in number over the next decade, as the mining and resources sector expands in Australia. Our findings suggest that health interventions, whether in the workplace or clinical settings, need to be informed by the demographic mix of the cohort of workers on entry as they are not a homogenous group, and targeted towards specific employment patterns (length of shifts and type of employment) to improve their current and future well-being. PMID- 22827812 TI - Optimization and comparison of knockdown efficacy between polymerase II expressed shRNA and artificial miRNA targeting luciferase and Apolipoprotein B100. AB - BACKGROUND: Controlling and limiting the expression of short hairpin RNA (shRNA) by using constitutive or tissue-specific polymerase II (pol II) expression can be a promising strategy to avoid RNAi toxicity. However, to date detailed studies on requirements for effective pol II shRNA expression and processing are not available. We investigated the optimal structural configuration of shRNA molecules, namely: hairpin location, stem length and termination signal required for effective pol II expression and compared it with an alternative strategy of avoiding toxicity by using artificial microRNA (miRNA) scaffolds. RESULTS: Highly effective shRNAs targeting luciferase (shLuc) or Apolipoprotein B100 (shApoB1 and shApoB2) were placed under the control of the pol II CMV promoter and expressed at +5 or +6 nucleotides (nt) with reference to the transcription start site (TSS). Different transcription termination signals (TTS), namely minimal polyadenylation (pA), poly T (T5) and U1 were also used. All pol II- expressed shRNA variants induced mild inhibition of Luciferase reporters carrying specific targets and none of them showed comparable efficacy to their polymerase III expressed H1-shRNA controls, regardless of hairpin position and termination signal used. Extending hairpin stem length from 20 basepairs (bp) to 21, 25 or 29 bp yielded only slight improvement in the overall efficacy. When shLuc, shApoB1 and shApoB2 were placed in an artificial miRNA scaffold, two out of three were as potent as the H1-shRNA controls. Quantification of small interfering RNA (siRNA) molecules showed that the artificial miRNA constructs expressed less molecules than H1-shRNAs and that CMV-shRNA expressed the lowest amount of siRNA molecules suggesting that RNAi processing in this case is least effective. Furthermore, CMV miApoB1 and CMV-miApoB2 were as effective as the corresponding H1-shApoB1 and H1 shApoB2 in inhibiting endogenous ApoB mRNA. CONCLUSION: Our results demonstrate that artificial miRNA have a better efficacy profile than shRNA expressed either from H1 or CMV promoter and will be used in the future for RNAi therapeutic development. PMID- 22827815 TI - Comparison of the flow characteristics of irrigants with standard and Max-i-Probe needles. AB - The objectives of this study were to determine the direction and pattern of flow of irrigating solutions inside simulated root canals with different irrigation needles; and to determine whether different needle designs increase the likelihood of irrigating solution passing through the apical foramen. Two types of needles were compared: a standard needle with a bevel and an open end, and a needle with a side opening and closed rounded tip. Observations of irrigant flow within the canals indicated that the side-venting needle can be dangerous if the needle gauge is small and it reaches the full length of the canal, since this allowed irrigants to flow into the periapical area. With the standard needle, the fluid did not go beyond the tip of the needle when minimal irrigating pressure was employed. As the size of canal increased, the fluid did not extrude beyond the tip of both needles. However, if the needles bound in the canals, then the fluid was forced away from the needle tip, and the pressure applied to the syringe was directly proportional to the distance the fluid flowed away from the needle tip. Both side-venting and standard needles can be used for irrigation safely and effectively if a dynamic irrigation technique (moving the needle up and down inside the canals while irrigating) is employed. PMID- 22827816 TI - Comparison of the canal centring ability of K3, Liberator and EZ Fill Safesiders by using spiral computed tomography. AB - The purpose of the study was to compare the canal centring ability of K3, Liberator and EZ Fill Safesiders by using spiral computed tomography (SCT). Forty curved mandibular premolars were selected. Before and after instrumentation teeth were scanned by spiral computed tomography and nine cross-sectional views of each tooth were obtained at 1.5 mm intervals from the apex. Canal centring ratio was calculated. Mean values were compared between different study groups by using one way ANOVA followed by Tukey - HSD procedure. At 1st, 2nd and 3rd levels, there was no statistical difference between groups. From 4th to 9th levels Safesider showed higher centring ratio, followed by Liberator and K3. Safesider showed better canal centring ability followed by Liberator and K3. PMID- 22827817 TI - An agar diffusion study comparing the antimicrobial activity of Nanoseal with some other endodontic sealers. AB - The aim of this study was to evaluate the antimicrobial activity of a new experimental nano-hydroxyapatite epoxy resin-based sealer (Nanoseal) with several other commercially available sealers; AH26, Tubliseal, Sealapex and Roekoseal against Enterococcus faecalis, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus sobrinus and Escherichia coli for up to 7 days. Agar diffusion was used in this study. Fifty Muller-Hinton agar plates were prepared and divided into five experimental groups (n = 10), for each micro-organism. Another 10 agar plates were used as positive and negative controls. Endodontic sealers were tested against each micro-organism. Inhibition zones produced were recorded. The results of this study showed that all test materials exhibited inhibition zones towards the tested micro-organisms for 7 days except for Roekoseal, which showed no inhibition zones. Nanoseal and AH26 exhibited similar zones of inhibition. Significant difference was found between Nanoseal and the other tested sealers (P < 0.001). PMID- 22827818 TI - Radiographic evaluation of the technical quality of root canal fillings performed by dental students. AB - The objective of this study was to evaluate radiographically the technical quality of root canal fillings performed by dental students at the School of Dentistry, University of the West Indies. The school's database between 2000 and 2004 was investigated for patients with completed root canal treatment. The final sample consisted of 198 patients with 288 root-filled teeth and 460 canals. The length, presence of voids, taper, curvature of canal and fractured instruments were recorded and scored. Chi-squared analysis was used to determine statistically significant differences between the technical quality of root fillings and tooth type. Sixty-three per cent, 27.6% and 72.2% of root-filled canals had adequate length, density and taper respectively. The overall acceptability of root fillings having adequate length and taper, absence of voids and no fractured instruments was found in 10.9% of canals. Changes in teaching methods may be required to improve the technical quality of root canal treatment done by dental students. PMID- 22827819 TI - Cytotoxicity of calcium enriched mixture cement compared with mineral trioxide aggregate and intermediate restorative material. AB - Calcium enriched mixture (CEM) cement has been recently invented by the last author. It is composed of calcium oxide, calcium phosphate, calcium silicate and calcium sulphate; however, it has a different chemical composition to mineral trioxide aggregate (MTA). The purpose of this ex vivo study was to investigate the cytotoxicity of CEM cement, and compare it with intermediate restorative material (IRM) and MTA. The materials were tested in fresh and set states on L929 fibroblasts to assess their cytotoxicity. The cell viability responses were evaluated with methyl-tetrazolium bromide assay and Elisa reader at 1, 24 and 168 h (7 days). The tested materials were eluted with L929 culture medium according to international standard organisation 109935 standard. Distilled water and culture medium served as positive and negative controls, respectively. Differences in cytotoxicity were evaluated by one-way anova and t-tests. The cytotoxicity of the materials was statistically different at the three time intervals (P < 0.01). The lowest cytotoxic values recorded were expressed by MTA subgroups followed by CEM cement; IRM subgroups were the most cytotoxic root end/dental material (P < 0.001). CEM cement and MTA are reasonable alternatives to IRM because of lower cytotoxicity. CEM cement also has good biocompatibility as well as lower estimated cost to MTA and seems to be a promising dental material. PMID- 22827820 TI - Effect of light-activated bleaching on pulp chamber temperature rise: an in vitro study. AB - This study aimed to compare the pulp chamber temperature changes that occur with the use of different light sources during vital bleaching with and without application of bleaching agents. One hundred and forty-four mandibular incisor teeth were divided into four groups (n = 36) according to the use of halogen light, light-emitting diode, 3 W and 1.5 W diode laser. The teeth in the main groups were divided into three subgroups (n = 12). First subgroup had no bleaching gel application. By White and Whiteness HP were applied with a thickness of 2 mm to the other subgroups respectively. The labial surfaces of the teeth were irradiated with a total time of 20 s. Temperature changes in the pulp chamber were measured and analysed by using anova and Tukey test. The 3 W diode laser induced the highest pulp chamber temperature rise (P = 0.000). Bleaching gel application reduced the temperature changes in the diode laser groups (P < 0.05). Diode laser activation during vital bleaching induces pulp chamber temperature rise, which may cause thermal tissue damage. PMID- 22827821 TI - Internal and external resorption in a lower molar with an associated endodontic periodontic lesion: a case report. AB - This article describes a unique case in which both internal and external inflammatory resorption and endodontic-periodontic lesions were present at the same time in the patient's left mandibular first molar. Based on clinical and radiographic findings, it was determined that the nature of this case was a pulpal infection-induced inflammatory resorption and furcation lesion. After root canal therapy, the furcation lesion and external inflammatory resorption were completely resolved. This case indicates that the correct diagnosis of the stimulating factor for tooth resorption and determination of the primary origin of endodontic-periodontic lesions are critical for clinical management and success. PMID- 22827823 TI - Further tribute to Dr Ernst Heinz Ehrmann OAM. PMID- 22827829 TI - Double spike isotope dilution GC-ICP-MS for evaluation of mercury species transformation in real fish samples using ultrasound-assisted extraction. AB - Sample preparation continues being a key factor to obtain fast and reliable quantification of Hg species. Assisted procedures enhance the efficiency and reduce the extraction time; however, collateral species transformations have been observed. Moreover, differential interconversions have been observed even between similar matrixes, which introduce an important uncertainty for real sample analysis. Trying to minimize Hg species transformations, we have tested a soft ultrasound-assisted extraction procedure. Species quantification and transformations have been evaluated using double spike isotope dilution analysis (IDA) together with gas chromatography inductively coupled plasma mass spectrometry (GC-ICP-MS) for a CRM material (Tort-2) and shark and swordfish muscle samples. Optimum extraction solution and sonication time led to quantitative extraction and accurate determination of MeHg and IHg in a short time, although different behaviors regarding species preservation were observed depending on the sample. Negligible species transformations were observed in the analysis of the CRM, while a small but significant demethylation factor was observed in the case of real samples. In comparison with other extraction procedures, species transformations became smaller, and fewer differences between fish species were found. Similar results were obtained for fresh and lyophilized samples of both fish samples, which permit one to analyze the fresh sample directly and save time in the sample preparation step. The high grade of species preservation and the affordability of the extraction procedure allow one to obtain accurate determinations even for routine laboratories using quantification techniques, which do not estimate species transformations. PMID- 22827830 TI - Structural and functional cardiac changes in myotonic dystrophy type 1: a cardiovascular magnetic resonance study. AB - BACKGROUND: Myotonic dystrophy type 1 (MD1) is a neuromuscular disorder with potential involvement of the heart and increased risk of sudden death. Considering the importance of cardiomyopathy as a predictor of prognosis, we aimed to systematically evaluate and describe structural and functional cardiac alterations in patients with MD1. METHODS: Eighty MD1 patients underwent physical examination, electrocardiography (ECG), echocardiography and cardiovascular magnetic resonance (CMR). Blood samples were taken for determination of NT-proBNP plasma levels and CTG repeat length. RESULTS: Functional and structural abnormalities were detected in 35 patients (44%). Left ventricular systolic dysfunction was found in 20 cases, left ventricular dilatation in 7 patients, and left ventricular hypertrophy in 6 patients. Myocardial fibrosis was seen in 10 patients (12.5%). In general, patients had low left ventricular mass indexes. Right ventricular involvement was uncommon and only seen together with left ventricular abnormalities. Functional or structural cardiac involvement was associated with age (p = 0.04), male gender (p < 0.001) and abnormal ECG (p < 0.001). Disease duration, CTG repeat length, severity of neuromuscular symptoms and NT-proBNP level did not predict the presence of myocardial abnormalities. CONCLUSIONS: CMR can be useful to detect early structural and functional myocardial abnormalities in patients with MD1. Myocardial involvement is strongly associated with conduction abnormalities, but a normal ECG does not exclude myocardial alterations. These findings lend support to the hypothesis that MD1 patients have a complex cardiac phenotype, including both myocardial and conduction system alteration. PMID- 22827832 TI - A water-soluble pillar[6]arene: synthesis, host-guest chemistry, and its application in dispersion of multiwalled carbon nanotubes in water. AB - The first water-soluble pillar[6]arene was synthesized. Its water solubility can be reversibly controlled by changing the pH. This solubility control was used in reversible transformations between nanotubes and vesicles and dispersion of multiwalled carbon nanotubes in water. PMID- 22827831 TI - A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers. AB - BACKGROUND: Next generation sequencing (NGS) technology has revolutionized genomic and genetic research. The pace of change in this area is rapid with three major new sequencing platforms having been released in 2011: Ion Torrent's PGM, Pacific Biosciences' RS and the Illumina MiSeq. Here we compare the results obtained with those platforms to the performance of the Illumina HiSeq, the current market leader. In order to compare these platforms, and get sufficient coverage depth to allow meaningful analysis, we have sequenced a set of 4 microbial genomes with mean GC content ranging from 19.3 to 67.7%. Together, these represent a comprehensive range of genome content. Here we report our analysis of that sequence data in terms of coverage distribution, bias, GC distribution, variant detection and accuracy. RESULTS: Sequence generated by Ion Torrent, MiSeq and Pacific Biosciences technologies displays near perfect coverage behaviour on GC-rich, neutral and moderately AT-rich genomes, but a profound bias was observed upon sequencing the extremely AT-rich genome of Plasmodium falciparum on the PGM, resulting in no coverage for approximately 30% of the genome. We analysed the ability to call variants from each platform and found that we could call slightly more variants from Ion Torrent data compared to MiSeq data, but at the expense of a higher false positive rate. Variant calling from Pacific Biosciences data was possible but higher coverage depth was required. Context specific errors were observed in both PGM and MiSeq data, but not in that from the Pacific Biosciences platform. CONCLUSIONS: All three fast turnaround sequencers evaluated here were able to generate usable sequence. However there are key differences between the quality of that data and the applications it will support. PMID- 22827833 TI - Reducing barriers associated with delivering health care services to migratory agricultural workers. AB - INTRODUCTION: Between one and two million migratory agricultural workers (MAWs), primarily from Mexico and Central America, leave their homes each year to plant, cultivate, harvest and pack fruits, vegetables, and nuts in the USA. While in the USA, most lack health insurance, a permanent residence, and a regular healthcare provider. Publications over the past two decades in the USA have reported that a majority of MAWs encounter barriers to receiving medical services. Migratory agricultural workers experience high rates of occupational illness and injury. Poor access to medical care continues to exacerbate health problems among members of this population related to their working environments. In most studies concerning healthcare access issues for this population, researchers collected their information from healthcare service providers; rarely have they included input from migratory agricultural workers. This study was different in that opinions about healthcare access issues were collected directly from MAWs. The primary purpose of this study was to describe issues related to barriers associated with the delivery of healthcare services to migratory agricultural workers. A secondary purpose was to suggest strategies for reducing these barriers. METHODS: In this study, data from focus group sessions were used to develop a survey questionnaire. Four certified bilingual interpreters were trained to administer the questionnaire. A total of 157 usable questionnaires were returned from MAWs living in employer-provided camps in Northwest Ohio. The statistical analyses were primarily descriptive. RESULTS: The most significant barriers hampering access to medical services among the 157 respondents were cost (n=113; 72.0%), crop demands (n=102; 65.0%), the lack of an interpreter (n=98; 62.4%), travel distance (n=88; 56.1%) and transportation (n=82; 52.2%). Approximately half (n=82; 52.2%) said that they had access to transportation for traveling to a medical clinic. As a group, respondents were willing to travel an average of 29.1 km (18.1 miles) (range 0-129 km [0-80 miles]) to obtain medical services. Female heads of households had significantly less access to transportation compared with male heads of households (t=2.35; df=74; p<0.05). CONCLUSIONS: Three general categories of barriers to health care for MAWs surfaced in this study: (1) work environment; (2) migratory agricultural worker resources; and (3) healthcare clinic practices. Work environment issues relate mostly to the employers. Resources are barriers for MAWs because they are poor and have limited funds for the cost of transportation to clinics and the fees associated with accessing health care. Most of the barriers identified related to healthcare clinic practices. Some strategies to address healthcare clinic practice barriers were developed by the group conducting the study. By listening to what MAWs described as barriers to health care, providers can help improve access which can reduce the use of high cost hospital emergency room care. PMID- 22827834 TI - Evaluation of an accurate mass approach for the simultaneous detection of drug and metabolite distributions via whole-body mass spectrometric imaging. AB - In drug discovery and development, in vitro absorption and metabolism assays along with in vivo pharmacokinetic (PK), pharmacodynamic (PD), and toxicokinetic (TK) studies are used to evaluate a potential drug candidate. More recently, imaging mass spectrometry approaches have been successfully reported to aid in the preclinical assessment of drug candidates, resulting in the rapid and noteworthy acceptance of the technique in pharmaceutical research. Traditionally, drug distribution studies via mass spectrometric imaging (MSI) are performed as targeted MS/MS analyses, where the analytes of interest, drug and/or metabolite, are known before the imaging experiment is performed. The study presented here describes a whole-body mass spectrometric imaging (WB-MSI) approach using a hybrid MALDI-LTQ-Orbitrap-MS to detect the distribution of reserpine at 2 h post a 20 mg/kg oral dose. This study effectively demonstrates the utility of obtaining accurate mass measurements across a wide mass range combined with postprocessing tools to efficiently identify drug and metabolite distributions without the need for any a priori knowledge. PMID- 22827835 TI - Reducing treatment delay for early intervention: evaluation of a community based crisis helpline. AB - BACKGROUND: A limited number of studies have assessed the pathways to care of patients experiencing psychosis for the first time. Helpline/clinic programs may offer patients who are still functional but have potential for crisis an alternative that is free from judgment. METHODS: In this study we report on patient calling a round-the-clock crisis helpline for suicide prevention supported by psychiatric facilities in Mumbai, India. Chi-square and test of mean differences were used to compare outcomes between first-episode patients and those with a previous history. RESULTS: Within five years, the helpline received 15,169 calls. Of those callers, 2341 (15.4%) experienced suicidal ideation. Two hundred and thirty four patients opting for counseling lasting 12 months agreed to a psychiatric assessment. Of those, 32 were fist time psychosis sufferers, whereas, 54 had previously been psychotic. Of all psychiatric assessments, the clinic received 94 patients with 'first-episode psychosis'. We found that the duration of illness was significantly shorter (17 vs. 28 months) and suicide attempts were fewer (16 vs. 21) in first-time psychosis sufferers compared to those with a treatment history. CONCLUSIONS: We conclude that some first-episode patients of schizophrenia and other disorders do access services by using helplines. We also argue that helplines may be somewhat immune to stigma, allowing patients a safe alternative when finding help. PMID- 22827836 TI - Allergic and irritant dermatitis: pathogenic and management aspects. PMID- 22827837 TI - Oxidative stress in allergic and irritant dermatitis: from basic research to clinical management. AB - Allergic and irritant skin diseases may be the results of representative inflammatory response in the skin. It has been established that inflammatory response includes reactive oxygen species, reactive nitrogen species, and free radicals. Subsequently, an imbalance between the oxidant and antioxidant components occurs; this is so-called oxidative stress. As various important roles of oxidative stress in contact dermatitis have been reported, controlling oxidative stress in these diseases could be a supplementary and/or novel therapeutic approach. However, there is little convincing clinical evidence that modulation of oxidative stress can be used therapeutically to modulate inflammatory response in allergic and irritant skin diseases. The reason for this discrepancy may be partially due to an insufficient understanding of the dynamics of oxidative stress in allergic and irritant skin diseases. This review introduces the importance of oxidative stress in allergic and irritant skin diseases from basic research to clinical management aspects. This review also introduces recent patents for the methods and compositions for the treatment of skin diseases with antioxidants. These methods may be helpful in treating allergic and irritant skin diseases through topical application of antioxidants. PMID- 22827838 TI - Therapeutic strategies in allergic contact dermatitis. AB - Due to its high prevalence, allergic contact dermatitis (ACD) has an important economic and occupational health impact on society. ACD presents as an inflammatory response to small molecules and involves both skin resident cells and activated skin infiltrating T cells. Activation of skin resident cells plays an essential role in the initial sensitization phase. A number of different pathways are crucially involved in this phase including the activation of pattern recognition receptors such as TLR, inflammasome activation and production of reactive oxygen species all of which contribute to release of cellular mediators such as IL-1 family members. Chemokines regulate steps in elicitation of adaptive T cell responses including the migration to and presentation of the contact allergen by skin derived antigen presenting cells in the draining lymph node as well as the recruitment of these activated, allergen reactive CD4+ and CD8+ cells back into the skin. The current therapeutic regimens are largely restricted to the avoidance of the contact allergen and the topical use of anti-inflammatory drugs such as glucocorticosteroids. Recent research, as highlighted by current patents, focus on the use of anti-oxidants, the induction of immunological tolerance, interference with cell signaling molecules and blocking of cytokines actively involved in ACD. PMID- 22827839 TI - Seqcrawler: biological data indexing and browsing platform. AB - BACKGROUND: Seqcrawler takes its roots in software like SRS or Lucegene. It provides an indexing platform to ease the search of data and meta-data in biological banks and it can scale to face the current flow of data. While many biological bank search tools are available on the Internet, mainly provided by large organizations to search their data, there is a lack of free and open source solutions to browse one's own set of data with a flexible query system and able to scale from a single computer to a cloud system. A personal index platform will help labs and bioinformaticians to search their meta-data but also to build a larger information system with custom subsets of data. RESULTS: The software is scalable from a single computer to a cloud-based infrastructure. It has been successfully tested in a private cloud with 3 index shards (pieces of index) hosting ~400 millions of sequence information (whole GenBank, UniProt, PDB and others) for a total size of 600 GB in a fault tolerant architecture (high availability). It has also been successfully integrated with software to add extra meta-data from blast results to enhance users' result analysis. CONCLUSIONS: Seqcrawler provides a complete open source search and store solution for labs or platforms needing to manage large amount of data/meta-data with a flexible and customizable web interface. All components (search engine, visualization and data storage), though independent, share a common and coherent data system that can be queried with a simple HTTP interface. The solution scales easily and can also provide a high availability infrastructure. PMID- 22827840 TI - Revealing the structure-property relationships of metal-organic frameworks for CO2 capture from flue gas. AB - It is of great importance to establish a quantitative structure-property relationship model that can correlate the separation performance of MOFs to their physicochemical features. In complement to the existing studies that screened the separation performance of MOFs from the adsorption selectivity calculated at infinite dilution, this work aims to build a QSPR model that can account for the CO(2)/N(2) mixture (15:85) selectivity of an extended series of MOFs with a very large chemical and topological diversity under industrial pressure condition. It was highlighted that the selectivity for this mixture under such conditions is dominated by the interplay of the difference of the isosteric heats of adsorption between the two gases and the porosity of the MOF adsorbents. On the basis of the interplay map of both factors that impact the adsorption selectivity, strategies were proposed to efficiently enhance the separation selectivity of MOFs for CO(2) capture from flue gas. As a typical illustration, it thus leads us to tune a new MOF with outstanding separation performance that will orientate the synthesis effort to be deployed. PMID- 22827841 TI - Sacrificing quality for quantity?: RE: Clinical benefits and cost-effectiveness of allogeneic red blood cell transfusion in severe symptomatic anemia A. M. Beliaev, R. J. Marshall, M. Gordon, W. Smith & J. A. Windsor. PMID- 22827842 TI - Influence of maternal age, gestational age and fetal gender on expression of immune mediators in amniotic fluid. AB - BACKGROUND: Variations in cytokine and immune mediator expression patterns in amniotic fluid due to gestational age, maternal age and fetal gender were investigated. FINDINGS: Amniotic fluid samples were obtained from 192 women, 82 with a mid-trimester amniocentesis (median gestational age 17 weeks) and 110 with a caesarean section not in labor (median gestational age 39 weeks). Amniotic fluid was screened by commercial ELISAs for the TH1/TH2/TH17 cytokines and immune mediators IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF alpha, GRO-alpha, MIP1alpha, MIP1beta, Histone, and IP10. Analysis was by Bonferroni correction for multiple comparisons. None of the 15 examined cytokines revealed any differences in expression patterns regarding fetal gender. Significant differences were found in IL-4, IL-10, IL-12, TNF- alpha, GRO-alpha and MIP1-beta with respect to gestational age and in GRO-alpha regarding maternal age. CONCLUSION: Cytokines utilized as biomarkers in the diagnosis of intrauterine infections are not influenced in their expression pattern by fetal gender but may vary with respect to maternal age and gestational age. PMID- 22827844 TI - Phase dependencies between longitudinal corneal apex displacement and cardiovascular signals: is the ocular pulse influenced by the electrical activity of the heart? AB - BACKGROUND: The aim was to establish phase relationships between the principal harmonic, related to the heart rate, of synchronically registered longitudinal corneal apex displacement (LCAD), blood pulsation (BP) and electrical heart activity signals in a group of healthy subjects. METHODS: Longitudinal corneal apex displacement was non-invasively measured using an ultrasonic distance sensor. Synchronously, electrocardiographic (ECG) and blood pulsation signals were acquired. As all considered signals are non-stationary (that is, their spectral characteristics vary in time), a reliable and repeatable phase estimation method was sought. For this, a range of phase estimators were tested in the windowed regime of simulated non-stationary signals. Two robust estimators that showed minimum mean square error performance, were selected for further analysis of real signals registered for seven subjects participating in the study. RESULTS: The windowed cross-correlation and the windowed minimum sum of squared error method achieved the best results among the estimators considered and their outputs were averaged to arrive at a robust phase estimator. Across the subjects, it was found that an increase in the time delay between the principal harmonic of BP and ECG signals, theta(BP,ECG), corresponds to a slight time delay increase between the corresponding harmonics of longitudinal corneal apex displacement and blood pulsation signals, theta(LCAD,BP) and a decrease in the time delay between those of longitudinal corneal apex displacement and ECG signals, theta(LCAD,ECG). Significant correlation (paired t-test, p < 0.05) were found between theta(BP,ECG) and theta(LCAD,BP) as well as between theta(BP,ECG) and theta(LCAD,ECG). There was no significant correlation found between theta(LCAD,BP) and theta(LCAD,ECG). CONCLUSION: The results indicate that longitudinal corneal apex displacement and correspondingly the ocular pulse phenomenon have not only a vascular origin but could also be influenced by the electrical activity of the heart. PMID- 22827843 TI - Indication for Co-evolution of Lactobacillus johnsonii with its hosts. AB - BACKGROUND: The intestinal microbiota, composed of complex bacterial populations, is host-specific and affected by environmental factors as well as host genetics. One important bacterial group is the lactic acid bacteria (LAB), which include many health-promoting strains. Here, we studied the genetic variation within a potentially probiotic LAB species, Lactobacillus johnsonii, isolated from various hosts. RESULTS: A wide survey of 104 fecal samples was carried out for the isolation of L. johnsonii. As part of the isolation procedure, terminal restriction fragment length polymorphism (tRFLP) was performed to identify L. johnsonii within a selected narrow spectrum of fecal LAB. The tRFLP results showed host specificity of two bacterial species, the Enterococcus faecium species cluster and Lactobacillus intestinalis, to different host taxonomic groups while the appearance of L. johnsonii and E. faecalis was not correlated with any taxonomic group. The survey ultimately resulted in the isolation of L. johnsonii from few host species. The genetic variation among the 47 L. johnsonii strains isolated from the various hosts was analyzed based on variation at simple sequence repeats (SSR) loci and multi-locus sequence typing (MLST) of conserved hypothetical genes. The genetic relationships among the strains inferred by each of the methods were similar, revealing three different clusters of L. johnsonii strains, each cluster consisting of strains from a different host, i.e. chickens, humans or mice. CONCLUSIONS: Our typing results support phylogenetic separation of L. johnsonii strains isolated from different animal hosts, suggesting specificity of L. johnsonii strains to their hosts. Taken together with the tRFLP results, that indicated the association of specific LAB species with the host taxonomy, our study supports co-evolution of the host and its intestinal lactic acid bacteria. PMID- 22827845 TI - Transitivity in health utility measurement: An experimental analysis. AB - Several experimental studies have observed substantial violations of transitivity for decisions between risky lotteries over monetary outcomes. The goal of our experiment is to test whether these violations also affect the evaluation of health states. A particular feature of our experimental design is that it takes into account the possible role of decision errors for generating violations of transitivity. Since we find neither substantial nor systematic deviations from transitive choice behaviour, we can conclude that previously reported violations do not seem to bias health utility measurement. PMID- 22827847 TI - VopB1 and VopD1 are essential for translocation of type III secretion system 1 effectors of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a pathogenic Vibrio species that causes food-borne acute gastroenteritis, often related to the consumption of raw or undercooked seafood. Vibrio parahaemolyticus has 2 type III secretion systems (T3SS1 and T3SS2). Here, we demonstrate that VP1657 (VopB1) and VP1656 (VopD1), which share sequence similarity with Pseudomonas genes popB (38%) and popD (36%), respectively, are essential for translocation of T3SS1 effectors into host cells. A VP1680CyaA fusion reporter system was constructed to observe effector translocation. Using this reporter assay we showed that the VopB1 and VopD1 deletion strains were unable to translocate VP1680 to host cell but that the secretion of VP1680 into the culture medium was not affected. VopB1 or VopD1 deletion strains did not enhance cytotoxicity and failed to activate mitogen activated protein kinases and secretion of interleukin-8, which depend on VP1680. Thus, we conclude that VopB1 and VopD1 are essential components of the translocon. To target VopB1 and VopD1 may have therapeutic potential for the treatment or prevention in V. parahaemolyticus infection. PMID- 22827846 TI - Influence of IL17A polymorphisms on the aberrant methylation of DAPK and CDH1 in non-cancerous gastric mucosa. AB - BACKGROUND: CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of IL-17 in inflammatory response to H. pylori colonization has been indicated. We investigated the influence of IL17A polymorphisms, -197 G > A (rs2275913) and *1249 C > T (rs3748067), on the methylation of DAPK and CDH1. METHODS: Gastric mucosal samples were obtained from 401 subjects without malignancies. Methylation status of gene was determined by MSP. The genotyping of IL17A was performed by PCR-SSCP. RESULTS: Methylations of DAPK and CDH1 were seen in 196 and 149 of all 401 subjects, respectively. Overall, *1249 T carrier was associated with a decreased risk for DAPK methylation, whereas -197 G > A was not. In the subjects older than 60 years old, *1249 T carrier was more strongly associated with gene methylation and -197 A carrier tended to be associated with an increased risk for CDH1 methylation. When evaluating by inflammation promoting haplotype (-197 mutant carrier with *1249 homozygote), this haplotype had a more strongly increased risk for both DAPK and CDH1 methylations in comparatively older subjects. Both atrophy and metaplasia scores were significantly increased with age in -197 A carrier or *1249 CC homozygote, whereas were not in -197 GG homozygote or *1249 T carrier. PG I/II ratio was more significantly decreased in -197 A carrier than in GG homozygote under influence of H. pylori infection. CONCLUSIONS: In -197 A allele carrier with *1249 CC homozygote, the methylations of both DAPK and CDH1 may be increased gradually, but more rapidly than the other genotypes, with age and altered gastric mucosal structure induced by H. pylori infection. PMID- 22827848 TI - Vertically aligned ZnO nanorods on hot filament chemical vapor deposition grown graphene oxide thin film substrate: solar energy conversion. AB - Vertically aligned zinc oxide (ZnO) nanorods (NRs) were grown by the low temperature hydrothermal method on graphene oxide (GO) coated FTO substrates, where GO was directly deposited on fluorine doped tin oxide (FTO) substrates using hydrogen (H(2), 65 sccm) and methane (CH(4), 50 sccm) through hot filament chemical vapor deposition (HFCVD) technique. The vertically aligned ZnO NRs were applied as effective photoanode for the fabrication of efficient dye sensitized solar cells (DSSCs). Highly uniform ZnO NRs were grown on GO deposited FTO substrate with the average length of ~2-4 MUm and diameter of ~200-300 nm. The possible mechanism of grown ZnO NRs clearly revealed the significant role of GO on FTO in architecting the aligned growth of ZnO NRs. The grown vertically aligned ZnO NRs possessed a typical wurtzite hexagonal crystal structure. The structural and the optical studies confirmed the formation of partial hydrogen bonding between surface functional groups of GO and ZnO NRs. A solar-to electricity conversion efficiency of ~2.5% was achieved by DSSC fabricated with ZnO NRs deposited on graphene oxide (GO-ZnO NRs) thin film photoanode. The presence of GO on FTO substrate expressively increased the surface area of GO-ZnO photoanode, which resulted in high dye loading as well as high light harvesting efficiency and thus ensued the increased photocurrent density and the improved performance of DSSCs. PMID- 22827849 TI - WOX2 and STIMPY-LIKE/WOX8 promote cotyledon boundary formation in Arabidopsis. AB - One of the key events in dicot plant embryogenesis is the emergence of the two cotyledon primordia, which marks the transition from radial symmetry to bilateral symmetry. In Arabidopsis thaliana, the three CUP-SHAPED COTYLEDON (CUC) genes are responsible for determining the boundary region between the cotyledons. However, the mechanisms controlling their transcription activation are not well understood. Previous studies found that several WOX family homeobox transcription factors are involved in embryo apical patterning and cotyledon development. Here we show that WOX2 and STIMPY-LIKE (STPL/WOX8) act redundantly to differentially regulate the expression of the CUC genes in promoting the establishment of the cotyledon boundary, without affecting the primary shoot meristem. Loss of both WOX2 and STPL results in reduced CUC2 and CUC3 expression in one side of the embryo, but an expansion of the CUC1 domain. Furthermore, we found that STPL is expressed in the embryo proper, and its activation is enhanced by the removal of WOX2, providing an explanation for the functional redundancy between WOX2 and STPL. Additional evidence also showed that WOX2 and STPL function independently in regulating different aspects of local auxin gradient formation during early embryogenesis. PMID- 22827850 TI - Extra-facial melasma: clinical, histopathological, and immunohistochemical case control study. AB - BACKGROUND: Extra-facial melasma is a prevalent dermatosis in some populations with special characteristics in relation to its clinical aspects and probable etiopathogenic factors. Few studies have attempted to address this alteration of pigmentation, which has become a challenge in clinical Dermatology. OBJECTIVE: To assess the clinical histopathological and immunohistochemical characteristics of extra-facial melasma, comparing affected, and unaffected sites. METHODS: Case control study with 45 patients in each group (melasma and disease-free volunteers), assessing their clinical characteristics. In 36 patients, biopsies were performed on the lesion and the normal perilesional skin. Specimens were stained with HE and Fontana-Masson, and melanocytes analysed by immunohistochemistry. Objective measurements were accomplished by a specifically designed image analysis software. RESULTS: The melasma group had a mean age +/- SD of 56.67 +/- 8 years, the majority of them were women (86.7%) and 82.1% of the female cases had reached menopause. There were no significant differences between groups in terms of presence of comorbidities, use of medications or hormone therapies. For extra-facial melasma patients, family history of this dermatose and of previous facial melasma was significantly higher than in the control group (P < 0.05). The HE staining showed increased rectification and basal hyperpigmentation, solar elastosis, and collagen degeneration in the pigmented area (P < 0.05). There was a significant increase in melanin density in melasma biopsies, but the immunohistochemical tests did not detect a difference between the groups in terms of number of melanocytes. CONCLUSION: Extra-facial melasma appears to be related to menopause, family history, and personal history of facial melasma, in the studied population. Histopathology revealed a pattern similar to what has been described for facial melasma, with signs of solar degeneration, and a similar number of melanocytes, when comparing patients, and controls, suggesting that the hyperpigmentation is most likely the result of abnormal melanin production or distribution. PMID- 22827851 TI - Bioluminescence imaging to track bacterial dissemination of Yersinia pestis using different routes of infection in mice. AB - BACKGROUND: Plague is caused by Yersinia pestis, a bacterium that disseminates inside of the host at remarkably high rates. Plague bacilli disrupt normal immune responses in the host allowing for systematic spread that is fatal if left untreated. How Y. pestis disseminates from the site of infection to deeper tissues is unknown. Dissemination studies for plague are typically performed in mice by determining the bacterial burden in specific organs at various time points. To follow bacterial dissemination during plague infections in mice we tested the possibility of using bioluminescence imaging (BLI), an alternative non invasive approach. Fully virulent Y. pestis was transformed with a plasmid containing the luxCDABE genes, making it able to produce light; this lux expressing strain was used to infect mice by subcutaneous, intradermal or intranasal inoculation. RESULTS: We successfully obtained images from infected animals and were able to follow bacterial dissemination over time for each of the three different routes of inoculation. We also compared the radiance signal from animals infected with a wild type strain and a Deltacaf1DeltapsaA mutant that we previously showed to be attenuated in colonization of the lymph node and systemic dissemination. Radiance signals from mice infected with the wild type strain were larger than values obtained from mice infected with the mutant strain (linear regression of normalized values, P<0.05). CONCLUSIONS: We demonstrate that BLI is useful for monitoring dissemination from multiple inoculation sites, and for characterization of mutants with defects in colonization or dissemination. PMID- 22827852 TI - Exposures to pharmaceutical dust at a mail order pharmacy. PMID- 22827853 TI - Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects. AB - Due to multiple beneficial effects, including control of disease activity, reduction in cardiovascular events and improved survival, hydroxychloroquine is now recommended long-term for all patients with systemic lupus erythematosus. However, patients must be made aware of the possible risk of retinal toxicity and have eye examinations to monitor for this complication. As hydroxychloroquine becomes more widely used in systemic lupus erythematosus, physicians must also be aware of rare but serious adverse effects, including neuromyotoxicity and cardiotoxicity. PMID- 22827854 TI - An overview of the neuro-cognitive processes involved in the encoding, consolidation, and retrieval of true and false memories. AB - Perception and memory are imperfect reconstructions of reality. These reconstructions are prone to be influenced by several factors, which may result in false memories. A false memory is the recollection of an event, or details of an episode, that did not actually occur. Memory formation comprises at least three different sub-processes: encoding, consolidation and the retrieval of the learned material. All of these sub-processes are vulnerable for specific errors and consequently may result in false memories. Whereas, processes like imagery, self-referential encoding or spreading activation can lead to the formation of false memories at encoding, semantic generalization during sleep and updating processes due to misleading post event information, in particular, are relevant at the consolidation stage. Finally at the retrieval stage, monitoring processes, which are assumed to be essential to reject false memories, are of specific importance. Different neuro-cognitive processes have been linked to the formation of true and false memories. Most consistently the medial temporal lobe and the medial and lateral prefrontal cortex have been reported with regard to the formation of true and false memories. Despite the fact that all phases entailing memory formation, consolidation of stored information and retrieval processes, are relevant for the forming of false memories, most studies focused on either memory encoding or retrieval. Thus, future studies should try to integrate data from all phases to give a more comprehensive view on systematic memory distortions. An initial outline is developed within this review to connect the different memory stages and research strategies. PMID- 22827855 TI - Gene therapy using IL-27 ameliorates Sjogren's syndrome-like autoimmune exocrinopathy. AB - INTRODUCTION: Sjogren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of TH17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS. METHODS: Recombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL 27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity. RESULTS: Mice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates. CONCLUSIONS: These data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating TH17 pro-inflammatory activity in autoimmune diseases where the TH17 system has been shown to play an important role in their pathogenesis. PMID- 22827857 TI - Fighting parasites and predators: how to deal with multiple threats? AB - BACKGROUND: Although inducible defences have been studied extensively, only little is known about how the presence of parasites might interfere with these anti-predator adaptations. Both parasites and predators are important factors shaping community structure and species composition of ecosystems. Here, we simultaneously exposed Daphnia magna to predator cues (released by the tadpole shrimp, Triops, or by a fish) and spores of the yeast parasite Metschnikowia sp. to determine how life history and morphological inducible defences against these two contrasting types of predators are affected by infection. RESULTS: The parasite suppressed some Triops-induced defences: Daphnia lost the ability to produce a greater number of larger offspring, a life-history adaptation to Triops predation. In contrast, the parasite did not suppress inducible defences against fish: induction (resulting in smaller body length of the mothers as well as of their offspring) and infection acted additively on the measured traits. Thus, fish-induced defences may be less costly than inducible defences against small invertebrate predators like Triops; the latter defences could no longer be expressed when the host had already invested in fighting off the parasite. CONCLUSIONS: In summary, our study suggests that as specific inducible defences differ in their costs, some might be suppressed if a target prey is additionally infected. Therefore, adding parasite pressure to predator-prey systems can help to elucidate the costs of inducible defences. PMID- 22827858 TI - Structure and dynamic properties of colloidal asphaltene aggregates. AB - The abundant literature involving asphaltene often contrasts dynamic measurements of asphaltene solutions, highlighting the presence of small particle sizes between 1 and 3 nm, with static scattering measurements, revealing larger aggregates with a radius of gyration around 7 nm. This work demonstrates the complementary use of the two techniques: a homemade dynamic light scattering setup adapted to dark and fluorescent solutions, and small-angle X-ray and neutron scattering. Asphaltene solutions in toluene are prepared by a centrifugation separation to investigate asphaltene polydispersity. These experiments demonstrate that asphaltene solutions are made of Brownian colloidal aggregates. The hydrodynamic radii of asphaltene aggregates are between 5 and 10 nm, while their radii of gyration are roughly comparable, between 3.7 and 7.7 nm. A small fraction of asphaltenes with hydrodynamic and gyration radii around 40 nm is found in the pellet of the centrifugation tube. The fractal character of the largest clusters is observed from small angle scattering nearly on a decade length scale. Previous results on aggregation mechanisms are confirmed ( Eyssautier, J., et al. J. Phys. Chem. B 2011 , 115 , 6827 ): nanoaggregates of 3 nm radius, and with hydrodynamic properties also frequently illustrated in the literature, aggregate to form fractal clusters with a dispersity of aggregation number. PMID- 22827856 TI - Evaluation of left ventricular torsion by cardiovascular magnetic resonance. AB - Recently there has been considerable interest in LV torsion and its relationship with symptomatic and pre-symptomatic disease processes. Torsion gives useful additional information about myocardial tissue performance in both systolic and diastolic function. CMR assessment of LV torsion is simply and efficiently performed. However, there is currently a wide variation in the reporting of torsional motion and the procedures used for its calculation. For example, torsion has been presented as twist (degrees), twist per length (degrees/mm), shear angle (degrees), and shear strain (dimensionless). This paper reviews current clinical applications and shows how torsion can give insights into LV mechanics and the influence of LV geometry and myocyte fiber architecture on cardiac function. Finally, it provides recommendations for CMR measurement protocols, attempts to stimulate standardization of torsion calculation, and suggests areas of useful future research. PMID- 22827859 TI - Transforming growth factor beta1 gene expression during vaginal wound healing in a rabbit menopause model. AB - OBJECTIVE: Surgical outcome following reconstructive pelvic surgery is largely dependent on the vaginal wound healing process. As peri- and post-menopausal women are the most likely candidates to undergo these surgeries, it is important to understand the effect of estrogen deficiency on this process. Transforming growth factor beta (TGFbeta) is an important mediator of wound healing. We sought to assess TGFbeta1 gene expression during the vaginal incisional wound healing process in a rabbit menopause model. DESIGN: Animal study. SETTING: Animal laboratory. SAMPLE: Sixty-three rabbits were used for this study. METHODS: Twenty one underwent bilateral oophorectomy, 21 underwent a sham surgery, and 21 served as controls. Eight weeks later, standardised full-thickness 6-mm diameter circular segments were excised from the vagina of all rabbits. Animals were killed sequentially, before wounding, and at 0, 4, 7, 14, 21 and 35 days after wounding, and the wounds were harvested. MAIN OUTCOME MEASURES: Wound closure and TGFbeta1 gene transcription, as measured by real-time polymerase chain reaction (PCR). RESULTS: Wound closure was significantly protracted (P < 0.02), whereas TGFbeta1 gene expression was significantly increased (P < 0.0001) during the wound healing process in oophorectomised rabbits, as compared with both control and sham groups. CONCLUSION: Oophorectomised rabbits show protracted incisional vaginal wound healing associated with increased TGFbeta1 gene transcription. PMID- 22827860 TI - Disturbed oscillatory brain dynamics in subcortical ischemic vascular dementia. AB - BACKGROUND: White matter hyperintensities (WMH) can lead to dementia but the underlying physiological mechanisms are unclear. We compared relative oscillatory power from electroencephalographic studies (EEGs) of 17 patients with subcortical ischemic vascular dementia, based on extensive white matter hyperintensities (SIVD-WMH) with 17 controls to investigate physiological changes underlying this diagnosis. RESULTS: Differences between the groups were large, with a decrease of relative power of fast activity in patients (alpha power 0.25 +/- 0.12 versus 0.38 +/- 0.13, p = 0.01; beta power 0.08 +/- 0.04 versus 0.19 +/- 0.07; p<0.001) and an increase in relative powers of slow activity in patients (theta power 0.32 +/- 0.11 versus 0.14 +/- 0.09; p<0.001 and delta power 0.31 +/- 0.14 versus 0.23 +/- 0.09; p<0.05). Lower relative beta power was related to worse cognitive performance in a linear regression analysis (standardized beta = 0.67, p<0.01). CONCLUSIONS: This pattern of disturbance in oscillatory brain activity indicate loss of connections between neurons, providing a first step in the understanding of cognitive dysfunction in SIVD-WMH. PMID- 22827861 TI - Significance of bacteria in oviposition and larval development of the sand fly Lutzomyia longipalpis. AB - BACKGROUND: Microbial ecology of phlebotomine sand flies is not well understood although bacteria likely play an important role in the sand fly biology and vector capacity for Leishmania parasites. In this study, we assessed the significance of the microbial community of rabbit feces in oviposition and larval development of Lutzomyia longipalpis as well as bacterial colonization of the gut of freshly emerged flies. METHODS: Sterile (by autoclaving) and non-sterile (control) rabbit feces were used in the two-choice assay to determine their oviposition attractiveness to sand fly females. Bacteria were identified by amplification and sequencing of the 16S rRNA gene with universal eubacterial primers. Sterile, control (non-sterile), and sterilized and inoculated rabbit feces were used to assess the significance of bacteria in L. longipalpis development. Newly emerged adult flies were surface-sterilized and screened for the bacterial population size and diversity by the culturing approach. The digestive tract of L4 sterile and control larvae was incubated with Phalloidin to visualize muscle tissues and DAPI to visualize nuclei. RESULTS: Two-choice behavioural assays revealed a great preference of L. longipalpis to lay eggs on rabbit feces with an active complex bacterial community (control) (85.8 % of eggs) in comparison to that of sterile (autoclaved) rabbit feces (14.2 %). Bioassays demonstrated that L. longipalpis larvae can develop in sterile rabbit feces although development time to adult stage was greatly extended (47 days) and survival of larvae was significantly lower (77.8 %) compared to that of larvae developing in the control rabbit feces (32 days and 91.7 %). Larval survival on sterilized rabbit feces inoculated with the individual bacterial isolates originating from this substrate varied greatly depending on a bacterial strain. Rhizobium radiobacter supported larval development to adult stage into the greatest extent (39 days, 88.0 %) in contrast to that of Bacillus spp. (76 days, 36.0 %). From the complex natural bacterial community of rabbit feces, R. radiobacter survived pupation and colonized the newly emerged females most successfully (82.6 % of all bacteria cultured); however, only 25 % of females were positive for bacteria in the digestive tract upon emergence. Immunohistochemistry did not reveal any obvious differences in anatomy of the digestive tract between control and axenic larvae. CONCLUSIONS: The bacterial community in the sand fly larval habitat affects oviposition and larval development although bacteria are not essential for successful development of L. longipalpis. Different bacteria contribute to larval development to various degrees and some, e.g. Rhizobium radiobacter, survive pupation and colonize the digestive tract of newly emerged females. With the establishment of the axenic rearing system, this study opens new venues to study the effect of bacteria on the gut epithelial immunity and vector competence of sand flies for Leishmania parasites with a goal to develop paratransgenic approaches for Leishmania control. PMID- 22827863 TI - The effect of seniority and education on departmental dictation utilization. AB - BACKGROUND: Electronic medical records (EMR) are considered the best solution to improved dissemination of health information for patients. The associated transcription caused a significant cost increase in an academic pediatric center. An educational campaign was implemented to achieve cost-effective transcriptions without compromising the number of EMR transcriptions. METHODS: We analyzed the effect of seniority on transcription times over a 4-month period. We also compared the dictation volume before and 4 months after educational interventions. This study was performed in a pediatric academic center with both inpatient and outpatient transcription utilization analyzed. All clinicians providing pediatric care and utilizing the hospital-based transcription over the study time period were analyzed. Interventions included targeted education about efficiencies in transcription, time-based dictation costs, avoidance of lengthy pauses and unnecessary detail, shortening of total transcriptions, superfluous phrases as well as structured templates. Level of training by postgraduate year of training and seniority within faculty were measured for impact on dictation time and effect of education to improve times. RESULTS: Learners in year one had an average dictation time of 7.5 +/- 2.2 minutes, which decreased with seniority to an average of 4.1 +/- 2.2 minutes for senior faculty (0.0007, ANOVA). After educational initiatives were implemented, there was progressive decline in dictation utilization. The total dictation time decreased from 8,750 minutes per month in August 2009 to 4,296 minutes in December of 2009 (p = 0.0045, unpaired t test). CONCLUSION: We identified a substantial need for education in dictation utilization and demonstrated that relatively simple interventions can result in substantial costs savings. PMID- 22827865 TI - Long-term care residents with cancer and their health care providers reflect on hope. AB - This study examined hope in long-term care residents with cancer from the perspectives of both residents and health care providers (HCPs). Clinical data established that the prevalence of a cancer diagnosis in the study facility (15%) was similar to other estimates in the literature. Eight experienced HCPs were interviewed. Ten residents with a cancer diagnosis were interviewed, and they completed the Herth Hope Index (HHI). Dimensions of hope and contextual factors that shape hope emerged as themes for both HCPs and residents, but reflected their different perspectives. HCPs identified hope as integral to care. HHI scores were high, indicating residents were generally hopeful. The study findings suggest that for the small but complex subgroup of long-term care (LTC) residents who have a diagnosis of cancer, hope is not lost, but rather it is relevant, nuanced, and possible to attain. PMID- 22827866 TI - Periodization of the early postnatal development in the rat with particular attention to the weaning period. AB - The early postnatal period is characterized by a great plasticity with critical windows in which any inadequate insult or intervention may be able to influence both positively and adversely postnatal growth and development. After birth the rat littermates enter the presuckling period (initial 6 hours terminated by the first nursing), characterized by transition from the amniotic fluid to the air, by the changes of the ambient temperature, by the termination of placental nutrition and by oxidative stress. After this stage the suckling period initiates and the littermates start to consume milk of their mothers. Comsumption of milk culminates on day 15, then decreases and terminates on postnatal day 28. The end of the suckling period and the onset of physiological weaning is determined by the moment when the youngs for the first time consume the solid food together with milk (postnatal day 17 in rats). On day 19 the first intake of drinking water occurs. The weaning period terminates by the last consumption of maternal milk - on postnatal day 28. It is necessary to stress that the duration of early postnatal periods is independent of the changes of body weight. The precise knowledge of individual ontogenetic periods critical for further development is crucial for the prediction and explanation of reactions to various pathogenetic stimuli both under experimental conditions and in clinical medicine. PMID- 22827867 TI - Models of epileptic seizures in immature rats. AB - Models of basic types of epileptic seizures are elaborated not only in adult but also in immature rodents. It is important because at least half of human epilepsies starts during infancy and childhood. This paper presents a review of chemically and electrically induced models of generalized convulsive and nonconvulsive (absence) seizures as well as models of partial simple (neocortical) and complex (limbic) seizures in immature rats. These models can also serve as a tool for study the development of central nervous system and motor abilities because the level of maturation is reflected in seizure semiology. Age-dependent models of epileptic seizures (absences and flexion seizures) are discussed. Models of seizures in immature animals should be used for testing of potential antiepileptic drugs. PMID- 22827868 TI - Ontogeny of the pain. AB - The article gives an overview of developmental aspects of the ontogeny of pain both in experimental models and in children. The whole article is devoted to the ontogenesis in pain perception and the possible influence on it. The role of endogenous opioids on the development of pain and other important substances such as serotonin, nerve growth factor (NGF) and nicotine are mentioned. There are also important differences of the ontogenesis of thermal and mechanical nociceptive stimulation. The physiological and pathophysiological findings are the backgrounds for principles of treatment, taking into account the special status of analgesics during ontogeny. In particular there are mentioned the special effects of endogenous opioids and especially morphine. It describes the role of vitamin D and erythropoietin during the development of pain perception. This article also mentioned the critical developmental periods in relation to the perception of pain. The attention is paid to stress and immunological changes during the ontogeny of pain. Another important role is played by microglia. The work is concluded by some statements about the use of physiological and pathophysiological findings during the treatment of pain in pediatric practice. Codein analgesia is also described because codein starts to be very modern drug with the dependence. PMID- 22827869 TI - Drugs in pregnancy: the effects on mother and her progeny. AB - Drug abuse during pregnancy is a growing problem in all developed countries all over the world. The drugs easily cross the placental barrier into the fetal body and are present also in the maternal milk. Therefore, it may affect the development of the child pre- as well as postnatally. The effects of prenatal drug exposure are long-lasting and persist until adulthood. The present review summarizes the clinical and experimental evidence showing how opioids and psychostimulants can affect maternal behavior of drug-abusing mother and the development of their offspring. PMID- 22827862 TI - Interacting epidemics? Sleep curtailment, insulin resistance, and obesity. AB - In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5-2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities. PMID- 22827871 TI - Cardiac tolerance to ischemia in neonatal spontaneously hypertensive rats. AB - Hypertension is the risk factor of serious cardiovascular diseases, such as ischemic heart disease and atherosclerosis. The aim of the present study was to analyze the development of cardiac tolerance to ischemia in neonatal spontaneously hypertensive rats (SHR) and possible protective effect of ischemic preconditioning (IP) or adaptation to intermittent high-altitude hypoxia (IHAH). For this purpose we used 1- and 10-day-old pups of SHR and their normotensive control Wistar Kyoto rats (WKY). Isolated hearts were perfused in the Langendorff mode with Krebs-Henseleit solution at constant pressure, temperature and rate. Cardiac tolerance to ischemia was expressed as a percentage of baseline values of developed force (DF) after global ischemia. IP was induced by three 3-min periods of global ischemia, each separated by 5-min periods of reperfusion. IHAH was simulated in barochamber (8 h/day, 5000 m) from postnatal day 1 to 10. Cardiac tolerance to ischemia in 1-day-old SHR was higher than in WKY. In both strains tolerance decreased after birth, and the difference disappeared. The high cardiac resistance in 1- and 10-day-old SHR and WKY could not be further increased by both IP and adaptation to IHAH. It may be concluded that hearts from newborn SHR are more tolerant to ischemia/reperfusion injury as compared to age-matched WKY; cardiac resistance decreased in both strains during the first ten days, similarly as in Wistar rats. PMID- 22827870 TI - Microarray analysis of normal and abnormal chick ventricular myocardial development. AB - The left and right ventricle originate from distinct parts of the cardiac tube, and several genes are known to be differentially expressed in these compartments. The aims of this study were to determine developmental differences in gene expression between the left and right ventricle, and to assess the effect of altered hemodynamic loading. RNA was extracted from isolated left and right normal chick embryonic ventricles at embryonic day 6, 8, and 10, and from day 8 left atrial ligated hearts with hypoplastic left and dilated right ventricles. cRNA was hybridized to Affymetrix Chicken Genome array according to manufacturer protocols. Microarray analysis identified 302 transcripts that were differentially expressed between the left and right ventricle. Comparative analysis detected 91 genes that were different in left ventricles of ligated hearts compared to age-matched ventricles, while 66 were different in the right ones. A large number of the changes could be interpreted as a delay of normal maturation. The approach described in this study could be used as one of the measures to gauge success of surgical procedures for congenital heart disease and help in determining the optimal time frame for intervention to prevent onset of irreversible changes. PMID- 22827872 TI - Pressure overload selectively increases n-3 PUFA in myocardial phospholipids during early postnatal period. AB - Increasing hemodynamic load during early postnatal development leads to rapid growth of the left ventricular (LV) myocardium, which is associated with membrane phospholipid (PL) remodeling characterized by n-3 polyunsaturated fatty acids (PUFA) accumulation. The aim of this study was to examine the influence of additional workload imposed early after birth when ventricular myocytes are still able to proliferate. Male Wistar rats were subjected to abdominal aortic constriction (AC) at postnatal day 2. Concentrations of PL and their fatty acid (FA) profiles in the LV were analyzed in AC, sham-operated (SO) and intact animals on postnatal days 2 (intact only), 5 and 10. AC resulted in LV enlargement by 22 % and 67 % at days 5 and 10, respectively, compared with age matched SO littermates. Concentrations of phosphatidylcholine, cardiolipin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and sphingomyelin decreased in AC myocardium, albeit with different time course and extent. The main effect of AC on FA remodeling consisted in the accumulation of n 3 PUFA in PL. The most striking effect of AC on FA composition was observed in phosphatidylinositol and cardiolipin. We conclude that excess workload imposed by AC inhibited the normal postnatal increase of PL concentration while further potentiating the accumulation of n-3 PUFA as an adaptive response of the developing myocardium to accelerated growth. PMID- 22827873 TI - Developmental changes of the sensitivity of cardiac and liver mitochondrial permeability transition pore to calcium load and oxidative stress. AB - Opening of the mitochondrial membrane permeability transition pore (MPTP) is an important factor in the activation of apoptotic and necrotic processes in mammalian cells. In a previous paper we have shown that cardiac mitochondria from neonatal rats are more resistant to calcium load than mitochondria from adult animals. In this study we have analyzed the ontogenetic development of this parameter both in heart and in liver mitochondria. We found that the high resistance of heart mitochondria decreases from day 14 to adulthood. On the other hand, we did not observe a similar age-dependent sensitivity in liver mitochondria, particularly in the neonatal period. Some significant but relatively smaller increase could be observed only after day 30. When compared with liver mitochondria cardiac mitochondria were more resistant also to the peroxide activating effect on calcium-induced mitochondrial swelling. These data thus indicate that the MPTP of heart mitochondria is better protected against damaging effects of the calcium load and oxidative stress. We can only speculate that the lower sensitivity to calcium-induced swelling may be related to the higher ischemic tolerance of the neonatal heart. PMID- 22827874 TI - Ontogenetic changes of lipofuscin-like pigments in the rat heart. AB - Increased generation of reactive oxygen species results in the formation of fluorescent end-products of lipid peroxidation - lipofuscin-like pigments (LFP). LFP increased up to six-fold from the fetal value in the rat heart immediately after birth. In the experimental design of this study the fetuses were sampled 1 day before birth, and then the samples were collected on postnatal days 1, 4, 7, 10, 15, 30, and 60. Males and females were compared on day 30 and 60 when the difference between right and left ventricle was studied as well. Four LFP fluorophores were analyzed: F355/440, F310/470, F350/450, F315/450 (excitation/emission, nm). All fluorophores decreased on day 4 relative to day 1, subsequent transient increases ended in a significant decrease on day 60. However, the LFP levels on day 60 are still about threefold higher than those in fetuses. Differences between male and female hearts were observed on day 30. The corresponding male ventricles contained by one third higher concentration of LFP than the female counterparts. The increase in LFP concentration in male ventricles on day 30 was only transient, no difference between corresponding male and female ventricles was found on day 60. The most distinguished feature in the male heart was a sharp LFP decrease in the right ventricle on day 60. PMID- 22827875 TI - Biological effects of selenium compounds with a particular attention to the ontogenetic development. AB - Selenium is a trace element that is essential for living organism. Its beneficial effect is, however, expressed in a very narrow dosage range: the high and low doses of selenium are connected with pathological manifestations. The toxicity depends on the chemical form of selenium, state of organism, interactions with heavy metals and on the stage of ontogenetic development. Whereas one dose of sodium selenite (20 micromol/kg b.w.) is lethal in adult rats, suckling rats are entirely resistant. However, within one week after administration of the same dose, cataract of eye lens developed. The highest incidence of cataract was observed in 10-day-old animals and it decreased until day 20. From postnatal day 20 to day 40 the rats were resistant to both the lethal and cataractogenic effects of selenium. The incidence of cataract may be suppressed by premature weaning, lower hydration of suckling, change of water soluble/water insoluble lens protein ratio, thyroxine treatment, and by interaction with mercury. By means of its oxidative and reduction properties, selenium is involved in the maintenance of the cell redox homeostasis. Typical example is its possible cardioprotective effect: selenium decreased number of arrhythmias, reduced infarct size and improved the contractile recovery after ischemia/reperfusion injury. Selenium supplementation may thus increase cardiac tolerance to ischemic damage. PMID- 22827876 TI - Age-dependent salt hypertension in Dahl rats: fifty years of research. AB - Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals. PMID- 22827877 TI - Hypoxia-induced lipid peroxidation in the brain during postnatal ontogenesis. AB - Reactive oxygen species (ROS) are common products of the physiological metabolic reactions, which are associated with cell signaling and with the pathogenesis of various nervous disorders. The brain tissue has the high rate of oxidative metabolic activity, high concentration of polyunsaturated fatty acids in membrane lipids, presence of iron ions and low capacity of antioxidant enzymes, which makes the brain very susceptible to ROS action and lipid peroxidation formation. Membranes of brain cortex show a higher production of thiobarbituric acid reactive substances (TBARS) in prooxidant system (ADP.Fe(3+)/NADPH) than membranes from the heart or kidney. Lipid peroxidation influences numerous cellular functions through membrane-bound receptors or enzymes. The rate of brain cortex Na(+),K(+)-ATPase inhibition correlates well with the increase of TBARS or conjugated dienes and with changes of membrane fluidity. The experimental model of short-term hypoxia (simulating an altitude of 9000 m for 30 min) shows remarkable increase in TBARS in four different parts of the rat brain (cortex, subcortical structures, cerebellum and medulla oblongata) during the postnatal development of Wistar rat of both sexes. Young rats and males are more sensitive to oxygen changes than adult rats and females, respectively. Under normoxia or hypobaric hypoxia both ontogenetic aspects and sex differences play a major role in establishing the activity of erythrocyte catalase, which is an important part of the antioxidant defense of the organism. Rats pretreated with L-carnitine (and its derivatives) have lower TBARS levels after the exposure to hypobaric hypoxia. The protective effect of L-carnitine is comparable with the effect of tocopherol, well-known reactive species scavenger. Moreover, the plasma lactate increases after a short-term hypobaric hypoxia and decreases in L-carnitine pretreated rats. Acute hypobaric hypoxia and/or L-carnitine-pretreatment modify serum but not brain lactate dehydrogenase activity. The obtained data seem to be important because the variations in oxygen tension represent specific signals of regulating the activity of many specific systems in the organism. PMID- 22827878 TI - Critical developmental periods in the pathogenesis of hypertension. AB - Hypertension is one of the major risk factor of cardiovascular diseases, but after a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. One reason is that blood pressure is a quantitative trait with multifactorial determination. Numerous genes, environmental factors as well as epigenetic factors should be considered. There is no doubt that although the full manifestation of hypertension and other cardiovascular diseases usually occurs predominantly in adulthood and/or senescence, the roots can be traced back to early ontogeny. The detailed knowledge of the ontogenetic changes occurring in the cardiovascular system of experimental animals during particular critical periods (developmental windows) could help to solve this problem in humans and might facilitate the age-specific prevention of human hypertension. We thus believe that this approach might contribute to the reduction of cardiovascular morbidity among susceptible individuals in the future. PMID- 22827879 TI - Unexpected outcome after sclerotherapy of simple renal cyst. AB - BACKGROUND: Simple renal cysts usually have benign clinical features. We report a rare case of papillary renal cell carcinoma (RCC) associated with a large recurrent simple cyst following sclerotherapy. CASE PRESENTATION: A 47-year-old Japanese woman received minocycline sclerotherapy for a large (9 cm in diameter) simple left renal cyst in May 2005. The cyst regrew, and second-line sclerotherapy with ethanol was performed in November 2005. Three years later, she developed papillary RCC on the wall of the recurrent renal cyst. Radical nephrectomy was performed, but the patient died of metastatic disease 15 months after surgery. CONCLUSION: Malignant transformation from recurrent simple renal cyst to RCC may occur in the years following sclerotherapy, underscoring the need for long-term follow-up. PMID- 22827880 TI - Projected climate-induced habitat loss for salmonids in the John Day River network, Oregon, U.S.A. AB - Climate change will likely have profound effects on cold-water species of freshwater fishes. As temperatures rise, cold-water fish distributions may shift and contract in response. Predicting the effects of projected stream warming in stream networks is complicated by the generally poor correlation between water temperature and air temperature. Spatial dependencies in stream networks are complex because the geography of stream processes is governed by dimensions of flow direction and network structure. Therefore, forecasting climate-driven range shifts of stream biota has lagged behind similar terrestrial modeling efforts. We predicted climate-induced changes in summer thermal habitat for 3 cold-water fish species-juvenile Chinook salmon, rainbow trout, and bull trout (Oncorhynchus tshawytscha, O. mykiss, and Salvelinus confluentus, respectively)-in the John Day River basin, northwestern United States. We used a spatially explicit statistical model designed to predict water temperature in stream networks on the basis of flow and spatial connectivity. The spatial distribution of stream temperature extremes during summers from 1993 through 2009 was largely governed by solar radiation and interannual extremes of air temperature. For a moderate climate change scenario, estimated declines by 2100 in the volume of habitat for Chinook salmon, rainbow trout, and bull trout were 69-95%, 51-87%, and 86-100%, respectively. Although some restoration strategies may be able to offset these projected effects, such forecasts point to how and where restoration and management efforts might focus. PMID- 22827881 TI - Private hospital accreditation and inducement of care under the ghanaian national insurance scheme. AB - The Ghanaian National Health Insurance Scheme pays providers according to the fee for service payment scheme, a method of payment that is likely to encourage inducement of care. The goal of this paper is to test for the presence of supplier induced demand among patients who received care in private, for profit, hospitals accredited to provide care to insured patients. An instrumental variable Poisson estimation was used to compare the demand curves for health care by insured outpatients in the public and private hospitals. The results showed that supplier induced demand existed in the private sector among patients within the ages 18 and 60 years. Impact on cost of care and patients' welfare is discussed. PMID- 22827882 TI - Parent and child experiences using a hydrophilic or reused PVC catheter for intermittent catheterisation. AB - AIMS AND OBJECTIVES: To highlight the challenges faced in adjusting to intermittent catheterisation for families and children affected by spina bifida. BACKGROUND: Toileting is a particular issue for children with spina bifida resulting in difficulty emptying their bladder. Management of incomplete emptying is intermittent catheterisation, which is now part of routine clinical care. The physical benefits of intermittent catheterisation are critical to renal health, and significant attention has been paid to this; less attention has been given to the personal aspects for the family or older child. DESIGN: A descriptive study of satisfaction with two products for intermittent catheterisation: polyvinyl chloride and hydrophilic catheters based on data obtained from a randomised controlled trial on urinary tract infections in catheter users. METHODS: At the end of each of the polyvinyl chloride and hydrophilic study arms, parents or older children completed a 'Satisfaction Questionnaire' and then participated in a follow-up interview. Data were analysed for emerging themes. CONCLUSIONS: Three themes emerged: adjustment, ease of use and self-reliance. Key findings include: increased independence and confidence of the child catheterising using the hydrophilic catheter, self-management strategies to successfully manipulate the slippery hydrophilic catheter and reasons for the lack of success, and identification of participants who preferred polyvinyl chloride catheters. Descriptive data revealed potential areas where a hydrophilic catheter could improve the lives of the family and child as well as noting the need for user choice in product selection. RELEVANCE TO CLINICAL PRACTICE: Listening to the stories of children and families increases the nurse's ability to act as a guide as families struggle to assist their children in reaching their potential. Incontinence has been demonstrated to be the cause of self-isolation potentially leading to a decreased sense of self-worth. Ambulatory care nurses play a large role in helping families find the routine and resources necessary to reduce the incidence of incontinence, in children with spina bifida. PMID- 22827884 TI - How receptive are patients to medical students in Australian hospitals? A cross sectional survey of a public and a private hospital. AB - BACKGROUND: Medical student numbers in Australian universities have more than doubled since 2000. There are concerns about the ability for existing clinical training sites to accommodate this increase in student numbers, and there have been calls to increase training in private hospitals. The receptiveness of patients in private hospitals will influence the success of such placements. AIMS: We aimed to evaluate whether patients in a private hospital are as receptive to medical students as patients in a public hospital. METHODS: Cross sectional survey of patients conducted at a private and a public teaching hospital in Melbourne, Australia. Main outcome measures were willingness to allow a medical student to participate in an interview, physical examination and procedures (electrocardiogram, venepuncture and digital rectal examination), and patient attitudes towards medical students as assessed by a series of 20 attitude statements and a summative attitude score. RESULTS: Patients at the private hospital were more willing than patients at the public hospital to allow a medical student to take their history unsupervised (112/146, 76.7% vs 90/141, 63.8%; P = 0.02). The distribution of patient willingness did not otherwise differ between hospitals for physical examination or procedures. There was no difference in the mean attitude score between hospitals (15.3 +/- 0.8 private vs 15.4 +/- 1.2 public, P = 0.38), and responses differed between hospitals for only four of the 20 attitude statements. CONCLUSIONS: Our findings suggest that patients in a private hospital are at least as receptive to medical students as patients in a public hospital. PMID- 22827883 TI - Aromatic interactions as control elements in stereoselective organic reactions. AB - This Account describes how attractive interactions of aromatic rings with other groups can influence and control the stereoselectivity of many reactions. Recent developments in theory have improved the accuracy in the modeling of aromatic interactions. Quantum mechanical modeling can now provide insights into the roles of these interactions at a level of detail not previously accessible, both for ground-state species and for transition states of chemical reactions. In this Account, we show how transition-state modeling led to the discovery of the influence of aryl groups on the stereoselectivities of several types of organic reactions, including asymmetric dihydroxylations, transfer hydrogenations, hetero Diels-Alder reactions, acyl transfers, and Claisen rearrangements. Our recent studies have also led to a novel mechanistic picture for two classes of (4 + 3) cycloadditions, both of which involve reactions of furans with oxyallyl intermediates. The first class of cycloadditions, developed by Hsung, features neutral oxyallyl intermediates that contain a chiral oxazolidinone auxiliary. Originally, it was thought that these cycloadditions relied on differential steric crowding of the two faces of a planar intermediate. Computations reveal a different picture and show that cycloaddition with furan takes place preferentially through the more crowded transition state: the furan adds on the same side as the Ph substituent of the oxazolidinone. The crowded transition state is stabilized by a CH-pi interaction between furan and Ph worth approximately 2 kcal/mol. Attractive interactions with aromatic rings also control the stereoselectivity in a second class of (4+3) cycloadditions involving chiral alkoxy siloxyallyl cations. Alkoxy groups derived from chiral alpha methylbenzyl alcohols favor crowded transition states, where a stabilizing CH-pi interaction is present between the furan and the Ar group. The cationic cycloadditions are stepwise, while the Hsung cycloadditions are concerted. Our results suggest that this form of CH- pi-directed stereocontrol is quite general and likely controls the stereoselectivities of other addition reactions in which one face of a planar intermediate bears a pendant aromatic substituent. PMID- 22827885 TI - The AgeWell study of behavior change to promote health and wellbeing in later life: study protocol for a randomized controlled trial. AB - BACKGROUND: Lifestyle factors playing a role in the development of late-life disability may be modifiable. There is a need for robust evidence about the potential for prevention of disability through behavior change interventions. METHODS/DESIGN: This feasibility study involves the development, implementation and initial testing of a behavior change intervention in a naturalistic setting. A small-scale randomized controlled trial (RCT) will investigate the implementation of a goal-setting intervention aimed at promoting behavior change in the domains of physical and cognitive activity in the context of a community resource center for over-50s. Healthy older participants attending the center (n = 75) will be randomized to one of three conditions: control (an interview involving a general discussion about the center); goal-setting (an interview involving identification of up to five personal goals in the domains of physical activity, cognitive activity, diet and health, and social engagement); or goal setting with mentoring (the goal-setting interview followed by bi-monthly telephone mentoring). All participants will be reassessed after 12 months. Primary outcomes are levels of physical and cognitive activity. Secondary outcomes address psychosocial (self-efficacy, mood, quality of life), cognitive (memory and executive function), and physical fitness (functional and metabolic) domains. Cost-effectiveness will also be examined. DISCUSSION: This study will provide information about the feasibility of a community-based lifestyle intervention model for over-50s and of the implementation of a goal-setting intervention for behavior change, together with initial evidence about the short term effects of goal-setting on behavior. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30080637 (http://www.controlled-trials.com). PMID- 22827886 TI - Impact of nystatin on Candida and the oral microbiome. PMID- 22827887 TI - Spontaneous aggregate transition in mixtures of a cationic gemini surfactant with a double-chain cationic surfactant. AB - Controllable aggregate transitions were realized by mixing two kinds of cationic surfactants, hexylene-1,6-bis(dodecyldimethylammonium bromide) (C(12)C(6)C(12)Br(2)) and didodecyldimethylammonium bromide (DDAB). It was found that two parameters are the main factors determining the aggregation behavior of the mixed system, the total concentration of DDAB and C(12)C(6)C(12)Br(2) (C(T)), and the mole fraction of DDAB in the mixtures of DDAB and C(12)C(6)C(12)Br(2) (X(DDAB)). How these two parameters act on the aggregate transitions was studied in detail by various measurements including surface tension, turbidity, electrical conductivity, zeta potential, isothermal titration microcalorimetry, dynamic light scattering, cryogenic transmission electron microscopy, and (1)H NMR. When C(T) was constant, spontaneous vesicle-to-micelle transitions were found with decreasing X(DDAB) at high C(T). When X(DDAB) was constant, aggregate transitions were generated by gradually increasing C(T), depending on different X(DDAB) ranges. At X(DDAB) < 0.6, small spherical aggregates formed first and then transferred to vesicles, and finally the vesicles transitioned to micelles. At X(DDAB) >= 0.6, the progressive increase in C(T) led to aggregate transitions on the order of the arising of vesicles, the continuous growth of vesicles, the disruption of vesicles into micelles, and the final coexistence of vesicles and micelles. The hydrophobic interaction and electrostatic repulsion between DDAB and C(12)C(6)C(12)Br(2) together with the related degree of ionization and hydration of the surfactants were gradually adjusted by changing the ratio and the total concentration of these two surfactants, which should be responsible for the complicated aggregation behavior. PMID- 22827888 TI - The growth of Pediatric Rheumatology: Pediatric Rheumatology European Society and the impact factor. PMID- 22827890 TI - Impact of anthropogenic and natural environmental changes on Echinococcus transmission in Ningxia Hui Autonomous Region, the People's Republic of China. AB - Echinococcus transmission is known to be affected by various environmental factors, which may be modified by human influence or natural events including global warming. Considerable population growth in the last fifty years in Ningxia Hui Autonomous Region (NHAR), the People's Republic of China (PRC), has led to dramatic increases in deforestation and modified agricultural practices. In turn, this has resulted in many changes in the habitats for the definitive and intermediate hosts of both Echinococcus granulosus and E. multilocularis, which have increased the risks for transmission of both parasites, affecting echinococcosis prevalence and human disease. Ecological environmental changes due to anthropogenic activities and natural events drive Echinococcus transmission and NHAR provides a notable example illustrating how human activity can impact on a parasitic infection of major public health significance. It is very important to continually monitor these environmental (including climatic) factors that drive the distribution of Echinococcus spp. and their impact on transmission to humans because such information is necessary to formulate reliable future public health policy for echinococcosis control programs and to prevent disease spread. PMID- 22827891 TI - Greetings from the editors. PMID- 22827889 TI - Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model. AB - BACKGROUND: Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear. RESULTS: In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. CONCLUSION: Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity. PMID- 22827892 TI - Re: Electromyographic activity of pelvic and lower limb muscles during postural tasks in people with benign joint hypermobility syndrome and non hypermobile people. A pilot study Greenwood NL, Duffell LD, Alexander CM & McGregor AH. Man Ther 2011;16:p. 623-628. PMID- 22827893 TI - The importance of habitat resistance for movement decisions in the common lizard, Lacerta vivipara. AB - BACKGROUND: Movement behaviour can be influenced by a multitude of biotic and abiotic factors. Here, we investigate the speed of movement in relation to environmental and individual phenotypic properties in subadult common lizards (Lacerta vivipara). We aim to disentangle the importance of substrate, cover, humidity, basking opportunity and individual phenotype on moving tendencies in 12 treatment combinations, at which each lizard was tested. RESULTS: We find that movement behaviour depends on the starting conditions, the physical properties of the dispersal corridor, and on the individuals' phenotype. Specifically, the presence of cover and substrate providing suitable traction in the corridor had positive effects on individual movement decisions. Additionally, we find high phenotypic variation in the propensity to move dependent on the presence of cover. Individual back patterns also strongly affected movement decisions in interaction with the physical properties of the dispersal corridor. CONCLUSIONS: Our results highlight the importance of understanding the habitat resistance for movement patterns, with humid habitats with covering vegetation providing the best conditions to initiate movement in the common lizard. In addition, population effects, differences in back pattern phenotype and individual plasticity were identified as key parameters influencing movement behaviour. PMID- 22827895 TI - Visualizing dopamine transporter integrity with iodine-123-FP-CIT SPECT in combination with high resolution MRI in the brain of the common marmoset monkey. AB - Considerable progress has been made in small animal single photon emission computed tomography (SPECT) imaging in the field of Parkinson's disease. In preclinical research, there is an increasing demand for in vivo imaging techniques to apply to animal models. Here, we report the first protocol for dopamine transporter (DAT) SPECT in common marmosets using the radioligand 123I-N omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane (123I-FP CIT). Serial SPECT images were obtained on an upgraded clinical scanner to determine the distribution kinetics of 123I-FP-CIT in the marmoset brain. After intravenous injection of approximately 60 MBq of the radiotracer 123I-FP-CIT, stable and specific striatal uptake was observed for at least 4h. Analysis of plasma samples showed rapid disappearance of the radiotracer from blood plasma within a few minutes after application, with activity declining to 4.1% of the administered activity. Structural magnetic resonance imaging (MRI) at 400 MUm resolution provided the details of the underlying anatomy. In a marmoset model of Parkinson's disease, which was generated by unilateral injections of 6 hydroxydopamine (6-OHDA) into the nigro-striatal projection pathway, complete loss of striatal DAT binding in combination with behavioral deficits was observed. The presented study demonstrates that 123I-FP-CIT SPECT is a suitable tool to investigate DAT integrity in preclinical studies on common marmosets. PMID- 22827894 TI - Structural requirements for effective oximes--evaluation of kinetic in vitro data with phosphylated human AChE and structurally different oximes. AB - Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge. PMID- 22827896 TI - Processed food consumption and risk of esophageal squamous cell carcinoma: A case control study in a high risk area. AB - This study was conducted to investigate the association between consumption of processed foods and esophageal cancer risk. A population-based case-control study was designed. For the present study, 254 patients with esophageal squamous cell carcinoma with pathological diagnoses were selected from Yanting during 2008 and 2010 and 254 community-based controls were selected from the same area, individually matched with cases by age and sex. Data on demographic, lifestyle and dietary factors were collected using food frequency questionnaires. A conditional logistic regression model was used to estimate the odds ratio (OR) with adjustments for potential confounders. Compared to the frequency of <1 time/week, the intake frequency of >3 times/week of preserved vegetables had a significant association with esophageal cancer (OR = 5.01, 95% confidence interval [CI] 2.07, 12.17). In stratified analyses, the OR of increasing intake of preserved vegetables for esophageal cancer were 2.02 in men (95% CI 1.18, 3.48), 3.15 in women (95% CI 1.28, 7.75), 2.41 (95% CI 1.45 4.01) in the persons <65 years old and 1.28 (95% CI 0.35, 4.65) in persons >=65 years old. Consumption of pickled vegetables was not associated significantly with esophageal cancer risk. Intake of salted meat with a frequency of >=1 time/week meant that the OR increased to 2.57 (95%CI 1.02, 6.43), but no significant trend or association in subgroup analysis was observed. Preserved vegetable consumption was associated with increased risk of esophageal cancer, while no association was found with pickled vegetables. PMID- 22827897 TI - Hashimoto's encephalopathy cases: Chinese experience. AB - BACKGROUND: Hashimoto's encephalopathy is a poorly understood syndrome consisting of heterogeneous neurological symptoms and high serum antithyroid antibody titers, typically responding to steroids. More clinical series studies are required to characterize the clinical, laboratory and imaging features, and outcomes, especially in the Chinese population. METHODS: We analyzed the clinical, laboratory, and imaging features and outcomes of thirteen consecutive patients with Hashimoto's encephalopathy diagnosed in Xuan Wu Hospital, Beijing from 2005 to 2010 retrospectively. RESULTS: Cognitive impairment (84.6%) and psychiatric symptoms (38.5%) were the most frequent symptoms. Seizures (30.8%) and myoclonus (7.7%) were less common than previously described. Three (23.1%) patients showed abnormal signals in hippocampus or temporal lobe, which were believed related to their memory disorders or seizures. MRI changes showed resolution paralleling clinical improvement in one patient. Among eight patients who received steroid therapy, five patients recovered, one patient improved with residual deficits, and two patients relapsed or had no effect. Among five non steroid treated patients, three patients experienced stable remission with antiepileptic drugs or general neurotrophic therapy, and two patients experienced continuous deterioration. CONCLUSIONS: Most patients with Hashimoto's encephalopathy showed good response to steroids. Some patients improved without steroid therapy. Considering its reversible course, we recommend that Hashimoto's encephalopathy should always be in the differential diagnosis while evaluating disorders of the central nervous system. PMID- 22827899 TI - Balance billing: the patients' perspective. AB - We study the effects of 'balance billing', i.e., allowing physicians to charge a fee from patients in addition to the fee paid by Medicare. First, we show that on pure efficiency grounds the optimal Medicare fee under balance billing is zero. An active Medicare policy thus can only be justified when distributional concerns are accounted for. Extending the analysis by Glazer and McGuire, we therefore analyze the optimal policy from the patients' point of view. We demonstrate that, from the patients' perspective, a positive fee can be superior under balance billing. Furthermore, patient welfare can be lower if balance billing is prohibited. In particular, this is the case if the administrative costs of Medicare are large. However, we cannot rule out that prohibiting balance billing may be superior. Finally, we show that payer fee discrimination increases patient welfare if Medicare's administrative costs are high or if Medicare's optimal fee under balance billing implies lower quality for fee-only patients.JEL classification: I11, I18, H51. PMID- 22827898 TI - Phylogenetic, molecular and drug-sensitivity analysis of HA and NA genes of human H3N2 influenza A viruses in Guangdong, China, 2007-2011. AB - Annual H3N2 subtype influenza outbreaks in Guangdong, China are a severe public health issue and require ongoing monitoring of emerging viral variants. The variation and evolution of haemagglutinin (HA) and neuraminidase (NA) genes of influenza isolates from Guangdong during 2007-2011 and others from GenBank were analysed using Lasergene 7.1 and MEGA 5.05, and serological analysis of antigens was determined by haemagglutination inhibition (HI). Susceptibility to antiviral drugs was correlated with genetic mutations. Phylogenetic analysis and alignment of HA and NA genes were performed on 18 Guangdong isolates and 26 global reference strains. The non-synonymous (dN) evolutionary rate of HA1 was 3.13 times that of HA2. Compared with the A/Perth/16/2009 vaccine HA gene, homologies of Guangdong isolates were between 98.8-99.7% and 98.0-98.4% in 2009 and 2010, respectively. Amino-acid substitutions were found in five epitopes of HA1 from Guangdong isolates between 2007 and 2011, especially in epitopes B (N160K) and D (K174R/N). The K189E/N/Q and T228A mutations in the receptor-binding site (RBS) occurred in the 2010 strains, which affected the antigenicity of HA1. The antigenicity of the epidemic H3N2 isolates in 2010 was somewhat different from that of A/Perth/16/2009. The Guangdong H3N2 isolates were determined to be oseltamivir-resistant with IC50 of 0.396 +/- 0.085 nmol/l (n=17) and zanamivir resistant with IC50 of 0.477 +/- 0.149 nmol/l (n=18). Variations were present in epitopes B and D, two sites in the RBS and two glycosylation sites in the Guangdong H3N2 HA1 gene. The majority of the Guangdong H3N2 isolates were sensitive to oseltamivir and zanamivir. Compared to the World Health Organization 2012 vaccine strains, Guangdong H3N2 strains varied genetically and antigenically to some degree. PMID- 22827900 TI - People living with HIV are receptive to HIV prevention interventions in clinical settings: a qualitative evaluation. AB - In the United States, HIV prevention services are increasingly being offered in the context of healthcare settings. This includes prioritizing prevention services for people living with HIV (PLWH), otherwise known as "prevention with positives." We conducted sixty in-depth interviews to explore patients' perceptions of clinic-based HIV prevention interventions targeting people living with HIV. The majority of patients were receptive to the prevention interventions. Patients described experiencing feeling fulfilled by communicating about issues related to HIV prevention when the conversations were specific to their situation and with an interventionist who was objective, yet empathic and non-judgmental. Provider-delivered interventions opened up new areas of prevention discussions with patients. Specialist-delivered interventions, specifically group-level interventions, provided opportunities to integrate participants into social networks that in turn provided social support and a reduction in social isolation. HIV prevention counseling benefited patients regardless of risk status. PMID- 22827902 TI - Let's talk about sex: development of a sexual health program for Nepali women. AB - The purpose of this study was to develop and test the feasibility of conducting a sexual health intervention for women in Nepal, a country with high political and economic instability and strong patriarchal systems. Of the 88 women enrolled, 100% retention was obtained over three sessions, and 85% completed a 1-month follow-up. Recruitment was so effective that some women were placed on a waitlist. All participants embraced the content and actively engaged in the intervention. Baseline results indicate HIV knowledge of the sample of educated women was low, and they did not often speak to other women about sex. Low knowledge about HIV and being comfortable discussing sex were associated with less frequent communication with others about sex. This study identified a great need for sexual health programs for women in Nepal, and we were able to effectively develop and implement an intervention to target this need. PMID- 22827903 TI - Risky relationships: targeting HIV prevention for women offenders. AB - HIV is a health issue for women offenders who are at particularly high risk. Women's prisons can be opportune settings for HIV prevention interventions. How women perceive partner relationships could be central to targeting HIV interventions. Consequently, this study examines changes in women offenders' risky relationships. Baseline and follow-up data are presented from 344 women offenders. Intent-to-treat analysis is used as well as analysis of covariance to control for baseline values. Findings indicate that women released to the community from prison who were randomized into the prevention intervention were significantly more likely to report changes in five of seven risky relationship thinking myths. Findings suggest that a relationship theory-based prevention intervention for reducing HIV risk could be promising for women offenders reentering the community after prison. Additional research is suggested. PMID- 22827901 TI - Field-based video pre-test counseling, oral testing, and telephonic post-test counseling: implementation of an HIV field testing package among high-risk Indian men. AB - In India, men who have sex with men (MSM) and truck drivers are high-risk groups that often do not access HIV testing due to stigma and high mobility. This study evaluated a field testing package (FTP) that identified HIV positive participants through video pre-test counseling, OraQuick oral fluid HIV testing, and telephonic post-test counseling and then connected them to government facilities. A total of 598 MSM and truck drivers participated in the FTP and completed surveys covering sociodemographics, HIV testing history, risk behaviors, and opinions on the FTP. MSM and truck drivers equally preferred video counseling, although MSM who had been previously tested preferred traditional methods. Nearly all participants preferred oral testing. Rates of counseling completion and linkage to government centers were low, with one-third of newly identified positives completing follow-up. With increased public-private coordination, this FTP could identify many hard-to-reach preliminary positive individuals and connect them to government testing and care. PMID- 22827904 TI - If you provide the test, they will take it: factors associated with HIV/STI Testing in a representative sample of homeless youth in Los Angeles. AB - Homeless youth are at high risk for human immunodeficiency virus (HIV) and other sexually transmitted infections (STI), yet those at greatest risk may never have been tested for HIV or STI. In a probability sample of sexually active homeless youth in Los Angeles (n = 305), this study identifies factors associated with HIV/STI testing status. Most youth (85%) had ever been tested and 47% had been tested in the past 3 months. Recent testing was significantly more likely among youth who self-identified as gay, were Hispanic, injected drugs, and used drop-in centers, and marginally more likely among youth with more depressive symptoms. Drop-in center use mediated the association of injection drug use with HIV/STI testing. HIV/STI testing was unrelated to sexual risk behavior. Drop-in centers can play an important role in facilitating testing, including among injection drug users, but more outreach is needed to encourage testing in other at-risk subgroups. PMID- 22827906 TI - Need for physician education on the benefits and risks of male circumcision in the United States. AB - Physicians may be called upon to counsel male patients or parents of newborn males regarding their decision to circumcise their newborn sons. The purpose of the present study was to describe physicians who do not understand the benefits and risks associated with male circumcision well enough to counsel parents of newborn male infants and adult men. A self-administered, cross-sectional electronic survey of physicians was conducted in 2008. We analyzed responses from 1,500 physicians (510 family practitioners, 490 internists, 250 pediatricians, and 250 obstetricians/gynecologists). Nearly 22% (n = 327/1500) reported they did not understand the risks and benefits of newborn male circumcision well enough to counsel parents and 40.3% (n = 504/1250) reported not understanding the risks and benefits well enough to counsel adult men. A substantial minority of physicians may need additional training and/or information about current male circumcision research to feel comfortable counseling parents of newborn male infants or adult men. PMID- 22827905 TI - HIV testing in recent college students: prevalence and correlates. AB - Prevalence and correlates of HIV testing were examined in a sample of 957 unmarried recent college students in the United States. Participants were asked about HIV testing, past-six-months sexual activities, lifetime treatment for sexually transmitted infections (STI), past-year health service utilization, and DSM-IV criteria for alcohol and other drug (AOD) dependence during the 2008-2009 academic year. Two in five (41.9%(wt)) were ever tested for HIV. Holding constant demographics, HIV testing was positively related to AOD dependence, frequency of unprotected sex, number of sex partners, having a physical exam by a medical professional, number of visits to a health provider for physical health problems, and lifetime STI treatment. Women were more likely than men to be tested for HIV despite similar levels of risky sex. Results demonstrate the feasibility of achieving high HIV testing rates in a college population. PMID- 22827908 TI - Measuring preschoolers' superstitious tendencies. AB - Superstitious behaviors have been studied extensively in adults and non-human species, but have not been systematically assessed in children. The purpose of the study is to develop and validate a method of measuring superstitious tendencies in young children based on an established learning paradigm. In two studies, 3-5-year-olds tapped a computer to make a target image appear. On half the trials, a sensory stimulus appeared at a random time before the target. Superstitious tendencies were measured by change in tapping during the presence of the sensory stimulus. Children's proportion of tapping increased during the presence of the sensory stimulus, indicating that children associated the sensory stimulus with the appearance of the target image, even though the two stimuli were not causally related. Implications for the development of superstitious tendencies and children's causal knowledge are discussed. PMID- 22827909 TI - Anaerobic methane oxidation in metalliferous hydrothermal sediments: influence on carbon flux and decoupling from sulfate reduction. AB - The anaerobic oxidation of methane (AOM) is a globally significant sink that regulates methane flux from sediments into the oceans and atmosphere. Here we examine mesophilic to thermophilic AOM in hydrothermal sediments recovered from the Middle Valley vent field, on the Juan de Fuca Ridge. Using continuous-flow sediment bioreactors and batch incubations, we characterized (i) the degree to which AOM contributes to net dissolved inorganic carbon flux, (ii) AOM and sulfate reduction (SR) rates as a function of temperature and (iii) the distribution and density of known anaerobic methanotrophs (ANMEs). In sediment bioreactors, inorganic carbon stable isotope mass balances results indicated that AOM accounted for between 16% and 86% of the inorganic carbon produced, underscoring the role of AOM in governing inorganic carbon flux from these sediments. At 90 degrees C, AOM occurred in the absence of SR, demonstrating a striking decoupling of AOM from SR. An abundance of Fe(III)-bearing minerals resembling mixed valent Fe oxides, such as green rust, suggests the potential for a coupling of AOM to Fe(III) reduction in these metalliferous sediments. While SR bacteria were only observed in cooler temperature sediments, ANMEs allied to ANME 1 ribotypes, including a putative ANME-1c group, were found across all temperature regimes and represented a substantial proportion of the archaeal community. In concert, these results extend and reshape our understanding of the nature of high temperature methane biogeochemistry, providing insight into the physiology and ecology of thermophilic anaerobic methanotrophy and suggesting that AOM may play a central role in regulating biological dissolved inorganic carbon fluxes to the deep ocean from the organic-poor, metalliferous sediments of the global mid-ocean ridge hydrothermal vent system. PMID- 22827910 TI - Father's experiences of involvement in the daily care of their child with developmental disability in a Chinese context. AB - AIMS AND OBJECTIVES: This study explored Taiwanese fathers' experience of involvement in the daily care of a child with developmental disability within Chinese culture. BACKGROUND: Most studies on parents' experiences of having a child with a disability have focused on mothers or mixed fathers' voices with mothers'. Focussing only on mothers and ignoring fathers may hinder the latter's engagement with their child's care and encourage traditional or detached fathering roles. DESIGN: A hermeneutic phenomenological approach was applied to explore and interpret fathers' experience. METHOD: Sixteen fathers were purposively sampled from a medical centre in central Taiwan. All participants were interviewed twice with semi-structured and in-depth interviews. All transcripts and journal notes were analysed with the hermeneutic circle to achieve thick descriptions that richly described the meaning of fathers' experience. RESULTS: Analysis of interviews with fathers on their experiences of raising the disabled child at home revealed three shared meanings: keeping hope alive, concerns about quality of medical care and maximising family function. CONCLUSIONS: Hope for their disabled child's good outcome and future was highly significant for these fathers, but hope was diminished when their child received poor medical care or their own ability was too poor to care for the disabled child. However, fathers still did not give up working for their children and for the well-being of their families and society. RELEVANCE TO CLINICAL PRACTICE: Nurses should acknowledge that fathers' involvement in their disabled child's care can contribute to the well-being of both child and family. Also, nurses should educate parents on the best possible ways to help their child. Finally, nurses need to encourage discussions between parents and professionals about their own and the family's situation to develop a trusting and equal parent professional relationship, thus alleviating fathers' concerns and better meeting the child's care needs. PMID- 22827911 TI - Mechanically activated catalyst mixing for high-yield boron nitride nanotube growth. AB - Boron nitride nanotubes (BNNTs) have many fascinating properties and a wide range of applications. An improved ball milling method has been developed for high-yield BNNT synthesis, in which metal nitrate, such as Fe(NO3)3, and amorphous boron powder are milled together to prepare a more effective precursor. The heating of the precursor in nitrogen-containing gas produces a high density of BNNTs with controlled structures. The chemical bonding and structure of the synthesized BNNTs are precisely probed by near-edge X-ray absorption fine structure spectroscopy. The higher efficiency of the precursor containing milling activated catalyst is revealed by thermogravimetric analyses. Detailed X-ray diffraction and X-ray photoelectron spectroscopy investigations disclose that during ball milling the Fe(NO3)3 decomposes to Fe which greatly accelerates the nitriding reaction and therefore increases the yield of BNNTs. This improved synthesis method brings the large-scale production and application of BNNTs one step closer. PMID- 22827912 TI - Which patients do I treat? An experimental study with economists and physicians. AB - This experiment investigates decisions made by prospective economists and physicians in an allocation problem which can be framed either medically or neutrally. The potential recipients differ with respect to their minimum needs as well as to how much they benefit from a treatment. We classify the allocators as either 'selfish', 'Rawlsian', or 'maximizing the number of recipients'. Economists tend to maximize their own payoff, whereas the physicians' choices are more in line with maximizing the number of recipients and with Rawlsianism. Regarding the framing, we observe that professional norms surface more clearly in familiar settings. Finally, we scrutinize how the probability of being served and the allocated quantity depend on a recipient's characteristics as well as on the allocator type.JEL Classification: A13, I19, C91, C72. PMID- 22827913 TI - Genetic characterization and molecular identification of the bloodmeal sources of the potential bluetongue vector Culicoides obsoletus in the Canary Islands, Spain. AB - BACKGROUND: Culicoides (Diptera: Ceratopogonidae) biting midges are vectors for a diversity of pathogens including bluetongue virus (BTV) that generate important economic losses. BTV has expanded its range in recent decades, probably due to the expansion of its main vector and the presence of other autochthonous competent vectors. Although the Canary Islands are still free of bluetongue disease (BTD), Spain and Europe have had to face up to a spread of bluetongue with disastrous consequences. Therefore, it is essential to identify the distribution of biting midges and understand their feeding patterns in areas susceptible to BTD. To that end, we captured biting midges on two farms in the Canary Islands (i) to identify the midge species in question and characterize their COI barcoding region and (ii) to ascertain the source of their bloodmeals using molecular tools. METHODS: Biting midges were captured using CDC traps baited with a 4-W blacklight (UV) bulb on Gran Canaria and on Tenerife. Biting midges were quantified and identified according to their wing patterns. A 688 bp segment of the mitochondrial COI gene of 20 biting midges (11 from Gran Canaria and 9 from Tenerife) were PCR amplified using the primers LCO1490 and HCO2198. Moreover, after selected all available females showing any rest of blood in their abdomen, a nested-PCR approach was used to amplify a fragment of the COI gene from vertebrate DNA contained in bloodmeals. The origin of bloodmeals was identified by comparison with the nucleotide-nucleotide basic alignment search tool (BLAST). RESULTS: The morphological identification of 491 female biting midges revealed the presence of a single morphospecies belonging to the Obsoletus group. When sequencing the barcoding region of the 20 females used to check genetic variability, we identified two haplotypes differing in a single base. Comparison analysis using the nucleotide-nucleotide basic alignment search tool (BLAST) showed that both haplotypes belong to Culicoides obsoletus, a potential BTV vector. As well, using molecular tools we identified the feeding sources of 136 biting midges and were able to confirm that C. obsoletus females feed on goats and sheep on both islands. CONCLUSIONS: These results confirm that the feeding pattern of C. obsoletus is a potentially important factor in BTV transmission to susceptible hosts in case of introduction into the archipelago. Consequently, in the Canary Islands it is essential to maintain vigilance of Culicoides-transmitted viruses such as BTV and the novel Schmallenberg virus. PMID- 22827914 TI - Identification of haplotype tag single nucleotide polymorphisms within the receptor for advanced glycation end products gene and their clinical relevance in patients with major trauma. AB - INTRODUCTION: The receptor for advanced glycation end products (RAGE) has been considered as one of the major pattern recognition receptors and plays an important role in the development of sepsis and multiple organ dysfunction in critical illnesses. Although genetic variants of the RAGE gene have been shown to be well associated with susceptibility to some inflammatory diseases, little is known about their clinical relevance in the development of sepsis in critical ill patients. METHODS: Four genetic variants were selected from the entire RAGE gene and genotyped using pyrosequencing and polymerase chain reaction-length polymorphism methods. Association studies were performed in two independent Chinese Han populations. RESULTS: Among the four genetic variants, only the rs1800625 polymorphism was significantly associated with sepsis morbidity rate and multiple organ dysfunction (MOD) scores in patients with major trauma both in Chongqing (n = 496) and Zhejiang (n = 232) districts, respectively. Results from ex vivo responsiveness of peripheral blood leukocytes indicated that the rs1800625 polymorphism was well associated with decreased production of TNFalpha. In addition, the rs1800625 polymorphism could significantly inhibit the promoter activities of the RAGE gene. CONCLUSIONS: The rs1800625 polymorphism is a functional variant, which might be used as a relevant risk estimate for the development of sepsis and multiple organ dysfunction syndrome in patients with major trauma. PMID- 22827916 TI - Modification of cocaine self-administration by buspirone (buspar(r)): potential involvement of D3 and D4 dopamine receptors. AB - Converging lines of evidence indicate that elevations in synaptic dopamine levels play a pivotal role in the reinforcing effects of cocaine, which are associated with its abuse liability. This evidence has led to the exploration of dopamine receptor blockers as pharmacotherapy for cocaine addiction. While neither D1 nor D2 receptor antagonists have proven effective, medications acting at two other potential targets, D3 and D4 receptors, have yet to be explored for this indication in the clinic. Buspirone, a 5-HT1A partial agonist approved for the treatment of anxiety, has been reported to also bind with high affinity to D3 and D4 receptors. In view of this biochemical profile, the present research was conducted to examine both the functional effects of buspirone on these receptors and, in non-human primates, its ability to modify the reinforcing effects of i.v. cocaine in a behaviourally selective manner. Radioligand binding studies confirmed that buspirone binds with high affinity to recombinant human D3 and D4 receptors (~98 and ~29 nm respectively). Live cell functional assays also revealed that buspirone, and its metabolites, function as antagonists at both D3 and D4 receptors. In behavioural studies, doses of buspirone that had inconsistent effects on food-maintained responding (0.1 or 0.3 mg/kg i.m.) produced a marked downward shift in the dose-effect function for cocaine maintained behaviour, reflecting substantial decreases in self-administration of one or more unit doses of i.v. cocaine in each subject. These results support the further evaluation of buspirone as a candidate medication for the management of cocaine addiction. PMID- 22827918 TI - The effect of job stress on smoking and alcohol consumption. AB - This paper examines the effect of job stress on two key health risk-behaviors: smoking and alcohol consumption, using data from the Canadian National Population Health Survey. Findings in the extant literature are inconclusive and are mainly based on standard models which can model differential responses to job stress only by observed characteristics. However, the effect of job stress on smoking and drinking may largely depend on unobserved characteristics such as: self control, stress-coping ability, personality traits and health preferences. Accordingly, we use a latent class model to capture heterogeneous responses to job stress. Our results suggest that the effects of job stress on smoking and alcohol consumption differ substantially for at least two "types" of individuals, light and heavy users. In particular, we find that job stress has a positive and statistically significant impact on smoking intensity, but only for light smokers, while it has a positive and significant impact on alcohol consumption mainly for heavy drinkers. These results provide suggestive evidence that the mixed findings in previous studies may partly be due to unobserved individual heterogeneity which is not captured by standard models. PMID- 22827917 TI - Can Andean medicine coexist with biomedical healthcare? A comparison of two rural communities in Peru and Bolivia. AB - BACKGROUND: It is commonly assumed that indigenous medical systems remain strong in developing countries because biomedicine is physically inaccessible or financially not affordable. This paper compares the health-seeking behavior of households from rural Andean communities at a Peruvian and a Bolivian study site. The main research question was whether the increased presence of biomedicine led to a displacement of Andean indigenous medical practices or to coexistence of the two healing traditions. METHODOLOGY: Open-ended interviews and free listing exercises were conducted between June 2006 and December 2008 with 18 households at each study site. Qualitative identification of households' therapeutic strategies and use of remedies was carried out by means of content analysis of interview transcriptions and inductive interference. Furthermore, a quantitative assessment of the incidence of culture-bound illnesses in local ethnobiological inventories was performed. RESULTS: Our findings indicate that the health-seeking behavior of the Andean households in this study is independent of the degree of availability of biomedical facilities in terms of quality of services provided, physical accessibility, and financial affordability, except for specific practices such as childbirth. Preference for natural remedies over pharmaceuticals coexists with biomedical healthcare that is both accessible and affordable. Furthermore, our results show that greater access to biomedicine does not lead to less prevalence of Andean indigenous medical knowledge, as represented by the levels of knowledge about culture-bound illnesses. CONCLUSIONS: The take-home lesson for health policy-makers from this study is that the main obstacle to use of biomedicine in resource-poor rural areas might not be infrastructural or economic alone. Rather, it may lie in lack of sufficient recognition by biomedical practitioners of the value and importance of indigenous medical systems. We propose that the implementation of health care in indigenous communities be designed as a process of joint development of complementary knowledge and practices from indigenous and biomedical health traditions. PMID- 22827915 TI - Developmental trajectory of the endocannabinoid system in human dorsolateral prefrontal cortex. AB - BACKGROUND: Endocannabinoids provide control over cortical neurotransmission. We investigated the developmental expression of key genes in the endocannabinoid system across human postnatal life and determined whether they correspond to the development of markers for inhibitory interneurons, which shape cortical development. We used microarray with qPCR validation and in situ hybridisation to quantify mRNA for the central endocannabinoid receptor CB(1)R, endocannabinoid synthetic enzymes (DAGLalpha for 2-arachidonylglycerol [2-AG] and NAPE-PLD for anandamide), and inactivating enzymes (MGL and ABHD6 for 2-AG and FAAH for anandamide) in human dorsolateral prefrontal cortex (39 days - 49 years). RESULTS: CB(1)R mRNA decreases until adulthood, particularly in layer II, after peaking between neonates and toddlers. DAGLalpha mRNA expression is lowest in early life and adulthood, peaking between school age and young adulthood. MGL expression declines after peaking in infancy, while ABHD6 increases from neonatal age. NAPE-PLD and FAAH expression increase steadily after infancy, peaking in adulthood. CONCLUSIONS: Stronger endocannabinoid regulation of presynaptic neurotransmission in both supragranular and infragranular cortical layers as indexed through higher CB(1)R mRNA may occur within the first few years of human life. After adolescence, higher mRNA levels of the anandamide synthetic and inactivating enzymes NAPE-PLD and FAAH suggest that a late developmental switch may occur where anandamide is more strongly regulated after adolescence than earlier in life. Thus, expression of key genes in the endocannabinoid system changes with maturation of cortical function. PMID- 22827919 TI - Health care costs associated with gestational diabetes mellitus among high-risk women--results from a randomised trial. AB - BACKGROUND: The costs of gestational diabetes mellitus (GDM) screening have been frequently reported, but total GDM-related health care costs compared to the health care costs of women without GDM have not been reported. The aim of this study was to analyse GDM-related health care costs among women with an elevated risk of GDM. METHODS: The study was based on a cluster-randomised GDM prevention trial (N = 848) carried out at maternity clinics, combined with data from the Finnish Medical Birth Register and Care Registers for Social Welfare and Health Care. Costs of outpatient visits to primary and secondary care, cost of inpatient hospital care before and after delivery, the use of insulin, delivery costs and babies' stay in the neonatal intensive care unit were analysed. Women who developed GDM were compared to those who were not diagnosed with GDM. RESULTS: Total mean health care costs adjusted for age, body mass index and education were 25.1% higher among women diagnosed with GDM (?6,432 vs. ?5,143, p < 0.001) than among women without GDM. The cost of inpatient visits was 44% higher and neonatal intensive care unit use was 49% higher in the GDM group than among women without GDM. The delivery costs were the largest single component in both groups. CONCLUSIONS: A confirmed GDM diagnosis was associated with a significant increase in total health care costs. Effective lifestyle counselling by primary health care providers may offer a means of reducing the high costs of secondary care. PMID- 22827921 TI - You're so vein: bundle sheath physiology, phylogeny and evolution in C3 and C4 plants. AB - Bundle sheath (BS) anatomy is found in most C4 lineages, associated with low inter-veinal distances (IVD) and high BS:mesophyll ratio (BS:MC). The origins, function and selective advantages of the BS in C3 lineages are relevant for understanding the environmental, molecular and phylogenetic determinants of C4 evolution. Suggested functions for BS have included structural support, hydraulic isolation, storage for water, ions, and carbohydrates, and photorespiratory carbon metabolism; we propose a central role for cavitation repair, consistent with the BS as a control centre on regulating stem and leaf hydraulic continuity. An analysis of BS traits in the phylogenetic lineages giving rise to C4 grasses (the 'PACMAD' clade) shows an initial enhancement in BS:MC ratio in C3 lineages, although IVD is similar to the Pooideae sister group. Using a global database, a well-developed BS in the C3 PACMAD lineages was associated with higher precipitation and temperatures in the habitat of origin on an annual basis, with the C3 to C4 progression defined by the aridity index (AI). Maintaining leaf hydraulic conductance and cavitation repair are consistent with increased evaporative demand and more seasonal precipitation as drivers, first for the C3 BS, and then C4 diversification, under declining CO(2) concentrations in the Palaeogene and Neogene. PMID- 22827920 TI - Effect of Alpinia zerumbet components on antioxidant and skin diseases-related enzymes. AB - BACKGROUND: The skin is chronically exposed to endogenous and environmental pro oxidant agents, leading to the harmful generation of reactive oxygen species. Antioxidant is vital substances which possess the ability to protect the body from damage cause by free radicals induce oxidative stress. Alpinia zerumbet, a traditionally important economic plant in Okinawa, contains several interesting bioactive constituents and possesses health promoting properties. In this regard, we carried out to test the inhibitory effect of crude extracts and isolated compounds from A. zerumbet on antioxidant and skin diseases-related enzymes. METHODS: The antioxidant activities were examined by DPPH, ABTS and PMS-NADH radical scavenging. Collagenase, elastase, hyaluronidase and tyrosinase were designed for enzymatic activities to investigate the inhibitory properties of test samples using a continuous spectrophotometric assay. The inhibitory capacity of test samples was presented at half maximal inhibitory concentration (IC50). RESULTS: The results showed that aqueous extract of the rhizome was found to have greater inhibitory effects than the others on both of antioxidant and skin diseases-related enzymes. Furthermore, 5,6-dehydrokawain (DK), dihydro-5,6 dehydrokawain (DDK) and 8(17),12-labdadiene-15,16-dial (labdadiene), isolated from rhizome, were tested for antioxidant and enzyme inhibitions. We found that DK showed higher inhibitory activities on DPPH, ABTS and PMS-NADH scavenging (IC50 = 122.14 +/- 1.40, 110.08 +/- 3.34 and 127.78 +/- 4.75 MUg/ml, respectively). It also had stronger inhibitory activities against collagenase, elastase, hyaluronidase and tyrosinase (IC50 = 24.93 +/- 0.97, 19.41 +/- 0.61, 19.48 +/- 0.24 and 76.67 +/- 0.50 MUg/ml, respectively) than DDK and labdadiene. CONCLUSION: Our results indicate that the rhizome aqueous extract proved to be the source of bioactive compounds against enzymes responsible for causing skin diseases. Moreover, DK could be used as a potent inhibitor and be further exploited to be used in anti-skin disease formulations. PMID- 22827922 TI - A modified Kakwani measure for health inequality. AB - We propose simple modifications for the Kakwani tax progressivity measure that make it suitable for evaluating access inequality for medical services. Our modification is to measure inequality using the ratio of the concentration index to the Gini coefficient instead of the difference between them. We also propose a measure using the Gini coefficient or concentration index of consumption expenditure as the denominator in the modified measure as an alternative type of modified measure. This measure can also be interpreted as the income/consumption expenditure elasticity evaluated at the mean. Additionally, we propose a decomposition method using expenditure components and provide an empirical example with Japanese data. PMID- 22827923 TI - In-hospital mortality after serious adverse events on medical and surgical nursing units: a mixed methods study. AB - AIMS AND OBJECTIVES: To investigate the circumstances of nursing care eight hours before serious adverse events (=SAE's) on medical and surgical nursing units with subsequent in-hospital mortality in order to identify the extent to which these SAE's were potentially preventable. BACKGROUND: The prevention of SAE 's in acute care is coming under increasing scrutiny, while the role nursing care plays in the prevention of acute critical deterioration of patients is unclear. METHODS: Retrospective review of patient records of 63 SAE's in a Belgian teaching hospital where death was the final outcome following a cardiac arrest team call or unplanned ICU admission from an acute care unit. Data from chart reviews were combined with data regarding working conditions on the nursing unit at the time of the events and experts' opinions regarding the preventability of the outcomes. Finally, a pilot survey of staff nurses about their experiences with deteriorating patients and knowledge of vital signs and call criteria was conducted independently of the chart abstractions and case reviews. RESULTS: Experts were almost five times more likely to designate a case as potentially preventable when a cardiac arrest team call was the terminal event and were 40% less likely to designate a case as potentially preventable when more observations were documented in patient records. Survey results revealed that nurses were often unaware that their patients were deteriorating before the crisis. Nurses also reported threshold levels for concern for abnormal vital signs that suggested they would call for assistance relatively late in clinical crises. CONCLUSION: Renewed attention to accurate recording, documentation and interpretation of vital signs in hospital nursing practice appears needed. RELEVANCE TO CLINICAL PRACTICE: Timely detection of deteriorating patients to assist staff to improve their outcomes appears to be jeopardised by a number of practices and factors and merits deeper study. PMID- 22827924 TI - Light and the outcome of the critically ill: an observational cohort study. AB - INTRODUCTION: Light before and during acute illness has been associated with both benefit and harm in animal models and small human studies. Our objective was to determine the associations of light duration (photoperiod) and intensity (insolation) before and during critical illness with hospital mortality in ICU patients. Based on the 'winter immunoenhancement' theory, we tested the hypothesis that a shorter photoperiod before critical illness is associated with improved survival. METHODS: We analyzed data from 11,439 patients admitted to 8 ICUs at the University of Pittsburgh Medical Center between June 30, 1999 and July 31, 2004. Daily photoperiod and insolation prior to and after ICU admission were estimated for each patient by using data provided by the United States Naval Observatory and National Aeronautics and Space Administration and direct measurement of light gradient from outside to bedside for each ICU room. Our primary outcome was hospital mortality. The association between light and risk of death was analyzed using multivariate analyses, adjusting for potential confounders, including severity of illness, case mix, and ICU type. RESULTS: The cohort had an average APACHE III of 52.9 and a hospital mortality of 10.7%. In total, 128 ICU beds were analyzed; 108 (84%) had windows. Pre-illness photoperiod ranged from 259 to 421 hours in the prior month. A shorter photoperiod was associated with a reduced risk of death: for each 1-hour decrease, the adjusted OR was 0.997 (0.994 to 0.999, p = 0.03). In the ICU, there was near complete (99.6%) degradation of natural light from outside to the ICU bed. Thus, light exposure once in the ICU approached zero; the 24-hour insolation was 0.005 +/- 0.003 kWh/m2 with little diurnal variation. There was no association between ICU photoperiod or insolation and mortality. CONCLUSIONS: Consistent with the winter immunoenhancement theory, a shorter photoperiod in the month before critical illness is associated with a reduced risk of death. Once in the ICU, patients are exposed to near negligible natural light despite the presence of windows. Further studies are warranted to determine the underlying mechanisms and whether manipulating light exposure, before or during ICU admission, can enhance survival. PMID- 22827925 TI - Genetic structure and mating system of wild cowpea populations in West Africa. AB - BACKGROUND: Cowpea is a highly inbred crop. It is part of a crop-weed complex, whose origin and dynamics is unknown, which is distributed across the African continent. This study examined outcrossing rates and genetic structures in 35 wild cowpea (Vigna unguiculata ssp. unguiculata var. spontanea) populations from West Africa, using 21 isozyme loci, 9 of them showing polymorphism. RESULTS: Outcrossing rates ranged from 1% to 9.5% (mean 3.4%), which classifies the wild cowpea breeding system as primarily selfing, though rare outcrossing events were detected in each population studied. Furthermore, the analyses of both the genetic structure of populations and the relationships between the wild and domesticated groups suggest possibilities of gene flow that are corroborated by field observations. CONCLUSIONS: As expected in a predominantly inbred breeding system, wild cowpea shows high levels of genetic differentiation and low levels of genetic diversity within populations. Gene flow from domesticated to wild cowpea does occur, although the lack of strong genetic swamping and modified seed morphology in the wild populations suggest that these introgressions should be rare. PMID- 22827926 TI - Validation of Aedes aegypti Aag-2 cells as a model for insect immune studies. AB - BACKGROUND: The understanding of mosquito immune responses can provide valuable tools for development of novel mosquito control strategies. Aiming the study at insect innate immunity, continuous insect cell lines have been established and used as research tools due to the fact that they constitute more homogeneous, sensitive, and reproducible systems than the insects from which they originated. More recently, Aag-2, an Aedes aegypti cell lineage, began to be frequently used as a model for studies of mosquito immunity. Nevertheless, to our knowledge, no study has systematically characterized the responses of Aag-2 cell line against different kinds of pathogens and compared its response to those exhibited by whole mosquitoes. For this reason, in this study we characterized gene expression profiles of the Aag-2 cell line in response to different kinds of immune challenges, such as Gram negative and positive bacteria, fungi and viruses, comparing the obtained results with the ones already described in the literature for whole mosquitoes. METHODS: Aedes aegypti Aag-2 cells were exposed to different immune stimuli (gram-positive and gram negative heat inactivated bacteria, zymosan or Sindbis virus) for 24 hours and the expression of selected marker genes from toll, IMD and Jak/STAT pathways was analyzed by qPCR. Also, cells were incubated with fluorescent latex beads for evaluation of its phagocytosis capacity. RESULTS: Aag-2 cells were stimulated with two concentrations of heat-killed Gram negative (Enterobacter cloacae) or Gram positive (Micrococcus luteus) bacteria, Zymosan or infected with Sindbis virus and the expression of key genes from the main immune related pathways, Toll, IMD and Jak/STAT, were investigated. Our results suggest that Toll and IMD pathways are activated in response to both Gram positive and negative bacteria and Zymosan in Aag-2 cells, displaying an immune profile similar to those described in the literature for whole mosquitoes. The same stimuli were also capable of activating Jak/STAT pathway in Aag-2 cells. Infection with Sindbis virus led to an up regulation of the transcription factor STAT but was not able to induce the expression of any other gene from any of the pathways assayed. We also showed that this cell line is able to phagocytose latex beads in culture. CONCLUSIONS: Our results characterize the expression profile of Aag-2 cells in response to different immune stimuli and demonstrate that this cell lineage is immune competent and closely resembles the response described for whole Ae. aegypti mosquitoes. Hence, our findings support the use of Aag-2 as a tool to comprehend Ae. aegypti immune response both at cellular and humoral levels. PMID- 22827927 TI - Silver nanoparticles administered to chicken affect VEGFA and FGF2 gene expression in breast muscle and heart. AB - Nanoparticles of colloidal silver (AgNano) can influence gene expression. Concerning trials of AgNano application in poultry nutrition, it is useful to reveal whether they affect the expression of genes crucial for bird development. AgNano were administered to broiler chickens as a water solution in two concentrations (10 and 20 ppm). After dissection of the birds, breast muscles and hearts were collected. Gene expression of FGF2 and VEGFA on the mRNA and protein levels were evaluated using quantitative polymerase chain reaction and enzyme linked immunosorbent assay methods. The results for gene expression in the breast muscle revealed changes on the mRNA level (FGF2 was up-regulated, P < 0.05) but not on the protein level. In the heart, 20 ppm of silver nanoparticles in drinking water increased the expression of VEGFA (P < 0.05), at the same time decreasing FGF2 expression both on the transcriptional and translational levels. Changes in the expression of these genes may lead to histological changes, but this needs to be proven using histological and immunohistochemical examination of tissues. In general, we showed that AgNano application in poultry feeding influences the expression of FGF2 and VEGFA genes on the mRNA and protein levels in growing chicken. PMID- 22827928 TI - The opioid placebo analgesia is mediated exclusively through MU-opioid receptor in rat. AB - Placebo analgesia is one of the most robust and best-studied placebo effects. Recent researches suggest that placebo analgesia activated the MU-opioid receptor signalling in the human brain. However, whether other opioid receptors are involved in the placebo analgesia remains unclear. We have previously evoked placebo responses in mice (Guo et al. 2010, 2011) and these mice may serve as a model for investigating placebo analgesia. In the present study, we tried to explore the site of action and types of opioid receptors involved in placebo response. Male Sprague-Dawley rats were trained with 10 mg/kg morphine for 4 d to establish the placebo analgesia model. This placebo analgesia can be blocked by injection of 5 mg/kg dose naloxone or by microinjection with naloxone (1, 3 or 10 MUg/rat) into rostral anterior cingulate cortex (rACC). Then, animals were tested after intra-rACC microinjection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP, a selective MU-opioid receptor antagonist) or naltrindole (NTI, a highly selective delta-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a highly selective kappa-opioid receptor antagonist). Our results showed that CTOP, but not NTI or nor-BNI, could reduce the pain threshold in placebo analgesia rats. It may be concluded that rACC is the key brain region involved in placebo analgesia and the opioid placebo analgesia is mediated exclusively through MU opioid receptor in rat. PMID- 22827929 TI - Regulation of adipose differentiation by fructose and GluT5. AB - Adipose tissue is an important metabolic organ that is crucial for whole-body insulin sensitivity and energy homeostasis. Highly refined fructose intake increases visceral adiposity although the mechanism(s) remain unclear. Differentiation of preadipocytes to mature adipocytes is a highly regulated process that is associated with characteristic sequential changes in adipocyte gene expression. We demonstrate that fructose treatment of murine 3T3-L1 cells incubated in standard differentiation medium increases adipogenesis and adipocyte related gene expression. We further show that the key fructose transporter, GluT5, is expressed in early-stage adipocyte differentiation but is not expressed in mature adipocytes. GluT5 overexpression or knockdown increased and decreased adipocyte differentiation, respectively, and treatment of 3T3-L1 cells with a specific GluT5 inhibitor decreased adipocyte differentiation. Epidymal white adipose tissue was reduced in GluT5-/- mice compared with wild-type mice, and mouse embryonic fibroblasts derived from GluT5-/- mice exhibited impaired adipocyte differentiation. Taken together, these results demonstrate that fructose and GluT5 play an important role in regulating adipose differentiation. PMID- 22827930 TI - Luteinizing hormone/human chorionic gonadotropin-mediated activation of mTORC1 signaling is required for androgen synthesis by theca-interstitial cells. AB - LH triggers the biosynthesis of androgens in the theca-interstitial (T-I) cells of ovary through the activation of a cAMP-dependent pathway. We have previously shown that LH/human chorionic gonadotropin (hCG) activates mammalian target of rapamycin complex 1 (mTORC1) signaling network, leading to cell proliferation. In the present study, we provide evidence that the LH/hCG-mediated activation of the mTORC1 signaling cascade is involved in the regulation of steroidogenic enzymes in androgen biosynthesis. Treatment with LH/hCG increased the expression of downstream targets of mTORC1, ribosomal protein S6 kinase 1, and eukaryotic initiation factor 4E as well as steroidogenic enzymes. LH/hCG-mediated stimulation of the steroidogenic enzyme mRNA was blocked by the mTORC1 inhibitor, rapamycin. This inhibitory effect was selective because rapamycin failed to block hCG-mediated increase in the expression of Star mRNA levels. Furthermore, pharmacological targeting of mTORC1 with rapamycin also blocked LH/hCG- or forskolin-induced expression of cAMP response element-binding protein (CREB) and steroidogenic enzymes (P450 side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase type 1, and 17alpha-hydroxylase/17,20 lyase) but produced no effect on steroidogenic acute regulatory protein levels. These results were further confirmed by demonstrating that the knockdown of mTOR using small interfering RNA selectively abrogated the LH/hCG-induced increase in steroidogenic enzyme expression, without affecting steroidogenic acute regulatory protein expression. LH/hCG-stimulated androgen production was also blocked by rapamycin. Furthermore, the pharmacological inhibition of mTORC1 or ribosomal protein S6 kinase 1 signaling prevented the LH/hCG-induced phosphorylation of CREB. Chromatin immunoprecipitation assays revealed the association of CREB with the proximal promoter of the Cyp17a1 gene in response to hCG, and this association was reduced by rapamycin treatment. Taken together, our findings show for the first time that LH/hCG-mediated activation of androgen biosynthesis is regulated by the mTORC1 signaling pathway in T-I cells. PMID- 22827932 TI - The medicalisation of revolt: a sociological analysis of medical cannabis users. AB - In a qualitative study, we investigated the medical motives of 100 Norwegian cannabis users, none of whom had legal access to medical cannabis. Cannabis was used therapeutically for conditions such as multiple sclerosis, attention deficit hyperactivity disorder and rheumatism, as well as for quality of life conditions such as quality of sleep, relaxation and wellbeing. The borders between medical and recreational cannabis use were blurred. This article identifies strategies of medical cannabis users to gain social acceptance. Several respondents downplayed effects such as intoxication and euphoria. Others used the language of medicine and knowledge of current research in psychopharmacology. Cannabis was contrasted with the potential for abuse of prescription medicines. The medical cannabis movement has had little success in Norway. Medical professionals are unable to accept that users may be more knowledgeable than experts and medical users cannot discard the values of traditional cannabis culture. Calls for medical cannabis use are thus perceived as a gambit in attempts to have cannabis legalised. We argue that, despite having had little effect on health authorities, the medical cannabis movement may be having the unintended effect of medicalising cannabis use and using it as a cure for everyday problems. PMID- 22827933 TI - Promoting vaccinations - an analysis of measures taken by German statutory health insurers. AB - INTRODUCTION: Prophylactic vaccinations play a significant role in health care. As a relatively cost-effective preventive measure they can help to avert transmissible diseases and thus protect not only the vaccinated individuals themselves but also those who have not been vaccinated. In order to achieve this, a high vaccination rate is necessary; for many prophylactic vaccinations this rate is not reached in Germany. In order to counteract this trend the importance of prophylactic vaccinations was upgraded in 2007 within the scope of the reform of the health system. The reimbursement of patients' vaccination fees was made compulsory for the statutory health insurance companies and statutory requirements were imposed on the insurers to ensure a nationwide provision of prophylactic vaccinations for insured persons. The objective of this paper is to evaluate to what extent the health insurance companies promote the increasing of vaccination coverage rate today and what measures are being used to present this topic to the public. METHODS: In order to assess the public presentation of the topic "prophylactic vaccinations" we have examined the websites of 68 statutory health insurance companies. We have assessed the attitude of the companies towards the promotion of participation in vaccination programs by conducting qualitative, structured interviews with representatives of 8 health insurers. RESULTS: Measures to promote vaccinations, such as information, recall offers, projects to educate people or even monetary incentives, are employed relatively extensively by the health insurers and are considered important. However, it became clear that the discussion about prophylactic vaccinations, in particular concerning the costs and benefits thereof, had not been completed yet within the companies. Vaccination-specific data is not collected or evaluated on a regular or even isolated basis. There are no concrete targets concerning specific vaccination rates and incentives are neither evaluated nor compared with one another. CONCLUSIONS: The relatively extensive range of measures used to promote the vaccination rate contrasts with insufficient knowledge about their efficacy and efficiency. There is an urgent requirement for more research here. PMID- 22827931 TI - Screening and managing cannabis use: comparing GP's and nurses' knowledge, beliefs, and behavior. AB - BACKGROUND: General practitioners (GPs) and nurses are ideally placed to address the significant unmet demand for the treatment of cannabis-related problems given the numbers of people who regularly seek their care. The aim of this study was to evaluate differences between GPs and nurses' perceived knowledge, beliefs, and behaviors toward cannabis use and its screening and management. METHODS: This study involved 161 nurses and 503 GPs who completed a survey distributed via conference satchels to delegates of Healthed seminars focused on topics relevant to women and children's health. Differences between GPs and nurses were analyzed using chi(2)- tests and two-sample t-tests, while logistic regression examined predictors of service provision. RESULTS: GPs were more likely than nurses to have engaged in cannabis-related service provision, but also more frequently reported barriers related to time, interest, and having more important issues to address. Nurses reported less knowledge, skills, and role legitimacy. Perceived screening skills predicted screening and referral to alcohol and other drug (AOD) services, while knowing a regular user increased the likelihood of referrals only. CONCLUSIONS: Approaches to increase cannabis-related screening and intervention may be improved by involving nurses, and by leveraging the relationship between nurses and doctors, in primary care. PMID- 22827934 TI - Immunological response in mice bearing LM3 breast tumor undergoing pulchellin treatment. AB - BACKGROUND: Ribosome-inactivating proteins (RIP) have been studied in the search for toxins that could be used as immunotoxins for cancer treatment. Pulchellin, a type 2 RIP, is suggested to induce immune responses that have a role in controlling cancer. METHODS: The percentage of dendritic cells and CD4(+) and CD8(+) T cells in the spleen (flow cytometry), cytokines' release by PECs and splenocytes (ELISA) and nitric oxide production by PECs (Griess assay) were determined from tumor-bearing mice injected intratumorally with 0.1 ml of pulchellin at 0.75 MUg/kg of body weight. Statistical analysis was performed by one-way ANOVA with Tukey's post hoc test. RESULTS: Pulchellin-treated mice showed significant immune system activation, characterized by increased release of IFN gamma and Th2 cytokines (IL-4 and IL-10), while IL-6 and TGF-beta levels were decreased. There was also an increase in macrophage's activation, as denoted by the higher percentage of macrophages expressing adhesion and costimulatory molecules (CD54 and CD80, respectively). CONCLUSIONS: Our results suggest that pulchellin is promising as an adjuvant in breast cancer treatment. PMID- 22827935 TI - Implementation and scientific evaluation of rehabilitative sports groups for prostate cancer patients: study protocol of the ProRehab Study. AB - BACKGROUND: Although treatment regimen have improved in the last few years, prostate cancer patients following a radical prostatectomy still experience severe disease- and treatment-related side effects, including urinary incontinence, erectile dysfunction and psychological issues. Despite high incidence rates and the common adverse effects there is a lack of supportive measures for male patients and specific physical exercise recommendations for prostate cancer patients during rehabilitation or in the aftercare are still missing. METHODS/DESIGN: The ProRehab Project aims to establish rehabilitative sports groups particularly for prostate cancer patients and to evaluate the effects of the offered exercise program. Starting 8-12 weeks after prostatectomy or combination therapy, prostate cancer patients will exercise for 15 months within a patient preference randomized controlled trial. One exercise session will be conducted within a pre-established rehabilitative sports group, while the other will be completed independently. Patients in the control group will not participate in the intervention. The main outcomes of the study include aerobic fitness, quality of life, incontinence and erectile dysfunction. DISCUSSION: By combining science, practice, and public relations the first rehabilitative sports groups for prostate cancer patients in Germany have been set up and thus contribute to the care structure for prostate cancer patients. By offering a 15 month physical exercise intervention that is conducted in supervised group sessions, long-term lifestyle changes and therefore improvements in quality of life in prostate cancer patients can be expected. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004184. PMID- 22827936 TI - Non-contact atomic force microscopy study of hydroxyl groups on the spinel MgAl2O4(100) surface. AB - Atom-resolved non-contact atomic force microscopy (NC-AFM) studies of the magnesium aluminate (MgAl(2)O(4)) surface have revealed that, contrary to expectations, the (100) surface is terminated by an aluminum and oxygen layer. Theoretical studies have suggested that hydrogen plays a strong role in stabilizing this surface through the formation of surface hydroxyl groups, but the previous studies did not discuss in depth the possible H configurations, the diffusion behaviour of hydrogen atoms and how the signature of adsorbed H is reflected in atom-resolved NC-AFM images. In this work, we combine first principles calculations with simulated and experimental NC-AFM images to investigate the role of hydrogen on the MgAl(2)O(4)(100) surface. By means of surface energy calculations based on density functional theory, we show that the presence of hydrogen adsorbed on the surface as hydroxyl groups is strongly predicted by surface stability considerations at all relevant partial pressures of H(2) and O(2). We then address the question of how such adsorbed hydrogen atoms are reflected in simulated NC-AFM images for the most stable surface hydroxyl groups, and compare with experimental atom-resolved NC-AFM data. In the appendices we provide details of the methods used to simulate NC-AFM using first principles methods and a virtual AFM. PMID- 22827937 TI - Karrikins force a rethink of strigolactone mode of action. AB - Strigolactones (SL) and karrikins (KAR) both contain essential butenolide moieties, and both require the F-box protein MAX2 to control seed germination and photomorphogenesis in Arabidopsis thaliana. A new discovery that SL and KAR also require related alpha/beta-hydrolase proteins for such activity suggests that they operate through a similar molecular mechanism. Based on structural similarity, a previously proposed mode of action for SL was also considered for KAR, but recent structure-activity studies suggest that this mechanism may not apply. Here we rationalise these observations into a hypothesis whereby different alpha/beta-hydrolases distinguish SL and KAR by virtue of their non-butenolide moieties and catalyze nucleophilic attack on the butenolide. The products would be different for SL and KAR, and in the case of SL they have no biological activity. The inference is that nucleophilic attack on SL and KAR by alpha/beta hydrolases is required for their bioactivity, but the hydrolysis products are not. PMID- 22827938 TI - Cooperative ethylene receptor signaling. AB - The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses by multiple ethylene receptors has yet to be fully addressed. Nevertheless, the ethylene receptor signal strength can be reflected by degrees in alteration of various ethylene response phenotypes and in expression levels of ethylene-inducible genes. This mini-review highlights studies that have advanced our understanding of cooperative ethylene receptor signaling. PMID- 22827940 TI - Pea DNA helicase 45 promotes salinity stress tolerance in IR64 rice with improved yield. AB - The helicases provide duplex unwinding function in an ATP-dependent manner and thereby play important role in almost all the nucleic acids transaction. Since stress reduces the protein synthesis by affecting the cellular gene expression machinery, so it is evident that molecules involved in nucleic acid processing including translation factors/helicases are likely to be affected. Earlier pea DNA helicase 45 (PDH45), a homolog of translation initiation factor 4A (eIF4A) was reported to play important role in salinity stress tolerance in tobacco and Bangladeshi rice variety Binnatoa. We report here the overexpression of PDH45 gene in the indica rice variety IR64, via Agrobacterium-mediated transformation. Molecular analysis of the transgenics revealed stable integration of the transgene in the T1 generation. Enhanced tolerance to salinity was observed in the plants transformed with PDH45 gene. Better physiological and yield performances including endogenous nutrient contents (N, P, K, Na) of the transgenics under salt treatment were observed as compared with wild type (WT), vector control and antisense transgenics. All these results indicated that the overexpression of PDH45 in the IR64 rice transgenics enable them to perform better with enhanced salinity stress tolerance and improved physiological traits. Based on the homology of PDH45 protein with eIF4A protein we suggest that it may act at the translational level to enhance or stabilize protein synthesis under stress conditions. PMID- 22827939 TI - The tomato yellow leaf curl virus (TYLCV) V2 protein interacts with the host papain-like cysteine protease CYP1. AB - The V2 protein of Tomato yellow leaf curl geminivirus (TYLCV) is an RNA-silencing suppressor that counteracts the innate immune response of the host plant. However, this anti-host defense function of V2 may include targeting of other defensive mechanisms of the plant. Specifically, we show that V2 recognizes and directly binds the tomato CYP1 protein, a member of the family of papain-like cysteine proteases which are involved in plant defense against diverse pathogens. This binding occurred both in vitro and in vivo, within living plant cells. The V2 binding site within mCYP1 was identified in the direct proximity to the papain like cysteine protease active site. PMID- 22827941 TI - Microarray analysis reveals overlapping and specific transcriptional responses to different plant hormones in rice. AB - Hormones exert pleiotropic effects on plant growth and development throughout the life cycle. Many of these effects are mediated at molecular level via altering gene expression. In this study, we investigated the exogenous effect of plant hormones, including auxin, cytokinin, abscisic acid, ethylene, salicylic acid and jasmonic acid, on the transcription of rice genes at whole genome level using microarray. Our analysis identified a total of 4171 genes involved in several biological processes, whose expression was altered significantly in the presence of different hormones. Further, 28% of these genes exhibited overlapping transcriptional responses in the presence of any two hormones, indicating crosstalk among plant hormones. In addition, we identified genes showing only a particular hormone-specific response, which can be used as hormone-specific markers. The results of this study will facilitate further studies in hormone biology in rice. PMID- 22827942 TI - Low concentration of LatB dramatically changes the microtubule organization and the timing of vegetative nucleus/generative cell entrance in tobacco pollen tubes. AB - Low concentration of LatB inhibits not only the actin polymerization, but also induces profound alteration of MT distribution in pollen tubes of Nicotiana tabacum. The short randomly oriented MTs in the apical and subapical regions, became organized as bundles forming subapical rings or basket-like structures, surrounding the apex. Moreover, the depolymerization of AFs in the cortical regions of the apex and subapical region affects the timing of entrance of the vegetative nucleus and generative cell into the pollen tube. PMID- 22827943 TI - The prolific ATL family of RING-H2 ubiquitin ligases. AB - An abundant class of E3 ubiquitin ligases encodes the RING-finger domain. The RING finger binds to the E2 ubiquitin-conjugating enzyme and brings together both the E2 and substrate. It is predicted that 477 RING finger E3 ligases exist in Arabidopsis thaliana. A particular family among them, named Arabidopsis Toxicos en Levadura (ATL), consists of 91 members that contain the RING-H2 variation and a hydrophobic domain located at the N-terminal end. Transmembrane E3 ligases are important in several biological processes. For instance, some transmembrane RING finger E3 ligases are main participants in the endoplasmic reticulum-associated degradation pathway that targets misfolded proteins. Functional analysis of a number of ATLs has shown that some of them regulate distinct pathways in plants. Several ATLs have been shown to participate in defense responses, while others play a role in the regulation of the carbon/nitrogen response during post germinative seedling growth transition, in the regulation of cell death during root development, in endosperm development, or in the transition to flowering under short day conditions. The ATL family has also been instrumental in evolution studies for showing how gene families are expanded in plant genomes. PMID- 22827944 TI - Role of the G-box element in regulation of chlorophyll biosynthesis in Arabidopsis roots. AB - Regulation of chlorophyll metabolism comprises strong transcriptional control together with a range of post-translational mechanisms during chloroplast biogenesis. Recently we reported that chlorophyll biosynthesis in Arabidopsis thaliana roots is regulated by auxin/cytokinin signaling via the combination of two transcription factors, LONG-HYPOCOTYL5 (HY5) and GOLDEN2-LIKE2 (GLK2). In this study, we examined the involvement of cis-elements in the expression of chlorophyll biosynthesis genes. Searches for predicted cis-elements in key chlorophyll biosynthesis genes and their co-expressed genes revealed coexistence of the G-box motif and the CCAATC motif, which may be targeted by HY5 and GLK factors, respectively, in their promoter regions. Deletion of the G-box from the promoter of the CHLH gene encoding the H subunit of Mg-chelatase resulted in the absence of its expression in roots but not in shoots, showing a differing involvement of the G-box in CHLH expression between shoots and roots. Our data suggest that transcription factors and cis-elements participating chlorophyll biosynthesis are substantially changed during organ differentiation, which may be linked to the differentiation of plastids. PMID- 22827945 TI - De novo post-pollen mitosis II tobacco pollen tube transcriptome. AB - In our previous study we applied the Agilent 44K tobacco gene chip to introduce and analyze the tobacco male gametophyte transcriptome in mature pollen and 4h pollen tubes. Here we extended our analysis post-pollen mitosis II (PMII) by including a new data set obtained from more advanced stage of the ongoing progamic phase - pollen tubes cultivated in vitro for 24 h. Pollen mitosis II marks key events in the control of male gametophyte development, the production of two sperm cells. In bicellular species covering cca 70% of angiosperms including Nicotiana tabacum, PMII takes place after pollen germination in growing pollen tube. We showed the stable and even slightly increasing complexity of tobacco male gametophyte transcriptome over long period of progamic phase-24 h of pollen tube growth. We also demonstrated the ongoing transcription activity and specific transcript accumulation in post-PMII pollen tubes cultivated in vitro. In all, we have identified 320 genes (2.2%) that were newly transcribed at least after 4h of pollen tube cultivation in vitro. Further, 699 genes (4.8%) showed over 5-fold increased accumulation after the 24h of cultivation. PMID- 22827946 TI - The function of calreticulin in plant immunity: new discoveries for an old protein. AB - Since its initial discovery as a high affinity Ca ( 2+) -binding protein in the sarcoplasmic reticulum and endoplasmic reticulum (ER), calreticulin (CRT) has been documented to be a multifunctional protein in both animal and plant cells. This protein is well recognized as a Ca ( 2+) -binding molecular chaperone that facilitates the folding of newly synthesized glycoproteins and regulates the Ca ( 2+) homeostasis in the ER lumen. However, functional relevance associated with its localization in other cellular compartments has also been reported. Recent studies suggest that both isoforms of plant CRTs (AtCRT1/2 and AtCRT3) are involved in regulating plant defense against biotrophic pathogens. Here we discuss the cellular functions of CRT and its connection to the emerging functions of AtCRTs in plant immunity. PMID- 22827947 TI - Interfacing protein lysine acetylation and protein phosphorylation: ancient modifications meet on ancient proteins. AB - Recognition that different protein covalent modifications can operate in concert to regulate a single protein has forced us to re-think the relationship between amino acid side chain modifications and protein function. Results presented by Tran et al. 2012 demonstrate the association of a protein phosphatase (PP2A) with a histone/lysine deacetylase (HDA14) on plant microtubules along with a histone/lysine acetyltransferase (ELP3). This finding reveals a regulatory interface between two prevalent covalent protein modifications, protein phosphorylation and acetylation, emphasizing the integrated complexity of post translational protein regulation found in nature. PMID- 22827948 TI - Modulation of ROS production and hormone levels by AHK5 during abiotic and biotic stress signaling. AB - Histidine kinases have been shown to mediate responses to endogenous and exogenous stimuli in organisms such as yeast, bacteria and plants. In the model plant Arabidopsis, histidine kinases have been shown to function in hormone signaling, and abiotic and biotic stress responses. More recently, the least characterized of the Arabidopsis histidine kinases, AHK5, was demonstrated to function in resistance toward the virulent bacterium Pseudomonas syringae pv tomato DC3000 (PstDC3000) and the necrotrophic fungus Botrytis cinerea, and as a negative regulator of tolerance toward salinity. Here, we present data which indicate that AHK5 also impacts on drought stress resistance and on the outcome of an incompatible interaction with avrRpm1-expressing PstDC3000 (PstDC3000 (avrRpm1)). We present a model which proposes a role for reactive oxygen species (ROS) and hormones in integrating abiotic and biotic stress responses via AHK5. PMID- 22827949 TI - PUB13, a U-box/ARM E3 ligase, regulates plant defense, cell death, and flowering time. AB - The ubiquitination pathway is involved in a variety of cellular processes in plant growth, development, and immune responses. However, the function of this pathway in connecting plant development and innate immunity is still largely unknown. Recently, we characterized the U-box/ARM E3 ubiquitin ligase PUB13, which regulates both immune responses and flowering time in Arabidopsis. Here, we show that the rice Spl11 gene can complement the cell death and flowering functions of PUB13 in the pub13 mutant. In addition, HFR1, which functions mainly in photomorphogenesis, was identified as one of the PUB13-interacting proteins through yeast two-hybrid screening and pull-down assays. Because the flowering phenotype of pub13 depends on photoperiod, we propose that PUB13 may regulate HFR1 to fine-tune photomorphogenesis and flowering time in Arabidopsis. PMID- 22827951 TI - Study of oligogalacturonides-triggered nitric oxide (NO) production provokes new questioning about the origin of NO biosynthesis in plants. AB - We investigated the production and function of nitric oxide (NO) in Arabidopsis thaliana leaf discs as well as whole plants elicited by oligogalacturonides (OGs). Using genetic, biochemical and pharmacological approaches, we provided evidence that OGs induced a Nitrate Reductase (NR)-dependent NO production together with an increased NR activity and NR transcripts accumulation. In addition, NO production was sensitive to the mammalian NOS inhibitor L-NAME. Intriguingly, L-NAME impaired OG-induced NR activity and did not further affect the remaining OG-induced NO production in the nia1nia2 mutant. These data suggest that the L-arginine and NR pathways, co-involved in NO production, do not work independently. Taking account these new data, we propose scenarios to explain NO production in response to biotic stress. PMID- 22827950 TI - New insights into an old story: pollen ROS also play a role in hay fever. AB - Reactive oxygen species (ROS) can exhibit negative and benign traits. In plants, ROS levels increase markedly during periods of environmental stress, and defense against pathogen attack. ROS form naturally as a by-product of normal oxygen metabolism, and evenly play an essential role in cell growth. The short ROS lifespan makes them ideal molecules to act in cell signaling, a role they share in both plants and animals. A particular plant organism, the pollen grain, may closely interact with human mucosa and an allergic inflammatory response often results. Pollen grain ROS represent a first, crucial signal which primes and magnifies a cascade of events in the allergic response. PMID- 22827952 TI - CRY1a influences the diurnal transcription of photoreceptor genes in tomato plants after gibberellin treatment. AB - Light is one of the most important environmental signal for plants. Involvement of hormones, such as gibberellic acid, in light regulated development has been known for many years, though the molecular mechanisms remain still largely unknown. To shed light on possible interactions between phyto-hormones and photoperceptive photoreceptors of tomato, in a recent work we investigated the molecular effects of exogenous gibberellin to cryptochrome and phytochrome transcripts in wild type tomato as well as in a mutant genotype with a non functional cryptochrome 1a and in a transgenic line overexpressing cryptochrome 2. Results highlight that following addition of gibberellin, cryptochrome and phytochrome transcription patterns are strongly modified, especially in cryptochrome 1a deficient plants. Our results suggest that cryptochrome mediated light responses can be modulated by gibberellin accumulation level, in tomato plants. PMID- 22827953 TI - Irrepressible, truncated auxin response factors: natural roles and applications in dissecting auxin gene regulation pathways. AB - The molecularly well-characterized auxin signal transduction pathway involves two evolutionarily conserved families interacting through their C-terminal domains III and IV: the Auxin Response Factors (ARFs) and their repressors the Aux/IAAs, to control auxin-responsive genes, among them genes involved in auxin transport. ( 1) (,) ( 2) We have developed a new genetic tool to study ARF function. Using MONOPTEROS (MP)/ARF5, we have generated a truncated version of MP (MPDelta), ( 3) which has lost the target domains for repression by Aux/IAA proteins. Besides exploring genetic interactions between MP and Aux/IAAs, we used this construct to trace MP's role in vascular patterning, a previously characterized auxin dependent process. ( 4) (,) ( 5) Here we summarize examples of naturally occurring truncated ARFs and summarize potential applications of truncated ARFs as analytical tools. PMID- 22827954 TI - Health and vulnerability to poverty in Ghana: evidence from the Ghana Living Standards Survey Round 5. AB - BACKGROUND: An understanding of the complex relationship between health status and welfare is crucial for critical policy interventions. However, the focus of most policies in developing regions has been on current welfare to the neglect of forward-looking welfare analysis. The absence of adequate research in the area of future poverty or vulnerability to poverty has also contributed to the focus on current welfare. The objectives of this study were to estimate vulnerability to poverty among households in Ghana and examine the relationship between health status and vulnerability to poverty. METHOD: The study used cross section data from the Fifth Round of the Ghana Living Standards Survey (GLSS 5) with a nationally representative sample of 8,687 households from all administrative regions in Ghana. A three-step Feasible Generalized Least Squares (FGLS) estimation procedure was employed to estimate vulnerability to poverty and to model the effect of health status on expected future consumption and variations in future consumption. Vulnerability to poverty estimates were also examined against various household characteristics. RESULTS: Using an upper poverty line, the estimates of vulnerability show that about 56% of households in Ghana are vulnerable to poverty in the future and this is higher than the currently observed poverty level of about 29%. Households with ill members were vulnerable to poverty. Moreover, households with poor hygiene conditions were also vulnerable to future poverty. The vulnerability to poverty estimates were, however, sensitive to the poverty line used and varied with household characteristics. CONCLUSION: The results imply that policies directed towards poverty reduction need to take into account the vulnerability of households to future poverty. Also, hygienic conditions and health status of households need not be overlooked in poverty reduction strategies. PMID- 22827956 TI - A patient with Down syndrome with a de novo derivative chromosome 21. AB - Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions. PMID- 22827955 TI - Ventilatory support in critically ill hematology patients with respiratory failure. AB - INTRODUCTION: Hematology patients admitted to the ICU frequently experience respiratory failure and require mechanical ventilation. Noninvasive mechanical ventilation (NIMV) may decrease the risk of intubation, but NIMV failure poses its own risks. METHODS: To establish the impact of ventilatory management and NIMV failure on outcome, data from a prospective, multicenter, observational study were analyzed. All hematology patients admitted to one of the 34 participating ICUs in a 17-month period were followed up. Data on demographics, diagnosis, severity, organ failure, and supportive therapies were recorded. A logistic regression analysis was done to evaluate the risk factors associated with death and NIVM failure. RESULTS: Of 450 patients, 300 required ventilatory support. A diagnosis of congestive heart failure and the initial use of NIMV significantly improved survival, whereas APACHE II score, allogeneic transplantation, and NIMV failure increased the risk of death. The risk factors associated with NIMV success were age, congestive heart failure, and bacteremia. Patients with NIMV failure experienced a more severe respiratory impairment than did those electively intubated. CONCLUSIONS: NIMV improves the outcome of hematology patients with respiratory insufficiency, but NIMV failure may have the opposite effect. A careful selection of patients with rapidly reversible causes of respiratory failure may increase NIMV success. PMID- 22827957 TI - 125I seed irradiation induces up-regulation of the genes associated with apoptosis and cell cycle arrest and inhibits growth of gastric cancer xenografts. AB - BACKGROUND: Iodine 125 (125I) seed irradiation can be used as an important supplementary treatment for unresectable advanced gastric cancer. Here, we aim to comprehensively elucidate the biological effects induced by 125I seed irradiation in human gastric cancer xenograft model by using global expression and DNA methylation analyses. METHODS: The 48 mice bearing NCI-N87 gastric cancer xenografts were randomly separated into 2 groups: sham seeds (O mCi) were implanted into the control group (n = 24); 125 l seeds (0.9 mCi) were implanted into the treatment group (n = 24). The mitotic index and apoptotic index were evaluated by quantitative morphometric analysis of the expression of proliferating cell nuclear antigen (PCNA) and in situ terminal transferase mediated fluorescein deoxy- UTP nick end labeling (TUNEL), respectively. Global gene expression changes induced by 125I seed irradiation were analyzed by using Nimblegen Human gene expression array. DNA methylation profile in the tumors from control group was investigated with methylated DNA immunoprecipitation (MeDIP) and Nimblegen CpG promoter microarrays. The changes in the methylation status of selected genes were further investigated by using MeDIP-PCR. RESULTS: 125I seed irradiation suppresses the growth of gastric cancer xenografts in nude mice. PCNA staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the 125I-induced tumor suppression in nude mouse model. Gene expression profiles revealed that the expression levels of several hundred genes, many of which are associated with apoptosis or cell cycle arrest, including BMF, MAPK8, BNIP3, RFWD3, CDKN2B and WNT9A, were upregulated following 125I seed irradiation. Furthermore, the up regulation of some of these genes, such as BNIP3 and WNT9A, was found to be associated with irradiation-induced DNA demethylation. CONCLUSIONS: This study revealed that 125I seed irradiation could significantly induce the up-regulation of apoptosis- and cell cycle-related genes in human gastric cancer xenografts. And some of the up-regulation might be attributed to 125I-irradiation induced demethylation in gene promoter regions. Collectively, these findings provided evidence for the efficacy of this modality for the treatment of gastric cancer. PMID- 22827958 TI - Simultaneous detection and differentiation of four closely related sweet potato potyviruses by a multiplex one-step RT-PCR. AB - Four closely related potyviruses, Sweet potato feathery mottle virus (SPFMV), Sweet potato virus C (SPVC), Sweet potato virus G (SPVG) and/or Sweet potato virus 2 (SPV2), are involved in sweet potato virus disease complexes worldwide. Identification and detection of these viruses are complicated by high similarity among their genomic sequences, frequent occurrence as mixed infections and low titer in many sweet potato cultivars. A one-tube multiplex reverse transcription PCR (mRT-PCR) assay was developed for simultaneous detection and differentiation of SPFMV, SPVC, SPVG and SPV2. Four specific forward primers unique to each virus and one reverse primer based on the region conserved in all four viruses were selected and used in the assay. The mRT-PCR assay was optimized for primer concentration and cycling conditions. It was tested using sweet potato plants infected naturally with one to four target viruses and then evaluated using field samples collected from southwestern China. The mRT-PCR assay is reliable and sensitive as a simple, rapid and cost-effective method to detect these pathogens in sweet potato. This assay will be useful to quarantine and certification programs and virus surveys when large numbers of samples are tested. PMID- 22827959 TI - The cobas p 630 instrument: a dedicated pre-analytic solution to optimize COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) system workflow and turn-around-time. AB - The cobas p 630, a fully automated pre-analytical instrument for primary tube handling recently introduced to complete the Cobas((r)) TaqMan systems portfolio, was evaluated in conjunction with: the COBAS((r)) AmpliPrep/COBAS((r)) TaqMan HBV Test, v2.0, COBAS((r)) AmpliPrep/COBAS((r)) TaqMan HCV Test, v1.0 and COBAS((r)) AmpliPrep/COBAS((r)) TaqMan HIV Test, v2.0. The instrument performance in transferring samples from primary to secondary tubes, its impact in improving COBAS((r)) AmpliPrep/COBAS((r)) TaqMan workflow and hands-on reduction and the risk of possible cross-contamination were assessed. Samples from 42 HBsAg positive, 42 HCV and 42 HIV antibody (Ab) positive patients as well as 21 healthy blood donors were processed with or without automated primary tubes. HIV, HCV and HBsAg positive samples showed a correlation index of 0.999, 0.987 and of 0.994, respectively. To assess for cross-contamination, high titer HBV DNA positive samples, HCV RNA and HIV RNA positive samples were distributed in the cobas p 630 in alternate tube positions, adjacent to negative control samples within the same rack. None of the healthy donor samples showed any reactivity. Based on these results, the cobas p 630 can improve workflow and sample tracing in laboratories performing molecular tests, and reduce turnaround time, errors, and risks. PMID- 22827960 TI - Computed tomography-guided permanent brachytherapy for locoregional recurrent gastric cancer. AB - BACKGROUND: Locoregional recurrence is the typical pattern of recurrence in gastric cancer, and cannot be removed by surgery in most of the patients. We aimed to evaluate the feasibility and efficacy of computed tomography (CT)-guided brachytherapy for patients with locoregional recurrent gastric cancer. MATERIALS AND METHODS: We reviewed the case histories of 28 patients with locoregional recurrent gastric cancer that were selected for CT- guided brachytherapy by a multidisciplinary team. The clinical data of the patients including patient characteristics, treatment parameters, short-term effects, and survival data were collected and analyzed. RESULTS: 15-75 125I seeds were implanted into each patient to produce a minimal peripheral dose (MPD) 100-160 Gy. Median day 0 dosimetry was significant for the following: V100 (the volume treated with the prescription dose) 95.8% (90.2-120.5%) and D90 (prescription dose received by at least 90% of the volume) 105.2% (98.0-124.6%) of prescription dose. No serious complications occurred during the study. Two months after brachytherapy, complete response, partial response and progressive disease were observed in 50.0%, 28.6% and 21.4% of patients, respectively. The median survival time was 22.0 +/- 5.2 months, and the 1, 2,and 3-year survival rate was 89 +/- 6%, 52 +/- 10% and 11 +/ 7%, respectively. A univariate analysis showed that the tumor size was a significant predictor of overall survival (P = 0.034). Patients with tumors <3 cm had relatively higher complete response rate (66.7%), compared to those with tumors >3 cm (30.8%). The PTV (planning target volume) smaller than 45 cm3 was significantly correlated with achieving complete tumor eradication in the treated region (P = 0.020). CONCLUSIONS: For selected patients with limited locoregional recurrent gastric cancer, CT-guided brachytherapy using 125I seeds implantation can provide a high local control rate, with minimal trauma. PMID- 22827961 TI - Serum levels of pigment epithelium-derived factor, a novel marker of insulin resistance, are independently associated with fasting apolipoprotein B48 levels in humans. AB - OBJECTIVES: Fasting apolipoprotein B48 (apoB48) levels are associated with postprandial hyperlipidemia and carotid artery intima-media thickness (IMT), one of the markers of metabolic derangements and atherosclerosis, respectively. However, it remains unknown whether fasting serum levels of apoB48 are independently correlated with insulin resistance and vascular inflammation in humans. DESIGN AND METHODS: The study involved 315 consecutive outpatients in our hospital (218 males and 97 females) with a mean age of 62.0 +/- 9.2. We examined which anthropometric, metabolic and inflammatory variables, including serum levels of pigment epithelium-derived factor (PEDF), a novel marker of insulin resistance were independently associated with fasting apoB48. Moreover, we investigated whether fasting apoB48 levels were correlated with atherosclerotic plaque inflammation evaluated by [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Carotid [(18)F]-FDG uptake, an index of vascular inflammation within the atherosclerotic plaques, was measured as blood-normalized standardized uptake value, known as the target-to-background ratio (TBR). RESULTS: Mean serum levels of apoB48, PEDF, carotid IMT and TBR values were 2.77 +/- 0.21 MUg/mL, 13.45 +/- 1.03 MUg/mL, 0.71 +/- 0.15 mm, and 1.43 +/- 0.21, respectively. Univariate analysis revealed that apoB48 levels were weakly, but not significantly associated with TBR (p=0.057). In multiple stepwise regression analysis, triglycerides (p<0.001), male (p=0.039), age (inversely, p=0.010), uric acid (p=0.007), medication for diabetes (p=0.029), and PEDF (p=0.049) were independently correlated to fasting apoB48 levels (R(2)=0.371). CONCLUSIONS: The present study reveals that serum levels of PEDF are independently associated with fasting apoB48 levels, suggesting that PEDF level is a novel biomarker that could reflect postprandial hyperlipidemia in humans. PMID- 22827962 TI - Convergence of adipocyte hypertrophy, telomere shortening and hypoadiponectinemia in obese subjects and in patients with type 2 diabetes. AB - OBJECTIVE: Although telomere shortening has been linked with type 2 diabetes and most variables of adiposity, a shortcoming of such studies is the measurement of telomere length in leukocytes. Therefore, we tested the association among adipocyte cell size, telomere length (both subcutaneous and visceral adipose tissue) and systemic levels of adiponectin in obese subjects and patients with type 2 diabetes compared to control subjects. METHODS: Human subcutaneous and visceral adipose tissues were obtained from the subjects who have undergone bariatric surgery or other abdominal surgeries. The study groups comprised: i) control subjects, ii) type 2 diabetes patients, iii) obese subjects without diabetes and iv) obese subjects with diabetes. Adipocyte cell size was measured by histological staining. Adiponectin levels were measured by ELISA. Telomere length was determined by Real-time PCR and lipid peroxidation was assessed by fluorimetry. RESULTS: Compared to control subjects, adipocyte size (both subcutaneous and visceral) from obese, diabetic and obese-diabetic subjects was significantly larger [p<0.001]. Individuals with adipose hypertrophy also exhibited shortened telomeres and hypoadiponectinemia. Pearson correlation analysis revealed that both visceral and subcutaneous fat cell size showed a positive correlation with FBS, HbA1c, HOMA-IR, LDL, total cholesterol, triglycerides and negatively correlated with HDL and adiponectin. Regression analysis revealed that the association between shortened telomeres and hypoadiponectinemia was lost when adjusted for adipocyte cell size. CONCLUSION: Adipocyte hypertrophy appears to be strongly associated with shortened telomeres, hypoadiponectinemia and poor glycemic and lipid control. Interestingly, these molecular alterations seen in lean diabetics reflect a state of 'metabolic obesity'. PMID- 22827963 TI - Adiponectin plasma levels decrease after surgery in pediatric patients with congenital heart disease. AB - OBJECTIVE: Adiponectin is a protein secreted by adipose tissue and involved in inflammatory process as well as in metabolic regulation. The aim of this study was to examine the response of plasma adiponectin to cardiac surgery in children with congenital defects to determine whether its measurement is associated to the response to injury. DESIGN AND METHODS: Twenty-five pediatric patients undergoing heart surgery for correction of congenital defects were studied. Adiponectin plasma levels, obtained pre- and three times postoperatively, were determined by dedicated ELISA. Brain natriuretic peptide (BNP) plasma levels were also determined. RESULTS: Adiponectin levels are highest in the first month of life (p=0.004 newborns vs. children) with a progressive fall in the next few years. After surgery, adiponectin increased slowly over a 1-month period, following an initial decrease in the first 3 days. CONCLUSIONS: Adiponectin could be involved in the acute response to injury although further investigation into the relationship between adiponectin, glucose regulation and inflammatory process is necessary to examine the issue of the adiponectin decrease after surgery from a more integrated prospective. PMID- 22827964 TI - Diurnal-and sex-related difference of metallothionein expression in mice. AB - BACKGROUND: Metallothionein (MT) is a small, cysteine-rich, metal-binding protein that plays an important role in protecting against toxicity of heavy metal and chemicals. This study was aimed to define diurnal and sex variation of MT in mice. METHODS: Adult mice were maintained in light- and temperature-controlled facilities for 2 weeks with light on at 8:00 and light off at 20:00. The blood, liver, and kidneys were collected every 4 h during the 24 h period. Total RNA was isolated, purified, and subjected to real-time RT-PCR analysis and MT protein was determined by western blot and the Cd/hemoglobin assay. RESULTS: The diurnal variations in mRNA levels of MT-1 and MT-2in liver were dramatic, up to a 40 foldpeak/trough ratio. MT mRNA levels in kidneys and blood also showed diurnal variation, up to 5-fold peak/trough ratio. The diurnal variation of MT mRNAs resembled the clock gene albumin site D-binding protein (Dbp), and was anti-phase to the clock gene Brain and Muscle ARNT-like Protein 1 (Bmal1) in liver and kidneys. The peaks of MT mRNA levels were higher in females than in males. Hepatic MT protein followed a similar pattern, with about a 3-fold difference. CONCLUSION: MT mRNA levels and protein showed diurnal- and sex-variation in liver, kidney, and blood of mice, which could impact the body defense against toxic stimuli. PMID- 22827965 TI - A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex. AB - The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D(5)R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D(5)R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D1 receptor but not the D(5)R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D(5)R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK 3beta. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression. PMID- 22827966 TI - Cold-acclimation limits low temperature induced photoinhibition by promoting a higher photochemical quantum yield and a more effective PSII restoration in darkness in the Antarctic rather than the Andean ecotype of Colobanthus quitensis Kunt Bartl (Cariophyllaceae). AB - BACKGROUND: Ecotypes of Colobanthus quitensis Kunt Bartl (Cariophyllaceae) from Andes Mountains and Maritime Antarctic grow under contrasting photoinhibitory conditions, reaching differential cold tolerance upon cold acclimation. Photoinhibition depends on the extent of photodamage and recovery capability. We propose that cold acclimation increases resistance to low-temperature-induced photoinhibition, limiting photodamage and promoting recovery under cold. Therefore, the Antarctic ecotype (cold hardiest) should be less photoinhibited and have better recovery from low-temperature-induced photoinhibition than the Andean ecotype. Both ecotypes were exposed to cold induced photoinhibitory treatment (PhT). Photoinhibition and recovery of photosystem II (PSII) was followed by fluorescence, CO2 exchange, and immunoblotting analyses. RESULTS: The same reduction (25%) in maximum PSII efficiency (Fv/Fm) was observed in both cold acclimated (CA) and non-acclimated (NA) plants under PhT. A full recovery was observed in CA plants of both ecotypes under dark conditions, but CA Antarctic plants recover faster than the Andean ecotype.Under PhT, CA plants maintain their quantum yield of PSII, while NA plants reduced it strongly (50% and 73% for Andean and Antarctic plants respectively). Cold acclimation induced the maintenance of PsaA and Cyt b6/f and reduced a 41% the excitation pressure in Antarctic plants, exhibiting the lowest level under PhT. xCold acclimation decreased significantly NPQs in both ecotypes, and reduced chlorophylls and D1 degradation in Andean plants under PhT.NA and CA plants were able to fully restore their normal photosynthesis, while CA Antarctic plants reached 50% higher photosynthetic rates after recovery, which was associated to electron fluxes maintenance under photoinhibitory conditions. CONCLUSIONS: Cold acclimation has a greater importance on the recovery process than on limiting photodamage. Cold acclimation determined the kinetic and extent of recovery process under darkness in both C. quitensis ecotypes. The greater recovery of PSII at low temperature in the Antarctic ecotype was related with its ability to maintain PsaA, Cyt b6/f and D1 protein after photoinhibitory conditions. This is probably due to either a higher stability of these polypeptides or to the maintenance of their turnover upon cold acclimation. In both cases, it is associated to the maintenance of electron drainage from the intersystem pool, which maintains QA more oxidized and may allow the synthesis of ATP and NADPH necessaries for the regeneration of ribulose 1,5-bisphosphate in the Calvin Cycle. This could be a key factor for C. quitensis success under the harsh conditions and the short growing period in the Maritime Antarctic. PMID- 22827967 TI - Costing of physical activity programmes in primary prevention: a review of the literature. AB - This literature review aims to analyse the costing methodology in economic analyses of primary preventive physical activity programmes. It demonstrates the usability of a recently published theoretical framework in practice, and may serve as a guide for future economic evaluation studies and for decision making.A comprehensive literature search was conducted to identify all relevant studies published before December 2009. All studies were analysed regarding their key economic findings and their costing methodology.In summary, 18 international economic analyses of primary preventive physical activity programmes were identified. Many of these studies conclude that the investigated intervention provides good value for money compared with alternatives (no intervention, usual care or different programme) or is even cost-saving. Although most studies did provide a description of the cost of the intervention programme, methodological details were often not displayed, and savings resulting from the health effects of the intervention were not always included sufficiently.This review shows the different costing methodologies used in the current health economic literature and compares them with a theoretical framework. The high variability regarding the costs assessment and the lack of transparency concerning the methods limits the comparability of the results, which points out the need for a handy minimal dataset of cost assessment. PMID- 22827968 TI - Effectiveness of interventions for hypertension care in the community--a meta analysis of controlled studies in China. AB - BACKGROUND: Hypertension is a serious public health problem in China and in other developing countries. Our aim is to conduct a systematic review of studies on the effectiveness of community interventions for hypertension management in China. METHODS: China National Knowledge Infrastructure, PubMed, and references of retrieved articles were searched to identify randomised or quasi-randomised controlled studies that evaluated community hypertension care in mainland China. One reviewer extracted and a second reviewer checked data from the included studies. RESULTS: We included 94 studies, 93 of which were in Chinese language, that evaluated the following interventions: health education, improved monitoring, family-support, self-management, healthcare management changes and training of providers. The study quality was generally poor, with high risk of biased outcome reporting and significant heterogeneity between studies. When reported, the vast majority of the included studies reported statistically significantly improved outcomes in the intervention group. By assuming zero treatment effects for missing outcomes, the weighted reduction in the intervention group was 6.9 (95% CI: 4.9 to 8.9) mm Hg for systolic BP, and 3.8 (95% CI: 2.6 to 5.0) mm Hg for diastolic BP. Exploratory subgroup analyses found no significant differences between different interventions. CONCLUSIONS: After taking account of possible reporting biases, a wide range of community interventions for hypertension care remain effective. The findings have implications for China and other low and middle income countries facing similar challenges. Because of significant heterogeneity and high risk of bias in the available studies, further well designed studies should be conducted in China to provide high quality evidence to inform policy decisions on hypertension control. PMID- 22827970 TI - MRI findings of intracranial malformations in a case with Fraser syndrome. PMID- 22827969 TI - Early cessation of breastfeeding amongst women in South Africa: an area needing urgent attention to improve child health. AB - BACKGROUND: Breastfeeding is a critical component of interventions to reduce child mortality. Exclusive breastfeeding practice is extremely low in South Africa and there has been no improvement in this over the past ten years largely due to fears of HIV transmission. Early cessation of breastfeeding has been found to have negative effects on child morbidity and survival in several studies in Africa. This paper reports on determinants of early breastfeeding cessation among women in South Africa. METHODS: This is a sub group analysis of a community-based cluster-randomized trial (PROMISE EBF) promoting exclusive breastfeeding in three South African sites (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal) between 2006 and 2008 (ClinicalTrials.gov no: NCT00397150). Infant feeding recall of 22 food and fluid items was collected at 3, 6, 12 and 24 weeks postpartum. Women's experiences of breast health problems were also collected at the same time points. 999 women who ever breastfed were included in the analysis. Univariable and multivariable logistic regression analysis adjusting for site, arm and cluster, was performed to determine predictors of stopping breastfeeding by 12 weeks postpartum. RESULTS: By 12 weeks postpartum, 20% of HIV-negative women and 40% of HIV-positive women had stopped all breastfeeding. About a third of women introduced other fluids, most commonly formula milk, within the first 3 days after birth. Antenatal intention not to breastfeed and being undecided about how to feed were most strongly associated with stopping breastfeeding by 12 weeks (Adjusted odds ratio, AOR 5.6, 95% CI 3.4 - 9.5 and AOR 4.1, 95% CI 1.6 - 10.8, respectively). Also important was self reported breast health problems associated with a 3-fold risk of stopping breastfeeding (AOR 3.1, 95%CI 1.7 - 5.7) and the mother having her own income doubled the risk of stopping breastfeeding (AOR 1.9, 95% CI 1.3 - 2.8). CONCLUSION: Early cessation of breastfeeding is common amongst both HIV-negative and positive women in South Africa. There is an urgent need to improve antenatal breastfeeding counselling taking into account the challenges faced by working women as well as early postnatal lactation support to prevent breast health problems. PMID- 22827971 TI - Economic burden of osteoporotic fractures in Austria. AB - OBJECTIVE: Osteoporotic fractures impose a huge economic burden on society. Though several cost of illness studies from other countries exist, no equivalent study has been conducted in Austria. Our study aims at assessing costs resulting from osteoporotic fractures in Austria in the year 2008 from a societal perspective. METHODS: We took both direct and indirect costs into consideration. Direct costs encompass medical costs such as expenses for pharmaceuticals, inpatient and outpatient medical care costs, as well as other medical services (e.g., occupational therapies). Non-medical direct costs include transportation costs and medical devices (e.g., wheel chairs or crutches). Indirect costs refer to costs of productivity losses due to absence of work. Moreover, we included costs for early retirement and opportunity costs of informal care provided by family members. For our analysis, we combined data of official statistics, expert estimates as well as unique patient surveys that are currently conducted in the course of an international osteoporotic fracture study in Austria. RESULTS: For the year 2008, the total annual financial burden incurred by osteoporotic fractures in Austria amounted to approx. ?685.2 million, the largest fraction of which was due to the opportunity cost of family care (30.2%), followed by costs for hospitalization (26.6%). CONCLUSIONS: The financial burden of osteoporotic fractures in Austria is substantial. Our findings may have implications for future economic analyses, and also support health care authorities in their decision making. PMID- 22827972 TI - Simple method of paraphimosis reduction revisited: point of technique and review of the literature. AB - Paraphimosis is a urologic emergency that has the potential for serious penile injury, including gangrene and tissue necrosis, if left unattended for a period of time. Multiple different techniques for reduction of paraphimosis have been proposed. We present a novel approach to paraphimosis reduction that utilizes CoFlex((r)), a flexible self-adhering bandage. We also present a detailed review of the literature of conservative management options for paraphimosis. PMID- 22827974 TI - Longitudinal change in telomere length and the chronic stress response in a randomized pilot biobehavioral clinical study: implications for cancer prevention. AB - Shortened telomere length is associated with increased cancer incidence and mortality. Populations experiencing chronic stress have accelerated telomere shortening. In this exploratory study, we examined associations between longitudinal changes in patient reported outcomes (PRO) of psychologic distress and peripheral blood mononuclear cell (PBMC) telomere length to test the hypothesis that modulation of the chronic stress response would also modulate telomere dynamics. Archived PBMC specimens (N = 22) were analyzed from a completed and reported randomized, longitudinal trial that showed a psychosocial telephone counseling intervention improved quality of life (QOL) and modulated stress-associated biomarkers in cervical cancer survivors. PROs and biospecimens were collected at baseline and 4 months postenrollment. Telomere length of archived PBMCs was evaluated using the flow-FISH assay. Longitudinal changes in psychologic distress, measured by the Brief Symptom Inventory-18, were significantly associated with increased telomere length within the CD14(+) (monocyte) population (r = -0.46, P = 0.043); a similar trend was observed for the CD14(-) population. Longitudinal changes in telomere length of the CD14(-) subset, primarily T lymphocytes, were associated with longitudinal increases in the naive T-cell population (r = 0.49, P = 0.052). Alterations in the chronic stress response were associated with modulation of telomere length in PBMCs, with evidence for mobilization of "younger" cells from progenitor populations. These data provide preliminary support for the (i) capacity to modulate the chronic stress response and the associated accelerated telomere shortening, (ii) inclusion of telomere length in the biobehavioral paradigm, and (iii) potential link between the chronic stress response and biologic mechanisms responsible for genomic integrity and carcinogenesis. PMID- 22827975 TI - An EMILIN1-negative microenvironment promotes tumor cell proliferation and lymph node invasion. AB - The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1(-/-) mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(alpha)anthracene/12-O-tetradecanoylphorbol 13-acetate (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1(-/-) mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2. In these tumors, PTEN expression was lower. Emilin1(-/-) mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors were also increased in Emilin1(-/-) mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype. PMID- 22827976 TI - Advancing the education mission. PMID- 22827973 TI - Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer. AB - Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade >=II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. PMID- 22827977 TI - Communication skills training: a United kingdom perspective. PMID- 22827979 TI - In support of residency training at an academic veterans hospital. PMID- 22827980 TI - Continuing medical education and maintenance of licensure. PMID- 22827981 TI - The urgent need for courses in medical and scientific English. PMID- 22827982 TI - Commentary: the modesto story: back to the future? AB - In this issue of Academic Medicine, Broderick and Nocella describe the creative use of an educational consortium model to bring community providers together to solve the fiscal crisis faced by the local family medicine residency program, which was sponsored by a single-program sponsoring (hospital) institution. The authors of this commentary explore the specific adaptation of the educational consortium model to the previously single-program-sponsor setting, provide current numbers of accredited residency programs sponsored by educational consortia and other institutions, and speculate on the consortium model's potential to enhance community engagement and support for graduate medical education (GME) in the various settings in which GME is conducted in the United States. PMID- 22827983 TI - Commentary: getting to the next phase in medical education--a role for the vice chair for education. AB - The author argues that a particular kind of departmental leadership is needed lest medical education become hostage both to distant management through regulatory metrics (which can displace local, institutional creativity) and to the financial pressures within the institution. Departmental chairs themselves have often been seen as barriers to successful integration and redesign of medical school curricula. The vice-chair for education is a critical figure in achieving this new kind of leadership.The author describes three forms of curriculum planning and management: phase 1, where the department chair makes the decisions; phase 2, dominated by regulation from above (in part a reaction to problems with the phase 1 approach); and phase 3, the author's vision of an approach in which decisions occur within departments but with an awareness of the institution as a collaborative system, and grounded in educational theory and research. The vice-chair for education would have a key role, carrying out interdepartmental planning and assessment for the chairs, who would provide them the needed time, training (in leadership and in educational theory and practice), support (from professional educators, with advanced degrees in education), and routes to academic advancement.Responding effectively to a complex and changing environment requires senior leaders at the middle-management level (such as vice chairs for education) who are well trained in both the content of their specialties and also in interpersonal and collaborative skills, and who have the desire to reach a common future. PMID- 22827985 TI - Commentary: narrative lessons from a Nigerian novelist: implications for medical education and care. AB - In her TED Talk entitled "The danger of a single story," Nigerian novelist Chimamanda Adichie shares stories about her life that illustrate the natural human tendency to interpret the lives of others in the context of what she describes as narrowly constructed and often stereotypical "single stories." These single-story views often portray others as wholly different from those constructing the stories, thereby diminishing the possibilities for genuine human connection. Referencing Adichie's talk, the author describes the narrative dissonance that so often distances patients from their physicians. He illustrates the dangers to patients that can result from single-story caregiving by physicians, sharing an example from his own experience in which unnecessary harm came to his patient because of his own single-story thinking. The author argues that these single-story dangers must be openly and consciously addressed in the training of doctors to counteract the tendency for their clinical and educational experiences to inculcate single stories by which physicians come to interpret their patients. He offers suggestions as to why single-story thinking arises in clinical practice and how to mitigate these forces in medical education. The author concludes by contending that the education of physicians, and caring for the sick, should be aimed at preserving the dignity of those being served, and he argues for an "equal humanity" model of the patient-physician relationship that engages patients in all dimensions of their multiple stories. PMID- 22827984 TI - Commentary: grading: what is it good for? AB - Grading students is a necessary but challenging activity. In this commentary, the authors respond to the compelling national data about clerkship grading in U.S. medical schools presented by Alexander and colleagues. They present perspectives and cautions for how the medical education community might perceive these findings and examine how the community can act to address them. The authors discuss several aspects of normative versus criterion-based grading, reliability, and educational theory to provide context for the results reported by Alexander and colleagues. To address variability among and within schools with regard to grading systems and terminology, the authors argue for more credible and transparent interpretation of what grades mean rather than inflexible regulation of grade distributions. PMID- 22827987 TI - Not only an introduction but also a reminder. PMID- 22827988 TI - Medicine and the arts. The practice: the scarlet letter [excerpt] by Nathaniel Hawthorne. Commentary. PMID- 22827990 TI - Mistake noted. PMID- 22827991 TI - Perspective: clinical communication education in the United Kingdom: some fresh insights. AB - Clinical communication education is now part of the core curriculum of every medical school in the United Kingdom and the United States. It has emerged over 30 years because of various societal, political, and policy drivers and is supported by an impressive evidence base.For a variety of reasons, however, clinical communication has become separated from other parts of medical education and tends to be positioned in the early years of the curriculum, when students have limited experience of being in the clinical workplace and working with patients. The teachers of clinical communication, whether medical-school-based or clinically based, may not share learning goals for the subject and this may, therefore, provide a disintegrated learning experience for students.Clinical communication teachers need to inject fresh thinking into the teaching and learning of the subject to unite it with clinical practice in the authentic clinical workplace. Engaging with theories of workplace learning, which aim to overcome the theory/practice gap in vocational education, may be the way forward. The author suggests various ways that this might be achieved-for example, by situating clinical communication education throughout the whole undergraduate curriculum, by integrating the topic of clinical communication with other areas of medical education, by developing coteaching and curriculum design partnerships between medical school and clinical workplace, and by developing a greater range of postgraduate education that offers opportunities for professional development in clinical communication for qualified doctors that is complementary with what is taught in undergraduate education. PMID- 22827992 TI - Humanities mini-course curricula for midcareer health professionals at the Penn State Milton S. Hershey Medical Center. AB - The field of medical humanities has traditionally focused on medical students and, more recently, on premedical undergraduates. Comparatively little formal humanities pedagogy has been dedicated to midcareer health professionals. To address this lack, the Department of Humanities at the Pennsylvania State University College of Medicine and the Milton S. Hershey Medical Center designed eight annual humanities mini-courses for faculty and staff throughout the college and medical center.These mini-courses fell into four categories: reading, reflection, and discussion; creative expression; technology; and ethics. They were geared toward midcareer health professionals who were seeking new intellectual and creative stimulation and variety in daily routine. They also provided humanities faculty the opportunity to devote attention to topics that capitalize on their professional training and that interest them personally.Participants indicated a high degree of satisfaction with the mini courses for four principal reasons: (1) learning the tools and methodologies of a new discipline or domain other than biomedicine, (2) using their minds and training in uncustomary ways, (3) forming new alliances with colleagues (which served to lessen the sense of professional isolation), and (4) enjoying a respite from the stressful flow of the workday. Humanities faculty facilitators provided more mixed responses but agreed that conducting the mini-courses had been a positive overall experience.Although this article provides a foundational framework for the development of a humanities mini-course series, the authors encourage others to replicate these curricula in other medical settings as an important step toward a robust pedagogy designed for midcareer health care professionals. PMID- 22827993 TI - AM last page. Alton Ochsner, MD. PMID- 22827994 TI - Metformin attenuates ventilator-induced lung injury. AB - INTRODUCTION: Diabetic patients may develop acute lung injury less often than non diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury. METHODS: Twenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ~17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ~7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF. RESULTS: High-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation. CONCLUSIONS: Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model. PMID- 22827995 TI - Notch and the survival of regulatory T cells: location is everything! AB - Signaling through the T cell receptor induces T lymphocytes to divide, differentiate, and perform numerous effector functions. Once activated, effector T cells are exquisitely sensitive to changes in available cytokines, particularly the survival cytokine interleukin-2 (IL-2). Removal of IL-2 rapidly initiates apoptosis in response to cytokine withdrawal. In contrast to effector T cells, regulatory T cells (T(regs)) are resistant to apoptosis induced by cytokine withdrawal. A study exploring the differences between these two T cell subsets reveals a role for Notch1 in protecting T(regs) from apoptosis. Protection from apoptosis induced by cytokine withdrawal correlated with Notch1 localization in the cytosol of T(regs) and its association with phosphatidylinositol 3-kinase and Rictor, a component of the mammalian target of rapamycin complex. Notch1 localization in the nucleus in effector T cells, on the other hand, was correlated with susceptibility to apoptosis induced by cytokine withdrawal. This study highlights how Notch1 can deliver opposing signals in different cellular contexts and suggests that localization of Notch1 can have a substantial influence on life-and-death decisions in T lymphocytes. PMID- 22827997 TI - Distinct spatial and molecular features of notch pathway assembly in regulatory T cells. AB - Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor-dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (T(regs)) in vitro and in vivo and was compromised by T cell-specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1( /-) T(regs) from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin complex 2 (mTORC2) for this cell survival function. Biochemical and imaging approaches revealed a membrane-proximal complex containing NICD and the mTORC2 component Rictor, and this complex was stabilized by specific interactions with the Notch ligand Delta-like-1 and mediated the survival of T(regs). Together, our evidence for the spatial control of Notch and the crosstalk of Notch signaling with other pathways reveals coupling between the localization of Notch and diverse intracellular signaling pathways. PMID- 22827996 TI - p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice. AB - Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to protect mice from myocardial injury after whole-heart irradiation. Mice with an endothelial cell-specific deletion of p53 succumbed to heart failure after whole-heart irradiation as a result of myocardial necrosis, systolic dysfunction, and cardiac hypertrophy. Moreover, the onset of cardiac dysfunction was preceded by alterations in myocardial vascular permeability and density, which resulted in cardiac ischemia and myocardial hypoxia. Mechanistic studies with primary cardiac endothelial cells irradiated in vitro indicated that p53 signaling caused mitotic arrest and protected cardiac endothelial cells from cell death resulting from abnormal mitosis or mitotic catastrophe. Furthermore, mice lacking the cyclin-dependent kinase inhibitor p21, which is a transcriptional target of p53, were also sensitized to myocardial injury after whole-heart irradiation. Together, our results demonstrate that the p53-p21 axis functions to prevent radiation-induced myocardial injury in mice. PMID- 22827998 TI - Screening for foot problems in children: is this practice justifiable? AB - Podiatry screening of children is a common practice, which occurs largely without adequate data to support the need for such activity. Such programs may be either formalised, or more ad hoc in nature, depending upon the use of guidelines or existing models. Although often not used, the well-established criteria for assessing the merits of screening programs can greatly increase the understanding as to whether such practices are actually worthwhile. This review examines the purpose of community health screening in the Australian context, as occurs for tuberculosis, breast, cervical and prostate cancers, and then examines podiatry screening practices for children with reference to the criteria of the World Health Organisation (WHO). Topically, the issue of paediatric foot posture forms the focus of this review, as it presents with great frequency to a range of clinicians. Comparison is made with developmental dysplasia of the hip, in which instance the WHO criteria are well met. Considering that the burden of the condition being screened for must be demonstrable, and that early identification must be found to be beneficial, in order to justify a screening program, there is no sound support for either continuing or establishing podiatry screenings for children. PMID- 22827999 TI - Anterior chamber angle measurements using Schwalbe's line with high-resolution fourier-domain optical coherence tomography. AB - PURPOSE: To use Fourier-domain optical coherence tomography (OCT) to measure the angle opening distance at Schwalbe's line (AOD-SL) and determine its value in anterior chamber angle assessment. METHODS: Horizontal scans of the nasal and temporal anterior chamber angles in glaucoma subjects were performed at 830 nm wavelength Fourier-domain OCT. Images were graded by 2 ophthalmologists who assessed the visibility of Schwalbe's line (SL), anterior limbus (AL), scleral spur (SS), and angle recess (AR). AOD-SL was measured with computer calipers. SL was manually identified by the termination of the corneal endothelium. Gonioscopy was used to classify anterior chamber angles according to a modified Shaffer system. Spearman rho analysis was performed to assess correlation between AOD-SL and modified Shaffer grade. A cutoff value of AOD-SL for diagnosing occludable angles (modified Shaffer grade <= 1) was determined by receiver operating characteristic (ROC) analyses. RESULTS: Thirty-five glaucoma subjects (65 eyes) were enrolled. SL, AL, AR, and SS were visible by OCT in 97.7%, 99.2%, 87.3%, and 80.8% of eyes, respectively. Nasal and temporal AOD-SLs were 322.6 +/- 200.2 um and 341.4 +/- 197.4 um, respectively. Correlation coefficients between AOD-SL and modified Shaffer grade were 0.80 (nasal) and 0.81 (temporal). The diagnostic cutoff value of AOD-SL for occludable angles was 290 um. The areas under the ROC curve, sensitivity, specificity values were 0.90, 0.80, 0.87 (nasal) and 0.90, 0.85, 0.77 (temporal), respectively. CONCLUSIONS: The measurement of AOD-SL by Fourier-domain OCT is highly correlated with gonioscopy and may be a useful noncontact method for assessing angle closure risk. PMID- 22828000 TI - Surgical output and clinic burden of glaucoma in lagos, Nigeria. AB - PURPOSE: To estimate the outpatient clinic burden and surgical workload related to glaucoma in Lagos, Nigeria. METHODS: A multicentre study involving the 2 tertiary eye institutions, 7 secondary eye centers with eye care facilities, and the largest private eye hospital in Lagos state, Nigeria. Data on outpatient department (OPD) visits were collected over a 4-week period, using a specially designed tally sheet. Theater records were examined in each hospital over a 1 year period (2009) for the number and types of glaucoma surgeries performed. RESULTS: A total of 6240 patients visited the OPD over the 4-week period, out of which 1577 (25.3%) were glaucoma patients. OPD visit per ophthalmologist were 274, 323, and 61, whereas glaucoma visits per ophthalmologist were 75, 70, and 23 in the tertiary, secondary, and private centers, respectively. Glaucoma surgeries constituted 8.6% of total surgeries (n=4050). Trabeculectomy with intraoperative 5-fluorouracil was the most common procedure (81.0%). Number of glaucoma surgeries per ophthalmologist per month in the tertiary, secondary, and private centers were 0.5, 0.9, and 1.4, respectively. Overall number of glaucoma surgery per ophthalmologist per month was 1. CONCLUSIONS: Glaucoma visits constitute a significant proportion of eye clinic visits in Lagos state, Nigeria, and therefore, necessary manpower, infrastructure, and equipments should be mobilized for its optimal management. Also, there is a relatively low output of glaucoma surgeries that needs to be further investigated and appropriate measures taken to manage it. PMID- 22828001 TI - Repair of eroded glaucoma drainage devices: mid-term outcomes. AB - PURPOSE: Glaucoma drainage devices (GDD) are used in the surgical management of medically refractory glaucoma. One late serious complication is erosion and exposure of the tube, clip, or plate. In this study, we evaluated the effectiveness of oral buccal mucous membrane allografts with corneal lamellar grafts for the repair of GDD erosions. METHODS: Retrospective consecutive observational case series. All patients who underwent buccal membrane transplants with corneal allografts for the repair of GDD erosions between 2006 and 2010 were included in this study. Primary outcomes were categorized as: (a) success: coverage of the GDD without further repair; (b) qualified success: minor perioperative complications or additional procedures required to maintain success; or (c) failure: GDD reerosion requiring surgery. RESULTS: Nineteen eyes from 17 patients with 20 GDDs were reviewed, of which there were 19 Ahmed valves and 1 Molteno implant. There were 16 cases of tube erosion, 2 cases of plate erosion, and 2 cases of pars plana clip erosion. The mean (SD) number of ocular surgeries before the buccal membrane transplant was 4.8 (2.9). The mean (SD) time to exposure from the original GDD procedure was 4.6 (3.7) years. Analysis of tube erosions alone showed a success rate of 94% after >= 1 buccal membrane repairs. Buccal membrane repairs in total were considered a surgical success in 85% of cases with a mean (SD) follow-up of 1.7 (1.2) years. CONCLUSIONS: Buccal membrane transplants are particularly useful in cases of tube erosion. PMID- 22828002 TI - Combining information from 3 anatomic regions in the diagnosis of glaucoma with time-domain optical coherence tomography. AB - PURPOSE: To improve the diagnosis of glaucoma by combining time-domain optical coherence tomography (TD-OCT) measurements of the optic disc, circumpapillary retinal nerve fiber layer (RNFL), and macular retinal thickness. PATIENTS AND METHODS: Ninety-six age-matched normal and 96 perimetric glaucoma participants were included in this observational, cross-sectional study. Or-logic, support vector machine, relevance vector machine, and linear discrimination function were used to analyze the performances of combined TD-OCT diagnostic variables. RESULTS: The area under the receiver-operating curve (AROC) was used to evaluate the diagnostic accuracy and to compare the diagnostic performance of single and combined anatomic variables. The best RNFL thickness variables were the inferior (AROC=0.900), overall (AROC=0.892), and superior quadrants (AROC=0.850). The best optic disc variables were horizontal integrated rim width (AROC=0.909), vertical integrated rim area (AROC=0.908), and cup/disc vertical ratio (AROC=0.890). All macular retinal thickness variables had AROCs of 0.829 or less. Combining the top 3 RNFL and optic disc variables in optimizing glaucoma diagnosis, support vector machine had the highest AROC, 0.954, followed by or-logic (AROC=0.946), linear discrimination function (AROC=0.946), and relevance vector machine (AROC=0.943). All combination diagnostic variables had significantly larger AROCs than any single diagnostic variable. There are no significant differences among the combination diagnostic indices. CONCLUSIONS: With TD-OCT, RNFL and optic disc variables had better diagnostic accuracy than macular retinal variables. Combining top RNFL and optic disc variables significantly improved diagnostic performance. Clinically, or-logic classification was the most practical analytical tool with sufficient accuracy to diagnose early glaucoma. PMID- 22828005 TI - Goniopuncture in the treatment of short-term post-Trabectome intraocular pressure elevation: a retrospective case series study. AB - PURPOSE: This study characterizes patients with post-Trabectome intraocular pressure (IOP) elevation induced by membrane growth and/or peripheral anterior synechiae and examines the results of Nd:YAG goniopuncture as its treatment. METHODS: All Trabectome cases received standard postoperative care and no pilocarpine was given. Two groups were identified: (1) Trabectome-goniopuncture (TG) and (2) Trabectome alone (without goniopuncture) (TA). IOP and number of glaucoma medications (NGM) were collected by retrospective review. Information on whether cataract extraction was combined to the Trabectome was also recorded. RESULTS: In TG group (n=8), pre-Trabectome IOP and NGM were 16.9+/-3.7 mm Hg and 2.5+/-1.0, respectively. IOP rose to 21.9+/-2.9 mm Hg before goniopuncture (P=0.03) but lowered to 16.1+/-4.8 mm Hg after the treatment (P=0.006). IOP reduction persisted at post-Trabectome 3 months (13.5+/-1.5 mm Hg), 6.5 months (15.3+/-9.3 mm Hg), and 10.5 months (13.4+/-1.0 mm Hg). No significant medication reduction was detected. In TA group (n=22), pre-Trabectome IOP and NGM were 18.1+/-2.5 mm Hg and 2.7+/-0.5, respectively. NGM was significantly lowered from post-Trabectome day 1 on (1.8+/-0.6, P=0.01) and IOP from 3 months on (15.2+/-1.8 mm Hg, P=0.03). Five (62.5%) TG cases and 18 (81.5%) TA cases underwent combined cataract extraction-Trabectome. Compared with the TA group, TG cases are associated with thinner pachymetry (P=0.034). CONCLUSIONS: Cleft closure may cause post-Trabectome pressure elevation. Not providing any medication-sparing effect, goniopuncture is, however, effective in lysing these closures and in normalizing the IOP back to its pre-Trabectome level. PMID- 22828003 TI - Differences in iris thickness among African Americans, Caucasian Americans, Hispanic Americans, Chinese Americans, and Filipino-Americans. AB - PURPOSE: To evaluate the capability of iris thickness parameters to explain the difference in primary angle-closure glaucoma prevalence among the different racial groups. METHODS: In this prospective study, 436 patients with open and narrow angles that met inclusion criteria were consecutively recruited from the UCSF general ophthalmology and glaucoma clinics to receive anterior segment optical coherence tomography imaging under standardized dark conditions. Images from 11 patients were removed due to poor visibility of the scleral spurs and the remaining images were analyzed using the Zhongshan Angle Assessment Program to assess the following measurements for the nasal and temporal angle of the anterior chamber: iris thickness at 750 and 2000 MUm from the scleral spurs and the maximum iris thickness at middle one third of the iris. Iris thickness parameters were compared among and within the following 5 different racial groups: African Americans, Caucasian Americans, Hispanic Americans, Chinese Americans, and Filipino-Americans. RESULTS: In comparing iris parameters among the open-angle racial groups, significant differences were found for nasal iris thickness at 750 and 2000 MUm from the scleral spurs in which Chinese Americans displayed the highest mean value (P=0.01, P<0.0001). Among the narrow-angle racial groups, significant difference was found for nasal iris thickness at 2000 MUm from the scleral in which Chinese Americans showed the highest mean value (P<0.0001). Significant difference was also found for temporal maximum iris thickness at middle one third of the iris in which African Americans exhibited the highest mean value (P=0.021). Iris thickness was modeled as a function of angle status using linear mixed-effects regression, adjusting for age, sex, pupil diameter, spherical equivalent, ethnicity, and the use of both eyes in patients. The iris thickness difference between the narrow-angle and open-angle groups was significant (P=0.0007). CONCLUSIONS: Racial groups that historically showed higher prevalence of primary angle-closure glaucoma possess thicker irides. PMID- 22828006 TI - Anterior chamber morphology before and after laser peripheral iridotomy determined by Scheimpflug technology in white patients with narrow angles. AB - PURPOSE: To investigate the changes of anterior segment morphology in patients with narrow angles using a rotating Scheimpflug camera before and after laser peripheral iridotomy (LPI). MATERIALS AND METHODS: Forty-six eyes of 46 patients classified as primary angle closure suspect, primary angle closure, primary angle closure glaucoma, acute angle closure glaucoma, fellow eyes of acute angle closure glaucoma, and iris plateau configuration were enrolled in this prospective interventional case series. Anterior chamber volume (ACV), anterior chamber depth (ACD), and anterior chamber angle (ACA) were evaluated with an Scheimpflug camera, before and after LPI. RESULTS: After LPI, the average anterior chamber depth increased from 1.88 +/- 0.36 to 1.93 +/- 0.32 mm (P=0.49). The mean ACV increased from 74.6 +/- 25 to 89.4 +/- 21.1 mm (P=0.003). The average ACA increased from 21.1 +/- 4.8 to 23.4 +/- 3.8 degrees (P=0.01). Eyes with synechial angle closure (primary angle closure and primary angle closure glaucoma) demonstrated a significantly smaller change in ACV compared with eyes with appositional angle closure (primary angle closure suspect). CONCLUSIONS: ACV and ACA determined by Scheimpflug technology increase to a statistically significant degree and this change appears to be more pronounced in cases of appositional angle closure. PMID- 22828007 TI - Ocular surface disease exacerbated glaucoma: optimizing the ocular surface improves intraocular pressure control. AB - PURPOSE: To describe a series of 4 patients with inadequately controlled primary open angle glaucoma and ocular surface disease (OSD) in whom a combination approach was used to manage the OSD resulting in improved intraocular pressure (IOP) control. PATIENTS AND METHODS: A retrospective review of the clinical notes of 4 patients referred to a tertiary surgical glaucoma service was performed. At the initial visit, measures to control the OSD were employed in all patients; twice-daily lid hygiene measures, a 3-month course of 50 mg daily oral doxycycline, topical carmellose sodium (celluvisc) 0.5% 4 to 6 times daily, and preservative-free equivalents of topical antiglaucoma medications as deemed appropriate, depending on the perceived severity of the OSD. RESULTS: Patients were reviewed for a maximum of 24 months after intervention. In all patients treatment resulted in a marked symptomatic and clinical improvement in the ocular surface with a reduction in hyperemia, meibomian gland dysfunction and superficial keratopathy. A reduction in the IOP also occurred in all patients, obviating the need for glaucoma drainage surgery during the study period. CONCLUSIONS: Patients with severe OSD often have glaucoma that is refractive to medical therapy. Furthermore, the surgical success of glaucoma filtering surgery is compromised in patients with scarring and inflammation of the conjunctiva. The term we postulate is "OSD exacerbated glaucoma." This is the first study to suggest that the use of a combination approach comprising medical treatment to manage the OSD in patients with primary open angle glaucoma may lead to an improvement in the IOP control and the management of glaucoma. PMID- 22828008 TI - Effects of a water-loading test on intraocular pressure and corneal hysteresis in young healthy subjects. AB - PURPOSE: To evaluate the influence of a water-loading test on corneal compensated intraocular pressure (IOPcc) and corneal hysteresis (CH) in young healthy subjects. MATERIALS AND METHODS: Forty healthy adult subjects (20 female and 20 male), with a mean age of 27.55+/-2.57 years (range, 24 to 35 y), participated in this prospective study. IOPcc and CH were measured for 1 eye from each participant with an Ocular Response Analyser. These measurements were taken before and 10, 20, and 30 minutes after water loading. RESULTS: Thirty-seven right and 3 left eyes of the 40 subjects fulfilled the study's inclusion criteria. A statistically significant increase in IOPcc was observed between 0 and 10 minutes (P=0.002) and a significant decrease between 10 and 30 minutes (P<0.001). We did not observe any statistically significant changes in CH. The Pearson correlation revealed that there was a weak negative correlation between IOPcc and CH measurements taken at the baseline, 10 minutes, and 30 minutes [r values were -0.275 (P=0.086), -0.369 (P=0.019), and -0.246 (P=0.125), respectively]. CONCLUSIONS: This study revealed changes in IOPcc and CH after a water-loading test, but only the change in the IOPcc measurement was statistically significant. The association of changes in IOP and CH identified in this study suggests that IOP changes might alter corneal biomechanical properties. PMID- 22828004 TI - The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables. AB - Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls, and the rationale for the GWAS study design. PMID- 22828009 TI - Assessment of the vision-specific quality of life using clustered visual field in glaucoma patients. AB - PURPOSE: To investigate the significance of vision-specific quality of life (QOL) in glaucoma patients based on the location of visual field defects. PATIENTS AND METHODS: We examined 336 eyes of 168 patients. The 25-item National Eye Institute Visual Function Questionnaire was used to evaluate patients' QOL. Visual field testing was performed using the Humphrey Field Analyzer; the visual field was divided into 10 clusters. We defined the eye with better mean deviation as the better eye and the fellow eye as the worse eye. A single linear regression analysis was applied to assess the significance of the relationship between QOL and the clustered visual field. RESULTS: The strongest correlation was observed in the lower paracentral visual field in the better eye. The lower peripheral visual field in the better eye also showed a good correlation. Correlation coefficients in the better eye were generally higher than those in the worse eye. For driving, the upper temporal visual field in the better eye was the most strongly correlated (r=0.509). For role limitation and peripheral vision, the lower peripheral visual field in the better eye had the highest correlation coefficients at 0.459 and 0.425, respectively. CONCLUSIONS: Overall, clusters in the lower hemifield in the better eye were more strongly correlated with QOL than those in the worse eye. In particular, the lower paracentral visual field in the better eye was correlated most strongly of all. Driving, however, strongly correlated with the upper hemifield in the better eye. PMID- 22828010 TI - Ahmed glaucoma valve implantation with tube insertion through the ciliary sulcus in pseudophakic/aphakic eyes. AB - PURPOSE: To report the efficacy and safety of Ahmed glaucoma valve (AGV) insertion into the ciliary sulcus in pseudophakic/aphakic patients. PATIENTS AND METHODS: A chart review was done on patients with uncontrolled glaucoma, who underwent AGV implantation with tube inserted into the ciliary sulcus. Baseline intraocular pressure (IOP) and number of medications were compared with that of postoperative follow-up visits. Surgical success was defined as last IOP <21 mm Hg and 20% reduction in IOP, without further surgery for complications or glaucoma control, and without loss of light perception. Postoperative complications were recorded. RESULTS: Twenty-three eyes of 23 patients were recruited with the mean follow-up of 9 months (range, 3 to 24 mo). The mean (SD) age of patients was 49.9 (16.9) years (range, 22 to 80 years). The mean (SD) IOP (mm Hg) was reduced from 37.9 (12.4) before surgery to 16.2 (3.6) at the last follow-up visit (P<0.001). The mean (SD) number of medications was reduced from 3.3 (0.9) preoperatively to 1 (1.1) at the last follow-up (P<0.001). Success rate was 18/23 (78.6%). Complications included endophthalmitis in 1 eye, tube exposure in 1 diabetic patient, and vitreous tube occlusion in 1 eye. No case of corneal decompensation or graft failure was seen during follow-up. CONCLUSIONS: Ciliary sulcus placement of the tube of AGV effectively reduces IOP and medication use in short term. It has the potential to lower corneal complications of anterior chamber tube insertion and avoids the need for pars plana vitrectomy and tube insertion in patients at higher risk of corneal decompensation. PMID- 22828011 TI - The impact of data transformations on concentration-response modeling. AB - Concentration-response studies are performed to investigate the potency of the substance under investigation. Data are typically evaluated using non-linear regression. A common model is the log-logistic model which includes parameters for lower and upper boundary of mean response, EC50 and Hill slope. Often, response and/or concentration data are transformed before proceeding with the analysis of their relationship. This is motivated by practical reasons, including comparability of results across different assays. We prove mathematically that a linear transformation of data will not change the EC50 and Hill slope estimates and only results in an identical transformation of the estimated parameters for lower and upper boundary of mean response. However, fixing some of the parameters may lead to erroneous estimates. This is of practical relevance when data are corrected for background signal and normalized by background corrected solvent control and a reduced model is used in which the response range is fixed between 100% and 0%. Computer simulations and a real data example are used to illustrate the impact of data transformations on parameter estimation. We further shed light on some common problems arising in the analysis of concentration-response data. Recommendations for practical implementation in concentration-response analysis are provided. PMID- 22828012 TI - Comparison of urinary and serum levels of di-22:6-bis(monoacylglycerol)phosphate as noninvasive biomarkers of phospholipidosis in rats. AB - Phospholipidosis (PLD), an abnormal accumulation of phospholipids within tissues, is observed during the preclinical testing of many pharmaceutical drugs. Diagnosis of PLD is currently based on morphologic criteria. An understanding of the clinical incidence of PLD and its possible relationship to adverse drug reactions has been hampered by the absence of noninvasive biomarkers for PLD. The uncommon phospholipid di-docosahexaenoyl bis(monoacylglycerol) phosphate (di-22:6 BMP) has been proposed as a potential urinary biomarker for PLD, but data on the utility of serum di-22:6-BMP measurements in diagnosing PLD is more limited. In this report, we compared the performance of serum and urinary di-22:6-BMP as biomarkers for PLD in rats treated with the PLD-inducing drugs amiodarone and 4,4'-diethylaminoethoxyhexestrol dihydrochloride or the hepatotoxicant acetaminophen (APAP). Serum levels of di-22:6-BMP showed a higher correlation to a generalized PLD incidence score than did levels in urine, but were unexpectedly elevated in rats with marked levels of APAP-induced liver necrosis. When samples were filtered based on serum ALT or liver histopathology thresholds, the diagnostic accuracy of serum di-22:6-BMP for PLD improved to the high level observed for urinary di-22:6-BMP without sample exclusion. These data help define the potential context-of-use of serum di-22:6-BMP as a non-clinical biomarker of PLD. PMID- 22828013 TI - Connection of European particle therapy centers and generation of a common particle database system within the European ULICE-framework. AB - BACKGROUND: To establish a common database on particle therapy for the evaluation of clinical studies integrating a large variety of voluminous datasets, different documentation styles, and various information systems, especially in the field of radiation oncology. METHODS: We developed a web-based documentation system for transnational and multicenter clinical studies in particle therapy. 560 patients have been treated from November 2009 to September 2011. Protons, carbon ions or a combination of both, as well as a combination with photons were applied. To date, 12 studies have been initiated and more are in preparation. RESULTS: It is possible to immediately access all patient information and exchange, store, process, and visualize text data, any DICOM images and multimedia data. Accessing the system and submitting clinical data is possible for internal and external users. Integrated into the hospital environment, data is imported both manually and automatically. Security and privacy protection as well as data validation and verification are ensured. Studies can be designed to fit individual needs. CONCLUSIONS: The described database provides a basis for documentation of large patient groups with specific and specialized questions to be answered. Having recently begun electronic documentation, it has become apparent that the benefits lie in the user-friendly and timely workflow for documentation. The ultimate goal is a simplification of research work, better study analyses quality and eventually, the improvement of treatment concepts by evaluating the effectiveness of particle therapy. PMID- 22828014 TI - Age-related changes in brain metabolites and cognitive function in APP/PS1 transgenic mice. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) and the Morris water maze (MWM) have played an important role in Alzheimer's disease (AD) research. The aim of this study was to determine whether (1)H-MRS and the MWM can detect for early AD in APP/PS1 transgenic (tg) mice. (1)H-MRS was performed in 20 tg mice and 15 wild type mice at 3, 5 and 8 months of age. The concentration of N-acetylaspartate (NAA), glutamate (Glu), myo-inositol (mI), choline (Cho) and creatine (Cr) in the hippocampus were measured, and the NAA/Cr, Glu/Cr, mI/Cr and Cho/Cr ratios were quantified. Additionally, the spatial learning and memory of the mice were evaluated by MWM. The (1)H-MRS revealed that mI levels in tg mice were significantly higher at 3 months of age compared to wt mice, while the NAA and Glu levels in 5- and 8-month-old tg mice were significantly decreased (p<0.05). Additionally, significant cognitive changes only occurred at 8 months of age in APP/PS1 tg mice. These results indicated that metabolic changes preceded overt cognitive dysfunctions in early-stage AD, suggesting that (1)H-MRS is a more sensitive biomarker for assessing early AD. PMID- 22828016 TI - Affordable Care Act: what does the Supreme Court decision mean? PMID- 22828015 TI - Moloney murine leukemia virus glyco-gag facilitates xenotropic murine leukemia virus-related virus replication through human APOBEC3-independent mechanisms. AB - BACKGROUND: One of the unique features of gammaretroviruses is that they contain an additional extended form of Gag, glyco-gag, which initiates in the leader sequence. MuLV glyco-gag, gPr80Gag, promotes retrovirus replication and disease progression. Although virtually all infectious MuLVs encode glyco-gag, XMRV (xenotropic murine leukemia virus-related virus) lacks the classical gPr80Gag sequence. We examined XMRV to determine if its leader sequence contains glyco-gag activity, whether the presence of conventional gPr80Gag affects replication of XMRV, and we describe the evolution of glyco-gag-deficient MuLVs in Mus. RESULTS: We introduced several mutations disrupting two putative but noncanonical glyco gag proteins in the leader sequence region in XMRV and found that those mutations did not affect virus release nor susceptibility to the antiviral activity of hA3G (human APOBEC3G). A chimeric XMRV encoding the Moloney MuLV (M-MuLV) leader sequence (MXMRV) demonstrated that M-MuLV glyco-gag facilitated MXMRV release and increased infectivity. Infectivity assays with several cell lines showed that glyco-gag increases XMRV infectivity in all cell lines tested, but the level of this increase varies in different cell lines. Because MuLV glyco-gag counteracts mouse APOBEC3, we investigated whether M-MuLV glyco-gag enhances XMRV infection by counteracting human APOBEC3. Comparison of hAPOBEC3 isoforms expressed in different cell lines indicated that hA3B was the most likely candidate for a restrictive hA3. However over-expression of hA3B showed no enhanced restriction of infection by XMRV compared to MXMRV. Endogenous MuLVs in the sequenced mouse genome were screened for canonical glyco-gag, which was identified in two clades of xenotropic MuLVs (X-MuLVs) and ecotropic MuLVs, but not in other X-MuLVs or in any polytropic MuLVs. CONCLUSIONS: M-MuLV glyco-gag facilitates XMRV replication, and the leader sequence region in XMRV does not encode proteins equivalent to M MuLV glyco-gag. The fact that the ability of glyco-gag to enhance XMRV infection varies in different cell lines suggests a glyco-gag sensitive restrictive factor that further reduces XMRV infectivity. The M-MuLV glyco-gag enhancement for XMRV replication is through a hAPOBEC3 independent mechanism. The absence of glyco-gag in MuLVs carried by western European mice suggests that loss of this sequence is a relatively recent event with limited subspecies distribution. PMID- 22828017 TI - Postanesthesia care unit visitation, anxiety, and experimental design. PMID- 22828019 TI - The incidence of and risk factors for emergence delirium in U.S. military combat veterans. AB - The purpose of this research was to identify the incidence and potential risk factors for emergence delirium (ED) in a U.S. military combat veteran surgical population at Naval Hospital Camp Pendleton. ED is a postanesthetic phenomenon that occurs immediately after emergence from general anesthesia and is characterized by agitation, confusion, and violent behavior. Clinical evidence suggests that ED is increasingly seen among military personnel returning from the wars in Iraq and Afghanistan, and that the incidence of anxiety, depression, and post-traumatic stress disorder (PTSD) are higher in this population than in noncombat troops or nonmilitary populations. The incidence of ED in this sample of 130 postoperative military personnel with combat exposure was 20% (n=26). Those previously diagnosed with a psychological disorder had a higher rate of ED (50%) than those who did not (17.5%), chi(2)=5.53, P<.05. There was a positive relationship between ED in veterans who reported greater amounts of anxiety, PTSD symptoms, and depression [state anxiety: r(128)=0.40, P<.001; trait anxiety: r(128)=0.40, P<.001; PTSD: r(128)=0.35, P<.001; and depression: r(128)=0.25, P=.002]. This study revealed the incidence of ED and identified anxiety, PTSD, and depression as risk factors. Regression modeling suggested that state-anxiety served as the best predictor. These findings increase clinicians' understanding of ED among combat veterans and give direction to future studies that should focus on preventive treatment. PMID- 22828020 TI - The effect of aromatherapy on postoperative nausea in women undergoing surgical procedures. AB - Postoperative nausea and vomiting (PONV) is a common source of patient discomfort and decreased satisfaction. Aromatherapy has been identified as a complementary modality for the prevention and management of PONV. The purpose of this study was to assess the effect of aromatherapy on the severity of postoperative nausea (PON) in women undergoing surgical procedures in the postanesthesia care unit. Women complaining of PON received traditional antiemetics, inhalation of peppermint oil, or saline vapor. A visual analog scale was used to rate nausea at the first complaint; at 5 minutes after intervention; and, if nausea persisted, at 10 minutes after intervention. At both 5 and 10 minutes, statistical analysis showed no significant differences between intervention and nausea rating. Obtaining eligible subjects was challenging. Although many women consented, most received intraoperative antiemetics and did not report nausea postoperatively. PMID- 22828021 TI - Risk factors of patients with and without postoperative nausea (PON). AB - This purpose of this analysis was to study risk factors of postoperative nausea (PON) and their strength. Data were obtained during the screening phase of a controlled clinical trial of aromatherapy for PON. In a sample of 1151 postsurgical subjects, 301 (26.2%) reported PON. Significant risk factors identified in the order of odds ratios for nausea were female gender, gastrointestinal surgery, use of volatile anesthesia gases, history of PON, history of motion sickness, and use of opioids after surgery. Although still over 1.0, the risk factors of length of surgery over 1 hour and gynecologic surgery had the lowest odds ratios. Likelihood of nausea increased significantly with the number of significant risk factors (P<.0001). Administration of preventive antiemetic medication also increased with the number of significant risk factors (P<.0001). Among 301 subjects reporting nausea, 49 (16.28%) received preventive medication. Despite prevention efforts, PON remains a substantial side effect for many surgical patients. PMID- 22828022 TI - Effect of acupressure on preoperative anxiety: a clinical trial. AB - Preoperative anxiety, as an emotional reaction, is common among patients undergoing surgery. The purpose of this study was to examine the effect of acupressure on preoperative anxiety before abdominal surgery. The 70 subjects of this clinical trial were randomly assigned into the acupressure group (n=35), which received acupressure at the true points, or the placebo group (n=35), which received acupressure at sham (false) points. Preoperative anxiety and vital signs before and after the intervention were measured in both groups. The findings demonstrated a reduction in the level of preoperative anxiety for both groups (P<.001). Furthermore, they showed a statistically significant difference between the mean of vital signs before and after the intervention in the acupressure group (P<.001) and only statistically significant results for cardiovascular (P=.016) and respiratory rates (P=.007) in the placebo group. Overall, findings revealed that acupressure at true points (third eye and Shen men) can reduce higher preoperative anxiety of patients before abdominal surgery and that it has had a more clinically beneficial effect than sham points. PMID- 22828023 TI - Ambulatory perianesthesia electronic documentation--a two-part series. Part 1: from paper to point and click. PMID- 22828024 TI - Nursing-sensitive indicators: their role in perianesthesia care. PMID- 22828025 TI - Advancing perianesthesia practice around the world. PMID- 22828027 TI - ASPAN passion in action: gifts from the heart. PMID- 22828026 TI - Fibromyalgia and surgery. PMID- 22828028 TI - Drug shortages in the perioperative setting: causes, impact, and strategies. PMID- 22828029 TI - Capnography for patient ventilatory status. PMID- 22828030 TI - Meeting notes from the 2011 ASA Annual Meeting. PMID- 22828031 TI - Meaningful and useful measures of performance: building a comprehensive dashboard of measures. PMID- 22828032 TI - Evaluation of splanchnic oximetry, Doppler flow velocimetry in the superior mesenteric artery and feeding tolerance in very low birth weight IUGR and non IUGR infants receiving bolus versus continuous enteral nutrition. AB - BACKGROUND: IUGR infants are thought to have impaired gut function after birth, which may result in intestinal disturbances, ranging from temporary intolerance to the enteral feeding to full-blown NEC.In literature there is no consensus regarding the impact of enteral feeding on intestinal blood flow and hence regarding the best regimen and the best rate of delivering the enteral nutrition. METHODS/DESIGN: This is a randomized, non-pharmacological, single-center, cross over study including 20 VLBW infants. Inclusion criteria * Weight at birth ranging: 700-1501 grams * Gestational age up to 25 weeks and 6 days * Written informed consent from parents or guardians Exclusion criteria * Major congenital abnormality * Patients enrolled in other trials * Significant multi-organ failure prior to trial entry * Pre-existing cutaneous disease not allowing the placement of the NIRS' probe. In the first 24 hours of life, between the 48th and 72nd hours of life, and during Minimal Enteral Feeding, all infants' intestinal perfusion will be evaluated with NIRS and a Doppler of the superior mesenteric artery will be executed.At the achievement of an enteral intake of 100 mL/Kg/day the patients (IUGR and NON IUGR separately) will be randomized in 2 groups: Group A (n=10) will receive a feed by bolus (in 10 minutes); then, after at least 3 hours, they will receive the same amount of formula administered in 3 hours. Group B (n=10) will receive a feed administered in 3 hours followed by a bolus administration of the same amount of formula (in 10 minutes) after at least 3 hours. On the randomization day intestinal and cerebral regional oximetry will be measured via NIRS. Intestinal and celebral oximetry will be measured before the feed and 30 minutes after the feed by bolus during the 3 hours nutrition the measurements will be performed before the feed, 30 minutes from the start of the nutrition and 30 minutes after the end of the gavage. An evaluation of blood flow velocity of the superior mesenteric artery will be performed meanwhile. The infants of the Group A will be fed with continuous nutrition until the achievement of full enteral feeding. The infants of the Group B will be fed by bolus until the achievement of full enteral feeding. DISCUSSION: Evaluations of intestinal oximetry and superior mesenteric artery blood flow after the feed may help in differentiating how the feeding regimen alters the splanchnic blood flow and oxygenation and if the changes induced by feeding are different in IUGR versus NON IUGR infants. TRIAL REGISTRATION NUMBER: NCT01341236. PMID- 22828034 TI - The national health insurance scheme: perceptions and experiences of health care providers and clients in two districts of Ghana. AB - BACKGROUND: Prepayments and risk pooling through social health insurance has been advocated by international development organizations. Social health insurance is seen as a mechanism that helps mobilize resources for health, pool risk, and provide more access to health care services for the poor. Hence Ghana implemented the National Health Insurance Scheme (NHIS) to help promote access to health care services for Ghanaians. The study examined the influence of the NHIS on the behavior of health care providers in their treatment of insured and uninsured clients. METHODS: The study took place in Bolgatanga (urban) and Builsa (rural) districts in Ghana. Data was collected through exit survey with 200 insured and uninsured clients, 15 in-depth interviews with health care providers and health insurance managers, and 8 focus group discussions with insured and uninsured community members. RESULTS: The NHIS promoted access for insured and mobilized revenue for health care providers. Both insured and uninsured were satisfied with care (survey finding). However, increased utilization of health care services by the insured leading to increased workloads for providers influenced their behavior towards the insured. Most of the insured perceived and experienced long waiting times, verbal abuse, not being physically examined and discrimination in favor of the affluent and uninsured. The insured attributed their experience to the fact that they were not making immediate payments for services. A core challenge of the NHIS was a delay in reimbursement which affected the operations of health facilities and hence influenced providers' behavior as well. Providers preferred clients who would make instant payments for health care services. Few of the uninsured were utilizing health facilities and visit only in critical conditions. This is due to the increased cost of health care services under the NHIS. CONCLUSION: The perceived opportunistic behavior of the insured by providers was responsible for the difference in the behavior of providers favoring the uninsured. Besides, the delay in reimbursement also accounted for providers' negative attitude towards the insured. There is urgent need to address these issues in order to promote confidence in the NHIS, as well as its sustainability for the achievement of universal coverage. PMID- 22828033 TI - Impact of alternative reimbursement strategies in the new cooperative medical scheme on caesarean delivery rates: a mixed-method study in rural China. AB - BACKGROUND: The rate of caesarean delivery (CD) in rural China has been rapidly increasing in recent decades. Due to the exorbitant costs associated with CD, paying for this expensive procedure is often a great challenge for the majority of rural families. Since 2003, the Chinese government has re-established the New Cooperative Medical Scheme (NCMS), aimed to improve the access of essential healthcare to rural residents and reduce financial burden owing to high out of pocket payments. This paper seeks to test the hypothesis that NCMS may provide service users and providers with financial incentives to select CD. It also assesses the effect of different health insurance reimbursement strategies of NCMS on CD rates in rural China. METHODS: Mixed quantitative and qualitative methods were adopted for data collection. Two cross-sectional household surveys were conducted with women having babies delivered in 2006 and 2009; 2326 and 1515 women, respectively, from the study sites were interviewed using structured questionnaires, to collect demographic and socio-economic data, maternal and child care characteristics and health-related expenditures. Focus group discussions (FGDs) and in-depth key informant interviews (KIIs) were undertaken with policy makers, health managers, providers and mothers to understand their perceptions of the influence of NCMS on the choices of delivery mode. RESULTS: The CD rates in the two study counties were 46.0 percent and 64.7 percent in 2006, increasing to 63.6 percent and 82.1 percent, respectively, in 2009. The study found that decisions on the selection of CD largely came from the pregnant women. Logistic regression analysis, after adjusting for socio-economic, maternal and fetal characteristics, did not indicate a significant effect of either proportional reimbursement or fixed amount reimbursement on the choice of CD for both study years. Interviews with stakeholders reflected that different reimbursable rates for CD and vaginal deliveries did not have a significant effect on controlling the rising CD rate in the study countries. CONCLUSION: NCMS reimbursement strategies adopted in the study counties of China did not have a significant effect on the selection of CD for baby deliveries. The rapid rise of the CD rates of rural China has remained a serious issue. Other effective measures, such as health education to increase awareness of mothers' knowledge, and improving training of health staff in evidence-based delivery care, maybe could do more to promote rational baby delivery in rural China. PMID- 22828035 TI - Automated criterion-based analysis for Cole parameters assessment from cerebral neonatal electrical bioimpedance spectroscopy measurements. AB - Hypothermia has been proven as an effective rescue therapy for infants with moderate or severe neonatal hypoxic ischemic encephalopathy. Hypoxia-ischemia alters the electrical impedance characteristics of the brain in neonates; therefore, spectroscopic analysis of the cerebral bioimpedance of the neonate may be useful for the detection of candidate neonates eligible for hypothermia treatment. Currently, in addition to the lack of reference bioimpedance data obtained from healthy neonates, there is no standardized approach established for bioimpedance spectroscopy data analysis. In this work, cerebral bioimpedance measurements (12 h postpartum) in a cross-section of 84 term and near-term healthy neonates were performed at the bedside in the post-natal ward. To characterize the impedance spectra, Cole parameters (R(0), R(infinity), f(C) and alpha) were extracted from the obtained measurements using an analysis process based on a best measurement and highest likelihood selection process. The results obtained in this study complement previously reported work and provide a standardized criterion-based method for data analysis. The availability of electrical bioimpedance spectroscopy reference data and the automatic criterion based analysis method might support the development of a non-invasive method for prompt selection of neonates eligible for cerebral hypothermic rescue therapy. PMID- 22828036 TI - Embedded ethics or fictitious facts? PMID- 22828037 TI - What does empirical research contribute to medical ethics? A methodological discussion using exemplary studies. PMID- 22828038 TI - How to relate the empirical to the normative: toward a phenomenologically informed hermeneutic approach to bioethics. PMID- 22828039 TI - Don't solve the issues! A plea for ambiguity within empirical ethics. PMID- 22828040 TI - Do our moral judgments need to be guided by principles? PMID- 22828041 TI - Toward methodological innovation in empirical ethics research. PMID- 22828042 TI - The normative relevance of cases: rhetoric and empirical ethics. PMID- 22828043 TI - Empirical ethics within rapidly changing practices: a forced detoxification program in psychiatry as a case example. PMID- 22828045 TI - How can empirical ethics improve medical practice? PMID- 22828044 TI - Lost in translation: cultural obstructions impede living kidney donation among minority ethnic patients. PMID- 22828046 TI - "How hard it is that we have to die": rethinking suicide liability for psychiatrists. PMID- 22828047 TI - Expression profiles of aquaporins in rat conjunctiva, cornea, lacrimal gland and Meibomian gland. AB - The aim of the study was to elucidate aquaporin (AQP) family member mRNA expression and protein expression/localization in the rat lacrimal functional unit. The mRNA expression of all rat AQPs (AQP0-9, 11-12) in palpebral, fornical, and bulbar conjunctiva, cornea, lacrimal gland, and Meibomian gland was measured by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and real time RT-PCR. Antibodies against AQP1, 3, 4, 5, 9, and 11 were used in Western blotting and immunohistochemistry to determine protein expression and distribution. Our study demonstrated characteristic AQP expression profiles in rat ocular tissues. AQP1, 3, 4, 5, 8, 9, 11, and 12 mRNA were detected in conjunctiva. AQP0, 1, 2, 3, 4, 5, 6, 11, and 12 mRNA were expressed in cornea. AQP0, 1, 2, 3, 4, 5, 7, 8, and 11 mRNA were detected in lacrimal gland. AQP1, 3, 4, 5, 7, 8, 9, 11, and 12 mRNA were identified in Meibomian gland. By Western blot, AQP1, 3, 5, and 11 were detected in conjunctiva; AQP1, 3, 5, and 11 were identified in cornea; AQP1, 3, 4, 5, and 11 were detected in lacrimal gland; and AQP1, 3, 4, 5, 9, and 11 were present in Meibomian gland. Immunohistochemistry localized AQPs to distinct sites in the various tissues. This study rigorously analyzed AQPs expression and localization in rat conjunctiva, cornea, lacrimal gland, and Meibomian gland tissues. Our findings provide a comprehensive platform for further investigation into the physiological or pathophysiological relevance of AQPs in ocular surface. PMID- 22828048 TI - Lipoxin A4 inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma. AB - Platelet-activating factor (PAF) is a bioactive lipid mediator with strong inflammatory properties. PAF induces the expression and activation of metalloproteinase-9 (MMP-9) in corneal epithelial cells and myofibroblasts, and delays epithelial wound healing in an organ culture system. Lipoxin A(4) (LXA(4)) is a lipid mediator involved in resolution of inflammation and cornea epithelial wound healing. We developed an in vivo mouse model of injury to the anterior stroma that is sustained by PAF and evaluated the action of LXA(4). In this model mice were treated with vehicle, PAF alone and in combination with PAF receptor antagonist LAU-0901 or LXA(4). Mice were euthanized 1, 2 and 7 days after injury and corneas were processed for histology (H&E staining) and immunofluorescence with antibodies for MMP-9, alpha-smooth muscle actin (alpha-SMA), fibronectin (FN) and neutrophil. Interleukin 1-alpha (IL-1alpha) and keratinocyte-derived chemokine (KC/CXCL1) were assayed by ELISA. Myeloperoxidase (MPO) activity was performed in corneal homogenates. In this in vivo model PAF inhibited epithelial wound healing that was blocked by the PAF receptor antagonist LAU-0901. Treatment with LXA(4) significantly reduced the injured area compared to PAF at 1 and 2 days of treatment. The strong stromal cell infiltration and MPO activity stimulated by PAF was also decreased with LXA(4) treatment. PAF increased MMP-9 and decreased FN expression compared to vehicle treatment and less alpha-SMA positive cells migrated to the wounded area. The PAF actions were reverted by LXA(4) treatment. The results demonstrated a powerful action of LXA(4) in protecting corneas with injuries that compromise the stroma by decreasing inflammation and increasing wound healing. PMID- 22828049 TI - Oxygen consumption and distribution in the Long-Evans rat retina. AB - The purpose of this study was to investigate the oxygen distribution and consumption in the pigmented Long-Evans rat retina in vivo during dark and light adaptation, and to compare these results to previous work on cat and albino rat. Double-barreled microelectrodes recorded both intraretinal PO(2) depth profiles and the electroretinogram (ERG), which was used to identify the boundaries of the retina. Light adaptation decreased photoreceptor oxygen consumption per unit volume (Q(av)) from 3.0 +/- 0.4 ml.100 g(-1) min(-1) (mean +/- SEM) in darkness to 1.8 +/- 0.2 ml.100 g(-1) min(-1) and increased minimum outer retinal PO(2) at the inner segments (P(min)) from 17.4 +/- 3.0 to 29.9 +/- 5.3 mmHg. The effects of light on outer retinal PO(2) and Q(av) were similar to those previously observed in cat, monkey, and albino rats; however, dark-adapted P(min) was higher in rat than cat. The parameters derived from fitting the oxygen diffusion model to the rat data were compared to those from cat. Oxygen consumption of the inner segments (Q(2)) and choroidal PO(2) (P(C)) in rat and cat were similar. P(min) was higher in rat than in cat for two reasons: first, rat photoreceptors have a shorter oxygen consuming region; and second, the retinal circulation supplied a greater fraction of consumed oxygen to rat photoreceptors. The average PO(2) across the inner retina (P(IR)) was not different in dark adaptation (25.4 +/- 4.8 mmHg) and light adaptation (28.8 +/- 5.4 mmHg) when measured from PO(2) profiles. However, with the microelectrode stationary at 9-18% retinal depth, a small consistent decrease in PO(2) occurred during illumination. Flickering light at 6 Hz decreased inner retinal PO(2) significantly more than an equivalent steady illumination, suggesting that changes in blood flow did not completely compensate for increased metabolism. This study comprehensively characterized rat retinal oxygenation in both light and dark, and determined the similarities and differences between rat and cat retinas. PMID- 22828051 TI - Effect of mitomycin C on the tensile properties of the upper lacrimal canaliculi in a rabbit model. AB - The upper lacrimal canaliculus consists of a tubular structure, and the tensile properties which in lacrimal tissues might contribute to structural integrity and tear drainage. We evaluated the characteristics of the tensile properties of the upper lacrimal canaliculi and the clinical implications of using a mitomycin C (MMC)-treated rabbit model. Mitomycin C (0.04%) was applied to the punctum of rabbits for 5 min, and the upper lacrimal tissues including the punctum were excised and attached to a forced transducer to record the tensile properties in a resting state 1 month later. The recording showed continuing decrement of basal tension with time in the lacrimal tissues treated with MMC in contrast with normal controls which maintained initial tension throughout the experiment. The rabbits were then randomly divided into the following 3 groups: vertical punctal incision with the MMC application group; vertical punctal incision with a balanced salt solution application group; and a balanced salt solution application only group. Four weeks after surgery, the puncta of rabbits treated with an incision and MMC application were more dilated clinically and showed less elasticity as compared with the other groups. Histological staining revealed that MMC treatment combined with incision decreased the amount of collagen and elastin fibers in the canaliculi. These results suggest that lacrimal canaliculi of rabbits have rheological basal tension and elasticity, which can be decreased by the use of MMC treatment. PMID- 22828050 TI - Parasympathetic influences on emmetropization in chicks: evidence for different mechanisms in form deprivation vs negative lens-induced myopia. AB - Ciliary ganglionectomy inhibits the development of myopia in chicks (Schmid et al., 1999), but has no effect on the compensatory responses to spectacle lenses (Schmid and Wildsoet, 1996). This study was done to assess the potential influence of the other parasympathetic input to the choroid, the pterygopalatine ganglia, on the choroidal and axial responses to retinal defocus, and to form deprivation. 4-5 week-old chicks had one of the following surgeries to one eye: (1) Section (X) of the autonomic part of cranial N VII (input to the pterygopalatine ganglia) (PPGX, n = 16), (2) PPGX plus ciliary ganglionectomy (PPG/CGX, n = 23) or (3) PPGX plus superior cervical ganglionectomy (PPG/SCGX, n = 10). Experimental eyes were fitted with positive or negative lenses, or diffusers, several days after surgery. In one group of PPG/CGX, eyes did not wear any devices (n = 8). Intact (no surgery) controls were done for all visual manipulations (lenses or diffusers). Sham surgeries were done for the PPG/CGX condition (n = 4). Ocular dimensions were measured using A-scan ultrasonography prior to the surgery, 5 days later when visual devices were placed on the eyes, at the end of lens- or diffuser-wear, and in the case of diffusers, 4 days after diffuser removal to look at "recovery". Refractive errors were measured using a Hartinger's refractometer. IOP was measured in 7 PPG/CGX birds 7d after surgery. PPGX/CGX resulted in choroidal thickening (125 MUm) and a decrease in IOP over one week post-surgery. It also prevented the development of myopia in response to form deprivation (X vs intact: 0.2 D vs -4.1 D; p < 0.005), by preventing the increase in axial elongation (250 MUm vs 670 MUm/5d; p < 0.005). In fact, growth rate slowed below normal (X vs fellow eyes: 250 MUm vs 489 MUm/5d; p = 0.002). By contrast, there were no effects of this lesion on the development of myopia in response to negative lenses (X vs intact: -5.4 D vs -5.3 D). All three lesions inhibited the compensatory choroidal thickening in response to myopic defocus (ANOVA, p = 0.0008), but had no effect on the thinning response to hyperopic defocus. These results argue for different underlying mechanisms for the growth responses to form deprivation vs negative lens wear. They also imply that choroidal thickening and thinning are not opposing elements of a single mechanism. PMID- 22828053 TI - The effects of drug market regulation on pharmaceutical prices in Europe: overview and evidence from the market of ACE inhibitors. AB - This study provides an overview of policy measures targeting pharmaceutical expenditure in Europe and analyses their impact on originator pharmaceutical prices. Panel data methods are used to examine the market of ACE Inhibitors in six European countries (Denmark, France, Germany, Netherlands, Sweden, United Kingdom) over period 1991-2006. We find that although some measures are effective in reducing originator prices, others appear to have an insignificant effect. Results suggest that supply side measures such as mandatory generic substitution, regressive pharmacy mark-ups and claw-backs are effective in reducing pharmaceuticals prices. Results are not as strong for demand side measures. Profit controls and the use of cost-effectiveness analysis appear to have a negative effect on prices, while results on reference pricing are inconclusive. Findings also indicate that, although originator prices are not immediately affected by generic entry, they may be influenced by changes in generic prices post patent expiry. PMID- 22828052 TI - The pathway of cell dismantling during programmed cell death in lace plant (Aponogeton madagascariensis) leaves. AB - BACKGROUND: Developmentally regulated programmed cell death (PCD) is the controlled death of cells that occurs throughout the life cycle of both plants and animals. The lace plant (Aponogeton madagascariensis) forms perforations between longitudinal and transverse veins in spaces known as areoles, via developmental PCD; cell death begins in the center of these areoles and develops towards the margin, creating a gradient of PCD. This gradient was examined using both long- and short-term live cell imaging, in addition to histochemical staining, in order to establish the order of cellular events that occur during PCD. RESULTS: The first visible change observed was the reduction in anthocyanin pigmentation, followed by initial chloroplast changes and the bundling of actin microfilaments. At this stage, an increased number of transvacuolar strands (TVS) was evident. Perhaps concurrently with this, increased numbers of vesicles, small mitochondrial aggregates, and perinuclear accumulation of both chloroplasts and mitochondria were observed. The invagination of the tonoplast membrane and the presence of vesicles, both containing organelle materials, suggested evidence for both micro- and macro-autophagy, respectively. Mitochondrial aggregates, as well as individual chloroplasts were subsequently seen undergoing Brownian motion in the vacuole. Following these changes, fragmentation of nuclear DNA, breakdown of actin microfilaments and early cell wall changes were detected. The vacuole then swelled, causing nuclear displacement towards the plasma membrane (PM) and tonoplast rupture followed closely, indicating mega-autophagy. Subsequent to tonoplast rupture, cessation of Brownian motion occurred, as well as the loss of mitochondrial membrane potential (DeltaPsim), nuclear shrinkage and PM collapse. Timing from tonoplast rupture to PM collapse was approximately 20 minutes. The entire process from initial chlorophyll reduction to PM collapse took approximately 48 hours. Approximately six hours following PM collapse, cell wall disappearance began and was nearly complete within 24 hours. CONCLUSION: Results showed that a consistent sequence of events occurred during the remodelling of lace plant leaves, which provides an excellent system to study developmental PCD in vivo. These findings can be used to compare and contrast with other developmental PCD examples in plants. PMID- 22828055 TI - Syndrome of inappropriate antidiuretic hormone and cerebral salt wasting in critically ill patients. PMID- 22828054 TI - A one-year observational study of all hospitalized acute poisonings in Oslo: complications, treatment and sequelae. AB - OBJECTIVES: Changes in poisoning trends may affect both complications and outcomes in patients with acute poisoning. This study reports the treatments given and the frequency of complications, also related to treatment, mortality and sequelae related to various toxic agents. METHODS: All acute poisonings in adults (>= 16 years) admitted to the five hospitals in Oslo were included consecutively during one year (2008 to 2009) in an observational cross-sectional multicenter study. A standardized form was completed by the treating physician, which covered the study aims. RESULTS: There were 1065 admissions in 912 patients. The median length of hospital stay was one day, and 49% were observed in an intensive care unit (ICU). Active treatment was given to 83%, and consisted of supportive therapy (70%), antidote(s) (38%), activated charcoal (16%) and gastric lavage (9%). The most commonly used antidotes were flumazenil (19%), naloxone (17%) and N-acetylcysteine (11%). The rate of treatment-related complications was 2.4% (21/884). Neither flumazenil, naloxone, nor the combination, was associated with convulsions or other complications. Among those receiving N-acetylcysteine, 5% (6/120) developed allergic reactions, one of which mandated discontinuation of treatment. Nineteen percent presented in a coma. Complications developed in 30%, compared with 18% in a 2003 study, mainly respiratory depression (12%), prolonged QTc interval (6%) and hypotension (5%). Eight patients died (0.8%) and five (0.5%) survived with permanent sequelae, mainly anoxic brain damage. DISCUSSION: Few patients stayed more than two days. The use of the ICU was liberal, considering that only one out of five presented in a coma. Antidotes were frequently given diagnostically. Although N acetylcysteine induced allergic reactions, most were mild and treatment discontinuation was only necessary once. The frequency of complications had almost doubled in five years, although the poisoning pattern was largely unchanged. However, few patients developed permanent sequelae. PMID- 22828057 TI - Maintaining professional boundaries in the pediatric intensive care unit. AB - Team members in the PICU need to have an understanding of the potential for professional boundary violations. These lines are dynamic and easily blurred and may be crossed during well-intentioned interactions. We hope that knowledge of the warning signs will help health care providers and patients and families remain in the zone of helpfulness.(3) PMID- 22828058 TI - Target temperature within 3 hours: community hospital's experience with therapeutic hypothermia. AB - Therapeutic hypothermia has been shown to improve neurological outcomes for patients who survive cardiac arrest. Timely cooling can be achieved by rapid initiation of a comprehensive targeted temperature protocol, which includes shivering assessment and management. The purpose of the study was to evaluate an updated therapeutic hypothermia protocol for patients who survive cardiac arrest. The first 6 patients who met inclusion criteria were placed on the updated protocol. These cases were compared with historical cases. Upon discharge or death, cases were analyzed for time to reach the target temperature, the use of paralytic agents, and discharge disposition. Patients placed on the updated protocol cooled 2 hours faster than did the patients from the historical cases (median = 179 vs 285 minutes). The use of paralytic agents appeared to safely accelerate the time to goal temperature. Four of the 6 patients were discharged home or to rehabilitation compared with only 1 patient from the historical cases. Implementing this evidence-based protocol for therapeutic hypothermia led to faster cooling. PMID- 22828059 TI - Pilot study evaluates nutrition for patients receiving mechanical circulatory support in the intensive care unit. AB - Establishing a nutrition protocol with an accompanying algorithm allows a multidisciplinary team to make decisions to maintain or improve nutrition-related outcomes during the intensive care unit (ICU) stay. This descriptive pilot study included subjects (N = 11) recruited from a convenient sample of patients admitted for surgical implantation of a mechanical circulatory support device. Nutritional and strength measures were compared across 3 time intervals: preoperatively, postoperative day 3, and within 48 hours of transfer from ICU. The mean age of the sample was 60 +/- 8 years. Overall, subjects maintained preoperative nutritional status demonstrated by a nonsignificant change in the nutritional and strength measures from the preoperative period compared to transfer from ICU. The nutrition protocol with algorithm provided a step-by-step approach to ensure a consistent nutritional plan of care. It also standardized nutritional care while ensuring safe practice. PMID- 22828060 TI - Providing safe passage: rapid sequence intubation for advanced practice nursing. AB - Rapid sequence intubation (RSI) is a lifesaving technique performed by advanced practice nurses when patients require endotracheal intubation but are at risk for gastric aspiration. In the acute care setting, the procedure often is indicated when critically ill or injured patients exhibit difficulty maintaining a patent airway and/or are displaying inadequate oxygenation and ventilation. The goal of this article is to provide advanced practice nurses with information that promotes safe and effective clinical decision making during RSI on the basis of the current state of the science. Standard RSI practices in stable patients are reviewed, and the need for individualized modifications of this "ideal" practice in unstable, critically ill patients is addressed. Factors predisposing a patient to difficult airway management, proper equipment, and patient preparation are highlighted, along with the relevant pharmacology. Finally, prevention of potential complications during RSI in the acute care setting is discussed. PMID- 22828062 TI - The tele-ICU: a new frontier in critical care nursing practice. PMID- 22828063 TI - Partnership for a healthy work environment: tele-ICU/ICU collaborative. AB - The tele-intensive care unit (ICU) provides a remote monitoring system that adds an additional layer of support for critically ill patients. However, to optimize contributions, the bedside team must incorporate this resource into the patient's plan of care. Using the American Association of Critical-Care Nurses' Healthy Work Environment Standards as a platform, we can create and nurture a new partnership model. Strategies that embrace the standards of skilled communication, true collaboration, and effective decision making become mutual goals for improving patient safety and outcomes. Joint communication guidelines facilitate timely and meaningful communication. Trust and the desire to cooperate encourage provider engagement to strengthen collaboration. The use of tele-ICU technology can assist in the interpretation and transformation of data to affect decision making at all levels to influence patient care. Through the lens of the healthy work environment, the tele-ICU/ICU partnership provides enhanced opportunities for improved patient care and team satisfaction. PMID- 22828064 TI - Tele-ICU "myth busters". AB - Tele-intensive care unit (ICU) technology has been proven to bridge the gap between available resources and quality care for many health care systems across the country. Tele-ICUs allow the standardization of care and provide a second set of eyes traditionally not available in the ICU. A growing body of literature supports the use of tele-ICUs based on improved outcomes and reduction in errors. To date, the literature has not effectively outlined the limitations of this technology related to response to changes in patient care, interventions, and interaction with the care team. This information can potentially have a profound impact on service expectations. Some misconceptions about tele-ICU technology include the following: tele-ICU is "watching" 24 hours a day, 7 days a week; tele ICU is a telemetry unit; tele-ICU is a stand-alone crisis intervention tool; tele ICU decreases staffing at the bedside; tele-ICU clinical roles are clearly defined and understood; and tele-ICUs are not cost-effective to operate. This article outlines the purpose of tele-ICU technology, reviews outcomes, and "busts" myths about tele-ICU technology. PMID- 22828065 TI - Tele-ICU partners enhance evidence-based practice: ventilator weaning initiative. AB - Evidence-based practice (EBP) has become more than just a trendy buzzword in health care; EBP validates care delivery methods and grants satisfaction to nurses in knowing the care they provide is based on valid, current information. Research-based enhancements are paramount to the advancement of nursing practice and prompt the implementation of creative methods to improve care. The advent of the tele-intensive care unit (ICU) introduces new members of the health care team to assist with implementation of EBP initiatives. This new partnership results in improved length of stay, mortality rates, and ventilator times for critical care patients. Current literature suggests that a clinician-driven, standardized ventilator management protocol is of significant benefit. Tele-ICU clinicians provide an interactive element to coordinate interdisciplinary team efforts. Enhanced communication, data evaluation, and timely intervention expedite the weaning process and reduce ventilator length of stay. Consistent collaboration between tele-ICU and bedside clinicians successfully improves patient outcomes through standardized adherence to best-practice initiatives. PMID- 22828066 TI - Perceptions of the care experience in critical care units enhanced by a tele-ICU. AB - The purpose of this study was to determine patients' and families' perceptions of care in 10 critical care units enhanced by a tele-intensive care unit (ICU) in a 5-hospital health care system. Patients and family members who had a critical care experience were approached for participation. An adapted version of the Schmidt Perception of Nursing Care Survey was administered. The Schmidt Perception of Nursing Care Survey factors--seeing the individual patient, explaining, responding, and watching over-were analyzed for 637 participants (263 before and 374 after the tele-ICU implementation). Analysis of data from patients and family members indicated significantly higher means for the following factors: seeing the individual patient (P =.004), responding (P =.002), and watching over (P =.006) only when there was an awareness by the patient and family members that the care team was at the bedside and at the tele-ICU command center. The perceptions of care in these cases may suggest an improved patient experience when a tele-ICU is part of the care team. PMID- 22828067 TI - Innovative use of tele-ICU in long-term acute care hospitals. AB - Tele-intensive care units (ICUs) typically provide remote monitoring for ICUs of acute care, short-stay hospitals. As part of a joint venture project to establish a long-term acute level of care, Good Shepherd Penn Partners became the first facility to use tele-ICU technology in a nontraditional setting. Long-term acute care hospitals care for patients with complex medical problems. We describe describes the benefits and challenges of integrating a tele-ICU program into a long-term acute care setting and the impact this model of care has on patient care outcomes. PMID- 22828068 TI - Virtual rapid response: the next evolution of tele-ICU. AB - The first of its kind in the Veterans Affairs (VA) system, the Denver VA Medical Center's tele-intensive care unit (ICU) program is unique because it is entirely nurse driven. A nontraditional tele-ICU model, the program was tailored to meet the needs of rural veterans by using critical care nursing expertise in Denver, Colorado. An experienced CCRN-certified nurse manages the system 24 hours a day, 7 days a week, from Eastern Colorado Health Care System. The virtual ICU provides rapid response interventions through virtual technology. This tele-ICU technology allows for a "virtual handshake" by nursing staff at the start of the shift and a report on potential patient issues. Clinical relationships have been strengthened between all 5 VA facilities in the Rocky Mountain Region, increasing the likelihood of early consultation at the onset of clinical decline of a patient. In addition, the tele-ICU nurse is available for immediate nursing consultation and support, coordinates point-to-point virtual consultation between physicians at the rural sites and specialists in Denver, and assists in expediting critical care transfers. The primary objectives for the tele-ICU program include improving quality and access of care to critical care services in rural sites, reducing community fee basis costs and frequency of transfers, and increasing collaboration and collegiality among nursing and medical staff in all Region 19's medical centers. PMID- 22828069 TI - ECG characteristics of acute pericarditis. PMID- 22828070 TI - PI(3)P-independent and -dependent pathways function together in a vacuolar translocation sequence to target malarial proteins to the host erythrocyte. AB - Malaria parasites export 'a secretome' of hundreds of proteins, including major virulence determinants, from their endoplasmic reticulum (ER), past the parasite plasma and vacuolar membranes to the host erythrocyte. The export mechanism is high affinity (nanomolar) binding of a host (cell) targeting (HT) motif RxLxE/D/Q to the lipid phosphatidylinositol 3-phosphate (PI(3)P) in the ER. Cleavage of the HT motif releases the secretory protein from the ER membrane. The HT motif is thought to be the only export signal resident in an N-terminal vacuolar translocation sequence (VTS) that quantitatively targets green fluorescent protein to the erythrocyte. We have previously shown that the R to A mutation in the HT motif, abrogates VTS binding to PI(3)P (K(d)>5 MUM). We now show that remarkably, the R to A mutant is exported to the host erythrocyte, for both membrane and soluble reporters, although the efficiency of export is reduced to ~30% of that seen with a complete VTS. Mass spectrometry indicates that the R to A mutant is cleaved at sites upstream of the HT motif. Antibodies to upstream sequences confirm that aberrantly cleaved R to A protein mutant is exported to the erythrocyte. These data suggest that export mechanisms, independent of PI(3)P as well as those dependent on PI(3)P, function together in a VTS to target parasite proteins to the host erythrocyte. PMID- 22828071 TI - Preservation of biological activity of glial cell line-derived neurotrophic factor (GDNF) after microencapsulation and sterilization by gamma irradiation. AB - A main issue in controlled delivery of biotechnological products from injectable biodegradable microspheres is to preserve their integrity and functional activity after the microencapsulation process and final sterilization. The present experimental work tested different technological approaches to maintain the biological activity of an encapsulated biotechnological product within PLGA [poly (lactic-co-glycolic acid)] microspheres (MS) after their sterilization by gamma irradiation. GDNF (glial cell line-derived neurotrophic factor), useful in the treatment of several neurodegenerative diseases, was chosen as a labile model protein. In the particular case of optic nerve degeneration, GDNF has been demonstrated to improve the damaged retinal ganglion cells (RGC) survival. GDNF was encapsulated in its molecular state by the water-in-oil-in-water (W/O/W) technique or as solid according to the solid-in-oil-in-water (S/O/W) method. Based on the S/O/W technique, GDNF was included in the PLGA microspheres alone (S/O/W 1) or in combination with an antioxidant (vitamin E, Vit E) (S/O/W 2). Microspheres were sterilized by gamma-irradiation (dose of 25 kGy) at room and low (-78 degrees C) temperatures. Functional activity of GDNF released from the different microspheres was evaluated both before and after sterilization in their potential target cells (retinal cells). Although none of the systems proposed achieved with the goal of totally retain the structural stability of the GDNF dimer, the protein released from the S/O/W 2 microspheres was clearly the most biologically active, showing significantly less retinal cell death than that released from either W/O/W or S/O/W 1 particles, even in low amounts of the neurotrophic factor. According to the results presented in this work, the biological activity of biotechnological products after microencapsulation and sterilization can be further preserved by the inclusion of the active molecule in its solid state in combination with antioxidants and using low temperature (-78 degrees C) during gamma irradiation exposure. PMID- 22828072 TI - Liposomal diclofenac eye drop formulations targeting the retina: formulation stability improvement using surface modification of liposomes. AB - An efficient liposomal formulation for targeting the retina was produced as an optimal means of distributing therapeutic agents to the retina. Diclofenac was used as a model compound for liposome encapsulation, and the release rate and distribution to the retina were investigated. The calcium acetate gradient method was found to be the optimal method for encapsulating diclofenac into liposomes. Entrapment efficiency using this method was greater than 97%, whereas conventional hydration method achieved 51.3%. The resultant formulation obtained with the gradient method caused aggregation and/or fusion of liposomes. To avoid inhibition of retinal delivery due to the aggregation of the carrier, surface modification was performed simultaneously with the gradient method. The increase in particle size of the liposomal formulation clearly was inhibited for a long time in the presence of polyvinyl alcohol or its derivative. This observation may be explained by surface modification of the liposomes by physisorption or anchoring effect of polymers on the surface of the lipid bilayer. Furthermore, the sustained release profile of the diclofenac formulation was retained after modification. An in vivo animal study revealed that concentration of the accumulated diclofenac in the retina-choroid was enhanced 1.8-fold by surface modified liposome entrapment compared to that of the unaltered diclofenac solution. PMID- 22828073 TI - Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma. AB - BACKGROUND: For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays) craniospinal irradiation (CSI). The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n <= 3) and have not considered the use of age-dependent target volumes in proton CSI. METHODS: Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2-16, BMI 16.4-37.9 kg/m2). Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue. RESULTS: Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V5, V10, V15, and V20 in the esophagus, heart, liver, thyroid, kidneys, and lungs) Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p <= 0.05) . Specifically, V15 and V20 in all six organs and V5, V10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI. CONCLUSIONS: Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for developing radiogenic late effects. Although the present study focused on medulloblastoma, our findings are generally applicable to other tumors that are treated with CSI. PMID- 22828074 TI - Opening of the TAR hairpin in the HIV-1 genome causes aberrant RNA dimerization and packaging. AB - BACKGROUND: The TAR hairpin is present at both the 5' and 3' end of the HIV-1 RNA genome. The 5' element binds the viral Tat protein and is essential for Tat mediated activation of transcription. We recently observed that complete TAR deletion is allowed in the context of an HIV-1 variant that does not depend on this Tat-TAR axis for transcription. Mutations that open the 5' stem-loop structure did however affect the leader RNA conformation and resulted in a severe replication defect. In this study, we set out to analyze which step of the HIV-1 replication cycle is affected by this conformational change of the leader RNA. RESULTS: We demonstrate that opening the 5' TAR structure through a deletion in either side of the stem region caused aberrant dimerization and reduced packaging of the unspliced viral RNA genome. In contrast, truncation of the TAR hairpin through deletions in both sides of the stem did not affect RNA dimer formation and packaging. CONCLUSIONS: These results demonstrate that, although the TAR hairpin is not essential for RNA dimerization and packaging, mutations in TAR can significantly affect these processes through misfolding of the relevant RNA signals. PMID- 22828075 TI - Torque expression of 0.018 and 0.022 inch conventional brackets. AB - The aim of this study was to assess the effect of the moments generated with low- and high-torque brackets. Four different bracket prescription-slot combinations of the same bracket type (Mini Diamond(r) Twin) were evaluated: high-torque 0.018 and 0.022 inch and low-torque 0.018 and 0.022 inch. These brackets were bonded on identical maxillary acrylic resin models with levelled and aligned teeth and each model was mounted on the orthodontic measurement and simulation system (OMSS). Ten specimens of 0.017 * 0.025 inch and ten 0.019 * 0.025 inch stainless steel archwires (ORMCO) were evaluated in the low- and high-torque 0.018 inch and 0.022 inch brackets, respectively. The wires were ligated with elastomerics into the brackets and each measurement was repeated once after religation. Two-way analysis of variance and t-test were conducted to compare the generated moments between wires at low- and high-torque brackets separately. The maximum moment generated by the 0.017 * 0.025 inch stainless steel archwire in the 0.018 inch brackets at +15 degrees ranged from 14.33 and 12.95 Nmm for the high- and low torque brackets, respectively. The measured torque in the 0.022 inch brackets with the 0.019 * 0.025 inch stainless steel archwire was 9.32 and 6.48 Nmm, respectively. The recorded differences of maximum moments between the high- and low-torque series were statistically significant. High-torque brackets produced higher moments compared with low-torque brackets. Additionally, in both high- and low-torque configurations, the thicker 0.019 * 0.025 inch steel archwire in the 0.022 inch slot system generated lower moments in comparison with the 0.017 * 0.025 inch steel archwire in the 0.018 inch slot system. PMID- 22828076 TI - Impacted maxillary canines and root resorptions of neighbouring teeth: a radiographic analysis using cone-beam computed tomography. AB - The study analyses the location of impacted maxillary canines and factors influencing root resorptions of adjacent teeth using cone-beam computed tomography (CBCT). In addition, the interrater reliability between observers of two different dental specialties for radiographic parameters will be evaluated. CBCT images of patients who were referred for radiographic localization of impacted maxillary canines and/or suspicion of root resorptions of adjacent teeth were included. The study analysed the exact three-dimensional location of the impacted canines in the anterior maxilla, frequency and extent of root resorptions, and potential influencing factors. To assess interrater agreement, Cohen's correlation parameters were calculated. This study comprises 113 patients with CBCT scans, and 134 impacted canines were analysed retrospectively. In the patients evaluated, 69 impacted canines were located palatally (51.49 per cent), 41 labially (30.60 per cent), and 24 (17.91 per cent) in the middle of the alveolar process. Root resorptions were found in 34 lateral incisors (25.37 per cent), 7 central incisors (5.22 per cent), 6 first premolars (4.48 per cent), and 1 second premolar (0.75 per cent). There was a significant correlation between root resorptions on adjacent teeth and localization of the impacted canine in relation to the bone, as well as vertical localization of the canine. Interrater agreement showed values of 0.546-0.877. CBCT provides accurate information about location of the impacted canine and prevalence and degree of root resorption of neighbouring teeth with high interrater correlation. This information is of great importance for surgeons and orthodontists for accurate diagnostics and interdisciplinary treatment planning. PMID- 22828077 TI - Stability of anterior open bite correction of adults treated with lingual appliances. AB - The aim of this study was to evaluate retrospectively the stability of treatment outcomes of adult anterior open bite (AOpB) cases, treated non-surgically, using a conservative approach with lingual orthodontics (LO). Thirty-nine adult AOpB patients consecutively treated by one operator (SG), with OrmcoTM Generation 7 LO brackets and a conservative treatment protocol, with or without extractions, were evaluated clinically before treatment, at the end of active orthodontic treatment, and after a follow-up period, divided into a short-term group (ST): 1 2 years post-treatment, and a long-term group (LT): more than 2 years and up to 11 years post-treatment. All patients had a positive overbite at the end of active treatment (T2). Stability of the open bite correction was seen in 87.2 per cent of the patients (T3). Relapse to a negative overbite was seen in one patient (2.5 per cent). Post-treatment improvement of the overbite was demonstrated, with no difference between the ST and the LT groups. Stability of the transverse molar relations was significantly correlated with stability of AOpB correction. The LO appliance with the presented treatment protocol is a viable procedure for AOpB correction in adult patients, who are not suitable for surgical procedures, to improve or to enhance facial aesthetics. Post-treatment improvement of the overbite was observed in patients treated with this treatment approach in this study. PMID- 22828078 TI - Is the use of the cervical vertebrae maturation method justified to determine skeletal age? A comparison of radiation dose of two strategies for skeletal age estimation. AB - The aim of this study was to assess effective doses of a lateral cephalogram radiograph with and without thyroid shield and compare the differences with the radiation dose of a hand-wrist radiograph. Thermoluminescent dosimeters were placed at 19 different sites in the head and neck of a tissue-equivalent human skull (RANDO phantom). Analogue lateral cephalograms with and without thyroid shield (67 kV, 250 mA, 10 mAs) and hand-wrist radiographs (40 kV, 250 mA, 10 mAs) were obtained. The effective doses were calculated using the 2007 International Commission on Radiological Protection recommendations. The effective dose for conventional lateral cephalogram without a thyroid shield was 5.03 microsieverts (uSv). By applying a thyroid shield to the RANDO phantom, a remarkable dose reduction of 1.73 uSv could be achieved. The effective dose of a conventional hand-wrist radiograph was calculated to be 0.16 uSv. Adding the effective dose of the hand-wrist radiograph to the effective dose of the lateral cephalogram with thyroid shield resulted in a cumulative effective dose of 3.46 uSv. Without thyroid shield, the effective dose of a lateral cephalogram was approximately 1.5 fold increased than the cumulative effective dose of a hand-wrist radiograph and a lateral cephalogram with thyroid shield. Thyroid is an organ that is very sensitive to radiation exposure. Its shielding will significantly reduce the effective dose. An additional hand-wrist radiograph, involving no vulnerable tissues, however, causes very little radiation risk. In accordance with the ALARA (As Low As Reasonably Achievable) principle, if an evaluation of skeletal age is indicated, an additional hand-wrist radiograph seems much more justifiable than removing the thyroid shield. PMID- 22828079 TI - Bite force and its association with stability following Class II/1 functional appliance treatment. AB - The aims of this study were to investigate the value of pre-treatment maximal molar bite force as a predictive variable in determining post-treatment changes and stability following functional appliance treatment in Class II malocclusion children. Twenty-eight Class II malocclusion children having undergone functional appliance treatment were followed for at least 1 year post-treatment. Maximal molar bite force measurements, lateral cephalograms, and study casts were taken before treatment, after treatment, and after post-treatment follow-up. Relationships between pre-treatment maximal molar bite force and dental or cephalometric changes post-treatment were examined. Patients were divided into stable and unstable groups, based on dental sagittal changes (overjet and molar relationship), and differences between the two groups of patients determined. Post-treatment changes varied widely. Thirteen children showed dentoalveolar sagittal relapse, namely a shift in molars towards a Class II relationship and an increase in overjet, while 15 did not. The unstable group demonstrated a lower pre-treatment maximal molar bite force, as well as a more obtuse gonial angle, than the stable group. The gonial angle was found to be negatively correlated to maximal molar bite force and may thus be a cephalometric indicator partly reflecting the functional condition of the masticatory muscles. Children with a lower pre-treatment maximal molar bite force were more prone to dentoalveolar sagittal relapse following functional appliance treatment. PMID- 22828080 TI - Reduced masticatory function is related to lower satellite cell numbers in masseter muscle. AB - The physiology of masseter muscles is known to change in response to functional demands, but the effect on the satellite cell (SC) population is not known. In this study, the hypothesis is tested that a decreased functional demand of the masseter muscle causes a reduction of SCs. To this end, twelve 5-week-old male Sprague-Dawley rats were put on a soft diet (SD, n = 6) or a hard diet (HD, n = 6) and sacrificed after 14 days. Paraffin sections of the superficial masseter and the m. digastricus (control muscle) were stained with haematoxylin and eosin for tissue survey and with anti-myosin heavy chain (MHC) for slow and fast fibres. Frozen sections of both muscles were double-stained for collagen type IV and Pax7. Slow MHC fibres were equally distributed in the m. digastricus but only localized in a small area of the m. masseter. No differences between HD or SD for the m. digastricus were found. The m. masseter had more SCs per fibre in HD than in SD (0.093 +/- 0.007 and 0.081 +/- 0.008, respectively; P = 0.027). The m. masseter had more fibres per surface area than the m. digastricus in rats with an SD group (758.1 +/- 101.6 and 568.4 +/- 85.6, P = 0.047) and a HD group (737.7 +/ 32.6 and 592.2 +/- 82.2; P = 0.007). The m. digastricus had more SCs per fibre than the m. masseter in the SD group (0.094 +/- 0.01 and 0.081 +/- 0.008; P = 0.039). These results suggest that reduced masseter muscle function is related to a lower number of SCs. Reduced muscle function might decrease microdamage and hence the requirement of SCs in the muscle fibres. PMID- 22828081 TI - Gingival recessions and the change of inclination of mandibular incisors during orthodontic treatment. AB - SUMMARY A recent systematic review demonstrated that, overall, orthodontic treatment might result in a small worsening of periodontal status. The aim of this retrospective study was to test the hypothesis that a change of mandibular incisor inclination promotes development of labial gingival recessions. One hundred and seventy-nine subjects who met the following inclusion criteria were selected: age 11-14 years at start of orthodontic treatment (TS), bonded retainer placed immediately after treatment (T0), dental casts and lateral cephalograms available pre-treatment (TS), post-treatment (T0), 2 years post-treatment (T2), and 5 years post-treatment (T5). Depending on the change of lower incisor inclination during treatment (DeltaInc_Incl), the sample was divided into three groups: Retro (N = 34; DeltaInc_Incl <= -1 degree), Stable (N = 22; DeltaInc_Incl > -1 degree and <=1 degree), and Pro (N = 123; DeltaInc_Incl > 1 degree). Clinical crown heights of mandibular incisors and the presence of gingival recessions in this region were assessed on plaster models. Fisher's exact tests, one-way analysis of variance, and regression models were used for analysis of inter-group differences. The mean increase of clinical crown heights (T0 to T5) of mandibular incisors ranged from 0.6 to 0.91 mm in the Retro, Stable, and Pro groups, respectively; the difference was not significant (P = 0.534). At T5, gingival recessions were present in 8.8, 4.5, and 16.3 per cent patients from the Retro, Stable, and Pro groups, respectively. The difference was not significant (P = 0.265). The change of lower incisors inclination during treatment did not affect development of labial gingival recessions in this patient group. PMID- 22828082 TI - Changes in prevalence, awareness, treatment and control of hypertension in Thai population, 2004-2009: Thai National Health Examination Survey III-IV. AB - OBJECTIVE: To determine the changes in prevalence, awareness, treatment and control of hypertension and their metabolic risk factors in Thai population between 2004 and 2009. METHODS: The Thai National Health Examination Survey (NHES) in 2004 and 2009 data were used. Blood pressure and anthropometric measurements were performed. Prevalence, awareness, treatment and control of hypertension of Thai population aged at least 15 years were calculated. Analyses were weighted to the probability of sampling. RESULTS: The prevalence of hypertension in 2004 and 2009 were relatively stable at approximately 21.0%. There was improvement in awareness of hypertension, from 18.2% for men and 33.0% for women in 2004 to 39.5 and 59.4% in 2009, respectively. The high blood pressure control rates improved from 4.8 to 14.4% for men and from 10.8 to 27.2% for women, respectively (all P < 0.05). The improvement in awareness, treatment and control of hypertension was also observed in individuals with diabetes, obesity and hypercholesterolemia. However, among hypertensive individuals, there were increases in proportions of obesity (BMI >= 25 kg/m(2)) between two surveys: from 39.1 to 47.5% in men and from 54.6 to 62.9% in women, respectively (all P < 0.05). CONCLUSION: Despite improvement in awareness and control of hypertension in Thai population, a large proportion of hypertensive individuals remained suboptimally controlled. Strengthening measures to control high blood pressure and metabolic risk factors, especially obesity and hypercholesterolemia, in individuals with hypertension are needed. PMID- 22828083 TI - Dual neural endopeptidase/endothelin-converting [corrected] enzyme inhibition improves endothelial function in mesenteric resistance arteries of young spontaneously hypertensive rats. AB - BACKGROUND: Endothelin-1 (ET1) is a potent vasoconstrictor peptide with pro mitogenic and pro-inflammatory properties and is therefore of interest in the development of endothelial dysfunction, endothelium-dependent flow-related remodeling, and hypertension-related remodeling. ET1 can be formed through cleavage of big ET1 by endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). METHOD: We investigated whether the dual NEP/ECE inhibitor SOL1 improves resistance artery function and structure in 12 weeks old spontaneously hypertensive rats (SHRs) and whether arterial structural responses to decreased (-90%) or increased (+100%) blood flow are impaired in young SHRs. To this end two groups of SHRs received chronic 4-week treatment at two different time points (4-8 and 8-12 weeks) prior to the experiment. We compared in-vitro effects of cyclo-oxygenase inhibition (1 MUmol/l indomethacine), nitric oxide synthase inhibition (100 MUmol/l N(omega)-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 MUmol/l acetylcholine (ACh) in isolated third-order mesenteric arteries of SHRs and aged-matched Wistar-Kyoto (WKY) rats. RESULTS: SOL1 had no effect on blood pressure in SHRs or WKY rats. ACh caused biphasic effects in mesenteric arteries of SHRs. The contractile component (endothelium-derived contractile factor) was absent in WKY and abolished by acute indomethacin administration or chronic SOL1 treatment. Endothelium-derived nitric oxide-type responses did not differ in both strains and were not influenced by SOL1 treatment. Endothelium-derived hyperpolarizing factor-type responses were severely impaired in SHRs as compared to WKY rats and were normalized by chronic SOL1 treatment. In first-order mesenteric arteries, outward flow-induced remodeling was impaired in SHRs. Chronic SOL1 treatment did not restore this response. CONCLUSION: Thus chronic SOL1 treatment during the development of hypertension in SHRs has no effect on blood pressure but improves several aspects of endothelium-dependent vasomotor responses but not arterial remodeling. PMID- 22828084 TI - Angiotensin II-induced mitochondrial reactive oxygen species and peroxiredoxin-3 expression in cardiac fibroblasts. AB - OBJECTIVE: The aim of this study was to determine whether angiotensin II (ANG II) affects the protein and mRNA expression of the mitochondrial antioxidant peroxiredoxin-3 (Prx-3) in cardiac fibroblasts, thereby contributing to the oxidative stress in the myocardium. METHOD: Cardiac fibroblasts (passage 2) from normal male adult rats were cultured to confluency and incubated in Dulbecco's modified Eagle's medium for 24 h. The cells were then preincubated with(out) the tested inhibitors for 1 h and further incubated with/without ANG II (1 MUmol/l) for 24 h. RESULTS: ANG II increased (P < 0.001) the mitochondrial production of reactive oxygen species in cardiac fibroblasts from 187.8 +/- 38.6 to 313.8 +/- 30.6 a.u./mg mitochondrial protein (n = 15). ANG II decreased (P < 0.01) the mRNA and protein expression of Prx-3 by 36.9 +/- 3.0% and 29.7 +/- 2.7% (n = 4), respectively. The ANG II-induced decrease in mRNA expression of Prx-3 was prevented by the angiotensin type 1 receptor blocker, losartan but not by the angiotensin type 2 receptor blocker, PD 123 319. CONCLUSION: Our data indicate that ANG II-stimulated mitochondrial reactive oxygen species production in rat cardiac fibroblasts is accompanied by a reduction in the expression of the mitochondrial antioxidant Prx-3, and thereby potentially contributing to oxidative stress in the myocard. PMID- 22828085 TI - Trends in blood pressure in 9 to 11-year-old children in the United Kingdom 1980 2008: the impact of obesity. AB - OBJECTIVES: High blood pressure (BP) is a major public health issue, both in the United Kingdom and worldwide. Although BP levels in UK adults are declining, there is little published information on BP trends in children, a particular concern in the context of the rising levels of childhood adiposity. Our aims are to determine whether BP in children has changed over time and whether the change reflected trends in adiposity. METHODS: We collated data from seven population based BP studies conducted in the United Kingdom between 1980 and 2008. Children of white European origin were included (9-11 years, mean 10.3 years). Adjustments were made to account for differences in mean ages, BP devices and cuff sizes used in different studies. RESULTS: Mean SBP increased over time both in boys and girls: annual increases were 0.45 mmHg (95% CI: 0.43, 0.48) for boys; 0.51 mmHg (0.49, 0.53) for girls. Mean BMI increased by 0.064 kg/m(2) (0.060, 0.068) per year for boys; 0.070 kg/m(2) (0.065, 0.074) for girls; the prevalence of overweight/obesity increased from 5.7 to 21.1% and from 9.7 to 24.1%, respectively. The SBP trends occurred both in children with low and high BMI, but were more marked in low BMI group; BMI explained only 15.3% (15.1%, 15.6%) of increases in SBP for boys and 14.9% (14.6%, 15.1%) for girls. The BMI/SBP association appeared to become weaker over time (P < 0.001 for negative interaction from 1984). There was only a modest annual increase in DBP (<0.1 mmHg). CONCLUSIONS: SBP levels have increased with time, but the increase is not explained by increased BMI. Further research is needed to identify the factors responsible. PMID- 22828087 TI - The conventional versus automated measurement of blood pressure in the office (CAMBO) trial: masked hypertension sub-study. AB - OBJECTIVES: To determine the prevalence of masked hypertension [normal office blood pressure (BP) with high awake ambulatory BP] using automated office BP (AOBP) or conventional manual office BP (MOBP) measurement in routine clinical practice. METHODS: The prevalence of masked hypertension was evaluated on three consecutive visits during a median 6 months period in patients with systolic hypertension randomized to management with AOBP (n = 140) or continued conventional MOBP (n = 112) in routine primary care practice. AOBP was recorded using the automated BpTRU device with the patient resting alone in a quiet examining room. All patients underwent 24-h ambulatory BP monitoring. RESULTS: The prevalence of masked hypertension on any one of three visits calculated using only SBP varied between 12 and 17% in the AOBP group compared with 19 and 22 % in the MOBP group. Masked hypertension was present on both of the first two visits in 7 and 12% and on all three visits in 6 and 7% of AOBP and MOBP patients, respectively. The prevalence for masked hypertension based upon both SBP and DBP was similar being 11-15% for AOBP and 19-20% for MOBP patients on single visits, but decreased to 6 and 10% when readings from the first two visits were used and to 4 and 6% when all three visits were used for the AOBP and MOBP groups, respectively. CONCLUSION: The prevalence of masked hypertension is lower with AOBP compared with MOBP. The number of patients with masked hypertension decreases if the criteria for having this condition need to be met on multiple visits. PMID- 22828086 TI - Oscillometric blood pressure percentiles for Polish normal-weight school-aged children and adolescents. AB - OBJECTIVE: The objective of this study was to construct blood pressure (BP) references with the use of a validated oscillometric device for normal-weight, school-aged children and adolescents and to study BP predictors. METHODS: BP was measured in 14 266 randomly selected, normal-weight Polish children and adolescents aged 7-18 years, who were free of chronic disease, using a validated oscillometric device (Datascope Accutor Plus). Height, weight and waist circumference were measured. BP percentiles were constructed for age and height simultaneously with the use of a polynomial regression model. The normative values of BP were compared with the US normal-weight reference, German oscillometric reference, and Polish auscultatory reference. RESULTS: Reference BP percentiles by sex, age and height are presented. At median height, the age specific differences in the 90th BP percentiles compared with German oscillometric reference ranged in the case of boys from -3 to 2 mmHg and from -5 to -1 mmHg, SBP and DBP, respectively, and in the case of girls from 0 to 3 mmHg and from -5 to -1 mmHg, SBP and DBP, respectively. As compared to weight, waist circumference was stronger SBP predictor in low birth weight boys. CONCLUSION: The study provides BP references for oscillmetric device, based on a current, nationally representative sample of normal-weight Polish children and adolescents. The normative values of BP were compared taking into consideration the height and BMI differences, the pubertal spurt, the methods of BP measurement and percentile construction. PMID- 22828088 TI - Hypertensive left ventricular hypertrophy: a mechanistic approach to optimizing regression assessed by cardiovascular magnetic resonance. AB - OBJECTIVES: Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not. METHODS: Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM). RESULTS: All BP indices were highly comparable at the start and end of the trial (P > 0.6 between groups). BP was reduced (always P < 0.0001) by 37/17 mmHg in the valsartan and moxonidine group and 38/19 mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P < 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9 g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3 g; -23.3 to -13.4) (P < 0.05). CONCLUSION: The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH. PMID- 22828089 TI - An update on biomarkers of heart failure in hypertensive patients. AB - Biomarkers should have high sensitivity, specificity, reproducibility, be cost effective, and provide incremental predictive or diagnostic utility over standard risk factors or tests. Despite numerous studies investigating biomarkers in heart failure (HF), there are only a few that predict HF in hypertensive patients. This article summarizes data from numerous studies concerning possible biomarkers of HF in hypertensive patients such as: serum uric acid (SUA), interleukins, monocyte chemoattractant protein one (MCP-1), cardiotrophin-1 (CT-1), carboxy terminal propeptide of procollagen type I (PICP), type I collagen telopeptide (CITP) and N-terminal propeptide of type III procollagen (PIIINP), metalloproteinases (MMPs), B-type natriuretic peptide (BNP) and its derivatives, glycoprotein CA125 and cystatin C. Early detection of patients of increased risk of hypertensive heart disease may result in early implementation of effective preventive strategies. Therefore, there is need to identify newer biomarkers, if they can improve risk prediction, identifying patients, in which earlier or more aggressive intervention will improve clinical outcomes. PMID- 22828092 TI - Office gynecology in the internet age. AB - Historically, the stethoscope is representative of the type of medical tool that dominated the clinician-patient interaction. In the future, electronic tools will dominate the clinician-patient interaction. Most electronic tools will be accessed through the internet. The internet will become a key portal for enhancing the doctor-patient relationship. PMID- 22828093 TI - Electronic medical records: caveats for users. AB - Electronic medical records are becoming a necessity for modern practice. The concepts needed to understand the readiness, selection, implementation, and optimization of electronic medical records are presented. PMID- 22828090 TI - Clinic and ambulatory blood pressure lowering effect of aliskiren/amlodipine/hydrochlorothiazide combination in patients with moderate-to severe hypertension: a randomized active-controlled trial. AB - OBJECTIVES: To evaluate the clinic and ambulatory blood pressure (BP)-lowering efficacy and safety of an aliskiren/amlodipine/hydrochlorothiazide (HCT) triple combination compared with the component dual combinations, in patients with moderate-to-severe hypertension. METHODS: This 8-week, double-blind, randomized, active-controlled study, after 1-4 weeks single-blind placebo run-in period, randomized 1191 patients to receive once-daily aliskiren/amlodipine 150/5 mg (n = 287), aliskiren/HCT 150/12.5 mg (n = 298), amlodipine/HCT 5/12.5 mg (n = 296), or aliskiren/amlodipine/HCT 150/5/12.5 mg (up-titrated from aliskiren/HCT 150/12.5 mg after initial 3 days) (n = 310) for 4 weeks, followed by forced titration to double the initial dose for the next 4 weeks. RESULTS: Baseline mean sitting SBP and DBP (msSBP/msDBP) was comparable among treatment groups. The aliskiren/amlodipine/HCT combination resulted in significant least squares mean reduction in msSBP/msDBP from baseline to endpoints (week 4, -30.7/-15.9 mmHg; week 8, -37.9/-20.6 mmHg), superior (P < 0.001) to each of the dual combinations. The triple combination was associated with -27.8 mmHg reduction in msSBP at week 2, significantly better than the dual combinations (P < 0.05). Significantly greater mean SBP/DBP-lowering effect for triple vs. dual combinations was also demonstrated through 24-h, daytime, and night-time ambulatory BP measurements. Significantly greater (P < 0.001) BP control (msSBP/msDBP < 140/90 mmHg) was achieved with triple combination in patients with moderate-to-severe (62.3%) and severe (57.5%) hypertension. CONCLUSION: Aliskiren/amlodipine/HCT at 150/5/12.5 mg (week 4) and 300/10/25 mg (week 8) provided statistically superior reductions in msSBP/msDBP and greater BP control rates vs. the dual combinations, and was well tolerated. The improved efficacy of BP reduction was evident within 2 weeks of initiating triple therapy even at low dose. PMID- 22828094 TI - Patient safety in the ambulatory OB/GYN setting. AB - The frequency of surgical procedures in the office setting is increasing, and patient safety in this setting now has an expanded focus. Methods and strategies, including Ambulatory Patient Safety Guidelines, results tracking, communication, and risk management principles, will be reviewed in this chapter. PMID- 22828095 TI - Office procedures: practical and safety considerations. AB - Gynecologic invasive procedures have moved into the physician's office due to improved reimbursement and convenience. Creating a just and safe office culture has generated robust conversations in the medical literature. This article reviews the foundational principles relating to safe practices in the office including: checklists, drills, selecting a safety officer, achieving office certification, medication usage, and engaging the patient in the safety culture. Reduction of medical errors in the office will require open dialogue between the stake holders: providers, insurers, patients, state and federal agencies, and educational bodies such as the American College of Obstetricians and Gynecologists. PMID- 22828096 TI - Office diagnosis and management of abnormal uterine bleeding. AB - Abnormal uterine bleeding is one of the most common presenting complaints encountered in a gynecologist's office or primary care setting. The availability of diagnostic tools, such as ultrasound, endometrial sampling, and diagnostic hysteroscopy has made it possible to promptly diagnose and treat an increasing number of menstrual disorders in an office setting. The incorporation of newer medical therapies: antifibrinolytic drugs, shorter hormone-free interval oral contraceptive pills, and levonorgestrel inserts along with office minimally invasive treatments operative hysteroscopy and endometrial ablations have proven to be powerful therapeutic arsenals to provide short-term relief of abnormal uterine bleeding, and potentially, avoiding or delaying the hysterectomy. PMID- 22828097 TI - Adolescent gynecology: special considerations for special patients. AB - Developments in the field of adolescent gynecology highlight the specific expertise and care required by this population. Given the ability to shape their future health choices, adolescents are a critical target for preventative health care. The approach to the evaluation and management of this unique population rests not only on the practitioner's adept ability to recognize the unique clinical challenges that may occur, but also rests on his/her understanding of these problems. Here, we review recent guidelines and practice patterns in the evaluation and management of issues in adolescent gynecology. PMID- 22828098 TI - Breast cancer screening: clinical, radiologic, and biochemical. AB - Breast cancer screening is a highly complex and more recently a controversial topic. Conventional screening includes breast self-examination, clinical breast examination, and screening mammography. Several newer imaging modalities have been introduced into the screening armamentarium including breast magnetic resonance imaging and whole-breast automated ultrasound. Novel imaging techniques like positron emission mammography are currently under clinical investigation in the hopes of improving the sensitivity of breast cancer screening. In addition, the development of biochemical assays, which employ minimally invasive sampling are also promising. PMID- 22828099 TI - HPV: diagnosis, prevention, and treatment. AB - Human papilloma virus (HPV) is the most common sexually transmitted disease in the world. Almost 80% of the world's population is exposed by the age of 50. HPV can cause oropharyngeal, genital, and anal cancers. It also causes genital warts. There is no cure for HPV but vaccines are available to prevent infection by the most common HPV viruses; unfortunately, usage is low. Most people will clear HPV spontaneously. Those who do not are at high risk for developing malignancy. Treatment mainstays are destruction and excision of the lesions. PMID- 22828100 TI - Osteoporosis: screening and treatment in women. AB - Osteoporosis is frequently called the silent disease because it lacks symptoms or signs until a fracture has occurred. Osteoporosis is common in aging women because of progressive postmenopausal bone loss. Fractures related to bone loss can result in reduced quality of life, lengthy hospital stays, long-term institutionalization, and death. Early diagnosis and treatment of low bone mass to reduce fracture risk is a cost-effective element of routine health care for women. With appropriate patient screening, ObGyn care providers can implement effective interventions before fractures occur, thereby improving patients' quality of life and reducing society's osteoporosis-related costs. PMID- 22828101 TI - The modern infertility evaluation. AB - The modern diagnostic evaluation of the infertile couple reflects a growing reliance on assisted reproductive technologies and the trend toward a more evidence-based medical practice. The recommended evaluation no longer includes some of the traditional diagnostic tests, applies other tests more selectively, and includes a new test that helps to define a couple's prognosis and best choice of treatment. All tests are easily performed, allowing clinicians to complete a basic but still thorough evaluation quickly and easily. PMID- 22828102 TI - What happened to WHI: menopausal hormonal therapy in 2012. AB - Menopause is characterized by amenorrhea for 1 year due to the cessation of ovarian function. The hormonal treatment of menopause has significantly altered since the publication of initial results from the Women's Health Initiative continuous, combined, conjugated equine estrogen with medroxyprogesterone acetate study arm in 2002. Current studies suggest that treatment should be individualized and that the lowest dose of estrogen providing relief should be used for the shortest period of time in menopausal women who experience vasomotor symptoms or urogenital atrophy. Future studies into different delivery mechanisms such as transdermal applications and different agents, such as tibolone and raloxifene, will help refine the treatment of menopause. PMID- 22828103 TI - Ambulatory obstetric care. Foreword. PMID- 22828104 TI - Ambulatory obstetric care. AB - Prenatal care is focused on improving the health of women and babies. Traditional models of prenatal care focus on individual provider-patient interactions. Newer models, including group prenatal care and specialty clinics, may be useful models in certain situations. PMID- 22828105 TI - Antepartum evaluation of the fetus and fetal well being. AB - Despite widespread use of many methods of antenatal testing, limited evidence exists to demonstrate effectiveness at improving perinatal outcomes. An exception is the use of Doppler ultrasound in monitoring high-risk pregnancies thought to be at risk of placental insufficiency. Otherwise, obstetricians should proceed with caution and approach the initiation of a testing protocol by obtaining an informed consent. When confronted with an abnormal test, clinicians should evaluate with a second antenatal test and consider administering betamethasone, performing amniocentesis to assess lung maturity, and/or repeating testing to minimize the chance of iatrogenic prematurity in case of a healthy fetus. PMID- 22828106 TI - Abnormal glucose metabolism: diagnosis and management in the ambulatory setting. AB - Abnormal glucose metabolism in pregnancy is a spectrum. This spectrum stretches from mild forms of glucose intolerance that do not rise to the level of diabetes, to diabetes that first occurs in pregnancy, as well as to pregravid forms of diabetes associated with end-organ disease. In this review, we first discuss risk factors common to all forms of abnormal glucose metabolism in pregnancy. A review of how abnormal glucose metabolism in pregnancy is diagnosed precedes discussion of perinatal risks associated with different degrees of glycemic aberration. We discuss how to intervene in the ambulatory setting to mitigate these risks. PMID- 22828107 TI - Ambulatory management of chronic hypertension in pregnancy. AB - Chronic hypertension in pregnancy is one of the most common medical diseases affecting pregnancy. It is associated with serious maternal and fetal complications, including superimposed pre-eclampsia, fetal growth restriction, premature delivery, placental abruption, and stillbirth. Baseline evaluation as early as possible is important to differentiate women with essential hypertension from those with severe hypertension, coexisting end-organ damage, and secondary causes of hypertension, as their risks of poor outcomes are increased. An optimal plan for maternal treatment and fetal surveillance can then be formulated. Coordination of care after delivery is important for long-term maternal health and future pregnancies. PMID- 22828108 TI - Ambulatory management of preterm labor. AB - The majority of patients with preterm labor will deliver at term, and universal treatment of preterm labor with tocolytics and antenatal corticosteroids results in widespread overtreatment while benefitting a minority of patients. Ambulatory strategies for preventing preterm birth and identifying at-risk patients are discussed. These include consideration of obstetric history, serial cervical length sonography, digital examination, and selective use of biomarker tests. Ambulatory therapies to reduce preterm birth include different formulations of progesterone and cerclage. Optimal use of antenatal corticosteroids is discussed, and a review of ambulatory management strategies for patients who are discharged home after tocolysis is conducted. PMID- 22828109 TI - Work and work-related stress in pregnancy. AB - Work, in general, does not increase the risks of pregnancy complications. Work that is stressful, physically, psychologically, or both, has deleterious effects on pregnancy. Stressful work increases the risks of miscarriage, preterm labor, preterm birth, low birth weight, and preeclampsia. The greater the stress, the greater the risks of pregnancy complications. Women with a history of pregnancy complications should be counseled about reducing stressful work before pregnancy. Women with stressful jobs should be followed closely during pregnancy, and if signs of preterm labor or delayed fetal growth develop, then occupational stress should be decreased or eliminated. Some occupations expose pregnant women to teratogens such as organic solvents, heavy metals, or pesticides. A careful work history should be part of every preconception and early pregnancy visit. PMID- 22828110 TI - Prevention and treatment of venous thromboembolism in pregnancy. AB - During pregnancy, women have a 4- to 5-fold increased risk of thromboembolism. Candidates for anticoagulation in pregnancy include women with current thrombosis, a history of thrombosis, risk factors for postpartum thrombosis, and some women with thrombophilia and a history of poor pregnancy outcome. Although, there are no large trials of anticoagulants in pregnancy and recommendations for their use are based on case series and the opinion of experts, observational studies demonstrate the benefit of heparins in reducing the risk of recurrent thromboembolism in pregnancy. A practical approach to the prevention and treatment of thromboembolism in pregnancy is outlined. PMID- 22828111 TI - Depression during pregnancy and postpartum. AB - Postpartum depression is the most common complication of pregnancy, affecting 10% to 15% of women. This condition continues to be underdiagnosed and undertreated despite increased awareness. Several risk factors have been identified including anxiety or depression during pregnancy, a history of depression, as well as increased life stressors. Treatment for depression has been found to be effective and generally safe during pregnancy and while breastfeeding. The risks and benefits of treatment must be carefully evaluated and balanced with the risk of no treatment. Careful screening may assist physicians for more timely diagnosis and intervention. PMID- 22828112 TI - Common respiratory issues in ambulatory obstetrics. AB - This article reviews the diagnosis and management of the most common respiratory conditions complicating pregnancy--asthma and influenza. We also review strategies for smoking cessation in pregnancy as, in addition to exacerbating all other pulmonary conditions, smoking is the most modifiable risk factor for poor pregnancy outcome. Moreover, the obstetrician frequently encounters each of these conditions in the ambulatory setting. A thorough knowledge of the normal pregnancy-induced physiological respiratory changes combined with a comprehensive understanding of how to manage these conditions, will provide the obstetrician with the armamentarium needed to optimize health outcomes for mothers and their fetuses. PMID- 22828113 TI - Headache and neurological disease in pregnancy. AB - A review of the approach in pregnancy to a very commonly encountered neurological disorder (headache), along with less commonly encountered neurological entities that none the less deserve the obstetrician's attention. Definitions of specific disorders and differential diagnoses are reviewed, along with treatment options and pregnancy-associated morbidities. Headache is reviewed first including the common primary headaches migraine and tension-type headache. The disabling neurological disorders-multiple sclerosis, cerebral palsy, and spinal cord injury are grouped due to common morbidities affecting pregnancy. Finally, Bell palsy is also reviewed. PMID- 22828114 TI - Renal disease in pregnancy ambulatory issues. AB - Acute and chronic renal disease will complicate prenatal care. Normal physiological changes during pregnancy make the urinary tract system more vulnerable to infectious complications or worsening of preexisting disease. Much of the focus of prenatal care includes screening for these concerns both at the onset of prenatal care and through the pregnancy and postpartum course. With careful and attentive care, the pregnancy outcome for women with significant renal disease has improved and the occurrence of renal injury or obstetric complications due to infectious insults has decreased. This manuscript reviews the current ambulatory prenatal care as it relates to the urinary tract in pregnancy. PMID- 22828115 TI - Abnormal pap smear and cervical cancer in pregnancy. AB - Pregnancy represents a unique opportunity to screen reproductive age women for cervical cancer and abnormal cervical cytology is relatively common in this population. In the absence of large, prospective clinical trials investigating the optimal management strategies for cervical dysplasia in pregnant women, consensus guidelines established by the American Society for Colposcopy and Cervical Pathology is available with considerations to this special patient population. Modalities for evaluation and management algorithms are reviewed and summarized from largely case series of pregnant women with cervical dysplasia and cervical cancer. PMID- 22828119 TI - The effect of clinician-patient alliance and communication on treatment adherence in mental health care: a systematic review. AB - BACKGROUND: Nonadherence to mental health treatment incurs clinical and economic burdens. The clinician-patient alliance, negotiated through clinical interaction, presents a critical intervention point. Recent medical reviews of communication and adherence behaviour exclude studies with psychiatric samples. The following examines the impact of clinician-patient alliance and communication on adherence in mental health, identifying the specific mechanisms that mobilise patient engagement. METHODS: In December 2010, a systematic search was conducted in Pubmed, PsychInfo, Web of Science, Cochrane Library, Embase and Cinahl and yielded 6672 titles. A secondary hand search was performed in relevant journals, grey literature and reference. RESULTS: 23 studies met the inclusion criteria for the review. The methodological quality overall was moderate. 17 studies reported positive associations with adherence, only four of which employed intervention designs. 10 studies examined the association between clinician-patient alliance and adherence. Subjective ratings of clinical communication styles and messages were assessed in 12 studies. 1 study examined the association between objectively rated communication and adherence. Meta-analysis was not possible due to heterogeneity of methods. Findings were presented as a narrative synthesis. CONCLUSIONS: Clinician-patient alliance and communication are associated with more favourable patient adherence. Further research of observer rated communication would better facilitate the application of findings in clinical practice. Establishing agreement on the tasks of treatment, utilising collaborative styles of communication and discussion of treatment specifics may be important for clinicians in promoting cooperation with regimens. These findings align with those in health communication. However, the benefits of shared decision making for adherence in mental health are less conclusive than in general medicine. PMID- 22828120 TI - A cost-benefit analysis on the specialization in departments of obstetrics and gynecology in Japan. AB - In April 2008, the specialization in departments of obstetrics and gynecology was conducted in Sennan area of Osaka prefecture in Japan, which aims at solving the problems of regional provision of obstetrical service. Under this specialization, the departments of obstetrics and gynecology in two city hospitals were combined as one medical center, whilst one hospital is in charge of the department of gynecology and the other one operates the department of obstetrics. In this paper, we implement a cost-benefit analysis to evaluate the validity of this specialization. The benefit-cost ratio is estimated at 1.367 under a basic scenario, indicating that the specialization can generate a net benefit. In addition, with a consideration of different kinds of uncertainty in the future, a number of sensitivity analyses are conducted. The results of these sensitivity analyses suggest that the specialization is valid in the sense that all the estimated benefit-cost ratios are above 1.0 in any case. PMID- 22828121 TI - From neurovascular coupling to neurovascular cascade: a study on neural, autonomic and vascular transients in attention. AB - Mental processes bring about neural, vascular and autonomic changes in the brain cortex. Due to the different nature of these modifications, their onsets show no synchrony and time dynamics is often strongly dissimilar. After acquiring data from a group of 16 subjects, we estimated temporal correlation between task and signals in order to assess possible influences induced by an attentive task on electroencephalographic (EEG), heart rate variability (HRV), oxy- and deoxy haemoglobin concentration signals. We also investigated correlations and time delays between couples of different biological signals. This allowed for the isolation of a subgroup of subjects showing similar tracks. Cardiac frequency and deoxy-haemoglobin signals displayed a strong positive correlation with the task design, while EEG alpha rhythm and oxygenation showed a negative correlation. Neural electrical response was nearly instantaneous with respect to the task progression, and autonomic response showed a mean delay of about 15 s and a slower hemodynamic response (mean delay above 20 s) was finally induced. Globally, the task elicited a cascade of responses, in which delays can be quantified. PMID- 22828122 TI - Changes in the nutrient content of american diets. AB - As obesity and being overweight continue to increase in the United States, public concern is growing about the quality of American diets. We compare the changes in nutrients contributed by major food groups in the periods 1953-1980 and 1981-2008 and find that there is reduced cholesterol intake and increased calcium intake, but the levels of food energy and total fats increase substantially. To understand how economic factors affect the overall nutritional quality of American diets, we estimate a complete food demand system and conduct a nutrient demand analysis. Among our findings, we conclude that some price manipulations such as subsidizing fruits and vegetables could be effective to increase produce consumption, but the effects of taxing fats to reduce the consumption of fats could be limited. Increasing income would improve intakes of nutrients such as calcium and various vitamins (likely now insufficient), but intakes of nutrients such as energy, saturated fats, and cholesterol (likely now excessive) would also rise with increased income. PMID- 22828123 TI - Designing cost-efficient randomized trials by using flexible recruitment strategies. AB - BACKGROUND: Sample size planning for clinical trials is usually based on detecting a target effect size of an intervention or treatment. Explicit incorporation of costs into such planning is considered in this article in the situation where effects of an intervention or treatment may depend on (interact with) baseline severity of the targeted symptom or disease. Because much larger sample sizes are usually required to establish such an interaction effect, investigators frequently conduct studies to establish a marginal effect of the intervention for individuals with a certain level of baseline severity. METHODS: We conduct a rigorous investigation on how to determine optimum baseline symptom or disease severity inclusion criteria so that the most cost-efficient design can be used. By using a regression model with an interaction term of treatment by symptom severity, power functions were derived for various levels of baseline symptom severity. Computer algorithms and mathematical optimization were used to determine the most cost-efficient research designs assuming either single- or dual-stage screening procedures. RESULTS: In the scenarios we considered, impressive cost savings can be achieved by informed selection of baseline symptom severity via the inclusion criteria. Further cost-savings can be achieved if a two stage screening procedure is used and there are some known, relatively inexpensively collected, pre-screening information. The amount of total cost savings are shown to depend on the ratio of the screening and intervention costs. In our investigation, we assumed that: 1) the cost of approaching available subjects for screening is constant, and 2) all variables are normally distributed. There is a need to carry out further investigations with more relaxed assumptions (e.g., skewed data distribution). CONCLUSIONS: As cost becomes a more and more prominent issue in modern clinical trials, cost-saving strategies will become more and more important. Strategies, such as the ones we propose here, can help to minimize costs while maximizing knowledge generation. PMID- 22828124 TI - The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. METHODS: 365 treatment-naive patients with T2DM (HbA1c 7.0%-10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c >=7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. RESULTS: At week 24, placebo subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). CONCLUSIONS: In treatment-naive patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00316082. PMID- 22828125 TI - Analysis of the status of Chinese clinical practice guidelines development. AB - BACKGROUND: The work of developing clinical practice guidelines began just a little more than ten years ago in China. Up to now, there have been few studies about them. OBJECTIVES: To review and analyze the status of Chinese clinical practice guidelines in 1997-2007. METHODS: All Chinese guidelines from 1997-2007 were collected, and made a regression analysis, and a citation analysis for evaluating the impact of guidelines. To analyze the developing quality, the most influential guidelines were evaluated with AGREE instrument, and each guideline was evaluated to check for any updating. In order to analyze the objective and target population, all guidelines were classified and counted separately according to disease/symptom center, and whether towards specialists or general practitioners. RESULTS: 143 guidelines were collected. An exponential function equation was established for the trend in the number of guidelines. The immediacy index in every year was very low while the average citation rate was not. Both the percentages of highly cited and never cited were high. For the evaluation with AGREE, only the average score of clarity and presentation was high (89.9%); the remaining were much lower. Editorial independence scored 0. Only 27 (18.9%) of 143 guidelines, were found to be evidence-based. Only a few had ever been updated, with an average updating interval of 5.2 years. Only 2.1% were symptom centered, and only 4.2% were aimed at general practitioners. CONCLUSION: Much progress has been obtained for Chinese guidelines development. However, there were still defects, and greater efforts should be made in the future. PMID- 22828126 TI - Synthesis of O-serogroup specific positive controls and real-time PCR standards for nine clinically relevant non-O157 STECs. AB - Non-O157 Shiga toxin producing Escherichia coli (STEC) are gaining recognition as human pathogens, but no standardized method exists to identify them. Sequence analysis revealed that STEC can be classified on the base of variable O antigen regions into different O serotypes. Polymerase chain reaction is a powerful technique for thorough screening and complex diagnosis for these pathogens, but requires a positive control to verify qualitative and/or quantitative DNA fragment amplification. Due to the pathogenic nature of STEC, controls are not readily available and cell culturing of STEC reference strains requires biosafety conditions of level 2 or higher. In order to bypass this limitation, controls of stacked O-type specific DNA-fragments coding for primer recognition sites were designed to screen for nine STEC serotypes frequently associated with human infection. The synthetic controls were amplified by PCR, cloned into a plasmid vector and transferred into bacteria host cells. Plasmids amplified by bacterial expression were purified, serially diluted and tested as standards for real-time PCR using SYBR Green and TaqMan assays. Utility of synthetic DNA controls was demonstrated in conventional and real-time PCR assays and validated with DNA from natural STEC strains. PMID- 22828127 TI - Evaluation of different storage methods to characterize the fecal bacterial communities of captive western lowland gorillas (Gorilla gorilla gorilla). AB - Freezing is considered to be the best method for long-term storage of bacterial DNA from feces; however this method cannot be usually applied for samples of wild primates collected in the challenging conditions of the tropical forest. In order to find an alternative conservation method of fecal samples from wild great apes, we compared freezing with other fixation methods. Fecal samples from 11 captive gorillas (Gorilla gorilla gorilla) from three Czech Zoos were stored using freezing, RNA Stabilization Reagent (RNAlater), and 96% ethanol. Subsequently, the samples were examined using culture-independent methods (PCR-DGGE, and Real time PCR) to qualitatively and quantitatively assess fecal microbiota composition and to compare differences among the storage methods. Noticeably, freezing samples resulted in the highest recoveries of DNA. No significant differences in DNA recovery were found between freezing and using RNAlater; however, significantly lower DNA concentrations were recovered from samples stored in 96% ethanol. Using PCR-DGGE we found that either 96% ethanol, RNAlater or freezing were suitable for preserving bacterial DNA; however fingerprints obtained from RNAlater storage were more similar to those obtained from the frozen method; in comparison to the patterns resulting from storing samples in ethanol. Using qPCR, frozen samples yielded the highest values of bacterial counts, with the exception of Enterobacteriaceae, which showed the highest numbers using samples stored in ethanol. Sequences of amplicons obtained from PCR-DGGE belonged to the families Clostridiaceae, Lactobacillaceae, Staphylococcaceae, and Lachnospiraceae, phylum Firmicutes; however most amplicons showed sequence similarity to previously uncultured microorganisms. Bacteria belonging to the phylum Firmicutes were the most frequently identified species in the fecal bacterial communities of captive western gorillas. The study showed that RNAlater is an optimal storage method when freezing is not possible. PMID- 22828129 TI - RNA interference of Marlin-1/Jakmip1 results in abnormal morphogenesis and migration of cortical pyramidal neurons. AB - The formation of the nervous systems requires processes that coordinate proliferation, differentiation and migration of neuronal cells, which extend axons, generate dendritic branching and establish synaptic connections during development. The structural organization and dynamic remodeling of the cytoskeleton and its association to the secretory pathway are critical determinants of cell morphogenesis and migration. Marlin-1 (Jakmip1) is a microtubule-associated protein predominantly expressed in neurons and lymphoid cells. Marlin-1 participates in polarized secretion in lymphocytes, but its functional association with the neuronal cytoskeleton and its contribution to brain development have not been explored. Combining in vitro and in vivo approaches we show that Marlin-1 contributes to the establishment of neuronal morphology. Marlin-1 associates to the cytoskeleton in neurites, is required for the maintenance of an intact Golgi apparatus and its depletion produces the down regulation of kinesin-1, a plus-end directed molecular motor with a central function in morphogenesis and migration. RNA interference of Marlin-1 in vivo results in abnormal migration of newborn pyramidal neurons during the formation of the cortex. Our results support the involvement of Marlin-1 in the acquisition of the complex architecture and migration of pyramidal neurons, two fundamental processes for the laminar layering of the cortex. PMID- 22828128 TI - Weighted phase lag index stability as an artifact resistant measure to detect cognitive EEG activity during locomotion. AB - BACKGROUND: High-density electroencephalography (EEG) with active electrodes allows for monitoring of electrocortical dynamics during human walking but movement artifacts have the potential to dominate the signal. One potential method for recovering cognitive brain dynamics in the presence of gait-related artifact is the Weighted Phase Lag Index. METHODS: We tested the ability of Weighted Phase Lag Index to recover event-related potentials during locomotion. Weighted Phase Lag Index is a functional connectivity measure that quantified how consistently 90 degrees (or 270 degrees ) phase 'lagging' one EEG signal was compared to another. 248-channel EEG was recorded as eight subjects performed a visual oddball discrimination and response task during standing and walking (0.8 or 1.2 m/s) on a treadmill. RESULTS: Applying Weighted Phase Lag Index across channels we were able to recover a p300-like cognitive response during walking. This response was similar to the classic amplitude-based p300 we also recovered during standing. We also showed that the Weighted Phase Lag Index detects more complex and variable activity patterns than traditional voltage-amplitude measures. This variability makes it challenging to compare brain activity over time and across subjects. In contrast, a statistical metric of the index's variability, calculated over a moving time window, provided a more generalized measure of behavior. Weighted Phase Lag Index Stability returned a peak change of 1.8% + -0.5% from baseline for the walking case and 3.9% + -1.3% for the standing case. CONCLUSIONS: These findings suggest that both Weighted Phase Lag Index and Weighted Phase Lag Index Stability have potential for the on-line analysis of cognitive dynamics within EEG during human movement. The latter may be more useful from extracting general principles of neural behavior across subjects and conditions. PMID- 22828131 TI - Pattern recognition assisted infrared library searching. AB - Pattern recognition methods have been used to develop search prefilters for infrared (IR) library searching. A two-step procedure has been employed. First, the wavelet packet tree is used to decompose each spectrum into wavelet coefficients that represent both the high and low frequency components of the signal. Second, a genetic algorithm for pattern recognition analysis is used to identify wavelet coefficients characteristic of functional group. Even in challenging trials involving carboxylic acids, compounds that possess both carbonyl and hydroxyl functionalities can be readily differentiated from carboxylic acids. The proposed search prefilters allow for the use of more sophisticated and correspondingly more time-consuming algorithms in IR spectral library matching because the size of the library can be culled down for a specific match using information from the search prefilter about the presence or absence of specific functional groups in the unknown. PMID- 22828132 TI - Link between O2SiH infrared band amplitude and porous silicon photoluminescence during ambient O3 oxidation. AB - We carefully evaluate how porous silicon (pSi) surface oxidation by ozone (O(3)) and the resulting changes in nanocrystallite surface chemistries (e.g., SiOSi, SiH(x) (x = 1-3), O(y)SiH (y = 1-2), and SiOH) influence the pSi photoluminescence (PL). We discover a relationship between the pSi PL and the O(2)SiH band amplitude. PMID- 22828133 TI - Improved colorimetric determination of chitosan concentrations by dye binding. AB - The increasing use of chitosan encourages the search for fast and sensitive methods to quantify its concentrations in water solutions. Recent colorimetric studies have suggested quantification by binding chitosan to Cibacron Brilliant Red 3B-A (BR) dye and measuring the absorbance at 575 nm related to the complex that is formed. This study presents an improved colorimetric technique based on the complexation reaction between BR and chitosan. However, instead of measuring the spectra of the dispersed chitosan-dye complex, the solution is centrifuged for the sedimentation of the colloids, and the concentration of the uncomplexed dye in the supernatant is measured. By performing this simple procedure, sensitivity can be improved to >2 ppm. Equilibration time did not influence the measurements. Charge measurements and bathochromic shift of the measured spectra might yield information about the mechanism of the interaction between the dye and the polymer. PMID- 22828134 TI - Interactions between SIRT1 and MAPK/ERK regulate neuronal apoptosis induced by traumatic brain injury in vitro and in vivo. AB - Traumatic brain injury (TBI) is a serious insult that frequently leads to neurological dysfunction or death. Silent information regulator family protein 1 (SIRT1), as the founding member of nicotinamide adenine dinucleotide (NAD) dependent deacetylases, has recently been demonstrated to have neuroprotective effect in several models of neurodegenerative diseases. The present study attempts to determine whether SIRT1 has a neuroprotective effect in the model of TBI, and further to investigate the possible regulatory mechanism of neuron death. Thus, we employ transection model in vitro and weight-drop model in vivo to mimic the insults of TBI. The study shows that the expressions of SIRT1, phosphorylation extracellular signal-regulated kinase (p-ERK) and cleaved Caspase 3 are induced after trauma injury in vitro or in vivo. Furthermore, inhibiting SIRT1 by pharmacological inhibitor salermide or SIRT1 siRNA significantly promotes apoptotic neuron death and reduces ERK1/2 activation induced by mechanical injury in vitro and in vivo. Inhibition of ERK1/2 activation with PD98059 or U0126 (two mitogen activated protein kinase kinase inhibitors) in vitro and in vivo significantly attenuates the SIRT1 and cleaved Caspase-3 expression to protect neuron against TBI-induced apoptosis. These results reveal that SIRT1 plays a neuroprotective effect against neuronal apoptosis induced by TBI. The interactions between SIRT1 and MAPK/ERK pathway regulate neuronal apoptosis induced by mechanical trauma injury in vitro and in vivo. PMID- 22828135 TI - The resveratrol analog 4,4'-dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells. AB - 4,4'-dihydroxy-trans-stilbene (DHS) is a synthetic analog of resveratrol, a phytoalexin known for its biological activities. We previously demonstrated that DHS exerts an antiproliferative effect on normal human fibroblasts that is higher than that of the natural parent molecule. No evidence regarding its role in human cancer cell lines has been found thus far. In this study, we investigated the effects of DHS both on chemical-induced transformation of BALB/c 3T3 mouse fibroblasts and on the proliferation and invasion of human breast cancer MCF-7 cells. The results showed that DHS markedly suppresses the two-stage (3 methylcholanthrene plus 12-O-tetradecanoylphorbol-13-acetate) cell transformation. Compared with resveratrol, DHS inhibited both anchorage-dependent and -independent MCF-7 growth more efficiently. In addition, a reduction in the number of cells in S-phase, characterized by a concomitant increase in the levels of p21 and p53 proteins, together with a strong inhibition of pRb protein phosphorylation, was observed in DHS-treated cells. Furthermore, DHS effected a strong reduction in matrix metalloproteinase-2 and -9 activities, concomitantly with a marked inhibition of cell adhesion to the extracellular matrix components as well as inhibition of cell migration and invasion. Importantly, modulation of the adhesion molecule E-cadherin was also found in DHS-treated cells. Taken together, these results demonstrate that the two 4,4'-hydroxyl groups on the stilbenic backbone make DHS a more active molecule than resveratrol in inhibiting neoplastic transformation, cancer cell proliferation and invasion. In conclusion, this study suggests that DHS could be a promising anticancer agent. PMID- 22828136 TI - PAQR3 plays a suppressive role in the tumorigenesis of colorectal cancers. AB - PAQR3 is a member of the progestin and adipoQ receptor (PAQR) family and was recently characterized as a spatial regulator that negatively modulates Ras/Raf/MEK/ERK signaling cascade. However, little is known about the physiological functions of PAQR3 in the tumorigenesis of colorectal cancers. The function of PAQR3 in colorectal cancer development in mice was analyzed by crossing Paqr3-depleted mice with Apc(Min/+) mice that have a germline mutation of the gene-encoding tumor suppressor adenomatous polyposis coli (APC). The survival time and tumor area in the small intestine of the Apc(Min/+) mice was significantly aggravated by Paqr3 deletion. The cell proliferation rate, anchorage-independent growth, EGF-stimulated ERK phosphorylation and EGF-induced nuclear accumulation of beta-catenin were inhibited by PAQR3 overexpression and enhanced by PAQR3 knockdown in SW-480 colorectal cancer cells. In humans, the expression level of PAQR3 was significantly decreased in colorectal cancer samples in comparison with adjacent normal tissues. In addition, the expression level of PAQR3 was inversely associated with tumor grade in the colorectal cancer samples. Collectively, our data reveal for the first time that PAQR3 has a tumor suppressor activity in the development of colorectal cancers. PMID- 22828137 TI - STK31 maintains the undifferentiated state of colon cancer cells. AB - The expression of serine/threonine kinase (STK) family is frequently altered in human cancers. However, the functions of these kinases in cancer development remain elusive. Here, we report that STK31 is robustly and heterogeneously expressed in colon cancer tissues and plays a critical role in determining the differentiation state of colon cancer cells. Knockdown or overexpression of STK31 induced or inhibited differentiation of colon cancer cells, respectively. Deletion of the STK domain abolished the inhibiting effect of STK31. Associated with differentiation, knockdown of STK31 resulted in significant suppression of tumorigenicity both in vitro and in vivo. Genome microarray analysis showed that knockdown of STK31 altered the expression profile of genes that are known to be involved in germ cell and cancer differentiation. Taken together, these results suggest that STK31 is able to control the differentiation state of colon cancer cells, which critically depends on its STK domain. The present findings may shed light on the new therapeutic approach against cancer by targeting STK31 and cancer differentiation. PMID- 22828139 TI - Incidence of venous thromboembolism in patients undergoing surgical treatment for malignancy by type of neoplasm: An analysis of ACS-NSQIP data from 2005 to 2010. AB - INTRODUCTION: This study investigates the incidence, relative risk, and adjusted odds ratio of venous thromboembolism (VTE) among patients with malignant neoplasms compared with those with benign neoplasms, as well as the incidence of outpatient VTE diagnosis. METHODS: We performed a retrospective cohort study of patients in the ACS-NSQIP database from 2005 to 2010 with a postoperative diagnosis of neoplasm. The incidence of 30-day VTE, post-VTE death, the incidence of postdischarge VTE diagnosis, and the relative risk of postoperative VTE was calculated by cancer site. Logistic regression was used to calculate an independent odds ratio for each neoplasm site, adjusting for age, gender, body mass index, and operative time. RESULTS: Of 208,200 patients, 159,752 had a malignant diagnosis of the sites of interest and 48,448 had benign/carcinoma in situ neoplasms. The incidence, relative risk, and odds ratio of 30-day VTE varied substantially by site of malignancy. The absolute incidence of outpatient VTE diagnosis varied by site and percent of VTE diagnosed as an outpatient was found to increase over time. CONCLUSION: Recommendations for VTE prophylaxis and duration of VTE prophylaxis for patients undergoing operations may benefit from tailoring to the specific type of malignancy. The increasing percentage of VTE events diagnosed as an outpatient may impact hospitals substantially as financial penalties for readmission are enacted. PMID- 22828138 TI - Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days. AB - We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9 trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10 epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs. PMID- 22828140 TI - Improvements in quality of life after surgery for benign hepatic tumors: Results from a dual center analysis. AB - BACKGROUND: Outcomes after operative management of benign hepatic lesions are ill defined. We sought to define patient-reported quality of life (QOL) postoperatively for benign hepatic tumors. METHODS: Patients who underwent surgery for benign liver lesions (n = 255) were invited to complete a QOL survey designed using validated assessment tools. Clinicopathologic data were collected from 2 participating hepatobiliary centers and correlated with QOL data. RESULTS: The response rate was 70.2%. Most patients had a benign cystic (41.9%) or solid (47.5%) tumor; 19 (10.6%) patients had an indeterminate lesion. The lesion was most often solitary (71.5%) and median size was 7.5 cm. Most benign lesions were either a simple cyst (35.8%), hemangioma (19.6%), focal nodular dysplasia (19.6%), or hepatic adenoma (16.9%). Presenting symptoms included abdominal pain (70.9%), nausea/vomiting (5.0%), and early satiety (5.0%). Surgery involved less than hemihepatectomy (68.2%); a laparoscopic approach was utilized in 40.8% of patients. Perioperative morbidity was 16%. Postoperatively, the proportion of patients who reported moderate-to-extreme pain decreased from 46.9% to 15.6% and 6.8% at 6 months and 1-year, respectively (P < .001). Patient self-reported mean pain scores also decreased over time (preoperative, 1.65 vs 6 months, 0.63 vs 1 year, 0.28; P < .001). Patients with "moderate-to-extreme" pain preoperatively were more likely to report an improvement in pain scores (odds ratio, 1.96; 95% confidence interval, 1.05-3.66; P = .03). Many patients reported overall improvement in general health (40.5%) and physical health (39.3%; P < .001). CONCLUSION: Surgery for benign liver lesions is associated with high patient satisfaction and improved QOL. Patients with significant preoperative symptoms derive the most benefit from surgery. PMID- 22828141 TI - Revisiting the effectiveness of interventions to decrease surgical site infections in colorectal surgery: A Bayesian perspective. AB - OBJECTIVE: To evaluate the evidence for interventions to decrease surgical site infections (SSIs) in colorectal operations using Bayesian meta-analysis. BACKGROUND: Interventions other than appropriate administration of prophylactic antibiotics to prevent SSIs have not been adopted widely, in part because of lack of recommendations for these interventions based on traditional meta-analyses. Bayesian methods can provide probabilities of specific thresholds of benefit, which may be more useful in guiding clinical decision making. We hypothesized that Bayesian meta-analytic methods would complement the interpretation of traditional analyses regarding the effectiveness of interventions to decrease SSIs. METHODS: We conducted a systematic search of the Cochrane database for reviews of interventions to decrease SSIs after colorectal surgery other than prophylactic antibiotics. Traditional and Bayesian meta-analyses were performed using RevMan (Nordic Cochrane Center, Copenhagen, Denmark) and WinBUGS (MRC Biostatistics Unit, Cambridge, UK). Bayesian posterior probabilities of any benefit, defined as a relative risk of <1, were calculated using skeptical, neutral, and enthusiastic prior probabilities. Probabilities were also calculated that interventions decreased SSIs by >=10%, and >=20% using neutral prior probability distributions. RESULTS: A total of 9 Cochrane reviews met the search criteria. Using traditional meta-analysis methods, only laparoscopic colorectal surgery resulted in a significant reduction in SSIs and a recommendation for use of the intervention. Using Bayesian analysis, several interventions that did not result in "significant" decreases in SSIs using traditional analytic methods had a >85% probability of benefit. Also, nonuse of 2 interventions (mechanical bowel preparation and adhesive drapes) had a high probability of decreasing SSIs compared with their use. CONCLUSION: Bayesian probabilities and traditional point estimates of treatment effect yield similar information in terms of potential effectiveness. Bayesian meta-analysis, however, provides complementary information on the probability of a large magnitude of effect. The clinical impact of using Bayesian methods to inform decisions about which interventions to institute first or which interventions to combine requires further study. PMID- 22828142 TI - Early results after laparoscopic sleeve gastrectomy in adolescents with morbid obesity. AB - BACKGROUND: Obesity has been identified as one of the most important public health concerns in both children and adolescents. Unfortunately, even the most comprehensive and aggressive multidisciplinary weight management programs have shown only modest weight loss results. There has been increasing enthusiasm for bariatric surgery for adolescent patients with morbid obesity. Because of the relatively high morbidity and mortality associated with gastric bypass surgery, we have begun to explore laparoscopic sleeve gastrectomy as an alternative. We hypothesized that it would be a safe and effective short-term strategy. METHODS: We have prospectively collected data from all patients undergoing bariatric surgery at our institution since the inception of our adolescent weight loss surgery program in January 2010. Baseline data collected included age, gender, race/ethnicity, height, weight, body mass index, and comorbid conditions. Postoperative data collected included the type of operation, length of stay, operative morbidity, the need for reoperation, and percent excess weight loss and body mass index at 3-month intervals. RESULTS: Twenty-three patients have undergone laparoscopic sleeve gastrectomy at our institution since January 2010. Of these, 18 were female and 5 were male. The mean age was 17.3 +/- 1.5 years of age. The mean preoperative weight was 149 +/- 30 kg with a body mass index of 52 +/- 9 kg/m(2). There were no intraoperative complications, and the only postoperative complication has been pancreatitis in 1 patient. The mean length of stay was 2.2 +/- 1.1 days. The mean follow-up was 10.9 +/- 7.4 months. The percent excess weight loss at 3 months, 6 months, and 1 year postoperatively was 32%, 38%, and 40%, respectively, in those who had reached these time points. CONCLUSION: Laparoscopic sleeve gastrectomy is a safe operation for adolescent patients with morbid obesity and represents an effective early treatment strategy with approximately 40% excess weight loss at 6 months and 1 year of follow-up. Because of the minimal morbidity associated with laparoscopic sleeve gastrectomy, it may be the optimal non-device surgical option for this select group of adolescent patients. PMID- 22828143 TI - Effect of metabolic syndrome on perioperative outcomes after liver surgery: A National Surgical Quality Improvement Program (NSQIP) analysis. AB - BACKGROUND: The problem of obesity has risen to epidemic levels in the United States. A subset of patients with obesity will have metabolic syndrome. We sought to examine the impact of metabolic syndrome on the risk of morbidity and mortality among a large cohort of patients who underwent hepatic resection. METHODS: Patients included in the National Surgical Quality Improvement Program (NSQIP) dataset who underwent hepatic resection between January 2005 and December 2008 were identified. Data on clinical characteristics, comorbidities, operative details, as well as postoperative complications and mortality were collected and analyzed. Patients with BMI >30 kg/m(2) who also had hypertension and diabetes were defined as having metabolic syndrome. RESULTS: A total of 3,973 patients who underwent a liver resection were identified. Overall mean body mass index was 28 kg/m(2); 31.7% patients were obese (>30 kg/m(2)). Of the patients who were obese, 256 (20%) had metabolic syndrome. Patients with metabolic syndrome were less likely to have had a major hepatectomy (>=hemi-hepatectomy, 36% vs 43%; P = .01) but had a greater mean number of red blood cell transfusions (1.6 vs 1; P = .02). The incidence of postoperative complications after hepatectomy was 23%. Patients with metabolic syndrome had a greater risk for reintubation (odds ratio [OR] 1.9; P = .02), >48 hours ventilator dependence (OR 2.0; P = .003), myocardial infarction (OR 5.5; P = .01) and superficial surgical-site infections (OR 1.7; P = .02) compared with nonmetabolic patients. Overall postoperative mortality was 3%. Metabolic syndrome was associated with an increased risk of postoperative death (OR 2.7; P = .001). CONCLUSION: The presence of metabolic syndrome was associated with a greater risk of perioperative complications. In addition, patients with metabolic syndrome had greater than a 2-fold increased risk of death after hepatic resection. PMID- 22828144 TI - Does payer status matter in predicting penetrating trauma outcomes? AB - BACKGROUND: Few data exist regarding payer status as a predictor of outcomes in penetrating trauma. This study determined whether insurance status impacts in hospital complications and mortality in gunshot and stab wound patients at our inner-city, level I trauma center. METHODS: Penetrating trauma admissions from 2005 to 2009 were reviewed for patient demographics, insurance, Injury Severity Score, complications, duration of stay, and mortality. RESULTS: A total of 1,347 penetrating trauma patients were admitted with 652 (48.4%) uninsured. Although uninsured patients were more likely to be male (93.3% vs 89.8%, P = .030), there was no difference in age, ISS, or number of radiologic, operative, or interventional procedures. Uninsured patients had lesser intensive care unit (4.4 vs 3.3 days; P = .049) and total hospital length of stay (10.2 vs 8.3; P = .049). No uninsured patients were placed into a rehabilitation facility at the time of discharge (0.0% vs 1.6%, P < .001). There was no difference in frequency of pulmonary complications, thromboembolic complications, sepsis, urinary tract infection, or wound infections. On multivariate analysis, being uninsured was not an independent predictor of in-hospital complications (1.010, 95% confidence interval 0.703-1.450, P = .959) or mortality (odds ratio 0.905, 95% confidence interval 0.523-1.566, P = .722). CONCLUSION: This is the first study to show that penetrating trauma patients who are uninsured have lesser duration of stay and decreased placement into a rehabilitation facility. Being uninsured added no additional risk of in-hospital complications or mortality. PMID- 22828145 TI - Payer status is associated with the use of prophylactic inferior vena cava filter in high-risk trauma patients. AB - BACKGROUND: It is controversial whether patients at high risk for pulmonary embolism (PE) should receive prophylactic inferior vena cava filters (IVC) filters. This lack of clarity creates the potential for variability and disparities in care. We hypothesized there would be differential use of prophylactic IVC filters for patients at high risk for PE on the basis of insurance status. METHODS: We performed a retrospective analysis using the National Trauma Databank (2002-2007). We included adult patients at high risk for PE (traumatic brain injury or spinal cord injury) and excluded patients with a diagnosis of deep venous thrombosis (DVT) or PE. Logistic regression was performed to control for confounders and a hierarchical mixed effects model was used to control for center. RESULTS: A prophylactic filter was placed in 3,331 (4.3%) patients in the study cohort. Patients without insurance had an IVC filter placed less often compared with those with any form of insurance (2.7% vs 4.9%, respectively). After adjusting for confounders, we found that patients without insurance were less likely to receive a prophylactic IVC filter, even when we controlled for center (OR 5.3, P < .001). CONCLUSION: When guidelines lack clarity, unconscious bias has the potential to create a system with different levels of care based on socioeconomic disparities. PMID- 22828146 TI - Development of a novel murine model of aortic aneurysms using peri-adventitial elastase. AB - BACKGROUND: Our aim was to establish a novel model of abdominal aortic aneurysms (AAA) in mice using application of peri-adventitial elastase. METHODS: C57BL/6J male mice underwent infrarenal peri-adventitial application of either (1) sodium chloride (control; n = 7), (2) porcine pancreatic elastase (PPE; n = 14), or (3) PPE and doxycycline (PPE + doxycycline 200 mg/kg; n = 11) for 14 days. Aortas were analyzed by video micrometry, immunohistochemistry, qualitative polymerase chain reaction, and zymography. Groups underwent Mann-Whitney U comparisons. RESULTS: At day 14 compared with baseline, control animals had minimal aortic dilation, whereas fusiform aneurysms were seen in PPE (control, 20 +/- 3%; PPE, 82 +/- 15%; P <= .003). Doxycycline abrogated aneurysm formation (PPE, 82 +/- 15%; PPE + doxycycline, 37 +/- 10%; P <= .03). Compared with control and PPE + doxycycline, immunohistochemistry demonstrated greater elastin fiber degradation, macrophage infiltration, and matrix metalloproteinase-9 expression in PPE. Ki-67 and cleaved caspase-3 were lower in control versus PPE. The loss of smooth muscle marker expression seen with PPE was preserved in PPE + doxycycline. Zymography confirmed that both MMP-2 and -9 were more active in PPE than PPE + doxycycline. CONCLUSION: Peri-adventitial application of elastase is a simple, reproducible in vivo model of aneurysm formation leading to consistent infrarenal aortic aneurysm development by day 14, with inflammatory cell infiltration and MMP upregulation. Doxycycline inhibits AAA progression in this model via limiting matrix degradation and preserving differentiated smooth muscle cells. PMID- 22828147 TI - Decreased coronary microvascular reactivity after cardioplegic arrest in patients with uncontrolled diabetes mellitus. AB - BACKGROUND: We investigated the effects of cardioplegic arrest and reperfusion on coronary arteriolar responses to endothelium-dependent and -independent vasodilators and associated signaling pathways in uncontrolled diabetic, well controlled diabetic, and case-matched nondiabetic patients undergoing coronary artery bypass graft surgery. METHODS: Coronary arterioles from harvested right atrial tissues were dissected pre- and post-cardioplegic arrest and reperfusion from uncontrolled diabetic (n = 10; hemoglobin A1c = 9.3 +/- 0.3), well controlled diabetic (n = 10; hemoglobin A1c = 6.2 +/- 0.2), and nondiabetic patients (n = 10; hemoglobin A1c = 5.1 +/- 0.1) undergoing coronary artery bypass graft surgery. RESULTS: The baseline microvascular response to adenosine 5' diphosphate, substance P, and sodium nitroprusside of arterioles from uncontrolled diabetic patients were decreased compared to the respective response from nondiabetic or well controlled diabetic patients (P < .05). The vasodilatory responses to adenosine 5'-diphosphate and substance P after cardioplegic arrest and reperfusion were significantly decreased in all 3 groups compared to pre cardioplegic arrest and reperfusion responses (P < .05). However, these decreases were more pronounced in the uncontrolled diabetic group (P < .05). The expression of protein kinase C-alpha, protein kinase C-beta, and protein oxidation in atrial tissues was significantly increased in the uncontrolled diabetic group compared to the nondiabetic or controlled diabetes groups. CONCLUSION: Uncontrolled diabetes is associated with endothelium-dependent and -independent vascular dysfunction of coronary arterioles. In addition, uncontrolled diabetes worsens the recovery of coronary arteriolar function after cardioplegic arrest and reperfusion. These alterations are associated with an increased expression/activation of protein kinase C-alpha and protein kinase C-beta and enhanced oxidative stress. PMID- 22828148 TI - Isoflurane prevents acute lung injury through ADP-mediated platelet inhibition. AB - BACKGROUND: Growing evidence suggests platelets are essential in posttraumatic, acute lung injury (ALI). Halogenated ethers interfere with the formation of platelet-granulocyte aggregates. The potential benefit of halogenated ethers has not been investigated in models of trauma/hemorrhagic shock (T/HS). Therefore, we hypothesized that isoflurane decreases T/HS-mediated ALI through platelet inhibition. METHODS: Sprague-Dawley rats (n = 47) were anesthetized by either pentobarbital or inhaled isoflurane and placed into (1) control, (2) trauma (laparotomy) sham shock, (3) T/HS (mean arterial pressure, 30 mmHg * 45 min), (4) pretreatment with an ADP receptor antagonist, or (5) T/HS with isoflurane initiated during resuscitation groups. ALI was determined by protein and pulmonary immunofluorescence bronchoalveolar lavage (BAL) fluid. Platelet Mapping specifically evaluated thrombin-independent inhibition of the ADP and AA pathways of platelet activation. RESULTS: Pretreatment with isoflurane abrogated ALI as measured by both BAL fluid protein and pulmonary immunofluorescence (P < .001). Platelet Mapping revealed specific inhibition of the platelet ADP-pathway with isoflurane (P < .001). Pretreatment with an ADP receptor antagonist decreased ALI to sham levels, confirming that specific platelet ADP inhibition decreases ALI. Isoflurane initiated during resuscitation also decreased ALI (P < .001). CONCLUSION: Isoflurane attenuates ALI through an antiplatelet mechanism, in part, through inhibition of the platelet ADP pathway. Isoflurane given postinjury also protects against ALI, and highlights the potential applications of this therapy in various clinical scenarios of ischemia/reperfusion. PMID- 22828151 TI - Advances in research and safeguarding for people with intellectual disabilities. PMID- 22828149 TI - Novel small interfering RNA cotargeting strategy as treatment for colorectal cancer. AB - BACKGROUND: RNA interference has the potential to be more selective than small molecule inhibitors and can be used to target proteins, such as Ras, that are currently undruggable. The purpose of our study was to determine the optimal cotargeting strategy of the commonly mutated PI3K/AKT/mTOR and Ras pathways by a selective RNA interference approach in colorectal cancer cell lines possessing coexistent PIK3CA and KRAS mutations. METHODS: Human colorectal cancer cell lines HCT116 and DLD-1 were treated with a panel of small interfering RNAs directed against the PI3K/AKT/mTOR and Ras pathways; proliferation, apoptosis, and protein expression were assessed. Combined treatment with small interfering RNA and 5 fluorouracil was then evaluated. RESULTS: PIK3CA and KRAS small interfering RNAs were most effective as single treatments; combined treatments with PIK3CA and KRAS small interfering RNA resulted in a more pronounced inhibition of colorectal cancer cell proliferation. Either KRAS small interfering RNA alone or combined PIK3CA and KRAS small interfering RNA treatments increased apoptosis in HCT116 cells but not in the DLD-1 cell line. Inhibition of 4E-BP1 phosphorylation correlated with increased apoptosis. In addition, small interfering RNA treatment combined with 5-fluorouracil further inhibited colorectal cancer cell proliferation. CONCLUSION: Combined PIK3CA and KRAS small interfering RNA treatments offer an effective therapy against colorectal cancer cells with coexisting mutations in both pathways. Decreased 4E-BP1 phosphorylation correlates with increased apoptosis and may provide a biomarker indicative of treatment success. In addition, small interfering RNA directed to PIK3CA and KRAS may be used to enhance the effects of current chemotherapy. PMID- 22828150 TI - Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. AB - BACKGROUND: p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. METHODS: p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. RESULTS: The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment (P = .21). However, the epithelial deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P = .008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm(2); P = .03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. CONCLUSION: Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease. PMID- 22828152 TI - The use of end-tidal carbon dioxide monitoring in patients with hypotension in the emergency department. AB - BACKGROUND: The aim of this study was to determine the usefulness of end tidal carbon dioxide (ETCO2) monitoring in hypotensive shock patients presenting to the ED. METHODS: This was a prospective observational study in a tertiary ED. One hundred three adults in shock with hypotension presenting to the ED were recruited into the study. They were grouped according to different types of shock, hypovolemic, cardiogenic, septic and others. Vital signs and ETCO2 were measured on presentation and at 30-min intervals up to 120 min. Blood gases and serum lactate levels were obtained on arrival. All patients were managed according to standard protocols and treatment regimes. Patient survival up to hospital admission and at 30 days was recorded. RESULTS: Mean ETCO2 for all patients on arrival was 29.07 +/- 9.96 mmHg. Average ETCO2 for patients in hypovolemic, cardiogenic and septic shock was 29.64 +/- 11.49, 28.60 +/- 9.87 and 27.81 +/- 7.39 mmHg, respectively. ETCO2 on arrival was positively correlated with systolic and diastolic BP, MAP, bicarbonate, base excess and lactate when analyzed in all shock patients. Early ETCO2 measurements were found to be significantly lower in patients who did not survive to hospital admission (p = 0.005). All patients who had ETCO2 <= 12mmHg died in the ED. However, normal ETCO2 does not ensure patient survival. CONCLUSION: The use of ETCO2 in the ED has great potential to be used as a method of non-invasive monitoring of patients in shock. PMID- 22828153 TI - Indication for surgery and the risk of postoperative nausea and vomiting after craniotomy: a case-control study. AB - BACKGROUND: The primary hypothesis of the study is that acoustic neuroma (AN) surgery and microvascular decompression (MVD) of cranial nerves increase the risk of postoperative nausea and vomiting (PONV). METHODS: We designed a retrospective case-control study matched on age, sex, and year of surgery (<=2005 and >2005). Year of surgery was noted as a potential confounder, because routine antiemetic prophylaxis was strongly encouraged at the study site in 2005. Cases of PONV in the recovery room were matched to controls in a 1:2 manner using a perioperative database. Charts were then reviewed for the following data: American Society of Anesthesiologists grade, smoking status, craniotomy location, craniotomy indication, and type of anesthetic administered. RESULTS: The final analysis included 117 cases that were matched with 185 controls. Patients had a mean age of 50 years (SD=13), and 65% were female. Overall, the majority of craniotomies were supratentorial (70%) and performed for tumor resection (41%). On multivariable analysis, MVD [odds ratio (OR)=6.7; 95% confidence interval (CI), 2.0-22.7; P=0.002], AN (OR=3.3; 95% CI, 1.0-11.0; P=0.05), and epilepsy surgery (OR=2.8; 95% CI, 1.1-7.5; P=0.04) were associated with an increased likelihood of PONV when compared with tumor surgery. There was effect modification of total intravenous anesthesia by location of surgery (P-interaction=0.02). The benefit of total intravenous anesthesia on PONV was observed in supratentorial (OR=0.41; 95% CI, 0.17-0.96; P=0.04) but not infratentorial location (OR=2.6; 95% CI, 0.78 8.7; P=0.11). CONCLUSIONS: MVD and AN resection were associated with an increased likelihood of PONV compared with craniotomies performed for other tumor resection. PMID- 22828154 TI - Multiple cervical levels: increased risk of dysphagia and dysphonia during anterior cervical discectomy. AB - BACKGROUND: Anterior cervical discectomy (ACD) is widely used for symptomatic cervical spine pathologies. The most common complications associated with this type of surgery are dysphagia and dysphonia; however, the risk factors associated with them have not been adequately elucidated. The purpose of this study is to assess the incidence of self-reported dysphagia and dysphonia and the associated risk factors after ACD. METHODS: This study used a retrospective chart review of 149 patients who underwent ACD at a tertiary care facility operating in the New York metropolitan area over a period of 21/2 years. Charts for ACD patients were reviewed by 6 trained researchers. Incidence rates for self-reported dysphagia and dysphonia were calculated using 95% exact confidence intervals (CI). Risk factors such as age, sex, surgical hours, number of disc levels, airway class, American Society of Anesthesiologists class, fiberoptic intubation, and intubation difficulty were assessed using logistic regression. RESULTS: The incidence of self-reported dysphagia was 12.1% (95% exact CI, 7.3%-18.4%); for dysphonia the self-reported incidence was 5.4% (95% exact CI, 2.3%-10.3%). Patients who underwent surgery at >=4 cervical levels had a significant 4-fold increased risk (odds ratio=4; 95% CI, 1.1-13.8) of developing dysphonia and/or dysphagia compared with patients who underwent surgery at a single surgical level. CONCLUSIONS: This study confirms previous findings that the risk of developing dysphagia and/or dysphonia increases with the number of surgical levels, with multiple cervical levels representing a significantly higher postoperative risk, as compared with surgery at 1 level. PMID- 22828155 TI - Fentanyl co-administration decreases the induction dose requirement of propofol in patients with supratentorial tumors and not in patients with spinal lesions. AB - BACKGROUND: The requirement of anesthetic drugs in a patient with an intracranial space-occupying lesion is of relevance to the neuroanesthetist. The requirement is often presumed to have reduced or at least altered. However, not much research has focused on this issue. Hence, we conducted this study to examine whether intracranial tumors reduce the induction dose of propofol in patients undergoing craniotomy based on plasma and effect site concentrations (Ce) of propofol and the effect of additional fentanyl. METHODS: A total of 80 patients were recruited into the study. The study group included patients with supratentorial tumors undergoing craniotomy, and the control group consisted of patients undergoing spinal surgeries. Patients in each group were randomized further to receive propofol alone or propofol preceded by fentanyl for induction of anesthesia. They were divided into the following groups: patients with supratentorial tumor receiving only propofol (group T1), or fentanyl and propofol (group T2); patients who were undergoing spinal surgery and receiving only propofol (group S1) or fentanyl and propofol (group S2). Anesthesia was induced with infusion of propofol through a Target Controlled Infusion pump. At the point of loss of verbal contact, plasma concentration (Cp) and Ce of propofol, time taken for loss of consciousness, and the total dose of propofol required were noted. Hemodynamic variables were recorded before and after induction of anesthesia. RESULTS: There were 19, 21, 19, and 21 patients in groups TI, T2, S1, and S2, respectively. In group T2 the Cp, Ce, time to loss of verbal contact, and dose required for induction were all significantly lower compared with the other groups. There were no significant differences in the study parameters between T1 and S1, whereas the differences were significant between T2 and S2 (Cp: 3.9+/-1.1 vs. 4.9+/-1.2 MUg/mL; Ce: 2.6+/-1.0 vs. 3.7+/-1.2 MUg/mL; P<0.05). CONCLUSIONS: Propofol dose for induction of anesthesia was significantly reduced when administered after fentanyl in patients with supratentorial tumors. Tumors per se without fentanyl coadministration do not decrease the propofol requirement for induction of anesthesia. PMID- 22828156 TI - Trend analysis of hospital admissions attributable to tobacco smoking, Northern Territory Aboriginal and non-Aboriginal populations, 1998 to 2009. AB - BACKGROUND: Tobacco smoking is a well-recognised risk factor for many diseases [1]. This study assesses the extent of smoking-attributable hospitalisation in the Northern Territory (NT) Aboriginal and non-Aboriginal populations, and examines smoking-attributable hospitalisation trends for the years 1998/99 to 2008/09. METHODS: Hospital discharge data were used for the analysis. The proportion of conditions attributable to tobacco smoking was calculated using the aetiological fraction method. Age-adjusted smoking-attributable hospitalisation rates were calculated to describe the impact of tobacco smoking on the health of Territorians. A negative binominal regression model was applied to examine trends in smoking-attributable hospitalisations. RESULTS: Aboriginal Territorians were found to have higher rates of smoking-attributable hospitalisation, with Aboriginal males more than three times and Aboriginal females more than four times more likely to be hospitalised for smoking-attributable conditions than their non-Aboriginal counterparts. The age-adjusted hospitalisation rate for Aboriginal males increased by 31% and for Aboriginal females by 18% during the study period. There were more modest increases for NT non-Aboriginal males and females (5% and 17% respectively). The increase among Aboriginal males occurred up until 2005/06 followed by moderation in the trend. There were small reductions in smoking-attributable hospitalisation rates among all populations in younger age groups (less than 25 years). CONCLUSIONS: Aboriginal Territorians experience much higher smoking-attributable hospitalisation rates than non-Aboriginal Territorians. The scale of the smoking burden and suggestion of recent moderation among Aboriginal men reinforce the importance of tobacco control interventions that are designed to meet the needs of the NT's diverse population groups. Preventing smoking and increasing smoking cessation rates remain priorities for public health interventions in the NT. PMID- 22828157 TI - Budgetary impact analysis of buprenorphine-naloxone combination (Suboxone(r)) in Spain. AB - BACKGROUND: Opioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial MU-opiod agonist and a kappa-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine naloxone (B/N) combination. METHODS: A budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (?, 2010). RESULTS: The number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is ?85,766,129; ?79,855,471 and ?79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be ?86,589,210; ?80,398,259 and ?79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is ?10.58; ?6.98 and ?7.34 in the first, second and third year respectively. CONCLUSION: Addition of B/N combination would imply a maximum incremental yearly cost of ?10.58 per patient compared to scenario only with methadone and would provide additional benefits. PMID- 22828159 TI - Assessment of a volume-dependent dynamic respiratory system compliance in ALI/ARDS by pooling breathing cycles. AB - New methods were developed to calculate the volume-dependent dynamic respiratory system compliance (C(rs)) in mechanically ventilated patients. Due to noise in respiratory signals and different characteristics of the methods, their results can considerably differ. The aim of the study was to establish a practical procedure to validate the estimation of intratidal dynamic C(rs). A total of 28 patients from intensive care units of eight German university hospitals with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) were studied retrospectively. Dynamic volume-dependent C(rs) was determined during ongoing mechanical ventilation with the SLICE method, dynostatic algorithm and adaptive slice method. Conventional two-point compliance C(2P) was calculated for comparison. A number of consecutive breathing cycles were pooled to reduce noise in the respiratory signals. C(rs)-volume curves produced with different methods converged when the number of pooling cycles increased (n >= 7). The mean volume dependent C(rs) of 20 breaths was highly correlated with mean C(2P) (C(2P,mean) = 0.945 * C(rs,mean) - 0.053, r(2) = 0.968, p < 0.0001). The Bland-Altman analysis indicated that C(2P,mean) was lower than C(rs,mean) (-2.4 +/- 6.4 ml cm(-1) H(2)O, mean bias +/- 2 SD), but not significant according to the paired t-test (p > 0.05). Methods for analyzing dynamic respiratory mechanics are sensitive to noise and will converge to a unique solution when the number of pooled cycles increases. Under steady-state conditions, assessment of the volume-dependent C(rs) in ALI/ARDS patients can be validated by pooling respiratory data of consecutive breaths regardless of which method is applied. Confidence in dynamic C(rs) determination may be increased with the proposed pooling. PMID- 22828158 TI - Faecal immunochemical test accuracy in patients referred for surveillance colonoscopy: a multi-centre cohort study. AB - BACKGROUND: Given the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population. METHODS: Cohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml). RESULTS: 1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds. CONCLUSIONS: In once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden. PMID- 22828160 TI - Flat-of-the-curve medicine: a new perspective on the production of health. AB - Health economists have studied the determinants of the expected value of health status as a function of medical and non-medical inputs, often finding small marginal effects of the former. However, medical inputs may have an additional benefit in the form of a reduced variability of health status. Using the standard deviation of life expectancy in 24 OECD countries between 1960 and 2005, a 10 percent increase of health care expenditure is associated with a decrease of an estimated 0.42 percent. Willingness to pay for such a reduction of uncertainty may well exceed the extra health care expenditure in the United States and Switzerland. This implies that even in these two countries with very high health care expenditure per capita, flat-of-the-curve medicine need not be wasteful.JEL Classification: I12, J10. PMID- 22828161 TI - Forest carbon in North America: annual storage and emissions from British Columbia's harvest, 1965-2065. AB - BACKGROUND: The default international accounting rules estimate the carbon emissions from forest products by assuming all harvest is immediately emitted to the atmosphere. This makes it difficult to assess the greenhouse gas (GHG) consequences of different forest management or manufacturing activities that maintain the storage of carbon. The Intergovernmental Panel on Climate Change (IPCC) addresses this issue by allowing other accounting methods. The objective of this paper is to provide a new model for estimating annual stock changes of carbon in harvested wood products (HWP). RESULTS: The model, British Columbia Harvested Wood Products version 1 (BC-HWPv1), estimates carbon stocks and fluxes for wood harvested in BC from 1965 to 2065, based on new parameters on local manufacturing, updated and new information for North America on consumption and disposal of wood and paper products, and updated parameters on methane management at landfills in the USA. Based on model results, reporting on emissions as they occur would substantially lower BC's greenhouse gas inventory in 2010 from 48 Mt CO2 to 26 Mt CO2 because of the long-term forest carbon storage in-use and in the non-degradable material in landfills. In addition, if offset projects created under BC's protocol reported 100 year cumulative emissions using the BC-HWPv1 the emissions would be lower by about 11%. CONCLUSIONS: This research showed that the IPCC default methods overestimate the emissions North America wood products. Future IPCC GHG accounting methods could include a lower emissions factor (e.g. 0.52) multiplied by the annual harvest, rather than the current multiplier of 1.0. The simulations demonstrated that the primary opportunities for climate change mitigation are in shifting from burning mill waste to using the wood for longer-lived products. PMID- 22828162 TI - Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. AB - Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73+/-3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding. PMID- 22828163 TI - Neural correlates of causality judgment in physical and social context--the reversed effects of space and time. AB - The perception of causal relationships is crucial to understanding and interacting with our physical and social environment. However, whether the same or different neural processes are involved in perceiving physical and social causality is unknown. Therefore, this study is focused on commonalities and differences in the neural correlates of causality perception in both contexts. During fMRI data-acquisition, participants judged causal relationships of objects in two types of animated video clips (physical/social) with similar manipulations of temporal and spatial stimulus characteristics. Four conditions were analyzed in a two-factorial design [physical causal (PC), physical non-causal (PNC), social causal (SC), social non-causal (SNC)]. We found that higher angles and longer time delays led to decreasing judgments of causality in the physical context, whereas the same manipulations led to increasing judgments in the social context. Instead of a common network for causal judgments (PC>PNC?SC>SNC), we found a reversed activation pattern for the factors context and judgment. PC and SNC [(PC>PNC)>(SC>SNC)] produced activations in the bilateral insula, the right angular and inferior frontal gyrus and the medial supplementary motor area. PNC and SC [(PC>PNC)<(SC>SNC)] produced activity in medial frontal, left superior temporal and anterior cingulate brain regions. Our data suggest, that the same brain regions contribute to the impression of physical and social causality. However, they demonstrate a reversed activation pattern that reflects the stimulus characteristics of the respective conditions. Thus, specific stimulus characteristics are crucial for the perception of causality. PMID- 22828164 TI - Science and technology for the mastership of probiotic applications in food products. AB - Probiotics, defined as live microorganisms which when consumed in adequate amounts confer a health benefit on the host, are a common part of our daily diet. Since their conception in the early 20th century, the health benefit applications of probiotics have been expanding, culminating in the recent challenge of health claim substantiation in Europe. This paper highlights the different application areas of probiotics, introduces the use of non-viable microorganisms to confer health benefits, and explains the recent regulatory challenges surrounding probiotics. It then describes in detail the different stages in the development of food products containing probiotic bacteria starting from the selection of suitable strains for industrial production. The description of production of probiotic powders with specific focus on strategies to maintain high viability during drying and storage then follows. The paper finishes with a discussion of probiotic stability in liquid products, followed by a description of the use of probiotics to improve nutrient bioavailability and digestibility of the food products, which they ferment or biotransform. PMID- 22828165 TI - Evaluation of the brain activation induced by functional electrical stimulation and voluntary contraction using functional magnetic resonance imaging. AB - BACKGROUND: To observe brain activation induced by functional electrical stimulation, voluntary contraction, and the combination of both using functional magnetic resonance imaging (fMRI). METHODS: Nineteen healthy young men were enrolled in the study. We employed a typical block design that consisted of three sessions: voluntary contraction only, functional electrical stimulation (FES) induced wrist extension, and finally simultaneous voluntary and FES-induced movement. MRI acquisition was performed on a 3.0 T MR system. To investigate activation in each session, one-sample t-tests were performed after correcting for false discovery rate (FDR; p < 0.05). To compare FES-induced movement and combined contraction, a two-sample t-test was performed using a contrast map (p < 0.01). RESULTS: In the voluntary contraction alone condition, brain activation was observed in the contralateral primary motor cortex (MI), thalamus, bilateral supplementary motor area (SMA), primary sensory cortex (SI), secondary somatosensory motor cortex (SII), caudate, and cerebellum (mainly ipsilateral). During FES-induced wrist movement, brain activation was observed in the contralateral MI, SI, SMA, thalamus, ipsilateral SII, and cerebellum. During FES induced movement combined with voluntary contraction, brain activation was found in the contralateral MI, anterior cingulate cortex (ACC), SMA, ipsilateral cerebellum, bilateral SII, and SI.The activated brain regions (number of voxels) of the MI, SI, cerebellum, and SMA were largest during voluntary contraction alone and smallest during FES alone. SII-activated brain regions were largest during voluntary contraction combined with FES and smallest during FES contraction alone. The brain activation extent (maximum t score) of the MI, SI, and SII was largest during voluntary contraction alone and smallest during FES alone. The brain activation extent of the cerebellum and SMA during voluntary contraction alone was similar during FES combined with voluntary contraction; however, cerebellum and SMA activation during FES movement alone was smaller than that of voluntary contraction alone or voluntary contraction combined with FES. Between FES movement alone and combined contraction, activated regions and extent due to combined contraction was significantly higher than that of FES movement alone in the ipsilateral cerebellum and the contralateral MI and SI. CONCLUSIONS: Voluntary contraction combined with FES may be more effective for brain activation than FES-only movements for rehabilitation therapy. In addition, voluntary effort is the most important factor in the therapeutic process. PMID- 22828166 TI - Orbital lymphangiomas: a review of management strategies. AB - PURPOSE OF REVIEW: Orbital lymphangiomas present a difficult management problem for the ophthalmologist. This review offers a strategy for managing the condition. RECENT FINDINGS: There have been recent publications discussing the use of intralesional fibrin glue to aid dissection and intralesional sclerosant to shrink the lesion. We discuss the evidence for these treatments and present a case in which these treatments were combined. SUMMARY: This review highlights the classification and presents management options for orbital lymphangioma. We encourage a holistic and individualized approach to the patients, recognizing the variety of clinical manifestations that the condition can cause. In the event of surgical excision, we present the evidence for the use of intralesional fibrin glue and intralesional sclerosant, and describe using both in the same case. PMID- 22828167 TI - Topical therapies for periorbital cutaneous malignancies: indications and treatment regimens. AB - PURPOSE OF REVIEW: To present a brief review of periorbital cutaneous tumorogenesis, highlighting the steps which might be amenable to topical treatments and then discuss the use of topical agents in the management of periorbital skin malignancy. RECENT FINDINGS: A rapid expansion in the understanding of the pathogenesis of melanoma and nonmelanoma skin cancer has allowed the development of a number of topical agents targeting specific tumor forming processes. Topical agents have been shown to be effective in the management of periorbital skin malignancy. SUMMARY: 5-Fluorouracil and imiquimod have established roles in the management of periorbital skin malignancy. Newer agents such as ingenol mebutate, tazarotene, and diclofenac gel probably have evolving roles that require further research but show promise. PMID- 22828168 TI - Alterations of specific biomarkers of metabolic pathways in vascular tree from patients with Type 2 diabetes. AB - The aims of this study were to check whether different biomarkers of inflammatory, apoptotic, immunological or lipid pathways had altered their expression in the occluded popliteal artery (OPA) compared with the internal mammary artery (IMA) and femoral vein (FV) and to examine whether glycemic control influenced the expression of these genes. The study included 20 patients with advanced atherosclerosis and type 2 diabetes mellitus, 15 of whom had peripheral arterial occlusive disease (PAOD), from whom samples of OPA and FV were collected. PAOD patients were classified based on their HbA1c as well (HbA1c <= 6.5) or poorly (HbA1c > 6.5) controlled patients. Controls for arteries without atherosclerosis comprised 5 IMA from patients with ischemic cardiomyopathy (ICM). mRNA, protein expression and histological studies were analyzed in IMA, OPA and FV. After analyzing 46 genes, OPA showed higher expression levels than IMA or FV for genes involved in thrombosis (F3), apoptosis (MMP2, MMP9, TIMP1 and TIM3), lipid metabolism (LRP1 and NDUFA), immune response (TLR2) and monocytes adhesion (CD83). Remarkably, MMP-9 expression was lower in OPA from well-controlled patients. In FV from diabetic patients with HbA1c <=6.5, gene expression levels of BCL2, CDKN1A, COX2, NDUFA and SREBP2 were higher than in FV from those with HbA1c >6.5. The atherosclerotic process in OPA from diabetic patients was associated with high expression levels of inflammatory, lipid metabolism and apoptotic biomarkers. The degree of glycemic control was associated with gene expression markers of apoptosis, lipid metabolism and antioxidants in FV. However, the effect of glycemic control on pro atherosclerotic gene expression was very low in arteries with established atherosclerosis. PMID- 22828170 TI - Translational proteomics. PMID- 22828172 TI - A randomized controlled trial of telephone-delivered cognitive-behavioral therapy for late-life anxiety disorders. AB - OBJECTIVES: Older adults face a number of barriers to receiving psychotherapy, such as a lack of transportation and access to providers. One way to overcome such barriers is to provide treatment by telephone. The purpose of this study was to examine the effects of cognitive behavioral therapy delivered by telephone (CBT-T) to older adults diagnosed with an anxiety disorder. DESIGN: Randomized controlled trial. SETTING: Participants' homes. PARTICIPANTS: Sixty participants age 60 and older with a diagnosis of generalized anxiety disorder, panic disorder, or anxiety disorder not otherwise specified. INTERVENTION: CBT-T versus information-only comparison. MEASUREMENTS: Coprimary outcomes included worry (Penn State Worry Questionnaire) and general anxiety (State Trait Anxiety Inventory). Secondary outcomes included clinician-rated anxiety (Hamilton Anxiety Rating Scale), anxiety sensitivity (Anxiety Sensitivity Index), depressive symptoms (Beck Depression Inventory), quality of life (SF-36), and sleep (Insomnia Severity Index). Assessments were completed prior to randomization, immediately upon completion of treatment, and 6 months after completing treatment. RESULTS: CBT-T was superior to information-only in reducing general anxiety (ES = 0.71), worry (ES = 0.61), anxiety sensitivity (ES = 0.85), and insomnia (ES = 0.82) at the posttreatment assessment; however, only the reductions in worry were maintained by the 6-month follow-up assessment (ES = 0.80). CONCLUSIONS: These results suggest that CBT-T may be efficacious in reducing anxiety and worry in older adults, but additional sessions may be needed to maintain these effects. PMID- 22828174 TI - Neurohypophyseal hormones protect against pentylenetetrazole-induced seizures in zebrafish: role of oxytocin-like and V1a-like receptor. AB - Oxytocin (OT) and arginine-vasopressin (AVP) are involved in the physiological response to different stressors like the occurrence of seizures which is regarded as a severe stress factor. Zebrafish (Danio rerio) is recently featured as a model of epilepsy but the role of neurohypophyseal hormones on this teleost is still unknown. We attempted to determine whether non-mammalian homologues like isotocin (IT) and vasotocin (AVT) affected pentylenetetrazole (PTZ)-induced seizures in adult zebrafish in comparison with OT/AVP. The mechanism was studied using the most selective OT and AVP receptor antagonists. Zebrafish were injected i.m. with increasing doses (0.1-40 ng/kg) of the neuropeptides 10 min before PTZ exposure. DesGly-NH2-d(CH2)5-[D-Tyr2,Thr4]OVT (desglyDTyrOVT) for OT receptor and SR49059 for V1a subtype receptor, were injected together with each agonist 20 min before PTZ exposure. All the peptides significantly decreased the number of seizures, increased the mean latency time to the first seizure and decreased lethality. This protective effect led to a dose-response curve following a U shaped form. IT was approximately 40 times more active than OT while AVT was 20 times more potent than AVP in reducing the number of seizures. DesglyDTyrOVT was more effective in antagonizing OT/IT, while SR49059 mainly blocked AVP/AVT induced protection against PTZ-induced seizures. The present findings provide direct evidence of an important involvement of IT/OT and AVP/AVT as anticonvulsant agents against PTZ-induced seizures with a receptor-mediated mechanism in zebrafish. These data reinforce zebrafish as an emerging experimental model to study and identify new antiepileptic drugs. PMID- 22828169 TI - Treatment of hyperprolactinemia: a systematic review and meta-analysis. AB - BACKGROUND: Hyperprolactinemia is a common endocrine disorder that can be associated with significant morbidity. We conducted a systematic review and meta analyses of outcomes of hyperprolactinemic patients, including microadenomas and macroadenomas, to provide evidence-based recommendations for practitioners. Through this review, we aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinemia. METHODS: We searched electronic databases, reviewed bibliographies of included articles, and contacted experts in the field. Eligible studies provided longitudinal follow-up of patients with hyperprolactinemia and evaluated outcomes of interest. We collected descriptive, quality and outcome data (tumor growth, visual field defects, infertility, sexual dysfunction, amenorrhea/oligomenorrhea and prolactin levels). RESULTS: After review, 8 randomized and 178 nonrandomized studies (over 3,000 patients) met inclusion criteria. Compared to no treatment, dopamine agonists significantly reduced prolactin level (weighted mean difference, -45; 95% confidence interval, -77 to -11) and the likelihood of persistent hyperprolactinemia (relative risk, 0.90; 95% confidence interval, 0.81 to 0.99). Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinemia, amenorrhea/oligomenorrhea, and galactorrhea. A large body of noncomparative literature showed dopamine agonists improved other patient-important outcomes. Low-to-moderate quality evidence supports improved outcomes with surgery and radiotherapy compared to no treatment in patients who were resistant to or intolerant of dopamine agonists. CONCLUSION: Our results provide evidence to support the use of dopamine agonists in reducing prolactin levels and persistent hyperprolactinemia, with cabergoline proving more efficacious than bromocriptine. Radiotherapy and surgery are useful in patients with resistance or intolerance to dopamine agonists. PMID- 22828173 TI - Distributions and trends in sexual behaviors and HIV incidence among men who have sex with men in China. AB - BACKGROUND: HIV prevalence is increasing at a concerning rate among men who have sex with men (MSM) in China. Numerous studies have reported on levels of behaviors of Chinese MSM for different types of sexual partnerships, such as regular, non-commercial casual and commercial. This study aims to investigate the trends HIV incidence rates in relation to their risk sexual behaviors and partnership types among Chinese MSM. METHOD: Through a comprehensive literature research from available English and Chinese literature databases, we collated relevant information of sexual behaviors of Chinese MSM. Further, with the utilization of a mathematical optimization approach, this study reconciles the distributions of sexual behavioral data over the last decade and infers the heterogeneous distributions of behavioral patterns among Chinese MSM. Distributions of high-risk behavioural indicators, including the number of sexual partners, number of sexual acts and condom usage in the past 6 months, are calibrated to available empirical data. Based on the resultant temporal trends in these distributions, the trends in HIV incidence rates associated with each type of partnership among MSM in China are also estimated. RESULTS: A total of 55 qualified articles have been identified. An average MSM has approximately 0.96 (95% CI, 0.59-1.18) regular, 3.75 (1.72-6.25) casual and 1.61 (0.97-2.78) commercial partners over a 6 month period and 4.33 (2.81-6.46), 1.42 (0.62-3.08), 1.48 (0.79-3.30) sexual acts per partnership respectively, corresponding to a total of 11.87 (8.87-15.25) acts. Condom usage has increased significantly during 2002-2010, at annual increases of 3.58% (2.98-4.12%), 5.55% (4.55-6.54%), and 5.03% (4.19-5.74%) for regular, casual and commercial partners respectively. These behavioral data implies an increase in HIV incidence of approximately 3.3 fold, from 2.04 (1.96-2.12) to 7.02 (6.71-7.35) per 1000 person-years during the same period. The proportion of new infections attributed to regular partnerships increased from 34% to 40%, whereas infections attributed to commercial partnerships reduced from 29% to 23% during 2002-2010. CONCLUSION: Regular partnerships are the main contributor of new HIV cases among MSM in China, public health intervention strategies are required to increase condom usage and HIV testing rates among regular partners to curb the growing trend HIV incidence. PMID- 22828175 TI - A 14-year-old girl with tuberculous otitis media and brain abscess. AB - Tuberculosis is a rare cause of chronic suppurative otitis media and mastoiditis. Intracranial complications are rare. The authors report a case of a 14-year-old girl with chronic otitis media of her right ear for 2 years. Her presentation was as follows: 10 days before admission she had a high fever, headache, alteration of consciousness and a generalised seizure. CT scanning of her brain showed right otomastoiditis with early brain abscess of the right cerebellum. She underwent right radical mastoidectomy and aspiration of the cerebellar abscess. The pus from the mastoid and cerebellar abscess was stained positive for acid-fast bacilli (AFB). The pus culture grew Mycobacterium tuberculosis (MTB). Her discharge diagnosis was tuberculous mastoiditis (TM) with cerebellar abscess. Long-term treatment plans included antituberculous drugs for 1 year. PMID- 22828176 TI - Potential cost-effectiveness and benefit-cost ratios of adult pneumococcal vaccination in Germany. AB - BACKGROUND: Invasive (IPD, defined as detection of pneumococci in sterile body fluids like meningitis or bacteremic pneumonia) and non-invasive Streptococcus pneumoniae infections (i.e. non-bacteremic pneumonia, otitis media) in adults are associated with substantial morbidity, mortality and costs. In Germany, Pneumococcal polysaccharide vaccination (PPV23) is recommended for all persons >60 years and for defined risk groups (age 5-59). The aim of this model was to estimate the potential cost-effectiveness and benefit-cost ratios of the adult vaccination program (18 years and older), considering the launch of the pneumococcal conjugate vaccine for adults (PCV13). METHODS: A cross-sectional steady state Markov model was developed to estimate the outcomes of PCV13, PPV23 vaccination schemes and 'no vaccination'. Conservative assumptions were made if no data were available for PCV13 and PPV23 respectively. The effectiveness of individual pneumococcal vaccination in adults was adjusted for expected indirect effects due to the vaccination in infants. Data on incidences, effectiveness and costs were derived from scientific literature and publicly available databases. All resources used are indicated. Benefit-cost ratios and cost-effectiveness were evaluated from the perspective of the German Statutory Health Insurance as well as from social perspective. RESULTS: Under the assumption that PCV13 has a comparable effectiveness to PCV7, a vaccination program with PCV13 revealed the potential to avoid a greater number of yearly cases and deaths in IPD and pneumonia in Germany compared to PPV23. For PCV13, the costs were shown to be overcompensated by monetary savings resulting from reduction in the use of health care services. These results would render the switch from PPV23 to PCV13 as a dominant strategy compared to PPV23 and 'no vaccination'. Given the correctness of the underlying assumptions every Euro spent on the PCV13 vaccination scheme yields savings of 2.09 ? (social perspective: 2.16 ?) compared to PPV23 and 1.27 ? (social perspective: 1.32 ?) compared to 'no vaccination', respectively. CONCLUSIONS: Results of the model indicate that the health economic benefit of immunizing adults with PCV13 can be expected to outperform the sole use of PPV23, if the effectiveness of PCV13 is comparable to the effectiveness of PCV7. PMID- 22828178 TI - Molecular evolution of the Asian francolins (Francolinus, Galliformes): a modern reappraisal of a classic study in speciation. AB - We investigated the evolution of the Asian francolins, five little known species in the genus Francolinus (Phasianidae). Evolutionary affinities of two of these species, F. gularis (swamp francolin) and F. pondicerianus (grey francolin), has long remained unclear. In contrast, the other three species, F. pintadeanus (Chinese francolin), F. pictus (painted francolin) and F. francolinus (black francolin) have been cast among the "spotted francolins" on a morphological and ecological basis. Previous molecular DNA investigations including Asian francolins mostly relied upon partial gene sequencing of one specimen per species (no more than three species and with the exclusion of F. pictus). Therefore, fundamental questions do persist. What relationship exists among the spotted and the other Asian francolins? What is the geographic origin of the black francolin, the species with the largest distribution range? How did the geological history influence the diversification of francolins across Asia? We sequenced the entire Control Region of the mitochondrial DNA in 228 samples of all five Asian francolin species, which were collected in 16 countries (from East Europe to East Asia). We constructed a molecular phylogeny according to four different procedures. We showed the monophyly of each of the Asian francolins and the spotted group, while that of the entire Asian group was presumed according to a biogeographical model we proposed. The splitting of the genus Francolinus occurred ~17.4 Ma (95% HPD: 13.4-22.1) while the spotted francolins diverged ~10.5 Ma (7.0-14.9). We resolved the most recent common ancestor to painted and black francolin as being in the Indian sub-continent, thus suggesting a westwards adaptive radiation of the latter. In Pakistan, we identified F. f. asiae representatives in the Northern Areas and in the Sindh. The latter represents a relict population of Indian fauna within the Pakistani range of the Great Rann of Kachchh. PMID- 22828177 TI - Behavioral health coaching for rural-living older adults with diabetes and depression: an open pilot of the HOPE Study. AB - BACKGROUND: Patients with diabetes are at increased risk for depression, compounding the burden of disease. When comorbid with diabetes, depression leads to poorer health outcomes and often complicates diabetes self-management. Unfortunately, treatment options for these complex patients are limited and comprehensive services are rarely available for patients in rural settings. METHODS: A small open trial was conducted to test the acceptability, feasibility and preliminary outcomes of a telephone-delivered coaching intervention for rural dwelling older adults with uncontrolled diabetes and comorbid, clinically significant depressive symptoms. A total of eight older adults were enrolled in Healthy Outcomes through Patient Empowerment (HOPE), a 10-session (12-week), telephone-based coaching intervention. Primary study constructs included measures of diabetes control (Hemoglobin [Hb] A1c), depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]), and diabetes-related distress (Problem Areas in Diabetes Scale [PAID]). Assessments were conducted at baseline, post intervention, and 6-month follow-up. Acceptability and feasibility were evaluated using patient surveys, focused exit interviews, and session attendance data. RESULTS: Clinically significant improvements were realized post-intervention and at 6-month follow-up for outcomes related to diabetes and depression. Effect sizes using Cohen's d were determined post-intervention and at 6-month follow-up, respectively, for HbA1c (d=0.36; d=0.28), PHQ-9 (d=1.48; d=1.67, and PAID (d=1.50; d=1.06) scores. Among study participants, HbA1c improved from baseline by a mean (M) of 1.13 (SD=1.70) post-intervention and M=0.84 (SD=1.62) at 6 months. Depression scores, measured by the PHQ-9, improved from baseline by M=5.14 (SD=2.27) post-intervention and M=7.03 (SD=4.43) at 6-month follow-up. PAID scores also improved by M=17.68 (SD=10.7) post-intervention and M=20.42 (SD=20.66) from baseline to 6-month follow-up. Case examples are provided for additional context and to more fully articulate salient intervention concepts. CONCLUSION: Although preliminary, data from this small open trial suggest that HOPE holds the potential to improve both physical (diabetes) and emotional (diabetes distress, depression) health outcomes and that changes can be maintained over a 6-month time period. As envisioned by the authors, HOPE may function as an extension of traditional primary care for rural-dwelling older adults with multiple comorbidities. A future randomized clinical trial will test HOPE's broader effectiveness with rural-dwelling older adults. TRIAL REGISTRATION: NCT01274715. PMID- 22828179 TI - Can one trust quantum simulators? AB - Various fundamental phenomena of strongly correlated quantum systems such as high T(c) superconductivity, the fractional quantum-Hall effect and quark confinement are still awaiting a universally accepted explanation. The main obstacle is the computational complexity of solving even the most simplified theoretical models which are designed to capture the relevant quantum correlations of the many-body system of interest. In his seminal 1982 paper (Feynman 1982 Int. J. Theor. Phys. 21 467), Richard Feynman suggested that such models might be solved by 'simulation' with a new type of computer whose constituent parts are effectively governed by a desired quantum many-body dynamics. Measurements on this engineered machine, now known as a 'quantum simulator,' would reveal some unknown or difficult to compute properties of a model of interest. We argue that a useful quantum simulator must satisfy four conditions: relevance, controllability, reliability and efficiency. We review the current state of the art of digital and analog quantum simulators. Whereas so far the majority of the focus, both theoretically and experimentally, has been on controllability of relevant models, we emphasize here the need for a careful analysis of reliability and efficiency in the presence of imperfections. We discuss how disorder and noise can impact these conditions, and illustrate our concerns with novel numerical simulations of a paradigmatic example: a disordered quantum spin chain governed by the Ising model in a transverse magnetic field. We find that disorder can decrease the reliability of an analog quantum simulator of this model, although large errors in local observables are introduced only for strong levels of disorder. We conclude that the answer to the question 'Can we trust quantum simulators?' is ... to some extent. PMID- 22828180 TI - Retraction: Disposable screen-printed sensors for determination of Duloxetine Hydrochloride. PMID- 22828181 TI - Brain network involved in visual processing of movement stimuli used in upper limb robotic training: an fMRI study. AB - BACKGROUND: The potential of robot-mediated therapy and virtual reality in neurorehabilitation is becoming of increasing importance. However, there is limited information, using neuroimaging, on the neural networks involved in training with these technologies. This study was intended to detect the brain network involved in the visual processing of movement during robotic training. The main aim was to investigate the existence of a common cerebral network able to assimilate biological (human upper limb) and non-biological (abstract object) movements, hence testing the suitability of the visual non-biological feedback provided by the InMotion2 Robot. METHODS: A visual functional Magnetic Resonance Imaging (fMRI) task was administered to 22 healthy subjects. The task required observation and retrieval of motor gestures and of the visual feedback used in robotic training. Functional activations of both biological and non-biological movements were examined to identify areas activated in both conditions, along with differential activity in upper limb vs. abstract object trials. Control of response was also tested by administering trials with congruent and incongruent reaching movements. RESULTS: The observation of upper limb and abstract object movements elicited similar patterns of activations according to a caudo-rostral pathway for the visual processing of movements (including specific areas of the occipital, temporal, parietal, and frontal lobes). Similarly, overlapping activations were found for the subsequent retrieval of the observed movement. Furthermore, activations of frontal cortical areas were associated with congruent trials more than with the incongruent ones. CONCLUSIONS: This study identified the neural pathway associated with visual processing of movement stimuli used in upper limb robot-mediated training and investigated the brain's ability to assimilate abstract object movements with human motor gestures. In both conditions, activations were elicited in cerebral areas involved in visual perception, sensory integration, recognition of movement, re-mapping on the somatosensory and motor cortex, storage in memory, and response control. Results from the congruent vs. incongruent trials revealed greater activity for the former condition than the latter in a network including cingulate cortex, right inferior and middle frontal gyrus that are involved in the go-signal and in decision control. Results on healthy subjects would suggest the appropriateness of an abstract visual feedback provided during motor training. The task contributes to highlight the potential of fMRI in improving the understanding of visual motor processes and may also be useful in detecting brain reorganisation during training. PMID- 22828182 TI - Mind the information gap: fertility rate and use of cesarean delivery and tocolytic hospitalizations in Taiwan. AB - BACKGROUND: Physician-induced demand (PID) is an important theory to test given the longstanding controversy surrounding it. Empirical health economists have been challenged to find natural experiments to test the theory because PID is tantamount to strong income effects. The data requirements are both a strong exogenous change in income and two types of treatment that are substitutes but have different net revenues. The theory implies that an exogenous fall in income would lead physicians to recoup their income by substituting a more expensive treatment for a less expensive treatment. This study takes advantages of the dramatic decline in the Taiwanese fertility rate to examine whether an exogenous and negative income shock to obstetricians and gynecologists (ob/gyns) affected the use of c-sections, which has a higher reimbursement rate than vaginal delivery under Taiwan's National Health Insurance system during the study period, and tocolytic hospitalizations. METHODS: The primary data were obtained from the 1996 to 2004 National Health Insurance Research Database in Taiwan. We hypothesized that a negative income shock to ob/gyns would cause them to provide more c-sections and tocolytic hospitalizations to less medically-informed pregnant women. Multinomial probit and probit models were estimated and the marginal effects of the interaction term were conducted to estimate the impacts of ob/gyn to birth ratio and the information gap. RESULTS: Our results showed that a decline in fertility did not lead ob/gyns to supply more c-sections to less medically-informed pregnant women, and that during fertility decline ob/gyns may supply more tocolytic hospitalizations to compensate their income loss, regardless of pregnant women's access to health information. CONCLUSION: The exogenous decline in the Taiwanese fertility rate and the use of detailed medical information and demographic attributes of pregnant women allowed us to avoid the endogeneity problem that threatened the validity of prior research. They also provide more accurate estimates of PID.JEL Classification: I10, I19, C23, C25. PMID- 22828183 TI - The use of biologic agents in pediatric inflammatory bowel disease. AB - PURPOSE OF REVIEW: Therapeutic options and approaches in inflammatory bowel disease (IBD) continue to evolve. This review will summarize the recent studies of treatment strategies, efficacy, safety and outcome of biological agents in the treatment of children with Crohn's disease and ulcerative colitis. RECENT FINDINGS: Although there has been little recent change in the number of biologicals easily available for the treatment of children, usage has broadened in pediatric IBD and new treatment strategies have emerged. The use of biologicals in refractory pediatric ulcerative colitis is now accepted, with evidence supporting their potential for maintenance therapy. In pediatric Crohn's disease, scheduled treatment regimens have shown superiority to episodic treatment. Although the 'top-down' approach with early use of biologicals produces superior remission rates in adults, there is still little evidence in children. Concomitant immunosuppression appears to reduce immunogenicity and improve therapeutic control, but there are added risks for infection and malignancy. SUMMARY: Biologicals now form an integral part of the treatment algorithm in childhood IBD and their use is likely to increase. Treatment regimens, particularly those involving concomitant immunosuppressants, need to take account of the perceptions of risk. PMID- 22828184 TI - Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy. AB - Although multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system (CNS), its highly complex pathogenesis clearly includes a significant vascular inflammatory component and many therapeutic approaches achieve benefit by direct or indirect effects on cerebrovascular endothelial cells. Cerebral endothelial cells create and separate the compartments of the peripheral circulation and CNS creating the blood-brain barrier (BBB), a selectively permeable boundary layer between these spaces. Interactions between activated leukocytes and cerebral endothelium play essential roles in mediating their trans-BBB diapedesis during normal immune surveillance and during pathogenesis of neuroinflammatory diseases like MS. Extravasation of activated and committed leukocytes from the peripheral circulation through the endothelial layer of the BBB into the CNS milieu is the most fundamental step in formation of MS lesions. During MS pathogenesis, once the activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration. Multiple clinical and basic scientific observations support endothelial cell 'stress' and apoptosis as a hallmark characteristic of MS. The manipulation of the endothelial biology aiming to block trans-endothelial migration of activated immune cells into the CNS is a potent form of treatment for MS achieving significant reductions in disease activity and new lesion formation. In particular, endothelial microparticles are now well-recognized as important biomarkers and mediators of this type of stress. In this review, we discuss recent findings and new advances in our knowledge regarding leukocyte migration through the endothelial frontier of the BBB and how this can be exploited toward treating MS patients. PMID- 22828185 TI - Temporal distribution of genetically homogenous 'free-living' Hematodinium sp. in a Delmarva coastal ecosystem. AB - BACKGROUND: Significant damage to crustacean fisheries worldwide has been associated with Hematodinium sp. It has been postulated that Hematodinium sp. requires passage through the water column and/or intermediate hosts to complete its life cycle. Thus, an understanding of the prevalence and seasonality of Hematodinium sp. within environmentally-derived samples should yield insight into potential modes of disease transmission, and how these relate to infection cycles in hosts. RESULTS: We conducted a two year survey, from 2010-2011, in which 48 of 546 (8.8%) of environmental samples from the Maryland and Virginia coastal bays were positive for Hematodinium sp. between April and November, as based upon endpoint PCR analysis specific to blue crab isolates. Detection in both water and sediment was roughly equivalent, and there were no obvious seasonal patterns. However, there was a high detection in April water samples, which was unanticipated owing to the fact that crabs infected with Hematodinium sp. have not been observed in this early month of the seasonal disease cycle. Focusing on three sites of high prevalence (Sinnickson, VA; Tom's Cove, VA; and Newport Bay, MD) Hematodinium sp. population diversity was analyzed using standard cloning methods. Of 131 clones, 109 (83.2%) were identical, 19 displayed a single nucleotide substitution, and 4 contain two nucleotide substitutions. CONCLUSIONS: Our data suggests a continuous presence of Hematodinium sp. in both water and sediment of a combined Maryland and Virginia coastal bay ecosystem. The detection of Hematodinium sp. in the water column in April is an earlier manifestation of the parasite than predicted, pointing to an as yet unknown stage in its development prior to infection. That the population is relatively homogenous ranging from April to November, at three distinct sites, supports a hypothesis that one species of Hematodinium is responsible for infections within the ecosystem. PMID- 22828186 TI - Sjogren-Larsson syndrome--unusual presentation with pathological femoral neck fracture: a case report. AB - Patients with Sjogren-Larsson syndrome, an autosomal recessive syndrome characterized by ichthyosis, spastic diplegia/quadriplegia, mental retardation and ocular features that include pigmentary changes in the retina, rarely present to the orthopaedic surgeon. We detail a rare and unusual presentation of Sjogren Larsson syndrome in an adolescent boy with bilateral femoral neck fractures. PMID- 22828187 TI - Horizontal intra-articular patellar dislocation resulting in quadriceps avulsion and medial patellofemoral ligament tear: a case report. AB - Intra-articular patellar dislocations are rare. We present a 13-year-old boy who sustained a complete horizontal intra-articular patellar dislocation following blunt trauma to the flexed knee. Closed reduction was unsuccessful and open reduction indicated a repairable quadriceps avulsion and medial patellofemoral ligament tear. He is the youngest patient to sustain a quadriceps rupture and the only patient to sustain a medial patellofemoral ligament tear to date. His flexed knee and the horizontally positioned patella (seen on lateral radiograph) were indicative of a complete rotational injury with extensor mechanism involvement. Open reduction allowed for the repair of both injuries and a favorable outcome. PMID- 22828188 TI - All tangled up: life in a quantum world. PMID- 22828190 TI - The effect of electroconvulsive therapy on blood glucose, creatinine levels, and lipid profile and its association with the type of psychiatric disorders. AB - Although the mechanism of electroconvulsive therapy (ECT) is not clearly known, its effects on hormones have been widely studied. However, there are controversies about the effect of ECT on blood glucose level. In addition, the possible effects of ECT on the blood cholesterol, LDL, HDL, and triglyceride levels are ignored research areas. The present study was conducted on 99 patients with major depressive disorder, bipolar mood disorder, or schizophrenia. Overall, two blood samples were taken. The first of which was taken before administering ECT and the second one was taken during 20 min after taking ECT while the patients were on fasting. The blood glucose, cholesterol, LDL, HDL, triglyceride, and creatinine levels were measured. The blood glucose and cholesterol levels after taking ECT were statistically more than those of pre-ECT. However, no significant difference was found between pre- and post-ECT regarding the levels of LDL, HDL, triglyceride, and creatinine. Moreover, the type of psychiatric disorder, weight, height, age, and gender did not predict the post-ECT glucose level. ECT may immediately increase the blood glucose and total cholesterol levels, while it does not affect any of the other mentioned parameters. These increases seem to be independent of the type of psychiatric disorders. PMID- 22828200 TI - Early childhood caries trends and surveillance shortcomings in the Czech Republic. AB - BACKGROUND: Despite the decline in childhood caries prevalence, seen particularly in 1980s, in recent years there have been reports that the declining trend has stopped or even reversed in some countries. The aim of the study was to analyse data from previous epidemiological studies on early childhood caries in the Czech Republic, conduct a secondary analysis of trend in dental caries prevalence, and discuss issues related to national oral health surveillance. METHODS: Since the 1990s, caries prevalence in preschool children was monitored by two independent bodies: Institute of Health Information and Statistics (IHIS) that conducted 5 cross-sectional surveys over the period 1994-2006, and Institute of Dental Research (IDR) that conducted 4 studies over the years 1998-2010. Both study series differed in methods of sample selection and approaches to examiner training. For the assessment of the caries prevalence trends, regression modelling was used for the following oral-health indicators: caries experience, mean number of teeth with untreated caries (dt) and percentage of caries-free children. RESULTS: In both study series, a significant overall trend of declining caries experience and level of untreated caries, and an increasing trend of percentage of caries-free children was observed (p < 0.05). In IHIS studies, caries experience reduced from 3.5 to 2.7; dt reduced from 2.2 to 1.5 and a proportion of caries-free children increased from 23.9 to 42.2%. In IDR studies, caries experience reduced from 3.7 to 2.98; dt reduced from 2.5 to 2.1 and a proportion of caries-free children increased from 26.7 to 44.9%. CONCLUSIONS: Both study series identified a significant decline of caries prevalence particularly in the 1990s and early 2000s. By the end of the investigated period, flattening of the caries decline was observed. The positive trend was observed in the absence of any systematic preventive initiatives on a population level. With respect to the above the authors assume that in the Czech Republic there still is a potential for further caries reduction in preschool population. This, however, cannot be expected without any health policy interventions. Oral health surveillance in the Czech Republic should be promoted by competent regulatory authorities. PMID- 22828203 TI - The incidence of depression and its risk factors in Dutch nursing homes and residential care homes. AB - OBJECTIVE: Although it is known that depression is highly prevalent in institutionalized older adults, little is known about its incidence and risk factors in nursing homes and residential care homes. The aim of this study was to investigate and compare the incidence and associated risk factors for depression in Dutch nursing homes and residential care homes. DESIGN: Data on depression were extracted from the Vrije Universiteit naturalistic cohort on routine care monitoring with the Minimum Data Set of the Resident Assessment Instrument. PARTICIPANTS: A total of 1,324 residents in six nursing homes and 1,723 residents in 23 residential care homes with an average follow-up of 1.2 years. MEASUREMENTS: Depression was defined as a clinical diagnosis according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria and the use of antidepressants. Residents with prevalent depression at baseline were excluded. RESULTS: The incidence rate was 13.6 per 100 person years in the nursing homes and 10.2 per 100 person years in the residential care homes. The independent risk factors for in-home depression for residents in nursing homes included dementia (OR: 1.7; 95% CI: 1.02-2.95) and a score of 3 or more on the Depression Rating Scale (odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.23 3.70). A protective effect was seen on the use of a hearing aid (OR: 0.3; 95% CI: 0.12-0.80). In the residential care homes, being male (OR: 2.1; 95% CI: 1.27 3.30), having cancer (OR: 2.9; 95% CI: 1.64-4.95), and a score of 2 or higher on the Cognitive Performance Scale (OR: 1.5; 95% CI: 1.05-2.22) increased the risk to develop depression. Age greater than 85 years (OR: 0.5; 95% CI: 0.31-0.67) and hearing impairment (OR: 0.8; 95% CI: 0.60-1.00) appeared to be protective. CONCLUSIONS: The incidence rate for depression in residents of Dutch nursing homes and residential care homes was high and the associated risk factors found may have important implications for staff. PMID- 22828202 TI - Depression interventions among racial and ethnic minority older adults: a systematic review across 20 years. AB - While there is strong evidence in support of geriatric depression treatments, much less is available with regard to older U.S. racial and ethnic minorities. The objectives of this review are to identify and appraise depression treatment studies tested with samples of U.S. racial and ethnic minority older adults. We include an appraisal of sociocultural adaptations made to the depression treatments in studies meeting our final criteria. Systematic search methods were utilized to identify research published between 1990 and 2010 that describe depression treatment outcomes for older adults by racial/ethnic group, or for samples of older adults who are primarily (i.e., >50%) racial/ethnic minorities. Twenty-three unduplicated articles included older adults and seven met all inclusion criteria. Favorable depression treatment effects were observed for older minorities across five studies that took place in different types of settings and with varying levels of sociocultural adaptations. The effectiveness of depression care remains mixed, although collaborative or integrated care shows promise for African Americans and Latinos. The degree to which the findings generalize to non-English-speaking, low acculturated, and low-income older persons, and to other older minority groups (i.e., Asian and Pacific Islanders, and American Indian and Alaska Natives), remains unclear. Given the high disease burden among older minorities with depression, it is imperative to provide timely, accessible, and effective depression treatments. Increasing their participation in behavioral health research should be a national priority. PMID- 22828204 TI - Community-based health insurance and social capital: a review. AB - Community-Based Health Insurance (CBHI) is an emerging concept for providing financial protection against the cost of illness and improving access to quality health services for low-income rural households who are excluded from formal insurance. CBHI is currently being provided in some rural areas in developing countries and there is ongoing research about its impact on the well-being of the poor in these areas. However, the success of CBHI revolves around the existence of social capital in the community. This has led researchers to explore the impact of CBHI on the well-being of the poor in rural areas, especially as it relates to social capital. The overall objective of this paper is to review recent developments that address the link between CBHI and social capital. Policy implications are also discussed. JEL CLASSIFICATION: C10, I15. PMID- 22828205 TI - Word reading threshold and mild cognitive impairment: a validation study. AB - BACKGROUND: It was previously found, in a pilot study, that Word Reading Threshold (WRT) test is abnormally prolonged in individuals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), with high sensitivity and specificity. This validation study examines the WRT test as a prognostic tool in MCI individuals. We wish to confirm in a larger group the sensitivity and specificity of the WRT test and determine whether it is influenced by deterioration on other cognitive domains. METHODS: We measured WRT in 60 MCI individuals, 29 AD patients, and 33 normal elderly control (NE). We followed the MCI individuals over 8 years to monitor who progressed to dementia. RESULTS: We found a statistically significant difference in WRT scores between the three groups. However, using the same cutoff of 85 milliseconds suggested by Massoud and his colleagues, we found lower diagnostic sensitivity (72%) and specificity (76%) when comparing NC and AD. Furthermore, the test did not clearly differentiate MCI individuals who progressed to dementia from those who did not. WRT was found to correlate to some degree with other cognitive domains, especially attention. CONCLUSIONS: We conclude that the WRT is insufficient alone as a diagnostic tool for prodromal AD. PMID- 22828207 TI - Associations between testosterone levels and incident prostate, lung, and colorectal cancer. A population-based study. AB - BACKGROUND: The relationship between testosterone and cancer is relatively unexplored. We sought to examine whether testosterone and related hormones are associated with incident prostate, lung, and colorectal cancer. METHODS: This was a population-based cohort study. Demographic and clinical predictors of cancer, and testosterone, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were measured between 2001 and 2004 in 3,635 community-dwelling men aged 70 to 88 years (mean 77 years). Cancer notifications were obtained via electronic record linkage until December 31, 2010. RESULTS: During a mean follow-up period of 6.7 +/- 1.8 years, there were 297, 104, and 82 cases of prostate, colorectal, and lung cancer. In adjusted competing risks proportional hazards models, each one SD increase in free testosterone was associated with a 9% increase in prostate cancer risk (95% confidence interval [CI], 1.00-1.18), but other hormones were not significantly associated. No significant associations were observed between hormonal parameters and colorectal cancer. Higher total testosterone was associated with lung cancer. Compared with the mean of 15 nmol/L, men with levels of 20 nmol/L were 1.38 times more likely to be cases (95% CI, 1.21-1.57), whereas those with levels of 30 nmol/L were 3.62 times more likely to be cases (95% CI, 2.53-5.18). Higher free testosterone was also associated with lung cancer, though SHBG and LH were not. Associations were maintained after exclusion of current smokers. CONCLUSIONS: Higher free testosterone was associated with incident prostate cancer. Higher testosterone levels may also be associated with lung cancer. IMPACT: Further studies should investigate whether these risks apply to men receiving testosterone therapy. PMID- 22828206 TI - Protective immunity to Japanese encephalitis virus associated with anti-NS1 antibodies in a mouse model. AB - BACKGROUND: Japanese encephalitis virus (JEV) is a major mosquito-borne pathogen that causes viral encephalitis throughout Asia. Vaccination with an inactive JEV particle or attenuated virus is an efficient preventative measure for controlling infection. Flavivirus NS1 protein is a glycoprotein secreted during viral replication that plays multiple roles in the viral life cycle and pathogenesis. Utilizing JEV NS1 as an antigen in viral vectors induces a limited protective immune response against infection. Previous studies using E. coli-expressed JEV NS1 to immunize mice induced protection against lethal challenge; however, the protection mechanism through cellular and humoral immune responses was not described. RESULTS: JEV NS1 was expressed in and purified from Drosophila S2 cells in a native glycosylated multimeric form, which induced T-cell and antibody responses in immunized C3H/HeN mice. Mice vaccinated with 1 MUg NS1 with or without water-in-oil adjuvant were partially protected against viral challenge and higher protection was observed in mice with higher antibody titers. IgG1 was preferentially elicited by an adjuvanted NS1 protein, whereas a larger load of IFN-gamma was produced in splenocytes from mice immunized with aqueous NS1. Mice that passively received anti-NS1 mouse polyclonal immune sera were protected, and this phenomenon was dose-dependent, whereas protection was low or delayed after the passive transfer of anti-NS1 MAbs. CONCLUSION: The purified NS1 subunit induced protective immunity in relation with anti-NS1 IgG1 antibodies. NS1 protein efficiently stimulated Th1-cell proliferation and IFN-gamma production. Protection against lethal challenge was elicited by passive transfer of anti-NS1 antisera, suggesting that anti-NS1 antibodies play a substantial role in anti viral immunity. PMID- 22828208 TI - 21 cm cosmology in the 21st century. AB - Imaging the Universe during the first hundreds of millions of years remains one of the exciting challenges facing modern cosmology. Observations of the redshifted 21 cm line of atomic hydrogen offer the potential of opening a new window into this epoch. This will transform our understanding of the formation of the first stars and galaxies and of the thermal history of the Universe. A new generation of radio telescopes is being constructed for this purpose with the first results starting to trickle in. In this review, we detail the physics that governs the 21 cm signal and describe what might be learnt from upcoming observations. We also generalize our discussion to intensity mapping of other atomic and molecular lines. PMID- 22828210 TI - Crossover replantation after bilateral traumatic lower limb amputations: a case report. AB - INTRODUCTION: Replantation of a limb to the contralateral stump after bilateral traumatic amputations is rare. To the best of our knowledge, there are only a few reports of crossover lower limb replantation in the literature. CASE PRESENTATION: We treated a 37-year-old Chinese woman with bilateral lower limb crush injuries sustained in a traffic accident. Her lower limb injuries were at different anatomic levels. We performed emergency bilateral amputations followed by crossover replantation. Five years later, the woman had recovered well, and had perfect movement and stability in her replanted leg. After reviewing the literature, we thought that presentation of our patient's case might provide useful information for clinicians. CONCLUSIONS: Crossover replantation should be considered when evaluating a patient with bilateral lower limb injuries, thus allowing the patient to touch the ground and stand using their own foot. PMID- 22828209 TI - Mechanism of folate deficiency-induced apoptosis in mouse embryonic stem cells: Cell cycle arrest/apoptosis in G1/G0 mediated by microRNA-302a and tumor suppressor gene Lats2. AB - Deficiencies in maternal diet, such as inadequate intake of folate, can inhibit normal development and lead to developmental defects. MicroRNAs (miRNAs) may play a role in mediating the effects of folate deficiency in the growing mammalian embryo, although conclusive evidences to support that possibility are not yet available. The goal of the present study was to investigate whether and how folate deprivation alters the properties of mouse embryonic stem cells (mESCs) in culture. For this purpose, mESCs were cultured in folate-deficient or complete culture medium. The results show that folate-deficient mESCs have a significantly higher rate of apoptosis, accumulate in G0/G1 and fail to proliferate. Expression profiling revealed several miRs and many mRNAs are differently expressed in folate-deficient cells. RT-PCR data confirmed differential expressions of 12 miRNAs in folate-deficient cells. Furthermore, bioinformatics analyses and in vitro studies suggested that miR-302a plays a critical role in mediating the effects of folate on cell proliferation and cell cycle-specific apoptosis by targeting Lats2 gene. Together, these results suggest that the effects of folate deficiency on mammalian development may be mediated by miRNAs that regulate proliferation and/or cell cycle progression in ESCs. PMID- 22828211 TI - Necrotizing sarcoid granulomatosis. AB - PURPOSE OF REVIEW: Necrotizing sarcoid granulomatosis (NSG) is rare. Its various clinical and histological presentations are ambiguous and confusing. Although sometimes limited only to the lungs, other organ systems can be involved. The disease affects primarily women in their late forties but has been documented in children. RECENT FINDINGS: There are two schools of thought regarding the taxonomical position of NSG. Some believe that it is an independent entity, whereas others argue that it is just another manifestation of sarcoidosis. This article will review the available, current and evidence-based information about clinical and basic science aspects of NSG. SUMMARY: Diagnosis of NSG is perplexing; its pathogenesis is a dilemma. The disease is frequently confused with other processes including malignancy, Wegener's granulomatosis, hypersensitivity pneumonitis, sarcoidosis and lymphoid granulomatosis. Its symptoms are nonspecific and a histology finding of necrotizing granuloma has many causes. Although no specific management tool or strategies are advocated, steroids, surgical resection of localized disease or sometimes watchful waiting are recommended. PMID- 22828212 TI - Recent developments in the physiological assessment of sarcoidosis: clinical implications. AB - PURPOSE OF REVIEW: This review emphasizes key findings in physiologic research of sarcoidosis reported over the past year. RECENT FINDINGS: Sarcoidosis, a multiorgan disease involving the formation of epithelioid-cell granulomas, is characterized by reduced lung volumes, compliance, and diffusion capacity (D(L)CO), and, in a small number of cases, by airflow limitation. Recent studies do not show a close relationship between changes in lung volume and radiographic stage. Fatigue and exercise limitation are characteristic of this condition, and can be assessed by health-related quality of life (HRQOL) instruments. Recent investigations have focused on the evaluation of the extent of parenchymal and nodal inflammatory activity by PET using 18F-fluorodeoxyglucose (FDG-PET imaging). Pulmonary hypertension in advanced cases of sarcoidosis contributes to increased physical impairment, and decreased HRQOL and survival. It is best associated with ambulatory desaturation, reduced D(L)CO, and abnormal cardiopulmonary exercise testing findings indicative of pulmonary vascular disease. If pulmonary hypertension is suspected, it should be screened for by echocardiography and confirmed by right heart catheterization. Selected patients with progressive disease unresponsive to medical therapy or with severe pulmonary hypertension should be considered for lung transplantation. Current criteria for lung transplantation include New York Heart Association functional class III-IV, pulmonary hypertension, and/or right atrial pressure at least 15 mmHg. SUMMARY: Periodic assessment of HRQOL measures, exercise-induced hypoxemia, and right sided cardiac pressures for pulmonary hypertension provides, to date, the best insight into the magnitude of physiologic impairment, serving as guideposts for management (including lung transplantation) and prognosis. PMID- 22828213 TI - Considerations about the effectiveness and cost effectiveness of therapies in the treatment of hyperphosphataemia. AB - Because of an elevated serum phosphate level, patients who suffer from chronic kidney failure frequently tend to have cardiovascular calcification and are therefore exposed to a higher probability of a fatal event. Phosphate binders are able to reduce these negative effects. Currently, there are primarily two groups of phosphate binders (calcium-containing and calcium-free phosphate binders) which are considered to be almost equally effective in terms of binding of free phosphate. There are, however, a few disadvantages of the two groups. While the calcium-containing binders are associated with an increased risk of hypercalcemia, which is dose dependent, calcium-free binders have been criticized as being too expensive. As the expenditure for patients suffering from chronic kidney failure increases from year to year, as a result of increasing prevalence, there is a growing need for an alternative to existing phosphate binders. The study presented here therefore summarizes available information for the novel combination preparation OsvaRen(r) (calcium acetate/magnesium carbonate) as an alternative therapy to the calcium-free phosphate binder Renagel(r) (sevelamer hydrochloride) and to calcium-containing preparations.The results of this systematic review showed that OsvaRen(r) is at least equally effective in the regulation of serum phosphate level as Renagel(r). In particular, OsvaRen(r) shows no clinically relevant difference in terms of the control of the serum calcium levels compared to Renagel(r) and thereby does not increase the risk of a hypercalcaemia, in contrast to pure calcium-based phosphate binders. On the other hand, Renagel(r) therapy is much more frequently associated with gastrointestinal side-effects, a tendency to result in higher tablet burden for patients and high medication costs. The CALMAG study showed that OsvaRen(r) was at least as effective and safe in terms of controlling serum phosphate and serum calcium levels as Renagel(r) while, at the same time, resulting in about 80% lower costs. In addition, OsvaRen(r) offers a lower risk of hypercalcaemia and associated subsequent costs and is thereby also superior to pure calcium-containing phosphate binders.Because of the effectiveness and tolerability of calcium acetate/magnesium carbonate, OsvaRen(r) offers a clinically suitable and, at the same time, cost-effective therapeutic option in the therapy of hyperphosphataemia. PMID- 22828214 TI - Cycling and walking for transport: Estimating net health effects from comparison of different transport mode users' self-reported physical activity. AB - BACKGROUND: There is comprehensive evidence of the positive health effects of physical activity, and transport authorities can enable this by developing infrastructure for cycling and walking. In particular, cycling to work or to school can be a relatively high intensity activity that by itself might suffice for maximum health gain. In this paper, we present estimates of net health effects that can be assumed for demand responses to infrastructure development. The estimation was based on comparing current cyclists/pedestrians against potential cyclists/pedestrians, applying the international physical activity questionnaire, which is a survey-based method for estimating metabolic equivalent task levels from self-reported types of physical activity, and their frequency, duration and level of intensity (moderate or vigorous).. By comparing between shares of individuals with medium or high intensity levels, within the segments of current cyclists/pedestrians and potential cyclists/pedestrians, we estimate the possible net health effects of potential new users of improved cycling/walking infrastructure. For an underpinning of the estimates, we also include the respondents' assessments of the extent to which cycling/walking for transport replaces other physical activity, and we carry out a regression of cycling/walking activity levels on individual characteristics and cycle/walk facility features. RESULTS: The estimated share of new regular cyclists obtaining net health gains was ca. 30%, while for new regular pedestrians this was only ca. 15%. These estimates are based on the assumption that the new users of improved cycle/walk facilities are best represented by self-declared potential users of such improved facilities. For potential cyclists/pedestrians, exercise was stated as the main motivation for physical active transport, but among current regular cyclists "fast and flexible" was just as important as exercising. Measured intensity levels from physically active transport increased with separate cycling/walking facilities, and were higher for those with higher education and living in urban areas, while they were lower for those with higher BMI and higher age. CONCLUSIONS: Since the share obtaining net health gains might have a huge impact on cost-benefit analysis of new or improved infrastructure for cyclists/pedestrians, it is of importance to estimate this share. A main limitation of our estimation is the cross-sectional design. There is a need for more case studies combining surveys and objective measurement of physical activity changes, preferably before and after the construction of new infrastructure. PMID- 22828224 TI - [Ingestion of sea water as cause of hypernatriemia and rhabdomyolysis in African migrants arriving in Lampedusa through the Strait of Sicily]. PMID- 22828225 TI - [Cervical cancer screening at a turning point in Italy]. PMID- 22828226 TI - [Adverse events assessment: a tool to improve hospitalization in Italy]. PMID- 22828227 TI - [Who decides what is needed to make decisions in public health?]. PMID- 22828228 TI - [Adverse events and preventable consequences: retrospective study in five large Italian hospitals]. AB - OBJECTIVE: To define the incidence of adverse events and their preventability in a representative sample of patients in five acute hospitals located in the North, the Centre and the South of Italy. Other objectives include the evaluation of the consequences of adverse events and their distribution according to specialties. DESIGN: Retrospective and multicentre study. The methodology is focused on the review of clinical records related to hospital admissions in the year 2008 with a sample of 5 hospitals belonging to the national healthcare system selected according to criteria of location (North, Centre and South of Italy) and complexity (regional reference hospitals). The clinical records included in the study were selected in a random way starting from the electronic archives of the hospital discharges of each participating centre. SETTING AND PARTICIPANTS: 7,573 clinical records were reviewed with a process of two stages managed by two reviewers each. The first stage of the review process involved 7 physicians, 1 nurse, 1 pharmacist and 1 biologist with skills and experiences in clinical risk management and in analysis of clinical documentation. The second stage was realized by 10 physicians (5 specialists, 3 experts in public health and 2 forensic physicians), also for the second stage every person involved had specific training in clinical risk management. The reviewers attended a 20-hour training course. MAIN OUTCOME MEASURES: Study of the incidence of adverse events identified during the admissions included. In the case of more than one adverse event for each admission, it is calculated the cumulative incidence of adverse events for each patient. We also considered the percentage of re-admitted patients for each adverse event, the percentage of adverse events which occurred in the phase of pre hospitalization and the degree of preventability of adverse events. A description of the identified adverse events was realized. The sample of the data included in the study was described in terms of included and excluded subjects with respect to the planned research design. Different products and results were tested and validated in the study and could be reused in the future research products. RESULTS: The overall average of the incidences of adverse events was 5.2%, the median was 5.5% and it is consistent with the expected results mentioned in the protocol of the study. The identified incidence of adverse events is lower than the median rate of international studies (9.2%). The distribution of adverse events for specialties underlines the majority of adverse events in the medical area (37.5%), in opposition to the results of other studies; the surgery is the second specialty for number of adverse events (30.1%), followed by the emergency room (6.2%) and obstetrics (4.4%). The study identified 56.7% of adverse events as preventable. The consequences of adverse events were classified in different typologies: the prolonged stay was the most frequent consequence, followed by the disability at discharge. The death of the patient had a median occurrence of 9.45%. The concordance between the two reviewers in the evaluation of the clinical records was very high (higher than 95%) except for two centres. CONCLUSIONS: The results were consistent with the results of other international studies similar in scope in terms of type of study (definition of the rate of adverse events) and epidemiological study design (retrospective study). The incidence rate, previously mentioned as 5.2%, coincides with the unfavorable rates of events determined in varied countries. The preventability resulted in an average of 56.7%. The variability of the results obtained in our inquiry are likely attributable to varied factors occurred during the study. PMID- 22828229 TI - [Definition and validation of a predictive model to identify patients with chronic obstructive pulmonary disease (COPD) from administrative databases]. AB - OBJECTIVE: To develop and validate a predictive model for the identification of patients with Chronic Obstructive Pulmonary Disease (COPD) among the resident population of the Lazio region, using information available in the regional administrative systems (SIS) as well as clinical data of a panel of COPD patients. SETTING AND PARTICIPANTS: All residents in the Lazio region over 40 years of age in 2007 (2,625,102 inhabitants) MAIN OUTCOME MEASURES: The predictive model was developed through record linkage of health care related consumption patterns among 428 panel patients with confirmed COPD diagnosis in 2006 and a control group of patients without COPD (selection from outpatients specialized health care registry, 1:4). Hospital admission for COPD was defined a priori to be sufficient to identify a COPD patient. For all other panel patients and controls, specific drug use (minimum 2 prescriptions during 12 months) and hospitalization for respiratory causes during the past 9 years were retrieved and compared between panel and control patients. COPD associated factors were selected through a Bootstrap- Stepwise (BS) procedure. The predictive model was validated through internal (cross-validation-bootstrap) and external validation (comparison with external COPD patients with confirmed diagnosis), and through comparison with other COPD identification approaches. RESULTS: The BS procedure identified the following predictors of COPD: consumption of beta 2 agonists, anticholinergics, corticosteroids, oxygen, and previous hospitalization for respiratory failure. For each patient, the expected probability of being affected by COPD was estimated. Depending on the cut-point of expected probability, sensibility ranged from 74.5% to 99.6% and specificity from 37.8% to 86.2%. Using the 0.30 cut-point, the model succeeded in identifying 67% of patients with diagnosis of COPD confirmed with spirometry. The predictive performance increased with increasing COPD severity. Prevalence of COPD turned out to be 7.8 %. The age specific estimation was similar to results from other approaches. CONCLUSION: The predictive model shows good performance to identify COPD patients, even if it does not allow to identify those patients who have not been registered in the regional health care service or do not request any public health care service. PMID- 22828230 TI - [The role of the quality of hospital discharge records on the comparative evaluation of outcomes: the example of chronic obstructive pulmonary disease (COPD)]. AB - OBJECTIVE: To analyse the results of the regional comparative evaluation of the outcome "thirty days mortality after admission for reacutized Chronic obstructive pulmonary disease (COPD)" before and after a reabstract study. DESIGN: Reabstract study of clinical records included in the regional comparative evaluation. SETTING AND PARTICIPANTS: 232 clinical records retrieved from Grassi Hospital archives (years 2006-2007) and reviewed by two physicians and one nurse specifically trained. MAIN OUTCOME MEASURES: Models performed before and after reabstract study for comparative evaluation of the outcome were compared. Blind coding of diagnosis and interventions/procedures was completed according to a standard grid consistent with regional guidelines for Hospital Discharge Record coding. Other information was registered, if present on discharge record: smoking habit, number of reacutizations occurred within previous year, use of oxigen and/or other therapies, pneumological visit at discharge. RESULTS: The majority (94%) of reviewed cases were confirmed as being cases of COPD. A total of 168 cases (72%) have been identified as reacutized COPD coherent with enrolment criteria of regional program, 49 (21%) have been identified as COPD and only 15 cases (6%) resulted not affected by COPD. Results of the regional comparative model were substantially unchanged for Grassi hospital (RR =23 vs RR =24). Accurateness of clinical documentation resulted inadequate especially regarding information at discharge (50% missing information on smoking habit, 83% on previous year reacutizations, 22% on follow-up organization after discharge). CONCLUSION: This study contributes to the debate on the role of administrative data on the comparative evaluation of health outcomes. Other relevant issues are to promote the collaboration among different health professionals working in the same hospital, and to increase the awareness of the importance of the quality of health and administrative data. PMID- 22828231 TI - [Building of a local deprivation index to measure the health status in the Liguria Region]. AB - AIMS: During the last twenty years, in the most of the European nations, studies on how measuring socioeconomic differences related to inequities in take in charge of patients, health care and outcomes have been developed. The aim of this paper is the computation of a Liguria Region Deprivation Index (IDR), able to describe the peculiar health characteristics of the Liguria population, economically and socially quite homogeneous, on the basis of the socioeconomic (SE) differences related to health outcomes according to the differences in general mortality. DESIGN: All the population and households variables from the 2001 Italian Census have been considered at municipal level and, for Genoa and Savona, at lower administrative area level, selecting only the ones significantly correlated to the general mortality by Pearson correlation. The Standard Mortality Ratios (SMR on 2001 standard Liguria population) for Overall Mortality by gender and age groups (0-64 years and 65+ years) have been used as dependent variables. In order to build the RDI and classify the areas on the basis of increasing socioeconomic deprivation, a multivariate methodology have been used by means of principal component factor analysis of the previous selected variables and k-means clustering of the geographical areas; then these results have been compared with the SMR by analysis of variance. Finally, the RDI has been applied to the SMR of some groups of principal causes of death (all tumours and cardiovascular, respiratory and digestive system diseases), in order to differentiate the population by health outcomes. RESULTS: Two factors have been identified: an economic-educational factor and a socio-familiar one. The first factor describes the educational level and occupation, while the second one the marital status, the family dimension and the house peculiarities. The clustering procedure has allowed to identify five groups of geographical areas, distributed by the increasing of the SE deprivation. The most problematic areas are located in the countryside or in some spot places of the seaside, far from the health care centres and with difficult access by travel connection. The association between RDI and overall mortality SMRs confirms the relationship between deprivation and mortality increases, according to a statistically significant linear trend. Similar relationships have been observed for cardiovascular and digestive system diseases, while no associations have been found for respiratory illness and overall cancers. CONCLUSIONS: The RDI is able to give information on the health differences in the population, by differentiating the mortality trend on the basis of specific situations of richness and social hardship. It is useful not only for disentangling by economic condition, but also by the resources of the social and familiar support to cope with the illness situations. So, the relationship between deprivation and mortality, according to a statistically significant linear trend, shows how groups of Liguria people suffer by a lack of familiar resources, which strongly reduces the possibility of a quick take in charge and the adhesion to the more adequate therapeutic procedure, till to fatal results. In this way, areas of aimed actions can be defined by the local decision makers, in order to optimize the health resources allocation and to reduce inequities. PMID- 22828232 TI - [Systematic review and meta-analysis of the prevalence of overweight and obesity among school-age children in Italy]. AB - OBJECTIVE: The objective of the study was to obtain reliable data from recent surveys carried out in Italy on the prevalence of overweight (OW) and obesity (OB) in children. DESIGN: We searched in MEDLINE/Pubmed and Scopus. The keywords included "overweight ", "obesity", "children", "aged 6-11 years", "Italy", associated to the boolean operators AND/OR. The limits applied to the research were: English AND/OR Italian language, publication time period January 2000 September 2010, target of 6-11 years; Body Mass Index assessed according to IOTF criteria. StatsDirect 2.7.8 was utilized to perform statistical analysis. RESULTS: 25 studies have been select, the percentage of overweight varied between 18% and 33,7% and obesity between 5,5% and 21,9%. The highest values were in Southern Italy (OW: 25,6%, CI95% 24,8-26,3; OB: 15,2%, CI95% 13-17,5) vs Central Italy (OW: 22,6%, CI95% 21-24,1; OB: 9,3%, CI95% 7,9-10,7) vs Northern Italy (OW: 21%, CI95% 19,6-22,3; OB: 8,2%, CI95% 6,8-9,7). CONCLUSION: A relevant prevalence of overweight and obesity was found In Italian children; the excess weight concerns one child out of four. There are significant differences in the prevalence of overweight and obesity in relation to geographical distribution (Northern, Central and Southern Italy), the high prevalence of overweight and obesity resulted statistically significant in the Southern compared to Central and Northern Italy. These differences are likely linked to different geographical areas in relation to socioeconomic and environmental condition that must be further investigated. There is a need of promoting better eating habits in young children in Italy, above all in areas with highest prevalence. PMID- 22828233 TI - [Mode of transport by car of 6-12-year-old children in Florence]. AB - OBJECTIVE: To estimate the use, during transport by car, of restraint/booster seats by children of 6-12 years old in Florence. DESIGN, SETTING AND PARTICIPANTS: To examine children's use, knowledge and behaviors regarding safety devices in cars, a questionnaire has been administered to 537 students attending 17 primary schools in Florence, during their visit to an area equipped for street education. Sociodemographic data (nationality, level of education and parents' work) have been collected as well to assess the socioeconomic membership. Collected data have been analyzed using SPSS 17.0. Chi squared test has been used to evaluate differences in the frequency of distribution of the use of safety devices by available variables. Univariate and multivariate logistic regressions have been used to calculate the degree of association among the modes of transport and the available variables. MAIN OUTCOME MEASURES: Prevalence of use of restraint/booster seats, risk of having been incorrectly transported. RESULTS: 39.1% children, during the last travel, has been correctly transported, i.e. on the booster seat with fastened seat belt, 38.0% only with fastened seat belt and 22.9% free.The risky behaviors were not so much related to socioeconomic indices, but rather to some geographical variables and parents' nationality (especially of the mother).Children whose parents were both Italian were more frequently transported correctly compared to foreigners. We also observed peculiar and different modes of transport within specific ethnic minorities. CONCLUSIONS: It is necessary to design and implement interventions aimed at promoting interventions for improving safety for the whole population, but with specific safeguarding social and territorial specificities as regards to territory and ethnicity. PMID- 22828234 TI - ["Let's play with the Earth": a project of environmental education for primary school children]. AB - OBJECTIVE: Raising awareness and knowledge in Pavia Public Primary School students, and indirectly in their parents, about environmental problems like waste recycling and energy saving, developing with games the concept of separate collection of rubbish; creating an environmentally conscious awareness and sense of responsibility towards sustainable behavior. DESIGN: The educational program lasted six months. Data collection was performed using anonymous questionnaires, administered to "treated" students at the beginning and at the end of the program. The "control" population only answered a single questionnaire at the end of the project. It was also carried out an assessment of the fallout of the project on parents, through a questionnaire at the beginning and at the end of the program. At the end of the educational intervention, a satisfaction questionnaire was administered to teachers. SETTING AND PARTICIPANTS: The enrolled population was composed of 1,358 students from 3rd, 4th and 5th classes of Public Primary Schools of the four Pavia School Districts: 938 "treated" students followed the program and 420 "controls" only answered the final questionnaire. MAIN OUTCOME MEASURES: The data concerning the pupils' knowledge are expressed in terms of frequencies: at first, we evaluated the comparison between "treated" students knowledge at the beginning and at the end of the program in each class, then we made the comparison between "treated" and "control" students at the end of the program. RESULTS: The comparison of the final questionnaires ("treated" students vs "controls") revealed in "treated" students higher knowledge of terms "waste" (94.5% vs 89.0%) and "separate collection" (97.3% vs 90.7%): the differences are statistically significant. Also the practice of separate collection of rubbish is more frequent in "treated" students' families than in "control" ones (83.5% vs 71.4%, p =0.0001).The analysis of teachers' satisfaction questionnaires showed positive ratings with high average scores for each item investigated. The analysis of parents' questionnaires revealed that 99.8% of them knows the meaning and 89% practice separate collection of rubbish. CONCLUSION: The program has proved effective in increasing students' short-term knowledge and making also families more interested in problems like waste recycling and separate collection of rubbish. The need of an awareness and environmental education campaign for the general population is apparent and the role of children, promoting knowledge and environmental behaviour changes in parents and community, has not to be underestimated. PMID- 22828235 TI - [Yellow mice and high-ranking macaques]. PMID- 22828236 TI - [Negationism: global warming and other skeptics]. PMID- 22828238 TI - [Doing, communicating, sharing]. PMID- 22828239 TI - [Regional pro capite funding: how to unscramble it]. PMID- 22828240 TI - An integrated health sector response to violence against women in Malaysia: lessons for supporting scale up. AB - BACKGROUND: Malaysia has been at the forefront of the development and scale up of One-Stop Crisis Centres (OSCC) - an integrated health sector model that provides comprehensive care to women and children experiencing physical, emotional and sexual abuse. This study explored the strengths and challenges faced during the scaling up of the OSCC model to two States in Malaysia in order to identify lessons for supporting successful scale-up. METHODS: In-depth interviews were conducted with health care providers, policy makers and key informants in 7 hospital facilities. This was complemented by a document analysis of hospital records and protocols. Data were coded and analysed using NVivo 7. RESULTS: The implementation of the OSCC model differed between hospital settings, with practise being influenced by organisational systems and constraints. Health providers generally tried to offer care to abused women, but they are not fully supported within their facility due to lack of training, time constraints, limited allocated budget, or lack of referral system to external support services. Non-specialised hospitals in both States struggled with a scarcity of specialised staff and limited referral options for abused women. Despite these challenges, even in more resource-constrained settings staff who took the initiative found it was possible to adapt to provide some level of OSCC services, such as referring women to local NGOs or community support groups, or training nurses to offer basic counselling. CONCLUSIONS: The national implementation of OSCC provides a potentially important source of support for women experiencing violence. Our findings confirm that pilot interventions for health sector responses to gender based violence can be scaled up only when there is a sound health infrastructure in place - in other words a supportive health system. Furthermore, the successful replication of the OSCC model in other similar settings requires that the model - and the system supporting it - needs to be flexible enough to allow adaptation of the service model to different types of facilities and levels of care, and to available resources and thus better support providers committed to delivering care to abused women. PMID- 22828241 TI - The protection of selenium on cadmium-induced inhibition of spermatogenesis via activating testosterone synthesis in mice. AB - Selenium (Se) is an essential trance element in testis. However, the potential protective effects of Se against cadmium (Cd)-induced reproductive toxicity remained to be elucidated. Male ICR mice were orally administered by gavage with Na2SeO3 (0.1, 0.2, 0.4 mg/kg BW) for 1h prior to CdCl2 (5 mg/kg BW) alone or in combination for 15, 25 or 35 days. Cd exposure caused a significant decrease in body weight, sperm concentration and motility as well as plasma testosterone level which was accompanied by decreased antioxidant enzymatic activity of SOD and GSH-Px and by increased lipid peroxidation (as malondialdehyde, MDA). Se pretreatment compensated deficits in the sperm parameters (concentration, motility and morphology) induced by Cd. Se (0.4 mg/kg BW) treatment significantly increased serum testosterone level that was reduced by Cd (on 15th, 25th and 35th day) (P<0.01). Se treatment ameliorated Cd-induced reduction in testicular steroidogenic acute regulatory (StAR) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities. The present study suggest that the protective potential of Se against Cd-induced reprotoxicity might be due to up-regulation StAR and testosterone synthetic enzyme activity, which could be useful for increasing testosterone synthesis for achieving optimum protection in sperm quality and spermatogenesis. PMID- 22828242 TI - Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid. AB - Severe acute exacerbation or liver failure induced by standard interferon alpha(IFN-alpha) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-alpha therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-alpha2a (Pegasys) treatment. One patient progressed into acute-on-chronic liver failure (ACLF) at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre ACLF) at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed. PMID- 22828243 TI - [Health technology assessment report: HPV DNA based primary screening for cervical cancer precursors]. AB - OBJECTIVE OF THE PROJECT: The introduction of the HPV test as a primary screening test will cause important changes in the screening system based on cytology. The purposes of this report are: to define the best screening policies with HPV-based screening on the basis of the resulting efficacy and of undesired effects; comparing them to cytology-based screening; to identify their best conditions of application; to evaluate economic cost, feasibility and impact on the organisation of services of such policy in the Italian situation. CONTENTS: This report contains a section on efficacy and undesired effects based on a systematic review of literature conducted in strict coordination with the preparation of a supplement to the European Guidelines for quality assurance in cervical cancer screening. This chapter corresponds to a preliminary version of the chapter of the European Guidelines on primary screening with HPV. The sections on costs, impact on organisation, and social, ethical and legal impact reflect the Italian situation; they are based on a review of the available Italian data (including unpublished data, mainly from on-going pilot projects) and on a structured analysis of what will result if the proposed protocol is applied to the Italian situation. RESULTS: Efficacy and undesired effects. There is clear scientific evidence that a screening based on validated tests for the DNA of oncogenic HPV as primary test and applying an appropriate protocol is more effective than screening based on cytology in preventing invasive cancers of the uterine cervix. In addition, it entails a limited--if any--increase of the undesired effects both in terms of unneeded referral to diagnostic work-up and in terms of over diagnosis and consequent overtreatment of spontaneously regressive lesions. The crucial elements of such protocol are the followings: HPV-positive women are not to be directly referred to colposcopy, but the use of triage systems is essential. The currently recommendable method is based on performing cytology in HPV positive women. If the result of this test is abnormal, the woman is immediately referred to colposcopy; if cytology is normal, the woman is invited to repeat a new HPV test after one year. In case such a test is still positive, the woman is referred to colposcopy; in case of negative result, the woman will be re-invited for a new screening round at the regular interval. In organised population-based screening programmes the interval after a negative primary HPV test should be at least 5 years. There is evidence that the 5-year cumulative risk of high-grade CIN after a negative HPV test is lower than the 3-year risk after a normal cytology. On the other hand, the probability of unneeded colposcopies and treatments would plausibly be relevant with 3-year intervals after a negative HPV test. HPV-based screening should not start before 30-35 years. There is evidence that below 30 years HPV-based screening leads to an increased overdiagnosis of CIN2 that would regress spontaneously, with consequent overtreatment. Some increase in overdiagnosis is plausible also between 30 and 34 years. Below such ages, cytological screening is the recommended test. Only tests for the DNA of oncogenic HPV, validated according to the European guidelines as for sensitivity and specificity for high-grade lesions, should be applied. There is no evidence that double testing with cytology and HPV is more protective than stand-alone HPV as primary test, although it entails a small and not relevant increase in sensitivity vs stand-alone HPV. On the contrary, there is evidence that double testing causes a substantial increase in referral to colposcopy and a decrease in its PPV. For this reason, if HPV is used as primary screening test, it is recommended not to add cytology in parallel. Cost and economic evaluation. It is estimated that, if the protocol described is applied, in the current Italian situation the overall costs of HPV-based screening are lower than those of conventional cytological screening applied at the current 3-year intervals, although the cost of each screening round is higher. Impact on organization. For reasons of quality and cost, both the interpretation of cytology and HPV testing require a centralisation. This need is particularly strong, in terms of costs, for HPV test execution. It is therefore recommended to perform the HPV test in a limited number of reference laboratories of large size. This also makes monitoring and evaluating the spontaneous activity easier. HPV-based screening entails problems of organisation related to the need of triage, to complex protocols and to reconversion of the activities of cytological interpretation. Social, ethical and legal impact. The communication of the result of the HPV test to women, particularly if positive, is a further crucial aspect in order to reduce not only the emotional impact, but also the possible risks that women are inappropriately managed or lost to follow-up. Great efforts must be put in the education of healthcare professionals, both directly involved in organised programmes or not, particularly private gynaecologists and general practitioners. RECOMMENDATIONS: In conclusion, the crucial requirement to introduce HPV-based screening programmes is the capacity to guarantee the application of appropriate screening protocols. If protocols do not respect the criteria described above they can cause relevant increase of undesired effects and costs compared to cytology-based screening. Therefore they should be avoided, except in studies able to provide clear evidence about human and economic costs. For this purpose, correct education and information both to healthcare professionals and to the population is needed. In the Italian situation, where organised screening and a relevant spontaneous activity coexist, their interaction is crucial. Actions directed to integrate them and to guarantee as more uniformity of interventions as possible are needed, in particular through the integration of registries and thorough monitoring and a progressive homogenization of protocols. In order to grant the safety of transition, it is needed that the HPV-based organised screening activities are strictly monitored and that the National Centre for Screening Monitoring (ONS) ensures coordination. Knowledge about HPV based screening is still rapidly evolving. It is possible that currently on-going researches suggest changes to the optimal protocols in the next few years, particularly as for the management of HPV positive women. In addition, studies on the validation of new assays were recently published and others are expected. It is suggested to exploit the organised screening activity to produce scientific evidence, in order to clarify the still uncertain aspects of optimal protocols. Different protocols in terms of screening intervals, age of application and management of HPV positive women should be studied in the frame of controlled implementation, through multicentre projects coordinated by ONS. Finally, it is suggested the creation of a National working group to promptly update the recommendations for screening and the list of assays to be considered as validated. On the bases of the results obtained in the first vaccinated cohorts reaching the screening age, for the future, it will be crucial to deliver specific recommendations to the population vaccinated against HPV during adolescence. PMID- 22828244 TI - Comparison of three multiplex PCR assays for the detection of respiratory viral infections: evaluation of xTAG respiratory virus panel fast assay, RespiFinder 19 assay and RespiFinder SMART 22 assay. AB - BACKGROUND: A broad spectrum of pathogens is causative for respiratory tract infections, but symptoms are mostly similar. Therefore, the identification of the causative viruses and bacteria is only feasible using multiplex PCR or several monoplex PCR tests in parallel. METHODS: The analytical sensitivity of three multiplex PCR assays, RespiFinder-19, RespiFinder-SMART-22 and xTAG-Respiratory Virus-Panel-Fast-Assay (RVP), were compared to monoplex real-time PCR with quantified standardized control material. All assays include the most common respiratory pathogens. RESULTS: To compare the analytical sensitivity of the multiplex assays, samples were inoculated with 13 different quantified viruses in the range of 10(1) to 10(5) copies/ml. Concordant results were received for rhinovirus, whereas the RVP detected influenzavirus, RSV and hMPV more frequently in low concentrations. The RespiFinder-19 and the RespiFinder-SMART-22 showed a higher analytical sensitivity for adenoviruses and coronaviruses, whereas the RVP was incapable to detect adenovirus and coronavirus in concentrations of 10(4) copies/ml. The RespiFinder-19 and RespiFinder-SMART-22A did not detect influenzaviruses (104 copies/ml) and RSV (10(3) copies/ml). The detection of all 13 viruses in one sample was only achieved using monoplex PCR. To analyze possible competitive amplification reactions between the different viruses, samples were further inoculated with only 4 different viruses in one sample. Compared to the detection of 13 viruses in parallel, only a few differences were found.The incidence of respiratory viruses was compared in tracheal secretion (TS) samples (n = 100) of mechanically ventilated patients in winter (n = 50) and summer (n = 50). In winter, respiratory viruses were detected in 32 TS samples (64%) by RespiFinder-19, whereas the detection rate with RVP was only 22%. The most frequent viruses were adenovirus (32%) and PIV-2 (20%). Multiple infections were detected in 16 TS samples (32%) by RespiFinder-19. Fewer infections were found in summer (RespiFinder-19: 20%; RVP: 6%). All positive results were verified using monoplex PCR. CONCLUSIONS: Multiplex PCR tests have a broad spectrum of pathogens to test at a time. Analysis of multiple inoculated samples revealed a different focus of the detected virus types by the three assays. Analysis of clinical samples showed a high concordance of detected viruses by the RespiFinder-19 compared to monoplex tests. PMID- 22828247 TI - Lung/chest expansion contributes to generation of pleasantness associated with dyspnoea relief. AB - Pleasantness associated with dyspnoea relief or 'respiratory pleasure' is considered as a particular sensory experience. The purpose of this study is to elucidate the mechanism of generation of this particular sensory experience. After taking deep breaths during normal breathing, 35 healthy subjects received three different magnitudes of inspiratory loads (light: 8.4; moderate: 23.4; severe: 70.5 cm H2O/L/s) to induce dyspnoeic sensation. We found that (1) deep breaths during normal breathing rarely induce 'respiratory pleasure', (2) a sudden removal of dyspnoea alone is not sufficient to produce 'respiratory pleasure', and (3) the generation of 'respiratory pleasure' can be observed when a sudden removal of dyspnoea accompanies a large increase in tidal volume (V(T)). In addition, qualitative assessment of 'respiratory pleasure' showed that this sensation is compatible with a strong, positively valenced sensation. These findings indicate that an increase in V(T) after removal of respiratory loading plays a crucial role in generation of 'respiratory pleasure' that is a specific sensory-emotional experience. PMID- 22828248 TI - Vemurafenib-induced neutrophilic panniculitis. AB - Vemurafenib is a targeted therapy, used in patients with metastatic cutaneous melanoma who carry the BRAF V600E mutation, with a relative reduction of 63% in the risk of death. Several adverse events have been described previously, such as photosensitivity or squamous-cell carcinomas. Two cases of panniculitis have been reported recently with two different selective BRAF inhibitors. We report two cases of neutrophilic panniculitis in patients treated by vemurafenib for a metastatic melanoma. Clinical and biological examinations showed no indications for an immune nor an infectious cause of neutrophilic panniculitis. Thus, we believe that vemurafenib caused this panniculitis. Treatment with vemurafenib was maintained in both patients because of the clinical and radiological tumoral responses. One patient showed spontaneous recovery, whereas the other patient presented several recurrences of panniculitis. We believe that physicians should be aware of this cutaneous side effect of vemurafenib, but it should not lead to discontinuation of this treatment. PMID- 22828249 TI - Successful desensitization in a case of Stevens-Johnson syndrome due to vemurafenib. AB - The BRAF inhibitor vemurafenib can cause severe cutaneous reactions, including Stevens-Johnson syndrome, particularly when administered after ipilimumab, which usually prevents further drug administration. We report the case of a patient with Stevens-Johnson syndrome due to vemurafenib, who was retreated with vemurafenib with a program of slow desensitization with dexamethasone and diphenhydramine. Vemurafenib was tolerated at a 50% dose after a 3-week desensitization. Desensitization may be possible in patients who develop Stevens Johnson syndrome after vemurafenib treatment. PMID- 22828250 TI - Changes in equity in out-of-pocket payments during the period of health care reforms: evidence from Hungary. AB - BACKGROUND: At the beginning of 2007, health care reforms were implemented in Hungary in order to decrease public expenditure on health care. Reforms involved the increase of co-payments for pharmaceuticals and the introduction of co payments for health care services. OBJECTIVE: The objective of this paper is to examine the progressivity of household expenditure on health care during the reform period, separately for expenditures on pharmaceuticals and medical devices, as well as for formal and informal patient payments for health care services. METHODS: We use data on household expenditure from the Household Budget Survey carried out by the Central Statistical Office of Hungary. We present household expenditure as a percentage of household income across different income quintiles and calculate Kakwani indexes as a measure of progressivity for a four years period (2005-2008): before, during and after the implementation of the health care reforms. RESULTS: We find that out-of-pocket payments on health care are highly regressive in Hungary with a Kakwani index of -0.22. In particular, households from the lowest income quintile spend an about three times larger share of their income on out-of-pocket payments (6-7 %) compared to households in the highest income quintile (2 %). Expenditures on pharmaceuticals and medical devices are the most regressive types of expenditure (Kakwani index -0.23/-0.24), and at the same time they represent a major part of the total household expenditure on health care (78-85 %). Informal payments are also regressive while expenditures on formal payments for services are the most proportional to income. We find that expenditures on formal payments became regressive after the introduction of user fees (Kakwani index -0.1). At the same time, we observe that expenditures on informal payments became less regressive during the reform period (Kakwani index increases from -0.20/-0.18 to -0.12.) CONCLUSIONS: More attention should be paid on the protection of low-income social groups when increasing or introducing co-payments especially for pharmaceuticals but also for services. Also, it is important to eliminate the practice of informal payments in order to improve equity in health care financing. PMID- 22828252 TI - Hyposensitization and desensitization in allergic contact dermatitis. AB - BACKGROUND: Acquired allergic contact dermatitis (ACD) causes significant morbidity. Certain occupations predispose workers to ACD, especially those that may damage the skin barrier. Allergic contact dermatitis has significant socioeconomic effects. Allergic contact dermatitis is difficult to treat, particularly if exposure is unavoidable. OBJECTIVE: The objective of this study was to establish the efficacy of intradermal steroid injections in inducing specific antigen hyposensitization when administered weekly into shifted patch test sites. METHODS: Prospective, open-label trial included 10 patients with ACD. Each week for up to 8 weeks, patients were patch-tested to their known allergen, and the patch-test site was injected with triamcinolone. Primary outcomes were clinical score, reaction size, erythema, and thermal characteristics. Statistical analysis included regression, correlation, repeated measures, and analysis of variance with contrast variables. RESULTS: Overall results suggest significant decreases in patch-testing reactions as evidenced by improved clinical scores, reaction sizes, and reduced heat production. In 3 patients, the patch test became negative. This desensitized state persisted for 2 months in 1 patient and for 4 months in the other 2 patients. CONCLUSIONS: Repetitive treatments of weekly, shifted, positive patch test sites with intradermal steroid injections show a tendency toward allergen-specific hyposensitivity and in some cases to nonreactivity at repeat patch testing. This finding may influence future management of ACD. PMID- 22828253 TI - Nummular eczema and contact allergy: a retrospective study. AB - BACKGROUND: Etiopathogenesis of nummular eczema is obscure; many causative factors have been proposed. Only a few studies investigated the relevance of contact allergy. OBJECTIVE: This retrospective study aimed to investigate the role of contact allergy in the underlying mechanism of nummular eczema. METHODS: From the 29,323 consecutive patients, we patch-tested for eczematous dermatitis of various type, 1022 (3.5%) with nummular eczema were enrolled. Data were collected for each patient, including age, sex, occupation, symptoms onset and duration, onset and spread sites, and clinical evidence or history of atopy. Histological analyses of acute phase lesions were carried out in some patients. RESULTS: Peak incidence of age at disease onset was found in the third decade of life. Predominant sites of lesions were upper (75.8%) and lower (64.5%) limbs, followed by trunk, dorsum of the hands, and face and neck. Three hundred thirty two (32.5%) of 1022 patients showed positive reactions to 1 or more allergens. Highest sensitization rates were found with nickel sulfate (10.2%), potassium dichromate (7.3%), and cobalt chloride (6.1%). Histopathology showed less pronounced spongiosis in atopic subjects and the elderly. CONCLUSIONS: Because this study demonstrates that contact allergy is common with nummular eczema, patch testing is strongly advisable in every patient with persistent nummular dermatitis. PMID- 22828254 TI - Contact allergy to sorbitans: a follow-up study. AB - BACKGROUND: Sorbitan sesquioleate (SSO), an emulsifier in many corticosteroids, was previously found positive in 8.9% of 112 dermatitis patients. OBJECTIVE: The objective of this study was to present data on 24 of 591 dermatitis patients with reactions to SSO and/or sorbitan monooleate (SMO) on patch testing. METHODS: A retrospective chart review was conducted on 591 consecutive dermatitis patients patch tested from November 2008 to May 2010. In addition to being tested to a modified North American Contact Dermatitis Group standard series, all patients were tested to a cosmetic series. RESULTS: Of the 591 patients tested, 24 reacted to SSO and/or SMO (4.1%), 19 (3.2%) reacted to SSO alone, 1 (0.17%) to SMO alone, and 4 (0.68%) reacted to both. Of the 24 sorbitan-allergic patients, 2 (8.3%) reacted to any of 4 corticosteroid screening chemicals tested. CONCLUSIONS: In this follow-up study, 4.1% of 591 dermatitis patients reacted to SSO and/or SMO. Given the presence of SSO in many popular topical corticosteroid formulations, clinicians should consider allergy to sorbitans when patients do not improve with topical corticosteroid therapy. PMID- 22828255 TI - Sensitization prevalence for benzalkonium chloride and benzethonium chloride. AB - BACKGROUND: Benzalkonium chloride (BAK) and benzethonium chloride (BEC) are well characterized skin irritants and rare sensitizers, but optimal testing for allergic contact dermatitis (ACD) is not established. OBJECTIVE: Sensitization prevalence was sought, and several patch testing concentrations and vehicles were compared. METHODS: One hundred forty-two patients tested to the standard screening series for evaluation of dermatitis consented to additional tests including BAK 0.15% aqueous (aq), BAK 0.15% petrolatum (pet), BEC 0.15% aq, and BEC 0.5% aq. Follow-up to assess clinical relevancy included early and late patch test reads, 1-month clinical follow-up, and long-term phone calls. Patients were categorized as definite, possible, or unlikely to have ACD to BAK and/or BEC. RESULTS: Atopy was not associated with patch test reactions (P = 0.154). Seventy five percent (6/8) of the patients with possible ACD to BAK had coreactions with BEC. Testing to both BAK 0.15% pet and 0.15% aq would have identified 91% of those with possible ACD to BAK, twice as many than if only BAK 0.1% aq from the standard series was used. CONCLUSION: Sensitization to BAK and BEC, although rare, does occur. Weak and morphologically irritant reactions at day 7 reading can be relevant. We recommend testing to BAK 0.15% aq and 0.15% pet to increase sensitivity and having patients undergo long-term follow-up. PMID- 22828256 TI - Vitamin E contact allergy: a controversial subject. AB - Although vitamin E has been described as a source of allergic contact dermatitis (ACD), in only a few cases a true sensitization has been confirmed. We describe 2 cases of suspected ACD to vitamin E products. Patch tests and repeated open application tests were performed with the patients' own offending products. Then, patch tests with tocopherol acetate at different concentrations and further patch tests and repeated open application tests with a new sample of the product were carried out. Whereas the first sessions of tests gave positive reactions, the last sessions of tests performed with new samples were negative. Based on these results, we conclude that both our patients probably developed a true vitamin E ACD. However, as vitamin E exerts an anti-inflammatory effect and is an unstable molecule and its allergic potential change during the time, when ACD to vitamin E is tested a bimodal behavior of this molecule may be expected. PMID- 22828257 TI - Irritant contact dermatitis to the brown marmorated stink bug, Halyomorpha halys. AB - The brown marmorated stink bug, Halyomorpha halys, is native to Asia (China, Taiwan, Japan, and the Korean peninsula). It was first found in Allentown, Pa, in 1996 and has since spread across wide areas of the Eastern United States. As of October 2010, at least 26 states have reported the presence of the brown marmorated stink bug. It is considered an invasive species, and to the best of scientific knowledge, it was accidently introduced into the United States through transportation of goods from Asia. To date, no reports of human disease have been published in the literature. Fruit crop workers have complained of a slight allergic reaction to the chemicals released by the bug. PMID- 22828258 TI - Fixed drug eruption to ingested propolis. AB - Fixed drug eruptions (FDEs) are a unique type of drug allergy in which skin lesions recur in the same location after each ingestion of the offending agent. More than 100 drugs have been implicated in causing FDEs. More recently, herbal medications and food additives have been implicated. Propolis is an important contact allergen, but has not previously been reported to cause FDE. We present the case of a patient with a 1-year history of a recurrent lesion on the shaft of his penis. He tested strongly positive to propolis and had been using a herbal supplement. A trial off this supplement was initiated, and his penile lesion cleared. The patient then rechallenged himself with his powder and developed the same reaction, biopsy-proven to be consistent with FDE. This case illustrates the utility of systemic (rechallenge) and topical (patch-testing) testing to identify the causative agent. It is interesting to note that our patient developed a reaction at the site of the patch test for propolis itself, rather than at the former reaction site. Our patient also illustrates the necessity of considering new causes for FDE when typical lesions are present. PMID- 22828259 TI - Nail injury and diquat exposure: forgotten but not gone. AB - Primary fingernail changes that result from chemical exposures are seldom encountered in clinical practice. A cluster investigation was conducted on employees at a pesticide packaging company. Six employees reported simultaneous onset of defects occurring in their fingernails, including nail discoloration, nail dimpling, and nail shedding. Multiple pesticides and herbicides including diquat were used in the facility at the time of the cluster onset. A literature review noted 6 articles published before 1975 documenting similar nail changes associated with paraquat, diquat, or other herbicide use. Only one such case report published after 1985 could be located. Diquat was the only material that was previously reported in the medical literature as causing nail defects and also in use at this facility. Diquat exposure is the most plausible explanation for the observed changes in these workers' fingernails. PMID- 22828260 TI - Periocular dermatitis from systemic exposure to nickel in a palatal expander and dental braces. PMID- 22828261 TI - Chemokine responses in palladium-induced lichenoid eruption: similarities to and differences from lichen planus. PMID- 22828262 TI - Chemical leukoderma from hair dye containing para-phenylenediamine. PMID- 22828263 TI - Turpentine sensitization in a nonsteroidal anti-inflammatory solution user. PMID- 22828264 TI - A nickel for your thoughts: determining relative nickel content using an analog color scale. PMID- 22828265 TI - Allergic contact dermatitis syndrome from bufexamac for nursing infant. PMID- 22828266 TI - Rubber glove dermatitis and allergy to dithiodimorpholine. PMID- 22828267 TI - Nickel exposure from household items: potential method of protection. PMID- 22828268 TI - Who gets a mammogram amongst European women aged 50-69 years? AB - On the basis of the Survey of Health, Ageing, and Retirement (SHARE), we analyse the determinants of who engages in mammography screening focusing on European women aged 50-69 years. A special emphasis is put on the measurement error of subjective life expectancy and on the measurement and impact of physician quality. Our main findings are that physician quality, better education, having a partner, younger age and better health are associated with higher rates of receipt. The impact of subjective life expectancy on screening decision substantially increases after taking measurement error into account. JEL CLASSIFICATION: C 36, I 11, I 18. PMID- 22828269 TI - Staff costs of hospital-based outpatient care of patients with cystic fibrosis. AB - BACKGROUND: This study identified per patient resource use and staff costs at a cystic fibrosis (CF) outpatient unit from the health care provider's perspective. METHODS: Personnel cost data were prospectively collected for all CF outpatients (n = 126) under routine conditions at the Charite Medical School Berlin in Germany over a six month study period. Patients were grouped according to age, sex and two severity categories. Ordinary least squares regression analysis was performed to determine the impact of various independent variables on personnel costs. RESULTS: The mean staff costs were ?142.3 per patient over six months of outpatient service. Services provided by physicians were the biggest contributor to staff costs. Patient age correlated significantly and negatively with mean total costs per patient. CONCLUSIONS: Age of patient is a significant determinant of staff costs for CF outpatient care. For a cost-covering remuneration of outpatient treatment it seems plausible to create separate reimbursement rates for two or three age groups and to consider additional costs due to tasks carried out by physicians without direct patient contact. The relatively low staff costs identified by our study reflect a staffing level not sufficient for specialist CF outpatient care. PMID- 22828271 TI - Healthy vs. unhealthy food: a strategic choice for firms and consumers. AB - In this paper, we carry out a theoretical analysis of the strategic choice made by firms regarding the type of food they market when they face consumers who care about the healthy/unhealthy attributes of the product but incur in emotional/health costs when the food they consume has unhealthy attributes. We consider a two-stage game. In the first stage, one of the firms chooses the unhealthy content of its product. In the second stage, both firms simultaneously decide their prices. We find that, depending on the parameters of the model, product differentiation can be maximal or less than maximal. The firm that produces the unhealthy food charges a higher price and obtains a larger share of the market unless the emotional/health costs and the unhealthy food production costs are relatively high. We also find that educational campaigns will not always reduce the demand for the unhealthy food or the degree of the unhealthy attribute.JEL Classification:I10, I18, L11. PMID- 22828270 TI - Use of substructure-specific carbohydrate binding modules to track changes in cellulose accessibility and surface morphology during the amorphogenesis step of enzymatic hydrolysis. AB - BACKGROUND: Cellulose amorphogenesis, described as the non-hydrolytic "opening up" or disruption of a cellulosic substrate, is becoming increasingly recognized as one of the key steps in the enzymatic deconstruction of cellulosic biomass when used as a feedstock for fuels and chemicals production. Although this process is thought to play a major role in facilitating hydrolysis, the lack of quantitative techniques capable of accurately describing the molecular-level changes occurring in the substrate during amorphogenesis has hindered our understanding of this process. RESULTS: In this work, techniques for measuring changes in cellulose accessibility are reviewed and a new quantitative assay method is described. Carbohydrate binding modules (CBMs) with specific affinities for crystalline (CBM2a) or amorphous (CBM44) cellulose were used to track specific changes in the surface morphology of cotton fibres during amorphogenesis. The extents of phosphoric acid-induced and Swollenin-induced changes to cellulose accessibility were successfully quantified using this technique. CONCLUSIONS: The adsorption of substructure-specific CBMs can be used to accurately quantify the extent of changes to cellulose accessibility induced by non-hydrolytic disruptive proteins. The technique provided a quick, accurate and quantitative measure of the accessibility of cellulosic substrates. Expanding the range of CBMs used for adsorption studies to include those specific for such compounds as xylan or mannan should also allow for the accurate quantitative tracking of the accessibility of these and other polymers within the lignocellulosic biomass matrix. PMID- 22828274 TI - Fingolimod inhibits PDGF-B-induced migration of vascular smooth muscle cell by down-regulating the S1PR1/S1PR3 pathway. AB - Platelet Derived Growth Factor (PDGF) and sphingosine-1-phosphate (S1P) pathways play a key role in mural cell recruitment during tumor growth and angiogenesis. Fingolimod, a S1P analogue, has been shown to exert antitumor and antiangiogenic properties. However, molecular targets and modes of action of fingolimod remain unclear. In this study, we confirmed the antagonizing action of S1P and PDGF-B on rat vascular smooth muscle cell (VSMCs) growth and migration. We then compared siRNA and/or fingolimod (100 nM) treatments on PDGFR-beta, S1PR1 S1PR2 and S1PR3 expression. Fingolimod induced a 50% reduction in S1PR3 protein expression which was cumulative with that obtained with anti-S1PR3 siRNA. We found that siRNA induced inhibition of both PDGFR-beta and S1PR3 was the most effective means to block VSMC migration induced by PDGF-B. Finally, we observed that fingolimod treatment associated with anti-S1PR1 siRNA principally inhibited VSMC growth while in combination with anti-S1PR3 siRNA it strongly inhibited VSMC migration. These results suggest that for rat VSMCs, the PDGFR-S1PR1 pathway is predominantly dedicated to cell growth while PDGFR-S1PR3 stimulates cell migration. As an S1P analogue, fingolimod is considered a potent activator of S1PR1 and S1PR3. However, its action on the PDGFR-S1PR platform appears to be dependent on S1PR1 and S1PR3 specific downregulation. Considering that the S1P pathway has already been shown to exert various crosstalks with tyrosine kinase pathways, it seems of great interest to evaluate fingolimod potential in combination with the numerous tyrosine kinase inhibitors used in oncology. PMID- 22828275 TI - Cholesterol photosensitized oxidation in food and biological systems. AB - Lipid oxidation is one of the main chemical degradations occurring in biological systems and leads to the formation of compounds that are related to aging and various chronic and degenerative diseases. The extent of oxidation will depend on the presence of antioxidants/pro-oxidants, the unsaturation degree of fatty acids, and environmental conditions. Lipid oxidation can also affect other molecules that have double bonds in their chemical structures, such as cholesterol. Cholesterol oxidation products (COPs) have been studied in depth, because of their negative and controversial biological effects. The formation of COPs can be particularly favored in the presence of light and photosensitizers, since they generate excited singlet oxygen that rapidly reacts with the double bond by a non radical mechanism and without any induction period. The present review intends to provide an overall and critical picture of cholesterol photosensitized oxidation in food and biological systems, and its possible impact on human health and well-being. PMID- 22828276 TI - Consumption of fructose- but not glucose-sweetened beverages for 10 weeks increases circulating concentrations of uric acid, retinol binding protein-4, and gamma-glutamyl transferase activity in overweight/obese humans. AB - BACKGROUND: Prospective studies in humans examining the effects of fructose consumption on biological markers associated with the development of metabolic syndrome are lacking. Therefore we investigated the relative effects of 10 wks of fructose or glucose consumption on plasma uric acid and RBP-4 concentrations, as well as liver enzyme (AST, ALT, and GGT) activities in men and women. METHODS: As part of a parallel arm study, older (age 40-72), overweight and obese male and female subjects (BMI 25-35 kg/m2) consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wks. Fasting and 24-h blood collections were performed at baseline and following 10 wks of intervention and plasma concentrations of uric acid, RBP-4 and liver enzyme activities were measured. RESULTS: Consumption of fructose, but not glucose, led to significant increases of 24-h uric acid profiles (P < 0.0001) and RBP-4 concentrations (P = 0.012), as well as plasma GGT activity (P = 0.04). Fasting plasma uric acid concentrations increased in both groups; however, the response was significantly greater in subjects consuming fructose (P = 0.002 for effect of sugar). Within the fructose group male subjects exhibited larger increases of RBP-4 levels than women (P = 0.024). CONCLUSIONS: These findings suggest that consumption of fructose at 25% of energy requirements for 10 wks, compared with isocaloric consumption of glucose, may contribute to the development of components of the metabolic syndrome by increasing circulating uric acid, GGT activity, suggesting alteration of hepatic function, and the production of RBP-4. PMID- 22828277 TI - Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications. AB - Protein disulfide isomerases (PDIs) are a family of foldases and chaperones primarily located at the endoplasmic reticulum that catalyze the formation and isomerization of disulfide bonds thereby facilitating protein folding. PDIs also perform important physiological functions in protein quality control, cell death, and cell signaling. Protein misfolding is involved in the etiology of the most common neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, Prion-related disorders, among others. Accumulating evidence indicate altered expression of PDIs as a prominent and common feature of these neurodegenerative conditions. Here we overview most recent advances in our understanding of the possible functional contribution of PDIs to neurodegeneration, depicting a complex and poorly understood scenario. Possible therapeutic benefits of targeting PDIs in a disease context and their use as biomarkers are discussed. PMID- 22828278 TI - Molecular basis for population variation: from SNPs to SAPs. AB - Single nucleotide polymorphisms (SNPs) are one type of genomic DNA variations in a population. Correspondingly, single amino-acid polymorphisms (SAPs) derived from non-synonymous SNPs represent protein variations in a population. Recently, using proteomic approaches, SAPs in the plasma proteomes of an Asian population were systematically identified for the first time. That study showed that heterozygous and homozygous proteins with various SAPs have different associations with particular traits in the population. Recent discoveries of widespread differences between RNA and DNA sequences indicate that RNA editing is also a source of SAPs--one that is independent of genomic SNPs. Furthermore, we argue that there are de novo SAPs that are not encoded by either DNA or RNA sequences. PMID- 22828279 TI - Yeast as a model to understand the interaction between genotype and the response to calorie restriction. AB - Calorie restriction is reported to enhance survival and delay the onset of age related decline in many different species. Several proteins have been proposed to play a role in mediating the response to calorie restriction, including the target of rapamycin kinase, sirtuins, and AMP kinase. An enhanced mechanistic understanding of calorie restriction has popularized the concept of "calorie restriction mimetics", drugs that mimic the beneficial effects of caloire restriction without requiring a reduction in nutrient intake. In theory, such drugs should delay the onset and progression of multiple age-related diseases, similar to calorie restriction in mammals. Despite the potential benefits of such calorie restriction mimetics, however, relatively little is known about the interaction between genetic variation and individual response to calorie restriction. Limited evidence from model systems indicates that genotype plays a large role in determining both the magnitude and direction of effect that calorie restriction has on longevity. Here we present an overview of these data from the perspective of using yeast as a model to study aging and describe an approach we are taking to further characterize the molecular mechanisms underlying genotype dependent responses to calorie restriction. PMID- 22828280 TI - The link between restriction endonuclease fidelity and oligomeric state: a study with Bse634I. AB - Type II restriction endonucleases (REases) exist in multiple oligomeric forms. The tetrameric REases have two DNA binding interfaces and must synapse two recognition sites to achieve cleavage. It was hypothesised that binding of two recognition sites by tetrameric enzymes contributes to their fidelity. Here, we experimentally determined the fidelity for Bse634I REase in different oligomeric states. Surprisingly, we find that tetramerisation does not increase REase fidelity in comparison to the dimeric variant. Instead, an inherent ability to act concertedly at two sites provides tetrameric REase with a safety-catch to prevent host DNA cleavage if a single unmodified site becomes available. PMID- 22828281 TI - Inositol polyphosphate 5-phosphatases; new players in the regulation of cilia and ciliopathies. AB - Phosphoinositides regulate numerous cellular events via the recruitment and activation of multiple lipid-binding effector proteins. The precise temporal and spatial regulation of phosphoinositide signals by the co-ordinated activities of phosphoinositide kinases and phosphatases is essential for homeostasis and development. Mutations in two inositol polyphosphate 5-phosphatases, INPP5E and OCRL, cause the cerebrorenal syndromes of Joubert and Lowe's, respectively. INPP5E and OCRL exhibit overlapping phosphoinositide substrate specificity and subcellular localisation, including an association with the primary cilia. Here, we review recent studies that identify a new role for these enzymes in the regulation of primary cilia function. Joubert syndrome has been extensively linked to primary cilia defects, and Lowe's may represent a new class of 'ciliopathy associated' syndromes. PMID- 22828283 TI - Reduction in resident microflora, and experimentally inoculated Salmonella enterica, on spinach leaves treated with vinegar and canola oil. AB - In this study, we explored the use of vinegar, or vinegar and canola oil as a salad dressing, to reduce bacterial levels on spinach leaves. We found that incubation of spinach leaves with various types of vinegar substantially reduced the predominantly gram-negative microflora. A similar response was observed when spinach leaves were incubated with white vinegar mixed in various proportions with canola oil, as used in salad dressing. We assessed the effects of vinegar, or vinegar and oil, on spinach leaves that had been experimentally inoculated with a cocktail of Salmonella enterica strains. Allowing the mixture to sit at room temperature for at least 20 min resulted in a substantial reduction (up to 2.0 log CFU) in numbers of S. enterica. Vinegar and oil caused a limited reduction in CFU (0.5 log) for spinach leaves experimentally inoculated with a cocktail of Listeria monocytogenes strains. These findings suggest that mixing spinach leaves with vinegar and oil as a salad dressing can reduce the bacterial load associated with the spinach leaves, including Salmonella if it is present. PMID- 22828282 TI - The C-terminal domain of human Rev1 contains independent binding sites for DNA polymerase eta and Rev7 subunit of polymerase zeta. AB - Human Rev1 is a translesion synthesis (TLS) DNA polymerase involved in bypass replication across sites of DNA damage and postreplicational gap-filling. Rev1 plays an essential structural role in TLS by providing a binding platform for other TLS polymerases that insert nucleotides across DNA lesions (poleta, poliota, polkappa) and extend the distorted primer-terminus (polsigma). We use NMR spectroscopy to demonstrate that the Rev1 C-terminal domain utilizes independent interaction interfaces to simultaneously bind a fragment of the 'inserter' poleta and Rev7 subunit of the 'extender' polsigma, thereby serving as a cassette that may accommodate several polymerases making them instantaneously available for TLS. PMID- 22828284 TI - Low tube voltage CT for improved detection of pancreatic cancer: detection threshold for small, simulated lesions. AB - BACKGROUND: Pancreatic ductal adenocarcinoma is associated with dismal prognosis. The detection of small pancreatic tumors which are still resectable is still a challenging problem.The aim of this study was to investigate the effect of decreasing the tube voltage from 120 to 80 kV on the detection of pancreatic tumors. METHODS: Three scanning protocols was used; one using the standard tube voltage (120 kV) and current (160 mA) and two using 80 kV but with different tube currents (500 and 675 mA) to achieve equivalent dose (15 mGy) and noise (15 HU) as that of the standard protocol.Tumors were simulated into collected CT phantom images. The attenuation in normal parenchyma at 120 kV was set at 130 HU, as measured previously in clinical examinations, and the tumor attenuation was assumed to differ 20 HU and was set at 110HU. By scanning and measuring of iodine solution with different concentrations the corresponding tumor and parenchyma attenuation at 80 kV was found to be 185 and 219 HU, respectively.To objectively evaluate the differences between the three protocols, a multi-reader multi-case receiver operating characteristic study was conducted, using three readers and 100 cases, each containing 0-3 lesions. RESULTS: The highest reader averaged figure-of-merit (FOM) was achieved for 80 kV and 675 mA (FOM=0,850), and the lowest for 120 kV (FOM=0,709). There was a significant difference between the three protocols (p<0,0001), when making an analysis of variance (ANOVA). Post-hoc analysis (students t-test) shows that there was a significant difference between 120 and 80 kV, but not between the two levels of tube currents at 80 kV. CONCLUSION: We conclude that when decreasing the tube voltage there is a significant improvement in tumor conspicuity. PMID- 22828285 TI - Hot flashes and antidepressant agents: uneasy bedfellows. PMID- 22828286 TI - The bone-promoting actions of formononetin in established osteopenia. PMID- 22828287 TI - Menopause and symptoms: are we too focused on hot flashes? PMID- 22828288 TI - A physiotherapist-delivered integrated exercise and pain coping skills training intervention for individuals with knee osteoarthritis: a randomised controlled trial protocol. AB - BACKGROUND: Knee osteoarthritis (OA) is a prevalent chronic musculoskeletal condition with no cure. Pain is the primary symptom and results from a complex interaction between structural changes, physical impairments and psychological factors. Much evidence supports the use of strengthening exercises to improve pain and physical function in this patient population. There is also a growing body of research examining the effects of psychologist-delivered pain coping skills training (PCST) particularly in other chronic pain conditions. Though typically provided separately, there are symptom, resource and personnel advantages of exercise and PCST being delivered together by a single healthcare professional. Physiotherapists are a logical choice to be trained to deliver a PCST intervention as they already have expertise in administering exercise for knee OA and are cognisant of the need for a biopsychosocial approach to management. No studies to date have examined the effects of an integrated exercise and PCST program delivered solely by physiotherapists in this population. The primary aim of this multisite randomised controlled trial is to investigate whether an integrated 12-week PCST and exercise treatment program delivered by physiotherapists is more efficacious than either program alone in treating pain and physical function in individuals with knee OA. METHODS/DESIGN: This will be an assessor-blinded, 3-arm randomised controlled trial of a 12-week intervention involving 10 physiotherapy visits together with home practice. Participants with symptomatic and radiographic knee OA will be recruited from the community in two cities in Australia and randomized into one of three groups: exercise alone, PCST alone, or integrated PCST and exercise. Randomisation will be stratified by city (Melbourne or Brisbane) and gender. Primary outcomes are overall average pain in the past week measured by a Visual Analogue Scale and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale. Secondary outcomes include global rating of change, muscle strength, functional performance, physical activity levels, health related quality of life and psychological factors. Measurements will be taken at baseline and immediately following the intervention (12 weeks) as well as at 32 weeks and 52 weeks to examine maintenance of any intervention effects. Specific assessment of adherence to the treatment program will also be made at weeks 22 and 42. Relative cost-effectiveness will be determined from health service usage and outcome data. DISCUSSION: The findings from this randomised controlled trial will provide evidence for the efficacy of an integrated PCST and exercise program delivered by physiotherapists in the management of painful and functionally limiting knee OA compared to either program alone. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference number: ACTRN12610000533099. PMID- 22828290 TI - Towards a generalized physicochemical framework. AB - Process models used for activated sludge, anaerobic digestion and in general wastewater treatment plant process design and optimization have traditionally focused on important biokinetic conversions. There is a growing realization that abiotic processes occurring in the wastewater (i.e. 'solvent') have a fundamental effect on plant performance. These processes include weak acid-base reactions (ionization), spontaneous or chemical dose-induced precipitate formation and chemical redox conversions, which influence pH, gas transfer, and directly or indirectly the biokinetic processes themselves. There is a large amount of fundamental information available (from chemical and other disciplines), which, due to its complexity and its diverse sources (originating from many different water and process environments), cannot be readily used in wastewater process design as yet. This position paper outlines the need, the methods, available knowledge and the fundamental approaches that would help to focus the effort of research groups to develop a physicochemical framework specifically in support of whole-plant process modeling. The findings are that, in general, existing models such as produced by the International Water Association for biological processes are limited by omission of key corrections such as non-ideal acid-base behavior, as well as major processes (e.g., ion precipitation). While the underlying chemistry is well understood, its applicability to wastewater applications is less well known. This justifies important further research, with both experimental and model development activities to clarify an approach to modeling of physicochemical processes. PMID- 22828291 TI - Characteristics of moisture and salinity of soil in Taklimakan Desert, China. AB - The Taklimakan desert is known as the largest dunefield in China and also as the world's second largest shifting sand desert. The Tarim Desert Highway, which is the first highway to cross the Taklimakan desert, was built for the purpose of oil and gas resources extraction in the Tarim area, as well as for the development of the southern area of the Xinjiang Uygur Autonomous Region. Shelterbelts have been planted along the highway to prevent shifting sand from burying the road. This paper analyzes the variations of moisture and salinity of the unirrigated desert soil under natural conditions in the center of Taklimakan Desert. A number of important findings indicating the moisture and salinity of the soil at capillary saturation zone were determined by the groundwater and related to the evaporation on the top. Salinity could be affected by vegetation, which was different from moisture in the soil. Meanwhile, clay layer played an important role in water preservation in the soil, which was also beneficial to the accumulation of salinity in soil. Compared with clay layer, vegetation was a decisive factor for the gathering of salinity. The findings were significant for reasonable adjustment of irrigation in the shelterbelts for the further development of the Tarim Desert Highway. PMID- 22828289 TI - Cigarette smoking and its association with serum lipid/lipoprotein among Chinese nonagenarians/centenarians. AB - OBJECTIVE: Cigarette smoking had been confirmed as an increased risk for dyslipidemia, but none of the evidence was from long-lived population. In present study, we detected relationship between cigarette smoking habits and serum lipid/lipoprotein (serum Triglyceride (TG), Total cholesterol (TC), Low-density lipoprotein (LDL) and high-density lipoprotein (HDL)) among Chinese Nonagenarians/Centenarian. METHODS: The present study analyzed data from the survey that was conducted on all residents aged 90 years or more in a district, there were 2,311,709 inhabitants in 2005. Unpaired Student's t test, chi2 test, and multiple logistic regression were used to analyze datas. RESULTS: The individuals included in the statistical analysis were 216 men and 445 women. Current smokers had lower level of TC (4.05 +/- 0.81 vs. 4.21 +/- 0.87, t = 2.403, P = 0.017) and lower prevalence of hypercholesteremia (9.62% vs. 15.13%, chi2 = 3.018,P = 0.049) than nonsmokers. Unadjusted and adjusted multiple logistic regressions showed that cigarette smoking was not associated with risk for abnormal serum lipid/lipoprotein. CONCLUSIONS: In summary, we found that among Chinese nonagenarians/centenarians, cigarette smoking habits were not associated with increased risk for dyslipidemia, which was different from the association of smoking habits with dyslipidemia in general population. PMID- 22828292 TI - Concept of an innovative water management system with decentralized water reclamation and cascading material-cycle for agricultural areas. AB - Unlike in urban areas where intensive water reclamation systems are available, development of decentralized technologies and systems is required for water use to be sustainable in agricultural areas. To overcome various water quality issues in those areas, a research project entitled 'Development of an innovative water management system with decentralized water reclamation and cascading material cycle for agricultural areas under the consideration of climate change' was launched in 2009. This paper introduces the concept of this research and provides detailed information on each of its research areas: (1) development of a diffuse agricultural pollution control technology using catch crops; (2) development of a decentralized differentiable treatment system for livestock and human excreta; and (3) development of a cascading material-cycle system for water pollution control and value-added production. The author also emphasizes that the innovative water management system for agricultural areas should incorporate a strategy for the voluntary collection of bio-resources. PMID- 22828293 TI - The situation of sanitary systems in rural areas in the Miyun catchment, China. AB - The Miyun Reservoir provides most of Beijing's drinking water. Despite its importance, the Miyun reservoir suffers from decreasing water quality caused by uncontrolled wastewater discharges, inadequate land use and over fertilization, which increase the pressure on soil and water resources. The major pollutants are nitrogen and phosphorus which emanate to some extent from untreated sewage. So far there is little data about the existing wastewater quantity and quality in rural settlements in northern China. This study was conducted in typical villages situated along upstream rivers in the catchment of the Miyun Reservoir. The main objective was to determine the current situation and efficiency of the wastewater treatment system in rural settlements. PMID- 22828295 TI - Study on the removal efficiency of UF membranes using bacteriophages in bench scale and semi-technical scale. AB - To determine the removal efficiency of ultrafiltration (UF) membranes for nano particles in the size range of viruses the state of the art uses challenge tests with virus-spiked water. This work focuses on bench-scale and semi-technical scale experiments. Different experimental parameters influencing the removal efficiency of the tested UF membrane modules were analyzed and evaluated for bench- and semi-technical scale experiments. Organic matter in the water matrix highly influenced the removal of the tested bacteriophages MS2 and phiX174. Less membrane fouling (low DeltaTMP) led to a reduced phage reduction. Increased flux positively affected phage removal in natural waters. The tested bacteriophages MS2 and phiX174 revealed different removal properties. MS2, which is widely used as a model organism to determine virus removal efficiencies of membranes, mostly showed a better removal than phiX174 for the natural water qualities tested. It seems that MS2 is possibly a less conservative surrogate for human enteric virus removal than phiX174. In bench-scale experiments log removal values (LRV) for MS2 of 2.5-6.0 and of 2.5-4.5 for phiX174 were obtained for the examined range of parameters. Phage removal obtained with differently fabricated semi-technical modules was quite variable for comparable parameter settings, indicating that module fabrication can lead to differing results. Potting temperature and module size were identified as influencing factors. In conclusion, careful attention has to be paid to the choice of experimental settings and module potting when using bench-scale or semi-technical scale experiments for UF membrane challenge tests. PMID- 22828294 TI - Energy saving system with high effluent quality for municipal sewage treatment by UASB-DHS. AB - An up-flow anaerobic sludge blanket (UASB) - down-flow hanging sponge (DHS) was applied to Japanese municipal sewage treatment, and its treatability, energy consumption, and sludge production were evaluated. The designed sewage load was 50 m(3)/d. The sewage typically had a chemical oxygen demand (COD) of 402 mg/L, a suspended solids (SS) content of 167 mg/L, and a temperature of 17-29 degrees C. The UASB and DHS exhibited theoretical hydraulic retention times of 9.7 and 2.5 h, respectively. The entire system was operated without temperature control. Operation was started with mesophilic anaerobic digested sludge for the UASB and various sponge media for the DHS. Continuous operational data suggest that although the cellulose decomposition and methanogenic process in the UASB are temperature sensitive, stable operation can be obtained by maintaining a satisfactory sludge volume index and sludge concentration. For the DHS, the cube type medium G3-2 offers superior filling rates, biological preservation and operational execution. The SS derived from the DHS contaminated the effluent but could be removed by optional sand filtration. A comparison with conventional activated sludge (CAS) treatment confirmed that this system is adequate for municipal sewage treatment, with an estimated energy requirement and excess sludge production approximately 75 and 85% less than those of CAS, respectively. PMID- 22828296 TI - Inorganic fractions in extracellular polymeric substance extracted from activated sludge and biofilm samples by different methods. AB - This study highlighted the inorganic fractions in the extracellular polymeric substance (EPS) extract from two activated sludges and one biofilm. Nine EPS extraction methods (centrifugation, sonication, cation exchange resin (CER) + sonication, CER, heating, formaldehyde + heating, formaldehyde + NaOH, ethanol and EDTA) were used in the study. The EPS extracts had large inorganic fractions, which ranged from 28% to 94% of the EPS dry weight. The EPS inorganic fraction was dependent on the source of the sludge and wastewater, the kinds of bacteria and the extraction method. The EPS extracts obtained by heating and sonication had smaller inorganic fractions than those obtained by centrifugation. The compositions of the inorganic fraction of EPS extracts obtained with CER and sonication + CER showed similar trends. The chemical extraction methods could contaminate the inorganic composition of EPS extracts by impurities, carrying over of the extractant itself or by changing the pH of the solution. Ethanol was the most effective extractant for obtaining inorganic ions. PMID- 22828297 TI - Diel vertical migration and nutrient transport of the dinoflagellate Peridinium bipes f. occultatum in a thermally stratified reservoir. AB - Field observations were conducted with respect to the vertical migration of the dinoflagellate Peridinium bipes and its influence on vertical nutrient transport in a stratified reservoir. P. bipes migrated vertically with circadian rhythms; that is, P. bipes migrated downward and accumulated in the top layer of the hypolimnion from evening to night and then migrated upward and accumulated in the epilimnion in the early morning. In the top layer of the hypolimnion, a rapid decrease in nutrient concentration was observed in the evening, presumably due to uptake by P. bipes. Active migration from the epilimnion to the top of the hypolimnion was also suggested by estimation of the descent velocity of P. bipes, which was advantageous for the uptake of nutrients. Moreover, based on the equilibrium of forces during migration, the energy cost of vertical migration could be inferred to be negligible. The results suggest that active vertical migration of P. bipes played an important role in nutrient transport between the hypolimnion and the epilimnion in a stratified reservoir. PMID- 22828298 TI - Effect of dosing regime on nitrification in a subsurface vertical flow treatment wetland system. AB - In this study, the effect of dosing regime on nitrification in a subsurface vertical flow treatment wetland system was investigated. The experimental unit was composed of four circular concrete tanks (1 m diameter and 80 cm deep), filled with gravel (1-2 cm) and planted with Cyperus alternifolius L. Synthetic wastewater with average chemical oxygen demand (COD) and ammonia nitrogen of 1,151 and 339 mg/L was fed into each tank. Different feeding and resting periods were applied: continuous flow (tank 1), 4 hrs on and 4 hrs off (tank 2), 1 hr on and 3 hrs off (tank 3) and 15 minutes on and 3 hrs 45 minutes off (tank 4). All four tanks were under the same hydraulic loading rate of 5 cm/day. After 165 days the reduction of total Kjeldahl nitrogen and ammonia nitrogen and the increase of nitrate nitrogen were greatest in tank 4, which had the shortest feeding period, while the continuous flow produced the lowest results. Effluent tanks 2 and 3 experienced similar levels of nitrification, both higher than that of tank 1. Thus supporting the idea that rapid dosing periods provide better aerobic conditions resulting in enhanced nitrification within the bed. Tank 4 had the highest removal rates for COD, and the continuous flow had the lowest. Tank 2 also exhibited a higher COD removal rate than tank 3, demonstrating that short dosing periods provide better within-bed oxidation and therefore offer higher removal efficiency. PMID- 22828299 TI - Impact of the surface characteristics of rainwater tank material on biofilm development. AB - In order to determine the impact of rainwater construction material on the development of a biofilm, three materials were tested: concrete, clay, and PVC. The biofilm attachment was initially more effective on clay coupons, but, after a period of three days, concrete coupons produced a greater quantity of biofilm than clay and PVC, in that order. The heterotrophic plate count in the rainwater indicated that this quantity tended to first increase following a rainfall, and then decrease. The new materials seemed to attach themselves to the existing biofilm on the wall and/or sediment in the form of small particles. The presence of fecal coliforms in the biofilm coupons was noted after major rainfall events, and this was correlated with the increase in fecal coliforms in the water. This study concluded that the most favorable support for biofilm development is concrete, clay, and PVC, in that order. PMID- 22828300 TI - Simultaneous optimization of multiple performance characteristics in coagulation flocculation process for Indian paper industry wastewater. AB - The goal of this study was to optimize the coagulation-flocculation process in wastewater generated from the paper and pulp industry using a grey relational analysis (GRA)-based Taguchi method. Process parameters included types and doses of natural coagulants and coagulant aid, and pH. To track the efficiency of the treatment process, the following responses were chosen for optimization: chemical oxygen demand (COD), total dissolved solids (TDS) and turbidity of wastewater, alone or in combination or all together. Analysis of variance showed that the type and dose of the coagulant aid were the most significant parameters, followed by pH and the dose of the coagulant; the type of coagulant used was found to be insignificant in the coagulation-flocculation process. Optimization of process parameters to achieve lower turbidity and greater removal of COD and TDS was verified in a separate confirmatory experiment, which showed improvements in COD and TDS removal and a decrease in turbidity of 8.2, 6.35 and 26.17%, respectively, with the application of the Taguchi method and GRA. PMID- 22828301 TI - Importance of the ammonia volatilization rates in shallow maturation ponds treating UASB reactor effluent. AB - This study aimed at determining the influence of ammonia volatilization on nitrogen removal in polishing (maturation) ponds treating sanitary effluent from upflow anaerobic sludge blanket (UASB) reactors in the city of Belo Horizonte, Brazil. An apparatus for the capture and absorption of volatilized ammonia in three polishing ponds in series was installed. Volatilized ammonia was captured by a chamber on the surface of the ponds and dissolved in boric acid solution, in order to estimate the amount of ammonia per unit surface area of each pond. Low rates of volatilization, below 0.2 kg/ha.d, in about 75% of samples from all the ponds, were observed. The mass balance of ammonia nitrogen of the ponds showed that the volatilization represented only about 2% of the total removal of nitrogen from the polishing ponds. The results obtained suggest that ammonia volatilization was a mechanism of little importance in nitrogen removal in the investigated polishing ponds. PMID- 22828302 TI - Rapid on-site multiplex assays for total and toxigenic Microcystis using real time PCR with microwave cell disruption. AB - A quantitative real-time polymerase chain reaction (qPCR) is a robust means by which to monitor toxin-producing cyanobacteria. However, qPCR usually requires DNA extraction, which is a time-consuming, labor-intensive pretreatment. To be able to quickly determine the potential of cyanotoxin contamination in the field, a rapid pretreatment method for DNA extraction and a portable qPCR device are needed. In this study, we applied a microwave-based method for the qPCR pretreatment and a multicolor portable qPCR with UPL and TaqMan probes to quantify toxigenic and total Microcystis. The method was tested using laboratory cultures of toxigenic Microcystis aeruginosa PCC7820. The qPCR results showed the cycle thresholds value (Ct value) correlated well with cell numbers, with detection limit at about 1,000 cells/ml. This scheme was applied in 22 environmental samples from six drinking water reservoirs (DWRs) in Taiwan. Although the results for qPCR were about four times higher than those of microscopic observation, good correlation between qPCR and microscope methods were obtained (r-square: 0.79, P < 0.01). The ratios of toxigenic Microcystis to total Microcystis in two reservoirs, Sin-Shan Reservoir and Shih-men Reservoir, were less than 10%. In three other reservoirs, Ren-Yi-Tan Reservoir, Nan-Hua Reservoir and Bao-Shan Reservoir, much higher (>46.1%) ratios were obtained. The scheme may assist quick assessment of the risk associated with toxic cyanobacteria in DWRs. PMID- 22828303 TI - Effects of ORP, recycling rate, and HRT on simultaneous sulfate reduction and sulfur production in expanded granular sludge bed (EGSB) reactors under micro aerobic conditions for treating molasses distillery wastewater. AB - An expanded granular sludge bed (EGSB) reactor was adopted to incubate the sludge biogranule that could simultaneously achieve sulfate reduction and sulfide reoxidization to elemental sulfur for treating molasses distillery wastewater. The EGSB reactor was operated for 175 days at 35 degrees C with a pH value of 7.0, chemical oxygen demand (COD) loading rate of 4.8 kg COD/(m3 d), and sulfate loading rate of 0.384 kg SO(4)(2-)/(m3 d). The optimal operation parameters, including the oxidation reduction potential (ORP), recycling rate, and hydraulic retention time (HRT), were established to obtain stable and acceptable removal efficiencies of COD, sulfate, and higher elemental sulfur production. With an ORP of -440 mV, a recycling rate of 300%, and HRT of 15 h, the COD and sulfate removal efficiencies were 73.4 and 61.3%, respectively. The elemental sulfur production ratio reached 30.1% when the elemental sulfur concentration in the effluent was 48.1 mg/L. The performance results were also confirmed by the mass balance calculation of sulfate, sulfide, and elemental sulfur over the EGSB reactor. PMID- 22828304 TI - Removal mechanisms of 17beta-estradiol and 17alpha-ethinylestradiol in membrane bioreactors. AB - The fate and behavior of natural and synthetic estrogens in wastewater treatment processes is currently of increasing concern all over the world. In this study, the removal mechanisms of a natural estrogen, 17beta-estradiol (E2), and a synthetic estrogen, 17alpha-ethinylestradiol (EE2) were investigated in membrane bioreactors (MBRs) with and without powdered activated carbon (PAC) addition. The experimental results showed that the average removal rates of E2 and EE2 by the MBR without PAC addition were 89.0 and 70.9%; PAC addition in the MBR increased the removal rate of E2 and EE2 by 3.4 and 15.8%, respectively. The greater impact of PAC dosing on EE2 removal was due to its greater hydrophobic property. Adsorption played a more important role in the removal mechanisms of EE2 than E2. Biodegradation was the dominant mechanism for the removal of E2 and EE2 in MBRs. Unlike their adsorption behavior, the biodegradation rates of both E2 and EE2 were not significantly different between the MBRs with and without PAC addition. PMID- 22828305 TI - Consideration of emerging pollutants in groundwater-based reuse concepts. AB - Elimination of pathogens and emerging pollutants represents a key factor in integrated water resources management in arid regions. Within the SMART Jordan Valley project it is the objective of this study to assess the occurrence and examine the elimination of selected emerging pollutants and pathogens in waste water treatment and aquifer recharge. In batch and soil column studies non chlorinated organophosphorous compounds (tri-n-butylphosphate, triphenylphosphate) and endocrine disruptors (e.g. 17-beta-estradiol, bisphenol A) proved to be biodegradable, while the X-ray contrast agents iomeprol and iopromide were eliminated in the soil columns only, and the chlorinated trialkylphosphates showed persistency. Treating waste water in a membrane bioreactor (MBR) in combination with powdered activated carbon (PAC) resulted in considerable removal rates also for the more persistent compounds such as the antiepileptic carbamazepine. Viruses were shown to be present in most of the Jordan Valley surface water samples. MBR treatment resulted in a decrease of MS2 bacteriophages used as model viruses. PMID- 22828306 TI - Potentials and limits of anaerobic digestion of sewage sludge: energy self sufficient municipal wastewater treatment plant? AB - Anaerobic digestion is the only energy-positive technology widely used in wastewater treatment. Full-scale data prove that the anaerobic digestion of sewage sludge can produce biogas that covers a substantial amount of the energy consumption of a wastewater treatment plant (WWTP). In this paper, we discuss possibilities for improving the digestion efficiency and biogas production from sewage sludge. Typical specific energy consumptions of municipal WWTPs per population equivalent are compared with the potential specific production of biogas to find the required/optimal digestion efficiency. Examples of technological measures to achieve such efficiency are presented. Our findings show that even a municipal WWTP with secondary biological treatment located in a moderate climate can come close to energy self-sufficiency. However, they also show that such self-sufficiency is dependent on: (i) the strict optimization of the total energy consumption of the plant, and (ii) an increase in the specific biogas production from sewage sludge to values around 600 L per kg of supplied volatile solids. PMID- 22828307 TI - Phytoremediation of atrazine by three emergent hydrophytes in a hydroponic system. AB - A hydroponic system was used to evaluate atrazine (ATZ) removal and uptake by three emergent hydrophytes, Iris pseudacorus, Lythrum salicaria and Acorus calamus, determining their potential as phytoremediation agents for ATZ contaminated water. After 20 days of exposure, the relative growth rate of plants in sterile conditions was less than in natural conditions. ATZ amount in a culture solution planted with emergent plants decreased significantly compared with an unplanted solution, and the removal rate of ATZ in natural conditions was greater than in sterile conditions (p < 0.05). The degradation contributions of I. pseudacorus, L. salicaria and A. calamus were 75.6, 65.5 and 61.8%, respectively. Those of the corresponding microbial population in the solution were 5.4, 11.4 and 17.4%, respectively. Emergent plants play a dominant role in reducing the ATZ level in the water body and could be used as phytoremediation agents. PMID- 22828308 TI - MBR fouling control and permeate quality enhancement by polyaluminium chloride dosage: a case study. AB - Scope of this study was to evaluate the effectiveness of a metal salt (polyaluminium chloride, PACl) dosage into a pilot-scale MBR (membrane bioreactor) in terms of fouling control and permeate quality enhancement, especially with reference to specific textile macro-pollutants (dyes and surfactants). The pilot plant was fed with a mixed domestic-textile wastewater (textile wastewater accounted for 65% of total flow and for 70% of total chemical oxygen demand, COD, load) and operated for 7.5 months without flux enhancers (step 1) and 3 months with the addition of PACl (step 2). The optimum dose was defined performing a jar-test campaign between step 1 and step 2 (12.5 mg gMLSS( 1) that corresponds to 0.4 g d(-1)). The addition of PACl resulted in a significant decrease of the filtration resistance due to cake layer formation (R(c), -65.4%) and of the irreversible fouling rate, evaluated as the average variation per unit time of the filtration resistance due to foulants adsorption on membrane pore wall (FR, -45.3%). As for permeate quality, removal rates related to total phosphorus and textile macro-parameters such as colour and anionic surfactants, increased by +64, +16 and +7%, respectively. No significant effect was observed on COD, non-ionic surfactants and nitrogen compounds removal. PMID- 22828309 TI - Recovery of calcium carbonate from waste gypsum and utilization for remediation of acid mine drainage from coal mines. AB - The recovery of calcium carbonate from waste gypsum (a waste product of the reverse osmosis (RO) desalination process) was tested using sodium carbonate. Batch recovery of calcium carbonate from waste gypsum slurries by reacting with sodium carbonate under ambient conditions was used to assess the technical feasibility of CaCO(3) recovery and its use for pre-treatment of acid mine drainage (AMD) from coal mines. The effect of key process parameters, such as the slurry concentration (%) and the molar ratio of sodium carbonate to gypsum were considered. It was observed that batch waste gypsum conversion significantly increased with decrease in the slurry concentration or increase in the molar ratio of sodium carbonate to gypsum. The CaCO(3) recovered from the bench-scale batch reactor demonstrated effective neutralization ability during AMD pre treatment compared with commercial laboratory grade CaCO(3). PMID- 22828310 TI - Optimization of diesel oil biodegradation in seawater using statistical experimental methodology. AB - Petroleum hydrocarbons released into the environment can be harmful to higher organisms, but they can be utilized by microorganisms as the sole source of energy for metabolism. To investigate the optimal conditions of diesel oil biodegradation, the Plackett-Burman (PB) design was used for the optimization in the first step, and N source (NaNO3), P source (KH2PO4) and pH were found to be significant factors affecting oil degradation. Then the response surface methodology (RSM) using a central composite design (CCD) was adopted for the augmentation of diesel oil biodegradation and a fitted quadratic model was obtained. The model F-value of 27.25 and the low probability value (<0.0001) indicate that the model is significant and that the concentration of NaNO3N, KH2PO4 and pH had significant effects on oil removal during the study. Three dimensional response surface plots were constructed by plotting the response (oil degradation efficiency) on the z-axis against any two independent variables, and the optimal biodegradation conditions of diesel oil (original total petroleum hydrocarbons 125 mg/L) were determined as follows: NaNO3 0.143 g, KH2PO4 0.022 g and pH 7.4. These results fit quite well with the C, N and P ratio in biological cells. Results from the present study might provide a new method to estimate the optimal nitrogen and phosphorus concentration in advance for oil biodegradation according to the composition of petroleum. PMID- 22828311 TI - Appropriate maximum holding times for analysis of total suspended solids concentration in water samples taken from open-channel waterways. AB - Many scientific laboratories follow, as standard practice, a relatively short maximum holding time (within 7 days) for the analysis of total suspended solids (TSS) in environmental water samples. In this study we have subsampled from bulk water samples stored at ~4 degrees C in the dark, then analysed for TSS at time intervals up to 105 days after collection. The nonsignificant differences in TSS results observed over time demonstrates that storage at ~4 degrees C in the dark is an effective method of preserving samples for TSS analysis, far past the 7-day standard practice. Extending the maximum holding time will ease the pressure on sample collectors and laboratory staff who until now have had to determine TSS within an impractically short period. PMID- 22828312 TI - Treatment of ametryn in wastewater by a hybrid MBR system: a lab-scale study. AB - Agricultural discharge of herbicides to the Great Barrier Reef (GBR) poses significant threat to the marine ecosystem. This study evaluates the performance of a hybrid treatment system consists of a membrane bioreactor (MBR), UV disinfection unit and a granular activated carbon (GAC) column in treating ametryn which is one of the major herbicides in agricultural discharges. While the MBR alone removes only 40% of ametryn at a hydraulic retention time of 7.8 h, the hybrid system removed ametryn to below detection levels. PMID- 22828313 TI - Experiments and 3D simulations of flow structures in junctions and their influence on location of flowmeters. AB - Open-channel junctions are common occurrences in sewer networks and flow rate measurement often occurs near these singularities. Local flow structures are 3D, impact on the representativeness of the local flow measurements and thus lead to deviations in the flow rate estimation. The present study aims (i) to measure and simulate the flow pattern in a junction flow, (ii) to analyse the impact of the junction on the velocity distribution according to the distance from the junction and thus (iii) to evaluate the typical error derived from the computation of the flow rate close to the junction. PMID- 22828314 TI - Photocatalytic reduction of Cr(VI) in aqueous solution using TiO2 nanoparticles prepared with various alcohols as solvent. AB - TiO2 nanoparticles were prepared with various linear alkyl chains of alcohols under a sol-gel process. The structure characterization and the photocatalytic reduction of hexavalent chromium of the TiO2 nanoparticles were investigated. The phase transformation temperature, crystal aggregation and surface area of prepared TiO2 samples were found to be strongly influenced by alcohol used. The phase transformation from anatase to rutile was retarded and the surface area was reduced for TiO2 prepared with alcohols of longer alkyl chain. TiO2 nanoparticles prepared with methanol or ethanol exhibited higher photocatalytic reduction activity of hexavalent chromium possibly due to greater and more positively charged surface area. PMID- 22828315 TI - Sorption of Cr(III) ion from aqueous solution by two kinds of modified diatomite. AB - Raw diatomite modified by microemulsion (DMM) and manganese oxide (MnD) were used for the removal of Cr(III) ions from aqueous solution. The characteristics and performance of these two types of modified diatomite on Cr(III) ion adsorption were compared. The results indicate that the Cr(III) ion adsorption capacities of diatomite were considerably improved after modifications by manganese oxide (MnO) and microemulsion. The surface area of MnD was increased because of the formation of MnO on the diatomite surface, and that of DMM was promoted owing to the existence of the hydrolyzed aromatic acid. Because of the stronger surface ionized function, the adsorption performance of Cr(III) ions in DMM was better than that in MnD. Within the experimental range of pH (i.e. 2.2-6.3), the Cr(III) ion removal of DMM (35-70%) was higher than that of MnD (33-59%) owing to the different electrostatic forces between the Cr(III) ion and the surface of the modified diatomite. The Cr(III) ion removal in MnD and DMM was improved with the increase of synthetic solution concentration in volumes from 0 to 2,500 mL. PMID- 22828316 TI - Removal of organic matter and phosphate using ferrihydrite for reduction of microbial regrowth potential. AB - Dissolved organic matter (DOM) and phosphate in reclaimed water promote microbial growth in distribution systems and deteriorate water quality. In this study, we tested ferrihydrite (Fh) for its potential to remove both DOM and phosphate in order to control bacterial regrowth. Adsorption kinetics on Fh revealed that phosphate has a higher affinity with Fh than has DOM. The removal efficiency of DOM increased at lower pH. Fourier transform infrared spectroscopy (FT-IR) spectra of freeze-dried Fh showed that adsorbed DOM was rich in carboxyl/hydroxyl functional groups, indicating anion exchange at Fh surfaces to be a major mechanism, especially at low pH. Fh preferentially removed DOM greater than 1,000 Da. Specific ultraviolet absorption (SUVA) at 254 nm and DOC results suggest Fh adsorption removes more hydrophilic DOM than the coagulation-sand filtration process. Reduction of bacterial regrowth potential (BRP) by Fh was comparable to that of the coagulation-sand filtration process, which indicated that phosphorus was not the rate-limiting factor of microbial growth. PMID- 22828317 TI - Chemical-oxidative scrubbing for the removal of hydrogen sulphide from raw biogas: potentials and economics. AB - In the present work chemical-oxidative scrubbing as a novel method for the desulphurisation of raw biogas is presented with a special focus on the process potentials and economics. The selective absorption of hydrogen sulphide from gas streams containing high amounts of carbon dioxide using caustic solutions is not trivial but has been treated in literature. However, the application of this method to biogas desulphurisation has not been established so far. Based on rigorous experimental work, an industrial-scale pilot plant has been designed, erected and commissioned at a biogas plant with biogas upgrading and gas grid injection in Austria. Data collected from the 12-month monitored operation has been used to elaborate performance as well as economic parameters for the novel desulphurisation method. The proposed technology offers significant operational advantages regarding the degree of automation and the flexibility towards fluctuations in process boundary conditions. Furthermore, the economic assessment revealed the high competitiveness of the chemical-oxidative scrubbing process compared with other desulphurisation technologies with the named advantageous operational behaviour. PMID- 22828318 TI - Determination of ammonia-oxidizing bacteria based on time-resolved fluorescence and tandem probe. AB - To study the ecology of ammonia-oxidizing bacteria (AOB), quantitative techniques are essential. In this report, the authors introduced an innovative method based on time-resolved fluorescence to quantify AOB as a representative of the major functional microorganisms in sewage water treatment. A bifunctional europium complex with the characteristics of long lifetime and intense luminescence was used as labels in the experiments. In the detection, the capture probe and dye labeled reporter probe could form a two-probe tandem with the target sequence, and the determination of target DNA was done by monitoring the time-resolved fluorescence signals of europium complex-labeled reporter probe left on the glass slide surface. The experiment conditions consisting of concentration of capture probe, hybridization temperature, hybridization time and washing time were optimized. This method presents satisfactory specificity to common bacteria such as Nitrobacter winogradskyi, Escherichia coli and Paenibacillus polymyxa. The detection limit was 3.65 * 10(-11)mol L(-1). This detection system enables us to rapidly and sensitively analyze the microbial population variety in sewage water treatment. PMID- 22828319 TI - Review on the fate of organic micropollutants in wastewater treatment and water reuse with membranes. AB - A brief review of the fate of micropollutants in membrane-based wastewater treatment due to sorption, stripping, biological degradation/transformation and membrane separation is discussed, to give an overview of these technologies due to the growing importance for water reuse purposes. Compared with conventional activated sludge treatment (CAS) micropollutant removal in membrane bioreactor (MBR) is slightly improved due to complete suspended solids removal and increased sludge age. For discharge to sensitive receiving waters advanced treatment, such as post-ozonation or activated carbon adsorption, is recommended. In water reuse plants nanofiltration (NF) and reverse osmosis (RO) efficiently reject micropollutants due to size exclusions as well as electrostatic and hydrophobic effects reaching potable quality. To remove micropollutants fully, additionally post-ozone or the addition of powdered activated carbon (PAC) have to be applied, which in parallel also reduce NDMA precursors. The concentrate has to be treated if disposed to sensitive receiving waters due to its high micropollutant concentration and ecotoxicity potential. The present review summarizes principles and capabilities for the most important membrane-based applications for wastewater treatment, i.e. porous membranes in MBRs (micro- or ultrafiltration) and dense membrane applications (NF and RO) for water reuse. PMID- 22828320 TI - Investigation on PLK2 and PLK3 substrate recognition. AB - Analyses of human phosphoproteome based on primary structure of the aminoacids surrounding the phosphor Ser/Thr suggest that a significant proportion of phosphosites is generated by a restricted number of acidophilic kinases, among which protein kinase CK2 plays a prominent role. Recently, new acidophilic kinases belonging to the Polo like kinase family have been characterized, with special reference to PLK1, PLK2, and PLK3 kinases. While some progress has been made in deciphering the PLK1-dependent phosphoproteome, very little is known about the targets of PLK2 and PLK3 kinases. In this report by using an in vitro approach, consisting of cell lysate phosphorylation, phosphoprotein separation by 2D gel electrophoresis and mass spectrometry, we describe the identification of new potential substrates of PLK2 and PLK3 kinases. We have identified and validated as in vitro PLK2 and PLK3 substrates HSP90, GRP-94, beta-tubulin, calumenin, and 14-3-3 epsilon. The phosphosites generated by PLK3 in these proteins have been identified by mass spectrometry analysis to get new insights about PLKs specificity determinants. These latter have been further corroborated by an in silico analysis of the PLKs substrate binding region. PMID- 22828321 TI - Ecological evaluation of executive functions in mild cognitive impairment and Alzheimer disease. AB - Executive deficits characterize the initial phases of Alzheimer disease (AD) and mild cognitive impairment (MCI), and are clinically correlated to neuropsychiatric symptoms and functional loss. The aim of this study was to determine the accuracy of the Behavioral Assessment of the Dysexecutive Syndrome test (BADS) for comparing the performance between patients with amnestic MCI (aMCI) and mild AD and for detecting early signs of alterations in executive functions. BADS was performed on 60 healthy controls, 20 patients with aMCI, and 40 mild probable AD patients (20 early-onset AD patients and 20 late-onset AD patients). Significant differences in battery performance were found among groups on the BADS subtests Rule Shift Cards, Program of Action, Zoo Map, 6 Modified Elements, and 3 total scores. Early changes in executive functions were detected in both AD (irrespective of age of onset) and aMCI patients. The BADS proved useful for differentiating between these patient groups. Our results confirmed the presence of early alterations in executive functions among aMCI and mild AD patients. PMID- 22828322 TI - Inhibitory dysfunction in frontotemporal dementia: a review. AB - Failure of inhibitory control is an early and consistent feature in patients suffering from frontotemporal dementia (FTD). This appears because of their pervasive ventromedial prefrontal atrophy-particularly in the orbitofrontal cortex-which has been linked to inhibitory dysfunction in studies on human and monkey lesions. However, the range of measures currently available to assess inhibitory processes in FTD is limited, and, as such, inhibitory dysfunction in FTD remains relatively underexplored. Subjective caregiver questionnaires are useful for defining disinhibition as it manifests behaviorally; however, endorsement of symptoms can vary largely across patients as it is contingent on the perceptiveness of the caregiver. The few objective neuropsychological tasks that tap directly into inhibitory functioning have potential, although they mostly rely on intact language and semantics, which can confound performance in FTD patients. An emergent possibility is to explore inhibitory functioning in FTD through nonverbal experimental tasks. Adaptation of such experimental tasks into clinical tools is a promising avenue for exploring one of the earliest behavioral features in FTD patients and concomitantly tap into their prevalent orbitofrontal cortex dysfunction. We suggest that improved characterization of early inhibitory dysfunction may facilitate more accurate diagnosis of FTD. PMID- 22828323 TI - Cultural diversity and views on Alzheimer disease in older African Americans. AB - Cultural constructs prevalent in older African Americans may influence their risk perceptions and knowledge of Alzheimer disease (AD). To examine this issue, we administered 3 sociocultural scales, the AD Knowledge Scale, and a Risk Perception questionnaire to 271 older African Americans who were recruited from a large community senior center and local churches. Higher Present Time Orientation was significantly related to perceptions of having little control over risks to health (P=0.004), God's Will in determining AD (P=0.001), and lower AD knowledge (P<0.0001) and marginally related to having little control over developing AD (P=0.052). Religiosity was marginally related to having little control over risks to health (P=0.055) and getting AD (P=0.057). Post hoc intergroup comparisons found significant differences in the highest versus lowest scoring Religiosity groups. There were no significant differences by Future Time Orientation. Most subjects (57.6%) were unaware that African Americans were at higher risk for AD than whites. These data indicate that cultural diversity within older African Americans may shape health perceptions and knowledge of AD. This diversity may contribute to disparities in the detection and treatment of AD in this high-risk population. PMID- 22828324 TI - Organizational boundaries of medical practice: the case of physician ownership of ancillary services. AB - Physician ownership of in-office ancillary services (IOASs) has come under increasing scrutiny. Advocates of argue that IOASs allow physicians to supervise the quality and coordination of care. Critics have argued that IOASs create financial incentives for physicians to increase ancillary service volume. In this paper we develop a conceptual framework to evaluate the tradeoffs associated with physician ownership of IOASs. There is some evidence supporting the existence of scope and transaction economies in IOASs. Improvement in flow and continuity of care are likely to generate scope economies and improvements in quality monitoring and reductions in consumer transaction costs are likely to generate transaction economies. Other factors include the capture of upstream and downstream profits, but these incentives are likely to be small compared to scope and transaction economies. Policy debates on the merits of IOASs should include an explicit assessment of these tradeoffs.This research was supported in part by funding from the American Association of Orthopaedic Surgeons (AAOS). PMID- 22828325 TI - Upper limb amputation due to a brachial arterial embolism associated with a superior mesenteric arterial embolism: a case report. AB - BACKGROUND: Acute mesenteric ischemia due to an embolism of the superior mesenteric artery is associated with a high mortality rate. Over 20 percent of acute mesenteric embolism cases consist of multiple emboli, and the long-term prognosis depends on the incidence of subsequent embolic events at other sites. The incidence of emboli in the upper extremity associated with a superior mesenteric arterial embolism has rarely been described. The signs and symptoms of ischemic change in the upper limb can be masked by other circumstances, such as postoperative conditions or complications. In these cases, a late presentation or delayed diagnosis and treatment can result in limb loss. CASE PRESENTATION: We present a rare case of a 67-year-old Japanese woman with atrial fibrillation who developed an embolic occlusion of the brachial artery associated with a superior mesenteric arterial embolism. She developed gangrene in her right hand, which had progressed to the point that amputation was necessary by the time the gastrointestinal surgeon had consulted the Department of Orthopedic Surgery. The brachial arterial embolism diagnosis was delayed by the severe abdominal symptoms and shock conditions that followed the emergency enterectomy, resulting in amputation of the upper limb despite anticoagulation therapy. In this case, multiple infarctions of the spleen were also observed, indicating a shower embolism. CONCLUSIONS: When treating a superior mesenteric arterial embolism in a patient with atrial fibrillation, the possibility of recurrent or multiple arterial thromboembolic events should be considered, even after the procedure is completed. PMID- 22828326 TI - How malaria parasites reduce the deformability of infected red blood cells. AB - The pathogenesis of malaria is largely due to stiffening of the infected red blood cells (RBCs). Contemporary understanding ascribes the loss of RBC deformability to a 10-fold increase in membrane stiffness caused by extra cross linking in the spectrin network. Local measurements by micropipette aspiration, however, have reported only an increase of ~3-fold in the shear modulus. We believe the discrepancy stems from the rigid parasite particles inside infected cells, and have carried out numerical simulations to demonstrate this mechanism. The cell membrane is represented by a set of discrete particles connected by linearly elastic springs. The cytosol is modeled as a homogeneous Newtonian fluid, and discretized by particles as in standard smoothed particle hydrodynamics. The malaria parasite is modeled as an aggregate of particles constrained to rigid-body motion. We simulate RBC stretching tests by optical tweezers in three dimensions. The results demonstrate that the presence of a sizeable parasite greatly reduces the ability of RBCs to deform under stretching. With the solid inclusion, the observed loss of deformability can be predicted quantitatively using the local membrane elasticity measured by micropipettes. PMID- 22828327 TI - Label-free imaging of membrane potential using membrane electromotility. AB - Electrical activity may cause observable changes in a cell's structure in the absence of exogenous reporter molecules. In this work, we report a low-coherence interferometric microscopy technique that can detect an optical signal correlated with the membrane potential changes in individual mammalian cells without exogenous labels. By measuring milliradian-scale phase shifts in the transmitted light, we can detect changes in the cells' membrane potential. We find that the observed optical signals are due to membrane electromotility, which causes the cells to deform in response to the membrane potential changes. We demonstrate wide-field imaging of the propagation of electrical stimuli in gap-junction coupled cell networks. Membrane electromotility-induced cell deformation may be useful as a reporter of electrical activity. PMID- 22828329 TI - Supramolecular structure of membrane-associated polypeptides by combining solid state NMR and molecular dynamics simulations. AB - Elemental biological functions such as molecular signal transduction are determined by the dynamic interplay between polypeptides and the membrane environment. Determining such supramolecular arrangements poses a significant challenge for classical structural biology methods. We introduce an iterative approach that combines magic-angle spinning solid-state NMR spectroscopy and atomistic molecular dynamics simulations for the determination of the structure and topology of membrane-bound systems with a resolution and level of accuracy difficult to obtain by either method alone. Our study focuses on the Shaker B ball peptide that is representative for rapid N-type inactivating domains of voltage-gated K(+) channels, associated with negatively charged lipid bilayers. PMID- 22828328 TI - Normal-mode-analysis-guided investigation of crucial intersubunit contacts in the cAMP-dependent gating in HCN channels. AB - Protein structures define a complex network of atomic interactions in three dimensions. Direct visualization of the structure and analysis of the interaction potential energy are not straightforward approaches to pinpoint the atomic contacts that are crucial for protein function. We used the tetrameric hyperpolarization-activated cAMP-regulated (HCN) channel as a model system to study the intersubunit contacts in cAMP-dependent gating. To obtain a systematic survey of the contacts between each pair of residues, we used normal-mode analysis, a computational approach for studying protein dynamics, and constructed the covariance matrix for C-alpha atoms. The significant contacts revealed by covariance analysis were further investigated by means of mutagenesis and functional assays. Among the mutant channels that show phenotypes different from those of the wild-type, we focused on two mutant channels that express opposite changes in cAMP-dependent gating. Subsequent biochemical assays on isolated C terminal fragments, including the cAMP binding domain, revealed only minimal effects on cAMP binding, suggesting the necessity of interpreting the cAMP dependent allosteric regulation at the whole-channel level. For this purpose, we applied the patch-clamp fluorometry technique and observed correlated changes in the dynamic, state-dependent cAMP binding in the mutant channels. This study not only provides further understanding of the intersubunit contacts in allosteric coupling in the HCN channel, it also illustrates an effective strategy for delineating important atomic contacts within a structure. PMID- 22828330 TI - Dynamic force spectroscopy on supported lipid bilayers: effect of temperature and sample preparation. AB - Biological membranes are constantly exposed to forces. The stress-strain relation in membranes determines the behavior of many integral membrane proteins or other membrane related-proteins that show a mechanosensitive behavior. Here, we studied by force spectroscopy the behavior of supported lipid bilayers (SLBs) subjected to forces perpendicular to their plane. We measured the lipid bilayer mechanical properties and the force required for the punch-through event characteristic of atomic force spectroscopy on SLBs as a function of the interleaflet coupling. We found that for an uncoupled bilayer, the overall tip penetration occurs sequentially through the two leaflets, giving rise to two penetration events. In the case of a bilayer with coupled leaflets, penetration of the atomic force microscope tip always occurred in a single step. Considering the dependence of the jump-through force value on the tip speed, we also studied the process in the context of dynamic force spectroscopy (DFS). We performed DFS experiments by changing the temperature and cantilever spring constant, and analyzed the results in the context of the developed theories for DFS. We found that experiments performed at different temperatures and with different cantilever spring constants enabled a more effective comparison of experimental data with theory in comparison with previously published data. PMID- 22828331 TI - Force-dependent detachment of kinesin-2 biases track switching at cytoskeletal filament intersections. AB - Intracellular trafficking of organelles often involves cytoskeletal track switching. Organelles such as melanosomes are transported by multiple motors including kinesin-2, dynein, and myosin-V, which drive switching between microtubules and actin filaments during dispersion and aggregation. Here, we used optical trapping to determine the unitary and ensemble forces of kinesin-2, and to reconstitute cargo switching at cytoskeletal intersections in a minimal system with kinesin-2 and myosin-V motors bound to beads. Single kinesin-2 motors exerted forces up to ~5 pN, similar to kinesin-1. However, kinesin-2 motors were more likely to detach at submaximal forces, and the duration of force maintenance was short as compared to kinesin-1. In multimotor assays, force increased with kinesin-2 density but was not affected by the presence of myosin-V. In crossed filament assays, switching frequencies of motor-bound beads were dependent on the starting track. At equal average forces, beads tended to switch from microtubules onto overlying actin filaments consistent with the relatively faster detachment of kinesin-2 at near-maximal forces. Thus, in addition to relative force, switching probability at filament intersections is determined by the dynamics of motor-filament interaction, such as the quick detachment of kinesin-2 under load. This may enable fine-tuning of filament switching in the cell. PMID- 22828332 TI - Negative-stain electron microscopy of inside-out FtsZ rings reconstituted on artificial membrane tubules show ribbons of protofilaments. AB - FtsZ, the primary cytoskeletal element of the Z ring, which constricts to divide bacteria, assembles into short, one-stranded filaments in vitro. These must be further assembled to make the Z ring in bacteria. Conventional electron microscopy (EM) has failed to image the Z ring or resolve its substructure. Here we describe a procedure that enabled us to image reconstructed, inside-out FtsZ rings by negative-stain EM, revealing the arrangement of filaments. We took advantage of a unique lipid that spontaneously forms 500 nm diameter tubules in solution. We optimized conditions for Z-ring assembly with fluorescence light microscopy and then prepared specimens for negative-stain EM. Reconstituted FtsZ rings, encircling the tubules, were clearly resolved. The rings appeared as ribbons of filaments packed side by side with virtually no space between neighboring filaments. The rings were separated by variable expanses of empty tubule as seen by light microscopy or EM. The width varied considerably from one ring to another, but each ring maintained a constant width around its circumference. The inside-out FtsZ rings moved back and forth along the tubules and exchanged subunits with solution, similarly to Z rings reconstituted outside or inside tubular liposomes. FtsZ from Escherichia coli and Mycobacterium tuberculosis assembled rings of similar structure, suggesting a universal structure across bacterial species. Previous models for the Z ring in bacteria have favored a structure of widely scattered filaments that are not in contact. The ribbon structure that we discovered here for reconstituted inside-out FtsZ rings provides what to our knowledge is new evidence that the Z ring in bacteria may involve lateral association of protofilaments. PMID- 22828333 TI - Weak interactions govern the viscosity of concentrated antibody solutions: high throughput analysis using the diffusion interaction parameter. AB - Weak protein-protein interactions are thought to modulate the viscoelastic properties of concentrated antibody solutions. Predicting the viscoelastic behavior of concentrated antibodies from their dilute solution behavior is of significant interest and remains a challenge. Here, we show that the diffusion interaction parameter (k(D)), a component of the osmotic second virial coefficient (B(2)) that is amenable to high-throughput measurement in dilute solutions, correlates well with the viscosity of concentrated monoclonal antibody (mAb) solutions. We measured the k(D) of 29 different mAbs (IgG(1) and IgG(4)) in four different solvent conditions (low and high ion normality) and found a linear dependence between k(D) and the exponential coefficient that describes the viscosity concentration profiles (|R| >= 0.9). Through experimentally measured effective charge measurements, under low ion normality where the electroviscous effect can dominate, we show that the mAb solution viscosity is poorly correlated with the mAb net charge (|R| <= 0.6). With this large data set, our results provide compelling evidence in support of weak intermolecular interactions, in contrast to the notion that the electroviscous effect is important in governing the viscoelastic behavior of concentrated mAb solutions. Our approach is particularly applicable as a screening tool for selecting mAbs with desirable viscosity properties early during lead candidate selection. PMID- 22828334 TI - The dynamic structure of thrombin in solution. AB - The backbone dynamics of human alpha-thrombin inhibited at the active site serine were analyzed using R(1), R(2), and heteronuclear NOE experiments, variable temperature TROSY 2D [(1)H-(15)N] correlation spectra, and R(ex) measurements. The N-terminus of the heavy chain, which is formed upon zymogen activation and inserts into the protein core, is highly ordered, as is much of the double beta barrel core. Some of the surface loops, by contrast, remain very dynamic with order parameters as low as 0.5 indicating significant motions on the ps-ns timescale. Regions of the protein that were thought to be dynamic in the zymogen and to become rigid upon activation, in particular the gamma-loop, the 180s loop, and the Na(+) binding site have order parameters below 0.8. Significant R(ex) was observed in most of the gamma-loop, in regions proximal to the light chain, and in the beta-sheet core. Accelerated molecular dynamics simulations yielded a molecular ensemble consistent with measured residual dipolar couplings that revealed dynamic motions up to milliseconds. Several regions, including the light chain and two proximal loops, did not appear highly dynamic on the ps-ns timescale, but had significant motions on slower timescales. PMID- 22828335 TI - Predicting the effect of ions on the conformation of the H-NS dimerization domain. AB - The histone-like nucleoid structuring protein (H-NS) is a DNA-organizing protein in bacteria. It contains a DNA-binding domain and a dimerization domain, connected by a flexible linker region. Dimerization occurs through the formation of a helical bundle, including a coiled-coil interaction motif. Two conformations have been resolved, for different sequences of Escherichia coli H-NS, resulting in an antiparallel coiled-coil for the shorter wild-type sequence, and a parallel coiled-coil for the longer C21S mutant. Because H-NS functions as a thermo- and osmosensor, these conformations may both be functionally relevant. Molecular simulation can complement experiments by modeling the dynamical time evolution of biomolecular systems in atomistic detail. We performed a molecular-dynamics study of the H-NS dimerization domain, showing that the parallel complex is sensitive to changes in salt conditions: it is unstable in absence of NaCl, but stable at physiological salt concentrations. In contrast, the stability of the antiparallel complex is not salt-dependent. The stability of the parallel complex also appears to be affected by mutation of the critical but nonconserved cysteine residue at position 21, whereas the antiparallel complex is not. Together, our simulations suggest that osmoregulation could be mediated by changes in the ratio of parallel and antiparallel-oriented H-NS dimers. PMID- 22828336 TI - Folding a protein with equal probability of being helix or hairpin. AB - We explore the possibility for the native structure of a protein being inherently multiconformational in an ab initio coarse-grained model. Based on the Wang Landau algorithm, the complete free energy landscape for the designed sequence 2DX4: INYWLAHAKAGYIVHWTA is constructed. It is shown that 2DX4 possesses two nearly degenerate native structures: one is a helix structure with the other a hairpinlike structure, and their free energy difference is <2% of that of local minima. Two degenerate native structures are stabilized by an energy barrier of ~10 kcal/mol. Furthermore, the hydrogen-bond and dipole-dipole interactions are found to be two major competing interactions in transforming one conformation into the other. Our results indicate that two degenerate native structures are stabilized by subtle balance between different interactions in proteins. In particular, for small proteins, balance between the hydrogen-bond and dipole dipole interactions happens for proteins of sizes being ~18 amino acids and is shown to the main driving mechanism for the occurrence of degeneracy. These results provide important clues to the study of native structures of proteins. PMID- 22828337 TI - Electron paramagnetic resonance characterization of tetrahydrobiopterin radical formation in bacterial nitric oxide synthase compared to mammalian nitric oxide synthase. AB - H(4)B is an essential catalytic cofactor of the mNOSs. It acts as an electron donor and activates the ferrous heme-oxygen complex intermediate during Arg oxidation (first step) and NOHA oxidation (second step) leading to nitric oxide and citrulline as final products. However, its role as a proton donor is still debated. Furthermore, its exact involvement has never been explored for other NOSs such as NOS-like proteins from bacteria. This article proposes a comparative study of the role of H(4)B between iNOS and bsNOS. In this work, we have used freeze-quench to stop the arginine and NOHA oxidation reactions and trap reaction intermediates. We have characterized these intermediates using multifrequency electron paramagnetic resonance. For the first time, to our knowledge, we report a radical formation for a nonmammalian NOS. The results indicate that bsNOS, like iNOS, has the capacity to generate a pterin radical during Arg oxidation. Our current electron paramagnetic resonance data suggest that this radical is protonated indicating that H(4)B may not transfer any proton. In the 2nd step, the radical trapped for iNOS is also suggested to be protonated as in the 1st step, whereas it was not possible to trap a radical for the bsNOS 2nd step. Our data highlight potential differences for the catalytic mechanism of NOHA oxidation between mammalian and bacterial NOSs. PMID- 22828338 TI - Competition between supercoils and toroids in single molecule DNA condensation. AB - The condensation of free DNA into toroidal structures in the presence of multivalent ions and polypeptides is well known. Recent single molecule experiments have shown that condensation into toroids occurs even when the DNA molecule is subjected to tensile forces. Here we show that the combined tension and torsion of DNA in the presence of condensing agents dramatically modifies this picture by introducing supercoiled DNA as a competing structure in addition to toroids. We combine a fluctuating elastic rod model of DNA with phenomenological models for DNA interaction in the presence of condensing agents to compute the minimum energy configuration for given tension and end-rotations. We show that for each tension there is a critical number of end-rotations above which the supercoiled solution is preferred and below which toroids are the preferred state. Our results closely match recent extension rotation experiments on DNA in the presence of spermine and other condensing agents. Motivated by this, we construct a phase diagram for the preferred DNA states as a function of tension and applied end-rotations and identify a region where new experiments or simulations are needed to determine the preferred state. PMID- 22828339 TI - Dynamical coupling of intrinsically disordered proteins and their hydration water: comparison with folded soluble and membrane proteins. AB - Hydration water is vital for various macromolecular biological activities, such as specific ligand recognition, enzyme activity, response to receptor binding, and energy transduction. Without hydration water, proteins would not fold correctly and would lack the conformational flexibility that animates their three dimensional structures. Motions in globular, soluble proteins are thought to be governed to a certain extent by hydration-water dynamics, yet it is not known whether this relationship holds true for other protein classes in general and whether, in turn, the structural nature of a protein also influences water motions. Here, we provide insight into the coupling between hydration-water dynamics and atomic motions in intrinsically disordered proteins (IDP), a largely unexplored class of proteins that, in contrast to folded proteins, lack a well defined three-dimensional structure. We investigated the human IDP tau, which is involved in the pathogenic processes accompanying Alzheimer disease. Combining neutron scattering and protein perdeuteration, we found similar atomic mean square displacements over a large temperature range for the tau protein and its hydration water, indicating intimate coupling between them. This is in contrast to the behavior of folded proteins of similar molecular weight, such as the globular, soluble maltose-binding protein and the membrane protein bacteriorhodopsin, which display moderate to weak coupling, respectively. The extracted mean square displacements also reveal a greater motional flexibility of IDP compared with globular, folded proteins and more restricted water motions on the IDP surface. The results provide evidence that protein and hydration-water motions mutually affect and shape each other, and that there is a gradient of coupling across different protein classes that may play a functional role in macromolecular activity in a cellular context. PMID- 22828340 TI - Effect of viscoelasticity on the analysis of single-molecule force spectroscopy on live cells. AB - Single-molecule force spectroscopy is used to probe the kinetics of receptor ligand bonds by applying mechanical forces to an intermediate media on which the molecules reside. When this intermediate media is a live cell, the viscoelastic properties can affect the calculation of rate constants. We theoretically investigate the effect of media viscoelasticity on the common assumption that the bond force is equal to the instantaneous applied force. Dynamic force spectroscopy is simulated between two cells of varying micromechanical properties adhered by a single bond with a constant kinetic off-rate. We show that cell and microvilli deformation, and hydrodynamic drag contribute to bond forces that can be 28-90% lower than the applied force for loading rates of 10(3)-10(7) pN/s, resulting in longer bond lifetimes. These longer bond lifetimes are not caused by changes in bond kinetics; rather, they are due to the mechanical response of the intermediate media on which the bonds reside. Under the assumption that the instantaneous bond force is equal to the applied force--thereby ignoring viscoelasticity--leads to 14-39% error in the determination of off-rates. We present an approach that incorporates viscoelastic properties in calculating the instantaneous bond force and kinetic dissociation parameter of the intermolecular bond. PMID- 22828341 TI - Flow directs surface-attached bacteria to twitch upstream. AB - Bacteria inhabit a wide variety of environments in which fluid flow is present, including healthcare and food processing settings and the vasculature of animals and plants. The motility of bacteria on surfaces in the presence of flow has not been well characterized. Here we focus on Pseudomonas aeruginosa, an opportunistic human pathogen that thrives in flow conditions such as in catheters and respiratory tracts. We investigate the effects of flow on P. aeruginosa cells and describe a mechanism in which surface shear stress orients surface-attached P. aeruginosa cells along the flow direction, causing cells to migrate against the flow direction while pivoting in a zig-zag motion. This upstream movement is due to the retraction of type IV pili by the ATPase motors PilT and PilU and results from the effects of flow on the polar localization of type IV pili. This directed upstream motility could be beneficial in environments where flow is present, allowing bacteria to colonize environments that cannot be reached by other surface-attached bacteria. PMID- 22828343 TI - Electron microscopy of biological specimens in liquid water. PMID- 22828342 TI - Mapping of mechanical strains and stresses around quiescent engineered three dimensional epithelial tissues. AB - Understanding how physical signals guide biological processes requires qualitative and quantitative knowledge of the mechanical forces generated and sensed by cells in a physiologically realistic three-dimensional (3D) context. Here, we used computational modeling and engineered epithelial tissues of precise geometry to define the experimental parameters that are required to measure directly the mechanical stress profile of 3D tissues embedded within native type I collagen. We found that to calculate the stresses accurately in these settings, we had to account for mechanical heterogeneities within the matrix, which we visualized and quantified using confocal reflectance and atomic force microscopy. Using this technique, we were able to obtain traction forces at the epithelium matrix interface, and to resolve and quantify patterns of mechanical stress throughout the surrounding matrix. We discovered that whereas single cells generate tension by contracting and pulling on the matrix, the contraction of multicellular tissues can also push against the matrix, causing emergent compression. Furthermore, tissue geometry defines the spatial distribution of mechanical stress across the epithelium, which communicates mechanically over distances spanning hundreds of micrometers. Spatially resolved mechanical maps can provide insight into the types and magnitudes of physical parameters that are sensed and interpreted by multicellular tissues during normal and pathological processes. PMID- 22828348 TI - LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis. AB - Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of the leucine transporter, a model for neurotransmitter MATs. By varying the presence of binding-pocket leucine substrate and sodium ions, we have sampled plausible conformational states representative of the substrate transport cycle. The resulting trajectories were analyzed using principal component analysis of transmembrane helices 1b and 6a. This analysis revealed seven unique structures: two of the obtained conformations are similar to the currently published crystallographic structures, one conformation is similar to a proposed open inward structure, and four conformations represent novel structures of potential importance to the transport cycle. Further analysis reveals that the presence of binding-pocket sodium ions is necessary to stabilize the locked-occluded and open-inward conformations. PMID- 22828349 TI - Hydration dynamics of hyaluronan and dextran. AB - Hyaluronan is a polysaccharide, which is ubiquitous in vertebrates and has been reported to be strongly hydrated in a biological environment. We study the hydration of hyaluronan in solution using the rotational dynamics of water as a probe. We measure these dynamics with polarization-resolved femtosecond-infrared and terahertz time-domain spectroscopies. Both experiments reveal that a subensemble of water molecules is slowed down in aqueous solutions of hyaluronan amounting to ~15 water molecules per disaccharide unit. This quantity is consistent with what would be expected for the first hydration shell. Comparison of these results to the water dynamics in aqueous dextran solution, a structurally similar polysaccharide, yields remarkably similar results. This suggests that the observed interaction with water is a common feature for hydrophilic polysaccharides and is not specific to hyaluronan. PMID- 22828350 TI - Myofilament length-dependent activation develops within 5 ms in guinea-pig myocardium. AB - Myofilament length-dependent activation is a universal property of striated muscle, yet the molecular mechanisms that underlie this phenomenon are incompletely understood. Additionally, the rate by which sarcomere length (SL) is sensed and then transduced to form length-dependent activation is unknown. Here, using isolated guinea-pig myocardium, we employed a rapid solution-switch single myofibril technique that allows for the study of contractile action/relaxation dynamics in the virtual absence of diffusion delays. We compared contraction kinetics obtained at submaximal activation at steady-state SL with contractions observed after rapid SL ramps to that same SL just before activation. Neither the activation and relaxation kinetics nor the final submaximal force development differed significantly between the two contraction modes for SL ramps as fast as 5 ms. We conclude that the transduction of the length signal by the cardiac sarcomere to modulate thin filament activation levels occurs virtually instantaneously, possibly resulting from structural rearrangements of the contractile proteins. PMID- 22828351 TI - The highly processive kinesin-8, Kip3, switches microtubule protofilaments with a bias toward the left. AB - Kinesin-1 motor proteins walk parallel to the protofilament axes of microtubules as they step from one tubulin dimer to the next. Is protofilament tracking an inherent property of processive kinesin motors, like kinesin-1, and what are the structural determinants underlying protofilament tracking? To address these questions, we investigated the tracking properties of the processive kinesin-8, Kip3. Using in vitro gliding motility assays, we found that Kip3 rotates microtubules counterclockwise around their longitudinal axes with periodicities of ~1 MUm. These rotations indicate that the motors switch protofilaments with a bias toward the left. Molecular modeling suggests 1), that the protofilament switching may be due to kinesin-8 having a longer neck linker than kinesin-1, and 2), that the leftward bias is due the asymmetric geometry of the motor neck linker complex. PMID- 22828352 TI - NADH distribution in live progenitor stem cells by phasor-fluorescence lifetime image microscopy. AB - NADH is a naturally fluorescent metabolite associated with cellular respiration. Exploiting the different fluorescence lifetime of free and bound NADH has the potential to quantify the relative amount of bound and free NADH, enhancing understanding of cellular processes including apoptosis, cancer pathology, and enzyme kinetics. We use the phasor-fluorescence lifetime image microscopy approach to spatially map NADH in both the free and bound forms of live undifferentiated and differentiated myoblast cells. The phasor approach graphically depicts the change in lifetime at a pixel level without the requirement for fitting the decay. Comparison of the spatial distribution of NADH in the nucleus of cells induced to differentiate through serum starvation and undifferentiated cells show differing distributions of bound and free NADH. Undifferentiated cells displayed a short lifetime indicative of free NADH in the nucleus and a longer lifetime attributed to the presence of bound NADH outside of the nucleus. Differentiating cells displayed redistribution of free NADH with decreased relative concentration of free NADH within the nucleus whereas the majority of NADH was found in the cytoplasm. PMID- 22828353 TI - Socio-economic inequality of immunization coverage in India. AB - To our knowledge, the present study provides a first time assessment of the contributions of socioeconomic determinants of immunization coverage in India using the recent National Family Health Survey data. Measurement of socioeconomic inequalities in health and health care, and understanding the determinants of such inequalities in terms of their contributions, are critical for health intervention strategies and for achieving equity in health care. A decomposition approach is applied to quantify the contributions from socio-demographic factors to inequality in immunization coverage. The results reveal that poor household economic status, mother's illiteracy, per capita state domestic product and proportion of illiterate at the state level is systematically related to 97% of predictable socioeconomic inequalities in full immunization coverage at the national level. These patterns of evidence suggest the need for immunization strategies targeted at different states and towards certain socioeconomic determinants as pointed out above in order to reduce socioeconomic inequalities in immunization coverage.JEL Classification: I10, I12. PMID- 22828355 TI - Using bibliometrics to advance your academic career. PMID- 22828356 TI - Excessive chest compression rate is associated with insufficient compression depth in prehospital cardiac arrest. AB - BACKGROUND AND GOAL OF STUDY: The relationship between chest compression rate and compression depth is unknown. In order to characterise this relationship, we performed an observational study in prehospital cardiac arrest patients. We hypothesised that faster compressions are associated with decreased depth. MATERIALS AND METHODS: In patients undergoing prehospital cardiopulmonary resuscitation by health care professionals, chest compression rate and depth were recorded using an accelerometer (E-series monitor-defibrillator, Zoll, U.S.A.). Compression depth was compared for rates <80/min, 80-120/min and >120/min. A difference in compression depth >=0.5 cm was considered clinically significant. Mixed models with repeated measurements of chest compression depth and rate (level 1) nested within patients (level 2) were used with compression rate as a continuous and as a categorical predictor of depth. Results are reported as means and standard error (SE). RESULTS AND DISCUSSION: One hundred and thirty-three consecutive patients were analysed (213,409 compressions). Of all compressions 2% were <80/min, 62% between 80 and 120/min and 36% >120/min, 36% were <4 cm deep, 45% between 4 and 5 cm, 19% >5 cm. In 77 out of 133 (58%) patients a statistically significant lower depth was observed for rates >120/min compared to rates 80-120/min, in 40 out of 133 (30%) this difference was also clinically significant. The mixed models predicted that the deepest compression (4.5 cm) occurred at a rate of 86/min, with progressively lower compression depths at higher rates. Rates >145/min would result in a depth <4 cm. Predicted compression depth for rates 80-120/min was on average 4.5 cm (SE 0.06) compared to 4.1 cm (SE 0.06) for compressions >120/min (mean difference 0.4 cm, P<0.001). Age and sex of the patient had no additional effect on depth. CONCLUSIONS: This study showed an association between higher compression rates and lower compression depths. Avoiding excessive compression rates may lead to more compressions of sufficient depth. PMID- 22828357 TI - Transthoracic impedance for the monitoring of quality of manual chest compression during cardiopulmonary resuscitation. AB - OBJECTIVE: The quality of cardiopulmonary resuscitation (CPR), especially adequate compression depth, is associated with return of spontaneous circulation (ROSC) and is therefore recommended to be measured routinely. In the current study, we investigated the relationship between changes of transthoracic impedance (TTI) measured through the defibrillation electrodes, chest compression depth and coronary perfusion pressure (CPP) in a porcine model of cardiac arrest. METHODS: In 14 male pigs weighing between 28 and 34 kg, ventricular fibrillation (VF) was electrically induced and untreated for 6 min. Animals were randomized to either optimal or suboptimal chest compression group. Optimal depth of manual compression in 7 pigs was defined as a decrease of 25% (50 mm) in anterior posterior diameter of the chest, while suboptimal compression was defined as 70% of the optimal depth (35 mm). After 2 min of chest compression, defibrillation was attempted with a 120-J rectilinear biphasic shock. RESULTS: There were no differences in baseline measurements between groups. All animals had ROSC after optimal compressions; this contrasted with suboptimal compressions, after which only 2 of the animals had ROSC (100% vs. 28.57%, p=0.021). The correlation coefficient was 0.89 between TTI amplitude and compression depth (p<0.001), 0.83 between TTI amplitude and CPP (p<0.001). CONCLUSION: Amplitude change of TTI was correlated with compression depth and CPP in this porcine model of cardiac arrest. The TTI measured from defibrillator electrodes, therefore has the potential to serve as an indicator to monitor the quality of chest compression and estimate CPP during CPR. PMID- 22828358 TI - Efficiency of primary care in rural Burkina Faso. A two-stage DEA analysis. AB - BACKGROUND: Providing health care services in Africa is hampered by severe scarcity of personnel, medical supplies and financial funds. Consequently, managers of health care institutions are called to measure and improve the efficiency of their facilities in order to provide the best possible services with their resources. However, very little is known about the efficiency of health care facilities in Africa and instruments of performance measurement are hardly applied in this context. OBJECTIVE: This study determines the relative efficiency of primary care facilities in Nouna, a rural health district in Burkina Faso. Furthermore, it analyses the factors influencing the efficiency of these institutions. METHODOLOGY: We apply a two-stage Data Envelopment Analysis (DEA) based on data from a comprehensive provider and household information system. In the first stage, the relative efficiency of each institution is calculated by a traditional DEA model. In the second stage, we identify the reasons for being inefficient by regression technique. RESULTS: The DEA projections suggest that inefficiency is mainly a result of poor utilization of health care facilities as they were either too big or the demand was too low. Regression results showed that distance is an important factor influencing the efficiency of a health care institution CONCLUSIONS: Compared to the findings of existing one-stage DEA analyses of health facilities in Africa, the share of relatively efficient units is slightly higher. The difference might be explained by a rather homogenous structure of the primary care facilities in the Burkina Faso sample. The study also indicates that improving the accessibility of primary care facilities will have a major impact on the efficiency of these institutions. Thus, health decision-makers are called to overcome the demand-side barriers in accessing health care. PMID- 22828359 TI - Evaluation of living liver donors using contrast enhanced multidetector CT - The radiologists impact on donor selection. AB - BACKGROUND: Living donor liver transplantation (LDLT) is a valuable and legitimate treatment for patients with end-stage liver disease. Computed tomography (CT) has proven to be an important tool in the process of donor evaluation. The purpose of this study was to evaluate the significance of CT in the donor selection process. METHODS: Between May 1999 and October 2010 170 candidate donors underwent biphasic CT. We retrospectively reviewed the results of the CT and liver volumetry, and assessed reasons for rejection. RESULTS: 89 candidates underwent partial liver resection (52.4%). Based on the results of liver CT and volumetry 22 candidates were excluded as donors (31% of the cases). Reasons included fatty liver (n = 9), vascular anatomical variants (n = 4), incidental finding of hemangioma and focal nodular hyperplasia (n = 1) and small (n = 5) or large for size (n = 5) graft volume. CONCLUSION: CT based imaging of the liver in combination with dedicated software plays a key role in the process of evaluation of candidates for LDLT. It may account for up to 1/3 of the contraindications for LDLT. PMID- 22828367 TI - Expression profile analysis of mycotoxin-related genes in cartilage with endemic osteochondropathy Kashin-Beck Disease. AB - BACKGROUND: Kashin-Beck Disease (KBD) is an endemic osteochondropathy. Mycotoxins are believed to play an important role in the pathogenesis of KBD. Because the molecular mechanism of mycotoxin-induced cartilage lesions remains unclear, there is not effective treatment for KBD now. To identify key genes involved in the mycotoxin-induced cartilage lesions, we compared the expression profiles of mycotoxin-related genes (MRG) between KBD cartilage and healthy cartilage. METHODS: Total RNA was isolated from cartilage samples, following by being amplified, labeled and hybridized to Agilent human whole genome microarray chip. qRT-PCR was conducted to validate the microarray data. 1,167 MRG were derived from the environmentally related genomic database Toxicogenomics. The microarray data of MRG was subjected to single gene and gene ontology (GO) expression analysis for identifying differently expressed genes and GO. RESULTS: We identified 7 up-regulated MRG and 2 down-regulated MRG in KBD cartilage, involved in collagen, apoptosis, metabolism and growth & development. GO expression analysis found that 4 apoptosis-related GO and 5 growth & development-related GO were significantly up-regulated in KBD cartilage. CONCLUSIONS: Based on the results of previous and our studies, we suggest that mycotoxins might contribute to the development of KBD through dysfunction of MRG involved in collagen, apoptosis and growth & development in cartilage. PMID- 22828370 TI - Haploidentical stem cell transplantation. AB - The feasibility of stem cell transplantation across the major histocompatibility barrier-as in haploidentical stem cell transplantation-has been proved for some time in several studies. The main limitations include a higher graft failure rate, delayed immune reconstitution after transplantation with high rates of life threatening infections, a higher incidence of post-transplant lymphoproliferative disease, and severe acute and chronic graft-versus-host disease. In an attempt to reduce the transplant-related morbidity/mortality, several techniques had been evaluated involving conditioning regimen intensity, graft engineering, post transplant cellular therapy and immunosuppression. This review will describe the current situation. It will also discuss initiatives and strategies to overcome the limitations associated with transplant across the MHC barrier. PMID- 22828371 TI - Lymphoproliferative disorders in pediatric liver allograft recipients: a review of 212 cases. AB - BACKGROUND AND OBJECTIVES: Due to the limited incidence of posttransplant lymphoproliferative disorders (PTLD) in pediatric liver graft recipients, there is a scarcity of data on the characteristics of the disease in this population. We aimed to analyze the special features and behavior of PTLD arising after pediatric liver transplantation. DESIGN: A comprehensive search of the literature was conducted for the available data on PTLD in pediatric liver recipients pediatric PTLD through a search of Pubmed and Google Scholar using appropriate terms. METHODS: We sought data on liver recipients younger than 18 years of age at the time of transplantation. From 51 reports, 43 fulfilled the inclusion criteria. Overall 250 cases of PTLD (212 pediatric PTLD) were found from 43 reports. Data on pediatric patients was compared to adults. RESULTS: Pediatric PTLD lesions were more likely of the polymorphic type (P=.004) and polyclonal (when age cut-off was defined at 12 years; P=.023). Remission rates, metastasis frequency and organ involvements were not different between the groups (P>.1 for all). Survival analysis showed no disparity between pediatric PTLD and adult patients (P>.1); but when data was reanalyzed for patients surviving at least 4 months post diagnosis, the log rank test showed that pediatric patients have a superior outcome compared to adults (P=.045). CONCLUSIONS: Pediatric liver recipients developing PTLD have relatively better disease presentation and behavior than that in adults. Stomach involvement was also more frequently seen in patients younger than 12 years, and should be more intensively evaluated. Future studies with a prospective approach and larger population size are needed for confirming our results. PMID- 22828372 TI - Intersite validations of the pixel-wise method for liver R2* analysis in transfusion-dependent thalassemia patients: a more accessible and affordable diagnostic technology. AB - BACKGROUND AND OBJECTIVES: MRI-R2* has been accepted as a clinical tool for monitoring iron overload in thalassemia patients, especially for monitoring liver iron concentration (LIC). The most optimal and practical method of analysis however, is still open to further investigations. Our objective was to investigate intra- and intersite observer variability of the pixel-wise method for liver R2* analysis in thalassemia patients using a mono-exponential with a constant offset model. PATIENTS AND METHODS: We performed 88 liver R2* measurements on 72 thalassemia major patients. A single breath-hold multi-echo gradient-echo sequence was acquired and analyzed at both the reference (REF) and local (LOC) sites. The analysis defined the region of interest in the whole liver parenchyma, excluding the great vessels, and were reported as median values. RESULTS: The R2* values from the REF and LOC were statistically comparable for all comparisons. The intrasite and intersite observer variation were 0.75% (less than 0.9%) and 2.5%, respectively, both of which are comparable to previous reports, but substantially lower than conventional region-based approaches. CONCLUSION: The low variation of the R2* also yielded excellent variation in the tabulated hepatic iron content. However, caution is required when comparing the results to different implementation methods and appropriate evaluation and validation of methodology for any new scan site is essential before its clinical use. PMID- 22828369 TI - CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy. AB - BACKGROUND: The ubiquity of protein-protein interactions in biological signaling offers ample opportunities for therapeutic intervention. We previously identified a peptide, designated CBD3, that suppressed inflammatory and neuropathic behavioral hypersensitivity in rodents by inhibiting the ability of collapsin response mediator protein 2 (CRMP-2) to bind to N-type voltage-activated calcium channels (CaV2.2) [Brittain et al. Nature Medicine 17:822-829 (2011)]. RESULTS AND DISCUSSION: Here, we utilized SPOTScan analysis to identify an optimized variation of the CBD3 peptide (CBD3A6K) that bound with greater affinity to Ca2+ channels. Molecular dynamics simulations demonstrated that the CBD3A6K peptide was more stable and less prone to the unfolding observed with the parent CBD3 peptide. This mutant peptide, conjugated to the cell penetrating motif of the HIV transduction domain protein TAT, exhibited greater anti-nociception in a rodent model of AIDS therapy-induced peripheral neuropathy when compared to the parent TAT-CBD3 peptide. Remarkably, intraperitoneal administration of TAT-CBD3A6K produced none of the minor side effects (i.e. tail kinking, body contortion) observed with the parent peptide. Interestingly, excitability of dissociated small diameter sensory neurons isolated from rats was also reduced by TAT-CBD3A6K peptide suggesting that suppression of excitability may be due to inhibition of T and R-type Ca2+ channels. TAT-CBD3A6K had no effect on depolarization-evoked calcitonin gene related peptide (CGRP) release compared to vehicle control. CONCLUSIONS: Collectively, these results establish TAT-CBD3A6K as a peptide therapeutic with greater efficacy in an AIDS therapy-induced model of peripheral neuropathy than its parent peptide, TAT-CBD3. Structural modifications of the CBD3 scaffold peptide may result in peptides with selectivity against a particular subset of voltage-gated calcium channels resulting in a multipharmacology of action on the target. PMID- 22828373 TI - Bcl-2 protein expression in mucoepidermoid carcinoma of salivary glands: a single institution experience. AB - BACKGROUND AND OBJECTIVES: Mucoepidermoid carcinoma is the most common salivary gland tumor with varying behavior among different histopathological grades. The objective of this study was to determine the expression of Bcl-2 protein in mucoepidermoid carcinoma (MEC) and to correlate with histological grades. METHODS: The records of 40 cases of MEC were collected from the histopathology department. Fresh slides were prepared and fresh diagnoses were made using the grading criteria for MEC. Immunohistochemical markers for Bcl-2 were applied and the results analyzed using the chi-square test. RESULTS: Of 40 cases, 20 were males and 20 were females. The range in age of the patients was 6 to 67 years mean (SD) was 42.6 (1.85) years. Twenty-two were low grade (55%), 11 high grade (27.5%) and 7 (17.5%) were intermediate grade MEC. Among these 40 cases, Bcl-2 expression was positive in 24 cases and negative in 16 cases. In 22 cases of low grade MEC, 19 were positive while only 3 were negative. In high-grade tumors, all 11 cases were found to have a negative expression of Bcl-2 protein. In intermediate-grade MEC, 5 cases showed positive expression while only 2 cases showed negative expression. CONCLUSION: Bcl-2 protein expression showed positive expression in low-grade and negative expression in high-grade MEC. Intermediate grade showed more than 50% positive results for Bcl-2. Correlation between grades of MEC and expression of Bcl-2 is statistically significant and can be used for the depicting the prognosis of MEC along with other prognostic and clinico pathological parameters. PMID- 22828374 TI - Clinicopathologic features and prognosis of triple-negative breast cancer in patients 40 years of age and younger in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Triple-negative breast cancer (TNBC) has a poor prognosis and overall survival (OS) compared to other types of breast cancer tumors. However, there is to date no evidence that this is also the case in Saudi Arabia. DESIGN AND SETTING: Retrospective review of breast cancer patients who were treated from January 2001 to December 2008 (517 patients) at the King AbdulAziz Medical City, Riyadh, Saudi Arabia. PATIENTS AND METHODS: Patients were selected as TNBC if all three markers of estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor (HER2) tested by immunohistochemistry as negative. They were then age- and stage-matched, and compared with non-TNBC patients to examine differences, if any, in their clinicopathologic features, prognosis and OS. RESULTS: Twenty-six patients with a follow up time of at least three years were identified as TNBC. Thirty-three patients who were age- and stage-matched were selected as the non-TNBC controls. Clinicopathologic results illustrated significantly more grade 3 tumors (P=.02) and CK 5/6 expression (P<.001) in the TNBC group compared to the non-TNBC group. TNBC patients aged <=40 years showed a significantly worse prognosis and OS compared to TNBC patients aged >40 years (P=.01), and when compared to the non TNBC group (P=.04). CONCLUSION: The incidence of TNBC in our cohort is similar to what has been illustrated in previous studies in Western population. There was no significant difference in 3-year survival between TNBC and non-TNBC groups. However, the aggressiveness of this type of tumor and OS is significantly higher in younger patients aged <=40 years, compared to those over 40 years of age. PMID- 22828376 TI - Myeloid sarcoma of the vulva post-bone marrow transplant presenting as isolated extramedullary relapse in a patient with acute myeloid leukemia. AB - Myeloid sarcoma is a tumor of myoblasts or immature myeloid cells occurring in an extramedullary site. Myeloid sarcoma of the female genital tract as an isolated initial presentation or isolated relapse is very rare as evidenced from a literature review. We report a case of vulvar myeloid sarcoma presenting as isolated relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplant (HSCT). A 41-year-old female diagnosed with AML M5 achieved remission with chemotherapy and underwent allogeneic HSCT from an HLA-matched sibling donor. The post-transplant period was complicated with chronic graft versus-host disease. At 10 months post-transplant, she presented with a vulvar mass of six weeks duration. Excisional biopsy of the vulvar mass confirmed the diagnosis of myeloid sarcoma as extramedullary relapse. Bone marrow biopsy was without evidence of leukemia. Involvement of the vulva, vaginal and adjacent cervical area only was confirmed. She received re-induction chemotherapy with clinical regression of both the vulvar, vaginal and the cervical masses; this was followed by radiation therapy to an extramedullary site. The correct diagnosis of myeloid sarcoma, particularly of an isolated mass in the genital area, is important because of its rarity and the need for appropriate institution of therapy. PMID- 22828375 TI - High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review. AB - BACKGROUND AND OBJECTIVES: In recent years, there has been an increasing role for stem cell transplantation in the management of retinoblastoma. The aim of this study was to systematically review the role high-dose chemotherapy followed by stem cell transplantation in the treatment of patients with metastatic or relapsed, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. DESIGN: Systematic literature review. METHODS: We performed an extensive PubMed database search on 25 February 2012 for studies describing the use of high-dose chemotherapy followed by stem cell transplantation in the management of patients with retinoblastoma. RESULTS: We located 15 studies that met the inclusion criteria and that included 101 patients. Following treatment for metastatic and relapsed disease, 44 of 77 patients (57.1%) were alive with no evidence of disease at the time of follow-up. However, a higher rate of local relapse developed in patients with CNS metastases (73.1%), which dropped to 47.1% in patients who received thiotepa. In patients with trilateral or bilateral advanced retinoblastoma, 5 of 7 (71.4%) with reported outcome data were alive with no evidence of disease at the time of follow-up. In patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension, 6 of 7 patients (85.7%) were alive with no evidence of disease at the time of follow-up. CONCLUSIONS: Durable tumor control is possible in patients with non-CNS metastases, trilateral or bilateral advanced retinoblastoma, and in patients with tumor at the surgical margin of the optic nerve and/or extrascleral extension. Patients with CNS metastases require thiotepa to improve tumor control. PMID- 22828377 TI - Post-dengue fever severe aplastic anemia: a rare association. AB - Dengue fever has rarely been reported as an etiology for aplastic anemia. An 8 year-old girl was admitted with fever, myalgia and petechiae. Dengue virus IgM antibodies were positive. She recovered completely, but her thrombocytopenia persisted. Six weeks later she became pancytopenic. A bone marrow aspirate and biopsy showed severe aplastic anemia. She was treated with antithymocytic immunoglobulin, methylprednisolone and cyclosporine. She became transfusion independent 6 months later. Dengue-virus induced aplastic anemia is a rare entity, but it must be identified early for better outcome. Immunosuppressive therapy can induce remission. PMID- 22828378 TI - Favorable outcome in a patient with vulvar mucormycosis during acute myeloid leukemia induction with medical management alone. PMID- 22828379 TI - Sponge eating: an unusual cause of severe anemia. PMID- 22828380 TI - Biomimetic poly(lactide) based fibrous scaffolds for ligament tissue engineering. AB - The aim of this study was to fabricate a fibrous scaffold that closely resembled the micro-structural architecture and mechanical properties of collagen fibres found in the anterior cruciate ligament (ACL). To achieve this aim, fibrous scaffolds were made by electrospinning L-lactide based polymers. L-Lactide was chosen primarily due to its demonstrated biocompatibility, biodegradability and high modulus. The electrospun fibres were collected in tension on a rotating wire mandrel. Upon treating these fibres in a heated aqueous environment, they possessed a crimp-like pattern having a wavelength and amplitude similar to that of native ACL collagen. Of the polymer fibre scaffolds studied, those made from poly(L-lactide-co-D,L-lactide) PLDLA exhibited the highest modulus and were also the most resilient to in vitro hydrolytic degradation, undergoing a slight decrease in modulus compared to the other polymeric fibres over a 6 month period. Bovine fibroblasts seeded on the wavy, crimp-like PLDLA fibres attached, proliferated and deposited extracellular matrix (ECM) molecules on the surface of the fibrous scaffold. In addition, the deposited ECM exhibited bundle formation that resembled the fascicles found in native ACL. These findings demonstrate the importance of replicating the geometric microenvironment in developing effective tissue engineering scaffolds. PMID- 22828382 TI - High-rate denitrification using polyethylene glycol gel carriers entrapping heterotrophic denitrifying bacteria. AB - This study evaluated the nitrogen removal performance of polyethylene glycol (PEG) gel carriers containing entrapped heterotrophic denitrifying bacteria. A laboratory-scale denitrification reactor was operated for treatment of synthetic nitrate wastewater. The nitrogen removal activity gradually increased in continuous feed experiments, reaching 4.4 kg N m(-3) d(-1) on day 16 (30 degrees C). A maximum nitrogen removal rate of 5.1 kg N m(-3) d(-1) was observed. A high nitrogen removal efficiency of 92% on average was observed at a high loading rate. In batch experiments, the denitrifying gel carriers were characterized by temperature. Nitrate and total nitrogen removal activities both increased with increasing temperature, reaching a maximum at 37 and 43 degrees C, respectively. Apparent activation energies for nitrate and nitrite reduction were 52.1 and 71.9 kJ mol(-1), respectively. Clone library analysis performed on the basis of the 16S rRNA gene revealed that Hyphomicrobium was mainly involved in denitrification in the methanol-fed denitrification reactors. PMID- 22828381 TI - Microstructural and mechanical differences between digested collagen-fibrin co gels and pure collagen and fibrin gels. AB - Collagen and fibrin are important extracellular matrix (ECM) components in the body, providing structural integrity to various tissues. These biopolymers are also common scaffolds used in tissue engineering. This study investigated how co gelation of collagen and fibrin affected the properties of each individual protein network. Collagen-fibrin co-gels were cast and subsequently digested using either plasmin or collagenase; the microstructure and mechanical behavior of the resulting networks were then compared with the respective pure collagen or fibrin gels of the same protein concentration. The morphologies of the collagen networks were further analyzed via three-dimensional network reconstruction from confocal image z-stacks. Both collagen and fibrin exhibited a decrease in mean fiber diameter when formed in co-gels compared with the pure gels. This microstructural change was accompanied by an increased failure strain and decreased tangent modulus for both collagen and fibrin following selective digestion of the co-gels. In addition, analysis of the reconstructed collagen networks indicated the presence of very long fibers and the clustering of fibrils, resulting in very high connectivities for collagen networks formed in co gels. PMID- 22828383 TI - Effect of plant species on water quality at the outlet of a sludge treatment wetland. AB - Sludge treatment wetlands are mainly used to reduce the volume of activated sludge, and the pollutants at the outlet are generally returned to the wastewater treatment plant. However, in cases where sludges are produced far from treatment plants not only must the sludge be treated, but the discharge of pollutants into the surrounding environment must also be limited. The aim of this study was to evaluate the efficiency of different plant species in optimising pollutant removal in a decentralised sludge treatment wetland. In addition, a new system design was assessed, in which the wetland was not completely drained, and a saturated layer was created using an overflow. The experimental setup consisted of 16 mesocosms in total, planted with monocultures of Phragmites australis, Typha angustifolia and Scirpus fluviatilis, and unplanted controls, each in four replicates. The experiment was conducted during the third summer of operation after setup. The system was fed with highly concentrated fish farm sludge at a load of 30 kg of total solids m(-2) yr(-1). Results showed that such wetlands were highly efficient, with removal rates between 94% and 99% for most pollutants. Planted systems generally outperformed the unplanted control, with a significantly lower mass of pollutants at the outlet of the sludge treatment wetland planted with Phragmites, followed by those with Typha and then Scirpus. The distinct influence of plant species on pollution removal was explained by the sequestration of nitrogen and phosphorus in plant tissues and by the rhizosphere effect, which enhance the biodegradation of organic matter, allowed the nitrification process and created redox conditions favourable to the sorption of phosphorus. Filtration and evapotranspiration rates played a major role in limiting the discharge of pollutants, and the impact was enhanced by the fact that the sludge treatment wetland was not completely drained. PMID- 22828384 TI - An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect. AB - Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability. PMID- 22828385 TI - A survey of standardised drug syringe label use in European anaesthesiology departments. AB - CONTEXT: Standardised drug syringe labelling may reduce drug errors, but data on drug syringe labelling use in European anaesthesiology departments are lacking. OBJECTIVES: Survey investigating if standardised drug syringe labelling is used, and if there are geographical, demographic and professional differences in hospitals with and without use of drug syringe labelling. DESIGN: Structured, web based anonymised questionnaire. SETTING: European anaesthesia departments. PARTICIPANTS: Members of the European Society of Anaesthesiology. INTERVENTION: Online survey from 2 February to 12 April 2011. MAIN OUTCOME MEASURE: Standardised drug syringe labelling use and, if yes, drug syringe labelling for insulin and norepinephrine. METHODS: Descriptive and comparative analyses of users and nonusers of standardised drug syringe labelling. RESULTS: One thousand and sixty-four of 4163 members (25.6%) from 72 countries participated, among whom 660 (62.0%) used standardised drug syringe labelling; in Northern and Western Europe, there were 428 users of drug syringe labelling and 112 nonusers, and in Southern and Eastern Europe, there were 184 users and 255 nonusers (P < 0.001). Three hundred and ninety-four (37%) respondents used standardised drug syringe labelling hospital-wide; 202 (30.1%) used International Organisation of Standardisation-based standardised drug syringe labelling, 101 (15.1%) used similar systems, 278 (41.5%) used other systems and 89 (13.3%) used labels supplied by drug manufacturers. The label colour for insulin was reported as white or 'none' in 519 (76.7%) answers and another colour in 158 (23.3%). The label colour for norepinephrine was reported as violet in 206 (30.4%) answers, white or 'none' in 226 (33.3%), red in 114 (16.8%) and another colour in 132 (19.5%). A standardised drug syringe labelling system supplied by the pharmaceutical industry was supported by 819 (76.9%) respondents, and not supported by 227 (21.3%). CONCLUSION: A majority of European anaesthesiology departments used standardised drug syringe labelling, with regional differences and mostly without following an international standard. Thus, there are options for quality improvement in drug syringe labelling. PMID- 22828386 TI - Clinical, methodological and theoretical issues in the assessment of cognition after anaesthesia and surgery: a review. AB - As people live longer, the burden of cognitive impairment to elderly patients, their families and society becomes increasingly common and important. The loss of independence, a reduction in the quality of life and increased mortality are possible correlates to the mental disintegration. Cognitive dysfunction following major surgery on the elderly is a significant problem which adds to other cognitive impairments caused by neurodegeneration, cerebrovascular impairments and other causes. There are challenges in reviewing the literature because of many methodological concerns. There is no standard definition; the diagnosis is made only by the results of neuropsychological tests which are not standardised for this purpose; test results are analysed by different statistical methods (some of them inappropriate); controls are often absent or poorly matched; and pre-existing mild cognitive impairment, which affects 10 to 20% of people older than 65 years and is similar to the subtle cognitive impairment following surgery, is not sought for and recognised. Reviews of the subject have varied from descriptions such as 'a well recognised and significant problem' to 'a hypothetical phenomenon for which there is no International Statistical Classification of Disease (ICD-9) code, and no Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) code'. This article examines both sides of the spectrum in a detailed review which explains the necessary psychological 'jargon', discusses the methods used and points to areas of future research. PMID- 22828388 TI - Intrinsically superparamagnetic Fe-hydroxyapatite nanoparticles positively influence osteoblast-like cell behaviour. AB - BACKGROUND: Superparamagnetic nanoparticles (MNPs) have been progressively explored for their potential in biomedical applications and in particular as a contrast agent for diagnostic imaging, for magnetic drug delivery and more recently for tissue engineering applications. Considering the importance of having safe MNPs for such applications, and the essential role of iron in bone remodelling, this study developed and analysed novel biocompatible and bioreabsorbable superparamagnetic nanoparticles, that avoid the use of poorly tolerated magnetite based nanoparticles, for bone tissue engineering applications. RESULTS: MNPs were obtained by doping hydroxyapatite (HA) with Fe ions, by directly substituting Fe2+ and Fe3+ into the HA structure yielding superparamagnetic bioactive phase. In the current study, we have investigated the effects of increasing concentrations (2000 MUg/ml; 1000 MUg/ml; 500 MUg/ml; 200 MUg/ml) of FeHA MNPs in vitro using Saos-2 human osteoblast-like cells cultured for 1, 3 and 7 days with and without the exposure to a static magnetic field of 320 mT. Results demonstrated not only a comparable osteoblast viability and morphology, but increased in cell proliferation, when compared to a commercially available Ha nanoparticles, even with the highest dose used. Furthermore, FeHA MNPs exposure to the static magnetic field resulted in a significant increase in cell proliferation throughout the experimental period, and higher osteoblast activity.In vivo preliminary results demonstrated good biocompatibility of FeHA superparamagnetic material four weeks after implantation into a critical size lesion of the rabbit condyle. CONCLUSIONS: The results of the current study suggest that these novel FeHA MNPs may be particularly relevant for strategies of bone tissue regeneration and open new perspectives for the application of a static magnetic field in a clinical setting of bone replacement, either for diagnostic imaging or magnetic drug delivery. PMID- 22828389 TI - Statin cost effectiveness in primary prevention: a systematic review of the recent cost-effectiveness literature in the United States. AB - BACKGROUND: The literature on the cost-effectiveness of statin drugs in primary prevention of coronary heart disease is complex. The objective of this study is to compare the disparate results of recent cost-effectiveness analyses of statins. FINDINGS: We conducted a systematic review of the literature on statin cost-effectiveness. The four studies that met inclusion criteria reported varying conclusions about the cost-effectiveness of statin treatment, without a clear consensus as to whether statins are cost-effective for primary prevention. However, after accounting for each study's assumptions about statin costs, we found substantial agreement among the studies. Studies that assumed statins to be more expensive found them to be less cost-effective, and vice-versa. Furthermore, treatment of low-risk groups became cost-effective as statins became less expensive. CONCLUSIONS: Drug price is the primary determinant of statin cost effectiveness within a given risk group. As more statin drugs become generic, patients at low risk for coronary disease may be treated cost-effectively. Though many factors must be weighed in any medical decision, from a cost-effectiveness perspective, statins may now be considered an appropriate therapy for many patients at low risk for heart disease. PMID- 22828390 TI - Cost-effectiveness analysis of antipsychotics in reducing schizophrenia relapses. AB - BACKGROUND: Schizophrenia is a severe form of mental illness which is associated with significant and long-lasting health, social and financial burdens.The aim of this project is to assess the efficiency of the antipsychotics used in Spain in reducing schizophrenia relapses under the Spanish Health System perspective. MATERIAL AND METHODS: A decision-analytic model was developed to explore the relative cost-effectiveness of five antipsychotic medications, amisulpride, aripiprazole, olanzapine, paliperidone Extended-Release (ER) and risperidone, compared to haloperidol, over a 1-year treatment period among people living in Spain with schizophrenia. The transition probabilities for assessed therapies were obtained from the systemic review and meta-analysis performed by National Institute for Health and Clinical Excellence (NICE). RESULTS: Paliperidone ER was the option that yielded more quality-adjusted life years (QALYs) gained per patient (0.7573). In addition, paliperidone ER was the least costly strategy (?3,062), followed by risperidone (?3,194), haloperidol (?3,322), olanzapine (?3,893), amisulpride (?4,247) and aripiprazole (?4,712).In the incremental cost effectiveness (ICE) analysis of the assessed antipsychotics compared to haloperidol, paliperidone ER and risperidone were dominant options. ICE ratios for other medications were ?23,621/QALY gained, ?91,584/QALY gained and ?94,558/QALY gained for olanzapine, amisulpride and aripiprazole, respectively. Deterministic sensitivity analysis showed that risperidone is always dominant when compared to haloperidol. Paliperidone ER is also dominant apart from the exception of the scenario with a 20% decrease in the probability of relapses. CONCLUSIONS: Our findings may be of interest to clinicians and others interested in outcomes and cost of mental health services among patients with schizophrenia.Paliperidone ER and risperidone were shown to be dominant therapies compared to haloperidol in Spain. It is worthwhile to highlight that schizophrenia is a highly incapacitating disease and choosing the most appropriate drug and formulation for a particular patient is crucial.The availability of more accurate local epidemiological data on schizophrenia would allow a better adaptation of the model avoiding some of the assumptions taken in our work. Future research could be focused on this. PMID- 22828392 TI - Measuring economic consequences of preterm birth - Methodological recommendations for the evaluation of personal burden on children and their caregivers. AB - This study aims to identify the impact of a preterm birth on financial and emotional burden from the families' perspective. Additionally, a comprehensive schedule of recommendations for a sufficient evaluation of all aspects of burden is developed. Based on the results of a literature search relevant categories and sub-domains for a questionnaire covering multiple aspects of associated financial and emotional burden are identified and converted into a recommendation scheme. Results of the literature search illustrate the large extend of burden of prematurity on parents. This results in substantial out-of-pocket expenditures (OOPE) and emotional distress to the parents besides the medical problems and further financial costs to the health insurance system. According to the results on infants' state of health, OOPE and emotional distress are significantly increased with decreasing gestational age. OOPE for transportation often amounts to the main parental cost dimension. Moreover there is some evidence for a high magnitude of reduced income and missed work days. The family perspective has to be taken into account when calculating the overall costs of preterm births from a societal point of view. However, in recent years economic evaluations were performed rather inhomogeneously in this field. For future studies a) direct medical costs, b) direct non-medical costs, c) indirect costs as well as d) intangible costs (in terms of emotional distress and reduced quality of life for caregivers and children) are the main categories that should be evaluated measuring personal burden of preterm birth on families adequately. A detailed list of specific sub-domains is given. Additionally, the recommendations are not restricted to application in infants born preterm and/or at low birth weight. PMID- 22828391 TI - Parasites, proteomes and systems: has Descartes' clock run out of time? AB - Systems biology aims to integrate multiple biological data types such as genomics, transcriptomics and proteomics across different levels of structure and scale; it represents an emerging paradigm in the scientific process which challenges the reductionism that has dominated biomedical research for hundreds of years. Systems biology will nevertheless only be successful if the technologies on which it is based are able to deliver the required type and quality of data. In this review we discuss how well positioned is proteomics to deliver the data necessary to support meaningful systems modelling in parasite biology. We summarise the current state of identification proteomics in parasites, but argue that a new generation of quantitative proteomics data is now needed to underpin effective systems modelling. We discuss the challenges faced to acquire more complete knowledge of protein post-translational modifications, protein turnover and protein-protein interactions in parasites. Finally we highlight the central role of proteome-informatics in ensuring that proteomics data is readily accessible to the user-community and can be translated and integrated with other relevant data types. PMID- 22828405 TI - Intra-operative locally injected pharmacotherapy as a novel strategy for adhesion prophylaxis. AB - BACKGROUND: Pharmacotherapy for peritoneal adhesion prophylaxis has been a focus for intensive research. Previous strategies included intravenous and intraperitoneal application of suitable pharmaceutical agents. However, success of these strategies in humans has been limited. Here we describe intra-operative local injection of pharmaceuticals as a novel strategy for adhesion prophylaxis. METHODS: N=208 peritoneal lesions were created in 26 adult Wistar rats. In each animal, lesions on one flank were randomly chosen for treatment with locally injected prednisolone whereas the contralateral side was injected with normal saline. Half of the animals were randomly selected for early adhesion scoring after 3 days. Adhesions were scored after 10 days in the other animals. RESULTS: One animal randomized into the late group died peri-operatively. In the early analysis group, 27% (14/52) of treated lesions were affected by adhesions, whereas 50% (26/52) of control lesions were affected by adhesions. This difference was statistically significant (p=0.02). In the late analysis group, 52% (25/48) of treated lesions were affected by adhesions, whereas 60% (29/48) of control lesions were affected by adhesions. This difference did not reach statistical significance. CONCLUSIONS: These experiments provide proof of principle that intra-operative local injection of pharmaceutical agents is a promising strategy for adhesion prophylaxis. Once sutiable agents become available this could become as common as local anesthesia for pain reduction. However, the effect of injected prednisolone diminishes before the vulnerable time-frame for adhesion formation closes. Therefore slow-release formulations and other agents with longer effect will need to be investigated in the future. PMID- 22828404 TI - Chronic treatment with a GPR30 antagonist impairs acquisition of a spatial learning task in young female rats. AB - We hypothesize that the beneficial effects of estradiol on cognitive performance may be mediated through GPR30, a putative membrane target of estrogens. Recently we showed that administration of a selective GPR30 agonist (G-1) to ovariectomized rats enhanced acquisition of a delayed matching-to-position (DMP) T-maze task and increased potassium-stimulated acetylcholine release in the hippocampus, similar to estradiol (E2) (Hammond et al., 2009). The present study tested whether treating with a selective GPR30 antagonist (G-15) would impair spatial learning in gonadally intact rats and in ovariectomized (OVX) rats treated with E2. As predicted, G-15 dose-dependently impaired DMP acquisition both in gonadally intact rats and in OVX rats treated with E2. G-15 specifically reduced the rate of acquisition, and this effect was associated with an increased predisposition to adopt a persistent turn. In contrast, G-15 alone at the highest dose had no significant effect on DMP acquisition in OVX controls. The effects were task dependent, as similar effects of G-15 were not observed in gonadally intact rats tested on an operant discrimination/reversal learning task motivated by the same food reward. This suggests that the effects on DMP acquisition were not due to effects on motivation for food. Effects of G-15 on DMP acquisition were similar to previously published work showing significant impairment produced by selective cholinergic denervation of the hippocampus. These data suggest that GPR30 can play an important role in mediating the effects of estradiol on spatial learning, possibly by mediating estradiol effects on basal forebrain cholinergic function. PMID- 22828406 TI - Association of Surgeons in Training Conference: Cardiff 2012. AB - The Association of Surgeons in Training (ASiT) is a professional body and registered charity working to promote excellence in surgical training for the benefit of junior doctors and patients alike. With a membership of over 2000 surgical trainees from all ten surgical specialities, the association provides support at both regional and national levels throughout the United Kingdom and Republic of Ireland. Originally founded in 1976, ASiT is independent of the National Health Service (NHS), Surgical Royal Colleges, and speciality associations. The 2012 Annual Conference in Cardiff City Hall brought together nearly 700 delegates for an educational weekend programme with expert guest speakers. Clinical updates were complimented by debates on current training in surgery, and the weekend included 6 pre-conference courses covering a diverse range of topics including laparoscopic skills, surgical drawing and a masterclass in journal club. A record number of 1168 abstract submissions were received and those successful competed for 18 awards representing L3500 in trainee prizes and bursaries. As the only national surgical trainee meeting for all specialities, ASiT continues to grow and we look forward to an even larger and more successful conference next year. PMID- 22828407 TI - Selective small molecule inhibitors of p110alpha and delta isoforms of phosphoinosityl-3-kinase are cytotoxic to human acute myeloid leukemia progenitors. AB - The phosphoinosityl-3-kinase (PI3K) pathway is frequently constitutively active in blast cells from acute myeloid leukemia (AML) patients. RNA and protein from all four catalytic isoforms of PI3K (p110alpha, beta, gamma, and delta) were expressed in 38 AML samples, which also showed expression of phosphorylated Akt Ser473, indicating PI3K activation. Initial treatment of 12 AML samples with inhibitors targeting each of the four isoforms demonstrated that p110alpha and delta inhibition are more effective in killing AML blast colony-forming cells (CFC) than p110beta or gamma inhibition. In subsequent experiments, AML CFC from 46 patient samples were treated with the p110alpha and delta selective inhibitors, PI3Kalpha inhibitor 2 or PCN5603, and dose-dependent progenitor kill and inhibition of phosphorylated Akt Ser473 expression was observed. AML samples were more sensitive to PI3Kalpha inhibitor 2 and PCN5603 killing than normal bone marrow or normal peripheral blood CFC (median IC(50) for AML and normal CFCs treated with PI3Kalpha inhibitor 2, 1.8 and 4.3 MUM, respectively, and for PCN5603, 1.9 and 6.2 MUM, respectively). Furthermore, treatment of AML cells with PCN5603 also decreased survival of more primitive leukemia progenitors identified in long-term culture (AML long-term culture initiating cells), while less toxicity toward normal bone marrow long-term culture initiating cells was observed. Selective inhibition of the p110alpha and delta isoforms of PI3K kills AML progenitors while causing relative sparing of analogous normal cells. PMID- 22828408 TI - Distinct aging effects for two types of inhibition in older adults: a near infrared spectroscopy study on the Simon task and the flanker task. AB - The present study examined age-related changes in inhibitory processes among older and younger adults in the flanker and Simon tasks in terms of behavioral performance and prefrontal brain activity by functional near-infrared spectroscopy. The flanker task requires a quick identification of a central target in the presence of surrounding distracters, whereas the Simon task requires an individual to respond with left and right key presses to nonspatial features of the stimulus presented in the left and right locations. The reaction times of two age groups were longer under incongruent conditions than under congruent conditions in both tasks, indicating that the flanker effect (interference suppression) and the Simon effect (response suppression) were evident. In agreement with previous studies, the magnitude of the effect for the Simon task was greater for the older adults than for the younger adults, whereas the two groups showed equivalent flanker effects. The results suggest that older adults have difficulties in response inhibition, but not in stimulus interference suppression. Enhanced activity was found in different brain regions across the two tasks among the older adults. The older adults showed more activity in the superior and middle frontal gyri of the left hemisphere than younger adults in the flanker task; they showed more activity in the bilateral superior frontal gyri in the Simon task. These results suggest that the underlying mechanisms of the inhibition processes for the two tasks are distinct: they rely on different brain regions and have differential vulnerabilities to aging. PMID- 22828409 TI - Enduring cortical alterations after a single in-vivo treatment of HIV-1 Tat. AB - HIV-1 proteins, including the transactivator of transcription (Tat), are believed to be involved in HIV-associated neurocognitive disorders by disrupting Ca2+ homeostasis, which leads to progressive dysregulation, damage, or death of neurons in the brain. We have found previously that bath-applied Tat abnormally increased Ca2+ influx through overactivated, voltage-sensitive L-type Ca2+ channels in pyramidal neurons within the rat medial prefrontal cortex (mPFC). However, it is unknown whether the Tat-induced Ca2+ dysregulation was mediated by increased activity and/or the number of the L-channels. This study tested the hypothesis that transient/early exposure to Tat in vivo promoted enduring L channel dysregulation in the mPFC without neuron loss. Accordingly, rats were administered a single intracerebroventricular injection of recombinant Tat (80 MUg/20 MUl; diluted by cerebrospinal fluids to pathophysiological concentrations) or vehicle. Rats were killed 14 days after injection for immunohistochemical assessments of the mPFC, motor cortex, caudate-putamen, and nucleus accumbens. Stereological estimates for positively stained cells indicated a significant increase in the number of cells expressing the pore-forming Ca(v)1.2-alpha1c subunit of L-channels in the mPFC compared with other regions in Tat-treated or vehicle-treated rat brains. Optical density measurements showed a Tat-induced increase in glial fibrillary acidic protein expression, indicating astrogliosis in the cortical regions. There was no significant loss of neurons in any brain region investigated. These findings indicate that transient Tat exposure in vivo induced enduring L-channel dysregulation and astrogliosis in the mPFC without neuron loss. Such maladaptations may contribute toward dysregulated Ca2+ homeostasis and neuropathology in the PFC in the early stages of HIV infection. PMID- 22828410 TI - Poly(A)-targeting molecular beacons: fluorescence resonance energy transfer-based in vitro quantitation and time-dependent imaging in live cells. AB - Quantitation of poly(A)-RNA, time-dependent visualization of intracellular poly(A)(+)-RNA localization in living mammalian cells, and time-resolved intracellular binding dynamics of molecular beacons at the single-molecule level using a fluorescence resonance energy transfer (FRET)-based molecular beacon are described. FRET-based molecular beacons were designed as poly(A)-targeting probes to be oligonucleotides that contained Cy5 and Cy3 fluorescent dyes at the strand ends and a poly(A)-targeting sequence inside the strand. Our ratiometric analysis using poly(A)-targeting probes allowed for highly specific and wide-ranging detection (from 1.25nM to 0.5MUM) of poly(A)-RNA, as well as for determination of K(d) values, and revealed a distribution of the probe itself and localization of the target RNA sequence in cells. Furthermore, time-dependent FRET-mediated fluorescence changes at the single-molecule level caused by the folding-induced gradual conformation changes in live cells were observed. PMID- 22828412 TI - Circulating tumor cells in young and elderly patients with colorectal cancer: "lupus et agnus". PMID- 22828411 TI - A strategy for the expression of recombinant proteins traditionally hard to purify. AB - We have developed a series of plasmid vectors for the soluble expression and subsequent purification of recombinant proteins that have historically proven to be extremely difficult to purify from Escherichia coli. Instead of dramatically overproducing the target protein, it is expressed at a low basal level that facilitates the correct folding of the recombinant protein and increases its solubility. Highly active recombinant proteins that are traditionally difficult to purify are readily purified using standard affinity tags and conventional chromatography. To demonstrate the utility of these vectors, we have expressed and purified full-length human DNA polymerases eta, iota, and nu from E. coli and show that the purified DNA polymerases are catalytically active in vitro. PMID- 22828413 TI - Transparent, highly flexible, all nanowire network germanium photodetectors. AB - We report on the fabrication and characterization of all nanowire (NW) network photodetectors. For this purpose, germanium (Ge) NW networks are used as active semiconducting elements, whereas single walled carbon nanotube (SWNT) and silver (Ag) NW networks are used as the contacts. Following their synthesis, all NW networks are deposited through simple solution based methods. Photoresponse characteristics and transparency of the photodetectors for different Ge NW densities are measured. The fabricated devices show a large response with short relaxation times (<10 ms), are flexible and transparent within the visible spectrum. PMID- 22828414 TI - Application of the antibiotic batumin for accurate and rapid identification of staphylococcal small colony variants. AB - BACKGROUND: Staphylococcus aureus is a major human pathogen causing significant morbidity and mortality. The S. aureus colonies in osteomyelitis, in patients with cystic fibrosis and patients with endoprosthesis rejection frequently have an atypical morphology, i.e. staphylococcal small-colony variants, which form a naturally occurring subpopulation of clinically important staphylococci. Identification of these small colony variants is difficult, because of the loss of typical phenotypic characteristics of these variants.We wanted to improve and simplify the diagnosis of staphylococcal infection using a diagnostic preparation, consisting of 5 MUg batumin paper disks. Batumin possesses a unique selective activity against all studied Staphylococcus spp., whereas all other species tested thus far are batumin resistant. We assessed the efficacy of the batumin diagnostic preparation to identify staphylococcal small colony variants, isolated from osteomyelitis patients. FINDINGS: With the batumin diagnostic preparation, all 30 tested staphylococcal small-colony variants had a growth inhibition zone around the disk of minimum 25 mm, accordant with the inhibition zones of the parent strains, isolated from the same patients. CONCLUSIONS: The batumin diagnostic preparation correctly identified the small-colony variants of S. aureus, S. haemolyticus and S. epidermidis as belonging to the genus Staphylococcus, which differ profoundly from parental strains and are difficult to identify with standard methods. Identification of staphylococcal small-colony variants with the batumin diagnostic preparation is technically simple and can facilitate practical laboratory work. PMID- 22828415 TI - Increasing cost of epinephrine autoinjectors. PMID- 22828416 TI - Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo. AB - BACKGROUND: Tissue factor (TF), a primary initiator of blood coagulation, also plays a pivotal role in angiogenesis. TF expression in the airways is associated with asthma, a disease characterized in part by subepithelial angiogenesis. OBJECTIVES: To determine potential sources of TF and the mechanisms of its availability in the lung microenvironment. METHODS: Normal human bronchial epithelial cells grown in air-liquid interface culture were subjected to a compressive stress of 30 cm H(2)O; this is comparable to that generated in the airway epithelium during bronchoconstriction in asthma. Conditioned media and cells were harvested to measure TF mRNA and TF protein. We also tested bronchoalveolar lavage fluid and airway biopsies from asthmatic patients and healthy controls for TF. RESULTS: TF mRNA was upregulated 2.2-fold after 3 hours of stress compared with unstressed cells. Intracellular and secreted TF proteins were enhanced 1.6-fold and more than 50-fold, respectively, compared with those of control cells after the onset of compression. The amount of TF in the bronchoalveolar lavage fluid from patients with asthma was found at mean concentrations that were 5 times greater than those of healthy controls. Immunohistochemical staining of endobronchial biopsies identified epithelial localization of TF with increased expression in asthma. Exosomes isolated from the conditioned media of normal human bronchial epithelial cells and the bronchoalveolar lavage fluid of asthmatic subjects by ultracentrifugation contained TF. CONCLUSIONS: Our in vitro and in vivo studies show that mechanically stressed bronchial epithelial cells are a source of secreted TF and that exosomes are potentially a key carrier of the TF signal. PMID- 22828418 TI - What factors affect intrapartum maternal temperature? A prospective cohort study: maternal intrapartum temperature. AB - BACKGROUND: In recent years, several reports have indicated that maternal temperature elevations during labor may also be observed in the absence of an infection. Presumed noninfectious causes of maternal temperature elevations include epidural analgesia, endogenous heat production generated by the contracting uterus, and delivery in an overheated room. To investigate the potential causes of noninfectious maternal temperature changes during labor, we conducted a prospective cohort study in women scheduled for labor induction. METHODS: We recorded hourly oral temperatures from admission to delivery. We calculated whether temperature changed during labor in 81 women. We then determined if body mass index, and duration of labor, or time from rupture of amniotic sac to delivery, or oxytocin dose, would affect maternal temperature. To evaluate the possible role of epidural analgesia, we compared the temperature slope before and after starting epidural analgesia. RESULTS: We observed an overall significant linear trend of temperature over time with an estimated temperature slope of +0.017 degrees C/h (P = 0.0093). Patients with a positive temperature trend had also a significantly longer time from rupture of membranes to delivery (P = 0.0077) and a higher body mass index (P = 0.0067). Epidural analgesia had no effect on the temperature trend. CONCLUSIONS: In our cohort of patients, there was an overall significant linear trend of temperature over time after correcting for heterogeneity among patients. Temperature increase was associated with higher body mass index values and longer time from rupture of membranes to delivery. Epidural analgesia had no effect on maternal temperature. PMID- 22828419 TI - Use of recombinant factor VIIa in patients with amniotic fluid embolism. PMID- 22828421 TI - Flow chart for amniotic fluid embolism management: a tricky tool. PMID- 22828423 TI - The devil in the details. PMID- 22828425 TI - Predictors of analgesic response to sympathetic blockade in complex regional syndrome type 1: no conclusive answers but best to get standard medical therapy right first. PMID- 22828427 TI - Considerations for evaluating the accuracy of hemoglobin monitoring. PMID- 22828429 TI - Perioperative ischemic optic neuropathy and spine surgery: are we asking the right questions? PMID- 22828430 TI - Could the open door crack on perioperative visual loss be even bigger? PMID- 22828431 TI - It's still the water. PMID- 22828433 TI - Understanding the mechanics of laryngospasm is crucial for proper treatment. PMID- 22828434 TI - Ebenezer Hopkins Frost. PMID- 22828439 TI - The small molecule calactin induces DNA damage and apoptosis in human leukemia cells. AB - We purified calactin from the roots of the Chinese herb Asclepias curassavica L. and analyzed its biologic effects in human leukemia cells. Our results showed that calactin treatment caused DNA damage and resulted in apoptosis. Increased phosphorylation levels of Chk2 and H2AX were observed and were reversed by the DNA damage inhibitor caffeine in calactin-treated cells. In addition, calactin treatment showed that a decrease in the expression of cell cycle regulatory proteins Cyclin B1, Cdk1, and Cdc25C was consistent with a G2/M phase arrest. Furthermore, calactin induced extracellular signal-regulated kinase (ERK) phosphorylation, activation of caspase-3, caspase-8, and caspase-9, and PARP cleavage. Pretreatment with the ERK inhibitor PD98059 significantly blocked the loss of viability in calactin-treated cells. It is indicated that calactin induced apoptosis may occur through an ERK signaling pathway. Our data suggest that calactin is a potential anticancer compound. PMID- 22828440 TI - The costs of schizophrenia and predictors of hospitalisation from the statutory health insurance perspective. AB - BACKGROUND: The aim of the study was to determine the costs of treating schizophrenia from the perspective of the statutory health insurance, as well as the identification of predictors of hospitalisation of formerly stable schizophrenia patients. METHODS: Claims data for the years 2004-2006 were analysed. Patients who did not have to be treated in a hospital as a result of an ICD diagnosis F20 both in the year 2005 as well as also in 2006 were defined as stable patients. In contrast, those patients who had to be treated in a hospital in 2006 because of a diagnosis of schizophrenia were defined as unstable. In addition to the overall healthcare costs, the costs specific to schizophrenia were also analysed. Also, based on binary logistic regression analysis, predictors for hospital treatment were determined. RESULTS: 8497 stable and 1449 unstable patients were identified. The schizophrenia specific costs for stable patients were ? 1605 and the overall costs were ? 4029 in 2006, respectively. Unstable patients had indication-specific costs amounting to ? 12864 and overall health care costs of ? 16824. For unstable patients, the costs of hospital treatment were identified as being a substantial cost area. Predictors for a higher probability of hospital treatment were: female patients, at least one rehabilitation measure, at least one stay in hospital in 2004, and being co morbid with substance abuse. In contrast, older patients, who were treated with concomitant medications, and if they received a continuous drug therapy in all quarters of a year had a lower probability of hospitalisation. In addition, an increased number of visits to a doctor reduced the probability of hospitalisation. The variable 'depot medication' were close to significance and the variable 'inability to work lasting more than six weeks' had, in contrast, no significant influence. CONCLUSIONS: The schizophrenia specific and overall health care costs of unstable patients were clearly higher than was the case with stable patients and mainly determined by inpatient hospital treatment. A range of potential predicting factors which can be extracted from routine claims data have a positive or negative influence on the probability of treatment in hospital. PMID- 22828441 TI - Growth of CdS nanocrystallites on graphene oxide Langmuir-Blodgett monolayers. AB - Large area GO-Cd composite Langmuir-Blodgett monolayers were transferred onto Si substrate by introducing Cd(2+) ions into the subphase. The changes in the behaviour of the Langmuir monolayer isotherm in the presence of Cd(2+) ions are attributed to changes in the microstructure and density of the GO sheets on the subphase surface. The uptake of Cd onto the GO monolayers and the effect of subsequent sulphidation were investigated by AFM, FTIR, Raman, XPS and HRTEM techniques. The incorporation of Cd into the GO monolayers causes some overlapping of sheets and extensive formation of wrinkles. Sulphidation of the GO Cd sheets results in the formation of uniformly distributed CdS nanocrystallites on the entire basal plane of the GO monolayers. The de-bonding of Cd with oxygen functional groups results in a reduction of the wrinkles. The GO sheets function primarily as a platform for the interaction of metal ions with oxygen functionalities and their structure and characteristic features are not affected by either uptake of Cd or formation of CdS. PMID- 22828442 TI - Lipoprotein lipase expression in unmutated CLL patients is the consequence of a demethylation process induced by the microenvironment. PMID- 22828443 TI - Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. AB - Tumor-associated B7-H1 molecules inhibit antitumor immunity in some malignancies. We found that B7-H1 expression on patient myeloma cells and human myeloma cell lines (HMCLs) was upregulated by cultivating the cells with autologous stromal cells and the human stromal cell line HS-5. Among major cytokines produced by HS 5 cells, interleukin (IL)-6-induced B7-H1 expression on HMCLs. Moreover, HS-5 cell-mediated B7-H1 expression was downregulated by inhibiting IL-6. B7-H1(+) HMCLs were more proliferative and less susceptible to antimyeloma chemotherapy compared with B7-H1(-) HMCLs. Moreover, the former cells showed higher levels of Bcl-2 and FasL expression than the latter. Finally, B7-H1 molecules on HMCLs induced T-cell apoptosis and anergy of tumor-specific T cells. Consistent with these in vitro observations, patients whose myeloma cells expressed high levels of B7-H1 had higher myeloma cell percentages in the bone marrow (BM) and higher serum lactate dehydrogenase levels compared with other myeloma patients. In addition, B7-H1 expression levels were often upregulated after myeloma patients relapsed or became refractory to therapy. Our data indicate that the BM microenvironment upregulates B7-H1 expression on myeloma cells, which links to the two biological actions of inducing T-cell downregulation and enhancing aggressive myeloma-cell characteristics. Modulating the B7-H1 pathway may be worthwhile in myeloma. PMID- 22828444 TI - A phase 1 study of concomitant high-dose lenalidomide and 5-azacitidine induction in the treatment of AML. PMID- 22828445 TI - EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia. AB - The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rgamma(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells. PMID- 22828446 TI - Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation. AB - Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that can expand in response to inflammatory signals. Predominantly studied in cancer, MDSCs suppress T cells utilizing various mechanisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy-related toxicity and alloreactivity increase inflammatory cytokines that might favor an MDSC accumulation. To address this question, circulating CD14(+)HLA-DR(low/neg) cells were studied retrospectively in 51 allo-HSCT patients. These cells represent one of the few well-described human MDSC subsets under physiological and pathological conditions. The frequency of CD14(+)HLA DR(low/neg) cells was significantly increased after allo-HSCT, especially in patients with acute graft-versus-host disease. Compared to healthy donor cells they were pSTAT1(low) (phosphorylated signal transducer and activator of transcription) and indoleamine 2,3-dioxygenase (IDO)(high). Serum levels of granulocyte colony-stimulating factor and interleukin-6, which both have been linked to MDSC induction, correlated positively with the frequency of CD14(+)HLA DR(low/neg) cells. In vitro dysfunction of patient T cells, such as reduced proliferative capacity or CD3zeta-chain expression, was rescued by blocking the IDO activity of CD14(+)HLA-DR(low/neg) cells. Overall, we identified a T-cell suppressive monocytic population that expands after allo-HSCT. The mechanisms responsible for such accumulation remain to be elucidated. It will be of great interest to prospectively investigate the influence of these cells on the graft versus-tumor and -host reaction. PMID- 22828448 TI - Quality of life results of balloon kyphoplasty versus non surgical management for osteoporotic vertebral fractures in Germany. AB - BACKGROUND: To compare improvement in quality of life (QoL) and symptoms' relief in vertebral compression fractures (VCF) due to osteoporosis for patients undergoing balloon kyphoplasty (BKP) to those undergoing non-surgical management (NSM) in a real-life setting. METHODS: In this prospective, comparative study, quality-of-life was evaluated in eight centres in Germany between 2005 and 2008, for 82 patients, with the EQ-5D questionnaire, and the Roland Morris Disability Questionnaire (RMDQ). RESULTS: BKP patients demonstrated a statistical and clinical significant higher improvement in EQ-5D than NSM patients, 0.44 and 0.25 from baseline to 12 months, respectively. Moreover, BKP patients showed a clinically relevant improvement in the RMDQ by 6.25 from baseline to 12 months, whereas NSM patients had no significant improvement in the RMDQ. CONCLUSIONS: This study demonstrates for VCF patients that in real-life quality of life for BKP patients improves more than for NSM patients; confirming the results of a large randomized clinical trial. PMID- 22828447 TI - Changes in the proteomic profile of adipose tissue-derived mesenchymal stem cells during passages. AB - BACKGROUND: Human mesenchymal stem cells (hMSC) have recently raised the attention because of their therapeutic potential in the novel context of regenerative medicine. However, the safety of these new and promising cellular products should be carefully defined before they can be used in the clinical setting, as. The protein expression profile of these cells might reveal potential hazards associated with senescence and tumoral transformation which may occur during culture. Proteomic is a valuable tool for hMSC characterization and identification of possible changes during expansion. RESULTS: We used Surface Enhanced Laser Desorption/Ionization-Time Of Flight-Mass Spectrometry (SELDI-ToF MS) to evaluate the presence of stable molecular markers in adipose tissue derived mesenchymal stem cells (AD-MSC) produced under conditions of good manufacturing practices (GMP). Proteomic patterns of cells prepared were consistent, with 4 up-regulated peaks (mass-to-charge ratio (m/z) 8950, 10087, 10345, and 13058) through subculture steps (P0-P7) with similar trend in three donors. Among the differentially expressed proteins found in the cytoplasmic and nuclear fractions, a cytoplasmic 10.1 kDa protein was upregulated during culture passages and was identified as S100A6 (Calcyclin). CONCLUSIONS: This study suggests for the first time that common variation could occur in AD-MSC from different donors, with the identification of S100A6, a protein prevalently related to cell proliferation and cell culture condition. These results support the hypothesis of common proteomic changes during MSCs expansion and could give important insight in the knowledge of molecular mechanisms intervening during MSC expansion. PMID- 22828449 TI - Ganglioside GM1 forces the redistribution of cholesterol in a biomimetic membrane. AB - Neutron reflectivity has been applied to investigate different mixed asymmetric lipid systems, in the form of single "supported+floating" bilayers, made of phospholipids, cholesterol and GM1 ganglioside (Neu5Acalpha2-3(Galbeta1 3GalNAcbeta1-4)Galbeta1-4Glcbeta1Cer)) in bio-similar mole ratios. Bilayer preparation was carried out layer-by-layer with the Langmuir-Blodgett Langmuir Schaefer techniques, allowing for compositional asymmetry in the system buildup. It is the first time that such a complex model membrane system is reported. Two important conclusions are drawn. First, it is experimentally shown that the presence of GM1 enforces an asymmetry in cholesterol distribution, opposite to what happens for a GM1-free membrane that, submitted to a similar procedure, results in a full symmetrization of cholesterol distribution. We underline that natural cholesterol has been used. Second, and most interesting, our results suggest that a preferential asymmetric distribution of GM1 and cholesterol is attained in a model membrane with biomimetic composition, revealing that a true coupling between the two molecular species occurs. PMID- 22828450 TI - Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods. AB - Recently, a polyethylene glycol (PEG)-modification method for liposomes prepared using pH-gradient method has been proposed. The differences in the pharmacokinetics and the impact on the antitumor effect were examined; however the impact of PEG-lipid molar weight has not been investigated yet. The main purpose of this study is to evaluate the impact of PEG-lipid molar weight against the differences in the pharmacokinetics, the drug-release profile, and the antitumor effect between the proposed PEG-modification method, called the post modification method, and the conventional PEG-modification method, called the pre modification method. Various comparative studies were performed using irinotecan as a general model drug. The results showed that PEG-lipid degradation could be markedly inhibited in the post-modification method. Furthermore, prolonged circulation time was observed in the post-modification method. The sustained drug release was observed in the post-modification method by the results of the drug releasing test in plasma. Moreover, a higher antitumor effect was observed in the post-modification method. It was also confirmed that the same behaviors were observed in all comparative studies even though the PEG molecular weight was lower. In conclusion, the post-modification method has the potential to be a valuable PEG-modification method that can achieve higher preservation stability of PEG-lipid, prolonged circulation time, and higher antitumor effect with only half the amount of PEG-lipid as compared to the pre-modification method. Furthermore, it was demonstrated that PEG(5000)-lipid would be more desirable than PEG(2000)-lipid since it requires much smaller amount of PEG-lipid to demonstrate the same performances. PMID- 22828451 TI - Associations among physician advice, physical activity, and socio-demographic groups in older Spanish adults. AB - This study examined the relationship between medical advice to engage in physical activity with type of demand required by physical activity and demographic variables. A cross-sectional study was developed, featuring a questionnaire on physicians' advice, and type of demand. The questionnaire was completed by a probability and nationwide sample of older adults in Spain (n = 933, M = 74.1, range 65-93), randomly selected using multistage sampling. More physically active older adults have, more often than the less active, received physicians' advice to engage in physical activity. There is a significant relationship between medical advice and type of demand (p < .01) and age (p < .05). However, no relationship was found between physician medical advice and gender, social class, or income. Physicians can effectively promote physical activity among sedentary older adults through appropriate advice. Consequently, health authorities should promote physicians' advising older patients to pursue physical activity. PMID- 22828452 TI - Visualization of the sentinel node in early-stage oral cancer: limited value of late static lymphoscintigraphy. AB - OBJECTIVE: Various lymphoscintigraphic imaging protocols exist for sentinel node (SN) identification in early-stage oral cancer. This study aimed to evaluate the clinical value of performing additional late lymphoscintigraphic imaging. METHODS: We retrospectively analysed early (directly following injection of 99mTc Nanocoll) and late (2-4 h after injection) imaging results of 60 early-stage (T1 T2, cN0) oral cancer patients scheduled for SN procedure. Lymphoscintigraphic results of late imaging were categorized into: (a) no visualization of additional hotspots considered to be SNs; (b) additional hotspots visualized that are considered to be SNs and (c) hotspots visualized only during late imaging. Histopathological results of the harvested SNs were related to the corresponding hotspot. RESULTS: In all patients (n=60) lymphoscintigraphy was able to visualize a hotspot that was identified as an SN. In 51/60 (85%) patients, early imaging was able to visualize at least one hotspot, whereas in 9/60 (15%) patients, mostly with oral cavity tumours other than mobile tongue and floor-of-mouth tumours, only late imaging was able to visualize hotspots. In 14/51 (27%) patients, late imaging resulted in additionally visualized hotspots marked as SNs, resulting in a more extensive surgical procedure. These additionally removed SNs appeared to be of no clinical relevance, as all SNs identified during early imaging correctly predicted whether the neck was positive or negative for cancer. CONCLUSION: Results of this study indicate that additional late lymphoscintigraphic imaging should be performed only in selected cases. PMID- 22828453 TI - The analysis of factors affecting the threshold on repeated 18F-FDG-PET/CT investigations measured by the PERCIST protocol in patients with esophageal carcinoma. AB - BACKGROUND: When applying the PET Response Criteria in Solid Tumors protocol, a threshold value based on standardized uptake value corrected to lean body mass (SUL) in liver parenchyma, or in the blood pool, is used: to metabolically specify a measurable lesion; to calculate metabolic tumor volume (mTV) and its product total lesion glycolysis (TLG); and as a limit for response measurement. The problem with using changes in glucose metabolism as a marker for response to therapy is its reproducibility on test-retest examinations. Therefore, before the evaluation of tumor treatment response, we verified our diagnostic protocol for homogeneity using the PET Response Criteria in Solid Tumors quality parameters. In addition, we analyzed the effect of the time span between examinations on the average value of SUL (SUL MEAN) in liver parenchyma at three different points: first at baseline (BL), after the first course of chemotherapy (ChT1), and finally after finishing therapy (ChT3). We also analyzed the influence of SUL MEAN variation on mTV and TLG. METHODS: Eighty-four patients with esophageal cancer were prospectively examined at BL using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG)-PET/CT; 53 of 84 patients were examined after ChT1, 47 of 84 after ChT3, and 41 of 84 underwent all three examinations. Coefficient of variance (CV) and relative differences (RDw) were assessed for test-retest liver SUL values. The influence of liver SUL MEAN to mTV and TLG was modeled on BL examinations by artificial changes in liver SUL MEAN by +/- 20%. RESULTS: No significant differences were found in test-retest liver SUL MEAN values. Comparing BL with ChT1, BL with ChT3, and ChT1 with ChT3, the CV of the liver SUL MEAN was 10.4, 10.7, and 10.3%; nevertheless, in 34.0, 38.3, and 36.6% of these examinations, respectively, the liver average SUL MEAN values exceeded the limit for inclusion in the study; that is, the difference was less than +/- 0.3 U and +/- 20%. The corresponding CV of blood background was 14.9, 16.5, and 17.2%. The artificial decrease of -20% in the liver SUL MEAN resulted in an increase of +43.6% in mTV and of +20.4% in TLG, whereas an increase of +20% in the liver SUL MEAN resulted in a decrease of -20.6% in mTV and -11.9% in TLG. CONCLUSION: SUL MEAN values in reference tissues (liver parenchyma or descending aorta) measured before chemotherapy did not differ significantly from those measured during chemotherapy. The CV of liver SUL MEAN was comparable to that seen in published data, but some patients had to be excluded from the study because of the individual variability of their mean liver SUL MEAN, which consequently hinders the clinical usage of mTV and TLG. Even in the standardized protocol, all potential sources of variability should be minimized. PMID- 22828454 TI - Comparing VO2max determined by using the relation between heart rate and accelerometry with submaximal estimated VO2max. AB - AIM: An exploratory study to identify parameters that can be used for estimating a subject's cardio-respiratory physical fitness level, expressed as VO2max, from a combination of heart rate and 3D accelerometer data. METHODS: Data were gathered from 41 healthy subjects (23 male, 18 female) aged between 20 and 29 years. The measurement protocol consisted of a sub-maximal single stage treadmill walking test for VO2max estimation followed by a walking test at two different speeds (4 and 5.5 kmh-1) for parameter determination. The relation between measured heart rate and accelerometer output at different walking speeds was used to get an indication of exercise intensity and the corresponding heart rate at that intensity. Regression analysis was performed using general subject measures (age, gender, weight, length, BMI) and intercept and slope of the relation between heart rate and accelerometer output during walking as independent variables to estimate the VO2max. RESULTS: A linear regression model using a combination of the slope and intercept parameters, together with gender revealed the highest percentage of explained variance (R2 = 0.90) and had a standard error of the estimate (SEE) of 2.052 mL O2kg-1min-1 with VO2max. Results are comparable with current commonly used sub-maximal laboratory tests to estimate VO2max. CONCLUSION: The combination of heart rate and accelerometer data seems promising for ambulant estimation of VO2max-. PMID- 22828455 TI - Physiological responses to self-paced exercise: effort-matched comparisons across running and rowing modalities. AB - AIM: The purpose of this study was to examine whether or not physiological responses to self-pacing are similar across different exercise modalities where the rating of perceived exertion (RPE) is matched. METHODS: Ten recreationally active adult male subjects completed baseline tests of peak oxygen uptake (.VO2) and subsequently on two separate occasions performed 20-min exercise bouts at RPE 15 (Hard) on both a motorized treadmill and a rowing ergometer. RESULTS: Mean relative work intensity (% of baseline peak (.VO2) for treadmill running was significantly higher than for rowing (86.1% vs. 83.7%) (P<0.05). Mean heart rates (174.7+/-5.9 vs. 165.5+/-6.6 b?min-1) and pre- to post-bout changes in blood lactate concentration (4.0+/-0.8 vs. 3.3+/-1.2 mmol/L) were also greater in the running trial than rowing (P<0.05). Baseline peak (.VO2 was positively correlated between modalities (r=0.63; P<0.05) as were the main trial mean (.VO2 (r=0.73; P<0.05) and heart rate (r=0.67; P<0.05) from the 20-min bouts. CONCLUSION: The elevated relative exercise intensity and physiological responses to motorized treadmill running suggests greater work outputs can be accomplished in this modality for the same perceived effort compared to rowing among recreationally active participants. PMID- 22828456 TI - Reliability of the physiological and metabolic responses to a field hockey specific treadmill protocol for elite female players. AB - AIM: The purpose of this study was to assess the reliability of the physiological and metabolic responses to a sport-specific treadmill protocol designed to simulate the activity pattern of elite women's field hockey match-play. METHODS: Eight elite female field hockey players completed two trials of the Field Hockey Intermittent Treadmill Protocol (FHITP) separated by 5 days. The protocol consisted of 50 min of intermittent treadmill running designed to replicate the demands of match-play. Heart rate was determined continuously using Polar Team monitors. Rectal temperature was recorded every 10 min and capillary blood samples were taken at rest, at half-time (immediately after the completion of the first half) and at the end of the protocol for analysis of blood glucose and lactate. RESULTS: Heart rate response (CV 3.5%, CI, 2.9% to 4.4%), rectal temperature (CV 0.6%, 95% CI, 0.5% to 0.8%) and blood glucose (CV 1.4%, 95% CI, 1.1% to 2.1%) were all reproducible. No systematic error was evident between trials for blood lactate response (P=0.289) to the FHITP, although the overall CV for the measurement was 14.2% (95% CI, 10.7% to 21.2%). CONCLUSION: It was concluded that the physiological and metabolic responses to the FHITP were highly reproducible with the recommendation that blood lactate concentrations are used in conjunction with heart rate or other key performance measures to assess performance. PMID- 22828457 TI - Effect of music-movement synchrony on exercise oxygen consumption. AB - AIM: Past research indicates that endurance is improved when exercise movements are synchronised with a musical beat, however it is unclear whether such benefits are associated with reduced metabolic cost. We compared oxygen consumption (.VO2) and related physiological effects of exercise conducted synchronously and asynchronously with music. METHODS: Three music tracks, each recorded at three different tempi (123, 130, and 137 beats.min-1), accompanied cycle ergometry at 65 pedal revolutions.min-1. Thus three randomly-assigned experimental conditions were administered: slow tempo asynchronous, synchronous, and fast tempo asynchronous. Exercise response of .VO2, HR, and ratings of perceived exertion (RPE), to each condition was monitored in 10 untrained male participants aged 21.7+/-0.8 years (mean+/-SD) who cycled for 12 min at 70% maximal heart rate (HR). RESULTS: Mean .VO2 differed among conditions (P=0.008), being lower in the synchronous (1.80+/-0.22 L.min-1) compared to the slow tempo asynchronous condition (1.94+/-0.21 L.min-1; P<0.05). There was no difference in HR or RPE among conditions, although HR showed a similar trend to .VO2. CONCLUSION: The present results indicate that exercise is more efficient when performed synchronously with music than when musical tempo is slightly slower than the rate of cyclical movement. PMID- 22828458 TI - Physiological demands and activity profiles during futsal match play according to competitive level. AB - AIM: The aims of this study were to examine and compare the physiological demands and activity profiles of players at different competitive levels during futsal match play. METHODS: Fifteen professional futsal players (elite group) and 15 university futsal players (amateur group) participated in the study. The players in each group were divided into three teams; each team consisted of 1 goalkeeper and 4 outfield players. All players were observed during two match simulated competitive games. The physiological demands were analyzed by measuring heart rate, estimated ?VO2 from an individual HR-?VO2 relationship, and earlobe-blood lactate concentration before and at the end of the match. Activity profiles were analyzed for whole game movement patterns using a computer-based tracking system. RESULTS: The physiological demands of the outfield players in the elite group was higher (P<0.05) than in the amateur group (%HRmax: 89.8+/-5.8 vs. 86.2+/-6.7%, %?VO2max: 77.9+/-9 vs. 73.1+/-6.2% and blood lactate: 5.5+/-1.4 vs. 5.1+/-1.5 mmol/L, respectively). Analysis of activity profiles of outfield players showed that the total distance covered of the elite group was higher (P<0.05) than that of the amateur group: (5087+/-1104 vs. 4528+/-1248 m, respectively). However, there were no significant differences in the physiological demands and activity profiles between the goalkeepers in the two groups (P>0.05). CONCLUSION: These results demonstrate that the higher physiological demands and activity profiles placed on elite players during the game could indicate the players' physical fitness reserves for the formulation of an optimized specific training program as well as being useful in the preparation of the athletes for competition. PMID- 22828459 TI - Correlation between explosive strength, aerobic power and repeated sprint ability in elite basketball players. AB - AIM: The aim of this study was to examine the relationship between explosive strength and aerobic power with basketball-specific repeated sprint ability in elite male basketball players. METHODS: Twenty-four elite basketball players (age 22.2+/-3.4 years, height 197.1+/-6.2 cm, weight 95.7+/-8.8 kg; training experience 11.0+/-3.1 years; mean+/-SD), participated in the study. Subjects performed countermovement jump (CMJ) test and incremental pseudo-ramp test protocol with measured CMJ height and VO2max, respectively. Specific repeated sprint ability (RSA) test was conducted, with total sprinting time (summation of 10 sprint times - RSAtot) and sprint decrement (fatigue index - RSAFI) calculated. RESULTS: Significant decrements in sprint performance from the eight 30-m sprint (P<0.05) were observed. Strong inverse correlation was found between CMJ and RSAtot (r=-0.74, P<0.01). No significant correlation was found between VO2max and RSA outcomes neither between CMJ and RSAFI. CONCLUSION: CMJ is a predictor of RSA in elite basketball players. It seems that coaches and strength and conditioning professionals should devote additional time for explosive strength development in elite basketball players during preparatory period to enhance RSA performance. PMID- 22828460 TI - Effect of astaxanthin supplementation on muscle damage and oxidative stress markers in elite young soccer players. AB - AIM: The purpose of the current study was to examine the effect of Astaxanthin (Asx) supplementation on muscle enzymes as indirect markers of muscle damage, oxidative stress markers and antioxidant response in elite young soccer players. METHODS: Thirty-two male elite soccer players were randomly assigned in a double blind fashion to Asx and placebo (P) group. After the 90 days of supplementation, the athletes performed a 2 hour acute exercise bout. Blood samples were obtained before and after 90 days of supplementation and after the exercise at the end of observational period for analysis of thiobarbituric acid-reacting substances (TBARS), advanced oxidation protein products (AOPP), superoxide anion (O2*-), total antioxidative status (TAS), sulphydril groups (SH), superoxide-dismutase (SOD), serum creatine kinase (CK) and aspartate aminotransferase (AST). RESULTS: TBARS and AOPP levels did not change throughout the study. Regular training significantly increased O2*- levels (main training effect, P<0.01). O2*- concentrations increased after the soccer exercise (main exercise effect, P<0.01), but these changes reached statistical significance only in the P group (exercise x supplementation effect, P<0.05). TAS levels decreased significantly post- exercise only in P group (P<0.01). Both Asx and P groups experienced increase in total SH groups content (by 21% and 9%, respectively) and supplementation effect was marginally significant (P=0.08). Basal SOD activity significantly decreased both in P and in Asx group by the end of the study (main training effect, P<0.01). All participants showed a significant decrease in basal CK and AST activities after 90 days (main training effect, P<0.01 and P<0.001, respectively). CK and AST activities in serum significantly increased as result of soccer exercise (main exercise effect, P<0.001 and P<0.01, respectively). Postexercise CK and AST levels were significantly lower in Asx group compared to P group (P<0.05) CONCLUSION: The results of the present study suggest that soccer training and soccer exercise are associated with excessive production of free radicals and oxidative stress, which might diminish antioxidant system efficiency. Supplementation with Asx could prevent exercise induced free radical production and depletion of non-enzymatic antioxidant defense in young soccer players. PMID- 22828461 TI - Ulnar variance related to biological and training characteristics and handgrip strength in Portuguese skeletally immature female gymnasts. AB - AIM: The aims of this study were to investigate the ulnar variance in a group of skeletally immature female gymnasts of different age and skill level and to investigate the left-right differences in ulnar variance and its relationship with biological and training characteristics and handgrip strength. METHODS: Thirty-three Portuguese skeletally immature female gymnasts (mean age 11.1 years) of different age-related categories completed a questionnaire detailing their training characteristics. Besides maturation, stature, body mass, and body composition, also handgrip strength of both hands were measured. Left and right ulnar variance was obtained using Hafner's procedure and skeletal age through the Tanner-Whitehouse 3-method. RESULTS: Mean skeletal age (10.1+/-1.9 yr) is one year younger than chronological age (11.1+/-2.1 yr) and this discrepancy becomes more pronounced with increasing age-category. Gymnasts presented on average 6.1 years of training and 16.7 hours/week. A negative mean value for both the left and right ulnar variance measures was observed (between -1.7 mm and -3.1 mm) but with increasing age-category there is a trend that ulnar variance becomes more positive (between +0.3 mm and -1 mm). Significant differences between right and left ulnar variance were demonstrated. Correlations between ulnar variance and biological and training characteristics and handgrip strength are rather low and not significant, except for skeletal age (r=0.38), stature (r=0.41) and fat-free mass (r=0.48). CONCLUSION: Despite some significant results the main results of this study do not directly support the thesis that gymnastics training or handgrip strength are associated with ulnar variance. PMID- 22828462 TI - High percentage of fat intakes, not low fat oxidation, may induce overweight cyclists. AB - AIM: There is a number of people who recreationally or professionally participate in regular physical activity that may contribute to reduce body fat and prevent weight gain. However, there are considerable numbers of the people who have excess body fat in this population. Therefore, this study tested the hypothesis that overweight cyclists may be affected by high level of fat oxidation and/or dietary fat intake. METHODS: Fourteen male cyclists aged 35-50 years participated in this study. All participants were defined as semi-professional cyclists and assigned to either normal cyclist group (NC, N.=7) or overwieht cyclist group (OC, N.=7) based on %body fat (OC>23%>NC). The participants underwent a maximal effort ergometer test and dietary analysis. Independent t-test and two-way ANOVA with repeated measures were used to analyze data. RESULTS: There were no differences between NC and OC for age, height, weight, body mass index, and all cardiopulmonary fitness variables at rest and during maximal effort ergometer test. However, this study found that total fat, especially saturated fat intake of OC was significantly higher compared to one of NC (total fat: 110.88+/-12.98 vs. 53.56+/-6.94, saturated fat: 36.92+/-5.98 vs. 16.65+/-3.41, P<0.05). CONCLUSION: The higher amount total fat intake, especially saturated fat intake not total calorie intake, may play a major role in body composition in endurance trained population. PMID- 22828463 TI - Influence of sex on ventricular remodeling in collegiate athletes. AB - AIM: Previous reports indicate that the "athlete's heart" is more prominent in males than females, but the mechanisms responsible for this sex difference have not been elucidated. This study examined male-female differences in cardiac mass and volume in highly trained athletes and normally active individuals to assess the relative contributions of pre-existing sex differences and sports training to cardiac findings. METHODS: Echocardiographic and electrocardiographic findings were compared between 20 male and 21 female collegiate athletes and 22 male and 29 female normally-active subjects. RESULTS: Cardiac mass (per kg lean body mass) was significantly greater in the male compared to female athletes (3.62+/-0.55 and 3.31+/-0.56 g.kg-1, respectively). A similar magnitude of difference in average relative cardiac mass was observed between the normally active males and females, and cardiac mass was greater in athletic versus nonathletic groups by +14.9% in the males and +13.3% in the females. Relative left ventricular volume was greater in the male athletes (47.5+/-6.3 ml*BSA-1.5) compared to male nonathletes (42.9+/-6.1 ml*BSA-1.5); no such difference was observed in the females. CONCLUSION: These findings suggest that sex differences in both the untrained state and magnitude of training response contribute to male-female differences in the "athlete's heart" PMID- 22828464 TI - Daily quality physical education in childhood and adult bone density. AB - AIM: Previous studies, mainly of self-selected athletes, have suggested that childhood activities can have a prolonged influence on bone mineral density. This investigation explored whether experimentally assigned daily quality physical education (PE) during childhood influenced bone density at an age of 42.8+/-1.5 years. METHODS: Participants from the Trois-Rivieres Longitudinal Study were divided into 4 groups: the first 2 groups (19 women and 21 men) had received 5 h/week of specialist-taught PE in primary school in 1970-1977, whereas the third and fourth groups (10 women and 10 men) had followed the standard PE programme of 40 min/week. RESULTS: Bone densities, measured by dual X-ray absorptiometry (lumbar vertebrae and femoral neck), did not differ significantly between experimental and control subjects. CONCLUSION: This result may reflect a normal or even a faster decrease of bone mineral density in experimental subjects over the 30 years since completion of the program, or an intervention that was designed to enhance cardiorespiratory and muscular fitness rather than bone health. PMID- 22828465 TI - The relationship between performance and flow state in tennis competition. AB - AIM: The study aimed to examine 1) the validity of the nine-factor flow model in tennis competition; 2) differences in flow state between athletes who won or lost their competition match; 3) the link between flow and subjective performance; and 4) flow dimensions as predictors of performance outcome METHODS: The sample consisted of 188 junior tennis players (115 male, 73 female) between 12 and 18 years of age. Participants' performance was recorded during junior ranking-list tournaments. Following the completion of a tennis competition match, participants completed the Flow State Scale-2 and a subjective performance outcome measure. RESULTS: Acceptable flow model fit indices of CFI, TLI, SRMR, and RMSEA were only found for winning athletes. The group of winning athletes scored significantly higher on all nine flow dimensions, except time transformation, than losing athletes, showing statistically significant differences for challenge-skills balance, clear goals, sense of control, and autotelic experience. Significant correlation coefficients were found between flow state and subjective performance assessments. The binary logistic regression revealed concentration on the task and sense of control to be significant predictors of performance outcome. The predictor variables explained 13% of the variance in games won. CONCLUSION: The study showed that athletes who win or lose perceived flow state differently. Studies using retrospective assessments need to be aware that subjective experience could be biased by performance outcomes. Pinpointing psychological variables and their impact on ecologically valid measures, such as performance results, would support the development of effective intervention studies to increase performance in sport competition. PMID- 22828466 TI - The effects of different exercise intensity on myokine and angiogenesis factors. AB - AIM: Myokines and angiogenesis factors, studies on trainings according to the difference of exercise intensity are not sufficient, and it has not been elucidated. Particularly, studies on the effect of resistance exercise according to the intensity of resistance exercise on blood myokines and angiogenesis may be essential in the metabolic process of angiogenesis and the formation of muscle. METHODS: The subjects of our studies were healthy male college students (N.=30) randomly assigned to the high intensity exercise group (N.=10), the moderate intensity exercise group (N.=10), and the control group (N.=10). The study was performed after obtaining a consent in advance, and the approval from the Institutional Review Board of Dong-A University Hospital. In the body composition test, height, weight, BMI (body mass index), %fat, and LBM (lean body mass) were measured by electric impedance. In blood analysis, myokines (interleukin (IL)-6, IL-8, IL-15) and angiogenesis factors (vascular endothelial growth factor (VEGF), angiopoietin (Ang)1, follistatin (FLRG)) were analyzed by ELISA methods. RESULTS: The results show %body fat and LBM of the three groups were significantly different (P<0.05). IL-6 and IL-8 of the three groups were significantly different (P<0.05). Particularly, IL-8 of RE60 (60% of 1RM) was shown to be significantly higher than other groups (P<0.05). IL-15 also showed significant differences with time (P<0.05). In addition, VEGF and Ang 1 showed significant differences with time (P<0.05), nonetheless, FLRG did not showed statistical differences. CONCLUSION: Many of muscle contraction through 8 weeks resistance exercise exerted positive effects on the concentration of blood myokines as well as angiogenesis. Particularly, in regard to blood myokines, moderate intensity exercise were more effective than high intensity exercise, which is considered to be due to that continuous muscle contraction of moderate intensity exercises exerted more positive effects on the elevation of the concentration of myokines than less muscle contraction of high intensity exercise. PMID- 22828467 TI - Isokinetic intervention in microtraumatic shoulder instability: an update. AB - AIM: Aim of the present study was to carry out a critical analysis of the use of isokinetic dynamometers for evaluation and rehabilitation in microtraumatic shoulder instability. METHODS: A non-systematic literature review was conducted on Medline using the following key words: "isokinetics", "shoulder instability", "evaluation", "rehabilitation". We also analyzed the related articles, and compiled a database of expert opinion. RESULTS: Despite a lack of consensus on testing modalities, lateral and medial rotator muscle strength can be safely and reliably assessed on isokinetic devices in subjects presenting with microtraumatic instability of the shoulder, before and after rehabilitation and/or surgery. There is considerable inter-individual variability in the results, leading to consider isokinetic testing as a useful examination before individualized rehabilitation. Its use as a muscle strengthening method in a global rehabilitation program seems interesting in order to correct rotator muscle strength deficiencies and/or asymmetries, which may be infra-clinical, even though strong scientific evidence is still lacking. CONCLUSION: Isokinetics is a safe tool for evaluation and seems to be effective in rehabilitation for microtraumatic instability of the shoulder. It would, however, be necessary to standardize practices thanks to rigorous clinical studies, so as to determine precisely the indications of this technique in the comprehensive management of shoulder instability. PMID- 22828468 TI - A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum. AB - Brachydactyly type C (BDC), a well-recognized autosomal dominant hand malformation, displays brachymesophalangy of the second, third, and fifth fingers, a short first metacarpal, hyperphalangy, and ulnar deviation of the index finger. An "angel-shaped phalanx" is a distinctive radiological sign that can be found in BDC and other skeletal dysplasias, such as angel-shaped phalango epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. BDC and ASPED result from mutations in the CDMP1 gene. We report here a Mexican patient with BDC and clinical features of ASPED who carries a novel mutation in CDMP1, confirming that BDC and ASPED are part of the CDMP1 mutational spectrum. Based on the large number of clinical features in common, we suggest that both anomalies are part of the same clinical spectrum. Supported by an extensive review of the literature, a possible genotype-phenotype correlation in the mutational spectrum of this gene is proposed. PMID- 22828477 TI - Taste loss in the elderly: epidemiology, causes and consequences. AB - Taste disorders are common among older people and may have serious consequences on their health status: each of the five main flavors (salty, sweet, sour, bitter and umami) has a specific function and a declining taste acuity or taste loss predisposes the elderly to a higher risk of developing certain diseases. Taste disorders often go unrecognized or underestimated in elderly people, however, and there is little medical literature on this issue. This study focused on analyzing the existing literature, paying particular attention to the causes of taste disorders in the elderly and their potential consequences. The most common causes of taste disorders are drug use (21.7%), zinc deficiency (14.5%) and oral and systemic diseases (7.4% and 6.4%, respectively). All these factors can have a negative effect on gustatory system deficiencies due to physiological changes associated with aging. Elderly people are liable to have several chronic diseases and to routinely need multiple medications, and this carries a particular risk of taste disorders or severe loss of the ability to taste the five basic flavors. It is noteworthy that the most useful drugs for treating chronic diseases typical of the elderly are also a potential cause of taste disorders, so periodically reviewing pharmacological therapies is not just a matter of good clinical practice, but also helps to prevent or contain taste disorders. Assessing gustatory function should be a part of any comprehensive geriatric assessment, especially in elderly hospital outpatients or inpatients, or institutionalized cases, with severe conditions that require multiple pharmacological therapies, as well as in elderly patients who are malnourished or at risk of malnutrition, with a view to limiting the modifiable causes of taste disorders. PMID- 22828479 TI - Electronic properties and charge transfer phenomena in Pt nanoparticles on gamma Al2O3: size, shape, support, and adsorbate effects. AB - This study presents a systematic detailed experimental and theoretical investigation of the electronic properties of size-controlled free and gamma Al(2)O(3)-supported Pt nanoparticles (NPs) and their evolution with decreasing NP size and adsorbate (H(2)) coverage. A combination of in situ X-ray absorption near-edge structure (XANES) and density functional theory (DFT) calculations revealed changes in the electronic characteristics of the NPs due to size, shape, NP-adsorbate (H(2)) and NP-support interactions. A correlation between the NP size, number of surface atoms and coordination of such atoms, and the maximum hydrogen coverage stabilized at a given temperature is established, with H/Pt ratios exceeding the 1 : 1 ratio previously reported for bulk Pt surfaces. PMID- 22828478 TI - C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle. AB - The protooncogene C-Myc (Myc) regulates cardiac hypertrophy. Myc promotes compensated cardiac function, suggesting that the operative mechanisms differ from those leading to heart failure. Myc regulation of substrate metabolism is a reasonable target, as Myc alters metabolism in other tissues. We hypothesize that Myc induced shifts in substrate utilization signal and promote compensated hypertrophy. We used cardiac specific Myc-inducible C57/BL6 male mice between 4-6 months old that develop hypertrophy with tamoxifen (tam) injections. Isolated working hearts and (13)Carbon ((13)C)-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing (13)C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and insulin. Studies were performed at pre-hypertrophy (3-days tam, 3dMyc), established hypertrophy (7-days tam, 7dMyc) or vehicle control (Cont). Non-transgenic siblings (NTG) received 7-days tam or vehicle to assess drug effect. Hypertrophy was assessed by echocardiograms and heart weights. Western blots were performed on key metabolic enzymes. Hypertrophy occurred in 7dMyc only. Cardiac function did not differ between groups. Tam alone did not affect substrate contributions in NTG. Substrate utilization was not significantly altered in 3dMyc versus Cont. The free fatty acid FC was significantly greater in 7dMyc versus Cont with decreased unlabeled Fc, which is predominately exogenous glucose. Free fatty acid flux to the citric acid cycle increased while lactate flux was diminished in 7dMyc compared to Cont. Total protein levels of a panel of key metabolic enzymes were unchanged; however total protein O-GlcNAcylation was increased in 7dMyc. Substrate utilization changes for the citric acid cycle did not precede hypertrophy; therefore they are not the primary signal for cardiac growth in this model. Free fatty acid utilization and oxidation increase at established hypertrophy. Understanding the mechanisms whereby this change maintained compensated function could provide useful information for developing metabolic therapies to treat heart failure. The molecular signaling for this metabolic change may occur through O-GlcNAcylation. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". PMID- 22828480 TI - beta1-adrenoceptor stimulation enhances the differentiation of mouse induced pluripotent stem cells into neural progenitor cells. AB - The cyclic AMP/protein kinase A signaling pathway is thought to be involved in neural differentiation of mesenchymal stem cells. In the present study, we examined the involvement of beta-adrenoceptor signaling on the differentiation of mouse induced pluripotent stem (iPS) cells into neural progenitor cells. Mouse iPS cells were cultured on ultra-low-attachment dishes to induce embryoid body (EB) formation. All-trans retinoic acid (ATRA, 1 MUM) and/or the beta adrenoceptor agonist l-isoproterenol (0.3 or 1 MUM) were added to the EB cultures for 4 days, then EBs were plated on gelatin-coated plates and cultured for 7 or 14 days. Subtype-specific antibody staining revealed that mouse iPS cells express beta(1)-adrenoceptors predominantly. Although treatment with l-isoproterenol alone did not affect the expression of Nestin (a specific marker for neural progenitor cells), l-isoproterenol significantly enhanced ATRA-induced Nestin expression. Pretreatment of EBs with either atenolol (a selective beta(1) adrenoceptor antagonist) or H89 (a protein kinase A inhibitor) significantly inhibited the l-isoproterenol-enhancement of ATRA-induced Nestin expression. In addition, the l-isoproterenol treatment significantly enhanced ATRA-induced expression of NeuN (a neuron-specific nuclear protein). These findings suggest that beta(1)-adrenoceptor stimulation enhances ATRA-induced neural differentiation of mouse iPS cells. PMID- 22828482 TI - Optimisation of HIV care and service delivery: doing more with less. AB - The unprecedented, successful collaborative international effort to provide universal access to HIV care, including effective antiretroviral therapy, has reached a crucial point. Global economic downturn, changing donor priorities, and competing priorities in the health sector threaten the target of provision of 15 million people with HIV/AIDS with treatment by 2015, as agreed by the UN General Assembly. This aspiration has received added impetus from the finding that treatment prevents transmission by reduction of infectiousness of patients. In this report we critically review success thus far and examine efforts to optimise delivery of HIV care including antiretroviral therapy in low-income and middle income countries for four main domains: treatment strategy, drug dosing, monitoring, and service delivery. PMID- 22828481 TI - 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. AB - BACKGROUND: New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. METHODS: In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer generated randomisation sequence to receive bedaquiline, bedaquiline pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. FINDINGS: The mean 14-day EBA of PA-824-moxifloxacin pyrazinamide (n=13; 0.233 [SD 0.128]) was significantly higher than that of bedaquiline (14; 0.061 [0.068]), bedaquiline-pyrazinamide (15; 0.131 [0.102]), bedaquiline-PA-824 (14; 0.114 [0.050]), but not PA-824-pyrazinamide (14; 0.154 [0.040]), and comparable with that of standard treatment (ten; 0.140 [0.094]). Treatments were well tolerated and appeared safe. One patient on PA-824 moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. INTERPRETATION: PA-824 moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. FUNDING: The Global Alliance for TB Drug Development (TB Alliance). PMID- 22828483 TI - Antiretroviral drug resistance in resource-limited settings. PMID- 22828484 TI - Treatment of tuberculosis: have we turned the corner? PMID- 22828486 TI - Studies of self-organization processes in nanoporous alumina membranes by small angle neutron scattering. AB - We performed studies of the self-organization processes in nanoporous alumina membranes at initial and late stages of aluminum anodization by using scanning electron microscopy (SEM) and small-angle neutron scattering (SANS). SEM observations indicated three stages in the self-organization of nanopores in alumina: (1) nucleation of random nanopores with a broad radius distribution, (2) narrowing the radius distribution and (3) slow evolution of the nanoporous structure towards ordering of nanopores into large domains. SANS studies revealed orientational correlation between ordered domains of nanopores, which is characterized by a small misorientation angle. For the samples with high aspect ratios of nanopores, the SANS patterns showed azimuthal smearing, which was attributed to the redistribution of nanopores between the domains during their growth. PMID- 22828485 TI - Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. AB - BACKGROUND: The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. METHODS: We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. FINDINGS: Study-level data were available for 26,102 patients from sub Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0.0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7.4% (4.3 to 12.7). We recorded an annual increase of 14% (0% to 29%; p=0.054) in southern Africa and a non-significant increase of 3% (-0.9 to 16; p=0.618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0.0001) and southern Africa (23% per year [7 to 42]; p=0.0049). No increase was noted for the other drug classes in any region. INTERPRETATION: Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle income countries--no changes in antiretroviral treatment guidelines are warranted at the moment. FUNDING: Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme. PMID- 22828487 TI - The structure, thermal properties and phase transformations of the cubic polymorph of magnesium tetrahydroborate. AB - The structure of the cubic polymorph of magnesium tetrahydroborate (gamma Mg(BH(4))(2)) has been determined in space group Ia3d from a structural database of the isoelectronic compound SiO(2); this has been corroborated by DFT calculations. The structure is found to concur with that recently determined by Filinchuk et al. (Y. Filinchuk, B. Richter, T. R. Jensen, V. Dmitriev, D. Chernyshov and H. Hagemann, Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201100675). The phase transformations and subsequent decomposition of gamma-Mg(BH(4))(2) on heating have been ascertained from variable-temperature synchrotron X-ray diffraction data combined with thermogravimetric and mass spectrometry measurements. At ~160 degrees C, conversion to a disordered variant of the beta-Mg(BH(4))(2) phase (denoted as beta') is observed along with a further unidentified polymorph. There is evidence of amorphous phases during decomposition but there is no direct crystallographic indication of the existence of Mg(B(12)H(12)) or other intermediate Mg-B-H compounds. MgH(2) and finally Mg are observed in the X-ray diffraction data after decomposition. PMID- 22828488 TI - Wolfe's part in the Italian Risorgimento and his skin graft. AB - A little known episode in the history of plastic surgery occurred during the Italian Risorgimento 150 years ago. Dr. J. R. Wolfe, who described the full thickness graft which bears his name, was involved with Garibaldi in the war to unite Italy. He crossed swords with an English nurse, Jessie White Mario, and was thrown into prison. The events were recorded in the Lancet as "A Neapolitan Outrage." This article gives the details of the sad story and goes on to describe the first attempts at full-thickness grafting to correct ectropion. Wolfe was not the first to carry out this procedure and the name of Lawson is rarely remembered. PMID- 22828489 TI - Formal dementia care among first nations in southwestern Ontario. AB - This article explores how dementia care is provided to First Nations communities in southwestern Ontario. Data were collected through in-depth interviews with health care providers and analysed using a constructivist grounded-theory methodology. Two interrelated frameworks for understanding dementia care were identified: a care delivery framework and a knowledge framework. The care delivery framework identified care goals, care elements being provided, care barriers, and strategies and solutions to deliver care and overcome barriers. The knowledge framework defined four groups of knowledge stakeholders: persons with dementia, informal care providers, formal care providers, and the First Nations community. It identified the knowledge each stakeholder held or needed and processes of sharing - or failing to share - knowledge in dementia care. Several barriers, many created by a lack of knowledge, negatively impacted dementia care. However, health care professionals had effective strategies for providing care, designed to overcome barriers and which encompassed elements of knowledge sharing. PMID- 22828495 TI - Genetic variants affecting the neural processing of human facial expressions: evidence using a genome-wide functional imaging approach. AB - Human faces present crucial visual information for social interaction. Specialized brain regions are involved in the perception of faces, with the fusiform face area (FFA) a key neuronal substrate. Face processing is genetically controlled, but by which specific genes is unknown. A genome-wide approach identified common single nucleotide polymorphisms (SNPs) associated with areas of increased brain activity in response to affective facial expressions, measured with functional magnetic resonance imaging. SNPs in 20 genetic regions were linked with neural responses to negative facial expressions in a Norwegian sample (n=246), which included patients with mental illness. Three genetic regions were linked with FFA activation in a further discovery experiment using positive facial expressions and involving many of the same individuals (n=284). Two of these three regions showed significant association with right FFA activation to negative facial expressions in an independent North American replication sample of healthy Caucasians (n=85, 3q26.31, P=0.004; 20p12.3, P=0.045). The activation patterns were particularly striking for the SNP in 3q26.31, which lies in a gene TMEM212; only the FFA was activated. The specialized function of this brain region suggests that TMEM212 could contribute to the innate architecture of face processing. PMID- 22828497 TI - Perceived barriers and motivating factors influencing student midwives' acceptance of rural postings in Ghana. AB - BACKGROUND: Research on the mal-distribution of health care workers has focused mainly on physicians and nurses. To meet the Millennium Development Goal Five and the reproductive needs of all women, it is predicted that an additional 334,000 midwives are needed. Despite the on-going efforts to increase this cadre of health workers there are still glaring gaps and inequities in distribution. The objectives of this study are to determine the perceived barriers and motivators influencing final year midwifery students' acceptance of rural postings in Ghana, West Africa. METHODS: An exploratory qualitative study using focus group interviews as the data collection strategy was conducted in two of the largest midwifery training schools in Ghana. All final year midwifery students from the two training schools were invited to participate in the focus groups. A purposive sample of 49 final year midwifery students participated in 6 focus groups. All students were women. Average age was 23.2 years. Glaser's constant comparative method of analysis was used to identify patterns or themes from the data. RESULTS: Three themes were identified through a broad inductive process: 1) social amenities; 2) professional life; and 3) further education/career advancement. Together they create the overarching theme, quality of life, we use to describe the influences on midwifery students' decision to accept a rural posting following graduation. CONCLUSIONS: In countries where there are too few health workers, deployment of midwives to rural postings is a continuing challenge. Until more midwives are attracted to work in rural, remote areas health inequities will exist and the targeted reduction for maternal mortality will remain elusive. PMID- 22828498 TI - Local in vivo GSK3beta knockdown promotes pancreatic beta cell and acinar cell regeneration in 90% pancreatectomized rat. AB - Endocrine and exocrine insufficiencies are associated with serious diseases such as diabetes and pancreatitis, respectively. Pancreatic cells retain the capacity to regenerate in the context of cell deficiency. The remnant pancreas after pancreatectomy (Px) is a valuable target for testing the efficiency of pharmacological interventions to stimulate cell regeneration. Here, we tested the ability of GSK3beta downregulation on the stimulation of beta- and acinar cell regeneration after 90% Px in adult rats. We developed an in vivo approach based on local silencing of GSK3beta, by delivering antisense morpholino oligonucleotides within the remnant pancreas of 90% pancreatectomized rats, and evaluated its impact on the regenerative potential of pancreatic beta and exocrine cells. beta-Cell (BC) mass was evaluated by morphometry. Cell proliferation and apoptosis were assessed by 5'bromo 2'deoxyuridine (BrdU) incorporation method and TUNEL assay, respectively. The expression of Sox9, Neurogenin-3 (Ngn3), and PDX1 was evaluated by immunohistochemistry. We show that intrapancreatic GSK3beta knockdown leads to increased BC mass (BCM) in 90% pancreatectomized rats by promoting both BC proliferation and differentiation. Moreover, downregulation of GSK3beta significantly improves exocrine growth and prevents acinar cell apoptosis in vivo. Our study designates GSK3beta as a viable drug target for therapeutic intervention on diseases of endocrine and exocrine pancreas associated with cell deficiency. PMID- 22828499 TI - Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques. AB - Hemophilia B is an excellent candidate for gene therapy because low levels of factor IX (FIX) (>=1%) result in clinically significant improvement of the bleeding diathesis. Helper-dependent adenoviral (HDAd) vectors can mediate long term transgene expression without chronic toxicity. To determine the potential for HDAd-mediated liver-directed hemophilia B gene therapy, we administered an HDAd expressing hFIX into rhesus macaques through a novel and minimally invasive balloon occlusion catheter-based method that permits preferential, high efficiency hepatocyte transduction with low, subtoxic vector doses. Animals given 1 * 10(12) and 1 * 10(11) virus particle (vp)/kg achieved therapeutic hFIX levels for the entire observation period (up to 1,029 days). At 3 * 10(10) and 1 * 10(10) vp/kg, only subtherapeutic hFIX levels were achieved which were not sustained long-term. Balloon occlusion administration of HDAd was well tolerated with negligible toxicity. Five of six animals developed inhibitors to hFIX. These results provide important information in assessing the clinical utility of HDAd for hemophilia B gene therapy. PMID- 22828500 TI - An oncolytic adenovirus enhanced for toll-like receptor 9 stimulation increases antitumor immune responses and tumor clearance. AB - Oncolytic viruses represent a multifaceted tool for cancer treatment. In addition to specific killing of cancer cells (oncolysis), these agents also provide danger signals prompting the immune system to stimulate an antitumor immune response. To increase adenovirus adjuvancy, we engineered the genome of Ad5D24 by inserting 18 immunostimulatory islands (Ad5D24-CpG). The toxicity and immunogenicity profile of Ad5D24-CpG showed that the safety of the maternal virus was retained. The efficacy of the CpG-enriched virus was assessed in a xenograft model of lung cancer where a significant increase in antitumor effect was seen in comparison with controls. When the experiment was repeated in animal depleted of natural killer (NK) cells, Ad5D24-CpG lost its advantage. The same was seen when Toll like receptor (TLR)9 was blocked systemically. In a syngeneic model of melanoma (B16-OVA), we observed a significant increase of OVA-specific T cells and a decrease of activation of myeloid-derived suppressor cells in Ad5D24-CpG-treated mice. In conclusion, we have generated the first genetically modified oncolytic adenovirus backbone able to enhance TLR9-stimulation for increased antitumor activity. PMID- 22828501 TI - Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. AB - The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75-IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics. PMID- 22828502 TI - A designed zinc-finger transcriptional repressor of phospholamban improves function of the failing heart. AB - Selective inhibition of disease-related proteins underpins the majority of successful drug-target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases. PMID- 22828503 TI - Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A. AB - Niemann-Pick disease Type A (NPA) is a neuronopathic lysosomal storage disease (LSD) caused by the loss of acid sphingomyelinase (ASM). The goals of the current study are to ascertain the levels of human ASM that are efficacious in ASM knockout (ASMKO) mice, and determine whether these levels can be attained in non human primates (NHPs) using a multiple parenchymal injection strategy. Intracranial injections of different doses of AAV1-hASM in ASMKO mice demonstrated that only a small amount of enzyme (<0.5 mg hASM/g tissue) was sufficient to increase survival, and that increasing the amount of hASM did not enhance this survival benefit until a new threshold level of >10 mg hASM/g tissue was reached. In monkeys, injection of 12 tracts of AAV1-hASM resulted in efficacious levels of enzyme in broad regions of the brain that was aided, in part, by axonal transport of adeno-associated virus (AAV) and movement through the perivascular space. This study demonstrates that a combination cortical, subcortical, and cerebellar injection protocol could provide therapeutic levels of hASM to regions of the NHP brain that are highly affected in NPA patients. The information from this study might help design new AAV-mediated enzyme replacement protocols for NPA and other neuronopathic LSDs in future clinical trials. PMID- 22828504 TI - Restoration of vision in the pde6beta-deficient dog, a large animal model of rod cone dystrophy. AB - Defects in the beta subunit of rod cGMP phosphodiesterase 6 (PDE6beta) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6beta deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6beta (n = 4) or AAV2/8RK.cpde6beta (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6beta- and AAV2/8RK.cpde6beta-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID- 22828506 TI - Regulatory role of mouse epidermal growth factor-like protein 8 in thymic epithelial cells. AB - Unlike epidermal growth factor-like protein 7 (EGFL7), which is a secreted protein implicated in the regulation of blood vessel formation and cell migration, little is known about the physiological function of EGFL8. Thymic epithelial cells (TECs) play a pivotal role in T-cell development by regulating cellular interactions and expression of growth factors, cytokines, and chemokines. In order to investigate the functional role of EGFL8 in TECs, we transfected TECs with an EGFL8-expressing vector to overexpress EGFL8 protein and with an EGFL8 siRNA to knockdown EGFL8 expression. EGFL8-silenced TECs showed significant increase in the number of adherent thymocytes by enhancing the expression of intercellular adhesion molecule-1 (ICAM-1), while the overexpression of EGFL8 inhibited the adherence of TECs to thymocytes by suppressing ICAM-1 expression. Furthermore, in vitro co-culture study revealed that knockdown of EGFL8 facilitated the maturation of thymocytes to CD4(+) and CD8(+) single-positive populations. These regulatory effects of EGFL8 in T-cell development were further confirmed by the results that knockdown of EGFL8 enhanced the expression of genes involved in thymopoiesis, such as interleukin-7 (IL-7), granulocyte/macrophage-colony stimulating factor (GM-CSF), and thymus expressed chemokine (TECK). Our data show that EGFL8 exerts inhibitory effects on TECs and thymocytes, suggesting that EGFL8 acts as a negative regulatory molecule in the development of T cells in the mouse thymus. PMID- 22828505 TI - Constitutive activation of the mTOR signaling pathway within the normal glomerulus. AB - Agents that target the activity of the mammalian target of rapamycin (mTOR) kinase in humans are associated with proteinuria. However, the mechanisms underlying mTOR activity and signaling within the kidney are poorly understood. In this study, we developed a sensitive immunofluorescence technique for the evaluation of activated pmTOR and its associated signals in situ. While we find that pmTOR is rarely expressed in normal non-renal tissues, we consistently find intense expression in glomeruli within normal mouse and human kidneys. Using double staining, we find that the expression of pmTOR co-localizes with nephrin in podocytes and expression appears minimal within other cell types in the glomerulus. In addition, we found that pmTOR was expressed on occasional renal tubular cells within mouse and human kidney specimens. We also evaluated mTOR signaling in magnetic bead-isolated glomeruli from normal mice and, by Western blot analysis, we confirmed function of the pathway in glomerular cells vs. interstitial cells. Furthermore, we found that the activity of the pathway as well as the expression of VEGF, a target of mTOR-induced signaling, were reduced within glomeruli of mice following treatment with rapamycin. Collectively, these findings demonstrate that the mTOR signaling pathway is constitutively hyperactive within podocytes. We suggest that pmTOR signaling functions to regulate glomerular homeostasis in part via the inducible expression of VEGF. PMID- 22828508 TI - Small-angle X-ray scattering reveals structural dynamics of the botulinum neurotoxin associating protein, nontoxic nonhemagglutinin. AB - In cell culture supernatants, the botulinum neurotoxin (BoNT) exists as part of a toxin complex (TC) in which nontoxic nonhemagglutinin (NTNHA) and/or hemagglutinins (HAs) are assembled onto the BoNT. A series of investigations indicated that formation of the TC is vital for delivery of the toxin to nerve cells through the digestive tract. In the assembly process, BoNT binds to NTNHA yielding M-TC, and it then matures into L-TC by further association with the HAs via NTNHA in the M-TC. Here, we report a crystal structure of the NTNHA from Clostridium botulinum serotype D strain 4947. Additionally, we performed small angle X-ray scattering (SAXS) analysis of the NTNHA and the M-TC to elucidate the solution structure. The crystal structure of D-4947 NTNHA revealed that BoNT and NTNHA share a closely related structure consisting of three domains. The SAXS image indicated that, even though the N-terminal two-thirds of the NTNHA molecule had an apparently similar conformation in both the crystal and solution structures, the C-terminal third of the molecule showed a more extended structure in the SAXS image than that seen in the crystallographic image. The discrepancy between the crystal and solution structures implies a high flexibility of the C terminal third domain of NTNHA, which is involved in binding to BoNT. Structural dynamics of the NTNHA molecule revealed by SAXS may explain its binding to BoNT to form the BoNT/NTNHA complex. PMID- 22828507 TI - ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response. AB - ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL 7Ralpha and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2Ralpha expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response. PMID- 22828509 TI - Crystal and solution structures disclose a putative transient state of mitogen activated protein kinase kinase 4. AB - Mitogen-activated protein kinase kinase 4 (MAP2K4) plays a crucial role in the stress-activated signal cascade and is enzymatically regulated by ligand or substrate binding, and/or post-translational modification. Crystal structures combined with small-angle X-ray scattering experiments revealed that the apo form of non-phosphorylated MAP2K4 (npMAP2K4) exists in a transient state which has a longer conformation compared with the typical kinase folding. Upon ATP-binding, the transient conformation adopted the configuration of typical kinase folding. In the absence of ATP-binding, the transient state of apo npMAP2K4 may shift to a state of aggregation via non-particular hydrophobic interactions as a result of the exposed hydrophobic residues. PMID- 22828510 TI - Enhancement of tubulin polymerization by Cl(-)-induced blockade of intrinsic GTPase. AB - In growing neurite of neuronal cells, it is suggested that alpha/beta-tubulin heterodimers assemble to form microtubule, and assembly of microtubule promotes neurite elongation. On the other hand, recent studies reveal importance of intracellular Cl(-) in regulation of various cellular functions such as cell cycle progression, differentiation, cell migration, and elongation of neurite in neuronal cells. In this study, we investigated effects of Cl(-) on in vitro tubulin polymerization. We found that efficiency of in vitro tubulin polymerization (the number of microtubule) was higher (3 to 5-fold) in Cl(-) containing solutions than that in Cl(-)-free solutions containing Br(-) or NO(3)( ). On the other hand, GTPase activity of tubulin was lower (2/3-fold) in Cl(-) containing solutions than that in Cl(-)-free solutions containing Br(-) or NO(3)( ). Efficiency of in vitro tubulin polymerization in solutions containing a non hydrolyzable analogue of GTP (GpCpp) instead of GTP was much higher than that in the presence of GTP. Effects of replacement of GTP with GpCpp on in vitro tubulin polymerization was weaker in Cl(-) solutions (10-fold increases) than that in Br( ) or NO(3)(-) solutions (20-fold increases), although the efficiency of in vitro tubulin polymerization in Cl(-) solutions containing GpCpp was still higher than that in Br(-) or NO(3)(-) solutions containing GpCpp. Our results suggest that a part of stimulatory effects of Cl(-) on in vitro tubulin polymerization is mediated via an inhibitory effect on GTPase activity of tubulin, although Cl(-) would also regulate in vitro tubulin polymerization by factors other than an inhibitory effect on GTPase activity. PMID- 22828511 TI - Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice. AB - Mast cells mediate allergies, hypersensitivities, host defense, and venom neutralization. An area of recent interest is the contribution of mast cells to inflammatory pain. Here we found that specific, local activation of mast cells produced plantar hyperalgesia in mice. Basic secretagogue compound 48/80 induced plantar mast cell degranulation accompanied by thermal hyperalgesia, tissue edema, and neutrophil influx in the hindpaws of ND4 Swiss mice. Blocking mast cell degranulation, neutrophil extravasation, and histamine signaling abrogated these responses. Compound 48/80 also produced edema, pain, and neutrophil influx in WT C57BL/6 but not in genetically mast cell-deficient C57BL/6-Kit(W-sh)(/)(W sh) mice. These responses were restored following plantar reconstitution with bone marrow-derived cultured mast cells. PMID- 22828513 TI - Biophysical studies with AICD-47 reveal unique binding behavior characteristic of an unfolded domain. AB - APP intracellular C-terminal domain (AICD-47), generated upon gamma-secretase cleavage of amyloid precursor's protein (APP), bears the signature of a classical intrinsically unstructured domain (IUD). Comparing the recent crystal structures of AICD-47 peptides bound to its different adaptors such as protein-tyrosine binding domain-2 (PTB2) of Fe65 and Src homology 2 (SH2) domain of growth factor receptor binding protein 2 (Grb2), the "conformational switching" of AICD-47 becomes evident. In order to understand different binding processes undertaken by this flexible molecule, upon recognizing different interfaces resulting in different 3D conformations, spectroscopic and calorimetric studies have been done. CD spectroscopy has revealed an overall random coil like structure in different pHs while TFE (2'-2'-2'-trifluoro ethanol) and HFIP (Hexa fluoro isopropanol) induced alpha-helicity to a certain extent. Binding of Tyr phosphorylated AICD-47 ((P)AICD-47) to Grb2-SH2 domain was carried out by a favorable enthalpic change (DeltaH=-197.5+/-6.2 kcal mole(-1) at 25 degrees C) and an unfavorable entropic contribution (DeltaS=-631 cal mol(-1) deg(-1) at 25 degrees C). Alternative conformation of AICD-47 in different biological contexts is another remarkable feature of IUDs which presumably has definitive roles in regulating Alzheimer's disease phenotype. PMID- 22828512 TI - Extracellular ATP attenuates ischemia-induced caspase-3 cleavage in human endothelial cells. AB - BACKGROUND: Apoptotic death of endothelial cells (EC) plays a crucial role for the development of ischemic injury. In the present study we investigated the impact of extracellular Adenosine-5'-triphosphate (ATP), either released from cells or exogenously added, on ischemia-induced apoptosis of human EC. METHODS AND RESULTS: To simulate ischemic conditions, cultured human umbilical vein endothelial cells (HUVEC) were exposed to 2 h of hypoxia (Po(2)<4mm Hg) in serum free medium. Ischemia led to a 1.7-fold (+/-0.4; P<0.05) increase in EC apoptosis compared to normoxic controls as assessed by immunoblotting and immunocytochemistry of cleaved caspase-3. Ischemia-induced apoptosis was accompanied by a 2.3-fold (+/-0.5; P<0.05) increase of extracellular ATP detected by using a luciferin/luciferase assay. Addition of the soluble ecto-ATPase apyrase, enhancing ATP degradation, increased ischemia-induced caspase-3 cleavage. Correspondingly, inhibition of ATP breakdown by addition of the selective ecto-ATPase inhibitor ARL67156 significantly reduced ischemia-induced apoptosis. Extracellular ATP acts on membrane-bound P2Y- and P2X-receptors to induce intracellular signaling. Both, ATP and the P2Y-receptor agonist UTP significantly reduced ischemia-induced apoptosis in an equipotent manner, whereas the P2X-receptor agonist alphabeta-me-ATP did not alter caspase-3 cleavage. The anti-apoptotic effects of ARL67156 and UTP were abrogated when P2-receptors were blocked by Suramin or PPADS. Furthermore, extracellular ATP led to an activation of MEK/ERK- and PI3K/Akt-signaling pathways. Accordingly, inhibition of MEK/ERK signaling by UO126 or inhibition of PI3K/Akt-signaling by LY294002 abolished the anti-apoptotic effects of ATP. CONCLUSION: The data of the present study indicate that extracellular ATP counteracts ischemia-induced apoptosis of human EC by activating a P2Y-receptor-mediated signaling reducing caspase-3 cleavage. PMID- 22828514 TI - Identification of ecdysone response elements (EcREs) in the Bombyx mori cathepsin D promoter. AB - Bombyx mori Cathepsin D (BmCatD) is specifically expressed in the fat body, and plays a critical role for the programmed cell death of the larval fat body and pupal gut during metamorphosis. To better understand the transcriptional control of BmCatD expression, we conducted this study to identify the ecdysone response elements (EcREs) in the BmCatD promoter and clarify their regulational functions. We inserted EcREs into a recombinant AcMNPV (Autographa californica multiple nucleopolyhedrovirus) vector and performed luciferase assay with a dual luciferase quantitative assay system. Three putative EcREs were located at positions -109 to -99, -836 to -826 and -856 to -846 relative to the transcription start site. Overlapping deletion studies of this EcRE region showed that the three EcREs could suppress the ectopic expression of the BmCatD promoter. EcRE mutations resulted in the loss of the fat body-specific expression of the BmCatD gene. These results suggest that the EcREs are vital for activation of the promoter by 20-hydroxyecdysone (20E) in the larval fat body and further support the crucial role of ecdysone signaling to control cathepsin D gene transcription. It may suggest that the heterodimeric complex EcR/USP mediates the activation of ecdysone-dependent BmCatD transcription in the larval fat body of B. mori. PMID- 22828515 TI - Generation and characterization of Tmeff2 mutant mice. AB - TMEFF2 is a single-transmembrane protein containing one EGF-like and two follistatin-like domains. Some studies implicated TMEFF2 as a tumor suppressor for prostate and other cancers, whereas others reported TMEFF2 functioning as a growth factor for neurons and other cells. To gain insights into the apparently conflicting roles of TMEFF2, we generated a null allele of Tmeff2 gene by replacing its first coding exon with human placental alkaline phosphatase cDNA (Tmeff2(PLAP)). Tmeff2(PLAP/PLAP) homozygous mutant mice are born normal, but show growth retardation and die around weaning age. Tmeff2 is widely expressed in the nervous system, and the Tmeff2(PLAP) knock-in allele enables the visualization of neuronal innervations of skin and internal organs with a simple alkaline phosphatase staining. Tmeff2 is also highly expressed in prostate gland and white adipose tissues (WAT). However, with the exception of reduced WAT mass, extensive anatomical and molecular analyses failed to detect any structural or molecular abnormalities in the brain, the spinal cord, the enteric nervous system, or the prostate in the Tmeff2 mutants. No tumors were found in Tmeff2 mutant mice. The Tmeff2(PLAP/PLAP) knock-in mouse is an useful tool for studying the in vivo biological functions of TMEFF2. PMID- 22828516 TI - Identification of the Mycobacterium marinum Apa antigen O-mannosylation sites reveals important glycosylation variability with the M. tuberculosis Apa homologue. AB - The 45/47 kDa Apa, an immuno-dominant antigen secreted by Mycobacterium tuberculosis is O-mannosylated at multiple sites. Glycosylation of Apa plays a key role in colonization and invasion of the host cells by M. tuberculosis through interactions of Apa with the host immune system C-type lectins. Mycobacterium marinum (M.ma) a fish pathogen, phylogenetically close to M. tuberculosis, induces a granulomatous response with features similar to those described for M. tuberculosis in human. Although M.ma possesses an Apa homologue, its glycosylation status is unknown, and whether this represents a crucial element in the pathophysiology induced by M.ma remains to be addressed. To this aim, we have identified two concanavalin A-reactive 45/47 kDa proteins from M.ma, which have been further purified by a two-step anion exchange chromatography process. Advanced liquid chromatography-nanoESI mass spectrometry-based proteomic analyses of peptides, derived from either tryptic digestion alone or in combination with the Asp-N endoproteinase, established that M.ma Apa possesses up to seven distinct O-mannosylated sites with mainly single mannose substitutions, which can be further extended at the Ser/Thr/Pro rich region near the N-terminus. This opens the way to further studies focussing on the involvement and biological functions of Apa O-mannosylation using the M.ma/zebrafish model. PMID- 22828517 TI - Volunteer for NAON: finding the value. PMID- 22828518 TI - Changing practice, preventing injury. PMID- 22828520 TI - Rheumatoid arthritis educational series: a nurse-led project. AB - Nurses in the rheumatology clinic at New York University Hospital for Joint Diseases realized a need to provide patients with rheumatoid arthritis with more healthcare information than was routinely given during clinic visits. This project goal was to support patient involvement in decision making and encourage participation in treatment planning. To address these concerns, a team of staff registered nurses developed an educational program based on various arthritis related topics. This article shares the experiences of these nurses as they developed and led a patient education project. Various elements of the project are discussed, including institutional history, program needs, project start-up, challenges, outcomes, and the lessons learned. PMID- 22828522 TI - Isolated macrodactyly of the foot: diagnosis and treatment. PMID- 22828524 TI - Oh, their aching backs! occupational injuries in nursing assistants. AB - PURPOSE: A substantive body of literature exists about nurses' risk for injury, but much less is known about musculoskeletal disorders, also termed ergonomic injuries, occurring in certified nurse aides (CNAs). To address this gap in the literature, and building on the extant research about workplace injuries in nurses, the aim of this study was to explore both the extent of and reasons for the occurrence of back injuries in CNAs. These data are important given that CNAs are essential members of healthcare teams with whom registered nurses (RNs) closely collaborate in caring for patients. DESIGN: Systematic random sampling was used to select 200 individuals from the State Board of Nursing's public list of nursing assistants that contained more than 2,000 names. These CNAs were mailed a survey that asked them about whether or not they had incurred injuries while working as CNAs and the circumstances under which these injuries occurred. METHODS: Thirty-five participants completed the 19-item, self-report survey regarding back injuries incurred while working. Questions asked about demographics, injuries at work, injury prevention training received at work and in their educational programs, and about factors least liked about their jobs. FINDINGS: : Almost 46% (n = 16) of the respondents reported having hurt themselves while lifting, moving, or helping a patient, with 40% (n = 14) specifically reporting having incurred a back injury. Eleven of the injured respondents (79%) were working in nursing homes at the time the injury occurred. Certified nurse aides also identified poor working relationships with RNs as a factor influencing their perceptions of work. CONCLUSIONS: As shown in earlier research with nurses, the high number of CNAs reporting a work-related injury that occurred while lifting or moving a patient is cause for alarm. It demonstrates the need for further research about this phenomenon as well as ongoing interventions to educate CNAs about injury prevention, particularly among those working in nursing home environments. PMID- 22828525 TI - Joint replacement and rapid mobilization: a clinical perspective on rapid arthroplasty mobilization protocol. AB - Rapid arthroplasty mobilization protocol (RAMP) is a multimodal approach that has been trialed and implemented over the past 9 years in an Australian hospital, on patients undergoing either a total hip or knee arthroplasty. The aim strongly focuses on improving patient outcomes, by alleviating many of the postoperative problems associated with total joint arthroplasty, such as pain control, early mobilization, nausea and vomiting, deep vein thrombosis, and increased length of hospital stay. In addition, RAMP is aimed at accelerating wellness to encourage a rapid return to optimum function within the individual. Key elements of this procedure are good communication and an understanding of the protocol by the patient, together with a clear understanding and knowledge of the postoperative care required by the orthopaedic nurses. PMID- 22828527 TI - Efficacy of and advocacy for postural screening in public schools. AB - PURPOSE: To investigate the efficacy of and advocacy for postural screening in public schools. METHODS: The results of postural screenings in 120 primary and secondary schools throughout one representative northeastern U.S. state were analyzed. Nurses were asked how many students were screened and how many students were diagnostically confirmed to have a postural concern. In addition, the nurses answered advocacy questions regarding continuation, value, and cost of the postural screening program. Chi-square analyses were performed on the nurse responses. RESULTS: Of the average 437 students screened, approximately 1% screens were confirmed diagnostically. School nurses believed that postural screening should be continued (chi = 11.904, p < .001), that it was a valuable program (chi = 28.00, p < .001), and that it was at a reasonable cost for their school system (chi = 42.68, p < .011). CONCLUSION: There is poor efficacy for a postural screening program in public schools; only a very small percentage of students are diagnostically identified. However, a statistically significant number of nurses surveyed advocated for continuation of the postural screening program, reported that it was a valuable health screen, and believed that it was at a reasonable cost for their school district. PMID- 22828528 TI - Best practices in orthopaedic inpatient care. AB - Most patients admitted in the hospital requiring skilled nursing care are at risk for adverse events or complications from their conditions and treatments. They require close observation during their hospital stays, and care providers must be prepared to detect and intervene quickly when complications occur. Orthopaedic patients are a unique surgical patient population in that their underlying physical conditions, operative locations, and comorbidities can place them at higher risk for complications or adverse events than many other surgical patients. Orthopaedic patients are usually admitted to general acute care surgical units where there are no monitoring devices and the staffing ratios are less intense. In the event that a higher level of surveillance is needed, current practice is to transfer the patient to a care area with telemetry or hardwired monitoring capability, which can result in deviation from the orthopaedic care pathway. In this article, we describe the implementation of best care practices that combine lower nurse to patient ratios, innovative and effective patient education, and continuous surveillance using novel technology in an orthopaedic unit. Data demonstrate that this multifaceted approach to high-quality orthopaedic care has contributed to better patient outcomes. PMID- 22828532 TI - Comparative study on methotrexate and hydroxychloroquine in the treatment of rheumatoid arthritis. AB - This study was done to see the efficacy and tolerability of methotrexate and hydroxychloroquine in the Treatment of Rheumatoid Arthritis. It was an open label controlled clinical trial, done in Mymensingh Medical college hospital. Fifty six patients were selected by random sampling method, 28 were included in methotrexate group and another 28 for hydroxychloroquine group using inclusion & exclusion criteria. Primary efficacy variables (DAS28, daily naproxen), secondary efficacy variables, and safety measurement variables studied both clinically & laboratory investigations. The data were analyzed by computer with the help of SPSS. The student's t test was used as test of significant. The mean age of the patients at diagnosis was almost identically distributed between methotrexate and hydroxychloroquine group (41.7+/-12.2 vs. 42.9+/-9.2 years, p=0.659). Disease activity at baseline was found to be almost homogeneous to each group except CRP which was observed to be significantly higher in methotrexate group than hydroxychloroquine group (p<0.001). Disease activity at 1 month of treatment reduced in the methotrexate group than those in hydroxychloroquine group (p<0.05 in each case). After 3 and 6 months of treatment, disease activity decreased significantly in both groups (p<0.001 and p<0.05 respectively). The average daily dose of NSAID (Naproxen) decreased significantly (p<0.001). Safety variables at 6 month were within normal physiological ranges and did not differ in groups (p>0.05) indicating that both methotrexate and hydroxychloroquine were effective and safe to use in rheumatoid arthritis. The difference in the incidence of adverse effects, total or individual, was almost nil. PMID- 22828533 TI - Evaluation of PCR with culture for the diagnosis of pulmonary tuberculosis. AB - Tuberculosis (TB) is a major public health problem in most developing countries. The present study was carried out among 100 clinically suspected pulmonary TB patients. One hundred sputum specimens were collected one from each of the suspects attending DOT'S corner of Mymensingh Medical College Hospital, Mymensingh, Bangladesh. The aim of the study was to evaluate the sensitivity and specificity of a polymerase chain reaction (PCR) based method detecting IS6110 sequence present in all Mycobacterium tuberculosis strains using sputum samples in comparison to culture on Lowenstein-Jensen mediums. The PCR was done using primers mtb1 & mtb2 which commonly target an insertion sequence of the organism (IS6110). Out of 100 samples, 18 (18%) showed PCR positive, whereas culture in Lowenstein-Jensen media were positive in 19(19%). In PCR 1 was false negative but none was false positive. In present study, sensitivity and specificity of PCR found 94.74% and 100% respectively. Analyzing the findings of the present study, it can be concluded that the PCR technique is a rapid and alternative method of culture on Lowenstein-Jensen medium for the diagnosis of pulmonary tuberculosis. In the present study, only presence or absence of M. tuberculosis was determined. PMID- 22828534 TI - Multiplex polymerase chain reaction for rapid identification of diarrheagenic Escherichia coli. AB - Despite the fact that diarrhaegenic Escherichia coli (DEC) has been identified as a major etiologic agent of childhood diarrhea which represent a major public health problem in developing countries, only a few studies have been performed in Bangladesh to identify these organisms. To detect DEC in patients with acute diarrhea, a total of 300 stool specimens were tested by multiplex polymerase chain reaction (PCR). The multiplex PCR was designed for the detection of target genes of "eae" for enteropathogenic E. coli (EPEC), "stx" for enterohemorrhagic E. coli (EHEC), "ipaH" for enteroinvasive E. coli (EIEC), "aspU", "CVD432" and "aggR" for enteroaggregative E. coli (EAEC) as well as "elt" and "est" for enterotoxigenic E. coli (ETEC). Out of 300 stool specimens collected from patients with acute diarrhea, the DEC was detected in 18% (54/300) cases. The dominating strain was ETEC (13%, 39/300), followed by EAEC (5%, 15/300) and no EHEC, EIEC and EPEC could be detected. Both heat-stable toxin (ST) and heat labile toxin (LT) genes of ETEC were detected in 66.68% (26/39) strains and only ST or LT as single gene was detected in 23.07% (9/39) or 10.25% (4/39) strains respectively. The multiplex PCR assay could be used as a rapid as well as efficient diagnostic tool for identification of DEC in the clinical laboratory settings. PMID- 22828535 TI - Comparison of post operative pain relief between paracetamol and wound infiltration with levobupivacaine in inguinal hernia repair. AB - The present study has been designed to compare the intensity of postoperative pain in children by wound infiltration with levobupivacaine with that provided by paracetamol administration per rectaly. This intervention study was carried out at the department of paediatric surgery, Mymensingh Medical College Hospital, Mymensingh and Dhaka Medical College Hospital, Dhaka, during the period of January 2009 to September 2010. A total of 120 patients were included in this study. Among them 60 patients in Group A (study group) where post incisional wound infiltration with levobupivacain after inguinal herniotomy before skin closure was done and 60 patients in Group B (control group) where paracetamol was given per rectally after induction of anaesthesia. Both groups were followed up post operatively for 23 hours. The intensity of post operative pain relief following inguinal hernia repair in children by wound infiltration with levobupivacaine is significantly higher than rectal administration of paracetamol. PMID- 22828536 TI - Anterior cervical discectomy and fusion without instrumentation for cervical spondylosis. AB - This prospective study included 50 patients receiving anterior cervical discectomy and fusion (ACDF) was conducted at Mymensingh Medical College Hospital, Mymensingh, Bangladesh. The study period was 1st July 2006 to 30th June 2010. This study was done to see the functional outcome of surgery in relation to duration of symptoms and age of the patient. The clinical information and relevant imaging of 50 consecutive patients, 41 male and 9 female, was reviewed at 1 year after surgery. All surgery was performed at no more than 2 contiguous levels, by one surgeon. After anterior discectomy alone, or combined with posterior vertebral body margin osteophytectomy, anterior bone grafting was performed at each level using a tricortical autogenous iliac crest bone block inserted under compression. All surgery was completed without internal fixation. A postoperative semirigid cervical collar was prescribed for 2 months. In 50 patients, there were 4 pseudarthroses (8%). Only 4% of the 50 patients had pain related to the donor site. The functional outcome was excellent to good (87.5%) when duration of symptoms less than 1 year and outcome was excellent to good (85.29%) when the age less than 50 years. These results tend to confirm published reports of most expected outcome related to young age and short duration of symptoms. Patients with technically successful fusions were less likely to have postoperative neck pain. Donor site pain was not a significant postoperative complication. ACDF is a safe, cheap and effective procedure for cervical spondylosis. In this series no major operative complications have occurred. No extra expenditure for plate and screw in this procedure. PMID- 22828537 TI - Thyroid hormone status in apparently healthy elderly persons. AB - Thyroid disorders are frequent in elderly population and difficult to recognize because of their atypical presentation, and the absence of classic signs and symptoms. Nonspecific symptoms, even in the absence of thyroid dysfunction, are common in this age group, including fatigue, anorexia, weight loss, failure to rehabilitate, and difficult to concentrate. Symptoms of aging can be confused easily with hypothyroidism. The interpretation of thyroid function tests is also cumbersome in aged individuals because of the difficulty in differentiating physiologic age-associated changes from alterations secondary to acute or chronic non-thyroidal illness. In the present study, a total 100 subjects were included. Subjects were divided into two groups: Group I - Control (n=50) and Group II - Case (n=50). Fifty apparently healthy young adults were taken as control (Group I) and 50 apparently healthy elderly subjects were included in case (Group II). Group I was subdivided into two groups- Group IA: young male (n=25) and Group IB: young female (n=25). Group II was also subdivided into two groups - Group IIA: elderly male (n=25) and Group IIB: elderly female (n=25). All the subjects were selected from the local community of Mymensingh Sadar, Mymensingh Medical College, Mymensingh and Community Based Medical College, Bangladesh, Mymensingh. In the present study, the difference of mean serum T3 concentration between Group I (control) and Group II (elderly subjects) was not found to be significant (p>0.05). Significant difference in serum TSH concentration between Group IA and Group IIA was to be found (p<0.001). The difference of mean serum T4 concentration between Group IB and Group IIB was not found significant (p>0.05). Significant difference in mean serum TSH concentration between Group IB and Group IIB was to be found (p<0.001). PMID- 22828538 TI - Laparoscopic versus open pyloromyotomy for infantile hypertropic pyloric stenosis: an early experience. AB - This prospective comparative study was conducted with an initial experience in the Department of Pediatric Surgery, Dhaka Shishu (Children) Hospital during the period of December 2007 to January 2009, with the infants of 2-12 weeks age, diagnosed as Hypertrophic pyloric stenosis. Patients selection was done by simple random technique by means of lottery. For open pyloromyotomy conventional method & for laparoscopic pyloromyotomy three trocher techniques was applied. In this study, among 60 cases with infantile hypertrophic pyloric stenosis, 30 cases were finally selected for analysis irrespectively both in laparoscopic (Group A) & in open pyloromyotomy (Group B) group. Patients were studied under variables of operative time, required time of full feeds after operation, post operative hospital stay & both per and post operative complications. Regarding operative time, in Group A, mean+/-SD operating time (in minutes) was 61.59+/-51.73 whereas in Group B it was 28.33+/-8.40 & P value was 0.001. The result was statistically significant. The mean+/-SD time (in hours) of full feeds (ad libitum) was 35.00+/ 31.70 hours in Group A compared to 28.95+/-10.99 hours in Group B and P value was found 0.342ns which was not statistically significant. On study of total length (in days) of post operative hospital stay, mean+/-SD was 3.09+/-2.25 & 2.58+/ 1.15days in laparoscopic group & open pyloromyotomy group respectively. The p value was 0.355ns, which was statistically insignificant. Again, on study of complications, per operatively 6(19.5%) patients had developed haemorrage, 1(3.33%) had mucosal perforation & 4(13.36%) had developed duodenal serosal injury in laparoscopic group whereas only 1(3.33%) patient in open pyloromyotomy group had nothing else except simple hemorrhage. The p value (0.051ns) was also statistically insignificant. In regard to post operative complications, 2(6.6%) patients had developed wound hematoma, 2(6.6%) had wound infection, 1(3.33 %) had developed wound dehiscence and incisional hernia respectively in Group A. But in group B there was no subject with any complication. This result was also statistically insignificant. So, the overall study results denote that, laparoscopic pyloromyotomy would not be considered as a superior procedure or as safe as that of traditional open pyloromyotomy for the beginners. PMID- 22828539 TI - Beta thalassemia in a tertiary care hospital with their chelation habit. AB - Beta-thalassemia which is one of the most common genetic disorders in Bangladesh encompasses a group of monogemic diseases that have reduced synthesis or no synthesis of one or more globin chain of haemoglobin. The defects involved are extremely heterogenous and give rise to a large phenotypic spectrum with patients that are almost asymptomatic to cases in which regular blood transfusions are required to sustain life. The aim of the study is to estimate the frequency of beta thalassemia among the blood recipients in the Day Care Centre of Transfusion Medicine Department of Mymensingh Medical College Hospital from July, 2009 to June, 2010 along with their chelation habit. Retrospective cross-sectional study with the sample size of 784, clinical and family data was collected and descriptive statistics were done in the Laboratory of Transfusion Medicine Department. Among the 784 subjects, the beta thalassemia was 521 (66.46%), among the thalassemic patients only 59(11.32%) take injection Dysferrioxamine (Dysferol), the iron chelating agent. Male are predominant than female (63.53%). Those of the affected patients 67.18% were in age group 6 to 20 years. Although beta thalassemia is one of the first monogemic diseases and represents a global health problem, only recently has the scientific community started to focus on the real molecular mechanisms that underline this disease, opening new & exciting therapeutic perspectives for thalassemic patients worldwide. It is concluded from our study that availability of blood transfusion facilities along with an orally and cheaper iron chelator is an urgent need to ensure the management of needy thalassemic patients in Bangladesh. PMID- 22828540 TI - Proteinuria is an independent risk factor for ischemic stroke among diabetic patients. AB - This study was done to assess the relationship between proteinuria and ischemic stroke in subjects with diabetes mellitus, and to determine whether proteinuria is an independent risk factor for stroke. This comparative study was conducted in Mymensingh Medical College Hospital from January 2009 to June 2010. It was done to establish the relationship between proteinuria (Microalbuminuria) and ischemic stroke among diabetic patients. Other risk factors were also assessed. Patients were divided in Group A - diabetic patients with ischemic stroke (n=50) and Group B diabetic patients without stroke (n=50). Mean age of the Group A & B were 60.16+/-8.33 and 57.19+/-7.73 years (p=0.068). Mean Blood sugar (2 hours after Break Fast) was 14.68+/-4.32mmol/L in Group A and 14.75+/-4.02mmol/L in Group B (p>0.05). Albumin Creatinine ratio was abnormal in 84.0% in Group A and 22.0% in Group A (p=0.001) [Odds ratio (95%CI) = 18.61 (6.78-51.09)]. Logistic regression analysis has also shown that microalbuminuria (ACR) is an independent risk factor for ischemic stroke (p=0.001), [Odds ratio (95%CI) = 19.811(5.915-66.348)]. In diabetic patients increased urinary protein is a risk factor for stroke. Estimation of urinary protein (Microalbuminuria) may be used as a predictor for ischemic stroke in patients with diabetes. PMID- 22828541 TI - Morphometric study of splenic volume in Bangladeshi cadaver. AB - To determine the volume of spleen of Bangladeshi people by water displacement method, this cross sectional descriptive study was carried out over 120 cadaveric spleen of which 87 male and 33 female, in the department of Anatomy of Mymensingh Medical College from July 2007 to June 2008. The maximum volume of male spleen was 200ml in group D (46-60 years) and female spleen was 150ml in group B (16-30 years). The minimum volume was 30ml in group A (up to15 years) in both male and female. The maximum mean volume of male was 84.23 ml in group B (16-30 years) and minimum mean volume was 47.75ml in group A (upto 15 years). The mean volume of female spleen was highest, 78.33ml in C (31-45 years) age group and lowest 45.62ml in A (upto 15 years) age group. From this study it was evident that the volume of spleen increases with age during childhood and adolescence remains stable in young adult and declined in older age groups. Volume of spleen shows positive correlation with age up to 60 years of age. Mean+/-SE volume of male spleen was 75.27+/-3.78ml, ranges from 30-200ml and in female; mean+/-SE volume was 60.51+/-4.90ml, ranges from 30-150ml. Here it is observed that volume of spleen was higher in male than in female but the difference was not statistically significant. PMID- 22828542 TI - Comparison between fine needle aspiration cytology with histopathology to validate accurate diagnosis of palpable breast lump. AB - A prospective study of 114 patients was conducted to assess the clinical correlation and diagnostic accuracy between FNAC and histopathology of breast lumps. Correlation was found out between clinical suspicion with FNAC and histopathological findings. The results obtained from histopathology were matched with those of FNAC and a correlation was sought based on statistical tests. Statistical analysis was performed on data and sensitivity and specificity with positive and negative predictive value were obtained. Although FNAC was performed on 114 patients presented with breast lump but histopathology available for 75 cases. Fifteen cases were found to be malignant on both FNAC and histopathology. For malignant lesion the sensitivity of the study was 96% and the specificity for malignant lesions was 100%. The positive predictive value was 100% and the negative predictive value was 95.12%. It was concluded that FNAC is a cheap, rapid, reliable and accurate test of diagnosing a palpable breast lump. It provides a good histological correlation, thus avoiding undue surgical biopsy prior to definitive surgery for malignancy. PMID- 22828544 TI - Role of intraoperative flexible Choledochoscopy in calculous biliary tract disease. AB - Ninety six percent of patients with overlooked bile duct stones required surgery within 5 years of cholecystectomy, every effort should be made to keep the incidence of retained stones minimum. The facilities of pre-operative ERCP are not always available. Examination of the bile ducts under direct vision with a choledochoscope seems a certain method of ensuring that there are no residual stone. A total of 26 patients were evaluated between the periods of 2004 to 2005. Age of the patients ranged from 20 to 70 years. The mean age is about 45.88 years approximately. Six (23.07%) cases had previous history of cholecystectomy. Peroperatively 14(53.84%) cases had only choledocholithiasis, 6(23.07%) cases had cholelithiasis with choledocholithiasis, 4(15.38%) cases had choledocholithiasis with hepatolithiasis and 2(7.69%) cases had Mirrizi's type II with choledocholithiasis. After Choledochoscopy, 22(84.61%) cases had complete blind clearance, 4(15.38%) cases had incomplete blind clearance. Twenty two (84.61%) cases did not require any Choledochoscopy guided stone extraction. Four (15.38%) cases required Choledochoscopy guided Dormia basket extraction. Twenty two (84.61%) cases have undergone T tube drainage, 4(15.38%) cases undergone Roux-en Y hepaticojejunostomy who had associated hepatolithiasis. In this series percentage of stone overlooked by instrumental exploration was 15.38 & percentage of residual stone in this study was 0%. PMID- 22828543 TI - Profile of infertility status of male in Dhaka city. AB - A cross sectional study was done to determine the important etiological profile of infertility status of male in Dhaka city. A total of eighty seven patients of male infertility were selected purposively. Among them, highest percentage of patients, 44(50.6%) were in between the 21-30 years old, 36(41.4%) had 6-10 years of post- marriage duration, 56(64.4%) patients stated that they stayed with their wife interruptedly, 54(62.1%) had primary infertility and 33(37.9%) had secondary infertility. It was found that among the patients 6(5.50%) had anti-sperm antibody, 45(40.9%) had sexually transmitted disease (STD), 41(37.3%) had varicocele, 2(1.80%) had loss of libido, 4(3.6%) had premature ejaculation and 12(10.9%) had hydrocele. It was observed that 14(12.7%) were tobacco user, 26(23.6%) were obese, 12(10.9%) had malnutrition, 7(6.4%) had exposure to heat etc and it was found that 61(70.1%) had free testosterone below the normal level and 51(58.6%) had prolactin level above the normal level. The semen analysis revealed that 48(55.2 %) had abnormal morphology of sperm, 26(29.9%) had feebly motile sperm and 27(31%) had non-motile sperm, 36(41.4%) had oligospermia, 6(6.9%) had azoospermia and 17(19.5%) had oligoasthenozoospermia. PMID- 22828546 TI - Serum levels of copper and zinc in newly diagnosed type-2 diabetic subjects. AB - Diabetes mellitus is a chronic metabolic disorder which affects carbohydrate, lipid and protein metabolism. There is a strong relation between some specific oligoelements and diabetes mellitus. The study was undertaken to determine serum levels of copper and zinc in 60 type 2 diabetic (Group I) and 60 healthy non diabetic subjects (Group II). Diabetic patients studied were without any complications. Serum copper and zinc were estimated by Atomic Absorption Spectrophotometer (AAS). The serum copper levels (144.00+/-12.87MUg/dl) significantly increased in Group I compared to Group II (138.50+/-11.00MUg/dl). On the other hand, the Plasma zinc (72.70+/-8.43MUg/dl) levels significantly decreased in type 2 diabetic patients compared to control group (75.92+/ 8.20MUg/dl). It is concluded that type 2 diabetes mellitus can result in changes in copper and zinc levels. However, it is difficult to draw any definite conclusion from this small study sample but may be suggested that estimation of both copper and zinc is better to be considered in those cases. PMID- 22828545 TI - Effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) for the treatment of neonates in presumed sepsis with neutropenia. AB - Bacterial sepsis continues to be an important cause of morbidity and mortality in neonates. In newborn with presumed sepsis, short-term treatment with rhG-CSF increased the neutrophil count and more importantly improved survival. The objective of the study was to evaluate the effect of rhG-CSF for the treatment of neonates in presumed sepsis with neutropenia. This interventional study was conducted in the Department of Neonatology, BSMMU, Dhaka during July 2009 to May 2010. Total 30 neonates of presumed sepsis with absolute neutrophil count <=5000/cumm, age<28 days and birth weight 1000-2000g were included in the study. A subcutaneous injection of rhG-CSF (10MUgm/kg/day) was administered to 15 neonates for 5 consecutive days (study group) and 15 neonates did not receive it (control group) in addition to standard antibiotic protocol for neonatal sepsis. Baseline characteristics of 30 neonates shows male/female ratio, weight on admission, gestational age were similar in both groups. Among 30 neonates of clinically presumed sepsis 7(23%) were culture proven. E. coli was the most common organism. After 24 hours of treatment mean ANC was increased more in study group (p<0.05) compared to control group. Mean ANC after 72 hours of treatment was increased significantly in study group than control group: 5940.00 versus 5706.00 (p=0.01). At the end of treatment, the mean ANC was higher than that of control (p=0.001). Twelve neonates in study group and ten neonates in control group survived to hospital discharge. The mortality rate in the study group 3/15(20%) and in control group 5/15(33%) were not significant. Duration of hospital stay was less in study group but not significant. The study concluded that before routine use of rhG-CSF in neonatal sepsis with neutropenia further large scale, multi-centre, randomized, placebo controlled trial are needed to validate the beneficial effect. PMID- 22828547 TI - Stature estimation from craniofacial anthropometry in Bangladeshi Garo adult females. AB - Estimation of stature is an important tool in forensic examination especially in unknown, highly decomposed, fragmentary and mutilated human remains. When the evidences are skeletal remains; forensic anthropology has put forward means to estimate the stature from the skeletal and even from fragmentary bones. Sometimes, craniofacial remains are brought in for forensic and postmortem examination. In such a situation, estimation of stature becomes equally important along with other parameters like age, sex, race, etc. Today, anthropometry plays an important role in industrial design, clothing design, ergonomics and architecture where statistical data about the distribution of body dimensions in the population are used to optimize products. It is well established that a single standard of craniofacial aesthetics is not appropriate for application to diverse racial and ethnic groups. Bangladesh is a country not only for the Bengalis; the country harbours many cultures and people of different races because of the colonial rules of the past regimes. Like other ethnic groups, the Garos (study subjects) have their own set of language, social structure, cultures and economic activities and religious values. In the above context, the present study was attempted to establish ethnic specific anthropometric data for the Bangladeshi Garo adult females. The study also attempted to find out the correlation of the craniofacial dimensions with stature and to determine multiplication factors. The study was an observational, cross-sectional and primarily descriptive in nature with some analytical components. The study was carried out with a total number of one hundred Garo adult females, aged between 25-45 years. Craniofacial dimension such as head circumference, head length, facial height from 'nasion' to 'gnathion', bizygomatic breadth and stature were measured using a measuring tape, spreading caliper, steel plate and steel tape and sliding caliper. The data were then statistically analyzed by computation to find out its normatic value. Study was also aimed to observe the possible correlation of them with the stature. Multiplication factors were estimated for estimating stature and comparison were made between 'estimated' values with the 'measured' values by using 't' test. The mean+/-SD of the head length, head circumference, facial height from 'nasion' to 'gnathion', bizygomatic breadth were 17.49+/-0.58cm, 51.56+/-1.49cm, 10.65+/-0.40cm, 13.47+/-0.52cm respectively and The mean+/-SD of the stature was 152.79+/-5.62cm. Head circumference showed significant positive correlation with stature (r=0.278 and p= 0.005) but head length (r= -0.029 and p=0.774), bizygomatic breadth (r= 0.143 & p=0.156) and facial height from 'nasion' to 'gnathion' (r=00.023 and p=0.818) did not reach statistically significant level with stature. No significant difference was found between the 'measured' and 'estimated' stature for head circumference, head length, bizygomatic breadth and facial height from 'nasion' to 'gnathion'. PMID- 22828548 TI - Day case Laparoscopic Cholecystectomy: experience at the Bangabandhu Sheikh Mujib Medical University. AB - Day case surgery offers convenience to the patients and cost saving to the healthcare institutes. In this prospective study, the authors reviewed their experience with day case Laparoscopic Cholecystectomy (LC) to determine its outcome in the government healthcare settings of Bangladesh. Selection criteria's for the day case LC were patients with symptomatic cholelithiasis with ASA (American Society of anesthesiologists) grade I or II, the availability of a responsible carer, absence of morbid obesity, low risk for concomitant presence of bile duct stones and domicile within Dhaka and around. Patients were admitted in the post operative ward as day case (DC) in the morning and were discharged on the next morning with a standard analgesia. Two hundred ten patients were admitted for LC as day cases over the last 7 years from October 2003 to October 2010 on the morning operation theatre lists. Five patients later required admission to the inpatient department for conversion to the open procedure. None of the patients was readmitted after discharge. Majority patients were followed up after 1st and 6th week. Two hundred seven patients attended for the follow up at the 1st week and 158 patients were reported for the 6th week. One hundred ninety six patients resumed their normal job or activities after one week. Patient's satisfaction was assessed by questionnaires. Two hundred five patients were either satisfied or very satisfied with the day-case procedure. It appears that for selected groups of patients, day-case LC can be safely done in government healthcare settings of Bangladesh with good patient satisfaction. PMID- 22828549 TI - Depression and its association with socio-demographic characteristics among type 2 diabetes mellitus patients of Bangladesh. AB - Diabetes mellitus is being increasingly recognized as a serious global health problem and is frequently associated with co-morbid depression. A cross sectional study was conducted among 178 adult type 2 diabetes mellitus patients attending Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh to find out influence of socio-demographic characteristics for occurrence of depression among them. Data were collected through face-to-face interview. Depressive symptoms were measured using Centre for Epidemiological Studies Depression Scale. Proportion of depression was found 34.8% which included 20.2% with severe depression and 14.6% with mild to moderate depression. Both mild to moderate and severe depression were significantly more common in female, odds ratios were 2.72 (95% CI=1.13-6.53) and 5.94 (95% CI=2.49 14.20), respectively. Currently not married respondents were also suffered from higher depressive symptoms. For mild to moderate depression odds ratio was 4.38 (95% CI=1.46-13.18) and for severe depression odds ratio was 9.51 (95% CI=3.69 24.50). Among socio-demographic characteristics marital status was identified as the best predictor of depression, which was followed by education upto secondary level, female sex and primary education. Depression was identified as a significant health problem among adult type 2 diabetes mellitus patients. Its association with socio-demographic characteristics should be considered while planning therapeutic approaches for diabetic patients. PMID- 22828550 TI - Genotypes of rotavirus diarrhoea in a children hospital of Bangladesh. AB - Globally, rotaviruses are the single most important etiologic agents of severe childhood dehydrating diarrhea that accounts for more than 125 million of cases, 25-55% of all hospital admissions for diarrhea and ~600,000 deaths every year. In Bangladesh, while overall diarrhea related deaths are declining, the proportion of diarrhea deaths due to rotavirus is increasing. This study was aimed at estimating the burden of rotavirus diarrhea and isolating the genotypes of rotavirus in a children hospital of Bangladesh; thereby endorsing a logical search for an appropriate rotavirus vaccine. This cross sectional study was carried out in the Institute of Child and Mother Health, Matuail, Dhaka, Bangladesh during 2006-2007. Children aged between one month and five years suffering form diarrhea were enrolled in the study. Stool samples were analyzed by ELISA for rotavirus antigen. The rotavirus-positive samples were further analyzed for genotype determination. Among 656 stool samples, 39.5% samples were positive for rotavirus antigen. The mean age of the children studied was 12+/-9.9 months; the peak being in the second half of infancy. G2 was identified as the most dominant genotype (45.5%) followed by G1 (24.8%), G12 (9.6%), G9 (8.5%) and G4 (2.1%) genotypes. Since G2 were found to be the predominant circulating rotavirus strain in this study and some other studies in Bangladesh, the recommended vaccine for prevention of rotavirus infection in Bangladesh should cover this strain to have maximum effectiveness. PMID- 22828551 TI - Primary total hip arthroplasty by cemented prosthesis in secondary osteoarthritis of the hip joint. AB - Cemented total hip arthroplasty has been being practiced successfully all over the world for the last 5 decades. Osteoarthritis is the most common indication of total hip arthroplasty. This study was done to observe the outcome of primary total hip arthroplasty by cemented prosthesis in secondary osteoarthritis of the hip joint. This prospective study was conducted at the department of Orthopaedics, Bangabandhu Sheikh Mujib Medical University and some private hospitals in Dhaka, Bangladesh from May 2008 to December 2009. Total 21 patients were evaluated. Among them 38.1% had rheumatoid arthritis, 19.1% had ankylosing spondylitis and 42.8% had avascular necrosis. Average duration of postoperative hospital stay was 14.09 days. Regarding the functional outcome, 76.2% patients had excellent, 19.1% had good and 4.8% had fair outcome. So out of 21 cases, 95.2% had satisfactory and 4.8% had unsatisfactory outcome. Cemented total hip arthroplasty is an effective procedure for the management of secondary osteoarthritis of the hip joint. PMID- 22828552 TI - Health related Quality of Life with HIV/AIDS in different stages of HIV infection. AB - Disease stages of HIV infection is one of the important predictor of Health related Quality of Life (HQoL) of the people living with HIV/AIDS. This cross sectional study was an attempt to compare the HQoL of HIV-infected patients across the three CDC stages of HIV-infection namely, asymptomatic, symptomatic, and AIDS-related conditions. A total of 82 patients, 28 in asymptomatic, 26 in symptomatic, and 28 in AIDS-related conditions, from three NGOs and one Infectious Disease Hospital (IDH) were interviewed using interviewer administered semi structured questionnaire developed by adopting "World Health Organization Quality of Life HIV BREF (WHOQOL-HIV BREF) instrument". Analysis revealed that AIDS-related conditions and symptomatic patients were experiencing significantly poorer quality of life than asymptomatic patients in the domain of physical (F=7.006, p <0.005), level of independence) F=6.552, p<0.005(, overall perception of health related quality of life (F=3.634, p<0.05) and overall general health perception (F=7.842, p<0.001). PMID- 22828553 TI - Assessment of renal function by estimation of fractional excretion of sodium in asphyxiated newborns. AB - This case control study was conducted in Neonatal unit of Dhaka Shishu (Children) Hospital to assess the validity of fractional excretion of sodium (FENa) as a reliable renal function test in asphyxiated newborns. Seventy five appropriate newborns aged between 0-120 hours were randomized in two groups, (Group I; n=50, cases or study group) and (Group II; n=25, controlled group). Blood urea, serum creatinine, serum electrolytes, urinary electrolytes, creatinine, osmolalities, specific gravity, FENa were estimated. Blood urea, Serum creatinine and FENa are increased in perinatal asphyxia. Controls were selected from newborns who had spontaneous breathing immediately after birth and with Apgar score >8 to 10 at 5 minutes. Mean blood urea and serum creatinine were raised in asphyxiated newborn. Blood urea mean+/-SD was 7.1+/-3.1mmol/L and serum creatinine mean+/-SD was 120.8+/-73.6MUmmol/L. Thirty four percent (34%) patients had raised level of blood urea and serum creatinine both, 18% patients had raised (>2.5%) FENa and 48% patients had raised blood urea in asphyxiated newborns. Hyponatremia was also found in asphyxiated newborns. Urinary sodium and creatinine excretion were also higher in the asphyxiated newborns than non asphyxiated newborns. Urinary volume and osmolality were similar in cases and controls. In this study 24% patients died, of which 62.5% were in HIE stage 3, 4.16% were in HIE stage 2 and 1% was in HIE stage 1. Elevated level of serum creatinine (130.0+/-60.0) and FENa (2.9+/ 1.4) were found in dead patients. Oliguria (0.99+/-0.6) was also found in dead asphyxiated newborns. Increase in fractional excretion of sodium (FENa) is shown to be directly related to the degree of renal impairment which is again directly related to the degree of asphyxia in the newborns. FENa can be used as an indicator of renal tubular dysfunction in the asphyxiated newborns. PMID- 22828554 TI - Nutritional parameters in children with cancer. AB - The study was conducted in the Departments of Pediatric Haemato-Oncology, Bangabandhu Sheikh Mujib Medical University, Shahbagh, Dhaka, Bangladesh from January 2007 to May 2009. Total 44 children (34 males and 10 females) aged between 10 months and 12 years with newly diagnosed malignancy. Nutritional status of 44 children with newly diagnosed malignancy was evaluated by anthropometric, hematological results and biochemical parameters before initiating therapy and response to therapy was assessed during follow up. Malnutrition was seen in 56.8% children by weight for age criteria (WFA <-2z). Low hemoglobin was found in 82% children, 25% had low total proteins (<5.7g/dL), 20.5% low serum albumin (<3.2g/dL), 27.3% low serum transferrin (<210mg/dL) and 16.3% low serum iron (<60MUg/dL). Mean anthropometric and biochemical parameters were higher among the survivors compared to non-survivors. Significant difference between the well nourished and the malnourished group was detected in the achievement of remission/response (69.5% vs. 38.1%), delays in therapy (8.7% vs. 38.1%) and mortality (30.5% vs. 61.9%). Complications like febrile neutropenia and bleeding were more in the malnourished group. A statistically significant higher incidence of infection was seen in children with serum iron <60MUg/dL than those with higher values of serum iron (42.8% vs. 8%). PMID- 22828555 TI - Spectrum of skin lesions of post-kala-azar dermal leishmaniasis in kala-azar endemic areas of Bangladesh. AB - Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL) and serves as a potential reservoir for Leishmania parasite. The study was aimed to evaluate the spectrum of skin lesions of PKDL in kala-azar endemic areas in Bangladesh. This cross sectional study was carried out to observe the characteristics of skin lesions among 250 PKDL cases. The suspected PKDL patients in highly endemic villages of Fulbaria Upazilla of Mymensingh district.were subjected to a dipstick test (rK39) for kala azar. The median time interval between diagnosing kala-azar and PKDL was 23 month (m-21, r- 0-60 months). The most common skin lesions were multiple symmetrical hypopigmented macules with irregular margins in 179(71.6%) cases followed by erythematous facial induration in 74(29.6%), papular in 33(13.2%), nodular in 28(11.2%) cases, combination of macules, papules, nodules and plaques in 88(35.2%) cases, annular in 7(2.8%) cases and Papillomatous mucosal growth in 2(0.8%) cases. Sites of involvement were mostly in face (92.4%), Trunk (84.8%), extremities (33.2%), oral mucosa and tongue (0.8%) and Genitalia (1.2%). Suspicion of PKDL on the basis of skin lesions will lead to early diagnosis and prompt treatment will impart an important role in prevention and eradication of Leishmaniasis in Bangladesh. PMID- 22828556 TI - Comparison of three fluid regimens for preloading in elective caesarean section under spinal anaesthesia. AB - The most common problem associated with subarachnoid block (SAB) for caesarean section remains the rapid onset of profound hypotension. This study was designed to compare the incidence of hypotension after preloading with Ringer's Lactate, Hydroxyethylstarch and combination prior to SAB in caesarean section. Ninety non labouring ASA grade 1 and 2, aged 20-35 years, weight and height was 45-60kg and 153-165cm respectively divided randomly into three groups. Group-RL received Ringer's Lactate 20ml/kg as preloading fluid. Group-H received Hydroxyethylstarch 6% 8ml/kg and Group-RLH received preloading fluid with combination of Ringer's Lactate 10ml/kg and Hydroxyethylstarch-6% 4ml/kg. Blood pressure (Systolic, Diastolic & Mean arterial pressure) was measured every 5 minute for 20 minute and every 10 minutes thereafter. Hypotension was less in Group-RLH (6.7%) whereas in Group-H and Group-RL hypotension was 20% and 47.7% respectively. Systolic blood pressure decreased significantly in all three groups. But the decreasing was less in Group-RLH than other two groups. Less IV fluid was required in Group-RLH (403ml) and Group-H (577ml) in comparison to Group-RL (1032ml) to prevent and treat peroperative hypotension. No ephedrine was needed in Group-RLH. Variation in Pulse rate was not significant in Group-RLH (p=0.061). But in other two groups it was highly significant (Group RL p<=0.001 and Group H p=0.004). There was no significant difference in neonatal outcome between three groups. Preloading with low volume colloid (4ml/kg) plus crystalloid (10ml/kg) is superior to crystalloid or colloid alone. PMID- 22828557 TI - Goldenhar syndrome. AB - A female child of 10 months age from Netrokona, Bangladesh was admitted in the department of ophthalmology, Mymensingh Medical College Hospital, Mymensingh on 20.01.12 with the complaints of swelling on both her eyes and swelling of area in front of both ears. The child is mentally alert. Her fixation reflex is central, steady and maintained. On examination whitish growth on limbus, hard in consistency, non mobile, non tender, fixed with underlying structure both eyes. There are pre auricular skin tags. There is no cardiac abnormality and ENT consultation done reveals normal except pre-auricular ear tags. X ray of mandible and maxilla shows hypoplasia of maxilla and mandible. Clinical examination and investigations confirmed the diagnosis as Goldenhar syndrome. PMID- 22828558 TI - Long-term survival in an un-operated single ventricle. AB - Single ventricle is a rare and complex congenital heart disease. Neonates with single ventricle have a high mortality. Survival into adulthood is rare without surgical intervention. A case of single ventricle with double inlet and double outlet combined with severe valvular pulmonary stenosis and mitral regurgitation (Grade II) is being reported here. A 36 years old man was admitted for bluish discoloration of lips, tongue and fingers; shortness of breath and recurrent palpitation. His ECG showed atrial fibrillation with fast ventricular rate. Chest X-Ray depicted an enlarged cardiac shadow and right sided pleural effusion. Final diagnosis was made by echocardiogram which demonstrated single ventricle with double inlet and double outlet, severe valvular pulmonary stenosis and mitral regurgitation (Grade II) with good ventricular systolic function. PMID- 22828559 TI - Carpenter syndrome: a case report. AB - Carpenter syndrome is a rare hereditary disorder known as Acrocephalopolysyndyctyly (ACPS) type II characterized by acrocephaly, facial dysmorphism, brachedyctyly, syndyctyly, preaxial polydyctyly, obesity, congenital heart disease, cryptorchidism, hypogenitalism, bony abnormalities and umbilical hernia. Carpenter syndrome is autosomal recessive disorder and prenatal diagnosis of this syndrome is possible by ultrasonogram during pregnancy. We reported a case of carpenter syndrome of 2.5 months old female infant of consanguineous parents who was admitted in the paediatric ward of Bangabandhu Sheikh Mujib Medical University (BSMMU) on 30th March 2010. She was diagnosed as a case of Carpenter syndrome having acrocephaly prominent ridge of sagital suture, polydactyly, syndyctyly on history, clinical examination findings and investigation reports. PMID- 22828560 TI - An epiphyseal osteochondroma causing mechanical symptoms in the knee. AB - A case of an epiphyseal osteochondroma in the anteromedial aspect of left tibia in a 4 year old girl, who was presented with knocking between knees and limping. Surgical excision of this bony growth was curative and resolved the mechanical symptoms completely. Interesting clinical and imaging features are presented. The possibility of solitary epiphyseal osteochondroma should be kept in mind for any bony lesion close to the joint, especially in a young child. Early excision of the lesion is recommended to avoid intra-articular development and mechanical block to joint motion. PMID- 22828561 TI - Hypothalamic hamartoma with precocious puberty: a case report. AB - Hypothalamic hamartoma (HH) is one of the most important causes of central precocious puberty in male children. Hamartomas are malformations composed of ectopic gonadotropic hormone (GnRH) neurons which secrete pulsatile gonadotropin releasing hormone. They are generally observed in children under 3 years. A case of 11/3 year-old male child presented with premature development of secondary sexual characters i.e., growth of pubic and axillary hair, enlargement of penis and acne over the face for the last 5 months. On physical examination, his height was 1.02 m and his weight 18kg, enlarged penile length of which 58mm; testicles were enlarged in size right one measuring 32X25mm and the left 30X23mm. His hematological and other biochemical investigations revealed no abnormality. Plain radiographic examination revealed radiological bone age of about 8-9 years. Endocrinological findings were as follows: Follicle stimulating hormone (FSH): 1.5mIU/ml, Luteinizing hormone (LH): 9.1mIU/ml, Testosterone: 701ng/dl (Testosterone level less than 30ng/dl in prepubertal age). Thyroid function tests were normal. Patient showed no adrenal pathology on ultrasound and his testicular parenchyma was homogeneous echotexture with the size of 30X22X16mm on the right (volume 5.4ml) and 30X20X15mm on the left (volume 4.6ml). With above physical & endocrinological findings and age of the child, it was suspected as a case of central precocious puberty. Subsequently MR imaging of the brain done & showed an oval non-enhancing pedunculated hypothalamic mass arising from the tubercinereum that was iso to hypointense to brain parenchyma on T1 - and intermediate signal on T2-weighted images, 20X10X10mm in diameter, extending into suprasellar cistern. During follow up after 06 months of starting conservative medication with gonadotropin-releasing hormone (GnRH) analog (Leuprolide acetate), his progression of puberty has been arrested and the testosterone level 18ng/dl, which is normal for his age. PMID- 22828562 TI - A primary hypertrophic osteoarthropathy or pachydermoperiostosis. AB - A young boy of 17 years presented with arthalgia and arthritis of multiple joints unresponsive to treatment, generalized clubbing and enlargement of distal part of the extremities for 5 years and hyperhidrosis for 3 years. On examination, thickening of the facial skin and seborrhoea were found associated with acne. The patient has a Marfanoid appearance with column like legs and spade like fingers. There was no evidence of cutis vertices gyrata. Mild anaemia was present and vital signs were within normal limits. Examination of the musculoskeletal system revealed pain and swelling of the knee, ankle, elbow, wrist and proximal & distal interphalangeal joints. The spine and gait were normal. Radiographs of the limbs revealed subperiosteal new bone formation. The patient was diagnosed as a case of the autosomal dominant disorder, Primary Hypertrophic Osteoarthropathy or Pachydermoperiostosis. PMID- 22828563 TI - A primary spinal hydatid cyst. AB - Hydatid disease occurs in humans as a result of faeco-oral contamination. Spinal hydatid cyst is a rare entity and a serious form of hydatid disease affecting less than 1% of the total cases of hydatid disease. Neural compression is common in vertebral hydatidosis where prognosis is always considered as very poor. Difficulty in management due to recurrence of this rare entity makes it a challenging disease to eradicate entirely. Efficacy of use of anthelminthic even after complete surgical removal is yet to be established. We are reporting diagnosis and management of a case of primary extradural and paraspinal hydatid cyst (HC) in an otherwise healthy patient who did not show any other evidence of systemic hydatid disease. The diagnosis was recognized preoperatively by magnetic resonance imaging (MRI) and confirmed postoperatively by histopathology. Surgical removal of the cysts/lesions was followed by anti-helminthic medication and recovery was satisfactory until the patient had recurrence after one year. The patient underwent surgery for the second time and was given anti-helminthic again for a longer period and was recurrence free for the next one year. PMID- 22828564 TI - Congenital hypertrichosis (Were Wolf Syndrome): a case report. AB - Hypertrichosis is abnormal increase in body hair, when it becomes extensive known as Were Wolf Syndrome. Any part of body can be affected and body hairs are longer and darker. Hairs may be of any type like lanugo, vellous or terminal. It may be present since birth or may occur later in life. A 8 years old boy was admitted in our hospital with excess body hair, he was diagnosed as a case of Were Wolf syndrome after excluding possible acquired causes of hypertrichosis. He had history of delayed developmental milestone and has been suffering from epilepsy. He was treated with developmental stimulation and anti epileptic drug. Then he was discharged after proper counseling. PMID- 22828565 TI - An adult-onset still's disease with autoimmune thyroiditis. AB - Adult-onset Still's disease is a rare inflammatory disorder of unknown etiology and has same clinical characteristics of the systemic form of juvenile rheumatoid arthritis. A 17 years old white female had arthralgias of multiple joints including small joints of hands. She had fever, rash, hepatosplenomegaly, and CRP 122mg/dl, ESR-91mm in 1st hour. She had also TSH - 6.24MUIU/mL, fT3 - 2.1pg/mL, fT4 - 1.36ng/dL and diagnosed as Adult-onset Still's disease with autoimmune thyroiditis. It is an inherited condition and is more common in women than in men. PMID- 22828566 TI - Cardiovascular complications of chronic renal failure - an updated review. AB - Chronic kidney disease (CKD) is a worldwide public health problem. Cardiovascular disease (CVD) is frequently associated with CKD, which is important because individuals with CKD are more likely to die from CVD than to develop kidney failure. CVD in CKD is treatable and potentially preventable and CKD appears to be a risk factor for CVD. In order of incidence and frequency systemic hypertension, left ventricular failure, congestive cardiac failure, ischemic heart disease, anaemic heart failure, rhythm disturbances, pericarditis with or without effusion, cardiac tamponade, uraemic cardiomyopathy are various cardiovascular complications encountered in patients with chronic renal failure. A patient may present with one or more complications of cardiovascular system. The survival rate and prognosis to a great extent depends on proper management of these complications. Use of regular dialysis and renal transplant has changed the death pattern in developed countries but it is still a major problem in developing country. The aim of this article is early detection of CKD and proper management of it thereby preventing the major cardiovascular complications. PMID- 22828567 TI - Cardiac contractility modulation device-new hope for refractory heart failure patients. AB - A large number of patients with advanced heart failure (HF) are refractory to optimal standard medical therapy. This has given rise to development and testing of a host of new device based therapies. One recent and potentially broadly applicable treatment under investigation is cardiac contractility modulation (CCM) electrical signals. The CCM signals are relatively high-voltage electrical impulses applied to the myocardium during the absolute refractory period. These signals do not initiate a new contraction or modify activation sequence as is the case with other therapies such as cardiac resynchronization therapy. Rather, CCM signals are intended to enhance systolic function of the failing myocardium. A device similar to a pacemaker is typically implanted in the right pectoral region. Three standard pacemaker leads are placed intravenously. One right arterial lead is used to sense atrial activity, and two right ventricular leads are used to sense ventricular activity and deliver the CCM pulse trains. The electrodes of the ventricular leads are placed on the right ventricular septum at least 2cm apart. In contrast to a Pacemaker and defibrillator the system is designed to modulate the strength of contraction of the heart muscle rather than the rhythm. Application of CCM signals to the failing heart is associated with improved gene expression which ultimately causes LV global, cellular and biochemical remodeling as a result improved LV systolic function. PMID- 22828568 TI - A bidirectional model for communication in the neurovascular unit. AB - The neurovascular unit is a coordinated and interactional system of neurons, astrocytes, and microvessels in the brain. A central autoregulation mechanism observed in this unit is functional hyperemia, in which the microvasculature dilates in response to local neural activity in order to meet the increased demand for blood flow and oxygen. We have developed the first interactional model of bidirectional signaling in the neurovascular unit. The vascular model includes a description of vasomotion, the vascular oscillatory response to transmural pressure, observed in vivo. The communication mechanisms in the model include neural synaptic glutamate and potassium signaling to the astrocytes, potassium signaling from the astrocyte to the microvasculature, and astrocytic mechanosensation of vascular changes. The model response of the astrocyte to arteriolar dilation is validated with recent in vivo and in vitro experimental results. The model reproduces for the first time the in vitro observed phenomenon in which arteriole radius and Ca(2+) oscillations, "vasomotion," are damped due to neural induced astrocytic signaling. PMID- 22828569 TI - Realistic enzymology for post-translational modification: zero-order ultrasensitivity revisited. AB - Unlimited ultrasensitivity in a kinase/phosphatase "futile cycle" has been a paradigmatic example of collective behaviour in multi-enzyme systems. However, its analysis has relied on the Michaelis-Menten reaction mechanism, which remains widely used despite a century of new knowledge. Modifying and demodifying enzymes accomplish different biochemical tasks; the donor that contributes the modifying group is often ignored without the impact of this time-scale separation being taken into account; and new forms of reversible modification are now known. We exploit new algebraic methods of steady-state analysis to reconcile the analysis of multi-enzyme systems with single-enzyme biochemistry using zero-order ultrasensitivity as an example. We identify the property of "strong irreversibility", in which product re-binding is disallowed. We show that unlimited ultrasensitivity is preserved for a class of complex, strongly irreversible reaction mechanisms and determine the corresponding saturation conditions. We show further that unlimited ultrasensitivity arises from a singularity in a novel "invariant" that summarises the algebraic relationship between modified and unmodified substrate. We find that this singularity also underlies knife-edge behaviour in allocation of substrate between modification states, which has implications for the coherence of futile cycles within an integrated tissue. When the enzymes are irreversible, but not strongly so, the singularity disappears in the form found here and unlimited ultrasensitivity may no longer be preserved. The methods introduced here are widely applicable to other reversible modification systems. PMID- 22828570 TI - Determinants of prolonged intensive care unit stay after cardiac surgery in the elderly. AB - OBJECTIVES: In the last decade, there has been a rapid increase in the number of elderly patients referred for cardiac surgery. Recent studies have identified risk factors for prolonged intensive care unit (ICU) stay in cardiac surgery patients. The aims of this study was to evaluate pre-operative risk factors for ICU stay longer than 3 days in a cardiac surgery elderly population, and whether prolonged ICU stay may influence disability, functional recovery and length of rehabilitation. METHODS: Two hundred and fifty elderly (>=65 years) cardiac surgery patients were consecutively evaluated at enter in cardiac rehabilitation after ICU dismissal from January 2008 to July 2009. Univariate and multivariate analyses for risk factors were performed for ICU stay longer than 3 days. Thereafter, 6-minute walking test (6MWT), Barthel Index (BI), BI percent recovery and length of stay (LOS) in rehabilitation were evaluated. RESULTS: Mean age was 72.9+/-4.8 yrs, 170 (68%) patients underwent cardiac surgery for coronary artery by-pass grafting (CABG), 56 (22.4%) for valve replacement and 24 (9.6%) for both CABG and valve replacement. Mean ICU stay was 1.9+/-1.5 days and 72 patients (28.8%) spent more than 3 days in ICU. Age, New York Heart Association class >=3, Cumulative Illness Rating Scale (CIRS) score, prevalence of stroke and renal failure were significantly higher in patients with than in those without ICU stay >=3 days. Off-pump CABG, Physical Activity Scale for the Elderly (PASE), BI and 6MWT were significantly lower in patients with than in those without ICU stay >=3 days. Multivariate analysis shows that female sex, a NYHA class >=3, CIRS and PASE score are predictors of ICU stay >=3 days independently of age, off-pump CABG, stroke and renal failure. Multiple linear regression shows that ICU stay >=3 days is negatively associated with 6MWT, BI at entry and BI percent recovery, whereas it is positively associated with a longer rehabilitation LOS. CONCLUSIONS: Pre-operative comprehensive assessment in the elderly could help to identify predictors of long ICU stay after cardiac surgery. This approach could help to better define the elderly cardiac surgery patients and their needs throughout the cardiac rehabilitation program in order to maximize functional capacity recovery, reducing disability and rehabilitation LOS. PMID- 22828572 TI - Neuronal activities of the vestibular nuclear complex during mechanically induced rhythmic jaw movements in rats. AB - We studied the neuronal activities of the vestibular nuclear complex (VN) neurons during rhythmic jaw movements in rats anesthetized with urethane. Rhythmic jaw movements were induced by mechanical stimulation of the palate mucosa. The firing rate of approximately 25% of VN neurons increased significantly, and that of 10% of VN neurons decreased significantly, during these rhythmic jaw movements. There was no correlation between the change in the firing rate and the phase of the rhythmic jaw movements (jaw-opening and jaw-closing phases). The neurons that were affected were intermingled in the VN. These results suggest that the VN neurons are involved in controlling jaw movements. PMID- 22828571 TI - The effect of chronic undernourishment on the synaptic depression of cutaneous pathways in the rat spinal cord. AB - The aim of this study was to determine the effect of chronic undernourishment on the amplitude depression of the first negative component in the cord dorsum potentials (N(1)-CDPs) caused by the conditioning stimulation of sensory cutaneous nerves in the rat spinal cord. Single electrical pulses (1Hz; 2 times threshold) applied to the sural (SU) nerve of control rats (n=14) produced CDPs with a first negative component (N(1)-CDPs) larger in amplitude (14.2+/-1.3%, p<0.01) than those recorded in chronically undernourished rats (n=14; 3 times threshold). The conditioning stimulation of the SP nerve (4 shocks at 300Hz, 3*T) in the control rats (n=5) evoked a long-lasting (~200ms) depression of the N(1) CDP (60.2+/-7.2%). In contrast such depression was smaller in magnitude (42.5+/ 5.7%, p<0.01) and time course (100-120ms) in undernourished rats (n=7). The systemic application of picrotoxin (PTX) reduced, but did not abolish the conditioned depression of the N(1)-CDPs and DRPs in both the control and undernourished rats. By assuming that the depression of the N(1)-CDPs is representative of presynaptic mechanisms, it is proposed that chronic undernourishment influence the activation of presynaptic neuronal pathways that regulate the transmitter release of cutaneous afferent fibers in the spinal cord and such effect could act as a compensatory mechanism that counterbalances the decreased activation of spinal neurons by the reduced afferent input in the rat. PMID- 22828573 TI - Auditing quality in kidney disease and diabetes: is the precise the enemy of the good? A commentary on difficulties auditing pathology results containing 'greater than' or 'less than' signs. PMID- 22828574 TI - Anything but engaged: user involvement in the context of a national electronic health record implementation. AB - BACKGROUND: The absence of meaningful end user engagement has repeatedly been highlighted as a key factor contributing to 'failed' implementations of electronic health records (EHRs), but achieving this is particularly challenging in the context of national scale initiatives. In 2002, the National Health Service (NHS) embarked on a so-called 'top-down' national implementation strategy aimed at introducing commercial, centrally procured, EHRs into hospitals throughout England. OBJECTIVE: We aimed to examine approaches to, and experiences of, user engagement in the context of a large-scale EHR implementation across purposefully selected hospital care providers implementing early versions of nationally procured software. METHODS: We conducted a qualitative, case-study based, socio-technically informed, longitudinal investigation, purposefully sampling and collecting data from four hospitals. Our data comprised a total of 123 semi-structured interviews with users and managers, 15 interviews with additional stakeholders, 43 hours of non-participant observations of meetings and system use, and relevant organisation-specific documents from each case study site. Analysis was thematic, building on an existing model of user engagement that was originally developed in the context of studying the implementation of relatively simple technologies in commercial settings. NVivo8 software was used to facilitate coding. RESULTS: Despite an enduring commitment to the vision of shared EHRs and an appreciation of their potential benefits, meaningful end user engagement was never achieved. Hospital staff were not consulted in systems choice, leading to frustration; they were then further alienated by the implementation of systems that they perceived as inadequately customised. Various efforts to achieve local engagement were attempted, but these were in effect risk mitigation strategies. We found the role of clinical champions to be important in these engagement efforts, but progress was hampered by the hierarchical structures within healthcare teams. As a result, engagement efforts focused mainly on clinical staff with inadequate consideration of management and administrative staff. CONCLUSIONS: This work has allowed us to further develop an existing model of user engagement from the commercial sector and adapt it to inform user engagement in the context of large-scale eHealth implementations. By identifying key points of possible engagement, disengagement and re-engagement, this model will we hope both help those planning similar large-scale EHR implementation efforts and act as a much needed catalyst to further research in this neglected field of enquiry. PMID- 22828575 TI - Emergency medicine residents' beliefs about contributing to a Google Docs presentation: a survey protocol. AB - BACKGROUND: Web 2.0 collaborative writing technologies have shown positive effects on medical education. One such technology, Google Docs(TM), offers collaborative writing applications that improve healthcare students' sharing of information. Since 2008, all graduating residents in emergency medicine in Canada have had access to an online Google Docs(TM) slideshow designed to help them share summaries of landmark articles in preparation for their Royal College of Physicians and Surgeons of Canada certification exam. A recent evaluation showed that contributions to the presentation were low. OBJECTIVE: This study will identify the factors that influence residents' decision to contribute or not to contribute to this online collaborative project. METHODS: Using the Theory of Planned Behaviour, semistructured interviews will be conducted with 25 graduating emergency medicine residents in Canada. Content from the interviews will be analysed to determine the most important beliefs in relation to the defined behaviour. CONCLUSION: To our knowledge, this study will be the first to use a theory based framework to identify healthcare trainees' salient beliefs concerning their decision whether to contribute to an online collaborative writing project using Google Docs(TM). PMID- 22828576 TI - Patterns of referral in a Canadian primary care electronic health record database: retrospective cross-sectional analysis. AB - BACKGROUND: Databases derived from primary care electronic health records (EHRs) are ideally suited to study clinical influences on referral patterns. This is the first study outside the United Kingdom to use an EHR database to describe rates of referral per patient from family physicians to specialists. OBJECTIVE: To use a primary care EHR database to describe referrals to specialist physicians; to partition variance in referral rates between the practice and patient levels. METHODS: Retrospective cross-sectional analysis of de-identified EHRs of 33 998 patients from 10 primary care practices in Ontario, Canada. The study cohort included all patients who visited their family physician 1 April 2007 to 31 March 2008 (n >= 24856). Specialist referrals for each patient were counted for 12 months following their index visit. Rates of referral were compared by sex, age, number of office visits, practice location and specialist type using t-tests or Pearson's correlation. Variance partitioning determined the proportion of variance in the overall referral rate accounted for by the practice and patient levels. RESULTS: In total, 7771 patients (31.3%) had one or more referrals. The overall referral rate was 455/1000 patients/year (95% CI, 444-465). Rates were higher for females, older patients and rural practices. The referral rate correlated with the number of family physician office visits. Ninety-two percent of the total variance in referral rates was attributable to the patient (vs. practice) level. CONCLUSIONS: A Canadian primary care EHR database showed similar patterns of referral to those reported from administrative databases. Most variance in referral rates is explained at the patient level. PMID- 22828577 TI - The comparison of cardiovascular risk scores using two methods of substituting missing risk factor data in patient medical records. AB - BACKGROUND: Targeted screening for cardiovascular disease (CVD) can be carried out using existing data from patient medical records. However, electronic medical records in UK general practice contain missing risk factor data for which values must be estimated to produce risk scores. OBJECTIVE: To compare two methods of substituting missing risk factor data; multiple imputation and the use of default National Health Survey values. METHODS: We took patient-level data from patients in 70 general practices in Ealing, North West London. We substituted missing risk factor data using the two methods, applied two risk scores (QRISK2 and JBS2) to the data and assessed differences between methods. RESULTS: Using multiple imputation, mean CVD risk scores were similar to those using default national survey values, a simple method of imputation. There were fewer patients designated as high risk (>20%) using multiple imputation, although differences were again small (10.3% compared with 11.7%; 3.0% compared with 3.4% in women). Agreement in high-risk classification between methods was high (Kappa = 0.91 in men; 0.90 in women). CONCLUSIONS: A simple method of substituting missing risk factor data can produce reliable estimates of CVD risk scores. Targeted screening for high CVD risk, using pre-existing electronic medical record data, does not require multiple imputation methods in risk estimation. PMID- 22828578 TI - Perceptions on the quality of records received via the GP2GP electronic transfer service: pilot online questionnaire study. AB - AIM: To obtain insight into the perceived quality of electronic records received by GP2GP transfer, from the perspective of staff within the receiving practice. METHODS: A pilot study using a self-completion online survey. We used textual analysis and descriptive statistics to report the findings. RESULTS: Respondents considered a significantly higher proportion of their own records to be accurate, complete and useful compared with records transferred from other practices (P<0.0001). However, very few respondents felt that a large proportion of records were fully inaccurate, incomplete or useless. Perceived accuracy, completeness and usefulness were positively associated with the proportion of electronic records requiring no modification when reconciled with paper records, and negatively associated with the proportion of records requiring major additional information when reconciled with paper records. There were no significant differences in perceived accuracy or completeness of GP2GP records according to which brand of GP electronic patient record system was used. CONCLUSION: The results suggest that respondents value the GP2GP record transfer system. They perceive issues with record quality, which require significant resources to rectify. Textual analysis suggests that difficulties in mapping data structures between systems may underlie some of the perceived issues. Further research is needed to confirm these initial findings on differential perception and explore their underlying causes. PMID- 22828579 TI - Using a data entry clerk to improve data quality in primary care electronic medical records: a pilot study. AB - BACKGROUND: The quality of electronic medical record (EMR) data is known to be problematic; research on improving these data is needed. OBJECTIVE: The primary objective was to explore the impact of using a data entry clerk to improve data quality in primary care EMRs. The secondary objective was to evaluate the feasibility of implementing this intervention. METHODS: We used a before and after design for this pilot study. The participants were 13 community based family physicians and four allied health professionals in Toronto, Canada. Using queries programmed by a data manager, a data clerk was tasked with re-entering EMR information as coded or structured data for chronic obstructive pulmonary disease (COPD), smoking, specialist designations and interprofessional encounter headers. We measured data quality before and three to six months after the intervention. We evaluated feasibility by measuring acceptability to clinicians and workload for the clerk. RESULTS: After the intervention, coded COPD entries increased by 38% (P = 0.0001, 95% CI 23 to 51%); identifiable data on smoking categories increased by 27% (P = 0.0001, 95% CI 26 to 29%); referrals with specialist designations increased by 20% (P = 0.0001, 95% CI 16 to 22%); and identifiable interprofessional headers increased by 10% (P = 0.45, 95 CI -3 to 23%). Overall, the intervention was rated as being at least moderately useful and moderately usable. The data entry clerk spent 127 hours restructuring data for 11 729 patients. CONCLUSIONS: Utilising a data manager for queries and a data clerk to re-enter data led to improvements in EMR data quality. Clinicians found this approach to be acceptable. PMID- 22828580 TI - Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. AB - INTRODUCTION: The degree of generalisability of patient databases to the general population is important for interpreting database research. This report describes the representativeness of The Health Improvement Network (THIN), a UK primary care database, of the UK population. METHODS: Demographics, deprivation (Townsend), Quality and Outcomes Framework (QOF) condition prevalence and deaths from THIN were compared with national statistical and QOF 2006/2007 data. RESULTS: Demographics were similar although THIN contained fewer people aged under 25 years. Condition prevalence was comparable, e.g. 3.5% diabetes prevalence in THIN, 3.7% nationally. More THIN patients lived in the most affluent areas (23.5% in THIN, 20% nationally). Between 1990 and 2009, standardised mortality ratio ranged from 0.81 (95% CI: 0.39-1.49; 1990) to 0.93 (95% CI: 0.48-1.64; 1995). Adjusting for demographics/deprivation, the 2006 THIN death rate was 9.08/1000 population close to the national death rate of 9.4/1000 population. CONCLUSION: THIN is generalisable to the UK for demographics, major condition prevalence and death rates adjusted for demographics and deprivation. PMID- 22828581 TI - Towards a terminologies support system in primary care. PMID- 22828582 TI - Potential dependent and structural selectivity of the oxygen reduction reaction on nitrogen-doped carbon nanotubes: a density functional theory study. AB - Nitrogen-doped carbon nanotubes (NCNTs) are attractive for electrocatalytic applications in fuel cells due to their low cost and high electrocatalytic activity. By using density functional theory calculations, the electrocatalytic mechanisms of the oxygen reduction reaction (ORR) under electrochemical conditions are studied at graphite-like N groups (N(G)) and pyridine-like N groups (N(P)) of NCNTs, in which the effect of electrode potentials on the activation energy (E(a)) and reaction energy (E(r)) is taken into account. The ORR occurs at both N(G) and N(P) defect sites via two different four-electron OOH and two-electron H(2)O(2) mechanisms. At the lower potential region, both mechanisms are simultaneously responsible for the reaction at N(G) and N(P) defect sites; while at higher potentials, the four-electron mechanism becomes dominant and the ORR at N(P) defect sites is more energetically favorable than that at N(G) defect sites. PMID- 22828583 TI - Effect of alicyclic ring size on the photophysical and photochemical properties of bis(arylidene)cycloalkanone compounds. AB - A series of bis(arylidene)cycloalkanone compounds based on cyclobutanone, cyclopentanone, cyclohexanone and cycloheptanone, C4-C7, respectively, with a D pi-A-pi-D structure containing the same donor and acceptor but different alicyclic rings was prepared. The effects of alicyclic ring size on the photophysical, photochemical and electrochemical properties of these compounds were investigated systematically. We found that an increase of the number of carbons in the central alicyclic ring leads to changes in geometry, which has significant effects on the conjugation, and photophysical and photochemical properties. These effects include decreases in the fluorescence quantum yield, transient lifetimes, peak extinction coefficients, and the singlet oxygen quantum yield with the increase of the ring size. The one-photon absorption spectra, the two-photon absorption (2PA) spectra, and the fluorescence spectra all show a hypsochromic shift with increasing ring size. The results of this study provide guidance for the design of new cycloketone-based D-pi-A-pi-D 2PA compounds for photopolymerization and photodynamic therapy applications. PMID- 22828584 TI - Multi-compartment neuron-glia co-culture platform for localized CNS axon-glia interaction study. AB - Formation of myelin sheaths by oligodendrocytes (OLs) in the central nervous system (CNS) is essential for rapid nerve impulse conduction. Reciprocal signaling between axons and OLs orchestrates myelinogenesis but remains largely elusive. In this study, we present a multi-compartment CNS neuron-glia microfluidic co-culture platform. The platform is capable of conducting parallel localized drug and biomolecule treatments while carrying out multiple co-culture conditions in a single device for studying axon-glia interactions at a higher throughput. The "micro-macro hybrid soft-lithography master fabrication" (MMHSM) technique enables a large number of precisely replicated PDMS devices incorporating both millimeter and micrometer scale structures to be rapidly fabricated without any manual reservoir punching processes. Axons grown from the neuronal somata were physically and fluidically isolated inside the six satellite axon/glia compartments for localized treatments. Astrocytes, when seeded and co cultured after the establishment of the isolated axons in the satellite axon/glia compartments, were found to physically damage the established axonal layer, as they tend to grow underneath the axons. In contrast, oligodendrocyte progenitor cells (OPCs) could be co-cultured successfully with the isolated axons and differentiated into mature myelin basic protein-expressing OLs with processes aligning to neighboring axons. OPCs inside the six axon/glia compartments were treated with a high concentration of ceramide (150 MUM) to confirm the fluidic isolation among the satellite compartments. In addition, isolated axons were treated with varying concentrations of chondroitin sulfate proteoglycan (CSPG, 0 25 MUg ml(-1)) within a single device to demonstrate the parallel localized biomolecular treatment capability of the device. These results indicate that the proposed platform can be used as a powerful tool to study CNS axonal biology and axon-glia interactions with the capacity for localized biomolecular treatments. PMID- 22828585 TI - Anisamide-targeted cyclodextrin nanoparticles for siRNA delivery to prostate tumours in mice. AB - A hepta-guanidino-beta-cyclodextrin (G-CD), its hepta-PEG conjugate (G-CD-PEG), and the corresponding anisamide-terminated PEG conjugate (G-CD-PEG-AA) have been synthesised and compared as delivery vectors for siRNA to prostate cancer cells and tumours in vivo. The G-CD-PEG-AA.siRNA formulations (in which anisamide targets the sigma receptor), but not the non-targeted formulations, induced prostate cell-specific internalisation of siRNA resulting in approximately 80% knockdown in vitro of the reporter gene, luciferase. Following intravenous administration of the anisamide-targeted formulation in a mouse prostate tumour model significant tumour inactivation with corresponding reductions in the level of vascular endothelial growth factor (VEGF) mRNA were achieved, without demonstrating enhanced toxicity. This data imply significant potential for anisamide-conjugated cyclodextrin vectors for targeted delivery of therapeutic siRNAs in the treatment of prostate cancer. PMID- 22828586 TI - Factors associated with 2009 monovalent H1N1 vaccine coverage: a cross sectional study of 1,308 patients with psoriasis in France. AB - BACKGROUND: Patients with immune-mediated inflammatory diseases like psoriasis are at increased risk of infection. Specific recommendations are available regarding vaccinations however the vaccination coverage in patients with chronic inflammatory diseases has received limited attention and studies are not available in patients with psoriasis. OBJECTIVES: To assess the coverage of 2009 monovalent H1N1 vaccination and to identify factors associated with vaccination among patients with psoriasis. METHODS: Patients member of the French psoriasis patients association were sent a self administrated anonymous questionnaire. It consisted in socio-demographic data, history of psoriasis, seasonal and vaccination status. Factors associated with vaccination for A/H1N1 influenza were identified and adjusted odds ratios (ORa) and prevalence ratios (PRa) were estimated with their 95% confidence intervals (95% CIs) using logistic regression models. RESULTS: 1308 psoriasis patients with a mean age of 58.2 years completed the study between September and December 2010. A total of 240 (19%) patients received the 2009 monovalent H1N1 vaccine. 25 out of 75 patients treated with biologics (33%) received the vaccine. Previous influenza seasonal (ORa (PRa)=10.2 (6.6) [6.1 (4.1)-16.9 (10.7)]), pneumococcal (ORa (PRa)=2.0 (1.6) [1.2 (1.1)-3.3 (2.3)]) and hepatitis B (ORa (PRa)=2.2 (1.7) [1.4 (1.1)-3.5 (2.5)]) vaccinations were independently associated with being vaccinated for influenza A(H1N1). CONCLUSION: This is the largest study conducted to assess the coverage of 2009 monovalent H1N1 vaccine among patients with psoriasis, a highly prevalent chronic inflammatory disease. This vaccination coverage is more than twice the one in the French general population, but still remained low for patients receiving immunosuppressants. The limited impact of specific recommendations, free vaccines and the massive national campaign warrant alternative strategies in case of future pandemics. PMID- 22828587 TI - Socioeconomic inequalities in completion of hepatitis B vaccine series among Korean women: results from a nationwide interview survey. AB - BACKGROUND: Hepatitis B virus (HBV) infection and its sequelae are major global health problems. This study was conducted to investigate the association between factors related to socioeconomic status and HBV vaccination in the general population of women in Korea. METHODS: Data from annual nationwide cross sectional interview surveys conducted between 2005 and 2008 were reviewed. These surveys included representative samples of cancer-free people and 4350 women interviewed within the study period were included in the present report. Polychotomous logistic regression was used in the analysis. RESULTS: The complete HBV coverage rate was 39.8%. Older age, lower household income and lower education level showed significant unfavorable influences on the completion of the HBV vaccine series (P-trend <0.001 for all three variables). Lack of private insurance and having a routine and manual job were also associated with a lower complete vaccination rate (OR: 0.69, 95% CI: 0.57-0.84; OR: 0.56, 95% CI: 0.38 0.82, respectively), whereas living in an urban area was related to a higher rate (OR: 1.18, 95% CI: 1.02-1.37). Older age, lower education level, and not having private insurance were associated with incomplete vaccination compared with unvaccination (P-trend 0.001, <0.001, OR: 0.68, 95% CI: 0.53-0.78, respectively). Among women of reproductive age, similar results were seen for education level, household income, and occupation. Significant disparities in vaccination status according to socioeconomic status, as indicated by the combination of household income and education level, were seen (P-trend <0.001). The most common reason for unvaccination was lack of knowledge about the necessity for HBV vaccination. CONCLUSION: Considering that vertical transmission is the most common source of HBV infection, vaccination of women is important to prevent HBV transmission to newborn infants. Therefore governmental strategies to reduce socioeconomic inequalities related to the completion of the HBV vaccine series among women should be implemented. PMID- 22828588 TI - Student nurses' reasons behind the decision to receive or decline influenza vaccine: a cross-sectional survey. AB - This cross-sectional questionnaire survey examined influenza vaccination among 430 student nurses. Only 12.2% (95% CI 9.1-15.3%) of student nurses received the seasonal vaccine regularly with 27.6% (95% CI 23.3-31.8%) ever having received seasonal or pandemic H1N1 vaccine. Intention to be vaccinated was associated with having previously been vaccinated (p<0.001) but not whether the vaccine was perceived as beneficial (p=0.36). Previous influenza illness was associated with having the influenza vaccine (p<0.001). The most frequently reported reason for receiving the seasonal influenza vaccine was being deemed at risk (42.4%) and for H1N1 vaccine was because it was offered for free (32.6%). For both vaccines the most reported reason for not being vaccinated was a perception of it not being needed. Student nurses form a substantial and influential part of the future healthcare workforce but to translate the widely held acceptance that influenza vaccine is beneficial into actual uptake, a more targeted and persuasive message is needed. PMID- 22828589 TI - Vaccination against hepatitis B with 4-double doses increases response rates and antibodies titers in HIV-infected adults. AB - BACKGROUND: Antibody responses to standard regimens of hepatitis B (HBV) vaccination are lower in HIV-infected subjects and the best hepatitis B vaccine schedule in this population is not known. OBJECTIVE: To assess the immunogenicity and to evaluate predictors of serologic response of a modified regimen of a HBV recombinant vaccine in a cohort of HIV-infected subjects. METHODS: HIV-infected subjects received 4 doses (40 MUg) of a recombinant HBV vaccine at 0, 1, 2 and 6 months. Demographic information as well as CD4 cell count and plasma viral load were assessed at baseline. Protective and strong responses were defined as an anti-HBs titer >=10 mIU/mL and >=100 mIU/mL, respectively and were evaluated one month after the third and the fourth doses. RESULTS: 163 HIV-infected individuals were evaluated 67 (40%) were male and median age was 37 years. Median CD4 cell count was 385 cells/mm(3) and 113 (70%) had undetectable HIV-1 viral load. Protective antibody response was observed in 83 and 91% and a strong antibody response was observed in 62 and 80% of the subjects after 3 and 4 doses, respectively. In a multivariate logistic model undetectable HIV-1 viral load and higher CD4 cell counts were independent predictors of a strong antibody response after 4 doses. Patients with undetectable HIV viral load were almost 3 times more likely to have anti-HBs titers above 100 mIU/mL than those with detectable viral load. CONCLUSIONS: A 4-double-dose regimen of a recombinant HBV vaccine increased response rates and determined higher antibody titers which may translate in prolonged protection against HBV. Inclusion of a fourth dose of HBV vaccine for HIV-infected subjects should be considered in the public health setting. PMID- 22828590 TI - Generation of recombinant bacillus Calmette-Guerin and Mycobacterium smegmatis expressing BfpA and intimin as vaccine vectors against enteropathogenic Escherichia coli. AB - Enteropathogenic Escherichia coli (EPEC) is an important cause of diarrhea in children. EPEC adheres to the intestinal epithelium and causes attaching and effacing (A/E) lesions. Recombinant Mycobacterium smegmatis (Smeg) and Mycobacterium bovis BCG strains were constructed to express either BfpA or intimin. The entire bfpA gene and a portion of the intimin gene were amplified by PCR from EPEC genomic DNA and inserted into the pMIP12 vector at the BamHI/KpnI sites. The pMIP_bfpA and pMIP_intimin vectors were introduced separately into Smeg and BCG. Recombinant clones were selected based on kanamycin resistance and designated rSmeg_pMIP_(bfpA or intimin) and rBCG_pMIP_(bfpA or intimin). The expression of bfpA and intimin was detected by Immunoblotting using polyclonal anti-BfpA and anti-intimin antibodies. The immunogenicity of these proteins was assessed in C57BL/6 mice by assaying the feces and serum for the presence of anti BfpA and anti-intimin IgA and IgG antibodies. TNF-alpha and INF-gamma were produced in vitro by spleen cells from mice immunized with recombinant BfpA, whereas TNF-gamma was produced in mice immunized with recombinant intimin. The adhesion of EPEC (E2348/69) to HEp-2 target cells was blocked by IgA or IgG antibodies from mice immunized with recombinant BfpA or intimin but not by antibodies from non-immunized mice. Immunogenic non-infectious vectors containing relevant EPEC virulence genes may be promising vaccine candidates. PMID- 22828592 TI - Bacterial interference for prevention of urinary tract infection. PMID- 22828594 TI - Primary maternal CMV infection during pregnancy: do we have a treatment option? PMID- 22828593 TI - A low-effort, clinic-wide intervention improves attendance for HIV primary care. AB - BACKGROUND: Retention in care for human immunodeficiency virus (HIV)-infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. METHODS: Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10,018 patients in 2008-2009 (preintervention period) and 11,039 patients in 2009-2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. RESULTS: Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept (P < .0001). Larger relative improvement for both outcomes was observed for new or reengaging patients, young patients and patients with elevated viral loads. Improved attendance among the new or reengaging patients was consistent across the 6 clinics, and less consistent across clinics for active patients. CONCLUSION: Targeted messages on staying in care, which were delivered at minimal effort and cost, improved clinic attendance, especially for new or reengaging patients, young patients, and those with elevated viral loads. PMID- 22828596 TI - Successful treatment of renal artery thromboembolism with low-dose prolonged infusion of tissue-typed plasminogen activator in a patient with mitral mechanical heart valve thrombosis under the guidance of multimodality imaging. AB - This case report describes the use of low-dose prolonged infusion of tissue-typed plasminogen activator in the treatment of renal artery thromboembolism secondary to prosthetic valve thrombosis, under the guidance of multimodality imaging. Thromboembolic occlusion of renal arteries is a rare disorder with serious consequences. It is generally associated with cardiac diseases and arrhytmias. Four consecutive doses of low-dose prolonged infusion of tissue-typed plasminogen activator [25 mg tissue-typed plasminogen activator (tpa) in 6 h] were administered to the patient. This case of renal artery thromboembolism secondary to mitral mechanical prosthetic valve thrombosis was successfully treated with low-dose prolonged infusion of tPA under the guidance of multimodality imaging with renal artery Doppler ultrasonography, multislice computerized tomographic angiography, renal angiography, two-dimensional and real-time three-dimensional transesophageal echocardiography. This case has demonstrated that low-dose prolonged infusion of tissue-typed plasminogen activator may be effective and well tolerated in the treatment of renal embolism. PMID- 22828597 TI - Association of sleep onset of acute coronary syndrome with sleep apnea syndrome and abnormal diurnal variation of hemostasis and adipokine levels. AB - Our aim was to examine the pathophysiology of sleep onset of acute coronary syndrome (ACS); in particular, we focused on the association of sleep onset of ACS, sleep-apnea syndrome (SAS), and diurnal variation of hemostasis and adipokine levels. Seventy-four patients (mean 60.0 years; 84% men) with ACS were cross-sectionally examined. They were examined by circulatory levels of hemostasis [plasminogen activator inhibitor-1 (PAI-1), D-dimer, soluble fibrin] and adipokines (adiponectin, visfatin) before and after sleep, and cardiorespiratory function. The severity of SAS was defined as mild to no SAS [apnea-hypopnea index (AHI) <15/h, n = 30], moderate SAS (AHI 15-30/h, n = 26), and severe SAS (AHI >30/h, n = 18). Nineteen patients (26%) were diagnosed with sleep onset of ACS, and these patients had a greater extent of morning increase from the night-time levels of PAI-1 (median PAI-1 increase: +37.1 vs. +27.3 ng/ml; P = 0.01) and visfatin (median visfatin increase: +0.40 vs. +0.00 ng/ml; P = 0.08) than those who had daytime onset of ACS. Among patients who had sleep onset of ACS, 89% were diagnosed with moderate to severe SAS. According to the severity of SAS, the morning increase from the night-time levels of PAI-1 and visfatin became greater (median PAI-1 increase: +23.7 vs. +29.2 vs. +39.3 ng/ml; median visfatin increase: 0.00 vs. 0.00 vs. +0.45 ng/ml; both P < 0.05), and these differences remained unchanged even after adjustment for significant covariates (both P < 0.05). Patients who have sleep onset of ACS are likely to have high prevalence of SAS and abnormal diurnal variations of PAI-1 and visfatin levels. PMID- 22828598 TI - Residual blood processing by centrifugation, cell salvage or ultrafiltration in cardiac surgery: effects on clinical hemostatic and ex-vivo rheological parameters. AB - The study compared the effects of three blood concentration techniques after cardiopulmonary bypass on clinical hemostatic and ex-vivo rheological parameters. Residual blood of patients undergoing elective cardiac surgery was processed by centrifugation, cell salvage or ultrafiltration, and retransfused (n = 17 per group). Study parameters included blood loss, (free) hemoglobin, hematocrit, fibrinogen and erythrocyte aggregation, deformability and 2,3-diphosphoglycerate content. Patient characteristics were similar between groups. Ultrafiltration was associated with the highest weight of the transfusion bag [649 +/- 261 vs. 320 +/ 134 g (centrifugation) and 391 +/- 158 g (cell salvage); P < 0.01]. Cell salvage resulted in the lowest hemolysis levels in the transfusion bag. Retransfusion of cell saver blood induced the largest gain in postoperative patient hemoglobin levels when compared to centrifugation and ultrafiltration, and was associated with the largest increase in 2,3-diphosphoglycerate when compared to ultrafiltration (Delta2,3-diphosphoglycerate 1.34 +/- 1.92 vs. -0.77 +/- 1.56 mmol/l; P = 0.03). Cell salvage is superior with respect to postoperative hemoglobin gain and washout of free hemoglobin when compared to centrifugation or ultrafiltration. PMID- 22828595 TI - Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. AB - BACKGROUND: The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS: The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS: In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS: Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point. PMID- 22828599 TI - Differing approaches to diagnosis and treatment of musculoskeletal complications of haemophilia in resource-rich and resource-limited settings. AB - Management of the musculoskeletal complications of haemophilia should be consistent in both RRS (resource-rich settings) and RLS (resource-limited settings). Due to the lack of available resources in RLS, physicians face challenges that may limit their options for procedures. This article aimed to define the role of different techniques for the management of the musculoskeletal complications of haemophilia in RRS and RLS. A review of recent literature on the topic has been performed. In RLS, ultrasonography can be used as a diagnostic tool instead of MRI; chemical synovectomy can be the first alternative instead of radiosynovectomy and arthroscopic synovectomy; percutaneous treatment of pseudotumours can be performed instead of open surgical removal; finally, autologous cancellous bone can be used to fill cysts and pseudotumours instead of cancellous bone obtained from the Bone Bank. All diagnostic tools and treatments recommended for RLS have been proven to be efficacious; however, the ideal diagnosis and treatment for the musculoskeletal complications of haemophilia in RRS include MRI, radiosynovectomy, arthroscopic knee and ankle debridement in the early stages of arthropathy, total knee arthroplasty and total ankle arthroplasty or ankle fusion (in advanced stages of arthropathy), and surgical removal of pseudotumours. Treatments considered ideal in RRS should be the first therapeutic option if available. However, secondary treatment options that are less costly and therefore more readily available in RLS are perfectly valid and efficacious. PMID- 22828606 TI - Association between patient and general practice characteristics and unplanned first-time admissions for cancer: observational study. AB - BACKGROUND: To identify patient and general practice (GP) characteristics associated with emergency (unplanned) first admissions for cancer in secondary care. METHODS: Patients who had a first-time admission with a primary diagnosis of cancer during 2007/08 to 2009/10 were identified from administrative hospital data. We modelled the associations between the odds of these admissions being unplanned and various patient and GP practice characteristics using national data sets, including the Quality and Outcomes Framework (QOF). RESULTS: There were 639,064 patients with a first-time admission for cancer, with 139,351 unplanned, from 7957 GP practices. The unplanned proportion ranged from 13.9% (patients aged 15-44 years) to 44.9% (patients aged 85 years and older, P<0.0001), with large variation by ethnicity (highest in Asians), deprivation, rurality and cancer type. In unadjusted analyses, all included patient and practice-level variables were statistically significant predictors of the admissions being unplanned. After adjustment, patient area-level deprivation was a key factor (most deprived compared with least deprived quintile OR 1.36, 95% CI 1.32-1.40). Higher total QOF performance protected against unplanned admission (OR 0.94 per 100 points; 95% CI 0.91-0.97); having no GPs with a UK primary medical qualification (OR 1.08, 95% CI 1.04-1.11) and being less able to offer appointments within 48 h were associated with higher odds. CONCLUSION: We have identified some patient and practice characteristics associated with a first-time admission for cancer being unplanned. The former could be used to help identify patients at high risk, while the latter raise questions about the role of practice organisation and staff training. PMID- 22828605 TI - The molecular basis for high affinity of a universal ligand for human bombesin receptor (BnR) family members. AB - There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. The synthetic Bn-analog, [D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]Bn(6-14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-receptor (CCK(A)R), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCK(A)R or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible receptor-peptide cation pi or H-bonding interactions are also important for determining its high affinity. PMID- 22828607 TI - Venous thromboembolism is a relevant and underestimated adverse event in cancer patients treated in phase I studies. AB - BACKGROUND: To investigate, retrospectively, the role of tumour histotype and antiangiogenic drugs for venous thromboembolism (VTE) development in advanced cancer patients treated in phase I studies. METHODS: Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organisation) were considered. RESULTS: Data of 1415 patients were included in the analysis: 526 (37.2%) patients were males, median age was 57.3 years (range: 13-85). Fifty-six (3.96%) patients developed a VTE. At multivariate analysis gynaecologic (hazard ratio (HR): 2.8, 95% confidence interval (CI): 1.29-6.23, P=0.009) and gastrointestinal tumours (HR: 3.23, 95% CI: 1.18-8.87, P=0.023) as well as combination regimens of cytotoxic and antiangiogenic agents (HR: 2.6, 95% CI: 1.11-6.30, P=0.028), white blood cell >11,000 MUl(-1) (HR: 2.59, 95% CI: 1.10 6.09, P=0.028) and haemoglobin<10 g dl(-1) (HR: 3.1, 95% CI: 1.07-8.94, P=0.037) were statistically correlated with VTE development. Venous thromboembolism was the fourth most common cause of drug discontinuation. The median time from first drug administration to discontinuation was 1.4 for VTE and 2.3 months for the other adverse events (P=0.02). CONCLUSION: Venous thromboembolism is a relatively common complication among patients treated in the context of phase I studies, and may lead to early drug discontinuation. A greater risk of developing VTE is associated with the diagnosis of gynaecologic and gastrointestinal tumours and the combined use of chemotherapy and antiangiogenic drugs. PMID- 22828608 TI - Expression of oestrogen receptor beta and prognosis of colorectal cancer. AB - BACKGROUND: Previous studies suggest that sex steroids influence colorectal cancer (CRC) carcinogenesis. The oestrogen receptor beta (ERbeta) is the predominantly expressed ER in the colon and loss of ERbeta in CRC has been associated with advanced cancer stages. METHODS: Information on vital status by the end of 2009 was obtained for 1262 CRC patients recruited between 2003 and 2007. The ERbeta expression was immunohistochemically measured and associations of ERbeta scores with overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) were evaluated using Cox proportional hazard models adjusted for prognostic factors, such as tumour stage and second primary tumours. RESULTS: Of the 1101 tumour samples with successful measurement, 535 were ERbeta negative (48.6%), 381 (34.6%) showed moderate and 185 (16.8%) showed high ERbeta expression. Compared with high ERbeta expression, lack of ERbeta was associated with higher cancer stages as well as greater tumour extent. In multivariate analyses, ERbeta negativity was associated with an increased hazard ratio for death (HR=1.61, 95% CI 1.09-2.40, P=0.02), death attributed to CRC (HR=1.54, 95% CI 0.99-2.39, P=0.06) as well as a poorer DFS (DFS HR=1.64, 95% CI 1.23-3.36, P=0.04). The associations were stronger in stage I-III patients (OS HR=2.20, 95% CI 1.28-4.06, P=0.007, DSS HR=2.38, 95% CI 1.20-5.39, P=0.02, respectively). CONCLUSIONS: Lack of ERbeta expression is associated with advanced cancer stages and independently associated with poor survival. PMID- 22828609 TI - Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies. AB - BACKGROUND: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ~15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. METHODS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage independent growth assays, as well as decreasing the capacity for tumour cell migration. RESULTS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. CONCLUSION: In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC. PMID- 22828610 TI - Online screening for distress, the 6th vital sign, in newly diagnosed oncology outpatients: randomised controlled trial of computerised vs personalised triage. AB - BACKGROUND: This randomised controlled trial examined the impact of screening for distress followed by two different triage methods on clinically relevant outcomes over a 12-month period. METHODS: Newly diagnosed patients attending a large tertiary cancer centre were randomised to one of the two conditions: (1) screening with computerised triage or (2) screening with personalised triage, both following standardised clinical triage algorithms. Patients completed the Distress Thermometer, Pain and Fatigue Thermometers, the Psychological Screen for Cancer (PSSCAN) Part C and questions on resource utilisation at baseline, 3, 6 and 12 months. RESULTS: In all, 3133 patients provided baseline data (67% of new patients); with 1709 (54.5%) retained at 12 months (15.4% deceased). Mixed effects models revealed that both groups experienced significant decreases in distress, anxiety, depression, pain and fatigue over time. People receiving personalised triage and people reporting higher symptom burden were more likely to access services, which was subsequently related to greater decreases in distress, anxiety and depression. Women may benefit more from personalised triage, whereas men may benefit more from a computerised triage model. CONCLUSION: Screening for distress is a viable intervention that has the potential to decrease symptom burden up to 12 months post diagnosis. The best model of screening may be to incorporate personalised triage for patients indicating high levels of depression and anxiety while providing computerised triage for others. PMID- 22828611 TI - A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. AB - BACKGROUND: The neutrophil lymphocyte ratio (NLR) has prognostic value in patients with a variety of cancers. Many chemotherapeutic trial databases hold information on white cell and neutrophil counts only. The aim of the present study was to compare the prognostic value of the NLR with a derived score (dNLR), composed of white cell and neutrophil counts. METHODS: Patients (n=27,031) who were sampled incidentally between 2000 and 2007 for neutrophil, lymphocyte and white cell counts, and also had a diagnosis of cancer (Scottish Cancer Registry), were identified. Of this group, 12,118 patients who had been sampled within 2 years of their cancer diagnosis were studied. RESULTS: On follow-up, there were 7366 deaths, of which 6198 (84%) were cancer deaths. The median time from blood sampling to diagnosis was 2.1 months. The area under the receiver-operating characteristic (ROC) curve for cancer-specific survival was 0.650 for the NLR and 0.640 for the dNLR. The NLR and dNLR were independently associated with survival in all cancers studied (all P<0.001). The optimal thresholds, on the basis of hazard ratios and area under the curve, were 4 : 1 for the NLR and 2 : 1 for the dNLR. CONCLUSION: The results of the present study show that the dNLR has similar prognostic value to the NLR. Therefore, the universally available dNLR is to be commended for use in the risk stratification of patients undergoing chemotherapy. PMID- 22828613 TI - THz conductivities of indium-tin-oxide nanowhiskers as a graded-refractive-index structure. AB - Indium-tin-oxide (ITO) nanowhiskers with attractive electrical and anti reflection properties were prepared by the glancing-angle electron-beam evaporation technique. Structural and crystalline properties of such nanostructures were examined by scanning transmission electron microscopy and X ray diffraction. Their frequency-dependent complex conductivities, refractive indices and absorption coefficients have been characterized with terahertz time domain spectroscopy (THz-TDS), in which the nanowhiskers were considered as a graded-refractive-index (GRIN) structure instead of the usual thin film model. The electrical properties of ITO GRIN structures are analyzed and fitted well with Drude-Smith model in the 0.2~2.0 THz band. Our results indicate that the ITO nanowhiskers and its bottom layer atop the substrate exhibit longer carrier scattering times than ITO thin films. This signifies that ITO nanowhiskers have an excellent crystallinity with large grain size, consistent with X-ray data. Besides, we show a strong backscattering effect and fully carrier localization in the ITO nanowhiskers. PMID- 22828614 TI - Optical absorption enhancement in a hybrid system photonic crystal - thin substrate for photovoltaic applications. AB - A hybrid approach for light trapping using photonic crystal nanostructures (nanorods, nanopillars or nanoholes) on top of an ultra thin film as a substrate is presented. The combination of a nanopatterned layer with a thin substrate shows an enhanced optical absorption than equivalent films without patterning and can compete in performance with nanostructured systems without a substrate. The designs are tested in four relevant materials: amorphous silicon (a-Si), crystalline silicon (Si), gallium arsenide (GaAs) and indium phosphide (InP). A consistent enhancement is observed for all of the materials when using a thin hybrid system (300 nm) even compared to the non patterned thin film with an anti reflective coating (ARC). A realistic solar cell structure composed of a hybrid system with a layer of indium tin oxide (ITO) an ARC and a back metal layer is performed, showing an 18% of improvement for the nanostructured device. PMID- 22828612 TI - A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas. AB - BACKGROUND: Papillary thyroid cancer (PTC) incidence increased dramatically in children after the Chernobyl accident, providing a unique opportunity to investigate the molecular features of radiation-induced thyroid cancer. In contrast to the previous studies that included age-related confounding factors, we investigated mRNA expression in PTC and in the normal contralateral tissues of patients exposed and non-exposed to the Chernobyl fallout, using age- and ethnicity-matched non-irradiated cohorts. METHODS: Forty-five patients were analysed by full-genome mRNA microarrays. Twenty-two patients have been exposed to the Chernobyl fallout; 23 others were age-matched and resident in the same regions of Ukraine, but were born after 1 March 1987, that is, were not exposed to 131I. RESULTS: A gene expression signature of 793 probes corresponding to 403 genes that permitted differentiation between normal tissues from patients exposed and from those who were not exposed to radiation was identified. The differences were confirmed by quantitative RT-PCR. Many deregulated pathways in the exposed normal tissues are related to cell proliferation. CONCLUSION: Our results suggest that a higher proliferation rate in normal thyroid could be related to radiation induced cancer either as a predisposition or as a consequence of radiation. The signature allows the identification of radiation-induced thyroid cancers. PMID- 22828615 TI - Design, fabrication and optical characterization of photonic crystal assisted thin film monocrystalline-silicon solar cells. AB - In this paper, we present the integration of an absorbing photonic crystal within a monocrystalline silicon thin film photovoltaic stack fabricated without epitaxy. Finite difference time domain optical simulations are performed in order to design one- and two-dimensional photonic crystals to assist crystalline silicon solar cells. The simulations show that the 1D and 2D patterned solar cell stacks would have an increased integrated absorption in the crystalline silicon layer would increase of respectively 38% and 50%, when compared to a similar but unpatterned stack, in the whole wavelength range between 300 nm and 1100 nm. In order to fabricate such patterned stacks, we developed an effective set of processes based on laser holographic lithography, reactive ion etching and inductively coupled plasma etching. Optical measurements performed on the patterned stacks highlight the significant absorption increase achieved in the whole wavelength range of interest, as expected by simulation. Moreover, we show that with this design, the angle of incidence has almost no influence on the absorption for angles as high as around 60 degrees . PMID- 22828616 TI - Light absorption enhancement in heterostructure organic solar cells through the integration of 1-D plasmonic gratings. AB - The integration of a plasmonic lamellar grating in a heterostructure organic solar cell as a light trapping mechanism is investigated with numerical Finite Elements simulations. A global optimization of all the geometric parameters has been performed. The obtained wide-band enhancement in optical absorption is correlated with both the propagating and the localized plasmonic modes of the structure, which have been identified and characterized in detail. PMID- 22828617 TI - Hybrid ultra-short Yb:YAG ceramic master-oscillator high-power fiber amplifier. AB - We demonstrated a hybrid ceramic master-oscillator high-power fiber amplifier with a diode-pumped Yb:YAG ceramic laser as the seeding oscillator, which was passively mode-locked at 103.29 MHz repetition rate around 1031 nm by using a semiconductor saturable absorption mirror, and a two-stage double-clad photonic crystal fiber amplifier, which power-scaled the ceramic laser oscillator up to an average power of 303 W. The amplified pulses were further compressed to 237 and 418 fs at 50 and 150 W output powers, respectively. The compressed pulses exhibited about 0.05% deviation from the Gaussian fit, implying that the high power fiber amplification induced neither observable temporal and spectral distortion nor significant nonlinear de-chirping of the chirped pulses. PMID- 22828618 TI - Light trapping limits in plasmonic solar cells: an analytical investigation. AB - We analytically investigate the light trapping performance in plasmonic solar cells with Si/metallic structures. We consider absorption enhancements for surface plasmon polaritons (SPPs) at planar Si/metal interfaces and localized surface plasmon resonances (LSPRs) for metallic spheres in a Si matrix. We discover that the enhancement factors at Si/metal interfaces are not bound to the conventional Lambertian limit, and strong absorption can be achieved around plasmonic resonant frequencies. In addition, those enhancements are greatly reduced as the fields decay away from the Si/metal interfaces. Therefore, localized plasmonic resonances can be used as efficient light trapping schemes for ultrathin Si solar cells (< 50 nm), while photonic guided mode enhancement is more appropriate for thicker films. PMID- 22828619 TI - Effective light trapping enhancement by plasmonic Ag nanoparticles on silicon pyramid surface. AB - Plasmonic Ag nanoparticles were deposited on the silicon pyramid structures to further reduce surface reflectance. Compared with the bare silicon pyramid surface, a dramatic reflectance reduction around 380 nm was observed and the weighted average surface reflectance from 300 nm to 1100 nm could be reduced about 3.4%. By a series of designed experiments combined with Mie theory calculations, the influences of the size, shape and density distribution of Ag nanoparticles on the surface reflectance reduction were investigated in detail. This study shows a practicable method to improve light trapping for the application to solar cells. PMID- 22828620 TI - Study on the effects of 5d energy locations of Ce3+ ions on NIR quantum cutting process in Y2SiO5: Ce3+, Yb3+. AB - The effects of the 5d energy locations of Ce3+ centers on the NIR quantum cutting process were studied in Y2SiO5 with two different substitutional Y3+ lattice sites for Ce3+ and Yb3+. Powder XRD and Rietveld refinement were used to characterize phase purity, crystal structure, lattice parameters and occupation fractions of Y2-x-yCexYbySiO5 (x = 0.002 and 0.3, y = 0-0.2). PLE and PL spectra show that both kinds of Ce3+ centers in Y2x-yCexYbySiO5 can cooperatively transfer energy to Yb3+-Yb3+ ions pair. The dependence of the integrated emission intensities of Ce3+ and Yb3+, decay lifetime (tau) of Ce3+, nonradiative energy transfer rate (KCe->Yb), cooperative energy transfer efficiency (etaCET) and quantum efficiency (etaQE) on the concentration of Yb3+ ions were studied in details. More importantly, these results demonstrate that the 5d energy locations of Ce3+ ions have a great influence on NIR quantum cutting process in Ce3+-Yb3+ system: the closer they are to twice the absorption energy (~20000 cm-1) of Yb3+, the higher the cooperative energy transfer efficiency from the lowest 5d excited state of Ce3+ to the Yb3+-Yb3+ ions pair. PMID- 22828621 TI - Wideband enhancement of infrared absorption in a direct band-gap semiconductor by using nonabsorptive pyramids. AB - Efficient trapping of the light in a photon absorber or a photodetector can improve its performance and reduce its cost. In this paper we investigate two designs for light-trapping in application to infrared absorption. Our numerical simulations demonstrate that nonabsorptive pyramids either located on top of an absorbing film or having embedded absorbing rods can efficiently enhance the absorption in the absorbing material. A spectrally averaged absorptance of 83% is achieved compared to an average absorptance of 28% for the optimized multilayer structure that has the same amount of absorbing material. This enhancement is explained by the coupled-mode theory. Similar designs can also be applied to solar cells. PMID- 22828622 TI - Enhanced scattering and absorption due to the presence of a particle close to an interface. AB - We study the influence of the presence of an interface on the scattering by a Rayleigh scatterer. The influence of an interface on the spontaneous emission has been known for many years. Here, we study the influence on the extinction cross section and absorption cross-section. We provide a detailed analysis of interference and near-field effects. We show that the presence of a Rayleigh scatterer may enhance the specular reflection or specular transmission under certain conditions. Finally, we analyze the enhancement of absorption in the bulk in the presence of a small scatterer. PMID- 22828623 TI - Simulation and analysis of the angular response of 1D dielectric nanophotonic light-trapping structures in thin-film photovoltaics. AB - Nanophotonics can guide the design of novel structures for light-trapping in ultra-thin photovoltaic cells. Here, we report on the systematic study of the effect of the angle of incidence of sunlight on the performance of such structures. We also conduct a parametric study of a sinusoidal grating and demonstrate that light intensity in the active region averaged over a range of input angles from 0 degrees to 80 degrees can be enhanced by more than 3 times compared to the bare device. Such a broadband light-trapping nanostructure can increase the total daily energy production of a fixed (non-tracking) device by over 60%, compared to a reference device with an anti-reflection coating. PMID- 22828624 TI - Absorption to reflection transition in selective solar coatings. AB - The optimum transition wavelength between high absorption and low emissivity for selective solar absorbers has been calculated in several prior treatises for an ideal system, where the emissivity is exactly zero in the infrared. However, no real coating can achieve such a low emissivity across the entire infrared with simultaneously high absorption in the visible. An emissivity of even a few percent radically changes the optimum wavelength separating the high and low absorption spectral bands. This behavior is described and calculated for AM0 and AM1.5 solar spectra with an infrared emissivity varying between 0 and 5%. With an emissivity of 5%, solar concentration of 10 times the AM1.5 spectrum the optimum transition wavelength is found to be 1.28 um and have a 957K equilibrium temperature. To demonstrate typical absorptions in optimized solar selective coatings, a four-layer sputtered Mo and SiO2 coating with absorption of 5% across the infrared is described experimentally and theoretically. PMID- 22828625 TI - Pronounced interannual variability in tropical South Pacific temperatures during Heinrich Stadial 1. AB - The early last glacial termination was characterized by intense North Atlantic cooling and weak overturning circulation. This interval between ~18,000 and 14,600 years ago, known as Heinrich Stadial 1, was accompanied by a disruption of global climate and has been suggested as a key factor for the termination. However, the response of interannual climate variability in the tropical Pacific (El Nino-Southern Oscillation) to Heinrich Stadial 1 is poorly understood. Here we use Sr/Ca in a fossil Tahiti coral to reconstruct tropical South Pacific sea surface temperature around 15,000 years ago at monthly resolution. Unlike today, interannual South Pacific sea surface temperature variability at typical El Nino Southern Oscillation periods was pronounced at Tahiti. Our results indicate that the El Nino-Southern Oscillation was active during Heinrich Stadial 1, consistent with climate model simulations of enhanced El Nino-Southern Oscillation variability at that time. Furthermore, a greater El Nino-Southern Oscillation influence in the South Pacific during Heinrich Stadial 1 is suggested, resulting from a southward expansion or shift of El Nino-Southern Oscillation sea surface temperature anomalies. PMID- 22828626 TI - Biomimetic layer-by-layer assembly of artificial nacre. AB - Nacre is a technologically remarkable organic-inorganic composite biomaterial. It consists of an ordered multilayer structure of crystalline calcium carbonate platelets separated by porous organic layers. This microstructure exhibits both optical iridescence and mechanical toughness, which transcend those of its constituent components. Replication of nacre is essential for understanding this complex biomineral, and paves the way for tough coatings fabricated from cheap abundant materials. Fabricating a calcitic nacre imitation with biologically similar optical and mechanical properties will likely require following all steps taken in biogenic nacre synthesis. Here we present a route to artificial nacre that mimics the natural layer-by-layer approach to fabricate a hierarchical crystalline multilayer material. Its structure-function relationship was confirmed by nacre-like mechanical properties and striking optical iridescence. Our biomimetic route uses the interplay of polymer-mediated mineral growth, combined with layer-by-layer deposition of porous organic films. This is the first successful attempt to replicate nacre, using CaCO(3). PMID- 22828629 TI - Plasmonic black gold by adiabatic nanofocusing and absorption of light in ultra sharp convex grooves. AB - Excitation of localized and delocalized surface plasmon resonances can be used for turning excellent reflectors of visible light, such as gold and silver, into efficient absorbers, whose wavelength, polarization or angular bandwidths are however necessarily limited owing to the resonant nature of surface plasmon excitations involved. Nonresonant absorption has so far been achieved by using combined nano- and micro-structural surface modifications and with composite materials involving metal nanoparticles embedded in dielectric layers. Here we realize nonresonant light absorption in a well-defined geometry by using ultra sharp convex metal grooves via adiabatic nanofocusing of gap surface plasmon modes excited by scattering off subwavelength-sized wedges. We demonstrate experimentally that two-dimensional arrays of sharp convex grooves in gold ensure efficient (>87%) broadband (450-850 nm) absorption of unpolarized light, reaching an average level of 96%. Efficient absorption of visible light by nanostructured metal surfaces open new exciting perspectives within plasmonics, especially for thermophotovoltaics. PMID- 22828627 TI - Unfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation. AB - OASIS is a member of the CREB/ATF family of transcription factors and modulates cell- or tissue-specific unfolded protein response signalling. Here we show that this modulation has a critical role in the differentiation of neural precursor cells into astrocytes. Cerebral cortices of mice specifically deficient in OASIS (Oasis(-/-)) contain fewer astrocytes and more neural precursor cells than those of wild-type mice during embryonic development. Furthermore, astrocyte differentiation is delayed in primary cultured Oasis(-/-) neural precursor cells. The transcription factor Gcm1, which is necessary for astrocyte differentiation in Drosophila, is revealed to be a target of OASIS. Introduction of Gcm1 into Oasis(-/-) neural precursor cells improves the delayed differentiation of neural precursor cells into astrocytes by accelerating demethylation of the Gfap promoter. Gcm1 expression is temporally controlled by the unfolded protein response through interactions between OASIS family members during astrocyte differentiation. Taken together, our findings demonstrate a novel mechanism by which OASIS and its associated family members are modulated by the unfolded protein response to finely control astrocyte differentiation. PMID- 22828628 TI - Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains. AB - Transcription activator-like effectors are sequence-specific DNA-binding proteins that harbour modular, repetitive DNA-binding domains. Transcription activator like effectors have enabled the creation of customizable designer transcriptional factors and sequence-specific nucleases for genome engineering. Here we report two improvements of the transcription activator-like effector toolbox for achieving efficient activation and repression of endogenous gene expression in mammalian cells. We show that the naturally occurring repeat-variable diresidue Asn-His (NH) has high biological activity and specificity for guanine, a highly prevalent base in mammalian genomes. We also report an effective transcription activator-like effector transcriptional repressor architecture for targeted inhibition of transcription in mammalian cells. These findings will improve the precision and effectiveness of genome engineering that can be achieved using transcription activator-like effectors. PMID- 22828630 TI - Structural correlations in the generation of polaron pairs in low-bandgap polymers for photovoltaics. AB - Polymeric semiconductors are materials where unique optical and electronic properties often originate from a tailored chemical structure. This allows for synthesizing conjugated macromolecules with ad hoc functionalities for organic electronics. In photovoltaics, donor-acceptor co-polymers, with moieties of different electron affinity alternating on the chain, have attracted considerable interest. The low bandgap offers optimal light-harvesting characteristics and has inspired work towards record power conversion efficiencies. Here we show for the first time how the chemical structure of donor and acceptor moieties controls the photogeneration of polaron pairs. We show that co-polymers with strong acceptors show large yields of polaron pair formation up to 24% of the initial photoexcitations as compared with a homopolymer (eta=8%). pi-conjugated spacers, separating the donor and acceptor centre of masses, have the beneficial role of increasing the recombination time. The results provide useful input into the understanding of polaron pair photogeneration in low-bandgap co-polymers for photovoltaics. PMID- 22828631 TI - Ambient-stable tetragonal phase in silver nanostructures. AB - Crystallization of noble metal atoms usually leads to the highly symmetric face centred cubic phase that represents the thermodynamically stable structure. Introducing defective microstructures into a metal crystal lattice may induce distortions to form non-face-centered cubic phases when the lateral dimensions of objects decrease down to nanometre scale. However, stable non-face-centered cubic phases have not been reported in noble metal nanoparticles. Here we report that a stable body-centred tetragonal phase is observed in silver nanoparticles with fivefold twinning even at ambient conditions. The body-centered tetragonal phase originates from the distortion of cubic silver lattices due to internal strains in the twinned nanoparticles. The lattice distortion in the centre of such a nanoparticle is larger than that in the surfaces, indicating that the nanoparticle is composed of a highly strained core encapsulated in a less strained sheath that helps stabilize the strained core. PMID- 22828632 TI - The role of heterodimerization between VEGFR-1 and VEGFR-2 in the regulation of endothelial cell homeostasis. AB - VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR(1-2)) in endothelial cells with a synthetic ligand that binds specifically to VEGFR(1-2). The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR(1-2) activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR(1-2) activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR(1-2) inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR 2 subunits and such heterodimers regulate endothelial cell homeostasis. PMID- 22828633 TI - Gating of cyclic nucleotide-gated channels is voltage dependent. AB - Cyclic nucleotide-gated channels belong to the family of voltage-gated ion channels, but pore opening requires the presence of intracellular cyclic nucleotides. In the presence of a saturating agonist, cyclic nucleotide-gated channel gating is voltage independent and it is not known why cyclic nucleotide gated channels are voltage-insensitive despite harbouring the S4-type voltage sensor. Here we report that, in the presence of Li(+), Na(+) and K(+), the gating of wild-type cyclic nucleotide-gated A1 and native cyclic nucleotide-gated channels is voltage independent, whereas their gating is highly voltage-dependent in the presence of Rb(+), Cs(+) and organic cations. Mutagenesis experiments show that voltage sensing occurs through a voltage sensor composed of charged/polar residues in the pore and of the S4-type voltage sensor. During evolution, cyclic nucleotide-gated channels lose their voltage-sensing ability when Na(+) or K(+) permeate so that the vertebrate photoreceptor cyclic nucleotide-gated channels are open at negative voltages, a necessary condition for phototransduction. PMID- 22828634 TI - Roles of icosahedral and crystal-like order in the hard spheres glass transition. AB - A link between structural ordering and slow dynamics has recently attracted much attention from the context of the origin of glassy slow dynamics. Candidates for such structural order are icosahedral, exotic amorphous and crystal-like. Each type of order is linked to a different scenario of glass transition. Here we experimentally access local structural order in polydisperse hard spheres by particle-level confocal microscopy. We identify the key structures as icosahedral and FCC-like order, both statistically associated with slow particles. However, when approaching the glass transition, the icosahedral order does not grow in size, whereas crystal-like order grows. It is the latter that governs the dynamics and is linked to dynamic heterogeneity. This questions the direct role of the local icosahedral ordering in glassy slow dynamics and suggests that the growing length scale of structural order is essential for the slowing down of dynamics and the non-local cooperativity in particle motion. PMID- 22828635 TI - Patterning symmetry in the rational design of colloidal crystals. AB - Colloidal particles have the right size to form ordered structures with periodicities comparable to the wavelength of visible light. The tantalizing colours of precious opals and the colour of some species of birds are examples of polycrystalline colloidal structures found in nature. Driven by the demands of several emergent technologies, efforts have been made to develop efficient, self assembly-based methodologies for generating colloidal single crystals with well defined morphologies. Somewhat unfortunately, these efforts are often frustrated by the formation of structures lacking long-range order. Here we show that the rational design of patch shape and symmetry can drive patchy colloids to crystallize in a single, selected morphology by structurally eliminating undesired polymorphs. We provide a proof of this concept through the numerical investigation of triblock Janus colloids. One particular choice of patch symmetry yields, via spontaneous crystallization, a pure tetrastack lattice, a structure with attractive photonic properties, whereas another one results in a colloidal clathrate-like structure, in both cases without any interfering polymorphs. PMID- 22828637 TI - Blockade of alpha2-adrenoceptors induces Arc gene expression in rat brain in a glutamate receptor-dependent manner: a combined qPCR, in situ hybridisation and immunocytochemistry study. AB - Studies of 5-HT-glutamate interactions suggest that activation of brain 5-HT(2A) receptors leads to an AMPA receptor-mediated induction of the immediate early (activity-dependent) gene, Arc (Arg3.1). In this respect, noradrenaline-glutamate interactions are poorly characterised. Here we investigated the influence on regional brain Arc gene expression of selective blockade of alpha(2) adrenoceptors in rats. Several complementary techniques were used: qPCR (mRNA, discrete tissue punches), in situ hybridisation (mRNA, sections) and immunocytochemistry. The alpha(2)-adrenoceptor antagonist, RX 821002, dose dependently and time-dependently (maximal effect 2 h) increased Arc mRNA levels as demonstrated both by qPCR and in situ hybridisation. The alpha(2)-adrenoceptor antagonist, atipamezole, also increased Arc mRNA in in situ hybridisation studies. Changes in Arc mRNA after RX 821002 were of similar magnitude in punches and intact tissue sections and region-specific, with effects being most pronounced in parietal cortex and caudate putamen, less robust in frontal cortex, and not detectable in hippocampal sub-regions. Both qPCR and in situ hybridisation studies demonstrated that RX 821002-induced Arc mRNA was blocked by the AMPA antagonist, GYKI 52466. Pretreatment with the NMDA antagonist MK 801 also prevented RX 821002-induced Arc mRNA, as did the mGluR5 antagonist MPEP, whilst the mGluR2/3 antagonist, LY341495, had no effect. Finally, immunocytochemical studies showed that RX 821002 increased Arc-immunoreactivity in cells in close apposition to alpha(2)-adrenoceptor-positive processes. Thus, employing three complementary techniques, these observations demonstrate that blockade of alpha(2)-adrenoceptors triggers brain expression of the immediate early gene, Arc, and that this effect involves the recruitment of AMPA, NMDA and mGluR5 but not mGluR2/3 glutamatergic receptors. PMID- 22828638 TI - Non-pharmacological cognitive enhancement. AB - The term "cognitive enhancement" usually characterizes interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health. While the current bioethical debate mainly concentrates on pharmaceuticals, according to the given characterization, cognitive enhancement also by non-pharmacological means has to be regarded as enhancement proper. Here we summarize empirical data on approaches using nutrition, physical exercise, sleep, meditation, mnemonic strategies, computer training, and brain stimulation for enhancing cognitive capabilities. Several of these non-pharmacological enhancement strategies seem to be more efficacious compared to currently available pharmaceuticals usually coined as cognitive enhancers. While many ethical arguments of the cognitive enhancement debate apply to both pharmacological and non-pharmacological enhancers, some of them appear in new light when considered on the background of non-pharmacological enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22828636 TI - Mixed antagonistic effects of the ginkgolides at recombinant human rho1 GABAC receptors. AB - The diterpene lactones of Ginkgo biloba, ginkgolides A, B and C are antagonists at a range of Cys-loop receptors. This study examined the effects of the ginkgolides at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp. The ginkgolides were moderately potent antagonists with IC(50)s in the MUM range. At 10 MUM, 30 MUM and 100 MUM, the ginkgolides caused rightward shifts of GABA dose-response curves and reduced maximal GABA responses, characteristic of noncompetitive antagonists, while the potencies showed a clear dependence on GABA concentration, indicating apparent competitive antagonism. This suggests that the ginkgolides exert a mixed-type antagonism at the rho(1) GABA(C) receptors. The ginkgolides did not exhibit any obvious use-dependent inhibition. Fitting of the data to a number of kinetic schemes suggests an allosteric inhibition as a possible mechanism of action of the ginkgolides which accounts for their inhibition of the responses without channel block or use-dependent inhibition. Kinetic modelling predicts that the ginkgolides exhibit saturation of antagonism at high concentrations of GABA, but this was only partially observed for ginkgolide B. It also suggests that there may be different binding sites in the closed and open states of the receptor, with a higher affinity for the receptor in the closed state. PMID- 22828639 TI - Muscarinic M4 receptors regulate GABAergic transmission in rat tuberomammillary nucleus neurons. AB - Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M(4) receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker, or in a Ca(2+)-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K(+) channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M(4) receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca(2+) influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M(4) receptors in more physiological conditions. The M(4) receptor-mediated modulation of GABAergic transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness. PMID- 22828640 TI - Splenomegaly and variceal bleeding in a ten-year-old HIV-infected girl with noncirrhotic portal hypertension. AB - Noncirrhotic portal hypertension is an uncommon liver disease of unknown origin, increasingly described in HIV-infected adults. Prolonged antiretroviral exposure, in particular to didanosine, and thrombophilic predisposition have been suggested as potential pathogenic factors. Data are limited in children. We describe a 10 year-old HIV-infected girl with noncirrhotic portal hypertension who presented with progressive spleen enlargement and variceal bleeding. PMID- 22828641 TI - Gut microbiota in children vaccinated with rotavirus vaccine. AB - To assess the effect that the rotavirus vaccine RotaTeq may have on the gut microbiota, this study searched for differences in intestinal bacterial composition between vaccinated and unvaccinated children. Bacterial diversity in fecal samples was evaluated by pyrosequencing of the 16S rRNA gene and taxonomic analyses using bioinformatics tools. No evidence of such differences was observed. PMID- 22828642 TI - Trough concentrations of vancomycin: adult therapeutic targets are not appropriate for children. AB - Despite the need for effective vancomycin therapy, there are few data guiding vancomycin monitoring in children. We reviewed retrospectively vancomycin use in children 1 month to 12 years of age. Initial and adjusted target trough vancomycin concentrations in serum were infrequently achieved regardless of the dosing schedule. Currently recommended trough concentrations need to be re examined with a more detailed pharmacokinetic study in children. PMID- 22828643 TI - Bacteriology of community-acquired invasive disease found in a multicountry prospective, population-based, epidemiological surveillance for Pneumococcus in children in Latin America. AB - Several bacteria cause community-acquired invasive bacterial disease in children; many are vaccine preventable. Knowledge of pathogens causing community-acquired invasive bacterial disease is important when selecting antimicrobial therapy and implementing vaccine prevention strategies. We describe bacteriology of community acquired invasive disease observed among 31,641 blood and sterile fluid cultures from children aged 28 days to 36 months in 3 Latin American countries over 2 years. PMID- 22828644 TI - High prevalence of X4/DM-tropic variants in children and adolescents infected with HIV-1 by vertical transmission. AB - BACKGROUND: We studied HIV coreceptor tropism in vertically HIV-infected children and adolescents with the objective of predicting the proportion of children and adolescents that could be treated with CCR5 (R5) antagonists. METHODS: One hundred eighteen multidrug-resistant pediatric patients (36 children and 82 adolescents) were enrolled in a cross-sectional study. Viral tropism was assessed using the new phenotypic HIV-1 tropism coreceptor assay information and Trofile. RESULTS: Of 118 antiretroviral-experienced HIV-infected children and adolescents, 49 (57.0%) had dual-tropic and 20 (23.3%) had X4-tropic viruses by tropism coreceptor assay information testing. Only 17 (19.7%) showed R5-tropic variants. HIV-1 coreceptor usage was not detectable in 32 of 118 (27%) patients. Among 24 children and 62 adolescents with tropism coreceptor assay information results, 17 (70.8%) children and 51 (82.2%) adolescents showed viruses with dual-tropic or X4 tropic variants. Additionally, Trofile (ES) was performed in 42 of 118 patients with HIV-1 RNA > 1000 copies/mL. No patient showed X4-tropic variants; dual tropic viruses were observed in 12 (28.6%) patients. In 6 (14.3%) patients, HIV tropism could not be determined. X4-tropic variants were more common in children (P = 0.031). CD4 T cell percentage was significantly lower in children (P = 0.011) and adolescents (P = 0.027) with R5-tropic viruses than in those with X4 tropic viruses. CONCLUSIONS: The presence of X4-tropic variants in more than 80% of our cohort of antiretroviral-experienced children and adolescents with vertical HIV-1 infection indicates a very limited role for CCR5 antagonists as part of salvage regimens for highly treatment-experienced vertically HIV-1 infected patients with extensive antiretroviral drug resistance and limited treatment options. PMID- 22828645 TI - Five-year antibody persistence and safety following a booster dose of combined Haemophilus influenzae type b-Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine. AB - BACKGROUND: Booster vaccination with the combined Haemophilus influenza type b Neisseria meningitides serogroup C-tetanus toxoid vaccine (Hib-MenC-TT) has been reported to induce different MenC antibody responses depending on the priming vaccines, with a possible impact on long-term protection. Here, the five-year persistence of immune responses induced by a booster dose of Hib-MenC-TT was evaluated in toddlers primed with either Hib-MenC-TT or MenC-TT. METHODS: This is the follow-up of a phase III, open, randomized study, in which a Hib-MenC-TT booster dose was given at 13.14 months of age to toddlers primed with either 3 doses of Hib-MenC-TT or 2 doses of MenC-TT in infancy. Children in the control group had received 3 primary doses and a booster dose of MenC-CRM197. Functional antibodies against MenC were measured by a serum bactericidal assay with rabbit complement (rSBA-MenC) and antibodies against Hib polyribosylribitol phosphate by enzyme-linked immunosorbent assay. Serious adverse events considered by the investigator to be possibly related to vaccination were to be reported throughout the study. RESULTS: At 66 months postbooster, rSBA-MenC titers >=8 were retained by 82.6% of children primed with Hib-MenC-TT, 94.1% of children primed with MenC TT, and 60.9% of children in the control group. All children who received the Hib MenC-TT booster dose retained anti- polyribosylribitol phosphate concentrations >=0.15 MUg/mL. No serious adverse events considered possibly related to vaccination were reported. CONCLUSIONS: There is evidence of good antibody persistence against MenC and Hib for more than five years postbooster vaccination with Hib-MenC TT in toddlers primed with Hib-MenC-TT or MenC-TT. PMID- 22828646 TI - Evaluation of the impact of interferon-gamma release assays on the management of childhood tuberculosis. AB - BACKGROUND: Interferon-gamma release assays are increasingly being used in low incidence settings, but there is little information on whether test results influence clinical decisions in children. METHODS: In June 2009, the Montreal Children's Hospital began implementing the QuantiFERON-TB Gold In-Tube (QFT) as a follow-up test to the tuberculin skin test (TST). Pediatric respirologists were asked to document how the QFT result changed their initial clinical management based on the TST. RESULTS: During a 2-year period, 399 children with TST and QFT results were recruited prospectively. The median age was 13 years. In the cohort, 83% were foreign-born and 82% were Bacille Calmette-Guerin vaccinated. The QFT was negative in 5 of 11 (45.5%) children diagnosed with active tuberculosis (TB). Among 55 TST+/QFT- children evaluated as TB contacts, the negative QFT changed the treatment decision in only 3 (5.5%), and isoniazid was prescribed to the remainder. In 201 TST+/QFT- children from targeted school and immigrant screening programs, a negative QFT result was used to withhold isoniazid in 145 (72.1%) children. These children were followed for 1 year, during which no TB cases occurred. In a multivariable analysis, history of TB contact and TST induration >=20 mm were associated with fewer changes in clinical decisions. CONCLUSIONS: Our cohort study showed that pediatric respirologists used negative QFT results to withhold isoniazid in most low-risk children who were referred for a positive TST found through targeted screening programs. In contrast, in almost all TST positive children who were evaluated as TB contacts, negative QFT results did not change clinical management. PMID- 22828647 TI - Rotavirus-related hospitalizations are responsible for high seasonal peaks in all cause pediatric hospitalizations. AB - BACKGROUND: Seasonal rotavirus (RV) epidemics partly overlap with those of other common childhood infections, thereby generating enormous, but poorly quantified, pressure on hospital resources during winter and spring. We assessed RV contribution to seasonal excess in all-cause pediatric hospitalizations and RV hospitalization incidence rate in an observational study. METHODS: The study was conducted among pediatric wards in 3 general hospitals and 1 pediatric tertiary care center. Numbers of RV hospitalizations were determined from 5-year data on confirmed RV hospitalizations and adjusted for RV underreporting, assessed through active surveillance for acute gastroenteritis during the 2011 RV season. Incidence rate and RV contribution to all-cause hospitalizations were determined on hospital administrative data and population statistics. RESULTS: RV accounted for 6.2% (95% confidence interval: 5.3-7.1) of all-cause pediatric hospitalizations among general hospitals and 3.1% (95% confidence interval: 2.9 3.3) at the tertiary care center, adjusted for the proportion RV underreporting among gastroenteritis patients (33%) as observed during active surveillance. Among general hospitals, there was a 30% increase in all-cause hospitalizations during the active season of common childhood infections compared with summer months. RV contributed 31% to seasonal excess in all-cause pediatric hospitalizations, representing 12.9% of hospitalizations between January and May. RV hospitalizations incidence rate in the population was 510/100,000 child-years <5 years (95% confidence interval: 420-600). CONCLUSION: RV is one of the main causes of seasonal peaks in pediatric hospitalizations, and as such contributes significantly to periodic high bed capacity pressures and associated adverse effects. RV vaccination benefits in this respect should be considered in decision making processes. PMID- 22828648 TI - Proximal focal humeral deficiency in a large breed dog. AB - A 26-week-old female Boerboel was referred for evaluation of progressive left thoracic limb lameness. Computed tomography and radiographic evaluation revealed radiolucency of the caudal region of the proximal humeral metaphysis, absence of the humeral head, and gross distortion of the glenoid. Given the severe glenohumeral deformation, arthrodesis of the left shoulder was performed using orthogonal locking bone plates, lag screw fixation, and bone grafting. Despite late implant failure, arthrodesis was successful in this case, and satisfactory limb function was restored. To the author's knowledge, this is the first report of a case of a focal developmental deficiency of the proximal humerus reported in a dog. PMID- 22828649 TI - Accuracy of emergency physician-performed ultrasound in detecting traumatic pneumothorax after a 2-h training course. AB - BACKGROUND: Pneumothorax is one of the leading causes of preventable death in trauma patients. Chest radiograph has a lower sensitivity than a computed tomography (CT) scan for the diagnosis of pneumothorax. OBJECTIVES: The objective of this study is to assess the accuracy of ultrasound (US) in diagnosing post traumatic pneumothorax using a simplified diagnostic algorithm. METHODS: This prospective study was carried out in two academic emergency departments with a combined annual emergency department census of 70 000 visits per year by convenient sampling. Emergency physicians underwent a 2-h training course using a two-step diagnostic algorithm. The trauma patients included suspected of having post-traumatic pneumothorax were evaluated by thoracic US and chest CT scan. The accuracy of US in identifying pneumothorax was measured by calculating the sensitivity, specificity, positive predictor value, and negative predictor value using CT scan as the gold standard. The performance of US was compared with chest radiograph, which was also done as a part of standard trauma care for all patients. RESULTS: From June 2009 until July 2009, a total of 153 patients were included. US had a sensitivity of 86.4%, a specificity of 100%, a positive predictor value of 100%, and a negative predictor value of 95.6%. Chest radiograph showed a sensitivity of 48.6%, a specificity of 100%, a positive predictor value of 100%, and a negative predictor value of 85.1%. The mean time to perform chest radiograph was 12 min, which was significantly higher than US, with a mean time of 2 min. All missed pneumothoraces in US evaluation were small in size. CONCLUSION: After just a 2-h training course, emergency physicians showed a good success rate in finding pneumothoraces. Thoracic US can be an easy to learn and an accurate diagnostic modality for the detection of traumatic pneumothorax in emergency departments. PMID- 22828650 TI - Do SmartSite antireflux valves limit the flow rate of 0.9% normal saline through intravenous cannulas? AB - The aim of the study was to determine whether the placement of a SmartSite antireflux valve between a bag of fluid with line giving set and an intravenous cannula decreases the flow rate. Fluid flow rates were compared in paired experiments with and without an antireflux valve using a pressure infuser or allowing fluid to flow by gravity only for four different sizes of intravenous cannulas (20-14 G). Antireflux valves significantly decreased the fluid flow rates for all cannula sizes, irrespective of whether a pressure infuser was used. The decrease in the flow rate was most marked for larger cannulas [gravity only: 14 G: 52% (95% confidence interval (CI): 37-68), 16 G: 39% (95% CI: 34-43); pressure bag: 14 G: 74% (95% CI: 70-78), 16 G: 56% (95% CI: 54-57); all P<0.001]. Where maximum fluid flow rates are desirable, clinicians should consider not using an antireflux valve. PMID- 22828651 TI - Cyanide poisoning by fire smoke inhalation: a European expert consensus. AB - Smoke inhalation is a common cause of cyanide poisoning during fires, resulting in injury and even death. In many cases of smoke inhalation, cyanide has increasingly been recognized as a significant toxicant. The diagnosis of cyanide poisoning remains very difficult, and failure to recognize it may result in inadequate or inappropriate treatment. Findings suggesting cyanide toxicity include the following: (a) a history of enclosed-space fire; (b) any alteration in the level of consciousness; (c) any cardiovascular changes (particularly inexplicable hypotension); and (d) elevated plasma lactate. The feasibility and safety of empiric treatment with hydroxocobalamin for fire smoke victims have been reported in the literature. On the basis of a literature review and a panel discussion, a group of European experts has proposed emergency management protocols for cyanide toxicity in fire smoke victims. PMID- 22828653 TI - FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer. AB - Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L--FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer. PMID- 22828654 TI - Traditional Chinese medicine for cancer? PMID- 22828655 TI - That the effects of smoking should be measured in pack-years: misconceptions 4. AB - Lung cancer incidence in smokers is roughly proportional to dose rate (cigarettes per day) but increases much more rapidly with duration of smoking. The assumption that the incidence rate is proportional to total lifetime dose (the product of dose rate and duration) has been known to be wrong for many years, but total dose in pack-years is still often included, either alone or together, with more fundamental parameters such as dose rate, in regression analysis of epidemiological data. This is mathematically unnecessary and scientifically unhelpful. PMID- 22828656 TI - That recognised risk factors can explain past and present international differences in breast cancer incidence: misconceptions 5. AB - Recent discussions on research priorities in the United States have revealed a widespread assumption that known risk factors entirely explain the historic international differences in rates of breast cancer. In fact, formal investigations of this question, both by modelling between-country differences and studies of migrants, indicate that an appreciable amount of the international differences in this disease remains unexplained. If this is not recognised, opportunities for research on breast cancer aetiology may be lost. PMID- 22828657 TI - Medication complexity, prescription behaviour and patient adherence at the interface between ambulatory and stationary medical care. AB - PURPOSE: A hospital stay is often accompanied by changes in medication therapy. The purpose of this study was to investigate the impact of a transfer across the interfaces on the complexity of therapeutic regimens and patient adherence as well as the attitudes of patients and general practitioners (GPs) towards pharmacotherapies. METHODS: This was a prospective observational study that analysed the complexity of medication therapies and the adherence and attitudes of internal medicine and urology patients towards their medication(s) at three time points (hospital admission, discharge and 6 weeks after discharge). GPs of the patients recruited to the study were questioned about the follow-up medication therapy and their opinion on the medication prescribed in hospital. RESULTS: At the time of hospital admission, 60.2 % of the study population were nonadherent. During hospitalization, the number decreased to 37.6 %, but increased to 61.2 % 6 weeks after discharge. Changes in the overall complexity of the therapy regimens were marginal and not statistically significant. Of the long term medication regimens, 48.6 % were modified during hospital stay. The patients preferred regimens with a minimum of drug administrations. GPs stated to be willing to continue hospital prescriptions but were restricted by financial budgets. CONCLUSION: The results of this study confirm that an increase in adherence during a hospital stay is only transient, underlining the need for interventions to ameliorate medication adherence. They also suggest that patients prefer simple regimens. Although GPs are willing to consider their patient's preferences on pharmacotherapy, they state limitations due to financial budgets. Further studies are needed that investigate the extent to which medication therapies can be simplified and the effect of simplification on adherence. PMID- 22828658 TI - Fiscal belt tightening: the continuing trend of radiologists seeing less pay for more work. PMID- 22828659 TI - Case of the month #178: intraosseous orbital meningioma presenting with diplopia and proptosis. PMID- 22828660 TI - Rhythmic priming enhances the phonological processing of speech. AB - While natural speech does not possess the same degree of temporal regularity found in music, there is recent evidence to suggest that temporal regularity enhances speech processing. The aim of this experiment was to examine whether speech processing would be enhanced by the prior presentation of a rhythmical prime. We recorded electrophysiological (EEG) and behavioural (reaction time) data while participants listened to nonsense words preceded by a simple rhythm. Results showed that speech processing was enhanced by the temporal expectations generated by the prime. Interestingly, beat and metrical structure of the prime had an effect on different ERP components elicited by the following word (N100, P300). These results indicate that using a musical-like rhythmic prime matched to the prosodic features of speech enhances phonological processing of spoken words and thus reveal a cross-domain effect of musical rhythm on the processing of speech rhythm. PMID- 22828661 TI - Components of the indirect effect in vaccine trials: identification of contagion and infectiousness effects. AB - Vaccination of one person may prevent the infection of another either because the vaccine prevents the first from being infected and from infecting the second, or because, even if the first person is infected, the vaccine may render the infection less infectious. We might refer to the first of these mechanisms as a contagion effect and the second as an infectiousness effect. In the simple setting of a randomized vaccine trial with households of size two, we use counterfactual theory under interference to provide formal definitions of a contagion effect and an unconditional infectiousness effect. Using ideas analogous to mediation analysis, we show that the indirect effect (the effect of one person's vaccine on another's outcome) can be decomposed into a contagion effect and an unconditional infectiousness effect on the risk difference, risk ratio, odds ratio, and vaccine efficacy scales. We provide identification assumptions for such contagion and unconditional infectiousness effects and describe a simple statistical technique to estimate these effects when they are identified. We also give a sensitivity analysis technique to assess how inferences would change under violations of the identification assumptions. The concepts and results of this paper are illustrated with hypothetical vaccine trial data. PMID- 22828664 TI - On the stability of a variety of organic photovoltaic devices by IPCE and in situ IPCE analyses--the ISOS-3 inter-laboratory collaboration. AB - This work is part of the inter-laboratory collaboration to study the stability of seven distinct sets of state-of-the-art organic photovoltaic (OPV) devices prepared by leading research laboratories. All devices have been shipped to and degraded at RISO-DTU up to 1830 hours in accordance with established ISOS-3 protocols under defined illumination conditions. In this work, we apply the Incident Photon-to-Electron Conversion Efficiency (IPCE) and the in situ IPCE techniques to determine the relation between solar cell performance and solar cell stability. Different ageing conditions were considered: accelerated full sun simulation, low level indoor fluorescent lighting and dark storage. The devices were also monitored under conditions of ambient and inert (N(2)) atmospheres, which allows for the identification of the solar cell materials more susceptible to degradation by ambient air (oxygen and moisture). The different OPVs configurations permitted the study of the intrinsic stability of the devices depending on: two different ITO-replacement alternatives, two different hole extraction layers (PEDOT:PSS and MoO(3)), and two different P3HT-based polymers. The response of un-encapsulated devices to ambient atmosphere offered insight into the importance of moisture in solar cell performance. Our results demonstrate that the IPCE and the in situ IPCE techniques are valuable analytical methods to understand device degradation and solar cell lifetime. PMID- 22828663 TI - A learning curve assessment of real-time sonoelastography of the prostate. AB - PURPOSE: To examine how much practice is essential to properly perform real-time sonoelastography (RTE) in the detection of PC. METHODS: RTE of the prostate was performed in 60 PC patients prior to radical prostatectomy (RP). All patients were examined by a novice and an expert observer in a blinded fashion. The novice's results were validated with the results of the expert. Kappa indexes, sensitivities, specificities as well as the duration of the examination were assessed. Learning curves (LC) were obtained by assessment of 16 (LC A) and eight (LC B) prostate sectors. Cochrane-Armitage trend test, Chi(2) test and t test for paired samples were used. RESULTS: For the 16-sector method (LC A), overall sensitivity and specificity were 58.2 and 77.7 % and, for the 8-sector method, 68.3 and 64.5 %, respectively. For LC A, sensitivity rose over the whole study period (p = 0.0055). As a result, no learning plateau was reached. In contrast, a learning plateau with no constant rise in sensitivity (p = 0.4667) was reached for LC B after 30 examined patients. The mean examination time for both observers was 7.9 min (+/-3.7). CONCLUSIONS: When being trained by an expert examiner, skills in RTE of the prostate can be obtained quickly. Performed by a trained examiner, the examination itself is little time-consuming. Thus, RTE represents a user- and patient-friendly tool that can easily be integrated into the day-to-day practice of urologists. PMID- 22828665 TI - Mastectomy in the era of implant-based reconstruction: should we be removing the pectoralis fascia? AB - Though removing of the pectorals fascia has always been routinely performed in modified radical mastectomy for invasive breast cancer, there is no evidence that this routine is justified. The authors present some of the scarce data found in literature, and discuss the advantages of living the pectorals fascia in situ to facilitate implant based reconstruction. PMID- 22828666 TI - Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin. AB - BACKGROUND: Studies indicate that extracts and purified components, including carnosic acid, from the herb rosemary display significant growth inhibitory activity on a variety of cancers. PURPOSE: This paper examines the ability of rosemary/carnosic acid to inhibit the growth of human breast cancer cells and to synergize with curcumin. MATERIALS AND METHODS: To do this, we treated human breast cancer cells with rosemary/carnosic acid and assessed effects on cell proliferation, cell cycle distribution, gene expression patterns, activity of the purified Na/K ATPase and combinations with curcumin. RESULTS: Rosemary/carnosic acid potently inhibits proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest. Further, carnosic acid is selective for MCF7 cells transfected for Her2, indicating that Her2 may function in its action. To reveal primary effects, we treated ER-negative breast cancer cells with carnosic acid for 6h. At a low dose, 5 MUg/ml (15 MUM), carnosic acid activated the expression of 3 genes, induced through the presence of antioxidant response elements, including genes involved in glutathione biosynthesis (CYP4F3, GCLC) and transport (SLC7A11). At a higher dose, 20 MUg/ml, carnosic acid activated the expression of antioxidant (AKR1C2, TNXRD1, HMOX1) and apoptosis (GDF15, PHLDA1, DDIT3) genes and suppressed the expression of inhibitor of transcription (ID3) and cell cycle (CDKN2C) genes. Carnosic acid exhibits synergy with turmeric/curcumin. These compounds inhibited the activity of the purified Na-K-ATPase which may contribute to this synergy. CONCLUSION: Rosemary/carnosic acid, alone or combined with curcumin, may be useful to prevent and treat ER-negative breast cancer. PMID- 22828667 TI - Radiographic landmarks for measurement of cranial tibial subluxation in the canine cruciate ligament deficient stifle. AB - OBJECTIVES: The primary objective was to develop a repeatable radiographic technique for assessment of cranial tibial subluxation (CTS) and test the intra observer and inter-observer repeatability of the chosen landmarks. A secondary objective was to determine the effects of digital radiographic magnification on CTS measurement repeatability. METHODS: Twenty-three normal canine pelvic limbs were used to determine the magnitude of CTS before and after transection of the cranial cruciate ligament. Mediolateral radiographs were taken with and without fiduciary markers in place. Three investigators measured the CTS using radiographically visible anatomic landmarks at two different magnifications. The total observed variabilities were assessed by inter-observer and intra-observer differences. Paired t-tests were used to determine the effect of magnification and marker presence on CTS measures. RESULTS: Measurement of the CTS from the caudal margin of the intercondylar fossa on the femur to the intercondylar eminence was the most repeatable. Poor correlation between the anatomic landmarks and the fiduciary bone markers was observed. We found no effect of magnification or presence or absence of bone markers on measurement of CTS. CLINICAL SIGNIFICANCE: Cranial tibial subluxation can be detected with the most repeatability by measuring between the caudal margin of the intercondylar fossa and the intercondylar eminence. Magnification of the digitized radiographic image had minimal effect on repeatability. This technique can be used for in vivo analysis of the canine cruciate ligament deficient stifle joint. PMID- 22828662 TI - Exposure to cats and dogs, and symptoms of asthma, rhinoconjunctivitis, and eczema. AB - BACKGROUND: Associations between exposure to cats and dogs and respiratory and allergic outcomes in children have been reported in affluent countries, but little is known about such associations in less-affluent countries. METHODS: The International Study of Asthma and Allergies in Childhood, phase 3 was carried out in children aged 6-7 years and adolescents aged 13-14 years across the world. Questions about cats and dogs in the home were included in an additional questionnaire. Using logistic regression, we investigated the association between such exposures and symptoms of asthma, rhinoconjunctivitis, and eczema. Adjustments were made for sex, region of the world, language, gross national income per capita, and 10 other covariates. RESULTS: Among children (6-7 years of age), cat exposure in the first year of life was associated with current symptoms of asthma, wheeze, rhinoconjunctivitis, and eczema, especially in less-affluent countries. Among adolescents (13-14 years of age), we found a positive association between exposure to cats or dogs and symptom prevalence in more affluent and less-affluent countries. The global multivariate odds ratios for children with complete covariate data were 1.17 (95% confidence interval = 1.08 1.29) for current symptoms of asthma, 1.13 (1.05-1.23) for rhinoconjunctivitis, and 1.38 (1.26-1.52) for eczema. Smaller odds ratios were found for exposure to only dogs. Exposure to only cats was associated with eczema. CONCLUSION: Early life exposure to cats is a risk factor for symptoms of asthma, rhinoconjunctivitis, and eczema in 6- to 7-year-old children, especially in less affluent countries. Current exposure to cats and dogs combined, and only to dogs, is a risk factor for symptom reporting by 13- to 14-year-old adolescents worldwide. PMID- 22828668 TI - Exaggerated blood pressure response to exercise in athletes: dysmetabolism or altered autonomic nervous system modulation? AB - BACKGROUND: The importance of exercise-induced exaggerated blood pressure (BP) response in endurance athletes is not known. OBJECTIVE: To assess the hemodynamic parameters and metabolic profile in athletes with an exaggerated BP response to exercise. METHODS: Forty-four endurance athletes underwent a maximal exercise test, a 24-h ambulatory blood pressure monitoring, a 24-h Holter assessment, and sampling of blood on two occasions: (a) during intense training and (b) following 3 weeks without training. RESULTS: During the training period, 11 athletes showed an exaggerated BP response to exercise, whereas seven of these 11 athletes also showed an exaggerated BP response during the resting period. Elevation in systolic BP was greater in athletes with an exaggerated BP response than athletes with a normal BP response to exercise (resting: 84 +/- 22 vs. 60 +/- 18 mmHg, P = 0.02; training: 100 +/- 21 vs. 70 +/- 18 mmHg, P = 0.004). During the training period, athletes with an exaggerated BP response to exercise showed higher systolic BP values on 24-h ambulatory blood pressure monitoring (136 +/- 15 vs. 118 +/- 8 mmHg, P = 0.02). During the resting period, athletes with an exaggerated BP response to exercise had lower apolipoprotein-A1 (1.3 +/- 0.1 vs. 1.5 +/- 0.2 g/l, P = 0.009), and higher SDNN (259 +/- 47 vs. 209 +/- 52 ms, P = 0.03) and pNN50 (0.4 +/- 0.1 vs. 0.3 +/- 0.1%, P = 0.05). CONCLUSION: These observations may represent the first sign of a slight metabolic disturbance associated with vascular wall abnormalities, although the parameters remain within normal values. PMID- 22828670 TI - Quality: everybody's business. PMID- 22828669 TI - Learning and working together in primary care: interprofessional education and quality. PMID- 22828672 TI - Interdisciplinary health research: perspectives from a process evaluation research team. AB - BACKGROUND: Interdisciplinary health research (IDHR) is increasingly encouraged and is often a specific requirement for research grants provided by health research funding councils worldwide. There is consensus that research expertise and scholarship from a diverse range of disciplines are necessary to examine questions relating to complex health and social concerns for which single disciplinary approaches have been found inadequate. METHODS: This paper reports on the experiences of an interdisciplinary process evaluation research team working in the field of stroke care. RESULTS: Realising the perceived benefits is less than straightforward; setting up and conducting IDHR can present researchers with a range of challenges at a strategic, practical and individual level. We identify how differences in disciplinary perspectives and skills impacted on our research practice. CONCLUSIONS: Whilst initially challenging, our different approaches to the research problem and the methods to address it, expanded conceptual and methodological understanding and proved of benefit for the research team and the study outputs. PMID- 22828671 TI - Hospitalfoodie: an interprofessional case study of the redesign of the nutritional management and monitoring system for vulnerable older hospital patients. AB - BACKGROUND: To date, a solution to the problem of hospital malnutrition in older patients in the UK has not been found through previous approaches using isolated interventions. AIMS: To identify opportunities for, and to develop and prototype a new food and nutritional management system able to meet individual patients' daily requirements. METHODS: Using an interprofessional team approach, design researchers worked alongside food scientists, dieticians, medical sociologists, ergonomists, computer scientists, technologists, key stakeholders and a 'food family' (those concerned with nutrition management, and food supply and delivery in hospital, i.e. food producers, caterers, ward staff, nurses dieticians, physicians, speech and occupational therapists), as well as with older people representatives. Through ethnography and workshop-based methods, major opportunities for service improvement were identified. An iterative design and development process was deployed using mixed methods including ethnography, mapping, personas, storyboarding, role-playing, enactment and narratives. Prototypes of interactive interfaces were developed to test the workability of an electronic nutritional management and monitoring system linked to a nutrition composition database. In parallel, new food products were developed, led by food scientists, and a catering supply and delivery system for ward-based food provision was also developed. The methods used to facilitate interprofessional collaboration, the engagement of the food family, and to develop the food and nutrition service concept are described. RESULTS: A demonstration prototype was displayed in exhibition format at a series of conferences to gather further feedback. CONCLUSION: Early responses to the 'hospitalfoodie' demonstration prototype were favourable and indicate that, with further development, the prototype may offer the means for improving nutritional care standards in hospitals and be adaptable for use across other patient groups. PMID- 22828673 TI - Placing interprofessional learning at the heart of improving practice: the activities and achievements of CLAHRC in Leicestershire, Northamptonshire and Rutland. AB - BACKGROUND: The National Institute for Health Research initiative 'collaborations for leadership in applied health research and care' (CLAHRC) in Leicestershire Northamptonshire and Rutland (LNR) is a partnership between the University of Leicester and NHS trusts in LNR that aims to reduce the second gap in translation (the long delay between conducting research and it having an impact on clinical practice). METHOD: CLAHRC-LNR appointed specialist staff as boundary spanners and knowledge brokers to improve links between academia and the NHS, and to facilitate a range of activities designed to increase the implementation of research evidence. An interprofessional and interdisciplinary approach is used and incorporates a range of activities including: applied research, service evaluation and pilot projects, education and training events, knowledge dissemination activities and developing networks to increase the use of research in the NHS partners. RESULTS: CLAHRC-LNR's close collaboration with partner NHS trusts has aided the development of a programme of applied research that aims to develop interprofessional teamworking to improve healthcare systems and patient outcomes. Co-ordinators (boundary spanners) have been appointed in trusts and have been crucial in facilitating interprofessional working. Activities include a successful programme of training and education courses within the NHS partner trusts using the principles of interprofessional education. CLAHRC-LNR is developing the use of knowledge exchange events and workshops as well as establishing communities of practice to bring together professionals from across LNR NHS trusts and the University of Leicester to share their expertise and build interprofessional relationships. CLAHRC fellows (knowledge brokers) are being appointed to work with co-ordinators to facilitate the use of research evidence in decision making in the trusts and clinical commissioning groups (CCGs). CONCLUSION: Interprofessional working is integral to the approach adopted by CLAHRC-LNR, running through many of its activities, and is proving vital to addressing and helping to close the second gap in translation. PMID- 22828674 TI - Recruiting children onto research studies by the Scottish Primary Care Research Network: a real team effort. AB - BACKGROUND: Recruiting for research studies is always a challenge, particularly in paediatric studies. Here we report on experiences recruiting children to five studies through primary care. METHODS: The Scottish Primary Care Research Network (SPCRN) has approval to identify for research studies eligible participants on primary care practice lists. The number of potential participants and the proportion recruited onto five paediatric studies are provided along with factors involved in recruiting practices and patients. RESULTS: A total of 4910 individuals were recruited, of whom 367 (7%) participated. Recruitment of practices varied between 7 and 44% for different studies. There was evidence that practices who had participated in previous studies were more likely to participate again. Patient participation was positively related to affluence and there was evidence that adults were more likely to participate than children. DISCUSSION: Despite the pressing clinical workload in primary care, many general practices are still able to make accommodation for research activity. What is required is effective communication between colleagues in primary care, researchers, the SPCRN and patients. Given that the majority of medicine is practiced in primary care, there is a desire for evidence-based medicine to be generated from primary care and the SPCRN and other networks can help to provide this. PMID- 22828675 TI - How much interprofessional education did I receive in my medical training? PMID- 22828676 TI - Debating the use of work-based learning and interprofessional education in promoting collaborative practice in primary care: a discussion paper. AB - BACKGROUND: The context of primary care in the UK is changing rapidly, underpinned by continuing policy drivers to ensure person-centred safe and effective practice. Undergraduate and postgraduate programmes for healthcare practitioners are increasingly using interprofessional education (IPE) as one route to engender greater understanding of others' roles and contributions to health care, with the suggestion that IPE leads to better integration and teamwork, and thus stronger collaborative practice. Access to education and professional development for those working in primary care is difficult, and individuals need the focus of learning to be clearly relevant to their practice. AIMS: To review and debate the evidence on the role of work-based learning and IPE in enhancing collaborative practice in primary care. METHOD: Literature search and critique of key papers relevant to primary care practice. RESULTS: The three themes emerged of IPE, workbased learning (WBL) and collaborative practice. There is a growing body of literature to support the positive outcomes of IPE and the utilisation of WBL in developing practice. A range of practitioners in a variety of work settings have used WBL approaches in the implementation of innovations and the development of communities of practice. However, little evidence exists to support these approaches in primary care. CONCLUSION: The application of WBL across primary care teams can support a positive and collaborative learning culture, resulting in changes to professional practice. PMID- 22828677 TI - Delivering quality improvements in patient care: the application of the Leicester Model of interprofessional education. AB - BACKGROUND: This paper places the importance of evidence-based models of interprofessional education (IPE) within the context of a changing National Health Service (NHS). The coalition government has placed integrated care at the heart of its vision for England's health system. Its principles are to put patients at the centre of the NHS, empower clinicians to lead commissioning and change the emphasis of measurement to quality clinical outcomes. As a result, NHS services are being increasingly tendered along evidence-based care pathways and commissioners are introducing payment by results tariffs, requiring providers to achieve quality outcomes as a requirement of full payment. AIM: We argue that in preparing the health and social care workforce for outcome-based practice, the development of technical skills should be complemented with skills for effective teamworking and collaborative practice. METHODS: This paper shares the achievements of the Leicester Model of IPE which is underpinned by theoretical models of learning and implemented entirely in clinical practice; mixed research methods demonstrate that its learning potential is as relevant today as when it was first implemented in 1996. RESULTS: Our extensive research evidence demonstrates that students and healthcare professionals undertaking these programmes are enabled to perceive care pathways from service and providers perspectives; they gain valuable insights into how teams balance task- and patient-related issues, offer clarity about the team's effectiveness and gain new insights into collaborative opportunities to address patients' needs. CONCLUSION: We demonstrate that models such as ours offer evidence-based solutions which will support the achievement of quality outcomes for service providers, many of whom are reviewing their business plans to address the financial implications of payment by results. The current NHS reforms provide a hugely important lever in which IPE can come of age - in return we need to ensure that our NHS colleagues are informed of its potential. PMID- 22828678 TI - Preparing students to work effectively in interprofessional health and social care teams. AB - Interprofessional education (IPE) has 'learning to work effectively in interprofessional teams' as one of its central learning outcomes. Whilst much is made in IPE of allocating health and social care students into interprofessional teams and setting them a task to complete, it has proved difficult to find a fair and equitable method of assessing how effective each individual has been in contributing to the task. This difficulty is compounded when the module is delivered predominantly online. This paper describes the recent push to establish meaningful educational outcomes for those involved in delivering IPE to pre registration health and social care students. It then describes the use of a web based peer assessment tool (Web PA) developed at Loughborough and Hull Universities (UK) which has been adapted by Glasgow Caledonian University (UK) for assessing the outcome of contributing effectively to IPE-related online group tasks. The paper outlines how the process of web-based peer assessment operates in theory and how it has been received in practice. An illustration is given that shows how the process successfully discriminates between those that are working effectively in interprofessional teams and those that are not. The value of the process is discussed. PMID- 22828679 TI - The introduction of an interprofessional education module: students' perceptions. AB - AIM: The purpose of this study was to examine health science students' perceptions of an interprofessional education (IPE) module delivered by means of problem-based learning (PBL). METHODS: Ninety-two students from four health science disciplines (medicine, physiotherapy, nursing and diagnostic imaging) elected to participate in this IPE PBL module. An evaluation was undertaken using a questionnaire with quantitative and qualitative components completed at the end of the module. Students were asked to evaluate aspects of the module relating to learning objectives, intellectual stimulation, resources, library information skills, work load and overall satisfaction. Open-ended questions asked students to comment on the best aspects of the module and areas for improvement. Quantitative data were analysed using SPSS version 18 and qualitative data using framework analysis methodology. RESULTS: Of the 92 students that participated in the module, 70 (78%) completed the questionnaire. Over 70% (n = 49) of students positively endorsed the module in terms of the statements posed. Overall satisfaction with the module was high, with 63 (91%) students reporting that they agreed or strongly agreed that they were satisfied with the module. Analysis of qualitative data revealed the following emerging themes in relation to the module: (1) collaboration (learning together with others from different professions); (2) structure (small group work, discussion, teamwork assessment procedures); and (3) content (problem diversity). CONCLUSIONS: The introduction of this IPE module for health science students was well received. Students valued the opportunity to work in small groups with individuals from other health science disciplines. Students highlighted module structure and content as being important elements for consideration when developing IPE. Further research is required in order to define whether improving communication and collaboration skills will ultimately lead to improved quality in patient care. PMID- 22828680 TI - Solvent-free ionic liquid electrolytes without elemental iodine for dye sensitized solar cells. AB - A new type of electrolyte with a sulfide/polysulfide redox couple and I(-) was prepared as a solvent-free ionic liquid for application in dye-sensitized solar cells, reaching efficiencies of 5.2-6.4% under AM 1.5G, 100 mW cm(-2) light illumination, and 6.6% efficiency was obtained under 0.1 sun irradiation. PMID- 22828681 TI - Effect of fluoroscopically guided caudal epidural steroid or local anesthetic injections in the treatment of lumbar disc herniation and radiculitis: a randomized, controlled, double blind trial with a two-year follow-up. AB - BACKGROUND: Lumbar disc herniation and radiculitis are common elements of low back and lower extremity pain. Among minimally invasive treatments, epidural injections are one of the most commonly performed interventions. However, the literature is mixed about their effectiveness in managing low back and lower extremity pain. In general, individual studies and systematic reviews of epidural steroid injections have been hampered by their study design, baseline differences between treatment groups, inadequate sample sizes, highly controlled settings, lack of validated outcome measures, and the inability to confirm the injectate location because fluoroscopy was not used. STUDY DESIGN: A randomized, controlled, double blind, active control trial. SETTING: A private, interventional pain management practice, specialty referral center in the United States. OBJECTIVES: To assess the effectiveness of fluoroscopically directed caudal epidural injections with local anesthetic with or without steroids in managing chronic low back and lower extremity pain in patients with disc herniation and radiculitis. METHODS: One hundred twenty patients were randomized to two groups: Group I received 10 mL caudal epidural injections of local anesthetic, lidocaine 0.5%; Group II patients received caudal epidural injections of 0.5% lidocaine, 9 mL, mixed with 1 mL of steroid. OUTCOME ASSESSMENT: Multiple outcome measures were utilized. The primary outcome measures were Numeric Rating Scale (NRS) and the Oswestry Disability Index 2.0 (ODI). Secondary outcome measures were employment status and opioid intake. Significant pain relief improvement was defined as 50% or more improvement in NRS and ODI scores. RESULTS: In the successful category, 77% of Group I had significant pain relief of >/= 50% and functional status improvement of >/= 50% reduction in ODI scores; in Group II it was 76%, whereas overall it was 60% and 65% in Groups I and II. Over the two years, Group I had an average number of procedures of 5.5 +/- 2.8; Group II was 5.3 +/- 2.4. Even though there was no significant difference in overall relief between the two groups, the average relief for each procedure was superior for steroids. LIMITATIONS: Presumed limitations of this evaluation include lack of a placebo group. CONCLUSION: Caudal epidural injections of local anesthetic with or without steroids might be an effective therapy for patients with disc herniation or radiculitis. The present evidence illustrates the potential superiority of steroids compared with local anesthetic at two year follow up based on average relief per procedure. TRIAL REGISTRATION: NCT00370799. PMID- 22828682 TI - The effect of epidural resiniferatoxin in the neuropathic pain rat model. AB - BACKGROUND: Resiniferatoxin (RTX) is a potent synthetic agonist for transient receptor potential vanilloid subtype 1 (TRPV1), which has a selectivity for antinociception. The analgesic effect of epidural RTX in a rat model of neuropathic pain has not yet been studied. OBJECTIVES: The purpose of this study was to evaluate the analgesic effect of epidural RTX on neuropathic pain in a rat model to mechanical and thermal stimulation. The dose-related behavior changes and side effects were also studied. STUDY DESIGN: A randomized, experimental trial. SETTING: Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital METHODS: A spinal nerve ligation model was prepared using male Sprague-Dawley rats (7 weeks old, weight 230-250 g). An epidural catheter was placed at the L4-L5 level. Each study group (n = 6) received a different dose of RTX: 100 ng, 500 ng, 1 MUg, 2 MUg, 4 MUg and 10 MUg. All substances were administered in 20 MUL volume doses. The control group (n = 6) received 20 MUL of normal saline. We evaluated the response to mechanical and thermal stimuli as well as the sedation score at both short-term (3 hours) and long-term (20 days) after the epidural RTX injection. RESULTS: Prolonged analgesia to thermal stimulation was preceded by a transient dose-dependent hyperalgesia (500 ng, 1 MUg) or sedation (>/= 2 MUg) during the initial 60 minutes after RTX administration. Marked sedation and hyperventilation were noted at higher doses (>/= 2 MUg), while 2 out of 6 rats died with a 10 MUg dose. ED50 for epidural RTX was 265 ng (95% confidence interval 216.1-324.9 ng). The increased latency to thermal stimulation continued for 20 days at RTX >/=1 MUg. But the threshold to mechanical stimulation increased only in the acute period and returned to the baseline after 3-5 days, regardless of the administered dose. LIMITATIONS: A histological examination by electron-microscopic staining was not performed. The observation period was not very long (20 days). CONCLUSION: RTX has potential to be used in an epidural route for neuropathic pain in a rat model with a relatively small amount, which produces transitory improvement of mechanical hypersensitivity and prolonged thermal analgesic response. PMID- 22828683 TI - Removal of a vertebral metastatic tumor compressing the spinal nerve roots via a single-port, transforaminal, endoscopic approach under monitored anesthesia care. AB - Spinal cord or nerve root compression from an epidural metastasis occurs in 5-10% of patients with cancer and in up to 40% of patients with preexisting nonspinal bone metastases. Most metastatic spine diseases arise from the vertebral column, with the posterior half of the vertebral body being the most common initial focus, and/or the paravertebral region, tracking along the spinal nerves to enter the spinal column via the intervertebral foramina. An 82-year-old man diagnosed with sigmoid colon cancer and liver metastases experienced intractable pain described as being like an electric shock on the right T11 dermatome. Imaging studies revealed a huge metastatic mass destroying the right posterior T11 body and pedicle and compressing the right posterior spinal cord and nerve roots. Even after using neuropathic medication and a neural blockade, the extreme paroxysmal pain continued. Considering his elderly, debilitated state and life expectancy, removal of the vertebral metastatic tumor compressing the spinal nerve roots via a single-port, transforaminal, endoscopic approach and percutaneous vertebroplasty (PVP) under monitored anesthetic care (MAC), rather than 3-port endoscopic surgery and corpectomy with or without fusion under general anesthesia with lung deflation, was decided upon and scheduled prior to radiotherapy. A needle was placed into the intervertebral foramen under fluoroscopy in the same manner as a transforaminal epidural block at T11. A guidewire was inserted into the needle after the needle stylet had been removed. An obturator dilator was inserted over the guidewire, and a working sleeve was inserted over the dilator. After the dilator was removed, a spinal endoscope with a 2.7 mm working channel was placed over the guidewire. Careful removal of the tumor emboli during verbal interaction with the patient was performed under MAC using dexmedetomidine, fentanyl, and ketorolac. PVP at T11 was performed through the right osteolytic pedicle. The paroxysmal pain disappeared immediately after the operation without any complications. Removal of a vertebral metastatic tumor compressing the spinal nerve roots via a single-port, transforaminal, endoscopic approach under monitored anesthesia care without lung deflation may be an effective and safe modality for minimally invasive pain management of a single-level spinal tumor metastasis causing intractable radicular pain in patients with cancer who have generalized debilitation. PMID- 22828684 TI - Cervical spinal cord stimulation with 5-column paddle lead in Raynaud's disease. AB - OBJECTIVE: To report a case of Raynaud disease and its successful treatment with spinal cord stimulation utilizing the newly designed five-column Penta lead paddle. Specific electrode design, programming characteristics, and surgical technique are also discussed in this case. DESIGN: Case Report. SETTING: University pain management center. BACKGROUND: A 65-year-old man with Raynaud disease presented with neck and upper extremity pain. The patient also had herniation and spondylosis of the lumbar spine and intervertebral disc disease of the cervical spine. An examination revealed venous changes, chronic ulceration, and digit discoloration in upper and lower extremities. METHOD: Conservative management and pharmacological treatment were ineffective. Sympathetic block produced significant but limited improvement. Treatment with spinal cord stimulation was tried after a successful 7-day trial. RESULTS: Initial stimulation of the cervical spine with two octapolar leads at the C2 level produced greater than 75% pain improvement. However, the patient lost coverage shortly after discharge due to lead migration which could not be regained with reprogramming. A revision with Penta lead paddles produced sustainable and significant paresthesia coverage. LIMITATIONS: A case report. CONCLUSION: We report the successful application of spinal cord stimulation utilizing a five column paddle lead in an individual with severe refractory Raynaud disease. PMID- 22828685 TI - Attenuation of mouse somatic and emotional inflammatory pain by hydralazine through scavenging acrolein and inhibiting neuronal activation. AB - BACKGROUND: Acrolein signaling is important during spinal cord injury; whether it is involved in somatic and emotional pain is not clear. Hydralazine is a potent antihypertensive drug and can scavenge acrolein efficiently. OBJECTIVE: We hypothesized that hydralazine decreases spinal level acrolein and renders analgesic effects with some side effects, which was tested in the current study. STUDY DESIGN: Subcutaneous injection of formalin was used to induce somatic and emotional pain responses. The spinal neuronal activation (FOS expression) and acrolein expression were evaluated at 2 hours after subcutaneous formalin injection. The possible side effects of hydralazine on the murine central nervous system or cardiovascular system were evaluated at one hour after hydralazine injection with open field, elevated plus maze and rotarod tests, or telemetrical measurement of mean artery blood pressure and heart rate. RESULTS: The subcutanous injection of formalin into the left hind paw induced significant somatic and emotional pain responses, evaluated by the biphasic spontaneous flinch/licking of the injected hind paw and interphase ultrasonic vocalizations during the one hour window after formalin injection. The spinal acrolein level was significantly increased and neurons were activated at 2 hours after formalin injection. Intraperitoneal injection of hydralazine (at 0.1, 1 or 10 mg/kg of body weight) at one hour before formalin challenging dose-dependently attenuated the formalin induced pain responses with an analgesic 50% effect dose ranging from 0.2 to 1 mg/kg of body weight. Furthermore, the neuronal activation and elevated acrolein expression were dose-dependently inhibited by hydralazine pretreatment. The side effects of intraperitoneal hydralazine on locomotion, anxiety, and motor coordination at one hour after hydralazine administration had negative results. The main side effects of hydralazine were an insignificant decrease of blood pressure and a significant increase of heart rates at high dose (10 mg/kg of body weight). LIMITATIONS: This study is limited because the analgesic effect of hydralazine was tested on only one type of acute inflammatory pain model; however, its effect on chronic inflammatory or neuropathic pain needs to be further investigated. CONCLUSIONS: Based on the above findings, hydralazine may find its new application of analgesia within a safe dose window (around one mg/kg of body weight) without causing severe side effects. PMID- 22828686 TI - Prevalence and characteristics of headache in Khoramabad, Iran. AB - BACKGROUND: Headache is a prevalent and disabling condition affecting people in all age groups worldwide, leading to low job performance and quality of life with a significant economic burden on societies. OBJECTIVE: We evaluated headache prevalence and characteristics and some probable associated factors in patients referring to neurology specialist clinics. STUDY DESIGN: Cross sectional study SETTING: Clinics of Khoramabad and also those referring to the emergency department of Khoramabad University Hospital. METHODS: One thousand patients with a chief concern of headache were assigned to the study. All patients filled out a structured questionnaire to gather demographic information and data on headache characteristics and associated factors, including past medical and psychiatric history, history of oral contraceptive pill (OCP) use, nonsteroidal anti inflammatory drug (NSAID) overuse, and menstruation. RESULTS: The total prevalence of primary headaches was 78.2%, with migraine (with and without aura) being the most prevalent type with a prevalence of 41.6% followed by tension type headache found in 31.6% of the study population. Primary headaches were significantly more common in women and younger age groups. Factors found associated with a significantly higher prevalence of primary headaches were lower economic level, higher educational level, occupation, OCP use and NSAIDs overuse. Secondary headaches, with a total prevalence of 20.1%, significantly increased in older age groups and higher economic levels and were significantly less prevalent in higher educational levels. LIMITATIONS: The study population is not quite representative of the general population of Iran. CONCLUSION: Results highlight the impact of socioeconomic factors on headache epidemiology in a developing country and demonstrate that OCPs and NSAIDs overuse might have an effect on the distribution of primary headaches. Further multicenter studies are needed to evaluate headache epidemiology in the whole country. PMID- 22828687 TI - Methylene blue in the treatment of discogenic low back pain. AB - BACKGROUND: The personal and societal impact of chronic low back pain is considerable. The intervertebral disc is considered the etiologic source in up to 40% of patients, with considerable previous efforts directed at developing reliable and efficacious treatments. Recent publications, including a double blind, randomized, placebo-controlled trial, using a one-time treatment of methylene blue, showed statistically significant, clinically relevant improvements in pain and function in the treatment groups. The postulated mechanism of action of methylene blue is denervation of small nociceptive fibers that grow into the annulus fibrosis, which are implicated in discogenic pain. STUDY DESIGN: Retrospective case series. SETTING: Academic pain management center. OBJECTIVES: To examine the outcomes for a cohort of patients treated with methylene blue for discogenic pain, discuss potential differences in selection and administration protocols and briefly review other proposed treatments for discogenic pain (e.g. intradiscal electrothermy therapy, intradiscal steroids, intradiscal biaccuplasty, rami communicans radiofrequency thermocoagulation, and chymopapain). METHODS: This case series examines the pain and functional outcomes in 8 patients treated with a one-time administration of methylene blue for discogenic back pain. Follow-up information was available between 2 months and over one year, depending on the patient. RESULTS: Application of this treatment for these 8 patients for discogenic pain diagnosed by provocation discography showed only one clinical success at our center. Four patients had a time-limited clinical response in pain and/or function between 2 weeks and 5 months. Patient specific data are outlined in detail herein. CONCLUSIONS: Low back pain ascribed to a discogenic source continues to be an elusive clinical entity to treat. We have reserved further treatment of methylene blue for discogenic pain until other controlled trials have been published. LIMITATIONS: A case series. PMID- 22828689 TI - Chirality counts? PMID- 22828688 TI - Efficacy of intrathecally administered dexmedetomidine versus dexmedetomidine with fentanyl in patients undergoing major abdominal cancer surgery. AB - BACKGROUND: Most of the clinical experience gained in the use of intrathecal alpha-2- adrenoceptor agonists has been described with clonidine. Human studies using a combination of intrathecal dexmedetomidine and local anesthetics are lacking. OBJECTIVES: A safety investigation and comparison of the analgesic efficacy of intrathecally administered dexmedetomidine or dexmedetomidine combined with fentanyl in patients undergoing major abdominal cancer surgery. STUDY DESIGN: A randomized, double-blind trial. SETTING: Academic medical center. METHODS: Ninety patients were randomly assigned to receive intrathecally either 10 mg bupivacaine 0.5% (control group, n = 30), or 10 mg bupivacaine 0.5% plus 5 MUg dexmedetomidine (dexmedetomidine group, n = 30), or 10 mg bupivacaine 0.5% plus 5 MUg dexmedetomidine and 25 MUg fentanyl (dexmedetomidine= group, n = 30). Assessment parameters included hemodynamics, sedation score, pain severity, time of first analgesics request, total analgesic consumption, and side effects in the first 24 hours. RESULTS: The mean intraoperative heart rate was significantly reduced in the dexmedetomidine group (P < 0.05) and the dexmedetomidine= group (P < 0.05) compared with the control group. Also, there was a significant reduction in mean intraoperative systolic and diastolic blood pressure in the dexmedetomidine group (P < 0.05) and the dexmedetomidine= group (P < 0.05) compared with the control group, with no significant differences in postoperative hemodynamics or sedation scores among all the study groups. The mean visual analog scale scores showed a significant reduction immediately and at 12 hours postoperatively in both the dexmedetomidine and dexmedetomidine= groups compared to the control group. The mean time of the first analgesic request was significantly prolonged in the dexmedetomidine group (3.30 +/- 0.87 hours, P < 0.01) and the dexmedetomidine= group (5.41 +/- 1.23 hours, P < 0.01) compared with the control group (0.23 +/- 0.11 hours). Moreover, postoperative tramadol consumption was significantly reduced in the dexmedetomidine (142.85 +/- 13.04 mg, P < 0.01) and the dexmedetomidine= (131.25 +/- 11.96 mg, P < 0.01) groups, compared with the control group (310.0 +/- 12.08 mg). No significant serious adverse effects were recorded during the study. LIMITATIONS: This study is limited by its sample size. CONCLUSION: Dexmedetomidine 5 MUg given intrathecally improves the quality and the duration of postoperative analgesia and also provides an analgesic sparing effect in patients undergoing major abdominal cancer surgery. Furthermore, the addition of intrathecal fentanyl 25 MUg has no valuable clinical effect. PMID- 22828690 TI - Aspirin-inspired analgesia: old drug, new mechanism, Sans Cox? PMID- 22828691 TI - The effectiveness of lumbar interlaminar epidural injections in managing chronic low back and lower extremity pain. AB - BACKGROUND: Intervertebral disc herniation, spinal stenosis, intervertebral disc degeneration without disc herniation, and post lumbar surgery syndrome are the most common diagnoses of chronic persistent low back and lower extremity symptoms, resulting in significant economic, societal, and health care impact. Epidural injections are one of the most commonly performed interventions in the United States in managing chronic low back pain. However the evidence is highly variable among different techniques utilized - namely interlaminar, caudal, and transforaminal - and for various conditions, namely - intervertebral disc herniation, spinal stenosis, and discogenic pain without disc herniation or radiculitis. Multiple systematic reviews conducted in the evaluation of the effectiveness of interlaminar epidural injections have been marred with controversy. Consequently, the debate continues with regards to the effectiveness, indications, and medical necessity of interlaminar epidural injections. STUDY DESIGN: A systematic review of lumbar interlaminar epidural injections with or without steroids. OBJECTIVE: To evaluate the effect of lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back and lower extremity pain emanating as a result of disc herniation or radiculitis, spinal stenosis, and chronic discogenic pain. METHODS: The available literature on lumbar interlaminar epidural injections with or without steroids in managing various types of chronic low back pain with or without lower extremity pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or limited based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. RESULTS: Overall, 82 lumbar interlaminar trials were identified. All non randomized studies without fluoroscopy and randomized trials not meeting the inclusion criteria were excluded. Overall, 15 randomized trials and 11 non randomized studies were included in the analysis. Analysis was derived mainly from fluoroscopically-guided randomized trials and non-randomized studies. The evidence is good for radiculitis secondary to disc herniation with local anesthetics and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids, with fluoroscopically-guided epidural injections. LIMITATIONS: The limitations of this study include that we were unable to perform meta-analysis for disc herniation, and the paucity of evidence for discogenic pain and spinal stenosis. Further, methodological criteria have been highly variable along with sample sizes. The studies were heterogenous. CONCLUSION: The evidence based on this systematic review is good for lumbar epidural injections under fluoroscopy for radiculitis secondary to disc herniation with local anesthetic and steroids, fair with local anesthetic only; whereas it is fair for radiculitis secondary to spinal stenosis with local anesthetic and steroids, and fair for axial pain without disc herniation with local anesthetic with or without steroids. PMID- 22828692 TI - Effectiveness of cervical epidural injections in the management of chronic neck and upper extremity pain. AB - BACKGROUND: Chronic persistent neck pain with or without upper extremity pain is common in the general adult population with prevalence of 48% for women and 38% for men, with persistent complaints in 22% of women and 16% of men. Multiple modalities of treatments are exploding in managing chronic neck pain along with increasing prevalence. However, there is a paucity of evidence for all modalities of treatments in managing chronic neck pain. Cervical epidural injections for managing chronic neck pain are one of the commonly performed interventions in the United States. However, the literature supporting cervical epidural steroids in managing chronic pain problems has been scant. STUDY DESIGN: A systematic review of cervical interlaminar epidural injections for cervical disc herniation, cervical axial discogenic pain, cervical central stenosis, and cervical postsurgery syndrome. OBJECTIVE: To evaluate the effect of cervical interlaminar epidural injections in managing various types of chronic neck and upper extremity pain emanating as a result of cervical spine pathology. METHODS: The available literature on cervical interlaminar epidural injections in managing chronic neck and upper extremity pain were reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, and limited based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to December 2011, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. RESULTS: For this systematic review, 34 studies were identified. Of these, 24 studies were excluded and a total of 9 randomized trials, with 2 duplicate studies, met inclusion criteria for methodological quality assessment. For cervical disc herniation, the evidence is good for cervical epidural with local anesthetic and steroids; whereas, it was fair with local anesthetic only. For axial or discogenic pain, the evidence is fair for local anesthetic, with or without steroids. For spinal stenosis, the evidence is fair for local anesthetic, with or without steroids. For postsurgery syndrome, the evidence is fair for local anesthetic, with or without steroids. LIMITATIONS: The limitations of this systematic review continue to be the paucity of literature. CONCLUSION: The evidence is good for radiculitis secondary to disc herniation with local anesthetics and steroids, fair with local anesthetic only; whereas, it is fair for local anesthetics with or without steroids, for axial or discogenic pain, pain of central spinal stenosis, and pain of post surgery syndrome. PMID- 22828693 TI - Percutaneous adhesiolysis in the management of chronic low back pain in post lumbar surgery syndrome and spinal stenosis: a systematic review. AB - BACKGROUND: Low back pain after either post lumbar surgery syndrome or spinal stenosis in the absence of surgery is a vexing problem. Post lumbar surgery syndrome can occur in any age group, while low back and radicular pain from spinal stenosis is a disease of aging. As the population ages, the incidence of symptomatic spinal stenosis will increase. There are currently limited treatment options for either group. Further surgery is not uniformly effective in relieving pain after previous surgery. While therapies are being developed to treat pain due to spinal stenosis, no therapy other than adhesiolysis will treat pain due to scarring. Adhesiolysis was developed as a means of removing epidural scarring leading directly or indirectly to compression, inflammation, swelling, or a decreased nutritional supply of nerve roots. Adhesiolysis utilizes a number of modalities in the effort to break up epidural scarring, including the use of a wire-bound catheter for mechanical adhesiolysis, placement of the catheter in the ventro-lateral aspect of the epidural space at the site of the exiting nerve root, and the use of high volumes of injectate, including local anesthetics and saline, either hypertonic or isotonic, along with steroids. STUDY DESIGN: A systematic review of percutaneous adhesiolysis in the treatment of refractory low back and leg pain due to post lumbar surgery syndrome or spinal stenosis. OBJECTIVE: To evaluate the effectiveness of percutaneous adhesiolysis in the treatment of refractory low back and leg pain due to post lumbar surgery syndrome or spinal stenosis. The severity of risks and adverse advents associated with percutaneous adhesiolysis were also evaluated. METHODS: The available literature on percutaneous adhesiolysis for the treatment of refractory low back and leg pain due to post lumbar surgery syndrome or spinal stenosis was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, and limited (or poor) based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to June 2012, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was pain relief of at least 6 months. Secondary outcome measures were improvement in functional status, change in psychological status, return to work, and reduction in opioid use or interventions. RESULTS: For this systematic review, 15 studies were identified and selected for review. Of these, 5 randomized controlled trials and 2 observational studies met the inclusion criteria. Applying the USPSTF criteria, these studies indicate that there is fair evidence that percutaneous adhesiolysis is effective in relieving low back and/or leg pain caused by post lumbar surgery syndrome and that there is fair evidence that percutaneous adhesiolysis is effective in relieving low back and/or leg pain caused by spinal stenosis.The incidence of complications from percutaneous adhesiolysis is low and the complications are generally minimal and self-limited. The procedure should be considered to be low risk for serious adverse events when performed by well trained physicians. LIMITATIONS: The limitations of this systematic review include the paucity of literature. CONCLUSION: In summary, there is fair evidence that percutaneous adhesiolysis is effective in relieving low back and/or leg pain due to post lumbar surgery syndrome or spinal stenosis. PMID- 22828695 TI - Diagnostic accuracy of thoracic facet joint nerve blocks: an update of the assessment of evidence. AB - BACKGROUND: Chronic mid back and upper back pain caused by thoracic facet joints has been reported in 34% to 48% of the patients based on their responses to controlled diagnostic blocks. Systematic reviews have established moderate evidence for controlled comparative local anesthetic blocks of thoracic facet joints in the diagnosis of mid back and upper back pain. OBJECTIVE: To determine the diagnostic accuracy of thoracic facet joint nerve blocks in the assessment of chronic upper back and mid back pain. STUDY DESIGN: Systematic review of the diagnostic accuracy of thoracic facet joint nerve blocks. METHODS: A methodological quality assessment of included studies was performed using Quality Appraisal of Reliability Studies (QAREL). Only diagnostic accuracy studies meeting at least 50% of the designated inclusion criteria were utilized for analysis. Studies scoring less than 50% are presented descriptively and critically analyzed. The level of evidence was classified as good, fair, and limited (or poor) based on the quality of evidence developed by the United States Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to March 2012, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: Controlled placebo or local anesthetic blocks were utilized using at least 50% pain relief as the reference standard. RESULTS: Three studies were identified utilizing controlled comparative local anesthetic blocks, with >= 50% pain relief as the criterion standard. The evidence is good for the diagnosis of thoracic pain of facet joint origin with controlled diagnostic blocks. LIMITATIONS: The limitations of this systematic review include a paucity of literature for the diagnosis of thoracic facet joint pain, with all included manuscripts originating from one group of authors. CONCLUSIONS: Based on this systematic review, the evidence for the diagnostic accuracy of thoracic facet joint injections is good. PMID- 22828694 TI - An update of evaluation of therapeutic thoracic facet joint interventions. AB - BACKGROUND: Chronic mid back and upper back pain caused by thoracic facet joints has been reported in 34% to 48% of patients based on responses to controlled diagnostic blocks. Systematic reviews have established moderate evidence for controlled comparative local anesthetic blocks of thoracic facet joints in the diagnosis of mid back and upper back pain, moderate evidence for therapeutic thoracic medial branch blocks, and limited evidence for radiofrequency neurotomy of thoracic medial branches. STUDY DESIGN: Systematic review of therapeutic thoracic facet joint interventions. OBJECTIVE: To determine the clinical utility of therapeutic thoracic facet joint interventions in the therapeutic management of chronic upper back and mid back pain. METHODS: The available literature for the utility of facet joint interventions in the therapeutic management of thoracic facet joint pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, and limited (or poor) based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to March 2012, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was pain relief (short-term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. RESULTS: For this systematic review, 13 studies were identified. Of these, 7 studies were excluded, and a total of 4 studies (after removal of duplicate publication) met inclusion criteria for methodological quality assessment with one randomized trial and 3 non-randomized studies. The evidence is fair for therapeutic thoracic facet joint nerve blocks, limited for thoracic radiofrequency neurotomy, and not available for thoracic intraarticular injections. LIMITATIONS: The limitation of this systematic review includes a paucity of literature. The only positive studies were of medial branch blocks performed by the same group of authors. CONCLUSION: The evidence for therapeutic facet joint interventions is fair for medial branch blocks, whereas it is not available for intraarticular injections, and limited for radiofrequency neurotomy due to lack of literature. PMID- 22828696 TI - A systematic evaluation of thoracic interlaminar epidural injections. AB - BACKGROUND: There is a paucity of literature on the use of epidural injections for the treatment of chronic mid and upper back pain due to disc herniation and radiculitis, axial or discogenic pain, spinal stenosis, post surgery syndrome, and post thoracotomy pain syndrome. STUDY DESIGN: A systematic review of therapeutic thoracic epidural injection therapy for chronic mid and upper back pain. OBJECTIVE: The objective of this systematic review is to determine the effects of thoracic interlaminar epidural injections with or without steroids, with or without fluoroscopy, and for various conditions including disc herniation and radiculitis, axial or discogenic pain, spinal stenosis, post thoracic surgery syndrome, and post thoracotomy pain syndrome. METHODS: The available literature on thoracic interlaminar epidural injections with or without steroids in managing various types of chronic mid and upper back pain was reviewed. The quality assessment and clinical relevance criteria utilized were the Cochrane Musculoskeletal Review Group criteria as utilized for interventional techniques for randomized trials and the criteria developed by the Newcastle-Ottawa Scale criteria for observational studies. The level of evidence was classified as good, fair, or limited (or poor) based on the quality of evidence developed by the U.S. Preventive Services Task Force (USPSTF). Data sources included relevant literature identified through searches of PubMed and EMBASE from 1966 to March 2012, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measure was pain relief (short term relief = up to 6 months and long-term > 6 months). Secondary outcome measures were improvement in functional status, psychological status, return to work, and reduction in opioid intake. RESULTS: For this review, 17 studies were identified, including studies examining adverse reactions. Only 2 studies were included: one randomized trial and one non-randomized or observational study. The results of this systematic review evaluating the effectiveness of thoracic epidural injections with or without steroids in managing chronic thoracic pain shows fair evidence with one randomized trial in patients with various causes; whereas the evidence is limited based on one non-randomized study evaluating chronic pain in post thoracotomy syndrome. LIMITATIONS: The limitations of this study include paucity of evidence. CONCLUSION: The evidence based on this systematic review for thoracic epidural injection in treating chronic thoracic pain is considered fair and limited for post thoracotomy pain. PMID- 22828697 TI - The long-term incidence of subsequent vertebral body fracture after vertebral augmentation therapy: a systemic review and meta-analysis. AB - BACKGROUND: Vertebroplasty and kyphoplasty have recently been used to treat painful osteoporotic compression fractures. Early clinical results have been encouraging, but very little is known about the consequences of augmentation with cement for adjacent, unaugmented levels. OBJECTIVE: This study performed a systemic review of the studies concerning whether the incidence of subsequent vertebral body fracture after vertebral augmentation therapy would be increased long-term. STUDY DESIGN: A meta-analysis of randomized controlled trials was performed comparing the long-term incidence of subsequent vertebral body fracture between vertebral augmentation surgeries like vertebroplasty and kyphoplasty and conventional nonsurgical management. SETTING: The MEDLINE, EMBASE, ISI Web of Science and Cochrane Library databases and abstracts published in annual proceedings were systematically searched for evidence. METHODS: Relevant reports were reviewed by 2 reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria. RESULTS: Pooled results from 2 randomized controlled trials showed no significant increase of the secondary fracture rate after vertebral augmentation therapy compared with that of conventional treatment (P = 0.07). Few large-sample randomized controlled trials were specifically performed to investigate new fractures as an outcome of vertebroplasty or kyphoplasty. LIMITATIONS: There were few data sources from which to extract abstracted data or published studies. There were only 2 randomized controlled trials that met criteria. CONCLUSIONS: Although vertebral augmentation therapies, such as vertebroplasty and kyphoplasty, have been widely used in clinics to treat patients' back pain caused by vertebral compression fractures due to osteoporosis, no evidence shows that they can increase the fracture of adjacent vertebral bodies. PMID- 22828698 TI - Erectile dysfunction as rare side effect in the simultaneous intrathecal application of morphine and clonidine. AB - We report on the case of a 52-year-old man who presented with a history of chronic neuropathic pain treated with intrathecal application of morphine for many years. In spite of significant dose escalation, considerable pain relief had not been achieved. Ziconotide had been tried but not only did it not provide pain relief, but it also caused severe side effects in this patient. A combination of morphine and clonidine was delivered by a programmable pump, slowly increasing the clonidine rate over several weeks. For ease of transition and minimization of hospitalization, which was a special concern to this patient, combining clonidine and morphine was chosen over monotherapy with hydromorphone, with both possibilities being described as equal alternatives in the literature. Considerable pain relief was achieved during week 2 at a clonidine dose of 0.040 mg/d, thereby decreasing the visual analog score (VAS) from 10 to 4. Yet, after developing erectile dysfunction and relative hypotension soon after beginning clonidine treatment, the patient decided not to continue with the combined application of morphine and clonidine. Treatment was therefore switched back to the former monotherapy with morphine. Thereafter, erectile dysfunction disappeared and blood pressure returned to habitual high levels. Although common in systemic application, erectile dysfunction caused by the intrathecal application of clonidine has not been described yet in the literature. In this patient, this rare side effect decisively impaired life quality, subjectively outweighing the considerable pain relief which could be achieved after formerly inefficacious treatment. Further and prospective investigation might be needed to estimate the connection of erectile dysfunction to intrathecal application of clonidine. PMID- 22828699 TI - Percutaneous vertebroplasty-induced adjacent vertebral compression fracture. AB - BACKGROUND: The risks associated with percutaneous vertebroplasty (PV) are low. Patients show marked improvement and are able to rapidly resume normal activities after PV. The sudden development of postoperative vertebral compression fracture (VCF) is a common complication, and additional PV is frequently performed in these cases. However, there have been no studies reporting acute compression fractures of an adjacent vertebra immediately after PV. OBJECTIVE: This case report presents a rare case in which the patient had to undergo a second PV because of PV-induced adjacent VCF. Further, we review previous studies and discuss the possible pathogenesis of this rare complication. STUDY DESIGN: Case report. SETTING: Pain management clinic. METHODS: A 62-year-old woman presented with a severe pain in the lower back, which started after she slipped. A radiograph showed severe vertebral collapse with a vertebral vacuum cleft in the T12 vertebral body. T1-weighted magnetic resonance imaging showed low signal intensity in T12, suggesting acute VCF, but the signals from the other vertebrae were normal. RESULTS: The patient underwent PV at T12. When the cannula was inserted into the fracture line of the vertebral body, reduction of the collapsed T12 was developed. Although the postoperative course was uneventful, the patient's pain did not resolve. Postoperative radiographic image obtained 4 hours after the PV showed reduction of T12 and adjacent acute VCF in T11. We performed a second PV at T11. However, 2 weeks later, adjacent acute VCF in L1 was developed and PV was performed. LIMITATIONS: This report describes a single case. CONCLUSION: To the best of our knowledge, this is the first case report of adjacent VCF that developed almost immediately after PV. Although the exact mechanism underlying this rare complication remains unclear, we assume that the VCF was induced by PV, although this was not proven. However, we suggest that the insertion of the cannula into the fracture line induced the iatrogenic dynamic mobility of the fractured vertebra. Reduction was caused by the cannula and positional gravity. The upward reduction may have had an effect on the upper and adjacent vertebrae. PMID- 22828700 TI - Vertebral augmentation of osteoporotic and malignant compression fractures: our viewpoint and experience in preventing cement leakage. PMID- 22828702 TI - Suspected respiratory depression associated with use of transdermal fentanyl patch. PMID- 22828703 TI - Heart failure assocated with pregabalin. PMID- 22828704 TI - Unclear mechanism of cardiopulmonary arrest following cervical epidural steroid injection. PMID- 22828706 TI - Proteomic study explores AGR2 as pro-metastatic protein in HCC. AB - Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide. The prognosis of patients with HCC still remains very dismal, mainly due to metastasis. We found that high-expression levels of AGR2 existed in metastatic HCC cell lines and patient samples. Overexpression of AGR2 was found to be correlated to the metastatic status of HCC cells, and inhibition of AGR2 by siRNA resulted in a dramatic decline in invasion abilities in metastatic cells in vitro. Overexpression of AGR2 increased the invasion of HCC cells in vitro and also in vivo with a nude mouse model. The tandem affinity purification (TAP) identified 18 AGR2-binding proteins and IPA analysis revealed that these proteins focus on MAPK and Caspase pathway. Therefore, we speculate that the overexpression of AGR2 can promote HCC metastasis, possibly by affecting MAPK and Caspase pathway through AGR2-interacting proteins. PMID- 22828707 TI - Operator versus core laboratory assessment of angiographic reperfusion markers in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - BACKGROUND: Thrombolysis In Myocardial Infarction (TIMI) flow and Myocardial Blush Grade (MBG) are important prognostic indicators before and after primary percutaneous coronary intervention (PCI) in ST-segment-elevation myocardial infarction; however, the concordance and relative prognostic utility of operator (Op) versus angiography core laboratory (ACL) assessed TIMI flow and MBG are unknown. METHODS AND RESULTS: Baseline and final Op and ACL TIMI flow and MBG assessment were compared from the Harmonizing Outcomes with RevascularIZatiON and Stents in AMI trial in 3345 patients undergoing primary PCI using Cohen's kappa coefficient. kappa Was highest for pre-PCI TIMI flow (0.51, representing moderate agreement) and lowest for post-PCI MBG (0.20, representing fair agreement). Discordance between Op and ACL for final TIMI flow (0 to 2 versus 3) occurred in 12.9% of patients and for final MBG (0 to 1 versus 2 to 3) in 22.4%. Among 415 patients with final TIMI flow 0 to 2 by ACL, Op scoring was TIMI flow 3 in 267 (64.3%). Similarly, among 706 patients with final MBG 0 to 1 by ACL, 563 (79.7%) were classified as MBG 2 to 3 by Op. Post-PCI TIMI 3 flow and MBG 2 to 3 strongly correlated with 3-year survival, as assessed by both Op and ACL (P<0.0001). Mortality was intermediate in patients in whom ACL and Op were discordant, without marked prognostic differences between the discordant groups. CONCLUSIONS: Op and ACL assessment of angiographic markers of reperfusion in ST-segment elevation myocardial infarction demonstrates fair to moderate agreement. Op tended to favorably grade unfavorable ACL results. Nonetheless, both Op and ACL assessment of reperfusion strongly inform prediction of 3-year mortality. PMID- 22828708 TI - Triflimide-catalyzed allyl-allyl cross-coupling: a metal-free allylic alkylation. AB - A highly efficient metal-free intermolecular C(sp3)-C(sp3) allyl-allyl cross coupling protocol between allyl acetates and allyltrimethylsilanes, which proceeded smoothly in the presence of catalytic triflimide to form 1,5-dienes with good to excellent regioselectivity, has been developed. PMID- 22828710 TI - Whole-body vibration: is there a causal relationship to specific imaging findings of the spine? AB - STUDY DESIGN: Systematic review. OBJECTIVE: To perform a systematic review of the available literature for those studies that evaluated the role of whole-body vibration (WBV) on the spine, using imaging modalities as well as an estimation of WBV exposure. SUMMARY OF BACKGROUND DATA: Numerous comparative studies have reported a possible association between the occurrence of spinal symptoms and exposure to WBV. These exposures have commonly been examined in the work environment largely through self-reported questionnaires only. From a scientific perspective, the majority of studies emphasize symptoms and lack objective medical evidence, such as spinal imaging, to help establish a specific spinal disorder. Because both neck and low back pain comprise symptoms that can arise from a host of factors including age, a casual link between spinal disorders and WBV cannot be affirmed. METHODS: MEDLINE and EMBASE were searched for studies related to WBV and spinal symptoms, diagnosis, and/or disorders. Our searches were limited to studies published prior to August 2011. The resulting 700 citations (after excluding 354 duplicates) were then screened by 3 independent reviewers on the basis of the following predetermined inclusion and exclusion criteria: inclusion-clinical studies with imaging evaluation (radiographs, computed tomographic scans, and/or magnetic resonance images) and documented WBV exposure (occupation, amount of WBV, and/or duration); exclusion-reliance solely on self-reporting of symptoms (neck pain, low back pain, and/or sciatica), those articles based on a clinical diagnosis without use of imaging, and in vitro/animal/biomechanical studies. RESULTS: Only 7 studies met the inclusion criteria for this systematic review. Included were 5 retrospective cohort and 2 cross-sectional studies. Although mixed results and conclusions were found, the majority of studies did not identify an association between WBV exposure and an abnormal spinal imaging finding indicating damage of the spine. We should also stress that each included study has limitations secondary to quantifying WBV exposure accurately, both as a single encounter and as a total exposure over years. CONCLUSION: Based on our results from this systematic review, no causality can be shown between WBV and abnormal spinal imaging findings. With the conflicting data available in the literature, WBV has not been established as a cause for objective spinal pathological changes on a scientific basis. PMID- 22828709 TI - A method to determine the displacement velocity field in the apical region of the Arabidopsis root. AB - In angiosperms, growth of the root apex is determined by the quiescent centre. All tissues of the root proper and the root cap are derived from initial cells that surround this zone. The diversity of cell lineages originated from these initials suggests an interesting variation of the displacement velocity within the root apex. However, little is known about this variation, especially in the most apical region including the root cap. This paper shows a method of determination of velocity field for this region taking the Arabidopsis root apex as example. Assuming the symplastic growth without a rotation around the root axis, the method combines mathematical modelling and two types of empirical data: the published velocity profile along the root axis above the quiescent centre, and dimensions of cell packet originated from the initials of epidermis and lateral root cap. The velocities, calculated for points of the axial section, vary in length and direction. Their length increases with distance from the quiescent centre, in the root cap at least twice slower than in the root proper, if points at similar distance from the quiescent centre are compared. The vector orientation depends on the position of a calculation point, the widest range of angular changes, reaching almost 90 degrees , in the lateral root cap. It is demonstrated how the velocity field is related to both distribution of growth rates and growth-resulted deformation of the cell wall system. Also changes in the field due to cell pattern asymmetry and differences in slope of the velocity profile are modelled. PMID- 22828711 TI - Visuo-oculomotor deficiency at early-stage idiopathic scoliosis in adolescent girls. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To determine whether adolescent idiopathic scoliosis (AIS) at onset is associated with oculomotor dysfunction and whether these oculomotor anomalies are correlated to the amplitude of the spine deformation. SUMMARY OF BACKGROUND DATA: AIS is related to abnormalities of postural control. To date, few studies have focused on visuo-oculomotor and vestibulo-ocular functions at early-stage AIS. METHODS: Fifty-three adolescent girls were diagnosed with AIS (mean age: 11.6 +/- 2.1 yr) on clinical and radiological criteria (mean Cobb angle: 14.8 degrees +/- 5.0 degrees ). Visuo oculomotor and vestibulo-ocular functions were studied with video-oculography, including saccades, smooth pursuit, caloric test, and pendular rotation, with visual vestibular ocular reflex and vestibulo-ocular reflex sequences. Two patient groups were defined according to the mean Cobb angle: group 1 included 29 patients with a Cobb angle from 5 degrees to 14 degrees and group 2 included 24 patients with a Cobb angle from 15 degrees to 25 degrees . RESULTS: The group 2 showed different saccade characteristics than group 1: higher latencies for saccade sequences characterized by temporal uncertainty and predictive direction; lower velocity regardless of the type of the saccades. No difference was observed for saccadic accuracy and smooth-pursuit gain. For the visual vestibular ocular reflex, group 2 showed lower total maximal slow-phase velocity than group 1, whereas the vestibulo-ocular reflex (tested in dark) did not differ between groups. No difference was observed concerning the caloric vestibular test. CONCLUSION: Patients with a Cobb angle of 15 degrees or more presented normal vestibulo-ocular responses but altered visuo-oculomotor functions, especially for the saccadic latency and velocity. This could be the result of a dysfunction of oculomotor pathways at cerebellar and/or brainstem level. These central disorders may be incriminated in the development of AIS. PMID- 22828712 TI - ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. PMID- 22828713 TI - Increased skin temperature in Alzheimer's disease is associated with sleepiness. AB - The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted. PMID- 22828714 TI - Multi-scale simulations of cardiac electrophysiology and mechanics using the University of Tokyo heart simulator. AB - The importance and need for an integrative mathematical modeling approach in the biological and medical fields is currently well recognized. Such an approach is crucial in understanding the complexity of hierarchical biological systems increasingly revealed by active researches in molecular and cellular biology. Particularly in cardiac functioning, modeling must cover such diverse phenomena as solid mechanics, fluid dynamics, electricity and biochemistry. Recent advancements in computational science and the development of high-performance computers have enabled the creation of multi-scale, multi-physics simulation heart models using the finite element method. Although whole heart or ventricular models of electrophysiology involving electro-mechanics with or without blood flow dynamics have been reported, to our knowledge no single model has yet succeeded in completely reproducing the behavior of the heart from the subcellular to whole organ levels. In this article, we present a brief methodology-focused review on some of the essential components for multi-scale, multi-physics heart modeling. A perspective of heart modeling in the era of high performance computing is also presented. PMID- 22828715 TI - Serum microRNA biomarkers for drug-induced liver injury. AB - New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation with existing biomarkers of liver injury and patient outcomes in acetaminophen toxicity, mechanisms of cellular microRNA release, and their potential advantages over current clinical biomarkers of DILI. PMID- 22828716 TI - Construction of an open-access QT database for detecting the proarrhythmia potential of marketed drugs: ECG-ViEW. AB - Information about the QT interval from surface electrocardiograms (ECGs) is essential for surveillance of the proarrhythmia potential of marketed drugs. However, ECG records obtained in daily practice cannot be easily used for this purpose without labor-intensive manual effort. This study was aimed at constructing an open-access QT database, the Electrocardiogram Vigilance with Electronic Data Warehouse (ECG-ViEW). This longitudinal observational database contains 710,369 measurements of QT and associated clinical data from 371,401 patients. The de-identified database is freely available at http://www.ecgview.org. PMID- 22828717 TI - Evolving molecular targets in the treatment of nonmalignant gastrointestinal diseases. AB - Novel treatments for gastrointestinal (GI) diseases are based on molecular targets. Novel pharmacologic and biological agents with greater selectivity and specificity are being developed for a variety of epithelial diseases, including eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), celiac disease, short bowel syndrome (SBS), and inflammatory bowel diseases (IBDs; Crohn's disease and ulcerative colitis). Motility and secretory agents are being developed for gastroparesis, irritable bowel syndrome (IBS), functional constipation, and diarrhea. Here we focus on data from clinical trials involving validated pharmacodynamic or patient response outcomes. PMID- 22828718 TI - Metabolic syndrome before and after initiation of antiretroviral therapy in treatment-naive HIV-infected individuals. AB - BACKGROUND: Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular disease and diabetes, many of which are associated with HIV and antiretroviral therapy (ART). We examined prevalence and incidence of MetS and risk factors for MetS in ART-naive HIV-infected individuals starting ART. METHODS: MetS, defined by the Adult Treatment Panel III criteria, was assessed at and after ART initiation in HIV-infected individuals who enrolled in selected AIDS Clinical Trials Group trials and were followed long-term after these trials as part of the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort. Cox proportional hazards models were used to examine risk factors of incident MetS. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) are reported. RESULTS: At ART initiation, the prevalence of MetS was 20%. After ART initiation, the incidence of MetS was 8.5 per 100 person-years. After adjusting for demographics and body mass index, the risk of MetS was decreased for CD4+ T-cell counts >50 cells per cubic millimeter (aHR = 0.62, 95% CI = 0.43 to 0.90 for CD4 >500), and the risk was increased for HIV-1 RNA >400 copies per milliliter (aHR = 1.55 (95% CI = 1.25 to 1.92) and use of a protease-inhibitor (PI)-based regimen [relative to no PI use, aHR = 1.25 (95% CI = 1.04 to 1.51) for any PI use]. CONCLUSIONS: In HIV-infected individuals on ART, virologic suppression and maintenance of high CD4+ T-cell counts may be potentially modifiable factors that can reduce the risk of MetS. The effect of MetS on the risk of cardiovascular disease and diabetes needs to be evaluated. PMID- 22828722 TI - Special quasirandom structures for gadolinia-doped ceria and related materials. AB - Gadolinia doped ceria in its doped or strained form is considered to be an electrolyte for solid oxide fuel cell applications. The simulation of the defect processes in these materials is complicated by the random distribution of the constituent atoms. We propose the use of the special quasirandom structure (SQS) approach as a computationally efficient way to describe the random nature of the local cation environment and the distribution of the oxygen vacancies. We have generated two 96-atom SQS cells describing 9% and 12% gadolinia doped ceria. These SQS cells are transferable and can be used to model related materials such as yttria stabilized zirconia. To demonstrate the applicability of the method we use density functional theory to investigate the influence of the local environment around a Y dopant in Y-codoped gadolinia doped ceria. It is energetically favourable if Y is not close to Gd or an oxygen vacancy. Moreover, Y-O bonds are found to be weaker than Gd-O bonds so that the conductivity of O ions is improved. PMID- 22828721 TI - Connection domain mutations during antiretroviral treatment failure in Mali: frequencies and impact on reverse transcriptase inhibitor activity. AB - Mutations in the connection domain (CD) of reverse transcriptase have been implicated in reverse transcriptase inhibitor (RTI) resistance, but this is controversial and little is known in non-B subtype HIV-1. We determined CD mutations prevalence in a population infected predominantly with CRF02_AG and investigated associations with phenotypic RTI resistance. Detected CD mutations were G335D (82.3%), A371V (69.8%), E399D (9.4%), N348I (5.2%), V365I (4.2), Y318F (2.1%), G333E (2.1%), and A360V (2.1%). Mutations were largely polymorphic and did not confer RTI resistance. The observed trend toward reduced likelihood of etravirine or nevirapine resistance in the presence of G335D should be investigated further. PMID- 22828723 TI - Sex difference in the effect of obesity on prognosis for patients undergoing percutaneous coronary intervention. AB - OBJECTIVES: To examine whether obesity has a similar effect on long-term prognosis between men and women undergoing a percutaneous coronary intervention (PCI). METHODS: We separately examined 3926 men and 2157 women undergoing PCI with drug-eluting stents between January 2004 and December 2006. All the patients were categorized according to BMI: normal weight (<25 kg/m(2)), overweight (25 29.9 kg/m(2)), and obese (>=30 kg/m(2)). The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiac death and nonfatal myocardial infarction. The median follow-up was 26 months. RESULTS: The MACE rate was significantly higher in obese than in normal-weight and overweight patients among men (6.8 vs. 3.5 vs. 4.2%; P=0.001) but not among women (5.1 vs. 4.4 vs. 4.1%; P=0.684). Further categorization of BMI showed a linear association between the risk of MACE and BMI in men, with a graded increase in obesity grade I (30-34.9 kg/m(2)) and grade II/III (>=35 kg/m(2)) groups compared with normal weight individuals [hazard ratio (HR) 1.94; 95% confidence interval (CI) 1.22 3.06; P=0.005 for obesity grade I and HR 2.62; 95% CI 1.50-4.56; P=0.001 for obesity grade II/III]. In women, the risk of MACE showed no difference in obesity grade I group, whereas there was a significant increase in the obesity grade II/III group compared with normal-weight patients (HR 2.15; 95% CI 1.10-4.18; P=0.025). CONCLUSION: In patients undergoing PCI, BMI is associated with a risk of MACE in both men and women. However, BMI exerts relatively less effect on women than on men. PMID- 22828724 TI - Serum chemerin levels are associated with the presence and extent of coronary artery disease. AB - OBJECTIVE: The aim of the study was to examine whether serum chemerin levels are associated with the presence and the extent of coronary artery disease (CAD). MATERIALS AND METHODS: A total of 132 patients with CAD and 56 patients without CAD who underwent coronary angiography for the evaluation of CAD were enrolled in this study. Serum levels of chemerin were measured using an enzyme-linked immunosorbent assay. RESULTS: Serum chemerin levels were significantly elevated in CAD patients compared with those without CAD. Multivariate logistic regression analysis showed that serum chemerin levels were significantly associated with the presence of CAD. In CAD patients, chemerin was positively correlated with BMI (r=0.274, P=0.001) and triglycerides (r=0.190, P=0.029), and yet correlated with low-density lipoprotein-cholesterol (r=0.228, P=0.008); the association of chemerin with triglycerides and low-density lipoprotein-cholesterol remained significant after adjusting for BMI (P<0.05 and P<0.01). At multiple stepwise regression analysis, serum chemerin levels were an independent predictor of the stenosis score (beta=0.193, P=0.034). CONCLUSION: Our data suggest that increased chemerin levels are associated with the presence of CAD and that serum chemerin levels may reflect the extent of coronary atherosclerosis. PMID- 22828725 TI - Privileged scaffolds in synthesis: 2,5-piperazinediones as templates for the preparation of structurally diverse heterocycles. AB - 2,5-Piperazinediones (2,5-diketopiperazines, DKPs) can be viewed as privileged building blocks for the synthesis of heterocyclic systems. This tutorial review aims at underscoring the large number and structural variety of nitrogen heterocycles that are available by suitable manipulation of DKP starting materials, including many bioactive compounds and natural products. PMID- 22828726 TI - Effects of a complete smoking ban on inpatients at an intermediate to long-term psychiatric facility. AB - The majority of research on reactions to smoking bans in psychiatric facilities focuses on staff feedback in acute inpatient settings. The purpose of this pilot study was to assess inpatient attitudes about a complete smoking ban in an intermediate to long-term psychiatric facility. One hundred inpatients were surveyed via questionnaire. Inpatients reported changes in smoking and improvements in health as a result of the ban, despite evidence of non-compliant smoking at the facility. There was evidence that inpatients perceived others' attitudes about the ban to be worse than reality. The findings from this pilot study suggest that consequences of smoking bans in psychiatric facilities are not as negative as some perceive. Smoking bans in intermediate to long-term settings may result in improvements in health among both smoking and non-smoking patients. PMID- 22828727 TI - Methoxyamine sensitizes the resistant glioblastoma T98G cell line to the alkylating agent temozolomide. AB - Chemoresistance represents a major obstacle to successful treatment for malignant glioma with temozolomide. N (7)-methyl-G and N (3)-methyl-A adducts comprise more than 80 % of DNA lesions induced by temozolomide and are processed by the base excision repair, suggesting that the cellular resistance could be caused, in part, by this efficient repair pathway, although few studies have focused on this subject. The aim of this study was to evaluate the cellular responses to temozolomide treatment associated with methoxyamine (blocker of base excision repair) in glioblastoma cell lines, in order to test the hypothesis that the blockage of base excision repair pathway might sensitize glioblastoma cells to temozolomide. For all the tested cell lines, only T98G showed significant differences between temozolomide and temozolomide plus methoxyamine treatment, observed by reduced survival rates, enhanced the levels of DNA damage, and induced an arrest at G2-phase. In addition, ~10 % of apoptotic cells (sub-G1 fraction) were observed at 48 h. Western blot analysis demonstrated that APE1 and FEN1 presented a slightly reduced expression levels under the combined treatment, probably due to AP sites blockade by methoxyamine, thus causing a minor requirement of base excision repair pathway downstream to the AP removal by APE1. On the other hand, PCNA expression in temozolomide plus methoxyamine-treated cells does not rule out the possibility that such alteration might be related to the blockage of cell cycle (G2-phase), as observed at 24 h of recovery time. The results obtained in the present study demonstrated the efficiency of methoxyamine to overcome glioblastoma resistance to temozolomide treatment. PMID- 22828728 TI - A cardiac tissue-specific binding agent of troponin I. AB - A fluorescently labeled, biphenylalanine-rich peptide was identified as a should be cardiac troponin I-specific binding agent with preferential staining affinity to myocardium tissues and extremely low staining to other stromal components. Fluorescence images demonstrate that this new peptide is an excellent contrast agent useful for examining troponin I structural distribution and expression density within heart tissue sections. It provides a clear contrast between myocardial cells and the surrounding collagen matrix. PMID- 22828729 TI - Nitrogen defects in wide band gap oxides: defect equilibria and electronic structure from first principles calculations. AB - The nitrogen related defect chemistry and electronic structure of wide band gap oxides are investigated by density functional theory defect calculations of N(O)(q), NH(O)(*), and (NH2)(O)(.) as well as V(O)(..) and OH(O)(.) in MgO, CaO, SrO, Al(2)O(3), In(2)O(3), Sc(2)O(3), Y(2)O(3), La(2)O(3), TiO(2), SnO(2), ZrO(2), BaZrO(3), and SrZrO(3). The N(O)(q) acceptor level is found to be deep and the binding energy of NH(O)(*) with respect to N(O)' and (OH(O)(.) is found to be significantly negative, i.e. binding, in all of the investigated oxides. The defect structure of the oxides was found to be remarkably similar under reducing and nitriding conditions (1 bar N(2), 1 bar H(2) and 1 * 10(-7) bar H(2)O): NH(O)(*) predominates at low temperatures and [N(O)'] = 2[V(O)(..) predominates at higher temperatures (>900 K for most of the oxides). Furthermore, we evaluate how the defect structure is affected by non-equilibrium conditions such as doping and quenching. In terms of electronic structure, N(O)' is found to introduce isolated N-2p states within the band gap, while the N-2p states of NH(O)(*) are shifted towards, or overlap with the VBM. Finally, we assess the effect of nitrogen incorporation on the proton conducting properties of oxides and comment on their corrosion resistance in nitriding atmospheres in light of the calculated defect structures. PMID- 22828730 TI - Intravenous acetate elicits a greater free fatty acid rebound in normal than hyperinsulinaemic humans. AB - BACKGROUND/OBJECTIVES: Colonic fermentation of dietary fiber may improve insulin sensitivity by the metabolic effects of short chain fatty acids (SCFA) in reducing free fatty acids (FFA). The main objectives of this study were to compare peripheral uptake of acetate (AC) in participants with normal (<40 pmol/l, NI) and high (>= 40 pmol/l, HI) plasma insulin, and the ability of AC to reduce FFA in both the groups. SUBJECTS/METHODS: Overnight fasted NI (n=9) and HI (n=9) participants were given an intravenous (IV) infusion of 140 mmol/l sodium acetate at three different rates over 90 min. The total amount of AC infused was 51.85 mmols. RESULTS: AC clearance in NI participants was not significantly different than that in HI participants (2.11 +/- 0.23 vs 2.09 +/- 0.24 ml/min). FFA fell in both the groups, but rebounded to a greater extent in NI than HI participants (time * group interaction, P=0.001). Significant correlations between insulin resistance (IR) indices (homeostasis model assessment of insulin resistance (HOMA-IR), Matsuda and insulinogenic index) vs FFA rebound during IV AC infusion were also observed. CONCLUSIONS: These findings suggest that AC uptake is similar in both the groups. Participants with lower plasma insulin and lower IR indices had a greater FFA rebound. These results support the hypothesis that increasing AC concentrations in the systemic circulation may reduce lipolysis and plasma FFA concentrations and thus improve insulin sensitivity. More in-depth studies are needed to look at the effects of SCFA on FFA metabolism in insulin-resistant participants. PMID- 22828731 TI - Diet macronutrient composition reported before treatment predicts BMI change in obese children: the role of lipids. AB - In this study, we tested the hypothesis that diet composition reported by children before the beginning of an obesity treatment program could be a predicting factor of the clinical outcome. A sample of 138 obese 6-16-year-old children and adolescents were recruited. Anthropometry and dietary habits were recorded. Each patient participated in a multidimensional treatment program in an outpatient obesity public service clinic. Therapy was based on a 6-month educational program on nutrition, lifestyle and physical activity. Children with a lipid intake above 34.7% of total energy had a 2.5 times higher chance of reducing at least 1.5 units of BMI with treatment than children with lower lipid intake. These results suggest that the assessment of habitual diet, in particular diet composition before starting treatment, may help to identify obese children who are more sensitive to intervention and those who need more specific nutritional assistance. PMID- 22828732 TI - Maternal diets with low healthy eating index or Mediterranean diet adherence scores are associated with high cord-blood insulin levels and insulin resistance markers at birth. AB - BACKGROUND/OBJECTIVES: Few studies have used healthy eating index (HEI) and mediterranean diet adherence (MDA) scores to evaluate the diet quality during pregnancy. To determine the relationship between first trimester diet quality and insulin sensitivity/resistance biomarkers at birth. SUBJECTS/METHODS: Cord-blood insulin sensitivity/resistance biomarkers of the offspring of 35 women whose diets were 'adequate' or 'inadequate' according to their HEI score (>70 or <= 70, respectively) and their 13-point MDA score (>= 7 or <7, respectively). RESULTS: Low HEI-score diets contained less (g/1000 kcal) carbohydrates (CHO; P=0.027) and fibre (P=0.011), and more fats (P<0.001) and cholesterol (P<0.001), and contributed (percentage contribution to total energy (%En)) fewer CHO (P=0.005), more fats (P=<0.001) and saturated fatty acid (SFA; P=0.002) than their high HEI score counterparts. Low MDA-score diets contained less (g/1000 kcal) fibre (P<0.001) and more cholesterol (P=0.05), had lower polyunsaturated fatty acids+monounsaturated fatty acid/SFA (PUFA+MUFA/SFA; P=0.05) and higher SFA/CHO (P=0.021) and omega-6/omega-3 PUFA ratios (P=0.044) than their respective counterparts. Women consuming the low HEI- or low MDA-score diets had low-fasting glycaemia (P=0.016 or P=0.025, respectively) but delivered infants with high insulinaemia (P=0.048 or P=0.017, respectively), homeostatic model assessment for insulin resistance (HOMA-IR; P=0.031 or P=0.049, respectively) and glycaemia (P=0.018 or P=0.048, respectively). The relative risk (RR) of high-neonatal glycaemia and insulinaemia were 7.6 (P=0.008) and 6.7 (P=0.017) for low vs high HEI-score groups. High HOMA-IR and high glucose RR were, respectively, 3.4 (P=0.043) and 3.9 (P=0.016) in neonates from the <7 MDA- vs >= 7 MDA-score group. These RRs were not affected by potential confounders. CONCLUSION: Maternal diets with low HEI- or MDA-scores during the first trimester of pregnancy negatively affect insulin resistance markers at birth. PMID- 22828733 TI - Transforming research for food and health in Europe. AB - Eating causes up to a quarter of premature deaths from chronic diseases in Europe through poor diet and excess consumption. FAHRE (Food and Health Research in Europe) was funded to determine needs and gaps in research structures and programmes. Most food research links towards agriculture and the environmental sciences, whereas most health research links towards clinical diseases, biochemical pathways and biology. Research on food and health together includes food safety research addressing biological and chemical contaminants, and biotechnology research supporting clinical nutrition. Research for healthy eating must draw on social and behavioural sciences for studies of policy, regulation and interventions. The food industry, across production, retail and catering, must be part of the research programme, and civil society. Better coordination and improved levels of funding are needed in the coming European research programme 'Horizon 2020', and national programmes linked in the Joint Programming Initiative. Transforming the research agenda can give great benefits to Europe's citizens. PMID- 22828734 TI - Randomised controlled trial of colostrum to improve intestinal function in patients with short bowel syndrome. AB - BACKGROUND/OBJECTIVES: Colostrum is rich in immunoregulatory, antimicrobial and trophic components supporting intestinal development and function in newborns. We assessed whether bovine colostrum could enhance intestinal adaptation and function in adult short bowel syndrome (SBS) patients. SUBJECTS/METHODS: Twelve SBS patients in this randomised cross-over study received 4 weeks oral supplement of bovine colostrum or an iso-energetic and iso-proteinaceous control (2.4 MJ/d, 500 ml/day) separated by a 4-week washout period. Patients were admitted four times for 72-h periods of fluid, electrolyte and nutrient balance studies. Meals, faeces and urine were weighed, and energy, macronutrient and electrolyte contents were analysed to calculate net nutrient uptake. Body composition was measured by dual-energy X-ray absorptiometry scans, and functional tests of handgrip strength and lung functions were performed. Eight patients completed the study and were included in the analysis. RESULTS: Both supplements (colostrum and control) not only increased protein (0.96 +/- 0.42 MJ/d, P=0.004 1.03 +/- 0.44 MJ/d, P=0.003) and energy (1.46 +/- 1.02 MJ/d, P=0.005, 1.76 +/- 1.46 MJ/d, P=0.01) absorption but also absolute faecal wet weight excretions (231 +/- 248 g/d, P=0.002, 319 +/- 299 g/d, P=0.03), compared with baseline measurements. Both supplements improved handgrip strength (P=0.03) while only the control supplement increased lean body mass (1.12 +/- 1.33 kg, P<0.049). Colostrum was not found to be superior to the control. CONCLUSION: Intake of high-protein milk supplements increased net nutrient absorption for adult SBS patients, but at the expense of increased diarrhoea. Despite high contents of bioactive factors, colostrum did not significantly improve intestinal absorption, body composition or functional tests compared with the control. PMID- 22828735 TI - The role of macrophage lineage cells in kidney graft rejection and survival. AB - Large numbers of macrophage lineage cells are present in transplants undergoing ischemia-reperfusion injury and rejection, and their presence correlates with a high probability of rejection. However, the extent to which monocytes and macrophages contribute to kidney graft rejection is poorly understood. The heterogeneity of the monocyte/macrophage lineage cells could be one of the reasons why these cells have been neglected up to now. Circulating monocytes can be divided into various subsets, which are able to give rise to tissue macrophages and dendritic cells. Macrophages are believed to be highly plastic cells that can respond to environmental signals by changing their phenotype and function. Macrophages have established roles in early and late kidney graft inflammation, tissue homeostasis, remodeling, and repair. In kidney transplantation, macrophages are believed to play a role in both damage and repair of the graft, depending on the type of macrophages involved, the environmental drive, and the time after transplantation. The heterogeneity and plasticity of monocytes and macrophages are obstacles to translating the functional relevance of this cell lineage to diagnostic and prognostic clinical parameters and to defining specific, macrophage-related, therapeutic targets. Recent evidence has indicated an immunomodulatory role for the so-called regulatory macrophages in induction of tolerance in kidney transplant recipients. In this article, we summarize current views on monocyte/macrophage immunobiology in kidney transplantation. Key issues for ongoing research are discussed. PMID- 22828736 TI - Kidney transplantation with and without simultaneous bilateral native nephrectomy in patients with polycystic kidney disease: a comparative retrospective study. AB - BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) often need to undergo native nephrectomy and are candidates for kidney transplantation. The necessity and timing of nephrectomy are controversial. Some authors recommend simultaneous bilateral native nephrectomy (SBN) as the preferred option in living-donor kidney transplantation (LDKT). These recommendations are based on small study populations. We therefore set out to study outcomes of LDKT with SBN, compared with LDKT alone in a larger single center cohort. METHODS: A consecutive series of 159 patients with ADPKD undergoing LDKT were included in the study. Of the 159 patients, 2 were excluded because of missing data, 79 underwent LDKT alone (group A), and 78 underwent LDKT with SBN (group B). Demographic data and intraoperative and postoperative data were collected from patient charts and the national kidney registry. RESULTS: There were no differences regarding background data. Group B experienced significantly longer operating times (183.7 vs. 319.3 min, P<0.001), a greater need for blood transfusions (0.1 vs. 1.6 units, P<0.001) and plasma products (35.1 vs. 438.3 mL, P<0.001), and longer hospital stays (11.8 vs. 15.4 days, P<0.001). It also experienced more intraoperative events and postoperative complications but fewer reoperations/reinterventions. There were no differences in patient and graft survival rates. CONCLUSIONS: SBN in patients undergoing LDKT for ADPKD does not have a significant negative impact on patient and graft survival rates. It obviates a separate surgical procedure but requires longer hospital stay. It may be associated with more postoperative complications and risk of graft loss. These considerations should be communicated to the recipient and the donor. PMID- 22828737 TI - Very large residual dipolar couplings from deuterated ubiquitin. AB - Main-chain (1)H(N)-(15)N residual dipolar couplings (RDCs) ranging from approximately -200 to 200 Hz have been measured for ubiquitin under strong alignment conditions in Pf1 phage. This represents a ten-fold increase in the degree of alignment over the typical weakly aligned samples. The measurements are made possible by extensive proton-dilution of the sample, achieved by deuteration of the protein with partial back-substitution of labile protons from 25 % H(2)O / 75 % D(2)O buffer. The spectral quality is further improved by application of deuterium decoupling. Since standard experiments using fixed-delay INEPT elements cannot accommodate a broad range of couplings, the measurements were conducted using J-resolved and J-modulated versions of the HSQC and TROSY sequences. Due to unusually large variations in dipolar couplings, the trosy (sharp) and anti-trosy (broad) signals are often found to be interchanged in the TROSY spectra. To distinguish between the two, we have relied on their respective (15)N linewidths. This strategy ultimately allowed us to determine the signs of RDCs. The fitting of the measured RDC values to the crystallographic coordinates of ubiquitin yields the quality factor Q = 0.16, which confirms the perturbation-free character of the Pf1 alignment. Our results demonstrate that RDC data can be successfully acquired not only in dilute liquid crystals, but also in more concentrated ones. As a general rule, the increase in liquid crystal concentration improves the stability of alignment media and makes them more tolerant to variations in sample conditions. The technical ability to measure RDCs under moderately strong alignment conditions may open the door for development of alternative alignment media, including new types of media that mimic biologically relevant systems. PMID- 22828738 TI - Regional cerebral perfusion in patients with Alzheimer's disease and mild cognitive impairment: effect of APOE epsilon4 allele. AB - INTRODUCTION: The objective of this study was to evaluate the effect of apolipoprotein E (APOE) epsilon 4 allele on regional cerebral perfusion (rCBF) changes using arterial spin labeling (ASL) magnetic resonance imaging (MRI) in subjects who are carriers or noncarriers of this risk factor for Alzheimer disease (AD). METHODS: Twenty-five subjects with AD, 25 with amnestic mild cognitive impairment (MCI) and 25 cognitively normal (CN) subjects underwent isotropic volumetric T1-weighted imaging and pulsed ASL MRI. All subjects were divided into carrier or noncarriers of the epsilon4 allele. Voxel-based statistical analyses were performed among groups on rCBF by ANOVA tests. In each subject group, we also evaluated the rCBF change between carrier and noncarrier groups. RESULTS: rCBF was significantly reduced in AD subjects compared to other subjects. In CN and AD subjects, rCBF in the carrier group was significantly reduced in several areas of the brain compared with that of the noncarrier group. In the carrier group, rCBF was significantly increased in the right parahippocampal gyrus, the bilateral cingulate gyri and the right posterior cingulate on the MCI group in addition to the right superior frontal gyrus in the AD group. CONCLUSION: rCBF in the CN and AD groups were significantly reduced in the subjects with the carriers of the epsilon4 allele, which is a risk factor for Alzheimer's disease. In addition, rCBF in the MCI group was significantly increased in subjects who were carriers. Therefore, rCBF can be used as a biomarker to show disease progression in areas of the brain of MCI subjects. PMID- 22828739 TI - ABO-incompatible kidney transplantation in elderly patients over 60 years of age. AB - INTRODUCTION: Patients aged 60 years and older represent the fastest-growing population with end-stage renal disease worldwide, and the need for a kidney transplant among this population is increasing. Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved, and the rates of graft survival in these patients are currently similar to those in recipients of ABO-compatible grafts. However, the outcomes of ABO incompatible kidney transplantation in elderly patients over 60 years of age have not been well studied yet. PATIENTS AND METHODS: We studied 4 elderly kidney transplant patients who received their grafts from ABO-incompatible living donors at our institution between December 2006 and December 2011, focusing on the immunosuppressive protocols, complications and graft survivals. The mean observation period was 21.5 months (range, 8 months to 62 months). Our immunosuppressive protocols were as follows: to remove the anti-A/B antibodies, the patients underwent 4-8 sessions of double-filtration plasmapheresis and/or plasma exchange prior to kidney transplantation until the anti-A/B titers were less than 1:16. For the patients with low anti-A/B titers (<1:512), the immunosuppressive protocol consisted of a single dose of rituximab (150 mg/m(2)). The patients with high anti-A/B antibody titers (>=1:512) underwent splenectomy and received 2 doses of rituximab. The pretransplant immunosuppressive protocol included B-lymphocyte suppression with 4 weeks of mycophenolate mofetil (0.5 g/day for low-titer protocol and 1 g/day for high-titer protocol). RESULTS: All 4 patients underwent successful transplantation. At the end of follow-up, their mean serum creatinine was 1.18 mg/dl. No patient experienced antibody-mediated rejection or acute cellular rejection. Late-onset neutropenia occurred in two cases. Two cases experienced cytomegalovirus reactivation by cytomegalovirus antigenemia. In one patient, diffuse hemorrhage required surgical intervention. However, there were no severe complications. CONCLUSIONS: Although a careful evaluation of patients is needed, ABO-incompatible kidney transplantation may become a viable treatment option for elderly patients with end-stage renal disease. PMID- 22828740 TI - High uric acid and low superoxide dismutase as possible predictors of all-cause and cardiovascular mortality in hemodialysis patients. AB - PURPOSE: We investigated the role of serum uric acid (sUA) and superoxide dismutase (SOD) as predictive factors for mortality in hemodialysis (HD) patients. METHODS: SOD, butyrylcholinesterase, and malondialdehyde were estimated spectrophotometrically and the other parameters by standard procedures. High sensitive C-reactive protein was assayed by a sandwich ELISA method. RESULTS: sUA among survivors (112.1 +/- 13.82 MUmol/L) was significantly lower than in deceased (160.8 +/- 16.81 MUmol/L, p < 0.001), while SOD was higher in survivors (31.8 +/- 6.61 kU/L) than among deceased (20.2 +/- 3.03, p < 0.05). Kaplan-Meier survival curves showed the greatest mortality risk in the highest tertile of basal sUA concentration (>= 127.11 MUmol/L, p < 0.001), and for SOD in the lowest tertile (<= 23.83 kU/L, p < 0.05). CONCLUSION: Our results suggest that high sUA and low SOD may predict all-cause and cardiovascular mortality in HD patients. PMID- 22828741 TI - First documented case of successful kidney transplantation from a donor with acute renal failure treated with dialysis. AB - There is a widening gap between the needs and possibilities of kidney transplantation. In order to solve the problem of organ shortage, the selection criteria for kidney donors have been less stringent over the last years. Favorable outcome of renal transplantation from deceased donors with acute renal failure requiring dialysis may have an important role in expanding the pool of donors. We present the case of two renal transplantations from a polytraumatized 20-years old donor with acute renal failure requiring dialysis. One recipient established good diuresis from the first post-transplant day and did not require hemodialysis. The second recipient had delayed graft function and was treated with 8 hemodialysis sessions. The patient was discharged with good diuresis and normal serum creatinine. After two years of follow-up, both recipients have normal graft function. According to our experience, kidneys from deceased young donors with acute renal failure requiring dialysis may be transplanted, in order to decrease the number of patients on transplantation waiting lists. PMID- 22828742 TI - Sturge-Weber syndrome coexisting with autosomal dominant polycystic kidney disease. PMID- 22828743 TI - In-hospital mortality in patients with renal dysfunction admitted for myocardial infarction: the Emilia-Romagna region of Italy database of hospital admissions. AB - BACKGROUND: In-hospital mortality of patients with myocardial infarction (MI) in different European populations and renal dysfunction is variable. We aimed to evaluate in-hospital mortality for MI in chronic kidney disease (CKD), in end stage renal disease (ESRD), and in subjects admitted for MI without renal dysfunction living in the Emilia-Romagna region of Italy. METHODS: We considered all cases of MI (first event) recorded in the database of hospital admissions of the region Emilia-Romagna of Italy, from January 1999 to December 2009. The criterion for inclusion was the presence, as a first discharge diagnosis, of acute MI (International Classification of Diseases, 9th Revision, Clinical Modification). The Charlson comorbidity index (CCI), with the exclusion of CKD, was calculated. The outcome variable was in-hospital mortality for MI, and its association with comorbidities, CKD and ESRD, was analyzed. RESULTS: During the considered period, 88,014 cases of first MI were recorded. The percentage of patients admitted with MI and died during hospitalization were higher in patients with ESRD (38.3 %) and CKD (16.5 %) than in those without renal dysfunction (14 %) (p < 0.01). In CKD and ESRD patients, data of in-hospital mortality for MI exhibited a twofold increase in the analyzed period. In-hospital mortality for MI was independently associated with age (OR 1.077, 95 % CI 1.075-1.080, p < 0.001), CCI excluding CKD (OR 1.101, 95 % CI 1.069-1.134, p < 0.001), cerebrovascular disease (OR 1.450, 95 % CI 1.349-1.557, p < 0.001), malignancy (OR 1.234, 95 % CI 1.153-1.320, p < 0.001), and ESRD (OR 4.137, 95 % CI 3.511-4.875, p < 0.001). CONCLUSIONS: As for the Emilia-Romagna region of Italy, in-hospital mortality for MI is increasing over the last years, and mortality seems to be related with patients' comorbidities and presence of advanced stages of CKD. PMID- 22828744 TI - Impact of a learning curve model in kidney transplantation on functional outcome and surgical complications in a small volume centre: does size really matter? AB - PURPOSE: To evaluate surgical complications and functional results of deceased donor renal transplantations (DDRT) in a small centre dependent on the surgeons level of experience and to derive a leaning-curve model for DDRT. METHODS: Three hundred and ninety-two recipients underwent DDRT at the Department of Urology, Bonn University. Operative procedures were performed by 18 various urological surgeons grouped in 5 levels of experience (LOE). Perioperative data, complications and graft survival after 12 months were recorded depending on LOEs. RESULTS: Operative time and warm ischaemia time significantly decreased after an experience of 40 DDRT. Complication rates and graft function after 12 months did not differ between all LOEs. CONCLUSIONS: Kidney transplantation in a small centre is a safe and effective procedure even if performed by surgeons under education. As a crucial finding, a surgeon climbing his learning curve becomes faster but not necessarily better. PMID- 22828745 TI - [Therapy of myopic choroidal neovascularization]. AB - Recently published studies have shown that myopic choroidal neovascularization (mCNV) is efficiently treated by anti-vascular endothelial growth factor (VEGF) drugs. Within a prospective executive study, photodynamic therapy failed to prove a significant difference over the duration of 2 years. Although a systematic evaluation of different retreatment algorithms still has to be done the administration of single injections depending on specialist assessment of morphological changes, predominantly spectral domain optical coherence tomography (SD-OCT) and fundus, has achieved a marked visual improvement. The experience of treating age-related macular degeneration should not be simply transferred to mCNV and an individual approach, not only for female patients of childbearing age, is necessary. PMID- 22828746 TI - [Evaluation of the self-tonometer Icare ONE in comparison to Goldmann applanation tonometry]. AB - OBJECTIVE: The aim of this clinical study was to demonstrate the practicability of self-measured intraocular pressure and to evaluate the reliability by comparing the data with those obtained by Goldmann applanation tonometry (GAT). METHODS: A total of 40 patients aged between 44 and 82 years with glaucoma were introduced to the handling of the tonometer. The self-measurements were done for 1-3 days following the medical measurement by GAT. The data were saved as "correct" or in the case of wrong handling as "false". The impressions of the patients were obtained by a questionnaire. RESULTS: A total number of 191 single measurements were registered by the Icare ONE and of these there were 97 (50.8%) signed "false". Of the patients 45% reached a maximum difference of +/-5 mmHg between GAT and self-measurement in every single measurement. In the subgroup of under 60-year-old patients 70% reached this result. There were no indications of a systematic error. Of the probands 60% considered the handling of the Icare ONE as difficult. Nevertheless, 80% could imagine using the self-tonometer at home. CONCLUSIONS: The differences between the self-measurements and the GAT were highly fluctuating in some cases. In the group of patients younger than 60 years the agreement was better, so problems with the handling of the Icare ONE may be an important factor. However, the acceptance in the patients tested was high and continuous pressure measurements at home could be reasonable. Advancements in the handling and reliability are needed to improve clinical application of the measured values. PMID- 22828747 TI - Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. AB - Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently. PMID- 22828748 TI - The same antidepressant elicits contrasting patterns of synaptic changes in the amygdala vs hippocampus. AB - As depression-like symptoms are often precipitated by some form of stress, animal models of stress have been used extensively to investigate cellular mechanisms of depression. Despite being implicated in the emotional symptoms of depression, the amygdala has received little attention compared to the hippocampus in the past studies of antidepressant action. Further, these investigations have not taken into account the contrasting effects of chronic stress on the hippocampus vs amygdala. If an antidepressant is to be equally effective in countering the differential effects of stress on both brain areas, then it is faced with the challenge of eliciting contrasting effects in these two structures. We tested this prediction by examining the impact of tianeptine, an antidepressant with proven clinical efficacy, on neurons of the lateral amygdala (LA) and hippocampal area CA1. Tianeptine reduces N-methyl-D-aspartate (NMDA)-receptor-mediated synaptic currents, without affecting alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) currents, in LA neurons. By contrast, tianeptine enhances both NMDA and AMPA currents in area CA1. Tianeptine also lowers action potential firing in LA neurons. As tianeptine modulates cellular metrics that, in addition to mediating amygdalar behavioral output, are also affected by stress, we tested if tianeptine succeeds in countering stress effects in the intact animal. We find that tianeptine prevents two important functional consequences of chronic stress induced plasticity in the amygdala--dendritic growth and enhanced anxiety-like behavior. These results provide evidence for antidepressant action on amygdalar neurons that are not only distinct from the hippocampus, but also protect against the debilitating impact of stress on amygdalar structure and function. PMID- 22828749 TI - PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3. AB - Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants. PMID- 22828752 TI - Susceptibility of testicular cell cultures of crab, Scylla serrata (Forskal) to white spot syndrome virus. AB - Testicular cell culture of crab, Scylla serrata (Forskal) was used to study the effects of White spot syndrome virus (WSSV). We are showing the susceptibility of cell culture of crabs to WSSV. The proliferating cell culture of testes were maintained for more than 4 months in a medium prepared from L15 and crab saline supplemented with epidermal growth factor. The cell cultures inoculated with different concentrations of virus showed distinct cytopathic effects such as change in cell appearance, shrinkage and cell lysis. WSSV infection of cultured cells was confirmed by Nested PCR technique. The incorporation of viral DNA in cultured cells was shown by RAPD profile generated using 10-mer primers. The controls that were not exposed to WSSV did not show cytopathic effects. This work shows the usefulness of proliferating testicular cell culture for studying WSSV infection using molecular tools. Thus, this report gains significance as it opens new vistas for diagnostics and drugs for WSSV. PMID- 22828750 TI - Central vasopressin V1A receptor blockade impedes hypothalamic-pituitary-adrenal habituation to repeated restraint stress exposure in adult male rats. AB - Previous studies suggest that central arginine vasopressin (AVP) signaling can inhibit the hypothalamic-pituitary-adrenal (HPA) axis. To test a role for the AVP V1A receptor in stress HPA axis habituation, adult male rats were exposed to 5 consecutive days of 3 h restraint with or without continuous intracerebroventricular infusion of the V1A receptor antagonist d(CH2)5Tyr(Me)AVP (10 MUg/day). Assessment of neuropeptide expression and HPA output under basal conditions revealed no effects of V1A receptor antagonism in stress naive animals. Between the first and last day of restraint exposure, controls showed marked declines in ACTH and corticosterone responses, and maintained plasma concentrations of testosterone. In contrast, V1A receptor antagonized animals displayed significantly smaller declines in ACTH and corticosterone responses, and a decrease in plasma testosterone. Despite their reduced expression of HPA axis habituation, antagonized animals continued to show stress-induced increases in AVP mRNA in the hypothalamic paraventricular nucleus and bed nucleus of the stria terminalis, and even higher levels of AVP expression in the medial amygdala relative to controls. The data leave open the nature and extent to which these and other AVP-containing pathways are recruited during repeated restraint, but nevertheless reveal a critical role for central V1A receptors in stress adaptation. As the effects of V1A receptor antagonism were restricted to the repeated restraint condition, we conclude that normal adaptation to stress involves a shift toward enhanced AVP utilization and/or V1A receptor signaling. PMID- 22828753 TI - Real-time in situ viability assessment in a 3D bioreactor with liver cells using resazurin assay. AB - Three-dimensional cultivation of human cells is promising especially for long term maintenance of specific functions and mimicking the in vivo tissue environment. However, direct viability assessment is very difficult in such systems. Commonly applied indirect methods such as glucose consumption, albumin or urea production are greatly affected by culture conditions, stress and time of cultivation and do not reflect the real time viability of the cells. In this study we established a real-time in situ viability assay namely; resazurin assay, in a 3D hollow-fiber bioreactor using human liver cells. Resazurin assay is based on the conversion of resazurin to a fluorescent dye by cytoplasmatic and mitochondrial enzymes. We show that the resazurin reagent in concentrations used in this study is non-toxic and could be rapidly removed out of the system. Moreover, we observed that dead cells do not affect the results of the assay. We optimized the assay on HepG2 cells and tested it with primary human hepatocytes. Moreover, we maintained primary human hepatocytes in the 3D bioreactor system in serum-free conditions and also assessed viability before and after the exposure to amiodarone using the resazurin assay. We show that this approach is applicable during long-term cultivation of cells in bioreactors under different conditions and can moreover be applied to pharmacological studies, e.g. investigation of chronic drug effects in such 3D bioreactors. PMID- 22828751 TI - Histone regulation in the CNS: basic principles of epigenetic plasticity. AB - Postmitotic neurons are subject to a vast array of environmental influences that require the nuclear integration of intracellular signaling events to promote a wide variety of neuroplastic states associated with synaptic function, circuit formation, and behavioral memory. Over the last decade, much attention has been paid to the roles of transcription and chromatin regulation in guiding fundamental aspects of neuronal function. A great deal of this work has centered on neurodevelopmental and adulthood plasticity, with increased focus in the areas of neuropharmacology and molecular psychiatry. Here, we attempt to provide a broad overview of chromatin regulation, as it relates to central nervous system (CNS) function, with specific emphasis on the modes of histone posttranslational modifications, chromatin remodeling, and histone variant exchange. Understanding the functions of chromatin in the context of the CNS will aid in the future development of pharmacological therapeutics aimed at alleviating devastating neurological disorders. PMID- 22828754 TI - Preprocedural imaging for patients with atrial fibrillation and heart failure. AB - Various electrophysiological procedures and device implantation has been shown to improve morbidity and mortality in patients with atrial fibrillation (AF) and patients with heart failure (HF). Noninvasive cardiac imaging is used extensively in the preprocedural patient selection and for procedural guidance. In this review, we will discuss the application of preprocedural cardiac imaging in patients with AF prior to pulmonary vein and left atrial ablation as well as insertion of left atrial occluder device. We also discuss the role of noninvasive cardiac imaging in the selection of appropriate HF patients for device therapy as well as their use in guiding implantation of biventricular pacemaker for cardiac resynchronization therapy by assessing left ventricular ejection fraction, coronary venous anatomy, mechanical dyssynchrony and myocardial scar. We describe new research associated with preprocedural imaging in these patient cohorts. PMID- 22828756 TI - Volumetric analysis of root canal fillings in primary teeth using spiral computed tomography: an in vitro study. AB - PURPOSE: The purpose of this study was to volumetrically analyze the efficacy of root canal fillings in primary teeth using spiral computed tomography (CT). METHODS: Root canals in 30 primary maxillary and mandibular molars were instrumented with K files to size 30, and the volumes of the canals were then measured using spiral CT. The teeth were randomly divided into 3 groups of 10 each, and 18 of the canals in each group were evaluated with spiral CT after obturation with zinc oxide eugenol paste, Metapex and Vitapex. The filled volume in each canal was mea- sured using spiral CT, and the percentage of obturated volume (POV) was calculated. The pre- and post-mean canal volume values within each group and the POV of the 3 groups were statistically analyzed using one-way analysis of variance and paired t tests. RESULTS: Filler voids were seen in all groups, but there was a statistically significant difference (P <.001) in the calculated POV. Vitapex showed 95% POV compared to Metapex (88%) and ZOE (84%). CONCLUSION: Voids were seen in all 3 filling materials. Vitapex showed the maximum percentage of obturated volume among the 3 groups. PMID- 22828757 TI - Assessment of an infant oral health education program on resident physician knowledge. AB - PURPOSE: The purpose of this study was to implement and evaluate the effect of an early childhood oral health education program given to physician residents at Columbia University Medical Center, New York City. It was hypothesized that a short training program in infant oral health would improve the oral health knowledge base of these future physicians and promote the age 1 dental visit. METHODS: A sample size of 92 physician residents participated in this study. A 1 hour seminar describing common dental findings, including poor oral hygiene and early childhood caries (ECC), was presented, and an identical 14 question pre- and post-test were completed. The pre- and post-tests were administered to all participants, and statistical differences between pre- and post-tests were calculated using a paired t-test (P <.05) and SAS 9.1 statistical software. RESULTS: There was an average of 77% correct responses on the pre-test and 90% correct responses following instruction (n=92, P <.001), with a mean improvement in the scores of 2 questions on the post-test. There was a significant improvement in the knowledge base of residents on topics related to ECC and its prevention and fluorides. CONCLUSION: A 1-hour seminar resulted in significantly improved post-test scores for physician residents about infant oral health. PMID- 22828755 TI - Ablating persistent atrial fibrillation successfully. AB - The ablation of persistent atrial fibrillation (AF) poses many challenges compared with ablation for paroxysmal AF, including greater procedural complexity, longer procedural time, unclear endpoints, increased patient comorbidity with a greater risk of procedural complications, and lower success rate. Nevertheless, using a combination of patient selection, careful procedural planning of both ablation strategy and endpoints, and by setting realistic patient expectations, successful ablation may be achieved. Further improvements will come from continued technical advances as well as from greater mechanistic understanding of persistent AF, including the physiologically-targeted ablation of localized rotors and focal sources that have recently been shown to maintain human AF. PMID- 22828758 TI - Standardized propolis extract and calcium hydroxide as pulpotomy agents in primary pig teeth. AB - PURPOSE: The purpose of this study was to evaluate the histological features of the pulp tissue in primary pig teeth submitted to pulpotomy and capped with calcium hydroxide-based and standardized propolis extract-based pastes, and the combination of these pastes. METHODS: Nine 4-month-old male pigs were used in this study, which were distributed into 4 groups, according to the studied pastes: Group 1-calcium hydroxide; Group2-standardized propolis extract; Group 3 combination of pastes 1 and 2 in the proportion 1:1; and Group 4-control. The teeth used for the pulpotomy were the 4 mandibular primary incisors. RESULTS: After 7, 21, and 42 days, the animals were killed and the teeth were re-moved for histological analysis. At 42 days, all teeth in Groups 1 to 3 presented a complete hardtissue barrier and the pulp tissue beneath was without inflammation. CONCLUSION: According to these findings, calcium hydroxide and standardized propolis extract favored the formation of a hard tissue barrier in primary pig teeth submitted to pulpotomy. PMID- 22828759 TI - Radiopacities of glass ionomer cements measured with direct digital radiographic system. AB - PURPOSE: The purpose of this study was to determine and compare the radiopacities of 5 glass ionomer cements (GICs) of different thickness using a digital radiographic system-storage phosphor plate. METHODS: The GICs tested were Vitremer, Vitrofil LC, Magic Glass, Vitromolar, and Maxxion, distributed into the orifices of 16 acrylic plates made to a thickness of 2 mm, 3 mm, 5 mm, and 6 mm. Each plate was radiographed 3 times, and the images obtained were processed by computer. The images were read 3 times using the VixWin 2000 program, totaling 720 readings of radiographic density. One-way analysis of variance was applied for statistical analysis with identification of differ- ences using Scheffe's multiple comparisons test (alpha=5%). RESULTS: All the GICs varied in radiopacity according to thickness. Maxxion showedthe lowest value of radiopacity, whereas Magic Glass displayed the highest level of radiopacity at all thicknesses studied. However, Vitremer and Vitrofil LC showed similar results. CONCLUSION: It is important to know GIC radiopacities to help differentiate them from tooth structure and carious lesions as well as to use them correctly. PMID- 22828760 TI - Glucosyltransferase B, immunoglobulin a, and caries experience among a group of Egyptian preschool children. AB - PURPOSE: Glucosyltransferase B enzyme (GtfB) plays an essential role in the pathogenesis of dental caries. It catalyzes the synthesis of water-insoluble glucan from sucrose, which is essential for accumulation of Streptococcus mutans in the dental biofilm. On the other hand, salivary immunoglobulin A (sIgA) plays a protective role in the same process. Therefore, the purpose of this study was to attempt to correlate glucosyltransferase B enzyme and immunoglobulin A levels in whole saliva with caries experience in preschool children. METHODS: Forty-five 3- to 6-year-old were examined clinically, and their caries experiences were recorded as decayed, missing, and filled teeth (dmft) scores. Unstimulated whole saliva was collected and analyzed for GtfB and IgA using enzyme-linked immunosorbent assay. RESULTS: Mixed-model analysis revealed that both GtfB and IgA are covariants regarding the effect on dmft scores (P =.008). GtfB levels displayed a simultaneous increase in caries experience (dmft) and number of carious lesions (d), while IgA levels were high in caries-free children and significantly lower values were obtained in the high caries group. CONCLUSION: Salivary IgA was negatively correlated with caries experience and inversely proportional with GtfB levels in the saliva of preschool children. PMID- 22828761 TI - Dental anomalies associated with unilateral and bilateral cleft lip and palate. AB - PURPOSE: The purpose of this study was to compare the prevalence of dental anomalies in the primary and permanent dentition of patients with unilateral (UCLP) and bilateral (BCLP) cleft lip with or without palate. METHODS: One hundred two complete clinical records were randomly selected for review from a university-based cleft palate clinic. Only nonsyndromic UCLP and BCLP cases were further selected for analysis of dental anomalies. The prevalence of 9 dental categories, including anomalies in number, crown structure, position, and maxillary-mandibular relationship, was assessed and compared between UCLP and BCLP cases using Fisher's exact test. RESULTS: Of the 102 charts evaluated, there were 67 cases of UCLP and 29 cases of BCLP for a total of 96 cases. There was a high prevalence of dental anomalies in primary and permanent teeth; 93% of UCLP cases and 96% of BCLP cases presented with at least 1 dental anomaly. Significant differences ( P <.05) were only found in the prevalence of anodontia of a single tooth (UCLP=39%, BCLP=14%), multiple anodontia (UCLP=22%, BCLP=54%), and anterior malocclusion (UCLP=15%, BCLP=41%). CONCLUSIONS: There is a high prevalence of dental anomalies associated with orofacial clefts regardless of whether they are unilateral or bilateral cleft lip with or without palate. PMID- 22828762 TI - Dental trauma management by New York City school nurses. AB - PURPOSE: The purpose of this study was to assess the knowledge and ability of school nurses in NYC to manage and properly treat traumatic dental injuries. METHODS: A survey questionnaire was sent to 160 randomly selected public schools and 40 randomly selected private schools in New York City. The questionnaire consisted of 24 multipart questions regarding background, personal experience, and knowledge of dental trauma. RESULTS: Seventy-four percent (74%) of the nurses rated their confidence in handling dental trauma in the middle range on a scale from 1 to 10. Sixty-two percent (62%) of nurses knew liquid was the optimal transportation method of an avulsed tooth; however, 52% of participants responded incorrectly that it was not appropriate to replant an avulsed permanent tooth. Ninety percent of nurses surveyed were interested in receiving further education in the management of dental trauma. CONCLUSION: This survey indicates that a gap of knowledge exists in the ability of school nurses to handle dental trauma. PMID- 22828763 TI - Multidisciplinary treatment of a subgingivally fractured tooth with indirect composite restoration: a case report. AB - In pediatric patients, anterior teeth with fractures that extend subgingivally require a complex treatment plan that addresses biologic, esthetic, and functional factors, such as mastication and speech. The purpose of this clinical report was to describe a technique using indirect composite restoration to restore a subgingivally fractured permanent maxillary right central incisor in a 10-year-old boy. Due to the complex nature of the treatment, a multidisciplinary approach was used to restore the tooth. The crown fragment was removed, and endodontic treatment was performed. The tooth was then extruded orthodontically. A glass fiber post was placed to improve retention, and an indirect composite restoration was placed. A clinical and radiographic evaluation at a follow-up appointment 1 year later confirmed that the technique used in this case can be a good option for restoring anterior teeth with subgingival fractures. PMID- 22828764 TI - Bilateral maxillary paramolars: a case report. AB - Supernumerary teeth are a common clinical and radiographic finding and may produce occlusal and dental problems. Supernumerary teeth can present in various forms and in any region of the mandible or maxilla, but have a predisposition for the anterior maxilla. The purpose of this paper was to present a case of supernumerary teeth located in the maxillary molar region bilaterally. PMID- 22828765 TI - Repair of perforating inflammatory root resorption in a previously traumatized incisor: 36-month follow-up. AB - Inflammatory root resorption is a serious complication of dental trauma, which leads to progressive loss of the root structure. The purpose of this report was to present a case of perforating inflammatory root resorption in a previously traumatized young incisor tooth with incomplete root development. A 12-year-old girl, who had suffered a traumatic dental injury 4 years earlier, was referred with symptoms of pain and swelling in a permanent maxillary central incisor. The tooth had been root-filled and had thin dentinal walls and a wide open apex. During retreatment, a perforating resorption site was observed on the root's distal aspect. Because the entire root canal filling could not be removed, the resorption site was repaired with white mineral trioxide aggregate in the presence of the remaining gutta-percha. Clinical and radiographic follow-up was conducted for 36 months, demonstrating arrest of the resorptive process, regeneration of the periradicular tissues, and re-establishment of the periodontal space. PMID- 22828766 TI - Infantile malignant osteopetrosis: report of 2 cases with osteomyelitis of the jaws. AB - Infantile malignant osteopetrosis (IMO) is an uncommon autosomal recessive disease characterized by dense, brittle, sclerotic, radiopaque bones, which generally results in neurological and hematological abnormalities. In general, IMO is fatal, as patients fail to grow and expire due to complications of the disease such as severe chronic anemia, bleeding, and/or infections. In children with IMO, the development of the dentition is seriously disturbed. Patients with infantile osteopetrosis have a variety of signs and symptoms, including osteomyelitis of the jaws, which frequently and generally resists treatment. Infections may eventually become lethal; hence, jaw infection control is an important aspect of the disease for dentists and oral surgeons to consider. The purpose of this case report was to present 2 rare cases of pediatric patients (one of them died due to respiratory failure at 10 years old) diagnosed with osteopetrosis complicated by osteomyelitis of the jaw. PMID- 22828767 TI - Dental manifestations of a pediatric patient with hyperimmunoglobulin e syndrome: a case report. AB - A 7-year-old girl with hyperimmunoglobulin E syndrome (HIES) presented to our clinic with tooth agenesis in both primary and permanent dentitions. The patient's serum immunoglobulin E level was elevated at 17,091 IU/ml, and her medical history indicated the occurrence of HIES, numerous skin abscesses, and recurrent infection by bacteria and/or fungi such as Candida from birth. She also suffered from heart disease. Dental manifestations included extensive caries, impaired root resorption of primary mandibular central incisors and absence of primary mandibular canines and permanent mandibular lateral incisors. Intraoral phenotypes in HIES patients have already been reported in detail, but no previous report has described abnormalities in the number of primary teeth in HIES patients. The purpose of this report was to describe the dental manifestations in the primary dentition of a hyperimmunoglobulin E syndrome patient and to emphasize the importance of preventive dental management from early childhood in compromised children, such as those with HIES. PMID- 22828768 TI - Leukocyte adhesion deficiency: a case report and review. AB - Leukocyte adhesion deficiency (LAD) is a rare inherited primary immunodeficiency disorder characterized by the presence of a defect of phagocytic function resulting from a lack of leukocyte cell surface expression of beta2 integrin molecules (CD11 and CD18) that are essential for leukocyte adhesion to endothelial cells and chemotaxis. A small number of patients with LAD-1 have a milder defect, with residual expression of CD18. These patients tend to survive beyond infancy; they manifest progressive severe periodontitis, leading to partial or total premature loss of the primary and permanent dentitions. Close cooperation with pediatricians and immunologists is often the key to successful management of pediatric patients with LAD. The purpose of this report was to present the case of a 5-year-old boy with moderate leukocyte adhesion deficiency 1 and severe periodontitis, cellulitis and illustrate the need for periodic oral checkups to avoid the progression of oral diseases and prevent premature tooth loss. PMID- 22828769 TI - Leiomyomatous hamartoma of the tongue in an infant: a case report. AB - A case of leiomyomatous hamartoma in the postmedian region of the dorsum of the tongue in a 3-year-old boy is reported. This lesion had been noticed at about 1 year of age but was left untreated. The intensity of the inner region of the mass was homogenous and similar to that of the surrounding tongue muscle on both T1- and T2-weighted images of an MRI. The mass was diagnosed as benign tumor of the tongue and resected. Histopathologically, nodular overgrowth of spindle cells containing eosinophilic cytoplasm was noted in the submucoepithelial connective tissue. In immunohistochemical staining, spindle cells were negative for S-100 protein and positive for vimentin and -SMA, suggesting that these cells were derived from smooth muscle. In the 10 months after surgery, there has been no recurrence of the lesion. To our knowledge, only 26 cases (including the present case) have been diagnosed histopathologically as leiomyomatous hamartoma in the oral cavity between 1945 and 2009. Clinical features, differential diagnosis, and treatment are discussed herein. PMID- 22828770 TI - Prosthetic rehabilitation of a child with Rapp-Hodgkin syndrome. AB - The purpose of this paper was to report the case of a 6-year-old male patient who was clinically diagnosed as having Rapp-Hodgkin syndrome-a variant of ectodermal dysplasia characterized by dysplastic disorders of the skin, hair, and nails associated with cleft lip and/or palate. The patient exhibited only the primary maxillary and mandibular canines bilaterally. Restorative treatment was performed on all primary canines, followed by aquisition of maxillary and mandibular impressions for fabrication of acrylic removable partial dentures with circumferential clasps on the primary canines. The dentures allowed recovery of the vertical dimension and excellent esthetics. Hypodontia of several teeth associated with ectodermal dysplasia, as in this case involving Rapp-Hodgkin syndrome, causes several functional and esthetic alterations. These disorders should be diagnosed and treated as early as possible to restore the normal function, allow adequate mastication and speech, enhance esthetics, and, consequently, promote the patient's self-esteem and social integration. PMID- 22828771 TI - Leisure-time physical activity and cardiovascular disease mortality: the Brisighella Heart Study. AB - OBJECTIVE: The aim of this study is to describe the relationship between self rated physical activity during leisure time and cardiovascular disease mortality in 2936 individuals of the cohort of the Brisighella Heart Study, a prospective, population-based, longitudinal, epidemiological survey. METHODS: Long-term (1988 2000) prognostic significance of physical activity was determined after adjustments for age, sex, smoking habits, low-density lipoprotein-cholesterol and history of type 2 diabetes. RESULTS: At baseline, 377 (25.3%) male and 496 (34.3%) female participants reported scarce-null physical activity, whereas 1112 (74.7%) men and 951 (65.7%) women reported medium-intense physical activity. In the entire population, cardiovascular mortality was three times higher in participants with sedentary physical activity than in those with medium-intense physical activity (P = 0.0001). These results have been confirmed in both men (P = 0.0001) and women (P = 0.0028). A categorical distribution of the population according to age showed a higher risk of cardiovascular death associated with sedentary physical activity only in the younger male particupants (P = 0.0032). CONCLUSION: On the basis of our data, physical activity is inversely related to cardiovascular mortality in a sample of the rural Mediterranean population with a highest risk in inactive men aged less than 65 years. PMID- 22828772 TI - Lytic failure in the current pharmacointensive ST-elevated acute myocardial infarction care: insights from a pilot real-world study. AB - BACKGROUND: Thrombolysis remains a very acceptable reperfusion option for ST elevated acute myocardial infarction (STEMI); however, it fails relatively frequently and unpredictably. AIM AND METHODS: To investigate correlates of lytic failure (according to the standard ST resolution criterion) in current pharmacointensive STEMI care (dual antiplatelets with antithrombin), we analyzed retrospectively clinical data and echocardiographic left ventricular systolic function before initiation of reperfusion treatment in Killip I-III STEMI patients admitted to our 'spoke' intensive cardiac care unit between 1 January and 31 December 2010. RESULTS: Of the 53 STEMI patients enrolled, 28% failed thrombolysis. Patients who did not reperfuse were less frequently active smokers (P < 0.05, odds ratio 4.33) and had a higher prevalence of hemodynamic instability [heart rate/SBP (i.e. shock index) >0.75; P < 0.05, odds ratio 13.45) and left ventricular systolic dysfunction (ejection fraction <45%; P < 0.005, odds ratio 11.14). In an exploratory multivariable logistic regression analysis, those variables were the only discriminators independently associated with lytic failure (adjusted odds ratio 8.74, 230.10, and 18.22, respectively, all P < 0.05). Moreover, the combined variables had a high accuracy for prediction of failed thrombolysis (all discriminators positive, 99% specificity and 83% positive predictive value). CONCLUSION: Our pilot study indicates that thrombolysis still fails in about one-third of STEMI patients despite the current pharmacointensive approach and suggests that failed ST resolution might be independently associated with nonsmoking habit and pretreatment hemodynamic instability and left ventricular systolic dysfunction. Larger trials are needed to verify the potential clinical implications of our preliminary observation. PMID- 22828773 TI - Aerobic exercise prescription in patients with chronic heart failure: a review in the beta-blocker era. AB - Aerobic exercise training is a well-established nonpharmacological tool in patients with clinically stable chronic heart failure. In recent years, beta blocker therapy has become a primary pharmacologic intervention in patients with chronic heart failure. Despite the undeniable improvements in patients, the beta blocker era has aroused uncertainties about aerobic exercise intensity prescription. It is well known that aerobic exercise prescription is performed by a percentage of the patient's heart rate reserve and the use of beta-blockers could interfere in this method. For this reason, the aim of this review is to provide an update about aerobic exercise prescription in patients with chronic heart failure who are using beta-blockers. PMID- 22828775 TI - Pathology of plaque haemorrhage and neovascularization of coronary artery. AB - Intraplaque haemorrhage (IPH) is thought to play crucial roles in plaque progression and plaque rupture, resulting in acute coronary syndromes, which are the leading causes of morbidity and mortality in the developed countries. IPH is a common finding in atherosclerotic plaques. In the past decade, the use of anti Glycophorin A antibodies that specifically and uniquely label membranes of the red cells triggered a cascade of pathologic and experimental studies concordantly documenting not only the presence but also the major role of IPH in plaque progression and complications. Moreover, recent studies have shown that plaque neovascularization is essential to IPH as a source of blood content. Although the mechanisms by which IPH impacts plaque progression and plaque rupture gradually become clear, several questions such as causes of angioneogenesis, identification and treatment of plaques with angioneogenesis are still unanswered. Further studies are needed to resolve these issues; however, the investigation of IPH without a histopathological approach is unconceivable. This review will focus on the pathology of IPH and plaque neovascularization, pathophysiology and potential clinical impact. PMID- 22828774 TI - Clinical outcome after surgical or percutaneous revascularization in coronary bypass graft failure. AB - AIMS: To describe long-term outcome following surgical and percutaneous revascularization in graft failure. METHODS: We analyzed consecutive patients with graft failure after heart-team assignment to percutaneous coronary intervention (PCI) or redo coronary artery bypass grafting (CABG) between 2003 and 2008. The primary endpoint was the composite of death, myocardial infarction (MI) or target vessel revascularization (TVR). Kaplan-Meier event rate estimates were calculated up to a 5-year follow-up. Independent predictors for outcomes were identified by backward selection in a multivariable Cox proportional hazard model. RESULTS: We identified 287 patients treated for graft failure: 243 with PCI and 44 with redo CABG. Patients undergoing PCI more frequently presented with ST-elevated myocardial infarction (STEMI) (P < 0.001), multivessel disease (P < 0.001), vein graft failure (P = 0.04), a history of MI (P < 0.001) and shorter time-to-graft failure (P = 0.001). Bare-metal stents (BMS) were used in 81.3% of the PCI-treated lesions and drug-eluting stents (DES) in 18.7%. The median follow up was 3.9 years. Five-year rate of composite all-cause death, MI or TVR was 57.6% after PCI and 51% after CABG (P = 0.51). Repeat revascularization [TVR and target lesion revascularization (TLR)] was 30.7 and 21.3% after PCI, and 8.0 and 3.2% following CABG (P = 0.009; P = 0.008). In the PCI group, BMS was associated with higher rates of TVR (35.1 vs. 12.6%; P = 0.04) and TLR (24.8 vs. 7.6%; P = 0.04), but similar rate of death or MI compared with DES. Independent predictors for the primary outcome were creatinine [hazard ratio 1.008 per MUmol/l, 95% confidence interval (CI) 1.005-1.011, P < 0.001] and peak creatine kinase MB (hazard ratio 1.001 per U/l, 95% CI 1.000-1.002, P = 0.027). CONCLUSION: Clinical outcomes are similarly poor after heart-team triage for surgical or percutaneous intervention in patients with graft failure. Repeat revascularization occurred more frequent after PCI, particularly following BMS implantation. PMID- 22828776 TI - C-reactive protein 1059G/C gene polymorphism, C-reactive protein levels and acute myocardial infarction. AB - AIMS: High-sensitivity C-reactive protein (hs-CRP) is an inflammatory marker, predicting the occurrence of acute myocardial infarction (AMI). Genetic predisposition to high baseline CRP might account for a high risk of heart diseases. Our study aimed at investigating an association of CRP 1059G/C gene polymorphism with plasma CRP levels and AMI in Egyptian patients. METHODS: Genotypes of 150 patients with AMI and 150 healthy sex and age-matched controls were analyzed using PCR-restriction fragment length polymorphism methods. hs-CRP concentrations were assessed. RESULTS: There was no significant association between CRP 1095G/C polymorphism and AMI. However, individuals with GG genotype had significantly higher plasma CRP concentration than those with GC and CC genotypes, in both controls (3.82 +/- 1.03 vs. 2.34 +/- 0.7; P = 0.001) and patients with AMI (8.39 +/- 2.6 vs. 6.67 +/- 2.4; P = 0.005). CONCLUSION: Our results revealed that CRP 1059G/C gene variation influences plasma CRP levels. Conversely, this polymorphism was not associated with the risk for AMI. PMID- 22828777 TI - Differential expression of the Toll-like receptor pathway and related genes of chicken bursa after experimental infection with infectious bursa disease virus. AB - Infectious bursa disease virus causes an acute infection in bursal B cells. The Toll-like receptor (TLR) signaling pathway plays a key role in innate immunity during virus infection. In this study, an Agilent microarray was used to investigate different transcriptional profiles of the TLR pathway and related genes of chicken bursa at 48 h after infection with IBDV, compared with simulated infection. Expression of >58 genes changed significantly. Forty-six genes associated with chicken bursa proinflammatory effects, chemotactic effects, and T cell stimulation were upregulated, which meant enhancement of these features. Twelve genes that are related to proliferation and differentiation of bursal cells were downregulated, implying suppression of these features. These results revealed that genes of the TLR pathway play an important role in the pathogenicity of IBDV infection. The findings are helpful for understanding the molecular basis of viral pathogenesis and the underlying mechanism of the host antiviral response. PMID- 22828778 TI - Novel serological tools for detection of Thottapalayam virus, a Soricomorpha borne hantavirus. AB - We developed serological tools for the detection of hantavirus-specific antibodies and hantavirus antigens in shrews. The work was focussed to generate Thottapalayam virus (TPMV)-specific monoclonal antibodies (mAbs) and anti-shrew immunoglobulin G (IgG) antibodies. The mAbs against TPMV nucleocapsid (N) protein were produced after immunization of BALB/c mice with recombinant TPMV N proteins expressed in Escherichia coli, baculovirus and Saccharomyces cerevisiae-mediated expression systems. In total, six TPMV N-protein-specific mAbs were generated that showed a characteristic fluorescent pattern in indirect immunofluorescence assay (IFA) using TPMV-infected Vero cells. Out of the six mAbs tested, five showed no cross-reaction to rodent-associated hantaviruses (Hantaan, Seoul, Puumala, Tula, Dobrava-Belgrade and Sin Nombre viruses) in IFA and enzyme-linked immunosorbent assay (ELISA), although one mAb reacted to Sin Nombre virus in IFA. None of the mAbs cross-reacted with an amino-terminal segment of the shrew-borne Asama virus N protein. Anti-shrew-IgG sera were prepared after immunization of rabbits and BALB/c-mice with protein-G-purified shrew IgG. TPMV-N-protein specific sera were raised by immunisation of Asian house shrews (Suncus murinus) with purified yeast-expressed TPMV N protein. Using these tools, an indirect ELISA was developed to detect TPMV-N-protein-specific antibodies in the sera of shrews. Using an established serological assay, high TPMV N protein specific antibody titres were measured in the sera of TPMV-N-protein-immunized and experimentally TPMV-infected shrews, whereas no cross-reactivity to other hantavirus N proteins was found. Therefore, the generated mAbs and the established ELISA system represent useful serological tools to detect TPMV, TPMV related virus antigens or hantavirus-specific antibodies in hantavirus-infected shrews. PMID- 22828780 TI - First complete and productive cell culture model for members of the genus Iridovirus. AB - Chilo iridescent virus (CIV; the type strain of the genus Iridovirus) replicates productively in larvae of the boll weevil, Anthonomus grandis. This study focuses on characterizing productive infections of a boll weevil cell line, BRL-AG-3A (AG3A), starting with CIV reared in the waxworm, Galleria mellonella. We show that CIV can be continually and productively passaged to high titer in AG3A cells. The replication of larval-derived CIV in AG3A was analyzed by observing viral DNA replication and restriction endonuclease digestion profiles, morphogenesis, and infectivity using TCID(50) assays with AG3A as an indicator cell line. The data showed that virus passaged in the AG3A host is stable. AG3A cells are more efficient than previously utilized CF-124T cells from Choristoneura fumiferana. This system constitutes a superior model for cellular and molecular studies on CIV; it represents the first complete, productive cell culture model for the replication of CIV or any member of the genus Iridovirus. PMID- 22828779 TI - Tick-borne encephalitis virus in Eastern Siberia: complete genome characteristics. AB - Tick-borne encephalitis (TBE) is one of the most important arboviral diseases across Eurasia. TBE virus (TBEV) is transmitted by tick bite and causes a potentially fatal neurological infection in humans. In the Russian Federation, TBE is endemic in most regions, with 3000-5000 cases of the disease annually. To characterise TBEV in Eastern Siberia, the complete genomes of five TBEV isolates from patients with different clinical manifestations were sequenced. The results show that the Siberian and Far Eastern subtypes of TBEV cause the disease in people in Eastern Siberia. Complete genome analysis revealed an unexpectedly high genetic variability within the Siberian subtype. PMID- 22828781 TI - The pan-genotype specificity of the hepatitis C virus anti-core monoclonal antibody C7-50 is contingent on the quasispecies profile of a population. AB - The inter/intra-genotype quasispecies makeup of hepatitis C virus (HCV) has retarded the development of antibodies capable of pan-genotype reactivity. Mutations, even in conserved domains, are tolerated to a degree. In this report, we characterise the pan-genotype specificity of the commercially available monoclonal anti-HCV core antibody C7-50. We demonstrate the antibody's ability to detect HCV core protein following infection of Huh7 cells with serum-derived HCV of genotypes 2-5 and that a single-site polymorphism in a genotype 3a core amino acid sequence is sufficient to disrupt antibody recognition of the epitope. This same polymorphism is a feature of genotype 3 viruses. PMID- 22828782 TI - Emission tuning in dinuclear gold complexes with diphosphanes containing alkyne and/or oligophenylene spacers. AB - Reaction of the diphosphanes P~P [PPh(2)(C(6)H(4))(n)PPh(2) (n = 1-5) and PPh(2)C[triple bond, length as m-dash]C(C(6)H(4))C[triple bond, length as m dash]CPPh(2)] with [AuX(tht)] (X = Cl, C(6)F(5)) in a 1 : 2 molar ratio affords dinuclear luminescent complexes of formula [(AuX)(2)(P~P)]. The photoemissive properties of these complexes are mainly controlled by the presence of the diphosphane ligand, specifically by the phenylene spacers of the diphosphanes. At room temperature fluorescent (IL) processes dominate the emissions, both in solution and in the solid state. Frozen solutions or solids at 77 K display dual emissions or only one emission attributed to ligand to ligand charge transfer (LL'CT) transitions from the auxiliary ligand (L) to phenylene spacers of the diphosphane (L'). PMID- 22828783 TI - Feature selection in computer-aided breast cancer diagnosis via dynamic contrast enhanced magnetic resonance images. AB - The accuracy of computer-aided diagnosis (CAD) for early detection and classification of breast cancer in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is dependent upon the features used by the CAD classifier. Here, we show that fast orthogonal search (FOS), which provides a more efficient iterative manner of computing stepwise regression feature selection, can select features with predictive value from a set of kinetic and texture candidate features computed from dynamic contrast-enhanced magnetic resonance images. FOS can in minutes search candidate feature sets of millions of terms, which may include cross-products of features up to second-, third- or fourth-order. This method is tested on a set of 83 DCE-MRI images, of which 20 are for cancerous and 63 for benign cases, using a leave-one-out trial. The features selected by FOS were used in a FOS predictor and nearest-neighbour predictor and had an area under the receiver operating curve (AUC) of 0.889 and 0.791 respectively. The FOS predictor AUC is significantly improved over the signal enhancement ratio predictor with an AUC of 0.706 (p = 0.0035 for the difference in the AUCs). Moreover, using FOS-selected features in a support vector machine increased the AUC over that resulting when the features were manually selected. PMID- 22828785 TI - Collision induced dissociation of doubly-charged ions: Coulomb explosion vs. neutral loss in [Ca(urea)]2+ gas phase unimolecular reactivity via chemical dynamics simulations. AB - In this paper we report different theoretical approaches to study the gas-phase unimolecular dissociation of the doubly-charged cation [Ca(urea)](2+), in order to rationalize recent experimental findings. Quantum mechanical plus molecular mechanical (QM/MM) direct chemical dynamics simulations were used to investigate collision induced dissociation (CID) and rotational-vibrational energy transfer for Ar + [Ca(urea)](2+) collisions. For the picosecond time-domain of the simulations, both neutral loss and Coulomb explosion reactions were found and the differences in their mechanisms elucidated. The loss of neutral urea subsequent to collision with Ar occurs via a shattering mechanism, while the formation of two singly-charged cations follows statistical (or almost statistical) dynamics. Vibrational-rotational energy transfer efficiencies obtained for trajectories that do not dissociate during the trajectory integration were used in conjunction with RRKM rate constants to approximate dissociation pathways assuming complete intramolecular vibrational energy redistribution (IVR) and statistical dynamics. This statistical limit predicts, as expected, that at long time the most stable species on the potential energy surface (PES) dominate. These results, coupled with experimental CID from which both neutral loss and Coulomb explosion products were obtained, show that the gas phase dissociation of this ion occurs by multiple mechanisms leading to different products and that reactivity on the complicated PES is dynamically complex. PMID- 22828784 TI - Peptoid transporters: effects of cationic, amphipathic structure on their cellular uptake. AB - Two cationic, amphipathic peptoids (poly-N-substituted glycines) were developed as new molecular transporters, which have extensive cellullar uptake and utilize different internalization mechanisms from purely cationic polyguanidine comparators. PMID- 22828786 TI - Comparing theories of health behavior using data from longitudinal studies: a comment on Gerend and Shepherd. PMID- 22828787 TI - A tribute to Bryan Joseph Cremin (1929-2012)--an Irishman and a South African legend. PMID- 22828788 TI - Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and back again. AB - The year 1952 marked the first use of subcutaneous immunoglobulin therapy to treat primary immunodeficiency disease. Subsequently, intramuscular and then intravenous administration became the norm in the United States and most of Europe. Intravenous immunoglobulin therapy, however, can be burdensome and often causes systemic side effects. To overcome obstacles presented by the intravenous route of administration, subcutaneous preparations were developed. To further enhance patient satisfaction, adherence, and quality of life, enzyme-enhanced subcutaneous immunoglobulin administration using hyaluronidase, an enzyme spreading agent, was studied. The dose and flow rate of traditional subcutaneous immunoglobulin infusion is limited by the inhibition of bulk fluid flow by the extracellular matrix. Recombinant human hyaluronidase, administered with or immediately prior to infusate, increases the absorption and dispersion of infused fluids and drugs. Results from a phase III clinical trial indicate that subcutaneous immunoglobulin infusion, facilitated by recombinant human hyaluronidase, is well tolerated, and delivers infusion volumes at treatment intervals and rates equivalent to intravenous administration. This review surveys the state of the art of immunoglobulin replacement therapy. PMID- 22828790 TI - Serum antibody to Porphyromonas gingivalis in chronic kidney disease. AB - Potentially significant associations between periodontal disease and chronic kidney disease (CKD) have been reported in recent studies. The aim of this cross sectional study was to investigate the association between serum antibody to the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) and CKD in 215 Japanese individuals, aged 79 yrs. Serum antibody levels to P. gingivalis were measured by enzyme-linked immunosorbent assay. An elevated serum antibody response was defined as the upper quartile and was compared with the bottom three quartiles. Participants were classified as having CKD when their glomerular filtration rate was between 15 and 59 mL/min/1.73 m(2). A multivariable logistic regression model was used to evaluate the association between elevated antibody status and the presence of CKD. Study participants with an elevated serum antibody to P. gingivalis were 2.6 times more likely to have CKD. The adjusted odds ratio of CKD for participants in the highest quartile of serum antibody to P. gingivalis was 2.59 (95% confidence interval, 1.05-6.34) when compared with others in lower quartiles after simultaneous adjustment for other covariates. In conclusion, the present study suggests that elevated serum antibody to P. gingivalis was significantly associated with decreased kidney function in a community-based cohort of elderly Japanese. PMID- 22828789 TI - ASC-dependent RIP2 kinase regulates reduced PGE2 production in chronic periodontitis. AB - Levels of prostaglandin E(2) (PGE(2)) and its processing enzyme, prostaglandin endoperoxide-synthase-2/ cyclooxygenase-2 (PTGS2/COX-2), are elevated in actively progressing periodontal lesions, but suppressed in chronic disease. COX-2 expression is regulated through inflammatory signaling that converges on the mitogen-activated protein kinase (MAPK) pathway. Emerging evidence suggests a role for the inflammatory adaptor protein, ASC/Pycard, in MAPK activation. We postulated that ASC may represent a mediator of the MAPK-mediated regulatory network of PGE(2) production. Using RNAi-mediated gene slicing, we demonstrated that ASC regulates COX-2 expression and PGE(2) production in THP1 monocytic cells following infection with Porphyromonas gingivalis (Pg). Production of PGE(2) did not require the inflammasome adaptor function of ASC, but was dependent on MAPK activation. Furthermore, the MAP kinase kinase kinase CARD domain-containing protein RIPK2 was induced by Pg in an ASC-dependent manner. Reduced ASC and RIPK2 levels were revealed by orthogonal comparison of the expression of the RIPK family in ASC-deficient THP1 cells with that in chronic periodontitis patients. We show that pharmacological inhibition of RIPK2 represses PGE(2) secretion, and RNAi-mediated silencing of RIPK2 leads to diminished MAPK activation and PGE(2) secretion. These findings identify a novel ASC-RIPK2 axis in the generation of PGE(2) that is repressed in patients diagnosed with chronic adult periodontitis. PMID- 22828791 TI - Integrated approach for disease management and growth enhancement of Sesamum indicum L. utilizing Azotobacter chroococcum TRA2 and chemical fertilizer. AB - Azotobacter chroococcum TRA2, an isolate of wheat rhizosphere displayed plant growth promoting attributes including indole acetic acid, HCN, siderophore production, solubilization of inorganic phosphate and fixation of atmospheric nitrogen. In addition, it showed strong antagonistic effect against Macrophomina phaseolina and Fusarium oxysporum. It also caused degradation and digestion of cell wall components, resulting in hyphal perforations, empty cell (halo) formation, shrinking and lysis of fungal mycelia along with significant degeneration of conidia. Fertilizer adaptive variant strain of A. chroococcum TRA2 was studied with Tn5 induced streptomycin resistant transconjugants of wild type tetracycline-resistant TRA2 (designated TRA2(tetra+strep+)) after different durations. The strain was significantly competent in rhizosphere, as its population increased by 15.29 % in rhizosphere of Sesamum indicum. Seed bacterization with the strain TRA2 resulted in significant increase in vegetative growth parameters and yield of sesame over the non-bacterized seeds. However, application of TRA2 with half dose of fertilizers showed sesame yield almost similar to that obtained by full dose treatment. Moreover, the oil yield increased by 24.20 %, while protein yield increased by 35.92 % in treatment receiving half dose of fertilizer along with TRA2 bacterized seeds, as compared to untreated control. PMID- 22828792 TI - A novel xylan degrading beta-D-xylosidase: purification and biochemical characterization. AB - Aspergillus ochraceus, a thermotolerant fungus isolated in Brazil from decomposing materials, produced an extracellular beta-xylosidase that was purified using DEAE-cellulose ion exchange chromatography, Sephadex G-100 and Biogel P-60 gel filtration. beta-xylosidase is a glycoprotein (39 % carbohydrate content) and has a molecular mass of 137 kDa by SDS-PAGE, with optimal temperature and pH at 70 degrees C and 3.0-5.5, respectively. beta-xylosidase was stable in acidic pH (3.0-6.0) and 70 degrees C for 1 h. The enzyme was activated by 5 mM MnCl2 (28 %) and MgCl2 (20 %) salts. The beta-xylosidase produced by A. ochraceus preferentially hydrolyzed p-nitrophenyl-beta-D xylopyranoside, exhibiting apparent K(m) and V(max) values of 0.66 mM and 39 U (mg protein)-1 respectively, and to a lesser extent p-nitrophenyl-beta-D glucopyranoside. The enzyme was able to hydrolyze xylan from different sources, suggesting a novel beta-D-xylosidase that degrades xylan. HPLC analysis revealed xylans of different compositions which allowed explaining the differences in specificity observed by beta-xylosidase. TLC confirmed the capacity of the enzyme in hydrolyzing xylan and larger xylo-oligosaccharides, as xylopentaose. PMID- 22828793 TI - Bacterial and archaeal phylogenetic diversity associated with swine sludge from an anaerobic treatment lagoon. AB - Over the last decades, the demand for pork products has increased significantly, along with concern about suitable waste management. Anaerobic-lagoon fermentation for swine-sludge stabilization is a good strategy, although little is known about the microbial communities in the lagoons. Here, we employed a cloning- and sequencing-based analysis of the 16S rRNA gene to characterize and quantify the prokaryotic community composition in a swine-waste-sludge anaerobic lagoon (SAL). DNA sequence analysis revealed that the SAL library harbored 15 bacterial phyla: Bacteroidetes, Cloroflexi, Proteobacteria, Firmicutes, Deinococcus-Thermus, Synergystetes, Gemmatimonadetes, Chlorobi, Fibrobacteres, Verrucomicrobia and candidates division OP5, OP8, WWE1, KSB1, WS6. The SAL library was generally dominated by carbohydrate-oxidizing bacteria. The archaeal sequences were related to the Crenarchaeota and Euryarchaeota phyla. Crenarchaeota predominated in the library, demonstrating that it is not restricted to high-temperature environments, being also responsible for ammonium oxidation in the anaerobic lagoon. Euryarchaeota sequences were associated with the hydrogenotrophic methanogens (Methanomicrobiales and Methanobacteriales). Quantitative PCR analysis revealed that the number of bacterial cells was at least three orders of magnitude higher than the number of archaeal cells in the SAL. The identified prokaryotic diversity was ecologically significant, particularly the archaeal community of hydrogenotrophic methanogens, which was responsible for methane production in the anaerobic lagoon. This study provided insight into the archaeal involvement in the overall oxidation of organic matter and the production of methane. Therefore, the treatment of swine waste in the sludge anaerobic lagoon could represent a potential inoculum for the start-up of municipal solid-waste digesters. PMID- 22828794 TI - Exploration and characterization of agriculturally and industrially important haloalkaliphilic bacteria from environmental samples of hypersaline Sambhar lake, India. AB - Screening of bacteria from Sambhar lake, an extreme hypersaline environment of India, led to the isolation of 93 haloalkaliphilic bacteria growing optimally in media with 2-25 % salt and 6-12 pH. Based on 16S rRNA gene sequences, 93 isolates were further categorized into 32 groups, with each group representing a different taxa belonging to 3 phyla (Firmicutes, Proteobacteria and Actinobacteria). Majority of the isolates (53.12 %) showed similarity with phylum Firmicutes which was followed by Proteobacteria (40.63 %) and Actinobacteria (6.25 %). The isolates belonging to 32 representative groups were further evaluated for the production of extracellular enzymes viz. amylase, cellulase, protease and xylanase, plant growth promoting attributes and BIOLOGTM substrate usage. Among all the isolates, xylanase producing isolates were in maximum (68 %) as compared to protease (56 %), cellulase (40 %), and amylase (37 %) producing strains. Similarly, among plant growth promoting activities, ammonia producing isolates were highest (56 %) when compared to those producing ACC deaminase (53 %), IAA (50 %), hydrogen cyanide (28 %), siderophore (21 %) and solubilizing P (34 %). Isolates showing enzymatic and PGP activities could be further utilized for promoting plant growth in saline affected area. PMID- 22828795 TI - Long-term changes in neointimal hyperplasia following implantation of bare metal stents assessed by integrated backscatter intravascular ultrasound. AB - In-stent restenosis (ISR) is a common phenomenon with bare metal stents (BMSs) in the early stage after implantation. However, ISR occurs at a lower rate with long time after BMS implantation. We assessed changes over time in neointimal hyperplasia following BMS implantation using integrated backscatter intravascular ultrasound (IB-IUVS). Thirty-six patients who received target lesion revascularization (TLR) to treat ISR were classified according to the duration of the interval between stent implantation and TLR: the early group (within first year n = 25) and the VL group (very late ISR >=5 years, n = 11). IB-IUVS was used to evaluate within-stent sites from the proximal to the distal edge of the stent. IB-IVUS color maps were then constructed by tracing the stent struts and vessel lumen. Neointimal tissue was classified as high-IB (IB <-29 dB; a representative cord of calcification), middle-IB (-49 dB <= IB < -29 dB; fibrosis), or low-IB ( 49 dB <= IB; lipid pool). We compared percent (%) volume, average %area of cross sectional area (CSA), and %area of minimum CSA of each component between the groups. There were no significant differences in %volume, average %area of CSA, or %area of minimum CSA for the high-IB component between groups. The %low-IB components were 20.0 +/- 8.8 % for volume, 20.1 +/- 8.9 % for mean CSA, and 17.6 +/- 8.5 % for minimum CSA in the early group. On the other hand, in the VL group, the %low-IB components were significantly increased to 31.8 +/- 7.9 % for volume (p < 0.01 vs. the early group), 31.2 +/- 7.6 % for mean CSA (p < 0.01 vs. the early group), and 33.1 +/- 12.3 % for minimum CSA (p < 0.01 vs. the early group). By contrast, the %middle-IB component showed a reduction in extended time, with %volume of the middle-IB decreasing from 78.3 +/- 8.1 to 66.4 +/- 7.1 %, average mean %area of CSA from 78.2 +/- 8.2 to 66.9 +/- 6.9 %, and % area of minimum CSA from 80.7 +/- 7.9 to 65.5 +/- 11.4 % (p < 0.01;. the early vs. the VL group). Our results suggest that in-stent neointimal tissues developing over time consist of an increased low-IB component and a decreased middle-IB component and may contribute an increased of lipidemic component and a decreased of fibrotic component. PMID- 22828797 TI - Left ventricular aneurysm repair without ventriculotomy. AB - We describe a simple technique for left ventricular aneurysm without ventriculotomy. After confirming there is no thrombus in the left ventricular aneurysm, the aneurysm is pushed into the left ventricle and fixed with horizontal mattress sutures and running vertical sutures. This technique has quite low risk of bleeding. PMID- 22828796 TI - Time to revisit role of transcatheter balloon aortic valvuloplasty: a bridge therapy to subsequent treatment case report. AB - Recently there has been a noticeable resurgence in the usage of percutaneous balloon aortic valvuloplasty (BAV) by the development of less invasive endovascular therapies including transcatheter aortic valve implantation (TAVI). We performed BAV in a 91-year-old man with end-stage severe symptomatic aortic stenosis (AS) and an impending abdominal aortic aneurysm (AAA) rupture who had been refused surgical treatment because of the comorbidities with stage V chronic kidney disease (CKD) and severe left ventricular dysfunction. Improvement in hemodynamics and kidney function was observed after BAV. Subsequently, we performed endovascular aneurysm repair (EVAR) successfully for AAA using iodinated contrast. No deterioration of kidney function was confirmed after the procedure. The patient was discharged without any adverse events. At present, the possibilities of TAVI or surgical aortic valve replacement (s-AVR) are under consideration as the definitive therapy for the upcoming aortic valve restenosis. In conclusion, this inoperable patient with multiple comorbidities was successfully treated, at lower risk, by catheter-based two-stage therapy. PMID- 22828798 TI - A role for kalirin in the response of rat medium spiny neurons to cocaine. AB - Kalirin-7 (Kal7), the major kalirin isoform in adult brain, plays a key role in the formation of dendritic spines in hippocampal/cortical neurons. Its role in the GABAergic medium spiny neurons (MSNs) of the nucleus accumbens (NAc) and striatum, the areas known to play a key role in the common reward pathway, is not as well understood. Although Kal7 expression in mouse NAc increased in response to cocaine, MSN dendritic spine density did not differ from that for the wild type in Kal7-null mice. Unlike wild-type mice, Kal7-null mice did not respond to cocaine with an increase in MSN dendritic spine density. To explore further the role of Kal7 in cocaine-induced alterations in MSN morphology, we turned to the rat. Based on immunostaining, both Kal7 and Kal12 are expressed at moderate levels in the MSNs of the NAc and striatum. Expression of Kal7 and Kal12 in MSNs of both areas increases after repeated cocaine treatments. Overexpression of Kal7 in cultured MSN neurons increases dendritic spine density, as observed in rats after long-term cocaine administration. Reducing endogenous expression of all major kalirin isoforms in cultured MSN neurons causes a decrease in total dendritic length and dendritic spine density. These data suggest that kalirin is essential for maintaining spine density in NAc MSNs under normal conditions and that Kal7 is an obligatory intermediate in the response of MSNs to repeated exposure to cocaine. PMID- 22828799 TI - Intrinsically low open probability of alpha7 nicotinic acetylcholine receptors can be overcome by positive allosteric modulation and serum factors leading to the generation of excitotoxic currents at physiological temperatures. AB - alpha7 nicotinic acetylcholine receptors (nAChRs) have been a puzzle since their discovery in brain and non-neuronal tissues. Maximal transient probability of an alpha7 nAChR being open with rapid agonist applications is only 0.002. The concentration dependence of alpha7 responses measured from transfected cells and Xenopus laevis oocytes shows the same disparity in potency estimations for peak currents and net charge, despite being studied at 1000-fold different time scales. In both cases the EC50 was approximately 10-fold lower for net charge than for peak currents. The equivalence of the data obtained at such disparate time scales indicates that desensitization of alpha7 is nearly instantaneous. At high levels of agonist occupancy, the receptor is preferentially converted to a ligand-bound nonconducting state, which can be destabilized by the positive allosteric modulator N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl) urea (PNU-120596). Such currents can be sufficiently large to be cytotoxic to the alpha7-expressing cells. Both the potentiating effect of PNU-120596 and the associated cytotoxicity have a high temperature dependence that can be compensated for by serum factors. Therefore, despite reduced potentiation at body temperatures, use of type II positive allosteric modulators may put cells that naturally express high levels of alpha7 nAChRs, such as neurons in the hippocampus and hypothalamus, at risk. With a low intrinsic open probability and high propensity toward the induction of nonconducting ligand-bound states, it is likely that the well documented regulation of signal transduction pathways by alpha7 nAChRs in cells such as those that regulate inflammation may be independent of ion channel activation and associated with the nonconducting conformational states. PMID- 22828800 TI - Activation of trimeric P2X2 receptors by fewer than three ATP molecules. AB - P2X receptors are trimeric membrane proteins. When they bind extracellular ATP, a conformational change occurs that opens a transmembrane ion channel. The ATP binding pocket is formed in a cleft between two subunits, and a critical amino acid residue for ATP contact is Lys69 (P2X2 numbering). In the present work, we sought to determine whether the binding of fewer than three ATP molecules could open the ion channel. We expressed eight concatenated cDNAs in human embryonic kidney cells, which encoded three serially joined, epitope-tagged, subunits with either Lys or Ala at position 69 (denoted as KKK, KKA, KAK, AKK, KAA, AKA, AAK, and AAA). Western blotting of surface-biotinylated proteins indicated that breakdown of concatemers to individual subunits was minimal. Recording of membrane currents in response to ATP (whole cell and excised outside-out patch) showed that all formed functional channels except AAK, AKA, and AAA. There was no difference in the kinetics of activation and deactivation among KKK, KKA, KAK, and AKK channels, and amplitude of the unitary conductances was in all cases not different from that found after expression of a single wild-type subunit. Currents through KKA and KAK receptors were larger than those observed for AKK receptors. The results indicate that trimeric P2X receptors containing only two intact binding sites can be readily activated by ATP. PMID- 22828801 TI - Casting a wider net: whole-cell assays to capture varied and biased signaling. AB - The observation of complex receptor behaviors has shown how ligands can have multiple efficacies and can also differentially stimulate certain cellular signaling pathways over others (i.e., biased signaling). Conventional pharmacological assays (usually proximal to the receptor) will detect ligands that produce the signal defined by the assay (i.e., Ca2+, cAMP, and others) but otherwise may miss biased ligands that produce little activation of pathways not measured by the assay. In theory, this is less of a hazard for generic whole-cell assays, which may be sensitive to multiple signaling inputs. Whole-cell assays have the advantage of detecting effects induced by a variety of receptor interactions with cytosolic proteins, including those that may be previously unknown. These ideas are discussed within the context of the high-throughput flow cytometry measurement of receptor internalization described by Wu et al. in the current issue of the journal. The internalization of receptors can be a useful therapeutic modality and the article by Wu et al. illustrates how this new assay, targeted to downstream cellular effects, can uncover unique ligand efficacies linked to receptor internalization. PMID- 22828804 TI - Computer-based gait analysis of dogs: evaluation of kinetic and kinematic parameters after cemented and cementless total hip replacement. AB - To date it is unclear whether cementless total hip replacement (THR) in dogs is of clinical advantage in comparison to cemented THR with regard to lameness improvement. Thus the aim of this study was to compare objectively the development of the gait pattern after cemented and cementless THR in dogs. For this purpose, 18 adult dogs with hip dysplasia underwent computer-based gait analysis on an instrumented treadmill prior to unilateral THR and then again ten days, four weeks and four months after surgery. Analysed kinetic parameters were symmetry indices (SI) of vertical ground reaction forces (GRF), which included peak vertical forces (PFz), mean vertical forces (MFz), vertical impulse (IFz), and vertical ground reaction forces of the arthroplasty limbs only. Analysed kinematic parameters were range-of-motion and the flexion and extension angles of hip, stifle and hock joints. The symmetry indice for PVF, MFz and IFz decreased to a value less than six in both THR groups four months after surgery, which is defined as not lame. Improvement in lameness of the arthroplasty limbs during the examination period of four months was not significantly different between the cemented and cementless groups. The results suggest that within a short-term observation period of four months after surgery, neither cementless nor cemented THR have a greater advantage with regard to lameness improvement. Additional studies with larger pools of subjects and longer time periods for follow-up examinations are necessary to verify these findings. PMID- 22828803 TI - A mass spectrometry-based immunosensor for bacteria using antibody-conjugated gold nanoparticles. AB - We have developed a simple mass spectrometry-based immunosensor using antibody (Ab)-modified gold nanoparticles (Ab-Au NPs) for the rapid quantitation of bacteria via the analysis of Au clusters under pulsed laser irradiation. PMID- 22828802 TI - Sustained activation of N-methyl-D-aspartate receptors in podoctyes leads to oxidative stress, mobilization of transient receptor potential canonical 6 channels, nuclear factor of activated T cells activation, and apoptotic cell death. AB - Atypical N-methyl-D-aspartate (NMDA) receptors are expressed in podocytes. Sustained (>=24 h) application of 50 to100 MUM NMDA to immortalized mouse podocytes evoked a marked increase in the production of reactive oxygen species(ROS) such as H2O2. This effect of NMDA was associated with increased cell surface expression of p47(phox), a cytosolic regulatory subunit of the NADPH oxidase NOX2. NMDA-evoked generation of ROS drove an increase in steady-state surface expression of transient receptor potential canonical (TRPC) 6 channels, which was blocked by the NMDA antagonist dizocilpine(MK-801) and by a membrane permeable scavenger of ROS. The effect of NMDA on TRPC6 was observed using cell surface biotinylation assays and also with whole-cell recordings made under conditions designed to facilitate detection of current through TRPC6. NMDA mobilization of TRPC6 channels was blocked by concurrent treatment with the NMDA antagonist MK-801 and by a membrane-permeable scavenger ofROS. Mobilization of TRPC6 was also evoked by L-homocysteic acid. NMDA treatment also increased nuclear localization of endogenous nuclear factor of activated T cells, which could be blocked by MK-801, by scavenging ROS, by the calcineurin inhibitor cyclosporine, and by the TRPC channel inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4 methoxyphenyl)propoxy]ethyl]imidazole (SKF-96365). NMDA treatment also evoked robust activation of Rho but not Rac,consistent with previous studies of downstream effectors of TRPC6 activation. Exposing cells to NMDA for 24 h reduced total and cell surface expression of the podocyte markers nephrin and podocin, but there was no loss of cells. With longer NMDA exposure (72 h), we observed loss of cells associated with nuclear fragmentation and increased expression of caspase-3, caspase-6, and Bax, suggesting an apoptotic process. PMID- 22828805 TI - Risk association between the NF-kappaB1 -94ins/delATTG promoter polymorphism and inflammatory bowel diseases: a meta-analysis. AB - BACKGROUND: Extensive investigation of the NF-kappaB1 -94ins/delATTG promoter polymorphism for risk association with ulcerative colitis (UC) and Crohn's disease (CD) risk has yielded conflicting results. AIMS: The objective of this meta-analysis was to evaluate the risk association between the NF-kappaB1 94ins/delATTG promoter polymorphism and UC and CD. METHODS: All eligible case control studies of the association of NF-kappaB1 -94ins/delATTG promoter polymorphism with UC and CD were identified in the Pubmed and Embase databases. From these data, odds ratios (OR) with 95 % confidence intervals (CI) were calculated. Meta-analysis was performed for alleles (D vs. W) and genotypes (DD + WD vs. WW, DD vs. WW + WD, DD vs. WW, WD vs. WW) in a fixed/random effects model. RESULTS: Nine case-control studies that included 4,447 cases (2,631 UC and 1,816 CD) and 2,195 controls were identified. Results indicated increased risk association of D allele carriers with UC (D vs. W: OR = 1.08, 95 % CI = 1.01 1.17, P = 0.03; DD vs. WW + WD: OR = 1.16, 95 % CI = 1.01-1.32, P = 0.04 and DD vs. WW: OR = 1.20, 95 % CI = 1.03-1.39, P = 0.02). No risk association was identified with CD. CONCLUSION: This meta-analysis indicated that the NF-kappaB1 94ins/delATTG promoter polymorphism is a risk factor for UC but not CD. PMID- 22828806 TI - Romiplostim in the management of thrombocytopenia in a patient with autoimmune hepatitis. PMID- 22828808 TI - Crossing the boundary between research and health care: P3G policy statement on return of results from population studies. PMID- 22828807 TI - 16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2. AB - Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2 p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11 Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis. PMID- 22828809 TI - Antimicrobial peptide diversity in the skin of the torrent frog, Amolops jingdongensis. AB - Antimicrobial peptide diversity has been found in some amphibians. The diversity of antimicrobial peptides may have resulted from the diversity of microorganisms encountered by amphibians. Peptidomics and genomics analyses were used to study antimicrobial peptide diversity in the skin secretions of the torrent frog, Amolops jingdongensis. Thirty-one antimicrobial peptides belonging to nine groups were identified in the skin secretions of this frog. Among them, there are two novel antimicrobial groups (jingdongin-1 and -2) with unique structural motifs. The other seven groups belong to known antimicrobial peptide families, namely brevinin-1, brevinin-2, odorranain-F, esculentin-2, temporin, amolopin-3, and ranacyclin. Combined with previous reports, more than 13 antimicrobial peptide groups have been identified from the genus Amolops. Most of these antimicrobial peptide groups are also found in amphibians belonging to the genus Rana or Odorrana which suggests a possible evolutionary connection among Amolops, Rana, and Odorrana. Two novel antimicrobial groups (jingdongin-1 and -2) were synthesized and their antimicrobial activities were assayed. Some of them showed strong antimicrobial abilities against microorganisms including Gram-negative and -positive bacteria, and fungi. The extreme diversity of antimicrobial peptides in the Amolops amphibians was demonstrated. In addition, several novel peptide templates were provided for antimicrobial agent design. PMID- 22828810 TI - Principal component analysis of the relationship between the D-amino acid concentrations and the taste of the sake. AB - We performed sensory evaluations on 141 bottles of sake and analyzed the relationship between the D-amino acid concentrations, and the taste of the sake using principal component analysis, which yielded seven principal components (PC1 7) that explained 100 % of the total variance in the data. PC1, which explains 33.6 % of the total variance, correlates most positively with strong taste and most negatively with balanced tastes. PC2, which explains 54.4 % of the total variance, correlates most positively with a sweet taste and most negatively with bitter and sour tastes. Sakes brewed with "Kimoto yeast starter" and "Yamahaimoto" had high scores for PC1 and PC2, and had strong taste in comparison with sakes brewed with "Sokujo-moto". When present at concentrations below 50 MUM, D-Ala did not affect the PC1 score, but all the sakes showed a high PC1 score, when the D-Ala was above 100 MUM. Similar observations were found for the D-Asp and D-Glu concentrations with regard to PC1, and the threshold concentrations of D-Asp and D-Glu that affected the taste were 33.8 and 33.3 MUM, respectively. Certain bacteria present in sake, especially lactic acid bacteria, produce D-Ala, D-Asp and D-Glu during storage, and these D-amino acids increased the PC1 score and produced a strong taste (Nojun). When D- and L-Ala were added to the sakes, the value for the umami taste in the sensory evaluation increased, with the effect of D-Ala being much stronger than that of L-Ala. The addition of 50-5,000 MUM DL-Ala did not effect on the aroma of the sakes at all. PMID- 22828811 TI - Modulation of taurine release in glucose-free media by glutamate receptors in hippocampal slices from developing and adult mice. AB - Taurine has been thought to protect neural cells against cell-damaging conditions to which the hippocampus is particularly vulnerable. We studied now how the release of preloaded [(3)H]taurine is regulated by glutamate receptors in glucose free media in slices prepared from the mouse hippocampus from developing (7 days old) and young adult (3 months old) mice, using a superfusion system. The lack of glucose enhanced taurine release more from slices from developing mice than from slices from adults. At both ages ionotropic glutamate agonists significantly increased the release in a receptor-mediated manner. Of the metabotropic glutamate receptors those belonging to the group III were effective. The release was enhanced in adult mice but attenuated in developing mice. Both effects were blocked by the receptor antagonists. The results show that glutamate receptors affect taurine release in the absence of glucose in which condition taurine should be neuroprotective. PMID- 22828812 TI - The 'normobaric oxygen paradox': does it increase haemoglobin? AB - BACKGROUND: A novel approach to increasing erythropoietin (EPO) using oxygen (O2) (the 'normobaric oxygen paradox') has been reported in healthy volunteers. We investigated whether the EPO increase is sufficient to induce erythropoiesis by comparing two protocols of O2 administration. METHODS: We compared the effect of daily versus alternate days 100% O2, breathed for 30 minutes, on haemoglobin concentrations during a 12-day period. Nine subjects underwent the two protocols six weeks apart. RESULTS: We observed a significant increase in haemoglobin (as a percentage of baseline) in the alternate-days group compared to the daily group and to baseline after four days (105.5 ? 5.7 % vs. 99.6 ? 3.3 % difference from baseline; P < 0.01). At the end of the experimental period, haemoglobin values increased significantly compared to baseline in both groups. There was a significant percentage rise in reticulocyte count in the alternate-days group compared to the daily group (182 ? 94 % vs. 93 ? 34 %; P < 0.001). CONCLUSION: The normobaric oxygen paradox seems effective in increasing haemoglobin in non anaemic, healthy volunteers, providing sufficient time is allowed between O2 applications. The exact time interval is not clearly defined by this study but should probably be at least or greater than two days. Further studies are needed to define more precisely clinical applications in the use of O2 as a pharmaceutical agent. PMID- 22828813 TI - Effect of a single pool dive on pulmonary function in asthmatic and non-asthmatic divers. AB - INTRODUCTION: The aim of this study was to evaluate the effect of a single, shallow, swimming pool scuba dive on pulmonary function in divers with asthma as compared to controls. Opinions concerning the risks of diving with asthma are still contradictory and inconclusive in the diving community. METHODS: Baseline pulmonary function tests (PFTs) were performed on a group of 22 divers with asthma and on a control group of 15 healthy divers. The same PFTs were repeated within 10 minutes after a single pool dive, at 5 metres' depth for 10 minutes. PFTs were measured using a portable Jaeger SpiroProTM device. Student's paired t tests and linear mixed effects model comparisons and interactions within the groups were used in the data analysis. RESULTS: Divers with asthma initially presented significantly lower values of FEV1/FVC%* (P < 0.01), FEF25* (P < 0.01), FEF50* (P < 0.001), FEF75* (P < 0.01) and FEF25-75* (P < 0.001) compared to controls. There were significant reductions in FEV1 (P < 0.01), FEV1/FVC% (P < 0.05), FEF50* (P < 0.01), FEF75* (P < 0.05) and FEF25-75* (P < 0.001) in the asthma group after the dive as compared to the control group. PEF was initially lower, although not significantly, in the asthma group and did not change significantly after the dive in either group (P > 0.05). CONCLUSIONS: A single, shallow, pool scuba dive to 5 metres' depth may impair function of small airways in asthmatic divers. More studies are necessary to estimate the risks when divers with asthma practise scuba diving. PFT results should be analysed after replicated dives in deeper pools and controlled open-water conditions. PMID- 22828814 TI - The effect of environmental pressure changes on the retentive strength of cements for orthodontic bands. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of environmental pressure changes on the retentive strength of orthodontic bands cemented with conventional glass ionomer cement or resin-modified glass ionomer cement. MATERIALS AND METHODS: Stainless steel bands were cemented to 80 extracted first and second molars in two equal groups comprising conventional glass ionomer cement and resin-modified glass ionomer cement. Each group was randomly divided into two sub-groups of 20 samples each, one sub-group to act as a control, and the other to be used experimentally. After seven days of storage, the experimental groups were subjected to simulated dives to 405 kPa [corrected] for 3 minutes, 15 times in a pressure pot, after which the force required to deband was tested using a universal testing machine. The data were statistically analysed using Student's t-tests, significance being assumed at P < 0.001. RESULTS: The retentive strength of bands cemented with conventional glass ionomer in the pressure-cycled group was statistically significantly less than that in the control group. No statistically significant difference in strength was found between the two groups cemented with resin-modified glass ionomer. CONCLUSIONS: This study showed that the retentive strength of bands cemented with conventional glass ionomer is reduced after pressure cycling. We suggest that dentists should consider using resin-modified glass ionomer cement for cementing orthodontic bands for patients who are divers and thus likely to be exposed to raised pressure cycling. PMID- 22828816 TI - Hyperbaric critical care patient data management system. AB - A patient data management system (PDMS) has been used for years in the intensive care unit (ICU) at the Karolinska University Hospital to provide bedside or remote clinical patient documentation and information. Data from monitors, mechanical ventilators and syringe pumps are fed into a central clinical information management system to monitor, display trends and record data of vital parameters, ventilator settings and drugs. In order to continue routine critical care monitoring and recording during hyperbaric oxygen therapy (HBOT), without endangering the safety demands of hyperbaric procedures, we have modified the PDMS system for hyperbaric use. Via an ethernet box placed inside the chamber, data are transmitted to the ClinisoftTM system through the local area network. By standardised risk-analysis procedures, in close cooperation between the hyperbaric and biomedical engineering departments, the chamber producer and the notifying body (Germanischer Lloyd), the ethernet box was modified to receive full safety approval by all parties. The PDMS is now functioning routinely during HBOT for intensive care patients so that data can be seen bedside and followed on line in the ICU. Data are also continuously stored on the clinical information management system for later clinical or research purposes. Work continues to obtain CE approval for hyperbaric use for modern syringe pumps and mechanical ventilators connected to the PDMS system. Improved documentation of ICU care will improve quality of care during HBOT and facilitate research and development in hyperbaric medicine. PMID- 22828815 TI - Hyperbaric oxygen therapy for vaso-occlusive crises in nine patients with sickle cell disease. AB - INTRODUCTION: Vaso-occlusive crisis (VOC) is the most frequent complication of sickle-cell disease and is associated with significant acute bone pain. OBJECTIVE: To evaluate the feasibility and efficacy of hyperbaric oxygen therapy (HBOT) for severe VOC. METHODS: We report our retrospective experience with HBOT in VOC in nine patients and 15 HBOT sessions. RESULTS: All nine patients had received appropriate conventional treatment prior to HBOT. Pain scores using a Visual Analog Scale (0 to 10) determined whether HBOT was effective or not in improving symptoms. While no change in pain score occurred before the HBOT session, pain scores fell significantly from 3.3 prior to HBOT to 1.9 24 hours after HBOT (P = 0.002). While morphine dosage increased before HBOT (median morphine dose 23 mg per day and 35.95 mg per day respectively on Day -2 and Day 1, P = 0.04), the median morphine dose one day after HBOT (Day +1 23 mg per day) tended to be lower than Day -1 (P = 0.08), and decreased to zero 2 days after HBOT (P = 0.004). Two patients had ear pain during compression, requiring rapid interruption of the HBOT session, although neither patient had any sequelae. CONCLUSION: HBOT is feasible in sickle cell disease and appears to be effective in reducing the pain of VOC rapidly. PMID- 22828817 TI - MRI features of spinal cord decompression sickness presenting as a Brown-Sequard syndrome. AB - Decompression sickness often manifests as central nervous system impairment. We report a 49-year-old woman who developed an unusual case of spinal cord decompression sickness presenting as complete Brown-Sequard syndrome. Initial MRI revealed increased signal intensity in the left side of the cervical cord at the level of C2-C3. A second MRI at 10 days post-injury showed signal abnormalities corresponding to an infarction in the posterior spinal artery territory. After two weeks of intensive treatment with various HBOT regimens, the clinical outcome was still poor, but at six months after the injury her neurological condition was greatly improved, with only slight impairment of proprioception on the left when walking remaining. PMID- 22828818 TI - A cost-analysis case study of radiation cystitis treatment including hyperbaric oxygen therapy. AB - AIM: To undertake an economic analysis of the direct costs of treating radiation cystitis from a purchaser perspective, comparing conservative, non-operative and surgical interventions with hyperbaric oxygen treatment (HBOT). METHODS: A male in his 60s with prostatic carcinoma consented to this study. Full details of treatment costs in AUD were obtained (AUD 1.0, approx. EUR 0.6). A detailed patient diary accurately cross-referenced the consultations, investigations, admissions and treatment. Costs were recorded on a spreadsheet, dated and grouped under eight major headings related to treatment. Costs were compared for radiation cystitis treatment pre- and post-HBOT, to calculate savings or losses. RESULTS: The study covered three years (including 2.5 years post successful HBOT). Costs prior to HBOT (139 days) were AUD32,571.42 at an average of AUD231.09 per day, 70% from inpatient fees. Direct HBOT costs were AUD12,014.95 for 38 treatments, AUD316.18 per treatment. Post-HBOT (897 days), healthcare costs were AUD17,113.42 (AUD19.08 per day), with no emergency admissions. HBOT reduced costs of inpatient admissions, consultations, investigations and procedures and provided a projected healthcare saving of AUD187,483.96 over a 2.5 year follow up. CONCLUSIONS: The cost of HBOT compared favourably against other costs, and HBOT may provide major health cost savings in this condition. There are significant hidden costs associated with radiation cystitis, not apparent to health funders, because the reasons for admissions and procedures are not easily captured with current information systems. PMID- 22828819 TI - A case of spinal epidural haematoma during breath-hold diving. AB - Spinal epidural haematoma (SEH) is a rare condition usually the result of bleeding of the epidural venous plexus that might present with acute spinal cord compression. It is often due to traumatic events, but 'spontaneous' cases have been described, usually related to different predisposing conditions, such as coagulopathies. A 47-year-old male presented with severe frontal headache and intense cervical pain which developed during a protracted breath-hold spearfishing session. A cervical spine MRI performed 12 days after symptom onset showed a small epidural blood collection on the left side of the spinal canal, at the C7-T1 level. One week later, blood was no longer present and the asymptomatic patient was discharged. Protracted minor trauma (neck flexion) and repeated Valsalva manoeuvres might have played a role in the genesis of this event. The role of decompression sickness is discussed as well. PMID- 22828820 TI - Cerebral venous air embolism treated with hyperbaric oxygen: a case report. AB - We present a case of cerebral venous gas embolism. Our patient made a complete neurological recovery after hyperbaric oxygen therapy (HBOT). The principles of HBOT, compressing and eliminating air bubbles and decreasing Beta-2 integrin function, thus improving microcirculation, can only be beneficial in a situation where neurological damage is likely. Retrograde cerebral venous gas embolism is a less well recognised variant of gas embolism than the arterial variant. Its existence as a different entity is better recognised in the forensic medicine and radiology literature than in other disciplines. There is evidence in the literature of patients dying from this complication and others seemingly experiencing very little effect. This case report highlights this condition, to encourage others to look out for it and report outcomes, and to serve as a reminder that peripheral lines may be a potential cause of gas embolism, although the portal of air entry in our case remains uncertain. PMID- 22828821 TI - HBO Evidence website. PMID- 22828822 TI - Safety of deep apneic diving. PMID- 22828825 TI - Variability in surgeons' perioperative practices may influence the incidence of low-output failure after coronary artery bypass grafting surgery. AB - BACKGROUND: Postoperative low-output failure (LOF) is an important contributor to morbidity and mortality after coronary artery bypass grafting surgery. We sought to understand which pre- and intra-operative factors contribute to postoperative LOF and to what degree the surgeon may influence rates of LOF. METHODS AND RESULTS: We identified 11 838 patients undergoing nonemergent, isolated coronary artery bypass grafting surgery using cardiopulmonary bypass by 32 surgeons at 8 centers in northern New England from 2001 to 2009. Our cohort included patients with preoperative ejection fractions >40%. Patients with preoperative intraaortic balloon pumps were excluded. LOF was defined as the need for >=2 inotropes at 48 hours, an intra- or post-operative intraaortic balloon pumps, or return to cardiopulmonary bypass (for hemodynamic reasons). Case volume varied across the 32 surgeons (limits, 80-766; median, 344). The overall rate of LOF was 4.3% (return to cardiopulmonary bypass, 2.6%; intraaortic balloon pumps, 1.0%; inotrope usage, 0.8%; combination, 1.0%). The predicted risk of LOF did not differ across surgeons, P=0.79, and the observed rates varied from 1.1% to 10.2%, P<0.001. Patients operated by low-rate surgeons had shorter clamp and bypass times, antegrade cardioplegia, longer maximum intervals between cardioplegia doses, lower cardioplegia volume per anastomosis or minute of ischemic time, and less hot-shot use. Patients operated on by higher LOF surgeons had higher rates of postoperative acute kidney injury. CONCLUSIONS: Rates of LOF significantly varied across surgeons and could not be explained solely by patient case mix, suggesting that variability in perioperative practices influences risk of LOF. PMID- 22828826 TI - Association of obstructive sleep apnea with risk of serious cardiovascular events: a systematic review and meta-analysis. AB - BACKGROUND: The relationship between obstructive sleep apnea (OSA) and cardiovascular events remains unclear. We conducted a systematic review to determine the incident risk of cardiovascular events among patients with OSA. METHODS AND RESULTS: We searched MEDLINE and EMBASE in January 2011 for prospective studies that followed up patients with OSA for incident ischemic heart disease, stroke, and cardiovascular mortality. Outcomes data were pooled using random effects meta-analysis and heterogeneity assessed with the I(2) statistic. Regression analysis was performed to evaluate the effects of different gradations of OSA severity based on apnea-hypopnea index. We identified 9 relevant studies from 1731 citations. OSA was associated with incident stroke in a meta-analysis of 5 studies (8435 participants), odds ratio (OR) 2.24; 95% confidence interval (CI), 1.57-3.19; I(2)=7%. A significant association was seen in studies that were predominantly on men; OR, 2.87; 95% CI, 1.91-4.31, whereas data on women were sparse. In the overall analysis of 6 studies (8785 participants), OSA was nonsignificantly associated with ischemic heart disease (OR, 1.56; 95% CI, 0.83-2.91), with significant findings in the 5 studies that recruited mainly men (OR, 1.92; 95% CI, 1.06-3.48). Substantial heterogeneity was noted (I(2)=74%). OSA was linked to cardiovascular death in 2 studies involving 2446 participants (OR, 2.09; 95% CI, 1.20-3.65, I(2)=0%). Regression analysis showed greater likelihood of stroke or cardiovascular events with increasing apnea-hypopnea index values. CONCLUSIONS: OSA appears to be associated with stroke, but the relationship with ischemic heart disease and cardiovascular mortality needs further research. PMID- 22828824 TI - Transplantation of the pancreas. AB - Pancreas transplantation consistently induces insulin-independence in beta-cell penic diabetic patients, but at the cost of major surgery and life-long immunosuppression. One year after grafting, patient survival rate now exceeds 95 % across recipient categories, while insulin independence is maintained in some 85 % of simultaneous pancreas and kidney recipients and in nearly 80 % of solitary pancreas transplant recipients. The half-life of the pancreas graft currently averages 16.7 years, being the longest among extrarenal grafts, and substantially matching the one of renal grafts from deceased donors. The difference between expected (100 %) and actual insulin-independence rate is mostly explained by technical failure in the postoperative phase, and rejection in the long-term period. Death with a functioning graft remains a further major issue, especially in uremic patients who have undergone prolonged periods of dialysis. Refinements in graft preservation, surgical techniques, immunosuppression, and prophylactic treatments are expected to further improve the results of pancreas transplantation. PMID- 22828827 TI - Demographics, trends, and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011. AB - BACKGROUND: There is a lack of clear diagnostic and management guidelines for acute myocarditis in the pediatric population. We used a multi-institutional database to characterize demographics, practice variability, and outcomes in this population. METHODS AND RESULTS: Patients with acute myocarditis (n=514) were identified from April 2006 to March 2011 using the Pediatric Health Information System database, and regional variations in management and outcomes were analyzed. Ninety-seven patients (18.9%) received extracorporeal membrane oxygenation, 22 (4.3%) received ventricular assist device, 21 (4.1%) received heart transplantation, and 37 (7.2%) died. Of the 104 patients who received extracorporeal membrane oxygenation or ventricular assist device, 17 (16.3%) had heart transplantation, 25 (24%) died, and 62 (59.6%) showed recovery of myocardial function. There was a decrease in the use of endomyocardial biopsy (P=0.03) and an increase in the use of magnetic resonance imaging (P<0.01) over the study period. Although the use of medications and procedures varied between different regions, the occurrence of death or heart transplantation showed no significant regional associations. The use of extracorporeal membrane oxygenation (odds ratio, 5.8; 95% confidence interval, 2.9-11.4; P<0.01), ventricular assist device (odds ratio, 8.2; 95% confidence interval, 2.7-24.9; P<0.01), and vasoactive medications (odds ratio, 5.7; 95% confidence interval, 1.2-26.1; P=0.03) was independently associated with death/transplantation. CONCLUSIONS: There is significant temporal and regional variation in the diagnostic modalities and management used for pediatric myocarditis, which continues to have high morbidity and mortality. Extracorporeal membrane oxygenation, ventricular assist device, and vasoactive medications are independently associated with increased mortality/transplantation. PMID- 22828828 TI - EGFR and HER2-Akt-mTOR signaling pathways are activated in subgroups of salivary gland carcinomas. AB - Salivary gland carcinomas encompass a wide spectrum of histological entities. To identify candidate therapeutic targets and innovative treatment options for these carcinomas, we examined epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), HER2, and phosphorylated forms of Akt (p-Akt) and mammalian target of rapamycin (p-mTOR) in 47 salivary gland tumors using immunohistochemistry. EGFR overexpression was found in 51 % of the tumors (24/47); in particular, EGFR overexpression occurred in mucoepidermoid (seven out of seven) and salivary duct carcinomas (9/12). Although EGFR amplification was not detected by fluorescence in situ hybridization analysis, increased copy number due to polysomy of chromosome 7, which houses EGFR, was observed in 4 of the 24 tumors with EGFR overexpression; this polysomy occurred most frequently in salivary duct carcinomas (three out of nine). HER2 overexpression was observed in 21 % (10/47) of all tumors; in these 10 tumors, HER2 gene amplification was found in seven cases. p-Akt was found in 51 % (24/47) of all tumors, most frequently in mucoepidermoid carcinomas (six out of seven). p-mTOR was found in 57 % of the latter (four out of seven). Consequently, different signaling cascades were found activated: (1) an EGFR/HER2(-Akt)-mTOR-dependent axis, with gene gains of HER2 and/or EGFR, activated in salivary duct carcinoma and carcinoma ex pleomorphic adenoma; (2) an EGFR(-Akt)-mTOR-dependent pathway activated in mucoepidermoid carcinoma or acinic cell carcinoma, without HER2 or EGFR gene alterations; and (3) an Akt-dependent pathway without EGFR/HER2 activation in other types. These findings indicate that phosphoprotein mapping of components in the EGFR/HER2-Akt mTOR pathways may be a useful guide to select appropriate targeting regimens. PMID- 22828829 TI - Application of X-Y separable 2-D array beamforming for increased frame rate and energy efficiency in handheld devices. AB - Two-dimensional arrays present significant beamforming computational challenges because of their high channel count and data rate. These challenges are even more stringent when incorporating a 2-D transducer array into a battery-powered hand held device, placing significant demands on power efficiency. Previous work in sonar and ultrasound indicates that 2-D array beamforming can be decomposed into two separable line-array beamforming operations. This has been used in conjunction with frequency-domain phase-based focusing to achieve fast volume imaging. In this paper, we analyze the imaging and computational performance of approximate near-field separable beamforming for high-quality delay-and-sum (DAS) beamforming and for a low-cost, phase-rotation-only beamforming method known as direct-sampled in-phase quadrature (DSIQ) beamforming. We show that when high quality time-delay interpolation is used, separable DAS focusing introduces no noticeable imaging degradation under practical conditions. Similar results for DSIQ focusing are observed. In addition, a slight modification to the DSIQ focusing method greatly increases imaging contrast, making it comparable to that of DAS, despite having a wider main lobe and higher side lobes resulting from the limitations of phase-only time-delay interpolation. Compared with non-separable 2 D imaging, up to a 20-fold increase in frame rate is possible with the separable method. When implemented on a smart-phone-oriented processor to focus data from a 60 x 60 channel array using a 40 x 40 aperture, the frame rate per C-mode volume slice increases from 16 to 255 Hz for DAS, and from 11 to 193 Hz for DSIQ. Energy usage per frame is similarly reduced from 75 to 4.8 mJ/ frame for DAS, and from 107 to 6.3 mJ/frame for DSIQ. We also show that the separable method outperforms 2-D FFT-based focusing by a factor of 1.64 at these data sizes. This data indicates that with the optimal design choices, separable 2-D beamforming can significantly improve frame rate and battery life for hand-held devices with 2-D arrays. PMID- 22828830 TI - FPGA-based reconfigurable processor for ultrafast interlaced ultrasound and photoacoustic imaging. AB - In this paper, we report, to the best of our knowledge, a unique field programmable gate array (FPGA)-based reconfigurable processor for real-time interlaced co-registered ultrasound and photoacoustic imaging and its application in imaging tumor dynamic response. The FPGA is used to control, acquire, store, delay-and-sum, and transfer the data for real-time co-registered imaging. The FPGA controls the ultrasound transmission and ultrasound and photoacoustic data acquisition process of a customized 16-channel module that contains all of the necessary analog and digital circuits. The 16-channel module is one of multiple modules plugged into a motherboard; their beamformed outputs are made available for a digital signal processor (DSP) to access using an external memory interface (EMIF). The FPGA performs a key role through ultrafast reconfiguration and adaptation of its structure to allow real-time switching between the two imaging modes, including transmission control, laser synchronization, internal memory structure, beamforming, and EMIF structure and memory size. It performs another role by parallel accessing of internal memories and multi-thread processing to reduce the transfer of data and the processing load on the DSP. Furthermore, because the laser will be pulsing even during ultrasound pulse-echo acquisition, the FPGA ensures that the laser pulses are far enough from the pulse-echo acquisitions by appropriate time-division multiplexing (TDM). A co-registered ultrasound and photoacoustic imaging system consisting of four FPGA modules (64 channels) is constructed, and its performance is demonstrated using phantom targets and in vivo mouse tumor models. PMID- 22828831 TI - System-on-chip design for ultrasonic target detection using split-spectrum processing and neural networks. AB - Ultrasonic detection and characterization of targets concealed by scattering noise is remarkably challenging. In this study, a neural network (NN) coupled to split-spectrum processing (SSP) is examined for target echo visibility enhancement using experimental measurements with input signal-to-noise ratio around 0 dB. The SSP-NN target detection system is trainable and consequently is capable of improving the target-to-clutter ratio by an average of 40 dB. The proposed system is exceptionally robust and outperforms the conventional techniques such as minimum, median, average, geometric mean, and polarity threshold detectors. For realtime imaging applications, a field-programmable gate array (FPGA)-based hardware platform is designed for system-onchip (SoC) realization of the SSP-NN target detection system. This platform is a hardware/software co-design system using parallel and pipelined multiplications and additions for highspeed operation and high computational throughput. PMID- 22828832 TI - A novel biomimetic sonarhead using beamforming technology to mimic bat echolocation. AB - A novel biomimetic sonarhead has been developed to allow researchers of bat echolocation behavior and biomimetic sonar to perform experiments with a system similar to the bat?s sensory system. The bat's echolocation-related transfer function (ERTF) is implemented using an array of receivers to implement the head related transfer function (HRTF), and an array of emitters mounted on a cylindrical manifold to implement the emission pattern of the bat. The complete system is controlled by a field-programmable gate array (FPGA) based embedded system connected through a USB interface. PMID- 22828833 TI - A reconfigurable and programmable FPGA-based system for nonstandard ultrasound methods. AB - The availability of programmable and reconfigurable ultrasound (US) research platforms may have a considerable impact on the advancement of ultrasound systems technology; indeed, they allow novel transmission strategies or challenging processing methods to be tested and experimentally refined. In this paper, the ULtrasound Advanced Open Platform (ULA-OP), recently developed in our University laboratory, is shown to be a flexible tool that can be easily adapted to a wide range of applications. Five nonstandard working modalities are illustrated. Vector Doppler and quasi-static elastography applications emphasize the real-time potential and versatility of the system. Flow-mediated dilation, pulse compression, and high-frame-rate imaging highlight the flexibility of data access at different points in the reception chain. For each modality, the role played by the onboard programmable devices is discussed. Experimental results are reported, indicating the relative performance of the system for each application. PMID- 22828834 TI - A single FPGA-based portable ultrasound imaging system for point-of-care applications. AB - We present a cost-effective portable ultrasound system based on a single field programmable gate array (FPGA) for point-of-care applications. In the portable ultrasound system developed, all the ultrasound signal and image processing modules, including an effective 32-channel receive beamformer with pseudo-dynamic focusing, are embedded in an FPGA chip. For overall system control, a mobile processor running Linux at 667 MHz is used. The scan-converted ultrasound image data from the FPGA are directly transferred to the system controller via external direct memory access without a video processing unit. The potable ultrasound system developed can provide real-time B-mode imaging with a maximum frame rate of 30, and it has a battery life of approximately 1.5 h. These results indicate that the single FPGA-based portable ultrasound system developed is able to meet the processing requirements in medical ultrasound imaging while providing improved flexibility for adapting to emerging POC applications. PMID- 22828835 TI - Embedded Doppler system for industrial in-line rheometry. AB - Rheological fluid behavior characterization is crucial for the industrial production of cosmetics, food, pharmaceutics, adhesive, sealants, etc. For example, the measurement of specific rheological features at every step of the production chain is critical for product quality control. Such measurements are often limited to laboratory tests on product specimens because of technical difficulties. In this work, we present an embedded system suitable for in-line rheometric evaluation of highly filled polyurethane-based adhesives. This system includes an ultrasound front-end and a digital signal processing section integrated in a low-cost field-programmable gate array. The system measures the real-time velocity profile developed in the pipe by the fluid, employing a Doppler multigate technique. The high-resolution velocity profile, combined with a pressure drop measurement, allows an accurate evaluation of the flow consistency index, K, and the flow behavior index, n, of the interrogated fluid. PMID- 22828836 TI - An ultrasonic imaging system based on a new SAFT approach and a GPU beamformer. AB - The design of newer ultrasonic imaging systems attempts to obtain low-cost, small sized devices with reduced power consumption that are capable of reaching high frame rates with high image quality. In this regard, synthetic aperture techniques have been very useful. They reduce hardware requirements and accelerate information capture. However, the beamforming process is still very slow, limiting the overall speed of the system. Recently, general-purpose computing on graphics processing unit techniques have been proposed as a way to accelerate image composition. They provide excellent computing power with which a very large volume of data can easily and quickly be processed. This paper describes a new system architecture that merges both principles. Thus, using a minimum-redundancy synthetic aperture technique to acquire the signals (2R-SAFT), and a graphics processing unit as a beamformer, we have developed a new scanner with full dynamic focusing, both on emission and reception, that attains real time imaging with very few resources. PMID- 22828837 TI - MPEG compression of ultrasound RF channel data for a real-time software-based imaging system. AB - Using software for beamforming in ultrasound systems provides high flexibility, and the large number of computations required in a software-based system can be performed in real time on a PC. However, the very large data transfer rate required from the ultrasound front-end to the PC host for real-time operation is a bottleneck which cannot be overcome without appropriate compression. Previous studies have examined JPEG compression of ultrasound RF channel data, but the schemes do not exploit temporal redundancy between adjacent frames. This study utilized MPEG technology to process the ultrasound RF data to increase the compression efficiency. Our results indicate that MPEG compression generally provides a better compression ratio than does JPEG compression. As an example, the compression ratio of MPEG compression in an 8-bit channel A/D data under 5 MUm interframe displacement is smaller than 0.13, thus allowing real-time data transfer requirements to be met. Moreover, the compression efficiency for motions in different directions is shown to be highly dependent on the frame-to-frame correlation. PMID- 22828838 TI - Vibro-acoustography beam formation with reconfigurable arrays. AB - In this work, we present a numerical study of the use of reconfigurable arrays (RCA) for vibro-acoustography (VA) beam formation. A parametric study of the aperture selection, number of channels, number of elements, focal distance, and steering parameters is presented to show the feasibility and evaluate the performance of VA imaging based on RCA. The transducer aperture was based on two concentric arrays driven by two continuous-wave or toneburst signals at slightly different frequencies. The mathematical model considers a homogeneous, isotropic, inviscid medium. The pointspread function of the system is calculated based on angular spectrum methods using the Fresnel approximation for rectangular sources. Simulations considering arrays with 50 x 50 to 200 x 200 elements with number of channels varying in the range of 32 to 128 are evaluated to identify the best configuration for VA. Advantages of two-dimensional and RCA arrays and aspects related to clinical importance of the RCA implementation in VA, such as spatial resolution, image frame rate, and commercial machine implementation, are discussed. It is concluded that RCA transducers can produce spatial resolution similar to confocal transducers and steering is possible in the elevational and azimuthal planes. Optimal settings for number of elements, number of channels, maximum steering, and focal distance are suggested for VA clinical applications. Furthermore, an optimization for beam steering based on the channel assignment is proposed for balancing the contribution of the two waves in the steered focus. PMID- 22828839 TI - An FPGA-based open platform for ultrasound biomicroscopy. AB - Ultrasound biomicroscopy (UBM) has been extensively applied to preclinical studies in small animal models. Individual animal study is unique and requires different utilization of the UBM system to accommodate different transducer characteristics, data acquisition strategies, signal processing, and image reconstruction methods. There is a demand for a flexible and open UBM platform to allow users to customize the system for various studies and have full access to experimental data. This paper presents the development of an open UBM platform (center frequency 20 to 80 MHz) for various preclinical studies. The platform design was based on a field-programmable gate array (FPGA) embedded in a printed circuit board to achieve B-mode imaging and directional pulsed-wave Doppler. Instead of hardware circuitry, most functions of the platform, such as filtering, envelope detection, and scan conversion, were achieved by FPGA programs; thus, the system architecture could be easily modified for specific applications. In addition, a novel digital quadrature demodulation algorithm was implemented for fast and accurate Doppler profiling. Finally, test results showed that the platform could offer a minimum detectable signal of 25 MUV, allowing a 51 dB dynamic range at 47 dB gain, and real-time imaging at more than 500 frames/s. Phantom and in vivo imaging experiments were conducted and the results demonstrated good system performance. PMID- 22828840 TI - Probabilistic inverse problem to characterize tissue-equivalent material mechanical properties. AB - The understanding of internal processes that affect the changes of consistency of soft tissue is a challenging problem. An ultrasound-monitoring Petri dish has been designed to monitor the evolution of relevant mechanical parameters during engineered tissue formation processes in real time. A better understanding of the measured ultrasonic signals required the use of numerical models of the ultrasound-tissue interactions. The extraction of relevant data and its evolution with sufficient sensitivity and accuracy is addressed by applying well-known signal processing techniques to both the experimental and numerically predicted measurements. In addition, a stochastic model-class selection formulation is used to rank which of the proposed interaction models are more plausible. The sensitivity of the system is verified by monitoring a gelation process. PMID- 22828841 TI - Conformal ultrasound imaging system for anatomical breast inspection. AB - Ultrasound tomography has considerable potential as a means of breast cancer detection because it reduces the operator-dependency observed in echography. A half-ring transducer array was designed based on breast anatomy, to obtain reflectivity images of the ductolobular structures using tomographic reconstruction procedures. The 3-MHz transducer array comprises 1024 elements set in a 190-degree circular arc with a radius of 100 mm. The front-end electronics incorporate 32 independent parallel transmit/receive channels and a 32-to-1024 multiplexer unit. The transmit and receive circuitries have a variable sampling frequency of up to 80 MHz and 12-bit precision. Arbitrary waveforms are synthesized to improve the signal-to-noise ratio and to increase the spatial resolution when working with low-contrast objects. The setup was calibrated with academic objects and a needle hydrophone to develop the data correction tools and specify the properties of the system. The backscattering field was recorded using a restricted aperture, and tomographic acquisitions were performed with a pair of 0.08-mm-diameter steel wires, a low-contrast 2-D breast phantom, and a breast shaped phantom containing inclusions. Data were processed with dedicated correction tools and a pulse compression technique. Objects were reconstructed using the elliptical back-projection algorithm. PMID- 22828842 TI - Ultrasonic scanner for in vivo measurement of cancellous bone properties from backscattered data. AB - A dedicated ultrasonic scanner for acquiring RF echoes backscattered from the trabecular bone was developed. The design of device is based on the goal of minimizing of custom electronics and computations executed solely on the main computer processor and the graphics card. The electronic encoder-digitizer module executing all of the transmission and reception functions is based on a single low-cost field programmable gate array (FPGA). The scanner is equipped with a mechanical sector-scan probe with a concave transducer with 50 mm focal length, center frequency of 1.5 MHz and 60% bandwidth at -6 dB. The example of femoral neck bone examination shows that the scanner can provide ultrasonic data from deeply located bones with the ultrasound penetrating the trabecular bone up to a depth of 20 mm. It is also shown that the RF echo data acquired with the scanner allow for the estimation of attenuation coefficient and frequency dependence of backscattering coefficient of trabecular bone. The values of the calculated parameters are in the range of corresponding in vitro data from the literature but their variation is relatively high. PMID- 22828843 TI - Respiration-induced movement correlation for synchronous noninvasive renal cancer surgery. AB - Noninvasive surgery (NIS), such as high-intensity focused ultrasound (HIFU)-based ablation or radiosurgery, is used for treating tumors and cancers in various parts of the body. The soft tissue targets (usually organs) deform and move as a result of physiological processes such as respiration. Moreover, other deformations induced during surgery by changes in patient position, changes in physical properties caused by repeated exposures and uncertainties resulting from cavitation also occur. In this paper, we present a correlation-based movement prediction technique to address respiration-induced movement of the urological organs while targeting through extracorporeal trans-abdominal route access. Among other organs, kidneys are worst affected during respiratory cycles, with significant three-dimensional displacements observed on the order of 20 mm. Remote access to renal targets such as renal carcinomas and cysts during noninvasive surgery, therefore, requires a tightly controlled real-time motion tracking and quantitative estimate for compensation routine to synchronize the energy source(s) for precise energy delivery to the intended regions. The correlation model finds a mapping between the movement patterns of external skin markers placed on the abdominal access window and the internal movement of the targeted kidney. The coarse estimate of position is then fine-tuned using the Adaptive Neuro-Fuzzy Inference System (ANFIS), thereby achieving a nonlinear mapping. The technical issues involved in this tracking scheme are threefold: the model must have sufficient accuracy in mapping the movement pattern; there must be an image-based tracking scheme to provide the organ position within allowable system latency; and the processing delay resulting from modeling and tracking must be within the achievable prediction horizon to accommodate the latency in the therapeutic delivery system. The concept was tested on ultrasound image sequences collected from 20 healthy volunteers. The results indicate that the modeling technique can be practically integrated into an image-guided noninvasive robotic surgical system with an indicative targeting accuracy of more than 94%. A comparative analysis showed the superiority of this technique over conventional linear mapping and modelfree blind search techniques. PMID- 22828844 TI - Implementation of a versatile research data acquisition system using a commercially available medical ultrasound scanner. AB - This paper describes the design and implementation of a versatile, open architecture research data acquisition system using a commercially available medical ultrasound scanner. The open architecture will allow researchers and clinicians to rapidly develop applications and move them relatively easy to the clinic. The system consists of a standard PC equipped with a camera link and an ultrasound scanner equipped with a research interface. The ultrasound scanner is an easy-to-use imaging device that is capable of generating high-quality images. In addition to supporting the acquisition of multiple data types, such as B-mode, M-mode, pulsed Doppler, and color flow imaging, the machine provides users with full control over imaging parameters such as transmit level, excitation waveform, beam angle, and focal depth. Beamformed RF data can be acquired from regions of interest throughout the image plane and stored to a file with a simple button press. For clinical trials and investigational purposes, when an identical image plane is desired for both an experimental and a reference data set, interleaved data can be captured. This form of data acquisition allows switching between multiple setups while maintaining identical transducer, scanner, region of interest, and recording time. Data acquisition is controlled through a graphical user interface running on the PC. This program implements an interface for third party software to interact with the application. A software development toolkit is developed to give researchers and clinicians the ability to utilize third party software for data analysis and flexible manipulation of control parameters. Because of the advantages of speed of acquisition and clinical benefit, research projects have successfully used the system to test and implement their customized solutions for different applications. Three examples of system use are presented in this paper: evaluation of synthetic aperture sequential beamformation, transverse oscillation for blood velocity estimation, and acquisition of spectral velocity data for evaluating aortic aneurysms. PMID- 22828845 TI - Front-end receiver electronics for a matrix transducer for 3-D transesophageal echocardiography. AB - There is a clear clinical need for creating 3-D images of the heart. One promising technique is the use of transesophageal echocardiography (TEE). To enable 3-D TEE, we are developing a miniature ultrasound probe containing a matrix piezoelectric transducer with more than 2000 elements. Because a gastroscopic tube cannot accommodate the cables needed to connect all transducer elements directly to an imaging system, a major challenge is to locally reduce the number of channels, while maintaining a sufficient signal-to-noise ratio. This can be achieved by using front-end receiver electronics bonded to the transducers to provide appropriate signal conditioning in the tip of the probe. This paper presents the design of such electronics, realizing time-gain compensation (TGC) and micro-beamforming using simple, low-power circuits. Prototypes of TGC amplifiers and micro-beamforming cells have been fabricated in 0.35-MUm CMOS technology. These prototype chips have been combined on a printed circuit board (PCB) to form an ultrasound-receiver system capable of reading and combining the signals of three transducer elements. Experimental results show that this design is a suitable candidate for 3-D TEE. PMID- 22828846 TI - An FPGA-based ultrasound imaging system using capacitive micromachined ultrasonic transducers. AB - We report the design and experimental results of a field-programmable gate array (FPGA)-based real-time ultrasound imaging system that uses a 16-element phased array capacitive micromachined ultrasonic transducer fabricated using a fusion bonding process. The imaging system consists of the transducer, discrete analog components situated on a custom-made circuit board, the FPGA, and a monitor. The FPGA program consists of five functional blocks: a main counter, transmit and receive beamformer, receive signal pre-processing, envelope detection, and display. No dedicated digital signal processor or personal computer is required for the imaging system. An experiment is carried out to obtain the sector B-scan of a 4-wire target. The ultrasound imaging system demonstrates the possibility of an integrated system-in-a-package solution. PMID- 22828847 TI - A 32 x 32 capacitive micromachined ultrasonic transducer array manufactured in standard CMOS. AB - As ultrasound imagers become increasingly portable and lower cost, breakthroughs in transducer technology will be needed to provide high-resolution, real-time 3-D imaging while maintaining the affordability needed for portable systems. This paper presents a 32 x 32 ultrasound array prototype, manufactured using a CMUT-in CMOS approach whereby ultrasonic transducer elements and readout circuits are integrated on a single chip using a standard integrated circuit manufacturing process in a commercial CMOS foundry. Only blanket wet-etch and sealing steps are added to complete the MEMS devices after the CMOS process. This process typically yields better than 99% working elements per array, with less than +/-1.5 dB variation in receive sensitivity among the 1024 individually addressable elements. The CMUT pulseecho frequency response is typically centered at 2.1 MHz with a -6 dB fractional bandwidth of 60%, and elements are arranged on a 250 MUm hexagonal grid (less than half-wavelength pitch). Multiplexers and CMOS buffers within the array are used to make on-chip routing manageable, reduce the number of physical output leads, and drive the transducer cable. The array has been interfaced to a commercial imager as well as a set of custom transmit and receive electronics, and volumetric images of nylon fishing line targets have been produced. PMID- 22828848 TI - Acoustic backing in 3-D integration of CMUT with front-end electronics. AB - Capacitive micromachined ultrasonic transducers (CMUTs) have shown promising qualities for medical imaging. However, there are still some problems to be investigated, and some challenges to overcome. Acoustic backing is necessary to prevent SAWs excited in the surface of the silicon substrate from affecting the transmit pattern from the array. In addition, echoes resulting from bulk waves in the substrate must be removed. There is growing interest in integrating electronic circuits to do some of the beamforming directly below the transducer array. This may be easier to achieve for CMUTs than for traditional piezoelectric transducers. We will present simulations showing that the thickness of the silicon substrate and thicknesses and acoustic properties of the bonding material must be considered, especially when designing highfrequency transducers. Through simulations, we compare the acoustic properties of 3-D stacks bonded with three different bonding techniques; solid-liquid interdiffusion (SLID) bonding, direct fusion bonding, and anisotropic conductive adhesives (ACA). We look at a CMUT array with a center frequency of 30 MHz and three silicon wafers underneath, having a total silicon thickness of 100 MUm. We find that fusion bonding is most beneficial if we want to prevent surface waves from damaging the array response, but SLID and ACA are also promising if bonding layer thicknesses can be reduced. PMID- 22828850 TI - A multifunctional, reconfigurable pulse generator for high-frequency ultrasound imaging. AB - High-frequency (>20 MHz) ultrasound (HFUS) imaging systems have made it possible to image small structures with fine spatial resolution. They find a variety of biomedical applications in dermatology, ophthalmology, intravascular imaging, and small-animal imaging. One critical technical challenge of HFUS is to generate high-voltage, high-frequency pulsed signals to effectively excite the transducer for a high SNR. This paper presents the development of a multifunctional, reconfigurable pulse generator for HFUS imaging. The pulse generator can produce a high-voltage unipolar pulse, a bipolar pulse, or arbitrary pulses for B-mode imaging, Doppler measurement, and modulated excitation imaging. The characteristics of the pulses, such as timing, waveform, and frequency are reconfigurable by a high-speed field-programmable gate array (FPGA). Customized software was developed to interface with the FPGA through a USB connector for pulse selection, and easy, flexible, real-time pulse management. The hardware was implemented in a compact, printed circuit board (PCB)-based scheme using state-of the-art electronics for costeffectiveness and fully digital control. Testing results show that the unipolar pulse can reach over 165 Vpp with a 6-dB bandwidth of 70 MHz, and the bipolar pulse and arbitrary pulses can reach 150 and 60 Vpp with central frequencies of 60 and 120 MHz, respectively. PMID- 22828849 TI - A look-up-table digital predistortion technique for high-voltage power amplifiers in ultrasonic applications. AB - In this paper, we present a digital predistortion technique to improve the linearity and power efficiency of a high-voltage class-AB power amplifier (PA) for ultrasound transmitters. The system is composed of a digital-to-analog converter (DAC), an analog-to-digital converter (ADC), and a field-programmable gate array (FPGA) in which the digital predistortion (DPD) algorithm is implemented. The DPD algorithm updates the error, which is the difference between the ideal signal and the attenuated distorted output signal, in the look-up table (LUT) memory during each cycle of a sinusoidal signal using the least-mean-square (LMS) algorithm. On the next signal cycle, the error data are used to equalize the signal with negative harmonic components to cancel the amplifier's nonlinear response. The algorithm also includes a linear interpolation method applied to the windowed sinusoidal signals for the B-mode and Doppler modes. The measurement test bench uses an arbitrary function generator as the DAC to generate the input signal, an oscilloscope as the ADC to capture the output waveform, and software to implement the DPD algorithm. The measurement results show that the proposed system is able to reduce the second-order harmonic distortion (HD2) by 20 dB and the third-order harmonic distortion (HD3) by 14.5 dB, while at the same time improving the power efficiency by 18%. PMID- 22828851 TI - An analytical nonlinear model for laminate multiferroic composites reproducing the DC magnetic bias dependent magnetoelectric properties. AB - In this work, we propose an analytical nonlinear model for laminate multiferroic composites in which the magnetic-field-induced strain in magnetostrictive phase is described by a standard square law taking the stress effect into account, whereas the ferroelectric phase retains a linear piezoelectric response. Furthermore, differing from previous models which assume uniform deformation, we take into account the stress attenuation and adopt non-uniform deformation along the layer thickness in both piezoelectric and magnetostrictive phases. Analysis of this model on L-T and L-L modes of sandwiched Terfenol-D/lead zirconate titanate/Terfenol-D composites can well reproduce the observed dc magnetic field (H(dc)) dependent magnetoelectric coefficients, which reach their maximum with the H(dc) all at about 500 Oe. The model also suggests that stress attenuation along the layer thickness in practical composites should be taken into account. Furthermore, the model also indicates that a high volume fraction of magnetostrictive phase is required to get giant magnetoelectric coupling, coinciding with existing models. PMID- 22828852 TI - Aberration correction by time reversal of moving speckle noise. AB - Focusing a wave through heterogeneous media is an important problem in medical ultrasound imaging. In such aberrating media, in the presence of a small number of point reflectors, iterative time reversal is a well-known method able to focus on the strongest reflector. However, in presence of speckle noise generated by many non-resolved scatterers, iterative time reversal alone does not work. In this paper, we propose the use of the echoes coming from moving particles in a flow, such as red blood cells, to generate a virtual point reflector by iterative time reversal. The construction of the virtual point reflector is performed by a coherent addition of independent realizations of speckle coming from moving particles. After focusing on a virtual point reflector, ultrasound images can be locally corrected inside an isoplanatic patch. An application for the correction of power Doppler images is presented. A theoretical analysis shows that this iterative method allows focusing on the point of maximal insonification of the uncorrected beam. PMID- 22828853 TI - Large improvement of the electrical impedance of imaging and high-intensity focused ultrasound (HIFU) phased arrays using multilayer piezoelectric ceramics coupled in lateral mode. AB - With a change in phased-array configuration from one dimension to two, the electrical impedance of the array elements is substantially increased because of their decreased width (w)-to-thickness (t) ratio. The most common way to compensate for this impedance increase is to employ electrical matching circuits at a high cost of fabrication complexity and effort. In this paper, we introduce a multilayer lateral-mode coupling method for phased-array construction. The direct comparison showed that the electrical impedance of a single-layer transducer driven in thickness mode is 1/(n2(1/(w/t))2) times that of an n-layer lateral mode transducer. A large reduction of the electrical impedance showed the impact and benefit of the lateral-mode coupling method. A one-dimensional linear 32-element 770-kHz imaging array and a 42-element 1.45-MHz high-intensity focused ultrasound (HIFU) phased array were fabricated. The averaged electrical impedances of each element were measured to be 58 Omega at the maximum phase angle of -1.2 degrees for the imaging array and 105 Omega at 0 degrees for the HIFU array. The imaging array had a center frequency of 770 kHz with an averaged 6-dB bandwidth of approximately 52%. For the HIFU array, the averaged maximum surface acoustic intensity was measured to be 32.8 W/cm2 before failure. PMID- 22828854 TI - Intravascular ultrasound detection and delivery of molecularly targeted microbubbles for gene delivery. AB - We are investigating the combination of microbubble-based targeted drug delivery and intravascular ultrasound (IVUS) imaging as a potential therapy to reduce incidence of restenosis following stent placement in atherosclerotic coronary arteries. The goal of these studies was to determine whether IVUS could be used to detect targeted microbubbles and enhance drug/gene delivery through targeting. Quiescent vascular smooth muscle cells (SMCs) were stimulated with cytokine IL 1beta to induce the inflammatory cell surface marker vascular cell adhesion molecule 1 (VCAM-1). Molecular-targeted (VCAM-1 Ab or IgG control Ab), fluorescent-labeled microbubbles were conjugated with plasmid DNA expressing green fluorescent protein (GFP, pMax-GFP) and exposed to the inflamed SMCs under flow to measure adhesion compared with control microbubbles. Gene delivery was performed using a modified IVUS catheter to generate 1.5-MHz ultrasound at 200 kPa. Detection of adherent microbubbles to inflamed SMCs in culture and flow chambers was measured using an IVUS catheter and scanner. VCAM-1-targeted microbubbles enhanced adhesion to inflamed SMCs 100-fold over nontargeted microbubbles. Compared with noninflamed SMCs, VCAM-1-targeted microbubbles exhibited a 7.9-fold increase in adhesion to IL-1beta-treated cells. Targeted microbubbles resulted in a 5.5-fold increase in plasmid DNA transfection over nontargeted microbubbles in conjunction with a focused 2.54-cm (1-in) diameter 1 MHz transducer and also enhanced transfection by the modified IVUS transducer at 1.5 MHz. Targeted microbubbles (at a density of 3 * 104 microbubbles/mm2) increased IVUS image intensity 13.2 dB over non-microbubble-coated surfaces. Rupture of microbubbles from the modified IVUS transducer resulted in a 53% reduction in image intensity. Taken together, these results indicate that IVUS may be used to detect targeted microbubbles to inflamed vasculature and subsequently deliver a gene/drug locally. PMID- 22828855 TI - Assessing and improving acoustic radiation force image quality using a 1.5-D transducer design. AB - A 1.5-D transducer array was proposed to improve acoustic radiation force impulse (ARFI) imaging signal-to-noise ratio (SNRARFI) and image contrast relative to a conventional 1-D array. To predict performance gains from the proposed 1.5-D transducer array, an analytical model for SNRARFI upper bound was derived. The analytical model and 1.5-D ARFI array were validated using a finite element modelbased numerical simulation framework. The analytical model demonstrated good agreement with numerical results (correlation coefficient = 0.995), and simulated lesion images yielded a significant (2.92 dB; p < 0.001) improvement in contrast tonoise ratio when rendered using the 1.5-D ARFI array. PMID- 22828856 TI - Turbinaria conoides (J. Agardh) sulfated polysaccharide protects rat's heart against myocardial injury. AB - In recent years, sulfated polysaccharide (fucoidan) is being marketed as a nutraceutical and food supplement because of its various established pharmacological activities. Hence this study was designed to investigate the protective effect of fucoidan extracted from Turbinaria conoides against isoproterenol induced myocardial injured rats. Biochemical assessment of myocardial injury was done by measuring the activities of creatine kinase, lactate dehydrogenase, membrane bound triphosphatases and minerals, which were significantly altered in isoproterenol administered rats. In addition, the enzyme mapping assay on the size of myocardial infarct also correlated with these biochemical parameters. Thus, the observed protective effects of sulfated polysaccharides of T. conoides against ISO induced myocardial injury are due to membrane stabilizing property and this property might be due to decreased lipid peroxidation. These results may trigger a renewed interest in the use of T. conoides fucoidan for myocardial injury. PMID- 22828857 TI - The utility of bispectral index monitoring for sedated patients treated with low dose remifentanil. AB - The aim of the present study was to determine the effect of low-dose remifentanil on the monitoring quality of the Bispectral index for mechanically ventilated patients. Twelve patients who underwent elective surgery and required mechanical ventilation post-operatively were enrolled in this study with written informed consent. Eligible patients were divided into two groups. Patients in the remifentanil group received low-dose remifentanil (0.05-0.125 MUg/kg/min) and propofol (1-3 mg/kg/h). Patients in the control group received propofol (1-3 mg/kg/h). Levels of sedation were evaluated by both the Richmond Agitation Sedation Scale (RASS) and BIS monitor (A2000-XP, version 4.0, Aspect Medical Systems, Newton, USA). Monitoring quality was assessed by a correlation between RASS and BIS values. These values were assessed by single regression analysis and a P value of <0.05 was considered significant. There was a significant correlation between RASS and BIS values (P = 3 * 10(-12), R (2) = 0.67) in the remifentanil group, but not in the control group (P = 0.50, R (2) = 0.057). The administration of low-dose remifentanil makes BIS a more precise tool for sedated patients under mechanical ventilation in the ICU. PMID- 22828858 TI - Hemodynamic management of cardiovascular failure by using PCO(2) venous-arterial difference. AB - The difference between mixed venous blood carbon dioxide tension (PvCO(2)) and arterial carbon dioxide tension (PaCO(2)), called ?PCO(2) has been proposed to better characterize the hemodynamic status. It depends on the global carbon dioxide (CO(2)) production, on cardiac output and on the complex relation between CO(2) tension and CO(2) content. The aim of this review is to detail the physiological background allowing adequate interpretation of ?PCO(2) at the bedside. Clinical and experimental data support the use of ?PCO(2) as a valuable help in the decision-making process in patients with hemodynamic instability. The difference between central venous CO(2) tension and arterial CO(2) tension, which is easy to obtain can substitute for ?PCO(2) to assess the adequacy of cardiac output. Differences between local tissue CO(2) tension and arterial CO(2) tension can also be obtained and provide data on the adequacy of local blood flow to the local metabolic conditions. PMID- 22828859 TI - Two-dimensional organometallic porous sheets with possible high-temperature ferromagnetism. AB - With the rapid development of modern nanotechnology, molecular self-assembly has become an important method to fabricate new functional devices, and to provide an arena for theoretical material designs. In this paper, we propose that freestanding two-dimensional organometallic porous sheets (PSs), which can be formed by molecular self-assembly on metal surfaces, are ideal low-dimensional magnetic materials with room-temperature ferromagnetism. Through comprehensive first-principles calculations, we show that the freestanding organometallic sheets, which are assembled by transition metals (TMs) (Mn and V) and benzene molecules, favor ferromagnetic coupling with strong exchange interactions. More importantly, we predict that the Curie-temperature of V-PS is close to room temperature using a simplified mean-field expression, compared to any organometallic sheets discovered previously. In terms of the recent progress in the molecular self-assembly approach, our results indicate great potential for building room-temperature magnetic organometallic sheets with small magnetic molecules. PMID- 22828860 TI - Antiaging effect of dietary chitosan supplementation on glutathione-dependent antioxidant system in young and aged rats. AB - Aging has been defined as the changes that occur in living organisms with the passage of time that lead to functional impairment and ultimately to death. Free radical-induced oxidative damage has long been thought to be the most important consequence of the aging process. In the present study, an attempt has been made to study the salubrious effects of dietary supplementation of chitosan on glutathione-dependent antioxidant defense system in young and aged rats. The dietary supplementation of chitosan significantly reduced the age-associated dyslipidemic abnormalities noted in the levels of total cholesterol, HDL cholesterol, and LDL-cholesterol in plasma and heart tissue. Its administration significantly (P < 0.05) attenuated the oxidative stress in the heart tissue of aged rats through the counteraction of free radical formation by maintaining the enzymatic [glutathione peroxidase (GPx) and glutathione reductase (GR)] and non enzymatic [reduced glutathione (GSH)] status at levels comparable to that of normal young rats. Our results conclude that dietary intake of chitosan restores the depleted myocardial antioxidant status and suggest that it could be an effective therapeutic agent in treatment of age-associated disorders where hypercholesterolemia and oxidative stress are the major causative factors. PMID- 22828861 TI - Safety and cost-effectiveness of shortening hospital follow-up after breast cancer treatment. AB - BACKGROUND: In the Netherlands, the first 5 years of follow-up after treatment for breast cancer are carried out in hospital with yearly mammography. After this, for patients aged over 60 years who have undergone mastectomy, there is a shift of care to the National Screening Programme (NSP) for mammography every 2 years. After breast-conserving therapy follow-up is perfomed by the general practitioner (GP), with mammography every second year and physical examination annually. The aim of this study was to evaluate the clinical effects and costs of four different strategies for follow-up after breast cancer treatment. METHODS: An extended and validated simulation model for breast cancer follow-up was used. The current guidelines for follow-up (baseline strategy) and three less intensive follow-up strategies were evaluated. The main outcome measure was the detection rate of small tumours (2 cm or smaller) and associated costs for each strategy. RESULTS: Shortening the follow-up time in hospital by shifting care to the NSP or GP after 2 years instead of 5 years of hospital follow-up, lowering the age of referral to the NSP or GP from 60 to 50 years, and termination of annual physical examination by the GP after hospital follow-up did not decrease the detection of small tumours. In addition, a substantial decrease in costs was observed with simplified follow-up. CONCLUSION: Decreasing hospital follow-up time, lowering the age of referral to the NSP or GP, and termination of annual physical examinations would lead to a substantial reduction in costs while maintaining the possibility of detecting small breast cancers. PMID- 22828862 TI - Microwave survey of the conformational landscape exhibited by the propeller molecule triethyl amine. AB - Conformational studies with quantum chemical methods yielded for the most stable conformer of triethyl amine a propeller-like structure belonging to the point group C(3), which corresponds to an oblate top. The microwave spectrum of this conformer with (14)N hyperfine splitting of all rotational transitions was assigned and molecular parameters were determined. The rotational constants were found to be A = B = 2.314873978(11) GHz, the (14)N quadrupole coupling constant chi(cc) = -5.2444(07) MHz. The observed spectrum could be reproduced within experimental accuracy. The standard deviation of a global fit with 48 rotational transitions is 1.5 kHz. The propeller-like structure seems to be energetically favorable and therefore also typical for related systems like triethyl phosphine, triisopropyl amine, tri-n-propyl amine, and tri-tert-butyl amine. Furthermore, the rotational transitions of two isotopologues, (13)C(2) and (13)C(5), could be measured in natural abundance and fitted with an excellent standard deviation. The C rotational constants could be determined to be 1.32681(96) GHz and 1.32989(18) GHz for the (13)C(2) and (13)C(5) isotopologues, respectively. PMID- 22828863 TI - Molecular basis of plant stress. PMID- 22828864 TI - Osmotic stress signaling via protein kinases. AB - Plants face various kinds of environmental stresses, including drought, salinity, and low temperature, which cause osmotic stress. An understanding of the plant signaling pathways that respond to osmotic stress is important for both basic biology and agriculture. In this review, we summarize recent investigations concerning the SNF1-related protein kinase (SnRK) 2 kinase family, which play central roles in osmotic stress responses. SnRK2s are activated by osmotic stress, and a mutant lacking SnRK2s is hypersensitive to osmotic stress. Many questions remain about the signaling pathway upstream and downstream of SnRK2s. Because some SnRK2s also functions in the abscisic acid (ABA) signaling pathway, which has recently been well clarified, study of SnRK2s in ABA signaling can provide clues regarding their roles in osmotic stress signaling. PMID- 22828865 TI - Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin. AB - Insulin/IGF-like signaling regulates the development, growth, fecundity, metabolic homeostasis, stress resistance and lifespan in worms, flies and mammals. Eight insulin-like peptides (DILP1-8) are found in Drosophila. Three of these (DILP2, 3 and 5) are produced by a set of median neurosecretory cells (insulin-producing cells, IPCs) in the brain. Activity in the IPCs of adult flies is regulated by glucose and several neurotransmitters and neuropeptides. One of these, short neuropeptide F (sNPF), regulates food intake, growth and Dilp transcript levels in IPCs via the sNPF receptor (sNPFR1) expressed on IPCs. Here we identify a set of brain neurons that utilizes sNPF to activate the IPCs. These sNPF-expressing neurons (dorsal lateral peptidergic neurons, DLPs) also produce the neuropeptide corazonin (CRZ) and have axon terminations impinging on IPCs. Knockdown of either sNPF or CRZ in DLPs extends survival in flies exposed to starvation and alters carbohydrate and lipid metabolism. Expression of sNPF in DLPs in the sNPF mutant background is sufficient to rescue wild-type metabolism and response to starvation. Since CRZ receptor RNAi in IPCs affects starvation resistance and metabolism, similar to peptide knockdown in DLPs, it is likely that also CRZ targets the IPCs. Knockdown of sNPF, but not CRZ in DLPs decreases transcription of Dilp2 and 5 in the brain, suggesting different mechanisms of action on IPCs of the two co-released peptides. Our findings indicate that sNPF and CRZ co-released from a small set of neurons regulate IPCs, stress resistance and metabolism in adult Drosophila. PMID- 22828867 TI - microRNA regulation of cancer-endothelial interactions: vesicular microRNAs on the move.... PMID- 22828866 TI - Pediatric indications for deep brain stimulation. AB - PURPOSE: Based on the success of deep brain stimulation (DBS) in the treatment of adult disorders, it is reasonable to assume that the application of DBS in the pediatric population is an emerging area worthy of study. The purpose of this paper is to outline the current movement disorder indications for DBS in the pediatric population, and to describe areas of investigation, including possible medically refractory psychiatric indications. METHODS: We performed a structured review of the English language literature from 1990 to 2011 related to studies of DBS in pediatrics using Medline and PubMed search results. RESULTS: Twenty-four reports of DBS in the pediatric population were found. Based on published data on the use of DBS for pediatric indications, there is a spectrum of clinical evidence for the use of DBS to treat different disorders. Dystonia, a disease associated with a low rate of remission and significant disability, is routinely treated with DBS and is currently the most promising pediatric application of DBS. We caution the application of DBS to conditions associated with a high remission rate later in adulthood, like obsessive-compulsive disorder and Tourette's syndrome. Moreover, epilepsy and obesity are currently being investigated as indications for DBS in the adult population; however, both are associated with significant morbidity in pediatrics. CONCLUSION: While currently dystonia is the most promising application of DBS in the pediatric population, multiple conditions currently being investigated in adults also afflict children and adolescents, and thus warrant further research. PMID- 22828868 TI - Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair. AB - Fanconi anaemia (FA) is a rare hereditary disorder characterized by genomic instability and cancer susceptibility. A key FA protein, FANCD2, is targeted to chromatin with its partner, FANCI, and plays a critical role in DNA crosslink repair. However, the molecular function of chromatin-bound FANCD2-FANCI is still poorly understood. In the present study, we found that FANCD2 possesses nucleosome-assembly activity in vitro. The mobility of histone H3 was reduced in FANCD2-knockdown cells following treatment with an interstrand DNA crosslinker, mitomycin C. Furthermore, cells harbouring FANCD2 mutations that were defective in nucleosome assembly displayed impaired survival upon cisplatin treatment. Although FANCI by itself lacked nucleosome-assembly activity, it significantly stimulated FANCD2-mediated nucleosome assembly. These observations suggest that FANCD2-FANCI may regulate chromatin dynamics during DNA repair. PMID- 22828869 TI - Regulation of human lung alveolar multipotent cells by a novel p38alpha MAPK/miR 17-92 axis. AB - The cellular and molecular mechanisms that control lung homeostasis and regeneration are still poorly understood. It has been proposed that a population of cells exists in the mouse lung with the potential to differentiate into all major lung bronchioalveolar epithelium cell types in homeostasis or in response to virus infection. A new population of E-Cad/Lgr6(+) putative stem cells has been isolated, and indefinitely expanded from human lungs, harbouring both, self renewal capacity and the potency to differentiate in vitro and in vivo. Recently, a putative population of human lung stem cells has been proposed as being c Kit(+). Unlike Integrin-alpha6(+) or c-Kit(+) cells, E-Cad/Lgr6(+) single-cell injections in the kidney capsule produce differentiated bronchioalveolar tissue, while retaining self-renewal, as they can undergo serial transplantations under the kidney capsule or in the lung. In addition, a signalling network involving the p38alpha pathway, the activation of p53 and the regulation of the miR-17-92 cluster has been identified. Disruption of the proper cross-regulation of this signalling axis might be involved in the promotion of human lung diseases. PMID- 22828870 TI - Prevention of surgical site infections in bone and joint procedures. AB - There is strong evidence that preoperative nasal S. aureus screening/decolonization will significantly reduce surgical site infections (SSIs) after joint prostheses implantation. There is some evidence that antibiotic-containing bone cement may lower SSI rates. Timely administration of perioperative systemic antibiotic prophylaxis is recommended for patients with implants who are undergoing dental treatment, urogenital surgery, upper endoscopy, sigmoidoscopy, or colonoscopy. Advanced skin disinfection by chlorhexidine-gluconate-impregnated cloths may be protective. There is evidence that clippers are favored for hair removal, rather than razors, but no significant advantage, as compared with other modes of hair removal, has been found. Antibiotic-coated intramedullary nails and antibiotic-impregnated bone grafts may be useful for the treatment of chronic bone infections. No recommendation can be made for wound dressing types. Laminar air flow systems do not seem to prevent SSI but may even cause harm, instead. There is a strong association between the annual number of surgical procedures and low SSI rates. PMID- 22828871 TI - Global flash multifocal electroretinogram: early detection of local functional changes and its correlations with optical coherence tomography and visual field tests in diabetic eyes. AB - PURPOSE: To investigate the correlations of the global flash multifocal electroretinogram (MOFO mfERG) with common clinical visual assessments--Humphrey perimetry and Stratus circumpapillary retinal nerve fiber layer (RNFL) thickness measurement in type II diabetic patients. METHODS: Forty-two diabetic patients participated in the study: Ten were free from diabetic retinopathy (DR), while the remainder suffered from mild to moderate nonproliferative diabetic retinopathy. Fourteen age-matched controls were recruited for comparison. MOFO mfERG measurements were made under high- and low-contrast conditions. Humphrey central 30-2 perimetry and Stratus OCT circumpapillary RNFL thickness measurements were also performed. Correlations between local values of implicit time and amplitude of the mfERG components [direct component (DC) and induced component (IC)], and perimetric sensitivity and RNFL thickness were evaluated by mapping the localized responses for the three subject groups. RESULTS: MOFO mfERG was superior to perimetry and RNFL assessments in showing differences between the diabetic groups (with and without DR) and the controls. All the MOFO mfERG amplitudes (except IC amplitude at high contrast) correlated better with perimetry findings (Pearson's r ranged from 0.23 to 0.36, p < 0.01) than did the mfERG implicit time at both high and low contrasts across all subject groups. No consistent correlation was found between the mfERG and RNFL assessments for any group or contrast conditions. The responses of the local MOFO mfERG correlated with local perimetric sensitivity but not with RNFL thickness. CONCLUSION: Early functional changes in the diabetic retina seem to occur before morphological changes in the RNFL. PMID- 22828872 TI - Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. AB - Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels. Our recent studies suggested that formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In the present study, we further investigated the molecular mechanisms involved in the induced apoptosis effect of formononetin on breast cancer cells. Our results suggested that formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. In contrast, formononetin could not inhibit the cell of growth of ER-negative breast cancer cells such as MDA-MB-435 S cells. We further found that formononetin activated MAPK signaling pathway in a dose-dependent manner, which resulted in the increased ratio of Bax/Bcl-2, and induced apoptosis on MCF-7 cells. However, when MCF-7 cells were pretreated with p38MAPK inhibitor SB203580 before formononetin, apoptosis induced by formononetin was significantly attenuated. Thus, we conclude that the induced apoptosis effect of formononetin on human breast cancer cells were related to Ras-p38MAPK pathway. Considering that red clover plants are widely used clinically, our results provide the foundation for future development of formononetin for treatment of ER-positive breast cancer. PMID- 22828873 TI - Formulation and evaluation of a particulate oral breast cancer vaccine. AB - Breast cancer being the most fatal form of cancer for female population, justifies exploration of immunotherapy as an alternative treatment. Here, we have formulated and evaluated an oral microparticulate breast cancer vaccine to provide a new line of therapy. The whole cell lysate of 4T07 murine breast cancer cells was incorporated in an aqueous polymer matrix and spray dried to formulate an enteric protected vaccine microparticle. These particles were characterized in vitro and then administered orally to female Balb/c mice in successive boosters. Serum antibody titers during the study were analyzed using enzyme-linked immunosorbent assay. Postvaccination animals were challenged with live 4T07 cells, and tumor growth was monitored. Flow cytometry studies were performed to analyze the role of T cells. Results show that the vaccine microparticles were 1 4 um in volume diameter and neutral in charge. The particles were protected enterically and had sustained-release profile. Serum antibody titers of vaccinated animals increased significantly after boosters compared with controls (p < 0.05). Tumor challenge studies revealed that vaccinated animals developed significantly smaller tumors (p < 0.05). Significantly higher numbers of CD4(+) cells occurred in vaccinated animals (p < 0.05). Thus, we conclude that the particulate oral breast cancer vaccine was effective in providing protective immune response in the murine model. PMID- 22828874 TI - Effects of different doses of ferutinin on bone formation/resorption in ovariectomized rats. AB - This study analyzes the effects of different doses of ferutinin on bone loss caused by estrogen deficiency in ovariectomized rats, in comparison with estradiol benzoate. Thirty female Sprague-Dawley rats were ovariectomized and treated for 30 days from the day after ovariectomy. Static/dynamic histomorphometric analyses were performed on trabecular and cortical bone of lumbar vertebrae and femurs. Very low weight increments were recorded only in all F-OVX groups, with respect to the others. Although the great differences in weight, that could imply a decrease of bone mass in F-OVX groups compared to the control ovariectomized group (C-OVX), trabecular bone in lumbar vertebrae did not show significant differences, suggesting that ferutinin, opposing estrogen deficiency, inhibits bone resorption. Newly formed cortical bone was always low in all F-OVX groups and high in C-OVX, suggesting that it is mainly devoted in answering mechanical demands. In contrast, in distal femoral metaphyses, trabecular bone was reduced and the number of osteoclasts was increased in C-OVX with respect to all other groups, suggesting that it is mainly devoted in answering metabolic demands; moreover, ferutinin dose of 2 mg/kg seemed to be more effective than the lower doses used and estrogens, particularly in those skeletal regions with higher metabolic activity. Our results suggest that the role of ferutinin in preventing osteoporosis caused by estrogen deficiency is expressed in decreasing bone erosion; moreover, in all F-OVX groups bone turnover is very low and seems correlated to the trivial body weight increase, which, in turn, depends on ferutinin treatment. PMID- 22828875 TI - p12(CDK2-AP1) inhibits breast cancer cell proliferation and in vivo tumor growth. AB - PURPOSE: p12(CDK2-AP1) is a growth suppressor that negatively regulates cyclin dependent kinase 2 (CDK2) activities and shows to interfere in DNA replication. Here, we aim to elucidate the role of p12(CDK2-AP1) in breast cancer progression. METHODS: Expression of p12(CDK2-AP1) protein was examined in 60 pairs of breast cancer specimens and adjacent non-tumor tissues using immunohistochemistry assay. Loss-of-function and gain-of-function analysis was performed on MCF-7 and MDA-MB 231 breast cancer cells. Routine assays including MTT, colony formation, flow cytometry, and tumorigenesis in nude mice were performed and cell cycle regulators were analyzed. RESULTS: p12(CDK2-AP1) was found to be significantly downregulated in 60 breast cancer tissues compared to corresponding non-tumorous tissues. The proliferation and colony formation ability was inhibited in cells that transduced with p12(CDK2-AP1) over-expression lentivirus, but enhanced in cells that transduced with p12(CDK2-AP1) RNAi lentivirus. p12(CDK2-AP1) over expression led to G0/G1 phase arrest in the cell cycle and caused expression changes of cell cycle-related genes (CDK2, CDK4, p16(Ink4A), p21(Cip1/Waf1)). Furthermore, p12(CDK2-AP1) over-expression inhibited in vivo tumor growth in immunodeficiency mice, supporting an inhibitory role for p12(CDK2-AP1) in breast cancer development. CONCLUSIONS: As a cell cycle regulator, p12(CDK2-AP1) is involved in the development of breast cancer and maybe a potential therapeutic candidate to suppress tumorigenicity in breast cancer. PMID- 22828876 TI - Retrospective comparison between minimally invasive plate osteosynthesis and open plating for tibial fractures in dogs. AB - OBJECTIVES: To compare fracture healing in diaphyseal tibial fractures stabilized using either minimally invasive plate osteosynthesis (MIPO) or open reduction and internal fixation (ORIF). METHODS: Dogs in each group were matched for type of fracture, age and body weight. Stage of healing was measured blindly every four weeks postoperatively until complete healing. Outcome variables including fracture length, plate length, plate bridging ratio, plate working length, healing grading, and fracture reduction were compared between groups using the Mann-Whitney test. Significant difference was set at p <0.05. RESULTS: Based on the definition of clinical union, at 30 days five out of eight dogs managed with MIPO had healed, while two of the eight of dogs managed with ORIF had healed. We did not find any significant differences in the other outcome measures. No complications were reported in the MIPO group whereas one major complication was reported in the ORIF group. CLINICAL SIGNIFICANCE: All dogs treated by MIPO healed rapidly without any complications, nevertheless the difference in radiographic healing between the two groups was not significant. PMID- 22828877 TI - Immunotoxic effects of environmental toxicants in fish - how to assess them? AB - Numerous environmental chemicals, both long-known toxicants such as persistent organic pollutants as well as emerging contaminants such as pharmaceuticals, are known to modulate immune parameters of wildlife species, what can have adverse consequences for the fitness of individuals including their capability to resist pathogen infections. Despite frequent field observations of impaired immunocompetence and increased disease incidence in contaminant-exposed wildlife populations, the potential relevance of immunotoxic effects for the ecological impact of chemicals is rarely considered in ecotoxicological risk assessment. A limiting factor in the assessment of immunotoxic effects might be the complexity of the immune system what makes it difficult (1) to select appropriate exposure and effect parameters out of the many immune parameters which could be measured, and (2) to evaluate the significance of the selected parameters for the overall fitness and immunocompetence of the organism. Here, we present - on the example of teleost fishes - a brief discussion of how to assess chemical impact on the immune system using parameters at different levels of complexity and integration: immune mediators, humoral immune effectors, cellular immune defenses, macroscopical and microscopical responses of lymphoid tissues and organs, and host resistance to pathogens. Importantly, adverse effects of chemicals on immunocompetence may be detectable only after immune system activation, e.g., after pathogen challenge, but not in the resting immune system of non-infected fish. Current limitations to further development and implementation of immunotoxicity assays and parameters in ecotoxicological risk assessment are not primarily due to technological constraints, but are related from insufficient knowledge of (1) possible modes of action in the immune system, (2) the importance of intra- and inter-species immune system variability for the response against chemical stressors, and (3) deficits in conceptual and mechanistic assessment of combination effects of chemicals and pathogens. PMID- 22828878 TI - Gender-specific modulation of immune system complement gene expression in marine medaka Oryzias melastigma following dietary exposure of BDE-47. AB - BDE-47 is one of the most widely found congeners of PBDEs in marine environments. The potential immunomodulatory effects of BDE-47 on fish complement system were studied using the marine medaka Oryzias melastigma as a model fish. Three-month old O. melastigma were subjected to short-term (5 days) and long-term (21 days) exposure to two concentrations of BDE-47 (low dose at 290 +/- 172 ng/day; high dose at 580 +/- 344 ng/day) via dietary uptake of BDE-47 encapsulated in Artemia nauplii. Body burdens of BDE-47 and other metabolic products were analyzed in the exposed and control fish. Only a small amount of debrominated product, BDE-28, was detected, while other metabolic products were all under detection limit. Transcriptional expression of six major complement system genes involved in complement activation: C1r/s (classical pathway), MBL-2 (lectin pathway), CFP (alternative pathway), F2 (coagulation pathway), C3 (the central component of complement system), and C9 (cell lysis) were quantified in the liver of marine medaka. Endogenous expression of all six complement system genes was found to be higher in males than in females (p < 0.05). Upon dietary exposure of marine medaka to BDE-47, expression of all six complement genes were downregulated in males at day 5 (or longer), whereas in females, MBl-2, CFP, and F2 mRNAs expression were upregulated, but C3 and C9 remained stable with exposure time and dose. A significant negative relationship was found between BDE-47 body burden and mRNA expression of C1r/s, CFP, and C3 in male fish (r = -0.8576 to -0.9447). The above findings on changes in complement gene expression patterns indicate the complement system may be compromised in male O. melastigma upon dietary exposure to BDE-47. Distinct gender difference in expression of six major complement system genes was evident in marine medaka under resting condition and dietary BDE 47 challenge. The immunomodulatory effects of BDE-47 on transcriptional expression of these complement components in marine medaka were likely induced by the parent compound instead of biotransformed products. Our results clearly demonstrate that future direction for fish immunotoxicology and risk assessment of immunosuppressive chemicals must include parallel evaluation for both genders. PMID- 22828879 TI - Nervous system disruption and concomitant behavioral abnormality in early hatched pufferfish larvae exposed to heavy oil. AB - BACKGROUND AND OBJECTIVE: Spills of heavy oil (HO) over the oceans have been proven to have an adverse effect on marine life. It has been hypothesized that exposure of early larvae of sinking eggs to HO leads largely to normal morphology, whereas abnormal organization of the developing neural scaffold is likely to be found. HO-induced disruption of the nervous system, which controls animal behavior, may in turn cause abnormalities in the swimming behavior of hatched larvae. To clarify the toxicological effects of HO, we performed exposure experiments and morphological and behavioral analyses in pufferfish (Takifugu rubripes) larvae. EXPERIMENTAL PROCEDURE: Fertilized eggs of pufferfish were exposed to 50 mg/L of HO for 8 days and transferred to fresh seawater before hatching. The hatched larvae were observed for their swimming behavior, morphological appearance, and construction of muscles and nervous system. RESULTS AND DISCUSSION: In HO-exposed larvae, we did not detect any anomaly of body morphology. However, they showed an abnormal swimming pattern and disorganized midbrain, a higher center controlling movement. Our results suggest that HO exposed fishes suffer developmental disorder of the brain that triggers an abnormal swimming behavior and that HO may be selectively toxic to the brain and cause physical disability throughout the life span of these fishes. PMID- 22828880 TI - Effects of perfluorinated compounds on development of zebrafish embryos. AB - Perfluorinated compounds (PFCs) have been widely used in industrial and consumer products and frequently detected in many environmental media. Potential reproductive effects of perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) have been reported in mice, rats and water birds. PFOS and PFOA were also confirmed developing toxicants towards zebrafish embryos; however, the reported effect concentrations were contradictory. Polyfluorinated alkylated phosphate ester surfactants (including FC807) are precursor of PFOS and PFOA; however, there is no published information about the effects of FC807 and PFNA on zebrafish embryos. Therefore, this study was conducted to determine the effects of these four PFCs on zebrafish embryos. Normal fertilized zebrafish embryos were selected to be exposed to several concentrations of PFOA, PFNA, PFOS or FC807 in 24-well cell culture plates. A digital camera was used to image morphological anomalies of embryos with a stereomicroscope. Embryos were observed through matching up to 96-h post fertilization (hpf) and rates of survival and abnormalities recorded. PFCs caused lethality in a concentration-dependent manner with potential toxicity in the order of PFOS > FC807 > PFNA > PFOA based on 72-h LC(50). Forty-eight-hour post fertilization pericardial edema and 72- or 96-hpf spine crooked malformation were all observed. PFOA, PFNA, PFOS and FC807 all caused structural abnormalities using early stages of development of zebrafish. The PFCs all retarded the development of zebrafish embryos. The toxicity of the PFCs was related to the length of the PFC chain and functional groups. PMID- 22828881 TI - Effects of perinatal exposure to bisphenol A and di(2-ethylhexyl)-phthalate on gonadal development of male mice. AB - PURPOSE: In this study, we investigated the effects of maternal transfer of bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) during gestational and weaning periods on gonadal development of male offspring. METHODS: Pregnant CD-1 mice were administered by gavages in corn oil with 0.1, 1, or 10 mg/kg/day of BPA and DEHP from gestational days (GD1-21) to the weaning period (postnatal days (PND) 1-21). RESULTS: Our data indicated that the exposure significantly reduced the male-to-female sex ratio and the sizes of the gonads of male pups as recorded at PND15. The testes of the perinatally exposed male pups were developed less and the expression levels of testicular anti-mullerian hormone, androgen receptor, cyclin A, and StAR were significantly lesser than the control male pups. The less developed testes were accompanied with significant reductions in the expression levels of Gnrh and Fsh at the hypothalamic-pituitary levels. The negative effects were found to be persistent in the sexually mature pups at PND42. CONCLUSION: Our data reveal that the maternal transfer of BPA and DEHP may impose negative influence on the development and functions of the reproductive system of male pups. PMID- 22828882 TI - Binding of triclosan to human serum albumin: insight into the molecular toxicity of emerging contaminant. AB - PURPOSE: The interaction between triclosan (TCS) and human serum albumin (HSA) was investigated in order to obtain the binding mechanism, binding constant, the type of binding force, the binding distance between the donor and acceptor, and the effect of TCS on the conformation change of HSA. METHODS: A HSA solution was added to the quartz cell and then titrated by successive addition of TCS. The fluorescence quenching spectra and synchronous spectra were recorded with the excitation and emission slits of the passage of band set at 10 and 20 nm. Three dimensional fluorescence spectra of HSA were recorded before and after the addition of TCS. The capillary electrophoresis was conducted with the pressure injection mode at 0.5 psi for 5 s, separation under 25 kV, and detection at 214 nm. RESULTS: Fluorescence data indicated the fluorescence quenching of HSA by TCS was static quenching, and the quenching constants (K ( a )) were 1.14 * 10(5), 8.75 * 10(4), 6.67 * 10(4), and 5.00 * 10(4) at 293, 298, 303, and 309 K, respectively. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS) for the interaction were calculated to be -37.9 kJ mol(-1) and 32.6 J mol(-1) K(-1). The binding distance between TCS and tryptophan residues of HSA was obtained to be 1.81 nm according to Forster nonradioactive energy transfer theory. The UV-Vis absorption spectroscopy, the synchronous fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, and circular dichroism spectroscopy revealed the alterations of HSA secondary structure in the presence of TCS. Finally, the interaction between TCS and HSA was further confirmed by capillary electrophoresis. CONCLUSIONS: TCS was bound to HSA to form the TCS-HSA complex, with the binding distance of 1.81 nm. Hydrophobic interaction and hydrogen bond were dominated in the binding. TCS could change the secondary conformation of HSA. This work provides an insight into noncovalent interaction between emerging pollutants and protein, helping to elucidate the toxic mechanism of such pollutants. PMID- 22828883 TI - Perfluorooctanoic acid (PFOA) acts as a tumor promoter on Syrian hamster embryo (SHE) cells. AB - Perfluorooctane sulfonate (PFOS) (C(8)F(17)SO(3)) and perfluorooctanoic acid (PFOA) (C(8)HF(15)O(2)) are synthetic chemicals widely used in industrial applications for their hydrophobic and oleophobic properties. They are persistent, bioaccumulative, and toxic to mammalian species. Their widespread distribution on earth and contamination of human serum raised concerns about long term side effects. They are suspected to be carcinogenic through a nongenotoxic mode of action, a mechanism supported by recent findings that PFOS induced cell transformation but no genotoxicity in Syrian hamster embryo (SHE) cells. In the present study, we evaluated carcinogenic potential of PFOA using the cell transformation assay on SHE cells. The chemical was applied alone or in combination with a nontransformant concentration of benzo[a]pyrene (BaP, 0.4 MUM) in order to detect PFOA ability to act as tumor initiator or tumor promoter. The results showed that PFOA tested alone in the range 3.7 * 10(-5) to 300 MUM did not induce SHE cell transformation frequency in a 7-day treatment. On the other side, the combination BaP/PFOA induced cell transformation at all PFOA concentrations tested, which revealed synergistic effects. No genotoxicity of PFOA on SHE cells was detected using the comet assay after 5 and 24 h of exposure. No significant increase in DNA breakage was found in BaP-initiated cells exposed to PFOA in a 7-day treatment. The whole results showed that PFOA acts as a tumor promoter and a nongenotoxic carcinogen. Cell transformation in initiated cells was observed at concentrations equivalent to the ones found in human serum of nonoccupationally and occupationally exposed populations. An involvement of PFOA in increased incidence of cancer recorded in occupationally exposed population cannot be ruled out. PMID- 22828884 TI - Lethal effects on different marine organisms, associated with sediment-seawater acidification deriving from CO2 leakage. AB - CO(2) leakages during carbon capture and storage in sub-seabed geological structures could produce potential impacts on the marine environment. To study lethal effects on marine organisms attributable to CO(2) seawater acidification, a bubbling CO(2) system was designed enabling a battery of different tests to be conducted, under laboratory conditions, employing various pH treatments (8.0, 7.5, 7.0, 6.5, 6.0, and 5.5). Assays were performed of three exposure routes (seawater, whole sediment, and sediment elutriate). Individuals of the clam (Ruditapes philippinarum) and early-life stages of the gilthead seabream, Sparus aurata, were exposed for 10 days and 72 h, respectively, to acidified clean seawater. S. aurata larvae were also exposed to acidified elutriate samples, and polychaete organisms of the specie Hediste diversicolor and clams R. philippinarum were also exposed for 10 days to estuarine whole sediment. In the fish larvae elutriate test, 100 % mortality was recorded at pH 6.0, after 48 h of exposure. Similar results were obtained in the clam sediment exposure test. In the other organisms, significant mortality (p < 0.05) was observed at pH values lower than 6.0. Very high lethal effects (calculating L[H(+)]50, defined as the H(+) concentration that causes lethal effects in 50 % of the population exposed) were detected in association with the lowest pH treatment for all the species. The implication of these results is that a severe decrease of seawater pH would cause high mortality in marine organisms of several different kinds and life stages. The study addresses the potential risks incurred due to CO(2) leakages in marine environments. PMID- 22828886 TI - Toxicity test using medaka (Oryzias latipes) early fry and concentrated sample water as an index of aquatic habitat condition. AB - The aim of the present study was to show a relationship between toxicity of 100 fold concentrated water and aquatic habitat conditions. Environmental waters are 100-fold concentrated with solid-phase extraction. Medaka early fry was exposed in these waters for 48 h. The number of death and disorder was counted at 1, 2, 3, 6, 12, 24, and 48 h; toxicity was expressed using inverse median effect time and median lethal time (ET (50)(-1), LT (50)(-1)). Average score per taxon (ASPT) for benthic animals and Index of Biotic Integrity (IBI) for fish were applied as indices of aquatic habitat conditions. The results of toxicity test were compared using ASPT and IBI. The different levels of toxicity were detected in the seawater of Japan. At the Husino River area, toxicity cannot be detected. In rivers, high toxicity appeared at urban districts without sewerage. By Spearman coefficient, the relationship between toxicity and high biochemical oxygen demand (BOD) were obtained. BOD household wastewater contains hydrophobic toxic matters; otherwise, seawater in industrial area does not show clear relationship between toxicity and chemical oxygen demand. Gas chromatography to mass spectrometry simultaneous analysis database may give an answer for the source of toxicity, but further test is required. Ratio of clear stream benthic animal sharply decreased over 0.25 of LT (50)(-1) or 0.5 of ET (50)(-1). Tolerant fish becomes dominant over 0.3 of LT (50)(-1) or 0.5-1.0 of ET (50)(-1). By Pearson product-moment correlation coefficient, correlation coefficient between toxicity and ASPT was obtained at -0.773 (ET (50)(-1)) and -0.742 (LT (50)(-1)) at 1 % level of significance with a high negative correlation. Toxicity (LT (50)(-1) ) has strong correlation with the ratio of tolerant species. By Pearson product-moment correlation coefficient, correlation coefficient between toxicity and IBI obtained were -0.155 (ET (50)(-1)) and -0.190 (LT (50)(-1)) at 1 % level of significance and has a low or no correlation between toxicity and IBI. Even with low toxic environmental waters, toxicity test using 100-fold concentrated and medaka early fly could detect acute toxicity. The detected toxicity seemed to limit the inhabiting aquatic species in the water body. PMID- 22828885 TI - Bioconcentration of two pharmaceuticals (benzodiazepines) and two personal care products (UV filters) in marine mussels (Mytilus galloprovincialis) under controlled laboratory conditions. AB - Bioaccumulation is essential for gaining insight into the impact of exposure to organic micropollutants in aquatic fauna. Data are currently available on the bioaccumulation of persistent organic pollutants, but there is very little documentation on the bioaccumulation of pharmaceuticals and personal care products (PPCPs). The bioconcentration of selected PPCPs was studied in marine mussels (Mytilus galloprovincialis). The selected PPCPs were two organic UV filters, i.e., 2-ethylhexyl-4-trimethoxycinnamate (EHMC) and octocrylene (OC), and two benzodiazepines (BZP), i.e., diazepam (DZP) and tetrazepam (TZP). Laboratory experiments were performed in which M. galloprovincialis was exposed to these compounds either directly from water, for the less lipophilic substances (BZP) or via spiked food for lipophilic UV filters. M. galloprovincialis uptook and eliminated BZP following first-order kinetics. The biological half-life (t (1/2)) of TZP was 1.4 days, resulting in a bioconcentration factor of 64 and 99 mL g(-1) dry weight (dw), respectively, for 2.3 and 14.5 MUg L(-1) of exposure, while the biological half-life (t (1/2)) of DZP was 0.4 days, resulting in a bioconcentration factor of 51 mL g(-1) dw for 13.2 MUg L(-1) of exposure. The uptake of UV filter was rapid in mussels, followed by elimination within 24 h. EHMC increased from 15 to 138 ng g(-1) dw in 1 h and decreased to 25 ng g(-1) after 24 h for 11.9 MUg L(-1) exposure. OC reached 839 ng g(-1) dw after 1 h and decreased to 33 ng g(-1) after 24 h for 11.6 MUg L(-1) exposure. However, EHMC and OC were slightly accumulated in 48 h, i.e., 38 and 60 ng g(-1) dw, respectively. PMID- 22828887 TI - Gas chromatography-mass spectrometry for metabolite profiling of Japanese medaka (Oryzias latipes) juveniles exposed to malathion. AB - PURPOSE: We evaluate malathion toxicity to Japanese medaka (Oryzias latipes) juveniles by using a mass spectrometry combined with gas chromatography (GC/MS) metabolomics approach. METHODS: Medaka were exposed to low (L) and high (H) concentrations (nominally 20 and 2,000 MUg/L, respectively) of water-borne malathion. Metabolites were extracted from the fish, derivatized, and analyzed by GC/MS. Identified metabolites were subjected to one-way analysis of variance and principal component analysis (PCA). We examined the variations in the amounts of the metabolites during the exposure period. RESULTS AND DISCUSSION: At 24 h, control, L, and H groups were separated along PC1, suggesting that the effects of malathion depended on exposure concentration. The PCA results at 96 h suggest that the metabolite profiles variations of the L and H groups differed, and thus that the effects of malathion in groups differed. At 24 h, the amounts of amino acids in both exposed groups were lower than the control group amounts, perhaps owing to accelerated protein synthesis. At 96 h, the amounts of almost all the amino acids increased in the L group but decreased in the H group relative to the control group amounts, suggesting the proteolysis occurred in the L group while protein synthesis continued in the H group, that the high malathion exposure affected the fish. In addition, at 96 h, gluconeogenesis may have been induced in the L group but not in H group. CONCLUSIONS: Malathion exposure may have altered the balance between protein synthesis and degradation and induced gluconeogenesis in medaka. Our results suggest that metabolomics will be useful for comprehensive evaluation of toxicity. PMID- 22828888 TI - Molecular cloning and expression of novel metallothionein (MT) gene in the polychaete Perinereis nuntia exposed to metals. AB - To report a novel metallothionein (MT) gene and evaluate its potency as a biomarker, we clone this MT gene and measured the expression levels in the metal exposed polychaete Perinereis nuntia. Accumulated metal contents and metallothionein-like proteins (MTLPs), which have been recognized as potential biomarkers, were compared with the relative mRNA expressions of the MT gene of P. nuntia (Pn-MT). In addition, the metal-binding affinity was estimated by recombinant Pn-MT protein. Pn-MT having high cysteine residues with three metal response elements in the promoter region closely clusters with those of other invertebrates. The accumulation patterns of metals were dependent on the exposure times in lead (Pb), cadmium (Cd), and copper (Cu) exposure. Particularly, both MTLP levels and relative mRNA expressions of MT were increased with accumulated metal contents and exposure time in P. nuntia exposed to Pb and Cd. There was no significant modulation of the Pn-MT gene in polychaetes exposed to Zn and As. However, the metal-binding ability of the recombinant Pn-MT protein provides a clear evidence for a high affinity of MT to several metal elements. These results suggest that Pn-MT would play an important role in the detoxification and/or sequestration of specific metals (e.g., Pb and Cd) in P. nuntia and have potential as a molecular biomarker in the monitoring of the marine environment using a polychaete. PMID- 22828891 TI - Our prestige is growing... PMID- 22828890 TI - An overall risk probability-based method for quantification of synergistic and antagonistic effects in health risk assessment for mixtures: theoretical concepts. AB - PURPOSE: In the assessment of health risks of environmental pollutants, the method of dose addition and the method of independent action are used to assess mixture effects when no synergistic and/or antagonistic effects are present. Currently, no method exists to quantify synergistic and/or antagonistic effects for mixtures. The purpose of this paper is to develop the theoretical concepts of an overall risk probability (ORP)-based method to quantify the synergistic and antagonistic effects in health risk assessment for mixtures. METHOD: The ORP for health effects of environmental chemicals was determined from the cumulative probabilities of exposure and effects. This method was used to calculate the ORP for independent mixtures and for mixtures with synergistic and antagonistic effects. RESULTS: For the independent mixtures, a mixture ORP can be calculated from the product of the ORPs of individual components. For systems of interacting mixtures, a synergistic coefficient and an antagonistic coefficient were defined respectively to quantify the ORPs of each individual component in the mixture. The component ORPs with synergistic and/or antagonistic effects were then used to calculate the total ORP for the mixture. CONCLUSIONS: An ORP-based method was developed to quantify synergistic and antagonistic effects in health risk assessment for mixtures. This represents a first method to generally quantify mixture effects of interacting toxicants. PMID- 22828889 TI - Production of monoclonal antibody and application in indirect competitive ELISA for detecting okadaic acid and dinophytoxin-1 in seafood. AB - BACKGROUND, AIM, AND SCOPE: Okadaic acid (OA) and analogues of dinophysistoxin (DTX) are key diarrheic shellfish poisoning (DSP) toxins, which possibly arouse DSP symptoms by consuming the contaminated shellfish. Because of the stable toxicity in high temperature and the long-term carcinogenicity, the outbreaks of DSP related to consumption of bivalve mollusks contaminated by DSP toxins pose a hazard to public health. Therefore, it is worth developing a fast and reliable analytical method for the detection of OA and analogues in shellfish. In this paper, an indirect competitive enzyme-linked immunosorbent assay (ELISA) (icELISA) for detecting OA and DTX-1 in seafood was developed based on monoclonal antibody (McAb). METHODS: The OA was conjugated to human immunoglobulin G (IgG) and bovine serum albumin (BSA) by the active ester method as the immune antigen and the detective antigen. The spleen cells from BALB/c mice immunized with OA IgG were fused with SP2/0 myeloma cells. A hybridoma cell line, which secreted McAb against OA, was selected by "limiting dilution" cloning. An icELISA was developed based on immobilized conjugate (OA-BSA) competing the McAb with the free OA in seafood sample. RESULTS: A hybridoma cell line, which secreted IgG1 subclass monoclonal antibody (McAb) against OA, was selected. The IC(50) of the McAb for OA and dinophytoxin-1 (DTX-1) were 4.40 and 3.89 ng/mL, respectively. Based on the McAb, an indirect competitive ELISA for detection of OA and DTX-1 in seafood was developed. The regression equation was y = 54.713x - 25.879 with a coefficient correlation of R (2) = 0.9729. The linear range and the limit of detection were 0.4-12.5 and 0.45 ng/mL, respectively. The average recovery of OA and DTX-1 spiked shellfish was 82.29% with the coefficient of variation of 7.67%. CONCLUSION: The developed icELISA is a fast, sensitive, and convenient assay for detecting of total amount of OA and DTX-1 in seafood. PMID- 22828892 TI - Are genetic counselors and the social service system for people with intellectual disability reaching rapprochement? AB - Recent advances in syndromic identification have resulted in genetic counselors providing services to increasing numbers of people with intellectual disability (ID) and their families. However, from the standpoint of professionals who support people with ID, genetic counselors are on the periphery of the extensive ID social service system. Reasons for this, based on a review of historical circumstances, definitional differences funding and a divergence of approaches, are critically presented and discussed. A model is offered that would allow for a closer working relationship and an integrated team approach that includes genetic counselors. PMID- 22828893 TI - Water-protein dynamic coupling and new opportunities for probing it at low to physiological temperatures in aqueous solutions. AB - Both the structure and dynamics of biomolecules are known to be essential for their biological function. In the dehydrated state, the function of biomolecules, such as proteins, is severely impeded, so hydration is required for bioactivity. The dynamics of the hydrated biomolecules and their hydration water are related - but how closely? The problem involves several layers of complexity. Even for water in the bulk state, the contribution from various dynamic components to the overall dynamics is not fully understood. In biological systems, the effects of confinement on the hydration water further complicate the picture. Even if the various components of the hydration water dynamics are properly understood, which of them are coupled to the protein dynamics, and how? The studies of protein dynamics over the wide temperature range, from physiological to low temperatures, provide some answers to these question. At low temperatures, both the protein and its hydration water behave as solids, with only vibrational degrees of freedom. As the temperature is increased, non-vibrational dynamic components start contributing to the measurable dynamics and eventually become dominant at physiological temperatures. Thus, the temperature dependence of the dynamics of protein and its hydration water may allow probing various dynamic components separately. In order to suppress the water freezing, the low-temperature studies of protein rely on either low-hydrated samples (essentially, hydrated protein powders), or cryo-protective solutions. Both approaches introduce the hydration environments not characteristic of the protein environments in living systems, which are typically aqueous protein solutions of various concentrations. In this paper, we discuss the coupling between the dynamic components of the protein and its hydration water by critical examining of the existing literature, and then propose that proteins can be studied in an aqueous solution that is remarkably similar in its dynamic properties to pure water, yet does not freeze down to about 200 K, even in the bulk form. The first experiment of this kind using quasielastic neutron scattering is discussed, and more experiments are proposed. PMID- 22828894 TI - Diamond nanowire--a challenge from extremes. AB - Crystalline diamond nanowires have been grown in a chemical vapor deposition (CVD) process under 900 degrees C and atmospheric pressure--an extraordinary find in diamond growth. These diamond nanowires are straight, thin and long, and uniform in diameter (60-90 nm) over their entire lengths of tens of microns. Extensive characterizations including electron microscopy and Raman spectroscopy were performed to confirm that the diamond nanowire has highly crystalline cubic diamond structure encased inside a graphitic or carbonaceous shell. Such a core shell structure suggests a potential formation mechanism in the framework of an effectively lowered Gibbs free energy due to nano-capillary and surface charge pressure. The capillary pressure (inversely proportional to the wire radius) can be sufficiently high to allow the diamond phase to be thermodynamically favorable in the inner core while the outer shell takes on the graphitic phase. The properties of diamond can manifest themselves differently in the nanowire morphology. Examples include single-photon emission of nitrogen-vacancy and electron field-emission. Whereas the former has received much attention in the literature, the latter turned out to be just as impressive and is show-cased here for the first time. PMID- 22828896 TI - Interference of aging media on the assessment of yeast chronological life span by propidium iodide staining. AB - An increasing number of researchers are using the Saccharomyces cerevisiae chronological aging model to gain insight into the post-mitotic cellular aging. Recently, an alternative approach to the traditional cellular viability assay by colony-forming unit (CFU) counts, based on the propidium iodide (PI) staining combined with flow cytometry (PI-FCM), was proposed for the assessment of yeast chronological aging. Since the chronological aging assessment shows variations particularly concerning the aging media, in this work, the influence of the most common aging media (exhausted media or water) on the assessment of chronological aging by PI staining was studied. Our results show that this methodology is highly affected by the aging media. Indeed, a correlation between CFU counts and the percentage of PI-stained cells is only achieved with the exhausted media. As such, the assessment of yeast chronological aging by PI-FCM water should not be used. PMID- 22828895 TI - Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. AB - RATIONALE: Atrial fibrillation (AF) is the most common cardiac arrhythmia, however the mechanism(s) causing AF remain poorly understood and therapy is suboptimal. The ryanodine receptor (RyR2) is the major calcium (Ca2+) release channel on the sarcoplasmic reticulum (SR) required for excitation-contraction coupling in cardiac muscle. OBJECTIVE: In the present study, we sought to determine whether intracellular diastolic SR Ca2+ leak via RyR2 plays a role in triggering AF and whether inhibiting this leak can prevent AF. METHODS AND RESULTS: We generated 3 knock-in mice with mutations introduced into RyR2 that result in leaky channels and cause exercise induced polymorphic ventricular tachycardia in humans [catecholaminergic polymorphic ventricular tachycardia (CPVT)]. We examined AF susceptibility in these three CPVT mouse models harboring RyR2 mutations to explore the role of diastolic SR Ca2+ leak in AF. AF was stimulated with an intra-esophageal burst pacing protocol in the 3 CPVT mouse models (RyR2-R2474S+/-, 70%; RyR2-N2386I+/-, 60%; RyR2-L433P+/-, 35.71%) but not in wild-type (WT) mice (P<0.05). Consistent with these in vivo results, there was a significant diastolic SR Ca2+ leak in atrial myocytes isolated from the CPVT mouse models. Calstabin2 (FKBP12.6) is an RyR2 subunit that stabilizes the closed state of RyR2 and prevents a Ca2+ leak through the channel. Atrial RyR2 from RyR2 R2474S+/- mice were oxidized, and the RyR2 macromolecular complex was depleted of calstabin2. The Rycal drug S107 stabilizes the closed state of RyR2 by inhibiting the oxidation/phosphorylation induced dissociation of calstabin2 from the channel. S107 reduced the diastolic SR Ca2+ leak in atrial myocytes and decreased burst pacing-induced AF in vivo. S107 did not reduce the increased prevalence of burst pacing-induced AF in calstabin2-deficient mice, confirming that calstabin2 is required for the mechanism of action of the drug. CONCLUSIONS: The present study demonstrates that RyR2-mediated diastolic SR Ca2+ leak in atrial myocytes is associated with AF in CPVT mice. Moreover, the Rycal S107 inhibited diastolic SR Ca2+ leak through RyR2 and pacing-induced AF associated with CPVT mutations. PMID- 22828897 TI - Algal exudates and stream organic matter influence the structure and function of denitrifying bacterial communities. AB - Within aquatic ecosystems, periphytic biofilms can be hot spots of denitrification, and previous work has suggested that algal taxa within periphyton can influence the species composition and activity of resident denitrifying bacteria. This study tested the hypothesis that algal species composition within biofilms influences the structure and function of associated denitrifying bacterial communities through the composition of organic exudates. A mixed population of bacteria was incubated with organic carbon isolated from one of seven algal species or from one of two streams that differed in anthropogenic inputs. Pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) revealed differences in the organic composition of algal exudates and stream waters, which, in turn, selected for distinct bacterial communities. Organic carbon source had a significant effect on potential denitrification rates (DNP) of the communities, with organics isolated from a stream with high anthropogenic inputs resulting in a bacterial community with the highest DNP. There was no correlation between DNP and numbers of denitrifiers (based on nirS copy numbers), but there was a strong relationship between the species composition of denitrifier communities (as indicated by tag pyrosequencing of nosZ genes) and DNP. Specifically, the relative abundance of Pseudomonas stutzeri-like nosZ sequences across treatments correlated significantly with DNP, and bacterial communities incubated with organic carbon from the stream with high anthropogenic inputs had the highest relative abundance of P. stutzeri-like nosZ sequences. These results demonstrate a significant relationship between bacterial community composition and function and provide evidence of the potential impacts of anthropogenic inputs on the structure and function of stream microbial communities. PMID- 22828898 TI - Comparison of the genetic determinism of two key phenological traits, flowering and maturity dates, in three Prunus species: peach, apricot and sweet cherry. AB - The present study investigates the genetic determinism of flowering and maturity dates, two traits highly affected by global climate change. Flowering and maturity dates were evaluated on five progenies from three Prunus species, peach, apricot and sweet cherry, during 3-8 years. Quantitative trait locus (QTL) detection was performed separately for each year and also by integrating data from all years together. High heritability estimates were obtained for flowering and maturity dates. Several QTLs for flowering and maturity dates were highly stable, detected each year of evaluation, suggesting that they were not affected by climatic variations. For flowering date, major QTLs were detected on linkage groups (LG) 4 for apricot and sweet cherry and on LG6 for peach. QTLs were identified on LG2, LG3, LG4 and LG7 for the three species. For maturity date, a major QTL was detected on LG4 in the three species. Using the peach genome sequence data, candidate genes underlying the major QTLs on LG4 and LG6 were investigated and key genes were identified. Our results provide a basis for the identification of genes involved in flowering and maturity dates that could be used to develop cultivar ideotypes adapted to future climatic conditions. PMID- 22828899 TI - Understanding the recent colonization history of a plant pathogenic fungus using population genetic tools and Approximate Bayesian Computation. AB - Understanding the processes by which new diseases are introduced in previously healthy areas is of major interest in elaborating prevention and management policies, as well as in understanding the dynamics of pathogen diversity at large spatial scale. In this study, we aimed to decipher the dispersal processes that have led to the emergence of the plant pathogenic fungus Microcyclus ulei, which is responsible for the South American Leaf Blight (SALB). This fungus has devastated rubber tree plantations across Latin America since the beginning of the twentieth century. As only imprecise historical information is available, the study of population evolutionary history based on population genetics appeared most appropriate. The distribution of genetic diversity in a continental sampling of four countries (Brazil, Ecuador, Guatemala and French Guiana) was studied using a set of 16 microsatellite markers developed specifically for this purpose. A very strong genetic structure was found (F(st)=0.70), demonstrating that there has been no regular gene flow between Latin American M. ulei populations. Strong bottlenecks probably occurred at the foundation of each population. The most likely scenario of colonization identified by the Approximate Bayesian Computation (ABC) method implemented in DIYABC suggested two independent sources from the Amazonian endemic area. The Brazilian, Ecuadorian and Guatemalan populations might stem from serial introductions through human-mediated movement of infected plant material from an unsampled source population, whereas the French Guiana population seems to have arisen from an independent colonization event through spore dispersal. PMID- 22828900 TI - Genetic monitoring reveals temporal stability over 30 years in a small, lake resident brown trout population. AB - Knowledge of the degree of temporal stability of population genetic structure and composition is important for understanding microevolutionary processes and addressing issues of human impact of natural populations. We know little about how representative single samples in time are to reflect population genetic constitution, and we explore the temporal genetic variability patterns over a 30 year period of annual sampling of a lake-resident brown trout (Salmo trutta) population, covering 37 consecutive cohorts and five generations. Levels of variation remain largely stable over this period, with no indication of substructuring within the lake. We detect genetic drift, however, and the genetically effective population size (N(e)) was assessed from allele-frequency shifts between consecutive cohorts using an unbiased estimator that accounts for the effect of overlapping generation. The overall mean N(e) is estimated as 74. We find indications that N(e) varies over time, but there is no obvious temporal trend. We also estimated N(e) using a one-sample approach based on linkage disequilibrium (LD) that does not account for the effect of overlapping generations. Combining one-sample estimates for all years gives an N(e) estimate of 76. This similarity between estimates may be coincidental or reflecting a general robustness of the LD approach to violations of the discrete generations assumption. In contrast to the observed genetic stability, body size and catch per effort have increased over the study period. Estimates of annual effective number of breeders (N(b)) correlated with catch per effort, suggesting that genetic monitoring can be used for detecting fluctuations in abundance. PMID- 22828901 TI - T cell responses: Silent commitment. PMID- 22828907 TI - Inflammation: IL-23 tees off enthesitis. PMID- 22828908 TI - Tolerance: PD1--a multitasking receptor. PMID- 22828909 TI - Mucosal immunology: Any old bugs won't do. PMID- 22828910 TI - Tolerance: Induced T(Reg) cells evolved to protect the fetus. PMID- 22828911 TI - Lighting the fires within: the cell biology of autoinflammatory diseases. AB - Autoinflammatory diseases are characterized by seemingly unprovoked pathological activation of the innate immune system in the absence of autoantibodies or autoreactive T cells. Discovery of the causative mutations underlying several monogenic autoinflammatory diseases has identified key regulators of innate immune responses. Recent studies have highlighted the role of misfolding, oligomerization and abnormal trafficking of pathogenic mutant proteins in triggering autoinflammation, and suggest that more common rheumatic diseases may have an autoinflammatory component. This coincides with recent discoveries of new links between endoplasmic reticulum stress and inflammatory signalling pathways, which support the emerging view that autoinflammatory diseases may be due to pathological dysregulation of stress-sensing pathways that normally function in host defence. PMID- 22828913 TI - Practical use of the new American Urological Association interstitial cystitis guidelines. AB - The American Urological Association recently developed guidelines to assist clinicians who evaluate and treat interstitial cystitis/bladder pain syndrome. Knowledge in this area continues to advance, and some of the guideline statements differ from what clinicians may have been previously taught. This review includes the 27 guideline statements, which address both evaluation and treatment. This review lists the guideline statements and, when applicable, comments on their practical implementation and the most recent research. Practical information includes the following: key questions that help in the differential diagnosis, when to perform cystoscopy and urodynamics, how to recognize and treat Hunner lesions, useful practical resources for patients and clinicians, information on elimination diet and stress management, initial selection of oral and intravesical medications, and description of advanced treatment options (limited to dedicated, experienced clinicians). PMID- 22828915 TI - Dumbbell mesenchymal chondrosarcoma: report of a rare case. PMID- 22828914 TI - Interscalene brachial plexus block for scapular and upper chest pain due to cervical radiculopathy: a randomized controlled clinical trial. AB - BACKGROUND: Animal experiments have shown that one of the pathways for pain originating from the cervical spine is the sympathetic trunk. However, there have been few reports regarding the cervical pain pathway and efficacy of interscalene brachial plexus block for upper limb, scapular and chest pain originating in the cervical spine in clinical cases. The purpose of the present study was to clarify the efficacy of interscalene brachial plexus block for upper limb, scapular and chest pain. METHODS: Patients (137 men and 223 women) who had cervical radicular pain were studied. The intensity of upper limb, scapular and chest pain was measured by using a VAS before injection and at 5 min and 7 days after injection. To evaluate the efficacy of interscalene brachial plexus block, patients with cervical radicular pain who had received NSAIDs for at least 2 weeks were randomized to interscalene brachial plexus block or control block groups. VAS scores were compared to assess the effects of injection and the pain pathway. RESULTS: The average VAS score for upper limb pain with or without scapular and chest pain was significantly reduced by interscalene brachial plexus block compared with control block at 5 min and 7 days after injection. After interscalene brachial plexus block, 89 patients reported symptoms of stellate ganglion block versus no patients after control block. Scapular and chest pain was significantly reduced in the patients with stellate ganglion block compared to those without stellate ganglion block. CONCLUSIONS: Interscalene brachial plexus block is useful for upper limb, scapular and chest pain due to disorders of the cervical spine. The scapular and chest pain pathway is more likely to be interrupted by an interscalene brachial plexus block that causes a stellate ganglion block compared to an interscalene brachial plexus block without stellate ganglion block. PMID- 22828912 TI - Recent progress in mucosal vaccine development: potential and limitations. AB - Most pathogens access the body through the mucosal membranes. Therefore, effective vaccines that protect at these sites are much needed. However, despite early success with the live attenuated oral polio vaccine over 50 years ago, only a few new mucosal vaccines have been subsequently launched. This is partly due to problems with developing safe and effective mucosal adjuvants. In the past decade, however, the successful development of live attenuated mucosal vaccines against influenza virus and rotavirus infections has boosted interest in this field, and great expectations for new mucosal vaccines lie ahead. Here, I discuss the expanding knowledge and strategies used in the development of mucosal vaccines. PMID- 22828918 TI - Delayed presentation of anorectal malformation for definitive surgery. AB - AIM: To retrospectively study the outcome of patients with anorectal malformations (ARM) presenting late for definitive procedure. METHODS: Patients with ARM presenting beyond 5 months of age managed from January 2008 to March 2012 were studied for clinical outcome. RESULTS: Ages at presentation varied from 5 months to 14 years, seven patients were older than 5 years of age. Of the 36 cases, 5 patients (3 boys and 2 girls) had presented with colostomy done elsewhere. Four patients had high anomalies. Of the 33 girls, 14 had rectovestibular fistula and 9 had anovestibular fistula. Bowel preparation with peglec was used in patients without colostomy. Preoperative retention enemas, laxatives and Hegar dilators were used for 3-11 days before surgery. On table irrigation was required in four. Patients without a covering colostomy were kept nil per oral for 5 days following surgery in prone/lateral position. Two patients had mild post-op wound infection, and were managed with local care. CONCLUSION: Delayed presentation of ARM especially in girls is quite common in developing countries. With proper perioperative care, these cases may be managed successfully with a single stage procedure in most cases. The mature tissue growth with age allows proper tissue dissection and good repair of the perineal body in girls. PMID- 22828916 TI - Mechanisms of acquired resistance to insulin-like growth factor 1 receptor inhibitor in MCF-7 breast cancer cell line. AB - The purpose of this study was to clarify the mechanism of acquired resistance to the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor NVP AEW541. We developed an acquired resistant model by continuously exposing MCF-7 breast cancer cells to NVP-AEW541 (MCF-7-NR). MCF-7 and MCF-7-NR were comparatively analyzed for cell signaling and cell growth. While phosphorylation of Akt was completely inhibited by 3 MUM NVP-AEW541 in both MCF-7 and MCF-7-NR, phosphorylation of S6K remained high only in MCF-7-NR, suggesting a disconnection between Akt and S6K in MCF-7-NR. Consistently, the mTOR inhibitor everolimus inhibited phosphorylation of S6K and cell growth equally in both lines. Screening of both lines for phosphorylation of 42 receptor tyrosine kinases with and without NVP-AEW541 showed that Tyro3 phosphorylation remained high only in MCF-7 NR. Protein expression of Tyro3 was found to be higher in MCF-7-NR than in MCF-7. Gene silencing of Tyro3 using siRNA resulted in reduced cell growth and cyclin D1 expression in both lines. While Tyro3 expression was inhibited by NVP-AEW541 and everolimus in MCF-7, it was reduced only by everolimus in MCF-7-NR. These findings suggested that cyclin D1 expression was regulated in a S6K/Tyro3 dependent manner in both MCF-7 and MCF-7-NR, and that the disconnection between IGF-1R/Akt and S6K may enable MCF-7-NR to keep cyclin D1 high in the presence of NVP-AEW541. In summary, acquired resistance to NVP-AEW541 appears to result from IGF-1R/Akt-independent activation of S6K and expression of Tyro3 and cyclin D1. PMID- 22828917 TI - A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration resistant prostate cancer. AB - PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade >= 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination treated patients achieved a confirmed >= 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies. PMID- 22828919 TI - Use of bathroom scales in measuring asymmetry of hindlimb static weight bearing in dogs with osteoarthritis. AB - OBJECTIVE: The study assessed the use and reliability of bathroom scales as an objective measurement tool, and setting a normal variance of static weight bearing between hindlimbs. METHODS: Two groups of dogs were tested: a healthy control group (n = 21) and a group (n = 43) of dogs with confirmed osteoarthritis in at least one stifle joint, with or without hip joint osteoarthritis. Static weight bearing was evaluated manually and measured with two bathroom scales. An orthopaedic examination was done and dynamic weight bearing was measured using a force platform. Radiographs were taken to confirm the presence of osteoarthritis, and dogs were divided into groups of severe and non-severe osteo- arthritic changes. Reliability by repeatability was tested using analysis of variance, and the congruity between static weight bearing and other evaluation methods with Kappa statistics and proportion of agreement. RESULTS: The difference between the hindlimbs proportional to the body weight in control dogs was 3.3% (+/- 2.7%). The repeatability of measuring static weight bearing in the hindlimbs of osteoarthritic dogs with bathroom scales was 81% with osteoarthritic limbs, and 70% for unaffected limbs. The sensitivity of static weight bearing measurements using bathroom scales was 39% and specificity 85%. CLINICAL SIGNIFICANCE: Bathroom scales are a reliable, simple, and cost-effective objective method for measuring static weight bearing and can be used as an outcome measure when rehabilitating dogs with osteoarthritic changes in the hindlimbs. PMID- 22828920 TI - Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes. AB - In this study we investigate the active constituents of the rhizome of Zingiber officinale, Roscoe (ginger) and determine their activity on glucose uptake in cultured L6 myotubes and the molecular mechanism underlying this action. Freeze dried ginger powder was extracted with ethyl acetate (1 kg/3 L) to give the total ginger extract, which was then separated into seven fractions, consisting of nonpolar to moderately polar compounds, using a short-column vacuum chromatographic method. The most active fraction (F7) was further purified for identification of its active components. The effect of the extract, fractions, and purified compounds on glucose uptake was evaluated using radioactive labelled 2-[1,2-3H]-deoxy-D-glucose in L6 myotubes. The pungent phenolic gingerol constituents were identified as the major active compounds in the ginger extract enhancing glucose uptake. (S)-[6]-Gingerol was the most abundant component among the gingerols, however, (S)-[8]-gingerol was the most potent on glucose uptake. The activity of (S)-[8]-gingerol was found to be associated primarily with an increase in surface distribution of GLUT4 protein on the L6 myotube plasma membrane, as detected by expression of hemagglutinin epitope-tagged GLUT4 in L6 muscle cells. The enhancement of glucose uptake in L6 rat skeletal muscle cells by the gingerol pungent principles of the ginger extract supports the potential of ginger and its pungent components for the prevention and management of hyperglycemia and type 2 diabetes. PMID- 22828921 TI - Therapeutic effectiveness of Galphimia glauca vs. lorazepam in generalized anxiety disorder. A controlled 15-week clinical trial. AB - Galphimia glauca Cav. has demonstrated anxiolytic activity attributable to nor seco-triterpenes denominated galphimines, the most active of which is galphimine B. Galphimine-B inhibits ventral tegmental area dopaminergic neurons and interacts with the serotoninergic system of the dorsal hippocampus. A previous clinical study that administered a G. glauca herbal medicinal product for 4 weeks evidenced high percentages of therapeutic effectiveness and safety in patients with generalized anxiety disorder. Based on the previous findings, the goal of the present study was to evaluate the effectiveness, safety, and tolerability of G. glauca herbal medicinal product administered during 15 weeks in patients with generalized anxiety disorder. STUDY DESIGN: double-blind, randomized, lorazepam controlled clinical trial. STUDY SUBJECTS: adult males and females, ambulatory, diagnosed with generalized anxiety disorder, with 20 or more points on the Hamilton anxiety scale, without data of depression, and without anxiolytic treatment in the previous month. Interventions were as follows. Experimental treatment: G. glauca herbal medicinal product in capsules containing the dry extract of G. glauca standardized in 0.175 mg of galphimine-B, one or two capsules twice a day, during 12 weeks plus 3 withdrawal weeks, and control treatment: lorazepam 0.5 mg with the same presentation and posology. PRIMARY OUTCOME: anxiolytic effectiveness (>= 50 % reduction of initial Hamilton anxiety scale score). SECONDARY OUTCOMES: tolerability and safety. One hundred ninety-one patients initiated the study with 94 in the experimental group. One hundred four patients concluded the study, 51 of these in the experimental group. Anxiolytic effectiveness, measured as 0 in a negative case and as 1 in a positive case, was assessed 593 times in the experimental group and 631 in the control; the mean effectiveness observed was 0.686 +/- 0.019 vs. 0.588 +/- 0.019 (repeated-measures ANOVA; p = 0.0003). In the same way, G. glauca-herbal medicinal product diminished the score in the Hamilton anxiety scale to 11.51 +/- 8.27 points and lorazepam to 12.40 +/- 8.07 points (repeated-measures ANOVA; p = 0.05). The tolerability analysis, which comprised patients who concluded the treatment plus 11 patients who withdrew due to adverse reactions did not show differences between treatments (p = 0.35), nor did therapeutic safety demonstrate differences between groups (p = 0.21). There were no cases of tolerance, intoxication, dependence, or suppression syndrome. We concluded that G. glauca herbal medicinal product, standardized in 0.175 mg of galphimine-B and administered for 15 weeks to patients with generalized anxiety disorder, showed greater anxiolytic effectiveness than that obtained with lorazepam, with high percentages of therapeutic tolerability and safety. PMID- 22828922 TI - Bulk atmospheric deposition of persistent toxic substances (PTS) along environmental gradients in Brazil. AB - Bulk atmospheric deposition measurements for selected persistent toxic substances (PTS) were performed along environment gradients (urban-suburban-rural-background sites) in Brazil. The aim with this work is to investigate the fate of PTS and their emissions in South America, particularly along environment transects. Bulk sampler systems (polyurethane foams, 1 * 1 m(2)) were fixed along environment gradients (urban-suburban-rural-background) over summer and winter periods (2005 2007) at sites of different climate zones of Brazil. Organochlorine pesticides (OCs) and polychlorinated biphenyls (PCBs) were analyzed by gas chromatography coupled to electron capture detector (Shimadzu 2010, 20i GC-ECD). Urban sites reported the highest deposition rates for all PTS, ranging from tens to thousands of pictograms per square meter per day. Basically, there were no obvious seasonal differences in deposition rate concentrations for PTS along the urban-suburban rural-background gradient. Dichlorodiphenyltrichloroethane (DDT) and its metabolites were the OCs most frequently detected at relatively high deposition rate levels (>1,000 pg m(-2) day(-1)). Other legacy and current-use pesticides such as hexachlorocyclohexanes, endosulfans, hexachlorcyclobenzine, dieldrin, aldrin, metoxichlor, and chlodanes were also detected at lower deposition rate levels (10-100 pg m(-2) day(-1)). PCBs were detected at extremely high deposition rate levels (1,000-10,000 pg m(-2) day(-1)) with highest contributions from the tetra-PCBs (PCB-52, PCB-44, PCB-66, PCB-81, and PCB-77) and penta-PCB congeners (PCB-101, PCB-105, PCB-114, PCB-118, and PCB-126). The greatest deposition rate concentrations for total PCBs were mainly detected at urban sites in connection with high population densities. The observed high deposition rate concentrations for PCBs and DDTs at urban sites are probably associated with old PTS stocks emissions. For PCBs in particular, the high levels are strongly associated with local population densities, highlighting the effect of local/regional urban sources on these target PTS. These results are important to show that even though the use of PTS is regulated, the deposition of selected PTS is still impacted by local and regional emissions in Brazil and may be related to the historical and continued emissions from old PTS stocks. PMID- 22828923 TI - Landfill mining from a deposit of the chlorine/organochlorine industry as source of dioxin contamination of animal feed and assessment of the responsible processes. AB - In 1997, the Polychlorinated dibenzo-para-dioxin (PCDD)/Polychlorinated dibenzofuran (PCDF) concentrations in dairy products in Germany and other European countries increased. The PCDD/PCDF source was contaminated lime used in Brazilian citrus pulp pellets. The contaminated lime was mined from an industrial dump site. However, the detailed origin of the PCDD/PCDFs in the lime was not revealed. This paper investigates the contamination origin and describes the link between lime milk from the dumpsite of a chlorine/organochlorine industry and the contaminated lime. The contaminated lime stem from mining at the corporate landfill of Solvay Indupa in Sao Paulo. The landfill was used for 40 years for deposition of production residues and closed in 1996. The factory operated/operates at least two processes with potentially high PCDD/PCDFs releases namely the oxychlorination process for production of ethylene dichloride (EDC) and the chlor-alkali process. The main landfilled waste was lime milk (1.4 million tons) from the vinyl chloride monomer production (via the acetylene process) along with residues from other processes. The PCDD/PCDF fingerprint revealed that most samples from the chemical landfill showed an EDC PCDD/PCDF pattern with a characteristic octachlorodibenzofuran dominance. The PCDD/PCDF pattern of a Rio Grande sediment samples downstream the facility showed a chlor alkali pattern with a minor impact of the EDC pattern. The case highlights that PCDD/PCDF- and persistent organic pollutants-contaminated sites need to be identified in a comprehensive manner as required by the Stockholm Convention (article 6) and controlled for their impact on the environment and human health. Landfill mining and reuse of materials from contaminated deposits should be prohibited. PMID- 22828924 TI - Effects of a constructional intervention on airborne and deposited particulate matter in the Portuguese National Tile Museum, Lisbon. AB - In the 1970s, a large ambulatory of the National Tile Museum, Lisbon, was closed with glass panes on both ground and first floor. Although this design was meant to protect the museum collection from ambient air pollutants, small openings between the glass panes remain, creating a semi-enclosed corridor. The effects of the glass panes on the indoor air quality were evaluated in a comparative study by monitoring the airborne particle concentration and the extent of particle deposition at the enclosed corridor as well as inside the museum building. Comparison of the indoor/outdoor ratio of airborne particle concentration demonstrated a high natural ventilation rate in the enclosed corridor as well as inside the museum building. PM(10) deposition velocities on vertical surfaces were estimated in the order of 3 * 10(-4) m s(-1) for both indoor locations. Also, the deposition rates of dark-coloured and black particles in specific were very similar at both indoor locations, causing visual degradation. The effectiveness of the glass panes in protecting the museum collection is discussed. PMID- 22828926 TI - Analysis of the health status of the homeless clients utilizing a free clinic. AB - The purpose of this study is to evaluate the health status of the homeless population who utilize a free clinic. The study specifically aims to compare the prevalence of asthma, diabetes, tuberculosis, mental health disorders, sexually transmitted diseases, sinus problems, and hepatitis among the homeless population. Investigators collected data from paper medical records during patient visits from 2004 to 2009. Diagnosed health conditions among the homeless population were compared to the general clinic users using logistic regression. There were several similarities between the general clinic and homeless population, however, the homeless population had statistically significant (p < 0.05) outcomes for diagnosed cases of tuberculosis, hepatitis, anxiety, and bipolar disorders. Prevalence of diabetes, sinus problems, asthma, diabetes, and depression were similar among both populations. The odds ratios among hepatitis, tuberculosis, STDs, bipolar disorder and anxiety disorder indicated the homeless had a significantly greater risk of developing hepatitis, tuberculosis, and bipolar disorder. This study adds to the literature by illustrating the characteristics of the homeless population who utilize the free health clinic and their medical conditions. Previous studies have shown the free clinic clients have a lower level of health than the general population. This study finds that the homeless clients of a free clinic have an even worse level of health than the general clinic clients. This research can contribute to the improvement of the healthcare delivery system in providing access to needed health care services for the homeless population. PMID- 22828925 TI - Down-regulation of miR-124/-214 in cutaneous squamous cell carcinoma mediates abnormal cell proliferation via the induction of ERK. AB - Squamous cell carcinoma (SCC) is one of the most common skin cancers. Because its potential to recur and metastasize leads to a poor prognosis and significant mortality, it is necessary to develop new early diagnostic tools and new therapeutic approaches. In this study, we found protein levels of ERK1 and ERK2 were increased in SCC cell lines without changing mRNA levels and that ERK1/2 mediates abnormal cell proliferation in these cells. Then, mechanisms underlying the overexpression of ERK1/2 in SCC were investigated focusing on microRNA. We found that miR-214 is the regulator of ERK1, whereas ERK2 is regulated by miR-124 and miR-214. Expression of miR-124 and miR-214 was significantly down-regulated in SCC in vitro and in vivo. Treatment with 5-aza-deoxycytidine and trichostatin A synergistically recovered the miR-124/-214 down-regulation in SCC cell line. However, bisulphite sequencing revealed the methylation status of miR-124/-214 promoter was not increased in the SCC cell line and tumor tissue. Taken together, the down-regulation of miR-124/-214 in SCC is most likely caused, at least in part, by hypermethylation of other promoter regions rather than the miR-124/-214 promoter. Supplementation of these microRNAs in the SCC cell line reduced the abnormal cell proliferation by normalizing ERK1/2 levels. Additionally, serum concentration of miR-124 was correlated with miR-124 expression levels in the tumor tissues and inversely correlated with tumor progression. On the other hand, miR-214 was not detected in the serum. Investigation of the regulatory mechanisms of keratinocyte proliferation by microRNA may lead to develop new biomarkers and treatments using microRNA. PMID- 22828927 TI - Molecular markers in peripheral blood of Iranian women with breast cancer. AB - A biomarker is a quantifiable laboratory measure of a disease specific biologically relevant molecule that can act as an indicator of a current or future disease state. The purpose of this study is to detect the expression of RNA biomarkers using Cytokeratin 19 (CK-19), Mammaglobin (MAM), Carcinoembryonic antigen (CEA), Mucin (MUC), C-Myc, erb-B2, a proliferation marker (Ki-67), Epidermal growth factor receptor (Her2/neu) and Estrogen receptor (ER) in Iranian women who were diagnosed with breast cancer. In this study, 90 samples; 60 cancer patients and 30 healthy controls were considered. 73.4 % patients were in stage I/II and 26.6 % were in stage III/IV. Patients were selected prior to the administration of any adjuvant systemic therapy. Total RNA extraction was obtained from peripheral blood of each patient and healthy control. Reverse transcription polymerase chain reaction (RT-PCR) method was used for detection of mRNA of the selected biomarkers of circulating breast cancer cells in blood. Molecular characterization is assessed as a method for early detection of breast cancer. For this purpose, eleven specific primers were selected and RT-PCR was used. The data of RT-PCR revealed that expression of MUC1, CK19, CEA, MAM, erbB 2, Ki67 and C-Myc biomarkers were significantly different between breast cancer patients and healthy controls. On the other hand, ERalpha, ERbeta and Her2 markers were not significantly different between the two mentioned groups. Biomarkers detection of breast cancer patients could be assessed as a diagnostic factor and its potential for conveying as a prognostic factor require further studies, with a larger number of patients. PMID- 22828928 TI - Insights into the elementary steps in Negishi coupling through kinetic investigations. AB - The Negishi coupling has been widely applied in organic synthesis, while relevant mechanistic studies are relatively rare. To obtain an understanding of the fundamental steps in the Negishi coupling, oxidative addition, transmetalation and reductive elimination, the kinetic investigation has served as one of the most important strategies. In this review, insights into the elementary steps in the Negishi coupling through kinetic investigations are summarized. PMID- 22828929 TI - DNA Metabolism: MMS19: CIA agent for DNA-linked affairs. PMID- 22828930 TI - Enhancing the photocatalytic efficiency of TiO2 nanopowders for H2 production by using non-noble transition metal co-catalysts. AB - Co and Ni-nanoclusters are attractive alternatives to Pt catalysts for hydrogen generation. These earth abundant elements when loaded onto the TiO(2) nanopowders surface act as efficient co-catalysts. Co, Ni-decorated TiO(2) photocatalysts display only three (3) times lower catalytic activities for H(2) evolution under UV illumination compared with Pt-decorated TiO(2) photocatalysts. PMID- 22828931 TI - Molecular characterization of Cryptosporidium in native beef calves in central Vietnam. AB - The aims of this study were to investigate the prevalence of Cryptosporidium and to characterize the genotype distribution of Cryptosporidium isolates in native beef calves 2-6 months old in Dac Lac province, central Vietnam. The presence of Cryptosporidium oocysts was determined using the modified Ziehl-Neelsen staining method. The overall prevalence on the sample and herd levels were 18.9% (44/232) and 50% (20/40), respectively. Genotyping based on PCR and sequence analysis of the 18 S rRNA gene revealed occurrence of the two nonzoonotic species Cryptosporidium ryanae and Cryptosporidium bovis, with the former as a dominant species in the animals. The absence of the zoonotic species Cryptosporidium parvum in calves examined suggests that the native beef calves 2-6 months old in the study area are unlikely to contribute to human cryptosporidiosis transmission. PMID- 22828932 TI - The kinetics of oocyst shedding and sporulation in two immunologically distinct strains of Eimeria maxima, GS and M6. AB - The kinetics of oocyst shedding and sporulation of two immunologically distinct strains of Eimeria maxima (GS and M6) were compared. Both strains had a prepatent period of approximately 120 h followed by peak oocyst shedding at 144-150 h post inoculation. Mean total oocyst output determined for each strain demonstrated that the fecundity of the M6 strain (12.8 * 10(3) +/- 1.95) of E. maxima was roughly twice that of the GS strain (6.9 * 10(3) +/- 3.33) when inoculated at the rate of 1,000 infective oocysts per bird. The process of oocyst sporulation was followed by repetitive sampling of sporulating oocysts at 26 degrees C with aeration over a 138 hour period. Sporulation was divided into five morphologically distinguishable stages whose abundance peaked at the following times during sporulation: unsporulated oocysts at 0 h; sporoblast anlagen at 18 h; sporoblasts without sporocyst walls at 22 h; and sporocysts without mature sporozoites at 38 h. The time to 50 % sporulation of E. maxima oocysts observed in the present study was approximately 53 h for both strains and all viable oocysts had completed sporulation by 60 h. In the present study, the prepatent periods, duration of oocyst shedding, and the relative kinetics of sporulation of the GS and M6 strains of E. maxima were found to be virtually identical despite the immunological distinctiveness of these two parasite strains. PMID- 22828933 TI - Observations on morphology of immature Lucilia porphyrina (Diptera: Calliphoridae), a fly species of forensic importance. AB - Lucilia porphyrina (Walker) is a blow fly of forensic importance, and shares its geographical distribution with a related forensically important species, Lucilia cuprina (Wiedemann). The immature stages of both species are similar in general appearance; therefore, correct identification should be given special consideration. This study highlighted the main features of L. porphyrina larvae, as observed under light microscopy and scanning electron microscopy. Particular attention is given to the anterior and posterior spiracles, cephalopharyngeal skeleton, and characteristics of the dorsal spines between the prothorax and mesothorax. In the third instar specifically, morphological information on L. porphyrina showed several features that are shared by L. cuprina, and therefore need certain identification to distinguish between them. Such key features are (1) greater posterior spiracle, (2) apparent inner projection between the middle and lower slits of the posterior spiracle, and (3) strongly sclerotized peritreme. The number of papillae on the anterior spiracle may be a supplement, five to nine and three to six in L. porphyrina and L. cuprina, respectively. The key for identifying third instar of forensically important flies in Thailand has been updated to include L. porphyrina. PMID- 22828934 TI - Prevalence of Acanthamoeba spp. (Sarcomastigophora: Acanthamoebidae) in wild populations of Aedes aegypti (Diptera: Culicidae). AB - Studies of interrelationship between microorganisms and mosquitoes are of great importance, since it can provide support for better understand related to biology, development and their control. In this way, it is known that mosquito larvae and free-living amoebae (FLA) normally occupy similar aquatic microhabitats. However, few studies have been conducted about such coexistence. For that reason, the objective of the present study was to verify the prevalence of Acanthamoeba spp. in wild populations of Aedes aegypti, as well as to characterize the genotypic lineage, and their possible pathogenicity through thermo- and osmotolerance. Amoebae were investigated in 60 pools, each containing ten larvae of A. aegypti, collected in Porto Alegre (Rio Grande do Sul, Brazil). The Acanthamoeba isolates were morphologically characterized and submitted to the polymerase chain reaction technique to confirm identification of the genus. In addition, genotype analyses as well as tests for presumptive pathogenicity in some samples were performed. Of the 60 pools examined, 54 (90 %) were positive for FLA. Of these isolates, 47 (87 %) belonged to the genus Acanthamoeba. The genotypic groups T4, T3 and T5 were identified, numbering 14 (53.8 %), ten (38.5 %) and two (7.7 %) isolates, respectively. The physiological tests performed with 14 strains showed that 12 (85.7 %) were non-pathogenic, while two (14.3 %) were considered as having low pathogenic potential. These results provide a basis for a better understanding of the interaction between these protozoan and mosquitoes in their natural habitat. This study is the first to report the isolation of Acanthamoeba spp. from wild mosquitoes. PMID- 22828935 TI - The repeatability of digital shade measurement--a clinical study. AB - OBJECTIVES: The intraoral VITA Easyshade spectrophotometer is a shade measurement system that provides for objective determination of the shade of natural teeth and of dental materials. Over a period of 2.5 years, this clinical study assessed the repeatability of VITA Easyshade measurement, using metal ceramic restorations and based on L*a*b* parameters. MATERIALS AND METHODS: Shade tests of 25 metal ceramic crowns were carried out objectively in 19 patients using VITA Easyshade and subjectively by a dentist. The measurements were taken using a separate positioning device at the time of insertion, after 14 days (baseline), after 6 months, after 1.5 years and after 2.5 years. RESULTS: ?E was calculated from ?L*, ?a*, ?b* data as a measure of the differences in shade. The average values during the follow-up controls were ?E 2 = 2.2 (6 months), ?E 3 = 2.3 (1.5 years) and ?E 4 = 2.0 (2.5 years). Subjective shade analysis during the follow-up controls did not reveal any changes in the ceramic veneer. CONCLUSIONS: The average of ?E = 2.1 represented the difference in color. The examiner could not detect any difference in color over the evaluation period of 2.5 years. CLINICAL RELEVANCE: Good results in terms of the repeatability and accuracy of VITA Easyshade measurements were reported in previous in vitro studies. Objective assessment under clinical conditions is required in order to evaluate the shade stability of tooth-colored restorative materials in the oral cavity. For this purpose, the quality and handling of VITA Easyshade must be verified from a clinical perspective. PMID- 22828936 TI - Conformation and stability properties of B17: I. Analytical investigations using circular dichroism. AB - Structural characterization of B17, the 17% N-terminal domain of apo B, was carried out using circular dichroic (CD) spectroscopy, where secondary and tertiary structures were studied as a function of temperature and pH. Mild acidic conditions that correlate with histidine protonation invoked a change in the alpha-helix and random coil contents of the protein, with no apparent change in the beta-sheet structural content. Specific changes in the structure of the protein that occur in response to temperature were also investigated to understand the stability and conformational changes of B17. Far- and near-UV CDs were used to probe the thermal changes in the protein. The protonation of some histidine residues was attributed to underlie the increase in the helical content of the protein. PMID- 22828937 TI - 50 years ago in CORR: Suppurative arthritis of the hip joint in infants. 1962. PMID- 22828938 TI - Expression of vitamin D-metabolizing enzymes in human adipose tissue -- the effect of obesity and diet-induced weight loss. AB - OBJECTIVE: Low vitamin D (VD) levels are common in obesity. We hypothesized that this may be due to metabolism of VD in adipose tissue (AT). Thus, we studied (1) whether the VD-metabolizing enzymes were expressed differently in AT of lean and obese individuals and in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and (2) whether their expression was influenced by weight loss. METHODS: Samples of SAT and VAT were analyzed for expression of the vitamin-D-25 hydroxylases CYP2R1, CYP2J2, CYP27A1 and CYP3A4, the 25-vitamin-D-1alpha hydroxylase CYP27B1, the catabolic vitamin-D-24-hydroxylase CYP24A1, and the vitamin D receptor, using reverse transcriptase-PCR. Moreover, plasma 25-hydroxy vitamin D (25OHD) level was measured and related to the expression of these enzymes. Samples of SAT and VAT from 20 lean women and 20 obese women, and samples of SAT from 17 obese subjects before and after a 10% weight loss were analyzed. RESULTS: A plasma 25OHD level <50 nmol l(-1) was highly prevalent in both lean (45%) and obese (90%) women (P<0.01). Plasma 25OHD increased by 27% after weight loss in the obese individuals (P<0.05). Expression levels of the 25 hydroxylase CYP2J2 and the 1alpha-hydroxylase CYP27B1 were decreased by 71% (P<0.0001) and 49% (P<0.05), respectively, in SAT of the obese. CYP24A1 did not differ between lean and obese women, but the expression was increased by 79% (P<0.05) after weight loss. CONCLUSION: Obesity is characterized by a decreased expression of the 25-hydroxylase CYP2J2 and the 1alpha-hydroxylase CYP27B1 in SAT, whereas the catabolic CYP24A1 does not differ between lean and obese women. However, the expression of CYP24A1 is increased after weight loss. Accordingly, AT has the capacity to metabolize VD locally, and this can be dynamically altered during obesity and weight loss. PMID- 22828939 TI - Enuresis--an unattended comorbidity of childhood obesity. AB - OBJECTIVE: Obstructive sleep apnea (OSA), attention deficit/hyperactivity disorder (ADHD), type 2 diabetes mellitus and psychopathological problems co occur at increased rates among both obese and enuretic children. We hypothesized that the prevalence of enuresis will be increased in obese children and adolescents. DESIGN: A cross-sectional study. SUBJECTS: 281 children and adolescents aged 7-18 years, who completed a questionnaire regarding enuresis, medical conditions and sociodemographic parameters; 158 were normal weight, 37 overweight (85th?BMI (body mass index)<95th percentiles) and 86 obese (BMI?95th percentile). MAIN OUTCOME MEASURE(S): Occurrence of enuresis among obese children and adolescents. RESULTS: Enuresis was reported in 14 (8.8%) normal weight, 6 (16%) overweight and 26 (30%) obese youth. Odds ratio (OR)=6.5, 95% confidence interval (CI)=2.67-15.78 for enuresis among obese compared with normal weight (P<0.0001). Each increment of one BMI-Z score unit was associated with an increased risk of enuresis, OR of 2.14, 95% CI (1.46-3.12), P=0.00008. Male gender (OR 2.84, 95% CI (1.10-5.58), P=0.028), first-degree relative with current/past enuresis (OR 4.24, 95% CI (1.62-11.08), P=0.003), voiding dysfunction symptoms (OR 3.067, 95% CI (1.05-9.00), P=0.041) and ADHD (OR 2.31, 95% CI (0.99-5.34), P=0.051) increased the risk of enuresis. OSA-related symptoms, academic achievements in school, sharing a bedroom, family size relative to number of rooms in home, parental education, family status and religious observance were not found to increase the risk for enuresis. CONCLUSIONS: Obese children are at increased risk for enuresis. Enuresis should be clarified during the primary workup of every obese child and adolescent. PMID- 22828940 TI - Synphilin-1 alters metabolic homeostasis in a novel Drosophila obesity model. AB - AIMS: The pathogenesis of obesity remains incompletely understood. Drosophila have conserved neuroendocrine and digestion systems with human and become an excellent system for studying energy homeostasis. Here, we reported a novel obesity Drosophila model, in which expression of human protein, synphilin-1 (SP1), in neurons fosters positive energy balance. SUBJECTS AND METHODS: To further understand the actions of SP1 in energy balance control, the upstream activation sequence UAS/GAL4 system was used to generate human SP1 transgenic Drosophila. We characterized a human SP1 transgenic Drosophila by assessing SP1 expression, fat lipid deposition, food intake and fly locomotor activity to determine the major behavioral changes and their consequences in the development of the obesity-like phenotype. RESULTS: Overexpression of SP1 in neurons, but not peripheral cells, increased the body weight of flies compared with that of non transgenic controls. SP1 increased food intake but did not affect locomotor activity. SP1 increased the levels of triacylglycerol, and the size of fat body cells and lipid droplets, indicating that SP1 increased lipid-fat disposition. Survival studies showed that SP1 transgenic flies were more resistant to food deprivation. SP1 regulated lipin gene expression that may participate in SP1 induced fat deposition and starvation resistance. CONCLUSION: These studies demonstrate that SP1 expression affects energy homeostasis in ways that enhance positive energy balance and provide a useful obesity model for future pathogenesis and therapeutic studies. PMID- 22828941 TI - Impact of REV-ERB alpha gene polymorphisms on obesity phenotypes in adult and adolescent samples. AB - BACKGROUND: REV-ERBalpha has been shown to regulate adipogenesis and lipid metabolism as well as to link the circadian timing system to whole body metabolic homeostasis. We thus tested whether polymorphisms in REV-ERBalpha could be associated with metabolic phenotypes in human population samples. METHODS: We analyzed the associations between 5 REV-ERBalpha polymorphisms and anthropometric (body weight, body mass index (BMI), waist and hip circumferences), biochemical (plasma lipid, glucose and insulin levels) and clinical (systolic and diastolic blood pressure) variables in three population-based studies (MONICA Lille n=1155 adults, MONA LISA Lille n=1170 adults and HELENA n=1155 adolescents). We assessed in vitro, the potential influence of one REV-ERBalpha polymorphism in transient transfection assays using two different cell lines. RESULTS: We observed significant and consistent associations between the T minor allele of the REV ERBalpha rs2071427 polymorphism (located in intron 1) and higher BMI (mean allele effect=+0.33 kg m(-2)) in the MONICA Lille (P=0.02), MONA LISA (P=0.02) and HELENA (P=0.03) studies. The odds ratios for obesity associated with this allele were 1.67 (1.00-2.79) (P=0.05) in MONICA Lille, 1.29 (1.01-1.65) (P=0.04) in MONA LISA Lille and the odds ratio for overweight was 1.48 (1.08-2.03) (P=0.01) in HELENA. In transfection experiments in human hepatocyte-derived cell lines, the REV-ERBalpha intron 1 directed the transcription of a luciferase reporter gene independently of the rs2071427 polymorphism. CONCLUSION: Our results suggest that the REV-ERBalpha rs2071427 polymorphism modulates body fat mass in both adult and young people. PMID- 22828942 TI - Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue. AB - OBJECTIVE: Obesity is associated with chronic inflammation of the adipose tissue, which contributes to obesity-associated complications such as insulin resistance and type 2 diabetes. Interleukin (IL)-33 acts via its receptor ST2 and is involved in the pathogenesis of inflammatory disorders including atherosclerosis and heart disease. IL-33 has been demonstrated to promote endothelial cell inflammatory response, but also anti-inflammatory and protective actions such as TH2 and M2 polarization of T cells and macrophages, respectively. IL-33 and ST2 have been shown to be expressed in human and murine adipose tissue. Our objective was to investigate alterations in obesity and a possible role of IL-33 in adipose tissue inflammation. SUBJECTS AND METHODS: We investigated severely obese patients (BMI>40 kg m(-2), n=20) and lean to overweight controls (BMI<30 kg m( 2); n=20) matched for age and sex, as well as diet-induced obese and db/db mice, in order to determine the impact of obesity on IL-33 and ST2 gene and protein expression levels in adipose tissue and blood, and their correlation with inflammatory and metabolic parameters. Furthermore, we examined the cellular source and location of IL-33 and ST2 in situ. RESULTS: IL-33 and ST2 expression levels were markedly elevated in omental and subcutaneous adipose tissue of severely obese humans and in diet-induced obese mice, but not in leptin receptor deficient db/db mice. In addition, soluble ST2, but not IL-33 serum levels, were elevated in obesity. The main source for IL-33 in adipose tissue were endothelial cells, which, in humans, exclusively expressed ST2 on their surface. IL-33 expression strongly correlated with leptin expression in human adipose tissue. CONCLUSIONS: Expression of IL-33 and its receptor ST2 in human adipose tissue is predominantly detectable in endothelial cells and increased by severe obesity indicating an autocrine action. Thus, the adipose tissue microvasculature could participate in obesity-associated inflammation and related complications via IL 33/ST2. PMID- 22828943 TI - Bariatric surgery and bone disease: from clinical perspective to molecular insights. AB - The use of bariatric surgery for the treatment of morbid obesity has increased annually for the last decade. Although many studies have demonstrated the efficacy and durability of bariatric surgery for weight loss, there are limited data regarding long-term side effects of these procedures. Recently, there has been an increased focus on the impact of bariatric surgery on bone metabolism. Bariatric surgery utilizes one or more of three mechanisms of action resulting in sustained weight loss. These include restriction (gastric banding, vertical banded gastroplasty and sleeve gastrectomy), malabsorption surgery with or without associated restriction (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion and jejunoileal bypass) and changes in gut-derived hormones that control energy metabolism also referred to as neuro-hormonal control of energy metabolism (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion, jejunoileal bypass, surgical procedures as above and gastric sleeve). Weight reduction has been associated with increased bone resorption but the mechanisms behind this have not yet been fully elucidated. Each of the mechanisms of action of bariatric surgery (restriction, malabsorption, neuro-hormonal control of energy metabolism) may uniquely affect bone resorption. In this paper we will review the current state of knowledge regarding the relationship between bariatric surgery and bone metabolism with emphasis on possible mechanisms of action such as malnutrition, hormonal interactions and mechanical unloading of the skeleton. Further, we suggest a future research agenda. PMID- 22828944 TI - Predicting academic and cognitive outcomes from weight status trajectories during childhood. AB - OBJECTIVE: To identify childhood body mass index (BMI) trajectories and to describe their association with subsequent academic and cognitive outcomes. STUDY DESIGN: Prospective cohort: Height and weight measured annually from 4 to 7 years. A mixture of regressions approach grouped children into BMI trajectories (n=1959 children; n=5754 BMI measures). Academic outcomes included teacher-rated progress and achievement. Cognitive outcomes measured by Kaufman's Assessment Battery for Children. Academic and cognitive outcomes were regressed according to BMI trajectories, controlling for family and individual covariates. Subjects drawn from Quebec Longitudinal Study of Child Development (Canada), a 1998 birth cohort (n=2120). RESULTS: Four clusters of BMI trajectories emerged: two healthy weight groups, one overweight group and one low weight group. Relative to healthy weight, belonging to the overweight or low weight clusters was negatively associated with cognitive and academic outcomes. With the exception of the low weight cluster, this relationship was insignificant in the adjusted model. CONCLUSIONS: Results suggest that during childhood being overweight does not increase risk for poor educational outcomes. Instead, being underweight may the increase risk for poorer cognitive outcomes. Further group-based trajectory modeling (GBTM) for BMI development over time is needed to confirm results. PMID- 22828945 TI - CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans. AB - OBJECTIVE: Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis. DESIGN AND SUBJECTS: To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23). RESULTS: Weight loss averaged 8.5+/-1.4 kg in the rimonabant, 1.7+/-1.0 kg in the placebo and 7.5+/ 0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups. CONCLUSIONS: We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss. PMID- 22828946 TI - The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity. AB - OBJECTIVE: The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation Endproducts (RAGE) leads to inflammation via the NF kappabeta (nuclear factor kappabeta) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery. DESIGN: We conducted a cross-sectional study and a 24 month longitudinal study. SUBJECTS: We included 85 patients (mean age: 41 +/- 12 years; mean body mass index (BMI): 45.4 +/- 7.9 kg m(-2)) with MO in comparison with 40 CO (mean age: 42 +/- 13 years; mean BMI: 26.0 +/- 5.5 kg m(-2)). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (Delta) of parameters were calculated. RESULTS: Patients with MO had significant lower sRAGE levels than CO: 1010 +/- 514 vs 1501 +/- 674 pg ml( 1); P<0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010 +/- 514 to 1261 +/- 710 pg ml(-1); P=0.008. In the correlation analysis, DeltasRAGE levels were associated with Delta1-h and Delta2-h postprandial glucose, Deltafasting insulin, Delta2-h postprandial insulin, DeltaHOMA (homeostatic model assessment)-insulin resistance (DeltaHOMA IR), Deltagamma-glutamyl transferase and Deltatriglycerides. In a multivariate model, Delta1-h and Delta2-h postprandial glucose, Delta2-h postprandial insulin and DeltaHOMA-IR predicted DeltasRAGE. CONCLUSION: Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality. PMID- 22828947 TI - Computed tomography of ununited anconeal process in the dog. AB - OBJECTIVE: The purpose of this study was to describe computed tomography (CT) features of the ununited anconeal process and relate them with the following elbow dysplasia signs: medial coronoid disease, medial humeral condyle changes, osteoarthritis (OA), and radioulnar incongruence. METHODS: Computed tomographic images of dogs older than six months with an ununited anconeal process were evaluated (n = 13). Ununited anconeal process features were described as being complete or incomplete, and the degree of displacement, volume, and presence of cysts and sclerosis were also evaluated. Medial coronoid disease was defined as an irregular medial coronoid process shape, presence of sclerosis and fragmentation. Medial humeral condyle changes were defined as subchondral bone flattening, lucencies, and sclerosis. Osteoarthritis was graded depending on the osteophytes size. Radioulnar incongruence was measured on a sagittal view at the base of the medial coronoid process. RESULTS: Eleven elbows had a complete and two had an incomplete ununited anconeal process. All ununited anconeal processes had cystic and sclerotic lesions. Seven ununited anconeal processes were displaced and six were non-displaced. Mean ununited anconeal process volume was 1.35 cm3 (0.61 cm3 - 2.08 cm3). Twelve elbows had signs of medial coronoid disease (4 of them with a fragmented medial coronoid process), and one elbow did not show any evidence of medial coronoid disease. Ten elbows had medial humeral condyle changes. One elbow had grade 1 OA, seven elbows had grade 2, and five elbows grade 3. All elbows had radioulnar incongruence: three elbows had a negative and 10 elbows had a positive radioulnar incongruence. Mean radioulnar incongruence was 1.49 mm (0.63 mm - 2.61 mm). Computed tomographic findings were similar in the majority of the elbows studied: complete ununited anconeal processes with signs of medial coronoid disease, positive radioulnar incongruence, high grade of OA, sclerotic medial humeral condyle changes, and large ununited anconeal process volumes. CLINICAL SIGNIFICANCE: Incomplete small ununited anconeal process volumes could be associated with a lower incidence of medial coronoid disease or medial humeral condyle changes. We recommend performing preoperative CT of elbows with an ununited anconeal process to evaluate concurrent lesions. PMID- 22828948 TI - Creation of an American Holistic Nurses Association research consultation program. AB - A goal of the American Holistic Nurses Association (AHNA) Research Committee is to prepare holistic nurses to conduct holistic nursing research. This article describes the creation of a Research Consultation Program and how the knowledge gained from the program will contribute to the development of a formal research mentor program. PMID- 22828949 TI - The use of simulation to instruct students on the provision of spiritual care: a pilot study. AB - Providing spiritual care is recognized as a significant aspect of nursing practice. This pilot study was designed to determine if simulation is an effective method for instructing nursing students in the provision of spiritual care. Fifty-two students participated in a simulation exercise that introduced concepts of spiritual care. Simulation was successful in improving students' attitudes toward patient spirituality, assessment of spiritual needs, ability to refer patients to the appropriate spiritual caregivers, and communication skills. Incorporating spiritual care instruction into curricula may prove to be valuable in increasing students' awareness of spiritual care for patients and incorporation of such care into their practice. PMID- 22828950 TI - Effects of therapeutic touch on anxiety, vital signs, and cardiac dysrhythmia in a sample of Iranian women undergoing cardiac catheterization: a quasi experimental study. AB - PURPOSE OF THE STUDY: To investigate the effects of Therapeutic Touch (TT) on anxiety, vital signs, and cardiac dysrhythmia in women undergoing cardiac catheterization. DESIGN: It was a quasi-experimental study. The participants had no history of hallucination, anxiety, or other psychological problems. Participants had to be conscious and have attained at least sixth-grade literacy level. Participants were randomly assigned into an intervention group (n = 23; received 10-15 minutes TT), a placebo group (n = 23; received 10-15 minutes simulated touch), and a control group (n = 23; did not receive any therapy). Data were collected using Spielberger's anxiety test, cardiac dysrhythmia checklist, and vital signs recording sheet. Statistical analyses were considered to be significant at alpha = .05 levels. FINDINGS: Sixty-nine women ranging in age from 35 to 65 years participated. TT significantly decreased state anxiety p < 0.0001 but not trait anxiety (p = .88), decreased the incidence of all cardiac dysrhythmias p < 0.0001 except premature ventricular contraction (p = .01), and regulated vital signs p < 0.0001 in the intervention group versus placebo and control group. CONCLUSIONS: TT is an effective approach for managing state anxiety, regulating vital signs, and decreasing the incidence of cardiac dysrhythmia during stressful situations, such as cardiac catheterization, in Iranian cardiac patients. PMID- 22828952 TI - From course assignment paper to publishable manuscript. AB - Both undergraduate and graduate nursing students are expected to write numerous papers in their educational programs; however, most of these papers are never published. Many students and faculty lack the skills needed to convert a course assignment paper to a publishable manuscript. The purpose of this article is to describe 10 steps that can transform a course assignment paper into a publishable manuscript. These steps include outlining, clarifying the topic, clearly stating the purpose, identifying an appropriate audience, revising with faculty's feedback, querying journal editors, revising to conform to journal's author guidelines, requesting and responding to peer feedback, and finally editing and proofreading prior to submitting the manuscript. Faculty members are encouraged to make writing assignments that students can then convert to publishable manuscripts. Such publications form an essential cornerstone of professional holistic nursing. PMID- 22828951 TI - Loneliness as experienced by women living with chronic illness in rural areas. AB - PURPOSE: The purposes were to identify loneliness in rural women with chronic conditions and to identify the major themes represented in their descriptions of their feelings of loneliness. DESIGN: This study was a secondary analysis of data collected during a 22-week computer-based support and health online intervention in which rural women participated in virtual forums that allowed them to share life experiences. METHOD: Quantitative data were gathered from participants' self reported loneliness via the UCLA Loneliness Scale. Qualitative data analysis consisted of seeking loneliness themes imbedded in the participants' online exchanges. FINDINGS: High scores on the loneliness scale indicated a high degree of expressed loneliness, with possible scores of 20 to 80. The range of scores for all participants (n = 57) was 21 to 68; for those in the upper quartile (n = 12), the range was 52 to 68. Loneliness themes identified were longing for loved ones, changing relationships, listening in the background, and impact of rural factors. CONCLUSIONS: Because loneliness has been described as a painful experience and can have long-reaching effects on an individual's health, it is a factor to be considered in planning nursing care for individuals who may be at risk because of physical and/or emotional isolation. PMID- 22828953 TI - Identification of the dichotomous role of age-related LCK in calorie restriction revealed by integrative analysis of cDNA microarray and interactome. AB - Among the many experimental paradigms used for the investigation of aging, the calorie restriction (CR) model has been proven to be the most useful in gerontological research. Exploration of the mechanisms underlying CR has produced a wealth of data. To identify key molecules controlled by aging and CR, we integrated data from 84 mouse and rat cDNA microarrays with a protein-protein interaction network. On the basis of this integrative analysis, we selected three genes that are upregulated in aging but downregulated by CR and two genes that are downregulated in aging but upregulated by CR. One of these key molecules is lymphocyte-specific protein tyrosine kinase (LCK). To further confirm this result on LCK, we performed a series of experiments in vitro and in vivo using kidneys obtained from aged ad libitum-fed and CR rats. Our major significant findings are as follows: (1) identification of LCK as a key molecule using integrative analysis; (2) confirmation that the age-related increase in LCK was modulated by CR and that protein tyrosine kinase activity was decreased using a LCK-specific inhibitor; and (3) upregulation of LCK leads to NF-kappaB activation in a ONOO(-) generation-dependent manner, which is modulated by CR. These results indicate that LCK could be considered a target attenuated by the anti-aging effects of CR. Integrative analysis of cDNA microarray and interactome data are powerful tools for identifying target molecules that are involved in the aging process and modulated by CR. PMID- 22828954 TI - Use of glucosamine and chondroitin in relation to mortality. AB - Glucosamine and chondroitin are products commonly used by older adults in the US and Europe. There is limited evidence that they have anti-inflammatory properties, which could provide risk reduction of several diseases. However, data on their long-term health effects is lacking. To evaluate whether use of glucosamine and chondroitin are associated with cause-specific and total mortality. Participants (n = 77,510) were members of a cohort study of Washington State (US) residents aged 50-76 years who entered the cohort in 2000-2002 by completing a baseline questionnaire that included questions on glucosamine and chondroitin use. Participants were followed for mortality through 2008 (n = 5,362 deaths). Hazard ratios (HR) for death adjusted for multiple covariates were estimated using Cox models. Current (baseline) glucosamine and chondroitin use were associated with a decreased risk of total mortality compared to never use. The adjusted HR associated with current use of glucosamine (with or without chondroitin) was 0.82 (95 % CI 0.75-0.90) and 0.86 (95 % CI 0.78-0.96) for chondroitin (included in two-thirds of glucosamine supplements). Current use of glucosamine was associated with a significant decreased risk of death from cancer (HR 0.87 95 % CI 0.76-0.98) and with a large risk reduction for death from respiratory diseases (HR 0.59 95 % CI 0.41-0.83). Use of glucosamine with or without chondroitin was associated with reduced total mortality and with reductions of several broad causes of death. Although bias cannot be ruled out, these results suggest that glucosamine may provide some mortality benefit. PMID- 22828955 TI - Socioeconomic inequalities in homicide mortality: a population-based comparative study of 12 European countries. AB - Recent research has suggested that violent mortality may be socially patterned and a potentially important source of health inequalities within and between countries. Against this background the current study assessed socioeconomic inequalities in homicide mortality across Europe. To do this, longitudinal and cross-sectional data were obtained from mortality registers and population censuses in 12 European countries. Educational level was used to indicate socioeconomic position. Age-standardized mortality rates were calculated for post, upper and lower secondary or less educational groups. The magnitude of inequalities was assessed using the relative and slope index of inequality. The analysis focused on the 35-64 age group. Educational inequalities in homicide mortality were present in all countries. Absolute inequalities in homicide mortality were larger in the eastern part of Europe and in Finland, consistent with their higher overall homicide rates. They contributed 2.5% at most (in Estonia) to the inequalities in total mortality. Relative inequalities were high in the northern and eastern part of Europe, but were low in Belgium, Switzerland and Slovenia. Patterns were less consistent among women. Socioeconomic inequalities in homicide are thus a universal phenomenon in Europe. Wide-ranging social and inter-sectoral health policies are now needed to address the risk of violent victimization that target both potential offenders and victims. PMID- 22828957 TI - Metachronous carcinomas in colorectum and its clinicopathological significance. AB - PURPOSE: The study was designed to examine the significance of colorectal metachronous carcinoma in a large cohort of patients. METHODS: Over a mean follow up period of 10 years, the clinicopathological features, microsatellite instability (MSI) and clinical follow-up of 56 patients with metachronous colorectal carcinoma were analysed. RESULTS: The prevalence of metachronous colorectal carcinoma was 2.1 %. The metachronous colorectal carcinomas appeared between 7 and 246 months (mean = 66 months) after surgical resection of the index colorectal carcinomas. Thirty-six per cent (n = 20) of the metachronous carcinoma occurred more than 5 years after the operation of the index carcinoma. Of the 56 patients, 20 % (n = 11) of the metachronous colorectal carcinomas were mucinous adenocarcinoma. Cancers detected in the secondary operations (metachronous colorectal carcinomas), when compared with the primary index cancers, were smaller, showed higher proportions of mucinous adenocarcinoma and more often located in the proximal colon. Patients with metachronous colorectal cancers had higher prevalence of mucinous adenocarcinoma, loss of staining for MSI markers and better survival rates than other patients with colorectal cancers. CONCLUSIONS: Patients with metachronous colorectal carcinomas have characteristic features, and attention to these features is important for better management of this group of cancer. PMID- 22828956 TI - Modulation of gut microbiota by antibiotics improves insulin signalling in high fat fed mice. AB - AIMS/HYPOTHESIS: A high-fat dietary intake induces obesity and subclinical inflammation, which play important roles in insulin resistance. Recent studies have suggested that increased concentrations of circulating lipopolysaccharide (LPS), promoted by changes in intestinal permeability, may have a pivotal role in insulin resistance. Thus, we investigated the effect of gut microbiota modulation on insulin resistance and macrophage infiltration. METHODS: Swiss mice were submitted to a high-fat diet with antibiotics or pair-feeding for 8 weeks. Metagenome analyses were performed on DNA samples from mouse faeces. Blood was collected to determine levels of glucose, insulin, LPS, cytokines and acetate. Liver, muscle and adipose tissue proteins were analysed by western blotting. In addition, liver and adipose tissue were analysed, blinded, using histology and immunohistochemistry. RESULTS: Antibiotic treatment greatly modified the gut microbiota, reducing levels of Bacteroidetes and Firmicutes, overall bacterial count and circulating LPS levels. This modulation reduced levels of fasting glucose, insulin, TNF-alpha and IL-6; reduced activation of toll-like receptor 4 (TLR4), c-Jun N-terminal kinase (JNK), inhibitor of kappa light polypeptide gene enhancer in B cells, kinase beta (IKKbeta) and phosphorylated IRS-1 Ser307; and consequently improved glucose tolerance and insulin tolerance and action in metabolically active tissues. In addition, there was an increase in portal levels of circulating acetate, which probably contributed to an increase in 5'-AMP activated protein kinase (AMPK) phosphorylation in mice. We observed a striking reduction in crown-like structures (CLS) and F4/80(+) macrophage cells in the adipose tissue of antibiotic-treated mice. CONCLUSIONS/INTERPRETATION: These results suggest that modulation of gut microbiota in obesity can improve insulin signalling and glucose tolerance by reducing circulating LPS levels and inflammatory signalling. Modulation also appears to increase levels of circulating acetate, which activates AMPK and finally leads to reduced macrophage infiltration. PMID- 22828958 TI - Single-incision laparoscopic colectomy versus conventional multiport laparoscopic colectomy: a meta-analysis of comparative studies. AB - OBJECTIVE: This study aimed to compare single-incision laparoscopic colectomy (SILC) to conventional multiport laparoscopic colectomy (MLC). BACKGROUND: Single incision laparoscopic surgery (SILS) is a minimally invasive technique being recently applied to colorectal surgery. A number of studies comparing SILC to conventional MLC have recently been published. METHODS: A literature search of PubMed and MEDLINE databases for studies comparing SILC to conventional MLC was conducted. The primary outcome measures for meta-analysis were postoperative complications, length of stay, and operative time. Secondary outcome measures were incision length, estimated blood loss, and number of lymph nodes harvested. RESULTS: Fifteen studies comparing 467 patients undergoing SILC to 539 patients undergoing conventional MLC were reviewed and the data pooled for analysis. Patients undergoing SILC had a shorter length of stay (pooled weighted mean difference (WMD) = -0.68; 95 % CI = -1.20 to -0.16; p = 0.0099), shorter incision length (pooled WMD = -1.37; 95 % CI = -2.74 to 0.000199; p = 0.05), less estimated blood loss (pooled WMD = -20.25; 95 % CI = -39.25 to -1.24; p = 0.037), and more lymph nodes harvested (pooled WMD = 1.75; 95 % CI = 0.12 to 3.38; p = 0.035), while there was no significant difference in the number of postoperative complications (pooled odds ratio = 0.83; 95 % CI = 0.57 to 1.20; p = 0.33) or operative time (pooled WMD = 5.06; 95 % CI = -2.91 to 13.03; p = 0.21). CONCLUSION: SILC appears to have comparable results to conventional MLC in the hands of experienced surgeons. Prospective randomized trials are necessary to define the relative benefits of one procedure over the other. PMID- 22828960 TI - Effects of low cardiopulmonary reserve on pancreatic leak following pancreaticoduodenectomy. AB - BACKGROUND: Postoperative complications are increased in patients with reduced cardiopulmonary reserve undergoing major surgery. Pancreatic leak is an important contributor to postoperative complications and death following pancreaticoduodenectomy. The aim of this study was to determine whether reduced cardiopulmonary reserve was a risk factor for pancreatic leak. METHODS: All patients who underwent pancreaticoduodenectomy between January 2006 and July 2010 were identified from a prospectively held database. Data analysis was restricted to those who underwent cardiopulmonary exercise testing during preoperative assessment. Pancreatic leak was defined as grade A, B or C according to the International Study Group on Pancreatic Fistula definition. An anaerobic threshold (AT) cut-off value of 10.1 ml per kg per min was used to identify patients with reduced cardiopulmonary reserve. Univariable and multivariable analyses were performed to identify other risk factors for pancreatic leak. RESULTS: Some 67 men and 57 women with a median age of 66 (range 37-82) years were identified. Low AT was significantly associated with pancreatic leak (45 versus 19.2 per cent in patients with greater cardiopulmonary reserve; P = 0.020), postoperative complications (70 versus 38.5 per cent; P = 0.013) and prolonged hospital stay (29.4 versus 17.5 days; P = 0.001). On multivariable analysis, an AT of 10.1 ml per kg per min or less was the only independent factor associated with pancreatic leak. CONCLUSION: Low cardiopulmonary reserve was associated with pancreatic leak following pancreaticoduodenectomy. AT seems a useful tool for stratifying the risk of postoperative complications. PMID- 22828961 TI - First total synthesis of dioxepine bastadin 3. AB - The synthesis of dioxepine bastadin 3, a tyrosine-tyramine derivative with a dibenzo-1,3-dioxepine scaffold that is rarely present among natural products, is described. The dibenzo-1,3-dioxepine ring was formed early in the sequence and the (E)-2-(hydroxyimino)-N-alkylamide was generated in the last step by oxidation of the 2-amino-N-alkylamide precursor. The presumably biogenetic late-stage ring formation starting from congener bastadin 3 failed. A new synthesis of this alkaloid was also developed. This new route requires a minimal use of protecting groups and the order of the two key steps was reversed relative to the route to dioxepine bastadin 3. PMID- 22828959 TI - Magnetic resonance imaging biomarkers in patients with progressive ataxia: current status and future direction. AB - A diagnostic challenge commonly encountered in neurology is that of an adult patient presenting with ataxia. The differential is vast and clinical assessment alone may not be sufficient due to considerable overlap between different causes of ataxia. Magnetic resonance (MR)-based biomarkers such as voxel-based morphometry, MR spectroscopy, diffusion-weighted and diffusion-tensor imaging and functional MR imaging are gaining great attention for their potential as indicators of disease. A number of studies have reported correlation with clinical severity and underlying pathophysiology, and in some cases, MR imaging has been shown to allow differentiation of conditions causing ataxia. However, despite recent advances, their sensitivity and specificity vary. In addition, questions remain over their validity and reproducibility, especially when applied in routine clinical practice. This article extensively reviews the current literature regarding MR-based biomarkers for the patient with predominantly adult onset ataxia. Imaging features characteristic of a particular ataxia are provided and features differentiating ataxia groups and subgroups are discussed. Finally, discussion will turn to the feasibility of applying these biomarkers in routine clinical practice. PMID- 22828964 TI - Utility of standard pharmacopeial and nonpharmacopeial methods in distinguishing folded, unfolded, and process variant forms of interferon alpha-2. AB - Standard pharmacopeial test methods for biologics broadly focus on identity (active substance and impurities) and function (activity and toxicity). However, it is less clear which, if any, of the methods can identify a subtle change in protein therapeutics such as misfolding, unusual product-related impurities, or sequence or folding variants that may result from differences in manufacturing processes. In this study, we test the ability of standard pharmacopeia monograph methods and other common physicochemical methods (including circular dichroism spectropolarimetry, fluorescence spectroscopy, thermal denaturation, mass spectrometry, and capillary electrophoresis) to differentiate folding variants [purposely denatured interferon (IFN) alpha-2] and sequence variants (deliberately truncated, or truncated and chemically modified) from the IFN alpha 2 reference standards. The results show that the standard pharmacopeial methods are of limited utility in detecting alterations in protein structure, even when those alterations include changes in primary structure. None of the pharmacopeial methods were clear probes of higher order structure. The nonpharmacopeial methods were somewhat more successful but not a single method was able to distinguish all variants tested from the authentic standard. Taken together, the data underscore the requirement to use several different and complementary methods and stress conditions to assess primary and higher order structure when assessing the comparability in potential biosimilar protein products. PMID- 22828962 TI - Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma. AB - OBJECTIVES: To investigate the role of immunological parameters in tumorigenesis of cervical cancer in women infected with high risk human papillomavirus (hr HPV), and determine whether key findings with human material can be recapitulated in the mouse TC1 carcinoma model which expresses hr-HPV epitopes. METHODS: Epithelial and lymphoid cells in cervical tissues were analyzed by immunohistochemistry and serum IL10 levels were determined by ELISA. Tumor draining lymph nodes were analyzed in the mouse TC1 model by flow cytometry. RESULTS: The mucosa was infiltrated by CD20+ and CD138+ cells already at cervical intraepithelial neoplasia 1 (CIN1) and infiltration increased in cervical intraepithelial neoplasia 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC), where it strongly correlated with infiltration by CD32B+ and FoxP3+ lymphocytes. GATA3+ and T-bet+ lymphoid cells were increased in ICC compared to normal, and expression in epithelial cells of the Th2 inflammation-promoting cytokine TSLP and of IDO1 was higher in CIN3/CIS and ICC. As a corollary, serum levels of IL10 were higher in women with CIN3/CIS or ICC than in normals. Finally we demonstrated in the mouse TC1 carcinoma, which expresses hr-HPV epitopes, an increase of cells expressing B cell or plasma cell markers or Fc receptors in tumor-draining than distal lymph nodes or spleen. CONCLUSIONS: hr-HPV initiates a local Th2 inflammation at an early stage, involving antibody forming cells, and fosters an immunosuppressive microenvironment that aids tumor progression. PMID- 22828965 TI - Isohericenone, a new cytotoxic isoindolinone alkaloid from Hericium erinaceum. PMID- 22828963 TI - Intervention effects on physical activity and insulin levels in men of Pakistani origin living in Oslo: a randomised controlled trial. AB - High prevalence of type 2 diabetes (T2D) is seen in some immigrant groups in Western countries, particularly in those from the Indian subcontinent. Our aims were to increase the physical activity (PA) level in a group of Pakistani immigrant men, and to see whether any increase was associated with reduced serum glucose and insulin concentrations. The intervention was developed in collaboration with the Pakistani community. It used a social cognitive theory framework and consisted of structured supervised group exercises, group lectures, individual counselling and telephone follow-up. One- hundred and fifty physically inactive Pakistani immigrant men living in Oslo, Norway, were randomised to either a control group or an intervention group. The 5-month intervention focused on increasing levels of PA, which were assessed by use of accelerometer (Actigraph MTI 7164) recordings. Risk of diabetes was assessed by serum glucose and insulin concentrations determined in a fasted state, and after an oral glucose tolerance test (OGTT). ANCOVA was used to assess differences between groups. There was a mean difference in PA between the two groups of 49 counts per minute per day, representing a 15 % (95 % CI = 8.7-21.2; P = 0.01) higher increase in total PA level in the intervention group than in the control group. Insulin values taken 2 h after an OGTT were reduced in the intervention group by 27 % (95 % CI = 18.9-35.0; P = 0.02) more than those in the control group. There were no differences in fasting or postprandial glucose values between the groups at the follow-up test. This type of intervention can increase PA and reduce serum insulin in Pakistani immigrant men, thereby presumably reducing their risk of T2D. PMID- 22828966 TI - Antibacterial, antifungal and antileishmanial activities of indolone-N-oxide derivatives. AB - An alarming increase in microbial resistance to traditional drugs and classical pharmacophores has spurred the search for new antimicrobial compounds. Indolone-N oxides (INODs) possess a redox pharmacophore with promising, recently established, antimalarial activities. In this study, the anti-infectious properties of a series of INODs were investigated. The antibacterial activity was evaluated against five bacterial strains Gram-positive (Staphylococcus aureus, Enterococcus hirae), Gram-negative (Pseudomonas aeruginosa, Escherichia coli) and acid-fast (Mycobacterium tuberculosis). The antifungal activity was assessed using two fungal strains (Aspergillus niger, Candida albicans). The antileishmanial activity was tested against two leishmanial strains, axenically cultured amastigote (Leishmania infantum, Leishmania amazonensis). The pharmacological activities are discussed as a function of structural and lipophilic characteristics. The Gram-positive bacterial strain E. hirae was found to be the most sensitive strain, whereas the Gram-negative E. coli was resistant to this family of compounds. One compound (64) was more potent than nalidixic acid against E. hirae, whereas another one (52) was equipotent as clotrimazole against C. albicans. INODs were microbe -cidal rather than -static. INODs showed good antitubercular activity in the low micromolar range (similar to ciprofloxacin). In addition, INOD-antiprotozoal potencies were confirmed against the leishmania parasite. INODs showed a broad spectrum of antimicrobial activity and offer a promising anti-infectious prototype worthy of being developed. PMID- 22828967 TI - Theoretical design study on photophysical property on oligomers based on spirobifluorene and carbazole-triphenylamine for PLED applications. AB - The photophysical properties of five blue light-emitting polymers based on spirobifluorene applied in polymer light-emitting diodes (PLED) materials have been studied by quantum chemistry. In order to understand the intrinsic reasons for the different performances displayed by the polymers, we carried out density functional theory (DFT) and Marcus theory investigations on their oligomers in terms of structure and properties stability, absorption and emission properties, and carrier injection and transport properties. Especially, some important parameters which had not been reported to our knowledge were given in this contribution, such as the ionization potentials (IPs), electron affinities (EAs), reorganization energies (lambda), ke/kh (the ratio between the electron transfer rate (ke) and hole transfer rate (kh)), and the radiative lifetimes (tau). The main results indicate that the co-oligomers of PCC-1, PCC-2, and PCC-3 with push pull interactions produced by the existing D-A segments have better carrier injection and transport properties than the oligomers of PSF and PCF. Especially PCC-2 co-oligomer, its large radiation lifetime (7.46 ns) and well balanced and adequate carrier transport guarantee its champion performance for PLED. The calculated results coincide with the experimental ones. Besides, PNF structurally similar to PCC-2 has similar photoelectric properties to PCC-2 in theory, and the fluorescence emission of PNF co-oligomer is superior to PCC-2 co-oligomer. Therefore, we predict that PNF is a promising candidate for PLED. PMID- 22828968 TI - Discrepancies in medication information for the primary care physician and the geriatric patient at discharge. AB - BACKGROUND: Medication discrepancies in discharge medication lists can lead to medication errors and adverse drug events following discharge. OBJECTIVE: To determine the incidence and type of discrepancies between the discharge letter for the primary care physician and the patient discharge medication list as well as identify possible patient-related determinants for experiencing discrepancies. METHODS: A retrospective, single-center, cohort study of patients discharged from the acute geriatric department of a Belgian university hospital between September 2009 and April 2010 was performed. Medications listed in the discharge letter for the primary care physician were compared with those in the patient discharge medication list. Based on the clinical pharmacist-acquired medication list at hospital admission and the medications administered during hospitalization, we determined for every discrepancy whether the medication listed in the discharge letter or the patient discharge medication list was correct. RESULTS: One hundred eighty-nine discharged patients (mean [SD] age 83.9 [5.7] years, 64.0% female) were included in the study. Almost half of these patients (90; 47.6%) had 1 or more discrepancies in medication information at discharge. The discharge letters were often more complete and accurate than the patient discharge medication lists. The most common discrepancies were omission of a brand name in the patient discharge medication list and omission of a drug in the discharge letter. Increasing numbers of drugs in the discharge medication list (OR 1.19; 95% CI 1.07 to 1.32; p = 0.001) and discharge letter (OR 1.18; 95% CI 1.07 to 1.32; p = 0.001) were associated with a higher risk for discrepancies. CONCLUSIONS: Discrepancies between the patient discharge medication list and the medication information in the discharge letter for the primary care physician occur frequently. This may be an important source of medication errors, as confusion and uncertainty about the correct discharge medications can originate from these discrepancies. Increasing numbers of drugs involve a higher risk for discrepancies. Medication reconciliation between both lists is warranted to avoid medication errors. PMID- 22828969 TI - Assessing pharmacy residents' knowledge of biostatistics and research study design. AB - BACKGROUND: Historically, clinicians have demonstrated a lack of confidence and poor aptitude for biostatistics as a tool for medical literature interpretation. Evaluation of pharmacy residents' ability to interpret biostatistics commonly used in peer-reviewed literature has not been previously conducted. OBJECTIVE: To evaluate the level of understanding and perception of biostatistics concepts among pharmacy residents. METHODS: A survey of postgraduate year 1 (PGY1) residents in American Society of Health-System Pharmacists-accredited residency programs was conducted in May 2009. The survey instrument consisted of 27 items, including 10 knowledge-based questions, and was distributed to residency programs for anonymous reporting via SurveyMonkey. The primary outcome of interest was biostatistics knowledge, defined as the percent total score of correct knowledge items. Statistical attitude and confidence questions were rated on a 5-point Likert-type scale (1 = strongly disagree, 5 = strongly agree). The t-test or 1 way analysis of variance was conducted, as appropriate, to assess for differences in mean biostatistics knowledge scores by respondent characteristics. Forward stepwise regression was used to identify which characteristics were independently associated with biostatistics knowledge. RESULTS: A total of 214 PGY1 residents responded to the online survey assessment, and a subset of respondents (n = 166) answered 1 or more of the biostatistics knowledge questions. Of those who responded to at least 1 knowledge assessment, the overall mean (SD) biostatistics knowledge score was 47.3% (18.50%; range 0-90). Overall, respondents were predominantly female (74%) and younger than 30 years (81%). Residents scored highest in the recognition of the purpose of a double-blind study (92.6%; 95% CI 88.52 to 96.67), interpretation of relative risk (75.8%; 95% CI 69.02 to 82.57), and identification of the appropriate analytic method for a nominal variable (69.4%; 95% CI 62.16 to 76.59). Bivariate analyses showed that there were statistically significant mean differences in knowledge scores by attitude (p = 0.001) and confidence (p < 0.001). The multivariate model showed that above average confidence ratings were associated with an absolute increase of 7.6% in biostatistics knowledge score (p < 0.019) compared to those whose confidence rating was at or below average. CONCLUSIONS: Overall, pharmacy residents' perception and understanding of biostatistics were poor in this assessment, which correlates with previous reports. Enhanced training in biostatistics and literature evaluation of both mentors and trainees should be incorporated in PharmD programs and residency training sites. PMID- 22828970 TI - Retrospective evaluation of enoxaparin dosing in patients 48 weeks' postmenstrual age or younger in a neonatal intensive care unit. AB - BACKGROUND: Enoxaparin is the anticoagulant of choice in neonates because of the ease of administration, predictable pharmacokinetics, and reduced adverse effects when compared to heparin. The Chest guidelines recommend that therapy in patients younger than 2 months should be initiated with enoxaparin 1.5 mg/kg administered subcutaneously twice daily. This starting dosage may be inadequate, leading to a delay in achieving therapeutic anti-factor Xa plasma concentrations. OBJECTIVE: To determine an enoxaparin dose for neonatal patients that achieves a therapeutic anti-factor Xa plasma concentration and compare that dose to the recommended enoxaparin dose per published guidelines for this patient population. METHODS: The study was designed as a single-center chart review. Eligible patients were identified by pharmacy anticoagulation records or a search of the electronic medical record for enoxaparin orders. Patients must have received enoxaparin subcutaneously twice daily and have had a postmenstrual age of 48 weeks or younger. Patients diagnosed with renal failure and those receiving prophylactic doses of enoxaparin were excluded. RESULTS: The mean (SD) initial dose of enoxaparin was 1.4 (0.3) mg/kg subcutaneously twice daily, resulting in 27 of 33 patients (81.8%) having a subtherapeutic anti-factor Xa concentration. A mean enoxaparin dose of 2.0 (0.5) mg/kg was required to achieve a therapeutic anti factor Xa plasma concentration (p < 0.001). Patients born prematurely required a higher enoxaparin dose (2.2 [0.5] mg/kg) than did those born at full-term gestation (1.8 [0.4] mg/kg; p < 0.05). CONCLUSIONS: For patients 48 weeks' postmenstrual age or younger who are treated in a neonatal intensive care unit, a higher initial dose of enoxaparin than that suggested by the Chest guidelines is required to attain a therapeutic antifactor Xa plasma concentration. Premature neonates require a larger starting dose of enoxaparin than do infants born at full-term gestation. PMID- 22828971 TI - Lurasidone: an atypical antipsychotic for schizophrenia. AB - OBJECTIVE: To provide a clinical overview of the antipsychotic lurasidone. DATA SOURCES: Articles were identified by searching the MEDLINE, PubMed, Cochrane Library, and EBSCO databases (through February 2012) using the key word lurasidone. The manufacturer provided information on unpublished Phase 2 and 3 trials. The Clinicaltrials.gov database was reviewed for the status of ongoing and upcoming trials. STUDY SELECTION AND DATA EXTRACTION: All clinical trials lasting longer than 3 weeks and published in the English language were selected for review. Additional documentation, including the product dossier, package insert, and poster presentations supplied by the publisher, was also evaluated. DATA SYNTHESIS: Lurasidone hydrochloride is an atypical antipsychotic that is approved for the treatment of schizophrenia. It is under investigation for treatment of bipolar I disorder. It should be administered with food, is pregnancy category B, is contraindicated for coadministration with strong CYP3A4 inducers and inhibitors, and requires dose adjustments with certain medications and in renal and hepatic impairment. Like other atypical antipsychotics, lurasidone possesses dopamine D(2) and serotonin 5-HT(2A) antagonism but exhibits little affinity for histamine H(1), alpha(1)-adrenergic, or cholinergic M1 receptors. Additionally, it is a potent 5-HT(7) antagonist, which may impact depression and cognition. Phase 3 trial results revealed that 40-80 mg administered once daily resulted in statistically significant improvements in schizophrenia symptomatology compared with placebo. Lurasidone's rate of metabolic adverse events is low relative to other atypical antipsychotics; however, this is offset by dose-dependent increases in somnolence, akathisia, and parkinsonism. CONCLUSIONS: Lurasidone has shown efficacy when compared to placebo in acute schizophrenia. Full characterization of the adverse effect profile and cognitive and affective benefits requires publication of trials with longer durations. PMID- 22828972 TI - Ranolazine-induced severe bladder hypotonia. AB - OBJECTIVE: To describe a case of acute urinary retention due to bladder hypotonia during ranolazine treatment. CASE SUMMARY: An 81-year-old male with multiple cardiovascular diseases was hospitalized for worsening angina and heart failure symptoms. Ranolazine 375 mg twice daily was started, in addition to ongoing therapy (clopidogrel 75 mg once daily, diltiazem 60 mg 3 times daily, isosorbide mononitrate 40 mg 3 times daily, carvedilol 6.25 mg twice daily, rosuvastatin 20 mg once daily, enoxaparin 5000 IU once daily, pentoxifylline 600 mg twice daily, pantoprazole 40 mg twice daily, enalapril 20 mg twice daily, furosemide 150 mg once daily, and spironolactone 37 mg once daily). Two months later, the ranolazine dose was increased to 500 mg twice daily; shortly thereafter, acute urinary retention occurred and persisted despite institution of alpha-lytic (alfuzosin) and antiandrogenic (dutasteride) therapy. A urodynamic study revealed that urinary retention was caused by severe hypocontractility of the detrusor muscle. Ranolazine was withdrawn and, within 2 days, the patient recovered his ability to void spontaneously; a second urodynamic study confirmed that detrusor contractility was substantially improved. Drug rechallenge was not performed due to the patient's clinical condition. Nevertheless, a phenotyping test to assess the activity of the cytochrome isoenzymes CYP3A4 and CYP2D6 (responsible for ranolazine metabolism) was performed, with dextromethorphan used as the probe drug. The urinary metabolic ratios indicated relatively low activity for CYP3A4 and intermediate activity for CYP2D6. DISCUSSION: The causal role of ranolazine in our case of bladder hypotonia is probable according to the Naranjo criteria. The mechanism of bladder dysfunction is tentatively ascribed to blockage of late sodium current in smooth muscle cells. Although drug plasma concentrations were not measured, they were probably elevated, since the metabolic activity of CYP3A4 was at the lower end of the reference range. Enzyme inhibition produced by diltiazem may have contributed to decreasing CYP3A4 activity. CONCLUSIONS: Acute urinary retention in elderly men taking ranolazine may be due to drug-induced bladder hypotonia. PMID- 22828973 TI - News flash: Old Mother Hubbard reports the cupboard is bare...time for the FDA to let droperidol out of the (black) box. AB - A quick way for a clinical pharmacist to eliminate himself or herself from "employee of the month" consideration is to mention the term medication shortage. Even with training geared toward maximizing resources, the cumulative disappearance of a plethora of medications for the treatment of nausea, vomiting, and/or primary headaches is almost too much for emergency medicine physicians to manage. With prochlorperazine, metoclopramide, promethazine, and ondansetron in increasingly short supply, it is time for the Food and Drug Administration to revisit droperidol's black box warning driven by QTc interval prolongation, given its questionable validity, and restore droperidol's place in the armamentarium of emergency medicine physicians. PMID- 22828974 TI - In vitro mechanical evaluation and comparison of two crimping devices for securing monofilament nylon and multifilament polyethylene for use in extracapsular stabilization of the canine stifle. AB - OBJECTIVE: To compare the tensile strength and stiffness of non-absorbable suture loops created with two types of crimping devices. METHODS: Loops of monofilament nylon leader line (MN) of 18 kg, 36 kg, and 45 kg multifilament polyethylene (MP) with a crimp and MP with a crimp and knot were mechanically tested to failure in quasistatic tensile loading after being created with either a wave pattern crimp device or three applications of a single crimp device. Each testing group consisted of five samples. Tensile loading to failure at a rate of 9.5 mm/s was used. Failure was defined as a sudden drop in the recorded force. RESULTS: All suture materials failed by breaking near the crimp tube with both crimp devices, with exception of the MP without knot, which slipped through the crimp tube using both devices. Sutures secured with the wave pattern crimping device were significantly stronger with a higher load yield, maximum load, displacement yield, failure displacement, and maximum displacement than the single crimp device. Loops of MP suture crimped by either device plus the addition of a surgeon's knot resulted in a significantly stronger construct than unknotted crimped MP constructs. Crimped MP combined with knot were significantly stiffer, but not stronger, than crimped 45 kg MN. CLINICAL SIGNIFICANCE: Performing extra- capsular repair for ruptured cranial cruciate ligaments with the wave pattern crimp system may result in lower failure rates due to the construct being significantly stronger than the single crimp system. PMID- 22828975 TI - Addressing challenges to providing peer-based recovery support. AB - As more systems of care deploy peer-based recovery support (P-BRS) programs, challenges to the effective use of P-BRS have emerged. These include external challenges, embedded in the organization and culture of traditionally organized services, and individual challenges, associated with the nonprofessional status of individual peer support staff members. The Living Centers, recovery resource centers providing P-BRS, have developed methods for addressing these challenges. These include organizing the P-BRS as stand-alone programs, having peer support staff and clients organize the P-BRS, emphasizing organizational values and culture as the basis for staff training, and implementing measures designed to encourage accountability among peer support staff. In the future, research into the types of barriers to P-BRS that may exist in traditionally organized behavioral health services and the types and content of training that contribute to the provision of P-BRS will facilitate the use of these services. PMID- 22828976 TI - Do client attributes moderate the effectiveness of a group cognitive behavioral therapy for depression in addiction treatment? AB - The study goal was to determine whether client attributes were associated with outcomes from group cognitive behavioral therapy for depression (GCBT-D) as delivered in community-based addiction treatment settings. Data from 299 depressed residential clients assigned to receive either usual care (N = 159) or usual care plus GCBT-D (N = 140) were examined. Potential moderators included gender, race/ethnicity, education, referral status, and problem substance use. Study outcomes at 6 months post-baseline included changes in depressive symptoms, mental health functioning, negative consequences from substance use, and percentage of days abstinent. Initial examination indicated that non-Hispanic Whites had significantly better outcomes than other racial/ethnic groups on two of the four outcomes. After correcting for multiple testing, none of the examined client attributes moderated the treatment effect. GCBT-D appears effective; however, the magnitude and consistency of treatment effects indicate that it may be less helpful among members of racial/ethnic minority groups and is worthy of future study. PMID- 22828977 TI - Investigation of organic pollutants in wastewater-irrigated soil and its DNA damage and oxidative damage on mice. AB - This work aimed to determine the DNA and oxidative damage on mice by mixtures of organic contaminants in wastewater-irrigated soil, in order to assess their usefulness as markers for this kind of pollution. Wastewater-irrigated soil samples in the vicinity of an industrial area in Tangshan, China were collected, and soil irrigated by underground water satisfying drinking water standards was used as control group. Organic pollutants were extracted from the soil using ultrasonic oscillation, and analyzed by gas chromatography-mass spectrometry (GC MS). Meanwhile, DNA damage on mice was determined by the Comet assay after oral gavage with the extracts, and changes in total superoxide dismutase (T-SOD) activity, glutathione peroxidase glutathione, GSH peroxidase (GSH-P(X)) activity and malondialdehyde content in serum of mice were investigated. The number of categories and concentrations of organic compounds in the wastewater-irrigated soil is more than those in groundwater-irrigated soil, as identified by the GC MS. The toxicity test of mice showed that compared with reagent control group, the activities of T-SOD and GSH-P(X) decreased; the tailing rate of peripheral blood lymphocyte of mice increased and was more than that of the control group. This shows that mammalian toxicity end points can be used to determine the joint toxicity of organic pollutants in soil. When there is no means to identify each and every pollutant in soil, it is feasible to evaluate the combined effects of various pollutants to determine the extent to which the soil is polluted. PMID- 22828978 TI - Public perception and economic implications of bottled water consumption in underprivileged urban areas. AB - This paper presents a comparative assessment of public perception of drinking water quality in two underprivileged urban areas in Lebanon and Jordan with nearly similar cultural and demographic characteristics. It compares the quality of bottled water to the quality of the drinking water supplied through the public network and examines the economic implications of bottled water consumption in the two study areas. Participants' perception of the quality of drinking water provided via the public network was generally negative, and bottled water was perceived to be of better quality in both areas, thus affecting drinking water preferences and consumption patterns. The results reveal that the quality of bottled water is questionable in areas that lack enforcement of water quality standards, thus adding to the burden of an already disadvantaged community. Both areas demonstrated a considerable cost incurred for purchasing bottled water in low income communities reaching up to 26 % of total income. PMID- 22828979 TI - Spatio-temporal footprints of urbanisation in Surat, the Diamond City of India (1990-2009). AB - Urbanisation is a ubiquitous phenomenon with greater prominence in developing nations. Urban expansion involves land conversions from vegetated moisture-rich to impervious moisture-deficient land surfaces. The urban land transformations alter biophysical parameters in a mode that promotes development of heat islands and degrades environmental health. This study elaborates relationships among various environmental variables using remote sensing dataset to study spatio temporal footprint of urbanisation in Surat city. Landsat Thematic Mapper satellite data were used in conjugation with geo-spatial techniques to study urbanisation and correlation among various satellite-derived biophysical parameters, [Normalised Difference Vegetation Index, Normalised Difference Built up Index, Normalised Difference Water Index, Normalised Difference Bareness Index, Modified NDWI and land surface temperature (LST)]. Land use land cover was prepared using hierarchical decision tree classification with an accuracy of 90.4 % (kappa = 0.88) for 1990 and 85 % (kappa = 0.81) for 2009. It was found that the city has expanded over 42.75 km(2) within a decade, and these changes resulted in elevated surface temperatures. For example, transformation from vegetation to built-up has resulted in 5.5 +/- 2.6 degrees C increase in land surface temperature, vegetation to fallow 6.7 +/- 3 degrees C, fallow to built-up is 3.5 +/- 2.9 degrees C and built-up to dense built-up is 5.3 +/- 2.8 degrees C. Directional profiling for LST was done to study spatial patterns of LST in and around Surat city. Emergence of two new LST peaks for 2009 was observed in N-S and NE-SW profiles. PMID- 22828980 TI - Temporal changes of soil respiration under different tree species. AB - Soil respiration rates were measured monthly (from April 2007 to March 2008) under four adjacent coniferous plantation sites [Oriental spruce (Picea orientalis L.), Austrian pine (Pinus nigra Arnold), Turkish fir (Abies bornmulleriana L.), and Scots pine (Pinus sylvestris L.)] and adjacent natural Sessile oak forest (Quercus petraea L.) in Belgrad Forest-Istanbul/Turkey. Also, soil moisture, soil temperature, and fine root biomass were determined to identify the underlying environmental variables among sites which are most likely causing differences in soil respiration. Mean annual soil moisture was determined to be between 6.3 % and 8.1 %, and mean annual temperature ranged from 13.0 degrees C to 14.2 degrees C under all species. Mean annual fine root biomass changed between 368.09 g/m(2) and 883.71 g/m(2) indicating significant differences among species. Except May 2007, monthly soil respiration rates show significantly difference among species. However, focusing on tree species, differences of mean annual respiration rates did not differ significantly. Mean annual soil respiration ranged from 0.56 to 1.09 g C/m(2)/day. The highest rates of soil respiration reached on autumn months and the lowest rates were determined on summer season. Soil temperature, soil moisture, and fine root biomass explain mean annual soil respiration rates at the highest under Austrian pine (R (2) = 0.562) and the lowest (R (2) = 0.223) under Turkish fir. PMID- 22828981 TI - Increasing oxidative stress tolerance and subculturing stability of Cordyceps militaris by overexpression of a glutathione peroxidase gene. AB - Like other filamentous fungi, the medicinal ascomycete Cordyceps militaris frequently degenerates during continuous maintenance in culture by showing loss of the ability to reproduce sexually or asexually. Degeneration of fungal cultures has been related with cellular accumulation of reactive oxygen species (ROS). In this study, an antioxidant glutathione peroxidase (Gpx) gene from Aspergillus nidulans was engineered into two C. militaris strains, i.e., the Cm01 strain which can fruit normally and the Cm04 strain which has lost the ability to form fruiting bodies on different media through subculturing. The results showed that the mitotically stable mutants had higher Gpx activities and stronger capacity to scavenge cellular ROS than their parental strains. Most significantly, the fruiting ability of Cm04 strain was restored by overexpression of the antioxidant enzyme. However, after being successively transferred for up to ten generations, two of three Cm04 mutants again lost the ability to fruit on insect pupae while Cm01 transformants remained fertile. This study confirms the relationship between fungal culture degeneration and cellular ROS accumulation. Our results indicate that genetic engineering with an antioxidant gene can be an effective way to reverse fungal degeneration during subculturing. PMID- 22828982 TI - Two different primary oxidation mechanisms during biotransformation of thymol by gram-positive bacteria of the genera Nocardia and Mycobacterium. AB - Thymol has antibacterial, antifungal, insecticidal, and antioxidative properties which are the basis for the wide use of this compound in the cosmetic, food, and pharmaceutical industries. Although thymol is a ubiquitously occurring substance in the environment, data about its degradation and detoxification by bacteria are sparse. Here, we show the existence of two different pathways for the biotransformation of thymol by Nocardia cyriacigeorgica and Mycobacterium neoaurum which were described for the first time for gram-positive bacteria. The first pathway starts with hydroxylation of thymol to thymohydroquinone (2 isopropyl-5-methylbenzene-1,4-diol) with subsequent oxidation to thymobenzoquinone (2-isopropyl-5-methyl-1,4-benzoquinone). The second pathway involves hydroxylation of the methyl group followed by oxidation to 3-hydroxy-4 isopropylbenzoic acid, possibly via the aldehyde 3-hydroxy-4 isopropylbenzaldehyde. It is noteworthy that the branched side chain of thymol was not oxidized. Similarities and differences of these oxidation processes with those of the gram-negative bacterium Pseudomonas putida, fungi, and plants are discussed and, in addition, the toxicity of thymol towards N. cyriacigeorgica and M. neoaurum was tested. The experiments showed a temporary growth inhibition with 0.025 % thymol. This was explained by degradation of thymol and the formation of products which are less toxic than thymol itself. PMID- 22828983 TI - Epidemiology, responses, and way forward: the silent epidemic of viral hepatitis and HIV coinfection in Vietnam. AB - Viral hepatitis is a disease of great concern to public health that is now met by a favorable momentum to combat the global epidemic. This article is intended to highlight the importance of viral hepatitis in the Vietnam population as well in the group of people living with HIV/AIDS (PLWHA). We reviewed available data on epidemiology and response on hepatitis B virus (HBV) and hepatitis C virus (HCV) and HIV coinfection in Vietnam. The hepatitis B surface antigen (HBsAg) prevalence in the general population ranged from 5.7% to 24.7%. The anti-HCV prevalence ranged from 0.38% to 4.3% in the general population, while among people who inject drugs (PWIDs) it ranged from 31% to 97.2%. The HBV prevalence among PLWHA is similar to the general population, while HCV/HIV coinfection is concentrated in some groups. Anti-HCV prevalence among HIV-infected PWIDs can be as high as 98.5%. Developing policies for diagnosis and treatment of chronic HBV and HCV infections are critical priorities in order to prevent clinical progression to cirrhosis and liver cancer. PMID- 22828985 TI - Continuous symmetry measures of irreducible representations: application to molecular orbitals. AB - The formalism of continuous symmetry measures is extended to describe the extent to which a function, such as a molecular orbital, transforms under the symmetry operations of a given point group according to each irreducible representation of this group. For distorted molecules we are able to calculate the degree to which any molecular orbital transforms with respect to the irreducible representations of the pseudosymmetry group that is valid for a higher symmetry, idealized geometry, showing which irreducible representations participate in each molecular orbital upon symmetry loss in the geometry of the nuclear framework. PMID- 22828984 TI - Psychotropic medications and mitochondrial toxicity. PMID- 22828986 TI - Randomized clinical trial of open hepatectomy with or without intermittent Pringle manoeuvre. AB - BACKGROUND: The intermittent Pringle manoeuvre (IPM) is commonly applied during liver resection. Few randomized trials have addressed its effectiveness in reducing blood loss and the results have been conflicting. The present study investigated the hypothesis that IPM could reduce blood loss during liver resection by 50 per cent. METHODS: Between May 2008 and April 2011, patients who underwent elective open hepatectomy were randomized into an IPM or no Pringle manoeuvre (NPM) group and stratified according to the presence or absence of cirrhosis. Data on demographics, type of hepatectomy, operative blood loss, duration of operation, mortality, morbidity and postoperative liver function were recorded and analysed. The primary endpoint was operative blood loss. RESULTS: There were 63 patients in each group. Median (range) operative blood loss was 370 (50-3600) ml in the IPM group versus 335 (40-3160) ml in the NPM group (P = 1.000). There were no differences in blood loss in different phases of the operation, blood loss per area of liver transected or blood transfusion rate, nor in total duration of operation or liver transection time. Postoperative serum alanine aminotransferase levels were higher in the IPM group (P < 0.001). There were more postoperative complications in the IPM group (41 versus 24 per cent; P = 0.036). CONCLUSION: The IPM did not reduce blood loss, but was associated with raised levels of postoperative liver parenchymal enzymes and more complications. REGISTRATION NUMBER: NCT00730743 (http://www.clinicaltrials.gov). PMID- 22828988 TI - Control of microenvironmental cues with a smart biomaterial composite promotes endothelial progenitor cell angiogenesis. AB - Smart biomaterials play a key role when aiming at successful tissue repair by means of regenerative medicine approaches, and are expected to contain chemical as well as mechanical cues that will guide the regenerative process. Recent advances in the understanding of stem cell biology and mechanosensing have shed new light onto the importance of the local microenvironment in determining cell fate. Herein we report the biological properties of a bioactive, biodegradable calcium phosphate glass/polylactic acid composite biomaterial that promotes bone marrow-derived endothelial progenitor cell (EPC) mobilisation, differentiation and angiogenesis through the creation of a controlled bone healing-like microenvironment. The angiogenic response is triggered by biochemical and mechanical cues provided by the composite, which activate two synergistic cell signalling pathways: a biochemical one mediated by the calcium-sensing receptor and a mechanosensitive one regulated by non-muscle myosin II contraction. Together, these signals promote a synergistic response by activating EPCs mediated VEGF and VEGFR-2 synthesis, which in turn promote progenitor cell homing, differentiation and tubulogenesis. These findings highlight the importance of controlling microenvironmental cues for stem/progenitor cell tissue engineering and offer exciting new therapeutical opportunities for biomaterial based vascularisation approaches and clinical applications. PMID- 22828989 TI - FGF18 augments osseointegration of intra-medullary implants in osteopenic FGFR3( /-) mice. AB - Enhancement of endogenous bone regeneration is a priority for integration of joint replacement hardware with host bone for stable fixation of the prosthesis. Fibroblast Growth Factor (FGF) 18 regulates skeletal development and could therefore have applications for bone regeneration and skeletal repair. This study was designed to determine if treatment with FGF 18 would promote bone regeneration and integration of orthopedic hardware in FGF receptor 3 deficient (FGFR3(-/-)) mice, previously characterized with impaired bone formation. Rigid nylon rods coated with 200 nm of titanium were implanted bilaterally in the femora of adult FGFR3(-/-) and FGFR3(+/+) mice to mimic human orthopedic hardware. At the time of surgery, LEFT femora received an intramedullary injection of 0.5 MUg FGF18 (Merck Serono) and RIGHT femora received PBS as a control. Treatment with FGF18 resulted in a significant increase in peri-implant bone formation in both FGFR3(+/+) and FGFR3(-/-) mice, with the peri-implant fibrous tissue frequently seen in FGFR3(-/-) mice being largely replaced by bone. The results of this pre-clinical study support the conjecture that FGF18 could be used in the clinical setting to promote integration of orthopedic hardware in poor quality bone. PMID- 22828990 TI - Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells. AB - Chondrocyte hypertrophy is one of the key physiological processes involved in the longitudinal growth of long bones, yet the regulation of hypertrophy is also becoming increasingly relevant for clinical application of mesenchymal stem cells (MSCs) and screening for drugs to treat hypertrophic osteoarthritis. The extraordinary cell volume increase during hypertrophy is accompanied by an up regulation of collagen X, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF), all which are targets of the runt-related transcription factor 2 (Runx2). Many pathways, including parathyroid hormone related protein (PTHrP)/Indian Hedgehog, Wingless/Int (Wnt)/beta-catenin, and transforming growth factor beta (TGF-beta)/Sma and Mad Related Family (Smad) pathways, can regulate hypertrophy, but factors as diverse as hypoxia, co culture, epigenetics and biomaterial composition can also potently affect Runx2 expression. Control of hypertrophic differentiation can be exploited both for cartilage repair, where a stable phenotype is desired, but also in bone regeneration, where hypertrophic cartilage could act as a template for endochondral bone formation. We hope this review will motivate the design of novel engineered microenvironments for skeletal regeneration applications. PMID- 22828991 TI - Chitosan drives anti-inflammatory macrophage polarisation and pro-inflammatory dendritic cell stimulation. AB - Macrophages and dendritic cells (DC) share the same precursor and play key roles in immunity. Modulation of their behaviour to achieve an optimal host response towards an implanted device is still a challenge. Here we compare the differentiation process and polarisation of these related cell populations and show that they exhibit different responses to chitosan (Ch), with human monocyte derived macrophages polarising towards an anti-inflammatory phenotype while their DC counterparts display pro-inflammatory features. Macrophages and DC, whose interactions with biomaterials are frequently analysed using fully differentiated cells, were cultured directly on Ch films, rather than exposed to the polymer after complete differentiation. Ch was the sole stimulating factor and activated both macrophages and DC, without leading to significant T cell proliferation. After 10 d on Ch, macrophages significantly down-regulated expression of pro inflammatory markers, CD86 and MHCII. Production of pro-inflammatory cytokines, particularly TNF-alpha, decreased with time for cells cultured on Ch, while anti inflammatory IL-10 and TGF-beta1, significantly increased. Altogether, these results suggest an M2c polarisation. Also, macrophage matrix metalloproteinase activity was augmented and cell motility was stimulated by Ch. Conversely, DC significantly enhanced CD86 expression, reduced IL-10 secretion and increased TNF alpha and IL-1beta levels. Our findings indicate that cells with a common precursor may display different responses, when challenged by the same biomaterial. Moreover, they help to further comprehend macrophage/DC interactions with Ch and the balance between pro- and anti-inflammatory signals associated with implant biomaterials. We propose that an overall pro-inflammatory reaction may hide the expression of anti-inflammatory cytokines, likely relevant for tissue repair/regeneration. PMID- 22828992 TI - Staining plastic blocks with triiodide to image cells and soft tissues in backscattered electron SEM of skeletal and dental tissues. AB - Backscattered electron scanning electron microscopy (BSE SEM) is an invaluable method for studying the histology of the hard, mineralised components of poly methyl methacrylate (PMMA) or other resin embedded skeletal and dental tissues. Intact tissues are studied in micro-milled or polished block faces with an electron-optical section thickness of the order of a half to one micron and with the area of the section as big as a whole--large or small--bone organ. However, BSE SEM does not give information concerning the distribution of uncalcified, 'soft', cellular and extracellular matrix components. This can be obtained by confocal microscopy of the same block and the two sorts of images merged but the blocks have to be studied in two microscope systems. The present work shows a new, simple and economic approach to visualising both components by using the triiodide ion in Lugol's iodine solution to stain the block surface prior to the application of any conductive coating--and the latter can be omitted if charging is suppressed by use of poor vacuum conditions in the SEM sample chamber. The method permits the use of archival tissue, and it will be valuable in studies of both normal growth and development and pathological changes in bones and joints, including osteoporosis and osteoarthritis, and tissue adaptation to implants. PMID- 22828993 TI - Abstracts from the ICBM 2012 Meeting. August 29-September 1, 2012. Budapest, Hungary. PMID- 22828994 TI - [New oral anticoagulants for the prevention of stroke. Open questions in geriatric patients]. AB - New oral anticoagulants for the prevention of stroke in patients with nonvalvular atrial fibrillation have been available for a few months, among them the reversible direct thrombin inhibitor dabigatran and the factor Xa antagonist rivaroxaban. These drugs are considered by some as a superior alternative to vitamin K antagonists. The lack of necessity for regular monitoring is advertised as a major advantage. Although atrial fibrillation is a disease with increasing prevalence with higher age, the suitability of the new drugs has not been extensively studied in multimorbid geriatric patients. Since dabigatran is contraindicated in patients with renal insufficiency, only the lower of the two approved dosages can usually be prescribed in elderly patients. For the lower dosage, however, no superiority in prevention of stroke has been documented but merely a reduction in major bleeding rates, although at a high number needed to treat. The requirement for a twice-daily dosage regimen, the lack of an anticoagulation monitoring option, the relatively short duration of action and the lack of an antidote may even prove to be crucial disadvantages in clinical practice in comparison to vitamin K antagonists. Until more data are available, the new oral anticoagulants should be prescribed with caution in geriatric patients. PMID- 22828995 TI - Binding trimethyllysine and other cationic guests in water with a series of indole-derived hosts: large differences in affinity from subtle changes in structure. AB - The binding of a series of indole-derived hosts to various ammonium cations in pure, buffered water is investigated using both solution phase (1)H NMR studies and computational modeling. These hosts can engage their targets via the cation pi interaction, electrostatic attraction, and the hydrophobic effect. The hydrophobic effect is shown to be a dominant influence in the strength of the binding interactions, both in terms of the hydrophobicity of the host and of the guest. Our findings show that small changes that reduce the host hydrophobic surface area without reducing either the number of negative charges or amount of aromatic surface area are found to significantly decrease binding. Additionally, the position of solubilizing charges is also shown to influence the preferred host geometry and resulting binding constants. PMID- 22828996 TI - A novel PET protocol for visualization of breast cancer resistance protein function at the blood-brain barrier. AB - Breast cancer resistance protein (BCRP) is the most abundant multidrug efflux transporter at the human blood-brain barrier (BBB), restricting brain distribution of various drugs. In this study, we developed a positron emission tomography (PET) protocol to visualize Bcrp function at the murine BBB, based on the dual P-glycoprotein (P-gp)/Bcrp substrate radiotracer [(11)C]tariquidar in combination with the Bcrp inhibitor Ko143. To eliminate the contribution of P-gp efflux to [(11)C]tariquidar brain distribution, we studied mice in which P-gp was genetically knocked out (Mdr1a/b((-/-)) mice) or chemically knocked out by pretreatment with cold tariquidar. We found that [(11)C]tariquidar brain uptake increased dose dependently after administration of escalating doses of Ko143, both in Mdr1a/b((-/-)) mice and in tariquidar pretreated wild-type mice. After 15 mg/kg Ko143, the maximum increase in [(11)C]tariquidar brain uptake relative to baseline scans was 6.3-fold in Mdr1a/b((-/-)) mice with a half-maximum effect dose of 4.98 mg/kg and 3.6-fold in tariquidar (8 mg/kg) pretreated wild-type mice, suggesting that the presented protocol is sensitive to visualize a range of different functional Bcrp activities at the murine BBB. We expect that this protocol can be translated to the clinic, because tariquidar can be safely administered to humans at doses that completely inhibit cerebral P-gp. PMID- 22828997 TI - Neurovascular uncoupling under mild hypoxic hypoxia: an EEG-fMRI study in rats. AB - The effects of oxygen availability on neurovascular coupling were investigated using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), in addition to the monitoring of physiological parameters, in 16 alpha-chloralose-anesthetized rats. Mild hypoxic hypoxia (oxygen saturation=83.6+/-12.1%) induced significant reductions in fMRI responses (P<0.05) to electrical stimulation in the forepaw, but EEG responses remained unchanged. In addition, the changes in oxygen saturation were linearly correlated with the changes in the fMRI responses. These data further emphasize the importance of oxygen availability, which may regulate neurovascular coupling via the oxygen-dependent enzymatic synthesis of messenger molecules. PMID- 22828998 TI - Visualization of altered neurovascular coupling in chronic stroke patients using multimodal functional MRI. AB - Evaluation of cortical reorganization in chronic stroke patients requires methods to accurately localize regions of neuronal activity. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is frequently employed; however, BOLD contrast depends on specific coupling relationships between the cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF), and volume (CBV), which may not exist following stroke. The aim of this study was to understand whether CBF-weighted (CBFw) and CBV-weighted (CBVw) fMRI could be used in sequence with BOLD to characterize neurovascular coupling mechanisms poststroke. Chronic stroke patients (n=11) with motor impairment and age-matched controls (n=11) performed four sets of unilateral motor tasks (60 seconds/30 seconds off/on) during CBFw, CBVw, and BOLD fMRI acquisition. While control participants elicited mean BOLD, CBFw, and CBVw responses in motor cortex (P<0.01), patients showed only mean changes in CBF (P<0.01) and CBV (P<0.01), but absent mean BOLD responses (P=0.20). BOLD intersubject variability was consistent with differing coupling indices between CBF, CBV, and CMRO(2). Thus, CBFw and/or CBVw fMRI may provide crucial information not apparent from BOLD in these patients. A table is provided outlining distinct vascular and metabolic uncoupling possibilities that elicit different BOLD responses, and the strengths and limitations of the multimodal protocol are summarized. PMID- 22829001 TI - A simple nickel bis(dithiolene) complex as an excellent n-type molecular semiconductor for field-effect transistors. AB - A simple nickel bis(dithiolene) complex has been developed as an excellent n-type molecular semiconductor for FETs, with an electron mobility of 0.11 cm(2) V(-1) s(-1) and an on/off ratio of 2 * 10(6) despite its small pi-conjugated system. Good FET stability in ambient conditions has also been observed. PMID- 22829000 TI - Bioaccumulation and distribution of metals in sediments and Avicenna marina tissues in the Hara Biosphere Reserve, Iran. AB - The metal pollution in Sediments and Avicenna marina tissues in the Hara Biosphere Reserve was monitored for Lead (Pb), Cadmium (Cd), and Nickel (Ni) with atomic absorption spectrometer. The results showed that the mean concentration of Pb, Cd, and Ni in the water and sediments were much higher than the recommended threshold limits in the most stations, also the highest means of Pb, Cd, and Ni were observed in Avicenna roots and it were 25.26 +/- 4.86, 2.17 +/- 0.74, and 26.72 +/- 6.17 (MUg g(-1)) respectively. Calculating BCF (bioconcentration factor) index illustrates that A. marina accumulates Pb, Cd, and Ni 1.62, 1.52 and 0.73 times greater than sediment levels respectively, So it can show that A. marina may be employed as a biological indicator exposure of Cd, Pb, and Ni with temporal monitoring, also the factories were main sources of metals contamination in the Hara Biosphere Reserve. PMID- 22829002 TI - The effect of APRV ventilation on ICP and cerebral hemodynamics. AB - BACKGROUND: Airway pressure release ventilation (APRV) is an alternative approach to the low-tidal volume "open-lung" ventilation strategy. APRV is associated with a higher mean airway pressure than conventional ventilation and has therefore not been evaluated in patients with acute neurological injuries. METHODS: Case report. RESULTS: We report a patient with severe progressive hypoxemia following a subarachnoid hemorrhage who was converted from pressure-controlled mechanical ventilation to APRV. This change in ventilatory mode was associated with a significant improvement in oxygenation and alveolar ventilation with an associated increase in cerebral blood flow and a negligible increase in intracranial pressure. CONCLUSION: APRV may safely be applied to neurocritically ill patients, and that this mode of ventilation may increase cerebral blood flow without increasing intracranial pressure. PMID- 22829003 TI - Temporomandibular joint injuries and ankylosis in the cat. AB - OBJECTIVE: To evaluate cause, location, treatment, and the clinical outcome of traumatic temporomandibular joint (TMJ) lesions and TMJ ankylosis in cats. METHODS: Cats with TMJ injuries were included in this study. Lesions were classified as luxations, fractures of the condylar process, and intra-articular temporal bone fractures. Signalment, cause and type of injuries, treatment methods, clinical outcome, complications and joint ankylosis were assessed and evaluated statistically. RESULTS: Temporomandibular joint lesions were observed in 82 of 161 cats with maxillofacial injuries. One hundred forty-nine TMJ lesions were determined in 112 joints. Falling was the most common cause and fractures of the condylar process were the most common types of injuries. Isolated TMJ injuries and caudal TMJ luxations were mainly caused by falling. Condylectomy was used in ankylosis, chronic luxation, reluxation and in two cases with multiple TMJ lesions. Ankylosis was observed in 10.97% of cases and was generally observed in fracture combinations of condylar process and mandibular fossa (chi2 = 8.52; p <0.05). No significant relationship between age and development of ankylosis (chi2 = 3.995; p >0.05) was found. CONCLUSION: In contrast to previous studies, traumatic TMJ lesions were observed in a considerable amount of cats with maxillofacial injuries, and fractures of the condylar process were the most common type. Lesions caused by falling were mostly simple, whereas vehicular trauma caused more complicated lesions. Ankylosis did not appear as a rare condition. Any cat with TMJ injury is susceptible to the development of ankylosis. PMID- 22828999 TI - Membrane-initiated estradiol actions mediate structural plasticity and reproduction. AB - Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERalpha and ERbeta, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERalpha has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERalpha is a ligand-gated transcription factor and not a typical membrane receptor, trafficking to the cell membrane requires post translational modifications. Two necessary modifications are palmitoylation and association with caveolins, a family of scaffolding proteins. In addition to their role in trafficking, caveolin proteins also serve to determine ERalpha interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ERalpha, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ERalpha-mGluR interactions have been demonstrated throughout the nervous system from hippocampus to striatum to hypothalamus to dorsal root ganglion (DRG) in both neurons and astrocytes. These combinations of ER and mGluR allow estradiol to have both facilitative and inhibitory actions in neurons. In hypothalamic astrocytes, the estradiol-mediated release of intracellular calcium stores regulating neurosteroid synthesis requires ERalpha-mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ERalpha mGluR1a signaling complex leads to the release of neurotransmitters and alteration of neuronal morphology. This review will examine estradiol membrane signaling (EMS) activating a limbic-hypothalamic lordosis regulating circuit, which involves ERalpha trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity. PMID- 22829004 TI - Cost effectiveness of treatment strategies for primary operable pancreatic head adenocarcinoma: do we have more scientific evidence to call for further centralization of care? PMID- 22829005 TI - Surgical delay of the nipple-areolar complex: a powerful technique to maximize nipple viability following nipple-sparing mastectomy. AB - OBJECTIVES: Nipple-sparing mastectomy (NSM) improves cosmetic outcome of mastectomy, but many patients are not candidates for this procedure because of concerns about nipple-areolar viability. Surgical delay is a technique that has been used for more than 400 years to improve survival of skin flaps. We used a surgical delay procedure to improve nipple viability in patients who were identified to be at high risk for nipple necrosis following NSM. METHODS: Patients at high risk for nipple necrosis following NSM underwent a surgical delay procedure 7-21 days prior to mastectomy. Subareolar biopsy and sentinel node biopsy, if indicated, were performed at the time of the delay procedure. Nipple viability was assessed before and after NSM. If the subareolar biopsy revealed malignancy, the NAC was removed at the time of mastectomy. RESULTS: 31 NAC in 20 patients underwent surgical delay. All of the NAC subjected to a surgical delay survived following the delay procedure. In 2 patients, the subareolar biopsy was positive and 3 NAC were removed at the time of mastectomy (1 for purposes of symmetry). Of the 28 delayed NAC left at the time of NSM, all survived the post-mastectomy course. CONCLUSION: A procedure to surgically delay the NAC 7-21 days prior to NSM is demonstrated to ensure viability of NAC in patients previously thought to be at high risk for nipple loss. PMID- 22829006 TI - Breast surgery outcomes as quality measures according to the NSQIP database. AB - BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) is a risk adjusted database designed to benchmark quality initiatives. NSQIP captures uniform morbidity variables for all operations and calculates expected morbidity probabilities. Given the frequent need for reoperation following breast conserving surgery (BCS) and mastectomy, we hypothesized that NSQIP may inaccurately reflect surgical morbidity after breast cancer operations. METHODS: Using the 2008 NSQIP database, we identified 24,447 breast surgery patients. We calculated the observed versus expected (O/E) morbidity ratios, compared them to other general surgery procedures, and analyzed the O/E morbidity ratios among benign and malignant breast diagnoses. RESULTS: The NSQIP database shows that breast surgery has an O/E morbidity ratio of 3.11, which is higher than other general surgery procedures. Additionally, breast operations for malignancy have higher O/E morbidity ratios (3.22) than those performed for benign disease (2.59). Analysis of malignant patients by CPT code revealed that BCS patients had an O/E morbidity ratio of 7.75 and attributed 89 % of morbidity to reoperation, whereas mastectomy patients had an O/E morbidity ratio of only 1.7. Elimination of the reoperation variable from morbidity calculations in breast surgery reduces the O/E morbidity ratio to less than expected in all breast procedures. DISCUSSION: Breast surgery has a higher O/E morbidity ratio than other general surgery procedures. Reoperations are expected in BCS for positive margins and in mastectomy for completion ALND. Breast surgeons should advocate for benchmarking by surgical site-specific metrics, because current NSQIP criteria may negatively affect the quality assessment of high-volume breast centers. PMID- 22829007 TI - Two-stage association study in Chinese Han identifies two independent associations in CCR1/CCR3 locus as candidate for Behcet's disease susceptibility. AB - Previous GWAS studies from Turkey suggested a potential risk locus at CCR1/CCR3 for Behcet's disease. However, this locus did not reach the GWAS significance threshold and has not yet been examined in other ethnic populations. The current study aimed to explore whether this locus was associated with Behcet's disease in Chinese Han and the functional role of the identified variants. A two-stage association study was performed in 653 patients and 1,685 controls using the iPLEX system. Real-time PCR was performed to examine the expression level of CCR1 and CCR3 genes. Haplotype analysis was used to construct the haplotype block. Logistic regression analysis was applied to calculate the independence of multiple associations. Bonferroni correction was applied to account for multiple testing. First stage analysis showed that ten SNPs, located in 3'UTR, 5'UTR in CCR1 or 5'UTR in CCR3, were significantly associated with Behcet's disease (P(c) = 0.018 to 1.3 * 10(-3)). The associations of six SNPs within this locus are independent after control for the genetic effect of rs17282391 using logistic regression analysis. Haplotype analysis identified three associated haplotypes: H3 (GTGAC), H6 (CCATTA) and H9 (CGA) (P(c) = 0.04 to 7.79 * 10(-4)). Three SNPs rs13084057, rs13092160 and rs13075270 showed consistent association in replication and combining studies (replication P(c) = 5.31 * 10(-5) to 1.44 * 10( 5); combining P(c) = 2.76 * 10(-7) to 6.50 * 10(-8)). Interestingly, eQTLs database reveals that SNP rs13092160 is eQTLs SNP, suggesting that this SNP is likely to be functional SNP that directly affects gene expression. The expression of CCR1 and CCR3 was increased in individuals with the CT genotype of rs13092160 (P < 0.05). No significant difference was found for the mRNA level of CCR1 and CCR3 between Behcet's patients and controls. These findings strongly indicate CCR1/CCR3 as a novel locus underlying Behcet's disease. PMID- 22829008 TI - Single-port endo-laparoscopic surgery (SPES) for totally extraperitoneal inguinal hernia: a critical appraisal of the chopstick repair. AB - PURPOSE: Developments in minimal access surgery brought a new concept: single port endolaparoscopic surgery (SPES). The aim of our study is to verify the safety and feasibility of SPES TEP hernia repair and report our initial clinical outcome. METHODS: We prospectively collected data of all patients who underwent SPES TEP repair from May 2009 to December 2010. Data regarding patient demographics, type, size and location of hernia, port devices used, type of mesh and fixation, operative time, complications, length of stay and cosmetic results were collected and analyzed. RESULTS: A total of 47 patients (36 M, 11 F) underwent 70 SPES TEP hernia repairs; median age was 53 years (range 22-80). 60 % had indirect hernia, 27.5 % direct, 8.5 % pantaloon, 2 % femoral and 2 % recurrent hernias. Mean hernia size was 1.91 +/- 0.67 cm. Port devices used include 33 Triport, 12 SILS and 2 SSL. We used anatomical mesh in 20; flat polypropylene in 10 and titanium-coated polypropylene mesh in 17 patients. Fixation of mesh was achieved in 18 patients with absorbable tacks, 8 with titanium tacks, 1 with fibrin glue, and no tack in 20 with anatomical mesh. No conversions occurred and small seroma was reported in 3 (6.3 %) patients. Mean operative time was 96.48 min (range: 50-150). Average hospital stay was 11.8 h (range: 9-26). Median follow-up was 11 months (range 6-18), and no recurrence was noted. 82.6 % patients were very satisfied, and 17.4 % were satisfied with the procedure. CONCLUSION: SPES TEP repair is a safe and feasible technique with good patient satisfaction. PMID- 22829011 TI - Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. AB - Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The development of meningioma in NBCCS patients is a rare event. Here, we report two cases of NBCCS in which meningiomas did develop. The first patient carried a germline mutation in one allele of PTCH1, c.290dupA (p.N97KfsX43). In addition, the meningioma sample carried a somatic mutation, c.307delG (p.Val103LeufsX15), in the other allele of the same gene, suggesting a second hit. This is the first case of NBCCS-associated meningioma explained by the standard two-hit hypothesis. The second patient had a germline nonsense mutation in the SUFU gene, c.550C>T (p.Q184X). SUFU is located downstream of PTCH1 in the sonic hedgehog signaling pathway. This is the second time a germline mutation in SUFU has been found to cause NBCCS. Together with the previous report describing three cases of non-NBCCS medulloblastoma carrying a germline mutation in this gene, individuals with a SUFU germline mutation are expected to have a markedly high risk of developing medulloblastoma and probably meningioma. PMID- 22829012 TI - Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway gliomas. AB - Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant cancer syndromes worldwide. Individuals with NF1 have a wide variety of clinical features including a strongly increased risk for pediatric brain tumors. The etiology of pediatric brain tumor development in NF1 is largely unknown. Recent studies have highlighted the contribution of parent-of-origin effects to tumorigenesis in sporadic cancers and cancer predisposition syndromes; however, there is limited data on this effect for cancers arising in NF1. To increase our understanding of brain tumor development in NF1, we conducted a multi-center retrospective chart review of 240 individuals with familial NF1 who were diagnosed with a pediatric brain tumor (optic pathway glioma; OPG) to determine whether a parent-of-origin effect exists overall or by the patient's sex. Overall, 50 % of individuals with familial NF1 and an OPG inherited the NF1 gene from their mother. Similarly, by sex, both males and females were as likely to inherit the NF1 gene from their mother as from their father, with 52 % and 48 % of females and males with OPGs inheriting the NF1 gene from their mother. In conclusion, in contrast to findings from other studies of sporadic cancers and cancer predisposition syndromes, our results indicate no parent-of-origin effect overall or by patient sex for OPGs in NF1. PMID- 22829013 TI - Portuguese c.156_157insAlu BRCA2 founder mutation: gastrointestinal and tongue neoplasias may be part of the phenotype. AB - We have screened BRCA2 c.156_157insAlu founder mutation in a cohort of 168 women with diagnosis of breast cancer referred for genetic counseling because of risk of being carriers of hereditary breast and ovarian cancer syndrome. Portuguese founder mutation BRCA2 c.156_157insAlu was identified in three unrelated breast cancer probands. Genotyping identified a common haplotype between markers D13S260 and D13S171, and allele sizes were compatible to those described in the Portuguese families. Allele sizes of marker D13S1246, however, were concordant in two families, suggesting that the haplotype may be larger in a subset of families. Tumor phenotypes in Brazilian families seem to reinforce the high prevalence of breast cancer among affected males. However, an apparent excess of gastrointestinal and tongue neoplasias were also observed in these families. Although these tumors are not part of the phenotypic spectrum of hereditary breast and ovarian cancer syndrome, they might be accounted for by other risk alleles contained in the founder haplotype region. PMID- 22829014 TI - Heterozygote FANCD2 mutations associated with childhood T Cell ALL and testicular seminoma. AB - Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities characterised by cellular cross linker hypersensitivity. FA is caused by mutations in any of so far 15 identified FANC genes, which encode proteins that interact in a common DNA damage response (DDR) pathway. Individuals with FA have a high risk of developing acute myeloid leukaemia (AML) and squamous cell carcinoma. An increased cancer risk has been firmly established for carriers of mutations in FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, RAD51C/FANCO and link the FA pathway to inherited breast and ovarian cancer. We describe a pedigree with FANCD2 mutations c.458T > C (p.Leu153Ser) and c.2715 + 1G > A (p.Glu906LeufsX4) with mild phenotype FA in the index case, T cell ALL in the Leu153Ser heterozygous brother and testicular seminoma in the p.Glu906LeufsX4 heterozygous father. Both FANCD2 alleles were present in the T Cell ALL and the seminoma. This links specific FANCD2 mutations to T cell ALL and seminoma without evidence of allelic loss in the tumour tissue. PMID- 22829015 TI - Novel mutations of OGG1 base excision repair pathway gene in laryngeal cancer patients. AB - OGG1 (The human 8-oxoguanine glycosylase 1) is the primary enzyme in BER (base excision repair) pathway, responsible for the excision of 7, 8-dihydro-8 oxoguanine (8-oxoG), a mutagenic base byproduct that occurs as a result of exposure to reactive oxygen species. OGG1 gene is highly polymorphic among humans and is mutated in cancer cells. In this case control study, all exons of OGG1 gene and its exon/intron boundaries were amplified in 210 laryngeal cancer cases and 210 matched controls and then analyzed by single stranded conformational polymorphism. Amplified products showing altered mobility patterns were sequenced and analyzed. Two silent (Gln718Gln, His699-700His) and three missense (Ala597, Thr608-610Pro and Glu707Lys) mutations were observed in exon 2. In addition to this one missense mutation (1578G > A) was also observed in 3'UTR region. We found a significant association between OGG1 mutations and laryngeal cancer and observed that His699-His700, silent mutation exhibited an enhanced risk of ~9.0 folds (OR = 9.07, 95 % CI = 4.73-17.39) and 1578G > A, missense mutation ~0.4 folds (OR = 0.37, 95 % CI = 0.15-0.90). Furthermore, a positive association of OGG1 mutations with smoking was observed in laryngeal cancer cases when compared to controls. Heavy smokers have higher incidence of OGG1 mutations when compared to light smokers in present study. Our results demonstrate that OGG1 mutations are associated with an increased risk of laryngeal cancer. OGG1 mutations were found to accumulate more of 8-OHdG in smokers, which may serve as a biomarker for early diagnosis of laryngeal cancer. PMID- 22829016 TI - Pre- and early in-hospital procedures in patients with acute coronary syndromes: first results of the "German chest pain unit registry". AB - BACKGROUND: In an attempt to improve the treatment of patients with acute coronary syndromes (ACS), a network of certified chest pain units (CPUs) has been recently established in Germany. METHODS: Data from patients admitted between December 2008 and September 2011 for ACS in 40 certified CPUs participating in the registry were prospectively collected. RESULTS: A total of 5,457 patients was admitted for ACS; 798 patients (14.6 %) were diagnosed with an ST-elevation myocardial infarction (STEMI), 2,244 (41.1 %) with a non-ST-elevation myocardial infarction (NSTEMI), and 2,415 (44.3 %) with unstable angina. The mean time to first medical contact was 2:08 h for STEMI patients. A pre-hospital ECG was available in 23.8 % of all ACS patients. Importantly, evidence of ST-segment elevation was present in 79.7 % of the STEMI patients already in this pre hospital ECG. As many as 76.6 % of the patients, independently of their symptoms and final diagnosis, received an ECG within 10 min of reaching the CPU. 98.2 % of STEMI patients underwent invasive diagnostics, with an in-hospital delay as little as 31 (11-75) min. CONCLUSION: The establishment of a nation-wide network of certified CPUs optimizes the medical treatment of patients with ACS while providing an ideal infrastructure to evaluate and improve, both on a nation-wide and a single center scale, the adherence to guidelines. The median delay between symptom onset and first medical contact remains high. Although performed relatively rarely, a pre-hospital ECG facilitates earlier diagnosis of a STEMI in a large majority of patients. The introduction of CPUs minimizes in-hospital delays and exploits the benefit of invasive diagnostics and treatment. PMID- 22829017 TI - Pro-thrombotic condition in a woman with peripartum cardiomyopathy treated with bromocriptine and an Impella LP 2.5 heart pump. PMID- 22829018 TI - Inhibitory effects of the transcription factor Ets-1 on the expression of type I collagen in TGF-beta1-stimulated renal epithelial cells. AB - Extracellular matrix (ECM) production and epithelial-mesenchymal transition (EMT) are important for phenotypic conversion in normal development and disease states such as tissue fibrosis. Transforming growth factor-beta1 (TGFbeta1) is one of the most potent inducers of ECM proteins, and its role in the pathogenesis of fibrosis is well established. Ets family is involved in a diverse array of biologic functions including cellular growth, migration, and differentiation. In the present study, we investigated whether Ets-1 has a role in ECM production and EMT in human renal tubuloepithelial cells (HKC cells). TGFbeta1 treatment increases Ets-1 expression and nuclear translocation in the HKC cells. Overexpression of recombinant Ets-1 suppressed transcription of alpha2(I) collagen (COL1A2) and type I collagen production in the TGFbeta1-activated HKC cells. From the experiments using specific inhibitors against Smad3 or mitogen activated protein (MAP) kinase pathways, Ets-1 has an inhibitory role for COL1A2 transcription and the p38 MAPK pathway participates in the negative contribution of Ets-1 in TGFbeta1/Smad3-activated renal cells. PMID- 22829021 TI - Sex and cardiovascular risk: are women advantaged or men disadvantaged? PMID- 22829019 TI - Long-term exposure to imatinib reduced cancer stem cell ability through induction of cell differentiation via activation of MAPK signaling in glioblastoma cells. AB - Glioblastoma multiforme (GBM) was shown to harbor therapy-resistant cancer stem cells that were major causes of recurrence. PDGFR (platelet-derived growth factor receptor) and c-Kit (stem cell factor receptor) signaling play important roles in initiation and maintenance of malignant glioma. This study demonstrated that long term culture with imatinib mesylate, the tyrosine kinase inhibitor against PDGFR and c-Kit resulted in reduced cancer stem cell ability in glioblastoma cells through cell differentiation. Derived from RG glioblastoma cells co-cultured with imatinib for 3 months, RG-IM cells showed distinct properties of cell cycle distribution and morphology in addition to significantly decreased ability to form aggregates and colonies in vitro and tumorigenicity in vivo. Increased expression of GFAP (astrocyte marker) and class III beta-tubulin isotype (Tuj1, neuron marker) were detected with morphology like neurons or astrocytes in RG-IM cells. Furthermore, decreased expression of stem cell markers, i.e., CD133, Oct 3/4, nestin, and Bmi1, and increased terminal neural cell markers, GFAP, Tuj1, etc., were identified in RG-IM at the mRNA level. All these markers were changed in RG cells when PDGFRB and c-Kit expression were double knocked down by siRNA. Cell differentiation agent, all-trans retinoic acid (ATRA) caused similar effect as that with imatinib in RG cells, while adding PDGF-B and SCF in RG-IM resulted in cell dedifferentiation to some extent. Moreover, differentiation in RG cells treated by imatinib or ATRA was mainly driven by MAPK signaling pathways. In summary, continuous inhibition on PDGFR and c-Kit signaling disturbed glioma stem cells biology in subsets of GBM cells and may have potentials in clinical applications. PMID- 22829020 TI - Dissociation of structural and functional phenotypes in cardiac myosin-binding protein C conditional knockout mice. AB - BACKGROUND: Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric protein that dynamically regulates thick-filament structure and function. In constitutive cMyBP-C knockout (cMyBP-C(-/-)) mice, loss of cMyBP-C has been linked to left ventricular dilation, cardiac hypertrophy, and systolic and diastolic dysfunction, although the pathogenesis of these phenotypes remains unclear. METHODS AND RESULTS: We generated cMyBP-C conditional knockout (cMyBP-C-cKO) mice expressing floxed cMyBP-C alleles and a tamoxifen-inducible Cre-recombinase fused to 2 mutated estrogen receptors to study the onset and progression of structural and functional phenotypes caused by the loss of cMyBP-C. In adult cMyBP-C-cKO mice, knockdown of cMyBP-C over a 2-month period resulted in a corresponding impairment of diastolic function and a concomitant abbreviation of systolic ejection, although contractile function was largely preserved. No significant changes in cardiac structure or morphology were immediately evident; however, mild hypertrophy developed after near-complete knockdown of cMyBP-C. In response to pressure overload induced by transaortic constriction, cMyBP-C-cKO mice treated with tamoxifen also developed greater cardiac hypertrophy, left ventricular dilation, and reduced contractile function. CONCLUSIONS: These results indicate that myocardial dysfunction is largely caused by the removal of cMyBP-C and occurs before the onset of cytoarchitectural remodeling in tamoxifen treated cMyBP-C-cKO myocardium. Moreover, near ablation of cMyBP-C in adult myocardium primarily leads to the development of hypertrophic cardiomyopathy in contrast to the dilated phenotype evident in cMyBP-C(-/-) mice, which highlights the importance of additional factors such as loading stress in determining the expression and progression of cMyBP-C-associated cardiomyopathy. PMID- 22829022 TI - Phosphodiesterase-5 and retargeting of subcellular cGMP signaling during pathological hypertrophy. PMID- 22829023 TI - Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). AB - BACKGROUND: Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients. METHODS AND RESULTS: The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical diagnosis for study entry, patient history, and concomitant medication. Patients were followed up until death or the end of the study (median, 56 months). Compared with male patients, female patients had a 19% significantly lower risk for the 4-fold end point and 21% for the 3-fold end point (after adjustment for study, treatment, and the above baseline values). Similarly, the adjusted risk for cardiovascular death (17%) and myocardial infarction (22%), but not for stroke and hospitalization for heart failure, was also significantly lower in women. Diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women. CONCLUSIONS: In our analysis made up of 70.3% male and 29.7% female patients, an ~20% lower risk for the combined cardiovascular end points in female patients was observed despite treatment with cardioprotective agents. This difference was driven primarily by a significantly lower incidence of myocardial infarction. Thus, we demonstrate in a large interventional trial that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101. PMID- 22829025 TI - Three cases of collagenous fibroma with rim enhancement on postcontrast T1 weighted images with fat suppression. AB - Collagenous fibroma, also known as desmoplastic fibroblastoma, is a benign fibrous soft tissue tumor showing gradual growth, commonly without aggressive local infiltration. Today, preoperative radiological diagnosis is important to avoid over-treatment and unnecessary extensive procedures, but is difficult because diagnostic imaging findings for collagenous fibroma have not been established. We report MR imaging findings of three collagenous fibromas in correlation with their histopathology. The characteristic rim enhancement on post contrast T1-weighted images with fat suppression was present in all three cases, and we consider this to represent the difference in vascularity between the outer capsule-like fibrous tissue and the inside of the tumor. PMID- 22829024 TI - Pathological cardiac hypertrophy alters intracellular targeting of phosphodiesterase type 5 from nitric oxide synthase-3 to natriuretic peptide signaling. AB - BACKGROUND: In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide- (specifically from nitric oxide synthase 3) but not natriuretic peptide (NP)-stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Because nitric oxide signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling. METHODS AND RESULTS: Mice with cardiac myocyte inducible PDE5 overexpression (P5(+)) were crossed to those lacking nitric oxide synthase 3 (N3(-)), and each model, the double cross, and controls were subjected to transaortic constriction. P5(+) mice developed worse dysfunction and hypertrophy and enhanced NP stimulation, whereas N3(-) mice were protected. However, P5(+)/N3(-) mice behaved similarly to P5(+) mice despite the lack of nitric oxide synthase 3-coupled cGMP generation, with protein kinase G activity suppressed in both models. PDE5 inhibition did not alter atrial natriuretic peptide-stimulated cGMP in the resting heart but augmented it in the transaortic constriction heart. This functional retargeting was associated with PDE5 translocation from sarcomeres to a dispersed distribution. P5(+) hearts exhibited higher oxidative stress, whereas P5(+)/N3(-) hearts had low levels (likely owing to the absence of nitric oxide synthase 3 uncoupling). This highlights the importance of myocyte protein kinase G activity as a protection for pathological remodeling. CONCLUSIONS: These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for natriuretic peptide-derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely affects the pathophysiological consequence and the therapeutic impact of PDE5 modulation in heart disease. PMID- 22829027 TI - Case report: unusual complication during outpatient continuous regional popliteal analgesia. AB - PURPOSE: Continuous regional anesthesia applied as pain therapy at home is clinically established standard practice after upper and lower limb surgery. Persistent motor block at discharge or after continuous infusion of local anesthetics, however, might lead to complications related to the insensate extremity. We report a rare case of a foot fracture due to stumbling after continuous sciatic nerve block at home and discuss the related clinical implications. CLINICAL FEATURES: After uncomplicated ambulatory foot surgery under regional anesthesia, a patient was discharged with a continuous sciatic popliteal nerve block for pain therapy at home. After stumbling, the patient remained symptom-free even until catheter removal three days after surgery. Radiography done one week after surgery revealed a styloid fracture of the fifth metatarsal bone. Her subsequent recovery was uneventful. CONCLUSIONS: The true incidence of complications related to falls at home associated with lower extremity blockade remains unknown, as symptoms of possible complications may be masked by the effects of the local anesthetic. However, with increasing use of postoperative regional anesthesia, it is mandatory to develop and adhere to clinical care maps, and to elaborate and teach strategies to further enhance patient safety. PMID- 22829026 TI - 3DMR osseous reconstructions of the shoulder using a gradient-echo based two point Dixon reconstruction: a feasibility study. AB - OBJECTIVE: To create 3DMR osseous models of the shoulder similar to 3DCT models using a gradient-echo-based two-point/Dixon sequence. MATERIALS AND METHODS: CT and 3TMR examinations of 7 cadaveric shoulders were obtained. Glenoid defects were created in 4 of the cadaveric shoulders. Each MR study included an axial Dixon 3D-dual-echo-time T1W-FLASH (acquisition time of 3 min/30 s). The water only image data from the Dixon sequence and CT data were post-processed using 3D software. The following measurements were obtained on the shoulders: surface area (SA), height/width of the glenoid and humeral head, and width of the biceps groove. The glenoid defects were measured on imaging and compared with measurements made on en face digital photographs of the glenoid fossae (reference standard). Paired t tests/ANOVA were used to assess the differences between the imaging modalities. RESULTS: The differences between the glenoid and humeral measurements were not statistically significant (cm): glenoid SA 0.12 +/- 0.04 (p = 0.45) and glenoid width 0.13 +/- 0.06 (p = 0.06) with no difference in glenoid height measurement; humeral head SA 0.07 +/- 0.12 (p = 0.42), humeral head height 0.03 +/- 0.06 (p = 0.42), humeral head width 0.07 +/- 0.06(p = 0.18), and biceps groove width 0.02 +/- 0.01 (p = 0.07). The mean/standard deviation difference between the reference standard and 3DMR measurements was 0.25 +/- 0.96 %/0.30 +/- 0.14 mm; 3DCT 0.25 +/- 0.96 /0.75 +/- 0.39 mm. There was no statistical difference between the measurements obtained on 3DMR and 3DCT (percentage, p = 0.45; mm, p = 0.20). CONCLUSION: Accurate 3D osseous models of the shoulder can be produced using a 3D two-point/Dixon sequence and can be added to MR examinations with a minor increase in imaging time, used to quantify glenoid loss, and may eliminate the need for pre-surgical CT examinations. PMID- 22829028 TI - Jump-starting telemedicine. PMID- 22829029 TI - External auditory canal cholesteatoma. PMID- 22829030 TI - Recurrent pre-B-cell acute lymphoblastic leukemia in the middle ear: a form of granulocytic sarcoma. PMID- 22829031 TI - Paranasal sinus mucocele. PMID- 22829032 TI - Allergic fungal rhinosinusitis in children. PMID- 22829033 TI - Expression and clinical significance of PLUNC protein in nasal polyp and chronic sinusitis tissue. AB - We conducted a study to validate the expression of PLUNC (palate, lung, and nasal epithelial clone) protein in nasal polyp and chronic sinusitis tissue by immunohistochemistry. We also explored the relationship between the intensity of positive immunohistochemical staining for PLUNC protein and postoperative therapeutic efficacy. Our study population consisted of 34 patients with nasal polyps and 30 with chronic sinusitis who had undergone surgical treatment, along with 18 healthy controls who did not undergo surgery. All samples were stained according to the streptavidin-peroxidase immunohistochemical method to examine PLUNC protein expression. The surgical patients were evaluated for clinical therapeutic efficacy 6 months postoperatively. The association between efficacy and the intensity of PLUNC protein positivity was examined by the Spearman rank correlation analysis. Intensity was rated as either +++(>50% positive cells), ++ (26 to 50% positive cells),+ (<=25% positive cells), or -(no positive cells). We found that the most common levels of PLUNC positivity were + in the patients with nasal polyps, +++ in the patients with chronic sinusitis, and ++ in the controls (p< 0.01). Analysis of the Spearman rank correlation indicated that the intensity of PLUNC protein expression was significantly correlated with postoperative therapeutic efficacy (p< 0.001). We conclude that PLUNC protein is an essential factor in the innate defense mechanism of the nasal mucosa. The immunohistochemical staining of PLUNC protein could have clinical benefit in terms of predicting therapeutic efficacy and outcomes in patients with nasal polyps or chronic sinusitis. PMID- 22829034 TI - Atypical presentation of mucoepidermoid carcinoma after radiation therapy for the treatment of keloids. AB - Radiation therapy to the head and neck for the treatment of benign diseases carries the potential for the late development of carcinoma. Low-dose radiation has been used as an adjunctive treatment for recurrent keloids, especially massive keloids, but the carcinogenic potential of ionizing radiation in this setting remains controversial. We report the case of a 37-year-old black woman with a history of severe earlobe keloids who had been first treated with resection and postoperative radiation at the age of 9 years. When she had reached the age of 36 years, she required reoperation for massive keloid scarring, after which she underwent a second course of postoperative radiation to the right side of her face and neck. Some 20 months after the second administration of radiation therapy, she developed a mucoepidermoid carcinoma in the right parotid gland. The tumor was successfully treated with surgery. PMID- 22829035 TI - Papillary carcinoma in a lingual thyroid: an unusual presentation. AB - A lingual thyroid is a mass of ectopic thyroid tissue located in the midline of the base of the tongue. Its estimated prevalence ranges from 1 in 3,000 to 1 in 10,000 population. We report the interesting case of a 28-year-old woman who presented with a primary papillary carcinoma in a lingual thyroid and a histologically normal thyroid gland. To the best of our knowledge, this case probably represents only the second reported case of a follicular variant of a papillary carcinoma arising in a lingual thyroid. PMID- 22829036 TI - Primary solitary extramedullary plasmacytoma of the tongue. AB - Extramedullary plasmacytomas are rare malignancies. Most cases (80%) are seen in the head and neck region, where they represent 1% of all head and neck malignancies. We report a case of an extramedullary plasmacytoma of the tongue that was treated successfully with three-dimensional conformal radiotherapy. The patient was a 50-year-old woman who was admitted to our hospital with bilateral pain and ulceration on the sides of her tongue. Findings on magnetic resonance imaging and positron-emission tomography did not demonstrate any mass within the tongue or any lymphatic or distant metastasis. A tissue biopsy identified a plasma cell neoplasm. The patient was treated with a total dose of 50 Gy delivered in 2-Gy daily fractions. After 54 months of post-treatment follow-up, she exhibited no sign of systemic myeloma or local recurrence. This case is presented not only for the rarity of the tumor type, but also for its unusual location. PMID- 22829037 TI - Skull base plasmacytoma with conductive hearing loss and an external auditory canal mass. AB - Skull base plasmacytomas are rare and difficult to differentiate clinically and radiologically from other tumors of the head and neck. Because of the risk of progression to multiple myeloma, early diagnosis is essential. We report the case of a 65-year-old woman who presented with left-sided conductive hearing loss and an external auditory canal mass. The tumor was removed along with much of the tympanic membrane, and it was found to be a plasmacytoma. The patient was subsequently diagnosed with multiple myeloma and treated with chemoradiation before being lost to follow-up. PMID- 22829038 TI - Primary laryngeal NK/T-cell non-Hodgkin lymphoma: a case report. AB - The estimated prevalence of extranodal non-Hodgkin lymphoma ranges from 10 to 35% of all cases; a finding in the larynx is extremely rare. We describe the case of a 77-year-old man who presented for evaluation of a 1-month history of minor swallowing difficulty, cough, and a foreign-body sensation in the throat. Fiberoptic endoscopy detected a tumor mass on the left aryepiglottic fold. Vocal fold mobility was normal. A biopsy specimen was obtained, and microscopic analysis revealed that the stratified squamous epithelium was partially eroded by abundant infiltrate that had occupied the entire submucosa. The submucosal infiltration consisted of lymphatic cells, including small, medium-sized, and large cells with an anaplastic appearance. On immunohistochemical analysis, the lymphoma cell population stained positive for CD3 and CD2, focally positive for CD56, and negative for CD4, CD5, and CD7. In addition, tumor cells expressed TIA 1, perforin, and granzyme B. A complete radiologic, pulmonologic, and hematologic workup found no other tumor. The patient underwent two cycles of chemotherapy followed by radiotherapy, and he experienced complete tumor regression. At the 1 year follow-up, findings on fiberoptic endoscopy of the larynx were normal, and positron-emission tomography found no evidence of a recurrence. The prognosis for this type of tumor is good when the diagnosis is made in the early phase of the disease. Long-term follow-up is advisable for the timely detection of possible local or distant recurrences, which are common. PMID- 22829039 TI - Unusual nasopharyngeal foreign body: a hooked iron rod. AB - Foreign bodies lodged in the nasopharynx are rare. We report a case of an unusual foreign body in the nasopharynx: a hooked iron rod. The patient was a 5-year-old girl. The foreign body had to be removed under general anesthesia. To the best of our knowledge, there has been no similar published report of a hooked iron rod in the nasopharynx. PMID- 22829040 TI - Subglottic thyroglossal duct cyst: a rare intralaryngeal presentation. AB - Thyroglossal duct cysts are common midline neck swellings that can present at any site along their migratory pathway. They are frequently situated just below the hyoid bone. Extension to the subglottic area is very rare; such an unusual presentation can complicate the diagnosis of a thyroglossal duct cyst. We report the case of a 30-year-old man who presented with a subglottic thyroglossal duct cyst and associated laryngeal symptoms. To the best of our knowledge, only 2 similar cases have been previously reported in the literature, both of which occurred in 2-year-old boys. We believe, therefore, that ours is the first reported case of a subglottic thyroglossal duct cyst in an adult. We discuss the clinical presentation, diagnosis, and treatment of our patient, and we summarize the literature on intralaryngeal thyroglossal duct cysts. PMID- 22829041 TI - Case report: leiomyosarcoma of the parapharyngeal space. AB - Leiomyosarcoma is usually found in the female genital tract, the retroperitoneum, the wall of the gastrointestinal tract, and subcutaneous tissues. An appearance of this malignant tumor in the parapharyngeal space is extremely rare and may be difficult to diagnose. Because of its rarity, little information exists on management and prognosis. We report the case of a 50-year-old man with a parapharyngeal space leiomyosarcoma who was treated with total excision of the tumor and postoperative radiotherapy. At follow-up 6 months postoperatively, he was well and free of disease. To the best of our knowledge, this is only the third case of a leiomyosarcoma in the parapharyngeal area to be reported in the literature. We discuss the diagnosis and treatment of leiomyosarcoma in this aspect. PMID- 22829042 TI - Fourth branchial cleft cyst with no identifiable tract: case report and treatment approach. AB - We describe a rare case of a fourth branchial cleft cyst that had no identifiable tract. The patient was a 23-year-old man who presented with recurring neck abscesses. After six similar episodes, computed tomography finally demonstrated that the most recent abscess had extended into the thyroid gland, a finding that led to the correct diagnosis. Extensive surgical extirpation of the cyst with an adjacent neck dissection was performed, and the patient remained symptom-free at 25 months of follow-up. The occurrence of a fourth branchial cleft cyst with no clear tract presents a surgical dilemma, as complete dissection cannot be guaranteed. Consequently, such patients are predisposed to recurrence. We propose that definitive management of a fourth branchial cleft cyst with no identifiable tract focus on eliminating the likely embryologically based path of bacterial seeding. This includes a hemithyroidectomy in conjunction with a selective neck dissection to cover all areas where a fourth branchial tract may lie within the neck. PMID- 22829043 TI - Staphylococcus aureus cavernous sinus thrombosis mimicking complicated fungal sinusitis. AB - Septic cavernous sinus thrombosis is a rare and potentially life-threatening complication of infections involving the paranasal sinuses or the middle one third of the face. We report a challenging case of cavernous sinus thrombosis to familiarize otolaryngologists with its clinical features, diagnosis, and management. The patient was a 45-year-old diabetic woman whose signs and symptoms mimicked those of complicated fungal sinusitis. She presented with fever, nausea without vomiting, frontal headache, bilateral ptosis and swelling, double vision, a partial loss of visual acuity in the left eye, and restricted lateral ocular movements. Her Snellen visual acuity had been reduced to 8/10 on the right and 6/10 on the left. Radiologic investigation revealed cavernous sinus extension of sphenoid sinusitis and a fungus-ball appearance in the sphenoid sinus. On the second day of her admission, the patient's vision was further reduced to 6/10 on the right and 2/10 on the left. She then underwent urgent bilateral anterior and posterior ethmoidectomy and sphenoidectomy. At postoperative follow-up, her vision had stabilized at 10/10 bilaterally. At 2 months after discharge, she exhibited no evidence of abducens nerve palsy, and her ocular function had returned to normal. The diagnosis of cavernous sinus thrombosis requires a high index of suspicion and confirmation by imaging. The favorable outcome in our case was attributable to early diagnosis, prompt initiation of appropriate intravenous antibiotic therapy, and surgical drainage by the skillful surgical team. PMID- 22829045 TI - Endoscopic view of sphenoid sinusitis adjacent to an intracranial aneurysm. PMID- 22829044 TI - Acute candidal pharyngolaryngitis. PMID- 22829046 TI - Dynasplint for the management of trismus after treatment of upper aerodigestive tract cancer: a retrospective study. PMID- 22829047 TI - Mesenchymal hamartomas of the pediatric head and neck. AB - We describe the fifth published report of a mesenchymal hamartoma presenting as a cheek mass. A 5-month-old infant was brought to our institution for evaluation of an enlarging left-sided congenital cheek mass. Over time, the lesion had begun to cause significant facial asymmetry and oral incompetence. Radiologic imaging revealed an approximate 2.5 * 3.5-cm, noncystic lesion located in the left buccal space, separate from the mandible and surrounding the salivary glands. Magnetic resonance imaging (MRI) sequences demonstrated an isointense, T1-weighted lesion with avid gadolinium uptake, and increased intensity of T2-weighted sequences. The patient subsequently underwent biopsy and subtotal resection through a left gingivobuccal incision with the goal of improving lip contour and facial symmetry. Histologic examination revealed an admixed arrangement of mature smooth muscle, vascular, adipose, and neural tissue elements within a slightly myxoid stroma, consistent with a mixed mesenchymal hamartoma. An 8-month postoperative MRI demonstrated near-total removal without evidence of regrowth. While rare, hamartomas should be included in the differential diagnosis of a slow-growing pediatric head and neck mass. Gross total resection may provide cure; however, given this lesion's benign nature, less-than-complete resection should be considered when lesions infiltrate opposing critical structures. Thorough clinical and histologic evaluation is critical to avoid overly aggressive treatment and unnecessary morbidity. PMID- 22829048 TI - The influence of physicochemical properties on the internal dose of trihalomethanes in humans following a controlled showering exposure. AB - Although disinfection of domestic water supply is crucial for protecting public health from waterborne diseases, this process forms potentially harmful by products, such as trihalomethanes (THMs). We evaluated the influence of physicochemical properties of four THMs (chloroform, bromodichloromethane, dibromochloromethane, and bromoform) on the internal dose after showering. One hundred volunteers showered for 10 min in a controlled setting with fixed water flow, air flow, and temperature. We measured THMs in shower water, shower air, bathroom air, and blood samples collected at various time intervals. The geometric mean (GM) for total THM concentration in shower water was 96.2 MUg/l. The GM of total THM in air increased from 5.8 MUg/m(3) pre shower to 351 MUg/m(3) during showering. Similarly, the GM of total-blood THM concentration increased from 16.5 ng/l pre shower to 299 ng/l at 10 min post shower. THM levels were significantly correlated between different matrices (e.g. dibromochloromethane levels) in water and air (r=0.941); blood and water (r=0.845); and blood and air (r=0.831). The slopes of best-fit lines for THM levels in water vs air and blood vs air increased with increasing partition coefficient of water/air and blood/air. The slope of the correlation plot of THM levels in water vs air decreased in a linear (r=0.995) fashion with increasing Henry's law constant. The physicochemical properties (volatility, partition coefficients, and Henry's law constant) are useful parameters for predicting THM movement between matrices and understanding THM exposure during showering. PMID- 22829049 TI - Performance of GPS-devices for environmental exposure assessment. AB - Integration of individual time-location patterns with spatially resolved exposure maps enables a more accurate estimation of personal exposures to environmental pollutants than using estimates at fixed locations. Current global positioning system (GPS) devices can be used to track an individual's location. However, information on GPS-performance in environmental exposure assessment is largely missing. We therefore performed two studies. First, a commute-study, where the commute of 12 individuals was tracked twice, testing GPS-performance for five transport modes and two wearing modes. Second, an urban-tracking study, where one individual was tracked repeatedly through different areas, focused on the effect of building obstruction on GPS-performance. The median error from the true path for walking was 3.7 m, biking 2.9 m, train 4.8 m, bus 4.9 m, and car 3.3 m. Errors were larger in a high-rise commercial area (median error=7.1 m) compared with a low-rise residential area (median error=2.2 m). Thus, GPS-performance largely depends on the transport mode and urban built-up. Although ~85% of all errors were <10 m, almost 1% of the errors were >50 m. Modern GPS-devices are useful tools for environmental exposure assessment, but large GPS-errors might affect estimates of exposures with high spatial variability. PMID- 22829050 TI - Impact of NO(x) emissions reduction policy on hospitalizations for respiratory disease in New York State. AB - To date, only a limited number of studies have examined the impact of ambient pollutant policy on respiratory morbidities. This accountability study examined the effect of a regional pollution control policy, namely, the US Environmental Protection Agency's (EPA) nitrogen oxides (NO(x)) Budget Trading Program (NBP), on respiratory health in New York State (NYS). Time-series analysis using generalized additive models was applied to assess changes in daily hospitalizations for respiratory diseases in NYS after the implementation of the NBP policy. Respiratory end points in the summers during the baseline period (1997-2000) were compared with those during the post-intervention period (2004 2006). Stratified analyses were also conducted to examine whether health impacts of the NBP differed by socio-demographic, regional, or clinical characteristics. Following the implementation of EPA's NBP policy, there were significant reductions in mean ozone levels (-2% to -9%) throughout NYS. After adjusting for time-varying variables, PM(2.5) concentration, and meteorological factors, significant post-intervention declines in respiratory admissions were observed in the Central (-10.18, 95% confidence interval (CI): -14.18, -6.01), Lower Hudson ( 11.05, 95% CI: -16.54, -5.19), and New York City Metro regions (-5.71, 95% CI: 7.39, -4.00), consistent with wind trajectory patterns. Stratified analyses suggest that admissions for asthma, chronic airway obstruction, among those 5-17 years old, self-payers, Medicaid-covered, and rural residents declined the most post-NBP. This study suggests that the NO(x) control policy may have had a positive impact on both air pollution levels statewide and respiratory health in some NYS regions. However, the effect varied by disease subgroups, region, and socio-demographic characteristics. PMID- 22829051 TI - The inhibitory effect of a polysaccharide from Codonopsis pilosula on tumor growth and metastasis in vitro. AB - In this study, we prepared an acidic polysaccharide (CPPA) from the roots of Codonopsis pilosula. The effects of CPPA on tumor cell growth, invasion, and migration were examined in vitro. The CPPA not only induced a potent inhibitory effect on the invasion and migration potential of human epithelial ovarian cancer HO-8910 cells in vitro, evaluated by wound healing, transwell and cell adhesion assays, but also had an efficient anti-proliferation effect on tumor cells. Moreover, the CD44 expression on the HO-8910 cells was also attenuated by CPPA treatment. Therefore, our results indicate that CPPA may be a potential candidate compound for the prevention of tumor metastasis, presumably by inhibiting invasion, migration and adhesion of tumor cells, as well as the CD44 expression on the tumor cells. PMID- 22829052 TI - Dynamic high pressure microfluidization-assisted extraction and antioxidant activities of lentinan. AB - Dynamic high pressure microfluidization (DHPM) was applied to assist the lentinan extraction. Response surface methodology (RSM), based on Box-Behnken design, was employed to optimize the DHPM-assisted extraction conditions of lentinan. Three main independent variables (DHPM pressure, ratio of water to raw material, extraction temperature) were taken into consideration. A yield of 7.200% was obtained under a modified condition (ratio of water to raw material of 65 mL/g, DHPM pressure of 147 MPa, extraction temperature of 83 degrees C), which matched well with the predicted value of the model. The molecular weight of the DHPM assisted extract and hot water extract was 913,329 and 965,361 Da, respectively. Compared to the traditional hot water extraction, the lentinan extracted by DHPM assisting had better scavenging capacity of hydroxyl radical, superoxide anion free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and nitrite. It could be concluded that the DHPM was a promising method to enhance the yield and antioxidant activity of lentinan during extraction. PMID- 22829054 TI - Microwave-assisted degradation of chitosan for a possible use in inhibiting crop pathogenic fungi. AB - Degradation of chitosan by H(2)O(2) under microwave irradiation was investigated. The oxidative degradation of chitosan was highly accelerated by microwave irradiation under the condition of low temperature and low concentration of H(2)O(2). The degraded chitosans with low molecular weight (M(w)) were characterized by gel permeation chromatography, Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, X-ray diffraction and elemental analysis. The decrease of M(w) led to transformation of crystal structure and increase of water solubility, whereas no significant chemical structure change in the backbone of chitosan was observed. Antifungal activities of chitosans with different M(w) against crop pathogenic fungi Phomopsis asparagi, Fusarium oxysoporum f. sp. Vasinfectum and Stemphylium solani were investigated at the concentrations of 100, 200 and 400 mg/L. All degraded chitosans with low M(w) exhibited enhanced antifungal activity compared with original chitosan and the chitosan of 41.2 kDa showed the highest activity. At 400 mg/L, the chitosan of 41.2 kDa inhibited growth of P. asparagi at 89.3%, stronger than polyoxin and triadimefon, the inhibitory effects of which were found to be 55.5% and 68.5%. All the results indicated that oxidative degradation under microwave irradiation was a promising technique for large-scale production of low M(w) chitosan for use in crop protection. PMID- 22829053 TI - Effects of silica nanoparticle supported ionic liquid as additive on thermal reversibility of human carbonic anhydrase II. AB - Silica nanoparticle supported imidazolium ionic liquid [SNImIL] was synthesized and utilized as a biocompatible additive for studying the thermal reversibility of human carbonic anhydrase II (HCA II). For this purpose, we prepared additive by modification of nanoparticles through the grafting of ionic liquids on the surface of nanoparticles (SNImIL). The SNImIL were fully characterized by Fourier transform infrared spectroscopy, scanning electron microscopy and thermo gravimetric analysis. The characterization of HCA II was investigated by various techniques including UV-vis and ANS fluorescence spectrophotometry, differential scanning calorimetry, and docking study. SNImIL induced disaggregation, enhanced protein stability and increased thermal reversibility of HCA II by up to 42% at pH 7.75. PMID- 22829055 TI - Dietary chitosan supplementation attenuates isoprenaline-induced oxidative stress in rat myocardium. AB - Despite considerable advances in diagnosis and management over the last three decades, acute myocardial infarction continues to be a major public health problem. It is predicted that ischemic heart diseases will constitute the major disease-burden worldwide in the year 2020. In the present study, an attempt has been made to examine the effects of dietary chitosan supplementation on lipid peroxidation and cardiac antioxidant defense system in isoprenaline-induced myocardial infarction in rats, an animal model of myocardial infarction in man. Dietary chitosan intake significantly attenuated the isoprenaline-induced lipid peroxidation and maintained the level of reduced glutathione at near normal. Its administration demonstrated an antioxidant effect by maintaining the activities of myocardial glutathione dependent antioxidant enzymes (glutathione peroxidase and glutathione-S-transferase) and antiperoxidative enzymes (superoxide dismutase and catalase) at levels comparable to that of controls. The results of the present study indicate that the salubrious effects of dietary supplementation of chitosan is probably related to a counteraction of free radicals and/or to normal maintenance of the activities of free radical enzymes and the level of GSH, which protect myocardial membrane against oxidative damage by decreasing lipid peroxidation. PMID- 22829056 TI - Microstructure-stability relations studies of porous chitosan microspheres supported palladium catalysts. AB - In this study, polyethylene glycol (PEG) with different molecular weight, polyvinyl pyrrolidone (PVP), and polyvinyl alcohol (PVA), are chosen as porogens for preparing chitosan base porous microsphere supported palladium catalyst for coupling reactions. The pore structure of the microspheres was controlled by the compatibility of chitosan and counterpart polymers. The prepared porous chitosan microspheres supported palladium heterogeneous catalysts have been evaluated using the well-established Ullmann reductive homocoupling and the Heck cross coupling reactions. The activities, stabilities and recyclability of the porous chitosan microspheres supported palladium catalysts are not only highly dependent upon the surface areas of the solid supports, but also upon the chemical properties of the water-soluble polymers. The degradation of the prepared heterogeneous palladium catalysts is mainly caused by a combination of the palladium leaching and the morphological transformation of the palladium species from the amorphous into the crystals. PMID- 22829057 TI - Antitussive and bronchodilatory effects of Lythrum salicaria polysaccharide polyphenolic conjugate. AB - A high molecular mass polysaccharide-polyphenolic conjugate has been isolated from flowering parts of Lythrum salicaria by hot alkaline extraction. Its chemical analysis revealed 74% of carbohydrates and 17% of phenolics. Compositional analysis of carbohydrate part showed a high GalA content (49%), Rha (25%), Gal (13%) and Ara (9%) residues, and indicated thus rhamnogalacturonan associated with arabinogalactan in Lythrum conjugate. Antitussive activity tests, performed in three doses of Lythrum conjugate - 25, 50 and 75 mg/kg of animal body weight, showed the reduction of the number of cough efforts even 5h after administration. However, their antitussive effects were lower in comparison with that of codeine, the strongest narcotic antitussive agent. The tests evaluating the influence of different doses on airways smooth muscle reactivity revealed more significant effect of Lythrum conjugate in comparison with that of salbutamol, a commercial bronchodilator used in a clinical practice. Measurements of specific airway resistance pointed at both, the dose-dependent bronchodilatory activity and possible participation of bronchodilation on antitussive effect of Lythrum conjugate. This study represents the first sight into pharmacodynamic properties of Lythrum polysaccharide-polyphenolic glycoconjugate. PMID- 22829058 TI - Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma. AB - BACKGROUND: A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes. METHODS: Patients (pts) diagnosed with LAPC who survived >2 months were identified from institutional databases. Clinical details were collected. Sequential re-staging scans were reviewed. Progression-free survival (PFS), time from progression to death (TTD), and overall survival (OS) were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Between 2005 and 2011, 40 pts were identified. Median age was 66 yrs (range, 43-74) and 60 % (n=24) were male. All pts received chemotherapy. Median OS was 11.3 months. Twenty patients (50 %) had local progression only (LP) and 16 (40 %) had metastatic progression (MP) at first documentation of progression, while four patients (10 %) had stable disease. PFS was 4.0 vs 5.6 months (hazard ratio (HR) 0.97; 95 % CI 0.49-1.93, p=0.94) for LP and MP, respectively. Three of the patients with LP (15 %) eventually developed metastatic disease after a median of 4.2 months (3.7-9.6). For MP patients, five had concurrent local progression. Sites of disease were lung (eight), peritoneum (five), liver (three), and bone (one). TTD for LP and MP was 5.6 vs 1.4 months (HR 0.62; 95 % CI 0.28-1.39, p=0.24) and OS was 13.2 vs 8.0 months (HR 0.59; 95 % CI 0.28-1.25, p=0.017), respectively. CONCLUSIONS: We identified two subgroups of LAPC with distinctive behavior, one local dominant progression with low predilection for metastases and another with rapid metastatic development and worse survival. Early recognition of these phenotypes might allow a more tailored treatment approach to improve outcome. PMID- 22829059 TI - Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6 imines and related tricyclic heterocycles. AB - 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is a virucidal heterocyclic compound active against various viruses, including HCV, HIV, and simian immunodeficiency virus. Using facile synthetic approaches that we developed for the synthesis of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic derivatives, the parallel structural optimizations of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 were investigated. Replacement of the 6-6-6 pyrimido[1,2 c][1,3]benzothiazin-6-imine framework with 5-6-6 or 6-6-5 derivatives led to a significant loss of anti-HIV activity, and introduction of a hydrophobic group at the 9- or 10-positions improved the potency. In addition, we demonstrated that the PD 404182 derivative exerts anti-HIV effects at an early stage of viral infection. PMID- 22829060 TI - Synthesis of lead chalcogenide nanocrystals and study of charge transfer in blends of PbSe nanocrystals and poly(3-hexylthiophene). AB - Nearly monodisperse lead chalcogenide (PbE, E = S, Se, or Te) semiconductor quantum dots of controllable shape have been produced via a novel synthesis which includes the occurrence of in situ formed Pb(0) particles. Tunable size and shape are achieved through appropriate choice of the precursor type and the stabilizer. As precursor, we use, on the one hand, lead oxide or lead acetate, on the other hand, tellurium, selenium, or sulfur powder dissolved in trioctylphosphine (TOP), tributylphosphine (TBP), or 1-octadecene (ODE). Oleic acid (OA) and various amines, as well as TOP and TBP are used for stabilization. With respect to possible application in hybrid solar cells, the surface of as-synthesized spherical PbSe nanocrystals was investigated by nuclear magnetic resonance (NMR), mass spectrometry (MS) and thermogravimetric analysis (TGA). As an important result, it was found that the surface is not mostly covered by oleic acid after synthesis, but by a phosphorus compound. We also applied a ligand exchange procedure with hexylamine and found evidence for the successful attachment of hexylamine to the nanocrystal surface. Additionally, charge separation between these nanoparticles and the conjugated polymer poly(3-hexylthiophene) (P3HT) is studied by electron spin resonance and photoinduced absorption spectroscopy. The spectra obtained suggest that charges can be produced successfully by photoinduced charge transfer. PMID- 22829061 TI - Advancing the surgical treatment of locally recurrent rectal cancer. PMID- 22829062 TI - A novel and highly sensitive acetyl-cholinesterase biosensor modified with hollow gold nanospheres. AB - In this work, a highly sensitive acetylcholinesterase (AChE) inhibition-based amperometric biosensor has been developed. Firstly, a glassy carbon electrode (GCE) was modified with chitosan (Chits). Then, hollow gold nanospheres (HGNs) were absorbed onto the surface of chitosan based on the strong affinity through electrostatic adsorption. After that, L-cysteine (L-cys) was assembled on HGNs through Au-S bond. The hollow gold nanospheres were prepared by using Co nanoparticles as sacrificial templates and characterized by scanning electron microscopy, transmission electron microscopy and ultraviolet spectra, respectively. Finally, AChE was immobilized with covalent binding via -COOH groups of L-cysteine onto the modified GCE. The AChE biosensor fabrication process was characterized by cyclic voltammetry and electrochemical impedance spectroscopy methods with the use of ferricyanide as an electrochemical redox indicator. Under optimum conditions, the inhibition rates of pesticides were proportional to their concentrations in the range of 0.1-150 and 0.1-200 MUg L( 1) for chlorpyrifos and carbofuran, respectively, the detection limits were 0.06 MUg L(-1) for chlorpyrifos and 0.08 MUg L(-1) for carbofuran. Moreover, the biosensor exhibited a good stability and reproducibility and was suitable for trace detection of pesticide residues in vegetables and fruits. PMID- 22829063 TI - Correction of severe congenital flexural carpal deformities with semicircular external skeletal fixation system in calves. AB - OBJECTIVE: To present a novel technique for the treatment of severe congenital flexural forelimb deformities in calves. METHODS: Thirteen calves of different breeds and sex with severe congenital flexural forelimb deformities were enrolled in the study. A semicircular external skeletal fixation system composed of 6 hole, 45 degrees carbon-fiber arches, 6 mm threaded rods, half-pin fixation bolts, 6 mm hexagonal nuts, and negative profile end-threaded half-pins were used for pancarpal arthrodesis. Complications, time to first use of the limb, fixator removal time, preoperative and postoperative sagittal plane angles of the fused joints, and functional outcomes were evaluated clinically and radiographically. Final assessments were determined according to functional and cosmetic outcomes. RESULTS: All of the surgically treated carpal joints obtained fusion. Seven of the calves started to use the limb immediately after recovering from anesthesia. In the other six calves, the time ranged from one to two days. Time to fixator removal ranged from 25 to 36 days (mean 30 days). Final outcome was excellent in 11 cases, and good in two cases. CLINICAL SIGNIFICANCE: The technique was found to be a useful method for the treatment of severe congenital flexural forelimb deformities in calves. The cost of the operation is negligible compared to the economic value of beef cattle. PMID- 22829064 TI - Estrogen receptor alpha as a key target of organochlorines to promote angiogenesis. AB - Epidemiological studies report that exposure to pesticides like chlordecone and lindane increases risk of cancer. They may act as endocrine disruptors via the activation of estrogen receptor alpha (ERalpha). Carcinogenesis involved angiogenesis and no available data regarding these organochlorines have been reported. The present study aimed at investigating the effects of lindane and chlordecone on cellular processes leading to angiogenesis through an involvement of ERalpha. Angiogenesis has been analyzed both in vitro, on human endothelial cells, and in vivo by quantifying neovascularization with the use of ECMgel(r) plug in mice. Both pesticides increased endothelial cell proliferation, migration and MMP2 activity. These toxics potentiated cell adhesion by enhancing FAK phosphorylation and stress fibers. The two organochlorines increased nitric oxide production via an enhancement of eNOS activity without modification of oxidative stress. Evidence has been provided that the two toxins increased in vivo neovascularization. Most interestingly, all the above processes were either partially or completely prevented after silencing of ERalpha. Altogether, these data highlight that organochlorines modulate cellular angiogenic processes through activation of ERalpha. This study further reinforces the harmful effects of these pesticides in carcinogenesis, particularly in the modulation of angiogenesis, a critical step in tumor promotion, through ERalpha. PMID- 22829065 TI - Translation, cultural adaptation, and validation of the Bath questionnaires and HAQ-S in Hindi for Indian patients with ankylosing spondylitis. AB - The disease activity and functional impact of ankylosing spondylitis (AS) is currently measured through various questionnaire instruments, the most popular of which are the Bath indices. However, Hindi versions for use in Indian patients are not available. This study aimed to fill this lacuna. Translation and cross cultural adaptation of the instruments--Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitits Metrology Index (BASMI), Bath Ankylosing Spondylitis Patient Global Score (BAS-G), and Health Assessment Questionnaire-Spondyloarthropathy (HAQ-S)--were done using standard guidelines. These were then self-administered to patients. The BASMI measurements, occiput-to wall distance, chest expansion (in centimeters), total enthesis count, ESR, and C reactive protein (CRP) were measured. To assess reliability, the patient was called back on day 14, and the questionnaires were again self-administered, and the intra-class correlation coefficient was calculated to assess reliability. Correlation of questionnaire scores with acute phase reactants, measurements, and enthesitis index were used to assess for construct validity. Some modifications were done in the Bath indices and HAQ-S for cross-cultural adaptation. For validation, 41 patients of ankylosing spondylitis with a mean age of 34 years (+/ 10.2) and disease duration of 5.8 years (+/-6.2) were included. The Bath Ankylosing Spondylitis Functional Index (BASFI), BASDAI, and HAQ-S showed good correlation among themselves (r = 0.69 to 0.84, p < 0.001), except for BAS-G with HAQ-S (r = 0.53, p < 0.001). Correlation between BASDAI and ESR (0.31, p = 0.05), CRP (0.48, p < 0.001), and enthesitis score (0.32, p = 0.045) was fair. Similarly, there was fair correlation of BASFI with ESR (0.55, p < 0.001), CRP (p = 0.60, p < 0.001), and various metrological measurements. These suggest convergent validity. However, there was a lack of correlation between metrological measurements and BASDAI, demonstrating divergent validity. The intra class correlation coefficients between baseline and retest were acceptable: BASDAI intra-class correlation coefficients (ICC) 0.87 (0.78-0.93), BASFI ICC 0.90 (0.82-0.94), BAS-G ICC 0.75 (0.58-0.86), and HAQ-S ICC 0.91 (0.84-0.95). The Hindi versions of the BASDAI, BASFI, BAS-G, and HAQ-S were found to be valid and reliable for use in Hindi-speaking Indian patients with ankylosing spondylitis. PMID- 22829067 TI - Often a missed type of pancreatitis: groove pancreatitis. PMID- 22829066 TI - Autonomic neural control of the cardiovascular system in patients with Behcet's disease in the absence of neurological involvement. AB - Behcet's disease (BD) is a chronic multi-system disease presenting with recurrent oral and genital ulceration, and relapsing uveitis. Heart rate recovery (HRR) after exercise is a marker of parasympathetic activity. A delayed recovery of systolic blood pressure (SBP) after exercise might reflect sympathetic hyperactivity. The analysis of variations in heart rate has also been used to determine the balance between sympathetic and vagal nerve activities in the heart. Our objective was to determine HRR, the SBP response to exercise and heart rate variability (HRV) in patients with BD in the absence of neurological involvement. The study population consisted of 32 patients with BD and 30 healthy controls who were matched with respect to age, sex, and physical activity. Heart rate recovery was calculated as the difference between heart rate at peak exercise and heart rate at 1, 2, and 3 min of recovery. Blood pressure recovery indexes were determined by dividing the systolic blood pressure at 2 and 3 min in recovery to the systolic blood pressure at peak exercise. In patients with BD, mean HRR at 1 min (HRR1) were not significantly different than that of controls (21 +/- 7 vs 20 +/- 7 bpm, p = 0.50). Although, resting mean SBP of patients with BD was higher than controls (121 +/- 13 vs 115 +/- 12 mmHg, p = 0.039), the SBP recovery indices of the patients with BD at 2 and 3 min were similar to those of controls (0.84 +/- 0.07 vs 0.84 +/- 0.09, p = 0.89 and 0.78 +/- 0.09 vs 0.78 +/- 0.08, p = 0.93, respectively). Both time domain and frequency domain parameters of patients with BD were similar to that of controls. This study shows that the patients with BD have normal HRR1 and normal SBP response to exercise and normal HRV. These findings might suggest unaltered autonomic neural control of the cardiovascular system in this disorder in the absence of neurological involvement. PMID- 22829068 TI - A new metallostar complex based on an aluminum(III) 8-hydroxyquinoline core as a potential bimodal contrast agent. AB - A ditopic DTPA monoamide derivative containing an 8-hydroxyquinoline moiety was synthesized and the corresponding gadolinium(III) complex ([Gd(H5)(H(2)O)](-)) was prepared. After adding aluminum(III), the 8-hydroxyquinoline part self assembled into a heteropolymetallic triscomplex [(Gd5)(3)Al(H(2)O)(3)](3-). The magnetic and optical properties of this metallostar compound were investigated in order to classify it as a potential in vitro bimodal contrast agent. The proton nuclear magnetic relaxation dispersion measurements indicated that the relaxivity r(1) of [Gd(H5)(H(2)O)](-) and [(Gd5)(3)Al(H(2)O)(3)](3-) at 20 MHz and 310 K equaled 6.17 s(-1) mM(-1) and 10.9 s(-1) mM(-1) per Gd(III) ion respectively. This corresponds to a relaxivity value of 32.7 s(-1) mM(-1) for the supramolecular complex containing three Gd(III) ions. The high relaxivity value is prominently caused by an increase of the rotational tumbling time tau(R) by a factor of 2.7 and 5.5 respectively, in comparison with the commercially used MRI contrast agent Gd(III)-DTPA (Magnevist(r)). Furthermore, upon UV irradiation, [(Gd5)(3)Al(H(2)O)(3)](3-) exposes green broad-band emission with a maximum at 543 nm. Regarding the high relaxivity and the photophysical properties of the [(Gd5)(3)Al(H(2)O)(3)](3-) metallostar compound, it can be considered as a lead compound for in vitro bimodal applications. PMID- 22829069 TI - Influence of density and background color to stress response, appetite, growth, and blind-side hypermelanosis of flounder, Paralichthys olivaceus. AB - To study the relevance of density and background color to stress response, appetite, and growth in olive flounder, Paralichthys olivaceus, we reared two duplicate groups of juveniles (total length 4.46 +/- 0.06 cm, body weight 0.77 +/ 0.03 g) in flat-bottom aquaria with dark-green (control) and white backgrounds for 120 days. We measured cortisol and glucose levels in blood and calculated the daily food intake, food conversion efficiency, survival rate, and growth rate. To study the relevance of density and background color to malpigmentation (hypermelanosis) on the blind side, we also compared malpigmented ratios and prepro-melanin-concentrating hormone mRNA activities in the brain between the dark-green and white background groups, as well as between a relatively lower density (60 days) and higher density (120 days). Although we measured relatively higher levels of cortisol and glucose in the white background group and over 200 % of coverage area [PCA]), the bright background failed to induce an acute stress response of more than 20 ng/ml cortisol and 40 mg/dl glucose both in 60 days and 120 days, but did enhance appetite and growth. Also, a bright background color delayed hyperpigmentation only at a low density below 200 % PCA, but did not inhibit malpigmentation at a high density of more than 200 % PCA. In addition, below 200 % PCA, expression of MCH mRNA was significantly higher in the white group, but the level was reversed and was lower in the white group at more than 200 % PCA. In conclusion, although did not induce a high stress response over 200 % PCA, the bright background color resulted in a moderate increasing of cortisol level in blood below 20 ng/ml and enhanced appetite and growth. Moreover, at a density below 200 % PCA, the bright color inhibited hypermelanosis with high MCH mRNA activity, but at more than 200 % PCA did not inhibit malpigmentation, and the fish showed low MCH mRNA activity, indicating that the inhibitory effect of a bright background color on hypermelanosis is density dependent. PMID- 22829070 TI - The sexually dimorphic adipose fin is an androgen target tissue in the brown trout (Salmo trutta fario). AB - An investigation has been described on the relationship of body length, age and sex with adipose fin length and the number of androgen receptor (AR)-containing cells in the adipose fin as a secondary sexual characteristic for brown trout (Salmo trutta fario). Firstly, body and adipose fin lengths of 2- to 5-year-old brown trout were measured. Thereafter, these fish were killed by decapitation, then their sexes were determined, and adipose fins were excised. The cellular bases of AR binding activities in the adipose fins were analyzed with an antibody against human/rat AR peptide. Immunocytochemistry and western blotting techniques were performed with this antibody. Analysis of morphological measurements indicated that body length and age had a linear relationship with adipose fin length. The coefficients of determination for the body length and age were 0.92 and 0.85 in the male fish and 0.76 and 0.73 in the female fish against the adipose fin length, respectively. At 2 years of age, cells in the adipose fin did not exhibit AR immunoreactivity. However, AR-immunopositive cells were abundant in the adipose fin of 3- to 5-year-old fish. Moreover, the number of AR immunopositive cells was significantly (P < 0.05) high in males and increased with age. These observations indicate that the adipose fin in the brown trout is a probable target for androgen action and that tissue function or development may to some extent be androgen dependent. In addition, it is likely that such an effect will be mediated by specific androgen receptors. PMID- 22829071 TI - How I treat splenomegaly in myelofibrosis. AB - Symptomatic splenomegaly, a frequent manifestation of myelofibrosis (MF), represents a therapeutic challenge. It is frequently accompanied by constitutional symptoms and by anemia or other cytopenias, which make treatment difficult, as the latter are often worsened by most current therapies. Cytoreductive treatment, usually hydroxyurea, is the first-line therapy, being effective in around 40% of the patients, although the effect is often short lived. The immunomodulatory drugs, such as thalidomide or lenalidomide, rarely show a substantial activity in reducing the splenomegaly. Splenectomy can be considered in patients refractory to drug treatment, but the procedure involves substantial morbidity as well as a certain mortality risk and, therefore, patient selection is important. For patients not eligible for splenectomy, transient relief of the symptoms can be obtained with local radiotherapy that, in turn, can induce severe and long-lasting cytopenias. Allogeneic hemopoietic stem cell transplantation is the only treatment with the potential for curing MF but, due to its associated morbidity and mortality, is usually restricted to a minority of patients with poor risk features. A new class of drugs, the JAK2 inhibitors, although also palliative, are promising in the splenomegaly of MF and will probably change the therapeutic algorithm of this disease. PMID- 22829072 TI - Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production. AB - Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-kappaB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity. PMID- 22829073 TI - The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapies. PMID- 22829074 TI - The role of androgen and androgen receptor in skin-related disorders. AB - Androgen and androgen receptor (AR) may play important roles in several skin related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for these androgen/AR-involved diseases, which target the synthesis of androgens or prevent its binding to AR, can cause significant adverse side effects. Based on the recent studies using AR knockout mice, it has been suggested that AR and androgens play distinct roles in the skin pathogenesis, and AR seems to be a better target than androgens for the treatment of these skin diseases. Here, we review recent studies of androgen/AR roles in several skin related disorders, including acne vulgaris, androgenetic alopecia and hirsutism, as well as cutaneous wound healing. PMID- 22829076 TI - Resistance of MLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation. AB - Mixed-lineage leukemia (MLL)-AFF1 (MLL-AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL-AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF alpha) was reported to contribute to the GVL effect. We showed that MLL-AFF1 positive ALL cell lines are resistant to TNF-alpha. To examine the mechanism of resistance to TNF-alpha of MLL-AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53 caspase 8-caspase 3 pathway were observed only in MLL-AFF1-positive ALL cell lines in the presence of TNF-alpha. The effect of S100A6 on resistance to TNF alpha by inhibition of the p53-caspase 8-caspase 3 pathway of MLL-AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL AFF1 transgenic mice. These results suggest that MLL-AFF1-positive ALL escapes from TNF-alpha-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53-caspase 8-caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL-AFF1-positive ALL in combination with allo-HSCT. PMID- 22829075 TI - Menin as a hub controlling mixed lineage leukemia. AB - Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs, and other partners such as the chromatin-associated protein LEDGF and the transcription factor C-Myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin-MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias. PMID- 22829077 TI - Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms. AB - Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3-23.3 (n=1), 9q33.1-34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31-36.33 (n=6), 17q21.2-q21.31 (n=5) and 17q25.1-25.3 (n=5) and deletions affecting 18p11.31-11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a 'HSC signature' (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal. PMID- 22829078 TI - FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia. AB - The t(10;11)(p13;q14) translocation results in the fusion of the CALM (clathrin assembly lymphoid myeloid leukemia protein) and AF10 genes. This translocation is observed in acute myeloblastic leukemia (AML M6), acute lymphoblastic leukemia (ALL) and malignant lymphoma. Using a yeast two-hybrid screen, the four and a half LIM domain protein 2 (FHL2) was identified as a CALM interacting protein. Recently, high expression of FHL2 in breast, gastric, colon, lung as well as in prostate cancer was shown to be associated with an adverse prognosis. The interaction between CALM and FHL2 was confirmed by glutathione S-transferase pulldown assay and co-immunoprecipitation experiments. The FHL2 interaction domain of CALM was mapped to amino acids 294-335 of CALM. The transcriptional activation capacity of FHL2 was reduced by CALM, but not by CALM/AF10, which suggests that regulation of FHL2 by CALM might be disturbed in CALM/AF10-positive leukemia. Extremely high expression of FHL2 was seen in acute erythroid leukemia (AML M6). FHL2 was also highly expressed in chronic myeloid leukemia and in AML with complex aberrant karyotype. These results suggest that FHL2 may play an important role in leukemogenesis, especially in the case of AML M6. PMID- 22829079 TI - AV-65, a novel Wnt/beta-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. AB - Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that beta-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/beta-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished beta-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high throughput transcriptional screening to identify candidates for anticancer drug discovery. PMID- 22829080 TI - Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia. AB - FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC(50)=22 n) and Janus kinase 2 (JAK2, IC(50)=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3 internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy. PMID- 22829081 TI - Patients with chronic myeloid leukemia treated with imatinib who showed the appearance of clonal cytogenetic abnormalities in Philadelphia chromosome negative cells. PMID- 22829082 TI - [Myofascial trigger points, pain, disability and quality of sleep in patients with chronic tension-type headache: a pilot study]. AB - INTRODUCTION. The referred pain induced by myofascial trigger points (MTP) and sleep disorders can be factors that contribute to chronic tension-type headache. AIM. To determine the relationship between MTP, intensity of pain, disability and quality of sleep in people with chronic tension-type headache. SUBJECTS AND METHODS. Participants in the study consisted of 16 patients with chronic tension type headache and 15 healthy controls. A visual analogue scale was used to measure the intensity of the pain, and the neck disability questionnaire and the Pittsburgh (quality of sleep) questionnaire were also employed. MTP were explored in the temporal, masseter, upper trapezius, suboccipital, sternocleidomastoid, splenius capitis, semispinalis capitis and anterior digastric muscles by a blind evaluator. RESULTS. The subjects with chronic tension-type headache had greater cervical disability (p < 0.001) than the controls, whereas the quality of sleep showed a tendency (p = 0.092). A positive correlation was found between the worst pain last week with the Pittsburgh questionnaire (r = 0.631; p = 0.009) and disability (r = 0.521; p = 0.046), as well as a positive correlation between disability and quality of sleep (r = 0.815; p < 0.001). The patients with headache displayed a higher number of MTP than the healthy controls (p < 0.001), the presence of active MTP being found exclusively in the patients. No association was found between the number of MTP and intensity of pain, disability or quality of sleep. CONCLUSIONS. Quality of sleep and active MTP can be different factors contributing to chronic tension-type headache. Nevertheless, the presence of MTP could also be an epiphenomenon of the pain. PMID- 22829083 TI - [Neurological, neuropsychological, and ophthalmological evolution after one year of docosahexaenoic acid supplementation in phenylketonuric patients]. AB - INTRODUCTION. Phenylketonuria (PKU) is an autosomal recessive metabolic disease caused by a deficiency of phenylalanine hydroxylase. The dietary therapy for the effective management of PKU, in particular the restriction of high-protein foods of animal-origin, compromises patients' intake of fat and distorts the n-3:n-6 ratio of essential fatty acids in the diet. This deficiency can contribute to neurological and visual impairment. AIM. To evaluate changes in white matter alterations, visual evoked potential (VEP) latencies and performance in executive and motor functions in a group of early and continuously treated PKU patients after supplementation with docosahexaneoic acid (DHA). PATIENTS AND METHODS. We selected 21 PKU patients with early diagnosis (age range: 9-25 years), on a Phe restricted diet and supplemented with PKU formula. Inclusion criteria were: low erythrocyte DHA values, prolonged P100 wave latencies in VEP and/or presence of white matter hyperintensities on brain magnetic resonance imaging (MRI), and intellectual quotient > 80. All patients were treated with DHA (10 mg/kg/day) for 12 months. Assessment was conducted at baseline and after 12 months of treatment, and included biochemical parameters, brain MRI, VEP, ophthalmologic evaluation and neuropsychological tests. RESULTS AND CONCLUSION. All the patients normalized the DHA levels after supplementation. Improvement in the P100 wave latencies, and fine motor skills was significant. No significant improvement in the other explorations was evident after supplementation. Further investigations seem advisable to establish a cause-effect relationship between DHA treatment and the slight improvement observed in some neurological functions. PMID- 22829084 TI - [Significance of complex analysis of electrical activity in temporal lobe epilepsy: electrocorticography]. AB - INTRODUCTION: Locating and excising epileptogenic zones is the traditional treatment in pharmacoresistant temporal lobe epilepsy. Some patients, however, continue to suffer from attacks even after surgery. Therefore, new hypotheses must be formulated in order to account for the apparent shortcomings of correctly performed surgical procedures. AIMS: An approach that is not traditional in the field, namely complex networks, is used to attempt to show that modifying the properties of the limbic network can lead to the elimination of the attacks, regardless of the location of the epileptogenic zones. PATIENTS AND METHODS: The intraoperative electrocorticographic recordings of 20 patients with pharmacoresistant temporal lobe epilepsy were utilised in the study. An analysis of complex networks was used to study the local synchronisation activity in the lateral and mesial cortex of the temporal lobe and, essentially, the zones with the highest temporal stability were determined. RESULTS: Those cortical zones with higher synchronic activity are associated with a greater temporal stability and when these zones are excised during surgery, the patient no longer suffers any disabling attacks. In contrast, when these zones are not excised, the patient continues to have attacks in the post-operative period. CONCLUSIONS: The findings support the hypothesis of the existence of a limbic network, which the lateral and mesial cortices of the temporal lobe are part of, and whose capacity to establish an overall synchronisation is affected when certain zones are removed. PMID- 22829085 TI - [Evaluation and quantification of spasticity: a review of the clinical, biomechanical and neurophysiological methods]. AB - INTRODUCTION: Spasticity is a sensory-motor disorder that affects about 85% of the patients with multiple sclerosis and between 65-78% of those with spinal cord injury, among other neurological conditions. Although hypertonia is generally easy to recognise clinically, quantifying it is quite a complex matter. The large number of clinical scales that exist and their subjectivity, the discrepancy between the spasticity perceived by the patient and the clinical measurement, as well as the lack of a general correlation between the neurophysiological measures and hypertonia, all make it especially difficult, in methodological terms, to perform a valid, reliable measurement of the degree of spasticity presented by the patient. AIMS: To review the main methods of evaluating spasticity published in the scientific literature and to carry out a description and critical analysis of their advantages, shortcomings and metric properties in patients with a neurological pathology. DEVELOPMENT: The different methods described for evaluating spasticity are reviewed and classified in three broad groups, namely, clinical scales specifically designed for such a purpose, biomechanical tests and neurophysiological methods. CONCLUSIONS: There is little agreement on the definition of spasticity and the need for the evaluators' training and experience when it comes to evaluating it. We recommend using a combination of the different evaluation instruments, such as the scales, biomechanical methods and neurophysiological measures reported in this study, to carry out a general diagnosis of the degree of spasticity present in the patient. PMID- 22829086 TI - [Infections and fingolimod]. AB - INTRODUCTION: Fingolimod is the first approved drug with oral availability for the treatment of relapsing multiple sclerosis. AIMS: To review the mechanism of action of fingolimod and its relationship with the development of infections. To propose preventive measures for those patients who are receiving the drug or will initiate a new treatment. In addition, the role of fingolimod in the development of progressive multifocal leukoencephalopathy on the basis of recent knowledge of its pathophysiology will be discussed. DEVELOPMENT: The mechanism of action of fingolimod is based on an antagonic effect on the sphingosine 1-phospate receptors that will generate an inhibition of the egress of naive and central memory lymphocytes into the bloodstream, allowing the free recirculation of memory effectors T lymphocytes. This effect will produce lymphopenia. Fingolimod associated lymphopenia is a consequence of lymphocyte redistribution, and it is selective and reversible. There is no evidence of higher number of opportunistic and non-opportunistic infections in comparison to placebo or interferon beta-1a in patients receiving fingolimod. However, two patients developed severe herpetic infections under fingolimod. CONCLUSIONS: Fingolimod induce a selective and reversible lymphopenia that, taking into account the most recent available data, does not seem to be associated with higher risk of opportunistic infections due to a preservation of immuno-surveillance. The risk of herpesvirus infection should be taken into consideration and more studies are warranted to confirm if an association of these infections with the use of fingolimod exists. PMID- 22829088 TI - [Cockayne syndrome: a new mutation in the ERCC8 gene]. PMID- 22829089 TI - [Primary lymphoma of the central nervous system located in the cerebellum]. PMID- 22829090 TI - [Prolonged hemiplegia as the only symptom of a simple focal nonconvulsive status epilepticus]. PMID- 22829092 TI - [Neurorehabilitation. Specific methods of assessment and treatment]. PMID- 22829091 TI - [Neurovascular emergencies in a tertiary hospital: ischaemic and haemorrhagic strokes]. PMID- 22829093 TI - Homogeneous electrochemical monitoring of exonuclease III activity and its application to nucleic acid testing by target recycling. AB - A simple and fast electrochemical nucleic acid assay based on a target recycling strategy and the release of a double-stranded DNA intercalating redox probe upon digestion of a specific duplex by exonuclease III is demonstrated. PMID- 22829094 TI - The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. AB - Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1-1 MU) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 MU) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL. PMID- 22829095 TI - A novel potent Fas agonist for selective depletion of tumor cells in hematopoietic transplants. AB - There remains a clear need for effective tumor cell purging in autologous stem cell transplantation (ASCT) where residual malignant cells within the autograft contribute to disease relapse. Here we propose the use of a novel Fas agonist with potent pro-apoptotic activity, termed MegaFasL, as an effective ex-vivo purging agent. MegaFasL selectively kills hematological cancer cells from lymphomas and leukemias and prevents tumor development at concentrations that do not reduce the functional capacity of human hematopoietic stem/progenitor cells both in in vitro and in in vivo transplantation models. These findings highlight the potential use of MegaFasL as an ex-vivo purging agent in ASCT. PMID- 22829096 TI - Imatinib causes epigenetic alterations of PTEN gene via upregulation of DNA methyltransferases and polycomb group proteins. AB - We have recently reported the possible imatinib-resistant mechanism; long-term exposure of leukemia cells to imatinib downregulated levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) via hypermethylation of its promoter region (Leukemia 2010; 24: 1631). The present study explored the molecular mechanisms by which imatinib caused methylation on the promoter region of this tumor suppressor gene in leukemia cells. Real-time reverse transcription PCR found that long-term exposure of chronic eosinophilic leukemia EOL-1 cells expressing FIP1L1/platelet-derived growth factor receptor-alpha to imatinib induced expression of DNA methyltransferase 3A (DNMT3A) and histone methyltransferase enhancer of zeste homolog 2 (EZH2), a family of polycomb group, thereby increasing methylation of the gene. Immunoprecipitation assay found the increased complex formation of DNMT3A and EZH2 proteins in these cells. Moreover, chromatin immunoprecipitation assay showed that amounts of both DNMT3A and EZH2 proteins bound around the promoter region of PTEN gene were increased in EOL-1 cells after exposure to imatinib. Furthermore, we found that levels of DNMT3A and EZH2 were strikingly increased in leukemia cells isolated from individuals with chronic myelogenous leukemia (n=1) and Philadelphia chromosome-positive acute lymphoblastic leukemia (n=2), who relapsed after treatment with imatinib compared with those isolated at their initial presentation. Taken together, imatinib could cause drug-resistance via recruitment of polycomb gene complex to the promoter region of the PTEN and downregulation of this gene's transcripts in leukemia patients. PMID- 22829097 TI - Small intrahepatic mass-forming cholangiocarcinoma: target sign on diffusion weighted imaging for differentiation from hepatocellular carcinoma. AB - PURPOSE: To determine the differential MRI features of small mass-forming intrahepatic cholangiocarcinoma (ICC) from hepatocellular carcinoma (HCC). METHODS: Sixty-four patients with pathologically proven small ICCs (n = 32) and HCCs (n = 32) (<= 3.0 cm in diameter) who had undergone preoperative gadoxetic acid-enhanced MRI and DWI were enrolled in this study. Images were analyzed for the shape of the lesions, the presence of biliary dilatation, hyperenhancement (>50 % of the tumor volume) or rim enhancement on the arterial phase, capsular enhancement, and the presence of target appearance (a central enhancement with hypointense rim) on the hepatobiliary phase and on DWI (a central hypointense area with a peripheral hyperintense rim). Statistical significance of these findings was determined by the chi(2) or Fisher's exact test. Multivariate analysis was performed to identify independent imaging findings that allow differentiation of the two diseases. RESULTS: Univariate analysis revealed that the following significant parameters favor ICC over HCC: lobulating shape, rim enhancement on arterial phase, target appearance on the hepatobiliary phase, and DWI (P < 0.05). Multivariate logistic regression analysis revealed that only target appearance on the DWI was a significant and independent variable predictive of ICC, as 24 ICCs (75.0 %) and one HCC (3.1 %) showed this feature (P = 0.0003). CONCLUSION: A target appearance on the DWI was the most reliable imaging feature for distinguishing small mass-forming ICC from small HCC. PMID- 22829098 TI - Torsion in wandering spleen: CT demonstration of whirl sign. AB - Wandering spleen is a rare occurrence. Torsion of the splenic pedicle is the major life-threatening complication of this entity. Preoperative diagnosis is based on radiological investigation. We report two consecutive cases, one adult and one child, in whom torsion in a wandering spleen was diagnosed based on a typical whirled appearance of the splenic vessels on computed tomography. We present a review of computed tomographic appearance of splenic torsion, and emphasize the "whirled appearance" as a specific sign for splenic torsion in wandering spleen. PMID- 22829099 TI - Target animacy influences chimpanzee handedness. AB - We employed a bottom-up, quantitative method to investigate great ape handedness. Our previous investigation of gorillas (Gorilla gorilla gorilla) demonstrated that contextual information influenced an individual's handedness toward target objects. Specifically, we found a significant right-hand bias for unimanual actions directed toward inanimate target objects but not for actions directed to animate target objects (Forrester et al. in Anim Cogn 14(6):903-907, 2011). Using the identical methodological technique, we investigated the spontaneous hand actions of nine captive chimpanzees (Pan troglodytes) during naturalistic, spontaneous behavior. We assessed both the frequencies and proportions of lateralized hand actions directed toward animate and inanimate targets employing focal follow video sampling. Like the gorillas, the chimpanzees demonstrated a right-handed bias for actions directed toward inanimate targets, but not toward animate targets. This pattern was evident at the group level and for the majority of subjects at the individual level. We postulate that a right-hand bias for only inanimate targets reflects the left hemisphere's dominant neural processing capabilities for objects that have functional properties (inanimate objects). We further speculate that a population-level right-hand bias is not a human-unique characteristic, but one that was inherited from a common human-ape ancestor. PMID- 22829100 TI - Anion binding in aqueous media by a tetra-triazolium macrocycle. AB - Three tetra-triazole macrocycles were synthesized in good yields by the copper(i) catalysed cycloaddition of bis-triazole azides and bis-alkynes. One of these was alkylated to give a cyclic tetra-triazolium receptor, which complexes anions strongly in competitive DMSO-water mixtures. In 1 : 1 DMSO-water, the tetracationic receptor exhibits a preference for the larger halides, bromide and iodide, with all halides associating more strongly than the oxoanion, acetate. The sulfate dianion is complexed far more strongly than any of the monobasic anions (K(a) > 10(4) M(-1)). Quantum mechanics/molecular mechanics simulations corroborate the experimentally determined anion binding selectivity trends. PMID- 22829101 TI - Women with one ovary in assisted reproduction technologies: a review of the literature. AB - BACKGROUND: A number of patients who have undergone assisted reproductive technology (ART) have only one ovary. PURPOSE: This article reviews the clinical implications of the absence of an ovary on the reproductive potential and the outcome in ART cycle. DATA SOURCES: MEDLINE, Pubmed, the Cochrane Controlled Trials Register, and Cochrane Database of Systematic Reviews from the 1980s through April 2010. STUDY SELECTION: Randomized, controlled trials; systematic reviews of trials; and observational studies; all restricted to English-language articles. DATA SYNTHESIS: This review includes 58 articles. Women with a single ovary did not, in general, respond as well to ovulation induction treatment than women with two ovaries in ART cycles. It appears however, that once women with a single ovary achieve the stage of embryo transfer, they can be reassured that their chances of having a child are the same as women with two ovaries. Whether the right or left ovary responds better to superovulation is a question which remains unanswered in the literature. LIMITATIONS: The authors could not address all management questions, and excluded non-English-language literature. PMID- 22829102 TI - Letrozole versus clomiphene citrate for superovulation in Egyptian women with unexplained infertility: a randomized controlled trial. AB - OBJECTIVES: To compare the efficacy of letrozole with clomiphene citrate (CC) in Egyptian women with unexplained infertility. STUDY DESIGN: This randomized controlled trial was conducted at Ain Shams University Hospital and Dar Al Hekma hospital between February 2010 and May 2011. PATIENTS AND METHODS: Two hundreds and seventy women with unexplained infertility were randomized into two groups using computer-generated randomization plan, and were given letrozole 2.5 mg/day from cycle day 3 to 7 (Letrozole group, n=136) or CC 100 mg/day from cycle day 3 to 7 (CC group, n=134). On day 9, the participants underwent a transvaginal sonography (TVS) every other day to monitor their ovulation and measure both endometrial thickness and Doppler flow indices of uterine and subendometrial vessels. Single injection of 10,000 IU of human chorionic gonadotropin (hCG) was given when the mean diameter of at least one ovarian follicle was >=18 mm, quantitative betahCG was done 2 weeks after hCG injection to diagnose chemical pregnancy. Clinical pregnancy was confirmed by observing a gestational sac with fetal echoes and pulsation 4 weeks after positive pregnancy test by TVS. RESULTS: Both groups were comparable with regard to the day of hCG administration (letrozole 13.4+/-5 vs CC 12.1+/-4.9, respectively, p=0.06). The mean number of mature follicles was significantly higher in CC group (2+/-0.9 vs 1+/-0.0, P=0.02). Serum estradiol was significantly greater in CC group (817+/-299 vs 364+/-149 pg/ml, P<0.001). The clinical pregnancy rate was significantly higher in letrozole group (23.07 vs 10.68%, P<0.001). There was statistically significant increase in endometrial receptivity in letrozole group as assessed by endometrial thickness and Doppler flow indices of uterine and subendometrial vessels. No serious side effects were reported in either group. CONCLUSION: Letrozole has beneficial effect on endometrium, an action that may improve the implantation and pregnancy rates in women with unexplained infertility. PMID- 22829103 TI - Management of peristomal tissue necrosis following prepubic urethrostomy in a cat. AB - This report describes the successful management of peristomal tissue necrosis following prepubic urethrostomy in a cat. The novel technique of temporary urethral ligation was used in combination with temporary tube cystostomy and vacuum assisted closure to allow for wound management prior to performing wound closure by utilization of a flank fold skin flap then definitive prepubic urethrostomy. Eleven month follow-up indicated excellent outcome with the cat having returned to normal behaviour apart from having adapted its posture to urinate. PMID- 22829104 TI - Sexual mixing and HIV risk among ethnic minority MSM in Britain. AB - We conducted a cross-sectional online survey of men who have sex with men (MSM) living in Britain in 2007-2008 to examine sexual mixing among ethnic minority MSM. The sample comprised 115 black, 112 South Asian, 47 Chinese and 4,434 white MSM who reported unprotected anal intercourse (UAI) in the previous 3 months. In each ethnic minority group, MSM were three times more likely to report UAI with a partner of the same ethnicity than would be expected by chance alone (chi(2) > 8.43, p < 0.05). Nonetheless, most (>80 %) ethnic minority MSM reported UAI with men from an ethnic group other than their own. In multivariable analysis there was statistical evidence that, compared with white British MSM, self-reported HIV seropositivity remained low for South Asian and Chinese MSM after adjusting for UAI with partners of the same ethnicity (e.g. South Asian MSM, adjusted odds ratio 0.35, 95 % CI 0.19-0.66). This analysis suggests that differences in self reported HIV seropositivity between ethnic minority and white MSM in Britain cannot be explained by sexual mixing with partners from the same ethnic group. PMID- 22829106 TI - Determining minimum staffing levels during snowstorms using an integrated simulation, regression, and reliability model. AB - Emergency medical services (EMS) provide life-saving care and hospital transport to patients with severe trauma or medical conditions. Severe weather events, such as snow events, may lead to adverse patient outcomes by increasing call volumes and service times. Adequate staffing levels during such weather events are critical for ensuring that patients receive timely care. To determine staffing levels that depend on weather, we propose a model that uses a discrete event simulation of a reliability model to identify minimum staffing levels that provide timely patient care, with regression used to provide the input parameters. The system is said to be reliable if there is a high degree of confidence that ambulances can immediately respond to a given proportion of patients (e.g., 99 %). Four weather scenarios capture varying levels of snow falling and snow on the ground. An innovative feature of our approach is that we evaluate the mitigating effects of different extrinsic response policies and intrinsic system adaptation. The models use data from Hanover County, Virginia to quantify how snow reduces EMS system reliability and necessitates increasing staffing levels. The model and its analysis can assist in EMS preparedness by providing a methodology to adjust staffing levels during weather events. A key observation is that when it is snowing, intrinsic system adaptation has similar effects on system reliability as one additional ambulance. PMID- 22829107 TI - Food insecurity: limitations of emergency food resources for our patients. AB - Rates of food insecurity are high among medically underserved patients. We analyzed food pantry responsiveness to the needs of medically ill cancer patients in New York City with the intent ofidentifying barriers to available food resources. Our data, collected from 60 pantries, suggest that the emergency food system is currently unable to accommodate patient needs. Accessibility issues include restricted service hours and documentation requirements. Food services were limited in quantity of food provided and the number of nutritious, palatable options. Additional emergency food resources and long-term approaches that provide ongoing food support to patients throughout their treatment period are needed. PMID- 22829108 TI - The tyrosine kinase inhibitor dasatinib (SPRYCEL) inhibits chondrocyte activity and proliferation. PMID- 22829109 TI - Signaling changes in the stem cell factor-AKT-S6 pathway in diagnostic AML samples are associated with disease relapse. PMID- 22829110 TI - Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial. PMID- 22829111 TI - Functional assessment of p53 in chronic lymphocytic leukemia. PMID- 22829112 TI - Human glioblastoma cells exposed to long-term hypoxia and nutrient starvation stimulated induction of secondary T-cell leukemia in mice. PMID- 22829113 TI - Genetics and democracy-what is the issue? AB - Current developments in genetics and genomics entail a number of changes and challenges for society as new knowledge and technology become common in the clinical setting and in society at large. The relationship between genetics and ethics has been much discussed during the last decade, while the relationship between genetics and the political arena-with terms such as rights, distribution, expertise, participation and democracy-has been less considered. The purpose of this article is to demonstrate the connection between genetics and democracy. In order to do this, we delineate a notion of democracy that incorporates process as well as substance values. On the basis of this notion of democracy and on claims of democratisation in the science and technology literature, we argue for the importance of considering genetic issues in a democratic manner. Having established this connection between genetics and democracy, we discuss this relation in three different contexts where the relationship between genetics and democracy becomes truly salient: the role of expertise, science and public participation, and individual responsibility and distributive justice. As developments within genetics and genomics advance with great speed, the importance and use of genetic knowledge within society can be expected to grow. However, this expanding societal importance of genetics might ultimately involve, interact with, or even confront important aspects within democratic rule and democratic decision-making. Moreover, we argue that the societal importance of genetic development makes it crucial to consider not only decision-making processes, but also the policy outcomes of these processes. This argument supports our process and substance notion of democracy, which implies that public participation, as a process value, must be complemented with a focus on the effects of policy decisions on democratic values such as distributive justice. PMID- 22829114 TI - Inclusion of medical genetics in primary health care: report of a pilot project in Brazil. PMID- 22829115 TI - Expression of p24 gag protein of bovine leukemia virus in insect cells and its use in immunodetection of the disease. AB - Bovine leukemia is a common retroviral infection of cattle. The disease is characterized by a strong immunological response to several viral proteins, but the antibodies against p24 and gp51 are predominant. In this study, a recombinant baculovirus containing the gag gene p24 was constructed and the protein, used as antigen, analyzed by western blot and an indirect in-house rp24-ELISA test. This allowed detecting the presence of antibodies for bovine leukemia virus in a panel of cattle sera. The authentication of the protein expands its potential use for different medical applications, from improved diagnosis of the disease to source of antigens to be included in a subunit vaccine. PMID- 22829116 TI - Fragmentation of toxicologically relevant drugs in negative-ion liquid chromatography-tandem mass spectrometry. AB - Negative-ion LC-MS analysis of drugs is applied far less frequently than positive ion LC-MS. Data on the interpretation of negative-ion MS-MS spectra are even more scarce. Therefore, following the recent review on the class-specific fragmentation of toxicologically relevant compounds in positive-ion MS-MS, it was decided to perform a similar study in negative-ion MS-MS. To this end, a set of over 500 negative-ion MS-MS spectra was collected from three libraries applied in toxicological general unknown screening and systematic toxicological analysis. The compounds involved were classified by chemical and therapeutic class. The MS MS spectra were manually interpreted and relevant interpretation data were searched for in the scientific literature. The emphasis in the discussion is on class-specific fragmentation, because discussing fragmentation of all individual compounds would take far too much space. Negative-ion MS-MS fragmentation is discussed for a wide variety of toxicologically relevant compounds, including dihydropyridine calcium channel blockers, diuretics, barbiturates, anti inflammatory drugs, anti-diabetics, sulfonamide and betalactam antibiotics, and a number of classes of pesticides. PMID- 22829118 TI - TOF-SIMS investigation of degradation pathways occurring in a variety of organic photovoltaic devices--the ISOS-3 inter-laboratory collaboration. AB - The present work is the fourth (and final) contribution to an inter-laboratory collaboration that was planned at the 3rd International Summit on Organic Photovoltaic Stability (ISOS-3). The collaboration involved six laboratories capable of producing seven distinct sets of OPV devices that were degraded under well-defined conditions in accordance with the ISOS-3 protocols. The degradation experiments lasted up to 1830 hours and involved more than 300 cells on more than 100 devices. The devices were analyzed and characterized at different points of their lifetimes by a large number of non-destructive and destructive techniques in order to identify specific degradation mechanisms responsible for the deterioration of the photovoltaic response. Work presented herein involves time of-flight secondary ion mass spectrometry (TOF-SIMS) in order to study chemical degradation in-plane as well as in-depth in the organic solar cells. Various degradation mechanisms were investigated and correlated with cell performance. For example, photo-oxidation of the active material was quantitatively studied as a function of cell performance. The large variety of cell architectures used (some with and some without encapsulation) enabled valuable comparisons and important conclusions to be drawn on degradation behaviour. This comprehensive investigation of OPV stability has significantly advanced the understanding of degradation behaviour in OPV devices, which is an important step towards large scale application of organic solar cells. PMID- 22829119 TI - A simple and sensitive HPLC-UV determination of 7-O-succinyl macrolactin A in rat plasma and urine and its application to a pharmacokinetic study. AB - A simple, sensitive and reproducible isocratic reversed-phase (C(18) ) high performance liquid chromatography (HPLC) method was developed to determine 7-O succinyl macrolactin A (SMA) in rat plasma and urine samples using UV detector set at 230 nm. Lamotrigine was used as internal standards (IS) to ensure the precision and accuracy of the method. The retention times of SMA and IS for the plasma sample were 9.2 and 4.4 min, respectively, and those for the urine samples were 7.9 and 4.3 min, respectively. The intra- and inter-day variations of the analytical responses, expressed in terms of relative standard deviation, were less than 14.9%. The accuracy, in terms of average analytical recovery, ranged from 90.4 to 119%. The lower limits of quantification of SMA in rat plasma and urine samples were 0.02 and 0.1 ug/mL, respectively. This method is applicable for the pharmacokinetic studies of SMA in rats. PMID- 22829120 TI - Distal radius definitive epiphysiodesis for management of Kienbock's disease in skeletally immature patients. AB - PURPOSE: Kienbock's disease is an unusual pathology with unknown aetiology within the pediatric population. Several treatment options have been described in the literature; however, there are neither large series nor homogeneous studies that have clarified which treatment is best. The aim of this study was to describe five cases in which definitive distal radius epiphysiodesis was performed as an alternative method to the classic distal radius shortening osteotomy in skeletally immature patients with Kienbock's disease. METHODS: The clinical charts and radiographs of four patients (five wrists) diagnosed as having Kienbock's disease and treated by definitive distal radius epiphysiodesis were reviewed. RESULTS: All patients were symptomatically free with full range of motion at 4.25 months (range, three to six months) after surgery. In all cases, shortening of the distal radius was achieved (p = 0.032). CONCLUSIONS: This new technique is a simple, effective, and minimally invasive procedure with low morbidity and good clinical and radiological outcomes. PMID- 22829123 TI - Feasibility of gene-immunotherapy using WT1-specific T-cell receptor gene transfer for infant acute lymphoblastic leukemia with MLL gene rearrangement. PMID- 22829122 TI - Time to internal fixation of femoral neck fractures in patients under sixty years -does this matter in the development of osteonecrosis of femoral head? AB - PURPOSE: Osteonecrosis of femoral head remains a major complication of femoral neck fractures. It has been postulated that early internal fixation drastically reduces the incidence of osteonecrosis of the femoral head. However, there is a paucity of literature looking at the effect of time delay to internal fixation on the development of this late complication. In this study, we aim to assess the effect of time delay and method of internal fixation on the development of osteonecrosis in those less than 60 years of age. METHODS: We retrospectively analysed 92 patients less than 60 years of age who presented with intracapsular neck of femur fractures that underwent internal fixation between 1999 and 2009. RESULTS: Of the 92 intracapsular fractures, 50 underwent fixation using cannulated screws, 32 using a dynamic hip screw, and ten using a dynamic hip screw with a derotation screw. In total, 13 patients (14.1 %) developed osteonecrosis of the femoral head, the highest incidence being in the cannulated screw fixation group with an osteonecrosis rate of 24 %. We did not find the time delay to internal fixation to be a significant predictor of the development of osteonecrosis. CONCLUSION: Our study demonstrated that the method of internal fixation rather than delay in internal fixation was more predictive of osteonecrosis of the femoral head. We did not find support to the current belief that early surgical fixation of neck of femur fractures reduces the risk of osteonecrosis in patients less than 60 years. PMID- 22829121 TI - Variations in bifid superior transverse scapular ligament as a possible factor of suprascapular entrapment: an anatomical study. AB - PURPOSE: The suprascapular region is the most common place for suprascapular nerve entrapment. The purpose of this research was to investigate the influence of the superior transverse scapular ligament (STSL) on the reduced space for suprascapular nerve passage at the suprascapular notch. Additionally, we precisely described other structures that seem important during arthroscopic and open procedures in this region. METHODS: The study was carried out on 96 formalin fixed cadaveric shoulders. After dissection of the suprascapular region the superior transverse scapular ligament was visualised. Measurements of the ligaments and area of the opening for the passage of the suprascapular nerve were taken using two independent methods: MultiScanBase v.14.02 software and electronic digimatic caliper. RESULTS: In three of 96 dissected shoulders (3.1 %), a bifid superior transverse scapular ligament was discovered. Morphologically, two subtypes of bifid STSL were distinguished. The first has medially separate superior and inferior bands and a common lateral attachment. In the second subtype, independent anterior and posterior parts are fixed to the lateral border of the suprascapular notch with a common medial attachment. Singular STSL in 93 of 96 shoulders was found. The mean area of the suprascapular opening in the specimens with singular STSL was larger than in the first subtype of bifid STSL and in the second subtype of bifid STSL with anterior coracoscapular ligament. CONCLUSION: Knowledge of the variations of the superior transverse scapular ligament is important for better understanding of the possible anatomical conditions that can promote suprascapular nerve entrapment. Its morphology should also be taken into particular consideration during surgical and arthroscopic procedures. PMID- 22829124 TI - FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes. AB - The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute myeloid leukemia (AML). Internal tandem duplications (ITD) of the juxtamembrane domain lead to the constitutive activation of the FLT3 kinase inducing the activation of multiple genes, which may result in the expression of leukemia-associated antigens (LAAs). We analyzed the regulation of LAA in FLT3-wild-type (WT)- and FLT3-ITD(+) myeloid cells to identify potential targets for antigen-specific immunotherapy for AML patients. Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL). Cytotoxic T-cell (CTL) clones against PR-3, RHAMM, Survivin and an AML-directed CTL clone recognized AML cell lines and primary AML blasts expressing FLT3-ITD, as well as FLT3-WT(+) myeloid dendritic cells in the presence of FL. Downregulation of FLT3 led to the abolishment of CTL recognition. Comparing our findings concerning LAA upregulation by the FLT3 kinase with those already made for the Bcr-Abl kinase, we found analogies in the LAA expression pattern. Antigens upregulated by both FLT3 and Bcr-Abl may be promising targets for the development of immunotherapeutical approaches against myeloid leukemia of different origin. PMID- 22829125 TI - The novel NF-kappaB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia. AB - Nuclear factor-kappaB (NF-kappaB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-kappaB inhibitor, IMD-0354 (N-(3, 5-bis trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IkappaBalpha by IkB kinases, thus preventing NF kappaB release. In this study, we investigated if IMD-0354 can inhibit NF-kappaB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-kappaB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD 0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-kappaB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo. PMID- 22829126 TI - Establishment of a standardized multiplex assay with the analytical performance required for quantitative measurement of BCR-ABL1 on the international reporting scale. AB - Accurate and standardized methods for the quantitative measurement of BCR-ABL1 are a prerequisite for monitoring of treatment response in t(9;22)-positive leukemia. Here, we describe a novel multiplex assay system based on the proven TaqMan and Armored RNA technologies and optimized for sensitive detection of three BCR-ABL1 fusion transcripts and ABL1 in a single reaction. Analytical experiments confirmed the absence of significant competition between the simultaneous amplification reactions and established the sensitivity, linearity and precision of the assay. Comparative studies with 115 clinical specimens resulted in high qualitative and quantitative agreement with independent singleplex laboratory-developed tests routinely used in clinical testing. Direct comparison with a reference laboratory calibrated to the international scale (IS) demonstrated minimal analytical bias between methods and an overall accuracy and precision within the performance range required for quantitative measurement of BCR-ABL1 on the IS. We conclude that detection of e1a2, b2a2, b3a2 and ABL1 can be achieved in a multiplex assay format compatible with IS reporting. Further clinical validation of the assay could improve the operational efficiency of clinical laboratories, increase their adherence to current recommendations for b2a2/b3a2 reporting on the IS and provide for the first time an opportunity to standardize e1a2-monitoring results. PMID- 22829127 TI - Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia. AB - One of the major obstacles of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) comes from the often months-long unpredictability of bone-marrow (BM) recovery. In this prospective study in children with newly diagnosed very severe AA (n=10), who were enrolled in the therapy study SAA-BFM 94, we found a dramatically reduced diversity of both CD4+ and CD8+ BM cells, as scored by comprehensive V-beta chain T-cell receptor (TCR) analysis. Strongly skewed TCR V-beta pattern was highly predictive for good or at least partial treatment response (n=6, CD8+ complexity scoring median 35.5, range 24-73). In contrast, IST in patients with rather moderate reduction of TCR V-beta diversity (n=4, CD8+ complexity scoring median 109.5, range 82-124) always failed (P=0.0095). If confirmed in a larger series of patients, TCR V-beta repertoire in BM may help to assign children with SAA up-front either to IST or to allogeneic stem-cell transplantation. PMID- 22829128 TI - DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. PMID- 22829130 TI - Direct genetic effects and their estimation from matched case-control data. AB - In genetic association studies, a single marker is often associated with multiple, correlated phenotypes (e.g., obesity and cardiovascular disease, or nicotine dependence and lung cancer). A pervasive question is then whether that marker exerts independent effects on all phenotypes. In this paper, we address this question by assessing whether there is a genetic effect on one phenotype that is not mediated through the other ones, so called direct genetic effect. Answering such question may represent an important step in the elucidation of the underlying biological mechanism. Under rather restrictive conditions, such direct genetic effects are known to be estimable by standard regression methods. Under more lenient conditions, in a prospective or unmatched case-control study, these effects can be estimated by using a previously proposed G-estimation method (Vansteelandt [2009] Epidemiology 20, 851-860). The present paper extends this method to matched case-control studies, and investigates the conditions under which this extension is valid. We illustrate the method on data from a matched case-control study, which we use to elucidate the pathway implications of a detected association between myocardial infarction and a genetic locus in the chromosomal region of the FTO gene. PMID- 22829131 TI - The high frequency and clinical feature of seronegative myasthenia gravis in Southern China. AB - Anti-acetylcholine receptor antibodies (anti-AChR-Ab) are responsible for the failure of neuromuscular junction in myasthenia gravis (MG). Some anti-AChR-Ab seronegative MG patients have anti-muscle-specific tyrosine kinase antibodies (anti-MuSk-Ab). Here, the anti-AChR-Ab was tested in 250 MG outpatients from Southern China. While anti-MuSk-Ab was tested in 66 patients who had no anti-AChR Ab in blood serum, but none of them was positive. The antibodies were measured by a radioimmunoprecipitation assay. The frequency of anti-AChR-Ab was 51.2 %. The percentage of anti-AChR-Ab in ocular type was lower than generalized type (44.9 vs. 66.2 %, P = 0.002). Seronegative MG was characterized by a lower percentage of thymoma than seropositive patients (P = 0.013). It seemed to be less severe in seronegative MG than seropositive MG in these 250 patients. In ocular type, seronegative MG mainly manifesting blepharoptosis but seldom diplopia or eyeball fixation related to ocular movement disability (P = 0.016). While in generalized type, seronegative MG was characterized by a lower percentage of bulbar muscle involvements than seropositive patients (P = 0.005). Logistic regression analysis revealed that bulbar weakness was affected by the existence of anti-AChR antibodies (OR = 3.524, P = 0.015). Besides, seronegative MG tended to be characterized by a lower percentage of neck extensor involvement, but this did not reach significance. The percentage of anti-AChR antibodies was much lower than other countries. Seronegative MG has characteristic clinical features that are different from features of the remaining seropositive MG. This emphasises the predictive value of anti-AChR antibodies analysis in MG patients. PMID- 22829132 TI - Normal pressure hydrocephalus in the spectrum of neurological complications of systemic lupus erythematosus. AB - Normal pressure hydrocephalus is an unusual manifestation of systemic lupus erythematosus and its pathogenesis is still unclear. We report the case of a 39 year-old white woman with systemic lupus erythematosus who developed magnetic gait, speech difficulties, progressive memory impairment, urinary incontinence and episodes of involuntary closure of the eyelids. Signs and symptoms, associated with ventriculomegaly and normal cerebrospinal fluid pressure, suggested normal pressure hydrocephalus, which as a complication of systemic lupus erythematosus believably develops due to the insidious inflammatory process that occurs in the meningeal tissues or to the vasculitis itself. Normal pressure hydrocephalus tends to develop secondary to trauma, infection or subarachnoid haemorrhage, but in 50 % of patients no aetiology is found. Shunt surgery is the only effective treatment, specifically for the gait disorder, which usually improves more than the cognitive symptoms. Since the tap-test showed a strongly positive result, a medium pressure ventriculoperitoneal shunt was inserted, further replaced by a high pressure one in view of the complications, with less than expected improvement. Subdural hematomas and empyemas developed, requiring surgery and antibiotic therapy. A new tap-test was positive, and the patient improved only after a programmable valve was finally placed. However, pressure regulation shall be continuously required, and shunt dysfunction might still develop in the long term. The few similar case reports in the literature are reviewed, confirming the rarity of this neurological complication of systemic lupus erythematosus. PMID- 22829133 TI - Atypical presentation of thalamic post-stroke pain. PMID- 22829134 TI - The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vdelta1 TCR. AB - alphabeta T-cell lines specific for sulfatide, an abundant myelin glycosphingolipid presented by various CD1 molecules, have been previously derived from PBMCs of patients with demyelinating diseases such as multiple sclerosis (MS) but also from healthy subjects. Using an unbiased tetramer-based MACS enrichment method to enrich for rare antigen-specific cells, we confirmed the presence of CD1d-sulfatide-specific T cells in all healthy individuals examined. Surprisingly, the great majority of fresh sulfatide-specific T cells belonged to the gammadelta lineage. Furthermore, these cells used the Vdelta1 TCR variable segment, which is uncommon in the blood but predominates in tissues such as the gut and specifically accumulates in MS lesions. Recombinant Vdelta1 TCRs from different individuals were shown to bind recombinant CD1d-sulfatide complexes in a sulfatide-specific manner. These results provide the first direct demonstration of MHC-like-restricted, antigen-specific recognition by gammadelta TCRs. Together with previous reports, they support the notion that human Vdelta1 T cells are enriched in CD1-specific T cells and suggest that the Vdelta1 T-cell population that accumulates in MS lesions might be enriched in CD1-sulfatide specific cells. PMID- 22829135 TI - AMD3100 sensitizes acute lymphoblastic leukemia cells to chemotherapy in vivo. PMID- 22829136 TI - The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations. AB - C-terminal mutations of CD20 constitute part of the mechanisms that resist rituximab therapy. Most CD20 having a C-terminal mutation was not recognized by L26 antibody. As the exact epitope of L26 has not been determined, expression and localization of mutated CD20 have not been completely elucidated. In this study, we revealed that the binding site of L26 monoclonal antibody is located in the C terminal cytoplasmic region of CD20 molecule, which was often lost in mutated CD20 molecules. This indicates that it is difficult to distinguish the mutation of CD20 from under expression of the CD20 protein. To detect comprehensive CD20 molecules including the resistant mutants, we developed a novel monoclonal antibody that recognizes the N-terminal cytoplasm region of CD20 molecule. We screened L26-negative cases with our antibody and found several mutations. A rituximab-binding analysis using the cryopreserved specimen that mutation was identified in CD20 molecules indicated that the C-terminal region of CD20 undertakes a critical role in presentation of the large loop in which the rituximab-binding site locates. Thus, combination of antibodies of two kinds of epitope permits the identification of C-terminal CD20 mutations associated with irreversible resistance to rituximab and may help the decision of the treatment strategy. PMID- 22829137 TI - Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for various malignant and non-malignant diseases. Many patients have now been followed for two or three decades posttransplant and are presumed to be cured. With the tremendous advances achieved in terms of supportive care, it is reasonable to expect outcomes to improve steadily and consequently increasing numbers of transplant survivors will be facing life after the initial transplant experience. Although long-term allo-HSCT survivors generally enjoy good health, for many others, cure or control of the underlying disease is not accompanied by full restoration of health. The burden of long-term morbidity borne by allo-HSCT survivors is substantial, and long-term follow-up of patients who received allo HSCT is now widely recommended. Immediate survival is no longer the sole concern after allo-HSCT. The goals should also include complete recovery of the overall health status with normal physical and psychological functioning. Long-term side effects after allo-HSCT include non-malignant organ or tissue dysfunction, changes in quality of life, infections related to abnormal immune reconstitution and secondary cancers. Many of these can be attributed to the deleterious effects of chronic graft-versus-host disease. The aims of this review are to provide an update on the recent research evidence in the field. PMID- 22829140 TI - Palladium-catalyzed alpha-regioselective allylic amination of Morita-Baylis Hillman acetates with simple aromatic amines. AB - An efficient allylic amination of Morita-Baylis-Hillman acetates with simple aromatic amines provided good yields with excellent alpha-regioselectivity (up to exclusive alpha-product) under the catalysis of Pd(2)(dba)(3)/ferrocene-type diphosphine ligand. PMID- 22829138 TI - Regulation of particulate matter-induced mucin secretion by transient receptor potential vanilloid 1 receptors. AB - Exposure to airborne particulate matter (PM) is a worldwide health problem. Previous studies have reported that PMs induced depolarizing currents and increased intracellular Ca(2+) in human bronchial epithelial cells. Ca(2+) plays important role in the regulation of mucus exocytosis, and mucin hypersecretion is a key pathological feature of inflammatory respiratory diseases. To explore more mechanisms underlying PM toxicity, we measured PM-induced mucin secretion in human bronchial epithelial (16HBE) cells. MUC5AC secretion and cyclic adenosine monophosphate (cAMP) level were detected by ELISA. Transient receptor potential vanilloid (TRPV)1 inward currents were examined by electrophysiology. Ca(2+) concentration was assessed by laser scanning confocal microscope. Exposure of PMs to 16HBE cells was found to induce mucin secretion, as a consequence of sustained Ca(2+) influx and cAMP increase through TRPV1 receptors. Mucin secretion was completely inhibited by TRPV1 receptor antagonist capsazepine. Removal of Ca(2+) by Ca(2+) chelator BAPTA or inhibition of protein kinase A (PKA) by the PKA inhibitors H-89 each partially reduced PC(2)s-induced mucin secretion. The combination of BAPTA and H-89 completely prevented mucin secretion mediated by PMs. These results suggest that PM induces mucin secretion through Ca(2+) influx and cAMP/PKA pathway by TRPV1 receptors in human bronchial epithelial cells, thereby providing a potential mechanism to reduce PM toxicity. PMID- 22829139 TI - Anti-inflammatory effect of 3,4-oxo-isopropylidene-shikimic acid on acetic acid induced colitis in rats. AB - The present work was done to investigate the possible effects of 3,4-oxo isopropylidene-shikimic acid (ISA) on acetic acid (AA)-induced colitis in rats. Colitis was induced by intracolonic injection of 6 % AA. Several parameters, including macroscopic score and biochemical parameters, were determined to assess the degree of protection. Biochemical parameters such as myeloperoxidase (MPO) activity, malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and inducible NO synthase (NOS) activities were measured following standard assay procedures. The study showed that treatment of rats for 6 days with ISA (100 and 200 mg/kg) was able to give complete protection against AA-induced colitis. Moreover, biochemical changes were reversed and brought toward control. These results suggest a beneficial effect of ISA against experimental colitis and the possible mechanism of the protective effects may be partly due to an antioxidant action. PMID- 22829142 TI - Alzheimer's disease: new perspectives on therapeutic targets and pathways. Foreword. PMID- 22829144 TI - No more free lunch: using RNA interference in the host to reduce growth of a parasitic plant. PMID- 22829143 TI - Mass spectrometry-based proteomics: the road to lung cancer biomarker discovery. AB - Lung cancer is the leading cause of cancer death in men and women in Western nations, and is among the deadliest cancers with a 5-year survival rate of 15%. The high mortality caused by lung cancer is attributable to a late-stage diagnosis and the lack of effective treatments. So, it is crucial to identify new biomarkers that could function not only to detect lung cancer at an early stage but also to shed light on the molecular mechanisms that underlie cancer development and serve as the basis for the development of novel therapeutic strategies. Considering that DNA-based biomarkers for lung cancer showed inadequate sensitivity, specificity, and reproducibility, proteomics could represent a better tool for the identification of useful biomarkers and therapeutic targets for this cancer type. Among the proteomics technologies, the most powerful tool is mass spectrometry. In this review, we describe studies that use mass spectrometry-based proteomics technologies to analyze tumor proteins and peptides, which might represent new diagnostic, prognostic, and predictive markers for lung cancer. We focus in particular on those findings that hold promise to impact significantly on the clinical management of this disease. PMID- 22829146 TI - A refined model of state transitions in plant thylakoid membranes. PMID- 22829145 TI - Nuclear ribosome biogenesis mediated by the DIM1A rRNA dimethylase is required for organized root growth and epidermal patterning in Arabidopsis. AB - Position-dependent patterning of hair and non-hair cells in the Arabidopsis thaliana root epidermis is a powerful system to study the molecular basis of cell fate specification. Here, we report an epidermal patterning mutant affecting the ADENOSINE DIMETHYL TRANSFERASE 1A (DIM1A) rRNA dimethylase gene, predicted to participate in rRNA posttranscriptional processing and base modification. Consistent with a role in ribosome biogenesis, DIM1A is preferentially expressed in regions of rapid growth, and its product is nuclear localized with nucleolus enrichment. Furthermore, DIM1A preferentially accumulates in the developing hair cells, and the dim1A point mutant alters the cell-specific expression of the transcriptional regulators GLABRA2, CAPRICE, and WEREWOLF. Together, these findings suggest that establishment of cell-specific gene expression during root epidermis development is dependent upon proper ribosome biogenesis, possibly due to the sensitivity of the cell fate decision to relatively small differences in gene regulatory activities. Consistent with its effect on the predicted S adenosyl-l-Met binding site, dim1A plants lack the two 18S rRNA base modifications but exhibit normal pre-rRNA processing. In addition to root epidermal defects, the dim1A mutant exhibits abnormal root meristem division, leaf development, and trichome branching. Together, these findings provide new insights into the importance of rRNA base modifications and translation regulation for plant growth and development. PMID- 22829147 TI - The time required for dormancy release in Arabidopsis is determined by DELAY OF GERMINATION1 protein levels in freshly harvested seeds. AB - Seed dormancy controls the start of a plant's life cycle by preventing germination of a viable seed in an unfavorable season. Freshly harvested seeds usually show a high level of dormancy, which is gradually released during dry storage (after-ripening). Abscisic acid (ABA) has been identified as an essential factor for the induction of dormancy, whereas gibberellins (GAs) are required for germination. The molecular mechanisms controlling seed dormancy are not well understood. DELAY OF GERMINATION1 (DOG1) was recently identified as a major regulator of dormancy in Arabidopsis thaliana. Here, we show that the DOG1 protein accumulates during seed maturation and remains stable throughout seed storage and imbibition. The levels of DOG1 protein in freshly harvested seeds highly correlate with dormancy. The DOG1 protein becomes modified during after ripening, and its levels in stored seeds do not correlate with germination potential. Although ABA levels in dog1 mutants are reduced and GA levels enhanced, we show that DOG1 does not regulate dormancy primarily via changes in hormone levels. We propose that DOG1 protein abundance in freshly harvested seeds acts as a timer for seed dormancy release, which functions largely independent from ABA. PMID- 22829149 TI - Pod corn is caused by rearrangement at the Tunicate1 locus. AB - Pod corn (Zea mays var tunicata) was once regarded as ancestral to cultivated maize, and was prized by pre-Columbian cultures for its magical properties. Tunicate1 (Tu1) is a dominant pod corn mutation in which kernels are completely enclosed in leaflike glumes. Here we show that Tu1 encodes a MADS box transcription factor expressed in leaves whose 5' regulatory region is fused by a 1.8-Mb chromosomal inversion to the 3' region of a gene expressed in the inflorescence. Both genes are further duplicated, accounting for classical derivative alleles isolated by recombination, and Tu1 transgenes interact with these derivative alleles in a dose-dependent manner. In young ear primordia, TU1 proteins are nuclearly localized in specific cells at the base of spikelet pair meristems. Tu1 branch determination defects resemble those in ramosa mutants, which encode regulatory proteins expressed in these same cells, accounting for synergism in double mutants discovered almost 100 years ago. The Tu1 rearrangement is not found in ancestral teosinte and arose after domestication of maize. PMID- 22829150 TI - Hydrogen-bonded assembly of methanol on Cu(111). AB - Investigation of methanol's surface chemistry on metals is a crucial step towards understanding the reactivity of this important chemical feedstock. Cu is a relevant metal for methanol synthesis and reforming, but due to the weak interaction of methanol with Cu, an atomic scale view of methanol's coverage dependent ordering and self-assembly on Cu(111), the most abundant facet of most nanoparticles, has not yet been possible. Low and variable temperature scanning tunneling microscopy coupled with density functional theory reveal a coverage dependent range of highly ordered structures stabilized by two hydrogen bonds per molecule. While extended chains that resemble the hydrogen-bonded zigzag structures reported for solid methanol are an efficient way to pack methanol at higher coverages, lower surface coverages yield isolated hexamer units. These hexamers form the same number of hydrogen bonds as the chains but appear to repel one another on the surface. Annealing treatments lead to the desorption of methanol with almost no decomposition. This data serves as a useful guide to both the preferred adsorption geometries and energies of a variety of methanol structures on Cu(111) surfaces as a function of surface coverage. PMID- 22829151 TI - Biofeedback assisted control of respiratory sinus arrhythmia as a biobehavioral intervention for depressive symptoms in patients after cardiac surgery: a preliminary study. AB - The current study investigated whether biofeedback training aimed at increasing respiratory sinus arrhythmia (RSA), a measure of cardiac vagal modulation, can reduce depressive symptoms in patients after cardiac surgery. This randomized controlled study enrolled 26 patients after first-time cardiac surgery. The patients were randomly assigned to an RSA-biofeedback group (N = 13) or to a treatment as usual group (N = 13). The biofeedback training consisted of five 45 min sessions designed to increase RSA. The outcome was assessed as changes in RSA and in the Centre for Epidemiologic Studies of Depression (CES-D) values from pre to post-training. Both groups were comparable for demographic and biomedical characteristics. RSA increased significantly in patients who underwent RSA biofeedback compared to controls. Moreover, the CES-D scores were reduced significantly from pre- to post-training in the RSA-biofeedback group compared to the controls. Changes in RSA were inversely related to changes in CES-D scores from pre- to post-training. These findings extend the effectiveness of RSA biofeedback for increasing vagal modulation as well as for reducing depressive symptoms in post-surgical patients. Overall, the current study also suggests that this biobehavioral intervention may add to the efficacy of postoperative risk reduction programs and rehabilitation protocols in cardiac surgery patients. PMID- 22829148 TI - Differential transit peptide recognition during preprotein binding and translocation into flowering plant plastids. AB - Despite the availability of thousands of transit peptide (TP) primary sequences, the structural and/or physicochemical properties that determine TP recognition by components of the chloroplast translocon are not well understood. By combining a series of in vitro and in vivo experiments, we reveal that TP recognition is determined by sequence-independent interactions and vectorial-specific recognition domains. Using both native and reversed TPs for two well-studied precursors, small subunit of ribulose-1,5-bis-phosphate carboxylase/oxygenase, and ferredoxin, we exposed these two modes of recognition. Toc34 receptor (34-kD subunit of the translocon of the outer envelope) recognition in vitro, preprotein binding in organellar, precursor binding in vivo, and the recognition of TPs by the major stromal molecular motor Hsp70 are specific for the physicochemical properties of the TP. However, translocation in organellar and in vivo demonstrates strong specificity to recognition domain organization. This organization specificity correlates with the N-terminal placement of a strong Hsp70 recognition element. These results are discussed in light of how individual translocon components sequentially interact with the precursor during binding and translocation and helps explain the apparent lack of sequence conservation in chloroplast TPs. PMID- 22829152 TI - The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells. AB - In Ph-positive (Ph(+)) leukemia, the quiescent cell state is one of the reasons for resistance to the BCR-ABL-kinase inhibitor, imatinib. In order to examine the mechanisms of resistance due to quiescence and the effect of the mammalian target of rapamycin inhibitor, everolimus, for such a resistant population, we used Ph(+) acute lymphoblastic leukemia patient cells serially xenotransplanted into NOD/SCID/IL2rgamma(null) (NOG) mice. Spleen cells from leukemic mice showed a higher percentage of slow-cycling G(0) cells in the CD34(+)CD38(-) population compared with the CD34(+)CD38(+) and CD34(-) populations. After ex vivo imatinib treatment, more residual cells were observed in the CD34(+)CD38(-) population than in the other populations. Although slow-cycling G(0) cells were insensitive to imatinib in spite of BCR-ABL and CrkL dephosphorylation, combination treatment with everolimus induced substantial cell death, including that of the CD34(+)CD38(-) population, with p70-S6 K dephosphorylation and decrease of MCL-1 expression. The leukemic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse system with the in vivo combination treatment with imatinib and everolimus showed a decrease of tumor burden including CD34(+) cells. These results imply that treatment with everolimus can overcome resistance to imatinib in Ph(+) leukemia due to quiescence. PMID- 22829153 TI - Rare mutations in DNMT3A in myeloproliferative neoplasms and myelodysplastic syndromes. PMID- 22829154 TI - A new hypothesis: imatinib affects leukemic stem cells in the same way it affects all other leukemic cells. PMID- 22829155 TI - Coexistence of primary myelofibrosis and chronic lymphocytic leukaemia: treatment of two different diseases with one agent. PMID- 22829156 TI - Inter- and intra-operator variability associated with extracapsular suture tensioning: an ex vivo study. AB - OBJECTIVES: To determine inter- and intra- operator variability associated with extracapsular suture tensioning as performed during lateral fabello-tibial suture placement. STUDY DESIGN: Ex vivo study. METHODS: Fifteen Greyhound cadaveric pelvic limbs were prepared by cutting the cranial cruciate ligament and placing an extracapsular fabello-tibial suture. On two occasions, three surgeons tensioned the extracapsular suture of each stifle. Stifles were returned to 135 degrees of flexion and the suture tension was measured using a commercially available suture tensioner with inbuilt tensiometer. STATISTICAL ANALYSIS: Intra operator and inter-operator agreement were assessed using the limits of agreement method. A linear mixed effects model was specified to assess the effect of operator, repeated estimates and stifle order on tension applied. RESULTS: The mean difference within the three operators ranged from 0 to 14.7N. With 95% limits of agreement, on most occasions for all three operators, the difference was between -31.7 and 41.0 N. The mean difference between the three operators ranged from 6.0 to 30.7 N. With 95% limits of agreement, on most occasions the difference between operators was between -25.6 and 62.5 N. CLINICAL SIGNIFICANCE: Marked variation exists in the tension applied during fabello-tibial suture application, both within and between surgeons. This variation may lead to inconsistent clinical outcomes. Further studies are required to determine the clinical consequences of this marked variation in extracapsular suture tensioning. PMID- 22829157 TI - The body as a living bioreactor: a feasibility study of pedicle flaps for tracheal transplantation. AB - Reconstruction of long-segment tracheal stenosis remains problematic. Ex vivo transplantation of stem cell-derived tracheas has been established in humans using external tissue bioreactors. These bioreactors, however, are not widely accessible. Thus, we are developing a rotational flap-based "internal bioreactor" to allow in vivo stem cell engraftment in a pre-vascularized recipient bed. This muscle will also then serve as a carrier for the transplanted trachea during rotation into position for airway reconstruction. Herein, we present a study investigating the feasibility of two pedicle muscle flaps for implantation and subsequent tracheal transplantation. Trapezius and latissimus flaps were raised using established surgical techniques. The length and width of each flap, along with the distance from the pedicle takeoff to the trachea, were measured. The overall ability of the flaps to reach the trachea was assessed. Twelve flaps were raised in 5 fresh adult human cadavers. For the trapezius flap, averages were: flap length of 16.4 cm, flap width of 5.95 cm at the tip, and distance from the pedicle takeoff to the trachea of 11.1 cm. For the latissimus dorsi flap, averages were: flap length of 35.4 cm, flap width of 7.25 cm at the tip, and distance from the pedicle takeoff to the trachea of 27.3 cm. All flaps showed sufficient durability and rotational ability. Our results show that both trapezius and latissimus dorsi flaps can be transposed into the neck to allow tension-free closure of tracheal defects. For cervical tracheal transplantation, both flaps are equally adequate. We believe that trapezius and latissimus dorsi muscle flaps are potential tracheal implantation beds in terms of vascular supply, durability, and rotational ability. PMID- 22829158 TI - Indications and outcome of subtotal petrosectomy for active middle ear implants. AB - The aim of this study was to describe the outcome and possible complications of subtotal petrosectomy (SP) for Vibrant Soundbridge (VSB) device surgery in a tertiary referral center. A secondary objective was the evaluation of hearing results in a subgroup of subjects who received the VSB device. Between 2009 and early 2011, 22 adult subjects with chronic otitis media (COM) underwent a SP, blind sac closure of the external auditory canal and abdominal fat obliteration to facilitate the application of an active middle ear implant (AMEI) in a staged procedure. Indications consisted of mixed hearing loss after previous tympanomastoplasty and failure of hearing rehabilitation with a hearing aid or bone conduction device in COM. Pre- and postoperative pure-tone audiograms were analyzed in respect to deterioration of inner ear function, unaided and aided (hearing aid, bone-anchored hearing aid and VSB) speech audiograms were compared to verify improvements in communications skills and functional gains. Incidence and type of complications were reviewed. No significant change was observed regarding mean bone conduction thresholds after the first stage procedure. Some minor wound healing problems were noted. Speech perception using the VSB (n = 16) showed a mean aided speech discrimination at 65-dB SPL of 75 % [standard deviation (SD) 28.7], at 80-dB SPL of 90 % (SD 25.1). Our results suggest that for selected patients with open mastoid cavities and chronic middle ear disease, SP with abdominal fat obliteration is an effective and safe technique to facilitate safe AMEI placement. PMID- 22829159 TI - Different reactions of human nasal and Eustachian tube mucosa after hyperbaric oxygen exposure: a pilot study. AB - Impairment of Eustachian tube function has been observed after hyperbaric oxygen treatment as well as after diving on oxygen used as breathing gas. The aim of the present study was to evaluate the influence of hyperbaric oxygen exposure on Eustachian tube ventilatory function and airflow characteristics of the nose. Six police task force divers performing two consecutive dives within a regular training schedule on oxygen were examined. Middle ear impedance, and nasal airflow velocities before and after diving as well as on the morning after the dive day were measured. Middle ear impedance decreased overnight in comparison to pre-dive values (P = 0.027) as well as compared to the value after the first dive (P = 0.032). Rhinoflowmetry did not reveal any changes of nasal airflow velocities related to the dives. Furthermore, no association between middle ear impedance and nasal airflow velocities was found. An impairment of Eustachian tube ventilatory function was obtained after hyperbaric oxygen exposure during dives employing oxygen as breathing gas. This impairment, however, was not associated with altered airflow characteristics of divers' noses. Thus, it seems unlikely that hyperbaric oxygen exerts an effect on the nasal mucosa similar to that on the Eustachian tube mucosa. PMID- 22829161 TI - Endovascular treatment of iliac vein compression syndrome (May-Thurner). AB - May-Thurner syndrome is a rare condition that results from narrowing of the left common iliac vein (CIV) lumen due to pulsatile compression from the right common iliac artery (CIA) as it crosses anterior to it. We present a case of 24-years old female with left lower limb deep venous thrombosis (DVT). Duplex ultrasonography revealed extensive left-sided DVT. Magnetic resonance venogram suggested DVT with left CIV being compressed by right CIA. Pharmaco-mechanical catheter directed thrombolysis-thrombectomy followed by left iliac vein stent placement restored patency to the venous system, with resolution of symptoms. PMID- 22829162 TI - Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex. AB - Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/ ) ) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blunted in Abcg5(-/-) mice. In contrast, biliary cholesterol secretion in T3-treated Lxra(+/+) and Lxra(-/-) mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. CONCLUSIONS: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect. PMID- 22829163 TI - Re-evaluation of phenotypic expression in undifferentiated-type early gastric adenocarcinomas using mucin core protein and CDX2. AB - BACKGROUND: Undifferentiated-type early gastric adenocarcinomas are generally classified into two groups: pure undifferentiated-type adenocarcinomas, which naturally develop as undifferentiated-type without a glandular component; and mixed differentiated/undifferentiated-type adenocarcinomas, which are associated with some vestigial glandular component and presumably develop from differentiated-type adenocarcinoma. The differences in phenotypic expression between these two groups were examined using mucin core protein and CDX2. METHODS: A total of 210 lesions of undifferentiated-type early gastric adenocarcinoma less than 25 mm in diameter were classified into four categories (gastric type, gastrointestinal type, intestinal type, and null type) based on their MUC5AC, MUC6, MUC2, and CDX2 immunoprofiles. RESULTS: Gastric type was significantly (p < 0.01) decreased and gastrointestinal type was significantly (p < 0.01) increased both in pure undifferentiated-type adenocarcinomas and in mixed differentiated/undifferentiated-type adenocarcinomas when CDX2 was applied to mucin core protein. In the pure undifferentiated-type adenocarcinomas, gastric type decreased and gastrointestinal type increased as tumor size increased (p < 0.05). In contrast, in the mixed differentiated/undifferentiated-type adenocarcinomas, gastrointestinal type was most common even in small-sized (<=10 mm) carcinomas and was generally stable regardless of tumor size. In submucosal carcinomas, gastrointestinal type decreased and gastric type and intestinal type increased during carcinoma invasion from the intramucosal to submucosal parts (p < 0.05). The positivity rates for all phenotypic markers, especially gastric markers, tended to decrease during submucosal invasion. CONCLUSIONS: CDX2 is a sensitive marker for assessing intestinal phenotypic expression, and it is likely that there are two different pathways of tumor progression in undifferentiated type adenocarcinoma of the stomach, according to phenotypic expression. PMID- 22829164 TI - Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database. AB - The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995-1999, 2000-2004, 2005-2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist-hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: -2.1, -1.6, -1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys. PMID- 22829166 TI - Virus reactivations and serology patterns following first-line therapy with alemtuzumab or fludarabine-based combination therapy in patients with chronic lymphocytic leukemia. PMID- 22829165 TI - Inhibition of Rac controls NPM-ALK-dependent lymphoma development and dissemination. AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is a tyrosine kinase oncogene responsible for the pathogenesis of the majority of human ALK-positive lymphomas. We recently reported that it activated the Rac1 GTPase in anaplastic large-cell lymphoma (ALCL), leading to Rac-dependent formation of active invadopodia required for invasiveness. Herein, we went further into the study of this pathway and used the inhibitor of Rac, NSC23766, to validate its potential as a molecular target in ALCL in vitro and in vivo in a xenograft model and in a conditional model of NPM-ALK transgenic mice. Our data demonstrate that Rac regulates important effectors of NPM-ALK-induced transformation such as Erk1/2, p38 and Akt. Moreover, inhibition of Rac signaling abrogates NPM-ALK-elicited disease progression and metastasis in mice, highlighting the potential of small GTPases and their regulators as additional therapic targets in lymphomas. PMID- 22829167 TI - Analysis of the interaction of induction regimens with p-glycoprotein expression in patients with acute myeloid leukaemia: results from the MRC AML15 trial. AB - Retrospective analyses in non-randomised cohorts suggest that regimens containing fludarabine/Ara C and/or idarubicin/ara C may be more effective than daunorubicin/AraC (DA)-containing regimens in cases of acute myeloid leukaemia (AML) overexpressing p-glycoprotein (Pgp). We prospectively measured Pgp protein and function by flow cytometry in CD45-gated blasts from 434 AML15 trial patients randomised to remission induction therapy with two courses of FLAG-Ida or DA+/ etoposide (DA/ADE). In all, 34% were positive for Pgp protein and 38% for function. Pgp protein-positive cases had a higher incidence of resistant disease (14% vs 5%), adjusted odds ratio 2.67 (1.14-6.24). There was a trend towards a higher cumulative incidence of relapse at 5 years for Pgp-positive cases (46% vs 55%), adjusted hazard ratio 1.42 (0.98-2.07) (P=0.06). For patients treated with FLAG-Ida, the complete remission (CR) rate was 86% for both Pgp-positive and Pgp negative patients. In patients treated with DA/ADE, 78% of Pgp-positive and 90% of Pgp-negative cases achieved CR (P=0.06). In analyses of overall survival, there was no interaction between treatment received and Pgp expression. Data for Pgp function followed similar trends. Our data suggest that FLAG-Ida may improve the remission rate for Pgp-positive AML, but the malignant clone is reduced rather than eradicated such that the relapse rate remains high in Pgp-positive patients. PMID- 22829169 TI - Acute promyelocytic leukaemia presenting with subarachnoid haemorrhage and complicated by central nervous system involvement. PMID- 22829168 TI - MicroRNA expression in tumor cells from Waldenstrom's macroglobulinemia reflects both their normal and malignant cell counterparts. AB - MicroRNAs (miRNAs) are involved in the regulation of many cellular processes including hematopoiesis, with the aberrant expression of differentiation-stage specific miRNA associated with lymphomagenesis. miRNA profiling has been essential for understanding the underlying biology of many hematological malignancies; however the miRNA signature of the diverse tumor clone associated with Waldenstrom's macroglobulinemia (WM), consisting of B lymphocytes, plasmacytes and lymphoplasmacytic cells, has not been characterized. We have investigated the expression of over 13 000 known and candidate miRNAs in both CD19(+) and CD138(+) WM tumor cells, as well as in their malignant and non malignant counterparts. Although neither CD19(+) nor CD138(+) WM cells were defined by a distinct miRNA profile, the combination of all WM cells revealed a unique miRNA transcriptome characterized by the dysregulation of many miRNAs previously identified as crucial for normal B-cell lineage differentiation. Specifically, miRNA-9(*)/152/182 were underexpressed in WM, whereas the expression of miRNA-21/125b/181a/193b/223/363 were notably increased (analysis of variance; P<0.0001). Future studies focusing on the effects of these dysregulated miRNAs will provide further insight into the mechanisms responsible for the pathogenesis of WM. PMID- 22829170 TI - MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias. AB - CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR 146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti leukemia drugs, for development of new therapeutic strategies. PMID- 22829171 TI - Myeloma cells suppress osteoblasts through sclerostin secretion. AB - Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of beta-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor kappa-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM. PMID- 22829172 TI - (1) H NMR spectral analysis and conformational behavior of n-alkanes in different chemical environments. AB - Alkyl chains are common structural units, for example in lipids, and their (1) H NMR spectral parameters offer valuable information about their conformational behavior in solvent environment. Even the spectra of short n-alkanes are complex, which is obviously a reason why their accurate spectral analyses have not been reported before. The present study reports the quantum mechanical analysis of (1) H NMR spectra of n-butane, n-pentane, n-hexane, and n-heptane. The spectral parameters were used to characterize the conformational behavior of n-alkanes. The temperature dependence analysis of coupling constants suggests that the enthalpy difference between the gauche (g) and trans (t) conformations (DeltaH(g) ) of n-butane in chloroform is 2.55-2.85 kJ mol(-1) . The difference between the trans-gauche (tg) and all-trans (tt) conformers of n-pentane (DeltaH(tg) ) seems to be 0.1-0.2 kJ mol(-1) higher. The coupling constant information shows that the t(n) conformations become more favored with longer chains, although not only for energetic reasons but also partly because the g(+) g(-) arrangements become sterically unfavorable, which decreases the number of favorable g(n) -type conformations. The analysis of the (1) H NMR spectra of n-pentane and n-hexane in solvents representing different chemical environments indicates that polar and spherical dimethyl sulfoxide favors clearly the g conformations, whereas n-hexane d(14) favors slightly the extended t(n) conformation. In addition to the intrinsic scientific importance for NMR spectral parameter prediction and molecular modeling in solution, the results provide some insights to behavior of hydrocarbon chains and their spectra in different chemical environments. PMID- 22829173 TI - Effects of multiple maternal relationship transitions on offspring antisocial behavior in childhood and adolescence: a cousin-comparison analysis. AB - Previous studies of the association between multiple parental relationship transitions (i.e., when a parent begins or terminates an intimate relationship involving cohabitation) and offspring antisocial behavior have varied in their efforts to rule out confounding influences, such as parental antisocial behavior and low income. They also have been limited in the representativeness of their samples. Thus, it remains unclear to what degree parents' multiple relationship transitions have independent effects on children's antisocial behavior. Analyses were conducted using data on 8,652 6-9-year-old, 6,911 10-13-year-old, and 6,495 14-17-year-old offspring of a nationally representative sample of U.S. women. Cousin-comparisons were used in combination with statistical covariates to evaluate the associations between maternal relationship transitions and offspring antisocial behavior in childhood and adolescence. Cousin-comparisons suggested that associations between maternal relationship transitions and antisocial behavior in childhood and early adolescence are largely explained by confounding factors. In contrast, the associations between maternal relationship transitions and offspring delinquency in late adolescence were robust to measured and unmeasured confounds. The present findings suggest that interventions aimed at reducing exposure to parental relationship transitions or addressing the psychosocial consequences of exposure to parental relationship transitions could reduce risk for offspring delinquency in late adolescence. PMID- 22829174 TI - Acute kidney injury following multiple wasp stings. AB - BACKGROUND: Common manifestations of hypersensitivity reactions to toxins of stinging insects range from local swelling to angioedema and anaphylaxis. Sometimes it may result in unusual manifestations like intravascular hemolysis, disseminated intravascular coagulation, rhabdomyolysis, etc. Acute kidney injury (AKI) due to immune-mediated acute interstitial nephritis is an extremely uncommon manifestation of insect stings. CASE-DIAGNOSIS/TREATMENT: A 9-year-old boy who developed renal failure from acute interstitial nephritis 7 days after getting stung by a swarm of wasps at multiple sites is described. He regained normal renal function after eight sessions of hemodialysis. CONCLUSIONS: Acute interstitial nephritis resulting in AKI may be either due to immune-mediated tubulointerstitial injury or acute cellular injury caused by obstruction by pigments like hemoglobin and myoglobin. Timely and appropriate supportive management usually cures the patient without any residual damage. The objective of reporting this case is to draw the attention of fellow clinicians towards the possibility of this unusual but life-threatening delayed complication in multiple wasp stings, even if there are no significant immediate reactions. PMID- 22829175 TI - Biomarkers of therapeutic response in primary nephrotic syndrome: response. PMID- 22829177 TI - The effect of external coaptation on plate deformation in an ex vivo model of canine pancarpal arthrodesis. AB - OBJECTIVES: Since external coaptation is applied clinically to prevent plate failure during healing in canine pancarpal arthrodesis (PCA), we tested the hypothesis that external coaptation does not significantly reduce plate strain in an experimental ex vivo model of canine PCA. METHODS: Ten thoracic limbs from healthy Greyhounds euthanatized for reasons un- related to the study were harvested and the carpus was stabilised with a dorsally applied 2.7/3.5 mm hybrid PCA plate. The strain in the plate adjacent to the most distal radial screw hole (R4) and the radial carpal bone (RCB) screw hole was measured as the limbs were loaded axially to a load that approximated that of controlled walking. Each limb was tested with and without external coaptation in place. RESULTS: Mean strain amplitude at the RCB was -177.2 MUepsilon (+/- 20.78) without external coaptation. Following cast application, strain reduced significantly to -34.7 MUepsilon (+/- 9.84) (p <0.002). Mean strain at R4 was -89.4 MUepsilon (+/- 22.10) without external support and -66.9 MUepsilon (+/- 10.74) following application of a cast. This reduction in recorded strain was not statistically significant. CLINICAL SIGNIFICANCE: The application of a cast to the distal portion of the limb significantly reduced strain in the 2.7/3.5 mm hybrid PCA plate, but the magnitude of the measured strain was low, suggesting that fatigue damage is unlikely to accumulate as a result of this type of loading and that external coaptation may not be necessary to prevent fatigue failure of the plate. PMID- 22829176 TI - Current insights into renal ciliopathies: what can genetics teach us? AB - Ciliopathies are a group of clinically and genetically overlapping disorders whose etiologies lie in defective cilia. These are antenna-like organelles on the apical surface of numerous cell types in a variety of tissues and organs, the kidney included. Cilia play essential roles during development and tissue homeostasis, and their dysfunction in the kidney has been associated with renal cyst formation and renal failure. Recently, the term "renal ciliopathies" was coined for those human genetic disorders that are characterized by nephronophthisis, cystic kidneys or renal cystic dysplasia. This review focuses on renal ciliopathies from a human genetics perspective. We survey the newest insights with respect to gene identification and genotype-phenotype correlations, and we reflect on candidate ciliopathies. The opportunities and challenges of next-generation sequencing (NGS) for genetic renal research and clinical DNA diagnostics are also reviewed, and we discuss the contribution of NGS to the development of personalized therapy for patients with renal ciliopathies. PMID- 22829178 TI - Negative tension of scroll wave filaments and turbulence in three-dimensional excitable media and application in cardiac dynamics. AB - Scroll waves are vortices that occur in three-dimensional excitable media. Scroll waves have been observed in a variety of systems including cardiac tissue, where they are associated with cardiac arrhythmias. The disorganization of scroll waves into chaotic behavior is thought to be the mechanism of ventricular fibrillation, whose lethality is widely known. One possible mechanism for this process of scroll wave instability is negative filament tension. It was discovered in 1987 in a simple two variables model of an excitable medium. Since that time, negative filament tension of scroll waves and the resulting complex, often turbulent dynamics was studied in many generic models of excitable media as well as in physiologically realistic models of cardiac tissue. In this article, we review the work in this area from the first simulations in FitzHugh-Nagumo type models to recent studies involving detailed ionic models of cardiac tissue. We discuss the relation of negative filament tension and tissue excitability and the effects of discreteness in the tissue on the filament tension. Finally, we consider the application of the negative tension mechanism to computational cardiology, where it may be regarded as a fundamental mechanism that explains differences in the onset of arrhythmias in thin and thick tissue. PMID- 22829179 TI - A note on the derivation of epidemic final sizes. AB - Final size relations are known for many epidemic models. The derivations are often tedious and difficult, involving indirect methods to solve a system of integro-differential equations. Often when the details of the disease or population change, the final size relation does not. An alternate approach to deriving final sizes has been suggested. This approach directly considers the underlying stochastic process of the epidemic rather than the approximating deterministic equations and gives insight into why the relations hold. It has not been widely used. We suspect that this is because it appears to be less rigorous. In this article, we investigate this approach more fully and show that under very weak assumptions (which are satisfied in all conditions we are aware of for which final size relations exist) it can be made rigorous. In particular, the assumptions must hold whenever integro-differential equations exist, but they may also hold in cases without such equations. Thus, the use of integro-differential equations to find a final size relation is unnecessary and a simpler, more general method can be applied. PMID- 22829180 TI - A model of oscillatory protein dynamics in bacteria. AB - Spatial oscillations of proteins in bacteria have recently attracted much attention. The cellular mechanism underlying these oscillations can be studied at molecular as well as at more macroscopic levels. We construct a minimal mathematical model with two proteins that is able to produce self-sustained regular pole-to-pole oscillations without having to take into account molecular details of the proteins and their interactions. The dynamics of the model is based solely on diffusion across the cell body and protein reactions at the poles, and is independent of stimuli coming from the environment. We solve the associated system of reaction-diffusion equations and perform a parameter scan to demonstrate robustness of the model for two possible sets of the reaction functions. PMID- 22829181 TI - Re-evaluating the use of Voronoi Tessellations in the assessment of oxygen supply from capillaries in muscle. AB - The ability to characterise capillary supply plays a key role in developing effective therapeutic interventions for numerous pathological conditions, such as capillary loss in skeletal or cardiac muscle. However, quantifying capillary supply is fraught with difficulties. Averaged measures such as capillary density or mean inter-capillary distance cannot account for the local geometry of the underlying capillary distribution, and thus can only highlight a tissue wide, global hypoxia. Detailed tissue geometry, such as muscle fibre size, has been incorporated into indices of capillary supply by considering the distribution of Voronoi tessellations generated from capillary locations in a plane perpendicular to muscle fibre orientation, implicitly assuming that each Voronoi polygon represents the area of supply of its enclosed capillary. Using a modelling framework to assess the capillary supply capacity under maximal sustainable conditions in muscle, we theoretically demonstrate that Voronoi tessellations often provide an accurate representation of the regions supplied by each capillary. However, we highlight that this use of Voronoi tessellations is inappropriate and inaccurate in the presence of extensive capillary rarefaction and pathological variations in oxygen tension of different capillaries. In such cases, oxygen flux trapping regions are developed to provide a more general representation of the capillary supply regions, in particular incorporating the additional influences of heterogeneity that are absent in the consideration of Voronoi tessellations. PMID- 22829182 TI - A hybrid discrete-continuum mathematical model of pattern prediction in the developing retinal vasculature. AB - Pathological angiogenesis has been extensively explored by the mathematical modelling community over the past few decades, specifically in the contexts of tumour-induced vascularisation and wound healing. However, there have been relatively few attempts to model angiogenesis associated with normal development, despite the availability of animal models with experimentally accessible and highly ordered vascular topologies: for example, growth and development of the vascular plexus layers in the murine retina. The current study aims to address this issue through the development of a hybrid discrete-continuum mathematical model of the developing retinal vasculature in neonatal mice that is closely coupled with an ongoing experimental programme. The model of the functional vasculature is informed by a range of morphological and molecular data obtained over a period of several days, from 6 days prior to birth to approximately 8 days after birth. The spatio-temporal formation of the superficial retinal vascular plexus (RVP) in wild-type mice occurs in a well-defined sequence. Prior to birth, astrocytes migrate from the optic nerve over the surface of the inner retina in response to a chemotactic gradient of PDGF-A, formed at an earlier stage by migrating retinal ganglion cells (RGCs). Astrocytes express a variety of chemotactic and haptotactic proteins, including VEGF and fibronectin (respectively), which subsequently induce endothelial cell sprouting and modulate growth of the RVP. The developing RVP is not an inert structure; however, the vascular bed adapts and remodels in response to a wide variety of metabolic and biomolecular stimuli. The main focus of this investigation is to understand how these interacting cellular, molecular, and metabolic cues regulate RVP growth and formation. In an earlier one-dimensional continuum model of astrocyte and endothelial migration, we showed that the measured frontal velocities of the two cell types could be accurately reproduced by means of a system of five coupled partial differential equations (Aubert et al. in Bull. Math. Biol. 73:2430-2451, 2011). However, this approach was unable to generate spatial information and structural detail for the entire retinal surface. Building upon this earlier work, a more realistic two-dimensional hybrid PDE-discrete model is derived here that tracks the migration of individual astrocytes and endothelial tip cells towards the outer retinal boundary. Blood perfusion is included throughout plexus development and the emergent retinal architectures adapt and remodel in response to various biological factors. The resulting in silico RVP structures are compared with whole-mounted retinal vasculatures at various stages of development, and the agreement is found to be excellent. Having successfully benchmarked the model against wild-type data, the effect of transgenic over expression of various genes is predicted, based on the ocular-specific expression of VEGF-A during murine development. These results can be used to help inform future experimental investigations of signalling pathways in ocular conditions characterised by aberrant angiogenesis. PMID- 22829183 TI - Quantifying the likelihood of co-existence for communities with asymmetric competition. AB - Trade-offs in performance of different ecological functions within a species are commonly offered as an explanation for co-existence in natural communities. Single trade-offs between competitive ability and other life history traits have been shown to support a large number of species, as a result of strong competitive asymmetry. We consider a single competition-fecundity trade-off in a homogeneous environment, and examine the effect of the form of asymmetry on the likelihood of species co-existing. We find conditions that allow co-existence of two species for a general competition function, and show that (1) two species can only co-exist if the competition function is sufficiently steep when the species are similar; (2) when competition is determined by a linear function, no more than two species can co-exist; (3) when the competition between two individuals is determined by a discontinuous step function, this single trade-off can support an arbitrarily large number of species. Further, we show analytically that as the degree of asymmetry in competition increases, the probability of a given number of species co-existing also increases, but note that even in the most favourable conditions, large numbers of species co-existing along a single trade-off is highly unlikely. On this basis, we suggest it is unlikely that single trade-offs are able to support high levels of bio-diversity without interacting other processes. PMID- 22829184 TI - Antileukemic activity of the HSP70 inhibitor pifithrin-MU in acute leukemia. AB - Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-MU (PFT-MU), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-MU significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 MU, and was highly active in primary AML blasts with a median IC50 of 8.9 MU (range 5.7-37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT MU induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-MU also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-MU enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-MU, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-MU in acute leukemias. PMID- 22829185 TI - Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. AB - Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC(50)) of <1 n, and had 30-50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene; IC(50)=11-120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS 018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs. PMID- 22829186 TI - BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph(+) acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy. PMID- 22829187 TI - Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells. AB - Malignant cells are known to have increased glucose uptake and accelerated glucose metabolism. Using liquid chromatography and mass spectrometry, we found that treatment of acute lymphoblastic leukemia (ALL) cells with the glucocorticoid (GC) dexamethasone (Dex) resulted in profound inhibition of glycolysis. We thus demonstrate that Dex reduced glucose consumption, glucose utilization and glucose uptake by leukemic cells. Furthermore, Dex treatment decreased the levels of the plasma membrane-associated glucose transporter GLUT1, thus revealing the mechanism for the inhibition of glucose uptake. Inhibition of glucose uptake correlated with induction of cell death in ALL cell lines and in leukemic blasts from ALL patients cultured ex vivo. Addition of di-methyl succinate could partially overcome cell death induced by Dex in RS4;11 cells, thereby further supporting the notion that inhibition of glycolysis contributes to the induction of apoptosis. Finally, Dex killed RS4;11 cells significantly more efficiently when cultured in lower glucose concentrations suggesting that modulation of glucose levels might influence the effectiveness of GC treatment in ALL. In summary, our data show that GC treatment blocks glucose uptake by leukemic cells leading to inhibition of glycolysis and that these effects play an important role in the induction of cell death by these drugs. PMID- 22829188 TI - A NIR BODIPY dye bearing 3,4,4a-trihydroxanthene moieties. AB - A novel 3,4,4a-trihydroxanthene-fused pyrrole 2 was synthesized by the reaction of 2,3,4,4a-tetrahydro-1H-xanthen-1-one with 3-phenyl-2H-azirine in the presence of LDA. Utilizing this pyrrole 2, a NIR BODIPY 1 (lambda(abs) = 732 nm, lambda(em) = 747 nm) has been prepared. The new BODIPY 1 was stable, non cytotoxic, and suited to labeling living cells for imaging assay in the NIR region. PMID- 22829192 TI - Mutations and deletions of the SUZ12 polycomb gene in myeloproliferative neoplasms. PMID- 22829191 TI - Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib. AB - The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of 'ATPase activity', 'cell adhesion' or 'tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI) resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance. PMID- 22829193 TI - Satisfaction in child and adolescent mental health services: translating users' feedback into measurement. AB - The present research addressed gaps in our current understanding of validity and quality of measurement provided by patient reported experience measures. We established the psychometric properties of a freely available experience of service questionnaire (ESQ), based on responses from 7,067 families of patients across 41 UK providers of child and adolescent mental health services, using the two-level latent trait modeling. Responses to the ESQ were subject to strong 'halo' effects, which were thought to represent the overall positive or negative affect towards one's treatment. Two strongly related constructs measured by the ESQ were interpreted as specific aspects of global satisfaction, namely satisfaction with care, and with environment. The Care construct was sensitive to differences between less satisfied patients, facilitating individual and service level problem evaluation. The effects of nesting within service providers were strong, with parental reports being the most reliable source of data for the between-provider comparisons. We provide a scoring protocol for converting the hand-scored ESQ to the model-based population-referenced scores with supplied standard errors, which can be used for benchmarking services as well as individual evaluations. PMID- 22829190 TI - A kinetic approach to assess oxidative metabolism related features in the bivalve Mya arenaria. AB - Electron paramagnetic resonance uses the resonant microwave radiation absorption of paramagnetic substances to detect highly reactive and, therefore, short-lived oxygen and nitrogen centered radicals. Previously, steady state concentrations of nitric oxide, ascorbyl radical (A.) and the labile iron pool (LIP) were determined in digestive gland of freshly collected animals from the North Sea bivalve Mya arenaria. The application of a simple kinetic analysis of these data based on elemental reactions allowed us to estimate the steady state concentrations of superoxide anion, the rate of A. disappearance and the content of unsaturated lipids. This analysis applied to a marine invertebrate opens the possibility of a mechanistic understanding of the complexity of free radical and LIP interactions in a metabolically slow, cold water organism under unstressed conditions. This data can be further used as a basis to assess the cellular response to stress in a simple system as the bivalve M. arenaria that can then be compared to cells of higher organisms. PMID- 22829195 TI - Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo. AB - The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway. PMID- 22829194 TI - Vitreous levels of oxidative stress biomarkers and the radical-scavenger alpha1 microglobulin/A1M in human rhegmatogenous retinal detachment. AB - PURPOSE: To explore oxidative stress and the radical scavenger alpha(1) microglobulin (A1M) in the vitreous body of human eyes with primary rhegmatogenous retinal detachment (RRD). METHODS: Levels of carbonyl groups, a marker of oxidative stress, and A1M were measured by ELISA and RIA in 14 vitreous samples derived from patients suffering from RRD, and compared with 14 samples from macula hole (MH) patients. Carbonyl group and A1M levels in RRD samples were statistically related to detachment characteristics. Analysis of total protein level, SDS-PAGE, and Western blotting of A1M was also performed. In a separate experiment, mRNA expression of A1M was measured by RT-PCR in rat retina explants. RESULTS: Levels of carbonyl groups and A1M varied widely in RRD vitreous samples, but were significantly higher in samples derived from eyes with large detachment area and macula-off status, while the presence of vitreous hemorrhage did not show any significant correlation. Compared with MH samples, RRD samples displayed significantly higher levels of A1M, whereas changes in total protein levels and carbonyl groups were not significant. Novel forms of A1M, not previously seen in plasma, were found in the vitreous body by Western blotting. Furthermore, A1M expression was seen in rat retina explants and was upregulated after 24 h of culturing. CONCLUSION: Oxidative stress is a prominent feature of human eyes with primary RRD, and is directly related to detachment severity. Affected eyes can launch a protective response in the form of the radical scavenger A1M possibly derived from the retina. The results thus indicate potential therapeutic cell loss prevention in RRD by employing the endogeneous radical scavenger A1M. PMID- 22829196 TI - Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score. AB - Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ?30 ml/min/1.73m(2), impaired lung function and KPS ?70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM. PMID- 22829198 TI - Sample size determination in clinical trials with multiple co-primary endpoints including mixed continuous and binary variables. AB - In the field of pharmaceutical drug development, there have been extensive discussions on the establishment of statistically significant results that demonstrate the efficacy of a new treatment with multiple co-primary endpoints. When designing a clinical trial with such multiple co-primary endpoints, it is critical to determine the appropriate sample size for indicating the statistical significance of all the co-primary endpoints with preserving the desired overall power because the type II error rate increases with the number of co-primary endpoints. We consider overall power functions and sample size determinations with multiple co-primary endpoints that consist of mixed continuous and binary variables, and provide numerical examples to illustrate the behavior of the overall power functions and sample sizes. In formulating the problem, we assume that response variables follow a multivariate normal distribution, where binary variables are observed in a dichotomized normal distribution with a certain point of dichotomy. Numerical examples show that the sample size decreases as the correlation increases when the individual powers of each endpoint are approximately and mutually equal. PMID- 22829197 TI - Further phenotypic characterization of the primitive lineage- CD34+CD38 CD90+CD45RA- hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia. AB - The most primitive hematopoietic stem cell (HSC)/progenitor cell (PC) population reported to date is characterized as being Lin-CD34+CD38-CD90+CD45R. We have a long-standing interest in comparing the characteristics of hematopoietic progenitor cell populations enriched from normal subjects and patients with chronic myelogenous leukemia (CML). In order to investigate further purification of HSCs and for potential targetable differences between the very primitive normal and CML stem/PCs, we have phenotypically compared the normal and CML Lin CD34+CD38-CD90+CD45RA- HSC/PC populations. The additional antigens analyzed were HLA-DR, the receptor tyrosine kinases c-kit and Tie2, the interleukin-3 cytokine receptor, CD33 and the activation antigen CD69, the latter of which was recently reported to be selectively elevated in cell lines expressing the Bcr-Abl tyrosine kinase. Notably, we found a strikingly low percentage of cells from the HSC/PC sub-population isolated from CML patients that were found to express the c-kit receptor (<1%) compared with the percentages of HSC/PCs expressing the c-kitR isolated from umbilical cord blood (50%) and mobilized peripheral blood (10%). Surprisingly, Tie2 receptor expression within the HSC/PC subset was extremely low from both normal and CML samples. Using in vivo transplantation studies, we provide evidence that HLA-DR, c-kitR, Tie2 and IL-3R may not be suitable markers for further partitioning of HSCs from the Lin-CD34+CD38-CD90+CD45RA- sub population. PMID- 22829199 TI - The European medicines agency review of eribulin for the treatment of patients with locally advanced or metastatic breast cancer: summary of the scientific assessment of the committee for medicinal products for human use. AB - The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website. PMID- 22829200 TI - Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants. AB - PURPOSE: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline variations in succinate dehydrogenase genes (SDHx) occur in approximately 10% PTEN mutation negative CS and CS-like (CSL) individuals (SDH(var+)). We previously showed that SDHx variants result in elevated reactive oxygen species (ROS), disruption of nicotinamide adenine dinucleotide (NAD) equilibrium, and destabilization of p53 hence apoptosis resistance in CS/CSL patient-derived lymphoblastoid cells. In the present study, we sought to address the tumorigenic impacts of increased ROS and the potential of protecting SDH(var+) cells with antioxidants. EXPERIMENTAL DESIGN: We measured the lipid peroxidation levels in patient-derived SDH(var+) lymphoblastoid cells and sequenced 74 controls or SDH(var+) germline DNA samples for mitochondrial hypervariable region II (HVRII) polymorphisms. SDH(var+) lymphoblastoid cells were treated with various antioxidants to check p53 expression and sub-G(1) cell population with cell-cycle analysis. RESULTS: We showed that elevated ROS results in higher lipid peroxidation in SDH(var+) cells. Accumulation of polymorphisms in mitochondrial HVRII was observed in SDH(var+) samples. Interestingly, alpha-tocopherol (vitamin E) treatment, but not other antioxidants, rescued SDH(var+) cells from apoptosis resistance and protected SDH(var+) cells from oxidative damage such as decreased lipid peroxidation as well as partially recovered p53 expression and NAD/NADH levels. CONCLUSIONS: We conclude that disruption of complex II because of SDHx variants leads to increased ROS generation, specifically accompanied by lipid peroxidation. The lipid soluble antioxidant alpha-tocopherol can selectively protect SDH(var+) cells from oxidative damage, apoptosis resistance, and rebalance redox metabolites NAD/NADH. PMID- 22829201 TI - The pivotal role of integrin beta1 in metastasis of head and neck squamous cell carcinoma. AB - PURPOSE: This study aimed to understand the prognostic value of integrin beta1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC. EXPERIMENTAL DESIGN: Archival HNSCC tissues including 99 nonmetastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin beta1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence-activated cell sorting was used to separate the integrin beta1(high/+) cell population from the integrin beta1(low/-) population in HNSCC cell lines. These two populations and integrin beta1 shRNA knockdown HNSCC cells were examined for the effect of integrin beta1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMP) were examined by zymography. RESULTS: Statistical analysis showed that integrin beta1 expression was significantly higher in the metastatic primary tumors than in the nonmetastatic tumors (42.6% vs. 24.8%, P < 0.0001 and P < 0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin beta1 expression was inversely correlated with overall survival (P = 0.035). The integrin beta1 knockdown or integrin beta1(low/-) HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (P < 0.001 and P < 0.05, respectively). Significantly reduced Matrigel invasion capability was also found in integrin beta1 knockdown or integrin beta1(low/-) HNSCC cells (P < 0.01). Finally, zymography results showed integrin beta1-affected HNSCC invasion by regulating MMP-2 activation. CONCLUSION: These findings indicate that integrin beta1 has a major impact on HNSCC prognosis through its regulation of metastasis. PMID- 22829203 TI - Personalized nanomedicine. AB - Personalized medicine aims to individualize chemotherapeutic interventions on the basis of ex vivo and in vivo information on patient- and disease-specific characteristics. By noninvasively visualizing how well image-guided nanomedicines that is, submicrometer-sized drug delivery systems containing both drugs and imaging agents within a single formulation, and designed to more specifically deliver drug molecules to pathologic sites-accumulate at the target site, patients likely to respond to nanomedicine-based therapeutic interventions may be preselected. In addition, by longitudinally monitoring how well patients respond to nanomedicine-based therapeutic interventions, drug doses and treatment protocols can be individualized and optimized during follow-up. Furthermore, noninvasive imaging information on the accumulation of nanomedicine formulations in potentially endangered healthy tissues may be used to exclude patients from further treatment. Consequently, combining noninvasive imaging with tumor targeted drug delivery seems to hold significant potential for personalizing nanomedicine-based chemotherapeutic interventions, to achieve delivery of the right drug to the right location in the right patient at the right time. PMID- 22829202 TI - Apricoxib, a novel inhibitor of COX-2, markedly improves standard therapy response in molecularly defined models of pancreatic cancer. AB - PURPOSE: COX-2 is expressed highly in pancreatic cancer and implicated in tumor progression. COX-2 inhibition can reduce tumor growth and augment therapy. The precise function of COX-2 in tumors remains poorly understood, but it is implicated in tumor angiogenesis, evasion of apoptosis, and induction of epithelial-to-mesenchymal transition (EMT). Current therapeutic regimens for pancreatic cancer are minimally effective, highlighting the need for novel treatment strategies. Here, we report that apricoxib, a novel COX-2 inhibitor in phase II clinical trials, significantly enhances the efficacy of gemcitabine/erlotinib in preclinical models of pancreatic cancer. EXPERIMENTAL DESIGN: Human pancreatic cell lines were evaluated in vitro and in vivo for response to apricoxib +/- standard-of-care therapy (gemcitabine + erlotinib). Tumor tissue underwent posttreatment analysis for cell proliferation, viability, and EMT phenotype. Vascular parameters were also determined. RESULTS: COX-2 inhibition reduced the IC(50) of gemcitabine +/- erlotinib in six pancreatic cancer cell lines tested in vitro. Furthermore, apricoxib increased the antitumor efficacy of standard combination therapy in several orthotopic xenograft models. In vivo apricoxib combination therapy was only effective at reducing tumor growth and metastasis in tumors with elevated COX-2 activity. In each model examined, treatment with apricoxib resulted in vascular normalization without a decrease in microvessel density and promotion of an epithelial phenotype by tumor cells regardless of basal COX-2 expression. CONCLUSIONS: Apricoxib robustly reverses EMT and augments standard therapy without reducing microvessel density and warrants further clinical evaluation in patients with pancreatic cancer. PMID- 22829204 TI - Silver-catalysed enantioselective addition of O-H and N-H bonds to allenes: a new model for stereoselectivity based on noncovalent interactions. AB - The ability of silver complexes to catalyse the enantioselective addition of O-H and N-H bonds to allenes is demonstrated for the first time by using optically active anionic ligands that were derived from oxophosphorus(V) acids as the sources of chirality. The intramolecular addition of acids, alcohols, and amines to allenes can be achieved with up to 73% ee. The exploitation of a C-H anomeric effect allowed the absolute configuration of a sample of 2-substituted tetrahydrofuran of low ee to be unambiguously assigned by comparison of the chiroptical ORD and VCD measurements with calculated spectra. In the second part of the work, the origin of the stereoselectivity was probed by DFT free-energy calculations of the transition states. A new model of enantiomeric differentiation was developed that was based on noncovalent interactions. This model allowed us to identify the source of stereoselectivity as weak attractive interactions; such dispersive forces are often overlooked in asymmetric catalysis. A new computational approach was developed that represents these interactions as colour-coded isosurfaces that are characterised by the reduced density-gradient profile. PMID- 22829205 TI - Oxygen surface exchange kinetics of SrTi(1-x)Fe(x)O(3-delta) mixed conducting oxides. AB - The oxygen surface exchange kinetics of mixed conducting perovskite oxides SrTi(1 x)Fe(x)O(3-delta) (x = 0, 0.01, 0.05, 0.35, 0.5) has been investigated as a function of temperature and oxygen partial pressure using the pulse-response (18)O-(16)O isotope exchange (PIE) technique. Arrhenius activation energies range from 140 kJ mol(-1) for x = 0 to 86 kJ mol(-1) for x = 0.5. Extrapolating the temperature dependence to the intermediate temperature range, 500-600 degrees C, indicates that the rate of oxygen exchange, in air, increases with increasing iron mole fraction, but saturates at the highest iron mole fraction for the given series. The observed behavior is concomitant with corresponding increases in both electronic and ionic conductivity with increasing x in SrTi(1-x)Fe(x)O(3-delta). Including literature data of related perovskite-type oxides Ba(0.5)Sr(0.5)Co(0.8)Fe(0.2)O(3-delta), La(0.6)Sr(0.4)Co(0.2)Fe(0.8)O(3-delta), La(0.6)Sr(0.4)CoO(3-delta), and Sm(0.5)Sr(0.5)CoO(3-delta), a linear relationship is observed in the log-log plot between oxygen exchange rate and oxide ionic conductivity with a slope fairly close to unity, suggesting that it is the magnitude of the oxide ionic conductivity that governs the rate of oxygen exchange in these solids. The distribution of oxygen isotopomers ((16)O(2), (16)O(18)O, (18)O(2)) in the effluent pulse can be interpreted on the basis of a two-step exchange mechanism for the isotopic exchange reaction. Accordingly, the observed power law dependence of the overall surface exchange rate on oxygen partial pressure turns out to be an apparent one, depending on the relative rates of both steps involved in the adopted two-step scheme. Supplementary research is, however, required to elucidate which of the two possible reaction schemes better reflects the actual kinetics of oxygen surface exchange on SrTi(1-x)Fe(x)O(3 delta). PMID- 22829206 TI - RNAi knockdown of rice SE5 gene is sensitive to the herbicide methyl viologen by the down-regulation of antioxidant defense. AB - Plant heme oxygenase (HO) catalyzes the oxygenation of heme to biliverdin, carbon monoxide (CO), and free iron (Fe(2+))-and Arabidopsis and rice (Oryza sativa) HOs are involved in light signaling. Here, we identified that the rice PHOTOPERIOD SENSITIVITY 5 (SE5) gene, which encoded a putative HO with high similarity to HO 1 from Arabidopsis (HY1), exhibited HO activity, and localized in the chloroplasts. Rice RNAi mutants silenced for SE5 were generated and displayed early flowering under long-day conditions, consistent with phenotypes of the null mutation in SE5 gene reported previously (se5 and s73). The herbicide methyl viologen (MV), which produces reactive oxygen species (ROS), was applied to determine whether SE5 regulates oxidative stress response. Compared with wild type, SE5 RNAi transgenic plants aggravated seedling growth inhibition, chlorophyll loss and ROS overproduction, and decreased the transcripts of some representative antioxidative genes. By contrast, administration of exogenous CO partially rescued corresponding MV hypersensitivity in the SE5 RNAi plants. Alleviation of seed germination inhibition, chlorophyll loss and ROS overproduction, as well as the induction of antioxidant defense were further observed when SE5 or HY1 was overexpressed in transgenic Arabidopsis plants, indicating that SE5 may be useful for molecular breeding designed to improve plant tolerance to oxidative stress. PMID- 22829207 TI - Salvage surgery for recurrent oropharyngeal cancer after chemoradiotherapy. AB - BACKGROUND: The current study aimed to assess the role of salvage surgery for failure cases of oropharyngeal cancer (OPC) undergoing initial chemoradiotherapy (CRT). METHODS: The data for 523 patients with previously untreated OPC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group (JCOG). RESULTS: Of the 170 patients who received CRT, 35 patients (21%) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between the two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1%, whereas those for the patients who received nonsurgical treatment were 16.3%. CONCLUSION: The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered. PMID- 22829209 TI - Having to fight. AB - Existing research that attempts to understand aggressive behavior often focuses on adults and/or individual traits. The present study used a Grounded Theory approach to develop a theoretical framework of how younger adolescents constructed an understanding of their own aggressive behavior within the social context of their lives. The participants were 11 adolescents (aged 12-16) who had previously been involved in incidents of aggression at a school for children with emotional and behavioral difficulties. The identified theoretical framework outlined that aggressive behavior was fundamental to an identity of toughness that participants sought to portray to others. This identity emerged in a hostile peer environment to prevent victimization and establish friendships. The findings are discussed in relation to their clinical implications, limitations, and possibilities for further research. PMID- 22829208 TI - Vital staining with iodine solution in oral cancer: iodine infiltration, cell proliferation, and glucose transporter 1. AB - BACKGROUND: Vital staining with iodine solution has been used to distinguish dysplastic/malignant oral epithelium from normal mucosa. However, little is known about its critical mechanism. The purpose of this study was to visualize how iodine infiltrates the oral epithelium and reacts with glycogen. In addition, we tested the hypothesis that higher cell proliferation requires increased energy consumption, and consequently exhausted glycogen may lead to a failure to be stained by iodine solution. METHODS: Fifteen frozen tissue samples of iodine stained and -unstained mucosa were obtained from 15 cases of oral squamous cell carcinoma (OSCC). Serial frozen sections were cut and examined with hematoxylin and eosin and periodic acid-Schiff methods and immunohistochemical staining for p53, Ki67 and glucose transporter 1 (GLUT 1). RESULTS: Iodine solution was able to penetrate normal epithelium to a maximum depth neighboring the parabasal layer, but iodine-stained areas were completely consistent with glycogen distribution only in the upper superficial layer. Iodine-negative epithelium presented significantly higher immunoreactions for P53 and GLUT 1 in basal, parabasal, and superficial layers, respectively, whereas the reaction for Ki67 in the superficial layer was higher than that in iodine-positive epithelium (Wilcoxon signed-rank test, P < 0.05). CONCLUSIONS: Iodine infiltrated and reacted with glycogen mainly in the upper superficial layer of the nonkeratinized epithelium. Both histological and molecular margins can be confirmed by iodine vital staining in OSCC. It is also suggested that high cell proliferation induced elevated glycolysis, resulting in an intraepithelial glycogen degradation and consequent failure to be stained by iodine solution. PMID- 22829210 TI - The relationship of negative self-schemas and insecure partner attachment styles with anger experience and expression among male batterers. AB - The purpose of the study was to explore how negative self-schemas and partner attachments were related to the experience and expression of anger (i.e., trait anger, inward and outward expression of anger) in a sample of male batterers (n = 40) who participated in court-mandated group services. They completed the Experience in Close Relationships (ECR), the Young Schema Questionnaire-2 (YSQ 2), the State-Trait Anger Expression Inventory-2 (STAXI-2), and a demographic sheet. Male batterers who experienced pervasive anger (i.e., trait anger) tended to experience negative self-schemas associated with the Impaired Limits domain (respecting the rights of others, insufficient self-control, entitlement). Male batterers who tended to suppress their anger tended to feel avoidantly attached to their romantic partner and endorsed negative self-schemas associated with the Disconnection and Rejection domain (abandonment, emotional deprivation, defectiveness/shame). Implications for clinical practice with male offenders and future research are discussed. PMID- 22829211 TI - The role of perpetrator motivation in two crime scenarios. AB - Undergraduate volunteers (n = 134) were randomly assigned in a 2 * 2 design that manipulated type of crime (rape vs. robbery) and perpetrator motivation (anger vs. desire). After reading one of the crime scenarios, participants responded to a series of attitude items regarding responsibility for the crime, assigned blame to agents mentioned in the scenario, and assigned a prison sentence to the perpetrator. A two-way ANOVA showed a significant interaction of motivation and crime (p = .026), with the victim rated least responsible in the anger-motivated rape scenario. Likewise, the assignment of blame produced a significant interaction of motivation and crime (p = .034); the victim was blamed the least in the anger-motivated rape scenario. Although the perpetrator was viewed as more responsible for the crime of rape than robbery (p = .022) and received a significantly longer sentence for rape (p < .001), perpetrator motivation did not affect perceptions of the perpetrator's responsibility for either crime. These results stand in contrast to those of Mitchell, Angelone, Kohlberger, and Hirschman (2009) and suggest their findings may have been the result of homophobic statements by the perpetrator rather than anger per se. PMID- 22829212 TI - Genetic risk for violent behavior and environmental exposure to disadvantage and violent crime: the case for gene-environment interaction. AB - Despite mounds of evidence to suggest that neighborhood structural factors predict violent behavior, almost no attention has been given to how these influences work synergistically (i.e., interact) with an individual's genetic propensity toward violent behavior. Indeed, two streams of research have, heretofore, flowed independently of one another. On one hand, criminologists have underscored the importance of neighborhood context in the etiology of violence. On the other hand, behavioral geneticists have argued that individual-level genetic propensities are important for understanding violence. The current study seeks to integrate these two compatible frameworks by exploring gene-environment interactions (GxE). Two GxEs were examined and supported by the data (i.e., the National Longitudinal Study of Adolescent Health). Using a scale of genetic risk based on three dopamine genes, the analysis revealed that genetic risk had a greater influence on violent behavior when the individual was also exposed to neighborhood disadvantage or when the individual was exposed to higher violent crime rates. The relevance of these findings for criminological theorizing was considered. PMID- 22829213 TI - The moderating effects of cluster B personality traits on violence reduction training: a mixed-model analysis. AB - Cognitive behavioral therapies have positive effects on anger and aggression; however, individuals differ in their response to treatment. The authors previously found that dynamic factors, such as increases in readiness to change, are associated with enhanced outcomes for violence reduction training. This study investigated how less dynamic factors, specifically Cluster B personality traits, moderate the effects of violence reduction training. The authors used mixed modeling to fit growth curves to 14 weeks of anger strategies data and evaluated whether the presence of Cluster B traits affected pretreatment anger levels and rates of change. As expected, overall levels of negative anger strategies decreased across the 14-week treatment. Participants with antisocial, borderline, and histrionic personality features reported higher rates of negative anger strategies, whereas those with narcissistic personality features reported fewer negative anger strategies. Those with antisocial personality features improved at a rate similar to the overall trend of those without Cluster B traits. Those with borderline and histrionic features improved at an accelerated rate. PMID- 22829214 TI - Does acute stress disorder predict posttraumatic stress disorder following bank robbery? AB - Unfortunately, the number of bank robberies is increasing and little is known about the subsequent risk of posttraumatic stress disorder (PTSD). Several studies have investigated the prediction of PTSD through the presence of acute stress disorder (ASD). However, there have only been a few studies following nonsexual assault. The present study investigated the predictive power of different aspects of the ASD diagnosis and symptom severity on PTSD prevalence and symptom severity in 132 bank employees. The PTSD diagnosis, based on the three core symptom clusters, was best identified using cutoff scores on the Acute Stress Disorder scale. ASD severity accounted for 40% and the inclusion of other risk factors accounted for 50% of the PTSD severity variance. In conclusion, results indicated that ASD appears to predict PTSD differently following nonsexual assault than other trauma types. ASD severity was a stronger predictor of PTSD than ASD diagnosis. PMID- 22829215 TI - Parental psychological violence and adolescent behavioral adjustment: the role of coping and social support. AB - The role of coping strategies (approach and avoidance) as a mediating factor between parental psychological violence and adolescent behavior problems, both internalized and externalized, as well as the protective role of social support were examined separately for boys and girls. A group of 278 adolescents (mean age: 14.2) were recruited in three high schools located in low, moderate, and high socioeconomic areas. Participants were in the seventh, eighth, and ninth grades, and each completed a self-administered questionnaire. The use of avoidant coping strategies partially mediated the link between parental psychological violence and behavior problems among girls. The use of approach coping strategies partially mediated the link between parental psychological violence and behavior problems among boys. In all cases, coping enhanced this link. No protective role of social support was found. On the contrary, this variable was found to increase the relationship between parental psychological violence and externalized behavior problems among boys. These findings suggest that interventions aimed at strengthening coping skills and social support in adolescents may not be effective in alleviating various behavioral symptoms associated with parental psychological violence. They highlight the importance of prevention of psychologically violent parental practices, instead of only reacting to the problem after it has occurred. PMID- 22829216 TI - Risk factors for domestic violence in Curacao. AB - One out of three people (25% of men, 38% of women) in Curacao have experienced some form of domestic violence at some point in their adult lives. The most significant risk factors for domestic violence in Curacao are the female gender, a young age, low education, and experiencing domestic violence victimization in childhood. Divorce, single parenthood, and unemployment increase the risk for women, but not for men. These findings are consistent with current literature on the subject. Further research on the context, nature, and severity of domestic violence in the Caribbean is necessary. Studies should preferably combine the strengths of national crime surveys and family conflict studies: nationally representative samples (including men and women) and questionnaires that include all possible experiences of psychological, physical, and sexual assaults by current and former partners, family, and friends. PMID- 22829217 TI - Facile metalation of silicon and germanium analogues of thiocarboxylic acids with a manganese(II) hydride precursor. AB - Synthesis and characterization of the first manganese(II)-containing heavier thiocarboxylate analogues, [L(Dip)Si(=S)OMnL(Dep)] (4; L(Dip)=CH[C(Me)N(2,6 iPr(2)C(6)H(3))](2), L(Dep)=CH[C(Me)N(2,6-Et(2)C(6)H(3))](2)) and [L(Dip)Ge(=S)OMnL(Dep)] (5) are described. They are accessible through reaction of the silicon and germanium analogues of the respective thiocarboxylic acids [L(Dip)E(=S)OH] (E=Si, Ge) with the beta-diketiminato (nacnac) manganese(II) hydride precursor [(L(Dep)Mn)(2)(MU-H)(2)] (3) in high yield. The first Mn nacnac hydride 3 has been prepared by the reaction of manganese bromide [(L(Dep)Mn)(2)(MU-Br)(2)] (2) with KBEt(3)H. Compounds 4 and 5 represent the first transition-metal heavier thiocarboxylates with the Si=S and Ge=S functionalities. All new compounds are paramagnetic and were characterized by elemental analysis, IR spectroscopy, MS (EI), and single-crystal X-ray diffraction analyses. Due to the N->E (E=Si, Ge) and E=S->Mn donor-acceptor interaction as well as the carboxylate-like pi-electron delocalization within the E(S)O moieties, the E=S double bonds in these compounds are resonance stabilized. PMID- 22829218 TI - Giant vesicles as cell models. AB - Tremendous progress has been made in recent years in understanding the working of the living cell, including its micro-anatomy, signalling networks, and regulation of genes. However, an understanding of cellular phenomena using fundamental laws starting from first principles is still very far away. Part of the reason is that a cell is an active and exquisitely complex system where every part is linked to the other. Thus, it is difficult or even impossible to design experiments that selectively and exclusively probe a chosen aspect of the cell. Various kinds of idealised systems and cell models have been used to circumvent this problem. An important example is a giant unilamellar vesicle (GUV, also called giant liposome), which provides a cell-sized confined volume to study biochemical reactions as well as self-assembly processes that occur on the membrane. The GUV membrane can be designed suitably to present selected, correctly-oriented cell membrane proteins, whose mobility is confined to two dimensions. Here, we present recent advances in GUV design and the use of GUVs as cell models that enable quantitative testing leading to insight into the working of real cells. We briefly recapitulate important classical concepts in membrane biophysics emphasising the advantages and limitations of GUVs. We then present results obtained over the last decades using GUVs, choosing the formation of membrane domains and cell adhesion as examples for in-depth treatment. Insight into cell adhesion obtained using micro-interferometry is treated in detail. We conclude by summarising the open questions and possible future directions. PMID- 22829219 TI - Trade-offs between biodiversity conservation and economic development in five tropical forest landscapes. AB - This study explores how conservation and development are interlinked and quantifies their reciprocal trade-offs. It identifies interventions which hold a promise to improve both conservation and development outcomes. The study finds that development trajectories can either be at the cost of conservation or can benefit conservation, but in all cases sustained poverty negatively affects conservation in the long term. Most scenarios with better outcomes for conservation come at a cost for development and the financial benefits of payments for environmental services (PES) are not sufficient to compensate for lost opportunities to earn cash. However, implementation of strategies for reducing emissions from deforestation and forest degradation in locations with low population densities come close to overcoming opportunity costs. Environmental services and subsistence income enhance the attractiveness of conservation scenarios to local people and in situations where these benefits are obvious, PES may provide the extra cash incentive to tip the balance in favor of such a scenario. The paper stresses the importance of external factors (such as industrial investments and the development of the national economy) in determining landscape scale outcomes, and suggests a negotiating and visioning role for conservation agencies. PMID- 22829220 TI - The population ecology of two tropical trees, Brachychiton diversifolius (Malvaceae) and Bombax ceiba (Bombaceae), harvested by Indigenous woodcarvers in Arnhem Land, Australia. AB - We describe the population ecology of two tropical deciduous trees, Bombax ceiba leiocarpum A. Robyns and Brachychiton diversifolius R. Br., which are in high demand for Indigenous sculpture production in Arnhem Land, Australia. We monitored tagged populations of both species at two locations for 2 years to examine their reproduction, growth, and survival rates and their response to harvest. Both species have similar life histories: they reproduce during the dry season (June-November) producing a high seed load, seed predation was high, seeds did not survive in the soil past the following wet season to form a seed bank, and germination rates were low and variable for both species. Average annual circumference growth rates were 1.07 cm year(-1) for B. ceiba and 0.98 cm year( 1) for B. diversifolius, with most of the growth occurring during the early wet season. Most (65-88 %) of the harvested B. ceiba and B. diversifolius stems coppiced. Coppice and stem size class were the main factors influencing tree growth rates with coppice stems growing up to six times faster than similar sized non-coppice stems. The survival of B. ceiba and B. diversifolius stems was size class dependent and affected by local site factors (e.g. fire and other disturbances) so that the smaller size classes had a low probability of survival. Given the resprouting potential of both species, their wild harvest is likely to have only minimal local impact on wild populations. However, further population modelling is required to determine whether the small and disjunct B. ceiba populations can sustain harvesting at current levels. PMID- 22829221 TI - Effects of grazing exclusion on soil properties and on ecosystem carbon and nitrogen storage in a sandy rangeland of Inner Mongolia, northern China. AB - The Horqin sandy rangeland of northern China is a seriously desertified region with a fragile ecology. The sandy alluvial and aeolian sediments have a coarse texture and loose structure and are therefore vulnerable to damage caused by grazing animals and wind erosion. We investigated whether grazing exclusion could enhance ecosystem carbon (C) and nitrogen (N) storage and thereby improve overall soil quality. We compared soil properties, C and N storage in biomass (aboveground and below-ground), and the total and light fraction soil organic matter between adjacent areas with continuous grazing and a 12-year grazing exclosure. The soil silt + clay content, organic C, total Kjeldahl N, available N and K, and cation-exchange capacity were significantly (P < 0.05) greater in the exclosure. We found that to a depth of 100 cm, the exclosure plots had greater light fraction C storage (by 267.2 g m(-2) = 73.3 %), light fraction N storage (by 16.6 g m(-2) = 105.7 %), total soil C storage (by 1174.4 g m(-2) = 43.9 %), and total N storage (by 91.1 g m(-2) = 31.3 %). Biomass C and N storage were also 205.0 and 8.0 g m(-2) greater (154.8 and 181.8 %, respectively). The increase was greatest in the light fraction organic matter and biomass and decreased with increasing depth in the soil. The results suggest that light fraction C and N respond more rapidly than total soil C and N to grazing exclusion and that vegetation recovers faster than soil. Our results confirmed that the degraded sandy rangeland is recovering and sequestering C after the removal of grazing pressure. PMID- 22829223 TI - Telepsychiatry in Africa -- a way forward? PMID- 22829222 TI - Liver grafts from CD39-overexpressing rodents are protected from ischemia reperfusion injury due to reduced numbers of resident CD4+ T cells. AB - Ischemia-reperfusion injury (IRI) is a major limiting event for successful liver transplantation, and CD4+ T cells and invariant natural killer T (iNKT) cells have been implicated in promoting IRI. We hypothesized that hepatic overexpression of CD39, an ectonucleotidase with antiinflammatory functions, will protect liver grafts after prolonged cold ischemia. CD39-transgenic (CD39tg) and wildtype (WT) mouse livers were transplanted into WT recipients after 18 hours cold storage and pathological analysis was performed 6 hours after transplantation. Serum levels of alanine aminotransferase and interleukin (IL)-6 were significantly reduced in recipients of CD39tg livers compared to recipients of WT livers. Furthermore, less severe histopathological injury was demonstrated in the CD39tg grafts. Immune analysis revealed that CD4+ T cells and iNKT cells were significantly decreased in number in the livers of untreated CD39tg mice. This was associated with a peripheral CD4+ T cell lymphopenia due to defective thymocyte maturation. To assess the relative importance of liver-resident CD4+ T cells and iNKT cells in mediating liver injury following extended cold preservation and transplantation, WT mice depleted of CD4+ T cells or mice genetically deficient in iNKT cells were used as donors. The absence of CD4+ T cells, but not iNKT cells, protected liver grafts from early IRI. CONCLUSION: Hepatic CD4+ T cells, but not iNKT cells, play a critical role in early IRI following extended cold preservation in a liver transplant model. PMID- 22829224 TI - Zoophilic recidivism in schizophrenia: a case report. PMID- 22829225 TI - Effectiveness and feasibility of telepsychiatry in resource constrained environments? A systematic review of the evidence. AB - OBJECTIVE: A review of systematic reviews of the effectiveness and feasibility of videoconference-based telepsychiatry services for resource constrained environments was conducted. Specifically with the aim of producing an evidence based review of the effectiveness and feasibility of videoconference-based telepsychiatry services in resource constrained countries like South Africa. METHODS: Eight key questions on telepsychiatry effectiveness and feasibility were identified and inclusion and exclusion criteria were developed. Review of citations from 2000-2011 from CINAHL, Medline, Pubmed, PsycInfo, EBSCOhost, SABINET, Cochrane Database of Systematic Reviews (CCTR), Cochrane Controlled Trial Registry (CCTR), Database of Abstracts of Reviews of Effectiveness (DARE), unpublished abstracts through NEXUS and internet search engines (Google/Google scholar) was conducted. RESULTS: Ten systematic reviews were included for review. Despite the methodological limitations and heterogeneity of the systematic reviews, there appears to be good evidence of effectiveness (reliability and improved outcomes) and feasibility (use, satisfaction, acceptability and cost) for videoconference-based telepsychiatry internationally. The application of this evidence in lower middle income countries is dependent on the integration of telepsychiatry into local health system contexts. CONCLUSION: Based on the evidence, resource constrained countries such as South Africa should be encouraged to develop telepsychiatry programs along with rigorous evaluation methods. PMID- 22829226 TI - Forensic telepsychiatry: a possible solution for South Africa? AB - OBJECTIVE: South Africa has a shortage of facilities and psychiatrists to assess adjudicative competence of prisoners awaiting assessment under sections 77 to 79 of the Criminal Procedures Act of 1977. Various solutions have been proposed by the Department of Health. The recent linking of a Magistrate's court and a prison by videoconferencing offers the opportunity to implement a forensic telepsychiatry service. The literature on forensic telepsychiatry for assessment of adjudicative competence was reviewed. METHOD: The electronic databases, PubMed, Scopus, Cinahl and Google Scholar were searched for papers on forensic telepsychiatry. The inclusion criterion was papers reporting the use of videoconferencing for assessment of adjudicative competence or for assessment for referral out of the judicial system, by psychiatrists or psychologists. RESULTS: 411 papers were found of which 13, published between 1997 and 2008 were relevant. The use of videoconferencing for forensic psychiatric assessment was reported from four countries. The courts in those jurisdictions have accepted the use of videoconferencing for assessment and no successful appeals have been mounted on the basis of the use of videoconferencing for assessment. User satisfaction has not been reported for assessing adjudicative competence. Forensic telepsychiatry has been found to be cost effective, improve access to scarce specialist skills and reduce transport of prisoners under guard to hospitals or psychiatrists to prisons. CONCLUSION: There is nothing in the literature to suggest that a forensic telepsychiatry service is not feasible in South Africa and a pilot project is being planned. PMID- 22829227 TI - Videoconference-based education for psychiatry registrars at the University of KwaZulu-Natal, South Africa. AB - OBJECTIVE: Psychiatry registrars form the backbone of specialized psychiatric service provision in South Africa. Medical schools are centralized while clinical services need to be widespread and accessible. Video-conferencing has the potential to link registrars at satellite hospitals with academic centers. The study thus evaluated of the use of videoconferencing in a Psychiatry Education Program delivered via videoconferencing. METHOD: To evaluate the implementation of the videoconference-based psychiatry registrar program, a pre- and post evaluative design was used. This involved all registrars in the 2008 and 2009 academic education program at the University of KwaZulu-Natal, South Africa. Access to education, satisfaction, suitability and costs of the psychiatry registrar education were studied. RESULTS: In the evaluation of the Registrar Program, general satisfaction with the videoconferencing program was reported, though concerns were expressed about the level of interaction using this mode, the quality of the transmitted pictures of the anatomy specimens and the quality of the sound. Access to education was improved with potential cost savings identified. CONCLUSION: Well supported and planned videoconference-based teaching is a feasible, cost-effective and acceptable method of supporting registrars at sites distant from academic centers. PMID- 22829228 TI - Developing telepsychiatry services in KwaZulu-Natal -- an action research study. AB - OBJECTIVE: In 2009, the Departments of Psychiatry and Telehealth of the University of KwaZulu-Natal (UKZN) initiated a three year project to develop telepsychiatry services in KwaZulu-Natal. This paper describes the challenges and opportunities of this project. METHOD: This was a collaborative, in situ health service project and an action research framework was adopted. Over the three years, following a needs assessment and an e-health Readiness Assessment, two action research cycles were completed. Cycle 1: The preparation, implementation and evaluation of educational material, technical requirements and clinical guidelines and clinical support materials. Cycle 2: Preparation and evaluation of educational and clinical outreach sessions. RESULTS: Videoconference education sessions were beneficial to health staff without post-qualification psychiatry training. A flexible format for education improved knowledge outcomes. Clinical sessions are feasible, but require administration and technical support for facilitation. With facilitator training, 128Kbps is a suitable bandwidth for education but 384Kbps is preferred for clinical consultation. CONCLUSION: Telepsychiatry offers tremendous potential to facilitate the three strategies suggested by the World Psychiatric Association to address the treatment gap, save time and costs and improve access to the small pool of specialist psychiatrists in resource constrained environments. PMID- 22829229 TI - A telepsychiatry model to support psychiatric outreach in the public sector in South Africa. AB - The access of rural Mental Health Care Users in South Africa to specialist psychiatrists and quality mental health care is currently sub-optimal. Health professionals and planners working in psychiatry lack a well-defined and feasible outreach model to facilitate the delivery of services to remote and rural areas. In response to this challenge, a three-year action research telepsychiatry study was undertaken by the Departments of Psychiatry and TeleHealth at the University of KwaZulu-Natal, to develop a telepsychiatry outreach model based on local research and international evidence. The Model draws on needs and infrastructure assessments of the designated psychiatric hospitals in the province, a review of the published international evidence on telepsychiatry and videoconference-based education, and an evaluation of local clinical and educational telepsychiatry implementations in KwaZulu-Natal. The Model proposed is "virtual", i.e. not bound to provincial or district referral patterns, aims not to add to the burden on the current workforce and is intended to be integrated into psychiatry outreach services and policy. The Model should be subjected to in situ testing for validation and implementation. It is hoped that an implementation of this Model will improve the access of Mental Health Care Users to specialist psychiatry care. PMID- 22829230 TI - Practice guidelines for videoconference-based telepsychiatry in South Africa. PMID- 22829231 TI - Colorectal cancer screening practices in Alabama: a survey of primary care physicians. AB - In order to inform efforts to increase screening rates for colorectal cancer (CRC), we conducted a survey of Alabama primary care physicians regarding CRC screening practices, educational preferences, and perceptions of obstacles to screening. A mail survey of 2,378 Alabama physicians in Family Medicine, Internal Medicine, and Obstetrics & Gynecology was conducted. Many physicians are not fully up-to-date with current CRC screening practices that could improve patient compliance with screening guidelines. One example is the potential use of high sensitivity stool tests, such as the fecal immunochemical test, instead of the no longer recommended low-sensitivity guaiac fecal occult blood tests. In addition, enhanced multimedia and web-based approaches to educating physicians and patients could be more fully utilized. Further, greater use of health information technologies could increase screening rates. Enhancing primary care physicians' knowledge of screening modalities and increasing their use of electronic technology could significantly improve colorectal cancer screening outcomes. PMID- 22829233 TI - The relationship between cardiac and liver iron evaluated by MR imaging in haematological malignancies and chronic liver disease. AB - Although iron overload is clinically significant, only limited data have been published on iron overload in haematological diseases. We investigated cardiac and liver iron accumulation by magnetic resonance imaging (MRI) in a cohort of 87 subjects who did not receive chelation, including 59 haematological patients. M HIC (MRI-based hepatic iron concentration, normal values <36 MUmol/g) is a non invasive, liver biopsy-calibrated method to analyse iron concentration. This method, calibrated to R2 (transverse relaxation rate), was used as a reference standard (M-HIC(R2)). Transfusions and ferritin were evaluated. Mean M-HIC(R2) and cardiac R(*) of all patients were 142 MUmol/g (95% CI, 114-170) and 36.4 1/s (95% CI, 34.2-38.5), respectively. M-HIC(R2) was higher in haematological patients than in patients with chronic liver disease or normal controls (P<0.001). Clearly elevated cardiac R2(*) was found in two myelodysplastic syndrome (MDS) patients with severe liver iron overload. A poor correlation was found between liver and cardiac iron (n=82, r=0.322, P=0.003), in contrast to a stronger correlation in MDS (n=7, r=0.905, P=0.005). In addition to transfusions, MDS seemed to be an independent factor in iron accumulation. In conclusion, the risk for cardiac iron overload in haematological diseases other than MDS is very low, despite the frequently found liver iron overload. PMID- 22829234 TI - Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations. AB - Multiple myeloma (MM) is a clinically and genetically heterogenous cancer where tumour cells have dysregulated expression of a D-type cyclin, often in association with a recurrent IgH translocation. Patients whose tumour cells express cyclin D2, with the translocation t(4;14) or t(14;16), generally have more proliferative disease and inferior outcomes. The phosphatidylinositol-3 kinase (PI3K) pathway is a major regulator of D-type cyclin expression and cell cycle entry. We evaluated the effect of PI3K pathway blockade on cell cycle behaviour in MM cells, investigating differences between cyclin D2- and cyclin D1 expressing tumours. MM cell lines and primary bone marrow CD138(+) MM cells were exposed to the pan-PI3K/mTOR inhibitor, PI-103, and assessed for cell cycle profiles, [(3)H]-thymidine uptake and cell cycle proteins. We report, in both cell lines and primary MM cells, that PI-103 induced cell cycle arrest with downregulation of cyclin D2 and CDK4/6 in MM cells expressing cyclin D2 via t(4;14) or t(14;16) translocations. Cells expressing cyclin D1 via t(11;14) were insensitive to PI-103, despite exhibiting inhibition of downstream signalling targets. In primary MM cells, PI-103 enhanced the anti-proliferative effects of anti-MM agents. Treatment paradigms including blockade of the PI3K/mTOR pathway should be targeted at patients with IgH translocations associated with cyclin D2 overexpression. PMID- 22829235 TI - Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression. AB - Calpains are intracellular cysteine proteases that have crucial roles in many physiological and pathological processes. Elevated calpain activity has been associated with many pathological states. Calpain inhibition can be protective or lethal depending on the context. Previous work has shown that c-myc transformation regulates calpain activity by suppressing calpastatin, the endogenous negative regulator of calpain. Here, we have investigated calpain activity in primary acute myelogenous leukemia (AML) blast cells. Calpain activity was heterogeneous and greatly elevated over a wide range in AML blast cells, with no correlation to FAB classification. Activity was particularly elevated in the CD34+CD38- enriched fraction compared with the CD34+CD38+ fraction. Treatment of the cells with the specific calpain inhibitor, PD150606, induced significant apoptosis in AML blast cells but not in normal equivalent cells. Sensitivity to calpain inhibition correlated with calpain activity and preferentially targeted CD34+CD38- cells. There was no correlation between calpain activity and p-ERK levels, suggesting the ras pathway may not be a major contributor to calpain activity in AML. A significant negative correlation existed between calpain activity and calpastatin, suggesting calpastatin is the major regulator of activity in these cells. Analysis of previously published microarray data from a variety of AML patients demonstrated a significant negative correlation between calpastatin and c-myc expression. Patients who achieved a complete remission had significantly lower calpain activity than those who had no response to treatment. Taken together, these results demonstrate elevated calpain activity in AML, anti-leukemic activity of calpain inhibition and prognostic potential of calpain activity measurement. PMID- 22829236 TI - Entourage: the immune microenvironment following follicular lymphoma. AB - In follicular lymphoma, nonmalignant immune cells are important. Follicular lymphoma depends on CD4+ cells, but CD8+ cells counteract it. We hypothesized that the presence of follicular lymphoma is associated with higher CD4+ than CD8+ cell numbers in the tumor microenvironment but not in the immune system. Using flow cytometry, pre-treatment and follow-up CD4/CD8 ratios were estimated in the bone marrow, blood and lymph nodes of untreated follicular lymphoma patients in two independent data sets (N(1)=121; N(2)=166). The ratios were analyzed for their relation with bone marrow lymphoma involvement. Bone marrows were also investigated with immunohistochemistry. In either data set, the bone marrow CD4/CD8 ratios were higher in bone marrows involved with lymphoma (P=0.043 and 0.0002, respectively). The mean CD4/CD8 ratio was 1.0 in uninvolved and 1.4 in involved bone marrows. Also higher in involved bone marrows were CD4/CD56 and CD3CD25/CD3 ratios. No blood or lymph node ratios differed between bone marrow negative and -positive patients. Sequential samples showed increased bone marrow CD4/CD8 ratios in all cases of progression to bone marrow involvement. Immunohistochemistry showed CD4+, CD57+, programmed death-1+, forkhead box protein 3+ and CD21+ cells accumulated inside the lymphoma infiltrates, whereas CD8+, CD56+ and CD68+ cells were outside the infiltrates. This study provides evidence in vivo that the microenvironment changes upon follicular lymphoma involvement. PMID- 22829238 TI - Drug-mediated inhibition of Fli-1 for the treatment of leukemia. AB - The Ets transcription factor, Fli-1 is activated in murine erythroleukemia and overexpressed in various human malignancies including Ewing's sarcoma, induced by the oncogenic fusion protein EWS/Fli-1. Recent studies by our group and others have demonstrated that Fli-1 plays a key role in tumorigenesis, and disrupting its oncogenic function may serve as a potential treatment option for malignancies associated with its overexpression. Herein, we describe the discovery of 30 anti Fli-1 compounds, characterized into six functional groups. Treatment of murine and human leukemic cell lines with select compounds inhibits Fli-1 protein or mRNA expression, resulting in proliferation arrest and apoptosis. This anti cancer effect was mediated, at least in part through direct inhibition of Fli-1 function, as anti-Fli-1 drug treatment inhibited Fli-1 DNA binding to target genes, such as SHIP-1 and gata-1, governing hematopoietic differentiation and proliferation. Furthermore, treatment with select Fli-1 inhibitors revealed a positive relationship between the loss of DNA-binding activity and Fli-1 phosphorylation. Accordingly, anti-Fli-1 drug treatment significantly inhibited leukemogenesis in a murine erythroleukemia model overexpressing Fli-1. This study demonstrates the ability of this drug-screening strategy to isolate effective anti-Fli-1 inhibitors and highlights their potential use for the treatment of malignancies overexpressing this oncogene. PMID- 22829237 TI - Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders. AB - Recent studies have demonstrated that one-third of known microRNAs (miRNAs) are stably detectable in plasma. Therefore, we assessed plasma miRNAs to investigate the dynamics of oncomir 17-92a, which is highly expressed in multiple myeloma (MM) patients. The plasma miR-92a level in symptomatic MM patients was significantly downregulated compared with normal subjects (P<0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. In contrast, miR-92a levels in peripheral blood CD8(+) or CD4(+) cells from MM patients were lower than those of normal subjects, and the miR-92a levels of the cells tended to correlate with plasma miR-92a levels. The plasma miR-92a level in the complete remission group became normalized, whereas the partial response (PR) and very good PR groups did not reach the normal range. In smoldering MM, the plasma miR 92a level did not show a significant difference compared with normal subjects. Our findings suggest that measurement of the plasma miR-92a level in MM patients could be useful for initiation of chemotherapy and monitoring disease status, and the level may represent, in part, the T-cell immunity status of these patients. PMID- 22829239 TI - Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations. AB - A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93-07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL. PMID- 22829240 TI - Treatment of liver metastases in patients with digestive neuroendocrine tumors. AB - BACKGROUND: Liver metastases are a strong prognostic indicator in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Therapeutic options for metastatic NETs are expanding and not mutually exclusive. AIMS: This paper reviews the literature relating to multidisciplinary approach towards GEP-NET metastases, to highlight advances in knowledge regarding these tumors, and to understand the interdisciplinary management of individual patients. METHODS: A PubMed search was performed for English-language publications from 1995 through 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for GEP-NET-related liver metastases were selected. RESULTS: There is considerable controversy regarding the optimal management of GEP-NET metastases. Although radical surgery still remains the gold standard, a variety of other therapeutic options are available for metastatic GEP-NETs, including loco regional chemotherapy/radiotherapy, radioembolization, systemic peptide receptor radionuclide therapy, biotherapy, and chemotherapy. In selected patients, liver transplantation should also be considered. Systemic somatostatin analogues and/or interferon show anti-proliferative effects, representing an appropriate first line treatment for most patients. In advanced metastatic NETs, recent options include targeted therapies (i.e., everolimus and sunitinib). CONCLUSIONS: It is evident that multidisciplinary care and multimodality treatments remain the cornerstone of management of NET patients. Since NETs often show a more indolent behavior compared to other malignancies, physicians should aim to preserve a satisfactory quality of life for the patient by personalizing the therapeutic approach according to the tumor's features and prognostic factors. PMID- 22829241 TI - Outcome after percutaneous cholecystostomy for acute cholecystitis: a single center experience. AB - BACKGROUND: Percutaneous cholecystostomy is an alternative treatment for acute cholecystitis patients with high surgical risk. METHODS: One hundred and sixty six patients consecutively treated by percutaneous cholecystostomy for acute cholecystitis in a single medical center were retrospectively reviewed. RESULTS: The cohort included 121 males and 45 females with mean age of 75.9 years. The overall inhospital mortality rate was 15.1 % (n = 25). Elevated serum creatinine level at diagnosis [odds ratio (OR) 1.497; p = 0.020], septic shock (OR 11.755; p = 0.001), and development of cholecystitis during admission (OR 7.256; p = 0.007) were predictive of inhospital mortality. Of 126 patients who recovered from calculous cholecystitis, 11 experienced recurrent cholecystitis within 2 months. Serum C-reactive protein (CRP) level >15 mg dl(-1) at diagnosis [hazard ratio (HR) 10.141; p = 0.027] and drainage duration of cholecystostomy longer than 2 weeks (HR 3.638; p = 0.039) were independent risk factors of early recurrence. The 53 patients who underwent cholecystectomy had an 18.9 % perioperative complication rate and no operation-related mortality. CONCLUSIONS: In-patients or those with septic shock or renal insufficiency have worse outcome. Prolonged drainage duration and high CRP level predict early recurrence. Removal of the drainage tube is recommended after resolution of the acute illness. PMID- 22829243 TI - Syndrome specificity and mother-child interactions: examining positive and negative parenting across contexts and time. AB - This study examined the extent to which child syndromes and observation context related to mothers' parenting behaviors. Longitudinal observations were conducted of parenting behavior across ages 3, 4, and 5 years during structured and unstructured activities. The 183 participants included mothers of children with autism spectrum disorders, cerebral palsy, Down syndrome, undifferentiated developmental delay, or typical cognitive development. Negative parenting behaviors were higher in structured activities and higher in mothers of children in all developmentally delayed groups. Positive parenting was higher in unstructured activities and especially high for mothers of children with Down syndrome. Despite differences found through direct observation of parenting children in different diagnostic groups, they are not as strong as syndrome-group differences found through more commonly used self-report questionnaires assessing domains like parenting stress. PMID- 22829244 TI - Are the autism and positive schizotypy spectra diametrically opposed in empathizing and systemizing? AB - Crespi and Badcock's (Behaviour Brain Sci 31: 241-261, 2008) novel theory, which presents autism and positive schizophrenia as diametrical opposites on a cognitive continuum, has received mixed support in the literature to date. The current study aimed to further assess the validity of this theory by investigating predictions in relation to empathizing and systemizing. Specifically, it is predicted by Crespi and Badcock that while mild autistic traits should be associated with a cognitive profile of superior mechanistic cognition (which overlaps with systemizing) but reduced mentalistic cognition (which overlaps with empathizing), positive schizotypy traits should be associated with the opposite profile of superior mentalistic but reduced mechanistic cognition. These predictions were tested in a student sample using a battery of self-report and behavioural measures. The pattern of results obtained provides no support for Crespi and Badcock's theory. PMID- 22829245 TI - Prevalence of psychotropic drug use in adults with intellectual disability: positive and negative findings from a large scale study. AB - The use of psychotropics by categories and the reason for their prescription was investigated in a large scale study of 4,069 adults with ID, including those with autism spectrum disorder, in New York State. Similar to other studies it was found that 58 % (2,361/4,069) received one or more psychotropics. Six percent received typical, while 39 % received atypical antipsychotics [corrected]. There was greater use of antidepressants (23 %), mood stabilizers (19 %), and antianxiety agents (16 %) relative to other studies. The use of anti-impulsives, stimulants and hypnotics was rare (1-2 %). Half of the psychotropics were prescribed for treatment of major psychiatric disorders, 13 % for control of challenging behaviors, and 38 % for both. Results indicated that the major psychiatric disorders, except anxiety disorder and autism, influenced the use of psychotropics and the number of medication used. These findings imply that although practitioners still rely too heavily on the use of antipsychotics in this population, there is a welcome shift in the prescription patterns relative to other studies. The practitioners appeared to use psychotropics primarily to treat diagnosed psychiatric disorders and not just to control aggressive behavior which suggests that evidence-based practice of psychiatry is playing an increasing role in the ID population. PMID- 22829246 TI - PCR artifacts can explain the reported biallelic JAK2 mutations. PMID- 22829247 TI - MicroRNA signatures in B-cell lymphomas. AB - Accurate lymphoma diagnosis, prognosis and therapy still require additional markers. We explore the potential relevance of microRNA (miRNA) expression in a large series that included all major B-cell non-Hodgkin lymphoma (NHL) types. The data generated were also used to identify miRNAs differentially expressed in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) samples. A series of 147 NHL samples and 15 controls were hybridized on a human miRNA one-color platform containing probes for 470 human miRNAs. Each lymphoma type was compared against the entire set of NHLs. BL was also directly compared with DLBCL, and 43 preselected miRNAs were analyzed in a new series of routinely processed samples of 28 BLs and 43 DLBCLs using quantitative reverse transcription-polymerase chain reaction. A signature of 128 miRNAs enabled the characterization of lymphoma neoplasms, reflecting the lymphoma type, cell of origin and/or discrete oncogene alterations. Comparative analysis of BL and DLBCL yielded 19 differentially expressed miRNAs, which were confirmed in a second confirmation series of 71 paraffin-embedded samples. The set of differentially expressed miRNAs found here expands the range of potential diagnostic markers for lymphoma diagnosis, especially when differential diagnosis of BL and DLBCL is required. PMID- 22829248 TI - Fetal programming and the risk of noncommunicable disease. AB - The "developmental origins of health and disease" (DOHaD) hypothesis proposes that environmental conditions during fetal and early post-natal development influence lifelong health and capacity through permanent effects on growth, structure and metabolism. This has been called 'programming'. The hypothesis is supported by epidemiological evidence in humans linking newborn size, and infant growth and nutrition, to adult health outcomes, and by experiments in animals showing that maternal under- and over-nutrition and other interventions (e.g., glucocorticoid exposure) during pregnancy lead to abnormal metabolism and body composition in the adult offspring. Early life programming is now thought to be important in the etiology of obesity, type 2 diabetes, and cardiovascular disease, opening up the possibility that these common diseases could be prevented by achieving optimal fetal and infant development. This is likely to have additional benefits for infant survival and human capital (e.g., improved cognitive performance and physical work capacity). Fetal nutrition is influenced by the mother's diet and body size and composition, but hard evidence that the nutrition of the human mother programmes chronic disease risk in her offspring is currently limited. Recent findings from follow-up of children born after randomised nutritional interventions in pregnancy are mixed, but show some evidence of beneficial effects on vascular function, lipid concentrations, glucose tolerance and insulin resistance. Work in experimental animals suggests that epigenetic phenomena, whereby gene expression is modified by DNA methylation, and which are sensitive to the nutritional environment in early life, may be one mechanism underlying programming. PMID- 22829249 TI - Congenital central hypoventilation syndrome with PHOX2B gene mutation: are we missing the diagnosis? AB - Congenital Central Hypoventilation Syndrome is a rare disorder of autonomic and central nervous system dysfunction with impaired control of breathing. The authors report a 37- d-old girl infant with recurrent apnea requiring repeated mechanical ventilation with no evidence of neuromuscular, cardiac or lung disease. A mutation analysis of PHOX2B gene revealed 25 polyalanine repeat expansion mutation on chromosome 4p12. This article aims at raising awareness among pediatricians about molecular basis and availability of confirmatory genetic testing for diagnosis and to help with prognosis in this disorder. PMID- 22829250 TI - Near fatal case of amlodipine poisoning in an infant. AB - An 11-mo-old infant received 12.5 times the maximum therapeutic dose of amlodipine as a result of a medication error in lieu of amoxicillin. He presented with vomiting, lethargy, breathlessness, muffled heart sounds and progressed to hypotensive shock within three hours of admission. He received mechanical ventilation, fluid therapy with normal saline and inotropes. But his parameters improved rapidly only after initiating him on insulin and dextrose infusion therapy (for 15 h) along with glucagon and calcium gluconate infusion (for 72 h). Calcium channel blockers (CCB) cause impaired insulin secretion causing hyperglycemia. High levels of blood sugar are of prognostic value rather than hemodynamic variables in CCB poisoning. A continuous infusion of 0.5 to 1 unit per kg body weight per hour of insulin along with supportive therapy including peritoneal dialysis (for deranged renal function) was used with success in managing amlodipine poisoning. PMID- 22829251 TI - Psychometric properties of the Arab Heritage Activity Card Sort. AB - The Activity Card Sort is a valid and reliable assessment tool that was created to assess Participation. It has been translated to several languages and adapted to different international cultures. The most recent version of this tool is the Arabic Heritage Activity Card Sort (A-ACS). The purpose of this study was to establish the psychometric properties of the new Arabic version in Jordanian adults. Forty three Jordanian patients with multiple sclerosis (MS) and 62 healthy adults were recruited to test the psychometric properties of the tool. The A-ACS correlated moderately with the participation index of the Mayo-Portland Adaptability Inventory (r = -0.458, p < 0.00) (concurrent validity), was able to discriminate between patients and healthy participants on the current and retained levels of participation (F = 5.09, p < 0.03; F = 6.01, p < 0.02, respectively) (discriminative validity), and correlated moderately with the total scores of the Mayo-Portland Adaptability Inventory (r = -0.458, p < 0.00) and the total score on the Arabic version of the self-report Performance Assessment of Self-care Skills (r = 0.581, p < 0.00) (convergent validity). The tool also showed good test-retest reliability (r = 0.80, p < 0.00) and excellent internal consistency (alpha = 0.90). The Arabic Heritage of the Activity Card Sort is a valid and reliable tool for Arabic-speaking occupational therapists to use when assessing participation in Jordanian patients with MS or healthy adults. Limitations of this study include using only one diagnostic group from Jordan and examining only the Recovery and Community Versions of the tool. Future studies are needed to examine further psychometric properties for patients with different diagnoses and from different countries in the Arabic region for all three versions of the A-ACS. PMID- 22829252 TI - Bulge-like asymmetric heterodye clustering in DNA duplex results in efficient quenching of background emission based on the maximized excitonic interaction. AB - Asymmetric dye clusters with a single fluorophore (Cy3) and multiple quenchers (4'-methylthioazobenzene-4-carboxylate, methyl red, and 4'-dimethylamino-2 nitroazobenzene-4-carboxylate) were prepared. The dye and one-to-five quenchers were tethered through D-threoninol to opposite strands of a DNA duplex. NMR analysis revealed that the clusters with a single fluorophore and two quenchers formed a sandwich-like structure (antiparallel H-aggregates). The melting temperatures of all the heteroclusters were almost the same, although structural distortion should become larger, as the number of quenchers increased. An asymmetric heterocluster of a single fluorophore and two quenchers showed larger excitonic interaction (i.e., hypochromicity of Cy3), than did a single Cy3 and a single quencher. Due to the larger exciton coupling between the dyes, the 1:2 heterocluster suppressed the background emission more efficiently than the 1:1 cluster. However, more quenchers did not enhance quenching efficiency due to the saturation of exciton coupling with two quenchers. Finally, this asymmetric 1:2 heterocluster was introduced into the stem region of a molecular beacon (MB; also known as an in-stem MB) targeting the fusion site in the L6 BCR-ABL fusion gene. With this MB design, the signal/background ratio was as high as 68 due to efficient suppression of background emission resulting from the maximized excitonic interaction. PMID- 22829253 TI - Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair. PMID- 22829254 TI - How to manage the transplant question in myelofibrosis. AB - Allogeneic stem cell transplantation remains the only curative therapy for myelofibrosis. Despite advances in transplant, the morbidity and the mortality of the procedure necessitate careful patient selection. In this manuscript, we describe the new prognostic scoring system to help select appropriate patients for transplant and less aggressive therapies. We explore the advances in non transplant therapy, such as with investigational agents. We review the blossoming literature on results of myeloablative, reduced intensity and alternative donor transplantation. Finally, we make recommendations for which patients are most likely to benefit from transplantation. PMID- 22829255 TI - Targeting MCL-1 sensitizes FLT3-ITD-positive leukemias to cytotoxic therapies. AB - Patients suffering from acute myeloid leukemias (AML) bearing FMS-like tyrosine kinase-3-internal tandem duplications (FLT3-ITD) have poor outcomes following cytarabine- and anthracyclin-based induction therapy. To a major part this is attributed to drug resistance of FLT3-ITD-positive leukemic cells. Against this background, we have devised an antibody array approach to identify proteins, which are differentially expressed by hematopoietic cells in relation to activated FLT3 signaling. Selective upregulation of antiapoptotic myeloid cell leukemia-1 (MCL-1) was found in FLT3-ITD-positive cell lines and primary mononuclear cells from AML patients as compared with FLT3-wild-type controls. Upregulation of MCL-1 was dependent on FLT3 signaling as confirmed by its reversion upon pharmacological inhibition of FLT3 activity by the kinase inhibitor PKC412 as well as siRNA-mediated suppression of FLT3. Heterologously expressed MCL-1 substituted for FLT3 signaling by conferring resistance of hematopoietic cells to antileukemia drugs such as cytarabine and daunorubicin, and to the proapoptotic BH3 mimetic ABT-737. Conversely, suppression of endogenous MCL-1 by siRNA or by flavopiridol treatment sensitized FLT3-ITD expressing hematopoietic cells to cytotoxic and targeted therapeutics. In conclusion, MCL-1 is an essential effector of FLT3-ITD-mediated drug resistance. Therapeutic targeting of MCL-1 is a promising strategy to overcome drug resistance in FLT3-ITD-positive AML. PMID- 22829256 TI - Application of the whole-transcriptome shotgun sequencing approach to the study of Philadelphia-positive acute lymphoblastic leukemia. AB - Although the pathogenesis of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is mainly related to the expression of the BCR-ABL1 fusion transcript, additional cooperating genetic lesions are supposed to be involved in its development and progression. Therefore, in an attempt to investigate the complex landscape of mutations, changes in expression profiles and alternative splicing (AS) events that can be observed in such disease, the leukemia transcriptome of a BCR-ABL1 positive ALL patient at diagnosis and at relapse was sequenced using a whole transcriptome shotgun sequencing (RNA-Seq) approach. A total of 13.9 and 15.8 million sequence reads was generated from de novo and relapsed samples, respectively, and aligned to the human genome reference sequence. This led to the identification of five validated missense mutations in genes involved in metabolic processes (DPEP1, TMEM46), transport (MVP), cell cycle regulation (ABL1) and catalytic activity (CTSZ), two of which resulted in acquired relapse variants. In all, 6390 and 4671 putative AS events were also detected, as well as expression levels for 18 315 and 18 795 genes, 28% of which were differentially expressed in the two disease phases. These data demonstrate that RNA-Seq is a suitable approach for identifying a wide spectrum of genetic alterations potentially involved in ALL. PMID- 22829257 TI - Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study. AB - Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4-15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O(2) therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O(2)/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O(2) hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health. PMID- 22829259 TI - DNA/polymeric micelle self-assembly mimicking chromatin compaction. PMID- 22829258 TI - Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. PMID- 22829260 TI - Does a learning curve exist in endorectal two-dimensional ultrasound accuracy? PMID- 22829261 TI - Regioselective hydration of alkynes by ironIII Lewis/Bronsted catalysis. AB - The triflimide iron(III) salt [Fe(NTf(2))(3)] promotes the direct hydration of terminal and internal alkynes with very good Markovnikov regioselectivities and high yields. The enhanced carbophilic Lewis acidity of the Fe(III) cation mediated by the weakly-coordinating triflimide anion is crucial for the catalytic activity. The iron(III) metal salt can be recycled in the form of the OPPh(3)/[Fe(NTf(2))(3)] system with similar activity and selectivity. However, spectroscopic and kinetic studies show that [Fe(NTf(2))(3)] hydrolyzes under the reaction conditions and that catalytically less active Bronsted species are formed, which points to a Lewis/Bronsted co-catalysis. This triflimide-based catalytic system is regioselective for the hydration of internal aryl-alkynes and opens the door to a new synthetic route to alkyl ketophenones. As a proof of concept, the synthesis of two antipsychotics Haloperidol and Melperone, with general butyrophenone-like structure, is shown. PMID- 22829263 TI - Are trials of intravascular infusions of autologous mesenchymal stem cells in patients with multiple system atrophy currently justified, and are they effective? PMID- 22829264 TI - Role of T cells in neuromyelitis optica. PMID- 22829265 TI - The ever-expanding spectrum of congenital muscular dystrophies. AB - Congenital muscular dystrophies are a highly heterogeneous group of conditions. In the last few years the identification of several new genes encoding for both glycosyltransferases and structural proteins has expanded the spectrum of the known forms. New classifications based on combined clinical, genetic and pathological data include all the recently discovered genes and allow an easier identification of the different forms and insight on pathogenetic mechanisms. The aim of this review is to discuss the most recent advances in this field, providing a conceptual framework to help the understanding of the responsible mechanisms and, when available, an update on the therapeutic perspectives. PMID- 22829266 TI - Oligodendrocytes and the early multiple sclerosis lesion. AB - There is little agreement among neuropathologists regarding the timing and nature of oligodendrocyte loss in multiple sclerosis (MS). This review describes changes that accompany acute oligodendrocyte loss in new lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic lesions exhibit cytopathic changes that include apoptosis of oligodendrocytes immunoreactive for caspase 3, phagocytosis of apoptotic oligodendrocytes, swelling of cells with abnormal nuclei, complement deposition, and lysis. These are nonspecific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged immunoglobulin (IgG)(+) microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood-brain barrier, and the presence of rare CD8 T cells. Myelin contacted by IgG(+) macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and gray matter plaques is scavenging activity directed at nonvital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica (NMO), including that demyelination in both is secondary to a loss of caspase 3-positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component. PMID- 22829267 TI - A randomized trial of mesenchymal stem cells in multiple system atrophy. AB - OBJECTIVE: Neuroprotective or regenerative strategies are invaluable in multiple system atrophy (MSA) due to its rapid progression with fatal prognosis. We evaluated the efficacy of autologous mesenchymal stem cells (MSC) in patients with MSA-cerebellar type (MSA-C). METHODS: Thirty-three patients with probable MSA-C and baseline unified MSA rating scale (UMSARS) scores ranging from 30 to 50 were randomly assigned to receive MSC (4 * 10(7) /injection) via intra-arterial and intravenous routes or placebo. The primary outcome was change in the total UMSARS scores from baseline throughout a 360-day follow-up period between groups. Secondary outcomes were changes in the UMSARS part II scores, cerebral glucose metabolism, gray matter density, and cognitive performance over a 360-day period. RESULTS: The mixed model analysis of neurological deficits revealed a significant interaction effect between treatment group and time, suggesting that the MSC group had a smaller increase in total and part II UMSARS scores compared with the placebo group (p = 0.047 and p = 0.008, respectively). Cerebral glucose metabolism and gray matter density at 360 days relative to the baseline were more extensively decreased in the cerebellum and the cerebral cortical areas, along with greater deterioration of frontal cognition in the placebo group compared with the MSC group. We found no serious adverse effects that were directly related to MSC treatment. However, intra-arterial infusion resulted in small ischemic lesions on magnetic resonance imaging. INTERPRETATION: MSC therapy could delay the progression of neurological deficits in patients with MSA-C, suggesting the potential of MSC therapy as a treatment candidate of MSA. PMID- 22829268 TI - Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. AB - OBJECTIVE: Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial. METHODS: One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III. RESULTS: Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p < 0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p < 0.001 for each); 3 mg/day was significantly superior to placebo on CIBIC-plus (p < 0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p < 0.001) at 5 and 10 mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups. INTERPRETATION: Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated. PMID- 22829269 TI - Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy. AB - OBJECTIVE: In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction. METHODS: Functional MRI was performed on 25 nondemented subjects with probable CAA (mean +/- standard deviation age, 70.2 +/- 7.8 years) and 12 healthy elderly controls (age, 75.3 +/- 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling). RESULTS: CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 +/- 0.28 vs 0.89 +/- 0.14; p < 0.01), prolonged time to peak (11.1 +/- 5.1 vs 6.4 +/- 1.8 seconds; p < 0.001), and prolonged time to baseline (16.5 +/- 6.7 vs 11.6 +/- 3.1 seconds; p < 0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 +/- 12.6 vs 45.0 +/- 10.0 ml/100 g/min, p = 0.8). INTERPRETATION: Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury. PMID- 22829270 TI - Seizure-induced brain-borne inflammation sustains seizure recurrence and blood brain barrier damage. AB - OBJECTIVE: Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human epileptogenic foci are known to promote seizures in animal models. We investigated whether seizures induce brain inflammation independently on extracerebral factors. We also investigated whether brain-borne inflammation is required and sufficient to maintain seizure activity and whether it causes blood brain barrier (BBB) impairment. We addressed these questions by studying the relation between seizures, inflammation, and BBB permeability in a brain preparation isolated from extracerebral compartments. METHODS: Epileptiform activity was induced by arterial perfusion of bicuculline in the in vitro isolated guinea pig brain. Seizure-induced brain inflammation was evaluated by quantitative immunohistochemical analysis of interleukin (IL)-1beta in parenchymal cells. BBB damage was assessed by extravasation of intravascular fluorescein isothiocyanate-albumin. The effects of arterially perfused anakinra, a human recombinant IL-1beta receptor antagonist, were investigated on epileptiform discharges, brain inflammation, and BBB damage. RESULTS: Seizure induction in the absence of extracerebral factors promoted the release of IL 1beta from brain resident cells and enhanced its biosynthesis in astrocytes. Anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown. INTERPRETATION: Seizures initiate brain inflammation in glia and promote BBB damage that is independent of either leukocytes or blood-borne inflammatory molecules. Brain inflammation contributes to the duration and recurrence of seizures. This study supports the use of specific anti-inflammatory drugs in clinical conditions that present with intractable recurrent seizures. PMID- 22829272 TI - Stroke recurrence in children with congenital heart disease. AB - OBJECTIVE: Pediatric arterial ischemic stroke (AIS) carries an important morbidity and mortality burden. Congenital heart disease (CHD) is among the most important risk factors for pediatric AIS. Data on stroke recurrence in childhood CHD are lacking, resulting in uncertainty regarding optimal strategies for preventing recurrence. METHODS: In the Canadian Pediatric Ischemic Stroke Registry-Toronto site, we identified children (birth to 18 years) with CHD diagnosed with AIS during 1992-2008. Data were abstracted from both stroke and cardiac surgery databases. Time-dependent outcomes (death and recurrent stroke) following sentinel stroke were parametrically modeled in competing risk analysis. Factors predicting stroke recurrence in parametric survival models were sought in parametric survival model analyses using backward variable selection of variables. RESULTS: A total of 135 patients (19 with recurrence, 116 without recurrence) were studied. In competing risk analysis, 10 years following sentinel stoke, 27% had experienced a stroke recurrence, 26% had died, and 47% were alive and free from recurrence. Stroke recurrence risk decreased over time from sentinel stroke. Approximately 50% of patients were receiving anticoagulation at recurrence. Significant factors associated with recurrence included the presence of a mechanical valve, prothrombotic condition, and an acute infection at the time of sentinel stroke. Hazard of mortality after recurrence was similar to mortality after sentinel stroke (hazard ratio, 1.3; p = 0.75). INTERPRETATION: Stroke recurrence was relatively common in neonates and children with CHD. Identified groups of patients at increased risk may require more aggressive secondary prophylaxis, especially in the early poststroke period. PMID- 22829271 TI - Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. AB - OBJECTIVE: A study was undertaken to characterize the plasticity of AMPA receptor (AMPAR)-mediated neurotransmission in the hippocampus during status epilepticus (SE). METHODS: SE was induced by pilocarpine, and animals were studied 10 minutes (refractory SE) or 60 minutes (late SE) after the onset of the first grade 5 seizures. AMPAR-mediated currents were recorded from CA1 pyramidal neurons and dentate granule cells (DGCs) by voltage clamp technique. The surface expression of GluA2 subunit on hippocampal membranes was determined using a biotinylation assay. GluA2 internalization and changes in intracellular calcium ([Ca](i)) levels were studied in hippocampal cultures using immunocytochemical and live imaging techniques. AMPAR antagonist treatment of SE was evaluated by video and electroencephalography. RESULTS: AMPAR-mediated currents recorded from CA1 neurons from refractory and late SE animals were inwardly rectifying, and philanthotoxin-sensitive; similar changes were observed in recordings obtained from DGCs from refractory SE animals. GluA2 subunit surface expression was reduced in the hippocampus during refractory and late SE. In cultured hippocampal pyramidal neurons, recurrent bursting diminished surface expression of the GluA2 subunit and enhanced its internalization rate. Recurrent bursting-induced increase in [Ca](i) levels was reduced by selective inhibition of GluA2-lacking AMPARs. GYKI-52466 terminated diazepam-refractory SE. INTERPRETATION: During SE, there is rapid, ongoing plasticity of AMPARs with the expression of GluA2-lacking AMPARs. These receptors provide another source of Ca(2+) entry into the principal neurons. Benzodiazepam-refractory SE can be terminated by AMPAR antagonism. The data identify AMPARs as a potential therapeutic target for the treatment of SE. PMID- 22829273 TI - Biophysical stimulation induces demyelination via an integrin-dependent mechanism. AB - OBJECTIVE: Chronic nerve compression (CNC) injuries occur when peripheral nerves are subjected to sustained mechanical forces, with increasing evidence implicating Schwann cells as key mediators. Integrins, a family of transmembrane adhesion molecules that are capable of intracellular signaling, have been implicated in a variety of biological processes such as myelination and nerve regeneration. In this study, we seek to define the physical stimuli mediating demyelination and to determine whether integrin plays a role in the demyelinating response. METHODS: We used a previously described in vitro model of CNC injury where myelinating neuron-Schwann cell cocultures were subjected to independent manipulations of hydrostatic pressure, hypoxia, and glucose deprivation in a custom bioreactor. We assessed whether demyelination increased in response to applied manipulation and determined whether integrin-associated signaling cascades are upregulated. RESULTS: Biophysical stimulation of neural tissue induced demyelination and Schwann cell proliferation without neuronal or glial cytotoxicity or apoptosis. Although glucose deprivation and hypoxia independently had minor effects on myelin stability, together they potentiated the demyelinating effects of hydrostatic compression, and in combination, significantly destabilized myelin. Biophysical stimuli transiently increased phosphorylation of the integrin-associated tyrosine kinase Src within Schwann cells. Silencing this integrin signaling cascade blocked Src activation and prevented pressure-induced demyelination. Colocalization analysis indicated that Src is localized within Schwann cells. INTERPRETATION: These results indicate that myelin is sensitive to CNC injury and support the novel concept that myelinating cocultures respond directly to mechanical loading via activating an integrin signaling cascade. PMID- 22829274 TI - Switching off micturition using deep brain stimulation at midbrain sites. AB - Most of the time the bladder is locked in storage mode, switching to voiding only when it is judged safe and/or socially appropriate to urinate. Here we show, in humans and rodents, that deep brain stimulation in the periaqueductal gray matter can rapidly and reversibly manipulate switching within the micturition control circuitry, to defer voiding and maintain urinary continence, even when the bladder is full. Manipulation of neural continence pathways by deep brain stimulation may offer new avenues for the treatment of urinary incontinence of central origin. PMID- 22829275 TI - Blood pressure and stroke prevention among people with cardiovascular disease. PMID- 22829278 TI - Pathogenesis of intracranial atherosclerosis. PMID- 22829282 TI - Revealing the bonding pattern from the molecular electron density using single exponential decay detector: an orbital-free alternative to the electron localization function. AB - We introduce a new tool (single exponential decay detector: SEDD) to extract information about bonding and localization in atoms, molecules, or molecular assemblies. The practical evaluation of SEDD does not require any explicit information about the orbitals. The only quantity needed is the electron density (calculated or experimental) and its derivatives up to the second order. PMID- 22829283 TI - Photobiocatalyzed asymmetric reduction of ketones using Chlorella sp. MK201. AB - Aromatic ketones were reduced using suspension culture of Chlorella sp. MK201 under fluorescent light illumination producing the corresponding chiral alcohols in high yields with excellent enantiomeric excess (ee). For example, 2',3',4',5',6'-pentafluoroacetophenone at 0.25 mg/ml was converted to the corresponding (S)-alcohol in 80 % yield with >99 % ee by 1 mg dry wt of Chlorella/ml in 12 h illumination (2,000 lux). PMID- 22829284 TI - Bovine prolactin elevates hTF expression directed by a tissue-specific goat beta casein promoter through prolactin receptor-mediated STAT5a activation. AB - Prolactin promotes the expression of exogenous human transferrin gene in the milk of transgenic mice. To elucidate this, a recombinant plasmid of bovine prolactin plus human transferrin vector was co-transfected into cultured murine mammary gland epithelial cells. Prolactin-receptor antagonist and shRNA corresponding to prolactin-receptor mRNA were added into the cell culture mixture to investigate the relations between prolactin-receptor and human transferrin expression after bovine prolactin inducement. Levels of human transferrin in the supernatants were increased under the presentation of bovine prolactin (from 1,076 +/- 115 to 1,886 +/- 114 pg/ml). With the treatment of prolactin-receptor antagonist or shRNA, human transferrin in cells was declined (1,886 +/- 113 vs. 1,233 +/- 85 pg/ml or 1,114 +/- 75 pg/ml, respectively). An inverse correlation was found between the dosage of prolactin-receptor antagonist and expression level of human transferrin. Real-time qRT-PCR analysis showed that the relative level of signal transducer and activator of transcription 5a (STAT5a) transcript in transfected cells correlated with expression levels of human transferrin in the supernatant of the same cells. Bovine prolactin thus improved the expression of human transferrin through such a possible mechanism that bovine prolactin activated STAT5a transcription expression via combined with prolactin-receptor and suggest a potential utility of the bovine prolactin for efficient expression of valuable pharmaceutical proteins in mammary glands of transgenic animals. PMID- 22829285 TI - Solid-liquid two-phase partitioning bioreactors (TPPBs) operated with waste polymers. Case study: 2,4-dichlorophenol biodegradation with used automobile tires as the partitioning phase. AB - Used automobile tire pieces were tested for their suitability as the sequestering phase in a two-phase partitioning bioreactor to treat 2,4-dichlorophenol (DCP). Abiotic sorption tests and equilibrium partitioning tests confirmed that tire "crumble" possesses very favourable properties for this application with DCP diffusivity (4.8 * 10(-8) cm(2)/s) and partition coefficient (31) values comparable to those of commercially available polymers. Biodegradation tests further validated the effectiveness of using waste tires to detoxify a DCP solution, and allow for enhanced biodegradation compared to conventional single phase operation. These results establish the potential of using a low-cost waste material to assist in the bioremediation of a toxic aqueous contaminant. PMID- 22829286 TI - Immobilization of glucansucrase for the production of gluco-oligosaccharides from Leuconostoc mesenteroides. AB - Glucansucrase from Leuconostoc mesenteroides was immobilized in 1 % (w/v) with sodium alginate to produce oligosaccharides. Glucansucrase gave three activity bands of approx. 240, 178, and 165 kDa after periodic acid-Schiff staining with sucrose. The immobilized enzyme had 40 % activity after ten batch reactions at 30 degrees C and 75 % activity after a month of storage at 4 degrees C, which is six times more stable than the free enzyme. Immobilized enzyme was more stable at lower (3.5-4.5) and higher (6.5-7.0) pH ranges and higher temperatures (35-40 degrees C) compared with the free enzyme. Immobilized and free glucansucrase were employed in the acceptor reaction with maltose and each produced gluco oligosaccharide ranging from trisaccharides to homologous pentasaccharides. PMID- 22829287 TI - Improved beta-carotene biosynthesis and gene transcription in Blakeslea trispora with arachidonic acid. AB - With 0.4 g l(-1) arachidonic acid (AA) added to the medium after 36 h fermentation, beta-carotene production in mated cultures of Blakeslea trispora was 73 % higher than that of the control at 690 mg l(-1). With the treatment of AA, the transcriptional levels of genes hmgR, carRA and carB, that are involved in carotene biosynthesis, increased by 31, 22 and 39 %, respectively. PMID- 22829288 TI - 15alpha-Hydroxylation of a steroid (13-ethyl-gon-4-en-3,17-dione) by Penicillium raistrickii in an ionic liquid/aqueous biphasic system. AB - Biphasic processes are used in whole-cell biotransformation to overcome the low water solubility of substrates and products as well as their inhibitory effects on the biocatalyst. Commercially available [NTf(2)]- and [PF(6)]-based ionic liquids (ILs) were used in a biphasic system for the 15alpha-hydroxylation of 13 ethyl-gon-4-en-3,17-dione by Penicillium raistrickii. With the substrate at 5 g l(-1) and a volume ratio of IL to buffer, buffer pH and cell density at, 1:9, 6.5, 16.8 g(DW) l(-1), respectively, the 15alpha-hydroxylation of 13-ethyl-gon-4 en-3,17-dione was achieved with a yield of 70 % after 72 h using [BMIm][NTf(2)] in a 50 ml biphasic system. This is compared to a 30 % yield in a monophasic aqueous system. This suggests the potential industrial application of ILs-based biphasic systems for steroid biotransformation. PMID- 22829289 TI - Expression signatures of intragenic miRNAs and their corresponding host genes in myeloid leukemia cells. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in gene regulation. Approximately half of miRNAs are located within known genes and called intragenic miRNAs. 408 human intragenic miRNAs and their corresponding host genes were analyzed for genomic organization and functional characterization. Using quantitative real-time PCR, the expression levels of a subset of intragenic miRNAs and their host genes were examined in diverse myeloid leukemia cell lines, and their regulation in response to pharmacological stimuli was also evaluated. Expression of miR-22 strongly correlated with both myeloid leukemia subtypes and the expression of its host gene C17orf91 (p < 0.05). The latter was absent in hematopoietic progenitors but abundant in erythroid and monocytic lineages. These results demonstrated that the expression signatures of miR-22 and C17orf91 are associated with developmental lineages and specific leukemia subtypes. PMID- 22829290 TI - Biosynthetic origin of the carbon skeleton of a novel anti-tumor compound, haloroquinone, from a marine-derived fungus, Halorosellinia sp. AB - PURPOSE OF WORK: The biosynthetic pathway of a new antitumor compound, haloroquinone, is elucidated to facilitate metabolic regulation for product accumulation and modification to produce new bioactive structural analogues of the compound. The biosynthetic origin of a novel promising protein kinase B inhibitor and anti-tumor compound, haloroquinone, from a marine-derived fungus, Halorosellinia sp. was clarified. The origin of carbon skeleton of haloroquinone was elucidated by feeding experiments with [2-(13)C]malonate and [1,2,3 (13)C(3)]malonate followed by (13)C-NMR analysis of the isolated compounds: 15 carbon atoms were derived from malonate, of which eight were from the methylene group and seven from the carboxyl group. The remaining one is probably obtained by O-methylation. Haloroquinone is thus synthesized via a polyketide pathway using malonyl-CoA as both the starter unit and the extender unit. PMID- 22829291 TI - Human liver stem cells improve liver injury in a model of fulminant liver failure. AB - Liver transplantation is currently the only effective therapy for fulminant liver failure, but its use is limited by the scarcity of organs for transplantation, high costs, and lifelong immunosuppression. Here we investigated whether human liver stem cells (HLSCs) protect from death in a lethal model of fulminant liver failure induced by intraperitoneal injection of D-galactosamine and lipopolysaccharide in SCID mice. We show that injection of HLSCs and of HLSC conditioned medium (CM) significantly attenuates mouse mortality in this model. Histopathological analysis of liver tissue showed reduction of liver apoptosis and enhancement of liver regeneration. By optical imaging we observed a preferential localization of labeled HLSCs within the liver. HLSCs were detected by immunohistochemistry in large liver vessels (at 24 hours) and in the liver parenchyma (after day 3). Fluorescence in situ hybridization analysis with the human pan-centromeric probe showed that positive cells were cytokeratin-negative at 24 hours. Coexpression of cytokeratin and human chromosome was observed at 7 and, to a lesser extent, at 21 days. HLSC-derived CM mimicked the effect of HLSCs in vivo. Composition analysis of the HLSC-CM revealed the presence of growth factors and cytokines with liver regenerative properties. In vitro experiments showed that HLSC-CM protected human hepatocytes from apoptosis and enhanced their proliferation. CONCLUSION: These data suggest that fulminant liver failure may potentially benefit from treatment with HLSCs or HLSC-CM. PMID- 22829292 TI - Does gender moderate medical students' assessments of unprofessional behavior? AB - BACKGROUND: Despite widespread acceptance of professionalism as a clinical competency, the role of certain contextual factors in assessing certain behaviors remains unknown. OBJECTIVE: To examine the potential moderating role of gender in assessing unprofessional behaviors during undergraduate medical training. DESIGN: Randomized, anonymous, self-administered questionnaire. PARTICIPANTS: Ninety seven (97) third-year students from a southeastern U.S. medical school (participation rate=95.1 %). MAIN MEASURES: Using a 4-point Likert-type scale, subjects reviewed two subsets of randomly administered, equally weighted hypothetical vignettes depicting potentially unprofessional behaviors that could occur during medical students' clinical training. Ratings were categorized from 1 -"Not a Problem" to 4 -"A Severe Problem", based on the perceived degree of unprofessionalism. In each written scenario, trainee gender was systematically varied. KEY RESULTS: Across all scenario subsets, male and female students' mean ratings of hypothetical behaviors did not differ significantly. Further, male and female students tended, on average, to rate behaviors similarly regardless of the trainee's gender. CONCLUSION: Study findings suggest that: (1) neither students' gender nor that of the hypothetical "actor" moderates the assessment of unprofessional behaviors; and (2) male and female students assign roughly the same overall rankings to potentially unprofessional behaviors. PMID- 22829293 TI - Impact of information leaflets on behavior of patients with gastroenteritis or tonsillitis: a cluster randomized trial in French primary care. AB - OBJECTIVE: To assess the impact of four patient information leaflets on patients' behavior in primary care. DESIGN: Cluster randomized multicenter controlled trial between November 2009 and January 2011. PARTICIPANTS: French adults and children consulting a participating primary care physician and diagnosed with gastroenteritis or tonsillitis. Patients were randomized to receive patient information leaflets or not, according to the cluster randomization of their primary care physician. INTERVENTION: Adult patients or adults accompanying a child diagnosed with gastroenteritis or tonsillitis were informed of the study. Physicians in the intervention group gave patients an information leaflet about their condition. Two weeks after the consultation patients (or their accompanying adult) answered a telephone questionnaire on their behavior and knowledge about the condition. MAIN MEASURES: The main and secondary outcomes, mean behavior and knowledge scores respectively, were calculated from the replies to this questionnaire. RESULTS: Twenty-four physicians included 400 patients. Twelve patients were lost to follow-up (3 %). In the group that received the patient information leaflet, patient behavior was closer to that recommended by the guidelines than in the control group (mean behavior score 4.9 versus 4.2, p < 0.01). Knowledge was better for adults receiving the leaflet than in the control group (mean knowledge score 4.2 versus 3.6, p < 0.01). There were fewer visits for the same symptoms by household members of patients given leaflets (23.4 % vs. 56.2 %, p < 0.01). CONCLUSION: Patient information leaflets given by the physician during the consultation significantly modify the patient's behavior and knowledge of the disease, compared with patients not receiving the leaflets, for the conditions studied. PMID- 22829294 TI - "Did I do as best as the system would let me?" Healthcare professional views on hospital to home care transitions. AB - BACKGROUND: Patients are vulnerable to poor quality, fragmented care as they transition from hospital to home. Few studies examine the discharge process from the perspectives of multiple healthcare professionals. OBJECTIVE: To understand care transitions from the perspective of diverse healthcare professionals, and identify recommendations for process improvement. DESIGN: Cross sectional qualitative study. PARTICIPANTS AND SETTING: Clinicians, care teams, and administrators from the inpatient general medicine services at one urban, academic hospital; two outpatient primary care clinics; and one Medicaid managed care plan. APPROACH: We conducted 13 focus groups and two in-depth interviews with participants prior to initiating a hospital-funded, multi-component transitional care intervention for uninsured and low-income publicly insured patients, the Care Transitions Innovation (C-TraIn). We used thematic analysis to identify emergent themes and a cross-case comparative analysis to describe variation by participant role and setting. KEY RESULTS: Poor transitional care reflected healthcare system fragmentation, limiting the ability of healthcare professionals to provide optimal patient care. Lack of standardized processes, poor multidisciplinary communication within the hospital, and fragmented communication across settings led to chaotic, unsystematic transitions, poor patient outcomes, and feelings of futility and dissatisfaction among providers. Patients with complex psychosocial needs were especially vulnerable during care transitions. Recommended changes to improve transitional care included improving hospital multidisciplinary hospital rounds, clarifying accountability as patients move across settings, standardizing discharge processes, and providing additional medical staff training. CONCLUSIONS: Hospital to home care transitions are critical junctures that can impact health outcomes, experience of care, and costs. Transitional care quality improvement initiatives must address system fragmentation, reduce communication barriers within and between settings, and ensure adequate professional training. PMID- 22829295 TI - The patient-centered medical home: an ethical analysis of principles and practice. AB - The patient-centered medical home (PCMH), with its focus on patient-centered care, holds promise as a way to reinvigorate the primary care of patients and as a necessary component of health care reform. While its tenets have been the subject of review, the ethical dimensions of the PCMH have not been fully explored. Consideration of the ethical foundations for the core principles of the PCMH can and should be part of the debate concerning its merits. The PCMH can align with the principles of medical ethics and potentially strengthen the patient-physician relationship and aspects of health care that patients value. Patient choice and these ethical considerations are central and at least as important as the economic and practical arguments in support of the PCMH, if not more so. Further, the ethical principles that support key concepts of the PCMH have implications for the design and implementation of the PCMH. This paper explores the PCMH in light of core principles of ethics and professionalism, with an emphasis both on how the concept of the PCMH may reinforce core ethical principles of medical practice and on further implications of these principles. PMID- 22829297 TI - Fractal dimension and Shannon's entropy analyses of the architectural complexity caused by the inflammatory reactions induced by highly crystalline poly(vinyl alcohol) microspheres implanted in subcutaneous tissues of the Wistar rats. AB - The results of the histopathological analyses after the implantation of highly crystalline PVA microspheres in subcutaneous tissues of Wistar rats are here in reported. Three different groups of PVA microparticles were systematically studied: highly crystalline, amorphous, and commercial ones. In addition to these experiments, complementary analyses of architectural complexity were performed using fractal dimension (FD), and Shannon's entropy (SE) concepts. The highly crystalline microspheres induced inflammatory reactions similar to the ones observed for the commercial ones, while the inflammatory reactions caused by the amorphous ones were less intense. Statistical analyses of the subcutaneous tissues of Wistar rats implanted with the highly crystalline microspheres resulted in FD and SE values significantly higher than the statistical parameters observed for the amorphous ones. The FD and SE parameters obtained for the subcutaneous tissues of Wistar rats implanted with crystalline and commercial microparticles were statistically similar. Briefly, the results indicated that the new highly crystalline microspheres had biocompatible behavior comparable to the commercial ones. In addition, statistical tools such as FD and SE analyses when combined with histopathological analyses can be useful tools to investigate the architectural complexity tissues caused by complex inflammatory reactions. PMID- 22829296 TI - Combining conformational sampling and selection to identify the binding mode of zinc-bound amyloid peptides with bifunctional molecules. AB - The pathogenesis of Alzheimer's disease (AD) has been suggested to be related with the aggregation of amyloid beta (Abeta) peptides. Metal ions (e.g. Cu, Fe, and Zn) are supposed to induce the aggregation of Abeta. Recent development of bifunctional molecules that are capable of interacting with Abeta and chelating biometal ions provides promising therapeutics to AD. However, the molecular mechanism for how Abeta, metal ions, and bifunctional molecules interact with each other is still elusive. In this study, the binding mode of Zn(2+)-bound Abeta with bifunctional molecules was investigated by the combination of conformational sampling of full-length Abeta peptides using replica exchange molecular dynamics simulations (REMD) and conformational selection using molecular docking and classical MD simulations. We demonstrate that Zn(2+)-bound Abeta((1-40)) and Abeta((1-42)) exhibit different conformational ensemble. Both Abeta peptides can adopt various conformations to recognize typical bifunctional molecules with different binding affinities. The bifunctional molecules exhibit their dual functions by first preferentially interfering with hydrophobic residues 17-21 and/or 30-35 of Zn(2+)-bound Abeta. Additional interactions with residues surrounding Zn(2+) could possibly disrupt interactions between Zn(2+) and Abeta, which then facilitate these small molecules to chelate Zn(2+). The binding free energy calculations further demonstrate that the association of Abeta with bifunctional molecules is driven by enthalpy. Our results provide a feasible approach to understand the recognition mechanism of disordered proteins with small molecules, which could be helpful to the design of novel AD drugs. PMID- 22829298 TI - Evaluation of detector material and radiation source position on Compton camera's ability for multitracer imaging. AB - We present a study on the effects of detector material, radionuclide source and source position on the Compton camera aimed at realistic characterization of the camera's performance in multitracer imaging as it relates to brain imaging. The GEANT4 Monte Carlo simulation software was used to model the physics of radiation transport and interactions with matter. Silicon (Si) and germanium (Ge) detectors were evaluated for the scatterer, and cadmium zinc telluride (CZT) and cerium doped lanthanum bromide (LaBr(3):Ce) were considered for the absorber. Image quality analyses suggest that the use of Si as the scatterer and CZT as the absorber would be preferred. Nevertheless, two simulated Compton camera models (Si/CZT and Si/LaBr(3):Ce Compton cameras) that are considered in this study demonstrated good capabilities for multitracer imaging in that four radiotracers within the nuclear medicine energy range are clearly visualized by the cameras. It is found however that beyond a range difference of about 2 cm for (113m)In and (18)F radiotracers in a brain phantom, there may be a need to rotate the Compton camera for efficient brain imaging. PMID- 22829299 TI - Measuring quality of life with the German Osteoporosis Quality of Life Questionnaire in women with osteoporosis. AB - OBJECTIVE: To evaluate quality of life in women suffering with osteoporosis with or without vertebral fractures for the first time with the German version of the osteoporosis quality of life questionnaire (OQLQ) and to correlate the German OQLQ with the medical outcome survey short-form health survey 36 (MOS SF-36). METHODS: In a cross-sectional study, the OQLQ and the MOS SF-36 were randomly administered to 100 postmenopausal osteoporotic women with a median age of 73.5 (quartiles 65.0; 80.0) years in order to evaluate their quality of life. RESULTS: Of the total number, 56 women had osteoporosis with at least one vertebral fracture and 44 women had osteoporosis without vertebral fracture. All items of the OQLQ as well as the MOS SF-36 showed significantly worse values for the women with vertebral fracture compared to those without vertebral fracture. Both questionnaires' domains evaluating physical wellbeing correlated strongly with each other, supporting the concept of convergent construct validity. The OQLQ domain "emotional function" showed higher correlations with different MOS SF-36 subscores than the MOS SF-36 subscore "role emotional" with the different OQLQ domains. CONCLUSION: The German version of the OQLQ was demonstrated to be feasible. Significantly, worse results in the German OQLQ for postmenopausal osteoporotic women compared to those without vertebral fracture revealed discriminant validity. The disease-targeted OQLQ seems to better reflect problems associated with low emotional wellbeing because of osteoporotic vertebral fracture. PMID- 22829300 TI - Vascular perforation by enterprise stent during stent-assisted coil embolization for intracranial aneurysm. PMID- 22829301 TI - Successful removal of a trapped biliary metallic stent delivery catheter using the percutaneous approach. PMID- 22829302 TI - Evaluation of the anti-migration effect of barbed prostatic stents: in vitro study in urethra-mimicking bovine pericardium phantoms. AB - PURPOSE: This study was designed to compare the migration rates of covered stents with eight, four, and zero barbs in urethra-mimicking bovine pericardium models. METHODS: Three types of polytetrafluoroethylene-covered retrievable self expandable prostatic stents, with eight, four, and zero barbs, were tested in bovine pericardium models, consisting of normal saline-filled acrylic containers with tubes at both ends and a replica of the human urethra. The barbs were 2 mm in length and projected 60 degrees toward the urinary bladder. The anti migration force (AMF) and resistance force against stent removal (RFSR) were measured by an automatic push-pull gauge system at a fixed rate (2 mm/s). RESULTS: Significant differences in AMF among the three stent types were detected (P < 0.001). Median AMF was far greater for eight-barbed than for four-barbed stents (11.96 vs. 7.55 N, P = 0.003). For stent removal, the difference between 4 and 8-barbed stents were not significant in median static (5.54 vs. 6.08 N, P = 0.15) or sliding (prostatic urethra, 5.32 vs. 5.59 N, P = 0.65; membranous urethra, 7.78 vs. 8.57 N, P = 0.364) RFSR. No perforations or scratched traces were observed during removal of these stents. CONCLUSIONS: The inclusion of eight barbs projecting 60 degrees toward the urinary bladder were not only effective against stent migration in this model but suggests that these stents may be suitable for the treatment of prostatic urethral strictures without severely irritating the tissue. However, whether these results translate into living urethral tissue is unclear, necessitating further studies. PMID- 22829303 TI - Comments on Reinhart et al.: consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. PMID- 22829305 TI - Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients: editors' reply to Zacharowski et al. PMID- 22829306 TI - A samarium "soluble" anode: a new source of SmI2 reagent for electrosynthetic application. PMID- 22829307 TI - A series of amino acid functionalized tripodal hexaamide anion receptors: ion pair-assisted capped-cleft formation by a pentafluorophenyl-functionalized amide. AB - A new series of tris(2-aminoethyl)amine (tren)-based L-alanine amino acid backboned tripodal hexaamide receptors (L1-L5) with various attached moieties based on electron-withdrawing fluoro groups and lipophilicity have been synthesized and characterized. Detailed binding studies of L1-L5 with different anions, such as halides (F(-), Cl(-), Br(-), and I(-)) and oxyanions (AcO(-), BzO(-) (Bz=benzoyl), NO(3)(-), H(2)PO(4)(-), and HSO(4)(-)), have been carried out by isothermal titration calorimetric (ITC) experiments in acetonitrile/dimethylsulfoxide (99.5:0.5 v/v) at 298 K. ITC titration experiments have clearly shown that receptors L1-L4 invariably form 1:1 complexes with Cl(-), AcO(-), BzO(-), and HSO(4)(-), whereas L5 forms a 1:1 complex only with AcO(-). In the case of Br(-), I(-), and NO(3)(-), no appreciable heat change is observed owing to weak interactions between these anions and receptors; this is further confirmed by (1)H NMR spectroscopy. The ITC binding studies of F(-) and H(2) PO(4)(-) do not fit well for a 1:1 binding model. Furthermore, ITC binding studies also revealed slightly higher selectivity of this series of receptors towards AcO(-) over Cl(-), BzO(-), and HSO(4)(-). Solid-state structural evidence for the recognition of Cl(-) by this new category of receptor was confirmed by single-crystal X-ray structural analysis of the complex of tetrabutylammonium chloride (TBACl) and L1. Single-crystal X-ray diffraction clearly showed that the pentafluorophenyl-functionalized amide receptor (L1) encapsulated Cl(-) in its cavity by hydrogen bonds from amides, and the cavity of L1 was capped with a TBA cation through hydrogen bonding and ion-pair interactions to form a capped-cleft orientation. To understand the role of the cationic counterpart in solution-state Cl(-) binding processes with this series of receptors (L1-L4), a detailed Cl(-) binding study was carried out with three different tetraalkylammonium (Me(4) N(+), Et(4) N(+), and Bu(4) N(+)) salts of Cl(-). The binding affinities of these receptors with different tetralkylammonium salts of Cl(-) gave binding constants with the TBA cation in the following order: butyl>ethyl>methyl. This study further supports the role of the TBA countercation in ion-pair recognition by this series of receptors. PMID- 22829309 TI - Quantifying the effect of covalently immobilized enzymes on biofilm formation by atomic force microscopy-based single-cell force spectroscopy. AB - A novel atomic force microscopy-based single-cell force spectroscopy assay to quantify the adhesion of bacterial cells to surfaces was developed. The assay was applied to quantify the effect of two biofilm-degrading enzymes, the protease Subtilisin A and glycoside hydrolase cellulase, on the attachment of the biofilm forming bacterial strain Cobetia marina. Insights on the mechanism of the initial adhesion and on the nature of the adhesion-mediating molecules were gained. The assay can be easily adapted to various other substrates, different bacterial strains and other fouling species (e.g., algae and diatoms). PMID- 22829308 TI - Measurement invariance of the SF-12 across European-American, Latina, and African American postpartum women. AB - PURPOSE: The purpose of this study was to determine whether a postpartum-specific version of the SF-12 was invariant across three ethnic groups. Specifically, we examined the presence of differential item functioning (DIF) among European American, Latina, and African-American mothers. DIF refers to differential endorsement of item responses that are not due to the construct being measured. DIF can result in biased group comparisons. METHODS: We analyzed cross-sectional data of postpartum women (n = 655) who delivered at an urban hospital in the northeast region of the USA. Multiple indicators multiple causes (MIMIC) model was used to examine differential item functioning. RESULTS: The analyses revealed the presence of DIF for three items: Item 1 "self-assessed general health," item 8 "bodily pain," and item 9 "calm and peaceful." Only two DIF effects were meaningful based on odds ratios and on the percentage of the total effect accounted for by the DIF effect. Specifically, African-American women differentially endorsed item 8 "bodily pain" when compared to European-American women (OR = 2.11, CI95 = 1.20, 3.71) and Latinas were more likely to endorse item 9 "calm and peaceful" when compared to European-American women (OR = 2.62, CI95 = 1.64, 4.17). CONCLUSION: The results of this study indicate that the SF-12 is to a great degree an invariant measure for the assessment of HRQoL among postpartum ethnically diverse women. More research is needed to examine other aspects of invariance (e.g., configural and metric) and longitudinal invariance in ethnically diverse samples. To better understand ethnic differences in health, future studies need to examine the factors that may underlie DIF effects in quality of life. PMID- 22829310 TI - Effects of griseofulvin on in vitro porcine oocyte maturation and embryo development. AB - Griseofulvin is an orally administered antifungal drug that affects microtubule formation in vitro and interferes with microtubule dynamics in vivo as clearly shown for mitotic cells in several cell systems. This article reports the effects of griseofulvin on in vitro maturation of porcine oocytes and subsequent effects on embryo development. Our results revealed a concentration-dependent effect on meiotic spindles with 20-40 MUM griseofulvin affecting oocyte maturation, and 40 MUM affecting fertilization and embryo development. These concentrations of griseofulvin did not affect mitochondrial and cortical granule distribution that also depend on microtubule and cytoskeletal functions during oocyte maturation. Specific effects on the meiotic spindle included spindle disorganization and aberrant chromosome separation displayed as prominent chromosome clusters in oocytes treated with 40 MUM griseofulvin. These results strongly suggested that griseofulvin affected porcine oocyte in vitro maturation and following embryo development by disturbing microtubule dynamics. PMID- 22829311 TI - Relaxation of the topological T1 process in a two-dimensional foam. AB - The so-called topological T1 process, during which bubbles within a foam exchange neighbours is studied. The Durand and Stone model (Phys. Rev. Lett., 97, 226101 (2006)) describes the growth of a film that is newly created during the T1 process, and also the evolution of surfactant concentration on this newly created film. Here some characteristic features of the Durand and Stone model (not previously described by Durand and Stone) are elucidated. In particular it is shown that the surfactant concentration on the newly created film is predicted to undergo an extremely rapid initial evolution, which occurs long before the film itself approaches anywhere near its final equilibrium length. Associated with this, the predicted length of the newly created film tends to exhibit an extremely rapid acceleration early on in its growth. An intermediate asymptotic analysis is developed to explain the above model predictions, by focussing on the regime when the film is several times larger than its initial length, but still several times smaller than its final length. A physical explanation is offered for these predictions in terms of slippage between material points instantaneously at the end of the newly created film, and the evolving location of the film endpoint itself: this slippage implies surfactant being transferred onto the newly created film from neighbouring films, overwhelming the amount of surfactant initially present. The implications of these predictions for the likely observations in an experimental study of the T1 process are discussed. PMID- 22829312 TI - Unresolved discrepancies between cannabinoid test results for infant urine. AB - BACKGROUND: False-positive drug screen results for tetrahydrocannabinol (THC) have been observed. This study investigated the rate of unconfirmed positive screen results in infant and noninfant urine samples and evaluated possible reasons for differences. METHODS: The rate of unconfirmed positive THC screen results for urine samples was determined retrospectively in 2 independent data sets (n = 14,859, reference laboratory; n = 21,807, hospital laboratory) by comparing positive immunoassay-based drug screen results with the associated results of confirmation tests. We then assessed the rate of positive THC screens for samples with varying likelihoods of cannabinoid presence to evaluate the contribution of infant-specific urine constituents to positive results. Finally, a method to detect a THC metabolite (11-hydroxy-Delta9-THC) that occurs in meconium was developed to determine its prevalence in infant urine. RESULTS: Positive screen results failed to confirm more frequently in samples from infants (47%) than in noninfants (0.8%). The hospital laboratory observed a similar discrepancy with a different immunoassay. Infant samples with a high likelihood of containing cannabinoids despite negative confirmatory results had a similar rate of positive screening results (50%, n = 20), whereas all samples with a low likelihood of containing cannabinoids screened negative (n = 23). 11-Hydroxy Delta9-THC was not detected in any infant urine sample tested (n = 16). CONCLUSIONS: Conventional confirmatory methods for THC may be inappropriate for urine samples from infants. Our results suggest that one or more currently unrecognized THC-associated compounds are responsible for positive THC screen results for infant urine, as opposed to an infant-associated interference. PMID- 22829313 TI - Quantifying the accuracy of a diagnostic test or marker. AB - BACKGROUND: In recent years, increasing focus has been directed to the methodology for evaluating (new) tests or biomarkers. A key step in the evaluation of a diagnostic test is the investigation into its accuracy. CONTENT: We reviewed the literature on how to assess the accuracy of diagnostic tests. Accuracy refers to the amount of agreement between the results of the test under evaluation (index test) and the results of a reference standard or test. The generally recommended approach is to use a prospective cohort design in patients who are suspected of having the disease of interest, in which each individual undergoes the index and same reference standard tests. This approach presents several challenges, including the problems that can arise with the verification of the index test results by the preferred reference standard test, the choice of cutoff value in case of a continuous index test result, and the determination of how to translate accuracy results to recommendations for clinical use. This first in a series of 4 reports presents an overview of the designs of single-test accuracy studies and the concepts of specificity, sensitivity, posterior probabilities (i.e., predictive values) for the presence of target disease, ROC curves, and likelihood ratios, all illustrated with empirical data from a study on the diagnosis of suspected deep venous thrombosis. Limitations of the concept of the diagnostic accuracy for a single test are also highlighted. CONCLUSIONS: The prospective cohort design in patients suspected of having the disease of interest is the optimal approach to estimate the accuracy of a diagnostic test. However, the accuracy of a diagnostic index test is not constant but varies across different clinical contexts, disease spectrums, and even patient subgroups. PMID- 22829314 TI - Quantitative structure-activity relationship analysis of a series of human renal organic anion transporter inhibitors. AB - Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co-administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening. PMID- 22829317 TI - Enantioselective synthesis of tertiary alpha-hydroxyketones from unfunctionalized ketones: palladium-catalyzed asymmetric allylic alkylation of enolates. PMID- 22829315 TI - RhoE is frequently down-regulated in hepatocellular carcinoma (HCC) and suppresses HCC invasion through antagonizing the Rho/Rho-kinase/myosin phosphatase target pathway. AB - Deregulation of Rho guanosine triphosphatase (GTPase) pathways plays an important role in tumorigenesis and metastasis of hepatocellular carcinoma (HCC). RhoE/Rnd3 belongs to an atypical subfamily of the RhoGTPase, the Rnd family, as it lacks the intrinsic GTPase activity and remains always in its active GTP-bound form. In this study we investigated the role of RhoE in HCC. We examined the expression of RhoE in primary HCC samples from patients predominantly infected with the hepatitis B virus (HBV) and found that the RhoE messenger RNA (mRNA) level was frequently down-regulated (83.1%, 59/71) in HCCs. Low expression of RhoE in the tumors was significantly associated with shorter disease-free survival (P = 0.020) of the patients. Knockdown of RhoE by short-hairpin RNA using a lentiviral approach led to increased cell motility and invasiveness in SMMC7721 and BEL7402 HCC cells. Moreover, in vivo an orthotopic liver injection model in nude mice further demonstrated that knockdown of RhoE enhanced local invasion of HCC cells in the livers, with more invasive tumor front and increased incidence of venous invasion. Mechanistically, stable knockdown of RhoE in HCC cells significantly enhanced the phosphorylation of myosin phosphatase, promoted assembly of stress fibers, and increased the formation of plasma membrane blebbings, all these changes and activities being associated with activation of the Rho/Rho-kinase (ROCK) pathway. CONCLUSION: RhoE was frequently down-regulated in predominantly HBV-associated HCCs and this down-regulation was associated with a more aggressive HCC phenotype. RhoE regulated the cytoskeleton remodeling and suppressed HCC motility and invasiveness by way of inhibiting the Rho/ROCK axis. PMID- 22829318 TI - Characterizing regulatory and functional differentiation between maize mesophyll and bundle sheath cells by transcriptomic analysis. AB - To study the regulatory and functional differentiation between the mesophyll (M) and bundle sheath (BS) cells of maize (Zea mays), we isolated large quantities of highly homogeneous M and BS cells from newly matured second leaves for transcriptome profiling by RNA sequencing. A total of 52,421 annotated genes with at least one read were found in the two transcriptomes. Defining a gene with more than one read per kilobase per million mapped reads as expressed, we identified 18,482 expressed genes; 14,972 were expressed in M cells, including 53 M-enriched transcription factor (TF) genes, whereas 17,269 were expressed in BS cells, including 214 BS-enriched TF genes. Interestingly, many TF gene families show a conspicuous BS preference in expression. Pathway analyses reveal differentiation between the two cell types in various functional categories, with the M cells playing more important roles in light reaction, protein synthesis and folding, tetrapyrrole synthesis, and RNA binding, while the BS cells specialize in transport, signaling, protein degradation and posttranslational modification, major carbon, hydrogen, and oxygen metabolism, cell division and organization, and development. Genes coding for several transporters involved in the shuttle of C(4) metabolites and BS cell wall development have been identified, to our knowledge, for the first time. This comprehensive data set will be useful for studying M/BS differentiation in regulation and function. PMID- 22829319 TI - Roles of four Arabidopsis U-box E3 ubiquitin ligases in negative regulation of abscisic acid-mediated drought stress responses. AB - AtPUB18 and AtPUB19 are homologous U-box E3 ubiquitin ligases in Arabidopsis (Arabidopsis thaliana). AtPUB19 is a negative regulator of abscisic acid (ABA) mediated drought responses, whereas the role of AtPUB18 in drought responses is unknown. Here, loss-of-function and overexpression tests identified AtPUB18 as a negative regulator in ABA-mediated stomatal closure and water stress responses. The atpub18-2atpub19-3 double mutant line displayed more sensitivity to ABA and enhanced drought tolerance than each single mutant plant; therefore, AtPUB18 and AtPUB19 are agonistic. Stomatal closure of the atpub18-2atpub19-3 mutant was hypersensitive to hydrogen peroxide (H(2)O(2)) but not to calcium, suggesting that AtPUB18 and AtPUB19 exert negative effects on the ABA signaling pathway downstream of H(2)O(2) and upstream of calcium. AtPUB22 and AtPUB23 are other U box E3 negative regulators of drought responses. Although atpub22atpub23 was more tolerant to drought stress relative to wild-type plants, its ABA-mediated stomatal movements were highly similar to those of wild-type plants. The atpub18 2atpub19-3atpub22atpub23 quadruple mutant exhibited enhanced tolerance to drought stress as compared with each atpub18-2atpub19-3 and atpub22atpub23 double mutant progeny; however, its stomatal behavior was almost identical to the atpub18 2atpub19-3 double mutant in the presence of ABA, H(2)O(2), and calcium. Overexpression of AtPUB18 and AtPUB19 in atpub22atpub23 effectively hindered ABA dependent stomatal closure, but overexpression of AtPUB22 and AtPUB23 in atpub18 2atpub19-3 did not inhibit ABA-enhanced stomatal closure, highlighting their ABA independent roles. Overall, these results suggest that AtPUB18 has a linked function with AtPUB19, but is independent from AtPUB22 and AtPUB23, in negative regulation of ABA-mediated drought stress responses. PMID- 22829320 TI - Unique drought resistance functions of the highly ABA-induced clade A protein phosphatase 2Cs. AB - Six Arabidopsis (Arabidopsis thaliana) clade A protein phosphatase 2Cs (PP2Cs) have established abscisic acid (ABA) signaling roles; however, phenotypic roles of the remaining three "HAI" PP2Cs, Highly ABA-Induced1 (HAI1), AKT1-Interacting PP2C1/HAI2, and HAI3, have remained unclear. HAI PP2C mutants had enhanced proline and osmoregulatory solute accumulation at low water potential, while mutants of other clade A PP2Cs had no or lesser effect on these drought resistance traits. hai1-2 also had increased expression of abiotic stress associated genes, including dehydrins and late embryogenesis abundant proteins, but decreased expression of several defense-related genes. Conversely, the HAI PP2Cs had relatively less impact on several ABA sensitivity phenotypes. HAI PP2C single mutants were unaffected in ABA sensitivity, while double and triple mutants were moderately hypersensitive in postgermination ABA response but ABA insensitive in germination. The HAI PP2Cs interacted most strongly with PYL5 and PYL7 to -10 of the PYL/RCAR ABA receptor family, with PYL7 to -10 interactions being relatively little affected by ABA in yeast two-hybrid assays. HAI1 had especially limited PYL interaction. Reduced expression of the main HAI1 interacting PYLs at low water potential when HAI1 expression was strongly induced also suggests limited PYL regulation and a role of HAI1 activity in negatively regulating specific drought resistance phenotypes. Overall, the HAI PP2Cs had greatest effect on ABA-independent low water potential phenotypes and lesser effect on classical ABA sensitivity phenotypes. Both this and their distinct PYL interaction demonstrate a new level of functional differentiation among the clade A PP2Cs and a point of cross talk between ABA-dependent and ABA-independent drought-associated signaling. PMID- 22829321 TI - Photosystem II photoinactivation, repair, and protection in marine centric diatoms. AB - Diatoms are important contributors to aquatic primary production, and can dominate phytoplankton communities under variable light regimes. We grew two marine diatoms, the small Thalassiosira pseudonana and the large Coscinodiscus radiatus, across a range of temperatures and treated them with a light challenge to understand their exploitation of variable light environments. In the smaller T. pseudonana, photosystem II (PSII) photoinactivation outran the clearance of PSII protein subunits, particularly in cells grown at sub- or supraoptimal temperatures. In turn the absorption cross section serving PSII photochemistry was down-regulated in T. pseudonana through induction of a sustained phase of nonphotochemical quenching that relaxed only slowly over 30 min of subsequent low light incubation. In contrast, in the larger diatom C. radiatus, PSII subunit turnover was sufficient to counteract a lower intrinsic susceptibility to photoinactivation, and C. radiatus thus did not need to induce sustained nonphotochemical quenching under the high-light treatment. T. pseudonana thus incurs an opportunity cost of sustained photosynthetic down-regulation after the end of an upward light shift, whereas the larger C. radiatus can maintain a balanced PSII repair cycle under comparable conditions. PMID- 22829322 TI - Photosynthetic adaptation to length of day is dependent on S-sulfocysteine synthase activity in the thylakoid lumen. AB - Arabidopsis (Arabidopsis thaliana) chloroplasts contain two O-acetyl serine(thiol)lyase (OASTL) homologs, OAS-B, which is an authentic OASTL, and CS26, which has S-sulfocysteine synthase activity. In contrast with OAS-B, the loss of CS26 function resulted in dramatic phenotypic changes, which were dependent on the light treatment. We have performed a detailed characterization of the photosynthetic and chlorophyll fluorescence parameters in cs26 plants compared with those of wild-type plants under short-day growth conditions (SD) and long-day growth conditions (LD). Under LD, the photosynthetic characterization, which was based on substomatal CO(2) concentrations and CO(2) concentration in the chloroplast curves, revealed significant reductions in most of the photosynthetic parameters for cs26, which were unchanged under SD. These parameters included net CO(2) assimilation rate, mesophyll conductance, and mitochondrial respiration at darkness. The analysis also showed that cs26 under LD required more absorbed quanta per driven electron flux and fixed CO(2). The nonphotochemical quenching values suggested that in cs26 plants, the excess electrons that are not used in photochemical reactions may form reactive oxygen species. A photoinhibitory effect was confirmed by the background fluorescence signal values under LD and SD, which were higher in young leaves compared with mature ones under SD. To hypothesize the role of CS26 in relation to the photosynthetic machinery, we addressed its location inside of the chloroplast. The activity determination and localization analyses that were performed using immunoblotting indicated the presence of an active CS26 enzyme exclusively in the thylakoid lumen. This finding was reinforced by the observation of marked alterations in many lumenal proteins in the cs26 mutant compared with the wild type. PMID- 22829323 TI - Percutaneous image-guided implantation of totally implantable venous access ports in the forearm or the chest? A patients' point of view. AB - PURPOSE: This study aimed to compare patients' satisfaction and impact on daily life after implantation of totally implantable venous access ports (TIVAP) in the forearm and the chest. METHODS: In this prospective study, 50 patients (mean age, 55.8 +/- 15.4 years) received three questionnaires on days 1, 30, and 90 after implantation in the forearm (n = 25) or the chest (n = 25). Knowledge concerning device function, comfort perception, and impact of TIVAP on daily activities were evaluated. Ratings were dichotomized depending on whether statements were agreed with or contradicted. Fisher's exact test was used to determine differences between the forearm port (FP) and chest port (CP) groups. RESULTS: There was no significant difference between the two groups with regard to unpleasant feelings (p = 0.09) and discomfort while puncturing (p = 0.06). Main fears in both groups were dysfunction and infection. The possibility of high-pressure injections via the TIVAP was rated important in both groups. More CP patients feared dislocation of their TIVAP during sleep (p < 0.05). CP patients experienced more negative perceptions while driving a car and wearing brassieres (p < 0.05) than FP patients. All patients would recommend their device. CONCLUSIONS: During certain activities, the FP device seems to be favorable, since it causes less discomfort than the CP. PMID- 22829324 TI - Mapping human dimensions of climate change research in the Canadian Arctic. AB - This study maps current understanding and research trends on the human dimensions of climate change (HDCC) in the eastern and central Canadian Arctic. Developing a systematic literature review methodology, 117 peer reviewed articles are identified and examined using quantitative and qualitative methods. The research highlights the rapid expansion of HDCC studies over the last decade. Early scholarship was dominated by work documenting Inuit observations of climate change, with research employing vulnerability concepts and terminology now common. Adaptation studies which seek to identify and evaluate opportunities to reduce vulnerability to climate change and take advantage of new opportunities remain in their infancy. Over the last 5 years there has been an increase social science-led research, with many studies employing key principles of community based research. We currently have baseline understanding of climate change impacts, adaptation, and vulnerability in the region, but key gaps are evident. Future research needs to target significant geographic disparities in understanding, consider risks and opportunities posed by climate change outside of the subsistence hunting sector, complement case study research with regional analyses, and focus on identifying and characterizing sustainable and feasible adaptation interventions. PMID- 22829325 TI - Distinct features between longitudinally extensive transverse myelitis presenting with and without anti-aquaporin 4 antibodies. AB - OBJECTIVES: Longitudinally extensive transverse myelitis (LETM) with spinal cord lesions spanning three or more vertebral segments is a key feature of neuromyelitis optica (NMO). However, the role of anti-aquaporin 4 (anti-AQP4) antibody, a sensitive biomarker of NMO, in the conversion of LETM to NMO remains uncertain. METHODS: Thirty first-ever LETM patients were retrospectively analysed and divided into two groups according to the presence of anti-AQP4 antibodies. RESULTS: Eighteen (60%) patients presented with anti-AQP4 antibodies. Fifteen (83.33%) anti-AQP4 (+) LETM patients converted to NMO, while only three of 12 (25%, p = 0.002) anti-AQP4 (-) LETM patients progressed to NMO, over a mean follow-up period of 5.63 years. Seven (38.89%) anti-AQP4 (+) and one (8.33%) anti AQP4 (-) LETM patients received interferon-beta1a treatment, respectively. Anti AQP4 (+) LETM patients demonstrated a higher immunogamma globulin (IgG) index (0.68 +/- 0.43 versus 0.47 +/- 0.19, p = 0.018), annual relapse rate (0.72 +/- 0.31 versus 0.42 +/- 0.17, p = 0.01) and Kurtzke Expanded Disability Status Scale (4.28 +/- 2.22 versus 2.67 +/- 2.26, p = 0.031), than anti-AQP4 (-) LETM patients. In spinal magnetic resonance imaging (MRIs), more than half (58.33%) of the anti-AQP4 (+) LETM patients were observed to have central grey matter predominant involvement in the axial view, while peripheral white matter predominant involvement (51.85%) was the most common pattern observed in the anti AQP4 (-) LETM patients. CONCLUSION: Anti-AQP4 (+) LETM demonstrated a high conversion rate to NMO (83.33%), suggesting that anti-AQP4 (+) LETM may represent an early, isolated syndrome of NMO spectrum disorder. The greater number of patients receiving interferon-beta treatment in anti-AQP4 (+) LETM may contribute to its high annual relapse rate. PMID- 22829326 TI - Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases. AB - The objective of this article is to report our experience on fingolimod suspension in multiple sclerosis patients. We evaluated clinical and magnetic resonance (MR) outcomes in six patients after fingolimod discontinuation. Within three months from fingolimod suspension, five subjects returned to pre-treatment disease activity; one patient, however, exhibited a clear rebound of clinical and MR activity. Our findings suggest that clinical and MR outcomes after fingolimod suspension can vary among patients. Systematic collection of clinical, laboratory and imaging data is highly advisable to identify subjects who are at higher risk of rebound and to define effective management strategies in these subjects. PMID- 22829327 TI - Nucleation-controlled distributed plasticity in penta-twinned silver nanowires. AB - A unique size-dependent strain hardening mechanism, that achieves both high strength and ductility, is demonstrated for penta-twinned Ag nanowires (NWs) through a combined experimental-computational approach. Thin Ag NWs are found to deform via the surface nucleation of stacking fault decahedrons (SFDs) in multiple plastic zones distributed along the NW. Twin boundaries lead to the formation of SFD chains that locally harden the NW and promote subsequent nucleation of SFDs at other locations. Due to surface undulations, chain reactions of SFD arrays are activated at stress concentrations and terminated as local stress decreases, revealing insensitivity to defects imparted by the twin structures. Thick NWs exhibit lower flow stress and number of distributed plastic zones due to the onset of necking accompanied by more complex dislocation structures. PMID- 22829328 TI - Sensitive near-infrared fluorescent probes for thiols based on Se-N bond cleavage: imaging in living cells and tissues. AB - Cy-NiSe and Cy-TfSe were designed and synthesized as sensitive near-infrared (NIR) fluorescent probes for detecting thiols on the basis of Se-N bond cleavage both in cells and in tissues. Since a donor-excited photoinduced electron transfer (d-PET) process occurs between the modulator and the fluorophore, Cy NiSe and Cy-TfSe have weak fluorescence. On titration with glutathione, the free dye exhibits significant fluorescence enhancement. The two probes are sensitive and selective for thiols over other relevant biological species. They can function rapidly at pH 7.4, and their emission lies in the NIR region. Confocal imaging confirms that Cy-NiSe and Cy-TfSe can be used for detecting thiols in living cells and tissues. PMID- 22829329 TI - TKA outcomes after prior bone and soft tissue knee surgery. AB - PURPOSE: Bone surgery around the knee joint could represent a more traumatic prior surgical procedure compared to soft tissue knee surgery and may predispose to differing postoperative total knee arthroplasty (TKA) outcomes. The objective of this study was to analyse the postoperative results as well as complications and failures in two groups of patients that had undergone knee surgery prior to primary TKA (bone surgery and soft tissue surgery) when compared to the no prior surgery group. METHODS: A retrospective and cohort series of 1,474 primary TKA were evaluated at minimum follow-up period of 2 years: 1,119 primary TKA underwent no prior surgery (1,119 patients) (group A), 85 primary TKA (85 patients) (group B) had prior bone procedure [high tibial osteotomy (n = 64), tibial plateau fracture (n = 10) and patellar realignment (n = 11)], and third group of 146 primary TKA (146 patients) (group C) had undergone a soft tissue procedure [arthroscopy (n = 60) and menisectomy (n = 86)] before primary TKA. All the patients underwent a clinical and radiological evaluation as well as International Knee Society (IKS) scores. RESULTS: Preoperatively, group B had 40 % of cases classified as stage IV knee arthritis (p < 0.02); while 57 % of cases in group A showed higher levels of knee malalignment (p = 0.001) and group C had lower BMI (p = 0.001). Intraoperative complications revealed no difference. Although group B had the poorest postoperative mean values of knee flexion, TKA procedure improved the preoperative mean values of knee flexion in all the study groups. The postoperative complications were more prevalent in group C (p < 0.001), while the percentage of revision TKA was similar for all study groups (p = 0.5). At 120-month follow-up, the Kaplan-Meier survival curve rates showed no difference (p = 0.29). CONCLUSION: This study confirms that prior knee surgery could be considered a clinical condition predisposed to higher postoperative complication rate in primary TKA compared to the no prior surgery group. After analysing the three study groups, group C showed a higher rate of postoperative local complications and lower IKS knee scores, while the group B showed the poorest postoperative mean values of knee flexion as well as the need for extended surgical approach (TTO approach) was more prevalent in this study group. However, statistical analysis did not reveal a direct correlation between the type of prior knee surgery and TKA failures. PMID- 22829331 TI - Comparison of two methods for designing calorimeters using stirred tank reactors. AB - Calorimetry is a robust method for online monitoring and controlling bioprocesses in stirred tank reactors. Up to now, reactor calorimeters have not been optimally constructed for pilot scale applications. Thus, the objective of this paper is to compare two different ways for designing reactor calorimeters and validate them. The "heat capacity" method based on the mass flow of the cooling liquid in the jacket was compared with the "heat transfer" method based on the heat transfer coefficient continuously measured in the cultivation of Escherichia coli VH33 in a 50 L stirred tank reactor. It was found that the values of the "heat transfer" method agreed very well with the calculated values from the oxygen consumption. By contrast, the curve of the "heat capacity" method deviated from that of the oxygen consumption calculated with the oxycaloric equivalent. In conclusion, the "heat transfer" method has been proven to have a higher degree of validity than the "heat capacity" method. Thus, it is a better and more robust means to measure heat generation of fermentations in stirred tank bioreactors on a pilot scale. PMID- 22829330 TI - Histological scoring systems for tissue-engineered, ex vivo and degenerative meniscus. AB - PURPOSE: Because its function is strictly related to the quality of meniscal tissue, one of the most important outcome measures for the evaluation of meniscal repair effectiveness is the assessment of histological features. Data on the validation and application of the histological scoring systems in research settings and specific fields of meniscal disorders are lacking. The available histological scoring systems to assess meniscal tissue were systematically evaluated. METHODS: Histological scoring systems for the analysis of degenerative meniscal changes, ex vivo and tissue-engineered meniscal repair were reviewed. Furthermore, the validity and applicability of the scoring systems were assessed. RESULTS: The Copenhaver classification and Mankin score have been modified to classify the degeneration of collagen bundles in the meniscal structure. The Pauli score seems to be a comprehensive and simple scoring system for the evaluation of both macroscopic and histologic meniscal changes related to ageing and osteoarthritic degeneration. The Zhang score may be used for ex vivo gene therapy in meniscus healing. The Ishida score seems to be the most adequate for the evaluation of tissue-engineered meniscal repair. CONCLUSION: Although several histological scoring systems are available to assess meniscal structure, only few of them have been validated for specific application in research settings. Validated scores are required to provide a standardized data collection to allow the comparison of results of different research groups. Further experimental and clinical studies are needed to find a comprehensive and validated histological scoring system in the field of meniscus repair. LEVEL OF EVIDENCE: Systematic review of Level III studies, Level III. PMID- 22829334 TI - A stand-alone mesoporous crystal structure model from in situ X-ray diffraction: nitrogen adsorption on 3D cagelike mesoporous silica SBA-16. AB - We present a modeling scheme to analyze cagelike silica mesoporous crystals based on in situ X-ray diffraction (XRD) data collected during gas adsorption desorption (physisorption) processes. Nitrogen physisorption on a silica mesoporous crystal of SBA-16 was directly monitored by using synchrotron in situ powder XRD measurements conducted at SPring-8. SBA-16 is a well-ordered mesoporous silica in which three-dimensional interconnected cagelike primary mesopores are located at the body-centered cubic lattice points. In addition, the surrounding silica matrix contains random microporous and mesoporous intrawall porosities that are significantly influential to the diffusion properties, and thus important to be quantified for this media. The in situ XRD data exhibits seven Bragg reflections throughout the measurements, and the present method allows one to obtain the maximal and stand-alone information about the pore structure (for example, the mesopore size, the matrix density, the intrawall porosity, and pore surface roughness) together with the nitrogen film evolution in the primary mesopores and the intrawall pore-filling in the silica matrix. We furthermore observe a macroscopic amount of nitrogen adsorbed assuming the density of the fluid, and confirm that the XRD "isotherm" recalculated from the analysis result is consistent with the conventional nitrogen isotherm on a semi quantitative level; however, these results suggest that the intrawall pores would have a greater contribution to the adsorption than considered based on the conventional isotherm analyses. The present method is readily extendable to any ordered mesopores wrapped by the wall matrix containing a certain intrawall porosity. PMID- 22829332 TI - Occult HBV infection. AB - The long-lasting persistence of hepatitis B virus (HBV) genomes in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for the HBV surface antigen (HBsAg) is termed occult HBV infection (OBI). Although in a minority of cases the lack of HBsAg detection is due to infection with variant viruses unrecognized by available assays (S-escape mutants), the typical OBI is related to replication-competent HBVs strongly suppressed in their replication activity. The causes of HBV suppression are not yet well clarified, although the host's immune surveillance and epigenetic mechanisms are likely involved. OBI is a worldwide diffused entity, but the available data of prevalence in various categories of individuals are often contrasting because of the different sensitivity and specificity of the methods used for its detection in many studies. OBI may have an impact in several different clinical contexts. In fact, it can be transmitted (i.e., through blood transfusion and liver transplantation) causing classic forms of hepatitis B in newly infected individuals. The development of an immunosuppressive status (mainly by immunotherapy or chemotherapy) may induce OBI reactivation and development of acute and often severe hepatitis. Finally, evidence suggests that OBI can favor the progression of liver fibrosis, in particular in HCV-infected patients. The possible contribution of OBI to the establishment of cirrhosis also implies its possible indirect role in the development of hepatocellular carcinoma. On the other hand, OBI may maintain most of the direct transforming properties of the overt HBV infection, such as the capacity to integrate in the host's genome and to synthesize pro-oncogenic proteins. PMID- 22829335 TI - Helical folding of conjugated oligo(phenyleneethynylene): chain-length dependence, solvent effects, and intermolecular assembly. AB - As a representative folding system that features a conjugated backbone, a series of monodispersed (o-phenyleneethynylene)-alt-(p-phenyleneethynylene) (PE) oligomers of varied chain length and different side chains were studied. Molecules with the same backbone but different side-chain structures were shown to exhibit similar helical conformations in respectively suitable solvents. Specifically, oligomers with dodecyloxy side chains folded into the helical structure in apolar aliphatic solvents, whereas an analogous oligomer with tri(ethylene glycol) (Tg) side chains adopted the same conformation in polar solvents. The fact that the oligomers with the same backbone manifested a similar folded conformation independent of side chains and the nature of the solvent confirmed the concept that the driving force for folding was the intramolecular aromatic stacking and solvophobic interactions. Although all were capable of inducing folding, different solvents were shown to bestow slightly varied folding stability. The chain-length dependence study revealed a nonlinear correlation between the folding stability with backbone chain length. A critical size of approximately 10 PE units was identified for the system, beyond which folding occurred. This observation corroborated the helical nature of the folded structure. Remarkably, based on the absorption and emission spectra, the effective conjugation length of the system extended more effectively under the folded state than under random conformations. Moreover, as evidenced by the optical spectra and dynamic light-scattering studies, intermolecular association took place among the helical oligomers with Tg side chains in aqueous solution. The demonstrated ability of such a conjugated foldamer in self-assembling into hierarchical supramolecular structures promises application potential for the system. PMID- 22829333 TI - HCV in liver transplantation. AB - HCV-related cirrhosis represents the leading indication for liver transplantation in the Western countries. HCV reinfection after liver transplantation occurs in virtually all patients transplanted for HCV-related liver disease Histological evidence of chronic HCV infection develops in 50 to 90 % of patients by 12 months after liver transplantation, and cirrhosis occurs in about 20 % of patients within 5 years after transplant. Several studies have evaluated host, viral, and transplant-related factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy. Donor age, steatosis, and immunogenetic factors are also relevant in determining the outcome in patients transplanted for HCV-related cirrhosis. A major step to prevent complications of HCV recurrence related to the rapid fibrosis is the posttransplant antiviral treatment. Two strategies have been tried: pre-emptive or other strategies as soon as possible after liver transplantation or elective therapy once there is histological evidence of recurrent hepatitis C. Retransplantation due to graft failure from recurrent hepatitis C is rarely an option in the era of organ shortage as it is associated with poor outcome, but many case needs to be considered early in the evolution of disease. New antivirals may change the outcome dramatically of patients transplanted for HCV cirrhosis. PMID- 22829336 TI - Ectopic expression of Kxhkn5 in the viviparous species Kalanchoe * Houghtonii induces a novel pattern of epiphyll development. AB - KxhKN5 (class 1 KNOX gene) was cloned from Kalanchoe * houghtonii with strong tendency to form epiphylls on leaves. KxhKN5 appear to be homologue of BP of A. thaliana on the basis of phylogeny, expression and phenotype analysis. Beside the modification of several plant and leaf traits, the appearance of epiphylls was drastically reduced by both the silencing and the over-expression of KxhKN5 in most of the generated clones. In silenced clones, epiphyll production followed the morphogenetic pathway of the WT plants: somatic embryos outbreak in the centre of each leaf-pedestal, grown in the notch between leaf indentations and were supported by a suspensor. The connection between the epiphyll and the mother plant did not include any vasculature and as a result, the epiphylls dropped easily from the mother plant. The most represented category of over expressor clones, disclosed a novel pattern of epiphyll development: the leaf-pedestals were absent and single bud outbreaks in each leaf notch. Buds developed into shoots which remained attached to the maternal plant by a strong vascular connection. The leaves supporting shoots, produced a thickened midrib and veins, and their lamina ceased expanding. Finally, the leaf/shoot structure resembles a lateral branch. The ectopic expression of KxhKN5 in K. * houghtonii induces a process comparable to the alternation of leaf and shoot formation in other species and support the idea, that it is the variation in shared molecular and developmental processes which produces the growth of specific structures. PMID- 22829337 TI - Synthesis and antimicrobial activities of a novel series of heterocyclic alpha aminophosphonates. AB - Two series of novel alpha-aminophosphonates having heterocyclic moieties were synthesized in high yields. The structures of the newly synthesized compounds were confirmed by their elemental analyses, IR, (1)H NMR and MS spectral data. These compounds were screened for their antibacterial activities against Escherichia coli (NCIM2065) as a Gram-negative bacterium, Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram-positive bacteria, and Candida albicans and Saccharomyces cerevisiae as fungi. The minimum inhibitory concentrations (MICs) of the synthesized compounds show high antibacterial and antifungal activities at low concentrations (10-1000 ug/mL). Furthermore, their lethal doses indicated that such compounds are safe for use as antimicrobial agents. PMID- 22829338 TI - Response to commentary: "Re-evaluation of the Big Blue(r) mouse assay of propiconazole suggests lack of mutagenicity". PMID- 22829339 TI - Testing goodness of fit in regression: a general approach for specified alternatives. AB - When fitting generalized linear models or the Cox proportional hazards model, it is important to have tools to test for lack of fit. Because lack of fit comes in all shapes and sizes, distinguishing among different types of lack of fit is of practical importance. We argue that an adequate diagnosis of lack of fit requires a specified alternative model. Such specification identifies the type of lack of fit the test is directed against so that if we reject the null hypothesis, we know the direction of the departure from the model. The goodness-of-fit approach of this paper allows to treat different types of lack of fit within a unified general framework and to consider many existing tests as special cases. Connections with penalized likelihood and random effects are discussed, and the application of the proposed approach is illustrated with medical examples. Tailored functions for goodness-of-fit testing have been implemented in the R package global test. PMID- 22829341 TI - Monodisperse poly(lactide-co-glycolic acid)-based nanocarriers for gene transfection. AB - This contribution describes a simple, aerosol-based method for fabricating monodisperse particles containing mixtures of poly(lactide-co-glycolic acid) [PLGA], protamine sulfate (Prot), and poly(l-lysine) [PLL] as nanocarriers for gene transfection. Aqueous solutions of PLGA, Prot, and PLL were collison atomized, and the resulting aerosolized droplets were dried "on the fly" to form solid particles, which then were electrostatically size-classified into 50, 100, and 200 nm mobility diameter samples. Measurements of cell viability and transfection reveal that the fabricated nanocarriers have a lower cytotoxicity (>85% in cell viability) and a higher transfection efficiency [>8.7 * 10(5) in relative light units (RLU) mg(-1) ] than does 25 kDa polyethyleneimine (~50% and 6.8 * 10(5) RLU mg(-1) ). PMID- 22829340 TI - Effect of moderate-intensity work rate increment on phase II tauVO2, functional gain and Delta[HHb]. AB - This study systematically examined the role of work rate (WR) increment on the kinetics of pulmonary oxygen uptake (VO(2p)) and near-infrared spectroscopy (NIRS)-derived muscle deoxygenation (Delta[HHb]) during moderate-intensity (Mod) cycling. Fourteen males (24 +/- 5 years) each completed four to eight repetitions of Mod transitions from 20 to 50, 70, 90, 110 and 130 W. VO(2p) and Delta[HHb] responses were modelled as a mono-exponential; responses were then scaled to a relative % of the respective response (0-100 %). The Delta[HHb]/VO(2) ratio was calculated as the average Delta[HHb]/VO(2) during the 20-120 s period of the on transient. When considered as a single group, neither the phase II VO(2p) time constant (tauVO(2p); 27 +/- 9, 26 +/- 11, 25 +/- 10, 27 +/- 14, 29 +/- 13 s for 50-130 W transitions, respectively) nor the Delta[HHb]/VO(2) ratio (1.04 +/- 0.13, 1.10 +/- 0.13, 1.08 +/- 0.07, 1.09 +/- 0.11, 1.09 +/- 0.09, respectively) was affected by WR (p > 0.05); yet, the VO(2) functional gain (G; DeltaVO(2)/DeltaWR) increased with increasing WR transitions (8.6 +/- 1.3, 9.1 +/ 1.2, 9.5 +/- 1.0, 9.5 +/- 1.0, 9.9 +/- 1.0 mL min(-1) W(-1); p < 0.05). When subjects were stratified into two groups [Fast (n = 6), tauVO(2p130W) < 25 s < tauVO(2p130W), Slower (n = 8)], a group by WR interaction was observed for tauVO(2p). The increasing functional G persisted (p < 0.05) and did not differ between groups (p > 0.05). The Delta[HHb]/VO(2) ratio was smaller (p < 0.05) in the Fast than Slower group, but was unaffected by WR. In conclusion, the present study demonstrated (1) a non-uniform effect of Mod WR increment on tauVO(2p); (2) that tauVO(2p) in the Slower group is likely determined by an O(2) delivery limitation; and (3) that increasing Mod WR increments elicits an increased functional G, regardless of the tauVO(2p) response. PMID- 22829342 TI - On the discrepant results in synchrony judgment and temporal-order judgment tasks: a quantitative model. AB - Research on the perception of temporal order uses either temporal-order judgment (TOJ) tasks or synchrony judgment (SJ) tasks, in both of which two stimuli are presented with some temporal delay and observers must judge the order of presentation. Results generally differ across tasks, raising concerns about whether they measure the same processes. We present a model including sensory and decisional parameters that places these tasks in a common framework that allows studying their implications on observed performance. TOJ tasks imply specific decisional components that explain the discrepancy of results obtained with TOJ and SJ tasks. The model is also tested against published data on audiovisual temporal-order judgments, and the fit is satisfactory, although model parameters are more accurately estimated with SJ tasks. Measures of latent point of subjective simultaneity and latent sensitivity are defined that are invariant across tasks by isolating the sensory parameters governing observed performance, whereas decisional parameters vary across tasks and account for observed differences across them. Our analyses concur with other evidence advising against the use of TOJ tasks in research on perception of temporal order. PMID- 22829344 TI - Probing the barrier for internal rotation of the retinal chromophore. PMID- 22829343 TI - Is the Web as good as the lab? Comparable performance from Web and lab in cognitive/perceptual experiments. AB - With the increasing sophistication and ubiquity of the Internet, behavioral research is on the cusp of a revolution that will do for population sampling what the computer did for stimulus control and measurement. It remains a common assumption, however, that data from self-selected Web samples must involve a trade-off between participant numbers and data quality. Concerns about data quality are heightened for performance-based cognitive and perceptual measures, particularly those that are timed or that involve complex stimuli. In experiments run with uncompensated, anonymous participants whose motivation for participation is unknown, reduced conscientiousness or lack of focus could produce results that would be difficult to interpret due to decreased overall performance, increased variability of performance, or increased measurement noise. Here, we addressed the question of data quality across a range of cognitive and perceptual tests. For three key performance metrics-mean performance, performance variance, and internal reliability-the results from self-selected Web samples did not differ systematically from those obtained from traditionally recruited and/or lab-tested samples. These findings demonstrate that collecting data from uncompensated, anonymous, unsupervised, self-selected participants need not reduce data quality, even for demanding cognitive and perceptual experiments. PMID- 22829345 TI - Gastric hypochlorhydria is associated with an exacerbation of dyspeptic symptoms in female patients. AB - BACKGROUND: Gender and gastric acid have been suggested to be independently involved in the pathophysiology of functional dyspepsia, but the interrelationship among gender, dyspeptic symptoms, and gastric acid secretion remains to be evaluated. We sought to explore this issue in dyspeptic patients. METHODS: A total of 89 outpatients (male, 36; mean age, 55.6 years) with dyspeptic symptoms were analyzed. The degree of dyspeptic symptoms was evaluated and scored using a symptom questionnaire consisting of 3 subcategories: dysmotility-related symptoms, reflux-related symptoms, and epigastric pain related symptoms. Stimulated gastric acid secretion was directly measured using an endoscopic gastrin test. RESULTS: The total symptom scores and the epigastric pain-related symptom scores were significantly higher in female patients than in male patients. The dysmotility-related and reflux-related symptom scores were also higher, but not significantly, in the female patients. Multiple regression analysis of age, gender, habitual drinking, smoking, Helicobacter pylori infection, and gastric acid secretion revealed that gender and gastric hypochlorhydria, defined as less than 2.1 mEq/10 min in the endoscopic gastrin test, were significantly associated with higher dyspeptic symptom scores. The total scores and the dysmotility-related scores were significantly higher in the patients with gastric hypochlorhydria than in those with gastric non hypochlorhydria, and this difference was found to be present only in females. CONCLUSIONS: Gastric hypochlorhydria in female dyspeptic patients may be involved in the exacerbation of dyspeptic symptoms. Differences in the responsiveness to gastric hypochlorhydria between males and females may be partly responsible for the gender differences in the prevalence and severity of dyspeptic symptoms. PMID- 22829346 TI - Human gastric cancer organizes neighboring lymphatic vessels via recruitment of bone marrow-derived lymphatic endothelial progenitor cells. AB - BACKGROUND: Lymphatic metastasis is a critical determinant of prognosis in human gastrointestinal cancers. Studies suggest that lymphatic metastasis has been linked to lymphangiogenesis, the growth of lymphatic vessels, while the mechanisms of tumor lymphangiogenesis remain poorly characterized. METHODS: Human gastric cancer cells, MKN45, were implanted under the gastric submucosa of nude mice receiving green fluorescent protein-positive bone marrow (BM) transplants. In addition, MKN45 cells were subcutaneously injected into the back of each mouse as a model of human tumor xenografts. The tumor tissue was analyzed 3 weeks after implantation. RESULTS: The mice with MKN45 cells represent recruitment and incorporation of BM-derived lymphatic endothelial progenitor cells (LEPC) into gastric lymphatics. Moreover, in a xenograft model, MKN45 cells induced lymphangiogenesis as well as recruitment of BM-derived LEPC in tumor lymphatics in a xenograft model. CONCLUSIONS: These findings of this study suggest that human gastric adenocarcinoma induces tumor lymphangiogenesis via recruitment of LEPC from BM. PMID- 22829347 TI - Lacrimal gland adenoid cystic carcinoma with high-grade transformation to myoepithelial carcinoma: report of a case and review of literature. AB - Adenoid cystic carcinoma (AdCC) is the most frequent malignant neoplasm of the lacrimal glands. Like its salivary gland counterpart, lacrimal AdCC can rarely undergo high-grade transformation ("dedifferentiation"). We herein report the clinical, radiographic and microscopic findings of a lacrimal gland AdCC with high grade transformation, occurring in a 39-year-old female patient. In contrast to salivary gland AdCC with high-grade transformation, which usually shows a high grade component with "ductal" differentiation, in the case presented, the "dedifferentiated" component showed morphologic and immunohistochemical features of myoepithelial differentiation. PMID- 22829348 TI - Potential applications of bioprocess technology in petroleum industry. AB - Petroleum refining is traditionally based on the use of physicochemical processes such as distillation and chemical catalysis that operate under high temperatures and pressures conditions, which are energy intensive and costly. Biotechnology has become an important tool for providing new approaches in petroleum industry during oil production, refining and processing as well as managing environmentally safe pollutant remediation and disposal practices. Earlier biotechnology applications in the petroleum industry were limited to microbial enhanced oil recovery, applications of bioremediation to contaminated marine shorelines, soils and sludges. The potential role of bioprocess technology in this industry has now expanded further into the areas of biorefining and upgrading of fuels, production of fine chemicals, control of souring during production and air VOC biofiltration. In this paper we provide an overview of the major applications of bioprocesses and technology development in the petroleum industry both in upstream and downstream areas and highlight future challenges and opportunities. PMID- 22829351 TI - Graphene-based nafion nanocomposite membranes: enhanced proton transport and water retention by novel organo-functionalized graphene oxide nanosheets. AB - Novel nanostructured organo-modified layered materials based on graphene oxide carrying various hydrophilic functional groups (-NH(2), -OH, -SO(3)H) are prepared and tested as nanofillers for the creation of innovative graphene-based Nafion nanocomposites. The hybrid membranes are characterized by a combination of analytical techniques, which show that highly homogeneous exfoliated nanocomposites are created. The pulsed field gradient NMR technique is used to measure the water self-diffusion coefficients. Remarkable behavior at temperatures up to 140 degrees C is observed for some composite membranes, thereby verifying the exceptional water retention property of these materials. Dynamic mechanical analysis shows that hybrid membranes are much stiffer and can withstand higher temperatures than pure Nafion. PMID- 22829350 TI - Dynamic kinetic resolution of 2,3-dihydrobenzo[b]furans: chemoenzymatic synthesis of analgesic agent BRL 37959. AB - An efficient asymmetric synthesis of (S)-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8 a) and (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8 b) was established. Key to the success was the highly stereoselective enzymatic kinetic resolution of the corresponding methyl or ethyl esters that was further developed into a dynamic process. As a reliable and fast tool for analysing the enantiomeric excess, HPLC coupled with a CD detector was utilized. The route was completed by a Friedel-Crafts acylation of ethyl (S)-5-chloro-2,3 dihydrobenzo[b]furan-3-carboxylate (7 c) followed by saponification leading to (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (2), an analgesic agent. PMID- 22829349 TI - Spontaneous pushing to prevent postpartum urinary incontinence: a randomized, controlled trial. AB - INTRODUCTION AND HYPOTHESIS: The risk for urinary incontinence can be 2.6-fold greater in women after pregnancy and childbirth compared with their never pregnant counterparts, with the incidence increasing with parity. We tested the hypothesis that the incidence of de novo postpartum urinary incontinence in primiparous women is reduced with the use of spontaneous pushing alone or in combination with perineal massage compared with women who experienced traditional directed pushing for second-stage management. METHODS: This was a prospective clinical trial enrolling and randomizing 249 women into a four-group design: (1) routine care with coached or directed pushing, (2) spontaneous self-directed pushing, (3) prenatal perineal massage initiated in the third trimester, and (4) the combination of spontaneous pushing plus perineal massage. Self-report of incontinence was assessed using analysis of variance (ANOVA) and covariance (ANCOVA) models in 145 remaining women at 12 months postpartum using the Leakage Index, which is sensitive to minor leakage. RESULTS: No statistical difference in the incidence of de novo postpartum incontinence was found based on method of pushing (spontaneous/directed) (P value = 0.57) or in combination with prenatal perineal massage (P value = 0.57). Fidelity to pushing treatment of type was assessed and between-groups crossover detected. CONCLUSIONS: Spontaneous pushing did not reduce the incidence of postpartum incontinence experienced by women 1 year after their first birth due to high cross-over between randomization groups. PMID- 22829352 TI - From a fluorescent chromophore in solution to an efficient emitter in the solid state. AB - Polycyclic aromatic hydrocarbons (PAHs) normally exhibit efficient fluorescence in dilute solutions, whereas their emission is significantly quenched in the aggregated state due to the formation of pi-aggregates/excimers. The rigid and planar structure of PAHs plays a positive role in terms of fluorescence in solution but a negative one in the aggregated state. To bestow PAHs a luminescent ability in the solid state, we constructed a non-coplanar PAH-substituted ethene. By using the planar PAH fluoranthene as a building block, a highly efficient solid-state emitter with a fluorescence quantum efficiency of unity in the aggregated state was obtained. OLEDs with contain the molecule as an emitter reach a luminance up to 20 520 cd m(-2) and an efficiency of 10 cd A(-1). PMID- 22829353 TI - Modeling the connection between primary and metastatic tumors. AB - We put forward a model for cancer metastasis as a migration phenomenon between tumor cell populations coexisting and evolving in two different habitats. One of them is a primary tumor and the other one is a secondary or metastatic tumor. The evolution of the different cell phenotype populations in each habitat is described by means of a simple quasispecies model allowing for a cascade of mutations between the different phenotypes in each habitat. The cell migration event is supposed to be unidirectional and take place continuously in time. The possible clinical outcomes of the model depending on the parameter space are analyzed and the effect of the resection of the primary tumor is studied. PMID- 22829354 TI - Sexing sperm of domestic animals. AB - The ability to preselect or predetermine the sex of offspring prior to conception is a highly desired technological tool for assisted female breeding programs specifically for milk production, and in males, for meat production and increasing livestock numbers. The current technology is based on the well-known differences in X- and Y-sperm in the amount of DNA. The technology uses modified flow cytometric instrumentation for sorting X- and Y-bearing sperm. The method can be validated on the basis of live births, laboratory reanalysis of sorted sperm for DNA content, and embryo biopsy for sex determination. Currently, the sex of animals has been predetermined with 90 % accuracy by sexing spermatozoa. In the bovine breeding industry, flow cytometric sperm sexing has not fulfilled its original promise. Sexed sperm doses are too expensive for widespread application while the fertility of sexed sperm doses is lower than unsexed ones. Essentially all bovine sexed semen is frozen and then applied through artificial insemination (AI) or in vitro fertilization. There is still a need in the animal breeding industry to develop a technique for sperm sexing that provides sufficient spermatozoa for AI doses, does not compromise sperm fertility, and is widely applicable to a range of species. In this review, we will summarize the current state-of-the-art in sex preselection in domestic animals and some wildlife species using flow cytometric sperm-sorting of X from Y sperm based on DNA differences. PMID- 22829355 TI - Estimation of mature live weight using some body measurements in Karya sheep. AB - The aim of this study was to determine models which will be used for the estimation of adult live weights based on some body measurements using multiple regression model in Karya sheep of different age groups. Animal material of the study consisted of a total of 215 Karya sheep. Least squares means for live weight, body length, rump height, withers height, back height, chest depth, chest girth, and chest width of Karya sheep in Adnan Menderes University Group Sheep Breeding Program elite flock and breeder flocks were found as 47.24 kg, 67.08, 68.29, 68.58, 66.97, 30.04, 93.24, and 18.29 cm, respectively. Karya ewes were put into five categories according to ages (2-6 years). High positive phenotypic correlation coefficients were observed between live weight and body measurements of animals in different age groups (2-6 years). Among the formed multiple regression models, the highest coefficients of determination (R(2)) were obtained from the models formed for body length or body length and chest girth together (R(2) = 0.79, R (2) = 0.87). It is concluded that live weight of Karya sheep can be estimated with a high accuracy using some body measurements and statistical methods. PMID- 22829356 TI - TRANSDIP: a trans-chelating ligand tailor-made for probing unusual Pd0 and PdII intermediates. AB - Forty years after Venanzi's seminal studies on trans-spanning diphosphines, a cavity-shaped trans chelator (TRANSDIP) has been used to monitor the stepwise formation of a carbon-carbon bond on a palladium centre. Furthermore, the ligand, which incorporates a cyclodextrin subunit, enabled the synthesis of the first eta(2)-dioxygen complex in which the M-O(2) unit is entrapped within a cavity. PMID- 22829358 TI - Meta-analysis methods and models with applications in evaluation of cholesterol lowering drugs. AB - In this paper, we propose a class of multivariate random effects models allowing for the inclusion of study-level covariates to carry out meta-analyses. As existing algorithms for computing maximum likelihood estimates often converge poorly or may not converge at all when the random effects are multi-dimensional, we develop an efficient expectation-maximization algorithm for fitting multi dimensional random effects regression models. In addition, we also develop a new methodology for carrying out variable selection with study-level covariates. We examine the performance of the proposed methodology via a simulation study. We apply the proposed methodology to analyze metadata from 26 studies involving statins as a monotherapy and in combination with ezetimibe. In particular, we compare the low-density lipoprotein cholesterol-lowering efficacy of monotherapy and combination therapy on two patient populations (naive and non-naive patients to statin monotherapy at baseline), controlling for aggregate covariates. The proposed methodology is quite general and can be applied in any meta-analysis setting for a wide range of scientific applications and therefore offers new analytic methods of clinical importance. PMID- 22829359 TI - Synthesis, photoluminescence properties and theoretical insights on 1,3-diphenyl 5-(9-anthryl)-2-pyrazoline and -1H-pyrazole. AB - 1,3-Diphenyl-5-(9-anthryl)-2-pyrazoline and 1,3-diphenyl-5-(9-anthryl)-1H pyrazole with an anthryl chromophore were synthesized and characterized using (1) H NMR, (13) C NMR, FT-IR, mass spectrometry and elemental analysis. Their optical properties were characterized by UV-vis absorption and fluorescence spectroscopy. It was observed that the absorption and fluorescence spectra of the two compounds showed a red shift with respect to that of anthracene. Pyrazole exhibited high fluorescent quantum yields (Phif = 0.90 in toluene) while pyrazoline showed nearly no fluorescence in solution. The significant fluorescence divergence of the two similar compounds was investigated theoretically through density functional theory (DFT) calculations. The energetically lowest-lying state S1 in the pyrazoline exhibited both characteristics of locally excited and electron transfer states that resulted in the fluorescence quenching of anthryl chromophore whereas the S1 state in the pyrazole corresponded to an optically allowed state that led to high fluorescence quantum yields in solutions. PMID- 22829357 TI - The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS. AB - Microglia are the resident immune cells and phagocytes of our central nervous system (CNS). While most work has focused on the rapid and robust responses of microglia during CNS disease and injury, emerging evidence suggests that these mysterious cells have important roles at CNS synapses in the healthy, intact CNS. Groundbreaking live imaging studies in the anesthetized, adult mouse demonstrated that microglia processes dynamically survey their environment and interact with other brain cells including neurons and astrocytes. More recent imaging studies have revealed that microglia dynamically interact with synapses where they appear to serve as "synaptic sensors," responding to changes in neural activity and neurotransmitter release. In the following review, we discuss the most recent work demonstrating that microglia play active roles at developing and mature synapses. We first discuss the important imaging studies that have led us to better understand the physical relationship between microglia and synapses in the healthy brain. Following this discussion, we review known molecular mechanisms and functional consequences of microglia-synapse interactions in the developing and mature CNS. Our current knowledge sheds new light on the critical functions of these mysterious cells in synapse development and function in the healthy CNS, but has also incited several new and interesting questions that remain to be explored. We discuss these open questions, and how the most recent findings in the healthy CNS may be related to pathologies associated with abnormal and/or loss of neural circuits. PMID- 22829360 TI - Methodology for jointly assessing myocardial infarct extent and regional contraction in 3-D CMRI. AB - Automated extraction of quantitative parameters from cardiac magnetic resonance images is crucial for the management of patients with myocardial infarct. This paper proposes a postprocessing procedure to jointly analyze Cine and delayed enhanced (DE) acquisitions, in order to provide an automatic quantification of myocardial contraction and enhancement parameters and a study of their relationship. For that purpose, the following processes are performed: 1) DE/Cine temporal synchronization and 3-D scan alignment, 2) 3-D DE/Cine rigid registration in a region about the heart, 3) myocardium segmentation on Cine-MRI and superimposition of the epicardial and endocardial contours on the DE images, 4) quantification of the myocardial infarct extent (MIE), 5) study of the regional contractile function using a new index, the amplitude to time ratio (ATR). The whole procedure was applied to ten patients with clinically proven myocardial infarction. The comparison between the MIE and the visually assessed regional function scores demonstrated that the MIE is highly related to the severity of the wall motion abnormality. In addition, it was shown that the newly developed regional myocardial contraction parameter (ATR) decreases significantly in delayed enhanced regions. This largely automated approach enables the combined study of regional MIE and left ventricular function. PMID- 22829361 TI - Nonlocal means denoising of ECG signals. AB - Patch-based methods have attracted significant attention in recent years within the field of image processing for a variety of problems including denoising, inpainting, and super-resolution interpolation. Despite their prevalence for processing 2-D signals, they have received little attention in the 1-D signal processing literature. In this letter, we explore application of one such method, the nonlocal means (NLM) approach, to the denoising of biomedical signals. Using ECG as an example, we demonstrate that a straightforward NLM-based denoising scheme provides signal-to-noise ratio improvements very similar to state of the art wavelet-based methods, while giving ~3 * or greater reduction in metrics measuring distortion of the denoised waveform. PMID- 22829362 TI - Toward morphological thoracic EIT: major signal sources correspond to respective organ locations in CT. AB - Lung and cardiovascular monitoring applications of electrical impedance tomography (EIT) require localization of relevant functional structures or organs of interest within the reconstructed images. We describe an algorithm for automatic detection of heart and lung regions in a time series of EIT images. Using EIT reconstruction based on anatomical models, candidate regions are identified in the frequency domain and image-based classification techniques applied. The algorithm was validated on a set of simultaneously recorded EIT and CT data in pigs. In all cases, identified regions in EIT images corresponded to those manually segmented in the matched CT image. Results demonstrate the ability of EIT technology to reconstruct relevant impedance changes at their anatomical locations, provided that information about the thoracic boundary shape (and electrode positions) are used for reconstruction. PMID- 22829364 TI - A system for the detection of pigment network in dermoscopy images using directional filters. AB - A pigment network is one of the most important dermoscopic structures. This paper describes an automatic system that performs its detection in dermoscopy images. The proposed system involves a set of sequential steps. First, a preprocessing algorithm is applied to the dermoscopy image. Then, a bank of directional filters and a connected component analysis are used in order to detect the "lines" of the pigment network. Finally, features are extracted from the detected network and used to train an AdaBoost algorithm to classify each lesion regarding the presence of the pigment network. The algorithm was tested on a dataset of 200 medically annotated images from the database of Hospital Pedro Hispano (Matosinhos), achieving a sensitivity = 91.1% and a specificity = 82.1%. PMID- 22829363 TI - Clinical microwave tomographic imaging of the calcaneus: a first-in-human case study of two subjects. AB - We have acquired 2-D and 3-D microwave tomographic images of the calcaneus bones of two patients to assess correlation of the microwave properties with X-ray density measures. The two volunteers were selected because each had one leg immobilized for at least six weeks during recovery from a lower leg injury. A soft-prior regularization technique was incorporated with the microwave imaging to quantitatively assess the bulk dielectric properties within the bone region. Good correlation was observed between both permittivity and conductivity and the computed tomography-derived density measures. These results represent the first clinical examples of microwave images of the calcaneus and some of the first 3-D tomographic images of any anatomical site in the living human. PMID- 22829365 TI - Historical background of gamete and embryo culture. AB - The first tissue culture media were developed nearly 150 years ago by Ludwig and Ringer. These were simple salt solutions, which were initially based on the chemical properties of blood serum. The second generation of culture media was developed more than a century later, in the 1970s, aiming to mimic the reproductive environment. In the 1990s, simplex optimization was used to design the third group of media, to some extent ignoring existing formulations and principles. Simultaneous with the development of culture media, it became evident that it was necessary to carefully control the culture conditions, including temperature, pH, osmolarity, and air quality. Equally important was the development of instruments and tools specifically designed for cell tissue culture such as the inverted microscope, the incubator, the Petri dish, sterile plasticware, the laminar flow cabinet, and air filtration equipment. PMID- 22829366 TI - Utility of animal models for human embryo culture development: rodents. AB - Advancements in clinical human embryo culture over the last 30-40 years have been supported by research conducted with embryos from rodent and domestic species. The mouse has been the primary rodent species that has contributed to improved embryo culture outcomes. Numerous parameters applied in the beginning of experiments, during progress of experiments, and as end-point measures provide varying degrees of rigor and interpretive strength and/or complexity. A nonexhaustive discussion of these parameters is presented with important emphasis on experimental design to obtain the greatest power of intraexperimental interpretation of inferior, equivalent, or improved culture conditions in the mouse model. Additionally, data are presented demonstrating the inherent flaw of overinterpretation of interexperimental outcome comparisons and caution of expectations of data translation from the mouse to the human embryo culture scenario. Finally, a materials, methods, and notes discussion enumerates important steps in use of mouse embryos as a bioassay tool, independent of whether they are being used in an experiment focused on quality control or improving culture conditions. PMID- 22829367 TI - Utility of animal models for human embryo culture development: domestic species. AB - Although the mouse is widely used as an animal model for the in vitro culture of human preimplantation embryos, arguments can be made for the validity of many domestic species as more relevant, applicable models of early human development. Here, we describe the advantages and disadvantages of domestic species as animal models to develop in vitro culture methods and conditions that successfully support human embryo development. In vitro embryo culture procedures are described and compared between species for the bovine, ovine, caprine, and porcine species. PMID- 22829368 TI - Utility of animal models for human embryo culture: nonhuman primates. AB - Nonhuman primates are the closest relatives to humans and therefore our most evolutionary close cousins. While marvelous insights are gleaned from studying rodents and other systems, it is impossible to envision how those mechanistic findings can be responsibly translated to the clinic without the appropriate use of nonhuman primates. Thankfully, noninvasive technologies now permit nonhuman primate studies without endangering the model itself. Work with primates is predicted to continue to lead the fields of reproductive and regenerative medicine for the rest of the twenty-first century. PMID- 22829369 TI - Media composition: salts and osmolality. AB - The main components of embryo culture media are salts, which dissociate into their component inorganic ions in aqueous solution. All embryo culture media contain the same six inorganic ions: Na(+), K(+), Cl(-), Ca(2+), Mg(2+), and SO(4)(2-), while most also contain PO(4)(2-). The salts that are used to formulate embryo culture media can be traced back to classic saline solutions, particularly Krebs-Ringer Bicarbonate (KRB), that were developed for somatic cells in the first half of the twentieth century. The salt and inorganic ion concentrations in the first successful defined mouse embryo culture medium, Whittens medium, were identical to those in KRB. These remained largely unchanged in embryo culture media for decades, with similar levels found in the standard mouse embryo culture medium, M16, formulated in the 1970s. Human embryos were initially cultured in undefined somatic cell media such as Earles and Hams F-10 with serum added. This changed in the mid-1980s, however, with the development of Quinns HTF, a defined medium specifically formulated for human embryo culture, in which the inorganic ion concentrations are similar to those in M16 and Whittens. While these media were useful both for experimental work and clinically, embryos suffered developmental blocks in all of them, with mouse embryos blocking at the 2-cell stage and human embryos at the 4- to 8-cell stage. Starting in the late 1980s, however, mouse embryo culture media were first developed that alleviated these developmental blocks. These media, CZB and KSOM, had much lower osmolalities than previous media, mainly due to lower inorganic ion concentrations. Indeed, lowering total inorganic ion concentration and osmolality proved key to understanding how media that supported complete preimplantation development in vitro can be formulated. A subsequent improvement was the addition of amino acids to culture media for both mouse and human embryos. At least in part, their beneficial effect during the cleavage stages of development is due to the presence in early preimplantation embryos of mechanisms for cell volume regulation that depend on the accumulation of amino acids as organic osmolytes to provide intracellular osmotic support. These amino acids, principally glycine, replace a portion of the intracellular inorganic ions that would otherwise be needed to maintain cell size, preventing the intracellular ionic strength from rising to deleterious levels and blocking development. Thus, the optimum salts levels, osmolality, and amino acid contents of culture media are not independent, but interact strongly because of their roles in cell volume regulation. In the absence of compounds that preimplantation embryos can use as organic osmolytes, embryos will develop only at lower osmolalities and salt concentrations in the medium. However, when organic osmolytes such as some amino acids are present, embryos will develop in culture at higher osmolarities that are similar to those they experience in tubal fluid in vivo. PMID- 22829370 TI - Media composition: energy sources and metabolism. AB - The preparation of defined culture media for embryo development has progressed from simple chemically defined media based on Krebs-Ringer bicarbonate, supplemented with glucose, bovine plasma albumin, antibiotics and utilizing a CO(2)-bicarbonate buffering system to more complete systems based around studies on the physiology and metabolism of the mammalian embryo. Although the concentration of substrates used in media can vary, there are many components that are quintessentially important for embryo development such as energy sources, that play a vital role in regulation of metabolism and hence viability. Here we describe the role of energy substrates within culture media and outline assays which can be utilized to measure embryo metabolism as a mechanism for determining embryo physiology and viability. PMID- 22829371 TI - Media composition: amino acids and cellular homeostasis. AB - Amino acids are beneficial for the developing preimplantation embryo and therefore form an important component of culture media. This chapter will critically review the importance of amino acids for preimplantation embryos and the impact of this research for the development of sequential culture media used in many assisted conception units. The advantages of culturing embryos in a full complement of amino acids, at close to physiological concentrations will be considered. Moreover, the noninvasive measurement of amino acid turnover by individual embryos, a method which holds great promise to assess developmental competency prior to transfer, will also be discussed. Thus, this chapter highlights the fundamental role of amino acids for the metabolic and homeostatic regulation of the preimplantation embryo. PMID- 22829372 TI - Media composition: macromolecules and embryo growth. AB - Most embryo culture media are still supplemented with proteins rather than with nonprotein macromolecules or recombinant protein products. HSA is probably the most common supplement followed by globulin-enriched preparations. Serum supplementation and Co-Culture of embryos belong to the past. Defined nonprotein or recombinant protein supplements are becoming a viable alternative during gamete and embryo manipulation procedures. Biological protein supplements are still preferred for any extended period of embryo culture. Understanding the goals and purpose of supplemented macromolecules in embryo culture media during each step of the laboratory IVF process should assist us in choosing the safest and most consistent macromolecule for each step, but also selecting a product that has the capability of delivering the best clinical outcome. Each batch of biological protein supplement is unique, even if supplied by the same manufacturer. Each lot of protein supplement typically contains many lot specific, potentially harmful, and unintended hormone and protein contaminants. Macromolecular embryo culture medium supplements should be identified as one of the highest risk factors in an IVF laboratory that may contribute towards clinical compromise. All efforts should be made to use a proven batch of supplement for as long as the expiration date will allow. The beneficial effect of more complex protein supplements is evident after the activation of the embryonic genome and probably due to the presence of growth factors. Lower live birth rates due to suboptimum protein supplementation may be a direct result of the preferential loss of female embryos. When deciding on a culture system, thought should be given specifically to the interaction between the culture medium and the macromolecular supplement. Ready-to-use pre-supplemented culture media may be advisable over a more complex product if a comprehensive macromolecular quality management program is not feasible. However, the question remains as to whether the increasing simplification of embryo culture media supplements is ready for large-scale clinical use. PMID- 22829373 TI - Media composition: antioxidants/chelators and cellular function. AB - Protection of embryos against oxidative insults during culture is necessary to maintain viability. Generation of excessive levels of reactive oxygen species (ROS) is triggered by various components of the in vitro environment, most of which embryos do not normally encounter in vivo. To compensate for these deficiencies in the culture environment, antioxidants and chelators are often used to control or suppress ROS levels as embryos develop. However, there is no consensus regarding dosage, time of exposure, or appropriate combinations of antioxidants and chelators in embryo culture. In order to elucidate this aspect of an embryo's chemical surroundings in vitro, we present the current knowledge on the function and effect of each antioxidant or chelator that is often included in an embryo culture medium. PMID- 22829374 TI - Media composition: pH and buffers. AB - The proper pH of media is a crucial parameter for optimizing efficacy of gamete and embryo culture. Selecting the right media pH and stabilizing this pH are important variables in minimizing intracellular stress and optimizing development. Regulation of intracellular (pHi) and extracellular pH (pHe) is discussed, as well as methods to prevent harmful pHe oscillations. Furthermore, proper approaches to ensure accurate measurement of media pHe are described. PMID- 22829375 TI - Media composition: growth factors. AB - Despite the fact that the fundamental principle underlying the most common method of culture media constitution is that of mimicking the natural environment of the preimplantation embryo, one major difference that remains between current embryo culture media and in vivo conditions is the absence of growth factors in vitro. Numerous growth factors are known to be present in the in vivo environment of human and nonhuman preimplantation embryos, often with peak concentrations corresponding to when fertilization and preimplantation embryo growth would occur. Although these growth factors are found in very small concentrations, they have a profound effect on tissue growth and differentiation through attachment to factor-specific receptors on cell surfaces. Receptors for many different growth factors have also been detected in human preimplantation embryos. Preimplantation embryos themselves express many growth factors. The growth factors and receptors are metabolically costly to produce, and thus their presence in the environment of the preimplantation embryo and in the embryo respectively strongly implies that embryos are designed to encounter and respond to the corresponding factors. Studies of embryo coculture also indirectly suggest that growth factors can improve in vitro development. Several animal and human studies attest to a probable beneficial effect of addition of growth factors to culture media. However, there is still ambiguity regarding the exact role of growth factors in embryonic development, the optimal dose of growth factors to be added to culture media, the combinatorial effect and endocrine of growth factors in embryonic development. PMID- 22829376 TI - Culture systems: single step. AB - Culture media to support development of zygotes to the blastocyst stage is based either on a single medium or sequential (two-step) media. Single medium culture either with or without day 3 renewal is associated with simplified laboratory protocols and lower costs compared with sequential medium. There are currently insufficient clinical data to conclude that one system, either single or sequential, is superior to the other with regard to clinical performance. This chapter summarizes the rationale for use of a single medium, along with supporting animal and human data for culturing embryos in a single medium, renewed or not renewed. PMID- 22829377 TI - Culture systems: sequential. AB - Methods for the culture of preimplantation human embryos evolved primarily from those used for mouse embryos. The initial method was usually culture in a single medium in microdrops of medium under oil for 2-3 days before transfer. Subsequently, extended culture over the whole preimplantation period was used. The debate at present is which system is best, a sequential series of media to accommodate changes in physiology and metabolism of the embryo from a 1-cell zygote to the differentiated blastocyst stage or a single-step culture regime using the same culture medium throughout the preimplantation period. Aspects of the advantages and disadvantages of these two culture systems will be discussed. PMID- 22829378 TI - Culture systems: embryo co-culture. AB - During the 1970s, domestic animal biotechnology, i.e., embryo transfer in farm animals, was confronted with the problem of embryonic developmental arrest observed in vitro, especially during the cycle in which maternal to zygotic transition (MZT) cycle takes place. In farm animals, obtaining blastocysts is mandatory, as transfer at earlier stages results in expulsion of the embryo from the vagina. In humans, the first attempts to obtain blastocysts with classical culture media were disappointing, and the use of a coculture strategy was naturally tempting: the first significant results of successful blastocyst development were obtained in the early 1980s, using trophoblastic tissue as a feeder layer in order to mimic an autocrine embryotrophic system. The next supporting cell systems were based on oviduct epithelial cells and uterine cells in order to achieve a paracrine effect. Non-hormone dependence was then demonstrated with the use of prepubertal cells, and finally with the use of established cell lines of nongenital origin (African Green Monkey Kidney, Vero cells). The embryotrophic properties are linked to features of "transport epithelia." Vero cells have been extensively used in human ART, and most of our knowledge about the human blastocyst was gathered with the use of this technology. Coculture is still in current use, but with systems that employ autologous uterine cells. Results following the use of this technology in human ART are superior to those observed with the use of sequential media. The benefit is linked to the release of free radical scavengers and growth factors by the feeder cells. In animal biotechnology, an important part of the "precious embryos," i.e., those resulting from cloning technology, involves coculture with buffalo rat liver (BRL) cells or Vero cells. PMID- 22829379 TI - Culture systems: low-oxygen culture. AB - The tension of oxygen measured in the oviducts of several mammals was 5-8.7 %, but this drops in the uterine milieu to <2 % in cows and primates. For embryo culture in human in vitro fertilization (IVF), a non-physiologic level of 20 % oxygen has been used for the past 30 years. However, several animal studies have shown that low levels of oxygen plays an important physiological role in reducing the high levels of detrimental reactive oxygen species within cells, influences the embryonic gene expression, helps with embryo metabolism of glucose, and enhances embryo development to blastocysts. However, clinical studies have given contradictory results. Nevertheless, in nearly all reports, some kind of improvement has been observed, either in embryo development or in implantation and no detriments have been reported. For these reasons, more and more IVF laboratories utilize low oxygen during embryo culture. PMID- 22829380 TI - Culture systems: embryo density. AB - Embryo density is defined as the embryo-to-volume ratio achieved during in vitro culture; in other words, it is the number of embryos in a defined volume of culture medium. The same density can be achieved by manipulating either the number of embryos in a given volume of medium, or manipulating the volume of the medium for a given number of embryos: for example, a microdrop with five embryos in a 50 MUl volume under oil has the same embryo-to-volume ratio (1:10 MUl) as a microdrop with one embryo in a 10 MUl volume under oil (1:10 MUl). Increased embryo density can improve mammalian embryo development in vitro; however, the mechanism(s) responsible for this effect may be different with respect to which method is used to increase embryo density.Standard, flat sterile plastic petri dishes are the most common, traditional platform for embryo culture. Microdrops under a mineral oil overlay can be prepared to control embryo density, but it is critical that dish preparation is consistent, where appropriate techniques are applied to prevent microdrop dehydration during preparation, and results of any data collection are reliable, and repeatable. There are newer dishes available from several manufacturers that are specifically designed for embryo culture; most are readily available for use with human embryos. The concept behind these newer dishes relies on fabrication of conical and smaller volume wells into the dish design, so that embryos rest at the lowest point in the wells, and where putative embryotrophic factors may concentrate.Embryo density is not usually considered by the embryologist as a technique in and of itself; rather, the decision to culture embryos in groups or individually is protocol-driven, and is based more on convenience or the need to collect data on individual embryos. Embryo density can be controlled, and as such, it can be utilized as a simple, yet effective tool to improve in vitro development of human embryos. PMID- 22829381 TI - Culture systems: air quality. AB - Poor laboratory air quality is a known hazard to the culture of human gametes and embryos. Embryologists and chemists have employed analytical methods for identifying and measuring bulk and select air pollutants to assess the risk they pose to the embryo culture system. However, contaminant concentrations that result in gamete or embryotoxicity are poorly defined. Combating the ill effects of poor air quality requires an understanding of how toxicants can infiltrate the laboratory, the incubator, and ultimately the culture media. A further understanding of site-specific air quality can then lead to the consideration of laboratory design and management strategies that can minimize the deleterious effects that air contamination may have on early embryonic development in vitro. PMID- 22829382 TI - Culture systems: mineral oil overlay. AB - Mineral oil overlay microdrop is commonly used during in vitro fertilization (IVF) procedures. Though mineral oil appears homogeneous, it is an undefined product that can vary in quality. Here, we describe the history, chemistry, processing, and optimal use of mineral oil for IVF and embryo culture. PMID- 22829383 TI - Culture systems: physiological and environmental factors that can affect the outcome of human ART. AB - Many aspects of the embryo culture environment have been shown to affect embryo development and the subsequent outcomes of human ART. It is now becoming increasingly evident that embryo and later development can be affected by events and conditions that occur before, perhaps long before, the oocytes and sperm are collected and brought together in the ART laboratory. These include diet and metabolic disorders, general health and disease, physical and psychological stress, exposure to environmental estrogens and other toxins, pharmaceuticals, alcohol, smoking, and drug abuse. This paper discusses the known and potential effects of season of the year (or temperature) and environmental air pollution on the outcomes of human ART. It may be useful to advise ART patients to avoid high environmental temperature and air pollution. In addition, it is important for clinical embryologists to recognize that adverse outcomes may result from such exposures, and to incorporate this into the analysis of clinic data for the purposes of quality management. PMID- 22829384 TI - Culture systems: fluid dynamic embryo culture systems (microfluidics). AB - The tubal/uterine lumen is a dynamic environment in which oocytes, eggs, and early embryos are submitted to different forces generated by cilia and peristaltic flow of tubal fluid. The movement of the tubal/uterine fluid, the chemical diversity, and their interaction produce a unique environment able to support embryo development and modulate gene expression. Although culture of embryos is supported in static and low complexity chemical conditions, application of fluidic dynamics in assisted reproduction technology to improve outcomes has been in development for almost a decade. Several attempts to build devices able to facilitate fertilization and embryo culture have been made, but dynamic fluidic devices are not yet available for mass scale use in clinical embryology laboratories. Indeed, such devices for embryo culture have been constructed and they are under evaluation in IRB approved studies. Fluid dynamic devices appear to enhance embryo development and they may be innovative resources for clinical and experimental embryology laboratories. This chapter reviews the principles and results of dynamic fluid systems, and the materials and methods required to produce microfunnel dynamic culture systems for use with embryos. PMID- 22829385 TI - Human embryo culture media comparisons. AB - Every program of assisted reproduction strives to maximize pregnancy outcomes from in vitro fertilization and selecting an embryo culture medium, or medium pair, consistent with high success rates is key to this process. The common approach is to replace an existing medium with a new one of interest in the overall culture system and then perform enough cycles of IVF to see if a difference is noted both in laboratory measures of embryo quality and in pregnancy. This approach may allow a laboratory to select one medium over another but the outcomes are only relevant to that program, given that there are well over 200 other variables that may influence the results in an IVF cycle. A study design that will allow for a more global application of IVF results, ones due to culture medium composition as the single variable, is suggested. To perform a study of this design, the center must have a patient caseload appropriate to meet study entrance criteria, success rates high enough to reveal a difference if one exists and a strong program of quality assurance and control in both the laboratory and clinic. Sibling oocytes are randomized to two study arms and embryos are evaluated on day 3 for quality grades. Inter and intra-observer variability are evaluated by kappa statistics and statistical power and study size estimates are performed to bring discriminatory capability to the study. Finally, the complications associated with extending such a study to include blastocyst production on day 5 or 6 are enumerated. PMID- 22829386 TI - Culture systems: embryo culture and monozygotic twinning. AB - The incidence of monozygotic twinning in pregnancies achieved with assisted reproductive technologies (ART) is significantly higher than spontaneously conceived pregnancies. The factors associated with ART that predispose the embryos to splitting are not well-characterized. Assisted hatching and extended embryo culture are two ART laboratory methods that have been risk factors for monozygotic twinning. The methods and strategies that may be employed to avoid monozygotic twinning are discussed in this chapter. PMID- 22829387 TI - Embryo culture and epigenetics. AB - During preimplantation development, major epigenetic reprogramming occurs, erasing gametic modifications, and establishing embryonic epigenetic modifications. Given the plasticity of these modifications, they are susceptible to disruption by assisted reproductive technologies, including embryo culture. The current state of evidence is presented for the effects of embryo culture on global DNA methylation and histone modifications, retroviral silencing, X inactivation, and genomic imprinting. Several salient points emerge from the literature; that culture in the absence of other procedures can lead to epigenetic perturbations; that all media are suboptimal; and that embryo response to in vitro culture is stochastic. We propose that embryos adapt to the suboptimal environment generated by embryo culture, including epigenetic adaptations, and that "quiet" embryos may be the least epigenetically compromised by in vitro culture. PMID- 22829388 TI - The therapeutic management of bleeding and thrombotic disorders complicating CNS malignancies. AB - OPINION STATEMENT: Patients with central nervous system (CNS) malignancies have a substantial risk for developing both thrombotic and bleeding disorders. The risk of venous thromboembolism (VTE) is substantially higher in these patients, both in the perioperative period and throughout their disease course. Patients with CNS malignancy harbor a latent hypercoagulability, which predisposes to VTE, as do postoperative immobility, hemiparesis, and other factors. The management of VTE in these patients is complex, given the significant morbidity and mortality associated with intratumoral hemorrhage. In the past, the perceived risk of intracranial hemorrhage limited the use of anticoagulation for the management of VTE with many favoring nonpharmacologic methods for prophylaxis and treatment. Inferior vena cava (IVC) filters have since lost favor at many centers given significant complications, which appear to be more frequent in patients with CNS malignancy. Recent studies have demonstrated safe and efficacious use of anticoagulation in these patients with a low incidence of intracranial hemorrhage. Treatment of established VTE is now recommended in this population with many centers favoring low-molecular-weight heparin (LMWH) versus oral warfarin for short- or long-term treatment. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, we recommend LMWH in patients with newly diagnosed VTE and a CNS malignancy. PMID- 22829389 TI - Oxime radical promoted dioxygenation, oxyamination, and diamination of alkenes: synthesis of isoxazolines and cyclic nitrones. PMID- 22829391 TI - Fusion of ultrasound B-mode and vibro-elastography images for automatic 3D segmentation of the prostate. AB - Prostate segmentation in B-mode images is a challenging task even when done manually by experts. In this paper we propose a 3D automatic prostate segmentation algorithm which makes use of information from both ultrasound B-mode and vibro-elastography data.We exploit the high contrast to noise ratio of vibro elastography images of the prostate, in addition to the commonly used B-mode images, to implement a 2D Active Shape Model (ASM)-based segmentation algorithm on the midgland image. The prostate model is deformed by a combination of two measures: the gray level similarity and the continuity of the prostate edge in both image types. The automatically obtained mid-gland contour is then used to initialize a 3D segmentation algorithm which models the prostate as a tapered and warped ellipsoid. Vibro-elastography images are used in addition to ultrasound images to improve boundary detection.We report a Dice similarity coefficient of 0.87+/-0.07 and 0.87+/-0.08 comparing the 2D automatic contours with manual contours of two observers on 61 images. For 11 cases, a whole gland volume error of 10.2+/-2.2% and 13.5+/-4.1% and whole gland volume difference of -7.2+/-9.1% and -13.3+/-12.6% between 3D automatic and manual surfaces of two observers is obtained. This is the first validated work showing the fusion of B-mode and vibro elastography data for automatic 3D segmentation of the prostate. PMID- 22829390 TI - Application of micro-computed tomography with iodine staining to cardiac imaging, segmentation, and computational model development. AB - Micro-computed tomography (micro-CT) has been widely used to generate high resolution 3-D tissue images from small animals nondestructively, especially for mineralized skeletal tissues. However, its application to the analysis of soft cardiovascular tissues has been limited by poor inter-tissue contrast. Recent ex vivo studies have shown that contrast between muscular and connective tissue in micro-CT images can be enhanced by staining with iodine. In the present study, we apply this novel technique for imaging of cardiovascular structures in canine hearts. We optimize the method to obtain high-resolution X-ray micro-CT images of the canine atria and its distinctive regions-including the Bachmann's bundle, atrioventricular node, pulmonary arteries and veins-with clear inter-tissue contrast. The imaging results are used to reconstruct and segment the detailed 3 D geometry of the atria. Structure tensor analysis shows that the arrangement of atrial fibers can also be characterized using the enhanced micro-CT images, as iodine preferentially accumulates within the muscular fibers rather than in connective tissues. This novel technique can be particularly useful in nondestructive imaging of 3-D cardiac architectures from large animals and humans, due to the combination of relatively high speed ( ~ 1 h/per scan of the large canine heart) and high voxel resolution (36 MUm) provided. In summary, contrast micro-CT facilitates fast and nondestructive imaging and segmenting of detailed 3-D cardiovascular geometries, as well as measuring fiber orientation, which are crucial in constructing biophysically detailed computational cardiac models. PMID- 22829392 TI - 3-D volume reconstruction of skin lesions for melanin and blood volume estimation and lesion severity analysis. AB - Subsurface information about skin lesions, such as the blood volume beneath the lesion, is important for the analysis of lesion severity towards early detection of skin cancer such as malignant melanoma. Depth information can be obtained from diffuse reflectance based multispectral transillumination images of the skin. An inverse volume reconstruction method is presented which uses a genetic algorithm optimization procedure with a novel population initialization routine and nudge operator based on the multispectral images to reconstruct the melanin and blood layer volume components. Forward model evaluation for fitness calculation is performed using a parallel processing voxel-based Monte Carlo simulation of light in skin. Reconstruction results for simulated lesions show excellent volume accuracy. Preliminary validation is also done using a set of 14 clinical lesions, categorized into lesion severity by an expert dermatologist. Using two features, the average blood layer thickness and the ratio of blood volume to total lesion volume, the lesions can be classified into mild and moderate/severe classes with 100% accuracy. The method therefore has excellent potential for detection and analysis of pre-malignant lesions. PMID- 22829393 TI - Is spreading depolarization characterized by an abrupt, massive release of gibbs free energy from the human brain cortex? AB - In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs-Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death. PMID- 22829394 TI - Molecular chaperones and co-chaperones in Parkinson disease. AB - Parkinson disease, a progressive neurodegenerative disorder, is caused by the pathological accumulation of proteins, including the ubiquitous presynaptic protein alpha-synuclein. Alterations in the metabolism of alpha-synuclein have clearly been linked to neurodegeneration, and early steps in the pathological sequence of this protein include the formation of oligomers, fibrils, and small aggregates. Targeting these early steps of oligomerization is one of the main therapeutic approaches in the quest to develop disease-modifying agents. Molecular chaperones, molecules that can mediate the proper folding and refolding of client proteins, are vital to cell function and survival and thus have been explored as potential therapeutic agents. Important to Parkinson disease, chaperones are capable of preventing alpha-synuclein misfolding, oligomerization, and aggregate formation as shown in vitro and in Parkinson disease animal models. Furthermore, chaperones and associated co-chaperones are closely linked to pathways of protein degradation, like the ubiquitin-proteasome system and autophagy, and are thus able to remove irreversibly misfolded proteins. In this review, we summarize the role of molecular chaperones in Parkinson disease models and discuss the importance of preserving protein homeostasis to prevent neurodegeneration. We also review the growing number of exciting studies that have targeted molecular chaperone function as a novel therapeutic approach. PMID- 22829395 TI - Models of care for the secondary prevention of osteoporotic fractures: a systematic review and meta-analysis. AB - Most people presenting with incident osteoporotic fractures are neither assessed nor treated for osteoporosis to reduce their risk of further fractures, despite the availability of effective treatments. We evaluated the effectiveness of published models of care for the secondary prevention of osteoporotic fractures. We searched eight medical literature databases to identify reports published between 1996 and 2011, describing models of care for secondary fracture prevention. Information extracted from each publication included study design, patient characteristics, identification strategies, assessment and treatment initiation strategies, as well as outcome measures (rates of bone mineral density (BMD) testing, osteoporosis treatment initiation, adherence, re-fractures and cost-effectiveness). Meta-analyses of studies with valid control groups were conducted for two outcome measures: BMD testing and osteoporosis treatment initiation. Out of 574 references, 42 articles were identified as analysable. These studies were grouped into four general models of care-type A: identification, assessment and treatment of patients as part of the service; type B: similar to A, without treatment initiation; type C: alerting patients plus primary care physicians; and type D: patient education only. Meta-regressions revealed a trend towards increased BMD testing (p = 0.06) and treatment initiation (p = 0.03) with increasing intensity of intervention. One type A service with a valid control group showed a significant decrease in re-fractures. Types A and B services were cost-effective, although definition of cost effectiveness varied between studies. Fully coordinated, intensive models of care for secondary fracture prevention are more effective in improving patient outcomes than approaches involving alerts and/or education only. PMID- 22829397 TI - Detection of recombinant growth hormone by evanescent cascaded waveguide coupler on silica-on-silicon. AB - An evanescent wave based biosensor is developed on the silica-on-silicon (SOS) with a cascaded waveguide coupler for the detection of recombinant growth hormone. So far, U -bends and tapered waveguides are demonstrated for increasing the penetration depth and enhancing sensitivity of the evanescent wave sensor. In this work, a monolithically integrated sensor platform containing a cascaded waveguide coupler with optical power splitters and combiners designed with S bends and tapper waveguides is demonstrated for an enhanced detection of recombinant growth hormone. In the cascaded waveguide coupler, a large surface area to bind the antibody with increased penetration depth of evanescent wave to excite the tagged-rbST is obtained by splitting the waveguide into multiple paths using Y splitters designed with s -bends and subsequently combining them back to a single waveguide through tapered waveguide and combiners. Hence a highly sensitive fluoroimmunoassay sensor is realized. Using the 2D FDTD (Finite difference time-domain method) simulation of waveguide with a point source in Rsoft FullWAVE, the fluorescence coupling efficiency of straight and bend section of waveguide is analyzed. The sensor is demonstrated for the detection of fluorescently-tagged recombinant growth hormone with the detection limit as low as 25 ng/ml. PMID- 22829396 TI - The interfascicular trigeminal nucleus: a precerebellar nucleus in the mouse defined by retrograde neuronal tracing and genetic fate mapping. AB - We have found a previously unreported precerebellar nucleus located among the emerging fibers of the motor root of the trigeminal nerve in the mouse, which we have called the interfascicular trigeminal nucleus (IF5). This nucleus had previously been named the tensor tympani part of the motor trigeminal nucleus (5TT) in rodent brain atlases, because it was thought to be a subset of small motor neurons of the motor trigeminal nucleus innervating the tensor tympani muscle. However, following injection of retrograde tracer in the cerebellum, the labeled neurons in IF5 were found to be choline acetyltransferase (ChAT) negative, indicating that they are not motor neurons. The cells of IF5 are strongly labeled in mice from Wnt1Cre and Atoh1 CreER lineage fate mapping, in common with the major precerebellar nuclei that arise from the rhombic lip and that issue mossy fibers. Analysis of sections from mouse Hoxa3, Hoxb1, and Egr2 Cre labeled lineages shows that the neurons of IF5 arise from rhombomeres caudal to rhombomere 4, most likely from rhombomeres 6-8. We conclude that IF5 is a significant precerebellar nucleus in the mouse that shares developmental gene expression characteristics with mossy fiber precerebellar nuclei that arise from the caudal rhombic lip. PMID- 22829398 TI - Impact of comorbidity on management and mortality in women diagnosed with breast cancer. AB - To investigate associations between comorbidity burden, management, and mortality in women with breast cancer. A total of 42,646 women diagnosed with breast cancer between 1992 and 2008 were identified in two Clinical Quality Registers in Central Sweden. Breast cancer-specific, conditional breast cancer, competing cause and all-cause mortality were estimated in relation to comorbidity burden assessed by the Charlson comorbidity index. All analyses were stratified by stage at diagnosis using competing risk analyses, and all-cause mortality was estimated as a function of follow-up time. Following adjustment for age and calendar period, breast conserving surgery was significantly less likely to be offered to women with severe comorbidity (OR 0.63; 95 % CI 0.58-0.69). Similarly, the proportion treated with radiotherapy, tamoxifen, or chemotherapy was lower in women with severe compared to those with no comorbidity. In women with early stage disease, breast cancer-specific mortality was higher among patients with severe comorbidity (sHR 1.47; 95 % CI 1.11-1.94). In all stages of breast cancer, conditional breast cancer and competing-cause mortality were elevated in women with severe comorbidity. For all stages, the relative risk of all-cause mortality between women with severe versus no comorbidity varied by time since diagnosis, and was most pronounced at early follow-up. Comorbidity affects treatment decisions and mortality. In women with early stage breast cancer, severe comorbidity was associated not only with conditional breast cancer, competing cause and all-cause mortality, but also breast cancer-specific mortality. The observed differences in breast cancer-specific mortality may be due to less extensive treatment, impaired tumor defense and differences in general health status and lifestyle factors. PMID- 22829399 TI - Adjuvant thyroid remnant ablation in patients with differentiated thyroid carcinoma confined to the thyroid: a comparison of ablation success with different activities of radioiodine (I-131). AB - OBJECTIVE: To assess efficiency of various I-131 activities on thyroid remnant ablation in thyroid cancer patients. The significance of patients' characteristics, pathologic features and levels of Tg were analyzed. PATIENTS AND METHODS: This study included 259 consecutive differentiated thyroid cancer patients, with disease confined to the thyroid, treated with I-131 after total thyroidectomy. Patients were divided into the three groups: 80 patients receiving low [1110-1850 MBq (30-50 mCi)], 121 intermediate [2775 MBq (75 mCi)] and 58 high [3700 MBq (100 mCi)] postoperative I-131 activities. Six to eight months after the application of radioiodine, measurements of TSH, Tg, anti-Tg antibodies (in hypothyroid state) together with ultrasound exam and whole-body scintigraphy were performed. RESULTS: The ablation was significantly more effective (after the first application) in patients receiving 100 mCi of I-131-89.7% than in patients receiving lower activities (P = 0.016). There was no significant difference in ablation rate between the 30-50 mCi (77.5%) and 75 mCi (70.2%) groups. In the group receiving 30-50 mCi, patients with solitary tumors had significantly higher ablation rate (P = 0.038). In patients receiving 75 mCi ablation rates were higher among older patients (P = 0.005), with infiltration of the single lobe (P = 0.005), and with solitary tumor (P = 0.012). The rates of successful ablation after the second application of I-131 (after 12-16 months) amounted to 96, 97 and 96% in the 30-50, 75 and 100 mCi groups, respectively. The activity of I-131 and age were independent factors for thyroid ablation failure after the first application of I-131 (model of binary logistic regression). CONCLUSION: The results of remnant ablation were satisfactory with all activities applied. Although after the first application of I-131 the activity of 100 mCi is significantly more effective in thyroid ablation than the administration of 30-50 mCi and 75 mCi, the ablation rates between all the three groups are similar (almost equal) after the second application. Thus, the activity to be administered may depend on patients' characteristics and a detailed consideration of the merits and demerits of each I-131 activity. PMID- 22829401 TI - Multimodal graph-based reranking for web image search. AB - This paper introduces a web image search reranking approach that explores multiple modalities in a graph-based learning scheme. Different from the conventional methods that usually adopt a single modality or integrate multiple modalities into a long feature vector, our approach can effectively integrate the learning of relevance scores, weights of modalities, and the distance metric and its scaling for each modality into a unified scheme. In this way, the effects of different modalities can be adaptively modulated and better reranking performance can be achieved. We conduct experiments on a large dataset that contains more than 1000 queries and 1 million images to evaluate our approach. Experimental results demonstrate that the proposed reranking approach is more robust than using each individual modality, and it also performs better than many existing methods. PMID- 22829402 TI - Shadow removal using bilateral filtering. AB - In this paper, we propose a simple but effective shadow removal method using a single input image. We first derive a 2-D intrinsic image from a single RGB camera image based solely on colors, particularly chromaticity. We next present a method to recover a 3-D intrinsic image based on bilateral filtering and the 2-D intrinsic image. The luminance contrast in regions with similar surface reflectance due to geometry and illumination variances is effectively reduced in the derived 3-D intrinsic image, while the contrast in regions with different surface reflectance is preserved. However, the intrinsic image contains incorrect luminance values. To obtain the correct luminance, we decompose the input RGB image and the intrinsic image. Each image is decomposed into a base layer and a detail layer. We obtain a shadow-free image by combining the base layer from the input RGB image and the detail layer from the intrinsic image such that the details of the intrinsic image are transferred to the input RGB image from which the correct luminance values can be obtained. Unlike previous methods, the presented technique is fully automatic and does not require shadow detection. PMID- 22829400 TI - Hollow copper sulfide nanoparticle-mediated transdermal drug delivery. AB - A photothermal ablation-enhanced transdermal drug delivery methodology is developed based on hollow copper sulfide nanoparticles (HCuSNPs) with intense photothermal coupling effects. Application of nanosecond-pulsed near-infrared laser allows rapid heating of the nanoparticles and instantaneous heat conduction. This provides very short periods of time but extremely high temperatures in local regions, with focused thermal ablation of the stratum corneum. The depth of skin perforations can be controlled by adjusting the laser power. Skin disruption by HCuSNP-mediated photothermal ablation significantly increases the permeability of human growth hormone. This technique offers compelling opportunities for macromolecular drug and vaccine delivery. PMID- 22829403 TI - Single image super-resolution with non-local means and steering kernel regression. AB - Image super-resolution (SR) reconstruction is essentially an ill-posed problem, so it is important to design an effective prior. For this purpose, we propose a novel image SR method by learning both non-local and local regularization priors from a given low-resolution image. The non-local prior takes advantage of the redundancy of similar patches in natural images, while the local prior assumes that a target pixel can be estimated by a weighted average of its neighbors. Based on the above considerations, we utilize the non-local means filter to learn a non-local prior and the steering kernel regression to learn a local prior. By assembling the two complementary regularization terms, we propose a maximum a posteriori probability framework for SR recovery. Thorough experimental results suggest that the proposed SR method can reconstruct higher quality results both quantitatively and perceptually. PMID- 22829404 TI - Turbid scene enhancement using multi-directional illumination fusion. AB - Ambient light is strongly attenuated in turbid media. Moreover, natural light is often more highly attenuated in some spectral bands, relative to others. Hence, imaging in turbid media often relies heavily on artificial sources for illumination. Scenes irradiated by an off-axis single point source have enhanced local object shadow edges, which may increase object visibility. However, the images may suffer from severe nonuniformity, regions of low signal (being distant from the source), and regions of strong backscatter. On the other hand, simultaneously illuminating the scene from multiple directions increases the backscatter and fills-in shadows, both of which degrade local contrast. Some previous methods tackle backscatter by scanning the scene, either temporally or spatially, requiring a large number of frames. We suggest using a few frames, in each of which wide field scene irradiance originates from a different direction. This way, shadow contrast can be maintained and backscatter can be minimized in each frame, while the sequence at large has a wider, more spatially uniform illumination. The frames are then fused by post processing to a single, clearer image. We demonstrate significant visibility enhancement underwater using as little as two frames. PMID- 22829405 TI - Efficient algorithm for nonconvex minimization and its application to PM regularization. AB - In image processing, nonconvex regularization has the ability to smooth homogeneous regions and sharpen edges but leads to challenging computation. We propose some iterative schemes to minimize the energy function with nonconvex edge-preserving potential. The schemes are derived from the duality-based algorithm proposed by Bermudez and Moreno and the fixed point iteration. The convergence is proved for the convex energy function with nonconvex potential and the linear convergence rate is given. Applying the proposed schemes to Perona and Malik's nonconvex regularization, we present some efficient algorithms based on our schemes, and show the approximate convergence behavior for nonconvex energy function. Experimental results are presented, which show the efficiency of our algorithms, including better denoised performance of nonconvex regularization, faster convergence speed, higher calculation precision, lower calculation cost under the same number of iterations, and less implementation time under the same peak signal noise ratio level. PMID- 22829406 TI - Robust weighted graph transformation matching for rigid and nonrigid image registration. AB - This paper presents an automatic point matching algorithm for establishing accurate match correspondences in two or more images. The proposed algorithm utilizes a group of feature points to explore their geometrical relationship in a graph arrangement. The algorithm starts with a set of matches (including outliers) between the two images. A set of nondirectional graphs is then generated for each feature and its K nearest matches (chosen from the initial set). Using the angular distances between edges that connect a feature point to its K nearest neighbors in the graph, the algorithm finds a graph in the second image that is similar to the first graph. In the case of a graph including outliers, the algorithm removes such outliers (one by one, according to their strength) from the graph and re-evaluates the angles until the two graphs are matched or discarded. This is a simple intuitive and robust algorithm that is inspired by a previous work. Experimental results demonstrate the superior performance of this algorithm under various conditions, such as rigid and nonrigid transformations, ambiguity due to partial occlusions or match correspondence multiplicity, scale, and larger view variation. PMID- 22829407 TI - Separable Markov random field model and its applications in low level vision. AB - This brief proposes a continuously-valued Markov random field (MRF) model with separable filter bank, denoted as MRFSepa, which significantly reduces the computational complexity in the MRF modeling. In this framework, we design a novel gradient-based discriminative learning method to learn the potential functions and separable filter banks. We learn MRFSepa models with 2-D and 3-D separable filter banks for the applications of gray-scale/color image denoising and color image demosaicing. By implementing MRFSepa model on graphics processing unit, we achieve real-time image denoising and fast image demosaicing with high quality results. PMID- 22829408 TI - Stereoselective synthesis of D- and L-carbocyclic nucleosides by enzymatically catalyzed kinetic resolution. AB - An efficient synthesis of (S)- or (R)-3-(benzyloxy-methyl)-cyclopent-3-enol was developed by appling an enzyme-catalyzed kinetic-resolution approach. This procedure allowed the syntheses of the enantiomeric building blocks (S)- and (R) cyclopentenol with high optical purity (>98 % ee). In contrast to previous approaches, the key advantage of this procedure is that the resolution is done on the level of enantiomers that only contain one stereogenic center. Owing to this feature, it was possible to chemically convert the enantiomers into each other. By using this route, the starting materials for the syntheses of carbocyclic D- and L-nucleoside analogues were readily accessible. 3',4'-Unsaturated D- or L carbocyclic nucleosides were obtained from the condensation of various nucleobases with (S)- or (R)-cyclopentenol. Functionalization of the double bond in 3'-deoxy-3',4'-didehydro-carba-D-thymidine led to a variety of new nucleoside analogues. By using the cycloSal approach, their corresponding phosphorylated metabolites were readily accessable. Moreover, a new synthetic route to carbocyclic 2'-deoxy-nucleosides was developed, thereby leading to D- and L-carba dT. D-Carba-dT was tested for antiviral activity against multidrug-resistance HIV 1 strain E2-2 and compared to the known antiviral agent d4T, as well as L-carba dT. Whilst L-carba-dT was found to be inactive, its D-analogue showed remarkably high activity against the resistant virus and significantly better than that of d4T. However, against the wild-type virus strain NL4/3, d4T was found to be more active than D-carba-dT. PMID- 22829409 TI - DFT calculations suggest a new type of self-protection and self-inhibition mechanism in the mammalian heme enzyme myeloperoxidase: nucleophilic addition of a functional water rather than one-electron reduction. AB - The mammalian heme enzyme myeloperoxidase (MPO) catalyzes the reaction of Cl(-) to the antimicrobial-effective molecule HOCl. During the catalytic cycle, a reactive intermediate "Compound I" (Cpd I) is generated. Cpd I has the ability to destroy the enzyme. Indeed, in the absence of any substrate, Cpd I decays with a half-life of 100 ms to an intermediate called Compound II (Cpd II), which is typically the one-electron reduced Cpd I. However, the nature of Cpd II, its spectroscopic properties, and the source of the additional electron are only poorly understood. On the basis of DFT and time-dependent (TD)-DFT quantum chemical calculations at the PBE0/6-31G* level, we propose an extended mechanism involving a new intermediate, which allows MPO to protect itself from self oxidation or self-destruction during the catalytic cycle. Because of its similarity in electronic structure to Cpd II, we named this intermediate Cpd II'. However, the suggested mechanism and our proposed functional structure of Cpd II' are based on the hypothesis that the heme is reduced by charge separation caused by reaction with a water molecule, and not, as is normally assumed, by the transfer of an electron. In the course of this investigation, we found a second intermediate, the reduced enzyme, towards which the new mechanism is equally transferable. In analogy to Cpd II', we named it Fe(II'). The proposed new intermediates Cpd II' and Fe(II') allow the experimental findings, which have been well documented in the literature for decades but not so far understood, to be explained for the first time. These encompass a) the spontaneous decay of Cpd I, b) the unusual (chlorin-like) UV/Vis, circular dichroism (CD), and resonance Raman spectra, c) the inability of reduced MPO to bind CO, d) the fact that MPO Cpd II reduces SCN(-) but not Cl(-), and e) the experimentally observed auto oxidation/auto-reduction features of the enzyme. Our new mechanism is also transferable to cytochromes, and could well be viable for heme enzymes in general. PMID- 22829410 TI - syn-Selective asymmetric Mannich reaction of sulfonyl imines with iminoesters catalyzed by the N,N,N-tridentate bis(imidazolidine)pyridine (PyBidine)-Cu(OTf)2 complex. PMID- 22829411 TI - Non-operative management of acute cholecystitis in the elderly. AB - BACKGROUND: Although cholecystectomy is the standard therapy for acute cholecystitis (AC), operative morbidity in the elderly may be high owing to medical co-morbidities and decreased physiological reserve. Outcomes of AC in the elderly have not been fully defined with regard to operative and long-term non operative management. METHODS: Patients aged 65 years or over admitted to a tertiary care centre with a diagnosis of AC between January 2000 and December 2009 were reviewed retrospectively. Patient data, operative and postoperative details were obtained. To determine cholecystectomy rates in the non-operative group, medical records were reviewed, and patients and families were interviewed. RESULTS: A total of 290 patients underwent cholecystectomy during the index admission, of whom 59 (20.3 per cent) required conversion to open operation. Fifty-eight of these patients experienced 98 complications, including acute respiratory failure (27), pneumonia (18), myocardial infarction (16) and sepsis (15). Some 185 patients had non-operative treatment, of whom 67 underwent percutaneous cholecystostomy. Forty-four patients subsequently had elective cholecystectomy, with a complication rate of 23 per cent. One hundred and twenty six patients were discharged without a plan for cholecystectomy; the rate of recurrent AC was 4 per cent among the two-thirds of patients followed to within 15 months of death. No deaths or major complications occurred among those with recurrent AC. CONCLUSION: Despite selection of the best elderly candidates for cholecystectomy, postoperative morbidity was significant. Medical management, with interval cholecystectomy only for recurrent AC, may be appropriate in selected patients. PMID- 22829412 TI - The frequency of antibodies against cyclic citrullinated peptides and rheumatoid factor in healthy population: a field study of rheumatoid arthritis from northern Turkey. AB - Rheumatoid arthritis (RA) is a chronic, systemic and an autoimmune disease characterized by inflammation of the synovial membrane that affects approximately 1 % of the total world population. Rheumatoid factor (RF) is a widely used auto antibody in diagnosis of the RA and found positive in 50-80 % of the patients but with a lower specificity. On the other hand, anti-cyclic citrullinated peptide (anti-CCP) is the latest serological marker with a specificity around 98 %. This field survey was conducted in different regions to investigate the frequency of RF and anti-CCP and also frequency of RA in a northern province of Turkey. This study was conducted in 70 local areas (12 urban and 58 rural) in the province of Tokat, which is located in northern Turkey. The population of Tokat was reported to be 828,000 at the last census and about 530,000 individuals aged > 18 years old. The study population of 941 subjects (462 male and 479 female; urban 501 and rural 440) was selected by random sampling method among 530,000 individuals. Of the 941 healthy controls assigned to the study, 479 of them were female (51 %) and 462 of them were males (49 %), and median age of all participants was 41 +/- 17. Twenty-six subjects were RF positive (2.8 %), and 9 patients were anti-CCP positive (1 %). The presence of both RF and anti-CCP antibodies has also been shown in two patients (0.2 %). In conclusion, we demonstrated that the frequency of RA was 0.53 %, RF presence was 2.8 %, and anti-CCP presence was 1 % in total 941 healthy subjects enrolled into study. PMID- 22829413 TI - Intravenous immunoglobulin in Henoch-Schonlein purpura complicated by cerebral hemorrhage. PMID- 22829415 TI - Medical students' attitude towards rheumatology training at foundation years' level in the UK and rationale behind the students' choice: results from a national survey. AB - The aims are to assess whether medical students are interested in rheumatology as a training post during post-medical-school and prior to specialty training that is covered by foundation years (FY) training in the UK, to determine the time spent in the undergraduate training in rheumatology and whether the desire for musculoskeletal (MsK) medicine training (rheumatology and orthopaedics taken together) is enhanced during FY training and to analyse the rationale behind their choice for rheumatology alone or combined with orthopaedics. An online questionnaire was distributed to all 31 UK medical schools, addressed to fourth-, fifth- and sixth-year medical students. The questionnaire was completed by 256 students from 11 of 31 medical schools existed in the UK in 2009. Most respondents (n = 156; 60.9 %) received 3 weeks (96 h) exposure to rheumatology, whilst one-fifth (n = 53; 20.7 %) had received no exposure in rheumatology. A total of 122 students of the 256 that responded (47.6 %) would like to do rheumatology as part of their training and 116 (45.3 %) would like to have more posts available in rheumatology. However, when asked to choose 6 specialties, out of 21, which would be most useful for post-university training, rheumatology was amongst the bottom three, attracting only 9.4 % of respondent students. A total of 68 of 256 (26.5 %) students, however, expressed a desire for MsK medicine: 44/256 (17.1 %) for orthopaedics and 24/256 (9.4 %) for rheumatology. From a total of 49 of 256 (19.1 %) open-ended responses obtained, 25 (51 %) were from those medical students willing to have exposure in MsK medicine: 15 of 44 (34 %) willing to have orthopaedics and 10 of 24 (41.6 %) willing to have rheumatology. Analysis of the responses revealed that it is mostly the specialty choice that guides towards specialty training. One in five of the medical students responded to had received (actual or perceived) no exposure to rheumatology during their undergraduate years. Career choice that derived mostly from undergraduate exposure is the driving force behind medical students' choice for foundation year training. PMID- 22829414 TI - Does cigarette smoking mitigate the severity of skin disease in systemic sclerosis? AB - Cigarette smoking has significant negative effects on vascular, pulmonary and gastrointestinal outcomes in systemic sclerosis (SSc). The objective of this study was to study the effect of cigarette smoking on the extent of skin disease in SSc. Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-reports. The extent of skin involvement was measured using the modified Rodnan skin score. The effect of smoking on the skin score was assessed using the comprehensive smoking index (CSI), which integrates smoking intensity, duration and time since cessation into a single covariate of smoking effect. The regression model was adjusted for gender, ethnicity and disease duration. This study included 606 SSc patients, of which 87 % were women and 90 % were white; mean disease duration was 11 (+/-9) years, and mean modified Rodnan skin score was 10 (+/-9). Of these, 16 % were current, 42 % past and 42 % never smokers. There was a 16 % reduction in skin score (odds ratio 0.84, 95 % confidence interval 0.75, 0.95, p = 0.0029) for every 0.1 unit change in CSI. The effect of smoking on skin disease appeared cumulative and irreversible. Smoking was significantly associated with less extensive skin disease in SSc. This hypothesis-generating study provides new avenues of research, especially insofar as the role of nicotine in SSc is concerned and given that safe nicotine replacement therapy exists. PMID- 22829416 TI - Elastic-Net Prefiltering for Two-Class Classification. AB - A two-stage linear-in-the-parameter model construction algorithm is proposed aimed at noisy two-class classification problems. The purpose of the first stage is to produce a prefiltered signal that is used as the desired output for the second stage which constructs a sparse linear-in-the-parameter classifier. The prefiltering stage is a two-level process aimed at maximizing a model's generalization capability, in which a new elastic-net model identification algorithm using singular value decomposition is employed at the lower level, and then, two regularization parameters are optimized using a particle-swarm optimization algorithm at the upper level by minimizing the leave-one-out (LOO) misclassification rate. It is shown that the LOO misclassification rate based on the resultant prefiltered signal can be analytically computed without splitting the data set, and the associated computational cost is minimal due to orthogonality. The second stage of sparse classifier construction is based on orthogonal forward regression with the D-optimality algorithm. Extensive simulations of this approach for noisy data sets illustrate the competitiveness of this approach to classification of noisy data problems. PMID- 22829417 TI - To kidney or not to kidney, when ... is the question. PMID- 22829418 TI - Influence of kinship on donors' mental burden in living donor liver transplantation. AB - In the context of living donor liver transplantation (LDLT), German transplantation law stipulates that donor candidates should primarily be relatives of the recipients or persons with distinct and close relationships. In this study, we investigated the influence of the relationship between the donor and the recipient on the donor's emotional strain before transplantation. Donors were categorized according to the following subgroups: (1) parents donating for their children, (2) children donating for their parents, (3) siblings, (4) spouses, (5) other relatives, and (6) nonrelatives. The sample consisted of 168 donor candidates. Anxiety (F = 2.8, P = 0.02), depression (F = 2.6, P = 0.03), and emotional quality of life (F = 3.1, P = 0.01) differed significantly according to the relationship between the donor and the recipient. In comparison with healthy controls, parents donating for their children were significantly less stressed before LDLT and demonstrated fewer anxiety (P < 0.01) and depression symptoms (P < 0.05). Adult children donating for their parents demonstrated the highest mental burden and the lowest emotional quality of life. However, this was not due to the responsibility of these children for their own families because differences between donors with children and donors without children could not be ascertained. This group should be given special attention before LDLT and during follow-up visits, and psychological help should be provided when it is necessary. PMID- 22829419 TI - Hepatitis B surface antigen as a marker for recurrent, metastatic hepatocellular carcinoma after liver transplantation. PMID- 22829421 TI - An amphiphilic dendrimer for effective delivery of small interfering RNA and gene silencing in vitro and in vivo. AB - An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimer vectors to deliver a heat shock protein 27 siRNA and produce potent gene silencing and anticancer activity in vitro and in vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases. PMID- 22829422 TI - A comparison of estimators to evaluate the discriminatory power of time-to-event models. AB - Discrimination measures for continuous time-to-event outcomes have become an important tool in medical decision making. The idea behind discrimination measures is to evaluate the performance of a prediction model by measuring its ability to distinguish between observations having an event and those having no event. Researchers proposed a variety of approaches to estimate discrimination measures from a set of right-censored data. These approaches rely on different regularity assumptions that are needed to ensure consistency of the respective estimators. Typical examples of regularity assumptions include the proportional hazards assumption in Cox regression and the random censoring assumption. Because regularity assumptions are often violated in practice, conducting a sensitivity analysis of the estimators is of considerable interest. The aim of the paper is to analyze and to compare the most popular estimators of discrimination measures for event time outcomes. On the basis of the results of an extensive simulation study and the analysis of molecular data, we investigate the behavior of the estimators in situations where the underlying regularity assumptions do not hold. We show that violations of the regularity assumptions may induce a nonignorable bias and may therefore result in biased medical decision making. PMID- 22829423 TI - Developmental dyslexia: exploring how much phonological and visual attention span disorders are linked to simultaneous auditory processing deficits. AB - The simultaneous auditory processing skills of 17 dyslexic children and 17 skilled readers were measured using a dichotic listening task. Results showed that the dyslexic children exhibited difficulties reporting syllabic material when presented simultaneously. As a measure of simultaneous visual processing, visual attention span skills were assessed in the dyslexic children. We presented the dyslexic children with a phonological short-term memory task and a phonemic awareness task to quantify their phonological skills. Visual attention spans correlated positively with individual scores obtained on the dichotic listening task while phonological skills did not correlate with either dichotic scores or visual attention span measures. Moreover, all the dyslexic children with a dichotic listening deficit showed a simultaneous visual processing deficit, and a substantial number of dyslexic children exhibited phonological processing deficits whether or not they exhibited low dichotic listening scores. These findings suggest that processing simultaneous auditory stimuli may be impaired in dyslexic children regardless of phonological processing difficulties and be linked to similar problems in the visual modality. PMID- 22829424 TI - Night-time EKG and HRV monitoring with bed sheet integrated textile electrodes. AB - A system for unobtrusive night-time electrocardiogram (EKG) and heart rate variability (HRV) monitoring as well as data analysis methods are presented, comparing bed sheet HR and HRV values with corresponding parameters obtained by a reference measurement. Our system uses eight embroidered textile electrodes attached laterally to a bed sheet for measuring bipolar contact EKG from multiple channels. The electrodes are arranged in a line so that at least two adjacent electrodes make sufficient skin contact. The focus of the signal processing development has been on selecting the best measurement channel for further analysis and minimizing the amount of incorrectly detected R-peaks. The test measurements were performed with four healthy men without previously known cardiac disorders and one who frequently had premature ventricular contractions (ectopic beats). For healthy test subjects, an average of 94.9% heartbeat detection coverage was achieved with the system during 29 measurement nights (in total 213.8 h of data). In most cases, the quality of the signal obtained from bed sheet electrodes is good enough for the computer-assisted cardiac arrhythmia detection. Applications for EKG derived RR-interval data include the calculation of HRV parameters that can be utilized in sleep quality analysis and other wellness-related topics as well as sleep apnoea detection. PMID- 22829425 TI - Establishment of parameters for congenital stenosis of the cervical spine: an anatomic descriptive analysis of 1,066 cadaveric specimens. AB - PURPOSE: Congenital cervical stenosis (CCS) occurs when the bony anatomy of the cervical canal is smaller than expected in the general population predisposing an individual to symptomatic neural compression. No studies have defined CCS based on the normal population. The diagnosis is currently made based on clinical impression from radiographic studies. The aim of this study is to establish parameters that are associated with CCS, based on anatomic measurements on a large sample of skeletal specimens. METHODS: From the Hamann-Todd collection at the Cleveland Museum of Natural History, 1,066 skeletal specimens were selected. Digital calipers were used to measure the sagittal canal diameter (SCD), interpedicular distance (IPD), and pedicle length. Canal area at each level was calculated using a geometric formula. A standard distribution was created and values that were 2 SD below mean were considered as congenitally stenotic. An analysis of deviance was performed to identify parameters that were associated with CCS. Regression analysis was used to determine odds ratios (OR) for CCS using these parameters. RESULTS: CCS was defined at each level as: C3/4 = 1.82 cm(2), C4/5 = 1.80 cm(2), C5/6 = 1.84 cm(2), C6/7 = 1.89 cm(2), C7/T1 = 1.88 cm(2). Values of SCD < 13 mm and IPD < 22.5 mm were associated with CCS and yielded sensitivities and specificities of 88-100 % at each level. Logistic regression demonstrated a significant association between these parameters and presence of CCS with OR > 18 at each level. CONCLUSIONS: Based on our study of a large population of adult skeletal specimens, we have defined CCS at each level. Values of SCD < 13 mm and IPD < 23 mm are strongly associated with the presence of CCS at all levels. PMID- 22829428 TI - Effects of manganese from a commercial multi-trace element supplement in a population sample of Canadian patients on long-term parenteral nutrition. AB - BACKGROUND: Long-term parenteral nutrition (PN) can be associated with micronutrient deficiency or toxicity depending on supplementation. Recently, hypermanganesemia and potential neurological toxicity were reported. The aim of this study was to assess the effect of manganese supplementation in a sample of patients on long-term PN receiving manganese (Mn) as part of a multi-trace element (TE) supplement. METHODS: A convenience sample of 16 patients underwent clinical and blood biochemical measurements as well as magnetic resonance imaging (MRI) of the brain. Descriptive statistics were performed. RESULTS: The mean daily Mn supplementation was 7.28 +/- 0.97 umol/d (400 +/- 53 ug/d), which was within the American Medical Association Nutrition Advisory Group guidelines of 2.73-14.56 MUmol/d (150-800 ug/d) but exceeded the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) 2002 recommendations of 1.09-1.82 umol/d (60-100 ug/d). The mean whole blood Mn level was 1.38 +/- 0.29 times the upper limit of normal (ULN), and 8 of 14 patients with blood measurements had Mn levels above ULN. On MRI, 81% of patients had high signals on T1-weighted images assumed to be Mn deposits in their basal ganglia. Two patients with positive MRI (15%) had a clinical diagnosis of Parkinson disease. Multiple neuropsychiatric complaints were reported, including depression (66%), lack of concentration (42%), memory disturbances (17%), and gait instability (8%). CONCLUSION: These results suggest that Mn status is elevated in these patients. Manganese supplementation should be used with caution in patients receiving long-term PN, and attention should be paid to the Mn content of multi-TE supplements. PMID- 22829427 TI - Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. AB - Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFbeta) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFbeta activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms. PMID- 22829429 TI - The coordination of NiII and Cu(II) ions to the polyhistidyl motif of Hpn protein: is it as strong as we think? AB - Hpn, one of Helicobacter pylori's nickel-accessory proteins, is an amazingly peculiar protein: Almost half of its sequence consists of polyhistidyl (poly-His) residues. Herein, we try to understand the origin of this naturally occurring sequence, thereby shedding some light on the bioinorganic chemistry of Hpn's numerous poly-His repeats. By using potentiometric, mass spectrometric, and various spectroscopic techniques, we studied the Ni(II) - and Cu(II) complexes of the wild-type Ac-THHHHYHGG-NH(2) fragment of Hpn and of its six analogues, in which consecutive residues (His or Tyr) were replaced by Ala (Ala-substitution or Ala-scan approaches), thereby resulting in Ac-TAHHHYHGG-NH(2), Ac-THAHHYHGG NH(2), Ac-THHAHYHGG-NH(2), Ac-THHHAYHGG-NH(2), Ac-THHHHAHGG-NH(2), and Ac THHHHYAGG-NH(2) peptides. We found that the His4 residue is critical for both Ni(II) - and Cu(II) -ion binding and the effectiveness of binding varies even if the substituted amino acid does not take part in the direct binding interactions. PMID- 22829430 TI - Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction. AB - OBJECTIVE: Excess vitamin A may interrupt vitamin D-mediated transcription of target genes. This study investigated whether serum 25-hydroxyvitamin D [25(OH)D] concentrations were associated with lung cancer mortality, and whether this association varied by excess circulating vitamin A and vitamin A/beta-carotene supplement use. METHOD: We analyzed 16,693 men and women in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Lung cancer mortality (n = 258, 104 were former smokers and 23 were never smokers) were identified through National Death Index as of 2006. Serum 25(OH)D was measured by a radioimmunoassay. Vitamin A biomarkers including serum retinol, beta-carotene, and retinyl esters were measured by HPLC. Supplement use for the past month was obtained by self-report. Multivariate-adjusted hazard ratios (HR) were estimated by Cox proportional hazard models. RESULTS: There was no association of serum 25(OH)D with overall lung cancer mortality. Among nonsmokers, >=44 vs. <44 nmol/L of serum 25(OH)D was associated with a decreased risk (HR = 0.53, 95 % CI = 0.31 0.92, former/never smokers and HR = 0.31, 95 % CI = 0.13-0.77, distant-former [quit >=20 years]/never smokers). The associations were not observed among participants with excess circulating vitamin A (serum retinyl esters >=7.0 MUg/dL or the ratio of retinyl esters to retinol >=0.08) or vitamin A/beta-carotene supplement users. However, statistical evidence to support effect modification of vitamin A was less clear. CONCLUSIONS: Serum 25(OH)D concentrations were inversely associated with lung cancer mortality in nonsmokers. The beneficial association was diminished among those with excess circulating vitamin A or vitamin A/beta-carotene supplement users. PMID- 22829431 TI - Associative blocking to reward-predicting cues is attenuated in ketamine users but can be modulated by images associated with drug use. AB - RATIONALE: Blocking is an associative learning process that is attenuated in schizophrenia, can be modulated by cue salience and is accompanied by changes in selective attention. Repeated exposure to ketamine can model aspects of schizophrenia, and frequent users selectively attend to images of the drug. OBJECTIVES: This study aimed to establish whether (1) ketamine users show attenuated blocking to reward-predicting cues and (2) drug cues can modulate blocking and cause overshadowing of neutral cues that are equally predictive of reward in these individuals. METHODS: Ketamine users (n = 18) and polydrug controls (n = 16) were assessed on the Drug Cue Reward Prediction Error Task, which indexes blocking and overshadowing to neutral and drug-related cues following Pavlovian reward conditioning. Schizotypy, depression, drug history and ketamine dependence were also assessed. RESULTS: Compared to controls, ketamine users showed elevated delusional, schizotypal and depressive symptoms, and a reduction in blocking as evidenced by higher accuracy to blocked cues. Drug related cues were resistant to blocking and seen as more important for earning money by ketamine users compared to controls. Both groups showed overshadowing of neutral cues by drug cues, and ketamine users gave both of these cues higher importance ratings than controls. CONCLUSIONS: These findings provide the first evidence that (1) glutamatergic perturbation is linked to a reduction in blocking and (2) blocking can be modulated by the presence of drug-related cues. The ability of drug cues to bias selective learning about 'alternative rewards' has implications for contingency management based addiction treatments. PMID- 22829432 TI - Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory. AB - RATIONALE: Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition. OBJECTIVE: The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories. METHODS: For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval. RESULTS: Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals' preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement. CONCLUSIONS: Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation. PMID- 22829434 TI - Direct alpha-functionalization of saturated cyclic amines. AB - Recent advances in synthetic methods for the direct alpha-functionalization of saturated cyclic amines are described. Methods are categorized according to the in situ formed reactive intermediate (alpha-amino cation, alpha-amino anion, and alpha-amino radical). Transition-metal-catalyzed reactions involving other intermediates have been treated as a separate and fourth class. PMID- 22829433 TI - Tolerance and sensitization to chronic escalating dose heroin following extended withdrawal in Fischer rats: possible role of mu-opioid receptors. AB - RATIONALE/OBJECTIVES: Heroin addiction is characterized by recurrent cycles of drug use, abstinence, and relapse. It is likely that neurobiological changes during chronic heroin exposure persist across withdrawal and impact behavioral responses to re-exposure. We hypothesized that, after extended withdrawal, heroin withdrawn rats would express behavioral tolerance and/or sensitization in response to heroin re-exposure and that these responses might be associated with altered mu-opioid receptor (MOPr) activity. METHODS: Male Fischer rats were exposed chronically to escalating doses of heroin (7.5-75 mg/kg/day), experienced acute spontaneous withdrawal and extended (10-day) abstinence, and were re exposed chronically to heroin. Homecage behaviors and locomotor activity in response to heroin, as well as somatic withdrawal signs, were recorded. Separate groups of rats were sacrificed after extended abstinence and MOPr expression and G-protein coupling were analyzed using [(3)H]DAMGO and [(35)S]GTPgammaS assays. RESULTS: The depth of behavioral stupor was lower during the initial days of heroin re-exposure compared to the initial days of the first exposure period. Behavioral responses (e.g., stereotypy) and locomotion were elevated in response to heroin re-exposure at low doses. Rats conditioned for heroin place preference during the chronic re-exposure period expressed heroin preference during acute withdrawal; this preference was stronger than rats conditioned during chronic heroin exposure that followed chronic saline and injection-free periods. Extended withdrawal was associated with increased MOPr expression in the caudate-putamen and frontal and cingulate cortices. No changes in G-protein coupling were identified. CONCLUSIONS: Aspects of tolerance/sensitization to heroin are present even after extended abstinence and may be associated with altered MOPr density. PMID- 22829435 TI - Monomer-dimer control and crystal engineering in TASPs. AB - We have reported a template assembled synthetic protein (cavitein Q4) as an unexpected dimer in the solid state and as a monomer-dimer equilibrium in solution. We have since reported an ability to bias a cavitein's monomer-dimer equilibrium in solution by sequence design involving histidine metal chelation or disulfide incorporation. However, little remains known about the forces contributing to dimeric cavitein crystal nucleation and lattice stabilization. We, therefore, designed glutamine variants to probe factors involved in dimeric cavitein crystallization. It was found that a key glutamate hydrogen-bonding interaction between dimers is integral to crystal formation and stabilization. Additionally, we obtained a crystal structure of a cavitein (Q4-E3H) designed to bias the dimeric structure via histidine metal coordination. The resolved structure indicates a histidine cluster interaction that likely accounts for the biased dimeric form observed in solution. PMID- 22829436 TI - Contrast-enhanced intraoperative ultrasonography using perfluorobutane microbubbles for the enumeration of colorectal liver metastases. AB - BACKGROUND: Intraoperative ultrasonography (IOUS) is considered the standard for the identification of liver metastases. Use of lipid-stabilized perfluorobutane microbubbles as an ultrasound contrast agent may improve this. The value of contrast-enhanced IOUS (CE-IOUS) in enumerating colorectal liver metastases was studied here. METHODS: CE-IOUS was performed in consecutive resections for colorectal liver metastases in 2007-2010. All patients underwent preoperative computed tomography. Magnetic resonance imaging was not carried out routinely. Conventional intraoperative examination including IOUS, and CE-IOUS with peripherally injected contrast were performed. The histopathological findings and 6-month follow-up images were used as the reference standard. RESULTS: The study group of 102 patients had a total of 315 lesions identified on preoperative imaging (2.4 lesions per operation; 129 operations). Conventional intraoperative examination including IOUS identified 350 lesions (2.7 per operation). CE-IOUS identified 370 lesions (2.9 per operation). The sensitivity, specificity and accuracy of CE-IOUS were 97.1, 59.1 and 93.2 per cent respectively. The CE-IOUS findings altered the surgical plan in 19 operations (14.7 per cent). CONCLUSION: CE-IOUS provided additional information to that obtained using contemporary preoperative imaging and conventional intraoperative examinations. PMID- 22829437 TI - From crime scene actions in stranger rape to prediction of rapist type: single victim or serial rapist? AB - The differences in crime scene actions in cases of stranger rape committed by convicted offenders were examined between 31 single-victim rapists and 35 serial rapists. Data were collected from police files, court verdicts, psychiatric evaluations, and criminal records. Findings indicate that the serial rapists were more criminally sophisticated than the single-victim rapists, during their first and second rapes. The single-victim rapists were significantly more likely to engage in the interpersonal involvement behavior of kissing the victim, and to engage in pre-assault alcohol use, than the serial rapists. There was, however, no significant difference in physically violent or sexual behaviors. To investigate the possibility of predicting rapist type, logistic regression analyses were performed. Results indicate that three behaviors in conjunction, kissed victim, controlled victim, and offender drank alcohol before the offense, predicted whether an unknown offender is a single-victim or serial rapist with a classification accuracy of 80.4%. The findings have implications for the classification of stranger rapists in offender profiling. PMID- 22829438 TI - Stress in turbulent economic times. PMID- 22829439 TI - The design and conduct of clinical trials to limit missing data. AB - This article summarizes recommendations on the design and conduct of clinical trials of a National Research Council study on missing data in clinical trials. Key findings of the study are that (a) substantial missing data is a serious problem that undermines the scientific credibility of causal conclusions from clinical trials; (b) the assumption that analysis methods can compensate for substantial missing data is not justified; hence (c) clinical trial design, including the choice of key causal estimands, the target population, and the length of the study, should include limiting missing data as one of its goals; (d) missing-data procedures should be discussed explicitly in the clinical trial protocol; (e) clinical trial conduct should take steps to limit the extent of missing data; (f) there is no universal method for handling missing data in the analysis of clinical trials - methods should be justified on the plausibility of the underlying scientific assumptions; and (g) when alternative assumptions are plausible, sensitivity analysis should be conducted to assess robustness of findings to these alternatives. This article focuses on the panel's recommendations on the design and conduct of clinical trials to limit missing data. A companion paper addresses the panel's findings on analysis methods. PMID- 22829440 TI - A tail with a thorn in it: second-generation antipsychotics hand in hand with statins. PMID- 22829441 TI - Template-free pseudomorphic synthesis of tungsten carbide nanorods. AB - A unique nanorod-structured tungsten carbide material with high specific surface area of 198 m(2) g(-1) is successfully synthesized for the first time by pseudomorphic transformation of chemically synthesized WO(3) nanorods through a high-temperature method. An electrocatalyst composed of Pt nanoparticles supported on WC nanorods demonstrates higher electrocatalytic activity for methanol electro-oxidation, better tolerance to CO poisoning, and superior performance for cathodic electrocatalytic hydrogen evolution than a Pt/C catalyst. This work provides a novel method to synthesize high-surface-area nanorod-structured WC materials by preparing oxide precursors with the desired external morphology, thus offering great potential for a broad range of applications of these materials in related reaction systems. PMID- 22829442 TI - An investigation of the adsorption of hydroxypropylmethyl cellulose 2910 5 mPa s and polyvinylpyrrolidone K90 around Naproxen nanocrystals. AB - The selection of the appropriate stabilizer for a nanosuspension is still based on trial-and-error and the amount of stabilizer is mostly determined as the lowest amount that results in a stable nanosuspension. Although nanosuspensions are often dried, it is currently not known if the stabilizer remains associated with the surface after drying. Hence, the purpose of this study was to investigate the association of two common pharmaceutical stabilizers [hydroxypropylmethyl cellulose (HPMC) 2910 5 mPa s and polyvinylpyrrolidone (PVP) K90] with the surface of Naproxen crystals. The association between drug and polymer after drying was investigated by evaluating the mixing glass transition temperature using modulated differential scanning calorimetry. Dynamic laser scattering was used to study the Naproxen-polymer association in suspension state. Association with the Naproxen surface was proven after drying for both polymers. A difference in behavior between HPMC and PVP was observed at the liquid-particle interface. In suspension state, the HPMC layer continuously increases in thickness when adding more polymer, whereas in contrast for PVP, the surface can become saturated. The conclusion is that the behavior in suspension determines the behavior of the stabilizer after drying and it is governed by the physicochemical properties of the polymers. PMID- 22829444 TI - beta-Lactones through catalytic asymmetric heterodimerization of ketenes. PMID- 22829443 TI - Major liver resection results in early exacerbation of insulin resistance, and may be a risk factor of developing overt diabetes in the future. AB - PURPOSE: This single center prospective cohort study evaluated the influence of hemihepatectomy on glucose homeostasis. METHODS: The study included 30 patients undergoing hemihepatectomy. All patients underwent an oral 75 g glucose tolerance test before (baseline), 1 week and 1 month after the surgery. Plasma glucose, insulin and glucagon were measured in the OGTT samples, and the HOMA index was calculated. The fasting levels of interleukin 6 and 1beta, tumor necrosis factor and adiponectin were assessed. RESULTS: The fasting plasma and 120-min post challenge mean glucose level increased during the study from 89.6 to 103.5 mg/dl (by 15.5 %) and from 136.4 to 162.2 (by 18.9 %; p = 0.51), respectively, accompanied by an increase in fasting glucagon (from 3.2 to 5.9 ng/mL; p = 0.043) and insulin (from 14.6 to 19.3 IU/mL) and by a decrease in plasma insulin at 60 min of OGTT (p = 0.34). An increase of IL-6 (p = 0.015) and TNF (from 49.7 to 53 pg/mL), and decrease of plasma APO (7658 to 5152 ng/mL) and exacerbation of insulin resistance (p = 0.007) were noted. CONCLUSION: Hemihepatectomy resulted in moderate disturbances in glucose homeostasis, in a majority of patients that was likely to be of minor clinical relevance. However, the patients might be at higher risk of developing overt diabetes following long-term survival. PMID- 22829445 TI - Ca3Sm3[Si9N17] and Ca3Yb3[Si9N17] nitridosilicates with interpenetrating nets that consist of star-shaped [N[4](SiN3)4] units and [Si5N16] supertetrahedra. AB - New nitridosilicates Ca(3)Sm(3)[Si(9)N(17)] and Ca(3)Yb(3)[Si(9)N(17)] were synthesized from the reactions of the pure metals (calcium and samarium/ytterbium) with silicon diimide "Si(NH)(2) " in a radio-frequency (rf) furnace at temperatures of up to 1650 degrees C. These isotypic compounds crystallize in the cubic space group P4(-)3m (no. 215) with lattice parameters a=739.50(3) pm; V=0.4044(1) nm(3); Z=1; wR(2) =0.029 (240 diffraction data, 26 parameters) for Ca(3)Sm(3)[Si(9)N(17)] and a=730.20(2) pm; V=0.3893(1) nm(3); wR(2) =0.039 (387 diffraction data, 27 parameters) for Ca(3)Yb(3)[Si(9)N(17)]. The new structure type of Ca(3)RE(3)[Si(9)N(17)] (RE=Sm, Yb) consists of two independent infinite networks, each of which have an expanded sphalerite (ZnS) topology in which the positions of the Zn and S atoms are replaced by voluminous [N([4])(SiN(3))(4)] units and [Si(5)N(16)] supertetrahedra, respectively, thereby displaying twofold interpenetration. As well, a structural description of Ca(3)Yb(3)[Si(9)N(17)], its thermal stability, and magnetic properties, as well as UV/Vis, IR, and Raman spectra, are presented. PMID- 22829446 TI - PROMIS pediatric measures in pediatric oncology: valid and clinically feasible indicators of patient-reported outcomes. AB - BACKGROUND: Establishing the ability of children and adolescents with cancer to complete the NIH-sponsored PROMIS pediatric measures electronically and the preliminary validity estimates of the measures (both full item banks and short forms) in pediatric oncology will contribute to our knowledge of the impact of cancer treatment on these young patients. PROCEDURES: A total of 203 8- to 17 year olds were administered eight PROMIS pediatric measures in a cross-sectional study design to establish known-group validity. Of the 200 who completed all or most of the items, a slight majority were male (55.5%) and white (54%). Patients were either undergoing treatment for cancer (n = 93) or in survivorship following treatment for cancer (n = 107). Measures were completed using computer interface during an in-person interaction with researchers. RESULTS: Only 3 of 203 participants did not complete the PROMIS pediatric measures. As hypothesized, participants in treatment were significantly different (worse) on parent-reported clinical indicators (blood counts, fatigue, and appetite) and on seven self reported measures (depression, anxiety, peer relationships, pain interference, fatigue, upper extremity function, and mobility) from participants in survivorship. Females reported worse fatigue, anger, and pain interference than males. Worse patient-reported outcomes for patients in active treatment persisted after adjusting for potential confounding variables. CONCLUSIONS: Children and adolescents in treatment for cancer or in survivorship and ranging from 8 to 17 years of age can complete multiple PROMIS pediatric measures using a computer interface during an outpatient clinic visit or inpatient admission. Findings establish known-group validity for PROMIS pediatric measures in pediatric oncology. PMID- 22829447 TI - Altered APP processing in insulin-resistant conditions is mediated by autophagosome accumulation via the inhibition of mammalian target of rapamycin pathway. AB - Insulin resistance, one of the major components of type 2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer's disease (AD), which is characterized by an abnormal accumulation of intra- and extracellular amyloid beta peptide (Abeta). Insulin resistance is known to increase Abeta generation, but the underlying mechanism that links insulin resistance to increased Abeta generation is unknown. In this study, we examined the effect of high-fat diet induced insulin resistance on amyloid precursor protein (APP) processing in mouse brains. We found that the induced insulin resistance promoted Abeta generation in the brain via altered insulin signal transduction, increased beta- and gamma secretase activities, and accumulation of autophagosomes. These findings were confirmed in diabetic db/db mice brains. Furthermore, in vitro experiments in insulin-resistant SH-SY5Y cells and primary cortical neurons confirmed the alteration of APP processing by insulin resistance-induced autophagosome accumulation. Defects in insulin signal transduction affect autophagic flux by inhibiting the mammalian target of rapamycin pathway, resulting in altered APP processing in these cell culture systems. Thus, the insulin resistance that underlies the pathogenesis of T2DM might also trigger accumulation of autophagosomes, leading to increased Abeta generation, which might be involved in the pathogenesis of AD. PMID- 22829449 TI - Genetic predisposition to high blood pressure associates with cardiovascular complications among patients with type 2 diabetes: two independent studies. AB - Hypertension and type 2 diabetes (T2D) commonly coexist, and both conditions are major risk factors for cardiovascular disease (CVD). We aimed to examine the association between genetic predisposition to high blood pressure and risk of CVD in individuals with T2D. The current study included 1,005 men and 1,299 women with T2D from the Health Professionals Follow-up Study and Nurses' Health Study, of whom 732 developed CVD. A genetic predisposition score was calculated on the basis of 29 established blood pressure-associated variants. The genetic predisposition score showed consistent associations with risk of CVD in men and women. In the combined results, each additional blood pressure-increasing allele was associated with a 6% increased risk of CVD (odds ratio [OR] 1.06 [95% CI 1.03 1.10]). The OR was 1.62 (1.22-2.14) for risk of CVD comparing the extreme quartiles of the genetic predisposition score. The genetic association for CVD risk was significantly stronger in patients with T2D than that estimated in the general populations by a meta-analysis (OR per SD of genetic score 1.22 [95% CI 1.10-1.35] vs. 1.10 [1.08-1.12]; I2 = 71%). Our data indicate that genetic predisposition to high blood pressure is associated with an increased risk of CVD in individuals with T2D. PMID- 22829448 TI - A prospective study of leukocyte telomere length and risk of type 2 diabetes in postmenopausal women. AB - Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women's Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90-1.11) in whites, 0.95 (0.85-1.06) in blacks, 0.96 (0.79-1.17) in Hispanics, and 0.88 (0.70-1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women. PMID- 22829450 TI - Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. AB - Aging is closely associated with muscle insulin resistance, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. We examined the hypothesis that muscle insulin resistance in healthy aging promotes increased hepatic de novo lipogenesis (DNL) and hyperlipidemia by altering the distribution pattern of postprandial energy storage. Healthy, normal weight, sedentary elderly subjects pair-matched to young subjects were given two high-carbohydrate meals followed by 13C/1H magnetic resonance spectroscopy measurements of postprandial changes in muscle and liver glycogen and lipid content, and assessment of DNL using 2H2O. Net muscle glycogen synthesis was reduced by 45% (P < 0.007) in the elderly subjects compared with the young, reflecting severe muscle insulin resistance. Net liver glycogen synthesis was similar between groups (elderly, 143 +/- 23 mmol/L vs. young, 138 +/- 13 mmol/L; P = NS). Hepatic DNL was more than twofold higher in the elderly than in the young subjects (elderly, 14.5 +/- 1.4% vs. young, 6.9 +/- 0.7%; P = 0.00015) and was associated with approximately threefold higher postprandial hepatic triglyceride (TG) content (P < 0.005) and increased fasting plasma TGs (elderly, 1.19 +/- 0.18 mmol/L vs. young, 0.74 +/- 0.11 mmol/L; P = 0.02). These results strongly support the hypothesis that muscle insulin resistance in aging promotes hyperlipidemia and NAFLD by altering the pattern of postprandial carbohydrate storage away from muscle glycogen and into hepatic DNL. PMID- 22829451 TI - AMP-activated protein kinase alpha1 protects against diet-induced insulin resistance and obesity. AB - AMP-activated protein kinase (AMPK) is an essential sensor of cellular energy status. Defects in the alpha2 catalytic subunit of AMPK (AMPKalpha1) are associated with metabolic syndrome. The current study investigated the role AMPKalpha1 in the pathogenesis of obesity and inflammation using male AMPKalpha1 deficent (AMPKalpha1(-/-)) mice and their wild-type (WT) littermates. After being fed a high-fat diet (HFD), global AMPKalpha1(-/-) mice gained more body weight and greater adiposity and exhibited systemic insulin resistance and metabolic dysfunction with increased severity in their adipose tissues compared with their WT littermates. Interestingly, upon HFD feeding, irradiated WT mice that received the bone marrow of AMPKalpha1(-/-) mice showed increased insulin resistance but not obesity, whereas irradiated AMPKalpha1(-/-) mice with WT bone marrow had a phenotype of metabolic dysregulation that was similar to that of global AMPKalpha1(-/-) mice. AMPKalpha1 deficiency in macrophages markedly increased the macrophage proinflammatory status. In addition, AMPKalpha1 knockdown enhanced adipocyte lipid accumulation and exacerbated the inflammatory response and insulin resistance. Together, these data show that AMPKalpha1 protects mice from diet-induced obesity and insulin resistance, demonstrating that AMPKalpha1 is a promising therapeutic target in the treatment of the metabolic syndrome. PMID- 22829453 TI - Hydrogen migrations in alkylcycloalkyl radicals: implications for chain-branching reactions in fuels. AB - A thorough understanding of the oxidation chemistry of cycloalkanes is integral to the development of alternative fuels and improving current fuel performance. An important class of reactions essential to this chemistry is the hydrogen migration; however, they have largely been omitted from the literature for cycloalkanes. The present work investigates all of the hydrogen migration reactions available to methylcyclopentane, ethylcyclopentane, methylcyclohexane, and ethylcyclohexane. The kinetic and thermodynamic parameters have been studied by a combination of computational methods and compared to their corresponding n alkyl and methylalkyl counterparts to determine the effect that the cycloalkane ring has on these reactions. In particular, although the alkylcycloalkyl activation energies for the dominant 1,4, 1,5, and 1,6 H-migration are higher than in n-alkyl and methylalkyl radicals, because several of the rotors needed to form the transition state are locked into place as part of the cycloalkane ring, the A-factors are higher for the alkylcycloalkyl reactions, making the rates closer to the noncyclic systems, at higher temperatures. The results presented here suggest that the relative importance of each H-migration pathway differs from the trends predicted by either the n-alkyl or methylalkyl radical systems. Of particular interest is the observation that since the barrier height of the 1,4 H-migration is only 3-5 kcal mol(-1) higher than the 1,5 H-migration in the methyl and ethylcycloalkyl radicals, compared to a difference of roughly 7 kcal mol(-1) in similar reactions for both the n-alkyl and methylalkyl radicals, the 1,4 H-migrations in alkylcycloalkyl radicals will be more important in the overall mechanism than would be predicted based on the n-alkyl and methylalkyl radicals. These results have important combustion model implications, particularly for fuels with high cycloalkane content. PMID- 22829452 TI - B-cell cross-presentation of autologous antigen precipitates diabetes. AB - For autoimmune conditions like type 1 diabetes to progress, self-reactive CD8+ T cells would need to interact with peptide-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I restricted fashion. However, the mechanisms by which autoantigen is cross presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-gamma+lysosomal-associated membrane protein 1+ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cell-dependent, interleukin-21-expressing Vbeta4+CD4+ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells. PMID- 22829455 TI - Mercapturic acids derived from toluene in rat urine samples: identification and measurement by gas chromatography-tandem mass spectrometry. AB - Toluene is one of the most widely used CMR chemicals in industry. Worker exposure to this compound is regulated in France, but new, more sensitive methods are required to effectively monitor this exposure. A gas chromatography-tandem mass spectrometry (GC-MS/MS) method was developed and fully validated for the simultaneous determination of urinary toluene mercapturic acids derived from side chain and ring oxidation, i.e., benzylmercapturic acid and the three isomers o-, m- and p-toluylmercapturic acids, respectively. The method involves a simple and efficient two-step preparation procedure consisting of liquid-liquid extraction of the urinary acids followed by a microwave-assisted esterification of the isolated compounds using 2-propanol. The method meets all the required validation criteria: high selectivity, intra-day and inter-day precision ranges between 1.0 % and 12.4 %, with close to 100 % recovery. Linearity has been shown over the reduced concentration range 0.03-0.5 mg/L whereas a multiplicative model (ln-ln transformation) had to be used to describe the full range of concentrations 0.03 20 mg/L. The limits of detection for the four analytes, ranging from 2.8 to 5.5 MUg/L, made the method suitable for their identification and quantification in urine from rats inhaling toluene in the 2 to 200 ppm concentration range. All urine samples from exposed rats contained measurable amounts of all metabolites. This is the first time that o- and m-toluylmercapturic acids have been shown to occur. Our results confirm the hypothesis that toluene mercapturic acids derived from ring oxidation exist in three forms. PMID- 22829454 TI - ALX4 gain-of-function mutations in nonsyndromic craniosynostosis. AB - Craniosynostosis is the early fusion of one or more sutures of the infant skull and is a common defect occurring in approximately 1 of every 2,500 live births. Nonsyndromic craniosynostosis (NSC) accounts for approximately 80% of all cases and is thought to have strong genetic determinants that are yet to be identified. ALX4 is a homeodomain transcription factor with known involvement in osteoblast regulation. By direct sequencing of the ALX4 coding region in sagittal or sagittal-suture-involved nonsyndromic craniosynostosis probands, we identified novel, nonsynonymous, familial variants in three of 203 individuals with NSC. Using dual-luciferase assay we show that two of these variants (V7F and K211E) confer a significant gain-of-function effect on ALX4. Our results suggest that ALX4 variants may have an impact on the genetic etiology of NSC. PMID- 22829456 TI - Jurors' use of standards of proof in decisions about punitive damages. AB - Standards of proof define the degree to which jurors must be satisfied that a fact is true, and plaintiffs in civil lawsuits assume the burden of proving their claims to the requisite standard of proof. Three standards-preponderance of evidence, clear and convincing evidence, and beyond a reasonable doubt-are used by different jurisdictions in trials involving liability for punitive damages. We investigated whether individual mock jurors apply these standards appropriately by instructing them to read two personal injury trial summaries and to use one of three standards in either qualitative or quantitative format when deciding punitive liability. Results showed that jurors tended not to incorporate the standard into their judgments: defendants were just as likely to be found liable when the plaintiff's burden was high ("beyond a reasonable doubt") as when the burden was low ("preponderance of evidence"). The format of the instruction also had a negligible effect. We suggest that nonuse of the standard of proof is related to jurors' preferences for less effortful or experiential processing in situations involving complicated or ambiguous material. PMID- 22829457 TI - Erythropoietin in the prevention of experimental burn progression. AB - BACKGROUND: Damage control is essential in first aid of burn lesions. The aim of the present study was to investigate whether systemic erythropoietin (EPO) administration could prevent secondary burn progression in an experimental model. METHODS: The burn comb model creates four rectangular burn surfaces intercalated by three unburned zones prone to progression. Twenty-one Wistar rats were randomized to a control group or to receive intraperitoneal EPO (500 units per kg) once a day for 5 days starting 45 min (EPO45min) or 6 h (EPO6h) after burn injury. Histological analyses assessing burn depth, inflammation and neoangiogenesis, planimetric evaluation of burn progression, and laser Doppler flowmetry to assess perfusion were performed after 1, 4 and 7 days. Final scarring time and contracture rate were assessed once a week. RESULTS: Burn progression was decreased significantly with EPO45min but not EPO6h; progression of burn depth stopped in the intermediate dermis (mean(s.e.m.) burn depth score 3.3(0.6) for EPO45min versus 4.7(0.3) and 5.0(0.0) for EPO6h and control respectively on day 7; P = 0.026) and the surface extension was significantly reduced (45(8), 65(4) and 78(4) respectively on day 7; P = 0.017). This was paralleled by faster re-establishment of perfusion with EPO45min (114(5) per cent on day 4 versus 85(6) and 91(3) per cent for EPO6h and control respectively; P = 0.096). The reduction in progression resulted in a decreased healing time (7.3(0.7) weeks for EPO45min versus 11.5(1.0) and 10.8(0.5) weeks for EPO6h and control; P = 0.020) and contracture rate (P = 0.024). CONCLUSION: Early EPO prevented burn progression, mainly by improved vascular perfusion. PMID- 22829458 TI - DNA-based plasmonic nanoarchitectures: from structural design to emerging applications. AB - Plasmonic nanoarchitectures refer to the well-defined groupings of elementary metallic nanoparticle building blocks. Such nanostructures have a plethora of technical applications in diagnostics, energy-harvesting, and nanophotonic circuits, to name a few. Nevertheless, it remains challenging to construct plasmonic nanoarchitectures at will inexpensively. Bottom-up self-assembly is promising to overcome these limitations, but such methods often produce defects and low-yields. For these purposes, DNA has emerged as a powerful nanomaterial beyond its genetic function in biology to either program or template synthesis of plasmonic nanostructures, or act as a ligand to mediate large-area self-assembly. In conjunction with top-down lithography, DNA-based strategies can afford excellent control over internal and overall structures of plasmonic nanoarchitectures. In this review, we outline the representative methodologies for building various well-defined plasmonic nanoarchitectures and cover their recent exciting applications. PMID- 22829460 TI - The excess electron in a boron nitride nanotube: pyramidal NBO charge distribution and remarkable first hyperpolarizability. AB - The unusual properties of species with excess electrons have attracted a lot of interest in recent years due to their wide applications in many promising fields. In this work, we find that the excess electron could be effectively bound by the B atoms of boron nitride nanotube (BNNT), which is inverted pyramidally distributed from B-rich edge to N-rich edge. Further, Li@B-BNNT and Li@N-BNNT are designed by doping the Li atom to the two edges of BNNT, respectively. Because of the interaction between the Li atom and BNNT, the 2s valence electron of Li becomes a loosely bound excess electron. Interestingly, the distribution of the excess electron in Li@N-BNNT is more diffuse and pyramidal from B-rich edge to N rich edge, which is fascinating compared with Li@B-BNNT. Correspondingly, the transition energy of Li@N-BNNT is 0.99 eV, which is obviously smaller than 2.65 eV of Li@B-BNNT. As a result, the first hyperpolarizability (3.40*10(4) a.u.) of Li@N-BNNT is dramatically larger (25 times) than 1.35*10(3) a.u. of Li@B-BNNT. Significantly, we find that the pyramidal distribution of the excess electron is the key factor to determine the first hyperpolarizability, which reveals useful information for scientists to develop new electro-optic applications of BNNTs. PMID- 22829459 TI - NIR-triggered release of caged nitric oxide using upconverting nanostructured materials. PMID- 22829461 TI - Pleural mesothelioma: forecasts of the death toll in the area of Casale Monferrato, Italy. AB - In the city of Casale Monferrato, the largest Italian factory that produced asbestos-cement goods was active from 1907 to 1985. Consequently, asbestos fibers scattered in the surrounding area and caused an enormous number of cases of pleural mesothelioma. Owing to the very long latency of this disease, many subjects have not exhibited its symptoms yet. The aim of this paper is to model and predict the future evolution of the number of deaths due to this disease among residents in the area around that city. The model used here is based on a cellular automata that is assumed to pass through three steps: exposure, contamination, and diagnosis. In this way, forecasts of the future evolution take into account the environmental conditions that changed over the last century because of different levels of plant activity. The model is fitted to annual diagnosis data from 1954 to 2008. Results show that deaths will not end until 2031 and that in the next two decades, at least 505 more subjects will be diagnosed with this disease. PMID- 22829463 TI - A versatile synthesis of Meyers' bicyclic lactams from furans: singlet-oxygen initiated reaction cascade. PMID- 22829462 TI - Hepatic immunosuppressive effects of systemically administered novel dextran methylprednisolone prodrugs with peptide linkers in rats. AB - The hepatic immunosuppressive activities of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP1) or five (DMP5) amino acids as linkers were studied in rats. At various times (0-2 weeks) after intravenous administration of single 5 mg/kg (MP equivalent) doses of each prodrug or MP succinate (MPS), livers were isolated and immunologically stimulated ex vivo with lipopolysaccharide. The concentrations of tumor necrosis factor (TNF)-alpha in the outlet perfusate were then quantitated to assess immune response. Additionally, the concentrations of DMP1, DMP5, and/or MP were measured in the liver. MPS, DMP5, or DMP1 injections caused a maximum of 48.9%, 63.5%, or 85.7% decrease in the TNF-alpha secretion into the perfusate, with the time above the 50% inhibitory effect being <5, <24, or 120 h, respectively. Additionally, the area under the effect-time curve for DMP1 was 11-fold or fourfold higher than that after the administration of MPS or DMP5, respectively. Relatively high concentrations of DMP1 were present in the liver even at the last sampling time of 2 weeks. These data suggest that a single intravenous dose of DMP1 produces an intense and sustained immunosuppression in the liver for a relatively long time, which may be useful in liver transplantation. PMID- 22829464 TI - Genetic and caregiving-based contributions to infant attachment: unique associations with distress reactivity and attachment security. AB - In the longitudinal study reported here, we examined genetic and caregiving-based contributions to individual differences in infant attachment classifications. For 154 mother-infant pairs, we rated mothers' responsiveness to their 6-month-old infants during naturalistic interactions and classified infants' attachment organization at 12 and 18 months using the Strange Situation procedure. These infants were later genotyped with respect to the serotonin-transporter-linked polymorphic region (5-HTTLPR). Maternal responsiveness uniquely predicted infants' attachment security. Infants' 5-HTTLPR variation uniquely predicted their subtype of attachment security at 12 months and their subtype of attachment insecurity at 12 and 18 months. The short allele for 5-HTTLPR was associated with attachment classifications characterized by higher emotional distress. These findings suggest that 5-HTTLPR variation contributes to infants' emotional reactivity and that the degree to which caregivers are responsive influences how effectively infants use their caregivers for emotion regulation. Theoretical implications for the study of genetic and caregiving influences are discussed. PMID- 22829465 TI - Brief wakeful resting boosts new memories over the long term. AB - A brief wakeful rest after new verbal learning enhances memory for several minutes. In the research reported here, we explored the possibility of extending this rest-induced memory enhancement over much longer periods. Participants were presented with two stories; one story was followed by a 10-min period of wakeful resting, and the other was followed by a 10-min period during which participants played a spot-the-difference game. In Experiment 1, wakeful resting led to significant enhancement of memory after a 15- to 30-min period and also after 7 days. In experiment 2, this striking enhancement of memory 7 days after learning was demonstrated even when no retrievals were imposed in the interim. The degree to which people can remember prose after 7 days is significantly affected by the cognitive activity that they engage in shortly after new learning takes place. We propose that wakeful resting after new learning allows new memory traces to be consolidated better and hence to be retained for much longer. PMID- 22829466 TI - Control of porosity by using isoreticular zeolitic imidazolate frameworks (IRZIFs) as a template for porous carbon synthesis. AB - Herein, by using isoreticular zeolitic imidazolate frameworks (IRZIFs) as a template, we report the synthesis, morphology, and gas adsorption properties of porous carbon synthesized by a nanocasting method at 1000 degrees C, in which furfuryl alcohol (FA) was used as a carbon source. By using IRZIFs with variable porosity as templates, we could achieve control over the carbon porosity and H(2) and CO(2) uptake. The resultant microporous carbon C-70, synthesized by using ZIF 70 as the template, is the most porous (Brunauer-Emmett-Teller (BET) surface area 1510 m(2) g(-1)). Carbon C-68, synthesized by using ZIF-68, has moderate porosity (BET surface area 1311 m(2) g(-1)), and C-69, synthesized by using ZIF-69, has the lowest porosity in this series (BET surface area 1171 m(2) g(-1)). The porous carbons C-70, C-68, and C-69, which have graphitic texture, have promising H(2) uptake capacities of 2.37, 2.15, and 1.96 wt %, respectively, at 77 K and 1 atm. Additionally, C-70, C-68, and C-69 show CO(2) uptake capacities of 5.45, 4.98, and 4.54 mmol g(-1), respectively, at 273 K and 1 atm. The gas uptake trends shown by C-70, C-68, and C-69 clearly indicate the dependence of carbon porosity on the host template. Moreover, the as-synthesized carbons C-70, C-68, and C-69 show variable conductivity. PMID- 22829467 TI - Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers. AB - Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease. PMID- 22829468 TI - The potential of electron beam radiation for simultaneous surface modification and bioresorption control of PLLA. AB - Bioresorbable polymers have been widely investigated as materials exhibiting significant potential for successful application in the fields of tissue engineering and drug delivery. Further to the ability to control degradation, surface engineering of polymers has been highlighted as a key method central to their development. Previous work has demonstrated the ability of electron beam (e beam) technology to control the degradation profiles and bioresorption of a number of commercially relevant bioresorbable polymers (poly-l-lactic acid (PLLA), L-lactide/DL-lactide co-polymer (PLDL) and poly(lactic-co-glycolic acid (PLGA)). This work investigates the further potential of e-beam technology to impart added biofunctionality through the manipulation of polymer (PLLA) surface properties. PLLA samples were subjected to e-beam treatments in air, with varying beam energies and doses. Surface characterization was then performed using contact angle analysis, X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and atomic force microscopy. Results demonstrated a significant increase in surface wettability post e-beam treatment. In correlation with this, XPS data showed the introduction of oxygen-containing functional groups to the surface of PLLA. Raman spectroscopy indicated chain scission in the near surface region of PLLA (as predicted). However, e-beam effects on surface properties were not shown to be dependent on beam energy or dose. E-beam irradiation did not seem to affect the surface roughness of PLLA as a direct consequence of the treatment. PMID- 22829469 TI - From monomers to pi stacks, from nonconductive to conductive: syntheses, characterization, and crystal structures of benzidine radical cations. AB - Salts that contain radical cations of benzidine (BZ), 3,3',5,5' tetramethylbenzidine (TMB), 2,2',6,6'-tetraisopropylbenzidine (TPB), and 4,4' terphenyldiamine (DATP) have been isolated with weakly coordinating anions [Al(OR(F))(4)](-) (OR(F) = OC(CF(3))(3)) or SbF(6)(-). They were prepared by reaction of the respective silver(I) salts with stoichiometric amounts of benzidine or its alkyl-substituted derivatives in CH(2)Cl(2). The salts were characterized by UV absorption and EPR spectroscopy as well as by their single crystal X-ray structures. Variable-temperature UV/Vis absorption spectra of BZ(.)(+)[Al(OR(F))(4)](-) and TMB(.)(+)[Al(OR(F))(4)](-) in acetonitrile indicate an equilibrium between monomeric free radical cations and a radical-cation dimer. In contrast, the absorption spectrum of TPB(.)(+)SbF(6)(-) in acetonitrile indicates that the oxidation of TPB only resulted in a monomeric radical cation. Single-crystal X-ray diffraction studies show that in the solid state BZ and its methylation derivative (TMB) form radical-cation pi dimers upon oxidation, whereas that modified with isopropyl groups (TPB) becomes a monomeric free radical cation. By increasing the chain length, pi stacks of pi dimers are obtained for the radical cation of DATP. The single-crystal conductivity measurements show that monomerized or pi-dimerized radicals (BZ(.)(+), TMB(.)(+), and TPB(.)(+)) are nonconductive, whereas the pi-stacked radical (DATP(.)(+)) is conductive. A conduction mechanism between chains through pi stacks is proposed. PMID- 22829470 TI - Per-subject characterization of bolus width in pulsed arterial spin labeling using bolus turbo sampling. AB - Quantification of cerebral blood flow using QUIPSSII pulsed arterial spin labeling requires that the QUIPSS saturation delay TI1 is shorter than the natural temporal bolus width. Yet the duration of the bolus of tagged spins entering the region of interest varies during vasoactive stimuli such as gaseous challenges or across subjects due to differences in blood velocity or vessel geometry. A new technique, bolus turbo sampling, to rapidly measure the duration of the inflowing bolus is presented. It allows to optimize the arterial spin labeling acquisition to ensure reliable quantification of perfusion while maximizing the arterial spin labeling signal by avoiding the use of unnecessarily short label durations. The average bolus width measured in the right and left middle cerebral artery territories using the bolus turbo sampling technique has a repeatability coefficient of 75 ms and correlates significantly with the TI1,max determined from a novel multi-TI1 protocol (R=0.65, P<0.05). The possibility to measure the bolus width under hypercapnia is demonstrated. PMID- 22829471 TI - IGF2: the Achilles' heel of p53-deficiency? PMID- 22829472 TI - Asymmetric inverse-electron-demand hetero-Diels-Alder reaction for the construction of bicyclic skeletons with multiple stereocenters by using a bifunctional organocatalytic strategy: an efficient approach to chiral macrolides. AB - We have performed the first bifunctional organocatalytic highly enantioselective inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones with enones to afford densely functionalized bicyclic skeletons that contain three stereocenters (up 82% yield, 10:1 d.r., and 97% ee). Unlike the previous IEDDAR catalytic strategy, this method features a double HOMO(dienophile)/ LUMO(diene) activated pathway. Moreover, this process provides a promising method for the construction of enantioenriched macrolides. PMID- 22829473 TI - Experimental and theoretical evidence for multiple Fe(IV) reactive intermediates in TAML-activator catalysis: rationalizing a counterintuitive reactivity order. PMID- 22829474 TI - Palladium-mediated phosphine-dependent chemoselective bisallylic alkylation leading to spirocarbocycles. AB - Cycles everywhere: The selectivity in the transformations of 1,3-diones to carbocycles by palladium-catalyzed bisallylic alkylations is strongly dependent on the phosphine that is employed. Moreover, synthesized vinylcyclopentenes can be easily transformed into cycloheptadiene derivatives through a carbon-carbon allylic bond cleavage. PMID- 22829475 TI - Estimation of a decreasing hazard of patients with acute coronary syndrome. AB - The Kaplan-Meier, Nelson-Aalen and Breslow estimators are widely used in the analysis of right-censored time to event data in medical applications. These methods are fully non-parametric and do not put any restriction on the shape of the hazard curve. In some applications, this leads to implausible estimates of the hazard course over time. With non-parametric shape-constrained estimation techniques, one can facilitate an increasing or decreasing hazard and thus generate estimators that better match the biological reasoning, without being as restrictive as parametric methods. We illustrate the advantage of such techniques in the analysis of a large clinical trial in cardiology. Simulation results show that in case the true hazard is monotone, the non-parametric shape-constrained estimators are more accurate than the traditional estimators on the hazard level. On the (cumulative) distribution function level, the shape-constrained estimators show similar performance as the traditional ones. PMID- 22829476 TI - Concurrent improvement in biocompatibility and bioinertness of diamond-like carbon films with nitrogen doping. AB - The surfaces of implantable biomaterials improving biocompatibility and bioinertness are critical for new application of bioimplantable devices. Diamond like carbon (DLC) film is a promising biomaterial with use for coating bioimplantable devices because of its good biocompatibility, bioinertness, and mechanical properties. In this study, concurrent improvement in biocompatibility and bioinertness of DLC films has been achieved using N-incorporation technique. The N doping degree was found to play an important role in affecting the biocompatibility and bioinertness of N-doped DLC films. The results indicated that the N-doped DLC films deposited at N(2) concentration of 5% could help to create suitable condition of surface/structure/adhesion combination of DLC films in the both affinity of the L929 mouse fibroblasts and electrochemical inertness in the Hank's balanced salt solutions (simulating human body fluids). N doping supports the attachment and proliferation of cells and prevents the permeation of electrolyte solutions, thereby simultaneity improved the biocompatibility and bioinertness of DLC films. This finding is useful for the fabrication and encapsulation of in vivo devices without induced immune response in the human body. PMID- 22829477 TI - Progression of experimental lesions of atherosclerosis: assessment by kinetic modeling of black-blood dynamic contrast-enhanced MRI. AB - Pharmacokinetic modeling of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is used to noninvasively characterize neovasculature and inflammation in atherosclerotic vessels by estimating perfusion characteristics, such as fractional plasma volume vp and transfer constant Ktrans. DCE-MRI has potential to study the evolution of nascent lesions involving early pathological changes. However, currently used bright-blood DCE-MRI approaches are difficult to apply to small lesions because of the difficulty in separating the signal in the thin vessel wall from the adjacent lumen. By suppressing the lumen signal, black blood DCE-MRI techniques potentially provide a better tool for early atherosclerotic lesion assessment. However, whether black-blood DCE-MRI can detect temporal changes in physiological kinetic parameters has not been investigated for atherosclerosis. This study of balloon-injured New Zealand White rabbits used a reference-region-based pharmacokinetic model of black-blood DCE MRI to evaluate temporal changes in early experimental atherosclerotic lesions of the abdominal aorta. Six rabbits were imaged at 3 and 6 months after injury. Ktrans was found to increase from 0.10+/-0.03 min(-1) to 0.14+/-0.05 min(-1) (P=0.01). In histological analysis of all twelve rabbits, Ktrans showed a significant correlation with macrophage content (R=0.70, P=0.01). These results suggest black-blood DCE-MRI and a reference-region kinetic model could be used to study plaque development and therapeutic response in vivo. PMID- 22829478 TI - Sonochemiluminescence from a single cavitation bubble in water. PMID- 22829479 TI - Macromolecule-to-amphiphile conversion process of a polyoxometalate-polymer hybrid and assembled hybrid vesicles. AB - We report our findings on the macromolecule-to-amphiphile conversion process of a polyoxometalate-polymer hybrid and the assembled hybrid vesicles formed by aggregation of the hybrid amphiphile. The polyoxometalate-polymer hybrid is composed of a polyoxometalate (POM) cluster, which is covered by five tetrabutylammonium (Bu(4)N(+)) countercations, and a polystyrene (PS) chain. Through a cation-exchange process the Bu(4)N(+) countercations can be replaced by protons to form a hybrid amphiphile composed of a hydrophilic, protonated POM cluster and a hydrophobic PS chain. By implementing a directed one-dimensional diffusion and analyzing the diffusion data, we confirmed that the diffusion of solvated protons rather than macromolecules or aggregates is the key factor controlling the conversion process. Once the giant hybrid amphiphiles were formed, they immediately assembled into kinetically favored vesicular aggregates. During subsequent annealing these vesicular aggregates were transformed into thermodynamically stable vesicular aggregates with a perfect vesicle structure. The success in the preparation of the POM-containing hybrid vesicles provides us with an opportunity of preparing POM-functionalized vesicles. PMID- 22829480 TI - Ruthenium(II) pyrazolyl-pyridyl-oxazolinyl complex catalysts for the asymmetric transfer hydrogenation of ketones. AB - Lowering the ketone: Ru(II) complexes containing a chiral pyridyl-based 1H pyrazolyl-oxazolinyl NNN ligand were synthesized and structurally characterized by X-ray crystallographic studies. These complex catalysts efficiently catalyzed the asymmetric transfer hydrogenation of ketones, reaching up to 99 % ee for the desired products. PMID- 22829482 TI - Myelinated nerve bundles developed on the plano-concave fibers containing nerve conduit. AB - Morphologically and chemically modified plano-concave fibers (PCFs) are designed as a unit of guided channels for supporting Schwann cells to facilitate mass transport and promote nerve regeneration. The surface-modified PCFs are imprinted with linearly patterned grooves (LPGs) to guide adherent Schwann cell elongation and axon extension. After being cocultured with PC12 neuron-like cells, Schwann cells differentiate into the myelinated type and interact with PC12 axons. The myelinated axons aggregate as a linear bundle and extend along the direction of LPGs on a PCF. The cross section of a myelin structure is examined using a transmission electron microscope. The PCFs can potentially bridge gaps in injured nerves, improving the therapeutic efficacy of nerve regeneration. PMID- 22829483 TI - Freestanding tin disulfide single-layers realizing efficient visible-light water splitting. PMID- 22829481 TI - Madecassoside, a triterpenoid saponin isolated from Centella asiatica herbs, protects endothelial cells against oxidative stress. AB - This study aimed to investigate the effect of madecassoside against oxidative stress-induced injury of endothelial cells. Hydrogen peroxide (H(2)O(2), 500 umol/L) was employed as an inducer of oxidative stress in human umbilical vein endothelial cells (HUVECs). Cell apoptosis was detected by Hoechst 33258 staining and flow cytometry. Caspase-3 activity and mitochondria membrane potential were further examined. As a result, madecassoside (10, 30, 100 umol/L) could reverse morphological changes, elevate cell viability, increase glutathione levels, and decrease lactate dehydrogenase and malondialdehyde levels caused by H(2)O(2) in a concentration-dependent manner. It attenuated apoptosis, preventing the activation of caspase-3 and the loss of mitochondria membrane potential, as well as the phosphorylation of p38 mitogen-activated protein kinase (MAPK) in HUVECs. These data suggested that madecassoside could protect HUVECs from oxidative injury, which was probably achieved by inhibiting cell apoptosis via protection of mitochondria membranes and downregulation of the activation of caspase-3 and p38 MAPK. PMID- 22829484 TI - Simultaneous single-quantum and triple-quantum-filtered MRI of 23Na (SISTINA). AB - The low MR sensitivity of the sodium nucleus and its low concentration in the human body constrain acquisition time. The use of both single-quantum and triple quantum sodium imaging is, therefore, restricted. In this work, we present a novel MRI sequence that interleaves an ultra-short echo time radial projection readout into the three-pulse triple-quantum preparation. This allows for simultaneous acquisition of tissue sodium concentration weighted as well as triple-quantum filtered images. Performance of the sequence is shown on phantoms. The method is demonstrated on six healthy informed volunteers and is applied to three cases of brain tumors. A comparison with images from tumor specific O-(2 [18F]fluoroethyl)-L-tyrosine positron emission tomography and standard MR images is presented. The combined information of the triple-quantum-filtered images with single-quantum images may enable a better understanding of tissue viability. Future studies can benefit from the evaluation of both contrasts with shortened acquisition times. PMID- 22829485 TI - Chemical and photochemical functionality of the first molecular bismuth vanadium oxide. AB - Anionic metal oxide clusters, so-called polyoxometalates, can be developed as molecular model compounds to mimic the chemical and photochemical reactivity of solid-state metal oxides on the molecular level. Inspired by the well-known visible-light photocatalyst BiVO(4), the first molecular bismuth vanadium oxide has been synthesized to investigate the chemical and photochemical similarities between the solid-state and molecular compounds. The cluster H(3)[(Bi(dmso)(3))(4)V(13)O(40)].ca. 4 DMSO was obtained from simple precursors in almost quantitative yield. Structural analysis showed that the cluster shell is based on the unusual all-vanadium epsilon-Keggin framework [epsilon V(12)O(40)](15-), which is stabilized by coordination of four Bi(III) centers. The acidic character of the three cluster protons was demonstrated by titration studies. The cluster shows promising photocatalytic properties in visible-light photooxidation reactions and has high activity (turnover number >1200), high quantum yield (Phi=7.6 %), and good recyclability, which make it a promising first example of a new class of heterometallic polyoxometalates. PMID- 22829486 TI - Beyond PICO: the SPIDER tool for qualitative evidence synthesis. AB - Standardized systematic search strategies facilitate rigor in research. Current search tools focus on retrieval of quantitative research. In this article we address issues relating to using existing search strategy tools, most typically the PICO (Population, Intervention, Comparison, Outcome) formulation for defining key elements of a review question, when searching for qualitative and mixed methods research studies. An alternative search strategy tool for qualitative/mixed methods research is outlined: SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type). We used both the SPIDER and PICO search strategy tools with a qualitative research question. We have used the SPIDER tool to advance thinking beyond PICO in its suitable application to qualitative and mixed methods research. However, we have highlighted once more the need for improved indexing of qualitative articles in databases. To constitute a viable alternative to PICO, SPIDER needs to be refined and tested on a wider range of topics. PMID- 22829487 TI - Developing maternal self-efficacy for feeding preterm babies in the neonatal unit. AB - Developing maternal self-efficacy offsets negative psychological consequences of premature birth, improving maternal well-being. We investigated women's experiences in a neonatal unit (NNU) in Scotland in semistructured interviews with 19 primiparous mothers of preterm babies. We explored their experience of preterm birth and development of self-efficacy in infant feeding behaviors, identifying emergent and a priori themes. Women reported experiencing loss and biographical disruption in relation to mothering, loss of autonomy, and searching for normality after premature birth. Providing breast milk symbolized embodied contact with their baby and increased maternal confidence. They developed motivation, knowledge, and perseverance and perceived success from positive feedback, primarily from their baby and health professionals' support and encouragement. Women actively constructed opportunities to develop ownership, control, and confidence in relation to interactions with their baby. We linked sources of self-efficacy with potential behavior change techniques to be used in practice to improve maternal confidence in the NNU. PMID- 22829488 TI - Minimum unit pricing for alcohol--the case for action is overwhelming. PMID- 22829489 TI - Assessing the validity of quality indicators: keep the context in mind! PMID- 22829490 TI - Setting targets for health 2020. PMID- 22829491 TI - WHO needs targets? PMID- 22829492 TI - Introducing a minimum unit price for alcohol in Scotland: considerations under European Law and the implications for European public health. PMID- 22829496 TI - Bluish-green BMes2-functionalized Pt(II) complexes for high efficiency PhOLEDs: impact of the BMes2 location on emission color. AB - New phosphorescent Pt(II) compounds based on dimesitylboron (BMes(2)) functionalized 2-phenylpyridyl (ppy) N,C-chelate ligands and an acetylacetonato ancillary ligand have been achieved. We have found that BMes(2) substitution at the 4'-position of the phenyl ring can blue-shift the phosphorescent emission energy of the Pt(II) compound by approximately 50 nm, compared to the 5'-BMes(2) substituted analogue, without substantial loss of luminescent quantum efficiencies. The emission color of the 4'-BMes(2) substituted Pt(II) compound, Pt(Bppy)(acac) (1) can be further tuned by the introduction of a substituent group at the 3'-position of the phenyl ring. A methyl substituent red-shifts the emission energy of 1 by approximately 10 nm whereas a fluoro substituent blue shifts the emission energy by about 6 nm. Using this strategy, three bright blue green phosphorescent Pt(II) compounds 1, 2 and 3 with emission energy at 481, 492, and 475 nm and Phi(PL)=0.43, 0.26 and 0.25, respectively, have been achieved. In addition, we have examined the impact of BMes(2) substitution on 3,5 dipyridylbenzene (dpb) N,C,N-chelate Pt(II) compounds by synthesizing compound 4, Pt(Bdpb)Cl, which has a BMes(2) group at the 4'-position of the benzene ring. Compound 4 has a phosphorescent emission band at 485 nm and Phi(PL)=0.70. Highly efficient blue-green electroluminescent (EL) devices with a double-layer structure and compounds 1, 3 or 4 as the phosphorescent dopant have been fabricated. At 100 cd m(-2) luminance, EL devices based on 1, 3 and 4 with an external quantum efficiency of 4.7, 6.5 and 13.4%, respectively, have been achieved. PMID- 22829497 TI - Development of a chemically extracted acellular muscle scaffold seeded with amniotic epithelial cells to promote spinal cord repair. AB - Bridging strategies are essential for spinal cord repair in order to provide a physical substrate allowing axons to grow across the site of spinal cord lesions. In this study, we have evaluated the therapeutic effects of adding amniotic epithelial cells to a unidirectionally oriented acellular muscle scaffold and have compared this with the effect of a scaffold alone. Chemically extracted acellular muscles, with or without amniotic epithelial cells, were implanted into the lateral hemisected adult rat thoracic spinal cord. Control rats were similarly injured. After 4 weeks, the acellular muscle scaffolds were found to be well integrated with the host tissue. The chemically extracted acellular muscle scaffold seeded with amniotic epithelial cells promoted axonal growth in a distinctly organized and linear fashion, induced sprouting of calcitonin gene related peptide positive axons, and was not associated with an astrocyte response. Compared with acellular muscle scaffolds alone, the addition of amniotic epithelial cells further promoted the remyelination of nerve fibers, sprouting of 5-hydroxytryptamine nerve fibers, relays of cortical motor-evoked potential and cortical somatosensory-evoked potential, and functional recovery. All these data together suggest that co-implantation of chemically extracted acellular muscle with amniotic epithelial cells may constitute a valuable approach to study and/or develop therapies for spinal cord injury. PMID- 22829498 TI - Multiscale charge injection and transport properties in self-assembled monolayers of biphenyl thiols with varying torsion angles. AB - This article describes the molecular structure-function relationship for a series of biphenylthiol derivatives with varying torsional degree of freedom in their molecular backbone when self-assembled on gold electrodes. These biphenylthiol molecules chemisorbed on Au exhibit different tilt angles with respect to the surface normal and different packing densities. The charge transport through the biphenylthiol self-assembled monolayers (SAMs) showed a characteristic decay trend with the effective monolayer thickness. Based on parallel pathways model the tunneling decay factor beta was estimated to be 0.27 A(-1). The hole mobility of poly(3-hexylthiophene)-based thin-film transistors incorporating a biphenylthiol SAM coating the Au source and drain electrodes revealed a dependence on the injection barrier with the highest occupied molecular orbital (HOMO) level of the semiconductor. The possible role of the resistivity of the SAMs on transistor electrodes on the threshold voltage shift is discussed. The control over the chemical structure, electronic properties, and packing order of the SAMs provides a versatile platform to regulate the charge injection in organic electronic devices. PMID- 22829500 TI - In vivo MRI of fresh stored osteochondral allograft transplantation with delayed gadolinium-enhanced MRI of cartilage: protocol considerations and recommendations. AB - The protocol for delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) was adapted for the evaluation of transplanted osteochondral allograft cartilage. Eight patients with focal grade 4 cartilage defects of the femoral condyle were treated with single cylindrical osteochondral allografts. At 1 and 2 years, dGEMRIC image sequences were acquired and regions of interest (ROIs) were drawn in repair and native control cartilage. Mean T1 values of region of interest were used to calculate established dGEMRIC metrics. The correlation was measured between the DeltaR1 and R1 -Post metrics for repair and native cartilage. T1 times were measured in deep and superficial zones of cartilage. A strong correlation was identified between full-thickness, deep, and superficial DeltaR1 and R1 -Post values for native cartilage and repair cartilage for all years (range: 0.893-1.0). The mean T1 times and DeltaR1 rate between deep and superficial regions of articular cartilage were statistically different for all regions of the distal femora analyzed at 1 year and 2 years after osteochondral allograft transplantation (P<0.05). The dGEMRIC pre-Gadolinium scan is unnecessary when evaluating transplanted osteochondral allograft cartilage. The observation of stratified T1 and DeltaR1 values indicates a need to re-evaluate the methodology behind the placement of region of interest in dGEMRIC. PMID- 22829501 TI - High-generation second-order nonlinear optical (NLO) Dendrimers that contain isolation chromophores: convenient synthesis by using click chemistry and their increased NLO effects. AB - Herein, high-generation dendrimers G4-NS and G5-NS, which contained 30 and 62 azo benzene chromophore moieties, respectively, were conveniently prepared in high purity and satisfied yields by a combination of divergent and convergent approaches, coupled with the utilization of the powerful Sharpless click reaction. These dendrimers possessed a regular structure of alternating layers of nitro-based and sulfonyl-based azo chromophores in which the sulfonyl-based azo chromophore moieties were utilized as co-isolation groups for the nitro-based moieties to achieve larger macroscopic second-order nonlinear optical (NLO) effects. These high-generation dendrimers (G4-NS and G5-NS) displayed very large NLO efficiencies (up to 253.0 pm V(-1)), which is, to the best of our knowledge, the record highest efficiency for simple azo-chromophore moieties. PMID- 22829502 TI - Far from the turmoil, a summer with EuroIntervention. PMID- 22829504 TI - Guide catheter extensions: where are they taking us? PMID- 22829503 TI - The Titan stent, just a good bare metal stent or more? PMID- 22829505 TI - The EAPCI: today the second largest association within the ESC...and tomorrow? PMID- 22829507 TI - Dedicated paclitaxel-eluting bifurcation stent BiOSS(r) (bifurcation optimisation stent system): 12-month results from a prospective registry of consecutive all comers population. AB - AIMS: Dedicated bifurcation stents seem to be the most promising solution for treating bifurcations. The aim of our study was to present the 12 months results of a new dedicated stent for coronary bifurcation lesions -the paclitaxel-eluting stent- BiOSS(r) Expert (Bifurcation Optimisation Stent System, Balton, Warsaw, Poland). METHODS AND RESULTS: Sixty-three patients with 65 lesions were enrolled in the registry. Forty-six % of the patients were classified as NSTEMI or unstable angina, 27% were diabetics, 30% had previous myocardial infarction and 48% had a history of previous revascularisation. In addition, hypertension and dyslipidaemia were the most common risk factors (58% and 40%). Sixty-five stents were successfully implanted (100% device success rate). The analysis of 30 days follow-up for 63 patients revealed good clinical results showing lack of death, target lesion revascularisation procedures (TLR) and target vessel revascularisation procedures (TVR). There were six (9,5%) cases of in-hospital raised troponin, however, only one showed an additional increase in CK-MB levels and was qualified as non-Q myocardial infarction (MI). There was a need for percutaneous coronary intervention (PCI) in a non-index vessel in one patient due to exertional angina. The analysis of 12-month follow-up for 63 patients revealed good clinical results. There were two (3.2%) cases of death (three and 10 months after index procedure). The first patient, in good physical shape, drowned, while the second was found dead by his family. There were no incidents of MI or stroke in the rest of the population. At 12 months there were seven (10.8% per lesion; 11.1% per patient) cases of TLR and nine (13.8% per lesion; 14.3% per patient) TVR. There were also 15 (23.8%) cases of PCI on vessels not related to BiOSS(r) Expert stent implantation. CONCLUSIONS: Our registry showed that bifurcation treatment with a single dedicated paclitaxel-eluting bifurcation stent, BiOSS(r) Expert is feasible and successful. The long-term clinical results are satisfactory in this high-risk patient population. PMID- 22829506 TI - A prospective randomised comparison of titanium-nitride-oxide-coated bioactive stents with everolimus-eluting stents in acute coronary syndrome: the BASE-ACS trial. AB - AIMS: Titanium-nitride-oxide-coated bioactive stents (BAS) have demonstrated a favourable outcome when compared with paclitaxel-eluting stents in patients with acute myocardial infarction (MI). In a prospective randomised non-inferiority study design, we compared the safety and efficacy of BAS versus everolimus eluting stents (EES) in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: We randomised 827 patients with ACS (1:1) to either BAS (417) or EES (410). The primary endpoint was a composite of cardiac death, non-fatal MI or ischaemia-driven target lesion revascularisation (TLR) at 12-month follow-up. Analyses were performed by intention to treat. At 12-month follow-up, the primary composite endpoint occurred in 9.6% of patients in the BAS group and 9.0% of those in the EES group (HR [hazard ratio] 1.04, 95% CI [confidence interval] 0.81 1.32, p=0.81, p for non-inferiority =0.001). Non-fatal MI was significantly less frequent in the BAS as compared with the EES group (2.2% vs. 5.9%, p=0.007). However, the individual rates of cardiac death and ischaemia-driven TLR were similar between the two groups (1.9% vs. 1.0%, p=0.39, and 6.5% vs. 4.9%, p=0.37, respectively). CONCLUSIONS: In patients presenting with ACS, BAS achieved a clinical outcome that was non-inferior to EES at 12-month follow-up. PMID- 22829508 TI - SPIRIT Women, evaluation of the safety and efficacy of the XIENCE V everolimus eluting stent system in female patients: referral time for coronary intervention and 2-year clinical outcomes. AB - AIMS: SPIRIT Women is the first interventional trial dedicated exclusively to women, focusing on symptoms at presentation, referral time to coronary intervention and the safety and performance of the XIENCE V stent. METHODS AND RESULTS: SPIRIT Women is a prospective, open-label, multicentre study in which 1,573 women were enrolled at 73 sites outside the United States. The primary endpoint is the composite of all death, Academic Research Consortium (ARC) defined myocardial infarction (MI) and target vessel revascularisation (TVR) at one year. Data collected included symptoms at presentation and referral to coronary intervention. To allow comparison by gender, the latter were compared to data from male patients from the SPIRIT V study. The one- and two-year composite of all death, MI and TVR was 12% and 15%, respectively. Target lesion revascularisation (TLR) and stent thrombosis (definite and probable) rates were 2.4% and 0.59%, respectively, at one year and 3.6% and 0.73%, at two years. The total referral time for coronary intervention in women was four days longer than for men in the SPIRIT V study. CONCLUSIONS: The XIENCE V stent is safe and effective with low TLR and stent thrombosis rates. More efforts remain to be made to increase the awareness of women and physicians of the risk for coronary artery disease (CAD). PMID- 22829509 TI - Usefulness and safety of the GuideLiner catheter to enhance intubation and support of guide catheters: insights from the Twente GuideLiner registry. AB - AIMS: Optimal ostial seating and adequate back-up of guide catheters are required for challenging percutaneous coronary interventions (PCI). The GuideLinerTM (GL) (Vascular Solutions Inc., Minneapolis, MN, USA) is a guide catheter extension system that provides active back-up support by deep coronary intubation. We aimed to assess feasibility and safety of GL-use in routine clinical practice. METHODS AND RESULTS: We prospectively recorded patient and procedural details, technical success, and in-hospital outcome of 65 consecutive patients undergoing "5-in-6" Fr GL-facilitated PCI of 70 target vessels. The GL was mainly used for PCI of complex coronary lesions: 97% (68/70) had American Heart Association/American College of Cardiology (AHA/ACC) lesion types B2/C; 53% (37/70) were distally located; and 23% (17/70) were heavily calcified. Indications were to increase back-up of the guide and facilitate stent delivery (59%; 41/70), achievement of coaxial alignment of the guide catheter (29%; 20/70), and selective contrast injections (13%; 9/70). Device success rate was 93% (65/70). There were no major complications and two minor complications managed without clinical sequelae: one air embolism and one stent dislodgement. CONCLUSIONS: GL-use resulted in increased back-up and guide catheter alignment for stent delivery in unfavourable tortuous coronary anatomies and complex, heavily calcified, and often distally located lesions, which otherwise may have been considered unsuitable for PCI. Procedural success rate was high and there were no major complications. PMID- 22829510 TI - PFO closure with the Premere PFO closure device: acute results and follow-up of 263 patients. AB - AIMS: The aim was to assess the safety and efficacy of percutaneous patent foramen ovale (PFO) closure with the Premere (St. Jude Medical, Inc., St. Paul, MN, USA) device. METHODS AND RESULTS: This is a prospective clinical and echocardiographic follow-up of 264 patients who underwent transcatheter PFO closure with planned implantation of the Premere device. Implantation was successful in 263 patients (99.6%). Complete closure demonstrated echocardiographically occurred in 92.7%. The 30-day adverse event rate was 5.4% (atrial fibrillation in six, pericardial effusion in three, acute coronary syndrome in two, pseudoaneurysm/fistula formation at the access site in two patients and device dislocation in one patient). At a mean follow-up of 19.3 months (+/-14.2 months) stroke or transient ischaemic attack (TIA) occurred in nine (3.5%) and thrombus formation on the left atrial anchor in one (0.4%) patient. CONCLUSIONS: These data demonstrate that PFO closure with the Premere closure device is safe and effective. Complication rates and efficacy are similar to previously studied devices. PMID- 22829511 TI - Clinical event committees in coronary stent trials: insights and recommendations based on experience in an unselected study population. AB - AIMS: To introduce the interested reader to the concepts of the Clinical Event Committee (CEC) work process with a focus on the adjudication of major endpoints in contemporary coronary stent trials. METHODS AND RESULTS: Endpoint adjudication by independent Clinical Events Committees (CEC) is critical to ensure the generation and recording of quality data in clinical outcome trials. CEC adjudication provides a standard, systematic and unbiased assessment of endpoints. For trials with relatively long-term clinical endpoints that span geographic regions and include diverse clinical presentations and practice patterns, this poses specific challenges. The recently published RESOLUTE All Comer coronary stent trial is used to illustrate some aspects of the CEC process. CONCLUSIONS: Understanding the CEC review process is important to guide the design of future trials and allow meaningful comparisons of event rates among trials. PMID- 22829512 TI - Emergency extracorporeal membrane oxygenation in a hospital without on-site cardiac surgical facilities. AB - AIMS: We report the feasibility and outcomes of emergency extracorporeal membrane oxygenation (ECMO) implantation by a cardiac catheterisation team in patients in severe cardiogenic shock or refractory cardiac arrest in a hospital without cardiac surgical facilities. METHODS AND RESULTS: This prospective cohort study involved 51 consecutive patients who had ECMO implantation (September 2006 - September 2010). Twenty-seven were in severe cardiogenic shock and 24 in refractory cardiac arrest (17 with out-of-hospital cardiac arrest; seven with in hospital cardiac arrest). Implantations were done via a percutaneous femoral approach by a local interventional cardiologist team, and in collaboration with the nearest cardiac surgical institution. Patients' mean age was 51+/-15 years; 38 (74.5%) were men. Stable ECMO implantation was achieved in 26/27 (96.3%) patients in severe cardiogenic shock and in 18/24 (75.0%) patients in refractory cardiac arrest. In-hospital complications occurred in 23/27 cardiogenic shock patients; 13/27 were discharged alive. In patients with refractory cardiac arrest, complications occurred in 20/24; 21/24 were disconnected from ECMO because of brain death or multiorgan failure occurring <=24 hours; one patient was discharged alive. CONCLUSIONS: Emergency ECMO implantation by an interventional cardiologist in a hospital without cardiac surgical facilities is feasible, with a failure rate concordant with the literature. PMID- 22829513 TI - How should I treat a patient with significant angina and a severe left anterior descending artery stenosis beyond the insertion of a left internal mammary artery jump graft (diagonal to LAD)? PMID- 22829514 TI - Percutaneous mechanical thrombectomy of left atrial appendage thrombus with bilateral neuro-embolic protection followed by closure of left atrial appendage. PMID- 22829515 TI - Left ventricular angiography with a Jacky radial catheter at high pressure leading to myocardial staining and opacification of the great cardiac vein and coronary sinus. PMID- 22829516 TI - Enzyme-mediated methodologies for protein modification and bioconjugate synthesis. AB - Bioconjugates are valuable tools in many fields, including protein engineering and environmental and therapeutic research. Chemical methods are commonly used to synthesize protein-protein and protein-functional molecule bioconjugates because they permit easy tethering through covalent bonds. However, chemical methods often produce heterogeneous products and lead to degradation of protein activity due to random modifications. Recently, a number of techniques for modifying proteins or synthesizing bioconjugates have been reported, including more sophisticated chemical modification methods, utilization of noncovalent affinity, and protein splicing. Enzymatic methods in particular have attracted much attention due to the substrate specificity of enzymes, which enables site specific tethering of proteins to other proteins or functional molecules. Here, we discuss newly developed methods for protein modification and bioconjugate synthesis that exploit the properties of acyltransferases, ligases, and other enzymes. PMID- 22829517 TI - Modelling production processes in a vehicle recycling plant. AB - The European Directive on end-of-life vehicles (ELVs) fundamentally changed the business philosophy of the European vehicle recycling system, which was exclusively profit-oriented. As the dominant participants of this system, vehicle recycling plants (VRPs) are especially affected by its implementation. For VRPs to successfully respond to the prescribed eco-efficiency quotas, investment will be needed to procure modern sorting equipment as well as to achieve full transformation of their production process. However, before VRPs decide to make this very important investment decision, it is necessary to determine the adequacy of such a decision in detail. Consequently, the following questions become unavoidable: Can modernly equipped VRPs conduct profitable business? Are eco-efficiency quotas actually attainable? How will the new changes in vehicle design influence VRPs? To provide answers to these essential questions, a production planning model of a modernly equipped VRP was first developed and then tested extensively using real data. Based on the answers provided by the proposed model testing analysis it was concluded that VRP transformation is not only necessary but completely justified and that the final success of the ELV Directive is realistic. PMID- 22829518 TI - Toward cardiovascular interventions guided by magnetic particle imaging: first instrument characterization. AB - Magnetic particle imaging has emerged as a new technique for the visualization and quantification of superparamagnetic iron oxide nanoparticles. It seems to be a very promising application for cardiovascular interventional radiology. A prerequisite for interventions is the artifact-free visualization of the required instruments and implants. Various commercially available catheters, guide wires, and a catheter experimentally coated with superparamagnetic iron oxide nanoparticles were tested regarding their signal characteristics using magnetic particle spectroscopy to evaluate their performance in magnetic particle imaging. The results indicate that signal-generating and non-signal-generating instruments can be distinguished. Furthermore, coating or loading non-signal-generating instruments with superparamagnetic iron oxide nanoparticles seems to be a promising approach, but optimized nanoparticles need yet to be developed. PMID- 22829519 TI - Polyacetylenes as enantiodifferentiating alignment media. PMID- 22829520 TI - Synthesis and characterization of sensitive hydrogels based on semi interpenetrated networks of poly[2-ethyl-(2-pyrrolidone) methacrylate] and hyaluronic acid. AB - Sensitive hydrogels attract interest due to their soft wet appearance and shape response to environmental variations. The synthesis and characterization of semi interpenetrated hydrogels obtained by radical-induced polymerization of 2-ethyl (2-pyrrolidone)methacrylate (EPM) in the presence of different concentrations of hyaluronic acid (HA) using N,N'-methylene-bisacrylamide or triethylene glycol dimethacrylate as crosslinker, followed by freeze-drying, are described. Polymeric systems were characterized by NMR, FTIR, SEM, TGA, and DMA. PEPMHA hydrogels' mechanical properties and swelling were found to be intimately related to HA concentration and crosslinker. The swelling response was assessed for temperature and pH variation in order to study the behavior of the hydrogels. We found that the presence of HA in PEPM polymeric systems induced a sensitivity to pH variation rather than temperature. Finally, the biocompatibility profile of the hydrogels was evaluated, using mesenchymal stem cells. Cell adhesion and proliferation results revealed the non-cytotoxicity of the systems. We estimate that PEPMHA hydrogels can be used for applications in tissue engineering and for the controlled release of bioactive compounds. PMID- 22829521 TI - Metal-metal interaction and flexible motion of triple-decker polypyridyl platinum(II) and palladium(II) complexes. PMID- 22829522 TI - Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) >=75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression. RESULTS: There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score <=0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01 1.45]; P = 0.04) and HOMA-IR (1.10 [1.02-1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20-1.95]; P = 0.001). CONCLUSIONS: Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD. PMID- 22829523 TI - Metabolic effects of high altitude trekking in patients with type 2 diabetes. AB - OBJECTIVE: Limited information is available regarding the metabolic effects of high altitude trekking in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirteen individuals with type 2 diabetes took part in a 12-day expedition to the summit of Mount Toubkal (altitude, 4,167 m), Morocco, after 6 months of exercise training. Energy expenditure, body weight, blood glucose, fasting insulin, lipids, and HbA(1c) were assessed. RESULTS: Training reduced fasting glucose (-0.7 +/- 0.9 mmol/L, P = 0.026) and increased exercise capacity (+0.3 +/- 0.3 W/kg, P = 0.005). High altitude trekking decreased fasting insulin concentrations (-3.8 +/- 3.2 MUU/L, P = 0.04), total cholesterol (-0.7 +/- 0.8 mmol/L, P = 0.008), and LDL cholesterol (-0.5 +/- 0.6 mmol/L, P = 0.007). CONCLUSIONS: High altitude trekking preceded by exercise training is feasible for patients with type 2 diabetes. It improves blood glucose, lipids, and fasting insulin concentrations, while glucose control is maintained. PMID- 22829524 TI - Statin intake is associated with decreased insulin sensitivity during cardiac surgery. AB - OBJECTIVE: Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS: In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS: We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ~20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 +/- 20 vs. 140 +/- 20 mg/dL; P < 0.001). The oscillation of blood glucose was larger in the statin group (SD, P < 0.001; CV, P = 0.001). Multiple regression analysis showed that statin use was independently associated with intraoperative insulin sensitivity (beta = -0.16; P = 0.03). CONCLUSIONS: Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients. PMID- 22829526 TI - Enantioselective nickel-catalyzed Michael additions of azaarylacetates and acetamides to nitroalkenes. PMID- 22829528 TI - Effects of phosphorus substituents on reactions of alpha-alkoxyphosphonium salts with nucleophiles. AB - The effects of phosphorus substituents on the reactivity of alpha alkoxyphosphonium salts with nucleophiles has been explored. Reactions of alpha alkoxyphosphonium salts, prepared from various acetals and tris(o tolyl)phosphine, with a variety of nucleophiles proceeded efficiently. These processes represent the first examples of high-yielding nucleophilic substitution reactions of alpha-alkoxyphosphonium salts. The reactivity of these salts was determined by a balance between steric and electronic factors, respectively, represented by cone angles theta and CO stretching frequencies nu (steric and electronic parameters, respectively). In addition, a novel reaction of alpha alkoxyphosphonium salts derived from Ph(3)P with Grignard reagents was observed to take place in the presence of O(2) to afford alcohols in good yields. A radical mechanism is proposed for this process that has gained support from isotope-labeling and radical-inhibition experiments. PMID- 22829527 TI - IL-1beta enhances cell adhesion to degraded fibronectin. AB - IL-1beta is a prominent proinflammatory cytokine that mediates degradation of extracellular matrix proteins through increased expression of matrix metalloproteinases, which involves a signaling pathway in adherent cells that is restricted by focal adhesions. Currently, the mechanism by which IL-1beta affects cell adhesion to matrix proteins is not defined, and it is not known whether degraded matrix proteins affect IL-1beta signaling. We examined adhesion-related IL-1beta signaling in fibroblasts attaching to native or MMP3-degraded fibronectin. IL-1beta increased cell attachment, resistance to shear force and the numbers of focal adhesions containing activated beta(1) integrins. IL-1beta enhanced attachment required FAK, kindlins 1/2, and talin. MMP3-degraded fibronectin-inhibited IL-1beta-enhanced cell adhesion and promoted spontaneous ERK activation that was independent of IL-1beta treatment. We conclude that IL 1beta enhances the adhesion of anchorage-dependent cells to MMP3-degraded fibronectin, which, in turn, is associated with deregulated cellular responses to IL-1beta. These data point to a novel role of IL-1beta as a proadhesive signaling molecule in inflammation that employs kindlins and talin to regulate adhesion. PMID- 22829529 TI - Biocatalytic conversion of lignocellulose to platform chemicals. AB - Naturally occurring lignocellulose can be used as a renewable resource for the sustainable production of platform chemicals that can in turn be converted to valuable fine chemicals, polymers, and fuels. The biocatalytic conversion of lignocellulose is a very promising approach due to its high selectivity, mild conditions, and low exergy loss. However, such biocatalytic processes are still seldom applied at the industrial scale since the single conversion steps (pretreatment, hydrolysis, and fermentation) may exhibit low conversion rates, low efficiencies, or high costs. The biocatalytic conversion of lignocellulose to platform chemicals is reviewed in this work. Structures and production rates of lignocellulose are described, and platform chemicals that may be produced from lignocellulose are summarized. Biocatalytic conversion of lignocellulose is distinguished from conventional non-selective approaches. All essential conversion steps used in biocatalytic approaches (pretreatment, hydrolysis, and fermentation) are reviewed in detail. Finally, potential interactions between these conversion steps are highlighted and the advantages as well as disadvantages of integrated process configurations are elucidated. In conclusion, a comprehensive understanding of the biocatalytic conversion of lignocellulose is provided in this review. PMID- 22829530 TI - Peptide chirality sensing by a cyclodextrin-polythiophene conjugate. AB - A new cyclodextrin-polythiophene conjugate (CDPT) has been prepared by attaching permethyl-alpha-cyclodextrins to polythiophene (PT) through a hexamethylene tether. Circular dichroism spectral examination of CDPT revealed that only a weak positive Cotton effect (Deltaepsilon=0.1 M(-1) cm(-1)) was induced at the main band of the PT in dimethyl sulfoxide and similarly weak bisignate signals in pure and aqueous methanol solutions, which indicates that the alpha-cyclodextrins appended to PT with a long tether are ineffective in inducing a homochiral structure in the PT backbone. Nevertheless, enantiomeric amino acids and dipeptides added to an aqueous methanolic solution of CDPT caused chirality dependent hypochromic changes in the UV/Vis spectra, which enabled us to sense these species and quantitatively determine the enantioselectivity by observing the difference in absorbance upon interaction with pairs of enantiomers. Enantiomeric D,D/L,L-dipeptide pairs rather than D/L-amino acid pairs were better differentiated in general, the highest DD/LL selectivity of 13.7 being observed for Phe-Phe. PMID- 22829531 TI - Light-controlled tools. AB - Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems--from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications. PMID- 22829533 TI - Biodegradable balloon-expandable self-locking polycaprolactone stents as buckling explants for the treatment of retinal detachment: an in vitro and in vivo study. AB - The purpose of this report was to develop biodegradable balloon-expandable self locking poly(epsilon-caprolactone) (PCL) stents for the treatment of retinal detachment. To create the biodegradable stents, polycaprolactone components were first fabricated by a laboratory-scale microinjection molding machine. The components were then assembled into mesh-like stents of 6 and 8 mm in diameter. A special geometry of the components was designed to self-lock the assembled stents after being expanded by balloons. Characterization of the biodegradable PCL stents was carried out. PCL stents exhibited comparable mechanical properties with that of silicone sponge. Neither significant amount of collapse pressure reduction nor weight loss of the stents was observed after being submerged in phosphate buffered saline for 30 days. In addition, the stents were also implanted in the episcleral space of 10 New Zealand white rabbits. The stents were placed in radial direction and left unsutured after balloon expansion. The stents achieved an efficient buckling effect in echographic and fundus photographic examinations. The ocular pressure was significantly elevated after stent implantation and gradually normalized after the second week. The computed tomography studies verified the hypothesis of minimal migration of the PCL stents. The in vivo result suggests that balloon-expandable biodegradable stents can potentially serve as an ideal indenting biomaterial in retinal detachment surgery. PMID- 22829532 TI - Biosynthesis and cellular localization of functional polyketides in the gastropod mollusc Scaphander lignarius. AB - Opisthobranchs belong to a subclass of highly evolved and specialised marine gastropods that rely on the use of secondary metabolites for their survival. Here we report the full elucidation of the biosynthesis of aromatic metabolites, lignarenones, in one of these gastropods, the cephalaspidean Scaphander lignarius. Feeding experiments with 2H- and 13C-labelled precursors revealed a mixed acetate/propionate polyketide pathway primed by benzoic acid. Phenylalanine ammonia lyase (PAL), unprecedented in animals, is central to the synthesis of this aromatic precursor by oxidative deamination of L-phenylalanine to cinnamic acid. Lignarenones are synthesised in the cytoplasm of specialised eukaryotic cells named Blochmann's glands, which are distributed in biosynthetic tissue localised in the vulnerable mantle of the mollusc. This result supports the hypothesis that this lineage of gastropods has acquired the genetic information to produce the chemical substances that they use for their survival. PMID- 22829534 TI - Dendritic metalloporphyrin-fullerene conjugates: changing the microenvironment around redox-active centers and its impact on charge-transfer reactions. AB - Photophysical investigations on a series of (2,4,6)-tris-substituted metalloporphyrin-fullerene conjugates revealed the effects of an electron-rich microenvironment surrounding the electron-donating porphyrin as a function of the metal center. On one hand, for all conjugates-water-soluble and non-water-soluble ultrafast charge separation was observed upon photoexcitation. On the other hand, when examining the charge recombination dynamics for the non-water-soluble conjugates it becomes obvious that the (2,4,6)-tris-substitution stabilizes the radical-ion-pair state relative to the mono-substitution in the ortho-, meta-, and para-position. The more efficient protection of the electron-donating porphyrin from solvation is thought to be the major cause for this impact. Nevertheless, the situation is slightly different for the water-soluble conjugates. At first glance, the radical-ion-pair state lifetimes are, also in the case of the (2,4,6)-tris-substitution, longer than for the mono-substituted ortho-, meta- and para-conjugates. Upon closer inspection, they fail, however, to exhibit any metal dependence. Competing with the protection from solvation of the dendrons, dipole-charge interactions impact the stabilization in the polar aqueous environment and, in turn, become the dominant force governing the electron-transfer dynamics. PMID- 22829535 TI - Finished bacterial genomes from shotgun sequence data. AB - Exceptionally accurate genome reference sequences have proven to be of great value to microbial researchers. Thus, to date, about 1800 bacterial genome assemblies have been "finished" at great expense with the aid of manual laboratory and computational processes that typically iterate over a period of months or even years. By applying a new laboratory design and new assembly algorithm to 16 samples, we demonstrate that assemblies exceeding finished quality can be obtained from whole-genome shotgun data and automated computation. Cost and time requirements are thus dramatically reduced. PMID- 22829536 TI - The sweet tooth of biopharmaceuticals: importance of recombinant protein glycosylation analysis. AB - Biopharmaceuticals currently represent the fastest growing sector of the pharmaceutical industry, mainly driven by a rapid expansion in the manufacture of recombinant protein-based drugs. Glycosylation is the most prominent post translational modification occurring on these protein drugs. It constitutes one of the critical quality attributes that requires thorough analysis for optimal efficacy and safety. This review examines the functional importance of glycosylation of recombinant protein drugs, illustrated using three examples of protein biopharmaceuticals: IgG antibodies, erythropoietin and glucocerebrosidase. Current analytical methods are reviewed as solutions for qualitative and quantitative measurements of glycosylation to monitor quality target product profiles of recombinant glycoprotein drugs. Finally, we propose a framework for designing the quality target product profile of recombinant glycoproteins and planning workflow for glycosylation analysis with the selection of available analytical methods and tools. PMID- 22829537 TI - Triaryl-1,3,5-triazinane-2,4,6-triones (isocyanurates) peripherally functionalized by donor groups: synthesis and study of their linear and nonlinear optical properties. AB - The linear optical (LO) and nonlinear optical (NLO) properties of a series of isocyanurates functionalized by donor arms at the periphery are reported herein. These octupolar derivatives were obtained in a straightforward way from commercial isocyanate derivatives and were fully characterized. Although several of these compounds are known, those that exhibited the largest NLO activities are all new compounds. In terms of second-order activity, several of these derivatives exhibit remarkable activity/transparency tradeoffs. In terms of third order activity, the longer derivatives with the stronger donor groups (X = NH(2), NMe(2), or NPh(2)) were shown to possess significant two-photon absorption cross sections. These strongly luminescent derivatives exhibit two-photon absorption cross sections up to 410 GM. DFT computations were also conducted to unravel their electronic structures and to rationalize their NLO properties. To our knowledge, the present study is the first concerned with the nonlinear optical properties of these original cyclotrimers. PMID- 22829538 TI - Fluorinated organocatalysts for the enantioselective epoxidation of enals: molecular preorganisation by the fluorine-iminium ion gauche effect. AB - The fluorine-iminium ion gauche effect is triggered upon union of a secondary beta-fluoroamine and an alpha,beta-unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of intermediates that are central to organocatalytic processes. The beta-fluoroamine (S)-2 (fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of alpha,beta-unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a beta-fluoroiminium motif. Epoxidations of challenging cyclic alpha,beta-disubstituted, beta,beta disubstituted and alpha,beta,beta-trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98% ee). PMID- 22829539 TI - Chemical proteomics reveals heat shock protein 60 to be the main cellular target of the marine bioactive sesterterpene suvanine. AB - Marine bioactive compounds are potential drug leads because of their diverse pharmacological effects against human diseases. The identification of their cellular targets is crucial for a rational approach to their application in medicinal chemistry. Thus, we have analyzed the cell interactome of suvanine, a sulfated tricyclic terpenoid of marine origin endowed with an interesting anti inflammatory activity, by application of a chemical proteomic approach. Heat Shock Protein 60, a chaperone involved in the inflammatory response, is the main cellular target of suvanine, which is also able to interfere with protein chaperone activity, giving evidence for its anti-inflammatory properties. PMID- 22829540 TI - Highly diastereo- and enantioselective cyclopropanation of 1,2-disubstituted alkenes. PMID- 22829541 TI - Effect of fiber crosslinking on collagen-fiber reinforced collagen-chondroitin-6 sulfate materials for regenerating load-bearing soft tissues. AB - Porous collagen-glycosaminoglycan structures are bioactive and exhibit a pore architecture favorable for both cellular infiltration and attachment; however, their inferior mechanical properties limit use, particularly in load-bearing situations. Reinforcement with collagen fibers may be a feasible route for enhancing the mechanical characteristics of these materials, providing potential for composites used for the repair and regeneration of soft tissue such as tendon, ligaments, and cartilage. Therefore, this study investigates the reinforcement of collagen-chondroitin-6-sulfate (C6S) porous structures with bundles of extruded, reconstituted type I collagen fibers. Fiber bundles were produced through extrusion and then, where applicable, crosslinked using a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide. Fibers were then submerged in the collagen-C6S matrix slurry before being lyophilized. A second 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N hydroxysuccinimide crosslinking process was then applied to the composite material before a secondary lyophilization cycle. Where bundles had been previously crosslinked, composites withstood a load of approximately 60 N before failure, the reinforcing fibers remained dense and a favorable matrix pore structure resulted, with good interaction between fiber and matrix. Fibers that had not been crosslinked before lyophilization showed significant internal porosity and a channel existed between them and the matrix. Mechanical properties were significantly reduced, but the additional porosity could prove favorable for cell migration and has potential for directing aligned tissue growth. PMID- 22829542 TI - Luminescence responsive charge transfer intercluster crystals. PMID- 22829543 TI - In vitro studies on the oxidative metabolism of 20(s)-ginsenoside Rh2 in human, monkey, dog, rat, and mouse liver microsomes, and human liver s9. AB - 20(S)-Ginsenoside Rh2 (Rh2)-containing products are widely used in Asia, Europe, and North America. However, extremely limited metabolism information greatly impedes the complete understanding of its clinical safety and effectiveness. The present study aims to systematically investigate the oxidative metabolism of Rh2 using a complementary set of in vitro models. Twenty-five oxidative metabolites were found using liquid chromatography-electrospray ionization ion-trap mass spectrometry. Six metabolites and a metabolic intermediate were synthesized. The metabolites were structurally identified as 26-hydroxy Rh2 (M1-1), (20S,24S) epoxydammarane-12,25-diol-3-beta-d-glucopyranoside (M1-3), (20S,24R) epoxydammarane-12,25-diol-3-beta-d-glucopyranoside (M1-5), 26,27-dihydroxy Rh2 (M3-6), (20S,24S)-epoxydammarane-12,25,26-triol-3-beta-d-glucopyranoside (M3-10), (20S,24R)-epoxydammarane-12,25,26-triol-3-beta-d-glucopyranoside (M3-11), and 26 aldehyde Rh2 on the basis of detailed mass spectrometry and nuclear magnetic resonance data analysis. Double-bond epoxidation followed by rearrangement and vinyl-methyl group hydroxylation represent the initial metabolic pathways generating monooxygenated metabolites M1-1 to M1-5. Further sequential metabolites (M2-M5) from the dehydrogenation and/or oxygenation of M1 were also detected. CYP3A4 was the predominant enzyme involved in the oxidative metabolism of Rh2, whereas alcohol dehydrogenase and aldehyde dehydrogenase mainly catalyzed the metabolic conversion of alcohol to the corresponding carboxylic acid. No significant differences were observed in the phase I metabolite profiles of Rh2 among the five species tested. Reactive epoxide metabolite formation in both humans and animals was evident. However, GSH conjugate M6 was detected only in cynomolgus monkey liver microsomal incubations. In conclusion, Rh2 is a good substrate for CYP3A4 and could undergo extensive oxidative metabolism under the catalysis of CYP3A4. PMID- 22829544 TI - Regulation of pregnane X receptor (PXR) function and UGT1A1 gene expression by posttranslational modification of PXR protein. AB - Human UDP-glucuronosyltransferase (UGT) 1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds such as bilirubin. The present study shows how cyclin-dependent kinase (CDK) inhibitor roscovitine stimulated the expression of UGT1A1 in HepG2 cells. Pregnane X receptor (PXR)-mediated transactivation of UGT1A1 reporter gene was more prominently enhanced by roscovitine, compared with the basal-, constitutive androstane receptor (CAR)-, and aryl hydrocarbon receptor-mediated activities. We determined the regulatory mechanism of UGT1A1 expression through PXR's stimulation by roscovitine. Although phosphomimetic mutations at Thr290 and Thr408 retained the PXR protein in cytoplasm and attenuated the induction of UGT1A1 expression by both roscovitine and rifampicin, a mutation at Ser350 specifically reduced the activity of PXR induced by roscovitine. Immunoprecipitation analysis revealed that the T290D but not T408D mutant protein remained in cytoplasm by forming a complex with heat shock protein 90 and cytoplasmic CAR retention protein, whereas treatment with proteasome inhibitor MG 132 accumulated the T408D mutant protein in cytoplasm. Transfection with anti CDK2 small interfering RNA (siRNA) but not anti-CDK1 or CDK5 siRNA led to enhanced expression of UGT1A1. S350D yellow fluorescent protein-PXR fusion protein could translocate from cytoplasm to nucleus similar to the wild-type protein but was detected as an acetylated protein, whose binding with retinoid X receptor (RXR) and histone deacetylase was impaired. Cotransfection with coactivator steroid receptor coactivator (SRC) 2 but not SRC-1 partly recovered its PXR activity. These results indicate that roscovitine stimulated the expression of UGT1A1 by inhibiting CDK2, which phosphorylated PXR at Ser350 to suppress binding with RXR and coactivator and maintain the acetylation of PXR protein. PMID- 22829545 TI - Statin use and microbleeds in patients with spontaneous intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Statins have been associated with increased risk of intracerebral hemorrhage (ICH), particularly in elderly patients with previous ICH. Recurrent ICH in the elderly is often related to cerebral amyloid angiopathy. Therefore, we investigated whether statin use is associated with increased prevalence and severity of microbleeds (MB), particularly cortico subcortical microbleeds (csMB), which are frequently observed in cerebral amyloid angiopathy. METHODS: We studied 163 consecutive patients with spontaneous ICH who underwent magnetic resonance imaging within 30 days of presentation. We retrieved clinical information and analyzed magnetic resonance imaging for the presence, location, and number of MB, which were divided into csMB or other (other MB). We performed group comparisons stratified by statin use and by the presence vs absence of any MB (csMB and/or other MB) or csMB alone. RESULTS: Sixty-four percent had lobar ICH. Overall, 53% had microbleeds and 39% had csMB. Statin users were older, had significantly lower cholesterol and low-density lipoprotein levels, and higher prevalence of hypertension, diabetes, dyslipidemia, and antiplatelet use. The prevalence and number of other MB were similar in statin treated and statin-untreated individuals. However, more statin-treated patients had csMB (57% vs 33%; P=0.007), with almost twice as many lesions (4.6 +/- 11.3 vs 2.4 +/- 8.0; P=0.007) compared with untreated patients. Age and statin use were independently associated with both the presence and increased number of MB (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.05; P=0.01 and OR, 2.72; 95% CI. 1.02-7.22; P=0.04, respectively) and csMB (OR, 1.03; 95% CI, 1.00 1.06; P=0.01 and OR, 4.15; 95% CI, 1.54-11.20; P<0.01) in multivariate analyses. CONCLUSIONS: Statin use in patients with ICH is independently associated with MB, especially csMB. Future studies are needed to confirm our findings and to investigate whether csMB can serve as a surrogate marker for ICH risk in statin treated patients. PMID- 22829546 TI - Near-term fetal hypoxia-ischemia in rabbits: MRI can predict muscle tone abnormalities and deep brain injury. AB - BACKGROUND AND PURPOSE: The pattern of antenatal brain injury varies with gestational age at the time of insult. Deep brain nuclei are often injured at older gestational ages. Having previously shown postnatal hypertonia after preterm fetal rabbit hypoxia-ischemia, the objective of this study was to investigate the causal relationship between the dynamic regional pattern of brain injury on MRI and the evolution of muscle tone in the near-term rabbit fetus. METHODS: Serial MRI was performed on New Zealand white rabbit fetuses to determine equipotency of fetal hypoxia-ischemia during uterine ischemia comparing 29 days gestation (E29, 92% gestation) with E22 and E25. E29 postnatal kits at 4, 24, and 72 hours after hypoxia-ischemia underwent T2- and diffusion-weighted imaging. Quantitative assessments of tone were made serially using a torque apparatus in addition to clinical assessments. RESULTS: Based on the brain apparent diffusion coefficient, 32 minutes of uterine ischemia was selected for E29 fetuses. At E30, 58% of the survivors manifested hind limb hypotonia. By E32, 71% of the hypotonic kits developed dystonic hypertonia. Marked and persistent apparent diffusion coefficient reduction in the basal ganglia, thalamus, and brain stem was predictive of these motor deficits. CONCLUSIONS: MRI observation of deep brain injury 6 to 24 hours after near-term hypoxia-ischemia predicts dystonic hypertonia postnatally. Torque-displacement measurements indicate that motor deficits in rabbits progressed from initial hypotonia to hypertonia, similar to human cerebral palsy, but in a compressed timeframe. The presence of deep brain injury and quantitative shift from hypo- to hypertonia may identify patients at risk for developing cerebral palsy. PMID- 22829547 TI - A pentapeptide monocyte locomotion inhibitory factor protects brain ischemia injury by targeting the eEF1A1/endothelial nitric oxide synthase pathway. AB - BACKGROUND AND PURPOSE: Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia. METHODS: A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry. RESULTS: MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression. CONCLUSIONS: In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway. PMID- 22829548 TI - Dramatic fluorescence enhancement of bare carbon dots through facile reduction chemistry. AB - Reduction of bare carbon dots (CDs) in aqueous NaBH(4) solution is a facile and effective approach to enhance their fluorescence without any surface coverage. CDs are treated with dilute aqueous NaBH(4) solutions, enhancing their quantum yields (QYs) successfully from 1.6 % to 16 % which is comparable to semiconductive QDs in aqueous environments. If pristine CDs are treated hydrothermally prior to reduction by NaBH(4), QYs reach 40.5 %. This value is among the highest QYs reported for bare CDs in the literature. The approach to enhance fluorescence through chemical reduction is generally applicable to other kinds of CDs synthesized by various methods. Alteration of the chemical structure of the CDs by NaBH(4)-reduction is analyzed by (13) C NMR, X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy, which demonstrate that the carbonyl group content is decreased after NaBH(4)-reduction, whereas the number of sp(3) type carbon defects is increased. The valence-band maxima (VBM) near the surface related to the surface energy bands of the CDs are estimated by XPS. VBM data show a semiconducting layer on the surface of the CDs, and the VBM of the CDs decrease with increasing NaBH(4)-reduction time. The layered graphite structures in the cores of the CDs are clearly observed by transmission electron microscopy (TEM). CDs could perhaps be regarded as semiconductive surface defect layers formed by chemical erosion over conductive graphite cores. Chemical reduction by NaBH(4) changes the surface-energy bands of the CDs, thus, enhances their fluorescence. The fluorescence properties of aqueous NaBH(4)-reduced CDs are also studied for possible biological applications. PMID- 22829549 TI - Facile synthesis of fluorine-substituted benzothiadiazole-based organic semiconductors and their use in solution-processed small-molecule organic solar cells. AB - A facile new protocol for the synthesis of iodinated derivatives of fluorinated benzothiadiazoles is demonstrated for the production of p-type semiconducting materials. The newly synthesized small-molecule compounds bis[TPA-diTh]-MonoF-BT and bis[TPA-diTh]-DiF-BT exhibited a power conversion efficiency of 2.95% and a high open-circuit voltage of 0.85 V in solution-processed small-molecule organic solar cells. PMID- 22829550 TI - Biomimetic soluble collagen purified from bones. AB - Type I collagen has been extensively exploited as a biomaterial for biomedical applications and drug delivery; however, small molecular alterations occurring during the isolation procedure and its interaction with residual bone extracellular matrix molecules or proteins might affect the overall material biocompatibility and performance. The aim of the current work is to study the potential alterations in collagen properties and organization associated with the absence of proteoglycans, which mimic pathological conditions associated with age related diseases. A new approach for evaluating the effect of proteoglycans on the properties of isolated type I collagen from the bone matrix is described. Additional treatment with guanidine hydrochloride was introduced to remove residual proteoglycans from the collagen matrix. The properties of the isolated collagen with/without guanidine hydrochloride treatment were investigated and compared with a commercial rabbit collagen as control. We demonstrate that the absence of proteoglycans in the isolated type I collagen affects its thermal properties, the extraction into its native structure, and its ability to hydrate and self-assemble into fibers. The fine control and tuning of all these features, linked to the absence of non-collagenous proteins as proteoglycans, offer the possibility of designing new strategies and biomaterials with advanced biomimetic properties aimed at regenerating bone tissue in the case of fragility and/or defects. PMID- 22829551 TI - Results of laparoscopic gastrectomy for early gastric cancer in high-risk patients - estimation of surgical risk of gastrectomy. AB - BACKGROUND/AIMS: Surgical risk of laparoscopic gastrectomy for gastric cancer in high risk patients was evaluated with E-PASS scoring system. METHODOLOGY: This study was based on 63 patients with gastric cancer who underwent laparoscopic gastrectomy; 14 patients belonging to high risk group (ASA>=3) and 49 classified as low risk group (ASA<=2). Fifty six patients who underwent conventional gastrectomy were used for comparison. RESULTS: Intra- and postoperative complications were found in 4 and 3 of 14 high risk patients, respectively. We found a significant correlation between E-PASS score and complications. E-PASS score in high risk group was significantly higher than the value in low risk group. The estimated in-hospital mortality rate was significantly different between the two groups. When conventional gastrectomy group for high risk patients was compared, postoperative morbidity and mortality rates were similar in two surgical procedures; however E-PASS score and the estimated in-hospital mortality rate with conventional gastrectomy were significantly higher than the value with laparoscopic gastrectomy. CONCLUSIONS: There were no fatal complications in high risk patients with laparoscopic gastrectomy and E-PASS score was within safety margin. Extension of laparoscopic surgery in high risk patients was feasible when careful procedure was performed by a surgical team. PMID- 22829552 TI - Postoperative functional evaluation after pylorus-preserving nearly-total gastrectomy with jejunal interposition for gastric cancer. AB - BACKGROUND/AIMS: Pylorus-preserving nearly-total gastrectomy (PPNTG) for gastric cancer is based on the principle that the operation prevents the rapid gastric emptying and reflux that occurs after traditional gastrectomy. In this study, we evaluate the postoperative functional status of patients undergoing PPNTG in comparison with total gastrectomy with Roux-en-Y reconstruction (TG-RY). METHODOLOGY: Ninety-six patients with gastric cancer underwent PPNTG or TG-RY at Nara Medical University Hospital. Short-term outcomes were analyzed retrospectively through medical records from hospitalization. Long-term outcomes were evaluated via questionnaires concerning postoperative function. RESULTS: Of the 96 cases, 32 underwent PPNTG and 64 underwent TG-RY. There were no significant differences in operation time, intraoperative blood loss, postoperative complications, or length of stay. Forty-eight patients responded to the questionnaire (PPNTG: 18, TG-RY: 30). The incidence of general malaise, headaches, chest pain, heartburn and cold sweats was significantly lower in the PPNTG group. Nutritional assessment revealed no differences between the groups. CONCLUSIONS: For gastric cancer of the proximal stomach, PPNTG is a safe alternative to TG-RY, and improves patients' long-term quality of life. PMID- 22829553 TI - Anorectal melanoma: review of 22 consecutive cases. AB - BACKGROUND/AIMS: To evaluate outcome and prognostic factors of patients with anorectal melanoma. METHODOLOGY: Twenty-two consecutive patients with anorectal melanoma received operation from 1993 through 2011 were reviewed. The definitions of stage I, II and III are local disease, locoregional lymphadenopathy and metastatic disease, respectively. RESULTS: The patients included 8 men and 14 women, aged from 36 to 83 years (mean, 58.4 years). At the end of the follow-up period, 19 patients died of disease and only 3 patients were alive with disease. Only two patients were alive longer than 5 years after operation. For stage I and II tumors that underwent clinical curative resection (n=17), stage II (p=0.04), tumor size >3 cm (p=0.008) and invasion depth to muscle (p=0.021) all showed poorer prognosis in overall survival. Though wide local excision (WLE) were performed in the patients with earlier tumors, there was no statistical difference in overall (p=0.063) and disease-free survival (p=0.333) between WLE and radical surgery. Furthermore, patients with WLE had more chance of local recurrence than radical surgery (6/7 vs. 3/10, p=0.050). Four salvage radical operations could be performed after local recurrence in WLE group. CONCLUSIONS: WLE increases the chance of local recurrence more than radical surgery. Care should be taken to avoid microseeding during performed WLE. PMID- 22829554 TI - Preoperative steroid administration in liver resection: a systematic review and meta-analysis. AB - BACKGROUND/AIMS: To investigate the outcome of preoperative steroid administration in patients undergoing liver resection using a systematic review and meta-analysis. METHODOLOGY: Literature on prospective randomized study of preoperative steroid administration in patients undergoing liver resection published between 1966 and July 2011 was retrieved. A systematic review and meta analysis were conducted to estimate the surgical stress, clinical benefit and safety. RESULTS: The reported surgical stress markers included serum IL-6, IL-10 and CRP. Meta-analysis showed that: 1) steroid group had lower serum IL-6 level on POD 1 and POD 3 (p<0.05), and 2) steroid group had lower serum CRP level on POD 3 (p<0.05) with no significant difference on POD 1 and POD 7. After stratifying by Pringle maneuver and steroid dosage, we found that: 1) intermittent Pringle maneuver might have a better effect in suppressing releasing IL-6; 2) both 30 mg/kg and a single dose of 500 mg benefited patients in suppressing releasing IL-6. The incidences of complications were almost the same between steroid group and control group. CONCLUSIONS: Preoperative steroid administration can reduce postoperative surgical stress and has a positive impact on the liver function in patients undergoing liver resection. It does not increase incidence of postoperative complication. PMID- 22829557 TI - Modified Roux-en-Y gastric bypass for type 2 diabetes mellitus in China. AB - BACKGROUND/AIMS: This study aimed to evaluate the efficacy of modified Roux-en-Y gastric bypass for type 2 diabetes mellitus. METHODOLOGY: Forty-five type 2 diabetes mellitus patients underwent modified Roux-en-Y gastric bypass at WeiFang People's Hospital. Data on patient demographics, fasting plasma glucose (FPG), body mass index (BMI), medication use, remission and hemoglobin A1c (HbAlc) were prospectively collected and analyzed. RESULTS: At 6 months after surgery, all of these 45 patients obtained remission or a marked improvement. FPG was in the normal range in 39 (86.7%) patients stopping medicine treatment for their diabetes. Six patients (13.3%) had an obvious reduced abnormal FPG and they only required lower drug dosage. No statistically significant differences were found between the obese or non-obese groups (p=0.311). The mean BMI dropped from 28.9+/ 3.0 kg/m2 to 27.4+/-2.8 kg/m2 (p=0.000) at the third month and 26.3+/-2.5 kg/m2 (p=0.000) at the sixth month. HbAlc decreased from their preoperative values of 7.4%+/-2.2% to 6.3%+/-1.5% (p=0.000) at the third month and 5.1%+/-0.9% (p=0.000) at the sixth month. CONCLUSIONS: Modified Roux-en-Y gastric bypass was effective in treating type 2 diabetes mellitus, independent of body mass index. PMID- 22829558 TI - Deleted in Colorectal Cancer (DCC) gene polymorphism is associated with H. pylori infection among susceptible Malays from the north-eastern region of Peninsular Malaysia. AB - BACKGROUND/AIMS: Using genome-wide case-control association approach, the current study aimed to determine whether genetic polymorphism(s) is/are associated with H. pylori infection among ethnic Malays from the north-eastern region of Peninsular Malaysia, a region with an exceptionally low prevalence for H. pylori infection and gastric cancer. METHODOLOGY: Twenty-three Malay subjects positive for H. pylori confirmed with urease test and histology were enrolled as "cases" and 37 subjects negative for H. pylori were "controls". Both groups were matched for age and environmental risks. Extracted DNA samples (QIAGEN, Germany) from the venous blood of study subjects were genotyped using the Human Mapping 50k xbal array (Affymetrix, USA). High throughput downstream analyses were then used to determine the significant SNP(s) associated with H. pylori infection. RESULTS: Out of 20,361 SNPs filtered using the genotype association test, the top 1% (203) significant SNPs were selected for functional enrichment analysis. Of the 15 "enriched" SNPs, the rs10502974 which was located within the intronic region of Deleted in Colorectal Cancer (DCC) gene was the SNP most significantly associated with H. pylori infection (p=0.00549). CONCLUSIONS: Ethnic Malays is genetically susceptible to H. pylori infection and is possibly mediated through a genetic variation in the DCC gene. PMID- 22829559 TI - Kinetics of the Fischer-Tropsch reaction. AB - Long carbon chains: Self-assembly of monomeric carbon intermediates into long chain hydrocarbons on catalytically reactive surface was studied when full reversibility of the chain growth is included in the kinetic model. Using Bronsted-Evans-Polanyi relations, the maximum chain growth as a function of the surface reactivity is predicted. PMID- 22829560 TI - The insertion of terminal phosphinidene complexes into the B-H bond of amine and phosphine boranes. PMID- 22829561 TI - Microgrooved patterns enhanced PC12 cell growth, orientation, neurite elongation, and neuritogenesis. AB - Understanding neurite outgrowth, orientation, and migration is important for the design of biomaterials that interface with the neuronal tissue. Micropatterns can significantly influence neurite outgrowth, neurite length, orientation, extracellular matrix expression, neuron differentiation, and migrating velocity. We analyzed the neuritogenesis and neurite outgrowth of PC12 cells in three dimensional Si wafer with various micropatterns fabricated using photolithography and etching techniques. When nerve growth factor was added into culture medium, PC12 cells started to grow neurites. Extended neurites were significantly affected by different patterns and displayed higher growth-associated protein-43 expression. Cellular performance including growth rate, bipolar phenotype elongation, neurite extension, and growth-associated protein-43 expression of the PC12 cells with a differentiated character are higher on a grooved substrate. However, the grooved pattern can restrict the motility of PC12 cells and decrease the velocity of cellular movement. The average of the number of neurites per cell is the highest on the pillar substrate, but their neurite length is the shortest. In contrast, actin and lamimin expression, motion track, angular deviation, and movement velocity of PC12 cells are most excellent on the planar Si wafer. These findings confirmed that topographical features can cooperatively act with nerve growth factor, signaling the regulation of the formation of neurites. PMID- 22829563 TI - On-bead screens sample narrower affinity ranges of protein-ligand interactions compared to equivalent solution assays. AB - Conceptually, on-bead screening is one of the most efficient high-throughput screening (HTS) methods. One of its inherent advantages is that the solid support has a dual function: it serves as a synthesis platform and as a screening compartment. Compound purification, cleavage and storage and extensive liquid handling are not necessary in bead-based HTS. Since the establishment of one-bead one-compound library synthesis, the properties of polymer beads in chemical reactions have been thoroughly investigated. However, the characterization of the kinetics and thermodynamics of protein-ligand interactions on the beads used for screening has received much less attention. Consequently, the majority of reported on-bead screens are based on empirically derived procedures, independent of measured equilibrium constants and rate constants of protein binding to ligands on beads. More often than not, on-bead screens reveal apparent high affinity binders through strong protein complexation on the matrix of the solid support. After decoding, resynthesis, and solution testing the primary hits turn out to be unexpectedly weak binders, or may even fall out of the detection limit of the solution assay. Only a quantitative comparison of on-bead binding and solution binding events will allow systematically investigating affinity differences as function of protein and small molecule properties. This will open up routes for optimized bead materials, blocking conditions and other improved assay procedures. By making use of the unique features of our previously introduced confocal nanoscanning (CONA) method, we investigated the kinetic and thermodynamic properties of protein-ligand interactions on TentaGel beads, a popular solid support for on-bead screening. The data obtained from these experiments allowed us to determine dissociation constants for the interaction of bead-immobilized ligands with soluble proteins. Our results therefore provide, for the first time, a comparison of on-bead versus solution binding thermodynamics. Our data indicate that affinity ranges found in on-bead screening are indeed narrower compared to equivalent interactions in homogeneous solution. A thorough physico-chemical understanding of the molecular recognition between proteins and surface bound ligands will further strengthen the role of on-bead screening as an ultimately cost-effective method in hit and lead finding. PMID- 22829564 TI - Naphthyl groups in chiral recognition: structures of salts and esters of 2 methoxy-2-naphthylpropanoic acids. AB - The crystal structures of salt 8, which was prepared from (R)-2-methoxy-2-(2 naphthyl)propanoic acid ((R)-MbetaNP acid, (R)-2) and (R)-1-phenylethylamine ((R) PEA, (R)-6), and salt 9, which was prepared from (R)-2-methoxy-2-(1 naphthyl)propanoic acid ((R)-MalphaNP acid, (R)-1) and (R)-1-(p-tolyl)ethylamine ((R)-TEA, (R)-7), were determined by X-ray crystallography. The MbetaNP and MalphaNP anions formed ion-pairs with the PEA and TEA cations, respectively, through a methoxy-group-assisted salt bridge and aromatic CH???pi interactions. The networks of salt bridges formed 2(1) columns in both salts. Finally, (S) (2E,6E)-(1-(2) H(1) )farnesol ((S)-13) was prepared from the reaction of (2E,6E) farnesal (11) with deuterated (R)-BINAL-H (i.e., (R)-BINAL-D). The enantiomeric excess of compound (S)-13 was determined by NMR analysis of (S)-MalphaNP ester 14. The solution-state structures of MalphaNP esters that were prepared from primary alcohols were also elucidated. PMID- 22829565 TI - Orthogonal addressable monolayers for integrating molecular logic. AB - Plug and play: The mimicking of integrated circuits by using two individual monolayers (molecular chips) is shown. These monolayers can be individually addressed using identical inputs. Upon combination of their optical outputs, the input/output characteristics of a molecular encoder is obtained. Since the encoder functionality is only displayed when both chips are active, the device behaves according to a plug-and-play principle (In=input; see picture). PMID- 22829566 TI - High mineral affinity of polyphosphoester ionomer-phospholipid vesicles. AB - Bone-specific drug delivery is important for the treatment of osteoporosis and osseous metastases. However, there have been limitations in the design of drug carriers having bone affinity. We synthesized amphiphilic polyphosphoester ionomers (CH-PHE) and modified them to 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles. The zeta-potential of the vesicles was decreased by immobilization of CH-PHE; the amount was influenced by the structure and fraction of CH-PHE. The release rate of 5-carboxyfluorescein from the vesicles could be controlled by changing the fraction of DOPC and CH-PHE. In particular, the release of CF from DOPC vesicles containing 3% CH-PHE was most reduced. In addition, the enzymatic degradation of DOPC was reduced by immobilization with polyphosphoester ionomers; enzyme tolerance was increased with an increase in the molar fraction of polyphosphoester ionomers. Hemolytic activity of the phospholipid vesicles bearing CH-PHE was infrequently observed and was similar to that of the DOPC vesicles. Although a decrease in the viability of mouse osteoblastic cells (MC3T3-E1) in contact with the vesicles bearing CH-PHE was observed when the DOPC concentration of the vesicles bearing 20 mol % CH-PHE with highly ionized units was greater than 200 MUM, the cytotoxicity was diminished by sodium salt formation of the CH-PHE. The affinity of the vesicles to calcium deposits generated by MC3T3-E1 cells was significantly improved by the immobilization polyphosphoesters. PMID- 22829567 TI - Behavior of lysozyme at the electrified water/room temperature ionic liquid interface. AB - Between the phases: The globular protein lysozyme was adsorbed and desorbed under electrochemical conditions at the water/room temperature ionic liquid microinterface array; the electrochemical desorption process provides a basis for protein detection at these interfaces. PMID- 22829568 TI - Changes in swallowing-related quality of life after parathyroidectomy for hyperparathyroidism: a prospective cohort study. AB - OBJECTIVE: To prospectively evaluate the impact of parathyroidectomy on swallowing-related quality of life using the Swallowing Quality Of Life (SWAL QOL) validated outcomes assessment tool. BACKGROUND: Many patients with primary hyperparathyroidism report nonspecific symptoms, such as fatigue, irritability, cognitive impairment, sleep disturbances, and dysphagia. To date, there have been no prospective studies evaluating swallowing function before and after parathyroid surgery. METHODS: Patients undergoing parathyroidectomy from September 2007 to January 2009 completed the SWAL-QOL questionnaire before and one year after surgery. Data were collected on demographic and clinicopathologic variables. Comparisons were made to determine the effect of surgery on patients' perceptions of swallowing function. RESULTS: Of 151 eligible patients, 102 (68%) completed the study. The mean patient age was 60 years, and 79% were female. A total of 73 patients (67%) had minimally invasive parathyroidectomies, whereas the remainder had bilateral explorations. In all, 83 patients (81%) had a parathyroid adenoma, 16 patients (16%) had hyperplasia, and 3 patients (3%) had a double adenoma on final pathologic interpretation. Mean preoperative SWAL-QOL scores were <90 for 4 of the 11 domains, indicating the perception of oropharyngeal dysphagia and diminished quality of life. Following parathyroidectomy, significant improvements were demonstrated in eight SWAL-QOL domains. CONCLUSIONS: Many patients with parathyroid disease have the perception of abnormal swallowing function. In these patients with symptoms of dysphagia, parathyroid surgery leads to significant improvements in many aspects of swallowing-related quality of life measured by the SWAL-QOL instrument. This study represents the first use of a condition-specific instrument to assess swallowing-related quality of life for patients with parathyroid disease before and after parathyroid surgery. PMID- 22829569 TI - Uterine leiomyosarcoma in asian patients: validation of the revised Federation of gynecology and obstetrics staging system and identification of prognostic classifiers. AB - BACKGROUND: In 2008, the Federation of Gynecology and Obstetrics (FIGO) revised their 1988 staging system for uterine leiomyosarcomas. In this article, we compare performance of the 2008 and 1988 FIGO systems. METHODS: Individual case data were manually culled. Staging was retrospectively assessed according to revised and 1998 FIGO criteria. Overall survival distribution was assessed by the Kaplan-Meier method. Harrell's concordance index was used to assess the discriminative ability of a fitted Cox model to predict overall survival. RESULTS: A total of 110 cases of uterine leiomyosarcomas were reviewed and data from 88 patients were analyzed. In all, 71% of cases were classified as stage I, 7% as stage II, 3% as stage III, and 19% as stage IV under the revised FIGO staging system. Nine patients (10.2%) were downstaged and none were upstaged. The revised FIGO system did not show a significant improvement over the 1988 FIGO system in the ability to discriminate the risk of death of patients between stages, with concordance indexes of 0.70 and 0.71, respectively. Most patients were classified as stage I with age, tumor grade, tumor size, and lymphovascular invasion as prognostic factors. CONCLUSION: The 2008 revised FIGO staging system for uterine leiomyosarcomas does not perform better than the 1988 system for uterine endometrial carcinomas. A better staging system is needed for these cases. PMID- 22829570 TI - Using variable precision rough set for selection and classification of biological knowledge integrated in DNA gene expression. AB - DNA microarrays have contributed to the exponential growth of genomic and experimental data in the last decade. This large amount of gene expression data has been used by researchers seeking diagnosis of diseases like cancer using machine learning methods. In turn, explicit biological knowledge about gene functions has also grown tremendously over the last decade. This work integrates explicit biological knowledge, provided as gene sets, into the classication process by means of Variable Precision Rough Set Theory (VPRS). The proposed model is able to highlight which part of the provided biological knowledge has been important for classification. This paper presents a novel model for microarray data classification which is able to incorporate prior biological knowledge in the form of gene sets. Based on this knowledge, we transform the input microarray data into supergenes, and then we apply rough set theory to select the most promising supergenes and to derive a set of easy interpretable classification rules. The proposed model is evaluated over three breast cancer microarrays datasets obtaining successful results compared to classical classification techniques. The experimental results shows that there are not significant differences between our model and classical techniques but it is able to provide a biological-interpretable explanation of how it classifies new samples. PMID- 22829562 TI - Cardiometabolic aspects of the polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic perturbations, in addition to chronic anovulation and factors related to androgen excess. In general, women live longer than men and develop cardiovascular disease at an older age. However, women with PCOS, as compared with age- and body mass index matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality. Further alterations in PCOS include an increased prevalence of sleep apnea, as well as various changes in the secretion and/or function of adipokines, adipose tissue-derived proinflammatory factors and gut hormones, all of them with direct or indirect influences on the complex signaling network that regulates metabolism, insulin sensitivity, and energy homeostasis. Reviews on the cardiometabolic aspects of PCOS are rare, and our knowledge from recent studies is expanding rapidly. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge, focusing on the alterations of cardiometabolic factors in women with PCOS. Further insight into this network of factors may facilitate finding therapeutic targets that should ameliorate not only ovarian dysfunction but also the various cardiometabolic alterations related to the syndrome. PMID- 22829571 TI - ADOPS--Automatic Detection Of Positively Selected Sites. AB - Maximum-likelihood methods based on models of codon substitution have been widely used to infer positively selected amino acid sites that are responsible for adaptive changes. Nevertheless, in order to use such an approach, software applications are required to align protein and DNA sequences, infer a phylogenetic tree and run the maximum-likelihood models. Therefore, a significant effort is made in order to prepare input files for the different software applications and in the analysis of the output of every analysis. In this paper we present the ADOPS (Automatic Detection Of Positively Selected Sites) software. It was developed with the goal of providing an automatic and flexible tool for detecting positively selected sites given a set of unaligned nucleotide sequence data. An example of the usefulness of such a pipeline is given by showing, under different conditions, positively selected amino acid sites in a set of 54 Coffea putative S-RNase sequences. ADOPS software is freely available and can be downloaded from http://sing.ei.uvigo.es/ADOPS. PMID- 22829572 TI - On the parameter optimization of Support Vector Machines for binary classification. AB - Classifying biological data is a common task in the biomedical context. Predicting the class of new, unknown information allows researchers to gain insight and make decisions based on the available data. Also, using classification methods often implies choosing the best parameters to obtain optimal class separation, and the number of parameters might be large in biological datasets. Support Vector Machines provide a well-established and powerful classification method to analyse data and find the minimal-risk separation between different classes. Finding that separation strongly depends on the available feature set and the tuning of hyper-parameters. Techniques for feature selection and SVM parameters optimization are known to improve classification accuracy, and its literature is extensive. In this paper we review the strategies that are used to improve the classification performance of SVMs and perform our own experimentation to study the influence of features and hyper-parameters in the optimization process, using several known kernels. PMID- 22829574 TI - Computational approaches to standard-compliant biofilm data for reliable analysis and integration. AB - The study of microorganism consortia, also known as biofilms, is associated to a number of applications in biotechnology, ecotechnology and clinical domains. Nowadays, biofilm studies are heterogeneous and data-intensive, encompassing different levels of analysis. Computational modelling of biofilm studies has become thus a requirement to make sense of these vast and ever-expanding biofilm data volumes. The rationale of the present work is a machine-readable format for representing biofilm studies and supporting biofilm data interchange and data integration. This format is supported by the Biofilm Science Ontology (BSO), the first ontology on biofilms information. The ontology is decomposed into a number of areas of interest, namely: the Experimental Procedure Ontology (EPO) which describes biofilm experimental procedures; the Colony Morphology Ontology (CMO) which characterises morphologically microorganism colonies; and other modules concerning biofilm phenotype, antimicrobial susceptibility and virulence traits. The overall objective behind BSO is to develop semantic resources to capture, represent and share data on biofilms and related experiments in a regularized fashion manner. Furthermore, the present work also introduces a framework in assistance of biofilm data interchange and analysis - BiofOmics (http://biofomics.org) - and a public repository on colony morphology signatures MorphoCol (http://stardust.deb.uminho.pt/morphocol). PMID- 22829573 TI - In silico strain optimization by adding reactions to metabolic models. AB - Nowadays, the concerns about the environment and the needs to increase the productivity at low costs, demand for the search of new ways to produce compounds with industrial interest. Based on the increasing knowledge of biological processes, through genome sequencing projects, and high-throughput experimental techniques as well as the available computational tools, the use of microorganisms has been considered as an approach to produce desirable compounds. However, this usually requires to manipulate these organisms by genetic engineering and/ or changing the enviromental conditions to make the production of these compounds possible. In many cases, it is necessary to enrich the genetic material of those microbes with hereologous pathways from other species and consequently adding the potential to produce novel compounds. This paper introduces a new plug-in for the OptFlux Metabolic Engineering platform, aimed at finding suitable sets of reactions to add to the genomes of selected microbes (wild type strain), as well as finding complementary sets of deletions, so that the mutant becomes able to overproduce compounds with industrial interest, while preserving their viability. The necessity of adding reactions to the metabolic model arises from existing gaps in the original model or motivated by the productions of new compounds by the organism. The optimization methods used are metaheuristics such as Evolutionary Algorithms and Simulated Annealing. The usefulness of this plug-in is demonstrated by a case study, regarding the production of vanillin by the bacterium E. coli. PMID- 22829575 TI - A rational framework for production decision making in blood establishments. AB - SAD_BaSe is a blood bank data analysis software, created to assist in the management of blood donations and the blood production chain in blood establishments. In particular, the system keeps track of several collection and production indicators, enables the definition of collection and production strategies, and the measurement of quality indicators required by the Quality Management System regulating the general operation of blood establishments. This paper describes the general scenario of blood establishments and its main requirements in terms of data management and analysis. It presents the architecture of SAD_BaSe and identifies its main contributions. Specifically, it brings forward the generation of customized reports driven by decision making needs and the use of data mining techniques in the analysis of donor suspensions and donation discards. PMID- 22829576 TI - Construction of coffee transcriptome networks based on gene annotation semantics. AB - Gene annotation is a process that encompasses multiple approaches on the analysis of nucleic acids or protein sequences in order to assign structural and functional characteristics to gene models. When thousands of gene models are being described in an organism genome, construction and visualization of gene networks impose novel challenges in the understanding of complex expression patterns and the generation of new knowledge in genomics research. In order to take advantage of accumulated text data after conventional gene sequence analysis, this work applied semantics in combination with visualization tools to build transcriptome networks from a set of coffee gene annotations. A set of selected coffee transcriptome sequences, chosen by the quality of the sequence comparison reported by Basic Local Alignment Search Tool (BLAST) and Interproscan, were filtered out by coverage, identity, length of the query, and e values. Meanwhile, term descriptors for molecular biology and biochemistry were obtained along the Wordnet dictionary in order to construct a Resource Description Framework (RDF) using Ruby scripts and Methontology to find associations between concepts. Relationships between sequence annotations and semantic concepts were graphically represented through a total of 6845 oriented vectors, which were reduced to 745 non-redundant associations. A large gene network connecting transcripts by way of relational concepts was created where detailed connections remain to be validated for biological significance based on current biochemical and genetics frameworks. Besides reusing text information in the generation of gene connections and for data mining purposes, this tool development opens the possibility to visualize complex and abundant transcriptome data, and triggers the formulation of new hypotheses in metabolic pathways analysis. PMID- 22829577 TI - Automatic knowledge extraction in sequencing analysis with multiagent system and grid computing. AB - Advances in bioinformatics have contributed towards a significant increase in available information. Information analysis requires the use of distributed computing systems to best engage the process of data analysis. This study proposes a multiagent system that incorporates grid technology to facilitate distributed data analysis by dynamically incorporating the roles associated to each specific case study. The system was applied to genetic sequencing data to extract relevant information about insertions, deletions or polymorphisms. PMID- 22829578 TI - Towards a classification approach using meta-biclustering: impact of discretization in the analysis of expression time series. AB - Biclustering has been recognized as a remarkably effective method for discovering local temporal expression patterns and unraveling potential regulatory mechanisms, essential to understanding complex biomedical processes, such as disease progression and drug response. In this work, we propose a classification approach based on meta-biclusters (a set of similar biclusters) applied to prognostic prediction. We use real clinical expression time series to predict the response of patients with multiple sclerosis to treatment with Interferon-beta. As compared to previous approaches, the main advantages of this strategy are the interpretability of the results and the reduction of data dimensionality, due to biclustering. This would allow the identification of the genes and time points which are most promising for explaining different types of response profiles, according to clinical knowledge. We assess the impact of different unsupervised and supervised discretization techniques on the classification accuracy. The experimental results show that, in many cases, the use of these discretization methods improves the classification accuracy, as compared to the use of the original features. PMID- 22829579 TI - Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function. AB - Current endeavors in the type 2 diabetes (T2D) field include gaining a better understanding of extracellular signaling pathways that regulate pancreatic islet function. Recent data suggest that both Bmp and Wnt pathways are operative in pancreatic islets and play a positive role in insulin secretion and glucose homeostasis. Our laboratory found the dual Bmp and Wnt antagonist Sostdc1 to be upregulated in a mouse model of islet dysmorphogenesis and nonimmune-mediated lean diabetes. Because Bmp signaling has been proposed to enhance beta-cell function, we evaluated the role of Sostdc1 in adult islet function using animals in which Sostdc1 was globally deleted. While Sostdc1-null animals exhibited no pancreas development phenotype, a subset of mutants exhibited enhanced insulin secretion and improved glucose homeostasis compared with control animals after 12 wk exposure to high-fat diet. Loss of Sostdc1 in the setting of metabolic stress results in altered expression of Bmp-responsive genes in islets but did not affect expression of Wnt target genes, suggesting that Sostdc1 primarily regulates the Bmp pathway in the murine pancreas. Furthermore, our data indicate that removal of Sostdc1 enhances the downregulation of the closely related Bmp inhibitors Ctgf and Gremlin in islets after 8-wk exposure to high-fat diet. These data imply that Sostdc1 regulates expression of these inhibitors and provide a means by which Sostdc1-null animals show enhanced insulin secretion and glucose homeostasis. Our studies provide insights into Bmp pathway regulation in the endocrine pancreas and reveal new avenues for improving beta-cell function under metabolic stress. PMID- 22829580 TI - Thyroid hormone and estradiol have overlapping effects on kidney glutathione S transferase-alpha gene expression. AB - alpha-Class GST (Gsta) represents an essential component of cellular antioxidant defense mechanisms in both the liver and the kidney. Estrogens and thyroid hormones (TH) play central roles in animal development, physiology, and behavior. Evidence of the overlapping functions of thyroid hormones and estrogens has been shown, although the molecular mechanisms are not always clear. We evaluated an interaction between TH and estradiol in regulating kidney Gsta expression and function. First, we observed that female mice expressed greater amounts of Gsta compared with males and showed an opposite pattern of expression in TRbeta knock in mice. To further investigate these sex differences, hypothyroidism was induced by a 5-propyl-2-thiouracil diet, and hyperthyroidism was induced by daily T3 injections. Hypothyroidism increased kidney Gsta expression in male mice but not in female mice, indicating that sex hormones could be influencing the regulation of Gsta by thyroid hormones. To analyze this hypothesis, ovariectomized females were subjected to hypo- and hyperthyroidism, which led to a male profile of Gsta expression. When hypo- or hyperthyroid ovariectomized mice were treated with 17beta-estradiol benzoate, we were able to confirm that estradiol was interfering with TH modulation; Gsta expression is increased by T3 when estradiol is present and decreased by T3 when estradiol is absent. Using proximal tubule cells, we also showed that estradiol and T3 worked together to modulate Gsta expression in an overlapping fashion. In summary, 1) the sex difference in the basal expression of Gsta impacts the detoxification process, 2) kidney Gsta expression is regulated by TH in males and females but in opposite directions, and 3) T3 and estradiol interact directly in renal proximal cells to regulate Gsta expression in females. PMID- 22829581 TI - GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility. AB - Glucagon-like peptides (GLP-1/2) are cosecreted from endocrine L cells in the gut and preproglucagonergic neurons in the brain. Peripheral GLP-2 action is essential for maintaining intestinal homeostasis, improving absorption efficiency and blood flow, promoting immune defense, and producing efficacy in treatment of gastrointestinal diseases. However, it is unknown if CNS GLP-2 plays a physiological role in the control of energy homeostasis. Since GLP-1/2 are cotranslated from preproglucagongene and coproduced by prohormone convertase-1, it is challenging to knockout GLP-2 only. Instead, our laboratory has generated a Glp2r-floxed mouse line to dissect cell-specific GLP-2 receptor GLP-2R) action in the regulation of energy balance. Our objective was to determine if GLP-2R in the hypothalamus modulates feeding behavior and gastric emptying. We show that Glp2r mRNA and protein are highly expressed in the arcuate nucleus and dorsomedial nucleus of the mouse hypothalamus. Using the Cre-LoxP system, we generated mice that lack Glp2r expression in POMC neurons (KO; mainly in the hypothalamus). The KO mice showed hyperphagic behavior (such as increases in food intake and meal frequency), accelerated gastric emptying (assessed by [(13)C]octanoic acid breath test), and late-onset obesity, yet there was no decrease in basal metabolic rate. Infusion of GLP-2 (2.5 nmol into the 4th ventricle) suppressed food intake and gastric emptying, while GLP-2-mediated effects were abolished in the melanocortin receptor-4 (MC4R) KO mice. We conclude that Glp2r deletion in POMC neurons enhances feeding behavior and gastric motility, whereas icv GLP-2R activation suppresses food intake and gastric emptying through the MC4R signaling pathway. This study indicates that CNS GLP-2R plays a physiological role in the control of feeding behavior and gastric emptying and that this is mediated probably through the melanocortin system. PMID- 22829582 TI - The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury. AB - The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of myocardial infarction followed by 3 or 24 h of reperfusion. At 10 min before reperfusion, diabetic mice were randomized to receive EUK134 (peroxynitrite scavenger), recombinant hTrx-1, nitrated Trx-1, apocynin (a NADPH oxidase inhibitor), or 1400W [an inducible nitric oxide synthase (iNOS) inhibitor] administration. The diabetic heart manifested increased RAGE expression and N(epsilon)-(carboxymethyl)lysine (CML, major advanced glycation end product subtype) content, reduced Trx-1 activity, and increased Trx nitration after MI/R. RAGE siRNA or administration of sRAGE in diabetic mice decreased MI/R-induced iNOS and gp91(phox) expression, reduced Trx nitration, preserved Trx activity, and decreased infarct size. Apocynin or 1400W significantly decreased nitrotyrosine production and restored Trx activity. Conversely, administration of either EUK134 or reduced hTrx, but not nitrated hTrx, attenuated MI/R-induced superoxide production, RAGE expression, and CML content and decreased cardiomyocyte apoptosis in diabetic mice. Collectively, we demonstrate that RAGE modulates the MI/R injury in a Trx nitrative inactivation fashion. Conversely, nitrative modification of Trx blocked its inhibitory effect upon RAGE expression in the diabetic heart. This is the first direct evidence demonstrating the alternative cross talk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions interfering with their interaction may be novel means of mitigating diabetic MI/R injury. PMID- 22829583 TI - Overexpression of manganese superoxide dismutase ameliorates high-fat diet induced insulin resistance in rat skeletal muscle. AB - Elevated mitochondrial reactive oxygen species have been suggested to play a causative role in some forms of muscle insulin resistance. However, the extent of their involvement in the development of diet-induced insulin resistance remains unclear. To investigate, manganese superoxide dismutase (MnSOD), a key mitochondrial-specific enzyme with antioxidant modality, was overexpressed, and the effect on in vivo muscle insulin resistance induced by a high-fat (HF) diet in rats was evaluated. Male Wistar rats were maintained on chow or HF diet. After 3 wk, in vivo electroporation (IVE) of MnSOD expression and empty vectors was undertaken in right and left tibialis cranialis (TC) muscles, respectively. After one more week, insulin action was evaluated using hyperinsulinemic euglycemic clamp, and tissues were subsequently analyzed for antioxidant enzyme capacity and markers of oxidative stress. MnSOD mRNA was overexpressed 4.5-fold, and protein levels were increased by 70%, with protein detected primarily in the mitochondrial fraction of muscle fibers. This was associated with elevated MnSOD and glutathione peroxidase activity, indicating that the overexpressed MnSOD was functionally active. The HF diet significantly reduced whole body and TC muscle insulin action, whereas overexpression of MnSOD in HF diet animals ameliorated this reduction in TC muscle glucose uptake by 50% (P < 0.05). Decreased protein carbonylation was seen in MnSOD overexpressing TC muscle in HF-treated animals (20% vs. contralateral control leg, P < 0.05), suggesting that this effect was mediated through an altered redox state. Thus interventions causing elevation of mitochondrial antioxidant activity may offer protection against diet-induced insulin resistance in skeletal muscle. PMID- 22829584 TI - Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity. AB - There is significant variability in diet-induced obesity (DIO) among humans and rodents, which has been associated with differences in intrinsic spontaneous physical activity (SPA). The orexin neuropeptides positively modulate SPA through multiple brain sites, but the effects of DIO on orexin's activity are not well understood. In this study, we tested the hypothesis that DIO sensitivity is mediated by decreased SPA and changes in the function of the orexins. As a DIO model, we used male Sprague-Dawley rats fed a high-fat (HF; 45% kcal from fat) or a low-fat (LF; 10% kcal from fat) diet for 10 wk. We measured SPA before and after HF or LF feeding and expression of orexin receptors by real-time PCR after dietary treatments. We tested DIO effects on orexin signaling by measuring SPA after injection of orexin A in the rostral lateral hypothalamus (RLH) before and after 10 wk of HF feeding. Finally, we tested whether daily orexin A RLH injections prevent DIO caused by HF feeding. Our results show that resistance to DIO is associated with an increase in SPA, SPA after injection of orexin A in RLH, and orexin receptor expression in sites that mediate orexin's effect on SPA, including RLH. We show that daily injections of orexin peptide in RLH prevent DIO without altering food intake. We estimate that the energetic cost of SPA after orexin A RLH injection accounts for approximately 61% of the extra caloric intake associated with HF intake, suggesting additional effects of orexins. In summary, our results suggest that variability in DIO sensitivity is mediated through adaptations in the activity of the orexin peptides and their receptors. PMID- 22829585 TI - Rho-kinase inhibition improves vasodilator responsiveness during hyperinsulinemia in the metabolic syndrome. AB - In patients with the metabolic syndrome (MetS), the facilitatory effect of insulin on forearm vasodilator responsiveness to different stimuli is impaired. Whether the RhoA/Rho kinase (ROCK) pathway is involved in this abnormality is unknown. We tested the hypotheses that, in MetS patients, ROCK inhibition with fasudil restores insulin-stimulated vasodilator reactivity and that oxidative stress plays a role in this mechanism. Endothelium-dependent and -independent forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were assessed in MetS patients (n = 8) and healthy controls (n = 5) before and after the addition of fasudil (200 MUg/min) to an intra arterial infusion of insulin (0.1 mU/kg/min). In MetS patients (n = 5), fasudil was also infused without hyperinsulinemia. The possible involvement of oxidative stress in the effect of fasudil during hyperinsulinemia was investigated in MetS patients (n = 5) by infusing vitamin C (25 mg/min). In MetS patients, compared with saline, fasudil enhanced endothelium-dependent and -independent vasodilator responses during insulin infusion (P < 0.001 and P = 0.008, respectively), but not in the absence of hyperinsulinemia (P = 0.25 and P = 0.13, respectively). By contrast, fasudil did not affect vasoreactivity to ACh and SNP during hyperinsulinemia in controls (P = 0.11 and P = 0.56, respectively). In MetS patients, fasudil added to insulin and vitamin C did not further enhance vasodilation to ACh and SNP (P = 0.15 and P = 0.43, respectively). In the forearm circulation of patients with the MetS, ROCK inhibition by fasudil improves endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia; increased oxidative stress seems to be involved in the pathophysiology of this phenomenon. PMID- 22829586 TI - Effects of glucose-6-phosphate dehydrogenase deficiency on the metabolic and cardiac responses to obesogenic or high-fructose diets. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human enzymopathy that affects cellular redox status and may lower flux into nonoxidative pathways of glucose metabolism. Oxidative stress may worsen systemic glucose tolerance and cardiometabolic syndrome. We hypothesized that G6PD deficiency exacerbates diet induced systemic metabolic dysfunction by increasing oxidative stress but in myocardium prevents diet-induced oxidative stress and pathology. WT and G6PD deficient (G6PDX) mice received a standard high-starch diet, a high-fat/high sucrose diet to induce obesity (DIO), or a high-fructose diet. After 31 wk, DIO increased adipose and body mass compared with the high-starch diet but to a greater extent in G6PDX than WT mice (24 and 20% lower, respectively). Serum free fatty acids were increased by 77% and triglycerides by 90% in G6PDX mice, but not in WT mice, by DIO and high-fructose intake. G6PD deficiency did not affect glucose tolerance or the increased insulin levels seen in WT mice. There was no diet-induced hypertension or cardiac dysfunction in either mouse strain. However, G6PD deficiency increased aconitase activity by 42% and blunted markers of nonoxidative glucose pathway activation in myocardium, including the hexosamine biosynthetic pathway activation and advanced glycation end product formation. These results reveal a complex interplay between diet-induced metabolic effects and G6PD deficiency, where G6PD deficiency decreases weight gain and hyperinsulinemia with DIO, but elevates serum free fatty acids, without affecting glucose tolerance. On the other hand, it modestly suppressed indexes of glucose flux into nonoxidative pathways in myocardium, suggesting potential protective effects. PMID- 22829587 TI - Phosphoregulation of the RNA-binding protein Hu antigen R (HuR) by Cdk5 affects centrosome function. AB - Hu antigen R (HuR) is an mRNA-binding protein belonging to the ELAV family. It is highly expressed in cancer and involved in cell survival and proliferation. The impact of post-translational regulation of HuR and resulting cellular effects are poorly understood. In the current report, we describe a direct interaction between HuR and Cdk5 in glioma. We determined that Cdk5 specifically phosphorylates HuR at the serine 202 residue in the unique hinge region. The molecular consequences of this interaction are an altered HuR ability to bind, stabilize, and promote translation of mRNAs. At the cellular level, the anomalous HuR phosphorylation at this site evokes robust defects in centrosome duplication and cohesion as well as arrest of cell cycle progression. Subcellular fractionation and immunofluorescence technique confirm a direct integration of HuR and Cdk5 with centrosomes. We propose that HuR stores mRNA in the centrosome and that HuR phosphorylation by Cdk5 controls de novo protein synthesis in near proximity to centrosomes and, thus, impacts centrosome function. PMID- 22829588 TI - Identification of a novel pathway of transforming growth factor-beta1 regulation by extracellular NAD+ in mouse macrophages: in vitro and in silico studies. AB - Extracellular beta-nicotinamide adenine dinucleotide (NAD(+)) is anti inflammatory. We hypothesized that NAD(+) would modulate the anti-inflammatory cytokine Transforming Growth Factor (TGF)-beta1. Indeed, NAD(+) led to increases in both active and latent cell-associated TGF-beta1 in RAW 264.7 mouse macrophages as well as in primary peritoneal macrophages isolated from both C3H/HeJ (TLR4-mutant) and C3H/HeOuJ (wild-type controls for C3H/HeJ) mice. NAD(+) acts partially via cyclic ADP-ribose (cADPR) and subsequent release of Ca(2+). Treatment of macrophages with the cADPR analog 3-deaza-cADPR or Ca(2+) ionophores recapitulated the effects of NAD(+) on TGF-beta1, whereas the cADPR antagonist 8 Br-cADPR, Ca(2+) chelation, and antagonism of L-type Ca(2+) channels suppressed these effects. The time and dose effects of NAD(+) on TGF-beta1 were complex and could be modeled both statistically and mathematically. Model-predicted levels of TGF-beta1 protein and mRNA were largely confirmed experimentally but also suggested the presence of other mechanisms of regulation of TGF-beta1 by NAD(+). Thus, in vitro and in silico evidence points to NAD(+) as a novel modulator of TGF-beta1. PMID- 22829589 TI - Frank-ter Haar syndrome protein Tks4 regulates epidermal growth factor-dependent cell migration. AB - Mutations in the SH3PXD2B gene coding for the Tks4 protein are responsible for the autosomal recessive Frank-ter Haar syndrome. Tks4, a substrate of Src tyrosine kinase, is implicated in the regulation of podosome formation. Here, we report a novel role for Tks4 in the EGF signaling pathway. In EGF-treated cells, Tks4 is tyrosine-phosphorylated and associated with the activated EGF receptor. This association is not direct but requires the presence of Src tyrosine kinase. In addition, treatment of cells with LY294002, an inhibitor of PI 3-kinase, or mutations of the PX domain reduces tyrosine phosphorylation and membrane translocation of Tks4. Furthermore, a PX domain mutant (R43W) Tks4 carrying a reported point mutation in a Frank-ter Haar syndrome patient showed aberrant intracellular expression and reduced phosphoinositide binding. Finally, silencing of Tks4 was shown to markedly inhibit HeLa cell migration in a Boyden chamber assay in response to EGF or serum. Our results therefore reveal a new function for Tks4 in the regulation of growth factor-dependent cell migration. PMID- 22829590 TI - Activated Ras protein accelerates cell cycle progression to perturb Madin-Darby canine kidney cystogenesis. AB - In a number of human cancer cells, K-RAS is frequently mutated and activated constitutively, culminating in the induction of continuous cell growth, a hallmark of cancer cells. It is still unclear, however, how the mutated K-RAS induces morphological abnormalities in cancerous tissues. To investigate the mechanism underlying the K-RAS-induced morphological changes, we utilized an auxin-dependent protein expression system, which enabled us to rapidly induce and evaluate constitutively active K-Ras in MDCK (Madin-Darby canine kidney) cysts, a model for polarized epithelial structure. Cells carrying the constitutively active KRasV12 gene were morphologically indistinguishable from normal cells in two-dimensional culture. However, in a gel of extracellular matrix, KRasV12 expressing cells failed to form a spherical cyst. When KRasV12 induction was delayed until after cyst formation, some cells in the cyst wall lost polarity and were extruded into and accumulated in the luminal space. With effector-specific mutants of KRasV12 and inhibitors for MEK and PI3-kinase, we found that both the Raf-MEK-ERK and PI3-kinase axes are necessary and sufficient for this phenotype. Live cell imaging with cell cycle indicators showed that KRasV12 expression promoted cell cycle progression, which was prevented by either MEK or PI3-kinase inhibitors. From these results, we provide a model wherein active-Ras induces cell cycle progression leading to apical cell extrusion through Raf and PI3 kinase in a cooperative manner. The system developed here can be applied to drug screening for various cancers originating from epithelial cells. PMID- 22829591 TI - Interaction between sleep and metabolism in Drosophila with altered octopamine signaling. AB - Sleep length and metabolic dysfunction are correlated, but the causal relationship between these processes is unclear. Octopamine promotes wakefulness in the fly by acting through the insulin-producing cells (IPCs) in the fly brain. To determine if insulin signaling mediates the effects of octopamine on sleep:wake behavior, we assayed flies in which insulin signaling activity was genetically altered. We found that increasing insulin signaling does not promote wake, nor does insulin appear to mediate the wake-promoting effects of octopamine. Octopamine also affects metabolism in invertebrate species, including, as we show here, Drosophila melanogaster. Triglycerides are decreased in mutants with compromised octopamine signaling and elevated in flies with increased activity of octopaminergic neurons. Interestingly, this effect is mediated at least partially by insulin, suggesting that effects of octopamine on metabolism are independent of its effects on sleep. We further investigated the relative contribution of metabolic and sleep phenotypes to the starvation response of flies with altered octopamine signaling. Hyperactivity (indicative of foraging) induced by starvation was elevated in octopamine receptor mutants, despite their high propensity for sleep, indicating that their metabolic state dictates their behavioral response under these conditions. Moreover, flies with increased octopamine signaling do not suppress sleep in response to starvation, even though they are normally hyper-aroused, most likely because of their high triglyceride levels. Together, these data suggest that observed correlations between sleep and metabolic phenotypes can result from shared molecular pathways rather than causality, and environmental conditions can lead to the dominance of one phenotype over the other. PMID- 22829592 TI - Caveosomal oxidative stress causes Src-p21ras activation and lysine 63 TRAF6 protein polyubiquitination in iron-induced M1 hepatic macrophage activation. AB - Proinflammatory M1 activation of hepatic macrophages (HM) is critical in pathogenesis of hepatitis, but its mechanisms are still elusive. Our earlier work demonstrates the role of ferrous iron (Fe(2+)) as a pathogen-associated molecular pattern-independent agonist for activation of IkappaB kinase (IKK) and NF-kappaB in HM via activation and interaction of p21(ras), transforming growth factor beta activated kinase-1 (TAK1), and phosphatidylinositol 3-kinase (PI3K) in caveosomes. However, iron-induced signaling upstream of these kinases is not known. Here we show that Fe(2+) induces generation of superoxide anion (O(2)()) in endosomes, reduces protein-tyrosine phosphatase (PTP) activity, and activates Src at 2~10 min of Fe(2+) addition to rat primary HM culture. Superoxide dismutase (SOD) blocks O(2)() generation, PTP inhibition, and Src activation. Fe(2+)-induced p21(ras) activity is abrogated with the Src inhibitor PP2 and SOD. Fe(2+) stimulates Lys(63)-linked polyubiquitination (polyUb) of TRAF6 in caveosomes, and a dominant negative K63R mutant of ubiquitin or SOD prevents iron induced TRAF6 polyUb and TAK1 activation. These results demonstrate that Fe(2+) generated O(2)() mediates p21(ras) and TAK1 activation via PTP inhibition and Lys(63)-polyUb of TRAF6 in caveosomes for proinflammatory M1 activation in HM. PMID- 22829593 TI - The in vivo role of androgen receptor SUMOylation as revealed by androgen insensitivity syndrome and prostate cancer mutations targeting the proline/glycine residues of synergy control motifs. AB - The androgen receptor (AR) mediates the effects of male sexual hormones on development and physiology. Alterations in AR function are central to reproductive disorders, prostate cancer, and Kennedy disease. AR activity is influenced by post-translational modifications, but their role in AR-based diseases is poorly understood. Conjugation by small ubiquitin-like modifier (SUMO) proteins at two synergy control (SC) motifs in AR exerts a promoter context-dependent inhibitory role. SC motifs are composed of a four-amino acid core that is often preceded and/or followed by nearby proline or glycine residues. The function of these flanking residues, however, has not been examined directly. Remarkably, several AR mutations associated with oligospermia and androgen insensitivity syndrome map to Pro-390, the conserved proline downstream of the first SC motif in AR. Similarly, mutations at Gly-524, downstream of the second SC motif, were recovered in recurrent prostate cancer samples. We now provide evidence that these clinically isolated substitutions lead to a partial loss of SC motif function and AR SUMOylation that affects multiple endogenous genes. Consistent with a structural role as terminators of secondary structure elements, substitution of Pro-390 by Gly fully supports both SC motif function and SUMOylation. As predicted from the functional properties of SC motifs, the clinically isolated mutations preferentially enhance transcription driven by genomic regions harboring multiple AR binding sites. The data support the view that alterations in AR SUMOylation play significant roles in AR-based diseases and offer novel SUMO-based therapeutic opportunities. PMID- 22829594 TI - Dynamics of major histocompatibility complex class I association with the human peptide-loading complex. AB - Although the human peptide-loading complex (PLC) is required for optimal major histocompatibility complex class I (MHC I) antigen presentation, its composition is still incompletely understood. The ratio of the transporter associated with antigen processing (TAP) and MHC I to tapasin, which is responsible for MHC I recruitment and peptide binding optimization, is particularly critical for modeling of the PLC. Here, we characterized the stoichiometry of the human PLC using both biophysical and biochemical approaches. By means of single-molecule pulldown (SiMPull), we determined a TAP/tapasin ratio of 1:2, consistent with previous studies of insect-cell microsomes, rat-human chimeric cells, and HeLa cells expressing truncated TAP subunits. We also report that the tapasin/MHC I ratio varies, with the PLC population comprising both 2:1 and 2:2 complexes, based on mutational and co-precipitation studies. The MHC I-saturated PLC may be particularly prevalent among peptide-selective alleles, such as HLA-C4. Additionally, MHC I association with the PLC increases when its peptide supply is reduced by inhibiting the proteasome or by blocking TAP-mediated peptide transport using viral inhibitors. Taken together, our results indicate that the composition of the human PLC varies under normal conditions and dynamically adapts to alterations in peptide supply that may arise during viral infection. These findings improve our understanding of the quality control of MHC I peptide loading and may aid the structural and functional modeling of the human PLC. PMID- 22829595 TI - The mitochondrial oxidase assembly protein1 (Oxa1) insertase forms a membrane pore in lipid bilayers. AB - The inner membrane of mitochondria is especially protein-rich. To direct proteins into the inner membrane, translocases mediate transport and membrane insertion of precursor proteins. Although the majority of mitochondrial proteins are imported from the cytoplasm, core subunits of respiratory chain complexes are inserted into the inner membrane from the matrix. Oxa1, a conserved membrane protein, mediates the insertion of mitochondrion-encoded precursors into the inner mitochondrial membrane. The molecular mechanism by which Oxa1 mediates insertion of membrane spans, entailing the translocation of hydrophilic domains across the inner membrane, is still unknown. We investigated if Oxa1 could act as a protein conducting channel for precursor transport. Using a biophysical approach, we show that Oxa1 can form a pore capable of accommodating a translocating protein segment. After purification and reconstitution, Oxa1 acts as a cation-selective channel that specifically responds to mitochondrial export signals. The aqueous pore formed by Oxa1 displays highly dynamic characteristics with a restriction zone diameter between 0.6 and 2 nm, which would suffice for polypeptide translocation across the membrane. Single channel analyses revealed four discrete channels per active unit, suggesting that the Oxa1 complex forms several cooperative hydrophilic pores in the inner membrane. Hence, Oxa1 behaves as a pore-forming translocase that is regulated in a membrane potential and substrate dependent manner. PMID- 22829596 TI - The extracellular and transmembrane domains of the gammaC and interleukin (IL)-13 receptor alpha1 chains, not their cytoplasmic domains, dictate the nature of signaling responses to IL-4 and IL-13. AB - Previously, we demonstrated that the gammaC subunit of type I IL-4 receptor was required for robust tyrosine phosphorylation of the downstream adapter protein, IRS-2, correlating with the expression of genes (ArgI, Retnla, and Chi3l3) characteristic of alternatively activated macrophages. We located an I4R-like motif (IRS-2 docking sequence) in the gammaC cytoplasmic domain but not in the IL 13Ralpha1. Thus, we predicted that the gammaC tail directed enhanced IRS-2 phosphorylation. To test this, IL-4 signaling responses were examined in a mutant of the key I4R motif tyrosine residue (Y325F) and different gammaC truncation mutants (gamma285, gamma308, gamma318, gamma323, and gammaFULL LENGTH (FL)) co expressed in L-cells or CHO cells with wild-type (WT) IL-4Ralpha. Surprisingly, IRS-1 phosphorylation was not diminished in Y325F L-cell mutants suggesting Tyr 325 was not required for the robust insulin receptor substrate response. IRS-2, STAT6, and JAK3 phosphorylation was observed in CHO cells expressing gamma323 and gammaFL but not in gamma318 and gamma285 mutants. In addition, when CHO cells expressed gamma318, gamma323, or gammaFL with IL-2Rbeta, IL-2 induced phospho STAT5 only in the gamma323 and gammaFL clones. Our data suggest that a smaller (5 amino acid) interval than previously determined is necessary for JAK3 activation/gammaC-mediated signaling in response to IL-4 and IL-2. Chimeric receptor chains of the gammaC tail fused to the IL-13Ralpha1 extracellular and transmembrane domain did not elicit robust IRS-2 phosphorylation in response to IL-13 suggesting that the extracellular/transmembrane domains of the IL-4/IL-13 receptor, not the cytoplasmic domains, control signaling efficiency. Understanding this pathway fully will lead to rational drug design for allergic disease. PMID- 22829597 TI - A unique loop structure in oncostatin M determines binding affinity toward oncostatin M receptor and leukemia inhibitory factor receptor. AB - Oncostatin M (OSM) and leukemia inhibitory factor are pleiotropic cytokines that belong to the interleukin-6 (IL-6) family. These cytokines play a crucial role in diverse biological events like inflammation, neuroprotection, hematopoiesis, metabolism, and development. The family is grouped together based on structural similarities and their ability to activate the transmembrane receptor glycoprotein 130 (gp130). The common structure among these cytokines defines the spacing and the orientation of binding sites for cell surface receptors. OSM is unique in this family as it can signal using heterodimers of gp130 with either leukemia inhibitory factor receptor (LIFR) (type I) or oncostatin M receptor (OSMR) (type II). We have identified a unique helical loop on OSM between its B and C helices that is not found on other IL-6 family cytokines. This loop is located near the "FXXK" motif in active site III, which is essential for OSM's binding to both LIFR and OSMR. In this study, we show that the BC loop does not play a role in OSM's unique ability to bind OSMR. Shortening of the loop enhanced OSM's interaction with OSMR and LIFR as shown by kinetic and equilibrium binding analysis, suggesting the loop may hinder receptor interactions. As a consequence of improved binding, these structurally modified OSMs exhibited enhanced biological activity, including suppressed proliferation of A375 melanoma cells. PMID- 22829598 TI - Inhibition of acetyl phosphate-dependent transcription by an acetylatable lysine on RNA polymerase. AB - The ability of bacteria to adapt to environmental changes has allowed these organisms to thrive in all parts of the globe. By monitoring their extracellular and intracellular environments, bacteria assure their most appropriate response for each environment. Post-translational modification of proteins is one mechanism by which cells respond to their changing environments. Here, we report that two post-translational modifications regulate transcription of the extracytoplasmic stress-responsive promoter cpxP: (i) acetyl phosphate-dependent phosphorylation of the response regulator CpxR and (ii) acetyl coenzyme A dependent acetylation of the alpha subunit of RNA polymerase. Together, these two post-translational modifications fine-tune cpxP transcription in response to changes in the intracellular environment. PMID- 22829599 TI - DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localize with P bodies. AB - Localization of DEF6 (SLAT/IBP), a Rho-family guanine nucleotide exchange factor, to the center of the immune synapse is dependent upon ITK, a Tec-family kinase that regulates the spatiotemporal organization of components of T cell signaling pathways and Cdc42-dependent actin polymerization. Here we demonstrate that ITK both interacts with DEF6 and phosphorylates DEF6 at tyrosine residues Tyr(210) and Tyr(222). Expression of a GFP-tagged Y210E-Y222E phosphomimic resulted in the formation of DEF6 cytoplasmic granules that co-localized with decapping enzyme 1 (DCP1), a marker of P-bodies; sites of mRNA degradation. Similarly treatment of cells with puromycin or sodium arsenite, reagents that arrest translation, also resulted in the accumulation of DEF6 in cytoplasmic granules. Bioinformatics analysis identified a glutamine-rich, heptad-repeat region; a feature of aggregating proteins, within the C-terminal region of DEF6 with the potential to promote granule formation through a phosphorylation-dependent unmasking of this region. These data suggest that in addition to its role as a GEF, DEF6 may also function in regulating mRNA translation. PMID- 22829600 TI - Toll/interleukin-1 receptor domain dimers as the platform for activation and enhanced inhibition of Toll-like receptor signaling. AB - TIR (Toll/IL-1 receptor) domains mediate interactions between TLR (Toll-like) or IL-1 family receptors and signaling adapters. While homotypic TIR domain interactions mediate receptor activation they are also usurped by microbial TIR domain containing proteins for immunosuppression. Here we show the role of a dimerized TIR domain platform for the suppression as well as for the activation of MyD88 signaling pathway. Coiled-coil dimerization domain, present in many bacterial TCPs, potently augments suppression of TLR/IL-1R signaling. The addition of a strong coiled-coil dimerization domain conferred the superior inhibition against the wide spectrum of TLRs and prevented the constitutive activation by a dimeric TIR platform. We propose a molecular model of MyD88 mediated signaling based on the dimerization of TIR domains as the limiting step. PMID- 22829603 TI - Production levels and health status in Iberian piglets at weaning. AB - The aim of this study was to describe the postweaning growth of Iberian piglets and its relationship with the occurrence of diarrhea. To assess these factors in response to different weaning ages, a total of 360 pure-breed Iberian piglets were studied. Three trials were conducted with 120 piglets from 24 litters randomly assigned to be weaned at 28 or 42 d of age (12 litters and 60 piglets each). In each trial and from each weaning age, 4 groups of 15 piglets were assembled with different sexes and sizes (3 litters by group and 5 animals from each litter; 12 replicates and 180 piglets/weaning age). The duration of study period was 42 d and all animals were weighed weekly from 21 to 63 d of age. Food intake and fecal consistency were examined with the same frequency. General linear models and chi-square procedure was used with SPSS statistical package to perform the analysis with a confidence interval of 95% (P < 0.005). Pearson and Spearman analyses were conducted to examine relationships between variables. At the beginning (P = 0.798) and end of the study (P = 0.450) there were no significant differences between piglet weights. After weaning, there were differences in food intake and in conversion rates (P < 0.001), but there were no differences in ADG for the whole study period (P = 0.335). All groups experienced a similar decline in production rates during the first week after weaning and similar recovery times during the next weeks. Both weaning groups had a similar overall prevalence (P = 0.044) and incidence of diarrheal onset (P = 0.467), and regression analysis showed relationships between postweaning diarrhea and the overall prevalence of piglets before weaning (P < 0.01) and food intake during first week postweaning (P < 0.01). Therefore, weaning age has a similar influence on postweaning growth and on postweaning diarrhea in Iberian piglets. PMID- 22829601 TI - Pervasive initiation and 3'-end formation of poxvirus postreplicative RNAs. AB - Poxviruses are large DNA viruses that replicate within the cytoplasm and encode a complete transcription system, including a multisubunit RNA polymerase, stage specific transcription factors, capping and methylating enzymes, and a poly(A) polymerase. Expression of the more than 200 open reading frames by vaccinia virus, the prototype poxvirus, is temporally regulated: early mRNAs are synthesized immediately after infection, whereas intermediate and late mRNAs are synthesized following genome replication. The postreplicative transcripts are heterogeneous in length and overlap the entire genome, which pose obstacles for high resolution mapping. We used tag-based methods in conjunction with high throughput cDNA sequencing to determine the precise 5'-capped and 3' polyadenylated ends of postreplicative RNAs. Polymerase slippage during initiation of intermediate and late RNA synthesis results in a 5'-poly(A) leader that allowed the unambiguous identification of true transcription start sites. Ninety RNA start sites were located just upstream of intermediate and late open reading frames, but many more appeared anomalous, occurring within coding and non coding regions, indicating pervasive transcription initiation. We confirmed the presence of functional promoter sequences upstream of representative anomalous start sites and demonstrated that alternative start sites within open reading frames could generate truncated isoforms of proteins. In an analogous manner, poly(A) sequences allowed accurate mapping of the numerous 3'-ends of postreplicative RNAs, which were preceded by a pyrimidine-rich sequence in the DNA coding strand. The distribution of postreplicative promoter sequences throughout the genome provides enormous transcriptional complexity, and the large number of previously unmapped RNAs may have novel functions. PMID- 22829604 TI - Dietary supplementation of conjugated linoleic acid in horses increases plasma conjugated linoleic acid and decreases plasma arachidonic acid but does not alter body fat. AB - Studies using dietary supplementation of eicosapentaenoic and docosahexaenoic fatty acids (FA) in horses report inconsistent anti-inflammatory results but consistently report an increase in plasma arachidonic acid (C20:4), the major substrate of cyclooxygenase (COX) II inflammatory pathway. Conjugated linoleic acid has shown anti-inflammatory effects in laboratory and food animal species, but effects of CLA supplementation in horses have not been reported. Our objective was to determine the effects of CLA supplementation on plasma CLA and C20:4 and body fat in healthy horses at maintenance. In a crossover study, 12 mature mares were blocked by breed, age, and BCS and separated into 2 treatment groups (n = 6/group). Groups were fed CLA and corn oil (CO; isocaloric control) for two 6-wk feeding periods, separated by a 4-wk period during which treatment was withheld. Corn oil or CLA supplement (55% mixed CLA isomers) was incorporated into diets at 0.01% BW/d. Mares were fed individually and restricted to dry lots to control forage intake. Rump fat thickness (RFT), BW, and BCS were measured before (d 0) and after (d 42) each feeding period. Blood was collected on d 0, 14, 28, and 42 of each 6-wk period for GLC analysis of plasma CLA isomers (cis-9, trans-11; trans-10, cis-12; and trans-9, trans-11) and C20:4. An ANOVA was conducted to compare the response of RFT, BW, and BCS of CLA-treated and control mares. A mixed methods analysis with repeated measures was used to detect differences in plasma FA concentrations. There were no differences in BW, RFT, or BCS between treatment groups. All CLA isomers present in the CLA supplement were greater in plasma of horses fed CLA compared with controls (P < 0.01). Additionally, plasma concentrations of C20:4 were decreased in horses fed CLA (P < 0.05). This decline in C20:4 may impact the COX II pathway and warrants further investigation. These results suggest that in an equine model, dietary CLA increases circulating concentrations of supplemented CLA isomers and decreases circulating C20:4. Examining physiological effects of CLA supplementation in horses at varying levels of growth, exercise, and progression of joint disease may offer insight to potential benefits of CLA in the horse. PMID- 22829602 TI - The antagonistic actions of endogenous interleukin-1beta and 15-deoxy-Delta12,14 prostaglandin J2 regulate the temporal synthesis of matrix metalloproteinase-9 in sheared chondrocytes. AB - Mechanical overloading of articular cartilage producing hydrostatic stress, tensile strain, and fluid flow results in irreversible cartilage erosion and osteoarthritis (OA). Application of high fluid shear to chondrocytes recapitulates the earmarks of OA as evidenced by the induction of proinflammatory cytokines and prostaglandins, which are capable of inducing the expression of matrix-degrading enzymes. Matrix metalloproteinase-9 (MMP-9) synthesis is detected at early but not late stages of OA. However, the underlying mechanism(s) of the MMP-9 temporal regulation remains unknown. Using the T/C-28a2 chondrocyte cell line as a model system, we demonstrated that high fluid shear induces a marked increase in MMP-9 expression at short shear exposure times (3-6 h), which falls below basal levels after prolonged shear exposure (12-48 h). High fluid shear stress induced the rapid and sustained synthesis of IL-1beta, activating PI3K, ERK1/2, and JNK, which are in turn responsible for MMP-9 expression. Prolonged shear exposure (>12 h) induced 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) synthesis, which exerted an antagonistic effect on IL-1beta-mediated PI3K-, ERK1/2-, and JNK-dependent NF-kappaB activation, thereby suppressing MMP-9 expression in human chondrocytes. Reconstructing the signaling network that regulates shear-mediated MMP-9 expression in human chondrocytes may provide insights for developing strategies to treat arthritic disorders. PMID- 22829605 TI - Standardized ileal digestibilities of crude protein, amino acids, and contents of antinutritional factors, mycotoxins, and isoflavones of European soybean meal imports fed to piglets. AB - A study with 3 experiments and 3 periods each was conducted to assess the protein value of soybean meal (SBM) batches that were imported into the European Union (EU) from Argentina, Brazil, or the United States (US). Six random SBM batches from each origin were analyzed for contents of CP, AA, ether extract, crude ash, NDF, ADF, oligosaccharides, isoflavones, mycotoxins, trypsin inhibitor activity (TIA), and protein dispersibility index. Piglets were used for determination of standardized ileal digestibilities (SID) of CP and AA in these 18 SBM batches. In each experiment, 12 piglets (initial BW = 5.6 +/- 0.7 kg) were surgically fitted with simple T-cannulas at the distal ileum. The piglets were randomly allotted to 18 semisynthetic assay diets, which included 1 of the 18 SBM batches from the 3 origins at an inclusion level of 250 g/kg (as-fed). Average content of CP was 480, 505, and 488 g/kg (as-fed) for Argentinean, Brazilian, and US SBM batches, respectively, and was greater for Brazilian SBM (P <= 0.05) compared with the other 2 origins. Contents of most AA were greater (P <= 0.05) in Brazilian compared with Argentinean SBM batches. Amino acid contents in US SBM batches ranged between those from Argentina and Brazil. Average TIA were 3.9, 5.1, and 3.4 mg trypsin inhibitor/g CP for Argentinean, Brazilian, and US SBM batches, and were greater (P <= 0.05) for Brazilian SBM compared with the other origins. Mycotoxins were detected in 8 out of 18 SBM batches, but all mycotoxin concentrations were less than their critical benchmarks. The contents of individual isoflavones varied considerably and differed (P <= 0.05) among SBM origins. The SID of CP, Arg, Phe, Thr, Trp, Asp, Gly, and Ser were greater (P <= 0.05) for US compared with Argentinean SBM batches, with intermediate values for Brazilian SBM batches. The obtained SID values were most variable within Argentinean SBM batches and most homogenous within US SBM batches, as indicated by great and small CV, respectively. However, SID of CP and AA were not affected (P > 0.05) by any of the chemical variables measured in this study, according to linear and quadratic regression analyses. Greatest SID values and good homogeneity between individual batches of the same origin were observed for US SBM. The results of this study with piglets will expand the database on SID of CP and AA in SBM from 3 of the major soybean-producing and processing countries. PMID- 22829606 TI - Providing supplemental milk to piglets preweaning improves the growth but not survival of gilt progeny compared with sow progeny. AB - Gilt progeny have lighter weaning weights and greater postweaning medication and mortality rates compared with the progeny of older parity sows. Because weaning weight has been positively correlated with postweaning survival, this study aimed to determine whether the provision of supplemental milk preweaning could improve weaning weight and subsequent weights as well as postweaning survival of gilt progeny. The study was replicated in summer and winter as the effects of supplemental milk were expected to vary with season. The progeny of 80 gilts (parity 0) and 80 sows (parity 2 to 5) were allocated to both treatments: with or without supplemental milk in these 2 seasons with 5 sheds/season. Litter size was standardized (10 to 11 piglets) and each piglet was weighed at birth, d 21, weaning (4 wk), and 10 wk of age. Medications and mortalities were recorded both preweaning and postweaning. Pigs were housed within treatment groups postweaning, and ADFI and G:F were measured. Gilt progeny were 200 g lighter at birth in both replicates (P < 0.001) and were 500 g lighter at weaning in the winter replicate (P < 0.05) compared with sow progeny. The provision of supplemental milk improved weaning weight for both gilt and sow progeny by 800 g in summer (P < 0.05) and by 350 g in winter (P < 0.05). This improvement in weaning weight had no effect on the incidence of death or disease in milk-supplemented progeny of either gilts or sows (P > 0.05). Supplemental milk disappearance (the daily difference between the volume of milk provided and the residue left in the drinker) was greater in summer than winter (by 130 mL/piglet d(-1); P < 0.05) as were the associated weaning weight benefits. The weaning weights of supplemented gilt progeny reached or exceeded that of nonsupplemented sow progeny. Gilt progeny had greater postweaning mortality (2.6%) and medication rates (6.2%) than sow progeny (1 and 2.2%, respectively; both P < 0.05) in both seasons, but medication rates were greater in winter (7.2%) for both treatment groups than in summer (1.9%; P < 0.05). Gilt progeny also had less postweaning ADFI than sow progeny in winter (528 and 636 g, respectively; P < 0.05) with no dam parity effect on G:F (both P > 0.05). The hypothesis that supplemental milk provision did increase gilt progeny weaning weight was supported (especially in summer) but the supplementation had no effect on postweaning weights and survival. Efforts to improve gilt progeny postweaning growth and survival need to be aimed at improving health and immunity, not just weaning weight. PMID- 22829607 TI - Rumen degradable protein supply affects microbial efficiency in continuous culture and growth in steers. AB - We hypothesized that microbial efficiency and output from fermentation in the rumen would be optimized when peptide supply was balanced with peptide requirement of ruminal microflora. This study was conducted to measure response of varying rumen degradable peptide (RDPep) supply on ruminal fermentation characteristics and steer growth. A continuous culture experiment was conducted with diets formulated to achieve a predicted RDPep balance (RDPep supplied above RDPep required) of -0.30 to 1.45% CP with rumen degradable N (RDN) balance (RDN supplied above RDN required) above dietary ammonia-N requirement of microbes. Two additional treatments had RDPep balances of -0.30 and 0.78% CP with insufficient ammonia-N supply to meet microbial requirements. Single-flow fermenters (N = 24; n = 6) were inoculated with rumen fluid and maintained anaerobically at 39 degrees C with a 0.06 h(-1) dilution rate. Inadequate RDN decreased OM digestion and microbial N flow, and increased rumen undegradable N (P < 0.01). Microbial efficiency decreased in RDN-deficient diets and was greatest when RDPep balance did not excessively exceed microbial requirement of RDPep predicted (P < 0.01). A growth study was conducted with 49 yearling, crossbred, Angus steers (initial BW 370 +/- 34 kg). Animals were assigned to 1 of 4 treatment groups by BW and further divided into 3 pens with 4 steers per pen to achieve similar initial pen weights. Treatments consisted of 4 isonitrogenous diets balanced for RDN but varying in predicted RDPep balance (0.55%, -0.02%, -0.25%, and -0.65% CP). Animals were maintained on treatment for 70 d with individual BW taken on d 0, 1, 21, 42, 70, and 71. Final BW decreased linearly with decreasing RDPep (P = 0.05). Average daily gain and G:F displayed a quadratic effect with greater ADG and G:F at greater and lesser RDPep levels (P = 0.02). We concluded that balancing RDPep supply to predicted requirement improved fermentation efficiency and microbial output, which in turn improved animal performance. PMID- 22829608 TI - Ricinoleic acid inhibits methanogenesis and fatty acid biohydrogenation in ruminal digesta from sheep and in bacterial cultures. AB - Ricinoleic acid (RA; 12-hydroxy-cis-9-18:1) is the main fatty acid component of castor oil. Although a precursor for CLA synthesis in lactic acid bacteria, RA was found previously not to form CLA in ruminal digesta but to have some inhibitory properties. The present study was undertaken to evaluate the potential of RA to modulate ruminal biohydrogenation and methanogenesis. Ruminal digesta from 4 sheep receiving a mixed hay-concentrate diet was incubated in vitro with 0.167 g/L of linoleic acid (LA; cis-9,cis-12-18:2) or with a combination of LA and RA or LA and castor oil (LA, RA, and castor oil added to a final concentration of 0.167 g/L) in the presence and absence of lipase. The CLA rumenic acid (cis-9,trans-11-18:2) accumulated when either RA or castor oil and lipase was present. Vaccenic acid (VA; trans-11-18:1) also accumulated, and a decrease of the rate of production of stearic acid (SA; 18:0) was observed. When LA was incubated with castor oil in the absence of lipase, no effects on biohydrogenation were observed. Ricinoleic acid at 0.02 g/L did not affect growth of Butyrivibrio fibrisolvens but it inhibited growth of Butyrivibrio proteoclasticus. Butyrivibrio proteoclasticus but not B. fibrisolvens metabolized RA to 12-hydroxystearate. Linoleic acid metabolism by B. proteoclasticus appeared to be unaffected by RA addition whereas rumenic acid accumulation increased (P = 0.015 at 12 h) when RA was added. A 28% decrease (P = 0.004) in methane was obtained in 24 h in vitro incubations of diluted buffered ruminal fluid with added 0.2 g RA/L. There was no effect on the total concentration of VFA after 24 h as a result of RA addition, but the molar proportions of acetate and butyrate were decreased (P = 0.041 and P < 0.001, respectively) whereas that of propionate increased (P < 0.001). It was concluded that, at least in vitro, RA or the combination of castor oil and lipase inhibit biohydrogenation, causing the accumulation of rumenic acid and VA, with potential health benefits for ruminant products. The effect appeared to be mediated via an inhibitory effect on the biohydrogenating activity of B. proteoclasticus. An added environmental benefit could be a concomitant decrease in methane emissions. In vivo studies are now required to confirm the potential of these additives. PMID- 22829609 TI - Modulation of intestinal glucose transport in response to reduced nitrogen supply in young goats. AB - The reduction of dietary protein is a common approach in ruminants to decrease the excretion of N because ruminants are able to recycle N efficiently by the rumino-hepatic circulation. In nonruminant species an impact on other metabolic pathways such as glucose metabolism was observed when dietary protein intake was reduced. However, an impact of dietary N reduction in goats on glucose metabolism especially on intestinal glucose absorption is questionable because ruminants have very efficient endogenous recycling mechanisms. Therefore, the aim of the present study was to characterize the intestinal absorption of glucose in growing goats kept on different N supply under isoenergetic conditions. The different CP concentrations (20, 16, 10, 9, and 7% CP) of the experimental diets were adjusted by adding urea to the rations. Intestinal flux rates of glucose were determined by Ussing chamber experiments. For a more mechanistic approach, the Na(+) dependent uptake of glucose into intestinal brush-border membrane vesicles (BBMV) and the expression patterns of the Na(+)-dependent glucose transporter SGLT1 and the glucose transporter 2 (GLUT2) were determined. Reduced N intake resulted in a decrease of plasma glucose (P < 0.001) and insulin (P = 0.004) concentrations whereas the intestinal flux rates of glucose were elevated (P < 0.001), which were inhibited by phlorizin. However, the uptake of glucose into intestinal BBMV was not changed whereas the expression of SGLT1 on mRNA (P < 0.05) and protein abundance (P = 0.03) was decreased in response to a reduced N intake. The mRNA expression of GLUT2 was not affected. From these data, it can be concluded that the intestinal absorption of glucose was modulated by changes in dietary N intake. It is suggested that intracellular metabolism or basolateral transport systems or both might be activated during this feeding regimen because the apical located SGLT1 might not be involved. Therefore, an impact of dietary N reduction on glucose metabolism in growing goats occurred as in monogastric animals. PMID- 22829611 TI - Do gastrointestinal taste receptors contribute to associative learning and foraging behavior? AB - Foraging behavior is an expression of learning, context, and experience arising from integration of sensory information obtained during feeding with postingestive consequences of food ingestion. Although it has been well established that gustatory and olfactory systems of the mouth and nose provide sensory information to the consumer (in the form of flavor), sweet and bitter taste receptors have recently been identified in the intestinal tract of humans and rodents. It remains possible that sensory information generated in the gut could contribute to the learning process. Thus, a series of experiments was conducted to determine if classical associative learning occurs when the conditional stimulus circumvents oronasal presentation via direct delivery to the gut or peritoneal cavity. Mice receiving an intragastric infusion of 5 mM sodium saccharin immediately followed by LiCl administration demonstrated a significant decrease in preference for 5 mM saccharin in 4 consecutive 23 h, 2-bottle preference tests versus water (P = 0.0053). Saccharin was highly preferred in mice receiving intragastric (IG) saccharin only or interperitoneal (i.p.) injection of LiCl only. This reduced preference indicated that mice "tasted" saccharin infused into the gut. However, efforts to replicate with a reduced infusion volume failed to result in decreased preference. To understand if there were alternative pathways for oral detection of infused saccharin, mice received intragastric infusions (5.4 mM) and i.p. injections (10.8 mM) of sodium fluorescein. Fluorescence was observed from the tongues and esophagi of mice infused with volumes of 0.5 mL or more or injected with volumes of 0.25 mL or greater. Interperitoneal injections of 5 mM saccharin in mice resulted in reduced preference for 5 mM saccharin presented orally in 2-bottle preference tests (P = 0.0287). Oral delivery of a 500-fold less concentration of saccharin (0.01 mM) during conditioning resulted in a similar preference expression as shown in the initial IG experiment. These results demonstrate that although compounds may be tasted in the mouth absent of oral contact, associative learning is attenuated. Therefore, intestinal taste receptors are unlikely to participate directly in learning and recognition of foods during foraging events. PMID- 22829612 TI - Effect of feed restriction on hormones, performance, carcass traits, and meat quality in immunocastrated pigs. AB - The aim of this study was to assess the effect of feed restriction applied to immunocastrated pigs in the period after the second vaccination (V2) against GnRH on hormonal status, performance, carcass traits, and meat quality. Immunocastrated pigs (IC) were compared with entire males (EM) and surgical castrates fed ad libitum. Pigs (Large White * Landrace) * Pietrain were either left entire or surgically castrated within 1 wk after birth (SC, n = 22). At 83 d of age, the entire males were further allotted to treatment groups (individual housing) of ad libitum fed EM (n = 24), ad libitum fed IC (IC-L, n = 21), or restrictively fed IC (IC-R, n = 21). At that time, the first vaccination (V1) was applied to IC-L and IC-R pigs. One week after V2 (age 130 d), feed restriction (~ 80% of the ad libitum feed intake of SC pigs) was applied to IC-R pigs. The experiment ended 5 wk after V2, when pigs were 165 d old. Immunocastration successfully reduced boar taint compounds and size of reproductive organs. At 130 d, serum leptin concentrations were similar in all groups, whereas IGF-I concentration was less in SC (P <= 0.002) than in the other groups. Three weeks after V2, leptin concentrations of both IC groups were in between EM (least) and SC (greatest). The reverse was observed for IGF-I. Feed restriction had no effect on leptin or IGF-I concentrations in IC pigs. In the period V1 to V2, performance differed mainly between EM and SC, whereas both IC groups had feed intake and feed conversion ratio similar to EM and intermediate daily BW gain, not differing from either EM or SC. After V2, IC-L pigs increased their feed intake to the concentrations of SC, with faster growth compared with the other 3 groups (P < 0.05) and fatter carcasses compared with EM pigs (P = 0.007). Similar performance and carcass leanness were observed for IC-R and EM pigs. During preslaughter handling more carcass lesions were noted in EM and IC-R than in IC-L or SC pigs (P < 0.002). Neither immunocastration nor feed restriction had any effect on meat quality, but EM had greater drip loss, less intramuscular fat, and decreased tenderness than SC pigs. In conclusion, restricting feed intake can increase production efficiency but also aggressiveness of IC pigs. PMID- 22829613 TI - Bacterial protein degradation by different rumen protozoal groups. AB - Bacterial predation by protozoa has the most deleterious effect on the efficiency of N use within the rumen, but differences in activity among protozoal groups are not completely understood. Two in vitro experiments were conducted to identify the protozoal groups more closely related with rumen N metabolism. Rumen protozoa were harvested from cattle and 7 protozoal fractions were generated immediately after sampling by filtration through different nylon meshes at 39 degrees C, under a CO(2) atmosphere to maintain their activity. Protozoa were incubated with (14)C-labeled bacteria to determine their bacterial breakdown capacity, according to the amount of acid-soluble radioactivity released. Epidinium tended to codistribute with Isotricha and Entodinium with Dasytricha; therefore, their activity was calculated together. This study demonstrated that big Diplodiniinae had the greatest activity per cell (100 ng bacterial CP per protozoa and hour), followed by Epidinium plus Isotricha (36.4), small Diplodiniinae (34.2), and Entodinium plus Dasytricha (14.8), respectively. However, the activity per unit of protozoal volume seemed to vary, depending on the protozoal taxonomy. Small Diplodiniinae had the greatest activity per volume (325 ng bacterial CP per protozoal mm(3) and hour), followed by big Diplodiniinae (154), Entodinium plus Dasytricha (104), and Entodinium plus Dasytricha (25.6). A second experiment was conducted using rumen fluid from holotrich-monofaunated sheep. This showed that holotrich protozoa had a limited bacterial breakdown capacity per cell (Isotricha 9.44 and Dasytricha 5.81 ng bacterial CP per protozoa and hour) and per protozoal volume (5.97 and 76.9 ng bacterial CP per protozoal mm(3) and hour, respectively). Therefore, our findings indicated that a typical protozoal population (10(6) total protozoa/mL composed by Entodinium sp. 88%, Epidinium sp. 7%, and other species 4%) is able to break down ~17% of available rumen bacteria every hour. Entodinium sp. is responsible for most of this bacterial breakdown (70 to 75%), followed by Epidinium sp. (16 to 24%), big Diplodiniinae (4 to 6%), and small Diplodiniinae (2 to 6%), whereas holotrich protozoa have a negligible activity (Dasytricha sp. 0.6 to 1.2% and Isotricha sp. 0.2 to 0.5%). This in vitro information must be carefully interpreted, but it can be used to indicate which protozoal groups should be suppressed to improve microbial protein synthesis in vivo. PMID- 22829614 TI - Alternative splicing and developmental and hormonal regulation of porcine comparative gene identification-58 (CGI-58) mRNA. AB - The process of lipolysis is essential for regulating the catabolism of cellular fat stores. Therefore, knowledge of lipolysis contributes to improving porcine production, such as reducing back fat, enhancing lean meat, and controlling marbling. Comparative gene identification-58 (CGI-58) plays an important role in the multi-enzyme-mediated process of lipolysis. It was identified as the co activator of adipose triglyceride lipase (ATGL), which performs the first step in breaking down triacylglycerol and generating diacylglycerol and NEFA. We cloned and sequenced the CGI-58 cDNA and deduced the AA sequences in 3 breeds of swine (Duroc, Berkshire, and Landrace). Homologies were found with the human, mouse, and chicken for the lipid droplet binding domain, the alpha/beta hydrolase domain, and the lysophosphatidic acid acyltransferase (LPAAT) domain, which demonstrates conservation of CGI-58 across species. An alternatively spliced isoform with an exon 3 deletion was identified. Interestingly, this unique isoform contains the lipid droplet-binding domain but lacks the LPAAT domain due to an open reading frame (ORF) shift that creates a premature stop codon. Furthermore, porcine CGI-58 is expressed in multiple organs and tissues but is most predominant in adipose tissue. Porcine adipose and stromal-vascular (SV) cell fractionation reveals that CGI-58 and ATGL are highly expressed (P < 0.01) in mature adipocytes. The expressions of both CGI-58 and ATGL mRNA were found to increase (P < 0.05) at d 6 of SV cell culture, confirming their upregulation during adipogenesis and differentiation. Also, the results from in vitro cell culture showed that insulin decreased (P < 0.05) the expressions of both CGI-58 and ATGL in a dose-dependent manner. Overall, these results report the cDNA and AA sequences of porcine CGI-58 with identification of its unique alternatively spliced variant. The results of the study also reveal the developmental and hormonal regulation of porcine CGI-58 gene, which contributes to the understanding of the role of CGI-58 in lipid metabolism. These findings suggest that CGI-58 may be a new target for enhancing the quality of pork products as well as offering the potential of CGI-58 for human obesity treatment. PMID- 22829615 TI - Effects of dietary inclusion and NaOH treatment of dried distillers grains with solubles on ruminal metabolism of feedlot cattle. AB - Dried distillers grains with solubles (DDGS) can decrease rumen pH because of their inherent acidity. Two replicated 4 * 4 Latin square experiments were conducted with ruminally fistulated heifers to determine the effects of dietary inclusion and NaOH treatment of DDGS on rumen metabolism. In Exp. 1, dietary treatments were 0%, 20%, 40%, or 60% DDGS on a DM basis. The remainder of the diet was 15% corn silage, 20% vitamin-mineral supplement, and corn (to replace DDGS) on a DM basis. Dry matter intake decreased (linear; P < 0.01) with increasing dietary inclusion of DDGS. Rumen pH was less than 5.3 from 1.5 to 12 h after feeding regardless of dietary DDGS inclusion, and mean rumen pH tended to decrease (linear; P = 0.08) with increasing DDGS. Rumen fluid S(2-) and rumen H(2)S gas concentrations increased (P < 0.01) with increasing DDGS inclusion at all time points postfeeding. At 3 h after feeding, ruminal concentrations of acetate, propionate, and total VFA increased linearly (P < 0.04) with increasing dietary inclusion of DDGS. Acetate to propionate ratio (A:P) ranged from 0.97 to 1.25 and was not affected (P = 0.88) by diet over time. In Exp. 2, dietary treatments were 1) 25% DDGS inclusion, untreated, 2) 60% DDGS inclusion, untreated, 3) 25% DDGS inclusion, treated with 2% NaOH, and 4) 60% DDGS inclusion, treated with 2% NaOH. Dry matter intake decreased (P < 0.01) when 60% DDGS was included in the diet regardless of NaOH treatment. Mean rumen pH was greater (P < 0.01) when NaOH-treated DDGS was fed regardless of dietary inclusion level. There were interactions (P <= 0.06) of NaOH treatment by DDGS inclusion by time for mean H(2)S and S(2-) concentrations. These interactions occurred because the magnitude of the response to NaOH treatment was greater for the 60% DDGS diets than for the 25% DDGS diets only from 1.5 to 9 h postfeeding. There were no interactions (P > 0.05) of NaOH treatment by DDGS inclusion on VFA concentrations. Acetate concentration decreased (P = 0.04) in cattle fed 60% DDGS diets at 0 h, but at 3 h postfeeding it tended to increase (P = 0.06). Total lactate was less than 1.30 for all dietary treatments at all time points. Treating DDGS with 2% NaOH may increase rumen pH and decrease H(2)S, thereby alleviating polioencephalomalacia. PMID- 22829616 TI - Qualitative behavioral assessment of transport-naive and transport-habituated sheep. AB - Objective and issue-neutral qualitative assessments of livestock behavior could provide a powerful assessment of welfare, augmenting quantitative measures such as autonomic and endocrine changes, which are often difficult to assess under many commercial livestock conditions. We set out to validate the use of qualitative behavioral assessment (QBA) in sheep using controlled experimental conditions (transport as a challenge) and comparing assessments against physiological variables. The behavioral expression of 14 Merino wethers, which had never experienced land transport, were assessed during their first road event (naive to transport), and then again on their seventh event, 8 d later (habituated to transport). Blood samples were collected immediately before loading and after unloading, and heart rate and core body temperature were measured continuously throughout each event. Continuous video footage recorded during each event was used to provide clips of individual animals that were shown to observers for QBA. There was significant consensus (P < 0.001) amongst 63 observers in terms of their assessment of the behavioral expression of the sheep. Transport-naive sheep were assessed as being more 'alert', 'anxious', and 'aware', whereas transport-habituated sheep were more 'comfortable', 'tired', and 'confident' (P = 0.015). Heart rate and heart rate variability, core body temperature and a stress leukogram were greater (P < 0.05) in sheep during the first (naive) event compared with the habituated event, and were significantly correlated with the QBA scores (P < 0.05). In conclusion, QBA is a valid, practical and informative measure of behavioral responses to transport. PMID- 22829617 TI - Cryopreservation of green fluorescent protein (GFP)-labeled primordial germ cells with GFP fused to the 3' untranslated region of the nanos gene by vitrification of Japanese eel (Anguilla japonica) somite stage embryos. AB - Primordial germ cells (PGC) are the only cell type in developing embryos with the potential to transmit genetic information to the next generation. In this study, PGC of Japanese eel (Anguilla japonica) were visualized by injection of mRNA synthesized from a construct carrying the green fluorescent protein (GFP) gene fused to the 3' untranslated region of the Japanese eel nanos gene. We investigated the feasibility of cryopreserving Japanese eel PGC by vitrification of dechorionated whole somite stage embryos. The GFP-labeled PGC were rapidly cooled using liquid nitrogen after exposure to a pretreatment solution containing 1.5 M cryoprotectant (methanol, dimethyl sulfoxide, and glycerol for 10 min and ethylene glycol for 10, 20, and 30 min) and a vitrification solution containing 3 M cryoprotectant and 0.5 M sucrose for 1, 5, and 10 min. Ethylene glycerol is an effective cryoprotectant for embryonic cells and shows no evidence of ice formation after thawing. Vitrified and thawed PGC were transplanted into blastula stage embryos from zebrafish (Danio rerio). The GFP-labeled PGC migrated toward the host gonadal ridge, suggesting maintenance of their normal migration motility. These techniques may assist in achieving inter- and intraspecies germ line chimers using donor Japanese eel PGC. PMID- 22829618 TI - Effect of rice and other cereal grains on growth performance, pig removal, and antibiotic treatment of weaned pigs under commercial conditions. AB - Three experiments were conducted to evaluate effects of rice and other cereal grains on growth performance and health of weanling pigs. Pigs (1,008 in Exp. 1 and 3 and 1,004 in Exp. 2; 21 d old) with an initial BW of 5.8 +/- 1.0 kg were used. Pigs in each experiment were divided into 3 BW blocks (heavy, medium, or light) in each of 4 rooms, resulting in 12 blocks per experiment. Each pen within a block had 20 or 21 pigs and equal sex distribution. Pens were allotted to dietary treatments in a randomized complete block design. Pigs were fed in a 4 phase feeding program with Phases 1 and 2 of 1 wk each and Phases 3 and 4 of 2 wk each. Diets were formulated to meet the same nutritional standards within each phase. In Exp. 1, effects of different cereal grains on pig performance and removal rate (mortality plus morbidity) were investigated. Pigs were fed 4 diets based on corn, barley, rolled oats, or rice as the only cereal grain. Over a 6-wk period, the ADG of pigs fed rice was greater (P < 0.01) than those pigs fed barley but not different from those pigs fed corn or rolled oats. Pigs fed corn or rice did not differ in ADFI, which was greater (P < 0.05) than those pigs fed barley. The overall removal rate of pigs fed rice or barley was reduced as compared with those pigs fed rolled oats (P < 0.05), and tended to be less than those pigs fed corn (P = 0.075). Experiment 2 was conducted to determine if the benefits observed in Exp. 1 could be obtained by feeding rice for less than 6 wk. Treatments included rice diets fed for 0, 1, 2, or 4 wk before changing to corn diets. All pigs received a common diet during wk 5 and 6. Pig performance and antibiotic treatments did not differ among dietary treatments. However, pigs fed rice for 1, 2, or 4 wk had a reduced overall removal rate (P < 0.05) compared with those fed corn. Experiment 3 was conducted to investigate if the amount of rice fed in wk 1 could be reduced without reducing pig performance. Rice replaced 0, 50, 75, or 100% of corn in Phase 1 diets. All pigs received a common diet from wk 2 to 6. No differences in pig performance or antibiotic treatments among dietary treatments were observed. However, pigs fed the diet with 100% rice had a reduced (P = 0.055) overall removal rate compared with pigs fed the corn diet. Generally, rice and corn improve pig performance as compared with barley. Rice can substitute for corn in nursery diets without detriment to pig performance and substantially reduces pig removals, even when fed for only 1 wk immediately after weaning. PMID- 22829619 TI - Double-muscled and conventional cattle have the same net energy requirements if these are related to mature and current body protein mass, and to gain composition. AB - The hypothesis tested in this paper is that double-muscled (DBM) and conventional cattle, considerably differing in body composition, have similar NE requirements when: a) NE(m) is scaled as a function of current (P(i)) and adult (P(m)) protein mass; and b) ME for gain (ME(g)) is estimated from protein (Pr) and lipid (Lr) retention and their partial ME use efficiencies, the k(p) and k(l) values, respectively. First, 2 databases were examined: 1 was developed combining well known literature information from comparative slaughter trials conducted on British beef steers; the other was based on a trial conducted using extremely lean DBM Piemontese bulls. From the first database, NE(m) was calculated to be 1.625 * P(i) / P(m) * P(m)(0.73) (MJ/kg(0.73)). From the second database, the daily ME(g) was determined as 22.8 MJ * Pr / k(p) + 38.74 MJ * Lr / k(l), assuming (from prior reports) that k(p) = 0.20 and k(l) = 0.75. Thereafter, ME(m) was defined as ME intake minus ME(g), and, hence, NE(m) was predicted as 1.625 * P(i) / P(m) * P(m)(0.73) (where 1.625 was the value obtained from the first dataset). The resulting k(m) (NE(m)/ME(m)) averaged 0.67. This k(m) value did not differ from that (0.65; P = 0.12) predicted by Garrett's equation, which uses dietary ME content as the only predictive variable. Second, the procedure was tested for the ability to detect effects on k(m) caused by increasing BW and dietary factors not estimable from the dietary ME content only. Data were gathered from a trial involving 48 DBM Piemontese bulls divided into 4 groups fed 1 of 4 diets differing in CP content (145 or 108 g/kg DM), with or without addition of 80 g/d of rumen-protected CLA (rpCLA). Bulls were examined at 3 consecutive periods of growth, corresponding to 365, 512 and 631 kg of average BW. All energy balance items were influenced by increasing BW, except k(m) (P = 0.61), in agreement with the expectation that NE(m) requirement depends on the degree of maturity (P(i)/P(m)) and the P(m)(0.73) of an animal, whereas k(m) reflects characteristics of the feed provided. The k(m) value was also influenced by the CP * rpCLA interaction (P = 0.013). We conclude that DBM and British beef steers have similar NE requirements when these are scaled as a function of P(i) and P(m), and gain composition, considering Pr, k(p), Lr and k(l). The proposed procedure will be useful to predict the energy requirements and feed use in cattle of different types that vary in BW, provided that body and gain compositions are known or accurately predicted. PMID- 22829620 TI - The effects of feeder adjustment and trough space on growth performance of finishing pigs. AB - Two studies were conducted to determine the effects of feeder adjustment and trough space on growth performance of finishing pigs. In Exp. 1, 234 pigs (initial BW 41.5 kg) were used in an 89-d trial. Pigs were randomly allotted to 1 of 3 treatments with 9 replications of 8 pigs/pen and 1 replicate with 6 pigs/pen. Treatments consisted of a minimum feeder gap setting of 1.27, 1.91, or 2.54 cm. Feeders were adjusted to a minimum gap setting, but the agitation plate could be moved upward to a maximum opening of 1.91, 2.54, or 3.18 cm, respectively. Feeder adjustments of 1.27, 1.91, and 2.54 cm averaged 28, 58, and 75% pan coverage, respectively. From d 0 to 58, increasing feeder gap improved (linear; P <= 0.04) ADG and ADFI, but decreased (linear; P < 0.05) G:F. Although the response was linear for ADG, no increase occurred (quadratic; P = 0.15) beyond the 1.91-cm feeder gap setting. From d 58 to 89, increasing feeder gap setting tended (linear; P = 0.08) to worsen G:F. Overall (d 0 to 89), pigs fed with increasing feeder gap had decreased (linear; P <0.03) G:F due to increased (linear; P <0.02) ADFI. In Exp. 2, 288 pigs (initial BW 41.3 kg) were used in a 91-d study to evaluate the effects of feeder trough space (4.45 vs. 8.9 cm/pig) and minimum feeder gap opening of 1.27 cm (narrow) vs. 2.54 cm (wide). The treatments were arranged in a 2 * 2 factorial with 6 replications per treatment. Feeder trough space was altered by having pens of either 8 to 16 pigs per pen with all pigs provided 0.74 m(2) floor space per pig. From d 0 to 56 and 56 to 91, no adjustment * space interactions or effects of trough space were observed. From d 0 to 56, pigs with the wide feeder gap setting had decreased (P < 0.02) G:F compared with those that had the narrow feeder gap setting. From d 56 to 91, pigs with the wider feeder gap setting had increased (P < 0.001) ADFI, but consequently had decreased (P < 0.01) G:F. Overall (d 0 to 91), no trough space * feeder adjustment interactions were observed. However, ADG tended to increase (P = 0.08) as feeder trough space increased from 4.45 to 8.9 cm/pig. Pigs fed with the wide feeder gap setting had increased (P < 0.01) feed disappearance and decreased (P < 0.01) G:F compared with pigs with the narrow feeder gap setting. These data indicate that pigs from 41 to 68 kg need approximately 58% pan coverage, whereas pigs greater than 68 kg should have approximately 28% pan coverage to optimize growth and reduce feed wastage. PMID- 22829621 TI - The effect of estrogen administration during early pregnancy upon the survival of single implanted pig embryos. AB - In the present study, we investigated the influence of exogenous estrogen on embryo survival after transfer into prepubertal gilts in which estrus had been induced. In the first experiment, estrus was induced in prepubertal gilts by the administration of 1,000 IU of eCG and 750 IU of hCG every 72 h. Several blastocysts were recovered on d 6 (d 0 is the day of hCG administration), and 1 embryo was transferred to the tip of 1 side of the uterine horn on d 6 (Control). In treated groups, after embryo transfer, 5 mg of estradiol benzoate (EB) was administered on d 11 (EB5mg-1) or d 11, d 13, and d 15 (EB5mg-3) or d 11, 12, 13, 14, and 15 (EB5mg-5) or 20 mg of estradiol dipropionate (EDP) was administered on d 11 (EDP20mg-1) or d 11 and d 14 (EDP20mg-2). Autopsy examinations were performed on d 53 to 60. Although nontreated gilts did not become pregnant, gilts in each of the estradiol-treated groups became pregnant. The greatest pregnancy rate (77.8%, 7/9) was obtained with EDP20mg-2 (EDP20mg-2 > control: P < 0.05). In a second experiment, 1 blastocyst was transferred to prepubertal gilts and treated with EDP20mg-2. Pregnancy in recipient pigs was confirmed by ultrasonography, and pigs were allowed to farrow. Embryo survival rate was high on d 30 of pregnancy (75%, 9/12) but had a tendency (P = 0.0995) to decline from d 30 to delivery (33.3%, 4/12). In a third experiment, prepubertal gilts were administered 5 mg of EDP on d 11 (EDB5mg-1) and d 11 and d 14 (EDP5mg-2). Autopsy examinations were performed on d 53 to 58. Pseudopregnancy rate was high for EDP5mg-2 (63.6%, 7/11) compared with EDP5mg-1 (0%, 0/11; P < 0.05). In a fourth experiment, prepubertal gilts were transferred 1 blastocyst and treated with EDP5mg-2. Pregnancy was confirmed in recipient pigs by ultrasonography, and pigs were subsequently allowed to farrow. Embryo survival rate remained unchanged from d 30 of pregnancy to delivery (66.7%; 8/12). One piglet died from dystocia, and 1 suffered from deformity involving double-breasted hooves and died 6 d after birth. There was no difference (P > 0.05) in survival rate on d 30 of pregnancy and weaning (50%, 6/12). Body weight at birth and at weaning did not differ from that reported in previous studies. In conclusion, this study showed that EDP5mg-2 treatment during early pregnancy leads to full-term development of a single embryo. PMID- 22829622 TI - Effects of an extract of plant flavonoids (Bioflavex) on rumen fermentation and performance in heifers fed high-concentrate diets. AB - To study the effects of an extract of plant flavonoids [Bioflavex (FL)] in cattle fed high-concentrate diets, 2 experiments were designed. In the first experiment, the effects of Bioflavex on the development of rumen acidosis was evaluated in 8 Holstein-Friesian crossbreed heifers (451 kg; SEM 14.3 kg of BW) using a crossover design. Each experimental period lasted 22 d; from d 1 to 20, the animals were fed rye grass, on d 21 the animals were fasted, and on d 22, rumen acidosis was induced by applying 5 kg of wheat without [ CONTROL: (CTR) heifers who did not receive Bioflavex] or with flavonoids [heifers who received FL; 300 mg/kg DM] through a rumen cannula. Rumen pH was recorded continuously (from d 19 to d 22). On d 22, average rumen pH was significantly (P < 0.01) higher in the FL animals (6.29; SEM = 0.031) than it was in the CTR heifers (5.98; SEM = 0.029). After the wheat application, the rumen VFA concentration increased (P < 0.01), the proportion of acetic acid decreased (P < 0.01), and lactate concentration (mmol/L) increased, but the increase was not as great (P = 0.09) in the FL as it was in the CTR heifers (0.41 to 1.35 mmol/L; SEM = 0.24). On d 22, Streptococcus bovis and Selenomonas ruminantium titers increased after the wheat application, but Megasphaera elsdenii titers increased (P < 0.05) only in the FL heifers. In the second experiment, the effect of Bioflavex on the performance and rumen fermentation in finishing heifers was evaluated. Forty-eight Fleckvieh heifers (initial BW = 317 kg; SEM = 5.34) were used in a completely randomized design. Heifers were assigned to 1 of 4 blocks based on their BW and, within each block, assigned to 1 of 2 pens (6 heifers/pen). In addition, 16 heifers (2/pen) were rumen cannulated. Individual BW and group consumption of concentrate and straw were recorded weekly until the animals reached the target slaughter weight. Supplementation with FL did not affect ADG, feed consumption, or feed conversion ratio. Rumen pH and molar proportions of propionate were greater (P < 0.01) and acetate proportion was less in the FL (P < 0.01) than they were in the CTR heifers. Flavonoid supplementation might be effective in improving rumen fermentation and reducing the incidence of rumen acidosis. This effect of flavonoids may be partially explained by increasing the numbers of lactate consuming microorganisms (e.g., M. elsdenii) in the rumen. PMID- 22829623 TI - Bacterial GRAS domain proteins throw new light on gibberellic acid response mechanisms. AB - SUMMARY: Gibberellic acids (GAs) are key plant hormones, regulating various aspects of growth and development, which have been at the center of the 'green revolution'. GRAS family proteins, the primary players in GA signaling pathways, remain poorly understood. Using sequence-profile searches, structural comparisons and phylogenetic analysis, we establish that the GRAS family first emerged in bacteria and belongs to the Rossmann fold methyltransferase superfamily. All bacterial and a subset of plant GRAS proteins are likely to function as small molecule methylases. The remaining plant versions have lost one or more AdoMet (SAM)-binding residues while preserving their substrate-binding residues. We predict that GRAS proteins might either modify or bind small molecules such as GAs or their derivatives. CONTACT: aravind@ncbi.nlm.nih.gov SUPPLEMENTARY INFORMATION: Supplementary Material for this article is available at Bioinformatics online. PMID- 22829624 TI - YAHA: fast and flexible long-read alignment with optimal breakpoint detection. AB - MOTIVATION: With improved short-read assembly algorithms and the recent development of long-read sequencers, split mapping will soon be the preferred method for structural variant (SV) detection. Yet, current alignment tools are not well suited for this. RESULTS: We present YAHA, a fast and flexible hash based aligner. YAHA is as fast and accurate as BWA-SW at finding the single best alignment per query and is dramatically faster and more sensitive than both SSAHA2 and MegaBLAST at finding all possible alignments. Unlike other aligners that report all, or one, alignment per query, or that use simple heuristics to select alignments, YAHA uses a directed acyclic graph to find the optimal set of alignments that cover a query using a biologically relevant breakpoint penalty. YAHA can also report multiple mappings per defined segment of the query. We show that YAHA detects more breakpoints in less time than BWA-SW across all SV classes, and especially excels at complex SVs comprising multiple breakpoints. AVAILABILITY: YAHA is currently supported on 64-bit Linux systems. Binaries and sample data are freely available for download from http://faculty.virginia.edu/irahall/YAHA. CONTACT: imh4y@virginia.edu. PMID- 22829625 TI - Nebula--a web-server for advanced ChIP-seq data analysis. AB - MOTIVATION: ChIP-seq consists of chromatin immunoprecipitation and deep sequencing of the extracted DNA fragments. It is the technique of choice for accurate characterization of the binding sites of transcription factors and other DNA-associated proteins. We present a web service, Nebula, which allows inexperienced users to perform a complete bioinformatics analysis of ChIP-seq data. RESULTS: Nebula was designed for both bioinformaticians and biologists. It is based on the Galaxy open source framework. Galaxy already includes a large number of functionalities for mapping reads and peak calling. We added the following to Galaxy: (i) peak calling with FindPeaks and a module for immunoprecipitation quality control, (ii) de novo motif discovery with ChIPMunk, (iii) calculation of the density and the cumulative distribution of peak locations relative to gene transcription start sites, (iv) annotation of peaks with genomic features and (v) annotation of genes with peak information. Nebula generates the graphs and the enrichment statistics at each step of the process. During Steps 3-5, Nebula optionally repeats the analysis on a control dataset and compares these results with those from the main dataset. Nebula can also incorporate gene expression (or gene modulation) data during these steps. In summary, Nebula is an innovative web service that provides an advanced ChIP-seq analysis pipeline providing ready-to-publish results. AVAILABILITY: Nebula is available at http://nebula.curie.fr/ SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22829626 TI - Folding RNA/DNA hybrid duplexes. AB - MOTIVATION: While there are numerous programs that can predict RNA or DNA secondary structures, a program that predicts RNA/DNA hetero-dimers is still missing. The lack of easy to use tools for predicting their structure may be in part responsible for the small number of reports of biologically relevant RNA/DNA hetero-dimers. RESULTS: We present here an extension to the widely used ViennaRNA Package (Lorenz et al., 2011) for the prediction of the structure of RNA/DNA hetero-dimers. AVAILABILITY: http://www.tbi.univie.ac.at/~ronny/RNA/vrna2.html CONTACT: ronny@tbi.univie.ac.at, berni@bioinf.uni-leipzig.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22829627 TI - Microparticles are the basic storage units for different proteins in platelet granules. AB - Platelets are circulating carriers of numerous proteins including coagulation and inflammation factors, cytokines, and angiogenesis regulatory factors. Understanding how platelets store and organize the proteins is crucial to understanding their role and function in the vast involved pathophysiological events. Therefore, in this study we hypothesized that microparticles are the basic storage units for different proteins in platelet granules. We utilized stimulated emission depletion microscopy to study the ultrastructure of platelets and the protein storage in granules. Our results demonstrated that P-selectin, fibrinogen, platelet factor 4 and vascular endothelial growth factor are all packaged and stored in individual sub-granule vesicles. The four proteins all exhibited ring-like distribution in the vesicles with a diameter of approximately 90 nm. We further discovered that one microparticle stores only one type of proteins. These results supported our hypothesis and have provided novel insights of how platelets systematically store and organize proteins in the granules. These insights have not only reevaluated the ultrastructure of platelets, but also provided a link connecting microparticles and platelets from structure to function and pathologies. The link is believed to benefit the understanding of how platelets regulate their pathophysiological participations, such as inflammation, angiogenesis, and tumor growth. PMID- 22829628 TI - Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders. AB - The importance of human leukocyte antigen (HLA) matching in unrelated donor transplantation for nonmalignant diseases (NMD) has yet to be defined. We analyzed data from 663 unrelated marrow and peripheral blood stem cell transplants performed from 1995 to 2007 for treatment of NMD. Transplantation from a donor mismatched at the HLA-A, -B, -C, or -DRB1, but not -DQB1 or -DPB1, loci was associated with higher mortality in multivariate analyses (P = .002). The hazard ratio for mortality for single (7/8) and double mismatched (6/8) transplants was 1.29 (0.97-1.72; P = .079) and 1.82 (1.30-2.55; P = .0004), respectively, compared with 8/8 matched transplants. HLA mismatches were not associated with acute or chronic GVHD, but were strongly associated with graft failure. After adjustment for other factors, the odds ratio for graft failure for 7/8 and 6/8 (allele and/or antigen) matched pairs compared with 8/8 matched transplants was 2.81 (1.74-4.54; P < .0001) and 2.22 (1.26-3.97; P = .006), respectively. Patients with NMD should receive transplants from allele matched (8/8) donors if possible. Unlike the case with malignancies, HLA mismatching in NMD is associated with graft failure rather than GVHD. PMID- 22829629 TI - Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms. AB - Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018. PMID- 22829630 TI - Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells. AB - Low linear energy transfer (LET) ionizing radiation (IR) is an important form of therapy for acute leukemias administered externally or as radioimmunotherapy. IR is also a potential source of DNA damage. High LET IR produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Therefore, understanding mechanisms of resistance is valuable. We created stable myeloid leukemia HL60 cell clones radioresistant to either gamma-rays or alpha-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of IR was observed, but resistance to clustered, complex alpha-particle damage was substantially lower than to equivalent doses of gamma-rays. The resistant phenotype was driven by changes in: apoptosis; late G2/M checkpoint accumulation that was indicative of increased genomic instability; stronger dependence on homology-directed repair; and more robust repair of DNA double-strand breaks and sublethal-type damage induced by gamma-rays, but not by alpha-particles. The more potent cytotoxicity of alpha-particles warrants their continued investigation as therapies for leukemia and other cancers. PMID- 22829632 TI - A 69-year-old male with chronic keratitis. PMID- 22829631 TI - The gene therapy journey for hemophilia: are we there yet? AB - Since the isolation and characterization of the genes for FVIII and FIX some 30 years ago, a longstanding goal of the field has been development of successful gene therapy for the hemophilias. In a landmark study published in 2011, Nathwani et al demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult males who underwent intravenous infusion of an adeno associated viral (AAV) vector expressing factor IX. These 6 subjects have now exhibited expression of FIX at levels ranging from 1% to 6% of normal for periods of > 2 years. This review discusses obstacles that were overcome to reach this goal and the next steps in clinical investigation. Safety issues that will need to be addressed before more widespread use of this approach are discussed. Efforts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be useful for persons with severe liver disease, who may not be candidates for gene transfer to liver, are also discussed. PMID- 22829633 TI - To differentiate Taenia eggs. PMID- 22829635 TI - Sensitivity and specificity of a competitive enzyme-linked immunosorbent assay relative to quantitative reverse transcriptase PCR for detection of Anaplasma marginale and A. phagocytophilum. PMID- 22829638 TI - Community-wide, contemporaneous circulation of a broad spectrum of human rhinoviruses in healthy Australian preschool-aged children during a 12-month period. AB - Human rhinovirus (HRV) replication triggers exacerbation of asthma and causes most acute respiratory illnesses (ARIs), which may manifest as influenza-like illness. The recent assignment of 60 previously unknown HRV types to a third HRV species, Human rhinovirus C, raised questions about the prevalence of these picornavirus types in the community, the extent of HRV diversity at a single site, and whether the HRVs have an equally diverse clinical impact on their hosts. We quantified HRV diversity, and there was no clinical impact attributable to HRV species and genotypes among a community population of preschool-aged children with ARI who provided respiratory samples during 2003. All HRV species were represented among 138 children with ARI, and 74 distinct HRV types were cocirculating. Fever accompanied 32.8% of HRV-positive ARI cases. HRVs were less likely than DNA viruses to be codetected with another virus, suggesting virus interference at the community level, demonstrated by the inverse correlation between influenza virus detection and HRV detection. PMID- 22829639 TI - Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. AB - The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial. Notwithstanding tenofovir gel use, women who acquired HIV had significantly higher systemic innate immune activation prior to infection than women who remained uninfected. Activation of both soluble (cytokine) and cellular (NK cells) immune mediators were associated with HIV acquisition, individually or in combination. Hence, an innate immune activation suppressant could be added to tenofovir gel as a potential combination gel strategy in developing the next generation of higher efficacy antiretroviral microbicides. PMID- 22829641 TI - Seasonality, timing, and climate drivers of influenza activity worldwide. AB - BACKGROUND: Although influenza is a vaccine-preventable disease that annually causes substantial disease burden, data on virus activity in tropical countries are limited. We analyzed publicly available influenza data to better understand the global circulation of influenza viruses. METHOD: We reviewed open-source, laboratory-confirmed influenza surveillance data. For each country, we abstracted data on the percentage of samples testing positive for influenza each epidemiologic week from the annual number of samples testing positive for influenza. The start of influenza season was defined as the first week when the proportion of samples that tested positive remained above the annual mean. We assessed the relationship between percentage of samples testing positive and mean monthly temperature with use of regression models. FINDINGS: We identified data on laboratory-confirmed influenza virus infection from 85 countries. More than one influenza epidemic period per year was more common in tropical countries (41%) than in temperate countries (15%). Year-round activity (ie, influenza virus identified each week having >= 10 specimens submitted) occurred in 3 (7%) of 43 temperate, 1 (17%) of 6 subtropical, and 11 (37%) of 30 tropical countries with available data (P = .006). Percentage positivity was associated with low temperature (P = .001). INTERPRETATION: Annual influenza epidemics occur in consistent temporal patterns depending on climate. PMID- 22829640 TI - Influenza A viruses target type II pneumocytes in the human lung. AB - BACKGROUND: Highly pathogenic avian H5N1 influenza viruses preferentially infect alveolar type II pneumocytes in human lung. However, it is unknown whether this cellular tropism contributes to high viral virulence because the primary target cells of other influenza viruses have not been systematically studied. METHODS: We provide the first comparison of the replication, tropism, and cytokine induction of human, highly pathogenic avian influenza A virus subtype H5N1 and other animal influenza A viruses in primary human lung organ cultures. RESULTS: Subytpe H5N1 and human-adapted subtype H1N1 and H3N2 viruses replicated efficiently in the lung tissue, whereas classic swine and low-pathogenicity avian viruses propagated only poorly. Nevertheless, all viruses examined were detected almost exclusively in type II pneumocytes, with a minor involvement of alveolar macrophages. Infection with avian viruses that have a low and high pathogenicity provoked a pronounced induction of cytokines and chemokines, while human and pandemic H1N1-2009 viruses triggered only weak responses. CONCLUSIONS: These findings show that differences in the pathogenic potential of influenza A viruses in the human lung cannot be attributed to a distinct cellular tropism. Rather, high or low viral pathogenicity is associated with a strain-specific capacity to productively replicate in type II pneumocytes and to cope with the induced cytokine response. PMID- 22829642 TI - Interruption of poliovirus transmission in Ghana: molecular epidemiology of wild type 1 poliovirus isolated from 1995 to 2008. AB - Described in detail is the molecular epidemiology of wild-type 1 poliovirus circulation in Ghana between 1995-2008, following the implementation of a surveillance system for cases of acute flaccid paralysis and poliovirus infection. Molecular phylogenetic analysis combined with a detailed evaluation of epidemiological indicators revealed that the geographical and temporal circulation of wild-type poliovirus in Ghana was determined by the quality of the implementation of global eradication strategies. The transmission of "indigenous" wild-type 1 poliovirus was eliminated in 1999. However, a drastic reduction in national immunization campaigns resulted in the importation in 2003 and 2008 of wild-type 1 poliovirus from neighboring countries. Both outbreaks were promptly interrupted following resumption of immunization activities. The results detailed here provide scientific evidence that supports the feasibility of polio eradication in Central West Africa, one of the remaining endemic areas for the disease, provided that comprehensive immunization campaigns and sensitive surveillance systems are in place. PMID- 22829644 TI - Safety and Immunogenicity of LC16m8, an Attenuated Smallpox Vaccine in Vaccinia Naive Adults. PMID- 22829643 TI - In enterovirus 71 encephalitis with cardio-respiratory compromise, elevated interleukin 1beta, interleukin 1 receptor antagonist, and granulocyte colony stimulating factor levels are markers of poor prognosis. AB - BACKGROUND: Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood. METHODS: We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died. RESULTS: Both pro inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1beta (IL-1beta), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%). CONCLUSIONS: Given that IL-1beta has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options. PMID- 22829645 TI - Staphylococcus aureus FhuD2 is involved in the early phase of staphylococcal dissemination and generates protective immunity in mice. AB - Iron availability plays an essential role in staphylococcal pathogenesis. We selected FhuD2, a lipoprotein involved in iron-hydroxamate uptake, as a novel vaccine candidate against Staphylococcus aureus. Unprecedented for staphylococcal lipoproteins, the protein was demonstrated to have a discrete, punctate localization on the bacterial surface. FhuD2 vaccination generated protective immunity against diverse clinical S. aureus isolates in murine infection models. Protection appeared to be associated with functional antibodies that were shown to mediate opsonophagocytosis, to be effective in passive transfer experiments, and to potentially block FhuD2-mediated siderophore uptake. Furthermore, the protein was found to be up-regulated in infected tissues and was required for staphylococcal dissemination and abscess formation. Herein we show that the staphylococcal iron-hydroxamate uptake system is important in invasive infection and functions as an efficacious vaccine target. PMID- 22829646 TI - Exogenous sialic acid transport contributes to group B streptococcus infection of mucosal surfaces. AB - By sequence analysis of available group B streptococcus (GBS) genomes, we discovered a conserved putative operon involved in the catabolism of sialic acid, containing a tripartite transporter formed by two integral membrane components and a sugar-binding unit, named SAL0039. Expression analysis in the presence of different substrates revealed that SAL0039 was specifically upregulated by the presence of sialic acid and downregulated when bacteria were grown in human blood or in the presence of a high concentration of glucose. The role of SAL0039 in sugar transport was supported by the inability of the sal0039 deletion mutant strain to import exogenous sialic acid and to grow in semidefined medium supplemented with this sugar. Furthermore, in vivo evidence showed that the presence of exogenous sialic acid significantly increased the capacity of GBS to infect mice at the mucosal level. These findings suggest that transport of sialic acid may also contribute to GBS infections. PMID- 22829648 TI - Aspergillus nidulans and chronic granulomatous disease: a unique host-pathogen interaction. AB - Invasive fungal infections are a major threat for patients suffering from chronic granulomatous disease (CGD), a primary immunodeficiency caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase. Interestingly, Aspergillus (Emericella) nidulans is the second most encountered mold in CGD patients, causing almost exclusively invasive infections in this specific host, and is characterized by its aggressive behavior. A proper diagnosis is complicated by the often mild clinical presentation, the low sensitivity of the currently used diagnostic tools, and the difficulties in accurate identification of the Emericella species. According to the hitherto accepted view on the role of the NADPH-oxidase in the innate host-defense pathway, the pathogenesis of A. nidulans in CGD cannot be explained. This synopsis covers the current understanding of invasive infections caused by A. nidulans in the CGD patient and is intended to direct further research by indicating gaps in our knowledge and to guide optimal management strategies. PMID- 22829649 TI - Reduction of HIV-1 load in semen during follow-up study of RV144 vaccine trial boosts interest for novel correlates of immune protection in genital mucosa. PMID- 22829650 TI - Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District, Kenya. AB - BACKGROUND: To understand and model the impact of pneumococcal conjugate vaccines at the population level, we need to know the transmission dynamics of individual pneumococcal serotypes. We estimated serotype-specific clearance and acquisition rates of nasopharyngeal colonization among Kenyan children. METHODS: Children aged 3-59 months who were identified as carriers in a cross-sectional survey were followed-up approximately 1, 2, 4, 8, 16, and 32 days later and monthly thereafter until culture of 2 consecutive swabs yielded an alternative serotype or no pneumococcus. Serotype-specific clearance rates were estimated by exponential regression of interval-censored carriage durations. Duration was estimated as the reciprocal of the clearance rate, and acquisition rates were estimated on the basis of prevalence and duration, assuming an equilibrium state. RESULTS: Of 2840 children sampled between October 2006 and December 2008, 1868 were carriers. The clearance rate was 0.032 episodes/day (95% confidence interval [CI], .030-.034), for a carriage duration of 31.3 days, and the rate varied by serotype (P< .0005). Carriage durations for the 28 serotypes with >= 10 carriers ranged from 6.7 to 50 days. Clearance rates increased with year of age, adjusted for serotype (hazard ratio, 1.21; 95% CI, 1.15-1.27). The acquisition rate was 0.061 episodes/day (95% CI, .055-.067), which did not vary with age. Serotype specific acquisition rates varied from 0.0002 to 0.0022 episodes/day. Serotype specific acquisition rates correlated with prevalence (r=0.91; P< .00005) and with acquisition rates measured in a separate study involving 1404 newborns in Kilifi (r=0.87; P< .00005). CONCLUSIONS: The large sample size and short swabbing intervals provide a precise description of the prevalence, duration, and acquisition of carriage of 28 pneumococcal serotypes. In Kilifi, young children experience approximately 8 episodes of carriage per year. The declining prevalence with age is attributable to increasing clearance rates. PMID- 22829651 TI - A new, robust, and nonradioactive approach for exploring N-myristoylation. AB - Myristoyl-CoA (CoA):protein N-myristoyltransferase (NMT) catalyzes protein modification through covalent attachment of a C14 fatty acid (myristic acid) to the N-terminal glycine of proteins, thus promoting protein-protein and protein membrane interactions. NMT is essential for the viability of numerous human pathogens and is also up-regulated in several tumors. Here we describe a new, nonradioactive, ELISA-based method for measuring NMT activity. After the NMT catalyzed reaction between a FLAG-tagged peptide and azido-dodecanoyl-CoA (analog of myristoyl-CoA), the resulting azido-dodecanoyl-peptide-FLAG was coupled to phosphine-biotin by Staudinger ligation, captured by plate-bound anti-FLAG antibodies and detected by streptavidin-peroxidase. The assay was validated with negative controls (including inhibitors), corroborated by HPLC analysis, and demonstrated to function with fresh or frozen tissues. Recombinant murine NMT1 and NMT2 were characterized using this new method. This versatile assay is applicable for exploring recombinant NMTs with regard to their activity, substrate specificity, and possible inhibitors as well as for measuring NMT activity in tissues. PMID- 22829652 TI - A comprehensive method for determination of fatty acids in the initial oral biofilm (pellicle). AB - The acquired pellicle is a tenacious organic layer covering the surface of teeth, protecting the underlying dental hard tissues. Lipids account for about one quarter of the pellicle's dry weight and are assumed to be of considerable importance for their protective properties. Nevertheless, only preliminary information is available about the nature of lipids in the pellicle. Gas chromatography coupled with electron impact ionization mass spectrometry was used to establish a convenient analytical protocol in order to obtain a qualitative and quantitative characterization of a wide range of FAs (C(12)-C(22)). In situ biofilm formation was performed on bovine enamel slabs mounted on individual splints carried by 10 subjects. A modified Folch extraction procedure was adopted to extract the lipids from the detached pellicle, followed by transesterification to fatty acid methyl esters using methanol and concentrated hydrochloric acid. Tridecanoic and nonadecanoic acid were used as internal standards suitable and reliable for robust, precise and accurate measurements. The present study demonstrates, for the first time, a procedure based on a combination of innovative specimen generation and convenient sample preparation with sensitive GC-MS analysis for the determination of the fatty acid profile of the initial oral biofilm. PMID- 22829654 TI - Searching for ways to switch on brown fat: are we getting warmer? AB - Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states. PMID- 22829653 TI - The acyl-CoA binding protein is required for normal epidermal barrier function in mice. AB - The acyl-CoA binding protein (ACBP) is a 10 kDa intracellular protein expressed in all eukaryotic species. Mice with targeted disruption of Acbp (ACBP(-/-) mice) are viable and fertile but present a visible skin and fur phenotype characterized by greasy fur and development of alopecia and scaling with age. Morphology and development of skin and appendages are normal in ACBP(-/-) mice; however, the stratum corneum display altered biophysical properties with reduced proton activity and decreased water content. Mass spectrometry analyses of lipids from epidermis and stratum corneum of ACBP(+/+) and ACBP(-/-) mice showed very similar composition, except for a significant and specific decrease in the very long chain free fatty acids (VLC-FFA) in stratum corneum of ACBP(-/-) mice. This finding indicates that ACBP is critically involved in the processes that lead to production of stratum corneum VLC-FFAs via complex phospholipids in the lamellar bodies. Importantly, we show that ACBP(-/-) mice display a ~50% increased transepidermal water loss compared with ACBP(+/+) mice. Furthermore, skin and fur sebum monoalkyl diacylglycerol (MADAG) levels are significantly increased, suggesting that ACBP limits MADAG synthesis in sebaceous glands. In summary, our study shows that ACBP is required for production of VLC-FFA for stratum corneum and for maintaining normal epidermal barrier function. PMID- 22829655 TI - Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor. AB - Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucine-rich domain (LRD) was predicted using charge charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR B2 to the TSHR. K1-18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1-18 light chain (LC) mimics binding of the TSH-alpha chain and the heavy chain (HC) mimics binding of the TSH beta chain. By contrast, M22 HC mimics the interactions of TSH-alpha while M22 LC mimics TSH-beta in interactions with the TSHR. The observed interactions in the M22-TSHR LRD and K1-70-TSHR LRD complexes (crystal structures) with TSH-TSHR LRD (comparative model) and K1-18-TSHR LRD (predictive binding) suggest that K1-18 and M22 interactions with the receptor may reflect interaction of thyroid stimulating autoantibodies in general. Furthermore, K1-70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general. Interactions involving the C-terminal part of the TSHR LRD may be important for receptor activation by autoantibodies. PMID- 22829657 TI - Perceptual alternations between unbound moving contours and bound shape motion engage a ventral/dorsal interplay. AB - Visual shape and motion information, processed in distinct brain regions, should be combined to elicit a unitary coherent percept of an object in motion. In an fMRI study, we identified brain regions underlying the perceptual binding of motion and shape independently of the features-contrast, motion, and shape-used to design the moving displays. These displays alternately elicited a bound (moving diamond) or an unbound (disconnected moving segments) percept, and were either physically unchanging yet perceptually bistable or physically changing over time. The joint analysis of the blood-oxygen-level-dependent (BOLD) signals recorded during bound or unbound perception with these different stimuli revealed a network comprising the occipital lobe and ventral and dorsal visual regions. Bound percepts correlated with in-phase BOLD increases within the occipital lobe and a ventral area and decreased activity in a dorsal area, while unbound percepts elicited moderate BOLD modulations in these regions. This network was similarly activated by bistable unchanging displays and by displays periodically changing over time. The uncovered interplay between the two regions is proposed to reflect a generic binding process that dynamically weights the perceptual evidence supporting the different shape and motion interpretations according to the reliability of the neural activity in these regions. PMID- 22829658 TI - Temporal dynamics of remapping captured by peri-saccadic continuous motion. AB - Different attention and saccade control areas contribute to space constancy by remapping target activity onto their expected post-saccadic locations. To visualize this dynamic remapping, we used a technique developed by Honda (2006) where a probe moved vertically while participants made a saccade across the motion path. Observers do not report any large excursions of the trace at the time of the saccade that would correspond to the classical peri-saccadic mislocalization effect. Instead, they reported that the motion trace appeared to be broken into two separate segments with a shift of approximately one-fifth of the saccade amplitude representing an overcompensation of the expected retinal displacement caused by the saccade. To measure the timing of this break in the trace, we introduced a second, physical shift that was the same size but opposite in direction to the saccade-induced shift. The trace appeared continuous most frequently when the physical shift was introduced at the midpoint of the saccade, suggesting that the compensation is in place when the saccade lands. Moreover, this simple linear shift made the combined traces appear continuous and linear, with no curvature. In contrast, Honda (2006) had reported that the pre- and post saccadic portion of the trace appeared aligned and that there was often a small, visible excursion of the trace at the time of the saccade. To compare our results more directly, we increased the contrast of our moving probe in a third experiment. Now some observers reported seeing a deviation in the motion path but the misalignment remained present. We conclude that the large deviations at the time of saccade are generally masked for a continuously moving target but that there is nevertheless a residual misalignment between pre- and post-saccadic coordinates of approximately 20% of the saccade amplitude that normally goes unnoticed. PMID- 22829656 TI - Effects of cancer-associated EPHA3 mutations on lung cancer. AB - BACKGROUND: Cancer genome sequencing efforts recently identified EPHA3, which encodes the EPHA3 receptor tyrosine kinase, as one of the most frequently mutated genes in lung cancer. Although receptor tyrosine kinase mutations often drive oncogenic conversion and tumorigenesis, the oncogenic potential of the EPHA3 mutations in lung cancer remains unknown. METHODS: We used immunoprecipitation, western blotting, and kinase assays to determine the activity and signaling of mutant EPHA3 receptors. A mutation-associated gene signature was generated from one large dataset, mapped to another training dataset with survival information, and tested in a third independent dataset. EPHA3 expression levels were determined by quantitative reverse transcription-polymerase chain reaction in paired normal-tumor clinical specimens and by immunohistochemistry in human lung cancer tissue microarrays. We assessed tumor growth in vivo using A549 and H1299 human lung carcinoma cell xenografts in mice (n = 7-8 mice per group). Tumor cell proliferation was measured by bromodeoxyuridine incorporation and apoptosis by multiple assays. All P values are from two-sided tests. RESULTS: At least two cancer-associated EPHA3 somatic mutations functioned as dominant inhibitors of the normal (wild type) EPHA3 protein. An EPHA3 mutation-associated gene signature that was associated with poor patient survival was identified. Moreover, EPHA3 gene copy numbers and/or expression levels were decreased in tumors from large cohorts of patients with lung cancer (eg, the gene was deleted in 157 of 371 [42%] primary lung adenocarcinomas). Reexpression of wild-type EPHA3 in human lung cancer lines increased apoptosis by suppression of AKT activation in vitro and inhibited the growth of tumor xenografts (eg, for H1299 cells, mean tumor volume with wild-type EPHA3 = 437.4 mm(3) vs control = 774.7 mm(3), P < .001). Tumor-suppressive effects of wild-type EPHA3 could be overridden in trans by dominant negative EPHA3 somatic mutations discovered in patients with lung cancer. CONCLUSION: Cancer-associated EPHA3 mutations attenuate the tumor suppressive effects of normal EPHA3 in lung cancer. PMID- 22829660 TI - Variations in the organization and delivery of the 'NHS health check' in primary care. AB - BACKGROUND: To evaluate the organization of the new cardiovascular risk assessment programme, NHS Health Checks, in general practices. METHODS: All 99 general practices in two inner London boroughs were invited to participate in a cross-sectional survey by completing an online questionnaire. RESULTS: Data were analysed for 66/99 (67%) eligible practices. Training attended for delivering the Health Check included measurement methods (43%), delivering risk information (65%) and advising on lifestyle change (62%). The Framingham risk score was used by 66% of practices, the QRisk score by 12% and both by 8%. Advice given to patients identified as high risk was 'usually' brief at 26% of practices, advice was given verbally at 92% of practices, in written form at 74% and through interactive visual materials at 29%. Statins were 'usually' prescribed to high risk patients by 34% of practices and antihypertensive drugs by 22%. The follow up of high-risk patients was by means of a register with regular recall at 51% of general practices. CONCLUSIONS: There is considerable diversity in general practices' implementation of the NHS Health Check. A formal quality assurance process may be required in order to optimize the implementation of the NHS cardiovascular risk assessment programme. PMID- 22829661 TI - The burden and impact of measles among the Gypsy-Traveller communities, Thames Valley, 2006-09. AB - BACKGROUND: Outbreaks of measles in Gypsy-Traveller communities are well recognized. Their contribution to the overall burden of disease is less clear. METHODS: Measles case-management information was collated retrospectively for the Thames Valley population comprising 2.2 million people over the 4-year period from 2006 to 09. Suspected cases notified by general practitioners and hospital clinicians were sent a saliva testing kit. Cases were defined as those whose measles IgM was positive. Risk factor information was collected and collated including vaccination and membership of the Gypsy-Traveller communities. RESULTS: Of 142 cases of laboratory confirmed measles, 63% were in Gypsy-Traveller communities. These included 10 family clusters and outbreaks confined to the Gypsy-Traveller communities and one with a wider spread. The pattern was consistent across the 4 years studied. Among the Gypsy-Traveller communities 27 of 55 cases eligible for measles, mumps and rubella (MMR) vaccination had received one MMR vaccination. Overall seven cases were admitted to hospital with either pneumonia or dehydration. CONCLUSION: These findings showed a more than 100-fold higher incidence in the Gypsy-Traveller communities than the rest of the population. The high burden of disease in the Gypsy-Traveller communities highlights the importance of targeting immunization resources towards these communities. PMID- 22829662 TI - Advantages and limitations of using national administrative data on obstetric blood transfusions to estimate the frequency of obstetric hemorrhages. AB - BACKGROUND: Obstetric hemorrhages are a frequent cause of maternal death all over the world, but are not routinely monitored. Health systems administrative databases could be used for this purpose, but data quality needs to be assessed. OBJECTIVES: Using blood transfusion data recorded in administrative databases to estimate the frequency of obstetric hemorrhages. Research design A population based study. Subjects Validation sub-sample: all mothers who gave birth in a French region in 2006-07 (35 123 pregnancies). Main study: all mothers who gave birth in France in 2006-07 (1 629 537 pregnancies). METHOD: Linkage and comparison of administrative data on blood transfusions with data from the French blood agency ('gold standard'), and, based on this validation, the construction of a multivariable regression model to correct the number of pregnant women identified as having received a transfusion in the national administrative database. RESULTS: The blood transfusion rate observed in the gold standard was 7.120/00. The sensitivity of the administrative data was estimated at 66.3% and the positive predictive value at 91.3%. The estimated total number of pregnant women who received blood transfusions in France in 2006-07 was 10 941 (6.710/00). CONCLUSIONS: The administrative data, available in most countries, can be used to estimate the frequency of obstetric hemorrhages. PMID- 22829663 TI - Epidemiology of clinical body mass index recording in an obese population in primary care: a cohort study. AB - BACKGROUND: Protecting and promoting the health of obese people is an important public health concern. This study evaluated the recording of body mass index and medical diagnostic codes for obesity in obese patients in UK primary care. METHODS: A cohort study was implemented in the UK General Practice Research Database. Subjects were aged 18-100 years and were diagnosed with obesity between 1997 and 2007. The frequency of obesity monitoring was evaluated. RESULTS: There were 67 000 obese patients at 127 family practices. The proportion of obese patients with no annual body mass index (BMI) record reached 65% of men and 63% of women in 2000, declining to 55 and 48% in 2009. Medical diagnostic codes for obesity were infrequently recorded. The mean BMI of obese patients increased to 35.5 kg/m(2) [95% confidence interval (CI): 35.4-35.7] in men and 37.0 kg/m(2) (95% CI: 36.9-37.1) in women by 2009. In 2009, 37% of obese men with BMI records, and 39% of women, showed a BMI increase of >=1 kg/m(2) since the previous reading. CONCLUSIONS: Obese patients do not have BMI values recorded regularly. The mean BMI of obese patients, and the proportion gaining weight over time, is increasing. Improved strategies for monitoring and managing obesity are required. PMID- 22829665 TI - Reconstitution of the central and peripheral nervous system during salamander tail regeneration. AB - We show that after tail amputation in Ambystoma mexicanum (Axolotl) the correct number and spacing of dorsal root ganglia are regenerated. By transplantation of spinal cord tissue and nonclonal neurospheres, we show that the central spinal cord represents a source of peripheral nervous system cells. Interestingly, melanophores migrate from preexisting precursors in the skin. Finally, we demonstrate that implantation of a clonally derived spinal cord neurosphere can result in reconstitution of all examined cell types in the regenerating central spinal cord, suggesting derivation of a cell with spinal cord stem cell properties. PMID- 22829666 TI - Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions. AB - In rodent sensory neurons, acid-sensing ion channel 3 (ASIC3) has recently emerged as a particularly important sensor of nonadaptive pain associated with tissue acidosis. However, little is known about the human ASIC3 channel, which includes three splice variants differing in their C-terminal domain (hASIC3a, hASIC3b, and hASIC3c). hASIC3a transcripts represent the main mRNAs expressed in both peripheral and central neuronal tissues (dorsal root ganglia [DRG], spinal cord, and brain), where a small proportion of hASIC3c transcripts is also detected. We show that hASIC3 channels (hASIC3a, hASIC3b, or hASIC3c) are able to directly sense extracellular pH changes not only during acidification (up to pH 5.0), but also during alkalization (up to pH 8.0), an original and inducible property yet unknown. When the external pH decreases, hASIC3 display a transient acid mode with brief activation that is relevant to the classical ASIC currents, as previously described. On the other hand, an external pH increase activates a sustained alkaline mode leading to a constitutive activity at resting pH. Both modes are inhibited by the APETx2 toxin, an ASIC3-type channel inhibitor. The alkaline sensitivity of hASIC3 is an intrinsic property of the channel, which is supported by the extracellular loop and involves two arginines (R68 and R83) only present in the human clone. hASIC3 is thus able to sense the extracellular pH in both directions and therefore to dynamically adapt its activity between pH 5.0 and 8.0, a property likely to participate in the fine tuning of neuronal membrane potential and to neuron sensitization in various pH environments. PMID- 22829667 TI - Unconventional initiator tRNAs sustain Escherichia coli. AB - Of all tRNAs, initiator tRNA is unique in its ability to start protein synthesis by directly binding the ribosomal P-site. This ability is believed to derive from the almost universal presence of three consecutive G-C base (3G-C) pairs in the anticodon stem of initiator tRNA. Consistent with the hypothesis, a plasmid-borne initiator tRNA with one, two, or all 3G-C pairs mutated displays negligible initiation activity when tested in a WT Escherichia coli cell. Given this, the occurrence of unconventional initiator tRNAs lacking the 3G-C pairs, as in some species of Mycoplasma and Rhizobium, is puzzling. We resolve the puzzle by showing that the poor activity of unconventional initiator tRNAs in E. coli is because of competition from a large pool of the endogenous WT initiator tRNA (possessing the 3G-C pairs). We show that E. coli can be sustained on an initiator tRNA lacking the first and third G-C pairs; thereby reducing the 3G-C rule to a mere middle G-C requirement. Two general inferences following from our findings, that the activity of a mutant gene product may depend on its abundance in the cell relative to that of the WT, and that promiscuous initiation with elongator tRNAs has the potential to enhance phenotypic diversity without affecting genomic integrity, have been discussed. PMID- 22829668 TI - Safety control for apoptotic irreversibility. PMID- 22829670 TI - Hurricane wind fields needed to assess risk to offshore wind farms. PMID- 22829671 TI - Suspect cubic diamond "impact" proxy and a suspect lonsdaleite identification. PMID- 22829672 TI - Inconsistent redefining of the carbon spherule "impact" proxy. PMID- 22829673 TI - Age models and the Younger Dryas Impact Hypothesis. PMID- 22829674 TI - Paleoecological changes at Lake Cuitzeo were not consistent with an extraterrestrial impact. PMID- 22829675 TI - Inconsistent impact hypotheses for the Younger Dryas. PMID- 22829669 TI - Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis. AB - Chronic hepatitis C may follow a mild and stable disease course or progress rapidly to cirrhosis and liver-related death. The mechanisms underlying the different rates of disease progression are unknown. Using serial, prospectively collected samples from cases of transfusion-associated hepatitis C, we identified outcome-specific features that predict long-term disease severity. Slowly progressing disease correlated with an early alanine aminotransferase peak and antibody seroconversion, transient control of viremia, and significant induction of IFN-gamma and MIP-1beta, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease correlated with persistent and significant elevations of alanine aminotransferase and the profibrogenic chemokine MCP-1 (CCL-2), greater viral diversity and divergence, and a higher rate of synonymous substitution. This study suggests that the long term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of hepatitis C virus and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis. PMID- 22829676 TI - Variation in Candida albicans EFG1 expression enables host-dependent changes in colonizing fungal populations. AB - To understand differences in host-Candida albicans interactions that occur during colonization of healthy or compromised hosts, production of phenotypic variants and colonization of healthy or immunodeficient mice by C. albicans were studied. We showed that activity of the transcription factor Efg1p exhibited cell-to-cell variability and identified Efg1p as a major regulator of colonization. In C. albicans populations colonizing the murine gastrointestinal tract, average expression of EFG1 differed depending on the immune status of the host. We propose that cellular heterogeneity in Efg1p activity allows the C. albicans colonizing population to differ depending on the immune status of the host, because selective pressure from a healthy host alters the composition of the population. These data are the first demonstration that differences in host immune status are associated with differences in gene expression in colonizing C. albicans cells. Altered gene expression in organisms colonizing immunocompromised hosts may begin the transition of C. albicans from a commensal to a pathogen. IMPORTANCE: In healthy people, the fungus Candida albicans colonizes the gastrointestinal tract and other sites without producing obvious pathology. In an immunocompromised patient, the organism can cause serious disease. The demonstration that the expression and activity of the C. albicans transcription factor Efg1p differs during colonization of healthy or immunocompromised mice shows that the organism adjusts its physiology when colonizing different hosts. Further, the effects of a healthy host on a heterogeneous C. albicans population containing cells with different levels of Efg1p activity show that selective pressure in the host can change the makeup of the population, allowing the population to respond to host immune status. The ability to sense host status may be key to the ability of C. albicans to colonize as a harmless commensal in some hosts but become a deadly pathogen in others. PMID- 22829677 TI - A herpes simplex virus 1 (McKrae) mutant lacking the glycoprotein K gene is unable to infect via neuronal axons and egress from neuronal cell bodies. AB - We have shown that the herpes simplex virus 1 (HSV-1) gK gene is essential for efficient replication and spread in the corneal epithelium and trigeminal ganglion neuroinvasion in mice (A. T. David, A. Baghian, T. P. Foster, V. N. Chouljenko, and K. G. Kousoulas, Curr. Eye Res. 33:455-467, 2008). To further investigate the role of gK in neuronal infection, we utilized a microfluidic chamber system separating neuronal cell bodies and axonal termini. HSV-1 (McKrae) engineered virus constitutively expressing enhanced green fluorescence protein (GFP) was efficiently transmitted in both a retrograde and an anterograde manner. These results were corroborated by expression of virion structural proteins in either chamber, as well as detection of viral genomes and infectious viruses. In contrast, efficient infection of either chamber with a gK-null virus did not result in infection of the apposed chamber. These results show that gK is an important determinant in virion axonal infection. Moreover, the inability of the gK-null virus to be transmitted in an anterograde manner suggests that virions acquire cytoplasmic envelopes prior to entering axons. IMPORTANCE: Herpes simplex virus 1 (HSV-1) enters mucosal epithelial cells and neurons via fusion of the viral envelope with cellular membranes, mediated by viral glycoprotein B (gB) in cooperation with other viral glycoproteins. Retrograde transport of virions to neuronal cell bodies (somata) establishes lifelong latent infection in ganglionic neurons. We have previously reported that gK binds gB and is required for gB mediated membrane fusion (Jambunatathan et al., J. Virol. 85:12910-12918, 2011; V. N. Chouljenko, A. V. Iyer, S. Chowdhury, J. Kim, and K. G. Kousoulas, J. Virol. 84:8596-8606, 2010). In the current study, we constructed a recombinant virus with the gK gene deleted in the highly virulent ocular HSV-1 strain McKrae. This recombinant virus failed to infect rat ganglionic neuronal axons alone or cocultured with Vero cells in microfluidic chambers. In addition, lack of gK expression prevented anterograde transmission of virions. These results suggest that gK is a critical determinant for neuronal infection and transmission. PMID- 22829679 TI - Enterococcus faecalis produces abundant extracellular structures containing DNA in the absence of cell lysis during early biofilm formation. AB - Enterococcus faecalis is a common Gram-positive commensal bacterium of the metazoan gastrointestinal tract capable of biofilm formation and an opportunistic pathogen of increasing clinical concern. Dogma has held that biofilms are slow growing structures, often taking days to form mature microcolonies. Here we report that extracellular DNA (eDNA) is an integral structural component of early E. faecalis biofilms (<=4 h postinoculation). Combining cationic dye-based biofilm matrix stabilization techniques with correlative immuno-scanning electron microscopy (SEM) and fluorescent techniques, we demonstrate that--in early E. faecalis biofilms--eDNA localizes to previously undescribed intercellular filamentous structures, as well as to thick mats of extruded extracellular matrix material. Both of these results are consistent with previous reports that early biofilms are exquisitely sensitive to exogenous DNase treatment. High-resolution SEM demonstrates a punctate labeling pattern in both structures, suggesting the presence of an additional, non-DNA constituent. Notably, the previously described fratricidal or lytic mechanism reported as the source of eDNA in older (>=24 h) E. faecalis biofilms does not appear to be at work under these conditions; extensive visual examination by SEM revealed a striking lack of lysed cells, and bulk biochemical assays also support an absence of significant lysis at these early time points. In addition, some cells demonstrated eDNA labeling localized at the septum, suggesting the possibility of DNA secretion from metabolically active cells. Overall, these data are consistent with a model in which a subpopulation of viable E. faecalis cells secrete or extrude DNA into the extracellular matrix. IMPORTANCE: This paper reports the production of extracellular DNA during early biofilm formation in Enterococcus faecalis. The work is significant because the mechanism of eDNA (extracellular DNA) production is independent of cell lysis and the DNA is confined to well-defined structures, suggesting a novel form of DNA secretion by viable cells. Previous models of biofilm formation in enterococci and related species propose cell lysis as the mechanism of DNA release. PMID- 22829678 TI - The metal ion-dependent adhesion site motif of the Enterococcus faecalis EbpA pilin mediates pilus function in catheter-associated urinary tract infection. AB - Though the bacterial opportunist Enterococcus faecalis causes a myriad of hospital-acquired infections (HAIs), including catheter-associated urinary tract infections (CAUTIs), little is known about the virulence mechanisms that it employs. However, the endocarditis- and biofilm-associated pilus (Ebp), a member of the sortase-assembled pilus family, was shown to play a role in a mouse model of E. faecalis ascending UTI. The Ebp pilus comprises the major EbpC shaft subunit and the EbpA and EbpB minor subunits. We investigated the biogenesis and function of Ebp pili in an experimental model of CAUTI using a panel of chromosomal pilin deletion mutants. A nonpiliated pilus knockout mutant (EbpABC( ) strain) was severely attenuated compared to its isogenic parent OG1RF in experimental CAUTI. In contrast, a nonpiliated ebpC deletion mutant (EbpC(-) strain) behaved similarly to OG1RF in vivo because it expressed EbpA and EbpB. Deletion of the minor pilin gene ebpA or ebpB perturbed pilus biogenesis and led to defects in experimental CAUTI. We discovered that the function of Ebp pili in vivo depended on a predicted metal ion-dependent adhesion site (MIDAS) motif in EbpA's von Willebrand factor A domain, a common protein domain among the tip subunits of sortase-assembled pili. Thus, this study identified the Ebp pilus as a virulence factor in E. faecalis CAUTI and also defined the molecular basis of this function, critical knowledge for the rational development of targeted therapeutics. IMPORTANCE: Catheter-associated urinary tract infections (CAUTIs), one of the most common hospital-acquired infections (HAIs), present considerable treatment challenges for physicians. Inherently resistant to several classes of antibiotics and with a propensity to acquire vancomycin resistance, enterococci are particularly worrisome etiologic agents of CAUTI. A detailed understanding of the molecular basis of Enterococcus faecalis pathogenesis in CAUTI is necessary for the development of preventative and therapeutic strategies. Our results elucidated the importance of the E. faecalis Ebp pilus and its subunits for enterococcal virulence in a mouse model of CAUTI. We further showed that the metal ion-dependent adhesion site (MIDAS) motif in EbpA is necessary for Ebp function in vivo. As this motif occurs in other sortase-assembled pili, our results have implications for the molecular basis of virulence not only in E. faecalis CAUTI but also in additional infections caused by enterococci and other Gram-positive pathogens. PMID- 22829680 TI - Cystic fibrosis: detecting changes in airway inflammation with FDG PET/CT. AB - PURPOSE: To determine if fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) imaging can depict a treatment effect from intravenous antibiotics for pulmonary exacerbation in cystic fibrosis (CF). MATERIALS AND METHODS: The study was approved by the institutional review board of the Hospital for Sick Children and by Health Canada. Consent was obtained from all subjects. Patients with CF who were between 6 and 18 years of age and were admitted for a pulmonary exacerbation were eligible for the study. FDG PET/CT examinations (with low-dose CT) were performed on days 1 and 14 of admission (+/ 72 hours). PET activity was quantified by using standardized uptake values (SUVs) through assessment of background activity (mean SUV [SUV(mean)]) and superimposed focal uptake (maximum SUV [SUV(max)]) for each lung zone. CT studies were scored by using the CF-CT model. SUVs from pre- and posttherapy studies were compared by using paired t tests. Unpaired t tests were used to compare data in patients with CF and data in 10 control subjects. RESULTS: Twenty patients with CF were enrolled. Antibiotic therapy resulted in a significant decrease in SUV(max) (mean difference, 2.3 +/- 2.1 [standard deviation], P < .0001). Pretherapy SUV(max) and SUV(mean) and posttherapy SUV(max) were significantly different from those in control subjects. The change in SUV(max) and percentage predicted forced expiratory volume in 1 second was negatively correlated. (R = -0.72, P = .004). Overall CF-CT scores significantly correlated with SUV(max) (R = 0.40, P = .01). CONCLUSION: FDG PET/CT is a useful tool for detecting inflammatory changes resulting from treatment for pulmonary exacerbations in pediatric patients with CF. Inflammatory changes detected by using FDG PET/CT correlated with lung function, sputum neutrophil counts, and CF-CT scores. Analyzing focal lung inflammation (with SUV(max)) may be a feasible way to measure airway inflammation in patients with CF. PMID- 22829681 TI - Working memory in patients with mild traumatic brain injury: functional MR imaging analysis. AB - PURPOSE: To analyze brain activation patterns in response to tests of working memory after a mild traumatic brain injury (MTBI). MATERIALS AND METHODS: Research ethics committee approval and patient written informed consent were obtained. Brain activation patterns in response to n-back working memory tasks (n = 1, 2, 3) were assessed with functional magnetic resonance (MR) imaging in 20 patients with MTBI within 1 month after their injury and in 18 healthy control subjects. In n-back working memory tasks, participants monitored a series of number stimuli and were to indicate when the presented number was the same as that presented n back previously. Nine (45%) MTBI patients underwent follow-up functional MR imaging studies 6 weeks later. Digit span, a memory test for how many numbers a person can remember in sequence, and continuous performance test (CPT), a test that measures a person's sustained and selective attention and impulsivity, were also performed before functional MR imaging studies and outside the imager for each participant. Clinical data were analyzed by using t and chi(2) tests. Within-group, between-group, and initial and follow-up differences of functional MR imaging data were analyzed by using one-sample, two-sample, and paired t tests, respectively. RESULTS: Groups were similar for sex (P = .75), years of education (P = .069), digit span (P = .37 for total score), CPT (P = .31, .27, and .43 for omission error, commission error, and hit reaction time, respectively), and accuracy of n-back working memory performance (P = .90, .11, and .39 for one-, two-, and three-back tasks, respectively). Brain activation patterns differed between MTBI patients and controls in response to increasing working memory loads (P < .01, uncorrected). Control subjects maintained their ability to increase activation in the working memory circuitry with each increase in working memory load. In contrast, MTBI patients were impaired in their ability to increase activation in working memory circuitry under both moderate and high working memory load conditions. However, MTBI patients did show cerebral plasticity, as evidenced by more activation in some areas outside and inside the working memory circuitry as compared with control subjects (P < .01, uncorrected). In the 6-week follow-up study, compared with baseline, MTBI patients showed an improvement of activation in response to increasing working memory loads (P < .05, uncorrected). CONCLUSION: MTBI-induced differences in working memory functional activity were observed even though differences in behavioral performance between MTBI patients and controls were absent, which suggests that this approach may increase sensitivity to MTBI compared with neuropsychological evaluation alone. PMID- 22829682 TI - Delayed parkinsonism after CO intoxication: evaluation of the substantia nigra with inversion-recovery MR imaging. AB - PURPOSE: To quantitatively investigate signal alterations of the substantia nigra in patients with delayed parkinsonism following CO intoxication, as seen on gray matter (GM)-suppressed inversion-recovery (IR) magnetic resonance (MR) images. MATERIALS AND METHODS: This prospective study was approved by the local institutional review board, and written informed consent was obtained from all subjects. Thirteen patients with delayed onset of CO-induced parkinsonism (nine men and four women; mean age, 40.3 years), 13 age-matched CO-intoxicated patients without parkinsonism, and 13 age-matched healthy volunteers were examined with GM suppressed IR MR imaging. The signal intensity of the substantia nigra was normalized to the adjacent normal-appearing white matter in the temporal lobe, followed by semiautomatic segmentation into medial, middle, and lateral parts by using a skeleton-based algorithm. Multivariate and univariate analyses and Spearman rank correlation test were performed to examine the relationships between variables. Clinical severity was assessed with the modified Hoehn and Yahr rating scale. RESULTS: The normalized signal ratios in the middle and lateral segments of the substantia nigra were significantly higher in those with CO-induced parkinsonism, compared with those with CO intoxication without parkinsonism or normal volunteers (P=.02). For the medial segments, the ratios showed no significant differences among the groups. The normalized signal ratios of substantia nigra were correlated with the severity of parkinsonism, particularly in the lateral segments (rho=0.927, P<.001). CONCLUSION: CO toxicity to the substantia nigra plays a role in pathophysiologic mechanisms of CO-induced parkinsonism. GM-suppressed IR MR imaging is a useful tool in depicting substantia nigra injury following CO intoxication. PMID- 22829683 TI - Renal cortical tumors: use of multiphasic contrast-enhanced MR imaging to differentiate benign and malignant histologic subtypes. AB - PURPOSE: To investigate the use of quantitative multiphasic contrast material enhanced magnetic resonance (MR) imaging in differentiating between common benign and malignant histologic subtypes of renal cortical tumors. MATERIALS AND METHODS: The institutional review board waived informed consent and approved this retrospective HIPAA-compliant study of 138 patients who underwent preoperative contrast-enhanced MR imaging during the period of January 2004-December 2008. At surgery, 152 renal tumors were identified (77 clear cell, 22 papillary, 18 chromophobe, and 10 unclassified carcinomas; 16 oncocytomas; nine angiomyolipomas). Three readers independently identified and measured the most enhanced area in each tumor and placed corresponding regions of interest in similar positions on images from the precontrast, corticomedullary, nephrographic, and excretory phases. The percentage change in signal intensity (%SI change) between precontrast imaging and each postcontrast phase was calculated. Interreader agreement was evaluated by using the overall concordance correlation coefficient (OCC). A linear mixed-effects model was used to estimate and compare the trajectories of the means of log %SI change across all phases between the six histologic subtypes. RESULTS: Interreader agreement was substantial to almost perfect (OCC, 0.77-0.88). The %SI change differed significantly between clear cell carcinomas and papillary and chromophobe carcinomas in all phases of enhancement (P < .0001-.0120). In addition, %SI change was significantly higher in angiomyolipomas than in clear cell carcinomas, but only in the corticomedullary phase (P = .0231). Enhancement did not differ significantly between clear cell carcinoma and oncocytoma in any phase (P = .2081 .6000). CONCLUSION: Quantitative multiphase contrast-enhanced MR imaging offers a widely available, reproducible method to characterize several histologic subtypes of renal cortical tumors, although it does not aid differentiation between clear cell carcinomas and oncocytomas. PMID- 22829684 TI - Quantification of coronary artery calcium on the basis of dual-energy coronary CT angiography. AB - PURPOSE: To evaluate the feasibility of using virtual noncontrast material enhanced (VNC) computed tomographic (CT) series derived from dual-energy CT imaging studies for coronary artery calcium quantification. MATERIALS AND METHODS: This HIPAA-compliant study was institutional review board approved; all patients provided written informed consent. Thirty-six patients prospectively underwent noncontrast-enhanced CT calcium scoring followed by coronary CT angiography performed in dual-energy mode. By using different reconstruction algorithms, three VNC series were generated and evaluated for noise and efficiency of virtual iodine removal. Two readers independently quantified calcium on VNC images and true noncontrast-enhanced conventional calcium scoring series. A leave-one-out cross validation was used to assess the accuracy of calcium score prediction from VNC series by means of linear regression. RESULTS: CT value histograms of the VNC series closely resembled the profile in the true noncontrast-enhanced series. There was excellent correlation between calcium volumes on the VNC series and true noncontrast-enhanced series on a per-patient (r = 0.94, P < .001, n = 36) and per-vessel (r = 0.94, 0.91, and 0.92 for the three coronary arteries, all P < .001, n = 36 each) level. The ability of a linear regression model to predict actual calcium scores from calcium volumes on VNC series was excellent (r = 0.82). Multiethnic Study of Atherosclerosis rankings that were derived from the predicted calcium scores also showed excellent agreement (intraclass correlation coefficient = 0.909). CONCLUSION: Coronary artery calcium identification and quantification based on dual-energy coronary CT angiographic studies may obviate the need for dedicated CT calcium scoring studies. PMID- 22829685 TI - Primary postpartum hemorrhage: outcome of pelvic arterial embolization in 251 patients at a single institution. AB - PURPOSE: To evaluate the safety and efficacy of pelvic arterial embolization (PAE) for the treatment of primary postpartum hemorrhage (PPH) and to determine the factors associated with clinical outcomes. MATERIALS AND METHODS: This retrospective single-center study was institutional review board approved, and informed consent was waived. Outcomes were analyzed in 251 patients who underwent PAE for primary PPH between January 2000 and February 2011. Mode of delivery, causes of bleeding, detailed laboratory and treatment records, and clinical outcomes were recorded. Clinical success was defined as cessation of bleeding after initial session of PAE without the need for additional PAE or surgery. Univariate and multivariate analyses were performed to determine the factors related to clinical outcomes. RESULTS: The clinical success rate was 86.5% (217 of 251). Among the 34 failed cases, 12 underwent repeat PAE, 16 underwent additional surgery, and three recovered with conservative management. Overall bleeding control was achieved in 98.0% (246 of 251) of the patients. Overall mortality was 2% (five of 251) after the first (n = 3) or second (n = 1) session of PAE or additional surgery (n = 1). Among the 113 patients with long-term follow-up, 110 (97.3%) maintained a regular menstrual cycle and 11 had successful pregnancies. Univariate analysis showed that cesarean section delivery, disseminated intravascular coagulation (DIC), and massive transfusion of more than 10 red blood cell units were related to failed PAE. Multivariate analysis showed that DIC (odds ratio, 0.36; P = .04) and massive transfusion (odds ratio, 0.10; P < .001) were significantly related to clinical failure. CONCLUSION: PAE is safe and effective for managing primary PPH. Patients with DIC and massive transfusion were likely to have poor results after PAE. PMID- 22829686 TI - Solitary pulmonary nodular lung adenocarcinoma: correlation of histopathologic scoring and patient survival with imaging biomarkers. AB - PURPOSE: To evaluate the usefulness of histopathologic scoring for survival prediction in patients with solitary pulmonary nodular (SPN) lung adenocarcinomas and to correlate the histopathologic scoring with the results of computed tomography (CT) and fluorine 18 fluorodeoxyglucose positron emission tomography (PET)/CT. MATERIALS AND METHODS: This retrospective study was institutional review board approved and the requirement for informed consent was waived. A total of 148 patients with SPN lung adenocarcinoma underwent PET/CT and CT. Correlations between histopathologic scores estimated by using two predominant histologic subtypes from each surgically resected specimen and the mass of the nodule at CT or maximum standardized uptake value (SUV(max)) at PET/CT were assessed. Disease-free survival (DFS) was estimated by using the Kaplan-Meier method, and the log-rank test was used to evaluate differences in each histopathologic subtype. RESULTS: In 135 (91%) patients, tumors had a mixed subtype. The most frequently observed histologic subtypes, in decreasing order, were acinar (51%), lepidic (18%), solid (10%), and papillary (9%). DFS rates at 5 years were higher than 90% for the group of patients with nodules that showed the lepidic growth pattern, and 50% for patients with nodules that showed the micropapillary pattern. The pathologic score proved to be a significant predictor of DFS (P < .001). Both SUV(max) and the mass of the nodule were closely correlated with pathologic score. CONCLUSION: Pathologic scoring appears to help predict DFS in patients with SPN lung adenocarcinoma and shows close correlation with imaging biomarkers including the mass of the nodule at CT and SUV(max) at PET/CT. PMID- 22829687 TI - Escherichia coli lipopolysaccharide administration transiently suppresses luteal structure and function in diestrous cows. AB - The objective was to characterize the effects of Escherichia coli lipopolysaccharide (LPS) endotoxin (given i.v.) on luteal structure and function. Seven nonlactating German Holstein cows, 5.1 +/- 0.8 years old (mean +/- s.e.m.), were given 10 ml saline on day 10 (ovulation=day 1) of a control estrous cycle. On day 10 of a subsequent cycle, they were given 0.5 MUg/kg LPS. Luteal size decreased (from 5.2 to 3.8 cm2, P<=0.05) within 24 h after LPS treatment and remained smaller throughout the remainder of the cycle. Luteal blood flow decreased by 34% (P<=0.05) within 3 h after LPS and remained lower for 72 h. Plasma progesterone (P4) concentrations increased (P<=0.05) within the first 3 h after LPS but subsequently declined. Following LPS treatment, plasma prostaglandin (PG) F metabolites concentrations were approximately tenfold higher in LPS-treated compared with control cows (9.2 vs 0.8 ng/ml, P<=0.05) within 30 min, whereas plasma PGE concentrations were nearly double (P<=0.05) at 1 h after LPS. At 12 h after treatment, levels of mRNA encoding Caspase-3 in biopsies of the corpus luteum (CL) were increased (P<=0.05), whereas those encoding StAR were decreased (P<=0.05) in cattle given LPS vs saline. The CASP3 protein was localized in the cytoplasm and/or nuclei of luteal cells, whereas StAR was detected in the cytosol of luteal cells. In the estrous cycle following treatment with either saline or LPS, there were no significant differences between groups on luteal size, plasma P4 concentrations, or gene expression. In conclusion, LPS treatment of diestrus cows transiently suppressed both the structure and function of the CL. PMID- 22829688 TI - Histological and endocrine characterisation of the annual luteal activity in Eurasian lynx (Lynx lynx). AB - Lynx presents a unique sexual cycle with persistent corpora lutea (CLs) and elevated serum progesterone (P4) throughout parturition and lactation. In other mammals, CLs normally disintegrate after parturition, therefore the aim of our study was to characterise the annual life cycle of lynx CLs. Ovaries from Eurasian lynxes were obtained from the National Veterinary Institute in Sweden, where tissues from killed lynx were stored at -20 degrees C. Ovaries from 66 animals were weighed; each corpus luteum was segmented for histology and hormone analysis. Ovary and CLs weights were constant throughout the year, peaking during pregnancy. In non-pregnant lynxes, the seasonal level of intraluteal steroids was steady for P4 (3.2+/-1.9 s.d. MUg/g, n=53) and total oestrogens (18.3+/-15.5 s.d. ng/g, n=53). Within histology slides, structurally intact luteal cells were found throughout the year with the highest incidence in March/April; evidence of luteal regression was predominantly found in post-breeding season. Ovaries from pregnant animals contained two types of CLs. Group A was bigger in size with large luteal cells (P4, 72.3+/-65.4 s.d. MUg/g; oestrogen, 454.0+/-52.4 s.d. ng/g). In contrast, group B were smaller, with greater luteal regression and lower steroid concentrations (P4, 8.3+/-2.9 s.d. MUg/g; oestrogen, 31.5+/-20.4 s.d. ng/g). Our results suggest that structural luteolysis proceeds throughout the year and into next breeding cycle, resulting in two CLs types on the same ovary. PMID- 22829689 TI - Comparison of patient characteristics and gout-related health-care resource utilization and costs in patients with frequent versus infrequent gouty arthritis attacks. AB - OBJECTIVE: To examine the association between frequent gouty arthritis and the presence of absolute/relative contraindications to gout therapies, and health care expenditure associated with frequent gouty arthritis. METHODS: This retrospective study used administrative claims to identify patients with gouty arthritis between 1 July 2005 and 30 June 2010. Patients with >=3 yearly gouty arthritis attacks (frequent gout) were matched 1:2 to patients with <3 yearly attacks (infrequent gout). Absolute and relative contraindications to gout medications were evaluated based on product labelling. Negative binomial regression and generalized linear models with logarithmic transformation were used for multivariate analysis of overall and gout-related health-care use and cost. RESULTS: Mean patient age was 58 years (n = 15 669) and 77% were men. Compared with patients with infrequent gout, those with frequent gout had higher rates of absolute/relative contraindications to NSAIDs (91.5% vs 78.7%, P < 0.0001), corticosteroids (96.4% vs 87.3%, P < 0.0001), allopurinol (51.0% vs 41.2%, P < 0.0001) and probenecid (13.4% vs 9.4%, P < 0.0001). Mean gout-related costs were $889 for frequent gout vs $210 for infrequent gout (P < 0.0001) and all-cause direct costs were $10 913 for frequent vs $10 685 for infrequent gout (P = ns). Mean all-cause outpatient visits among patients with comorbidities compared with those without were 25.8 vs 11.8 among frequent and 19.7 vs 9.0 among infrequent (both P < 0.001) groups. Gout-related costs were higher among frequent gout patients with comorbidities than those without comorbidities ($886 vs $513, P = 0.03). CONCLUSION: Patients with frequent gouty arthritis are likely to have absolute and/or relative contraindications to gout medications and higher gout-related treatment costs. PMID- 22829690 TI - Peroxisome proliferator-activated receptor-gamma expression in monocytes/macrophages from rheumatoid arthritis patients: relation to disease activity and therapy efficacy--a pilot study. AB - OBJECTIVES: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is expressed by different cell types in the joints and plays a relevant anti inflammatory role in various diseases. This pilot study aimed to evaluate PPARgamma expression in monocytes/macrophages isolated from RA patients as compared with healthy subjects, the relationships between PPARgamma expression, MMP-9 activity and disease, and the influence of therapy with anti-rheumatic drugs on these parameters. METHODS: Thirty RA patients of both sexes (treated with CSs and MTX, mainly) and 15 healthy volunteers were enrolled in this study. Disease severity was evaluated by the 28-joint disease activity score (DAS-28). Monocytes and monocyte-derived macrophages (MDMs) were isolated by standard procedures. PPARgamma protein and mRNA expression were assessed by immunoblotting and real-time PCR, respectively; MMP-9 activity was determined by gelatin zymography. Moreover, we checked the ability of 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ, a PPARgamma agonist), MTX and methylprednisolone (MP) to affect PPARgamma expression and lipopolysaccharide (LPS)-induced MMP-9 activity. RESULTS: Monocytes/MDMs from RA patients have significantly enhanced PPARgamma expression (both protein and mRNA) and MMP-9 activity as compared with healthy donors. Interestingly, cells from patients with less active disease (DAS 28 <3.2) present higher PPARgamma protein expression and lower MMP-9 activity than RA patients with DAS-28 >3.2. At therapeutic concentrations, MTX and MP increase in vitro PPARgamma protein expression and inhibit LPS-induced MMP-9 activity. CONCLUSION: PPARgamma expression in human monocytes/MDMs could represent an indicator of disease activity and therapy efficacy in RA because patients with a DAS-28 score <3.2 show the highest expression. PMID- 22829691 TI - Comparison of joint destruction between standard- and low-dose etanercept in rheumatoid arthritis from the Prevention of Cartilage Destruction by Etanercept (PRECEPT) study. AB - OBJECTIVE: To evaluate the prevention of joint destruction and clinical efficacy of low-dose etanercept (ETN) (25 mg/week) compared with standard-dose ETN (50 mg/week) in RA. METHODS: In this prospective, randomized, open-label study, 70 patients were assigned to receive ETN at either 50 or 25 mg/week for 52 weeks. The primary endpoint was the variation in modified total Sharp score (mTSS), and secondary endpoints were variations in disease activity score in 28 joints (DAS 28), modified HAQ and adverse event rate. Values of mTSS were calculated at baseline and after 52 weeks. Non-progression was estimated as DeltamTSS <=0.5, and the non-progression rate was compared between groups. RESULTS: Mean values at baseline were as follows: disease duration 9.2 years; DAS-28 5.45; and annual progression of mTSS 26.1. No significant differences in background were seen between groups. At 52 weeks, the non-progression rate was significantly less in the 25 mg/week group (36.7%) than in the 50 mg/week group (67.7%) (P = 0.041). Mean DeltamTSS was higher at 25 mg/week (1.03) than at 50 mg/week (-0.13). DAS-28 was significantly improved at 4 weeks, and the effect of treatment lasted for 52 weeks in both groups. No differences in adverse event rates were seen between groups. CONCLUSION: Low-dose ETN is not inferior to standard-dose ETN in terms of effects on clinical manifestations. However, in terms of the radiographic non progression rate, the effects of low-dose ETN may be inferior to the effects of standard-dose ETN. TRIAL REGISTRATION: UMIN Clinical Trials Registry, http://www.umin.ac.jp/ctr/, UMIN000001798. PMID- 22829693 TI - Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. PMID- 22829694 TI - Malignancy as a comorbidity in rheumatic diseases. AB - Patients with systemic autoimmune rheumatic diseases, particularly RA, SLE, SS and idiopathic inflammatory myopathies, are at increased risk of developing malignancies. Cancer occurrence adds to the disease burden in these patients, adversely affecting quality of life and life expectancy. This risk is related to the pathobiology of the underlying rheumatic disease including the inflammatory burden, immunological defects, and personal and environmental exposure such as smoking and some viral infections. Immunomodulatory therapies, especially chemotherapeutic agents, are also associated with an increased risk of cancer in these conditions. The decision to use immunomodulating therapies in patients with rheumatic disease must take into account the disease severity, expectations for disease control, comorbidities and host and environmental risk factors for cancer. Effective screening and monitoring strategies are important in reducing the risk of cancer in these patients. PMID- 22829695 TI - [18F]fluorodeoxyglucose positron emission tomography imaging in a case of relapsing polychondritis. PMID- 22829696 TI - A spurious haemoglobin A(1c) result associated with double heterozygote for haemoglobin Raleigh (beta1[NA1]Val -> Ala) and alpha(+)-thalassaemia. AB - BACKGROUND: Accurate measurement of haemoglobin A(1c) (HbA(1c)) is useful for long-term glycaemic control in patients with diabetes. Many Hb variants can interfere with HbA(1c) measurement and cause inaccurate results. METHODS: The subject was a 31-year-old Thai man who was discovered because of an unexpected HbA(1c) result; other diabetic parameters were within the normal range. Abnormal Hb was investigated using automated high-pressure liquid chromatography (HPLC) and a capillary electrophoresis system. Mutation analysis was done by cDNA sequencing, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex allele-specific PCR assays. RESULTS: Evaluation of HbA(1c) by cation-exchange HPLC showed a value of 34.9% (reference interval, 4.0 6.0%), but a value of only 4.0% (reference value, 4.8-5.9%) was found with a turbidimetric immunoassay. Haematological analysis revealed a mild anaemia but other parameters were within the normal range. Hb-HPLC analysis demonstrated an unknown Hb variant (47.0%) separating from HbA (46.7%), but capillary electrophoresis identified no abnormal peaks. Mutation analysis identified the Hb Raleigh (beta1[NA1]Val -> Ala [GTG -> GCG]) mutation in combination with an alpha(+)-thalassaemia, a hitherto undescribed association. The Hb Raleigh mutation could be detected by PCR-RFLP or a multiplex allele-specific PCR assay. CONCLUSIONS: Hb Raleigh can cause falsely increased HbA(1c) values on cation exchange HPLC. Definitive diagnosis of this variant using combined Hb and DNA analyses is therefore essential. PMID- 22829697 TI - Causes of discordance between thyroglobulin antibody assays. AB - BACKGROUND: Anti-thyroglobulin (Anti-Tg) assays show poor concordance. METHODS: We have investigated concordance and the causes of discordance between Abbott, Roche and Immulite Anti-Tg assays in 606 patients followed up for differentiated thyroid cancer (DTC). The reference range (RR) or lower reporting limit (LRL) was used to classify samples as negative or positive. RESULTS: Anti-Tg prevalence ranged between 6% and 55% depending on the method and cut-off. Concordance was 45% using LRL and 75% using RR. Specimens between the RR and LRL using the Immulite and Roche assays were identified that were positive by the Abbott assay and showed poor recovery of Tg in the Tg assay. This suggests misclassification using the RR. Anti-Tg International Reference Preparation (IRP) concentrations measured by the Roche and Abbott methods agreed well but patient samples did not. This is likely to be due to the heterogeneity of Anti-Tg. The Immulite assay appeared less sensitive than the Abbott and Roche based on investigations using the IRP and the low prevalence of Anti-Tg in the DTC patients (6-8%). Interference by Tg (>1000 MUg/L) in the Roche assay was also identified as a cause of assay discordance. CONCLUSIONS: Anti-Tg is used as a tumour marker for DTC and to predict interference in Tg assays themselves and hence inform clinicians of reported Tg concentrations. We have identified several causes of Anti-Tg assay discordance. This includes variation in assay sensitivity and interference from Tg, the heterogeneity of Anti-Tg and the use of different cut offs to classify samples as antibody-positive or -negative. PMID- 22829698 TI - Effect of fenofibrate treatment for hyperlipidaemia on serum creatinine and cystatin C. AB - BACKGROUND: The increase in creatinine in patients on fibrate therapy is well recognized, but its mechanism is not clearly understood. A study by Hottelart et al. suggested that fibrate-induced creatininaemia was due to the effect of fibrates on creatinine metabolism as opposed to a decline in renal function. To address this hypothesis, we have monitored renal function in a group of hyperlipidaemic patients before commencing fibrate treatment and after three months of therapy. METHODS: We studied 12 subjects (10 men, 2 women), median age 43.5 y (range 33-70 y). Serum creatinine, cystatin C, creatine kinase and fasting lipids were measured. RESULTS: We observed statistically significant increases in concentrations of serum creatinine (P < 0.005) and cystatin C(P < 0.01). Concentrations of both analytes increased in 10 (83.3%) of the patients. In these patients, the median increases were 15.1% (range 5.5-23.2%) for creatinine and 9.9% (range 1.1-26.1%) for cystatin C. CONCLUSIONS: These results suggest that the decrease in estimated glomerular filtration rate, observed in patients undergoing fibrate therapy, is a genuine effect on kidney function rather than a change in creatinine metabolism as previously postulated, since the rises in serum creatinine concentration were reflected by rises in cystatin C, an independent marker of renal function. PMID- 22829699 TI - Quercetin protects macrophages from oxidized low-density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress-C/EBP homologous protein pathway. AB - Quercetin (QUE), a member of the bioflavonoid family, has been proposed to have antioxidative, anti-inflammatory and antihypertensive properties. This study was designed to investigate the protective effect of QUE on oxidized low-density lipoprotein (ox-LDL)-induced cytotoxicity in RAW264.7 macrophages and specifically the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis. Our results showed that treatment with QUE (20, 40 and 80 MUmol/L) significantly attenuated ox-LDL-induced cholesterol accumulation in macrophages and foam cell formation in a dose-dependent manner. Similar to tunicamycin (TM), a classical ER stress inducer, ox-LDL reduced cell viability and induced apoptosis in RAW264.7 macrophages. The cytotoxic effects of ox-LDL and TM were significantly inhibited by QUE treatment. Interestingly, we found that QUE also significantly suppressed the ox-LDL- and TM-induced activation of ER stress signaling events, including the phosphorylation of inositol-requiring enzyme 1 (IRE1), translocation of activating transcription factor 6 (ATF6) from the cytoplasm to the nucleus and upregulation of X-box binding protein 1. In addition, exposure of RAW264.7 macrophages to ox-LDL or TM resulted in a significant increase in the expression of CHOP, a transcription factor regulated by IRE1 and ATF6 under conditions of ER stress, as well as a decrease in Bcl-2 transcript and protein concentrations. QUE blocked these effects in a dose-dependent manner. These data indicate that QUE can protect RAW264.7 cells from ox-LDL-induced apoptosis and that the mechanism at least partially involves its ability to inhibit the ER stress-CHOP signaling pathway. PMID- 22829700 TI - Efficient cardiomyogenic differentiation of bone marrow mesenchymal stromal cells by combination of Wnt11 and bone morphogenetic protein 2. AB - Wnt11 and bone morphogenetic protein 2 (BMP-2) are key signaling factors for stem cell differentiation into functional cardiomyocytes (CMs). In this study, we elucidate the biological effect of BMP-2 and Wnt11 on bone marrow mesenchymal stromal cells (BM-MSCs) that differentiate into myocardial-like cells in a simulated myocardial microenvironment in vitro. A cell co-culture system was established with recombinant Wnt11 treatment of NIH/3T3 cells and CMs. BMP-2 was added in a diverse schedule to induce cardiomyogenic differentiation of BM-MSCs co-cultured under various conditions. The levels of cardiac-specific markers Nkx2.5, alpha-myosin heavy chain (alpha-MHC), beta-myosin heavy chain (beta-MHC) and cardiac troponin I (cTnI) were determined by reverse transcriptase polymerase chain reaction and immunocytochemistry to evaluate cardiomyogenic differentiation. Wnt11 or BMP-2 used on their own to differentiate BM-MSCs resulted in no expression of alpha-MHC and cTnI. Wnt11 alone in a myocardial microenvironment enhanced cardiomyogenic differentiation. BMP-2 demonstrated a dose-dependent effect on BM-MSC differentiation into myocardial-like cells. Addition of BMP to BM-MSCs at various time points resulted in varying effects on cardiomyogenic differentiation. The combination of Wnt11 and BMP-2 treatment in a temporal manner significantly enhanced cardiomyogenic differentiation of BM-MSCs, with high expressions of alpha-MHC, beta-MHC, Nkx2.5 and cTnI upon co-culture with CMs. Our study demonstrates that the combination of Wnt11 and BMP-2 effectively promotes cardiomyogenic differentiation of BM-MSCs in vitro. The synergistic effect of Wnt11 and BMP-2 on the cardiomyogenic differentiation of BM MSCs is further enhanced in a myocardial microenvironment. PMID- 22829702 TI - SERPINB3 expression on B-cell surface in autoimmune diseases and hepatitis C virus-related chronic liver infection. AB - SERPINB3 is a serine protease inhibitor with pleiotropic functions. It is involved in several physiological and pathological processes, where it appears to exert antiapoptotic effects. Little is known about its expression on immune system cells, the major players in mechanisms of viral defense and autoimmune disorders. The aim of this study was to characterize the expression of SERPINB3 on the surface of peripheral blood mononuclear cell subsets in both normal subjects and in patients with chronic viral infections and autoimmune diseases. Sixty-two patients were analyzed by flow cytometric analysis, including 45 with hepatitis C virus (HCV)-related chronic liver disease and 17 with systemic lupus erythematosus (SLE). SERPINB3 was expressed on B lymphocytes in 79% of the controls, in 32% of the HCV-infected patients and in none of the SLE patients. Surface localization of SERPINB3 was confirmed by confocal microscopy. SERPINB3 positivity was associated with CD27 reactivity (r = 0.98), but not to other activation molecules (CD69, CD71, CD86 and CXCR3). SERPINB3 is physiologically expressed on the surface of CD27(+) B lymphocytes, but its expression is reduced in HCV viral infection and not detectable in SLE patients. These results may suggest a role for SERPINB3 in B-cell defects typically found in viral infections and autoimmune disorders. PMID- 22829703 TI - Immunohistochemical detection of differentially localized up-regulation of lysyl oxidase and down-regulation of matrix metalloproteinase-1 in rhesus monkey model of chronic myocardial infarction. AB - Myocardial remodeling after ischemic infarction is characterized by collagen accumulation leading to replacement and interstitial fibrosis. Type I and III collagens are predominant components in cardiac fibrosis. Lysyl oxidase (LOX) facilitates the cross-linking of type I and III fibrils, resulting in the formation of stiff fibers and their subsequent tissue deposition. However, the matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes, function in the degradation of the collagen components of extracellular matrix. Tissue inhibitors for MMPs (TIMPs) manipulate the action of MMPs. To understand the contribution of these molecules to cardiac fibrosis, we developed a rhesus monkey model to determine the changes in LOX, MMP1 and TIMP1 in relation to collagen deposition after myocardial ischemic infarction. Male rhesus monkeys were subjected to left anterior descending artery ligation along with sham-operated controls. Histological examination and immunochemistry were performed eight weeks after the ischemic injury. The results showed that both type I and III collagens were increased in the scar area and in the interstitium, and the ratio of type I/III collagens also increased in the scar area but not in the interstitium. The expression of LOX was up-regulated, but the expression of MMP1 was down-regulated in residual myocytes of the scar area and the border zone. The expression of TIMP1 was not changed. The data thus demonstrated that the collagen deposition in infarcted myocardium is correlated with an enhanced cross-linking capacity and a decreased degradation process. PMID- 22829701 TI - DNA damage and neurotoxicity of chronic alcohol abuse. AB - Chronic alcohol abuse results in a variety of pathological effects including damage to the brain. The causes of alcohol-induced brain pathology are presently unclear. Several mechanisms of pathogenicity of chronic alcoholism have been proposed, including accumulation of DNA damage in the absence of repair, resulting in genomic instability and death of neurons. Genomic instability is a unified genetic mechanism leading to a variety of neurodegenerative disorders. Ethanol also likely interacts with various metabolic pathways, including one carbon metabolism (OCM). OCM is critical for the synthesis of DNA precursors, essential for DNA repair, and as a methyl donor for various methylation events, including DNA methylation. Both DNA repair and DNA methylation are critical for maintaining genomic stability. In this review, we outline the role of DNA damage and DNA repair dysfunction in chronic alcohol-induced neurodegeneration. PMID- 22829704 TI - Extracellular signal-regulated kinase plays a proapoptotic role in podocytes after reactive oxygen species treatment and inhibition of integrin-extracellular matrix interaction. AB - The effect of reactive oxygen species (ROS) and blocking integrin-extracellular matrix (ECM) interaction on apoptosis in podocytes, and the related signal transduction pathways remain unclear. Primary cultured rat podocytes were exposed to ROS. Integrin-ECM interaction was inhibited with anti-beta1-integrin monoclonal antibody (mAb) or RGDS (Arg-Gly-Asp-Ser). Extracellular signal regulated kinase (ERK) activation was evaluated with Western blotting. U0126 was used to inhibit ERK activation. Terminal deoxynucleotidyl transferase-mediated dUTP-peroxidase nick end-labeling of DNA (TUNEL) was used to evaluate apoptosis. We found that ROS-treated podocytes exhibited increased apoptosis, and both anti beta1-integrin mAb and RGDS induce apoptosis. Addition of ROS to either anti beta1-integrin mAb or RGDS enhanced apoptosis in both conditions. ERK activation was increased by either ROS or blocking integrin-ECM interaction. Preincubation with U0126 decreased apoptosis induced by ROS, anti-beta1-integrin mAb or RGDS, respectively. Our study demonstrated that ROS and blocking integrin-ECM interaction induce podocyte apoptosis, which is mediated by ERK activation. PMID- 22829706 TI - Do we need non-human primate research? PMID- 22829705 TI - Acidic pH conditions mimicking degenerative intervertebral discs impair the survival and biological behavior of human adipose-derived mesenchymal stem cells. AB - This study was designed to examine the survival and biological behavior of adipose-derived mesenchymal stem cells (ADMSCs) under an intervertebral disc (IVD)-like acidic environment. Human ADMSCs isolated from two age groups were cultured under four different pH levels (pH 7.4, 7.1, 6.8 and 6.5) which mimicked the standard condition and the normal, mildly degenerated and severely degenerated IVD. Cell viability was measured by fluorescein isothiocyanate Annexin-V/propidium iodide staining, and cell proliferation was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. The expression of aggrecan, collagen-I, collagen-II, matrix metalloproteinase-2 (MMP 2), tissue inhibitor of metalloproteinase-3 (TIMP-3), p53 and caspase-3 at the mRNA level was examined by realtime quantitative polymerase chain reaction, and the expression of aggrecan, collagen-I, collagen-II, MMP-2 and TIMP-3 at the protein level was measured by enzyme-linked immunosorbent assay. Acidic pH inhibited the viability and proliferation, and the expression of aggrecan, collagen-I and collagen-II of ADMSCs from both age groups. ADMSCs harvested from young and mature donors exhibited similar responses to the acidic pH, although cells from young donors appeared less sensitive to the low pH levels. The results demonstrated that acidic pH in IVD may be an important deleterious factor for ADMSC-based IVD regeneration. ADMSCs harvested from young donors may be more suitable to be utilized for the implantation into degenerated IVD, and the implantations may be more effective at an early stage of IVD degeneration when the pH of matrix acidity is higher than 6.8. PMID- 22829707 TI - The fallacy of ratio correction to address confounding factors. AB - Scientists aspire to measure cause and effect. Unfortunately confounding variables, ones that are associated with both the probable cause and the outcome, can lead to an association that is true but potentially misleading. For example, altered body weight is often observed in a gene knockout; however, many other variables, such as lean mass, will also change as the body weight changes. This leaves the researcher asking whether the change in that variable is expected for that change in weight. Ratio correction, which is often referred to as normalization, is a method used commonly to remove the effect of a confounding variable. Although ratio correction is used widely in biological research, it is not the method recommended in the statistical literature to address confounding factors; instead regression methods such as the analysis of covariance (ANCOVA) are proposed. This method examines the difference in means after adjusting for the confounding relationship. Using real data, this manuscript demonstrates how the ratio correction approach is flawed and can result in erroneous calls of significance leading to inappropriate biological conclusions. This arises as some of the underlying assumptions are not met. The manuscript goes on to demonstrate that researchers should use ANCOVA, and discusses how graphical tools can be used readily to judge the robustness of this method. This study is therefore a clear example of why assumption testing is an important component of a study and thus why it is included in the Animal Research: Reporting of In Vivo Experiment (ARRIVE) guidelines. PMID- 22829708 TI - Three-dimensional Bragg coherent diffraction imaging of an extended ZnO crystal. AB - A complex three-dimensional quantitative image of an extended zinc oxide (ZnO) crystal has been obtained using Bragg coherent diffraction imaging integrated with ptychography. By scanning a 2.5 um-long arm of a ZnO tetrapod across a 1.3 um X-ray beam with fine step sizes while measuring a three-dimensional diffraction pattern at each scan spot, the three-dimensional electron density and projected displacement field of the entire crystal were recovered. The simultaneously reconstructed complex wavefront of the illumination combined with its coherence properties determined by a partial coherence analysis implemented in the reconstruction process provide a comprehensive characterization of the incident X-ray beam. PMID- 22829710 TI - Expression of Somatostatin Receptor (SSTR) Subtypes (SSTR-1, 2A, 3, 4 and 5) in Neuroendocrine Tumors Using Real-time RT-PCR Method and Immunohistochemistry. AB - Molecule targeting therapy using somatostatin (SS) analogues has become a widely accepted modality to treat neuroendocrine tumors (NETs), particularly gastrointestinal (GI) and pancreatic endocrine tumors. On the other hand, little is known about the expression of somatostatin receptor (SSTR) subtypes in neuroendocrine carcinomas (NECs). We investigated the expression of SSTR subtypes (SSTR-1, 2A, 3, 4 and 5) using real-time reverse transcription polymerase chain reaction (RT-PCR) method and immunohistochemistry in 32 neuroendocrine neoplasms (9 NET G1, 2 NET G2, 18 NECs G3 and 3 mixed NEC G3) of various primary sites. Expression of more than two SSTR subtypes was detected in all neuroendocrine neoplasms examined. Expression of SSTR-2A mRNA was significantly higher than other subtypes. In addition, mRNA expression of SSTR-3 and SSTR-5 was significantly low or below the detection level except for gastroduodenal NET G1. No significant difference of the expression of SSTR subtypes was observed between the NET and NEC groups. The expression of protein and mRNA was generally well correlated. In conclusion, NECs would be a good candidate for molecule targeting therapy using SS analogues, and the expression of SSTR-2A can be useful as a biomarker of neuroendocrine differentiation. We have demonstrated that NEC G3 small cell type shows a different expression profile of SSTR subtypes compared with NET and NEC non-small cell type. PMID- 22829709 TI - Environmental Enrichment during Gestation Improves Behavior Consequences and Synaptic Plasticity in Hippocampus of Prenatal-Stressed Offspring Rats. AB - Prenatal stress can result in various behavior deficits in offspring. Here we tested the effects of environmental enrichment during gestation used as a preventive strategy on the behavior deficits of prenatal-stressed offspring rats as well as the underlying structure basis. We compared the effect size of environmental enrichment during gestation on prenatal-stressed offspring to that of environmental enrichment after weaning. Our results showed that environmental enrichment during gestation partially prevented anxiety and the damage in learning and memory in prenatal-stressed offspring as evaluated by elevated plus maze test and Morris water maze test. At the same time, environmental enrichment during gestation inhibited the decrease in spine density of CA1 and dentate gyrus neurons and preserved the expression of synaptophysin and glucocorticoid receptors (GRs) in the hippocampus of prenatal-stressed offspring. There was no significant difference in offspring behavior between 7-day environmental enrichment during gestation and 14-day offspring environmental enrichment after weaning. These data suggest that environmental enrichment during gestation effectively prevented the behavior deficits and the abnormal synapse structures in prenatal-stressed offspring, and that it can be used as an efficient preventive strategy against prenatal stresses. PMID- 22829711 TI - Acute regeneration and chronic acellular transformation of rabbit cryopreserved aortic allografts. AB - An analysis of rabbit cryopreserved aortic allografts excised on postoperative days (POD) 2, 5, 11, 60, 210, 360, and 720, as well as controls that were untransplanted native aortas and cryopreserved aortas, was performed. On POD2, the number of medial smooth muscle cells in the allografts was reduced to approximately 50%. Ki-67 analysis revealed that medial smooth muscle cells in the allografts proliferated from the 2nd day. By the 11th day, their proliferation ceased and the number of medial smooth muscle cells was restored to almost at the same level as in the controls. Polymorphic microsatellite DNA marker analysis disclosed that the restored medial smooth muscle cells were of donor origin. From 7 months through 2 years, the media of cryopreserved aortic allografts were transformed into acellular structures, in which the elastic fibers were preserved. On the other hand, newly accumulated smooth muscle cells were observed in the adventitia just outside of acellular media after 7 months. In some cases, scattered lamellar calcium deposition was observed in the same regions. This study presents a comprehensive documentation of regeneration and acellular transformation in cryopreserved aortic allografts based on short and long-term analysis. PMID- 22829712 TI - Regional Differences in the Neuronal Expression of Cyclooxygenase-2 (COX-2) in the Newborn Pig Brain. AB - Cyclooxygenase (COX)-2 is the major constitutively expressed COX isoform in the newborn brain. COX-2 derived prostanoids and reactive oxygen species appear to play a major role in the mechanism of perinatal hypoxic-ischemic injury in the newborn piglet, an accepted animal model of the human term neonate. The study aimed to quantitatively determine COX-2 immunopositive neurons in different brain regions in piglets under normoxic conditions (n=15), and 4 hours after 10 min asphyxia (n=11). Asphyxia did not induce significant changes in neuronal COX-2 expression of any studied brain areas. In contrast, there was a marked regional difference in all experimental groups. Thus, significant difference was observed between fronto-parietal and temporo-occipital regions: 59+/-4% and 67+/-3% versus 41+/-2%* and 31+/-3%* respectively (mean+/-SEM, data are pooled from all subjects, n=26, *p<0.05, vs. fronto-parietal region). In the hippocampus, COX-2 immunopositivity was rare (highest expression in CA1 region: 14+/-2%). The studied subcortical areas showed negligible COX-2 staining. Our findings suggest that asphyxia does not significantly alter the pattern of neuronal COX-2 expression in the early reventilation period. Furthermore, based on the striking differences observed in cortical neuronal COX-2 distribution, the contribution of COX-2 mediated neuronal injury after asphyxia may also show region-specific differences. PMID- 22829713 TI - In Vivo Real-Time Imaging of Exogenous HGF-Triggered Cell Migration in Rat Intact Soleus Muscles. AB - The transplantation of myogenic cells is a potentially effective therapy for muscular dystrophy. However, this therapy has achieved little success because the diffusion of transplanted myogenic cells is limited. Hepatocyte growth factor (HGF) is one of the primary triggers to induce myogenic cell migration in vitro. However, to our knowledge, whether exogenous HGF can trigger the migration of myogenic cells (i.e. satellite cells) in intact skeletal muscles in vivo has not been reported. We previously reported a novel in vivo real-time imaging method in rat skeletal muscles. Therefore, the present study examined the relationship between exogenous HGF treatment and cell migration in rat intact soleus muscles using this imaging method. As a result, it was indicated that the cell migration velocity was enhanced in response to increasing exogenous HGF concentration in skeletal muscles. Furthermore, the expression of MyoD was induced in satellite cells in response to HGF treatment. We first demonstrated in vivo real-time imaging of cell migration triggered by exogenous HGF in intact soleus muscles. The experimental method used in the present study will be a useful tool to understand further the regulatory mechanism of HGF-induced satellite cell migration in skeletal muscles in vivo. PMID- 22829714 TI - Types of parvalbumin-containing retinotectal ganglion cells in mouse. AB - The calcium-binding protein parvalbumin (PV) occurs in the retinal ganglion cells (RGCs) of various vertebrate species. In the present study, we aimed to identify the types of PV-containing RGCs that project to the superior colliculus (SC) in the mouse. We injected retrograde tracer dextran into the mouse SC to label RGCs. PV-containing RGCs were first identified by immunocytochemistry and then neurons double-labeled with dextran and PV were iontophoretically injected with a lipophilic dye, DiI. Subsequently, confocal microscopy was used to characterize the morphologic classification of the PV-immunoreactive (IR) retinotectal ganglion cells on the basis of dendritic field size, branching pattern, and stratification within the inner plexiform layer. Among the 8 different types of PV-containing RGCs in the mouse retina, we found all 8 types of RGCs projecting to the SC. The RGCs were heterogeneous in morphology. The combined approach of using tracer injection and a single cell injection after immunocytochemistry on a particular protein will provide valuable data to further understand the functional features of the RGCs which constitute the retinotectal pathway. PMID- 22829715 TI - A New Electrospray Aerosol Generator with High Particle Transmission Efficiency. AB - A new single-capillary electrospray (ES) aerosol generator has been developed for monodisperse particle production with maximal transmission efficiency. The new generator consists of both a spray chamber in a point-to-orifice-plate configuration and a charge reduction chamber that can hold up to 4 Nuclespot ionizers (Model P-2042, NRD Inc.). The 2 chambers are partitioned by an orifice plate. To optimize the particle transmission efficiency of the prototype, a systematic study was performed on the generator by varying the system setup and operation. Two key dimensions of the generator setup, the orifice diameter and the distance from the capillary tip to the orifice plate, were varied. Fluorescence analysis was applied to characterize the loss of ES-generated particles at different locations of the prototype. It was found that particle loss in the generator could be reduced by either increasing the orifice diameter or decreasing the distance between the capillary tip and the orifice plate. Increasing either the total radioactivity of the ionizers or the flowrate of the particle carrier gas also further decreased the particle loss in the system. The maximum particle transmission efficiency of 88.0% was obtained with the spray chamber fully opened to the charge reduction chamber, the capillary tip at the same level as the orifice plate, and 4 bipolar ionizers installed. PMID- 22829717 TI - Single nucleotide polymorphisms (SNPs) for genome wide association studies (GWAS) and molecule of the month Nitric Oxide Synthase, multiple interactive pathways for three similar genes, Nitric Oxide Synthase-1, -2, -3 (NOS-1, -2, -3). PMID- 22829716 TI - Inflammatory marker sTREM-1 reflects the clinical stage and respiratory tract obstruction in allergic asthma bronchiale patients and correlates with number of neutrophils. AB - The knowledge that asthma is an inflammatory disorder has prompted us to investigate the plasma levels of a new inflammatory marker sTREM-1 that is released from the surfaces of activated neutrophils and monocytes. The plasma levels of sTREM-1 were analysed by a sandwich ELISA test in the cohort of 76 patients with allergic asthma bronchiale and 39 healthy controls. Our results revealed more than 3.5 times higher levels of sTREM-1 in AB patients (92.3 pg/mL +/- 125.6) compared with healthy subjects (25.7 pg/mL +/- 9.2; P = 0.0001). Higher levels of sTREM-1 were found also in patients with exacerbated AB (170.5 pg/mL +/- 78.2) compared with nonexacerbated AB patients (59.1 +/- 78.2; P < 0.0001), patients with respiratory tract obstruction (176.4 pg/mL +/- 177.8), than those without obstruction (51.99 pg/mL +/- 64.0; P < 0.0001) and patients with anti-IgE therapy (P < 0.0001). Levels of sTREM-1 correlated with number of leucocytes (P = 0.002), and absolute number of neutrophils (P = 0.001). Elevated plasma levels of sTREM-1 reflect the severity, state of exacerbation, presence of respiratory tract obstruction in AB patients and together with increased number of neutrophils point to the role of neutrophils in inflammation accompanying AB. PMID- 22829718 TI - An alphabetic code based atomic level molecular similarity search in databases. AB - Atomic level molecular similarity and diversity studies have gained considerable importance through their wide application in Bioinformatics and Chemo-informatics for drug design. The availability of large volumes of data on chemical compounds requires new methodologies for efficient and effective searching of its archives in less time with optimal computational power. We describe an alphabetic algorithm for similarity searching based on atom-atom bonding preference for ligands. We represented 170 cyclindependent kinase 2 inhibitors using strings of pre-defined alphabets for searching using known protein sequence alignment tools. Thus, a common pattern was extracted using this set of compounds for database searching to retrieve similar active compounds. Area under the receiver operating characteristic (ROC) curve was used for the discrimination of similar and dissimilar compounds in the databases. An average retrieval rate of about 60% is obtained in cross-validation using the home-grown dataset and the directory of useful decoys (DUD, formally known as the ZINC database) data. This will help in the effective retrieval of similar compounds using database search. PMID- 22829719 TI - In silico model of DSF synthase RpfF protein from Xanthomonas oryzae pv. Oryzae: a novel target for bacterial blight of rice disease. AB - BACKGROUND: Rice plant diseases play a major role as biological constraints on production. One of such rice disease is bacterial leaf blight, caused by Xanthomonas oryzae pv. Oryzae (Xoo). The diffusible signal factor (DSF) synthesized by Xoo has a major role in virulence to rice plant. The DSF synthase RpfF protein, which is related to crotonase superfamily is responsible for the maintaining concentration of DSF. DSF-dependent quorum sensing (QS) system adopts protein- protein interaction mechanism to auto regulates the production of DSF. The antibacterial activity of pesticides against Xoo has not yet been completely understood. Three dimensional structure of RpfF protein was predicted using homology modeling method by MODELLER 9V9 software, SWISS MODEL and GENO3D online tools and structures were validated by Ramachandran plot, TM-Score and RMSD. 3D structure of RpfF (accession number AAL06345) was predicted using DSF synthase of Xanthomonas campestris pv. campestris (Xcc) (PDB ID: 3M6M) as a template. The stereo chemical check reveals the structure developed from the modeller was the best one and the potential ligand binding sites were identified by CASTp Server. The predicted RpfF model provides insight into its structure, active sites and aid in the development of novel inhibitors to control bacterial leaf blight in rice plant. DSF synthase RpfF protein could be used as a novel target to control infection. PMID- 22829720 TI - CARd: Carbon distribution analysis program for protein sequences. AB - Carbon distribution is responsible for stability and structure of proteins. Arrangement of carbon along the protein sequence is depends on how the amino acids are organized and is guided by mRNAs. An atomic level revision is important for understanding these codes. This will ultimately help in identification of disorders and suggest mutations. For this purpose a carbon distribution analysis program has been developed. This program captures the hydrophobic / hydrophilic / disordered regions in a protein. The program gives accurate results. The calculations are precise and sensitive to single amino acid resolution. This program is to help in mutational studies leading to protein stabilisation. PMID- 22829721 TI - Interactions of intergenic microRNAs with mRNAs of genes involved in carcinogenesis. AB - miRNAs regulate gene expression by binding with mRNAs of many genes. Studying their effects on genes involved in oncogenesis is important in cancer diagnostics and therapeutics. The RNAHybrid 2.1 program was used to predict the strong miRNA binding sites (p < 0.0005) in target mRNAs. The program Finder 2.2 was created to verify 784 intergenic miRNAs (ig-miRNA) origin. Among 54 considered oncogenes and tumor suppressor genes, 47 genes are the best targets for ig-miRNAs. Accordingly, these genes are strongly regulated by 111 ig-miRNAs. Some miRNAs bind several mRNAs, and some mRNAs have several binding sites for miRNAs. Of the 54 mRNAs, 21.8%, 43.0%, and 35.2% of the miRNA binding sites are present in the 5'UTRs, CDSes, and 3'UTRs, respectively. The average density of the binding sites for miRNAs in the 5'UTR was 4.4 times and 4.1 times greater than in the CDS and the 3'UTR, respectively. Three types of interactions between miRNAs and mRNAs were identified, which differ according to the region of the miRNA bound to the mRNA: 1) binding occurs predominantly via the 3'-region of the miRNA; 2) binding occurs predominantly through the central region of the miRNA; and 3) binding occurs predominantly via the 5'-region of the miRNA. Several miRNAs effectively regulate only one gene, and this information could be useful in molecular medicine to modulate translation of the target mRNA. We recommend described new sites for validation by experimental investigation. PMID- 22829722 TI - Bioinformatics prediction of siRNAs as potential antiviral agents against dengue viruses. AB - Dengue virus (DENV 1-4) represents the major emerging arthropod-borne viral infection in the world. Currently, there is neither an available vaccine nor a specific treatment. Hence, there is a need of antiviral drugs for these viral infections; we describe the prediction of short interfering RNA (siRNA) as potential therapeutic agents against the four DENV serotypes. Our strategy was to carry out a series of multiple alignments using ClustalX program to find conserved sequences among the four DENV serotype genomes to obtain a consensus sequence for siRNAs design. A highly conserved sequence among the four DENV serotypes, located in the encoding sequence for NS4B and NS5 proteins was found. A total of 2,893 complete DENV genomes were downloaded from the NCBI, and after a depuration procedure to identify identical sequences, 220 complete DENV genomes were left. They were edited to select the NS4B and NS5 sequences, which were aligned to obtain a consensus sequence. Three different servers were used for siRNA design, and the resulting siRNAs were aligned to identify the most prevalent sequences. Three siRNAs were chosen, one targeted the genome region that codifies for NS4B protein and the other two; the region for NS5 protein. Predicted secondary structure for DENV genomes was used to demonstrate that the siRNAs were able to target the viral genome forming double stranded structures, necessary to activate the RNA silencing machinery. PMID- 22829723 TI - Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity. AB - Obesity and patient morbidity has become a health concern worldwide. Obesity is associated with over activity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis and insulin resistance. Hypothalamic cannabinoid-1 receptor (CB1R) inverse agonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity but displayed neuropsychiatric side effects. Hence, there is a need to develop therapeutics which employs blocking peripheral CB1 receptors and still achieve substantial weight loss. In view of the same, adipose tissue CB1 receptors are employed for this study since it is more specific in reducing visceral fat. Computer aided structure based virtual screening finds application to screen novel inhibitors and develop highly selective and potential drug. The rational drug design requires crystal structure for the CB1 receptor. However, the structure for the CB1 receptor is not available in its native form. Thus, we modelled the crystal structure using a lipid G-Protein coupled receptor (PDB: 3V2W, chain A) as template. Furthermore, we have screened a herbal ligand Quercetin [- 2- (3, 4 dihydroxyphenyl) - 3, 5, 7-trihydroxychromen-4-one] a flavonol present in Mimosa pudica based on its better pharmacokinetics and bioavailability profile. This ligand was selected as an ideal lead molecule. The docking of quercetin with CB1 receptor showed a binding energy of -6.56 Kcal/mol with 4 hydrogen bonds, in comparison to the known drug Rimonabant. This data finds application in proposing antagonism of CB1 receptor with Quercetin, for controlling obesity. PMID- 22829724 TI - FunSys: Software for functional analysis of prokaryotic transcriptome and proteome. AB - The vast amount of data produced by next-generation sequencing (NGS) has necessitated the development of computational tools to assist in understanding the myriad functions performed by the biological macromolecules involved in heredity. In this work, we developed the FunSys programme, a stand-alone tool with an user friendly interface that enables us to evaluate and correlate differential expression patterns from RNA sequencing and proteomics datasets. The FunSys generates charts and reports based on the results of the analysis of differential expression to aid the interpretation of the results. AVAILABILITY: The database is available for free at https://sourceforge.net/projects/funsysufpa/ PMID- 22829725 TI - Bacterial genome mapper: A comparative bacterial genome mapping tool. AB - Recently, next generation sequencing (NGS) technologies have led to a revolutionary increase in sequencing speed and costefficacy. Consequently, a vast number of contigs from many recently sequenced bacterial genomes remain to be accurately mapped and annotated, requiring the development of more convenient bioinformatics programs. In this paper, we present a newly developed web-based bioinformatics program, Bacterial Genome Mapper, which is suitable for mapping and annotating contigs that have been assembled from bacterial genome sequence raw data. By constructing a multiple alignment map between target contig sequences and two reference bacterial genome sequences, this program also provides very useful comparative genomics analysis of draft bacterial genomes. AVAILABILITY: The database is available for free at http://mbgm.kribb.re.kr. PMID- 22829726 TI - Actinobase: Database on molecular diversity, phylogeny and biocatalytic potential of salt tolerant alkaliphilic actinomycetes. AB - Actinobase is a relational database of molecular diversity, phylogeny and biocatalytic potential of haloalkaliphilic actinomycetes. The main objective of this data base is to provide easy access to range of information, data storage, comparison and analysis apart from reduced data redundancy, data entry, storage, retrieval costs and improve data security. Information related to habitat, cell morphology, Gram reaction, biochemical characterization and molecular features would allow researchers in understanding identification and stress adaptation of the existing and new candidates belonging to salt tolerant alkaliphilic actinomycetes. The PHP front end helps to add nucleotides and protein sequence of reported entries which directly help researchers to obtain the required details. Analysis of the genus wise status of the salt tolerant alkaliphilic actinomycetes indicated 6 different genera among the 40 classified entries of the salt tolerant alkaliphilic actinomycetes. The results represented wide spread occurrence of salt tolerant alkaliphilic actinomycetes belonging to diverse taxonomic positions. Entries and information related to actinomycetes in the database are publicly accessible at http://www.actinobase.in. On clustalW/X multiple sequence alignment of the alkaline protease gene sequences, different clusters emerged among the groups. The narrow search and limit options of the constructed database provided comparable information. The user friendly access to PHP front end facilitates would facilitate addition of sequences of reported entries. AVAILABILITY: The database is available for free at http://www.actinobase.in. PMID- 22829727 TI - On the utility of alternative amino acid scripts. AB - In this work we propose the hypothesis that replacing the current system of representing the chemical entities known as amino acids using Latin letters with one of several possible alternative symbolic representations will bring significant benefits to the human construction, modification, and analysis of multiple protein sequence alignments. We propose ways in which this might be done without prescribing the choice of actual scripts used. Specifically we propose and explore three ways to encode amino acid texts using novel symbolic alphabets free from precedents. Primary orthographic encoding is the direct substitution of a new alphabet for the standard, Latin-based amino acid code. Secondary encoding imposes static residue groupings onto the orthography of the alphabet by manipulating the shape and/or orientation of amino acid symbols. Tertiary encoding renders each residue as a composite symbol; each such symbol thus representing several alternative amino acid groupings simultaneously. We also propose that the use of a new group-focussed alphabet will free the colouring of amino acid residues often used as a tool to facilitate the representation or construction of multiple alignments for other purposes, possibly to indicate dynamic properties of an alignment such as position-wise residue conservation. PMID- 22829728 TI - Comparison and correlation of binding mode of ATP in the kinase domains of Hexokinase family. AB - Hexokinases (HKs) are the enzymes that catalyses the ATP dependent phosphorylation of Hexose sugars to Hexose-6-Phosphate (Hex-6-P). There exist four different forms of HKs namely HK-I, HK-II, HK-III and HK-IV and all of them share a common ATP binding site core surrounded by more variable sequence that determine substrate affinities. Although they share a common binding site but they differ in their kinetic functions, hence the present study is aimed to analyze the binding mode of ATP. The analysis revealed that the four ATP binding domains are showing 13 identical, 7 similar and 6 dissimilar residues with similar structural conformation. Molecular docking of ATP into the kinase domains using Molecular Operating Environment (MOE) soft ware tool clearly showed the variation in the binding mode of ATP with variable docking scores. This probably explains the variable phosphorylation rates among hexokinases family. PMID- 22829729 TI - Diversity of Streptomyces spp. in Eastern Himalayan region - computational RNomics approach to phylogeny. AB - Isolation and characterization of actinomycetes from soil samples from altitudinal gradient of North-East India were investigated for computational RNomics based phylogeny. A total of 52 diverse isolates of Streptomyces from the soil samples were isolated on four different media and from these 6 isolates were selected on the basis of cultural characteristics, microscopic and biochemical studies. Sequencing of 16S rDNA of the selected isolates identified them to belong to six different species of Streptomyces. The molecular morphometric and physico-kinetic analysis of 16S rRNA sequences were performed to predict the diversity of the genus. The computational RNomics study revealed the significance of the structural RNA based phylogenetic analysis in a relatively diverse group of Streptomyces. PMID- 22829730 TI - Qualitative and Quantitative analysis of 3D predicted arachidonate 15 lipoxygenase-B (15-LOX-2) from Homo sapiens. AB - 15-Lipoxygenase-2 protein has been reported to play an important role in normal development of prostate, lung, skin, and cornea tissues. It behaves as a suppressor of prostate cancer development by restricting cell cycle progression and implicating a possible protective role against tumor formation. On the basis of the above report, we selected 15-LOX-2 protein to study the structural classification and functional relationship with associated protein network at computational level. Sequence alignment and protein functional study shows that it contains a highly conserved LOX motif. PLAT domain with PF01477 and LH2 domain with PF00305 were successfully observed. Arachidonate 5-lipoxygenase (PDB ID: 3O8Y) was selected as a template with 42% identity. 3D structure was successfully predicted and verified. Qualitative analysis suggests that the predicted model was reliable and stable with best quality. Quantitative study shows that the model contained expected volume and area with best resolution. Predicted and best evaluated model has been successfully deposited to PMDB database with PMDB ID PM0078035. Active site identification revealed GLU(369), ALA(370), LEU(371), THR(372), HIS(373), LEU(374), HIS(376), SER(377), HIS(378), THR(385), LEU(389), HIS(394), PHE(399), LYS(400), LEU(401), ILE(403) and PRO(404) residues may play a major role during protein-protein, protein-drug and protein-cofactor interactions. STRING database result indicated that IL (4), GPX (2 and 4), PPARG, PTGS (1 and 2), CYP (2J2, 2C8, 4A11 and 2B6), PLA (2G2A, 2G4A, 2G1B and 2G6) and A LOX (5, 15, 12 and 12B) members from their respective gene families have network based functional association with 15-LOX-2. PMID- 22829731 TI - Screening and structural evaluation of deleterious Non-Synonymous SNPs of ePHA2 gene involved in susceptibility to cataract formation. AB - Age-related cataract is clinically and genetically heterogeneous disorder affecting the ocular lens, and the leading cause of vision loss and blindness worldwide. Here we screened nonsynonymous single nucleotide polymorphisms (nsSNPs) of a novel gene, EPHA2 responsible for age related cataracts. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nsSNPs and their effect on protein was predicted by PolyPhen and SIFT respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the EPHA2 protein was evaluated by using SWISSPDB viewer and NOMAD-Ref server. Our analysis revealed 16 SNPs as nonsynonymous out of which 6 nsSNPs, namely rs11543934, rs2291806, rs1058371, rs1058370, rs79100278 and rs113882203 were found to be least stable by I-Mutant 2.0 with DDG value of > -1.0. nsSNPs, namely rs35903225, rs2291806, rs1058372, rs1058370, rs79100278 and rs113882203 showed a highly deleterious tolerance index score of 0.00 by SIFT server. Four nsSNPs namely rs11543934, rs2291806, rs1058370 and rs113882203 were found to be probably damaging with PSIC score of >= 2. 0 by Polyp hen server. Three nsSNPs namely, rs11543934, rs2291806 and rs1058370 were found to be highly polymorphic with a risk score of 3-4 with a possible effect of Non-conservative change and splicing regulation by FASTSNP. The total energy and RMSD value was higher for the mutant type structure compared to the native type structure. We concluded that the nsSNP namely rs2291806 as the potential functional polymorphic that is likely to have functional impact on the EPHA2 gene. PMID- 22829732 TI - Designing of Protein Kinase C beta-II Inhibitors against Diabetic complications: Structure Based Drug Design, Induced Fit docking and analysis of active site conformational changes. AB - Protein Kinase C beta-II (PKC beta-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC beta-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC beta-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC beta-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC beta-II. Based on the HTVs results and the nature of active site residues of PKC beta-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC beta-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC beta-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC beta-II were observed for the back bone Calpha atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC beta-II. PMID- 22829733 TI - Computational analysis of human and mouse CREB3L4 Protein. AB - CREB3L4 is a member of the CREB/ATF transcription factor family, characterized by their regulation of gene expression through the cAMP-responsive element. Previous studies identified this protein in mice and humans. Whereas CREB3L4 in mice (referred to as Tisp40) is found in the testes and functions in spermatogenesis, human CREB3L4 is primarily detected in the prostate and has been implicated in cancer. We conducted computational analyses to compare the structural homology between murine Tisp40alpha human CREB3L4. Our results reveal that the primary and secondary structures of the two proteins contain high similarity. Additionally, predicted helical transmembrane structure reveals that the proteins likely have similar structure and function. This study offers preliminary findings that support the translation of mouse Tisp40alpha findings into human models, based on structural homology. PMID- 22829734 TI - TPX: Biomedical literature search made easy. AB - TPX is a web-based PubMed search enhancement tool that enables faster article searching using analysis and exploration features. These features include identification of relevant biomedical concepts from search results with linkouts to source databases, concept based article categorization, concept assisted search and filtering, query refinement. A distinguishing feature here is the ability to add user-defined concept names and/or concept types for named entity recognition. The tool allows contextual exploration of knowledge sources by providing concept association maps derived from the MEDLINE repository. It also has a full-text search mode that can be configured on request to access local text repositories, incorporating entity co-occurrence search at sentence/paragraph levels. Local text files can also be analyzed on-the-fly. AVAILABILITY: http://tpx.atc.tcs.com PMID- 22829735 TI - RAmiRNA: Software suite for generation of SVMbased prediction models of mature miRNAs. AB - MicroRNAs (miRNAs) are short endogenous non-coding RNA molecules that regulate protein coding gene expression in animals, plants, fungi, algae and viruses through the RNA interference pathway. By virtue of their base complementarity, mature miRNAs stop the process of translation, thus acting as one of the important molecules in vivo. Attempts to predict precursor-miRNAs and mature miRNAs have been achieved in a significant number of model organisms but development of prediction models aiming at relatively less studied organisms are rare. In this work, we provide a suite of standalone softwares called RAmiRNA (RAdicalmiRNA detector), to solve the problem of custom development of prediction models for mature miRNAs using support vector machine (SVM) learning. RAmiRNA could be used to develop SVM based model for prediction of mature miRNAs in an organism or a group of organisms in a UNIX based local machine. Additionally RAmiRNA generates training accuracy for a quick estimation of prediction ability of generated model. AVAILABILITY: The database is available for free at http://ircb.iiita.ac.in. PMID- 22829736 TI - Universal fingerprinting chip server. AB - The Virtual Hybridization approach predicts the most probable hybridization sites across a target nucleic acid of known sequence, including both perfect and mismatched pairings. Potential hybridization sites, having a user-defined minimum number of bases that are paired with the oligonucleotide probe, are first identified. Then free energy values are evaluated for each potential hybridization site, and if it has a calculated free energy of equal or higher negative value than a user-defined free energy cut-off value, it is considered as a site of high probability of hybridization. The Universal Fingerprinting Chip Applications Server contains the software for visualizing predicted hybridization patterns, which yields a simulated hybridization fingerprint that can be compared with experimentally derived fingerprints or with a virtual fingerprint arising from a different sample. AVAILABILITY: The database is available for free at http://bioinformatica.homelinux.org/UFCVH/ PMID- 22829737 TI - Identification & Characterization of lactobacillus salavarius bacteriocins and its relevance in cancer therapeutics. AB - Therapeutic agents with a goal to eradicate cancer needs to capable of inhibiting the growth and kill, any preformed tumor and should also inhibit oncogenic transformation of normal cells to cancer cells. Bacteriocins are bacterial proteins produced to prevent the growth of competing microorganisms in a particular biological niche and have been proved to possess antineoplastic activity. The entire genome of Lactobacillus salavarius was scanned for putative bacteriocins and subsequently these bacteriocins were characterized by subjecting them as functional annotation algorithms. Azurin is a well characterized bacteriocins with proven cytostatic and apoptotic effect against human cancer cell and was taken as control. Functional characterization revealed that the three bacteriocins Lsl_003, Lsl_0510, Lsl_0554 possessed functional properties very similar to that of Azurin. Molecular screening of these bacteriocins against the common cancer targets p53, Rb1 and AR revealed that Lsl_0510 possessed highest binding affinity towards the all the three receptors making it to ideal candidate for future cancer therapeutics. ABBREVIATIONS: P53 - Protein 53, Rb1 - Retinoblastoma 1, AR - Androgen Receptor, Lsl - Lactobacillus salavarius. PMID- 22829738 TI - Identification of drought responsive proteins using gene ontology hierarchy. AB - The availability of the complete genome sequences has facilitated access to essential information to identify proteins. The determination of Arabidopsis genome sequence has had a great impact to annotate data. The genome sequencing of Sorghum bicolor has been only recently completed and hither to the global response to abiotic stresses in this important crop remains largely unexplored. We used 2-D gel electrophoresis based proteomic approach refined with MALDI-TOF to analyze drought-stress response proteins in sorghum. Major changes in protein complement of sorghum were observed in hydroponic cultures at 96 hours under drought stress. Six most highly expressed proteins were excised for functional identification. Here, we developed a method to obtain functional distances between GO terms and analyzed distance values to allocate shortest path (SP) in GO hierarchy. The shortest paths for expressed proteins were noted for most informative common ancestor (MICA) terms, viz. binding, catalytic activity and primary metabolic process. We observed the expressed proteins belonged to the functional group of signal transduction mechanisms, carbohydrate transport and metabolism. These identified functions of proteins suggest a different mechanism of drought-stress tolerant in sorghum. The novel approach applied in this study may have great importance in further identifying proteins involved in abiotic and biotic stress conditions in crops. PMID- 22829739 TI - Molecular differentiation of Peroxysome proliferator activated receptor coactivator-1 among different breeds of Bubalus bubalis. AB - Peroxysome proliferator activated receptor coactivator-1 gene (PPARGC1A) is a positional and functional candidate gene for milk fat yield. It has key role in energy, fat and glucose metabolism. Single nucleotide polymorphisms (SNPs) in Exon-8 of PPARGC1A are reported to be associated with milk fat yield in dairy cattle. In the present investigation PPARGC1A was partially amplified (around 767bp) by designing gene specific primer and confirm by sequencing the amplicon and its comparison with the PPARGC1A gene of bovine. Comparative study of PPARGC1A among different breeds of buffaloes reveals different level of mutations with respect to its gene sequence 0.013-1.69% and protein sequence 0.42% to 2.99%, Similarly the protein structures modeled from their sequences were compared by structural superposition that shows variations (RMSD) from 0.736 to 1.507. Furthermore, the sequences were used to generate a dendrogram. It reveals that Murrah and reference are very close to each other, similarly Toda, Bhadawari and Surti are closely related, whereas Pandharpuri is separated from both the cluster. Especially the variations are more at the binding site of this protein that may be the cause that different breeds have different percentage of milk fat. Further study is underway to detect polymorphism and associate them with milk fat related traits in buffalo. PMID- 22829740 TI - Molecular screening of compounds to the predicted Protein-Protein Interaction site of Rb1-E7 with p53- E6 in HPV. AB - Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. Human Papillomaviruses (HPVs) which are heterogeneous groups of small double stranded DNA viruses are considered as the primary cause of cervical cancer, involved in 90% of all Cervical Cancers. Two early HPV genes, E6 and E7, are known to play crucial role in tumor formation. E6 binds with p53 and prevents its translocation and thereby inhibit the ability of p53 to activate or repress target genes. E7 binds to hypophosphorylated Rb and thereby induces cells to enter into premature S-phase by disrupting Rb-E2F complexes. The strategy of the research work was to target the site of interaction of Rb1 -E7 & p53-E6. A total of 88 compounds were selected for molecular screening, based on comprehensive literature survey for natural compounds with anti-cancer activity. Molecular docking analysis was carried out with Molegro Virtual Docker, to screen the 88 chosen compounds and rank them according to their binding affinity towards the site of interaction of the viral oncoproteins and human tumor suppressor proteins. The docking result revealed that Nicandrenone a member of Withanolides family of chemical compounds as the most likely molecule that can be used as a candidate drug against HPV induced cervical cancer. ABBREVIATIONS: HPV - Human Papiloma Virus, HTSP - Human Tumor Suppressor Proteins, VOP - Viral oncoproteins. PMID- 22829741 TI - Prevalence of metabolic syndrome and gender differences. AB - In a comparative study, involving 500 subjects with 294 males and 206 females aged 30 years and above, data were collected from NIMS (National Institute of Medical Sciences) hospital and research centre and controls from the general population whose age and sex were matched with subjects during the years 2010 - 2011. Metabolic syndrome was present both in women and men corresponding to 29% and 23% of the women's and men's sample, respectively. The prevalence was higher in women than in men. In women, elevated BMI, low HDL cholesterol, increased waist circumference and hyperglycemia were significantly larger contributors to the metabolic syndrome while in men these were hypertension and elevated triglycerides. The contribution of several metabolic components to the metabolic syndrome is different in men and women. This might contribute to gender specific differences in the relative risk of metabolic complications such as insulin resistance. PMID- 22829742 TI - Cloning and characterization of two neuropeptide genes from cereal cyst nematode, Heterodera avanae from India. AB - The cereal cyst nematode, Heterodera avenae (Wollenweber, 1924) is one of the most important plant parasitic nematodes of cereals. It is an obligate sedentary endo parasite causing considerable crop losses in wheat, barley and oats worldwide. FMRFamide-like peptides (FLPs) play critical role as neurotransmitters or neuromodulators in the nervous system and proposed as one of the important targets for the plant parasitic nematode management. Therefore, for the first time we have cloned and characterized two neuropeptide genes (flp-12 and flp-16) from the cDNA library of feeding female of H. avenae. Sequence analysis of FLPs revealed that both the neuropeptides are closely related with the parasitic as well as free-living nematodes. The flp-12 contains putative 22 residue long signal peptide at N-terminal suggesting its association with extra-cellular functions, while flp-16 does not contain signal peptide. Besides this, we have found highly conserved motif KFEFIRF in flp-12 and RFGK motif in flp-16. These two flp genes could be interesting and potential targets for functional validation to explore their utility for designing management strategies. PMID- 22829743 TI - Synonymous codon usage in Thermosynechococcus elongatus (cyanobacteria) identifies the factors shaping codon usage variation. AB - Analysis of synonymous codon usage pattern in the genome of a thermophilic cyanobacterium, Thermosynechococcus elongatus BP-1 using multivariate statistical analysis revealed a single major explanatory axis accounting for codon usage variation in the organism. This axis is correlated with the GC content at third base of synonymous codons (GC3s) in correspondence analysis taking T. elongatus genes. A negative correlation was observed between effective number of codons i.e. Nc and GC3s. Results suggested a mutational bias as the major factor in shaping codon usage in this cyanobacterium. In comparison to the lowly expressed genes, highly expressed genes of this organism possess significantly higher proportion of pyrimidine-ending codons suggesting that besides, mutational bias, translational selection also influenced codon usage variation in T. elongatus. Correspondence analysis of relative synonymous codon usage (RSCU) with A, T, G, C at third positions (A3s, T3s, G3s, C3s, respectively) also supported this fact and expression levels of genes and gene length also influenced codon usage. A role of translational accuracy was identified in dictating the codon usage variation of this genome. Results indicated that although mutational bias is the major factor in shaping codon usage in T. elongatus, factors like translational selection, translational accuracy and gene expression level also influenced codon usage variation. PMID- 22829744 TI - shRNAPred (version 1.0): An open source and standalone software for short hairpin RNA (shRNA) prediction. AB - The small hairpin RNAs (shRNA) are useful in many ways like identification of trait specific molecular markers, gene silencing and characterization of a species. In public domain, hardly there exists any standalone software for shRNA prediction. Hence, a software shRNAPred (1.0) is proposed here to offer a user friendly Command-line User Interface (CUI) to predict 'shRNA-like' regions from a large set of nucleotide sequences. The software is developed using PERL Version 5.12.5 taking into account the parameters such as stem and loop length combinations, specific loop sequence, GC content, melting temperature, position specific nucleotides, low complexity filter, etc. Each of the parameters is assigned with a specific score and based on which the software ranks the predicted shRNAs. The high scored shRNAs obtained from the software are depicted as potential shRNAs and provided to the user in the form of a text file. The proposed software also allows the user to customize certain parameters while predicting specific shRNAs of his interest. The shRNAPred (1.0) is open access software available for academic users. It can be downloaded freely along with user manual, example dataset and output for easy understanding and implementation. AVAILABILITY: The database is available for free at http://bioinformatics.iasri.res.in/EDA/downloads/shRNAPred_v1.0.exe. PMID- 22829745 TI - CyanoEXpress: A web database for exploration and visualisation of the integrated transcriptome of cyanobacterium Synechocystis sp. PCC6803. AB - Synechocystis sp. PCC6803 is one of the best studied cyanobacteria and an important model organism for our understanding of photosynthesis. The early availability of its complete genome sequence initiated numerous transcriptome studies, which have generated a wealth of expression data. Analysis of the accumulated data can be a powerful tool to study transcription in a comprehensive manner and to reveal underlying regulatory mechanisms, as well as to annotate genes whose functions are yet unknown. However, use of divergent microarray platforms, as well as distributed data storage make meta-analyses of Synechocystis expression data highly challenging, especially for researchers with limited bioinformatic expertise and resources. To facilitate utilisation of the accumulated expression data for a wider research community, we have developed CyanoEXpress, a web database for interactive exploration and visualisation of transcriptional response patterns in Synechocystis. CyanoEXpress currently comprises expression data for 3073 genes and 178 environmental and genetic perturbations obtained in 31 independent studies. At present, CyanoEXpress constitutes the most comprehensive collection of expression data available for Synechocystis and can be freely accessed. AVAILABILITY: The database is available for free at http://cyanoexpress.sysbiolab.eu. PMID- 22829746 TI - BioParishodhana: A novel graphical interface integrating BLAST, ClustalW, primer3 and restriction digestion tools. AB - Bioinformatics has emerged as an integral part of life sciences and biomedical research. The bioinformatics tools developed so far exist individually and do not cross talk leading biologists to spend more time in formatting the output from one tool as input for another tool. This leads to huge loss of time and cost. We herein have made platform which integrates the tools in a way that the output of one program can be directly used as input of another and does not need any modifications. Tools for similarity search, primer designing, and restriction enzyme digestion are required in almost all biological research; therefore we initially tried to integrate these tools. BioParisodhana platform optimizes the time spend in browsing and downloading applications and is an interactive, effective and user friendly. AVAILABILITY: The database is available for free at http://resource.ibab.ac.in/bioparishodhana.html. PMID- 22829747 TI - Syphilis Infection during pregnancy: fetal risks and clinical management. AB - Congenital syphilis is still a cause of perinatal morbidity and mortality. Untreated maternal infection leads to adverse pregnancy outcomes, including early fetal loss, stillbirth, prematurity, low birth weight, neonatal and infant death, and congenital disease among newborns. Clinical manifestations of congenital syphilis are influenced by gestational age, stage of maternal syphilis, maternal treatment, and immunological response of the fetus. It has been traditionally classified in early congenital syphilis and late congenital syphilis. Diagnosis of maternal infection is based on clinical findings, serological tests, and direct identification of treponemes in clinical specimens. Adequate treatment of maternal infection is effective for preventing maternal transmission to the fetus and for treating fetal infection. Prenatal diagnosis of congenital syphilis includes noninvasive and invasive diagnosis. Serological screening during pregnancy and during preconception period should be performed to reduce the incidence of congenital syphilis. PMID- 22829748 TI - Utility and safety of ERCP in the elderly: a comparative study in iran. AB - Background. The present study sought and compared the utility and safety of endoscopic retrograde cholangiopancreatography (ERCP) in the elderly and younger people in a great sample of Iranian population. Methods. Our study involved 780 patients undergoing diagnostic and therapeutic ERCP at the Taleghani hospital in Tehran between 2010 and 2011; among them, 558 patients were less than 70 years old and others were 70 years old or older. The patients were prospectively identified and data including clinical and biochemical features, ERCP procedures, ERCP diagnosis, and ERCP complications were gathered on them prospectively. Results. Clinical manifestations were comparable in young and older groups except for hepatosplenomegaly and constipation that were more prevalent in the elderly. Laboratory findings were similar in both groups other than mean levels of alkaline phosphatase, hemoglobin and albumin levels, which were higher in the elderly group. Selective biliary cannulation was technically more successful in the younger than in others (89.0% versus 81.8%). Common bile duct stone was the most frequent diagnosis in both young and older groups (36.6% and 45.9%, resp.), whereas ERCP was reported to be normal in 13.4% of the younger and 5.0% of the elderly patients. Post-ERCP complications were observed in 4.8% of patients aged less than 70 years in comparison with 2.3% of patients aged over 70 years. The most frequent complication was pancreatitis that was significantly more developed in young than older patients (3.6% versus 1.5%; OR: 8.216, P = 0.015). Conclusion. Diagnostic ERCP is safe and well tolerated in the elderly and even associated with significantly less risk than the younger. PMID- 22829749 TI - Comparison of next-generation sequencing systems. AB - With fast development and wide applications of next-generation sequencing (NGS) technologies, genomic sequence information is within reach to aid the achievement of goals to decode life mysteries, make better crops, detect pathogens, and improve life qualities. NGS systems are typically represented by SOLiD/Ion Torrent PGM from Life Sciences, Genome Analyzer/HiSeq 2000/MiSeq from Illumina, and GS FLX Titanium/GS Junior from Roche. Beijing Genomics Institute (BGI), which possesses the world's biggest sequencing capacity, has multiple NGS systems including 137 HiSeq 2000, 27 SOLiD, one Ion Torrent PGM, one MiSeq, and one 454 sequencer. We have accumulated extensive experience in sample handling, sequencing, and bioinformatics analysis. In this paper, technologies of these systems are reviewed, and first-hand data from extensive experience is summarized and analyzed to discuss the advantages and specifics associated with each sequencing system. At last, applications of NGS are summarized. PMID- 22829750 TI - The effects of chronic ingestion of mercuric chloride on fertility and testosterone levels in male Sprague Dawley rats. AB - Although male infertility is well researched, the effects of inorganic mercury on male reproduction and fertility are less well known. Studies pertaining to mercury and male fertility identified reduced concentration of testosterone in the serum of male workers, a toxic influence on fertility of organic mercury compounds within concentrations at the workplace, and increased days to pregnancy. We evaluated the effect of chronic mercuric chloride (HgCl(2)) exposure in male rats on reproductive endpoints. Thirty-day old male Sprague Dawley rats (n = 31) were exposed to 0.0, 1.0, or 2.0 mg/kg/day of HgCl(2) via gavage. After 60 days exposure, they were housed with nonexposed females for 21 days. A survivor analysis revealed the exposed animals took longer to impregnate the females and had a lower rate of impregnation. Further statistical analysis revealed a lower correlation between testicular testosterone levels and days to impregnate, and also lower sperm counts in the epididymis head and body of the exposed males. The results indicate that HgCl(2) exposure had significant adverse effects on male rat reproduction endpoints including fertility at a dose that was not clinically toxic. PMID- 22829751 TI - Evolutionary conservation and diversification of the translation initiation apparatus in trypanosomatids. AB - Trypanosomatids are ancient eukaryotic parasites that migrate between insect vectors and mammalian hosts, causing a range of diseases in humans and domestic animals. Trypanosomatids feature a multitude of unusual molecular features, including polycistronic transcription and subsequent processing by trans-splicing and polyadenylation. Regulation of protein coding genes is posttranscriptional and thus, translation regulation is fundamental for activating the developmental program of gene expression. The spliced-leader RNA is attached to all mRNAs. It contains an unusual hypermethylated cap-4 structure in its 5' end. The cap binding complex, eIF4F, has gone through evolutionary changes in accordance with the requirement to bind cap-4. The eIF4F components in trypanosomatids are highly diverged from their orthologs in higher eukaryotes, and their potential functions are discussed. The cap-binding activity in all eukaryotes is a target for regulation and plays a similar role in trypanosomatids. Recent studies revealed a novel eIF4E-interacting protein, involved in directing stage-specific and stress induced translation pathways. Translation regulation during stress also follows unusual regulatory cues, as the increased translation of Hsp83 following heat stress is driven by a defined element in the 3' UTR, unlike higher eukaryotes. Overall, the environmental switches experienced by trypanosomatids during their life cycle seem to affect their translational machinery in unique ways. PMID- 22829752 TI - Identification and Characterization of MicroRNAs in Macaca fascicularis by EST Analysis. AB - MicroRNAs (miRNAs) are small noncoding RNAs which repress gene expression at the posttranscriptional level. In this study, an expressed sequence tag (EST)-based combined method was applied for the detection of miRNAs in Macaca fascicularis which is used as a model animal extensively in medical experiments, particularly those involved with neuroscience and disease. Initially, previously known miRNA sequences from metazoans were used to blast with the EST databases of Macaca fascicularis, and then a range of filtering criteria was conducted to remove some pseudo ones. At last a total of 8 novel conserved miRNAs were identified; their functions were further predicted and analyzed. Together, our study provides insight into miRNAs and their functions in Macaca fascicularis, indicating that the EST analysis is an efficient and affordable alternative approach for identifying novel miRNA candidates. PMID- 22829753 TI - Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma. AB - Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers. PMID- 22829754 TI - Shaping the dynamics of a bidirectional neural interface. AB - Progress in decoding neural signals has enabled the development of interfaces that translate cortical brain activities into commands for operating robotic arms and other devices. The electrical stimulation of sensory areas provides a means to create artificial sensory information about the state of a device. Taken together, neural activity recording and microstimulation techniques allow us to embed a portion of the central nervous system within a closed-loop system, whose behavior emerges from the combined dynamical properties of its neural and artificial components. In this study we asked if it is possible to concurrently regulate this bidirectional brain-machine interaction so as to shape a desired dynamical behavior of the combined system. To this end, we followed a well-known biological pathway. In vertebrates, the communications between brain and limb mechanics are mediated by the spinal cord, which combines brain instructions with sensory information and organizes coordinated patterns of muscle forces driving the limbs along dynamically stable trajectories. We report the creation and testing of the first neural interface that emulates this sensory-motor interaction. The interface organizes a bidirectional communication between sensory and motor areas of the brain of anaesthetized rats and an external dynamical object with programmable properties. The system includes (a) a motor interface decoding signals from a motor cortical area, and (b) a sensory interface encoding the state of the external object into electrical stimuli to a somatosensory area. The interactions between brain activities and the state of the external object generate a family of trajectories converging upon a selected equilibrium point from arbitrary starting locations. Thus, the bidirectional interface establishes the possibility to specify not only a particular movement trajectory but an entire family of motions, which includes the prescribed reactions to unexpected perturbations. PMID- 22829755 TI - Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity. AB - Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of beta-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and its impact on overall system performance once integrated. PMID- 22829756 TI - Individual rules for trail pattern formation in Argentine ants (Linepithema humile). AB - We studied the formation of trail patterns by Argentine ants exploring an empty arena. Using a novel imaging and analysis technique we estimated pheromone concentrations at all spatial positions in the experimental arena and at different times. Then we derived the response function of individual ants to pheromone concentrations by looking at correlations between concentrations and changes in speed or direction of the ants. Ants were found to turn in response to local pheromone concentrations, while their speed was largely unaffected by these concentrations. Ants did not integrate pheromone concentrations over time, with the concentration of pheromone in a 1 cm radius in front of the ant determining the turning angle. The response to pheromone was found to follow a Weber's Law, such that the difference between quantities of pheromone on the two sides of the ant divided by their sum determines the magnitude of the turning angle. This proportional response is in apparent contradiction with the well-established non linear choice function used in the literature to model the results of binary bridge experiments in ant colonies (Deneubourg et al. 1990). However, agent based simulations implementing the Weber's Law response function led to the formation of trails and reproduced results reported in the literature. We show analytically that a sigmoidal response, analogous to that in the classical Deneubourg model for collective decision making, can be derived from the individual Weber-type response to pheromone concentrations that we have established in our experiments when directional noise around the preferred direction of movement of the ants is assumed. PMID- 22829757 TI - GDP release preferentially occurs on the phosphate side in heterotrimeric G proteins. AB - After extra-cellular stimulation of G-Protein Coupled Receptors (GPCRs), GDP/GTP exchange appears as the key, rate limiting step of the intracellular activation cycle of heterotrimeric G-proteins. Despite the availability of a large number of X-ray structures, the mechanism of GDP release out of heterotrimeric G-proteins still remains unknown at the molecular level. Starting from the available X-ray structure, extensive unconstrained/constrained molecular dynamics simulations were performed on the complete membrane-anchored Gi heterotrimer complexed to GDP, for a total simulation time overcoming 500 ns. By combining Targeted Molecular Dynamics (TMD) and free energy profiles reconstruction by umbrella sampling, our data suggest that the release of GDP was much more favored on its phosphate side. Interestingly, upon the forced extraction of GDP on this side, the whole protein encountered large, collective motions in perfect agreement with those we described previously including a domain to domain motion between the two ras-like and helical sub-domains of G(alpha). PMID- 22829758 TI - Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed; while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs. PMID- 22829759 TI - Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites. AB - Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors. PMID- 22829760 TI - A preformed binding interface in the unbound ensemble of an intrinsically disordered protein: evidence from molecular simulations. AB - Intrinsically disordered proteins play an important role in cellular signalling, mediated by their interactions with other biomolecules. A key question concerns the nature of their binding mechanism, and whether the bound structure is induced only by proximity to the binding partner. This is difficult to answer through experiment alone because of the very heterogeneous nature of the unbound ensemble, and the probable rapid interconversion of the various unbound structures. Here we report the most extensive set of simulations on NCBD to date: we use large-scale replica exchange molecular dynamics to explore the unbound state. An important feature of the study is the use of an atomistic force field that has been parametrised against experimental data for weakly structured peptides, together with an accurate explicit water model. Neither the force field nor the starting conformations are biased towards a particular structure. The regions of NCBD that have high helical propensity in the simulations correspond closely to helices in the 'core' unbound conformation determined by NMR, although no single member of the simulated unbound ensemble closely resembles the core conformation, or either of the two known bound conformations. We have validated the results against NMR spectroscopy and SAXS measurements, obtaining reasonable agreement. The two helices which most stabilise the binding of NCBD with ACTR are formed readily; the third helix, which is less important for binding but is involved in most of the intraprotein contacts of NCBD in the bound conformation, is formed more rarely, and tends not to coexist with the other helices. These results support a mechanism by which NCBD gains the advantages of disorder, while forming binding-competent structures in the unbound state. We obtain support for this mechanism from coarse-grained simulations of NCBD with, and without, its binding partner. PMID- 22829761 TI - A range-normalization model of context-dependent choice: a new model and evidence. AB - Most utility theories of choice assume that the introduction of an irrelevant option (called the decoy) to a choice set does not change the preference between existing options. On the contrary, a wealth of behavioral data demonstrates the dependence of preference on the decoy and on the context in which the options are presented. Nevertheless, neural mechanisms underlying context-dependent preference are poorly understood. In order to shed light on these mechanisms, we design and perform a novel experiment to measure within-subject decoy effects. We find within-subject decoy effects similar to what have been shown previously with between-subject designs. More importantly, we find that not only are the decoy effects correlated, pointing to similar underlying mechanisms, but also these effects increase with the distance of the decoy from the original options. To explain these observations, we construct a plausible neuronal model that can account for decoy effects based on the trial-by-trial adjustment of neural representations to the set of available options. This adjustment mechanism, which we call range normalization, occurs when the nervous system is required to represent different stimuli distinguishably, while being limited to using bounded neural activity. The proposed model captures our experimental observations and makes new predictions about the influence of the choice set size on the decoy effects, which are in contrast to previous models of context-dependent choice preference. Critically, unlike previous psychological models, the computational resource required by our range-normalization model does not increase exponentially as the set size increases. Our results show that context-dependent choice behavior, which is commonly perceived as an irrational response to the presence of irrelevant options, could be a natural consequence of the biophysical limits of neural representation in the brain. PMID- 22829763 TI - Fungal disease and the developing story of bat white-nose syndrome. PMID- 22829762 TI - Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells. AB - Vaccines may help reduce the growing incidence of fungal infections in immune suppressed patients. We have found that, even in the absence of CD4(+) T-cell help, vaccine-induced CD8(+) T cells persist and confer resistance against Blastomyces dermatitidis and Histoplasma capsulatum. Type 1 cytokines contribute to that resistance, but they also are dispensable. Although the role of T helper 17 cells in immunity to fungi is debated, IL-17 producing CD8(+) T cells (Tc17 cells) have not been investigated. Here, we show that Tc17 cells are indispensable in antifungal vaccine immunity in hosts lacking CD4(+) T cells. Tc17 cells are induced upon vaccination, recruited to the lung on pulmonary infection, and act non-redundantly in mediating protection in a manner that requires neutrophils. Tc17 cells did not influence type I immunity, nor did the lack of IL-12 signaling augment Tc17 cells, indicating a distinct lineage and function. IL-6 was required for Tc17 differentiation and immunity, but IL-1R1 and Dectin-1 signaling was unexpectedly dispensable. Tc17 cells expressed surface CXCR3 and CCR6, but only the latter was essential in recruitment to the lung. Although IL-17 producing T cells are believed to be short-lived, effector Tc17 cells expressed low levels of KLRG1 and high levels of the transcription factor TCF-1, predicting their long-term survival and stem-cell like behavior. Our work has implications for designing vaccines against fungal infections in immune suppressed patients. PMID- 22829764 TI - Pathogenicity and transmissibility of North American triple reassortant swine influenza A viruses in ferrets. AB - North American triple reassortant swine (TRS) influenza A viruses have caused sporadic human infections since 2005, but human-to-human transmission has not been documented. These viruses have six gene segments (PB2, PB1, PA, HA, NP, and NS) closely related to those of the 2009 H1N1 pandemic viruses. Therefore, understanding of these viruses' pathogenicity and transmissibility may help to identify determinants of virulence of the 2009 H1N1 pandemic viruses and to elucidate potential human health threats posed by the TRS viruses. Here we evaluated in a ferret model the pathogenicity and transmissibility of three groups of North American TRS viruses containing swine-like and/or human-like HA and NA gene segments. The study was designed only to detect informative and significant patterns in the transmissibility and pathogenicity of these three groups of viruses. We observed that irrespective of their HA and NA lineages, the TRS viruses were moderately pathogenic in ferrets and grew efficiently in both the upper and lower respiratory tracts. All North American TRS viruses studied were transmitted between ferrets via direct contact. However, their transmissibility by respiratory droplets was related to their HA and NA lineages: TRS viruses with human-like HA and NA were transmitted most efficiently, those with swine-like HA and NA were transmitted minimally or not transmitted, and those with swine-like HA and human-like NA (N2) showed intermediate transmissibility. We conclude that the lineages of HA and NA may play a crucial role in the respiratory droplet transmissibility of these viruses. These findings have important implications for pandemic planning and warrant confirmation. PMID- 22829765 TI - Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China. AB - A key observation about the human immune response to repeated exposure to influenza A is that the first strain infecting an individual apparently produces the strongest adaptive immune response. Although antibody titers measure that response, the interpretation of titers to multiple strains--from the same sera- in terms of infection history is clouded by age effects, cross reactivity and immune waning. From July to September 2009, we collected serum samples from 151 residents of Guangdong Province, China, 7 to 81 years of age. Neutralization tests were performed against strains representing six antigenic clusters of H3N2 influenza circulating between 1968 and 2008, and three recent locally circulating strains. Patterns of neutralization titers were compared based on age at time of testing and age at time of the first isolation of each virus. Neutralization titers were highest for H3N2 strains that circulated in an individual's first decade of life (peaking at 7 years). Further, across strains and ages at testing, statistical models strongly supported a pattern of titers declining smoothly with age at the time a strain was first isolated. Those born 10 or more years after a strain emerged generally had undetectable neutralization titers to that strain (<1:10). Among those over 60 at time of testing, titers tended to increase with age. The observed pattern in H3N2 neutralization titers can be characterized as one of antigenic seniority: repeated exposure and the immune response combine to produce antibody titers that are higher to more 'senior' strains encountered earlier in life. PMID- 22829766 TI - A cytotoxic type III secretion effector of Vibrio parahaemolyticus targets vacuolar H+-ATPase subunit c and ruptures host cell lysosomes. AB - Vibrio parahaemolyticus is one of the human pathogenic vibrios. During the infection of mammalian cells, this pathogen exhibits cytotoxicity that is dependent on its type III secretion system (T3SS1). VepA, an effector protein secreted via the T3SS1, plays a major role in the T3SS1-dependent cytotoxicity of V. parahaemolyticus. However, the mechanism by which VepA is involved in T3SS1 dependent cytotoxicity is unknown. Here, we found that protein transfection of VepA into HeLa cells resulted in cell death, indicating that VepA alone is cytotoxic. The ectopic expression of VepA in yeast Saccharomyces cerevisiae interferes with yeast growth, indicating that VepA is also toxic in yeast. A yeast genome-wide screen identified the yeast gene VMA3 as essential for the growth inhibition of yeast by VepA. Although VMA3 encodes subunit c of the vacuolar H(+)-ATPase (V-ATPase), the toxicity of VepA was independent of the function of V-ATPases. In HeLa cells, knockdown of V-ATPase subunit c decreased VepA-mediated cytotoxicity. We also demonstrated that VepA interacted with V ATPase subunit c, whereas a carboxyl-terminally truncated mutant of VepA (VepADeltaC), which does not show toxicity, did not. During infection, lysosomal contents leaked into the cytosol, revealing that lysosomal membrane permeabilization occurred prior to cell lysis. In a cell-free system, VepA was sufficient to induce the release of cathepsin D from isolated lysosomes. Therefore, our data suggest that the bacterial effector VepA targets subunit c of V-ATPase and induces the rupture of host cell lysosomes and subsequent cell death. PMID- 22829767 TI - Structure-guided alterations of the gp41-directed HIV-1 broadly neutralizing antibody 2F5 reveal new properties regarding its neutralizing function. AB - The broadly neutralizing HIV-1 antibody 2F5 recognizes an epitope in the gp41 membrane proximal external region (MPER). The MPER adopts a helical conformation as free peptide, as post-fusogenic forms of gp41, and when bound to the 4E10 monoclonal antibody (Mab). However, when bound to 2F5, the epitope is an extended loop. The antibody-peptide structure reveals binding between the heavy and light chains with most the long, hydrophobic CDRH3 not contacting peptide. However, mutagenesis identifies this loop as critical for binding, neutralization and for putative hydrophobic membrane interactions. Here, we examined length requirements of the 2F5 CDRH3 and plasticity regarding binding and neutralization. We generated 2F5 variants possessing either longer or shorter CDRH3s and assessed function. The CDRH3 tolerated elongations and reductions up to four residues, displaying a range of binding affinities and retaining some neutralizing capacity. 2F5 antibody variants selective recognition of conformationally distinctive MPER probes suggests a new role for the CDRH3 loop in destabilizing the helical MPER. Binding and neutralization were enhanced by targeted tryptophan substitutions recapitulating fully the activities of the wild-type 2F5 antibody in a shorter CDRH3 variant. MPER alanine scanning revealed binding contacts of this variant downstream of the 2F5 core epitope, into the 4E10 epitope region. This variant displayed increased reactivity to cardiolipin-beta-2-glycoprotein. Tyrosine replacements maintained neutralization while eliminating cardiolipin beta-2-glycoprotein interaction. The data suggest a new mechanism of action, important for vaccine design, in which the 2F5 CDRH3 contacts and destabilizes the MPER helix downstream of its core epitope to allow induction of the extended loop conformation. PMID- 22829768 TI - The pore-forming toxin beta hemolysin/cytolysin triggers p38 MAPK-dependent IL-10 production in macrophages and inhibits innate immunity. AB - Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns and immune-compromised adults. The pore-forming toxin (PFT) beta hemolysin/cytolysin (betah/c) is a major virulence factor for GBS, which is generally attributed to its cytolytic functions. Here we show betah/c has immunomodulatory properties on macrophages at sub-lytic concentrations. betah/c mediated activation of p38 MAPK drives expression of the anti-inflammatory and immunosuppressive cytokine IL-10, and inhibits both IL-12 and NOS2 expression in GBS-infected macrophages, which are critical factors in host defense. Isogenic mutant bacteria lacking betah/c fail to activate p38-mediated IL-10 production in macrophages and promote increased IL-12 and NOS2 expression. Furthermore, targeted deletion of p38 in macrophages increases resistance to invasive GBS infection in mice, associated with impaired IL-10 induction and increased IL-12 production in vivo. These data suggest p38 MAPK activation by betah/c contributes to evasion of host defense through induction of IL-10 expression and inhibition of macrophage activation, a new mechanism of action for a PFT and a novel anti inflammatory role for p38 in the pathogenesis of invasive bacterial infection. Our studies suggest p38 MAPK may represent a new therapeutic target to blunt virulence and improve clinical outcome of invasive GBS infection. PMID- 22829769 TI - Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection. AB - Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease. PMID- 22829770 TI - Mgat1-dependent N-glycosylation of membrane components primes Drosophila melanogaster blood cells for the cellular encapsulation response. AB - In nature, larvae of the fruitfly Drosophila melanogaster are commonly infected by parasitoid wasps, and so have evolved a robust immune response to counter wasp infection. In this response, fly immune cells form a multilayered capsule surrounding the wasp egg, leading to death of the parasite. Many of the molecular mechanisms underlying this encapsulation response are conserved with human immune responses. Our findings suggest that protein N-glycosylation, a common protein post-translational modification of human immune proteins, may be one such conserved mechanism. We found that membrane proteins on Drosophila immune cells are N-glycosylated in a temporally specific manner following wasp infection. Furthermore we have identified mutations in eight genes encoding enzymes of the N glycosylation pathway that decrease fly resistance to wasp infection. More specifically, loss of protein N-glycosylation in immune cells following wasp infection led to the formation of defective capsules, which disintegrated over time and were thereby unsuccessful at preventing wasp development. Interestingly, we also found that one species of Drosophila parasitoid wasp, Leptopilina victoriae, targets protein N-glycosylation as part of its virulence mechanism, and that overexpression of an N-glycosylation enzyme could confer resistance against this wasp species to otherwise susceptible flies. Taken together, these findings demonstrate that protein N-glycosylation is a key player in Drosophila cellular encapsulation and suggest that this response may provide a novel model to study conserved roles of protein glycosylation in immunity. PMID- 22829772 TI - Differential impact of the HEN1 homolog HENN-1 on 21U and 26G RNAs in the germline of Caenorhabditis elegans. AB - RNA interference (RNAi)-related pathways affect gene activity by sequence specific recruitment of Ago proteins to mRNA target molecules. The sequence specificity of this process stems from small RNA (sRNA) co-factors bound by the Ago protein. Stability of sRNA molecules in some pathways is in part regulated by Hen1-mediated methylation of their 3' ends. Here we describe the effects of the Caenorhabditis elegans HEN1 RNA-methyl-transferase homolog, HENN-1, on the different RNAi pathways in this nematode. We reveal differential effects of HENN 1 on the two pathways that are known to employ methylated sRNA molecules: the 26G and 21U pathways. Surprisingly, in the germline, stability of 21U RNAs, the C. elegans piRNAs, is only mildly affected by loss of methylation; and introduction of artificial 21U target RNA does not further destabilize non-methylated 21U RNAs. In contrast, most 26G RNAs display reduced stability and respond to loss of HENN-1 by displaying increased 3'-uridylation frequencies. Within the 26G RNA class, we find that specifically ERGO-1-bound 26G RNAs are modified by HENN-1, while ALG-3/ALG-4-bound 26G RNAs are not. Global gene expression analysis of henn 1 mutants reveals mild effects, including down-regulation of many germline expressed genes. Our data suggest that, apart from direct effects of reduced 26G RNA levels of henn-1 on gene expression, most effects on global gene expression are indirect. These studies further refine our understanding of endogenous RNAi in C. elegans and the roles for Hen1 like enzymes in these pathways. PMID- 22829771 TI - Evidence of inbreeding depression on human height. AB - Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (chi(2) = 83.89, df = 1; p = 5.2 * 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance. PMID- 22829773 TI - The chicken frizzle feather is due to an alpha-keratin (KRT75) mutation that causes a defective rachis. AB - Feathers have complex forms and are an excellent model to study the development and evolution of morphologies. Existing chicken feather mutants are especially useful for identifying genetic determinants of feather formation. This study focused on the gene F, underlying the frizzle feather trait that has a characteristic curled feather rachis and barbs in domestic chickens. Our developmental biology studies identified defects in feather medulla formation, and physical studies revealed that the frizzle feather curls in a stepwise manner. The frizzle gene is transmitted in an autosomal incomplete dominant mode. A whole-genome linkage scan of five pedigrees with 2678 SNPs revealed association of the frizzle locus with a keratin gene-enriched region within the linkage group E22C19W28_E50C23. Sequence analyses of the keratin gene cluster identified a 69 bp in-frame deletion in a conserved region of KRT75, an alpha-keratin gene. Retroviral-mediated expression of the mutated F cDNA in the wild-type rectrix qualitatively changed the bending of the rachis with some features of frizzle feathers including irregular kinks, severe bending near their distal ends, and substantially higher variations among samples in comparison to normal feathers. These results confirmed KRT75 as the F gene. This study demonstrates the potential of our approach for identifying genetic determinants of feather forms. PMID- 22829774 TI - Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. AB - The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers. PMID- 22829775 TI - Induction of cytoprotective pathways is central to the extension of lifespan conferred by multiple longevity pathways. AB - Many genetic and physiological treatments that extend lifespan also confer resistance to a variety of stressors, suggesting that cytoprotective mechanisms underpin the regulation of longevity. It has not been established, however, whether the induction of cytoprotective pathways is essential for lifespan extension or merely correlated. Using a panel of GFP-fused stress response genes, we identified the suites of cytoprotective pathways upregulated by 160 gene inactivations known to increase Caenorhabditis elegans longevity, including the mitochondrial UPR (hsp-6, hsp-60), the ER UPR (hsp-4), ROS response (sod-3, gst 4), and xenobiotic detoxification (gst-4). We then screened for other gene inactivations that disrupt the induction of these responses by xenobiotic or genetic triggers, identifying 29 gene inactivations required for cytoprotective gene expression. If cytoprotective responses contribute directly to lifespan extension, inactivation of these genes would be expected to compromise the extension of lifespan conferred by decreased insulin/IGF-1 signaling, caloric restriction, or the inhibition of mitochondrial function. We find that inactivation of 25 of 29 cytoprotection-regulatory genes shortens the extension of longevity normally induced by decreased insulin/IGF-1 signaling, disruption of mitochondrial function, or caloric restriction, without disrupting normal longevity nearly as dramatically. These data demonstrate that induction of cytoprotective pathways is central to longevity extension and identify a large set of new genetic components of the pathways that detect cellular damage and couple that detection to downstream cytoprotective effectors. PMID- 22829777 TI - Balancing selection at the tomato RCR3 Guardee gene family maintains variation in strength of pathogen defense. AB - Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the "Guard Hypothesis," R proteins (the "guards") can sense modification of target molecules in the host (the "guardees") by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the "guardee effector" interface for pathogen recognition, natural selection acts on the "guard-guardee" interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen. PMID- 22829779 TI - The Aspergillus nidulans MAPK module AnSte11-Ste50-Ste7-Fus3 controls development and secondary metabolism. AB - The sexual Fus3 MAP kinase module of yeast is highly conserved in eukaryotes and transmits external signals from the plasma membrane to the nucleus. We show here that the module of the filamentous fungus Aspergillus nidulans (An) consists of the AnFus3 MAP kinase, the upstream kinases AnSte7 and AnSte11, and the AnSte50 adaptor. The fungal MAPK module controls the coordination of fungal development and secondary metabolite production. It lacks the membrane docking yeast Ste5 scaffold homolog; but, similar to yeast, the entire MAPK module's proteins interact with each other at the plasma membrane. AnFus3 is the only subunit with the potential to enter the nucleus from the nuclear envelope. AnFus3 interacts with the conserved nuclear transcription factor AnSte12 to initiate sexual development and phosphorylates VeA, which is a major regulatory protein required for sexual development and coordinated secondary metabolite production. Our data suggest that not only Fus3, but even the entire MAPK module complex of four physically interacting proteins, can migrate from plasma membrane to nuclear envelope. PMID- 22829778 TI - RsfA (YbeB) proteins are conserved ribosomal silencing factors. AB - The YbeB (DUF143) family of uncharacterized proteins is encoded by almost all bacterial and eukaryotic genomes but not archaea. While they have been shown to be associated with ribosomes, their molecular function remains unclear. Here we show that YbeB is a ribosomal silencing factor (RsfA) in the stationary growth phase and during the transition from rich to poor media. A knock-out of the rsfA gene shows two strong phenotypes: (i) the viability of the mutant cells are sharply impaired during stationary phase (as shown by viability competition assays), and (ii) during transition from rich to poor media the mutant cells adapt slowly and show a growth block of more than 10 hours (as shown by growth competition assays). RsfA silences translation by binding to the L14 protein of the large ribosomal subunit and, as a consequence, impairs subunit joining (as shown by molecular modeling, reporter gene analysis, in vitro translation assays, and sucrose gradient analysis). This particular interaction is conserved in all species tested, including Escherichia coli, Treponema pallidum, Streptococcus pneumoniae, Synechocystis PCC 6803, as well as human mitochondria and maize chloroplasts (as demonstrated by yeast two-hybrid tests, pull-downs, and mutagenesis). RsfA is unrelated to the eukaryotic ribosomal anti-association/60S assembly factor eIF6, which also binds to L14, and is the first such factor in bacteria and organelles. RsfA helps cells to adapt to slow-growth/stationary phase conditions by down-regulating protein synthesis, one of the most energy consuming processes in both bacterial and eukaryotic cells. PMID- 22829780 TI - The secreted immunoglobulin domain proteins ZIG-5 and ZIG-8 cooperate with L1CAM/SAX-7 to maintain nervous system integrity. AB - During nervous system development, neuronal cell bodies and their axodendritic projections are precisely positioned through transiently expressed patterning cues. We show here that two neuronally expressed, secreted immunoglobulin (Ig) domain-containing proteins, ZIG-5 and ZIG-8, have no detectable role during embryonic nervous system development of the nematode Caenorhabditis elegans but are jointly required for neuronal soma and ventral cord axons to maintain their correct position throughout postembryonic life of the animal. The maintenance defects observed upon removal of zig-5 and zig-8 are similar to those observed upon complete loss of the SAX-7 protein, the C. elegans ortholog of the L1CAM family of adhesion proteins, which have been implicated in several neurological diseases. SAX-7 exists in two isoforms: a canonical, long isoform (SAX-7L) and a more adhesive shorter isoform lacking the first two Ig domains (SAX-7S). Unexpectedly, the normally essential function of ZIG-5 and ZIG-8 in maintaining neuronal soma and axon position is completely suppressed by genetic removal of the long SAX-7L isoform. Overexpression of the short isoform SAX-7S also abrogates the need for ZIG-5 and ZIG-8. Conversely, overexpression of the long isoform disrupts adhesion, irrespective of the presence of the ZIG proteins. These findings suggest an unexpected interdependency of distinct Ig domain proteins, with one isoform of SAX-7, SAX-7L, inhibiting the function of the most adhesive isoform, SAX-7S, and this inhibition being relieved by ZIG-5 and ZIG-8. Apart from extending our understanding of dedicated neuronal maintenance mechanisms, these findings provide novel insights into adhesive and anti-adhesive functions of IgCAM proteins. PMID- 22829776 TI - A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. AB - Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 * 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 * 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 * 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 * 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 * 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 * 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 * 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 * 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 * 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 * 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 * 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 * 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 * 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3 TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. PMID- 22829781 TI - Histone H2B monoubiquitination facilitates the rapid modulation of gene expression during Arabidopsis photomorphogenesis. AB - Profiling of DNA and histone modifications has recently allowed the establishment of reference epigenomes from several model organisms. This identified a major chromatin state for active genes that contains monoubiquitinated H2B (H2Bub), a mark linked to transcription elongation. However, assessment of dynamic chromatin changes during the reprogramming of gene expression in response to extrinsic or developmental signals has been more difficult. Here we used the major developmental switch that Arabidopsis thaliana plants undergo upon their initial perception of light, known as photomorphogenesis, as a paradigm to assess spatial and temporal dynamics of monoubiquitinated H2B (H2Bub) and its impact on transcriptional responses. The process involves rapid and extensive transcriptional reprogramming and represents a developmental window well suited to studying cell division-independent chromatin changes. Genome-wide H2Bub distribution was determined together with transcriptome profiles at three time points during early photomorphogenesis. This revealed de novo marking of 177 genes upon the first hour of illumination, illustrating the dynamic nature of H2Bub enrichment in a genomic context. Gene upregulation was associated with H2Bub enrichment, while H2Bub levels generally remained stable during gene downregulation. We further report that H2Bub influences the modulation of gene expression, as both gene up- and downregulation were globally weaker in hub1 mutant plants that lack H2Bub. H2Bub-dependent regulation notably impacted genes with fast and transient light induction, and several circadian clock components whose mRNA levels are tightly regulated by sharp oscillations. Based on these findings, we propose that H2B monoubiquitination is part of a transcription coupled, chromatin-based mechanism to rapidly modulate gene expression. PMID- 22829782 TI - Reversal of PCNA ubiquitylation by Ubp10 in Saccharomyces cerevisiae. AB - Regulation of PCNA ubiquitylation plays a key role in the tolerance to DNA damage in eukaryotes. Although the evolutionary conserved mechanism of PCNA ubiquitylation is well understood, the deubiquitylation of ubPCNA remains poorly characterized. Here, we show that the histone H2B(K123) ubiquitin protease Ubp10 also deubiquitylates ubPCNA in Saccharomyces cerevisiae. Our results sustain that Ubp10-dependent deubiquitylation of the sliding clamp PCNA normally takes place during S phase, likely in response to the simple presence of ubPCNA. In agreement with this, we show that Ubp10 forms a complex with PCNA in vivo. Interestingly, we also show that deletion of UBP10 alters in different ways the interaction of PCNA with DNA polymerase zeta-associated protein Rev1 and with accessory subunit Rev7. While deletion of UBP10 enhances PCNA-Rev1 interaction, it decreases significantly Rev7 binding to the sliding clamp. Finally, we report that Ubp10 counteracts Rad18 E3-ubiquitin ligase activity on PCNA at lysine 164 in such a manner that deregulation of Ubp10 expression causes tolerance impairment and MMS hypersensitivity. PMID- 22829783 TI - The Caenorhabditis elegans gene mfap-1 encodes a nuclear protein that affects alternative splicing. AB - RNA splicing is a major regulatory mechanism for controlling eukaryotic gene expression. By generating various splice isoforms from a single pre-mRNA, alternative splicing plays a key role in promoting the evolving complexity of metazoans. Numerous splicing factors have been identified. However, the in vivo functions of many splicing factors remain to be understood. In vivo studies are essential for understanding the molecular mechanisms of RNA splicing and the biology of numerous RNA splicing-related diseases. We previously isolated a Caenorhabditis elegans mutant defective in an essential gene from a genetic screen for suppressors of the rubberband Unc phenotype of unc-93(e1500) animals. This mutant contains missense mutations in two adjacent codons of the C. elegans microfibrillar-associated protein 1 gene mfap-1. mfap-1(n4564 n5214) suppresses the Unc phenotypes of different rubberband Unc mutants in a pattern similar to that of mutations in the splicing factor genes uaf-1 (the C. elegans U2AF large subunit gene) and sfa-1 (the C. elegans SF1/BBP gene). We used the endogenous gene tos-1 as a reporter for splicing and detected increased intron 1 retention and exon 3 skipping of tos-1 transcripts in mfap-1(n4564 n5214) animals. Using a yeast two-hybrid screen, we isolated splicing factors as potential MFAP-1 interactors. Our studies indicate that C. elegans mfap-1 encodes a splicing factor that can affect alternative splicing. PMID- 22829784 TI - GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program. AB - The antagonistic actions of Polycomb and Trithorax are responsible for proper cell fate determination in mammalian tissues. In the epidermis, a self-renewing epithelium, previous work has shown that release from Polycomb repression only partially explains differentiation gene activation. We now show that Trithorax is also a key regulator of epidermal differentiation, not only through activation of genes repressed by Polycomb in progenitor cells, but also through activation of genes independent of regulation by Polycomb. The differentiation associated transcription factor GRHL3/GET1 recruits the ubiquitously expressed Trithorax complex to a subset of differentiation genes. PMID- 22829786 TI - U.S. EPA authority to use cumulative risk assessments in environmental decision making. AB - Conventionally, in its decision-making, the U.S. EPA has evaluated the effects and risks associated with a single pollutant in a single exposure medium. In reality, people are exposed to mixtures of pollutants or to the same pollutant through a variety of media, including the air, water, and food. It is now more recognized than before that environmental exposure to pollutants occurs via multiple exposure routes and pathways, including inhalation, ingestion, and dermal absorption. Moreover, chemical, biologic, radiologic, physical, and psychologic stressors are all acknowledged as affecting human health. Although many EPA offices attempt to consider cumulative risk assessment and cumulative effects in various ways, there is no Agency-wide policy for considering these risks and the effects of exposure to these risks when making environmental decisions. This article examines how U.S. courts might assess EPA's general authority and discretion to use cumulative risk assessment as the basis for developing data in support of environmental decision-making, and how courts might assess the validity of a cumulative risk assessment methodology itself. PMID- 22829785 TI - Genomic data reveal a complex making of humans. AB - In the last few years, two paradigms underlying human evolution have crumbled. Modern humans have not totally replaced previous hominins without any admixture, and the expected signatures of adaptations to new environments are surprisingly lacking at the genomic level. Here we review current evidence about archaic admixture and lack of strong selective sweeps in humans. We underline the need to properly model differential admixture in various populations to correctly reconstruct past demography. We also stress the importance of taking into account the spatial dimension of human evolution, which proceeded by a series of range expansions that could have promoted both the introgression of archaic genes and background selection. PMID- 22829787 TI - Road dust lead (Pb) in two neighborhoods of urban Atlanta, (GA, USA). AB - Road dust continues to be a major potential reservoir of Pb in the urban environment, and an important potential component of child Pb exposure. This study presents ICP-AES analyses of metals in 72 samples of road dust (<250 um) collected in the urban core of Atlanta, Georgia. In the Downtown area, median Pb concentrations are ~63 mg/kg Pb, with high values of 278 mg/kg. For comparison, median Pb values in a nearby residential neighborhood (also in the urban core) were ~93 mg/kg, with a high of 972 mg/kg. Geospatial variability is high, with significant variation observed over tens to hundreds of meters. Spearman Rank Correlation tests suggest that Pb and other metals (Cu, Ni, V, Zn) are associated with iron and manganese oxide phases in the residential area, as reported in other cities. However, Pb in the Downtown area is not correlated with the others, suggesting a difference in source or transport history. Given these complexities and the expected differences between road dust and soil Pb, future efforts to assess exposure risk should therefore be based on spatially distributed sampling at very high spatial resolution. PMID- 22829788 TI - Spatial autocorrelation analysis of Chinese inter-provincial industrial chemical oxygen demand discharge. AB - A spatial autocorrelation analysis method is adopted to process the spatial dynamic change of industrial Chemical Oxygen Demand (COD) discharge in China over the past 15 years. Studies show that amount and intensity of industrial COD discharges are on a decrease, and the tendency is more remarkable for discharge intensity. There are large differences between inter-provincial discharge amount and intensity, and with different spatial differentiation features. Global spatial autocorrelation analysis reveals that Global Moran's I of discharge amount and intensity is on the decrease. In space, there is an evolution from an agglomeration pattern to a discretization pattern. Local spatial autocorrelation analysis shows that the agglomeration area of industrial COD discharge amount and intensity varies greatly in space with time. Stringent environmental regulations and increased funding for environmental protections are the crucial factors to cut down industrial COD discharge amount and intensity. PMID- 22829789 TI - Molecular detection and drug resistance of Mycobacterium tuberculosis complex from cattle at a dairy farm in the Nkonkobe region of South Africa: a pilot study. AB - Mycobacterium tuberculosis complex (MTBC) causes tuberculosis (TB) in humans and animals. We investigated the presence of MTBC in cattle milk and its drug resistance using polymerase chain reaction (PCR). Two hundred samples (100 mL each) were obtained from a dairy farm in the Nkonkobe region of South Africa. The samples were processed using the modified Petroff method. DNA was isolated using a Zymo Bacterial DNA kit and amplified using Seeplex((r)) MTB Nested ACE assay. The Genotype((r)) Mycobacterium tuberculosis-multidrug resistantplus (MTBDRplus) assay was used to perform drug susceptibility and detection of mutations conferring resistance to isoniazid (INH) and rifampicin (RIF). Eleven samples tested positive for MTBC DNA using the Seeplex((r)) MTB Nested ACE assay. The Genotype((r)) MTBDRplus assay showed that 10/11 samples were resistant to both INH and RIF i.e., multi-drug resistant (MDR). The most and least frequent rpoB mutations detected in RIF resistant samples were H526Y (9/10) and D516V (2/10) respectively. None of the INH resistant samples harbored mutations in the katG gene. However, all of them harbored the T8A mutation in the inhA gene. These results have clinical and epidemiological significance and calls for further studies and necessary actions to delineate the situation. PMID- 22829790 TI - Scenario simulation-based assessment of trip difficulty for urban residents under rainstorm waterlogging. AB - In this study, an experiment was performed to assess the trip difficulty for urban residents of different age groups walking in various depths of water, and the data were corroborated with the real urban rainstorm waterlogging scenarios in downtown (Daoli district) Ha-Erbin (China). Mathematical models of urban rainstorm waterlogging were constructed using scenario simulation methods, aided by the GIS spatial analysis technology and hydrodynamic analysis of the waterway systems in the study area. Then these models were used to evaluate the impact of waterlogging on the safety of residents walking in the affected area. Results are summarized as: (1) for an urban rainstorm waterlogging scenario reoccurring once every 10 years, three grid regions would have waterlogging above 0.5 m moving at a velocity of 1.5 m/s. Under this scenario, waterlogging would accumulate on traffic roads only in small areas, affecting the safety and mobility of residents walking in the neighborhood; (2) for an urban rainstorm waterlogging scenario reoccurring once every 20 years, 13 grids experienced the same waterlogging situation affecting a larger area of the city; (3) for an urban rainstorm waterlogging scenario reoccurring once every 50 years, 86 grid regions were affected (waterlogging above 0.5 m moving at 1.5 m/s), and those areas would become impassable for residents. PMID- 22829793 TI - Thermostable bacterial bioflocculant produced by Cobetia spp. isolated from Algoa Bay (South Africa). AB - A novel bioflocculant-producing bacteria was isolated from sediment samples of Algoa Bay in the Eastern Cape Province of South Africa and the effect of culture conditions on the bioflocculant production was investigated. Analysis of the partial nucleotide sequence of the 16S rDNA of the bacteria revealed 99% similarity to Cobetia sp. L222 and the sequence was deposited in GenBank as Cobetia sp. OAUIFE (accession number JF799092). Cultivation condition studies revealed that bioflocculant production was optimal with an inoculum size of 2% (v/v), initial pH of 6.0, Mn(2+) as the metal ion, and glucose as the carbon source. Metal ions, including Na(+), K(+), Li(+), Ca(2+)and Mg(2+) stimulated bioflocculant production, resulting in flocculating activity of above 90%. This crude bioflocculant is thermally stable, with about 78% of its flocculating activity remaining after heating at 100 degrees C for 25 min. Analysis of the purified bioflocculant revealed it to be an acidic extracellular polysaccharide. PMID- 22829791 TI - Mechanism of generation of therapy related leukemia in response to anti topoisomerase II agents. AB - Type II DNA topoisomerases have the ability to generate a transient DNA double strand break through which a second duplex can be passed; an activity essential for DNA decatenation and unknotting. Topoisomerase poisons stabilize the normally transient topoisomerase-induced DSBs and are potent and widely used anticancer drugs. However, their use is associated with therapy-related secondary leukemia, often bearing 11q23 translocations involving the MLL gene. We will explain recent discoveries in the fields of topoisomerase biology and transcription that have consequences for our understanding of the etiology of leukemia, especially therapy-related secondary leukemia and describe how these findings may help minimize the occurrence of these neoplasias. PMID- 22829792 TI - Prevalence of multiple antibiotics resistant (MAR) Pseudomonas species in the final effluents of three municipal wastewater treatment facilities in South Africa. AB - The final effluents of three (Alice, Dimbaza, and East London) wastewater treatment plants (WWTPs) were evaluated to determine their physicochemical quality and prevalence of multiple antibiotics resistant (MAR) Pseudomonas species, between August 2007 and July 2008. The annual mean total Pseudomonas count (TPC) was 1.20 * 10(4) (cfu/100 mL), 1.08 * 10(4) (cfu/100 mL), and 2.66 * 10(4) (cfu/100 mL), for the Alice, Dimbaza, and East London WWTPs respectively. The effluents were generally compliant with recommended limits for pH, temperature, TDS, DO, nitrite and nitrate; but fell short of target standards for turbidity, COD, and phosphate. The tested isolates were highly sensitive to gentamicin (100%), ofloxacin (100%), clindamycin (90%), erythromycin (90%) and nitrofurantoin (80%); whereas high resistance was observed against the penicillins (90-100%), rifampin (90%), sulphamethoxazole (90%) and the cephems (70%). MAR index ranged between 0.26 and 0.58. The study demonstrated that MAR Pseudomonas species were quite prevalent in the final effluents of WWTPs in South Africa; and this can lead to serious health risk for communities that depend on the effluent-receiving waters for sundry purposes. PMID- 22829794 TI - Gain-framed messages do not motivate sun protection: a meta-analytic review of randomized trials comparing gain-framed and loss-framed appeals for promoting skin cancer prevention. AB - Persuading people to undertake actions to prevent skin cancer is an important public health challenge. A number of studies have compared the effectiveness of gain-framed and loss-framed appeals in this domain, often expecting gain-framed appeals to be more persuasive. A meta-analytic review (k = 33, N = 4,168), however, finds no significant difference in the persuasiveness of gain- and loss framed appeals for encouraging skin cancer prevention. This conclusion is unaffected by differences in the specific protective action advocated or by differences in the kind of outcomes invoked. But the results offer an intimation that men might be more susceptible to framing variations in this domain--with loss-framed appeals potentially having a persuasive advantage. PMID- 22829795 TI - Human health and climate change: leverage points for adaptation in urban environments. AB - The design of adaptation strategies that promote urban health and well-being in the face of climate change requires an understanding of the feedback interactions that take place between the dynamical state of a city, the health of its people, and the state of the planet. Complexity, contingency and uncertainty combine to impede the growth of such systemic understandings. In this paper we suggest that the collaborative development of conceptual models can help a group to identify potential leverage points for effective adaptation. We describe a three-step procedure that leads from the development of a high-level system template, through the selection of a problem space that contains one or more of the group's adaptive challenges, to a specific conceptual model of a sub-system of importance to the group. This procedure is illustrated by a case study of urban dwellers' maladaptive dependence on private motor vehicles. We conclude that a system dynamics approach, revolving around the collaborative construction of a set of conceptual models, can help communities to improve their adaptive capacity, and so better meet the challenge of maintaining, and even improving, urban health in the face of climate change. PMID- 22829796 TI - The US/Mexico border: a binational approach to framing challenges and constructing solutions for improving farmworkers' lives. AB - Mexican migrant and seasonal farmworkers in the US-Mexico border region face health hazards and occupational risks and are becoming commonly known in the public health literature. According to several studies, farmworkers have high levels of chronic diseases such as diabetes and respiratory problems, are at risk for infectious diseases, and experience among the highest incidences of work related injuries of any profession. The findings from two studies are considered and presented with the objective of contributing to an overall understanding of migrant farmworkers as a workforce moving across national boundaries and affected by the work environments and health stressors both shared and unique to each context. We propose a binational approach to comprehensively address the health problems and socioeconomic challenges faced by migrant and seasonal farmworkers. In this paper we present the results of two distinct but complementary studies of farmworker health on the Arizona-Sonora border. PMID- 22829797 TI - Determination of polycyclic aromatic hydrocarbons in industrial harbor sediments by GC-MS. AB - Analysis of the 16 polycyclic aromatic hydrocarbons (PAHs) of the US Environmental Protection Agency priority pollutant list was carried out in sediment samples of an industrial port in the southern Kaohsiung Harbor of Taiwan which is supposed to be extensively polluted by industrial wastewater discharges. The determination and quantification of PAHs in sediment samples were performed using gas chromatography coupled to mass spectrometry (GC-MS) with the aid of deuterated PAH internal standards and surrogate standards. The total concentrations of the 16 PAHs varied from 4,425 to 51,261 ng/g dw, with a mean concentration of 13,196 ng/g dw. The PAHs concentration is relatively high in the river mouth region, and gradually diminishes toward the harbor region. Diagnostic ratios showed that the possible source of PAHs in the industrial port area could be coal combustion. As compared with the US Sediment Quality Guidelines (SQGs), the various observed levels of PAHs exceeded the effects range median (ERM), and could thus cause acute biological damages. The results can be used for regular monitoring, and future pollution prevention and management should target the various industries in this region for reducing pollution. PMID- 22829798 TI - Cigarette litter: smokers' attitudes and behaviors. AB - Cigarette butts are consistently the most collected items in litter clean-up efforts, which are a costly burden to local economies. In addition, tobacco waste may be detrimental to our natural environment. The tobacco industry has conducted or funded numerous studies on smokers' littering knowledge and behavior, however, non-industry sponsored research is rare. We sought to examine whether demographics and smokers' knowledge and beliefs toward cigarette waste as litter predicts littering behavior. Smokers aged 18 and older (n = 1,000) were interviewed about their knowledge and beliefs towards cigarette waste as litter. Respondents were members of the Research Now panel, an online panel of over three million respondents in the United States. Multivariate logistic regressions were conducted to determine factors significantly predictive of ever having littered cigarette butts or having littered cigarette butts within the past month (p-value < 0.05). The majority (74.1%) of smokers reported having littered cigarette butts at least once in their life, by disposing of them on the ground or throwing them out of a car window. Over half (55.7%) reported disposing of cigarette butts on the ground, in a sewer/gutter, or down a drain in the past month. Those who did not consider cigarette butts to be litter were over three and half times as likely to report having ever littered cigarette butts (OR = 3.68, 95%CI = 2.04, 6.66) and four times as likely to have littered cigarette butts in the past month (OR = 4.00, 95%CI = 2.53, 6.32). Males were significantly more likely to have littered cigarette butts in the past month compared to females (OR = 1.49, 95%CI = 1.14, 1.94). Holding the belief that cigarette butts are not litter was the only belief in this study that predicted ever or past-month littering of cigarette waste. Messages in anti-cigarette-litter campaigns should emphasize that cigarette butts are not just litter but are toxic waste and are harmful when disposed of improperly. PMID- 22829799 TI - Differential exposure to hazardous air pollution in the United States: a multilevel analysis of urbanization and neighborhood socioeconomic deprivation. AB - Population exposure to multiple chemicals in air presents significant challenges for environmental public health. Air quality regulations distinguish criteria air pollutants (CAPs) (e.g., ozone, PM2.5) from hazardous air pollutants (HAPs)-187 chemicals which include carcinogens and others that are associated with respiratory, cardiovascular, neurological and numerous other non-cancer health effects. Evidence of the public's cumulative exposure and the health effects of HAPs are quite limited. A multilevel model is used to assess differential exposure to HAP respiratory, neurological, and cancer hazards (2005) related to the Townsend Index of Socioeconomic Deprivation (TSI), after adjustment for regional population size and economic activity, and local population density. We found significant positive associations between tract TSI and respiratory and cancer HAP exposure hazards, and smaller effects for neurological HAPs. Tracts in the top quintile of TSI have between 38%-60% higher HAP exposure than the bottom quintile; increasing population size from the bottom quintile to the top quintile modifies HAP exposure hazard related to TSI, increasing cancer HAP exposure hazard by 6% to 20% and increasing respiratory HAP exposure hazard by 12% to 27%. This study demonstrates the value of social epidemiological methods for analyzing differential exposure and advancing cumulative risk assessment. PMID- 22829800 TI - Decomposition analysis of wastewater pollutant discharges in industrial sectors of China (2001-2009) using the LMDI I Method. AB - China's industry accounts for 46.8% of the national Gross Domestic Product (GDP) and plays an important strategic role in its economic growth. On the other hand, industrial wastewater is also the major source of water pollution. In order to examine the relationship between the underlying driving forces and various environmental indicators, values of two critical industrial wastewater pollutant discharge parameters (Chemical Oxygen Demand (COD) and ammonia nitrogen (NH(4) N)), between 2001 and 2009, were decomposed into three factors: i.e., production effects (caused by change in the scale of economic activity), structure effects (caused by change in economic structure) and intensity effects (caused by change in technological level of each sector), using additive version of the Logarithmic Mean Divisia Index (LMDI I) decomposition method. Results showed that: (1) the average annual effect of COD discharges in China was -2.99%, whereas the production effect, the structure effect, and the intensity effect were 14.64%, 1.39%, and -16.24%, respectively. Similarly, the average effect of NH(4)-N discharges was -4.03%, while the production effect, the structure effect, and the intensity effect were 16.18%, -2.88%, and -17.33%, respectively; (2) the production effect was the major factor responsible for the increase in COD and NH(4)-N discharges, accounting for 45% and 44% of the total contribution, respectively; (3) the intensity effect, which accounted for 50% and 48% of the total contribution, respectively, exerted a dominant decremental effect on COD and NH(4)-N discharges; intensity effect was further decomposed into cleaner production effect and pollution abatement effect with the cleaner production effect accounting for 60% and 55% of the reduction of COD and NH(4)-N, respectively; (4) the major contributors to incremental COD and NH(4)-N discharges were divided among industrial sub-sectors and the top contributors were identified. Potential restructuring and regulation measures were proposed for pollutant reduction. PMID- 22829801 TI - Psychosocial correlates of sunburn among young adult women. AB - Skin cancer is an increasingly common disease, particularly among young adult women. Sunburn early in life is a risk factor for skin cancer. Few studies have reported on psychosocial correlates of sunburn. The current study consisted of an online survey of undergraduate women from a university in the northeastern part of the USA. A logistic regression demonstrated that young women who reported a history of four or more sunburns were significantly more likely to report fair skin, higher perceived susceptibility to skin cancer, greater perceived benefits of tanning (e.g., appearance enhancement), lower perceived control over skin protection, and more frequent sunscreen use. Sunbathing was not associated with a greater number of sunburns. These results suggest that young women who sunburn more often possess other skin cancer risk factors, are aware of their susceptibility to skin cancer, and try to use sunscreen, but feel limited control over their skin protection behavior and are not less likely to sunbathe than others. Therefore, interventions are needed to assist high risk young women in asserting more control over their sun protection behavior and perhaps improve the effectiveness of the sunscreen or other skin protection methods they do employ. PMID- 22829802 TI - Prevalence of acute respiratory infections in women and children in Western Sierra Leone due to smoke from wood and charcoal stoves. AB - Combustion of biomass fuels (wood and charcoal) for cooking releases smoke that contains health damaging pollutants. Women and children are the most affected. Exposure to biomass smoke is associated with acute respiratory infections (ARI). This study investigated the prevalence of ARI potentially caused by smoke from wood and charcoal stoves in Western Sierra Leone, as these two fuels are the predominant fuel types used for cooking. A cross sectional study was conducted for 520 women age 15-45 years; and 520 children under 5 years of age in homes that burn wood and charcoal. A questionnaire assessing demographic, household and exposure characteristics and ARI was administered to every woman who further gave information for the child. Suspended particulate matter (SPM) was continuously monitored in fifteen homes. ARI prevalence revealed 32% and 24% for women, 64% and 44% for children in homes with wood and charcoal stoves, respectively. After adjusting for potential confounders for each group, the odds ratio of having suffered from ARI was similar for women, but remained large for children in homes with wood stoves relative to charcoal stoves (OR = 1.14, 95%CI: 0.71-1.82) and (OR = 2.03, 95%CI: 1.31-3.13), respectively. ARI prevalence was higher for children in homes with wood stoves compared with homes with charcoal stoves, but ARI prevalence for both types of fuels is higher compared with reported prevalence elsewhere. To achieve a reduction in ARI would require switching from wood and charcoal to cleaner fuels. PMID- 22829803 TI - Prenatal rosiglitazone administration to neonatal rat pups does not alter the adult metabolic phenotype. AB - Prenatally administered rosiglitazone (RGZ) is effective in enhancing lung maturity; however, its long-term safety remains unknown. This study aimed to determine the effects of prenatally administered RGZ on the metabolic phenotype of adult rats. Methods. Pregnant Sprague-Dawley rat dams were administered either placebo or RGZ at embryonic days 18 and 19. Between 12 and 20 weeks of age, the rats underwent glucose and insulin tolerance tests and de novo fatty acid synthesis assays. The lungs, liver, skeletal muscle, and fat tissue were processed by Western hybridization for peroxisome proliferator-activated receptor (PPAR)gamma, adipose differentiation-related protein (ADRP), and surfactant proteins B (SPB) and C (SPC). Plasma was assayed for triglycerides, cholesterol, insulin, glucagon, and troponin-I levels. Lungs were also morphometrically analyzed. Results. Insulin and glucose challenges, de novo fatty acid synthesis, and all serum assays revealed no differences among all groups. Western hybridization for PPARgamma, ADRP, SPB, and SPC in lung, liver, muscle, and fat tissue showed equal levels. Histologic analyses showed a similar number of alveoli and septal thickness in all experimental groups. Conclusions. When administered prenatally, RGZ does not affect long-term fetal programming and may be safe for enhancing fetal lung maturation. PMID- 22829805 TI - Circulating levels of microRNA from children with newly diagnosed type 1 diabetes and healthy controls: evidence that miR-25 associates to residual beta-cell function and glycaemic control during disease progression. AB - This study aims to identify key miRNAs in circulation, which predict ongoing beta cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRNAs expression levels to beta-cell function and glycaemic control. Global miRNA sequencing analyses were performed on sera pools from two T1D cohorts (n = 275 and 129, resp.) and one control group (n = 151). We identified twelve upregulated human miRNAs in T1D patients (miR-152, miR-30a-5p, miR-181a, miR-24, miR-148a, miR-210, miR-27a, miR-29a, miR-26a, miR-27b, miR-25, miR-200a); several of these miRNAs were linked to apoptosis and beta-cell networks. Furthermore, we identified miR 25 as negatively associated with residual beta-cell function (est.: -0.12, P = 0.0037), and positively associated with glycaemic control (HbA1c) (est.: 0.11, P = 0.0035) 3 months after onset [corrected]. In conclusion this study demonstrates that miR-25 might be a "tissue-specific" miRNA for glycaemic control 3 months after diagnosis in new onset T1D children and therefore supports the role of circulating miRNAs as predictive biomarkers for tissue physiopathology and potential intervention targets. PMID- 22829804 TI - The metabolic syndrome, oxidative stress, environment, and cardiovascular disease: the great exploration. AB - The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome. PMID- 22829806 TI - Effects of rosiglitazone with insulin combination therapy on oxidative stress and lipid profile in left ventricular muscles of diabetic rats. AB - PURPOSE: In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation. METHODS AND MATERIALS: Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mg kg(-1)), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3 nitrotyrosine levels in left ventricular muscle were measured. RESULT: Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3 nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3 nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05). CONCLUSION: Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective. PMID- 22829808 TI - Comparison between Single-Dose Esomeprazole- and Pantoprazole-Based Triple Therapy on the Effectiveness for Helicobacter pylori Eradication in Taiwanese Population. AB - Background and Study Aims. To compare the effectiveness of two regimens, single dose esomeprazole- and pantoprazole-based triple therapy, for Helicobacter pylori (H. pylori) eradication. Patients and Methods. A total of 453 patients were enrolled for H. pylori eradication. They were randomly assigned to either EAC group (Esomeprazole 40 mg once daily, Amoxicillin 1 g twice daily, Clarithromycin 500 mg twice daily for 7 days) or PAC group (Pantoprazole 40 mg twice daily, Amoxicillin 1 g twice daily, Clarithromycin 500 mg twice daily for 7 days). Follow-up endoscopy or urea breath test was scheduled 12-16 weeks after the eradication to evaluate the therapeutic response. Results. Higher eradication rate in EAC group than PAC group was shown by intention-to-treat analysis (EAC 72% versus PAC 55%, P < 0.05) and per-protocol analysis (EAC 91% versus PAC 72%, P < 0.05). The incidence of adverse effects (EAC 19% versus PAC 17%, P = 0.712) and the compliance (EAC 87% versus PAC 91%, P = 0.083) were comparable between these 2 groups. Conclusions. Single-dose esomeprazole-based triple therapy is effective for H. pylori eradication. PMID- 22829807 TI - Pathogenesis of Helicobacter pylori-Related Gastroduodenal Diseases from Molecular Epidemiological Studies. AB - Helicobacter pylori is a major human pathogen that infects the stomach and produces inflammation that is responsible for various gastroduodenal diseases. Despite the high prevalence of H. pylori infections in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than in other countries. The incidence of gastric cancer also tends to decrease from north to south in East Asia. Data from molecular epidemiological studies show that this variation in different geographic areas could be explained in part by different types of H. pylori virulence factors, especially CagA, VacA, and OipA. H. pylori infection is thought to be involved in both gastric cancer and duodenal ulcer, which are at opposite ends of the disease spectrum. This discrepancy can also be explained in part by another H. pylori factor, DupA, as well as by CagA typing (East Asian type versus Western type). H. pylori has a genome of approximately 1,600 genes; therefore, there might be other novel virulence factors. Because genome wide analyses using whole-genome sequencing technology give a broad view of the genome of H. pylori, we hope that next-generation sequencers will enable us to efficiently investigate novel virulence factors. PMID- 22829810 TI - DSD and Professionalism from a Multilateral View: Supplementing the Consensus Statement on the Basis of a Qualitative Survey. AB - Treatment and support of a child with DSD calls for experience and expertise in diagnosis, surgical techniques, understanding of psychosocial issues, and recognizing and accepting the significance of individual values of children, families, and support groups. The range of what is considered "appropriate" care and treatment is still very broad and critics point at major gaps between ethical guidelines and current clinical practice. Based on a qualitative study with 27 members of multidisciplinary teams and support groups, we supplement the professional consensus statements and current ethical guidelines with 14 requirements from four different perspectives, to characterize more fully the responsible treatment and support of children and families affected by DSD. Overall, our findings highlight the importance of close collaborations between different experts and a shift from the often simplified dispute about genital surgeries to a more holistic perspective with a long-term management strategy, which should serve as a cornerstone not only for clinical practice but also for future research and evaluation studies. PMID- 22829809 TI - Recent Insights into Antibiotic Resistance in Helicobacter pylori Eradication. AB - Antibiotics have been useful in the treatment of H. pylori-related benign and malignant gastroduodenal diseases. However, emergence of antibiotic resistance often decreases the eradication rates of H. pylori infections. Many factors have been implicated as causes of treatment failure, but the main antibiotic resistance mechanisms described to date are due to point mutations on the bacterial chromosome, a consequence of a significantly phenotypic variation in H. pylori. The prevalence of antibiotic (e.g., clarithromycin, metronidazole, tetracycline, amoxicillin, and furazolidone) resistance varies among different countries; it appears to be partly determined by geographical factors. Since the worldwide increase in the rate of antibiotic resistance represents a problem of relevance, some studies have been performed in order to identify highly active and well-tolerated anti-H. pylori therapies including sequential, concomitant quadruple, hybrid, and quadruple therapy. These represent a promising alternatives in the effort to overcome the problem of resistance. The aim of this paper is to review the current status of antibiotic resistance in H. pylori eradication, highlighting the evolutionary processes in detail at alternative approaches to treatment in the past decade. The underlying resistance mechanisms will be also followed. PMID- 22829811 TI - Epigenetic alterations in bladder cancer and their potential clinical implications. AB - Urothelial carcinoma (UC), the most common type of bladder cancer, is one of the most expensive malignancies to treat due to its high rate of recurrence. The characterization of the genetic alterations associated with UC has revealed the presence of two mutually exclusive molecular pathways along which distinct genetic abnormalities contribute to the formation of invasive and noninvasive tumors. Here, we focus on the epigenetic alterations found in UC, including the presence of an epigenetic field defect throughout bladders with tumors. A distinct hypomethylation pattern was found in noninvasive tumors, whereas widespread hypermethylation was found in invasive tumors, indicating the two pathways given rise to two tumor types also differ epigenetically. Since certain epigenetic alterations precede histopathological changes, they can serve as excellent markers for the development of diagnostic, prognostic, and surveillance tools. In addition, their dynamic nature and reversibility with pharmacological interventions open new and exciting avenues for therapies. The epigenetic abnormalities associated with UC would make it an excellent target for epigenetic therapy, which is currently approved for the treatment of a few hematological malignancies. Future research is needed to address efficacy and potential toxicity issues before it can be implemented as a therapeutic strategy for solid tumors. PMID- 22829812 TI - Impact of Residual Fragments following Endourological Treatments in Renal Stones. AB - Today, shock wave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), and flexible ureterorenoscopy (URS) are the most widely used modalities for the management of renal stones. In earlier series, treatment success of renal calculi assessed with KUB radiography, ultrasound, or intravenous pyelography which are less sensitive than CT that leads to be diversity of study results in reporting outcome. Residual fragments (RFs) after interventional therapies may cause pain, infection, or obstruction. The size and location of RFs following SWL and PCNL are the major predictors for clinical significant symptoms and stone events requiring intervention. There is no consensus regarding schedule for followup of SWL, PCNL, and flexible URS. Active monitoring can be recommended when the stones become symptomatic, increase in size, or need intervention. RFs <4 mm after SWL and <2 mm after PCNL and flexible URS could be actively monitored on an annual basis with CT. Early repeat SWL and second-look endoscopy are recommended after primary SWL and PCNL, respectively. There is insufficient data for flexible URS, but RFs can be easily treated with repeat URS. Finally, medical therapy should be tailored based on the stone analysis and metabolic workup that may be helpful to prevent regrowth of the RFs. PMID- 22829813 TI - Local Infiltration Analgesia for Postoperative Pain Control following Total Hip Arthroplasty: A Systematic Review. AB - Local infiltration analgesia (LIA) is an analgesic technique that has gained popularity since it was first brought to widespread attention by Kerr and Kohan in 2008. The technique involves the infiltration of a large volume dilute solution of a long-acting local anesthetic agent, often with adjuvants (e.g., epinephrine, ketorolac, an opioid), throughout the wound at the time of surgery. The analgesic effect duration can then be prolonged by the placement of a catheter to the surgical site for postoperative administration of further local anesthetic. The technique has been adopted for use for postoperative analgesia following a range of surgical procedures (orthopedic, general, gynecological, and breast surgeries). The primary objective of this paper was to determine, based on the current evidence, if LIA is superior when compared to no intervention, placebo, and alternative analgesic methods in patients following total hip arthroplasty, in terms of certain outcome measures. The outcomes considered were postoperative analgesia scores, joint function/rehabilitation, and length of hospital stay. Secondary objectives were to review available evidence and current knowledge regarding the pharmacokinetics of local anesthetic and adjuvant drugs when administered in this way and the occurrence of adverse events. PMID- 22829814 TI - An exploration of apathy and impulsivity in Parkinson disease. AB - Background. Apathy and impulsivity in Parkinson disease (PD) are associated with clinically significant behavioral disorders. Aim. To explore the phenomenology, distribution, and clinical correlates of these two behaviors. Methods. In PD participants (n = 99) without dementia we explored the distribution of measures of motivation and impulsivity using univariate methods. We then undertook factor analysis to define specific underlying dimensions of apathy and impulsivity. Regression models were developed to determine the associated demographic and clinical features of the derived dimensions. Results. The factor analysis of apathy (AES-C) revealed a two-factor solution: "cognitive-behavior" and "social indifference". The factor analysis of impulsivity (BIS-11) revealed a five-factor solution: "inattention"; "impetuosity"; "personal security"; "planning"; and "future orientation". Apathy was significantly associated with: age, age of motor symptom onset (positive correlation), disease stage, motor symptom severity, and depression. Impulsivity was significantly associated with: age of motor symptom onset (negative correlation), gambling and anxiety scores, and motor complications. We observed an overlap of apathy and impulsivity in some participants. Conclusion. In PD, apathy and impulsivity have specific phenomenological profiles and are associated with particular clinical phenotypes. In spite of this, there is some overlap of behaviors which may suggests common aspects in the pathology underlying motivation and reward processes. PMID- 22829815 TI - The dragon and the tiger: realties in the control of tuberculosis. AB - India and China are two Asian super-powers with developing economies carried on the shoulders of their booming populations. This growth can only be sustained by nurturing their "human resource". However increasing reports of insufficient public health (PH) initiatives in India when compared to the aggressive PH system of China may prove to be the Achilles' heels for India. This review compares the PH system in India and China for combating Tuberculosis (TB), the disease responsible for maximum mortality and morbidity by a single infectious agent. While China has acknowledged the disease load and thereafter has methodically improved its reporting, detection, diagnosis and treatment, India is still in denial of the imminent health risk. The Indian PH system still considers TB as a "facultative" disease for which the required control measures are already in place and functioning. Globally, India and China recorded the highest Multi-Drug Resistant TB (MDR) cases notified in 2010 (64000 and 63000, respectively). Additionally non-government sources reported extremely high proportions of MDR in India. Here we have compared the medical, social and economic approaches of the two nations towards better management and control of TB. Does India have lessons to learn from China? PMID- 22829816 TI - Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated nature of these cellular responses presently confounds our understanding of ethanol-induced hepatopathy. In this paper, we assessed the pathological contribution of oxidative stress and ER stress in a time-course mouse model of early-stage ALD. Ethanol-treated mice exhibited significant hepatic panlobular steatosis and elevated plasma ALT values compared to isocaloric controls. Oxidative stress was observed in the ethanol treated animals through a significant increase in hepatic TBARS and immunohistochemical staining of 4-HNE-modified proteins. Hepatic glutathione (GSH) levels were significantly decreased as a consequence of decreased CBS activity, increased GSH utilization, and increased protein glutathionylation. At the same time, immunoblot analysis of the PERK, IRE1alpha, ATF6, and SREBP pathways reveals no significant role for these UPR pathways in the etiology of hepatic steatosis associated with early-stage ALD. Collectively, our results indicate a primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response. PMID- 22829817 TI - Mining the virgin land of neurotoxicology: a novel paradigm of neurotoxic peptides action on glycosylated voltage-gated sodium channels. AB - Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs. PMID- 22829818 TI - Obesity differentially affects phenotypes of polycystic ovary syndrome. AB - Obesity or overweight affect most of patients with polycystic ovary syndrome (PCOS). Phenotypes are the clinical characteristics produced by the interaction of heredity and environment in a disease or syndrome. Phenotypes of PCOS have been described on the presence of clinical hyperandrogenism, oligoovulation and polycystic ovaries. The insulin resistance is present in the majority of patients with obesity and/or PCOS and it is more frequent and of greater magnitude in obese than in non obese PCOS patients. Levels of sexual hormone binding globulin are decreased, and levels of free androgens are increased in obese PCOS patients. Weight loss treatment is important for overweight or obese PCOS patients, but not necessary for normal weight PCOS patients, who only need to avoid increasing their body weight. Obesity decreases or delays several infertility treatments. The differences in the hormonal and metabolic profile, as well as the different focus and response to treatment between obese and non obese PCOS patients suggest that obesity has to be considered as a characteristic for classification of PCOS phenotypes. PMID- 22829819 TI - Markers of Sleep-Disordered Breathing and Prediabetes in US Adults. AB - Background. Prediabetes is a preclinical stage in the hyperglycemia continuum where subjects are at increased risk of developing diabetes. Several studies reported a positive association between markers of sleep-disordered breathing (SDB) and diabetes. However, few studies investigated the relationship between SDB markers and prediabetes. Methods. We examined 5,685 participants >=20 years from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. The exposure of interest was SDB markers including sleep duration, snoring, snorting, and daytime sleepiness. The outcome was prediabetes (n = 2058), among subjects free of diabetes. Results. SDB markers were associated with prediabetes. Compared to those without any sleep disturbance, the multivariable odds ratio (OR) (95% confidence interval (CI)) of prediabetes among those with three or more SDB markers was 1.69 (1.28-2.22). In subgroup analyses, the association between SDB markers and prediabetes was stronger among women (OR (95% CI) = 2.09 (1.36-3.23) when compared to men (1.52 (1.00-2.35)) and was present among non-Hispanic whites (2.66 (1.92-3.69)) and Mexican Americans (1.99 (1.13-3.48)), but not among non Hispanic blacks (1.10 (0.70-1.73)). Conclusion. SDB markers were associated with prediabetes. This association was stronger in women and was present mainly in non Hispanic whites and Mexican Americans. PMID- 22829820 TI - Breast imaging: how we manage diagnostic technology at a multidisciplinary breast center. AB - This paper discusses the most important aspects and problems related to the management of breast cancer imaging, at a center specialized in breast pathology. We review the established and emerging diagnostic techniques, their indications, and peculiarities: digital mammography, CAD systems, and the recent digital breast tomosynthesis, ultrasound and complementary elastography, molecular imaging techniques, magnetic resonance imaging, advanced sequences (diffusion), and positron emission mammography (PEM). The adequate integration and rational management of these techniques is essential, but this is not always easy, in order to achieve a successful diagnosis. PMID- 22829823 TI - Short implants in partially edentuolous maxillae and mandibles: a 10 to 20 years retrospective evaluation. AB - Purpose. Evaluation of the short implant (8 mm in height) long-term prognosis and of the implant site influence on the prognosis. Methods. A longitudinal study was carried out on 121 patients (57 males and 64 females) consecutively treated with 257 implants. 108 implants were short. Results. Four (3.6%) short implants supporting fixed partial prostheses failed. Similarly, three standard implants supporting fixed partial prostheses and one supporting single-crown prosthesis failed. Mean marginal bone loss (MBL) and probing depth (PD) of short and standard implants were statistically comparable (P > .05). The 20-year cumulative survival rates of short and standard implants were 92.3 and 95.9%, respectively. The cumulative success rates were 78.3 and 81.4%. The survival rates of short implants in posterior and anterior regions were comparable: 95 and 96.4%, respectively. The difference between survival rates was not significant (P > .05). Conclusions. The high reliability of short implants in supporting fixed prostheses was confirmed. Short and standard implants long-term prognoses were not significantly different. The prognosis of short implants in posterior regions was comparable to that of in anterior regions. Nevertheless, a larger sample is required to confirm this trend. PMID- 22829821 TI - Human herpesviridae methods of natural killer cell evasion. AB - Human herpesviruses cause diseases of considerable morbidity and mortality, ranging from encephalitis to hematologic malignancies. As evidence emerges about the role of innate immunity and natural killer (NK) cells in the control of herpesvirus infection, evidence of viral methods of innate immune evasion grows as well. These methods include interference with the ligands on infected cell surfaces that bind NK cell activating or inhibitory receptors. This paper summarizes the most extensively studied NK cell receptor/ligand pairs and then describes the methods of NK cell evasion used by all eight herpesviruses through these receptors and ligands. Although great strides have been made in elucidating their mechanisms, there is still a disparity between viruses in the amount of knowledge regarding innate immune evasion. Further research of herpesvirus innate immune evasion can provide insight for circumventing viral mechanisms in future therapies. PMID- 22829822 TI - In Silico and In Vitro Comparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors. AB - Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors-raltegravir (RAL), elvitegravir (ELV) and L731,988-were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naive infected patients. Our in silico and in vitro studies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs. PMID- 22829825 TI - Repair of a perforated sinus membrane with a subepithelial palatal conjunctive flap: technique report and evaluation. AB - The maxillary sinus grafting procedure has proven to be an acceptable modality for bone augmentation to provide a base for endosseous implants, routinely used for the rehabilitation of posterior maxilla. Perforation of the membrane is the most common complication in this type of procedure. This paper presents a technique for repairing a perforated Schneiderian membrane with a conjunctive connective tissue graft harvested from the palate and shows the histological and radiographic evaluation of the results. Ten consecutives cases with the occurrence of membrane perforation were included in this study. All were repaired with a flap of tissue removed from the palatine portion near to the surgical site. The technique is demonstrated through a clinical case. The results showed successful integration of 88.8% of the implants after 12 months from prosthesis installation. Histological evaluation of the samples showed that the use of nanocrystalized hydroxyapatite showed an adequate stimulation of bone neoformation within 6 months. Radiographic evaluation revealed a small apical implant bone loss, not compromising their anchorages and proservation. Thus, it can be concluded that the use of conjunctive technique with collected palate flap for sealing the perforation of the membrane of the sinus may have predictable result. PMID- 22829824 TI - Microbiota associated with infections of the jaws. AB - The microbial infections involving the craniofacial skeleton, particularly maxilla and mandible, have direct relationship with the dental biofilm, with predominance of obligate anaerobes. In some patients, these infections may spread to bone marrow or facial soft tissues, producing severe and life-threatening septic conditions. In such cases, local treatment associated with systemic antimicrobials should be used in order to eradicate the sources of contamination. This paper discuss the possibility of spread of these infections and their clinical implications for dentistry, as well as their etiology and aspects related to microbial virulence and pathogenesis. PMID- 22829826 TI - Pathogenicity of Treponema denticola Wild-Type and Mutant Strain Tested by an Active Mode of Periodontal Infection Using Microinjection. AB - The available passive mode of periodontal infections in mice requires high efficiency of bacterial attachment and invasiveness and is not always suitable to test the pathogenicity of genetically engineered mutant strains. We developed an active mode of oral infection, using microinjection in the marginal gingiva of mice, to test the pathogenicity of a genetically engineered Treponema denticola mutant strain deficient in intermediate-like filaments, compared to the wild-type strain. This targeted mode of infection inoculates the bacterial strain to be tested directly at a lesion site (needle entry point) located at the future periodontal lesion site. The efficiency of T. denticola wild-type strain to elicit bone loss contrasted with the lack of pathogenicity of the intermediate like filament deficient mutant strain in comparison to the sham infection. The periodontal microinjection oral model in mice can be used for a variety of applications complementary to the passive mode of periodontal infection in context of pathogenicity testing. PMID- 22829827 TI - Advanced surface modifications for blood-contacting surfaces of medical devices. PMID- 22829828 TI - Soft and hard tissue management in implant therapy-part I: surgical concepts. AB - Implant therapy has become a reliable and predictable treatment alternative for the replacement of missing teeth with conventional removable and fixed partial dentures. Recently though, in the pursuit for improved esthetics, the literature has dedicated a considerable amount of its research on the successful maintenance and regeneration of the surrounding gingiva and bone, which are lost following extraction of a tooth. Thoroughly analyzing the anatomic situation and well planned treatment has become a requirement, because incorrectly planned and positioned implants may jeopardize long-term esthetic and functional prognosis. In addition, many types of biocompatible materials, autogenous hard and soft tissue grafts, and different surgical techniques have been developed, and their viability has been investigated. As a result, implant specialists have gained a greater understanding of the dynamics and anatomical and biological concepts of the periodontium and peri-implant tissues both at the surgical and prosthetic phases of treatment, which contributes to better soft and hard tissue management (SHTM). This may further contribute to achieving a superior final result which is obtained by having a harmonious soft tissue profile, a correctly placed and contoured final restoration, and the reestablishment of masticatory function and phonetics. PMID- 22829829 TI - Antifungal activity of chitosan nanoparticles and correlation with their physical properties. AB - The need of natural antimicrobials is paramount to avoid harmful synthetic chemicals. The study aimed to determine the antifungal activity of natural compound chitosan and its nanoparticles forms against Candida albicans, Fusarium solani and Aspergillus niger. Chitosan nanoparticles were prepared from low (LMW), high molecular weight (HMW) chitosan and its derivative, trimethyl chitosan (TMC). Particle size was increased when chitosan/TMC concentration was increased from 1 to 3 mg/mL. Their zeta potential ranged from +22 to +55 mV. Chitosan nanoparticles prepared from different concentrations of LMW and HMW were also found to serve a better inhibitory activity against C. albicans (MIC(LMW) = 0.25-0.86 mg/mL and MIC(HMW) = 0.6-1.0 mg/mL) and F. solani (MIC(LMW) = 0.86-1.2 mg/mL and MIC(HMW) = 0.5-1.2 mg/mL) compared to the solution form (MIC = 3 mg/mL for both MWs and species). This inhibitory effect was also influenced by particle size and zeta potential of chitosan nanoparticles. Besides, Aspergillus niger was found to be resistant to chitosan nanoparticles except for nanoparticles prepared from higher concentrations of HMW. Antifungal activity of nanoparticles prepared from TMC was negligible. The parent compound therefore could be formulated and applied as a natural antifungal agent into nanoparticles form to enhance its antifungal activity. PMID- 22829830 TI - WIPI-1 Positive Autophagosome-Like Vesicles Entrap Pathogenic Staphylococcus aureus for Lysosomal Degradation. AB - Invading pathogens provoke the autophagic machinery and, in a process termed xenophagy, the host cell survives because autophagy is employed as a safeguard for pathogens that escaped phagosomes. However, some pathogens can manipulate the autophagic pathway and replicate within the niche of generated autophagosome-like vesicles. By automated fluorescence-based high content analyses, we demonstrate that Staphylococcus aureus strains (USA300, HG001, SA113) stimulate autophagy and become entrapped in intracellular PtdIns(3)P-enriched vesicles that are decorated with human WIPI-1, an essential PtdIns(3)P effector of canonical autophagy and membrane protein of both phagophores and autophagosomes. Further, agr-positive S. aureus (USA300, HG001) strains were more efficiently entrapped in WIPI-1 positive autophagosome-like vesicles when compared to agr-negative cells (SA113). By confocal and electron microscopy we provide evidence that single- and multiple Staphylococci entrapped undergo cell division. Moreover, the number of WIPI-1 positive autophagosome-like vesicles entrapping Staphylococci significantly increased upon (i) lysosomal inhibition by bafilomycin A(1) and (ii) blocking PIKfyve-mediated PtdIns(3,5)P(2) generation by YM201636. In summary, our results provide evidence that the PtdIns(3)P effector function of WIPI-1 is utilized during xenophagy of Staphylococcus aureus. We suggest that invading S. aureus cells become entrapped in autophagosome-like WIPI-1 positive vesicles targeted for lysosomal degradation in nonprofessional host cells. PMID- 22829831 TI - Targeting metabolism and autophagy in the context of haematologic malignancies. AB - Autophagy is a cellular process that maintains the homeostasis of the normal cell. It not only allows for cell survival in times of metabolic stress with nutrient recycling but also is able to lead to cell death when required. During malignant transformation the cell is able to proliferate and survive. This is due to altered cell metabolism and the presence of altered genetic changes that maintain the cell survival. Metabolism was considered an innocent bystander that was a consequence of the increased nutrient requirement for the survival and proliferation of haematological malignancies. The interdependency of metabolism and cellular mechanisms such as autophagy are becoming more evident and important. This interdependence contributes to increased cancer progression and drug resistance. In this paper we aim to discuss autophagy, how it pertains to metabolism in the context of hematologic malignancies, and the implications for therapy. PMID- 22829832 TI - Redox regulation of cysteine-dependent enzymes in neurodegeneration. AB - Evidence of increased oxidative stress has been found in various neurodegenerative diseases and conditions. While it is unclear whether oxidative stress is a cause or effect, protein, lipid, and DNA have all been found to be susceptible to oxidant-induced modifications that alter their function. Results of clinical trials based on the oxidative-stress theory have been mixed, though data continues to indicate that prevention of high levels of oxidative stress is beneficial for health and increases longevity. Due to the highly reactive nature of the sulfhydryl group, the focus of this paper is on the impact of oxidative stress on cysteine-dependent enzymes and how oxidative stress may contribute to neurological dysfunction through this selected group of proteins. PMID- 22829833 TI - Caloric Restriction and the Nutrient-Sensing PGC-1alpha in Mitochondrial Homeostasis: New Perspectives in Neurodegeneration. AB - Mitochondrial activity progressively declines during ageing and in many neurodegenerative diseases. Caloric restriction (CR) has been suggested as a dietary intervention that is able to postpone the detrimental aspects of aging as it ameliorates mitochondrial performance. This effect is partially due to increased mitochondrial biogenesis. The nutrient-sensing PGC-1alpha is a transcriptional coactivator that promotes the expression of mitochondrial genes and is induced by CR. It is believed that many of the mitochondrial and metabolic benefits of CR are due to increased PGC-1alpha activity. The increase of PGC 1alpha is also positively linked to neuroprotection and its decrement has been involved in the pathogenesis of many neurodegenerative diseases. This paper aims to summarize the current knowledge about the role of PGC-1alpha in neuronal homeostasis and the beneficial effects of CR on mitochondrial biogenesis and function. We also discuss how PGC-1alpha-governed pathways could be used as target for nutritional intervention to prevent neurodegeneration. PMID- 22829834 TI - Through the looking glass: visualizing leukemia growth, migration, and engraftment using fluorescent transgenic zebrafish. AB - Zebrafish have emerged as a powerful model of development and cancer. Human, mouse, and zebrafish malignancies exhibit striking histopathologic and molecular similarities, underscoring the remarkable conservation of genetic pathways required to induce cancer. Zebrafish are uniquely suited for large-scale studies in which hundreds of animals can be used to investigate cancer processes. Moreover, zebrafish are small in size, optically clear during development, and amenable to genetic manipulation. Facile transgenic approaches and new technologies in gene inactivation have provided much needed genomic resources to interrogate the function of specific oncogenic and tumor suppressor pathways in cancer. This manuscript focuses on the unique attribute of labeling leukemia cells with fluorescent proteins and directly visualizing cancer processes in vivo including tumor growth, dissemination, and intravasation into the vasculature. We will also discuss the use of fluorescent transgenic approaches and cell transplantation to assess leukemia-propagating cell frequency and response to chemotherapy. PMID- 22829835 TI - Lenalidomide in the treatment of young patients with multiple myeloma: from induction to consolidation/maintenance therapy. AB - Multiple myeloma is the second most common hematologic malignancy. It accounts for 20,580 new cancer cases in the USA in 2009, including 11,680 cases in men, 8,900 cases in women, and 10,580 deaths overall. Although the disease remains still incurable, outcomes have improved substantially over recent years thanks to the use of high-dose therapy and the availability of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib. Various trials have shown the advantages linked to the use of novel agents in the transplant and not-transplant settings. In particular, this paper will present an overview of the results achieved with lenalidomide-containing combinations in patients eligible for high-dose therapies, namely, young patients. The advantages obtained should always be outweighed with the toxicity profile associated with the regimen used. Therefore, here, we will also provide a description of the main adverse events associated with lenalidomide and its combination. PMID- 22829836 TI - Diagnosing Patients with Age-Related Hearing Loss and Tinnitus: Supporting GP Clinical Engagement through Innovation and Pathway Redesign in Audiology Services. AB - The public health challenge of hearing impairment is growing, as age is the major determinant of hearing loss. Almost one in four (22.6%) over 75-year olds reports moderate or severe worry because of hearing problems. There is a 40% comorbidity of tinnitus and balance disorders. Good outcomes depend on early presentation and appropriate referral. This paper describes how the NHS Improvement Programme in England used service improvement methodologies to identify referral pathways and tools which were most likely to make significant improvements in diagnosing hearing loss, effective referrals and better patient outcomes. An audiometric screening device was used in GP surgeries to enable thresholds for effective referrals to be measured in the surgery. Revised referral criteria, the use of this device, new "assess and fit" technology in the audiology clinic, and direct access pathways can transform audiology service delivery so that patient outcomes are measurably better. This, in turn, changes the experience of GPs, so they are more likely to refer patients who can benefit from treatment. At the end of 2011, 51 GP practices in one of the audiology pilot areas had bought HearCheck screeners, a substantial development from the 4 practices who first engaged with the pilot. PMID- 22829837 TI - A description of skeletal manifestation in adult case of morquio syndrome: radiographic and MRI appearance. AB - We report on a rare case of Morquio syndrome, an autosomal recessive mucopolysaccharidosis including type IVA, a deficiency of N-acetylgalctosamine-6 sulfatase and type IVB a deficiency of beta-galactosidase. A 43-year-old female patient affected by IVB Morquio syndrome underwent instrumental investigation. Conventional plain films of the entire spine, pelvis, chest and knees together with magnetic resonance imaging of the entire column, hip, knees, and ankles demonstrated the characteristics of skeletal changes of this disease. The main abnormalities were platyspondily and hypoplasia of the odontoid process, genua valga deformity and severe multiple degenerative changes of the hips, knees, and ankle joints. Radiographs and above all magnetic resonance imaging are crucial to provide substantial information about the gravity, evolution of the skeletal and joints changes, and the rehabilitation strategies to be followed. PMID- 22829838 TI - Pyogenic sacroiliitis in children: two case reports. AB - Pyogenic sacroiliitis is rare and accounts for approximately 1-2% of osteoarticular infections in children. Considerable delay between presentation and diagnosis is recognized. Two cases of pyogenic sacroiliitis are described. The first case is a 28-month-old girl presented with acute onset of fever, pain in the left hip, and limpness. Computed tomography (CT), bone scans, and magnetic resonance imaging (MRI) of the pelvis showed characteristic findings of infectious sacroiliitis, and blood cultures were negatives. The second case is a 13-year-old girl presented with acute onset of fever, pain in the right hip, and buttock, with inability to walk. The diagnosis of pyogenic sacroiliitis was confirmed by bone scans, and CT of the pelvis and blood cultures have identified Proteus mirabilis. The two children recovered fully after 6 weeks of antimicrobial therapy. Pyogenic sacroiliitis is an uncommon disease in children. The key to successful management is early diagnosis in which CT, bone scans, and MRI findings play a crucial role. If the diagnosis is established promptly, most patients can be managed successfully with antimicrobial therapy. PMID- 22829839 TI - Isolated invasive endomyocardial cystic echinococcosis presenting with heart failure. AB - Cardiac cystic echinococcosis is a rarely encountered parasitic infestation caused by Echinococcus granulasus larvae. Cystic echinococcosis hydatid composes 0.5-2% of all human cystic echinococcosis cases. Isolated cardiac involvement is very rare. Cardiac cystic echinococcosis hydatid generally accompanies another organ involvement, however, it might be isolated as in the present case and although rare and it can cause heart failure. We present a case of isolated apical cardiac cystic echinococcosis hydatid which leads to heart failure. PMID- 22829840 TI - Radiation-induced peripheral malignant nerve sheath tumor arising from vestibular schwannoma after linac-based stereotactic radiation therapy: a case report and review of literatures. AB - In recent years the use of stereotactic radiation for vestibular schwannomas has increased worldwide. However, malignant transformation associated with radiation, although uncommon, has been reported in recent publications. We present a case of the 34 year-old female who had left vestibular schwannoma and who underwent surgery and postoperative stereotactic radiotherapy (SRT), hypofraction in 2005. At 6 years after SRT, the patient came with left facial palsy and severe headache. CT brain revealed progression in size with cystic and hemorrhagic changes of the preexisting tumor at left CPA with new obstructive hydrocephalus. Partial tumor removal was done, and the pathological report was malignant peripheral nerve sheath tumor (MPNST). Regarding the uncertainty of carcinogenesis risk, we should still practice radiation therapy with caution, especially in the young patient with tumor predisposition syndrome. Because of low incidence of MPNST after radiation, it should not be a major decision about giving radiotherapy. However, with the poor prognosis of MPNST, this possibility should be explained to the patient before radiation treatment option. PMID- 22829841 TI - Refractory Clostridium difficile Infection Successfully Treated with Tigecycline, Rifaximin, and Vancomycin. AB - The occurrence of Clostridium difficile colitis is on the rise and has become more difficult to manage with standard therapy. Thus, the need for alternative treatments is essential. Tigecycline is a glycylcycline antibiotic that has been shown to be effective against C. difficile through several published case reports and in in vitro studies. We present a case of C. difficile colitis that failed to respond to metronidazole and oral vancomycin therapy, but improved on a combination of rifaximin, tigecycline, and vancomycin. PMID- 22829843 TI - Pancreatic metastasis of high-grade papillary serous ovarian carcinoma mimicking primary pancreas cancer: a case report. AB - Introduction. Reports of epithelial ovarian carcinomas metastatic to the pancreas are very rare. We herein present a metastasis of high grade papillary serous ovarian cancer to mid portion of pancreas. Case. A 42-year-old patient was admitted with a non-specified malignant cystic lesion in midportion of pancreas. She had a history of surgical treatment for papillary serous ovarian adenocarcinoma. A cystic lesion was revealed by an abdominal computerized tomography (CT) performed in her follow up . It was considered as primary mid portion of pancreatic cancer and a distal pancreatectomy was performed. The final pathology showed high-grade papillary serous adenocarcinoma morphologically similar to the previously diagnosed ovarian cancer. Discussion. Metastatic pancreatic cancers should be considered in patients who present with a solitary pancreatic mass and had a previous non-pancreatic malignancy. Differential diagnosis of primary pancreatic neoplasm from metastatic malignancy may be very difficult. A biopsy for tissue confirmation is required to differentiate primary and secondary pancreatic tumors. Although, the value of surgical resection is poorly documented, resection may be considered in selected patients. Conclusion. Pancreatic metastasis of ovarian papillary serous adenocarcinoma has to be kept in mind when a patient with pancreatic mass has a history of ovarian malignancy. PMID- 22829842 TI - Aortic dissection and renal failure in a patient with severe hypothyroidism. AB - Acute aortic dissection (AAD) is a life-threatening condition associated with high morbidity and mortality. The most important recognized acquired cause that leads to dissection is chronic arterial hypertension. With respect to the anuria and renal failure, aortic dissection is not something that is always considered and is still not a very common presentation unless both renal arteries come off the false lumen of the dissection. However, when present, preoperative renal failure in patients with acute type B dissection has been noted to be an independent predictor of mortality. Early recognition and diagnosis is the key and as noted by previous studies as well, almost a third of these patients are initially worked up for other causes until later when they are diagnosed with aortic dissection. Here we present a case of a patient presenting with severe hypothyroidism, long-standing hypertension, and anuria. Through the case, we highlight the importance of having aortic dissection as an important differential in patients presenting with anuria who have a long standing history of uncontrolled hypertension. Pathophysiology relating to severe hypothyroidism induced renal dysfunction is also discussed. PMID- 22829844 TI - Adolescent metabolic syndrome risk is increased with higher infancy weight gain and decreased with longer breast feeding. AB - Background. Prevalence of the metabolic syndrome is increasing in pediatric age groups worldwide. Meeting the criteria for the metabolic syndrome puts children at risk for later cardiovascular and metabolic disease. Methods. Using linear regression, we examined the association between infant weight gain from birth to 3 months and risk for the metabolic syndrome among 16- to 17-year-old Chilean adolescents (n = 357), accounting for the extent of breastfeeding in infancy and known covariates including gender, birth weight, and socioeconomic status. Results. Participants were approximately half male (51%), born at 40 weeks of gestation weighing 3.5 kg, and 48% were exclusively breastfed for >=90 days. Factors independently associated with increased risk of metabolic syndrome in adolescence were faster weight gain in the first 3 months of life (B = 0.16, P < 0.05) and male gender (B = 0.24, P < 0.05). Breastfeeding as the sole source of milk for >=90 days was associated with significantly decreased risk of metabolic syndrome (B = -0.16). Conclusion. This study adds to current knowledge about early infant growth and breastfeeding and their long-term health effects. PMID- 22829845 TI - Chronic kidney disease: highlights for the general pediatrician. AB - Chronic kidney disease in the pediatric population has been increasing. Early detection and treatment can slow down the progression of kidney disease and help prevent the development of end stage renal disease. In addition, as the kidney function declines, there are many pathophysiologic interactions with other organ systems that need to be monitored and treated. In particular, because of impaired vitamin D metabolism, calcium and phosphorus homeostasis is dysregulated and results in secondary bone disease. Anemia is common due to a number of factors including impaired erythropoietin production. Growth is often impacted by chronic kidney disease but can be improved by proper treatment. Complications of chronic kidney disease can be minimized by proper monitoring and treatment of these parameters. The general pediatrician plays a critical role in this process. PMID- 22829847 TI - Comment on "therapeutic effects and biomarkers in sublingual immunotherapy: a review". AB - Numerous sublingual immunotherapy studies have shown efficacy using a wide variety of dosing regimens. Despite a few grade III and one anaphylactic reaction due to a patient over-dose, there have been no fatal reactions resulting from sublingual immunotherapy treatment. Although safer than SCIT, SLIT is still immunotherapy. Special consideration should be given to what will ensure the highest level of safety for the patient given his or her history, exam and allergy test results. Dosing levels for sublingual immunotherapy should be based on what is therapeutically effective for each individual patient and adjusted accordingly throughout the treatment course. PMID- 22829846 TI - Rhinosinusitis and aspirin-exacerbated respiratory disease. AB - Rhinosinusitis is a feature of aspirin-exacerbated respiratory disease (AERD), which in the initial phase is manifested as nasal congestion, mostly affecting females at the age of around 30 years on average. Subsequently, nasal inflammation progresses to chronic eosinophilic rhinosinusitis, asthma, nasal polyposis, and intolerance to aspirin and to other NSAIDs. While it has been long established that NSAIDs cause inhibition of cyclooxygenase-1 (COX-1), leading to excessive metabolism of arachidonic acid (AA) to cysteinyl-leukotrienes (cys LTs), there is now evidence that both cytokines and staphylococcus superantigens amplify the inflammatory process exacerbating the disease. This paper gives a brief overview of the development of chronic rhinosinusitis (CRS) in sensitive patients, and we share our experience in the diagnosis and management of CRS in AERD. PMID- 22829848 TI - History of cesarean section associated with childhood onset of T1DM in Newfoundland and Labrador, Canada. AB - OBJECTIVES: Newfoundland and Labrador (NL) has one of the highest incidences of Type 1 diabetes mellitus (T1DM) worldwide. Rates of T1DM are increasing and the search for environmental factors that may be contributing to this increase is continuing. METHODS: This was a population-based case control design involving the linkage of data from a diabetes database with live birth registration data. 266 children aged 0-15 years with T1DM were compared to age- and gender-matched controls. Chi-square analysis and multivariate conditional logistic regression were carried out to assess maternal and infant factors (including maternal age, marital status, education, T1DM, hypertension, birth order, delivery method, gestational age, size-for-gestational-age, and birth weight). RESULTS: Cases of T1DM were more likely to be large-for-gestational-age (P = 0.024) and delivered by C-section (P = 0.009) as compared to controls. C-section delivery was associated with increased risk of T1DM (HR 1.41, P = 0.015) when birth weight and gestational age were included in the model, but not when size-for-gestational-age was included (HR 1.3, P = 0.076). CONCLUSIONS: Birth by C-section was found to be a risk factor for the development of T1DM in a region with high rates of T1DM and birth by C-section. These findings may have an impact on health practice, health care planning, and future research. PMID- 22829849 TI - Double allogenic mesenchymal stem cells transplantations could not enhance therapeutic effect compared with single transplantation in systemic lupus erythematosus. AB - The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles. However, the optimum frequency of the MSCs transplantation (MSCT) is unknown. This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation. Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT. Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. SLE disease activity index (SLEDAI) and serologic features were evaluated. Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup. This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients. PMID- 22829850 TI - Immunological HCV-associated thrombocytopenia: short review. AB - Infection with Hepatitis C virus (HCV) is affecting about 3% of the world's population, leading to liver damage, end-stage liver disease, and development of hepatocellular carcinoma, being thus the first indication for liver transplantation in the USA. Apart from the cirrhotic-liver-derived clinical signs and symptoms several conditions with immunological origin can also arise, such as, glomerulonephritis, pulmonary fibrosis, and thrombocytopenia. HCV-related autoimmune thrombocytopenia shows specific pathogenetic characteristics as well as symptoms and signs that differ in severity and frequency from symptoms in patients that are not HCV infected. Aim of this short paper is to estimate the epidemiological characteristics of the disease, to investigate the pathogenesis and clinical manifestation, and to propose treatment strategies according to the pertinent literature. PMID- 22829852 TI - Immunity to human immunodeficiency virus (HIV) infection. PMID- 22829851 TI - Vitamin D in early childhood and the effect on immunity to Mycobacterium tuberculosis. AB - A potential role for vitamin D as a therapeutic immunomodulator in tuberculosis (TB) has been recognised for over 150 years, but has only recently returned to the centre of the research arena due to the increasing awareness of the global vitamin D deficiency epidemic. As early as birth a child is often deficient in vitamin D, which may not only affect their bone metabolism but also modulate their immune function, contributing to the increased susceptibility to many infections seen early in life. Recent studies have begun to explain the mechanisms by which vitamin D affects immunity. Antimicrobial peptides are induced in conjunction with stimulation of innate pattern recognition receptors enhancing immunity to particular infections. In contrast the role of vitamin D within the adaptive immune response appears to be more regulatory in function, perhaps as a mechanism to reduce unwanted inflammation. In this paper we focus on the effect of vitamin D on immunity to TB. Where much of the attention has been paid by past reviews to the role of vitamin D in adult TB patients, this paper, where possible, focuses on research in paediatric populations. PMID- 22829853 TI - Cancer, inflammation, and insights from ayurveda. AB - A recent, exciting discovery relates to the concept of "shared pathology" between cancer and metabolic syndrome. One major pathway common to cancer and metabolic syndrome is chronic inflammation, which is a major driving force in carcinogenesis. Indeed, chronic inflammation precedes most cancers and is considered a "hallmark" of the neoplastic process. We discuss molecular and biochemical evidence which links diet, obesity, abnormal lipid metabolism, and type 2 diabetes mellitus with chronic inflammation. We also explain how each of these factors is linked with biochemical aberrations of carcinogenesis and the prevalence and risk of cancer. While there are reliable biomarkers for chronic inflammation, there are few markers for a mechanistic link between early inflammation and digestive disorders. Discovery of such a marker could lead to identification of a new subtype of patients with digestive disorders that predispose them to cancer and/or metabolic syndrome. In this context, we discuss the ayurvedic concept of "Ama" which is thought to be a toxic, proinflammatory waste-product of improper digestion. We then develop hypotheses and outline preclinical and clinical experiments designed to prove whether "Ama" can serve as a novel and reliable biomarker that links abnormal digestive status, with the onset of chronic inflammation. PMID- 22829854 TI - Triterpenoid-Rich Extract from Antrodia camphorata Improves Physical Fatigue and Exercise Performance in Mice. AB - Antrodia camphorata (AC) is an endemic mushroom that grows in Taiwan. We investigated the fatigue-alleviating effects of AC on endurance capacity in swim exercised and weight-loading mice. Male Institute of Cancer Research (ICR) strain mice from 3 groups (n = 10 per group in each test) were orally administered AC fruiting body extract for 7 days at 0, 50, and 200 mg/kg/day, designated vehicle, AC-50, and AC-200, respectively. Trend analysis revealed that AC treatments increased grip strength. AC dose-dependently increased swim time, blood glucose, and muscular and hepatic glycogen levels and dose-dependently decreased plasma lactate and ammonia levels and creatine kinase activity. The increase in swimming endurance with AC administration was caused by an increase in liver and muscle glycogen deposition. A. camphorata may have potential for use in ergogenic and antifatigue activities. PMID- 22829855 TI - Tocotrienol supplementation improves late-phase fracture healing compared to alpha-tocopherol in a rat model of postmenopausal osteoporosis: a biomechanical evaluation. AB - This study investigated the effects of alpha-tocopherol and palm oil tocotrienol supplementations on bone fracture healing in postmenopausal osteoporosis rats. 32 female Sprague-Dawley rats were divided into four groups. The first group was sham operated (SO), while the others were ovariectomised. After 2 months, the right femora were fractured under anesthesia and fixed with K-wire. The SO and ovariectomised-control rats (OVXC) were given olive oil (vehicle), while both the alpha-tocopherol (ATF) and tocotrienol-enriched fraction (TEF) groups were given alpha-tocopherol and tocotrienol-enriched fraction, respectively, at the dose of 60 mg/kg via oral gavages 6 days per week for 8 weeks. The rats were then euthanized and the femora dissected out for bone biomechanical testing to assess their strength. The callous of the TEF group had significantly higher stress parameter than the SO and OVXC groups. Only the SO group showed significantly higher strain parameter compared to the other treatment groups. The load parameter of the OVXC and ATF groups was significantly lower than the SO group. There was no significant difference in the Young's modulus between the groups. In conclusion, tocotrienol is better than alpha-tocopherol in improving the biomechanical properties of the fracture callous in postmenopausal osteoporosis rat model. PMID- 22829856 TI - Acute and Chronic Administrations of Rheum palmatum Reduced the Bioavailability of Phenytoin in Rats: A New Herb-Drug Interaction. AB - The rhizome of Rheum palmatum (RP) is a commonly used herb in clinical Chinese medicine. Phenytoin (PHT) is an antiepileptic with narrow therapeutic window. This study investigated the acute and chronic effects of RP on the pharmacokinetics of PHT in rat. Rats were orally administered with PHT (200 mg/kg) with and without RP decoction (single dose and seven doses of 2 g/kg) in a crossover design. The serum concentrations of PHT, PHT glucuronide (PHT-G), 4 hydroxyphenytoin (HPPH), and HPPH glucuronide (HPPH-G) were determined by HPLC method. Cell line models were used to identify the underlying mechanisms. The results showed that coadministration of single dose or multiple doses of RP significantly decreased the C(max) and AUC(0-t) as well as the K(10) of PHT, PHT G, HPPH, and HPPH-G. Cell line studies revealed that RP significantly induced the P-gp-mediated efflux of PHT and inhibited the MRP-2-medicated transport of PHT and HPPH. In conclusion, acute and chronic coadministrations of RP markedly decreased the oral bioavailability of PHT via activation of P-gp, although the MRP-2-mediated excretion of PHT was inhibited. It is recommended that caution should be exercised during concurrent use of RP and PHT. PMID- 22829857 TI - Long-Term Consumption of Platycodi Radix Ameliorates Obesity and Insulin Resistance via the Activation of AMPK Pathways. AB - This study was designed to evaluate the effects and mechanism of Platycodi radix, having white balloon flower (Platycodon grandiflorum for. albiflorum (Honda) H. Hara) on obesity and insulin resistance. The extracts of Platycodi radix with white balloon flower were tested in cultured cells and administered into mice on a high-fat diet. The Platycodi radix activated the AMPK/ACC phosphorylation in C2C12 myotubes and also suppressed adipocyte differentiation in 3T3-L1 cells. In experimental animal, it suppressed the weight gain of obese mice and ameliorated obesity-induced insulin resistance. It also reduced the elevated circulating mediators, including triglyceride (TG), T-CHO, leptin, resistin, and monocyte chemotactic protein (MCP)-1 in obesity. As shown in C2C12 myotubes, the administration of Platycodi radix extracts also recovered the AMPK/ACC phosphorylation in the muscle of obese mice. These results suggest that Platycodi radix with white balloon flower ameliorates obesity and insulin resistance in obese mice via the activation of AMPK/ACC pathways and reductions of adipocyte differentiation. PMID- 22829858 TI - Clinical Distribution and Molecular Basis of Traditional Chinese Medicine ZHENG in Cancer. AB - In traditional Chinese medicine (TCM) clinical practice, ZHENG (also known as syndrome) helps to guide design of individualized treatment strategies. In this study, we investigated the clinical use of ZHENG in TCM-treated cancer patients by systematically analyzing data from all relevant reports in the Chinese language scientific literature. We aimed to determine the clinical ZHENG distributions in six common cancers (lung, liver, gastric, breast, colorectal, and pancreatic) with the expectation of uncovering a theoretical basis for TCM ZHENG as a clinical cancer treatment. In addition, we also reviewed the molecular basis underlying Xue-Yu (blood stasis), Shi-Re (dampness-heat), Yin-Xu (Yin deficiency), and Pi-Xu (spleen deficiency) ZHENG that are commonly found in cancer patients. The results from our summary study provide insights into the potential utility of TCM ZHENG and may contribute to a better understanding of the molecular basis of TCM ZHENG in cancer. PMID- 22829859 TI - Alleviation of Morphine Withdrawal Signs but Not Tolerance by the Essential Oil of Kelussia odoratissima Mozaff. AB - The aim of the present study was to assess the effects of chronic and acute treatment of the essential oil (EO) of Kelussia odoratissima Mozaff. on the development of morphine tolerance and dependence in mice. Mice were rendered tolerant to and dependent on morphine by subcutaneous injection of morphine over a period of 5 days. Tolerance was assessed using the tail-pinch test and withdrawal signs of morphine were precipitated by injecting naloxone 2 h after the final morphine injection. Repeated injection of the EO of K. odoratissima (5 and 10 mg/kg) for 4 days significantly suppressed morphine-withdrawal jumps, a sign of the development of dependence to opiate as assessed by naloxone precipitation withdrawal on day 5 of testing. A single injection (25, 50, 100 mg/kg) of the EO on day 5, 1 h prior to morphine failed to produce any significant change in morphine withdrawal signs. Neither the acute nor the chronic administration of EO of the K. odoratissima did significantly influence the development of tolerance to the analgesic effect of morphine. Alleviation in morphine signs of withdrawal after chronic injection with K. odoratissima is indicative of reversal of neuronal adaptation that takes place during morphine presence in the brain. PMID- 22829860 TI - How to design the control group in randomized controlled trials of acupuncture? AB - In evidence-based medicine, randomized controlled trials (RCTs) are the preferred method for evaluating the efficacy of interventions. In regard to acupuncture RCTs, the most difficult issues are the design of the control group and implementation of the principle of "double-blinding." We compared the advantages and limitations associated with different control group designs in acupuncture RCTs, to assist researchers in this field. PMID- 22829861 TI - Plant ethnoveterinary practices in two pyrenean territories of catalonia (iberian peninsula) and in two areas of the balearic islands and comparison with ethnobotanical uses in human medicine. AB - This paper presents the results of an ethnobotanical study centred in veterinarian uses in two Catalan Pyrenean regions (Alt Emporda -AE- and High River Ter Valley -AT-, Iberian peninsula) and two Balearic Islands areas (Formentera -FO- and northeastern Mallorca -MA-). In the areas studied, 97 plant species have been claimed to be useful for veterinary purposes. A total of 306 veterinary use reports have been gathered and analysed. The ten most reported plants are Tanacetum parthenium (24 use reports), Parietaria officinalis (15), Ranunculus parnassifolius (14), Meum athamanticum (13), Olea europaea (13), Quercus ilex (12), Ruta chalepensis (12), Sambucus nigra (10) and Thymus vulgaris (10). According to comprehensive reviews, a high number of novelties for plant ethnoveterinary are contributed: 34 species and one subspecies, 11 genera, and three families have not been reported in previous works in this field, and 21 species had only been mentioned once. Several ethnoveterinary uses are coincidental with those in human medicine. Although ethnoveterinary practices are less relevant than in the past in the territories considered, as in all industrialised countries, the knowledge on plant properties and applications is still rich and constitutes a large pool of evidence for phytotherapy, both in domestic animals and humans. PMID- 22829862 TI - Origins of the New Latino Underclass. AB - Over the past four decades, the Latino population of the United States was transformed from a small, ethnically segmented population of Mexicans in the southwest, Puerto Ricans in New York, and Cubans in Miami into a large national population dominated by Mexicans, Central Americans, and South Americans. This transformation occurred through mass immigration, much of it undocumented, to the point where large fractions of non-Caribbean Hispanics lack legal protections and rights in the United States. Rising illegality is critical to understanding the disadvantaged status of Latinos today. The unauthorized population began to grow after avenues for legal entry were curtailed in 1965. The consequent rise in undocumented migration enabled political and bureaucratic entrepreneurs to frame Latino migration as a grave threat to the nation, leading to a rising frequency of negative framings in the media, a growing conservative reaction, and increasingly restrictive immigration and border policies that generated more apprehensions. Rising apprehensions, in turn, further enflamed the conservative reaction to produce even harsher enforcement and more still more apprehensions, yielding a self-feeding cycle in which apprehensions kept rising even though undocumented inflows had stabilized. The consequent militarization of the border had the perverse effect of reducing rates of out-migration rather than inhibiting in-migration, leading to a sharp rise in net undocumented population and rapid growth of the undocumented population. As a result, a majority of Mexican, Central American, and South American immigrants are presently undocumented at a time when unauthorized migrants are subject to increasing sanctions from authorities and the public, yielding down-ward pressure on the status and well being of Latinos in the United States. PMID- 22829863 TI - Improvement of landfill leachate biodegradability with ultrasonic process. AB - Landfills leachates are known to contain recalcitrant and/or non-biodegradable organic substances and biological processes are not efficient in these cases. A promising alternative to complete oxidation of biorecalcitrant leachate is the use of ultrasonic process as pre-treatment to convert initially biorecalcitrant compounds to more readily biodegradable intermediates. The objectives of this study are to investigate the effect of ultrasonic process on biodegradability improvement. After the optimization by factorial design, the ultrasonic were applied in the treatment of raw leachates using a batch wise mode. For this, different scenarios were tested with regard to power intensities of 70 and 110 W, frequencies of 30, 45 and 60 KHz, reaction times of 30, 60, 90 and 120 minutes and pH of 3, 7 and 10. For determining the effects of catalysts on sonication efficiencies, 5 mg/l of TiO(2) and ZnO have been also used. Results showed that when applied as relatively brief pre-treatment systems, the sonocatalysis processes induce several modifications of the matrix, which results in significant enhancement of its biodegradability. For this reason, the integrated chemical-biological systems proposed here represent a suitable solution for the treatment of landfill leachate samples. PMID- 22829864 TI - Role of endothelial AADC in cardiac synthesis of serotonin and nitrates accumulation. AB - Serotonin (5-HT) regulates different cardiac functions by acting directly on cardiomyocytes, fibroblasts and endothelial cells. Today, it is widely accepted that activated platelets represent a major source of 5-HT. In contrast, a supposed production of 5-HT in the heart is still controversial. To address this issue, we investigated the expression and localization of 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and L-aromatic amino acid decarboxylase (AADC) in the heart. We also evaluated their involvement in cardiac production of 5-HT. TPH1 was weakly expressed in mouse and rat heart and appeared restricted to mast cells. Degranulation of mast cells by compound 48/80 did not modify 5-HT cardiac content in mice. Western blots and immunolabelling experiments showed an abundant expression of AADC in the mouse and rat heart and its co-localization with endothelial cells. Incubation of cardiac homogenate with the AADC substrate (5-hydroxy-L-tryptophan) 5-HTP or intraperitoneal injection of 5-HTP in mice significantly increased cardiac 5-HT. These effects were prevented by the AADC inhibitor benserazide. Finally, 5-HTP administration in mice increased phosphorylation of aortic nitric oxide synthase 3 at Ser (1177) as well as accumulation of nitrates in cardiac tissue. This suggests that the increase in 5 HT production by AADC leads to activation of endothelial and cardiac nitric oxide pathway. These data show that endothelial AADC plays an important role in cardiac synthesis of 5-HT and possibly in 5-HT-dependent regulation of nitric oxide generation. PMID- 22829865 TI - Quantification of HER expression and dimerization in patients' tumor samples using time-resolved Forster resonance energy transfer. AB - Following the development of targeted therapies against EGFR and HER2, two members of the human epidermal receptor (HER) family of receptor tyrosine kinases, much interest has been focused on their expression in tumors. However, knowing the expression levels of individual receptors may not be sufficient to predict drug response. Here, we describe the development of antibody-based time resolved Forster resonance energy transfer (TR-FRET) assays for the comprehensive analysis not only of EGFR and HER2 expression in tumor cryosections, but also of their activation through quantification of HER homo- or heterodimers. First, EGFR and HER2 expression levels were quantified in 18 breast tumors and the results were compared with those obtained by using reference methods. The EGFR number per cell determined by TR-FRET was significantly correlated with EGFR mRNA copy number (P<0.0001). Moreover, our method detected HER2 overexpression with 100% specificity and sensibility, as confirmed by the standard IHC, FISH and qPCR analyses. EGFR and HER2 dimerization was then assessed, using as controls xenograft tumors from cell lines with known dimer expression profiles. Our results show that quantification of HER dimerization provides information about receptor activation that cannot be obtained by quantification of single receptors. Quantifying HER expression and dimerization by TR-FRET assays might help identifying novel clinical markers for optimizing patients' treatment in oncology. PMID- 22829866 TI - Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments. AB - The seven WhiB proteins of Mycobacterium tuberculosis (M.tb) are widely believed to be redox-sensing transcription factors due to their binding of iron-sulfur clusters and similarities to DNA binding proteins. Here, we explored the nature of this hypothesized relationship. We exposed M.tb to physiologic conditions such as gradual hypoxia, nitric oxide (NO), cyclic AMP and in vivo conditions, and measured transcription of the whiB genes. We found whiB3 to be induced both by hypoxia and NO, whiB7 to be induced in macrophage-like cells, and whiB4 to be induced in mouse lung. Cyclic AMP induced whiB1,-2, -4, -6 and -7. Our data indicate that the M.tb whiB genes are induced independently by various stimuli which may add versatility to their suggested redox-sensing properties. PMID- 22829867 TI - A comparative analysis of polyfunctional T cells and secreted cytokines induced by Bacille Calmette-Guerin immunisation in children and adults. AB - BCG vaccine is one of the most commonly-administered vaccines worldwide. Studies suggest the protective efficacy of BCG against TB is better for children than for adults. One potential explanation is that BCG induces a better protective immune response in children. Twenty six children and adults were immunised with BCG. The proportion of Th1-cytokine-producing mycobacterial-specific T cells, and the concentrations of secreted cytokines, were measured before and 10 weeks after BCG immunisation. A significant increase in the proportion of mycobacterial-specific cytokine-producing T cells was observed in both age groups. After BCG immunisation, children and adults had comparable proportions of mycobacterial specific polyfunctional CD4 T cells when measured relative to the total number of CD4 T cells. However, relative to the subset of Th-1-cytokine-producing CD4 T cells, the proportion of polyfunctional cells was greater in children. Concentrations of secreted cytokines were comparable in children and adults. These findings suggest that the mycobacterial-specific cell-mediated immune response induced by BCG immunisation in children and adults is similar. The implication of a shift to a more polyfunctional immune response within the Th1 cytokine-producing CD4 T cells in children is uncertain as this aspect of the immune response has not been assessed as a potential correlate of protection against TB. PMID- 22829868 TI - A probabilistic fragment-based protein structure prediction algorithm. AB - Conformational sampling is one of the bottlenecks in fragment-based protein structure prediction approaches. They generally start with a coarse-grained optimization where mainchain atoms and centroids of side chains are considered, followed by a fine-grained optimization with an all-atom representation of proteins. It is during this coarse-grained phase that fragment-based methods sample intensely the conformational space. If the native-like region is sampled more, the accuracy of the final all-atom predictions may be improved accordingly. In this work we present EdaFold, a new method for fragment-based protein structure prediction based on an Estimation of Distribution Algorithm. Fragment based approaches build protein models by assembling short fragments from known protein structures. Whereas the probability mass functions over the fragment libraries are uniform in the usual case, we propose an algorithm that learns from previously generated decoys and steers the search toward native-like regions. A comparison with Rosetta AbInitio protocol shows that EdaFold is able to generate models with lower energies and to enhance the percentage of near-native coarse grained decoys on a benchmark of [Formula: see text] proteins. The best coarse grained models produced by both methods were refined into all-atom models and used in molecular replacement. All atom decoys produced out of EdaFold's decoy set reach high enough accuracy to solve the crystallographic phase problem by molecular replacement for some test proteins. EdaFold showed a higher success rate in molecular replacement when compared to Rosetta. Our study suggests that improving low resolution coarse-grained decoys allows computational methods to avoid subsequent sampling issues during all-atom refinement and to produce better all-atom models. EdaFold can be downloaded from http://www.riken.jp/zhangiru/software.html [corrected]. PMID- 22829869 TI - Selective endothelial overexpression of arginase II induces endothelial dysfunction and hypertension and enhances atherosclerosis in mice. AB - BACKGROUND: Cardiovascular disorders associated with endothelial dysfunction, such as atherosclerosis, have decreased nitric oxide (NO) bioavailability. Arginase in the vasculature can compete with eNOS for L-arginine and has been implicated in atherosclerosis. The aim of this study was to evaluate the effect of endothelial-specific elevation of arginase II expression on endothelial function and the development of atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: Transgenic mice on a C57BL/6 background with endothelial-specific overexpression of human arginase II (hArgII) gene under the control of the Tie2 promoter were produced. The hArgII mice had elevated tissue arginase activity except in liver and in resident peritoneal macrophages, confirming endothelial specificity of the transgene. Using small-vessel myography, aorta from these mice exhibited endothelial dysfunction when compared to their non-transgenic littermate controls. The blood pressure of the hArgII mice was 17% higher than their littermate controls and, when crossed with apoE -/- mice, hArgII mice had increased aortic atherosclerotic lesions. CONCLUSION: We conclude that overexpression of arginase II in the endothelium is detrimental to the cardiovascular system. PMID- 22829871 TI - Web search queries can predict stock market volumes. AB - We live in a computerized and networked society where many of our actions leave a digital trace and affect other people's actions. This has lead to the emergence of a new data-driven research field: mathematical methods of computer science, statistical physics and sociometry provide insights on a wide range of disciplines ranging from social science to human mobility. A recent important discovery is that search engine traffic (i.e., the number of requests submitted by users to search engines on the www) can be used to track and, in some cases, to anticipate the dynamics of social phenomena. Successful examples include unemployment levels, car and home sales, and epidemics spreading. Few recent works applied this approach to stock prices and market sentiment. However, it remains unclear if trends in financial markets can be anticipated by the collective wisdom of on-line users on the web. Here we show that daily trading volumes of stocks traded in NASDAQ-100 are correlated with daily volumes of queries related to the same stocks. In particular, query volumes anticipate in many cases peaks of trading by one day or more. Our analysis is carried out on a unique dataset of queries, submitted to an important web search engine, which enable us to investigate also the user behavior. We show that the query volume dynamics emerges from the collective but seemingly uncoordinated activity of many users. These findings contribute to the debate on the identification of early warnings of financial systemic risk, based on the activity of users of the www. PMID- 22829870 TI - The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. AB - Glucose induces insulin release from pancreatic beta-cells by stimulating ATP synthesis, membrane depolarisation and Ca(2+) influx. As well as activating ATP consuming processes, cytosolic Ca(2+) increases may also potentiate mitochondrial ATP synthesis. Until recently, the ability to study the role of mitochondrial Ca(2+) transport in glucose-stimulated insulin secretion has been hindered by the absence of suitable approaches either to suppress Ca(2+) uptake into these organelles, or to examine the impact on beta-cell excitability. Here, we have combined patch-clamp electrophysiology with simultaneous real-time imaging of compartmentalised changes in Ca(2+) and ATP/ADP ratio in single primary mouse beta-cells, using recombinant targeted (Pericam or Perceval, respectively) as well as entrapped intracellular (Fura-Red), probes. Through shRNA-mediated silencing we show that the recently-identified mitochondrial Ca(2+) uniporter, MCU, is required for depolarisation-induced mitochondrial Ca(2+) increases, and for a sustained increase in cytosolic ATP/ADP ratio. By contrast, silencing of the mitochondrial Na(+)-Ca(2+) exchanger NCLX affected the kinetics of glucose induced changes in, but not steady state values of, cytosolic ATP/ADP. Exposure to gluco-lipotoxic conditions delayed both mitochondrial Ca(2+) uptake and cytosolic ATP/ADP ratio increases without affecting the expression of either gene. Mitochondrial Ca(2+) accumulation, mediated by MCU and modulated by NCLX, is thus required for normal glucose sensing by pancreatic beta-cells, and becomes defective in conditions mimicking the diabetic milieu. PMID- 22829872 TI - Classification of lung cancer tumors based on structural and physicochemical properties of proteins by bioinformatics models. AB - Rapid distinction between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) tumors is very important in diagnosis of this disease. Furthermore sequence-derived structural and physicochemical descriptors are very useful for machine learning prediction of protein structural and functional classes, classifying proteins and the prediction performance. Herein, in this study is the classification of lung tumors based on 1497 attributes derived from structural and physicochemical properties of protein sequences (based on genes defined by microarray analysis) investigated through a combination of attribute weighting, supervised and unsupervised clustering algorithms. Eighty percent of the weighting methods selected features such as autocorrelation, dipeptide composition and distribution of hydrophobicity as the most important protein attributes in classification of SCLC, NSCLC and COMMON classes of lung tumors. The same results were observed by most tree induction algorithms while descriptors of hydrophobicity distribution were high in protein sequences COMMON in both groups and distribution of charge in these proteins was very low; showing COMMON proteins were very hydrophobic. Furthermore, compositions of polar dipeptide in SCLC proteins were higher than NSCLC proteins. Some clustering models (alone or in combination with attribute weighting algorithms) were able to nearly classify SCLC and NSCLC proteins. Random Forest tree induction algorithm, calculated on leaves one-out and 10-fold cross validation) shows more than 86% accuracy in clustering and predicting three different lung cancer tumors. Here for the first time the application of data mining tools to effectively classify three classes of lung cancer tumors regarding the importance of dipeptide composition, autocorrelation and distribution descriptor has been reported. PMID- 22829874 TI - Security and privacy qualities of medical devices: an analysis of FDA postmarket surveillance. AB - BACKGROUND: Medical devices increasingly depend on computing functions such as wireless communication and Internet connectivity for software-based control of therapies and network-based transmission of patients' stored medical information. These computing capabilities introduce security and privacy risks, yet little is known about the prevalence of such risks within the clinical setting. METHODS: We used three comprehensive, publicly available databases maintained by the Food and Drug Administration (FDA) to evaluate recalls and adverse events related to security and privacy risks of medical devices. RESULTS: Review of weekly enforcement reports identified 1,845 recalls; 605 (32.8%) of these included computers, 35 (1.9%) stored patient data, and 31 (1.7%) were capable of wireless communication. Searches of databases specific to recalls and adverse events identified only one event with a specific connection to security or privacy. Software-related recalls were relatively common, and most (81.8%) mentioned the possibility of upgrades, though only half of these provided specific instructions for the update mechanism. CONCLUSIONS: Our review of recalls and adverse events from federal government databases reveals sharp inconsistencies with databases at individual providers with respect to security and privacy risks. Recalls related to software may increase security risks because of unprotected update and correction mechanisms. To detect signals of security and privacy problems that adversely affect public health, federal postmarket surveillance strategies should rethink how to effectively and efficiently collect data on security and privacy problems in devices that increasingly depend on computing systems susceptible to malware. PMID- 22829873 TI - Imaging the spatio-temporal dynamics of supragranular activity in the rat somatosensory cortex in response to stimulation of the paws. AB - We employed voltage-sensitive dye (VSD) imaging to investigate the spatio temporal dynamics of the responses of the supragranular somatosensory cortex to stimulation of the four paws in urethane-anesthetized rats. We obtained the following main results. (1) Stimulation of the contralateral forepaw evoked VSD responses with greater amplitude and smaller latency than stimulation of the contralateral hindpaw, and ipsilateral VSD responses had a lower amplitude and greater latency than contralateral responses. (2) While the contralateral stimulation initially activated only one focus, the ipsilateral stimulation initially activated two foci: one focus was typically medial to the focus activated by contralateral stimulation and was stereotaxically localized in the motor cortex; the other focus was typically posterior to the focus activated by contralateral stimulation and was stereotaxically localized in the somatosensory cortex. (3) Forepaw and hindpaw somatosensory stimuli activated large areas of the sensorimotor cortex, well beyond the forepaw and hindpaw somatosensory areas of classical somatotopic maps, and forepaw stimuli activated larger cortical areas with greater activation velocity than hindpaw stimuli. (4) Stimulation of the forepaw and hindpaw evoked different cortical activation dynamics: forepaw responses displayed a clear medial directionality, whereas hindpaw responses were much more uniform in all directions. In conclusion, this work offers a complete spatio-temporal map of the supragranular VSD cortical activation in response to stimulation of the paws, showing important somatotopic differences between contralateral and ipsilateral maps as well as differences in the spatio-temporal activation dynamics in response to forepaw and hindpaw stimuli. PMID- 22829875 TI - Using GFP video to track 3D movement and conditional gene expression in free moving flies. AB - BACKGROUND: In vivo imaging and quantification of fluorescent reporter molecules is increasingly useful in biomedical research. For example, tracking animal movement in 3D with simultaneous quantification of fluorescent transgenic reporters allows for correlations between behavior, aging and gene expression. However implementation has been hindered in the past by the complexity of operating the systems. RESULTS: We report significant technical improvements and user-friendly software (called FluoreScore) that enables tracking of 3D movement and the dynamics of gene expression in adult Drosophila, using two cameras and recorded GFP videos. Expression of a transgenic construct encoding eGFP was induced in free-moving adult flies using the Gene-Switch system and RU486 drug feeding. The time course of induction of eGFP expression was readily quantified from internal tissues including central nervous tissue. CONCLUSIONS: FluoreScore should facilitate a variety of future studies involving quantification of movement behaviors and fluorescent molecules in free-moving animals. PMID- 22829876 TI - Registration accuracy and quality of real-life images. AB - BACKGROUND: A common registration problem for the application of consumer device is to align all the acquired image sequences into a complete scene. Image alignment requires a registration algorithm that will compensate as much as possible for geometric variability among images. However, images captured views from a real scene usually produce different distortions. Some are derived from the optic characteristics of image sensors, and others are caused by the specific scenes and objects. METHODOLOGY/PRINCIPAL FINDINGS: An image registration algorithm considering the perspective projection is proposed for the application of consumer devices in this study. It exploits a multiresolution wavelet-based method to extract significant features. An analytic differential approach is then proposed to achieve fast convergence of point matching. Finally, the registration accuracy is further refined to obtain subpixel precision by a feature-based modified Levenberg-Marquardt method. Due to its feature-based and nonlinear characteristic, it converges considerably faster than most other methods. In addition, vignette compensation and color difference adjustment are also performed to further improve the quality of registration results. CONCLUSIONS/SIGNIFICANCE: The performance of the proposed method is evaluated by testing the synthetic and real images acquired by a hand-held digital still camera and in comparison with two registration techniques in terms of the squared sum of intensity differences (SSD) and correlation coefficient (CC). The results indicate that the proposed method is promising in registration accuracy and quality, which are statistically significantly better than other two approaches. PMID- 22829877 TI - Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes. AB - The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM. PMID- 22829878 TI - Association of a BMP9 haplotype with ossification of the posterior longitudinal ligament (OPLL) in a Chinese population. AB - Direct or ex vivo BMP9 adenoviral gene therapy can induce massive bone formation at the injection sites and clearly promote spinal fusion. A comprehensive analysis of the osteogenic activity indicated that BMP9 was one of the most potent inducers of osteogenic differentiation both in vitro and in vivo among 14 types of human BMPs. However, genetic variations and whether they correlated with OPLL were not considered. We have sequenced the complete BMP9 gene in 450 patients with OPLL and in 550 matched controls. Analyses were performed on single markers and haplotypes. Single marker tests identified 6 SNPs, among which the minor alleles of rs7923671 (T>C; P=0.0026; OR: 1.33, CI: 1.10-1.60), rs75024165 (C>T, Thr304Met; P<0.001; OR: 1.76, CI: 1.47-2.12) and rs34379100 (A>C; P<0.001; OR: 1.52, CI: 1.27-1.82) were associated with OPLL. Logistic regression analysis showed that the additive model of rs75024165 (TT vs. CT vs. CC; P<0.001; OR: 1.74) and rs34379100 (CC vs. AC vs. AA; P=0.003; OR: 1.95) retained statistical significance when adjusted for clinical and demographic characteristics. Linkage disequilibrium (LD) analysis identified one 3 kb block of intense LD in BMP9 and one specific haplotype, CTCA (P<0.001; OR: 2.37), that contained the OPLL associated risk alleles and was a risk factor for OPLL. This haplotype is associated with increased severity of OPLL, as shown by the distribution of ossified vertebrae in patients with OPLL (P=0.001). In summary, in the Chinese population studied, SNPs in the BMP9 gene appear to contribute to the risk of OPLL in association with certain clinical and demographic characteristics. The severity of OPLL seems to be mediated predominantly by genetic variations in a 3kb BMP9 locus with the specific haplotype CTCA. PMID- 22829879 TI - Cryptic diversity in Indo-Australian rainbowfishes revealed by DNA barcoding: implications for conservation in a biodiversity hotspot candidate. AB - The rainbowfishes of the family Melanotaeniidae represent one of the largest radiations of freshwater fishes from the Indo-Australian archipelago. A total of 75 nominal species have been described, among which several have become very popular among tropical fish hobbyists because of their tendency to form large schools of colourful individuals. Facing habitat loss and competition or predation by introduced species, this group has become a priority in the conservation of ornamental fishes in Indonesia. In this context, several expeditions have been conducted between 2007 and 2010 in Indonesian Papua with the aim to initiate a large-scale survey of the genetic resources in this group. We assessed the diversity of the Papua rainbowfishes with DNA barcoding. We sequenced the mitochondrial COI gene for 350 specimens belonging to 53 nominal species throughout the Indo-Australian archipelago. Unexpected levels of cryptic diversity and endemism were detected since additional cryptic lineages were detected in several watersheds from the Vogelkop and the Lengguru massif. DNA barcoding supports the presence of nearly 30 evolutionary lineages among the 15 nominal species sampled in the Vogelkop and all these lineages are endemic to a single lake or watershed. This result highlights that the diversity of the family has been largely underestimated and urges for the identification of conservation priorities in Papua. PMID- 22829880 TI - Ectopically expressed perforin-1 is proapoptotic in tumor cell lines by increasing caspase-3 activity and the nuclear translocation of cytochrome C. AB - Perforin-1 (PRF), a cytotoxic lymphocyte pore-forming protein, plays an important role in the action of cytotoxic T cells and natural killer cells in that it causes the lysis of abnormal body cells and the elimination of virus-infected cells and tumors. Upon degranulation, PRF inserts itself into the target cell's plasma membrane, forming a pore. The subsequent translocation of pro-apoptotic granzymes (including granzyme B, A, M et al.) into the cytoplasm provides the proteases with access to numerous protein substrates that promote apoptosis after cleavage. These proteases are believed to be the main executioners of target cell apoptosis. Although the PRF and granzyme components are both critical to this process and in some way involved in inducing cell death in target cells, the inhibition of tumor growth could still be efficient in granzyme-deficient mice. It is unclear whether PRF alone can suppress tumors. In this study, we discovered that forced ectopic expression of PRF alone, in the absence of granzymes, could mediate cell death in cancer cells. Notably, transient expression of both full length and truncated active-form PRF in human Hep G2, SK-BR-3, and HeLa cells was found to induce apparent cell growth inhibition and cell death, as evidenced by chromosome condensation and DNA fragmentation, increased caspase-3 activity, and the release of apoptosis inducing factor (AIF) and cytochrome c from the mitochondria. This PRF-induced cell death could be abrogated by pan-caspase inhibitor (Z-VAD) and mitochondria protector (TAT-BH4). The implication of these results is that ectopically expressed PRF has apoptosis-inducing abilities, and PRF alone is sufficient to induce apoptotic cell death in cells with ectopic expression. Taking this into consideration, our results suggest the possibility of using PRF as a pro-apoptotic gene for tumor therapeutics. PMID- 22829881 TI - Transferrin coated nanoparticles: study of the bionano interface in human plasma. AB - It is now well established that the surface of nanoparticles (NPs) in a biological environment is immediately modified by the adsorption of biomolecules with the formation of a protein corona and it is also accepted that the protein corona, rather than the original nanoparticle surface, defines a new biological identity. Consequently, a methodology to effectively study the interaction between nanomaterials and the biological corona encountered within an organism is a key objective in nanoscience for understanding the impact of the nanoparticle protein interactions on the biological response in vitro and in vivo. Here, we outline an integrated methodology to address the different aspects governing the formation and the function of the protein corona of polystyrene nanoparticles coated with Transferrin by different strategies. Protein-NP complexes are studied both in situ (in human plasma, full corona FC) and after washing (hard corona, HC) in terms of structural properties, composition and second-order interactions with protein microarrays. Human protein microarrays are used to effectively study NP-corona/proteins interactions addressing the growing demand to advance investigations of the extrinsic function of corona complexes. Our data highlight the importance of this methodology as an analysis to be used in advance of the application of engineered NPs in biological environments. PMID- 22829883 TI - Learning that circumcision is protective against HIV: risk compensation among men and women in Cape Town, South Africa. AB - OBJECTIVES: We examined whether knowledge of the HIV-protective benefits of male circumcision (MC) led to risk compensating behavior in a traditionally circumcising population in South Africa. We extend the current literature by examining risk compensation among women, which has hitherto been unexplored. METHODS: We used data on Xhosa men and women from the 2009 Cape Area Panel Study. Respondents were asked if they had heard that MC reduces a man's risk of contracting HIV, about their perceived risk of contracting HIV, and condom use. For each gender group we assessed whether risk perception and condom use differed by knowledge of the protective benefits of MC using bivariate and then multivariate models controlling for demographic characteristics, HIV knowledge/beliefs, and previous sexual behaviors. In a further check for confounding, we used data from the 2005 wave to assess whether individuals who would eventually become informed about the protective benefits of circumcision were already different in terms of HIV risk perception and condom use. RESULTS: 34% of men (n=453) and 27% of women (n=690) had heard that circumcision reduces a man's risk of HIV infection. Informed men perceived slightly higher risk of contracting HIV and were more likely to use condoms at last sex (p<0.10). Informed women perceived lower HIV risk (p<0.05), were less likely to use condoms both at last sex (p<0.10) and more generally (p<0.01), and more likely to forego condoms with partners of positive or unknown serostatus (p<0.01). The results were robust to covariate adjustment, excluding people living with HIV, and accounting for risk perceptions and condom use in 2005. CONCLUSIONS: We find evidence consistent with risk compensation among women but not men. Further attention should be paid to the role of new information regarding MC, and drivers of HIV risk more broadly, in modulating sexual behavior among women. PMID- 22829882 TI - Cell recruitment and cytokines in skin mice sensitized with the vaccine adjuvants: saponin, incomplete Freund's adjuvant, and monophosphoryl lipid A. AB - Vaccine adjuvants are substances associated with antigens that are fundamental to the formation of an intense, durable, and fast immune response. In this context, the use of vaccine adjuvants to generate an effective cellular immune response is crucial for the design and development of vaccines against visceral leishmaniasis. The objective of this study was to evaluate innate inflammatory response induced by the vaccine adjuvants saponin (SAP), incomplete Freund's adjuvant (IFA), and monophosphoryl lipid A (MPL). After a single dose of adjuvant was injected into the skin of mice, we analyzed inflammatory reaction, selective cell migration, and cytokine production at the injection site, and inflammatory cell influx in the peripheral blood. We found that all vaccine adjuvants were able to promote cell recruitment to the site without tissue damage. In addition, they induced selective migration of neutrophils, macrophages, and lymphocytes. The influx of neutrophils was notable at 12 h in all groups, but at other time points it was most evident after inoculation with SAP. With regard to cytokines, the SAP led to production of interleukin (IL)-2, IL-6, and IL-4. IFA promoted production of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-6, IL 17, IL-4, and IL-10. We also observed that MPL induced high production of IL-2, TNF-alpha, and IFN-gamma, in addition to IL-6, IL-17, and IL-10. In peripheral blood, values of certain cell populations in the local response changed after stimulation. Our data demonstrate that the three vaccine adjuvants stimulate the early events of innate immune response at the injection site, suggesting their ability to increase the immunogenicity of co-administered antigens. Moreover, this work provides relevant information about elements of innate and acquired immune response induced by vaccine adjuvants administered alone. PMID- 22829884 TI - Habitat-specific locomotor variation among Chinese hook snout carp (Opsariichthys bidens) along a river. AB - The Wujiang River is a tributary of the upper Yangtze River that shows great variations in its flow regime and habitat condition. Dams have been built along the Wujiang River and have altered the habitats profoundly enough that they may give rise to reproductive isolation. To test whether the swimming performance and morphology of the Chinese hook snout carp (Opsariichthys bidens), varied among habitats and whether the possible differences had a genetic basis, we measured the steady and unsteady swimming performance, external body shape and genetic distance among fish collected from both the main and tributary streams of the upper, middle and lower reaches along the river. We also measured the routine energy expenditure (RMR), maximum metabolic rate (MMR), cost of transport (COT) and calculated the optimal swimming speed. The steady swimming capacity, RMR, MMR and optimal swimming speed were all higher and the COT was lower in the upper reach or tributary streams compared with the lower reach or main stream. However, unsteady swimming performance showed no variation among collecting sites. Flow regimes as suggested by river slope and water velocity were positively correlated with steady swimming performance but not with unsteady swimming performance. Predation stress were significantly related with body morphology and hence energy cost during swimming but not U(crit) value. The fish from only one population (Hao-Kou) showed relatively high genetic differentiation compared with the other populations. Fish from the upper reach or tributary streams exhibited improved steady swimming performance through improved respiratory capacity and lower energy expenditure during swimming at the cost of higher maintenance metabolism. There was no correlation between the steady and unsteady swimming performance at either the population or the individual levels. These results suggest that a trade-off between steady and unsteady swimming does not occur in O. bidens. PMID- 22829885 TI - Validating a shortened depression scale (10 item CES-D) among HIV-positive people in British Columbia, Canada. AB - OBJECTIVE: To establish the reliability and validity of a shortened (10-item) depression scale used among HIV-positive patients enrolled in the Drug Treatment Program in British Columbia, Canada. METHODS: The 10-item CES-D (Center for Epidemiologic Studies Depression Scale) was examined among 563 participants who initiated antiretroviral therapy (ART) between August 1, 1996 and June 30, 2002. Internal consistency of the scale was measured by Cronbach's alpha. Using the original CES-D 20 as primary criteria, comparisons were made using the Kappa statistic. Predictive accuracy of CES-D 10 was assessed by calculating sensitivity, specificity, positive predictive values and negative predictive values. Factor analysis was also performed to determine if the CES-D 10 contained the same factors of positive and negative affect found in the original development of the CES-D. RESULTS: The correlation between the original and the shortened scale is very high (Spearman correlation coefficient =0.97 (P<0.001). Internal consistency reliability coefficients of the CES-D 10 were satisfactory (Cronbach alpha=0.88). The CES-D 10 showed comparable accuracy to the original CES-D 20 in classifying participants with depressive symptoms (Kappa=0.82, P<0.001). Sensitivity of CES-D 10 was 91%; specificity was 92%; and positive predictive value was 92%. Factor analysis demonstrates that CES-D 10 contains the same underlying factors of positive and negative affect found in the original development of the CES-D 20. CONCLUSION: The 10-item CES-D is a comparable tool to measure depressive symptoms among HIV-positive research participants. PMID- 22829886 TI - The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma. AB - Histone deacetylase (HDAC) inhibitors, especially vorinostat, are currently under investigation as potential adjuncts in the treatment of neuroblastoma. The effect of vorinostat co-treatment on the development of resistance to other chemotherapeutic agents is unknown. In the present study, we treated two human neuroblastoma cell lines [SK-N-SH and SK-N-Be(2)C] with progressively increasing doses of doxorubicin under two conditions: with and without vorinsotat co therapy. The resultant doxorubicin-resistant (DoxR) and vorinostat-treated doxorubicin resistant (DoxR-v) cells were equally resistant to doxorubicin despite significantly lower P-glycoprotein expression in the DoxR-v cells. Whole genome analysis was performed using the Ilumina Human HT-12 v4 Expression Beadchip to identify genes with differential expression unique to the DoxR-v cells. We uncovered a number of genes whose differential expression in the DoxR-v cells might contribute to their resistant phenotype, including hypoxia inducible factor-2. Finally, we used Gene Ontology to categorize the biological functions of the differentially expressed genes unique to the DoxR-v cells and found that genes involved in cellular metabolism were especially affected. PMID- 22829887 TI - Establishment of animal model of dual liver transplantation in rat. AB - The animal model of the whole-size and reduced-size liver transplantation in both rat and mouse has been successfully established. Because of the difficulties and complexities in microsurgical technology, the animal model of dual liver transplantation was still not established for twelve years since the first human dual liver transplantation has been made a success. There is an essential need to establish this animal model to lay a basic foundation for clinical practice. To study the physiological and histopathological changes of dual liver transplantation, "Y" type vein from the cross part between vena cava and two iliac of donor and "Y' type prosthesis were employed to recanalize portal vein and the bile duct between dual liver grafts and recipient. The dual right upper lobes about 45-50% of the recipient liver volume were taken as donor, one was orthotopically implanted at its original position, the other was rotated 180 degrees sagitally and heterotopically positioned in the left upper quadrant. Microcirculation parameters, liver function, immunohistochemistry and survival were analyzed to evaluate the function of dual liver grafts. No significant difference in the hepatic microcirculatory flow was found between two grafts in the first 90 minutes after reperfusion. Light and electronic microscope showed the liver architecture was maintained without obvious features of cellular destruction and the continuity of the endothelium was preserved. Only 3 heterotopically positioned graft appeared patchy desquamation of endothelial cell, mitochondrial swelling and hepatocytes cytoplasmic vacuolization. Immunohistochemistry revealed there is no difference in hepatocyte activity and the ability of endothelia to contract and relax after reperfusion between dual grafts. Dual grafts made a rapid amelioration of liver function after reperfusion. 7 rats survived more than 7 days with survival rate of 58.3.%. Using "Y" type vein and bile duct prosthesis, we successfully established a novel rat model of dual right upper liver lobe transplantation. PMID- 22829888 TI - Gene expression profiling of dendritic cells in different physiological stages under Cordyceps sinensis treatment. AB - Cordyceps sinensis (CS) has been commonly used as herbal medicine and a health supplement in China for over two thousand years. Although previous studies have demonstrated that CS has benefits in immunoregulation and anti-inflammation, the precise mechanism by which CS affects immunomodulation is still unclear. In this study, we exploited duplicate sets of loop-design microarray experiments to examine two different batches of CS and analyze the effects of CS on dendritic cells (DCs), in different physiology stages: naive stage and inflammatory stage. Immature DCs were treated with CS, lipopolysaccharide (LPS), or LPS plus CS (LPS/CS) for two days, and the gene expression profiles were examined using cDNA microarrays. The results of two loop-design microarray experiments showed good intersection rates. The expression level of common genes found in both loop design microarray experiments was consistent, and the correlation coefficients (Rs), were higher than 0.96. Through intersection analysis of microarray results, we identified 295 intersecting significantly differentially expressed (SDE) genes of the three different treatments (CS, LPS, and LPS/CS), which participated mainly in the adjustment of immune response and the regulation of cell proliferation and death. Genes regulated uniquely by CS treatment were significantly involved in the regulation of focal adhesion pathway, ECM-receptor interaction pathway, and hematopoietic cell lineage pathway. Unique LPS regulated genes were significantly involved in the regulation of Toll-like receptor signaling pathway, systemic lupus erythematosus pathway, and complement and coagulation cascades pathway. Unique LPS/CS regulated genes were significantly involved in the regulation of oxidative phosphorylation pathway. These results could provide useful information in further study of the pharmacological mechanisms of CS. This study also demonstrates that with a rigorous experimental design, the biological effects of a complex compound can be reliably studied by a complex system like cDNA microarray. PMID- 22829889 TI - Automated cell identification and tracking using nanoparticle moving-light displays. AB - An automated technique for the identification, tracking and analysis of biological cells is presented. It is based on the use of nanoparticles, enclosed within intra-cellular vesicles, to produce clusters of discrete, point-like fluorescent, light sources within the cells. Computational analysis of these light ensembles in successive time frames of a movie sequence, using k-means clustering and particle tracking algorithms, provides robust and automated discrimination of live cells and their motion and a quantitative measure of their proliferation. This approach is a cytometric version of the moving light display technique which is widely used for analyzing the biological motion of humans and animals. We use the endocytosis of CdTe/ZnS, core-shell quantum dots to produce the light displays within an A549, epithelial, lung cancer cell line, using time lapse imaging with frame acquisition every 5 minutes over a 40 hour time period. The nanoparticle moving light displays provide simultaneous collection of cell motility data, resolution of mitotic traversal dynamics and identification of familial relationships allowing construction of multi-parameter lineage trees. PMID- 22829890 TI - Reevaluation of ANS binding to human and bovine serum albumins: key role of equilibrium microdialysis in ligand - receptor binding characterization. AB - In this work we return to the problem of the determination of ligand-receptor binding stoichiometry and binding constants. In many cases the ligand is a fluorescent dye which has low fluorescence quantum yield in free state but forms highly fluorescent complex with target receptor. That is why many researchers use dye fluorescence for determination of its binding parameters with receptor, but they leave out of account that fluorescence intensity is proportional to the part of the light absorbed by the solution rather than to the concentration of bound dye. We showed how ligand-receptor binding parameters can be determined by spectrophotometry of the solutions prepared by equilibrium microdialysis. We determined the binding parameters of ANS - human serum albumin (HSA) and ANS - bovine serum albumin (BSA) interaction, absorption spectra, concentration and molar extinction coefficient, as well as fluorescence quantum yield of the bound dye. It was found that HSA and BSA have two binding modes with significantly different affinity to ANS. Correct determination of the binding parameters of ligand-receptor interaction is important for fundamental investigations and practical aspects of molecule medicine and pharmaceutics. The data obtained for albumins are important in connection with their role as drugs transporters. PMID- 22829891 TI - Extending body space in immersive virtual reality: a very long arm illusion. AB - Recent studies have shown that a fake body part can be incorporated into human body representation through synchronous multisensory stimulation on the fake and corresponding real body part - the most famous example being the Rubber Hand Illusion. However, the extent to which gross asymmetries in the fake body can be assimilated remains unknown. Participants experienced, through a head-tracked stereo head-mounted display a virtual body coincident with their real body. There were 5 conditions in a between-groups experiment, with 10 participants per condition. In all conditions there was visuo-motor congruence between the real and virtual dominant arm. In an Incongruent condition (I), where the virtual arm length was equal to the real length, there was visuo-tactile incongruence. In four Congruent conditions there was visuo-tactile congruence, but the virtual arm lengths were either equal to (C1), double (C2), triple (C3) or quadruple (C4) the real ones. Questionnaire scores and defensive withdrawal movements in response to a threat showed that the overall level of ownership was high in both C1 and I, and there was no significant difference between these conditions. Additionally, participants experienced ownership over the virtual arm up to three times the length of the real one, and less strongly at four times the length. The illusion did decline, however, with the length of the virtual arm. In the C2-C4 conditions although a measure of proprioceptive drift positively correlated with virtual arm length, there was no correlation between the drift and ownership of the virtual arm, suggesting different underlying mechanisms between ownership and drift. Overall, these findings extend and enrich previous results that multisensory and sensorimotor information can reconstruct our perception of the body shape, size and symmetry even when this is not consistent with normal body proportions. PMID- 22829892 TI - Neural repetition effects in the medial temporal lobe complex are modulated by previous encoding experience. AB - It remains an intriguing question why the medial temporal lobe (MTL) can display either attenuation or enhancement of neural activity following repetition of previously studied items. To isolate the role of encoding experience itself, we assessed neural repetition effects in the absence of any ongoing task demand or intentional orientation to retrieve. Experiment 1 showed that the hippocampus and surrounding MTL regions displayed neural repetition suppression (RS) upon repetition of past items that were merely attended during an earlier study phase but this was not the case following re-occurrence of items that had been encoded into working memory (WM). In this latter case a trend toward neural repetition enhancement (RE) was observed, though this was highly variable across individuals. Interestingly, participants with a higher degree of neural RE in the MTL complex displayed higher memory sensitivity in a later, surprise recognition test. Experiment 2 showed that massive exposure at encoding effected a change in the neural architecture supporting incidental repetition effects, with regions of the posterior parietal and ventral-frontal cortex in addition to the hippocampus displaying neural RE, while no neural RS was observed. The nature of encoding experience therefore modulates the expression of neural repetition effects in the MTL and the neocortex in the absence of memory goals. PMID- 22829893 TI - Incidence analyses and space-time cluster detection of hepatitis C in Fujian Province of China from 2006 to 2010. AB - BACKGROUND: There is limited epidemiologic information about the incidence of hepatitis C in China, and few studies have applied space-time scan statistic to detect clusters of hepatitis C and made adjustment for temporal trend and relative risk of regions. METHODOLOGY AND PRINCIPAL FINDINGS: We analyzed the temporal changes and characteristics of incidence of hepatitis C in Fujian Province from 2006 through 2010. The discrete Poisson model of space-time scan statistic was chosen for cluster detection. Data on new cases of hepatitis C were obtained from the Center for Disease Control and Prevention of Fujian Province. Between 2006 and 2010, there was an annualized increase in the incidence of hepatitis C of 23.0 percent, from 928 cases (2.63 per 100,000 persons) to 2,180 cases (6.01 per 100,000 persons). The incidence among women increased more rapidly. The cumulative incidence showed that people who were over 60 years had the highest risk to suffer hepatitis C (52.51 per 100,000 persons), and women had lower risk compared to men (OR=0.69). Putian had the highest cumulative incidence among all the regions (86.95 per 100,000 persons). The most likely cluster was identified in Putian during March to August in 2009 without adjustment, but it shifted to three contiguous cities with a two-month duration after adjustment for temporal trend and relative risk of regions. CONCLUSIONS/SIGNIFICANCE: The incidence of hepatitis C is increasing in Fujian Province, and women are at a more rapid pace. The space-time scan statistic is useful as a screening tool for clusters of hepatitis C, with adjustment for temporal trend and relative risk of regions recommended. PMID- 22829894 TI - To eat or not to eat? Debris selectivity by marine turtles. AB - Marine debris is a growing problem for wildlife, and has been documented to affect more than 267 species worldwide. We investigated the prevalence of marine debris ingestion in 115 sea turtles stranded in Queensland between 2006-2011, and assessed how the ingestion rates differ between species (Eretmochelys imbricata vs. Chelonia mydas) and by turtle size class (smaller oceanic feeders vs. larger benthic feeders). Concurrently, we conducted 25 beach surveys to estimate the composition of the debris present in the marine environment. Based on this proxy measurement of debris availability, we modeled turtles' debris preferences (color and type) using a resource selection function, a method traditionally used for habitat and food selection. We found no significant difference in the overall probability of ingesting debris between the two species studied, both of which have similar life histories. Curved carapace length, however, was inversely correlated with the probability of ingesting debris; 54.5% of pelagic sized turtles had ingested debris, whereas only 25% of benthic feeding turtles were found with debris in their gastrointestinal system. Benthic and pelagic sized turtles also exhibited different selectivity ratios for debris ingestion. Benthic phase turtles had a strong selectivity for soft, clear plastic, lending support to the hypothesis that sea turtles ingest debris because it resembles natural prey items such as jellyfish. Pelagic turtles were much less selective in their feeding, though they showed a trend towards selectivity for rubber items such as balloons. Most ingested items were plastic and were positively buoyant. This study highlights the need to address increasing amounts of plastic in the marine environment, and provides evidence for the disproportionate ingestion of balloons by marine turtles. PMID- 22829895 TI - Generalization of the dynamic clamp concept in neurophysiology and behavior. AB - The idea of closed-loop interaction in in vitro and in vivo electrophysiology has been successfully implemented in the dynamic clamp concept strongly impacting the research of membrane and synaptic properties of neurons. In this paper we show that this concept can be easily generalized to build other kinds of closed-loop protocols beyond (or in addition to) electrical stimulation and recording in neurophysiology and behavioral studies for neuroethology. In particular, we illustrate three different examples of goal-driven real-time closed-loop interactions with drug microinjectors, mechanical devices and video event driven stimulation. Modern activity-dependent stimulation protocols can be used to reveal dynamics (otherwise hidden under traditional stimulation techniques), achieve control of natural and pathological states, induce learning, bridge between disparate levels of analysis and for a further automation of experiments. We argue that closed-loop interaction calls for novel real time analysis, prediction and control tools and a new perspective for designing stimulus response experiments, which can have a large impact in neuroscience research. PMID- 22829896 TI - Incidence of epileptiform EEG activity in children during mask induction of anaesthesia with brief administration of 8% sevoflurane. AB - BACKGROUND: A high incidence of epileptiform activity in the electroencephalogram (EEG) was reported in children undergoing mask induction of anaesthesia with administration of high doses of sevoflurane for 5 minutes and longer. This study was performed to investigate whether reducing the time of exposure to a high inhaled sevoflurane concentration would affect the incidence of epileptiform EEG activity. It was hypothesized that no epileptiform activity would occur, when the inhaled sevoflurane concentration would be reduced from 8% to 4% immediately after the loss of consciousness. METHODOLOGY/PRINCIPAL FINDINGS: 70 children (age 7-96 months, ASA I-II, premedication with midazolam) were anaesthetized with 8% sevoflurane in 100% oxygen via face mask. Immediately after loss of consciousness, the sevoflurane concentration was reduced to 4%. EEGs were recorded continuously and were later analyzed visually with regard to epileptiform EEG patterns. Sevoflurane at a concentration of 8% was given for 1.2 +/- 0.4 min (mean +/- SD). In 14 children (20%) epileptiform EEG patterns without motor manifestations were observed (delta with spikes (DSP), rhythmic polyspikes (PSR), epileptiform discharges (PED) in 10, 10, 4 children (14%, 14%, 6%)). 38 children (54%) had slow, rhythmic delta waves with high amplitudes (DS) appearing on average before DSP. CONCLUSIONS/SIGNIFICANCE: The hypothesis that no epileptiform potentials would occur during induction of anaesthesia with a reduction of the inspired sevoflurane concentration from 8% to 4% directly after LOC was not proved. Even if 8% sevoflurane is administered only briefly for induction of anaesthesia, epileptiform EEG activity may be observed in children despite premedication with midazolam. PMID- 22829898 TI - A model-based method for gene dependency measurement. AB - Many computational methods have been widely used to identify transcription regulatory interactions based on gene expression profiles. The selection of dependency measure is very important for successful regulatory network inference. In this paper, we develop a new method-DBoMM (Difference in BIC of Mixture Models)-for estimating dependency of gene by fitting the gene expression profiles into mixture Gaussian models. We show that DBoMM out-performs 4 other existing methods, including Kendall's tau correlation (TAU), Pearson Correlation (COR), Euclidean distance (EUC) and Mutual information (MI) using Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, Arabidopsis thaliana data and synthetic data. DBoMM can also identify condition-dependent regulatory interactions and is robust to noisy data. Of the 741 Escherichia coli regulatory interactions inferred by DBoMM at a 60% true positive rate, 65 are previously known interactions and 676 are novel predictions. To validate the new prediction, the promoter sequences of target genes regulated by the same transcription factors were analyzed and significant motifs were identified. PMID- 22829899 TI - Temporal structure in audiovisual sensory selection. AB - In natural environments, sensory information is embedded in temporally contiguous streams of events. This is typically the case when seeing and listening to a speaker or when engaged in scene analysis. In such contexts, two mechanisms are needed to single out and build a reliable representation of an event (or object): the temporal parsing of information and the selection of relevant information in the stream. It has previously been shown that rhythmic events naturally build temporal expectations that improve sensory processing at predictable points in time. Here, we asked to which extent temporal regularities can improve the detection and identification of events across sensory modalities. To do so, we used a dynamic visual conjunction search task accompanied by auditory cues synchronized or not with the color change of the target (horizontal or vertical bar). Sounds synchronized with the visual target improved search efficiency for temporal rates below 1.4 Hz but did not affect efficiency above that stimulation rate. Desynchronized auditory cues consistently impaired visual search below 3.3 Hz. Our results are interpreted in the context of the Dynamic Attending Theory: specifically, we suggest that a cognitive operation structures events in time irrespective of the sensory modality of input. Our results further support and specify recent neurophysiological findings by showing strong temporal selectivity for audiovisual integration in the auditory-driven improvement of visual search efficiency. PMID- 22829900 TI - Mating plugs in polyandrous giants: which sex produces them, when, how and why? AB - BACKGROUND: Males usually produce mating plugs to reduce sperm competition. However, females can conceivably also produce mating plugs in order to prevent unwanted, superfluous and energetically costly matings. In spiders-appropriate models for testing plugging biology hypotheses-mating plugs may consist of male genital parts and/or of amorphous covers consisting of glandular or sperm secretions. In the giant wood spider Nephila pilipes, a highly sexually dimorphic and polygamous species, males are known to produce ineffective embolic plugs through genital damage, but nothing is known about the origin and function of additional conspicuous amorphous plugs (AP) covering female genitals. METHODOLOGY: We tested alternative hypotheses of the nature and function of AP in N. pilipes by staging mating trials with varying degrees of polyandry. No APs were ever formed during mating trials, which rules out the possibility of male AP formation. Instead, those females that oviposited produced the AP from a liquid secreted during egg sac formation. Polyandrous females were more likely to lay eggs and to produce the AP, as were those that mated longer and with more total insertions. Our further tests revealed that, in spite of being a side product of egg sac production, AP, when hardened, prevented any subsequent copulation. CONCLUSIONS: We conclude that in the giant wood spider (Nephila pilipes), the amorphous mating plugs are not produced by the males, that repeated copulations (most likely polyandrous) are necessary for egg fertilization and AP formation, and that the AP represents a female adaptation to sexual conflict through prevention of unwanted, excessive copulations. Considering the largely unknown origin of amorphous plugs in spiders, we predict that a similar pattern might be detected in other clades, which would help elucidate the evolutionary interplay of various selection pressures responsible for the origin and maintenance of mating plugs. PMID- 22829897 TI - Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. AB - ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders. PMID- 22829901 TI - Tolerability of a fully maturated cheese in cow's milk allergic children: biochemical, immunochemical, and clinical aspects. AB - BACKGROUND: From patients' reports and our preliminary observations, a fully maturated cheese (Parmigiano-Reggiano; PR) seems to be well tolerated by a subset of cow's milk (CM) allergic patients. OBJECTIVE AND METHODS: To biochemically and immunologically characterize PR samples at different maturation stage and to verify PR tolerability in CM allergic children. Seventy patients, with suspected CM allergy, were enrolled. IgE to CM, alpha-lactalbumin (ALA), beta-lactoglobulin (BLG) and caseins (CAS) were tested using ImmunoCAP, ISAC103 and skin prick test. Patients underwent a double-blind, placebo-controlled food challenge with CM, and an open food challenge with 36 months-maturated PR. Extracts obtained from PR samples were biochemically analyzed in order to determine protein and peptide contents. Pepsin and trypsin-chymotrypsin-pepsin simulated digestions were applied to PR extracts. Each PR extract was investigated by IgE Single Point Highest Inhibition Achievable assay (SPHIAa). The efficiency analysis was carried out using CM and PR oral challenges as gold standards. RESULTS: The IgE binding to milk allergens was 100% inhibited by almost all PR preparations; the only difference was for CAS, mainly alpha(S1)-CAS. Sixteen patients sensitized to CM tolerated both CM and PR; 29 patients tolerated PR only; 21 patients, reacted to both CM and PR, whereas 4 patients reactive to CM refused to ingest PR. ROC analysis showed that the absence of IgE to BLG measured by ISAC could be a good marker of PR tolerance. The SPHIAa using digested PR preparations showed a marked effect on IgE binding to CAS and almost none on ALA and BLG. CONCLUSIONS: 58% of patients clinically reactive to CM tolerated fully maturated PR. The preliminary digestion of CAS induced by PR maturation process, facilitating a further loss of allergenic reactivity during gut digestion, might explain the tolerance. This hypothesis seems to work when no IgE sensitization to ISAC BLG is detected. PMID- 22829902 TI - A metric of influential spreading during contagion dynamics through the air transportation network. AB - The spread of infectious diseases at the global scale is mediated by long-range human travel. Our ability to predict the impact of an outbreak on human health requires understanding the spatiotemporal signature of early-time spreading from a specific location. Here, we show that network topology, geography, traffic structure and individual mobility patterns are all essential for accurate predictions of disease spreading. Specifically, we study contagion dynamics through the air transportation network by means of a stochastic agent-tracking model that accounts for the spatial distribution of airports, detailed air traffic and the correlated nature of mobility patterns and waiting-time distributions of individual agents. From the simulation results and the empirical air-travel data, we formulate a metric of influential spreading--the geographic spreading centrality--which accounts for spatial organization and the hierarchical structure of the network traffic, and provides an accurate measure of the early-time spreading power of individual nodes. PMID- 22829905 TI - Temporal patterns of medications dispensed to children and adolescents in a national insured population. AB - This study aimed to comprehensively describe prevalence and temporal dispensing patterns for medications prescribed to children and adolescents in the United States. Participants were 1.6 million children (49% female) under 18 years old enrolled in a nation-wide, employer-provided insurance plan. All medication claims from 1999-2006 were reviewed retrospectively. Drugs were assigned to 16 broad therapeutic categories. Effects of trend over time, seasonality, age and gender on overall and within category prevalence were examined. RESULTS: Mean monthly prevalence for dispensed medications was 23.5% (range 19.4-27.5), with highest rates in winter and lowest in July. The age group with the highest prevalence was one-year-old children. On average each month, 17.1% of all children were dispensed a single drug and 6.4% were dispensed two or more. Over time, prevalence for two or more drugs did not change, but the proportion of children dispensed a single drug decreased (slope -.02%, p= .001). Overall, boys had higher monthly rates than girls (average difference 0.9%, p= .002). However, differences by gender were greatest during middle childhood, especially for respiratory and central nervous system agents. Contraceptives accounted for a large proportion of dispensed medication to older teenage girls. Rates for the drugs with the highest prevalence in this study were moderately correlated (average Pearson r.66) with those from a previously published national survey. CONCLUSION: On average, nearly one quarter of a population of insured children in the United States was dispensed medication each month. This rate decreased somewhat over time, primarily because proportionally fewer children were dispensed a single medication. The rate for two or more drugs dispensed simultaneously remained steady. PMID- 22829904 TI - Overexpression of TGF-beta1 in macrophages reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice. AB - Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-beta1 (transforming growth factor beta1) and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-beta1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-beta1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E) knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE(-/-) mice, animals with macrophage specific TGF-beta1 overexpression developed significantly less atherosclerosis after 24 weeks on the WTD (Western type diet) as indicated by aortic plaque area en face (p<0.05). Reduced atherosclerotic lesion development was associated with significantly less macrophages (p<0.05 after both 8 and 24 weeks on the WTD), significantly more smooth muscle cells (SMCs; p<0.01 after 24 weeks on the WTD), significantly more collagen (p<0.01 and p<0.05 after 16 and 24 weeks on the WTD, respectively) without significant differences of inner aortic arch intima thickness or the number of total macrophages in the mice pointing to a plaque stabilizing effect of macrophage-specific TGF-beta1 overexpression. Our data shows that macrophage specific TGF-beta1 overexpression reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice. PMID- 22829903 TI - The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. AB - OBJECTIVE: The SLC30A8 gene encodes the islet-specific transporter ZnT-8, which is hypothesized to provide zinc for insulin-crystal formation. A polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes. Several groups have examined the effect of global Slc30a8 gene deletion but the results have been highly variable, perhaps due to the mixed 129SvEv/C57BL/6J genetic background of the mice studied. We therefore sought to remove the conflicting effect of 129SvEv-specific modifier genes. METHODS: The impact of Slc30a8 deletion was examined in the context of the pure C57BL/6J genetic background. RESULTS: Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin levels and no change in glucose-stimulated insulin secretion (GSIS) from isolated islets in marked contrast to the ~50% and ~35% decrease, respectively, in both parameters observed in male mixed genetic background Slc30a8 KO mice. This observation suggests that 129SvEv-specific modifier genes modulate the impact of Slc30a8 deletion. In contrast, female C57BL/6J Slc30a8 KO mice had reduced (~20%) fasting insulin levels, though this was not associated with a change in fasting blood glucose (FBG), or GSIS from isolated islets. This observation indicates that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation as to why impaired insulin secretion is not accompanied by elevated FBG is unclear. Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance. CONCLUSIONS: Our data suggest that, despite a marked reduction in islet zinc content, the absence of ZnT-8 does not have a substantial impact on mouse physiology. PMID- 22829906 TI - Applying the net-benefit framework for analyzing and presenting cost effectiveness analysis of a maternal and newborn health intervention. AB - BACKGROUND: Coverage of maternal and newborn health (MNH) interventions is often influenced by important determinants and decision makers are often concerned with equity issues. The net-benefit framework developed and applied alongside clinical trials and in pharmacoeconomics offers the potential for exploring how cost effectiveness of MNH interventions varies at the margin by important covariates as well as for handling uncertainties around the ICER estimate. AIM: We applied the net-benefit framework to analyze cost-effectiveness of the Skilled Care Initiative and assessed relative advantages over a standard computation of incremental cost effectiveness ratios. METHODS: Household and facility surveys were carried out from January to July 2006 in Ouargaye district (where the Skilled Care Initiative was implemented) and Diapaga (comparison site) district in Burkina Faso. Pregnancy-related and perinatal mortality were retrospectively assessed and data were collected on place of delivery, education, asset ownership, place, and distance to health facilities, costs borne by households for institutional delivery, and cost of standard provision of maternal care. Descriptive and regression analyses were performed. RESULTS: There was a 30% increase in institutional births in the intervention district compared to 10% increase in comparison district, and a significant reduction of perinatal mortality rates (OR 0.75, CI 0.70-0.80) in intervention district. The incremental cost for achieving one additional institutional delivery in Ouargaye district compared to Diapaga district was estimated to be 170 international dollars and varied significantly by covariates. However, the joint probability distribution (net-benefit framework) of the effectiveness measure (institutional delivery), the cost data and covariates indicated distance to health facilities as the single most important determinant of the cost-effectiveness analysis with implications for policy making. CONCLUSION: The net-benefit framework, the application of which requires household-level effects and cost data, has proven more insightful (than traditional ICER) in presenting and interpreting cost effectiveness results of the Skilled Care Initiative. PMID- 22829907 TI - Heart failure and preserved left ventricular function: long term clinical outcome. AB - BACKGROUND: Patients with heart failure (HF) have a poor prognosis. The proportion of patients with HF and preserved left ventricular function (LVF) is increasing. Long term prognosis of HF with preserved LVF may not be so benign. OBJECTIVES: To evaluate the long term clinical outcome of patients with HF and preserved LVF and predictors of outcome. METHODS: We prospectively evaluated 309 patients hospitalized with a definite clinical diagnosis of HF. Patients were followed for a mean of 6.5 years for clinical outcome. RESULTS: More than a third (36%) of the patients had preserved systolic LVF based on echocardiography. The long term survival rate in this group was poor and not significantly different from patients with reduced LVF (28% vs 23% respectively, P=0.2). The adjusted survival rate by Cox regression analysis was also not significantly different (hazard ratio 1.16, 95% confidence interval 0.87-1.55, P=0.31). The event free survival from death or heart failure re-hospitalization was also low in both groups and not significantly different between patients with preserved vs. reduced LVF (12% vs. 10% respectively, P=0.2). Predictors of mortality in patients with preserved LVF were age, functional capacity and serum urea levels. CONCLUSIONS: The long term clinical outcome of patients with heart failure and preserved LVF is poor and not significantly different from patients with reduced LVF. PMID- 22829908 TI - Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. AB - Epigenetic modification of DNA by cytosine methylation to produce 5 methylcytosine (5mC) has become well-recognized as an important epigenetic process in human health and disease. Recently, further modification of 5mC by the ten eleven translocated (TET) family of enzymes to produce 5 hydroxymethylcytosine (5hmC) has been described. In the present study, we used immunohistochemistry to evaluate the distribution of 5hmC in human brain during different periods of development and in a large series of gliomas (n=225). We found that during development, 5hmC levels are high in more differentiated compartments like the fetal cortex, but low in the periventricular progenitor cell regions. In adults, we found 5hmC levels to be highest in the cortex, but present in all intrinsic cell types in the brain including stromal elements. In brain tumors, 5hmC levels were high in low grade tumors and reduced in malignant glioma, but did not exhibit any correlation with IDH1 mutation status. Additionally, we identified a significant relationship between low levels of 5hmC and reduced survival in malignant glioma. This observation was further supported by in silico analysis showing differential expression of genes involved in 5hmC homeostasis in aggressive subsets of glioblastoma. Finally, we show that several genes involved in regulating the levels of 5hmC are also prognostic in malignant glioma. These findings suggest that 5hmC regulation in malignant glioma may represent an important determinant of tumor differentiation and aggressive behavior, as well as a potential therapeutic target. PMID- 22829909 TI - Perivascular-like cells contribute to the stability of the vascular network of osteogenic tissue formed from cell sheet-based constructs. AB - In recent years several studies have been supporting the existence of a close relationship in terms of function and progeny between Mesenchymal Stem Cells (MSCs) and Pericytes. This concept has opened new perspectives for the application of MSCs in Tissue Engineering (TE), with special interest for the pre vascularization of cell dense constructs. In this work, cell sheet technology was used to create a scaffold-free construct composed of osteogenic, endothelial and perivascular-like (CD146(+)) cells for improved in vivo vessel formation, maturation and stability. The CD146 pericyte-associated phenotype was induced from human bone marrow mesenchymal stem cells (hBMSCs) by the supplementation of standard culture medium with TGF-beta1. Co-cultured cell sheets were obtained by culturing perivascular-like (CD146(+)) cells and human umbilical vein endothelial cells (HUVECs) on an hBMSCs monolayer maintained in osteogenic medium for 7 days. The perivascular-like (CD146(+)) cells and the HUVECs migrated and organized over the collagen-rich osteogenic cell sheet, suggesting the existence of cross-talk involving the co-cultured cell types. Furthermore the presence of that particular ECM produced by the osteoblastic cells was shown to be the key regulator for the singular observed organization. The osteogenic and angiogenic character of the proposed constructs was assessed in vivo. Immunohistochemistry analysis of the explants revealed the integration of HUVECs with the host vasculature as well as the osteogenic potential of the created construct, by the expression of osteocalcin. Additionally, the analysis of the diameter of human CD146 positive blood vessels showed a higher mean vessel diameter for the co-cultured cell sheet condition, reinforcing the advantage of the proposed model regarding blood vessels maturation and stability and for the in vitro pre-vascularization of TE constructs. PMID- 22829910 TI - Circulating tumor cells in melanoma patients. AB - Circulating tumor cells (CTCs) are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (~400X) from blood of melanoma patients using a simple centrifugation device (OncoQuick), and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF) were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively) compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001). There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001), and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (~50%) stained for both pan-cytokeratin (KRT) markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14). Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA) may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs). The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids, and their role in metastatic progression. PMID- 22829913 TI - Maternal smoking during pregnancy predicts adult offspring cardiovascular risk factors - evidence from a community-based large birth cohort study. AB - BACKGROUND: Maternal smoking during pregnancy is associated with offspring obesity. However, little is known about whether maternal smoking in pregnancy predicts other offspring cardiovascular risk factors including waist circumference (WC), waist-hip-ratio (WHR), pulse rate (PR), systolic (SBP), and diastolic blood pressure (DBP). METHODS: We studied a sub-sample of 2038 (50% males) young adults who were born in Brisbane, Australia to investigate the prospective association of maternal smoking during pregnancy with young adult cardiovascular risk factors. We compared offspring mean BMI, WC, WHR, SBP, DBP and PR and the risk of being overweight and obese at 21 years by three mutually exclusive categories of maternal smoking status defined as never smoked, smoked before and/or after pregnancy but not in pregnancy or smoked during pregnancy and other times. RESULTS: Offspring of mothers who smoked during pregnancy had greater mean BMI, WC, WHR and PR and they were at greater risk of being obese at 21 years compared to offspring of those mothers who never smoked. The mean of these risk factors among those adult offspring whose mothers stopped smoking during pregnancy, but who then smoked at other times in the child's life, were similar to those mothers who never smoked. These results were independent of a range of potential confounding factors. CONCLUSION: The findings of this study suggest a prospective association of maternal smoking during pregnancy and offspring obesity as well as PR in adulthood, and reinforce the need to persuade pregnant women not to smoke. PMID- 22829912 TI - Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to TRAIL induced apoptosis. AB - Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase 3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in beta-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated beta-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer. PMID- 22829911 TI - Cre-mediated stress affects sirtuin expression levels, peroxisome biogenesis and metabolism, antioxidant and proinflammatory signaling pathways. AB - Cre-mediated excision of loxP sites is widely used in mice to manipulate gene function in a tissue-specific manner. To analyze phenotypic alterations related to Cre-expression, we have used AMH-Cre-transgenic mice as a model system. Different Cre expression levels were obtained by investigation of C57BL/6J wild type as well as heterozygous and homozygous AMH-Cre-mice. Our results indicate that Cre-expression itself in Sertoli cells already has led to oxidative stress and lipid peroxidation (4-HNE lysine adducts), inducing PPARalpha/gamma, peroxisome proliferation and alterations of peroxisome biogenesis (PEX5, PEX13 and PEX14) as well as metabolic proteins (ABCD1, ABCD3, MFP1, thiolase B, catalase). In addition to the strong catalase increase, a NRF2- and FOXO3 mediated antioxidative response (HMOX1 of the endoplasmic reticulum and mitochondrial SOD2) and a NF-kappaB activation were noted. TGFbeta1 and proinflammatory cytokines like IL1, IL6 and TNFalpha were upregulated and stress related signaling pathways were induced. Sertoli cell mRNA-microarray analysis revealed an increase of TNFR2-signaling components. 53BP1 recruitment and expression levels for DNA repair genes as well as for p53 were elevated and the ones for related sirtuin deacetylases affected (SIRT 1, 3-7) in Sertoli cells. Under chronic Cre-mediated DNA damage conditions a strong downregulation of Sirt1 was observed, suggesting that the decrease of this important coordinator between DNA repair and metabolic signaling might induce the repression release of major transcription factors regulating metabolic and cytokine-mediated stress pathways. Indeed, caspase-3 was activated and increased germ cell apoptosis was observed, suggesting paracrine effects. In conclusion, the observed wide stress-induced effects and metabolic alterations suggest that it is essential to use the correct control animals (Cre/Wt) with matched Cre expression levels to differentiate between Cre-mediated and specific gene-knock out-mediated effects. PMID- 22829914 TI - Serine protease inhibitor attenuates ovalbumin induced inflammation in mouse model of allergic airway disease. AB - BACKGROUND: Serine proteases promote inflammation and tissue remodeling by activating proteinase-activated receptors, urokinase, metalloproteinases and angiotensin. In the present study, 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) a serine protease inhibitor was evaluated for prophylactic and therapeutic treatment in mouse model of airway allergy. METHODS: BALB/c mice were sensitized by i.p route and challenged with ovalbumin. They were treated i.n. with 2, 10 and 50 ug of AEBSF, one hour before or after challenge and euthanized to collect BALF (bronchoalveolar lavage fluid), blood and lungs. Proteolytic activity, total cell/eosinophil/neutrophil count eosinophil peroxidase activity (EPO), IL-4, IL-5, IL-10, IL-13, cysteinyl leukotrienes and 8-isoprostane were determined in BALF and immunoglobulins were measured in serum. H&E and PAS stained lung sections were examined for cellular infiltration and airway inflammation. RESULTS: Mice exposed to ovalbumin and treated with PBS showed increased cellular infiltration in lungs and higher serum IgE, IgG1 and IgG2a levels as compared to sham mice. Treatment with AEBSF reduced total cells/eosinophil/neutrophil infiltration. Both prophylactic and therapeutic AEBSF treatment of 10 or 50 ug reduced serum IgE and IgG1 significantly (p<0.05) than control. AEBSF treatment reduced the proteolytic activity in BALF. IL-4 IL-5 and IL-13 levels decreased significantly (p<0.05) after AEBSF treatment while IL-10 levels increased significantly (p<0.05) in BALF. Airway inflammation and goblet cell hyperplasia reduced as demonstrated by lung histopathology, EPO activity and cysteinyl leukotrienes in BALF after treatment. AEBSF treatment also suppressed oxidative stress in terms of 8-isoprostane in BALF. Among the treatment doses, 10 or 50 ug of AEBSF were most effective in reducing the inflammatory parameters. CONCLUSIONS: Prophylactic and therapeutic treatment with serine protease inhibitor attenuates the airway inflammation in mouse model of airway allergy and have potential for adjunct therapy. PMID- 22829915 TI - Structure-function analysis of Rny1 in tRNA cleavage and growth inhibition. AB - T2 ribonucleases are conserved nucleases that affect a variety of processes in eukaryotic cells including the regulation of self-incompatibility by S-RNases in plants, modulation of host immune cell responses by viral and schistosome T2 enzymes, and neurological development and tumor progression in humans. These roles for RNaseT2's can be due to catalytic or catalytic-independent functions of the molecule. Despite this broad importance, the features of RNaseT2 proteins that modulate catalytic and catalytic-independent functions are poorly understood. Herein, we analyze the features of Rny1 in Saccharomyces cerevisiae to determine the requirements for cleaving tRNA in vivo and for inhibiting cellular growth in a catalytic-independent manner. We demonstrate that catalytic independent inhibition of growth is a combinatorial property of the protein and is affected by a fungal-specific C-terminal extension, the conserved catalytic core, and the presence of a signal peptide. Catalytic functions of Rny1 are independent of the C-terminal extension, are affected by many mutations in the catalytic core, and also require a signal peptide. Biochemical flotation assays reveal that in rny1Delta cells, some tRNA molecules associate with membranes suggesting that cleavage of tRNAs by Rny1 can involve either tRNA association with, or uptake into, membrane compartments. PMID- 22829916 TI - High avidity cytotoxic T lymphocytes can be selected into the memory pool but they are exquisitely sensitive to functional impairment. AB - High avidity cytotoxic T lymphocytes (CTL) are important in viral clearance and anti-tumor immunity, however, mechanisms for their optimal generation and maintenance in vivo remain unclear. Immunizing mice with an antibody-DNA vaccine encoding a single CTL epitope, induces a 100 fold higher avidity response than peptide vaccination with the identical epitope. The high avidity response is retained into memory and can be efficiently reactivated with an antibody-DNA boost. In contrast, reactivation of high avidity CTL with peptide, stimulated responses with a significant drop in avidity, suggesting loss or conversion of the high avidity CTL to lower avidity. Similarly, high avidity T cells maintained ex vivo were exquisitely sensitive to signaling with low doses of peptide (1 ng/ml) giving optimal TCR stimulation and resulting in retained avidity, proliferation and ability to kill specific targets. In contrast, high avidity T cells maintained ex vivo with supraoptimal TCR stimulation (10 ug/ml peptide) resulted in reduced avidity and failure to kill tumor cells. They also failed to proliferate, showed a significant increase in apoptosis and expressed high levels of the exhaustion marker programmed death-1 (PD-1) and low levels of the lymphocyte-activation gene 3 (LAG-3). This suggests high avidity T cells are recruited to the memory pool but can be lost by supraoptimal stimulation in vitro and in vivo. This is characterized by loss of function and an increase in cell death. The remaining CTL, exhibit low functional avidity that is reflected in reduced anti-tumor activity. This could contribute to failure of the immune system to control the growth of tumors and has implications for vaccination strategies and adoptive transfer of T cells. PMID- 22829917 TI - Identification and characterization of Eimeria tenella apical membrane antigen-1 (AMA1). AB - Apical membrane antigen-1 (AMA1) is a micronemal protein of apicomplexan parasites that appears to be essential during the invasion of host cells. In this study, a full-length cDNA of AMA1 was identified from Eimeria tenella (Et) using expressed sequence tag and the rapid amplification of cDNA ends technique. EtAMA1 had an open reading frame of 1608 bp encoding a protein of 535 amino acids. Quantitative real-time PCR analysis revealed that EtAMA1 was expressed at higher levels in sporozoites than in the other developmental stages (unsporulated oocysts, sporulated oocysts and second-generation merozoites). The ectodomain sequence was expressed as recombinant EtAMA1 (rEtAMA1) and rabbit polyclonal antibodies raised against the rEtAMA1 recognized a 58-kDa native parasite protein by Western Blotting and had a potent inhibitory effect on parasite invasion, decreasing it by approximately 70%. Immunofluorescence analysis and immunohistochemistry analysis showed EtAMA1 might play an important role in sporozoite invasion and development. PMID- 22829919 TI - The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial. AB - BACKGROUND: New regimens for intermittent preventive treatment in pregnancy (IPTp) against malaria are needed as the effectiveness of the standard two-dose sulfadoxine-pyrimethamine (SP) regimen is under threat. Previous trials have shown that IPTp with monthly SP benefits HIV-positive primi- and secundigravidae, but there is no conclusive evidence of the possible benefits of this regimen to HIV-negative women, or to a population comprising of both HIV-positive and negative women of different gravidities. METHODS: This study analyzed 484 samples collected at delivery as part of a randomized, partially placebo controlled clinical trial, conducted in rural Malawi between 2003 and 2007. The study included pregnant women regardless of their gravidity or HIV-infection status. The participants received SP twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The main outcome was the prevalence of peripheral Plasmodium falciparum malaria at delivery diagnosed with a real-time polymerase chain reaction (PCR) assay. FINDINGS: Overall prevalence of PCR-diagnosed peripheral P. falciparum malaria at delivery was 10.5%. Compared with the controls, participants in the monthly SP group had a risk ratio (95% CI) of 0.33 (0.17 to 0.64, P<0.001) and those in the AZI-SP group 0.23 (0.11 to 0.48, P<0.001) for malaria at delivery. When only HIV-negative participants were analyzed, the corresponding figures were 0.26 (0.12 to 0.57, P<0.001) for women in the monthly SP group, and 0.24 (0.11 to 0.53, P<0.001) for those in the AZI-SP group. CONCLUSIONS: Our results suggest that increasing the frequency of SP administration during pregnancy improves the efficacy against malaria at delivery among HIV-negative women, as well as a population consisting of both HIV-positive and -negative pregnant women of all gravidities, in a setting of relatively low but holoendemic malaria transmission, frequent use of bed nets and high SP resistance. PMID- 22829918 TI - Cytosolic entry of Shiga-like toxin a chain from the yeast endoplasmic reticulum requires catalytically active Hrd1p. AB - BACKGROUND: Escherichia coli Shiga-like toxin 1 normally traffics to the endoplasmic reticulum (ER) in sensitive mammalian cells from where the catalytic A chain (SLTxA1) dislocates to the cytosol to inactivate ribosomes. Currently, no molecular details of the dislocation process are available. To investigate the mechanism of the dislocation step we expressed SLTxA1 in the ER of Saccharomyces cerevisiae. METHODOLOGY AND PRINCIPAL FINDINGS: Using a combination of growth studies and biochemical tracking in yeast knock-out strains we show that SLTxA1 follows an ER-associated degradation (ERAD) pathway to enter the cytosol in a step mediated by the transmembrane Hrd1p ubiquitin ligase complex. ER-to-cytosol dislocation of the bulk population of SLTxA1 requires Cdc48p and its ubiquitin handling co-factor Npl4p, and this population of toxin is terminally dispatched by proteasomal degradation. A small sub-population of SLTxA1 uncouples from this classical ERAD pathway and recovers catalytic activity in the cytosol. The pathway that leads to toxicity is also Hrd1p-dependent but, unlike that for the related ricin A chain toxin, SLTxA1 dislocation does require the catalytic cysteine of Hrd1p. However it does not depend on canonical ubiquitylation since toxin variants lacking endogenous lysyl residues also utilize this pathway, and furthermore there is no requirement for a number of Cdc48p co-factors. CONCLUSIONS AND SIGNIFICANCE: The fraction of SLTxA1 that disengages from the ERAD pathway thus does so upstream of Cdc48p interactions and downstream of Hrd1p interactions, in a step that possibly involves de-ubiquitylation. Mechanistically therefore, the dislocation of this toxin is quite distinct from that of conventional ERAD substrates that are normally degraded, and the toxins partially characterised to date that do not require the catalytic cysteine of the major Hrd1p component of the dislocation apparatus. PMID- 22829920 TI - HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study. AB - BACKGROUND: The ANRS EP45 "Aging" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. METHODS: 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm(3). ROS (reactive oxygen species) production and DeltaPsim (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. RESULTS: Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and DeltaPsim) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. CONCLUSIONS: In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging. PMID- 22829921 TI - Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 agonist, promotes potent systemic and mucosal responses to intranasal immunization with HIVgp140. AB - Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellular immune responses in both the systemic and mucosal compartments. Based on the known immunological linkage between the upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for the induction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 together with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responses were compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatly enhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG and IgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with high numbers of gp140 specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cell responses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Our results show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses, both systemically and mucosally. PMID- 22829922 TI - Metabolite profiles reveal energy failure and impaired beta-oxidation in liver of mice with complex III deficiency due to a BCS1L mutation. AB - BACKGROUND & AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. PMID- 22829923 TI - Geometrical microfeature cues for directing tubulogenesis of endothelial cells. AB - Angiogenesis, the formation of new blood vessels by sprouting from pre-existing ones, is critical for the establishment and maintenance of complex tissues. Angiogenesis is usually triggered by soluble growth factors such as VEGF. However, geometrical cues also play an important role in this process. Here we report the induction of angiogenesis solely by SVVYGLR peptide micropatterning on polymer surfaces. SVVYGLR peptide stripes were micropatterned onto polymer surfaces by photolithography to study their effects on endothelial cell (EC) behavior. Our results showed that the EC behaviors (cell spreading, orientation and migration) were significantly more guided and regulated on narrower SVVYGLR micropatterns (10 and 50 um) than on larger stripes (100 um). Also, EC morphogenesis into tube formation was switched on onto the smaller patterns. We illustrated that the central lumen of tubular structures can be formed by only one-to-four cells due to geometrical constraints on the micropatterns which mediated cell-substrate adhesion and generated a correct maturation of adherens junctions. In addition, sprouting of ECs and vascular networks were also induced by geometrical cues on surfaces micropatterned with SVVYGLR peptides. These micropatterned surfaces provide opportunities for mimicking angiogenesis by peptide modification instead of exogenous growth factors. The organization of ECs into tubular structures and the induction of sprouting angiogenesis are important towards the fabrication of vascularized tissues, and this work has great potential applications in tissue engineering and tissue regeneration. PMID- 22829924 TI - Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer. AB - Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild type 3'-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells. PMID- 22829925 TI - Using poison center exposure calls to predict methadone poisoning deaths. AB - PURPOSE: There are more drug overdose deaths in the Untied States than motor vehicle fatalities. Yet the US vital statistics reporting system is of limited value because the data are delayed by four years. Poison centers report data within an hour of the event, but previous studies suggested a small proportion of poisoning deaths are reported to poison centers (PC). In an era of improved electronic surveillance capabilities, exposure calls to PCs may be an alternate indicator of trends in overdose mortality. METHODS: We used PC call counts for methadone that were reported to the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS(r)) System in 2006 and 2007. US death certificate data were used to identify deaths due to methadone. Linear regression was used to quantify the relationship of deaths and poison center calls. RESULTS: Compared to decedents, poison center callers tended to be younger, more often female, at home and less likely to require medical attention. A strong association was found with PC calls and methadone mortality (b=0.88, se=0.42, t=9.5, df=1, p<0.0001, R(2) =0.77). These findings were robust to large changes in a sensitivity analysis assessing the impact of underreporting of methadone overdose deaths. CONCLUSIONS: Our results suggest that calls to poison centers for methadone are correlated with poisoning mortality as identified on death certificates. Calls received by poison centers may be used for timely surveillance of mortality due to methadone. In the midst of the prescription opioid overdose epidemic, electronic surveillance tools that report in real-time are powerful public health tools. PMID- 22829927 TI - Lung function and breathing pattern in subjects developing high altitude pulmonary edema. AB - INTRODUCTION: The purpose of the study was to comprehensively evaluate physiologic changes associated with development of high altitude pulmonary edema (HAPE). We tested whether changes in pulmonary function and breathing pattern would herald clinically overt HAPE at an early stage. METHODS: In 18 mountaineers, spirometry, diffusing capacity, nitrogen washout, nocturnal ventilation and pulse oximetry were recorded at 490 m and during 3 days after rapid ascent to 4559 m. Findings were compared among subjects developing HAPE and those remaining well (controls). RESULTS: In 8 subjects subsequently developing radiographically documented HAPE at 4559 m, median FVC declined to 82% of low altitude baseline while closing volume increased to 164% of baseline (P<0.05, both instances). In 10 controls, FVC decreased slightly (to 93% baseline, P<0.05) but significantly less than in subjects with HAPE and closing volume remained unchanged. Sniff nasal pressure was reduced in both subjects with and without subsequent HAPE. During nights at 4559 m, mean nocturnal oxygen saturation dropped to lower values while minute ventilation, the number of periodic breathing cycles and heart rate were higher (60%; 8.6 L/min; 97 cycles/h; 94 beats/min, respectively) in subjects subsequently developing HAPE than in controls (73%; 5.1 L/min; 48 cycles/h; 79 beats/min; P<0.05 vs. HAPE, all instances). CONCLUSION: The results comprehensively represent the pattern of physiologic alterations that precede overt HAPE. The changes in lung function are consistent with reduced lung compliance and impaired gas exchange. Pronounced nocturnal hypoxemia, ventilatory control instability and sympathetic stimulation are further signs of subsequent overt HAPE. PMID- 22829926 TI - Protein inhibitor of activated STAT, PIASy regulates alpha-smooth muscle actin expression by interacting with E12 in mesangial cells. AB - Phenotypic transformation of mesangial cells (MCs) is implicated in the development of glomerular disease; however, the mechanisms underlying their altered genetic program is still unclear. alpha-smooth muscle actin (alpha-SMA) is known to be a crucial marker for phenotypic transformation of MCs. Recently, E boxes and the class I basic helix-loop-helix proteins, such as E12 have been shown to regulatealpha-SMA expression. Therefore, we tried to identify a novel E12 binding protein in MCs and to examine its role in glomerulonephritis. We found that PIASy, one of the protein inhibitors of activated STAT family protein, interacted with E12 by yeast two-hybrid screens and coimmunopreciptation assays. Overexpression of E12 significantly enhanced thealpha-SMA promoter activity, and the increase was blocked by co-transfection of PIASy, but not by a PIASy RING mutant. In vivo sumoylation assays revealed that PIASy was a SUMO E3 ligase for E12. Furthermore, transforming growth factor-beta (TGF-beta) treatment induced expression of both PIASy and E12, consistent with alpha-SMA expression. Moreover, reduced expression of PIASy protein by siRNA specific for PIASy resulted in increased TGF-beta-mediated alpha-SMA expression. In vivo, PIASy and E12 were dramatically upregulated along with alpha-SMA and TGF-beta in the proliferative phase of Thy1 glomerulonephritis. Furthermore, an association between PIASy and E12 proteins was observed at day 6 by IP-western blotting, but not at day 0. These results suggest that TGF-beta up-regulates PIASy expression in MCs to down regulatealpha-SMA gene transcription by the interaction with E12. PMID- 22829928 TI - Distribution and functions of TonB-dependent transporters in marine bacteria and environments: implications for dissolved organic matter utilization. AB - BACKGROUND: Bacteria play critical roles in marine nutrient cycles by incorporating and redistributing dissolved organic matter (DOM) and inorganic nutrients in the ocean. TonB-dependent transporter (TBDT) proteins allow Gram negative bacteria to take up scarce resources from nutrient-limiting environments as well as siderophores, heme, vitamin B12, and recently identified carbohydrates. Thus, the characterization of TBDT distribution and functions is essential to better understand the contribution TBDT to DOM assimilation and its consequences on nutrient cycling in the environment. METHODOLOGY/PRINCIPAL FINDINGS: This study presents the distribution of encoded known and putative TBDT proteins in the genomes of microorganisms and from the Global Ocean Survey data. Using a Lek clustering algorithm and substrate specificities, the TBDT sequences were mainly classified into the following three groups: (1) DOM transporters; (2) Siderophores/Vitamins transporters; and (3) Heme/Hemophores/Iron(heme)-binding protein transporters. Diverse TBDTs were found in the genomes of oligotroph Citromicrobium bathyomarinum JL354 and Citromicrobium sp JLT1363 and were highly expressed in the stationary phase of bacterial growth. The results show that the Gammaproteobacteria and the Cytophaga-Flavobacterium-Bacteroides (CFB) group bacteria accounted for the majority of the TBDT gene pool in marine surface waters. CONCLUSIONS/SIGNIFICANCE: The results of this study confirm the ecological importance of TBDTs in DOM assimilation for bacteria in marine environments owing to a wide range of substrate utilization potential in the ubiquitous Gammaproteobacteria and CFB group bacteria. PMID- 22829929 TI - Anabaenolysins, novel cytolytic lipopeptides from benthic Anabaena cyanobacteria. AB - Two novel cyclic lipopeptides, anabaenolysin A and anabaenolysin B, were isolated from two benthic cyanobacterial strains of the genus Anabaena. This novel class of cyanobacterial lipopeptides has a general structure of a small peptide ring consisting of four amino acids from which two are proteinogenic and two unusual; glycine(1), glycine(2), 2-(3-amino-5-oxytetrahydrofuran-2-yl)-2-hydroxyacetic acid(3) and a long unsaturated C(18) beta-amino acid(4) with a conjugated triene structure. They are distinguished by the presence of a conjugated dienic structure in the C18 beta-amino acid present in anabaenolysin A but not in anabaenolysin B. Conjugated triene structure generates a typical UV spectrum for anabaenolysins for easy recognition. Anabaenolysin A constituted up to 400 ppm of the cyanobacterial dry weight. We found evidence of thirteen variants of anabaenolysins in one cyanobacterial strain. This suggests that the anabaenolysins are an important class of secondary metabolites in benthic Anabaena cyanobacteria. Both anabaenolysin A and B had cytolytic activity on a number of mammalian cell lines. PMID- 22829930 TI - A replication study confirms the association of dendritic cell immunoreceptor (DCIR) polymorphisms with ACPA - negative RA in a large Asian cohort. AB - OBJECTIVES: Dendritic cell immunoreceptor (DCIR) has been implicated in development of autoimmune disorders in rodent and DCIR polymorphisms were associated with anti-citrullinated proteins antibodies (ACPA)-negative rheumatoid arthritis (RA) in Swedish Caucasians. This study was undertaken to further investigate whether DCIR polymorphisms are also risk factors for the development of RA in four Asian populations originated from China and Malaysia. METHODS: We genotyped two DCIR SNPs rs2377422 and rs10840759 in Han Chinese population (1,193 cases, 1,278 controls), to assess their association with RA. Subsequently, rs2377422 was further genotyped in three independent cohorts of Malaysian-Chinese subjects (MY_Chinese, 254 cases, 206 controls), Malay subjects (MY_ Malay, 515 cases, 986 controls), and Malaysian-Indian subjects (MY_Indian, 378 cases, 285 controls), to seek confirmation of association in various ethnic groups. Meta analysis was preformed to evaluate the contribution of rs2377422 polymorphisms to the development of ACPA-negative RA in distinct ethnic groups. Finally, we carried out association analysis of rs2377422 polymorphisms with DCIR mRNA expression levels. RESULTS: DCIR rs2377422 was found to be significantly associated with ACPA -negative RA in Han Chinese (OR 1.92, 95% CI 1.27-2.90, P=0.0020). Meta-analysis confirms DCIR rs2377422 as a risk factor for ACPA negative RA across distinct ethnic groups (OR(overall) =1.17, 95% CI 1.06-1.30, P=0.003). The SNP rs2377422 polymorphism showed significant association with DCIR mRNA expression level, i.e. RA-risk CC genotype exhibit a significant increase in the expression of DCIR (P=0.0023, Kruskal-Wallis). CONCLUSIONS: Our data provide evidence for association between DCIR rs2377422 and RA in non-Caucasian populations and confirm the influence of DCIR polymorphisms on RA susceptibility, especially on ACPA-negative RA. PMID- 22829931 TI - Scanning laser optical tomography resolves structural plasticity during regeneration in an insect brain. AB - BACKGROUND: Optical Projection Tomography (OPT) is a microscopic technique that generates three dimensional images from whole mount samples the size of which exceeds the maximum focal depth of confocal laser scanning microscopes. As an advancement of conventional emission-OPT, Scanning Laser Optical Tomography (SLOTy) allows simultaneous detection of fluorescence and absorbance with high sensitivity. In the present study, we employ SLOTy in a paradigm of brain plasticity in an insect model system. METHODOLOGY: We visualize and quantify volumetric changes in sensory information procession centers in the adult locust, Locusta migratoria. Olfactory receptor neurons, which project from the antenna into the brain, are axotomized by crushing the antennal nerve or ablating the entire antenna. We follow the resulting degeneration and regeneration in the olfactory centers (antennal lobes and mushroom bodies) by measuring their size in reconstructed SLOTy images with respect to the untreated control side. Within three weeks post treatment antennal lobes with ablated antennae lose as much as 60% of their initial volume. In contrast, antennal lobes with crushed antennal nerves initially shrink as well, but regain size back to normal within three weeks. The combined application of transmission-and fluorescence projections of Neurobiotin labeled axotomized fibers confirms that recovery of normal size is restored by regenerated afferents. Remarkably, SLOTy images reveal that degeneration of olfactory receptor axons has a trans-synaptic effect on second order brain centers and leads to size reduction of the mushroom body calyx. CONCLUSIONS: This study demonstrates that SLOTy is a suitable method for rapid screening of volumetric plasticity in insect brains and suggests its application also to vertebrate preparations. PMID- 22829932 TI - Independent studies using deep sequencing resolve the same set of core bacterial species dominating gut communities of honey bees. AB - Starting in 2003, numerous studies using culture-independent methodologies to characterize the gut microbiota of honey bees have retrieved a consistent and distinctive set of eight bacterial species, based on near identity of the 16S rRNA gene sequences. A recent study [Mattila HR, Rios D, Walker-Sperling VE, Roeselers G, Newton ILG (2012) Characterization of the active microbiotas associated with honey bees reveals healthier and broader communities when colonies are genetically diverse. PLoS ONE 7(3): e32962], using pyrosequencing of the V1-V2 hypervariable region of the 16S rRNA gene, reported finding entirely novel bacterial species in honey bee guts, and used taxonomic assignments from these reads to predict metabolic activities based on known metabolisms of cultivable species. To better understand this discrepancy, we analyzed the Mattila et al. pyrotag dataset. In contrast to the conclusions of Mattila et al., we found that the large majority of pyrotag sequences belonged to clusters for which representative sequences were identical to sequences from previously identified core species of the bee microbiota. On average, they represent 95% of the bacteria in each worker bee in the Mattila et al. dataset, a slightly lower value than that found in other studies. Some colonies contain small proportions of other bacteria, mostly species of Enterobacteriaceae. Reanalysis of the Mattila et al. dataset also did not support a relationship between abundances of Bifidobacterium and of putative pathogens or a significant difference in gut communities between colonies from queens that were singly or multiply mated. Additionally, consistent with previous studies, the dataset supports the occurrence of considerable strain variation within core species, even within single colonies. The roles of these bacteria within bees, or the implications of the strain variation, are not yet clear. PMID- 22829933 TI - TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation. AB - NOD2, the nucleotide-binding domain and leucine-rich repeat containing gene family (NLR) member 2 is involved in mediating antimicrobial responses. Dysfunctional NOD2 activity can lead to severe inflammatory disorders, but the regulation of NOD2 is still poorly understood. Recently, proteins of the tripartite motif (TRIM) protein family have emerged as regulators of innate immune responses by acting as E3 ubiquitin ligases. We identified TRIM27 as a new specific binding partner for NOD2. We show that NOD2 physically interacts with TRIM27 via the nucleotide-binding domain, and that NOD2 activation enhances this interaction. Dependent on functional TRIM27, ectopically expressed NOD2 is ubiquitinated with K48-linked ubiquitin chains followed by proteasomal degradation. Accordingly, TRIM27 affects NOD2-mediated pro-inflammatory responses. NOD2 mutations are linked to susceptibility to Crohn's disease. We found that TRIM27 expression is increased in Crohn's disease patients, underscoring a physiological role of TRIM27 in regulating NOD2 signaling. In HeLa cells, TRIM27 is partially localized in the nucleus. We revealed that ectopically expressed NOD2 can shuttle to the nucleus in a Walker A dependent manner, suggesting that NOD2 and TRIM27 might functionally cooperate in the nucleus.We conclude that TRIM27 negatively regulates NOD2-mediated signaling by degradation of NOD2 and suggest that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases. PMID- 22829934 TI - Assessment of TP53 mutations in benign and malignant salivary gland neoplasms. AB - Despite advances in the understanding of the pathogenesis of salivary gland neoplasms (SGN), the molecular pathways associated with enhanced tumor growth and cell survival remain to be established. The aim of the present study was to investigate whether TP53 mutations are relevant to SGN pathogenesis and if they impact on p53 protein expression. The study included 18 benign and 18 malignant SGN samples. Two polymorphic microsatellite markers at the TP53 genetic locus were chosen to assess loss of heterozygosity (LOH) in the samples that had matched normal DNA. The TP53 exons 2-11 were amplified by PCR, and all of the products were sequenced. Reverse transcription-PCR of the TP53 open reading frame (ORF) was carried out in the samples that had fresh tissue available, and immunohistochemistry for the p53 protein was performed in all samples. TP53 LOH was only found in two pleomorphic adenomas. We found two missense mutations in exon 7 (one in a pleomorphic adenoma and the other in a polymorphous low grade adenocarcinoma), another in exon 8 (in a carcinoma ex pleomorphic adenoma) and a fourth missense mutation in exon 10 (in a mucoepidermoid carcinoma). In addition, a nonsense mutation was found in exon 8 of an adenoid cystic carcinoma. Several intronic and exonic SNPs were detected. Although almost all of the malignant samples were immunopositive for p53, approximately 37% of the benign samples were positive, including the sample harboring the missense mutation and one of the samples that showed LOH. The complete TP53 ORF could be amplified in all samples analyzed, including the IHC negative samples, the samples showing LOH and one sample displaying a missense mutation. In summary, our results show that TP53 mutations are not a frequent event in SGN and that p53 immunopositivity might not be associated with sequence mutations in SGN. PMID- 22829935 TI - Acyl coenzyme A synthetase long-chain 1 (ACSL1) gene polymorphism (rs6552828) and elite endurance athletic status: a replication study. AB - The aim of this study was to determine the association between the rs6552828 polymorphism in acyl coenzyme A synthetase (ACSL1) and elite endurance athletic status. We studied 82 Caucasian (Spanish) World/Olympic-class endurance male athletes, and a group of sex and ethnically matched healthy young adults (controls, n=197). The analyses were replicated in a cohort of a different ethnic origin (Chinese of the Han ethnic group), composed of elite endurance athletes (runners) [cases, n=241 (128 male)] and healthy sedentary adults [controls, n=504 (267 male)]. In the Spanish cohort, genotype (P=0.591) and minor allele (A) frequencies were similar in cases and controls (P=0.978). In the Chinese cohort, genotype (P=0.973) and minor allele (G) frequencies were comparable in female endurance athletes and sedentary controls (P=0.881), whereas in males the frequency of the G allele was higher in endurance athletes (0.40) compared with their controls (0.32, P=0.040). The odds ratio (95%CI) for an elite endurance Chinese athlete to carry the G allele compared with ethnically matched controls was 1.381 (1.015-1.880) (P-value=0.04). Our findings suggest that the ACSL1 gene polymorphism rs6552828 is not associated with elite endurance athletic status in Caucasians, yet a marginal association seems to exist for the Chinese (Han) male population. PMID- 22829936 TI - Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. AB - Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n=13) or no treatment (vehicle, n=17) for 12 weeks. Sham operated rats (n=12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A' waves] and a decrease of E/A and E'/A' ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF beta, CTGF) and hypertrophic (ANP, beta-MHC and alpha-skeletal muscle actin) markers, as well as TGF-beta and phosphorylated NF-kappaB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120=227 +/- 11 vs vehicle =224 +/- 8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-beta and phosphorylated NF-kappaB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner. PMID- 22829937 TI - Downregulation of polo-like kinase 4 in hepatocellular carcinoma associates with poor prognosis. AB - Polo-like kinase 4 (PLK4), belonging to serine/threonine kinase family, is critical for centriole replication and cell cycle progression. PLK4 has been proposed as a tumor suppressor in hepatocellular carcinoma (HCC). However, its expression and significance in HCC have not been well studied. In the present study, we found that PLK4 was markedly downregulated in both HCC cell lines and fresh cancer tissues, using quantitative real-time-PCR and western blot. Immunohistochemistry data also revealed that decreased expression of PLK4 was present in 72.4% (178/246) of HCC tissues, compared with the corresponding adjacent nontumorous tissues. Furthermore, PLK4 expression significantly correlated with clinicopathological parameters, including clinical stage (P=0.034), serum alpha-fetoprotein (AFP) (P=0.019) and tumor size (P=0.032). Moreover, HCC patients with low PLK4 expression survived shorter than those with high PLK4 expression, as indicated by overall survival (P=0.002) and disease-free survival (P=0.012) assessed by the Kaplan-Meier method. In addition, multivariate analysis suggested PLK4 as an independent predictor of overall survival (HR, 0.556; 95%CI, 0.376-0.822; P=0.003) and disease-free survival (HR, 0.547; 95%CI, 0.382-0.783; P=0.001). Collectively, our study demonstrated that PLK4 was remarkably downregulated in HCC and could be served as a potential prognostic marker for patients with this deadly disease. PMID- 22829938 TI - A novel source of methylglyoxal and glyoxal in retina: implications for age related macular degeneration. AB - Aging of retinal pigment epithelial (RPE) cells of the eye is marked by accumulations of bisretinoid fluorophores; two of the compounds within this lipofuscin mixture are A2E and all-trans-retinal dimer. These pigments are implicated in pathological mechanisms involved in some vision-threatening disorders including age-related macular degeneration (AMD). Studies have shown that bisretinoids are photosensitive compounds that undergo photooxidation and photodegradation when irradiated with short wavelength visible light. Utilizing ultra performance liquid chromatography (UPLC) with electrospray ionization mass spectrometry (ESI-MS) we demonstrate that photodegradation of A2E and all-trans retinal dimer generates the dicarbonyls glyoxal (GO) and methylglyoxal (MG), that are known to modify proteins by advanced glycation endproduct (AGE) formation. By extracellular trapping with aminoguanidine, we established that these oxo aldehydes are released from irradiated A2E-containing RPE cells. Enzyme-linked immunosorbant assays (ELISA) revealed that the substrate underlying A2E containing RPE was AGE-modified after irradiation. This AGE deposition was suppressed by prior treatment of the cells with aminoguanidine. AGE-modification causes structural and functional impairment of proteins. In chronic diseases such as diabetes and atherosclerosis, MG and GO modify proteins by non-enzymatic glycation and oxidation reactions. AGE-modified proteins are also components of drusen, the sub-RPE deposits that confer increased risk of AMD onset. These results indicate that photodegraded RPE bisretinoid is likely to be a previously unknown source of MG and GO in the eye. PMID- 22829940 TI - Effect of intravitreal anti-vascular endothelial growth factor therapy on the risk of arterial thromboembolic events: a meta-analysis. AB - BACKGROUND: Intravitreal anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are used in ocular neovascular diseases. A consensus has emerged that intravenous anti-VEGF can increase the risk of arterial thromboembolic events. However, the role of intravitreal anti-VEGF in arterial thromboembolism is controversial. Therefore, we did a systematic review and meta analysis to investigate the effects of intravitreal anti-VEGF on the risk of arterial thromboembolic events. METHODS: Electronic databases were searched to identify relevant randomized clinical trials comparing intravitreal anti-VEGF with controls. Criteria for inclusion in our meta-analysis included a study duration of no less than 12 months, the use of a randomized control group not receiving any intravitreal active agent, and the availability of outcome data for arterial thromboembolic events, myocardial infarction, cerebrovascular accidents, and vascular death. The risk ratios and 95% CIs were calculated using a fixed effects or random-effects model, depending on the heterogeneity of the included studies. RESULTS: A total of 4942 patients with a variety of ocular neovascular diseases from 13 randomized controlled trials were identified and included for analysis. There was no significant difference between intravitreal anti-VEGF and control in the risk of all events, with risk ratios of 0.87 (95% CI, 0.64 to 1.19) for arterial thromboembolic events, 0.96 (95% CI, 0.55-1.68) for cerebrovascular accidents, 0.69 (95% CI 0.40-1.21) for myocardial infarctions, and 0.68 (95% CI, 0.37-1.27) for vascular death. CONCLUSIONS: The strength evidence suggests that the intravitreal use of anti-VEGF antibodies is not associated with an increased risk of arterial thromboembolic events. PMID- 22829939 TI - AFLP genome scan to detect genetic structure and candidate loci under selection for local adaptation of the invasive weed Mikania micrantha. AB - Why some species become successful invaders is an important issue in invasive biology. However, limited genomic resources make it very difficult for identifying candidate genes involved in invasiveness. Mikania micrantha H.B.K. (Asteraceae), one of the world's most invasive weeds, has adapted rapidly in response to novel environments since its introduction to southern China. In its genome, we expect to find outlier loci under selection for local adaptation, critical to dissecting the molecular mechanisms of invasiveness. An explorative amplified fragment length polymorphism (AFLP) genome scan was used to detect candidate loci under selection in 28 M. micrantha populations across its entire introduced range in southern China. We also estimated population genetic parameters, bottleneck signatures, and linkage disequilibrium. In binary characters, such as presence or absence of AFLP bands, if all four character combinations are present, it is referred to as a character incompatibility. Since character incompatibility is deemed to be rare in populations with extensive asexual reproduction, a character incompatibility analysis was also performed in order to infer the predominant mating system in the introduced M. micrantha populations. Out of 483 AFLP loci examined using stringent significance criteria, 14 highly credible outlier loci were identified by Dfdist and Bayescan. Moreover, remarkable genetic variation, multiple introductions, substantial bottlenecks and character compatibility were found to occur in M. micrantha. Thus local adaptation at the genome level indeed exists in M. micrantha, and may represent a major evolutionary mechanism of successful invasion. Interactions between genetic diversity, multiple introductions, and reproductive modes contribute to increase the capacity of adaptive evolution. PMID- 22829941 TI - Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B. AB - BACKGROUND: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner. METHODOLOGY/PRINCIPAL FINDINGS: Optical imaging of uptake kinetics revealed co-localization of grB with recycling endosomes (Rab9/11) as early as 5 min after internalization, with late endosomes (Rab7) after 30 min, and the lysosomal compartment (LAMP1/2) after 60 to 120 min. Active caspase-3-mediated apoptosis was induced in mouse CT26 monolayer cells and 3D tumor spheroids, but not in normal mouse endothelial cells. Granzyme B selectively reduced the proportion of membrane Hsp70-positive cells in CT26 tumor spheroids. Consecutive i.v. injections of recombinant human grB into mice bearing membrane Hsp70-positive CT26 tumors resulted in significant tumor suppression, and a detailed inspection of normal mouse organs revealed that the administration of anti-tumoral concentrations of grB elicited no clinicopathological changes. CONCLUSIONS/SIGNIFICANCE: These findings support the future clinical evaluation of human grB as a potential adjuvant therapeutic agent, especially for treating immunosuppressed patients that bear membrane Hsp70-positive tumors. PMID- 22829942 TI - Design and characterization of auxotrophy-based amino acid biosensors. AB - Efficient and inexpensive methods are required for the high-throughput quantification of amino acids in physiological fluids or microbial cell cultures. Here we develop an array of Escherichia coli biosensors to sensitively quantify eleven different amino acids. By using online databases, genes involved in amino acid biosynthesis were identified that - upon deletion - should render the corresponding mutant auxotrophic for one particular amino acid. This rational design strategy suggested genes involved in the biosynthesis of arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, and tyrosine as potential genetic targets. A detailed phenotypic characterization of the corresponding single-gene deletion mutants indeed confirmed that these strains could neither grow on a minimal medium lacking amino acids nor transform any other proteinogenic amino acid into the focal one. Site-specific integration of the egfp gene into the chromosome of each biosensor decreased the detection limit of the GFP-labeled cells by 30% relative to turbidometric measurements. Finally, using the biosensors to determine the amino acid concentration in the supernatants of two amino acid overproducing E. coli strains (i.e. DeltahisL and DeltatdcC) both turbidometrically and via GFP fluorescence emission and comparing the results to conventional HPLC measurements confirmed the utility of the developed biosensor system. Taken together, our study provides not only a genotypically and phenotypically well-characterized set of publicly available amino acid biosensors, but also demonstrates the feasibility of the rational design strategy used. PMID- 22829943 TI - Cofactor binding protects flavodoxin against oxidative stress. AB - In organisms, various protective mechanisms against oxidative damaging of proteins exist. Here, we show that cofactor binding is among these mechanisms, because flavin mononucleotide (FMN) protects Azotobacter vinelandii flavodoxin against hydrogen peroxide-induced oxidation. We identify an oxidation sensitive cysteine residue in a functionally important loop close to the cofactor, i.e., Cys69. Oxidative stress causes dimerization of apoflavodoxin (i.e., flavodoxin without cofactor), and leads to consecutive formation of sulfinate and sulfonate states of Cys69. Use of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) reveals that Cys69 modification to a sulfenic acid is a transient intermediate during oxidation. Dithiothreitol converts sulfenic acid and disulfide into thiols, whereas the sulfinate and sulfonate forms of Cys69 are irreversible with respect to this reagent. A variable fraction of Cys69 in freshly isolated flavodoxin is in the sulfenic acid state, but neither oxidation to sulfinic and sulfonic acid nor formation of intermolecular disulfides is observed under oxidising conditions. Furthermore, flavodoxin does not react appreciably with NBD-Cl. Besides its primary role as redox-active moiety, binding of flavin leads to considerably improved stability against protein unfolding and to strong protection against irreversible oxidation and other covalent thiol modifications. Thus, cofactors can protect proteins against oxidation and modification. PMID- 22829944 TI - Combination treatment of rosuvastatin or atorvastatin, with regular exercise improves arterial wall stiffness in patients with coronary artery disease. AB - OBJECTIVE: Statin- and exercise-therapy are both clinically beneficial by preventing cardiovascular events in patients with coronary artery disease (CAD). However, there is no information on the vascular effects of the combination of statins and exercise on arterial wall stiffness in CAD patients. METHODS: The present study is a sub-analysis of PRESET study that determined the effects of 20 week treatment with statins (rosuvastatin, n=14, atorvastatin, n=14) combined with regular exercise on arterial wall stiffness assessed by measurement of brachial and ankle pulse wave velocity (baPWV) in CAD patients. RESULTS: The combination of statins and regular exercise significantly improved exercise capacity, lipid profile, including low- and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hs-CRP), baPWV (baseline: 1747 +/- 355, at 20 weeks of treatment: 1627 +/- 271 cm/s, p=0.008), and basophil count (baseline: 42 +/- 32, 20 weeks: 26 +/- 15 cells/uL, p=0.007), but had no effect on blood pressure (baseline: 125 +/- 22, 20 weeks: 121 +/- 16 mmHg). Changes in baPWV correlated significantly with changes in basophil count (r=0.488, p=0.008), but not with age, lipids profile, exercise capacity, or hs-CRP. CONCLUSION: In CAD patients, the combination treatment with statins and exercise resulted in significant amelioration of arterial wall stiffness, at least in part, through reduction of circulating basophils. PMID- 22829945 TI - Identification of catalytic residues using a novel feature that integrates the microenvironment and geometrical location properties of residues. AB - Enzymes play a fundamental role in almost all biological processes and identification of catalytic residues is a crucial step for deciphering the biological functions and understanding the underlying catalytic mechanisms. In this work, we developed a novel structural feature called MEDscore to identify catalytic residues, which integrated the microenvironment (ME) and geometrical properties of amino acid residues. Firstly, we converted a residue's ME into a series of spatially neighboring residue pairs, whose likelihood of being located in a catalytic ME was deduced from a benchmark enzyme dataset. We then calculated an ME-based score, termed as MEscore, by summing up the likelihood of all residue pairs. Secondly, we defined a parameter called Dscore to measure the relative distance of a residue to the center of the protein, provided that catalytic residues are typically located in the center of the protein structure. Finally, we defined the MEDscore feature based on an effective nonlinear integration of MEscore and Dscore. When evaluated on a well-prepared benchmark dataset using five-fold cross-validation tests, MEDscore achieved a robust performance in identifying catalytic residues with an AUC1.0 of 0.889. At a <= 10% false positive rate control, MEDscore correctly identified approximately 70% of the catalytic residues. Remarkably, MEDscore achieved a competitive performance compared with the residue conservation score (e.g. CONscore), the most informative singular feature predominantly employed to identify catalytic residues. To the best of our knowledge, MEDscore is the first singular structural feature exhibiting such an advantage. More importantly, we found that MEDscore is complementary with CONscore and a significantly improved performance can be achieved by combining CONscore with MEDscore in a linear manner. As an implementation of this work, MEDscore has been made freely accessible at http://protein.cau.edu.cn/mepi/. PMID- 22829946 TI - TH17, TH22 and Treg cells are enriched in the healthy human cecum. AB - There is increasing evidence that dysregulation of CD4(+) T cell populations leads to intestinal inflammation, but the regional distribution of these populations throughout the intestinal tract in healthy individuals remains unclear. Here, we show that T(H)17, T(H)22 and T(Reg) cells are enriched in the healthy human cecum compared to the terminal ileum and sigmoid colon, whereas T(H)1 and T(H)2 cells do not significantly vary by location. Transcriptional profiling analysis of paired pinch biopsies from different regions of the intestine identified significant differences in the metabolic state of the terminal ileum, cecum, and sigmoid colon. An increased proportion of T(H)17 cells was positively associated with expression of resistin (RETN) and negatively associated with expression of trefoil factor 1 (TFF1). These results suggest that CD4(+) T helper cells that are important in maintaining mucosal barrier function may be enriched in the cecum as a result of metabolic differences of the surrounding microenvironment. PMID- 22829947 TI - Comprehensive identification and annotation of cell type-specific and ubiquitous CTCF-binding sites in the human genome. AB - Chromatin insulators are DNA elements that regulate the level of gene expression either by preventing gene silencing through the maintenance of heterochromatin boundaries or by preventing gene activation by blocking interactions between enhancers and promoters. CCCTC-binding factor (CTCF), a ubiquitously expressed 11 zinc-finger DNA-binding protein, is the only protein implicated in the establishment of insulators in vertebrates. While CTCF has been implicated in diverse regulatory functions, CTCF has only been studied in a limited number of cell types across human genome. Thus, it is not clear whether the identified cell type-specific differences in CTCF-binding sites are functionally significant. Here, we identify and characterize cell type-specific and ubiquitous CTCF-binding sites in the human genome across 38 cell types designated by the Encyclopedia of DNA Elements (ENCODE) consortium. These cell type-specific and ubiquitous CTCF binding sites show uniquely versatile transcriptional functions and characteristic chromatin features. In addition, we confirm the insulator barrier function of CTCF-binding and explore the novel function of CTCF in DNA replication. These results represent a critical step toward the comprehensive and systematic understanding of CTCF-dependent insulators and their versatile roles in the human genome. PMID- 22829949 TI - Age and sex composition of seals killed by polar bears in the eastern Beaufort Sea. AB - BACKGROUND: Polar bears (Ursus maritimus) of the Beaufort Sea enter hyperphagia in spring and gain fat reserves to survive periods of low prey availability. We collected information on seals killed by polar bears (n=650) and hunting attempts on ringed seal (Pusa hispida) lairs (n=1396) observed from a helicopter during polar bear mark-recapture studies in the eastern Beaufort Sea in spring in 1985 2011. We investigated how temporal shifts in ringed seal reproduction affect kill composition and the intraspecific vulnerabilities of ringed seals to polar bear predation. PRINCIPAL FINDINGS: Polar bears primarily preyed on ringed seals (90.2%) while bearded seals (Erignathus barbatus) only comprised 9.8% of the kills, but 33% of the biomass. Adults comprised 43.6% (150/344) of the ringed seals killed, while their pups comprised 38.4% (132/344). Juvenile ringed seals were killed at the lowest proportion, comprising 18.0% (62/344) of the ringed seal kills. The proportion of ringed seal pups was highest between 2007-2011, in association with high ringed seal productivity. Half of the adult ringed seal kills were >= 21 years (60/121), and kill rates of adults increased following the peak of parturition. Determination of sex from DNA revealed that polar bears killed adult male and adult female ringed seals equally (0.50, n=78). The number of hunting attempts at ringed seal subnivean lair sites was positively correlated with the number of pup kills (r(2) =0.30, P=0.04), but was not correlated with the number of adult kills (P=0.37). CONCLUSIONS/SIGNIFICANCE: Results are consistent with decadal trends in ringed seal productivity, with low numbers of pups killed by polar bears in spring in years of low pup productivity, and conversely when pup productivity was high. Vulnerability of adult ringed seals to predation increased in relation to reproductive activities and age, but not gender. PMID- 22829948 TI - Elevated CO2 reduces the resistance and tolerance of tomato plants to Helicoverpa armigera by suppressing the JA signaling pathway. AB - Both resistance and tolerance, which are two strategies that plants use to limit biotic stress, are affected by the abiotic environment including atmospheric CO(2) levels. We tested the hypothesis that elevated CO(2) would reduce resistance (i.e., the ability to prevent damage) but enhance tolerance (i.e., the ability to regrow and compensate for damage after the damage has occurred) of tomato plants to the cotton bollworm, Helicoverpa armigera. The results showed that elevated CO(2) reduced resistance by decreasing the jasmonic acid (JA) level and activities of lipoxygenase, proteinase inhibitors, and polyphenol oxidase in wild-type (WT) plants infested with H. armigera. Consequently, the activities of total protease, trypsin-like enzymes, and weak and active alkaline trypsin-like enzymes increased in the midgut of H. armigera when fed on WT plants grown under elevated CO(2). Unexpectedly, the tolerance of the WT to H. armigera (in terms of photosynthetic rate, activity of sucrose phosphate synthases, flower number, and plant biomass and height) was also reduced by elevated CO(2). Under ambient CO(2), the expression of resistance and tolerance to H. armigera was much greater in wild type than in spr2 (a JA-deficient genotype) plants, but elevated CO(2) reduced these differences of the resistance and tolerance between WT and spr2 plants. The results suggest that the JA signaling pathway contributes to both plant resistance and tolerance to herbivorous insects and that by suppressing the JA signaling pathway, elevated CO(2) will simultaneously reduce the resistance and tolerance of tomato plants. PMID- 22829950 TI - Wallerian degeneration in central nervous system: dynamic associations between diffusion indices and their underlying pathology. AB - BACKGROUND: Although diffusion tensor imaging has been used to monitor Wallerian degeneration, the exact relationship between the evolution of diffusion indices and its underlying pathology, especially in central nervous system, remains largely unknown. Here we aimed to address this question using a cat Wallerian degeneration model of corticospinal tract. METHODOLOGY/PRINCIPAL FINDINGS: Twenty five domestic mature Felis catus were included in the present study. The evolution of diffusion indices, including mean diffusivity (MD), fractional anisotropy (FA), primary (lambda1) and transverse eigenvalues (lambda23) of the degenerated corticospinal tract, were observed at baseline (before modeling) and at 2, 4, 6, 8, 10, 15, 20, 25, 30, 45 and 60 days after modeling in 4 cats. Pathological examinations were performed at eight time points mentioned above. Wallerian degeneration can be detected as early as the 2nd day after modeling by both diffusion tensor imaging and pathology. According to the evolution of diffusion indices, Wallerian degeneration can be classified into 2 stages. During the early stage (within 8 days after modeling), progressive disintegration of axons and myelin sheaths underlies the decreases in FA and lambda1 and the increase in lambda23. However, during the late stage (after 8 days), the gradual increases in FA, MD and lambda1 and the unchanged lambda23 seem to be a comprehensive reflection of the pathological processes including microglia activation, myelin clearance, and astrocytosis. CONCLUSIONS/SIGNIFICANCE: Our findings help the understanding of the altered diffusion indices in the context of pathology and suggest that diffusion tensor imaging has the potential to monitor the processes of Wallerian degeneration in the central nervous system in vivo after acute damage. PMID- 22829951 TI - A porcine circovirus type 2 (PCV2) mutant with 234 amino acids in capsid protein showed more virulence in vivo, compared with classical PCV2a/b strain. AB - BACKGROUND: Porcine circovirus type 2 (PCV2) is considered to be the primary causative agent of postweaning multisystemic wasting syndrome (PMWS), which has become a serious economic problem for the swine industry worldwide. The major genotypes, PCV2a and PCV2b, are highly prevalent in the pig population and are present worldwide. However, another newly emerging PCV2b genotype mutant, which has a mutation in its ORF2-encoded capsid protein, has been sporadically present in China, as well as in other countries. It is therefore important to determine the relative virulence of the newly emerging PCV2b genotype mutant, compared with the existing PCV2a and PCV2b genotypes, and to investigate whether the newly emerging mutant virus induces more severe illness. METHODOLOGY/PRINCIPAL FINDINGS: Twenty healthy, 30-day-old, commercial piglets served as controls or were challenged with PCV2a, PCV2b and the newly emerging mutant virus. A series of indexes representing different parameters were adopted to evaluate virulence, including clinical signs, serological detection, viral load and distribution, changes in immune cell subsets in the peripheral blood, and evaluation of pathological lesions. The newly emerging PCV2 mutant demonstrated more severe signs compatible with PMWS, characterized by wasting, coughing, dyspnea, diarrhea, rough hair-coat and depression. Moreover, the pathological lesions and viremia, as well as the viral loads in lymph nodes, tonsils and spleen, were significantly more severe (P<0.05) for piglets challenged with the newly emerging mutant compared with those in the groups challenged with PCV2a and PCV2b. In addition, a significantly lower average daily weight gain (P<0.05) was recorded in the group challenged with the newly emerging PCV2 mutant than in the groups challenged with the prevailing PCV2a and PCV2b. CONCLUSIONS: This is believed to be the first report to confirm the enhanced virulence of the newly emerging PCV2 mutant in vivo. PMID- 22829952 TI - A functional +61G/A polymorphism in epidermal growth factor is associated with glioma risk among Asians. AB - BACKGROUND: Epidermal growth factor (EGF), a potent mitogenic protein, plays an important role in the development of cancers, including glioma. Previous studies showed that the EGF +61G/A polymorphism (rs4444903) may lead to an alteration in EGF production and/or activity, which can result in individual susceptibility to glioma. However, published data regarding the association between the +61G/A polymorphism and glioma risk was contradictory. OBJECTIVE: The aim of this study was to perform a meta-analysis of eligible studies to derive precise estimation of the association of EGF +61G/A with glioma risk. METHODS: We performed a pooled analysis of seven published studies that included 1,613 glioma cases and 2,267 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. RESULTS: Overall, no significant associations between the EGF +61G/A polymorphism and glioma cancer risk were found for AA versus GG (OR=0.95, 95% CI=0.62-1.45), GA versus GG (OR=0.94, 95% CI=0.72-1.22), AA/GA versus GG (OR=0.93, 95% CI=0.70 1.23), and AA versus GA/GG (OR=1.04, 95% CI=0.77-1.39). However, in the stratified analysis by ethnicity, the EGF +61G/A polymorphism had a higher risk of glioma development among Asians, but a lower risk among Caucasians. CONCLUSIONS: Taken together, the results suggest that the EGF +61G/A polymorphism may contribute to the susceptibility of glioma in different ethnic groups. PMID- 22829953 TI - Effects of anthropogenic disturbance and climate on patterns of bat fly parasitism. AB - Environmental conditions, including anthropogenic disturbance, can significantly alter host and parasite communities. Yet, our current knowledge is based mainly on endoparasites, while ectoparasites remain little studied. We studied the indirect effects of anthropogenic disturbance (human population density) and climate (temperature, precipitation and elevation) on abundance of highly host specific bat flies in four Neotropical bat species across 43 localities in Venezuela. We formulated a set of 11 a priori hypotheses that included a combination of the two effectors and host species. Statistically, each of these hypotheses was represented by a zero-inflated negative binomial mixture model, allowing us to control for excess zeros in the data. The best model was selected using Akaike's information criteria. Fly abundance was affected by anthropogenic disturbance in Artibeus planirostris, Carollia perspicillata and Pteronotus parnellii, but not Desmodus rotundus. Climate affected fly abundance in all bat species, suggesting mediation of these effects via the host or by direct effects on flies. We conclude that human disturbance may play a role in shaping bat-bat fly interactions. Different processes could determine fly abundance in the different bat species. PMID- 22829954 TI - A novel vector-based method for exclusive overexpression of star-form microRNAs. AB - The roles of microRNAs (miRNAs) as important regulators of gene expression have been studied intensively. Although most of these investigations have involved the highly expressed form of the two mature miRNA species, increasing evidence points to essential roles for star-form microRNAs (miRNA*), which are usually expressed at much lower levels. Owing to the nature of miRNA biogenesis, it is challenging to use plasmids containing miRNA coding sequences for gain-of-function experiments concerning the roles of microRNA* species. Synthetic microRNA mimics could introduce specific miRNA* species into cells, but this transient overexpression system has many shortcomings. Here, we report that specific miRNA* species can be overexpressed by introducing artificially designed stem-loop sequences into short hairpin RNA (shRNA) overexpression vectors. By our prototypic plasmid, designed to overexpress hsa-miR-146b-3p, we successfully expressed high levels of hsa-miR-146b-3p without detectable change of hsa-miR 146b-5p. Functional analysis involving luciferase reporter assays showed that, like natural miRNAs, the overexpressed hsa-miR-146b-3p inhibited target gene expression by 3'UTR seed pairing. Our demonstration that this method could overexpress two other miRNAs suggests that the approach should be broadly applicable. Our novel strategy opens the way for exclusively stable overexpression of miRNA* species and analyzing their unique functions both in vitro and in vivo. PMID- 22829956 TI - Detailed analysis of apoptosis and delayed luminescence of human leukemia Jurkat T cells after proton irradiation and treatments with oxidant agents and flavonoids. AB - Following previous work, we investigated in more detail the relationship between apoptosis and delayed luminescence (DL) in human leukemia Jurkat T cells under a wide variety of treatments. We used menadione and hydrogen peroxide to induce oxidative stress and two flavonoids, quercetin, and epigallocatechin gallate, applied alone or in combination with menadione or H(2)O(2). 62 MeV proton beams were used to irradiate cells under a uniform dose of 2 or 10 Gy, respectively. We assessed apoptosis, cell cycle distributions, and DL. Menadione, H(2)O(2) and quercetin were potent inducers of apoptosis and DL inhibitors. Quercetin decreased clonogenic survival and the NAD(P)H level in a dose-dependent manner. Proton irradiation with 2 Gy but not 10 Gy increased the apoptotic rate. However, both doses induced a substantial G(2)/M arrest. Quercetin reduced apoptosis and prolonged the G(2)/M arrest induced by radiation. DL spectroscopy indicated that proton irradiation disrupted the electron flow within Complex I of the mitochondrial respiratory chain, thus explaining the massive necrosis induced by 10 Gy of protons and also suggested an equivalent action of menadione and quercetin at the level of the Fe/S center N2, which may be mediated by their binding to a common site within Complex I, probably the rotenone-binding site. PMID- 22829955 TI - Exercise in the metabolic syndrome. AB - The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism. PMID- 22829958 TI - Erythrocyte antioxidant protection of rose hips (Rosa spp.). AB - Rose hips are popular in health promoting products as the fruits contain high content of bioactive compounds. The aim of this study was to investigate whether health benefits are attributable to ascorbic acid, phenols, or other rose-hip derived compounds. Freeze-dried powder of rose hips was preextracted with metaphosphoric acid and the sample was then sequentially eluted on a C(18) column. The degree of amelioration of oxidative damage was determined in an erythrocyte in vitro bioassay by comparing the effects of a reducing agent on erythrocytes alone or on erythrocytes pretreated with berry extracts. The maximum protection against oxidative stress, 59.4 +/- 4.0% (mean +/- standard deviation), was achieved when incubating the cells with the first eluted meta-phosphoric extract. Removal of ascorbic acid from this extract increased the protection against oxidative stress to 67.9 +/- 1.9%. The protection from the 20% and 100% methanol extracts was 20.8 +/- 8.2% and 5.0 +/- 3.2%, respectively. Antioxidant uptake was confirmed by measurement of catechin by HPLC-ESI-MS in the 20% methanol extract. The fact that all sequentially eluted extracts studied contributed to protective effects on the erythrocytes indicates that rose hips contain a promising level of clinically relevant antioxidant protection. PMID- 22829957 TI - The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. AB - Although it has been long believed that new neurons were only generated during development, there is now growing evidence indicating that at least two regions in the brain are capable of continuously generating functional neurons: the subventricular zone and the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (AHN) is a widely observed phenomenon verified in different adult mammalian species including humans. Factors such as environmental enrichment, voluntary exercise, and diet have been linked to increased levels of AHN. Conversely, aging, stress, anxiety and depression have been suggested to hinder it. However, the mechanisms underlying these effects are still unclear and yet to be determined. In this paper, we discuss some recent findings addressing the effects of different dietary polyphenols on hippocampal cell proliferation and differentiation, models of anxiety, and depression as well as some proposed molecular mechanisms underlying those effects with particular focus on those related to AHN. As a whole, dietary polyphenols seem to exert positive effects on anxiety and depression, possibly in part via regulation of AHN. Studies on the effects of dietary polyphenols on behaviour and AHN may play an important role in the approach to use diet as part of the therapeutic interventions for mental health-related conditions. PMID- 22829960 TI - Alterations in nitric oxide synthase in the aged CNS. AB - Aging is associated with neuronal loss, gross weight reduction of the brain, and glial proliferation in the cortex, all of which lead to functional changes in the brain. It is known that oxidative stress is a critical factor in the pathogenesis of aging; additionally, growing evidence suggests that excessive nitric oxide (NO) production contributes to the aging process. However, it is still unclear how NO plays a role in the aging process. This paper describes age-related changes in the activity of NADPH-diaphorase (NADPH-d), a marker for neurons containing nitric oxide synthase (NOS), in many CNS regions. Understanding these changes may provide a novel perspective in identifying the aging mechanism. PMID- 22829961 TI - Schizandrin, an antioxidant lignan from Schisandra chinensis, ameliorates Abeta1 42-induced memory impairment in mice. AB - In the present study, we examined the effect of schisandrin (SCH) of Schisandra chinensis on the amyloid-beta(1-42)- (Abeta(1-42)-) induced memory impairment in mice and elucidated the possible antioxidative mechanism. Mice were intracerebroventricular (i.c.v.) injected with the aggregated Abeta(1-42) and then treated with SCH (4, 12, and 36 mg/kg body weight) or donepezil (DPZ), a reference drug (0.65 mg/kg) by intragastric infusion for 14 days. Noncognitive disturbances and cognitive performance were evaluated by locomotor activity test, Y-maze test, and water maze test. Antioxidative enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and levels of malondialdehyde (MDA), glutathione (GSH), and oxidized glutathione (GSSG) within the cerebral cortex and hippocampus of mice were measured to elucidate the mechanism. Our results showed that SCH significantly improved Abeta(1-42)-induced short-term and spatial reference memory impairments in Y-maze test and water maze test. Furthermore, in the cerebral cortex and hippocampus of mice, SOD and GSH-px activities, GSH level, and GSH/GSSG ratio were increased, and levels of MDA and GSSG were decreased by the treatment of SCH. These results suggest that SCH is a potential cognitive enhancer against Alzheimer's disease through antioxidative action. PMID- 22829959 TI - Oxidative stress in genetic mouse models of Parkinson's disease. AB - There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, gene-environment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease. PMID- 22829962 TI - Protective effects of aspirin from cardiac hypertrophy and oxidative stress in cardiomyopathic hamsters. AB - OBJECTIVE: To evaluate the capacity of chronic ASA therapy to prevent cardiac alterations and increased oxidative stress in cardiomyopathic hamsters. METHODS AND RESULTS: Male Syrian cardiomyopathic and age-matched inbred control hamsters received ASA orally from the age of 60 days. Animals were sacrificed at the age of 150, 250, and 350 days to evaluate the time course of cardiac hypertrophy and cardiovascular tissue superoxide anion (O(2)(-)) production. At the age of 150 days, the ventricular weight over body weight ratio, resting heart rate, and cardiovascular O(2)(-) production were much higher in cardiomyopathic hamsters than those in control. At the age of 250 days, in addition to the continual deterioration of these parameters with age, the blood pressure started to fall and the signs of heart failure appeared. In these cardiomyopathic hamsters, chronic ASA treatment (a) completely prevented elevated O(2)(-) production and the NAD(P)H oxidase activity, (b) significantly slowed down the development of the cardiac hypertrophy and fibrosis. CONCLUSIONS: Chronic ASA treatment significantly prevents the deterioration of cardiac function and structure as well as the increased oxidative stress in the cardiomyopathic hamster. Our findings suggest that ASA presents a therapeutic potential to prevent cardiac dysfunction. PMID- 22829963 TI - Preconditioning and acute effects of flavonoids in protecting cardiomyocytes from oxidative cell death. AB - While flavonoids can reportedly protect against cardiac ischemia-reperfusion injury, the relative effectiveness of different flavonoids and the mechanisms involved are unclear. We compared protection by different flavonoids using rat embryonic ventricular H9c2 cells subjected to simulated ischemia-reperfusion (IR) and to tert-butyl hydroperoxide (t-buOOH). Characterization of the IR model showed the relative contributions of glucose, serum, and oxygen deprivation to cell death. With long-term (2-3 day) pretreatment before IR the best protection was given by catechin, epigallocatechin gallate, proanthocyanidins, and ascorbate, which protected at all doses. Quercetin protected (34%) at 5 MUM but was cytotoxic at higher doses. Cyanidin protected mildly (10-15%) at 5 and 20 MUM, while delphinidin had no effect at 5 MUM and was cytotoxic at higher doses. Comparing long-term and acute protection by catechin, a higher concentration was needed for benefit with acute (1 hr) pretreatment. With a pure oxidative stress (t-buOOH) only quercetin significantly protected with 3-day pretreatment, while with short-term (1 h) pretreatments protection was best with quercetin and epigallocatechin gallate. The results suggest catechins to be especially useful as IR preconditioning agents, while quercetin and epigallocatechin gallate may be the most protective acutely in situations of oxidative stress. PMID- 22829964 TI - Wine polyphenols: potential agents in neuroprotection. AB - There are numerous studies indicating that a moderate consumption of red wine provides certain health benefits, such as the protection against neurodegenerative diseases. This protective effect is most likely due to the presence of phenolic compounds in wine. Wine polyphenolic compounds are well known for the antioxidant properties. Oxidative stress is involved in many forms of cellular and molecular deterioration. This damage can lead to cell death and various neurodegenerative disorders, such as Parkinson's or Alzheimer's diseases. Extensive investigations have been undertaken to determine the neuroprotective effects of wine-related polyphenols. In this review we present the neuroprotective abilities of the major classes of wine-related polyphenols. PMID- 22829965 TI - Reactive oxygen species in the signaling and adaptation of multicellular microbial communities. AB - One of the universal traits of microorganisms is their ability to form multicellular structures, the cells of which differentiate and communicate via various signaling molecules. Reactive oxygen species (ROS), and hydrogen peroxide in particular, have recently become well-established signaling molecules in higher eukaryotes, but still little is known about the regulatory functions of ROS in microbial structures. Here we summarize current knowledge on the possible roles of ROS during the development of colonies and biofilms, representatives of microbial multicellularity. In Saccharomyces cerevisiae colonies, ROS are predicted to participate in regulatory events involved in the induction of ammonia signaling and later on in programmed cell death in the colony center. While the latter process seems to be induced by the total ROS, the former event is likely to be regulated by ROS-homeostasis, possibly H(2)O(2)-homeostasis between the cytosol and mitochondria. In Candida albicans biofilms, the predicted signaling role of ROS is linked with quorum sensing molecule farnesol that significantly affects biofilm formation. In bacterial biofilms, ROS induce genetic variability, promote cell death in specific biofilm regions, and possibly regulate biofilm development. Thus, the number of examples suggesting ROS as signaling molecules and effectors in the development of microbial multicellularity is rapidly increasing. PMID- 22829966 TI - Rationally engineered nanoparticles target multiple myeloma cells, overcome cell adhesion-mediated drug resistance, and show enhanced efficacy in vivo. AB - In the continuing search for effective cancer treatments, we report the rational engineering of a multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-adhesion functionalities. Very late antigen-4 (VLA-4) mediated adhesion of multiple myeloma (MM) cells to bone marrow stroma confers MM cells with cell-adhesion-mediated drug resistance (CAM-DR). In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin (Dox) conjugates, simultaneously, to selectively target MM cells and to overcome CAM-DR. Dox was conjugated to the nanoparticles through an acid-sensitive hydrazone bond. VLA-4 antagonist peptides were conjugated via a multifaceted synthetic procedure for generating precisely controlled number of targeting functionalities. The nanoparticles were efficiently internalized by MM cells and induced cytotoxicity. Mechanistic studies revealed that nanoparticles induced DNA double-strand breaks and apoptosis in MM cells. Importantly, multifunctional nanoparticles overcame CAM-DR, and were more efficacious than Dox when MM cells were cultured on fibronectin-coated plates. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors with ~10 fold more drug accumulation and demonstrated dramatic tumor growth inhibition with a reduced overall systemic toxicity. Altogether, we demonstrate the disease driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM. PMID- 22829968 TI - Clonal evolution in UKE-1 cell line leading to an increase in JAK2 copy number. PMID- 22829969 TI - Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model. AB - We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients. PMID- 22829970 TI - Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib. AB - Heat shock protein 90 (Hsp90) is a promising target for anti-tumor therapy. We previously reported the anti-tumor activity of a novel Hsp90 inhibitor, KW-2478, in multiple myeloma (MM) as a single agent. In this study, we examined the combinational effect of KW-2478 and bortezomib, a proteasome inhibitor, in vitro and in vivo. In vitro, KW-2478 enhanced bortezomib-induced cell growth inhibition, both in MM cell lines and primary patient MM cells. The combination of KW-2478 and bortezomib also induced caspase activation in MM cell lines. Interestingly, the combination synergistically enhanced the expression of Hsp70B, a homolog of Hsp70, in human MM cells and peripheral blood mononuclear cells, indicating Hsp70B could be a surrogate biomarker for the combination of Hsp90 and proteasome inhibitors. In vivo, the combination of KW-2478 with bortezomib showed synergistic anti-tumor activity without significant body weight loss in a subcutaneously inoculated human myeloma model. Furthermore, the combination also showed synergistic reduction of tumor burden in bone marrow in an orthotopic myeloma model. Our results strongly suggest that combination of KW-2478 with bortezomib could exhibit enhanced anti-tumor activity against human myeloma. PMID- 22829971 TI - The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. AB - Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations. PMID- 22829972 TI - Does increasing the JAK2V617F assay sensitivity allow to identify more patients with MPN? PMID- 22829967 TI - Pediatric T- and NK-cell lymphomas: new biologic insights and treatment strategies. AB - T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms. PMID- 22829973 TI - Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells. AB - The c-Myb gene encodes the p75(c-Myb) isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is p(c-Mybex9b), which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein-protein interactions and negative regulation. In hematopoietic cells, expression of p(c-Mybex9b) accounts for 10-15% of total c Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of p(c-Mybex9b) and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75(c-Myb), p(c-Mybex9b) is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of p(c Mybex9b) enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of p(c-Mybex9b) reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34(+) cells, without affecting the levels of p75(c-Myb). Together, these studies indicate that expression of the low-abundance p(c-Mybex9b) isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells. PMID- 22829974 TI - Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR-ABL-positive ALL. AB - We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49-76) and 58% (95% CI, 43-70), respectively. Prognostic factor analysis revealed that the major BCR-ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49-9.08); P=0.005 and HR, 6.25 (95% CI, 1.88-20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21-8.50); P=0.019 and HR, 6.92 (95% CI, 2.09-22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR-ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted. PMID- 22829975 TI - Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy. AB - Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or gamma-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL. PMID- 22829976 TI - Enhancement of myeloma development mediated though myeloma cell-Th2 cell interactions after microbial antigen presentation by myeloma cells and DCs. AB - Microbial agents are regarded as a potential cause of tumors, but their direct effects on tumors, such as myeloma, are not well studied. Our studies demonstrated that expression of HLA-DR and CD40 on the myeloma cell membrane surface is upregulated by interferon-gamma and/or microbial antigens (Ags). Unlike prior studies, our study showed that Th2 cells cannot promote myeloma growth directly. However, Bacillus Calmette-Guerin Vaccine (BCGV)-specific Th2 cells stimulated by BCGV-loaded dendritic cells (DCs) promoted myeloma clonogenicity directly when the myeloma cells expressed major histocompatibility complex Class-II molecules (MHC-II) and took up BCGV Ag. B-cell lymphoma 6 (Bcl 6) protein expression and the proportion of HLA-DR(+) or CD40(+) cells were higher in colonies of Th2 cell-stimulated myeloma cells. Furthermore, anti-HLA-DR or neutralizing CD40 antibody could prevent this increase in Bcl-6 expression and colony number. These results indicate that microbes and microbial Ag-specific Th2 cells may directly impact the biology of myeloma and contribute to tumor progression. Activation may be limited to MHC-II(+) myeloma cells that retain B cell and stem cell characteristics. Taken together, our data suggest that factors involved in microbial Ag presentation, such as DCs, Th2 cells and so on, are potential targets for myeloma therapeutic intervention. PMID- 22829977 TI - T-cell immunotherapy with a chimeric receptor against CD38 is effective in eradicating chemotherapy-resistant B-cell lymphoma cells overexpressing survivin induced by BMI-1. PMID- 22829978 TI - Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells. AB - The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells. PMID- 22829979 TI - Chemico-genetic strategies to inhibit the leukemic potential of threonine aspartase-1. PMID- 22829980 TI - beta1 integrin deletion enhances progression of prostate cancer in the TRAMP mouse model. AB - beta1 integrin regulates the response of both normal and cancer cells to their local environment. Although mis-localised in prostate cancer, the role beta1 integrin plays in prostate development and carcinogenesis remains unknown. To assess the role of beta1 integrin in vivo, we conditionally deleted beta1 integrin from prostate epithelium and subsequently crossed these mice to the TRAMP prostate carcinogenesis model. Deletion of beta1 integrin following castration and subsequent androgen supplementation resulted in an expansion of the p63-positive basal cell population and decreased differentiation. Consistent with these findings, deletion of beta1 integrin in TRAMP mice decreased animal survival, decreased retention of normal prostate morphology, increased the percentage of tissue with poorly differentiated carcinoma, and increased cell proliferation. This study demonstrates that beta1 integrin regulates several aspects of normal prostate development and in contrast to its role in several other tissues, its loss is associated with increased rates of prostate tumour progression. PMID- 22829981 TI - Fractal cartography of urban areas. AB - In a world in which the pace of cities is increasing, prompt access to relevant information is crucial to the understanding and regulation of land use and its evolution in time. In spite of this, characterization and regulation of urban areas remains a complex process, requiring expert human intervention, analysis and judgment. Here we carry out a spatio-temporal fractal analysis of a metropolitan area, based on which we develop a model which generates a cartographic representation and classification of built-up areas, identifying (and even predicting) those areas requiring the most proximate planning and regulation. Furthermore, we show how different types of urban areas identified by the model co-evolve with the city, requiring policy regulation to be flexible and adaptive, acting just in time. The algorithmic implementation of the model is applicable to any built-up area and simple enough to pave the way for the automatic classification of urban areas worldwide. PMID- 22829982 TI - Spatial distribution of prokaryotic symbionts and ammoxidation, denitrifier bacteria in marine sponge Astrosclera willeyana. AB - The present knowledge of microbial community mainly focus on total sponge, the spatial distribution of microbes in sponges is rarely known, especially those with potential ecological functions. In this study, based on gene library and ? LIBSHUFF analysis, the spatial distribution of prokaryotic symbionts and nitrogen cycling genes in the cortex and endosome sections of sponge Astrosclera willeyana were investigated. A significance difference of bacterial phylotypes between the cortex and endosome was revealed. For example Bacteroidetes, Frankineae and Propionibacterineae were detected only in the endosome, whereas Cyanobacteria, Planctomycetacia and Micrococcineae were only associated with the cortex. Some branches of alpha-Proteobacteria, gamma-Proteobacteria, Corynebacterineae, Acidimicobidae, Crenarchaeota and Euryarchaeota also showed distribution difference. Bacterial denitrifiers and ammonia oxidizing bacteria (AOB) were observed using nirS and amoA genes as markers. Particularly, AOB were only associated with the endosome. This study highlighted the spatial distribution of bacterial symbionts especially those with ammonia oxidization function. PMID- 22829983 TI - Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. AB - FUS is an RNA-binding protein that regulates transcription, alternative splicing, and mRNA transport. Aberrations of FUS are causally associated with familial and sporadic ALS/FTLD. We analyzed FUS-mediated transcriptions and alternative splicing events in mouse primary cortical neurons using exon arrays. We also characterized FUS-binding RNA sites in the mouse cerebrum with HITS-CLIP. We found that FUS-binding sites tend to form stable secondary structures. Analysis of position-dependence of FUS-binding sites disclosed scattered binding of FUS to and around the alternatively spliced exons including those associated with neurodegeneration such as Mapt, Camk2a, and Fmr1. We also found that FUS is often bound to the antisense RNA strand at the promoter regions. Global analysis of these FUS-tags and the expression profiles disclosed that binding of FUS to the promoter antisense strand downregulates transcriptions of the coding strand. Our analysis revealed that FUS regulates alternative splicing events and transcriptions in a position-dependent manner. PMID- 22829984 TI - Avicenna and cataracts: a new analysis of contributions to diagnosis and treatment from the canon. AB - BACKGROUND: Physicians in ancient Persia played an important role in the development of medicine in the medieval era. One of the most influential figures of this era was Abu Ali Sina or Ibn Sina, known as Avicenna in the western world. The author of more than 200 books on medicine and philosophy, Avicenna followed and further expanded on the tradition of western philosophy and medicine introduced by Aristotle, Hippocrates and Galen. Few researchers have looked into the different medical issues in his best known work, the Canon of Medicine, particularly with regard to ophthalmology. In this analysis, Avicenna's views on and contributions to the diagnosis and treatment of cataracts in his Canon were elucidated. METHODS: We first reviewed an electronic copy of the Canon and then reviewed other important sources in traditional medicine including the Kamel-al Sanaeh, Al-Havi (Continents) and Zakhireh-kharazmshahi, available in the Avicenna Special Traditional Medicine Library of Shiraz University of Medical Sciences. We also searched Medline, Embase, Scopus, Iranmedex and Science Iranian Database (SID) with these keywords: "traditional medicine," "Avicenna," "cataract", "Canon", "history", "ophthalmology" and "eye disorders". RESULTS: According to the Canon, nozul-al-maa or cataract is an obstructive disease in which external moisture accumulates between the aqueous humor and the corneal membrane and prevents images from entering the eye. Avicenna classified cataracts on the basis of size, density and color. According to size, he identified two types of cataracts including complete and partial obstruction. According to the Canon, surgical intervention was necessary only for certain indications. Avicenna believed that opacity in the initial stages of cataract could be diminished by medicines and foods, and described several medicines for cataracts. He believed that surgery should be postponed until the liquid accumulation stopped, and the cataract reached its mature state. After surgery, according to Avicenna, the patient should avoid headache-inducing situations because headaches could lead to edema of the layers of the eye. He further emphasized that the patient's psychological status played an important role in the success of surgery. CONCLUSION: An important aspect of Avicenna's contribution to the medical management of cataracts was that he believed they could be cured by medication and nutrition in their early stages without the need for surgery. He also considered the patient's mental status as an important factor contributing to the postoperative prognosis. Our review of Avicenna's writings on eye disorders in the Canon of Medicine suggests that he had a rigorous approach to the diagnosis and management of patients suffering from eye disorders. PMID- 22829985 TI - Subcutaneous forehead island flap for nasal reconstruction. AB - BACKGROUND: Reconstruction of nasal skin after tumor resection is imperative for full patient rehabilitation; and use of similar skin is necessary to achieve best esthetic and functional results. METHODS: This clinical series study represent management of patients with large nasal defects (up to 4x7 cm) using subcutaneous pedicle island paramedian forehead flap, during a period of 2007-2009, 8 patients with large nasal defects were repaired with this flap, among them 5 patients were male and 3 patients were female with mean age of 53 years, all cases were reconstructed with island pedicle flap in a single stage. RESULTS: Good and satisfying results were achieved in all cases except for one case that was operated again for debulking of flap. CONCLUSION: Island paramedian forehead flap provides esthetic and functional results in a single stage reconstruction of defects with various sizes and locations. This variation of forehead flap is a good choice especially for those patients that have problems with cost or problem with multistage reconstruction of nasal defects. PMID- 22829986 TI - Effect of intrathecal midazolam in the severity of pain in cesarean section: a randomized controlled trail. AB - BACKGROUND: The benzodiazepines are used primarily for anxiolysis, amnesia and sedation. However, recent investigations have shown that some forms of this group of drugs have also direct effect on pain. This study aims to determine the effect of midazolam in reducing the severity of pain in women scheduled for elective cesarean section. METHODS: In a prospective, double blind randomized controlled trial, two groups parallel study, was conducted in Imam Reza/Moatazedi Hospital, an affiliate of Kermanshah University of Medical Sciences. Parturient women who met study inclusion criteria were consecutively assigned into either experimental (n=62) or control groups (n=62). Women in the experimental group received bupivacaine (10 mg) plus intrathecal midazolam (2 mg/ml) (BM) and those in the control group received bupivacaine plus normal saline (BNS). The outcome pain severity was measured by Verbal Numerical Rating Scale. RESULTS: In comparison with the BNS group, mothers in the BM group reported a significant relief in pain (15 min and 120 min) after the surgery. There were no significant differences between the groups regarding the intensity of pain 5, 30, 60 and 240 min after the surgery. The average time until the first dose of additional analgesic, per mother's request was 142.18+/-55.19 min in the BNS vs 178.06+/-77.33 min in the BM group. CONCLUSION: Combination of bupivacaine plus intrathecal midazolam was an effective anesthetic technique to provide improvement in pain. The onset of sedation was faster in the BM group compared with the BNS group. The duration of effective analgesia, and the time for regression of sensory analgesia was the same in both groups in our study. However, incidence of nausea and vomiting was higher in the experimental group. PMID- 22829987 TI - Seroepidemiology of HBV infection in South-East of iran; a population based study. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major risk factor of cirrhosis and hepatocellular carcinoma affecting billions of people globally. Since information on its prevalence in general population is mandatory for formulating effective policies, this population based serological survey was conducted in Sistan and Baluchistan, where no previous epidemiological data were available. METHODS: Using random cluster sampling 3989 healthy subjects were selected from 9 districts of Sistan and Baluchistan Province in southeastern Iran. The subjects' age ranged from 6 to 65 years old. Serum samples were tested for HBcAb, HBsAg. Screening tests were carried out by the third generation of ELISA. Various risk factors were recorded and multivariate analysis was performed. RESULTS: The prevalence of HBsAg and HBcAb in Sistan and Baluchistan was 3.38% (95% CI 2.85; 3.98) and 23.58% (95% CI 22.29; 24.93) respectively. We found 8 cases of positive anti-HDV antibody. Predictors of HBsAg or HBcAb in multivariate analysis were age, marital status and addiction. CONCLUSION: The rate of HBV infection in Sistan and Baluchistan was higher than other parts of Iran. Approximately 25% of general population in this province had previous exposure to HBV and 3% were HBsAg carriers. Intrafamilial and addiction were major routes of HBV transmission in this province. PMID- 22829988 TI - Comparative screening of Chlamydia trachomatis infection in women population in tehran, iran. AB - BACKGROUND: There are more than 30 different sexually transmissible agents while the most common one is Chlamydia trachomatis. In this prospective study, we decided to compare the prevalence of infection in symptomatic and asymptomatic females. METHODS: Two hundred sixty urine samples of women in two groups (symptomatic and asymptomatic) were collected from patients attending Mehrad Hospital in Tehran, Iran and tested by polymerase chain reaction. RESULTS: Thirty nine women in both groups were infected (14.99%), while 27/130 subjects were in symptomatic group (20.76%), compared with 12/130 person in asymptomatic group (9.23%). No statistically significant difference was found between two groups. Data analysis showed infection with C. trachomatis in symptomatic women to be significantly associated with history of sexually transmitted infections, white blood cells in urine and epithelial cells in urine. CONCLUSION: The present study recommends that targeted screening programs in high risk sexually active women (like as individuals who had a history of STIs) are needed as part of case finding strategies and treatment. PMID- 22829989 TI - Characteristics of care and caregivers of Alzheimer's patients in elderly care homes: a qualitative research. AB - BACKGROUND: Due to the increase in the number of Alzheimer's patients in Iran and also the limitation of cultural knowledge about caring of these patients, this study was designed to explore the perceptions of Iranian caregivers about caring Alzheimer patients in the elderly care homes. METHODS: A qualitative content analysis method was conducted on two elderly care homes of Shiraz/Iran, during 2009-2011. Fourteen key informants (10 women and 4 men, between 25-35 years of age), who had been working in elderly care homes caring for the elderly with Alzheimer disease for about 1-11 years (Mean=30 months) were selected by purposive sampling method. The caring experience and ability of transferring their experience to others were the main criteria for selection of the participants. They were participated in 2 focus groups and 4 interviews. RESULTS: Nearly, 800 initial codes were extracted and categorized into 3 groups of "multidimensional care", "going along with the patients" and "need to be professional" and 12 subcategories. Although several aspects of care were mentioned by the participants but the main aspect was physical care. Infantilizing the patients was the main feature of care and caring personality was an important characteristic of caregivers. CONCLUSION: An appropriate schedule of care considering main categories and subcategories of this research based on cultural context should be prepared. Moreover, consistent promotion of the schedule, employment of trained staff and plans for continued education for them can improve the quality of care and patient's life in elderly care homes. PMID- 22829990 TI - Helicopter emergency medical service in fars province: the referral trauma center of South of iran. AB - BACKGROUND: Considering the limited available resources, high cost of the helicopter emergency medical service (HEMS), and high load of trauma patients especially in our centers, a careful assessment of HEMS in our center seemed to be necessary for trauma patients. METHODS: From April 2001 to September 2007, the data of all patients transferred by HEMS were extracted including: Annual number of services, clinical category, number of proper or improper services, and rescue time for HEMS and ground ambulance. The criteria for the properly transferred group included: Death or being operated in the first 24 hours of admission, admission in ICU care units, and transfer of more than three patients in one mission. Others were considered as improper group. RESULTS: In this period through 185 flights, 225 victims were transferred. The most common reason of HEMS dispatching was trauma. The most difference of rescue time between ground ambulance and HEMS was recorded in Lamerd that was transferring patients with HEMS needed 3 hours less than ground ambulance. However, in Sarvestan, Dashte Arjan, and Marvdasht, transferred patients with ground ambulance needed less time than air transfer. Most of transferred patients were from Kazeroon, Nourabad and Lamerd respectively while 46.3% of patients were in the proper group, and the rest were considered as improper group. CONCLUSION: Our study revealed that helicopter dispatch to the cities like Lamerd, Lar, Khonj, Abadeh can be more effective, whereas, for the towns like Marvdasht, Dashte-Arjan, Sarvestan, Sepidan, Saadatshar, Tang Abolhayat use of HEMS should be limited to specific conditions. Our study showed inclusion of physicians in the decision making team increased the number of transferred cases. PMID- 22829991 TI - Development of a valid and reliable diabetes empowerment scale: an Iranian version. AB - BACKGROUND: Patient empowerment can enhance the outcomes of care such as metabolic control as well as quality of their life. This study evaluates the Iranian version for development of a valid and reliable diabetes empowerment scale. METHODS: Validity and reliability of Iranian version of Diabetes Empowerment Scale (DES-LF) were measured through a cross-sectional study. DES-LF was evaluated through a qualitative and quantitative study by 160 type 2 diabetic patients. RESULTS: Reliability and validity of the scale and its 3 subscales, namely, managing the psychosocial aspects of diabetes (alpha=0.94), assessing dissatisfaction and readiness to change (alpha=0.96), and setting and achieving diabetes goals (alpha=0.96) were approved by a psychometric analysis. CONCLUSION: Findings approved the reliability and validity of the Iranian version of DES-LF for patient education and psychosocial interventions among Iranian people with type 2 diabetes. PMID- 22829992 TI - Second Generation of HIV Surveillance System: A Pattern for Iran. AB - BACKGROUND: For the purpose of minimizing the HIV/AIDS epidemic effects, one of the programs is the promotion of scientific methods and setting of the suitable surveillance systems. The present research was conducted to design the HIV/AIDS surveillance system in Iran applying WHO recommendations and the experience of some countries. METHODS: In 2009, based on the country's requirements, the HIV/AIDS surveillance system was proposed and designed for Iran. The Delphi technique was utilized to find the views of experts. Data analysis was conducted based on a comparison of the attributes of the HIV/AIDS surveillance systems in the countries under consideration using a descriptive and theoretical analysis. RESULTS: The model was approved obtaining the final score of 36.3 out of 44, viz 82.5%. CONCLUSION: Designing and performing of the HIV/AIDS surveillance pattern in the direction of "second generation of HIV/AIDS surveillance" can be considered as an important step in the improvement of the patient's control and precaution of HIV/AIDS. PMID- 22829993 TI - Primary Solitary Osseous Hodgkin's Lymphoma: A Case Report and Review of the Literature. PMID- 22829994 TI - The effect of ondansetron in prevention of postoperative shivering after general anesthesia in gynecological surgery. PMID- 22829995 TI - The views of medical students on elder discrimination. PMID- 22829996 TI - Target organ damage in hypertension. PMID- 22829997 TI - Use of fluorochrome-labeled inhibitors of caspases to detect neuronal apoptosis in the whole-mounted lamprey brain after spinal cord injury. AB - Apoptosis is a major feature in neural development and important in traumatic diseases. The presence of active caspases is a widely accepted marker of apoptosis. We report here the development of a method to study neuronal apoptotic death in whole-mounted brain preparations using fluorochrome-labeled inhibitors of caspases (FLICA). As a model we used axotomy-induced retrograde neuronal death in the CNS of larval sea lampreys. Once inside the cell, the FLICA reagents bind covalently to active caspases causing apoptotic cells to fluoresce, whereas nonapoptotic cells remain unstained. The fluorescent probe, the poly caspase inhibitor FAM-VAD-FMK, was applied to whole-mounted brain preparations of larval sea lampreys 2 weeks after a complete spinal cord (SC) transection. Specific labeling occurred only in identifiable spinal-projecting neurons of the brainstem previously shown to undergo apoptotic neuronal death at later times after SC transection. These neurons also exhibited intense labeling 2 weeks after a complete SC transection when a specific caspase-8 inhibitor (FAM-LETD-FMK) served as the probe. In this study we show that FLICA reagents can be used to detect specific activated caspases in identified neurons of the whole-mounted lamprey brain. Our results suggest that axotomy may cause neuronal apoptosis by activation of the extrinsic apoptotic pathway. PMID- 22829998 TI - Perioperative optimization of patients undergoing bariatric surgery. AB - Bariatric surgery is fast becoming an efficient and safe method of weight reduction, especially for patients in whom conservative measures have failed. As the obese population of the world increases, so will the number of patients requesting or requiring surgical weight loss methods. Bariatric patients however have numerous co-morbidities that make their operative course more difficult, and therefore is important to have a good understanding of the important issues surrounding their pre, peri and post operative management. This article aims to educate the reader about optimal management of the bariatric surgical patient. PMID- 22829999 TI - TB and HIV Therapeutics: Pharmacology Research Priorities. AB - An unprecedented number of investigational drugs are in the development pipeline for the treatment of tuberculosis. Among patients with tuberculosis, co-infection with HIV is common, and concurrent treatment of tuberculosis and HIV is now the standard of care. To ensure that combinations of anti-tuberculosis drugs and antiretrovirals are safe and are tested at doses most likely to be effective, selected pharmacokinetic studies based on knowledge of their metabolic pathways and their capacity to induce or inhibit metabolizing enzymes of companion drugs must be conducted. Drug interaction studies should be followed up by evaluations in larger populations to evaluate safety and pharmacodynamics more fully. Involving patients with HIV in trials of TB drugs early in development enhances the knowledge gained from the trials and will ensure that promising new tuberculosis treatments are available to patients with HIV as early as possible. In this review, we summarize current and planned pharmacokinetic and drug interaction studies involving investigational and licensed tuberculosis drugs and antiretrovirals and suggest priorities for tuberculosis-HIV pharmacokinetic, pharmacodynamic, and drug-drug interaction studies for the future. Priority studies for children and pregnant women with HIV and tuberculosis co-infection are briefly discussed. PMID- 22830000 TI - Foetal haemoglobin, erythrocytes containing foetal haemoglobin, and hematological features in congolese patients with sickle cell anaemia. AB - High HbF levels and F cells are correlated with reduced morbidity and mortality in sickle cell disease (SCD). This paper was designed to determine the HbF and F cells levels in Congolese sickle cell anemia (SCA) patients in order to determine their impact on the expression of SCD. Population and Method. HbF levels were measured in 89 SCA patients (mean age 11.4 yrs) using a standard HPLC method. F cell quantitation was done in a second group of SCA patients (n = 42, mean age 8.9 yrs) and compared with a control group (n = 47, mean age 5 yrs). F cells were quantified by a cytofluorometric system (MoAb-HbF-FITC; cut off at 0.5%). Results. The mean value of HbF was 7.2% +/- 5.0 with heterogeneous distribution, most patients (76%) having HbF < 8%. Mean values of F-cells in SCA patients and control group were 5.4% +/- 7.6 (median: 2.19%; range 0,0-30,3%) and 0.5% +/- 1.6 (median 0.0, range 0-5.18), respectively. SCA patients with F cells >4.5% developed less painful crisis and had higher percentage of reticulocytes. Conclusion. Congolese SCA patients displayed low levels of HbF and F-cells that contribute to the severity of SCD. PMID- 22830001 TI - Trends of Components of the Metabolic Syndrome in German First Graders Throughout 10 Years: The PEP Family Heart Study. AB - Although childhood overweight and obesity are increasing worldwide, some countries report trends for stabilization. However, the trend for the potentially atherogenic components of the metabolic syndrome (MetS) in children and adolescents is not well understood. Therefore, the purpose of this study was to analyze the trend of the five components of over 10 years in 2228 first graders aged 6 years. Waist circumference (WC) remained mainly unchanged between 1994 and 2003 whereas the other four components continuously decreased. In boys and girls mean values of triglycerides (-25.9% and -28.6%, resp.), HDL cholesterol (-19.8% and -23.4%, resp.), fasting glucose (-7.3% and -9%, resp.), systolic (-3.8% and 4.1%, resp.), and diastolic (-10.2% and -9.7%, resp.) blood pressure significantly decreased. Whereas the prevalence of abdominal adiposity was stable at baseline and after 10 years (-1% in boys and +2% in girls), the prevalence of hypertension, hypertriglyceridemia, low HDL-C, and glucose was very low without any trend. PMID- 22830002 TI - Assessment of metformin as an additional treatment to therapeutic lifestyle changes in pediatric patients with metabolic syndrome. AB - Objective. To assess the effectiveness of metformin and therapeutic lifestyle changes (TLCs) in a clinical setting, compared to TLC alone in adolescents with metabolic syndrome (MS). Methodology. This study was a retrospective trial consisting of 60 patients, aged 8-18 years, who were treated for MS at an outpatient clinic. Two groups were formed: the metformin group (M group) and the control group (C group). The M group had been given metformin along with TLC, and the C group had been given TLC alone. Several outcome measures were obtained; the main outcome measure was measuring the change in percentile and z-score of weight and BMI. Results. There were no significant differences between the two groups at the conclusion of the study, except for height percentile (P = 0.02) and z-score (P = 0.03). Both groups showed promising significant intragroup decreases in weight z-score but BMI percentile and z-score were only significantly decreased in the M group. Conclusion. Metformin at an average dose of 1033 mg, when added to TLC, did not show any clinically important efficacy compared to TLC alone in a pediatric population with MS. However, both groups made significant changes in a positive direction, which may be solely due to TLC. PMID- 22830003 TI - Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer. AB - Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5 fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes. PMID- 22830006 TI - Building the clinical bridge to support nursing effectiveness science. PMID- 22830005 TI - Nursing Challenges in Motivating Nursing Students through Clinical Education: A Grounded Theory Study. AB - Nurses are the first role models for students in clinical settings. They can have a significant role on students' motivation. The purpose of this study was to explore the understanding of nursing students and instructors concerning the role of nurses in motivating nursing students through clinical education. The sampling was first started purposefully and continued with theoretical sampling. The study collected qualitative data through semistructured and interactive interviews with 16 nursing students and 4 nursing instructors. All interviews were recorded, transcribed, and analyzed using grounded theory approach. One important pattern emerged in this study was the "concerns of becoming a nurse," which itself consisted of three categories: "nurses clinical competency," "nurses as full scale mirror of the future," and "Monitoring and modeling through clinical education" (as the core variable). The findings showed that the nurses' manners of performance as well as the profession's prospect have a fundamental role in the process of formation of motivation through clinical education. Students find an insight into the nursing profession by substituting themselves in the place of a nurse, and as result, are or are not motivated towards the clinical education. PMID- 22830004 TI - Fertility-sparing surgery for early-stage cervical cancer. AB - Nowadays cervical cancer is diagnosed in many women who still want to have children. This led to the need to provide fertility-sparing treatments. The main goal is to maintain reproductive ability without decreasing overall and recurrence-free survival. In this article, we review data on procedures for fertility preservation, namely, vaginal and abdominal trachelectomy, less invasive surgery and neoadjuvant chemotherapy. For each one, oncological and obstetrical outcomes are analyzed. Comparing to traditionally offered radical hysterectomy, the overall oncologic safety is good, with promising obstetrical outcomes. PMID- 22830007 TI - The impact of invisibility on the health of migrant farmworkers in the southeastern United States: a case study from georgia. AB - Migrant farmworkers represent one of the most marginalized and underserved populations in the United States. Acculturation theory cannot be easily mapped onto the transnational experience of migrant farmworkers, who navigate multiple physical and cultural spaces yearly, and who are not recognized by the state they constitute, "the Citizen's Other" (Kerber, 2009). This paper utilizes narrative analysis of a case study to illustrate, through the relationship of the narrator to migrant farmworkers and years of participant observation by the coauthors, how isolation from family and community, as well as invisibility within institutions, affect the health and well-being of migrant farmworkers in southeastern Georgia. Invisibility of farmworkers within institutions, such as health care, the educational system, social services, domestic violence shelters, and churches contribute to illness among farmworkers. The dominant American discourse surrounding immigration policy addresses the strain immigrants put on the social systems, educational system, and the health care system. Nurses who work with farmworkers are well positioned to bring the subjective experience of farmworkers to light, especially for those engaged with socially just policies. Those who contribute to the abundant agricultural produce that feeds Americans deserve the recognition upon which social integration depends. PMID- 22830008 TI - Oral health. PMID- 22830009 TI - Nursing leadership in a rapidly aging society: implications of "the future of nursing" report in Japan. AB - The recent US Institute of Medicine (IOM) report about the future of nursing highlights the areas where nurses can serve, contribute, and move forward to improve health care in the United States. Japanese nursing scholars examined the IOM report for its implications in the Japanese context and explored the future of nursing in Japan. The purpose of this paper is to provide support for the premise that the report's recommendations could have implications for the future of nursing outside of the United States, especially in Japan. Particular areas and activities by nurses in Japan will be presented as examples of nurses taking leadership in designing care for the rapidly aging society of Japan. PMID- 22830010 TI - Patient participation in surgical treatment decision making from the patients' perspective: validation of an instrument. AB - The aim of this paper is to describe the development of a new, brief, easy-to administer self-reported instrument designed to assess patient participation in decision making in surgical treatment. We describe item generation, psychometric testing, and validity of the instrument. The final scale consisted of four factors: information dissemination (5 items), formulation of options (4 items), integration of information (4 items), and control (3 items). The analysis demonstrated a reasonable level of construct validity and reliability. The instrument applies to patients in surgical wards and can be used to identify the health services that are being provided and the areas that could strengthen patient participation. PMID- 22830011 TI - Putting the evidence into preceptor preparation. AB - The term evidence-based practice refers to the utilization of knowledge derived from research. Nursing practice, however, is not limited to clinical practice but also encompasses nursing education. It is, therefore, equally important that teaching preparation is derived from evidence also. The purpose of this study was to examine whether an evidence-based approach to preceptor preparation influenced preceptors in a assuming that role. A qualitative method using semistructured interviews was used to collect data. A total of 29 preceptors were interviewed. Constant comparative analysis facilitated examination of the data. Findings indicate that preceptors were afforded an opportunity to participate in a preparatory process that was engaging, enriching, and critically reflective/reflexive. This study has generated empirical evidence that can (a) contribute substantively to effective preceptor preparation, (b) promote best teaching practices in the clinical setting, and (c) enhance the preceptorship experience for nursing students. PMID- 22830013 TI - Increased Cell-Matrix Adhesion upon Constitutive Activation of Rho Proteins by Cytotoxic Necrotizing Factors from E. Coli and Y. Pseudotuberculosis. AB - Cytotoxic necrotizing factors (CNFs) encompass a class of autotransporter toxins produced by uropathogenic E. coli (CNF1) or Y. pseudotuberculosis (CNFy). CNF toxins deamidate and thereby constitutively activate RhoA, Rac1, and Cdc42. In this study, the effects of CNF1 on cell-matrix adhesion are analysed using functional cell-adhesion assays. CNF1 strongly increased cell-matrix binding of suspended Hela cells and decreased the susceptibly of cells to trypsin-induced cell detachment. Increased cell-matrix binding was also observed upon treatment of Hela cells with isomeric CNFy, that specifically deamidates RhoA. Increased cell-matrix binding thus appears to depend on RhoA deamidation. In contrast, increased cell spreading was specifically observed upon CNF1 treatment, suggesting that it rather depended on Rac1/Cdc42 deamidation. Increased cell matrix adhesion is further presented to result in reduced cell migration of adherent cells. In contrast, migration of suspended cells was not affected upon treatment with CNF1 or CNFy. CNF1 and CNFy thus reduced cell migration specifically under the condition of pre-established cell-matrix adhesion. PMID- 22830012 TI - Antiangiogenic therapy for glioma. AB - Currently, antiangiogenic agents are routinely used for the treatment of patients with glioma. However, despite advances in pharmacological and surgical therapy, glioma remains an incurable disease. Indeed, the formation of an abnormal tumor vasculature and the invasion of glioma cells along neuronal tracts are proposed to comprise the major factors that are attributed to the therapeutic resistance of these tumors. The development of curative therapeutic modalities for the treatment of glioma requires further investigation of the molecular mechanisms regulating angiogenesis and invasion. In this review, we discuss the molecular characteristics of angiogenesis and invasion in human malignant glioma, we present several available drugs that are used or can potentially be utilized for the inhibition of angiogenesis in glioma, and we focus our attention on the key mediators of the molecular mechanisms underlying the resistance of glioma to antiangiogenic therapy. PMID- 22830014 TI - Progress in therapy development for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS. PMID- 22830015 TI - Pathological roles of wild-type cu, zn-superoxide dismutase in amyotrophic lateral sclerosis. AB - Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, many in vitro and in vivo studies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1 positive inclusions in spinal motor neurons is a pathological hallmark in SOD1 related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations in sod1 gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS. PMID- 22830016 TI - A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression. AB - Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of -1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of -.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline. PMID- 22830018 TI - Screening for Microalbuminuria in HIV-Positive Children in Enugu. AB - Background. Human immunodeficiency virus associated nephropathy (HIVAN) is a rapidly progressive chronic renal parenchymal disease that occurs in HIV-infected individuals and manifests commonly as proteinuria, which is preceded by microalbuminuria (MA). This clinical entity is defined as a spot urine albumin of 20-200 mg/L. Objectives. To determine the prevalence of microalbuminuria in HIV positive children in UNTH, Enugu and compare it with that of HIV-negative children. Methods. A total of 154 HIV positive children aged 18 months to 14 years and 154 HIV-negative children of corresponding attributes were screened for microalbuminuria, using Micral test II strip which has a sensitivity of 90-99%. Results. No child among the groups (HIV positive and negative) had microalbuminuria. Majority (96.0%) of HIV-positive children had nonadvanced HIV disease at the time of the study (P = 0.00). About 77.3% were using HAART (P < 0.0001), the mean CD4 cell count of the subjects was 709.2 +/- 443.9 cells/mm(3); while 78.0% had nonsevere immunosuppression (P = 0.00). Furthermore, HIV-positive children with severe immunosuppression were younger and had shorter duration of treatment. Conclusion. Microalbuminuria may not be very common in Nigerian children irrespective of their HIV status. PMID- 22830017 TI - Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance. AB - Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF IR signaling has been shown to improve response to trastuzumab in trastuzumab naive and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over expressing breast cancers that have progressed on trastuzumab treatment. PMID- 22830019 TI - Renal Development and Blood Pressure in Offspring from Dams Submitted to High Sodium Intake during Pregnancy and Lactation. AB - Exposure to an adverse environment in utero appears to programme physiology and metabolism permanently, with long-term consequences for health of the fetus or offspring. It was observed that the offspring from dams submitted to high-sodium intake during pregnancy present disturbances in renal development and in blood pressure. These alterations were associated with lower plasma levels of angiotensin II (AII) and changes in renal AII receptor I (AT(1)) and mitogen activated protein kinase (MAPK) expressions during post natal kidney development. Clinical and experimental evidence show that the renin-angiotensin system (RAS) participates in renal development. Many effects of AII are mediated through MAPK pathways. Extracellular signal-regulated protein kinases (ERKs) play a pivotal role in cellular proliferation and differentiation. In conclusion, high-sodium intake during pregnancy and lactation can provoke disturbances in renal development in offspring leading to functional and structural alterations that persist in adult life. These changes can be related at least in part with the decrease in RAS activity considering that this system has an important role in renal development. PMID- 22830020 TI - Hippo and rassf1a Pathways: A Growing Affair. AB - First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases. PMID- 22830022 TI - "Convivencia" groups: building active and healthy communities of older adults in Brazil. AB - In old age, social groups can be a crucial component for health and well-being. In 2009-2010, a follow-up survey was carried out in Florianopolis, Brazil to understand the impact of a variety of programs established since 2002 that were designed to enhance social activities among the older adult population. This study employed two surveys within the population of older adults in Florianopolis. The first survey interviewed a total of 875 older adults in 2002, and the second survey involved 1,705 older adults between 2009 and 2010. By 2010, many new programs were offered in the community and the enrollment of older adults in social programs followed similar trends. "Convivencia" groups stood out as extremely popular social groups among this population. This paper discusses some of the potential outcomes associated with participation in "convivencia" groups. PMID- 22830023 TI - Response to acute psychophysical stress and 24-hour glycemic control in healthy older people. AB - We examined the relation between stress reactivity and 24 h glycemic control in 17 inactive, healthy older people (>=60 years) under both a novel psychophysical stress and a seated control condition. Plasma cortisol was measured over the course of the stress and recovery periods. Glycemic control was determined over the subsequent 3 h from an oral glucose tolerance test (OGTT) and over 24 h via continuous glucose monitoring (CGM). We observed significant (P < 0.05) elevations in perceived stress, cardiovascular activity, and peak cortisol response at 30 min (10.6 +/- 3.1 versus 8.6 +/- 2.6 MUg.dL(-1), resp.) during the stress compared with the control condition; however, 3 h OGTT glucose and insulin responses were similar between conditions. The CGM data suggested a 30-40 min postchallenge delay in peak glucose response and attenuated glucose clearance over the 6 h following the stress condition, but these alterations were not statistically significant. Healthy older people may demonstrate minimal disruption in metabolic resiliency following everyday psychological stress. PMID- 22830021 TI - Dynamic Association between HIV-1 Gag and Membrane Domains. AB - HIV-1 particle assembly is driven by the structural protein Gag. Gag binds to and multimerizes on the inner leaflet of the plasma membrane, eventually resulting in formation of spherical particles. During virus spread among T cells, Gag accumulates to the plasma membrane domain that, together with target cell membrane, forms a cell junction known as the virological synapse. While Gag association with plasma membrane microdomains has been implicated in virus assembly and cell-to-cell transmission, recent studies suggest that, rather than merely accumulating to pre-existing microdomains, Gag plays an active role in reorganizing the microdomains via its multimerization activity. In this paper, we will discuss this emerging view of Gag microdomain interactions. Relationships between Gag multimerization and microdomain association will be further discussed in the context of Gag localization to T-cell uropods and virological synapses. PMID- 22830025 TI - Transcriptional Regulation of the p53 Tumor Suppressor Gene in S-Phase of the Cell-Cycle and the Cellular Response to DNA Damage. AB - The p53 tumor suppressor induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage or other cellular stressors and thus participates in maintaining genome stability. Numerous studies have demonstrated that p53 transcription is activated before or during early S-phase in cells progressing from G(0)/G(1) into S-phase through the combined action of two DNA-binding factors RBP-Jkappa and C/EBPbeta-2. Here, we review evidence that this induction occurs to provide available p53 mRNA in order to prepare the cell for DNA damage in S-phase, this ensuring a rapid response to DNA damage before exiting this stage of the cell cycle. PMID- 22830024 TI - The mutations associated with dilated cardiomyopathy. AB - Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM). The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes. PMID- 22830027 TI - Analysis on the incidence of the fibularis quartus muscle using magnetic resonance imaging. AB - Objective. Quantify the presence of the fibularis quartus muscle and correlate it with the individual's sex and concomitant presence of the fibularis tertius muscle. Materials and Methods. We evaluated 211 magnetic resonance examinations (43.13% men and 56.87% women) on the ankle and hindfoot, produced between 2009 and 2011. Results. The fourth fibularis muscle was found to be present in 7.62% of the examinations and 75% of these also contained the fibularis tertius muscle. Conclusion. The incidence of the fourth fibularis muscle is variable; moreover, its incidence does not depend on the individual's gender or the presence of the fibularis tertius muscle. PMID- 22830026 TI - Developmental perturbation induced by maternal asthma during pregnancy: the short and long-term impacts on offspring. AB - Maternal asthma is a common disease to complicate human pregnancy. Epidemiological studies have identified that asthma during pregnancy increases the risk of a number of poor outcomes for the neonate including growth restriction, lower birthweight, preterm delivery, neonatal resuscitation, and stillbirth. Asthma therefore represents a significant health burden to society and could have an impact on the lifelong health of the children of women with asthma. Our research has identified that maternal asthma in pregnancy induces placental dysfunction and developmental perturbation in the fetus in a sex specific manner. These alterations in development could increase the risk of metabolic disease in adulthood of children of asthmatic mothers, especially females. In this paper, we will discuss the evidence currently available that supports the hypothesis that children of mothers with asthma may be at risk of lifelong health complications which include diabetes and hypertension. PMID- 22830028 TI - Expression and Function of Ephrin-B1 and Its Cognate Receptor EphB2 in Human Abdominal Aortic Aneurysm. AB - We examined the expression of ephrin-B1 and its cognate receptor EphB2, key regulators of angiogenesis and embryogenesis, in human abdominal aortic aneurysm (AAA) and analyzed their functional roles in cell migration. From 10 patients (9 males and 1 female; age, 68.5 +/- 2.4) who underwent vascular surgery for AAA, we obtained AAA and adjacent control tissues. Using real-time RT-PCR, we analyzed expression of ephrin-B1 and EphB2. We also histologically localized these molecules in AAA tissues. Finally, effects of ephrin-B1 and EphB2 on inflammatory cell chemotaxis were examined by cell migration assay. Expression levels of ephrin-B1 (0.410 +/- 0.046 versus 1.198 +/- 0.252, P = 0.027) and EphB2 (0.764 +/ 0.212 versus 1.272 +/- 0.137, P = 0.594) were higher in AAA than normal control. Both ephrin-B1 and EphB2 were expressed in macrophages, T lymphocytes, and endothelial cells within AAA. In chemotaxis assay, ephrin-B1 and EphB2 inhibited mononuclear-cell chemotaxis induced by stromal derived factor-1 down to 54.7 +/- 12.7% (P = 0.01) and 50.7 +/- 13.1% (P = 0.01), respectively. These data suggest that ephrin-B1 and EphB2 might be functional in human adult inflammatory cells and involved in the pathogenesis of AAA, although specific roles of these molecules should further be sought. PMID- 22830029 TI - A Model of Left Ventricular Dysfunction Complicated by CAWS Arteritis in DBA/2 Mice. AB - It was reported previously that a Candida albicans water-soluble fraction (CAWS), including a mannoprotein and beta-glucan complex, has strong potency in inducing fatal necrotizing arteritis in DBA/2 mice. In this study, histopathological changes and cardiac function were investigated in this system. One mg/day of CAWS was given to DBA/2 mice via peritoneal injection for five days. The CAWS-treated DBA/2 mice were induced aortitis and died at an incidence of 100% within several weeks. Histological findings included stenosis in the left ventricular outflow tract (LVOT) and severe inflammatory changes of the aortic valve with fibrinoid necrosis. Cardiomegaly was observed and heart weight increased 1.62 fold (P < 0.01). Echocardiography revealed a severe reduction in contractility and dilatation of the cavity in the left ventricle (LV): LV fractional shortening (LVFS) decreased from 71% to 38% (P < 0.01), and the LV end-diastolic diameter (LVDd) increased from 2.21 mm to 3.26 mm (P < 0.01). The titer of BNP mRNA increased in the CAWS-treated group. Severe inflammatory changes resulting from CAWS brought about lethal LV dysfunction by aortic valve deformation with LVOT stenosis. This system is proposed as an easy and useful experimental model of heart failure because CAWS arteritis can be induced by CAWS injection alone. PMID- 22830030 TI - Reversible cerebral vasoconstriction syndrome: an important cause of acute severe headache. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized and important cause of acute headache. The majority of these patients develop potentially serious neurological complications. Rigorous investigation is required to exclude other significant differential diagnoses. Differentiating RCVS from subarachnoid haemorrhage (SAH) and primary angiitis of the central nervous system (PACNS) may be difficult but has important therapeutic implications. This paper describes what is currently known about the epidemiology, pathophysiology, clinical, and diagnostic features of the syndrome, an approach to investigation, a summary of treatments, and what is known of prognosis. PMID- 22830031 TI - Basal cell carcinoma in asians: a retrospective analysis of ten patients. AB - Background. Few studies have been done that characterize basal cell carcinoma (BCC) in Asians because this tumor is relatively uncommon in this population group. Objective. To characterize BCC in Asians. Methods. We retrospectively examined fifteen patient variables and eight tumor variables of ten Asian patients with BCC and compared these results to those of thirty matched Caucasian controls with BCC. Results. Asians developed their first BCC at an older age than the age of first BCC in Caucasian controls (68.9 years versus 58.3 years; P < 0.05). During their lifetime, Asians had fewer BCCs than the number of BCCs in Caucasian controls (1.11 versus 5.41; P < 0.02), despite a similar estimated lifetime daily sun exposure (hours/day) for both groups. Compared to BCCs in Caucasian controls, a higher percentage of BCCs in Asians were clinically pigmented (50.0% versus 3.3%; P < 0.01). Conclusion. Asians develop BCCs later in life and develop fewer BCCs over their lifetime than Caucasians, despite similar estimated lifetime daily sun exposure. This finding is probably due to skin pigmentation in Asians being more protective of ultraviolet light than skin pigmentation in Caucasians. PMID- 22830033 TI - Nanoparticles for Targeted Delivery of Active Agents against Tumor Cells. PMID- 22830032 TI - Index of CD34+ Cells and Mononuclear Cells in the Bone Marrow of Spinal Cord Injury Patients of Different Age Groups: A Comparative Analysis. AB - Introduction. Recent evidence of safety and efficacy of Bone Marrow Mononuclear Cells (BMMNC) in spinal cord injury makes the Bone Marrow (BM) CD34+ percentage and the BMMNC count gain significance. The indices of BM that change with body mass index and aging in general population have been reported but seldom in Spinal Cord Injury (SCI) victims, whose parameters of relevance differ from general population. Herein, we report the indices of BMMNC in SCI victims. Materials and Methods. BMMNCs of 332 SCI patients were isolated under GMP protocols. Cell count by Trypan blue method and CD34+ cells by flow cytometry were documented and analysed across ages and gender. Results. The average BMMNC per ml in the age groups 0-20, 21-40, 41-60, and 61-80 years were 4.71, 4.03, 3.67, and 3.02 million and the CD34+ were 1.05%, 1.04%, 0.94%, and 0.93% respectively. The decline in CD34+ was sharp between 20-40 and 40-60 age groups. Females of reproductive age group had lesser CD34+. Conclusion. The BMMNC and CD34+ percentages decline with aging in SCI victims. Their lower values in females during reproductive age should be analysed for relevance to hormonal influence. This study offers reference values of BMMNC and CD34+ of SCI victims for successful clinical application. PMID- 22830034 TI - Use of the signature Fatty Acid 16:1omega5 as a tool to determine the distribution of arbuscular mycorrhizal fungi in soil. AB - Biomass estimation of arbuscular mycorrhiza (AM) fungi, widespread plant root symbionts, commonly employs lipid biomarkers, predominantly the fatty acid 16:1omega5. We briefly reviewed the application of this signature fatty acid, followed by a case study comparing biochemical markers with microscopic techniques in an arable soil following a change to AM non-host plants after 27 years of continuous host crops, that is, two successive cropping seasons with wheat followed by amaranth. After switching to the non-host amaranth, spore biomass estimated by the neutral lipid fatty acid (NLFA) 16:1omega5 decreased to almost nil, whereas microscopic spore counts decreased by about 50% only. In contrast, AM hyphal biomass assessed by the phospholipid (PLFA) 16:1omega5 was greater under amaranth than wheat. The application of PLFA 16:1omega5 as biomarker was hampered by background level derived from bacteria, and further enhanced by its incorporation from degrading spores used as microbial resource. Meanwhile, biochemical and morphological assessments showed negative correlation for spores and none for hyphal biomass. In conclusion, the NLFA 16:1omega5 appears to be a feasible indicator for AM fungi of the Glomales group in the complex field soils, whereas the use of PLFA 16:1omega5 for hyphae is unsuitable and should be restricted to controlled laboratory studies. PMID- 22830035 TI - Involvement of the ligninolytic system of white-rot and litter-decomposing fungi in the degradation of polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) are natural and anthropogenic aromatic hydrocarbons with two or more fused benzene rings. Because of their ubiquitous occurrence, recalcitrance, bioaccumulation potential and carcinogenic activity, PAHs are a significant environmental concern. Ligninolytic fungi, such as Phanerochaete chrysosporium, Bjerkandera adusta, and Pleurotus ostreatus, have the capacity of PAH degradation. The enzymes involved in the degradation of PAHs are ligninolytic and include lignin peroxidase, versatile peroxidase, Mn peroxidase, and laccase. This paper summarizes the data available on PAH degradation by fungi belonging to different ecophysiological groups (white-rot and litter-decomposing fungi) under submerged cultivation and during mycoremediation of PAH-contaminated soils. The role of the ligninolytic enzymes of these fungi in PAH degradation is discussed. PMID- 22830036 TI - IRS1 Expression in Hepatic Tissue and Leukocytes in Chronic Hepatitis C Virus Infected Patients: A Comparative Study. AB - Aims. To determine lymphocyte IRS (IRS1 cells) in HCV patients, correlating it to liver IRS (IRS 1liver) and HOMA-IR. This study tested the hypothesis that IRS1 cells expression can be used as insulin resistance (IR) marker in HCV-infected patients. IRS1 cells were not studied before in HCV infection. Materials and Methods. HCV chronically infected patients, naive, nonobese, noncirrhotic, and nondiabetic were prospectively included and compared to controls (blood donors). Blood was taken, and leukocytes were separated. IRS1 was determined by real-time PCR. Liver tissue was obtained from transplant donors as controls. Results. 41 HCV-positive patients were included, 26 males (60.5%); mean age of 45 (+/-7.9); 33 (80.5%) from genotype 1. 6 out of 12 controls were males (50%); mean age was 26.7 (+/-3.2). There was expression of IRS1 in leukocytes. The median IRS1 cells (HCV) were 0.061 (0.004 to 0.469); the median IRS 1liver (HCV) was 0.0003 (0.00002 to 0.0186)-lower than in controls (resp., P = 0.005 and P = 0.018). HOMA IR had an inverse correlation with IRS 1liver (P = 0.04). There was no correlation between IRS1 liver and IRS1 cells (P = 0.930). Conclusions. There was expression of IRS1 in leukocytes. IRS1 cells and IRS1 liver were lower in HCV patients than in controls. PMID- 22830038 TI - Hematological Manifestations of SLE at Initial Presentation: Is It Underestimated? AB - SLE can present with hematological manifestations alone or along with features of other system involvement. With a low index of clinical suspicion or inadequate follow up the diagnosis may be delayed or missed at the time of presentation, in those with hematological abnormalities as the initial manifestation. An observational study was conducted among patients of SLE, in a tertiary referral centre of North Kerala, with the purpose of estimating the proportion of patients with hematological manifestations as the initial presentation of the disease and to study their nature. It was observed that 82% of the patients had hematological manifestations at presentation. It is the most common presenting manifestation of SLE in people of North Kerala. Autoimmune hypothyroidism was one of the common coexisting abnormalities in these patients, which is not included in the American College of Rheumatology (ACR) criteria for diagnosis. Arthritis was uncommon among those who presented with hematological manifestations. A significant number of patients do not satisfy the ACR criteria at the time of diagnosis but do so on follow up. The ACR criteria are weak to diagnose such patients and therefore need revision. We therefore propose an alternative to ACR criteria as "Kozhikode criteria for SLE". PMID- 22830037 TI - Endoscopic management of portal hypertension. AB - Cirrhosis is the leading cause of portal hypertension worldwide, with the development of bleeding gastroesophageal varices being one of the most life threatening consequences. Endoscopy plays an indispensible role in the diagnosis, staging, and prophylactic or active management of varices. With the expected future refinements in endoscopic technology, capsule endoscopy may one day replace traditional gastroscopy as a diagnostic modality, whereas endoscopic ultrasound may more precisely guide interventional therapy for gastric varices. PMID- 22830039 TI - Cutaneous manifestations in patients with chronic kidney disease on maintenance hemodialysis. AB - Cutaneous disorders can precede or follow the initiation of hemodialysis treatment. We evaluated the prevalence of various dermatological manifestations in patients undergoing hemodialysis at least twice a week for minimum of three months at our center. Patients were excluded if they were undergoing hemodialysis less than twice a week or on hemodialysis secondary to ESRD following graft dysfunction. One hundred and forty-three patients were evaluated. Among them, there were 113 male and 30 females. Among the skin changes, pruritus accounted for 56%, Xerosis was observed in 52%, Diffuse blackish hyper pigmentation was seen in 40%. Skin infections was seen in 53% of patients, of these fungal, bacterial and viral infections were 27.2%, 14.6%, and 11.2%, respectively. Kyrle's disease was observed only in 6.9%. Other skin manifestations include eczema 4.8%, psoriasis 2.7%, and drug rash 2.1%. Nail changes were observed in 46 patients of whom 27 patients had onychomycosis. Other changes include discoloration, onycholysis, and splinter hemorrhages. Hair changes were observed in 21.7%. Mucosal changes were seen in 27.3%. In our study, pruritus, xerosis, and pigmentation were higher among skin changes. Recognition and management of some of these dermatological manifestations vastly reduce the morbidity and improve the quality of life. PMID- 22830040 TI - Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy. AB - Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function (reflecting peripheral small C-fiber status), with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing's protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < 0.05), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated. PMID- 22830041 TI - Steroid-induced diabetes: is it just unmasking of type 2 diabetes? AB - Aims. We compared the demographic profile and clinical characteristics of individuals with new onset steroid-induced diabetes (NOSID) to Type 2 diabetes (T2DM) patients with and without steroid treatment. Methods. The demographic profile and clinical characteristics of 60 individuals who developed NOSID were examined and matched to 60 type 2 diabetes patients receiving steroid therapy (T2DM+S) and 360 diabetic patients not on steroids (T2DM) for age, duration of diabetes, HbA1c, gender, and ethnicity. Results. Patients who developed NOSID had less family history of diabetes (P <= 0.05) and were less overweight (P <= 0.02). NOSID was more commonly treated with insulin. Despite a matching duration of diabetes and glycaemic control, significantly less retinopathy was found in the group of patients with NOSID (P < 0.03). Conclusions. It appears that steroid treatment primarily precipitated diabetes in a group of individuals otherwise less affected by risk factors of diabetes at that point in time, rather than just opportunistically unmasking preexisting diabetes. Furthermore, the absence of retinopathy suggests that patients with NOSID had not been exposed to long periods of hyperglycaemia. However, the impact of the underlying conditions necessitating steroid treatment and concomitant medications such as immunosuppressants on diabetes development remain to be defined. PMID- 22830042 TI - Regional variation on rates of bronchopulmonary dysplasia and associated risk factors. AB - Background. An abnormally high incidence (44%) of bronchopulmonary dysplasia with variations in rates among cities was observed in Colombia among premature infants. Objective. To identify risk factors that could explain the observed high incidence and regional variations of bronchopulmonary dysplasia. Study Design. A case-control study was designed for testing the hypothesis that differences in the disease rates were not explained by differences in city-of-birth specific population characteristics or by differences in respiratory management practices in the first 7 days of life, among cities. Results. Multivariate analysis showed that premature rupture of membranes, exposure to mechanical ventilation after received nasal CPAP, no surfactant exposure, use of rescue surfactant (instead of early surfactant), PDA, sepsis and the median daily FIO(2), were associated with a higher risk of dysplasia. Significant differences between cases and controls were found among cities. Models exploring for associations between city of birth and dysplasia showed that being born in the highest altitude city (Bogota) was associated with a higher risk of dysplasia (OR 1.82 95% CI 1.31-2.53). Conclusions. Bronchopulmonary dysplasia was manly explained by traditional risk factors. Findings suggest that altitude may play an important role in the development of this disease. Prenatal steroids did not appear to be protective at high altitude. PMID- 22830043 TI - Neural Circuit in the Dorsal Raphe Nucleus Responsible for Cannabinoid-Mediated Increases in 5-HT Efflux in the Nucleus Accumbens of the Rat Brain. AB - In vivo microdialysis was used in this study to reveal the role of cannabinoids in regulating serotonin (5-HT) efflux in the nucleus accumbens (NAcc) and dorsal raphe nucleus (DRN). The cannabinoid CB1 receptor agonists WIN55212-2 and CP55940 systematically administered to rats caused significant increases in 5-HT efflux in the NAcc but failed to have an effect in the DRN. To reveal mechanisms underlying regionally selective responses, we tested the hypothesis that cannabinoids have both direct and indirect effects on 5-HT efflux, depending on the location of CB1 receptors in the neural circuit between DRN and NAcc. We showed that the direct effect of cannabinoids caused a reduction in 5-HT efflux whereas the indirect effect resulted in an increase. Furthermore, the indirect effect was blocked by the GABA(A) receptor antagonist bicuculline in the DRN, suggesting that the action is likely due to a presynaptic inhibition on GABAergic activity that exerts a tonic influence on neuronal circuits regulating 5-HT efflux. Involvement of GABAergic neurons was confirmed by measuring changes in GABA efflux. Taken together, our study suggests that cannabinoids may have direct and indirect effects on the 5-HT regulatory circuits, resulting in regionally selective changes of 5-HT efflux in the brain. PMID- 22830045 TI - An Algorithm for the Preclinical Screening of Anticancer Drugs Effective against Brain Tumors. AB - The anticancer drugs screening program is a long and expensive process. It is estimated that only 5% of drugs entering clinical trials are approved by the FDA. Moreover, many of the drugs that enter clinical trials are often of limited use in clinical practice, and most cancers remain untreatable. Brain tumors are particularly difficult to treat due to the presence of the blood brain barrier that limits the penetration of anticancer drugs. Additionally the isolation from most brain tumors of putative cancer stem cells and novel models of cancer stem cell biology suggest that anticancer drugs should be delivered for prolonged time and at higher concentrations to deplete any potential tumorigenic cell. In this paper, current concepts of cancer stem cell biology and novel concepts of anticancer drugs screening are integrated to develop a seven-steps algorithm as a guideline for the preclinical evaluation of active compounds for the treatment of brain tumors. The flexibility of the algorithm allows the inclusion of alternative studies to exhaustively investigate anticancer drugs and creates multiple opportunities where decisions to engage or not in early clinical trials can be made providing a useful tool for translational research in neurooncology. PMID- 22830044 TI - Beyond dopamine: glutamate as a target for future antipsychotics. AB - The dopamine hypothesis of schizophrenia remains the primary theoretical framework for the pharmacological treatment of the disorder. Despite various lines of evidence of dopaminergic abnormalities and reasonable efficacy of current antipsychotic medication, a significant proportion of patients show suboptimal treatment responses, poor tolerability, and a subsequent lack of treatment concordance. In recent decades, intriguing evidence for the critical involvement of other neurotransmitter systems in the pathophysiology of schizophrenia has emerged, most notably of dysfunctions within the glutamate pathways. Consequently, the glutamate synapse has arisen as a promising target for urgently needed novel antipsychotic compounds-particularly in regards to debilitating negative and cognitive symptoms poorly controlled by currently available drugs. In this paper, recent findings integrating glutamatergic and dopaminergic abnormalities in schizophrenia and their implications for novel pharmacological targets are discussed. An overview of compounds in various stages of development is given: drugs enhancing NMDA receptor function as well as metabotropic glutamate receptor (mGluR) agonist and positive allosteric modulators (PAMs) are emphasised. Together with other agents more indirectly affecting glutamatergic neurotransmission, their potential future role in the pharmacotherapy of schizophrenia is critically evaluated. PMID- 22830046 TI - Mapping the Diagnosis Axis of an Interface Terminology to the NANDA International Taxonomy. AB - Background. Nursing terminologies are designed to support nursing practice but, as with any other clinical tool, they should be evaluated. Cross-mapping is a formal method for examining the validity of the existing controlled vocabularies. Objectives. The study aims to assess the inclusiveness and expressiveness of the nursing diagnosis axis of a newly implemented interface terminology by cross mapping with the NANDA-I taxonomy. Design/Methods. The study applied a descriptive design, using a cross-sectional, bidirectional mapping strategy. The sample included 728 concepts from both vocabularies. Concept cross-mapping was carried out to identify one-to-one, negative, and hierarchical connections. The analysis was conducted using descriptive statistics. Results. Agreement of the raters' mapping achieved 97%. More than 60% of the nursing diagnosis concepts in the NANDA-I taxonomy were mapped to concepts in the diagnosis axis of the new interface terminology; 71.1% were reversely mapped. Conclusions. Main results for outcome measures suggest that the diagnosis axis of this interface terminology meets the validity criterion of cross-mapping when mapped from and to the NANDA-I taxonomy. PMID- 22830047 TI - Prognostic factors and recurrence in breast cancer: experience at the national cancer institute of Mexico. AB - The purpose of this study was to analyze the prognostic and predictive factors that relate to locoregional or distant recurrences in breast cancer patients who have been treated at the National Cancer Institute of Mexico. Multivariate, time dependent Cox regression analyses indicate that the pN status (positive versus negative lymph node; P = 0.003; HR (hazard ratio), 3.47; CI (confidence interval), 1.52-7.91) and the pathological complete response of the patient to neoadjuvant chemotherapy (yes versus no; P = 0.061; HR, 0.38; CI, 0.14-1.04) were important prognostic factors for recurrence. PMID- 22830048 TI - Symptom distress associated with biopsy in women with suspect breast lesions. AB - Purpose. To investigate symptom distress, quality of life, affective states, and inflammatory biomarkers before and after breast biopsy in women undergoing breast biopsy. Methods. A convenience sample of 47 women undergoing breast biopsy was assessed at the pre- and post-biopsy visits. The assessments included evaluation of fatigue, anxiety, depression, sleep disturbances, positive and negative affect, quality of life using validated self report measures, and a blood draw to determine markers of inflammation. Results. At the postbiopsy visit, a total of 15 participants were diagnosed with breast cancer, and 32 participants received negative biopsy result. The mean anxiety and sleep disturbances scores were in the clinically significant range for the total sample and for the biopsy positive (BC+) and biopsy negative (BC-) subgroups at both time points. For both subgroups, anxiety and sleep disturbances scores did not change significantly from pre- to post-biopsy. A subpopulation of participants in both groups reported moderate-to-severe anxiety, depression and fatigue levels at both time points. The inflammatory markers did not show consistent associations with psychosocial symptoms. Conclusions. A subset of participants in BC+ and BC- subgroups experience heightened symptom distress and negative impact on quality of life at both pre- and post-biopsy time points. PMID- 22830049 TI - Central Venous Line Placement prior to Gastric Bypass Improves Operating Room Efficiency. AB - Background. Bariatric surgery has increased across America. Venous access is difficult in these patients. Anesthesiologists often utilize valuable operating room (OR) time acquiring reliable intravenous lines. Our objective was to determine if outpatient central venous line (CVL) placement improves OR efficiency and professional reimbursement for CVL insertion. Methods. In our bariatric practice, selected surgery patients have outpatient CVLs placed during prophylactic vena cava filter placement. In a cohort of 268 gastric bypass patients operated between 1/01 and 11/06, we compared time-to-incision between 106 with pre-established CVLs and 162 without. In addition, we determined professional compensation rates for CVLs placed outpatient versus CVLs inserted in the OR. Results. Patients with preoperative (outpatient) CVLs required 35.6 +/ 12.5 minutes to skin incision compared with 42.5 +/- 13.9 minutes for controls (P < 0.0001), and 34.9% had skin incision in <30 minutes compared with 16.4% of controls. Radiologists collected 28.2% of outpatient billings for CPT code 36556, compared with anesthesiologists who collected <1% when placing CVLs in the OR. Conclusions. Outpatient CVLs prior to gastric bypass improve efficiency in the OR with earlier skin incision. Professional reimbursement is better for outpatient CVLs than intraoperative inpatient CVLs. PMID- 22830050 TI - External validation of an artificial neural network and two nomograms for prostate cancer detection. AB - Background. Multivariate models are used to increase prostate cancer (PCa) detection rate and to reduce unnecessary biopsies. An external validation of the artificial neural network (ANN) "ProstataClass" (ANN-Charite) was performed with daily routine data. Materials and Methods. The individual ANN predictions were generated with the use of the ANN application for PSA and free PSA assays, which rely on age, tPSA, %fPSA, prostate volume, and DRE (ANN-Charite). Diagnostic validity of tPSA, %fPSA, and the ANN was evaluated by ROC curve analysis and comparisons of observed versus predicted probabilities. Results. Overall, 101 (35.8%) PCa were detected. The areas under the ROC curve (AUCs) were 0.501 for tPSA, 0.669 for %fPSA, 0.694 for ANN-Charite, 0.713 for nomogram I, and 0.742 for nomogram II, showing a significant advantage for nomogram II (P = 0.009) compared with %fPSA while the other model did not differ from %fPSA (P = 0.15 and P = 0.41). All models overestimated the predicted PCa probability. Conclusions. Beside ROC analysis, calibration is an important tool to determine the true value of using a model in clinical practice. The worth of multivariate models is limited when external validations were performed without knowledge of the circumstances of the model's development. PMID- 22830051 TI - Regulation of Ca2+/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal. AB - Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser(831), increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr(286)) CaMKIIalpha expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety. PMID- 22830053 TI - Hippocampal neurogenesis, cognitive deficits and affective disorder in Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases. PMID- 22830052 TI - Understanding the pathogenesis of Angelman syndrome through animal models. AB - Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of function mutations of the maternally inherited UBE3A gene located within chromosome 15q11-q13. The UBE3A gene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention. PMID- 22830055 TI - Microemulsion drug delivery system: for bioavailability enhancement of ampelopsin. AB - Ampelopsin, one of the most common flavonoids, reported to possess numerous pharmacological activities and shows poor aqueous solubility. The purpose of this study was to enhance the dissolution rate and bioavailability of this drug by developing a novel delivery system that is microemulsion (ME) and to study the effect of microemulsion (ME) on the oral bioavailability of ampelopsin. Capmul MCM-based ME formulation with Cremophor EL as surfactant and Transcutol as cosurfactant was developed for oral delivery of ampelopsin. Optimised ME was evaluated for its transparency, viscosity, percentage assay and so forth. Solubilisation capacity of the ME system was also determined. The prepared ME was compared with the pure drug solution and commercially available tablet for in vitro drug release. The optimised ME formulation containing ampelopsin, Capmul MCM (5.5%), Cremophor EL (25%), Transcutol P (8.5%), and distilled water showed higher in vitro drug release, as compared to plain drug suspension and the suspension of commercially available tablet. These results demonstrate the potential use of ME for improving the bioavailability of poor water soluble compounds, such as ampelopsin. PMID- 22830054 TI - GABAergic neuron specification in the spinal cord, the cerebellum, and the cochlear nucleus. AB - In the nervous system, there are a wide variety of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics. These various types of neurons can be classified into two groups: excitatory and inhibitory neurons. The elaborate balance of the activities of the two types is very important to elicit higher brain function, because its imbalance may cause neurological disorders, such as epilepsy and hyperalgesia. In the central nervous system, inhibitory neurons are mainly represented by GABAergic ones with some exceptions such as glycinergic. Although the machinery to specify GABAergic neurons was first studied in the telencephalon, identification of key molecules, such as pancreatic transcription factor 1a (Ptf1a), as well as recently developed genetic lineage-tracing methods led to the better understanding of GABAergic specification in other brain regions, such as the spinal cord, the cerebellum, and the cochlear nucleus. PMID- 22830056 TI - Drug solubility: importance and enhancement techniques. AB - Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics. PMID- 22830057 TI - Effects of Aqueous Extract of Fresh Leaves of Abroma augusta L. on Oral Absorption of Glucose and Metformin Hydrochloride in Experimental Rats. AB - To get better control in disease conditions, many people take herbs with conventional medicines, therefore, posing a risk of potential pharmacokinetic interactions between herbs and conventional drugs. The aqueous extract of the fresh leaves of Abroma augusta L. (Family: Sterculiaceae, Bengali name: Ulatkambal, English name: Devil's cotton, DC) is viscous and used traditionally to treat diabetes mellitus. This study was done to investigate the probable mechanism by which the aqueous extract of Abroma augusta L. is beneficial in managing type 2 DM and to observe the effects of this extract on absorption of metformin hydrochloride from the gastrointestinal tract. Studies were conducted in healthy Long Evans rats using Na-carboxymethyl cellulose (CMC) as positive control. Both Na-CMC and WSF of DC significantly (P < 0.05) reduced the absorption of glucose administered orally in fasted rats. On the other hand, WSF of DC significantly (P < 0.05) reduced the absorption of metformin hydrochloride in alloxan-induced diabetic rats. The results of this study suggest that WSF of DC may be beneficial in diabetic patients to improve glycemic control but should not be coadministered with metformin HCl for management of type 2 diabetes mellitus. PMID- 22830058 TI - Unusual foreign bodies in the orofacial region. AB - Foreign bodies may be deposited in the oral cavity either by traumatic injury or iatrogenically. Among the commonly encountered iatrogenic foreign bodies are restorative materials like amalgam, obturation materials, broken instruments, needles, and so forth. The discovery of foreign bodies in the teeth is a special situation, which is often diagnosed accidentally. Detailed case history, clinical and radiographic examinations are necessary to come to a conclusion about the nature, size, location of the foreign body, and the difficulty involved in its retrieval. It is more common to find this situation in children as it is a well known fact that children often tend to have the habit of placing foreign objects in the mouth. Sometimes the foreign objects get stuck in the root canals of the teeth, which the children do not reveal to their parents due to fear. These foreign objects may act as a potential source of infection and may later lead to a painful condition. This paper discusses the presence of unusual foreign bodies a tip of the metallic compass, stapler pin, copper strip, and a broken sewing needle impregnated in the gingiva and their management. PMID- 22830059 TI - Multidisciplinary management of a fractured premolar: a case report with followup. AB - The general dental practitioner must consider orthodontic extrusion of a tooth when a subgingival defect, such as, crown fracture occurs before prosthetic rehabilitation, especially in the aesthetic zone. Extrusion enables the root portion to be elevated which exposes sound tooth structure for placement of restorative margins. This case report describes the multidisciplinary management of a fractured upper first premolar in a general dental practice. The forced orthodontic eruption is achieved by an endodontic attachment and sectional fixed appliance with an offset placed in the wire. The ability to extrude premolars with this method is complicated by heavy occlusal forces, occlusal interferences, and short clinical crown length. The tooth was restored with a titanium post, composite core, and porcelain fused to metal crown. The entire course of treatment was carried out under National Health Scheme, UK and as a part of vocational training. The 21 months followup showed no change in occlusal contacts or gingival level. PMID- 22830060 TI - Odontogenic myxoma of the mandible. AB - Odontogenic myxomas are benign but locally aggressive neoplasms found almost exclusively in the jaws and arise only occasionally in other bones. We present a rare case of odontogenic myxoma occurring in the mandible of a 19-year-old male patient with a brief review of clinical and radiological features, and diagnostic and operative dilemmas in managing the same. PMID- 22830062 TI - Prosthodontic rehabilitation of the patient with severely worn dentition: a case report. AB - The management of tooth wear has been a subject of increasing interest from both preventive and restorative points of view. This paper describes the full mouth rehabilitation of a 63-year-old bruxer man with a severely worn dentition and other dental problems including unsuitable restorations and several missing teeth. The treatment entailed using cast posts and cores, metal-ceramic restorations, and a removable partial denture. As with the treatment procedure of such cases, equal-intensity centric occlusal contacts on all teeth and an anterior guidance in harmony with functional jaw movements were especially taken into account. PMID- 22830061 TI - A rare root canal configuration of maxillary second molar: a case report. AB - A thorough knowledge of root canal morphology is a prerequisite for the endodontic therapy. The maxillary molars, especially the second molars, have the most complicated root canal system in permanent dentition. There are many variations in canal number and configuration in maxillary molars. Treatment may be unsuccessful because the dentist may fail to recognize the unusual canal configuration. The present paper describes a case of a right maxillary second molar with a canal configuration rarely reported in the literature. The tooth had four roots with four root canals, two individual palatal roots (mesiopalatal and distopalatal) with their own separate canals. The mesiobuccal and distobuccal root had normal anatomy. This paper may intensify the complexity of maxillary molar variation and is intended to reinforce clinician's awareness of the rare morphology of root canals. PMID- 22830063 TI - Francisella tularensis Bacteremia: A Case Report from Sudan. AB - Francisella tularensis is a highly virulent intracellular gram-negative bacterium. The organism is usually isolated from wild and domestic animals and invertebrate. Man gets infection by direct contact with those animals or their products but the most common mode of transmission is via arthropod vectors. The disease is endemic in North America, parts of Europe, and Asia but has never been reported in Africa. A 29-year old male living in a rural area of Southern Sudan has been maintained on continuous ambulatory peritoneal dialysis for two years. He presented to our center in May 2010 complaining of fever, dry cough, shortness of breath, and abdominal discomfort for four days. He was very ill, pale, and dehydrated. There were enlarged tender submandibular lymph nodes, but no mouth ulcers or other palpable lymph nodes. Peritonitis was excluded by effluent white blood cell count and culture. Empiric antibiotic treatment with ceftriaxon, and ciprofloxacin was started. Gram-negative coccobacilli were isolated by blood culture. The organism was identified as Francisella tularensis. We started him on a ten-day course of gentamicin after which he improved. This is, to the best of our knowledge, the first reported case of bacteremia caused by Francisella tularensis in Sudan. PMID- 22830064 TI - Nontoxigenic Vibrio cholerae Septicemia in an Immunocompromised Patient. AB - We report a recent case of non-O1, non-O139, nontoxigenic Vibrio cholerae septicemia in a post-liver-transplant immunocompromised patient associated with prior seafood consumption. Non-O1, non-O139 V. cholerae strains have been reported in several cases of extraintestinal infections and seem to be emerging infectious agents especially in patients with immunocompromising conditions. PMID- 22830065 TI - An underreported consequence of obesity in pregnancy: patient-prosthesis mismatch. AB - As the rate of obesity increases in childbearing-aged women, so too will the complications of obesity in pregnancy. An uncommon and likely underreported complication occurs in obese women who have received prepregnancy cardiac valve replacement with a prosthesis that is inadequately sized for body habitus, a condition referred to as patient-prosthesis mismatch (PPM). The physiologic changes of pregnancy as well as the increased weight gain combine to exacerbate PPM. We report a case of PPM that necessitated prosthesis replacement at 16-week gestation. As the incidence of this clinical scenario increases, it is important to understand the implications of prosthesis sizing, as well as the repercussions of having cardiopulmonary surgery to correct the undersized valve prosthesis while pregnant. PMID- 22830066 TI - Orbital apex syndrome in herpes zoster ophthalmicus. AB - Orbital apex syndrome is a rare manifestation of Herpes Zoster Ophthalmicus. Herein we report on a case of orbital apex syndrome secondary to Herpes Zoster Ophthalmicus. A 75 year-old male complained of vision loss, conjunctival hyperemia and proptosis on the left eye, was referred to our clinic. Visual acuity was 5/10 Snellen lines and he had conjunctival hyperemia, chemosis, minimal nuclear cataract and proptosis on the left eye. A diagnosis of orbital pseudotumor was demonstrated firstly. The patient received oral and topical corticosteroids, antiinflammatory and antibiotic agents. On day 2, vesiculopustular lesions were observed, Herpes Zoster Ophthalmicus was diagnosed and corticosteroid treatment stopped, oral acyclovir treatment initiated. Two days later, total ophthalmoplegia, ptosis and significant visual loss were observed on the left. The diagnosis of orbital apex syndrome was considered and the patient commenced on an intravenous acyclovir treatment. After the improvement of acute symptoms, a tapering dose of oral cortisone treatment initiated to accelarate the recovery of ophthalmoplegia. At 5-month follow-up, ptosis and ocular motility showed improvement. VA did not significantly improve because of cataract and choroidal detachment on the left. We conclude that ophthalmoplegia secondary to Herpes Zoster Ophthalmicus responds favourably to intravenous acyclovir and steroids. PMID- 22830067 TI - Isolated avulsion of the common hepatic duct from blunt abdominal trauma. AB - Isolated extrahepatic biliary tract injury following blunt abdominal trauma is rare. The underlying pathogenic mechanisms remain obscure, but include shear and/or compression forces on the biliary system. Associated morbidity rates are high and largely the result of delays in diagnosis. Imaging modalities commonly employed for diagnosis include ultrasonography, computed tomography, nuclear medicine, and magnetic resonance imaging. Percutaneous and endoscopic techniques have been used both for diagnosis and treatment. Treatment options are dictated by the stability of the patient and the extent of bile duct and concomitant injuries. In this paper, we discuss a case of isolated avulsion of the hepatic duct confluence following blunt trauma that was successfully managed with Roux-en Y hepaticojejunostomy. To our knowledge, this specific injury pattern has not been previously reported. PMID- 22830068 TI - Simultaneous acute cholecystitis and acute appendicitis treated by a single laparoscopic operation. AB - While acute appendicitis and acute cholecystitis are both common, they are only rarely seen simultaneously. The clinical presentation and hospital course of a 45 year-old female with concurrent acute appendicitis and acute cholecystitis is presented. The laparoscopic approach is ideal for dealing with multiple, simultaenous abdominal pathologies. PMID- 22830069 TI - Focal urethral stricturing following intraurethral mitomycin-C gel and the use of a penile clamp. AB - We present a case of a 51-year-old gentleman, previously diagnosed with high grade superficial transitional cell carcinoma of the bladder and treated with intravesical mitomycin C and BCG, who developed serial recurrences in the prostatic urethra. This was resected and treated further with intraurethral mitomycin-C gel. He subsequently developed an almost impassable distal penile urethral stricture, corresponding to the site of penile clamp application which we hypothesise is secondary to a combination of the mitomycin-C gel and penile clamp pressure. PMID- 22830070 TI - Conservative management of unusual keratinising squamous metaplasia of the bladder in a 28-year-old female and overview of the literature. AB - Keratinizing squamous metaplasia of the bladder is rare and is usually associated with urinary tract infections and chronic irritation. It is considered a precancerous condition of squamous cell carcinoma, especially when more than 50% of the bladder surface is affected. Medical treatment cannot eradicate this lesion. When it is limited to a small area of the bladder, transurethral resection is possible. Annual cystoscopy with multiple biopsies as well as annual upper tract imaging is proposed in the follow up of these patients. We present a preliminary 2-year followup report of a keratinizing squamous metaplasia of the bladder in a 28-year-old female patient with no previous risk factors. PMID- 22830071 TI - Admission hyperglycemia and acute myocardial infarction: outcomes and potential therapies for diabetics and nondiabetics. AB - Hyperglycemia, in both diabetic and nondiabetic patients, has a significant negative impact on the morbidity and mortality of patients presenting with an acute myocardial infarction (AMI). Contemporary evidence indicates that persistent hyperglycemia after initial hospital admission continues to exert negative effects on AMI patients. There have been a number of studies demonstrating the benefit of tight glucose control in patients presenting with AMI, but a lack of convincing clinical data has led to loose guidelines and poor implementation of glucose targets for this group of patients. The CREATE-ECLA study, which hypothesized that a fixed high dose of glucose, insulin, and potassium (GIK) would change myocardial substrate utilization from free fatty acids to glucose and therefore protect ischemic myocardium, failed to demonstrate improved clinical outcomes in AMI patients. Studies that specifically investigated intensive insulin therapy, including DIGAMI-2 and HI-5, also failed to improve clinical outcomes such as mortality. There are a number of reasons that these trials may have fallen short, including the inability to reach glucose targets and inadequate power. There is now a need for a large placebo-controlled randomized trial with an adequate sample size and adherence to glucose targets in order to establish the benefit of treating hyperglycemia in patients presenting with AMI. PMID- 22830073 TI - Chinese-language montreal cognitive assessment for cantonese or mandarin speakers: age, education, and gender effects. AB - The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean +/- SD) was 23.8 +/- 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1-6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7-11 and 12-20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers. PMID- 22830075 TI - Ultrasensitive electrochemical immunoassay based on graphene oxide-Ag composites for rapid determination of clenbuterol. AB - We report the development of an ultrasensitive amperometric biosensor based on Ag nanoparticles-decorated graphene oxide nanosheets (GO) (Ag-GO) for the rapid detection of clenbuterol (CLB). The morphology and structure of the Ag-GO labeled CLB (Ag-GO-CLB) were characterized by transmission electron microscope (TEM), atomic force microscope (AFM), and ultraviolet-visible spectroscope (UV-vis). The immunosensor was prepared by covalently immobilizing capture antibodies on a multi-walled carbon nanotubes-modified glassy carbon electrode. Through competitive immunoreactions, the Ag-GO-CLB nanocomposites were captured on the immunosensor and the silver was measured by positive differential pulse voltammetry (DPV) in KCl solution for the detection of antigen. The experimental results show a linear response over the range from 0.01 to 10.0 ng mL(-1) with a lower detection limit of 6.8 pg mL(-1) (signal-to-noise ratio of 3). The Ag-GO based immunosensor offers a simple and convenient route for metal-immunoassay labels, which can avoid the complicated and time-consuming dissolving of metal component for ultrasensitive determination. Moreover, the electrochemical immunoassay shows acceptable specificity and stability and is suitable for the determination of CLB in real samples. PMID- 22830072 TI - Depression in patients with cardiovascular disease. AB - It has been widely suggested that depression negatively affects patients with cardiovascular disease. There are several pathophysiological mechanisms as well as behavioral processes linking depression and cardiac events. Improvements in nursing and medical care have prolonged survival of this patient population; however, this beneficial outcome has led to increased prevalence of depression. Since mortality rates in chronic heart failure patients remain extremely high, it might be as equally important to screen for depression and there are several valid and reliable screening tools that healthcare personnel could easily employ to identify patients at greater risk. Consultation should be provided by a multidisciplinary team, consisting of cardiologists, psychiatrists, and hospital or community nurses so as to carefully plan, execute, and evaluate medical intervention and implement lifestyle changes. We aim to systematically review the existing knowledge regarding current definitions, prognostic implications, pathophysiological mechanisms, and current and future treatment options in patients with depression and cardiovascular disease, specifically those with heart failure. PMID- 22830074 TI - Modulating P2X7 Receptor Signaling during Rheumatoid Arthritis: New Therapeutic Approaches for Bisphosphonates. AB - P2X7 receptor-mediated purinergic signaling is a well-known mechanism involved in bone remodeling. The P2X7 receptor has been implicated in the pathophysiology of various bone and cartilage diseases, including rheumatoid arthritis (RA), a widespread and complex chronic inflammatory disorder. The P2X7 receptor induces the release into the synovial fluid of the proinflammatory factors (e.g., interleukin-1beta, prostaglandins, and proteases) responsible for the clinical symptoms of RA. Thus, the P2X7 receptor is emerging as a novel anti-inflammatory therapeutic target, and various selective P2X7 receptor antagonists are under clinical trials. Extracellular ATP signaling acting through the P2X7 receptor is a complex and dynamic scenario, which varies over the course of inflammation. This signaling is partially modulated by the activity of ectonucleotidases, which degrade extracellular ATP to generate other active molecules such as adenosine or pyrophosphates. Recent evidence suggests differential extracellular metabolism of ATP during the resolution of inflammation to generate pyrophosphates. Extracellular pyrophosphate dampens proinflammatory signaling by promoting alternative macrophage activation. Our paper shows that bisphosphonates are metabolically stable pyrophosphate analogues that are able to mimic the anti inflammatory function of pyrophosphates. Bisphosphonates are arising per se as promising anti-inflammatory drugs to treat RA, and this therapy could be improved when administrated in combination with P2X7 receptor antagonists. PMID- 22830090 TI - The impact of retirement on health in Canada. AB - This study estimates the impact of retirement on subsequent health outcomes as measured by self-reported health status. The empirical study is based on seven longitudinal waves of the Canadian National Population Health Survey, spanning 1994 through 2006. To account for biases due to unobserved individual-specific heterogeneity, this study uses a fixed-effects method. The results indicate that retirement has a positive but insignificant impact on self-reported health status. The study further examined this issue using different subgroups based on gender and income and again found that retirement has no significant impact on health status. PMID- 22830091 TI - What do women know about government services and benefits? AB - This article examines how much women know about government services and benefits and discusses why this type of knowledge matters. Using data from a survey as well as focus groups conducted in Montreal and Toronto, we show that the women who are most likely to need information about these programs are often the least likely to be aware of them. This is especially true of low-income women, older women, and women who came to Canada as immigrants. We end by suggesting some steps that could be taken to address these knowledge gaps. PMID- 22830092 TI - Sexual portraits: Edward Melcarth and homoeroticism in modern American art. AB - Although one will not find Edward Melcarth (1914-73) in the best recent histories of male homosexuality and American art, he was not always so spectral. Named in Life magazine in 1950 as one of the best young American artists, he exhibited as a painter, draftsman and sculptor and also practised as an illustrator, photographer and designer. His work survives in the Forbes Collection, in the Smithsonian Institution and in the art archives at the Kinsey Institute. We argue that Melcarth's vision of the erotic was far broader than the traditional categories of sexuality that are perpetuated in art histories of homoeroticism in modern America - and that such a revisioning enables a reinterpretation of some of the better known images of homosexual art. PMID- 22830093 TI - Story-telling, women's authority and the "Old Wife's Tale": "The Story of the Bottle of Medicine". AB - The focus of this article is a single personal narrative - a Shetland woman's telling of a story about two girls on a journey to fetch a cure for a sick relative from a wise woman. The story is treated as a cultural document which offers the historian a conduit to a past that is respectful of indigenous woman centred interpretations of how that past was experienced and understood. The "story of the bottle of medicine" is more than a skilful telling of a local tale; it is a memory practice that provides a path to a deeper and more nuanced understanding of a culture. Applying perspectives from anthropology, oral history and narrative analysis, three sets of questions are addressed: the issue of authenticity; the significance of the narrative structure and storytelling strategies employed; and the nature of the female performance. Ultimately the article asks what this story can tell us about women's interpretation of their own history. PMID- 22830094 TI - "Hunnish scenes" and a "Virgin birth": a 1920s case of sexual and bodily ignorance. AB - When, in June 1921, a clairvoyant informed Christabel Russell, to her great surprise, that she was pregnant, her husband denied paternity and petitioned for divorce on grounds of adultery. The Hon. John Russell claimed that on the very few occasions that they had slept in the same bed in their two and half years of marriage, his method of birth control (which she referred to disapprovingly as "Hunnish scenes") had made pregnancy impossible. What added to the sensational nature of the case was the revelation that whilst pregnant, Christabel's hymen was unbroken - hence the claims of a "virgin birth." Two divorce trials and two appeals followed. The first trial ended inconclusively, the second trial was won for John Russell by the eminent barrister Sir Edward Marshall-Hall, but on the second appeal, in the House of Lords, it was ruled that evidence questioning the legitimacy of a child born in wedlock was inadmissible. The decree nisi was rescinded and the baby was legitimized. PMID- 22830096 TI - Fat, desire and disgust in the colonial imagination. AB - This article tracks the relatively unexamined ways in which ethnographic, travel and medical knowledge interrelated in the construction of fat stereotypes in the nineteenth century, often plotted along a temporal curve from 'primitive' corpulence to 'civilized' moderation. By showing how the complementary insights of medicine and ethnography circulated in beauty manuals, weight-loss guides and popular ethnographic books - all of which were aimed at middle-class readers and thus crystallize certain bourgeois attitudes of the time - it argues that the pronounced denigration of fat that emerged in Britain and France by the early twentieth century acquired some of its edge through this ongoing tendency to depict desire for and acceptance of fat as fundamentally 'savage' or 'uncivilized' traits. This tension between fat and 'civilization' was by no means univocal or stable. Rather, this analysis shows, a complex and wide-ranging series of similarities and differences, identifications and refusals can be traced between British and French perceptions of their own bodies and desires and the shortcomings they saw in foreign cultures. It sheds light as well on those aspects of their own societies that seemed 'primitive' in ways that bore an uncomfortable similarity to the colonial peoples they governed, demonstrating how a gendered, yet ultimately unstable, double standard was sustained for much of the nineteenth century. Finally it reveals a subtle and persistent racial subtext to the anti-fat discourses that would become more aggressive in the twentieth century and which are ubiquitous today. PMID- 22830097 TI - Sex in an Imperial war zone: transnational encounters in Second World War India. AB - This article suggests how the waging of war in an imperial setting may have reshaped military and civilian relations in India from 1939-45. The number of troops stationed in India had repercussions for society and local politics. The article investigates widespread prostitution as one aspect of the gendered wartime economy. Indian prostitution was closely linked to militarization and to the effects of the 1943 Bengal famine. The article also argues this was symptomatic of a more far-reaching renegotiation of the interactions between men and women in the Indian Empire of the 1940s. Other Indian, European, North American and Anglo-Indian women worked as nurses, with the Red Cross and in a variety of roles towards the war effort. Women were subject to new social and sexual demands due to the increased numbers of troops stationed in India in the 1940s. PMID- 22830098 TI - Skin lighteners, Black consumers and Jewish entrepreneurs in South Africa. AB - This article considers the rise and decline of South Africa's lucrative and controversial skin-lighteners market through examination of the business history of the largest manufacturers, Abraham and Solomon Krok, and their evolving personas as millionaires and philanthropists. Such examination reveals how the country's skin-lighteners trade emerged as part of the broader growth of a black consumer market after the Second World War and how elements of that market became the target of anti-apartheid protests in subsequent decades. It also demonstrates how the Kroks' experiences as second-generation Jewish immigrants shaped their involvement in the trade and how, later, their self-identification as Jewish philanthropists informed their efforts to rehabilitate their reputations following South Africa's 1990 ban on all skin lighteners. Such efforts include the building of Johannesburg's highly acclaimed Apartheid Museum, modelled after the United States Holocaust Memorial Museum. This article explores the profound ironies that some South Africans see in the fact that a museum dedicated to commemorating those who suffered under and, ultimately, triumphed against state racism was financed by a family fortune generated through the sale of skin lighteners to black consumers. PMID- 22830099 TI - Management & marketing: orthodontic marketing through online social networks. PMID- 22830100 TI - Independently owned pharmacy closures in rural America. AB - The closure of rural independently owned pharmacies, including pharmacies that are the sole source of access to local pharmacy services, from 2003 through 2011 coincides with the implementation of two major policies related to payment for prescription medications: (1) Medicare prescription drug discount cards were introduced on January 1, 2004; and (2) the Medicare prescription drug benefit (Part D) began on January 1, 2006. In this brief, we focus on rural pharmacy closure because of the potential threat such closures present to access to any local pharmacy services in a community. Services include providing medications from local stock without delay or travel, overseeing administration of medications to nursing homes and hospitals, and patient consultation. PMID- 22830101 TI - [The history and activities of Kirov State Medical Academy and its dental school are described in the article]. PMID- 22830102 TI - [Professor V.F. Voino-Iasenetskii (Holy Hierarch Lucus): his life and role in Russian dental school development]. AB - The paper describes life and works of professor V.F. Voyno-Yaseneckiy (Holy Hierarch Lucas). Surgeon and Archibishop, he was officially glorified by the Patriarchate of Russia. Voyno-Yaseneckiy's early works represent the guidelines for regional anesthesia and his, Notes on Purulent Surgery, published in 1934 lad the foundation for an entire medical specialty. PMID- 22830103 TI - [For your health VINAR cares]. PMID- 22830104 TI - [Use of short porous-surfaced implants in alveolar bone deficient sites]. PMID- 22830105 TI - [G.E. Sukhareva (the 120(th) anniversary of birth)]. PMID- 22830106 TI - [Factors of immune defense in the cerebrospinal fluid in viral infections of the central nervous system]. PMID- 22830107 TI - [Effect of pharmacotherapy on cognitive dysfunction after traumatic brain injury]. PMID- 22830108 TI - [To question the safety of non-steroid anti-inflammatory drugs]. PMID- 22830109 TI - [Post-stroke apathy]. PMID- 22830110 TI - [Outlook of surgical treatment of servicemen with pathology of knee joint in the specialized orthopedo-traumatology department]. AB - Analyzed data from annual reports of major trauma districts, chiefs of departments of hospitals and centers and reviewed the frequency and structure of surgical interventions on the knee, made in the last 5 years (2005-2010) in health care facilities the Defense Ministry. The frequency of the most typical injuries and diseases of the knee joint in different categories of servicemen. An integrated laboratory and endoscopic examination of patients with reactive arthritis, associated with latent urogenital infection and how the underlying disease and disease associated surgical pathology knee. Formulated evidence-based recommendations for improving the organization of surgical treatment of soldiers with the pathology of the knee. PMID- 22830111 TI - [Organization of medical support U.S. Armed Forces]. AB - The article describes the structure of the medical service of the U.S. Army, presented by seven corps,principles of planning of capabilities of medical services and their management, personnel policy of the Medical Service, that focuses on the staffing of the medical service of the officers of the possibilities. Organization of medical care during the combat theater provided by 4 echelons is represented. The first echelon "battlefield-Battalion", the second- "brigade combat team", the third is the rear of the theater of operations, the fourth--stationary hospitals outside the theater of operations. The basic direction of reducing the medical costs of all the troops: military personnel, their families, civilian employees of the Ministry of Defence, members of their families, veterans of military service and their families. PMID- 22830112 TI - [About some features of formation of "spots of Vishnevsky" in general hypothermia]. AB - The article describes the features of formation of "spots of Vishnevsky", in general hypothermia. It is proved that the wedge shape of hemorrhages in the gastric mucosa caused by swelling and discrepancy of the paries of stomach pits with the filling of forming wedge-shaped cavity with blood from the arrosive capillaries. It is noted that the dynamics of accumulation of PAS-positive material in the gastric pits in the gastric mucosa in case of total of hypothermia is directly dependent on the growth of intracellular acidosis and disintegration of plasmolemma of parietal cells. PMID- 22830113 TI - [Reconstructive correction of refractive-accommodative disorders in military personnel--operators of visual-intensive work with myopia]. AB - The authors propose an integrated method of rehabilitation of the vision (a course of physiotherapy and incentive effects, additional medical and non pharmacological treatment, application of self-correction), which provides military specialists--operators of visual-intensive work after the excimer laser correction of myopia higher level of visual performance, prevention of accommodative disorders, the progression of of myopia and astenopicheskih states. PMID- 22830115 TI - [Examination of the contamination aetiological agent of legionellosis in the water supply systems of medical treatment facilities]. AB - This study considers the features of colonization of water distribution systems by Legionella in large multi-type health-care facilities in Moscow-city, Russia. The investigation of 16 pavilions in 5 multi-type health-care facilities had found the hith level of hot water systems contaminated by Legionella pneumophila (68%), including the risk units. Among the different species of Legionella pneumophila, circulating in hot water systems of health-care facilities, the following strains had prevailed: the serogroup 6 (44%), 5 (26%) and 1 (13%). The findings conclude that certain prevention measures should be taken for microbial control and ensuring water safety in water systems of health-care facilities to prevent the nosocomial cases of legionellosis. PMID- 22830114 TI - [Correction of anxiety and psychosomatic disorders in a clinic for former combatants]. AB - Psychological personality disorder among former combatants and their relationship to subsequent psychosomatic disorders are examined. For this purpose, in health centers performed clinical and psychological examination of 105 fighters and 100 military personnel who were not taking part in hostilities (control group) aged 27 to 40 years, three groups are outlined: low (24.7%), moderate (64.8%) and high (10.5%) anxiety level, represented by their clinical characteristics. Studies have shown that combat stress can contribute to postreaktive change not only the psyche combatant, but also the development of persistent psychosomatic disorders. The methods and results of treatment and preventive advice are given. PMID- 22830116 TI - [About the complex system of requirements on the everyday safety of servicemen]. AB - The article is based on studies of medical and technical problems of habitability, livelihoods, military; environment and service troops justified the structure and content of the complex system requirements on the everyday safety of servicemen. It summarizes the scientific and educational methods to the accounting of the human factor in military facilities. Allowable limits and hygienic standards are the foundation of life safety of personnel. Extreme conditions are characterized by emergencies and injury. PMID- 22830117 TI - [About the problem of high-altitude decompression sickness and its treatment]. AB - It gives the idea of the modern conception of intravascular aerogenesis. It reviews the modern methods of diagnostics and treatment of altitude decompression sickness and gives guidelines to the doctor's actions by rendering medical aid in case of altitude decompression sickness. PMID- 22830118 TI - [Epidemiologic support of troops during the Great Patriotic War]. AB - The article is dedicated to the analysis of experience of domestic military preventive medicine during the Great Patriotic War. It describes the methods used and the means of protection of troops, volume control activities carried out. The authors state that these measures had provided epidemiological welfare of troops, expressed in a relatively small proportion of infectious diseases among all diseases of the soldiers. PMID- 22830119 TI - [Nikolay Terentevich Potyomkin (on the occasion of 90th anniversary of the birth)]. AB - The article is confined to the 90th anniversary of the birth of famous organizer of medical arrangement of Russian Navy, participant of the Great Patriotic War, Honored Doctor of RSFSR, major-general of Medical Service Nikolay Terentyevich Potyomkin (1.05.1922-9.11.1994). He leaded Medical Service of Russian Navy almost 10 years, from January 1976 till November 1985, and made the contribution to development of organization of medical arrangement of oceanic nuclear missile Navy of our country. N. T. Potyomkin made the contribution to development of organization of medical arrangement of the ships and shore objects of Russian Navy. He paid attention to improvement of delivery of health care to complement, drawing active service in the seven seas. PMID- 22830120 TI - [From the memories about father--colonel of medical service A. E. Ender]. AB - The article is made as memories, written by Inna Lukina--daughter of famous military physician Anany Efimovich Ender--in 2012 at the instance of editorial staff Central figure of the essay--participant of two World wars and three revolutions. The most interesting part of the memories is referred to period of the Great Patriotic War, when A. E. Ender leaded medical evacuation hospital No 3240. During the war medical evacuation hospital was displaced 17 times at Stalingrad, South-Western, Don, Central and 1st Belorussian fronts and made a long way 5000 kilometers in length from Rostov-on-Don to Berlin. A. E. Ender was the chef of military hospital No 104 of the administration of commandant of Soviet sector of Berlin from September 1946. During 1950 he worked at senior division of the University of Rostov-on-Don, than he worked as a senior lecturer at senior division of the Rostov State Medical University. PMID- 22830121 TI - On the front lines. Updating the training & care capabilities of law officers. PMID- 22830122 TI - Crisis management. Rudy Giuliani advocates for managing things, not people. PMID- 22830123 TI - Extra set of hands. Emergency physicians assist their prehospital counterparts. PMID- 22830124 TI - Numbers. Reflections on the value of one. PMID- 22830125 TI - Miracle in the desert. Cardiac case at remote burning man event presents challenges. AB - This was a miraculous case that illustrates the importance of seamless interaction between field EMS crews and physicians. First, this case occurred in one of the most austere and hostile environments imaginable. Next, it included a patient who was resuscitated from pulseless v tach with a precordial thump performed by a paramedic crew. The patient was subsequently evaluated and diagnosed with a thoracic aorta dissection by medical staff in a tent (with a diagnosis made by plain chest X-ray) and emergently transported 150 miles to a hospital where successful surgery was carried out. It truly was a "perfect storm," or perhaps, it was the general goodwill and spirit of Burning Man. Or maybe those crystals that were everywhere actually worked. PMID- 22830126 TI - Beyond the tape. Law enforcement officers make major impact as initial care providers. PMID- 22830127 TI - Prepared for the worst. Tactical training offers many be benefits to EMS. PMID- 22830129 TI - What's buggin' EMS. How to rid your rigs of a bedbug infestation. PMID- 22830128 TI - Partners in crime. EMS provides a training program for local law enforcement. PMID- 22830130 TI - Breaking barriers. Practice cultural sensitivity to provide care to immigrant communities. PMID- 22830131 TI - Multiple airways. Rapid assessment is key for managing numerous patients. AB - Encountering a situation that necessitates the assessment and management of patients requiring airway management can present a significant challenge. It will require a different thought process and set of decision-making skills that vary from the routine practice of airway management during a single patient encounter. Rapid triaging of the need for airway management is important. Creating a categorization of those patients who simply need supplemental oxygen from those who require assistance with the mechanical opening of the airway, a need for positive-pressure ventilation and those who require protection from aspiration can be a useful starting place for the creation of a treatment plan. Treatment decisions will depend on the amount of equipment and personnel resources that are available. Non-traditional decision procedures and positioning may need to be implemented, such as placing patients in a lateral recumbent position to use gravity to assist in keeping the airway patent. In the setting of multiple patient encounters requiring airway management, it's important to consider the length of time each procedure will take and the amount of equipment that will be required. A rapid securing of the airway by a supraglottic device in suitable patients may be favored over traditional approaches of ETI secondary to the relative complexity of the procedure. PMID- 22830132 TI - Gluten-free diet: definition and applications. PMID- 22830133 TI - Demographic pattern of male breast cancer: an institutional based study. AB - BACKGROUND: Male breast cancer incidence rises with age with peak in the 6th & 7th decade. It is one of the rare diseases and accounts for less than 1% of all malignancies worldwide. It is usually diagnosed in the late stage with poor prognosis. OBJECTIVE: The purpose of this study was to know the demographic pattern and tumour characteristic of breast cancer in men reported at Institute of Radiotherapy and Nuclear Medicine (IRNUM), Peshawar. METHODS: Retrospective data was collected from the (IRNUM), Peshawar for a period of three years (2006 2008). The evaluation was done from the histopathological reports of mastectomy and biopsy specimens. All male patients in the age group 26-86 year with breast cancer were included in the study. The age of the patients and tumour characteristics recorded were size, grade, type, skin involvement and stage. RESULTS: Total number of male patients with breast cancer were 31 (2.1%) out of the total patients with breast malignancy during the study period with the mean age of 58.3 years. Tumour size ranged from 2 to 12 Cm. with average of 3.6 Cm. Invasive ductal carcinoma was found in 87%, papillary carcinoma in 6.5%, each of malignant fibrous histocytoma and sarcoma in 3.2% cases. Maximum number of patients was of grade II (41%).Patients in whom stage of the disease was known were 22 cases with 45.5% had stage III disease and 32% had stage IV disease. Skin involvement was found positive in 8 (25.8%). CONCLUSION: Due to poor health care system breast cancer is diagnosed in a late stage of the disease and prognosis is poor. PMID- 22830134 TI - Prevalence of long QT syndrome and other cardiac defects in deaf-mute children. AB - BACKGROUND: Long QT syndrome is considered a fatal disease because of its association with ventricular arrhythmias and sudden cardiac death. Objectives of study were to determine the prevalence of long QT syndrome and other heart diseases, in deaf-mute children. METHODS: A Cross-sectional descriptive study was conducted at Cholistan special education centre and Cardiology department, Sheikh Zayed hospital Rahim Yar Khan, Pakistan in September 2006. A total of 104 congenitally deaf-mute children were assessed. Height, weight and blood pressure measured, 12-lead electrocardiogram done and QTc calculated using Bazette's formula. Children with prolonged QTc underwent 24-hour ambulatory ECG recording. All were auscultated following complete protocol. A child with murmur was further evaluated with colour Doppler echocardiography. Audiometry was performed on all the children and the result interpreted according to WHO recommendations. Diagnosis of LQTS was based on Revised Schwartz criteria. RESULTS: Out of 104 children, 62 were male with mean age 11.89 yrs. The average systolic and diastolic BP was 97/67 mmHg. Average height was 126 Cm. All children had moderate to severe bilateral sensorineural hearing loss (40-80 dB). One child had associated Patent Ductus Arteriosis. Fifteen had an innocent murmur. Prevalence of congenital heart disease was found to be 0.1/1000. Four children had QT interval more than 440 mSec, (range 0.46-0.47 mSec.). Both genders were equally affected. Three children had high probability of LQTS and one had intermediate probability. Screening of family of these 4 patients showed prolonged QT interval in the sibling of one patient. CONCLUSION: Our study highlights the significant prevalence of Jervell Lange-Nielsen Syndrome in Pakistani deaf-mute children, which may be associated to the high level of consanguinity in this region. Awareness of this syndrome among health care providers is needed as timely diagnosis and subsequent treatment may prevent fatal complications. PMID- 22830135 TI - Risk profile for breast carcinoma and tumour histopathology of medical uninsured patients in Pakistan. AB - BACKGROUND: Breast carcinoma is an unpredictable disease in the sense that some patients may die at early disease stage due to wide-spread metastasis within six months to one year, while others may survive longer. This study was aimed to evaluate the risk factors for breast carcinoma occurrence and histopathological features of breast carcinoma developed in the social and economical conditions of Pakistan. METHODS: A total of 224 female breast cancer diagnosed patients with uncovered medical insurance visiting at the Oncology clinic of a teaching hospital at Karachi, Pakistan were selected for the study. Two hundred and twenty four (224) healthy female subjects free of any cancer diagnosis were selected as control from different areas of the city. Information on stress, occupation, life history, and life style was obtained through personal interviews. Breast tumour pathology was evaluated for histological grade, lymph node metastasis and hormone receptor status by using standard methods. Student's t-test, Chi-square test and ANOVA were used for comparison. RESULTS: Breast cancer patients in significantly high percentage reported early marriages, abortion occurrence, stressful life style, family cancer history and past disease suffering from diabetes and hypertension. Life style including aerosol chewing and fat rich food intake was significantly high among the patients (p<0.05). On histopathological analysis, patients at the age of 40 years and below were identified in significantly high percentage with tumour grade III, 1-3 lymph node metastasis and hormone receptor negative type. Increasing age was associated with low tumour grade and less percentage of lymph node metastasis. Significantly high percentage of patients were presented with hormone receptor positive tumour (p<0.05). CONCLUSION: The contributing factors for breast carcinoma occurrence were related to life history and life-style of the patients. Medical insurance uncovered patients at initial diagnosis were presented in significantly high percentage with advanced disease including high tumour grade and lymph node metastasis due to less use of preventive and screening service which delays the diagnosis, effecting both survival and treatment cost. PMID- 22830136 TI - Rate and risk factors for surgical site infection at a tertiary care facility in Peshawar, Pakistan. AB - BACKGROUND: Surgical site infections (SSI) are among the most common complications in surgical patients and have serious consequences for outcomes and costs. This study aimed to determine the rates and risk factors affecting surgical site infections and their incidence at Surgical 'C' Unit, Khyber Teaching Hospital, Peshawar, Pakistan. The study was conducted to compare with rates obtained by large international multi-centre studies. METHODS: A review of all general surgical interventions involving an incision, excluding anal procedures, performed between December 2008 and March 2009 (n=269) was undertaken. Various clinical parameters were recorded. Infection rates were calculated. Data were analysed using the Fisher's exact test. RESULTS: The overall SSI rate was 9.294%, 4.88% in clean cases (C), 8.39% in clean contaminated cases (CC), and 20.45% in contaminated or dirty cases (D). There were significantly higher surgical site infection rates among patients with combined American Society of Anaesthesiologists scores II and III than those with ASA score I in clean contaminated (p=0.0007), and dirty cases (p=0.0212). There were also significantly higher surgical site infection rates among patients with combined Co-morbidity Scale score 1-6 than those with no comorbid factors in clean contaminated (p=0.0002). Surgical site infection rate was highest in gastrointestinal system surgeries. CONCLUSION: The Surgical site infections can be minimised by adopting international protocols for surveillance. PMID- 22830137 TI - Review of prescriber approach towards rational drug practice in hospitalised patients. AB - BACKGROUND: The rational drug prescribing practice is an important health concern around the globe that not only interferes patient's life but also the socioeconomic issues. OBJECTIVE: The aim of current study was to evaluate the rational use of drug, prescribing behaviour of consultant physicians, role of medical team members in irrational therapy and form the basis for providing necessary information to the policy makers. METHODS: This cross-sectional study was conducted involving a set of 340 medication orders containing about 1,755 medications prescribed to patients in DHQ Teaching Hospital DI Khan, Pakistan from March to July 2009. The WHO operational package for monitoring and assessing country pharmaceutical situations indicators were used for data collection. RESULTS: Among drugs prescribed per average encounter, 75% were dispensed from hospital pharmacy. Generally about 22.3% encounters of overdosing, 16.16% drug duplication, 24.25% drug-drug interactions, 3.5% adverse drug effects and 3.8% cases of contraindications were recorded. The proportion of consultations with antibiotics and injectables prescribed was 80% and 57% respectively. Likewise not less than 70% patients were prescribed NSAIDS, 67% steroids, 55% vitamin supplements, and 34% oral re-hydration solutions. Minimum 5 drugs per prescription were recorded and 70% of prescriptions were reported with high cost of therapy. CONCLUSION: The drug practice among hospitalised patients was clearly irrational accompanied by high levels of medication error. An accurate prescribing decision, appropriate treatment, and rational use of drugs are major needs of the day to ensure safe medication practice. PMID- 22830138 TI - Alkaline phosphatase as a screening test for osteomalacia. AB - BACKGROUND: Vitamin D deficiency remains common in children and adults in Pakistan despite adequate sunlight exposure. Diagnosis in adults is usually delayed and is made following pathological fractures that result in significant morbidity. The objective of this study was to see whether Serum Alkaline Phosphatase levels could be used as a screening test for osteomalacia. METHODS: The Study was conducted at Fatima Hospital, Baqai Medical University, Gadap, Karachi, between July 2002 and June 2005. Serum calcium levels are commonly used to screen patients suspected of osteomalacia, and raised serum alkaline phosphatase (SALP) is considered a diagnostic finding. We used SALP to screen patients who presented with back or non-specific aches and pain of more than six months duration. RESULTS: Three hundred thirty-four (334) patients were screened of which 116 (35%) had raised SALP. Osteomalacia was diagnosed in 92 (79.3%) of these 116 either by plain radiographs, bone biopsy or isotope bone scan. Fifty four (53.4%) of the 101 cases had a normal level of serum calcium. CONCLUSIONS: Osteomalacia is likely to be missed if only serum calcium is used to screen patients. Serum Alkaline Phosphate should be used as the preferred method for screening these patients. PMID- 22830139 TI - Pattern, management and outcome of urological complications in first post transplant year in 50 cases of renal transplant. AB - BACKGROUND: Chronic renal failure needs substitutive treatment such as haemodialysis and peritoneal dialysis for the patients to survive. Kidney transplantation improves survival of patients with chronic renal failure. This study was conducted to identify the pattern, management and outcome of urological complications in first post-transplant year in 50 cases of renal transplant recipients. METHODS: This case series study was conducted in the Department of Urology and Transplantation, Mayo Hospital, Lahore, during the period of three years, from Jan 2006 to Dec 2008. All 50 patients were admitted through outdoor department, Dialysis Unit, and directly referred from other hospitals. Donor and recipient were evaluated thoroughly by history, examination, and laboratory investigations. All donors were live related donors. After getting the proper tissue typing and HLA-matching transplant was done and recipients were thoroughly observed for the development of any urological complication in first post transplant year. RESULTS: Total 8 (16%) subjects developed complications. Urinary leakage was noticed in 3 patients. In one patient leakage stopped spontaneously while in remaining two patients surgical procedure was carried out. Two patients developed uro-sepsis due to intractable UTI. Both were successfully treated with broad spectrum anti biotic. Ureteric stenosis was noticed in 2 subjects. Indwelling JJ stent was placed in one case while remaining case was dealt with uretroneocystostomy. One cases developed Vesico-ureteric reflux. He was treated surgically. CONCLUSION: Early diagnosis and treatment of urological complication may prevent the further morbidity and decline in graft function. PMID- 22830140 TI - Helicobacter pylori infection in patients with calcular cholecystitis: a hospital based study. AB - BACKGROUND: Helicobacter pylori, a gram negative bacillus has been recognised as a public health problem and approximately half of the world population has H. pylori infection causes chronic gastritis, peptic ulcer disease and gastric malignancies. Objective of this study was to determine the frequency of H. pylori infection in patients of chronic calcular cholecystitis. METHODS: This cross sectional descriptive study was conducted at Liaquat University Hospital, Hyderabad, Pakistan from April 2010 to September 2010. All patients with history of gallstone presented with acute abdominal pain, dyspepsia, bloating and epigastric discomfort and diagnosed as calcular cholecystitis were further evaluated for the detection of H. pylori by serology and histopathology. Frequency and percentage of H. pylori infection in patients with calcular cholecystitis was calculated. RESULT: Total 100 patients of cholelithiasis underwent laparoscopic cholecystectomy were recruited. The pain in upper right part of the abdomen was observed in all 100 patients, fever in 75%, nausea and vomiting in 68%, loss of appetite in 45%, feeling of tiredness or weakness in 22%, headache in 38%, chills in 52%, backache in 58%, pain under the right shoulder in 45%, heartburn in 67%, belching in 54%, indigestion in 80%, dyspepsia in 90%, bloating in 88%, and epigastric discomfort in 85% patients. Eighty-two percent patients had family history of gallstones. The mean age of overall study population was 48.72 +/- 8.78 years and mean age of H. pylori infected calcular cholecystitis patients was 47.98 +/- 5.43 years in male and 48.76 +/- 6.68 years in females. The H. pylori infection was identified in 55% patients with calcular cholecystitis, of which 32.7% were males and 67.3% were females (p=0.03, statistically significant). Majority of females (60%) had > or = 40 U/ml antibody titre (p=0.917, non-significant). CONCLUSION: A possible relationship was identified between Helicobacter pylori and calcular cholecystitis. PMID- 22830141 TI - Fine needle aspiration cytology: sensitivity and specificity in thyroid lesions. AB - BACKGROUND: Thyroid enlargement is one of the common problems in patients presenting at outpatients department of ENT particularly in females. Thyroid nodules are common, thyroid cancer is uncommon and the most common way for it to present is as a solitary thyroid nodule. This study was conducted to evaluate the sensitivity and specificity of Fine Needle Aspiration Cytology (FNAC) in thyroid diseases. METHOD: This prospective analytic study was conducted at ENT Department of Karachi Medical and Dental College/Abbasi Shaheed Hospital during year 2004-8. One hundred and five cases were enrolled who underwent thyroid surgery after complete evaluation by history, clinical examination, Thyroid profile, Thyroid Scintigraphy, Ultrasound neck and FNAC. In cases which were revealed malignant by FNAC, CT scan were done to see the extent of disease and neck node status. Surgery was done in all cases and specimens sent for histopathology. RESULTS: Male to female ratio of the patients was 1:8.5. Most common lesion was benign nodule (96). Malignant lesions were 9 in FNAC. In histopathology, the benign nodules were 92, and malignant cases were 13. Sensitivity of FNAC was 61.53% and specificity was 98.9%. CONCLUSION: FNAC in Thyroid has high sensitivity and specificity. PMID- 22830142 TI - Assessment of metered dose inhaler technique in patients with chronic lung disease at government hospitals of Rawalpindi. AB - BACKGROUND: Metered dose inhalers (MDIs) are an affective modality of treatment for fast relief from asthma flare-ups and other symptoms, and are often used by asthmatic athletes. It has got lots of benefits and some drawbacks depending on usage technique. With proper technique and training drawbacks can be minimised. The objective of this study was to assess the metered dose inhaler technique in patients with chronic lung disease at government hospitals of Rawalpindi. METHODS: A cross-sectional study was conducted in three government hospitals of Rawalpindi. The inhalation technique was assessed in six steps. RESULTS: Clear evidence showed that only 24% patient could perform all the steps correctly. Percentages of people that followed individual steps properly were: preparation (87.5%), exhalation (53.85%), lip closure (68.27%), inhalation (56.73%), breath holding (27.88%) and puff interval (36.54%). CONCLUSION: This study showed that a number of patients in government hospitals of Rawalpindi were unable to use metered-dose-inhaler properly and therefore indicates the need to make people aware of this technique either by counselling or arranging seminars. PMID- 22830143 TI - Presentations of tuberculosis in northern Pakistan. AB - BACKGROUND: Tuberculosis (TB), which is a very common droplet infection. If untreated, the disease may be fatal within 5 years in more than half of cases. The aim of this hospital based descriptive study was to see mode of its presentation in our set-up. METHOD: The study was conducted in Medical Unit, Ayub Teaching Hospital, Abbottabad and 500 diagnosed cases of tuberculosis were included in this study. History regarding presenting symptoms, age, sex, etc. was taken. RESULTS: Out of the 500 patients, 277 (55.4%) were male and 223 (44.6%) were female. Two-hundred-three (40.5%) were in age group 21-35 years, 136 (27.1%) were in age group 36-50 years, 141 (28.1%) were in age group 51-65 years while 20 (4%) were above 65 years of age. Three-hundred-and-eighty (76%) presented as Pulmonary TB, 47 (9.4%) as Abdominal TB, 45 (9%) as TB Meningitis, 13 (2.6%) as Pott's Disease. 7 (1.4%) as TB Lymphadenitis, 6 (1.2%) as Constrictive Pericarditis, 1 (0.2%) as Psoas Abscess and 1 (0.2%) as TB Orchitis. CONCLUSION: TB in its various forms remains a killer disease in our part of the world. The commonest presentation is Pulmonary TB which is probably due to three major factors namely poor hygienic practices, late diagnosis and non-compliance. PMID- 22830144 TI - Assessment of patient satisfaction with mental health services in a tertiary care setting. AB - BACKGROUND: Patients' opinion regarding services has acquired great importance. Patient satisfaction is playing an increasingly important role in quality of care reforms and health-care delivery. The study aimed to measure patient satisfaction in a tertiary care hospital in order to know the patients' perspectives and expectations of the services and make appropriate improvements accordingly. METHODS: This was a cross-sectional study conducted at the Out-patient and Inpatient Departments of the Institute of Psychiatry, Benazir Bhutto Hospital, Rawalpindi, for a period of 8 months from October 2008 till June 2009. Sample size was 246 patients; which included 123 participants from Out-patient and In patient departments each. Patients aged 18 and above, of both genders, who gave informed written consent, were consecutively recruited for the study. Learning disabled patients, frankly psychotic and those with severe cognitive impairment and severe co-morbid physical illnesses were excluded. Performa was filled in by the participants for their demographic details. The Client Satisfaction Questionnaire-8 was then orally administered in the native language (Urdu/Punjabi) to assess the degree of patient satisfaction. RESULTS: Among the participants, 72% were mostly satisfied, 18.7% mildly satisfied and 9.3% dissatisfied with the psychiatric care. Age was significantly associated with satisfaction however no such associations could be found for gender and economic status. CONCLUSION: Majority of the patients were satisfied with the psychiatric services. The younger people were more satisfied. Gender and economic status had no influence on patient satisfaction. PMID- 22830145 TI - Health impact caused by poor water and sanitation in district Abbottabad. AB - BACKGROUND: Large proportions of people still do not have excess to safe drinking water and proper sanitation. METHODS: Qualitative and quantitative approaches were used to assess the health impacts. Random households were selected. Information was collected from questionnaire through interview schedule method, group discussion and observation checklist. RESULTS: People rated water and sanitation condition in urban as: 10% very good, 27% good, 20% bad, 43% very bad, and none of them said we don't know While in rural areas they rated 10% very good, 36% good, 44% bad, 6% very bad, and 4% of them said we don't know. Water sources in selected urban and rural areas were different. 37% in urban and 68% in rural area depended on bore wells as water source, 22% depended on hand pumps. In urban areas, the disease ratio was typhoid 20%, hepatitis 13%, diarrhoea 27%, skin infection 23%, stomach problems 53% and allergies 33%. In rural areas, after stomach problems, diarrhoea, hepatitis and typhoid ratio was very high as compared to urban area. In rural community, 70% were unaware of poor water and sanitation consequences on health. CONCLUSION: The water and sanitation condition in urban as well as in rural community is poor but in rural community it is even worse The drinking water was contaminated with E. coli, Enterobacter, Salmonella and Clostridium. This observation was correlated with prevalence of many water born diseases especially in rural communities of Abbottabad. PMID- 22830146 TI - Diagnostic validity of leukocyte esterase dipstick test for diagnosis of spontaneous bacterial peritonitis in cirrhotic patients. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically treatable source. Spontaneous bacterial peritonitis (SBP) is one of the severe complications in patients with cirrhosis and ascites. Without early antibiotic treatment, this complication is associated with high mortality rate, so early diagnosis and treatment of SBP is therefore necessary for survival. Leukocyte esterase dipstick test can rapidly diagnose the SBP. Objectives were to find out the diagnostic accuracy of leukocyte esterase dipstick test for the diagnosis of spontaneous bacterial peritonitis. METHODS: This cross-sectional, validation study was conducted from January 2009 to June 2009 at Medical Unit-II, Chandka Medical College Hospital Larkana. All the Patients with cirrhosis and ascites of either gender were included in this study. Paracentesis were performed on admission. The ascitic fluid obtained at bedside was immediately tested with reagent strip Multistix 10 SG. Ascitic fluid was then analysed for PMN cell count. The result of reagent strip was compared with ascitic fluid PMN cell count for determination of sensitivity, specificity, PPV and NPV of the test, while taking ascitic fluid PMN count > or = 250/mm3 as standard for diagnosis of SBP. Leukocyte esterase dipstick read positive from +1 to +3 reaction while negative and trace reaction regarded as negative test result. RESULTS: Total ninety four patients were enrolled in this study. Ninety-four Ascitic fluid samples were obtained. SBP was diagnosed in 52 (55.3%) patients, 42 (44.7%) patients were negative for SBP by manual cell count. The sensitivity, specificity, PPV, NPV of leukocyte esterase dipstick test to diagnose SBP were 92%, 95%, 96%, 90% respectively. CONCLUSION: The leukocyte esterase dipstick test can be used as rapid test for diagnosis of SBP due to its high diagnostic validity. PMID- 22830147 TI - Periodontal status of first molars during orthodontic treatment. AB - BACKGROUND: The most important aetiological factor of periodontal disease is plaque deposition around gingival margin. The aim of the study was to investigate the negative changes in periodontal health (increase in pocket depth) of first molars in fixed orthodontic treatment and to discuss the available options to avoid it. METHODS: Group A (6 month of treatment) comprised of 45 patients, compared to Group B (12 month of treatment) comprised of 45 patients. Initial pocket depth of first molars checked before placement of molar bands in both groups of patients, then for Group A patients pocket depth evaluated after 6 month of treatment and for Group B patients pocket depth evaluated after 12 month of treatment period. RESULTS: In patients with 6 months of treatment the pocket depth of molars mostly falls between 1.5 and 2.0 mm. In some severe cases it exceeded 3 mm. In patients at 12 months of treatment pocket depth was greater than 6 month group and it mostly fell in the range of 2.0-2.5 mm. CONCLUSION: Increase in pocket depth showed that plaque deposition leads to periodontal destruction around molar bands. Patient motivation to maintain oral hygiene and regular scaling will minimise hazardous effects. PMID- 22830148 TI - Diabetic foot infections and their management in a tertiary care hospital. AB - BACKGROUND: Diabetic foot is a common complication of diabetes world over. We conducted this study to determine common microbiological pathogens in Diabetic Foot Infections (DFI) at a tertiary care hospital and their management. METHODS: In this observational study deep wound swabs of all admitted diabetic patients were taken, pathogens isolated, antibiotic used and its response depending on complete resolution of symptoms and biochemical markers were recorded. Data were analysed on SPSS-11. RESULTS: A total of 114 cases were recorded. Sixty-eight (59%) cases had ulcers on forefoot, 28 (25%) mid-foot and 18 (16%) hind-foot. One hundred and four pathogens were isolated from wound swabs after debridement. Commonest pathogen isolated was Staphylococcus aureus (52, 46%) followed by E. coli (11, 10%), MRSA was found in 10 (9%) cases, streptococcus in 6 (5%) and pseudomonas in 5 (4%) cases. Polymicrobial infection was also seen in a few cases. Surgical intervention included superficial debridement in 88 (77%) cases, toe amputation/forefoot amputation in 19 (17%) cases, and below/above knee (major) amputation in 7 (6%) cases. Commonest antibiotic used was Cefoperazone/Sulbactam in 43 (38%) cases, alone or in combination, followed by Ceftraixone 36 (33%) cases. Linezolid was used for MRSA. Ninety-four (82%) patients responded to treatment and- were recorded as 'cured'. CONCLUSION: Diabetic Foot ulcers often present with serious foot infections. Commonest pathogens are Staph. aureus, E. coli, Pseudomonas spp. and MRSA. Treatment was effective with Cefoperazone/Sulbactam and Ceftraixone. MRSA was treated successfully with Linezolid. PMID- 22830149 TI - Anterior arch crowding--a possible predictor for mandibular third molar impaction. AB - BACKGROUND: Impaction of the 3rd molar is a high incident problem occurring in up to 73% of young adults in Europe. Appropriate follow-up routines and optimal timing for surgical removal of the 3rd molars can be established in patients judged to be at increased risk of impaction. The purpose of this study was to identify risk factors for mandibular 3rd molar impaction in adolescent orthodontic patients and to establish anterior arch crowding as a predictive model for mandibular 3rd molar impaction. METHODS: Pre-treatment Orthopantomogram (OPG) of 158 orthodontic patients with the evidence of anterior arch crowding on pre-treatment study models were evaluated for mandibular third molar position. RESULTS: Out of 158 patients, 45 were male and 113 were female. Ninety-seven (61%) of the patients showed anterior arch crowding with a space discrepancy of 5 10 mm calculated on the pretreatment study models. Fifty-seven patients showed 107 third molar impactions. Anterior arch crowding in these patients was ranging from 7-10 mm. Out of 107 impacted third molars 73 were Mesioangular 14 were Distoangular 6 were Vertical and 14 were Horizontal. CONCLUSION: If the arch size is smaller as compared to the tooth size the evidence of lack of space would be there in anterior segment as crowding and in posterior segment as 3rd molar impaction. PMID- 22830150 TI - Antipsychotic treatment and weight gain: does risperidone behave differently in Pakistani psychiatric patients? AB - BACKGROUND: Studies from the Western world have shown that antipsychotic medications in psychiatric patients result in weight gain and other metabolic diseases. This study was undertaken to investigate whether any one of the five most commonly prescribed antipsychotics, (risperidone, olanzepine, trifluoperazine, quetiapine and haloperidol) could behave differently in terms of causing weight gain among patients attending the psychiatric outpatient clinics in a tertiary care hospital in Karachi, Pakistan. METHODS: For this retrospective cohort study, data were collected from outpatient records of the Aga Khan University Hospital, from 2003 to 2007. Demographic and clinical data were analysed. Repeated measures ANOVA, using a linear mixed model approach was used to assess weight gain over time due to the use of antipsychotic medications. RESULTS: A total of 124 subject records (68 males and 56 females) were evaluated. One-way ANOVA revealed that the groups being prescribed with antipsychotics were comparable with respect to age, duration of treatment and weight measurements. Frequencies were calculated which showed that weight increases significantly over time with respect to the prescribed antipsychotic medications, except for risperidone. Repeated measures ANOVA using the linear mixed model approach showed that the serial weight measurements were significantly different across the follow up times (p<0.05). CONCLUSION: Four of the commonly prescribed antipsychotic drugs do result in an increase in weight; however risperidone has no such effect, making it an option in-treating psychiatric disorders without worrying for any gain in weight. In view of the increased prevalence of obesity and other metabolic diseases, measures should be taken towards careful prescription of antipsychotic medications. PMID- 22830151 TI - Influence of gender, BMI, and ethnicity on serum ALT levels of healthy students of a medical school. AB - BACKGROUND: Alanine Aminotransferase (ALT) is an enzyme found in liver and indicates injury to hepatocytes. It is influenced by various factors. The objectives of this study were to identify the correlates of ALT activity among healthy medical students of Army Medical College, National University of Sciences and Technology, aged 18-22 years. This was to establish the mean ALT levels of the students and compare them with those in various parts of the world and observe various correlations that exist and factors that may influence ALT levels. METHODS: This population included 143 volunteer students (93 men and 50 women) selected on the basis of negative answers to a detailed medical questionnaire including past medical history, drug and alcohol consumption, on the absence of clinical signs of liver disease, on the negativity of serological testing for Hepatitis B and C virus. RESULTS: The mean ALT level of the entire population was 28.7 IU/L. A major sex-difference in ALT value was observed, the mean ALT value being higher in men than in women (32.1 +/- 21.7 vs. 22.6 +/- 9.7 IU/L, p<0.004). According to WHO criteria for Asians, normal BMI was taken from 18.5-23.0 Kg/m2. There was a positive significant correlation between serum ALT level and BMI (p<0.002). ALT level strongly correlates with body mass index and gender. There was no significant variation in ALT levels among Punjabis and Sindhis, Balochis, Pathans, and Kashmiris. CONCLUSION: We suggest the need of taking into account these parameters in a clinical interpretation of ALT level. PMID- 22830152 TI - Importance of polymerase chain reaction in diagnosis of pulmonary and extra pulmonary tuberculosis. AB - BACKGROUND: Pakistan ranks 8th on the list of 22 high-burden tuberculosis (TB) countries in the world according to the World Health Organization's (WHO) Global Tuberculosis Control 2009. Including other reasons the main cause is improper and late diagnosis of the disease. PCR may play an important role to control the disease with its rapid, sensitive and specific diagnosis. But in Pakistan due to lake of knowledge about this latest technique we are not using this technique appropriately. Clinicians still trust on conventional methods of TB diagnosis, which are time consuming or insensitive. The present study was arranged to highlight the importance of PCR in TB diagnosis in pulmonary and extra-pulmonary cases and its comparison with conventional methods. METHODS: Samples obtained from 290 patients of suspected TB (pulmonary or extra-pulmonary) were subjected to ZN smear examination, LJ medium culture and PCR test by amplifying 541bp fragment of Mycobacterium tuberculosis complex genome. The present prospective study is performed at Shalamar Hospital Lahore from November 2008 to November 2010. RESULTS: A distinctly difference was observed in the test results done by PCR and other conventional techniques in pulmonary or extra-pulmonary tuberculosis samples (p<0.001). The sensitivity of different tests was 68.62% for PCR, 26.90% for LJ medium culture, and 14.14% for ZN smear examination (p<0.05). However, there was no significant difference between different tests as for as specificity was concerned. PCR test sensitivity in pulmonary and extra-pulmonary clinical samples was 78.34 and 61.76% respectively, being significantly higher (p<0.05) when compared with sensitivity of other tests. The mean detection time for M. tuberculosis was 25 days by LJ medium culture and less than 1 day by smear examination and PCR test. CONCLUSION: PCR test is more sensitive than ZN smear examination and LJ medium culture for the diagnosis of TB in pulmonary and extrapulmonary clinical samples. PMID- 22830153 TI - Effect of maternal anaemia on birth weight. AB - BACKGROUND: Anaemia is a common medical problem in pregnancy. The extent up to which, maternal anaemia effects maternal and neonatal health is still uncertain. Maternal anaemia is commonly considered a risk factor for low birth weight (LBW) babies. Some studies have demonstrated a strong association between low haemoglobin before delivery and LBW babies. However, others have not found a significant association. Therefore, there is insufficient information to assess the overall adverse impact of anaemia during pregnancy. The aim of this study was to determine whether maternal anaemia would affect the birth weight of the baby and compare this with that of non-anaemic mothers. It was a cross-sectional comparative study carried out at the maternity ward of Fauji Foundation Hospital, Rawalpindi. METHODS: One hundred subjects divided into two groups each containing 50 subjects on the basis of consecutive non probability sampling were included in the study. Group-A included 50 Anaemic pregnant women and Group-B 50 non-anaemic pregnant women. Information was collected by direct interviewing method through a precoded structured questionnaire. The Hb level and birth weights were taken from the labour room record. RESULTS: The mean age of the mothers in anaemic group was found to be older than the non anaemic group, i.e., (29.44 versus 27.98), though the difference was statistically non significant. The number of low birth weight infants (64%) was statistically very highly significantly more (p<0.001) in the anaemic group of mothers than the non anaemic group (10%). CONCLUSION: The results of this study show an association of maternal anaemia in pregnancy with increased risk of LBW babies. PMID- 22830154 TI - Frequency and severity of neutropenia in diffuse large B-cell non Hodgkin's lymphoma after first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolone. AB - BACKGROUND: Chemotherapy used for malignant diseases may produce severe neutropenia in first cycle which may compel for dose modification and early termination of therapy. This descriptive cross sectional study was planned to see the frequency and severity of neutropenia after first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolon in patients of diffuse large B-cell non Hodgkin's lymphoma presenting at Oncology Department Combined Military Hospital Rawalpindi from August 2009 to July 2010. METHODS: Thirty patients of diffuse large B-cell non Hodgkin's lymphoma diagnosed on lymph node biopsy presenting for the first time at Oncology Department Combined Military Hospital Rawalpindi were included. They were admitted in the ward and evaluated with history, physical examination and staging investigations. Patients were then planned for first cycle of chemotherapy comprising cyclophosphamide, doxorubicin, and vincristine with prednisolon. After the first cycle of chemotherapy they were monitored for expected neutropenia in the ward. The neutrophil counts were repeated on days 7 and 10 following chemotherapy. Neutropenia was graded as defined in the operational definition and all the data was entered on a specially designed data card. RESULTS: As much as 3.3% of patients suffered from grade IV neutropenia (absolute neutrophil count of <0.5x10(9)/L), 3.3% had grade III neutropenia (absolute neutrophil count of 0.5x10(9)/L-0.9x10(9)/L), 6.6% had Grade II neutropenia (absolute neutrophil count 1.0x10(9)/L-1.4x10(9)/L and 10% had Grade I neutropenia (absolute neutrophil count 1.5x10(9)/L-1.9x10(9)/L. CONCLUSION: Overall 23.2% suffered from neutropenia of all grades post 1st cycle of chemotherapy comprising cyclophosphamide, doxorubicin, vincristine with prednisolon in diffuse large B cell non Hodgkin's lymphoma. Further studies are required to find the risk factors to predict this complication in our population. PMID- 22830155 TI - Assessment of male reproductive health by conventional method of semen analysis. AB - BACKGROUND: Data available over the past twenty years reveal that in approximately 30% of cases of infertility, pathology is found in man alone, and in another 20% both man and woman are abnormal. Therefore, the male factor is at least partly responsible in about 50% of infertile couples. The longer a couple remains sub fertile, the worse is their chance for an effective cure. This study was planned to analyse the complete semen picture of infertile men for assigning the specific cause to male infertility related to concentration, motility and morphology and to know the distribution and pattern of male infertility in the various subclasses in Pakistani population. METHODS: It was a prospective descriptive analytical study conducted at Department of Reproductive Physiology/Health, Public Health Divisions, National Institute of Health (NIH), Islamabad. One thousand five hundred twenty-one (1,521) infertile male patients, and 97 proven fathers, taken as a control. Conventional semen analysis was performed on all samples. RESULTS: Out of 1,521 infertile men, 13.3% were azoospermic, 23.2% oligozoospermic, 0.9% polyzoospermic, 14.5% normozoospermic, 35.2% asthenozoospermic 10.5% oligoasthenozoospermic and 2.4% teratozoospermic. Sperm concentration and active motility of proven fathers, was significantly higher (p<0.05) than the normal concentration group. Least liquefaction time was recorded in case of polyzoospermic subjects, and highest for azoospermic cases. Although, the liquefaction time of azoospermic and oligozoospermic subjects varied non-significantly (p>0.05) with the proven fathers. Normal forms were significantly higher (p<0.05) among the proven fathers and polyzoospermic cases, in comparison with the other groups. Head defects were more in teratozoospermic group, followed by oligoasthenozoospermic and oligozoospermic patients. Neck defects were more profound in oligoasthenozoospermic and oligozoospermic patients, while, tail defect showed significant increase in teratozoospermic and asthenozoospermic cases only. Head and neck defect varied significantly (p<0.05) with proven fathers in all groups, while tail defect varied significantly (p<0.05) in oligozoospermic, asthenozoospermic and teratozoospermic groups only when compared with proven fathers. CONCLUSIONS: Complete semen analysis which provides important information about the quality and quantity of the sperm, should be performed before reaching a final conclusion. PMID- 22830156 TI - Evaluation of Pro-C global for identification of defects in protein C/S anticoagulant pathway. AB - BACKGROUND: Detection of protein C and S deficiency forms a major investigation in the laboratory evaluation of thrombophilia screening. It has key role in the diagnosis of protein C and S deficiency. The objective of this study is to determine the utility of ProC Global as a screening test for identifying the defects of protein C and S anticoagulant pathways. METHODS: Two Hundred patients with venous thromboembolism were studied at the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi, from October 2004 to March 2006. ProC Global test (Dade Behring Diagnostics) was performed and was followed up by protein C and S assays. ProC Global is an activated partial thromboplastin time based assay in which Protac (snake venom from Aghistroden contortrix) is used for activation of the endogenous protein C of the plasma sample. The protein C activation time in the presence of the activator was set in relation to a parallel determination of PCAT/O with addition of a buffer instead of activator reagent. The ratio PCAT: PCAT/O was transformed in normalized ratio by relating them to a calibrator. Control plasma for normal range and ProC control plasma for pathological range (Dade Behring Diagnostics) were assayed in each run for quality control. RESULTS: A total of 200 patients, 132 (66%) males and 68 (34%) females with age ranging from 1 to 68 years were studied. ProC Global was positive in 29/200 (14.5%) patients. ProC Global was found to be 86% sensitive, 94% specific and its overall efficiency turned out to be 94%. CONCLUSION: Pro-C Global can be used effectively as a screening test to detect abnormalities in protein C and S anticoagulant pathways. PMID- 22830157 TI - Maternal mortality in a tertiary care hospital. AB - BACKGROUND: Death of a woman during pregnancy and child birth is an extremely tragic event. It is a waste of a precious life that leaves great feeling of grief and pain for the family and hospital staff and has devastating influence on the community overall. Maternal morbidity and mortality can be prevented by awareness of reproductive health in a community, availability, and utilisation of organised antenatal care, skilled intrapartum management and careful postnatal follow up. Objective was to analyse the pattern of maternal mortality over the period of five years in a tertiary level hospital receiving high risk referred patients form periphery. METHODS: All patients admitted in Gynae 'A' Unit, Ayub Teaching Hospital from January 2006 to December 2010 were included in the study and number and causes of maternal deaths were noted. RESULTS: During these 5 years there were 78 maternal deaths out of 11,997 obstetrical admissions. There were 7,380 total births and 78 maternal deaths during the study period and Maternal Mortality Rate was 1,057/100,000. The main cause of maternal death was eclampsia and its complications (28.2%). CONCLUSION: Eclampsia is the leading cause of maternal mortality in our setup. Proper and timely referral is an important measure to prevent it. PMID- 22830158 TI - Serum bilirubin and antioxidant levels in first degree relatives of patients with ischemic heart disease and normal subjects. AB - BACKGROUND: Coronary diseases appear to result from an overbalance between radical-generating, compared with radical-scavenging systems, a condition called as oxidative stress. Total antioxidant status (TAS) in human plasma reflects the balance between oxidants and antioxidants in each system. Bilirubin has been considered an antioxidant, with capacity to remove reactive species of oxygen. Present study tried to measure the total antioxidant status of first degree relatives of patients with IHD. Study also tried to evaluate the prognostic role of serum bilirubin in disease prevention or progression. METHODS: Seventy five apparently healthy subjects in age group 20-50 years, comprising equal number of males and females, who were first degree relatives of ischemic heart disease patients, were included in the study. Family members were divided on the bases of their numbers, i.e., one family member (Group-A), 2 family members (Group-B) and more than 3 family members (Group-C). Study was cross sectional and carried out in a period of 6 months (Jun 2008-Jan 2009). Subjects with letter of consent were taken from general population. Seventy five healthy age matched people with no history of ischemic heart disease in family were taken as control. An overnight fasting blood sample was taken. Total antioxidant status was determined using a commercially available kit. Serum bilirubin was estimated by auto analyzer. RESULTS: Family history of ischemic heart disease with serum bilirubin showed a significant negative correlation (p<0.05). But the values of TAS failed to show any significant correlation with the family history. It was observed that the value of serum bilirubin was decreased significantly (p<0.05) with an increased number of family members. Total antioxidant status failed to show any significant difference among all the three groups. CONCLUSION: Our data demonstrated that reduced serum levels of bilirubin were seen in people with a higher prevalence of coronary artery disease in the family. The levels of serum bilirubin showed a downward trend with an increase in number of family members affected with ischemic heart disease. Present study failed to show a definite association of total antioxidant status with family history of ischemic heart disease. Additional studies are still necessary on large number of first degree relatives to confirm and demonstrate the association of these findings with clinical outcomes. PMID- 22830159 TI - Incidence of methicillin resistant Staphylococcus aureus in Peshawar. AB - BACKGROUND: There is considerable variation in the percentage of isolates of methicillin resistant Staphylococcus aureus (MRSA). There are several mechanisms for methicillin resistance. The most important is low affinity of penicillin binding proteins for beta-lactam antibiotics. The objectives of this study were to establish the pattern of MRSA incidence in Peshawar in recent years, and to identify high risk groups for acquiring infection amongst the city population. METHOD: All positive MRSA cases reported at city laboratory were employed in the study. These were recorded over the time period elapsing from 2009 to 2011. For each patient, records were looked at for age, sex, specimen tested positive, hospital/community acquired and if hospital acquired then which particular hospital within the city was infection contracted at. Also patient records were addressed for any immune system abnormalities, any operation conducted, presence or absence of diabetes and any history of intravenous drug use. RESULTS: There were a total of 929 MRSA cases in our study, of which 538 were males and 391 were females. MRSA frequency for the year 2009 was 207, for 2010 it was 284 and for 2011 it was 438. The frequency of MRSA increased by 54% from the year 2009 to 2011. CONCLUSION: A potentially alarming increase in MRSA incidence within the city has been observed in recent years threatening to rise further judging the current trend. Those at a high risk of contracting infection include males aged between 20-29 years, hospitalised, diabetics, immune system compromised, and individuals with a history of IV drug use. PMID- 22830160 TI - Epidemiology of acquired aplastic anaemia in Pakistan. AB - BACKGROUND: Acquired aplastic anaemia is a rare disease which results in morbidity and mortality at a young age. This study was carried out to determine the clinical presentation, haematological parameters and association factors of acquired aplastic anaemia in a cohort of Pakistani patients. METHODS: This was a cross-sectional study conducted at Haematology Department, Shaikh Zayed Hospital, Lahore over 7 years from June 2000 to July 2007. Eighty-two patients of acquired aplastic anaemia were enrolled in the study by non-probability purposive sampling. Their diagnosis was confirmed by complete blood count, bone marrow aspirate and trephine biopsy. The cohort was classified on the basis of severity and the epidemiological, clinical and haematological parameters were analysed. RESULTS: Of the 82 enrolled patients of acquired aplastic anaemia, 49 (59.8%) were males and 33 (40.2%) were females. Mean age of the patients was 27.93 +/- 18.7 years with a range of 1-80 years. The male to female ratio was 1.48:1. Bone marrow cellularity was less than 25 % in 31 (38.0%) cases and between 25-30% in 51 (62%) of patients. Most of the cases were clinically severe aplastic anaemia (68%). In 62 (76%) of the cases no association factors predisposing to aplastic anaemia could be identified. CONCLUSION: Acquired Aplastic anaemia is a disease of all ages. In the second decade and the elderly predominantly severe clinical stages were seen. Males presented at a younger age while females presented at all ages with a somewhat similar incidence. No association factors of Aplastic Anaemia could be identified in majority of the patients. PMID- 22830161 TI - Pattern of dyslipidemia in adult diabetic subjects in the community hospital of district Swat. AB - BACKGROUND: The incidence of diabetes is growing at dramatic rates around the word and its complications are associated with significant health and financial burdens, warranting strong and comprehensive prevention efforts. The objective of the present study was to evaluate the pattern of dyslipidemia in the adult diabetic patients in Saidu Teaching Hospital, Saidu Sharif, Swat. METHODS: The study comprised of 100 subjects, 50 subjects with diabetes and 50 (non-diabetic) controls. The serum Cholesterol, Triglycerides, High-density Lipoprotein Cholesterol (HDL-C) and Low-density Lipoprotein-Cholesterol (LDL-C), blood sugar (random and fasting), blood pressure (systolic and diastolic) of Diabetic subjects were compared with Control subjects. RESULTS: Diabetic subjects had high mean value of Triglycerides and LDL-C (but statistically nonsignificant), low level of HDL-C (statistically highly significant) and high blood pressure as compared to Control subjects. CONCLUSION: Dyslipidemia is a potent predictor of cardiovascular morbidity and mortality in diabetic patients. PMID- 22830162 TI - Coverage and causes of missed Haemophilus influenzae type B vaccination in urban and rural areas of Peshawar. AB - BACKGROUND: Haemophilus influenza type b (Hib) is a major cause of morbidity and mortality in Pakistan. Hib vaccine was introduced in 2009 in EPI programme. The purpose of this study was to find out the coverage and factors associated with non-immunization of Hib in urban and rural areas of Peshawar. METHODS: Data was collected through random sampling in Peshawar University, Peshawar Saddar, Hashtnagri, Naway Kalay and Pawaka from 9th to 19th of June 2010. A questionnaire was used to interview parents of 600 children aged 1 year and below about demographics, Hib vaccination status, reasons for missed vaccination and views on immunization. Pearson's Chi-square test was used for statistical testing, and p<0.05 was considered significant. RESULTS: Completely vaccinated children were 64.2%, 25% not vaccinated at all, and 11% were incompletely vaccinated. The reasons for not vaccinating were lack of awareness (26%), family problem/mother busy (18%), centre too far (16.9%), wrong ideas (12.2%), fear of reaction (5.4%), child illness (8.1%) and miscellaneous causes (13.7%). CONCLUSION: Low Hib vaccination coverage in Peshawar is mainly due to low awareness among people, poor economic conditions and illiteracy. PMID- 22830163 TI - A comparison between open and closed hemorrhoidectomy. AB - BACKGROUND: Haemorrhoidectomy is associated with complications including pain, bleeding and wound infection which can result prolonged hospital stay. Haemorrhoidectomy is considered to provide a better outcome in terms of postoperative pain and wound healing. Aims were to compare postoperative pain, bleeding, operating time and wound healing in patients undergoing open and closed haemorrhoidectomy. METHODS: This comparative study was conducted in the surgical department at Fauji Foundation Hospital, Rawalpindi from December 13, 2006 to December 31, 2011. Consecutive patients, both male and female, presenting with 3rd and 4th degree haemorrhoids in the surgical Outpatient Department were included in this study. Half of the patients were assigned to the open haemorrhoidectomy group while the other half was put in the closed haemorrhoidectomy group. Each patient was evaluated by detailed history and examination. Both digital rectal examination (DRE) and proctoscopy were done to confirm the diagnosis. RESULTS: A total of 260 patients were assessed, 130 in each group. In the open group, 52 patients experienced mild pain and 78 moderate while in the closed group, 30 patients experienced mild pain, 87 moderate and 13 patients severe pain. All 130 patients in the closed group showed complete wound healing after 2 weeks as compared to only 66 patients in the open group with a p<0.001. Early and late postoperative bleeding was similar in both groups. CONCLUSIONS: The closed technique provides a better outcome in terms of less postoperative bleeding and complete wound healing, but it is associated with more pain. PMID- 22830164 TI - Frequencies of congenital anomalies among newborns admitted in nursery of Ayub Teaching Hospital Abbottabad, Pakistan. AB - BACKGROUND: Congenital anomalies play a significant role in perinatal and neonatal morbidity and mortality. The frequency of these congenital anomalies varies in different populations. Objective of this study was to find out the frequencies of congenital anomalies admitted in nursery of Ayub Teaching Hospital, Abbottabad. METHODS: In this descriptive, cross-sectional study all patients admitted in NICU from October 2009 to January 2010 were included. The patients were examined for major and minor congenital anomalies. The observations were recorded in tabulated form. RESULTS: A total of 2,360 patients were admitted in NICU during the study period. One hundred patients were noted to have congenital anomalies. The most frequent anomalies involved the central nervous system (31%). Meningomyelocele was the commonest defect (71%, 22 out of 31 cases of CNS defects), among these males were more (77%, 17 out of 22 of meningomyelocele cases) than females (14 out of 31). These were followed by patients born with congenital heart defects (16%). Patients with urogenital anomalies (6%) were all male except for one who had ambiguous genitalia. CONCLUSIONS: Cases of meningomyelocele were the commonest presenting congenital anomaly. More stress should be laid on the role of peri-conceptional vitamin supplementation like folic acid for the primary prevention of congenital defects. PMID- 22830165 TI - Epidemiology and outcome in patients of diabetic foot. AB - BACKGROUND: The aim of study was detailed analysis of the presentation of diabetic foot ulcers, characteristics and predictors of outcome (incidence of amputation in neuropathic, ischemic, neuro ischemic) in patients presenting with diabetic foot at our hospital. METHODS: This prospective analytic study was conducted from January 2009-August 2010 at POF Hospital Wah Cantt. Diabetic patients who presented with foot ulcers were enrolled in this study. Demographics of patients along with ulcer size, type, site and Grade according to Wagner Classification were recorded. Wounds were managed with daily dressings, nursing care and de-sloughing of necrotic tissue along with appropriate antibiotic cover. Patients were followed over period until wound healed completely or a lower limb amputation performed, the outcome noted and patient was deemed to have completed study. RESULTS: One hundred and fifteen patients with mean age 55.46 +/- 8.23 years, both male and female were included in this study. Out of 115 patients 111 patients had Type-II diabetes while only 4 p resented with Type-I. Mean Duration of diabetes was 14.61 +/- 2.17 years. With respect to underlying causes 18.3% foot ulcers were ischemic, 22.6% were neuropathic and 59% were neuro-ischemic. Median ulcer size was 74% of ulcer classified as Wagner grade-II and III while 24% were of Grade-V. Lower limb amputation were performed in 25% of patients whereas limb salvage achieved in 75% of patients with wounds healed (median healing time 5 (3-10 weeks). CONCLUSION: Preservation of the limb function without endangering the patient must be a goal of treating diabetic foot. Once foot amputation is successful, rehabilitation with orthotic or prosthetic devices may allow years of a functional extremity along with preventive measures like cessation of smoking, dailyfoot hygiene and foot inspection. PMID- 22830166 TI - Comparison of serum creatine kinase estimation with short tandem repeats based linkage analysis in carriers and affected children of Duchenne muscular dystrophy. AB - BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive lethal, genetic disorder characterised by progressive weakness of skeletal muscles which is untreatable and transmitted to males by carrier females. Advances in laboratory techniques now focus direct mutational analysis as the most reliable and indirect analysis based on Short Tandem Repeats (STR) based linkage analysis as feasible, inexpensive, and efficient method for carrier detection and prenatal diagnosis. The objective of this study was to compare the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic efficiency of Serum Creatine Kinase (SCK) with Short Tandem Repeats (STR) based linkage analysis in carriers and affected children of Duchenne Muscular Dystrophy. METHODS: The study was carried out from Dec 2006 to Dec 2007 in families having index clinical cases of DMD who were referred from different hospitals for evaluation/workup of DMD. SCK was done as a preliminary investigation in all index cases. The PCR assay with STR based linkage analysis with Intron 44, 45, 49 and 50 of DMD gene were performed in all families. Six families were informative with Intron 44 of DMD gene and one family was non informative with all four intronic markers of DMD. SCK analyses were done in all the family members and compared with PCR analysis in informative families. SCK was not performed on Chorionic villous sample (CVS) done for prenatal diagnosis of DMD, and CVS and non-informative family members were excluded from the study. RESULTS: In carriers of DMD, the sensitivity and negative predictive value of SCK were 33.3%, and specificity and positive predictive were 100% with diagnostic efficiency of 50%. In affected cases of DMD the sensitivity and negative predictive value of SCK were 100%, and specificity and positive predictive were 91% and 88.8% respectively and diagnostic efficiency of 94.1%. CONCLUSION: The SCK is an excellent screening test for affected cases of DMD. For carrier identification we have to resort on PCR analysis so as to provide safer diagnostic tool for genetic counselling and prenatal diagnosis. PMID- 22830167 TI - Diagnostic accuracy of endometrial curettage in endometrial pathology. AB - BACKGROUND: Abnormal uterine bleeding is one of the most frequent problems in life of an adult female. Uterine curettage or biopsy remains a preferred sampling procedure for diagnosis of the endometrial pathology. The objective of this study was to compare the sensitivity, specificity, positive and negative predictive value of endometrial curettage. PATIENTS AND METHODS: This validation study was carried out at the Department of Histopathology, Army Medical College Rawalpindi in collaboration with Military Hospital, Rawalpindi from January to December 2010. The study included 50 curettage and subsequent hysterectomy specimen of the same patients. Non-probability sampling technique was used to divide patients into two groups with 50 patients in each group. One group was of endometrial curettage having endometrial pathology (group A). Second group was of subsequent hysterectomy specimen of the same patients (group B). RESULTS: Endometrial curettage was found most accurate in diagnosing endometrial carcinoma. Sensitivity of endometrial curettage was found to be 33% whereas specificity and positive predictive value was found to be 100% each. Negative predictive value was found to be 93.1%. CONCLUSION: Endometrial biopsy is a sensitive and a specific test in and is accurate in diagnosing endometrial pathology. It is found most accurate in diagnosing endometrial carcinoma. PMID- 22830168 TI - Availability and affordability of essential medicines: exploring the health seeking behaviours and health service utilisation for children under-5 years living in squatter settlement of Karachi, Pakistan. AB - BACKGROUND: Child health outcomes in the poor communities are largely affected by the non-availability of essential medicines at government health facilities and non-affordability of prescribed medicines at private retail pharmacies. This phenomenon largely defines health seeking behaviours and health service utilisation patterns of the families of the children. METHODS: Using observational visits, we examined the shelf-availability of medicines for children less than 5 years of age at a rural health centre and conducted focus group discussions with the mothers to explore the effects of non-availability and non-affordability of medicines. We also validated all information by interviewing the health care providers of the area. RESULTS: We found that erratic and insufficient supply of essential medicines at the government health facility and a limited purchasing power to buy medicines from a retail pharmacy, led to considerable 'financial burden' on the poor people, non-compliance with the treatment, health care seeking from informal health providers and healer shopping. This trend has a serious repercussion on the health seeking behaviours and of course the health outcomes, especially among children. CONCLUSION: On the users' side, health education and health promotion campaign must be instituted to explain the adverse effects on child health ensure appropriate health care seeking behaviours. For the supply side, the health care authorities must ensure the availability of essential medicines for the children at the government facilities. Local community representatives must be involved in the matters related to medicines stock management at the facility. PMID- 22830169 TI - Antimicrobial susceptibility pattern of Staphylococcus aureus on clinical isolates and efficacy of laboratory tests to diagnose MRSA: a multi-centre study. AB - BACKGROUND: The global problem of increasing trend in antimicrobial resistance is particularly pressing in the developing countries, where the Methicillin Resistant Staphylococcus aureus (MRSA) is often the severe casual agent in hospital-acquired infections. METHODS: This multi-centre surveillance prospective study was planned to define the magnitude of problem of MRSA among clinical isolates from four teaching hospitals of Lahore Pakistan; Mayo, Services, Jinnah and Shaikh Zayed Hospitals during April 2006-March 2008. Identification of organisms was done by the standard Microbiology methods. MRSA isolates identified on Kirby-Bauer disc diffusion were further evaluated by minimum inhibitory concentration on BD Phoenix system and detection of mecA gene by pulsed-field gel electrophoresis (PFGE) PCR. RESULTS: Of the total 1,102 S. aureus isolates, oxacillin resistance was found in 462 on disc diffusion and 420 on MIC while mecA gene was detected from 307 strains. The prevalence of MRSA among S. aureus isolates was 41.9%, 38.1% and 27.9% on disc diffusion, MIC, and mecA gene detection respectively. Hospital acquired-MRSA strains were multi drug resistant while community acquired-MRSA showed susceptibility to clindamycin (63%), ciprofloxacin (24.2%) and SMZ/TMP (3.9%). In diagnosing MRSA, the sensitivity and specificity rates of disc diffusion test were 100% and 83.7% while MIC 96.2% and 93.3% respectively. CONCLUSION: There is an increasing trend in emergence MRSA and the conventional method of antimicrobial susceptibility testing showed false positive tests. This is the reason of misuse of vancomycin by physicians which may further increase MRSA in Pakistan. Therefore, molecular diagnostic facilities are recommended to avoid false-susceptible results. PMID- 22830170 TI - Platelet count in malaria patients. AB - BACKGROUND: Malaria is a major health problem in the tropics with high morbidity and mortality. This study is conducted to analyse the effects of malaria on platelets. METHODS: This prospective study was conducted on 200 diagnosed cases of malaria in Department of Medicine, LUMHS, Jamshoro/Hyderabad from February to December 2010. The diagnosis of malaria was carried out by thin and thick blood films. Platelet count was performed using an automated counter. Thrombocytopenia was classified as mild (50-150x10(3) cells/microl), moderate (20-50x10(3) cells/microl) and severe (<20x10(3) cell/microl). RESULTS: The age of patients ranged from 16 to 80 (28 +/- 10.5) years, median age was 30 years. Among the study population, males were 124 (62%) and females were 76 (38%). Out of them 105 (52.5%) were cases of Plasmodium falciparum, 93 (46.5%) were of P. vivax, and 2 (1%) were of P. malaria. The data showed that 171 (85.5%) patients were having low platelet count; 141 (70.5%) had mild, 21 (10.5%) moderate, and 9 (4.5%) had severe thrombocytopenia. Twenty-nine (14.5%) patients had normal platelet count. CONCLUSION: Malaria is associated with different degrees of low platelet count with rarely increased bleeding tendency. PMID- 22830172 TI - School health promotion--international perspectives and role of health care professionals. AB - BACKGROUND: Schools have great potential in health promotion; however, this is often neglected area and fewer efforts are done in exploring status of school health promotion in Pakistan. This paper attempts to outline brief historical background of school health promotion in Pakistan; presents critical review of some international school health promotion perspectives; and finally explore opportunities and role of healthcare professionals in Pakistan's context. METHODS: A critical review of peer-reviewed literature divided into two broad themes of international perspectives on school health promotion, and role of healthcare professionals. Results are presented in cross-cutting themes and in narrative style. RESULTS: School health promotion is very diverse phenomenon, situated in respective cultural contexts. Programmes pesent a range of characteristics from focusing on integrated approach to health education to behavioural changes; and from involving youngsters to policy advocacy. Like the programmes, role of healthcare professionals is also varied and dynamic and without clearly defining their role, development of effective health promotion programmes is difficult. CONCLUSION: School health promotion could be facilitated by appropriate trainings for healthcare professionals and evidence-based policy changes. PMID- 22830171 TI - Nurses' knowledge of evidence-based guidelines for prevention of ventilator associated pneumonia in critical care areas: a pre and post test design. AB - BACKGROUND: Ventilator associated pneumonia (VAP) is a common hospital acquired pneumonia in ventilated patients. VAP is associated with increased morbidity, mortality duration of hospitalization and cost of treatment. Critical care nurses are usually unaware of evidence based preventive guidelines for VAP, resulting in negative impact on all aspects of patient care. This study investigated the impact of a 5-hour teaching module on nurses' knowledge to practice evidence based guidelines for the prevention of VAP. METHODS: This study was conducted at a private tertiary care teaching hospital in Karachi, Pakistan. Single group pre test design was used. Forty nurses were included in the study. The knowledge of nurses was assessed before, immediately after and 4 weeks after the intervention. The final sample (n=40) was selected on the basis of the set inclusion criteria. The demographic data sheet was used to collect relevant information about the participants. Knowledge was assessed through a self-developed validated tool, consisting of multiple choice questions. The difference in knowledge was analysed through repeated measures of analysis of variance. The mean scores at 3 time points were compared using the Tukey's multiple comparison procedure. RESULTS: Knowledge scores of participants increased significantly after the educational intervention in the first post-test; however, there was a decline in the score in post-test 2. CONCLUSION: the 5-hour teaching module significantly enhanced nurses' knowledge towards evidence based guidelines for the prevention of VAP. Further research is needed to assess the impact of training on nursing practice and to explore factors affecting attitudinal change. PMID- 22830173 TI - Evaluation techniques in Punjab, Pakistan: eight years of reforms in health professional education. AB - Pakistan, the most populated country in the WHO Eastern Mediterranean region has a population of over 170 million, spread over five provinces and four federally administered areas. It has a growth rate of 1.9%. Punjab is the most populous and developed province with an estimated population in 2010 of 81 million. In 2008, Punjab's development index of 0.60 and a literacy rate of 80% were the highest in the country. In Pakistan, the number of doctors and nurses has risen from 48 to 71 per 100,000 and from 16 to 30 per 100,000, respectively between 1990 and 2003. The major challenge, still, is the imbalance of the population to health-care workers ratio. At the time of creation of Pakistan, King Edward Medical College was the only fully functioning medical college. Over the years, as a result of health reform initiatives, a number of government medical colleges were established in the country. University of Health Sciences, Lahore was established in 2002, having sole jurisdiction over all medical, dental and allied health institutes in the province with the aim of moving medical education towards an outcome-based patient and community-oriented competency-driven system. This paper attempts to clarify how initiatives and reforms in the evaluation process have helped the UHS realise its aims. Evaluation in all branches of higher education has long been taken as a means to an end. The focus of UHS on teacher-training, introduction of behavioural sciences as a compulsory subject and setting up an outcome-based evaluation process, has established a knowledge-acquisition medical education atmosphere. The challenges in the future relate to sustainability through capacity-building and staying abreast with the Best Evidence Medical Education practices worldwide, implementing them to fit our local needs and resources. PMID- 22830174 TI - Infectious diseases of Afghan immigrants in the United States: review of published reports. AB - Infectious diseases of immigrants may differ from patients born and resident in the same country, especially if immigrants from Africa or Asia live in Europe or North America. Because the available information is limited published reports of infections of Afghan immigrants in the United States and other countries were analysed. Four reports from the US and 15 reports from other countries were identified [7, (46.7%) Pakistan, 5 (33.3%) Iran, 1 (6.7%) United Kingdom, 1 (6.7%) Germany, 1 (6.7%) Israel)]. Reports from the US were case reports or case series of infections with gastro-intestinal parasites and Mycobacterium tuberculosis (1, 25%), Echinococcus species (2, 50%), and Plasmodium vivax (1, 25%). Reports from other countries were case reports, case series, or surveys and investigated infections with Echinococcus species (2, 13%), Hepatitis B virus (HBV) (1, 6.7%), M. tuberculosis (6, 40%), P. falciparum (1, 6.7%), Leishmania tropica (3, 20%), Fasciola hepatica (1, 6.7%), and M. leprae (1, 6.7%). The reports suggest that Echinococcus species and L. tropica infections can be encountered in Afghan immigrants in the US, and the frequency of a positive PPD (purified protein derivative) response or HBsAg test was increased. An infectious diseases database specific for the country of residence readily available to clinicians treating Afghan patients outside of Afghanistan may be useful. PMID- 22830175 TI - Huge sub-mandibular gland tumour. AB - Salivary gland neoplasms are a diverse group of tumours and appropriate treatment depends on adequate understanding of the pathophysiologic behaviour of each tumour type. Most (95%) salivary glands occur in adults. Benign tumours are slow growing tumours and attain a considerable size before presenting to surgeon. We report a case of huge tumour of left submandibular gland that presented in our surgical outpatient department, and had developed over last twenty years. It was diagnosed as a benign mixed tumour of salivary gland and was successfully excised. Histopathology confirmed it to be a benign pleomorphic adenoma. PMID- 22830176 TI - Undetected common variable immune deficiency in a young adult of Pakistani descent. AB - Common variable immune deficiency (CVID) is a syndrome which is due to deficiency of humoral immune response resulting in increased susceptibility to infections We report a case of CVID in a 24-year-old male whopresented with a history of recurrent pneumonias. PMID- 22830177 TI - IRB chairs' perspectives on genotype-driven research recruitment. PMID- 22830178 TI - IRB review and public health biobanking: a case study of the Michigan BioTrust for Health. PMID- 22830179 TI - Informational risk, institutional review, and autonomy in the proposed changes to the common rule. PMID- 22830180 TI - Management strategies for acute headache in the emergency department. AB - Approximately 2.1 million patients per year present to United States emergency departments with a primary headache disorder. For emergency clinicians, the responsibility is twofold: First, exclude causes of headaches that pose immediate threats to the life and welfare of patients. Second, provide safe, effective, and rapid treatment of symptoms, while facilitating discharge from the emergency department with appropriate follow-up. While emergency management focuses on identification and treatment of life-threatening causes of headache, such as subarachnoid hemorrhage or bacterial meningitis, there is a tendency to misdiagnose specific primary headache disorders and fail to provide consistent, effective treatments in accordance with published guidelines. These mistakes can be avoided by resisting the temptation to label patients with specific primary headache diagnoses and by adopting a consistent, reproducible strategy for treatment of primary headache disorders in the emergency department that is evidence-based and effective. PMID- 22830181 TI - Running into trouble. Heat-related illnesses follow a summer race. PMID- 22830182 TI - Taxi calls. Do we underestimate transports home? PMID- 22830184 TI - Just one click. Working with informed consumers. PMID- 22830183 TI - CHF treatment: is furosemide on the way out? Rethinking the pulmonary edema cocktail. PMID- 22830185 TI - How to conduct EMS exercises and drills. Properly preplanning your exercises increases preparedness and yields valuable data. PMID- 22830186 TI - How to succeed in the interview process. Learn how to ACE your interview and come out on TOP. PMID- 22830187 TI - Stress, emotion and learning: considerations for the EMS educator. Do we adequately prepare students for the real world? PMID- 22830188 TI - What's your EMS story? Advocating for EMS means educating about EMS. PMID- 22830189 TI - Therapeutic hypothermia in the field: How cardiac arrest patients benefit from early cooling. PMID- 22830190 TI - [The influence of lectin isoforms of Bacillus subtilis saprophytic strain IMV B 7014 on viability of normal and cancer cells in vitro]. AB - Structural and functional polymorphism of saprophytic bacterium lectin was demonstrated to be due to subunit organization of the molecule as it was shown for many lectins of plant and animal origin. Three isoforms of extracellular sialic acid-specific lectin produced by Bacillus subtilis saprophytic strain IMV B-7014 were discovered that differed for physicochemical and biological properties. The influence of the lectin isoforms on mammalian cells proliferation and morphology in vitro depends both on the subunit organization of the protein molecule and the type of cells under study. PMID- 22830191 TI - [Biologically active substances of preparation avercom]. AB - The preparation avercom created on the basis of ethanol extracts from the biomass of Streptomyces avermitilis UCM Ac-2179, contains an antiparasitic antibiotic avermectin, as well as a complex of biologically active substances: amino acids, lipids, including nonsaturated fatty acids, and phytohormones, particularly: auxins, cytokinins, hybberellins. The above mentioned complex is characterized by nematocidical, phytostimulating and elicitor effect upon plants which has been confirmed with the results of production experiments on the cucumber variety Angelina. PMID- 22830192 TI - [The influence of teichoic acids from probiotic lactobacilli on microbial adhesion to epithelial cells]. AB - The effect of teichoic acids from lactobacillus strains on their adhesion to human buccal epithellium has been studied. It is shown that preliminary treatment of epithellium cells by teichoic acids caused a decrease of adhesion of L. plantarum 11/16, L. plantarum 195D strains by 39 and 30%, respectively. The influence of teichoic acid from lactobacilli on the adhesion of opportunistic microbial strains has been studied. It is established that teichoic acids from both lactobacilli strains brought to the decrease of adhesion of C. albicans to 29-34%. Teichoic acid from the strain L. plantarum 195D stimulated the adhesion of S. aureus 2.25 times, while teichoic acid from L. plantarum 11/16 did not influence the staphylococcal adhesion. There was also no effect of the studied teichoic acid on the adhesion of E. coli. PMID- 22830193 TI - [Influence of granulated bacterial preparation complex action on the growth and yield of barley]. AB - The influence of granulated bacterial preparation of complex action on the growth and yield of barley (H. distichum L.) has been studied. The treatment of barley seeds by this preparation has been established to have a very significant effect on the mass of 1000 grains, grain natural weight and to increase the yield of plants, but to different degree. Consequently, the interaction of certain barley varieties with bacteria-components of the preparation is rather specific. It has been displayed that the treatment of grains of different barley varieties by the bacterial preparation takes a very significant influence on the function of microbial associations in the rhizosphere. PMID- 22830194 TI - [Species composition of agents of the horsetail common (Equisetum arvense L.) bacteriosises]. AB - Bacterial diseases of weeds horsetail common (Equisetum arvense L.) were revealed in the crops of wheat and soya in the fields of Kyiv and Vinnitsia Regions of Ukraine. The distinctive symptoms of bacterial affections on the root neck, on stalks of vegetative and spore shoots, on twigs were brown, dark brown or almost black necrotic spots of oblong form. The necroses increased in size, embraced the stalks. The stalks broke, the plants dried up. Patterns of affected plants, isolated and identified phytopathogenic bacteria Pseudomonas syringae, Pectobacterium carotovorum subsp. carotovorum, Pantoea agglomerans and Curtobacterium sp. were analyzed These bacteria caused pathological process on the horsetail common, wheat and soy under the conditions of artificial inoculation. The composition of bacteria species was different in different years depending on temperature conditions of vegetative period. PMID- 22830195 TI - [Amylolytic activity of Fusarium LK:FR. and Alternaria NEES:FR. species]. AB - A comparative study of saprophytic, plant pathogenic and endophytic strains of different Fusarium and Alternaria species was conducted. It was shown that amylolytic activity of Fusarium strains of different trophic groups was low or absent. Plant pathogenic Alternaria spp. strains possessed middle and high activity while endophytic ones had middle activity. Amylolytic activity of the studied Fusarium spp. and Alternaria spp. strains varied on the strain level. The dependence of amylolytic activity of the studied strains on species and organs of host plants, which they were isolated from, was not established. Correlation between the rate of linear growth of the studied strains on the media with soluble starch and amylolytic activity level was not shown. PMID- 22830196 TI - [Herbicide activity of some micromycetes]. AB - Screening of phytotoxic properties of 5 micromycete strains were made concerning cultivated plants and weeds. All of the strains show phytotoxic activity of different levels. In particular, the cultural filtrates of Penicillium sp. 10-51 and Aspergillus niveus 2411 suppressed the growth of seeds of Galinsoga parviflora, Amaranthus retroflexus and Capsella bursa pastoris. The cultural filtrate of Ulocladium consortiale 960 suppressed the growth of Panicum capillare and Setaria viridis. The greatest phytotoxic activity was shown by the cultural filtrates of Myrothecium cinctum 903 and 910, on the one hand, both of them suppressed the growth of seeds of E. virgata completely, but, on the other hand, they did not take any effect on the seeds of radish. PMID- 22830197 TI - [Microscopic fungi in the air of film documents depositories]. AB - Microscopic fungi of the studied 5 film documents depositories in Kyiv are presented by 14 species of 8 genera of the division Ascomycota (Chaetomium sp.) and the group Anamorphic fungi (13 species 7 genera). Among the isolated species there are generally accepted active destructors of various products and materials, in particular of a cine-film (A. niger, A. versicolor, representatives of genus Penicillium) and species which are potentially dangerous for the human health (A. fumigatus, A. niger, A. versicolor, Geotrichum candidum, P. expansum, Stachybotrys chartarum). The species A. fumigatus, Chaetomium sp., Cladosporium oxysporum have been identified in the air of film depositories for the first time. An individual approach to identifying species-indicators of microbiological quality of the air in film documents depositories is proposed and discussed. PMID- 22830198 TI - Antibacterial activity of cerium colloids against opportunistic microorganisms in vitro. AB - The CeO2 sol with the size of nanoparticles 2-4 nm has been synthesized. It has been determined that the synthesized nanocrystalline cerium has antibacterial activity in vitro against different groups of opportunistic microorganisms: clinical strains of Escherichia coli, Staphylococcus aureus and Candida albicans. The rate of viability depression of test-cultures depends on the concentration of cerium dioxide nanoparticles and time of incubation. It is shown that the sol interacts with the bacterial cell surface. It is suggested that the observed differences of antibacterial action of nanocrystalline cerium dioxide can be related to the structural characteristics of the cell surface. PMID- 22830199 TI - Microbial growth fluctuating in response to solar-terrestrial activity variations. AB - Populations of microorganisms display fluctuations in the variable physiological and biochemical properties during cultivation under constant laboratory conditions. A series of explanations were proposed for this phenomenon, and different factors were studied as possible regulators. It was found that such fluctuations possess cosmic rhythms, but no factor(s) were proposed that could sufficiently explain and predict the magnitude of changes that happened on a daily basis in the long-term experiments. In this study we investigated specific growth rate fluctuations of Saccharomyces cerevisiae yeasts that were marked daily during cultivation under constant conditions. The effects of different solar and terrestrial factors were then analysed. The significant correlation indices were found for growth rate fluctuations against solar wind speed and the number of flares M on the Sun. These two factors determined the cyclic nature of the growth rate fluctuations, and thus its general course of increase or decrease. The effects of several other factors (Flares C number, planetary A index variation, and changes in the atmospheric factors such as temperature and humidity) and their two-way interactions were significant in producing an equation to describe the magnitude of changes of the yeast's growth parameters. The R2 of the equation achieved 91% and adjusted R2 was 78%. It is obvious that temperature and humidity are the factors that cannot directly influence the yeast populations under laboratory conditions and thus we suppose that they only reflect modifications of the really important factor(s) that take place in the Earth's atmosphere. We have concluded that different solar and terrestrial factors are responsible for the fluctuations in the daily kinetic parameters of the yeast growth. PMID- 22830200 TI - [Production of purified human recombinant alpha2b-interferon]. AB - Technology for producing biologically active recombinant alpha2b-interferon is based on creating a bacterial producer strain containing the cDNA of human interferon alpha. The authors have obtained two producers of recombinant alpha2b interferon, the synthesis of the target protein in them occurs in the inclusion bodies. The schemes of isolation and purification of biologically active recombinant alpha2b-interferon have been developed. The drug purity was approximately 97-98%. Biological activity in the culture of sensory cells in the cytopathic test was 4.2*10(8)ME/mg. PMID- 22830201 TI - Cholesterol-lowering activity of lactic acid bacteria probiotic strains in vivo. AB - Cholesterol-lowering activity of probiotic strains of lactic acid bacteria genera Lactobacillus and Bifidobacterium in the in vivo experiments on the model of experimental hypercholesterolemia in mice was studied. It is established that the prophylactic scheme of introduction of probiotic cultures is more effective than therapeutic one for the manifestation of cholesteraze activity of probiotic cultures. The most effective were the cultures: L. acidophilus and B. bifidum, as well as the composition B. bifidum + B. longum. Cholesterol-lowering activity of the studied strains and their compositions in this experiment ranged between 40 78%. It is noted that cholesteraze activity of other studied strains was not lower and in some cases, higher than that of most of the drugs currently used in cholesterinozis. PMID- 22830202 TI - [Biological activity of Budvicia aquatica lipopolysaccharides]. AB - The fatty acid composition of lipopolysaccharides (LPS) lipids A of Budvicia aquatica strains (n = 6)--representatives of Enterobacteriaceae new species are studied for the first time. It was established that fatty acids with the length of carbon chains from C12 to C18 are presented. All of B. aquatica strains tested have been found to contain 3-hydroxytetradecanoic acid (23.1-43.8%, depending on the strain), which was predominat and characteristic of representatives of Enterobacteriaceae family. LPS of the tested strains displayed toxicity and pyrogeneity. PMID- 22830203 TI - [Codon bias and nucleotide substitutions in soybean dwarf virus]. AB - Computational analysis of codon usage bias and spontaneous nucleotide substitutions in six strains of soybean dwarf virus was performed. It was shown that synonymous codon usage in the virus genes varies widely depending on the gene, gene overlapping, codon, codon's two first nucleotides, mononucleotide context located upstream and downstream of the codon, GC-content in virus-encoded genes and in the third codon position. Overlapping of genes causes a 2.5-fold decrease of the total number of nucleotide substitutions, 2.8-4.3-fold decrease of the number of synonymous substitutions in the third codon position, 1.4-1.6 fold decrease of the dicodon content in genes. At the same time there is a significant increase of nonsynonymous substitutions in the second codon position as well as a high codon bias (Fop = 0.94-1.0) and correlation between the nucleotide content in genes and in the third codon positions (r = 0.73-0.74). The results obtained evidence for selection of dicodons in the viral genes. PMID- 22830204 TI - [Rheumatoid arthritis: problems and significance of personalized medicine]. AB - The last decade is prominent for significant progress in research in the field of mechanisms underlying development of rheumatoid arthritis (RA) opening new prospects in pathogenetic treatment of this disease. A great success of RA pharmacotherapy during the last 10 year period is design of novel genetically engineered biological medicines. Achievements of molecular biology, pharmacological genetics and biological infornmation science promote an individual approach to treatment of RA patients within a new conception of individual medicine which considers personal aspects of genomic and proteomic sciences. This novel approach to treatment of RA patients can improve RA outcomes and noticeably reduce cost of the treatmnent. PMID- 22830205 TI - [Tocilizumab impact on blood cholesterine transport and early manifestation of atherosclerosis in patients with rheumatoid arthritis]. AB - AIM: To evaluate tocilizumab (TLZ) effects on blood lipids composition and severity of carotid arteries (CA) atherosclerosis in rheumatoid arthritis (RA) patients after 24 week TLZ treatment. MATERIAL AND METHODS: Before and 24 weeks after TLZ treatment 43 RA patients (33 women and 10 men) were examined by DAS 28 index, for blood serum concentration of cholesterol, triglycerides (TG), LPHD and LPLD cholesterol. The drug was injected intravenously in drops in a dose 8 mg/kg each 4 weeks. RESULTS: A 24 week TLZ treatment produced satisfactory and good anti-inflammatory effects in RA patients. Hypoalphalipoproteinemia incidence and atherogenicity index (AI) reduced 3 and 5 times, respectively (p < 0.05). Elevated levels of cholesterol, TG, LDPL cholesterol occurred with the same frequency before and after TLZ treatment. Cholesterol rose by 11.6%, LPHD cholesterol--by 48.9%, TG lowered by 7%, Al--by 31.9% (p < 0.05). LDLP cholesterol decreased Blood lipids composition shifts were associated with marked reduction in the disease activity: decreased concentration of C-reactive protein, IgM rheumatoid factor, DAS28 index, improvement of the patient functional status. Maximal thickness of the intima-media complex of CA increased by 8.2%. Atherosclerotic plaques were revealed before and after treatment in 17 (41.4%) patients from 41, in 5 (12.2%) patients the plaques arose after 6 months and in 5 (12.2%) patients the number of plaques increased. CONCLUSION: Because of both positive and negative effects of IL-6 receptor inhibitors on blood lipids, combined treatment of RA must include statins for correction of dyslipidemia. PMID- 22830206 TI - [Frax-assisted prediction of fractures in patients with rheumatoid arthritis]. AB - AIM: To determine an absolute risk of fractures in patients with rheumatoid arthritis (RA) with the FRAX procedure (fracture risk assessment tool) for choice of further prophylactic, therapeutic and rehabilitative measures. MATERIAL AND METHODS: The trial included 611 RA females over 49 years of age of 834 RA patients from 2004 data base RA entrees. All the patients were assessed for fracture risk with FRAX basing on clinical data without densitometry. Distribution into fracture risk groups was made by a graphic age-risk scheme. RESULTS: High or moderate fracture risk was registered in 58.6% RA examinees. These patients were older than those with a low fracture risk, they had lower body mass index, longer menopause, higher disease activity more often had extra articular manifestations of the disease. Therefore, duration of their glucocorticosteroid treatment was longer Patients with high and moderate fracture risks more frequently had functional insufficiency of the third degree, fractures of skeletal bones in the past. CONCLUSION: The FRAX method for assessment of an absolute fracture risk in RA patients detects subjects with elevated risk of fractures. This facilitates timely and qualitative administration of medical care, lowers costs of examination, improves treatment and rehabilitation of patients with osteoporosis and its complications. PMID- 22830207 TI - [Survival of patients with pulmonary arterial hypertension, associated with systemic sclerosis]. AB - AIM: To study survival of patients with a natural course of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SS). MATERIAL AND METHODS: Twenty SD patients with PAH and 71 SS patients free of PAH were followed up for 10 years (1998-2008) when therapy with specific pulmonary vasodilators was not available. Survival curves for both groups were plotted by Kaplan-Mayer method. RESULTS: One-, 3- and 5-year survival were 85, 25 and 5%, respectively, in the SS PAH group and 99, 82 and 77% in the SS group, respectively. The differences were significant (p < 0.001). Survival median in the group SS-PAH was 32 months. CONCLUSION: The above evidence is comparable to the results obtained earlier and demonstrate a fatal outcome of the disease in the absence of therapy with specific pulmonary vasodilators. PMID- 22830208 TI - [Immunological disorders and cytokine profile in systemic and localized sclerosis]. AB - AIM: Comparative study of disorders in cellular immunity and cytokine profile in systemic and localized sclerosis (SS, LS). MATERIAL AND METHODS: Parameters of cellular immunity and cytokine profile were examined in 58 systemic sclerosis patients (24 patients with SS, 34 patients with LS and 33 healthy donors). The examination protocol included assay of circulating immune complexes (CIC), serum cytokines (IL-lbeta, IL-4, IL-6, TNF), DNA antibodies, assessment of oxygen dependent and non-oxygen-dependent functions of circulating neutrophils and monocytes, identification of lymphocytic phenotype. RESULTS: Elevated levels of CIC, proinflammatory cytokines in SS and LS, antibodies to native double-chain DNA in LS were found. Free radical oxidation of neutrophils in LS was higher only by one parameter in SS--by all spontaneous tests of neutrophils and monocytes. Non-oxygen-dependent metabolism of phagocytes was enhanced only in SS. Patients with LS and SS have subnormal count of lymphocytes CD3+, CD4+, CD11b+ in the presence of elevated count of lymphocytes CD8+, CD16+ as well as activation markers--CD19+, CD25+, CD95+ and HLA-DR+ cells. CD25+ lymphocytes count is higher in SS than in LS. CONCLUSION: The study of metabolism of circulating phagocytes, cytokine profile lymphocytic phenotype can be used for differential diagnosis of LS with SS. PMID- 22830209 TI - [Cardiovascular complications and endothelial dysfunction in primary vasculitis]. AB - Russian and foreign data on development of atherosclerosis in patients with primary vasculitis are analysed. The discussion covers the role of risk factors, features of pathogenesis of atherosclerosis in primary vasculitis, diagnostic and therapeutic methods in this disease. PMID- 22830210 TI - [HCV-associated cryoglobulinemic vasculitis]. AB - AIM: To analyze clinical and laboratory features of cryoglobulinemic vasculitis (CGEV) associated with HCV infection. MATERIAL AND METHODS: We examined 61 patients with clinical manifestation of CGEV in 2006-2011. CGEV was associated with autoimmune diseases in 31 patients (51%), with HCV infection in 21 patients (34.4%), essential (idiopathic) ctyoglobulinemia in 8 patients (13%) and lymphoproliferative diseases in 1 patient (1.6%). 21 patients with HCV-associated CGEV were studied for main clinical and laboratory manifestations of the disease. Kidney and liver involvement was confirmed morphologically and immunomorphologically. Electroneurophysiological investigation evaluated peripheral nervous system involvement. Biopsy of parotid, lacrimal glands., peripheral lymph nodes, splenectomy and bone marrow trephine biopsy with morphological study and immunohistochemistry were used to identify type of lymphoma. Characteristics of monoclonal secretion were assessed with high resolution electrophoresis in agarose gel with subsequent immunofixation of sera and concentrated urine. RESULTS: Liver involvement was detected in 66% of patients with HCV-associated CGEV 34% patients were chronic HCV carriers with persistently normal liver function tests. Common rheumatologic manifestations of HCV-associated CGEV were skin lesions (90%), arthralgia (85%), frequent peripheral nervous system involvement (52%) and glomerulonephritis (38%). Prevalent immunological markers of CGEV associated with HCV were mixed monoclonal cryoglobulinemia with rheumatoid factor activity (62%), rare polyclonal (34%) and olygoclonal (4%) cryoglobulinemia, low levels of C4 compliment fraction (80%). Patients with mixed monoclonal cryoglobulinemia often developed clinical manifestations of Sjogren's syndrome (23%) and malignant lymphoproliferative diseases (14%). CGEV is a prognostically adverse sign in HCV infected patients and caused death of 14% patients even in a short period of follow-up (1-2 years). PMID- 22830211 TI - [Knee joint osteoarthrosis: risk factors of rapid progression]. AB - AIM: To study risk factors of knee joint osteoarthrosis (KJO) progression within 5 years since the disease onset. MATERIAL AND METHODS: We examined 158 females with primary KJO (by ACR criteria). Each patient's record contained demographic and disease history information, pain score in the knee joints by visual analog scale and joint status. All the patients have undergone standard rhoentgenography of the knee joints in two projections and two-energy x-ray densitometry of the lumbar spine, the neck of the femur (NF), subchondral condyles of the femur and of the tibia. RESULTS: We found factors promoting rapid progression of gonarthrosis within the first 5 years of the disease: high body mass index and mineral bone density (MBD) in subchondral parts of the tibia, low MBD in NF and bone marrow edema in the tibia. CONCLUSION: We revealed factors contributing to rapid progression of gonarthrosis in initial disease. MBD of the axial skeleton and subchondral MBD among them. Using established variables it is possible to distinguish a cohort ofpatients with initial signs of OA who need earlier treatment. This is of practical inmportance and can improve the disease prognosis. PMID- 22830212 TI - [Survival of gout patients]. AB - AIM: To assess survival and lethal outcome risk fahctors in gout patients. MATERIAL AND METHODS: The study included 286 gout patients (246 males, 86% and 49 females, 14%) treated for gout in the Research Institute of Rheumatology from 2001 to 2006. From 2010 to May 2011 a telephone survey was made to obtain information about death of the above examinees. After the survey clinical condition of the dead patients was compared to that of survivors. RESULTS: Of 286 participants of the trial, 38 did not response. By information from the relatives, there were 31 (12.5%) lethal outcomes of 248 patients. A cause of death in 20 patients, irrespective of age, were cardiovascular complications, 6 patients died of cancer; one patient--of chronic renal failure, one--of infection, one--of trauma and 2 - of unknown cause. Median of age at death was 62.1 years, median of gout duration--12.8 years. 65% of the deceased patients had risk factors of cardiovascular complications (type 2 diabetes mellitus, coronary heart disease, acute myocardial infarction, stroke, chronic cardiac failure). Median of time since examination in the clinic to death was 4.3 years. CONCLUSION: Gout patients' mortality is high. 7-year survival was 85% in high overall mortality. 2/3 patients died of cardiovascular diseases. Survival of gout patients with normuricemia is the same ofthose with hyperuricemia. A high level of highly sensitive CRP is a factor of poor prognosis (death) for gout patients. PMID- 22830213 TI - [The levels of plasminogen and inhibitor of plasminogen activators of type 1 in antiphospholipid syndrome]. AB - AIM: To estimate the levels of of plasminogen (Pg) and inhibitor of plasminogen activators of type 1 (IPA-1) in patients with antiphospholipid syndrome (APS) and to reveal correlations between their content and clinical-laboratory characteristics of APS. MATERIAL AND METHODS: A Pg level was measured in 78 APS patients: 35 of them had systemic lupus erythematosus (SLE), 43 had primary APS and 19 with idiopathic thrombosis (IT). IPA-1 was detected in 63 APS patients: in 26, 37 and 18 patients, respectively. The control group consisted of 10 subjects free of autoimmune disease and thrombosis. The patients were matched by age. Pg and IPA-1 levels were estimated kinetically. The Pg level was stratified. normal (1.5-2.0 mcM high (above 2.0 mcM), low (under 1.5 mcM). Thromboses in the past occurred in 67 patients: arterial (n=32), venous (n=53), of combined localization (n=14). RESULTS: Of 78 APS patients, Pg level was normal in 34 (44%), high--in 20 (25%), low--in 24 (31%). Of 43 primary APS patients, low Pg was in 8 (19%), of 35 patients with SLE+APS--in 16 (46%) patients. A Pg concentration (1.59 [1.4; 1.98] mcM) was significantly less in APS patients with thrombosis than in patients with IT (2.4 [1.74; 2.99] mcM). Pg tended to lower levels than in the controls (1.95 [1.63; 2.26] mcM). IPA-I varied in primary APS from 0.45 to >1 nM, in SLE+APS- from 0.44 to >1 nM, in IT--from 0.65 to 0.81 nM. The levels of active IPA-1 in all the patients with APS and IT were higher than in healthy donors and varied from 0.44 to >1 nM Most of APS patients had high level of IPA-1--52 (83%) (IPA-1 from 0.1 to 1), of them 22 (85%) patients with SLE+APS and 30 (73%)--with primary APS. 11 (17%) APS patients had high IPA-1 (>1), of them 4 (15%) with SLE+APS and 7 (27%) with primary APS. All IT patients had moderately high IPA-1 level. CONCLUSION: A low level of Pg in APS patients was seen significantly more frequently than in IT patients and controls and was associated with thrombosis, primarily arterial. Moderate high IPA-1 occurred in 83% of 63 APS patients, high- in 17%. IT patients had moderately high IPA-1. High IPA-1 was associated in APS with thrombosis, primarily arterial. PMID- 22830214 TI - [Multislice computed tomoangiography in assessment of coronary stent lumen]. AB - The treatment of coronary artery stenosis has progressively shifted over the past decades from surgical (bypasses) to percutaneous (stenting). Recent introduction of drug-eluting stents further reduced the occurrence of in-stent re-stenosis (ISR). However a non-negligible number of patients need imaging tests when symptoms recur Multi-Slice computed Coronary Angiography (CT-CA) is a clinical reality for evaluation of coronary artery stenosis, but still under evaluation in the follow-up of coronary stents. Several factors may impair proper depiction of in-stent lumen even with the most recent CT equipments. In highly selected populations CT-CA may play a clinical role even though the performance requirements both from the technical standpoint (i.e., CT scanner) and from the training (i.e., operators'experience) are still very demanding. In the meantime CT technology should improve towards higher contrast, spatial and temporal resolution in order to achieve the results that may be proper for clinical implementation. PMID- 22830215 TI - [Postprandial angina pectoris]. AB - The article present literature and original data on rare cases of postprandial angina which is a symptom of postprandial syndrome. The latter is characterized with dyslipidemia, endothelial dysfinction, proinflammatory and prothrombogenic shifts in the blood. PMID- 22830216 TI - [Anemia in patients with rheumatoid arthritis]. AB - Anemia is characterized by a reduced count of red blood cells and/or low hemoglobin content in blood. The article reviews basic information on pathogenesis, differential diagnosis and treatment of anemia in patients with rheumatoid arthritis (RA). Anemia in this case is characterized as anemia of a chronic disease. Strong evidence is presented on effective treatment of anemia in RA patients with tocilizumab both in combination with methotrexate and other basic anti-inflammatory drugs and monotherapy in a dose 8 mg/kg. PMID- 22830217 TI - [Current trends in classification and treatment of systemic vasculitis associated with anti-neutrophilic cytoplasmic antibodies: results of 2011]. AB - Systemic vasculitis (SV) pathogenetically associated with anti-neutrophilic cytoplasmic antibodies (ANCA) is the subject of intensive research in present-day rheumatology. There were noticeable changes in ANCA-associated SV (ANCA-SV) nomenclature in 2011 as well as mid-term success was achieved in the study of biological anti-B-cell therapy in this disease. European recommendations on rituximab administration in ANCA-SV have been developed Russian Register of ANCA SV patients on rituximab treatment is presented. State-of the art in ANCA-SV research is reviewed. PMID- 22830218 TI - [Enteropathy induced by nonsteroid anti-inflammatory drugs: pathogenesis, diagnosis, treatment]. AB - Nonsteroid anti-inflammatory drugs (nSAD) are among most often used medicines. Development of complications in patients taking NSAD is still an important problem. Negative NSAD influence on the upper part of the gastrointestinal tract is well-known as it is responsible for frequent complications. NSAD impact on a distal part of the gastrointestinal tract is studied much less, especially small bowel lesions. The article presents literature data about pathogenesis, diagnosis, treatment and prevention of NSAD-induced enteropathy. The article is addressed to a wide range of readers to attract attention to NSAD-enteropathy problem. PMID- 22830219 TI - [Inflammatory bowel diseases in the XXI century]. AB - Modern strategy of the treatment of inflammatory bowel disease (IBD), aimed at molecular targets of inflammation, is described in the article. It has reviewed the successe and failure of anticytokine therapy based on the application of Infliximab, Adalimumab and Certolizumab. The Results of Priority researchs of transplantation of mesenchymal stromal cells (MSCs) in the Central Scientific Research Institute of Gastroenterology are shown in the article. Clinical observations of patients with ulcerative colitis (UC) and Crohn's disease (CD) showed that intravenous infusion of allogeneic MSCs significantly increases the duration of remission, reduces the risk of recurrence and is comparable to the effectiveness of Infliximab. The use of MSCs allowed to cancel the corticosteroids and cytotoxic agents, except 5-ASA drugs, in the majority of patients with UC and CD. MSCs have a multidirectional regulatory impact on the inflammatory process: stimulate the functional activity of the suppressed immune system, reduce the intensity of the autoimmune reactions and the activity of immunopathological processes. The program and indications for treatment with MSCs are developed and suggested for clinical practice. Transplantation of MSCs is indicated in patients with hormone resistant, hormone-dependent forms of IBD characterized by high activity of the inflammatory process at the early stages of the disease. Accumulated clinical experience demonstrates the reducing of antibodies to infliximab after systemic MSC transplantation that helps to prevent and to overcome the secondary inneficiencies of anticytokine therapy. It has been possible to achieve significant improvement and even complete elimination of disease activity in patients resistant to all previous treatments. PMID- 22830220 TI - [Three variants of pathogenesis and therapy of chronic constipation]. AB - Constipation--is a frequent clinical syndrome, which occurs in approximately 15 25% of population. Investigations carried out during the last decade have contributed to a better understanding of the basic mechanisms of chronic constipation (CC), in particular its relationship to colonic transit and anorectal function. All possible causes affecting the occurance of constipation (methabolic, deficiency of fiber, medicines) should be taken into consideration at the patient's examination and anorectal pathology should be excluded. Functional chronic constipation consists of three subtypes: slow transit constipation, dyssynergetic defecation and IBS with predominance of constipation. Rome criteria are useful guidelines for diagnosis of functional constipation. Treatment should be based on evidence-based diagnosis of CC variants. Treatment of an inert colon should be based on enterokinetic type prucalopride and lubiprostone. The possibilities of biophydbectherapy should obligatory be used in dyssynergetic defecation treatment. PMID- 22830221 TI - [Immunogenetic predisposition to chronic nonspecific inflammatory bowel disease]. AB - Immunology has grown beyond the classic doctrine of immunity to infectious diseases, and gradually covered the problems of general physiology and pathology, genetics, embryology, transplantation, oncology and many other disciplines. A new direction has appeared--immunogenetics, which should help to answer questions the disposition and/or resistance to disease, as well as influence of environmental factors on implementation of predisposition to the development of pathology. Much attention is paid to investigation of HLA in IBD. These data indicate a significant polymorphism of major histocompatibility complex antigens in this disease in different countries. The aim of our study was to investigate the immunogenetic susceptibility and resistance to the development of ulcerative colitis (UC), and Crohn's disease (CD), the character of their flow, as well as the associated extraintestinal manifestations, in particular predisposition development of bronchial obstruction (BO) in patients with inflammatory bowel disease (IBD). A study of DNA frozen blood samples of 75 patients with IBD of both sexes has been conducted. The obtained results have been compared with the results of the study 1700 of samples of umbilical cord blood of newborns (apparently healthy children), born at 37-41 weeks' gestation in Moscow (control). The group of patients with UC revealed a positive association of HLA specificities-B*38, HLA-Cw*12 and HLA-DRV1*15, which can be regarded as potentially high risk of developing the disease. The presence of the specificity of HLA-DQV1*02 can be considered as a factor in resistance to the development of UC. High risk of developing Crohn's disease among residents of Moscow associated with groups of alleles of HLA B*41, HLA-B*56, HLA-Cw*05, HLA-Cw*08, HLA-DRV1*01, HLA-DRV1*11, HLA-DQV1*04, and the presence of specificity of HLA-DQV1*05 can be considered as a factor of resistance to the development of BC. High risk of developing BO in patients with IBD is associated with specificities HLA-DQB1*02, DQB1*03, DRB1*15. PMID- 22830222 TI - [The role of bile acids in the pathogenesis of chronic diarrhea]. AB - Chronic diarrhea syndrome results from excess colonic bile acids. Fibroblast growth factor 19 (FGF19), produced in the ileum is response to bile acid absorption, regulates hepatic bile acids synthesis. Bile acid malabsorption can be found in various gastrointestinal conditions: the greatest losses bile acids with excrements were marked at patients with surgical resection of terminal ileum. The maintenance in daily colonic excess bile at patients with postholecystectomy exceed more than in three times the indicators noted at control subjects, but at the patients with irritable bowel sindrom did not exceed the norm. Effective remedies in treatment chologenic diarrhea were bile acid sequestran. PMID- 22830223 TI - [Isolation of antibodies to Chlamydia and Mycoplasma pneumoniae during the immunosuppressive therapy of patients with inflammatory bowel disease]. AB - Detection of IgM and IgG Chlamydia and Mycoplasma pneumoniae indicates an aggravation of intracellular infections, including, possibly, due to immunosuppressive therapy. It is possible that the intracellular infection may mediate the occurrence of certain extraintestinal manifestations of inflammatory bowel disease (IBD), such as bronchitis, pneumonia, etc. Chronic persistent chlamydial and mycoplasmal infections lead to disruption of both cellular and humoral immunity, resulting in the formation of autoimmune processes in patients with IBD, and in the future--reduce the immune status against the immunosuppressive therapy. Detection of antibodies to Chlamydia and Mycoplasma pneumoniae accompanies with increased total immunoglobulin IgM, IgG in blood serum. Determining the level of proinflammatory and antiinflammatory cytokines in the acute stage of the disease allows to evaluate the activity of the inflammatory process and the nature of the immune response to intracellular infection. THE CONCLUSION: to prevent extraintestinal septic complications in patients with IgM antibodies to Chlamydia and Mycoplasma pneumoniae, is recommended to combine the long-term immunosuppressive therapy of IBD with antibiotic therapy, usually with macrolides. PMID- 22830224 TI - [Dynamics of proinflammatory cytokines during biologic therapy of inflammatory bowel disease]. AB - Chronic inflammation in IBD is accompanied by an imbalance in the production of Tx1 and Tx2 cytokines. Imbalance of cytokine profile is important pathogenetic importance in chronic inflammatory process, since the formation of defective immune response to pathogenic agent promotes recurrence of the disease. Analysis of the dynamics of proinflammatory cytokines allows both the activity of inflammatory process and effectiveness. Increased levels of proinflammatory cytokines: TNF-alpha, IFN-gamma, IL-2, IL-5, IL-8, IL-12, IL-15 in serum of patients with IBD, indicate their possible involvement in the mechanisms of development of CD and UC. Increasing content of these cytokines is accompanied by increased activity of disease, which can be used in diagnose IBD activity. PMID- 22830225 TI - [Coordination of the myoelectrical activity of the large and small intestine]. AB - Coordination of the myoelectrical activity of the large and small intestine was studied. Pacemaker cells of intestine are predominantly located at the proximal divisions of large and small intestine and have an increased spontaneous slow wave activity, which ensures the distribution of excitation in smooth muscle underlying intestines. Due to the ileocecal coordination by sequential motor activity of small and large intestine is provided. The distal direction gradient of slow waves frequency reduction was established. Pacemaker cells possess certain structural specificity and is specialized in the spontaneous bioelectric activity. PMID- 22830227 TI - [Changes in neuromediator regulation of the small intestine in experimental alcoholic intoxication]. AB - The effect of ethanol on the bioamin containing structures of the jejunum and ileum walls at different periods of chronic alcoholic intoxication was investigated. The quantitative description of the catecholamine and serotonin content in the enterocytes of epithelial lining villi, submucosa mast cells, crypt enterocytes and muscle membrane is given for the first time by means of luminescent microscopy and cyto spectrofluorimetry. It was established that in the initial period of chronic alcohol intoxication for 60 days in rats increased serotonin effect on intestinal functional structures was observed. On longer terms there is a disturbance of relationships of biogenic amines and the regulating role of catecholamines starts to prevail. PMID- 22830226 TI - [Multipurpose psyllium monotherapy in patients with diverticular disease]. AB - The purpose of the research was the study of the prebiotic and hypolipidemic effects of 12-week treatment by psillium of patients with uncomplicated diverticular disease and hyperlipidemia. It has been established that the examined medicine has not any by-effects, normalizes intestinal motility and lowers a pain syndrome and flatulence. Prebiotic effect has proved by higher concentration of short-chain fatty acids in faeces and reduction of anaerobic index. Psillium certainly reduces levels of hyperlipidemia and could be recommended as hypolipidemic remedy for monotherapy as long as base datum of cholesterol is less than 6,4 mmol/l. PMID- 22830228 TI - [Variants of the duodenum-preserving proximal resection of the pancreas with narrow and broad pancreatic duct]. AB - The analysis of the proximal duodenum-preserving resection in 85 patients with CP with narrow and wide GPP has been carried out. Completed 39 proximal resections according to Beger with clinic modification and 46 in the Bern's version. Found statistically significant decrease in pain in both groups after surgery (p = 0.002). The data of Quality of life in both groups after the operation are comparable and are not statistically different. Beger operation with clinic modification and the Bern's version is equally effective in treatment patients with CP with both narrow and wide main pancreatic duct. PMID- 22830229 TI - [Inflammatory bowel disease and pregnancy]. AB - Inflammatory bowel disease (IBD) in pregnant women in their characteristics do not differ from general population, unless they had operations on the pelvic organs. Women with a first pregnancy, regardless of the activity of IBD have an increased risk of adverse pregnancy and high risk births. Most treatment methods are compatible with pregnancy and breastfeeding. Women affected by IBD should discuss their plans for pregnancy with the doctor first in order to know the possible dangers. Every patient in the IBD during pregnancy must be observed by a gastroenterologist, accoucheur and pediatrician to ensure peace of mother and child. PMID- 22830230 TI - [Intolerance of gluten--a new disease or undiagnosed celiac disease]. AB - The prevalence of celiac disease is about 1% in the population and is growing due to the wide use of immunological methods of diagnosis. In recent years, in-depth research of the celiac disease has led not only to an increase in the number of patients with celiac disease, but also to the emergence of a broad spectrum of diseases associated with the ingestion of gluten. In this regard, a new pathology, known as "gluten intolerance or gluten sensitivity", attracted special attention of researchers. Studies in recent years have established that patients with this pathology may have both gastrointestinal symptoms and extraintestinal manifestations. Examinations of such patients usually do not find histological changes of the mucous membrane of the small intestine and autoimmune antibodies (to tissue transglutaminase (tTG) and endomysial (EMA)); however an increased level of gliadin antibodies (AGA) is often observed. Allergy to gluten is also absent. A gluten-free diet for such patients, like in case of the celiac disease, leads to the disappearance of clinical symptoms. Exact criteria for the diagnosis of this nosology have not been identified so far, but most researchers believe that prevalence of "gluten intolerance" is much higher than that of celiac disease. PMID- 22830231 TI - [Principles and perspectives of primary biliary cirrhosis therapy]. AB - A survey of existing methods of pathogenetic and symptomatic treatment of primary biliary cirrhosis has been made and it has reviewed prospective directions of its therapy. Is also presents a retrospective analysis of our own data of S adenosylmethionine (Heptral) in 27 patients PBC receiving UDCA basic therapy. In its application intravenously of 400 mg 2 times daily for 3 weeks showed a reduction in the severity of pruritus, assessed by visual analogue scale, a subjective decrease fatigability and a decrease level of serum bilirubin. PMID- 22830232 TI - [Experience with thiotriazoline in the treatment of patients with alcoholic liver disease]. PMID- 22830233 TI - [Certolizumab pegol--new possibilities in the treatment of Crohn's disease]. PMID- 22830234 TI - [Probiotics in the treatment of functional intestinal diseases]. AB - OBJECTIVE: to evaluate the clinical effectiveness of biocomplexes "Normoflorin L, B" in the treatment of functional bowel disease with constipation syndrome. The study involved 30 patients with functional bowel disease (Rome criteria III, 2006), with irritable bowel syndrome with predominance of constipatio--16 people with functional constipation--14 people. The criteria of efficacy were: the dynamics of clinical symptoms, bacteriological examination of feces before and after treatment, intestinal transit time of Activated Charcoa- "carbolen" test the definition of short-chain fatty acids (SFA) in the feces by gas-liquid chromatography before and after treatment. The results of the study. In Normoflorin therapy there comes normalization of intestinal motor activity; positive changes in colon ecosystem, consisting of changes of methabolic activity of colonic microflora and its generic composition, normalization of anaerobic aerobic relations, restoration of intracavitary redox potential of the luminal environment; eliminating the symptoms of intestinal dyspepsia (rumbling, flatulence). Bio-complexes Normofloriny are characterized by good tolerability and safety. The positive effect of "aftereffect" of drugs persists for at least 2 weeks. These data allow us to recommend the use of bio-complexes Normofloriny in treatment of functional bowel disease. These data allow to recommend the use of bio-complexes Normofloriny in treatment of functional bowel disease. PMID- 22830235 TI - [Celiac disease is a 33-year-old man with periodic disease]. AB - The article presents a clinical case of a 33-year-old Armenian man, who suffered from two rare diseases: Familial Mediterranean fever and celiac. The diagnosis of Familial Mediterranean fever: abdominal-feverish form, is confirmed by genetic markers. The morphological study of duodenal mucosa's specimens confirms the celiac. PMID- 22830237 TI - [Report on participation in the 7th International Congress on studying Crohn's Disease and Ulcerative Colitis (ECCO) (15-18 February, 2012), Barcelona (Spain)]. PMID- 22830236 TI - [Complete elimination of cytomegalovirus without antiviral therapy after systemic transplantation of mesenchymal bone marrow stromal cells in a patient with ulcerative colitis]. AB - Cytomegalovirus infection (CMV) has become in the last 15-20 years one of the most important problems of scientific research and clinical high attention. This is due to new information discovered about its leading role in the origin, development, and the outcome of a large group of serious diseases. Cytomegalovirus (CMV) is one of the most common causative agents of opportunistic infections (OI) in patients with IBD, which are mandatory feature of the state of immunodeficiency. Numerous studies in vivo and in vitro studies have demonstrated that mesenchymal stromal cells (MSCs) suppress immune reactions to allogeneic stimulation, but not the invasion of infection, as well as themselves possess antiviral and antimicrobial activity, as demonstrated in this clinical case. PMID- 22830238 TI - [Report on participation in the 182-th International "Falk Symposium" on Prevention and Treatment of Colorectal Cancer (February 8-11, 2012) in Munich (Germany)]. PMID- 22830239 TI - [The features of system organization of the brain activity during different sleep stages and transition states]. AB - Electropoligraphical study of the natural night sleep in 16 adults with the use of correlation, coherent, cluster and factor analysis were used to obtain new data describing the active nature of sleep, which is expressed especially in periods of falling asleep and the transition from one stage to another. It is shown that the process of falling asleep and deeper sleep is accompanied by intense reorganization of cortico-subcortical relations, which is reflected in the dynamics ofcrosscorrelation and coherent estimates of interrelations of biopotentials of the brain. The results of factor analysis of multichannel EEG heterogeneity of the transition process from wakefulness to sleep is manifested in significant changes of I, II and III factors weight during I(B) stage of sleep, which may reflect changes in the degree of contribution of the main integrative brain systems in the reorganization of its integral activity. A considerable increase in the I factor weight (reflecting the generalized modulatory brainstem effect on the cortex), along with a decrease in the balance of factors II and III (associated with organization of fronto-occipital and interhemispheric interactions) clearly indicates a special role of sleep synchronizing influences from the brain stem in the development of this initial stage. Reduction of EEG interhemispheric interrelations in the anterior and inferior frontal areas with the deepening of sleep may be indication of the reorganization of the frontal areas activity associated with the coordinated increasing of inactivation process in the cortex of both hemispheres. Degree of stability of the spatial structure of interregional interactions of different brain cortex areas (according to the analysis of average dispersion of crosscorrelation EEG relations) increases on falling asleep with the onset of stage I(A), but with the transition to the stage I(B) there is a significant increase of instability of values EEG crosscorrelation. With the deepening of sleep the subsequent decrease of the dispersion of EEG crosscorrelations in frontal cortex is revealed. During REM sleep the dispersion levels of inter regional interactions increases as much as possible, especially for EEG crosscorrelations of posterotemporal and inferiofrontal parts of both hemispheres. PMID- 22830240 TI - [Recognition of the spatially transformed objects in men and women: an analysis of the behavior and evoked potentials]. AB - In 16 men and 15 women analyzed the accuracy, reaction time and visual evoked potentials during the recognition of familiar objects at different levels of spatial transformation. We used the three levels of transformation: in a fixed position relative to each other details were carried out (1) the displacement of all the details in the radial direction and (2 and 3) a similar shift in conjunction with the rotation of all the details of the figure by +/- 0-45 and +/ 45-90 degrees. The task performance was not dependent on gender: the transformation of the image led to a deterioration of identification with the most identification impairment in the case of maximal details' rotation. Changes in evoked potentials (ERP) are different for men and women. Only in men early (100 ms after stimulus) response of the parietal cortex associated with the level of figure transformation: the more rotation evoked the higher the response. In women figure transformation evoked the ERP changes in the time window of negativity N170, they are associated with figure ungrouping but not with details rotation, and are localized in other visual areas--occipital and temporal. The data obtained are discussed in light of theory of gender specificity of the visual representations of space. PMID- 22830241 TI - [Fractal characteristics of the functional state of the brain in patients with anxious phobic disorders]. AB - The task of estimation of the functional state of the human brain during psychotherapeutic treatment of psychogenic pain in patients with anxious phobic disorders is examined. For solving the task the methods of spectral and multifractal analyses of EEG fragments are applied during the perception of psychogenic pain and its removal by the psychorelaxation technique. Contrary to power spectra singularity spectra allow to distinguish EEGs quanitatively in the examined functional states of the human brain. The pain suppression in patients with anxious phobic disorders during psychorelaxation is accompanied by changing the width of the singularity spectrum and approximation of this multifractal partameter to the value corresponding to a healthy subject. PMID- 22830242 TI - [Bilateral frontal theta-waves in EEG of 7-8-year-old children with learning difficulties: qualitative and quantitative analysis]. AB - We analyzed EEG recorded in the rest condition (eye closed) in 22 children aged from 7 to 8 years old who experienced learning difficulties and whose EEG recordings were characterized by sporadic short-term appearance of bilateral synchronous slow waves over the frontal and/or central cortices--frontal theta waves (FTW). The vector autoregressive modeling was used in order to assess the strength of directed cortico-cortical functional connectivity pattern for FTW and for surrounding EEG. The comparison of the two patterns showed that FTW is characterized by diffuse strengthening of the functional links connecting frontal, central and (to some extent) temporal cortices as well as the links directed to the above regions from the other cortical areas. The results of the study suggest that FTW is most probably caused by the common for the fronto central cortices neuronal theta activity synchronized via cortico-subcortical links. This suggestion is in a good agreement with the view that FTW reflects the alterations in functioning of fronto-thalamic system. PMID- 22830243 TI - [Psychophysiological factors of readiness children of 6 years to education at school]. AB - Research was spent according to principles of biomedical ethics. Healthy children of 6 years have taken part in him (n = 120). In the course of research the psychophysiological factors defining readiness of children of 6 years to education at school are identified: "selectivity of voluntary attention" (the factor I); "the general working capacity" (the factor II); "a physiological maturity" (the factor III); "sensorimotor coordination of voluntary movement" (the factor IV). Factors I, II, IV correspond with activity of three blocks of the brain allocated with A.R. Lurija within the limits of structurally functional model of work of a brain as a substratum of mental activity. The carried out research has revealed interrelation of some indicators of readiness for education at school with parametres of physical working capacity. PMID- 22830244 TI - [Acuity and hyperacuity for pupils of 11-17 years old]. AB - Estimations of hyperacuity and visual acuity (VA) have been compared in schoolchildren aged 11-17 years with normal vision. VA was measured using Landolt Cs and Tumbling Es. Hyperacuity was measured by vernier stimuli. Acuity estimations depended on the test stimuli. They were in 1.1 times over for Landolt Cs than for Tumbling Es. Hyperacuity estimations exceeded VA in 1.25-4.1 times. They were almost twice as high among pupils of 16 years compared to 13-year-olds, in contrast to estimates of VA, which practically did not change with age. Binocular VA was significantly higher monocular VA in 1.05 times regardless of age. The ratio between the binocular and monocular hyperacuity estimates for thirteen years pupils in average was equal to 1.9, while for sixteen years pupils -1.2. We discuss the contribution of binocular vision in the development of mechanisms of VA and hyperacuity in ontogenesis and the difference between these mechanisms. PMID- 22830245 TI - [Abnormalities in mutual influences of upper and lower limbs in patients with stroke]. AB - Previously, in healthy subjects the common pattern of muscle activation and specifics of interlimb neuron connections during performance of rhythmic separate and simultaneous movements of arms and legs in the lying position, which reflect functional meaningful of interlimb interactions, were shown. The aim of this research was to investigate such mutual influences of upper and lower limbs during the execution of similar motor tasks by patients with stroke. In sixteen poststroke patients with different stage of hemiparesis arms movements together with or without legs movements were performed, while lying supine. It was demonstrated that the common pattern of muscle activity distribution under the execution of voluntary cyclic movements by both arms was disordered. Passive rhythmic movements of each arm caused the phased EMG activity in shoulder muscles in patients with mild hemiparesis, but no activation was observed in patients with severe paresis. The loading of nonparetic arm resulted in an increasing of activity in shoulder flexor muscles of paretic arm in patients with weak paresis (which was typical for healthy subjects), while it not exerted essential influences in patients with severe paresis. Under connecting the cyclic movements of arms with stepping movements of legs in diagonal synergy the activity in proximal muscles of both arms was decreased irrespective of the paresis degree, as it was seeing in healthy subjects. Simultaneous arms and legs movements did not change the muscle activity in non-paretic leg in both groups of patients, but in some muscles of paretic leg the activity even decreased. The results obtained revealed important features of poststroke motor disturbances, which caused the changes of interlimb interaction and in great degree depended on the level of paresis. The data of investigation can be of a great importance for developing the new methods for rehabilitative procedure in patients with stroke. PMID- 22830246 TI - Reaction time and movement duration influence on end point accuracy in a fast reaching task. AB - In labor and sport physiology a great deal of interest concerns the conceptual model of governance of both rapid and precise target-directed movements. Widely known in the theory of motor control, Fitts' paradigm determines the time of motion, calculated from the distance to the target and the diameter of the target. However this paradigm does not take into account the time of preparation for movement, which can have a significant impact on accuracy. In addition, the literature highlights little evidence of temporal and spatial asymmetry in the production of fast and accurate movements. The aim of our work was to investigate the influence of the duration of the preparatory phase (reaction time - T(R)) and duration of protractile motion of the arm (T(M)) on the speed and accuracy of movement. Also, the in-dividual asymmetry of the temporal characteristics and accuracy of performance of movements were studied. We measured three aspects of translational motion of the arm to the computerized target: reaction time (T(R), s), time of motion of the arm (T(M), s), and error in the achievement of the target (deltaL, mm). The group of participants consisted of 12 healthy, right handed, untrained girls, each of whom completed 5 series of 10 discrete movements by each of the left and right arms. Mathematical analysis of the results revealed the existence of five models of performance. Each model was represented in the participant's performance with different probability. The combination of high speed and high precision when the arm moved towards the target was found only in model 5, which combines a long period of preparation for the movement (T(R)) and a short time of motion (T(M)). The probability of its occurrence in the untrained subjects was very low (2-3%). We suggest that it may be possible to develop special methods of training, geared towards the ability to increase the probability of appearance of this model. Asymmetry of motor action appeared clearly evident only in the parameter of accuracy (right arm committed the least errors), especially when the reaction time (T(R)) and movement time (T(M)) were close to average values of the sample. This result enables us to recommend this method for the determination of "handedness". The results allow us to conclude that in the process of development of new motor skills which include both precise and rapid movements we must take into account the initial values of reaction time. We also think that Fitts' existing formula should be modified by including the parameter of reaction time. PMID- 22830247 TI - [Effect of intensive 24-hour shift work on reliability of operators' activity]. AB - Psychophysiological peculiarities of the effect of 24-hour shift work on psychophysiological indices of an operator's efficiency have been considered. It is found that significant manifestations of the fatigue have been developed in servicemen-operators as a result of daily shift-work. The informative psychophysiological characteristics, which can be used as reliable indicators of fatigue level, have been distinguished. A hypothesis has been proposed on the availability of several compensatory mechanisms in maintenance of the work capacity in operators in long-term shift work. An integral index of the reliability of operators' activity has been developed, allowing to assess the quality of work, using a wide range of intensities of the proposed signals as well as to receive data on the overall possibilities of an operator to process information at the given level of reliability. PMID- 22830248 TI - [Investigation of biophysical features of interaction between 0.1 Hz oscillations in heart rate variability and distal blood flow variability]. AB - We studied biophysical features of interaction between 0.1 Hz oscillations in heart rate variability (HRV) and distal blood flow (DBF) variability in healthy subjects and patients after acute myocardial infarction (MI). 125 patients after acute MI (72 male and 53 female) aged between 30 and 83 years and 33 healthy subjects (23 male and 10 female) aged between 20 and 46 years were included in the study. The duration of prospective study of MI patients was one year. We estimated the delay in coupling between 0.1 Hz oscillations in H RV and DBF variability. It is found out that in healthy subjects the delay in coupling from heart rate to DBF is less than delay in coupling from DBF to heart rate. Acute MI results mainly in disruption of coupling from heart rate to DBF. This coupling is partially restored in one year after acute MI, but the delay in coupling remains significantly smaller than in healthy subjects. The features of coupling from DBF to heart rate are restored in MI patients within three weeks after infarction. After this period the delay in this coupling in MI patients is approximately the same as it is in healthy subjects. PMID- 22830249 TI - [Effect of opioid peptides on oxygen-dependent microbicidity of peripheral blood neutrophils]. AB - Investigation ofopioid peptide effect on the production of reactive oxygen species by neutrophils in non-fractionated leukocyte suspension and in purified fraction of peripheral blood neutrophils is disclosed in this work. It was determined that selective delta- and micro-agonists of peptide origin stimulated the spontaneous and suppressed 15 mkg/ml zymosan-induced LDCL (luminol-dependent chemiluminescence) reaction of neutrophils in leukocyte suspension. beta endorphin was found to render less marked suppressive action on 15 mkg/ml zymosan induced LDCL, and delta2-agonist deltorphin 2 promoted 15 mkg/ml zymosan-induced LDCL only toward the 25 minutes of the experiment. beta-endorphin and selective d and m- agonists did not affect the spontaneous and suppressed 15 mkg/ml and 150 mkg/ml zymosan-induced neutrophil LDCL. Therefore, opioid peptides play essential role in the process of direct and indirect regulation of oxygen-dependent system of neutrophil granulocyte bactericidal activity. PMID- 22830250 TI - [Reconstruction of associative protein networks connected with processes of sodium exchange' regulation and sodium deposition in healthy volunteers by urine proteome analysis]. AB - The study was conducted during the experiment with 105-day isolation in experimental complex. In the present investigation we collected urine samples from 6 healthy volunteers. The physical activity, diurnal rhythm, temperature parameters and level of oxygen and carbon dioxide were controlled during the experiment. According to the program, food intake (electrolytes, water, calories, fat, carbohydrates, protein, vitamins, etc.) on each stage of experiment was normalized. All samples were analyzed using mass spectrometer of an ionic cyclotron resonance with transformation of Fure LTQ FT MS (Thermo) on the basis of the AMT-tags (accurate mass and time tags) approach. Among more than 20 000 we found out 690 proteotypical proteins and we identified about 600 urine proteins. For physiological interpretation of the proteome data we used computer systems ANDCell and ANDVisio. Clustering of proteins and application of these systems revealed proteins that are most closely associated with the regime of sodium intake, as well as build the network of their interactions. PMID- 22830251 TI - [Blood serum concentration of lipids and lipoproteins and body composition]. AB - The purpose of this study is the analysis of the relationship of blood serum apolipoprotein E (apoE), total cholesterol (TC), triglycerides (TG) and high density and low-density lipoproteins (HDL, LDL), with body mass index (BMI), relative body surface area (RBSA) and body muscle (BM) and body fat (BF). The subjects are males and females aged 14-16 (adolescent age group 1: n1M = 141, n1F = 151) and 18-25 (young adult group 2, n2M = 16, n2F = 46). Significant correlations of serum TG and HDL with somatometric indicators were not observed. In the female samples, TC content directly correlates (p < 0.05) with BF (r1 = 0.164; r2 = 0.418) and negatively correlates with BM (r1 = -0.165; r2 = -0.352). The blood serum concentration of apoE is significantly correlated with body composition in adolescent females (for BF r1 = -0.168; for BM r1 = 0.266; p < 0.05); in males 14-16 years old, the both correlations have a significance level p < 0.06. In young adult females TC and LDL content negatively correlates with RBSA (r2 = -0.386 and -0.377 respectively; p < 0.05) and positively correlates with BMI (r2 = 0.413 and 0.415 respectively; p < 0.05). Adolescent females and young adult females have opposite relationships between FC and apoE concentration. In females 14-15 years old apoE concentration decreases as FC increases. In females 16-17 the correlation disappears, and in older females apoE concentration and FC increase together. PMID- 22830252 TI - [Sex differences in drug action: the role of multidrug-resistance proteins (MRPs)]. AB - The mechanisms of participation of multidrug-resistance proteins (MRPs) in sex difference pattern of drug efficiency and side effects have been analyzed. MRPs structure, their tissue and cellular localization, substrate specificity, and functions have been considered. Regulation of expression and activity of MRPs by endogenous metabolites, signal compounds, including sex hormones, as well as by drug agents have been represented. The role of nuclear receptors in the regulation of MRPs expression has been demonstrated. The data on sex differences in hepatic and renal MRPs expression and expression of nuclear receptors, participating in their induction, have been shown. The participation of MRPs in the formation of sex differences of drug pharmacokinetics has been discussed. Sex differences in representation and functional activity of MRPs in such excretory organs as liver and kidney was concluded would play the essential role in sex dependence of pharmacokinetics and efficiency of drug action. PMID- 22830253 TI - [Theories of biological evolution from the viewpoint of the modern systemic biology]. AB - Theories of biological evolution advanced in the last 200 years are reviewed from the viewpoint of advances of modern genetics. The theory of gene networks as a key direction of systemic biology is a link connecting different evolutionary theories. PMID- 22830254 TI - Recent progress of salinity tolerance research in plants. AB - This paper reviews the most recent research progress in the field of salt tolerance for plants such as Arabidopsis, tomato, wheat, rice and cotton. Salinity tolerance is defined and classified, and research advances in the physiology, cellular biology and molecular biology of salt tolerance are presented. Additionally, transgenic breeding advances are profiled and the studies on quantitative trait locus are given; finally, an outlook for future salinity resistance research is proposed. PMID- 22830255 TI - [Increase in NETO2 gene expression is a potential molecular genetic marker in renal and lung cancers]. AB - Multiple changes in the genome, transcriptome, and proteome are frequent in cancer cells. A search for molecular markers based on DNA, mRNA, or proteins is a main method to develop early specific diagnostics for cancer. While universal markers are still unavailable, similar trends are known for the expression patterns of particular genes in certain epithelial tumors. A bioinformatic screening of transcriptomic databases identified the NETO2 gene as a new potential promising marker of renal cancer. A substantial increase in NETO2 mRNA level was detected in 90% clear-cell renal cell carcinomas, 70% of non-small cell lung cancers, and 50% of papillary renal cancers by real-time PCR. The NETO2 mRNA level was increased to a lesser extent in cervical carcinoma and colon cancer and tended to decrease in cancer of the stomach. The NETO2 gene, which codes for a membrane glycoprotein with an unclear function, was assumed to provide a new promising marker for early diagnosis in renal cancer and non-small cell lung cancer. PMID- 22830256 TI - [Mutants of Burkholderia cenocepacia with a change in synthesis of N-acyl homoserine lactones--signal molecules of Quorum Sensing regulation]. AB - By means of plasposon mutagenesis, mutants of Burkholderia cenocepacia 370 with the change in production of N-acyl-homoserine lactones (AHL), signal molecules of the Quorum Sensing system of regulation, were obtained. To localize plasposon insertions in mutant strains, fragments of chromosomal DNA containing plasposons were cloned, adjacent DNA regions sequenced, and a search for homologous nucleotide sequences in the GeneBank was initiated. It has been shown that the insertion of plasposon into gene lon encoding lon proteinase drastically decreases AHL synthesis. Upon insertion of plasposon into gene pps encoding phosphoenolpyruvate-synthase, enhancement of AHL production is observed. In mutant carrying inactivated gene lon, a strong decline of extracellular protease activity, hemolytic, and chitinolytic activities was observed in comparison with the original strain; lipase activity was not changed in this mutant. Mutation in gene pps did not affect these properties of B. cenocepacia 370. Mutations in genes lon and pps reduced the virulence of bacteria upon infection of mice. PMID- 22830257 TI - [Cytogenetic comparison of N-genome Aegilops L. species]. AB - Differential C-banding and in situ hybridization were employed in a cytogenetic comparison of thee N-genome Aegilops species: diploid Ae. uniaristata, tetraploid Ae. ventricosa, and hexaploid Ae. recta. The formation of Ae. recta was shown to involve only minor functional modifications of the parental genomes, while intraspecific divergence was accompanied by large genome rearrangements, namely, translocations involving the total chromosome arms of all of the three genomes. The formation of tetraploid Ae. ventricosa involved substantial structural chromosome rearrangements, including a partial deletion of the short arm of chromosome 5D, including the nucleolus-organizing region; a redistribution of C bands on chromosomes of the D and N genomes along with a reduction of the heterochromatin content; and a considerable decrease in the hybridization intensity of the pAs1 repeat. Chromosomes of the Ae. ventricosa D genome were more similar to chromosomes of the Ae. crassa D1 genome than to Ae. tauschii chromosomes. PMID- 22830258 TI - Identification of Ppd-B1 alleles in common wheat cultivars by CAPS marker. AB - Photoperiod response is a major determinant of the duration of growth stages in common wheat. In common wheat, many genes play a role in determining flowering time, but the Ppd genes located on the homoeologous group 2 play a major role. Of these Ppd-B1 is located on the short arm of 2B. In 107 common wheat cultivars grown in Poland and neighboring countries, the identification of Ppd-B1 alleles using in-del analysis by using a CAPS markers was investigated. 87 cultivars were shown to carry dominant Ppd-B1 alleles. This shows that Ppd-B1 alleles is have been widely used in common wheat breeding programme in these countries. Recessive ppd-B1 alleles were found only in 20 cultivars (12 Polish, 5 former Soviet Union, 2 German, 1 Swedish). PMID- 22830259 TI - [The polymorphism and distribution of B chromosomes in germline and somatic cells of Tscherskia triton de Winton (Rodentia, Cricetinae)]. AB - The karyotypes of 13 greater long-tailed hamsters (Tscherskia triton de Winton, 1899) (eight males and five females) from Primorskii krai (Russia), including six males and one female from the vicinity of the city of Ussuriisk and two males and four females from the vicinity of the village of Pogranichnyi, have been studied. The karyotypes of five males (four from the vicinity of Ussuriisk and one from the vicinity of Pogranichnyi) have been found to contain one or two small acrocentric B chromosomes each. In males with B chromosomes, each germline cell contains one or two B chromosomes. The proportion of somatic cells carrying B chromosomes varies from 34.9 to 55.9% in these males. Karyological study of a total of 45 Tscherskia triton (30 males and 15 females) from Primorskii krai has been performed, B chromosomes being found in only five males (11.1%). In T. triton populations of Korea and China, also only a few animals have been found to carry one or two B chromosomes. The greater long-tailed hamster belongs to the monotypic genus Tscherskia; the animals described earlier under the names T. (Cricettilus) triton albipes Ognev, 1914 and T. (Cricettilus) triton nestor Thomas, 1907 belong to the only species in the genus, T. triton de Winton, 1899. PMID- 22830260 TI - The study of the SNP in the corticotropin-releasing hormone gene (exon 2) and milk production traits in cattle. AB - The aim of this study was estimate the relations between CRH C22G and milk production traits (milk yield, yield of protein and fat, content of protein and fat in milk). The study was carried on 169 Polish Holstein-Friesian strain Red and-White cows kept in the south-western region of Poland. The CRH C22G (exon 2) polymorphisms were detected using PCR-RFLP method. The genotype and allele frequencies were estimated and they were as follows: CC - 0.89, CG - 0.09, GG - 0.02; C - 0.93, G - 0.07. Statistically significant (P < or = 0.05) associations between CRH C22G genotypes and milk production traits like milk yield and protein yield in the second lactation were found. Moreover, the obtained results should be verified by conducting research on a larger group of animals and various cattle breeds. PMID- 22830261 TI - [Population genetics of hereditary diseases in the child population of the Republic of Bashkortostan, Chuvashia, and Udmurtia]. AB - The results of integrated study of the genetic structure and prevalence of monogenic hereditary diseases (MHDs) in the child population of three republics of Russia are summarized. Eight raions (districts) of the Republic of Bashkortostan and six districts of each Republic of Chuvashia and Republic of Udmurtia has been surveyed. The total population surveyed was 782184 people, with children accounting for 24.67% of them (192992 children). The loads of autosomal dominant (AD), autosomal recessive (AR), and X-linked MHDs have been calculated separately for urban and rural populations; differences between individual populations in the MHD load have been found. The differentiation of subpopulations with respect to MHD prevalence is explained by differences in the degree of subdivision. The MHD spectrum in the child population of the three republics comprises 222 disease entities, including 121 AD, 83 AR, and 18 X linked diseases. Group of highly prevalent MHDs in regional child populations have been determined. The mean fitness of MHD patients in Bashkortostan has been calculated; it is 0.87, 0.04 and 0.16 for AD, AR, and X-linked diseases, respectively. Analysis has demonstrated that the prevalence rates of MHDs in the child populations of the republics of Chuvashia, Udmurtia, and Bashkortostan are 1, 1.2, and 1.4%, respectively. PMID- 22830262 TI - [Coat color mutation frequencies in domestic cat populations of Primorskii krai, Russia]. AB - The frequencies of mutant coat color genes have been estimated in the cat populations of five settlements in Primorskii krai, Russia: two cities (Partizansk and Spassk-Dal'nii), a town (Khorol'), and two villages (Dmitrievka and Brovnichi). The genetic profiles of these populations have been found to be relatively homogenous and to correspond of the cat population of the city of Vladivostok studied earlier. No considerable differences in gene frequencies have been found between urban and rural cat populations. The data suggest a common origin of all domestic cat populations of Primorskii krai. PMID- 22830263 TI - [Testing of microsatellite primers with different populations of Eurasian spruces Picea abies (L.) Karst. and Picea obovata Ledeb]. AB - From a clone library containing microsatellite DNA fragments of Norwegian spruce, seven pairs of primers were selected. These primers were tested to be the markers in the genetic structure analysis of nine populations of Eurasian spruce species Picea abies (L.) Karst. and Picea obovata Ledeb. Five pairs of these primers identified polymorphic loci with the allele numbers from 6 to 15. In the populations examined, the observed and expected heterozygosity values assessed at five loci varied from 0.1778 to 0.6556 and from 0.7800 to 0.900, respectively. In the populations examined, the values of F(st) index varied from 0.0691 to 0.2551 with the mean value of 0.1318. On the dendrogram based on Nei genetic distances, the populations formed three groups: Pskov-Ciscarpathia, Komi-Tatarstan Arkhangelsk, Kazakhstan-Karelia(natural)-Karelia(culture)-Krasnoyarsk. Five of the primer pairs tested proved useful for analysis of the population genetic structure in Eurasian spruce species. PMID- 22830264 TI - [Polymorphism of mitochondrial DNA and distribution of cytoplasmic symbionts in the populations of two-spot ladybird beetle Adalia bipunctata]. AB - In geographically distant populations of ladybird beetle Adalia bipunctata from Eurasia mitotypes and infection with symbiotic bacteria Spiroplasma and Rickettsia were determined. All populations examined demonstrated mtDNA polymorphism and striking differences in prevalence of bacteria (from about 50% of individuals infected with Spiroplasma in St.-Petersburg population and 50% of the Rickettsia prevalence in Kem' population to complete absence of bacteria in the population from Archangelsk). In the populations studied a total of 14 mitotypes were discovered, including two mitotypes that were remarkably different from the others in nucleotide composition. Mitotype 10, which was the most different from all the others, was found in all populations from Germany to Transbaikalia, excluding the population from Tashkent. Linkage disequilibrium between mitotype 10 and the Rickettsia infection was confirmed. Infection with the Spiroplasma bacteria was typical of the individuals with haplotype 1 and relative to it. The results obtained supported the conclusion on the association between infection with Spiroplasma and Rickettsia and certain mitotype of A. bipunctata, which was the consequence of either absence or rare horizontal transfer of symbionts and ancientness of the first contact between the bacteria and A. bipunctata ladybird beetles. PMID- 22830265 TI - [Association of rs10912745 and rs4916375 polymorphisms located in the cluster of flavin-containing monooxygenase genes, with ischaemic cardioembolic stroke]. AB - Twenty-one SNPs located in the cluster of genes FMO1-FMO2-FMO3-FMO4 and adjacent areas were analyzed in the patients with ischaemic cardioembolic stroke and in the control group. Significant differences between these samples were found in the distribution of genotype and allele differences in two polymorphic loci, rs10912745 and rs4916375. It was shown that these polymorphic loci are associated with the risk of ischaemic cardioembolic stroke development. PMID- 22830266 TI - [Phylogeny of salmonids (Salmoniformes, Salmonidae) and its molecular dating: analysis of nuclear RAG1 gene]. AB - The phylogenetic relationships among 26 species of salmonid fishes (family Salmonidae) were studied using the RAG1 gene as phylogenetic marker. No unambiguous relationships between thymallins, coregonins, and salmonins it was possible to establish. It seems likely, that divergence of these lineages took place during rather short time interval (about 3 to 4 million years). The thymallins are thought to be the first radiated lineage. The genera of the subfamily Salmoninae form two distinct monophyletic groups, represented by (1) Brachymystax and Hucho and (2) Salmo, Parahucho, Salvelinus, Parasalmo and Oncorhynchus. Ancestral forms of these two evolutionary lineages could diverge at the Oligocene-Miocene boundary (about 24 million years ago). It is suggested that diversification of the main lineages within the second group was rather rapid, and took place in middle Miocene (about 19-16 million years ago). Moreover, the lineages of Salvelinus, Parasalmo and Oncorhynchus were the latest to diverge. It seems likely that divergence of the Prosopium and Corergouns ancestral lineages occurred during the same time interval. PMID- 22830267 TI - [Features of epithelial-bacterial interactions in bacterial vaginosis]. AB - AIM: Study of features of interactions of mucosal epitheliocytes of vagina with dominant and associative vaginal microsymbionts in bacterial vaginosis. MATERIALS AND METHODS: Changes in growth characteristics and ability to form biofilms of Staphylococcus aureus, Escherichia coli, Lactobacillus spp. under the influence of secretory products of vaginal epitheliocytes obtained from 36 women with bacterial vaginosis and 32 practically healthy women were studied. RESULTS: Vaginal epitheliocytes of women with bacterial vaginosis were shown to change their functional activity during contact with microorganisms and their secretory products, causing differential influence on the properties of symbiont bacteria. A suppression of growth of dominant microsymbionts--lactobacilli, mostly their peroxide producing biovars, and a weakening of suppressing effect on the growth of biomass of associative microorganisms accompanied by stimulation of their ability to form biofilms was noted. Preliminary contact of an epitheliocyte with bacterial cell or its supernatant increased the intensity of the changes of properties of bacteria under the influence of secretory products of epitheliocytes. CONCLUSION: Suppression of growth of lactobacilli (mostly their peroxide producing biovars) and stimulation of the ability to for biofilms of the associative microorganisms as a result of bacterial-epithelial interactions in bacterial vaginosis determine mechanisms of formation and stability of pathomicrobiocenosis and a reduction of colonization resistance of vaginal biotope. PMID- 22830268 TI - [Prevalence of glucosyl transferase Lgt among Legionella pneumophila strains isolated from various sources]. AB - AIM: Determine various members of Lgt glucosyl transferase family among microorganisms of Legionellaceae genus from museum collection and legionellae strains recently isolated in the Russian Federation and Germany. MATERIALS AND METHODS: Presence of 3 types of glucosyl transferase were determined in 73 strains of L. pneumophila and Legionella spp. Glucosyl transferase activity of 3 types (Lgt1, Lgt2 and Lgt3) was determined by western blotting and PCR method. RESULTS: Lgt1 and Lgt3 were detected only in members of L. pneumophila independently of isolation source and were absent in Legionella spp. strains. Lgt2 is absent in Legionella spp. strains and is detected in not all the L. pneumophila strains. Comparative analysis of detection frequency of Lgt2 in clinical strains and L. pneumophila strains isolated from the environment showed that the protein is detected in clinical strains more frequently (46%) compared with strains from the environment (23%). CONCLUSION: Lgt1 and Lgt3 as species specific markers could be used for practical purposes for identification of L. pneumophila strains. High frequency of Lgt2 isolation in clinical strains of L. pneumophila isolated from lung tissue in lethal cases of legionellosis compared with strains isolated from the environment requires a more detailed study of functional activity and substrate specificity of the glucosyl transferase. PMID- 22830269 TI - [Persistence properties of Corynebacterium non diphtheriae circulating in Rostov on-Don and Rostov region]. AB - AIM: Characterize persistence properties and antibiotic sensitivity of Corynebacterium non diphtheriae circulating in Rostov-on-Don and Rostov Region. MATERIALS AND METHODS: DNase, anti-immunoglobulin activity, hemagglutinating activity, antagonistic properties and antibiotic sensitivity of Corynebacterium non diphtheriae strains isolated from patients with inflammatory diseases of urogenital tract, pregnant women and individuals undertaking prophylactic examination were studied. RESULTS: Lack of antagonistic interactions of C. non diphtheriae with members of opportunistic microorganisms, high anti immunoglobulin activity against IgM and IgA, lack of hemagglutinating activity were established. Cefazolin and benzylpenicillin had the highest antibacterial activity against C. non diphtheriae, azithromycin and lincomycin--the lowest. CONCLUSION: Population level of C. non diphtheriae during urogenital tract disease diagnostics is necessary. Determination of their sensitivity to a wide specter of antibacterial preparations is reasonable for optimal selection of therapeutic agents. PMID- 22830270 TI - [Refinement of taxonomic position of Lactobacillus genus probiotic strains by 16S rDNA and rpoA gene sequencing]. AB - AIM: Revision of the species identification of collection lactobacilli strains based on 16S rDNA and rpoA gene sequencing. MATERIALS AND METHODS: 52 lactobacilli cultures that present mostly Gamaleya Research Institute of Epidemiology and Microbiology (GIMC) collection were studied. 16S rDNA gene fragments were amplified by using Lb16a, Lb16b, 16S-midford, 16S-midrev primers. 2 different reverse primers were used for the analysis of rpoA gene depending on lactobacilli species. DNA fragments sequencing was performed with 3130 Genetic Analyzer (Applied Biosystems/Hitachi) with primers used for amplification. RESULTS: The effectiveness of sequencing of 2 targets for differentiation of species within lactobacilli phylogenetic groups was shown. Species diversity was demonstrated for GIMC lactobacilli strain collection that includes members of 9 species. All the strains marked previously as L. acidophilus were determined to belong to L. helveticus. Strains belonging to recently discovered L. farraginis species that has promising application in agriculture were detected. CONCLUSION: Genetic passports of original strains of 9 species of lactobacilli that are promising for further research. PMID- 22830271 TI - [Standard algorithm of molecular typing of Yersinia pestis strains]. AB - AIM: Development of the standard algorithm of molecular typing of Yersinia pestis that ensures establishing of subspecies, biovar and focus membership of the studied isolate. Determination of the characteristic strain genotypes of plague infectious agent of main and nonmain subspecies from various natural foci of plague of the Russian Federation and the near abroad. MATERIALS AND METHODS: Genotyping of 192 natural Y. pestis strains of main and nonmain subspecies was performed by using PCR methods, multilocus sequencing and multilocus analysis of variable tandem repeat number. RESULTS: A standard algorithm of molecular typing of plague infectious agent including several stages of Yersinia pestis differentiation by membership: in main and nonmain subspecies, various biovars of the main subspecies, specific subspecies; natural foci and geographic territories was developed. The algorithm is based on 3 typing methods--PCR, multilocus sequence typing and multilocus analysis of variable tandem repeat number using standard DNA targets--life support genes (terC, ilvN, inv, glpD, napA, rhaS and araC) and 7 loci of variable tandem repeats (ms01, ms04, ms06, ms07, ms46, ms62, ms70). The effectiveness of the developed algorithm is shown on the large number of natural Y. pestis strains. Characteristic sequence types of Y. pestis strains of various subspecies and biovars as well as MLVA7 genotypes of strains from natural foci of plague of the Russian Federation and the near abroad were established. CONCLUSION: The application of the developed algorithm will increase the effectiveness of epidemiologic monitoring of plague infectious agent, and analysis of epidemics and outbreaks of plague with establishing the source of origin of the strain and routes of introduction of the infection. PMID- 22830272 TI - [Production of hybrid protein OprF-OprL of Pseudomonas aeruginosa]. AB - AIM: Production of preparation consisting of amino acid sequences of 2 proteins of outer membrane--OprF and OprI--of P. aeruginosa and study of its protective properties from experimental P. aeruginosa infection. MATERIALS AND METHODS: Nucleotide sequences coding OprF protein (1 kb) as well as its C-terminal region (0.6 kb) and OprI protein (0.25 kb) were integrated into pQE-30 plasmid (QIAGEN). And oprF gene (C-terminal region of oprF in variant 2) and oprI gene were combined and cloned sequentially into a single vector. E. coli M15 strain cells (QIAGEN) were used for the production of producent strains of recombinant proteins. Protein products were analyzed by electrophoresis in polyacrylamide gel by Lammle. Purification of recombinant proteins was performed by affinity chromatography in Ni-sepharose columns. Live virulent culture P. aeruginosa PA 170015 strain was used for the analysis of protective properties of recombinant proteins. RESULTS: 2 hybrid recombinant proteins were produced including amino acid sequences of F and I proteins of outer membrane (OprF and OprI) of P. aeruginosa. Recombinant protein 1 included whole size sequences of OprF and OprI and protein 2--C-terminal region (including amino acid residues 192-342) of OprF and whole size sequence of OprI. These recombinant proteins after 2 immunizations protected mice from the experimental intraperitoneal infection with P. aeruginosa. Hybrid protein consisting of whole size sequences had the best protective effect. CONCLUSION: The results obtained open a perspective for further immunobiological testing of hybrid recombinant protein OprF-OprI with the aim of creating immunopreparations for prophylaxis of P. aeruginosa infection. PMID- 22830273 TI - [Economical effectiveness of vaccination of cohort of children aged 2 years against chickenpox in the Russian Federation]. AB - AIM: Perform calculation of the economical effectiveness of realization of a program of vaccination of children aged 2 years against chickenpox (CP) in the Russian Federation. MATERIALS AND METHODS: Data of Federal service on customers rights protection and human well-being surveillance on evaluation of morbidity and losses caused by CP in the Russian Federation in 2008 - 2010 were used. A cohort of children (1 760 000) aged 2 years subject to vaccination against CP in 2011, evaluation of cost of 1 case of the infection, the amount of losses per vaccination of 1 child were approximately determined; analysis of prevented losses by implementation ofvaccination program by using mathematical modeling methods was performed. RESULTS: Without vaccination program in the Russian Federation the cost of losses per 1 case of CP related to hospitalization and outpatient visits as well as temporary disability of one of the parent in various age groups was: for children aged 1 - 2 years--8 333 RUB (Russian rubles), 3 - 6 years--21 171 RUB, 7 - 14 years--21 295 RUB. The cost of vaccination against CP of 1 child including 2 doses of vaccines with physician examination and vaccination procedure would be 1600 RUB. In the case of realization of vaccination program against CP in 2011 of children aged 2 years its cost would be 2 488.9 million RUB. Cost prevention already exceeds the cost of vaccination in 1 age cohort of children at year 2 and in 5 years the amount of prevented losses would exceed 15 billion RUB per 1 vaccinated cohort and would continue to increase steadily. CONCLUSION: The performed calculations show that vaccination against CP in the Russian Federation is a highly efficient investment. Self sufficiency of a program implemented in 2011 may be obtained already at the start of year 2 after the realization and by 2016 the net economical benefit would be around 8 milliards RUB. PMID- 22830274 TI - [Economic effectiveness of vaccination against rotavirus infection in the Russian Federation]. AB - AIM: Perform pharmacoeconomic analysis of the effectiveness of implementation of vaccination program against rotavirus infection in the Russian Federation. MATERIALS AND METHODS: Cost-benefit analytical method was used for the evaluation of economic effectiveness of vaccination against rotavirus infection in the Russian Federation. The number of early vaccinated--1 800 000 individuals, the number of rotavirus enteritis cases in 0 - 5 age cohort--166 215, were determined. The effectiveness of vaccination against rotavirus gastroenteritis was adopted from ATP (according-to-protocol) clinical trial data and was 83.8% cases at a 95% vaccination level. The cost of a case of rotavirus infection according to calculations in the Russian Federation is 17 394 RUB (Russian rubles), and the cost of vaccination of 1 child--1000 RUB. RESULTS: The cost of realization of program of vaccination against rotavirus infection would be 1.7 billion RUB per year. The number of prevented cases of rotavirus infection per year in the cohort of children aged up to 5 years would be 148 114. Net benefit of vaccination of newborn children in the Russian Federation would be 866 million RUB. CONCLUSION: Implementation of program of vaccination against rotavirus infection in the Russian Federation would promote the decrease of morbidity and economical efficiency. The cost of vaccination program is 1.5 times less than the amount of expenses related to infection. PMID- 22830276 TI - [Intestine microbiocenosis in mechanical jaundice caused by obturation of biliary ducts]. AB - AIM: Study the composition of bile and feces microflora in patients with mechanical jaundice of various geneses. MATERIALS AND METHODS: 66 feces and 25 bile samples during nasobiliary decompression were studied bacteriologically. RESULTS: In all patients disorders of normal intestine microflora were detected. Patient bile in 84% of cases was infected by bacteria among which enterococci and urease positive enterobacteria predominated. In 30% of cases in patients identical species of bacteria were simultaneously detected in bile samples and in high titers (6.0 - 6.5 lg CFU/ml) in feces. CONCLUSION: In mechanical jaundice caused by biliary duct obturation in all the patients dysbiotic events of digestive tract are registered, that defines the necessity to improve bacteriological examination of patients with mechanical jaundice and reasonability of disrupted normal intestine microflora correction. PMID- 22830275 TI - [Dynamics of microsymbiocenoses of upper respiratory tract in normal state and in pathology]. AB - AIM: Study of features of interaction of bacteria in microsymbiocenoses of upper respiratory tract in dynamics in individuals with various state of health: healthy individuals, individuals after tonsillitis and bacteria carriers. MATERIALS AND METHODS: Modification of pathogenicity factors (hemolytic, lecitovitellase, lysozyme and anti-lysozyme activity) in intermicrobial interactions of 226 strains of microorganisms isolated during quintuple analysis of upper respiratory tract biocenoses of examined individuals was studied. A hierarchical structure of each microbiocenosis was built based on the data obtained, and its temporal dynamics evaluated. RESULTS: Microbial composition of mucous membrane of tonsils was more constant independent of state of health when compared with the nasal cavity. Normoflora that does not influence expression of pathogenicity factors and symbiont persistence was predominate and persisted for a long period in healthy individuals and bacteria carriers, whereas in individuals after tonsillitis opportunistic strains with a high communicative activity (leaders) that increase symbiont pathogenicity persisted for a long time. CONCLUSION: The revealed differences in biocenoses dynamics of 2 biotopes of upper respiratory tract in healthy individuals, bacteria carriers and individuals after tonsillitis may be used to forecast stable health and development of dysbiotic disorders. PMID- 22830277 TI - [Formation of digestive tract microflora of neonates in dynamics]. AB - AIM: Comparative study of the microbiota of neonates in relation to vaginal and intestinal microflora state of conditionally healthy primipara pregnant women. MATERIALS AND METHODS: Bacteriological study of vaginal and intestinal microflora of 24 conditionally healthy primipara pregnant women at week 32 and 38 of pregnancy as well as bacteriological study of meconium and feces at day 5 of their neonates was performed. RESULTS: Despite detection of lactobacilli by delivery in all the pregnant women their quantity was significantly lower than normal. In colon microflora dysbiotic changes corresponding to grade 1 (46.7%) and 2 (53.3%) dysbacteriosis were detected. In 60.0% of cases of conditionally healthy neonates various microorganism species were isolated from meconium. At day 5 in feces of neonates at natural feeding lactobacilli (85.8%), bifidobacteria and escherichia (71.4% each), enterococci (100%) were detected. CONCLUSION: The course of dysbiotic changes in vagina and intestines of conditionally healthy pregnant women had subclinical level. Detection of microorganisms in meconium in conditionally healthy neonates could be explained by translocation mechanism. PMID- 22830278 TI - [Influence of active forms of oxygen on adhesive characteristics and biofilm production by bacteria]. AB - AIM: Study of influence of low concentrations of active forms of oxygen on the ability of bacteria to form biofilms and their adhesive characteristics. MATERIALS AND METHODS: Modification of the studied properties of bacteria was performed by treatment of the bacteria with hydrogen peroxide or hydroxyl radicals at concentrations of 0.5 mM that causes death of 5 - 7% of cells and non lethal - 0.05 and 0.005 mM. Adhesive characteristics of Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Klebsiella pneumoniae bacteria were determined by using human erythrocytes. The degree of biofilm formation in plates modified by collagen from human fibroblasts was determined by the amount of bound crystal violet. RESULTS: A significant decrease (7 - 17%) of the adhesion of E. coli, S. aureus, K. pneumoniae to erythrocytes under the influence of hydrogen peroxide and hydroxyl radicals at the concentrations of 0.5 and 0.05 mM when compared with the control was detected. 11 - 40% stimulation of E. coli, S. aureus, K. pneumoniae biofilm formation by active forms of oxygen in all the used concentrations with simultaneous insignificant biomass growth increase was noted. Active forms of oxygen did not influence significantly the studied properties of B. subtilis. CONCLUSION: Active oxygen forms have regulatory influence on the character of interaction of bacteria with surfaces colonized by them, that determines structural-functional state of microbial biocenoses. PMID- 22830279 TI - [Pathogenesis of intestinal dysbacteriosis]. AB - AIM: Study mechanism of the development of intestine dysbiosis on the experimental model of mice from the position of reinforcement of translocation of opportunistic Gram negative enterobacteria (OGNE) from the intestine lumen into the system blood flow and the possibility of its correction by lactoglobulin preparations. MATERIALS AND METHODS: Experimental medicinal dysbacteriosis of the intestine was reproduced in mice by using gentamycin. Changes of immunologic parameters in the animals during translocation of Gram negative enterobacteria and their LPS from the intestine lumen into system blood flow were studied. RESULTS: During intestine dysbioses a pronounced inflammatory reaction was shown to develop at a local level with the increase of the amount of proinflammatory cytokines with the sequence IL-1beta - IFNgamma- IL-6 and reinforcement of formation of anti-endotoxin antibodies. Changes in the parameters of allergization of macroorganism under the influence of LPS occurred synchronously with the increase of amount of (OGNE) including escherichia with altered lactase activity in the background of its translocation into extrinsic biotopes. In decompensated variant of dysbiosis a pronounced activation of immune reactive spleen cells was noted. Immunobiologic preparations (lactoglobulin and low molecular peptides of immune colostrum) administered to the animals in parallel with the antibiotic caused deintoxication and desensitizing effect and reduced the side effect of its action. CONCLUSION: A scheme of development of dysbiotic disorders in the intestine from the position of reinforcement of translocation of (OGNE) from the intestine lumen into the system blood flow is proposed and mechanisms of positive effect of lactoglobulin preparations and low molecular peptides of immune colostrum that are perspective for the correction of this state are explained. PMID- 22830280 TI - [Role of Chlamydia trachomatis and Chlamydophila pneumoniae in damage of eye posterior segment structures]. AB - AIM: Study the ability of Chlamydia trachomatis and Chlamydophila pneumoniae to damage structures of eye posterior segment, features of development of such infectious process, its morphological and clinical characteristics. MATERIALS AND METHODS: 6 rabbits with confirmed absence of C. trachomatis, C. pneumoniae were used in the study. 3 animals were infected with C. trachomatis culture and 3 animals--with C. pneumoniae culture. Subconjunctival and intravitreal mode of infectious agent introduction were used, as well as instillation of its culture into conjunctival sac. Microbiological diagnostics included microscopy with direct immunofluorescence, culture method and determination of antibody titers. Infectious process was studied by using ophthalmologic methods and histological examination. Observation period was 4 months. RESULTS: In all the animals a development of infectious process at early stages after the infection was confirmed. Conjunctivitis symptoms, inflammatory exudation into vitreous humor, chorioretinal inflammation loci, disorders in transparency of optical media and detachment of retina were clinical manifestations. In 2 animals infected with C. trachomatis severe panuveitis was noted. In 4 animals infectious process assumed subclinical characteristics (infection with both C. trachomatis or C. pneumoniae). In pathomorphologic studies data on the ability of C. trachomatis and C. pneumoniae to cause damage to cells of retina, pigment epithelium and choroid were obtained. CONCLUSION: C. trachomatis and C. pneumoniae may play a significant role in pathology of vitreous humor, retina, pigment epithelium and choroid. PMID- 22830281 TI - [Recognition of commensal microflora by pattern recognition receptors in human physiology and pathology]. AB - Contemporary data on the interaction of commensal microflora and Toll-like pattern recognition receptors are presented. These receptors recognize normal intestine microflora in physiological conditions, and this interaction is necessary for the maintenance of homeostasis and damage reparation of the intestine, for the induction of heat shock cytoprotective proteins. As a side effect in disruption of immunologic tolerance and misbalance of protective immunological mechanisms, multiorgan pathologic changes of organs and tissues may develop, including chronic inflammation processes of various localization. PMID- 22830283 TI - [Problems of epidemiology and diagnostics of leptospiroses in Siberia and Far East]. AB - Multi-year literature data as well as materials of the Reference centre of monitoring of natural foci infections of Irkutsk Research Institute of Plague Control of Siberia and the Far East regarding epidemiology, epizootology and laboratory diagnostics of leptospiroses in Siberia and the Far East are analyzed and summarized in the review. Situation on leptospiroses in the region has changed significantly. In 50 - 70s of the 20th century diseases were registered ubiquitously in the form of outbreaks, group and single cases. Currently a low level of sporadic morbidity is noted in separate subjects of the Russian Federation. The contemporary state of the problem remains insufficiently clear, this demands the expansion of studies, creation of modern databases, as well as introduction into the practice of highly sensitive methods of express diagnostics in a complex with bacteriologic and serologic methods. PMID- 22830282 TI - [Genetic analysis of biochemical differences of Yersinia pestis strains]. AB - Literature data and results of our experimental studies on genetic base of biochemical differentiation of Yersinia pestis strains of various subspecies and biovars are summarized in the review. Data on variability of genes coding biochemical features (sugar and alcohol fermentation, nitrate reduction), the differential development of which are the base of existing phenotypic schemes of Y. pestis strains classification, are presented. Variability of these genes was shown to have possible use for the development of genetic classification of Y. pestis strains of various subspecies and biovars. PMID- 22830284 TI - [Cowpox: features of spread after cancellation of mandatory pox immunization]. AB - Features of spread of cowpox in the contemporary conditions are examined. A decrease of population immunity to pox in the population of Russia caused by cancellation of pox immunization, hidden circulation of cowpox virus in various species of rodents, as well as lack of vigilance to pathogenic orthopoxviurses in healthcare workers were noted to create the real preconditions for the emergence of infection of humans caused by cowpox virus. Thereby presence of means of express laboratory diagnostics of cowpox and means of effective medical protection for the prevention of development of this disease in the population of Russia becomes an actual necessity. PMID- 22830285 TI - [Possible method of eradication of poliomyelitis as an infection]. AB - Problem of poliomyelitis eradication is examined in the review. After the eradication of wild poliovirus, vaccine poliomyelitis virus continues to circulate in the human population. In rare cases it can cause the development of the disease. The authors describe disadvantages of the use of oral and inactivated poliomyelitis vaccines and note that by using oral poliomyelitis vaccine and eradication only of wild poliovirus, eradication of poliomyelitis as an infection will not succeed. As one of the approaches to reach this goal the authors propose the use of various enterovirus interference. Use of live enterovirus vaccine is described and its advantages and disadvantages are examined. PMID- 22830286 TI - [Epidemiologic and economic effectiveness of school closure during influenza epidemics and pandemics]. AB - Epidemiologic and economic effectiveness of school closure during influenza epidemics and pandemics is discussed. Optimal effect of school closure is observed when this measure is taken at the start of the epidemic or pandemic and for a sufficiently long time. School closure during high morbidity among schoolchildren, in the middle (at the peak) and by the end of epidemic or pandemic does not influence significantly the spread of influenza or morbidity. Significant economic losses and other negative consequences of school closure are noted. School closure may be the most appropriate during the emergence of influenza pandemic when the pandemic vaccine is not yet available, however timely mass immunization of schoolchildren against influenza may be a more appropriate measure than school closure for the reduction of influenza morbidity and spread during seasonal influenza epidemics. PMID- 22830287 TI - Update on treatment of hereditary angioedema. AB - BACKGROUND: Hereditary Angioedema (HAE) is a rare disease characterized by recurrent, self-limiting episodes of swelling. New therapies have recently emerged and are now available; however, many physicians are not aware of the new medications, and their indications and contraindications. OBJECTIVE: To update allergists and primary care physicians on new advances in HAE therapies. DATA SOURCES: A PubMed literature search was used to develop this manuscript. STUDY SELECTIONS: English language peer-reviewed angioedema articles were selected. High quality Phase II and III placebo-controlled clinical trials were reviewed and summarized. RESULTS: Until 2008, therapy for HAE consisted of symptom relief with narcotics, hydration and fresh frozen plasma (FFP). Androgens and FFP are frequently used despite multiple, significant side effects. Newer therapies include C1-inhibitor--both human plasma derived and recombinant--as well as contact system modulators such as ecallantide and icatibant. All of these products can be used for treatment of acute attacks of HAE, and C1-inhibitors can also be used for prophylaxis. CONCLUSION: New, disease-specific therapies have recently emerged which are more efficacious, are proven to work by placebo controlled studies, have minimal adverse effects, and can be utilized for the treatment of HAE. PMID- 22830288 TI - Convenient, rapid and economic detection and semi-quantification of American cockroach allergen in the environment. AB - BACKGROUND: Measuring allergen levels in the environment provides useful information to guide the management of allergic patients. A laboratory-based test kit sandwich ELISA for quantification of Per a 9, the major allergen of Periplaneta americana was recently developed. However, it is not suitable for screening. OBJECTIVE: To develop a simple, rapid, and economic format for semi quantification of Per a 9 assay using dot-blot ELISA technique. METHODS: The efficacy of direct dot-blot ELISA and sandwich dot-blot ELISA was evaluated. Direct dot-blot ELISA was selected for further modification into 6 protocols. The selected protocol of direct dot-blot was further compared with the laboratory based test kit, sandwich ELISA. RESULTS: The lowest detection limits in protocols no. 1-6 were 3.9, 15.6, 15.6, 62.5, 125 and 62.5 microg/ml of native Per a 9 whereas time required for each protocol was 145, 45, 30, 26, 18 and 26 minutes, respectively. The sensitivity of direct dot-ELISA was 3.9 microg/ml of Per a 9. Protocol no. 3 was the most suitable assay because its detection limits were as low as 15.6 microg/ml of CR allergen and the total process took only 30 minutes. In comparison with the 2 days required for laboratory sandwich ELISA, the selected protocol provided a similar yield of allergen detection but it offers significant savings of time. Additionally, this method could be easily interpreted by various groups of people. CONCLUSION: This modified direct dot blot ELISA is the first membrane ELISA which is a semiquantitative test appropriate for screening American cockroach allergen owing to its simplicity, speed and good yield. PMID- 22830289 TI - Antigen-specific activities of CD8+ T cells in the nasal mucosa of patients with nasal allergy. AB - BACKGROUND: The prevalence of chronic rhinitis is increasing rapidly. Its pathogenesis is not fully understood but immune inflammation is one plausible causative factor. Antigen specific CD8+ T cells play a critical role in the induction of chronic inflammation. This study aims to investigate the role of antigen specific CD8+ T cells in the pathogenesis of chronic AR. METHODS: Nasal mucosal epithelial samples obtained by the surface of the nasal mucosaof patients with AR complicated with inferior turbinate hypertrophy. Exosomes were purified from the scratching samples and examined by immune gold electron microscopy. Cell culture models were employed to evaluate the effect of exosomes on modulating CD8+ T cell activity. RESULTS: Exosomes purified from patients with chronic AR carried microbial products, Staphylococcal enterotoxin B (SEB), and airborne antigen, Derp1. Dendritic cells pulsed by SEB/Derp1-carrying exosomes showed high levels of CD80, CD86 and the major histocompatibility class I (MHCI). Exosome pulsed dendritic cells could induce naive CD3+ T cells to differentiate into CD8+ T cells. Upon exposure to a specific antigen, the CD8+ T cells released granzyme B and perforin and more than 30% antigen specific CD8+ T cells proliferated. CONCLUSIONS: Antigen specific CD8+ T cells play an important role in the pathogenesis of chronic AR complicated with inferior turbinate hypertrophy. PMID- 22830290 TI - Non-mitogen containing conditioned medium for hybridoma production and single cell cloning. AB - BACKGROUND: The hybridoma technique is the standard method for production of monoclonal antibodies of interest. However, the newly formed hybridomas and cells at low density often grow poorly or die. This is the major obstacle to production of monoclonal antibodies. OBJECTIVE: The aim of this study was to establish a method for preparation of conditioned medium in the absence of mitogen for promoting the growth of hybridomas after cell fusion and during single cell cloning. METHODS: Culture supernatants were obtained from the cultures of BW5147 mouse thymoma cells without mitogen stimulation. Novel conditioned mediums were investigated for their ability to support hybridoma single-cell cloning and hybridoma production. RESULTS: We demonstrated that these conditioned mediums could support hybridoma single-cell growth, both for stable and newly generated hybridomas, at a level equal to the commercial conditioned medium BM-Condimed H1. The conditioned medium was most effective at a final concentration of 20% with the basal medium supplemented with 10% fetal calf serum. The novel conditioned medium could also be effectively employed for generation of hybridomas secreting various monoclonal antibodies. Interestingly, fibroblast overgrowth in the post fusion wells was markedly reduced when using the novel conditioned medium, as compared to the commercial BM-Condimed H1, likely due to the absence of mitogen in the conditioned medium. CONCLUSION: We describe the method for production of a novel conditioned medium for hybridoma technology. This method is simple, needing no special technology or sophisticated equipment. The novel conditioned medium is, therefore, recommended for use in place of expensive commercial conditioned medium for hybridoma technology, especially in resource-limited countries. PMID- 22830291 TI - The use of acridine orange and glutaraldehyde-fixed chicken red blood cells for absolute counting of residual white blood cells in leuco-depleted packed red blood cells. AB - BACKGROUND: We have previously developed an affordable flow cytometric method for absolute cell count using glutaraldehyde-fixed chicken red blood cells. However, its use is limited to CD4+ T cells. In the current investigation, we studied the potential use of glutaraldehyde-fixed chicken RBCs to determine the number of residual white blood cells (rWBCs) in WBC-reduced blood component. METHODS: Acridine orange (AO) was used to identify leucocytes in serial diluted blood samples ranging from 0.65 to 1,000 cells/microL. The absolute number of AO stained leucocytes were determined by using a known number of glutaraldehyde fixed chicken RBCs on flow cytometer. The results were compared with the expected value and the absolute count determined by BD Leucocount (Becton Dickinson Bioscience). In addition, the stability of AO stained leucocytes and sample stability at various time points were measured. Reproducibility of the assay method was also addressed. RESULTS: There was a good correlation in the number of leucocytes between our new method and the expected numbers from serially diluted blood samples (r2 = 0.99, y = 1.04x + 0.50, p < 0.001). Furthermore, absolute leucocyte counts determined by the new method correlated well with those obtained from BD Leucocount (r2 = 0.99, y = 1.31 x - 6.37, p < 0.001). FL-1 intensity and the absolute number of AO stained leucocytes were stable for at least 24 hours after staining. Samples stored at 4 degrees C were stable for 48 hours and CV of the assay was at an acceptable level. CONCLUSION: This flow cytometric method for absolute leucocyte counts using AO and glutaraldehyde-fixed chicken RBCs is a simple, rapid, reliable and inexpensive method for routine monitoring of low levels of leucocytes in blood products. PMID- 22830292 TI - Comparison of leukotriene receptor antagonists in addition to inhaled corticosteroid and inhaled corticosteroid alone in the treatment of adolescents and adults with bronchial asthma: a meta-analysis. AB - BACKGROUND: Leukotriene receptor antagonists (LTRA) have been recommended as treatment for persistent asthma. It is not clear whether oral LTRA in combination with inhaled corticosteroids (ICS) confers any additional benefit over ICS alone. OBJECTIVE: This meta-analysis was conducted to review the evidence for the benefits and risks of ICS-LTRA in comparison to ICS alone in bronchial asthma. METHODS: MEDLINE, EMBASE, LILACS, and CINAHL databases were searched for studies published through Aug 20, 2011. Studies comparing ICS-LTRA and ICS and those comparing ICS-LTRA and high-dose ICS were examined separately. Studies were pooled to yield odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). RESULTS: Eight trials in which ICS-LTRA was compared with the same dose of ICS and five in which ICS-LTRA was compared with high-dose ICS were identified. In adults with mild to moderate asthma, the combination of ICS-LTRA improves the control of asthma when compared with same dose of ICS as monotherapy. The effects of ICS-LTRA therapy are similar to those of high-dose ICS in asthma control, but high-dose ICS is superior to ICS-LTRA with regard to improvement in some pulmonary function indices. CONCLUSIONS: In adults with mild to moderate asthma, though the effects were minimal, the combination of ICS-LTRA is recommended, when comparing its effects with the same dose ICS as monotherapy. The relative merits of ICS-LTRA and high-dose ICS therapy are uncertain and more research is needed. PMID- 22830293 TI - Enhancement of clara cell 10-kD protein (CC10) production from nasal epithelial cells by fexofenadine hydrochloride. AB - BACKGROUND: Clara cell 10-kD protein (CC10) is well known to be an immuno suppressive protein secreted from airway epithelial cells after inflammatory stimulation and is involved in the development of allergic disorders. Although histamine H1 receptor antagonists are used for the treatment of allergic disorders, the influence of the agents on CC10 production is not well understood. In the present study, we examined the influence of a histamine H1 receptor antagonist, fexofenadine hydrochloride (FEX) on CC10 production in vitro and in vivo. METHODS: Nasal epithelial cells (5 x 10(6) cells/ml) were stimulated with 20 ng/ml TNF-alpha in the presence of various concentrations of FEX for 24 hours. CC10 levels in culture supernatants were examined by ELISA. Patients with Japanese cedar pollinosis were treated orally with FEX twice a day at a single dose of 60 mg for two weeks during Japanese cedar pollen season (February 2011 to April 2011). CC10 levels in nasal secretions were also examined by ELISA. RESULTS: The addition of FEX into cell cultures caused increase in CC10 production induced by TNF-alpha stimulation, and the minimum concentration that caused significant increase was 200 ng/ml. Oral administration of FEX also increased CC10 levels in nasal secretions from pollinosis patients along with attenuation of clinical symptoms. CONCLUSION: The ability of FEX to enhance CC10 production may account, at least in part, for the clinical efficacy of the agent in allergic disorders, including allergic rhinitis. PMID- 22830294 TI - Pediatric acute and chronic rhinosinusitis: comparison of clinical characteristics and outcome of treatment. AB - BACKGROUND: Rhinosinusitis (RS) is a common problem in children. There are very few published studies comparing acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) in children. OBJECTIVE: To determine the clinical manifestations in children with ARS and CRS. METHODS: One hundred and fifty-four patients with a clinical diagnosis of RS were enrolled. ARS was defined as persistent symptoms for more than 10 days but less than 4 weeks and CRS was defined as persistent symptoms for longer than 8 weeks. Patients were interviewed to obtain demographic and clinical data. Physical findings and medications were recorded. All patients underwent radiographic studies. Allergy and immunological testing were done in selected case. All data were compared between the ARS and CRS groups. RESULTS: One hundred and three patients were classified as having ARS and fifty-one had CRS. Their mean (+/- SD) age was 5.9 +/- 3.3 years. Allergic rhinitis was common in the chronic rhinosinusitis group. The most common main complaints in acute and chronic rhinosinusitis were cough and rhinorrhea. There was no significant difference in symptoms between both groups, except for periorbital pain and sleep apnea which were found more frequently in the chronic group. Sixty five percents of ARS and 58.8% of CRS had abnormal x-ray findings. Adenoid hypertrophy was found in the CRS group. There was overall improvement after 14.6 +/- 3.82 days and 22.35 +/- 5.04 days (mean) of antibiotic treatment in the ARS and CRS groups, respectively. None of the patient underwent sinus surgery. CONCLUSION: The most common RS symptoms were rhinorrhea and cough. Patients with allergic rhinitis had a higher risk of developing chronic rhinosinusitis. Patients with ARS and CRS were successfully treated with medical treatment. PMID- 22830295 TI - Prevalence and risk factor for symptomatic avascular necrosis development in Thai systemic lupus erythematosus patients. AB - BACKGROUND: Avascular necrosis (AVN) has been reported in systemic lupus erythematosus (SLE) and most SLE patients suffer from this problem. OBJECTIVES: To study the prevalence of AVN in Thai SLE patients and to determine the risk factors for developing AVN. METHODS: A retrospective study was performed, between January 1, 1995 and August 31, 2005, on patients over 15 years of age in Khon Kaen, Thailand. RESULTS: The medical records of 736 SLE patients were reviewed. The female to male ratio was 15.4:1. The prevalence of AVN was 8.8%. The average age at the time of AVN detection was 27 years (range, 18-54) and the average duration of disease 69 months (range, 12-112). All cases were AVN of the hip joint. The factors correlated with AVN included: long duration of disease, history of previous septic arthritis in the ipsilateral hip to the AVN development, hematological involvement, gastrointestinal involvement, arthritis and cutaneous vasculitis. After regression analysis, hematological involvement and long duration of disease were associated with AVN with a respective odds ratio of 3.13 (95% CI 1.13-8.54) and 1.01 (95% CI 1.00-1.02). Neither high-dose steroid nor antimalarial treatment were correlated with AVN in our study and 4.6% (n = 3) of patients had never received steroid therapy during the follow-up period. CONCLUSION: Prevalence of symptomatic AVN was 8.8% in our SLE patients. A longer duration of disease and hematological involvement were associated with AVN development. PMID- 22830296 TI - Comparison of irritatant reactions between using lyophilized and commercial food allergen extracts in atopy patch tests in a normal population. AB - BACKGROUND: Several authors have investigated the use of the atopy patch tests (APT) for the diagnosis of non-IgE mediated food allergy, primarily in patients with atopic dermatitis and digestive disorders. However, one of the difficulties in atopy patch testing is the lack of standardization. Several commercial APTs containing freeze-dried food extracts are now available, but their diagnostic accuracy is still largely undefined. The objective of this study is to evaluate the irritant reactions and safety of atopy patch tests in healthy subjects by using lyophilized and commercial food allergen extracts. METHODS: A cross sectional study was carried out in healthy volunteers. Atopy patches using lyophilized and commercial allergens, including cow's milk, egg, wheat, soy and shrimp, were assessed. Additionally, commercial extracts of house dust mite (D. pteronyssinus 10,000 AU/ml, D. farinae 10,000 AU/ml) and American cockroach were also evaluated. RESULTS: Eighteen healthy volunteers (13 women, median age 26 years) were enrolled. All APT results, both from using lyophilized and commercial allergen extracts, showed no reactions. There were no systemic allergic reactions or irritant reactions observed. CONCLUSION: APTs using lyophilized and commercial food allergen extracts and commercial extracts of house dust mite and American cockroach showed no irritant reactions in Thai non-atopic subjects. PMID- 22830297 TI - Successful desensitization with un-fractionated heparin in a patient with heparin allergy and tolerance to fondaparinux. AB - Immediate hypersensitivity to low molecular weight heparin (LMWH) is rare, and we present here a case with an anaphylaxis-like symptoms to enoxaparin. The diagnosis of hypersensitivity to enoxaparin was confirmed by the clinical picture and positive skin tests. In this case, palmo-plantal itching after application of heparin was an early sign of immediate type hypersensitivity. His skin and provocation tests showed cross-reactivity with other types of LMWHs and un fractionated heparin (UFH). Fondaparinux and desensitization with UFH were found to be safe alternative treatment options in this patient with heparin allergy. PMID- 22830298 TI - Anaphylaxis induced by lentil inhalation. AB - Anaphylaxis is a rapid onset serious allergic reaction which may be fatal. Foods are the most common allergens leading to anaphylaxis especially for childhood. Most of the food-induced anaphylactic reactions take place after ingestion of the allergic food and only a few cases exist with anaphylactic reactions induced by inhalation of foods such as peanut, soybean and lupine. The case we present is unusual in that an 8 1/2-year-old boy developed anaphylaxis with the inhalation of steam from boiling lentils. PMID- 22830300 TI - Copper-catalyzed oxaziridine-mediated oxidation of C-H bonds. AB - The highly regio- and chemoselective oxidation of activated C-H bonds has been observed via copper-catalyzed reactions of oxaziridines. The oxidation proceeded with a variety of substrates, primarily comprising allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C-H bond. The mechanism of the reaction is proposed to involve single-electron transfer to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final single-electron transfer event. The involvement of allylic radical intermediates was supported by a radical-trapping experiment with TEMPO. PMID- 22830299 TI - Gene expression profiling of Escherichia coli in response to interactions with the lettuce rhizosphere. AB - AIMS: The objective of this study was to examine transcriptional changes in Escherichia coli when the bacterium was growing in the lettuce rhizoshpere. METHODS AND RESULTS: A combination of microarray analyses, colonization assays and confocal microscopy was used to gain a more complete understanding of bacterial genes involved in the colonization and growth of E. coli K12 in the lettuce root rhizosphere using a novel hydroponic assay system. After 3 days of interaction with lettuce roots, E. coli genes involved in protein synthesis, stress responses and attachment were up-regulated. Mutants in curli production (crl, csgA) and flagella synthesis (fliN) had a reduced capacity to attach to roots as determined by bacterial counts and by confocal laser scanning microscopy. CONCLUSIONS: This study indicates that E. coli K12 has the capability to colonize lettuce roots by using attachment genes and can readily adapt to the rhizosphere of lettuce plants. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study show curli production and biofilm modulation genes are important for rhizosphere colonization and may provide useful targets to disrupt this process. Further studies using pathogenic strains will provide additional information about lettuce-E. coli interactions. PMID- 22830301 TI - Understanding reactivity and stereoselectivity in palladium-catalyzed diastereoselective sp3 C-H bond activation: intermediate characterization and computational studies. AB - The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd(II)-catalyzed sp(3) C-H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C-H insertion intermediate by X-ray paved the way for further investigations into C-H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C-H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C-H activation occurs at the monomeric Pd center and that the most preferred transition state for C-H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C-H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C-H bonds and Pd-OAc bonds is crucial for C H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr substituted oxazolines. PMID- 22830302 TI - Fine needle aspiration cytology of primary mucormycosis of the breast in a young immunocompetent pregnant woman. PMID- 22830303 TI - Signs of general inflammation and kidney function are associated with the ocular features of acute Puumala hantavirus infection. AB - BACKGROUND: Puumala hantavirus (PUUV) causes nephropathia epidemica (NE), a type of viral haemorrhagic fever with renal syndrome (HFRS). This febrile infection may affect the kidneys, central nervous system (CNS), and the eye. Acute illness is associated with increased tissue permeability and tissue oedema, and many patients experience reduced vision. The aim of this study was to explore the physiological events associated with the ocular features of acute NE. METHODS: This was a prospective study of 46 NE patients who were examined during the acute infection and 1 month after hospitalization. Visual acuity, refraction, intraocular pressure (IOP), and ocular dimensions were evaluated. Cerebrospinal fluid and blood samples were collected, brain magnetic resonance imaging and electroencephalography were recorded, and HLA haplotype was analyzed. The degrees of tissue oedema and fluid imbalance were evaluated. RESULTS: CNS examinations did not reveal the source of the ocular changes in acute NE. The plasma C reactive protein concentration correlated with the lens thickness and the IOP. The plasma creatinine level was associated with the change in anterior chamber depth. However, oliguric and polyuric patients displayed similar ocular findings. Patients positive for the DR3-DQ2 haplotype experienced the least diminished visual acuity. CONCLUSIONS: The level of systemic inflammation rather than CNS involvement appears to account for the ocular changes during acute PUUV infection, and the severity of kidney dysfunction may also have a significant role. In addition, the genetic properties of the host may well explain the ocular features of acute hantavirus infection. PMID- 22830304 TI - Correction to isolation of alpaca antihapten heavy chain single domain antibodies for development of sensitive immunoassay. PMID- 22830305 TI - Recording of the full-field electroretinogram in minipigs. AB - PURPOSE: To test a simple electroretinographic protocol on a representative sample of minipigs. ANIMAL STUDIED: Minipig. PROCEDURES: Electroretinogram recordings were conducted on 162 healthy minipigs (81 males and 81 females) aged 4-6 months. After a 1.5-h light-adaptation period, the animals were anesthetized with general anesthesia. First, binocular full-field photopic electroretinogram recordings were conducted under photopic conditions. Subsequently, scotopic electroretinogram recordings were conducted during dark-adaptation periods every 4 min for a 20-min period. At the end of this period, the maximal combined rod cone response was recorded by measuring the retinal response to a single high intensity flash. We used sclerocorneal clip electrodes as active electrodes and needle electrodes as reference and ground electrodes. RESULTS: The a-wave and b wave peak times and amplitudes have been measured and statistically analyzed. For each of the statistical comparisons, normality and homogeneity of variances were evaluated. No significant gender differences were observed, with the exception of a higher b-wave amplitude for the photopic ERG recordings observed in females when compared to males (48.14 +/- 12.909 MUV vs. 42.88 +/- 10.666 MUV; P = 0.005). The process of dark adaptation was evaluated, and the maximal combined rod-cone response was measured (a- and b-waves amplitude and peak time). CONCLUSIONS: We conducted photopic and scotopic electroretinogram recordings from a protocol based on light adaptation followed by dark adaptation using sclerocorneal clip electrodes, which allows quick assembly and examination. PMID- 22830306 TI - Utilizing the reaction of degeneration test for individuals with focal paralysis. AB - BACKGROUND AND PURPOSE: Neuromuscular electrical stimulation (NMES) is a modality sometimes used to help strengthen weak muscles. On occasion, however, the targeted muscles do not respond to the current delivered. No response to electrical stimulation should raise the consideration of unsuspected peripheral nerve damage. Two case studies are presented showing how absence of response was due to unsuspected peripheral neuropathy, which had not been considered in either of the original referral diagnoses. CASE DESCRIPTIONS: The first individual sustained head trauma and did not respond to NMES to facilitate finger flexor contractions in the left hand. This prompted a reaction of degeneration test (R/D test) which revealed evidence of a median nerve lesion. The second individual presented with right ankle dorsiflexor and evertor paralysis following a right total hip replacement. The R/D test helped rule out a central nervous system lesion by revealing evidence of right peroneal nerve degeneration. CONCLUSION: The case reports show how clinical suspicion followed by simple R/D testing can be used to screen for nerve damage, prompting further electrodiagnostic work up of individuals with profound weakness and or paralysis. PMID- 22830307 TI - Oral immunotherapy in hen's egg-allergic children increases a hypo-proliferative subset of CD4+ T cells that could constitute a marker of tolerance achievement. AB - BACKGROUND: Food allergy affects a significant number of children and its prevalence, and persistence is undergoing an important increase in the last years. Specific oral tolerance induction (SOTI) is a promising therapy for food allergy. However, little is known about the immune mechanisms implicated in the desensitization to allergens. Our purpose was to study which immune parameters are modified during the process of tolerance achievement with the goal of identifying markers of tolerance induction. METHODS: We performed an extensive immune analysis in 19 allergic children following SOTI with hen's egg before and after the immunotherapy. Changes in lymphocyte subpopulations and serum cytokines were identified in children with desensitization achievement. RESULTS: Sixteen children achieved complete tolerance to egg, and the immune analysis reveals that desensitization was accompanied in all the cases by a significant decrease in the percentage and absolute counts of effector-memory CD4+ T cells (T(EM) ) and a marked increase in the absolute counts of a subset of CD4(+) CD38(+) CD45RO(-) cells. Additionally, we also observed a marked reduction in the plasma levels of different Th1 and Th2 cytokines after tolerance achievement. CONCLUSIONS: Acquisition of tolerance in children after oral immunotherapy is accompanied by a decrease in the T(EM) population and the increase in a particular subset of CD4+ T cells with a hypo-proliferative and non-reactive phenotype. This hypo proliferative subset of cells could constitute a marker of the development of oral tolerance, and the study of this subset could contribute to the better understanding of the immune responses in allergic subjects. PMID- 22830308 TI - Synthesis, structural elucidation, and application of a pyrazolylpyridine molybdenum oxide composite as a heterogeneous catalyst for olefin epoxidation. AB - The reaction of [MoO(2)Cl(2)(pypzEA)] (1) (pypzEA = ethyl[3-(pyridin-2-yl)-1H pyrazol-1-yl]acetate) with water in a Teflon-lined stainless steel autoclave (100 degrees C) or in an open reflux system leads to the isolation of the molybdenum oxide/pyrazolylpyridine composite material [Mo(2)O(6)(HpypzA)] (2; HpypzA = [3 (pyridinium-2-yl)-1H-pyrazol-1-yl]acetate). The solid state structure of 2 was solved through single crystal and powder X-ray diffraction analyses in conjunction with information derived from FT-IR and (13)C CP MAS NMR spectroscopies and elemental analyses. In the asymmetric unit of 2, two crystallographically distinct Mo(6+) centers are bridged by a syn,syn-carboxylate group of HpypzA. The periodic repetition of these units along the a axis of the unit cell leads to the formation of a one-dimensional composite polymer, (infinity)(1)[Mo(2)O(6)(HpypzA)]. The outstretched pyrazolylpyridine groups of adjacent polymers interdigitate to form a zipper-like motif, generating strong onset pi-pi contacts between adjacent rings of coordinated HpypzA molecules. The composite oxide 2 is a stable heterogeneous catalyst for liquid-phase olefin epoxidation. PMID- 22830309 TI - Antiallergic effect of Picholine olive oil-in-water emulsions through beta hexosaminidase release inhibition and characterization of their physicochemical properties. AB - The inhibitory effect of Picholine olive oil from Montpellier in Southern France on the chemical mediator release in type I allergy, using rat basophilic leukemia (RBL-2H3) cells, was investigated. Oil-in-water (O/W) emulsions prepared using Picholine olive oil showed an inhibitory effect on the chemical mediator release and decreased expressions of genes related to type I allergy in RBL-2H3 cells. We then measured the phenolic compounds present in Picholine olive oil using high performance liquid chromatography and investigated some physical properties, such as droplet size, size distribution, viscosity, and surface tension of the resulting olive O/W emulsions. Our findings indicate that Picholine olive oil has high flavonoids content, especially apigenin, and the prepared emulsion of Picholine olive oil resulted in a considerable small size distribution, with an average droplet size of 170 nm. PMID- 22830310 TI - Supported lipopolysaccharide bilayers. AB - In this report, the formation of supported lipopolysaccharide bilayers (LPS-SLBs) is studied with extracted native and glycoengineered LPS from Escherichia coli ( E. coli ) and Salmonella enterica sv typhimurium ( S. typhimurium ) to assemble a platform that allows measurement of LPS membrane structure and the detection of membrane tethered saccharide-protein interactions. We present quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescence recovery after photobleaching (FRAP) characterization of LPS-SLBs with different LPS species, having, for example, different molecular weights, that show successful formation of SLBs through vesicle fusion on SiO(2) surfaces with LPS fractions up to 50 wt %. The thickness of the LPS bilayers were investigated with AFM force-distance measurements which showed only a slight thickness increase compared to pure POPC SLBs. The E. coli LPS were chosen to study the saccharide protein interaction between the Htype II glycan epitope and the Ralstonia solanacearum lectin (RSL). RSL specifically recognizes fucose sugars, which are present in the used Htype II glycan epitope and absent in the epitopes LPS1 and EY2. We show via fluorescence microscopy that the specific, but weak and multivalent interaction can be detected and discriminated on the LPS-SLB platform. PMID- 22830311 TI - The economic efficiency of sampling size: the case of beef trim. AB - The economically optimal sample size in a food safety test balances the marginal costs and marginal benefits of increasing the sample size. We provide a method for selecting the sample size when testing beef trim for Escherichia coli O157:H7 that equates the averted costs of recalls and health damages from contaminated meats sold to consumers with the increased costs of testing while allowing for uncertainty about the underlying prevalence rates of contamination. Using simulations, we show that, in most cases, the optimal sample size is larger than the current sample size of 60 and, in some cases, it exceeds 120. Moreover, lots with a lower prevalence rate have a higher expected damage because contamination is more difficult to detect. Our simulations indicate that these lots have a higher optimal sampling rate. PMID- 22830312 TI - Characteristics and application of inner ear CT in 20 cases of sensorineural hearing loss in children. AB - CONCLUSION: This study shows that a number of children with sensorineural hearing loss (SNHL) have inner ear malformations demonstrated by multi-slice spiral computed tomography (MSCT). MSCT allows a comprehensive assessment of various congenital inner ear malformations through high quality multiplanar reformation (MPR) and can display the site and degree of the malformation three-dimensionally and intuitively. This is very useful for cochlear implantation. OBJECTIVE: To evaluate the feasibility and usability of MSCT in pediatric SNHL with inner ear malformations. METHODS: Sixty-five patients were diagnosed with SNHL by brainstem auditory evoked response (BAER). Inner ear MSCT scan and coronal MPR reconstruction were performed in all cases. RESULTS: This study demonstrated 20 cases (33 ears) with inner ear malformations, which included 10 ears with cochlear malformations, 7 with vestibular malformations, 5 with semicircular canal malformations, 8 with internal auditory canal (IAC) malformations, and 15 with vestibular malformations. Cochlear malformations included one ear with Michel deformity, two ears with common cavity deformity, one with cochlear aplasia, one with hypoplastic cochlea, two with incomplete partition type I, and three with incomplete partition type II (Mondini deformity). PMID- 22830313 TI - Left ventricular hypertrabeculation/noncompaction with epilepsy, other heart defects, minor facial anomalies and new copy number variants. AB - BACKGROUND: Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology which has been described in children as well as in adults with and without chromosomal aberrations. LVHT has been reported in association with various cardiac and extracardiac abnormalities like epilepsy and facial dysmorphism. CASE PRESENTATION: A unique combination of LVHT, atrial septal defect, pulmonary valve stenosis, aortic stenosis, epilepsy and minor facial anomalies is presented in a 5.5 years old girl. Microarray-based genomic hybridization (array-CGH) detected six previously not described copy number variants (CNVs) inherited from a clinically unaffected father and minimally affected mother, thus, most likely, not clinically significant but rare benign variants. CONCLUSIONS: Despite this complex phenotype de novo microdeletions or microduplications were not detected by array CGH. Further investigations, such as whole exome sequencing, could reveal point mutations and small indels as the possible cause. PMID- 22830314 TI - In silico studies of Echinococcus granulosus FABPs. AB - Fatty acid (FA) binding proteins are small intracellular proteins whose members exhibit great diversity and low similarity at the primary structure level, but a highly conserved three-dimensional structure. Characterised by a high-affinity non-covalent binding of hydrophobic ligands, these proteins have a molecular mass of 14-15 kDa with a characteristic beta-barrel structure. Members of this family have been identified along the zoological scale, with Platyhelminthes being the more primitive organisms where they have been reported. Two FA binding proteins (FABPs), EgFABP1 and EgFABP2, with 88% similarity have been identified in Echinococcus granulosus. In an effort to understand why two such similar proteins are expressed by this organism, we performed an in silico analysis of the binding capabilities of both proteins. The crystallographic structure of EgFABP1 was utilised as a template to model EgFABP2, and both were docked against palmitate, oleate, linoleate and arachidonate. The docked structures were submitted to 4 ns molecular dynamics simulations, and their protein-ligand interaction energies were measured. The collected data demonstrated that linoleate and arachidonate had the higher interaction energies when bound to EgFABP1 and that palmitate and linoleate had the higher interaction energies when bound to EgFABP2. External and internal binding surfaces were analysed, showing differences at both levels. Internal surface compositions suggested that both proteins could have preferences for certain FAs. Comparisons of the holo and apo forms of each protein indicated that the ligand imposed subtle, but specific modifications that could trigger surface signals. The differences found between the proteins under study suggest that they could have functional uniqueness in the parasite's metabolism. PMID- 22830316 TI - The influence of perfluorinated substituents on the nucleophilic reactivities of silyl enol ethers. AB - The fluorinated trimethylsilyl enol ethers 3a-c were synthesized, and the kinetics of their reactions with the benzhydrylium ions 4 was studied by UV-vis spectroscopy in dichloromethane. Comparison with nonfluorinated analogues shows that replacement of CH(3) by CF(3) reduces the nucleophilic reactivity by 8 orders of magnitude, while the exchange of C(6)H(5) by C(6)F(5) retards the reactions by 4.5 orders of magnitude. PMID- 22830317 TI - Why peer evaluation by students should be part of the medical school learning environment. PMID- 22830315 TI - Microalgal biofactories: a promising approach towards sustainable omega-3 fatty acid production. AB - Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide significant health benefits and this has led to an increased consumption as dietary supplements. Omega-3 fatty acids EPA and DHA are found in animals, transgenic plants, fungi and many microorganisms but are typically extracted from fatty fish, putting additional pressures on global fish stocks. As primary producers, many marine microalgae are rich in EPA (C20:5) and DHA (C22:6) and present a promising source of omega-3 fatty acids. Several heterotrophic microalgae have been used as biofactories for omega-3 fatty acids commercially, but a strong interest in autotrophic microalgae has emerged in recent years as microalgae are being developed as biofuel crops. This paper provides an overview of microalgal biotechnology and production platforms for the development of omega 3 fatty acids EPA and DHA. It refers to implications in current biotechnological uses of microalgae as aquaculture feed and future biofuel crops and explores potential applications of metabolic engineering and selective breeding to accumulate large amounts of omega-3 fatty acids in autotrophic microalgae. PMID- 22830318 TI - Managing curriculum transformation within strict university governance structures: an example from Damascus University Medical School. AB - As the world of medical education moves forward, it becomes increasingly clear that the transformative process is not as easy a process for all. Across the globe, there appears to be many barriers that obstruct or threaten innovation and change, most of which cause almost insurmountable problems to many schools. If transformative education is to result in an equitable raising of standards across such an unlevel playing field, schools have to find ways in overcoming these barriers. One seemingly common barrier to development occurs when medical schools are trapped within strict University governance structures; rules and regulations which are frequently inappropriate and obstructive to the transformation that must occur in today's medical educational paradigm. The Faculty of Medicine at Damascus University, one of the oldest and foremost medical schools in the Middle East, is one such school where rigid rules and regulations and traditional values are obstructing transformative change. This paper describes the problems, which the authors believe to be common to many, and explores how attempts have been made to overcome them and move the school into the twenty-first century. It is the ultimate purpose of this paper to raise awareness of the issue, share the lessons learned in order to assist others who are experiencing similar problems and possibly create opportunities for dialogue between schools. PMID- 22830319 TI - Defiance, compliance, or alliance? How we developed a medical professionalism curriculum that deliberately connects to cultural context. AB - BACKGROUND: In the age of globalization, non-Western medical educators seem too eager to conform to Western educational approaches and may, thereby, undermine the pursuit of local curricular needs. AIMS: To develop a medical professionalism curriculum that explicitly considered local cultural needs and social expectations. METHOD: We used a systematic six-step approach to develop the curriculum. RESULTS: We engaged local stakeholders (physicians, allied health professionals, and members of the public) in a nominal group process to identify professionalism competencies. Students and faculty participated in a survey and/or focus groups to determine learner/faculty needs. Teachers drafted goals and objectives related to locally valued competencies. We designed and implemented educational strategies to develop students' competencies that meet local societal expectations, such as involving family members in decision making. We plan to use multi-source feedback and a portfolio to assess students, which reinforces a definition of integrity that encompasses not only congruence between individual values and behaviors, but also achieving harmony among all stakeholders. We plan to reinforce the formal curriculum with faculty development and attention to the hidden curriculum. CONCLUSIONS: Based upon our experience and reflection, we offer some practical methods for integrating local cultural values and societal needs in professionalism education. PMID- 22830320 TI - Testing the validity of a scenario-based questionnaire to assess the ethical sensitivity of undergraduate medical students. AB - BACKGROUND: Although medical educators acknowledge the importance of ethics in medical training, there are few validated instruments to assess ethical decision making. One instrument is the Ethics in Health Care Questionnaire--version 2 (EHCQ-2). The instrument consists of 12 scenarios, each posing an ethical problem in health care, and asking for a decision and rationale. The responses are subjectively scored in four domains: response, issue identification, issue sophistication, and values. GOALS: This study was intended to examine the inter rater and inter-case reliability of the AHCQ-2 and validity against a national licensing examination of the EHCQ-2 in an international sample. METHODS: A total of 20 final year McMaster students and 45 final year Glasgow students participated in the study. All questionnaires were scored by multiple raters. Generalizability theory was used to examine inter-rater, inter-case and overall test reliability. Validity was assessed by comparing EHCQ-2 scores with scores on the Canadian written licensing examination, both total score and score for the ethics subsection. RESULTS: For both samples, reliability was quite low. Except for the first task, which is multiple choice, inter-rater reliability was 0.08 0.54, and inter-case reliability was 0.14-0.61. Overall test reliability was 0.12 0.54. Correlation between EHCQ-2 task scores and the licensing examination scores ranged from 0.07 to 0.40; there was no evidence that the correlation was higher with the ethics subsection. CONCLUSIONS: The reliability and validity of the measure remains quite low, consistent with other measures of ethical decision making. However, this does not limit the utility of the instrument as a tool to generate discussion on ethical issues in medicine. PMID- 22830321 TI - Internal medicine house officers' attitudes and experience with patients who overstep patient-physician boundaries. AB - Maintenance of appropriate social boundaries is an essential aspect of patient care. Given limited clinical experience, house officers may be especially vulnerable to such transgressions. We studied the frequency of patients' transgressions of boundaries and house officer responses to these transgressions. An online survey was administered to internal medicine house officers at the University of Michigan Health System that addressed the frequency of patient physician boundary transgressions, house officer responses to transgressions, and the perceived need for education regarding transgressions. The frequency of reported patient transgressions of various boundaries during the past 6 months ranged from 0 to more than 30. The most common reported incident was being called by their first name, and the least common incidents included patients engaging/attempting to engage in sexual contact and attempting to give expensive gifts. Most respondents denied the need for education regarding appropriate boundaries with patients; however, most perceived a need for training on how to respond to transgressions. Overall, there was a wide range in reported frequencies of transgressions. The frequency of transgressions reported by house officers was greater than what is previously described for attending physicians though their responses to transgressions were similar. PMID- 22830322 TI - The importance of social and collaborative learning for online continuing medical education (OCME): directions for future development and research. AB - BACKGROUND: There is an increasing use of online continuing medical education (OCME), but the potential use of social and collaborative learning to change professional performance and improve patient care has yet to be fully realised. METHODS: The integration of the main themes from the presentations and comments from participants at a symposium at AMEE 2011. RESULTS: Sociological perspectives on change in professional performance highlight the need for social and collaborative learning in OCME so that learners can share information (explicit knowledge) and opinion (tacit knowledge). The educational topic should be relevant to the complexity of professional practice and use iterative cycles of implementation and critical reflection in social networks so that proposed solutions can be tested in actual practice. The challenge of developing effective online discussions for collaborative learning is recognised. CONCLUSION: The provision of OCME requires a shift in both policy and practice to emphasise the importance of social and collaborative learning. Further research is recommended, especially to evaluate the implementation and impact of social and collaborative learning for OCME on patient care and the use of newer Web 2.0 approaches. PMID- 22830323 TI - Guiding principles for the development of global health education curricula in undergraduate medical education. AB - BACKGROUND: Global health education (GHE) at undergraduate medical institutions has expanded significantly over the last 30 years, but many questions remain regarding the best practices for the development and implementation of global health programs. AIM: To identify key themes essential to the development of GHE programs. METHOD: We discuss five themes relevant to GHE in the context of existing literature and practice. RESULTS: The following themes are essential to the development of GHE programs: the definition and scope of GHE, student competencies in global health, the challenges and opportunities associated with inter-institutional relationships, principles for GHE student placements, and the evaluation of GHE programs. We place these themes in the context of current literature and practice, and provide practical guidance on how these themes might be successfully implemented by institutions seeking to develop or refine GHE programs. CONCLUSIONS: Institutions developing or evaluating GHE programs should focus on these themes as they build their global health curricula. PMID- 22830324 TI - Predicting success in graduate entry medical students undertaking a graduate entry medical program. AB - BACKGROUND: Success in undergraduate medical courses in the UK can be predicted by school exit examination (A level) grades. There are no documented predictors of success in UK graduate entry medicine (GEM) courses. This study looks at the examination performance of GEM students to identify factors which may predict success; of particular interest was A level score. METHODS: Data was collected for students graduating in 2004, 2005 and 2006, including demographic details (age and gender), details of previous academic achievement (A level total score and prior degree) and examination results at several points during the degree course. RESULTS: Study group comprised 285 students. Statistical analyses identified no significant variables when looking at clinical examinations. Analysis of pass/fail data for written examinations showed no relationship with A level score. However, both percentage data for the final written examination and the analysis of the award of honours showed A level scores of AAB or higher were associated with better performance (p<0.001). DISCUSSION: A prime objective of introducing GEM programs was to diversify admissions to medical school. In trying to achieve this, medical schools have changed selection criteria. The findings in this study justify this by proving that A level score was not associated with success in either clinical examinations or passing written examinations. Despite this, very high achievements at A level do predict high achievement during medical school. CONCLUSIONS: This study shows that selecting graduate medical students with the basic requirement of an upper-second class honours degree is justifiable and does not disadvantage students who may not have achieved high scores in school leaver examinations. PMID- 22830325 TI - Medical student perspective: working toward specific and actionable clinical clerkship feedback. AB - BACKGROUND: Feedback on the wards is an important component of medical student education. Medical schools have incorporated formalized feedback mechanisms such as clinical encounter cards and standardized patient encounters into clinical curricula. However, the system could be further improved as medical students frequently feel uncomfortable requesting feedback, and are often dissatisfied with the quality of the feedback they receive. AIMS: This article explores the shortcomings of the existing medical student feedback system and examines the relevant literature in an effort to shed light on areas in which the system can be enhanced. The discussion focuses on resident-provided feedback but is broadly applicable to delivering feedback in general. METHODS: A review of the organizational psychology and business administration literature on fostering effective feedback was performed. These insights were then applied to the setting of medical education. RESULTS: Providing effective feedback requires training and forethought. Feedback itself should be specific and actionable. CONCLUSION: Utilizing these strategies will help medical students and educators get the most out of existing feedback systems. PMID- 22830326 TI - Making the most of study leave budgets for junior doctors--from acute hospitals to postgraduate schools. PMID- 22830327 TI - Using virtual patients to teach medical ethics, medical law and medical professionalism. PMID- 22830328 TI - In the wake of higher education reform: the admission criterion mean baccalaureate grade revisited. PMID- 22830330 TI - Bullous skin reaction seen after extravasation of calcium gluconate. AB - Intravenous (IV) calcium is usually given to temporarily treat the effects of hyperkalaemia on muscle and heart. When extravasation of a calcium gluconate infusion occurs, there may be rapid and marked swelling and erythema, with signs of soft-tissue necrosis or infection, and ensuing extensive local calcification, called calcinosis cutis. We report a 26-year-old woman who was hospitalized for exacerbation of acute intermittent porphyria. She had a history of hypertension and chronic renal failure. On the second day of her hospitalization, she developed hyperpotassaemia (6.7 mEq/L potassium; normal range 3.5-5 mEq/L). She was given an IV infusion of 10 mL calcium gluconate into the left dorsal pedal vein. Bullous skin reactions occurred in the infusion area nearly 2 h after administration. The patient's leg was elevated and the lesions cleaned with 0.9% saline. By day 9 of hospitalization, the lesions had markedly regressed. Several drugs have been associated with dermoepidermal blistering as an adverse drug reaction, but there is only one existing report in the literature about this side effect associated with calcium gluconate. Clinicians should be alert to the possibility of bullous skin reactions, which may be a predictor of extravasation and necrosis, when treating patients with IV calcium gluconate. PMID- 22830331 TI - Genetic differences and phenotypic plasticity in body size between high- and low altitude populations of the ground beetle Carabus tosanus. AB - The body size of a univoltine carabid beetle Carabus tosanus on Shikoku Island, Japan, was clearly smaller in higher-altitude populations (subspecies), which possibly represents incipient speciation. To explore the determinants of altitudinal differences in body size in this species, we studied the degree of phenotypic plasticity by conducting rearing experiments at two constant temperatures and examined genetic differences through interpopulation crosses. At 15 degrees C, C. tosanus had a longer developmental period and a shorter adult body than at 20 degrees C. Nevertheless, variation in body size due to temperature effects (phenotypic plasticity) was small compared to the interpopulation differences, which suggests substantial genetic differences between populations (subspecies) at different altitudes. In F(1) offspring from crosses between a low-altitude (subspecies tosanus) and a high-altitude population (subspecies ishizuchianus), adult body length was affected by the genotypes of both parents, with an interaction effect of parental genotype and offspring sex. Further analyses revealed that adult body length was affected by sex-linked factors in addition to autosomal factors. These genetic differences in body size may have resulted from adaptations to different altitudes and may be important for the process of incipient speciation because body size differences could contribute to premating reproductive isolation. PMID- 22830332 TI - Developing ROS scavenging agents for pharmacological purposes: recent advances in design of manganese-based complexes with anti-inflammatory and anti- nociceptive activity. AB - Reactive oxygen and nitrogen species, which are normal products of cell metabolism, may play a dual beneficial/deleterious role, depending on local concentration and mode of generation. As such, they have been identified as key pathogenic factors for many inflammatory and degenerative disorders, carcinogenesis, nociception and ageing. In this perspective, low molecular weight transition metal complexes with organic ligands have been and are still viewed as promising pharmaceutical agents with antioxidant/free radical scavenging properties, owing to their ability to interact and/or react with reactive oxygen or nitrogen species and counterbalance excessive endogenous free radical generation in biological systems. Among these compounds, manganese(II/III) complexes have resulted effective as ROS scavengers both in vitro and in vivo. In particular, Mn(III) complexes with porphyrins and salen derivatives as well as Mn(II) complexes with macrocyclic pentaamines and polyamine-polycarboxylic acids have been recently analyzed as ROS scavengers for therapeutic purposes. In this article, we summarize the chemical and biological properties of manganese complexes with low molecular weight synthetic ligands as scavengers of pro oxidant species, with particular attention to the mechanisms operating at the metal center in the scavenging process. A proper design of the organic scaffolds may yield manganese complexes capable to catalyze different scavenging reactions, including superoxide and/or hydrogen peroxide dismutation and peroxynitrite decomposition. These manganese complexes can be viewed either as a novel class of drugs helpful to reduce oxidative tissue injury or as useful tools to get further light on the role played by ROS in biological systems. PMID- 22830333 TI - Mitochondria as potential targets of flavonoids: focus on adipocytes and endothelial cells. AB - Obesity is a major public health problem, resulting from an excess of energy storage and/or a default of energy expenditure leading to the increased occurrence of cardiovascular risk factors that favour the development of vascular complications. As a consequence, many studies are interested to find novel therapeutic chemical including flavonoids that appear to be promising natural compounds to treat obesity and its complications. Several in vitro studies addressed the mechanisms involved that might explain their beneficial effects, on adipocytes and endothelial cells, two cell types that play major role in obesity and its vascular complications. Besides the well-described antioxidant properties of flavonoids, at least a part of their beneficial effects on these cell types might be explained by their action on the regulation of mitochondrial function. In this review, we will therefore focus on the pathophysiological role of mitochondria in regulating endothelial and adipocyte functions. In addition, we will present some of the more promising flavonoids, important in human diet, including flavanols, flavonols, isoflavones, anthocyanins, flavanones and flavones; and their potential effects to improve endothelial or adipocyte functions via the mitochondria. PMID- 22830334 TI - Derivatives of resveratrol: potential agents in prevention and treatment of cardiovascular disease. AB - Resveratrol (3,5,4'-trans-trihydroxystilbene) is a naturally occurring phytoalexin that is found in medicinal plants, grape skin, peanuts and red wine. Resveratrol exhibits a remarkable range of biological activities, including anticancer activity, antitubulin activity, anti-cardiovascular disease activity, etc. Several other natural products are structurally similar to resveratrol and also present in food. In addition, a series of resveratrol derivatives have been synthesized by the addition of defined functional groups to increase the potency or enhance the activity of specific properties of resveratrol. These resveratrol derivatives might provide promising functions as cardiovascular disease chemopreventive agents. In this review, we will attempt to summarize the main developments of resveratrol derivatives in cardiovascular disease and the main developments have occurred in derivatives of resveratrol's structure-activity relationship and cardiovascular disease over the last couple of decades. PMID- 22830335 TI - Natural product MDM2 inhibitors: anticancer activity and mechanisms of action. AB - The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future. PMID- 22830336 TI - Synthesis of biologically active bridged diazabicycloheptanes. AB - The chemistry underlying how diazabicycloheptanes are assembled is described, subdivided according to chemical structure of two types, the 3,6 diazabicyclo[3.1.1]heptane and the 2,5-diazabicyclo[2.2.1]heptane ring system. Detailed information on myriad of activities of compounds derived from the two scaffolds are reported. PMID- 22830337 TI - Proteomics to unravel platelet-related diseases and identify novel anti-platelet drugs. AB - Blood platelets play a fundamental role in primary haemostasis and wound repair, but are also involved in several thrombotic and bleeding disorders for which the underlying mechanisms are still largely unknown. Elucidating platelet biology would help in finding novel disease biomarkers and drug targets in complex and/or genetically unknown platelet-related disorders. Proteomics, which allows studying thousands of gene products at once, represents an efficient tool to quali quantitatively analyze and compare the platelet protein patterns of different samples (i.e. control/patient, treated/untreated, drug sensitive/resistant), to investigate post-translation modifications, protein-protein interactions and the underlying molecular pathways. This review gives an overview of the applications of proteomic strategies to study platelet biology and function, as well as to unravel differences in protein expression according to specific platelet conditions (i.e. basic versus activated), compartments (i.e. membrane or granules) and fractions (i.e. phosphoproteins and glycoproteins). The use of innovative powerful proteomic technologies can lead to the identification of proteins whose expression is altered in pathological conditions, allowing the identification of candidate biomarkers for: i) understanding the molecular defects underlying platelet disorders, ii) obtaining novel insights in more complex diseases that involve platelets, iii) unraveling the drug mode of action or identifying the mechanisms of drug resistance and iv) detecting novel therapeutic antiplatelet targets based on fundamental platelet research studies. Several studies on how proteomics proved to be useful in our understanding of platelet function and its diseases are discussed. Eventually, this could result in the discovery of novel drug targets for antiplatelet therapy. PMID- 22830338 TI - Physicochemical strategies for inhibition of amyloid fibril formation: an overview of recent advances. AB - Protein aggregation and amyloid fibrillation can lead to several serious human diseases and protein drug ineffectiveness. The complexity and dynamics of protein folding present unique challenges for elucidating the molecular mechanisms involved in protein aggregation and designing effective amyloid inhibitors. Continuous development of creative approaches to identify an ultimate solution for controlling protein aggregation in biopharmaceuticals and clinical pathology is clearly required. This review describes and discusses the most recent advances on the physicochemical strategies for inhibiting protein aggregation and amyloid fibrillation, with emphasis on giving a brief overview of creative approaches and chemistries used. Physical strategies for inhibiting amyloid fibril formation, including high hydrostatic pressure, low temperature, and laser irradiation, are critically evaluated. Recent advances in chemical strategies including small molecules, metal chelators, and nanomaterials, as well as in the use of biomolecules (peptide, protein, nucleic acid, and saccharide) as amyloid inhibitors, are also highlighted. PMID- 22830339 TI - (Iso)flav(an)ones, chalcones, catechins, and theaflavins as anticarcinogens: mechanisms, anti-multidrug resistance and QSAR studies. AB - Flavonoids have shown anticarcinogenic activity in cancer cell lines, animal models, and some human studies. Quantitative structure-activity relationship (QSAR) models have become useful tools for identification of promising lead compounds in anticancer drug development. However, epidemiological and clinical studies are still scarce. Compounds with flavonoid scaffold have been the subject of many mechanistic studies in cells, but information on human chemopreventive properties is still missing. The knowledge of the mechanisms of action, anti multidrug resistance, and QSAR studies on flavonoids and related compounds may help to enhance research on these compounds and their bioactivity. Therefore, once the issue is introduced, the mechanisms involved, and QSAR studies developed to predict the activity and toxicity of these chemicals to biological systems are discussed. QSAR studies on flavonoids as inhibitors of breast cancer resistance protein (BCRP/ABCG2), 17beta-hydroxysteroid dehydrogenase (17beta-HSD), PIM-1 kinase and cyclin-dependent kinases (CDKs) are analyzed. Combined treatment of flavonoids with TRAIL and current chemotherapy agents is also discussed as a promising cancer chemoprevention and/or therapy. PMID- 22830340 TI - Toxins from Physalia physalis (Cnidaria) raise the intracellular Ca(2+) of beta cells and promote insulin secretion. AB - Physalia physalis is a marine cnidarian from which high molecular weight toxins with hemolytic and neurotoxic effects have been isolated. In the present work, two novel toxins, PpV9.4 and PpV19.3 were purified from P. physalis by bioactive guideline isolation. It involved two steps of column chromatography, gel filtration and RP-HPLC. The molecular weights were 550.7 and 4720.9 Da for PpV9.4 and PpV19.3, respectively. In the light of the Edman sequencing results, the structure of these toxins included the presence of modified amino acids. Both toxins increased the percentage of insulin secreting beta-cells and induced cytosolic Ca2+ elevation. To date, this is the first report of low molecular weight toxins increasing insulin secretion purified from cnidarians, by constituting a new approach to the study of beta-cells physiology. PMID- 22830341 TI - The bioisosteric concept applied to cannabinoid ligands. AB - Bioisosterism is widely used in medicinal chemistry as an approach aimed at either rationally modifying a hit compound into a more potent and/or selective molecule or a lead compound into a more drug-like one. Two different cannabinoid receptors have been cloned from mammalian tissues, the CB1 receptor, mostly expressed in brain, and the CB2 receptor, mostly expressed in the immune system, both regulating a variety of physiological functions. Synthetic cannabinoids have been developed that act as highly selective agonists or antagonists/inverse agonists at one or other of these receptor types with the ultimate goal of modulating the endocannabinoid system. This review takes into account the use of the bioisosteric substitution in the field of cannabinoid ligands as a tool for improving both their pharmacodynamic and pharmacokinetic properties. PMID- 22830342 TI - Machine learning techniques and drug design. AB - The interest in the application of machine learning techniques (MLT) as drug design tools is growing in the last decades. The reason for this is related to the fact that the drug design is very complex and requires the use of hybrid techniques. A brief review of some MLT such as self-organizing maps, multilayer perceptron, bayesian neural networks, counter-propagation neural network and support vector machines is described in this paper. A comparison between the performance of the described methods and some classical statistical methods (such as partial least squares and multiple linear regression) shows that MLT have significant advantages. Nowadays, the number of studies in medicinal chemistry that employ these techniques has considerably increased, in particular the use of support vector machines. The state of the art and the future trends of MLT applications encompass the use of these techniques to construct more reliable QSAR models. The models obtained from MLT can be used in virtual screening studies as well as filters to develop/discovery new chemicals. An important challenge in the drug design field is the prediction of pharmacokinetic and toxicity properties, which can avoid failures in the clinical phases. Therefore, this review provides a critical point of view on the main MLT and shows their potential ability as a valuable tool in drug design. PMID- 22830343 TI - Current trends in the chemotherapy of colorectal cancer. AB - The increase in the therapeutic arsenal in the last 20 years, has given rise to changes in treating colorectal cancer (CRC) with only pyrimidines to combine several cytotoxic drugs. However, the present question is to determine the optimal sequence of this combination. This review presents an update of data on chemical and clinical features of chemotherapy used for colorectal cancer and the mechanisms of cellular resistance and potential predictive and prognostic biomarkers, which may contribute to a better selection of a therapeutic strategy. PMID- 22830344 TI - Emerging anticoagulant therapies for atrial fibrillation: new options, new challenges. AB - Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with an increased risk of stroke and systemic embolism. Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin, has historically been the mainstay of long-term thromboprophylaxis in AF patients. However, although highly effective, VKAs have a number of limitations that make their use difficult and cumbersome in clinical practice. They have a slow onset and offset of action, narrow therapeutic window, marked dose-response variability, and multiple food and drug interactions, and require frequent coagulation monitoring and dose adjustments. To overcome VKA drawbacks, several new oral anticoagulants have been recently developed for use in AF, and three of them, the direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban, have completed phase III trials. New agents have proven to be noninferior or superior to warfarin for AF-related stroke prevention, with similar or better safety profiles. These new drugs, with their predictable anticoagulant effect that allows for fixed dosing with no need for coagulation monitoring, have the potential to greatly simplify anticoagulation therapy for AF. Dabigatran etexilate and rivaroxaban are already approved in the United States and Europe for stroke prevention in nonvalvular AF, and dabigatran etexilate has entered current AF guidelines as an alternative to warfarin. However, some issues with new compounds are still unresolved, such as the lack of antidotes and standardized tests to measure drug activity. Active postmarketing monitoring surveillance of effectiveness and safety is required in the implementation of new anticoagulant therapies. PMID- 22830346 TI - Novel approaches in the synthesis of batracylin and its analogs: rebirth of an old player? AB - Batracylin (8-aminoisoindol[1,2-b]-quinasolin-12(10H)-one, BAT), a heterocyclic amine, was isolated in 1978 (NCI, Bethesda, USA) in the course of search for the new anticancer drugs. It showed high in vitro and in vivo anticancer activities against murine leukemia P338 and colon adenocarcinoma 38. Mechanism of action of BAT is still not completely clear. It was reported, that BAT is a topoisomerase II inhibitor and induces unscheduled DNA synthesis (UDS) in non-proliferating cells. Low solubility of BAT in water, high toxicity and necessity of high drug dosing are major limitations of its use as a chemotherapeutic drug. As a result, new BAT analogs were synthesized to improve its pharmacological properties. The modifications of BAT chemical structure include various substituents introduced to isoindoloquinazoline moiety (Cl, Br, NO(2), CH(2), NH(2), Me, CO(2)Me, OMe). It has been shown that the desamino derivative and the 8-aza analog of BAT retained the ability to inhibit topoisomerase II but did not induce unscheduled DNA synthesis. While less active than BAT, these analogs were cytotoxic toward CCRF-CEM leukemia cells. The isoindolo [2,1-a]benzimidazole derivatives were inactive as topoisomerase II inhibitors and, in general, failed to exhibit comparable antitumor activity or to induce unscheduled DNA synthesis. Batracylin was acylated with aminoacids, dipeptides, tripeptides to increase its solubility in water. Other modifications include introduction of nitrogen atom to ring A or D, extension of polycyclic ring 4, reduction of ring B from six- to five-membered one, and obtaining of benzimidazole, indole or derivatives containing a fucose ring. A series of novel BAT analogs bearing sugar residues and thiocarbonyl aminoacids, which provided better solubility in water and high cytostatic activity have been designed. Also, new azabatracylines, where aniline ring was replaced by pyridine or other substituted quinazolines, have been obtained. This paper reviews the most important approaches in batracylin synthesis and its analogs and presents structure-reactivity relationships for these compounds. PMID- 22830345 TI - Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. AB - Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN. PMID- 22830347 TI - A targeted therapy for protein and lipid kinases in chronic lymphocytic leukemia. AB - Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kdelta-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL. PMID- 22830348 TI - Peptides as therapeutics with enhanced bioactivity. AB - The development of techniques for efficient peptide production renewed interest in peptides as therapeutics. Numerous modifications for improving stability, transport and affinity profiles now exist. Several new adjuvant and carrier systems have also been developed, enhancing the immunogenicity of peptides thus allowing their development as vaccines. This review describes the established and experimental approaches for manufacturing peptide drugs and highlights the techniques currently used for improving their drug like properties. PMID- 22830349 TI - 2-Arylindoles: a privileged molecular scaffold with potent, broad-ranging pharmacological activity. AB - Privileged structures bind to multiple receptors with high affinity, thus aiding the development of novel biologically active compounds. Indoles are classed as privileged structures, and as a result of the indole nucleus being present in a broad range of biologically active molecules, it has been suggested that indoles probably represent the most important of all structural classes in drug discovery. Amongst the indole class of compounds is a particular subset - 2 arylindoles - which appear to be a most promising lead for drug development. This review summarises the wide-ranging activities of 2-arylindoles and some of their important biological activities reported in the literature over the past two decades. PMID- 22830350 TI - Design, synthesis and biological activity of new polyenolic inhibitors of matrix metalloproteinases: a focus on chemically-modified curcumins. AB - Matrix metalloproteinases (MMPs) are essential for the degradation and turnover of components of the extracellular matrix (ECM) and, when pathologically elevated, mediate connective tissue loss (including bone destruction) in various inflammatory and other diseases. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of Doxycycline are FDA approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. Because the C-11/ C-12 diketonic moiety of the tetracyclines is primarily responsible, through zinc-binding, for MMP inhibition, we have uniquely modified curcumin as a "core" molecule, since it contains a similar enolic system and is known to have beneficial effects in diseases where connective-tissue loss occurs. Specifically we have developed new congeners which exhibit improved zinc binding and solubility, and potent reduction of excessive MMP levels and activity. We now describe a series of curcuminoid bi- and tri-carbonylmethanes in which all of these properties are substantially improved. An N phenylaminocarbonyl derivative of bis-demethoxycurcumin (CMC2.24) was selected as the "lead" substance because it showed superior potency in vitro (i.e., the lowest IC(50)) against a series of neutral proteases (MMPs) associated with tissue erosion. Moreover, CMC2.24 administered to diabetic rats orally (30mg/kg), reduced the secretion of pathologically-excessive levels of MMP-9 to normal in cultured peritoneal macrophages with no evidence of toxicity. Thus, this (and other similar novel) compound(s) may be useful in various diseases of connective tissue loss. PMID- 22830351 TI - pKa, zinc- and serum albumin-binding of curcumin and two novel biologically active chemically-modified curcumins. AB - The pH equilibria and the zinc ion and bovine serum albumin (BSA) binding behavior of curcumin and two chemically modified curcumins (CMCs), namely 4 methoxycarbonylcurcumin (CMC 2.5) and 4-phenylaminocarbonyl bis-demethoxy curcumin (CMC 2.24), were studied, in order to understand the basis of their differential effects on the zinc-enzyme matrix metalloproteinases (MMPs) as well as the effect of charge state on their behavior in vivo. Moreover, all three compounds transform rapidly in the pH range 5-10, CMC 2.5 largely in one step, and CMC 2.24 and curcumin first in a rapid process to an intermediate form that still displays an enolic and two phenolic hydrogen-ion equilibria, and then more slowly to forms absorbing primarily in the lower UV and lacking the strong absorbance in the visible characteristic of the enol-centered chromophore. The binding of these compounds in one of the hydrophobic pockets of the major transport protein, serum albumin, was therefore studied. CMC 2.24 binds more strongly to BSA than curcumin, with a dissociation constant of 0.56+/-0.08 MUM compared to 1.32+/-0.17 MUM. Binding to BSA shifts the decomposition half-lives from tens of seconds to tens of hours. The zero-time acid dissociation constants (pK(a)) for species H(3)D, H(2)D(-), and HD(2-) are 8.41, 9.94 and 11.2; 6.98, 8.40 and 9.8; and 6.50 and 8.82 ; for curcumin, CMC 2.24, and CMC 2.5 respectively (there is no distinguishable pK(a3) for CMC 2.5). Zn(2+) binds most strongly to CMC 2.24 compared to CMC 2.5 and curcumin, with dissociation constants of 0.77+/-0.02, 1.88+/-0.07, and 1.39+/-0.09 mM. The increased acidity and Zn(2+) and BSA affinities of CMC 2.24 correlate with its greater biological activity. PMID- 22830352 TI - Protein kinase C-theta inhibitors: a novel therapy for inflammatory disorders. AB - PKC-theta is a serine/threonine specific protein kinase and its activation depends upon the concentration of diacylglycerol (DAG) and phospholipids (phosphatidylserine). PKC-theta phosphorylates a variety of proteins that are known to be involved in the diverse cellular signaling pathways. It is predominantly expressed in the T-cells and localized in the center of immunological synapse upon T-cell receptor (TCR) and CD28 signaling. Activation of PKC-theta leads to the activation of various transcription factors in the nuclei of T-cells, e.g. NF-kappaB, NFAT, c-Jun, c-Fos and AP-1 that further control the proliferation and differentiation of T-cells. Defective T-cell activation in turn leads to the aberrant expression of apoptosis related proteins that cause the poor T-cell survival. Researchers have found that T-cells deficient in PKC-theta exhibit reduced interleukin-2 (IL-2) production. Apart from this role on IL-2 expression, it also plays crucial roles in the proliferation, differentiation and survival of the T-cells, which make it an attractive therapeutic target for a variety of immunological and T-cell mediated diseases. Hence, new molecules capable of modulating the expression or biological activity of PKC-theta are being developed and tested for their potential as novel therapy for several T-cells mediated disease conditions such as multiple sclerosis, rheumatoid arthritis, asthma, inflammatory bowel disease and organ transplantation, etc. In the present review, we tried to integrate the recent discoveries on PKC-theta including its pharmacology and therapeutic potential, along with brief update on its inhibitor molecules. PMID- 22830353 TI - Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. AB - Based on the cancer stem cell (CSC) concept model, a small population of cells with unique self-renewal properties and malignant potential exists in tumors. Immunohistochemistry was performed to detect the expression of CSC markers, CD133 and CD44, in a series of pediatric tumors. The association between expression of these markers and tumor characteristics was then analyzed. In Wilms tumors (WT), a significant positive correlation was found between expression of CD133 and the National Wilms Tumor Stage (NWTS) (p = 0.047). In neuroblastomas (NB), expression of CD133 was positively correlated with the International Neuroblastoma Staging System (INSS) (p-value = 0.012), indicating that the rate of CD133 positivity increased with the stage of these tumors. CD133, as a putative stem cell marker, is associated with more advanced stages of Wilms and NB tumors; therefore, this molecule can be a potential clinical prognostic marker in children suffering from NB or Wilms tumor. PMID- 22830354 TI - Ecological mechanisms underlying arthropod species diversity in grasslands. AB - Arthropods are an important component of grassland systems, contributing significantly to biodiversity and ecosystem structure and function. Climate, fire, and grazing by large herbivores are important drivers in grasslands worldwide. Arthropod responses to these drivers are highly variable and clear patterns are difficult to find, but responses are largely indirect with respect to changes in resources, species interactions, habitat structure, and habitat heterogeneity resulting from interactions among fire, grazing, and climate. Here, we review these ecological mechanisms influencing grassland arthropod diversity. We summarize hypotheses describing species diversity at local and regional scales and then discuss specific factors that may affect arthropod diversity in grassland systems. These factors include direct and indirect effects of grazing, fire, and climate, species interactions, above- and belowground interactions, and landscape-level effects. PMID- 22830355 TI - Comparative simulation studies of native and single-site mutant human beta defensin-1 peptides. AB - Human defensins play important roles in a broad range of biological functions, such as microbial defense and immunity. Yet, little is known about their molecular properties, i.e. secondary structure stability, structural variability, important side chain interactions, surface charge distribution, and resistance to thermal fluctuations, and how these properties are related to their functions. To assess these factors, we studied the native human beta-defensin-1 monomer and dimer as well as several single-site mutants using molecular dynamics simulations. The results showed that disulfide bonds are important determinants in maintaining the defensins' structural integrity, as no structural transitions were observed at 300 K and only minor structural unfolding was detected upon heating to 500 K. The alpha-helix was less thermally stable than the core beta sheet structure held together by hydrogen bonds and hydrophobic interactions. The monomer alpha-helix stability was directly correlated, whereas the end-to-end distance was inversely correlated to the experimentally measured beta-defensin-1 chemotactic activity, in the order: mutant 2 (Gln24Glu) > mutant 3 (Lys31Ala) = wild type > mutant 1 (Asn4Ala). The structural stability of the beta-defensin-1 dimer species exhibited an inverse correlation to their chemotactic activity. In dimers formed by mutants 2 and 3, we observed sliding of one monomer upon the surface of the other in the absence of unbinding. This dynamic sliding feature may enhance the molecular oligomerization of beta-defensin-1 peptides contributing to their antibacterial activity. It could also help these peptides orient correctly in the CC chemokine receptor 6 binding site, thereby initiating their chemotactic activity. In agreement with this notion, the remarkable sliding behavior was observed only for the mutants with the highest chemotactic activity. PMID- 22830356 TI - Swedish guidelines on the management of community-acquired pneumonia in immunocompetent adults--Swedish Society of Infectious Diseases 2012. AB - This document presents the 2012 evidence based guidelines of the Swedish Society of Infectious Diseases for the in- hospital management of adult immunocompetent patients with community-acquired pneumonia (CAP). The prognostic score 'CRB-65' is recommended for the initial assessment of all CAP patients, and should be regarded as an aid for decision-making concerning the level of care required, microbiological investigation, and antibiotic treatment. Due to the favourable antibiotic resistance situation in Sweden, an initial narrow-spectrum antibiotic treatment primarily directed at Streptococcus pneumoniae is recommended in most situations. The recommended treatment for patients with severe CAP (CRB-65 score 2) is penicillin G in most situations. In critically ill patients (CRB-65 score 3 4), combination therapy with cefotaxime/macrolide or penicillin G/fluoroquinolone is recommended. A thorough microbiological investigation should be undertaken in all patients, including blood cultures, respiratory tract sampling, and urine antigens, with the addition of extensive sampling for more uncommon respiratory pathogens in the case of severe disease. Recommended measures for the prevention of CAP include vaccination for influenza and pneumococci, as well as smoking cessation. PMID- 22830357 TI - The over-expression of miR-34a fails to block DoHH2 lymphoma cell proliferation by reducing p53 via c-MYC down-regulation. AB - MicroRNAs (miRNAs) might behave as tumor suppressors and for that they are under consideration as novel therapeutic drugs. We tested the tumor suppressor activity of miRNA-34a (miR-34a) by measuring cell proliferation of the follicular lymphoma cell line DoHH2 transfected with this miRNA. We report that miR-34a did not inhibit cell proliferation notwithstanding a marked down-regulation of c-MYC. Interestingly, DoHH2 transfected cells showed a significant p53 down-regulation, suggesting that c-MYC positively controls p53 and the failed inhibition of cell proliferation is probably due to the down-regulation of the c-MYC/p53 axis. In keeping with this, c-MYC silencing also down-regulated p53 and had no effect on cell proliferation. In accordance with this hypothesis, etoposide or nutlin-3 treatment or a small interfering RNA (siRNA) against BCL6 (B-cell lymphoma 6) inhibited the proliferation of DoHH2 cells by up-regulating p53 without affecting either miR-34a or c-MYC levels. These results indicate that the proliferation is controlled by the regulatory axis c-MYC/p53 and suggest that paradoxically miR 34a behaves as a pro-proliferative rather than an anti-proliferative miRNA in DoHH2 cells. PMID- 22830358 TI - Migraine, headaches, and cognition. AB - OBJECTIVES AND BACKGROUND: The possible effects of migraine on executive abilities remain controversial; hence, we studied inter-ictal cognitive performance of individuals with migraine and non migraine headaches (NMH) compared with headache free controls. DESIGN AND METHOD: In a cross-sectional observational study, taking place in primary care, adults aged 50 or above were evaluated by a neurobehavioral battery including several executive measures. Present history of headache was sought, and migraine was diagnosed by the ID Migraine questionnaire. The effect of headache type on cognitive measures was analyzed with multiple regression with adjustment by diagnosis, age, gender, education, and depressive symptoms. RESULTS: Among 478 participants, 23.2% reported current headache, of whom 50 were NMH, and 61 were migraine headaches. No group differences were found in the majority of cognitive measures. Compared with controls, migraine subjects performed worse on a test of attention, while NMH participants presented more intrusions and worse discriminability in memory recognition plus a lower performance on semantic memory tests. CONCLUSION: The presence of headaches in late adulthood was related to a worse performance on few measures of executive functioning, suggesting that cognitive impact is not specific to migraine but might be associated to headache. PMID- 22830359 TI - Examining demographic and socio-economic correlates of accurate knowledge about blood donation among African migrants in Australia. AB - OBJECTIVES: To develop and test a knowledge questionnaire about blood donation in African migrant communities in Australia, which is applicable to other communities, and to assess the relationship between the demographic and socio economic characteristics and knowledge of the African migrant community. METHODS: Using a cross-sectional survey of 425 African migrants and refugees living in Victoria and South Australia, we assessed the knowledge questionnaire for readability, item difficulty, point-biserial correlation and reliability. The relationships between demographic and socio-economic factors and knowledge about blood donation were then evaluated using hierarchical multiple regression. RESULTS: The knowledge scale was found to have good psychometric properties and to be reliable: a Flesch reading ease score of 64.7; an average index of item difficulty of 0.42; a point-biserial correlation of 0.38 and a Kuder-Richardson 20 coefficient of 0.78 indicating strong internal consistency. A quarter of respondents (26.1%; 95% CI: 21.9, 30.3) had poor knowledge about issues related to blood donation; 51.1% (95% CI: 46.3, 55.8) had moderate knowledge and 22.8% (95% CI: 18.8, 26.8) were highly knowledgeable. Factors associated with blood donation knowledge were religion, pre-migration area of residence, country of birth, length of stay in Australia, and previous blood donation status. Age, gender, educational attainment, migration and employment status were non significant. CONCLUSION: Knowledge and awareness of issues associated with blood donation is important in regard to blood donation decisions, and this article has developed a measure using African migrant communities in Australia that has appropriate psychographic properties. The measure can, therefore, be used by researchers when studying the role of knowledge in relation to blood donation across cultural groups in Australia and other countries. It also identifies that demographic characteristics affect knowledge, which suggests that targeted interventions might be needed, especially when dealing with migrant and refugee communities. PMID- 22830360 TI - Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance. AB - Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine deficiency and has been described in three patients with epileptic encephalopathy. There is no established treatment for this condition.Here, we describe a therapeutic trial consisting of enteral and parenteral glutamine supplementation in a four year old patient with GS deficiency. The patient received increasing doses of glutamine up to 1020 mg/kg/day. The effect of this glutamine supplementation was monitored clinically, biochemically, and by studies of the electroencephalogram (EEG) as well as by brain magnetic resonance imaging and spectroscopy.Treatment was well tolerated and clinical monitoring showed improved alertness. Concentrations of plasma glutamine normalized while levels in cerebrospinal fluid increased but remained below the lower reference range. The EEG showed clear improvement and spectroscopy revealed increasing concentrations of glutamine and glutamate in brain tissue. Concomitantly, there was no worsening of pre-existing chronic hyperammonemia.In conclusion, supplementation of glutamine is a safe therapeutic option for inherited GS deficiency since it corrects the peripheral biochemical phenotype and partially also improves the central biochemical phenotype. There was some clinical improvement but the patient had a long standing severe encephalopathy. Earlier supplementation with glutamine might have prevented some of the neuronal damage. PMID- 22830361 TI - Estimating frequencies of virulent isolates in field populations of a plant pathogenic fungus, Leptosphaeria maculans, using high-throughput pyrosequencing. AB - AIM: To develop a pyrosequencing assay to monitor the frequency of alleles of an avirulence gene, AvrLm4, in populations of sexual spores of Leptosphaeria maculans, a fungal pathogen of canola (Brassica napus). METHODS AND RESULTS: The predominant mutation in AvrLm4 responsible for virulence to the corresponding resistance gene, Rlm4, is a single nucleotide polymorphism (SNP) at base 358. Pyrosequencing primers were designed to amplify a 90-bp region that included this SNP. The assay was developed and validated by analysing the frequency of AvrLm4 in isolate mixtures of different proportions. Furthermore, the frequency of avrLm4 (virulence allele) determined by pyrosequencing of populations of sexual spores was consistent with the frequency of avrLm4 determined by Sanger sequencing of the entire AvrLm4 gene from single isolates cultured from the same stubble. CONCLUSION: This high-throughput assay can play an important role in predicting the risk of resistance breakdown in crops. SIGNIFICANCE AND IMPACT OF THE STUDY: Similar assays can be applied to monitor frequencies of fungicide resistance in pathogens of crops and to assay diversity in microbial soil communities such as in soil samples from bat caves where white-nose syndrome has been detected. PMID- 22830362 TI - Peanut seed storage proteins are responsible for clinical reactivity in Spanish peanut-allergic children. AB - BACKGROUND: Seed storage proteins (SSP; Ara h 1, Ara h 2, Ara h 3) have been shown to be major peanut allergens, although recently, peanut lipid transfer protein has been reported to be an important allergen in the Mediterranean area. We sought to investigate the sensitization pattern to peanut SSP and vegetable pan-allergens in a group of peanut-allergic children compared with a peanut tolerant group. METHODS: One hundred and twenty-three children who presented with food allergy were included in the study. Tolerance to peanut ingestion was assessed. Specific IgE was determined by ImmunoCAP, and microarray ISAC was performed. Sensitization frequencies and levels of specific IgE were compared between groups. RESULTS: Fifty-five of 123 children presented symptoms upon contact or ingestion. Frequency of sensitization to Ara h 1, Ara h 2, and Ara h 3 was 60.0%, 72.7%, and 43.6%, respectively, in the group of allergic children vs. 7.4%, 1.5%, and 7.4% in the group of tolerant children. Levels of specific IgE against Ara h 1, Ara h 2, and Ara h 3 were significantly higher in the allergic group (p < 0.001). The frequency of sensitization and the levels of specific IgE against Cor a 8 (36.4% vs. 16.2%) were significantly higher in the allergic children, whereas no significant differences were found for Pru p 3. No differences were seen for other pan-allergens. Patients sensitized to SSP, regardless of sensitization to nsLTP, were allergic rather than tolerant. CONCLUSION: In our population, peanut-allergic children were mainly sensitive to SSP. A few patients were also sensitive to some nsLTPs. No differences were shown in other pan-allergens. PMID- 22830373 TI - British HIV Association guidelines for the management of HIV infection in pregnant women 2012. AB - The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of human immunodeficiency virus (HIV) positive pregnant women in the UK. The scope includes guidance on the use of antiretroviral therapy (ART) both to prevent HIV mother-to-child transmission (MTCT) and for the welfare of the mother herself, guidance on mode of delivery and recommendations in specific patient populations where other factors need to be taken into consideration,such as coinfection with other agents. The guidelines are aimed at clinical professionals directly involved with, and responsible for, the care of pregnant women with HIV infection. PMID- 22830363 TI - Secretory signal peptide modification for optimized antibody-fragment expression secretion in Leishmania tarentolae. AB - BACKGROUND: Secretory signal peptides (SPs) are well-known sequence motifs targeting proteins for translocation across the endoplasmic reticulum membrane. After passing through the secretory pathway, most proteins are secreted to the environment. Here, we describe the modification of an expression vector containing the SP from secreted acid phosphatase 1 (SAP1) of Leishmania mexicana for optimized protein expression-secretion in the eukaryotic parasite Leishmania tarentolae with regard to recombinant antibody fragments. For experimental design the online tool SignalP was used, which predicts the presence and location of SPs and their cleavage sites in polypeptides. To evaluate the signal peptide cleavage site as well as changes of expression, SPs were N-terminally linked to single chain Fragment variables (scFv's). The ability of L. tarentolae to express complex eukaryotic proteins with highly diverse post-translational modifications and its easy bacteria-like handling, makes the parasite a promising expression system for secretory proteins. RESULTS: We generated four vectors with different SP-sequence modifications based on in-silico analyses with SignalP in respect to cleavage probability and location, named pLTEX-2 to pLTEX-5. To evaluate their functionality, we cloned four individual scFv-fragments into the vectors and transfected all 16 constructs into L. tarentolae. Independently from the expressed scFv, pLTEX-5 derived constructs showed the highest expression rate, followed by pLTEX-4 and pLTEX-2, whereas only low amounts of protein could be obtained from pLTEX-3 clones, indicating dysfunction of the SP. Next, we analysed the SP cleavage sites by Edman degradation. For pLTEX-2, -4, and -5 derived scFv's, the results corresponded to in-silico predictions, whereas pLTEX-3 derived scFv's contained one additional amino-acid (AA). CONCLUSIONS: The obtained results demonstrate the importance of SP-sequence optimization for efficient expression-secretion of scFv's. We could successfully demonstrate that minor modifications in the AA-sequence in the c-region of the natural SP from SAP1, based on in-silico predictions following the (-3, -1) rule, resulted in different expression-secretion rates of the protein of interest. The yield of scFv production could be improved close to one order of magnitude. Therefore, SP sequence optimization is a viable option to increase the overall yield of recombinant protein production. PMID- 22830364 TI - British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. AB - The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection with antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naive to therapy; (ii)support of patients on treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines. PMID- 22830386 TI - Tailoring the exchange interaction in covalently linked basic carboxylate clusters through bridging ligand selection. AB - We are reporting new dimeric units of basic carboxylates bearing the {Fe(III)(2)M(II)O} motif for M = Co and Ni, covalently bound through the tetradentate bridging (LL) 2,2'-azopyiridine (azpy) and 2,3-di(2 pyridyl)quinoxaline ligands (dpq). We structurally characterized the hexanuclear clusters, and their magnetic properties have been fully analyzed. DFT calculations have been performed as a supplementary tool. All results evidence a weak antiferromagnetic interaction through the bridging ligands between isolated spin ground states arising from intra-Fe(2)MO core exchange couplings. Together with the pioneer 2,2'-bipyrimidine bridged systems, the new complexes reported constitute a family of complexes where the exchange interaction can be tuned by the selection of the bridging LL type ligand. PMID- 22830387 TI - The costs of parental care: a meta-analysis of the trade-off between parental effort and survival in birds. AB - A fundamental premise of life-history theory is that organisms that increase current reproductive investment suffer increased mortality. Possibly the most studied life-history phenotypic relationship is the trade-off between parental effort and survival. However, evidence supporting this trade-off is equivocal. Here, we conducted a meta-analysis to test the generality of this tenet. Using experimental studies that manipulated parental effort in birds, we show that (i) the effect of parental effort on survival was similar across species regardless of phylogeny; (ii) individuals that experienced reduced parental effort had similar survival probabilities than control individuals, regardless of sex; and (iii) males that experienced increased parental effort were less likely to survive than control males, whereas females that experienced increased effort were just as likely to survive as control females. Our results suggest that the trade-off between parental effort and survival is more complex than previously assumed. Finally, our study provides recommendations of unexplored avenues of future research into life-history trade-offs. PMID- 22830388 TI - A black beam borne by an incandescent field self-traps in a photopolymerizing medium. AB - We report that a self-trapped black optical beam that is spatially and temporally incoherent forms spontaneously in a nascent photopolymerization system. The black beam inscribes a permanent cylindrical channel, which prevents the propagation of visible light even under passive conditions (in the absence of polymerization). The finding opens a powerful new mechanism to manipulate light signals from incoherent sources such as LEDs through selective suppression of light propagation. This contrasts with approaches employed by photonic crystals and optical waveguides, which concentrate and guide light intensity within spatially localized regions. The self-trapped black beam forms when a broad incandescent beam bearing a negligible depression was launched into a photopolymerizable medium. Because of refractive index changes caused by polymerization, the depression narrows, deepens, and continually rejects the visible spectrum of light until it stabilizes as a black beam that propagates over long distances (? effective Rayleigh range) without significant divergence. As refractive index changes due to polymerization are irreversible, the cylindrical region occupied by the self-trapped black beam is inscribed as a black channel waveguide in the medium. PMID- 22830389 TI - Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study. AB - BACKGROUND: Methotrexate (MTX) is the 'gold-standard' drug for the treatment of severe psoriasis. In the absence of any consensus on an optimum dose of MTX for psoriasis, there is wide variation in prescribing patterns between dermatologists, resulting in variable or delayed therapeutic effects. AIM: To identify the most effective fixed single weekly dose of oral MTX with acceptable side-effects in the treatment of severe plaque-type psoriasis. METHODS: This was a prospective, randomized, double-blind, parallel-group, dose-ranging study, which enrolled 60 patients of both genders (aged 18-62 years) with severe chronic plaque-type psoriasis. Patients were randomly assigned to one of two groups: group A was treated with MTX 10 mg once weekly, and group B was treated with 25 mg MTX once weekly. The main outcome measure was change in Psoriasis Area and Severity Index (PASI) between the two groups from baseline to 12 weeks. RESULTS: Of the 60 patients, 51 (85%) completed the 12-week study. At the end of the study, 24 patients (92.3%) in the MTX 25 mg group had achieved a 75% reduction in PASI (PASI 75) from baseline, compared with 18 patients (72%) in the MTX 10 mg group (P>0.05). Mean time in weeks to achieve PASI 75 was significantly shorter in the MTX 25mg group (7.92+/-1.91) than in the MTX 10mg group (9.47+/-2.29) (P<0.05). In addition, 20 patients (69%) in the MTX 25mg group achieved 100% reduction in PASI compared with 9 patients (30%) in the MTX 10mg group within 12weeks of the study period (P<0.01). Adverse effects were generally mild, and were noted in 43.1% of the 51 patients who completed the study, with no significant difference in frequency between the two groups, although they were less severe in the 10mg group. CONCLUSIONS: MTX 25mg is an effective dose as monotherapy for the treatment of severe psoriasis, whereas the 10mg dose is slow to act and less effective, but has a less severe side-effect profile. PMID- 22830390 TI - Nucleophilic addition of Grignard reagents to 3-acylindoles: stereoselective synthesis of highly substituted indoline scaffolds. AB - 3-Acylindoles undergo nucleophilic-type reactions with Grignard reagents to efficiently afford either cis- or trans-substituted indolines, depending on the different quenching procedures. The enolate intermediate could be trapped by aryl acyl chlorides to provide indolines bearing a quaternary carbon center with high stereoselectivity. In contrast, the use of benzyl bromide as an electrophile results in the fragmentation of the indole ring. The indoline products could be easily transformed into indoles through oxidation with DDQ in a one-pot manner. PMID- 22830391 TI - Immunomodulatory effect of polysaccharides from submerged cultured Cordyceps gunnii. AB - CONTEXT: The genus Cordyceps (Clavicipitaceae) is a group of entomopathogenic fungi that is widely used as tonic food or invigorant with broad-spectrum medicinal properties in China. Cordyceps gunnii (Berk.)Berk (C. gunnii), is also well known as the Chinese rare caterpillar fungus and has similar pharmacological activities with Cordyceps sinensis (C. sinensis). Polysaccharides (PS) from various Cordyceps species have demonstrated many interesting biological activities, including antitumor, immunopotentiation, hypoglycemic, and hypocholesterolemic activities. OBJECTIVE: To investigate the effect of C. gunnii PS on the immunostimulatory antitumor function and expression of immune related cytokines in normal, immuno-suppressive, and H22-bearing mice, respectively. METHODS: C. gunnii PS were extracted with hot water at 80 degrees C for 2 h. Normal, immuno-suppressive, and H22-bearing mice were treated with PS respectively. By detecting the value of macrophage phagocytic index, proliferation of lymphocytes, natural killer (NK) cell activity and expression of related cytokines, interleukin (IL-4), tumor necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-gamma), and tumor inhibition index in H22-bearing mice additionally, the effect of PS on immunostimulatory antitumor function and its mechanism were studied. RESULTS: The total sugar content of the PS was determined to be 95% after purification. PS markedly increased the thymus and spleen indexes, the macrophage phagocytosis, the proliferation of splenic cells, and the level of IFN-gamma and TNF-alpha. In tumor growth inhibition test, PS showed remarkable inhibition effects. CONCLUSION: PS from the C. gunnii could enhance nonspecific immunological function, humoral immunity, cellular immunity in mice, and inhibit tumor growth. PMID- 22830392 TI - Sonochemical coatings of ZnO and CuO nanoparticles inhibit Streptococcus mutans biofilm formation on teeth model. AB - Antibiotic resistance has prompted the search for new agents that can inhibit bacterial growth. We recently reported on the antibiofilm activities of nanosized ZnO and CuO nanoparticles (NPs) synthesized by using sonochemical irradiation. In this study, we examined the antibacterial activity of ZnO and CuO NPs in a powder form and also examined the antibiofilm behavior of teeth surfaces that were coated with ZnO and CuO NPs using sonochemistry. Free ZnO and CuO NPs inhibited biofilm formation of Streptococcus mutans . Furthermore, by using the sonochemical procedure, we were able to coat teeth surfaces that inhibited bacterial colonization. PMID- 22830393 TI - Values and risk perceptions: a cross-cultural examination. AB - This article examines the relationship between values and risk perceptions regarding terror attacks. The participants in the study are university students from Turkey (n = 536) and Israel (n = 298). Schwartz value theory (1992, 1994) is applied to conceptualize and measure values. Cognitive (perceived likelihood and perceived severity) and emotional (fear, helplessness, anger, distress, insecurity, hopelessness, sadness, and anxiety) responses about the potential of (i) being personally exposed to a terror attack, and (ii) a terror attack that may occur in one's country are assessed to measure risk perceptions. Comparison of the two groups suggests that the Turkish participants are significantly more emotional about terror risks than the Israeli respondents. Both groups perceive the risk of a terror attack that may occur in their country more likely than the risk of being personally exposed to a terror attack. No significant differences are found in emotional representations and perceived severity ratings regarding these risks. Results provide support for the existence of a link between values and risk perceptions of terror attacks. In both countries, self-direction values are negatively related to emotional representations, whereas security values are positively correlated with emotions; hedonism and stimulation values are negatively related to perceived likelihood. Current findings are discussed in relation to previous results, theoretical approaches (the social amplification of risk framework and cultural theory of risk), and practical implications (increasing community support for a course of action, training programs for risk communicators). PMID- 22830394 TI - Homology modeling and docking studies of FabH (beta-ketoacyl-ACP synthase III) enzyme involved in type II fatty acid biosynthesis of Chlorella variabilis: a potential algal feedstock for biofuel production. AB - The concept of using microalgae as an alternative renewable source of biofuel has gained much importance in recent years. However, its commercial feasibility is still an area of concern for researchers. Unraveling the fatty acid metabolic pathway and understanding structural features of various key enzymes regulating the process will provide valuable insights to target microalgae for augmented oil content. FabH (beta-ketoacyl-acyl carrier protein synthase; KAS III) is a condensing enzyme catalyzing the initial elongation step of type II fatty acid biosynthetic process and acyl carrier protein (ACP) facilitates the shuttling of the fatty acyl intermediates to the active site of the respective enzymes in the pathway. In the present study, a reliable three-dimensional structure of FabH from Chlorella variabilis, an oleaginous green microalga was modeled and subsequently the key residues involved in substrate binding were determined by employing protein-protein docking and molecular dynamics (MD) simulation protocols. The FabH-ACP complex having the lowest docking energy score showed the binding of ACP to the electropositive FabH surface with strong hydrogen bond interactions. The MD simulation results indicated that the substrate-complexed FabH adopted a more stable conformation than the free enzyme. Further, the FabH structure retained its stability throughout the simulation although noticeable displacements were observed in the loop regions. Molecular simulation studies suggested the importance of crucial hydrogen bonding of the conserved Arg(91) of FabH with Glu(53) and Asp(56) of ACP for exhibiting high affinity between the enzyme and substrate. The molecular modeling results are consistent with available experimental results on the flexibility of FabH and the present study provides first in silico insights into the structural and dynamical aspect of catalytic mechanism of FabH, which could be used for further site-specific mutagenic experiments to develop engineered high oil-yielding microalgal strains for biofuel production. PMID- 22830395 TI - Regulation of plasmin generation by the annexin A2 heterotetramer: a shift in perspective. PMID- 22830396 TI - Cancer cell-derived supernatants that support the carcinogenic process: a future cancer therapy target? PMID- 22830399 TI - Should human papillomavirus DNA testing be offered in combination with cytology or as a sole primary screening test in cervical cancer prevention? AB - Evaluation of: Rijkaart DC, Berkhof J, van Kemenade FJ et al. HPV DNA testing in population-based cervical screening (VUSA-Screen study): results and implications. Br. J. Cancer 106(5), 975-981 (2012). Previous studies have shown that the combination of high-risk human papillomavirus (HPV) testing and cytology increases sensitivity for the detection of cervical intraepithelial neoplasia 3, a surrogate end point for the reduction of cervical cancer. This paper addressed three questions regarding the implementation of high-risk HPV testing within a cervical screening program. The main question addressed was whether high-risk HPV testing should be provided as a standalone primary screen or in combination with cytology. Management of HPV-positive women and the optimum age for HPV testing were also examined. Results identified limited benefit from co-testing compared with HPV testing alone and emphasized the importance of repeat testing for HPV positive women with negative cytology triage at baseline, in all women from 30 years of age onwards. PMID- 22830398 TI - Cediranib: a VEGF receptor tyrosine kinase inhibitor. AB - Cediranib is a potent inhibitor of the VEGF family receptor tyrosine kinases, and a new agent in cancer treatment. The drug has shown promising activity in a variety of solid malignancies, in preclinical models and in clinical trials. Its pharmacokinetics allow for a convenient once-daily administration, with a toxicity profile that is very similar to other VEGF inhibitors. Its main side effects include hypertension, nausea, dysphonia, fatigue and diarrhea. Adverse events seem to be manageable, especially when used in doses lower than 45 mg/day. Studies have shown some activity as a single agent or in combination in advanced tumors, but not enough to secure its approval for routine use up to now. Clinical trials are still evaluating the role of cediranib in combination chemotherapy with cytotoxic agents. PMID- 22830402 TI - New diagnostics for melanoma detection: from artificial intelligence to RNA microarrays. AB - Early detection of melanoma remains crucial to ensuring a favorable prognosis. Dermoscopy and total body photography are well-established noninvasive aids that increase the diagnostic accuracy of dermatologists in their daily routine, beyond that of a naked-eye examination. New noninvasive diagnostic techniques, such as reflectance confocal microscopy, multispectral digital imaging and RNA microarrays, are currently being investigated to determine their utility for melanoma detection. This review presents emerging technologies for noninvasive melanoma diagnosis, and discusses their advantages and limitations. PMID- 22830400 TI - Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. AB - Large granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disorder of cytotoxic lymphocytes characterized by an expansion of CD3(+) cytotoxic T lymphocytes or CD3(-) natural killer cells. Patients present with various cytopenias including neutropenia, anemia and thrombocytopenia. In addition, there is an association of T-cell large granular lymphocytic leukemia with rheumatoid arthritis. It is believed that LGL leukemia begins as an antigen-driven immune response with subsequent constitutive activation of cytotoxic T lymphocytes or natural killer cells through PDGF and IL-15 contributing to their survival. Consequently, this leads to a dysregulation of apoptosis and dysfunction of the activation-induced cell death pathway. Treatment of LGL leukemia is based on a low-dose immunosuppressive regimen using methotrexate or cyclophosphamide. However, no standard of therapy has been established, as large prospective trials have not been conducted. In addition, some patients are refractory to treatment. The lack of a curative therapy for LGL leukemia means that new treatment options are needed. Insight into the various dysregulated signaling pathways in LGL leukemia may provide novel therapeutic treatment modalities. PMID- 22830401 TI - The multifaceted actions of PTHrP in skeletal metastasis. AB - PTHrP, identified during the elucidation of mediators of malignancy-induced hypercalcemia, plays numerous roles in normal physiology as well as pathological conditions. Recent data support direct functions of PTHrP in metastasis, particularly from tumors with strong bone tropism. Bone provides a unique metastatic environment because of mineralization and the diverse cell populations in the bone marrow. PTHrP is a key regulator of tumor-bone interactions and regulates cells in the bone microenvironment through proliferative and prosurvival activities that prime the 'seed' and the 'soil' of the metastatic lesion. This review highlights recent findings regarding the role of PTHrP in skeletal metastasis, including direct actions in tumor cells, as well as alterations in the bone microenvironment and future perspectives involving the potential roles of PTHrP in the premetastatic niche, and tumor dormancy. PMID- 22830403 TI - Preclinical models in electrochemotherapy: the role of veterinary patients. AB - Electrochemotherapy is a tumor treatment that adapts the systemic or local delivery of anticancer drugs by the application of permeabilizing electric pulses with appropriate amplitude and waveforms. This allows the use of lipophobic drugs, which frequently have a narrow therapeutic index, with a decreased morbidity for the patient, while maintaining appropriate anticancer efficacy. Electrochemotherapy is used in humans for the treatment of cutaneous neoplasms or the palliation of skin tumor metastases, and a standard operating procedure has been devised. In veterinary oncology, the electrochemotherapy approach is gaining popularity, becoming a first-line treatment in consideration of its high efficacy and low toxicity. This review summarizes the state of the art in veterinary oncology as a preclinical model. PMID- 22830404 TI - Ten challenges in the management of neuroblastoma. AB - Neuroblastoma is a complex disease with many contradictions and challenges. It is, by and large, a cancer of babies and preschool children, but it does occur, albeit increasingly rarely, in older children, adolescents and young adults. The prognosis is very variable, with outcome related to age, stage and molecular pathology. Neuroblastoma may behave in an almost benign way, with spontaneous regression in some infants, but the majority of older patients have high-risk disease, which is usually fatal, despite best current treatments. As a rare disease, international collaboration is essential to run clinical trials of adequate statistical power to answer important questions in a reasonable time frame. High-risk disease requires multimodality therapy including chemotherapy, surgery and radiotherapy as well as biological and immunological treatments for optimal outcomes. Innovative treatment approaches, sometimes associated with appreciable toxicity, offer hope for the future but, despite parental wishes, cannot be generally implemented without adequate assessment in clinical trials. PMID- 22830405 TI - Expression of podoplanin is a rare event in sporadic gastrointestinal stromal tumors and does not influence prognosis. AB - AIMS: Podoplanin overexpression is associated with worse prognosis in several human cancers. In gastrointestinal stromal tumors (GISTs) very few data on the expression of podoplanin exist, but it seems to be frequently overexpressed in pediatric/syndromic GISTs. We investigated podoplanin expression and its clinical relevance in a large series of sporadic GISTs. METHODS: Podoplanin expression was determined immunohistochemically in 145 sporadic adult GISTs. Aneuploidies of 1p36 and 1q25 were investigated using FISH, and KIT and PDGFRA genes were investigated by sequencing. RESULTS: Overexpression of podoplanin was observed in eight (5.6%) GISTs and no association with amplification of 1p36 or KIT or PDGFRA mutations was seen. The amount of podoplanin expression was not associated with clinical risk factors or patient survival. CONCLUSION: Overexpression of podoplanin is a rare event in sporadic GISTs and is not associated with amplification of 1p36 or with KIT or PDGFRA mutations, which indicates limited pathobiological or clinical relevance. PMID- 22830406 TI - PARP cleavage and perturbance in mitochondrial membrane potential by 3-alpha propionyloxy-beta-boswellic acid results in cancer cell death and tumor regression in murine models. AB - BACKGROUND: Apoptotic induction in cancer cells has become a major focus of anticancer therapeutics. In this regard, beta-boswellic acids, naturally occurring pentacyclic triterpenes, have demonstrated antiproliferative and cytotoxic effects against different types of cancers. Surprisingly, not much has been reported regarding the chemical modifications or preparation of structural analogs of the key constituents of beta-boswellic acid. AIM: The anticancer activity of 3-alpha-propionyloxy-beta-boswellic acid (POBA) was investigated and this article reports for the first time that the triterpenoid ring of the boswellic acid derivative POBA is targeting the PI3K pathway. MATERIALS & METHODS: Induction of apoptosis of the semi-synthetic derivative of beta boswellic acid-POBA in vitro was analyzed using a battery of human cancer cell lines followed by cell cycle phase distribution, further validated by DNA fragmentation, and was found to cause mitochondrial membrane potential loss with ultrastructural changes, as observed by electron microscopy studies and expression study using PARP cleavage, as well as validated by in vivo anti-tumor activity. RESULTS: The cytotoxicity data revealed the sensitivity of various human cancer cell lines of varied tissue origin to beta-boswellic acid, which robustly induced cell cycle arrest, DNA fragmentation and loss of mitochondrial membrane potential. Morphological studies of the effects of POBA revealed loss of surface projections, chromatin condensation, apoptotic body formation and POBA mediated PARP cleavage. For in vivo therapeutic experiments, murine tumor models were treated with POBA and the treatment resulted in a significantly higher level of growth inhibition and apoptosis was significantly induced. CONCLUSION: These findings demonstrate that acyl substituents/groups in the main skeleton of beta boswellic acid have the potential to be potent chemotherapeutic agents. PMID- 22830407 TI - 'What matters to me': an international online survey of people treating, affected by and living with lung cancer. AB - AIM: Lung cancer is a common malignancy that occurs worldwide and generally has a poor prognosis. Its diagnosis presents significant physical and emotional challenges for patients and their family, friends and caregivers (FFCs). This study aimed to gain insights into patients' and FFCs' perspectives regarding lung cancer and its treatment, as well as physicians' perceptions of patients' thoughts about their illness. PATIENTS & METHODS: An international online survey was conducted, assessing 113 patients diagnosed with non-small-cell lung cancer, 70 corresponding FFCs and 188 treating physicians. Data were collected using an interactive internet-based tool, in order to establish respondents' priorities. RESULTS: Interesting differences between patients', FFCs' and physicians' perspectives on lung cancer were revealed. For all respondents, the primary feeling about lung cancer was described as "sadness". Patients were more likely to express a determination to be positive, whereas fear was a common response for FFCs and was a perspective also reported by physicians. Physicians' views on how they had communicated disease information were more positive than those of the patients, with many patients detecting physician hesitancy to communicate negative news. CONCLUSION: This study provides important insights into the self reported thoughts and feelings of patients with lung cancer, their personal networks of FFCs and the physicians who care for them. PMID- 22830409 TI - Area-selective growth of functional molecular architectures. AB - Over the last two decades, organic semiconductors have attracted increasing attention because of the applications of their inorganic counterparts in a growing number of devices. At the same time, the further success of these materials will require device processing techniques for organic semiconductors that produce high performance and high integration over large areas. Conventional top-down patterning techniques based on photolithography have served powerful methods for the surface patterning of inorganic materials. However, researchers cannot simply transfer these techniques to organic semiconductors because organic semiconductors can include small, fragile organic molecules. Alternatively, researchers have developed several nonconventional techniques, including shadow mask, printing, and vapor jet writing. However, no leading technique has emerged, and researchers are still trying to realize batch-to-batch, and even device-to device, reproducibility. This Account summarizes recent research in our group aimed at developing methods for patterning small organic molecules that are compatible with standard device processing procedures for inorganic semiconductors. Our concept is based on classic growth dynamics by gas-phase deposition but leads to different selective growth mechanisms: "pre-patterning and patterned growth" instead of the traditional "film growth and patterning." As a result, both "foreign body" and "step edge", two possible nucleation positions for atoms and molecules during thin film growth process, can be enlarged to the mesotropic scale to define molecules within pre-determined areas. The techniques can do more than patterning. We demonstrate that these techniques can produce heteropatterning of organic structures that cannot be obtained by conventional photolithography and printing techniques. Through a combination of different growth modes, we can separate molecules at given locations on the mesotropic scale, which could lead to applications in the production of organic solar cells. Taking advantage of the differences in emission of molecules in different aggregation states, we can achieve tunable single, double- and triple-color patterns using two types of molecules. We also show that these materials can lead to devices with improved performance in features such as carrier mobility. In addition, we believe that this new photographic compatible procedure in small molecular organic semiconductors can address some issues in device performance, such as carrier transport in organic field effect transistors, by controlling domain size and numbers, and allow researchers to explore new nanoscale properties of these materials. The techniques are still in their infancy, and further research is needed to make them applicable, such as transferring the technology to cheap substrates, for example, glass and flexible plastic. For organic electronics, high-level integration, addressable, and cross-talk free device arrays are critical for producing high-performance devices at a low fabrication cost. PMID- 22830410 TI - Intraneural metastasis of gastric carcinoma leads to sciatic nerve palsy. AB - BACKGROUND: Soft tissue metastases, in particular intraneural metastasis, from any carcinomas seldom occur. To our knowledge, no case of sciatic nerve palsy due to intraneural metastasis of gastric carcinoma is reported in the literature. CASE PRESENTATION: A case is reported of a 82-year old woman with sciatic nerve palsy with intraneural metastasis of gastric carcinoma. Although she had undergone partial gastrectomy with T2b, N0, M0 two years ago and primary site was cured, she developed sciatic nerve palsy from the carcinoma metastasis directly to the nerve. Operative resection and Histological examination revealed poorly differentiated adenocarcinoma, the same as her primary site adenocarcinoma. CONCLUSIONS: Sciatica is usually caused by a herniated disc or spinal canal stenosis. Sciatic nerve palsy may be caused by nondiscogenic etiologies that may be either intrapelvic or extrapelvic. It is important to image the entire course of the nerve to distinguish these etiologies quickly. The longer the nerve compression the less likely a palsy will recover. Surgery is a good intervention that simultaneously obtains a tissue diagnosis and decompresses the nerve. PMID- 22830411 TI - Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. AB - OBJECTIVES: To estimate the prevalence and distribution of chronic migraine (CM) in the US population and compare the age- and sex-specific profiles of headache related disability in persons with CM and episodic migraine. BACKGROUND: Global estimates of CM prevalence using various definitions typically range from 1.4% to 2.2%, but the influence of sociodemographic factors has not been completely characterized. METHODS: The American Migraine Prevalence and Prevention Study mailed surveys to a sample of 120,000 US households selected to represent the US population. Data on headache frequency, symptoms, sociodemographics, and headache related disability (using the Migraine Disability Assessment Scale) were obtained. Modified Silberstein-Lipton criteria were used to classify CM (meeting International Classification of Headache Disorders, second edition, criteria for migraine with a headache frequency of >=15 days over the preceding 3 months). RESULTS: Surveys were returned by 162,756 individuals aged >=12 years; 19,189 individuals (11.79%) met International Classification of Headache Disorders, second edition, criteria for migraine (17.27% of females; 5.72% of males), and 0.91% met criteria for CM (1.29% of females; 0.48% of males). Relative to 12 to 17 year olds, the age- and sex-specific prevalence for CM peaked in the 40s at 1.89% (prevalence ratio 4.57; 95% confidence interval 3.13-6.67) for females and 0.79% (prevalence ratio 3.35; 95% confidence interval 1.99-5.63) for males. In univariate and adjusted models, CM prevalence was inversely related to annual household income. Lower income groups had higher rates of CM. Individuals with CM had greater headache-related disability than those with episodic migraine and were more likely to be in the highest Migraine Disability Assessment Scale grade (37.96% vs. 9.50%, respectively). Headache-related disability was highest among females with CM compared with males. CM represented 7.68% of migraine cases overall, and the proportion generally increased with age. CONCLUSIONS: In the US population, the prevalence of CM was nearly 1%. In adjusted models, CM prevalence was highest among females, in mid-life, and in households with the lowest annual income. Severe headache-related disability was more common among persons with CM and most common among females with CM. PMID- 22830412 TI - Volatile compound profiling for the identification of Gram-negative bacteria by ion-molecule reaction-mass spectrometry. AB - AIMS: Fast and reliable methods for the early detection and identification of micro-organism are of high interest. In addition to established methods, direct mass spectrometry-based analysis of volatile compounds (VCs) emitted by micro organisms has recently been shown to allow species differentiation. Thus, a large number of pathogenic Gram-negative bacteria, which comprised Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Pseudomonas aeruginosa, Proteus vulgaris and Serratia marcescens, were subjected to headspace VC composition analysis using direct mass spectrometry in a low sample volume that allows for automation. METHODS AND RESULTS: Ion-molecule reaction-mass spectrometry (IMR-MS) was applied to headspace analysis of the above bacterial samples incubated at 37 degrees C starting with 10(2) CFU ml(-1) . Measurements of sample VC composition were performed at 4, 8 and 24 h. Microbial growth was detected in all samples after 8 h. After 24 h, species specific mass spectra were obtained allowing differentiation between bacterial species. CONCLUSIONS: IMR-MS provided rapid growth detection and identification of micro-organisms using a cumulative end-point model with a short analysis time of 3 min per sample. SIGNIFICANCE AND IMPACT OF THE STUDY: Following further validation, the presented method of bacterial sample headspace VC analysis has the potential to be used for bacteria differentiation. PMID- 22830413 TI - RNA sequencing: platform selection, experimental design, and data interpretation. PMID- 22830415 TI - In vitro miconazole susceptibility of meticillin-resistant Staphylococcus pseudintermedius and Staphylococcus aureus. AB - BACKGROUND: The emergence and dissemination of meticillin-resistant staphylococci has created significant treatment challenges in veterinary medicine and increased interest in topical therapy for superficial infections. Concern has been expressed regarding the use of some topical antimicrobials in animals because of the potential for emergence of resistance, and additional options are required. Miconazole has limited antibacterial properties that include antistaphylococcal activity. HYPOTHESIS/OBJECTIVES: The objective of this study was to assess the in vitro susceptibility of Staphylococcus pseudintermedius and Staphylococcus aureus to miconazole. METHODS: In vitro susceptibility of 112 meticillin-resistant S. pseudintermedius (MRSP), 53 meticillin-resistant S. aureus (MRSA) and 37 meticillin-susceptible S. pseudintermedius (MSSP) to miconazole was assessed using agar dilution. RESULTS: The minimal inhibitory concentration (MIC) range, MIC(50) and MIC(90) for MRSP were 1-8, 2 and 4 MUg/mL, respectively. Corresponding results for MRSA were 1-8, 2 and 6 MUg/mL, and for MSSP 1-4, 2 and 2 MUg/mL. The MIC for MSSP was a significantly lower MIC than that for both MRSP (P = 0.006) and MRSA (P < 0.001), while the MIC for MRSP was significantly lower than that for MRSA (P = 0.001). CONCLUSIONS AND CLINICAL IMPORTANCE: These in vitro data suggest that miconazole could be a useful therapeutic option for superficial infections caused by meticillin-susceptible and meticillin-resistant staphylococci, but proper clinical investigation is required. PMID- 22830416 TI - Mental and physical attributes defining world-class Norwegian athletes: content analysis of interviews. AB - This study reports the results of a content analysis of interviews with 28 Norwegian world-class athletes and 28 controls, matched for gender, age, and type of sport. Semi-structured interviews explored their perceptions of their best performance. The interviews were analyzed using the ATLAS.ti and yielded 20 higher-order codes. Nine higher-order codes were categorized as inner-oriented, five were categorized as outer-oriented, and six were a combination of inner- and outer-oriented. Statistical analysis, using the Mann-Whitney test, showed significant group differences for seven higher-order codes: (a) two outer oriented codes relating to "mastery--achievements" and "training--outer"; and (b) five inner-oriented codes relating to "mental preparation," "self-reliance," "training--inner," "wholeness," "performance--inner," and "growth orientation." These findings highlight the importance of both inner- and outer-oriented development for high-level achievement in sports--the "mental game" is as important as the physical game, both during training and competitions. Previously published quantitative data reported higher levels of brain integration, faster habitation to a loud tone, and higher ego and moral development in these world class athletes. These findings are interpreted in light of a Unified Theory of Performance, which proposes that higher mind-brain development provides a basis for higher performance in any activity. PMID- 22830417 TI - Oxidative phosphorylation gene transcription in whitefish species pairs reveals patterns of parallel and nonparallel physiological divergence. AB - Across multiple lakes in North America, lake whitefish (Coregonus clupeaformis) have independently evolved 'dwarf' and 'normal' sympatric species pairs that exhibit pronounced phenotypic and genetic divergence. In particular, traits associated with metabolism have been shown to be highly differentiated between whitefish species. Here, we examine the transcription of genes associated with the five mitochondrial and nuclear genome-encoded oxidative phosphorylation (OXPHOS) complexes, the primary physiological mechanism responsible for the production of ATP, in whitefish species pairs from Cliff Lake and Webster Lake in Maine, USA. We observed OXPHOS gene transcription divergence between dwarf and normal whitefish in each of the two lakes, with the former exhibiting transcription upregulation for genes associated with each of the OXPHOS complexes. We also observed a significant influence of lake on transcription levels for some of the genes, indicating that inter-lake ecological or genetic differences are contributing to variation in OXPHOS gene transcription levels. Together, our results support the hypothesis that metabolic divergence is a critical adaptation involved in whitefish speciation and implicate OXPHOS gene upregulation as a factor involved in meeting the enhanced energetic demands of dwarf whitefish. Further studies are now needed to evaluate the contribution of genetically vs. plasticity driven variation in transcription associated with this critical physiological pathway. PMID- 22830418 TI - Guest editorial: ethics matters in aged care. PMID- 22830419 TI - Pain and dementia: an overview of the literature. AB - This paper discusses how pain and its undertreatment impacts upon older people with dementia. It outlines how the contributing factors to the underassessment of pain are numerous and includes dementia-related factors (such as loss of communication ability) and health professional-related factors (such as inappropriate or non-application of a pain-assessment tool and deficit knowledge regarding pain mechanisms and/or dementia). Pharmacological and non pharmacological treatment options for pain are noted as important but are not the focus of this paper. PMID- 22830420 TI - Pain and dementia--an application to practice: an example. AB - There are fundamental clinical implications around assessment and evaluation of pain as well as management strategies for pain that have the potential of impacting and improving client outcomes. It is these principles that have been used to develop a training module on pain and dementia with widespread application to a range of settings. This study serves to provide an overview of this process as it translates evidence of pain in people living with dementia to practice for clinicians working in the field. PMID- 22830421 TI - What is pain? A phenomenological approach to understanding. AB - This paper presents four phenomenological accounts of pain which describe: the pain at the time of the experience; the meaning the pain had at the time of the experience (reflection in); and the meaning of the experience looking back on it (reflection upon). Specifically, the accounts describe pain that is emotional, cognitive and physical (acute and chronic). By exploring the essence of pain using very personal accounts, we encourage nurses to reflect on how their own understanding of pain and individual responses to pain can impact on how they in turn recognise, assess and manage pain in older people and especially those living with dementia. Paper 1 highlights the under-assessment of pain in older people with dementia. By confronting readers with this paper's phenomenological approach, it is hoped that they will be challenged to address this situation. PMID- 22830423 TI - SnTox5-Snn5: a novel Stagonospora nodorum effector-wheat gene interaction and its relationship with the SnToxA-Tsn1 and SnTox3-Snn3-B1 interactions. AB - The Stagonospora nodorum-wheat interaction involves multiple pathogen-produced necrotrophic effectors that interact directly or indirectly with specific host gene products to induce the disease Stagonospora nodorum blotch (SNB). Here, we used a tetraploid wheat mapping population to identify and characterize a sixth effector-host gene interaction in the wheat-S. nodorum system. Initial characterization of the effector SnTox5 indicated that it is a proteinaceous necrotrophic effector that induces necrosis on host lines harbouring the Snn5 sensitivity gene, which was mapped to the long arm of wheat chromosome 4B. On the basis of ultrafiltration, SnTox5 is probably in the size range 10-30 kDa. Analysis of SNB development in the mapping population indicated that the SnTox5 Snn5 interaction explains 37%-63% of the variation, demonstrating that this interaction plays a significant role in disease development. When the SnTox5-Snn5 and SnToxA-Tsn1 interactions occurred together, the level of SNB was increased significantly. Similar to several other interactions in this system, the SnTox5 Snn5 interaction is light dependent, suggesting that multiple interactions may exploit the same pathways to cause disease. PMID- 22830422 TI - Inhibition of phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model. AB - BACKGROUND: We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated. RESULTS: Among the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis. CONCLUSIONS: These results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we found that PDE4B is a promising candidate for a therapeutic target as well as prognostic molecular marker in CRC. Further elucidation of the signaling network of PDE4B2 in 3 DC would provide a better understanding of CRC in vivo. PMID- 22830424 TI - Formal syntheses of naturally occurring welwitindolinones. AB - The formal syntheses of N-methylwelwitindolinone C isothiocyanate, N methylwelwitindolinone C isonitrile, N-methylwelwitindolinone D isonitrile, 3 hydroxy-N-methylwelwitindolinone C isothiocyanate, and 3-hydroxy-N methylwelwitindolinone C isonitrile are reported. The synthesis features several novel processes, including a Lewis acid mediated coupling between a benzylic-type heteroaromatic alcohol and a highly functionalized silyl ketene acetal, an intramolecular enolate arylation, and a regioselective, Pd(0)-catalyzed pi allylic cyclization of a gamma-benzoyloxy enone moiety that is revealed by unmasking a furan ring. PMID- 22830425 TI - In primary health care, never prescribe antibiotics to patients suspected of having an uncomplicated sore throat caused by group A beta-haemolytic streptococci without first confirming the presence of this bacterium. AB - BACKGROUND: There are several consensus-describing decision rules for patients in primary health care with a sore throat. The objective of this study was to estimate the number of unnecessary antibiotic prescriptions in primary health care given to patients with a sore throat, due to these different decision rules. A further aim was to suggest revised rules for decision-making in primary health care, when a sore throat caused by group A beta-haemolytic streptococci (GAS) is suspected. METHODS: The design was a reanalysis of previously published articles describing the prevalence of GAS and physician behaviour when treating patients with a sore throat. The risk of unnecessary antibiotic prescribing in different situations was estimated and applied to the Swedish population. RESULTS: Introducing the rule of never prescribing antibiotics without first confirming the presence of GAS would result in an annual reduction in Sweden of 20,360 25,192 unnecessary antibiotic prescriptions in children and 65,311-98,160 in adults. CONCLUSIONS: The single most important rule in primary health care to minimize the risk of unnecessary antibiotic prescription to patients with an uncomplicated sore throat, and where an infection with GAS is suspected, is to never prescribe antibiotics at the first visit without first confirming the presence of this bacterium. Adding more decision rules may to some extent further reduce the number of unnecessary antibiotic prescriptions. PMID- 22830427 TI - Triple C-H bond activation of a nickel-bound methyl group: synthesis and X-ray structure of a carbide cluster (NiCp)6(MU6-C). AB - A new hexanuclear cyclopentadienylnickel carbide cluster (NiCp)(6)(MU(6)-C) (1) was obtained through the thermolysis of the alkene complex [NiCp(CH(3))(eta(2) CH(2)?CHC(4)H(9))] (4). The X-ray molecular structure of 1 (monoclinic; P2(1)/c; Ni-C(carbide) = 1.767(4)-2.109(4) A) reveals a highly deformed octahedral arrangement of nickel atoms with two octahedron edges opened (Ni-Ni bonding distances = 2.410(1)-2.623(1) A, Ni...Ni nonbonding distances = 3.107(2) and 3.108(2) A). Cluster 1 is the first example of a homoleptic, cyclopentadienylnickel carbide cluster. Moreover, (13)C-labeling studies proved that the carbido ligand in cluster 1 originated from the Ni-bound methyl group. This transformation requires a triple C-H bond activation in the methyl group, which has not been observed so far for late transition metal compounds. PMID- 22830426 TI - Stable isotope labeling with amino acids in Drosophila for quantifying proteins and modifications. AB - Drosophila melanogaster is a common animal model for genetics studies, and quantitative proteomics studies of the fly are emerging. Here, we present in detail the development of a procedure to incorporate stable isotope-labeled amino acids into the fly proteome. In the method of stable isotope labeling with amino acids in Drosophila melanogaster (SILAC fly), flies were fed with SILAC-labeled yeast grown with modified media, enabling near complete labeling in a single generation. Biological variation in the proteome among individual flies was evaluated in a series of null experiments. We further applied the SILAC fly method to profile proteins from a model of fragile X syndrome, the most common cause of inherited mental retardation in human. The analysis identified a number of altered proteins in the disease model, including actin-binding protein profilin and microtubulin-associated protein futsch. The change of both proteins was validated by immunoblotting analysis. Moreover, we extended the SILAC fly strategy to study the dynamics of protein ubiquitination during the fly life span (from day 1 to day 30), by measuring the level of ubiquitin along with two major polyubiquitin chains (K48 and K63 linkages). The results show that the abundance of protein ubiquitination and the two major linkages do not change significantly within the measured age range. Together, the data demonstrate the application of the SILAC principle in D. melanogaster, facilitating the integration of powerful fly genomics with emerging proteomics. PMID- 22830428 TI - Tension-type headache or migraine? Adolescents' pain descriptions are of little help. AB - OBJECTIVE: The aim of this study was to investigate the utility of pain descriptors (pain quality, pain intensity) assessed in a questionnaire to discriminate tension-type headache (TTH) from TTH plus migraine in a sample of adolescents. BACKGROUND: Epidemiological studies assess pain characteristics via questionnaire and estimate prevalence rates based on these pain descriptions. According to International Headache Society criteria, the subjective pain quality and intensity for TTH and migraine differs and therefore should be able to discriminate the 2 diagnoses. The discriminative ability between TTH and TTH plus migraine may be a special challenge. DESIGN AND METHODS: One hundred twenty-two adolescents with pure TTH and 110 adolescents with TTH plus migraine aged 11-18 years presenting to a tertiary pediatric pain clinic were included in the study. Questionnaire reports of pain intensity and quality were compared with physician's diagnosis as the gold standard. Mean differences as well as receiver operating characteristics were analyzed. RESULTS: Adolescents with TTH plus migraine reported more pulsating and less intense pain compared with pure TTH. Receiver operating characteristic analysis indicated that pain descriptors did not discriminate between groups. Diagnostic utility of descriptors was similarly low for older adolescents and parental proxy reports. CONCLUSIONS: Pain intensity and quality assessed by questionnaires are not suitable to discriminate TTH from TTH plus migraine. This may lead to inaccurate prevalence estimates in epidemiological studies and may mislead practitioners in forming diagnostic hypotheses. The exclusion of these pain descriptors in questionnaires should be considered. More research systematically assessing the diagnostic utility of verbal pain descriptors in primary care and epidemiological samples is needed. PMID- 22830429 TI - Design strategy for a near-infrared fluorescence probe for matrix metalloproteinase utilizing highly cell permeable boron dipyrromethene. AB - Near-infrared (NIR) fluorescence probes are especially useful for simple and noninvasive in vivo imaging inside the body because of low autofluorescence and high tissue transparency in the NIR region compared with other wavelength regions. However, existing NIR fluorescence probes for matrix metalloproteinases (MMPs), which are tumor, atherosclerosis, and inflammation markers, have various disadvantages, especially as regards sensitivity. Here, we report a novel design strategy to obtain a NIR fluorescence probe that is rapidly internalized by free diffusion and well retained intracellularly after activation by extracellular MMPs. We designed and synthesized four candidate probes, each consisting of a cell permeable or nonpermeable NIR fluorescent dye as a Forster resonance energy transfer (FRET) donor linked to the NIR dark quencher BHQ-3 as a FRET acceptor via a MMP substrate peptide. We applied these probes for detection of the MMP activity of cultured HT-1080 cells, which express MMP2 and MT1-MMP, by fluorescence microscopy. Among them, the probe incorporating BODIPY650/665, BODIPY-MMP, clearly visualized the MMP activity as an increment of fluorescence inside the cells. We then applied this probe to a mouse xenograft tumor model prepared with HT-1080 cells. Following intratumoral injection of the probe, MMP activity could be visualized for much longer with BODIPY-MMP than with the probe containing SulfoCy5, which is cell impermeable and consequently readily washed out of the tissue. This simple design strategy should be applicable to develop a range of sensitive, rapidly responsive NIR fluorescence probes not only for MMP activity, but also for other proteases. PMID- 22830430 TI - Open access and online publishing: a new frontier in nursing? PMID- 22830431 TI - Detection of Shiga toxin variants among Shiga toxin-forming Escherichia coli isolates from animal stool, meat and human stool samples in India. AB - AIM: To study the prevalence and distribution of various variants in the stx gene of Shiga toxin-producing Escherichia coli (STEC) isolated from diverse environmental sources (animal stool, meat) and human illness, from a large geographic area in India, and to understand the association between variants, serotype distribution and human disease. METHODS AND RESULTS: A surveillance for STEC was conducted in the semi-urban and rural areas of Punjab, Himachal, Haryana and Chandigarh. Shiga toxin-producing Escherichia coli isolates (80 animal stool, 39 meat, 21 human stool from diarrhoea and HUS cases) were characterized for stx variants by PCR. Shiga-like toxin (Stx) was detected using Ridascreen-EIA assay. Variant stx2c was the most common (25.1%), followed by stx1d (13%), stx1c (10.7%) and stx2d (9.2%), whereas stx2e, stx2f and stx2g were absent. Only 8/21 (38%) human isolates harboured stx variants, of which stx2c and stx2d were found in 2 and 1 isolates, respectively. The low frequency of carriage of these potentially more pathogenic variants may explain the low severity of human illness seen in India. Shiga-like toxin was detected in only 42 of the isolates positive for the stx genes probably due to the low levels of toxins produced. Serogroup distribution was found to be diverse, suggesting the lack of any predominant circulating type. CONCLUSIONS: The presence of stx variants 1c, 1d, 2c and stx2d in diverse environmental and human sources in India was demonstrated. The prevalence of the most common subtype stx2c found in this study in animal isolates may pose a threat to the public health. We report the subtyping of human STEC isolates and report the presence of stx1d subtype for the first time from India. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrated the presence of potentially pathogenic subtypes in the environmental specimens which may act as a reservoir for human infections. Serogroups new to India were also reported. PMID- 22830432 TI - Carboxylesterase-triggered hydrolysis of nanoparticle PEGylating agents. AB - Despite the importance of PEGylation in achieving long nanoparticle circulation times, many nanoparticles are coated with PEGylating agents susceptible to enzymatic degradation. In this study, solid lipid nanoparticles (SLNs) prepared with ester-containing compounds were evaluated for their stability in the presence of carboxylesterase. SLN suspensions became turbid within 30 min of enzymatic exposure, indicating possible disassociation of a portion of the nanoparticles. The particle size of SLNs incubated with the enzyme was smaller than the size of controls, although their morphologies appeared similar in transmission electron microscopy images. Although SLNs offered some protection over micelles, PEG6000 monostearate was rapidly degraded within 15 min. Hydrolysis of polysorbate 60 was much slower, reaching only 36% in 2 h. These studies reveal the importance of confirming the stability of PEG surface coatings prior to undertaking in vivo experiments in small animal models, which can have considerably higher plasma esterase activity than humans. PMID- 22830434 TI - Getting the methods right--the foundation of patient-centered outcomes research. PMID- 22830435 TI - Mortality and access to care among adults after state Medicaid expansions. AB - BACKGROUND: Several states have expanded Medicaid eligibility for adults in the past decade, and the Affordable Care Act allows states to expand Medicaid dramatically in 2014. Yet the effect of such changes on adults' health remains unclear. We examined whether Medicaid expansions were associated with changes in mortality and other health-related measures. METHODS: We compared three states that substantially expanded adult Medicaid eligibility since 2000 (New York, Maine, and Arizona) with neighboring states without expansions. The sample consisted of adults between the ages of 20 and 64 years who were observed 5 years before and after the expansions, from 1997 through 2007. The primary outcome was all-cause county-level mortality among 68,012 year- and county-specific observations in the Compressed Mortality File of the Centers for Disease Control and Prevention. Secondary outcomes were rates of insurance coverage, delayed care because of costs, and self-reported health among 169,124 persons in the Current Population Survey and 192,148 persons in the Behavioral Risk Factor Surveillance System. RESULTS: Medicaid expansions were associated with a significant reduction in adjusted all-cause mortality (by 19.6 deaths per 100,000 adults, for a relative reduction of 6.1%; P=0.001). Mortality reductions were greatest among older adults, nonwhites, and residents of poorer counties. Expansions increased Medicaid coverage (by 2.2 percentage points, for a relative increase of 24.7%; P=0.01), decreased rates of uninsurance (by 3.2 percentage points, for a relative reduction of 14.7%; P<0.001), decreased rates of delayed care because of costs (by 2.9 percentage points, for a relative reduction of 21.3%; P=0.002), and increased rates of self-reported health status of "excellent" or "very good" (by 2.2 percentage points, for a relative increase of 3.4%; P=0.04). CONCLUSIONS: State Medicaid expansions to cover low-income adults were significantly associated with reduced mortality as well as improved coverage, access to care, and self-reported health. PMID- 22830436 TI - The Supreme Court and the future of Medicaid. PMID- 22830438 TI - Fibroproliferative disorders: from biochemical analysis to targeted therapies Frauenchiemsee, Germany. 25-30 September 2010. Abstracts. PMID- 22830437 TI - Possible mechanisms of action of the aqueous extract of Artocarpus altilis (breadfruit) leaves in producing hypotension in normotensive Sprague-Dawley rats. AB - CONTEXT AND OBJECTIVES: Artocarpus altilis (Parkinson) Fosberg (Moraceae) (breadfruit) leaves are used as an antihypertensive remedy. We investigated the possible mechanisms of action of its aqueous extract and its effect on cytochromes P450 (CYP) enzyme activities. MATERIALS AND METHODS: Intravenous administration of an aqueous leaf extract (20.88-146.18 mg/kg) of A. altilis on mean arterial pressure and heart rate were recorded via cannulation of the carotid artery on anaesthetized normotensive Sprague-Dawley rats. Recordings of the contractile activity of the aortic rings to the extract (0.71-4.26 mg/mL) were studied using standard organ bath techniques. Inhibitions of human CYP3A4 and CYP2D6 enzyme activities were evaluated by means of a fluorometric assay in 96 well plates using heterologously expressed microsomes. RESULTS: A. altilis caused significant (p < 0.05) hypotensive and bradycardiac responses unaffected by atropine (2 mg/kg) and mepyramine (5 mg/kg), but attenuated by propranolol (1 mg/kg) and N(G)-nitro-L-arginine methyl ester (5 mg/kg). The extract (0.71-4.26 mg/mL) significantly (p < 0.05) relaxed phenylephrine (10-9-10-4 M) and 80 mM KCl induced contractions in endothelium intact and denuded aortic rings; and caused a significant (p < 0.05) rightward shift of the Ca2+ dose-response curves in Ca2+ free Kreb's solution. Moderate inhibitions of cytochrome P450s (CYP3A4 and CYP2D6) enzyme activities with IC50 values of 0.695 +/- 0.187 and 0.512 +/- 0.131 mg/mL, respectively, were produced. CONCLUSION: A. altilis exhibits negative chronotropic and hypotensive effects through alpha-adrenoceptor and Ca2+ channel antagonism. Drug adversity effects are unlikely if the aqueous leaf extract is consumed with other medications reliant on CYP3A4 and CYP2D6 metabolism. This study thus provides scientific evidence for the use of the breadfruit in the treatment of hypertension. PMID- 22830439 TI - Effects of malnutrition on oxidative burst functions and infection episodes in children with acute lymphoblastic leukemia. AB - INTRODUCTION: The aim of this study was to determine the effect of malnutrition on oxidative burst functions (OBF) of neutrophils in children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Twenty-eight patients with ALL and thirty healthy controls were enrolled to the study. Thirteen patients with ALL were found to have malnutrition. While neutrophil OBF of ALL patients without malnutrition were studied both before induction chemotherapy and 3 months after, the same functions in ALL patients with malnutrition were studied both before induction chemotherapy and when the nutritional status improved. Control group were studied at admission and 3 months later. RESULTS: The OBF of ALL patients with and without malnutrition before induction chemotherapy were found to be significantly lower than the control group (P = 0.009), whereas the OBF were found to be similar in both patient groups with ALL (P = 0.27). The median infection episode rate and the duration of antibiotics therapy during the study period were similar in both patient groups with ALL. The repeated OBF of both patient groups with ALL were shown to increase to similar values with the control group in the third month of chemotherapy (P = 0.002). The median infection episode rate during the first month of chemotherapy was shown to decrease significantly during the third month of chemotherapy in both patient with ALL groups (P < 0.001). CONCLUSIONS: We have not been able to demonstrate an overt effect of malnutrition on OBF. However, our results still need to be verified via further larger scaled studies of OBF in leukemic children with and without malnutrition. PMID- 22830440 TI - Enhanced sampling of molecular dynamics simulation of peptides and proteins by double coupling to thermal bath. AB - Low sampling efficiency in conformational space is the well-known problem for conventional molecular dynamics. It greatly increases the difficulty for molecules to find the transition path to native state, and costs amount of CPU time. To accelerate the sampling, in this paper, we re-couple the critical degrees of freedom in the molecule to environment temperature, like dihedrals in generalized coordinates or nonhydrogen atoms in Cartesian coordinate. After applying to ALA dipeptide model, we find that this modified molecular dynamics greatly enhances the sampling behavior in the conformational space and provides more information about the state-to-state transition, while conventional molecular dynamics fails to do so. Moreover, from the results of 16 independent 100 ns simulations by the new method, it shows that trpzip2 has one-half chances to reach the naive state in all the trajectories, which is greatly higher than conventional molecular dynamics. Such an improvement would provide a potential way for searching the conformational space or predicting the most stable states of peptides and proteins. PMID- 22830441 TI - Atrial support pacing in heart failure: results from the multicenter PEGASUS CRT trial. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) efficacy trials to date used atrial-synchronous biventricular pacing wherein there is no or minimal atrial pacing. However, bradycardia and chronotropic incompetence are common in this patient population. This trial was designed to evaluate the effect of atrial support pacing among heart failure patients receiving a CRT defibrillator. METHODS AND RESULTS: PEGASUS CRT was a multicenter, 3-arm, randomized study. At 6 weeks, patients were randomized to DDD mode at a lower rate of 40 bpm (DDD-40; control arm), or one of the following 2 treatment arms: DDD-70, or DDDR-40. The primary endpoint was a clinical composite endpoint that included all-cause mortality, heart failure events, NYHA functional class, and patient global self assessment. Subjects were classified as improved, unchanged, or worsened at 12 months. There were 1,433 patients randomized, of whom 66% were male, mean age was 67 +/- 11 years, and mean left ventricular ejection fraction was 23 +/- 7%. The average follow-up time was 10.5 +/- 3.5 months and 1,309 patients contributed to the primary endpoint. No significant differences were observed in the composite endpoint between either of the 2 treatment arms compared to the control arm (P>0.05 for both comparisons). Additionally, there were no differences among the groups in mortality or heart failure events. CONCLUSION: In advanced heart failure patients treated with CRT, atrial support pacing did not improve clinical outcomes compared to atrial tracking. However, atrial pacing did not adversely affect mortality or heart failure events. PMID- 22830442 TI - Physical exercise on the rat ventral prostate: steroid hormone receptors, apoptosis and cell proliferation. AB - Studies have investigated the effect of exercise on prostate cancer risk. However, there are still doubts regarding the correlation between physical activity and the steroid hormones with respect to the reduction of the risk for prostatic lesions. We evaluated the levels of corticosterone, dihydrotestosterone (DHT), testosterone, estradiol, and steroid hormone receptors, and investigated the relationship between apoptosis and cell proliferation in the rat ventral prostate after training. Two groups were included in this study: control and trained. The trained group was submitted to training for 13 weeks (1 week of adaptation). Two days after the last training session, all animals were euthanized, and the intermediate and distal regions of the ventral prostate were collected and processed for immunohistochemistry, Western blotting and hormonal analyses. Physical exercise increased the corticosterone plasma, DHT and testosterone. In addition, androgen receptor expression was lower and estrogen receptor (ER) alpha and ER beta expression were higher in the trained group. However, the trained group showed disruption of the ratio of apoptotic to proliferating cells, indicating a predominance of apoptosis. We conclude that physical exercise alters the sex hormones and their receptors and is associated with the disruption of the balance between apoptosis and cell proliferation in the rat ventral prostate. PMID- 22830444 TI - Study of the air-water interfacial properties of biodegradable polyesters and their block copolymers with poly(ethylene glycol). AB - It has been reported that the surface pressure-area isotherm of poly(D,L-lactic acid-ran-glycolic acid) (PLGA) at the air-water interface exhibits several interesting features: (1) a plateau at intermediate compression levels, (2) a sharp rise in surface pressure upon further compression, and (3) marked surface pressure-area hysteresis during compression-expansion cycles. To investigate the molecular origin of this behavior, we conducted an extensive set of surface pressure and AFM imaging measurements with PLGA materials having several different molecular weights and also a poly(D,L-lactic acid-ran-glycolic acid-ran caprolactone) (PLGACL) material in which the caprolactone monomers were incorporated as a plasticizing component. The results suggest that (i) the plateau in the surface pressure-area isotherm of PLGA (or PLGACL) occurs because of the formation (and collapse) of a continuous monolayer of the polymer under continuous compression; (ii) the PLGA monolayer becomes significantly resistant to compression at high compression because under that condition the collapsed domains become large enough to become glassy (such behavior was not observed in the nonglassy PLGACL sample); and (iii) the isotherm hysteresis is due to a coarsening of the collapsed domains that occurs under high-compression conditions. We also investigated the monolayer properties of PEG-PLGA and PEG PLGACL diblock copolymers. The results demonstrate that the tendency of PLGA (or PLGACL) to spread on water allows the polymer to be used as an anchoring block to form a smooth biodegradable monolayer of block copolymers at the air-water interface. These diblock copolymer monolayers exhibit protein resistance. PMID- 22830443 TI - Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer. AB - BACKGROUND: Successful treatment of solid tumors relies on the ability of drugs to penetrate into the tumor tissue. METHODS: We examined the correlation of panitumumab (an anti-epidermal growth factor [EGFR] antibody) tumor penetration and EGFR saturation, a potential obstacle in large molecule drug delivery, using pharmacokinetics, pharmacodynamics, and tumor growth rate in an A431 epidermoid carcinoma xenograft model of human cancer. To determine receptor saturation, receptor occupancy, and levels of proliferation markers, immunohistochemical and flow cytometric methods were used. Pharmacokinetic data and modeling were used to calculate growth characteristics of panitumumab-treated tumors. RESULTS: Treatment with panitumumab in vivo inhibited pEGFR, Ki67 and pMAPK levels vs control. Tumor penetration and receptor saturation were dose- and time-dependent, reaching 100% and 78%, respectively. Significant tumor inhibition and eradication (p < 0.05) were observed; plasma concentration associated with tumor eradication was estimated to be 0.2 MUg/ml. The tumor inhibition model was able to describe the mean tumor growth and death rates. CONCLUSIONS: These data demonstrate that the antitumor activity of panitumumab correlates with its ability to penetrate into tumor tissue, occupy and inhibit activation of EGFR, and inhibit markers of proliferation and MAPK signaling. PMID- 22830445 TI - DrugLogit: logistic discrimination between drugs and nondrugs including disease specificity by assigning probabilities based on molecular properties. AB - The increasing knowledge of both structure and activity of compounds provides a good basis for enhancing the pharmacological characterization of chemical libraries. In addition, pharmacology can be seen as incorporating both advances from molecular biology as well as chemical sciences, with innovative insight provided from studying target-ligand data from a ligand molecular point of view. Predictions and profiling of libraries of drug candidates have previously focused mainly on certain cases of oral bioavailability. Inclusion of other administration routes and disease-specificity would improve the precision of drug profiling. In this work, recent data are extended, and a probability-based approach is introduced for quantitative and gradual classification of compounds into categories of drugs/nondrugs, as well as for disease- or organ-specificity. Using experimental data of over 1067 compounds and multivariate logistic regressions, the classification shows good performance in training and independent test cases. The regressions have high statistical significance in terms of the robustness of coefficients and 95% confidence intervals provided by a 1000-fold bootstrapping resampling. Besides their good predictive power, the classification functions remain chemically interpretable, containing only one to five variables in total, and the physicochemical terms involved can be easily calculated. The present approach is useful for an improved description and filtering of compound libraries. It can also be applied sequentially or in combinations of filters, as well as adapted to particular use cases. The scores and equations may be able to suggest possible routes for compound or library modification. The data is made available for reuse by others, and the equations are freely accessible at http://hermes.chem.ut.ee/~alfx/druglogit.html. PMID- 22830446 TI - Effects of continuity of care by a primary midwife (caseload midwifery) on caesarean section rates in women of low obstetric risk: the COSMOS randomised controlled trial. AB - OBJECTIVE: To determine whether primary midwife care (caseload midwifery) decreases the caesarean section rate compared with standard maternity care. DESIGN: Randomised controlled trial. SETTING: Tertiary-care women's hospital in Melbourne, Australia. POPULATION: A total of 2314 low-risk pregnant women. METHODS: Women randomised to caseload received antenatal, intrapartum and postpartum care from a primary midwife with some care by 'back-up' midwives. Women randomised to standard care received either midwifery or obstetric-trainee care with varying levels of continuity, or community-based general practitioner care. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: caesarean birth. Secondary outcomes included instrumental vaginal births, analgesia, perineal trauma, induction of labour, infant admission to special/neonatal intensive care, gestational age, Apgar scores and birthweight. RESULTS: In total 2314 women were randomised-1156 to caseload and 1158 to standard care. Women allocated to caseload were less likely to have a caesarean section (19.4% versus 24.9%; risk ratio [RR] 0.78; 95% CI 0.67-0.91; P = 0.001); more likely to have a spontaneous vaginal birth (63.0% versus 55.7%; RR 1.13; 95% CI 1.06-1.21; P < 0.001); less likely to have epidural analgesia (30.5% versus 34.6%; RR 0.88; 95% CI 0.79 0.996; P = 0.04) and less likely to have an episiotomy (23.1% versus 29.4%; RR 0.79; 95% CI 0.67-0.92; P = 0.003). Infants of women allocated to caseload were less likely to be admitted to special or neonatal intensive care (4.0% versus 6.4%; RR 0.63; 95% CI 0.44-0.90; P = 0.01). No infant outcomes favoured standard care. CONCLUSION: In settings with a relatively high baseline caesarean section rate, caseload midwifery for women at low obstetric risk in early pregnancy shows promise for reducing caesarean births. PMID- 22830447 TI - Changes of endocrine and ultrasound markers as ovarian aging in modifying the Stages of Reproductive Aging Workshop (STRAW) staging system with subclassification of mid reproductive age stage. AB - OBJECTIVE: To demonstrate the changes of ovarian aging markers across the Stages of Reproductive Aging Workshop (STRAW) stages and modify it with subclassification of mid reproductive age stage (MR). DESIGN: Healthy females were classified according to the STRAW system. Serum basal FSH, LH, E2, and anti Mullerian hormone (AMH) were detected, FSH/LH ratio calculated, and antral follicle counts (AFCs) determined in follicular phase. RESULTS: Progression through the whole STRAW stages under MR stage subdivided is associated with elevations in FSH, LH, FSH/LH ratio and decreases in E2, AMH and AFCs (p < 0.001). Both serum AMH and AFCs decreased early (after 25 years) and significantly (p < 0.01) with chronological age in MR stage. 0.982 ng/ml AMH and 3 antral follicles (low level of MR 25-30 years) were set as cutoffs to distinguish MR stage into early mid reproductive age (EMR) and late mid reproductive age (LMR) stages. The women in EMR stage compared with LMR could retrieve more oocytes in IVF treatment (p < 0.05) and has a higher pregnancy chance (57.9%) though not significant. CONCLUSION(S): The early and marked fall in serum AMH levels and AFCs suggest fine markers to further categorize and define the MR stage, demonstrating disparate reproductive aging period with reduced ovarian reserve in young age across the STRAW stages. PMID- 22830448 TI - Enantioselective construction of 3-hydroxy oxindoles via decarboxylative addition of beta-ketoacids to isatins. AB - The first highly enantioselective decarboxylative addition of beta-ketoacids to isatins mediated by a bifunctional tertiary amine-thiourea catalyst has been developed, allowing facile synthesis of biologically important 3-hydroxy oxindoles in good yields and excellent enantioselectivities. The method reported represents a valuable approach of utilizing beta-ketoacids as synthetic equivalents of aryl/alkyl methyl ketone enolates. PMID- 22830450 TI - Genetics & sport: bioethical concerns. AB - This paper provides an overview of the ethical issues pertaining to the use of genetic insights and techniques in sport. Initially, it considers a range of scientific findings that have stimulated debate about the ethical issues associated with genetics applied to sport. It also outlines some of the early policy responses to these discoveries from world leading sports organizations, along with knowledge about actual use of gene technologies in sport. Subsequently, it considers the challenges with distinguishing between therapeutic use and human enhancement within genetic science, which is a particularly important issue for the world of sport. Next, particular attention is given to the use of genetic information, which raises questions about the legitimacy and reliability of genetic tests, along with the potential public value of having DNA databanks to economize in health care. Finally, the ethics of gene transfer are considered, inviting questions into the values of sport and humanity. It argues that, while gene modification may seem conceptually similar to other forms of doping, the requirements upon athletes are such that new forms of enhancement become increasingly necessary to discover. Insofar as genetic science is able to create safer, more effective techniques of human modification, then it may be an appealing route through which to modify athletes to safeguard the future of elite sports as enterprises of human excellence. PMID- 22830449 TI - Revisiting oxytocin through the medium of isonitriles. AB - The reaction of thioamino acids and N-terminal peptides, mediated by hindered isonitriles and hydroxybenzotriazole, gives rise to peptide bonds. In one pathway, oxytocin was synthesized by eight such reiterative amidations. In another stereospecific track, oxytocin was constructed by native chemical ligation, wherein the two building blocks were assembled by thioacid amine amidation. The NMR spectra of oxytocin and dihydrooxytocin suggest a high level of preorganization in the latter, perhaps favoring oxidative folding. PMID- 22830451 TI - Genetic enhancement in sport: just another form of doping? AB - Patented genetic technologies such as the ACTN3 genetic test are adding a new dimension to the types of performance enhancement available to elite athletes. Organized sports organizations and governments are seeking to prevent athletes' use of biomedical enhancements. This paper discusses how these interdiction efforts will affect the use and availability of genetic technologies that can enhance athletic performance. The paper provides a working definition of enhancement, and in light of that definition and the concerns of the sports community, reviews genetic enhancement as a result of varied technologies, including, genetic testing to identify innate athletic ability, performance enhancing drugs developed with genetic science and technology, pharmacogenetics, enhancement through reproductive technologies, somatic gene transfer, and germ line gene transfer. PMID- 22830452 TI - Synthetic approaches to (smif)2Ti (smif = 1,3-di-(2-pyridyl)-2-azaallyl) reveal redox non-innocence and C-C bond-formation. AB - Attempted syntheses of (smif)(2)Ti (smif =1,3-di-(2-pyridyl)-2-azaallyl) based on metatheses of TiCl(n)L(m) (n = 2-4) with M(smif) (M = Li, Na), in the presence of a reducing agent (Na/Hg) when necessary, failed, but several apparent Ti(II) species were identified by X-ray crystallography and multidimensional NMR spectroscopy: (smif){Li(smif-smif)}Ti (1, X-ray), [(smif)Ti](2)(MU kappa(3),kappa(3)-N,N(py)(2)-smif,smif) (2), (smif)Ti(kappa(3)-N,N(py)(2) smif,(smif)H) (3), and (smif)Ti(dpma) (4, dpma = di-2-pyridylmethyl-amide). NMR spectroscopy and K-edge XAS showed that each compound possesses ligands that are redox noninnnocent, such that d(1) Ti(III) centers AF-couple to ligand radicals: (smif){Li(smif-smif)(2-)}Ti(III) (1), [(smif(2-))Ti(III)](2)(MU-kappa(3),kappa(3) N,N(py)(2)-smif,smif) (2), [(smif(2-))Ti(III)](kappa(3)-N,N(py)(2)-smif,(smif)H) (3), and (smif(2-))Ti(III)(dpma) (4). The instability of (smif)(2)Ti relative to its C-C coupled dimer, 2, is rationalized via the complementary nature of the amide and smif radical dianion ligands, which are also common to 3 and 4. Calculations support this contention. PMID- 22830454 TI - Treatment of pandemic influenza A (H1N1) 2009-associated encephalopathy in children. AB - BACKGROUND: The novel pandemic influenza A (H1N1) 2009 virus (influenza A(H1N1)pdm09) caused an epidemic of critical illness, with some patients developing fatal encephalopathy as well as pneumonia. METHODS: To investigate the actual efficacy of treatments, we investigated data from questionnaires regarding 207 cases that occurred between September 2009 and February 2010. RESULTS: The outcomes were recorded in 188 of the 207 cases; 16 of 188 patients died, while 23 had sequelae. Anti-influenza drugs in patients with severe coma (Glasgow coma scale score of <= 8) were statistically effective. In 165 out of 199 cases, steroid pulse treatment with methylprednisolone was given at an early stage. Other intensive treatments were mostly administered in serious cases. CONCLUSIONS: Controlled studies are needed to investigate the efficacy of other treatments except for anti-influenza drugs. PMID- 22830453 TI - Luminal A and luminal B (HER2 negative) subtypes of breast cancer consist of a mixture of tumors with different genotype. AB - BACKGROUND: The St Gallen International Expert Consensus 2011 has proposed a new classification system for breast cancer. The purpose of this study was to elucidate the relationship between the breast cancer subtypes determined by the new classification system and genomic characteristics. METHODS: Invasive breast cancers (n = 363) were immunohistochemically classified as follows: 111 (30.6%) as luminal A, 95 (26.2%) as luminal B (HER2 negative), 69 (19.0%) as luminal B (HER2 positive), 41 (11.3%) as HER2, and 47 (12.9%) as basal-like subtypes. RESULTS: The high expression of Ki-67 antigen was detected in 236 tumors; no cases of luminal A subtype showed high expression of the Ki-67 antigen, but more than 85% of tumors of the other subtypes showed high expression. In addition, DNA ploidy and chromosomal instability (CIN) were assessed using imaging cytometry and FISH, respectively. In this series, 336 (92.6%) tumors consisted of 129 diploid/CIN- and 207 aneuploid/CIN + tumors. Diploid/CIN- and aneuploid/CIN+ features were detected in 64.9% and 27.9% of luminal A, 41.1% and 49.5% of luminal B (HER2-), 11.6% and 81.2% of luminal B (HER2+), 4.9% and 90.2% of HER2, and 17.0% and 76.6% of basal-like subtypes, respectively. Unlike the luminal B (HER2+), HER2 and basal-like subtypes, the luminal A and luminal B (HER2-) subtypes were heterogeneous in terms of DNA ploidy and CIN. CONCLUSIONS: It is reasonable to propose that the luminal A and luminal B (HER2-) subtypes should be further divided into two subgroups, diploid/CIN- and aneuploid/CIN+, based on their underlying genomic status. PMID- 22830455 TI - Cobalamin status in sickle cell disease. AB - INTRODUCTION: Some studies comparing serum cobalamin in individuals with and without sickle cell disease (SCD) have suggested a higher prevalence of cobalamin deficiency in SCD but others have not. Our aim was to prospectively compare cobalamin status in African-Americans with and without SCD. METHODS: We analyzed blood samples from 86 subjects in two groups: SCD (n = 29) and non-SCD (n = 57). Serum cobalamin, folate, homocysteine, methylmalonic acid (MMA), anti-intrinsic factor antibody, Helicobacter pylori antibody, and gastrin were measured and compared. RESULTS: The median cobalamin was 235 pM in the SCD group vs. 292 pM in the non-SCD group (P-value = 0.014). No significant differences in MMA or homocysteine were seen. Using the criteria of a low cobalamin and an elevated MMA or an elevated MMA alone, cobalamin deficiency was suggested in 4 (13.8%) in the SCD group and 6 (10.5%) in the non-SCD group. Two of these SCD patients and four of these control subjects had chronic renal disease, which may lead to elevated MMA in the absence of cobalamin deficiency. The remaining four met criteria for cobalamin deficiency, 2 (6.9%) in the SCD group and 2 (3.5%) in the non-SCD group (P = 0.6). CONCLUSION: A lower cobalamin was observed in SCD patients without a higher prevalence of cobalamin deficiency. The inclusion of haptocorrin and holotranscobalamin measurement in future studies may provide a better assessment of cobalamin status in this patient group. PMID- 22830457 TI - Spontaneous bilateral internal carotid artery dissection presenting with right hemifacial pain. PMID- 22830456 TI - Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents. AB - BACKGROUND: Infantile spasms (IS; West syndrome) is a severe form of encephalopathy that typically affects infants younger than 2 years old. Pediatricians, pediatric neurologists, and other pediatric health care providers are all potentially key early contacts for families who have an infant with IS. The objective of this article is to assist pediatric health care providers in the detection of the disease and in the counseling and guidance of families who have an infant with IS. METHODS: Treatment guidelines, consensus reports, and original research studies are reviewed to provide an update regarding the diagnosis and treatment of infants with IS. Web sites were searched for educational and supportive resource content relevant to providers and families of patients with IS. RESULTS: Early detection of IS and pediatrician referral to a pediatric neurologist for further evaluation and initiation of treatment may improve prognosis. Family education and the establishment of a multidisciplinary continuum of care are important components of care for the majority of patients with IS. The focus of the continuum of care varies across diagnosis, initiation of treatment, and short- and long-term needs. Several on-line educational and supportive resources for families and caregivers of patients with IS were identified. CONCLUSIONS: Given the possibility of poor developmental outcomes in IS, including the emergence of other seizure disorders and cognitive and developmental problems, early recognition, referral, and treatment of IS are important for optimal patient outcomes. Dissemination of and access to educational and supportive resources for families and caregivers across the lifespan of the child with IS is an urgent need. Pediatric health care providers are well positioned to address these needs. PMID- 22830458 TI - Surface shear rheology of saponin adsorption layers. AB - Saponins are a wide class of natural surfactants, with molecules containing a rigid hydrophobic group (triterpenoid or steroid), connected via glycoside bonds to hydrophilic oligosaccharide chains. These surfactants are very good foam stabiliziers and emulsifiers, and show a range of nontrivial biological activities. The molecular mechanisms behind these unusual properties are unknown, and, therefore, the saponins have attracted significant research interest in recent years. In our previous study (Stanimirova et al. Langmuir 2011, 27, 12486 12498), we showed that the triterpenoid saponins extracted from Quillaja saponaria plant (Quillaja saponins) formed adsorption layers with unusually high surface dilatational elasticity, 280 +/- 30 mN/m. In this Article, we study the shear rheological properties of the adsorption layers of Quillaja saponins. In addition, we study the surface shear rheological properties of Yucca saponins, which are of steroid type. The experimental results show that the adsorption layers of Yucca saponins exhibit purely viscous rheological response, even at the lowest shear stress applied, whereas the adsorption layers of Quillaja saponins behave like a viscoelastic two-dimensional body. For Quillaja saponins, a single master curve describes the data for the viscoelastic creep compliance versus deformation time, up to a certain critical value of the applied shear stress. Above this value, the layer compliance increases, and the adsorption layers eventually transform into viscous ones. The experimental creep-recovery curves for the viscoelastic layers are fitted very well by compound Voigt rheological model. The obtained results are discussed from the viewpoint of the layer structure and the possible molecular mechanisms, governing the rheological response of the saponin adsorption layers. PMID- 22830459 TI - Olympic medicine. PMID- 22830460 TI - Value-based purchasing--national programs to move from volume to value. PMID- 22830461 TI - The cost-effectiveness of environmental approaches to disease prevention. PMID- 22830462 TI - Coronary CT angiography versus standard evaluation in acute chest pain. AB - BACKGROUND: It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS: In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS: The rate of acute coronary syndromes among 1000 patients with a mean (+/-SD) age of 54+/-8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65). CONCLUSIONS: In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT II ClinicalTrials.gov number, NCT01084239.). PMID- 22830465 TI - Tuberculosis in children. PMID- 22830464 TI - Antibiotic prevention of acute exacerbations of COPD. PMID- 22830466 TI - Images in clinical medicine. A scalp nevus. PMID- 22830463 TI - Sirolimus and secondary skin-cancer prevention in kidney transplantation. AB - BACKGROUND: Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS: In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS: Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS: Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.). PMID- 22830467 TI - Case records of the Massachusetts General Hospital. Case 23-2012. A 59-year-old man with abdominal pain and weight loss. PMID- 22830468 TI - Coronary CT angiography for acute chest pain. PMID- 22830469 TI - The natriuretic peptides and fat metabolism. PMID- 22830471 TI - Radiotherapy plus chemotherapy in muscle-invasive bladder cancer. PMID- 22830472 TI - Radiotherapy plus chemotherapy in muscle-invasive bladder cancer. PMID- 22830473 TI - Radiotherapy plus chemotherapy in muscle-invasive bladder cancer. PMID- 22830475 TI - Premier pay for performance and patient outcomes. PMID- 22830476 TI - Premier pay for performance and patient outcomes. PMID- 22830477 TI - Premier pay for performance and patient outcomes. PMID- 22830479 TI - Insulin-pump therapy for type 1 diabetes mellitus. PMID- 22830481 TI - Telomerase mutations and the pulmonary fibrosis-bone marrow failure syndrome complex. PMID- 22830482 TI - Failures of cobalamin assays in pernicious anemia. PMID- 22830483 TI - Images in clinical medicine. Duodenal Dieulafoy's lesion. PMID- 22830485 TI - Transition-metal-free C-arylation at room temperature by arynes. AB - A facile, fluoride-induced transition-metal-free chemoselective alpha-arylation of beta-dicarbonyl compounds (malonamide esters) at room temperature using aryne intermediates has been demonstrated. Selective mono- or diarylation and generation of a quaternary benzylic stereocenter have also been achieved. The methodology will be highly useful for the synthesis of a library of CNS depressant barbiturate drugs like Phenobarbital. PMID- 22830486 TI - A qualitative study of factors influencing different generations of Newfoundland and Saskatchewan trained physicians to leave a work location. AB - BACKGROUND: Some studies have suggested that young physicians may have different expectations and practice behaviours than their older generational counterparts, including their reasons for wanting to remain or leave a community. This study examined the factors associated with a physician's decision to leave a work location. We compared different generations of physicians to assess whether these factors have changed over generations. METHODS: We conducted semi-structured, qualitative interviews with 48 physicians who graduated from two Canadian medical schools. We asked each physician about the number and nature of work location changes and the factors related to their decisions to leave each location. Interview transcripts and notes were analysed using a thematic analysis approach. RESULTS: Dissatisfaction with the working environment was the most frequently cited reason for leaving a location for physicians of all generations. Elements which contributed to the quality of the work environment included the collaborative nature of the practice, the relationship with administrators, and access to resources and personnel. For younger physicians, the work environment had to meet their personal expectations for work-life balance. While remuneration level was given by some physicians as the key reason for leaving a location, for others it was the "last straw" if the work environment was poor. A small number of older generation physicians moved in response to political events and/or policies CONCLUSIONS: We documented generational differences in physicians' reasons for choosing a work location. We found that a poor work environment was universally the most important reason why a physician chose to leave a location. A few physicians who were unsatisfied with their work location identified level of remuneration as an additional reason for leaving. Some older generation physicians cited political climate as a reason for leaving a work location. While economic factors have largely been the focus of recruitment and retention initiatives, our findings highlight the importance of the work environment and organizational culture on the retention of physicians of all generations. PMID- 22830487 TI - Antinociceptive, antidiarrheal, and neuropharmacological activities of Barringtonia acutangula. AB - CONTEXT: Barringtonia acutangula (L.) Gaertn. (Lecythidaceae) has been used in folk medicine in the treatment of arthralgia, chest pain, dysmenorrhea, inflammation, hemorrhoids, diarrhea, and also in psychological disorders. OBJECTIVE: To investigate the antinociceptive, antidiarrheal, and neuropharmacological effect of the methanol extract of B. acutangula leaves and seeds in mice. MATERIALS AND METHODS: The extracts (200 and 400 mg/kg; p.o.) were tested for antinociceptive activity by acetic acid-induced writhing, hot plate and tail immersion models; castor oil- and magnesium sulphate-induced diarrheal models were used to evaluate antidiarrheal activity whereas hole cross and open field models were employed for testing neuropharmacological activity. RESULTS: Both extracts exhibited significant antinociceptive effect (p < 0.001) in acetic acid and heat induced pain models in a dose-dependent manner. The extracts prolonged the latency period to the thermal stimuli in both hot plate and tail immersion test. The extracts also showed significant inhibition of defecation (p < 0.001, 0.01) in both diarrheal models. Again, the spontaneous motor activity was decreased (p < 0.001) by the extracts in both hole cross and open field test. DISCUSSION AND CONCLUSION: The results of this study suggest that the methanol extracts of B. acutangula leaves and seeds possess good antinociceptive, antidiarrheal, and central nervous system (CNS) depressant activities. This study validates the use of this plant in traditional medicine. PMID- 22830488 TI - Adolescent elite athletes' cigarette smoking, use of snus, and alcohol. AB - The purpose was to examine cigarette smoking, use of snus, alcohol, and performance-enhancing illicit drugs among adolescent elite athletes and controls, and possible gender and sport group differences. First-year students at 16 Norwegian Elite Sport High Schools (n = 677) and two randomly selected high schools (controls, n = 421) were invited to participate. Totally, 602 athletes (89%) and 354 (84%) controls completed the questionnaire. More controls than athletes were smoking, using snus, and drinking alcohol. Competing in team sports was associated with use of snus [odds ratio = 2.8, 95% confidence interval (CI) 1.6 to 4.7] and a similar percentage of male and female handball (22.2% vs 18.8%) and soccer players (15.7% vs 15.0%) reported using snus. For controls, not participating in organized sport was a predictor for smoking (odds ratio = 4.9, 95% CI 2.2 to 10.9). Female athletes were more prone to drink alcohol than males (46.3% vs 31.0%, P < 0.001). Only, 1.2% athletes and 2.8% controls reported use of performance-enhancing illicit drugs. In conclusion, use of legal drugs is less common among athletes, but this relationship depends on type of sport and competition level. The association between team sports and use of snus suggests that sport subcultures play a role. PMID- 22830489 TI - Myocardium of the superior vena cava, coronary sinus, vein of Marshall, and the pulmonary vein ostia: gross anatomic studies in 620 hearts. AB - INTRODUCTION: Radiofrequency ablation for atrial fibrillation (AF) frequently involves energy delivery at the ostia of the thoracic veins. Detailed evaluation of the myocardium extending into the caval veins, vein of Marshall, as well as at the pulmonary vein ostia has not been completely evaluated. METHODS AND RESULTS: Post-mortem assessment of 620 formalin-fixed hearts (mean age 60 +/- 23 years, 44% female) was performed. The hearts were examined for integrity of venous structures and their atrial connections. Systematic gross anatomic evaluation including measurements on myocardial extensions in these veins was performed. Macroscopic myocardial extensions into pulmonary veins were noted in 99% of specimens evaluated and were circumferentially symmetric (99.6%). Myocardial extensions into the superior vena cava (SVC) occurred in 78% with the majority being circumferentially asymmetric (61%). Occasionally, myocardium extended into the azygos vein (6%). There were no myocardial extensions in the inferior vena cava (IVC). In some cases, the right atrial pectinate muscle extended into the coronary sinus (7%). The vein of Marshall was consistently located anterior to the left-sided pulmonary veins and posterior to the left atrial appendage, overlying the left atrial endocardial ridge. CONCLUSIONS: Myocardial extensions into the pulmonary veins are usually circumferential at the ostia validating the necessity for wide area rather than segmental ablation to isolate these veins during AF ablation. Myocardial extensions into the SVC are common and less likely to be circumferential, whereas extensions into the IVC are not present. The left atrial ridge is a reliable endocardial target for radiofrequency ablation of the vein of Marshall. PMID- 22830490 TI - Omeprazole improves the anti-obesity and antidiabetic effects of exendin-4 in db/db mice (-4 db/db)*. AB - BACKGROUND: In addition to its glucoregulatory actions, exendin-4, a stable glucagon-like peptide-1 receptor agonist, exhibits protective effects in the pancreas and anti-obesity effects. Suitable combination treatment with other anti obesity or pancreas protective agents would be an effective approach to optimize these additional effects. In the present study, we investigated the effects of the addition of omeprazole, a proton pump inhibitor, to exendin-4 in db/db mice, an experimental model of obesity and type 2 diabetes. METHODS: The effects repeated dose treatment for 14 days with exendin-4 (8 MUg/kg, s.c.) and omeprazole (30 mg/kg, s.c.) on glycemic control, food intake, and body weight were determined in obese and hyperglycemic db/db mice. The effects of these treatments on plasma gastrin, ghrelin, and leptin levels were determined, along with effects on nausea-like symptoms. The pancreatic effects of the repeated dose treatment were assessed by measuring %HbA1c in the circulation as well as pancreatic insulin and glucagon content and glucokinase activity. RESULTS: Combination treatment resulted in significant decreases in plasma leptin and ghrelin levels after repeated dosing. Omeprazole improved the anorectic and body weight-lowering effects and reversed the inhibitory effect of exendin-4 on gastrin levels after repeated dose treatment. The 14-day combination treatment significantly reduced glucose excursion and improved insulin levels, with a concomitant decrease in %HbA1c levels. It also improved glucokinase activity and pancreatic insulin content, with a significant decrease in glucagon content. CONCLUSIONS: Combined treatment with omeprazole with exendin-4 reduces food intake and body weight gain, most likely through changes in plasma ghrelin and leptin levels, and improves pancreatic insulin and glucagon content by improving glucokinase activity. PMID- 22830491 TI - A robust metal-organic framework constructed from alkoxo-bridged binuclear nodes and hexamethylenetetramine spacers: crystal structure and sorption studies. AB - A neutral 3D metal-organic framework, (3)(infinity)[Cu(2)(mand)(2)(hmt)].H(2)O (1), was constructed from binuclear Cu(2)O(2) alkoxo-bridged nodes, generated by the doubly deprotonated mandelic acid. The nodes are connected by hexamethylenetetramine (hmt) spacers, which act as biconnective bridging ligands, and by carboxylato groups. Channels are observed along the crystallographic c axis. The water molecules from the channels can be easily removed, preserving the architecture of the crystal, which is stable up to 280 degrees C. The Langmuir surface area was found to be 610 m(2) g(-1). The sorption ability of 1 was investigated using H(2) and CO(2). PMID- 22830492 TI - Pharmacophore fingerprint-based approach to binding site subpocket similarity and its application to bioisostere replacement. AB - Bioisosteres have been defined as structurally different molecules or substructures that can form comparable intermolecular interactions, and therefore, fragments that bind to similar protein structures exhibit a degree of bioisosterism. We present KRIPO (Key Representation of Interaction in POckets): a new method for quantifying the similarities of binding site subpockets based on pharmacophore fingerprints. The binding site fingerprints have been optimized to improve their performance for both intra- and interprotein family comparisons. A range of attributes of the fingerprints was considered in the optimization, including the placement of pharmacophore features, whether or not the fingerprints are fuzzified, and the resolution and complexity of the pharmacophore fingerprints (2-, 3-, and 4-point fingerprints). Fuzzy 3-point pharmacophore fingerprints were found to represent the optimal balance between computational resource requirements and the identification of potential replacements. The complete PDB was converted into a database comprising almost 300,000 optimized fingerprints of local binding sites together with their associated ligand fragments. The value of the approach is demonstrated by application to two crystal structures from the Protein Data Bank: (1) a MAP kinase P38 structure in complex with a pyridinylimidazole inhibitor (1A9U) and (2) a complex of thrombin with melagatran (1K22). Potentially valuable bioisosteric replacements for all subpockets of the two studied protein are identified. PMID- 22830493 TI - Implications of post-bronchoscopy sputum smear in pulmonary tuberculosis. PMID- 22830494 TI - Traumatic events, other operational stressors and physical and mental health reported by Australian Defence Force personnel following peacekeeping and war like deployments. AB - BACKGROUND: The association between stressful events on warlike deployments and subsequent mental health problems has been established. Less is known about the effects of stressful events on peacekeeping deployments. METHODS: Two cross sectional studies of the Australian Defence Force were used to contrast the prevalence of exposures reported by a group deployed on a peacekeeping operation (Bougainville, n = 1704) and those reported by a group deployed on operations which included warlike and non-warlike exposures (East Timor, n = 1333). A principal components analysis was used to identify groupings of non-traumatic exposures on deployment. Multiple regression models were used to assess the association between self-reported objective and subjective exposures, stressors on deployment and subsequent physical and mental health outcomes. RESULTS: The principal components analysis produced four groups of non-traumatic stressors which were consistent between the peacekeeping and more warlike deployments. These were labelled 'separation', 'different culture', 'other people' and 'work frustration'. Higher levels of traumatic and non-traumatic exposures were reported by veterans of East Timor compared to Bougainville. Higher levels of subjective traumatic exposures were associated with increased rates of PTSD in East Timor veterans and more physical and psychological health symptoms in both deployed groups. In Bougainville and East Timor veterans some non-traumatic deployment stressors were also associated with worse health outcomes. CONCLUSION: Strategies to best prepare, identify and treat those exposed to traumatic events and other stressors on deployment should be considered for Defence personnel deployed on both warlike and peacekeeping operations. PMID- 22830496 TI - Morphological features of cells along Marx's line of the marginal conjunctiva of the human eyelid. AB - PURPOSE: The aim of this paper was to assess the morphological features of cells stained with rose Bengal along the human eyelid marginal zone (Marx's line). METHODS: Impression cytology (IC) specimens were taken using a Millicell-CM filter unit placed across Marx's line of the lower eyelid of 10 healthy male adults (aged 18 to 57 years). In vivo staining with rose Bengal was used in some subjects to highlight the line. The filters were stained with Giemsa. Cell and nucleus areas and dimensions were measured and nucleo-cytoplasmic ratios estimated using different calculations. RESULTS: The width of the Marx's line was up to 0.3 mm. The impression cytological specimens included three to eight lines of squamous-appearing cells. The cells had average cell areas ranging from 702 to 1,119 MUm(2) (group mean and SD of 894 +/- 136 MUm(2)). Most cells (average 93 +/ 4 per cent) contained a nucleus but with sizes from 3 to 124 MUm(2) including a proportion (40 per cent) of pyknotic nuclei. The average nuclear areas ranged from 13.7 to 57.9 MUm(2), with a group mean area of 37.0 +/- 15.0 MUm(2). Nucleus to-cytoplasm ratios were typical of squamous cells with NUCYT (area of nucleus / cell area - area of nucleus) mean values of 0.046 +/- 0.017, while the CYT/NUC (cell length - length of nucleus / length of nucleus) was 5.85 +/- 1.55. CONCLUSIONS: These preliminary results indicate that cells along the Marx's line are moderate-sized squamous cells with nuclei smaller than in normal bulbar conjunctival cells or pyknotic (shrunken) or the cells may be anucleate. PMID- 22830495 TI - Spontaneous behavioral responses in the orofacial region: a model of trigeminal pain in mouse. AB - OBJECTIVES: To develop a translational mouse model for the study and measurement of non-evoked pain in the orofacial region by establishing markers of nociceptive specific grooming behaviors in the mouse. BACKGROUND: Some of the most prevalent and debilitating conditions involve pain in the trigeminal distribution. Although there are current therapies for these pain conditions, for many patients, they are far from optimal. Understanding the pathophysiology of pain disorders arising from structures innervated by the trigeminal nerve is still limited, and most animal behavioral models focus on the measurement of evoked pain. In patients, spontaneous (non-evoked) pain responses provide a more accurate representation of the pain experience than do responses that are evoked by an artificial stimulus. Therefore, the development of animal models that measure spontaneous nociceptive behaviors may provide a significant translational tool for a better understanding of pain neurobiology. METHODS: C57BL/6 mice received either an injection of 0.9% saline solution or complete Freund's adjuvant into the right masseter muscle. Animals were video-recorded and then analyzed by an observer blind to the experiment group. The duration of different facial grooming patterns performed in the area of injection were measured. After 2 hours, mice were euthanized and perfused, and the brainstem was removed. Fos protein expression in the trigeminal nucleus caudalis was quantified using immunohistochemistry to investigate nociceptive-specific neuronal activation. A separate group of animals was treated with morphine sulfate to determine the nociceptive-specific nature of their behaviors. RESULTS: We characterized and quantified 3 distinct patterns of acute grooming behaviors: forepaw rubbing, lower lip skin/cheek rubbing against enclosure floor, and hindpaw scratching. These behaviors occurred with a reproducible frequency and time course, and were inhibited by the analgesic morphine. Complete Freund's adjuvant-injected animals also showed Fos labeling consistent with neuronal activation in nociceptive-specific pathways of the trigeminal nucleus after 2 hours. CONCLUSIONS: These behaviors and their correlated cellular responses represent a model of trigeminal pain that can be used to better understand basic mechanisms of orofacial pain and identify new therapeutic approaches to this common and challenging condition. PMID- 22830497 TI - New cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines. AB - The design and synthesis of hydroxyethylamine isosteres as inhibitors of cathepsin D based on SAR data have been accomplished. A library of 96 of these hydroxyethylamine isosteres are described and many have proven to be very potent inhibitors of human cathepsin D activity as measured using a fluorometric assay technique, via peptide substrate Ac-Glu-Glu(Edans)-Lys-Pro-Ile-Cys-Phe-Phe-Arg Leu-Gly-Lys(Methyl Red)-Glu-NH(2). Compounds showing strongest inhibition of cathepsin D activity were those that contain a hydroxyethyl-N'-2- or N'-(4 chlorophenyl)piperazine moiety (IC(50) values range from 0.55 to 8.5 nM), with N' (2-pyrimidyl)piperizine (IC(50) values range from 0.5 to 21.6 nM), with N-N'- L piperazinocolinamide (IC(50) values range from 0.001 - 0.25 nM), or N-N'-L piperazinocolin-N-methylamide (IC(50) values range from 0.015 - 7.3 nM). PMID- 22830498 TI - Antimitotic activity on sea urchin embryonic cells of seven antiparasitic Morita Baylis-Hillman adducts: a potential new class of anticancer drugs. AB - In the present work we described improvements in the 1-7 antiparasitic Morita Baylis-Hillman Adducts synthesis and their antimitotic activity on sea urchin embryonic cells. The 2-[Hydroxy(2-nitrophenyl)methyl]acrylonitrile (1) and 2 [Hydroxy(4-bromophenyl) methyl]acrylonitrile (4) were the most effective compounds to block the progression to embryonic morula stage (EC(50) = 75.8 MUM and 72.6 MUM, respectively). Compounds 1 and 4 were also effective in blocking the first cell division but to a lesser extent. The 2-[Hydroxy(pyridin-4 yl)methyl]acrylonitrile (7) exhibited a strong inhibition of cell divisions and progression to the first cleavage and morula stage. Fluorescent dye extrusion assay suggests that these adducts are not ABC protein substrates, which confers an additional interest in these new class of potential anticancer drugs. PMID- 22830499 TI - A cross-sectional study of pandemic influenza health literacy and the effect of a public health campaign. AB - BACKGROUND: To ascertain the understanding of 2009 pandemic (H1N1) influenza and relevant infection control measures in an emergency department population and to assess the effectiveness of education campaigns in informing the public about the pandemic. METHODS: Questionnaires were administered to patients, visitors, non clinical staff and volunteers. Data were collected on knowledge, preventative measures, information sources, attitudes to government and media reporting, perceived seriousness, behaviour change and intended compliance with future measures. Results were used to construct an overall knowledge score. RESULTS: There were 252 participants. Traditional forms of mass media (138 [55%]) remained the principal information source. Approximately 70% (176) accurately described mode of transmission and recommended precautions and 68% (175) reported behaviour change because of the pandemic. Gaps in knowledge included failure to identify certain high risk groups. Recall of government campaigns was significantly associated with a higher knowledge score. 60% (151) thought that authorities and media had exaggerated the threat; only 40% (101) would comply with recommended measures in a future pandemic. CONCLUSIONS: The knowledge regarding pandemic influenza was high in this population and positively affected by official campaigns. Pandemic planning should address knowledge gaps and the impression that authorities had exaggerated the public-health threat. PMID- 22830500 TI - Effect of size and dose on the biodistribution of graphene oxide in mice. AB - AIM: Graphene oxide (GO) has promising applications in bioimaging, diagnostics and therapeutics. This work studied the effects of size and injection dose on the biodistribution of GO to accelerate the development of a GO-based drug. METHODS: GO samples were intravenously injected into mice. The content of GO in organs/tissues at different time points was measured using an (125)I-labeling technique. GO in the liver and lungs was further confirmed by both Raman spectroscopic and TEM observations. The dispersion state of GO in serum was evaluated by flow cytometry. RESULTS: Regardless of size, GO was cleared from the blood quickly and accumulated mainly in the liver and lungs. The uptake of GO in lungs increased with increasing injection dose and size. The dispersion state (i.e., size of the GO-protein complex in blood) dominated the biodistribution. CONCLUSION: The size and dose of GO affected its fate in vivo. For medical applications, small-sized GO with suitable funtionalization is recommended. PMID- 22830501 TI - Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles. AB - The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping. AIM: We investigate the in vivo implementation of HPPS for siRNA delivery. METHOD & RESULTS: After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect. CONCLUSION: HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo. PMID- 22830503 TI - Microcalorimetric study of the adsorption of PEGylated lysozyme and PEG on a mildly hydrophobic resin: influence of ammonium sulfate. AB - Adsorption of native as well as mono-, di-, and tri-PEGylated lysozyme on Toyopearl PPG-600M, a mildly hydrophobic resin is studied by isothermal titration calorimetry and by independent adsorption equilibrium measurements in sodium phosphate buffer at pH 7.0 and 25 degrees C. For PEGylation two different PEG sizes are used (5 and 10 kDa) which leads to six different forms of PEGylated lysozyme all of which are systematically studied. Additionally, the adsorption of five pure PEGs is explored. The ammonium sulfate concentration is varied from 600 to 1200 mM. The molar enthalpy of adsorption Deltah(p)(ads) is determined from the calorimetric and the adsorption equilibrium data. It is found to be endothermic in all experiments. The comparison of the adsorption of different PEGylated forms shows that the adsorption of PEGylated lysozyme is driven by the adsorption of the PEG chain. The results provide insight into the adsorption mechanisms of polymer-modified proteins on hydrophobic chromatographic resins. PMID- 22830502 TI - Preliminary study of injury from heating systemically delivered, nontargeted dextran-superparamagnetic iron oxide nanoparticles in mice. AB - AIM: To assess the potential for injury to normal tissues in mice due to heating systemically delivered magnetic nanoparticles in an alternating magnetic field (AMF). MATERIALS & METHODS: Twenty three male nude mice received intravenous injections of dextran-superparamagnetic iron oxide nanoparticles on days 1-3. On day 6, they were exposed to AMF. On day 7, blood, liver and spleen were harvested and analyzed. RESULTS: Iron deposits were detected in the liver and spleen. Mice that had received a high-particle dose and a high AMF experienced increased mortality, elevated liver enzymes and significant liver and spleen necrosis. Mice treated with low-dose superparamagnetic iron oxide nanoparticles and a low AMF survived, but had elevated enzyme levels and local necrosis in the spleen. CONCLUSION: Magnetic nanoparticles producing only modest heat output can cause damage, and even death, when sequestered in sufficient concentrations. Dextran superparamagnetic iron oxide nanoparticles are deposited in the liver and spleen, making these the sites of potential toxicity. Original submitted 16 August 2011; Revised submitted 21 March 2012; Published online 26 July 2012. PMID- 22830504 TI - Current-voltage characteristics in macroporous silicon/SiOx/SnO2:F heterojunctions. AB - We study the electrical characteristics of macroporous silicon/transparent conductor oxide junctions obtained by the deposition of fluorine doped-SnO2 onto macroporous silicon thin films using the spray pyrolysis technique. Macroporous silicon was prepared by the electrochemical anodization of a silicon wafer to produce pore sizes ranging between 0.9 to 1.2 MUm in diameter. Scanning electronic microscopy was performed to confirm the pore filling and surface coverage. The transport of charge carriers through the interface was studied by measuring the current-voltage curves in the dark and under illumination. In the best configuration, we obtain a modest open-circuit voltage of about 70 mV and a short-circuit current of 3.5 mA/cm2 at an illumination of 110 mW/cm2. In order to analyze the effects of the illumination on the electrical properties of the junction, we proposed a model of two opposing diodes, each one associated with an independent current source. We obtain a good accordance between the experimental data and the model. The current-voltage curves in illuminated conditions are well fitted with the same parameters obtained in the dark where only the photocurrent intensities in the diodes are free parameters. PMID- 22830505 TI - Mean arterial pressure following prolonged exercise in the heat: influence of training status and fluid replacement. AB - Prolonged exercise in the heat without fluid replacement represents a significant challenge to the regulation of mean arterial pressure (MAP). It is unknown, however, if MAP is equally challenged during the post-exercise period, and whether regular endurance exercise training can provide any benefit to its regulation. We examined MAP (Finometer) in eight trained (T) and eight untrained (UT) individuals prior to, and following, 120 min of cycling at 42 degrees C with (HYD) and without (DEHY) fluid replacement. Exercise during DEHY induced significant hyperthermia (T: 39.20 +/- 0.52 degrees C vs UT: 38.70 +/- 0.36 degrees C, P = 0.941) and body weight losses (T: 3.4 +/- 1.2% vs UT: 2.7 +/- 0.9%, P = 0.332), which did not differ between groups. Although MAP was equally reduced 5 min into the post-exercise period of DEHY (T: -20 +/- 11 mmHg vs UT: 22 +/- 13 mmHg, P = 0.800), its subsequent recovery was significantly different between groups (P = 0.037). While MAP returned to pre-exercise values in UT (-1 +/- 3 mmHg), it remained reduced in T (-9 +/- 3 mmHg, P = 0.028). No differences in MAP post-exercise were observed between groups during HYD. These data suggest that trained men exhibit a greater level of post-exercise hypotension following prolonged exercise in the heat without fluid replacement. Furthermore, fluid replacement reverses the sustained post-exercise hypotension observed in trained individuals. PMID- 22830507 TI - Child and adolescent suicide. PMID- 22830506 TI - Young male daily smokers are nicotine dependent and experience several unsuccessful quit attempts. AB - OBJECTIVE: Previous studies on smoking cessation have generally been conducted with adolescents or adults. Very little is known about the cessation attempts, their success, and/or use of pharmacological aids in young adult smokers who want to quit. The present study aimed to investigate quitting attempts in a group of both young male daily and occasional smokers. DESIGN AND SUBJECTS: 614 male smokers aged 18-26 years completed a standardized questionnaire about their smoking habits, quit attempts, and aids used in smoking cessation. RESULTS: Nearly all daily smokers (95.3%, 95% CI 93.1-96.8) were nicotine addicted to some extend according to the standardized questionnaire, and the more addicted they were, the more often they had tried to quit (p = 0.025). Of the daily smokers, 55.6% (95% CI 51.3-59.9) had made quit attempts and 36.2% (95% CI 32.1-40.4) had used nicotine replacement therapy (NRT). In all, 34.1% (95% CI 25.2-44.3) of all occasional smokers reported having intended to quit but they had seldom made more than one attempt whereas 20.2% of daily smokers had made at least three attempts. The stronger the nicotine dependence in daily smokers was, the more likely the subject was to have attempted to use NRT (quite dependent 23.8% vs. totally dependent 48.9%) (p < 0.001). CONCLUSIONS: A high proportion of young male daily smokers were nicotine addicted. Young smokers make many unsuccessful attempts to stop smoking using nicotine replacement therapy (NRT) on their own. A better availability of professional cessation services directed to young adult smokers is needed. PMID- 22830508 TI - Exploring the relationship among ADHD, stimulants, and substance abuse. AB - TOPIC: There is an ongoing debate among prescribers concerning the risk of inadvertently contributing to the initiation of substance abuse (SA) in children and adolescents through the use of stimulants in the treatment of attention deficit/hyperactivity disorder (ADHD). Psychiatric nurses at all levels of practice must be informed about this important discourse in order to provide accurate and timely interventions to clients and their families. PURPOSE: This literature review explores the current state of prescriptive stimulant use for ADHD and the possible links to SA. Developmental, genetic, and neuro-chemical theories of the disorder that may contribute to SA as well as the burden of comorbidity are considered. The impact of gender, cultural, legal, and ethical influences on diagnostic and treatment recommendations is also included. SOURCE: U.S. and other English language articles were identified through PubMed and the Cumulated Index of Nursing and Allied Health Literature. These sources were used to determine the current practice of stimulant prescription and the prevalence of SA as a comorbidity to other child psychiatric disorders including ADHD. Textbooks were consulted for information regarding relevant neurochemistry, genetics, and psychopharmacology. CONCLUSIONS: The authors conclude that the use of stimulants is appropriate for children and adolescents with ADHD when opportunities for screening, family and child education, and counseling concerning SA are consistently integrated into the ongoing treatment regimen. PMID- 22830509 TI - Sources of stress and coping in American college students who have been diagnosed with depression. AB - PURPOSE: The study aims to explore the sources of stress in American college students who had been treated for depression and to discern their coping mechanisms. ORGANIZING FRAMEWORK: A phenomenological approach using Seidman's guide to in-depth qualitative interviews using a three-part approach was used in the study. METHOD: Online in-depth interviews utilizing e-mail with asynchronous communication were used. FINDINGS: Sources of stress included roommate issues, academic problems, financial and career concerns, and pressure from family. Exercise, talking to friends, self-talk, deep breathing, journaling, marijuana use, and listening to music were common coping mechanisms. CONCLUSIONS: College students who have been treated for depression are under increasing stress today from a variety of sources. Nonmedical methods of coping were often cited as more effective than medication therapy. PMID- 22830510 TI - Assessing the educational needs of mental health nurses working in an adolescent inpatient psychiatric ward in Japan. AB - PROBLEM: In Japan, preregistration education is not sufficient to prepare nurses to work as child adolescent mental health nurses. METHODS: Nominal group technique (NGT) using focus group discussions, and Knowles' Adult Learning Theory, were used to examine the continuing educational needs of nurses in a Japanese adolescent mental health unit. FINDINGS: Nurses caring for adolescent patients with mental health issues need continuing education. This research demonstrates the utility of nominal group technique in needs analysis in this context. CONCLUSIONS: Educational priorities include instruction on patients' developmental stage, promoting patient self-sufficiency, and strategies for meeting the needs of families. A family-centered care approach is recommended. PMID- 22830511 TI - Changes in stress and coping during late childhood and preadolescence. AB - PROBLEM: Little is known about what produces stress in preadolescents. METHODS: Secondary data analysis using hierarchical linear modeling was performed to determine how stressors and coping changed over time in 1,568 preadolescents (51% Hispanic) in 28 public schools. FINDINGS: Over time, participants experienced most stressors less intensely, but intensity varied by gender. Children in lower grades and girls found that coping strategies used were more effective compared with those in upper grades or boys. There were several interactions of grade level, sex, and ethnicity. CONCLUSION: Changes in stress and coping among preadolescents have implications for nurses concerned with mental health. PMID- 22830512 TI - Autism and the cognitive processing triad: a case for revising the criteria in the diagnostic and statistical manual. AB - TOPIC: The next iteration of the Diagnostic and Statistical Manual of Mental Disorders is due for release in May 2013. The current diagnostic criteria for autism are based on a behavioral triad of impairment, which has been helpful for diagnosis and identifying the need for intervention, but is not useful with regard to developing interventions. Revised diagnostic criteria are needed to better inform research and therapeutic intervention. PURPOSE: This article examines the research underpinning the behavioral triad of impairment to consider alternative explanations and a more useful framing for diagnosis and intervention. SOURCES: Contemporary research and literature on autism were used in this study. CONCLUSIONS: It is proposed that the cognitive processing triad of impaired abstraction, impaired theory of mind, and impaired linguistic processing become the triad of impairment for autism in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. These are investigable at the diagnostic level and can usefully inform intervention. Further, in addressing the debate on whether restrictive and repetitive behavior should remain central to diagnosis or be replaced by a deficit in imagination, the authors argue that both behavioral manifestations are underpinned by impaired abstraction. PMID- 22830513 TI - Ambiguity and violence in adolescent dating relationships. AB - PROBLEM: Little is known about dyadic processes that lead to adolescent dating violence. The purpose of this study was to examine the phenomenon of relationship ambiguity in adolescent dating relationships to better understand how ambiguity contributes to violence and aggression between dating partners. METHODS: Data were drawn from 88 narratives of young adults who had participated in a study on adolescent dating violence. Interpretive phenomenology was used to produce an in depth description of the phenomenon of relationship ambiguity. FINDINGS: Relationship ambiguity results in differing expectations between partners regarding closeness and intimacy, fidelity, and obligation. These differences lead to conflicts that set the stage for violence and aggression in adolescent dating relationships. CONCLUSIONS: A series of recommendations for clinicians working with adolescents are presented. PMID- 22830514 TI - Developing schools' capacities to respond to community crisis: the Tennessee initiative. AB - TOPIC: The development and implementation of a statewide initiative addressing mental health issues within schools postcrisis. PURPOSE: The potential for a community crisis occurs every day. After a crisis, schools are practical, logical, and effective places to help students recover from a tragedy. If crisis related trauma is not addressed adequately, it can impact academic outcomes such as reading achievement, grade point average, and overall academic performance. For these reasons, it is imperative that school administrators support students in the aftermath of a crisis. CONCLUSIONS: This ongoing project continues in an effort to support students, faculty, and staff after a traumatic event within the Tennessee public school system. PMID- 22830515 TI - Is financial gain to blame for the growing ADHD epidemic? PMID- 22830516 TI - Controlled positioning of nanoparticles on graphene by noninvasive AFM lithography. AB - Atomic force microscopy is shown to be an excellent lithographic technique to directly deposit nanoparticles on graphene by capillary transport without any previous functionalization of neither the nanoparticles nor the graphene surface while preserving its integrity and conductivity properties. Moreover this technique allows for (sub)micrometric control on the positioning thanks to a new three-step protocol that has been designed with this aim. With this methodology the exact target coordinates are registered by scanning the tip over the predetermined area previous to its coating with the ink and deposition. As a proof-of-concept, this strategy has successfully allowed the controlled deposition of few nanoparticles on 1 MUm(2) preselected sites of a graphene surface with high accuracy. PMID- 22830517 TI - Lidocaine/tetracaine peel in topical anesthesia prior to laser-assisted hair removal: Phase-II and Phase-III study results. AB - BACKGROUND: Patient comfort is essential during dermatologic procedures. OBJECTIVES: To evaluate anesthetic efficacy in laser-assisted hair removal of a self-occluding topical anesthetic (lidocaine 70 mg/g and tetracaine 70 mg/g, "LT peel"), which air-dries and can be peeled off 30 min post-application. METHODS: Studies A (Phase-II) and B (Phase-III) were randomized, double-blind, placebo controlled and paired. Applications of LT peel and placebo were concurrent: in Study A, 60 subjects were randomized to 30, 45, or 60-min groups, and in Study B, 50 subjects had 30-min applications. After drug removal, the investigator assessed for erythema, edema, and blanching. Efficacy evaluations followed the procedure: subject's pain [Visual Analog Scale (VAS), no to worst pain (0 - 100)], subject's/investigator's impression of anesthetic adequacy, and investigator's pain ratings. Adverse events (AEs) were recorded. RESULTS: VAS scores were significantly lower (p < 0.05) for LT peel: mean scores were 26.7 for LT Peel vs. 44.3 for placebo (Study A total population, similar between application times) and 23 vs. 31.7 (Study B), respectively. For both studies, subject's/investigator's ratings favored LT peel (p < 0.05 vs. placebo). Mild skin reactions occurred more frequently for LT peel. CONCLUSIONS: After a 30-min application, LT peel was effective and well-tolerated in providing anesthesia for laser-assisted hair removal. PMID- 22830518 TI - Cardiac implantable electronic device-related endocarditis: a 12-year single centre experience. AB - BACKGROUND: The incidence of cardiac implantable electrical device endocarditis (CIEDE) is increasing, but CIEDE remains a relatively poorly described infection. This case series describes our experience of the condition at a tertiary referral centre in London over a 12-y period. METHODS: We identified cases using an endocarditis database containing prospectively collected clinical and microbiological information. We also used data recorded in an electronic database of all cardiac implantable electrical device-related procedures. RESULTS: Thirty cases of CIEDE were treated at our institution during the study period. Presentation was most commonly with fever, and 93% of our patients had positive blood cultures. Vegetations were identified on echocardiography in only 70% of patients, although a transoesophageal echocardiogram (TOE) was performed in only half of the cases. Sixty-seven percent of our cases were defined as definite endocarditis according to the modified Duke criteria for infective endocarditis. Twenty-three patients underwent percutaneous explantation of their infected CIED (including 6 patients with vegetations greater than 10 mm in diameter), while 5 underwent surgical explantation. The overall in-hospital mortality was 17%. CONCLUSIONS: Our data confirm the life-threatening nature of CIEDE in a UK population. In addition, our experience suggests that percutaneous extraction of devices with large adherent vegetations may be safe, and that the selective use of TOE may not compromise outcomes. Lastly, we show that the modified Duke criteria do not perform very well with this condition, suggesting a need for specific, validated criteria for diagnosing CIEDE. PMID- 22830519 TI - The role of fitness in the association between fatness and cardiometabolic risk from childhood to adolescence. AB - BACKGROUND: Fatness and fitness both influence cardiometabolic risk. OBJECTIVE: The purpose of this study was to investigate whether childhood fatness and increasing fatness from childhood to adolescence are associated with cardiometabolic risk during adolescence and how fitness affects this association. SUBJECTS AND METHODS: Of 565 adolescents (283 boys and 282 girls) from the TRacking Adolescents Individual Life Survey (TRAILS) data on anthropometric parameters (age 11 and 16), metabolic parameters, and fitness (age 16) were available. Body mass index and skinfolds were used as measures for fatness. Increasing fatness was calculated by subtracting Z-scores for fatness at age 11 from Z-score fatness at age 16. Cardiometabolic risk was calculated as the average of the standardized means of mean arterial pressure, fasting serum triglycerides, high-density lipoprotein-cholesterol, glucose, and waist circumference. Insulin resistance was calculated by homeostasis model assessment insulin resistance (HOMA-IR). Fitness was estimated as maximal oxygen consumption (VO(2) max) during a shuttle run test. RESULTS: Boys showed a higher clustered cardiometabolic risk when compared to girls (p < 0.01). Childhood fatness (age 11) and increasing fatness were independently associated with cardiometabolic risk during adolescence. In boys, high fitness was related to a reduced effect of increasing fatness on clustered cardiometabolic risk. Childhood fatness, increasing fatness, and fitness were independently associated with HOMA-IR. Moreover, in boys this association was dependent of fatness. CONCLUSIONS: Childhood fatness and increasing fatness are associated with increased cardiometabolic risk and HOMA-IR during adolescence, but a good fitness attenuates this association especially in fat boys. PMID- 22830520 TI - Interaction between the heme and a G-quartet in a heme-DNA complex. AB - The structure of a complex between heme(Fe(3+)) and a parallel G-quadruplex DNA formed from a single repeat sequence of the human telomere, d(TTAGGG), has been characterized by (1)H NMR. The study demonstrated that the heme(Fe(3+)) is sandwiched between the 3'-terminal G-quartets of the G-quadruplex DNA. Hence, the net +1 charge of the heme(Fe(3+)) in the complex is surrounded by the eight carbonyl oxygen atoms of the G-quartets. Interaction between the heme Fe(3+) and G-quartets in the complex was clearly manifested in the solvent (1)H/(2)H isotope effect on the NMR parameters of paramagnetically shifted heme methyl proton signals, and interaction of the heme Fe(3+) with the eight carbonyl oxygen atoms of the two G-quartets was shown to provide a strong and axially symmetric ligand field surrounding the heme Fe(3+), yielding a heme(Fe(3+)) low-spin species with a highly symmetric heme electronic structure. This finding provides new insights as to the design of the molecular architecture and functional properties of various heme-DNA complexes. PMID- 22830521 TI - Ab initio reaction kinetics of hydrogen abstraction from methyl formate by hydrogen, methyl, oxygen, hydroxyl, and hydroperoxy radicals. AB - Combustion of renewable biofuels, including energy-dense biodiesel, is expected to contribute significantly toward meeting future energy demands in the transportation sector. Elucidating detailed reaction mechanisms will be crucial to understanding biodiesel combustion, and hydrogen abstraction reactions are expected to dominate biodiesel combustion during ignition. In this work, we investigate hydrogen abstraction by the radicals H., CH(3)., O., HO(2)., and OH. from methyl formate, the simplest surrogate for complex biodiesels. We evaluate the H abstraction barrier heights and reaction enthalpies, using multireference correlated wave function methods including size-extensivity corrections and extrapolation to the complete basis set limit. The barrier heights predicted for abstraction by H., CH(3)., and O. are in excellent agreement with derived experimental values, with errors <=1 kcal/mol. We also predict the reaction energetics for forming reactant complexes, transition states, and product complexes for reactions involving HO(2). and OH.. High-pressure-limit rate constants are computed using transition state theory within the separable hindered-rotor approximation for torsions and the harmonic oscillator approximation for other vibrational modes. The predicted rate constants differ significantly from those appearing in the latest combustion kinetics models of these reactions. PMID- 22830523 TI - Retinal angiomatous proliferation responds safely to a double dose (1.0 mg) of ranibizumab. AB - A 77-year-old man presented with sudden foggy central vision in the right eye. The visual acuity (VA) was 6/60 (R) and 6/6 (L). Funduscopy revealed superficial macular haemorrhage in the right eye. Using fluorescein angiography and indocyanine green angiography, retinal angiomatous proliferation was confirmed. Two intra-vitreal injections of bevacizumab were given but the VA did not improve. Following this, he received an intra-vitreal injection of ranibizumab. Regression of the retinal angiomatous proliferation was observed and the VA of the right eye returned to 6/10. Simultaneously, his left eye suffered from sudden visual loss and retinal angiomatous proliferation was diagnosed. Three intra vitreal injections of ranibizumab were given. Regression of the retinal angiomatous proliferation was observed and the VA of the left eye was stabilised. Another 80-year-old man complained of sudden distorted vision in his left eye. Funduscopy and optical coherence tomography (OCT) revealed superficial macular haemorrhage and retinal pigment epithelial detachment (RPED). The VA was 6/12 and retinal angiomatous proliferation was diagnosed. He received an intra-vitreous injection of bevacizumab followed by photodynamic therapy (PDT). The RPED was resolved; however, the VA dropped to 2/60. Optical coherent tomography, fluorescein angiography and indocyanine green angiography were used to indentify retinal angiomatous proliferation. Intra-vitreal injection(s) of a double dose (1 mg) of ranibizumab is a worthwhile treatment, as it can stabilise and even improve the VA without significant side effects. PMID- 22830524 TI - Short-term postoperative non-supine positioning versus strict face-down positioning in macular hole surgery. AB - PURPOSE: The purpose of this study was to compare the efficacy of short-term non supine positioning (NSP) and strict face-down positioning (FDP) in the repair of macular hole (MH). METHODS: We retrospectively reviewed all MH repairs over a 27 month period (2008-2010). Inclusion criteria were idiopathic full thickness stage 2-4 MH treated by a single surgeon with 23-gauge pars plana vitrectomy, internal limiting membrane peeling and gas tamponade, followed by postoperative short-term NSP (for 5 days) or strict FDP (for 3-4 days). NSP was achieved by fastening a tennis ball to the back of the nightshirt. Outcome measures were anatomical MH closure verified by optical coherence tomography and postoperative visual acuity. RESULTS: A total of 67 eyes (64 patients) met the inclusion criteria. The median follow-up period was 6.6 months (range, 4.7-19.8 months). The closure rates following a single operation were 30/33 (90.9%) in the FDP group, and 31/34 (91.2%) in the NSP group, respectively (p = 0.97). The FDP group improved 2.9 ETDRS lines, and 23 eyes (69.7%) gained two or more ETDRS lines. The NSP group improved 2.7 ETDRS lines (p = 1.00), and 25 eyes (73.5%) gained two or more ETDRS lines. The closure rates in the MH subgroup with diameters larger than 400 MUm were 20/23 (87.0%) and 15/17 (88.2%) in the FDP group and the NSP group, respectively (p = 0.96). CONCLUSION: The study indicates that short-term NSP is equally effective as strict FDP in the repair of MH. Contrary to previous reports, even large MH did not seem to benefit from FDP. PMID- 22830525 TI - Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats. AB - BACKGROUND: Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes. Although mild or moderate hypoglycemia is not life-threatening, if recurrent, it may cause cognitive impairment. In the present study, we sought to determine whether R/M hypoglycemia leads to neuronal death, dendritic injury, or cognitive impairment. METHODS: The experiments were conducted in normal and in diabetic rats. Rats were subjected to moderate hypoglycemia by insulin without anesthesia. Oxidative stress was evaluated by 4-Hydroxy-2-nonenal immunostaining and neuronal death was determined by Fluoro-Jade B staining 7 days after R/M hypoglycemia. To test whether oxidative injury caused by NADPH oxidase activation, an NADPH oxidase inhibitor, apocynin, was used. Cognitive function was assessed by Barnes maze and open field tests at 6 weeks after R/M hypoglycemia. RESULTS: The present study found that oxidative injury was detected in the dendritic area of the hippocampus after R/M hypoglycemia. Sparse neuronal death was found in the cortex, but no neuronal death was detected in the hippocampus. Significant cognitive impairment and thinning of the CA1 dendritic region was detected 6 weeks after hypoglycemia. Oxidative injury, cognitive impairment, and hippocampal thinning after R/M hypoglycemia were more severe in diabetic rats than in non diabetic rats. Oxidative damage in the hippocampal CA1 dendritic area and microglial activation were reduced by the NADPH oxidase inhibitor, apocynin. CONCLUSION: The present study suggests that oxidative injury of the hippocampal CA1 dendritic region by R/M hypoglycemia is associated with chronic cognitive impairment in diabetic patients. The present study further suggests that NADPH oxidase inhibition may prevent R/M hypoglycemia-induced hippocampal dendritic injury. PMID- 22830526 TI - A novel mass assay to quantify the bioactive lipid PtdIns3P in various biological samples. AB - PtdIns3P is recognized as an important player in the control of the endocytotic pathway and in autophagy. Recent data also suggest that PtdIns3P contributes to molecular mechanisms taking place at the plasma membrane and at the midbody during cytokinesis. This lipid is present in low amounts in mammalian cells and remains difficult to quantify either by traditional techniques based on radiolabelling followed by HPLC to separate the different phosphatidylinositol monophosphates, or by high-sensitive liquid chromatography coupled to MS, which is still under development. In the present study, we describe a mass assay to quantify this lipid from various biological samples using the recombinant PtdIns3P 5-kinase, PIKfyve. Using this assay, we show an increase in the mass level of PtdIns3P in mouse and human platelets following stimulation, loss of this lipid in Vps34-deficient yeasts and its relative enrichment in early endosomes isolated from BHK cells. PMID- 22830527 TI - Effects of tendon viscoelasticity in Achilles tendinosis on explosive performance and clinical severity in athletes. AB - The aim was to compare viscoelastic properties of Achilles tendons between legs in elite athletes with unilateral tendinosis, and to investigate relationships between the properties and explosive performance and clinical severity. Seventeen male athletes (mean +/- standard deviation age, 27.3 +/- 2.0 years) who had unilateral, chronic middle-portion tendinopathy of the Achilles tendon were assessed by the Victorian Institute of Sport Assessment questionnaire, measurements of tendon viscoelastic properties, voluntary electromechanical delay (EMD), normalized rate of force development (RFD), and one-leg hopping distance. Compared with the non-injured leg, the tendinopathic leg showed reduced tendon stiffness (-19.2%. P < 0.001), greater mechanical hysteresis (+21.2%, P = 0.004), lower elastic energy storage and release (-14.2%, P = 0.002 and -19.1%, P < 0.001), lower normalized RFD at one-fourth (-16.3%, P = 0.02), 2/4 (-17.3%, P = 0.006), and three-fourths maximal voluntary contraction (-13.7%, P = 0.02), longer soleus and medial gastrocnemius voluntary EMD (+26.9%, P = 0.009 and +24.0%, P = 0.004), and shorter hopping distances (-34.1%, P < 0.001). Tendon stiffness was correlated with normalized RFD, voluntary EMD in the medial gastrocnemius, and hopping distances (r ranged from -0.35 to 0.64, P < 0.05). Hysteresis was correlated to the soleus voluntary EMD and hopping distances (r = 0.42 and -0.39, P < 0.05). We concluded that altered tendon viscoelastic properties in Achilles tendinosis affect explosive performance in athletes. PMID- 22830529 TI - Interprofessional education in the USA: current activities and future directions. PMID- 22830528 TI - A multi-level analysis of the relationship between environmental factors and questing Ixodes ricinus dynamics in Belgium. AB - BACKGROUND: Ticks are the most important pathogen vectors in Europe. They are known to be influenced by environmental factors, but these links are usually studied at specific temporal or spatial scales. Focusing on Ixodes ricinus in Belgium, we attempt to bridge the gap between current "single-sided" studies that focus on temporal or spatial variation only. Here, spatial and temporal patterns of ticks are modelled together. METHODS: A multi-level analysis of the Ixodes ricinus patterns in Belgium was performed. Joint effects of weather, habitat quality and hunting on field sampled tick abundance were examined at two levels, namely, sampling level, which is associated with temporal dynamics, and site level, which is related to spatial dynamics. Independent variables were collected from standard weather station records, game management data and remote sensing based land cover data. RESULTS: At sampling level, only a marginally significant effect of daily relative humidity and temperature on the abundance of questing nymphs was identified. Average wind speed of seven days prior to the sampling day was found important to both questing nymphs and adults. At site level, a group of landscape-level forest fragmentation indices were highlighted for both questing nymph and adult abundance, including the nearest-neighbour distance, the shape and the aggregation level of forest patches. No cross-level effects or spatial autocorrelation were found. CONCLUSIONS: Nymphal and adult ticks responded differently to environmental variables at different spatial and temporal scales. Our results can advise spatio-temporal extents of environment data collection for continuing empirical investigations and potential parameters for biological tick models. PMID- 22830530 TI - Attitudes of medical school deans toward interprofessional education in Western Pacific Region countries. AB - To examine the attitudes of medical school deans toward interprofessional education (IPE) and collaborative practice (CP), we conducted survey research in the Western Pacific Region. This regional survey was conducted as a collaborative research project with the World Health Organization. A survey was distributed to the medical school deans in Malaysia, the Philippines, Republic of Korea and Japan. Thirty-five surveys were returned from four countries. The survey demonstrated that many medical school deans have positive attitudes toward IPE and CP. However, respondents also reported that it is not easy to introduce interprofessional learning in their academic settings. It is suggested that collaboration between education systems and health systems is needed to introduce IPE in the academic setting. The possible role of international organizations is mentioned. This information helps to identify local efforts on which global health organizations and national governments can build. PMID- 22830531 TI - "Understanding where you're coming from": discovering an [inter]professional identity through becoming a peer facilitator. AB - Peer facilitation offers an innovative and effective means of promoting interprofessional learning (IPL) between health and social care students. This paper highlights the benefits that peer facilitators themselves experience from involvement in assisting junior colleagues to engage with IPL in an online context. The setting for the inquiry is an online interprofessional learning pathway shared by two higher education institutions in the UK. Insights have been developed over a 3-year period through collaborative inquiry with 41 peer facilitators, academic tutors and the students who benefitted from their input. This paper which focuses on peer facilitators' application data, interview data and written reflections explores the instrumental, cognitive and personal gains experienced. However, more fundamentally, theorizing findings in relation to identity theory we substantiate the claim that the role provides opportunity for testing and refining important aspects of both professional and interprofessional identities. PMID- 22830532 TI - Interprofessional non-technical skills for surgeons in disaster response: a qualitative study of the Australian perspective. AB - Interprofessional non-technical skills for surgeons in disaster response have not yet been developed. The aims of this study were to identify the non-technical skills required of surgeons in disaster response and training for disaster response and to explore the barriers and facilitators to interprofessional practice in surgical teams responding to disasters. Twenty health professionals, with prior experience in natural disaster response or education, participated in semi-structured in-depth interviews. A qualitative matrix analysis design was used to thematically analyze the data. Non-technical skills for surgeons in disaster response identified in this study included skills for austere environments, cognitive strategies and interprofessional skills. Skills for austere environments were physical self-care including survival skills, psychological self-care, flexibility, adaptability, innovation and improvisation. Cognitive strategies identified in this study were "big picture" thinking, situational awareness, critical thinking, problem solving and creativity. Interprofessional attributes include communication, team-player, sense of humor, cultural competency and conflict resolution skills. "Interprofessionalism" in disaster teams also emerged as a key factor in this study and incorporated elements of effective teamwork, clear leadership, role adjustment and conflict resolution. The majority of participants held the belief that surgeons needed training in non-technical skills in order to achieve best practice in disaster response. Surgeons considerring becoming involved in disaster management should be trained in these skills, and these skills should be incorporated into disaster preparation courses with an interprofessional focus. PMID- 22830533 TI - Inappropriate prescribing for older people admitted to an intermediate-care nursing home unit and hospital wards. AB - OBJECTIVE: To identify inappropriate prescribing among older patients on admission to and discharge from an intermediate-care nursing home unit and hospital wards, and to compare changes during stay within and between these groups. DESIGN: Observational study. SETTING AND SUBJECTS: Altogether 400 community-dwelling people aged >= 70 years, on consecutive emergency admittance to hospital wards of internal medicine and orthopaedic surgery, were randomized to an intermediate-care nursing home unit or hospital wards; 290 (157 at the intermediate-care nursing home unit and 133 in hospital wards) were eligible for this sub-study. MAIN OUTCOME MEASURES: Prevalence on admission and discharge of potentially inappropriate medications (Norwegian general practice [NORGEP] criteria) and drug-drug interactions; changes during stay. RESULTS: The mean (SD) age was 84.7 (6.2) years; 71% were women. From admission to discharge, the mean numbers of drugs prescribed per person increased from 6.0 (3.3) to 9.3 (3.8), p < 0.01. The prevalence of potentially inappropriate medications increased from 24% to 35%, p < 0.01; concomitant use of >= 3 psychotropic/opioid drugs and drug combinations including non-steroid anti-inflammatory drugs (NSAIDs) increased significantly. Serious drug-drug interactions were scarce both on admission and discharge (0.7%). CONCLUSIONS: Inappropriate prescribing was prevalent among older people acutely admitted to hospital, and the prevalence was not reduced during stay at an intermediate-care nursing home unit specially designed for these patients. PMID- 22830534 TI - Bariatric surgery for adolescents. AB - Obesity is no longer just an adult disease. An increasing number of youth are overweight, defined as body mass index (BMI) at or greater than the 95th percentile for age (1). Between 2009 and 2010, 16.9% of children aged 2-19 yr were classified as overweight based on BMI (2), as compared with only 5% of children affected by obesity in 1976-1980 (3). This is a problem of enormous proportion from a public health standpoint, as without intervention these children will grow up to become overweight and obese adults. For an obese child, the risk of becoming an obese adult may be as high as 77%, compared with 7%for a child of healthy weight (4). Morbid obesity is a major risk factor for later complications such as cardiovascular disease, type 2 diabetes, obstructive sleep apnea (OSA), polycystic ovary syndrome (PCOS), and degenerative joint disease (4 10). Obesity is also an expensive problem: the US government spends $147 billion yearly on obesity-related healthcare costs (11). Thus, there is an urgent need to target obesity in the pediatric population, before the expensive and life threatening consequences of obesity manifest. Unfortunately, the effectiveness of medical treatments for obesity is limited. Behaviorally based dietary and physical activity interventions offer little benefit for pediatric obesity, while pharmacologic therapy is also limited and carries low success rates and recidivism (12-14) (Table 1). PMID- 22830535 TI - Prognostic accuracy of five simple scales in childhood bacterial meningitis. PMID- 22830536 TI - Docking simulation study and kinase selectivity of f152A1 and its analogs. AB - f152A1 is a potent inhibitor of MAP kinases and TNFalpha-transcription. When f152A1 and its analogs are assayed against ERK2, MEK1, and MEKK1, these compounds show different inhibition profiles. It is considered that the highly reactive cis enone moiety and modifications of the 14-membered resorcylic lactone ring may determine their kinase selectivity and potency. In order to clarify the different potencies of these compounds toward MAP kinases, conformational analysis, molecular orbital studies, and docking simulation studies using model structures of ERK2, MEK1, and MEKK1 have been performed. These studies have revealed that (i) ligand binding does not depend on chemical bonding but on molecular interaction (molecular orbital analysis), (ii) the cis-enone moiety of inhibitors is in the range of Michael addition reaction with the Cys166 residue in ERK2 (docking simulation study), and (iii) molecular shape of M1(8) conformations is the best fit for the ATP binding site of kinases. Considering the molecular docking analysis of these inhibitors in these kinases, molecular shape will be most important to their corresponding kinases activities. PMID- 22830537 TI - Effect of surface treatments on microtensile bond strength of repaired aged silorane resin composite. AB - OBJECTIVE: This laboratory study compared the repaired microtensile bond strengths of aged silorane resin composite using different surface treatments and either silorane or methacrylate resin composite. METHODS: One hundred eight silorane resin composite blocks (Filtek LS) were fabricated and aged by thermocycling between 8 degrees C and 48 degrees C (5000 cycles). A control (solid resin composite) and four surface treatment groups (no treatment, acid treatment, aluminum oxide sandblasting, and diamond bur abrasion) were tested (N=12 blocks, 108 beams/group). Each treatment group was randomly divided in half and repaired with either silorane resin composite (LS adhesive) or methacrylate resin composite (Filtek Z250/Single Bond Plus). After 24 hours in 37 degrees C distilled water, microtensile bond strength testing was performed using a non trimming technique. Surface topography after surface treatment was analyzed using scanning electron microscopy (SEM). Failure mode was examined using optical microscopy (50*). RESULTS: Weibull-distribution survival analysis revealed that aluminum oxide sandblasting followed by silorane or methacrylate resin composite and acid treatment with methacrylate resin composite provided insignificant differences from the control (p>0.05). All other groups were significantly lower than the control. Failure was primarily adhesive in all groups. CONCLUSION: Aluminum oxide sandblasting produced microtensile bond strength not different from the cohesive strength of silorane resin composite. After aluminum oxide sandblasting, aged silorane resin composite can be repaired with either silorane resin composite with LS system adhesive or methacrylate resin composite with methacrylate dental adhesive. PMID- 22830538 TI - Observation of an organic acid mediated spin state transition in a Co(II)-Schiff base complex: an EPR, HYSCORE, and DFT study. AB - The interactions of a weak organic acid (acetic acid, HOAc) with a toluene solution of the Co(II)-Schiff base type complex, (R,R')-N,N'-bis(3,5-di-tert butylsalicylidene)-1,2-cyclohexane-diamino Co(II) (labeled [Co(1)]), was investigated using EPR, HYSCORE, and DFT computations. This activated [Co(II)(1)] system is extremely important within the context of asymmetric catalysts (notably the hydrolytic kinetic resolution of epoxides) despite the lack of detailed structural information about the nature of the paramagnetic species present. Under anaerobic conditions, the LS [Co(II)(1)] complex with a |yz, (2)A(2)> ground state is converted into a low-spin (LS) and a high-spin (HS) complex in the presence of the acid. The newly formed LS state is assigned to the coordinated [Co(II)(1)]-(HOAc) complex, possessing a |z(2), (2)A(1)> ground state (species A; g(x) = 2.42, g(y) = 2.28, g(z) = 2.02, A(x) = 100, A(y) = 120, A(z) = 310 MHz). The newly formed HS state is assigned to an acetate coordinated [Co(II)(1)]-(OAc(-)) complex, possessing an S = 3/2 spin ground state (species B, responsible for a broad EPR signal with g ~ 4.6). These spin ground states were confirmed with DFT calculations using the hybrid BP86 and B3LYP functionals. Under aerobic conditions, the LS and HS complexes (species A and B) are not observed; instead, a new HS complex (species C) is formed. This complex is tentatively assigned to a paramagnetic superoxo bridged dimer (AcO( ))[Co(II)(1)...O(2)(-)Co(III)(1)](HOAc), as distinct from the more common diamagnetic peroxo bridged dimers. Species C is characterized by a very broad HS EPR signal (g(x) = 5.1, g(y) = 3.9, g(z) = 2.1) and is reversibly formed by oxygenation of the LS [Co(II)(1)]-(HOAc) complex to the superoxo complex [Co(III)(1)O(2)(-)](HOAc), which subsequently forms the association complex C by interaction with the HS [Co(II)(1)](OAc(-)) species. The LS and HS complexes were also identified using other organic acids (benzoic and propanoic acid). Thermal annealing-quenching experiments revealed the additional presence of [Co(III)(1)O(2)(-)](HOAc) adducts, corroborating the presence of species C and the presence of diamagnetic dimer complexes in the solution, such as the EPR silent (HOAc)[Co(III)(1)(O(2)(2-))Co(III)(1)](HOAc). Overall, it appears that a facile interconversion of the [Co(1)] complex, possessing a LS ground state, occurs in the presence of acetic acid, producing both HS and LS Co(II) states, prior to formation of the oxidized active form of the catalyst, [Co(III)(1)](OAc( )). PMID- 22830539 TI - Medication coaching program for patients with minor stroke or TIA: a pilot study. AB - BACKGROUND: Patients who are hospitalized with a first or recurrent stroke often are discharged with new medications or adjustment to the doses of pre-admission medications, which can be confusing and pose safety issues if misunderstood. The purpose of this pilot study was to assess the feasibility of medication coaching via telephone after discharge in patients with stroke. METHODS: Two-arm pilot study of a medication coaching program with 30 patients (20 intervention, 10 control). Consecutive patients admitted with stroke or TIA with at least 2 medications changed between admission and discharge were included. The medication coach contacted intervention arm patients post-discharge via phone call to discuss risk factors, review medications and triage patients' questions to a stroke nurse and/or pharmacist. Intervention and control participants were contacted at 3 months for outcomes. The main outcomes were feasibility (appropriateness of script, ability to reach participants, and provide requested information) and participant evaluation of medication coaching. RESULTS: The median lengths of the coaching and follow-up calls with requested answers to these questions were 27 minutes and 12 minutes, respectively, and participant evaluations of the coaching were positive. The intervention participants were more likely to have seen their primary care provider than were control participants by 3 months post discharge. CONCLUSIONS: This medication coaching study executed early after discharge demonstrated feasibility of coaching and educating stroke patients with a trained coach. Results from our small pilot showed a possible trend towards improved appointment-keeping with primary care providers in those who received coaching. PMID- 22830540 TI - High production of interleukin-10 and interferon-gamma in influenza-associated MERS in the early phase. AB - Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) occurs in various diseases and pathologies, and the clinical symptoms are not consistent with the impaired region. The mechanism of the region specificity is unclear. We investigated the cytokine profiling in cerebrospinal fluid (CSF) and serum obtained from a child with MERS during influenza infection, and compared them with those of serious another serious type of influenza-associated encephalopathy. There was no elevation of Interleukin (IL)-1beta, which induces convulsion. The inhibitory cytokines of IL-10 and IFN-gamma were elevated in the early phase in CSF. Comparing them with other patients, the elevation of the cytokine levels were generally mild. Considering that the prognosis of this MERS case was favorable and high levels of inhibitory cytokines including IL-10 and IFN-gamma might work to localize the lesion and to prevent sequelae. PMID- 22830541 TI - Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine. AB - Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the central nervous system. We describe a previously healthy 2-year old boy with ADEM, who exhibited high fever, lethargy, and recurrent seizures at 25 days after H1N1 influenza vaccination. To our knowledge, there has been only one report of ADEM following the 2009 H1N1 influenza vaccine, although such vaccination is accompanied with optic neuritis apart from this case. Thus, this is the first case of ADEM without optic neuritis, following the 2009 H1N1 influenza vaccination. Although vaccine-associated ADEM remains rare, the increasing number of influenza vaccinations might increase the incidence of ADEM. We still need to pay attention to the occurrence of ADEM and treat patients with steroid therapy. PMID- 22830542 TI - Microscopic polyangiitis in a girl with severe anemia and no respiratory symptoms. AB - ANCA-positive microscopic polyangiitis is a rare in children. We reported an 11 year-old girl without respiratory symptoms with sever anemia which shows signs of hemolytic anemia in test data. Chest X-ray and computed tomography scans suggested alveolar hemorrhage. The patent developed night hypoxia and moderate proteinuria. Serum MPO-antibody was highly positive and renal biopsy demonstrated segmental necrosis or crescent formation. A diagnosis of microscopic polyangiitis was made. She responded to pulsed methylprednisolon and pulsed Endoxan therapy. Microscopic polyangitiis should be considered early in the differential diagnosis of patients presenting with anemia of an unknown origin. PMID- 22830543 TI - Hyper-eosinophilia in granular acute B-cell lymphoblastic leukemia with myeloid antigen expression. AB - Acute lymphoblastic leukemia with eosinophilia (ALLEo) is a rare but a distinctive clinical entity. Clinical features of idiopathic hyper-eosinophilic syndrome (HES) can be seen in patients with ALLEo. We report a 10-year-old girl, in whom HES was initially suspected but further investigation confirmed the diagnosis of acute B-cell lymphoblastic leukemia with myeloid antigen expression. Clinical response to chemotherapy was excellent with achievement of complete remission for 4 years. Serum interleukin-3 and -5 were elevated at presentation and normalized with disappearance of eosinophilia after induction therapy, supporting the reactive nature of eosinophilia in ALLEo. Hematologic malignancy should be considered in patients with hyper-eosinophilia, before attributing it to HES. PMID- 22830544 TI - Atomoxetine improves communication in a girl with semantic-pragmatic disorder. AB - This report describes the case of an ADHD girl (hereafter referred to as K) with semantic-pragmatic disorder, she was treated with atomoxetine. K was a 9-year-old girl. She had difficulty understanding words or sentences, finding words, and producing sentences. K also displayed symptoms of severe inattentiveness. K was diagnosed with DSM-IV-defined(1) ADHD, predominantly the inattentive type. Her communication impairment was considered symptomatic of semantic-pragmatic disorder. K was started on atomoxetine, the dose was increased to 50 mg/day (dosage based on weight: 1.8 mg/kg). Her communication activities were improved a few weeks after atomoxetine 50 mg/day was administered. She was unable to organize information pertaining to words, and so could not use words in expressive language. These problems were mitigated through the administration of atomoxetine. Further prospective studies are needed to better understand the therapeutic effects of atomoxetine in patients with semantic-pragmatic disorder. PMID- 22830545 TI - Nephrotic syndrome complicated by renal and cerebral infarctions in a 14-year-old girl. AB - Venous thrombosis is a well-known complication of nephrotic syndrome (NS), while arterial thrombosis is rare. We know of no reports of children with this complication. Here we report a case of 14-year-old girl with NS, who complicated with renal and cerebral infarctions resulting from arterial thrombosis. Urinary examination showed heavy proteinuria. She had intravascular dehydration. Serum albumin was 0.9 g/dL. Contrast-enhanced computed tomography (CT) showed a low attenuation area in the right kidney. Decreased blood flow in the right middle cerebral artery was observed on MRA and also on multi-detector-row head CT. Urokinase and heparin were given. Cerebral infarction was treated neuroprotectively by i.v. infusion of edaravone. Comprehensive assessment of intravascular dehydration and the coagulation-fibrinolysis system is needed to guide decisions concerning prophylactic anticoagulation therapy. Better understanding of NS and its risks, as well as the necessity of drug therapy, may help teenagers to accept and cooperate with treatment. PMID- 22830546 TI - Successful treatment of a patient with tumor necrosis factor receptor-associated periodic syndrome using a half-dose of etanercept. AB - TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations of TNFRSF1A gene and characterized by recurrent febrile episodes of prolonged duration and initial good response to steroids. Etanercept, a TNF blocker, has been used as a putative molecular-targeted agent for TRAPS, with some patients showing limited efficacy. Here, we report a patient with TRAPS who recovered from steroid dependency by etanercept and kept remission with a reduced dose of etanercept. The pathophysiology of TRAPS still remains to be elucidated and several hypotheses have been proposed. In the most recent hypothesis, the concerted action of wild-type and mutant TNF receptors plays an important role in provoking enhanced inflammation in TRAPS. The excellent response to etanercept in our patient suggested that there is heterogeneity in TRAPS patients in terms of the contribution of normal TNF signaling to autoinflammation. PMID- 22830548 TI - Myocarditis in a pediatric case of pandemic 2009H1N1 influenza. AB - We report a 6-year-old boy with no major disease history or allergic conditions initially presented with pneumonia, progressed to acute respiratory distress syndrome and acute myocarditis caused by pandemic 2009H1N1 influenza diagnosed with RT-PCR testing, successfully managed with mechanical ventilation and percutaneous cardiopulmonary support system. Marked transient elevation of IgE in acute phase of the disease and the subsequent diagnosis of atopic asthma in our patient suggested a possible role of an underlying allergic condition in the clinicopathological process. Critically ill 2009H1N1-infected patient with acute respiratory failure should carefully be physiologically monitored together with serial assessment of biomarkers aiming at a favorable cardiac outcome by giving the timely diagnosis and intervention. PMID- 22830547 TI - Left atrium thrombus in an extremely low-birthweight infant with late-onset circulatory dysfunction. AB - A left atrium thrombus, potentially a life-threatening complication, is an extremely rare in early infancy. Most cases are caused by mal-placement of central venous catheters or related to congenital heart diseases with left atrial blood congestion. Here we present an extremely low birth weight infant who developed a left atrial thrombus during the course of late onset circulatory dysfunction. The thrombus was successfully treated by recombinant tissue plasminogen activator. A hemodynamically unstable condition like late onset circulatory dysfunction should be taken into consideration as a potential risk condition of this rare disease. PMID- 22830549 TI - Treat the patient not the X-ray! PMID- 22830550 TI - Chlamydia pneumoniae infection presenting with angioedema in an adolescent. PMID- 22830551 TI - Carotid artery thrombosis in a child with membranous nephropathy associated with factor V Leiden mutation. PMID- 22830552 TI - Inguinal ectopic scrotum in a neonate: case report and literature review. PMID- 22830553 TI - Respiratory papillomatosis primarily arising in the trachea. PMID- 22830554 TI - Anatomical condition mimicking superior mesenteric artery syndrome might cause duodenal involvement in Henoch-Schonlein purpura. PMID- 22830555 TI - Role of MRI and EEG in the initial evaluation of children with headaches. PMID- 22830556 TI - Advanced paternal age and impaired childhood cognitive development: Reply. PMID- 22830557 TI - Aminolysis of a model nerve agent: a computational reaction mechanism study of O,S-dimethyl methylphosphonothiolate. AB - The mechanism for the aminolysis of a model nerve agent, O,S-dimethyl methylphosphonothiolate, is investigated both at density functional level using M062X method with 6-311++G(d,p) basis set and at ab initio level using the second order Moller-Plesset perturbation theory (MP2) with the 6-311+G(d,p) basis set. The catalytic role of an additional NH(3) and H(2)O molecule is also examined. The solvent effects of acetonitrile, ethanol, and water are taken into account employing the conductor-like screening model (COSMO) at the single-point M062X/6 311++G(d,p) level of theory. Two possible dissociation pathways, methanethiol and methyl alcohol dissociations, along with two different neutral mechanisms, a concerted one and a stepwise route through two neutral intermediates, for each pathway are investigated. Hyperconjugation stabilization that has an effect on the stability of generated transition states are investigated by natural bond order (NBO) approach. Additionally, quantum theory of atoms in molecules analysis is performed to evaluate the bond critical (BCP) properties and to quantify strength of different types of interactions. The calculated results predict that the reaction of O,S-dimethyl methylphosphonothiolate with NH(3) gives rise to parallel P-S and P-O bond cleavages, and in each cleavage the neutral stepwise route is always favorable than the concerted one. The mechanism of NH(3) and H(2)O as catalyst is nearly similar, and they facilitate the shuttle of proton to accelerate the reaction. The steps involving the H(2)O-mediated proton transfer are the most suitable ones. The first steps for the stepwise process, the formation of neutral intermediate, are the rate-determining step. It is observed that in the presence of catalyst the reaction in the stepwise path possesses almost half the activation energy of the uncatalyzed one. A bond-order analysis using Wiberg bond indexes obtained by NBO calculation predicts that usually all individual steps of the reactions occur in a concerted fashion showing equal progress along different reaction coordinates. PMID- 22830559 TI - Spectral domain optical coherence tomography finding in posterior microphthalmos. AB - An eight-year-old boy presented with decreased vision in both eyes. At presentation, the visual acuity was 6/60 in both eyes with high plus spheres. Anterior segment examination was normal. Fundus examination and spectral domain optical coherence tomography were consistent with posterior microphthalmos and showed an elevated foveal contour and fold in the outer plexiform layer. External limiting membrane, photoreceptor and retinal pigment epithelium were not involved in the fold. To the best of our knowledge this is the first such case report with optical coherence tomography imaging of the retinal layer involved in a case of posterior microphthalmos. PMID- 22830560 TI - Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats. AB - BACKGROUND: In sepsis syndromes the severity of the inflammation triggers microvascular dysfunction and early organ failure. We studied the effects of anti inflammatory vagus nerve stimulation on the cerebral microcirculatory integrity in an endotoxinemic rat model. METHODS: In both control and endotoxinemic (5 mg/kg lipopolysaccharide i.v.) rats, the effect of cervical bilateral vagotomy with or without left-sided distal vagus nerve stimulation were compared to non vagotomized, nonstimulated group (sham). Neurovascular coupling was analyzed by electrical forepaw stimulation, EEG, and cortical laser-Doppler flow recording. Resting cerebral blood flow, evoked potentials and hemodynamic responses, were obtained over a period of 4.5 hours. Regulation of the nitric oxide system (iNOS expression and nitrite/nitrate measurements), cytokines (IFN-gamma, TNF-alpha, IL 6, IL-10), hypoxic and apoptosis signaling molecules (HIF-2alpha, Bax) were measured at the end of experiments. RESULTS: In endotoxinemic rats, vagus nerve stimulation tended to increase anti-inflammatory cytokine levels and resulted in a stabile hemodynamic response (28 +/- 13%; versus baseline). Vagotomized animals incurred a pro-inflammatory response (7 +/- 4%; P < 0.0001 versus baseline) and produced more HIF-2alpha than vagotomized vagus nerve stimulated (VNS) animals. Evoked potential amplitudes were stabilized in VNS (15 +/- 7 MUV; n.s. versus baseline) as compared to vagotomised rats (8 +/- 5 MUV; P < 0.001 versus baseline). However, no effects were observed on apoptosis markers or nitric oxide levels. CONCLUSIONS: Vagus nerve stimulation in endotoxinemic rats had a positive effect on neurovascular coupling and stabilized evoked potentials. PMID- 22830561 TI - Highly selective zeolite membranes as explosive preconcentrators. AB - Highly selective thin zeolite MFI membranes are synthesized on porous stainless steel and alpha-alumina supports using a seeded growth method. An ultraviolet (UV) light treatment is employed as a low temperature alternative to remove the organic structure-directing agent (SDA) to avoid membrane cracking. The feasibility of the use of the MFI membranes as an explosive preconcentrator is examined by measuring the permeation of nitrogen (N(2), an air surrogate) and 1,3,5-trimethylbenzene (TMB) (a 2,4,6-trinitrotoluene (TNT) surrogate) in a mixture of N(2) and TMB. High N(2)/TMB selectivity (>10,000) and reasonable N(2) flux (13.5 mmol/m(2).s) are observed. On the basis of the flux, a hollow fiber array based preconcentrator is proposed and estimated to provide 1000* concentration within about 1 min using a hollow fiber with a 50 MUm internal radius. This high performance explosive preconcentrator may open a new venue for the detection of subppb or lower level of explosives simply in conjunction with conventional explosives detectors. PMID- 22830563 TI - Switchable nonlinear optical properties of eta5-monocyclopentadienylmetal complexes: a DFT approach. AB - Density functional theory (DFT) calculations have been carried out to investigate the switching of the second-order nonlinear optical (NLO) properties of eta(5) monocyclopentadienyliron(II) and ruthenium(II) model complexes presenting 5-(3 (thiophen-2-yl)benzo[c]thiophen-1-yl)thiophene-2-carbonitrile as a ligand. The switching properties were induced by redox means. Both oxidation and reduction stimulus have been considered, and calculations have been performed both for the complexes and for the free benzo[c]thiophene derivative ligand in order to elucidate the role played by the organometallic fragment on the second-order NLO properties of these complexes. B3LYP, CAM-B3LYP, and M06 functionals were used for our calculations. The results show some important structural changes upon oxidation/reduction that are accompanied by significant differences on the corresponding second-order NLO properties. TD-DFT calculations show that these differences on the second-order NLO response upon oxidation/reduction are due to a change in the charge transfer pattern, in which the organometallic iron and ruthenium moieties play an important role. The calculated static hyperpolarizabilities were found to be strongly functional dependent. CAM-B3LYP, however, seems to predict more reliable structural and optical data as well as hyperpolarizabilities when compared to experimental data. The use of this functional predicts that the studied complexes can be viewed as acting as redox second-order NLO switches, in particular using oxidation stimulus. The beta(tot) value of one-electron oxidized species is at least ~8.3 times (for Ru complex) and ~5.5 times (for Fe complex) as large as that of its nonoxidized counterparts. PMID- 22830562 TI - Gesture's role in speaking, learning, and creating language. AB - When speakers talk, they gesture. The goal of this review is to investigate the contribution that these gestures make to how we communicate and think. Gesture can play a role in communication and thought at many timespans. We explore, in turn, gesture's contribution to how language is produced and understood in the moment; its contribution to how we learn language and other cognitive skills; and its contribution to how language is created over generations, over childhood, and on the spot. We find that the gestures speakers produce when they talk are integral to communication and can be harnessed in a number of ways. (a) Gesture reflects speakers' thoughts, often their unspoken thoughts, and thus can serve as a window onto cognition. Encouraging speakers to gesture can thus provide another route for teachers, clinicians, interviewers, etc., to better understand their communication partners. (b) Gesture can change speakers' thoughts. Encouraging gesture thus has the potential to change how students, patients, witnesses, etc., think about a problem and, as a result, alter the course of learning, therapy, or an interchange. (c) Gesture provides building blocks that can be used to construct a language. By watching how children and adults who do not already have a language put those blocks together, we can observe the process of language creation. Our hands are with us at all times and thus provide researchers and learners with an ever-present tool for understanding how we talk and think. PMID- 22830564 TI - Intranasal trigeminal chemosensitivity in patients with postviral and post traumatic olfactory dysfunction. AB - CONCLUSIONS: The olfactory and intranasal trigeminal systems are closely connected. With regard to intranasal trigeminal event-related potential (ERP), patients with olfactory dysfunction (OD) showed longer latency and lower amplitude, which indicated decreased trigeminal sensitivity. Different age, etiology, and olfactory status also affect trigeminal sensitivity differently. OBJECTIVE: OD is a common symptom in the rhinology clinic. ERP is considered an important method to evaluate chemosensitivity. The aim of this study was to investigate changes of intranasal trigeminal sense in patients with postviral OD (PVOD) and post-traumatic OD (PTOD). METHODS: A total of 96 participants (30 healthy adults and 66 patients with OD) aged 20-65 years were investigated. The T&T olfactometer, the Sniffin' Sticks olfactory test, and trigeminal ERPs (tERPs) were used. We evaluated trigeminal sensitivity influenced by different factors (age, etiology, and olfactory status) in healthy subjects with normal olfactory function and in patients with PVOD and PTOD. RESULTS: Patients with OD showed higher trigeminal thresholds than normal controls. Compared with controls, N1/P2 latencies of tERPs increased and amplitudes decreased in patients with OD. Older subjects showed longer latencies and lower amplitudes than young subjects in both controls and the OD group. Patients with PTOD exhibited worse psychophysical olfactory function and decreased trigeminal sensitivity. PMID- 22830565 TI - Zoonotic diseases associated with free-roaming cats. AB - Free-roaming cat populations have been identified as a significant public health threat and are a source for several zoonotic diseases including rabies, toxoplasmosis, cutaneous larval migrans because of various nematode parasites, plague, tularemia and murine typhus. Several of these diseases are reported to cause mortality in humans and can cause other important health issues including abortion, blindness, pruritic skin rashes and other various symptoms. A recent case of rabies in a young girl from California that likely was transmitted by a free-roaming cat underscores that free-roaming cats can be a source of zoonotic diseases. Increased attention has been placed on trap-neuter-release (TNR) programmes as a viable tool to manage cat populations. However, some studies have shown that TNR leads to increased immigration of unneutered cats into neutered populations as well as increased kitten survival in neutered groups. These compensatory mechanisms in neutered groups leading to increased kitten survival and immigration would confound rabies vaccination campaigns and produce naive populations of cats that can serve as source of zoonotic disease agents owing to lack of immunity. This manuscript is a review of the various diseases of free roaming cats and the public health implications associated with the cat populations. PMID- 22830566 TI - The need for evidence-based planning for VISION 2020. PMID- 22830568 TI - Written on the body? Individual differences between British adults who do and do not obtain a first tattoo. AB - This study compared individual psychological differences of individuals who do and not obtain their first tattoo. A total of 136 British residents visiting a tattoo parlour completed measures of the Big Five personality factors, Sensation Seeking, Need for Uniqueness, distinctive appearance investment, attitudes to authority, and sociosexual orientation. As compared to individuals who did not subsequently obtain a tattoo, individuals that did were significantly less conscientious, more extraverted, more willing to engage in sexual relations in the absence of commitment, and had higher scores on sensation seeking, Need for Uniqueness, and distinctive appearance investment. The effect sizes of uncovered differences were small-to-moderate (eta(p)(2) =.07-.14). These results are discussed in relation to the mainstreaming of tattoos in contemporary, post industrialised societies. PMID- 22830569 TI - Phenylpropargyl radicals and their dimerization products: an IR/UV double resonance study. AB - Two C(9)H(7) isomers, 1-phenylpropargyl and 3-phenylpropargyl, have been studied by IR/UV double resonance spectroscopy in a free jet. The species are possible intermediates in the formation of soot and polycyclic aromatic hydrocarbons (PAH). The radicals are generated by flash pyrolysis from the corresponding bromides and ionized at 255-297 nm in a one-color, two-photon process. Mid infrared radiation between 500 and 1800 cm(-1) is provided by a free electron laser (FEL). It is shown that the two radicals can be distinguished by their infrared spectra. In addition, we studied the dimerization products originating from the phenylpropargyl self-reaction. We utilize the fact that the pyrolysis tube can be considered to be a flow reactor permitting us to investigate the chemistry in such a thermal reactor. Dimerization of phenylpropargyl produces predominately species with m/z = 228 and 230. A surprisingly high selectivity has been found: The species with m/z = 230 is identified to be para-terphenyl, whereas m/z = 228 can be assigned to 1-phenylethynyl-naphthalene. The results allow to derive a mechanism for the dimerization of phenylpropargyl and suggest hitherto unexplored pathways to the formation of soot and PAH. PMID- 22830571 TI - Geographic origin is a significant determinant of human papillomavirus prevalence in oesophageal squamous cell carcinoma: systematic review and meta-analysis. AB - BACKGROUND: Since the first reports in 1982 suggesting an aetiological role for human papillomavirus (HPV) in a subset of oesophageal squamous cell carcinomas (ESCC), the literature reporting HPV detection in ESCC has expanded rapidly. However no formal meta-analysis of this literature has been published yet. The objective of this study was to perform a systematic review and formal meta analysis of the literature reporting HPV detection in ESCC. METHODS: MEDLINE and Current Contents were searched through March 2012. The effect size was calculated as event rates and their 95% confidence interval (95% CI), with homogeneity testing using Cochran's Q and I2 statistics. Meta-regression was used to test the impact of study-level covariates (HPV detection method, geographic origin of study) on effect size, and potential publication bias was estimated using funnel plot symmetry (Begg and Mazumdar rank correlation, Egger's regression, and Duval and Tweedie's trim and fill method). RESULTS: Of the 1177 abstracts found, 152 studies were determined to be eligible for this meta-analysis. These 152 studies covered a total of 10,234 ESCC cases, analysed by different HPV detection methods in different geographic regions. Of these 10,234 cases, 3135 (30.6%) tested HPV positive, translating to an effect size of 0.372 (95% CI 0.360-0.384; fixed effects model) and 0.290 (95% CI 0.251-0.31; random effects model). When stratified by HPV detection technique, there was a significant heterogeneity between the studies, but importantly, the between-strata summary comparison was not significant (random effects model; p = 0.440). In contrast, there was significant heterogeneity between the studies from the different geographic regions. In the maximum likelihood meta-regression, HPV detection method was not a significant study-level covariate, in contrast to the geographic origin of the study, which had a significant impact (p = 0.00005) on the summary effect size estimates. No evidence for significant publication bias was found in funnel plot symmetry testing. In the sensitivity analysis, all meta-analytic results appeared robust to all (n = 151) one-by-one study removals. CONCLUSIONS: These meta analysis results indicate that the reported wide variability in HPV detection rates in ESCC is not due to the HPV detection techniques, but is explained by the geographic origin of the study. These data substantiate the recently elaborated concept that ESCC might have a different aetiology in low-incidence and high incidence geographic regions, HPV playing an important role only in the latter. PMID- 22830570 TI - Abrogated RANKL expression in properdin-deficient mice is associated with better outcome from collagen-antibody-induced arthritis. AB - INTRODUCTION: Properdin amplifies the alternative pathway of complement activation. In the present study, we evaluated its role in the development of collagen antibody-induced arthritis (CAIA). METHODS: Arthritis was induced by intraperitoneal injection of a collagen antibody cocktail into properdin deficient (KO) and wild-type (WT) C57BL/6 mice. Symptoms of disease were evaluated daily. The degree of joint damage was assessed histologically and with immunostaining for bone-resorption markers. Phenotypes of cell populations, their receptor expression, and intracellular cytokine production were determined with flow cytometry. Osteoclast differentiation of bone marrow (BM) precursors was evaluated by staining for tartrate-resistant acid phosphatase (TRAP). RESULTS: Properdin-deficient mice developed less severe CAIA than did WT mice. They showed significantly improved clinical scores and downregulated expression of bone resorption markers in the joints at day 10 of disease. The frequencies of Ly6G+CD11b+ cells were fewer in BM, blood, and synovial fluid (SF) of KO than of WT CAIA mice. The receptor activator of nuclear factor kappaB ligand (RANKL) was downregulated on arthritic KO neutrophils from BM and the periphery. Decreased C5a amounts in KO SF contributed to lower frequencies of CD5aR+-bearing neutrophils. In blood, surface C5aR was detected on KO Ly6G+ cells as a result of low receptor engagement. Circulating CD4+ T cells had an altered ability to produce interleukin (IL)-17 and interferon (IFN)-gamma and to express RANKL. In KO CAIA mice, decreased frequencies of CD4+ T cells in the spleen were related to low CD86 expression on Ly6GhighCD11b+ cells. Arthritic KO T cells spontaneously secreted IFN-gamma but not IL-17 and IL-6, and responded to restimulation with less-vigorous cytokine production in comparison to WT cells. Fewer TRAP-positive mature osteoclasts were found in KO BM cell cultures. CONCLUSIONS: Our data show that the active involvement of properdin in arthritis is related to an increased proinflammatory cytokine production and RANKL expression on immune cells and to a stimulation of the RANKL-dependent osteoclast differentiation. PMID- 22830572 TI - Hospital outcomes for patients with stage III and IV lung cancer admitted to the intensive care unit for sepsis-related acute respiratory failure. AB - BACKGROUND: In recent years, intensive care for cancer patients has improved and treatment of critically ill cancer patients has become increasingly aggressive over time. However, not all cancer patients would benefit from aggressive care, especially those with late-stage cancer. OBJECTIVE: We aimed to investigate the outcome of late-stage lung cancer patients with sepsis-related respiratory failure and identify predictors of mortality. METHODS: From 2007 to 2008, consecutive stage III and IV lung cancer patients admitted to an intensive care unit (ICU) of a teritiary medical center in Taiwan for sepsis-related respiratory failure were retrospectively enrolled. Data at baseline and upon ICU admission were collected. In-hospital survival was analyzed. Variables of the survivors to hospital discharge and patients who died were compared by uni- and multivariate analyses. RESULTS: Seventy patients were enrolled. During a mean follow-up period of 30.10 days, 29 (41.4%) patients survived to hospital discharge and 41(58.6%) died. Compared with the survivors, the patients who died had poor performance status, lower serum albumin level, higher percentage of disseminated intravascular coagulation, and more severe organ dysfunction as disclosed by higher Sequential Organ Failure Assessment (SOFA) scores. Multivariate analyses revealed that SOFA score (p=0.026) was the only independent predictor of mortality; 44.8 % (13/29) of survivors were weaned from ventilator during hospitalization. CONCLUSION: Among late-stage lung cancer patients with sepsis related respiratory failure, those with lower SOFA scores seemed to have better survival rate and may benefit from intensive care in the ICU. Early palliative care should be considered for all patients with advanced lung cancer, and hospice care is suggested for those with sepsis-respiratory failure and high SOFA scores. PMID- 22830573 TI - Repetition and spacing effects on true and false recognition in the DRM paradigm. AB - With the Deese-Roediger-McDermott (DRM) paradigm, the repetition effect on false memory had never been clarified. More importantly, the spacing effect on false memory was never directly investigated. So, we carried out two experiments to examine these effects on true and false recognition. In experiment 1, participants studied DRM lists which were presented one, three or five times. In experiment 2, we manipulated the repetition mode (massed vs. spaced with a short interval or a long interval) to explore the spacing effect. The results showed that true recognition increased monotonically with list repetition (experiment 1) and repetition spacing (experiment 2). The most striking finding was a similar spacing effect but no repetition effect on false recognition. Thus, these results were principally discussed in the light of the activation-monitoring framework. PMID- 22830574 TI - How good is perceived health-related quality of life in patients treated for non functioning pituitary adenomas? PMID- 22830575 TI - Mitochondrial DNA haplogroup associated with hereditary hearing loss in a Japanese population. AB - CONCLUSION: Haplogroup D4b, especially subhaplogroup D4b2, may be one of the modifiers associated with the phenotypic expression of hereditary hearing loss (HL). OBJECTIVES: The present study investigated the association between suspected hereditary HL and 12 major mtDNA haplogroups in a Japanese population. Besides the mutations of mitochondrial DNA, many modifiers including environmental factors and genetic polymorphisms are involved in HL. METHODS: The subjects comprised 373 unrelated Japanese patients with suspected hereditary HL and 480 controls. Twenty of the 373 patients were excluded from the study because the m.1555A>G or the m.3243A>G mutation had been detected in them. The mitochondrial haplotypes were classified into 12 major Japanese haplogroups (i.e. F, B, A, N9a, N9b, M7a, M7b, G1, G2, D4a, D4b, and D5). The frequency of each haplogroup in patients with HL was compared with that of the controls using the chi-squared test. RESULTS: The frequency of the HL patients carrying the mitochondrial haplogroup D4b was significantly higher than that of the controls (37/353 [10.5%] vs 31/480 [6.5%]; OR 1.70 [95% CI 1.03-2.79, p = 0.036]) and evidence for enhancement was found in subhaplogroup D4b2 (32/353 [9.1%] vs 24/480 [5%], OR 1.89 [95% CI 1.09-3.28, p = 0.021]). PMID- 22830578 TI - Effects of magnetic doping on weak antilocalization in narrow Bi2Se3 nanoribbons. AB - We report low-temperature, magnetotransport measurements of ferrocene-doped Bi(2)Se(3) nanoribbons grown by vapor-liquid-solid method. The Kondo effect, a saturating resistance upturn at low temperatures, is observed in these ribbons to indicate presence of localized impurity spins. Magnetoconductances of the ferrocene-doped ribbons display both weak localization and weak antilocalization, which is in contrast with those of undoped ribbons that show only weak antilocalization. We show that the observed magnetoconductances are governed by a one-dimensional localization theory that includes spin orbit coupling and magnetic impurity scattering, yielding various scattering and dephasing lengths for Bi(2)Se(3). The power law decay of the dephasing length on temperature also reflects one-dimensional localization regime in these narrow Bi(2)Se(3) nanoribbons. The emergence of weak localization in ferrocene-doped Bi(2)Se(3) nanoribbons presents ferrocene as an effective magnetic dopant source. PMID- 22830579 TI - Dual diagnosis, as described by those who experience the disorder: using the Internet as a source of data. AB - The complexity of providing treatment for people with dual diagnosis is well recognized. For the purpose of this paper, the World Health Organization definition of dual diagnosis was used; that is, a person diagnosed with an alcohol or drug use problem in addition to mental illness. This research explored the personal narratives of those who experience dual diagnosis using the Internet as a data source. An important consideration in using the Internet as a data source was that Web forums can offer a sense of anonymity, allowing people to share very detailed and personal information, and providing a rich source of qualitative data. The results produced five emergent themes: spiralling out of control - again!, getting help and giving support, treating both the addiction and mental illness, having meaning and being active, and being honest with self and others. The results indicate that individuals who experience dual diagnosis are often left to navigate their personal treatment requirements across two diverse systems, and were generally not satisfied with the conflictual advice received across these two systems (i.e. alcohol and other drug and mental health services). This study has produced valuable insights related to consumer perceived service barriers and enablers. PMID- 22830580 TI - Prevalence and predictors of vitamin D deficiency in non-supplemented women with systemic lupus erythematosus in the Mediterranean region: a cohort study. AB - OBJECTIVES: Over the past few years researchers have suggested that vitamin D plays a diverse role in autoimmune diseases such as systemic lupus erythematosus (SLE). We sought to determine the prevalence and predictors of vitamin D deficiency in a cohort of non-supplemented female SLE patients from the Mediterranean region. METHODS: We carried out a prospective cohort study on all SLE patients who had visited the Department of Rheumatology at the Parc de Salut MAR (Barcelona, Spain) between June 2007 and December 2008, excluding those who had been taking vitamin D supplements (total: 73 patients, all female). For each patient, demographic information was collected; scores were measured for disease severity [SLE Disease Activity Index (SLEDAI)] and structural damage [Systemic Lupus International Collaborating Clinic/American College of Rheumatology, (SLICC/ACR) Damage Index]; pharmacological treatment was recorded; analytical variables were analysed; and plasma levels of 25-hydroxy vitamin D [25(OH)D] were quantified. RESULTS: Among the patients in our cohort, 68.5% [95% confidence interval (CI) 60.3-79.2] exhibited vitamin D deficiency [plasma level of 25(OH)D < 30 ng/mL]. The predictors for vitamin D deficiency were daily sunscreen use [odds ratio (OR) 1.67, p = 0.02] and high body mass index (BMI) (OR 1.32 when adjusted for seasons and patient age, p = 0.04). We did not find any correlation between vitamin D deficiency and SLEDAI score (p = 0.31), SLICC/ACR score (p = 0.82), or any other of the variables. CONCLUSIONS: Vitamin D insufficiency is highly prevalent among SLE patients, even in southern regions. Sunscreen use and obesity increase the risk. Clinicians should be aware of these factors and supplement SLE patients at risk of vitamin D deficiency accordingly. PMID- 22830582 TI - Strong-field ionization and coulomb explosion of chlorine weakly bound to small water clusters. AB - Clusters exhibit an enhancement in ionization rates under intense, ultrafast laser pulses compared to their molecular/atomic counterparts. Studies of ionization enhancement of weakly bound molecules to clusters have not been previously characterized and quantified. We demonstrate that weakly bound ClO to (H(2)O)(n) (n = 1-12) clusters and weakly bound HCl to (H(2)O)(n) (n = 1-12) clusters produce high atomic charge states of chlorine via Coulomb explosion. Density functional theory (DFT) was used to qualitatively compare the interaction energy of ClO with respect to the number of water molecules as well as HCl with respect to the number of water molecules. The chlorine ion signal intensity for each atomic charge state was observed to be dependent on the molecule-cluster bond strength. The observed ionization enhancement was quantified using semiclassical tunneling theory, and it was found that the Cl(3+-5+) and O(2+) charge states are enhanced in ionization. Possible mechanisms of ionization enhancement are explored for weakly bound chlorine species. PMID- 22830581 TI - Measurement of multiple biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter guided therapy. AB - INTRODUCTION: This study was carried out to investigate the prognostic utility of biomarkers in advanced stage heart failure (HF) patients requiring ICU admission for pulmonary artery catheter (PAC) guided therapy. METHODS: Thirty patients admitted to an ICU for PAC guided HF therapy were enrolled; concentrations of soluble ST2 (sST2), highly sensitive troponin I, an experimental ultrasensitive troponin I, amino-terminal pro-B type natriuretic peptide, cystatin C, and myeloperoxidase were measured over the first 48 hours. Outcomes included response of filling pressures and hemodynamics to tailored therapy and 90-day event-free survival (death, left ventricular assist device implantation, transplant). RESULTS: Of the biomarkers evaluated, only sST2 concentrations were higher in those who failed to achieve goals for central venous pressure ((CVP), 225.3 versus 104.6 ng/mL; P = 0.003) and pulmonary capillary wedge pressure ((PCWP), 181.7 versus 88.2 ng/mL; P = 0.05). Only sST2 concentrations were associated with adverse events (186.7 versus 92.2 ng/mL; P = 0.01). In age-adjusted Cox proportional hazards analysis, an elevated sST2 during the first 48 hours following ICU admission independently predicted 90-day outcomes (Hazard Ratio = 5.53; P = 0.03) superior to the Simplified Acute Physiology Score for this application; in Kaplan-Meier analysis the risk associated with elevated sST2 concentrations was present early and sustained through the duration of follow-up (log rank P = 0.01). CONCLUSIONS: In patients undergoing HF therapy guided by invasive monitoring, sST2 concentrations were associated with impending failure to reduce filling pressures and predicted impending events. Elevated sST2 values early in the ICU course theoretically could assist therapeutic decision-making in advanced stage HF patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00595738. PMID- 22830583 TI - Swallowed needle resulting in right ventricular foreign body. PMID- 22830584 TI - Chip-capillary hybrid device for automated transfer of sample preseparated by capillary isoelectric focusing to parallel capillary gel electrophoresis for two dimensional protein separation. AB - In this article, we introduce a chip-capillary hybrid device to integrate capillary isoelectric focusing (CIEF) with parallel capillary sodium dodecyl sulfate- polyacrylamide gel electrophoresis (SDS-PAGE) or capillary gel electrophoresis (CGE) toward automating two-dimensional (2D) protein separations. The hybrid device consists of three chips that are butted together. The middle chip can be moved between two positions to reroute the fluidic paths, which enables the performance of CIEF and injection of proteins partially resolved by CIEF to CGE capillaries for parallel CGE separations in a continuous and automated fashion. Capillaries are attached to the other two chips to facilitate CIEF and CGE separations and to extend the effective lengths of CGE columns. Specifically, we illustrate the working principle of the hybrid device, develop protocols for producing and preparing the hybrid device, and demonstrate the feasibility of using this hybrid device for automated injection of CIEF-separated sample to parallel CGE for 2D protein separations. Potentials and problems associated with the hybrid device are also discussed. PMID- 22830585 TI - Solvent-dependent gating motions of an extremophilic lipase from Pseudomonas aeruginosa. AB - Understanding how organic solvent-stable proteins can function in anhydrous and often complex solutions is essential for the study of the interaction of protein and molecular immiscible interfaces and the design of efficient industrial enzymes in nonaqueous solvents. Using an extremophilic lipase from Pseudomonas aeruginosa as an example, we investigated the conformational dynamics of an organic solvent-tolerant enzyme in complex solvent milieux. Four 100-ns molecular dynamics simulations of the lipase were performed in solvent systems: water, hexane, and two mixtures of hexane and water, 5% and 95% (w/w) hexane. Our results show a solvent-dependent structural change of the protein, especially in the region that regulates the admission of the substrate. We observed that the lipase is much less flexible in hexane than in aqueous solution or at the immiscible interface. Quantified by the size of the accessible channel, the lipase in water has a closed-gate conformation and no access to the active site, while in the hexane-containing systems, the lipase is at various degrees of open gate state, with the immiscible interface setup being in the widely open conformation ensembles. The composition of explicit solvents in the access channel showed a significant influence on the conformational dynamics of the protein. Interestingly, the slowest step (bottleneck) of the hexane-induced conformational switch seems to be correlated with the slow dehydration dynamics of the channel. PMID- 22830586 TI - On the kinetics of anaerobic power. AB - BACKGROUND: This study investigated two different mathematical models for the kinetics of anaerobic power. Model 1 assumes that the work power is linear with the work rate, while Model 2 assumes a linear relationship between the alactic anaerobic power and the rate of change of the aerobic power. In order to test these models, a cross country skier ran with poles on a treadmill at different exercise intensities. The aerobic power, based on the measured oxygen uptake, was used as input to the models, whereas the simulated blood lactate concentration was compared with experimental results. Thereafter, the metabolic rate from phosphocreatine break down was calculated theoretically. Finally, the models were used to compare phosphocreatine break down during continuous and interval exercises. RESULTS: Good similarity was found between experimental and simulated blood lactate concentration during steady state exercise intensities. The measured blood lactate concentrations were lower than simulated for intensities above the lactate threshold, but higher than simulated during recovery after high intensity exercise when the simulated lactate concentration was averaged over the whole lactate space. This fit was improved when the simulated lactate concentration was separated into two compartments; muscles + internal organs and blood. Model 2 gave a better behavior of alactic energy than Model 1 when compared against invasive measurements presented in the literature. During continuous exercise, Model 2 showed that the alactic energy storage decreased with time, whereas Model 1 showed a minimum value when steady state aerobic conditions were achieved. During interval exercise the two models showed similar patterns of alactic energy. CONCLUSIONS: The current study provides useful insight on the kinetics of anaerobic power. Overall, our data indicate that blood lactate levels can be accurately modeled during steady state, and suggests a linear relationship between the alactic anaerobic power and the rate of change of the aerobic power. PMID- 22830587 TI - Breaking bad news in a Southeast European population: a survey among cancer patients in Albania. AB - OBJECTIVE: The purpose of this study was to explore the attitudes of cancer patients, their family, and community members in Albania, a post-communist country in Southeast Europe, regarding breaking bad news. METHODS: One hundred and fifty consecutive cancer patients, 150 respective relatives, and an age-sex residence matched sample of 150 individuals in Tirana district were interviewed from September 2009-January 2010 about attitudes related to diagnosis disclosure. Logistic regression was used to assess the association of diagnosis disclosure with demographic characteristics. RESULTS: Community members were the most in favor, whereas the patients' relatives were the least in favor of diagnosis disclosure. Most of the patients, who were aware of their diagnosis, were not satisfied with the disclosure approach employed by the medical staff. The odds of favoring diagnosis disclosure were significantly higher among younger, male, urban, and more educated patients. CONCLUSION: This survey identified important characteristics of cancer patients, their relatives, and a community-based sample in Albania that could predict the willingness to disclose a fatal diagnosis. Establishment of a formal training of health professionals regarding breaking bad news should be considered in order to ensure a proper approach of communicating diagnosis to cancer patients in transitional Albania. PMID- 22830589 TI - Chemical intercalation of zerovalent metals into 2D layered Bi2Se3 nanoribbons. AB - We have developed a chemical method to intercalate a variety of zerovalent metal atoms into two-dimensional (2D) layered Bi(2)Se(3) chalcogenide nanoribbons. We use a chemical reaction, such as a disproportionation redox reaction, to generate dilute zerovalent metal atoms in a refluxing solution, which intercalate into the layered Bi(2)Se(3) structure. The zerovalent nature of the intercalant allows superstoichiometric intercalation of metal atoms such as Ag, Au, Co, Cu, Fe, In, Ni, and Sn. We foresee the impact of this methodology in establishing novel fundamental physical behaviors and in possible energy applications. PMID- 22830588 TI - Impaired propulsive motility in the distal but not proximal colon of BK channel beta1-subunit knockout mice. AB - BACKGROUND: Large-conductance Ca(2+) -activated K(+) (BK) channels regulate smooth muscle tone. The BK channel beta1-subunit increases Ca(2+) sensitivity of the alpha-subunit in smooth muscle. We studied beta1-subunit knockout (KO) mice to determine if gastrointestinal (GI) motility was altered. METHODS: Colonic and intestinal longitudinal muscle reactivity to bethanechol and colonic migrating motor complexes (CMMCs) were measured in vitro. Gastric emptying and small intestinal transit were measured in vivo. Colonic motility was assessed in vivo by measuring fecal output and glass bead expulsion time. Myoelectric activity of distal colon smooth muscle was measured in vitro using intracellular microelectrodes. KEY RESULTS: Bethanechol-induced contractions were larger in the distal colon of beta1-subunit KO compared to wild type (WT) mice; there were no differences in bethanechol reactivity in the duodenum, ileum, or proximal colon of WT vsbeta1-subunit KO mice. There were more retrogradely propagated CMMCs in the distal colon of beta1-subunit KO compared to WT mice. Gastrointestinal transit was unaffected by beta1-subunit KO. Fecal output was decreased and glass bead expulsion times were increased in beta1-subunit KO mice. Membrane potential of distal colon smooth muscle cells from beta1-subunit KO mice was depolarized with higher action potential frequency compared to WT mice. Paxilline (BK channel blocker) depolarized smooth muscle cells and increased action potential frequency in WT distal colon. CONCLUSIONS & INFERENCES: BK channels play a prominent role in smooth muscle function only in the distal colon of mice. Defects in smooth muscle BK channel function disrupt colonic motility causing constipation. PMID- 22830590 TI - A case of endogenous endophthalmitis complicated by neutropenia following bacteremia with Streptococcus mitis resistant to beta-lactam antibiotics. AB - This report is focused on a case of endogenous endophthalmitis following Streptococcus mitis bacteremia that occurred during chemotherapy for acute myeloid leukemia, despite broad-spectrum beta-lactam antibiotics and vancomycin. The patient partially recovered visual acuity. In conclusion, Streptococcus mitis bacteremia complicated by febrile neutropenia may cause endogenous endophthalmitis within a very short timeframe. PMID- 22830591 TI - 3rd Nordic Meeting on Genetics and Pathogenesis of Inflammatory Diseases. PMID- 22830594 TI - Asymmetric allylic alkylation of isatin-derived Morita-Baylis-Hillman carbonates with nitroalkanes. AB - A stereoselective allylic alkylation of isatin-derived Morita-Baylis-Hillman (MBH) carbonates with nitroalkanes has been developed. In the presence of 10 mol % beta-isocupreidine (beta-ICD), 3,3'-disubstituted oxindoles were prepared with moderate diastereoselectivities and excellent enantioselectivities. PMID- 22830595 TI - Eating-related problems among 13-15 year old Swedish adolescents: frequency and stability over a one-year period. AB - The frequency of eating-related problems in young adolescents, and their stability over a one-year period, was studied by the RiBED-8 (Risk Behaviours related to Eating Disorders, 8 items) in a community sample of 13-15 year old adolescents who took part in a prospective study with a 2-wave longitudinal design. The RiBED-8 was found to have good reliability and construct validity among the girls, although it did not show equally convincing psychometric properties among boys. With a cut-off of at least three critical answers on the RiBED-8, 28.5-31.0% of the girls were seen as risk cases for the development of eating disorder. Of those girls who were risk cases at Time 1, a majority (68.8%) remained so at Time 2; of those girls who were not risk cases at Time 1, 16.1% became risk cases at Time 2. It is suggested that the RiBED-8 is a brief, easily administered instrument that may be potentially useful in screening for eating related problems among girls. PMID- 22830596 TI - Expression of chondroitin-glucuronate C5-epimerase and cellular immune responses in patients with hepatocellular carcinoma. AB - BACKGROUND & AIMS: Chondroitin-glucuronate C5-epimerase is an enzyme that converts D-glucuronic acid to L-iduronic acid residues in dermatan sulphate biosynthesis. It is also identified to be a tumour-associated antigen recognized by cytotoxic T cells (CTLs) and its enhanced expression in many cancers has been reported. In the present study, we investigated the usefulness of this molecule as an immunotherapeutic target in hepatocellular carcinoma (HCC). METHODS: The expression of chondroitin-glucuronate C5-epimerase in hepatoma cell lines and HCC tissues was confirmed by immunofluorescence and immunohistochemical analysis. CTL responses were investigated by several immunological techniques using peripheral blood mononuclear cells (PBMCs) or tumour-infiltrating lymphocytes. To determine the safety of immunotherapy using chondroitin-glucuronate C5-epimerase-derived peptide, 12 patients with HCC were administered s.c. vaccinations of the peptides and analysed. RESULTS: Chondroitin-glucuronate C5-epimerase was expressed in HCC cell lines and human tissues including alpha-foetoprotein (AFP)-negative individuals. Chondroitin-glucuronate C5-epimerase-specific CTLs could be generated by stimulating PBMCs of HCC patients with peptides and they showed cytotoxicity against HCC cells expressing the protein. The frequency of CTL precursors investigated by enzyme-linked immunospot (ELISPOT) assay was 0-34 cells/3 * 10(5) PBMCs and the infiltration of interferon-gamma-producing CTLs into the tumour site was confirmed. In the vaccination study, no severe adverse events were observed and the peptide-specific CTLs were induced in 4 of 12 patients tested. CONCLUSIONS: Chondroitin-glucuronate C5-epimerase is a potential candidate for tumour antigen with immunogenicity and the peptides derived from this antigen could be useful in HCC immunotherapy. PMID- 22830597 TI - Social network analysis of Equidae movements and its application to risk-based surveillance and to control of spread of potential Equidae diseases. AB - Movements of animals and animal products are one of the most important ways of disease introduction and spread between regions and countries. Maybe one of the most complex animal species in terms of diversity of uses, nature and extent of movements are equidae, for which animal movement records are usually not available. The study presented here is the first characterization of a complete and reliable network of equidae movements in Castile and Leon, which is one of the most important equidae production regions of Spain. Social network analysis and space-time cluster analysis were used to describe the contact patterns of the equidae network and to identify the most important premises, areas and time periods for potential disease introduction or spread into the region. The studied network was complex, with very heterogeneous types of premises and diverse nature and extent of the movements compared with other livestock species, which have important implications for prevention and control of equidae diseases. Centrality measures revealed that production and reproduction farms and centres of livestock competition were the most important type of premises in the studied network. Cluster analyses allowed to identify seventeen significant spatio-temporal clusters of premises at high risk of dispatching or receiving equidae, which formed four interconnected compartments. These clusters were mainly located in the north-west region and in the second part of the year. The results of this study may be useful to design risk-based surveillance and control programmes of equidae diseases and increase the speed of detection and control of potential secondary outbreaks in future epidemics. Consequently, these results will help to minimize the great economic and sanitary impact of equidae diseases. The analytical approach used here may be easily extended to characterize the equidae movement patterns in other countries and regions of the world. PMID- 22830598 TI - Guest inclusion in cucurbiturils studied by ESR and DFT: the case of nitroxide radicals and spin adducts of DMPO and MNP. AB - We present an ESR and DFT study of the interaction of cucurbiturils CB[6], CB[7], and CB[8] with di-tert-butyl nitroxide ((CH(3))(3)C)(2)NO (DTBN) and with spin adducts of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and 2-methyl-2-nitrosopropane (MNP). The primary goal was to understand the structural parameters that determine the inclusion mechanism in the CBs using DTBN, a nitroxide with great sensitivity to the local environment. In addition, we focused on the interactions with CBs of the spin adducts DMPO/OH and MNP/CH(2)COOH generated in aqueous CH(3)COOH. A range of interactions between DTBN and CBs was identified for pH 3.2, 7, and 10. No complexation of DTBN with CB[6] was deduced in this pH range. The interaction between DTBN and CB[7] is evident at all pH values: "in" and "out" nitroxides, with (14)N hyperfine splitting, a(N), values of 15.5 and 17.1 G, respectively, were detected by ESR. Interaction of DTBN with CB[8] was also detected for all pH values, and the only species had a(N) = 16.4 G, a result that can be rationalized by an "in" nitroxide in a less hydrophobic environment compared to CB[7]. Computational studies indicated that the DTBN complex with CB[7] is thermodynamically favored compared to that in CB[8]; the orientations of the NO group are parallel to the CB[7] plane and perpendicular to the CB[8] plane (pointing toward the annulus). Addition of sodium ions led to the ESR detection of a three-component complex between CB[7], DTBN, and the cations; the ternary complex was not detected for CB[8]. The DMPO/OH spin adduct was stabilized in the presence of CB[7], but the effect on a(N) was negligible, indicating that the N-O group is located outside the CB cavity. Computational studies indicated more favorable energetics of complexation for DMPO/OH in CB[7] compared to DTBN. An increase of a(N) was detected in the presence of CB[7] for the MNP/CH(2)COOH adduct generated in CH(3)COOH, a result that was assigned to the generation of the three-component radical between the spin adduct, sodium cations, and CB[7]. PMID- 22830601 TI - Systemic steroids in the treatment of psoriasis: what is fact, what is fiction? AB - BACKGROUND: The use of systemic steroids in the treatment of psoriasis is not recommended by dermatological textbooks and guidelines because of the risk of disease deterioration after dose reduction or withdrawal. In contrast to these recommendations, a recent analysis using data from a German nationwide healthcare insurance revealed that systemic steroids were the most frequently prescribed drugs for psoriasis by general practitioners, internal medicine physicians and dermatologists. OBJECTIVE: As there is an obvious discrepancy between the use of systemic steroids for psoriasis and the reported adverse effects, a non systematic literature search starting 1950 until today was performed to address beneficial and adverse effect of systemic steroids in psoriasis. METHODS: Non systematic literature search. RESULTS: Regarding the widespread use of systemic steroids in psoriasis and other medical conditions taking the high prevalence of psoriasis of 2-3% at least in Caucasians into consideration, there is a remarkable lack of literature addressing adverse effects such as rebound, pustular or erythrodermic flares or even new occurrence of psoriasis in patients with a negative disease history. CONCLUSION: A re-evaluation of the treatment of psoriasis and/or psoriatic arthritis with systemic steroids is necessary. PMID- 22830599 TI - Staphylococcus epidermidis pan-genome sequence analysis reveals diversity of skin commensal and hospital infection-associated isolates. AB - BACKGROUND: While Staphylococcus epidermidis is commonly isolated from healthy human skin, it is also the most frequent cause of nosocomial infections on indwelling medical devices. Despite its importance, few genome sequences existed and the most frequent hospital-associated lineage, ST2, had not been fully sequenced. RESULTS: We cultivated 71 commensal S. epidermidis isolates from 15 skin sites and compared them with 28 nosocomial isolates from venous catheters and blood cultures. We produced 21 commensal and 9 nosocomial draft genomes, and annotated and compared their gene content, phylogenetic relatedness and biochemical functions. The commensal strains had an open pan-genome with 80% core genes and 20% variable genes. The variable genome was characterized by an overabundance of transposable elements, transcription factors and transporters. Biochemical diversity, as assayed by antibiotic resistance and in vitro biofilm formation, demonstrated the varied phenotypic consequences of this genomic diversity. The nosocomial isolates exhibited both large-scale rearrangements and single-nucleotide variation. We showed that S. epidermidis genomes separate into two phylogenetic groups, one consisting only of commensals. The formate dehydrogenase gene, present only in commensals, is a discriminatory marker between the two groups. CONCLUSIONS: Commensal skin S. epidermidis have an open pan-genome and show considerable diversity between isolates, even when derived from a single individual or body site. For ST2, the most common nosocomial lineage, we detect variation between three independent isolates sequenced. Finally, phylogenetic analyses revealed a previously unrecognized group of S. epidermidis strains characterized by reduced virulence and formate dehydrogenase, which we propose as a clinical molecular marker. PMID- 22830602 TI - Best performances by men and women open-water swimmers during the 'English Channel Swim' from 1900 to 2010. AB - Little research has examined ultra-endurance swimming performances. The 'English Channel Swim', where swimmers have to cover a distance of 32 km between England and France represents a unique long-distance, open-water, sea-swimming challenge, and each year swimmers from all over the world try to succeed in this challenge. The best times in minutes and the nationality of successful men and women swimmers were analysed from 1900 to 2010. A total of 1,533 swimmers (455 women and 1,078 men) from more than 40 countries have successfully completed the 'English Channel Swim'. Great Britain was the country most represented, with 38% of the total, followed by the United States with 20%. Swim speed has increased progressively for both sexes (P < 0.001) but was lower for women than for men (0.68 +/- 0.15 m . s-1 vs 0.71 +/- 0.16 m . s-1 respectively, P < 0.01). However, the best annual performances did not differ between the sexes (men: 0.89 +/- 0.20 m . s-1; women: 0.84 +/- 0.18 m . s-1, P > 0.05). The results suggest that the performance of women open-water ultra-distance swimmers may be similar to that of men. Further studies investigating anthropometrical and physiological characteristics of open-water ultra-swimmers are needed to compare men's and women's open-water ultra-swim performances. PMID- 22830600 TI - An expanded model of HIV cell entry phenotype based on multi-parameter single cell data. AB - BACKGROUND: Entry of human immunodeficiency virus type 1 (HIV-1) into the host cell involves interactions between the viral envelope glycoproteins (Env) and the cellular receptor CD4 as well as a coreceptor molecule (most importantly CCR5 or CXCR4). Viral preference for a specific coreceptor (tropism) is in particular determined by the third variable loop (V3) of the Env glycoprotein gp120. The approval and use of a coreceptor antagonist for antiretroviral therapy make detailed understanding of tropism and its accurate prediction from patient derived virus isolates essential. The aim of the present study is the development of an extended description of the HIV entry phenotype reflecting its co dependence on several key determinants as the basis for a more accurate prediction of HIV-1 entry phenotype from genotypic data. RESULTS: Here, we established a new protocol of quantitation and computational analysis of the dependence of HIV entry efficiency on receptor and coreceptor cell surface levels as well as viral V3 loop sequence and the presence of two prototypic coreceptor antagonists in varying concentrations. Based on data collected at the single-cell level, we constructed regression models of the HIV-1 entry phenotype integrating the measured determinants. We developed a multivariate phenotype descriptor, termed phenotype vector, which facilitates a more detailed characterization of HIV entry phenotypes than currently used binary tropism classifications. For some of the tested virus variants, the multivariant phenotype vector revealed substantial divergences from existing tropism predictions. We also developed methods for computational prediction of the entry phenotypes based on the V3 sequence and performed an extrapolating calculation of the effectiveness of this computational procedure. CONCLUSIONS: Our study of the HIV cell entry phenotype and the novel multivariate representation developed here contributes to a more detailed understanding of this phenotype and offers potential for future application in the effective administration of entry inhibitors in antiretroviral therapies. PMID- 22830603 TI - Recovery of evidence-based practice. AB - Consumer recovery is now enshrined in the national mental health policy of many countries. If this construct, which stems from the consumer/user/survivor movement, is truly to be the official and formal goal of mental health services, then it must be the yardstick against which evidence-based practice (EBP) is judged. From a consumer-recovery perspective, this paper re-examines aspects of services chosen for study, methodologies, outcomes measures, and standards of evidence associated with EBP, those previously having been identified as deficient and in need of expansion. One of the significant differences between previous investigations and the present study is that the work, writing, perspectives, and advocacy of the consumer movement has developed to such a degree that we now have a much more extensive body of material upon which to critique EBP and inform and support the expansion of EBP. Our examination reinforces previous findings and the ongoing need for expansion. The consumer recovery-focused direction, resources, frameworks, and approaches identified through the present paper should be used to expand the aspects of services chosen for study, methodologies, outcomes measures, and standards of evidence. This expansion will ultimately enable services to practice in a manner consistent with the key characteristics of supporting personal recovery. PMID- 22830604 TI - Transcatheter aortic valve replacement using DynaCT. AB - We report a successful transcatheter aortic valve replacement (TAVR) using syngo DynaCT (Siemens AG, Forchheim, Germany) in an 86-year-old man who had severe aortic valve stenosis. Syngo DynaCT is a cross-sectional radiological imaging system that facilitates intraoperative imaging via interventional angiographic systems; this navigation system is useful during TAVR, especially in cases of poor calcification at the annulus. PMID- 22830605 TI - Analysis of changes in gene expression and metabolic profiles induced by silica coated magnetic nanoparticles. AB - Magnetic nanoparticles (MNPs) have proven themselves to be useful in biomedical research; however, previous reports were insufficient to address the potential dangers of nanoparticles. Here, we investigated gene expression and metabolic changes based on the microarray and gas chromatography-mass spectrometry with human embryo kidney 293 cells treated with MNPs@SiO(2)(RITC), a silica-coated MNP containing Rhodamine B isothiocyanate (RITC). In addition, measurement of reactive oxygen species (ROS) and ATP analysis were performed to evaluate the effect of MNPs@SiO(2)(RITC) on mitochondrial function. Compared to the nontreated control, glutamic acid was increased by more than 2.0-fold, and expression of genes related to the glutamic acid metabolic pathway was also disturbed in 1.0 MUg/MUL of MNPs@SiO(2)(RITC)-treated cells. Furthermore, increases in ROS concentration and mitochondrial damage were observed in this MNPs@SiO(2)(RITC) concentration. The organic acids related to the Krebs cycle were also disturbed, and the capacity of ATP synthesis was decreased in cell treated with an overdose of MNPs@SiO(2)(RITC). Collectively, these results suggest that overdose (1.0 MUg/MUL) of MNPs caused transcriptomic and metabolic disturbance. In addition, we suggest that a combination of gene expression and metabolic profiles will provide more detailed and sensitive toxicological evaluation for nanoparticles. PMID- 22830607 TI - Non-pedicled vs vascular pedicled nasal flap in repair of cerebrospinal fluid rhinorrhea. AB - CONCLUSIONS: In our study, pedicled nasal flap (NF) did not provide better results than free nasal graft (NG) for primary closure of cerebrospinal fluid (CSF) rhinorrhea. In the future, a multicenter randomized study would be needed to confirm this result. The choice of surgical technique will depend on the surgeon's experience, and the position and size of the defect. OBJECTIVES: To evaluate our results in repairing CSF leaks, comparing the two techniques we used: free NG and pedicled NF. METHODS: A total of 33 patients diagnosed with CSF rhinorrhea were operated on between June 2000 and May 2010; 17 were women. The mean age was 44.7 years (+/- 13.0). Twenty-two (66.6%) NFs of the middle and lower turbinate and septum were performed, the rest being NGs of the middle and lower turbinate only. A descriptive statistical analysis and a Kaplan-Meier survival analysis were carried out and the log-rank statistic was used to compare both techniques. RESULTS: In the present study, 78% of defects were closed in all cases; NF was used in 86% (19) and NG in 63.63% (7). The mean follow-up was 71.5 (95% confidence interval (CI), 56.9-86.1) months. There were no statistically significant differences (p > 0.05). PMID- 22830608 TI - Ultrasmall sub-10 nm near-infrared fluorescent mesoporous silica nanoparticles. AB - Ultrasmall sub-10 nm nanoprobes and carriers are of significant interest due to their favorable biodistribution characteristics in in vivo experiments. Here we describe the one-pot synthesis of PEGylated mesoporous silica nanoparticles with a single pore, tunable sizes around 9 nm and narrow size distributions that can be labeled with near-infrared dye Cy5.5. Particles are characterized by a combination of transmission electron microscopy, dynamic light scattering, fluorescence correlation spectroscopy, optical spectroscopy, nuclear magnetic resonance spectroscopy, and nitrogen sorption/desorption measurements. The possibility to distinguish an "inside" and "outside" may render these particles an interesting subject for further studies in sensing, drug delivery, and theranostics applications. PMID- 22830609 TI - Morbidity and mortality in ageing HIV-infected haemophilia patients. AB - Over 25 years of follow-up is now available for HIV-infected haemophilia patients. The aim of this study was to retrospectively asses the morbidity and mortality of HIV infection and the effects of HAART in these patients. Data on HIV infection, its treatment and all types of comorbidity were collected from medical records of all 60 HIV-positive haemophilia patients who were treated at the Van Creveldkliniek since 1980 and compared with data from 152 HIV-negative patients with severe haemophilia and the general age-matched male population. AIDS developed in 27 patients (45%), while 31 patients died (52%). Death was solely or partially AIDS-related in 71%. Development of AIDS and AIDS-related deaths declined strongly after the introduction of HAART. Only one major ischaemic cardiovascular event occurred in our study population. Of the 27 patients who were still treated at our clinic in 2010, 25 (93%) were on HAART. They had more often hypertension and diabetes, but less often overweight and obesity and lower cholesterol levels than the general population. The occurrence of spontaneous intracranial bleeding was higher in HIV-positive haemophilia patients on HAART than in HIV-negative patients with severe haemophilia (16.6 vs. 1.2 per 1000 patient years). Since the introduction of HAART, the impact of HIV infection on morbidity and survival has decreased. The increased prevalences of hypertension and diabetes, however, warrant regular screening. HIV-positive haemophilia patients on HAART appear to have an increased risk of spontaneous intracranial bleeding. PMID- 22830610 TI - Performance of a rapid molecular multiplex assay for the detection of influenza and picornaviruses. AB - BACKGROUND: Multiplex assays are a new strategy for diagnosing respiratory infections. These assays are better than those based on cultures or antigen detection, but few data are available for comparing them to monoplex polymerase chain reactions (PCRs). This study evaluated the performance of the Luminex xTAG Respiratory Viral Panel (RVP) Fast assay with reference to 2 real-time PCR assays for detecting type A influenza H1 viruses and human enteroviruses and rhinoviruses. METHODS: This was an analysis of nasal swab specimens obtained from 590 outpatients suffering from acute respiratory tract disease between September 2009 and February 2010. RESULTS: The RVP Fast assay performed well in less than 4 h for detecting type A influenza H1 viruses, particularly (H1N1)pdm09, and human entero/rhinoviruses, with 95.2% and 90.05% agreement, respectively, when compared to monoplex real-time PCR assays. This multiplex assay also detected at least 1 virus in 69.3% of the specimens and detected multiple infections in 40 samples. CONCLUSIONS: The multiplex assay detected clinically important viruses in a single genomic test. It will thus be useful for detecting several viruses causing respiratory tract disorders. PMID- 22830611 TI - Cell-free supernatants from probiotic Lactobacillus casei and Lactobacillus rhamnosus GG decrease colon cancer cell invasion in vitro. AB - Probiotics have been shown to have a preventative role in colorectal carcinogenesis but research concerning their prophylactic potential in the later stages of colorectal cancer, specifically metastasis is limited. This study explored the potential of cell-free supernatants (CFS) from 2 probiotic Lactobacillus sp., Lactobacillus casei and Lactobacillus rhamnosus GG, to inhibit colon cancer cell invasion by influencing matrix metalloproteinase-9 (MMP-9) activity and levels of the tight junction protein zona occludens-1 (ZO-1) in cultured metastatic human colorectal carcinoma cells. HCT-116 cells were treated with CFS from L. casei, L. rhamnosus, or Bacteroides thetaiotaomicron (a gut commensal); or with uninoculated bacterial growth media. Treatment with CFS from both Lactobacillus sp. decreased colorectal cell invasion but treatment with CFS from B. thetaiotaomicron did not. CFS from both Lactobacillus sp. decreased MMP-9 and increased ZO-1 protein levels. L. rhamnosus CFS also lowered MMP-9 activity. To begin elucidating the secreted bacterial factor conveying these responses, Lactobacillus sp. CFS were fractionated into defined molecular weight ranges and cell invasion assessed. Fractionation revealed that the inhibitory activity was contained primarily in the >100 kDa and 50-100 kDa fractions, suggesting the inhibitory compound may be a macromolecule such as a protein, nucleic acid, or a polysaccharide. PMID- 22830612 TI - Trichothecenes and zearalenone production by Fusarium equiseti and Fusarium semitectum species isolated from Argentinean soybean. AB - Fusarium equiseti and Fusarium semitectum represent the most abundant species in the Fusarium complex isolated from flowers, soybean pods and seeds in Argentina. The aim of the present study was to assess the production of major type A and type B trichothecenes (diacetoxyscirpenol, neosolaniol, T-2 toxin and HT-2 toxin, nivalenol, deoxynivalenol) and zearalenone by 40 F. equiseti and 22 F. semitectum isolates on rice culture. Mycotoxins were determined by HPLC with fluorescence detection after derivatisation with 1-anthronylnitrile for type A trichothecenes (i.e. diacetoxyscirpenol, neosolaniol, T-2 toxin and HT-2 toxin), by HPLC with UV detection for type B trichothecenes (i.e. nivalenol and deoxynivalenol), and by TLC for zearalenone. A total of 22 of 40 F. equiseti isolates produced diacetoxyscirpenol, nivalenol and ZEA alone or in combination, whereas only two of 20 F. semitectum isolates were nivalenol and ZEA producers. Both Fusarium species did not produce any deoxynivalenol, neosolaniol, T-2 toxin and HT-2 toxin. The variable retention in toxigenicity displayed by both fungal species suggests that these species have a saprophytic lifestyle in the soybean agroecosystem in Argentina. PMID- 22830613 TI - Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor related apoptosis-inducing ligand-induced apoptosis. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells. PMID- 22830614 TI - Combination of skin-directed therapy and oral etoposide for smoldering adult T cell leukemia/lymphoma with skin involvement. AB - Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients' survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL. PMID- 22830615 TI - Low incidence of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in Tianjin, northern China. AB - The purpose of this study was to examine the incidence of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma of the elderly in a representative northern Chinese population. Overall, 212 cases of primary diffuse large B-cell lymphoma were analyzed for EBV-positive status by detection of EBV-encoded RNA using in situ hybridization. Immunophenotypic identity was verified by a streptavidin-biotin peroxidase detection system using the markers CD20, CD3, CD10, BCL6 and MUM1. The prevalence of EBV-positive diffuse large B-cell lymphoma in elderly northern Chinese patients was 3.8% (eight of 212). All eight cases were negative for CD10 and BCL6 immunostaining. The incidence is less frequent than that of southern China and other East-Asian countries. Patients tend to be older, present with a non-germinal center B-cell-like immunophenotype and have a poor outcome. PMID- 22830616 TI - Mediators of the shame-guilt-psychological adjustment relationship. AB - A college student sample (109 women, 90 men) was administered measures of psychological adjustment, shame, guilt, personal fear of invalidity, and aspects of empathy, including personal distress in emergencies and fantasy involvement. Consistent with previous studies, shame but not guilt was significantly positively correlated with poor psychological adjustment. Path analyses with bootstrapped mediation tests indicated that the shame-adjustment relationship was significantly mediated by fear of invalidity, personal distress, and fantasy involvement. A novel finding was that the relationship between guilt and maladjustment was significantly mediated by proneness to fantasy. The findings are discussed in terms of an integrated theory of the shame-fear/distress maladjustment relationship as a framework for understanding the maladaptive, individualistic shame experience. PMID- 22830617 TI - Extreme sensitivity of the spin-splitting and 0.7 anomaly to confining potential in one-dimensional nanoelectronic devices. AB - Quantum point contacts (QPCs) have shown promise as nanoscale spin-selective components for spintronic applications and are of fundamental interest in the study of electron many-body effects such as the 0.7 * 2e(2)/h anomaly. We report on the dependence of the 1D Lande g-factor g and 0.7 anomaly on electron density and confinement in QPCs with two different top-gate architectures. We obtain g values up to 2.8 for the lowest 1D subband, significantly exceeding previous in plane g-factor values in AlGaAs/GaAs QPCs and approaching that in InGaAs/InP QPCs. We show that g is highly sensitive to confinement potential, particularly for the lowest 1D subband. This suggests careful management of the QPC's confinement potential may enable the high g desirable for spintronic applications without resorting to narrow-gap materials such as InAs or InSb. The 0.7 anomaly and zero-bias peak are also highly sensitive to confining potential, explaining the conflicting density dependencies of the 0.7 anomaly in the literature. PMID- 22830618 TI - Drug Fever: a descriptive cohort study from the French national pharmacovigilance database. AB - BACKGROUND: Although known as a rare adverse drug reaction (ADR), drug fever (DF) remains an important issue in medicine, with the risk of leading to inappropriate and potentially harmful diagnostic and therapeutic interventions. Only sparse data regarding DF have been published. OBJECTIVE: The aim of the study was to investigate which drugs were associated with DF, and report outcomes. METHODS: Cases of DF without skin reactions were selected from all ADRs reported from 1986 to 2007 in the French National Pharmacovigilance Database. Drugs potentially responsible for DF were assessed using a qualitative case-by-case analysis (Naranjo's criteria) and quantitative measurement (proportional reporting ratio [PRR]). A drug was implicated as the cause of DF when the following criteria were validated: three or more cases and PRR of at least two with a Chi-squared value of at least four. RESULTS: A total of 167 DF cases involving 115 drugs were eligible. Based on the PRR, 22 drugs were significantly associated with DF. Antibacterials represented the most frequently reported drugs, including amikacin (PRR 39.6 [95% CI 23.6, 69.0], oxacillin (9.1 [3.6, 23.4]), cefotaxime (5.5 [2.0, 15.3]), ceftriaxone (5.4 [2.6, 11.3]), rifampicin (4.0 [1.8, 9.2]), vancomycin (4.0 [1.4, 11.5]), ciprofloxacin (3.1 [1.2, 8.0]), isoniazid (3.9 [1.4, 11.4]), pristinamycin (3.1 [1.0, 9.1]) and cotrimoxazole (2.6 [1.2, 5.8]). Median time [interquartile range] from drug administration to fever onset was 2 days [1.0 10.5]. A diagnosis of DF was made following cessation of the suspected drugs (3 days [1.0-11.5] after fever onset. Drug rechallenge was performed (38.0%), resulting in recurrence of DF in all cases. DF resulted in life-threatening events (0.6%), hospitalization or prolonged hospital stay (24.5%) and persistent disability (0.6%). Final outcome was favourable in 96.9% of cases after drug discontinuation. CONCLUSION: Diagnosing DF is challenging. Based on this large series, antibacterials remain the major class of drugs responsible for DF. PMID- 22830619 TI - Highly selective detection of single-nucleotide polymorphisms using a quartz crystal microbalance biosensor based on the toehold-mediated strand displacement reaction. AB - Toehold-mediated strand displacement reaction (SDR) is first introduced to develop a simple quartz crystal microbalance (QCM) biosensor without an enzyme or label at normal temperature for highly selective and sensitive detection of single-nucleotide polymorphism (SNP) in the p53 tumor suppressor gene. A hairpin capture probe with an external toehold is designed and immobilized on the gold electrode surface of QCM. A successive SDR is initiated by the target sequence hybridization with the toehold domain and ends with the unfolding of the capture probe. Finally, the open-loop capture probe hybridizes with the streptavidin coupled reporter probe as an efficient mass amplifier to enhance the QCM signal. The proposed biosensor displays remarkable specificity to target the p53 gene fragment against single-base mutant sequences (e.g., the largest discrimination factor is 63 to C-C mismatch) and high sensitivity with the detection limit of 0.3 nM at 20 degrees C. As the crucial component of the fabricated biosensor for providing the high discrimination capability, the design rationale of the capture probe is further verified by fluorescence sensing and atomic force microscopy imaging. Additionally, a recovery of 84.1% is obtained when detecting the target sequence in spiked HeLa cells lysate, demonstrating the feasibility of employing this biosensor in detecting SNPs in biological samples. PMID- 22830620 TI - Acquisition of CD4-dependence by CD4-independent SIV passaged in human peripheral blood mononuclear cells. AB - BACKGROUND: Chemokine receptors (CKRs), the primordial receptors for primate lentiviruses, are sufficient to mediate virus-cell fusion. Several different fusogenic CKRs and related receptors provide a broad potential host cell range, presumably advantageous for viral spread within a given infected individual, and across species. By contrast, the additional constraint of obligatory CD4 binding, just prior to CKR engagement, radically restricts potential host cells within an individual (or lymph node microenvironment), and might also limit xenotransmission, as CD4 sequences vary among primates. In spite of these potential drawbacks, CD4 dependent entry for SIV and HIV is the rule rather than the exception, and is generally thought to have evolved by selection for 1) stabilization of virus-cell surface interactions, and 2) conformational shielding of readily neutralized CKR binding epitopes. CD4 binding residues of SIV and HIV envelope are recessed, (relatively hidden from immune detection) and may exhibit a strong degree of automimicry, thus benefitting from self tolerance.Documented evolution, within individual macaques, of neutralization-resistant CD4-dependent SIV, derived from CD4-independent inocula, supports these ideas, but does not explain CD4's exclusive role as the penultimate receptor-even more striking, given the wide diversity of CKRs and other surface molecules that can serve as actual fusion receptors for SIV. We, therefore, explored the additional, non exclusive, hypothesis that surface CD4 on leukocytes is a marker of a more favorable host cell environment, as compared to CD8, NK, or B cell surface markers. RESULTS: We demonstrate progressive in vitro evolution of two SIV strains to CD4-dependence (and CXCR4 tropism) in normal human PBMCs (hPBMCs). The two CD4-independent strains of SIV tested developed nearly complete CD4 dependence over several months of serial passage in hPBMCs, correlating with a limited number of non-synonymous env region mutations, some previously reported to be determinants of CD4-dependency. The initial ability of SIV stocks to grow to significant (albeit, relatively low) levels in CD4(-), CD14(-) cells was also lost with long term passage. Rapid emergence and subsequent prominence of G -> A and A -> G mutations within env regions associated with CD4 dependence was seen. CONCLUSIONS: Progressive acquisition of strict CD4 tropism, independent of immunoselection, supports the idea that surface CD4 identifies optimal host cells having intracellular environments most favorable to viral replication. The prominence of mutations involving G to A, or A to G, suggests that APOBEC 3 mediated infidelity may facilitate rapid switching of cell surface receptor usage within SIV swarms encountering fluctuating availability of optimal CD4+CKR+ targets. These observations of non-immune selection are compatible with, and may accelerate, simultaneous selection for previously described CD4-dependent neutralization resistance in vivo. PMID- 22830622 TI - Tai Chi exercise and auricular acupressure for people with rheumatoid arthritis: an evaluation study. AB - AIMS AND OBJECTIVES: (i) To assess the effectiveness of Tai Chi exercise in people with rheumatoid arthritis (RA). (ii) To ascertain if Tai Chi and auricular acupressure have a potentiation effect in controlling pain. (iii) To evaluate the acceptability and enjoyment of the classes. BACKGROUND: Tai Chi has been suggested as a suitable exercise for people with arthritis and specific programmes have been developed. Auricular acupressure is a therapeutic method by which points on the ear are stimulated to treat various disorders. DESIGN: A pragmatic non-randomised before/after study to compare the effects of the interventions. METHODS: People with RA (n=21) were recruited and allocated into two groups. Both groups followed a Tai Chi exercise programme, twice a week for 12 weeks, but one group (n=14) had, in addition, the auricular acupressure. Physical symptoms and function, pain, quality of life and self-efficacy were measured in both groups before and after the programme. Acceptability and enjoyment were assessed at the end. RESULTS: At 12 weeks, both groups had achieved statistically significant improvements in balance, grip strength, pinch strength, 50 foot walk time self reported joint pain, swollen joint count, tender joint count and in self efficacy in relation to pain control. All participants stated that they enjoyed the classes. There was no evidence to suggest that the auricular acupressure enhanced the effects of the Tai Chi intervention. CONCLUSION: The classes appeared to be mentally as well as physically helpful to participants. RELEVANCE TO CLINICAL PRACTICE: People with a chronic debilitating disease such as RA should be encouraged to undertake gentle strengthening exercise such as Tai Chi because of its potential for physical and psychological improvements. PMID- 22830621 TI - Key anticipated regulatory issues for clinical use of human induced pluripotent stem cells. AB - The production of human induced pluripotent stem cells (hiPSCs) has greatly expanded the realm of possible stem cell-based regenerative medicine therapies and has particularly exciting potential for autologous therapies. However, future therapies based on hiPSCs will first have to address not only similar regulatory issues as those facing human embryonic stem cells with the US FDA and international regulatory agencies, but also hiPSCs have raised unique concerns as well. While the first possible clinical use of hiPSCs remains down the road, as a field it would be wise for us to anticipate potential roadblocks and begin formulating solutions. In this article, I discuss the potential regulatory issues facing hiPSCs and propose some potential changes in the direction of the field in response. PMID- 22830623 TI - Melanocytic lesions with eczematous reaction (Meyerson's phenomenon) - a histopathologic analysis of 64 cases. AB - BACKGROUND: Eczematous (spongiotic) reaction in melanocytic lesions (Meyerson's phenomenon) has not been systematically analyzed and has not been convincingly documented in melanoma. METHODS: We analyzed 64 consecutive melanocytic lesions with spongiotic reaction, occurring in 57 patients (age range 14-81 years; mean, 39 years; 30 females, 27 males) including 16 common acquired nevi, 3 nevi with congenital features, 2 Spitz nevi, 29 dysplastic nevi, 6 in situ and 8 invasive melanomas. RESULTS: The intensity of the spongiotic reaction was graded as mild in 24 (38%), moderate in 22 (34%) and marked in 18 (28%) lesions. It was moderate/marked in 6 of 14 (43%) in situ or invasive melanomas. Upward migration of melanocytes in the epidermis was noted in 7 (33%) non-dysplastic and 10 (34%) dysplastic nevi but was generally limited to the lower half of the epidermis. Moderate/severe cytologic atypia was found in 14 (48%) dysplastic nevi and all melanomas but not in non-dysplastic nevi. CONCLUSIONS: Prominent spongiotic reaction with eosinophils in the inflammatory infiltrate can affect all types of melanocytic lesions. Upward migration involving the uppermost layers of the epidermis, especially when extensive and present in areas with a less pronounced spongiotic reaction, and moderate/severe cytologic atypia indicate a melanoma. PMID- 22830624 TI - Shell biofilm-associated nitrous oxide production in marine molluscs: processes, precursors and relative importance. AB - Emission of the greenhouse gas nitrous oxide (N2 O) from freshwater and terrestrial invertebrates has exclusively been ascribed to N2 O production by ingested denitrifying bacteria in the anoxic gut of the animals. Our study of marine molluscs now shows that also microbial biofilms on shell surfaces are important sites of N2 O production. The shell biofilms of Mytilus edulis, Littorina littorea and Hinia reticulata contributed 18-94% to the total animal associated N2 O emission. Nitrification and denitrification were equally important sources of N2 O in shell biofilms as revealed by (15) N-stable isotope experiments with dissected shells. Microsensor measurements confirmed that both nitrification and denitrification can occur in shell biofilms due to a heterogeneous oxygen distribution. Accordingly, ammonium, nitrite and nitrate were important drivers of N2 O production in the shell biofilm of the three mollusc species. Ammonium excretion by the animals was found to be sufficient to sustain N2 O production in the shell biofilm. Apparently, the animals provide a nutrient-enriched microenvironment that stimulates growth and N2 O production of the shell biofilm. This animal-induced stimulation was demonstrated in a long term microcosm experiment with the snail H. reticulata, where shell biofilms exhibited the highest N2 O emission rates when the animal was still living inside the shell. PMID- 22830625 TI - A complete sequence of Saccharomyces paradoxus mitochondrial genome that restores the respiration in S. cerevisiae. AB - We determined the complete sequence of 71 355-bp-long mitochondrial genome from Saccharomyces paradoxus entirely by direct sequencing of purified mitochondrial DNA (mtDNA). This mtDNA possesses the same features as its close relative Saccharomyces cerevisiae - A + T content 85.9%, set of genes coding for the three components of cytochrome oxidase, cytochrome b, three subunits of ATPase, both ribosomal subunits, gene for ribosomal protein, rnpB gene, tRNA package (24) and yeast genetic code. Genes are interrupted by nine group I and group II introns, two of which are in positions unknown in S. cerevisiae, but recognized in Saccharomyces pastorianus. The gene products are related to S. cerevisiae, and the identity of amino acid residues varies from 100% for cox2 to 83% for rps3. The remarkable differences from S. cerevisiae are (1) different gene order (translocation of trnF-trnT1-trnV-cox3-trnfM-rnpb-trnP and transposition of trnW rns), (2) occurrence of two unusual GI introns, (3) eight active ori elements, and (4) reduced number of GC clusters and divergent intergenic spacers. Despite these facts, the sequenced S. paradoxus mtDNA introduced to S. cerevisiae was able to support the respiratory function to the same extent as the original mtDNAs. PMID- 22830627 TI - Drivers of change in hunter offtake and hunting strategies in Sendje, Equatorial Guinea. AB - Economic development in Africa is expected to increase levels of bushmeat hunting through rising demand for meat and improved transport infrastructure. However, few studies have tracked long-term changes in hunter behavior as a means of testing this prediction. We evaluated changes in hunter behavior in a rural community in Equatorial Guinea over a period of rapid national economic growth, during which time road access to the regional capital greatly improved. We conducted offtake surveys (Supporting Information) over 3 7-week periods at the same time of year in 1998, 2003, and 2010 and conducted hunter and household interviews (Supporting Information) in 2003 and 2010. We tested whether relations existed among catch, hunting effort, hunting strategy, and income earned through hunting and other livelihoods in 2003 and 2010. Although village offtake increased from 1775 kg in 1998 to 4172 kg in 2003, it decreased in 2010 to 1361 kg. Aggregate catch per unit effort (i.e., number of carcasses caught per hunter and per trap) decreased from 2003 to 2010, and the majority of hunters reported a decrease in abundance of local fauna. Although these results are indicative of unsustainable hunting, cumulative changes in offtake and catch per unit effort were driven by a contraction in the total area hunted following an out-migration of 29 of the village's hunters, most of whom left to gain employment in the construction industry, after 2003. Hunters operating in both 2003 and 2010 hunted closer to the village because an increased abundance of elephants posed a danger and because they desired to earn income through other activities. Our study provides an example of national economic development contributing to a reduction in the intensity and extent of hunting. PMID- 22830626 TI - Developmental features of DNA methylation during activation of the embryonic zebrafish genome. AB - BACKGROUND: Zygotic genome activation (ZGA) occurs at the mid-blastula transition (MBT) in zebrafish and is a period of extensive chromatin remodeling. Genome scale gametic demethylation and remethylation occurs after fertilization, during blastula stages, but how ZGA relates to promoter DNA methylation states is unknown. Using methylated DNA immunoprecipitation coupled to high-density microarray hybridization, we characterize genome-wide promoter DNA methylation dynamics before, during and after ZGA onset, in relation to changes in post translational histone modifications and gene expression. RESULTS: We show methylation of thousands of promoters before ZGA and additional methylation after ZGA, finding more dynamic methylation -1 to 0 kb upstream of the transcription start site than downstream. The MBT is marked by differential methylation of high and low CpG promoters, and we identify hypomethylated promoters that are mostly CG-rich and remain hypomethylated through the MBT. Hypomethylated regions constitute a platform for H3K4me3, whereas H3K9me3 preferentially associates with methylated regions. H3K27me3 associates with either methylation state depending on its coincidence with H3K4me3 or H3K9me3. Cohorts of genes differentially expressed through the MBT period display distinct promoter methylation patterns related to CG content rather than transcriptional fate. Lastly, although a significant proportion of genes methylated in sperm are unmethylated in embryos, over 90% of genes methylated in embryos are also methylated in sperm. CONCLUSIONS: Our results suggest a pre-patterning of developmental gene expression potential by a combination of DNA hypomethylation and H3K4 trimethylation on CG-rich promoters, and are consistent with a transmission of DNA methylation states from gametes to early embryos. PMID- 22830628 TI - Abstracts of the 2nd Innsbruck Hypothermia Symposium. Portoroz, Slovenia. June 7 9, 2012. PMID- 22830629 TI - Management options for intraparotid facial nerve schwannoma. AB - CONCLUSION: Limited intraparotid facial nerve schwannoma (IFNS) and IFNS with intratemporal involvement should be managed separately because of their different characteristics. Limited IFNS with House-Brackman (HB) grade <= II should undergo tumor removal only if it can be resected easily off the nerve. For IFNS with intratemporal involvement and a HB grade <= II, a conservative treatment (i.e. wait-and-see alone, or bone decompression) is recommended. OBJECTIVE: To provide management options for IFNS. METHODS: From 1996 to 2011, seven cases of IFNS underwent surgical treatment. Clinical and radiologic findings, surgical approach, and preoperative and postoperative facial nerve function were analyzed retrospectively. RESULTS: Three IFNSs extended into the mastoid (43%). Two of the three patients with mastoid extension progressed to HB grade IV after the operation because the facial nerve was sacrificed, whereas the other one who underwent biopsy and decompression remained at HB grade II. Four limited IFNSs (57%) presented with grades I-II, three of which were removed while preserving facial nerve function and the other was removed by cystic decompression. No recurrence or significant growth of the non-resected schwannoma was observed. PMID- 22830630 TI - Current saturation in field emission from H-passivated Si nanowires. AB - This paper explores the field emission (FE) properties of highly crystalline Si nanowires (NWs) with controlled surface passivation. The NWs were batch-grown by the vapor-liquid-solid process using Au catalysts with no intentional doping. The FE current-voltage characteristics showed quasi-ideal current saturation that resembles those predicted by the basic theory for emission from semiconductors, even at room temperature. In the saturation region, the currents were extremely sensitive to temperature and also increased linearly with voltage drop along the nanowire. The latter permits the estimation of the doping concentration and the carrier lifetime, which is limited by surface recombination. The conductivity could be tuned over 2 orders of magnitude by in situ hydrogen passivation/desorption cycles. This work highlights the role of dangling bonds in surface leakage currents and demonstrates the use of hydrogen passivation for optimizing the FE characteristics of Si NWs. PMID- 22830632 TI - The influence of curcumin, quercetin, and eicosapentaenoic acid on the expression of phase II detoxification enzymes in the intestinal cell lines HT-29, Caco-2, HuTu 80, and LT97. AB - Curcumin, quercetin, and eicosapentaenoic acid (EPA) are 3 natural compounds with the capacity to reduce adenoma burden in patients with familial adenomatous polyposis (FAP). The mechanistic basis of this anticarcinogenic capacity is largely unknown, but it was suggested that induction of detoxification enzymes is involved. Therefore, the effects of low-dose curcumin, quercetin, and EPA on phase II detoxification enzymes UDP-glucuronosyltransferase (UGT), glutathione S transferase (GST), as well as on glutathione (GSH) content were analyzed in 4 cell line models of intestinal carcinogenesis. HT-29, HuTu 80, and Caco-2 intestinal cancer cells and LT97 colon adenoma cells from a patient with FAP were treated with low-dose noncytotoxic concentrations of curcumin, quercetin, and EPA. GST enzyme activity was measured by spectrophotometry, and expression of GSTA1, GSTM1, GSTP1, GSTT1, and UGT1 by Western blotting. Cytosolic GSH levels were determined by high performance liquid chromatography. An inducing effect of curcumin and quercetin on GST or UGT was seen in Caco-2, LT97, and HuTu 80 cells. GSH levels were reduced by quercetin and EPA in HT-29 cells and induced by curcumin in Caco-2 cells. In LT97 cells, GST activity and expression was reduced, but UGT1 expression was induced by curcumin and quercetin; whereas EPA only decreased GST or UGT levels. In summary, enhancement of the detoxification capacity by low dose of the potential anticarcinogens curcumin, quercetin, or EPA seems only a minor factor in explaining their anticarcinogenic properties. PMID- 22830633 TI - Counting the cost of not costing HIV health facilities accurately: pay now, or pay more later. AB - The HIV pandemic continues to be one of our greatest contemporary public health threats. Policy makers in many middle- and low-income countries are in the process of scaling up HIV prevention, treatment and care services in the context of a reduction in international HIV funding due to the global economic downturn. In order to scale up services that are sustainable in the long term, policy makers and implementers need to have access to robust and contemporary strategic information, including financial information on expenditure and cost, in order to be able to plan, implement, monitor and evaluate HIV services. A major problem in middle- and low-income countries continues to be a lack of basic information on the use of services, their cost, outcome and impact, while those few costing studies that have been performed were often not done in a standardized fashion. Some researchers handle this by transposing information from one country to another, developing mathematical or statistical models that rest on assumptions or information that may not be applicable, or using top-down costing methods that only provide global financial costs rather than using bottom-up ingredients-based costing. While these methods provide answers in the short term, countries should develop systematic data collection systems to store, transfer and produce robust and contemporary strategic financial information for stakeholders at local, sub national and national levels. National aggregated information should act as the main source of financial data for international donors, agencies or other organizations involved with the global HIV response. This paper describes the financial information required by policy makers and other stakeholders to enable them to make evidence-informed decisions and reviews the quantity and quality of the financial information available, as indicated by cost studies published between 1981 and 2008. Among the lessons learned from reviewing these studies, a need was identified for providing countries with practical guidance to produce reliable and standardized costing data to monitor performance, as countries want to improve programmes and services, and have to demonstrate an efficient use of resources. Finally, the issues raised in this paper relate to the provision of all areas of healthcare in countries and it is going to be increasingly important to leverage the lessons learned from the HIV experience and use resources more effectively and efficiently to improve health systems in general. PMID- 22830634 TI - Reactive flow in silicon electrodes assisted by the insertion of lithium. AB - In the search for high-energy density materials for Li-ion batteries, silicon has emerged as a promising candidate for anodes due to its ability to absorb a large number of Li atoms. Lithiation of Si leads to large deformation and concurrent changes in its mechanical properties, from a brittle material in its pure form to a material that can sustain large inelastic deformation in the lithiated form. These remarkable changes in behavior pose a challenge to theoretical treatment of the material properties. Here, we provide a detailed picture of the origin of changes in the mechanical properties, based on first-principles calculations of the atomic-scale structural and electronic properties in a model amorphous silicon (a-Si) structure. We regard the reactive flow of lithiated silicon as a nonequilibrium process consisting of concurrent Li insertion driven by unbalanced chemical potential and flow driven by deviatoric stress. The reaction enables the material to flow at a lower level of stress. Our theoretical model is in excellent quantitative agreement with experimental measurements of lithiation induced stress on a Si thin film. PMID- 22830635 TI - Hepatocyte growth factor in saliva of patients with renal failure and periodontal disease. AB - BACKGROUND: Hepatocyte growth factor (HGF), endogenous cytokine with pleiotropic repairing and regeneration properties in relation to most tissues and organs, contributes to the progression of periodontal disease (PD). Furthermore, PD is a significant health problem in patients with chronic renal failure (CRF). The role of HGF in the development of PD in this specific population was not a subject of research so far. MATERIAL AND METHODS: The following groups were enrolled in the study: (1) 26 chronic hemodialysis (HD) subjects, (2) 26 patients treated by continuous ambulatory peritoneal dialysis (CAPD), (3) 28 predialysis CRF patients, (4) 26 subjects with advanced PD (without coexisting diseases), and (5) 20 healthy subjects without PDs. HGF level in saliva was measured using the immunoenzymatic method. Gingival index, papillary bleeding index, plaque index, and the loss of clinical attachment level were evaluated. RESULTS: The HGF level in saliva of HD patients was twice higher than in that of subjects with healthy periodontium. Direct relationships between proper HGF level in saliva and the indices GI, PBI, and PI in CAPD-treated patients and with more severe PD were shown. It was found that PD is most advanced in HD patients, moderately in CAPD treated patients and to the smallest extent in predialysis CRF patients. CONCLUSIONS: The HGF level in mixed saliva is the index of PD progression in subjects without renal failure and in CAPD-treated patients. PD is common in renal failure patients and is a significant problem concerning general health status. PMID- 22830636 TI - Theoretical study of the electronic spectra of small molecules that incorporate analogues of the copper-cysteine bond. AB - The copper-sulfur bond that binds cysteinate to the metal center is a key factor in the spectroscopy of blue copper proteins. We present theoretical calculations describing the electronically excited states of small molecules, including CuSH, CuSCH(3), (CH(3))(2)SCuSH, (imidazole)-CuSH, and (imidazole)(2)-CuSH, derived from the active site of blue copper proteins that contain the copper-sulfur bond in order to identify small molecular systems that have electronic structure that is analogous to the active site of the proteins. Both neutral and cationic forms are studied since these represent the reduced and oxidized forms of the protein, respectively. For CuSH and CuSH(+), excitation energies from time-dependent density functional theory with the B97-1 exchange-correlation functional agree well with the available experimental data and multireference configuration interaction calculations. For the positive ions, the singly occupied molecular orbital is formed from an antibonding combination of a 3d orbital on copper and a 3p(pi) orbital on sulfur, which is analogous to the protein. This leads several of the molecules to have qualitatively similar electronic spectra to the proteins. For the neutral molecules, changes in the nature of the low lying virtual orbitals leads the predicted electronic spectra to vary substantially between the different molecules. In particular, addition of a ligand bonded directly to copper results in the low-lying excited states observed in CuSH and CuSCH(3) to be absent or shifted to higher energies. PMID- 22830637 TI - Effect of skin pH for wrinkle formation on Asian: Korean, Vietnamese and Singaporean. AB - BACKGROUND: Skin pH may be influenced by various factors, such as hydration of stratum corneum, rate of sebum excretion rate, transepidermal water loss (TEWL) and sweating in relation to skin ageing. OBJECTIVE: The aim of this study was to evaluate the correlation between skin pH and wrinkle formation that is directly related to ageing. In addition, we investigated the factors related to skin ageing by comparing the association between skin pH and other skin properties. METHODS: Three hundred volunteers were selected from three countries: Korea, Vietnam and Singapore. Hydration on the stratum corneum, the rate of sebum excretion rate, melanin index, TEWL and skin temperature on the cheek were measured in a controlled room, and wrinkle length and depth using replicas were compared with skin pH variation. RESULTS: The mean and standard deviation of skin surface pH among the three countries were 5.510 +/- 0.625. The greatest gap of skin pH that revealed significant differences for skin properties was represented between the Koreans and the Vietnamese. For all three countries, skin hydration, melanin contents, wrinkle length, wrinkle depth and skin temperature were significantly correlated with skin pH. Factors related to skin moisturizing, such as skin hydration, sebum excretion rate and skin temperature, were negatively correlated with skin pH. Wrinkle length and depth decreased as skin pH became more acidic. CONCLUSIONS: Skin properties displayed various values depending on skin pH. In particular, wrinkle formation significantly decreased as skin pH becomes more acidic. We conclude that skin pH is determined by skin properties, such as skin hydration, sebum excretion rate, melanin concentration, TEWL and skin temperature that affects wrinkle formation. PMID- 22830638 TI - Co-infection by two linezolid-resistant coagulase-negative staphylococci with two different resistance determinants. AB - Linezolid resistance among Gram-positive pathogens is being reported with increasing frequency. We examined 14 linezolid-resistant coagulase-negative staphylococci (CoNS) isolated from blood cultures obtained from patients admitted to the Intensive Care Unit of Vicenza General Hospital, Italy. The species identification yielded 10 Staphylococcus epidermidis, 3 Staphylococcus hominis, and 1 Staphylococcus capitis. Minimal inhibitory concentrations of linezolid ranged between 16 and 32 mg/l. By sequencing domain V of the 23S rRNA gene, 4 isolates were found to harbour a G2576T mutation and 10 isolates a G2447T mutation. None of the strains under study presented either the cfr gene or cardinal mutations in the L3, L4, or L22 riboproteins. In this clinical collection of linezolid-resistant CoNS the G2447T mutation was dominantly associated with S. epidermidis, while the G2576T mutation was found in other CoNS species. Two different CoNS species endowed with either mutation were isolated from 2 patients. PMID- 22830639 TI - Hallmarks of human "immunosenescence": adaptation or dysregulation? AB - Is immunosenescence an intrinsic ageing process leading to dysregulation of immunity or an adaptive response of the individual to pathogen exposure? Age associated differences in bone marrow immune cell output and thymic involution suggest the former. Accepted hallmarks of immunosenescence (decreased numbers and percentages of peripheral naive T cells, especially CD8 + cells, and accumulations of memory T cells, especially late-stage differentiated CD8+ cells) suggest the latter, viewed as the result of depletion of the reservoir of naive cells over time by contact with pathogens and their conversion to memory cells, the basis of adaptive immunity. Thymic involution beginning early in life limits the generation of naive cells such that the adult is believed to rely to a great extent on the naive cell pool produced mostly before puberty. Thus, these hallmarks of immunosenescence would be markedly affected by the history of the individual's exposure to pathogens. It would be predicted that in modern industrialized populations, the cumulative effects of antigenic "stressors" would be lower than in less hygienic societies, whereas intrinsic processes might be more similar in different populations. Identifying such stressors and taking steps to nullify their impact could therefore result in delayed immunosenescence and contribute significantly to improving public health. Here, I discuss some of the available data bearing on this prediction. PMID- 22830640 TI - Capillary ion chromatography at high pressure and temperature. AB - The application of high pressure and temperature in ion chromatography (IC) can significantly improve the efficiency and reduce the analysis time. In this work, the kinetic-performance limits of capillary IC columns with inner diameters of 400 MUm packed with 4 and 7 MUm macroporous anion-exchange particles were investigated employing a capillary ion-exchange instrument allowing column pressures up to 34 MPa and column temperatures up to 80 degrees C. Plate heights below 10 MUm could be realized using capillary columns packed with 4 MUm particles. Compared to conventional IC using 7 MUm particles and pressures up to 21 MPa, a 40% improvement in plate number could be achieved when working at the kinetic performance limits at 34 MPa and using columns packed with 4 MUm particles. Using coupled columns with a total length of 400 mm, a mixture of seven anions was separated within 7.5 min while yielding 20,000 plates. Increasing the temperature improved the performance limits when operating in the C-term region (for fast IC separation using columns <75 cm). Temperature also affected the retention properties and hence the selectivity. At higher temperature, retention for monovalent ions was mainly governed by ion diameter. An increase in retention with temperature was observed for small ions, and there was a decrease for ions having a larger diameter. The retention factor for divalent and trivalent anions increased with temperature. PMID- 22830641 TI - Knowledge of blood transfusion among nurses. AB - AIMS AND OBJECTIVES: To measure nurses' knowledge of blood transfusion in the United Arab Emirates. BACKGROUND: Blood transfusion is a fundamental aspect of nursing practice and nurses' knowledge of it is essential for safe practice. Yet little is known about their blood transfusion practice and the knowledge that underpins it. The few studies that have investigated this topic previously have shown deficiencies in both knowledge and practice. To date, no such study has been carried out in the Middle East. DESIGNS: A descriptive, cross-sectional study. METHODS: A random sample of 248 nurses from two general hospitals in the Emirate of Abu Dhabi. The response rate was 94AE3%. A knowledge questionnaire comprising six sections and 49 items was developed for this study. Data were analysed using descriptive and inferential statistics. RESULTS: The overall knowledge scores of nurses were generally low ranging from 27-56 of a possible score of 70. Data analysis revealed knowledge deficits in several key aspects of blood transfusion. There were statistically significant relationship between nurses' knowledge and the work setting, the country where they trained and type of qualifications. CONCLUSION: This survey highlighted knowledge deficits which could be detrimental to patient safety. These results have implications for nursing education, policy and practice. RELEVANCE TO CLINICAL PRACTICE: Nurses have the responsibility to update their knowledge of and skills in carrying out blood transfusion. The tool developed in this study may be useful for educators and managers to identify gaps in knowledge and inform decisions to address them. PMID- 22830642 TI - Granuloma annulare-like eruption associated with B-cell chronic lymphocytic leukemia. AB - BACKGROUND: Cutaneous granulomatous inflammation can occur in patients with T cell lymphoma and Hodgkin disease. We describe the unusual microscopic pattern of a granuloma annulare (GA)-like eruption co-existing with B-cell chronic lymphocytic leukemia (B-CLL). METHODS: We reviewed the histopathology and immunophenotype of skin biopsies from two patients with B-CLL and cutaneous lesions resembling GA. RESULTS: Both patients had symptomatic cutaneous lesions clinically resembling GA; one had lesions refractory to standard dermatologic therapy. Histopathology showed GA-like palisaded histiocytic infiltration, with subtle collections of lymphocytes interspersed among the granulomatous inflammation. Immunohistochemistry showed strong expression of CD20 and CD79a, with aberrant CD5 co-expression, confirming cutaneous involvement by B-CLL. CONCLUSIONS: Co-existence of a GA-like infiltrate and cutaneous B-CLL raises the possibility that granulomatous inflammation occurs as a secondary response to dermal infiltration by leukemic cells. Because histopathologic findings can be subtle, knowledge of this association is essential to avoid overlooking the diagnosis. Regardless of whether histopathology reflects a reactive or primary phenomenon, documentation of cutaneous involvement by B-CLL may serve as a rationale for specific treatment of the underlying B-CLL in patients with skin lesions unresponsive to dermatologic therapy and for whom there is no other justification for leukemia-targeted therapy. PMID- 22830643 TI - Analysis of UDP-D-apiose/UDP-D-xylose synthase-catalyzed conversion of UDP-D apiose phosphonate to UDP-D-xylose phosphonate: implications for a retroaldol aldol mechanism. AB - UDP-D-apiose/UDP-D-xylose synthase (AXS) catalyzes the conversion of UDP-D glucuronic acid to UDP-D-apiose and UDP-D-xylose. An acetyl-protected phosphonate analogue of UDP-D-apiose was synthesized and used in an in situ HPLC assay to demonstrate for the first time the ability of AXS to interconvert the two reaction products. Density functional theory calculations provided insight into the energetics of this process and the apparent inability of AXS to catalyze the conversion of UDP-D-xylose to UDP-D-apiose. The data suggest that this observation is unlikely to be due to an unfavorable equilibrium but rather results from substrate inhibition by the most stable chair conformation of UDP-D xylose. The detection of xylose cyclic phosphonate as the turnover product reveals significant new details about the AXS-catalyzed reaction and supports the proposed retroaldol-aldol mechanism of catalysis. PMID- 22830644 TI - The Burkholderia cenocepacia sensor kinase hybrid AtsR is a global regulator modulating quorum-sensing signalling. AB - Burkholderia cenocepacia is commonly found in the environment and also as an important opportunistic pathogen infecting patients with cystic fibrosis. Successful infection by this bacterium requires coordinated expression of virulence factors, which is achieved through different quorum sensing (QS) regulatory systems. Biofilm formation and Type 6 secretion system (T6SS) expression in B. cenocepacia K56-2 are positively regulated by QS and negatively regulated by the sensor kinase hybrid AtsR. This study reveals that in addition to affecting biofilm and T6SS activity, the deletion of atsR in B. cenocepacia leads to overproduction of other QS-regulated virulence determinants including proteases and swarming motility. Expression of the QS genes, cepIR and cciIR, was upregulated in the DeltaatsR mutant and resulted in early and increased N acylhomoserine lactone (AHL) production, suggesting that AtsR plays a role in controlling the timing and fine-tuning of virulence gene expression by modulating QS signalling. Furthermore, a DeltaatsRDeltacepIDeltacciI mutant could partially upregulate the same virulence determinants indicating that AtsR also modulates the expression of virulence genes by a second mechanism, independently of any AHL production. Together, our results strongly suggest that AtsR is a global virulence regulator in B. cenocepacia. PMID- 22830645 TI - What brain signals are suitable for feedback control of deep brain stimulation in Parkinson's disease? AB - Feedback control of deep brain stimulation (DBS) in Parkinson's disease has great potential to improve efficacy, reduce side effects, and decrease the cost of treatment. In this, the timing and intensity of stimulation are titrated according to biomarkers that capture current clinical state. Stimulation may be at standard high frequency or intelligently patterned to directly modify specific pathological rhythms. The search for and validation of appropriate feedback signals are therefore crucial. Signals recorded from the DBS electrode currently appear to be the most promising source of feedback. In particular, beta-frequency band oscillations in the local field potential recorded at the stimulation target may capture variation in bradykinesia and rigidity across patients, but this remains to be confirmed within patients. Biomarkers that reliably reflect other impairments, such as tremor, also need to be established. Finally, whether brain signals are causally important needs to be established before stimulation can be specifically patterned rather than delivered at empirically defined high frequency. PMID- 22830647 TI - N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB334867), a hypocretin receptor-1 antagonist, preferentially prevents ethanol seeking: comparison with natural reward seeking. AB - Orexins/hypocretins (Orx/Hcrt) are hypothalamic peptides that regulate a wide range of physiological processes and have been shown to be recruited by drugs of abuse. This study was designed to test the effect of the specific Orx/Hcrt receptor-1 (Hcrt-r1) antagonist, N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin 4-yl urea (SB334867), on reinstatement elicited by ethanol (EtOH)-associated stimuli versus stimuli associated with a conventional reinforcer [i.e. SuperSac, consisting of 3% glucose and 0.125% saccharin (w/v)]. SB334867 (1-10 mg/kg, i.p.) dose-dependently reduced reinstatement induced by the EtOH- but not SuperSac associated stimuli. These findings support a differential role of Hcrt-r1 in mediating EtOH seeking versus natural reward seeking. PMID- 22830649 TI - Vestibular-evoked myogenic potential in response to bone-conducted sound in patients with otosclerosis. AB - CONCLUSION: Saccular dysfunction is a major cause of balance problems in patients with otosclerosis. Vestibular-evoked myogenic potential in response to bone conducted sound (BC-VEMP) testing is useful for diagnosis of these patients. OBJECTIVES: The purpose of this study was to elucidate the origin of balance problems in patients with otosclerosis using BC-VEMP. METHODS: Subjects comprised 25 patients with unoperated otosclerosis (9 men and 16 women). They were divided into two groups depending on type of balance problems. Results of cochleo vestibular functions including pure-tone audiometry, caloric testing, and BC-VEMP testing were compared between the two groups. RESULTS: Ten patients had complained of dizziness and/or vertigo (disequilibrium group), and the other 15 patients had not (Non-disequilibrium group). Nine patients showed abnormal results on BC-VEMP testing in the disequilibrium group, while one patient had abnormal results in the non-disequilibrium group (p < 0.001). PMID- 22830646 TI - Walks4work: rationale and study design to investigate walking at lunchtime in the workplace setting. AB - BACKGROUND: Following recruitment of a private sector company, an 8 week lunchtime walking intervention was implemented to examine the effect of the intervention on modifiable cardiovascular disease risk factors, and further to see if walking environment had any further effect on the cardiovascular disease risk factors. METHODS: For phase 1 of the study participants were divided into three groups, two lunchtime walking intervention groups to walk around either an urban or natural environment twice a week during their lunch break over an 8 week period. The third group was a waiting-list control who would be invited to join the walking groups after phase 1. In phase 2 all participants were encouraged to walk during their lunch break on self-selecting routes. Health checks were completed at baseline, end of phase 1 and end of phase 2 in order to measure the impact of the intervention on cardiovascular disease risk. The primary outcome variables of heart rate and heart rate variability were measured to assess autonomic function associated with cardiovascular disease. Secondary outcome variables (Body mass index, blood pressure, fitness, autonomic response to a stressor) related to cardiovascular disease were also measured. The efficacy of the intervention in increasing physical activity was objectively monitored throughout the 8-weeks using an accelerometer device. DISCUSSION: The results of this study will help in developing interventions with low researcher input with high participant output that may be implemented in the workplace. If effective, this study will highlight the contribution that natural environments can make in the reduction of modifiable cardiovascular disease risk factors within the workplace. PMID- 22830650 TI - Engineered mutations change the structure and stability of a virus-like particle. AB - The single-coat protein (CP) of bacteriophage Qbeta self-assembles into T = 3 icosahedral virus-like particles (VLPs), of interest for a wide range of applications. These VLPs are very stable, but identification of the specific molecular determinants of this stability is lacking. To investigate these determinants along with manipulations that confer more capabilities to our VLP material, we manipulated the CP primary structure to test the importance of various putative stabilizing interactions. Optimization of a procedure to incorporate fused CP subunits allowed for good control over the average number of covalent dimers in each VLP. We confirmed that the disulfide linkages are the most important stabilizing elements for the capsid and that acidic conditions significantly enhance the resistance of VLPs to thermal degradation. Interdimer interactions were found to be less important for VLP assembly than intradimer interactions. Finally, a single point mutation in the CP resulted in a population of smaller VLPs in three distinct structural forms. PMID- 22830652 TI - Evolution of nesting height in an endangered Hawaiian forest bird in response to a non-native predator. AB - The majority of bird extinctions since 1800 have occurred on islands, and non native predators have been the greatest threat to the persistence of island birds. Island endemic species often lack life-history traits and behaviors that reduce the probability of predation and they can become evolutionarily trapped if they are unable to adapt, but few studies have examined the ability of island species to respond to novel predators. The greatest threat to the persistence of the Oahu Elepaio (Chasiempis ibidis), an endangered Hawaiian forest bird, is nest predation by non-native black rats (Rattus rattus). I examined whether Oahu Elepaio nest placement has changed at the individual and population levels in response to rat predation by measuring nest height and determining whether each nest produced offspring from 1996 to 2011. Average height of Oahu Elepaio nests increased 50% over this 16-year period, from 7.9 m (SE 1.7) to 12.0 m (SE 1.1). There was no net change in height of sequential nests made by individual birds, which means individual elepaios have not learned to place nests higher. Nests <=3 m off the ground produced offspring less often, and the proportion of such nests declined over time, which suggests that nest-building behavior has evolved through natural selection by predation. Nest success increased over time, which may increase the probability of long-term persistence of the species. Rat control may facilitate the evolution of nesting height by slowing the rate of population decline and providing time for this adaptive response to spread through the population. PMID- 22830651 TI - Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress. AB - The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine. PMID- 22830661 TI - Letter to the Editor on Al Ghazal Pet al. "Investigation of new co-factorsin 49 patients with pyodermagangrenosum". J Dtsch Dermatol Ges2012; 10: 251-257. PMID- 22830664 TI - Emotional expressivity in older and younger adults' descriptions of personal memories. AB - BACKGROUND/STUDY CONTEXT: According to the socioemotional selectivity theory (SST; Mather & Carstensen, 2003, Psychological Sciences, 14, 409-415), aging is associated with greater motivation to regulate emotions. The authors propose that the language people use to describe personal memories provides an index of age differences in emotional self-regulation. METHODS: In the present article, the authors reanalyzed three previously published studies in which older (aged 60-88) and younger (aged 17-33) participants described emotional and neutral memories from their recent and distant pasts. The authors analyzed the language of the memories using Pennebaker, Booth, and Francis's (2007) Linguistic Inquiry Word Count program (Austin, TX: LIWC Inc.), which calculates the percentage of positive and negative emotion words. RESULTS: In Studies 1 and 2, older adults used more positive emotion words than did younger adults to describe their autobiographical memories from the recent past, particularly when these were of a neutral valence. In Study 3, older adults used more positive emotion words when describing more recent memories (from the past 5 years) but not when describing distant childhood or adolescent memories. CONCLUSION: The authors suggest that these age differences in emotional expressivity support SST, and represent an as yet unreported age difference that may stem from differences in motivation to regulate emotion. PMID- 22830653 TI - DNA origami with double-stranded DNA as a unified scaffold. AB - Scaffolded DNA origami is a widely used technology for self-assembling precisely structured nanoscale objects that contain a large number of addressable features. Typical scaffolds are long, single strands of DNA (ssDNA) that are folded into distinct shapes through the action of many, short ssDNA staples that are complementary to several different domains of the scaffold. However, sources of long single-stranded DNA are scarce, limiting the size and complexity of structures that can be assembled. Here we demonstrated that dsDNA (double stranded DNA) scaffolds can be directly used to fabricate integrated DNA origami structures that incorporate both of the constituent ssDNA molecules. Two basic principles were employed in the design of scaffold folding paths: folding path asymmetry and periodic convergence of the two ssDNA scaffold strands. Asymmetry in the folding path minimizes unwanted complementarity between staples, and incorporating an offset between the folding paths of each ssDNA scaffold strand reduces the number of times that complementary portions of the strands are brought into close proximity with one another, both of which decrease the likelihood of dsDNA scaffold recovery. Meanwhile, the folding paths of the two ssDNA scaffold strands were designed to periodically converge to promote the assembly of a single, unified structure rather than two individual ones. Our results reveal that this basic strategy can be used to reliably assemble integrated DNA nanostructures from dsDNA scaffolds. PMID- 22830665 TI - Susceptibility to distraction during reading in young, young-old, and old-old adults. AB - BACKGROUND/STUDY CONTEXT: Susceptibility to distraction during reading may increase with age, resulting in comprehension errors. Neurological integrity and cognitive reserve are possible covariates of age-related distraction susceptibility. The current study investigated distraction susceptibility in three age groups (young, young-old, and old-old), and examined the covariation patterns of variable sets associated with neurological integrity and cognitive reserve. METHODS: Participants responded to comprehension questions after reading stories that included semantically related or semantically unrelated distractors. Neurological integrity measures consisted of Mini-Mental State Examination, Selective Reminding, and Category Fluency. Cognitive reserve measures consisted of education and vocabulary. RESULTS: Old-old adults were more likely than young and young-old adults to select distractors when responding to comprehension questions (24.02%, 11.95%, 3.68%, respectively). Age-related distraction variance significantly overlapped neurological variance, and became more transparent after cognitive reserve variance was controlled. CONCLUSION: This study augments previous age-related distraction research by highlighting (a) the increase in distraction susceptibility in adults over 79, particularly when distractors are semantically related; (b) the influence of age-related neurological integrity on distraction; and (c) the possibility that education and verbal experience may decrease distraction susceptibility, consistent with cognitive reserve frameworks. PMID- 22830666 TI - Self-regulation and eudaimonic well-being across adulthood. AB - BACKGROUND/STUDY CONTEXT: The authors developed and tested a model to examine the developmental self-regulatory pathways that lead to optimal eudaimonic well-being across adulthood. METHODS: Measures of goal adjustment, optimization, possible selves, and well-being were obtained from 590 adults ranging in age from 17 to 94. Structural equation modeling was used to determine the whether there were age differential pathways among the developmental self-regulatory processes and well being. RESULTS: The model predicts interactions among age, hoped-for possible selves, age-sensitive developmental processes (i.e., goal adjustment, optimization), and psychological well-being. Results showed direct effects of goal adjustment on well-being and indirect effects of goal adjustment and optimization on well-being through hoped-for possible selves. There were significant age differences in the indirect effects of goal adjustment on possible selves and well-being, such that, by age 55, these pathways disappear, and the role of future self-representations diminish. CONCLUSIONS: Findings indicate that the role of possible selves in regulating self-motivated development changes across the adult life span. PMID- 22830667 TI - Visual search for features and conjunctions following declines in the useful field of view. AB - BACKGROUND/STUDY CONTEXT: Typical measures for assessing the useful field (UFOV) of view involve many components of attention. The objective of the current experiment was to examine differences in visual search efficiency for older individuals with and without UFOV impairment. METHODS: The authors used a computerized screening instrument to assess the useful field of view and to characterize participants as having an impaired or normal UFOV. Participants also performed two visual search tasks, a feature search (e.g., search for a green target among red distractors) or a conjunction search (e.g., a green target with a gap on its left or right side among red distractors with gaps on the left or right and green distractors with gaps on the top or bottom). RESULTS: Visual search performance did not differ between UFOV impaired and unimpaired individuals when searching for a basic feature. However, search efficiency was lower for impaired individuals than unimpaired individuals when searching for a conjunction of features. CONCLUSION: The results suggest that UFOV decline in normal aging is associated with conjunction search. This finding suggests that the underlying cause of UFOV decline may arise from an overall decline in attentional efficiency. Because the useful field of view is a reliable predictor of driving safety, the results suggest that decline in the everyday visual behavior of older adults might arise from attentional declines. PMID- 22830668 TI - Changes in the perception and the psychological structure of musical emotions with advancing age. AB - BACKGROUND/STUDY CONTEXT: To date, little is known about how advancing age may impact perception of emotions in music. This study was designed to test whether there are age-related changes in emotional judgments and psychological structure for musical emotions. METHODS: Twenty-five older (64-81 years) and 25 younger (18 30 years) listeners performed emotional judgments and free categorization tasks on happy, peaceful, sad, and threatening musical excerpts. Correlations, analysis of covariance (ANCOVA), and multidimensional scaling analyses were conducted to examine the effect of age on emotional judgments and categorization performances. RESULTS: Compared with younger adults, older adults did not discriminate the arousal difference between peaceful and threatening excerpts and showed higher association between arousal and valence judgments. The multidimensional scaling analysis indicated that the emotional space showed by older listeners did not fit younger listeners' bidimensional valence-arousal structure. There was also a better categorization for happy excerpts among the older group. CONCLUSION: Altogether, these data are consistent with the view that advancing age may result in the reduction of emotional complexity and a distortion of the emotional processing in a positive direction. PMID- 22830671 TI - Low funding has potential to start United States National Institutes of Health peer review down a path of unintended consequences. PMID- 22830669 TI - Effects of age and task characteristics on continuous motor tracking performance. AB - BACKGROUND/STUDY CONTEXT: Much has been written regarding age-related changes in sensory and motor functions, general slowing of the nervous system, and deficiencies in inhibition. Few studies, however, have attempted to define how each of these factors may contribute to poorer accuracy of motor performance with aging. The purpose of this study was to examine whether these changes were best explained by speed of task or stimulus-response compatibility. METHODS: Twenty four younger (M = 19.5; 18-22 years) and older (M = 72.5; 65-82 years) adults used knee movement to track a computer-generated disc along a computer-generated sinusoidal wave that either moved at 50 or 70 cm/s. Stimulus-response compatibility consisted of leg and disc movement in the same direction and stimulus-response incompatibility consisted of leg and disc movement in the opposite direction. Performance was analyzed using a mixed-design analysis of variance (ANOVA). RESULTS: Younger adults performed better than older adults in all conditions. Magnitudes of error between the stimulus-compatible and stimulus incompatible conditions were greater for the old group compared to the young group. Both of these findings were consistent with the hypotheses. Inconsistent with the hypothesis, speed of task did not contribute to age-related differences in accuracy of motor performance in either cognitive load conditions. CONCLUSION: Differences in performance could be attributed to age-related changes in selective inhibition. Future research should focus on examining the potential consequences of decreased inhibition among older adults when completing various activities of daily living and what interventions might mitigate these consequences. PMID- 22830672 TI - Acute liver failure resulting from discontinuation of nucleoside analogues in chronic hepatitis B patients: a report of two cases. AB - Lamivudine, adefovir, telbivudine, and entecavir are nucleoside analogues that can inhibit hepatitis B virus replication and are licensed in China by the Food and Drug Administration. This study presents the cases of 2 patients who were chronically infected with HBV and suffered hepatic failure resulting from withdrawal of telbivudine and adefovir, respectively. PMID- 22830673 TI - Extremely high tunability and low loss in nanoscaffold ferroelectric films. AB - There are numerous radio frequency and microwave device applications which require materials with high electrical tunability and low dielectric loss. For phased array antenna applications there is also a need for materials which can operate above room temperature and which have a low temperature coefficient of capacitance. We have created a nanoscaffold composite ferroelectric material containing Ba(0.6)Sr(0.4)TiO(3) and Sm(2)O(3) which has a very high tunability which scales inversely with loss. This behavior is opposite to what has been demonstrated in any previous report. Furthermore, the materials operate from room temperature to above 150 degrees C, while maintaining high tunability and low temperature coefficient of tunability. This new paradigm in dielectric property control comes about because of a vertical strain control mechanism which leads to high tetragonality (c/a ratio of 1.0126) in the BSTO. Tunability values of 75% (200 kV/cm field) were achieved at room temperature in micrometer thick films, the value remaining to >50% at 160 degrees C. Low dielectric loss values of <0.01 were also achieved, significantly lower than reference pure films. PMID- 22830674 TI - Clinical assessment, design and performance testing of mobile shower commodes for adults with spinal cord injury: an exploratory review. AB - PURPOSE: The purpose of this article is to explore evidence concerning clinical assessment, design and performance testing of mobile shower commodes used by adults with spinal cord injury (SCI). METHOD: Searches of electronic databases, conference proceedings and key journals were undertaken with no restriction on language or study design. Keywords included spinal cord injury, lesion, sanichair, sanitary chair, shower chair, bowel chair and commode. RESULTS: A total of 20 publications were included in this review. Common approaches to clinical assessments were questionnaires and observational analysis to assess bowel care routines, function and skin integrity. Design features addressed access for bowel care, postural support, transfers, stability, use in wet environments and skin integrity. Objective performance measures addressed requirements for static stability, backward-sloping seat angles, arm supports and seat materials. CONCLUSIONS: Evidence reviewed was of low methodological quality and lacking in validated instruments to guide clinical practice. Further high quality research is needed to identify bathing, showering and personal hygiene tasks affecting mobile shower commodes use and to develop validated clinical assessment tools. Performance testing to published standards is also needed. PMID- 22830675 TI - Communication: On the origin of the non-Arrhenius behavior in water reorientation dynamics. AB - We combine molecular dynamics simulations and analytic modeling to determine the origin of the non-Arrhenius temperature dependence of liquid water's reorientation and hydrogen-bond dynamics between 235 K and 350 K. We present a quantitative model connecting hydrogen-bond exchange dynamics to local structural fluctuations, measured by the asphericity of Voronoi cells associated with each water molecule. For a fixed local structure the regular Arrhenius behavior is recovered, and the global anomalous temperature dependence is demonstrated to essentially result from a continuous shift in the unimodal structure distribution upon cooling. The non-Arrhenius behavior can thus be explained without invoking an equilibrium between distinct structures. In addition, the large width of the homogeneous structural distribution is shown to cause a growing dynamical heterogeneity and a non-exponential relaxation at low temperature. PMID- 22830676 TI - Communication: Shock adiabat of atomic nitrogen at megabar pressures. AB - We use spherical cellular method combined with a self-consistent density functional approach (quasizone method) to calculate the band structure and bulk properties of atomic nitrogen at megabar pressures and densities 3.2/3.6 g/cm(3). Thermodynamic functions and shock adiabat calculated by this method correspond to recent measurements, showing a sharp increase in pressure along the shock adiabat in this range of densities. PMID- 22830677 TI - Transition-density-fragment interaction combined with transfer integral approach for excitation-energy transfer via charge-transfer states. AB - A transition-density-fragment interaction (TDFI) combined with a transfer integral (TI) method is proposed. The TDFI method was previously developed for describing electronic Coulomb interaction, which was applied to excitation-energy transfer (EET) [K. J. Fujimoto and S. Hayashi, J. Am. Chem. Soc. 131, 14152 (2009)] and exciton-coupled circular dichroism spectra [K. J. Fujimoto, J. Chem. Phys. 133, 124101 (2010)]. In the present study, the TDFI method is extended to the exchange interaction, and hence it is combined with the TI method for applying to the EET via charge-transfer (CT) states. In this scheme, the overlap correction is also taken into account. To check the TDFI-TI accuracy, several test calculations are performed to an ethylene dimer. As a result, the TDFI-TI method gives a much improved description of the electronic coupling, compared with the previous TDFI method. Based on the successful description of the electronic coupling, the decomposition analysis is also performed with the TDFI TI method. The present analysis clearly shows a large contribution from the Coulomb interaction in most of the cases, and a significant influence of the CT states at the small separation. In addition, the exchange interaction is found to be small in this system. The present approach is useful for analyzing and understanding the mechanism of EET. PMID- 22830678 TI - Scalable properties of metal clusters: a comparative study of modern exchange correlation functionals. AB - The performance of eight generalized gradient approximation exchange-correlation (xc) functionals is assessed by a series of scalar relativistic all-electron calculations on octahedral palladium model clusters Pd(n) with n = 13, 19, 38, 55, 79, 147 and the analogous clusters Au(n) (for n up through 79). For these model systems, we determined the cohesive energies and average bond lengths of the optimized octahedral structures. We extrapolate these values to the bulk limits and compare with the corresponding experimental values. While the well established functionals BP, PBE, and PW91 are the most accurate at predicting energies, the more recent forms PBEsol, VMTsol, and VT{84}sol significantly improve the accuracy of geometries. The observed trends are largely similar for both Pd and Au. In the same spirit, we also studied the scalability of the ionization potentials and electron affinities of the Pd clusters, and extrapolated those quantities to estimates of the work function. Overall, the xc functionals can be classified into four distinct groups according to the accuracy of the computed parameters. These results allow a judicious selection of xc approximations for treating transition metal clusters. PMID- 22830679 TI - On the accuracy of explicitly correlated coupled-cluster interaction energies- have orbital results been beaten yet? AB - The basis set convergence of weak interaction energies for dimers of noble gases helium through krypton is studied for six variants of the explicitly correlated, frozen geminal coupled-cluster singles, doubles, and noniterative triples [CCSD(T)-F12] approach: the CCSD(T)-F12a, CCSD(T)-F12b, and CCSD(T)(F12*) methods with scaled and unscaled triples. These dimers were chosen because CCSD(T) complete-basis-set (CBS) limit benchmarks are available for them to a particularly high precision. The dependence of interaction energies on the auxiliary basis sets has been investigated and it was found that the default resolution-of-identity sets cc-pVXZ/JKFIT are far from adequate in this case. Overall, employing the explicitly correlated approach clearly speeds up the basis set convergence of CCSD(T) interaction energies, however, quite surprisingly, the improvement is not as large as the one achieved by a simple addition of bond functions to the orbital basis set. Bond functions substantially improve the CCSD(T)-F12 interaction energies as well. For small and moderate bases with bond functions, the accuracy delivered by the CCSD(T)-F12 approach cannot be matched by conventional CCSD(T). However, the latter method in the largest available bases still delivers the CBS limit to a better precision than CCSD(T)-F12 in the largest bases available for that approach. Our calculations suggest that the primary reason for the limited accuracy of the large-basis CCSD(T)-F12 treatment are the approximations made at the CCSD-F12 level and the non-explicitly correlated treatment of triples. In contrast, the explicitly correlated second order Moller-Plesset perturbation theory (MP2-F12) approach is able to pinpoint the complete-basis-set limit MP2 interaction energies of rare gas dimers to a better precision than conventional MP2. Finally, we report and analyze an unexpected failure of the CCSD(T)-F12 method to deliver the core-core and core valence correlation corrections to interaction energies consistently and accurately. PMID- 22830680 TI - The role of the magnetic orbitals in the calculation of the magnetic coupling constants from multireference perturbation theory methods. AB - The use of multireference perturbation theory (MRPT) for the calculation of the magnetic coupling in binuclear complexes has shown to give poor results if applied on a minimal active space complete active space self-consistent field (CASSCF) wavefunction. In this work, we identify the origin of this problem in the starting CASSCF orbitals, which are exceedingly localized on the metal atoms. Focusing on the case of antiferromagnetic systems, it is shown that the form of the active orbitals has a dramatic effect on the relative description of the neutral and ionic structures. Finally, a simple and computational inexpensive strategy is proposed for the calculation of a set of magnetic orbitals describing in a more balanced way the neutral and ionic structures. The use of these orbitals, instead the CASSCF ones, in minimal active space MRPT2 calculations leads to a marked improvement of the J values, which become in reasonable agreement with those obtained with the expensive high level difference dedicated configuration interaction approach and with the experimental values. PMID- 22830681 TI - An algorithm to find minimum free-energy paths using umbrella integration. AB - The calculation of free-energy barriers by umbrella sampling and many other methods is hampered by the necessity for an a priori choice of the reaction coordinate along which to sample. We avoid this problem by providing a method to search for saddle points on the free-energy surface in many coordinates. The necessary gradients and Hessians of the free energy are obtained by multidimensional umbrella integration. We construct the minimum free-energy path by following the gradient down to minima on the free-energy surface. The change of free energy along the path is obtained by integrating out all coordinates orthogonal to the path. While we expect the method to be applicable to large systems, we test it on the alanine dipeptide in vacuum. The minima, transition states, and free-energy barriers agree well with those obtained previously with other methods. PMID- 22830682 TI - Automatic identification of model reductions for discrete stochastic simulation. AB - Multiple time scales in cellular chemical reaction systems present a challenge for the efficiency of stochastic simulation. Numerous model reductions have been proposed to accelerate the simulation of chemically reacting systems by exploiting time scale separation. However, these are often identified and deployed manually, requiring expert knowledge. This is time-consuming, prone to error, and opportunities for model reduction may be missed, particularly for large models. We propose an automatic model analysis algorithm using an adaptively weighted Petri net to dynamically identify opportunities for model reductions for both the stochastic simulation algorithm and tau-leaping simulation, with no requirement of expert knowledge input. Results are presented to demonstrate the utility and effectiveness of this approach. PMID- 22830683 TI - Treating molecules in arbitrary spin states using the parametric two-electron reduced-density-matrix method. AB - Minimizing the electronic energy with respect to a parameterized two-electron reduced density matrix (2-RDM) is known as a parametric variational 2-RDM method. The parametric 2-RDM method with the M 2-RDM parametrization [D. A. Mazziotti, Phys. Rev. Lett. 101, 253002 (2008)] is extended to treat molecules in arbitrary spin states. Like its singlet counterpart, the M parametric 2-RDM method for arbitrary spin states is derived using approximate N-representability conditions, which allow it to capture more correlation energy than coupled cluster with single and double excitations at a lower computational cost. We present energies, optimized bond lengths, potential energy curves, and occupation numbers for a set of molecules in a variety of spin states using the M and K parametric 2-RDM methods as well as several wavefunction methods. We show that the M parametric 2 RDM method can describe bond breaking of open-shell molecules like triplet B(2) and singlet and triplet OH(+) even in the presence of strong correlation. Finally, the computed 2-RDMs are shown to be nearly N-representable at both equilibrium and non-equilibrium geometries. PMID- 22830684 TI - Polaronic discontinuities induced by off-diagonal coupling. AB - In this paper, we study a form of the Holstein molecular crystal model in which the influence of lattice vibrations on the transfers of electronic excitations between neighboring sites (off-diagonal coupling) is taken into account. Using the Toyozawa Ansatz and the Lanczos algorithm, the Holstein Hamiltonian with two types of off-diagonal coupling is studied focusing on a number of analyticity issues in the ground state. For finite-sized lattices and antisymmetric coupling, a sequence of discontinuities are found in the polaron energy dispersion, the size of the ground-state phonon cloud, and the linearized von Neumann entropy used to quantify the quantum entanglement between the exciton and the phonons in the ground state. Such behavior is accompanied by a shift of the ground-state crystal momentum from zero to nonzero values as the coupling strength is increased. In the thermodynamic limit, all discontinuities associated with antisymmetric coupling vanish except the one corresponding to the initial departure of the ground-state wavevector from the Brillouin zone center. For the case of symmetric off-diagonal coupling, a smooth crossover is found to exist in all parameters regimes. PMID- 22830685 TI - Exciton transport in thin-film cyanine dye J-aggregates. AB - We present a theoretical model for the study of exciton dynamics in J-aggregated monolayers of fluorescent dyes. The excitonic evolution is described by a Monte Carlo wave function approach which allows for a unified description of the quantum (ballistic) and classical (diffusive) propagation of an exciton on a lattice in different parameter regimes. The transition between the ballistic and diffusive regime is controlled by static and dynamic disorder. As an example, the model is applied to three cyanine dye J-aggregates: TC, TDBC, and U3. Each of the molecule-specific structure and excitation parameters are estimated using time dependent density functional theory. The exciton diffusion coefficients are calculated and analyzed for different degrees of film disorder and are correlated to the physical properties and the structural arrangement of molecules in the aggregates. Further, exciton transport is anisotropic and dependent on the initial exciton energy. The upper-bound estimation of the exciton diffusion length in the TDBC thin-film J-aggregate is of the order of hundreds of nanometers, which is in good qualitative agreement with the diffusion length estimated from experiments. PMID- 22830686 TI - Pair diffusion, hydrodynamic interactions, and available volume in dense fluids. AB - We calculate the pair diffusion coefficient D(r) as a function of the distance r between two hard sphere particles in a dense monodisperse fluid. The distance dependent pair diffusion coefficient describes the hydrodynamic interactions between particles in a fluid that are central to theories of polymer and colloid dynamics. We determine D(r) from the propagators (Green's functions) of particle pairs obtained from molecular dynamics simulations. At distances exceeding ~3 molecular diameters, the calculated pair diffusion coefficients are in excellent agreement with predictions from exact macroscopic hydrodynamic theory for large Brownian particles suspended in a solvent bath, as well as the Oseen approximation. However, the asymptotic 1/r distance dependence of D(r) associated with hydrodynamic effects emerges only after the pair distance dynamics has been followed for relatively long times, indicating non-negligible memory effects in the pair diffusion at short times. Deviations of the calculated D(r) from the hydrodynamic models at short distances r reflect the underlying many-body fluid structure, and are found to be correlated to differences in the local available volume. The procedure used here to determine the pair diffusion coefficients can also be used for single-particle diffusion in confinement with spherical symmetry. PMID- 22830687 TI - Free energy decomposition analysis of bonding and nonbonding interactions in solution. AB - A free energy decomposition analysis algorithm for bonding and nonbonding interactions in various solvated environments, named energy decomposition analysis-polarizable continuum model (EDA-PCM), is implemented based on the localized molecular orbital-energy decomposition analysis (LMO-EDA) method, which is recently developed for interaction analysis in gas phase [P. F. Su and H. Li, J. Chem. Phys. 130, 074109 (2009)]. For single determinant wave functions, the EDA-PCM method divides the interaction energy into electrostatic, exchange, repulsion, polarization, desolvation, and dispersion terms. In the EDA-PCM scheme, the homogeneous solvated environment can be treated by the integral equation formulation of PCM (IEFPCM) or conductor-like polarizable continuum model (CPCM) method, while the heterogeneous solvated environment is handled by the Het-CPCM method. The EDA-PCM is able to obtain physically meaningful interaction analysis in different dielectric environments along the whole potential energy surfaces. Test calculations by MP2 and DFT functionals with homogeneous and heterogeneous solvation, involving hydrogen bonding, vdW interaction, metal-ligand binding, cation-pi, and ionic interaction, show the robustness and adaptability of the EDA-PCM method. The computational results stress the importance of solvation effects to the intermolecular interactions in solvated environments. PMID- 22830688 TI - On solving the master equation in spatially periodic systems. AB - We present a new method for solving the master equation for a system evolving on a spatially periodic network of states. The network contains 2(nu) images of a "unit cell" of n states, arranged along one direction with periodic boundary conditions at the ends. We analyze the structure of the symmetrized (2(nu)n) * (2(nu)n) rate constant matrix for this system and derive a recursive scheme for determining its eigenvalues and eigenvectors, and therefore analytically expressing the time-dependent probabilities of all states in the network, based on diagonalizations of n * n matrices formed by consideration of a single unit cell. We apply our new method to the problem of low-temperature, low-occupancy diffusion of xenon in the zeolite silicalite-1 using the states, interstate transitions, and transition state theory-based rate constants previously derived by June et al. [J. Phys. Chem. 95, 8866 (1991)]. The new method yields a diffusion tensor for this system which differs by less than 3% from the values derived previously via kinetic Monte Carlo (KMC) simulations and confirmed by new KMC simulations conducted in the present work. The computational requirements of the new method are compared against those of KMC, numerical solution of the master equation by the Euler method, and direct molecular dynamics. In the problem of diffusion of xenon in silicalite-1, the new method is shown to be faster than these alternative methods by factors of about 3.177 * 10(4), 4.237 * 10(3), and 1.75 * 10(7), respectively. The computational savings and ease of setting up calculations afforded by the new method of master equation solution by recursive reduction of dimensionality in diagonalizing the rate constant matrix make it attractive as a means of predicting long-time dynamical phenomena in spatially periodic systems from atomic-level information. PMID- 22830689 TI - Entangled trajectory molecular dynamics in multidimensional systems: two dimensional quantum tunneling through the Eckart barrier. AB - In this paper, we extend the entangled trajectory molecular dynamics (ETMD) method to multidimensional systems. The integrodifferential form of the evolution equation for the Wigner function is employed, allowing general potentials not represented as a polynomial to be treated. As the example, the method is applied to a two-dimensional model of scattering from an Eckart barrier. The results of ETMD are in good agreement with quantum hydrodynamics and exact quantum simulations. By comparing the quantum and classical trajectory in phase space, the quantum tunneling phenomenon is interpreted vividly. PMID- 22830690 TI - Efficient method to include nuclear quantum effects in the determination of phase boundaries. AB - We developed a methodology to assess nuclear quantum effects in phase boundaries calculations that is based on the dynamical integration of Clausius-Clapeyron equation using path integral simulations. The technique employs non-equilibrium simulations that are very efficient. The approach was applied to the calculation of the melting line of Ne in an interval of pressures ranging from 1 to 3366 bar. Our results show a very good agreement with both experimental findings and results from previous calculations. The methodology can be applied to solid and liquid phases, without limitations regarding anharmonicities. The method allows the computation of coexistence lines for wide intervals of pressure and temperature using, in principle, a single simulation. PMID- 22830691 TI - Scalar fundamental measure theory for hard spheres in three dimensions: application to hydrophobic solvation. AB - Hard-sphere mixtures provide one a solvable reference system that can be used to improve the density functional theory of realistic molecular fluids. We show how the Kierlik-Rosinberg's scalar version of the fundamental measure density functional theory of hard spheres [E. Kierlik and M. L. Rosinberg, Phys. Rev. A 42, 3382 (1990)], which presents computational advantages with respect to the original Rosenfeld's vectorial formulation or its extensions, can be implemented and minimized in three dimensions to describe fluid mixtures in complex environments. This implementation is used as a basis for defining a molecular density functional theory of water around molecular hydrophobic solutes of arbitrary shape. PMID- 22830692 TI - Optimizing conical intersections of solvated molecules: the combined spin-flip density functional theory/effective fragment potential method. AB - Solvent effects on a potential energy surface crossing are investigated by optimizing a conical intersection (CI) in solution. To this end, the analytic energy gradient has been derived and implemented for the collinear spin-flip density functional theory (SFDFT) combined with the effective fragment potential (EFP) solvent model. The new method is applied to the azomethane-water cluster and the chromophore of green fluorescent protein in aqueous solution. These applications illustrate not only dramatic changes in the CI geometries but also strong stabilization of the CI in a polar solvent. Furthermore, the CI geometries obtained by the hybrid SFDFT/EFP scheme reproduce those by the full SFDFT, indicating that the SFDFT/EFP method is an efficient and promising approach for understanding nonadiabatic processes in solution. PMID- 22830693 TI - On the design of experiments for determining ternary mixture free energies from static light scattering data using a nonlinear partial differential equation. AB - We mathematically design sets of static light scattering experiments to provide for model-independent measurements of ternary liquid mixing free energies to a desired level of accuracy. A parabolic partial differential equation (PDE), linearized from the full nonlinear PDE [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008)], describes how data noise affects the free energies to be inferred. The linearized PDE creates a net of spacelike characteristic curves and orthogonal, timelike curves in the composition triangle, and this net governs diffusion of information coming from light scattering measurements to the free energy. Free energy perturbations induced by a light scattering perturbation diffuse along the characteristic curves and towards their concave sides, with a diffusivity that is proportional to the local characteristic curvature radius. Consequently, static light scattering can determine mixing free energies in regions with convex characteristic curve boundaries, given suitable boundary data. The dielectric coefficient is a Lyapunov function for the dynamical system whose trajectories are PDE characteristics. Information diffusion is heterogeneous and system-dependent in the composition triangle, since the characteristics depend on molecular interactions and are tangent to liquid-liquid phase separation coexistence loci at critical points. We find scaling relations that link free energy accuracy, total measurement time, the number of samples, and the interpolation method, and identify the key quantitative tradeoffs between devoting time to measuring more samples, or fewer samples more accurately. For each total measurement time there are optimal sample numbers beyond which more will not improve free energy accuracy. We estimate the degree to which many-point interpolation and optimized measurement concentrations can improve accuracy and save time. For a modest light scattering setup, a sample calculation shows that less than two minutes of measurement time is, in principle, sufficient to determine the dimensionless mixing free energy of a non-associating ternary mixture to within an integrated error norm of 0.003. These findings establish a quantitative framework for designing light scattering experiments to determine the Gibbs free energy of ternary liquid mixtures. PMID- 22830694 TI - Mathematical and computational aspects of quaternary liquid mixing free energy measurement using light scattering. AB - We provide a mathematical and computational analysis of light scattering measurement of mixing free energies of quaternary isotropic liquids. In previous work, we analyzed mathematical and experimental design considerations for the ternary mixture case [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008); C. Wahle, D. Ross, and G. Thurston, J. Chem. Phys. 137, 034201 (2012)]. Here, we review and introduce dimension-free general formulations of the fully nonlinear partial differential equation (PDE) and its linearization, a basis for applying the method to composition spaces of any dimension, in principle. With numerical analysis of the PDE as applied to the light scattering implied by a test free energy and dielectric gradient combination, we show that values of the Rayleigh ratio within the quaternary composition tetrahedron can be used to correctly reconstruct the composition dependence of the free energy. We then extend the analysis to the case of a finite number of data points, measured with noise. In this context the linearized PDE describes the relevant diffusion of information from light scattering noise to the free energy. The fully nonlinear PDE creates a special set of curves in the composition tetrahedron, collections of which form characteristics of the nonlinear and linear PDEs, and we show that the information diffusion has a time-like direction along the positive normals to these curves. With use of Monte Carlo simulations of light scattering experiments, we find that for a modest laboratory light scattering setup, about 100-200 samples and 100 s of measurement time are enough to be able to measure the mixing free energy over the entire quaternary composition tetrahedron, to within an L(2) error norm of 10(-3). The present method can help quantify thermodynamics of quaternary isotropic liquid mixtures. PMID- 22830695 TI - On inferring liquid-liquid phase boundaries and tie lines from ternary mixture light scattering. AB - We investigate the possibility of using light scattering data in the single-phase regions of a ternary liquid mixture phase diagram to infer ternary mixture coexistence curves, and to infer tie lines joining the compositions of isotropic liquid phases in thermodynamic equilibrium. Previous analyses of a nonlinear light scattering partial differential equation (LSPDE) show that it provides for reconstruction of ternary [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008); C. Wahle, D. Ross, and G. Thurston, J. Chem. Phys. 137, 034201 (2012)] and quaternary [C. Wahle, D. Ross, and G. Thurston, J. Chem. Phys. 137, 034202 (2012)] mixing free energies from light scattering data, and that if the coexistence curves are already known, it can also yield ternary tie lines and triangles [D. Ross, G. Thurston, and C. Lutzer, J. Chem. Phys. 129, 064106 (2008)]. Here, we show that the LSPDE can be used more generally, to infer phase boundaries and tie lines from light scattering data in the single-phase region, without prior knowledge of the coexistence curve, if the single-phase region is connected. The method extends the fact that the reciprocal light scattering intensity approaches zero at the thermodynamic spinodal. Expressing the free energy as the sum of ideal and excess parts leads to a natural family of Pade approximants for the reciprocal Rayleigh ratio. To test the method, we evaluate the single-phase reciprocal Rayleigh ratio resulting from the mean-field, regular solution model on a fine grid. We then use a low-order approximant to extrapolate the reciprocal Rayleigh ratio into metastable and unstable regions. In the metastable zone, the extrapolation estimates light scattering prior to nucleation and growth of a new phase. In the unstable zone, the extrapolation produces a negative function that in the present context is a computational convenience. The original and extrapolated reciprocal light scattering are jointly used as input to solving the LSPDE to deduce the mixing free energy and its convex hull. When projected onto the composition triangle, the boundary of the convexified part of the free energy is the phase boundary, and lines on the convexified region along which the second directional derivative is zero are the tie lines. We find that the tie lines and phase boundaries so deduced agree well with their exact values. This work is a step toward developing methods for inferring phase boundaries from real light scattering intensities measured with noise, from mixtures having compositions on a coarser grid. PMID- 22830696 TI - Reactions of Nb2 and Nb3 with CO, D2, N2, and O2: reconciling experimental kinetics with density functional theory-calculated reaction profiles. AB - Calculated energy profiles for the reactions of neutral Nb(2) and Nb(3) metal clusters with CO, D(2), N(2), and O(2) are presented. In each reaction path, both a physisorption energy minimum, where the reactant remains intact, and a chemisorption energy minimum, where the reactant has dissociated, are calculated and linked by saddle points. We calculate branching ratios for the forward (dissociative) and reverse reactions which we compare with the experimental kinetic data. It is found that a combination of average thermal energies and barrier heights leads to wide variation in branching ratios which compares favourably to previously determined experimental reaction rates. PMID- 22830697 TI - Quenching molecular photodissociation by intermolecular Coulombic decay. AB - In this paper we study the impact of interatomic Coulombic decay (ICD) on molecular photodissociation. The investigation reveals the hitherto unrecognized ability of ICD to quench processes involving nuclear rearrangements. Numerical computations of the nuclear dynamics, initiated by photoexciting the B(1)Sigma(+) Rydberg state of CO in CO.Mg complexes, are carried out. The efficiencies of ICD and photoinduced predissociation are compared for the four lowest vibrational levels of the corresponding electronic state. We also show the impact of CO vibrations on the ICD electron spectrum. Finally, we discuss the growing efficiency of ICD to quench the dissociation as the number of neighboring Mg atoms is increased. PMID- 22830698 TI - Theoretical investigation of the He-I2(E3Pig) ion-pair state: ab initio intermolecular potential and vibrational levels. AB - We present a theoretical study on the potential energy surface and vibrational bound states of the E electronic excited state of the HeI(2) van der Waals system. The interaction energies are computed using accurate ab initio methods and large basis sets. Relativistic small-core effective core potentials in conjunction with a quintuple-zeta quality basis set are employed for the heavy iodine atoms in multireference configuration interaction calculations for the (3)A' and (3)A" states. For the representation of the potential energy surface we used a general interpolation technique for constructing potential surfaces from ab initio data based on the reproducing kernel Hilbert space method. The surface presents global and local minima for T-shaped configurations with well-depths of 33.2 and 4.6 cm(-1), respectively. Vibrational energies and states are computed through variational quantum mechanical calculations. We found that the binding energy of the HeI(2)(E) T-shaped isomer is 16.85 cm(-1), in excellent agreement with recent experimental measurements. In lieu of more experimental data we also report our predictions on higher vibrational levels and we analyze the influence of the underlying surface on them. This is the first attempt to represent the potential surface of such a highly excited electronic state of a van der Waals complex, and it demonstrates the capability of the ab initio technology to provide accurate results for carrying out reliable studies to model experimental data. PMID- 22830699 TI - Uptake of atmospheric molecules by ice nanoparticles: pickup cross sections. AB - Uptake of several atmospheric molecules on free ice nanoparticles was investigated. Typical examples were chosen: water, methane, NO(x) species (NO, NO(2)), hydrogen halides (HCl, HBr), and volatile organic compounds (CH(3)OH, CH(3)CH(2)OH). The cross sections for pickup of these molecules on ice nanoparticles (H(2)O)(N) with the mean size of N~260 (diameter ~2.3 nm) were measured in a molecular beam experiment. These cross sections were determined from the cluster beam velocity decrease due to the momentum transfer during the pickup process. For water molecules molecular dynamics simulations were performed to learn the details of the pickup process. The experimental results for water are in good agreement with the simulations. The pickup cross sections of ice particles of several nanometers in diameter can be more than 3 times larger than the geometrical cross sections of these particles. This can have significant consequences in modelling of atmospheric ice nanoparticles, e.g., their growth. PMID- 22830700 TI - Branching ratio measurements of the predissociation of 12C16O by time-slice velocity-map ion imaging in the energy region from 108,000 to 110,500 cm(-1). AB - Direct branching ratio measurements of the three lowest dissociation channels of (12)C(16)O that produce C((3)P) + O((3)P), C((1)D) + O((3)P), and C((3)P) + O((1)D) are reported in the vacuum ultraviolet region from 108,000 cm(-1) (92.59 nm) to 110,500 cm(-1) (90.50 nm) using the time-slice velocity-map ion imaging and nonlinear resonant four-wave mixing techniques. Rotationally, resolved carbon ion yield spectra for both (1)Sigma(+) and (1)Pi bands of CO in this region have been obtained. Our measurements using this technique show that the branching ratio in this energy region, especially the relative percentages of the two spin forbidden channels, is strongly dependent on the particular electronic and vibrational energy levels of CO that are excited. PMID- 22830701 TI - Population transfer and rapid passage effects in a low pressure gas using a continuous wave quantum cascade laser. AB - A continuous wave quantum cascade laser (cw-QCL) operating at 10 MUm has been used to record absorption spectra of low pressure samples of OCS in an astigmatic Herriott cell. As a result of the frequency chirp of the laser, the spectra show clearly the effects of rapid passage on the absorption line shape. At the low chirp rates that can be obtained with the cw-QCL, population transfer between rovibrational quantum states is predicted to be much more efficient than in typical pulsed QCL experiments. This optical pumping is investigated by solving the Maxwell Bloch equations to simulate the propagation of the laser radiation through an inhomogeneously broadened two-level system. The calculated absorption profiles show good quantitative agreement with those measured experimentally over a range of chirp rates and optical thicknesses. It is predicted that at a low chirp rate of 0.13 MHz ns(-1), the population transfer between rovibrational quantum states is 12%, considerably more than that obtained at the higher chirp rates utilised in pulsed QCL experiments. PMID- 22830702 TI - Mass-analyzed threshold ionization of an excited state of lanthanum dioxide. AB - LaO(2) was produced in a pulsed laser-vaporization molecular beam source and studied by mass-analyzed threshold ionization (MATI) spectroscopy and ab initio electronic structure calculations. The calculations included density functional theory, second-order perturbation theory, coupled cluster theory, and complete active space self-consistent field methods. The adiabatic ionization energy of the molecule and vibrational frequencies of the molecule and its cation were measured accurately for the first time from the MATI spectrum. Numerous ionization processes of lanthanum dioxide, peroxide, and superoxide were considered; the (3)B(2) <- (4)B(2) electronic transition of the dioxide was assigned upon comparison with the observed spectrum. The ionization energy and O La-O bending frequency of the (4)B(2) neutral state are 4.9760 (6) eV and 92 cm( 1), respectively. The La-O stretching and O-La-O bending frequencies of the (3)B(2) cationic state are 656 and 122 cm(-1), respectively. The (4)B(2) state is formed by two electron transfer from lanthanum to oxygen atoms, and the (3)B(2) state is produced by the further removal of a lanthanum 6s-based electron. PMID- 22830703 TI - Photoracemization and excited state relaxation through non-adiabatic pathways in chromium (III) oxalate ions. AB - Computational studies on the photochemistry of the open-shell chromium oxalate [Cr(C(2)O(4))(3)](3-) ion, including its non-adiabatic relaxation pathways, have been performed. The presence of the peaked conical intersection of a quasi-Jahn Teller type, connecting the (4)T state with (4)A(2) ground state, accounts for the observed photoinduced racemization. This involves the rupture of one of the Cr-O bonds and the complex forms an unstable trigonal bipyramid form that connects both ground state stereoisomers with the excited quartet manifold. Intersystem crossing seams have been located between the (4)T and lower lying (2)E state which can quench the quartet reaction and lead to (2)E -> (4)A(2) emission. PMID- 22830704 TI - First principles study of cobalt hydride, CoH, and its ions CoH+ and CoH-. AB - The electronic structure of the diatomic species CoH, CoH(+), and CoH(-) have been studied mainly by multireference configuration interaction (MRCI) methods and basis sets of quintuple quality. The restricted coupled-cluster with iterative singles + doubles + quasi-perturbative connected triples, RCCSD(T), approach was also employed, limited however to the ground states only. At the MRCI level we have constructed 27 (CoH), 24 (CoH(+)), and 12 (CoH(-)) potential energy curves correlating adiabatically to six, seven, and two energy channels, respectively. For the ground states scalar relativistic and core-subvalence effects have been taken into account. We report energetics, spectroscopic parameters, dipole moments, excitation energies, and spin-orbit coupling constants. Our CoH calculated results are in accord with experiment, but there is an interesting discrepancy between theory and experiment concerning the dipole moment, the former being significantly larger than the latter. Experimental results on CoH(+) and CoH(-) are scarce. The ground state of CoH, CoH(+), and CoH(-) are definitely of (3)Phi, (4)Phi, and (4)Phi symmetries with calculated (experimental) dissociation energies D(0)(0) = 46.4 +/- 0.5(45.0 +/- 1.2), 49.6(47 +/- 2), and 45.6(43.1 +/- 1.2) kcal/mol, respectively. In all 24 calculated CoH states, a Co-to-H charge transfer of 0.2-0.3 e(-) is recorded; in CoH(-), however, the negative charge resides almost exclusively on the Co atom. PMID- 22830705 TI - Highly selective adsorption of methanol in carbon nanotubes immersed in methanol water solution. AB - The systems of open-ended carbon nanotubes (CNTs) immersed in methanol-water solution are studied by molecular dynamics simulations. For the (6,6) CNT, nearly pure methanol is found to preferentially occupy interior space of the CNT. Even when the mass fraction (MF) of methanol in bulk solution is as low as 1%, the methanol MF within the CNT is still more than 90%. For CNTs with larger diameters, the methanol concentrations within CNTs are also much higher than those outside CNTs. The methanol selectivity decreases with increasing CNT diameter, but not monotonically. From microscopic structural analyses, we find that the primary reason for the high selectivity of methanol by CNTs lies on high preference of methanol in the first solvation shell near the inner wall of CNT, which stems from a synergy effect of the van der Waals interaction between CNT and the methyl groups of methanol, together with the hydrogen bonding interaction among the liquid molecules. This synergy effect may be of general significance and extended to other systems, such as ethanol aqueous solution and methanol/ethanol mixture. The selective adsorption of methanol over water in CNTs may find applications in separation of water and methanol, detection of methanol, and preservation of methanol purity in fuel cells. PMID- 22830706 TI - Disentangling molecular motions involved in the glass transition of a twist-bend nematic liquid crystal through dielectric studies. AB - Broadband dielectric spectroscopy spanning frequencies from 10(-2) to 1.9 * 10(9) Hz has been used to study the molecular orientational dynamics of the glass forming liquid crystal 1",7"-bis (4-cyanobiphenyl-4'-yl)heptane (CB7CB) over a wide temperature range of the twist-bend nematic phase. In such a mesophase two different relaxation processes have been observed, as expected theoretically, to contribute to the imaginary part of the complex dielectric permittivity. For measurements on aligned samples, the processes contribute to the dielectric response to different extents depending on the orientation of the alignment axis (parallel or perpendicular) with respect to the probing electric field direction. The low-frequency relaxation mode (denoted by MU(1)) is attributed to a flip-flop motion of the dipolar groups parallel to the director. The high-frequency relaxation mode (denoted by MU(2)) is associated with precessional motions of the dipolar groups about the director. The MU(1)-and MU(2)-modes are predominant in the parallel and perpendicular alignments, respectively. Relaxation times for both modes in the different alignments have been obtained over a wide temperature range down to near the glass transition temperature. Different analytic functions used to characterize the temperature dependence of the relaxation times of the two modes are considered. Among them, the critical-like description via the dynamic scaling model seems to give not only quite good numerical fittings, but also provides a consistent physical picture of the orientational dynamics on approaching the glass transition. PMID- 22830707 TI - Nanosize icosahedral quasicrystal in Mg90Ca10 glass: an ab initio molecular dynamics study. AB - Rapid solidification of Mg(90)Ca(10) from its liquid state is studied by means of an ab initio molecular dynamics technique, and its local structure is investigated by various analyzing methods. The liquid and amorphous states are found to have slightly different short range order even though the perfect and defective icosahedral bonding environments are major bonding elements of both liquid and amorphous states. Perfect icosahedrons with a small frequency exist in the liquid state, more develop during the cooling process and they become the leading building units in the glass state, indicating an icosahedral short range order in Mg(90)Ca(10) glass. Also the linked icosahedrons lead to an icosahedral medium range order. Furthermore, an ordered arrangement of some icosahedrons in the hexagonal symmetry is observed in the glass model, representing a nanoscale icosahedral quasicrystalline phase in Mg(90)Ca(10) glass. PMID- 22830708 TI - Local theory for ions in binary liquid mixtures. AB - The influence of ions on the bulk phase behavior of binary liquid mixtures acting as their solvents and on the corresponding interfacial structures close to a planar wall is investigated by means of density functional theory based on local descriptions of the effective interactions between ions and their solvents. The bilinear coupling approximation (BCA), which has been used in numerous previous related investigations, is compared with a novel local density approximation (LDA) for the ion-solvent interactions. It turns out that within BCA the bulk phase diagrams, the two-point correlation functions, and critical adsorption exhibit qualitative features which are not compatible with the available experimental data. These discrepancies do not occur within the proposed LDA. Further experimental investigations are suggested which assess the reliability of the proposed LDA. This approach allows one to obtain a consistent and rather general understanding of the effects of ions on solvent properties. From our analysis we infer, in particular, that there can be an experimentally detectable influence of ions on binary liquid mixtures due to steric effects but not due to charge effects. PMID- 22830709 TI - Computer simulations of nematic drops: coupling between drop shape and nematic order. AB - We perform Monte Carlo computer simulations of nematic drops in equilibrium with their vapor using a Gay-Berne interaction between the rod-like molecules. To generate the drops, we initially perform NPT simulations close to the nematic vapor coexistence region, allow the system to equilibrate and subsequently induce a sudden volume expansion, followed with NVT simulations. The resultant drops coexist with their vapor and are generally not spherical but elongated, have the rod-like particles tangentially aligned at the surface and an overall nematic orientation along the main axis of the drop. We find that the drop eccentricity increases with increasing molecular elongation, kappa. For small kappa the nematic texture in the drop is bipolar with two surface defects, or boojums, maximizing their distance along this same axis. For sufficiently high kappa, the shape of the drop becomes singular in the vicinity of the defects, and there is a crossover to an almost homogeneous texture; this reflects a transition from a spheroidal to a spindle-like drop. PMID- 22830710 TI - An extended formula of site-site Smoluchowski-Vlasov equation for electrolyte solution and infinitely dilute solution. AB - Solvation dynamics is one of the central subjects in solution chemistry. Site site Smoluchowski-Vlasov (SSSV) equation is a diffusion equation for molecular liquid to analytically calculate the van Hove time correlation function. However, the application has been limited to simple solvent system such as liquid water because of the difficulty in solving the equation. In this study, an extended treatment of SSSV equation is proposed, which is applicable to a wide range of solution systems including mixed solution, electrolyte solution, and infinitely dilute solution. The present treatment realizes computation of the dynamics in LiCl aqueous solution, NaCl aqueous solution, and infinitely dilute aqueous solution of Li(+) and Cs(+) at the molecular level. PMID- 22830711 TI - Phase diagram of a two-dimensional system with anomalous liquid properties. AB - Using Monte Carlo simulation techniques, we calculate the phase diagram for a square-shoulder square-well potential in two dimensions that has been previously shown to exhibit liquid anomalies consistent with a metastable liquid-liquid critical point. We consider the liquid, gas, and five crystal phases, and find that all the melting lines are first order, despite a small range of metastability. One melting line exhibits a temperature maximum, as well as a pressure maximum that implies inverse melting over a small range in pressure. PMID- 22830712 TI - Long-range hydrogen-bond structure in aqueous solutions and the vapor-water interface. AB - There is a considerable disagreement about the extent to which solutes perturb water structure. On the one hand, studies that analyse structure directly only show local structuring in a solute's first and possibly second hydration shells. On the other hand, thermodynamic and kinetic data imply indirectly that structuring occurs much further away. Here, the hydrogen-bond structure of water around halide anions, alkali cations, noble-gas solutes, and at the vapor-water interface is examined using molecular dynamics simulations. In addition to the expected perturbation in the first hydration shell, deviations from bulk behavior are observed at longer range in the rest of the simulation box. In particular, at the longer range, there is an excess of acceptors around halide anions, an excess of donors around alkali cations, weakly enhanced tetrahedrality and an oscillating excess and deficiency of donors and acceptors around noble-gas solutes, and enhanced tetrahedrality at the vapor-water interface. The structuring compensates for the short-range perturbation in water-water hydrogen bonds induced by the solute. Rather than being confined close to the solute, it is spread over as many water molecules as possible, presumably to minimize the perturbation to each water molecule. PMID- 22830713 TI - Aggregation in dilute aqueous tert-butyl alcohol solutions: insights from large scale simulations. AB - Molecular dynamics simulations employing up to 64,000 particles are used to investigate aggregation and microheterogeneity in aqueous tert-butyl alcohol (TBA) solutions for TBA mole fractions X(t) <= 0.1. Four different force fields are considered. It is shown that the results obtained can be strongly dependent on the particular force field employed, and can be significantly influenced by system size. Two of the force fields considered show TBA aggregation in the concentration range X(t) ~ 0.03 - 0.06. For these models, systems of 64,000 particles are minimally sufficient to accommodate the TBA aggregates. The structures resulting from TBA aggregation do not have a well-defined size and shape, as one might find in micellar systems, but are better described as TBA rich and water-rich regions. All pair correlation functions exhibit long-range oscillatory behavior with wavelengths that are much larger than molecular length scales. The oscillations are not strongly damped and the correlations can easily exceed the size of the simulation cell, even for the low TBA concentrations considered here. We note that these long-range correlations pose a serious problem if one wishes to obtain certain physical properties such as Kirkwood-Buff integrals from simulation results. In contrast, two other force fields that we consider show little sign of aggregation for X(t) ? 0.08. In our 64,000 particle simulations all four models considered show demixing-like behavior for X(t) ? 0.1, although such behavior is not evident in smaller systems of 2000 particles. The meaning of the demixing-like behavior is unclear. Since real TBA-water solutions do not demix, it might be an indication that all four models we consider poorly represent the real system. Alternatively, it might be an artifact of finite system size. Possibly, the apparent demixing indicates that for X(t) ? 0.1, the stable TBA aggregates are simply too large to fit into the simulation cell. Our results provide a view of the possible nature of microheterogeneity in dilute TBA-water solutions, and of the associated long correlation lengths. It is clear that system size can be a very important factor in simulations of these solutions, and must be taken into account in the evaluation and development of TBA-water force fields. PMID- 22830714 TI - Static dielectric constants and molecular dipole distributions of liquid water and ice-Ih investigated by the PAW-PBE exchange-correlation functional. AB - The static dielectric constants, epsilon(s), of ice-Ih and liquid water were calculated using density functional theory with the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional and the projector-augmented-wave (PAW) approach. Proton disordered ice configurations and uncorrelated liquid configurations were sampled with the electrostatic switching method using force fields specially designed to facilitate the ab initio free energy perturbation calculations. Our results indicate that PAW-PBE underestimates the epsilon(s) of both ice-Ih and liquid water but predicts the ratio of ice and water epsilon(s) in good agreement with experimental measurements. PAW-PBE gives average water dipole moments of 2.50 D in ice-Ih and 2.48 D in the liquid. Our results show that the fixed-charge water models developed by adaptive force matching can reproduce the PAW-PBE dipole moments with an error of approximately 5%. The ice and liquid models created in this work have polarizabilities of 1.32 A(3) and 1.30 A(3), respectively, along the HOH bisector direction. PMID- 22830715 TI - Thermodynamic scaling of alpha-relaxation time and viscosity stems from the Johari-Goldstein beta-relaxation or the primitive relaxation of the coupling model. AB - By now it is well established that the structural alpha-relaxation time, tau(alpha), of non-associated small molecular and polymeric glass-formers obey thermodynamic scaling. In other words, tau(alpha) is a function Phi of the product variable, rho(gamma)/T, where rho is the density and T the temperature. The constant gamma as well as the function, tau(alpha) = Phi(rho(gamma)/T), is material dependent. Actually this dependence of tau(alpha) on rho(gamma)/T originates from the dependence on the same product variable of the Johari Goldstein beta-relaxation time, tau(beta), or the primitive relaxation time, tau(0), of the coupling model. To support this assertion, we give evidences from various sources itemized as follows. (1) The invariance of the relation between tau(alpha) and tau(beta) or tau(0) to widely different combinations of pressure and temperature. (2) Experimental dielectric and viscosity data of glass-forming van der Waals liquids and polymer. (3) Molecular dynamics simulations of binary Lennard-Jones (LJ) models, the Lewis-Wahnstrom model of ortho-terphenyl, 1,4 polybutadiene, a room temperature ionic liquid, 1-ethyl-3-methylimidazolium nitrate, and a molten salt 2Ca(NO(3))(2).3KNO(3) (CKN). (4) Both diffusivity and structural relaxation time, as well as the breakdown of Stokes-Einstein relation in CKN obey thermodynamic scaling by rho(gamma)/T with the same gamma. (5) In polymers, the chain normal mode relaxation time, tau(N), is another function of rho(gamma)/T with the same gamma as segmental relaxation time tau(alpha). (6) While the data of tau(alpha) from simulations for the full LJ binary mixture obey very well the thermodynamic scaling, it is strongly violated when the LJ interaction potential is truncated beyond typical inter-particle distance, although in both cases the repulsive pair potentials coincide for some distances. PMID- 22830716 TI - Photodetachment and electron reactivity in 1-methyl-1-butyl-pyrrolidinium bis(trifluoromethylsulfonyl)amide. AB - The transient absorption spectrum in the range 500 nm-1000 nm was measured with ultrafast time resolution on a flowing neat, aliphatic, room-temperature ionic liquid following anion photodetachment. In this region the spectrum was shown to be a combination of absorption from the electron and the hole. Spectrally resolved electron quenching determined a bimodal shape for the hole spectrum in agreement with recent computational predictions on a smaller aliphatic ionic liquid [Margulis et al., J. Am. Chem. Soc. 133, 20186 (2011)]. For time delays beyond 15 ps, spectral evolution qualitatively agrees with recent radiolysis experiments [Wishart et al., Faraday Discuss. 154, 353 (2012)]. However, the shape of the spectrum is different, reflecting the contrast in ionization energy between the two methods. Previously unobserved reactivity of the electron was found with a time constant of 300 fs. The results demonstrate solvent control of the rate coefficient for reaction between the electron and proton, with a rapid decline in the rate within the first picosecond. PMID- 22830717 TI - Spin-lattice relaxation of the methyl group protons in solids revisited: damped quantum rotation approach. AB - Proton spin-lattice relaxation of the methyl group in solids had been one of the most thoroughly addressed theoretical problems in nuclear magnetic resonance (NMR) spectroscopy, considered at different levels of sophistication. For systems with substantial quantum tunneling effects, several quantum mechanical treatments were reported, although in practical applications the quantum models were always augmented with or replaced by the classical jump model. However, the latter has recently proved invalid in the description of NMR line shape effects in variable temperature spectra of hindered methyl groups, while the competing theory of damped quantum rotation (DQR) was shown to be adequate. In this work, the spin lattice relaxation issue for the methyl protons is readdressed using the latter theory. The main outcome is that, while the existing formulas for the relaxation rates remain unchanged, the crucial parameter entering them, the correlation time of the relevant random process, need to be reinterpreted. It proves to be the inverse of one of the two quantum-rate constants entering the DQR model, neither of which, when taken separately, can be related to the jump process. It can be identified with one describing the life-time broadening of the tunnel peaks in inelastic neutron scattering (INS) spectra of the methyl groups. Such a relationship between the relaxation and INS effects was reported from another laboratory long ago, but only for the low-temperature limit where thermal population of the excited torsional levels of the methyl group can be neglected. The whole spectrum of cases encountered in practical relaxation studies on protonated methyl groups is addressed for the first time. Preliminary experimental confirmation of this novel approach is reported, based on already published NMR data for a single crystal of methylmalonic acid. The once extensively debated issues of quenching of the coherent tunneling and of the classical limit in the dynamics of the methyl groups are readdressed and presented in a consistent manner. PMID- 22830718 TI - Density functional theory model study of size and structure effects on water dissociation by platinum nanoparticles. AB - Size and structure effects on the homolytic water dissociation reaction mediated by Pt nanoparticles have been investigated through density functional theory calculations carried out on a series of cubooctahedral Pt(n) nanoparticles of increasing sizes (n = 13, 19, 38, 55, 79, and 140). Water adsorption energy is not significantly influenced by the nanoparticle size. However, activation energy barrier strongly depends on the particle size. In general, the activation energy barrier increases with nanoparticles size, varying from 0.30 eV for Pt(19) to 0.70 eV for Pt(140). For the largest particle the calculated barrier is very close to that predicted for water dissociation on Pt(111) (0.78 eV) even though the reaction mediated by the Pt nanoparticles involves adsorption sites not present on the extended surface. PMID- 22830719 TI - Spinodal decomposition and droplets entrapment in monotectic solidification. AB - In this article, we present two models to simulate solidification morphologies in monotectic alloys. With the first model, we investigate the morphological evolution under the influence of spinodal decomposition. The model requires that a gradient energy contribution for the concentration field should be incorporated, in order to stabilize phase separation when the liquid concentration is inside the region of miscibility gap. The free energy of the system in this model is derived from direct interpolation of the bulk energy densities. This, however, results in simulation regions in nanometer scale due to contributions from the chemical free energy of the system to the total surface excess. With the second model, our purpose is to develop a phase-field model to simulate scales that are larger than nanometer, where the departures from equilibrium are very small resulting in phase concentrations outside the spinodal region. In view of this, we exclude the concentration gradient contribution to the grand chemical potential functional, and develop a model based on [M. Plapp, Phys. Rev. E 84, 031601 (2011); A. Choudhury and B. Nestler, Phys. Rev. E 85, 021602 (2012)]. The advantage is that the free energy excess across the interface at equilibrium disappears, and hence it is easier to derive the required surface energies with higher interface widths. Due to this benefit, we employ the method to simulate the dynamic entrapment process in the monotectic reaction and study the influence of liquid(1) - liquid(2) surface energy and undercooling on the entrapment process. PMID- 22830720 TI - Comparison of thermodynamic stabilities and mechanical properties of CO2, SiO2, and GeO2 polymorphs by first-principles calculations. AB - The recent discovery that molecular CO(2) transforms under compression into carbon four-coordinated, 3-dimensional network solid phases has generated considerable interests on possible new phases in the fourth-main-group elemental oxides. Based on density-functional theory calculations, we have investigated the thermodynamic stability, mechanical properties and electronic structure of proposed guest-free clathrates, quartz and cristobalite phases for CO(2), SiO(2), and GeO(2), and the dry ice phase for CO(2). It was predicted that a GeO(2) clathrate, likely a semiconductor, could be synthesized presumably with some suitable guest molecules. The hypothetical CO(2) guest-free clathrate phase was found hardly to be formed due to the large energy difference with respect to the other polymorphs. This phase is unstable at all pressures, which is also implied by its different electronic structure in comparison with SiO(2) and GeO(2). Finally, the SiO(2) clathrate presents a uniquely high bulk modulus, which is higher than that of quartz and three times of the experimental data, might not be a weak point of ab-initio calculations such as pseudopotentials, correlation functional etc., instead it can be readily understood by the constraint as imposed by the high symmetry. Either temperature or an "exhausted" relaxation (without any symmetry constraint) can remedy this problem. PMID- 22830721 TI - Theoretical study on the effects of nitrogen and methyl substitution on tris-(8 hydroxyquinoline) aluminum: an efficient exciton blocking layer for organic photovoltaic cells. AB - We studied the effect of nitrogen and methyl substitution on tris-(8 hydroxyquinoline) aluminum (Alq(3)) with density functional theory, which has been adopted as an exciton blocking layer (EBL) in organic photovoltaic cells (OPVCs). The substitution of electron withdrawing nitrogen on the phenoxide moiety of Alq(3) lowers the highest molecular orbital (HOMO) level, thus photogenerated excitons can be effectively blocked in OPVC. Additional substitution of methyl on the pyridine moiety makes that Alq(3) has a smaller electron reorganization energy, which results in higher electron mobility with keeping HOMO level almost intact. Therefore, nitrogen and methyl simultaneous substitution shows high performance both in exciton blocking and electron mobility. This is the origins of the short circuit current enhancement in OPVC with 4-hydroxy-8-methyl-1,5-naphthyridine aluminum chelate (Alq(3) with the substitution of both nitrogen and methyl group) EBL. PMID- 22830722 TI - A comparative density functional study of the high-pressure phases of solid ZnX, CdX, and HgX (X = S, Se, and Te): trends and relativistic effects. AB - The pressure dependence of bulk properties for the group 12 chalcogenides MX (M = Zn, Cd, Hg; X = S, Se, Te) from density functional theory are presented. Energy volume and corresponding enthalpy-pressure relationships are determined to obtain the transition paths and properties of various high-pressure phases. The influence of relativistic effects is discussed with the aim to explain the unique behavior of the mercury chalcogenides as compared to the lighter zinc and cadmium homologs at high pressures. The neglect of relativistic effects leads to a more CdX like behavior of the mercury chalcogenides, and the pronounced change in coordination of the cinnabar phase at high pressures is due to relativistic effects. PMID- 22830723 TI - Large electronic bandwidth in solution-processable pyrene crystals: the role of close-packed crystal structure. AB - We examine the interdependence of structural and electronic properties of two substituted pyrene crystals by means of combined spectroscopic probes and density functional theory calculations. Substituted pyrenes are useful model systems to unravel the interplay of crystal structure and electronic properties in organic semiconductors. To study the effect of steric encumbrance on the crystalline arrangement of two 1,3,6,8-tetraalkynylpyrene derivatives, one features linear n hexyl side groups while the other contains branched trimethylsilyl groups. Both derivatives form triclinic crystal structures when grown from solution, but the electronic dispersion behavior is significantly different due to differences in pi-pi overlap along the pi-stacking axis. Both systems display dispersion of around 0.45 eV in the valence band, suggesting a high intrinsic hole mobility. However, the direction of the dispersion is different: it is primarily along the pi-stacking axis in the trimethylsilyl-substituted derivative, but less aligned with this crystal axis in the hexyl-substituted molecule. This is a direct consequence of the differences in co-facial pi electron overlap revealed by the crystallographic studies. We find that photophysical defects, ascribed to excimer like states, point to the importance of localized trap states. PMID- 22830724 TI - Wettability of pristine and alkyl-functionalized graphane. AB - Graphane is a hydrogenated form of graphene with high bandgap and planar structure insensitive to a broad range of chemical substitutions. We describe an atomistic simulation approach to predict wetting properties of this new material. We determine the contact angle to be 73 degrees . The lower hydrophobicity compared to graphene is explained by the increased planar density of carbon atoms while we demonstrate that the presence of partial charges on carbon and hydrogen atoms plays only a minor role. We further examine the effects of graphane functionalization by alkyl groups of increasing chain lengths. The gradual increase in contact angle with chain length offers a precise control of surface wettability. A saturated contact angle of 114 degrees is reached in butylated form. We find the saturation of contact angle with respect to the length of the functional groups to coincide with the loss of water's ability to penetrate the n alkyl molecular brush and interact with carbon atoms of the underlying lattice. Since no experimental data have yet become available, our modeling results provide the first estimate of the wettability of graphane. The results also show how its alkyl functionalization provides the basis for a variety of chemical modifications to tune hydrophilicity while preserving the planar geometry of the substrate. PMID- 22830725 TI - Effects of image charges, interfacial charge discreteness, and surface roughness on the zeta potential of spherical electric double layers. AB - We investigate the effects of image charges, interfacial charge discreteness, and surface roughness on spherical electric double layer structures in electrolyte solutions with divalent counterions in the setting of the primitive model. By using Monte Carlo simulations and the image charge method, the zeta potential profile and the integrated charge distribution function are computed for varying surface charge strengths and salt concentrations. Systematic comparisons were carried out between three distinct models for interfacial charges: (1) SURF1 with uniform surface charges, (2) SURF2 with discrete point charges on the interface, and (3) SURF3 with discrete interfacial charges and finite excluded volume. By comparing the integrated charge distribution function and the zeta potential profile, we argue that the potential at the distance of one ion diameter from the macroion surface is a suitable location to define the zeta potential. In SURF2 model, we find that image charge effects strongly enhance charge inversion for monovalent interfacial charges, and strongly suppress charge inversion for multivalent interfacial charges. For SURF3, the image charge effect becomes much smaller. Finally, with image charges in action, we find that excluded volumes (in SURF3) suppress charge inversion for monovalent interfacial charges and enhance charge inversion for multivalent interfacial charges. Overall, our results demonstrate that all these aspects, i.e., image charges, interfacial charge discreteness, their excluding volumes, have significant impacts on zeta potentials of electric double layers. PMID- 22830726 TI - Band gaps and structural properties of graphene halides and their derivates: a hybrid functional study with localized orbital basis sets. AB - Density functional theory calculations of the electronic structure of graphane and stoichiometrically halogenated graphene derivatives (fluorographene and other analogous graphene halides) show: (i) localized orbital basis sets can be successfully and effectively used for such two-dimensional materials; (ii) several functionals predict that the band gap of graphane is greater than that of fluorographene, whereas HSE06 gives the opposite trend; (iii) HSE06 functional predicts quite good values of band gaps with respect to benchmark theoretical and experimental data; (iv) the zero band gap of graphene is opened by hydrogenation and halogenation and strongly depends on the chemical composition of mixed graphene halides; (v) the stability of graphene halides decreases sharply with increasing size of the halogen atom--fluorographene is stable, whereas graphene iodide spontaneously decomposes. In terms of band gap and stability, the C(2)FBr and C(2)HBr derivatives seem to be promising materials, e.g., for (opto)electronics applications, because their band gaps are similar to those of conventional semiconductors, and they are expected to be stable under ambient conditions. The results indicate that other fluorinated compounds (C(a)H(b)F(c) and C(a)F(b)Y(c), Y = Cl, Br, I) are stable insulators. PMID- 22830727 TI - Derivation of free energy expressions for tube models from coarse-grained slip link models. AB - We present the free energy of a single-chain mean-field model for polymer melt dynamics, which uses a continuous (tube-like) approximation to the discrete entanglements with surrounding chains, but, in contrast to previous tube models, includes fluctuations in the number density of Kuhn steps along the primitive path and in the degree of entanglement. The free energy is obtained from that of the slip-link model with fluctuating entanglement positions [J. D. Schieber and K. Horio, J. Chem. Phys. 132, 074905 (2010)] by taking the continuous limit of (functions of) the discrete Kuhn-step numbers and end-to-end vectors of the strands between entanglements. This coarse-graining from a more-detailed level of description has the advantage that no ad hoc arguments need to be introduced. Moreover, the thermodynamic consistency of the slip-link model [J. D. Schieber, J. Non-Equilib. Thermodyn. 28, 179 (2003)] can be preserved. Fluctuations in the positions of entanglements lead to a harmonic bending term in the free energy of the continuous chain, similar to that derived by Read et al. [Macromolecules 41, 6843 (2008)] starting from a modified GLaMM model [R. S. Graham, A. E. Likhtman, T. C. B. McLeish, and S. T. Milner, J. Rheol. 47, 1171 (2003)]. If these fluctuations are set to zero, the free energy becomes purely Gaussian and corresponds to the continuous limit of the original slip-link model, with affinely moving entanglements [J. D. Schieber, J. Chem. Phys. 118, 5162 (2003)]. The free energy reduces to that of Read et al. under their assumptions of a homogeneous Kuhn-step number density and a constant degree of entanglement. Finally, we show how a transformation of the primitive-path coordinate can be applied to make the degree of entanglement an outcome of the model instead of a variable. In summary, this paper constitutes a first step towards a unified mathematical formulation of tube models. The next step will be to formulate the dynamics of the primitive-path conformation and the entanglement density along the primitive path. Now that the free energy is known, statistical mechanics can be employed for this purpose. PMID- 22830728 TI - Counterion adsorption theory of dilute polyelectrolyte solutions: apparent molecular weight, second virial coefficient, and intermolecular structure factor. AB - Polyelectrolyte chains are well known to be strongly correlated even in extremely dilute solutions in the absence of additional strong electrolytes. Such correlations result in severe difficulties in interpreting light scattering measurements in the determination of the molecular weight, radius of gyration, and the second virial coefficient of charged macromolecules at lower ionic strengths from added strong electrolytes. By accounting for charge-regularization of the polyelectrolyte by the counterions, we present a theory of the apparent molecular weight, second virial coefficient, and the intermolecular structure factor in dilute polyelectrolyte solutions in terms of concentrations of the polymer and the added strong electrolyte. The counterion adsorption of the polyelectrolyte chains to differing levels at different concentrations of the strong electrolyte can lead to even an order of magnitude discrepancy in the molecular weight inferred from light scattering measurements. Based on counterion mediated charge regularization, the second virial coefficient of the polyelectrolyte and the interchain structure factor are derived self consistently. The effect of the interchain correlations, dominating at lower salt concentrations, on the inference of the radius of gyration and on molecular weight is derived. Conditions for the onset of nonmonotonic scattering wave vector dependence of scattered intensity upon lowering the electrolyte concentration and interpretation of the apparent radius of gyration are derived in terms of the counterion adsorption mechanism. PMID- 22830729 TI - Simulation study on the translocation of a partially charged polymer through a nanopore. AB - The translocation of a partially charged polymer through a neutral nanopore under external electrical field is studied by using dynamic Monte Carlo method on a simple cubic lattice. One monomer in the polymer is charged and it suffers a driving force when it locates inside the pore. Two time scales, mean first passage time tau(FP) with the first monomer restricted to never draw back into cis side and translocation time tau for polymer continuously threading through nanopore, are calculated. The first passage time tau(FP) decreases with the increase in the driving force f, and the dependence of tau(FP) on the position of charged monomer M is in agreement with the theoretical results using Fokker Planck equation [A. Mohan, A. B. Kolomeisky, and M. Pasquali, J. Chem. Phys. 128, 125104 (2008)]. But the dependence of tau on M shows a different behavior: It increases with f for M < N/2 with N the polymer length. The novel behavior of tau is explained qualitatively from dynamics of polymer during the translocation process and from the free energy landscape. PMID- 22830731 TI - Structural characteristics of yeast F1-ATPase before and after 16-degree rotation of the gamma subunit: theoretical analysis focused on the water-entropy effect. AB - We have recently proposed a novel picture of the rotation mechanism for F(1) ATPase [T. Yoshidome, Y. Ito, M. Ikeguchi, and M. Kinoshita, J. Am. Chem. Soc. 133, 4030 (2011)]. In the picture, the asymmetric packing in F(1)-ATPase, originating from the water-entropy effect, plays the key role in the rotation. Here, we analyze the differences between the experimentally determined structures of yeast F(1)-ATPase before and after 16 degrees rotation of the gamma subunit with the emphasis on the water-entropy effect. For each of these structures, we calculate the hydration entropies of three sub-complexes comprising the gamma subunit, one of the beta subunits, and two alpha subunits adjacent to them. The beta(E), beta(TP), and beta(DP) subunits are involved in sub-complexes I, II, and III, respectively. The calculation is performed using a hybrid of the angle dependent integral equation theory combined with the molecular model for water and the morphometric approach. The absolute value of the hydration entropy is in the following order: sub-complex I > sub-complex II > sub-complex III. The packing efficiency of the sub-complex follows the opposite order. The rotation gives rise to less efficient packing in sub-complex III and a corresponding water entropy loss. However, the other two sub-complexes, accompanying water-entropy gains, become more efficiently packed. These results are consistent with our picture of the rotation mechanism, supporting its validity. The water-entropy analysis shows that the interfaces of alpha(DP)-beta(DP) and alpha(E)-beta(E) become more open after the rotation, which is in accord with the experimental observation. PMID- 22830730 TI - Coexistence of phases in a protein heterodimer. AB - A heterodimer consisting of two or more different kinds of proteins can display an enormous number of distinct molecular architectures. The conformational entropy is an essential ingredient in the Helmholtz free energy and, consequently, these heterodimers can have a very complex phase structure. Here, it is proposed that there is a state of proteins, in which the different components of a heterodimer exist in different phases. For this purpose, the structures in the protein data bank (PDB) have been analyzed, with radius of gyration as the order parameter. Two major classes of heterodimers with their protein components coexisting in different phases have been identified. An example is the PDB structure 3DXC. This is a transcriptionally active dimer. One of the components is an isoform of the intra-cellular domain of the Alzheimer disease related amyloid precursor protein (AICD), and the other is a nuclear multidomain adaptor protein in the Fe65 family. It is concluded from the radius of gyration that neither of the two components in this dimer is in its own collapsed phase, corresponding to a biologically active protein. The UNRES energy function has been utilized to confirm that, if the two components are separated from each other, each of them collapses. The results presented in this work show that heterodimers whose protein components coexist in different phases, can have intriguing physical properties with potentially important biological consequences. PMID- 22830732 TI - Molecular modeling of mechanical stresses on proteins in glassy matrices: formalism. AB - We present an expression for the calculation of microscopic stresses in molecular simulation, which is compatible with the use of electrostatic lattice sums such as the Ewald sum, with the presence of many-body interactions, and which allows local stresses to be calculated on surfaces of arbitrarily complex shape. The ultimate goal of this work is to investigate microscopic stresses on proteins in glassy matrices, which are used in the pharmaceutical industry for the long-term storage and stabilization of labile biomolecules. We demonstrate the formalism's usefulness through selected results on ubiquitin and an alpha-keratin fragment, in liquid and glassy states. We find that atomic-level normal stresses on hydrophilic side-chains exhibit a similar fingerprint in both proteins, and protein-level normal stresses increase upon vitrification. Both proteins experience compressive stresses of the order of 10(2) bar in the glassy state. PMID- 22830733 TI - Steady-state fluctuations of a genetic feedback loop: an exact solution. AB - Genetic feedback loops in cells break detailed balance and involve bimolecular reactions; hence, exact solutions revealing the nature of the stochastic fluctuations in these loops are lacking. We here consider the master equation for a gene regulatory feedback loop: a gene produces protein which then binds to the promoter of the same gene and regulates its expression. The protein degrades in its free and bound forms. This network breaks detailed balance and involves a single bimolecular reaction step. We provide an exact solution of the steady state master equation for arbitrary values of the parameters, and present simplified solutions for a number of special cases. The full parametric dependence of the analytical non-equilibrium steady-state probability distribution is verified by direct numerical solution of the master equations. For the case where the degradation rate of bound and free protein is the same, our solution is at variance with a previous claim of an exact solution [J. E. M. Hornos, D. Schultz, G. C. P. Innocentini, J. Wang, A. M. Walczak, J. N. Onuchic, and P. G. Wolynes, Phys. Rev. E 72, 051907 (2005), and subsequent studies]. We show explicitly that this is due to an unphysical formulation of the underlying master equation in those studies. PMID- 22830734 TI - Note: Microsecond long atomistic simulation of supercooled water. PMID- 22830737 TI - Point/Counterpoint: recent data show that mammographic screening of asymptomatic women is effective and essential. PMID- 22830738 TI - Variance analysis of x-ray CT sinograms in the presence of electronic noise background. AB - PURPOSE: Low-dose x-ray computed tomography (CT) is clinically desired. Accurate noise modeling is a fundamental issue for low-dose CT image reconstruction via statistics-based sinogram restoration or statistical iterative image reconstruction. In this paper, the authors analyzed the statistical moments of low-dose CT data in the presence of electronic noise background. METHODS: The authors first studied the statistical moment properties of detected signals in CT transmission domain, where the noise of detected signals is considered as quanta fluctuation upon electronic noise background. Then the authors derived, via the Taylor expansion, a new formula for the mean-variance relationship of the detected signals in CT sinogram domain, wherein the image formation becomes a linear operation between the sinogram data and the unknown image, rather than a nonlinear operation in the CT transmission domain. To get insight into the derived new formula by experiments, an anthropomorphic torso phantom was scanned repeatedly by a commercial CT scanner at five different mAs levels from 100 down to 17. RESULTS: The results demonstrated that the electronic noise background is significant when low-mAs (or low-dose) scan is performed. CONCLUSIONS: The influence of the electronic noise background should be considered in low-dose CT imaging. PMID- 22830739 TI - Monte Carlo computed machine-specific correction factors for reference dosimetry of TomoTherapy static beam for several ion chambers. AB - PURPOSE: To determine k(Q(msr),Q(o) ) (f(msr),f(o) ) correction factors for machine-specific reference (msr) conditions by Monte Carlo (MC) simulations for reference dosimetry of TomoTherapy static beams for ion chambers Exradin A1SL, A12; PTW 30006, 31010 Semiflex, 31014 PinPoint, 31018 microLion; NE 2571. METHODS: For the calibration of TomoTherapy units, reference conditions specified in current codes of practice like IAEA/TRS-398 and AAPM/TG-51 cannot be realized. To cope with this issue, Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] described a new formalism introducing msr factors k(Q(msr),Q(o) ) (f(msr),f(o) ) for reference dosimetry, applicable to static TomoTherapy beams. In this study, those factors were computed directly using MC simulations for Q(0) corresponding to a simplified (60)Co beam in TRS-398 reference conditions (at 10 cm depth). The msr conditions were a 10 * 5 cm(2) TomoTherapy beam, source-surface distance of 85 cm and 10 cm depth. The chambers were modeled according to technical drawings using the egs++ package and the MC simulations were run with the egs_chamber user code. Phase-space files used as the source input were produced using PENELOPE after simulation of a simplified (60)Co beam and the TomoTherapy treatment head modeled according to technical drawings. Correlated sampling, intermediate phase space storage, and photon cross-section enhancement variance reduction techniques were used. The simulations were stopped when the combined standard uncertainty was below 0.2%. RESULTS: Computed k(Q(msr),Q(o) ) (f(msr),f(o) ) values were all close to one, in a range from 0.991 for the PinPoint chamber to 1.000 for the Exradin A12 with a statistical uncertainty below 0.2%. Considering a beam quality Q defined as the TPR(20,10) for a 6 MV Elekta photon beam (0.661), the additional correction k(Q(msr,)Q) (f(msr,)f(ref) ) to k(Q,Q(o) ) defined in Alfonso et al. [Med. Phys. 35, 5179-5186 (2008)] formalism was in a range from 0.997 to 1.004. CONCLUSION: The MC computed factors in this study are in agreement with measured factors for chamber types already studied in literature. This work provides msr correction factors for additional chambers used in reference dosimetry. All of them were close to one (within 1%). PMID- 22830740 TI - Technical note: patient-specific quality assurance methods for TomoDirect(TM) whole breast treatment delivery. AB - PURPOSE: To investigate the feasibility of implementing a novel approach for patient-specific QA of TomoDirect(TM) whole breast treatment. METHODS: The most currently used TomoTherapy DQA method, consisting in the verification of the 2D dose distribution in a coronal or sagittal plane of the Cheese Phantom by means of gafchromic films, was compared with an alternative approach based on the use of two commercially available diode arrays, MapCHECK2(TM) and ArcCHECK(TM). The TomoDirect(TM) plans of twenty patients with a primary unilateral breast cancer were applied to a CT scan of the Cheese Phantom and a MVCT dataset of the diode arrays. Then measurements of 2D dose distribution were performed and compared with the calculated ones using the gamma analysis method with different sets of DTA and DD criteria (3%-3 mm, 3%-2 mm). The sensitivity of the diode arrays to detect delivery and setup errors was also investigated. RESULTS: The measured dose distributions showed excellent agreement with the TPS calculations for each detector, with averaged fractions of passed Gamma values greater than 95%. The percentage of points satisfying the constraint Gamma < 1 was significantly higher for MapCHECK2(TM) than for ArcCHECK(TM) and gafchromic films using both the 3%-3 mm and 3%-2 mm gamma criteria. Both the diode arrays show a good sensitivity to delivery and setup errors using a 3%-2 mm gamma criteria. CONCLUSIONS: MapCHECK2TM and ArcCHECK(TM) may fulfill the demands of an adequate system for TomoDirect(TM) patient-specific QA. PMID- 22830741 TI - Noise spatial nonuniformity and the impact of statistical image reconstruction in CT myocardial perfusion imaging. AB - PURPOSE: To achieve high temporal resolution in CT myocardial perfusion imaging (MPI), images are often reconstructed using filtered backprojection (FBP) algorithms from data acquired within a short-scan angular range. However, the variation in the central angle from one time frame to the next in gated short scans has been shown to create detrimental partial scan artifacts when performing quantitative MPI measurements. This study has two main purposes. (1) To demonstrate the existence of a distinct detrimental effect in short-scan FBP, i.e., the introduction of a nonuniform spatial image noise distribution; this nonuniformity can lead to unexpectedly high image noise and streaking artifacts, which may affect CT MPI quantification. (2) To demonstrate that statistical image reconstruction (SIR) algorithms can be a potential solution to address the nonuniform spatial noise distribution problem and can also lead to radiation dose reduction in the context of CT MPI. METHODS: Projection datasets from a numerically simulated perfusion phantom and an in vivo animal myocardial perfusion CT scan were used in this study. In the numerical phantom, multiple realizations of Poisson noise were added to projection data at each time frame to investigate the spatial distribution of noise. Images from all datasets were reconstructed using both FBP and SIR reconstruction algorithms. To quantify the spatial distribution of noise, the mean and standard deviation were measured in several regions of interest (ROIs) and analyzed across time frames. In the in vivo study, two low-dose scans at tube currents of 25 and 50 mA were reconstructed using FBP and SIR. Quantitative perfusion metrics, namely, the normalized upslope (NUS), myocardial blood volume (MBV), and first moment transit time (FMT), were measured for two ROIs and compared to reference values obtained from a high-dose scan performed at 500 mA. RESULTS: Images reconstructed using FBP showed a highly nonuniform spatial distribution of noise. This spatial nonuniformity led to large fluctuations in the temporal direction. In the numerical phantom study, the level of noise was shown to vary by as much as 87% within a given image, and as much as 110% between different time frames for a ROI far from isocenter. The spatially nonuniform noise pattern was shown to correlate with the source trajectory and the object structure. In contrast, images reconstructed using SIR showed a highly uniform spatial distribution of noise, leading to smaller unexpected noise fluctuations in the temporal direction when a short scan angular range was used. In the numerical phantom study, the noise varied by less than 37% within a given image, and by less than 20% between different time frames. Also, the noise standard deviation in SIR images was on average half of that of FBP images. In the in vivo studies, the deviation observed between quantitative perfusion metrics measured from low-dose scans and high-dose scans was mitigated when SIR was used instead of FBP to reconstruct images. CONCLUSIONS: (1) Images reconstructed using FBP suffered from nonuniform spatial noise levels. This nonuniformity is another manifestation of the detrimental effects caused by short-scan reconstruction in CT MPI. (2) Images reconstructed using SIR had a much lower and more uniform noise level and thus can be used as a potential solution to address the FBP nonuniformity. (3) Given the improvement in the accuracy of the perfusion metrics when using SIR, it may be desirable to use a statistical reconstruction framework to perform low-dose dynamic CT MPI. PMID- 22830742 TI - Decision support system for localizing prostate cancer based on multiparametric magnetic resonance imaging. AB - PURPOSE: There is a growing need to localize prostate cancers on magnetic resonance imaging (MRI) to facilitate the use of image guided biopsy, focal therapy, and active surveillance follow up. Our goal was to develop a decision support system (DSS) for detecting and localizing peripheral zone prostate cancers by using machine learning approach to calculate a cancer probability map from multiparametric MR images (MP-MRI). METHODS: This IRB approved Health Insurance Portability and Accountability Act compliant retrospective study consisted of 31 patients (mean age and serum prostate specific antigen of 60.4 and 6.62 ng/ml, respectively) who had MP-MRI at 3 T followed by radical prostatectomy. Seven patients were excluded due to technical issues with their MP MRI (e.g., motion artifact, failure to perform all sequences). Cancer and normal regions were identified in the peripheral zone by correlating them to whole mount histology slides of the excised prostatectomy specimens. To facilitate the correlation, tissue blocks matching the MR slices were obtained using a MR-based patient-specific mold. Segmented regions on the MP-MRI were correlated to histopathology and used as training sets for the learning system that generated the cancer probability maps. Leave-one-patient-out cross-validation on the cancer and normal regions was performed to determine the learning system's efficacy, an evolutionary strategies approach (also known as a genetic algorithm) was used to find the optimal values for a set of parameters, and finally a cancer probability map was generated. RESULTS: For the 24 patients that were used in the study, 225 cancer and 264 noncancerous regions were identified from the region maps. The efficacy of DSS was first determined without optimizing support vector machines (SVM) parameters, where a region having a cancer probability greater than or equal to 50% was considered as a correct classification. The nonoptimized system had an f-measure of 85% and the Kappa coefficient of 71% (Rater's agreement, where raters are DSS and ground truth histology). The efficacy of the DSS after optimizing SVM parameters using a genetic algorithm had an f-measure of 89% and a Kappa coefficient of 80%. Thus, after optimization of the DSS there was a 4% increase in the f-measure and a 9% increase in the Kappa coefficient. CONCLUSIONS: This DSS provides a cancer probability map for peripheral zone prostate tumors based on endorectal MP-MRI. These cancer probability maps can potentially aid radiologists in accurately localizing peripheral zone prostate cancers for planning targeted biopsies, focal therapy, and follow up for active surveillance. PMID- 22830743 TI - Experimental evaluation of a spatial resampling technique to improve the accuracy of pencil-beam dose calculation in proton therapy. AB - PURPOSE: In proton therapy, pencil-beam algorithms (PBAs) are the most widely used dose calculation methods. However, the PB calculations that employ one dimensional density scaling neglect the effects of lateral density heterogeneity on the dose distributions, whereas some particles included in such pencil beams could overextend beyond the interface of the density heterogeneity. We have simplified a pencil-beam redefinition algorithm (PBRA), which was proposed for electron therapy, by a spatial resampling technique toward an application for proton therapy. The purpose of this study is to evaluate the calculation results of the spatial resampling technique in terms of lateral density heterogeneity by comparison with the dose distributions that were measured in heterogeneous slab phantoms. METHODS: The pencil beams are characterized for multiple residual-range (i.e., proton energy) bins. To simplify the PBRA, the given pencil beams are resampled on one or two transport planes, in which smaller sub-beams that are parallel to each other are generated. We addressed the problem of lateral density heterogeneity comparing the calculation results to the dose distributions measured at different depths in heterogeneous slab phantoms using a two dimensional detector. Two heterogeneity slab phantoms, namely, phantoms A and B, were designed for the measurements and calculations. In phantom A, the heterogeneity slab was placed close to the surface. On the other hand, in phantom B, it was placed close to the Bragg peak in the mono-energetic proton beam. RESULTS: In measurements, lateral dose profiles showed a dose reduction and increment in the vicinity of x = 0 mm in both phantoms at depths z = 142 and 161 mm due to lateral particle disequilibrium. In phantom B, these dose reduction/increment effects were higher/lower, respectively, than those in phantom A. This is because a longer distance from the surface to the heterogeneous slab increases the strength of proton scattering. Sub-beams, which were generated from the resampling plane, formed a detouring/overextending path that was different from that of elemental pencil beams. Therefore, when the spatial resampling was implemented at the surface and immediately upstream of the lateral heterogeneity, the calculation could predict these dose reduction/increment effects. Without the resampling procedure, these dose reduction/increment effects could not be predicted in both phantoms owing to the blurring of the pencil beam. We found that the PBA with the spatial resampling technique predicted the dose reduction/increment at the dose profiles in both phantoms when the sampling plane was defined immediately upstream of the heterogeneous slab. CONCLUSIONS: We have demonstrated the implementation of a spatial resampling technique for pencil-beam calculation to address the problem of lateral density heterogeneity. While further validation is required for clinical use, this study suggests that the spatial resampling technique can make a significant contribution to proton therapy. PMID- 22830744 TI - Towards task-based assessment of CT performance: system and object MTF across different reconstruction algorithms. AB - PURPOSE: To investigate a measurement method for evaluating the resolution properties of CT imaging systems across reconstruction algorithms, dose, and contrast. METHODS: An algorithm was developed to extract the task-based modulation transfer function (MTF) from disk images generated from the rod inserts in the ACR phantom (model 464 Gammex, WI). These inserts are conventionally employed for HU accuracy assessment. The edge of the disk objects was analyzed to determine the edge-spread function, which was differentiated to yield the line-spread function and Fourier-transformed to generate the object specific MTF for task-based assessment, denoted MTF(Task). The proposed MTF measurement method was validated against the conventional wire technique and further applied to measure the MTF of CT images reconstructed with an adaptive statistical iterative algorithm (ASIR) and a model-based iterative (MBIR) algorithm. Results were further compared to the standard filtered back projection (FBP) algorithm. Measurements were performed and compared across different doses and contrast levels to ascertain the MTF(Task) dependencies on those factors. RESULTS: For the FBP reconstructed images, the MTF(Task) measured with the inserts were the same as the MTF measured from the wire-based method. For the ASIR and MBIR data, the MTF(Task) using the high contrast insert was similar to the wire-based MTF and equal or superior to that of FBP. However, results for the MTF(Task) measured using the low-contrast inserts, the MTF(Task) for ASIR and MBIR data was lower than for the FBP, which was constant throughout all measurements. Similarly, as a function of mA, the MTF(Task) for ASIR and MBIR varied as a function of noise--with MTF(Task) being proportional to mA. Overall greater variability of MTF(Task) across dose and contrast was observed for MBIR than for ASIR. CONCLUSIONS: This approach provides a method for assessing the task-based MTF of a CT system using conventional and iterative reconstructions. Results demonstrated that the object-specific MTF can vary as a function of dose and contrast. The analysis highlighted the paradigm shift for iterative reconstructions when compared to FBP, where iterative reconstructions generally offer superior noise performance but with varying resolution as a function of dose and contrast. The MTF(Task) generated by this method is expected to provide a more comprehensive assessment of image resolution across different reconstruction algorithms and imaging tasks. PMID- 22830745 TI - Quality indicators and technique for analyzing permanent I-125 prostate seed implants: seven years postimplant dosimetry evaluation. AB - PURPOSE: The roles of postimplant dosimetry (PID) after permanent I-125 implant are to identify and rectify inadequate implants, assess the dosimetric quality indicators, and evaluate dose to the organs at risk. The aim of the current work was to assess the progress of prostate implant quality via postimplant dosimetry over seven years. METHODS: The following factors were investigated to assess the PID results obtained over seven years: the improvement in implant technique, the computed tomography (CT) delineation-based PID versus ultrasound-CT (US-CT) fusion-based PID, and the evolution of parameters such as D90 and NDR (natural dose ratio). The correlation between dosimetric parameters and clinical outcomes were also evaluated. RESULTS: The seven years PID learning curve shows clear changes in dosimetric trend for the 265 patients studied. Manual target contouring on CT was shown to overestimate the prostate volume when compared to ultrasound data, translating to CT-based D90 values being lower than US-CT D90. It was found that NDR does not contribute with additional dosimetric information to postimplant dosimetry evaluation. Patient follow-up data show that 4.7% patients have relapsed, and urinary retention was reported in 2.7% of the patients. CONCLUSIONS: CT-based PID was found less reliable than US-CT fusion based PID due to target volume overestimation. This result shows the biased interpretation of low D90 values based on CT-based targeting, providing unreliable correlations between D90 and relapse probability. The low urinary retention statistics are in accordance with the PID data for the organ, as only 5.2% of patients had their PID D10 > 218 Gy, i.e., above the recommended GEC ESTRO guidelines. Besides the "learning" component, the PID D90 curve is influenced by the PID technique. PMID- 22830746 TI - Transmission of broad W/Rh and W/Al (target/filter) x-ray beams operated at 25-49 kVp through common shielding materials. AB - PURPOSE: To provide transmission data for broad 25-39 kVp (kilovolt peak) W/Rh and 25-49 kVp W/Al (target/filter, W-tungsten, Rh-rhodium, and Al-aluminum) x-ray beams through common shielding materials, such as lead, concrete, gypsum wallboard, wood, steel, and plate glass. METHODS: The unfiltered W-target x-ray spectra measured on a Selenia Dimensions system (Hologic Inc., Bedford, MA) set at 20-49 kVp were, respectively, filtered using 50-MUm Rh and 700-MUm Al, and were subsequently used for Monte Carlo calculations. The transmission of broad x ray beams through shielding materials was simulated using Geant4 low energy electromagnetic physics package with photon- and electron-processes above 250 eV, including photoelectric effect, Compton scattering, and Rayleigh scattering. The calculated transmission data were fitted using Archer equation with a robust fitting algorithm. RESULTS: The transmission of broad x-ray beams through the above-mentioned shielding materials was calculated down to about 10(-5) for 25-39 kVp W/Rh and 25-49 kVp W/Al. The fitted results of alpha, beta, and gamma in Archer equation were provided. The alpha values of kVp >= 40 were approximately consistent with those of NCRP Report No. 147. CONCLUSIONS: These data provide inputs for the shielding designs of x-ray imaging facilities with W-anode x-ray beams, such as from Selenia Dimensions. PMID- 22830748 TI - Evaluation of the potential utility of flat panel CT for quantifying relative contrast enhancement. AB - PURPOSE: Certain directed oncologic therapies seek to take advantage of the fact that tumors are typically more susceptible to directed therapeutic agents than normal tissue owing to their extensive networks of poorly formed, leaky vasculature. If differences between the vascularity of normal and tumor tissues could be quantified, patients could be selected for or excluded from directed treatments on the basis of this difference. However, angiographic imaging techniques such as digital subtraction angiography (DSA) yield two-dimensional data that may be inadequate for this task. As a first step, the authors evaluated the feasibility of using a commercial implementation of flat panel computed tomography (FPCT) to quantify differences in enhancement of a simulated tumor compared with normal tissue based on differences in CT number measured in precontrast and postcontrast scans. METHODS: To evaluate the FPCT scanner studied, the authors scanned several phantoms containing simulated normal and tumor tissues. In the first experiment, the authors used an anthropomorphic phantom containing inclusions representing normal, tumor, and bone tissue to evaluate the constancy of CT numbers in scans repeated at clinically relevant intervals of 1 and 3 min. The authors then scanned gelatin phantoms containing dilutions of iodinated contrast to evaluate the accuracy of relative contrast enhancement measurements for a clinical FPCT system. Data were analyzed using widely available software. RESULTS: CT numbers measured in identical locations were constant over both scan intervals evaluated. Measured relative contrast enhancement values were accurate compared with known relative contrast enhancement values. Care must be taken to avoid artifacts in reconstructed images when placing regions of interest. CONCLUSIONS: Despite its limitations, FPCT in the interventional laboratory can be used to quantify relative contrast enhancement in phantoms. This is accomplished by measuring CT number in simulated tumor and normal tissue on precontrast and postcontrast scans. This information opens the door for refinement of technique in an effort to use such a technique to plan directed therapies. PMID- 22830747 TI - Spatially regularized T(1) estimation from variable flip angles MRI. AB - PURPOSE: To develop efficient algorithms for fast voxel-by-voxel quantification of tissue longitudinal relaxation time (T(1)) from variable flip angles magnetic resonance images (MRI) to reduce voxel-level noise without blurring tissue edges. METHODS: T(1) estimations regularized by total variation (TV) and quadratic penalty are developed to measure T(1) from fast variable flip angles MRI and to reduce voxel-level noise without decreasing the accuracy of the estimates. First, a quadratic surrogate for a log likelihood cost function of T(1) estimation is derived based upon the majorization principle, and then the TV-regularized surrogate function is optimized by the fast iterative shrinkage thresholding algorithm. A fast optimization algorithm for the quadratically regularized T(1) estimation is also presented. The proposed methods are evaluated by the simulated and experimental MR data. RESULTS: The means of the T(1) values in the simulated brain data estimated by the conventional, TV-regularized, and quadratically regularized methods have less than 3% error from the true T(1) in both GM and WM tissues with image noise up to 9%. The relative standard deviations (SDs) of the T(1) values estimated by the conventional method are more than 12% and 15% when the images have 7% and 9% noise, respectively. In comparison, the TV-regularized and quadratically regularized methods are able to suppress the relative SDs of the estimated T(1) to be less than 2% and 3%, respectively, regardless of the image noise level. However, the quadratically regularized method tends to overblur the edges compared to the TV-regularized method. CONCLUSIONS: The spatially regularized methods improve quality of T(1) estimation from multiflip angles MRI. Quantification of dynamic contrast-enhanced MRI can benefit from the high quality measurement of native T(1). PMID- 22830749 TI - A combined dose calculation and verification method for a small animal precision irradiator based on onboard imaging. AB - PURPOSE: Novel small animal precision microirradiators (micro-IR) are becoming available for preclinical use and are often equipped with onboard imaging (OBI) devices. We investigated the use of OBI as a means to infer the accuracy of the delivered treatment plan. METHODS: Monte Carlo modeling of the micro-IR including an elliptical Gaussian electron beam incident on the x-ray tube was used to score dose and to continue photon transport to the plane of the OBI device. A model of the OBI detector response was used to generate simulated onboard images. Experimental OBI was performed at 225 kVp, gain/offset and scatter-glare were corrected. Simulated and experimentally obtained onboard images of phantoms and a mouse specimen were compared for a range of photon beam sizes from 2.5 cm down to 0.1 cm. RESULTS: Simulated OBI can be used in small animal radiotherapy to determine if a treatment plan was delivered according to the prescription within an uncertainty of 5% for beams as small as 4 mm in diameter. For collimated beams smaller than 4 mm, beam profile differences remain primarily in the penumbra region of the smallest beams, which may be tolerable for specific preclinical micro-IR investigations. CONCLUSIONS: Comparing simulated to acquired OBI during small animal treatment radiotherapy represents a useful treatment delivery tool. PMID- 22830750 TI - The Cole relaxation frequency as a parameter to identify cancer in breast tissue. AB - PURPOSE: To correlate the Cole relaxation frequencies obtained from measurements of the electrical properties of breast tissue to the presence or absence of cancer. METHODS: Four-lead impedance measurements were obtained on ex vivo specimens extracted during surgery from 187 volunteer patients. Data were acquired with a commercial Solartron impedance bridge employing 4-lead Ag-AgCl or blackened platinum (BPt) electrodes at frequencies logarithmically spaced from 1 Hz to 3.2 * 10(7) Hz utilizing 6-10 frequencies per decade. The Cole frequencies obtained from these measurements were correlated with the tissue health status (cancer or noncancer) obtained from histological analysis of the specimens. RESULTS: Analysis of the impedance measurements showed that the Cole relaxation frequencies correlated to the presence or absence of cancer in the examined tissue with a sensitivity up to 100% (95% CI, 99%-100%) and a specificity up to 85% (95% CI, 79%-91%) based on the ROC curve of the data with the Cole frequency as the classifier. CONCLUSIONS: The results show that the Cole frequency alone is a viable classifier for malignant breast anomalies. Results of the current work are consistent with recent bioimpedance measurements on single cell and cell suspension breast cell lines. PMID- 22830751 TI - Influence of photon energy cuts on PET Monte Carlo simulation results. AB - PURPOSE: The purpose of this work is to study the influence of photon energy cuts on the results of positron emission tomography (PET) Monte Carlo (MC) simulations. METHODS: MC simulations of PET scans of a box phantom and the NEMA image quality phantom are performed for 32 photon energy cut values in the interval 0.3-350 keV using a well-validated numerical model of a PET scanner. The simulations are performed with two MC codes, egs_pet and GEANT4 Application for Tomographic Emission (GATE). The effect of photon energy cuts on the recorded number of singles, primary, scattered, random, and total coincidences as well as on the simulation time and noise-equivalent count rate is evaluated by comparing the results for higher cuts to those for 1 keV cut. To evaluate the effect of cuts on the quality of reconstructed images, MC generated sinograms of PET scans of the NEMA image quality phantom are reconstructed with iterative statistical reconstruction. The effects of photon cuts on the contrast recovery coefficients and on the comparison of images by means of commonly used similarity measures are studied. RESULTS: For the scanner investigated in this study, which uses bismuth germanate crystals, the transport of Bi X(K) rays must be simulated in order to obtain unbiased estimates for the number of singles, true, scattered, and random coincidences as well as for an unbiased estimate of the noise-equivalent count rate. Photon energy cuts higher than 170 keV lead to absorption of Compton scattered photons and strongly increase the number of recorded coincidences of all types and the noise-equivalent count rate. The effect of photon cuts on the reconstructed images and the similarity measures used for their comparison is statistically significant for very high cuts (e.g., 350 keV). The simulation time decreases slowly with the increase of the photon cut. CONCLUSIONS: The simulation of the transport of characteristic x rays plays an important role, if an accurate modeling of a PET scanner system is to be achieved. The simulation time decreases slowly with the increase of the cut which, combined with the accuracy loss at high cuts, means that the usage of high photon energy cuts is not recommended for the acceleration of MC simulations. PMID- 22830752 TI - An algorithm for PET tumor volume and activity quantification: without specifying camera's point spread function (PSF). AB - PURPOSE: The authors have developed an algorithm for segmentation and removal of the partial volume effect (PVE) of tumors in positron emission tomography (PET) images. The algorithm accurately measures functional volume (FV) and activity concentration (AC) of tumors independent of the camera's full width half maximum (FWHM). METHODS: A novel iterative histogram thresholding (HT) algorithm is developed to segment the tumors in PET images, which have low resolution and suffer from inherent noise in the image. The algorithm is initiated by manually drawing a region of interest (ROI). The segmented tumors are subjected to the iterative deconvolution thresholding segmentation (IDTS) algorithm, where the Van Cittert's method of deconvolution is used for correcting PVE. The IDTS algorithm is fully automated and accurately measures the FV and AC, and stops once it reaches convergence. The convergence criteria or stopping conditions are developed in such a way that the algorithm does not rely on estimating the FWHM of the point spread function (PSF) to perform the deconvolution process. The algorithm described here was tested in phantom studies, where hollow spheres (0.5 16 ml) were used to represent tumors with a homogeneous activity distribution, and an irregular shaped volume was used to represent a tumor with a heterogeneous activity distribution. The phantom studies were performed with different signal to background ratios (SBR) and with different acquisition times (1 min, 3 min, and 5 min). The parameters in the algorithm were also changed (FWHM and matrix size of the Gaussian function) to check the accuracy of the algorithm. Simulated data were also used to test the algorithm with tumors having heterogeneous activity distribution. RESULTS: The results show that changing the size and shape of the ROI during initiation of the algorithm had no significant impact on the FV. An average FV overestimation of 30% and an average AC underestimation of 35% were observed for the smallest tumor (0.5 ml) over the entire range of noise and SBR level. The difference in average FV and AC estimations from the actual volumes were less than 5% as the tumor size increased to 16 ml. For tumors with heterogeneous activity profile, the overall volume error was less than 10%. The average overestimation of FV was less than 10% and classification error was around 11%. CONCLUSIONS: The algorithm developed herein was extensively tested and is not dependent on accurately quantifying the camera's PSF. This feature demonstrates the robustness of the algorithm and enables it to be applied on a wide range of noise and SBR within an image. The ultimate goal of the algorithm is to be able to be operated independent of the camera type used and the reconstruction algorithm deployed. PMID- 22830753 TI - Development of a novel ArcCHECK(TM) insert for routine quality assurance of VMAT delivery including dose calculation with inhomogeneities. AB - PURPOSE: To design a versatile, nonhomogeneous insert for the dose verification phantom ArcCHECK(TM) (Sun Nuclear Corp., FL) and to demonstrate its usefulness for the verification of dose distributions in inhomogeneous media. As an example, we demonstrate it can be used clinically for routine quality assurance of two volumetric modulated arc therapy (VMAT) systems for lung stereotactic body radiation therapy (SBRT): SmartArc((r)) (Pinnacle(3), Philips Radiation Oncology Systems, Fitchburg, WI) and RapidArc((r)) (Eclipse(TM), Varian Medical Systems, Palo Alto, CA). METHODS: The cylindrical detector array ArcCHECK(TM) has a retractable homogeneous acrylic insert. In this work, we designed and manufactured a customized heterogeneous insert with densities that simulate soft tissue, lung, bone, and air. The insert offers several possible heterogeneity configurations and multiple locations for point dose measurements. SmartArc((r)) and RapidArc((r)) plans for lung SBRT were generated and copied to ArcCHECK(TM) for each inhomogeneity configuration. Dose delivery was done on a Varian 2100 ix linac. The evaluation of dose distributions was based on gamma analysis of the diode measurements and point doses measurements at different positions near the inhomogeneities. RESULTS: The insert was successfully manufactured and tested with different measurements of VMAT plans. Dose distributions measured with the homogeneous insert showed gamma passing rates similar to our clinical results (~99%) for both treatment-planning systems. Using nonhomogeneous inserts decreased the passing rates by up to 3.6% in the examples studied. Overall, SmartArc((r)) plans showed better gamma passing rates for nonhomogeneous measurements. The discrepancy between calculated and measured point doses was increased up to 6.5% for the nonhomogeneous insert depending on the inhomogeneity configuration and measurement location. SmartArc((r)) and RapidArc((r)) plans had similar plan quality but RapidArc((r)) plans had significantly higher monitor units (up to 70%). CONCLUSIONS: A versatile, nonhomogeneous insert was developed for ArcCHECK(TM) for an easy and quick evaluation of dose calculations with nonhomogeneous media and for comparison of different treatment planning systems. The device was tested for SmartArc((r)) and RapidArc((r)) plans for lung SBRT, showing the uncertainties of dose calculations with inhomogeneities. The new insert combines the convenience of the ArcCHECK(TM) and the possibility of assessing dose distributions in inhomogeneous media. PMID- 22830754 TI - Volume-of-interest cone-beam CT using a 2.35 MV beam generated with a carbon target. AB - PURPOSE: This is a proof-of-concept study addressing volume of interest (VOI) cone beam CT (CBCT) imaging using an x-ray beam produced by 2.35 MeV electrons incident on a carbon linear accelerator target. Methodology is presented relevant to VOI CBCT image acquisition and reconstruction. Sample image data are given to demonstrate and compare two approaches to minimizing artifacts arising from reconstruction with truncated projections. Dosimetric measurements quantify the potential dose reduction of VOI acquisition relative to full-field CBCT. The dependence of contrast-to-noise ratio (CNR) on VOI dimension is investigated. METHODS: A paradigm is presented linking the treatment planning process with the imaging technique, allowing definition of an imaging VOI to be tailored to the geometry of the patient. Missing data in truncated projection images are completed using a priori information in the form of digitally reconstructed radiographs (DRRs) generated from the planning CT set. This method is compared to a simpler technique of extrapolating truncated projection data prior to reconstruction. The utility of these approaches is shown through imaging of a geometric phantom and the head-and-neck section of a lamb. The total scatter factor of the 2.35 MV/carbon beam on field size is measured and compared to a standard therapeutic beam to estimate the comparative dose reduction inside the VOI. Thermoluminescent dosimeters and Gafchromic film measurements are used to compare the imaging dose distributions for the 2.35 MV/carbon beam between VOI and full-field techniques. The dependence of CNR on VOI dimension is measured for VOIs ranging from 4 to 15 cm diameter. RESULTS: Without compensating for missing data outside of truncated projections prior to reconstruction, pronounced boundary artifacts are present, in three dimensions, within 2-3 cm of the edges of the VOI. These artifacts, as well as cupping inside the VOI, can be reduced substantially using either the DRR filling or extrapolation techniques presented. Compared to 6 MV, the 2.35 MV/carbon beam shows a substantially greater dependence of total scatter factor on field size, indicating a comparative advantage of the VOI approach when combined with the low-Z target beam. Dosimetric measurements in the anthropomorphic head phantom demonstrate a dose reduction by up to 15% and 75% inside and outside of the VOI, respectively, compared to full-field imaging. For the 2.35 MV/carbon beam, CNR was shown to be approximately invariant with VOI dimension for bone and lung objects. CONCLUSIONS: The low-Z target, VOI CBCT technique appears to be feasible and combines the desirable characteristics of the low-Z target beam with regard to CNR, with the capacity to localize the imaging dose to the anatomy relevant to the image guidance task. PMID- 22830755 TI - Development of a phantom to evaluate the positioning accuracy of patient immobilization systems using thermoplastic mask and polyurethane cradle. AB - PURPOSE: The purpose of this study was to develop a new phantom to evaluate the positioning accuracy of patient immobilization systems. METHODS: The phantom was made of papers formed into a human shape, paper clay, and filling rigid polyester. Acrylonitrile butadiene styrene (ABS) pipes were inserted at anterior posterior (A-P) and right-left (R-L) directions in the phantom to give static load by pulling ropes through the pipes. First, the positioning precision of the phantom utilizing a target locating system (TLS) was evaluated by moving the phantom on a couch along inferior-superior (I-S), A-P, and R-L directions in a range from -5 mm to +5 mm. The phantom's positions detected with the TLS were compared with values measured by a vernier caliper. Second, the phantom movements in a tensile test were chosen from patient movements determined from 15 patients treated for intracranial lesions and immobilized with a thermoplastic mask and polyurethane cradle. The phantom movement was given by minimum or maximum values of patient movements in each direction. Finally, the relationship between phantom movements and the static load in the tensile test was characterized from measurements using the new phantom and the TLS. RESULTS: The differences in all positions between the vernier caliper measurement and the TLS detected values were within 0.2 mm with frequencies of 100%, 95%, and 90% in I-S, A-P, and R-L directions, respectively. The phantom movements according to patient movements in clinical application in I-S, A-P, and R-L directions were within 0.58 mm, 0.94 mm, and 0.93 mm from the mean value plus standard deviation, respectively. The regression lines between the phantom movements and static load were given by y = 0.359x, y = 0.241x, and y = 0.451x in I-S, A-P, and R-L directions, respectively, where x is the phantom movement (mm) and y is the static load (kgf). The relationship between the phantom movements and static load may represent the performance of inhibiting patient movements, so the accuracy of the immobilization system in the intracranial lesion will be estimated in advance by basic tensile test on the new phantom. CONCLUSIONS: The newly developed phantom was useful to evaluate the accuracy of immobilization systems for a Cyberknife system for intracranial lesions. PMID- 22830756 TI - VMAT QA: measurement-guided 4D dose reconstruction on a patient. AB - PURPOSE: To develop and validate a volume-modulated arc therapy (VMAT) quality assurance (QA) tool that takes as input a time-resolved, low-density (~10 mm) cylindrical surface dose map from a commercial helical diode array, and outputs a high density, volumetric, time-resolved dose matrix on an arbitrary patient dataset. This first validation study is limited to a homogeneous "patient." METHODS: A VMAT treatment is delivered to a diode array phantom (ARCCHECK, Sun Nuclear Corp., Melbourne, FL). 3DVH software (Sun Nuclear) derives the high density volumetric dose using measurement-guided dose reconstruction (MGDR). MGDR cylindrical phantom results are then used to perturb the three-dimensional (3D) treatment planning dose on the patient dataset, producing a semiempirical volumetric dose grid. Four-dimensional (4D) dose reconstruction on the patient is also possible by morphing individual sub-beam doses instead of the composite. For conventional (3D) dose comparison two methods were developed, using the four plans (Multi-Target, C-shape, Mock Prostate, and Head and Neck), including their structures and objectives, from the AAPM TG-119 report. First, 3DVH and treatment planning system (TPS) cumulative point doses were compared to ion chamber in a cube water-equivalent phantom ("patient"). The shape of the phantom is different from the ARCCHECK and furthermore the targets were placed asymmetrically. Second, coronal and sagittal absolute film dose distributions in the cube were compared with 3DVH and TPS. For time-resolved (4D) comparisons, three tests were performed. First, volumetric dose differences were calculated between the 3D MGDR and cumulative time-resolved patient (4D MGDR) dose at the end of delivery, where they ideally should be identical. Second, time-resolved (10 Hz sampling rate) ion chamber doses were compared to cumulative point dose vs time curves from 4D MGDR. Finally, accelerator output was varied to assess the linearity of the 4D MGDR with global fluence change. RESULTS: Across four TG-119 plans, the average PTV point dose difference in the cube between 3DVH and ion chamber is 0.1 +/- 1.0%. Average film vs TPS gamma-analysis passing rates are 83.0%, 91.1%, and 98.4% for 1%/2 mm, 2%/2 mm, and 3%/3 mm threshold combinations, respectively, while average film vs 3DVH gamma-analysis passing rates are 88.6%, 96.1%, and 99.5% for the same respective criteria. 4D MGDR was also sufficiently accurate. First, for 99.5% voxels in each case, the doses from 3D and 4D MGDR at the end of delivery agree within 0.5% local dose-error/1 mm distance. Moreover, all failing voxels are confined to the edge of the cylindrical reconstruction volume. Second, dose vs time curves track between the ion chamber and 4D MGDR within 1%. Finally, 4D MGDR dose changes linearly with the accelerator output: the difference between cumulative ion chamber and MGDR dose changed by no more than 1% (randomly) with the output variation range of 10%. CONCLUSIONS: Even for a well-commissioned TPS, comparison metrics show better agreement on average to MGDR than to TPS on the arbitrary-shaped measurable "patient." The method requires no more accelerator time than standard QA, while producing more clinically relevant information. Validation in a heterogeneous thoracic phantom is under way, as is the ultimate application of 4D MGDR to virtual motion studies. PMID- 22830757 TI - X-ray phase-shifts-based method of volumetric breast density measurement. AB - PURPOSE: The high breast density is one of the biggest risk factors for breast cancer. Identifying patient having persistent high breast density is important for breast cancer screening and prevention. In this work the authors propose for the first time an x-ray phase-shifts-based method of breast density measurement. METHODS: When x ray traverses the breast, x ray gets not only its intensity attenuated but also its phase shifted. Studying the x-ray phase-shifts generated by the breast tissues, we derived a general formula for determining the volumetric breast density from the breast phase map. The volumetric breast density is reconstructed by retrieving the breast phase map from just a single phase-sensitive projection of the breast, through the use of an innovative phase retrieval method based on the phase-attenuation duality. In order to numerically validate this phase-shifts-based method for measuring the volumetric breast density, the authors performed computer simulations with a digitally simulated anthropomorphic breast phantom. RESULTS: Using the proposed phase-shifts-based method, we reconstructed the breast phantom's volumetric breast density, which differs from the phantom's intrinsic breast density by only 0.06%. In the presence of noises in the projection image, the reconstructed volumetric breast density differs from the phantom's intrinsic breast density by only 1.79% for a projection signal-to-noise-ratio (SNR) of 34. The error in reconstructed breast density is further reduced to 1.61% and 1.55% for SNR = 68 and SNR = 134, respectively, achieving good accuracies in the breast density determination. CONCLUSIONS: The authors proposed an x-ray phase-shifts-based method of measuring the volumetric breast density. The simulation results numerically validated the proposed method as a novel method of breast density measurement with good accuracies. PMID- 22830758 TI - Nonrigid registration-based coronary artery motion correction for cardiac computed tomography. AB - PURPOSE: X-ray computed tomography angiography (CTA) is the modality of choice to noninvasively monitor and diagnose heart disease with coronary artery health and stenosis detection being of particular interest. Reliable, clinically relevant coronary artery imaging mandates high spatiotemporal resolution. However, advances in intrinsic scanner spatial resolution (CT scanners are available which combine nearly 900 detector columns with focal spot oversampling) can be tempered by motion blurring, particularly in patients with unstable heartbeats. As a result, recently numerous methods have been devised to improve coronary CTA imaging. Solutions involving hardware, multisector algorithms, or beta-blockers are limited by cost, oversimplifying assumptions about cardiac motion, and populations showing contraindications to drugs, respectively. This work introduces an inexpensive algorithmic solution that retrospectively improves the temporal resolution of coronary CTA without significantly affecting spatial resolution. METHODS: Given the goal of ruling out coronary stenosis, the method focuses on "deblurring" the coronary arteries. The approach makes no assumptions about cardiac motion, can be used on exams acquired at high heart rates (even over 75 beats/min), and draws on a fast and accurate three-dimensional (3D) nonrigid bidirectional labeled point matching approach to estimate the trajectories of the coronary arteries during image acquisition. Motion compensation is achieved by employing a 3D warping of a series of partial reconstructions based on the estimated motion fields. Each of these partial reconstructions is created from data acquired over a short time interval. For brevity, the algorithm "Subphasic Warp and Add" (SWA) reconstruction. RESULTS: The performance of the new motion estimation-compensation approach was evaluated by a systematic observer study conducted using nine human cardiac CTA exams acquired over a range of average heart rates between 68 and 86 beats/min. Algorithm performance was based-lined against exams reconstructed using standard filtered-backprojection (FBP). The study was performed by three experienced reviewers using the American Heart Association's 15-segment model. All vessel segments were evaluated to quantify their viability to allow a clinical diagnosis before and after motion estimation-compensation using SWA. To the best of the authors' knowledge this is the first such observer study to show that an image processing-based software approach can improve the clinical diagnostic value of CTA for coronary artery evaluation. CONCLUSIONS: Results from the observer study show that the SWA method described here can dramatically reduce coronary artery motion and preserve real pathology, without affecting spatial resolution. In particular, the method successfully mitigated motion artifacts in 75% of all initially nondiagnostic coronary artery segments, and in over 45% of the cases this improvement was enough to make a previously nondiagnostic vessel segment clinically diagnostic. PMID- 22830759 TI - Data mining framework for fatty liver disease classification in ultrasound: a hybrid feature extraction paradigm. AB - PURPOSE: Fatty liver disease (FLD) is an increasing prevalent disease that can be reversed if detected early. Ultrasound is the safest and ubiquitous method for identifying FLD. Since expert sonographers are required to accurately interpret the liver ultrasound images, lack of the same will result in interobserver variability. For more objective interpretation, high accuracy, and quick second opinions, computer aided diagnostic (CAD) techniques may be exploited. The purpose of this work is to develop one such CAD technique for accurate classification of normal livers and abnormal livers affected by FLD. METHODS: In this paper, the authors present a CAD technique (called Symtosis) that uses a novel combination of significant features based on the texture, wavelet transform, and higher order spectra of the liver ultrasound images in various supervised learning-based classifiers in order to determine parameters that classify normal and FLD-affected abnormal livers. RESULTS: On evaluating the proposed technique on a database of 58 abnormal and 42 normal liver ultrasound images, the authors were able to achieve a high classification accuracy of 93.3% using the decision tree classifier. CONCLUSIONS: This high accuracy added to the completely automated classification procedure makes the authors' proposed technique highly suitable for clinical deployment and usage. PMID- 22830760 TI - Eye tracking and gating system for proton therapy of orbital tumors. AB - PURPOSE: A new motion-based gated proton therapy for the treatment of orbital tumors using real-time eye-tracking system was designed and evaluated. METHODS: We developed our system by image-pattern matching, using a normalized cross correlation technique with LabVIEW 8.6 and Vision Assistant 8.6 (National Instruments, Austin, TX). To measure the pixel spacing of an image consistently, four different calibration modes such as the point-detection, the edge-detection, the line-measurement, and the manual measurement mode were suggested and used. After these methods were applied to proton therapy, gating was performed, and radiation dose distributions were evaluated. RESULTS: Moving phantom verification measurements resulted in errors of less than 0.1 mm for given ranges of translation. Dosimetric evaluation of the beam-gating system versus nongated treatment delivery with a moving phantom shows that while there was only 0.83 mm growth in lateral penumbra for gated radiotherapy, there was 4.95 mm growth in lateral penumbra in case of nongated exposure. The analysis from clinical results suggests that the average of eye movements depends distinctively on each patient by showing 0.44 mm, 0.45 mm, and 0.86 mm for three patients, respectively. CONCLUSIONS: The developed automatic eye-tracking based beam-gating system enabled us to perform high-precision proton radiotherapy of orbital tumors. PMID- 22830761 TI - Mechanical bioeffects of pulsed high intensity focused ultrasound on a simple neural model. AB - PURPOSE: To study how pressure pulses affect nerves through mechanisms that are neither thermal nor cavitational, and investigate how the effects are related to cumulative radiation-force impulse (CRFI). Applications include traumatic brain injury and acoustic neuromodulation. METHODS: A simple neural model consisting of the giant axon of a live earthworm was exposed to trains of pressure pulses produced by an 825 kHz focused ultrasound transducer. The peak negative pressure of the pulses and duty cycle of the pulse train were controlled so that neither cavitation nor significant temperature rise occurred. The amplitude and conduction velocity of action-potentials triggered in the worm were measured as the magnitude of the pulses and number of pulses in the pulse trains were varied. RESULTS: The functionality of the axons decreased when sufficient pulse energy was applied. The level of CRFI at which the observed effects occur is consistent with the lower levels of injury observed in this study relative to blast tubes. The relevant CRFI values are also comparable to CRFI values in other studies showing measureable changes in action-potential amplitudes and velocities. Plotting the measured action-potential amplitudes and conduction velocities from different experiments with widely varying exposure regimens against the single parameter of CRFI yielded values that agreed within 21% in terms of amplitude and 5% in velocity. A predictive model based on the assumption that the temporal rate of decay of action-potential amplitude and velocity is linearly proportional the radiation force experienced by the axon predicted the experimental amplitudes and conduction velocities to within about 20% agreement. CONCLUSIONS: The functionality of axons decreased due to noncavitational mechanical effects. The radiation force, possibly by inducing changes in ion-channel permeability, appears to be a possible mechanism for explaining the observed degradation. The CRFI is also a promising parameter for quantifying neural bioeffects during exposure to pressure waves, and for predicting axon functionality. PMID- 22830762 TI - Hyperpolarized (3)He pulmonary functional magnetic resonance imaging prior to radiation therapy. AB - PURPOSE: Radiation-induced lung injury (RILI) is the primary dose-limiting toxicity for radiation therapy of the lung, and although the effects of radiation dose on RILI development have been well characterized, the influence of chronic obstructive pulmonary disease (COPD) on the development of RILI and other outcomes is not well understood. The purpose of this small pilot study was to evaluate the relationship between hyperpolarized (3)He magnetic resonance imaging (MRI) measurements of COPD with RILI and 12-month survival in lung cancer patients undergoing radical radiotherapy and to evaluate the feasibility of pulmonary functional MRI as an image guidance/planning tool for radiation therapy. METHODS: Fifteen non-small cell and small cell lung cancer patients underwent pulmonary function tests, x-ray computed tomography (CT), and hyperpolarized (3)He MRI prior to radical radiation therapy (>=60 Gy). Conventional thoracic (1)H and hyperpolarized (3)He MRI were acquired to generate ventilation defect percent and the apparent diffusion coefficient for the ipsilateral and contralateral lungs independently. CT was acquired postradiation therapy and qualitatively evaluated for radiological evidence of RILI and 12 month survival was reported. RESULTS: Hyperpolarized (3)He MRI measurements of COPD classified 10/15 subjects with contralateral lung COPD (CLC), and five subjects without COPD [contralateral lung normal (CLN)]. Of the 10 subjects with CLC, only four had a previous clinical diagnosis of COPD. CT images were acquired postradiation therapy for 13 subjects, and for eight (62%) of these there was qualitative evidence of RILI, including 5/9 CLC and 3/4 CLN subjects. The one year survival was 2/10 for CLC and 3/5 for CLN subjects. CONCLUSIONS: In this small pilot study, we report the use of (3)He MRI to stratify lung cancer patients based on MRI evidence of COPD and showed that comorbid COPD was present in the majority of lung cancer subjects stratified for radiation therapy. Lung cancer patients with imaging evidence of COPD did not have an increased incidence of RILI compared to patients without COPD. However, preliminary data presented here indicated that one-year survival in COPD subjects was lower than expected based on previously published survival rates, which may have implications for radiation therapy in lung cancer patients with comorbid COPD. PMID- 22830763 TI - A fully four-dimensional, iterative motion estimation and compensation method for cardiac CT. AB - PURPOSE: To develop a new fully four-dimensional (4D), iterative image reconstruction algorithm for cardiac CT that alternates the following two methods: estimation of a time-dependent motion vector field (MVF) of the heart from image data and reconstruction of images using the estimated MVF and projection data. METHODS: Volumetric image data at different cardiac phase points were obtained using electrocardiogram-gated CT. Motion estimation (ME) and motion compensated image reconstruction (MCR) were performed alternately until convergence was achieved. The ME method estimated the cardiac MVF using 4D nonrigid image registration between a cardiac reference phase and all the other phases. The nonrigid deformation of the heart was modeled using cubic B-splines. The cost function consisted of a sum of squared weighted differences and spatial and temporal regularization terms. A nested conjugate gradient optimization algorithm was applied to minimize the cost function and estimate the MVFs. Cardiac images were reconstructed using a motion-tracking algorithm that utilized the MVFs estimated by the ME method. The reconstructed images supplied the input to the ME of the next iteration. The performance of the proposed method was evaluated using four patient data sets acquired with a 64-slice CT scanner. The heart rates of the patients ranged from 52 to 71 beats/min. RESULTS: Motion artifacts were significantly reduced, and the image quality increased with the number of iterations. Without MCR, the right coronary artery (RCA) was deformed into an arc in axial images of rapid phases. With the proposed method the RCA appeared sharper and was reconstructed similar in shape to the reconstruction at the quiescent phase at mid-diastole. The boundary between the interventricular septum and the right ventricle was also clearer and sharper using the proposed algorithm. The steepness of the transition range at a rapid phase (35% R-R) was increased from 6.8 HU/pixel to 11.5 HU/pixel. The ME-MCR algorithm converged in just four iterations. CONCLUSION: We developed a fully 4D image reconstruction method that alternates ME and MCR algorithms in an iterative fashion. Performance tests using clinical patient data resulted in reduced motion artifacts. PMID- 22830764 TI - Simultaneous PET/MR imaging: MR-based attenuation correction of local radiofrequency surface coils. AB - PURPOSE: In simultaneous positron emission tomography/magnetic resonance (PET/MR) imaging, local receiver surface radiofrequency (RF) coils are positioned in the field-of-view (FOV) of the PET detector during PET/MR data acquisition and potentially attenuate the PET signal. For flexible body RF surface coils placed on top of the patient's body, MR-based attenuation correction (AC) is an unsolved problem since the RF coils are not inherently visible in MR images and their individual position in the FOV is patient specific and not known a priori. The aim of this work was to quantify the effect of local body RF coils used in the Biograph mMR hybrid PET/MR system on PET emission data and to present techniques for MR-based position determination of these specific local RF coils. METHODS: Acquisitions of a homogeneous phantom were performed on a whole-body PET/MRI scanner. Two different PET emission scans were performed, with and without the local body matrix RF coil placed on the top of the phantom. For position determination of the coil, two methods were applied. First, cod liver oil capsules were attached to the surface of the coil and second, an ultrashort echo time (UTE) sequence was used. PET images were reconstructed in five different ways: (1) PET reference scan without the coil, (2) PET scan with the coil, but omitting the coil in AC (PET/MR scanning conditions), (3) AC of the coil using a CT scan of the same phantom setup and registration via capsules, (4) same setup as 3, but registration was done using UTE images, neglecting the capsules, and (5) registration using the capsules, but the CT was performed with the coil placed flat on the CT table and the outer regions of the coil were cropped. The activity concentrations were then compared to the reference scan. For clinical evaluation of the concept, the presented methods were also evaluated on a patient. RESULTS: The oil capsules were visible in the MR and CT images and image registration was straightforward. The UTE images show only parts of the coil's plastic housing and image registration was more difficult. The overall loss of true counts due to the presence of the surface coil is 4.7%. However, a spatially dependent analysis shows larger deviation (10%-15% attenuation) of the activity concentration in the top part of the phantom close to the coil. When accounting for the RF coil for PET AC, attenuation due to the RF coil could mostly be corrected. These results of the phantom studies were confirmed by the patient measurements. CONCLUSIONS: Disregarding local coils in PET AC can lead to a bias of the AC PET images that is regional dependent. The closer the analyzed region is located to the coil, the higher the bias. Cod liver oil capsules or the UTE sequence can be used for RF coil position determination. The middle part of the examined RF coil hosting the preamplifiers and electronic components provides the highest attenuating part. Consequently, emphasis should be put on correcting for this portion of the RF coils with the suggested methods. PMID- 22830765 TI - Dose optimization with first-order total-variation minimization for dense angularly sampled and sparse intensity modulated radiation therapy (DASSIM-RT). AB - PURPOSE: A new treatment scheme coined as dense angularly sampled and sparse intensity modulated radiation therapy (DASSIM-RT) has recently been proposed to bridge the gap between IMRT and VMAT. By increasing the angular sampling of radiation beams while eliminating dispensable segments of the incident fields, DASSIM-RT is capable of providing improved conformity in dose distributions while maintaining high delivery efficiency. The fact that DASSIM-RT utilizes a large number of incident beams represents a major computational challenge for the clinical applications of this powerful treatment scheme. The purpose of this work is to provide a practical solution to the DASSIM-RT inverse planning problem. METHODS: The inverse planning problem is formulated as a fluence-map optimization problem with total-variation (TV) minimization. A newly released L1-solver, template for first-order conic solver (TFOCS), was adopted in this work. TFOCS achieves faster convergence with less memory usage as compared with conventional quadratic programming (QP) for the TV form through the effective use of conic forms, dual-variable updates, and optimal first-order approaches. As such, it is tailored to specifically address the computational challenges of large-scale optimization in DASSIM-RT inverse planning. Two clinical cases (a prostate and a head and neck case) are used to evaluate the effectiveness and efficiency of the proposed planning technique. DASSIM-RT plans with 15 and 30 beams are compared with conventional IMRT plans with 7 beams in terms of plan quality and delivery efficiency, which are quantified by conformation number (CN), the total number of segments and modulation index, respectively. For optimization efficiency, the QP based approach was compared with the proposed algorithm for the DASSIM-RT plans with 15 beams for both cases. RESULTS: Plan quality improves with an increasing number of incident beams, while the total number of segments is maintained to be about the same in both cases. For the prostate patient, the conformation number to the target was 0.7509, 0.7565, and 0.7611 with 80 segments for IMRT with 7 beams, and DASSIM-RT with 15 and 30 beams, respectively. For the head and neck (HN) patient with a complicated target shape, conformation numbers of the three treatment plans were 0.7554, 0.7758, and 0.7819 with 75 segments for all beam configurations. With respect to the dose sparing to the critical structures, the organs such as the femoral heads in the prostate case and the brainstem and spinal cord in the HN case were better protected with DASSIM-RT. For both cases, the delivery efficiency has been greatly improved as the beam angular sampling increases with the similar or better conformal dose distribution. Compared with conventional quadratic programming approaches, first-order TFOCS-based optimization achieves far faster convergence and smaller memory requirements in DASSIM-RT. CONCLUSIONS: The new optimization algorithm TFOCS provides a practical and timely solution to the DASSIM-RT or other inverse planning problem requiring large memory space. The new treatment scheme is shown to outperform conventional IMRT in terms of dose conformity to both the targetand the critical structures, while maintaining high delivery efficiency. PMID- 22830767 TI - NPIP: A skew line needle configuration optimization system for HDR brachytherapy. AB - PURPOSE: In this study, the authors introduce skew line needle configurations for high dose rate (HDR) brachytherapy and needle planning by integer program (NPIP), a computational method for generating these configurations. NPIP generates needle configurations that are specific to the anatomy of the patient, avoid critical structures near the penile bulb and other healthy structures, and avoid needle collisions inside the body. METHODS: NPIP consisted of three major components: a method for generating a set of candidate needles, a needle selection component that chose a candidate needle subset to be inserted, and a dose planner for verifying that the final needle configuration could meet dose objectives. NPIP was used to compute needle configurations for prostate cancer data sets from patients previously treated at our clinic. NPIP took two user-parameters: a number of candidate needles, and needle coverage radius, delta. The candidate needle set consisted of 5000 needles, and a range of delta values was used to compute different needle configurations for each patient. Dose plans were computed for each needle configuration. The number of needles generated and dosimetry were analyzed and compared to the physician implant. RESULTS: NPIP computed at least one needle configuration for every patient that met dose objectives, avoided healthy structures and needle collisions, and used as many or fewer needles than standard practice. These needle configurations corresponded to a narrow range of delta values, which could be used as default values if this system is used in practice. The average end-to-end runtime for this implementation of NPIP was 286 s, but there was a wide variation from case to case. CONCLUSIONS: The authors have shown that NPIP can automatically generate skew line needle configurations with the aforementioned properties, and that given the correct input parameters, NPIP can generate needle configurations which meet dose objectives and use as many or fewer needles than the current HDR brachytherapy workflow. Combined with robot assisted brachytherapy, this system has the potential to reduce side effects associated with treatment. A physical trial should be done to test the implant feasibility of NPIP needle configurations. PMID- 22830766 TI - Resolution evaluation of MR images reconstructed by iterative thresholding algorithms for compressed sensing. AB - PURPOSE: Magnetic resonance imaging systems usually feature linear and shift invariant (stationary) transform characteristics. The point spread function or equivalently the modulation transfer function may thus be used for an objective quality assessment of imaging modalities. The recently introduced theory of compressed sensing, however, incorporates nonlinear and nonstationary reconstruction algorithms into the magnetic resonance imaging process which prohibits the usage of the classical point spread function and therefore the according evaluation. METHODS: In this work, a local point spread function concept was applied to assess the quality of magnetic resonance images which were reconstructed by an iterative soft thresholding algorithm for compressed sensing. The width of the main lobe of the local point spread function was used to perform studies on the spatial and temporal resolution properties of both numerical phantom and in vivo images. The impact of k-space sampling patterns as well as additional sparsifying transforms on the local spatial image resolution was investigated. In addition, the local temporal resolution of image series, which were reconstructed by exploiting spatiotemporal sparsity, was determined. Finally, the dependency of the local resolution on the thresholding parameter of the algorithm was examined. RESULTS: The sampling patterns as well as the additional sparsifying transform showed a distinct impact on the local image resolution of the phantom image. The reconstructions, which were using x-f-space as a sparse transform domain showed slight temporal blurring for dynamic parts of the imaged object. The local image resolution had a dependence on the thresholding parameter, which allowed for optimizing the reconstruction. CONCLUSIONS: Local point spread functions enable the evaluation of the local spatial and temporal resolution of images reconstructed with the nonlinear and nonstationary iterative soft thresholding algorithm. By determining the influence of thresholding parameter and sampling pattern chosen on this model-based reconstruction, the method allows selecting appropriate acquisition parameters and thus improving the results. PMID- 22830768 TI - A method for determining the modulation transfer function from thick microwire profiles measured with x-ray microcomputed tomography. AB - PURPOSE: This study describes a model-dependent method to determine the modulation transfer function (MTF) in the transversal plane, obtained by a microcomputed tomography (micro-CT) system from profiles of a thick wire phantom instead of a thin wire phantom, and the study evaluates the feasibility of the proposed method in the MTF determination of micro-CT systems. METHODS: The MTF is generally calculated as the absolute value of the normalized Fourier transform from the point spread function obtained by scanning a thin wire phantom. Since the wire is not a point source, the raw MTF is corrected for the finite size of the wire phantom; a wire with too large a diameter introduces inaccuracies in the MTF values. Therefore, we solved the MTF determination from profiles of a thick wire phantom via MTF modeling on the basis of the symmetric Levy function that generalizes Gaussian and Lorentzian functions. We then applied the method to profiles of wire phantoms (1 mm, 2 mm, and 3 mm in diameter) measured by a clinical CT system to evaluate the applicable diameter range of the thick wire phantom. Two types of reconstruction kernels (standard and sharp) were used in the clinical CT. The performance of the method was evaluated using microwire phantoms (10 and 30 MUm in diameter) measured by a synchrotron radiation micro-CT (SRMUCT) system, in which the Shepp-Logan filter and Ramachandran Lakshminarayanan filter were used as the reconstruction kernel. The MTFs obtained using thin wire phantoms of 0.1 mm and 3 MUm in diameter were regarded as the gold standard MTFs for the clinical CT and SRMUCT, respectively. The root-mean square error (RMSE) and relative error (RE) of the 10% value of the MTF were used to measure the difference between the MTF determined by the method and the gold standard. RESULTS: The mean RMSEs for two types of reconstruction kernels of three wire phantoms (1, 2, and 3 mm in diameter) were 0.0085, 0.012, and 0.021, respectively. The mean REs for the 1-, 2-, and 3-mm wire phantoms gave the same values of 2.0%, 3.5%, and 3.5%, respectively, for two types of reconstruction kernel. The MTFs determined from thick wire phantoms reveal the spatial resolution for the two kernels. The mean RMSEs for two types of reconstruction kernels of the microwire phantoms of 10 and 30 MUm in diameter were 0.0045 and 0.0035, respectively. The mean REs of the two wire phantoms of 10 and 30 MUm diameter had 4.0% and 3.1%, respectively, for two types of reconstruction kernel. CONCLUSIONS: Experimental data presented in this paper support the effectiveness of the model-dependent method based on the symmetric Levy function. We conclude that the method is a useful approach for measuring the spatial resolution in the x/y-scan plane (transversal orientation) of micro-CT systems by substituting a thick wire phantom for a thin wire phantom. PMID- 22830769 TI - Model-based dose calculations for (125)I lung brachytherapy. AB - PURPOSE: Model-baseddose calculations (MBDCs) are performed using patient computed tomography (CT) data for patients treated with intraoperative (125)I lung brachytherapy at the Mayo Clinic Rochester. Various metallic artifact correction and tissue assignment schemes are considered and their effects on dose distributions are studied. Dose distributions are compared to those calculated under TG-43 assumptions. METHODS: Dose distributions for six patients are calculated using phantoms derived from patient CT data and the EGSnrc user-code BrachyDose. (125)I (GE Healthcare/Oncura model 6711) seeds are fully modeled. Four metallic artifact correction schemes are applied to the CT data phantoms: (1) no correction, (2) a filtered back-projection on a modified virtual sinogram, (3) the reassignment of CT numbers above a threshold in the vicinity of the seeds, and (4) a combination of (2) and (3). Tissue assignment is based on voxel CT number and mass density is assigned using a CT number to mass density calibration. Three tissue assignment schemes with varying levels of detail (20, 11, and 5 tissues) are applied to metallic artifact corrected phantoms. Simulations are also performed under TG-43 assumptions, i.e., seeds in homogeneous water with no interseed attenuation. RESULTS: Significant dose differences (up to 40% for D(90)) are observed between uncorrected and metallic artifact corrected phantoms. For phantoms created with metallic artifact correction schemes (3) and (4), dose volume metrics are generally in good agreement (less than 2% differences for all patients) although there are significant local dose differences. The application of the three tissue assignment schemes results in differences of up to 8% for D(90); these differences vary between patients. Significant dose differences are seen between fully modeled and TG-43 calculations with TG-43 underestimating the dose (up to 36% in D(90)) for larger volumes containing higher proportions of healthy lung tissue. CONCLUSIONS: Metallic artifact correction is necessary for accurate application of MBDCs for lung brachytherapy; simpler threshold replacement methods may be sufficient for early adopters concerned with clinical dose metrics. Rigorous determination of voxel tissue parameters and tissue assignment is required for accurate dose calculations as different tissue assignment schemes can result in significantly different dose distributions. Significant differences are seen between MBDCs and TG-43 dose distributions with TG-43 underestimating dose in volumes containing healthy lung tissue. PMID- 22830770 TI - Comparison of action levels for patient-specific quality assurance of intensity modulated radiation therapy and volumetric modulated arc therapy treatments. AB - PURPOSE: To perform a comprehensive and systematic comparison of fixed-beam IMRT and volumetric modulated arc therapy (VMAT) patient-specific QA measurements for a common set of geometries using typical measurement methods. METHODS: Fixed-beam IMRT and VMAT plans were constructed for structure set geometries provided by AAPM Task Group 119. The plans were repeatedly delivered across multiple measurement sessions, and the resulting dose distributions were measured with (1) radiochromic film and ionization chamber and (2) a commercial two-dimensional diode array. The resulting QA measurements from each delivery technique were then analyzed, compared, and tested for statistically significant differences. RESULTS: Although differences were noted between QA results for some plans, neither modality showed consistently better agreement of measured and planned doses: of the 22 comparisons, IMRT showed better QA results in 11 cases, and VMAT showed better QA results in 11 cases. No statistically significant differences (p < 0.05) between IMRT and VMAT QA results were found for point doses measured with an ionization chamber, planar doses measured with radiochromic film, or planar doses measured with a two-dimensional diode array. CONCLUSIONS: These results suggest that it is appropriate to apply patient-specific QA action levels derived from fixed-beam IMRT to VMAT. PMID- 22830771 TI - A comparison study of image features between FFDM and film mammogram images. AB - PURPOSE: This work is to provide a direct, quantitative comparison of image features measured by film and full-field digital mammography (FFDM). The purpose is to investigate whether there is any systematic difference between film and FFDM in terms of quantitative image features and their influence on the performance of a computer-aided diagnosis (CAD) system. METHODS: The authors make use of a set of matched film-FFDM image pairs acquired from cadaver breast specimens with simulated microcalcifications consisting of bone and teeth fragments using both a GE digital mammography system and a screen-film system. To quantify the image features, the authors consider a set of 12 textural features of lesion regions and six image features of individual microcalcifications (MCs). The authors first conduct a direct comparison on these quantitative features extracted from film and FFDM images. The authors then study the performance of a CAD classifier for discriminating between MCs and false positives (FPs) when the classifier is trained on images of different types (film, FFDM, or both). RESULTS: For all the features considered, the quantitative results show a high degree of correlation between features extracted from film and FFDM, with the correlation coefficients ranging from 0.7326 to 0.9602 for the different features. Based on a Fisher sign rank test, there was no significant difference observed between the features extracted from film and those from FFDM. For both MC detection and discrimination of FPs from MCs, FFDM had a slight but statistically significant advantage in performance; however, when the classifiers were trained on different types of images (acquired with FFDM or SFM) for discriminating MCs from FPs, there was little difference. CONCLUSIONS: The results indicate good agreement between film and FFDM in quantitative image features. While FFDM images provide better detection performance in MCs, FFDM and film images may be interchangeable for the purposes of training CAD algorithms, and a single CAD algorithm may be applied to either type of images. PMID- 22830772 TI - Improved parkinsonism diagnosis using a partial least squares based approach. AB - PURPOSE: An accurate and early diagnosis of Parkinsonian syndrome (PS) is nowadays a challenge. This syndrome includes several pathologies with similar symptoms (Parkinson's disease, multisystem atrophy, progressive supranuclear palsy, corticobasal degeneration and others) which make the diagnosis more difficult. (123)I-ioflupane allows to obtain in vivo images of the brain that can be used to assist the PS diagnosis and provides a way to improve its accuracy. METHODS: In this paper, we show a novel method to automatically classify (123)I ioflupane images into two groups: controls or PS. The proposed methodology analyzes separately each hemisphere of the brain by means of a novel approach based on partial least squares (PLS) and support vector machine. RESULTS: A database with 189 (123)I-ioflupane images (94 controls and 95 pathological images) was used for evaluation purposes. The application of the proposed method based on PLS yields high accuracy rates up to 94.7% with sensitivity = 93.7% and specificity = 95.7%, outperforming previous approaches based on singular value decomposition, which are used as a reference. CONCLUSIONS: The use of advanced techniques based on classical signal analysis and their application to each hemisphere of the brain separately improves the (assisted) diagnosis of PS. PMID- 22830773 TI - Hysterosalpingography using a flat panel unit: evaluation and optimization of ovarian radiation dose. AB - PURPOSE: The aim of the present study was the evaluation and optimization of radiation dose to the ovaries (D) in hysterosalpingography (HSG). METHODS: The study included a phantom study and a clinical one. In the phantom study, we evaluated imaging results for different geometrical setups and irradiation conditions. In the clinical study, 34 women were assigned into three different fluoroscopy modes and D was estimated with direct cervical TLD measurements. RESULTS: In the phantom study, we used a source-to-image-distance (SID) of 110 cm and a field diagonal of 48 cm, and thus decreased air KERMA rate (KR) by 19% and 70%, respectively, for beam filtration: 4 mm Al and 0.9 mm Cu (Low dose). The least radiation exposure was accomplished by using the 3.75 pps fluoroscopy mode in conjunction with beam filtration: Low dose. In the clinical study, D normalized to 50 s of fluoroscopy time with a 3.75 pps fluoroscopy mode reached a value of 0.45 +/- 0.04 mGy. Observers' evaluation of diagnostic image quality did not significantly differ for the three different modes of acquisition that were compared. CONCLUSIONS: Digital spot radiographs could be omitted in modern flat panel systems during HSG. Fluoroscopy image acquisitions in a modern flat panel unit at 3.75 pps and a beam filtration of 4 mm Al and 0.9 mm Cu demonstrate acceptable image quality with an average D equal to 0.45 mGy. This value is lower compared to the studied literature. For these reasons, the proposed method may be recommended for routine HSG examination in order to limit radiation exposure to the ovaries. PMID- 22830774 TI - Microfocus x-ray imaging of traceable pointlike (22)Na sources for quality control. AB - PURPOSE: The purpose of this study is to propose a microfocus x-ray imaging technique for observing the internal structure of small radioactive sources and evaluating geometrical errors quantitatively, and to apply this technique to traceable pointlike (22)Na sources, which were designed for positron emission tomography calibration, for the purpose of quality control of the pointlike sources. METHODS: A microfocus x-ray imaging system with a focus size of 0.001 mm was used to obtain projection x-ray images and x-ray CT images of five pointlike source samples, which were manufactured during 2009-2012. The obtained projection and tomographic images were used to observe the internal structure and evaluate geometrical errors quantitatively. Monte Carlo simulation was used to evaluate the effect of possible geometrical errors on the intensity and uniformity of 0.511 MeV annihilation photon pairs emitted from the sources. RESULTS: Geometrical errors were evaluated with sufficient precision using projection x ray images. CT images were used for observing the internal structure intuitively. As a result, four of the five examined samples were within the tolerance to maintain the total uncertainty below +/-0.5%, given the source radioactivity; however, one sample was found to be defective. CONCLUSIONS: This quality control procedure is crucial and offers an important basis for using the pointlike (22)Na source as a basic calibration tool. The microfocus x-ray imaging approach is a promising technique for visual and quantitative evaluation of the internal geometry of small radioactive sources. PMID- 22830775 TI - An artificial neural network (ANN)-based lung-tumor motion predictor for intrafractional MR tumor tracking. AB - PURPOSE: To address practical issues of implementing artificial neural networks (ANN) for lung-tumor motion prediction in MRI-based intrafractional lung-tumor tracking. METHODS: A feedforward four-layered ANN structure is used to predict future tumor positions. A back-propagation algorithm is used for ANN learning. Adaptive learning is incorporated by continuously updating weights and learning rate during prediction. An ANN training scheme specific for MRI-based tracking is developed. A multiple-ANN structure is developed to reduce tracking failures caused by the lower imaging rates of MRI. We used particle swarm optimization to optimize the ANN structure and initial weights (IW) for each patient and treatment fraction. Prediction accuracy is evaluated using the 1D superior inferior lung-tumor motions of 29 lung cancer patients for system delays of 120 520 ms, in increments of 80 ms. The result is compared with four different scenarios: (1), (2) ANN structure optimization + with/without IW optimization, and (3), (4) no ANN structure optimization + with/without IW optimization, respectively. An additional simulation is performed to assess the value of optimizing the ANN structure for each treatment fraction. RESULTS: For 120-520 ms system delays, mean RMSE values (ranges 0.0-2.8 mm from 29 patients) of 0.5-0.9 mm are observed, respectively. Using patient specific ANN structures, a 30%-60% decrease in mean RMSE values is observed as a result of IW optimization, alone. No significant advantages in prediction performance are observed, however, by optimizing for each fraction. CONCLUSIONS: A new ANN-based lung-tumor motion predictor is developed for MRI-based intrafractional tumor tracking. The prediction accuracy of our predictor is evaluated using a realistic simulated MR imaging rate and system delays. For 120-520 ms system delays, mean RMSE values of 0.5-0.9 mm (ranges 0.0-2.8 mm from 29 patients) are achieved. Further, the advantage of patient specific ANN structure and IW in lung-tumor motion prediction is demonstrated by a 30%-60% decrease in mean RMSE values. PMID- 22830776 TI - Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with (177)Lu- and (90)Y-BR96 mAbs. AB - PURPOSE: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. METHODS: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with (90)Y- and (177)Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. RESULTS: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for (177)Lu and 12.5 Gy for (90)Y. CONCLUSIONS: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from 225 g to 300 g, appeared to have no substantial effect for the estimated absorbed dose. PMID- 22830777 TI - Biophysical modeling of brain tumor progression: from unconditionally stable explicit time integration to an inverse problem with parabolic PDE constraints for model calibration. AB - PURPOSE: A novel unconditionally stable, explicit numerical method is introduced to the field of modeling brain cancer progression on a tissue level together with an inverse problem (IP) based on optimal control theory that allows for automated model calibration with respect to observations in clinical imaging data. METHODS: Biophysical models of cancer progression on a tissue level are in general based on the assumption that the spatiotemporal spread of cancerous cells is determined by cell division and net migration. These processes are typically described in terms of a parabolic partial differential equation (PDE). In the present work a parallelized implementation of an unconditionally stable, explicit Euler (EE(?)) time integration method for the solution of this PDE is detailed. The key idea of the discussed EE(?) method is to relax the strong stability requirement on the spectral radius of the coefficient matrix by introducing a subdivision regime for a given outer time step. The performance is related to common implicit numerical methods. To quantify the numerical error, a simplified model that has a closed form solution is considered. To allow for a systematic, phenomenological validation a novel approach for automated model calibration on the basis of observations in medical imaging data is developed. The resulting IP is based on optimal control theory and manifests as a large scale, PDE constrained optimization problem. RESULTS: The numerical error of the EE(?) method is at the order of standard implicit numerical methods. The computing times are well below those obtained for implicit methods and by that demonstrate efficiency. Qualitative and quantitative analysis in 12 patients demonstrates that the obtained results are in strong agreement with observations in medical imaging data. Rating simulation success in terms of the mean overlap between model predictions and manual expert segmentations yields a success rate of 75% (9 out of 12 patients). CONCLUSIONS: The discussed EE(?) method provides desirable features for image-based model calibration or hybrid image registration algorithms in which the model serves as a biophysical prior. This is due to (i) ease of implementation, (ii) low memory requirements, (iii) efficiency, (iv) a straightforward interface for parameter updates, and (v) the fact that the method is inherently matrix-free. The explicit time integration method is confirmed via experiments for automated model calibration. Qualitative and quantitative analysis demonstrates that the proposed framework allows for recovering observations in medical imaging data and by that phenomenological model validity. PMID- 22830778 TI - Near-field thermoacoustic imaging with transmission line pulsers. AB - PURPOSE: Near-field radiofrequency thermoacoustic (NRT) tomography has been recently introduced for imaging electromagnetic (EM) properties of tissues using ultrawideband, high-energy impulses, which induce thermoacoustic responses. Operation in the near-field allows for more effective energy coupling into tissue, compared to using radiating sources, which in turn enables the use of shorter excitation pulses and leads to higher image resolution. This work aimed at investigating transmission lines as a method to generate excitation pulses to improve the NRT resolution over previous implementations without compromising the energy coupled into tissue. METHODS: The authors implemented a number of custom made transmission lines to overcome the challenges of the broadband nature of the impulse excitation required in NRT. The authors further constructed phantoms and investigated the performance of the lines in regard to the pulse duration, energy coupling and the resulting resolution, and image quality achieved. Finally, the authors employed mice in order to investigate the performance of the approach in tissue imaging. RESULTS: The authors found that the use of transmission lines resulted in the generation of RF impulses in the range of tens of nanoseconds and shorter. This performance resulted to resolution improvements over previous thermoacoustic imaging implementations, reaching 45 MUm resolution, while retaining several tens to hundreds of milli-Joules of energy per pulse. This performance further allowed the visualization and clear differentiation of different mouse structures such as the heart, lung, or spinal cord. CONCLUSIONS: The use of transmission lines significantly improved the NRT performance leading to high thermoacoustic tomography imaging quality by coupling adequate amounts of energy within short times at a relatively low cost. PMID- 22830779 TI - Characterization of imaging performance in differential phase contrast CT compared with the conventional CT: spectrum of noise equivalent quanta NEQ(k). AB - PURPOSE: Differential phase contrast CT (DPC-CT) is emerging as a new technology to improve the contrast sensitivity of conventional attenuation-based CT. The noise equivalent quanta as a function over spatial frequency, i.e., the spectrum of noise equivalent quanta NEQ(k), is a decisive indicator of the signal and noise transfer properties of an imaging system. In this work, we derive the functional form of NEQ(k) in DPC-CT. Via system modeling, analysis, and computer simulation, we evaluate and verify the derived NEQ(k) and compare it with that of the conventional attenuation-based CT. METHODS: The DPC-CT is implemented with x ray tube and gratings. The x-ray propagation and data acquisition are modeled and simulated through Fresnel and Fourier analysis. A monochromatic x-ray source (30 keV) is assumed to exclude any system imperfection and interference caused by scatter and beam hardening, while a 360 degrees full scan is carried out in data acquisition to avoid any weighting scheme that may disrupt noise randomness. Adequate upsampling is implemented to simulate the x-ray beam's propagation through the gratings G(1) and G(2) with periods 8 and 4 MUm, respectively, while the intergrating distance is 193.6 mm (1/16 of the Talbot distance). The dimensions of the detector cell for data acquisition are 32 * 32, 64 * 64, 96 * 96, and 128 * 128 MUm(2), respectively, corresponding to a 40.96 * 40.96 mm(2) field of view in data acquisition. An air phantom is employed to obtain the noise power spectrum NPS(k), spectrum of noise equivalent quanta NEQ(k), and detective quantum efficiency DQE(k). A cylindrical water phantom at 5.1 mm diameter and complex refraction coefficient n = 1 - delta + ibeta = 1 -2.5604 * 10(-7) + i1.2353 * 10(-10) is placed in air to measure the edge transfer function, line spread function and then modulation transfer function MTF(k), of both DPC-CT and the conventional attenuation-based CT. The x-ray flux is set at 5 * 10(6) photon/cm(2) per projection and observes the Poisson distribution, which is consistent with that of a micro-CT for preclinical applications. Approximately 360 regions, each at 128 * 128 matrix, are used to calculate the NPS(k) via 2D Fourier transform, in which adequate zero padding is carried out to avoid aliasing in noise. RESULTS: The preliminary data show that the DPC-CT possesses a signal transfer property [MTF(k)] comparable to that of the conventional attenuation-based CT. Meanwhile, though there exists a radical difference in their noise power spectrum NPS(k) (trait 1/|k| in DPC-CT but |k| in the conventional attenuation-based CT) the NEQ(k) and DQE(k) of DPC-CT and the conventional attenuation-based CT are in principle identical. CONCLUSIONS: Under the framework of ideal observer study, the joint signal and noise transfer property NEQ(k) and detective quantum efficiency DQE(k) of DPC-CT are essentially the same as those of the conventional attenuation-based CT. The findings reported in this paper may provide insightful guidelines on the research, development, and performance optimization of DPC-CT for extensive preclinical and clinical applications in the future. PMID- 22830781 TI - Dosimetric characterization of a synthetic single crystal diamond detector in clinical radiation therapy small photon beams. AB - PURPOSE: To determine the potentialities of synthetic single crystal diamond Schottky diodes for accurate dose measurements in radiation therapy small photon beams. METHODS: The dosimetric properties of a diamond-based detector were assessed by comparison with a reference microionization chamber. The diamond device was operated at zero bias voltage under irradiation with high-energy radiotherapic photon beams. The stability of the detector response and its dose and dose rate dependence were measured. Different square field sizes ranging from 1 * 1 cm(2) to 10 * 10 cm(2) were used during comparative dose distribution measurements by means of percentage depth dose curves (PDDs), lateral beam profiles, and output factors. The angular and temperature dependence of the diamond detector response were also studied. RESULTS: The detector response shows a deviation from linearity of less than +/-0.5% in the 0.01-7 Gy range and dose rate dependence below +/-0.5% in the 1-6 Gy/min range. PDDs and output factors are in good agreement with those measured by the reference ionization chamber within 1%. No angular dependence is observed by rotating the detector along its axis, while ~3.5% maximum difference is measured by varying the radiation incidence angle in the polar direction. The temperature dependence was investigated as well and a +/-0.2% variation of the detector response is found in the 18-40 degrees C range. CONCLUSIONS: The obtained results indicate the investigated synthetic diamond-based detector as a candidate for small field clinical radiation dosimetry in advanced radiation therapy techniques. PMID- 22830780 TI - Displacement and strain estimation for evaluation of arterial wall stiffness using a familial hypercholesterolemia swine model of atherosclerosis. AB - PURPOSE: To track variations in the deformation of the arterial wall noninvasively by estimating the accumulated displacement and strain over a cardiac cycle may provide useful indicators of vascular health. METHODS: In this paper, we propose an approach to track a region of interest (ROI) locally and estimate arterial stiffness variation in a familial hypercholesterolemic swine model of spontaneous atherosclerosis that allows for systematic and reproducible study of progression of the disease mechanism. RESULTS: Strain and displacement indices may be derived from the variations of the accumulated displacement and accumulated strain (obtained from the gradient of the accumulated displacement) over a cardiac cycle to predict not only the likelihood of developing vascular diseases, but also the sites where they may occur. Currently, an ROI thickness value of less than one mm within the arterial wall is necessary for the axial accumulated displacement and strain to obtain reproducible estimates. CONCLUSIONS: Accumulated axial displacement and strain estimation on the artery wall shown in this paper indicate the repeatability of these measurements over several cardiac cycles and over five familial hypercholesterolemic swine. Our results also demonstrate the need for a small region of interest within the arterial walls for accurate and robust estimates of arterial function. PMID- 22830782 TI - A modified hypoxia-based TCP model to investigate the clinical outcome of stereotactic hypofractionated regimes for early stage non-small-cell lung cancer (NSCLC). AB - PURPOSE: Stereotactic body radiotherapy (SBRT) has been applied to lung tumors at different stages and sizes with good local tumor control (LC) rates. The linear quadratic model (LQM), in its basic formulation, does not seem to be appropriate to describe the response to radiotherapy for clinical trials, based on a few fractions. Thus, the main aim of this work was to develop a model, which takes into account the hypoxic cells and their reoxygenation. METHODS: A parameter named B has been introduced in a modified tumor control probability (TCP) from LQM and linear-quadratic-linear model (LQLM), and represents the fraction of hypoxic cells that survive and become oxygenated after each irradiation. Based on published trials evaluating LC at 3 yr (LC3), values of B were obtained by maximum likelihood minimization between predicted TCP and clinical LC3. Two oxygen enhancement ratio (OER) parameter sets (1 and 2) from literature have been adopted to calculate the B-factors. Initial hypoxic cell fractions (eta(h)) from 0.05 to 0.50 were assumed. Log-likelihood (L) and Akaike information criterion (AIC) were determined in an independent clinical validation dataset. RESULTS: The B-values of modified TCPs spanned the whole interval from 0 to 1, depending on the fractionation scheme (number of fractions and dose/fraction), showing a maximum (close to 1) at doses/fraction of 8-12 Gy. The B-values calculated using the OER parameter set 1 exhibited a smoother falloff than set 2. An analytical expression was derived to describe the B-value's dependence on the fractionation scheme. The R(2)-adjusted values varied from 0.63 to 0.67 for LQ models and OER set 1 and from 0.75 to 0.78 for LQ model and OER set 2. Lower values of R(2) adjusted were found for LQLM and both OER sets. L and AIC, calculated using a fraction of eta(h) = 0.15 and the B-value from the authors analytical expression were higher than for other eta(h)-values, irrespective of model or OER set. CONCLUSIONS: The authors model allows to predict the clinical outcome associated with SBRT treatment, taking into account both direct killing and indirect vasculature or stromal damage. PMID- 22830783 TI - Commissioning a CT-compatible LDR tandem and ovoid applicator using Monte Carlo calculation and 3D dosimetry. AB - PURPOSE: To determine the geometric and dose attenuation characteristics of a new commercially available CT-compatible LDR tandem and ovoid (T&O) applicator using Monte Carlo calculation and 3D dosimetry. METHODS: For geometric characterization, we quantified physical dimensions and investigated a systematic difference found to exist between nominal ovoid angle and the angle at which the afterloading buckets fall within the ovoid. For dosimetric characterization, we determined source attenuation through asymmetric gold shielding in the buckets using Monte Carlo simulations and 3D dosimetry. Monte Carlo code MCNP5 was used to simulate 1.5 * 10(9) photon histories from a (137)Cs source placed in the bucket to achieve statistical uncertainty of 1% at a 6 cm distance. For 3D dosimetry, the distribution about an unshielded source was first measured to evaluate the system for (137)Cs, after which the distribution was measured about sources placed in each bucket. Cylindrical PRESAGE((r)) dosimeters (9.5 cm diameter, 9.2 cm height) with a central channel bored for source placement were supplied by Heuris Inc. The dosimeters were scanned with the Duke Large field of view Optical CT-Scanner before and after delivering a nominal dose at 1 cm of 5-8 Gy. During irradiation the dosimeter was placed in a water phantom to provide backscatter. Optical CT scan time lasted 15 min during which 720 projections were acquired at 0.5 degrees increments, and a 3D distribution was reconstructed with a (0.05 cm)(3) isotropic voxel size. The distributions about the buckets were used to calculate a 3D distribution of transmission rate through the bucket, which was applied to a clinical CT-based T&O implant plan. RESULTS: The systematic difference in bucket angle relative to the nominal ovoid angle (105 degrees ) was 3.1 degrees -4.7 degrees . A systematic difference in bucket angle of 1 degrees , 5 degrees , and 10 degrees caused a 1% +/- 0.1%, 1.7% +/- 0.4%, and 2.6% +/- 0.7% increase in rectal dose, respectively, with smaller effect to dose to Point A, bladder, sigmoid, and bowel. For 3D dosimetry, 90.6% of voxels had a 3D gamma-index (criteria = 0.1 cm, 3% local signal) below 1.0 when comparing measured and expected dose about the unshielded source. Dose transmission through the gold shielding at a radial distance of 1 cm was 85.9% +/ 0.2%, 83.4% +/- 0.7%, and 82.5% +/- 2.2% for Monte Carlo, and measurement for left and right buckets, respectively. Dose transmission was lowest at oblique angles from the bucket with a minimum of 56.7% +/- 0.8%, 65.6% +/- 1.7%, and 57.5% +/- 1.6%, respectively. For a clinical T&O plan, attenuation from the buckets leads to a decrease in average Point A dose of ~3.2% and decrease in D(2cc) to bladder, rectum, bowel, and sigmoid of 5%, 18%, 6%, and 12%, respectively. CONCLUSIONS: Differences between dummy and afterloading bucket position in the ovoids is minor compared to effects from asymmetric ovoid shielding, for which rectal dose is most affected. 3D dosimetry can fulfill a novel role in verifying Monte Carlo calculations of complex dose distributions as are common about brachytherapy sources and applicators. PMID- 22830785 TI - Radiation shielding materials and radiation scatter effects for interventional radiology (IR) physicians. AB - PURPOSE: To measure the attenuation effectiveness and minimize the weight of new non-Pb radiation shielding materials used for radiation protection by interventional radiology (IR) physicians, to compare the accuracy of the different standard measurement geometries of these materials, and to determine x ray qualities that correspond to the scattered radiation that IR physicians typically encounter. METHODS: Radiation attenuation capabilities of non-Pb materials were investigated. Typically, most studies of non-Pb materials have focused on the attenuating properties of metal powders. In this study, layers of materials incorporating non-Pb powdered compounds such as Bi(2)O(3), Gd(2)O(3), and BaSO(4) were measured individually, as bilayers, and as a Bi(2)O(3)-loaded hand cream. Attenuation measurements were performed in narrow-beam (fluorescence excluded) and broad beam (fluorescence included) geometries, demonstrating that these different geometries provided significantly different results. The Monte Carlo (MC) program EGSnrc was used to calculate the resulting spectra after attenuation by radiation shielding materials, and scattered x-ray spectra after 90 degrees scattering of eight ASTM Standard primary x-ray beams. Surrogate x ray qualities that corresponded to these scattered spectra were tabulated. RESULTS: Radiation shielding materials incorporating Bi(2)O(3) were found to provide equivalent or superior attenuation compared with commercial Pb-based and non-Pb materials across the 60-130 kVp energy range. Measurements were made for single layers of the Bi(2)O(3) compound and for bilayers where the ordering was low atomic number (Z) layer closest to x-ray source/high Z (Bi(2)O(3)) layer farthest from the x-ray source. Narrow-beam Standard test methods which do not include the contribution from fluorescence overestimated the attenuating capabilities of Pb and non-Pb materials. Measurements of a newly developed, quick drying, and easily removable Bi(2)O(3)-loaded hand cream demonstrated better attenuation capabilities than commercial Bi(2)O(3)-loaded gloves. Scattered radiation measurements and MC simulations illustrated that the spectra resulting from 90 degrees scattering of primary x-ray beam qualities can be approximated by surrogate x-ray qualities which are more representative of the radiation actually encountered by IR physicians. A table of surrogate qualities of the eight ASTM F2547-06 Standard qualities was compiled. CONCLUSIONS: New non-Pb compound materials, particularly single layers or bilayers incorporating Bi(2)O(3), can reduce the weight of radiation protection materials while providing equivalent or better protection compared to Pb-based materials. Attenuation measurements in geometries that exclude the contribution from fluorescence substantially underestimate the quantity of transmitted radiation. A new Bi(2)O(3)-loaded hand cream demonstrated a novel and effective approach for hand protection. Standard testing protocols for radiation protection materials used by IR physicians specify a wider kVp range than is necessary. A more realistic range would acknowledge the lower kVp resulting from scatter and allow IR physicians to confidently utilize lighter-weight materials while still receiving adequate protection. Standards protocols incorporating the adjustments described in this work would maintain the safety of IR personnel and lessen the physical repercussions of long hours wearing unnecessarily heavy radiation protection garments. PMID- 22830784 TI - Coagulation of human prostate volumes with MRI-controlled transurethral ultrasound therapy: results in gel phantoms. AB - PURPOSE: The feasibility and safety of magnetic resonance imaging (MRI) controlled transurethral ultrasound therapy were demonstrated recently in a preliminary human study in which a small subvolume of prostate tissue was treated prior to radical prostatectomy. Translation of this technology to full clinical use, however, requires the capability to generate thermal coagulation in a volume up to that of the prostate gland itself. The aim of this study was to investigate the parameters required to treat a full 3D human prostate accurately with a multi element transurethral applicator and multiplanar MR temperature control. METHODS: The approach was a combination of simulations (to select appropriate parameters) followed by experimental confirmation in tissue-mimicking phantoms. A ten channel, MRI-compatible transurethral ultrasound therapy system was evaluated using six human prostate models (average volume: 36 cm(3)) obtained from the preliminary human feasibility study. Real-time multiplanar MR thermometry at 3 T was used to control the spatial heating pattern in up to nine planes simultaneously. Treatment strategies incorporated both single (4.6 or 8.1 MHz) and dual (4.6 and 14.4 MHz) frequencies, as well as maximum acoustic surface powers of 10 or 20 W cm(-2). RESULTS: Treatments at 4.6 MHz were capable of coagulating a volume equivalent to 97% of the prostate. Increasing power from 10 to 20 W cm(-2) reduced treatment times by approximately 50% with full treatments taking 26 +/- 3 min at a coagulation rate of 1.8 +/- 0.4 cm(3) min(-1). A dual frequency 4.6/14.4 MHz treatment strategy was shown to be the most effective configuration for achieving full human prostate treatment while maintaining good treatment accuracy for small treatment radii. The dual-frequency approach reduced overtreatment close to the prostate base and apex, confirming the simulations. CONCLUSIONS: This study reinforces the capability of MRI-controlled transurethral ultrasound therapy to treat full prostate volumes in a short treatment time with good spatial targeting accuracy and provides key parameters necessary for the next clinical trial. PMID- 22830787 TI - Sub-second high dose rate brachytherapy Monte Carlo dose calculations with bGPUMCD. AB - PURPOSE: To establish the accuracy and speed of bGPUMCD, a GPU-oriented Monte Carlo code used for high dose rate brachytherapy dose calculations. The first objective is to evaluate the time required for dose calculation when full Monte Carlo generated dose distribution kernels are used for plan optimization. The second objective is to assess the accuracy and speed when recalculating pre optimized plans, consisting of many dwell positions. METHODS: bGPUMCD is tested with three clinical treatment plans : one prostate case, one breast case, and one rectum case with a shielded applicator. Reference distributions, generated with GEANT4, are used as a basis of comparison. Calculations of full dose distributions of pre-optimized treatment plans as well as single dwell dosimetry are performed. Single source dosimetry, based on TG-43 parameters reproduction, is also presented for the microSelectron V2 (Nucletron, Veenendaal, The Netherlands). RESULTS: In timing experiments, the computation of single dwell position dose kernels takes between 0.25 and 0.5 s. bGPUMCD can compute full dose distributions of previously optimized plans in ~2 s. bGPUMCD is capable of computing pre-optimized brachytherapy plans within 1% for the prostate case and 2% for the breast and shielded applicator cases, when comparing the dosimetric parameters D90 and V100 of the reference (GEANT4) and bGPUMCD distributions. For all voxels within the target, an absolute average difference of approximately 1% is found for the prostate case, less than 2% for the breast case and less than 2% for the rectum case with shielded applicator. Larger point differences (>5%) are found within bony regions in the prostate case, where bGPUMCD underdoses compared to GEANT4. Single source dosimetry results are mostly within 2% for the radial function and within 1%-4% for the anisotropic function. CONCLUSIONS: bGPUMCD has the potential to allow for fast MC dose calculation in a clinical setting for all phases of HDR treatment planning, from dose kernel calculations for plan optimization to plan recalculation. PMID- 22830786 TI - Interactive semiautomatic contour delineation using statistical conditional random fields framework. AB - PURPOSE: Contouring a normal anatomical structure during radiation treatment planning requires significant time and effort. The authors present a fast and accurate semiautomatic contour delineation method to reduce the time and effort required of expert users. METHODS: Following an initial segmentation on one CT slice, the user marks the target organ and nontarget pixels with a few simple brush strokes. The algorithm calculates statistics from this information that, in turn, determines the parameters of an energy function containing both boundary and regional components. The method uses a conditional random field graphical model to define the energy function to be minimized for obtaining an estimated optimal segmentation, and a graph partition algorithm to efficiently solve the energy function minimization. Organ boundary statistics are estimated from the segmentation and propagated to subsequent images; regional statistics are estimated from the simple brush strokes that are either propagated or redrawn as needed on subsequent images. This greatly reduces the user input needed and speeds up segmentations. The proposed method can be further accelerated with graph-based interpolation of alternating slices in place of user-guided segmentation. CT images from phantom and patients were used to evaluate this method. The authors determined the sensitivity and specificity of organ segmentations using physician-drawn contours as ground truth, as well as the predicted-to-ground truth surface distances. Finally, three physicians evaluated the contours for subjective acceptability. Interobserver and intraobserver analysis was also performed and Bland-Altman plots were used to evaluate agreement. RESULTS: Liver and kidney segmentations in patient volumetric CT images show that boundary samples provided on a single CT slice can be reused through the entire 3D stack of images to obtain accurate segmentation. In liver, our method has better sensitivity and specificity (0.925 and 0.995) than region growing (0.897 and 0.995) and level set methods (0.912 and 0.985) as well as shorter mean predicted-to-ground truth distance (2.13 mm) compared to regional growing (4.58 mm) and level set methods (8.55 mm and 4.74 mm). Similar results are observed in kidney segmentation. Physician evaluation of ten liver cases showed that 83% of contours did not need any modification, while 6% of contours needed modifications as assessed by two or more evaluators. In interobserver and intraobserver analysis, Bland-Altman plots showed our method to have better repeatability than the manual method while the delineation time was 15% faster on average. CONCLUSIONS: Our method achieves high accuracy in liver and kidney segmentation and considerably reduces the time and labor required for contour delineation. Since it extracts purely statistical information from the samples interactively specified by expert users, the method avoids heuristic assumptions commonly used by other methods. In addition, the method can be expanded to 3D directly without modification because the underlying graphical framework and graph partition optimization method fit naturally with the image grid structure. PMID- 22830788 TI - Beam generation and planar imaging at energies below 2.40 MeV with carbon and aluminum linear accelerator targets. AB - PURPOSE: Recent work has demonstrated improvement of image quality with low-Z linear accelerator targets and energies as low as 3.5 MV. In this paper, the authors lower the incident electron beam energy between 1.90 and 2.35 MeV and assess the improvement of megavoltage planar image quality with the use of carbon and aluminum linear accelerator targets. METHODS: The bending magnet shunt current was adjusted in a Varian linear accelerator to allow selection of mean electron energy between 1.90 and 2.35 MeV. Linac set points were altered to increase beam current to allow experimental imaging in a practical time frame. Electron energy was determined through comparison of measured and Monte Carlo modeled depth dose curves. Planar image CNR and spatial resolution measurements were performed to quantify the improvement of image quality. Magnitudes of improvement are explained with reference to Monte Carlo generated energy spectra. RESULTS: After modifications to the linac, beam current was increased by a factor greater than four and incident electron energy was determined to have an adjustable range from 1.90 MeV to 2.35 MeV. CNR of cortical bone was increased by a factor ranging from 6.2 to 7.4 and 3.7 to 4.3 for thin and thick phantoms, respectively, compared to a 6 MV therapeutic beam for both aluminum and carbon targets. Spatial resolution was degraded slightly, with a relative change of 3% and 10% at 0.20 lp/mm and 0.40 lp/mm, respectively, when reducing energy from 2.35 to 1.90 MV. The percentage of diagnostic x-rays for the beams examined here, ranges from 46% to 54%. CONCLUSION: It is possible to produce a large fraction of diagnostic energy x-rays by lowering the beam energy below 2.35 MV. By lowering the beam energy to 1.90 MV or 2.35 MV, CNR improves by factors ranging from 3.7 to 7.4 compared to a 6 MV therapy beam, with only a slight degradation of spatial resolution when lowering the energy from 2.35 MV to 1.90 MV. PMID- 22830789 TI - Near-infrared spectral tomography integrated with digital breast tomosynthesis: effects of tissue scattering on optical data acquisition design. AB - PURPOSE: Design optimization and phantom validation of an integrated digital breast tomosynthesis (DBT) and near-infrared spectral tomography (NIRST) system targeting improvement in sensitivity and specificity of breast cancer detection is presented. Factors affecting instrumentation design include minimization of cost, complexity, and examination time while maintaining high fidelity NIRST measurements with sufficient information to recover accurate optical property maps. METHODS: Reconstructed DBT slices from eight patients with abnormal mammograms provided anatomical information for the NIRST simulations. A limited frequency domain (FD) and extensive continuous wave (CW) NIRST system was modeled. The FD components provided tissue scattering estimations used in the reconstruction of the CW data. Scattering estimates were perturbed to study the effects on hemoglobin recovery. Breast mimicking agar phantoms with inclusions were imaged using the combined DBT/NIRST system for comparison with simulation results. RESULTS: Patient simulations derived from DBT images show successful reconstruction of both normal and malignant lesions in the breast. They also demonstrate the importance of accurately quantifying tissue scattering. Specifically, 20% errors in optical scattering resulted in 22.6% or 35.1% error in quantification of total hemoglobin concentrations, depending on whether scattering was over- or underestimated, respectively. Limited frequency-domain optical signal sampling provided two regions scattering estimates (for fat and fibroglandular tissues) that led to hemoglobin concentrations that reduced the error in the tumor region by 31% relative to when a single estimate of optical scattering was used throughout the breast volume of interest. Acquiring frequency domain data with six wavelengths instead of three did not significantly improve the hemoglobin concentration estimates. Simulation results were confirmed through experiments in two-region breast mimicking gelatin phantoms. CONCLUSIONS: Accurate characterization of scattering is necessary for quantification of hemoglobin. Based on this study, a system design is described to optimally combine breast tomosynthesis with NIRST. PMID- 22830790 TI - Accelerated barrier optimization compressed sensing (ABOCS) reconstruction for cone-beam CT: phantom studies. AB - PURPOSE: Recent advances in compressed sensing (CS) enable accurate CT image reconstruction from highly undersampled and noisy projection measurements, due to the sparsifiable feature of most CT images using total variation (TV). These novel reconstruction methods have demonstrated advantages in clinical applications where radiation dose reduction is critical, such as onboard cone beam CT (CBCT) imaging in radiation therapy. The image reconstruction using CS is formulated as either a constrained problem to minimize the TV objective within a small and fixed data fidelity error, or an unconstrained problem to minimize the data fidelity error with TV regularization. However, the conventional solutions to the above two formulations are either computationally inefficient or involved with inconsistent regularization parameter tuning, which significantly limit the clinical use of CS-based iterative reconstruction. In this paper, we propose an optimization algorithm for CS reconstruction which overcomes the above two drawbacks. METHODS: The data fidelity tolerance of CS reconstruction can be well estimated based on the measured data, as most of the projection errors are from Poisson noise after effective data correction for scatter and beam-hardening effects. We therefore adopt the TV optimization framework with a data fidelity constraint. To accelerate the convergence, we first convert such a constrained optimization using a logarithmic barrier method into a form similar to that of the conventional TV regularization based reconstruction but with an automatically adjusted penalty weight. The problem is then solved efficiently by gradient projection with an adaptive Barzilai-Borwein step-size selection scheme. The proposed algorithm is referred to as accelerated barrier optimization for CS (ABOCS), and evaluated using both digital and physical phantom studies. RESULTS: ABOCS directly estimates the data fidelity tolerance from the raw projection data. Therefore, as demonstrated in both digital Shepp-Logan and physical head phantom studies, consistent reconstruction performances are achieved using the same algorithm parameters on scans with different noise levels and/or on different objects. On the contrary, the penalty weight in a TV regularization based method needs to be fine-tuned in a large range (up to seven times) to maintain the reconstructed image quality. The improvement of ABOCS on computational efficiency is demonstrated in the comparisons with adaptive steepest-descent-projection-onto-convex-sets (ASD-POCS), an existing CS reconstruction algorithm also using constrained optimization. ASD-POCS alternatively minimizes the TV objective using adaptive steepest descent (ASD) and the data fidelity error using projection onto convex sets (POCS). For similar image qualities of the Shepp-Logan phantom, ABOCS requires less computation time than ASD-POCS in MATLAB by more than one order of magnitude. CONCLUSIONS: We propose ABOCS for CBCT reconstruction. As compared to other published CS-based algorithms, our method has attractive features of fast convergence and consistent parameter settings for different datasets. These advantages have been demonstrated on phantom studies. PMID- 22830791 TI - Generalizing the mean intercept length tensor for gray-level images. AB - PURPOSE: The mean intercept length tensor is the most used technique to estimate microstructure orientation and anisotropy of trabecular bone. This paper proposes an efficient extension of this technique to gray-scale images based on a closed formulation of the mean intercept length tensor and a generalization using different angular convolution kernels. METHODS: First, the extended Gaussian image is computed for the binary or gray-scale image. Second, the intercepts are computed for all possible orientations through an angular convolution with the half-cosine function. Finally, the tensor is computed by means of the covariance matrix. The complexity of the method is O(n + m) in contrast with O(nm) of traditional implementations, where n is the number of voxels in the image and m is the number of orientations used in the computations. The method is generalized by applying other angular convolution kernels instead of the half-cosine function. As a result, the anisotropy of the tensor can be controlled while keeping the eigenvectors intact. RESULTS: The proposed extension to gray-scale yields accurate results for reliable computations of the extended Gaussian image and, unlike the traditional methodology, is not affected by artifacts generated by discretizations during the sampling of different orientations. CONCLUSIONS: Experiments show that the computations on both binary and gray-scale images are correlated, and that computations in gray-scale are more robust, enabling the use of the mean intercept length tensor to clinical examinations of trabecular bone. The use of kernels based on the von Mises-Fisher distribution is promising as the anisotropy can be adjusted with a parameter in order to improve its power to predict mechanical properties of trabecular bone. PMID- 22830792 TI - Comment on the "report of AAPM TG 204: size-specific dose estimates (SSDE) in pediatric and adult body CT examinations" [report of AAPM TG 204, 2011]. PMID- 22830927 TI - A randomised trial of nursing interventions supporting recovery of the postmastectomy patient. AB - AIMS AND OBJECTIVES: This ABC to recovery study evaluated the combined and separate components of preoperative education and the effectiveness of wearing the Papilla Gown. BACKGROUND: Surgical removal of the breast may lead to activity limitation, self-image issues, discomfort and later complication of lymphoedema. Design. This study used experimental and longitudinal design. METHODS: One hundred and forty-five women undergoing mastectomies for stages two and three breast cancer were randomised into four groups: education and Papilla Gown, education only, gown only and control. The outcomes of activity (A), body image (B), comfort (C), knowledge and lymphoedema were assessed at baseline and/or 1 week and 6 months using three measures. All 145 participants completed the study questionnaires at first two measures, and forty-six of these participants completed the questionnaires at 6 months postoperatively. The setting for the study included two clinics and hospitals. To examine statistical significance at each time point after surgery, 2-way anovas were performed on ABC, knowledge and tape measurement to see whether there were any statistically significant differences between the four groups. All reported p-values are two sided. All statistical analyses were performed using sas 9.2 for Windows. RESULTS: The mean age of the sample was 55 years. The study revealed that women who received the combined intervention demonstrated greater activity. Women who wore the gown only had a greater comfort level and decreased lymphoedema. Women that received preoperative education experienced increased knowledge. CONCLUSIONS: Outcomes suggest that the combined intervention (ABCs to recovery) can improve recovery following mastectomy. Relevance to clinical practice. The results will be used to further modify the intervention and to increase awareness of nurse practitioners and other healthcare professionals of the specific needs of postmastectomy patients. PMID- 22830928 TI - Mechanisms of the antinociceptive action of (-) epicatechin obtained from the hydroalcoholic fraction of Combretum leprosum Mart & Eic in rodents. AB - BACKGROUND: The mechanisms of the antinociceptive activity of (-) epicatechin (EPI), a compound isolated from the hydroalcoholic fraction of Combreum leprosum Mart & Eicher. METHODS: were assessed in the model of chemical nociception induced by glutamate (20 MUmol/paw). To evaluate the mechanisms involved, the animals , male Swiss mice (25-30 g), received EPI (50 mg/kg p.o.) after pretreatment with naloxone (2 mg/kg s.c. opioid antagonist), glibenclamide (2 mg/kg s.c. antagonist K + channels sensitive to ATP), ketanserin (0.3 mg/kg s.c. antagonist of receptor 5-HT(2A)), yoimbine (0.15 mg/kg s.c. alpha2 adrenergic receptor antagonist), pindolol (1 mg/kg s.c. 5-HT1(a)/1(b) receptor antagonist), atropine (0.1 mg/kg s.c. muscarinic antagonist) and caffeine (3 mg/kg s.c. adenosine receptor antagonist), ondansetron (0.5 mg/kg s.c. for 5-HT(3) receptor) and L-arginine (600 mg/kg i.p.). RESULTS: The antinociceptive effect of EPI was reversed by pretreatment with naloxone and glibenclamide, ketanserin, yoimbine, atropine and pindolol, which demonstrates the involvement of opioid receptors and potassium channels sensitive to ATP, the serotoninergic (receptor 5HT(1A) and 5HT(2A)), adrenergic (receptor alpha 2) and cholinergic (muscarinic receptor) systems in the activities that were observed. The effects of EPI, however, were not reversed by pretreatment with caffeine, L-arginine or ondansetron, which shows that there is no involvement of 5HT(3) receptors or the purinergic and nitrergic systems in the antinociceptive effect of EPI. In the Open Field and Rotarod test, EPI had no significant effect, which shows that there was no central nervous system depressant or muscle relaxant effect on the results. CONCLUSIONS: This study demonstrates that the antinociceptive activity of EPI in the glutamate model involves the participation of the opioid system, serotonin, adrenergic and cholinergic. PMID- 22830929 TI - Erythema gyratum repens is not an obligate paraneoplastic disease: a systematic review of the literature and personal experience. AB - BACKGROUND: Erythema gyratum repens (EGR) is a rare clinical entity that is considered to be an obligatory paraneoplastic disease. According to the literature, an underlying neoplasm can be detected in 82% of the cases. OBJECTIVES: The aim of this systemic review was to evaluate the association of EGR with malignancies or other non-neoplastic conditions. METHODS: The medical records of patients seen at the Section of Dermatology, University of Genoa between 1990 and 2010, in whom a diagnosis of EGR had been made, were reviewed for evidence of systemic associations. A systematic search of the Cochrane library, EMBASE, Pubmed and MEDLINE databases was also conducted. Key search term used in the review was 'erythema gyratum repens'. RESULTS: Four patients with a diagnosis of EGR have been retrieved from our medical records. One case was idiopathic, one was associated with a bronchial carcinoma and two were associated with drug-intake. One hundred and twelve original cases of EGR were selected from the literature for detailed review. Among these, 58 cases (70%) were associated with an underlying neoplasm, 25 cases (30%) were non-paraneoplastic and 29 cases have been considered as different dermatoses mimicking EGR in their clinical presentation ('EGR-like' eruption). CONCLUSION: EGR should no longer be considered as an obligate paraneoplastic syndrome as the cases that are not associated with neoplasm are more than expected. In addition to searching an underlying neoplasm, dermatologists should be aware about the possibility of other associations including also drug-intake. PMID- 22830930 TI - Development of one-step TaqMan(r) real-time reverse transcription-PCR and conventional reverse transcription-PCR assays for the detection of equine rhinitis A and B viruses. AB - BACKGROUND: Equine rhinitis viruses A and B (ERAV and ERBV) are common equine respiratory viruses belonging to the family Picornaviridae. Sero-surveillance studies have shown that these two viral infections are prevalent in many countries. Currently, the diagnosis of ERAV and ERBV infections in horses is mainly based on virus isolation (VI). However, the sensitivity of VI testing varies between laboratories due to inefficient viral growth in cell culture and lack of cytopathic effect. Therefore, the objective of this study was to develop molecular diagnostic assays (real-time RT-PCR [rRT-PCR] and conventional RT-PCR [cRT-PCR] assays) to detect and distinguish ERAV from ERBV without the inherent problems traditionally associated with laboratory diagnosis of these infections. RESULTS: Three rRT-PCR assays targeting the 5'-UTR of ERAV and ERBV were developed. One assay was specific for ERAV, with the two remaining assays specific for ERBV. Additionally, six cRT-PCR assays targeting the 5'-UTR and 3D polymerase regions of ERAV and ERBV were developed. Both rRT-PCR and cRT-PCR assays were evaluated using RNA extracted from 21 archived tissue culture fluid (TCF) samples previously confirmed to be positive for ERAV (n = 11) or ERBV (n = 10) with mono-specific rabbit antisera. The ERAV rRT-PCR and cRT-PCR assays could only detect ERAV isolates and not ERBV isolates. Similarly, the ERBV rRT-PCR and cRT-PCR assays could only detect ERBV isolates and not ERAV isolates. None of the rRT-PCR or cRT-PCR assays cross-reacted with any of the other common equine respiratory viruses. With the exception of one cRT-PCR assay, the detection limit of all of these assays was 1 plaque forming unit per ml (pfu/ml). CONCLUSION: The newly developed rRT-PCR and cRT-PCR assays provide improved diagnostic capability for the detection and differentiation of ERAV and ERBV. However, a larger number of clinical specimens will need to be tested before each assay is adequately validated for the detection of ERAV and/or ERBV in suspect cases of either viral infection. PMID- 22830931 TI - Mollicutes-related endobacteria thrive inside liverwort-associated arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal fungi (AMF) can host Gram-positive endobacteria (BLOs) in their cytoplasm. These have been identified as Mollicutes-related microbes based on an inventory of AMF spores from fungal collections. Bacteria-like organisms (BLOs) of unknown identity have also been reported in the cytoplasm of AMF associated with liverworts, the earliest-diverged extant lineage of land plants. A combination of morphological, molecular and phylogenetic analyses revealed that three samples of two liverwort species (Conocephalum conicum and Lunularia cruciata) growing spontaneously in a botanical garden harboured AMF belonging to Glomerales, and these, in turn, hosted coccoid BLOs. 16S rDNA sequences from these BLOs clustered with the Mollicutes sequences identified from the spore collections but revealed the presence of novel phylotypes. Electron microscopy and fluorescence in situ hybridization (FISH) confirmed the presence of BLOs inside the cytoplasm of AMF hyphae colonizing the liverwort thalli. The high genetic variability of BLOs in liverwort-AMF associations thriving in the same ecological niche raises questions about the mechanisms underlying such diversity. PMID- 22830932 TI - Associations between fruit and vegetable intake, leisure-time physical activity, sitting time and self-rated health among older adults: cross-sectional data from the WELL study. AB - BACKGROUND: Lifestyle behaviours, such as healthy diet, physical activity and sedentary behaviour, are key elements of healthy ageing and important modifiable risk factors in the prevention of chronic diseases. Little is known about the relationship between these behaviours in older adults. The purpose of this study was to explore the relationship between fruit and vegetable (F&V) intake, leisure time physical activity (LTPA) and sitting time (ST), and their association with self-rated health in older adults. METHODS: This cross-sectional study comprised 3,644 older adults (48% men) aged 55-65 years, who participated in the Wellbeing, Eating and Exercise for a Long Life ("WELL") study. Respondents completed a postal survey about their health and their eating and physical activity behaviours in 2010 (38% response rate). Spearman's coefficient (rho) was used to evaluate the relationship between F&V intake, LTPA and ST. Their individual and shared associations with self-rated health were examined using ordinal logistic regression models, stratified by sex and adjusted for confounders (BMI, smoking, long-term illness and socio-demographic characteristics). RESULTS: The correlations between F&V intake, LTPA and ST were low. F&V intake and LTPA were positively associated with self-rated health. Each additional serving of F&V or MET-hour of LTPA were associated with approximately 10% higher likelihood of reporting health as good or better among women and men. The association between ST and self-rated health was not significant in the multivariate analysis. A significant interaction was found (ST*F&V intake). The effect of F&V intake on self-rated health increased with increasing ST in women, whereas the effect decreased with increasing ST in men. CONCLUSIONS: This study contributes to the scarce literature related to lifestyle behaviours and their association with health indicators among older adults. The findings suggest that a modest increase in F&V intake, or LTPA could have a marked effect on the health of older adults. Further research is needed to fully understand the correlates and determinants of lifestyle behaviours, particularly sitting time, in this age group. PMID- 22830933 TI - Chemical molecule-induced light-activated system for anticancer and antifungal activities. AB - Except for chemotherapy, surgery, and radiotherapy, photodynamic therapy (PDT) as new therapy modality is already in wide clinic use for the treatment of various diseases. The major bottleneck of this technique is the requirement of outer light source, which always limits effective application of PDT to the lesions in deeper tissue. Here, we first report a new modality for treating cancer and microbial infections, which is activated by chemical molecules instead of outer light irradiation. In this system, in situ bioluminescence of luminol can be absorbed by a cationic oligo(p-phenylene vinylene) (OPV) that acts as the photosensitizer through bioluminescence resonance energy transfer (BRET) process. The excited OPV sensitizes oxygen molecule in the surroundings to produce reactive oxygen species (ROS) that kill the adjacent cancer cells in vitro and in vivo, and pathogenic microbes. By avoiding the use of light irradiation, this work opens a new therapy modality to tumor and pathogen infections. PMID- 22830934 TI - Plasmon emission quantum yield of single gold nanorods as a function of aspect ratio. AB - We report on the one-photon photoluminescence of gold nanorods with different aspect ratios. We measured photoluminescence and scattering spectra from 82 gold nanorods using single-particle spectroscopy. We found that the emission and scattering spectra closely resemble each other independent of the nanorod aspect ratio. We assign the photoluminescence to the radiative decay of the longitudinal surface plasmon generated after fast interconversion from excited electron-hole pairs that were initially created by 532 nm excitation. The emission intensity was converted to the quantum yield and was found to approximately exponentially decrease as the energy difference between the excitation and emission wavelength increased for gold nanorods with plasmon resonances between 600 and 800 nm. We compare this plasmon emission to its molecular analogue, fluorescence. PMID- 22830935 TI - Fear of intimacy with helping professionals scale: reliability and validity of English and Mandarin versions. AB - In this study the authors examine the reliability and validity of the Fear of Intimacy with Helping Professionals Scale (FIS-HP) with Chinese (N = 150) and American (N = 145) elderly persons. Factor analysis using principal component analysis with a varimax rotation was used to examine the FIS-HP factor structure for both samples. A three factor solution emerged for both samples. The FIS-HP has acceptable internal consistency reliability with both the United States and China samples. Correlation analysis supported five of the six hypotheses related to convergent validity. English and Mandarin versions of the scale are presented. PMID- 22830936 TI - The effect of neighborhood on crime and safety: a review of the evidence. AB - There is a growing, multidisciplinary body of evidence on the effects that neighborhoods have on family outcomes. This evidence is important for social workers as we work with clients and communities from a person-in-environment perspective. In this article the authors present findings from a systematic, integrative review of neighborhood effects specifically for crime and safety. Thirty-seven research studies using random samples from urban, U.S. areas between 2002 and 2008 are reviewed. Findings suggest socio-demographic characteristics of neighborhoods and neighborhood processes are both predictive of crime and safety. Further, some neighborhood conditions may affect crime and safety in unexpected ways. Implications for social work practice, neighborhood interventions, and evidence-based practice are discussed. PMID- 22830937 TI - Exploring resiliency factors of older African American Katrina survivors. AB - Through this qualitative study the author explores the resiliency processes demonstrated by older African American Hurricane Katrina survivors who relocated in the aftermath of the storm and were consequently faced with difficult challenges. In-depth interviews were used to assess the multidimensional characteristics of resiliency that enabled these older adults to deal with adversity. These findings highlight distinct processes reflecting resiliency: (a) Trusting in a higher power, and the importance of (b) living in the present, (c) activating resources, (d) creating community, and (e) doing for others. The author concludes this study with suggestions on how these findings may inform social work practice with older adults. PMID- 22830939 TI - A comparison of sanctions in African American and White TANF leavers. AB - In this study the authors explore racial disparities in the uses of sanctions and the different impact of sanctions on the economic well-being of African American and White TANF leavers. The study analyzed 907 African American and 1,336 White welfare leavers from the 1999 and 2002 data of the NSAF. Chi-square results show that sanctions are more significantly imposed to African Americans than Whites. On the other hand, regression results show that the impact of sanctions on the employment and family income of African Americans and Whites are comparable. Implications suggest that states need to have an appropriate sanction process, training programs for caseworkers, or other policy changes to reduce the racial disparities. PMID- 22830938 TI - Knowledge translation efforts in child and youth mental health: a systematic review. AB - The availability of knowledge translation strategies that have been empirically studied and proven useful is a critical prerequisite to narrowing the research-to practice gap in child and youth mental health. Through this review the authors sought to determine the current state of scientific knowledge of the effectiveness of knowledge translation approaches in child and youth mental health by conducting a systematic review of the research evidence. The findings and quality of the 12 included studies are discussed. Future work of high methodological quality that explores a broader range of knowledge translation strategies and practitioners to which they are applied and that also attends to implementation process is recommended. PMID- 22830940 TI - Social group work practice: an evidence-based approach. PMID- 22830941 TI - Unilateral cochlear nerve hypoplasia in children with mild to moderate hearing loss. AB - CONCLUSION: Even if hearing loss is mild to moderate, the presence of cochlear nerve (CN) hypoplasia associated with retrocochlear disorders should be considered. OBJECTIVES: CN hypoplasia is a term that refers to an absent cochlear nerve on high-resolution magnetic resonance imaging (MRI). Most cases of CN hypoplasia are associated with profound hearing loss. The present study reports six pediatric cases of unilateral CN hypoplasia with mild to moderate hearing loss. METHODS: Between May 2008 and April 2011, pure-tone hearing tests were performed in 17 patients who were diagnosed with CN hypoplasia on high resolution for evaluation of unilateral sensorineural hearing loss at the National Center for Child Health and Development. Of these, six patients had average hearing levels in the affected ears of < 60 dB and were therefore included in this study. RESULTS: All six ears with CN hypoplasia were associated with CN canal stenosis. DPOAEs were present in one (17%) of the six affected ears. The ABR thresholds of the ears with CN hypoplasia were significantly elevated compared with 1-4 kHz pure-tone hearing levels in one of three cases. In two of five cases, the maximum word recognition scores of the affected ears were poor compared with pure-tone hearing levels. PMID- 22830942 TI - Ofatumumab, the first human anti-CD20 monoclonal antibody for the treatment of B cell hematologic malignancies. AB - Ofatumumab is the first human anti-CD20 monoclonal antibody to be approved for patients in the United States and the European Union. Ofatumumab received accelerated approval from the U.S. Food and Drug Administration in October 2009 and was granted a conditional marketing authorization by the European Medicines Agency in April 2010 for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab, based on interim results of a pivotal phase 2 trial. Preliminary positive results for ofatumumab in combination with chemotherapy in patients with CLL are currently being confirmed in larger randomized trials in both the frontline setting and the relapsed/refractory setting. Ofatumumab has also shown potential in treating B cell non-Hodgkin's lymphoma, such as follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and Waldenstrom's macroglobulinemia. Additional trials are ongoing to confirm activity of ofatumumab as monotherapy and in combination with chemotherapy in patients with FL or DLBCL. PMID- 22830943 TI - Effect of a 2-hydroxylated fatty acid on cholesterol-rich membrane domains. AB - 2-Hydroxyoleic acid (2OHOA) is a synthetic fatty acid with antihypertensive properties that is able to alter structural membranes properties. The main purpose of this study was to analyze the effect of 2OHOA on the membrane architecture in cholesterol (Cho)-rich domains. For this purpose, model membranes mimicking the composition of lipid rafts and PC- or PE-Cho-rich domains were examined in the absence and presence of 2OHOA by synchrotron X-ray diffraction, atomic force microscopy (AFM) and microcalorimetry (DSC) techniques. Our results demonstrate that 2OHOA phase separates from lipid raft domains and affects the lateral organization of lipids in the membrane. In model raft membranes, 2OHOA interacted with the sphingomyelin (SM) gel phase increasing the thickness of the water layer, which should lead to increased bilayer fluidity. The hydrogen binding competition between 2OHOA and Cho could favour the enrichment of 2OHOA in SM domains separated from the SM-Cho domains, resulting in an enhanced phase separation into SM-2OHOA-rich liquid-disordered (non-raft) and SM-Cho-rich liquid ordered (raft) domains. The segregation into 2OHOA-rich/Cho-poor and 2OHOA poor/Cho-rich domains was also observed in PC bilayers. PMID- 22830944 TI - Analysis of soluble lignin in sugarcane by ultrahigh performance liquid chromatography-tandem mass spectrometry with a do-it-yourself oligomer database. AB - Lignin is a polymer found in the cell wall of plants and is one of the main obstacles to the implementation of second-generation ethanol production because it confers the recalcitrance of the lignocellulosic material. The recalcitrance of biomass is affected by the amount of lignin, by its monomer composition, and the way the monomers are arranged in the plant cell wall. Analysis of lignin structure demands mass spectrometry analysis, and identification of oligomers is usually based on libraries produced by laborious protocols. A robust method to build a do-it-yourself lignin oligomer library was tested. This library can be built using commercially available enzymes, standards, and reagents and is relatively easy to accomplish. An ultrahigh performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the separation and characterization of monomers and oligomers was developed and was equally applicable to the synthetic lignin and to soluble lignin extracted from a sample of sugar cane. PMID- 22830945 TI - Screening of patients with tuberculosis for diabetes mellitus in China. AB - OBJECTIVE: There is a high burden of both diabetes (DM) and tuberculosis (TB) in China, and this study aimed to assess feasibility and results of screening patients with TB for DM within the routine healthcare setting of six health facilities. METHOD: Agreement on how to screen, monitor and record was reached in May 2011 at a stakeholders' meeting, and training was carried out for staff in the six facilities in July 2011. Implementation started in September 2011, and we report on 7 months of activities up to 31 March 2012. RESULTS: There were 8886 registered patients with TB. They were first asked whether they had DM. If the answer was no, they were screened with a random blood glucose (RBG) followed by fasting blood glucose (FBG) in those with RBG >= 6.1 mm (one facility) or with an initial FBG (five facilities). Those with FBG >= 7.0 mm were referred to DM clinics for diagnostic confirmation with a second FBG. Altogether, 1090 (12.4%) patients with DM were identified, of whom 863 (9.7%) had a known diagnosis of DM. Of 8023 patients who needed screening for DM, 7947 (99%) were screened. This resulted in a new diagnosis of DM in 227 patients (2.9% of screened patients), and of these, 226 were enrolled to DM care. In addition, 575 (7.8%) persons had impaired fasting glucose (FBG 6.1 to <7.0 mm). Prevalence of DM was significantly higher in patients in health facilities serving urban populations (14.0%) than rural populations (10.6%) and higher in hospital patients (13.5%) than those attending TB clinics (8.5%). CONCLUSION: This pilot project shows that it is feasible to screen patients with TB for DM in the routine setting, resulting in a high yield of patients with known and newly diagnosed disease. Free blood tests for glucose measurement and integration of TB and DM services may improve the diagnosis and management of dually affected patients. PMID- 22830946 TI - Kinematic comparison of the wrist movements that are possible with a biomechatronics wrist prosthesis and a body-powered prosthesis: a preliminary study. AB - PURPOSE: This study examined the kinematic differences between a body-powered prosthesis and a biomechatronics prosthesis as a transradial amputee performed activities that involve flexion/extension and supination/pronation of the wrist. METHOD: The subject's wrist movements were calculated and compared as he completed a wrist range of motion test involving simulated flexion/extension and supination/pronation. RESULTS: The results revealed that, under the test conditions, the body-powered prosthesis limits an individual's ability to complete four different tasks of wrist movement especially when it comes to complete the supination/pronation movement. Conversely, while using biomechatronics wrist prosthesis, the user was able to compensate for limited wrist motion through an ability to achieve a greater range of wrist movement. CONCLUSIONS: The biomechatronics wrist prosthesis provides a greater degree of freedom of wrist flexion/extension and supination/pronation movements. PMID- 22830947 TI - Perineural invasion in basal cell carcinomas is generally not re-excision perineural invasion. PMID- 22830948 TI - Invasive aspergillosis among heart transplant recipients is rare but causes rapid death due to septic shock and multiple organ dysfunction syndrome. AB - Between 2000 and 2011, proven or probable invasive aspergillosis (IA) was diagnosed in 1.7% (8/455) of heart transplant (HTx) recipients at our center, in the absence of antifungal prophylaxis. All patients had invasive pulmonary infections and 75% (6/8) were diagnosed during 2 separate 3-month periods. Cases were notable for their association with septic shock and multiple organ dysfunction syndrome (MODS) (75%, 6/8 each), non-specific clinical and radiographic findings, and rapid mortality despite mould-active antifungal therapy (88%, 7/8; occuring at a median 11 days after diagnosis). All patients had predisposing conditions known to be risk factors for IA. For patients with early IA (within 90 days of HTx), conditions included hemodialysis, thoracic re operation, and the presence of another case in the institution within the preceding 3 months. For late-onset IA, conditions included hemodialysis and receipt of augmented immunosuppression. Clinicians should suspect IA in HTx recipients with risk factors who present with non-specific and unexplained respiratory syndromes, including those in septic shock and MODS, and institute prompt antifungal therapy without waiting for the results of cultures or other diagnostic tests. PMID- 22830949 TI - Model studies on the synthesis of madangamine alkaloids. Assembly of the macrocyclic rings. AB - Using simplified model derivatives, the assembly of the macrocyclic rings of madangamines, including the 13- and 14-membered D rings of madangamines C-E, the all-cis-triunsaturated 15-membered D ring of madangamine A, and the (Z,Z) unsaturated 11-membered E ring common to madangamines A-E, has been studied. PMID- 22830950 TI - Biophysical studies of mutated K562 DNA (erythroleukemic cells) binding to adriamycin and daunomycin reveal that mutations induce structural changes influencing binding behavior. AB - K562 cells are erythroleukemic cells derived from a chronic myeloid leukemia patient in blast crisis. Comparison of the genome from K562 cells and normal human genome has been very useful strategy, in uncovering eight genes, implicated in acute myeloid leukemia (AML). These genes carry mutations in K562 genome and the role of these mutations in the progression and treatment of AML is still not known. Consequences of these mutations on drug DNA binding are also not known exactly. In the present study, mutation induced structural changes in K562 genome, compared to normal genome, are identified by Fourier transform infra red (FTIR) and circular dichroism (CD) spectroscopy. These structural changes in native K562 DNA favor stronger binding with binding constants 2.0 * 108 and 1.9 * 109 M-1 with antileukemic drugs adriamycin and daunomycin (DNM), respectively, compared to normal DNA. On binding, these drugs disrupt the native B form structure of normal DNA to a greater extent, compared to A-like structure of K562 DNA. Fluorescence and absorption studies reveal higher intercalation as well as mixed groove binding of these drugs with K562 DNA compared to normal DNA. Among the drugs, DNM has higher affinity for K562 DNA. PMID- 22830951 TI - Screening patients with diabetes mellitus for tuberculosis in China. AB - OBJECTIVE: There is a high burden of both diabetes (DM) and tuberculosis (TB) in China, and as DM increases the risk of TB and adversely affects TB treatment outcomes, there is a need for bidirectional screening of the two diseases. How this is best performed is not well determined. In this pilot project in China, we aimed to assess the feasibility and results of screening DM patients for TB within the routine healthcare setting of five DM clinics. METHOD: Agreement on how to screen, monitor and record was reached in May 2011 at a national stakeholders meeting, and training was carried out for staff in the five clinics in July 2011. Implementation started in September 2011, and we report on 7 months of activities up to 31 March 2012. DM patients were screened for TB at each clinic attendance using a symptom-based enquiry, and those positive to any symptom were referred for TB investigations. RESULTS: In the three quarters, 72% of 3174 patients, 79% of 7196 patients and 68% of 4972 patients were recorded as having been screened for TB, resulting in 7 patients found who were already known to have TB, 92 with a positive TB symptom screen and 48 of these newly diagnosed with TB as a result of referral and investigation. All patients except one were started on anti-TB treatment. TB case notification rates in screened DM patients were several times higher than those of the general population, were highest for the five sites combined in the final quarter (774/100 000) and were highest in one of the five clinics in the final quarter (804/100 000) where there was intensive in-house training, special assignment of staff for screening and colocation of services. CONCLUSION: This pilot project shows that it is feasible to carry out screening of DM patients for TB resulting in high detection rates of TB. This has major public health and patient-related implications. PMID- 22830953 TI - Enantioselective halocyclization using reagents tailored for chiral anion phase transfer catalysis. AB - A chiral anion phase-transfer system for enantioselective halogenation is described. Highly insoluble, ionic reagents were developed as electrophilic bromine and iodine sources, and application of this system to o-anilidostyrenes afforded halogenated 4H-3,1-benzoxazines with excellent yield and enantioselectivity. PMID- 22830952 TI - N-Terminal labeling of filamentous phage to create cancer marker imaging agents. AB - We report a convenient new technique for the labeling of filamentous phage capsid proteins. Previous reports have shown that phage coat protein residues can be modified, but the lack of chemically distinct amino acids in the coat protein sequences makes it difficult to attach high levels of synthetic molecules without altering the binding capabilities of the phage. To modify the phage with polymer chains, imaging groups, and other molecules, we have developed chemistry to convert the N-terminal amines of the ~4200 coat proteins into ketone groups. These sites can then serve as chemospecific handles for the attachment of alkoxyamine groups through oxime formation. Specifically, we demonstrate the attachment of fluorophores and up to 3000 molecules of 2 kDa poly(ethylene glycol) (PEG2k) to each of the phage capsids without significantly affecting the binding of phage-displayed antibody fragments to EGFR and HER2 (two important epidermal growth factor receptors). We also demonstrate the utility of the modified phage for the characterization of breast cancer cells using multicolor fluorescence microscopy. Due to the widespread use of filamentous phage as display platforms for peptide and protein evolution, we envision that the ability to attach large numbers of synthetic functional groups to their coat proteins will be of significant value to the biological and materials communities. PMID- 22830954 TI - Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism. AB - Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established. PMID- 22830955 TI - Leaf senescence in plants: from model plants to crops, still so many unknowns. PMID- 22830957 TI - Experimental model of facial paralysis by nerve compression in primates (Callithrix sp.): a new model of facial paralysis in small nonhuman primates. AB - CONCLUSION: We conclude that facial nerve injury induced by compression is associated with a reasonable time window (4 weeks) that allows possible neurotrophic effects to be analyzed. Additionally, there are no hints of cross innervation by the contralateral facial nerve or parallel innervation by other nerves in the hemiface ipsilateral to the injured nerve. OBJECTIVE: The aim of this work was to develop an experimental model of facial nerve injury in nonhuman primates (Callithrix sp.). METHODS: In this study, individuals of the non-human primate species Callithrix sp. were subjected to three different types of facial nerve injury, and they were observed for 27 days after surgery by video to record their facial movements. RESULTS: Two types of nerve compression caused severe initial facial paralysis followed by gradual recovery until normal levels were reached at the end of the evaluation period. Injury induced by nerve resection was followed by a complete lack of facial movement recovery. PMID- 22830956 TI - The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries. AB - AIMS: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). METHODS: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management. RESULTS: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (+/-s.d.) were: age 62 +/- 12 years; body mass index (BMI) 29.3 +/- 5.4 kg/m(2); diabetes duration 10 +/- 7 years; haemoglobin A1c (HbA1c) 8.9 +/- 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 +/- 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 +/- 6 U (0.16 +/- 0.09 U/kg) to 22 +/- 16 U (0.27 +/- 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c. CONCLUSIONS: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs. PMID- 22830958 TI - Freezing-induced cellular and membrane dehydration in the presence of cryoprotective agents. AB - FTIR and cryomicroscopy have been used to study mouse embryonic fibroblast cells (3T3) during freezing in the absence and presence of DMSO and glycerol. The results show that cell volume changes as observed by cryomicroscopy typically end at temperatures above -15 degrees C, whereas membrane phase changes may continue until temperatures as low as -30 degrees C. This implies that cellular dehydration precedes dehydration of the bound water surrounding the phospholipid head groups. Both DMSO and glycerol increase the membrane hydraulic permeability at subzero temperature and reduce the activation energy for water transport. Cryoprotective agents facilitate dehydration to continue at low subzero temperatures thereby decreasing the incidence of intracellular ice formation. The increased subzero membrane hydraulic permeability likely plays an important role in the cryoprotective action of DMSO and glycerol. In the presence of DMSO water permeability was found to be greater compared to that in the presence of glycerol. Two temperature regimes were identified in an Arrhenius plot of the membrane hydraulic permeability. The activation energy for water transport at temperature ranging from 0 to -10 degrees C was found to be greater than that below -10 degrees C. The non-linear Arrhenius behavior of Lp has been implemented in the water transport model to simulate cell volume changes during freezing. At a cooling rate of 1 degrees C min(-1), ~5% of the initial osmotically active water volume is trapped inside the cells at -30 degrees C. PMID- 22830959 TI - Overestimating population sizes of rare clonal plants. PMID- 22830962 TI - Span: spike pattern association neuron for learning spatio-temporal spike patterns. AB - Spiking Neural Networks (SNN) were shown to be suitable tools for the processing of spatio-temporal information. However, due to their inherent complexity, the formulation of efficient supervised learning algorithms for SNN is difficult and remains an important problem in the research area. This article presents SPAN - a spiking neuron that is able to learn associations of arbitrary spike trains in a supervised fashion allowing the processing of spatio-temporal information encoded in the precise timing of spikes. The idea of the proposed algorithm is to transform spike trains during the learning phase into analog signals so that common mathematical operations can be performed on them. Using this conversion, it is possible to apply the well-known Widrow-Hoff rule directly to the transformed spike trains in order to adjust the synaptic weights and to achieve a desired input/output spike behavior of the neuron. In the presented experimental analysis, the proposed learning algorithm is evaluated regarding its learning capabilities, its memory capacity, its robustness to noisy stimuli and its classification performance. Differences and similarities of SPAN regarding two related algorithms, ReSuMe and Chronotron, are discussed. PMID- 22830960 TI - Mixing and matching siderophore clusters: structure and biosynthesis of serratiochelins from Serratia sp. V4. AB - Interrogation of the evolutionary history underlying the remarkable structures and biological activities of natural products has been complicated by not knowing the functions they have evolved to fulfill. Siderophores-soluble, low molecular weight compounds-have an easily understood and measured function: acquiring iron from the environment. Bacteria engage in a fierce competition to acquire iron, which rewards the production of siderophores that bind iron tightly and cannot be used or pirated by competitors. The structures and biosyntheses of "odd" siderophores can reveal the evolutionary strategy that led to their creation. We report a new Serratia strain that produces serratiochelin and an analog of serratiochelin. A genetic approach located the serratiochelin gene cluster, and targeted mutations in several genes implicated in serratiochelin biosynthesis were generated. Bioinformatic analyses and mutagenesis results demonstrate that genes from two well-known siderophore clusters, the Escherichia coli enterobactin cluster and the Vibrio cholera vibriobactin cluster, were shuffled to produce a new siderophore biosynthetic pathway. These results highlight how modular siderophore gene clusters can be mixed and matched during evolution to generate structural diversity in siderophores. PMID- 22830963 TI - From sensors to spikes: evolving receptive fields to enhance sensorimotor information in a robot-arm. AB - In biological systems, instead of actual encoders at different joints, proprioception signals are acquired through distributed receptive fields. In robotics, a single and accurate sensor output per link (encoder) is commonly used to track the position and the velocity. Interfacing bio-inspired control systems with spiking neural networks emulating the cerebellum with conventional robots is not a straight forward task. Therefore, it is necessary to adapt this one dimensional measure (encoder output) into a multidimensional space (inputs for a spiking neural network) to connect, for instance, the spiking cerebellar architecture; i.e. a translation from an analog space into a distributed population coding in terms of spikes. This paper analyzes how evolved receptive fields (optimized towards information transmission) can efficiently generate a sensorimotor representation that facilitates its discrimination from other "sensorimotor states". This can be seen as an abstraction of the Cuneate Nucleus (CN) functionality in a robot-arm scenario. We model the CN as a spiking neuron population coding in time according to the response of mechanoreceptors during a multi-joint movement in a robot joint space. An encoding scheme that takes into account the relative spiking time of the signals propagating from peripheral nerve fibers to second-order somatosensory neurons is proposed. Due to the enormous number of possible encodings, we have applied an evolutionary algorithm to evolve the sensory receptive field representation from random to optimized encoding. Following the nature-inspired analogy, evolved configurations have shown to outperform simple hand-tuned configurations and other homogenized configurations based on the solution provided by the optimization engine (evolutionary algorithm). We have used artificial evolutionary engines as the optimization tool to circumvent nonlinearity responses in receptive fields. PMID- 22830964 TI - Hardware implementation of stochastic spiking neural networks. AB - Spiking Neural Networks, the last generation of Artificial Neural Networks, are characterized by its bio-inspired nature and by a higher computational capacity with respect to other neural models. In real biological neurons, stochastic processes represent an important mechanism of neural behavior and are responsible of its special arithmetic capabilities. In this work we present a simple hardware implementation of spiking neurons that considers this probabilistic nature. The advantage of the proposed implementation is that it is fully digital and therefore can be massively implemented in Field Programmable Gate Arrays. The high computational capabilities of the proposed model are demonstrated by the study of both feed-forward and recurrent networks that are able to implement high speed signal filtering and to solve complex systems of linear equations. PMID- 22830965 TI - Presynaptic learning and memory with a persistent firing neuron and a habituating synapse: a model of short term persistent habituation. AB - Our paper explores the interaction of persistent firing axonal and presynaptic processes in the generation of short term memory for habituation. We first propose a model of a sensory neuron whose axon is able to switch between passive conduction and persistent firing states, thereby triggering short term retention to the stimulus. Then we propose a model of a habituating synapse and explore all nine of the behavioral characteristics of short term habituation in a two neuron circuit. We couple the persistent firing neuron to the habituation synapse and investigate the behavior of short term retention of habituating response. Simulations show that, depending on the amount of synaptic resources, persistent firing either results in continued habituation or maintains the response, both leading to longer recovery times. The effectiveness of the model as an element in a bio-inspired memory system is discussed. PMID- 22830966 TI - Modeling fluctuations in default-mode brain network using a spiking neural network. AB - Recently, numerous attempts have been made to understand the dynamic behavior of complex brain systems using neural network models. The fluctuations in blood oxygen-level-dependent (BOLD) brain signals at less than 0.1 Hz have been observed by functional magnetic resonance imaging (fMRI) for subjects in a resting state. This phenomenon is referred to as a "default-mode brain network." In this study, we model the default-mode brain network by functionally connecting neural communities composed of spiking neurons in a complex network. Through computational simulations of the model, including transmission delays and complex connectivity, the network dynamics of the neural system and its behavior are discussed. The results show that the power spectrum of the modeled fluctuations in the neuron firing patterns is consistent with the default-mode brain network's BOLD signals when transmission delays, a characteristic property of the brain, have finite values in a given range. PMID- 22830967 TI - Relationship between applicability of current-based synapses and uniformity of firing patterns. AB - The purpose of this paper is to identify situations in neural network modeling where current-based synapses are applicable. The applicability of current-based synapse model for studying post-transient behavior of neural networks is discussed in terms of average synaptic current strength induced by per spike during one firing cycle of a neuron (or briefly per spike synaptic current strength). It was found that current-based synapse models are applicable in both situations where both the interspike intervals of the neurons and the distribution of firing times of the neurons are uniform, and where the firing of all neurons is synchronized. If neither the interspike intervals nor the distribution of firing times of the neurons is uniform or the reversal potential is between the rest and threshold potentials, current-based synapse models may be oversimplified. PMID- 22830968 TI - Influencing integrated medicine, living the butterfly effect, and touching lives globally through the Journal of Alternative and Complementary Medicine: in memory of Barbara Nell Perrin March 3, 1952 - June 4, 2012. PMID- 22830969 TI - Efficacy of a short-term yoga-based lifestyle intervention in reducing stress and inflammation: preliminary results. AB - OBJECTIVES: Previously it was shown that a brief yoga-based lifestyle intervention was efficacious in reducing oxidative stress and risk of chronic diseases even in a short duration. The objective of this study was to assess the efficacy of this intervention in reducing stress and inflammation in patients with chronic inflammatory diseases. DESIGN: This study reports preliminary results from a nonrandomized prospective ongoing study with pre-post design. SETTING/LOCATION: The study was conducted at the Integral Health Clinic, an outpatient facility conducting these yoga-based lifestyle intervention programs for prevention and management of chronic diseases. SUBJECTS: Patients with chronic inflammatory diseases and overweight/obese subjects were included while physically challenged, and those on other interventions were excluded from the study. INTERVENTION: A pretested intervention program included asanas (postures), pranayama (breathing exercises), stress management, group discussions, lectures, and individualized advice. OUTCOME MEASURES: There was a reduction in stress (plasma cortisol and beta-endorphin) and inflammation (interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha) at day 0 versus day 10. RESULTS: Eighty-six (86) patients (44 female, 42 male, 40.07 +/- 13.91 years) attended this program. Overall, the mean level of cortisol decreased from baseline to day 10 (149.95 +/- 46.07, 129.07 +/- 33.30 ng/mL; p=0.001) while beta-endorphins increased from baseline to day 10 (3.53 +/- 0.88, 4.06 +/- 0.79 ng/mL; p=0.024). Also, there was reduction from baseline to day 10 in mean levels of IL-6 (2.16 +/- 0.42, 1.94 +/- 0.10 pg/mL, p=0.036) and TNF-alpha (2.85 +/- 0.59, 1.95 +/- 0.32 pg/mL, p=0.002). CONCLUSIONS: This brief yoga-based lifestyle intervention reduced the markers of stress and inflammation as early as 10 days in patients with chronic diseases; however, complete results of this study will confirm whether this program has utility as complementary and alternative therapy. PMID- 22830970 TI - Efficacy of traditional Japanese herbal medicines-Keishikajutsubuto (TJ-18) and Bushi-matsu (TJ-3022)-against postherpetic neuralgia aggravated by self-reported cold stimulation: a case series. AB - OBJECTIVES: It has been reported that postherpetic neuralgia (PHN) in patients over 60 years of age is aggravated under cold stimulation and is often difficult to treat. Keishikajutsubuto (TJ-18) and Bushi-matsu (TJ-3022) are traditional Japanese herbal medicines and have long been used to treat neuralgia and arthralgia, which are aggravated following cold stimulation. This study was designed to evaluate the effectiveness of combined TJ-18 and TJ-3022 therapy in cases of PHN aggravated by self-reported cold stimulation. DESIGN: Fifteen (15) PHN patients aged 60 years and over were examined. Patients were aware of the persistent pain despite other treatments; pain was generally aggravated following exposure to cold stimulation. First, TJ-18 (7.5 g/day) was administered to patients, and then TJ-3022 (1.0 g/day) was also administered and progressively increased by 0.5-1.0 g increments every 2-4 weeks, until stable improvement was achieved, which was rated using the visual analogue scale (VAS). Analgesic effects were evaluated using the VAS during each patient visit. OUTCOME MEASURES: Background variables, responses to treatment (time course of VAS rating, VAS improvement rate), the amount of additional TJ-3022 administered, and adverse reactions were analyzed. RESULTS: Twelve (12) of the 15 patients completed the entire trial. Patient ages were 61-85 years, the male-to-female ratio was 4:8, and length of time after onset of herpes zoster was 2-92 months. In 3 patients, oral TJ-18 treatment was not possible due to hot flash or gastric discomfort. The VAS improvement rate for patients being orally administered both TJ-18 and TJ 3022 was 76.5+/-27.7% (mean+/-standard deviation). The additional TJ-3022 dose was 1.0-5.0 g/day. Twelve (12) patients have been treated without serious adverse reactions. CONCLUSIONS: TJ-18 and TJ-3022 combination treatment is a promising means of treating intractable PHN, which has a self-reported tendency to aggravate pain under cold stimulation. PMID- 22830971 TI - Chia seed supplementation and disease risk factors in overweight women: a metabolomics investigation. AB - OBJECTIVE/SETTING: This study assessed the effectiveness of milled and whole chia seed in altering disease risk factors in overweight, postmenopausal women using a metabolomics approach. DESIGN/INTERVENTION: Subjects were randomized to chia seed (whole or milled) and placebo (poppy seed) groups, and under double-blinded procedures ingested 25 g chia seed or placebo supplements each day for 10 weeks. SUBJECTS: Subjects included 62 overweight (body-mass index 25 kg/m(2) and higher), nondiseased, nonsmoking, postmenopausal women, ages 49-75 years, with analysis based on the 56 subjects who completed all phases of the study. OUTCOME MEASURES: Pre- and poststudy measures included body mass and composition, blood pressure and augmentation index, serum lipid profile, inflammation markers from fasting blood samples, plasma fatty acids, and metabolic profiling using gas chromatography-mass spectrometry with multivariate statistical methods including principal component analysis and partial least-square discriminant analysis (PLS DA). RESULTS: Plasma alpha-linolenic acid (N=ALA) increased 58% (interaction effect, p=0.002) and eicosapentaenoic acid (EPA) 39% (p=0.016) in the milled chia seed group (N=14) compared to nonsignificant changes in the whole chia seed (N=16) and placebo (N=26) groups. Pre-to-post measures of body composition, inflammation, blood pressure, augmentation index, and lipoproteins did not differ between chia seed (whole or milled) and placebo groups (all interaction effects, p>0.05). Global metabolic difference scores for each group calculated through PLS DA models were nonsignificant (Q(2)Y<0.40), and fold-changes for 28 targeted metabolites associated with inflammation and disease risk factors did not differ between groups. CONCLUSIONS: Ingestion of 25 g/day milled chia seed compared to whole chia seed or placebo for 10 weeks by overweight women increased plasma ALA and EPA, but had no influence on inflammation or disease risk factors using both traditional and metabolomics-based measures. PMID- 22830972 TI - A complex, nonlinear dynamic systems perspective on Ayurveda and Ayurvedic research. AB - The fields of complexity theory and nonlinear dynamic systems (NDS) are relevant for analyzing the theory and practice of Ayurvedic medicine from a Western scientific perspective. Ayurvedic definitions of health map clearly onto the tenets of both systems and complexity theory and focus primarily on the preservation of organismic equanimity. Health care research informed by NDS and complexity theory would prioritize (1) ascertaining patterns reflected in whole systems as opposed to isolating components; (2) relationships and dynamic interaction rather than static end-points; (3) transitions, change and cumulative effects, consistent with delivery of therapeutic packages in the reality of the clinical setting; and (4) simultaneously exploring both local and global levels of healing phenomena. NDS and complexity theory are useful in examining nonlinear transitions between states of health and illness; the qualitative nature of shifts in health status; and looking at emergent properties and behaviors stemming from interactions between organismic and environmental systems. Complexity and NDS theory also demonstrate promise for enhancing the suitability of research strategies applied to Ayurvedic medicine through utilizing core concepts such as initial conditions, emergent properties, fractal patterns, and critical fluctuations. In the Ayurvedic paradigm, multiple scales and their interactions are addressed simultaneously, necessitating data collection on change patterns that occur on continuums of both time and space, and are viewed as complementary rather than isolated and discrete. Serious consideration of Ayurvedic clinical understandings will necessitate new measurement options that can account for the relevance of both context and environmental factors, in terms of local biology and the processual features of the clinical encounter. Relevant research design issues will need to address clinical tailoring strategies and provide mechanisms for mapping patterns of change that account for the contiguous, self-replicating, cumulative, and synergistic theories associated with successful Ayurvedic treatment approaches. PMID- 22830973 TI - Ayurvedic intervention in metastatic liver disease. AB - BACKGROUND: Ayurvedic medicines are often considered effective for treating chronic and lifestyle-related diseases only and have not been thoroughly evaluated for treating acute or terminal illnesses. A prospective evaluation of Ayurvedic intervention was proposed for a patient who had metastatic liver disease with abnormal liver functions. The reason given for this was that no other conventional therapies were feasible in this case, and the family and caregivers were not willing to opt for any other intervention. MATERIALS AND METHODS: A diagnosed patient with metastatic liver disease that included abnormal liver functions and symptomatic presentation was treated with Ayurvedic therapies and was observed for 10 days for any possible changes. RESULTS: A substantial clinical and biochemical improvement was observed in this patient after 10 days of treatment. This improvement was noted to be consistent at a 1-week follow-up after the patient was discharged from the hospital. CONCLUSIONS: This case offers an opportunity to reconsider whether or not the toxic potentials of heavy metals used in Ayurvedic agents outweigh the possible benefits for treating patients with well-defined, incurable clinical conditions. PMID- 22830974 TI - Evaluation of the effectiveness of hospital discharge planning and follow-up in the primary care of patients with chronic obstructive pulmonary disease. AB - AIMS AND OBJECTIVES: To evaluate the effectiveness of protocolised intervention for hospital discharge and follow-up in the primary care of patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: Chronic obstructive pulmonary disease is one of the main causes of morbidity and mortality internationally. DESIGN: A quasi-experimental design was adopted, with a control group and it was pseudorandomised by services. METHODS: Patients with COPD admitted to two tertiary-level public hospitals in Spain were recruited (2007-2008). The outcome variables included: readmission rate, patient satisfaction (LOPSS12), quality of life (St. George's Respiratory Questionnaire) and level of knowledge about COPD. 48 hours after admission, both groups were evaluated by specialist coordinating nurses. At the hospital, a coordinating nurse visited each patient in the experimental group every 24 hours to identify the main caregiver, provide information about the disease, explain treatment, identify care problems and needs and facilitate communication between professionals. 24 hours after discharge, the coordinating nurses informed the primary care nurses about patient discharge. The two nurses made the first home visit together. There were follow up phone calls at 2, 6, 12 and 24 weeks after discharge. A total of 143 patients were recruited (Intervention group=56; Control group=87). RESULTS: The results showed a significant improvement in the evolution of quality of life, at 12 and 24 weeks after discharge; the level of knowledge about COPD revealed significant differences between the groups. There were no differences according to satisfaction or readmission rate. Multivariate analysis (non-conditional logistic regression) showed the intervention to be ineffective in reducing the readmission rate. CONCLUSIONS: The planning of discharge for patients with COPD is effective in terms of improving the patients' quality of life and level of knowledge about the disease. RELEVANCE TO CLINICAL PRACTICE: The characteristics of patients with COPD make it necessary to include them in hospital discharge planning programmes. PMID- 22830975 TI - The experiences of commercial kidney donors: thematic synthesis of qualitative research. AB - Commercial transplantation has expanded because of the shortage of kidneys for transplantation. This study aims to synthesize qualitative studies on the experiences and perspectives of living commercial kidney donors. We conducted a comprehensive literature search in electronic databases to April 2011 and consulted experts to identify unpublished studies. Thematic synthesis was used to analyze the findings. Seven studies involving over 676 commercial kidney donors were included. Three major themes were identified: desperation (the participants' decision to sell their kidney was forced by poverty, debt, or to fulfill a family obligation); despair (destroyed body integrity, shame and secrecy, dehumanized and dispirited, loss of livelihood, heightened sense of vulnerability, disappointment, and regret); and debasement (deception by brokers and recipients, victimized by the hospital, stigmatized by community, and rejected by family). Commercial kidney transplantation is reported to result in ramifications for the donors' mental, physical, and social well-being. Not only do they remain in poverty, they lose dignity, sense of purpose, respect, relationships, and livelihood. Review of this published literature supports the need for effective implementation of the WHO guiding principles and legislated regulation to deter potential recipients and healthcare providers from pursuing commercial transplantation. PMID- 22830976 TI - Rapid quantitative profiling of N-glycan by the glycan-labeling method using 3 aminoquinoline/alpha-cyano-4-hydroxycinnamic acid. AB - Protein glycosylation is a crucial phenomenon for understanding protein functions, since its patterns and degree are associated with many biological processes, such as intercellular signaling and immune response. We previously reported a novel glycan-labeling method using a 3-ainoquinoline/alpha-cyano-4 hydroxycinnamic acid (3-AQ/CHCA) liquid matrix for highly sensitive detection by matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS). In the present study, we examined the practicality of this method for qualitative and quantitative glycan profile analysis. We first investigated the reproducibility of the data for 16 N-glycans prepared from human epidermal growth factor receptor type 2 (HER2). All of the data obtained in intra-assays and interassays were highly correlated with statistical significance (R(2) > 0.9, p < 0.05). In addition, the HER2 glycosylation pattern differed significantly between different breast cancer cell lines SK-BR-3 and BT474 in a comparative analysis of profile data. Finally, the quantitative capability of this method was examined by using PA-labeled monosialylated N-glycan as an internal standard (IS). Using IS for AQ-labeled neutral and sialylated standard glycans, the ion peak intensity was highly linear (R(2) > 0.9) from 0.5 to 5000 fmol. Furthermore, using IS for HER2 N-glycans, all of the N-glycans were highly linear with their dilution factors (R(2) > 0.9). These results suggest that our developed AQ labeling method enabled rapid qualitative and quantitative analyses of glycans. This glycan analysis method should contribute to the field of biomarker discovery and biomedicine in applications such as quality control of biotechnology-based drugs. PMID- 22830978 TI - Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudata. AB - Many algal species contain relatively high concentrations of polysaccharide substances, a number of which have been shown to have anti-inflammatory and/or immunomodulatory activity. In this study, we evaluated the anti-inflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction (PLS) extracted from the algae Gracilaria caudata. The antiinflammatory activity of PLS was evaluated using several inflammatory agents (carrageenan, dextran, bradykinin, and histamine) to induce paw edema and peritonitis in Swiss mice. Samples of the paw tissue and peritoneal fluid were removed to determine myeloperoxidase (MPO) activity or TNF-alpha and IL-1beta levels, respectively. Mechanical hypernociception was induced by subcutaneous injection of carrageenan into the plantar surface of the paw. Pretreatment of mice by intraperitoneal administration of PLS (2.5, 5, and 10 mg/kg) significantly and dose-dependently reduced carrageenan-induced paw edema (p < 0.05) compared to vehicle-treated mice. Similarly, PLS 10 mg/kg effectively inhibited edema induced by dextran and histamine; however, edema induced by bradykinin was unaffected by PLS. PLS 10 mg/kg inhibited total and differential peritoneal leukocyte counts following carrageenan-induced peritonitis. Furthermore, PLS reduced carrageenan-increased MPO activity in paws and reduced cytokine levels in the peritoneal cavity. Finally PLS pretreatment also reduced hypernociception 3-4 h after carrageenan. We conclude that PLS reduces the inflammatory response and hypernociception in mice by reducing neutrophil migration and cytokines concentration. PMID- 22830980 TI - Metabolism and disposition of [14C]n-butyl-p-hydroxybenzoate in male and female Harlan Sprague Dawley rats following oral administration and dermal application. AB - n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring labelled [(14)C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t(1/2) = 3-4 min) and human (t(1/2) = 20-30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [(14)C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well absorbed (>83%) and eliminated chiefly in urine (83-84%); <= 1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation. PMID- 22830977 TI - Finding minimum gene subsets with heuristic breadth-first search algorithm for robust tumor classification. AB - BACKGROUND: Previous studies on tumor classification based on gene expression profiles suggest that gene selection plays a key role in improving the classification performance. Moreover, finding important tumor-related genes with the highest accuracy is a very important task because these genes might serve as tumor biomarkers, which is of great benefit to not only tumor molecular diagnosis but also drug development. RESULTS: This paper proposes a novel gene selection method with rich biomedical meaning based on Heuristic Breadth-first Search Algorithm (HBSA) to find as many optimal gene subsets as possible. Due to the curse of dimensionality, this type of method could suffer from over-fitting and selection bias problems. To address these potential problems, a HBSA-based ensemble classifier is constructed using majority voting strategy from individual classifiers constructed by the selected gene subsets, and a novel HBSA-based gene ranking method is designed to find important tumor-related genes by measuring the significance of genes using their occurrence frequencies in the selected gene subsets. The experimental results on nine tumor datasets including three pairs of cross-platform datasets indicate that the proposed method can not only obtain better generalization performance but also find many important tumor-related genes. CONCLUSIONS: It is found that the frequencies of the selected genes follow a power-law distribution, indicating that only a few top-ranked genes can be used as potential diagnosis biomarkers. Moreover, the top-ranked genes leading to very high prediction accuracy are closely related to specific tumor subtype and even hub genes. Compared with other related methods, the proposed method can achieve higher prediction accuracy with fewer genes. Moreover, they are further justified by analyzing the top-ranked genes in the context of individual gene function, biological pathway, and protein-protein interaction network. PMID- 22830981 TI - Prediction of drug concentration-time profiles of therapeutic proteins in humans from animals. AB - The main objective of this work is to evaluate two methods to predict concentration-time profiles of therapeutic proteins in humans in a multi compartment system using animal pharmacokinetic parameters. The prediction of concentration-time profiles in humans in a multi-compartment system was based on two proposed methods (volumes of distribution and pharmacokinetic constants) of Mordenti. Seven protein drugs (5 monoclonal antibodies, one epoetin, and one thrombin inhibitor) from the literature were chosen that were described by two compartment model in both humans and animals. Two- compartment model parameters (CL, V(c), V(ss), V(beta), alpha, A, beta and B) at least from 3 animals were scaled to humans and then were used to predict plasma concentrations-time profiles in humans. The results showed that both the methods provided almost similar concentration-time profiles for most of the drugs. It appears that the proposed methods of Mordenti can be used for reasonably accurate prediction of concentration-time profiles of therapeutic proteins in humans. PMID- 22830982 TI - Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips. AB - We present characterization of the metabolic performance of human cryopreserved hepatocytes cultivated in a platform of parallelized microfluidic biochips. The RTqPCR analysis revealed that the mRNA levels of the cytochromes P450 (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) were reduced after the adhesion period (when compared to the post-thawing step). The microfluidic perfusion played a part in stabilizing and partially recovering the levels of the HNF4alpha, PXR, OAPT2, CYP 1A2, 2B6, 2C19 and 3A4 mRNA on contrary to non-perfused cultures. Fluorescein diacetate staining and P-gp mRNA level illustrated the hepatocytes' polarity in the biochips. Drug metabolism was assessed using midazolam, tolbutamide, caffeine, omeprazole, dextromethorphan, acetaminophen and repaglinide as probes. Metabolite detection and quantification revealed that CYP1A2 (via the detection of paraxanthine), CYP3A4 (via 1-OH-midazolam, and omeprazole sulfone detection), CYP2C8 (via hydroxyl-repaglinide detection), CYP2C19 (via hydroxy-omeprazole detection) and CYP2D6 (via dextrorphan detection) were functional in our microfluidic configurations. Furthermore, the RTqPCR analysis showed that the drugs acted as inductors leading to overexpression of mRNA levels when compared to post-thawing values (such as for HNF4alpha, PXR and CYP3A4 by dextromethorpahn and omeprazole). Finally, intrinsic in vitro biochip clearances were extracted using a PBPK model for predictions. The biochip predictions were compared to literature in vitro data and in vivo situations. PMID- 22830983 TI - Softer zwitterionic nanogels for longer circulation and lower splenic accumulation. AB - Zwitterionic nanogels of varying stiffness were prepared by tuning their cross linking densities and reactant contents. In vivo studies of these nanogels show that softer nanogels pass through physiological barriers, especially the splenic filtration, more easily than their stiffer counterparts, consequently leading to longer circulation half-life and lower splenic accumulation. Results from this work emphasize the role of stiffness in designing long-circulating nanoparticles. PMID- 22830985 TI - Metastatic small cell neuroendocrine carcinoma of the breast. AB - Cutaneous metastases from internal malignancies in women overwhelmingly emanate from the breast and typically exhibit features of an adenocarcinoma, although other histopathologic patterns may also be seen. Neuroendocrine breast carcinoma represents an uncommon variant of mammary carcinoma with fewer than 40 cases of the small cell subcategory reported. As with other small cell carcinomas, they may exhibit Merkel cell-like features and appropriate diagnosis of these tumor deposits often turns on clinical history and an appropriate immunohistochemical profile. Herein, we report the first known patient with cutaneous metastases from a small cell neuroendocrine breast carcinoma. PMID- 22830984 TI - Knowledge exchange in the Pacific: The TROPIC (Translational Research into Obesity Prevention Policies for Communities) project. AB - BACKGROUND: Policies targeting obesogenic environments and behaviours are critical to counter rising obesity rates and lifestyle-related non-communicable diseases (NCDs). Policies are likely to be most effective and enduring when they are based on the best available evidence. Evidence-informed policy making is especially challenging in countries with limited resources. The Pacific TROPIC (Translational Research for Obesity Prevention in Communities) project aims to implement and evaluate a tailored knowledge-brokering approach to evidence informed policy making to address obesity in Fiji, a Pacific nation challenged by increasingly high rates of obesity and concomitant NCDs. METHODS: The TROPIC project draws on the concept of 'knowledge exchange' between policy developers (individuals; organisations) and researchers to deliver a knowledge broking programme that maps policy environments, conducts workshops on evidence-informed policy making, supports the development of evidence-informed policy briefs, and embeds evidence-informed policy making into organisational culture. Recruitment of government and nongovernment organisational representatives will be based on potential to: develop policies relevant to obesity, reach broad audiences, and commit to resourcing staff and building a culture that supports evidence-informed policy development. Workshops will increase awareness of both obesity and policy cycles, as well as develop participants' skills in accessing, assessing and applying relevant evidence to policy briefs. The knowledge-broking team will then support participants to: 1) develop evidence-informed policy briefs that are both commensurate with national and organisational plans and also informed by evidence from the Pacific Obesity Prevention in Communities project and elsewhere; and 2) collaborate with participating organisations to embed evidence-informed policy making structures and processes. This knowledge broking initiative will be evaluated via data from semi-structured interviews, a validated self-assessment tool, process diaries and outputs. DISCUSSION: Public health interventions have rarely targeted evidence-informed policy making structures and processes to reduce obesity and NCDs. This study will empirically advance understanding of knowledge broking processes to extend evidence-informed policy making skills and develop a suite of national obesity-related policies that can potentially improve population health outcomes. PMID- 22830986 TI - Improved model systems for bacterial membranes from differing species: the importance of varying composition in PE/PG/cardiolipin ternary mixtures. AB - Steady-state fluorescence anisotropy and dynamic light scattering (DLS) were used to determine the thermotropic properties of lipid systems that act as models for bacterial membranes of Yersinia kristensenii and Proteus mirabilis. Lipid proportions of PE:PG:CL of 0.60:0.20:0.20 and 0.80:0.15:0.05, were used in order to mimic these two membranes respectively. We observed that the introduction of cardiolipin (CL) as a third lipid component of any PE:PG mixture, changes the system's properties considerably. The results obtained by these two techniques show that the main transition temperatures obtained are undoubtedly CL-dependent. Additionally AFM experiments were performed and these results show that even at small concentration CL produces important changes not only in the membrane thermotropic properties, but also in the bilayer structure. In summary, we were able to compare how low and high CL concentration affect bacterial membrane model system properties which can provide a further explanation for the different antibiotic susceptibilities reported for Y. kristensenii and P. mirabilis. PMID- 22830987 TI - Body mass index and the efficacy of needle-free jet injection for the administration of rapid-acting insulin analogs, a post hoc analysis. AB - We recently showed in a euglycaemic glucose clamp study among 18 healthy volunteers that using jet injectors rather than conventional pens significantly improved the time-action profiles of rapid-acting insulin analogs. Here, we investigated whether such profiles were modified by body mass index (BMI) and related weight parameters by comparing insulin administration by jet injection to that by conventional pen in subgroups defined by BMI, waist-to-hip ratio, waist circumference and insulin dose. After conventional administration, times to peak insulin levels (T-INS(max)) occurred 31.1 [95% confidence interval (CI) 13.7 48.5] min later and time to maximum glucose requirement (T-GIR(max)) 56.9 (95%CI 26.6-87.3) min later in more obese (BMI > 23.6 kg/m(2)) than in lean subjects (BMI < 23.6 kg/m(2)). In contrast, T-INS(max) and T-GIR(max) were similar in subjects with high and low BMI, when insulin was administered by jet injection. We conclude that using jet injection for insulin administration may especially benefit subjects with higher body weight. PMID- 22830988 TI - Expression of autophagy 8 (Atg8) and its role in the midgut and other organs of the greater wax moth, Galleria mellonella, during metamorphic remodelling and under starvation. AB - A 345 base pair cDNA encoding autophagy 8 (Atg8) of Galleria mellonella (GmAtg8) was cloned and sequenced. The deduced protein was estimated to be 118 amino acids long. Structural comparison and phylogenetic analysis showed that GmAtg8 belong to the Atg8 family of ubiquitin-like proteins. It is predicted to contain four beta-sheets and four alpha-helices. It also contains a highly conserved glycine residue at the C-terminal, as well as highly conserved Phe77 and Ph79 at a recognition cleavage site of Atg4 and Tyr49, and Leu50 at a site for activation of the lipidated form of Atg8 by Atg7 and Atg3. The developmental expression profile demonstrated that GmAtg8 transcript and its protein products are expressed in such organs as the midgut, ovary, Malpighian tubules, fat body and silk gland. In the midgut and silk gland, GmAtg8 transcript and its protein products increased during metamorphosis and under starvation, but decreased after re-feeding. Expression of autophagy seems to precede apoptosis in the midgut transformation from larva to pupa and pupa to adult during metamorphosis. Some waves overlap with apoptotic waves, particularly at early stages, but others are unique in terms of site and timing. PMID- 22830989 TI - Donor race and outcomes in kidney transplant recipients. AB - BACKGROUND: African Americans are at greater risk to reach end-stage renal disease and this risk may carry over in a kidney transplant recipient after kidney transplantation. METHODS: Linking the five-yr patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, we identified 13 692 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function risks were estimated by Cox's regression (hazard ratio [HR] and 95% confidence interval) and logistic regression, respectively. RESULTS: Patients were 48 +/- 14 yr old and included 39% women and 26% patients with diabetes. After adjusting for several relevant clinical and transplant-related variables, African American donor race was associated with higher all-cause mortality, with HR of 1.39 (1.09-1.78) for all-cause mortality, 1.80 (1.17-2.76) for cardiovascular mortality, 1.30 (1.03 1.64) for death-censored graft loss and 1.31 (1.10-1.57) for combined outcome over the six-yr observation period. In the non-African American recipient subcohort, but not in the African American recipient subcohort, African American donor race was associated with higher risk of death-censored graft loss (2.24 [1.44-3.49]) in our fully adjusted model. CONCLUSIONS: African American donor race was associated with increased all-cause and cardiovascular mortality and graft loss. PMID- 22830990 TI - Inhibitors of TLR-4, NF-kappaB, and SAPK/JNK signaling reduce the toxic effect of lipopolysaccharide on RAW 264.7 cells. AB - The present study was designed to examine and compare the effects of three suppressors on the cytokine response in tandem with examining: the synthesis of inducible forms of heat shock proteins; HSP72 and HSP90alpha; activities of NF kappaB and SAPK/JNK signaling pathways; and TLR4 expression. Pre-treatment with inhibitors offers promise as protective means to lower the activity of these cascades, thereby circumventing the formation of excessive amounts of pro inflammatory molecules. Three inhibitors of TLR4, SAPK/JNK, and NF-kappaB signaling, namely CLI-095, SP600125, and IKK Inhibitor XII, respectively, were added to cultured RAW 264.7 macrophages before the Escherichia coli lipopolysaccharide (LPS) application. Treatments of RAW 264.7 cells with each of the inhibitors resulted in a reduced response to LPS as was visualized by a decrease of TNF-alpha, IL-1, and IFN-gamma production. In addition, inhibitors of the NF-kappaB and SAPK/JNK signaling reduced IL-6 production in LPS-treated cells, whereas the IKK inhibitor XII also decreased IL-10 production. Further, the NO production in LPS-stimulated macrophages was significantly reduced following application of CLI-095 or IKK inhibitor XII. The results also showed that the inhibitors suppressed TLR4 production and decreased phosphorylation of NF-kappaB and SAPK/JNK proteins, thereby preventing the activation NF-kappaB and SAPK/JNK signaling pathways in LPS-activated cells. In addition, the production of inducible heat shock proteins, HSP72 and HSP90-alpha, was reduced in LPS stimulated RAW 264.7 cells pre-treated with inhibitors. These results suggest that inhibitors CLI-095, SP600125, and IKK inhibitor XII demonstrate potential effectiveness in the reduction of the inflammatory response by mechanisms involving both the cellular defense system and cellular signaling. In conclusion, suppressor of NF-kappaB cascade, IKK inhibitor XII, seems to be the most effective anti-toxic agent among studied inhibitors. PMID- 22830991 TI - Comparison of the effect of calcium gluconate and batroxobin on the release of transforming growth factor beta 1 in canine platelet concentrates. AB - BACKGROUND: The clinical use of autologous platelet concentrates (also known as platelet-rich plasma) on the field of regenerative therapy, in the last decade has been the subject of several studies especially in equine medicine and surgery. The objectives of this study was: 1) to describe and compare the cellular population in whole blood, lower fraction (A) and upper fraction (B) of platelet concentrates, 2) to measure and compare the transforming growth factor beta 1 (TGF-beta1) concentration in plasma and both platelet concentrates after be activated with calcium gluconate or batroxobin plus calcium gluconate and, 3) to determine correlations between cell counts in platelet concentrates and concentrations of TGF-beta1. Blood samples were taken from 16 dogs for complete blood count, plasma collection and platelet concentrates preparation. The platelet concentrates (PC) were arbitrarily divided into two fractions, specifically, PC-A (lower fraction) and PC-B (upper fraction). The Platelet concentrates were analyzed by hemogram. After activated with calcium gluconate or batroxobin plus calcium gluconate, TGF-beta1 concentration was determined in supernatants of platelet concentrates and plasma. RESULTS: There were differences statistically significant (P < 0.05) for the platelet count and leukocyte count and TGF-beta1 concentration between whole blood, plasma and both platelet concentrates. A significant correlation was found between the number of platelets in both platelet concentrates and TGF-beta1 concentration. Platelet collection efficiency was 46.34% and 28.16% for PC-A and PC-B, respectively. TGF-beta1 concentration efficiency for PC activated with calcium gluconate was 47.75% and 31.77%, for PC-A and PC-B, respectively. PC activated with batroxobin plus CG showed 46.87% and 32.24% for PC-A and PC-B, respectively. CONCLUSIONS: The methodology used in this study allows the concentration of a number of platelets and TGF-beta1 that might be acceptable for a biological effect for clinical or experimental use as a regenerative therapy in dogs. PMID- 22830993 TI - High molecular weight poly(butylene succinate-co-butylene furandicarboxylate) copolyesters: from catalyzed polycondensation reaction to thermomechanical properties. AB - Novel potentially biobased aliphatic-aromatic copolyesters poly(butylene succinate-co-butylene furandicarboxylate) (PBSFs) in full composition range were successfully synthesized from 2,5-furandicarboxylic acid (FA), succinic acid (SA), and 1,4-butanediol (BDO) via an esterification and polycondensation process using tetrabutyl titanate (TBT) or TBT/La(acac)(3) as catalyst. The copolyesters were characterized by size exclusion chromatography (SEC), Fourier transform infrared (FTIR), (1)H NMR, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), and their tensile properties were also evaluated. The weight average molecular weight (M(w)) ranges from 39,000 to 89,000 g/mol. The copolyesters are random copolymers whose composition is well controlled by the feed ratio of the diacid monomers. PBSFs have excellent thermal stability. The glass transition temperature (T(g)) increases continuously with phi(BF) and agrees well with the Fox equation. The crystallizability and T(m) decrease with increasing butylene furandicarboxylate (BF) unit content (phi(BF)) from 0 to 40 mol %, but rise again at phi(BF) of 50-100 mol %. Consequently, the tensile modulus and strength decrease, and the elongation at break increases with phi(BF) in the range of 0-40 mol %. At higher phi(BF), the modulus and strength increase and the ultimate elongation decreases. Thus, depending on phi(BF), the structure and properties of PBSFs can be tuned ranging from crystalline polymers possessing good tensile modulus (360-1800 MPa) and strength (20-35 MPa) to nearly amorphous polymer of low T(g) and high elongation (~600%), and therefore they may find applications in thermoplastics as well as elastomers or impact modifiers. PMID- 22830992 TI - Development and validation of a high-content screening assay to identify inhibitors of cytoplasmic dynein-mediated transport of glucocorticoid receptor to the nucleus. AB - Rapid ligand-induced trafficking of glucocorticoid nuclear hormone receptor (GR) from the cytoplasm to the nucleus is an extensively studied model for intracellular retrograde cargo transport employed in constructive morphogenesis and many other cellular functions. Unfortunately, potent and selective small molecule disruptors of this process are lacking, which has restricted pharmacological investigations. We describe here the development and validation of a 384-well high-content screening (HCS) assay to identify inhibitors of the rapid ligand-induced retrograde translocation of cytoplasmic glucocorticoid nuclear hormone receptor green fluorescent fusion protein (GR-GFP) into the nuclei of 3617.4 mouse mammary adenocarcinoma cells. We selected 3617.4 cells, because they express GR-GFP under the control of a tetracycline (Tet)-repressible promoter and are exceptionally amenable to image acquisition and analysis procedures. Initially, we investigated the time-dependent expression of GR-GFP in 3617.4 cells under Tet-on and Tet-off control to determine the optimal conditions to measure dexamethasone (Dex)-induced GR-GFP nuclear translocation on the ArrayScan-VTI automated imaging platform. We then miniaturized the assay into a 384-well format and validated the performance of the GR-GFP nuclear translocation HCS assay in our 3-day assay signal window and dimethylsulfoxide validation tests. The molecular chaperone heat shock protein 90 (Hsp90) plays an essential role in the regulation of GR steroid binding affinity and ligand-induced retrograde trafficking to the nucleus. We verified that the GR-GFP HCS assay captured the concentration-dependent inhibition of GR-GFP nuclear translocation by 17-AAG, a benzoquinone ansamycin that selectively blocks the binding and hydrolysis of ATP by Hsp90. We screened the 1280 compound library of pharmacologically active compounds set in the Dex-induced GR-GFP nuclear translocation assay and used the multi-parameter HCS data to eliminate cytotoxic compounds and fluorescent outliers. We identified five qualified hits that inhibited the rapid retrograde trafficking of GR-GFP in a concentration-dependent manner: Bay 11-7085, 4-phenyl-3-furoxancarbonitrile, parthenolide, apomorphine, and 6-nitroso-1,2-benzopyrone. The data presented here demonstrate that the GR GFP HCS assay provides an effective phenotypic screen and support the proposition that screening a larger library of diversity compounds will yield novel small molecule probes that will enable the further exploration of intracellular retrograde transport of cargo along microtubules, a process which is essential to the morphogenesis and function of all cells. PMID- 22830994 TI - Copper(I)-catalyzed regio- and chemoselective single and double addition of nucleophilic silicon to propargylic chlorides and phosphates. AB - Copper(I)-catalyzed propargylic substitution of linear precursors with (Me(2)PhSi)(2)Zn predominantly yields the gamma isomer independent of the propargylic leaving group. The thus formed allenylic silane reacts regioselectively with another equivalent of (Me(2)PhSi)(2)Zn, yielding a bifunctional building block with allylic and vinylic silicon groups. The reaction rates of both steps are well-balanced for chloride (gamma:alpha >= 99:1) where the propargylic displacement occurs quantitatively prior to the addition step. Substitutions of alpha-branched propargylic phosphates are also reported. PMID- 22830995 TI - Global-mean temperature change from shipping toward 2050: improved representation of the indirect aerosol effect in simple climate models. AB - We utilize a range of emission scenarios for shipping to determine the induced global-mean radiative forcing and temperature change. Ship emission scenarios consistent with the new regulations on nitrogen oxides (NO(x)) and sulfur dioxide (SO(2)) from the International Maritime Organization and two of the Representative Concentration Pathways are used as input to a simple climate model (SCM). Based on a complex aerosol-climate model we develop and test new parametrizations of the indirect aerosol effect (IAE) in the SCM that account for nonlinearities in radiative forcing of ship-induced IAE. We find that shipping causes a net global cooling impact throughout the period 1900-2050 across all parametrizations and scenarios. However, calculated total net global-mean temperature change in 2050 ranges from -0.03[-0.07,-0.002] degrees C to -0.3[ 0.6,-0.2] degrees C in the A1B scenario. This wide range across parametrizations emphasizes the importance of properly representing the IAE in SCMs and to reflect the uncertainties from complex global models. Furthermore, our calculations show that the future ship-induced temperature response is likely a continued cooling if SO(2) and NO(x) emissions continue to increase due to a strong increase in activity, despite current emission regulations. However, such cooling does not negate the need for continued efforts to reduce CO(2) emissions, since residual warming from CO(2) is long-lived. PMID- 22830996 TI - Base-catalyzed dehydration of 3-substituted benzene cis-1,2-dihydrodiols: stabilization of a cyclohexadienide anion intermediate by negative aromatic hyperconjugation. AB - Evidence that a 1,2-dihydroxycyclohexadienide anion is stabilized by aromatic "negative hyperconjugation" is described. It complements an earlier inference of "positive" hyperconjugative aromaticity for the cyclohexadienyl cation. The anion is a reactive intermediate in the dehydration of benzene cis-1,2-dihydrodiol to phenol. Rate constants for 3-substituted benzene cis-dihydrodiols are correlated by sigma(-) values with rho = 3.2. Solvent isotope effects for the reactions are k(H(2)O)/k(D(2)O) = 1.2-1.8. These measurements are consistent with reaction via a carbanion intermediate or a concerted reaction with a "carbanion-like" transition state. These and other experimental results confirm that the reaction proceeds by a stepwise mechanism, with a change in rate-determining step from proton transfer to the loss of hydroxide ion from the intermediate. Hydrogen isotope exchange accompanying dehydration of the parent benzene cis-1,2 dihydrodiol was not found, and thus, the proton transfer step is subject to internal return. A rate constant of ~10(11) s(-1), corresponding to rotational relaxation of the aqueous solvent, is assigned to loss of hydroxide ion from the intermediate. The rate constant for internal return therefore falls in the range 10(11)-10(12) s(-1). From these limiting values and the measured rate constant for hydroxide-catalyzed dehydration, a pK(a) of 30.8 +/- 0.5 was determined for formation of the anion. Although loss of hydroxide ion is hugely exothermic, a concerted reaction is not enforced by the instability of the intermediate. Stabilization by negative hyperconjugation is proposed for 1,2 dihydroxycyclohexadienide and similar anions, and this proposal is supported by additional experimental evidence and by computational results, including evidence for a diatropic ("aromatic") ring current in 3,3-difluorocyclohexadienyl anion. PMID- 22830997 TI - Development and clinical evaluation of Prevnar 13, a 13-valent pneumocococcal CRM197 conjugate vaccine. AB - Pneumococcus is the leading cause of bacterial illness in children worldwide. The development, clinical evaluation, and postlicensure impact of the pneumococcal CRM(197) protein conjugate vaccine, PCV13, (Prevnar 13(r)) builds upon the excellent safety and substantial effectiveness of PCV7 (Prevnar(r)) in preventing pneumococcal disease in children. PCV13 adds pneumococcal serotypes 1, 3, 5, 6A, 7F, and 19A to serotypes 4, 6B, 9V, 14, 18C, 19F, 23F in PCV7 to provide comprehensive coverage for over 85% of epidemiologically important pneumococcal serotypes in the United States and throughout the world. PCV13 development required demonstration of immunologic responses to the 13 serotypes contained in the vaccine that were noninferior to the responses elicited by PCV7, and demonstration of a satisfactory safety profile. Studies were also performed to demonstrate compatibility with other childhood vaccines. Now licensed in many countries worldwide, PCV13 shows significant promise for expanded protection against pneumococcal disease in children. PMID- 22830998 TI - Analysis of sequence, structure of GAPDH of Leishmania donovani and its interactions. AB - Drug resistance acquired by Leishmania donovani (Ldv) is a major problem in the treatment and control of visceral leishmaniasis (VL). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a major glycolytic enzyme has been targeted as is found in other protozoan which cause diseases like sleeping sickness. GAPDH gene of Ldv (AG83 strain) was amplified, sequenced, and modeled on the basis of crystal structure of Leishmania mexicana. The model of the Ldv GAPDH exhibited NAD binding domain with Rossmann folding. Virtual screening of different experimentally proved compounds with the crystal and the modeled structures of GAPDH of Leishmania strains revealed diverse binding affinities of different compounds. Comparison of binding affinities (based on different programs) of compounds revealed that discovery studio v2.5 (Ligandfit) was able to predict the most hit compounds, the best hit compounds against GAPDH of Leishmania strains are hydrazine, vetrazine, and benzyl carbazate. It is predicted that patients suffering from both VL and cardiac disorders (atrial fibrillation) may benefit if they are treated with warfarin in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome. PMID- 22830999 TI - Expression of ENaC in LPS-induced inflammation of middle ear mucosa. AB - CONCLUSION: The expression of all three subunits of the epithelial sodium channel (ENaC) decreased after the lipopolysaccharide (LPS) injection and normalized as the fluid collection resolved. This implies that fluid collection in acute otitis media may be caused by the inhibition of ENaC function. OBJECTIVES: We investigated the expression levels of subunits of ENaC after an injection of LPS into the middle ear cavity of rats. METHODS: Seventy-two Sprague-Dawley rats were assigned randomly into the five groups that received an LPS injection and the control group. A transtympanic injection of LPS (1 mg/ml) was done and rats were sacrificed 6, 12, 24, 72, and 120 h after the procedure. Real-time RT-PCR was carried out for ENaC-alpha, -beta, -gamma, and immunohistochemistry was performed for ENaC-alpha and -beta. RESULTS: The level of ENaC-alpha expression decreased 0.50-fold and 0.55-fold at 6 and 12 h, respectively (p < 0.05), but it normalized at 24 h. It increased 3.64-fold at 72 h and 3.24-fold at 120 h (p < 0.05). At 6 and 12 h after the LPS injection into the middle ear cavity, inflammation was induced and ENaC-alpha immunoreactivity decreased. At 24 h, ENaC-alpha immunoreactivity was normalized, then at 72 and 120 h after the injection it was increased. PMID- 22831154 TI - Inferring transcript phylogenies. AB - Alternative splicing, an unknown mechanism 20 years ago, is now recognized as a major mechanism for proteome and transcriptome diversity, particularly in mammals some researchers conjecture that up to 90% of human genes are alternatively spliced. Despite much research on exon and intron evolution, little is known about the evolution of transcripts. In this paper, we present a model of transcript evolution and an associated algorithm to reconstruct transcript phylogenies. The evolution of the gene structure-exons and introns-is used as basis for the reconstruction of transcript phylogenies. We apply our model and reconstruction algorithm on two well-studied genes, MAG and PAX6, obtaining results consistent with current knowledge and thereby providing evidence that a phylogenetic analysis of transcripts is feasible and likely to be informative. PMID- 22831155 TI - Neuroinflammation: a contributing factor to the pathogenesis of cancer cachexia. AB - The clinical journey of cancer patients is frequently complicated by the development of a complex and multifaceted syndrome, the main features of which are reduced appetite, decreased food intake, progressive weight loss, and wasting of muscle mass and adipose tissue, which is not prevented by the provision of calories and proteins. This syndrome, termed Cachexia, is responsible for increased morbidity, reduced survival, and impinged quality of life of cancer patients. The pathogenesis is complex and involves deranged metabolism of peripheral tissues and profound alterations of brain neurochemistry. Recent studies indicate that brain neurochemistry is perturbed during tumor growth by cancer-induced increased intrahypothalamic expression of proinflammatory cytokines. The attending neurochemical chaos mediates the anorexigenic behavioral responses associated to cancer cachexia, but recent data seem to suggest that neuronal output also may be involved in the metabolic changes occurring at the peripheral level. PMID- 22831156 TI - Counteracting inflammation: a promising therapy in cachexia. AB - Disease progression in cancer is dependent on the complex interaction between the tumor and the host inflammatory response. Indeed, both the tumor and the patient produce cytokines that act on multiple target sites such as bone marrow, myocytes, hepatocytes, adipocytes, endothelial cells, and neurons, where they produce a complex cascade of biological responses leading to the wasting associated with cachexia. The cytokines that have been involved in this cachectic response are TNF-alpha, IL-1, IL-6, and interferon-gamma. Interestingly, these cytokines share the same metabolic effects, and their activities are closely interrelated. In many cases these cytokines exhibit synergic effects when administered together. Therefore, therapeutic strategies- either nutritional or pharmacological-have been based on either blocking their synthesis or their action. PMID- 22831157 TI - Is tissue cross-talk important in cancer cachexia? AB - Recent work suggests molecular cross-talk between adipose tissue and muscle that occurs through adipokines and myokines. These molecules act in an endocrine fashion to play an intricate role in regulating body composition in both health and disease. Studies in exercise physiology have focused on the molecular cross talk between adipose tissue and muscle that occurs through adipokines and myokines and on the role these molecules may play in chronic diseases. Similarly, integrative physiology in obesity and diabetes has long emphasised the importance of chronic inflammation, increased adipocyte lipolysis, and increased levels of circulating free fatty acids in the adipose-muscle cross-talk that contributes to lipotoxicity and insulin resistance in muscle. Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, quality of life, and duration of survival. Although cachexia in patients with cancer is characterized by systemic inflammation, increased lipolysis, insulin resistance, and reduced physical activity, there has been little effort to manipulate the integrative physiology of adipose tissue and muscle tissue for therapeutic gain. PMID- 22831158 TI - Efficacy of ghrelin in cancer cachexia: clinical trials and a novel treatment by rikkunshito. AB - Cachexia is characterized by decreased food intake, increased energy expenditure, and muscle wasting. It is observed in 80% of patients with advanced-stage cancer and is a major source of decreased quality of life and increased morbidity and mortality in cancer patients. Ghrelin plays an important role in stimulating hunger and maintaining energy homeostasis and is the first-line treatment option for cancer cachexia. Several studies in rodent models and clinical trials have demonstrated that ghrelin or ghrelin receptor (GHS-R) agonists are effective in the treatment of cancer cachexia; however, further large-scale long-term clinical trials are needed to confirm sustained effects. Recently, the traditional Japanese medicine rikkunshito has been shown to increase food intake in rats with cancer or administered chemotherapeutics. The orexigenic effect of rikkunshito is involved in the stimulation of endogenous ghrelin secretion by blocking the serotonin (5-HT) 2b/2c receptor pathway and the enhancement of GHS-R activity. A potentiator of ghrelin signaling such as rikkunshito may represent a novel approach for the treatment of cancer cachexia. PMID- 22831159 TI - Therapeutic exercise in cancer cachexia. AB - This review takes into account experimental and clinical evidence to provide an overview of the rationale for the use of exercise in cancer cachexia, its clinical application, and future developments. Studies targeting cachectic patients have demonstrated that even in advanced disease peripheral muscle has the capacity to respond to exercise training. Effects of exercise include enhancing muscle protein synthesis, attenuating the catabolic effects of cachexia, and modulating levels of inflammation. Nonetheless, there are challenges in applying therapeutic exercise, particularly once cachexia is established, and not all patients are able or willing to undertake programs currently being offered. Strategies to make exercise a more accessible therapy are required and could include offering it earlier in the course of the disease, at lower intensities, and in various forms, including novel approaches. In conclusion, the use of therapeutic exercise has a sound rationale, even in patients with advanced disease and cachexia, and has the potential to help maintain or slow the loss of physical function. Because of practical issues with its application, further study is required to examine if the benefits achieved in small studies can be translated to a wider clinical population. PMID- 22831160 TI - The cachexia clinic: from staging to managing nutritional and functional problems in advanced cancer patients. AB - Panels of experts have agreed on the definition of cancer cachexia stages (CCS). We evaluated the clinical relevance of these stages and proposed ways to apply the CCSs to the clinical practice via standardized methods. The CCS were applied to 207 patients with advanced non-small-cell lung or gastrointestinal cancers from the Human Cancer Cachexia Database via consensus among the coauthors. Patients were categorized as noncachectic, precachectic, cachectic, and in refractory cachexia. Through analysis of variance, chi2, and Kaplan-Meier analyses, we tested the relationships between CCSs and selected outcomes. The CCS were significantly correlated (P < 0.05) with patient-centered indicators, including overall symptom burden, quality of life, tolerability to chemotherapy, body composition, hospital stay, and survival. However, precachectic and cachectic patients behaved similarly in all these outcomes but were significantly different from noncachectic and refractory cachectic patients. The average scores for the abridged Patient-Generated Subjective Global Assessment (aPG-SGA) corresponded well with the CCSs and reflected nicely the cut-off scores recommended for the nutritional triage of cancer patients. In addition to the aPG SGA, we proposed the Edmonton Symptom Assessment System and routine laboratory tests for the triage of patients with refractory cachexia, for whom comfort care is the primary goal. The cachexia clinic hosted by the McGill Nutrition and Performance Laboratory offers a model for diagnosing more precisely the pathophysiology and severity of precachectic and cachectic conditions. The cachexia clinic, by working closely with palliative care programs, may offer the best environment for a comprehensive and personalized approach to the nutritional and functional problems in advanced cancer patients. PMID- 22831161 TI - Multitargeted treatment of cancer cachexia. AB - Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. The prominent clinical feature of cachexia is weight loss in adults. Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown frequently are associated with cachexia. One single therapy may not be completely successful in the treatment of cachexia because of the complexity of the pathogenesis and symptoms of the cachexia syndrome. Among effective treatments, progestogens currently are considered the best available treatment option and are the only approved drugs in Europe for the treatment of cancer- and AIDS-related cachexia. However, they have limited efficacy in treating cancer cachexia. However, thalidomide, selective COX-2 inhibitors, ghrelin mimetics, and selective androgen receptor modulators showed promising results but should be defined further and confirmed in clinical trials. Therefore, to date, despite several years of coordinated efforts in basic and clinical research, the practice guidelines for the prevention and treatment of cancer-related anorexia cachexia syndrome (CACS) are lacking. The management of CACS is a complex challenge that should address the different causes underlying this clinical event. Recent studies showed that integrated, multitargeted approaches are more effective than single-agent approaches for the treatment of CACS. Further clinical trials to improve and refine current strategies to counteract cancer cachexia using multimodal interventions, including nutritional supplementation, anabolic agents, and antiinflammatory drugs along with an appropriate physical exercise program, are warranted. PMID- 22831162 TI - Cancer cachexia: from molecular mechanisms to patient's care. AB - Cancer cachexia is a disabling syndrome because of the complex interactions between the tumor, host metabolism, and proinflammatory cytokines that increases patients' morbidity and mortality. Considering the recent new definition and classification of cachexia, we aimed to review cancer cachexia from its underlying mechanisms to the clinical approach. Cancer cachexia is featured by a disruption in energy balance, metabolic changes, a decrease in fat mass, depletion of skeletal muscle mass, and perturbations in proinflammatory cytokines. Diagnostic effort should be focused on the recognition of precachexia to prevent or delay changes in body composition and nutritional complications secondary to cancer. From the point of disease diagnosis, every cancer patient needs continuous monitoring to receive effective, tailored nutritional and metabolic support. To date, practical guidelines to counteract cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. A single therapy may not be effective; only a multimodal approach involving different treatment combinations is more likely to be successful in the prevention and treatment of cancer cachexia. PMID- 22831163 TI - Preface: cancer cachexia, from basic research to clinical application: a paradigmatic translational research journey. PMID- 22831164 TI - Living kidney donors--a prospective study of quality of life before and after kidney donation. AB - Although the safety of living kidney donation has been well established, prospective studies examining the physical and psychosocial aspects of the donor's quality of life are still scarce. Thus, the purpose of this prospective work was to assess the quality of life of 50 consecutive donors before and after kidney transplantation. All donors were asked to respond to both a donor questionnaire and the short-form 36-item health survey (SF-36). Interviews were individually conducted before, three months after, and over one yr after transplantation. Donation was considered a positive experience by all patients and had no impact on any physical or psychosocial aspect of the donor's life. Improved self-esteem and better quality of life after donation were reported in 52% of the cases. All donors would donate again and encouraged donation. SF-36 data indicated improvement in post-donation mental and physical scores among living donors closely related to recipient. Overall, most donors had a positive experience, felt no changes in quality of life, experienced enhanced self-esteem, would donate again, and recommended donation. PMID- 22831165 TI - Household knowledge, attitudes and practices related to pet contact and associated zoonoses in Ontario, Canada. AB - BACKGROUND: Many human infections are transmitted through contact with animals (zoonoses), including household pets. Although pet ownership is common in most countries and non-pet owners may have frequent contact with pets, there is limited knowledge of the public's pet contact practices and awareness of zoonotic disease risks from pets. The objective of this study was to characterize the general public's knowledge, attitudes and risks related to pet ownership and animal contact in southern Ontario, Canada. METHODS: A self-administered questionnaire was distributed to individuals at two multi-physician clinics in Waterloo, Ontario, Canada during 2010. A single adult from each household was invited to participate in the study. RESULTS: Seventy five percent (641/853) of individuals approached completed the questionnaire. Pet ownership and contact were common; 64% of participants had a pet in their household and 37% of non-pet owning households had a member with at least weekly animal contact outside the home. Pet ownership was high (55%) for households with individuals at higher risk for infections (i.e., < 5 yrs, >= 65 yrs, immunocompromised). Most respondents (64%) indicated that they had never received information regarding pet-associated disease risks. When given a list of 11 infectious pathogens, respondents were only able to correctly classify just over half on their potential to be transmitted from pets to people (mean 6.4); independently, pet owners and those who recalled receiving information in the past about this topic were able to make significantly more correct identifications. Pet (36%) and non-pet owning households (10%) reported dog or cat bites or scratches during the preceding year. Households with individuals at higher risk for an infection did not differ from the remaining households regarding their perceived disease risk of pets, zoonotic disease knowledge, recall of being asked by their medical provider if they owned any pets, or recall of having received information regarding pet associated disease risks and preventive measures. CONCLUSIONS: These results suggest that there is a need for accessible zoonotic disease information for both pet and non-owning households, with additional efforts made by veterinary, human and public health personnel. Immediate educational efforts directed toward households with individuals at higher risk to infections are especially needed. PMID- 22831166 TI - Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk. AB - AIM: To examine the impact of diabetes duration, chronic pancreatitis and other factors on pancreatic cancer risk. METHODS: This retrospective cohort study using the UK General Practice Research Database compared pancreatic cancer incidence and risk in patients with type 2 diabetes mellitus (T2DM) versus patients without diabetes. Multivariate Cox regression adjusting for age, sex, history of chronic pancreatitis, gallbladder disease, obesity, smoking and alcohol use and Charlson comorbidity index was used to estimate hazard ratio (HR) [95% confidence interval, CI]. Analyses were repeated using various time windows for diabetes duration. RESULTS: A total of 1903 incident pancreatic cancers were identified, 436 in patients with T2DM (78.76 per 100 000 person-years [95% CI: 71.54, 86.51]) and 1467 in patients without diabetes (11.46 per 100 000 person-years [10.88, 12.06]). Pancreatic cancer risk was significant for T2DM (adjusted HR 1.80 [1.52, 2.14]), increasing age, history of chronic pancreatitis and tobacco use. For patients with chronic pancreatitis and T2DM, the adjusted HR was 12.12 [6.02, 24.40]. Incidence was highest in patients with >=5 year duration of T2DM. In patient populations with duration of T2DM ranging from >=1 to >=5 years, adjusted HRs remained significant but point estimates attenuated slightly with longer duration of T2DM. CONCLUSIONS: Patients with T2DM had an 80% increased risk of pancreatic cancer versus patients without diabetes. Patients with T2DM and chronic pancreatitis were 12 times more likely to develop pancreatic cancer. PMID- 22831167 TI - Model membrane platforms to study protein-membrane interactions. AB - Constituting functional interactions between proteins and lipid membranes is one of the essential features of cellular membranes. The major challenge of quantitatively studying these interactions in living cells is the multitude of involved components that are difficult, if not impossible, to simultaneously control. Therefore, there is great need for simplified but still sufficiently detailed model systems to investigate the key constituents of biological processes. To specifically focus on interactions between membrane proteins and lipids, several membrane models have been introduced which recapitulate to varying degrees the complexity and physicochemical nature of biological membranes. Here, we summarize the presently most widely used minimal model membrane systems, namely Supported Lipid Bilayers (SLBs), Giant Unilamellar Vesicles (GUVs) and Giant Plasma Membrane Vesicles (GPMVs) and their applications for protein-membrane interactions. PMID- 22831168 TI - Genotyping and surveillance for scrapie in Finnish sheep. AB - BACKGROUND: The progression of scrapie is known to be influenced by the amino acid polymorphisms of the host prion protein (PrP) gene. There is no breeding programme for TSE resistance in sheep in Finland, but a scrapie control programme has been in place since 1995. In this study we have analysed PrP genotypes of total of 928 purebred and crossbred sheep together with the data of scrapie survey carried out in Finland during 2002-2008 in order to gain knowledge of the genotype distribution and scrapie prevalence in Finnish sheep. RESULTS: The ARQ/ARQ genotype was the most common genotype in all breeds studied. ARR allele frequency was less than 12% in purebred Finnish sheep and in most genotypes heterozygous for ARR, the second allele was ARQ. The VRQ allele was not detected in the Grey race sheep of Kainuu or in the Aland sheep, and it was present in less than 6% of the Finnish Landrace sheep. Leucine was the most prominent amino acid found in codon 141. In addition, one novel prion dimorphisms of Q220L was detected. During the scrapie survey of over 15 000 sheep in 2002-2008, no classical scrapie cases and only five atypical scrapie cases were detected. CONCLUSIONS: The results indicate that the Finnish sheep populations have genetically little resistance to classical scrapie, but no classical scrapie was detected during an extensive survey in 2002-2008. However, five atypical scrapie cases emerged; thus, the disease is present in the Finnish sheep population at a low level. PMID- 22831169 TI - Generic method for attaching biomolecules via avidin-biotin complexes immobilized on films of regenerated and nanofibrillar cellulose. AB - We investigated the adsorption and chemical conjugation of avidin and its deglycosylated form, neutravidin, on films of regenerated and nanofibrillar cellulose. The dynamics and extent of biomolecular attachment were monitored in situ by quartz crystal microbalance microgravimetry and ex situ via surface analyses with atomic force microscopy and X-ray photoelectron spectroscopy. The installation of carboxyl groups on cellulose after modification with carboxymethylated cellulose (CMC) or TEMPO-oxidation significantly increases physisorption of avidins, which can be then covalently conjugated by using 1 ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride/N-hydroxysuccinimide (EDS/NHS) coupling chemistries. The developed cellulose-avidin biointerfaces are able to scavenge biotinylated molecules from solution as demonstrated by successful surface complexation of biotinylated bovine serum albumin (Biotin-BSA) and antihuman immunoglobulin G (Biotin-anti-hIgG). Finally, we show that cellulose substrates carrying immobilized anti-hIgG are effective in detecting human immunoglobulin G (hIgG) from fluid matrices. PMID- 22831170 TI - Serum levels of metalloproteinases and their inhibitors during infection with pathogens having integrin receptor-mediated cellular entry. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with numerous roles in the normal immune response to infection. However, excess MMP activity following infection may lead to immunopathological processes that cause tissue damage. Their activity in normal tissues is subject to tight control, which is regulated by its specific endogenous tissue inhibitors (TIMPs). It is known that MMPs bind to cell surface proteins (e.g. integrins) and that such interactions can have modulatory effects on MMP functionality. The objective of this study was to determine whether there are differences in MMP and TIMP production during the acute phase of infection with different pathogens that use beta-integrins as their receptors for cell entry. METHODS: We measured the total amounts of soluble MMP-2, MMP-9, TIMP-1, and TIMP-2 in the sera from patients infected with Dobrava virus (DOBV), Coxiella burnetii, or uropathogenic Escherichia coli. Statistical analyses were used to correlate MMP/TIMP serum levels with different clinical laboratory parameters. RESULTS: The results showed that both of the bacterial infections generally manifested the stronger effect on MMP production, while in contrast, viral infection introduced stronger changes to metalloproteinase inhibitors. MMPs and TIMPs were significantly correlated with some of the clinical laboratory parameters in both bacterial infections, but no correlations were found for DOBV infection. CONCLUSIONS: These findings suggest diverse mechanisms by which MMP activity could be implicated in the pathology of these 2 bacterial infections versus the viral DOBV infection, despite the type of their cellular entry receptors. PMID- 22831171 TI - Disruption of redox homeostasis leads to oxidative DNA damage in spermatocytes of Wolbachia-infected Drosophila simulans. AB - Molecular interactions between symbiotic bacteria and their animal hosts are, as yet, poorly understood. The most widespread bacterial endosymbiont, Wolbachia pipientis, occurs in high density in testes of infected Drosophila simulans and causes cytoplasmic incompatibility (CI), a form of male-derived zygotic lethality. Wolbachia grow and divide within host vacuoles that generate reactive oxygen species (ROS), which in turn stimulate the up-regulation of antioxidant enzymes. These enzymes appear to protect the host from ROS-mediated damage, as there is no obvious fitness cost to Drosophila carrying Wolbachia infections. We have now determined that DNA from Wolbachia-infected mosquito Aedes albopictus (Aa23) cells shows a higher amount of the base 8-oxo-deoxyguanosine, a marker of oxidative DNA damage, than DNA from uninfected cells, and that Wolbachia infection in D. simulans is associated with an increase in DNA strand breaks in meiotic spermatocytes. Feeding exogenous antioxidants to male and female D. simulans dramatically increased Wolbachia numbers with no obvious effects on host fitness. These results suggest that ROS-induced DNA damage in sperm nuclei may contribute to the modification characteristic of CI expression in Wolbachia infected males and that Wolbachia density is sensitive to redox balance in these flies. PMID- 22831172 TI - Vacuum-deposited small-molecule organic solar cells with high power conversion efficiencies by judicious molecular design and device optimization. AB - Three new tailor-made molecules (DPDCTB, DPDCPB, and DTDCPB) were strategically designed and convergently synthesized as donor materials for small-molecule organic solar cells. These compounds possess a donor-acceptor-acceptor molecular architecture, in which various electron-donating moieties are connected to an electron-withdrawing dicyanovinylene moiety through another electron-accepting 2,1,3-benzothiadiazole block. The molecular structures and crystal packings of DTDCPB and the previously reported DTDCTB were characterized by single-crystal X ray crystallography. Photophysical and electrochemical properties as well as energy levels of this series of donor molecules were thoroughly investigated, affording clear structure-property relationships. By delicate manipulation of the trade-off between the photovoltage and the photocurrent via molecular structure engineering together with device optimizations, which included fine-tuning the layer thicknesses and the donor:acceptor blended ratio in the bulk heterojunction layer, vacuum-deposited hybrid planar-mixed heterojunction devices utilizing DTDCPB as the donor and C(70) as the acceptor showed the best performance with a power conversion efficiency (PCE) of 6.6 +/- 0.2% (the highest PCE of 6.8%), along with an open-circuit voltage (V(oc)) of 0.93 +/- 0.02 V, a short-circuit current density (J(sc)) of 13.48 +/- 0.27 mA/cm(2), and a fill factor (FF) of 0.53 +/- 0.02, under 1 sun (100 mW/cm(2)) AM 1.5G simulated solar illumination. PMID- 22831174 TI - Comparison of hearing outcome using a Nitinol versus Teflon prosthesis in stapedotomy. AB - CONCLUSION: The time-tested, readily available, and cost-effective Teflon(r) piston continues to have equivocal results to the newer Nitinol piston. OBJECTIVE: To compare hearing outcome using a Nitinol versus Teflon piston in stapes surgery and to ascertain the feasibility of using the Nitinol piston. METHODS: Forty patients between 18 and 45 years of age were selected and randomly allocated into two groups of 20 each and the study was conducted between September 2007 and March 2009 at Maulana Azad Medical College. RESULTS: There was no significant difference between the two groups in the postoperative air-bone gap and air-bone gap closure at 1, 2, 3, and 6 months. PMID- 22831173 TI - The NsrR regulon in nitrosative stress resistance of Salmonella enterica serovar Typhimurium. AB - Nitric oxide (NO.) is an important mediator of innate immunity. The facultative intracellular pathogen Salmonella has evolved mechanisms to detoxify and evade the antimicrobial actions of host-derived NO. produced during infection. Expression of the NO.-detoxifying flavohaemoglobin Hmp is controlled by the NO. sensing transcriptional repressor NsrR and is required for Salmonella virulence. In this study we show that NsrR responds to very low NO. concentrations, suggesting that it plays a primary role in the nitrosative stress response. Additionally, we have defined the NsrR regulon in Salmonella enterica sv. Typhimurium 14028s using transcriptional microarray, qRT-PCR and in silico methods. A novel NsrR-regulated gene designated STM1808 has been identified, along with hmp, hcp-hcr, yeaR-yoaG, ygbA and ytfE. STM1808 and ygbA are important for S. Typhimurium growth during nitrosative stress, and the hcp-hcr locus plays a supportive role in NO. detoxification. ICP-MS analysis of purified STM1808 suggests that it is a zinc metalloprotein, with histidine residues H32 and H82 required for NO. resistance and zinc binding. Moreover, STM1808 and ytfE promote Salmonella growth during systemic infection of mice. Collectively, these findings demonstrate that NsrR-regulated genes in addition to hmp are important for NO. detoxification, nitrosative stress resistance and Salmonella virulence. PMID- 22831175 TI - Complete denture displacement following open-mouth reline. AB - In 21 complete denture wearers, six upper and 15 lower denture relines were performed with the open-mouth technique. The centric relation (CR) was recorded with the Central-Bearing-Point (CBP) method three times before and three times after the reline. For each registration, the right and left condylar position was recorded in three dimensions using a custom-made measuring device. The average denture displacement from an initial reference position (CR) was calculated for each registration. An upper denture reline leads to a mean displacement of 2.5 mm, both in the right and left condylar area. With an average of 2.0 mm, this displacement was smaller following a lower denture reline (right and left mean, 1.6 mm). The precision of the CBP-registrations proved 0.5 mm before and 0.3 mm after reline; hence, the measured condylar displacement after reline could not attribute to a methodological bias. This clinical-experimental study demonstrates that relining complete dentures with the open-mouth technique may lead to a substantial denture shift and thus imply inevitably clinically relevant occlusal discrepancies. It is therefore important to carefully check the occlusion at denture delivery and remount the prostheses if necessary. PMID- 22831176 TI - Differential scanning calorimetric approach to study the effect of melting region upon transcription initiation by T7 RNA polymerase and role of high affinity GTP binding. AB - Transcription initiation by T7 RNA polymerase is a multistep process consisting of the transition from closed to open complex. The promoters of bacteriophage T7 share a consensus sequence of 23 base pairs, from -17 to +6, relative to transcription start site (+1). In the present study, we have characterized T7 RNA polymerase-promoter complexes by means of fluorescence spectroscopy and differential scanning calorimetry. We have examined the effect of high affinity GTP binding upon the equilibrium of the transition from closed to open complex. We have employed the promoter containing 23 base pair consensus sequence and two variants containing Adenine-Thymine and Guanine-Cytosine stretches in the melting region of the promoter sequence. Variation in the nucleotide sequence of melting region does not have any effect upon the affinity of promoter-T7 RNAP complex. On the other hand, alteration of the base sequence in the melting region of the promoter affects the isomerization process among the closed and open complexes. When the initiating nucleotide GTP is prebound to T7 RNA Polymerase, the isomerization process is affected only in case of the promoter with consensus sequence. PMID- 22831177 TI - The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. AB - Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), an essential cytokine for the formation, function, and survival of osteoclasts. The role of excessive RANKL as a contributor to conditions characterized by bone loss or bone destruction has been well studied. With its novel mechanism of action, denosumab offers a significant advance in the treatment of postmenopausal osteoporosis; bone loss associated with hormone ablation therapy in women with breast cancer and men with prostate cancer; and the prevention of skeletal related events in patients with bone metastases from solid tumors by offering clinical benefit to these patients in need. PMID- 22831178 TI - The utilization of solid organs for transplantation in the setting of infection with multidrug-resistant organisms: an expert opinion. AB - Organ transplantation remains the optimal treatment for many patients suffering from end-stage organ disease. Increasing numbers of patients admitted to intensive care units, among them potential heart-beating, brain-dead organ donors, are exposed to infections with multidrug-resistant organisms, in particular carbapenem-resistant Klebsiella pneumoniae (CR-KP). An extensive literature search failed to reveal any information regarding the eligibility for transplantation of organs from such donors. For this reason, in 2009, the Israel Transplant Center, together with the Israeli Society for Infectious Diseases, established a working group with the intention of developing a national-specific approach to the use of these organs. In this viewpoint article, we present an algorithm based on expert opinion and our clinical experience with a donor who was found to be an asymptomatic carrier of CR-KP. PMID- 22831179 TI - Molecules and fossils reveal punctuated diversification in Caribbean "faviid" corals. AB - BACKGROUND: Even with well-known sampling biases, the fossil record is key to understanding macro-evolutionary patterns. During the Miocene to Pleistocene in the Caribbean Sea, the fossil record of scleractinian corals shows a remarkable period of rapid diversification followed by massive extinction. Here we combine a time-calibrated molecular phylogeny based on three nuclear introns with an updated fossil stratigraphy to examine patterns of radiation and extinction in Caribbean corals within the traditional family Faviidae. RESULTS: Concatenated phylogenetic analysis showed most species of Caribbean faviids were monophyletic, with the exception of two Manicina species. The time-calibrated tree revealed the stem group originated around the closure of the Tethys Sea (17.0 Ma), while the genus Manicina diversified during the Late Miocene (8.20 Ma), when increased sedimentation and productivity may have favored free-living, heterotrophic species. Reef and shallow water specialists, represented by Diploria and Favia, originate at the beginning of the Pliocene (5 - 6 Ma) as the Isthmus of Panama shoaled and regional productivity declined. CONCLUSIONS: Later origination of the stem group than predicted from the fossil record corroborates the hypothesis of morphological convergence in Diploria and Favia genera. Our data support the rapid evolution of morphological and life-history traits among faviid corals that can be linked to Mio-Pliocene environmental changes. PMID- 22831180 TI - Origin of thermal degradation of Sr(2-x)Si5N8:Eu(x) phosphors in air for light emitting diodes. AB - The orange-red emitting phosphors based on M(2)Si(5)N(8):Eu (M = Sr, Ba) are widely utilized in white light-emitting diodes (WLEDs) because of their improvement of the color rendering index (CRI), which is brilliant for warm white light emission. Nitride-based phosphors are adopted in high-performance applications because of their excellent thermal and chemical stabilities. A series of nitridosilicate phosphor compounds, M(2-x)Si(5)N(8):Eu(x) (M = Sr, Ba), were prepared by solid-state reaction. The thermal degradation in air was only observed in Sr(2-x)Si(5)N(8):Eu(x) with x = 0.10, but it did not appear in Sr(2 x)Si(5)N(8):Eu(x) with x = 0.02 and Ba analogue with x = 0.10. This is an unprecedented investigation to study this phenomenon in the stable nitrides. The crystal structural variation upon heating treatment of these compounds was carried out using the in situ XRD measurements. The valence of Eu ions in these compounds was determined by electron spectroscopy for chemical analysis (ESCA) and X-ray absorption near-edge structure (XANES) spectroscopy. The morphology of these materials was examined by transmission electron microscopy (TEM). Combining all results, it is concluded that the origin of the thermal degradation in Sr(2 x)Si(5)N(8):Eu(x) with x = 0.10 is due to the formation of an amorphous layer on the surface of the nitride phosphor grain during oxidative heating treatment, which results in the oxidation of Eu ions from divalent to trivalent. This study provides a new perspective for the impact of the degradation problem as a consequence of heating processes in luminescent materials. PMID- 22831181 TI - Direct C-H carboxylation with carbon dioxide using 1,2,3-triazol-5-ylidene copper(I) complexes. AB - 1,2,3-Triazol-5-ylidene copper(I) complexes (tzNHC-Cu) efficiently catalyzed the direct C-H carboxylation of benzoxazole and benzothiazole derivatives with CO(2) to give the corresponding esters in excellent yields after treatment with alkyl iodide. The tzNHC copper(I) complex, i.e., [(TPr)CuCl], worked somewhat more effectively than the corresponding imidazol-2-ylidene copper(I) complex [(IPr)CuCl] to give the carboxylation product in higher yields. PMID- 22831182 TI - Adherence to a low-fat vs. low-carbohydrate diet differs by insulin resistance status. AB - Previous research shows diminished weight loss success in insulin-resistant (IR) women assigned to a low-fat (LF) diet compared to those assigned to a low carbohydrate (LC) diet. These secondary analyses examined the relationship between insulin-resistance status and dietary adherence to either a LF-diet or LC diet among 81 free-living, overweight/obese women [age = 41.9 +/- 5.7 years; body mass index (BMI) = 32.6 +/- 3.6 kg/m(2)]. This study found differential adherence by insulin-resistance status only to a LF-diet, not a LC-diet. IR participants were less likely to adhere and lose weight on a LF-diet compared to insulin sensitive (IS) participants assigned to the same diet. There were no significant differences between IR and IS participants assigned to LC-diet in relative adherence or weight loss. These results suggest that insulin resistance status may affect dietary adherence to weight loss diets, resulting in higher recidivism and diminished weight loss success of IR participants advised to follow LF-diets for weight loss. PMID- 22831183 TI - Venous lactate levels can be used to identify patients with poor outcome following community-onset norovirus enteritis. AB - BACKGROUND: Norovirus enteritis (NVE) can be fatal in frail patients. High blood lactate levels indicate hypoperfusion and predict mortality in many infectious diseases. The objective was to determine the frequency and association with mortality of elevated lactate levels in patients with community-onset NVE. METHODS: A retrospective cohort study was performed. All hospitalized adult patients with community-onset NVE verified by polymerase chain reaction during the period August 2008 to June 2009 were included. Vital signs and venous lactate on arrival, co-morbid conditions, and time of death were registered. The outcome measure was 30-day all-cause mortality. RESULTS: Eighty-two patients with a median age of 77 y (interquartile range (IQR) 53-86 y) were included, of whom 47 (57%) were female and 49 (60%) had at least 1 major co-morbid condition. Lactate levels were above the upper limit of normal (ULN; 1.6 mmol/l) in 45 patients (55%). The overall 30-day mortality rate was 7% (6/82). Mortality was 18% (5/28) with lactate >= 2.4 mmol/l (> 50% above the ULN) on admission compared to 2% (1/54) with lactate < 2.4 mmol/l (p < 0.05). Patients who died had a higher median lactate level compared to survivors: 4.5 (IQR 2.7-7.9) mmol/l vs 1.7 (IQR 1.3-2.5) mmol/l, respectively (p < 0.01). The adjusted odds ratio for death within 30 days for a 1 mmol/l increase in lactate was 2.5 (95% confidence interval 1.003-6.3, p = 0.049). CONCLUSIONS: We observed a high proportion of patients with elevated lactate levels in community-onset NVE. Lactate elevation could predict mortality. Measurement of blood lactate may be a valuable tool in the clinical management of patients with a suspected norovirus infection. PMID- 22831273 TI - Is the metabolic syndrome a "small baby" syndrome?: the bogalusa heart study. AB - BACKGROUND: Metabolic syndrome has been called a "small baby syndrome," but other analyses suggest that postnatal growth is more important than birthweight, or that large babies are also at risk. The aim of this analysis was to examine whether there was a relationship between both low and high birthweight and metabolic syndrome, using multiple definitions of metabolic syndrome, and to determine whether this relationship varied by body size across the life course. METHODS: Data from the Bogalusa Heart Study, a study of cardiovascular disease in children and young adults, were linked to birth certificate data. Metabolic syndrome was defined by the National Cholesterol Education Program, the International Diabetes Foundation, and the World Health Organization (WHO) definition. Small-for-gestational-age (SGA) was defined as birthweight <10(th) percentile by sex for gestational age and large-for-gestational-age (LGA) as birthweight >90(th) percentile. Birthweight-for-gestational-age was also examined as a continuous predictor. Chi-squared tests and logistic regression were used to examine the relationship between birth size and metabolic syndrome. RESULTS: Higher birthweight-for-gestational-age was associated with a reduced risk of metabolic syndrome, especially by the WHO definition. After adjustment for body mass index (BMI), categorized birthweight was associated with metabolic syndrome, with the protective associations with LGA being stronger than the positive associations with SGA. Among the individual components of metabolic syndrome, higher waist circumference was associated with both SGA and LGA after BMI was controlled for. Effects of SGA and BMI at any age were largely independent rather than interactive. CONCLUSIONS: SGA is associated with some, but not all, components of metabolic syndrome. The relationship between SGA and metabolic syndrome is partially confounded by later BMI. PMID- 22831274 TI - Interaction effects between sender and receiver processes in indirect transmission of Campylobacter jejuni between broilers. AB - BACKGROUND: Infectious diseases in plants, animals and humans are often transmitted indirectly between hosts (or between groups of hosts), i.e. via some route through the environment instead of via direct contacts between these hosts. Here we study indirect transmission experimentally, using transmission of Campylobacter jejuni (C. jejuni) between spatially separated broilers as a model system. We distinguish three stages in the process of indirect transmission; (1) an infectious "sender" excretes the agent, after which (2) the agent is transported via some route to a susceptible "receiver", and subsequently (3) the receiver becomes colonised by the agent. The role of the sender and receiver side (stage 1 and stage 3) was studied here by using acidification of the drinking water as a modulation mechanism. RESULTS: In the experiment one control group and three treatment groups were monitored for the presence of C. jejuni by taking daily cloacal swabs. The three treatments consisted of acidification of the drinking water of the inoculated animals (the senders), acidification of the drinking water of the susceptible animals (the receivers) or acidification of the drinking water of both inoculated and susceptible animals. In the control group 12 animals got colonised out of a possible 40, in each treatment groups 3 animals out of a possible 40 were found colonised with C. jejuni. CONCLUSIONS: The results of the experiments show a significant decrease in transmission rate (beta) between the control groups and treatment groups (p < 0.01 for all groups) but not between different treatments; there is a significant negative interaction effect when both the sender and the receiver group receive acidified drinking water (p = 0.01). This negative interaction effect could be due to selection of bacteria already at the sender side thereby diminishing the effect of acidification at the receiver side. PMID- 22831275 TI - From brain to bridge: masticatory function and dental implants. AB - Masticatory function is an important aspect of oral health, and oral rehabilitation should aim to maintain or restore adequate function. The present qualitative review is the joint effort of a group of clinicians and researchers with experiences ranging from basic and clinical oral neuroscience to management of patients with dental implants. The aim is to provide a short summary for the clinician of the many aspects related to masticatory function (including quality of life) and rehabilitation with dental implants. While there are many reviews on the tissue responses to dental implants and technical aspects, the functional aspects have received relatively little focus. PMID- 22831276 TI - Disrupting the mTOR signaling network as a potential strategy for the enhancement of cancer radiotherapy. AB - Radiotherapy (RT) allows for tumor control through the cytotoxic action of ionizing radiation (IR). Although modern technologies permit precise IR delivery to the tumor mass while minimizing exposure of surrounding healthy tissues, the efficacy of RT remains limited by the intrinsic or acquired radioresistance of many tumors. There is thus an ongoing search for agents that augment the sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting components of signaling pathways involved in tumor growth and radioresistance. Here, we review the evidence suggesting that disabling one of these components, the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein complexes, which regulate cell growth and other processes implicated in tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked by the microbial product rapamycin and its analogs (collectively designated rapamycins) that are approved for cancer treatment, and is frequently hyperactivated in malignant cells. In several, but not all human cancer cell lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple mechanisms, including the promotion of autophagic cell death. Rapamycins also potentiated fractionated RT in tumor xenograft models, in part by suppressing tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater efficiency than rapamycins. These encouraging data have led to early clinical trials of rapamycins and catalytic mTOR inhibitors combined with RT in various cancers. PMID- 22831277 TI - Chemotherapy and target therapy in the management of adult high- grade gliomas. AB - Adult high grade gliomas (HGG) are the most frequent and fatal primary central nervous system (CNS) tumors. Despite recent advances in the knowledge of the pathology and the molecular features of this neoplasm, its prognosis remains poor. In the last years temozolomide (TMZ) has dramatically changed the life expectancy of these patients: the association of this drug with radiotherapy (RT), followed by TMZ alone, is the current standard of care. However, malignant gliomas often remain resistant to chemotherapy (CHT). Therefore, preclinical and clinical research efforts have been directed on identifying and understanding the different mechanisms of chemo-resistance operating in this subset of tumors,in order to develop effective strategies to overcome resistance. Moreover, the evidence of alterations in signal transduction pathways underlying tumor progression, has increased the number of trials investigating molecular target agents, such as anti-epidermal growth factor receptor (EGFR) and anti- vascular endothelial growth factor (VEGF) signaling. The purpose of this review is to point out the current standard of treatment and to explore new available target therapies in HGG. PMID- 22831278 TI - Perspectives on mTOR inhibitors for castration-refractory prostate cancer. AB - The phosphatidylinositol 3'-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway contributes to prostate cancer progression and transition to androgen-independent disease. Furthermore, recent microarray analysis demonstrates that this pathway is often deregulated during prostate cancer progression. Thus, targeting of PI3K/AKT/mTOR may present a promising therapy for castration-refractory prostate cancer (CRPC). In recent years, several interesting strategies have been developed that interfere with distinct components of the PI3K/AKT/mTOR cascade. This article discusses many of the mechanisms involved, specifically in the context of prostate cancer. In addition, we present an overview of preliminary data on the activity of mTOR inhibitors and on the key steps to evaluate which of these compounds are most suitable for the treatment of prostate cancer. Particular emphasis is also placed on the development of novel perspectives to improve the poor prognosis of patients with CRPC. PMID- 22831279 TI - Molecular determinants of inactivation of the resuscitation promoting factor B from Mycobacterium tuberculosis. AB - Inactivation of revival of Mycobacterium tuberculosis from dormancy is one of the main goals of the WHO Global Plan to stop tuberculosis (TB) 2011-2015, given the huge reservoir of latently infected individuals. This process requires a group of secreted proteins, denoted as resuscitation-promoting factors (Rpfs). Of these, RpfB is the sole member indispensable for resuscitation in vivo. The first class of inhibitors of RpfB was identified among 2-nitrophenylthiocyanates. However, their inactivation mechanism is hitherto not known. To gain insight into the inactivation mechanism of one of the most promising RpfB inhibitors, 4-benzoyl-2 nitrophenyl thiocyanate, NPT7, we have performed replica exchange molecular dynamics (REMD) simulations, starting from the crystal structure of RpfB catalytic domain, derived in this study. We validated our results by resuscitation experiments of M. tuberculosis cultures. The atomic resolution crystal structure of RpfB catalytic domain identified the potential of the enzyme catalytic cleft to bind benzene rings. REMD simulations, 48 replicas, identified the key interactions for the binding of NPT7 to RpfB catalytic site. Of these, an important role is played by the thiocyanate group of NPT7. Consistently, we prove that the substitution of this group implies a complete loss of RpfB inactivation. Our results provide valuable information for modifications of NPT7 structure to enhance its binding affinity to RpfB, with the final aim of developing second generation inhibitors of therapeutic interest in TB eradication strategy. PMID- 22831282 TI - Metabolic profiling of the methylerythritol phosphate pathway reveals the source of post-illumination isoprene burst from leaves. AB - The methylerythritol phosphate (MEP) pathway in plants produces the prenyl precursors for all plastidic isoprenoids, including carotenoids and quinones. The MEP pathway is also responsible for synthesis of approximately 600 Tg of isoprene per year, the largest non-methane hydrocarbon flux into the atmosphere. There have been few studies of the regulation of the MEP pathway in plants under physiological conditions. In this study, we combined gas exchange techniques and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) and measured the profile of MEP pathway metabolites under different conditions. We report that in the MEP pathway, metabolites immediately preceding steps requiring reducing power were in high concentration. Inhibition of the MEP pathway by fosmidomycin caused deoxyxylulose phosphate accumulation in leaves as expected. Evidence is presented that accumulation of MEP pathway intermediates, primarily methylerythritol cyclodiphosphate, is responsible for the post-illumination isoprene burst phenomenon. Pools of intermediate metabolites stayed at approximately the same level 10 min after light was turned off, but declined eventually under prolonged darkness. In contrast, a strong inhibition of the second-to-last step of the MEP pathway caused suppression of isoprene emission in pure N(2). Our study suggests that reducing equivalents may be a key regulator of the MEP pathway and therefore isoprene emission from leaves. PMID- 22831283 TI - Reduced gut microbial diversity in early life is associated with later development of eczema but not atopy in high-risk infants. AB - BACKGROUND: Alterations in intestinal microflora have been linked to the development of allergic disease. Recent studies suggest that healthy infant immune development may depend on the establishment of a diverse gut microbiota rather than the presence or absence of specific microbial strains. OBJECTIVES: We investigated the relationship between diversity of gut microbiota in the early postnatal period and subsequent development of eczema and atopy in the first year of life. METHODS: Fecal samples were collected 1 wk after birth from 98 infants at high risk of allergic disease, who were followed prospectively to age 12 months. Fecal microbial diversity was assessed by terminal restriction fragment length polymorphism (T-RFLP) using restriction enzymes Sau96I and AluI, with a greater number of peaks representing greater diversity of bacterial communities. RESULTS: Microbial diversity at day 7 was significantly lower in infants with eczema at age 12 months as compared to infants without eczema (AluI mean number of peaks 13.1 vs. 15.5, p = 0.003, 95% CI for difference in means -3.9, -0.8; Sau96I 14.7 vs. 17.2, p = 0.03, 95% CI -4.9, -0.3). No differences were observed for atopic compared to non-atopic infants, or infants with two allergic parents compared to those with one or no allergic parent. CONCLUSIONS: A more diverse intestinal microbiota in the first week of life is associated with a reduced risk of subsequent eczema in infants at increased risk of allergic disease. Interventions that enhance microbial diversity in early life may provide an effective means for the prevention of eczema in high-risk infants. PMID- 22831284 TI - Objective evaluation of neck muscle tension and static balance in patients with chronic dizziness. AB - CONCLUSION: Increase in the average value of bilateral neck muscle tension (ANT) indicates the increase in neck muscle tension to stabilize static posture resulting from vestibular compensation. Asymmetry of neck muscle tension was closely related to postural imbalance. OBJECTIVE: Patients with dizziness often complain of neck symptoms with stiff neck. This study was conducted to clarify the pathophysiological mechanism of neck symptoms in patients with dizziness. METHODS: We objectively measured bilateral trapezius muscle tension in patients with chronic dizziness and determined its relationship with static postural perturbation. The study included 26 patients with chronic dizziness caused by unilateral vestibular deficit and 24 healthy controls. The tension of bilateral trapezius muscles was objectively measured using a neck muscle tension meter. ANT and the ratio (right/left) of the bilateral neck muscle tension (RNT) were calculated. Static posturography was performed to measure total length of path (LNG). RESULTS: ANT was negatively correlated to LNG under the eyes closed (EC) condition only in the case of the patients (r = -0.44, p < 0.05). In the case of both the controls and the patients with a unilateral vestibular deficit, RNT was positively correlated to LNG under the EC condition. PMID- 22831285 TI - Automated identification and susceptibility determination directly from blood cultures facilitates early targeted antibiotic therapy. AB - BACKGROUND: The increasing prevalence of antibiotic resistance is challenging established empirical treatments, making early identification and susceptibility determination more important. To avoid time-consuming overnight cultures, a previously published method for the rapid identification and susceptibility testing of blood cultures was instituted at Molde Hospital. The time saved compared to the standard method, and how often the results could have led to a change in the empirical antibiotic treatment compared to Gram stain from cultures, were evaluated. MATERIAL AND METHODS: All positive blood cultures with Gram-negative bacilli obtained between March and December 2010 were included in the study (n = 69). Accuracy and turn-around times were compared to those of the standard methods. The empirical antibiotic treatment was recorded when consulting the clinician about the results. RESULTS: Correct identification was obtained in 66/69 (95.7%) of the isolates. Correct susceptibility determination was obtained in 758/759 (99.9%) of the tests. Oral reports to the clinician were given on average 11 h 22 min earlier for identification, and 10 h 51 min earlier for susceptibility determination, compared to the standard methods. With optimal handling we could have managed 17 h 26 min and 16 h 14 min, respectively. In 14/69 cases the empirical treatment included no effective or appropriate antibiotics. 7 of these 14 would not have been changed to working antibiotic treatment based on Gram stain alone. CONCLUSION: The rapid method was found to be accurate and showed the potential for the initiation of effective antibiotic treatment more than 16 h earlier for 10% of the patients in this small sample. PMID- 22831286 TI - Effects of chronic consumption of fruit and vegetable puree-based drinks on vasodilation, plasma oxidative stability and antioxidant status. AB - BACKGROUND: Fruit and vegetable-rich diets are associated with a reduced cardiovascular disease (CVD) risk. This protective effect may be a result of the phytochemicals present within fruits and vegetables (F&V). However, there can be considerable variation in the content of phytochemical composition of whole F&V depending on growing location, cultivar, season and agricultural practices, etc. Therefore, the present study investigated the effects of consuming fruits and vegetables as puree-based drinks (FVPD) daily on vasodilation, phytochemical bioavailability, antioxidant status and other CVD risk factors. FVPD was chosen to provide a standardised source of F&V material that could be delivered from the same batch to all subjects during each treatment arm of the study. METHODS: Thirty-nine subjects completed the randomised, controlled, cross-over dietary intervention. Subjects were randomised to consume 200 mL of FVPD (or fruit flavoured control), daily for 6 weeks with an 8-week washout period between treatments. Dietary intake was measured using two 5-day diet records during each cross-over arm of the study. Blood and urine samples were collected before and after each intervention and vasodilation assessed in 19 subjects using laser Doppler imaging with iontophoresis. RESULTS: FVPD significantly increased dietary vitamin C and carotenoids (P < 0.001), and concomitantly increased plasma alpha- and beta-carotene (P < 0.001) with a near-significant increase in endothelium dependent vasodilation (P = 0.060). CONCLUSIONS: Overall, the findings obtained in the present study showed that FVPD were a useful vehicle to increase fruit and vegetable intake, significantly increasing dietary and plasma phytochemical concentrations with a trend towards increased endothelium-dependent vasodilation. PMID- 22831287 TI - Oral vitamin E absorption in English Cocker Spaniels with familial vitamin E deficiency and retinal pigment epithelial dystrophy. AB - BACKGROUND: Retinal Pigment Epithelial Dystrophy (RPED) with neuroaxonal degeneration in English Cocker Spaniels (ECS) is associated with systemic vitamin E deficiency in the absence of dietary insufficiency. OBJECTIVE: To evaluate the ability of ECS with RPED to absorb orally administered vitamin E and establish a basis for vitamin E supplementation in affected dogs. ANIMALS STUDIED: 8 RPED affected ECS and five clinically normal dogs. PROCEDURES: An oral vitamin E tolerance test (OVETT) was conducted in each dog. Blood samples were obtained prior to and at 3, 6, 9, 12, 24, 120, and 240 h following oral administration of 90 iu/kg of RRR-alpha-tocopherol. Plasma alpha tocopherol (alphaTOC) content was measured by normal phase, high-performance liquid chromatography, and indices of vitamin E absorption calculated. RESULTS: There was marked variation in OVETT results between individuals. In RPED-affected ECS, mean peak plasma alphaTOC concentration (17.87 +/- 13.21 MUg/mL), attained after administration of a large oral dose of the vitamin, was significantly lower than the mean peak plasma alphaTOC concentration attained in normal dogs (47.61 +/- 17.17 MUg/mL; P < 0.005). However, the plasma concentrations achieved in 7/8 RPED-affected dogs remained within the normal reference range for plasma alphaTOC in vitamin E replete dogs, for at least 12 h postdose. CONCLUSIONS: Vitamin E-deficient ECS with RPED are capable of absorbing orally administered vitamin E. Twice daily administration of 600-900 iu tocopherol is likely to restore plasma vitamin E concentrations to the normal range in most affected dogs. PMID- 22831386 TI - Biomass conversion to high value chemicals: from furfural to chiral hydrofuroins in two steps. AB - Catalytic asymmetric transfer hydrogenation of rac-furoin and furil produces hydrofuroin with up to 99% ee and 9:1 dr. This reaction provides an exceptionally easy access to optically active hydrofuroins in two straightforward steps from biomass-derived furfural (global production 200,000-300,000 t annually) using benzoin condensation. PMID- 22831280 TI - Allotetraploid Mimulus sookensis are highly interfertile despite independent origins. AB - Polyploidy (whole-genome duplication) has contributed significantly to angiosperm evolution and diversification. To date, it has been found that most polyploids are the result of multiple formation events, which may contribute to genetic diversity and affect interfertility among polyploid lineages of independent origin. A recently discovered allotetraploid derivative of Mimulus guttatus and M. nasutus, Mimulus sookensis, is found throughout the valleys of western Oregon and Vancouver Island. Here, we analyse the patterns of nucleotide diversity at three chloroplast and six nuclear loci in M. guttatus, M. nasutus and M. sookensis, to gain insight into the formation of M. sookensis. By analysing the patterns of genetic variation seen in the diploid progenitors in comparison with the variation seen in M. sookensis, we are able to show that M. sookensis has recurrently formed. We also observed that most M. sookensis individuals are fixed heterozygotes at all of the nuclear loci examined, suggesting that duplicate gene loss is not extensive in M. sookensis. To assess the possibility that hybridization among M. sookensis has contributed to genetic diversity, we conducted crossing experiments within M. sookensis. We found that M. sookensis of independent origin are highly interfertile, suggesting that crossing barriers do not exist within M. sookensis, and that hybridization among M. sookensis may result in new recombinant genotypes. Together, the data suggest that although recurrent origins may be common, they can contribute to genetic diversity without contributing to reproductive isolation among independently arisen polyploid lineages. PMID- 22831387 TI - Recovery of physical activity levels in adolescents after lower limb fractures: a longitudinal, accelerometry-based activity monitor study. AB - BACKGROUND: In adolescents, loss of bone mineral mass usually occurs during phases of reduced physical activity (PA), such as when an injured extremity spends several weeks in a cast. We recorded the PA of adolescents with lower limb fractures during the cast immobilization, at 6 and at 18 months after the fracture, and we compared these values with those of healthy controls. METHODS: Fifty adolescents with a first episode of limb fracture and a control group of 50 healthy cases were recruited for the study through an advertisement placed at the University Children's Hospital of Geneva, Switzerland. PA was assessed during cast immobilization and at 6- and 18-month follow-up by accelerometer measurement (Actigraph((r)) 7164, MTI, Fort Walton Beach, FL, USA). Patients and their healthy peers were matched for gender and age. Time spent in PA at each level of intensity was determined for each participant and expressed in minutes and as a percentage of total valid time. RESULTS: From the 50 initial teenagers with fractures, 44 sustained functional evaluations at 6 months follow-up, whereas only 38 patients were studied at 18 months. The total PA count (total number of counts/min) was lower in patients with lower limb fractures (-62.4%) compared with healthy controls (p<0.0001) during cast immobilization. Similarly, time spent in moderate-to-vigorous PA was lower by 76.6% (p<0.0001), and vigorous PA was reduced by 84.4% (p<0.0001) in patients with cast immobilization for lower limb injuries compared to healthy controls values. At 6 and 18 months after the fracture, the mean PA level of injured adolescents was comparable to those of healthy teenagers (-2.3%, and -1.8%, respectively).Importantly, we observed that time spent in vigorous PA, which reflects high-intensity forces beneficial to skeletal health, returned to similar values between both groups from the six month follow-up in adolescents who sustained a fracture. However, a definitive reduction in time spent in moderate PA was observed among patients with a lower limb fracture at 18 months, when comparing with healthy controls values (p = 0.0174). CONCLUSIONS: As cast immobilization and reduced PA are known to induce bone mineral loss, this study provides important information to quantify the decrease of skeletal loading in adolescents with limb fractures. The results of this study demonstrate that the amount of skeletal loading returns to normal values in adolescents with lower limb fractures after bone healing and is probably linked to an overall better pattern of functional recovery among this age group. When comparing both populations of adolescents, a definitive decrease in time spent in moderate-to-vigorous PA was observed among patients with a lower limb fracture at 18 months and may suggest a modification of lifestyle. The high rate of missing data (26.5%) due to above all non compliance with monitor wearing among teenagers complicates the data analysis, and requires a more cautious interpretation of the results. Future studies using accelerometer to monitor PA in adolescents should therefore include strategies for improving the rate of adherence and minimizing the ratio of missing data. PMID- 22831388 TI - Patients' perspectives on the implementation of intra-dialytic cycling--a phenomenographic study. AB - BACKGROUND: Adults undergoing haemodialysis have significantly reduced physical capacity and run a high risk of developing cardiovascular complications. Research has shown that intra-dialytic cycling has many evidence-based health effects, but implementation is rare within renal clinical practice. This may be due to several causes, and this study focuses on the patients' perspective. This perspective has seldom been taken into account when aiming to assess and improve the implementation of clinical research. The aim of this study was to describe how adults undergoing in-centre haemodialysis treatment experienced an implementation process of intra-dialytic cycling. It aimed to identify potential motivators and barriers to the implementation process from a patient perspective. METHODS: Maximum-variation purposive sampling was used. Data were collected until saturation, through semistructured interviews, which were analysed using phenomenography. RESULTS: The implementation of intra-dialytic cycling was experienced as positive, as it had beneficial effects on physical and psychological well-being. It was easy to perform and did not intrude on patients' spare time. These factors increased the acceptance of the implementation and supported the maintenance of intra-dialytic cycling as an evidence-based routine within their haemodialysis care. The patients did, however, experience some barriers to accepting the implementation of intra-dialytic cycling. These barriers were sometimes so strong that they outweighed the participants' knowledge of the advantages of intra-dialytic cycling and the research evidence of its benefits. The barriers sometimes also outweighed the participants' own wish to cycle. The barriers that we identified concerned not only the patients but also the work situation of the haemodialysis nurses. CONCLUSIONS: Consideration of the motivators and barriers that we have identified can be used in direct care to improve the implementation of intra-dialytic cycling. PMID- 22831389 TI - Self-assembled plasmonic vesicles of SERS-encoded amphiphilic gold nanoparticles for cancer cell targeting and traceable intracellular drug delivery. AB - We report the development of bioconjugated plasmonic vesicles assembled from SERS encoded amphiphilic gold nanoparticles for cancer-targeted drug delivery. This new type of plasmonic assemblies with a hollow cavity can play multifunctional roles as delivery carriers for anticancer drugs and SERS-active plasmonic imaging probes to specifically label targeted cancer cells and monitor intracellular drug delivery. We have shown that the pH-responsive disassembly of the plasmonic vesicle, stimulated by the hydrophobic-to-hydrophilic transition of the hydrophobic brushes in acidic intracellular compartments, allows for triggered intracellular drug release. Because self-assembled plasmonic vesicles exhibit significantly different plasmonic properties and greatly enhanced SERS intensity in comparison with single gold nanoparticles due to strong interparticle plasmonic coupling, disassembly of the vesicles in endocytic compartments leads to dramatic changes in scattering properties and SERS signals, which can serve as independent feedback mechanisms to signal cargo release from the vesicles. The unique structural and optical properties of the plasmonic vesicle have made it a promising platform for targeted combination therapy and theranostic applications by taking advantage of recent advances in gold nanostructure based in vivo bioimaging and photothermal therapy and their loading capacity for both hydrophilic (nucleic acids and proteins) and hydrophobic (small molecules) therapeutic agents. PMID- 22831390 TI - The atypical cannabinoid O-1602: targets, actions, and the central nervous system. AB - O-1602 is a cannabidiol analogue that does not bind with high affinity to either the cannabinoid CB1 receptor or CB2 receptor. However, there is evidence that O 1602 has significant effects in the central nervous system as well as other parts of the body. Depending upon the model, O-1602 has anti-inflammatory or pronociceptive effects, mediated through a number of distinct receptors. This article reviews the evidence for functional effects of O-1602, particularly in the CNS, and describes its known targets as they relate to these effects. These include the abnormal cannabidiol (Abn- CBD) receptor and GPR55. The GPR18 receptor has been identified with the Abn-CBD receptor, and therefore the evidence that O-1602 also acts at GPR18 is also reviewed. Finally, the evidence that these receptor targets are expressed in the CNS and the phenotypes of cells expressing these targets is discussed, concluding with a discussion of the prospects for O-1602 as a therapeutic agent in the CNS. PMID- 22831391 TI - Introduction: Understanding the signalling mechanisms in molecular physiology and diseases. PMID- 22831393 TI - The effects of structural variations of thiophene-containing Ru(II) complexes on the acid-base and DNA binding properties. AB - A phenylthiophenyl-bearing Ru(II) complex of [Ru(bpy)2(Hbptip)](PF6)2 {bpy = 2,2' bipyridine, Hbptip = 2-(4-phenylthiophen-2-yl)-1H-imidazo[4,5 f][1,10]phenanthroline} was synthesized and characterized by elemental analysis, 1H NMR spectroscopy, and electrospray ionization mass spectrometry. The ground- and excited-state acid-base properties of the complex were studied by UV-visible absorption and photoluminescence spectrophotometric pH titrations and the negative logarithm values of the ground-state acid ionization constants were derived to be pK(a1) = 1.31 +/- 0.09 and pK(a2) = 5.71 +/- 0.11 with the pK(a2) associated deprotonation/protonation process occurring over 3 pK(a) units more acidic than thiophenyl-free parent complex of [Ru(bpy)2(Hpip)]2+ {Hpip = 2-phenyl 1H-imidazo[4,5-f][1,10]phenanthroline}. The calf thymus DNA-binding properties of [Ru(bpy)2(Hbptip)]2+ in Tris-HCl buffer (pH 7.1 and 50 mM NaCl) were investigated by DNA viscosities and density functional theoretical calculations as well as UV visible and emission spectroscopy techniques of UV-visible and luminescence titrations, steady-state emission quenching by [Fe(CN)6]4-, DNA competitive binding with ethidium bromide, DNA melting experiments, and reverse salt effects. The complex was evidenced to bind to the DNA intercalatively with binding affinity being greater than those for previously reported analogs of [Ru(bpy)2(Hip)]2+, [Ru(bpy)2(Htip)]2+, and [Ru(bpy)2(Haptip)]2+ {Hip = 1H imidazo[4,5-f][1,10]phenanthroline, Htip = 2-thiophenimidazo[4,5 f][1,10]phenanthroline, Haptip = 2-(5-phenylthiophen-2-yl)-1H-imidazo[4,5 f][1,10]phenanthroline}. PMID- 22831392 TI - SNP variation in the promoter of the PRKAG3 gene and association with meat quality traits in pig. AB - BACKGROUND: The PRKAG3 gene encodes the gamma3 subunit of adenosine monophosphate activated protein kinase (AMPK), a protein that plays a key role in energy metabolism in skeletal muscle. Non-synonymous single nucleotide polymorphisms (SNPs) in this gene such as I199V are associated with important pork quality traits. The objective of this study was to investigate the relationship between gene expression of the PRKAG3 gene, SNP variation in the PRKAG3 promoter and meat quality phenotypes in pork. RESULTS: PRKAG3 gene expression was found to correlate with a number of traits relating to glycolytic potential (GP) and intramuscular fat (IMF) in three phenotypically diverse F1 crosses comprising of 31 Large White, 23 Duroc and 32 Pietrain sire breeds. The majority of associations were observed in the Large White cross. There was a significant association between genotype at the g.-311A>G locus and PRKAG3 gene expression in the Large White cross. In the same population, ten novel SNPs were identified within a 1.3 kb region spanning the promoter and from this three major haplotypes were inferred. Two tagging SNPs (g.-995A>G and g.-311A>G) characterised the haplotypes within the promoter region being studied. These two SNPs were subsequently genotyped in larger populations consisting of Large White (n = 98), Duroc (n = 99) and Pietrain (n = 98) purebreds. Four major haplotypes including promoter SNP's g.-995A>G and g.-311A>G and I199V were inferred. In the Large White breed, HAP1 was associated with IMF% in the M. longissmus thoracis et lumborum (LTL) and driploss%. HAP2 was associated with IMFL% GP-influenced traits pH at 24 hr in LTL (pHULT), pH at 45 min in LTL (pH(45)LT) and pH at 45 min in the M. semimembranosus muscle (pH(45)SM). HAP3 was associated with driploss%, pHULT pH(45)LT and b* Minolta. In the Duroc breed, associations were observed between HAP1 and driploss% and pHUSM. No associations were observed with the remaining haplotypes (HAP2, HAP3 and HAP4) in the Duroc breed. The Pietrain breed was monomorphic in the promoter region. The I199V locus was associated with several GP-influenced traits across all three breeds and IMF% in the Large White and Pietrain breed. No significant difference in promoter function was observed for the three main promoter haplotypes when tested in vitro. CONCLUSION: Gene expression levels of the porcine PRKAG3 are associated with meat quality phenotypes relating to glycolytic potential and IMF% in the Large White breed, while SNP variation in the promoter region of the gene is associated with PRKAG3 gene expression and meat quality phenotypes. PMID- 22831394 TI - Improving English proficiency: new challenge for medical teachers in China. PMID- 22831395 TI - Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia. AB - Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty-one CLL patients were analysed following transplant; 18-month overall survival (OS), event-free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P <= 0.0001, P <= 0.0001, and P = 0.02). In patients with high risk interphase cytogenetics, CK remained predictive of worse OS (P = 0.02) and EFS (P = 0.009). These findings support further evaluation of metaphase karyotype in transplant risk assessment. PMID- 22831396 TI - Association between human papillomavirus DNA and temporal arteritis. AB - BACKGROUND: To examine the relationship between human papillomavirus (HPV) and giant cell arteritis (GCA) of the temporal artery. METHODS: The study group consisted of 22 cases of histologically positive/biopsy confirmed GCA. The control groups consisted of 21 histologically negative temporal artery biopsies and fifteen cases of vascular margins of nephrectomies. For detection of the presence of HPV, two methods were used: 1) polymerase chain reaction (PCR) with INNO-LiPA HPV Genotyping Extra, 2) CervistaTM HPV HR. All cases were from the files of the Barnes-Jewish Hospital and Washington University in St. Louis. RESULTS: HPV DNA was detected by PCR and genotyping in 16 of 22 (73%) histologically positive cases of GCA and in only five of 21 (24%) histologically negative temporal artery biopsies. Among the vascular margin controls, only three of 15 (20%) were positive for HPV DNA. The second, independent method (CervistaTM) confirmed the aforesaid results with 100% concordance with the exception of three cases which had low genomic DNA for which it was not possible to perform the test. The differences in HPV positivity between the histologically positive and negative temporal artery biopsies and between the histologically positive temporal artery biopsies and controls were both statistically significant (p = 0.001 and 0.002, respectively). CONCLUSIONS: The results of our study revealed a statistically significant association between HPV positivity and biopsy confirmed temporal giant cell arteritis GCA (p = 0.001). Further studies are necessary to elucidate the pathophysiology underlying this association. PMID- 22831397 TI - Cyclic fatigue resistance of two reciprocating nickel-titanium instruments after immersion in sodium hypochlorite. AB - AIM: To assess resistance to cyclic fatigue of reciprocating nickel-titanium ( NiTi ) files (Reciproc and WaveOne) after immersion in NaOCl solution over several time periods. METHODOLOGY: A total of 90 new Reciproc R25 and WaveOne Primary were tested. The 45 files of the same brand were randomly assigned to three groups (n = 15) and submitted to the following immersion protocol in 5% NaOCl at 37 degrees C for 16 mm: no immersion (control), 1 or 5 min dynamically. The dynamic immersion and the following cyclic fatigue tests were performed using the appropriate preset reciprocation modes ('RECIPROC ALL' or 'WAVEONE ALL') in a specially designed endodontic motor. Resistance to cyclic fatigue was determined by recording time to fracture (TtF) in a stainless steel artificial canal with a 60 degrees angle of curvature and 5 mm radius of curvature. The artificial canal was manufactured reproducing the instrument's size and taper. Data were analysed by 2-way analyses of variance. RESULTS: Resistance to cyclic fatigue of the same NiTi file was not significantly affected by immersion in NaOCl . Reciproc R25 was associated with a higher cyclic fatigue resistance in all groups compared to WaveOne Primary (P < 0.0001). CONCLUSIONS: Reciprocating dynamic immersion in NaOCl for 1 or 5 min did not reduce the cyclic fatigue resistance of NiTi files significantly. However, the type of reciprocating instrument influenced cyclic fatigue resistance with Reciproc R25 being more resistant than WaveOne Primary. PMID- 22831398 TI - Nonreproducibility of "snap-frozen" rectal biopsies for later use in ex vivo explant infectibility studies. AB - Sexual transmission accounts for the majority of new HIV infections worldwide with sexually exposed cervicovaginal and colorectal mucosae being primary sites of infection. Two recent Phase 1 rectal microbicide trials included, as an ancillary endpoint, suppression of ex vivo HIV infection of in vivo microbicide exposed rectal mucosal tissue biopsies. Both trials demonstrated significant suppression of biopsy infectibility in drug-exposed versus placebo-exposed tissue. This potential early biomarker of efficacy has raised the feasibility of utilizing "snap-frozen" tissue samples, acquired at multiple trial sites to be shipped for central processing, providing a mechanism to correlate tissue drug concentrations with a functional index of HIV prevention. While previous reports have indicated acceptable comparability of fresh versus freeze-thawed cervicovaginal tissue samples, no similar evaluations with colorectal tissue biopsies have been done. In this study, rectal biopsies from healthy, HIV seronegative participants were assessed for structural integrity (histology), viability (MTT assays), and tissue infectibility to compare results from fresh versus combinations of freeze/thaw protocols. Results indicated that while all protocols showed equivalent viability with fresh samples (MTT), histology documented poor preservation of tissue integrity following freezing. Infectibility results from freeze-thawed colorectal tissue were markedly lower (usually<25% of fresh samples) and varied greatly and unpredictably. Centralized colorectal tissue infectibility assays using biopsies from remote trial sites cannot currently be supported under these protocols. PMID- 22831399 TI - Sex differences in fear memory and extinction of mice with forebrain-specific disruption of the mineralocorticoid receptor. AB - Previous studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain-specific deletion of the MR gene (MR(CaMKCre) ) were unable to show extinction of contextual fear, and could not discriminate between cue and context fear unlike control mice. In the present study, male and female (MR(CaMKCre) ) mice and control littermates were used to study sex-specific fear conditioning, memory performance and extinction. The fear conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. We observed that at the end of the conditioning all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MR(CaMKCre) mice remembered and feared the context more than the control mice. Furthermore, female MR(CaMKCre) mice were not able to extinguish this memory even on the second day of memory testing. The female mutants also could not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MR(CaMKCre) mice and the controls showed extinction and were capable to discriminate, although the MR(CaMKCre) mice needed more time before they started extinction. These findings further support the relevance of MR for behavioral flexibility and extinction of fear-motivated behavior. In conclusion, the loss of MR in the forebrain results in large differences in emotional and cognitive behaviors between female and male mice, which suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders. PMID- 22831400 TI - Head-to-tail and back-to-back dimerization of an open-cage fullerene derivative through pi-pi interaction-based self-assembly. AB - Open-cage fullerene derivative 2, C(59)(O)(4)(NAr)(2) (Ar = p-tBuC(6)H(4)), was prepared from 1, C(60)(O)(4)(OH)(2)(NAr)(2), through processes involving decarbonylation and elimination of the two hydroxyl groups. The phenyl groups in compound 2 act as chelating ligands for the fullerene cage and induce partial dimerization of 2 in solution. The single crystal X-ray structure of 2 shows strong intradimer pi-pi interactions and also weaker interdimer CH-pi and pi-pi interactions. PMID- 22831401 TI - Evaluation of interactive effects on the ionic conduction properties of polymer gel electrolytes. AB - Ionic mobility of electrolyte materials is essentially determined by the nanoscale interactions, the ion-ion interactions and ion-solvent interactions. We quantitatively evaluated the interactive situation of the lithium polymer gel electrolytes through the measurements of ionic conductivity and diffusion coefficients of the mobile species of the lithium polymer electrolytes. The interactive force between the cation and anion in the gel depended on the mixing ratio of the binary solvent, ethylene carbonate plus dimethyl carbonate (EC/DMC). The gel with the solvent (3:7 EC:DMC) showed minimal cation-anion interaction, which is the cause of the highest ionic mobility compared with those of the other gels with different solvents. This suggests that the cation-anion interaction does not simply depend on the dielectric constant of the solvent but is associated with the solvation condition of the lithium. In the case of the gel with the 3:7 EC/DMC solvent, most of the EC species strongly coordinate to a lithium ion, forming the stable solvated lithium, Li(EC)(3)(+), and there are no residual EC species for exchange with them. As a result, the solvating EC species would be a barrier that restricts the anion attack to the lithium leading to the smallest cation-anion interaction. On the other hand, interaction between the cation and polar sites, hydroxyl and oxygen groups of ether of the polyvinyl butyral (PVB) and polyethylene oxide (PEO) polymer, respectively, in the gels was another dominant factor responsible for cation mobility. It increased with increasing polar site concentration per lithium. In case of the PVB gels, cation anion interaction increased with an increasing polymer fraction of the gel contrary to the independent feature of PEO gels with the change of the polymer fraction. This indicates that the cation-anion interaction is associated with the polymer structure of the gel characterized by the kind and configuration of polar groups, molecular weight, and network morphology of the polymer. PMID- 22831456 TI - Abstracts of the Twenty-First Annual Computational Neuroscience Meeting, CNS*2012. Decatur, Georgia, USA. July 21-26, 2012. PMID- 22831455 TI - A designer bleomycin with significantly improved DNA cleavage activity. AB - The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy BLM Z represents the most potent BLM analogue known to date. The fact that 6' deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug. PMID- 22831457 TI - A brief intervention to improve food allergy knowledge among US pediatricians: lessons learned. AB - OBJECTIVE: To evaluate a brief educational tool for pediatricians developed to address known gaps in food allergy knowledge. STUDY DESIGN: Pre- and post assessments were administered to a convenience sample of 61 US pediatricians completing the Food Allergy Comprehension Tool between February and March of 2010. McNemar's and Wilcoxon signed rank tests were used to determine whether clinical knowledge of food allergy and level of comfort in caring for food allergic children increased significantly after reviewing the tool. Logistic regression models were used to measure the association of participant characteristics with increased knowledge and comfort. RESULTS: Sixty-one percent of surveyed physicians answered more knowledge questions correctly after reviewing the tool. Significantly more participants correctly indicated that anaphylaxis poses the greatest threat to teenagers rather than young children, and correctly rejected chronic nasal problems as a symptom of food allergy (p < 0.05). Comfort in caring for food-allergic children increased significantly on all items post-intervention (p < 0.05). Odds of increased knowledge and comfort were significantly higher among pediatricians without previous training in food allergy. CONCLUSION: The Food Allergy Comprehension Tool is a rapid way to address known knowledge gaps among pediatricians and to identify areas in need of further intervention. We recommend integration of the tool with current food allergy guidelines. PMID- 22831459 TI - Retrieving novel C5aR antagonists using a hybrid ligand-based virtual screening protocol based on SVM classification and pharmacophore models. AB - C5aR antagonists have been thought as potential immune mediators in various inflammatory and autoimmune diseases, and discovery of C5aR antagonists has attracted much attention in recent years. The discovery of C5aR antagonists was usually achieved through high-throughput screening, which usually suffered a high cost and a low success rate. Currently, the fast developing computer-aided virtual screening (VS) methods provide economic and rapid approaches to the lead discovery. In this account, we proposed a hybrid ligand-based VS protocol that is based on support vector machine (SVM) classification and pharmacophore models for retrieving novel C5aR antagonists. Performance evaluation of this hybrid VS protocol in virtual screening against a large independent test set, T-CHEM, showed that the hybrid VS approach significantly increased the hit rate and enrichment factor compared with the individual SVM classification model-based VS and pharmacophore model-based VS, as well as molecular docking-based VS in that the receptor structure was created by homology modeling. The hybrid VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally, a total of 20 compounds were selected from the top ranking hits, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future. PMID- 22831458 TI - Budget impact analysis of ustekinumab in the management of moderate to severe psoriasis in Greece. AB - BACKGROUND: The purpose of this study was to estimate the annual and per-patient budget impact of the treatment of moderate to severe psoriasis in Greece before and after the introduction of ustekinumab. METHODS: A budget impact model was constructed from a national health system perspective to depict the clinical and economic aspects of psoriasis treatment over 5 years. The model included drug acquisition, monitoring, and administration costs for both the induction and maintenance years for patients in a treatment mix with etanercept, adalimumab, infliximab, with or without ustekinumab. It also considered the resource utilization for non-responders. Greek treatment patterns and resource utilization data were derived from 110 interviews with dermatologists conducted in February 2009 and evaluated by an expert panel of 18 key opinion leaders. Officially published sources were used to derive the unit costs. Costs of adverse events and indirect costs were excluded from the analysis. Treatment response was defined as the probability of achieving a PASI 50, PASI 75, or PASI 90 response, based on published clinical trial data. RESULTS: The inclusion of ustekinumab in the biological treatment mix for moderate to severe psoriasis is predicted to lead to total per-patient savings of ?443 and ?900 in years 1 and 5 of its introduction, respectively. The cost savings were attributed to reduced administration costs, reduced hospitalizations for non-responders, and improved efficacy. These results were mainly driven by the low number of administrations required with ustekinumab over a 5 year treatment period (22 for ustekinumab, compared with 272 for etanercept, 131 for adalimumab, and 36 for infliximab). CONCLUSIONS: The inclusion of ustekinumab in the treatment of moderate to severe psoriasis in Greece is anticipated to have short- and long-term health and economic benefits, both on an annual and per-patient basis. PMID- 22831460 TI - Nimodipine inhibits IL-1beta release stimulated by amyloid beta from microglia. AB - BACKGROUND AND PURPOSE: There is growing evidence that inflammation plays a major role in the pathogenesis of neural damage caused by deposition of amyloid beta (Abeta) in the brain. Nimodipine has received attention as a drug that might improve learning and reduce cognitive deficits in Alzheimer's disease, but the mechanism of action is poorly known. In this study, we tested the hypothesis that nimodipine inhibited Abeta-stimulated IL-1beta release from microglia. EXPERIMENTAL APPROACH: Cultures of N13 microglia cells or primary mouse microglia were treated with nimodipine, and intracellular accumulation and release of IL 1beta in response to Abeta or to the P2 receptor agonists ATP and benzoyl ATP (BzATP) were measured. Accumulation of IL-1beta was measured in vivo after intrahippocampal inoculation of Abeta in the absence or presence of nimodipine. The effect of nimodipine on Abeta-triggered cytotoxicity was also investigated. KEY RESULTS: We show here that nimodipine dose-dependently inhibited Abeta stimulated IL-1beta synthesis and release from primary microglia and microglia cell lines. Furthermore, nimodipine also inhibited Abeta-induced IL-1betain vivo accumulation at concentrations known to be reached in the CNS. Finally, nimodipine protected microglia from Abeta-dependent cytotoxicity. CONCLUSION AND IMPLICATIONS: These data suggest that alleviation of symptoms of Alzheimer's disease following nimodipine administration might be due to an anti-inflammatory effect and point to a novel role for nimodipine as a centrally acting anti inflammatory drug. PMID- 22831461 TI - A review on human toxoplasmosis. AB - Toxoplasmosis is a worldwide infection caused by the intracellular parasite Toxoplasma gondii. At least a third of the world human population are infected with the parasite, making it one of the most successful parasitic infections. Primary maternal infection may cause health-threatening sequelae for the foetus, or even cause death in uterus. Reactivation of a latent infection in immune deficiency conditions such as AIDS and organ transplantation can cause fatal toxoplasmic encephalitis. Toxoplasmosis is a major cause of retinochoroiditis, especially in individuals with an impaired immune system. Despite the usually 'asymptomatic' nature of the infection, a significant burden imposed by the parasite necessitates the implementation of effective means for the prevention, diagnosis, and management of this disease. Laboratory diagnosis, i.e. PCR and serologic assays, plays the main role in the diagnosis of congenital infection and assists in the confirmatory diagnosis of toxoplasmic encephalitis and ocular toxoplasmosis. Here, we briefly review general aspects of Toxoplasma infection and focus on the diagnostic methods currently used in medical laboratories for the diagnosis of Toxoplasma infection. PMID- 22831462 TI - Effects of fatty acids on cardioprotection by pre-ischaemic inhibition of the malate-aspartate shuttle. AB - 1. The malate-aspartate shuttle (MAS) is the main pathway for balancing extra- and intramitochondrial glucose metabolism. Pre-ischaemic shutdown of the MAS by aminooxyacetate (AOA) mimics ischaemic preconditioning (IPC) in rat glucose perfused hearts. The aim of the present study was to determine the effects of fatty acids (FA) on cardioprotection by pre-ischaemic inhibition of the MAS. 2. Isolated rat hearts were divided into four groups (control; pre-ischaemic AOA (0.2 mmol/L); IPC; and AOA + IPC) and were perfused with 11 mmol/L glucose, 3% bovine serum albumin plus 0, 0.4 or 1.2 mmol/L FA. The perfusion protocol included 30 min global no-flow ischaemia and 120 min reperfusion. Infarct size (IS), haemodynamic recovery, glucose oxidation and lactate release were evaluated in all four groups. 3. Pre-ischaemic AOA reduced the IS of the left ventricle in hearts perfused with 0, 0.4 and 1.2 mmol/L FA compared with that in control hearts (26 +/- 2% vs 53 +/- 4%, 29 +/- 3% vs 53 +/- 4% and 61 +/- 4% vs 81 +/- 3%, respectively; P < 0.01 for all). After 2 h reperfusion, AOA improved haemodynamic recovery in the absence (52 +/- 2 vs 27 +/- 3 mmHg in the AOA and control groups, respectively; P < 0.001) but not in the presence, of FA. Both IPC and AOA + IPC reduced IS and improved haemodynamic recovery regardless of FA levels. Postischaemic glucose oxidation was suppressed by FA and did not differ significantly between the different groups. 4. In conclusion, the reduction in IS induced by pre-ischaemic MAS shutdown is not compromised by physiological FA concentrations. Transient MAS shutdown may be involved in IPC, but is not sufficient on its own as the underlying mechanism for IPC. PMID- 22831463 TI - Drawbacks and benefits associated with inter-organizational collaboration along the discovery-development-delivery continuum: a cancer research network case study. AB - BACKGROUND: The scientific process around cancer research begins with scientific discovery, followed by development of interventions, and finally delivery of needed interventions to people with cancer. Numerous studies have identified substantial gaps between discovery and delivery in health research. Team science has been identified as a possible solution for closing the discovery to delivery gap; however, little is known about effective ways of collaborating within teams and across organizations. The purpose of this study was to determine benefits and drawbacks associated with organizational collaboration across the discovery development-delivery research continuum. METHODS: Representatives of organizations working on cancer research across a state answered a survey about how they collaborated with other cancer research organizations in the state and what benefits and drawbacks they experienced while collaborating. We used exponential random graph modeling to determine the association between these benefits and drawbacks and the presence of a collaboration tie between any two network members. RESULTS: Different drawbacks and benefits were associated with discovery, development, and delivery collaborations. The only consistent association across all three was with the drawback of difficulty due to geographic differences, which was negatively associated with collaboration, indicating that those organizations that had collaborated were less likely to perceive a barrier related to geography. The benefit, enhanced access to other knowledge, was positive and significant in the development and delivery networks, indicating that collaborating organizations viewed improved knowledge exchange as a benefit of collaboration. 'Acquisition of additional funding or other resources' and 'development of new tools and methods' were negatively significantly related to collaboration in these networks. So, although improved knowledge access was an outcome of collaboration, more tangible outcomes were not being realized. In the development network, those who collaborated were less likely to see 'enhanced influence on treatment and policy' and 'greater quality or frequency of publications' as benefits of collaboration. CONCLUSION: With the exception of the positive association between knowledge transfer and collaboration and the negative association between geography and collaboration, the significant relationships identified in this study all reflected challenges associated with inter-organizational collaboration. Understanding network structures and the perceived drawbacks and benefits associated with collaboration will allow researchers to build and funders to support successful collaborative teams and perhaps aid in closing the discovery to delivery gap. PMID- 22831465 TI - Long-acting somatostatin analogues decrease blood transfusion requirements in patients with refractory gastrointestinal bleeding associated with angiodysplasia. AB - BACKGROUND: Gastrointestinal angiodysplasias (GIADs) may be the cause of recurrent bleeding, despite endoscopic treatment. AIM: To evaluate the effect of long-acting somatostatin analogues on blood transfusion requirements, in patients with refractory bleeding due to GIADs. METHODS: Consecutive patients with recurrent bleeding from GIADs were enrolled. They received somatostatin analogue treatment for at least 6 months. The efficacy was evaluated in terms of blood transfusions, frequency of bleeding episodes and haemoglobin level during 6 months of treatment (Period During) compared to a 6-months' period before treatment (Period Before). RESULTS: Fifteen patients were enrolled from 2007 to 2010. The median duration of somatostatin analogue treatment was 12 months (range: 6-36). The number of transfusions significantly decreased in Period During compared with Period Before [median number: 2 (0-14) vs. 10 (6-24); P < 0.001]. The percentage of patients who experienced a bleeding event was lower during somatostatin analogues treatment (20% vs. 73%; P = 0.01). The mean haemoglobin level was significantly higher when somatostatin analogues were offered [median: 10 g/dL (9-13) vs. 7 (5-8.5); P < 0.001]. None of the patients discontinued treatment due to side effects. CONCLUSIONS: Long-acting somatostatin analogues treatment decreased transfusion needs in patients with refractory bleeding from gastrointestinal angiodysplasias. Bleeding episodes were limited and haemoglobin improved during treatment. Long-acting somatostatin analogues may represent an option for the management of patients with chronic bleeding due to gastrointestinal angiodysplasias. PMID- 22831466 TI - Anti-doping analysis and the Olympics. PMID- 22831464 TI - Bursting as a source of non-linear determinism in the firing patterns of nigral dopamine neurons. AB - Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single-spikes and phasic bursts that encode information for certain types of reward-related learning and behavior. Non-linear dynamical analysis has previously demonstrated the presence of a non-linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non-linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non-linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter-spike interval data recorded in vivo from bursting and non-bursting DA neurons in the chloral hydrate-anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non-linear determinism in their firing patterns, whereas non-bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter-burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane-anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate-anesthetized rats. These results strongly indicate that bursting activity is the main source of low dimensional, non-linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons. PMID- 22831467 TI - Half a century of challenges. PMID- 22831468 TI - Current limitations in analytical strategies. PMID- 22831469 TI - Ethical considerations in anti-doping analysis. PMID- 22831471 TI - Interview: partnering with the industry: the Olympic laboratory model. AB - David A Cowan and Campbell P Barker speak to Ryan De Vooght-Johnson at Bioanalysis in May 2012 about the partnership between industry and academia for the setup and running of the doping-control laboratory for the London 2012 Olympic Games. David A Cowan is Director of the London 2012 anti-doping laboratory as well as Director of the King's College London Drug Control Centre, the UK's only WADA-accredited anti-doping laboratory, and Head of the Department of Forensic Science and Drug Monitoring. Cowan co-founded the Drug Control Centre in 1978 and became its Director in 1990. He has published extensively in the field of pharmaceutical analysis, especially as it relates to detecting drug administration in sport, and was awarded a personal chair in pharmaceutical toxicology in 1996. Cowan became Head of the Department of Forensic Science and Drug Monitoring at King's College London in 2002. He has served on a number of national and international committees, including the Council of Europe Working Party Investigating Drug Abuse in Sport that led to the first World Anti-Doping Convention, the Laboratory Representative on the International Olympic Committee's Medical Commission, and WADA's Laboratory Accreditation Subcommittee. He is a member of the Crippen Club for Distinguished Toxicologists. In 1998 he was awarded the IOC Trophy for Sport Ethics by the BOA. He was a founding member of the World Association of Anti-Doping Scientists and became its first President serving on its Executive Board between 2001 and 2004. He was a Visiting Laboratory Director at the Salt Lake City Winter Olympic Games 2002, where the first novel erythropoiesis-stimulating protein (NESP) positive was discovered. He was also a senior advisory scientist at both the Turin Winter Olympic Games in 2006 and the Beijing Olympic Games in 2008. He was also a member of the IOC Medical Commission for the Sydney Olympic Games in 2000 and the Vancouver Winter Olympic Games in 2010. The Drug Control Centre undertook the sample analysis during the 2002 Manchester Commonwealth Games and Cowan was Co-Director of the laboratory for the Commonwealth Games in Kuala Lumpur in 1998. Cowan, who has directed the laboratory at King's College London for many years, was a member of the bid team making the presentation to the International Olympic Committee in February 2005. Campbell P Barker has been leading GlaxoSmithKline's delivery of the London 2012 laboratory services since September 2009. Prior to that time he was Director of Global Strategic Projects in GlaxoSmithKline's Consumer Healthcare business from 2006, and from 1994 to 2006 he worked in R&D for Procter & Gamble. Barker holds a PhD in chemistry from the University of Durham. PMID- 22831472 TI - Analytical progresses of the International Olympic Committee and World Anti Doping Agency Olympic laboratories. AB - The Summer Olympic Games constitute the biggest concentration of human sports and activities in a particular place and time since 776 BCE, when the written history of the Olympic Games in Olympia began. Summer and Winter Olympic anti-doping laboratories, accredited by the International Olympic Committee in the past and the World Anti-Doping Agency in the present times, acquire worldwide interest to apply all new analytical advancements in the fight against doping in sports, hoping that this major human event will not become dirty by association with this negative phenomenon. This article summarizes the new analytical progresses, technologies and knowledge used by the Olympic laboratories, which for the vast majority of them are, eventually, incorporated into routine anti-doping analysis. PMID- 22831473 TI - Detection of erythropoiesis-stimulating agents in human anti-doping control: past, present and future. AB - Stimulation of erythropoiesis is one of the most efficient ways of doping. This type of doping is advantageous for aerobic physical exercise and of particular interest to endurance athletes. Erythropoiesis, which takes place in bone marrow, is under the control of EPO, a hormone secreted primarily by the kidneys when the arterial oxygen tension decreases. In certain pathological disorders, such as chronic renal failure, the production of EPO is insufficient and results in anemia. The pharmaceutical industry has, thus, been very interested in developing drugs that stimulate erythropoiesis. With this aim, various strategies have been, and continue to be, envisaged, giving rise to an expanding range of drugs that are good candidates for doping. Anti-doping control has had to deal with this situation by developing appropriate methods for their detection. This article presents an overview of both the drugs and the corresponding methods of detection, and thus follows a roughly chronological order. PMID- 22831474 TI - Analytical challenges in the detection of peptide hormones for anti-doping purposes. AB - Although significant progress has been achieved during the past few years with the introduction of new assays and analytical methodologies, the detection and quantification of protein analytes, in particular of peptide hormones, continues to pose analytical challenges for the World Anti-Doping Agency-accredited anti doping laboratories. In this article, the latest achievements in the application of MS-based methodologies and specific biochemical and immunological assays to detect some of the prohibited substances listed in section S2 of the World Anti Doping Agency List of Prohibited Substances and Methods are reviewed. In addition, we look towards the future by focusing on some of the most promising analytical approaches under development for the detection of so-called 'biomarkers of doping'. PMID- 22831475 TI - Ensuring high quality in anti-doping laboratories. AB - The worldwide network of World Anti-Doping Agency (WADA)-accredited anti-doping laboratories plays a fundamental role in supporting the global fight against doping in sport. This role is dependent on the ability to provide accurate, reliable and comparable data in identifying and measuring the presence of prohibited substances and methods. The accredited laboratories participate in WADA's External Quality Assessment Scheme (EQAS) program, which provides the structure to continuously assess and improve laboratory performance in compliance to the requirements of the International Standard for Laboratories and related Technical Documents. The WADA EQAS is comprised of various programs, including a blind EQAS, a double-blind EQAS and an educational EQAS, each with specific goals with regard to monitoring and improving laboratory competence. In this article, the anti-doping rules and processes that govern granting and maintenance of WADA laboratory accreditation, aimed at ensuring a high-quality of laboratory operations within the framework of the global fight against doping in sport, are reviewed. PMID- 22831476 TI - Harmonization of anti-doping rules in a global context (World Anti-Doping Agency laboratory accreditation perspective). AB - This article provides a review of the leading role of the World Anti-Doping Agency (WADA) in the context of the global fight against doping in sport and the harmonization of anti-doping rules worldwide through the implementation of the World Anti-Doping Program. Particular emphasis is given to the WADA-laboratory accreditation program, which is coordinated by the Science Department of WADA in conjunction with the Laboratory Expert Group, and the cooperation with the international accreditation community through International Laboratory Accreditation Cooperation and other organizations, all of which contribute to constant improvement of laboratory performance in the global fight against doping in sport. A perspective is provided of the means to refine the existing anti doping rules and programs to ensure continuous improvement in order to face growing sophisticated challenges. A viewpoint on WADA's desire to embrace cooperation with other international organizations whose knowledge can contribute to the fight against doping in sport is acknowledged. PMID- 22831477 TI - Potential and limitations of alternative specimens in doping control. AB - Alternative specimens (e.g., hair and saliva) are well established in forensic toxicology and provide significant benefits as noninvasive, inexpensive alternatives to blood with access to improved long-term retrospection. Based on these experiences, the question of potential applications and limitations of alternative specimens in doping control arose. Compounds prohibited at all times (e.g., clenbuterol, beta(2) agonists, estrogen-receptor modulators) may be successfully tested and clearly interpreted in alternative specimens. In contrast, prohibition of certain compounds in sport are limited to time ranges (e.g., stimulants are only prohibited in-competition), dosages or administration routes (e.g., systemic uptake of glucocorticosteroids). This cannot be properly differentiated by semiquantitative tests (e.g., hair analyses), but may be distinguished in saliva. Similarly, proof of external administration of endogenous steroids (e.g., testosterone) only seems to be achievable by quantitative analysis of saliva. Moreover, the retrospective monitoring of the relevance of social drugs or upcoming (unapproved) substances represents promising applications of hair tests in doping control. PMID- 22831478 TI - Preparation and accreditation of anti-doping laboratories for the Olympic Games. AB - This article outlines the process of preparation of an anti-doping laboratory in view of the activities to be performed on the occasion of the Olympic Games, focusing in particular on the accreditation requirements of the World Anti-Doping Agency (WADA) and ISO/IEC 17025, as well as on the additional obligations required by the International Olympic Committee, which is the testing authority responsible for the anti-doping activities at the Olympics. Due to the elevated workload expected on the occasion of the Olympic Games, the designated anti doping laboratory needs to increase its analytical capacity (samples processed/time) and capability by increasing the laboratory's resources in terms of space, instrumentation and personnel. Two representative cases, one related to the Winter Olympic Games (Torino 2006) and one related to the Summer Olympic Games (Beijing 2008), are presented in detail, in order to discuss the main aspects of compliance with both the WADA and ISO/IEC 17025 accreditation requirements. PMID- 22831479 TI - 2011 lAAF World Championships in Daegu: blood tests for all athletes in the framework of the Athlete Biological Passport. AB - The 2011 International Association of Athletics Federation (IAAF) World Championships took place in Daegu, Korea. For the first time, all athletes were blood tested prior to the competition in order to give a clear signal to the world athletic community of the wish to enter into the era of the Athlete Biological Passport and fight against doping in their sport. The hematological parameters were measured on site. Thus, a mobile-accredited laboratory for blood testing was created in Daegu. Two serum tubes were collected for clinical chemistry and hormonal analyses in order to build the bases of the endocrine and the androgen (steroid) modules of the Athlete Biological Passport in blood. This paper describes some of the main challenges the project faced with regard to the large number of athletes, competing in different disciplines, and the logistic problems that had to be solved for smart implementation of one of the most complex operations organized in the last decade in the fight against doping. PMID- 22831480 TI - Current implementation and future of the Athlete Biological Passport. AB - During the last four decades, the main instrument at the disposal of anti-doping authorities has been the detection of prohibited substances in biological samples collected from athletes. However, the availability of substances identical to those produced by the human body, such as EPO, testosterone and GH, necessitated a new drug-testing paradigm. From the early 2000's, the Athlete Biological Passport (ABP) was proposed as an alternative means to drug testing. Doping leaves a characteristic fingerprint on the biology of the athlete and the ABP is used to prove the act of doping from the detection of that fingerprint. Once a biomarker of doping is implemented in the ABP, it will continue to remain valid and should be able to detect the physiological changes brought on by performance enhancing drugs that have not yet been invented. However, the sensitivity of the ABP to detect doping is limited if the physiological result of a low level of doping remains within the individual's own reference range. Recent advances in proteomics and metabolomics show the huge potential of the ABP. PMID- 22831481 TI - Measurement uncertainty in anti-doping quantitative analysis for prohibited threshold substances. AB - The standards of laboratory performance of the World Anti-Doping Agency (WADA) accredited laboratories are defined in the WADA International Standard for Laboratories and its associated Technical Documents. These sets of rules aim to harmonize the production of valid laboratory test results and evidentiary data as well as the reporting of laboratory analytical findings. The determination of anti-doping rule violations in sport made on the basis of analytical quantitative confirmatory analyses for the presence of prohibited threshold substances, in particular, requires the application of specific compliance decision rules, which are established in the WADA Technical Document on Decision Limits. In this article, the use of measurement uncertainty information in the establishment of compliance Decision Limits and in evaluating the performance of a laboratory's quantitative analytical procedures over time and in relation to other laboratories through WADA's External Quality Assessment Scheme program is reviewed and discussed. Furthermore, a perspective is provided on the emerging challenges associated with the harmonization of the quantitative measurement of large-molecular weight biomolecules. PMID- 22831482 TI - Evolving concepts and techniques for anti-doping. AB - Technical advances are being made in many areas of biotechnology and genetics that are facilitating the detection of doping in sport. These improvements have been catalyzed by the need to counter the ever-increasing sophistication of the community of athletes and their retinues who are intent on the illicit use of physical, pharmacological and genetic tools and methods to enhance athletic performance, in contravention of established international ethical and legal standards and of international treaty. The methods described in this article present a partial and general picture of only some of these advances. PMID- 22831483 TI - Abuse of medicines for performance enhancement in sport: why is this a problem for the pharmaceutical industry? AB - The misuse of medicines for performance enhancement in sport (doping) is not approved by regulatory agencies, and is illegal in many countries. In addition to the 'traditional' doping agents such as steroids, beta-blockers and blood transfusions, the list of agents and techniques used in doping is increasing and now includes newer medicines such as erythropoiesis-stimulating agents and growth hormones. Innovative new medicines are of particular interest as would-be dopers may believe them to be undetectable by current methods. Close collaboration between the biopharmaceutical industry and anti-doping agencies such as the World Anti-Doping Agency is critical to a successful anti-doping strategy. Industry is ideally placed to identify the doping potential of new medicines at early stages and to support early development of detection assays. A strong, united front between the biopharmaceutical industry and anti-doping agencies is essential to counter the misuse of medicines for performance enhancement, as well as to promote fair play and clean sport. PMID- 22831484 TI - Challenges and perspectives in anti-doping testing. AB - In less than 10 years after the implementation of the World Anti-Doping Code and of the International Standard for Laboratories and its related Technical Documents, the analysis of human samples for the purpose of anti-doping testing has undergone a noticeable evolution. The research programs developed by the anti doping organizations, and in particular the World Anti-Doping Agency (WADA), have created an unprecedented momentum in anti-doping science to strengthen the existing analytical methods, as well as to support the development and implementation of new and more sophisticated methodologies by the WADA-accredited laboratories. The integration of technical novelties into the analytical menus has been stimulated by the never-ending challenges posed by the adoption of more complex doping regimens by some athletes and their entourage. This increased sophistication of doping practices has also been reflected in the addition of new doping substances or methods on the WADA Prohibited Substances and Methods List. The integration of new anti-doping scientific paradigms with the development of the Athlete Biological Passport or the foreseen implementation of genomic- and proteomic-based tests constantly reshapes the environment of anti-doping analysis. This article provides a multiangle perspective on some of the key analytical challenges that anti-doping analytical science will face in 2012 and beyond. PMID- 22831485 TI - Construction of interglycosidic N-O linkage via direct glycosylation of sugar oximes. AB - Direct glycosylation of sugar oximes and HONHFmoc has been realized for the first time by using glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh(3)AuOTf, providing an effective approach to the synthesis of N-O linked saccharides, which are of great biological interest. PMID- 22831487 TI - Macromolecular systems understood through multiscale and enhanced sampling techniques. PMID- 22831486 TI - Enhancing the performance of nanofiltration membranes by modifying the active layer with aramide dendrimers. AB - The fully aromatic polyamide active layer of a commercial nanofiltration membrane was modified with three generations (G1, G2, and G3) of aramide dendrimers, all with oligoethylene glycol chains on their peripheries. Permeation experiments revealed that the rejection of Rhodamine WT, used as a surrogate for organic contaminants, improved 1-2 orders of magnitude for membranes modified with G2 and G3 dendrimers at loadings of 0.7-3.5 MUg/cm(2) (dendrimer layer thicknesses of ~1 6 nm) compared to the performance of unmodified membranes. In contrast, the corresponding water permeability of dendrimer-modified membranes decreased by only ~30%. Although an enhancement in the rejection of H(3)AsO(3), NaCl, and BaCl(2) was also observed for dendritic membranes, the effect was less pronounced than that for rhodamine WT. Characterization of membranes modified with 3.5 MUg/cm(2) dendrimers G2 and G3 by Rutherford backscattering spectrometry with the aid of heavy ion probes (Ag(+) and Ba(2+)) revealed that accessibility of the larger Ba(2+) probe to carboxylate groups on the active layer decreased for the membranes modified with dendrimers. PMID- 22831489 TI - [A boy with blunt scrotal trauma]. AB - Blunt scrotal trauma, mostly induced by sports injuries, can cause a testis rupture. Patient exhibit extreme pain and swollen tender testicle. Direct ultrasonography can identify a rupture of the tunica albuginea. A rupture or a suspicion thereof requires a surgical exploration. Delay of diagnosis can cause irreversible damage to the testicle. PMID- 22831490 TI - [Breast-conserving surgery for breast cancer: still much to be gained]. AB - OBJECTIVE: To conduct qualitative research into breast-conserving surgery for palpable and non-palpable breast tumours and the various methods of excising these, measured by the volume exised and surgical radicality. DESIGN: Retrospective, multicentre study. METHOD: The pathology reports from 726 patients who had undergone breast-conserving surgery for invasive breast cancer were reviewed for excision volume and radicality. Any excess resected breast tissue was expressed by a Calculated Resection Ratio (CRR) and calculated by dividing the volume of the surgical specimen by the tumour volume plus an ideal 1-cm margin of tumour-free breast tissue. A CRR of 1.0 meant that the volume excised was ideal; a CRR of 2.0 meant that twice the necessary amount of tissue had been removed. RESULTS: Of all the 726 tumours, 72% appeared to be palpable. The median CRR in this group was 2.2 (range: 0.1 - 43.0) and the percentage of tumour involved margins (irradicality) was 22.5%. Of all the non-palpable tumour (n = 201) excisions, 58% had been guided by wire-localisation, 26% by ultrasonography, and 16% by ROLL (Radio-guided Occult Lesion Localization). The CRRs were 2.8, 3.2 and 3.8, respectively (p < 0.05). Ultrasound-guided surgery resulted in the lowest rate of tumour-involved margins (ultrasound-guided: 3.8%, wire-guided localisation: 21.4%, ROLL: 25.0% (p = 0.05)). CONCLUSION: Breast-conserving surgery is associated with an average of a 2 to 4-fold removal of excessive tissue. Nevertheless, 1 out of 5 excisions are not radical. Ultrasound-guided surgery for non-palpable breast cancer is the most effective method for achieving radical excision. A multicentre, prospective, randomised trial has been started to assess whether ultrasound-guided lumpectomy for palpable breast cancer can lead to optimisation of the excision volume and radicality. PMID- 22831491 TI - [Perinatal health in Rotterdam, the Netherlands--experiences after 2 years of 'Ready for a baby']. AB - The primary goal of the Rotterdam-based health programme 'Ready for a baby' is an improvement in perinatal results via improved, risk-directed care shared across disciplines. After 2 years we conclude that many women who are or who will become pregnant lack knowledge about perinatal risk factors. They are, however, positive about preconception care. High-risk groups can best be accessed via group-based education; results of individual preconceptual care consultations are still limited. We developed and tested a new risk-screening instrument to screen pregnant women during the first antenatal consultation. We directed more attention to non-medical risks, which are often poverty-related. The experiences from our Rotterdam-based programme provide the incentive to experiment with programme-based preconception care, new risk selection during pregnancy and accessing high-risk groups in other communities in the Netherlands. PMID- 22831492 TI - [Underlying causes of diabetes mellitus]. AB - In patients with hyperglycaemia plus obesity and cardiovascular disease, the diagnosis of type 2 diabetes mellitus is likely to be made and this is usually followed by the start of antihyperglycaemic therapy. This pragmatic approach, however, does not always turn out to be the correct one. We describe two patients with occult conditions that had caused or aggravated diabetes mellitus (DM): a 46 year-old man with acromegaly and a 41-year-old woman with Cushing's disease. After neurosurgeries were performed, the requirement for antihyperglycaemic treatment markedly decreased (case 2) or even disappeared (case 1). Physicians treating patients with DM should ask themselves what the cause of the disease could be; the recognition and treatment of that underlying condition may substantially decrease the amount of insulin required and may even cause the disappearance of DM altogether. PMID- 22831493 TI - [Reversible neurological deficit years after high grade glioma--the SMART syndrome]. AB - BACKGROUND: Survival in patients with high grade glioma has been extended in recent years as a result of more intensive therapy. As a consequence, more late term complications of treatment may be observed. CASE DESCRIPTION: A 69-year-old woman presented at the outpatient department of Neurology with headache and loss of strength in the left arm. She had been treated 7 years previously for a high grade glioma with resection and radiotherapy. One year later she had received chemotherapy for a local recurrence. Since then she was free of complaints. At investigation a left sided hemiparesis was found. As recurrence of the tumour was suspected, MR imaging of the brain was performed, which showed abnormalities suggestive for the so called 'stroke-like migraine attacks after radiotherapy' (SMART) syndrome. The further clinical course, with spontaneous recovery of strength within a few weeks and the regression of the cortical hyperintensity on MRI, confirmed the probable diagnosis. CONCLUSION: The SMART syndrome is a relatively unknown condition and should be included in the differential diagnosis in patients who present with new complaints long after cerebral radiotherapy. PMID- 22831494 TI - [Helicobacter pylori-induced thrombocytopenia]. AB - Immune thrombocytopenic purpura (ITP) is a multicausal disease. In the majority of cases, autoimmune antibodies against thrombocytes and other autoimmune processes play a role. However, in about 20% of cases an underlying cause can be identified. Recently, Helicobacter pylori infection was recognized as one of these underlying causes. We present two patients with ITP in whom a significant increase of thrombocytes occurred after eradication of H. pylori. In the first patient, a 75-year-old man, experimental therapy was withheld. The second patient, a 47-year-old man, never received immunosuppressive medication. H. pylori screening and eradication should be standard practice in the work up of a patient with thrombocytopenia. Despite the lack of clear pathophysiological understanding, in a minority of ITP cases there is evidence of a correlation between H. pylori infection and ITP. Tests and treatment are non-invasive, cheap and without major side-effects. In the event of a platelet response, expensive immunosuppressive treatment with significant side effects may be avoided. PMID- 22831495 TI - [How can breast-conserving surgery be improved even more?]. AB - Due to population-wide screening and increased awareness of breast cancer by women, more early-stage diagnoses are being made. Breast-conserving surgery, performed according to well-established guidelines, results in the same level of local control and long-term survival as mastectomy for the same indication. The Dutch Cancer Registry has demonstrated an average local relapse rate at 5 years of about 3% in a follow-up study of breast-cancer patients. A study published in this issue show a high complete resection rate and less excised tissue volume as compared to other localisation techniques or excision by palpation only. There are two provisions: the tumour and its gross delineation must be visible by ultrasound, and the breast surgeon needs to learn the technique and apply it sensibly. Generally speaking, ultrasound-guided breast-conserving resection of invasive breast cancer may well lead to more initially complete resections and better cosmetic results. PMID- 22831496 TI - Using naturalistic driving data to identify variables associated with infrequent, occasional, and consistent seat belt use. AB - Seat belt use is one of the most effective countermeasures to reduce traffic fatalities and injuries. The success of efforts to increase use is measured by road side observations and self-report questionnaires. These methods have shortcomings, with the former requiring a binary point estimate and the latter being subjective. The 100-car naturalistic driving study presented a unique opportunity to study seat belt use in that seat belt status was known for every trip each driver made during a 12-month period. Drivers were grouped into infrequent, occasional, or consistent seat belt users based on the frequency of belt use. Analyses were then completed to assess if these groups differed on several measures including personality, demographics, self-reported driving style variables as well as measures from the 100-car study instrumentation suite (average trip speed, trips per day). In addition, detailed analyses of the occasional belt user group were completed to identify factors that were predictive of occasional belt users wearing their belts. The analyses indicated that consistent seat belt users took fewer trips per day, and that increased average trip speed was associated with increased belt use among occasional belt users. The results of this project may help focus messaging efforts to convert occasional and inconsistent seat belt users to consistent users. PMID- 22831497 TI - Safety models incorporating graph theory based transit indicators. AB - There is a considerable need for tools to enable the evaluation of the safety of transit networks at the planning stage. One interesting approach for the planning of public transportation systems is the study of networks. Network techniques involve the analysis of systems by viewing them as a graph composed of a set of vertices (nodes) and edges (links). Once the transport system is visualized as a graph, various network properties can be evaluated based on the relationships between the network elements. Several indicators can be calculated including connectivity, coverage, directness and complexity, among others. The main objective of this study is to investigate the relationship between network-based transit indicators and safety. The study develops macro-level collision prediction models that explicitly incorporate transit physical and operational elements and transit network indicators as explanatory variables. Several macro level (zonal) collision prediction models were developed using a generalized linear regression technique, assuming a negative binomial error structure. The models were grouped into four main themes: transit infrastructure, transit network topology, transit route design, and transit performance and operations. The safety models showed that collisions were significantly associated with transit network properties such as: connectivity, coverage, overlapping degree and the Local Index of Transit Availability. As well, the models showed a significant relationship between collisions and some transit physical and operational attributes such as the number of routes, frequency of routes, bus density, length of bus and 3+ priority lanes. PMID- 22831498 TI - Small sample sizes, overextraction, and unrealistic expectations: A commentary on M. Mattsson. AB - In a recent article about the Manchester Driver Behaviour Questionnaire (DBQ), Mattsson (2012) concluded that the factor structure was not invariant across subgroups of respondents. This commentary contests this conclusion. PMID- 22831499 TI - The licensing and safety of older drivers in Britain. AB - Driving licence holding in Britain is increasing for older people, particularly older women. Licence holding by men aged 40-69 has saturated at about 90%, and for women aged 30-59 at about 78%. Drivers begin to surrender licences after age 70. By age 90, 38% of women and 25% of men who held a licence at age 70 have surrendered their licences. The paper shows the numbers of car drivers of different ages killed and injured in accidents since 1975 and the fatality and casualty rates per driver and per mile driven. The safety of older drivers is improving faster than that of younger age groups. The number of car driver fatalities aged 70 and over was highest between 1990 and 2004, and has subsequently reduced by almost 40%. For drivers aged 80 and over, the peak was in 2004 and the number has subsequently reduced by almost 50%. The paper uses demographic projections, forecast licence holding and the trends in fatality rates to project the numbers of fatalities for drivers of different ages in Britain. This shows that fatalities among older drivers aged are likely to continue to reduce. Fatality rates for older road users are increased by the fragility of older persons. This disguises the fact that the accident involvement rate for older drivers does not increase with age until after age 75 or 80. PMID- 22831544 TI - Superior semicircular canal dehiscence in East Asian women with osteoporosis. AB - BACKGROUND: Superior semicircular canal dehiscence (SSCD) may cause Tullio phenomenon (sound-induced vertigo) or Hennebert sign (valsalva-induced vertigo) due to the absence of bone overlying the SSC. We document a case series of elderly East Asian women with atypical SSCD symptoms, radiologically confirmed dehiscence and concurrent osteoporosis. METHODS: A retrospective record review was performed on patients with dizziness, vertigo, and/or imbalance from a neurology clinic in a community health center serving the East Asian population in Boston. SSCD was confirmed by multi-detector, high-resolution CT of the temporal bone (with Poschl and Stenvers reformations) and osteoporosis was documented by bone mineral density (BMD) scans. RESULTS: Of the 496 patients seen in the neurology clinic of a community health center from 2008 to 2010, 76 (17.3%) had symptoms of dizziness, vertigo, and/or imbalance. Five (6.6%) had confirmed SSCD by multi-detector, high-resolution CT of the temporal bone with longitudinal areas of dehiscence along the long axis of SSC, ranging from 0.4 to 3.0 mm, as seen on the Poschl view. Two of the 5 patients experienced motion induced vertigo, two fell due to disequilibrium, and one had chronic dizziness. None had a history of head trauma, otologic surgery, or active intracerebral disease. On neurological examination, two patients had inducible vertigo on Dix Hallpike maneuver and none experienced cerebellar deficit, Tullio phenomenon, or Hennebert sign. All had documented osteoporosis or osteopenia by BMD scans. Three of them had definite osteoporosis, with T-scores < -2.5 in the axial spine, while another had osteopenia with a T-score of -2.3 in the left femur. CONCLUSIONS: We describe an unusual presentation of SSCD without Tullio phenomenon or Hennebert sign in a population of elderly, East Asian women. There may be an association of SSCD and osteoporosis in this population. Further research is needed to determine the incidence and prevalence of this disorder, as well as the relationship of age, race, osteoporosis risk, and the development of SSCD. PMID- 22831545 TI - Assessment of Aspergillus sensitization or persistent carriage as a factor in lung function impairment in cystic fibrosis patients. AB - BACKGROUND: Cystic fibrosis (CF) patients presenting with persistent carriage of, or sensitization to, Aspergillus fumigatus are often treated with antifungal therapies because the presence of the fungus is commonly thought to impede lung function, even in the absence of allergic bronchopulmonary aspergillosis (ABPA). The aim of this study was to assess Aspergillus-related status modulating the forced expiratory volume in 1 s (FEV1) of CF patients. METHODS: From 1995 to 2007, 251 patients were evaluated. Demographic data, cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations, body mass index, and FEV(1) were recorded. The presence of A. fumigatus and Pseudomonas aeruginosa in sputum and the levels of A. fumigatus precipitin, total IgE (t-IgE), and specific anti-A. fumigatus IgE (Af-IgE) were determined. Patients were divided into 3 groups: (1) ABPA: A. fumigatus precipitin >=3 lines, Af-IgE > 0.35 IU/ml, and t IgE >=500 IU/ml; (2) sensitization: Af-IgE > 0.35 IU/ml but t-IgE < 500 IU/ml; and (3) persistent carriage: Af-IgE <= 0.35 IU/ml with either an A. fumigatus persistent positive culture or an A. fumigatus precipitin >=3 lines, provided this serological finding had been found associated with at least 1 A. fumigatus positive culture. The remaining patients represented the control group. A multivariate analysis was carried out with FEV(1) as the outcome variable. RESULTS: ABPA, sensitization, and persistent carriage were significantly associated with a larger decline in FEV1 compared with the control group, with odds ratios of 15.9, 14.9, and 10.7, respectively. This association was independent of other associated factors (P. aeruginosa transient detection, age, being underweight, and low FEV1 at baseline). CONCLUSIONS: In addition to ABPA, sensitization and persistent carriage appear to have an impact on pulmonary function in CF patients. PMID- 22831547 TI - Measurement of Ara h 1-, 2-, and 3-specific IgE antibodies is useful in diagnosis of peanut allergy in Japanese children. AB - BACKGROUND: Food challenges are time-consuming, expensive, and not always possible to perform. Therefore, new tools to diagnose food allergy are desired. The aim was to evaluate IgE antibodies to peanut allergens in the diagnosis of peanut allergy in Japanese children using ImmunoCAP((r)) and IgE immunoblotting. METHODS: The study included 2-13-yr-old consecutive patients (n = 57) referred to our specialist clinic for investigation of current peanut allergy using food challenge. All children had a previous doctor's diagnosis of peanut allergy and were on elimination diet. Serum samples were analyzed for IgE reactivity to peanut, recombinant (r) Ara h 1, 2, 3, 5, 8, and 9. IgE immunoblotting (n = 23) was performed using extracts from raw and roasted peanut. RESULTS: Twenty-six of the children failed (allergic group), and 31 passed the peanut challenge (tolerant group). The rAra h 2 ImmunoCAP test was superior in its ability to differentiate between children in the allergic and tolerant groups with a sensitivity and specificity of 88% and 84%, respectively (cutoff, 0.35 kU(A)/l). The combination of rAra h 1, 2, and 3 resulted in a higher specificity (94%) when IgE to all of them was the criteria for positivity. ImmunoCAP generally showed a good agreement with immunoblotting using both raw and roasted peanut for IgE reactivity to Ara h 1, 2, and 3. CONCLUSIONS: Measurement of IgE antibodies to rAra h 1, 2, and 3 is useful in the diagnosis of peanut allergy and in the investigation of reactions to raw and roasted peanut. PMID- 22831548 TI - Effectiveness of community-based comprehensive healthy lifestyle promotion on cardiovascular disease risk factors in a rural Vietnamese population: a quasi experimental study. AB - BACKGROUND: Health promotion is a key component for primary prevention of cardiovascular disease (CVD). This study evaluated the impact of healthy lifestyle promotion campaigns on CVD risk factors (CVDRF) in the general population in the context of a community-based programme on hypertension management. METHODS: A quasi-experimental intervention study was carried out in two rural communes of Vietnam from 2006 to 2009. In the intervention commune, a hypertensive-targeted management programme integrated with a community-targeted health promotion was initiated, while no new programme, apart from conventional healthcare services, was provided in the reference commune. Health promotion campaigns focused on smoking cessation, reducing alcohol consumption, encouraging physical activity and reducing salty diets. Repeated cross-sectional surveys in local adult population aged 25 years and over were undertaken to assess changes in blood pressure (BP) and behavioural CVDRFs (smoking, alcohol consumption, physical inactivity and salty diet) in both communes before and after the 3-year intervention. RESULTS: Overall 4,650 adults above 25 years old were surveyed, in four randomly independent samples covering both communes at baseline and after the 3-year intervention. Although physical inactivity and obesity increased over time in the intervention commune, there was a significant reduction in systolic and diastolic BP (3.3 and 4.7 mmHg in women versus 3.0 and 4.6 mmHg in men respectively) in the general population at the intervention commune. Health promotion reduced levels of salty diets but had insignificant impact on the prevalence of daily smoking or heavy alcohol consumption. CONCLUSION: Community targeted healthy lifestyle promotion can significantly improve some CVDRFs in the general population in a rural area over a relatively short time span. Limited effects on a context-bound CVDRF like smoking suggested that higher intensity of intervention, a supportive environment or a gender approach are required to maximize the effectiveness and maintain the sustainability of the health intervention. PMID- 22831549 TI - Hydrogen sulfide inhibits the translational expression of hypoxia-inducible factor-1alpha. AB - BACKGROUND AND PURPOSE: The accumulation of hypoxia-inducible factor-1alpha (HIF 1alpha) is under the influence of hydrogen sulfide (H(2) S), which regulates hypoxia responses. The regulation of HIF-1alpha accumulation by H(2) S has been shown, but the mechanisms for this effect are largely elusive and controversial. This study aimed at addressing the controversial mechanisms for and the functional importance of the interaction of H(2) S and HIF-1alpha protein. EXPERIMENTAL APPROACH: HIF-1alpha protein levels and HIF-1alpha transcriptional activity were detected by Western blotting and luciferase assay. The mechanisms for H(2) S-regulated HIF-1alpha protein levels were determined using short interfering RNA transfection, co-immunoprecipitation and 7-methyl-GTP sepharose 4B pull-down assay. Angiogenic activity was evaluated using tube formation assay in EA.hy926 cells. KEY RESULTS: The accumulation of HIF-1alpha protein under hypoxia (1% O(2) ) or hypoxia-mimetic conditions was reversed by sodium hydrosulfide (NaHS). This effect of NaHS was not altered after blocking the ubiquitin-proteasomal pathway for HIF-1alpha degradation; however, blockade of protein translation with cycloheximide abolished the effect of NaHS on the half life of HIF-1alpha protein. Knockdown of eukaryotic translation initiation factor 2alpha (eIF2alpha) suppressed the effect of NaHS on HIF-1alpha protein accumulation under hypoxia. NaHS inhibited the expression of VEGF under hypoxia. It also decreased in vitro capillary tube formation and cell proliferation of EA.hy926 cells under hypoxia, but stimulated the tube formation under normoxia. CONCLUSIONS AND IMPLICATIONS: H(2) S suppresses HIF-1alpha translation by enhancing eIF2alpha phosphorylation under hypoxia. The interaction of H(2) S and HIF-1alpha inhibits the angiogenic activity of vascular endothelial cells under hypoxia through the down-regulation of VEGF. PMID- 22831550 TI - Systematic review of knowledge translation strategies in the allied health professions. AB - BACKGROUND: Knowledge translation (KT) aims to close the research-practice gap in order to realize and maximize the benefits of research within the practice setting. Previous studies have investigated KT strategies in nursing and medicine; however, the present study is the first systematic review of the effectiveness of a variety of KT interventions in five allied health disciplines: dietetics, occupational therapy, pharmacy, physiotherapy, and speech-language pathology. METHODS: A health research librarian developed and implemented search strategies in eight electronic databases (MEDLINE, CINAHL, ERIC, PASCAL, EMBASE, IPA, Scopus, CENTRAL) using language (English) and date restrictions (1985 to March 2010). Other relevant sources were manually searched. Two reviewers independently screened the titles and abstracts, reviewed full-text articles, performed data extraction, and performed quality assessment. Within each profession, evidence tables were created, grouping and analyzing data by research design, KT strategy, targeted behaviour, and primary outcome. The published descriptions of the KT interventions were compared to the Workgroup for Intervention Development and Evaluation Research (WIDER) Recommendations to Improve the Reporting of the Content of Behaviour Change Interventions. RESULTS: A total of 2,638 articles were located and the titles and abstracts were screened. Of those, 1,172 full-text articles were reviewed and subsequently 32 studies were included in the systematic review. A variety of single (n = 15) and multiple (n = 17) KT interventions were identified, with educational meetings being the predominant KT strategy (n = 11). The majority of primary outcomes were identified as professional/process outcomes (n = 25); however, patient outcomes (n = 4), economic outcomes (n = 2), and multiple primary outcomes (n = 1) were also represented. Generally, the studies were of low methodological quality. Outcome reporting bias was common and precluded clear determination of intervention effectiveness. In the majority of studies, the interventions demonstrated mixed effects on primary outcomes, and only four studies demonstrated statistically significant, positive effects on primary outcomes. None of the studies satisfied the four WIDER Recommendations. CONCLUSIONS: Across five allied health professions, equivocal results, low methodological quality, and outcome reporting bias limited our ability to recommend one KT strategy over another. Further research employing the WIDER Recommendations is needed to inform the development and implementation of effective KT interventions in allied health. PMID- 22831551 TI - Herbal hepatotoxicity: a critical review. AB - This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements. PMID- 22831552 TI - Investigation of quaternary ammonium silane-coated sand filter for the removal of bacteria and viruses from drinking water. AB - AIMS: To develop an anti-microbial filter media using an attached quaternary ammonium compound (QAC) and evaluate its performance under conditions relevant to household drinking water treatment in developing countries. METHODS AND RESULTS: Silica sand was coated with dimethyloctadecyl [3-(trimethoxysilyl) propyl] ammonium chloride via covalent silane chemistry. Filter columns packed with coated media were challenged with micro-organisms under different water quality conditions. The anti-bacterial properties were investigated by visualizing Escherichia coli (E. coli) attachment to coated media under fluorescence microscopy combined with a live/dead stain. A 9-cm columns with a filtration velocity of 18 m h(-1) achieved log(10) removals of 1.7 for E. coli, 1.8 for MS2 coliphage, 1.9 for Poliovirus type 3 and 0.36 for Adenovirus type 2, compared to 0.1-0.3 log(10) removals of E. coli and MS2 by uncoated sand. Removal scaled linearly with column length and decreased with increasing ionic strength, flow velocity, filtration time and humic acid presence. Escherichia coli attached to QAC-coated sand were observed to be membrane-permeable, providing evidence of inactivation. CONCLUSIONS: Filtration with QAC-coated sand provided higher removal of bacteria and viruses than filtration with uncoated sand. However, major limitations included rapid fouling by micro-organisms and natural organic matter and low removal of viruses PRD1 and Adenovirus 2. SIGNIFICANCE AND IMPACT OF THE STUDY: QAC-coated media may be promising for household water treatment. However, more research is needed on long-term performance, options to reduce fouling and inactivation mechanisms. PMID- 22831553 TI - Synthesis and biological evaluation of a novel (177)Lu-DOTA-[Gly(3) cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]alpha-MSH(3-13) analogue for melanocortin-1 receptor-positive tumor targeting. AB - In this study, a novel alpha-melanocyte stimulating hormone (alpha-MSH) analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled [Gly(3) cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]alpha-MSH(3-13) (DOTA-GMSH) for melanocortin-1 receptor (MC-1R) targeting was newly synthesized, radiolabeled with (177)Lu, and in vitro and in vivo characterized. (177)Lu-labeled peptides were prepared with a high radiolabeling yield (>98%), and its Log p value was 2.89. No degradation was observed not only by serum incubation at 37 degrees C for 7 days but also by an HPLC analysis of radioactive metabolites in urine. A cell binding assay revealed that an inhibitory concentration of 50% (IC(50)) of the peptide was 3.80 nM. The tumor-to-blood ratio, which was 14.27 at 2 hours p.i., was increased to 56.37 at 24 hours p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and was rapidly cleared from the blood pool. We, therefore, conclude that (177)Lu-DOTA-GMSH has promising characteristics for application in nuclear medicine, namely for the diagnosis of MC-1R over-expressing tumors. PMID- 22831554 TI - Swept field laser confocal microscopy for enhanced spatial and temporal resolution in live-cell imaging. AB - Confocal fluorescence microscopy is a broadly used imaging technique that enhances the signal-to-noise ratio by removing out of focal plane fluorescence. Confocal microscopes come with a variety of modifications depending on the particular experimental goals. Microscopes, illumination pathways, and light collection were originally focused upon obtaining the highest resolution image possible, typically on fixed tissue. More recently, live-cell confocal imaging has gained importance. Since measured signals are often rapid or transient, thus requiring higher sampling rates, specializations are included to enhance spatial and temporal resolution while maintaining tissue viability. Thus, a balance between image quality, temporal resolution, and tissue viability is needed. A subtype of confocal imaging, termed swept field confocal (SFC) microscopy, can image live cells at high rates while maintaining confocality. SFC systems can use a pinhole array to obtain high spatial resolution, similar to spinning disc systems. In addition, SFC imaging can achieve faster rates by using a slit to sweep the light across the entire image plane, thus requiring a single scan to generate an image. Coupled to a high-speed charge-coupled device camera and a laser illumination source, images can be obtained at greater than 1,000 frames per second while maintaining confocality. PMID- 22831555 TI - Impact of ambient temperature on children's health: a systematic review. AB - Children are vulnerable to temperature extremes. This paper aimed to review the literature regarding the relationship between ambient temperature and children's health and to propose future research directions. A literature search was conducted in February 2012 using the databases including PubMed, ProQuest, ScienceDirect, Scopus and Web of Science. Empirical studies regarding the impact of ambient temperature on children's mortality and morbidity were included. The existing literature indicates that very young children, especially children under one year of age, are particularly vulnerable to heat-related deaths. Hot and cold temperatures mainly affect cases of infectious diseases among children, including gastrointestinal diseases, malaria, hand, foot and mouse disease, and respiratory diseases. Pediatric allergic diseases, like eczema, are also sensitive to temperature extremes. During heat waves, the incidences of renal disease, fever and electrolyte imbalance among children increase significantly. Future research is needed to examine the balance between hot- and cold-temperature related mortality and morbidity among children; evaluate the impacts of cold spells on cause-specific mortality in children; identify the most sensitive temperature exposure and health outcomes to quantify the impact of temperature extremes on children; elucidate the possible modifiers of the temperature and children's health relationship; and project children's disease burden under different climate change scenarios. PMID- 22831556 TI - Short-term exposure to sulfur dioxide and daily mortality in 17 Chinese cities: the China air pollution and health effects study (CAPES). AB - Sulfur dioxide (SO(2)) is a major air pollutant and has significant impacts upon human health. Few multi-city studies in Asia have examined the acute health effects of SO(2). As part of the China Air Pollution and Health Effects Study (CAPES), this study aimed at investigating the short-term association between SO(2) and daily mortality in 17 Chinese cities. We applied two-stage Bayesian hierarchical models to obtain city-specific and national average estimates for SO(2). In each city, we used Poisson regression models incorporating natural spline smoothing functions to adjust for long-term and seasonal trend of mortality, as well as other time-varying covariates. We examined the associations by age, gender and education status. As a result, the combined analysis showed that an increase of 10 MUg/m(3) of two-day moving averaged SO(2) was associated with 0.75% [95% posterior interval (PI), 0.47 to 1.02], 0.83% (0.95% PI, 0.47 to 1.19) and 1.25% (95% PI, 0.78 to 1.73) increase of total, cardiovascular and respiratory mortality, respectively. The effects of SO(2) appeared more evident among the elderly. These associations were generally independent of particles with aerodynamic diameter <10 MUm (PM(10)) but did not persist after adjustment for nitrogen dioxide (NO(2)). In conclusions, this largest epidemiologic study of air pollution in China to date suggests that short-term exposure to SO(2) is associated with increased mortality risk; however, these associations may be attributable to SO(2) serving as a surrogate of other substances. Further studies are needed to tackle the independent health effect of SO(2). PMID- 22831557 TI - Photoreactivity of fluoroquinolones: nature of aryl cations generated in water. AB - The nature of stabilized aryl cations generated from photodehalogenations of fluoroquinolones in aqueous media has been studied by comparing the photophysical and photochemical behavior of lomefloxacin (LFX) and its N(4')-acetylated form (ALFX). Photoproduct studies, laser flash photolysis, and emission measurements have shown that this small peripheral modification produces important changes in the properties of the singlet aryl cations generated. Also, in basic medium, a new photodehalogenation pathway for 6,8-dihalogenated fluoroquinolones has been observed. PMID- 22831558 TI - Formation and stabilization of combustion-generated, environmentally persistent radicals on Ni(II)O supported on a silica surface. AB - Previous studies have indicated environmentally persistent free radicals (EPFRs) are formed when hydroxyl- and chlorine-substituted aromatics chemisorbed on Cu(II)O and Fe(III)(2)O(3) surfaces and were stabilized through their interactions with the surface metal cation. The current study reports our laboratory investigation on the formation and stabilization of EPFRs on a Ni(II)O surface. The EPFRs were produced by the chemisorption of adsorbates on the supported metal oxide surface and transfer of an electron from the adsorbate to the metal center, resulting in reduction of the metal cation. Depending on the temperature and the nature of the adsorbate, more than one type of organic radical was formed. A phenoxyl-type radical, with g-value between 2.0029 and 2.0044, and a semiquinone-type radical, with g-value from 2.0050 to as high as 2.0081, were observed. The half-lives on Ni(II)O were long and ranged from 1.5 to 5.2 days, which were similar to what were observed on Fe(III)(2)O(3). The yields of the EPFRs formed on Ni(II)O were ~8* higher than on Cu(II)O and ~50* higher than on Fe(III)(2)O(3). PMID- 22831559 TI - Biomimetic liposome- and polymersome-based multicompartmentalized assemblies. AB - Liposomes and polymersomes have attracted significant attention and have emerged as versatile materials for therapeutic delivery and in the design of artificial cells and organelles. Through the judicious choice of building blocks, these synthetic carriers can be readily engineered with tailored interfacial properties, offering new possibilities for the design of advanced assemblies with specific permeability, stability, stimuli response, and targeting capabilities. In this feature article, we highlight recent studies on biomimetic liposome- and polymersome-based multicompartmentalized assemblies en route toward the development of artificial cells, microreactors, and therapeutic delivery carriers. The strategies employed to produce these carriers are outlined, and the properties that contribute to their performance are discussed. Applications of these biomimetic assemblies are highlighted, and finally, areas that require additional investigation for the future development of these assemblies as next generation therapeutic systems are outlined. PMID- 22831560 TI - Burst firing in gonadotrophin-releasing hormone neurones does not require ionotrophic GABA or glutamate receptor activation. AB - Burst firing is a feature of many neuroendocrine cell types, including the hypothalamic gonadotrophin-releasing hormone (GnRH) neurones that control fertility. The role of intrinsic and extrinsic influences in generating GnRH neurone burst firing is presently unclear. In the present study, we investigated the role of fast amino acid transmission in burst firing by examining the effects of receptor antagonists on bursting displayed by green fluorescent protein GnRH neurones in sagittal brain slices prepared from adult male mice. Blockade of AMPA and NMDA glutamate receptors with a cocktail of CNQX and AP5 was found to have no effects on burst firing in GnRH neurones. The frequency of bursts, dynamics of individual bursts, or percentage of firing clustered in bursts was not altered. Similarly, GABA(A) receptor antagonists bicuculline and picrotoxin had no effects upon burst firing in GnRH neurones. To examine the importance of both glutamate and GABA ionotrophic signalling, a cocktail including picrotoxin, CNQX and AP5 was used but, again, this was found to have no effects on GnRH neurone burst firing. To further question the impact of endogenous amino acid release on burst firing, electrical activation of anteroventral periventricular nuclei GABA/glutamate inputs to GnRH neurones was undertaken and found to have no impact on burst firing. Taken together, these observations indicate that bursting in GnRH neurones is not dependent upon acute ionotrophic GABA and glutamate signalling and suggest that extrinsic inputs to GnRH neurones acting through AMPA, NMDA and GABA(A) receptors are unlikely to be required for burst initiation in these cells. PMID- 22831561 TI - Probability and possibility-based representations of uncertainty in fault tree analysis. AB - Expert knowledge is an important source of input to risk analysis. In practice, experts might be reluctant to characterize their knowledge and the related (epistemic) uncertainty using precise probabilities. The theory of possibility allows for imprecision in probability assignments. The associated possibilistic representation of epistemic uncertainty can be combined with, and transformed into, a probabilistic representation; in this article, we show this with reference to a simple fault tree analysis. We apply an integrated (hybrid) probabilistic-possibilistic computational framework for the joint propagation of the epistemic uncertainty on the values of the (limiting relative frequency) probabilities of the basic events of the fault tree, and we use possibility probability (probability-possibility) transformations for propagating the epistemic uncertainty within purely probabilistic and possibilistic settings. The results of the different approaches (hybrid, probabilistic, and possibilistic) are compared with respect to the representation of uncertainty about the top event (limiting relative frequency) probability. Both the rationale underpinning the approaches and the computational efforts they require are critically examined. We conclude that the approaches relevant in a given setting depend on the purpose of the risk analysis, and that further research is required to make the possibilistic approaches operational in a risk analysis context. PMID- 22831562 TI - The impact of ethnic population dynamics on neonatal ECMO outcomes: a single urban institutional study. AB - INTRODUCTION: Neonatal extracorporeal membrane oxygenation ECMO has been clinically used for the last 25 y. It has been an effective tool for both cardiac and non cardiac conditions. The impact of ethno-demographic changes on ECMO outcomes however remains unknown. We evaluated a single institution's experience with non cardiac neonatal ECMO over a 28-y period. METHODS: A retrospective review of all neonates undergoing noncardiac ECMO between the y 1984 and 2011 was conducted and stratified into year groups I, II, III (<=1990, 1991-2000, and >=2001). Demographic, clinical, and outcome data were collected. The patient specifics, ECMO type, ECMO length, blood use, complications, and outcomes were analyzed. Univariate, bivariate, and multivariate analyses were then performed. RESULTS: Data was available for 827 patients. The number of African-American and Hispanic patients increased over the last 27 y (27.5% versus 45.0% and 3.3% versus 21.5%, year group I versus year group III, respectively). The proportion of congenital diaphragmatic hernia (CDH) patients by ethnicity also increased for African-Americans and Hispanics between the two year groups (22.0% to 33.0% and 4.9% to 33.0%, respectively). Similar pattern was noted for non-CDH diagnoses. Low birth weight, low APGAR scores, CDH, primary pulmonary hypertension, central nervous system hemorrhage, and ECMO were independent predictors of mortality. Ethnicity, in itself however, was not associated with mortality on adjusted analysis. CONCLUSION: More African-Americans and Hispanics have required ECMO over the years with a concurrent decrease in the number of Caucasians. While ethnicity was not an independent predictor of mortality, it appears to be a surrogate for fatal but sometime preventable diagnoses among minorities. Further investigations are needed to better delineate the reason behind this disparity. PMID- 22831563 TI - Novel treatments for acute pancreatitis: possibility or pipe dream? PMID- 22831564 TI - Cold ischemia/reperfusion injury in a mouse model of partial liver transplantation. AB - BACKGROUND: Injury to partial liver grafts as a result of ischemia reperfusion remains an important factor in the outcome after transplantation in rodents. Although well described in rats, extended preservation has not been studied in a mouse model of partial liver transplantation. The aim of this study was to develop a model of cold ischemia/reperfusion injury in mouse partial liver transplantation. MATERIALS AND METHODS: Partial liver transplantation was performed in C57BL/6 mice. The liver grafts were stored in 4 degrees C University of Wisconsin solution for different periods of preservation. The liver grafts were transplanted and reduced to 50% by removing the left lobe before the restoration of portal vein flow. Survival was monitored, and hepatocellular injury was examined by histopathologic staining. RESULTS: Survival after partial liver transplantation was 100%, 88%, 89%, and 0% at 2 wk for cold preservation of 1, 4, 8, and 12 h, respectively. Histologic studies showed that microvascular and hepatocyte injury were limited in grafts with short preservation time (1, 4 h). Eight hours of cold ischemia led to focal necrosis. Twelve hours of storage resulted in liver graft failure in all recipients with histology showing extensive hepatic necrosis. CONCLUSIONS: This study suggests partial liver transplantation can be performed in mice with satisfying graft survival. Increasing lengths of cold storage are associated with the progression of tissue injury and decreasing survival. PMID- 22831565 TI - Competence and confidence: taking medical education from apprenticeship to mentorship. PMID- 22831566 TI - Is bone scintigraphy indicated in surgical work-up for hepatocellular carcinoma patients? AB - BACKGROUND: Patients with hepatocellular carcinoma (HCC) undergo extensive staging investigations when being assessed for surgical resection. The aim of this study was to assess the use and yield of baseline bone scintigraphy in patients with HCC necessitating high-risk surgical resection. MATERIAL AND METHODS: All patients diagnosed with HCC between 2000 and 2010 within a tertiary referral center were reviewed. Recurrence and survival rates were compared between patients with and without bone scintigraphy in their preoperative work up. RESULTS: A total of 366 patients were diagnosed with resectable HCC. In the work-up for resection 137 HCC patients (41%) underwent bone scintigraphy, which showed bone metastases in 3 (2%). There was no significant difference in long term survival between patients with and without bone scintigraphy. None of the patients with a positive bone scintigraphy died due to skeletal bone metastases. Only one patient had an indication for bone scintigraphy based on clinical suspicion. Two patients were found to have asymptomatic skeletal metastases prior to surgery. Symptomatic skeletal metastases were identified at an estimated cost of ?27,008 per case. CONCLUSIONS: Clinically unsuspicious bone lesions turned out to be metastases in two patients, with an estimated cost of ?27,008 per case. Recurrence rate and disease-free and overall survival showed no significant difference between patients with and without preoperative baseline bone scintigraphy. There is no justification for routine preoperative bone scintigraphy to detect asymptomatic skeletal metastases in patients with resectable HCC. PMID- 22831567 TI - Role of operative therapy in treatment of metastatic gastrointestinal stromal tumors. AB - BACKGROUND: Operative resection of metastatic gastrointestinal stromal tumors (GIST) is controversial. Current treatment strategies rely on the response to tyrosine kinase inhibitors (TKIs), with resultant individualization of operative intervention. We investigated the role of operative therapy in patients with metastatic GIST. METHODS: This retrospective cohort study included all consecutive patients treated for metastatic and/or recurrent GIST from January 2002 to June 2011. The patients were stratified by the use of operative therapy and disease response to TKI therapy. Kaplan-Meier survival analyses with log-rank comparisons tested the effects of operative therapy and the response to TKIs on survival. RESULTS: Of the 438 patients treated for GIST during the study period, 87 (median age 61 y, interquartile range 50-71; 55% male) had metastatic GIST (84% metastatic, 3% recurrent, and 13% metastatic and recurrent). Of these patients, 54 (62%) underwent operative exploration. Subtotal resection for palliative debulking (R2 resection) were performed in 19 patients; 32 patients underwent R0 resection. Operative intervention was associated with improved overall survival (OS) compared with systemic therapy alone (1 y OS, 98% versus 80% and 5-y OS, 65% versus 11%, respectively; P < 0.001). A TKI was used before resection in 32 patients. The disease response was partial in 13 patients, stable in 10, and progressive in 9. The 1- and 5-y OS and progression-free survival were strongly associated with the preoperative response to TKI and an R0 resection (all P <= 0.002). CONCLUSIONS: Among patients with metastatic GIST, preoperative response to TKI therapy and margin-negative resection were strongly associated with improved progression-free and OS. PMID- 22831568 TI - "It's for a good cause, isn't it?" - Exploring views of South African TB research participants on sample storage and re-use. AB - BACKGROUND: The banking of biological samples raises a number of ethical issues in relation to the storage, export and re-use of samples. Whilst there is a growing body of literature exploring participant perspectives in North America and Europe, hardly any studies have been reported in Africa. This is problematic in particular in light of the growing amount of research taking place in Africa, and with the rise of biobanking practices also on the African continent. In order to investigate the perspectives of African research participants, we conducted a study with research participants in a TB study in the Western Cape, South Africa. METHODS: Semi-structured interviews were conducted using an interview guide which drew on the most prominent themes expressed in current literature on sample storage, re-use and exportation. Interviews were conducted in Afrikaans and subsequently translated into English by the same interviewer. Interviews were transcribed verbatim and analysed qualitatively. RESULTS: The results of our study indicate that the majority of participants were supportive of giving one time consent to the storage and re-use of their samples. The concept of research being for a "good cause" was a central prerequisite. Additionally, a significant minority requested that they be re-contacted if a future use was not stipulated on the original consent. There was also considerable variation in how participants understood the concept of a 'good cause', with participants describing three distinct categories of research, of which two were generally thought to constitute 'good cause' research. Research that was for-profit was considered to fall outside the spectrum of 'good cause' research. Participants displayed confidence in the abilities of the researchers to make future decisions regarding sample use, but seemed unaware of the role of ethics committees in either this process or more generally. CONCLUSIONS: Participants expressed a wide and complex range of views about issues of sample storage and re-use, and they showed a great deal of trust in researchers. Participants' willingness to have their samples stored and re-used is consistent with findings from existing studies. However, in contrast to existing literature, participants were generally not in favour of for-profit research. Further research needs to be done to explore these ideas in other communities, both in South Africa and other countries. PMID- 22831569 TI - Use of a 'microecologic technique' to study crime incidents around methadone maintenance treatment centers - a response: The journal publishes both invited and unsolicited letters. PMID- 22831570 TI - Experiences of care planning in England: interviews with patients with long term conditions. AB - BACKGROUND: The prevalence and impact of long term conditions continues to rise. Care planning for people with long term conditions has been a policy priority in England for chronic disease management. However, it is not clear how care planning is currently understood, translated and implemented in primary care. This study explores experience of care planning in patients with long term conditions in three areas in England. METHODS: We conducted semi-structured interviews with 23 predominantly elderly patients with multiple long term conditions. The interviews were designed to explore variations in and emergent experiences of care planning. Qualitative analysis of interview transcripts involved reflexively coding and re-coding data into categories and themes. RESULTS: No participants reported experiencing explicit care planning discussions or receiving written documentation setting out a negotiated care plan and they were unfamiliar with the term 'care planning'. However, most described some components of care planning which occurred over a number of contacts with health care professionals which we term "reactive" care planning. Here, key elements of care planning including goal setting and action planning were rare. Additionally, poor continuity and coordination of care, lack of time in consultations, and patient concerns about what was legitimate to discuss with the doctor were described. CONCLUSIONS: Amongst this population, elements of care planning were present in their accounts, but a structured, comprehensive process and consequent written record (as outlined in English Department of Health policy) was not evident. Further research needs to explore the advantages and disadvantages of different approaches to care planning for different patient groups. PMID- 22831632 TI - A systematic review of educational interventions to change behaviour of prescribers in hospital settings, with a particular emphasis on new prescribers. AB - AIMS: Prescribing is a complex task and a high risk area of clinical practice. Poor prescribing occurs across staff grades and settings but new prescribers are attributed much of the blame. New prescribers may not be confident or even competent to prescribe and probably have different support and development needs than their more experienced colleagues. Unfortunately, little is known about what interventions are effective in this group. Previous systematic reviews have not distinguished between different grades of staff, have been narrow in scope and are now out of date. Therefore, to inform the design of educational interventions to change prescribing behaviour, particularly that of new prescibers, we conducted a systematic review of existing hospital-based interventions. METHODS: Embase, Medline, SIGLE, Cinahl and PsychINFO were searched for relevant studies published 1994-2010. Studies describing interventions to change the behaviour of prescribers in hospital settings were included, with an emphasis on new prescibers. The bibliographies of included papers were also searched for relevant studies. Interventions and effectiveness were classified using existing frameworks and the quality of studies was assessed using a validated instrument. RESULTS: Sixty-four studies were included in the review. Only 13% of interventions specifically targeted new prescribers. Most interventions (72%) were deemed effective in changing behaviour but no particular type stood out as most effective. CONCLUSION: Very few studies have tailored educational interventions to meet needs of new prescribers, or distinguished between new and experienced prescribers. Educational development and research will be required to improve this important aspect of early clinical practice. PMID- 22831633 TI - Transepithelial transport of theasinensins through Caco-2 cell monolayers and their absorption in Sprague-Dawley rats after oral administration. AB - The aim of this study is to illustrate the in vivo and in vitro absorption of theasinensins B and A that are (-)-epigallocatechin-3-O-gallate (EGCG)-(-) epigallocatechin (EGC) dimer and EGCG dimer, respectively, and their transport pathway across the intestinal membrane. Our animal study by a single oral administration to rats demonstrated the intact absorption of theasinensins into the blood system, which was estimated to be a >10-fold lower absorption amount than EGCG. The in vitro absorption study indicated that theasinensins can be transported across Caco-2 cell monolayers, while their permeability coefficients were also >10-fold lower than those of EGCG and EGC. Transport experiments using cytochalasin D or quercetin as a tight junction (TJ) modulator and a non saturable permeation revealed that theasinensins were transported across Caco-2 cells in a TJ paracellular diffusion route. In conclusion, the dimers of condensed catechins, theasinensins B and A, can be absorbed intact into rat blood and transported across Caco-2 cell monolayers probably through a TJ paracellular pathway. PMID- 22831634 TI - Changes in the aerobic faecal flora of patients treated with antibiotics for acute intra-abdominal infection. AB - BACKGROUND: An open observational study was performed to investigate changes in the rectal flora and antibiotic susceptibility among faecal bacteria in patients treated with antibiotics for acute intra-abdominal infection. METHODS: One hundred and forty patients with acute intra-abdominal infection requiring antibiotic treatment and hospitalization were included. Eight surgical units from the southern part of Sweden participated, between January 2006 and November 2007. Antibiotic treatments were according to local guidelines. Rectal swabs were obtained on admission (sample 1) and 2-14 days after the end of antibiotic treatment (sample 2). Aerobic bacteria and yeasts were analysed. The material was divided into 2 groups: 1 group with Enterobacteriaceae and 1 group with non fermentative Gram-negative bacteria. The susceptibility to antibiotics in each group was compared between samples 1 and 2. RESULTS: The main finding of this study on patients with severe intra-abdominal infections was a shift in the aerobic faecal flora following antibiotic treatment, from Escherichia coli to other more resistant Enterobacteriaceae, Enterococcus faecium, and yeasts. The susceptibility to cephalosporins and piperacillin-tazobactam decreased in Enterobacteriaceae. CONCLUSIONS: Following antibiotic treatment, a shift in the aerobic rectal flora to species with intrinsic antibiotic resistance was observed. This indicates that the emergence of resistance is not due to new mutations, but rather to selection of more resistant species. This should be taken into account when designing treatments for secondary intra-abdominal infections. PMID- 22831635 TI - Response to "is liposomal amphotericin B really safety in neonates?". PMID- 22831636 TI - Maternal preeclampsia is associated with increased risk of necrotizing enterocolitis in preterm infants. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is an important cause of mortality and morbidity in preterm infants. AIMS: To evaluate the effect of maternal preeclampsia on the development and severity of NEC in premature infants. STUDY DESIGN: Prospective observational study in a tertiary neonatal intensive care unit. SUBJECTS: The preterm infants of <= 37 gestational age who were consecutively hospitalized were enrolled. The study group contained preterm infants born to a preeclamptic mother and the comparison group contained preterm infants born to a normotensive mother. OUTCOME MEASURES: The primary outcome was to determine the association between preeclampsia and NEC. RESULTS: A total of 88 infants had NEC diagnosis. The incidence of NEC in infants born to preeclamptic mothers (22.9%) was significantly higher compared with those born to normotensive mothers (14.6%). According to NEC stages, NEC was more advanced in preeclamptic mother infants. NEC developed significantly earlier in infants with NEC in the study group. The duration of NEC was also significantly longer in infants born to preeclamptic mothers. In multiple logistic regression model, preeclampsia was found to be predictive of NEC with an odds ratio of 1.74 (95% confidence interval 0.64-0.92). CONCLUSIONS: Maternal preeclampsia may be an important risk factor for the development of NEC in premature infants as NEC incidence and severity of NEC were found to be significantly higher in premature infants born to preeclamptic mothers. The onset of NEC was significantly earlier and duration of NEC was longer in these infants. PMID- 22831637 TI - Acute cardiovascular responses in preterm infants at 34-39 weeks of gestational age. AB - BACKGROUND: Premature infants demonstrate immature physiological control mechanisms; however their acute cardiovascular control has not yet been widely studied. AIM: The aim of this study was to analyze heart rate (HR) and blood pressure (BP) control in preterm infants. SUBJECTS: Twenty preterm infants with a mean gestational age of 31 +/- 2.4 (26-34) weeks at birth were evaluated at a gestational age of 36 +/- 1.5 (34-39) weeks. Results were compared to twenty, healthy, full-term, control infants studied at the age of 12 +/- 3 weeks. OUTCOME MEASURES: HR and BP responses to 45 degrees head-up tilt and side motion tests during non-rapid eye movement sleep were analyzed. In addition, HR responses to spontaneous arousals from non-rapid eye movement sleep were evaluated. RESULTS: Preterm infants showed significantly smaller initial HR and BP responses compared with controls in head-up tilt (HR p=0.0005, systolic BP p=0.02, diastolic BP p=0.01) and side motion tests (HR p=0.002, systolic BP p<0.0001, diastolic BP p<0.0001). Furthermore, in tilt tests, preterm infants presented with greater intersubject variability in BP responses than controls (systolic BP p=0.009, diastolic BP p=0005). Preterm HR responses to spontaneous arousals were similar to controls. CONCLUSIONS: This study indicates immature vestibulo-mediated cardiovascular control in preterm infants compared with term infants. This is seen as attenuated BP responses to side motion test and more labile acute BP control to postural challenge. PMID- 22831638 TI - Genomes for jeans: cotton genomics for engineering superior fiber. AB - Twenty years ago, scientists predicted that better understanding of fiber development would lead to novel ways to engineer superior cotton fiber. Advances in genetic resources, DNA markers, DNA sequence information, and gene expression data have indeed provided new insights into fiber initiation, elongation and maturation. Many exciting applications of this knowledge offer the potential to select better cotton genotypes more effectively in mainstream breeding programs or engineer genotypes with improved agronomic and/or quality traits. Here, we discuss recent progress in understanding genes involved in fiber development, and their regulation and manipulation to engineer improved fibers. Better understanding of quantitative trait loci/gene interactions that influence fiber quality and yield may help to tailor superior cotton genotypes to diverse environments. PMID- 22831639 TI - Axon degeneration and regeneration: insights from Drosophila models of nerve injury. AB - Axon degeneration is the pivotal pathological event of acute traumatic neural injury as well as many chronic neurodegenerative diseases. It is an active cellular program and yet molecularly distinct from cell death. Much effort is devoted toward understanding the nature of axon degeneration and promoting axon regeneration. However, the fundamental mechanisms of self-destruction of damaged axons remain unclear, and there are still few treatments for traumatic brain injury (TBI) or spinal cord injury (SCI). Genetically approachable model organisms such as Drosophila melanogaster, the fruit fly, have proven exceptionally successful in modeling human neurodegenerative diseases. More recently, this success has been extended into the field of acute axon injury and regeneration. In this review, we discuss recent findings, focusing on how these models hold promise for accelerating mechanistic insight into axon injury and identifying potential therapeutic targets for TBI and SCI. PMID- 22831640 TI - Diversity of clathrin function: new tricks for an old protein. AB - Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. Detailed knowledge of clathrin biochemistry, structure, and interacting proteins has accumulated since the first observation, almost 50 years ago, of its role in receptor-mediated endocytosis of yolk protein. This review summarizes that knowledge, and focuses on properties of the clathrin heavy and light chain subunits and interaction of the latter with Hip proteins, to address the diversity of clathrin function beyond conventional receptor-mediated endocytosis. The distinct functions of the two human clathrin isoforms (CHC17 and CHC22) are discussed, highlighting CHC22's specialized involvement in traffic of the GLUT4 glucose transporter and consequent role in human glucose metabolism. Analysis of clathrin light chain function and interaction with the actin-binding Hip proteins during bacterial infection defines a novel actin-organizing function for CHC17 clathrin. By considering these diverse clathrin functions, along with intracellular sorting roles and influences on mitosis, further relevance of clathrin function to human health and disease is established. PMID- 22831641 TI - A man for all seasons: reflections on the life and legacy of George Palade. AB - In this perspective, I review the scientific career of George E. Palade, the man many consider to be the father of cell biology. Palade's scientific contributions spanned more than 50 years (from the late 1940s to 2001) and were amazingly diverse and fundamental. He is best known for his discovery of ribosomes, for establishing their role in protein synthesis, and for delineation of the secretory pathway. In addition to these groundbreaking contributions, he also developed basic techniques for tissue preservation and cell fractionation that allowed rapid progress during the early days of cell biology, and he and his collaborators provided the first description of the mitochondrial cristae, neuronal synapses, junctional complexes in epithelia, plasmalemmal vesicles, and Weibel-Palade bodies in endothelium, among others. He and his collaborators also contributed key experimental data to our understanding not only of protein synthesis and the secretory process but also of membrane biogenesis and vascular permeability. In addition to his scientific discoveries, he had a profound impact on the lives of many cell biologists and served the scientific community tirelessly while making major contributions to the development of cell biology in three major institutions. PMID- 22831642 TI - Multivesicular body morphogenesis. AB - Multivesicular bodies (MVBs) are unique organelles in the endocytic pathway that contain vesicles in their lumen. Sorting and incorporation of material into such vesicles is a critical cellular process that has been intensely studied following discovery of the ESCRT (endosomal sorting complex required for transport) machinery just more than a decade ago. In this review, we summarize current understanding of the cellular functions of MVBs and how the ESCRT machinery contributes to MVB morphogenesis. We also highlight the importance of MVBs and ESCRTs in human health. We identify critical areas in which further mechanistic and spatiotemporal studies in living cells will advance this exciting area of research. PMID- 22831643 TI - Facial paralysis during air travel: case series and literature review. AB - OBJECTIVE: We report three cases of recurrent, unilateral facial palsy associated with air travel. METHOD: The three cases are presented, along with a brief literature review concerning barotrauma and its association with air travel and facial palsy. RESULTS: All three patients experienced unilateral facial paralysis during air travel, accompanied by additional symptoms which varied between cases. Symptoms resolved spontaneously in all cases. Two patients received ventilation tube insertion to prevent further recurrence. Computed tomography scanning revealed no bony defect in two patients, while the third exhibited dehiscence of the facial canal which may have contributed to the condition. CONCLUSION: Available evidence suggests that eustachian tube dysfunction can contribute to increased pressure within the middle ear, leading to neuropraxia of the facial nerve. Cases of facial paralysis associated with air travel are under-reported. Since there is no evidence-based management protocol for this condition, further investigation of its pathology is encouraged in order to improve our understanding. PMID- 22831645 TI - Characterization of oil-free and oil-loaded liquid-crystalline particles stabilized by negatively charged stabilizer citrem. AB - The present study was designed to evaluate the effect of the negatively charged food-grade emulsifier citrem on the internal nanostructures of oil-free and oil loaded aqueous dispersions of phytantriol (PHYT) and glyceryl monooleate (GMO). To our knowledge, this is the first report in the literature on the utilization of this charged stabilizing agent in the formation of aqueous dispersions consisting of well-ordered interiors (either inverted-type hexagonal (H(2)) phases or inverted-type microemulsion systems). Synchrotron small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were used to characterize the dispersed and the corresponding nondispersed phases of inverted-type nonlamellar liquid-crystalline phases and microemulsions. The results suggest a transition between different internal nanostructures of the aqueous dispersions after the addition of the stabilizer. In addition to the main function of citrem as a stabilizer that adheres to the surface of the dispersed particles, it has a significant impact on the internal nanostructures, which is governed by the following factors: (1) its penetration between the hydrophobic tails of the lipid molecules and (2) its degree of incorporation into the lipid water interfacial area. In the presence of citrem, the formation of aqueous dispersions with functionalized hydrophilic domains by the enlargement of the hydrophilic nanochannels of the internal H(2) phase in hexosomes and the hydrophilic core of the L(2) phase in emulsified microemulsions (EMEs) could be particularly attractive for solubilizing and controlling the release of positively charged drugs. PMID- 22831646 TI - An experimental study on tympanic membrane reconstruction with acellular dermal matrix. AB - CONCLUSION: Acellular dermal matrix (ADM) can be used as a substitute for tympanic membrane (TM) reconstruction. OBJECTIVE: To investigate the effectiveness of ADM in the treatment of TM perforations. METHODS: Fifty guinea pigs were used to create TM perforations. The perforations of the left TM were repaired with ADM by patch technique in 28 guinea pigs and by underlay technique in 22 guinea pigs. The right ears were used as the control group by establishing TM perforation but without TM reconstruction. The morphological and structural status of the grafts was observed by immunohistochemistry and scanning electron microscopy. RESULTS: There was no statistically significant difference in TM perforation closure between the ADM patch technique group and the ADM underlay technique group, but these groups had a higher success rate in closing TM perforation than the control group. The healed TMs with ADM had the same characteristics as normal TM on histological examination. PMID- 22831644 TI - The omega3-polyunsaturated fatty acid derivatives AVX001 and AVX002 directly inhibit cytosolic phospholipase A(2) and suppress PGE(2) formation in mesangial cells. AB - BACKGROUND AND PURPOSE: omega3-polyunsaturated fatty acids (omega3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized. EXPERIMENTAL APPROACH: Here we report on two new cPLA(2) inhibitors, the omega3-derivatives AVX001 and AVX002, and their effects on inflammatory PGE(2) production in cultures of renal mesangial cells. KEY RESULTS: AVX001 and AVX002 dose-dependently inhibited the group IVA cytosolic phospholipase A(2) (cPLA(2) ) in an in vitro activity assay with similar IC(50) values for AVX001 and AVX002, whereas the known cPLA(2) inhibitor AACOCF(3) was less potent and docosahexaenoic acid (DHA) was inactive. In renal mesangial cells, AVX001 and AVX002 suppressed IL-1beta-induced PGE(2) synthesis. Mechanistically, this effect occurred by a down-regulation of IL-1beta induced group IIA-sPLA(2) protein expression, mRNA expression and promoter activity. A similar but less potent effect was seen with AACOCF(3) and no effect was seen with DHA. As gene expression of sPLA(2) is known to be regulated by the transcription factor NF-kappaB, we further investigated NF-kappaB activation. Both compounds prevented NF-kappaB activation by blocking degradation of the inhibitor of kappaB. CONCLUSIONS AND IMPLICATIONS: These data show for the first time that the novel cPLA(2) inhibitors AVX001 and AVX002 exert an anti inflammatory effect in cultures of renal mesangial cells and reduce the pro inflammatory mediator PGE(2) through an inhibitory effect on NF-kappaB activation. Therefore, these compounds may represent promising novel drugs for the treatment of inflammatory disorders. PMID- 22831647 TI - Hydrological tracers using nanobiotechnology: proof of concept. AB - In order to answer questions that involve differentiating among multiple and potentially interacting hydrological flowpaths, it would be ideal to use multiple tracers with identical transport properties that can nonetheless be distinguished from each other. This paper describes the development and proof of concept of a new kind of engineered tracer system that allows a large number of individual tracers to be simultaneously distinguished from one another. This new tracer is composed of polylactic acid (PLA) microspheres into which short strands of synthetic DNA and paramagnetic iron oxide nanoparticles are incorporated. The synthetic DNA serves as the "label" or "tag" in our tracers that allow us to distinguish one tracer from another, and paramagnetic iron oxide nanoparticles are included in the tracer to facilitate magnetic concentration of the tracers in potentially dilute water samples. Some potential advantages of this tracer concept include: virtually limitless uniquely labeled tracers, highly sensitive detection, and relatively moderate expense. Three proof-of-concept experiments at scales ranging from orders of 10 cm to 100 m demonstrated the use of the tracer system. PMID- 22831649 TI - Elevation of tau protein levels in the cerebrospinal fluid of children with West syndrome. AB - PURPOSE: West syndrome is an epileptic encephalopathy with a poor developmental outcome. Tau protein levels in the cerebrospinal fluid (CSF) are reported to be markers of axonal damage and neurodegeneration. This study aimed to investigate axonal damage and the effects of adrenocorticotropic hormone (ACTH) therapy on axons in West syndrome, as measured by tau protein levels in CSF. METHODS: Tau protein levels in CSF before and after ACTH therapy were determined by an enzyme linked immunosorbent assay in 26 children with West syndrome. Of these 26 children, 18 were symptomatic, and 8 had a cryptogenic form of West syndrome. A group of 41 unaffected children was included in the study as a control group. RESULTS: The levels of tau protein in CSF were significantly higher in children with West syndrome than in the control group, and these levels remained high after ACTH therapy. ACTH therapy was effective for 20 of the 26 children with West syndrome, and their CSF tau protein levels were significantly higher after ACTH therapy than before therapy. CONCLUSION: Our results suggest that axonal damage occurs in West syndrome, as judged by tau protein levels in CSF. PMID- 22831650 TI - Histiocytic sarcoma of the brain. AB - Histiocytic sarcoma is a rare malignant neoplasm of the lympho-hematopoietic system that usually occurs in the skin, lymph nodes and intestinal tract. We present a 36-year-old woman with a rare histiocytic sarcoma with isolated central nervous system (CNS) involvement of multifocal circumscribed lesions. Biopsy of the brain lesions showed diffuse proliferation of pleomorphic histiocytes that were immunopositive for CD45, CD68 and CD163. Various cytokeratins and markers of lymphoma, melanoma, germ cell tumours and primary CNS tumours were negative. Examination of bone marrow trephine and a whole-body positron emission tomography scan showed no evidence of involvement of any other organ systems, thus establishing the primary nature of the lesion. The neoplastic cells uniquely showed eosinophilic globules within the cytoplasm, which were positive for CD68. These globules were shown by electron microscopy to be collections of lysosomes. A thorough discussion of the differential diagnosis and literature review is included. PMID- 22831651 TI - Erythroplasia of Queyrat refractory to photodynamic therapy. PMID- 22831648 TI - Do physician communication skills influence screening mammography utilization? AB - BACKGROUND: The quality of physician communication skills influences health related decisions, including use of cancer screening tests. We assessed whether patient-physician communication examination scores in a national, standardized clinical skills examination predicted future use of screening mammography (SM). METHODS: Cohort study of 413 physicians taking the Medical Council of Canada clinical skills examination between 1993 and 1996, with follow up until 2006. Administrative claims for SM performed within 12 months of a comprehensive health maintenance visit for women 50-69 years old were reviewed. Multivariable regression was used to estimate the relationship between physician communication skills exam score and patients' SM use while controlling for other factors. RESULTS: Overall, 33.8 % of 96,708 eligible women who visited study physicians between 1993 and 2006 had an SM in the 12 months following an index visit. Patient-related factors associated with increased SM use included higher income, non-urban residence, low Charlson co-morbidity index, prior benign breast biopsy and an interval >12 months since the previous mammogram. Physician-related factors associated with increased use of SM included female sex, surgical specialty, and higher communication skills score. After adjusting for physician and patient-related factors, the odds of SM increased by 24 % for 2SD increase in communication score (OR: 1.24, 95 % CI: 1.11 - 1.38). This impact was even greater in urban areas (OR 1.30, 95 % CI: 1.16, 1.46) and did not vary with practice experience (interaction p-value 0.74). CONCLUSION: Physicians with better communication skills documented by a standardized licensing examination were more successful at obtaining SM for their patients. PMID- 22831652 TI - Measurement of single soybean seed attributes by near-infrared technologies. A comparative study. AB - Four near-infrared spectrophotometers, and their associated spectral collection methods, were tested and compared for measuring three soybean single-seed attributes: weight (g), protein (%), and oil (%). Using partial least-squares (PLS) and four preprocessing methods, the attribute that was significantly most easily predicted was seed weight (RPD > 3 on average) and protein the least. The performance of all instruments differed from each other. Performances for oil and protein predictions were correlated with the instrument sampling system, with the best predictions using spectra taken from more than one seed angle. This was facilitated by the seed spinning or tumbling during spectral collection as opposed to static sampling methods. From the preprocessing methods utilized, no single one gave the best overall performances but weight measurements were often more successful with raw spectra, whereas protein and oil predictions were often enhanced by SNV and SNV + detrending. PMID- 22831653 TI - Chemical vapor deposition of porous GaN particles on silicon. AB - We present a technique for the direct deposition of nanoporous GaN particles on Si substrates without requiring any post-growth treatment. The internal morphology of the nanoporous GaN particles deposited on Si substrates by using a simple chemical vapor deposition approach was investigated, and straight nanopores with diameters ranging between 50 and 100 nm were observed. Cathodoluminescence characterization revealed a sharp and well-defined near band edge emission at ~365 nm. This approach simplifies other methods used for this purpose, such as etching and corrosion techniques that can damage the semiconductor structure and modify its properties. PMID- 22831702 TI - Severe primary cytomegalovirus infection in the immunocompetent adult patient: a case series. AB - Primary cytomegalovirus (CMV) infection is rare in immunocompetent adults, even rarer in elderly patients. Little is known about the severity of symptoms and the clinical course in this patient group. In children and younger adults, CMV mostly presents as an asymptomatic disease or a self-limiting mild mononucleosis-like syndrome. We describe the clinical course of an unusually severe primary CMV infection in a 69-y-old otherwise healthy man, as well as 6 other severe cases in immunocompetent adults at our institution, and compare them to adult cases from the literature. CMV primary infection and antiviral treatment should be considered in immunocompetent elderly persons presenting with a severe mononucleosis-like syndrome. PMID- 22831701 TI - Intact catecholamine inputs to the forebrain are required for appropriate regulation of corticotrophin-releasing hormone and vasopressin gene expression by corticosterone in the rat paraventricular nucleus. AB - Corticotrophin-releasing hormone (CRH) neuroendocrine neurones in the paraventricular nucleus of the hypothalamus (PVH) drive adrenocorticotrophic hormone (ACTH) and thereby glucocorticoid release from pituitary corticotrophs and the adrenal cortex, respectively. Glucocorticoids suppress the ability of neuroendocrine corticotrophin-releasing hormone (CRH) neurones to synthesise and release ACTH secretogogues. Despite the importance of glucocorticoids as regulatory signals to CRH neurones in the extended time domain, how and where they act in this capacity is still not fully understood. Ascending catecholamine projections encode important cardiovascular, metabolic and other visceral information to the rat PVH and surrounding hypothalamus. These afferents have previously been implicated as targets for glucocorticoid action, including a role in the feedback regulation of PVH neuroendocrine neurones. To determine the contribution of these neurones to the long-term actions of corticosterone on CRH and vasopressin (AVP) gene expression in the PVH, we used an immunocytotoxin (a conjugate of the cytotoxin saporin and an antibody against dopamine-beta hydroxylase) that specifically ablates adrenergic and noradrenergic neurones. Lesions were administered to intact animals and to adrenalectomised animals with either no corticosterone or corticosterone replacement that provided levels above those required to normalise Crh expression. The ability of elevated levels of corticosterone to suppress Crh expression was abolished in animals lacking catecholaminergic innervation of the PVH. No effect was seen in the absence of corticosterone or in animals with intact adrenals. Furthermore, Avp expression, which is increased in CRH neurones following adrenalectomy, was suppressed in adrenalectomised catecholaminergic-lesioned animals. Interactions between corticosterone and catecholaminergic projections to the hypothalamus therefore make significant contributions to the regulation of Crh and Avp expression. However, the importance of catecholamine inputs is only apparent when circulating corticosterone concentrations are maintained either below or above those required to maintain the activity of the hypothalamic-pituitary-adrenal axis that is seen in intact animals. PMID- 22831703 TI - A systematic review of disability awareness interventions for children and youth. AB - PURPOSE: Children's lack of knowledge about disability can adversely impact their attitudes toward people with disabilities. The purpose of this study is to review the common elements of effective disability awareness interventions. METHODS: A systematic review of disability awareness interventions for children and youth was conducted to assess the effective components of these interventions. Electronic searches were conducted using OVID, CENTRAL, PsychInfo, ERIC, Social Science Citation Index, GreyNET Scopus and Google Scholar. The inclusion criteria included (i) an intervention raising awareness about disability, (ii) school-age children with the average age between 5-19 years old, (iii) at least one measurable outcome focusing on knowledge about disability or attitudes towards and/or acceptance of people with a disability and (iv) published article or grey literature. RESULTS: Of the 1031 articles that were identified in the search, 42 met the criteria to be included in the review. We classified the disability awareness interventions into 5 broad types including (i) social contact, (ii) simulation, (iii) curriculum, (iv) multi-media curriculum and (v) multiple components. Thirty-four studies showed an improvement in attitudes towards and/or acceptance of peers with disabilities. Eight of these studies also demonstrated an improvement in knowledge of people with disabilities. Five of the interventions found no support for improving knowledge about, or acceptance of people with disabilities. CONCLUSION: Disability awareness interventions can successfully improve children's knowledge about and attitudes towards peers with a disability; they should include several different components over multiple sessions. RELEVANCE: These findings are being used to further develop disability awareness interventions to help improve the social inclusion and participation of children with disabilities within mainstream classrooms. PMID- 22831704 TI - A prospective study of learning, memory, and executive function in new MDMA users. AB - AIMS: It is still unclear if cognitive abnormalities in human 3,4 methylenedioxymeth-amphetamine (MDMA) users existed before the beginning of use or if other confounders could explain the deficits. The present study was conducted in order to assess the relationship between beginning MDMA use and subsequent cognitive performance and to overcome previous methodological shortcomings. DESIGN: A prospective cohort study in new MDMA users between 2006 and 2009 with a follow-up duration of 12 months. SETTING AND PARTICIPANTS: Of the 149 almost MDMA-naive subjects examined at the initial assessment, 109 subjects participated again after 1 year. During this period, 43 subjects did not use any other illicit substance apart from cannabis; 23 subjects used more than 10 pills MDMA (mean = 33.6). These groups then were compared by means of multivariate analyses of variance. MEASUREMENTS: Change scores between the initial examination and follow-up on a neuropsychological test battery including measures of learning, memory, and frontal executive functions [Auditiv-Verbaler Lerntest (AVLT), Lern- und Gedachtnistest (LGT) 3, digit span test, digit symbol test, Stroop task, Trail-making test]. In addition, a comprehensive number of possibly relevant confounders including age, general intelligence, cannabis use, alcohol use, cigarette use, medical treatment, participation in sports, nutrition, sleep patterns and subjective wellbeing was assessed. FINDINGS: Groups did not differ in any of the potential confounders. However, significant effects of immediate and delayed recall of a visual paired associates learning task between MDMA users and controls were found (respectively, F ((1,64)) = 11.43, P = 0.001, eta(2) = 0.136 and F ((1,64)) = 11.08, P = 0.002, eta(2) = 0.144). No significant differences on the other neuropsychological tests were found. CONCLUSIONS: MDMA appears to impair visual paired associates learning in new users, suggesting serotonergic dysfunction in hippocampal regions as a consequence of MDMA use. PMID- 22831705 TI - Quartz crystal microbalance analysis of DNA-templated calcium phosphate mineralization. AB - A quartz crystal microbalance (QCM) sensor was developed for the quantitation of calcium phosphate mineralization and the assessment of DNA as a template molecule. Inherent advantages of QCM, such as nanogram sensitivity, temporal resolution, surface-based measurements, and flow capabilities, were leveraged in the design of this sensor, and in-line fluidic mixing was used to control precursor reaction. This research shows that DNA, a highly programmable anionic polymer, is able to template and control mineralization of calcium phosphate, with nucleation occurring in less than 15 min and initial rates ranging from 4 to 8 ng/min. FT-IR measurements show mineralized material to be calcium phosphate resembling hydroxyapatite (HAP) when a DNA template is used. DNA is a promising mineralization template, and the QCM proves to be a dynamic technique for a broad range of heterogeneous mineralization experiments in complement to classic, diffusion-limited, end-point analysis techniques. PMID- 22831706 TI - The prediction of CSF gusher in cochlear implants with inner ear abnormality. AB - CONCLUSION: The incidence rate of the cerebrospinal fluid (CSF) gusher in cochlear implant with inner ear abnormality is 30%. Bony defect in the fundus of the internal acoustic meatus is most often responsible for the occurrence of CSF gusher. This feature of the CT scan can be used to predict the occurrence of a CSF gusher. OBJECTIVE: To predict the occurrence of CSF gusher in cochlear implants with inner ear abnormality. METHODS: This was a retrospective analysis of 442 patients with inner ear abnormality who underwent cochlear implantation from February 1998 to July 2011. The patients were reviewed for the findings on temporal high resolution computed tomography (HRCT) scans and the complication of CSF gusher in cochlear implantation. RESULTS: Among the 422 cases, 134 (30%) suffered from the complication of CSF gusher during the operation. They were all found to have a bony defect in the fundus of the internal acoustic meatus on the CT scans. PMID- 22831707 TI - Measurement of nitrosamine and nitramine formation from NOx reactions with amines during amine-based carbon dioxide capture for postcombustion carbon sequestration. AB - With years of full-scale experience for precombustion CO(2) capture, amine-based technologies are emerging as the prime contender for postcombustion CO(2) capture. However, concerns for postcombustion applications have focused on the possible contamination of air or drinking water supplies downwind by potentially carcinogenic N-nitrosamines and N-nitramines released following their formation by NO(x) reactions with amines within the capture unit. Analytical methods for N nitrosamines in drinking waters were adapted to measure specific N-nitrosamines and N-nitramines and total N-nitrosamines in solvent and washwater samples. The high levels of amines, aldehydes, and nitrite in these samples presented a risk for the artifactual formation of N-nitrosamines during sample storage or analysis. Application of a 30-fold molar excess of sulfamic acid to nitrite at pH 2 destroyed nitrite with no significant risk of artifactual nitrosation of amines. Analysis of aqueous morpholine solutions purged with different gas-phase NO and NO(2) concentrations indicated that N-nitrosamine formation generally exceeds N-nitramine formation. The total N-nitrosamine formation rate was at least an order of magnitude higher for the secondary amine piperazine (PZ) than for the primary amines 2-amino-2-methyl-1-propanol (AMP) and monoethanolamine (MEA) and the tertiary amine methyldiethanolamine (MDEA). Analysis of pilot washwater samples indicated a 59 MUM total N-nitrosamine concentration for a system operated with a 25% AMP/15% PZ solvent, but only 0.73 MUM for a 35% MEA solvent. Unfortunately, a greater fraction of the total N-nitrosamine signal was uncharacterized for the MEA-associated washwater. At a 0.73 MUM total N nitrosamine concentration, a ~25000-fold reduction in concentration is needed between washwater units and downwind drinking water supplies to meet proposed permit limits. PMID- 22831709 TI - Mycobacterium chelonae infection: a complication of tattooing. AB - We describe an outbreak of Mycobacterium chelonae infection in four young immunocompetent patients who were tattooed by the same artist. All had been previously tattooed without complication, but following the latest tattooing session, they all developed a very similar papular eruption confined to skin that had been newly coloured light grey. On histological examination of the eruption, granulomatous inflammation with microabscess formation was seen, in association with the tattoo pigment. Skin cultures grown under optimal conditions grew M. chelonae, sensitive to clarithromycin, from one patient. M. chelonae was also cultured from the contents and nozzle of an opened bottle of light-grey ink from the tattoo parlour frequented by the patients. Dermatologists should consider mycobacterial infection in patients who develop inflammatory changes within a new tattoo. PMID- 22831708 TI - High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). AB - BACKGROUND: The incidence of cardiac events is higher in patients with diabetes than in people without diabetes. The Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound in Japanese Subjects (COSMOS) demonstrated significant plaque regression in Japanese patients with chronic coronary disease after 76 weeks of rosuvastatin (2.5 mg once daily, up titrated to a maximum of 20 mg/day to achieve LDL cholesterol <80 mg/dl). METHODS: In this subanalysis of COSMOS, we examined the association between HbA1c and plaque regression in 40 patients with HbA1c >=6.5% (high group) and 86 patients with HbA1c <6.5% (low group). RESULTS: In multivariate analyses, HbA1c and plaque volume at baseline were major determinants of plaque regression. LDL cholesterol decreased by 37% and 39% in the high and low groups, respectively, while HDL cholesterol increased by 16% and 22%, respectively. The reduction in plaque volume was significantly (p = 0.04) greater in the low group (from 71.0 +/ 39.9 to 64.7 +/- 34.7 mm(3)) than in the high group (from 74.3 +/- 34.2 to 71.4 +/- 32.3 mm(3)). Vessel volume increased in the high group but not in the low group (change from baseline: +4.2% vs -0.8%, p = 0.02). Change in plaque volume was significantly correlated with baseline HbA1c. CONCLUSIONS: Despite similar improvements in lipid levels, plaque regression was less pronounced in patients with high HbA1c levels compared with those with low levels. Tight glucose control during statin therapy may enhance plaque regression in patients with stable coronary disease. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT00329160. PMID- 22831747 TI - Effect of enzymatic deamidation of soy protein by protein-glutaminase on the flavor-binding properties of the protein under aqueous conditions. AB - The effect of the enzymatic deamidation by protein-glutaminase (PG) on flavor binding properties of soy protein isolate (SPI) under aqueous conditions was evaluated by a modified equilibrium dialysis (ultrafiltration) technique. Binding parameters, such as number of binding sites (n) and binding constants (K), were derived from Klotz plots. The partial deamidation of SPI by PG (43.7% degree of deamidation) decreased overall flavor-binding affinity (nK) at 25 degrees C for both vanillin and maltol by approximately 9- and 4-fold, respectively. The thermodynamic parameters of binding indicated that the flavor-protein interactions were spontaneous (negative DeltaG degrees ) and that the driving force of the interactions shifted from entropy to enthalpy driven as a result of deamidation. Deamidation of soy protein caused a change in the mechanism of binding from hydrophobic interactions or covalent bonding (Schiff base formation) to weaker van der Waals forces or hydrogen bonding. PMID- 22831748 TI - Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. AB - Mutations in the pancreatic ATP sensitive K(+) channel proteins [sulfonyluea receptor 1 (SUR1) and inward rectifier K(+) channel Kir6.2 (Kir6.2), encoded by ATP-binding cassette transporter subfamily C member 8 (ABCC8) and potassium channel J11 (KCNJ11), respectively], are the most common cause of neonatal diabetes. We describe the clinical presentation and molecular characterization of Asian Indian children with neonatal diabetes mellitus and monogenic syndromes of diabetes. We sequenced KCNJ11, ABCC8 and insulin (INS) genes in 33 unrelated Indian probands with onset of diabetes below one year of age. A total of 12 mutations were identified which included ABCC8 mutations in seven, KCNJ11 mutations in three and INS mutations in two children. The Asp212Tyr mutation in ABCC8 was novel. We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)]. Children carrying the KCNJ11 (Cys42Arg, Arg201Cys) and ABCC8 (Val86Ala, Asp212Tyr) mutations have been successfully switched over from insulin therapy to oral sulfonylurea. Our study is the first large genetic screening study of neonatal diabetes in India. PMID- 22831749 TI - Single molecule imaging approach to membrane protein stoichiometry. AB - Recent technical advances have enabled the imaging of single fluorescent molecules. The application of single molecule visualization techniques has opened up new avenues of experimentation in biology at the molecular level. In this article, we review the application of single fluorescent molecule visualization and analysis to an important problem, that of subunit stoichiometry in membrane proteins, with particular emphasis on our approach. Single fluorescent molecules, coupled to fluorescent proteins, are localized in the membranes of cells. The molecules are then exposed to continuous low-level excitation until their fluorescent emissions reach background levels. The high sensitivity of modern instrumentation has enabled direct observations of discrete step decreases in the fluorescence of single molecules, which represent the bleaching of single fluorophores. By counting the number of steps over a large number of single molecules, an average step count is determined from which the stoichiometry is deduced using a binomial model. We examined the stoichiometry of a protein, prestin, that is central to mammalian hearing. We discuss how we prepared, identified, and imaged single molecules of prestin. The methodological considerations behind our approach are described and compared to similar procedures in other laboratories. PMID- 22831750 TI - Clinical outcomes of high-dose-rate brachytherapy and external beam radiotherapy in the management of clinically localized prostate cancer. AB - PURPOSE: To report prostate-specific antigen (PSA) relapse-free survival and treatment-related toxicity outcomes after combining high-dose-rate (HDR) brachytherapy with external beam radiotherapy (EBRT) for patients with clinically localized prostate cancer. METHODS AND MATERIALS: Between 1998 and 2009, 229 patients were treated with HDR brachytherapy followed 3 weeks later by supplemental EBRT. The HDR brachytherapy boost consisted of three fractions of (192)Ir (5.5-7.5Gy per fraction), and EBRT consisted of intensity-modulated radiotherapy delivering an additional 45.0-50.4Gy directed to the prostate gland and seminal vesicles. Median follow-up was 61 months. RESULTS: Seven-year PSA relapse-free survival for low-, intermediate-, and high-risk patients were 95%, 90%, and 57%, respectively (p<0.001). Among high-risk patients treated with biological equivalent doses in excess of 190Gy, 7-year PSA relapse-free survival was 81%. In multivariate analysis, Gleason scores of >=8 predicted for increased risk of biochemical failure, whereas the use of short-term neoadjuvant androgen deprivation therapy did not influence tumor-control outcomes even among intermediate- or high-risk patients. Seven-year incidence of distant metastases for low-, intermediate-, and high-risk patients were 5%, 3%, and 17%, respectively. Seven-year incidence of late Grade 2 and 3 genitourinary toxicities were 22.1% and 4.9%, respectively and the 7-year incidence of Grade 2 and 3 gastrointestinal toxicities were 1% and 0.4%, respectively. CONCLUSION: HDR prostate brachytherapy in conjunction with supplemental EBRT results in excellent biochemical relapse-free survival rates with a low incidence of severe late genitourinary or gastrointestinal toxicities. The use of short-term neoadjuvant androgen deprivation did not influence long-term biochemical tumor control in this cohort. PMID- 22831751 TI - Parasites pitched against nature: Pitch Lake water protects guppies (Poecilia reticulata) from microbial and gyrodactylid infections. AB - SUMMARY The enemy release hypothesis proposes that in parasite depleted habitats, populations will experience relaxed selection and become more susceptible (or less tolerant) to pathogenic infections. Here, we focus on a population of guppies (Poecilia reticulata) that are found in an extreme environment (the Pitch Lake, Trinidad) and examine whether this habitat represents a refuge from parasites. We investigated the efficacy of pitch in preventing microbial infections in Pitch Lake guppies, by exposing them to dechlorinated water, and reducing gyrodactylid infections on non-Pitch Lake guppies by transferring them to Pitch Lake water. We show that (i) natural prevalence of ectoparasites in the Pitch Lake is low compared to reference populations, (ii) Pitch Lake guppies transferred into aquarium water develop microbial infections, and (iii) experimentally infected guppies are cured of their gyrodactylid infections both by natural Pitch Lake water and by dechlorinated water containing solid pitch. These results indicate a role for Pitch Lake water in the defence of guppies from their parasites and suggest that Pitch Lake guppies might have undergone enemy release in this extreme environment. The Pitch Lake provides an ideal ecosystem for studies on immune gene evolution in the absence of parasites and long-term evolutionary implications of hydrocarbon pollution for vertebrates. PMID- 22831752 TI - Analysis and comparison of clinical results of bilateral sagittal split ramus osteotomy performed with the use of monocortical locking plate fixation or bicortical screw fixation. AB - OBJECTIVE: The aim of this study was to compare clinical results of bilateral sagittal split ramus osteotomy (BSSRO) with the use of monocortical locking plate or bicortical screw fixation. STUDY DESIGN: Fifty-five patients underwent BSSRO for prognathism, using either monocortical locking plate (group A; n = 28) or bicortical screw (group B; n = 27) osseofixation. No intermaxillary fixation was done after surgery. Groups were subdivided according to presence or absence of mandibular asymmetry. Time course changes in condylar and skeletal stability were measured on lateral and posteroanterior cephalograms and axial radiographs before surgery and at 3 and 6 months after surgery. RESULTS: In facial symmetry subjects, the change in angle of the longitudinal axis of the condyle in group A was significantly greater than that for group B up to 3 months after surgery, but no significant differences were found in facial asymmetry subjects. CONCLUSIONS: The findings of this study suggest that monocortical fixation using the locking plate system to stabilize SSRO is as reliable as bicortical screw fixation regardless of facial asymmetry. PMID- 22831753 TI - Surgical site infection prophylaxis strategies for cardiothoracic surgery: a decision-analytic model. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of invasive surgical site infection (SSI) in the USA. Antimicrobial prophylaxis for SSI typically includes a cephalosporin. Vancomycin is used to provide MRSA coverage, but the timing of administration is challenging. Linezolid is an attractive agent for SSI prophylaxis, particularly for the prevention of SSI due to MRSA. METHODS: We developed a decision-analytic model to evaluate linezolid use for cardiothoracic SSI prophylaxis. A theoretical cohort of 10,000 cardiothoracic surgery patients was followed through 2 stages: (1) occurrence of SSI, and (2) mortality after SSI. All patients were administered cefuroxime, vancomycin, or linezolid between 1 and 180 min prior to surgical incision. SSIs were categorized into 3 pathogen categories: (1) methicillin-susceptible Gram positive, (2) methicillin-resistant Gram-positive, and (3) other organisms. The most effective strategy resulted in the fewest SSIs. Assumptions for antibiotic effectiveness, impact of administration time, and pathogens were based on the published literature. RESULTS: Compared with cefuroxime, there was a 1% increase in the total number of SSIs in the linezolid group (mean SSI increase = 7), while there was a 12% increase in the vancomycin group (mean SSI increase = 86). Linezolid prophylaxis resulted in fewer SSIs due to methicillin-resistant Gram positive infections (n = 108) compared with cefuroxime (n = 200, 46% reduction in the linezolid group) and vancomycin (n = 119, 9% reduction in the linezolid group). CONCLUSIONS: This simulation indicates that linezolid may offer benefits for SSI prophylaxis over existing prophylactic agents, particularly for the prevention of SSI due to Gram-positive methicillin-resistant pathogens. PMID- 22831754 TI - Collodion baby and loricrin keratoderma: a case report and mutation analysis. AB - Hereditary palmoplantar keratodermas (PPK) comprise a clinically and genetically heterogeneous group of genodermatoses, which share the characteristic of impaired epidermal differentiation, resulting in prominent palmoplantar hyperkeratosis. Molecular genetic analyses have helped characterize the underlying genetic defects in an increasing number of hereditary PPKs over the past two decades, and thus a pathophysiological classificaiton seems more reasonable. Today PPK can be classified based on defects in keratins, loricrin, desmosomes, connexins and cathepsins. In this report, we describe a 22-year-old man who had been born a collodion baby, and later developed diffuse PPK with pseudoainhum and generalized ichthyosis. His mother and grandmother had similar characteristics. Direct sequencing of genomic DNA identified a frameshift insertion mutation (730insG) in the loricrin gene. This family had the typical presentation of loricrin keratoderma. It also indicates that collodion baby may be the first presentation in patients with loricrin keratoderma. PMID- 22831755 TI - Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder. AB - Linkage and fine mapping studies have established that the neuregulin 3 gene (NRG3) is a susceptibility locus for schizophrenia. Association studies of this disorder have implicated NRG3 variants in both psychotic symptoms and attention performance. Psychotic symptoms and cognitive deficits are also frequent features of bipolar disorder. The aims of the present study were to extend analysis of the association between NRG3 and psychotic symptoms and attention in schizophrenia and to determine whether these associations also apply to bipolar disorder. A total of 358 patients with schizophrenia and 111 patients with bipolar disorder were included. Psychotic symptoms were evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and attention performance was assessed using the Trail Making Test (TMT). Symptoms and performance scores were then tested for association with the NRG3 variant rs6584400. A significant association was found between the number of rs6584400 minor alleles and the total OPCRIT score for psychotic symptoms in patients with schizophrenia. Moreover, in both schizophrenia and bipolar disorder patients, minor allele carriers of rs6584400 outperformed homozygous major allele carriers in the TMT. The results suggest that rs6584400 is associated with psychotic symptoms and attention performance in schizophrenia. The finding of a significant association between rs6584400 and attention performance in bipolar disorder supports the hypothesis that this NRG3 variant confers genetic susceptibility to cognitive deficits in both schizophrenia and bipolar disorder. PMID- 22831756 TI - Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature. AB - BACKGROUND: Summarizing the epidemiology of major depressive disorder (MDD) at a global level is complicated by significant heterogeneity in the data. The aim of this study is to present a global summary of the prevalence and incidence of MDD, accounting for sources of bias, and dealing with heterogeneity. Findings are informing MDD burden quantification in the Global Burden of Disease (GBD) 2010 Study. METHOD: A systematic review of prevalence and incidence of MDD was undertaken. Electronic databases Medline, PsycINFO and EMBASE were searched. Community-representative studies adhering to suitable diagnostic nomenclature were included. A meta-regression was conducted to explore sources of heterogeneity in prevalence and guide the stratification of data in a meta analysis. RESULTS: The literature search identified 116 prevalence and four incidence studies. Prevalence period, sex, year of study, depression subtype, survey instrument, age and region were significant determinants of prevalence, explaining 57.7% of the variability between studies. The global point prevalence of MDD, adjusting for methodological differences, was 4.7% (4.4-5.0%). The pooled annual incidence was 3.0% (2.4-3.8%), clearly at odds with the pooled prevalence estimates and the previously reported average duration of 30 weeks for an episode of MDD. CONCLUSIONS: Our findings provide a comprehensive and up-to-date profile of the prevalence of MDD globally. Region and study methodology influenced the prevalence of MDD. This needs to be considered in the GBD 2010 study and in investigations into the ecological determinants of MDD. Good-quality estimates from low-/middle-income countries were sparse. More accurate data on incidence are also required. PMID- 22831757 TI - Treatment of 'refractory' epilepsy: syncope incognito unmasked by implantable ambulatory electrocardiographical recordings. PMID- 22831758 TI - Evaporite caprock integrity: an experimental study of reactive mineralogy and pore-scale heterogeneity during brine-CO2 exposure. AB - We present characterization and geochemical data from a core-flooding experiment on a sample from the Three Fingers evaporite unit forming the lower extent of caprock at the Weyburn-Midale reservoir, Canada. This low-permeability sample was characterized in detail using X-ray computed microtomography before and after exposure to CO(2)-acidified brine, allowing mineral phase and voidspace distributions to be quantified in three dimensions. Solution chemistry indicated that CO(2)-acidified brine preferentially dissolved dolomite until saturation was attained, while anhydrite remained unreactive. Dolomite dissolution contributed to increases in bulk permeability through the formation of a localized channel, guided by microfractures as well as porosity and reactive phase distributions aligned with depositional bedding. An indirect effect of carbonate mineral reactivity with CO(2)-acidified solution is voidspace generation through physical transport of anhydrite freed from the rock matrix following dissolution of dolomite. The development of high permeability fast pathways in this experiment highlights the role of carbonate content and potential fracture orientations in evaporite caprock formations considered for both geologic carbon sequestration and CO(2)-enhanced oil recovery operations. PMID- 22831759 TI - The influence of identity elements on the aminoacylation of tRNA(Arg) by plant and Escherichia coli arginyl-tRNA synthetases. AB - Identity elements determine the accurate recognition between tRNAs and aminoacyl tRNA synthetases. The arginine system from yeast and Escherichia coli has been studied extensively in the past. However, information about the enzymes from higher eukaryotes is limited and plant aminoacyl-tRNA synthetases have been largely ignored in this respect. We have designed in vitro tRNA transcripts, based on the soybean tRNA(Arg) primary structure, aiming to investigate its specific aminoacylation by two recombinant plant arginyl-tRNA synthetases and to compare this with the enzyme from E. coli. Identity elements at positions 20 and 35 in plants parallel those previously established for bacteria. Cryptic identity elements in the plant system that are not revealed within a tRNA(Arg) consensus sequence compiled from isodecoders corresponding to nine distinct cytoplasmic, mitochondrial and plastid isoaccepting sequences are located in the acceptor stem. Additionally, it has been shown that U20a and A38 are essential for a fully efficient cognate E. coli arginylation, whereas, for the plant arginyl-tRNA synthetases, these bases can be replaced by G20a and C38 with full retention of activity. G10, a constituent of the 10:25:45 tertiary interaction, is essential for both plant and E. coli activity. Amino acid recognition in terms of discriminating between arginine and canavanine by the arginyl-tRNA synthetase from both kingdoms may be manipulated by changes at different sites within the tRNA structure. PMID- 22831760 TI - Lead tolerance and phytoremediation potential of Brazilian leguminous tree species at the seedling stage. AB - A greenhouse pot experiment was conducted to evaluate the potential of three Brazilian leguminous woody species, Mimosa caesalpiniaefolia, Erythrina speciosa and Schizolobium parahyba, for the revegetation of lead- (Pb-) contaminated areas. The response of seedlings to increasing Pb concentrations (0, 250, 500 and 1000 mg kg(-1)) in the soil was studied. In addition to Pb accumulation and translocation, the following parameters were assessed: chlorophyll, nitrate, ammonia, lipid peroxidation (MDA) and free amino acid content; seedling growth; and nitrogenase activity. No differences were observed in the germination of woody species seeds sown in soils with or without Pb addition. M. caesalpiniaefolia did not show visual symptoms of Pb toxicity, while the other two species demonstrated stress symptoms, including reduced shoot biomass yield, leaf area and height. Biochemical analyses of plant tissues revealed markedly different responses to increasing Pb concentrations, such as changes in foliar soluble amino acid composition in S. parahyba; changes in ammonia and nitrate content in E. speciosa, M. caesalpiniaefolia and S. parahyba; and changes in MDA content in S. parahyba. The levels of chlorophyll a and b and carotenoid were affected in the species studied. For the Nitrogen-fixing (N(2)-fixing) species E. speciosa, an increase of Pb in the soil affected nodule formation and growth, which led to reduced nitrogenase activity in seedlings. The concentration of Pb in shoots and roots increased with the Pb concentration in soil. However, most of the Pb absorbed accumulated in the roots, and only a small fraction was translocated to aboveground parts. These findings were confirmed by the low bioconcentration factor (BCF) and translocation factor (TF) values for the three species. The tolerance index (TI) values suggested that M. caesalpiniaefolia, a N(2)-fixing tree, was the species that was most tolerant to high Pb concentrations in soil, while E. speciosa and S. parahyba showed moderate tolerance. Of the three Brazilian native woody species studied, M. caesalpiniaefolia was found to have the highest Pb tolerance and phytostabilisation potential in Pb-contaminated soils. PMID- 22831761 TI - Sensory evaluation of baked chicken wrapped with antimicrobial apple and tomato edible films formulated with cinnamaldehyde and carvacrol. AB - The addition of plant essential oils to edible films and coatings has been shown to protect against bacterial pathogens and spoilage while also enhancing sensory properties of foods. This study evaluated the effect of adding 0.5 and 0.75% carvacrol (active ingredient of oregano oil) to apple- and tomato-based film forming solutions and 0.5 and 0.75% cinnamaldehyde (active ingredient of cinnamon oil) to apple-based film-forming solutions on sensory properties of cooked chicken wrapped with these films. Paired preference tests indicated no difference between baked chicken wrapped with tomato and apple films containing 0.5% carvacrol and cinnamaldehyde compared to chicken wrapped with tomato or apple films without the plant antimicrobials. The taste panel indicated a higher preference for carvacrol-containing tomato-coated chicken over the corresponding apple coating. There was also a higher preference for cinnamaldehyde-containing apple films over corresponding carvacrol-containing wrapping. Films containing antibacterial active compounds derived from essential oils can be used to protect raw chicken pieces against bacterial contamination without adversely affecting preferences of wrapped chicken pieces after baking. PMID- 22831762 TI - siRNA-mediated silence of protease-activated receptor-1 minimizes ischemic injury of cerebral cortex through HSP70 and MAP2. AB - Cerebral ischemic stroke is a prevalent disease in senior individuals. The anticoagulation and thrombolysis to recover blood supply as well as the diminution of neural excitotoxicity to protect brain cells have not shown to fully improve stroke patients. The comprehensive mechanisms and medication specificity remain to be addressed. The silence of specific mRNAs by RNA interference provides revenues for such goals. We examined whether the silence of protease-activated receptor-1 (PAR-1) by siRNA protects brain tissues from ischemic injury. In three groups of Wistar rats, their lateral ventricles received the injections of lentiviral vectors carrying siRNA for PAR1, small RNA in mismatching PAR1 or saline. A week after the injections, these rats were treated by one side of middle cerebral artery occlusion (MCAO). The scores of neurological deficits, the volume of ischemic infarction and the expressions of PAR-1, HSP-70 and MAP-2 were measured in 24h of MCAO. Our results show that the silence of PAR-1 significantly reduces neurological deficits and infarction volume, as well as elevates HSP-70 and MAP-2 expressions. Thus, the knock-down of PAR1 minimizes the ischemic impairments of cerebral cortex via HSP70 and MAP-2 pathways. PMID- 22831763 TI - Diagnostic utility of NMO/AQP4-IgG in evaluating CNS inflammatory disease in Thai patients. AB - Epidemiological studies in Thailand have reported that inflammatory demyelinating diseases (IDDs) commonly affect the optic nerve and spinal cord. We investigated the diagnostic utility of aquaporin (AQP)-4-IgG testing in 31 consecutive patients evaluated for CNS IDDs in 3 academic Thai hospital neurology clinics between February 2008 and January 2009. Patients were classified into 3 clinical diagnostic groups: Neuromyelitis optica (NMO, n=10) multiple sclerosis (MS, n=5) and unclassified IDD (n=16). All sera were tested blindly by cell binding (Euroimmun) assay (CBA). Sera were also tested by indirect immunofluorescence assay (IFA) and ELISA (RSR/Kronus). After initial screening by CBA, AQP4-IgG was detected in 6 NMO patients (60%); 3 of the 4 seronegative cases were receiving immunosuppressants. AQP4-IgG was detected in 13 unclassified IDD cases (81%), but in no MS cases. Cell binding assay and ELISA were more sensitive than IFA (p=0.0004). The 81% seropositivity rate in "unclassified" patients suggests that AQP4 autoimmunity accounts for a significant proportion of Thai CNS inflammatory demyelinating disease, especially those with optic neuritis or transverse myelitis, with or without abnormal brain MRI, in whom a specific diagnosis or clear-cut treatment approach is unclear. PMID- 22831764 TI - Different neurological conditions between urban and rural samples from central Colombia. AB - OBJECTIVES: Despite availability of neuroepidemiological data, urban-rural differences on neurological diseases have almost never been considered. Our goal is to identify differences in the frequency of neurological conditions between a rural and an urban sample from central Colombia. METHODS: We compared frequencies of neurological encounters of an urban sample from Bogota (N=2932), to our rural sample from Tunja (N=2664), collected both circa to 2000. The classification of neurological conditions used is based on the 9th revision of the International Classification of Diseases, clinical modification. A clustered sampling was used. Information collection was performed in a format designed for this purpose and already used in Colombia. RESULTS: Highly significant statistical differences (p<0.0001) were found for cerebrovascular diseases, seizure disorder, headache, Parkinson's disease and other movement disorders, and, inflammatory (infectious) conditions. Neurodevelopmental disorders (p=0.0029), dizziness and balance problems (p=0.0018), and neuropathies (p=0.0007), also showed statistically significant differences. CONCLUSIONS: Our study showed significant differences on all categories and diagnostics between the samples. Cerebrovascular disease the most frequent reason of neurological consultation in the rural sample could be confounded by sociodemographic (aging of the population, urbanization process), or the concomitant presence of medical (chronic pulmonary) and/or environmental (air pollution) conditions. PMID- 22831765 TI - Stases are associated with blood-brain barrier damage and a restricted activation of coagulation in SHRSP. AB - Cerebral small vessel disease (CSVD) is a chronically proceeding pathology of small brain vessels associated with white matter lesions, lacunar infarcts, brain atrophy and microbleeds. CSVD leads to slowly increasing cognitive and functional deficits but may also cause stroke-like symptoms, if vessels in critical brain areas are affected. Spontaneously hypertensive stroke-prone rats (SHRSP) exhibit several vascular risk factors, develop infarcts and hemorrhages and therefore represent a relevant model for the study of CSVD. Using this animal model, we recently demonstrated that intravasal accumulations of erythrocytes, we interpreted as stases, stand at the beginning of a pathological vascular cascade. After stases microbleeds occur, which are followed by reactive microthromboses. Bleeds and thromboses finally cause hemorrhagic infarcts. Immunohistochemical stainings show, that plasma proteins like IgG are deposited in the walls of vessels affected by stases. Further, we found small clots and thread-shaped aggregations of thrombocytes as well as thread-shaped structures of von Willebrand-Factor within stases. Thus, we conclude that blood-brain barrier damages occur in the neighborhood of stases and stases seem to be associated with a restricted activation of blood coagulation without formation of obstructive thromboses. Finally, we demonstrate that small vessel damage rarely appears in the cerebellum. Even animals with multiple cerebral infarcts may be free of any cerebellar vascular pathology. PMID- 22831766 TI - [Description of hospital discharges in patients with systemic lupus erythematosus]. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that mainly affects young women and whose mortality is increasing for this age group. OBJECTIVES: We used the national registry of Hospital discharges in Spain based on the study of the Minimum Basic Data Set (MBDS) to analyze hospital discharges of patients whose diagnosis included that of LES. MATERIAL AND METHODS: A cross sectional, descriptive study was performed of all episodes coded as having LES using ICD-9-MC coding system of the patients hospitalized within the period 2005 2008. RESULTS: A total of 5,464 episodes were identified, 1,855 (33%) as main diagnosis and 3,609 (66%) as secondary diagnosis. Patients having LES the main diagnosis were younger (41.56 +/- 17.55 vs 56.07 +/- 19.01 years; P < .001), had fewer elective admittances (62.5 vs 84.8%; P<.001), lower comorbidity as measured by the Charlson's index (Charlson>2; 18 vs 35%; P<.001) and lower mortality (1.1 vs 5.4%; P < .001). CONCLUSIONS: Patients admitted to internal medicine departments in Spain with a diagnosis of LES accounts for 0.3% of the total. Two different groups of patients are identified. The first group was younger, had lower comorbidity and were in the early phases of diagnosis and/or treatment. The second group was more numerous, older, with a higher comorbidity, with admittances frequently related to infections or cardiovascular complications and higher mortality rate. PMID- 22831767 TI - Analytical models of steady-state plumes undergoing sequential first-order degradation. PMID- 22831769 TI - Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? AB - Clozapine remains the drug of choice for treatment resistant schizophrenia, but is associated with potentially life threatening side effects, including agranulocytosis and myocarditis. Immunological mechanisms may be involved in the development of these side effects or in the unique antipsychotic efficacy in subgroups of schizophrenia patients. This systematic review presents the immunomodulatory effects of clozapine from human in vitro and in vivo studies and relates these findings to the developments of adverse and therapeutic effects of clozapine. Several studies confirm the immunomodulatory actions of clozapine, but only few studies investigated their relationship to the unique adverse and therapeutic effects of clozapine. During the first month of clozapine treatment, up to 50% of patients develop fever and flu like symptoms, which is seemingly driven by increased cytokines. Within the same time period, the risk of side effects with a suspected immunological mechanism peaks. Patients developing fever during the first weeks of treatment should have a thorough physical examination, and measurements of white blood cell count, absolute neutrophil count, ECG, C reactive protein, creatinine kinase, and troponin to exclude infection, agranulocytosis, myocarditis and neuroleptic malignant syndrome. To what degree the unique antipsychotic efficacy of clozapine in subgroups of schizophrenia patients is related to its immunomodulatory effects has not been studied. Research relating the immunomodulatory actions of clozapine and its early markers to clinically relevant adverse and therapeutic outcomes is hoped to provide new leads for the understanding of the pathophysiology of schizophrenia and aid the development of novel treatment targets. PMID- 22831768 TI - Structural dynamics of nucleosomes at single-molecule resolution. AB - The detailed mechanisms of how DNA that is assembled around a histone core can be accessed by DNA-binding proteins for transcription, replication, or repair, remain elusive nearly 40 years after Kornberg's nucleosome model was proposed. Uncovering the structural dynamics of nucleosomes is a crucial step in elucidating the mechanisms regulating genome accessibility. This requires the deconvolution of multiple structural states within an ensemble. Recent advances in single-molecule methods enable unprecedented efficiency in examining subpopulation dynamics. In this review, we summarize studies of nucleosome structure and dynamics from single-molecule approaches and how they advance our understanding of the mechanisms that govern DNA transactions. PMID- 22831770 TI - On the boundaries of blunt affect/alogia across severe mental illness: implications for Research Domain Criteria. AB - There is growing awareness that reduced expressive behaviors (e.g., blunt affect, alogia, psychomotor retardation) are characteristic of a range of psychiatric conditions, including mood and schizophrenia-spectrum disorders. From a Research Domain Criteria (RDoC) perspective, it would be critical to determine whether these symptoms manifest similarly across diagnostic groups--as they may share common pathophysiological underpinnings. The present study employed computerized acoustic analysis of speech produced in reaction to a range of visual stimuli in 48 stable outpatients with schizophrenia and mood disorders to offer preliminary understanding of this issue. Speaking assessments were administered 1 week-apart to examine how temporal stability might vary as a function of clinical diagnosis and symptom severity. Speech characteristics generally did not differ between groups and were similarly, and for the most part, highly stable over time. Aspects of speech were significantly associated with severity of psychosis and negative symptoms, but not with clinical depression/anxiety severity. Moreover, stability of speech characteristics generally did not vary as a function of diagnostic group or clinical severity. The magnitudes of group differences were almost exclusively in the negligible to small range. Speech production was associated with social functioning deficits. In sum, these preliminary data suggest that speech variables tap a stable and clinically important facet of psychopathology that cut across diagnostic categories. Computerized acoustic analysis of speech appears to be a promising method for understanding the pathological manifestation of these variables. PMID- 22831771 TI - Social support and functional outcomes in an early intervention program. AB - OBJECTIVE: To examine social support at initiation of treatment of psychosis and after one year of treatment as predictors of functioning at five year follow-up. METHODS: Early social support was assessed for 132 patients. Follow-up assessments included number of weeks of full-time occupation, number of weeks on a disability pension and global assessment of functioning. RESULTS: One year ratings of social support better predicted occupational activity at follow-up than initial social support. Social support predicted functional outcomes independently of other early characteristics. CONCLUSIONS: Findings support the importance of interventions to improve the level of support of individuals with psychotic disorders. PMID- 22831773 TI - A 3D interactive multi-object segmentation tool using local robust statistics driven active contours. AB - Extracting anatomical and functional significant structures renders one of the important tasks for both the theoretical study of the medical image analysis, and the clinical and practical community. In the past, much work has been dedicated only to the algorithmic development. Nevertheless, for clinical end users, a well designed algorithm with an interactive software is necessary for an algorithm to be utilized in their daily work. Furthermore, the software would better be open sourced in order to be used and validated by not only the authors but also the entire community. Therefore, the contribution of the present work is twofolds: first, we propose a new robust statistics based conformal metric and the conformal area driven multiple active contour framework, to simultaneously extract multiple targets from MR and CT medical imagery in 3D. Second, an open source graphically interactive 3D segmentation tool based on the aforementioned contour evolution is implemented and is publicly available for end users on multiple platforms. In using this software for the segmentation task, the process is initiated by the user drawn strokes (seeds) in the target region in the image. Then, the local robust statistics are used to describe the object features, and such features are learned adaptively from the seeds under a non-parametric estimation scheme. Subsequently, several active contours evolve simultaneously with their interactions being motivated by the principles of action and reaction this not only guarantees mutual exclusiveness among the contours, but also no longer relies upon the assumption that the multiple objects fill the entire image domain, which was tacitly or explicitly assumed in many previous works. In doing so, the contours interact and converge to equilibrium at the desired positions of the desired multiple objects. Furthermore, with the aim of not only validating the algorithm and the software, but also demonstrating how the tool is to be used, we provide the reader reproducible experiments that demonstrate the capability of the proposed segmentation tool on several public available data sets. PMID- 22831774 TI - Mammography segmentation with maximum likelihood active contours. AB - We present a computer-aided approach to segmenting suspicious lesions in digital mammograms, based on a novel maximum likelihood active contour model using level sets (MLACMLS). The algorithm estimates the segmentation contour that best separates the lesion from the background using the Gamma distribution to model the intensity of both regions (foreground and background). The Gamma distribution parameters are estimated by the algorithm. We evaluate the performance of MLACMLS on real mammographic images. Our results are compared to those of two leading related methods: The adaptive level set-based segmentation method (ALSSM) and the spiculation segmentation using level sets (SSLS) approach, and show higher segmentation accuracy (MLACMLS: 86.85% vs. ALSSM: 74.32% and SSLS: 57.11%). Moreover, our results are qualitatively compared with those of the Active Contour Without Edge (ACWOE) and show a better performance. Further, the suitability of using ML as the objective function as opposed to the KL divergence and to the energy functional of the ACWOE is also demonstrated. Our algorithm is also shown to be robust to the selection of a required single seed point. PMID- 22831772 TI - Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging. AB - BACKGROUND: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (1H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS: We used single voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria. PMID- 22831775 TI - Robust 3-D reconstruction of surfaces from image focus by local cross-sectional multivariate statistical analyses: application to human ex vivo corneal endotheliums. AB - The considered problem of 3-D reconstruction consists in computationally and passively recovering both topography and texture of a scene surface observed by optical sectioning with a limited depth-of-field imaging system (typically a conventional optical microscope). Throughout a sequence of registered 2-D images, the concepts of shape-from-focus and extended-depth-of-field involve recovering both topography (depth map) and texture image of the surface by researching in focus information, respectively. Toward that aim, traditional approaches generally follow a 2-D sectional way and thereby fail to deal with noisy and disturbed acquisitions, quite frequent in transmitted light observations and of interest in this paper. Such examples are the acquisitions of human ex vivo corneal endotheliums from the medical issue addressed in this paper, which are mainly damaged by cellular fragments in the sample immersion medium and by emphasized contrast reversals. To achieve with such noisy and disturbed acquisitions, a new focus analysis is introduced that originally adopts a 3-D strategy throughout the image sequence. This method exploits simultaneously all available cross-sectional cues that effectively strengthens the robustness. More precisely, it locally performs multivariate statistical analyses over cross sectional spatial windows so as to find sectional in-focus positions. Comparisons to state-of-the-art methods on both synthetic data and real acquisitions from the deal-with medical issue demonstrate the efficiency and the robustness of the proposed approach. PMID- 22831776 TI - Effects of FSH and LH on ovarian and follicular blood flow, follicular growth and oocyte developmental competence in young and old mares. AB - Objectives of the experiment were to determine the effects of mare age and gonadotropin treatments on dominant follicle vascularity, ovarian blood flow and dominant follicle growth and to associate follicular vascularity with oocyte developmental capacity. Growing follicles >30 mm from young (4-9 years) and old (>20 years) mares were assessed for blood flow using color Doppler ultrasonography before maturation induction with recombinant equine LH (eLH) and immediately prior to oocyte collection at 20-24 h after eLH. Pulsed Doppler was used to obtain resistance indices of ovarian arteries ipsilateral to preovulatory follicles. For eFSH-treated estrous cycles, eFSH administration was started after detection of a cohort of follicles >=20 to <25 mm and continued until a follicle >30 mm. Oocytes were harvested using transvaginal, ultrasonic-guided aspirations and cultured and injected with sperm at 40 +/- 1 h after eLH. Presumptive zygotes were incubated, and rates of cleavage (>=2 cells) and blastocyst formation were obtained. Embryos were transferred nonsurgically into recipients' uteri, and pregnancy rates were assessed. Vascularity (number of color pixels per total pixels) was higher (P=0.003) in the follicles of old compared to young mares, with no significant interaction of eFSH or eLH. Effects of eFSH and time from eLH on follicle vascularity were not significant. The vascularity of follicles associated with oocytes that did compared to those that did not form blastocysts was greater (P=0.048), although follicular vascularity was less (P=0.02) for follicles associated with oocytes that did compared to those that did not develop into pregnancies. Resistance indices were not different for age, eFSH treatment, time after eLH administration and oocyte developmental potential. Growth of the dominant follicle was not associated with vascularity, although advanced age tended (P=0.09) to have a negative effect on follicle growth. PMID- 22831777 TI - 18F-FDG-PET-based tumor delineation in cervical cancer: threshold contouring and lesion volumes. AB - OBJECTIVE: To evaluate a semi-automated PET-image tumor segmentation algorithm for gross tumor volume (GTV) delineation in patients with locally advanced cervical cancer. MATERIAL AND METHODS: Thirty-two patients with locally advanced cervical cancer were retrospectively evaluated. Semi-automated PET-image-based GTV delineation was applied using a previous established algorithm (GTV2SD) and 2 fixed threshold-based methods (GTV40% and GTV50%). GTV2SD was determined as the pixel with the mean value plus 2-standard deviation of the liver intensity, and GTV40% and GTV50% with 40% and 50% of the maximum tumor intensity (Tmax), respectively. The derived volumes were then compared with the GTVs generated manually using MR (GTVMR). RESULTS: The mean value of GTV2SD, GTV40% and GTV50% was 85.3cc, 16.2cc and 24.1cc, respectively. Good agreement was noticed between GTV2SD and GTVMR (rho=0.88). GTV40% and GTV50% showed weaker correlation with GTVMR (rho=0.68 and rho=0.71, respectively). CONCLUSIONS: This study provides preliminary evidence that metabolic tumor volume delineation is feasible using computer-generated measurements in (18)F-FDG PET images. Generation of PET-based tumor volumes is affected by the choice of threshold level used. Metabolic tumor bulk calculated using the pixel with the mean value plus 2-standard deviations of the liver intensity (GTV2SD) correlates better with the MR-derived tumor volumes. The method is a simple and clinically applicable approach to generate PET-derived GTV for radiation therapy planning of cervical cancer. PMID- 22831778 TI - Extraordinary reticulate hyperpigmentation occurring after Bier block. PMID- 22831779 TI - Thalamic mechanisms in language: a reconsideration based on recent findings and concepts. AB - Recent literature on thalamic aphasia and thalamic activity during neuroimaging is selectively reviewed followed by a consideration of recent anatomic and physiological findings regarding thalamic structure and functions. It is concluded that four related corticothalamic and/or thalamocortical mechanisms impact language processing: (1) selective engagement of task-relevant cortical areas in a heightened state of responsiveness in part through the nucleus reticularis (NR), (2) passing information from one cortical area to another through corticothalamo-cortical mechanisms, (3) sharpening the focus on task relevant information through corticothalamo-cortical feedback mechanisms, and (4) selection of one language unit over another in the expression of a concept, accomplished in concert with basal ganglia loops. The relationship and interaction of these mechanisms is discussed and integrated with thalamic aphasia and neuroimaging data into a theory of thalamic functions in language. PMID- 22831780 TI - A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. AB - Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal 'moyamoya' collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal 'moyamoya' collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of 'moyamoya' should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life threatening aortic dissection. PMID- 22831781 TI - Theta burst stimulation reduces disability during the activities of daily living in spatial neglect. AB - Left-sided spatial neglect is a common neurological syndrome following right hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour. PMID- 22831782 TI - A 2-screw fixation technique for subtalar joint fusion: a retrospective case series introducing a novel 2-screw fixation construct with operative pearls. AB - A variety of fixation methods are used in fusion of the subtalar joint (STJ) including 1 screw and 2 screw constructs. The rate of union is generally high for STJ fusion, regardless of the fixation method, provided the joint surfaces have been properly prepared and compressed and the patient avoids premature stress on the fusion site. Certain populations are known to have an increased risk of nonunion or delayed union including diabetics, smokers, and those undergoing revision of failed fusion. In this high-risk patient population, we propose that our novel 2-screw construct might have advantages over traditional fixation constructs without identified disadvantages. The technique is simple enough to be used in all primary and revision STJ fusion procedures, and this has become our practice. In the present study, 15 feet in 15 consecutive patients who underwent STJ fusion using a novel 2-screw fixation construct were retrospectively reviewed to assess the fusion outcome and complications. Specifically, we offer a novel 2 screw construct that offers the stability of the traditional parallel 2-screw construct while maintaining a maximum raw bone surface area at the posterior facet achieved by single-screw fixation. A retrospective review of radiographs taken 10 weeks postoperatively indentified a 100% fusion rate (15 of 15). All patients in our series achieved fusion, including several high-risk cases, and no significant complications were identified. PMID- 22831783 TI - Yellow skin discoloration induced by quinacrine in a patient with cutaneous lupus erythematosus. PMID- 22831784 TI - Allergic contact dermatitis due to chlorocresol in topical corticosteroids. PMID- 22831785 TI - Nystatin-Induced Acute Generalized Exanthematous Pustulosis. PMID- 22831786 TI - Analysis of operating room activities in the dermatology department at Hospital Universitario de Fuenlabrada (2005-2010). AB - OBJECTIVE: To analyze data corresponding to patients who underwent dermatological surgery in an operating room. MATERIAL AND METHODS: This was a descriptive, retrospective study of operating room activities in the dermatology department of Hospital Universitario de Fuenlabrada in Madrid between January 2005 and December 2010. We analyzed the relative frequency of a range of patient and procedure related variables, as well as substitution and cancellation rates, the proportional risk of complications, and operating room efficiency. RESULTS: In the period analyzed, 11,516 patients underwent surgery: 9351 required minor surgery, 1998 major ambulatory surgery, and 167 surgery requiring hospitalization. Simple excision was the most common procedure (64.7%), and in the majority of cases (85%), the condition was benign. The mean number of patients treated per day was 9.7, and mean operating room efficiency was 71.9%. CONCLUSIONS: Accurate record-keeping is essential for analyzing operating room activities and comparing results with those from other centers. The analysis of patterns over time shows the effect of changes made on different indicators. In our case, a decrease in operating room efficiency was seen with an increase in the number of patients per day undergoing surgery. PMID- 22831788 TI - Neuropsychological evidence for abnormal neurodevelopment associated with early onset psychoses. AB - BACKGROUND: The longitudinal neuropsychological study of first-episode early onset psychosis (EOP) patients, whose brain maturation is still in progress at the time of illness onset, provides a unique opportunity to compare their cognitive development with that of healthy subjects, in search of specific patterns resulting from the interaction between neurodevelopmental processes and the presence of psychotic disorders. Method Seventy-five first-episode EOP patients (schizophrenia n = 35; bipolar disorder n = 17; other forms of psychosis n = 23) with a mean age of 15.53 years were assessed with a neuropsychological battery that included measures of attention, working memory, memory and executive functions within 6 months following the onset of the first psychotic symptom (baseline) and 2 years later. Psychotic symptoms were assessed at both times with the Positive and Negative Symptom Scale (PANSS). Seventy-nine healthy subjects matched for age and education served as controls. RESULTS: EOP patients showed significant cognitive impairment at both baseline and the 2-year follow-up, with no significant differences between diagnostic groups at either time. Both healthy controls and EOP patients improved in all cognitive measures, except for patient working memory. Improvement in patient attention lost significance after controlling for psychotic symptom reduction. No significant time/diagnosis interaction was found among patients (p > 0.405). CONCLUSIONS: Cognitive impairment in EOP is already present at the first episode, and cognitive development seems to be arrested early in EOP patients compared to their healthy peers, at least for some cognitive functions. These and previous similar results support the neurodevelopmental hypothesis of psychosis. PMID- 22831789 TI - A rare presentation of chest pain and syncope: massive right atrial myxoma. PMID- 22831790 TI - Re: Potential years of life lost due to urogenital cancer in the United States: trends from 1972 to 2006 based on data from the SEER database: M. H. Kamel, P. C. Moore, N. K. Bissada and S. M. Heshmat. J Urol 2012; 187: 868-871. PMID- 22831787 TI - Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. AB - Protein-protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of 'druggable' protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets. PMID- 22831792 TI - Re: Is intracytoplasmic sperm injection overused?: B. Hodes-Wertz, C. M. Mullin, A. Adler, N. Noyes, J. A. Grifo and A. S. Berkeley. J Urol 2012; 187: 602-606. PMID- 22831793 TI - Perceptions of Utah ranchers toward carbon sequestration: policy implications for US rangelands. AB - Enhanced carbon sequestration is one means to mitigate climate change. Rangelands are arid and semi-arid lands, typified by relatively low and variable levels of net primary productivity, where carbon sequestration might be increased via alterations in land management. Rangelands are vast in size and dominate the land area in the western US and worldwide. It has been estimated that privately owned rangelands in the US could sequester an additional 60 million tons of carbon annually, roughly equal to five percent of the US annual CO(2) emissions. Ranchers are the target population that could implement changes in rangeland management to promote carbon sequestration, but little is known about how they might receive such programs. Therefore, for Utah, we conducted a combined mail and telephone survey of 495 randomly selected ranchers to assess their knowledge of and attitude toward carbon sequestration, possible benefits of carbon sequestration as perceived by ranchers, and factors influencing their likelihood of participating in carbon sequestration programs. Overall, despite that 70 percent of respondents had little or no self-reported knowledge about carbon sequestration, 63 percent had negative views about it. Ranchers reporting the most knowledge also tended to have the most negative attitudes. The least important benefit that might accrue to ranchers from carbon sequestration was seen as climate change mitigation, while the most important benefit was improved land stewardship. Only four percent of respondents indicated an unconditional willingness to participate in carbon sequestration programs, but 71 percent could be interested depending on new information received. Before carbon sequestration programs are developed for rangelands, further research is needed to clarify why more knowledge of carbon sequestration can lead to greater skepticism of relevant programs. We respect this finding, as it may be based on well-founded rancher concerns such as technical or administrative efficacy. If such concerns can be overcome, extension efforts should be tailored to emphasize the ecological merits of carbon sequestration for rangeland management, which will facilitate the ability of ranchers to achieve their personal goals. PMID- 22831794 TI - Contour ripping is more beneficial than composted manure for restoring degraded rangelands in Central Texas. AB - Rangelands in the United States that have been the site of military training exercises have suffered extensive ecological damage, largely because of soil compaction, creation of ruts, and damage to or destruction of vegetation--all of which lead to higher runoff and accelerated erosion. In this paper we report on a study carried out within the Fort Hood Military Reservation in Central Texas, where we evaluated the extent to which application of composted dairy manure and contour ripping affect soil infiltrability, amount of runoff, and nutrient concentrations in runoff. We conducted experiments at two locations, using rainfall simulation at one and monitoring discharge from small (0.3-ha) watersheds at the other. At the rainfall simulation site, we used six levels of compost application: 4, 8, 12, 16, 20, and 24 Mg/ha. We found that compost application had little effect on runoff, soil infiltration, sediment production, or nutrient concentrations in the runoff--except at the micro-watershed scale (12 and 24 Mg/ha); in this case, nutrient concentrations in runoff were initially high (for the rainfall simulations done immediately after compost application). In contrast, contour ripping--carried out 22 months after compost application on two of the micro-watersheds--was highly effective: runoff on the treated micro watershed was reduced by half compared with the untreated micro-watershed. Our results suggest that (1) one-time applications of composted dairy manure do little to enhance infiltration of degraded rangelands over the short term (at the same time, these experiments demonstrated that compost application poses very little risk to water quality); and (2) for degraded rangelands with limited infiltration capacity, contour ripping is an effective strategy for increasing infiltration rates. PMID- 22831796 TI - Novel and recurrent C1 inhibitor gene mutations in nine Japanese patients with hereditary angioedema. PMID- 22831795 TI - Crystal structure and chitin oligosaccharide-binding mode of a 'loopful' family GH19 chitinase from rye, Secale cereale, seeds. AB - The substrate-binding mode of a 26-kDa GH19 chitinase from rye, Secale cereale, seeds (RSC-c) was investigated by crystallography, site-directed mutagenesis and NMR spectroscopy. The crystal structure of RSC-c in a complex with an N acetylglucosamine tetramer, (GlcNAc)(4) , was successfully solved, and revealed the binding mode of the tetramer to be an aglycon-binding site, subsites +1, +2, +3, and +4. These are the first crystallographic data showing the oligosaccharide binding mode of a family GH19 chitinase. From HPLC analysis of the enzymatic reaction products, mutation of Trp72 to alanine was found to affect the product distribution obtained from the substrate, p-nitrophenyl penta-N-acetyl-beta chitopentaoside. Mutational experiments confirmed the crystallographic finding that the Trp72 side chain interacts with the +4 moiety of the bound substrate. To further confirm the crystallographic data, binding experiments were also conducted in solution using NMR spectroscopy. Several signals in the (1) H-(15) N HSQC spectrum of the stable isotope-labeled RSC-c were affected upon addition of (GlcNAc)(4) . Signal assignments revealed that most signals responsive to the addition of (GlcNAc)(4) are derived from amino acids located at the surface of the aglycon-binding site. The binding mode deduced from NMR binding experiments in solution was consistent with that from the crystal structure. PMID- 22831797 TI - Synthesis and characterization of a (68)Ga-labeled N-(2 diethylaminoethyl)benzamide derivative as potential PET probe for malignant melanoma. AB - Radiolabeled benzamides have been reported to be attractive agents for targeting malignant melanoma as they bind melanin and display high accumulation in melanoma cells. Herein, we report the synthesis and bioevaluation of a novel (68)Ga labeled benzamide as a potential PET agent for malignant melanoma. The novel radiotracer was synthesized in good radiochemical yields (80% decay corrected yield) and high specific radioactivity (10 GBq/MUmol). Cellular uptake of (68)Ga SCN-NOTA-BZA was significantly higher in B16F10 cells (mouse melanoma) treated with L-tyrosine. Biodistribution and micro-PET studies of (68)Ga-SCN-NOTA-BZA in B16F10-bearing mice showed selective uptake into the tumor. The radiotracer was cleared via renal excretion without further metabolism. These results demonstrate that (68)Ga-SCN-NOTA-BZA is a potential PET probe for malignant melanoma. PMID- 22831798 TI - Suppressive effects of coumarins from Mammea siamensis on inducible nitric oxide synthase expression in RAW264.7 cells. AB - A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit nitric oxide (NO) production in lipopolysaccharide-activated RAW264.7 cells. From the extract, two new geranylated coumarins, mammeasins A (1) and B (2), were isolated together with 17 known compounds including 15 coumarins. The structures of 1 and 2 were determined on the basis of their spectroscopic properties as well as of their chemical evidence. Among the isolates, 1 (IC(50) = 1.8 MUM), 2 (6.4 MUM), surangins B (3, 5.0 MUM), C (4, 6.8 MUM), and D (5, 6.2 MUM), kayeassamins E (7, 6.1 MUM), F (8, 6.0 MUM), and G (9, 0.8 MUM), mammea A/AD (11, 1.3 MUM), and mammea E/BB (16, 7.9 MUM) showed NO production inhibitory activity. Compounds 1, 9, and 11 were found to inhibit induction of inducible nitric oxide synthase (iNOS). With regard to mechanism of action of these active constituents (1, 9, and 11), suppression of STAT1 activation is suggested to be mainly involved in their suppression of iNOS induction. PMID- 22831799 TI - Syntheses and in vitro evaluation of decalinvesamicol analogues as potential imaging probes for vesicular acetylcholine transporter (VAChT). AB - A series of vesamicol analogues, o-iodo-trans-decalinvesamicol (OIDV) or o-bromo trans-decalinvesamicol (OBDV), were synthesized and their affinities to vesicular acetylcholine transporter (VAChT) and sigma receptors (sigma-1, sigma-2) were evaluated by in vitro binding assays using rat cerebral or liver membranes. OIDV and OBDV showed greater binding affinity to VAChT (K(i) = 20.5 +/- 5.6 and 13.8 +/- 1.2 nM, respectively) than did vesamicol (K(i) = 33.9 +/- 18.1 nM) with low affinity to sigma receptors. A saturation binding assay in rat cerebral membranes revealed that [(125)I]OIDV had a single high affinity binding site with a K(d) value of 1.73 nM and a B(max) value of 164.4 fmol/mg protein. [(125)I]OIDV revealed little competition with inhibitors, which possessed specific affinity to each sigma (sigma-1 and sigma-2), serotonin (5-HT(1A) and 5-HT(2A)), noradrenaline, and muscarinic acetylcholine receptors. In addition, BBB penetration of [(125)I]OIDV was verified in in vivo. The results of the binding studies indicated that OIDV and OBDV had great potential to be VAChT imaging probes with high affinity and selectivity. PMID- 22831800 TI - Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities. AB - Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl ~ allyl > reverse-prenyl groups. Among the series synthesized, the 3a ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a reverse-prenyl derivative indicated modest BuChE selectivity. PMID- 22831801 TI - Virtual screening leads to the discovery of novel non-nucleotide P2Y1 receptor antagonists. AB - The P2Y(1) receptor (P2Y(1)R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y(1)R ligands and the putative shape and size of the receptor binding pocket, we have identified novel antagonist hits of MUM affinity derived from a N,N'-bis arylurea chemotype. Unlike the vast majority of known P2Y(1)R antagonists, these drug-like compounds do not have a nucleotidic scaffold or highly negatively charged phosphate groups. Hence, our compounds may provide a direction for the development of receptor probes with altered physicochemical properties. PMID- 22831802 TI - Small molecules that protect against beta-amyloid-induced cytotoxicity by inhibiting aggregation of beta-amyloid. AB - Aggregated beta-amyloid (Abeta) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Abeta aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce Abeta-induced cytotoxicity by inhibiting Abeta aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (Abeta burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of Abeta(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD. PMID- 22831803 TI - New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase. AB - Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2. PMID- 22831804 TI - Bromate formation from bromide oxidation by the UV/persulfate process. AB - Bromate formation from bromide oxidation by the UV/persulfate process was investigated, along with changes in pH, persulfate dosages, and bromide concentrations in ultrapure water and in bromide-spiked real water. In general, the bromate formation increased with increasing persulfate dosage and bromide concentration. The bromate formation was initiated and primarily driven by sulfate radicals (SO(4)(*-)) and involved the formation of hypobromous acid/hypobromite (HOBr/OBr(-)) as an intermediate and bromate as the final product. Under the test conditions, the rate of the first step driven by SO(4)(* ) is slower than that of the second step. Direct UV photolysis of HOBr/OBr(-) to form bromate and the photolysis of bromate are insignificant. The bromate formation was similar for pH 4-7 but decreased over 90% with increasing pH from 7 to above 9. Less bromate was formed in the real water sample than in ultrapure water, which was primarily attributable to the presence of natural organic matter that reacts with bromine atoms, HOBr/OBr(-) and SO(4)(*-). The extent of bromate formation and degradation of micropollutants are nevertheless coupled processes unless intermediate bromine species are consumed by NOM in real water. PMID- 22831805 TI - A comparative study of visual function of young myopic adults wearing contact lenses vs. spectacles. AB - PURPOSE: To evaluate the impact of contact lenses wear vs. spectacles wear on visual function of young adults with mild to moderate myopia. METHODS: 57 students (27 male and 30 female) with a mean age of 23 years old participated in the study. Their mean best corrected visual acuity was 10/10 binocularly, all suffered from mild to moderate myopia (-3.75 sph/SD 1.25 sph) and they were both contact lenses and spectacles wearers. The VF-14 questionnaire was administered to assess the contact lenses wear vs. spectacles wear impact score on general daily living among the young individuals. It was used translated in Greek after following the 'translation-back translation' procedure. RESULTS: The mean VF-14 score among spectacles and contact lenses wearers was 100 and 86.78 (SD 4.08) respectively. Although there was a significant difference between the two groups (p<0.05), both scores were related to a satisfactory functional vision for daily living. The contact lenses wearers were facing difficulty especially while driving at night, seeing steps, as well as doing fine handwork (i.e. sewing, knitting or carpentry). CONCLUSIONS: The use of both spectacles and contact lenses provides satisfactory visual functioning for daily activities in young individuals suffering from mild to moderate myopia. However, there is a spectacles' wear superiority in personal satisfaction when compared to contact lenses. PMID- 22831806 TI - Bimanual capsulorrhexis using Sinskey hook. AB - An adequately sized, intact capsulorhexis is a key to the outcome of any phacoemulsification procedure. Cystitome is widely used to create a continuous curvilinear capsulorhexis. A 'frozen' capsule (crumpled capsule) mixed with viscoelastic and cortex, however can result in loss of control while using a cystitome. The Sinskey's hook introduced through the side-port, can stabilize the globe as well as work in coordination with the cystitome to spread out the jumbled up anterior capsule allowing visualization of the tear edge in the Bimanual technique. The capsulorhexis is thereby completed comfortably obviating the need of capsulorhexis forceps or repeated injection of ophthalmic viscosurgical device. PMID- 22831807 TI - Capsular tension segment in a case of microspherophakia. AB - BACKGROUND: A child with microspherophakia is described who was managed with scleral fixation of the loose capsular bag using Ahmed capsular tension segment and the small capsular bag was expanded using a standard capsular tension ring. METHODS: The child presented initially with lenticular myopia and concomitant glaucoma for which he was treated with peripheral iridotomy alone. The IOP remained uncontrolled after iridotomy procedure. Therefore, bimanual clear lens aspiration was performed; standard capsular tension ring was implanted 'in the bag' and Ahmed capsular tension segment was sutured to the sclera to stabilize the capsular complex. Foldable acrylic IOL was then injected into the bag. RESULTS: Postoperatively, the child had an unaided acuity of 20/30 on ETDRS. The IOL was centered well and the capsular bag had expanded due to the effect of CTR. CONCLUSIONS: This 'dual support' technique takes advantage of using both CTR and CTS to overcome the generalized zonulopathy found in cases of microspherophakia. It effectively counteracts lenticular myopia, treats glaucoma, strengthens the capsular bag and does not entail the future risk of IOL-bag dislocation. PMID- 22831808 TI - Preoperative intravascular balloon catheters and surgical outcomes in pregnancies complicated by placenta accreta: a management paradox. AB - OBJECTIVE: The objective of the study was to compare outcomes between patients who did and did not receive preoperative uterine artery balloon catheters in the setting placenta accreta. STUDY DESIGN: This was a retrospective case-control study of patients with placenta accreta from 1990 to 2011. RESULTS: Records from 117 patients with pathology-proven accreta were reviewed. Fifty-nine patients (50.4%) had uterine artery balloons (UABs) placed preoperatively. The mean estimated blood loss (EBL) was lower (2165 mL vs 2837 mL; P = .02) for the group that had UABs compared with the group that did not. There were more cases with an EBL greater than 2500 mL and massive transfusions of packed red blood cells (>6 units) in the group that did not have UABs. Percreta was diagnosed more often on final pathology in the group with UABs. Surgical times did not differ between the 2 groups. Two patients (3.3%) had complications related to the UABs. CONCLUSION: Preoperative placement of UABs is relatively safe and is associated with a reduced EBL and fewer massive transfusions compared with a group without UABs. PMID- 22831809 TI - "Early" versus "late" 23-week infant outcomes. AB - OBJECTIVE: To determine whether survival is different in "early" (23(0/7)-23(3/7) weeks) vs "late" (23(4/7)-23(6/7) weeks) infants. STUDY DESIGN: Records of 126 consecutive liveborn infants delivered at 23(0/7) to 23(6/7) weeks' gestation from 2001-2010 were examined using the Vermont Oxford Network database. Infants born at 23 0/7 to 23 3/7 weeks were grouped into "early" and those at 23 4/7 to 23 6/7 weeks were "late." Clinical characteristics were compared between groups and multivariate analyses were used to predict survival. RESULTS: Seventy-two infants were early and 54 were late. Survival was 25% vs 56%, respectively (P < .001). The early group was less likely to receive steroids (43% vs 65%; P = .016) and had a lower mean birthweight (547 g vs 596 g; P < .001). No difference in other factors was seen between groups. No change in survival was observed during the study period in either group. CONCLUSION: Late 23-week infants have improved survival compared with early infants. Delaying delivery as little as 24-96 hours may improve survival for 23-week infants. PMID- 22831810 TI - Obstetrical anal sphincter laceration and anal incontinence 5-10 years after childbirth. AB - OBJECTIVE: The purpose of this study was to investigate the long-term impact of anal sphincter laceration on anal incontinence. STUDY DESIGN: Five to 10 years after first delivery, anal incontinence and other bowel symptoms were measured with the Epidemiology of Prolapse and Incontinence Questionnaire and the short form of the Colorectal-Anal Impact Questionnaire. Obstetric exposures were assessed with review of hospital records. Symptoms and quality-of-life impact were compared among 90 women with at least 1 anal sphincter laceration, 320 women who delivered vaginally without sphincter laceration, and 527 women who delivered by cesarean delivery. RESULTS: Women who sustained an anal sphincter laceration were most likely to report anal incontinence (odds ratio, 2.32; 95% confidence interval, 1.27-4.26) and reported the greatest negative impact on quality of life. Anal incontinence and quality-of-life scores were similar between women who delivered by cesarean section and those who delivered vaginally without sphincter laceration. CONCLUSION: Anal sphincter laceration is associated with anal incontinence 5-10 years after delivery. PMID- 22831811 TI - Successful conservative management of a large iatrogenic vesicovaginal fistula after loop electrosurgical excision procedure. AB - A 40-year-old G3P3 woman with grade 3 cervical intraepithelial neoplasia underwent loop electrosurgical excision procedure complicated by a large vesicovaginal fistula. She was initially managed with an indwelling Foley catheter to allow for fistula maturation. During planned surgical repair it was discovered that the fistula had closed spontaneously. PMID- 22831812 TI - What is the optimal time for delivery in women with gestational hypertension? AB - OBJECTIVE: To assess the optimal timing of delivery for women with gestational hypertension. STUDY DESIGN: A multicenter database that contained 228,668 deliveries was used to extract data on gravidas with gestational hypertension. The week-specific rates of maternal and neonatal morbidity/mortality were calculated after induction of labor. Point wise 95% confidence intervals were calculated around each of these gestational age-specific rates. RESULTS: After induction of labor, the rate of maternal morbidity/mortality reached a nadir of 89.9 per 1000 live births (95% confidence interval, 68.1-111.8) at 38-38 6/7 weeks' gestation, although the rate of neonatal morbidity/mortality fell to 10.5 per 1000 live births (95% confidence interval, 2.8-18.2) at 39-39 6/7 weeks. There were only 3 total stillbirths in our study cohort. CONCLUSION: In women with gestational hypertension, induction of labor between 38- and 39-weeks' balances the lowest maternal and neonatal morbidity/mortality. PMID- 22831813 TI - Making a 'U-turn' with sterile adhesive tapes to optimize outcomes in nose and lip reconstruction. PMID- 22831814 TI - Metal-on-metal hips. PMID- 22831815 TI - Public stigmatization of different mental disorders: a comprehensive attitude survey. PMID- 22831816 TI - Bioluminescence-based identification of nisin producers - a rapid and simple screening method for nisinogenic bacteria in food samples. AB - We present a simple and rapid method for screening nisin producers that directly identifies nisinogenic bacteria by induction of bioluminescence within the Lactococcus lactis NZ9800lux biosensor strain (Immonen and Karp, 2007, Biosensors and Bioelectronics 22, 1982-7). An overlay of putative nisinogenic colonies with the biosensor strain gives identification results within 1h. Functionality and specificity of the method were verified by screening nisin producers among 144 raw milk colonies and a panel of 91 lactococcal strains. Studies performed on strains and colonies that did not induce bioluminescence but inhibited growth of the biosensor demonstrated that only nisinogenic bacteria can cause induction. Bacteria known to produce bacteriocins other than nisin failed to induce bioluminescence, further verifying the specificity of the assay. We discovered a non-inducing but inhibitory lactococcal strain harboring a modified nisin Z gene, and demonstrated that the source of the inhibitory action is not a non-inducing variant of nisin, but a bacteriocin of lower molecular weight. The concentration of nisin producers in a raw milk sample was 1.3 * 10(2)CFU/ml. We identified from raw milk a total of seven nisin Z producing L. lactis subsp. lactis colonies, which were shown by genetic fingerprinting to belong to three different groups. Among the panel of 91 lactococci, four strains were nisin A producers, and one strain harbored the modified nisin Z gene. The method presented here is robust, cost-effective and simple to perform, and avoids the pitfalls of traditional screening methods by directly specifying the identity of the inhibitory substance. PMID- 22831817 TI - The effects of essential oils carvacrol and thymol on growth of Penicillium digitatum and P. italicum involved in lemon decay. AB - In this work the antifungal efficacy of thymol, carvacrol and the mixture of both pure essential oils has been proved against Penicillium digitatum and Penicillium italicum, by using in vitro (liquid media, PDA plates and disk growth) and in vivo (lemon) tests. Results indicated that both essential oils were effective in inhibiting fungal growth in all in vitro tests, with the highest efficacy displayed by thymol. In addition, the application of wax with thymol and carvacrol to lemons inoculated with P. digitatum demonstrated the reduction of decay (expressed as percentage of infected fruit surface) in a concentration dependent manner, as well as reduced respiration rate, ethylene production and total acidity losses. Thus, the application of these essential oils together with wax in the citrus packing lines could be considered as good alternatives to reduce the use of synthetic fungicides. PMID- 22831818 TI - Incongruence between the cps type 2 genotype and host-related phenotypes of an Enterococcus faecalis food isolate. AB - Enterococcus faecalis is a nosocomial opportunistic pathogen, but is also found in fermented food products where it plays a fundamental role in the fermentation process. Previously, we have described the non-starter E. faecalis cheese isolate QA29b as harboring virulence genes and proven to be virulent in Galleria mellonella virulence model. In this study, we further characterized this food strain concerning traits relevant for the host-pathogen relationship. QA29b was found to belong to sequence type (ST) 72, a common ST among food isolates, and thus we consider it as a good representative of food E. faecalis strains. It demonstrated high ability to form biofilms, to adhere to epithelial cells and was readily eliminated by J774.A1 macrophage cells. Despite carrying the cps locus associated with the capsular polysaccharide CPS 2 type, cps genes were not expressed, likely due to an IS6770 inserted in the cpsC-cpsK promoter region. This work constitutes the first study of traits important for interaction, colonization and infection in the host performed on a good representative of E. faecalis food isolates. Reported results stress the need for a reliable serotyping assay of E. faecalis, as cps genotyping may not be reliable. Overall, QA29b characterization shows that despite its virulence potential in an insect model, this food strain is readily eliminated by mammalian macrophages. Thus, fine tuned approaches combining cellular and mammalian models are needed to address and elucidate the multifactorial aspect of virulence potential associated with food isolates. PMID- 22831819 TI - Behaviour of non-stressed and stressed Listeria monocytogenes and Campylobacter jejuni cells on fresh chicken burger meat packaged under modified atmosphere and inoculated with protective culture. AB - Numerous investigations have provided evidence that chicken products are a source of Listeria monocytogenes and Campylobacter jejuni. Different strategies applied in final products are needed to prevent consumers' contamination. In this work, the combination of modified atmosphere packaging (MAP) and protective culture to control the growth of freeze stressed and non-stressed L. monocytogenes and C. jejuni on fresh chicken meat burger was studied. Meat burgers were inoculated with L. monocytogenes, C. jejuni and Leuconostoc pseudomesenteroides PCK 18, as protective strain against L. monocytogenes. Prior to the addition of the protective culture, half of the L. monocytogenes and C. jejuni - inoculated meat was frozen at -18 degrees C for 48 h to subject cells to stress. Following the addition of the protective culture, meat burgers were packaged in air or MAP (50% CO(2)/50% O(2)) and stored under refrigeration conditions. L. monocytogenes counts were not reduced by the freezing temperature applied; however, the addition of Lc. pseudomesenteroides PCK 18 reduced its counts for 0.90 log cfu/g when chicken meat burgers were packaged under MAP. Furthermore, freezing stress was an effective strategy to reduce C. jejuni counts but only in combination with a high-O(2) MAP, it was completely eliminated. Chicken meat burgers' shelf-life under aerobic packaging conditions was reduced by the effect of freeze-thawing, while the use of MAP extended the product's shelf-life till 21days. Therefore, the combination of freezing, protective culture and MAP could extend the shelf life and enhance the food safety of this kind of chicken products. PMID- 22831820 TI - Salmonella can reach tomato fruits on plants exposed to aerosols formed by rain. AB - Outbreaks of Salmonella enterica have been associated with tomatoes and traced back to production areas but the spread of Salmonella in agricultural fields is still poorly understood. Post-rain Salmonella transfer from a point source to the air and then to tomato plants was evaluated. GFP-labeled kanamycin-resistant S. enterica serovar Typhimurium (10(8)CFU/mL) with and without expression of the rdar morphotype (rough colonies; cells with fimbriae and cellulose) was used as the point source in the center of a rain simulator. Rain intensities of 60 and 110 mm/h were applied for 5, 10, 20, and 30 min. Petri dishes with lactose broth and tomato plants with fruit (50-80 cm high) were placed in the simulator after the rain had ceased. Salmonella recovery from air was maximum (300 CFU/plate) after a rain episode of 60 mm/h for 10 min at distances of at least 85.5 cm above the source and when the rdar morphotype strain was used. Small scale experiments showed that the smooth-colony strain without fimbriae precipitated from the air in significantly higher numbers than the rdar strain. Transfer of aerial Salmonella with the rdar morphotype to tomato fruits on plants followed a beta distribution (2.5950, 4.7393) within the generalized range from 0 to 30 min of rain. Results show for the first time that Salmonella may transfer from rain to the air and contaminate tomato fruits at levels that could possibly be infectious to humans. PMID- 22831821 TI - Parental consent to participation in a randomised trial in children: associated child, family, and physician factors. AB - BACKGROUND: Low participation rates in randomised controlled trials involving children are almost a universal problem, leading to high cost and low statistical power. Trial, parent/family, child, and physician factors have been reported to influence parental willingness to consent for paediatric trials. PURPOSE: To identify modifiable and unmodifiable factors associated with parental consent. METHODS: Demographic and clinical characteristics of children and their families and physician characteristics associated with parental consent were evaluated in a recent randomised placebo-controlled trial of prophylactic antibiotics to prevent recurrent urinary tract infection. RESULTS: Of 1109 eligible children identified (mean age, 2.0 years), 412 parents (37.2%) consented. On a multivariate analysis, the only modifiable factor associated with consent was request for consent by a member of the research study team rather than by a member of the clinical team (risk ratio (RR) = 1.9, 95% confidence interval (CI): 1.2-2.9). The unmodifiable factors significantly associated with consent were age of the child (>=4 years) (RR = 1.2, 95% CI: 1.1-1.4), presence of vesicoureteric reflux (RR = 1.5, 95% CI: 1.3-1.8), inpatient management of the index infection (RR = 0.8, 95% CI: 0.7-0.9), and multiple (>=4) symptoms at presentation (RR = 1.3, 95% CI: 1.1-1.5). LIMITATIONS: We have reported data from only one of the four participating centres in this trial. Data on non-consenters in other participating centres were not completely collected. Data on characteristics of the recruiting physician were limited. These findings are applicable for those considering a single randomised controlled trial. CONCLUSIONS: Parent, child, and physician factors are associated with consent for trial participation, with most not being modifiable. Having a member of the research study team approach the parent for consent appears to be the only feasible strategy for increasing recruitment to randomised trials in this setting. PMID- 22831823 TI - The role of within-language vocabulary size in children's semantic development: evidence from bilingual children. AB - This study tested whether bilingual children show a lag in semantic development (the schematic-categorical shift) relative to monolingual children due to smaller vocabularies within a language. Twenty French-English bilingual and twenty English monolingual children (seven to ten years old) participated in a picture naming task in English. Their errors were coded for schematic or categorical relations. The bilingual children made more schematic errors than monolinguals, a difference that was accounted for statistically by vocabulary score differences. This result suggests that within-language vocabulary size is one important factor in semantic development and may explain why bilingual children sometimes show a lag relative to monolingual children in one of their languages, perhaps the language in which they have received less formal instruction. PMID- 22831822 TI - Comparison of the sensitivity of a pre-MRI questionnaire and point of care eGFR testing for detection of impaired renal function. AB - RATIONALE AND OBJECTIVES: The Food and Drug Administration recommends renal function estimation using laboratory testing for patients at risk for chronically reduced kidney function before the administration of gadolinium-based contrast agents (GBCAs). Point-of-care (POC) estimated glomerular filtration rate (eGFR) testing was added to the pre-magnetic resonance (MR) questionnaire at our institution in June 2008 for all patients undergoing a contrast-enhanced MR exam. This study was done to evaluate the effectiveness of a pre-MR screening questionnaire about kidney disease and to assess POC eGFR detection of additional patients at risk for nephrogenic systemic fibrosis. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board and determined to be Health Insurance Portability and Accountability Act compliant. Medical records, laboratory data, and pre-MR questionnaires of all patients who presented for contrast-enhanced MR scans during October 2008 were reviewed. The National Kidney Disease Education Program isotope-dilution mass spectrometry-traceable Modification of Diet in Renal Disease equation was used to calculate eGFRs using the POC creatinine laboratory value, age, race, and gender. Sensitivity and specificity were calculated using 2 * 2 tables, and 95% confidence intervals were calculated with exact binomial confidence intervals. RESULTS: A total of 1167 individuals presented for contrast-enhanced MR scans. Of 13 individuals on dialysis, 2 did not report renal disease. Of 1154 individuals not on dialysis, 25 had an eGFR <30 mL/min/1.73 m(2) (95% CI 1.41%-3.18%). Of these 25, 13 did and 12 did not report renal disease. The sensitivity of the questionnaire for identifying patients with an eGFR <30 mL/min/1.73 m(2) was 63.2%. POC eGFR estimations identified a prevalence of 2.17% (95% CI: 1.41%-3.18%) of the total individuals not on dialysis, with an eGFR <30 mL/min/1.73 m(2). Patients who denied kidney dysfunction had a 1.08% (95% CI: 0.56%-1.88%) posttest probability of having an eGFR <30 mL/min/1.73 m(2). CONCLUSIONS: POC eGFR testing identified a significant number of individuals with renal dysfunction not found by the pre MR imaging questionnaire alone. PMID- 22831824 TI - Compounded bioidentical menopausal hormone therapy. AB - Although improvement in long-term health is no longer an indication for menopausal hormone therapy, evidence supporting fewer adverse events in younger women, combined with its high overall effectiveness, has reinforced its usefulness for short-term treatment of menopausal symptoms. Menopausal therapy has been provided not only by commercially available products but also by compounding, or creation of an individualized preparation in response to a health care provider's prescription to create a medication tailored to the specialized needs of an individual patient. The Women's Health Initiative findings, coupled with an increase in the direct-to-consumer marketing and media promotion of compounded bioidentical hormonal preparations as safe and effective alternatives to conventional menopausal hormone therapy, have led to a recent increase in the popularity of compounded bioidentical hormones as well as an increase in questions about the use of these preparations. Not only is evidence lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy, but these claims also pose the additional risks of variable purity and potency and lack efficacy and safety data. The Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists and the Practice Committee of the American Society for Reproductive Medicine provide an overview of the major issues of concern surrounding compounded bioidentical menopausal hormone therapy and provide recommendations for patient counseling. PMID- 22831826 TI - The Pediatric Assessment Triangle: accuracy of its application by nurses in the triage of children. AB - INTRODUCTION: The Pediatric Assessment Triangle (PAT) is a rapid evaluation tool that establishes a child's clinical status and his or her category of illness to direct initial management priorities. Recently the PAT has been incorporated widely into the pediatric resuscitation curriculum. Although intuitive, its performance characteristics have yet to be quantified. The purpose of this research is to determine quantitatively its accuracy, reliability, and validity as applied by nurses at triage. METHODS: In this prospective observational study, triage nurses performed the PAT on all patients presenting to the pediatric emergency department of an urban teaching hospital. Researchers performed blinded chart review using the physician's initial assessment and final diagnosis as the criterion standard for comparison. RESULTS: A total of 528 children were included in the analysis. Likelihood ratios (LRs) were found for instability and category of pathophysiology using the PAT. Children deemed stable by initial PAT were almost 10 times more likely to be stable on further assessment (LR 0.12, 95% confidence interval [CI] 0.06-0.25). The PAT further specified categories of pathophysiology: respiratory distress (LR+ 4, 95% CI 3.1-4.8), respiratory failure (LR+ 12, 95% CI 4.0-37), shock (LR+ 4.2, 95% CI 3.1-5.6), central nervous system/metabolic disorder (LR+ 7, 95% CI 4.3-11), and cardiopulmonary failure (LR+ 49, 95% CI 20-120). DISCUSSION: The structured assessment of the initial PAT, as performed by nurses in triage, readily and reliably identifies high acuity pediatric patients and their category of pathophysiology. The PAT is highly predictive of the child's clinical status on further evaluation. PMID- 22831827 TI - Comparing subcutaneous fluid infusion with intravenous fluid infusion in children. AB - INTRODUCTION: This study examined subcutaneous (SC) infusion as a parenteral alternative for children with mild to moderate illness. The purpose was to compare the difference in infusion start time of parenteral fluid between an initial SC order and an initial intravenous (IV) order. In addition, the number of needlesticks a child received for each method was evaluated. This study also sought to address the following question: If SC fluids were given and an IV attempt was made later, did the administration of SC fluids enhance the success of venous cannulation? METHODS: A retrospective descriptive design was used for review of medical records for 36 children from November 2008 to May 2010 who had received SC fluids only or received SC fluids after 2 or more failed IV attempts. RESULTS: The IV/SC group had significantly longer time to infusion (M = 97.33 minutes) than did the SC group (M = 20.95 minutes; U = .000; P < .001). The IV/SC group included the number of needlesticks for the intravenous attempts plus the needle stick needed for the subcutaneous infusion. A significant difference was found between the 2 groups (mean IV = 4.87; mean SC = 1; Z = .000; P < .001). DISCUSSION: In a child who is not seriously ill, SC infusions appear to facilitate the initiation of parenteral rehydration. SC infusions minimized the number of needlesticks a child endured. More study is needed to determine if SC fluids enhance success of subsequent venous cannulation. PMID- 22831825 TI - Age at last birth in relation to risk of endometrial cancer: pooled analysis in the epidemiology of endometrial cancer consortium. AB - Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years. PMID- 22831828 TI - Vulnerable child pedestrians in rapidly motorizing developing countries. PMID- 22831829 TI - A 48-year-old woman with chloride gas toxicity. PMID- 22831830 TI - Discovery of the novel HLA-DRB1*09:01:08 allele in a Taiwanese volunteer bone marrow donor and identification of the probable HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*09:01:08. AB - We report here the novel variant of HLA-DRB1*09:01, DRB1*09:01:08, discovered in a Taiwanese volunteer bone marrow donor by a sequence-based typing (SBT) method. The DNA sequence of DRB1*09:01:08 is identical to the sequence of DRB1*09:01:02 in exon 2 except a silent mutation at nucleotide position 261(C->T) (GCC->GCT at codon 58). We hypothesize DRB1*09:01:08 was probably derived from DRB1*09:01:02 via a nucleotide point mutation event. The plausible HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*09:01:08 was deduced as A*02:07-B*46:01 DRB1*09:01:08. PMID- 22831832 TI - Ag(I)/V(V) heterobimetallic frameworks generated from novel-type {Ag2(VO2F2)2(triazole)4} secondary building blocks: a new aspect in the design of SVOF hybrids. AB - A series of new silver(I)-containing MOFs [Ag(2)(tr(2)ad)(2)](ClO(4))(2) (1), [Ag(2)(VO(2)F(2))(2)(tr(2)ad)(2)].H(2)O (2), [Ag(2)(VO(2)F(2))(2)(tr(2)eth)(2)(H(2)O)(2)] (3), and [Ag(2)(VO(2)F(2))(2)(tr(2)cy)(2)].4H(2)O (4) supported by 4-substituted bifunctional 1,2,4-triazole ligands (tr(2)ad = 1,3-bis(1,2,4-triazol-4 yl)adamantane, tr(2)eth = 1,2-bis(1,2,4-triazol-4-yl)ethane, tr(2)cy = trans-1,4 bis(1,2,4-triazol-4-yl)cyclohexane) were hydrothermally synthesized and structurally characterized. In these complexes, the triazole heterocycle as an N(1),N(2)-bridge links either two adjacent Ag-Ag or Ag-V centers at short distances forming polynuclear clusters. The crystal structure of compound 1 is based on cationic {Ag(2)(tr)(4)}(2+) fragments connected in a 2D rhombohedral grid network with (4,4) topology. The neighboring layers are tightly packed into a 3D array by means of argentophilic interactions (Ag...Ag 3.28 A). Bridging between different metal atoms through the triazole groups assists formation of heterobimetallic Ag(I)/V(V) secondary building blocks in a linear V-Ag-Ag-V sequence that is observed in complexes 2-4. These unprecedented tetranuclear {Ag(2)(VO(2)F(2))(2)(tr)(4)} units (the intermetal Ag-Ag and Ag-V distances are 4.24-4.36 and 3.74-3.81 A, respectively), in which vanadium(V) oxofluoride units possess distorted trigonal bipyramidal environment {VO(2)F(2)N}-, are incorporated into 1D ribbon (2) or 2D square nets (3, 4) using bitopic MU(4) triazole ligands. The valence bond calculation for vanadium atoms shows +V oxidation state in the corresponding compounds. Thermal stability and photoluminescence properties were studied for all reported coordination polymers. PMID- 22831831 TI - Oro-palatal dysplasia Bettex-Graf--clinical findings, genetic background, treatment. AB - Oro-palatal dysplasia Bettex-Graf is an extremely rare syndrome consisting of microstomia, U-shaped cleft palate and micrognathia. Only two affected families have been reported before. We present the clinical findings, treatment and 13 year follow-up in a patient with this rare syndrome. The possible linkage to the fragile site 16q22 has been supported, contrary to earlier statements of its non pathogenic character. The analysis of clinical symptoms and reference to the literature suggests, that ankyloglossia is a part of oropalatal dysplasia, whereas hypodontia is associated with the cleft itself. The authors postulate that a 20mm intercommissural distance allows acceptable function without the need for surgical correction. PMID- 22831833 TI - MAP kinases and histone modification. AB - Signal transduction pathways alter the gene expression program in response to extracellular or intracellular cues. Mitogen-activated protein kinases (MAPKs) govern numerous cellular processes including cell growth, stress response, apoptosis, and differentiation. In the past decade, MAPKs have been shown to regulate the transcription machinery and associate with chromatin-modifying complexes. Moreover, recent studies demonstrate that several MAPKs bind directly to chromatin at target genes. This review highlights the recent discoveries of MAPK signaling in regard to histone modifications and chromatin regulation. Evidence suggesting that further unknown mechanisms integrate signal transduction with chromatin biology is discussed. PMID- 22831835 TI - Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. PMID- 22831834 TI - New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells. AB - The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5 azathioprine and gamma-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages. PMID- 22831836 TI - SUV39H1 orchestrates temporal dynamics of centromeric methylation essential for faithful chromosome segregation in mitosis. AB - Histone methylation performs multiple functions such as DNA replication, transcription regulation, heterochromatin formation, and chromatin condensation. How this methylation gradient is orchestrated in the centromere during chromosome segregation is not known. Here we examine the temporal dynamics of protein methylation in the centromere by SUV39H1 methyltransferase, a key mitotic regulator, using fluorescence resonance energy transfer-based sensors in living HeLa cells and immunofluorescence of native SUV39H1 substrates. A quantitative analysis of methylation dynamics, using centromere-targeted sensors, reveals a temporal change during chromosome segregation. These dynamics result in an accurate chromosome congression to and alignment at the equator as an inhibition of methylation dynamics using SUV39H1 inhibitor perturbs chromosome congression in living HeLa cells. Surprisingly, this inhibition of methylation results in a brief increase in Aurora B kinase activity and an enrichment of microtubule depolymerase MCAK in the centromere with a concomitant kinetochore-microtubule destabilization and a reduced tension across the sister kinetochores with ultimate chromosome misalignments. We reason that SUV39H1 generates a gradient of methylation marks at the kinetochore that provides spatiotemporal information essential for accurate chromosome segregation in mitosis. PMID- 22831837 TI - Association of Toll-like receptor 4 gene polymorphisms in Japanese subjects with primary open-angle, normal-tension, and exfoliation glaucoma. AB - PURPOSE: To determine whether polymorphisms in the Toll-like receptor 4 (TLR4) gene are associated with primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and exfoliation glaucoma (XFG) in Japanese individuals. DESIGN: Genetic association study. METHODS: SETTING: Multicenter study. STUDY POPULATION: One hundred eighty-four unrelated Japanese patients with POAG, 365 unrelated patients with NTG, and 109 unrelated patients with XFG from 5 hospitals. PROCEDURES: Genomic DNA was extracted from leukocytes of the peripheral blood, and 8 polymorphisms in the TLR4 genes were amplified by polymerase chain reaction (PCR) and directly sequenced. Allele and genotype frequencies and the inferred haplotypes were estimated. MAIN OUTCOME MEASURES: Differences in allele and genotype frequencies and haplotypes between subjects with POAG, NTG, and XFG. RESULTS: The allele frequency of rs2149356 of the TLR4 gene in the POAG, NTG, and XFG groups was the most significantly different from that of the control group (minor allele frequency 0.446, 0.395, 0.404, vs 0.308; P = .000058, P = .0030, and P = .015). The allele frequencies of the 5 TLR4 SNPs were higher in all of the glaucoma groups than that in the control group. The statistics of genotypes of TLR4 were approximately the same for all allele frequencies. The haplotypic frequencies with Tag SNPs studied earlier showed that only POAG was statistically significant. Other haplotypes, such as rs10759930, rs1927914, rs1927911, and rs2149356, had higher statistical significance (overall P = .00078 in POAG, overall P = .018 in NTG, and overall P = .014 in XFG). CONCLUSIONS: This study demonstrated that TLR4 polymorphisms are associated with NTG in the Japanese, and they also play a role in the pathogenesis of POAG and XFG. PMID- 22831838 TI - Photodynamic therapy with or without intravitreal bevacizumab for polypoidal choroidal vasculopathy: two years of follow-up. AB - PURPOSE: To compare the long-term results of the efficacy of photodynamic therapy (PDT) with or without intravitreal bevacizumab (IVB) injections for polypoidal choroidal vasculopathy. DESIGN: Retrospective, comparative, interventional case series. METHODS: We included 69 eyes of 69 patients with macula-involved polypoidal choroidal vasculopathy. All patients were followed up for more than 2 years. We compared the treatment outcomes between groups and investigated the factors influencing visual improvement at 24 months of follow-up. RESULTS: Thirty six patients received PDT combined with IVB and 33 patients received PDT monotherapy. At 3 months, the mean logarithm of minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 0.73 to 0.53 in the combined therapy group (P < .001) and from 0.79 to 0.72 in the PDT monotherapy group (P = .02), with a significant difference in treatment efficacy between the 2 groups (P < .001). However, the improvements in BCVA were not statistically significant after 21 months in the combined therapy group and 15 months in the monotherapy group. The difference in treatment efficacy between the 2 groups was not significant after 6 months. Initial BCVA (P = .005), lesion size (P = .011), patient age (P = .018), and location of polyps (P = .006) significantly predicted the final visual outcome rather than treatment modality (P = .243). CONCLUSIONS: PDT combined with IVB for symptomatic PCV was temporarily superior to PDT monotherapy, and the treatment efficacy decreased with time. Initial BCVA, lesion size, and location were more significant than treatment modality as the factors influencing final visual improvement. PMID- 22831839 TI - The societal burden of blindness secondary to retinopathy of prematurity in Lima, Peru. AB - PURPOSE: To determine the cost-effectiveness of laser treatment for retinopathy of prematurity (ROP) in Lima, Peru. DESIGN: A cost-of-illness study (in US dollars) to determine the direct cost of treatment, the indirect lifetime cost of blindness, and the quality-adjusted life years. METHODS: The direct cost of ROP related treatment was determined by reviewing data retrospectively from a social security sector hospital. The indirect cost was determined using national economic data of Peru published by the Central Information Agency (CIA), including the per capita gross domestic product, the sex-adjusted income distribution, and years spent in the work force. Indirect costs per child that were avoided by treatment were calculated using the known natural history of ROP vs evidence-based treatment. RESULTS: For ROP-related neonatal blindness in Peru, we estimate the total indirect cost saving at $197,753 per child and the direct cost of laser treatment at $2496 per child. The societal lifetime cost saving per child is estimated at $195,257. The mean annual income per educated adult in Peru is $8000 and treating 1 child is equivalent to employing 24 educated Peruvians per year. The generational cost savings for society is approximately $516 million, or the equivalent of 64,500 educated Peruvian work years. CONCLUSIONS: The societal burden of blindness far exceeds the costs of treatment per child. Proper screening and treatment of ROP prevents blindness and leads to substantial cost savings for society. Public health policy in Peru and other middle-income countries should consider financial impact when allocating healthcare resources. PMID- 22831840 TI - Clonal expansion accounts for an excess of antimicrobial resistance in Staphylococcus aureus colonising HIV-positive individuals in Lagos, Nigeria. AB - Nasal colonisation with Staphylococcus aureus is a risk factor for invasive infection in human immunodeficiency virus (HIV)-positive individuals. This study aimed to characterise colonising S. aureus from regions with a high HIV prevalence. Single nasal swabs were taken from a total of 374 HIV-positive and 370 healthy individuals. Overall, 202 S. aureus carriers were detected. Compared with healthy individuals, HIV-positive subjects were more likely to be S. aureus nasal carriers (33% vs. 21%; P=0.0001). Isolates from HIV-positive individuals were more often resistant to meticillin (16% vs. 8%; P=0.13), chloramphenicol (47% vs. 16%; P<0.0001), sulfamethoxazole/trimethoprim (SXT) (90% vs. 55%; P<0.0001) and ciprofloxacin (18% vs. 0%; P<0.0001). Strains belonging to the spa clonal complexes 3772/ST25 and 064/ST8 were significantly more often isolated from HIV-positive individuals and exhibited greater resistance to ciprofloxacin, SXT and chloramphenicol (spa-CC 3772) or to meticillin (spa-CC 064), respectively. Panton-Valentine leukocidin gene content was high overall and was equally distributed between isolates from HIV-positive and healthy individuals (33% vs. 30%). Genotypic characteristics of colonising isolates were similar to those reported to cause invasive infection in Nigeria. The HIV pandemic contributes to the evolution of antimicrobial resistance in S. aureus. Measures to contain antimicrobial resistance of S. aureus in Nigeria must target risk groups such as HIV-positive individuals. PMID- 22831841 TI - Transferable mechanisms of quinolone resistance. AB - Quinolones were introduced into clinical practice in the late 1960s. Although quinolone resistance was described early, no transferable mechanism of quinolone resistance (TMQR) was confirmed until 1998. To date, five different TMQRs have been described in the literature, including target protection (Qnr), quinolone modification (AAC(6')-Ib-cr), plasmid-encoded efflux systems (e.g. QepA or OqxAB, amongst others), effect on bacterial growth rates and natural transformation. Although TMQRs usually only result in a slight increase in the minimum inhibitory concentrations of quinolones, they possess an additive effect and may facilitate the acquisition of full quinolone resistance. The emergence of new related genes may continue in the next years. PMID- 22831842 TI - Efficacy of tigecycline/colistin combination in a pneumonia model caused by extensively drug-resistant Acinetobacter baumannii. AB - Due to increasing drug resistance, available antimicrobial options are limited in the treatment of Acinetobacter baumannii infections. Particularly in cases caused by extensively drug-resistant (XDR) A. baumannii, combination regimens must also be taken into consideration. In this study, the efficacies of tigecycline, colistin and tigecycline/colistin combination on bacterial counts in lung tissue were investigated in a rat pneumonia model. One A. baumannii strain resistant to all antimicrobial agents except tigecycline and colistin was selected for the study. In vivo studies revealed a >3 log reduction in bacterial counts in the tigecycline, colistin and combination groups at 24 h and 48 h compared with the control group. No significant differences were determined between colistin, tigecycline and combination groups (P>0.05). On the other hand, differences between treatment groups and the control group were statistically significant (P=0.01). A greater reduction in bacterial counts was observed at 48 h compared with 24 h in the tigecycline group than in the colistin group (P=0.038 and P=0.139, respectively); the most significant decrease between 24 h and 48 h was observed in the combination group (P=0.014). Despite detection of in vitro synergistic activity in this study, no statistically significant differences were found between colistin, tigecycline and combination treatments in terms of efficacy on bacterial counts in lung tissue. In the treatment of infections with a high mortality rate such as pneumonia caused by XDR A. baumannii, combining tigecycline with colistin during the first 48 h and continuing treatment with one of these agents seems a rational approach. PMID- 22831843 TI - Social networks, support and early psychosis: a systematic review. AB - Background. There is strong evidence that those with a long-standing psychotic disorder have fewer social contacts and less social support than comparison groups. There is less research on the extent of social contacts and support prior to or at the onset of psychosis. In the light of recent evidence implicating a range of social experiences and contexts at the onset of psychosis, it is relevant to establish whether social networks and support diminished before or at the time of onset and whether the absence of such supports might contribute to risk, either directly or indirectly. We, therefore, conducted a systematic review of this literature to establish what is currently known about the relationship between social networks, support and early psychosis. Methods. We identified all studies investigating social networks and support in first episode psychosis samples and in general population samples with measures of psychotic experiences or schizotype by conducting systematic searches of electronic databases using pre defined search terms and criteria. Findings were synthesized using non quantitative approaches. Results. Thirty-eight papers were identified that met inclusion criteria. There was marked methodological heterogeneity, which limits the capacity to draw direct comparisons. Nonetheless, the existing literature suggests social networks (particularly close friends) and support diminished both among first episode samples and among non-clinical samples reporting psychotic experiences or with schizotype traits, compared with varying comparison groups. These differences may be more marked for men and for those from minority ethnic populations. Conclusions. Tentatively, reduced social networks and support appear to pre-date onset of psychotic disorder. However, the substantial methodological heterogeneity among the existing studies makes comparisons difficult and suggests a need for more robust and comparable studies on networks, support and early psychosis. PMID- 22831844 TI - Metagenomics: microbial diversity through a scratched lens. AB - Since nucleic acids were first extracted directly from the environment and sequenced, metagenomics has grown to one of the most data-rich and pervasive techniques for understanding the taxonomic and functional diversity of microbial communities. In the last decade, cheaper sequencing has democratized the application of metagenomics and generated billions of reads, revealing staggering microbial diversity and functional complexity. However, cheaper sequencing has come at the cost of reduced sequence length, resulting in poor gene annotation and overestimates of bacterial richness and abundance. Recent improvements in sequencing technology are beginning to provide reads of sufficient length for accurate annotation and assembly of whole operons and beyond, that will once again enable experimental testing of gene function and re-capture the early successes of metagenomic investigations. PMID- 22831845 TI - Trying to get rid of protozoan parasites. PMID- 22831846 TI - Characteristics related to protection order use among victims of intimate partner violence. AB - One increasingly important resource for victims of intimate partner violence (IPV) is domestic violence civil protection orders (POs). Using a transdisciplinary framework, this article critically examines the use of POs by IPV victims seeking shelter services. Previous contact with police and medical professionals are the strongest predictors of having obtained a PO; education level, income, age, race, and having children in the shelter are also significant predictors of having obtained a PO. These findings are discussed in the context of previous research on help-seeking behaviors and the growing body of transdisciplinary research on violence against women. PMID- 22831847 TI - Who died? The murder of collaterals related to intimate partner conflict. AB - Using data from the Murder in Britain Study, the authors focus on murders that are related to intimate partner conflict but involve the killing of a person other than the intimate partner. Intimate partner collateral murders (IPCM) include children, allies, and new partners. The findings expand the number and types of murder associated with intimate partner conflict, characterize the three main types of collaterals, compare the childhood and adulthood of the perpetrators of intimate partner murder [IPM] (n = 104) and IPCM (n = 62), and reflect similarities and differences. Various disciplinary approaches are reflected in the research design, data collection, findings, and conclusions. PMID- 22831848 TI - "There's so much at stake": sexual minority youth discuss dating violence. AB - The purpose of this study was to explore perceptions of dating violence among a sample of sexual minority youth. Focus groups were conducted as part of a larger study that surveyed 109 sexual minority youth between the ages of 18 and 24 years. Participants identified four main themes contributing to dating violence among same-sex couples: homophobia (societal and internalized); negotiating socially prescribed gender roles; assumed female connection; and other relationship issues. Such information is essential for determining the need for and content of dating violence services, including education, safety planning, and referrals for mental and physical health services for sexual minority youth. PMID- 22831849 TI - Canonical dependency analysis based on squared-loss mutual information. AB - Canonical correlation analysis (CCA) is a classical dimensionality reduction technique for two sets of variables that iteratively finds projection directions with maximum correlation. Although CCA is still in vital use in many practical application areas, recent real-world data often contain more complicated nonlinear correlations that cannot be properly captured by classical CCA. In this paper, we thus propose an extension of CCA that can effectively capture such complicated nonlinear correlations through statistical dependency maximization. The proposed method, which we call least-squares canonical dependency analysis (LSCDA), is based on a squared-loss variant of mutual information, and it has various useful properties besides its ability to capture higher-order correlations: for example, it can simultaneously find multiple projection directions (i.e., subspaces), it does not involve density estimation, and it is equipped with a model selection strategy. We demonstrate the usefulness of LSCDA through various experiments on artificial and real-world datasets. PMID- 22831850 TI - Maxi-Min discriminant analysis via online learning. AB - Linear Discriminant Analysis (LDA) is an important dimensionality reduction algorithm, but its performance is usually limited on multi-class data. Such limitation is incurred by the fact that LDA actually maximizes the average divergence among classes, whereby similar classes with smaller divergence tend to be merged in the subspace. To address this problem, we propose a novel dimensionality reduction method called Maxi-Min Discriminant Analysis (MMDA). In contrast to the traditional LDA, MMDA attempts to find a low-dimensional subspace by maximizing the minimal (worst-case) divergence among classes. This "minimal" setting overcomes the problem of LDA that tends to merge similar classes with smaller divergence when used for multi-class data. We formulate MMDA as a convex problem and further as a large-margin learning problem. One key contribution is that we design an efficient online learning algorithm to solve the involved problem, making the proposed method applicable to large scale data. Experimental results on various datasets demonstrate the efficiency and the efficacy of our proposed method against five other competitive approaches, and the scalability to the data with thousands of classes. PMID- 22831851 TI - Identification of two novel HLA-A alleles: A*24:199 and A*02:324. AB - Here, we describe two new HLA-A alleles: A*24:199 and A*02:324. The two new variants are attributed to a single nucleotide mutation namely A->C for A*24:199 and G->A for A*02:324. Both point mutations are responsible for a change in translated amino acids. PMID- 22831852 TI - Mitochondrial oxidative stress and the metabolic syndrome. AB - The current epidemic of the metabolic syndrome in the developed world is largely due to overnutrition and lack of physical activity. However, the underlying causes by which chronic overnutrition interacts with genotype and physical inactivity to generate the metabolic syndrome phenotype are complex, and include multiple metabolic and physiological alterations. Mitochondrial oxidative stress has been suggested to contribute to the metabolic syndrome, but the mechanisms and significance are unclear. Here we review how disruption of mitochondrial metabolism and increased oxidative stress may occur during overnutrition coupled with limited physical activity. From this we suggest a unifying hypothesis to integrate what is known about mitochondrial involvement in the metabolic syndrome that points to testable hypotheses and novel therapeutic approaches. PMID- 22831853 TI - Solifenacin plus tamsulosin combination treatment in men with lower urinary tract symptoms and bladder outlet obstruction: a randomized controlled trial. AB - BACKGROUND: Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB). OBJECTIVE: To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for >=3 mo, total International Prostate Symptom Score (IPSS) >=8, BOO index >=20, maximum urinary flow rate (Q(max)) <=12 ml/s, and voided volume >=120 ml. INTERVENTIONS: Once daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary (safety) measurements: Q(max) and detrusor pressure at Q(max) (P(det)Q(max)). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo. RESULTS AND LIMITATIONS: Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P(det)Q(max) and Q(max). Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate specific antigen level were not measured. CONCLUSIONS: TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P(det)Q(max) and Q(max) in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention. PMID- 22831854 TI - The effect of RAFT-derived cationic block copolymer structure on gene silencing efficiency. AB - In this work a series of ABA tri-block copolymers was prepared from oligo(ethylene glycol) methyl ether methacrylate (OEGMA(475)) and N,N dimethylaminoethyl methacrylate (DMAEMA) to investigate the effect of polymer composition on cell viability, siRNA uptake, serum stability and gene silencing. Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization was used as the method of polymer synthesis as this technique allows the preparation of well-defined block copolymers with low polydispersity. Eight block copolymers were prepared by systematically varying the central cationic block (DMAEMA) length from 38 to 192 monomer units and the outer hydrophilic block (OEGMA(475)) from 7 to 69 units. The polymers were characterized using size exclusion chromatography and (1)H NMR. Chinese Hamster Ovary-GFP and Human Embryonic Kidney 293 cells were used to assay cell viability while the efficiency of block copolymers to complex with siRNA was evaluated by agarose gel electrophoresis. The ability of the polymer-siRNA complexes to enter into cells and to silence the targeted reporter gene enhanced green fluorescent protein (EGFP) was measured by using a CHO-GFP silencing assay. The length of the central cationic block appears to be the key structural parameter that has a significant effect on cell viability and gene silencing efficiency with block lengths of 110-120 monomer units being the optimum. The ABA block copolymer architecture is also critical with the outer hydrophilic blocks contributing to serum stability and overall efficiency of the polymer as a delivery system. PMID- 22831855 TI - Drawing lithography for microneedles: a review of fundamentals and biomedical applications. AB - A microneedle is a three-dimensional (3D) micromechanical structure and has been in the spotlight recently as a drug delivery system (DDS). Because a microneedle delivers the target drug after penetrating the skin barrier, the therapeutic effects of microneedles proceed from its 3D structural geometry. Various types of microneedles have been fabricated using subtractive micromanufacturing methods which are based on the inherently planar two-dimensional (2D) geometries. However, traditional subtractive processes are limited for flexible structural microneedles and makes functional biomedical applications for efficient drug delivery difficult. The authors of the present study propose drawing lithography as a unique additive process for the fabrication of a microneedle directly from 2D planar substrates, thus overcoming a subtractive process shortcoming. The present article provides the first overview of the principal drawing lithography technology: fundamentals and biomedical applications. The continuous drawing technique for an ultrahigh-aspect ratio (UHAR) hollow microneedle, stepwise controlled drawing technique for a dissolving microneedle, and drawing technique with antidromic isolation for a hybrid electro-microneedle (HEM) are reviewed, and efficient biomedical applications by drawing lithography-mediated microneedles as an innovative drug and gene delivery system are described. Drawing lithography herein can provide a great breakthrough in the development of materials science and biotechnology. PMID- 22831856 TI - New type F lineage-related Tn1546 and a vanA/vanB type vancomycin-resistant Enterococcus faecium isolated from patients in Dammam, Saudi Arabia during 2006 2007. AB - Knowledge regarding vancomycin-resistant enterococci (VRE) from Middle Eastern countries is scarce. We therefore investigated the antimicrobial resistance profiles and genetic relationships of VRE Enterococcus faecium isolates obtained from patients attending the King Fahad Specialist Hospital, Dammam, during 2006 2007. The predominant VRE comprised 20 vanB, five vanA and one vanA/vanB type isolates, which tended to fall into two genetic clusters that were identifiable phenotypically by their susceptibility to tetracycline. Multi-locus sequence typing of a random selection of isolates showed that they were part of clonal cluster 17, showing the importance of this genotype in nosocomial VRE infections in Saudi Arabia. Further analysis showed that four of the vanA genotype isolates possessed a new type F Tn1546 transposon, associated with IS1216V and IS1251. Finally, E. faecium vanA/B isolates are rarely reported in the clinical setting including in Saudi Arabia. PMID- 22831857 TI - Structural markers observed with endoscopic 3-dimensional optical coherence tomography correlating with Barrett's esophagus radiofrequency ablation treatment response (with videos). AB - BACKGROUND: Radiofrequency ablation (RFA) is effective for treating Barrett's esophagus (BE) but often involves multiple endoscopy sessions over several months to achieve complete response. OBJECTIVE: Identify structural markers that correlate with treatment response by using 3-dimensional (3-D) optical coherence tomography (OCT; 3-D OCT). DESIGN: Cross-sectional. SETTING: Single teaching hospital. PATIENTS: Thirty-three patients, 32 male and 1 female, with short segment (<3 cm) BE undergoing RFA treatment. INTERVENTION: Patients were treated with focal RFA, and 3-D OCT was performed at the gastroesophageal junction before and immediately after the RFA treatment. Patients were re-examined with standard endoscopy 6 to 8 weeks later and had biopsies to rule out BE if not visibly evident. MAIN OUTCOME MEASUREMENTS: The thickness of BE epithelium before RFA and the presence of residual gland-like structures immediately after RFA were determined by using 3-D OCT. The presence of BE at follow-up was assessed endoscopically. RESULTS: BE mucosa was significantly thinner in patients who achieved complete eradication of intestinal metaplasia than in patients who did not achieve complete eradication of intestinal metaplasia at follow-up (257 +/- 60 MUm vs 403 +/- 86 MUm; P < .0001). A threshold thickness of 333 MUm derived from receiver operating characteristic curves corresponded to a 92.3% sensitivity, 85% specificity, and 87.9% accuracy in predicting the presence of BE at follow-up. The presence of OCT-visible glands immediately after RFA also correlated with the presence of residual BE at follow-up (83.3% sensitivity, 95% specificity, 90.6% accuracy). LIMITATIONS: Single center, cross-sectional study in which only patients with short-segment BE were examined. CONCLUSION: Three dimensional OCT assessment of BE thickness and residual glands during RFA sessions correlated with treatment response. Three-dimensional OCT may predict responses to RFA or aid in making real-time RFA retreatment decisions in the future. PMID- 22831859 TI - A comparative study on the effects of barite, ilmenite and bentonite on four suspension feeding bivalves. AB - The impact of drilling mud components on the filtration activity and survival of bivalve molluscs was investigated by exposing them to suspensions of 'standard' barite, finely milled barite, ilmenite and bentonite in sea water. Introduction of the components stimulated filtration activity in all four bivalves. In addition, the introduction of standard barite and ilmenite both had lethal effects, with none of the bivalves surviving the full duration of the experiments. In-vivo observations of the gill surfaces provided direct evidence of physical damage caused by the administration of barite and ilmenite. A marked difference between filtration activity and survival of animals dosed with 'standard' barite and 'fine' barite suggests that the observed effects were primarily caused by physical interference with gill function. The results also suggest that the use of fine barite in offshore drilling may provide a more favourable environmental impact profile than the use of ilmenite. PMID- 22831858 TI - A comprehensive approach to the management of acute endoscopic perforations (with videos). PMID- 22831860 TI - Comment on Chang and Zhao (2012) "The Fukushima Nuclear Power Station incident and marine pollution". PMID- 22831861 TI - Chesapeake Bay nutrient pollution: contribution from the land application of sewage sludge in Virginia. AB - Human health concerns and the dissemination of anthropogenic substances with unknown consequences are the reasons most often given why disposal of municipal sewage sludge in landfills or using the organic waste as biofuel is preferable to land application. But no "fertilizer" causes more nitrogen pollution than sludge when applied according to Virginia law. Poultry litter is the only other "fertilizer" that causes more phosphorus pollution than sludge. Cost savings by the few farmers in Virginia who use sludge are far less than the costs of the nitrogen pollution they cause. A ban on the land application of all forms of animal waste is very cost-effective and would reduce Chesapeake Bay nutrient pollution by 25%. PMID- 22831862 TI - Daily physical complaints and hippocampal function: an fMRI study of pain modulation by anxiety. AB - Pain is a popular physical complaint in human. It is known that experimental anxiety modulates pain processing through hippocampal amplification, whereas it is not known whether a similar experimental reaction is related to daily physical complaints known as 'somatization'. The purpose of this study is to investigate the neural correlates of pain modulation induced by anxiety, particularly in the hippocampus, and how individual differences in this neural reaction relate to somatization. We measured neural response to noxious electrical stimulations, as well as the response to the preceding visual anticipatory cues (which induced low anxiety or high anxiety), by functional magnetic resonance imaging (fMRI). Individual daily physical symptoms were assessed by using the somatization subscale of the Symptom Checklist 90 revised (SCL-90-R). Correlation coefficients between the neural activations and the somatization scores were calculated. We found that manifestation of daily physical symptoms was related to smaller differences in hippocampus activation between high and low anxiety states, suggesting that the ability of the hippocampus to distinguish anxiety states was weakened by the chronic condition that caused the daily physical symptoms. The proper inhibition of neural activation in low anxiety states in the hippocampus and the anterior insula was observed to occur in companionship with lower daily physical complaints. These findings indicate that anxiety's alteration of the network that includes the hippocampus and that is associated with pain modulation underlies the manifestation of somatization. PMID- 22831863 TI - Special section on gaze-independent brain-computer interfaces. PMID- 22831864 TI - Evaluation of the effect of PVA tape supplemented with 2.26% fluoride on enamel demineralization using microhardness assessment and scanning electron microscopy: in vitro study. AB - OBJECTIVE: This in vitro study was designed to evaluate the effectiveness of experimental 2.26% fluoride-polyvinyl alcohol (F-PVA) tape in inhibition of enamel demineralization using enamel surface microhardness (SMH) analysis and scanning electron microscopy (SEM) examination. DESIGN: Enamel specimens (n=60) prepared from bovine incisor teeth with microhardness ranging from 260 to 370Knoop hardness number (KHN) were pooled and randomly assigned to four groups: control group, F-PVA tape group, F-varnish group, and CPP-ACFP group. After topical application of agents in each group, pH-cycling was processed. Then, SMH was measured and the percentage loss of surface microhardness (%SML) was calculated. For the SEM examination, five sample specimens in each group were treated and the morphologic character was evaluated. RESULTS: After pH-cycling, the SMH values of the enamel specimens of F-PVA tape and F-varnish group were significantly higher than that of CPP-ACFP group, there was no significant difference between F-PVA tape and F-varnish group. With SEM examination, enamel surface in the F-PVA tape group showed mild irregularity in general and numerous spherical and ovoid crystals formed on the enamel surface were also observed. The density of crystals was higher than that of both control group and CPP-ACFP group. CONCLUSION: F-PVA tape is effective in inhibition of enamel demineralization. The inhibition potential of enamel demineralization of F-PVA tape is comparable with that of fluoride varnish and greater than that of CPP ACFP. With the significant advantages of excellent physical properties, ease of application, and improved safety, F-PVA tape can be used not only for professional treatment, but also in a home-use delivery system. PMID- 22831865 TI - Intra-familial comparison of supragingival dental plaque microflora using the checkerboard DNA-DNA hybridisation technique. AB - OBJECTIVE: The aims of the present study were to correlate the quantified supragingival plaque bacteria between mothers and their children and identify possible microbial associations. DESIGN: A total of 86 mothers and their 4- to 6 year-old and 12- to 16-year-old children participated. Pooled supragingival plaque samples were obtained from interproximal sites between teeth 16/15, 25/26, 35/36 and 46/45 in mothers and older children and teeth 55/54, 64/65, 74/75 and 85/84 in younger children. All the samples were individually analysed for their content of 18 bacterial strains using checkerboard DNA-DNA hybridisation (whole genomic probes). Microbial associations were sought using cluster analysis (dendrogram) for all three age groups together, while community ordination techniques were used for each of the three groups separately. RESULTS: Three complexes were formed from the dendrogram in addition to associations between these complexes and remaining bacterial strains. Principal component analysis results were similar in all three groups. The correlation analyses of bacterial counts between mothers and their children showed a significant association for most of the bacterial strains (p<0.05 or 0.01). CONCLUSIONS: Supragingival plaque microbiota are correlated between mothers and their children. In addition, similar supragingival plaque microbial associations are present in family members.. PMID- 22831866 TI - Highly reliable quantification of proteins such as members of the HSP70 superfamily based on the grey scale index via immune detection stained bands on a Western blot. AB - The HSP70 superfamily is a reliable biomarker for hyperthermia, hypothermia and hypoxia. The Enzyme-linked Immunosorbent Assay (ELISA) respectively immunohistochemically staining methods are the typically used techniques for the quantification of those proteins. As the costs for reagents and devices as well as the work schedule of these methods are immense it was the goal of our study to develop an easy and reliable method to quantify the concentration of specific proteins. We established a procedure to measure the relative concentration of proteins fixed on ROTI((r)) PVDF membranes via Western blot, calculating the relative protein concentration in dependency to the grey scale index of the normalized and digitalized pictures of the bands on the blots. PMID- 22831867 TI - Commentary on 'No benefit from carotid intervention in fatal stroke prevention for >80 years patients'. PMID- 22831869 TI - Prophylactic perioperative anti-thrombotics in open and endovascular abdominal aortic aneurysm (AAA) surgery: a systematic review. AB - OBJECTIVE: Heparin is used worldwide by vascular surgeons as prophylaxis for arterial thrombo-embolic complications during open and endovascular arterial surgery. Possible harmful effect of heparin use is more perioperative blood loss, resulting in a higher morbidity and mortality. To evaluate the evidence for the use of heparin during aorto-iliac arterial surgery a review was performed. METHODS: A systematic review was performed of literature from MEDLINE, EMBASE and Cochrane databases, last search performed on March 8, 2012. RESULTS: For open surgery for abdominal aortic aneurysm (AAA), only 5 studies were eligible for review and for endovascular aneurysm repair (EVAR) only 1 study. Overall methodological quality of the included studies was poor. One randomised trial could be retrieved. Possible harmful effects of heparin were found of increasing operation time, more blood loss and more transfusion requirements when heparin was used for open AAA surgery in one study. No data were found comparing heparin to no intervention for EVAR. One study compared heparin to a direct thrombin antagonist during EVAR, showing no differences in clinical outcomes. CONCLUSION: Despite limitations this review showed no compelling evidence on the beneficiary effect of the prophylactic perioperative use of heparin during open surgery for (r)AAA. Authors will promote a randomised controlled multi-center trial on this topic for elective open surgical repair of AAA. PMID- 22831870 TI - Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography. AB - OBJECTIVES: The study aims to investigate lymphatic-system malformations and proposes a classification of primary lymphoedema based on comprehensive imaging data of both lymph vessel- and lymph-node abnormalities. MATERIALS AND METHODS: A total of 378 patients with primary lymphoedema of the lower extremity were examined with magnetic resonance lymphangiography (MRL) using gadobenate dimeglumine as contrast agent. Lymph vessels and drainage lymph nodes were evaluated, leading to the proposal of the classification of primary lymphoedema and the relative proportions. RESULTS: A total of 63 (17%) patients exhibited defects of the inguinal lymph nodes with mild or moderate dilatation of afferent lymph vessels. A total of 123 (32%) patients exhibited lymphatic anomalies as lymphatic aplasia, hypoplasia or hyperplasia with no obvious defect of the drainage lymph nodes. The involvement of both lymph vessel- and lymph-node abnormalities in the affected limb was found in 192 (51%) patients. The primary lymphoedema was classified as three major types as: (1) lymph nodes affected only; (2) lymph vessel affected only with three subtypes and (3) both lymph vessel and lymph node affected with subgroups. CONCLUSIONS: A comprehensive classification of lymphatic-system malformation in primary lymphoedema is proposed, which clearly defines the location and pathologic characteristics of both lymphatics and lymph node and may lead to further study of the aetiology as well as rational treatment of the disease. PMID- 22831871 TI - Commentary on 'Effects of statin therapy on abdominal aortic aneurysm growth: a meta-analysis and meta-regression of observational comparative studies'. PMID- 22831872 TI - Generic health-related quality of life is significantly worse in varicose vein patients with lower limb symptoms independent of CEAP clinical grade. AB - OBJECTIVES: To determine the relationship between lower limb symptoms and generic health-related quality of life (HRQL) in patients with varicose veins (VV). METHODS: 284 patients on the waiting list for VV treatment completed the Short Form-12 (SF12) and a questionnaire asking about the presence of lower limb symptoms commonly attributed to venous disease (pain or ache, itching, tingling, cramp, restless legs, a feeling of swelling, and heaviness). RESULTS: Median age was 57 years (interquartile range 45-67); 100 (35%) were male, and 182 (64%) had CEAP clinical grade 2 or 3 disease. Jonckheere-Terpstra test for trend revealed that both physical (P < .0005) and mental (P = .001) HRQL worsened as the reported number of symptoms increased. Patients reporting tingling (P = .016, Mann-Whitney U test), cramp (P = .001), restless legs (P < .0005), swelling (P < .0005), and heaviness (P < .0005) had a significantly worse physical HRQL than those who did not. Mental HRQL was also significantly worse in patients with tingling (P = .010), cramp (P = .008), restless legs (P = .040), swelling (P = .001), and heaviness (P = .035). These significant relationships remained, and pain was also correlated with worse physical HRQL (P = .011), when linear regression was performed to control for CEAP clinical grade, age and sex. CONCLUSIONS: Physical and mental HRQL is significantly worse in VV patients with lower limb symptoms irrespective of the clinical stage of disease. This observation confirms that VV are not primarily a cosmetic problem and that NHS rationing of treatment to those with CEAP C4-6 disease excludes many patients who would benefit from intervention in terms of HRQL. Generic HRQL instruments also allow comparison with interventions for other chronic conditions. PMID- 22831873 TI - Updating guidelines published by the European Society of Vascular Surgery. PMID- 22831874 TI - Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study. AB - OBJECTIVE: Apart from its role in bone metabolism, vitamin D may also influence cardiovascular disease. The objective of this study was: (1) to determine the effect of a single, oral, high-dose vitamin D supplementation on endothelial function and arterial stiffness in patients with peripheral arterial disease (PAD) and (2) to investigate the impact of this supplementation on coagulation and inflammation parameters. METHODS: In this double-blind, placebo-controlled, interventional pilot study, we screened 76 Caucasian patients with PAD for vitamin D deficiency. Sixty-two were randomised to receive a single, oral supplementation of 100,000 IU vitamin D3 or placebo. At baseline and after 1 month, we measured serum vitamin D and parathormone levels, and surrogate parameters for cardiovascular disease. RESULTS: Sixty-five of 76 patients (86%) had low 25-hydroxyvitamin D levels (<30 ng ml(-1)); of those, 62 agreed to participate in the study. At baseline, only parathormone was related to vitamin D. In supplemented patients, vitamin D levels increased from 16.3 +/- 6.7 to 24.3 +/- 6.2 ng ml(-1) (P < 0.001), with wide variations between single patients; in the placebo group vitamin levels did not change. Seasonal factors accounted for a decrease of vitamin D levels by 8 ng ml(-1) between summer and winter. After 1 month, none of the measured parameters was influenced by vitamin substitution. CONCLUSION: In this pilot study, most patients with PAD were vitamin D deficient. Vitamin D supplementation increased serum 25-hydroxyvitamin D without influencing endothelial function, arterial stiffness, coagulation and inflammation parameters, although the study was underpowered for definite conclusions. PMID- 22831875 TI - Synthesis and characterization of rhodium complexes with phosphine-stabilized germylenes. AB - The reaction of phosphine-stabilized germylenes (1a,b) with dimer complex [Rh(2)(MU-Cl)(2)(COD)(2)] leads to the corresponding phosphine-germylene-Rh(I) complexes (2a,b). Interestingly, the stability of these complexes depends strongly on the nature of the substituent of the germylene fragment. Indeed, the complex (2a) with the chloro-germylene ligand isomerizes into a metallacycle rhodium complex (3a) via germylene insertion into the Rh-Cl bond, while the complex with the phenyl-substituted germylene (2b) was isolated and represents the first stable Rh(I)-germylene complex with a Rh-Cl bond. PMID- 22831876 TI - Ethical aspects of clinical placebo use: what do laypeople think? AB - The study aimed to assess the attitudes of laypeople toward clinical placebo use. One of three imaginary stories was presented randomly in a popular news portal and participants (6,404 individuals) were asked to rate nine statements about it. In the stories, placebo therapy was used in a deceptive way. Following the success of the treatment, the patient was informed that the remedy contained no active substances. Along with self-report of attitudes, questionnaires measuring dispositional optimism, somatosensory amplification and beliefs about the scientific validity of complementary and alternative medicine and holistic health were also completed. According to participants' ratings, helping patients is more important than avoiding deception. They did not think that they would have felt deceived in the described situation or that treatment would have been successful in a fully informed case. Patients' attitude toward deceptive placebo use appears to be more pragmatic than has been previously supposed. PMID- 22831878 TI - Influence of catechol-O-methyltransferase Val158Met polymorphism on startle response in the presence of high estradiol levels. AB - INTRODUCTION: both human and animal studies have shown a somewhat complex COMT-by sex interaction effect on brain function and dysfunction. A functional variation in the gene coding for the catechol-O-methyltransferase (COMT) enzyme, which metabolizes dopamine and noradrenaline, has been related to executive and emotional functions, and to sex dimorphism. AIM: to investigate if COMT Val158Met genotype influences startle response in pregnant women, given their physiologically elevated estradiol levels. METHODS: seventy-three pregnant women were assessed in gestational week 38 for acoustic startle response, measured by electromyography of the blink reflex, during control condition, positive and negative anticipation stimuli, and pleasant and unpleasant image stimuli. A blood sample was taken for measurement of estradiol levels and genetic analysis. RESULTS: the results indicated a COMT Val158Met effect on startle response across all conditions (main effect of genotype, F(2,70=3.58), p=0.033), where Val/Val women displayed higher startle magnitudes than Val/Met carriers (Cohen's d=0.71). No significant difference by genotype was found in affective modulation. The findings also suggested an estrogen dose-dependent effect of COMT Val158Met on startle reflex. Among women with higher pregnancy-induced estradiol levels, Val/Val carriers had markedly higher startle response across conditions than heterozygotes (Cohen's d=1.36; F(4,21=11.07); p=0.003), while this effect was not present in women with estradiol levels under the median concentration. CONCLUSIONS: the observed effect of COMT Val158Met by estradiol on overall startle response is likely to be due to a variable noradrenergic transmission depending on COMT activity in a possible interaction with estradiol. PMID- 22831877 TI - Ratite nonmonophyly: independent evidence from 40 novel Loci. AB - Large-scale multilocus studies have become common in molecular phylogenetics, but the best way to interpret these studies when their results strongly conflict with prior information about phylogeny remains unclear. An example of such a conflict is provided by the ratites (the large flightless birds of southern land masses, including ostriches, emus, and rheas). Ratite monophyly is strongly supported by both morphological data and many earlier molecular studies and is used as a textbook example of vicariance biogeography. However, recent studies have indicated that ratites are not monophyletic; instead, the volant tinamous nest inside the ratites rather than forming their sister group within the avian superorder Palaeognathae. Large-scale studies can exhibit biases that reflect a number of factors, including limitations in the fit of the evolutionary models used for analyses and problems with sequence alignment, so the unexpected conclusion that ratites are not monophyletic needs to be rigorously evaluated. A rigorous approach to testing novel hypotheses generated by large-scale studies is to collect independent evidence (i.e., excluding the loci and/or traits used to generate the hypotheses). We used 40 nuclear loci not used in previous studies that investigated the relationship among ratites and tinamous. Our results strongly support the recent molecular studies, revealing that the deepest branch within Palaeognathae separates the ostrich from other members of the clade, rather than the traditional hypothesis that separates the tinamous from the ratites. To ensure these results reflected evolutionary history, we examined potential biases in types of loci used, heterotachy, alignment biases, and discordance between gene trees and the species tree. All analyses consistently supported nonmonophyly of the ratites and no confounding biases were identified. This confirmation that ratites are not monophyletic using independent evidence will hopefully stimulate further comparative research on paleognath development and genetics that might reveal the basis of the morphological convergence in these large, flightless birds. PMID- 22831879 TI - Gamma delta (gammadelta) T-cells are critical in the up-regulation of inducible nitric oxide synthase at the burn wound site. AB - BACKGROUND: The high incidence of morbidity and mortality following major burn can in part be attributed to immune derangements and wound healing complications. Inflammation plays an important role in wound healing, of which inducible nitric oxide synthase (iNOS) derived nitric oxide is a central mediator. T-cells of the gammadelta TCR lineage have also been shown to be important in healing of the burn wound site. Nonetheless, the role of gammadelta T-cells in the regulation of the burn wound iNOS expression is unknown. METHODS: Wildtype (WT) and delta TCR( /-) male C57BL/6 mice were subjected to burn (3rd degree, 12.5% TBSA) or sham treatment. Three days after injury, skin samples from non-injured and the burn wound were collected and analyzed for the expression of iNOS and cytokines and chemokine levels. In a second series of experiments, WT mice were subjected to burn and left untreated or treated with the iNOS inhibitor, L-Nil. Skin cytokine and chemokine levels were assessed 3days thereafter. RESULTS: Burn induced an 18 fold increase in iNOS expression at the wound site as compared to the uninjured skin of WT sham mice. In delta TCR(-/-) mice iNOS expression at the wound site was significantly lower than that of the WT group. Burn also induced increased levels of IL-1beta, IL-6, G-CSF, TNF-alpha, KC, MCP-1, MIP-1alpha and MIP-1beta at the wound site in WT and delta TCR(-/-) mice, but G-CSF, TNF-alpha, and MIP 1beta levels were greater in delta TCR(-/-) mice. Inhibition of iNOS activity in WT mice with L-Nil suppressed burn wound levels of IL-1beta, G-CSF, and MIP 1alpha, whereas IL-6, TNF-alpha, KC, MCP-1 and MIP-1beta were unaffected. CONCLUSIONS: T-cells of the gammadelta TCR lineage significantly contribute to the up-regulation of iNOS expression which contributes to wound inflammation. PMID- 22831881 TI - Quantification of utero-placental vascularization in a rabbit model of IUGR with three-dimensional power Doppler angiography. AB - OBJECTIVES: Our objective was to evaluate the 3D power Doppler angiography (PDA) in terms of feasibility and ability to detect placental hypo-perfusion in an experimental rabbit model of intrauterine growth restriction (IUGR). STUDY DESIGN: 14 pregnant females were treated with NG-nitro-L-arginine methylester (L NAME), a nitric oxide synthase inhibitor, from day 24 to day 28 of gestation, to induce an IUGR. Concomitantly, 8 pregnant rabbits were used as controls. On day 28, 3D power Doppler indices were quantified in each utero-placental unit. Morphological examination of the placentas for the control group (n = 4) and the L-NAME group (500 mg/day, n = 4) were performed with immunohistochemical staining to discriminate the fetal capillaries in the labyrinthine area. RESULTS: A total of 180 live fetuses were obtained, 108 from the L-NAME group and 72 from the control group. G28 fetal weight was significantly lower in the L-NAME group than in the control group (27.40 +/- 0.55 g vs 33.14 +/- 0.62 g, p < 0.0001). In the L NAME group the vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly lower than in the control group (2.6 [1.4; 6.0] vs 7.6 [3.5; 12.6], p < 0.05; 28.7 [26.5; 31.3] vs 32.9 [28.3; 38.1], p < 0.05; 0.8 [0.4; 1.8] vs 2.5 [1.1; 4.1], p < 0.05, for VI, FI and VFI, respectively). Morphological examinations revealed a substantial disorganization of the placental vascular architecture in the L-NAME group. CONCLUSION: This experimental study demonstrates that quantitative 3D PDA indices are sensitive enough to detect placental vascular insufficiency in an experimental rabbit model of IUGR. PMID- 22831882 TI - Application of solid phase microextraction on dental composite resin analysis. AB - A direct immersion solid phase microextraction (DI-SPME) method was developed for the analysis of dentin monomers in saliva. Dentine monomers, such as triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA) and 2,2-bis-[4-(2 hydroxy-3-methacryloyloxypropoxy) phenyl]-propane (Bis-GMA), have a high molecular weight and a low vapor pressure. The polydimethylsiloxane/divinylbenzene (PDMS/DVB) fiber with a medium polarity was employed for DI-SPME, and 215 nm of detection wavelength was found to be optimum in the chromatogram of HPLC measurement. The calibration range for DI-SPME was 0.30-300 MUg/mL with correlation coefficients (r) greater than 0.998 for each analyte. The DI-SPME method achieved good accuracy (recovery 96.1-101.2%) and precision (2.30-8.15% CV) for both intra- and inter-day assays of quality control samples for three target compounds. Method validation was performed on standards dissolved in blank saliva, and there was no significant difference (p>0.2) between the DI-SPME method and the liquid injection method. However, the detection limit of DI-SPME was as low as 0.03, 0.27 and 0.06 MUg/mL for TEGDMA, UDMA and Bis-GMA, respectively. Real sample analyses were performed on commercial dentin products after curing for the leaching measurement. In summary, DI-SPME is a more sensitive method that requires less sample pretreatment procedures to measure the resin materials leached in saliva. PMID- 22831880 TI - Gene targeting in primary human trophoblasts. AB - Studies in primary human trophoblasts provide critical insights into placental function in normal and complicated pregnancies. Mechanistic studies in these cells require experimental tools to modulate gene expression. Lipid-based methods to transfect primary trophoblasts are fairly simple to use and allow for the efficient delivery of nucleic acids, but potential toxic effects limit these methods. Viral vectors are versatile transfection tools of native trophoblastic or foreign cDNAs, providing high transfection efficiency, low toxicity and stable DNA integration into the trophoblast genome. RNA interference (RNAi), using small interfering RNA (siRNA) or microRNA, constitutes a powerful approach to silence trophoblast genes. However, off-target effects, such as regulation of unintended complementary transcripts, inflammatory responses and saturation of the endogenous RNAi machinery, are significant concerns. Strategies to minimize off target effects include using multiple individual siRNAs, elimination of pro inflammatory sequences in the siRNA construct and chemical modification of a nucleotide in the guide strand or of the ribose moiety. Tools for efficient gene targeting in primary human trophoblasts are currently available, albeit not yet extensively validated. These methods are critical for exploring the function of human trophoblast genes and may provide a foundation for the future application of gene therapy that targets placental trophoblasts. PMID- 22831883 TI - Application of a sensitive and specific LC-MS/MS method for determination of chinensinaphthol methyl ether in rat plasma for a bioavailability study. AB - Chinensinaphthol methyl ether (CME) is a potential pharmacologically active ingredient isolated from the dried plants of Justicia procumbens L. (Acanthaceae). A sensitive and specific LC-MS/MS method was developed and validated for the analysis of CME in rat plasma using buspirone as the internal standard (IS). The analyte was extracted with ethyl acetate and chromatographed on a reverse-phase Agilent Zorbax-C18 110 A column (50 mm * 2.1mm, 3.5 MUm). Elution was achieved with a gradient mobile phase consisting of water and acetonitrile both containing 0.1% formic acid at a flow rate of 0.40 mL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 394.5->346.0 and 386.1->122.0 for CME and IS, respectively. The assay was shown to be linear over the range of 0.50-500 ng/mL, with a lower limit of quantification of 0.50 ng/mL. The method was shown to be reproducible and reliable with the inter- and intra-day accuracy and precision were within +/-15%. The assay has been successfully used for pharmacokinetic evaluation of CME after intravenous and oral administration of 1.80 mg/kg CME in rats. The oral absolute bioavailability (F) of CME was estimated to be 3.2+/-0.2% with an elimination half-life (t1/2) value of 2.4+/-0.8h, suggesting its poor absorption and/or strong metabolism in vivo. PMID- 22831884 TI - Ophthalmate detection in human plasma with LC-MS-MS. AB - Based on animal experimentations, ophthalmate (OPH) has recently been suggested as a potential plasma biomarker to probe hepatic GSH homeostasis. Up until now, the inability to accurately determine OPH concentrations in human plasma prohibited further studies of OPH metabolism in humans. This study therefore aimed to study the influence of delayed sample preparation on OPH concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Venous plasma samples from 5 healthy human volunteers were incubated for varying times (5, 30, 60 and 120 min) at temperatures of 4 degrees C and 37 degrees C to investigate potential enzymatic degradation. At 37 degrees C, the decrease in OPH reached significance after 120 min (74.6% (range: 56.2-100.0%; p<0.0001)). At 4 degrees C, the same trend was observed but did not reach significance. These findings indicate ongoing enzymatic activity, stressing the need for immediate sample deproteinization to obtain reliable plasma concentrations. To investigate the feasibility of the here developed method, baseline arterial plasma values of 21 patients scheduled for partial liver resection were determined to be 0.06+/-0.03 MUmol/l (mean+/-s.d.). In addition, in pooled samples from 3 patients, an OPH calibration curve was spiked to arterial plasma, arterial whole blood and liver biopsy material, resulting in a linear calibration curve in all cases. Individual measurements of baseline samples revealed that both arterial whole blood and liver biopsy material contained significant levels of endogenous OPH, namely 16.1 (11.8-16.4) MUmol/l and 80.0 (191.8-349.2) MUmol/kg, respectively. In conclusion, the present LC-MS/MS assay enables the accurate measurement of OPH in human plasma, whole blood and liver biopsies. Freshly prepared samples and immediate deproteinization are mandatory to block enzymatic degradation. PMID- 22831885 TI - Glucagon-like peptide-1 agonist exendin-4 leads to reduction of weight and caloric intake in a rat model of hypothalamic obesity. AB - BACKGROUND: Hypothalamic obesity caused by damage of medial hypothalamic nuclei presents a therapeutic challenge. Glucagon-like peptide-1 agonist exenatide (synthetic version of exendin-4 (Ex4)), used for treatment of diabetes, causes weight loss via hindbrain signaling. METHODS: We tested Ex4 in an established rat model of medial hypothalamic lesions. Lesion and control animals were administered either daily intraperitoneal injections of 1 ug.kg(-1) Ex4 or saline for 9 days. RESULTS: In our rat model, a significant difference in percent baseline food intake (lesion -20.8%, control -13.6%; p < 0.001) and percent change in body weight (lesion -4.9%/9 days, control -3.2%/9 days; p < 0.05) was observed during Ex4 treatment compared with saline. CONCLUSION: Ex4 resulted in reduction of food intake and body weight. Follow-up studies are required to further elucidate its effects on energy homeostasis and to establish Ex4 as a potential drug for treatment of hypothalamic obesity. PMID- 22831886 TI - Prevalence of livestock-associated MRSA on Dutch broiler farms and in people living and/or working on these farms. AB - This study aimed to determine the prevalence and risk factors for methicillin resistant Staphylococcus aureus (MRSA) on 50 Dutch broiler farms. Of 145 persons living and/or working on these farms, eight tested positive for MRSA (5.5%). Investigation of 250 pooled throat samples of broilers and 755 dust samples resulted in four farms where MRSA-positive samples were present (8.0%). All isolates belonged to the CC398 complex. Living and/or working on a MRSA-positive farm was a risk for MRSA carriage; 66.7% of people on positive farms were MRSA positive vs. 1.5% on negative farms (P<0.0001). Due to the low number of positive farms and persons, and high similarity in farm management, it was impossible to draw statistically valid conclusions on other risk factors. For broiler farming, both farm and human MRSA prevalence seem much lower than for pig or veal farming. However, MRSA carriage in people living and/or working on broiler farms is higher compared to the general human population in The Netherlands (5.5% vs. <0.1%). As broiler husbandry systems are not unique to The Netherlands, this might imply that people in contact with live broilers are at risk for MRSA carriage worldwide. PMID- 22831887 TI - Sleep disturbances after fast-track hip and knee arthroplasty. AB - BACKGROUND: Major surgery is followed by pronounced sleep disturbances after traditional perioperative care potentially leading to prolonged recovery. The aim was to evaluate the rapid eye movement (REM) sleep duration and sleep architecture before and after fast-track hip and knee replacement with length of stay (LOS) <3 days. The primary endpoint was REM sleep duration on the first postoperative night compared with before operation. METHODS: Ten subjects (>=60 yr) receiving spinal anaesthesia and multimodal opioid-sparing postoperative analgesia for total hip or knee arthroplasty were included. Ambulatory polysomnography was performed one night before operation at home, continuously during hospitalization, and on the fourth postoperative night at home. Sleep staging was performed according to the American Academy of Sleep Medicine manual. Opioid use, pain, and inflammatory response (C-reactive protein) were also evaluated. RESULTS: The mean LOS was 1.5 (1-2) days. The mean REM sleep time decreased from a mean of 18.2 (9.5-23.5)% of total sleep time to 1.2 (0-5.8)% on the first postoperative night (P=0.002); awake time increased from 19.1 (3.7 44.4)% to 44.3 (12.2-70.6)% (P=0.009); and sleep architecture on the first postoperative night was more disturbed than before operation. Sleep architecture normalized on the fourth postoperative night. There was no association between opioid use, pain scores, and inflammatory response with a disturbed sleep pattern. CONCLUSIONS: Despite ultra-short LOS and provision of spinal anaesthesia with multimodal opioid-sparing analgesia, REM sleep was almost eliminated on the first postoperative night after fast-track orthopaedic surgery but returned to pre-admission levels when at home on the fourth postoperative night. PMID- 22831888 TI - Randomized, double-blind comparison of oral aprepitant alone compared with aprepitant and transdermal scopolamine for prevention of postoperative nausea and vomiting. AB - BACKGROUND: Aprepitant blocks the emetic effects of substance P. Scopolamine antagonizes muscarinic type 1 and histamine type 1 receptors. This study compares monotherapy and multimodal therapy by looking at complete response, nausea, vomiting, and rescue medication in patients at high risk for postoperative nausea and vomiting (PONV) treated with oral aprepitant with or without scopolamine. METHODS: We enrolled 120 patients in this randomized, double-blind trial. Inclusion criteria were: >18 yr old, ASA I-III, two or more Apfel four-point risk factors, undergoing an elective surgical procedure with a high risk of PONV expected to last at least 60 min. The primary outcome variable was complete response, that is, no emesis and no rescue therapy from 0 to 24 h. The outcomes measured included the incidences of nausea, vomiting, their composite, and the need for rescue medication. RESULTS: The aprepitant alone and aprepitant with scopolamine did not differ in complete responses (63% vs 57%, P=0.57) or net clinical benefit (26% vs 19%, P=0.38). The number who did not experience PONV and who used rescue medication did not differ. The incidence of PONV in the post anaesthesia care unit did not differ nor did the use of rescue medications. CONCLUSIONS: This trial evaluating the effectiveness of aprepitant alone and in combination with scopolamine showed no difference between treatment groups. The primary objective, complete response, and secondary objectives, incidences of nausea, vomiting, their composite, and the need for rescue medication, all showed no statistical difference. PMID- 22831889 TI - Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy. AB - BACKGROUND: Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics. METHODS: A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis. RESULTS: Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6 49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively). CONCLUSIONS: In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results. PMID- 22831890 TI - Lidocaine/tetracaine patch (Rapydan) for topical anaesthesia before arterial access: a double-blind, randomized trial. AB - BACKGROUND: Arterial catheterization is painful and is associated with patient stress and anxiety. Analgesia is usually provided by subcutaneous injection of local anaesthetic. An alternative is topical anaesthesia, such as Rapydan which is a novel topical anaesthetic patch containing 70 mg each of lidocaine and tetracaine. We therefore tested the hypothesis that Rapydan patch analgesia is non-inferior to subcutaneous local anaesthetic. METHODS: Ninety patients undergoing elective major cardiac surgery were included in this prospective, double-blind clinical trial. Patients were randomly assigned to receive either a lidocaine/tetracaine patch, followed by subcutaneous injection 0.5 ml of normal saline solution, or placebo patch with subsequent subcutaneous injection of 0.5 ml of lidocaine 1%. Pain during arterial catheterization using 100-mm-long visual analogue scale (VAS) was the primary outcome. Other outcomes were pain during anaesthetic/saline injection and plasma tetracaine concentrations. RESULTS: VAS pain scores during arterial puncture were comparable in both groups and Rapydan was non-inferior to subcutaneous lidocaine. Pain scores at the time of subcutaneous injection were significantly lower (better) in patients assigned to the lidocaine/tetracaine patch than to lidocaine (P=0.001). Plasma tetracaine concentrations never exceeded the detection limit of 25 ng ml(-1) at any time in any patient. CONCLUSIONS: Both the lidocaine/tetracaine patch and subcutaneous injection of lidocaine provided comparable pain control during arterial catheter insertion. Subcutaneous lidocaine caused discomfort during injection, whereas the lidocaine/tetracaine patch required placement 20 min before the procedure. Given adequate time, the patch provided better overall analgesia by obviating the need for subcutaneous infiltration. PMID- 22831891 TI - Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population. PMID- 22831892 TI - Chronic pain after inguinal hernia repair in children. AB - BACKGROUND: The prevalence of moderate-to-severe pain after inguinal hernia repair (IHR) in adults is ~ 10%. Two studies with very long follow-up periods (16.8 and 49 yr, respectively) have, however, suggested that the risk of developing chronic pain is much lower in children. The purpose of the present study was to examine the prevalence of chronic pain 6-48 months after IHR in children. METHODS: Postal questionnaires were sent to 156 children who had undergone IHR between the age of 6 months and 12 yr. The children were asked to recall the duration of postoperative pain, if necessary with help from their parents, and to describe the intensity and character of their pain, if the pain was still present. Children with chronic pain were offered quantitative sensory testing (QST), and a surgical examination, including ultrasound, in order to exclude hernia recurrence. RESULTS: Ninety-eight children, mean (sd) age 7.8 (2.6) yr, answered the questionnaire. Their age at the time of surgery was mean (sd) 4.6 (2.4) yr, and the follow-up period was mean (sd) 3.2 (1.3) yr. Five children (5.1%, 95% confidence interval: 0.75-9.5) had pain located in the inguinal region, and three of these children underwent further examination. There was no hernia recurrence, but QST revealed pinprick hyperalgesia and decreased pressure pain thresholds on the operated side in all three children. CONCLUSIONS: The prevalence of chronic pain after IHR in children is 5.1%, which is lower than the prevalence reported after adult hernia repair. PMID- 22831893 TI - Eye-gaze independent EEG-based brain-computer interfaces for communication. AB - The present review systematically examines the literature reporting gaze independent interaction modalities in non-invasive brain-computer interfaces (BCIs) for communication. BCIs measure signals related to specific brain activity and translate them into device control signals. This technology can be used to provide users with severe motor disability (e.g. late stage amyotrophic lateral sclerosis (ALS); acquired brain injury) with an assistive device that does not rely on muscular contraction. Most of the studies on BCIs explored mental tasks and paradigms using visual modality. Considering that in ALS patients the oculomotor control can deteriorate and also other potential users could have impaired visual function, tactile and auditory modalities have been investigated over the past years to seek alternative BCI systems which are independent from vision. In addition, various attentional mechanisms, such as covert attention and feature-directed attention, have been investigated to develop gaze independent visual-based BCI paradigms. Three areas of research were considered in the present review: (i) auditory BCIs, (ii) tactile BCIs and (iii) independent visual BCIs. Out of a total of 130 search results, 34 articles were selected on the basis of pre-defined exclusion criteria. Thirteen articles dealt with independent visual BCIs, 15 reported on auditory BCIs and the last six on tactile BCIs, respectively. From the review of the available literature, it can be concluded that a crucial point is represented by the trade-off between BCI systems/paradigms with high accuracy and speed, but highly demanding in terms of attention and memory load, and systems requiring lower cognitive effort but with a limited amount of communicable information. These issues should be considered as priorities to be explored in future studies to meet users' requirements in a real-life scenario. PMID- 22831894 TI - Sesquiterpenes from the conifer root rot pathogen Heterobasidion occidentale. AB - Investigation of the production of secondary metabolites of Heterobasidion occidentale led to the isolation and identification of six sesquiterpenes (illudolone A and B, illudolactone A and B, deoxyfomannosin A and B) along with the well-known sesquiterpene fomannosin and the previously described benzohydrofuran fomannoxin. The structures and relative configurations of the compounds were determined by 1D and 2D NMR spectroscopic analysis as well as by HRMS. Their absolute configuration and biosynthesis were suggested and discussed in relation to fomannosin. Four compounds showed growth inhibiting activity against several basidiomycetes, Phlebiopsis gigantea, Phanerochaete chrysosporium and H. occidentale, and toxicity towards the moss Physcomitrella patens. In addition, one compound displayed activity against the bacterium Variovorax paradoxus as well as against the ascomycete Fusarium oxysporum. PMID- 22831895 TI - MicroRNAs function as tumor suppressors or oncogenes: aberrant expression of microRNAs in head and neck squamous cell carcinoma. AB - MicroRNAs (miRNAs) are endogenous short non-coding RNA molecules that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Bioinformatic analyses predict that miRNAs regulate more than 30% of protein coding genes. To date, 1921 human mature miRNAs have been registered in miRBase release 18.0 (http://microrna.sanger.ac.uk/). A growing body of evidence suggests that miRNAs are aberrantly expressed in many human carcinomas and that they play key roles in the initiation, development and metastasis of human cancers, including head and neck squamous cell carcinoma (HNSCC). In this review, eight genome-wide miRNA expression profiles were used to selected aberrantly expressed miRNAs (up-regulated and down-regulated miRNAs) in HNSCC clinical specimens including our miRNA profiles of hypopharyngeal and maxillary sinus squamous cell carcinoma. We discuss recent findings on the aberrant expression of miRNAs and their contribution to human HNSCC oncogenesis. PMID- 22831896 TI - Allergic fungal rhinosinusitis infiltrating anterior skull base and clivus. AB - Bone erosion and skull base invasion are often suggestive of a malignant mass in paranasal and nasal cavities. Nevertheless, forms of chronic rhinosinusitis, such as allergic fungal rhinosinusitis (AFRS), could mimic malignant features. Here, we report AFRS patient with orbital, anterior cranial fossa, Turkish saddle and clivus erosion. A 48-year-old Caucasian female with history of drug-resistant headache, nasal obstruction and anosmia was referred to our institution. Imaging showed hyperdense featureless tissue with signs of medial orbital wall, cribiform lamina and clivus erosions and encasement of right internal carotid artery. Massive amounts of thick and grayish mucoid material were evacuated during surgery. In case of bony erosion, malignancy should always be excluded. Often the correct diagnosis will be obtained only by operative specimens. AFRS could usually be managed endoscopically. Appropriate medical management of the AFRS should be administered in order to prevent relapses. PMID- 22831897 TI - Evolution of sex chromosomes ZW of Schistosoma mansoni inferred from chromosome paint and BAC mapping analyses. AB - Chromosomes of schistosome parasites among digenetic flukes have a unique evolution because they exhibit the sex chromosomes ZW, which are not found in the other groups of flukes that are hermaphrodites. We conducted molecular cytogenetic analyses for investigating the sex chromosome evolution using chromosome paint analysis and BAC clones mapping. To carry this out, we developed a technique for making paint probes of genomic DNA from a single scraped chromosome segment using a chromosome microdissection system, and a FISH mapping technique for BAC clones. Paint probes clearly identified each of the 8 pairs of chromosomes by a different fluorochrome color. Combination analysis of chromosome paint analysis with Z/W probes and chromosome mapping with 93 BAC clones revealed that the W chromosome of Schistosoma mansoni has evolved by at least four inversion events and heterochromatinization. Nine of 93 BAC clones hybridized with both the Z and W chromosomes, but the locations were different between Z and W chromosomes. The homologous regions were estimated to have moved from the original Z chromosome to the differentiated W chromosome by three inversions events that occurred before W heterohcromatinization. An inversion that was observed in the heterochromatic region of the W chromosome likely occurred after W heterochromatinization. These inversions and heterochromatinization are hypothesized to be the key factors that promoted the evolution of the W chromosome of S. mansoni. PMID- 22831898 TI - Formation of specific configurations at stereogenic nitrogen centers upon their coordination to zinc and mercury. AB - The coordination of (R,R)-tetramethylcyclohexane-1,2-diamine derivatives with stereogenic nitrogen centers to zinc and mercury halides is investigated. It is shown that the resulting complexes display one specific configuration at the stereogenic nitrogen centers. This fact is unusual due to the fast inversion of nitrogen centers but highly desirable as the stereoinformation of the ligands is brought closer to the metal centers of the potential catalysts. A combination of NMR studies and quantum chemical calculations gives insight into the selective formation of one specific configuration at the stereogenic nitrogen centers of the zinc complexes. PMID- 22831899 TI - Adolescent endometriosis in China: a retrospective analysis of 63 cases. AB - STUDY OBJECTIVE: To investigate the clinical presentations, diagnosis, treatment modalities and prognosis of endometriosis in adolescents in China. DESIGN: Retrospective study. SETTING: Data were collected from records of the Peking Union Medical College Hospital from 1992-2010. PARTICIPANTS: This study consisted of 63 patients <=20 years old with surgically diagnosed endometriosis. Their clinical presentations, auxiliary examinations, surgical outcomes, and post operative medical treatments were analyzed. The follow-up information of 35 cases was collected. RESULTS: Mean age at diagnosis was 18.41 +/- 1.84 years with a much earlier disease onset in adolescents with genital tract malformations. Of the 35 patients with follow-up time that ranged from 12-98 months, nine in 15 patients who didn't proceed with medical treatment after operation had a recurence (9/15), seven in 15 patients who took oral contraceptive pills (OCP) or progestin only pills had reoccurrence recurred (7/15), and none of the five patients received gonadotropin-releasing hormone agonist (GnRHa) therapy recurred (0/5). In this study, multiple sites lesions was defined as more than one site being involved of the following four sites: the left ovary, the right ovary, the rectovaginal pouch and the uterosacral ligament. Among the 15 cases without postoperative medical therapy, all five cases with multiple sites lesions had recurrence (5/5), while only four of the other 10 cases had relapse (4/10). The difference was of statistical significance (Fisher exact test, P = 0.044). CONCLUSION: Multiple sites lesions found in operation was a risk factor of recurrence. GnRHa was effective to prevent the recurrence. PMID- 22831900 TI - Human papillomavirus vaccination in female pediatric cancer survivors. AB - STUDY OBJECTIVE: Survivors of childhood malignancy may be at increased risk for HPV infection for biological and cognitive/behavioral reasons. HPV vaccination is currently recommended for females 11-12 years old with catch up vaccination up to age 26 years. The objective of this cross-sectional study was to determine the prevalence of HPV vaccination among female pediatric cancer survivors, age 11-18 years, at Texas Children's Hospital. STUDY DESIGN, SETTING, AND PARTICIPANTS: A 42-question survey was distributed to parents/guardians of 172 long-term cancer survivors from August-November of 2010. Data were analyzed using frequencies, t tests, and chi-square analyses. MAIN OUTCOME MEASURES: Prevalence of HPV vaccination (intention and completion). RESULTS: Sixty-six persons (38%) responded. The median current age of survivors was 14 years. Most were white/non Hispanic (48%) or white/Hispanic (37%). Seventy-one percent had discussed HPV vaccination with a healthcare provider. The overall rate of HPV vaccination (>= 1 dose) was 32%, including 5% of those age 11-12 years (n = 1 of 21), 36% of those age 13-17 years (n = 13 of 36), and 78% of those age 18 years (n = 7 of 9). Of those whose children had not been immunized, 36% intended to do so in the future. Factors associated with HPV vaccination included age >=13 years, report of sexual activity, and report of having discussed HPV vaccination with a healthcare provider. CONCLUSION: The rate of HPV vaccination among female pediatric cancer survivors is not appreciably different than that seen in the general population. PMID- 22831901 TI - Menstrual suppression with the levonorgestrel intrauterine system in girls with developmental delay. AB - STUDY OBJECTIVE: To describe the experiences of 21 girls with developmental delay accompanied by multiple other medical problems, seen over a 3-year interval, who underwent insertion of the levonorgestrel intrauterine system (LNG-IUS) for menstrual suppression. STUDY DESIGN: Retrospective chart review. SETTING: A referral pediatric and adolescent gynecology clinic within a tertiary care medical center with referrals from community pediatricians, pediatric subspecialists including developmental and behavioral pediatricians, community gynecologists, and adolescent medicine specialists. PARTICIPANTS: Adolescents and young women with developmental delay and multiple comorbid conditions who were seen for consultation with their families requesting menstrual suppression. INTERVENTIONS: Participants were offered hormonal options, for menstrual suppression including the LNG-IUS. MAIN OUTCOME MEASURES: Satisfaction with menstrual suppression among families electing the LNG-IUS. RESULTS: Adolescents and young women seen at CCHMC with developmental delay and multiple comorbid conditions with requests for menstrual suppression were offered hormonal options, including the LNG-IUS. Twenty-one families chose this option. Fifteen of 21 girls had previously used hormonal menstrual suppression. General anesthesia was required for 20 of 21 insertions, and 9 of 20 of these insertions were combined with other surgical procedures. There were no unsuccessful insertions or major complications. Mean duration of follow-up was 11 months, and families were satisfied with this option for menstrual suppression. There was 1 request for removal. CONCLUSIONS: LNG-IUS for menstrual suppression, in girls with developmental delay and multiple comorbid medical conditions for which amenorrhea is desirable and therapeutic, appears promising. PMID- 22831903 TI - Ferriman-Gallwey scores, serum androgen and mullerian inhibiting substance levels in hirstute adolescent girls. AB - OBJECTIVE: To study Ferriman-Gallwey (FG) scoring in adolescents with an aim to correlate these scores with serum androgens and mullerian inhibiting substance (MIS). DESIGN: Cross sectional study. SETTING: Pediatric and Adolescent Gynecology Clinic of a university hospital. PATIENTS: Twenty-four hirsute adolescent girls age 12-19 with a FG score of 6 or greater. INTERVENTIONS: FG examination and collection of serum levels of MIS, total testosterone, free testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, cortisol, and androstenedione. MAIN OUTCOME MEASURES: Correlation between FG scores in adolescents and serum androgens and MIS. RESULTS: Weak correlations were seen between FG score and FSH, free-testosterone, total testosterone, and cortisol. Increasing FG scores correlated with an increase in cortisol. As FG score increased, FSH, free-testosterone, and total testosterone decreased. There was no statistical relationship between FG score and LH, androstenedione, prolactin, and MIS. There were weak positive correlations between MIS levels and FSH, total testosterone, and androstenedione. There was no evidence for a linear relationship between MIS levels and LH, free testosterone, cortisol, prolactin, and FG score. CONCLUSIONS: The utility of FG scoring in adolescents is unknown. There were no direct correlations found with MIS levels and FG score. MIS was not found to be a predictor of hirsutism. A larger study is needed to assess the clinical relevance of FG scoring and presence of underlying causes of hirsutism in adolescents. PMID- 22831902 TI - Predictors of healthy birth outcome in adolescents: a positive deviance approach. AB - STUDY OBJECTIVE: Pregnant adolescents experience elevated rates of adverse birth outcomes compared to older mothers. Positive deviance inquiry is the identification of uncommon behaviors and traits that result in better health outcomes for individuals in a population that shares similar risks. The purpose of our study was to utilize a positive deviance framework to identify sociodemographic and behavioral characteristics associated with a healthy birth outcome among adolescents. DESIGN: This is a retrospective cohort study design. SETTING: We performed a secondary data analysis of vital records data from the State of Louisiana between January 1, 1995 and December 31, 2007. PARTICIPANTS: Data included birth certificates from 35,013 Louisiana mothers age <=19. MAIN OUTCOME MEASURE: A healthy birth was defined as having an infant of weight between 2500 g and 4000 g, delivered vaginally without induction or instrumented delivery and in the absence of pregnancy, obstetric, or neonatal complications and anomalies. RESULTS: Twenty-one percent of the study population was classified as positive deviants with healthy births. Multivariate log-linear regression was used to model predictors of healthy birth. Adolescents who were older, non-black, multiparous, non-smoking, married, gained a medium amount of weight, had a longer inter-pregnancy interval or received adequate prenatal care were most likely to experience a healthy pregnancy and birth. Ethnicity, alcohol use, father's information on the birth certificate and paternal characteristics did not significantly predict a positive birth outcome. CONCLUSION: Characterizing positive deviant adolescents may help identify special populations for targeted intervention and important modifiable behaviors for the promotion of better birth outcomes in all young mothers. PMID- 22831904 TI - Deaths due to medical error: jumbo jets or just small propeller planes? PMID- 22831905 TI - Saccharification of poplar biomass by using lignocellulases from Pholiota adiposa. AB - A basidiomycetous fungus, identified as Pholiota adiposa SKU0714 on the basis of morphological and phylogenetic analyses, was found to secrete efficient lignocellulose degrading enzymes. The strain showed maximum endoglucanase, cellobiohydrolase and beta-glucosidase activities of 26, 32 and 39 U/mL, respectively and also secreted xylanase, laccase, mannanase, and lignin peroxidase with activities of 1680, 0.12, 65 and 0.41 U/mL, respectively when grown with rice straw as a carbon source. Among the various plant biomasses tested for saccharification, poplar biomass produced the maximum amount of reducing sugar. Response surface methodology was used to optimize hydrolysis parameters. A maximum saccharification yield of 83.4% (667 mg/g-substrate), the highest yield from any plant biomass, was obtained with Populus biomass after 24h of hydrolysis. P. adiposa was proven to be a good choice for the production of reducing sugars from cellulosic biomass. PMID- 22831906 TI - Introducing the tactile speller: an ERP-based brain-computer interface for communication. AB - In this study, a tactile speller was developed and compared with existing visual speller paradigms in terms of classification performance and elicited event related potentials (ERPs). The fingertips of healthy participants were stimulated with short mechanical taps while electroencephalographic activity was measured. The letters of the alphabet were allocated to different fingers and subjects could select one of the fingers by silently counting the number of taps on that finger. The offline and online performance of the tactile speller was compared to the overt and covert attention visual matrix speller and the covert attention Hex o-Spell speller. For the tactile speller, binary target versus non-target classification accuracy was 67% on average. Classification and decoding accuracies of the tactile speller were lower than the overt matrix speller, but higher than the covert matrix speller, and similar to Hex-o-Spell. The average maximum information transfer rate of the tactile speller was 7.8 bits min(-1) (1.51 char min(-1)), with the best subject reaching a bit-rate of 27 bits min(-1) (5.22 char min(-1)). An increased amplitude of the P300 ERP component was found in response to attended stimuli versus unattended stimuli in all speller types. In addition, the tactile and overt matrix spellers also used the N2 component for discriminating between targets and non-targets. Overall, this study shows that it is possible to use a tactile speller for communication. The tactile speller provides a useful alternative to the visual speller, especially for people whose eye gaze is impaired. PMID- 22831907 TI - Physical impairments in cognitively impaired older people: implications for risk of falls. AB - BACKGROUND: Cognitively impaired older people fall twice as often as their cognitively intact counterparts. There is, however, limited information on factors that increase the risk of falls in this population. This study aimed to determine whether a group of cognitively impaired older people (CIG) perform worse than a matched group of cognitively intact older people (NCIG) on a profile of physical performance and mobility tests. METHODS: One hundred and thirty-eight cognitively impaired and 276 age and gender matched cognitively intact community dwelling older adults (>60 years) took part in the study. Participants completed a detailed physical performance battery from which composite fall risk scores were derived. Falls were measured prospectively for 12 months with monthly falls diaries, telephone calls, and by regularly contacting participants' "person responsible." RESULTS: The CIG performed worse than the NCIG in tests of reaction time, muscle strength (grip and quadriceps), balance (sway on floor, sway on foam, controlled leaning balance and near tandem standing ability), and mobility (sit to stand, timed up and go (TUG) and steps required to turn 180 degrees). The CIG had significantly higher composite fall risk scores than the NCIG and fell significantly more during follow-up (Multiple falls (2+): CIG 43%; NCIG 21%). CONCLUSIONS: Fall risk in the CIG was significantly increased due to multiple physical impairments. Physical profiles provide a means of quantifying the extent of impairment in older people with cognitive impairment and potential direction for targeting interventions for reducing fall risk. PMID- 22831908 TI - Generalized chorea with abnormal 18F-fluorodeoxyglucose positron emission tomography findings in a patient with hyperthyroidism. PMID- 22831909 TI - Psychiatric factors related to sexual functioning in patients with Parkinson's disease. AB - INTRODUCTION: This research deals with the topic of sexual life among people suffering from Parkinson's disease (PD) and with selected factors related to sexual functioning in these patients. Parkinson's disease is a serious chronic disease whose symptoms as well as treatment substantially affect the sexual life of the patients. Despite this fact, very little published work has dealt with this topic. AIM: This research focuses on describing the structure of deterioration of sexual functions of the patients suffering from PD, and statistical analysis of the interdependence of selected factors (age, duration of the disease, subjective score of the impact of the disease, depression, anxiety) as well as the patients' sexual satisfaction. The most substantial factors influencing sexual satisfaction of men and women with PD are analysed and their impact assessed, the greatest stress being put on psychiatric factors. METHODS: The research project examined a group of 103 people with PD. In order to identify the specifics of the patients' sexual lives, two questionnaire-sets were designed (separate for men and women), containing psychological (BDI-II, STAI) and sexological (FSFI, IIEF, GRISS) questionnaires. MAIN OUTCOME MEASURES: The main outcome measures were depression, state and trait anxiety, sexual satisfaction, erectile function, the Female Sexual Function Index. RESULTS: The acquired data was statistically elaborated using the programme SPSS. The results of the sexological questionnaires show a decrease in overall sexual functioning and the presence of sexual dysfunctions related to PD. With the help of regression models it was elicited that in case of men with this illness, the most influential factor on their sexual life is depression and their subjective scoring of the illness, in the case of women the prevailing factors are depression and anxiety. CONCLUSIONS: Sexuality for people suffering from Parkinson's disease is a very complex issue and psychiatric factors (depression, anxiety) have an important impact on the sexual functioning of the patients. PMID- 22831910 TI - The differential yet concurrent contributions of motor, cognitive and affective disturbance to freezing of gait in Parkinson's disease. AB - OBJECTIVES: We sought to concurrently examine the specific motor, cognitive and affective contributions to self-reported FOG symptoms. PATIENTS AND METHODS: Ninety-six patients with Parkinson's disease completed the validated freezing of gait questionnaire and had their motor function scored on section three of the Unified Parkinson's Disease Rating Scale questionnaire. A 5-choice reaction time task was administered in order to measure cognitive processing speed and the Beck Depression Inventory was utilised to assess affective disturbance. RESULTS: The results showed that after controlling disease duration and dopaminergic medication dose, the triad of motor disability, cognitive processing speed and affective symptoms were all significant independent predictors of scores on the freezing of gait questionnaire. CONCLUSIONS: These findings suggest the need to consider the interplay between distinct motor, cognitive and affective domains in aetiological studies of freezing and the development of future therapies. PMID- 22831911 TI - Validation of a patient satisfaction questionnaire in primary health care. AB - BACKGROUND: Improvement in patient satisfaction with healthcare services can be evaluated by satisfaction questionnaires of high construct validity. OBJECTIVES: To establish the dimensions and construct validity of a 20-item patient satisfaction questionnaire to assess satisfaction with general practice services. SUBJECTS: In total, 1314 adult patients of both genders, who were users of healthcare services at the General Medicine Department of Health Centre Valjevo in Serbia for two consecutive years, were included in the study. METHODS: Multidimensional scaling (MDS) was employed to identify similarities and dissimilarities among items comprising the satisfaction questionnaire. Patient satisfaction dimensions were estimated by principal component analysis for categorical data (CATAPCA). RESULTS: The MDS model configuration derived two dimensions: (1) patient satisfaction with the timeliness of healthcare service provision; and (2) patient centredness related to doctors' and nurses' commitment towards their health. In the CATAPCA model, two dimensions of patient satisfaction were found: the first dimension patient satisfaction with medical staff and the second dimension was indicative of contextual patient dissatisfaction. CONCLUSIONS: This study shows that the applied patient satisfaction questionnaire has high validity and reliability. It also has high sensitivity for longitudinal measurements, as well as good discriminatory power in measuring the different levels of patient satisfaction. PMID- 22831914 TI - Kv3 channels modulate calcium signals induced by fast firing patterns in the rat retinal ganglion cells. AB - Expression of non-inactivating Kv3.1/Kv3.2 potassium channels determines fast spiking phenotype of many types of neurones including retinal ganglion cells (RGCs); furthermore Kv3 channels regulate neurotransmitter release from presynaptic terminals. In the present study we investigated how inhibition of Kv3 channel by low TEA concentrations modifies firing properties and Ca2+ influx in the rat RGCs. Experiments were performed on the whole-mount retinal preparations from 4 to 6 weeks old Wistar rats using simultaneous whole cell patch clamp and intracellular Ca2+ measurements in combination with single-cell RT-PCR. In response to 500-ms depolarization step the RGCs demonstrated fast firing tonic behaviour with a mean frequency of spiking 61+/-5 Hz (n=28). All of the tonic cells tested (n=9) expressed specific mRNA for either Kv3.1 or Kv3.2 or for both channels. Bath applications of TEA (250 MUM, 500 MUM and 1 mM) modified firing patterns dose-dependently as follows: firing frequency was decreased, mean action potential (AP) half-width increased and mean amplitude of after hyperpolarization was reduced. The amplitude of the Ca2+ signals induced by the cells firing was linearly dependent on number of APs with a mean slope of 7.3+/-0.9 nM per one AP (n=8). APs widening by TEA increased the slope of the amplitude vs. AP number plots in a dose-dependent manner: 250 MUM of TEA increased the mean slope value to 9.5+/-1.2 nM/AP, 500 MUM to 12.4+/-2.4 nM/AP and 1 mM to 13.2+/-2.9 nM/AP (n=6). All these parameters, as well as the cells firing properties, were significantly different from controls and from each other except between 500 MUM and 1 mM. This is consistent with the pharmacological properties of Kv3.1/Kv3.2 channels: the TEA IC50 is in the range 150-300 MUM with almost complete block at 1 mM. This suggests that Kv3.1/Kv3.2 channels underlie the fast firing of the rat RGCs and provide at a given firing frequency 1.8-fold restriction Ca2+ influx, thus protecting the cells from its cytotoxic action. PMID- 22831913 TI - In vivo analysis of the calcium signature in the plant Golgi apparatus reveals unique dynamics. AB - The Golgi apparatus is thought to play a role in calcium homeostasis in plant cells. However, the calcium dynamics in this organelle is unknown in plants. To monitor the [Ca2+]Golgiin vivo, we obtained and analyzed Arabidopsis thaliana plants that express aequorin in the Golgi. Our results show that free [Ca2+] levels in the Golgi are higher than in the cytosol (0.70 MUM vs. 0.05 MUM, respectively). Stimuli such as cold shock, mechanical stimulation and hyperosmotic stress, led to a transient increase in cytosolic calcium; however, no instant change in the [Ca2+]Golgi concentration was detected. Nevertheless, a delayed increase in the [Ca2+]Golgi up to 2-3 MUM was observed. Cyclopiazonic acid and thapsigargin inhibited the stimuli-induced [Ca2+]Golgi increase, suggesting that [Ca2+]Golgi levels are dependent upon the activity of Ca2+ ATPases. Treatment of these plants with the synthetic auxin analog, 2,4 dichlorophenoxy acetic acid (2,4-D), produced a slow decrease of free calcium in the organelle. Our results indicate that the plant Golgi apparatus is not involved in the generation of cytosolic calcium transients and exhibits its own dynamics modulated in part by the activity of Ca2+ pumps and hormones. PMID- 22831915 TI - Copper(I) complexes with trispyrazolylmethane ligands: synthesis, characterization, and catalytic activity in cross-coupling reactions. AB - Three novel Cu(I) complexes bearing tris(pyrazolyl)methane ligands, Tpm(x), have been prepared from reactions of equimolar amounts of CuI and the ligands Tpm, (HC(pz)(3)), Tpm*, (HC(3,5-Me(2)-pz)(3)), and Tpm(Ms), (HC(3-Ms-pz)(3)). X-ray diffraction studies have shown that the Tpm and Tpm(Ms) derivatives exhibit a 2:1 Cu:ligand ratio, whereas the Tpm* complex is a mononuclear species in nature. The latter has been employed as a precatalyst in the arylation of amides and aromatic thiols with good activity. The synthesis of a Tpm*Cu(I)-phthalimidate, a feasible intermediate in this catalytic process, has also been performed. Low temperature (1)H NMR studies in CDCl(3) have indicated that this complex exists in solution as a mixture of two, neutral and ionic forms. Conductivity measurements have reinforced this proposal, the ionic form predominating in a very polar solvent such as DMSO. The reaction of Tpm*Cu(I)-phthalimidate with iodobenzene afforded the expected C-N coupling product in 76% yield accounting for its role as an intermediate in this transformation. PMID- 22831912 TI - Observations of calcium dynamics in cortical secretory vesicles. AB - Calcium (Ca(2+)) dynamics were evaluated in fluorescently labeled sea urchin secretory vesicles using confocal microscopy. 71% of the vesicles examined exhibited one or more transient increases in the fluorescence signal that was damped in time. The detection of transient increases in signal was dependent upon the affinity of the fluorescence indicator; the free Ca(2+) concentration in the secretory vesicles was estimated to be in the range of ~10 to 100 MUM. Non-linear stochastic analysis revealed the presence of extra variance in the Ca(2+) dependent fluorescence signal. This noise process increased linearly with the amplitude of the Ca(2+) signal. Both the magnitude and spatial properties of this noise process were dependent upon the activity of vesicle p-type (Ca(v)2.1) Ca(2+) channels. Blocking the p-type Ca(2+) channels with omega-agatoxin decreased signal variance, and altered the spatial noise pattern within the vesicle. These fluorescence signal properties are consistent with vesicle Ca(2+) dynamics and not simply due to obvious physical properties such as gross movement artifacts or pH driven changes in Ca(2+) indicator fluorescence. The results suggest that the free Ca(2+) content of cortical secretory vesicles is dynamic; this property may modulate the exocytotic fusion process. PMID- 22831917 TI - Regional differences in human ependymal and subventricular zone cytoarchitecture are unchanged in neuropsychiatric disease. AB - Much work has focused on the possible contribution of adult hippocampal neurogenesis to neuropsychiatric diseases. The hippocampal subgranular zone and the other stem cell-containing neurogenic niche, the subventricular zone (SVZ), share several cytological features and are regulated by some of the same molecular mechanisms. However, very little is known about the SVZ in neuropsychiatric disorders. This is important since it surrounds the lateral ventricles and in schizophrenia ventricular enlargement frequently follows forebrain nuclei shrinkage. Also, adult neurogenesis has been implicated in pharmacotherapy for affective disorders and many of the molecules associated with neuropsychiatric disorders affect SVZ biology. To assess the neurogenic niche, we examined material from 60 humans (Stanley Collection) and characterized the cytoarchitecture of the SVZ and ependymal layer in age-, sex- and post mortem interval-matched controls, and patients diagnosed with schizophrenia, bipolar illness, and depression (n = 15 each). There is a paucity of post mortem brains available for study in these diseases, so to maximize the number of possible parameters examined here, we quantified individual sections rather than a large series. Previous work showed that multiple sclerosis is associated with increased width of the hypocellular gap, a cell-sparse region that typifies the human SVZ. Statistically there were no differences between disease groups and controls in the width of the hypocellular gap or in the density of cells in the hypocellular gap. Because ventricular enlargement in schizophrenia may disrupt ependymal cells, we quantified them, but observed no difference between diagnostic groups and controls. There are significant differences in the prevalence of neuropsychiatric illness between the sexes. Therefore, we looked for male versus female differences, but did not observe any in the parameters quantified. We next turned to a finer spatial resolution and asked if there were differences amongst the disease groups in dorsal ventral subdivisions of the SVZ. Similar to when we treated the SVZ as a whole, we did not find such differences. However, compared to the dorsal SVZ, the ventral SVZ had a wider hypocellular gap and more ependymal cells in all four groups. In contrast, cell density was similar in dorsal ventral subregions of the SVZ hypocellular gap. These results show that though there are regional differences in the SVZ in humans, neuropsychiatric disorders do not seem to alter several fundamental histological features of this adult neurogenic zone. PMID- 22831918 TI - Treatment with glucagon-like Peptide-1 agonist exendin-4 in a patient with hypothalamic obesity secondary to intracranial tumor. AB - BACKGROUND/AIMS: Patients with hypothalamic tumors frequently experience severe obesity, and its treatment with diet, exercise, and/or pharmacologic treatment has had limited effect. Glucagon-like peptide-1 agonist exenatide (exendin-4), used for treatment of type 2 diabetes, causes persistent weight loss via signaling in the brainstem. METHODS: We report the case of a 17-year-old patient with obesity resulting from a hypothalamic germ cell tumor. He was treated by chemoradiotherapy and exenatide at a dose of 5 ug subcutaneously twice daily. RESULTS: Exenatide resulted in a 29-kg weight loss (BMI reduction from 37.1 to 29.1) after 2.5 years of treatment; significant weight gain occurred shortly after exenatide was discontinued. CONCLUSION: Exenatide resulted in considerable reduction of body weight in a patient with severe hypothalamic obesity. This novel observation requires follow-up clinical studies for establishing the effects of exenatide in patients with disrupted hypothalamic energy regulatory pathways. PMID- 22831916 TI - Effects of a physical activity behavior change intervention on inflammation and related health outcomes in breast cancer survivors: pilot randomized trial. AB - BACKGROUND: The goal of this pilot study was to determine the magnitude and direction of intervention effect sizes for inflammatory-related serum markers and relevant health outcomes among breast cancer survivors (BCSs) receiving a physical activity behavior change intervention compared with usual care. METHODS: This randomized controlled trial enrolled 28 stage I, II, or IIIA BCSs who were post-primary treatment and not regular exercisers. Participants were assigned to either a 3-month physical activity behavior change intervention group (ING) or usual care group (UCG). Intervention included supervised aerobic (150 weekly minutes, moderate-intensity) and resistance (2 sessions per week) exercise that gradually shifted to home-based exercise. Outcomes were assessed at baseline and 3 months. RESULTS: Cardiorespiratory fitness significantly improved in the ING versus the UCG (between-group difference = 3.8 mL/kg/min; d = 1.1; P = .015). Self-reported sleep latency was significantly reduced in the ING versus the UCG (between group difference = -0.5; d = -1.2; P = .02) as was serum leptin (between group difference = -9.0 ng/mL; d = -1.0; P = .031). Small to medium nonsignificant negative effect sizes were noted for interleukin (IL)-10 and tumor necrosis factor (TNF)-alpha and ratios of IL-6 to IL-10, IL-8 to IL-10, and TNF alpha to IL-10, whereas nonsignificant positive effect sizes were noted for IL-6 and high-molecular-weight adiponectin. CONCLUSIONS: Physical activity behavior change interventions in BCSs can achieve large effect size changes for several health outcomes. Although effect sizes for inflammatory markers were often small and not significant, changes were in the hypothesized direction for all except IL 6 and IL-10. PMID- 22831919 TI - Natural stimuli improve auditory BCIs with respect to ergonomics and performance. AB - Moving from well-controlled, brisk artificial stimuli to natural and less controlled stimuli seems counter-intuitive for event-related potential (ERP) studies. As natural stimuli typically contain a richer internal structure, they might introduce higher levels of variance and jitter in the ERP responses. Both characteristics are unfavorable for a good single-trial classification of ERPs in the context of a multi-class brain-computer interface (BCI) system, where the class-discriminant information between target stimuli and non-target stimuli must be maximized. For the application in an auditory BCI system, however, the transition from simple artificial tones to natural syllables can be useful despite the variance introduced. In the presented study, healthy users (N = 9) participated in an offline auditory nine-class BCI experiment with artificial and natural stimuli. It is shown that the use of syllables as natural stimuli does not only improve the users' ergonomic ratings; also the classification performance is increased. Moreover, natural stimuli obtain a better balance in multi-class decisions, such that the number of systematic confusions between the nine classes is reduced. Hopefully, our findings may contribute to make auditory BCI paradigms more user friendly and applicable for patients. PMID- 22831920 TI - Carboxypeptidase I from triticale grains and the hydrolysis of salt-soluble fractions of storage proteins. AB - Carboxypeptidase I was purified from triticale grains (*Triticosecale Wittm.) by a 5-step purification procedure including gel filtration, cation-exchange chromatography and affinity chromatography. The enzyme was purified 595.9 fold with a 1.58% recovery. Triticale carboxypeptidase I is a homodimer with a molecular weight of 124.2 kDa and a subunit weight of 55.2 kDa. Each subunit is composed of two polypeptide chains (33.4 and 21.3 kDa). Serine was found in the active site of triticale carboxypeptidase I; DFP (diisopropylflourophosphate) and other applied inhibitors of serine proteases inhibited the enzyme activity. Triticale carboxypeptidase I hydrolyzes N-CBZ-dipeptide (N-carbobenzoxy dipeptide) substrates at low pH. N-CBZ-Phe-Ala, N-CBZ-Phe-Leu and N-CBZ-Ala-Met were hydrolyzed with the highest rates. The lowest K(m) value and the highest k(cat)/K(m) ratio were observed for hydrolysis of N-CBZ-Phe-Ala. Studies on the amino acid sequence revealed that the purified enzyme is homologous to carboxypeptidase I from barley. Analyses of conserved regions in the sequence of triticale carboxypeptidase I revealed the presence of Ser, Asp and His that compose the catalytic triad. Intact storage proteins were poor substrates for carboxypeptidases. Carboxypeptidase I together with carboxypeptidase III effectively degraded albumins proteolytically modified by endopeptidase EP8. Modified globulins were degraded at a slower rate, and all three carboxypeptidases were required for a significantly increased activity. Studies of the expression of the carboxypeptidase I gene revealed that the synthesis of the enzyme occurs mainly in the scutellum of the grain. The enzyme is also expressed in the aleurone layer of the grains, although its function in this tissue is unknown. PMID- 22831921 TI - In the line of duty: a study of ambulance drivers during the 2010 conflict in Kashmir. AB - PURPOSE: The purpose of this study was to identify the problems faced by ambulance drivers working in a conflict zone. METHODS: This study was conducted on ambulance drivers working for the four major hospitals in Kashmir, India. The drivers were interviewed and asked a series of 30 work-related questions. The individual interviews were conducted over a three-month period in the valley of Kashmir that was affected by continuous violence, strict curfew, and strikes. RESULTS: A total of 35 ambulance drivers were interviewed. Drivers worked an average of 60 h/wk, and they drove an average of 160 km/d. Twenty-nine (83%) of the drivers experienced >1 threat of physical harm; 18 (54%) experienced physical assaults; and 31 (89%) reported evidence of psychological morbidity associated with their jobs. CONCLUSIONS: The atmosphere of conflict on the streets of Kashmir impacted the ambulance drivers adversely, both physically as well as mentally. The stress faced by these professionals in conflict zones during their duty hours should be recognized, and corrective measures must be put in place. PMID- 22831922 TI - Abbreviated Injury Scale: not a reliable basis for summation of injury severity in trauma facilities? AB - BACKGROUND: Injury severity is most frequently classified using the Abbreviated Injury Scale (AIS) as a basis for the Injury Severity Score (ISS) and the New Injury Severity Score (NISS), which are used for assessment of overall injury severity in the multiply injured patient and in outcome prediction. European trauma registries recommended the AIS 2008 edition, but the levels of inter-rater agreement and reliability of ISS and NISS, associated with its use, have not been reported. METHODS: Nineteen Norwegian AIS-certified trauma registry coders were invited to score 50 real, anonymised patient medical records using AIS 2008. Rater agreements for ISS and NISS were analysed using Bland-Altman plots with 95% limits of agreement (LoA). A clinically acceptable LoA range was set at +/- 9 units. Reliability was analysed using a two-way mixed model intraclass correlation coefficient (ICC) statistics with corresponding 95% confidence intervals (CI) and hierarchical agglomerative clustering. RESULTS: Ten coders submitted their coding results. Of their AIS codes, 2189 (61.5%) agreed with a reference standard, 1187 (31.1%) real injuries were missed, and 392 non-existing injuries were recorded. All LoAs were wider than the predefined, clinically acceptable limit of +/- 9, for both ISS and NISS. The joint ICC (range) between each rater and the reference standard was 0.51 (0.29,0.86) for ISS and 0.51 (0.27,0.78) for NISS. The joint ICC (range) for inter-rater reliability was 0.49 (0.19,0.85) for ISS and 0.49 (0.16,0.82) for NISS. Univariate linear regression analyses indicated a significant relationship between the number of correctly AIS coded injuries and total number of cases coded during the rater's career, but no significant relationship between the rater-against-reference ISS and NISS ICC values and total number of cases coded during the rater's career. CONCLUSIONS: Based on AIS 2008, ISS and NISS were not reliable for summarising anatomic injury severity in this study. This result indicates a limitation in their use as benchmarking tools for trauma system performance. PMID- 22831923 TI - Evacuation of wounded with intracranial injury to a hospital without neurosurgical service versus primary evacuation to a level I trauma centre. AB - BACKGROUND: Several studies have shown that delay in neurosurgical intervention worsens the neurologic outcome. However, rapid evacuation of wounded sustaining intracranial injury (ICI) to the nearest hospital may have some advantages, as the nearest hospital ER may be a better environment to prevent a secondary brain injury than the ambulance. Also, evacuation to a referral centre of all the wounded suspected in the field to have ICI will result in high rates of over triage. In order to create a factual basis for triage and resource utilization of wounded with possible ICI, we measured the delay in neurosurgical intervention of wounded with ICI that were evacuated to a hospital without neurosurgery service, the Western Galilee Hospital (WGH), Naharia, Israel, and its impact on morbidity and mortality. METHODS AND MATERIALS: A retrospective case-control study was conducted for a period of 29 months. The study population included wounded over the age of two years, sustaining blunt ICI as diagnosed by CT scan that were evacuated to the WGH and later transferred to a level 1 trauma centre, Rambam Health Care Campus (RHCC), Haifa. Wounded were included only if the abbreviated injury score (AIS) of any other body system did not exceed 2. A control group of 29 wounded (one per month) was matched by random selection of wounded who met the inclusion criteria, primarily evacuated to RHCC and underwent neurosurgical intervention. Demographic data, anatomical characteristics of the injury, physiological parameters of injury severity, treatment at the ER, the schedules of neurosurgical interventions, ICU and hospital stay and discharge destination were recorded. Comparison between the groups was performed by Chi-square test for nominal variables, Fisher's exact test for 2*2 contingency tables, and Student's t test for numeric variables. The statistical significance was set at 5% (p<0.05). RESULTS: 162 wounded that were evacuated to WGH and later transferred to RHCC were included in the study. 31(19.1%) of them required invasive neurosurgical intervention. The wounded that needed neurosurgical intervention were transferred earlier: 165.7 (SD 61.1) min on average from arrival to WGH to arrival RHCC, compared to 217.8 (SD 152.9) min for those who did not need any intervention (p<0.005). The demographic variables, injury characteristics, physiological parameters and ER treatment of the wounded that underwent neurosurgical intervention were similar whether the wounded were transferred from WGH or arrived directly to RHCC. The time passed until neurosurgical intervention, was significantly shorter for wounded admitted directly to RHCC: 2h and 13.9 min (133.9 (SD 71.9)min) on average from admission to intervention compared to 4h and 47.6 min (287.6 (SD 107.5)min) on average from WGH admission to neurosurgical intervention (p<0.001). Lengths of ICU stay and hospital stay were similar in both groups. Two patients from each group died. 12 wounded admitted directly to RHCC group and 8 wounded transferred from WGH were discharged to a neurological rehabilitation. CONCLUSIONS: Only a minority of wounded with an intracranial bleeding require neurosurgical intervention, but primary evacuation of these wounded to a hospital with no neurosurgery service results in an unacceptable delay in neurosurgical intervention. In this study, we did not find that this delay had an influence on prognosis, but a larger sample and a prolonged follow up are probably needed. A faster neurosurgical intervention can be achieved by a direct evacuation from the field to a level 1 trauma centre, or by expedition of the transfer process. PMID- 22831924 TI - Internship and community service require revision. PMID- 22831925 TI - Sudden cardiac arrest in the young - a call to action. PMID- 22831926 TI - Register on the mental health information centre of Southern Africa database. PMID- 22831927 TI - Is Hahnemann's therapeutic system a mystica? PMID- 22831928 TI - The occupational illnesses of grandparents. PMID- 22831929 TI - The South African paediatric tumour registry - 25 years of activity. PMID- 22831930 TI - Teenage pregnancies/HIV prevention - doctors help fill official hiatus. PMID- 22831931 TI - Government could help prison TB victims - activists. PMID- 22831932 TI - Local fetal alcohol syndrome pioneer wins global award. PMID- 22831933 TI - High MDRTB risk for healthcare workers 'unnecessary'. PMID- 22831936 TI - Prevention of infective endocarditis in developing countries - justifiable caution? AB - The internationally accepted practice of prescribing prophylactic antibiotics to individuals at risk of infective endocarditis has come under scrutiny. There are no published high-quality randomised controlled trials of the intervention, but new insights have emerged. Bacteraemic episodes are common following simple activities such as brushing teeth. Endocarditis following procedures is extremely rare, and systematic reviews of the evidence for prophylactic antibiotics have failed to demonstrate efficacy. PMID- 22831937 TI - Slaves of the state - medical internship and community service in South Africa. AB - Owing to a chronic shortage of medical staff in South Africa, sleep-deprived medical interns and community service doctors work up to 200 hours of overtime per month under the state's commuted overtime policy. Nurses moonlight in circumvention of the Basic Conditions of Employment Act. For trainee doctors, overtime over 80 hours is unpaid, and rendered involuntarily under threat of not qualifying to practise medicine in South Africa. As forced labour, and sleep deprivation amounting to cruel and degrading treatment, it is outlawed in international law. No other professional group in the country is subjected to such levels of exploitation and discrimination by the state. These abuses should be challenged under the Constitution. Solutions include the installation of electronic time-recording in state hospitals, cessation of unpaid overtime, limits on medical intern shifts to a maximum of 16 hours, and an investigation by the Human Rights Commission of South Africa. PMID- 22831938 TI - A Somalia mission experience. AB - Reports about The Horn of Africa Famine Crisis in 2011 flooded our news bulletins and newspapers. Yet the nations of the world failed to respond and alleviate the unfolding disaster. In August 2011, the Gift of the Givers Foundation mobilised what was to become the largest humanitarian mission ever conducted by an African organisation. Almost a year later, the effort continues, changing the face of disaster medicine as we know it. PMID- 22831939 TI - Loeys-Dietz syndrome: a possible solution for Akhenaten's and his family's mystery syndrome. AB - The presence of a familial disease among royal members of 18th dynasty of the new kingdom who ruled in Egypt from the mid-16th to the early 11th centuries BC has been established, largely prompted by the bizarre body shape of Akhenaten (the iconoclastic pharaoh of this dynasty) and his family, as demonstrated in statues and artwork. It had been thought previously that this was an expression of a revolutionised artistic style that followed radical reforms by Akhenaten of Egyptian society, but recent studies on mummies confirmed the presence of a constellation of corresponding pathologies. Several illnesses have been suggested to solve this enigma; we propose Loeys-Dietz syndrome as a probable diagnosis for this genetic affliction within the royal family. PMID- 22831940 TI - Ascites as an initial presentation of spontaneously ruptured hydatid cyst. AB - We describe the diagnosis of a 77-year-old woman admitted to our outpatient department with a 3-month history of abdominal bloating and distension. Abdominal computed tomography revealed a large cystic lesion in the posterior segment of the right hepatic lobe, with a separated germinal layer and widespread ascites with dense internal echoes and septal appearance. The result of a serum Echinococcus indirect haemagglutination test was positive and findings were indicative of the spontaneous rupture of a hydatid cyst into the peritoneal cavity without trauma. Ascites is rarely seen in the course of hydatid disease, but can result from cyst rupture into the peritoneal cavity. This should be considered in the differential diagnosis of ascites, especially in areas such as Turkey, where hydatid disease in endemic. PMID- 22831941 TI - Solar ultraviolet radiation exposure and human health in South Africa: finding a balance. PMID- 22831942 TI - Moving beyond access: towards a quality-orientated substance abuse treatment system in South Africa. PMID- 22831943 TI - Foreign advertisements for doctors in the SAMJ 2006 - 2010. AB - BACKGROUND: There is much concern about the migration of health professionals from developing countries, and the contribution of active recruitment to the phenomenon. One active recruitment strategy is advertisements in professional journals and other media. OBJECTIVE: To establish the trends in foreign advertisements for doctors placed in the South African Medical Journal (SAMJ) from January 2006 to December 2010. METHODS: A retrospective review was conducted of 60 issues of the SAMJ published in the preview years. Printed journals were scanned for foreign advertisements. The findings were compared with a review of 2000 - 2004 in the same journal. RESULTS: There were 1 176 foreign advertisements placed in the SAMJ in the review period, reducing from 355 in 2006 to 121 in 2010. The countries placing the most advertisements were Australia (n=428, 36.4%), Canada (n=286, 24.3%), New Zealand (n=191, 16.2%) and the UK (n=108, 9.2%). Compared with the earlier findings, there was a reduction in advertisements for the top countries, excepting Australia. The top 4 countries remained the same for the 2 review periods, but the order changed, with Australia superseding the UK. CONCLUSION: The number of foreign advertisements placed in the SAMJ declined over the period under review, and there was a change in ranking of the top 4 advertising countries. These findings are discussed from the perspective of global human resources for health initiatives. PMID- 22831944 TI - Osteosarcoma presentation stages at a tumour unit in South Africa. AB - BACKGROUND: Osteosarcoma is the most common malignant bone tumour found in children and adolescents. Changed treatment protocols have resulted in improved survival and the opportunity for limb salvage surgery. Despite these advances, the outcome is mainly determined by the stage of disease at presentation, making early referral to a tumour unit essential. METHODS: Between July 2009 and October 2011, 25 consecutive patients were diagnosed with biopsy-confirmed osteosarcoma. Their records were reviewed and information extracted regarding clinical presentation, histological subtype and stage of disease. RESULTS: Twenty-four patients met the inclusion and exclusion criteria. Conventional osteosarcoma was the most common histological diagnosis encountered; 16 out of 24 (66.7%) patients had metastases at presentation; 6 of the remaining had advanced local disease with very large tumours or pathological fractures that precluded limb salvage surgery. CONCLUSION: The great majority of patients referred to our tumour unit present with locally advanced or metastatic disease, which limits treatment options and adversely affects survival. Increased awareness, a high index of suspicion and appropriate early referral is crucial to enable limb salvage surgery and increase disease-free survival rates. PMID- 22831945 TI - Plasma sarcosine does not distinguish early and advanced stages of prostate cancer. AB - INTRODUCTION: Diagnosis of prostate cancer by prostate specific antigen (PSA) is error-prone and cannot distinguish benign prostatic hyperplasia (BPH) from malignant disease, nor identify aggressive and indolent types. METHODS: We determined serum sarcosine (N-methylglycine) in 328 cancer patients by gas chromatography (GC)/mass spectroscopy (MS) and searched for correlations with early (stage T1/T2) and advanced (stage T3/T4) disease. RESULTS: Serum sarcosine of male control patients ranged from 1.7 umol/l to 4.8 umol/l. In prostate cancer patients, sarcosine ranged from 2.8 umol/l to 20.1 umol/l. Expressed as the sarcosine/alanine ratio, serum control values were 9.4 +/- 5.5 x 10(-3) (mean +/- SD) compared with 21.6 +/- 9.0; 28.5 +/- 16.6; 22.7 +/- 7.7 and 22.2 +/- 11.0 for patients diagnosed with T1, T2, T3 and T4 prostate tumours, respectively. The small differences between T1, T2, T3 and T4 patients were not statistically significant (p=0.51). However, the conventional PSA marker significantly correlated with T stage in these patients (r=0.63; p<0.009). CONCLUSIONS: The median sarcosine/alanine ratios among patients with early and advanced prostatic cancer ranged from 21.6 +/- 9.0 to 28.5 +/- 16.6 and were fairly constant, showing no statistically significant differences between T-stages. The results are consistent with published data in urine and serum which find differences between controls and patients with metastatic prostate cancer to be small and sarcosine to be uninformative regarding prostate cancer progression. By multi comparison of PSA with T-stages in the same group of patients, we found significant correlations confirming the well-known merits and limitations of this marker. PMID- 22831946 TI - Profile of cause of death assigned to adults on antiretroviral therapy in Soweto. AB - This retrospective cohort study describes causes of death in 305 patients (baseline median CD4 count 26/MUl) from 2 943 adults on antiretroviral therapy. Acute sepsis (20%), tuberculosis (18%) and Mycobacterium avium complex (MAC) bacteraemia (14%) were the most common causes. Mortality owing to the disease was 66% for MAC bacteraemia and 23% for non-Hodgkin's lymphoma. In 37 patients dying beyond one year on ART, virological failure was present in 11 (30%), and non-HIV related causes of death occurred in 10. The main causes were acute sepsis (6), tuberculosis (7) and chronic medical conditions (5). Initiating ART at higher CD4 counts should reduce early mortality. PMID- 22831947 TI - Inherited polyglutamine spinocerebellar ataxias in South Africa. AB - OBJECTIVE: To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). METHODS: Paper based clinical reports in the University of Cape Town laboratory and the NHLS electronic patient record database spanning a 24-year period were mined for information regarding the molecular diagnosis, ethnicity and CAG repeat length for individuals referred for molecular genetic testing for the polyglutamine SCAs. RESULTS: SCA1 and 7 are the most frequent types of polyglutamine SCA in the SA patient population, followed by SCA2, 3 and 6. SCA1 is the most common type in the coloured, white and Indian populations, whereas the majority of indigenous black African patients are affected with SCA7 and 2. Of individuals tested, 22% were found to be positive for one of the polyglutamine SCAs. CONCLUSION: Although trends in the frequency and distribution of the polyglutamine SCAs in SA have not changed significantly since our previous study in 2003, they differ remarkably from those reported elsewhere, and reflect the unique genetic and demographic background of SA. The provision of accurate and complete patient information and family history is crucial to the diagnostic process, to enable comprehensive epidemiological studies and assist in developing therapeutic and patient management strategies. PMID- 22831948 TI - Traditional eye medication and pterygium occurrence in Limpopo Province. AB - BACKGROUND: The relative importance of environmental and hereditary factors in the occurrence of pterygium in African blacks has not been reported. AIM: To investigate the relative significance of factors associated with pterygium occurrence. METHODS: This was a prospective case-controlled study where 150 pterygium patients and 150 controls participated. Interviews were conducted, eyes examined and multivariate analysis done. The families of 51 pterygium cases and 50 controls were examined for presence of pterygium. RESULTS: Of 150 cases and 150 controls, 79 (52.6%) and 60 (40%) used traditional eye drops (odds ratio (OR) 2.03; p=0.009. Ten cases (6.6%) and 26 controls (17.3%) had unstable tear film (OR 0.30; p=0.007. Forty-six cases (30.6%) and 15 controls (10%) reported a positive family history (OR 3.93; p<0.001). Groups of 3 - 5 pterygium cases in a household occurred in 36 of 51 pterygium families (70.5%) v. 1 of 50 controls (2%). CONCLUSIONS: Pterygium occurrence was associated with the use of traditional eye drops, a positive family history and having groups of diagnosed pterygium-affected relatives. However, unstable tear film seemed protective against pterygium occurrence. PMID- 22831949 TI - Do South African universities provide the required training platforms for otolaryngology specialist training? AB - BACKGROUND: Concern exists about the quality of specialist training platforms at South African universities and teaching hospitals. METHOD: We conducted an audit of the quality of training at South African otolaryngology (ENT) training institutions from the perspective of the registrars. RESULTS: Some institutions were deficient in terms of supervision, theatre time, access to teaching aids and research tools, and range of surgery, and do not provide the required training platforms for ENT specialist training. Five out of 8 institutions have produced <2 publications in peer-reviewed journals over the past 5 years. CONCLUSIONS: The HPCSA fails to adequately police the quality of training in South Africa. Training programme shortcomings must urgently be addressed to ensure proper education and training of otolaryngologists. PMID- 22831950 TI - Allergic rhinitis in South Africa: 2012 guidelines. AB - BACKGROUND: Allergic rhinitis (AR) is an important disease in South Africa. The South African Allergic Rhinitis Working Group (SAARWG) has published previous guidelines for AR diagnosis and management. Areas of concern have arisen that require additional information, including the management of AR in infancy, appropriate and inappropriate allergy testing, cost of AR management, diagnosis and distinguishing the condition from sinusitis, use of over-the-counter medications, and the concept of the 'united airway'. RECOMMENDATIONS: Clinicians should consider the possibility of AR in infants with recurrent nasal symptoms. Allergy testing should be used wisely and based on local allergens. Total IgE testing is not routinely required to prove allergy. Acute and chronic sinusitis should be considered in conjunction with AR; treatment of rhinitis will improve these conditions. Over-the-counter medications should be used sparingly and with caution. Concern for long-term use of topical decongestants must be noted. Asthma should always be considered in AR diagnosis. Immunotherapy is available in SA and may be extremely useful in selected AR patients. CONCLUSION: The SAARWG proposed an algorithm for the diagnosis and management of rhinitis in South Africa. AR is common, important and troubling to patients; therefore, every effort should be made to target therapy correctly. Patient education is important in the management of AR. PMID- 22831951 TI - South African guidelines for the management of Gaucher disease, 2011. AB - BACKGROUND: Gaucher disease is an autosomal recessive lysosomal glycosphingolipid storage disorder resulting from a deficiency of lysosomal enzyme acid beta glucosidase (glucocerebrosidase). This partial enzyme deficiency results in accumulation of glycosphingolipid-laden macrophages (Gaucher cells) throughout the liver, spleen, bone marrow, skeleton, lungs and brain (only in types 2 and 3). OBJECTIVE: These guidelines aim to provide a standard of care for patients with Gaucher disease in keeping with international standards, but also realistic for South Africa, and to provide a shared-care model for treating physicians and funders regarding care for these patients. RECOMMENDATIONS: All healthcare professionals involved in the diagnosis and management of Gaucher disease should take note of and implement these guidelines in clinical practice as far as possible. VALIDATION: These guidelines were developed through consensus by the Lysosomal Storage Disorder Medical Advisory Board. They are largely based on the UK 2005 National Guidelines for Gaucher Disease, but include new treatment recommendations for enzyme replacement therapy based on subsequent publications. The Southern African Society for Human Genetics (SASHG) (who have endorsed the guidelines) and the National Osteoporosis Foundation of South Africa (NOFSA) provided valuable input. GUIDELINES SPONSOR: Genzyme initiated the project and sponsored the meetings of the Advisory Board and all costs generated by these meetings. CONCLUSION: It is intended that these guidelines will enable all patients suffering from Gaucher disease to be diagnosed and offered the best possible care available. PMID- 22831953 TI - Relationships among changes in C-reactive protein and cardiovascular disease risk factors with lifestyle interventions. AB - BACKGROUND AND AIMS: Inflammation plays a role in the development of cardiovascular disease (CVD). Elevated levels of the inflammatory marker, C reactive protein (CRP), are cross-sectionally associated with traditional CVD risk factors and are being considered as an emerging CVD risk factor. In a secondary data analysis, we examined changes in CRP and several CVD risk factors after one-year diet and physical activity interventions to assess whether CRP changed concurrently with other risk factors, or was independent of the traditional risk factors. METHODS AND RESULTS: Data were analyzed from 143 men and 133 women with dyslipidemia who were randomized to one-year interventions of low-fat diet only, physical activity only, diet plus physical activity, or control. Plasma high-sensitivity CRP, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides (TG), fasting and 2-hr blood glucose and insulin, blood pressure (BP), and waist circumference were obtained at baseline and follow-up. Multiple linear regression models were used to predict CRP change based on other risk factor changes, controlling for age, race, alcohol intake, and hormone replacement therapy. Treatment groups were combined for analysis. Baseline mean (SD) CRP levels were 1.3 +/- 1.3 (men) and 1.9 +/- 1.8 mg/L (women), with mean changes of -0.11 +/- 1.3 and -0.17 +/- 1.5 mg/L, respectively. Plasma CRP change was negatively associated with TG change in men (p = 0.003) and women (p = 0.05), positively associated with change in systolic BP in men (p = 0.01), but was not associated with changes in the other risk factors. CONCLUSION: Dietary and/or physical activity induced changes in CRP may be largely independent of traditional CVD risk factors in persons with dyslipidemia. PMID- 22831954 TI - Dairy product intake in relation to glucose regulation indices and risk of type 2 diabetes. AB - BACKGROUND AND AIM: A high intake of dairy has been linked to lower risk of type 2 diabetes (T2D). The relationship between dairy intake and glucose metabolism is still not well understood. The aim of this study was to investigate the relation between the intake of total dairy and dairy subgroups and T2D and measures of glucose metabolism. METHODS AND RESULTS: A total of 5953 Danish men and women aged 30-60 years without baseline diabetes or cardiovascular diseases were included in this prospective analysis. The dairy intake at baseline was categorised into low-fat dairy, full-fat dairy, milk and milk products, cheese and fermented dairy. Fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), HbA1c, insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B) were considered at 5-year follow-up. In the maximally-adjusted model (demographics, lifestyle factors, dietary factors and waist), cheese intake was inversely associated with 2hPG (beta = -0.048, 95% CI -0.095; -0.001). Fermented dairy intake was inversely associated with FPG (beta = -0.028, 95% CI -0.048; -0.008) and HbA1c (beta = -0.016, 95% CI -0.030; -0.001). Total dairy intake and the dairy subgroups were not related to HOMA-IR and HOMA-B in the maximally-adjusted model. Furthermore, there was no significant association between intake of total dairy or any of the dairy subgroups and incidence of T2D. CONCLUSION: Our data suggest a modest beneficial effect of cheese and fermented dairy on glucose regulation measures; however, this did not translate into a significant association with incident T2D. PMID- 22831955 TI - The TNF-alpha/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. AB - The proliferation-specific transcription factor Forkhead box M1 (FoxM1) acts as a master regulator of cancer cell growth and survival and plays an important role in the development of hepatocellular carcinoma. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-alphaalpha induced FoxM1 expression and transactivated its promoter activity in hepatoma cells. Serial 5" deletion and site-directed mutagenesis revealed that the induction of FoxM1 expression by TNF-alpha was dependent upon the hypoxia-inducible factor 1 (HIF1)-1 and HIF1-3/4 binding sites within the FoxM1 promoter. Furthermore, at the transcriptional level, the stabilization of HIF-1alpha via reactive oxygen species generation led to the binding of HIF-1alpha to the FoxM1 promoter and resulted in increased FoxM1 expression. The inhibition of both HIF-1alpha expression and reactive oxygen species generation significantly decreased TNF-alpha-induced FoxM1 overexpression. Consequently, the upregulation of FoxM1 promoted the proliferation of hepatoma cells and enhanced their resistance to TNF-alpha induced apoptosis. Consistently, there was a positive correlation between HIF 1alpha and FoxM1 expression in 406 human hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-alpha/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis. PMID- 22831957 TI - [IgG4-related sclerosing disease: computed tomography and magnetic resonance imaging findings]. PMID- 22831956 TI - Intraductal administration of a polymeric nanoparticle formulation of curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in a rodent chemical carcinogenesis model: Implications for breast cancer chemoprevention in at-risk populations. AB - Multiple lines of evidence support a role for curcumin in cancer chemoprevention. Nonetheless, despite its reported efficacy and safety profile, clinical translation of curcumin has been hampered by low oral bioavailability, requiring infeasible 'mega' doses for achieving detectable tissue levels. We have engineered a polymeric nanoparticle encapsulated formulation of curcumin (NanoCurc) to harness its full therapeutic potential. In the current study, we assessed the chemoprevention efficacy of NanoCurc administered via direct intraductal (i.duc) injection in a chemical carcinogen-induced rodent mammary cancer model. Specifically, Sprague-Dawley rats exposed to systemic N-methyl-N nitrosourea were randomized to receive either oral free curcumin at a previously reported 'mega' dose (200mg/kg) or by direct i.duc injection of free curcumin or NanoCurc, respectively, each delivering 168 ug equivalent of curcumin per rodent teat (a ~20-fold lower dose per animal compared to oral administration). All three chemoprevention modalities resulted in significantly lower mammary tumor incidence compared with control rats; however, there was no significant difference in cancer incidence between the oral dosing and either i.duc arms. On the other hand, mean tumor size, was significantly smaller in the i.duc NanoCurc cohort compared with i.duc free curcumin (P < 0.0001), suggesting the possibility of better resectability for 'breakthrough' cancers. Reduction in cancer incidence was associated with significant decrease in nuclear factor -kappaB activation in the NanoCurc treated mammary epithelium explants, compared to either control or oral curcumin-administered rats. Our studies confirm the potential for i.duc NanoCurc as an alternative to the oral route for breast cancer chemoprevention in high-risk cohorts. PMID- 22831958 TI - Nutritional screening model in tertiary medical unit in Croatia. AB - BACKGROUND/AIMS: Malnutrition of hospitalized patients is often undetected and untreated due to poor awareness and insufficient knowledge of the attending hospital staff. Nutritional screening has not been part of the daily routine in Croatian hospitals. Our aim was to implement nutritional screening as part of the routine medical examination and to assess the nutritional risk at admission for all hospitalized patients. METHODS: All patients hospitalized in departments of internal medicine in tertiary hospitals in Croatia were screened at entry using the Nutrition Risk Screening 2002 (NRS 2002). RESULTS: Between October and December 2010, 1,696 patients were screened and analyzed (948 males and 748 females). 329 (19.4%) had an NRS 2002 score >=3 and were considered to be at nutritional risk. An NRS 2002 score >=3 was identified as a significant predictor of the length of hospital stay (beta coefficient = 0.06, p = 0.027) and fatal outcome (OR = 6.18, p < 0.001). Only 32.8% of malnourished patients received some nutritional support. CONCLUSIONS: Every fifth patient hospitalized in a general medical department in Croatia is at nutritional risk and the majority of them does not receive nutritional support. More effort is needed to implement nutritional standards in daily clinical practice. PMID- 22831959 TI - Real-time decoding of the direction of covert visuospatial attention. AB - Brain-computer interfaces (BCIs) make it possible to translate a person's intentions into actions without depending on the muscular system. Brain activity is measured and classified into commands, thereby creating a direct link between the mind and the environment, enabling, e.g., cursor control or navigation of a wheelchair or robot. Most BCI research is conducted with scalp EEG but recent developments move toward intracranial electrodes for paralyzed people. The vast majority of BCI studies focus on the motor system as the appropriate target for recording and decoding movement intentions. However, properties of the visual system may make the visual system an attractive and intuitive alternative. We report on a study investigating feasibility of decoding covert visuospatial attention in real time, exploiting the full potential of a 7 T MRI scanner to obtain the necessary signal quality, capitalizing on earlier fMRI studies indicating that covert visuospatial attention changes activity in the visual areas that respond to stimuli presented in the attended area of the visual field. Healthy volunteers were instructed to shift their attention from the center of the screen to one of four static targets in the periphery, without moving their eyes from the center. During the first part of the fMRI-run, the relevant brain regions were located using incremental statistical analysis. During the second part, the activity in these regions was extracted and classified, and the subject was given visual feedback of the result. Performance was assessed as the number of trials where the real-time classifier correctly identified the direction of attention. On average, 80% of trials were correctly classified (chance level <25%) based on a single image volume, indicating very high decoding performance. While we restricted the experiment to five attention target regions (four peripheral and one central), the number of directions can be higher provided the brain activity patterns can be distinguished. In summary, the visual system promises to be an effective target for BCI control. PMID- 22831960 TI - Congenital occipital encephalocele with Dabska tumor: report of an unusual case. AB - Encephaloceles arise from developmental defects in neural tube formation. These lesions contain brain and meninges which herniate through a defect in the skull. These may present as isolated malformations or rarely be associated with brain tumors. We hereby discuss a case of an unusual association of an occipital encephalocele with papillary intralymphatic angioendothelioma or Dabska tumor arising from the sac itself. The patient underwent resection of the herniated brain tissue with repair and closure of the dural defect. Histopathological examination revealed evidence of Dabska tumor from the sac. This is the first case report of the association of an occipital encephalocele with a rare vascular tumor, i.e. papillary intralymphatic angioendothelioma. PMID- 22831961 TI - Putting Descartes before the horse: Quantum theories of consciousness: Comment on "Consciousness, biology, and quantum hypotheses" by Baars & Edelman. PMID- 22831962 TI - From "Neural correlates of consciousness" to "Neural causes of consciousness": A commentary on "Consciousness, biology and quantum hypotheses", by Bernard J. Baars and David E. Edelman. PMID- 22831963 TI - Nanosecond pulsed powers - alternative approaches to cell membrane manipulation: Comment on "Physical methods for genetic transformation in plants" by Rivera et al. PMID- 22831965 TI - The impact of stress on paramedic performance during simulated critical events. AB - OBJECTIVES: Substantial research demonstrates that the stressors accompanying the profession of paramedicine can lead to mental health concerns. In contrast, little is known about the effects of stress on paramedics' ability to care for patients during stressful events. In this study, we examined paramedics' acute stress responses and performance during simulated high-stress scenarios. METHODS: Twenty-two advanced care paramedics participated in simulated low-stress and high stress clinical scenarios. The paramedics provided salivary cortisol samples and completed an anxiety questionnaire at baseline and following each scenario. Clinical performance was videotaped and scored on a checklist of specific actions and a global rating of performance. The paramedics also completed patient care documentation following each scenario. RESULTS: The paramedics demonstrated greater increases in anxiety (P < .05) and salivary cortisol levels (P < .05) in response to the high-stress scenario compared to the low-stress scenario. Global rating scores were significantly lower in the high-stress scenario than in the low-stress scenario (P < .05). Checklist scores were not significantly different between the two scenarios (P = .12). There were more errors of commission (reporting information not present in the scenario) in the patient care documentation following the high-stress scenario than following the low-stress scenario (P < .05). In contrast, there were no differences in omission errors (failing to recall information present in the scenario) between the two scenarios (P = .34). CONCLUSION: Clinical performance and documentation appear vulnerable to the impact of acute stress. This highlights the importance of developing systems and training interventions aimed at supporting and preparing emergency workers who face acute stressors as part of their every day work responsibilities. PMID- 22831964 TI - The impact of MRI white matter hyperintensities on dementia in Parkinson's disease in relation to the homocysteine level and other vascular risk factors. AB - BACKGROUND: The role of white matter hyperintensities (WMH) and homocysteine (Hcy) and other vascular risk factors in the pathogenesis of Parkinson's disease (PD) dementia (PDD) remains unclear. OBJECTIVE: The aim of the study was to assess the impact of WMH, Hcy and other biochemical and vascular risk factors on PDD. METHODS: A total of 192 patients with PD and 184 age- and sex-matched healthy controls were included. A semistructured interview was used to assess demographic and clinical variables with respect to vascular risk factors (arterial hypertension, diabetes mellitus, atrial fibrillation, ischemic heart disease, obliterative atherosclerosis, hypercholesterolemia, smoking, alcohol intake). Unified Parkinson's Disease Rating Scale score, Hoehn-Yahr staging and the Schwab-England activities of daily living scale were used to assess motor abilities and activities of daily living. A complex neuropsychological examination with a battery of tests was used to classify patients into a group with dementia (PDD) and a group without dementia (PD). Neuroradiological examination of MRI scans included visual rating scales for WMH (according to the Wahlund and Erkinjunntti rating scales) and the Scheltens scale for hippocampal atrophy. Blood samples for Hcy, folate, vitamin B12, fibrinogen, lipids, glucose, creatinine, transaminases and thyroid stimulating hormone (TSH) were examined. RESULTS: Among all patients, 57 (29.7%) fulfilled the diagnostic criteria for dementia. Significantly higher Hcy plasma levels were noted in PD and PDD groups compared to controls (p < 0.05) and in PDD when compared to PD (p < 0.05). According to multivariate regression analysis, WMH (Erkinjuntti scale), high Hcy, low vitamin B12 and folate plasma levels were independent risk factors for PDD. Vascular risk factors did not play any role in the pathogenesis of PDD and WMH. CONCLUSIONS: WMH along with Hcy, folate and vitamin B12 may impact cognition in PD. Therapy with vitamin B12, folate and catechol-O-methyltransferase inhibitors may play a potential protective role against PDD. PMID- 22831966 TI - Sulphonamide-induced remission in rheumatoid arthritis--a thought-provoking prescribing error. PMID- 22831968 TI - Global gene expression profiling of human lung epithelial cells after exposure to nanosilver. AB - The toxic effects of silver nanoparticles (AgNPs) on cells are well established, but only limited studies on the effect of AgNPs and silver ions on the cellular transcriptome have been performed. In this study, the effect of AgNPs on the gene expression in the human lung epithelial cell line A549 exposed to 12.1 ug/ml AgNPs (EC20) for 24 and 48h was compared with the response to control and silver ion (Ag(+)) treated cells (1.3 ug/ml) using microarray analysis. Twenty four hours to AgNP altered the regulation of more than 1000 genes (more than twofold regulation), whereas considerably fewer genes responded to Ag(+) (133 genes). The upregulated genes included members of the metallothionein, heat shock protein, and histone families. As expected from the induction of meta l lothionein and heat shock protein genes, Ag(+) and AgNP treatment resulted in intracellular production of reactive oxygen species but did not induce apoptosis or necrosis at the concentrations used in this study. In addition, the exposure to AgNPs influenced the cell cycle and led to an arrest in the G2/M phase as shown by cell cycle studies by flow cytometry and microscopy. In conclusion, although the transcriptional response to Ag(+) exposure was highly related to the response caused by AgNPs, our findings suggest that AgNPs, due to their particulate form, affect exposed cells in a more complex way. PMID- 22831969 TI - Cadmium intake and systemic exposure in postmenopausal women and age-matched men who smoke cigarettes. AB - Mean blood cadmium (B-Cd) concentrations are two- to threefold higher in smokers than in nonsmokers. The basis for this phenomenon is not well understood. We conducted a detailed, multifaceted study of cadmium exposure in smokers. Groups were older smokers (62+/-4 years, n = 25, 20% male) and nonsmokers (62+/-3 years, n = 16, 31% male). Each subject's cigarettes were machine smoked, generating individually paired measures of inhaled cadmium (I-Cd) versus B-Cd; I-Cd and B-Cd were each evaluated three times, at monthly intervals. Urine cadmium (U-Cd) was analyzed for comparison. In four smokers, a duplicate-diet study was conducted, along with a kinetic study of plasma cadmium versus B-Cd. Female smokers had a mean B-Cd of 1.21ng Cd/ml, with a nearly 10-fold range (0.29-2.74ng Cd/ml); nonsmokers had a lower mean B-Cd, 0.35ng Cd/ml (p < 0.05), and narrower range (0.20-0.61ng Cd/ml). Means and ranges for males were similar. Estimates of cadmium amounts inhaled daily for our subjects smoking >= 20 cigarettes/day were far less than the 15 ug Cd reported to be ingested daily via diet. This I-Cd amount was too low to alone explain the 3.5-fold elevation of B-Cd in our smokers, even assuming greater cadmium absorption via lungs than gastrointestinal tract; cadmium accumulated in smokers' lungs may provide the added cadmium. Finally, B-Cd appeared to be linearly related to I-Cd values in 75% of smokers, whereas 25% had far higher B-Cd, implying a possible heterogeneity among smokers regarding circulating cadmium concentrations and potentially cadmium toxicity. PMID- 22831970 TI - Genotoxicity of 2,6- and 3,5-dimethylaniline in cultured mammalian cells: the role of reactive oxygen species. AB - Several alkylanilines with structures more complex than toluidines have been associated epidemiologically with human cancer. Their mechanism of action remains largely undetermined, and there is no reported evidence that it replicates that of multicyclic aromatic amines even though the principal metabolic pathways of P450-mediated hydroxylation and phase II conjugation are very similar. As a means to elucidate their mechanisms of action, lethality and mutagenicity in the adenine phosphoribosyltransferase (aprt (+/-)) gene induced in several Chinese hamster ovary cell types by 2,6- and 3,5-dimethylaniline (2,6-DMA, 3,5-DMA) and their N- and ring-hydroxyl derivatives (N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5 DMAP) were assessed. Dose-response relationships were determined in the parental AA8 cell line, its repair-deficient UV5 subclone and other repair-deficient 5P3NAT2 or -proficient 5P3NAT2R9 subclones engineered to express mouse cytochrome P4501A2 (CYP1A2) and human N-acetyltransferase (NAT2), and also in AS52 cells harboring the bacterial guanine-hypoxanthine phosphoribosyltransferase (gpt) gene. Mutations in the gpt gene of AS52 cells were characterized and found to be dominated by G:C to A:T and A:T to G:C transitions. Separately, treatment of AS52 cells with N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5-DMAP, and 3,5-DMAP led to intracellular production of reactive oxygen species (ROS) for at least 24h after removal of the mutagens in every case. Using the comet assay, DNA strand breaks were observed in a dose-dependent manner in AS52 cells when treated with each of the four N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, and 3,5-DMAP derivatives. Comparative evaluation of the results indicates that the principal mechanism of mutagenic action is likely to be through redox cycling of intracellularly bound aminophenol/quinone imine structures to generate ROS rather than through formation of covalent DNA adducts. PMID- 22831971 TI - Group-level impact of work environment dimensions on burnout experiences among nurses: a multivariate multilevel probit model. AB - BACKGROUND: Nurses' work environments are associated with burnout experiences among nurses. The RN4CAST project provides data on these constructs within a four level structure (nurse, nursing unit, hospital, and country), implying more complicated multilevel analysis strategies than have been used in previous efforts studying this relationship. OBJECTIVES: First, to explore and investigate the effect of the nursing unit, hospital, and country level variability on the relationship between dimensions of nurses' work environment and dimensions of burnout. Second, to explore the significance of the nursing unit, hospital, and country level variability among the burnout dimensions. DESIGN: Data from the RN4CAST project were available from a cross-sectional survey among 23,446 nurses in 2087 nursing units in 352 hospitals in 11 countries. METHODS: Nurse-reported information on their work environment (managerial support for nursing, doctor nurse collegial relations, and promotion of care quality) and burnout experiences (emotional exhaustion, depersonalization and personal accomplishment) were available. We specified ecological measures of the nurse work environment dimensions at the three organizational levels and combined these with individual level outcomes within a series of multilevel statistical models. The final model was a multivariate multilevel probit model in which we modeled the work environment and burnout dimensions jointly. RESULTS: Doctor-nurse collegial relations affected all burnout dimensions, but at the unit level only. For the dimension of promotion of care quality, the effect of the ecological exposure on burnout was pronounced at both the nursing unit and the hospital level for all three burnout dimensions. Findings for the dimensions of managerial support for nursing were ambiguous. CONCLUSION: Nurse work environment dynamics are related to nurses' burnout experiences at both the nursing unit and the hospital level. This implies that both hospital-wide and unit-specific interventions should be considered to achieve excellent work environments. The correlation structure among the three burnout outcomes varies across countries, but is stable between hospitals within countries and between nursing units within hospitals. PMID- 22831972 TI - Next-generation approaches to the microbial ecology of food fermentations. AB - Food fermentations have enhanced human health since the dawn of time and remain a prevalent means of food processing and preservation. Due to their cultural and nutritional importance, many of these foods have been studied in detail using molecular tools, leading to enhancements in quality and safety. Furthermore, recent advances in high-throughput sequencing technology are revolutionizing the study of food microbial ecology, deepening insight into complex fermentation systems. This review provides insight into novel applications of select molecular techniques, particularly next-generation sequencing technology, for analysis of microbial communities in fermented foods. We present a guideline for integrated molecular analysis of food microbial ecology and a starting point for implementing next-generation analysis of food systems. PMID- 22831973 TI - Anticoagulant activities of oleanolic acid via inhibition of tissue factor expressions. AB - Oleanolic acid (OA), a triterpenoid known for its anti-inflammatory and anti cancer properties, is commonly present in several medicinal plants but its anticoagulant activities have not been studied. Here, the anticoagulant properties of OA were determined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrin polymerization as well as cell-based thrombin and activated factor X (FXa) generation activities. Data showed OA prolonged aPTT and PT significantly and inhibited thrombin catalyzed fibrin polymerization. In addition, OA inhibited the activities of thrombin and FXa and inhibited the generation of thrombin or FXa in human endothelial cells. OA also inhibited TNF-alpha-induced tissue factor expression on human endothelial cells. In accordance with these anticoagulant activities, OA showed an anticoagulant effect in vivo. These results indicate that OA possesses antithrombotic activities and suggest that daily consumption of a herb containing OA may be preventing thrombosis in pathological states. PMID- 22831974 TI - Central energy metabolism remains robust in acute steatotic hepatocytes challenged by a high free fatty acid load. AB - Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by an accumulation of lipids (triglycerides) in hepatocytes and is often accompanied by high plasma levels of free fatty acids (FFA). In this study, we compared the energy metabolism in acute steatotic and non-steatotic primary mouse hepatocytes. Acute steatosis was induced by pre incubation with high concentrations of oleate and palmitate. Labeling experiments were conducted using [U-(13)C(5),U-(15)N(2)] glutamine. Metabolite concentrations and mass isotopomer distributions of intracellular metabolites were measured and applied for metabolic flux estimation using transient 13C metabolic flux analysis. FFAs were efficiently taken up and almost completely incorporated into triglycerides (TAGs). In spite of high FFA uptake rates and the high synthesis rate of TAGs, central energy metabolism was not significantly changed in acute steatotic cells. Fatty acid beta-oxidation does not significantly contribute to the detoxification of FFAs under the applied conditions. PMID- 22831975 TI - The inhibitory effects of Nardostachys jatamansi on alcoholic chronic pancreatitis. AB - Nardostachys jatamansi (NJ) belonging to the Valerianaceae family has been used as a remedy for gastrointestinal inflammatory diseases for decades. However, the potential for NJ to ameliorate alcoholic chronic pancreatitis (ACP) is unknown. The aim of this study was to examine the inhibitory effects of NJ on ACP. C57black/6 mice received ethanol injections intraperitoneally for 3 weeks against a background of cerulein-induced acute pancreatitis. During ACP, NJ was ad libitum administrated orally with water. After 3 weeks of treatment, the pancreas was harvested for histological examination. NJ treatment increased the pancreatic acinar cell survival (confirmed by amylase level testing) and reduced collagen deposition and pancreatic stellate cell (PSC) activation. In addition, NJ treatment reduced the activation but not death of PSC. In conclusion, our results suggest that NJ attenuated ACP through the inhibition of PSC activation. PMID- 22831976 TI - Cross-immunizing potential of tumor MAGE-A epitopes recognized by HLA-A*02:01 restricted cytotoxic T lymphocytes. AB - Almost all melanoma cells express at least one member of the MAGE-A antigen family, making the cytotoxic T cells (CTLs) epitopes with cross-immunizing potential in this family attractive candidates for the broad spectrum of anti melanoma immunotherapy. In this study, four highly homologous peptides (P264: FLWGPRALA, P264I9: FLWGPRALI, P264V9: FLWGPRALV, and P264H8: FLWGPRAHA) from the MAGE-A antigens were selected by homologous alignment. All four peptides showed high binding affinity and stability to HLA-A*02:01 molecules, and could prime CTL immune responses in human PBMCs and in HLA-A*02:01/K(b) transgenic mice. CTLs elicited by the four epitope peptides could cross-lyse tumor cells expressing the mutual target antigens, except MAGE-A11 which was not tested. However, CTLs induced by P264V9 and P264I9 showed the strongest target cell lysis capabilities, suggesting both peptides may represent the common CTL epitopes shared by the eight MAGE-A antigens, which could induce more potent and broad-spectrum antitumor responses in immunotherapy. PMID- 22831977 TI - Increased expression of interleukin-1beta in triglyceride-induced macrophage cell death is mediated by p38 MAP kinase. AB - Triglycerides (TG) are implicated in the development of atherosclerosis through formation of foam cells and induction of macrophage cell death. In this study, we report that addition of exogenous TG induced cell death in phorbol 12-myristate 13-acetate-differentiated THP-1 human macrophages. TG treatment induced a dramatic decrease in interleukin-1beta (IL-1beta) mRNA expression in a dose- and time-dependent manner. The expression of granulocyte macrophage colony stimulating factor and platelet endothelial cell adhesion molecule remained unchanged. To identify signaling pathways involved in TG-induced downregulation of IL-1beta, we added p38 MAPK, protein kinase C (PKC) or c-Raf1 specific inhibitors. We found that inhibition of p38 MAPK alleviated the TG-induced downregulation of IL-1beta, whereas inhibition of PKC and c-Raf1 had no effect. This is the first report showing decreased IL-1beta expression during TG-induced cell death in a human macrophage line. Our results suggest that downregulation of IL-1beta expression by TG-treated macrophages may play a role during atherogenesis. PMID- 22831978 TI - 1H NMR-based metabolite profiling of diet-induced obesity in a mouse mode. AB - High-fat diets (HFD) and high-carbohydrate diets (HCD)- induced obesity through different pathways, but the metabolic differences between these diets are not fully understood. Therefore, we applied proton nuclear magnetic resonance ((1)H NMR)-based metabolomics to compare the metabolic patterns between C57BL/6 mice fed HCD and those fed HFD. Principal component analysis derived from (1)H NMR spectra of urine showed a clear separation between the HCD and HFD groups. Based on the changes in urinary metabolites, the slow rate of weight gain in mice fed the HCD related to activation of the tricarboxylic acid cycle (resulting in increased levels of citrate and succinate in HCD mice), while the HFD affected nicotinamide metabolism (increased levels of 1-methylnicotineamide, nicotinamide N-oxide in HFD mice), which leads to systemic oxidative stress. In addition, perturbation of gut microflora metabolism was also related to different metabolic patterns of those two diets. These findings demonstrate that (1)H NMR-based metabolomics can identify diet-dependent perturbations in biological pathways. PMID- 22831979 TI - A critical review of magnetic resonance spectroscopy studies of obsessive compulsive disorder. AB - Functional neuroimaging studies have converged to suggest that cortico-striatal thalamo-cortical (CSTC) circuit dysfunction is a core pathophysiologic feature of obsessive-compulsive disorder (OCD). Now, complementary approaches examining regional neurochemistry are beginning to yield additional insights with regard to the neurobiology of aberrant CSTC circuitry in OCD. In particular, proton magnetic resonance spectroscopy, which allows for the in vivo quantification of various neurochemicals in the CSTC circuit and other brain regions, has recently been used extensively in studies of OCD patients. In this review, we summarize the diverse and often seemingly inconsistent findings of these studies, consider methodological factors that might help to explain these inconsistencies, and discuss several convergent findings that tentatively seem to be emerging. We conclude with suggestions for possible future proton magnetic resonance spectroscopy studies in OCD. PMID- 22831980 TI - Confirmation that the AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. AB - BACKGROUND: Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect. METHODS: In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis. RESULTS: The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]). CONCLUSIONS: Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users. PMID- 22831982 TI - HIPEC in T4a colon cancer: a defendable treatment to improve oncologic outcome? AB - BACKGROUND: Adequate estimation of the potential benefits of 'adjuvant' hyperthermia and intraperitoneal chemotherapy (HIPEC) in T4 patients through assessment of the burden of peritoneal carcinomatosis (PC) in T4 tumors and the risk of PC as the only metastatic site. PATIENTS AND METHODS: Analysis of prospectively collected data on patients who underwent surgery for colon cancer (Jan 2004-Jan 2007). RESULTS: About 379 patients (M/F = 204/175) were included, with a median age of 71.8 years (range 35.4-95.0): 39 stage I, 126 stage II, 89 stage III, 116 stage IV disease (+9 with unknown stage). The median follow-up was 34.8months [range 0.0-79.4]. The 3- and 5-year overall survival rates (OS) were 68.4% (95% confidence interval (CI) 63.9%-72.4%) and 60.3% (95%CI 55.6%-64.7%). Relapse analysis was restricted to stages II-III T3 (N = 154) and T4 tumors (N = 19) with complete relapse data, of which 13.2% developed PC. PC has a detrimental effect on OS [HR 6.3 (95%CI: 3.1-13.0, P < 0.0001)]. 50% of T4a and 20% of T4b developed PC. The 1- and 3-year PC percentage was significantly lower for T3 (4.5% and 9.3%) than T4 tumors (15.6% and 36.7%) (P = 0.008). PC was the only metastatic site in 3/15 T3 [proportion 0.20, 95%CI (0.043-0.481)] and 5/8 T4 tumors with PC [proportion 0.625, 95%CI (0.245-0.915)] (P = 0.071). CONCLUSIONS: T4a colon tumors have a significantly higher risk of developing PC. Twenty-five percent (5/19) of stages II-III T4 tumors develop PC as the only metastatic site. This could define the possible window of opportunity for adjuvant HIPEC to prevent PC. PMID- 22831981 TI - Telomeres and early-life stress: an overview. AB - The long-term sequelae of adverse early-life experiences have long been a focus in psychiatry, with a historic neurobiological emphasis on physiological systems that are demonstrably stress-responsive, such as the hypothalamic-pituitary adrenal axis and neuroimmune function. However, there has been increasing recognition in the general medical literature that such sequelae might encompass more pervasive alterations in health status and physiology. Recent findings in telomere biology have suggested a new avenue for exploring the adverse health effects of childhood maltreatment. Telomere length in proliferative tissues declines with cell replication and the effect can be accelerated by such factors as inflammation, oxidative stress, radiation, and toxins. Reduced telomere length, as a proxy for cellular aging, has been associated with numerous chronic somatic diseases that are generally considered to be diseases of aging, such as diabetes, cancer, and heart disease. More recently, shorter telomeres have been demonstrated in several psychiatric conditions, particularly depression. Sustained psychosocial stress of a variety of types in adulthood appears to be associated with shorter telomeres. Now, emerging work suggests a robust, and perhaps dose-dependent, relationship with early-life stress. These findings present new opportunities to reconceptualize the complex relationships between experience, physical and psychiatric disease, and aging. PMID- 22831983 TI - Glycemic index, glycemic load and cancer risk. AB - BACKGROUND: Dietary glycemic index (GI) and glycemic load (GL) have been related to the risk of selected cancers, but the issue remains open. PATIENTS AND METHODS: Mailed questionnaires were completed between 1994 and 1997 in eight Canadian provinces for incident, histologically confirmed cases of the stomach (n=1182), colon (n=1727), rectum (n=1447), liver (n=309), pancreas (n=628), lung (n=3341), breast (n=2362), ovary (n=442), prostate (n=1799), testis (n=686), kidney (n=1345), bladder (n=1029), brain (n=1009), non-Hodgkin's lymphomas (NHL, n=1666), leukemias (n=1069), multiple myelomas (n=343), and 5039 population controls. Dietary information on eating habits 2 years before participants' enrollment in the study was obtained using a validated food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (CI) were derived by unconditional logistic regression including recognized confounding factors. RESULTS: Dietary GI was positively associated with the risk of prostate cancer (OR, 1.26 for the highest versus the lowest quartile). A higher dietary GL significantly increased the risk of colorectal (OR, 1.28), rectal (OR, 1.44) and pancreatic (OR, 1.41) cancers. No other significant associations were found. CONCLUSIONS: Our findings suggest that a diet high in GI and GL is associated with increased risk of selected cancers. PMID- 22831984 TI - Adjuvant therapy in primary GIST: state-of-the-art. AB - BACKGROUND: The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. MATERIALS AND METHODS: A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. RESULTS: Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. CONCLUSIONS: Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management. PMID- 22831985 TI - Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. AB - BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (>=60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR. PMID- 22831986 TI - Management and challenges of corticosteroid therapy in men with metastatic castrate-resistant prostate cancer. AB - Extensive clinical development in metastatic castrate-resistant prostate cancer (mCRPC) has led to the introduction of three new agents in little more than a year, with more on the horizon. With the exception of autologous cellular immunotherapy, all of the agents approved by the US Food and Drug Administration for the treatment of mCRPC are approved for use in combination with corticosteroids. Corticosteroids play a crucial role in the management of men with mCRPC, but the availability of multiple lines of therapy that include corticosteroids raises potential toxicity considerations. In addition, the immunosuppressive effects of corticosteroids may alter the efficacy of immunotherapies. The recent increase in treatment options with different mechanisms of action raises the importance of understanding how corticosteroids are used and the implications of such use on treatment selection and sequencing. A number of corticosteroids with varied potencies are used in general medical practice at varying doses. The differences in potency, dose, and disease settings in which corticosteroids are used complicate the ability to fully understand the impact that any one corticosteroid can have, such as prednisone in prostate cancer. This article reviews the published literature on corticosteroid use in advanced cancer, focusing on their role in mCRPC. PMID- 22831987 TI - Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium. AB - INTRODUCTION: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3. METHODS: We conducted a multi center phase II trial of cediranib in patients with unresectable, histologically confirmed MM who had received <=1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. RESULTS: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed >=grade 3 hypertension (8.5 vs. 4.1 months, p=0.024). CONCLUSION: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated. PMID- 22831988 TI - Capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective single-center study. AB - BACKGROUND: Palliative chemotherapy is currently the primary therapeutic approach in the treatment of advanced biliary tract cancer (BTC). Our aim was to assess the efficacy and safety of capecitabine plus cisplatin as first-line chemotherapy for patients with advanced BTC and to analyze the relationship between the level of CA19-9 and clinical outcome. METHODS: We retrospectively reviewed the records of patients who had unresectable, metastatic or recurrent BTC who were treated with capecitabine plus cisplatin. Capecitabine was administered orally at a dose of 1,000 mg/m(2) twice a day for 14 days, followed by a 1-week rest period. Cisplatin was administered intravenously on days 1 and 8 at a dose of 30 mg/m(2) for 60 min every 3 weeks. RESULTS: A total of 176 patients were enrolled. Among the 143 assessable patients, 24 (17%) had a partial response. A complete response was radiologically confirmed in 1 patient who had gallbladder cancer. Sixty-two patients (43%) had stable disease and 56 patients (39%) had progressive disease. With a median follow-up of 5.7 months, the median time-to-progression (TTP) was 3.7 months (95% CI 3.1-4.3) and the median overall survival (OS) was 7.4 months (95% CI 6.1-8.7). There was a significant positive correlation between CA19-9 response and TTP (r = 0.66, p = 0.01). CA19-9 response was also significantly correlated with OS (r = 0.57, p < 0.01). The most common grade 3/4 toxicities were nausea/vomiting [12 patients (6.8%)]. CONCLUSIONS: Our results indicate that the capecitabine/cisplatin regimen is well tolerated and has moderate activity against advanced BTC. The CA19-9 response may be a suitable surrogate marker for patients with BTC who are treated with capecitabine/cisplatin. PMID- 22831989 TI - Does bimodal stimulus presentation increase ERP components usable in BCIs? AB - Event-related potential (ERP)-based brain-computer interfaces (BCIs) employ differences in brain responses to attended and ignored stimuli. Typically, visual stimuli are used. Tactile stimuli have recently been suggested as a gaze independent alternative. Bimodal stimuli could evoke additional brain activity due to multisensory integration which may be of use in BCIs. We investigated the effect of visual-tactile stimulus presentation on the chain of ERP components, BCI performance (classification accuracies and bitrates) and participants' task performance (counting of targets). Ten participants were instructed to navigate a visual display by attending (spatially) to targets in sequences of either visual, tactile or visual-tactile stimuli. We observe that attending to visual-tactile (compared to either visual or tactile) stimuli results in an enhanced early ERP component (N1). This bimodal N1 may enhance BCI performance, as suggested by a nonsignificant positive trend in offline classification accuracies. A late ERP component (P300) is reduced when attending to visual-tactile compared to visual stimuli, which is consistent with the nonsignificant negative trend of participants' task performance. We discuss these findings in the light of affected spatial attention at high-level compared to low-level stimulus processing. Furthermore, we evaluate bimodal BCIs from a practical perspective and for future applications. PMID- 22831990 TI - Bruising encounters in veterinary forensics. PMID- 22831991 TI - Bayesian estimation of the true prevalence, sensitivity and specificity of the Rose Bengal and indirect ELISA tests in the diagnosis of bovine brucellosis. AB - Serology is the most convenient method for detecting brucellosis but the efficient use of such tests in disease control requires evaluation of diagnostic performance and discriminative ability. The objective of this study was to assess the performance of the Rose Bengal test (RBT) and an indirect ELISA (iELISA) in diagnosing brucellosis in 995 serum samples collected from cattle in the Ivory Coast between 2005 and 2009. A Bayesian approach was used to evaluate the two tests by estimating their sensitivities and specificities. The correlation adjusted sensitivity of the iELISA was estimated to be 96.1% (credibility interval [CrI], 92.7-99.8), whereas that of the RBT was 54.9% (CrI, 23.5-95.1). High correlation-adjusted specificities were found for both tests (95.0%; [CrI, 91.1-99.6] for the iELISA and 97.7%; [CrI, 95.3-99.4] for the RBT, respectively). The true prevalence of brucellosis was estimated from the serum samples to be 4.6% (95%; [CrI, 0.6-9.5]). The level of agreement between the two tests was evaluated using indices of agreement (n=995). Good agreement was found for negative results (96.6%; confidence interval [CI], 95.7-97.4), a finding supported by an estimated significant correlation of 0.37 (95%; CI, 0.01-0.73) within the sera testing negative. Agreement was lower for sera testing positive (52.2% CI: 41.9-62.5). The findings highlight the importance of using these two tests in combination as part of any brucellosis control programme. PMID- 22831992 TI - Comparison of the virulence of European and North American genotypes of porcine reproductive and respiratory syndrome virus in experimentally infected pigs. AB - The objective of this study was to compare the virulence of Korean types 1 and 2 porcine reproductive and respiratory syndrome virus (PRRSV) isolated from weaned pigs with respiratory disease. Affected pigs were within the same herd and animals infected with type 2 virus had significantly higher mean rectal temperatures than those with type 1 virus between days 2 and 9 post-inoculation (P<0.05). Similarly, mean serum viral titres, expressed as tissue culture infective doses 50% (TCID50)/mL, as well as macroscopic and microscopic pulmonary lesion scores, were significantly higher at multiple time points in pigs infected with type 2 PRRSV compared to those infected with type 1 virus. Mean numbers of PRRSV-positive cells/unit area of lungs and lymph nodes were also significantly higher in type 2 PRRSV infected pigs. This study demonstrates that type 2 PRRSV is more virulent than type 1 PRRSV in this experimental setting as reflected by the pulmonary pathology induced, the extent of virus distribution, and oral shedding of the virus. PMID- 22831993 TI - A simple novel measure of passive transfer of maternal immunoglobulin is predictive of preweaning mortality in piglets. AB - Two factors that contribute to preweaning mortality in piglets are the initiation of lactation by sows and their ability to nurse their piglets. The objective of this study was to determine if the quantification of the transfer of immunoglobulins (Igs) from sow to piglet could act as a measure of these sow factors in terms of their influence on preweaning mortality. To measure passive transfer, a simple, rapid Ig immunocrit method was developed. For validation, the smallest piglets from 204 gilts were sacrificed on day 1 after birth and blood was collected. Piglet serum Ig concentrations were measured three ways: (1) by protein A sepharose precipitation, SDS-PAGE, and densitometry of the IgG heavy chain; (2) by precipitation of Ig with (NH(4))(2)SO(4) followed by spectrophotometric measurement; and (3) by precipitation of Ig with (NH(4))(2)SO(4) and measurement of the ratio of precipitate to sample volume using a hematocrit microcapillary (the Ig immunocrit method). Results from the (NH(4))(2)SO(4) methods correlated (r=0.86) with those obtained using SDS-PAGE. Day 1 weights and immunocrit ratios and preweaning survival data were then collected from every piglet from first (n=90), and second (n=145) parity sows. Bodyweight and immunocrit ratios accounted for 4.8% and 16.7% (P<0.01) of the variation in preweaning mortality, respectively. Litter average immunocrit ratios were not correlated with preweaning mortality. In conclusion, the Ig immunocrit method is a simple, rapid measure of passive transfer from sow to piglet, and is useful in assessing the initiation of colostrum and the nursing ability of sows, and the effect of these events on preweaning piglet mortality. PMID- 22831995 TI - Understanding the role of depression and anxiety on cardiovascular disease risk, using structural equation modeling; the mediating effect of the Mediterranean diet and physical activity: the ATTICA study. AB - PURPOSE: To evaluate the mediating role of behavioral patterns, such as adherence to the Mediterranean diet and physical activity status, in the relationship between depression, anxiety, and the cardiovascular disease (CVD) risk score HellenicSCORE. METHODS: In the context of the ATTICA study, a cross-sectional survey, 453 men (45 +/- 13 years) and 400 women (44 +/- 18 years), with complete psychological evaluation were studied. Participants were without any evidence of cardiovascular or other chronic disease. Depression was assessed with the Zung Self-Rating Depression Scale and anxious state by the Spielberger State Anxiety Inventory Scale. Physical activity was assessed using the International Physical Activity Questionnaire and adherence to the Mediterranean diet was assessed by the MedDietScore. Structural equation modeling methodology was implemented in the statistical analysis. RESULTS: Five latent depression and anxiety factors were revealed and associated with CVD risk score through mediation of physical activity status and adherence to the Mediterranean diet with very good fit to the data (chi(2)/df ratio = 2.34; root mean square error of approximation = 0.021; 90% confidence interval, 0.020-0.022; comparative fit index = 0.951). Significant total effect on CVD risk was found for the "anxiety-worry" latent factor, and this effect was through the inverse relationship of "anxiety-worry" with MedDietScore (P = .002). Moreover, "positive feelings" latent construct was associated with lower CVD risk, and this seems to be through the higher adherence to the Mediterranean diet (P = .01). CONCLUSIONS: Adherence to the Mediterranean diet seems to mediate the unfavorable effect of depression and anxiety on CVD risk. PMID- 22831994 TI - Seroepidemiology of Epstein-Barr virus and cytomegalovirus among Israeli male young adults. AB - PURPOSE: To assess the seroprevalence and seroconversion of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Immunoglobulin G (IgG) antibodies and identify associated socioeconomic and smoking variables among male young adults in Israel, to explore health disparities and aid prevention efforts. METHODS: A population based seroprevalence study of EBV and CMV IgG antibodies in a systematic sample of Israeli males upon recruitment to mandatory military service during 1994-2004. Associations between socioeconomic and smoking variables and the seroprevalence of EBV/CMV were evaluated, controlling for possible confounders. A subset of seronegative subjects was assessed for seroconversion upon discharge from military service. RESULTS: Overall seroprevalence rates were 87% for EBV and 59% for CMV. An association between the seroprevalence of EBV and CMV was observed. Seroconversion was 56% for EBV as compared with 31% for CMV. Lower paternal education was found to be associated with both EBV and CMV seroprevalence. Lower socioeconomic status, North African origin, and urban residence were found to be associated with CMV seropositivity, as was smoking for EBV seropositivity. CONCLUSIONS: Socioeconomic disparities exist in the seroprevalence rates of CMV and EBV among Israeli male young adults. The results of the study could aid public health efforts and determine target populations when a vaccine becomes available. PMID- 22831996 TI - Zeolite Y encapsulated with Fe-TiO2 for ultrasound-assisted degradation of amaranth dye in water. AB - A new heterogeneous catalyst for sonocatalytic degradation of amaranth dye in water was synthesized by introducing titania into the pores of zeolite (NaY) through ion exchange method while Fe (III) was immobilized on the encapsulated titanium via impregnation method. XRD results could not detect any peaks for titanium oxide or Fe(2)O(3) due to its low loading. The UV-vis analysis proved a blue shift toward shorter wavelength after the loading of Ti into NaY while a red shift was detected after the loading of Fe into the encapsulated titanium. Different reaction variables such as TiO(2) content, amount of Fe, pH values, amount of hydrogen peroxide, catalyst loading and the initial dye concentration were studied to estimate their effect on the decolorization efficiency of amaranth. The maximum decolorization efficiency achieved was 97.5% at a solution pH of 2.5, catalyst dosage of 2 g/L, 20 mmol/100 mL of H(2)O(2) and initial dye concentration of 10 mg/L. The new heterogeneous catalyst Fe/Ti-NaY was a promising catalyst for this reaction and showed minimum Fe leaching at the end of the reaction. PMID- 22831997 TI - Evaluation of the stability of uranyl peroxo-carbonato complex ions in carbonate media at different temperatures. AB - This work studied the stability of peroxide in uranyl peroxo carbonato complex ions in a carbonate solution with hydrogen peroxide using absorption and Raman spectroscopies, and evaluated the temperature dependence of the decomposition characteristics of uranyl peroxo carbonato complex ions in the solution. The uranyl peroxo carbonato complex ions self-decomposed more rapidly into uranyl tris-carbonato complex ions in higher temperature carbonate solutions. The concentration of peroxide in the solution without free hydrogen peroxide represents the concentration of uranyl peroxo carbonato complex ions in a mixture of uranyl peroxo carbonato complex and uranyl tris-carbonato complex ions. The self-decomposition of the uranyl peroxo carbonato complex ions was a first order reaction, and its activation energy was evaluated to be 7.144*10(3) J mol(-1). The precipitation of sodium uranium oxide hydroxide occurred when the amount of uranyl tris-carbonato complex ions generated from the decomposition of the uranyl peroxo carbonato complex ions exceeded the solubility of uranyl tris-carbonato ions in the solution at the solution temperature. PMID- 22831998 TI - Sensitive determination of trace mercury by UV-visible diffuse reflectance spectroscopy after complexation and membrane filtration-enrichment. AB - A simple, sensitive and selective solid phase reflectometry method is proposed for the determination of trace mercury in aqueous samples. The complexation reagent dithizone was firstly injected into the properly buffered solution with vigorous stirring, which started a simultaneous formation of nanoparticles suspension of dithizone and its complexation reaction with the mercury(II) ions to make Hg-dithizone nanoparticles. After a definite time, the mixture was filtered with membrane, and then quantified directly on the surface of the membrane by using integrating sphere accessory of the UV-visible spectrophotometer. The quantitative analysis was carried out at a wavelength of 485 nm since it yielded the largest difference in diffuse reflectance spectra before and after reaction with mercury(II).A good linear correlation in the range of 0.2-4.0 MUg/L with a squared correlation coefficient (R(2)) of 0.9944 and a detection limit of 0.12 MUg/L were obtained. The accuracy of the method was evaluated by the analysis of spiked mercury(II) concentrations determined using this method along with those determined by the atomic fluorescence mercury vapourmeter and the results obtained were in good agreement. The proposed method was applied to the determination of mercury in tap water and river water samples with the recovery in an acceptable range (95.7-105.3%). PMID- 22831999 TI - Influence of bioturbation on bioavailability and toxicity of PAHs in sediment from an electronic waste recycling site in South China. AB - The present study examined the effects of bioturbation by the oligochaete Lumbriculus variegatus on bioavailability and toxicity of sediment-associated polycyclic aromatic hydrocarbons (PAHs) to the oligochaete and the epi-benthic amphipod Hyalella azteca. Various densities of L. variegatus in sediment were used to represent different levels of bioturbation. Total sediment concentration declined with increasing worm density, but bioavailability of PAHs estimated using the biomimetic extractions showed no significant difference among treatments with different worm densities. Alternatively, PAH bioaccumulation by L. variegatus decreased and the growth of the worms was reduced at the highest worm density, which was probably due to overcrowding of organisms, food competition and increasing release of PAHs by bioturbation. Additionally, co exposure with high density of L. variegatus to contaminated sediment significantly increased PAH accumulation and mortality of H. azteca. The increased toxicity was probably because of the transport of sediment-associated contaminants to sediment surface and water column by the bioturbation by L. variegatus. Overall, the present study showed that bioturbation may alter the toxicity of contaminants in sediment to other organisms, thus the presence of benthic invertebrates and their interactions with the sediment should be considered in future sediment risk assessment. PMID- 22832000 TI - Food limitation in Chironomus tepperi: effects on survival, sex ratios and development across two generations. AB - Species from the Dipteran family Chironomidae are widely used in laboratory and field studies to identify toxicity in freshwater environments. However, toxicity assessments can be influenced by food availability, which can alter endpoints in assays including viability, sex ratios and development time. The aim of this study was to determine if food limitation affected the endpoints used in toxicity tests with the Australian model organism, Chironomus tepperi, including responses in offspring. First instar larvae were subjected to food treatments with larval density controlled and offspring were either raised under the same food conditions as their parents or under standard conditions. In lower food density treatments adults in the F0 generation experienced delayed emergence and females produced fewer egg masses. F0 diet affected the performance of F1 to continued exposure and there was evidence that the quality of the offspring was compromised. Although sex ratios were not skewed, males and females responded differently to food limitation, especially in the F1 generation where female development was more delayed. These results demonstrate that endpoints used in toxicity evaluation in C. tepperi also respond to food availability, highlighting the need to control for food in both laboratory and field toxicity studies. Multiple generations should ideally be exposed to stressors under laboratory conditions to elucidate likely long term effects in the field. PMID- 22832001 TI - Effects of arsenic on growth and photosystem II (PSII) activity of Microcystis aeruginosa. AB - Effects of arsenic on growth, pigments content, oxygen evolution and photosystem II (PSII) activity of Microcystis aeruginosa were investigated in the present study. Various concentrations of As(III) did not show significant effects on growth and total carotenoids content within 24 h of treatment. After 48 h of treatment, 10 mg L(-1) As(III) significantly inhibited the growth and synthesis of carotenoids of M. aeruginosa, while As(III) at concentrations ranging from 0 to 1 mg L(-1) showed no significant inhibition. Chlorophyll a synthesis, oxygen evolution and chlorophyll fluorescence were more sensitive to As(III) exposure than carotenoid synthesis and growth. Chlorophyll a content, fast fluorescence rise transients and fluorescence decay kinetics appeared to be affected after the cells were exposed to 1 and 10 mg L(-1) As(III) for more than 24 h. Treatment with 10 mg L(-1) As(III) for 24 h or longer led to flattening of the fluorescence transient and drastic decrease of amplitude of fast phase of QA- reoxidation kinetics. Exposure to As(III) mainly inhibited the quantum yield for primary photochemistry, density of reaction centers and photosynthesis performance index, and increased the dissipated energy. The decrease in amplitude of the fast and middle phases further revealed that once electron transfer from QA- to QB was inhibited by As(III), more QA- was reoxidized via S2(QAQB)- charge recombination. As(III) stress may result in an increased stability of the S2QB- and S2QA- recombination. PMID- 22832002 TI - Chelator effects on bioconcentration and translocation of cadmium by hyperaccumulators, Tagetes patula and Impatiens walleriana. AB - French marigold (Tagetes patula) and impatiens (Impatiens walleriana) can act as hyperaccumulator plants for removal of cadmium (Cd) from contaminated sites. In this study, an exponential decay model was used to predict the maximum removal of Cd from artificially spiked soils by impatiens. Application of a chelator, EDTA, was also assessed for effects on the bioconcentration (BCF) and translocation (TF) factors of the two species with four replicates. Exposure to Cd significantly decreased the biomass of two plant species. Impatiens and French marigold accumulated Cd at a rate of 200-1200 mg Cd kg(-1) in shoots, with BCFs and TFs of 8.5-15 and 1.7-2.6, respectively. PMID- 22832003 TI - Accumulation of multiple copies of maize minichromosomes. AB - Multiple copies of B chromosomes in maize (Zea mays) can accumulate in the genome using the B chromosome's accumulation mechanism, specifically nondisjunction at the second pollen mitosis and preferential fertilization of the egg. Using this mechanism, we accumulated 4 different-sized minichromosomes derived from the B chromosome to test the chromosome limits of the cell. The accumulation of normal B chromosomes is associated with multiple phenotypes including white stripes and asymmetric leaf blades, but when minichromosomes are accumulated these symptoms are absent. We also found that multiple B chromosome-derived minichromosomes can coexist with A chromosome-derived minichromosomes. During the years that these experiments were conducted, we found many B chromosome rearrangements and fragments, 2 recoverable A chromosome fragments, and observed a minichromosome breakage-fusion-bridge cycle in roots. PMID- 22832004 TI - Pulse pressure amplification, pressure waveform calibration and clinical applications. AB - Obtaining pulse pressure non-invasively from applanation tonometry requires the calibration of pressure waveform with brachial systolic and diastolic blood pressure. In the literature, several calibration methodologies are applied, and clinical studies disagree about the predictive value of central hemodynamic parameters. Our aim was to compare 4 calibration methodologies and assess the usefulness of pulse pressure amplification as an index independent of calibration. We investigated 108 subjects with tonometry in carotid, femoral, brachial, radial and dorsalis-pedis arteries; pulse pressure amplification between arterial waveforms was calculated. Four methods to calibrate the waveforms were compared: the 1/3 rule, the 40% rule, the integral of radial and brachial waveforms. Pulse pressure amplification in 5 arterial territories (carotid-femoral, carotid-brachial, carotid-radial and carotid-pedis amplifications; femoral-pedis amplification) was studied. Pulse pressure was successfully measured non-invasively at the 5 arterial sites. Pulse pressure was markedly dependent on calibration, with differences up to 18 mmHg between methods. Calculation of pulse pressure amplification eliminated effects of calibration method. Furthermore, pulse pressure amplifications in the 5 arterial sites presented a distinct pattern of clinical/biological determinants: heart rate and body height were common determinants of carotid to brachial, radial and femoral amplifications; diabetes was related to carotid to brachial amplification and pulse wave velocity to femoral to pedis amplification. In conclusion, the calibration of pulse pressure will influence results of clinical trials, but calculation of pulse pressure amplification can avoid this. We also suggest that the alteration of amplification in each arterial territory might be considered as a signal of clinical/subclinical damage. PMID- 22832006 TI - Influence of S. aureus exosecretions on cytokine profile in bovine leukocyte cultures in vitro. AB - The aim of the research was to evaluate the in vitro effect of Staphylococcus aureus exosecretions on the expression of genes encoding IL-2 and IL-12 and secretion of IFN-gamma and TNF-alpha, in bovine leukocyte cultures in vitro. The research was based on 30 S. aureus isolates collected from milk samples from cows with clinical mastitis. Supernatants prepared from the bacterial liquid cultures, which were used to treat leukocytes, were divided into three groups: one with superantigen-like properties, one with leukotoxic-like properties and the one without superantigen or leukotoxic-like properties. The MNC, PMN and MIX (consisted of MNC and PMN leukocytes) cultures were grown and treated with the supernatants. The work shows that the effect on the cytokine gene expression and cytokine secretion caused by S. aureus exosecretions is mainly due to the presence of virulence factors connected with superantigen-like activity and less with leukotoxic-like activity whereas exosecretions of other activity are not or only slightly involved in this process. PMID- 22832007 TI - Editorial overview. PMID- 22832005 TI - Comparison of regional body composition and its relation with cardiometabolic risk between BMI-matched young and old subjects. AB - OBJECTIVE: Difference in regional body composition between young and old people may be related with differential cardiometabolic risks. We investigated regional body composition in BMI-matched young and old subjects to compare its relation with cardiometabolic risk. METHODS: We recruited 1:3 gender- and BMI-matched 86 young subjects (mean age 27.3 +/- 2.9 years) and 258 older subjects (75.6 +/- 8.2 years) from a community. Abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) and muscle area at mid-thigh level were evaluated by computed tomography. Fat depots in the gynoid area and lower extremity were measured by dual energy X ray absorptiometry. Adiponectin, retinol binding protein-4 (RBP-4), and C reactive protein (CRP) concentrations, pulse wave velocity (PWV) and ankle brachial index (ABI) were measured for cardiometabolic risk. RESULTS: VAT was greater in older subjects while SAT was almost the same, resulting in twice higher VAT/SAT ratio in older men and women (1.03 +/- 0.37 and 0.57 +/- 0.18) than younger counterparts (0.55 +/- 0.24 and 0.23 +/- 0.23) (both P < 0.01). Fat mass in the gynoid area and lower extremity was smaller in older subjects than younger subjects. The VAT correlated with adiponectin level negatively and RBP-4 level positively while gynoid fat correlated with them in opposite direction. The CRP levels negatively correlated with mid-thigh muscle in older subjects. Older subjects had higher PWV and lower ABI compared to BMI-matched younger counterparts. CONCLUSION: In conclusion, older adults in this cohort had increased visceral fat and decreased gynoid and lower extremity fat, along with less muscle mass. These findings may help explain the worse cardiometabolic profiles in the elderly who have the same BMI as the young. PMID- 22832008 TI - Per-oral endoscopic myotomy: hope at the end of the tunnel. PMID- 22832009 TI - Management of a dichorionic twin pregnancy with a normal fetus and an androgenetic diploid complete hydatidiform mole. AB - We describe a rare case of complete hydatidiform mole with twin live fetus (CHMTF) confirmed by histopathology, flow cytometry, and polymerase chain reaction techniques. No malformations were observed, fetal karyotype was normal and beta-human chorionic gonadotropin levels were increased (>100,000 IU/ml). Once the patient had been informed of the risks, it was decided to continue the pregnancy, but termination of pregnancy was necessary at week 13 + 5 due to maternal complications consisting of hyperthyroidism, hypertension and vaginal bleeding, followed by persistent trophoblastic disease (PTD). Patients diagnosed with CHMTF should be informed of all known risks, including the considerable risk of PTD, which is similar to - or according to some reports - even higher than that associated with a singleton complete mole and is not increased by continuing pregnancy. Due to the low number of series published, evidence-based clinical management guidelines are lacking. PMID- 22832010 TI - New 1,3,4-bisthiadiazolines: synthesis, characterization and antimicrobial evaluations. AB - The bisthiadiazolines 4a-4g have been synthesized in good yields from the cyclization reactions of bisthiosemicarbazones 3a-3g with acetic anhydride. The condensation reaction of dibenzaldehydes 2a-2g with thiosemicarbazide in alcoholic medium provided 3a-3g and former were obtained from the O-alkylation of 3-hydroxybenzaldehyde with suitable 1,omega-dibromoalkanes under alkaline conditions in the presence of dry EtOH/DMF. The intermediates 3a-3g and bishetrocyclics 4a-4g were also screened for their in vitro antimicrobial activities against seven bacterial strains (Klubsellia pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Straphylococcus aureus, Bacillius subtilis, Pseudomonas fluorescens and Streptoccus pyrogens) and five fungi strains (Aspergillius janus, Pencillium glabrum, Fusarium oxysporum, Aspergillus sclerotiorum, Aspergillus niger). The compounds 3f, 3g, 4f &4g were found to be significantly active against the tested microorganisms. PMID- 22832011 TI - Interaction of S-methyl methanethiosulfonate with DPPC bilayer. AB - The present study is a first step towards the investigation of S-methyl methanethiosulfonate (MMTS) interaction with membrane model systems like liposomes. In this paper, the interaction of MMTS with dipalmitoylphosphatidylcholine (DPPC) bilayers was studied by FTIR and SERS spectroscopy. Lysolipid effect on vesicle stability was studied. The results show that MMTS interacts to different extents with the phosphate and carbonyl groups of membranes in the gel and the liquid crystalline states. To gain a deeper insight into MMTS properties that may be potentially helpful in the design of new drugs with therapeutic effects, we performed theoretical studies that may be the basis for the design of their mode of action. PMID- 22832012 TI - Evolutionary models of extended phenotypes. AB - A variety of theoretical models incorporate phenotypes expressed in the external environment, but a core question is whether such traits generate dynamics that alter evolution. This has proven to be a challenging and controversial proposition. However, several recent modelling frameworks provide insight: indirect genetic effect (IGE) models, niche construction models, and evolutionary feedback models. These distinct approaches converge upon the observation that gene action at a distance generates feedback that expands the range of trait values and evolutionary rates that we should expect to observe in empirical studies. Such conceptual replication provides solid evidence that traits with extended effects have important evolutionary consequences, but more empirical work is needed to evaluate the predictive power of different modelling approaches. PMID- 22832013 TI - Neuron-glial interactions in the developing cerebellum. AB - Advances in microscopy allow one to probe the structure of neurons and their interactions with astrocytes in brain slices and in vivo at ever increasing resolution. Moreover, the dynamic interactions between the cells can be examined in live preparation. In this paper we discuss how a variety of imaging approaches: confocal microscopy, electron microscopy, and multiphoton time-lapse microscopy are employed to probe neuron glia interactions in the developing cerebellum. PMID- 22832014 TI - Functional characterization of two almond C-repeat-binding factors involved in cold response. AB - Low temperature plays a crucial role in seasonal development of woody plants and may directly impact crop production, more particularly in temperate fruit trees. Given its high genetic variability and adaptability to different climatic conditions, almond (Prunus dulcis Mill.) is an interesting model to understand the mechanisms regulating low temperature sensing in fruit trees. In this paper, we report the cloning and characterization of two genes (PdCBF1 and PdCBF2) belonging to the C-repeat-binding factor (CBF) family of transcription factors. Southern blotting analysis showed that this family is composed of at least five members. In almond shoots propagated in vitro, transcription of these genes was rapidly induced by low temperature, suggesting an involvement in cold acclimation. Transactivation assays showed that PdCBF1 and PdCBF2 could bind to dehydration responsive element/C-repeat containing sequences, as activators of gene expression. In addition, induction of both PdCBFs by cold was higher towards the end of the day, which agreed with the expression pattern of PdDehydrin1, a predicted CBF target gene. Furthermore, PdCBF1 and PdCBF2 were also transiently induced by abscisic acid and drought treatments. Considering the bin mapping analysis that correlated PdCBFs and PdDHN1 (respectively in linkage groups 5 and 7) with two different quantitative trait locicontrolling blooming time, it is relevant to perform further association studies that may validate their effect on this trait. PMID- 22832015 TI - Developing and testing methods for deriving preference-based measures of health from condition-specific measures (and other patient-based measures of outcome). AB - OBJECTIVES: Generic preference-based measures such as EQ-5D are widely used to estimate quality-adjusted life-years but may not be available or, more importantly, appropriate in some medical conditions. Condition-specific preference-based measures (CSPBMs) provide an alternative to generic measures that may be more relevant in some conditions. This project conducted five studies to examine issues in the development and use of CSPBMS: (1) literature review of measures; (2) deriving health states values for classifications with highly correlated dimensions; (3) impact of condition labelling; (4) impact of add-on dimensions; and (5) comparative performance of measures. DESIGN: (1) Systematic search and literature review; (2) and (5) psychometric analyses on existing data; (2), (3) and (4) valuation surveys and survey analyses. SETTING: Valuation surveys conducted using face-to-face interviews in the respondents' homes. PARTICIPANTS: Valuation surveys conducted using representative samples of the UK general population. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The project developed a CSPBM CORE-6D and analyses AQL-5D, CORE-6D, EORTC-8D, EQ-5D, OAB-5D and SF-6D data. RESULTS: (1) There was substantial variability in methods used to develop CSPBMs. (2) A new method for generating states using Rasch analysis was undertaken, which successfully dealt with the problem of highly correlated domains. (3) Condition labels affected utility values but this was dependent on the condition and severity of the health state. (4) Adding on an extra dimension affected health-state values and preference weights for other dimensions. (5) The performance of CSPBMs was comparable with that of their parent instrument and of generic preference-based measures with better performance for discrimination between severity groups. CONCLUSIONS: CSPBMs have an important role for economic evaluation, for which generic measures are inappropriate. However, their use in economic evaluation may be compromised by naming the condition; the exclusion of side effects and comorbidities; and focusing effects. Whether a reduction in comparability should be accepted depends on the extent of any gain in validity and responsiveness. This will depend on the condition and measure in question. Research agenda: (1) The appropriateness of generic preference-based measures should be examined in more conditions (and compared with CSPBMs). (2) Further quantitative and qualitative work is requested into the impact of, and reasons for labelling effects. (3) Use of add-ons for condition-specific measures (for side effects and comorbidities) and as a solution to the limitation of generic measures should be explored. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22832016 TI - Bimonthly regimen of high-dose leucovorin, infusional 5-fluorouracil, epirubicin and cisplatin (modified ECF) as adjuvant chemotherapy in resected gastric adenocarcinoma. AB - BACKGROUND: The administration of the de Gramont regimen in combination with cisplatin and epirubicin (modified ECF) has previously been reported as a treatment for advanced gastric cancer, but here we report this regimen combination in an adjuvant setting for the first time. METHODS: Forty-eight patients with curatively resected gastric cancer were treated. Each 2-week cycle consisted of epirubicin (50 mg/m(2)), cisplatin (50 mg/m(2)), 5-fluorouracil (5 FU) IV bolus (400 mg/m(2)) and 5-FU IV (2,400 mg/m(2)) over 46 h plus leucovorin IV (400 mg/m(2)) over 2 h. Postoperative chemoradiotherapy was also administered to the patients when indicated. We retrospectively reviewed the patients who were treated with modified ECF. RESULTS: The median disease-free survival (DFS) was 40.7 months and the 1-, 3- and 5-year DFS rates were 78.5, 55.7 and 44.6%, respectively. The most common grade 3-4 toxicities were hematological and gastrointestinal. CONCLUSION: A modified ECF regimen may be an effective and convenient treatment with tolerable toxicities for the adjuvant treatment of gastric cancer. It may provide an alternative regimen to the standard ECF when a continuous ambulatory infusion pump is not feasible or not preferred by the patient. PMID- 22832017 TI - Exploring motion VEPs for gaze-independent communication. AB - Motion visually evoked potentials (mVEPs) have recently been explored as input features for brain-computer interfaces, in particular for the implementation of visual spellers. Due to low contrast and luminance requirements, motion-based intensification is less discomforting to the user than conventional approaches. So far, mVEP spellers were operated in the overt attention mode, wherein eye movements were allowed. However, the dependence on eye movements limits clinical applicability. Hence, the purpose of this study was to evaluate the suitability of mVEPs for gaze-independent communication. Sixteen healthy volunteers participated in an online study. We used a conventional speller layout wherein the possible selections are presented at different spatial locations both in the overt attention mode (fixation of the target) and the covert attention mode (central fixation). Additionally, we tested an alternative speller layout wherein all stimuli are sequentially presented at the same spatial location (foveal stimulation), i.e. eye movements are not required for selection. As can be expected, classification performance breaks down when switching from the overt to the covert operation. Despite reduced performance in the covert setting, conventional mVEP spellers are still potentially useful for users with severely impaired eye movements. In particular, they may offer advantages--such as less visual fatigue--over spellers using flashing stimuli. Importantly, the novel mVEP speller presented here recovers good performance in a gaze-independent setting by resorting to the foveal stimulation. PMID- 22832018 TI - Secretory carcinoma of breast: clinicopathologic study of 8 cases. AB - Our aim was to describe clinicopathologic features of secretory carcinoma on a cohort of cases. We retrieved reported cases of secretory carcinoma of breast (SCB) in the Section of Histopathology, Department of Pathology & Microbiology, Aga Khan University Hospital Karachi, from May 2004 to December 2011. The slides were reviewed, and clinicopathologic features were noted. A total of 8 cases of SCB were found. The age ranged from 17 to 60 years (median, 41 years) with a female to male ratio of 7:1. Lumpectomy was done in 6 cases, and mastectomy, in 2 cases. The tumor size ranged from 2.5 to 10 cm (mean, 5.5 cm). Histologically, abundant extra- and intracellular secretory material was seen in all cases. Most of the tumors showed mixtures of patterns with dominant microcystic and papillary patterns. In situ component was seen in only 1 case. Lymph node metastases were seen in both cases with lymph node sampling. In conclusion, SCB is a rare type of ductal breast carcinoma. The papillary pattern of SCB is rare according to published data but was seen in most of our cases. In situ secretory carcinoma is even rarer, and to date, we have seen a single case only. Although most occur in women, these can be seen in men as well. PMID- 22832019 TI - Epidemiological and clinical features of cutaneous leishmaniases in Jenin District, Palestine, including characterisation of the causative agents in clinical samples. AB - During 2002-2009, 466 cases of cutaneous leishmaniasis (CL) were reported from Jenin District, Palestine, affecting both genders. The average annual incidence was 23 cases per 100000 inhabitants, increasing with age in children. Most cases presented a single lesion, generally on the face. Diagnosis and species identification was done by applying internal transcribed spacer 1 (ITS1) RFLP analysis to 47 isolates, of which 44 (93.6%) were Leishmania tropica and 3 (6.4%) were L. major. RFLP analysis was also performed on 256 skin tissue scrapings spotted onto filter papers, showing that 138 (53.9%) were positive, of which 50.7% were infected with L. tropica, 17.4% with L. major and 2.9% with L. donovani s.l., and 29.0% could not be identified. This is the first report from Palestine on human CL caused by L. infantum. Nine of the strains of L. tropica were subjected to multilocus enzyme electrophoresis, six of which belonged to the zymodeme MON-137 and three to a new zymodeme (MON-307). This separation was corroborated by excreted factor serotyping. This observation modifies the classical epidemiological view of CL in Palestine. Jenin District is an active focus of CL caused by L. tropica, where Phlebotomus sergenti, the putative vector, is abundant. These data suggest that CL is a zoonotic infection, but an animal reservoir has not been found. PMID- 22832020 TI - Prevalence and genetic diversity of Bartonella species in sika deer (Cervus nippon) in Japan. AB - We report the first description of Bartonella prevalence and genetic diversity in 64 Honshu sika deer (Cervus nippon centralis) and 18 Yezo sika deer (Cervus nippon yesoensis) in Japan. Overall, Bartonella bacteremia prevalence was 41.5% (34/82). The prevalence in wild deer parasitized with ticks and deer keds was 61.8% (34/55), whereas no isolates were detected in captive deer (0/27) free of ectoparasites. The isolates belonged to 11 genogroups based on a combination of the gltA and rpoB gene sequences. Phylogenetic analysis of concatenated sequences of the ftsZ, gltA, ribC, and rpoB genes of 11 representative isolates showed that Japanese sika deer harbor three Bartonella species, including B. capreoli and two novel Bartonella species. All Yezo deer's isolates were identical to B. capreoli B28980 strain isolated from an elk in the USA, based on the sequences of the ftsZ, gltA, and rpoB genes. In contrast, the isolates from Honshu deer showed a higher genetic diversity. PMID- 22832021 TI - Recommendations for the reporting of foot and ankle models. AB - Multiple marker sets and models are currently available for assessing foot and ankle kinematics in gait. Despite the presence of such a wide variety of models, the reporting of methodological designs remains inconsistent and lacks clearly defined standards. This review highlights the variability found when reporting biomechanical model parameters, methodological design, and model reliability. Further, the review clearly demonstrates the need for a consensus of what methodological considerations to report in manuscripts, which focus on the topic of foot and ankle biomechanics. We propose five minimum reporting standards, that we believe will ensure the transparency of methods and begin to allow the community to move towards standard modelling practice. The strict adherence to these standards should ultimately improve the interpretation and clinical useability of foot and ankle marker sets and their corresponding models. PMID- 22832022 TI - Evaluating the effectiveness of a memory aid system. AB - BACKGROUND: The ability to remember future intentions is compromised in both healthy and cognitively impaired older adults. Assistive technology provides older adults with promising solutions to cope with this age-related problem. However, the effectiveness and efficiency of such systems as memory aids is seldom evaluated in controlled, randomized trials. OBJECTIVES: We evaluated the effectiveness of a memory aid system, the InBad (engl. InBath), for bathroom related daily care. Conceptually, the InBad learns user behavior patterns and detects deviations from the learned pattern in order to notify the user of a forgotten task. METHODS: We simulated a challenging morning routine consisting of 22 bathroom activities with a sample of 60 healthy older adults. Participants were randomly assigned to three groups: (1) 'no memory support', i.e., participants received no support at all, (2) 'list support', i.e., participants could retrieve a list of all activities, and (3) 'system support', i.e., participants received prompts for specific activities that had not yet been executed. RESULTS: Both support groups executed significantly more activities compared to the 'no support' group. In addition, system support resulted in significantly better performance compared to list support with no significant differences between the two groups in overall task duration. CONCLUSION: The assistive support system was the most effective and efficient memory aid. The results suggest that assistive technology has the potential to enable older adults to remain safe and independent in their own home. PMID- 22832023 TI - Comparative analyses in Lotus: the cytogenetic map of Lotus uliginosus Schkuhr. AB - A comparative cytogenetic map was built for Lotusuliginosus (2n = 12), expanding previous analyses that revealed intra- and interspecific chromosomal rearrangements in the model legume L. japonicus, L. filicaulis, and L. burttii. This species is positioned in a sister clade of the previously-mapped species and is proposed as one of the progenitors of L. corniculatus, the main forage crop of the genus. The cytogenetic map allowed the location of 12 genomic regions to be compared between these species. A high macrosynteny was revealed, but it was interrupted by a translocation involving chromosomes 3 and 5, a new rearrangement for the genus. Also, a transposition on chromosome 2 was found in L. japonicus 'Miyakojima'. Furthermore, changes in the number, size, and position of rDNA sites were observed, as well as an intraspecific size heteromorphism of the 5S rDNA site on L. uliginosus chromosome 6. The karyotype differences observed are proportional to the phylogenetic distance among these species. PMID- 22832024 TI - Crystal structure of a minimal eIF4E-Cup complex reveals a general mechanism of eIF4E regulation in translational repression. AB - Cup is an eIF4E-binding protein (4E-BP) that plays a central role in translational regulation of localized mRNAs during early Drosophila development. In particular, Cup is required for repressing translation of the maternally contributed oskar, nanos, and gurken mRNAs, all of which are essential for embryonic body axis determination. Here, we present the 2.8 A resolution crystal structure of a minimal eIF4E-Cup assembly, consisting of the interacting regions of the two proteins. In the structure, two separate segments of Cup contact two orthogonal faces of eIF4E. The eIF4E-binding consensus motif of Cup (YXXXXLPhi) binds the convex side of eIF4E similarly to the consensus of other eIF4E-binding proteins, such as 4E-BPs and eIF4G. The second, noncanonical, eIF4E-binding site of Cup binds laterally and perpendicularly to the eIF4E beta-sheet. Mutations of Cup at this binding site were shown to reduce binding to eIF4E and to promote the destabilization of the associated mRNA. Comparison with the binding mode of eIF4G to eIF4E suggests that Cup and eIF4G binding would be mutually exclusive at both binding sites. This shows how a common molecular surface of eIF4E might recognize different proteins acting at different times in the same pathway. The structure provides insight into the mechanism by which Cup disrupts eIF4E-eIF4G interaction and has broader implications for understanding the role of 4E-BPs in translational regulation. PMID- 22832025 TI - Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage. AB - The removal of intervening sequences (introns) from a primary RNA transcript is catalyzed by the spliceosome, a large ribonucleoprotein complex. At the start of each splicing cycle, the spliceosome assembles anew in a sequentially ordered manner on the pre-mRNA intron to be removed. We describe here the identification of a series of naphthalen-2-yl hydroxamate compounds that inhibit pre-mRNA splicing in vitro with mid- to high-micromolar values of IC(50). These hydroxamates stall spliceosome assembly at the A complex stage. A structure activity analysis of lead compounds revealed three pharmacophores that are essential for splicing inhibition. Specifically, a hydroxamate as a zinc-binding group and a 6-methoxynaphthalene cap group are both critical, and a linker chain comprising eight to nine methylene groups is also important, for the specific binding to the docking site of a target protein molecule and precise positioning of the zinc binding group. As we found no correlation between the inhibition patterns of known histone deacetylases on the one hand and pre-mRNA splicing on the other, we conclude that these compounds may function through the inhibition of the activities of other, at present, unknown spliceosome-associated zinc metalloprotein(s). PMID- 22832026 TI - RNA editing of protein sequences: a rare event in human transcriptomes. AB - RNA editing, the post-transcriptional recoding of RNA molecules, has broad potential implications for gene expression. Several recent studies of human transcriptomes reported a high number of differences between DNA and RNA, including events not explained by any known mammalian RNA-editing mechanism. However, RNA-editing estimates differ by orders of magnitude, since technical limitations of high-throughput sequencing have been sometimes overlooked and sequencing errors have been confounded with editing sites. Here, we developed a series of computational approaches to analyze the extent of this process in the human transcriptome, identifying and addressing the major sources of error of a large-scale approach. We apply the detection pipeline to deep sequencing data from lymphoblastoid cell lines expressing ADAR1 at high levels, and show that noncanonical editing is unlikely to occur, with at least 85%-98% of candidate sites being the result of sequencing and mapping artifacts. By implementing a method to detect intronless gene duplications, we show that most noncanonical sites previously validated originate in read mismapping within these regions. Canonical A-to-G editing, on the other hand, is widespread in noncoding Alu sequences and rare in exonic and coding regions, where the validation rate also dropped. The genomic distribution of editing sites we find, together with the lack of consistency across studies or biological replicates, suggest a minor quantitative impact of this process in the overall recoding of protein sequences. We propose instead a primary role of ADAR1 protein as a defense system against elements potentially damaging to the genome. PMID- 22832027 TI - T-cell receptor excision circles and repertoire diversity in children with profound T-cell immunodeficiency. AB - BACKGROUND/PURPOSE(S): Approximately 40% of patients with profound T-cell immunodeficiency have no identified molecular basis. Early assessment of T-cell impairment is vital for medical intervention, if hematopoietic stem cell transplantation is needed. The dynamics of T-cell receptor excision circles (TRECs) revealing recent thymic output of naive T cell and T-cell receptor (TCR) repertoire diversity reflecting broader responses to multiple antigens, are both important in resisting infections. METHODS: The TRECs value and TCR repertoire diversity were evaluated from peripheral blood mononuclear cells in patients with primary severe T cell immunodeficiency, to elucidate the T-cell response. RESULTS: In seven children with <30% of normal phytohemagglutinin (PHA) stimulated lymphocyte proliferation, including two IL2RG (Try74Gly and Arg226Lys, X-linked) and one RAG2 mutations [(Ser205Tyr) and (del 1366T, frameshift, 484stop); autosomal recessive], lower TRECs value and oligo- and restricted TCR diversity patterns, were associated with increased susceptibility to opportunistic infections, but not inversely correlated to the severity and frequency of infections. Three patients had successful cord blood stem cell transplantation which reconstructed the T cell immunodeficiency, with normalized TRECs value and TCR repertoire diversity at 6 months post-transplant, without clinical events. CONCLUSION: Low TRECs value and restricted TCR repertoire diversity can help in the early diagnosis of T cell immunodeficiency before irreversible sequelae and in the monitoring of post-transplantation T-cell immune reconstruction. PMID- 22832028 TI - Clinical characteristics and outcome of patients with community-onset Klebsiella pneumoniae bacteremia requiring intensive care. AB - BACKGROUND: Klebsiella pneumoniae (K. pneumoniae) is the major pathogen of community-acquired pyogenic infections in Taiwan and can lead to poor prognosis in critically ill patients complicated with bacteremia. This study investigated the characteristics and outcome of patients with community-onset K. pneumoniae bacteremia who required intensive care. METHOD: Adult patients with community onset K. pneumoniae bacteremia requiring intensive care were retrospectively analyzed, compared with those treated in ordinary wards, and determined for risk factors for infection-related mortality and long-term mortality at a medical center in Taiwan over a 3-year period. RESULTS: Among the 309 patients with community-onset K. pneumoniae bacteremia, 58 patients (18.8%) required intensive care. Respiratory tract infection [Odds ratio (OR) = 3.67, 95% confidence interval (CI) = 1.79-7.50, p < 0.001] was the independent risk factor for ICU admission. Infection-related mortality was 34.5%. Higher APACHE II score (OR = 1.43; 95% CI = 1.02-2.01; p = 0.041) and underlying malignant neoplasm (OR = 35.48; 95% CI = 2.54-495.57; p = 0.008) were independent predictors of infection related mortality on multivariate logistic regression. One-year overall mortality was 58.6% and malignant neoplasm was the predisposing factor for poor long-term outcome. CONCLUSION: Nearly one fifth of patients with community-onset K. pneumoniae bacteremia required intensive care and this was associated with high mortality and poor long-term prognosis. Physicians should recognize the distinct characteristics and risk factors for mortality among these patients. PMID- 22832030 TI - [Efficacy of prophylactic treatment of intraocular pressure spikes due to intravitreal injections]. AB - PURPOSE: The purpose of this study was to evaluate intraocular pressure increase after intravitreal injections (IVIs) and the effect of prophylactic pressure lowering medications. METHODS: A prospective study of 210 anti-vascular endothelial growth factor (VEGF) IVI (0.05 mL of bevacizumab or ranibizumab), that were divided into five groups, group 1: no intraocular pressure (IOP) lowering medication (n=50); group 2: apraclonidine 1 % one drop 2 hours prior to IVI (n=50); group 3: acetazolamide 250 mg 2 hours prior (n=50); group 4: fixed combination brimonidine+timolol (n=30); group 5: fixed combination dorzolamide+timolol (n=30). IOP was measured before, immediately after (T1), 15 min after (T15) and 45 min after (T45) the IVI using a Perkins tonometer. RESULTS: The mean IOP peak in group 1 was 46.4 +/- 4.8 mmHg at T1, 21.7 +/- 5.7 mmHg at T15 and 15.4 +/- 4.3 mmHg at T45. Apraclonidine 1 % and the fixed combinations produced a significant reduction of IOP at every time point, of around 9 mmHg at T1. The reduction in IOP obtained with acetazolamide was not significant versus group 1 at T1 (-1.6 mmHg, P=0.12), but became significant at T15 and T45 (respectively, P=0.011 and P=0.015). CONCLUSIONS: IOP spikes are high but transient following IVI. Acetazolamide proved to be ineffective in preventing this spike. Topical medications, however, produced a significant reduction in IOP spike as well as in the duration of the increased pressure, with no significant difference between fixed combinations and 1 % apraclonidine at T1. It would seem advisable to prevent this IOP spike in the case of repeated injections, particularly in patients with glaucoma. PMID- 22832032 TI - Lingual electrotactile stimulation as an alternative sensory feedback pathway for brain-computer interface applications. AB - This article describes a new method of providing feedback during a brain-computer interface movement task using a non-invasive, high-resolution electrotactile vision substitution system. We compared the accuracy and movement times during a center-out cursor movement task, and found that the task performance with tactile feedback was comparable to visual feedback for 11 participants. These subjects were able to modulate the chosen BCI EEG features during both feedback modalities, indicating that the type of feedback chosen does not matter provided that the task information is clearly conveyed through the chosen medium. In addition, we tested a blind subject with the tactile feedback system, and found that the training time, accuracy, and movement times were indistinguishable from results obtained from subjects using visual feedback. We believe that BCI systems with alternative feedback pathways should be explored, allowing individuals with severe motor disabilities and accompanying reduced visual and sensory capabilities to effectively use a BCI. PMID- 22832033 TI - In vitro activity of tigecycline and molecular characterization of extended spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates from a university hospital in south-western Germany. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing organisms are spreading worldwide in hospital and community settings. METHODS: A total of 328 unduplicated ESBL-producing Enterobacteriaceae isolated in 2008 and 2009 at the University Hospital of Tubingen were analysed retrospectively. RESULTS: Escherichia coli (n = 253) and Klebsiella spp. (n = 46) were the most frequent ESBL-producing species. The ESBL rates among E. coli and Klebsiella spp. increased from 3.8 and 2.1%, respectively, in 2008, to 5.2 and 2.4%, respectively, in 2009. Two E. coli and 3 Klebsiella pneumoniae ESBL producers were non-susceptible to ertapenem, most likely due to loss of porins. Antimicrobial susceptibility testing of selected, molecularly characterized ESBL producers revealed susceptibility to tigecycline among 97.9% (191/195) of the E. coli and 78.8% (26/33) of the K. pneumoniae isolates. PCR analysis and sequencing showed the presence of CTX-M-type enzymes in 91.3% of the E. coli and 87.9% of the K. pneumoniae isolates, whereby bla(CTX-M-15) was the most frequent ESBL gene both in E. coli (50.0%) and K. pneumoniae (51.5%). Only 7 single cases of potential patient-to-patient transmissions of E. coli strains were observed. CONCLUSIONS: Our data suggest that the increase in ESBL-producing E. coli and K. pneumoniae isolates at our hospital is mainly caused by growing import of Enterobacteriaceae harbouring CTX-M-type ESBLs. PMID- 22832034 TI - Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous esomeprazole in children 0 to 17 years of age. AB - BACKGROUND: Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. OBJECTIVE: The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. METHODS: In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6 11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. RESULTS: Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(tau) ranged from 6.9 MUmol . h/L (10 mg, 6-11 years) to 17.6 MUmol . h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 MUmol/L (0.5 mg/kg, 0-1 month) to 10.5 MUmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. CONCLUSIONS: Intravenous esomeprazole at doses resulting in targeted AUC(tau) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019. PMID- 22832035 TI - Low 25-hydroxyvitamin D levels and low bone density assessed by quantitative ultrasonometry in a cohort of postmenopausal Italian nuns. AB - This study was aimed at evaluating the effect of clothing style on bone mass and fractures in 70 postmenopausal nuns residing in a monastery in Naples. Sixty healthy women matched for age, body mass index, and menopausal status were enrolled as controls. Each participant underwent measurement by quantitative ultrasonometry (QUS) using a DBM Sonic Bone Profiler (IGEA S.p.A., Carpi, Modena, Italy) at proximal phalanges, responded to questionnaires regarding lifestyle, calcium intake, medical history, including clinical fragility fractures, and was submitted to routine biochemical assessment. A significant reduction in ultrasonometric parameters of bone mass was found in nuns compared with controls (p from 0.007 to <0.0001). 25-hydroxyvitamin D (25-OH vit D) levels were reduced by more than 50% in nuns (9.8 +/- 4.2 vs 23.5 +/- 5.7 nmol/L; p < 0.0001), whereas their estimated daily calcium intake was higher (1.004 +/- 0.23 vs 0.721 +/- 0.25 g of controls; p = 0.0007). Age at menopause was significantly lower in nuns' group (p = 0.016). Incidence of fractures was higher in nuns (39% vs 10%; p = 0.0029), and the best predictors of fractures were age at menopause (odds ratio [OR]: 1.12; 95% confidence interval [CI]: 1.01-1.30), amplitude-dependent speed of sound T-score (OR: 1.15; 95% CI: 1.03-1.63), and bone transmission time T score (OR: 1.30; 95% CI: 1.15-1.81). This study documented low 25-OH vit D levels, increased frequency of clinical fractures, and low bone mass detected by QUS in Southern Italian nuns. PMID- 22832036 TI - The effect of 99mTc on dual-energy X-ray absorptiometry measurement of body composition and bone mineral density. AB - Whether the gamma-emission by radioisotopes influences the outcome of dual-energy X-ray absorptiometry (DXA) measurements is not fully elucidated. The aim of this study was to evaluate the effect of antecedent administration of 99mTc on DXA measurements regarding body composition and bone mineral density (BMD) using a K edge filter scanner. The phantom measurements were performed by placing a urinary bladder phantom containing 40 mL of radioisotope solution on the pelvic region of a whole-body phantom. Twenty-seven patients attending our department for a routine examination involving the administration of a tracer marked with 99mTc were included. The patients underwent a whole-body DXA scan before and within 2 h after tracer injection using a GE/Lunar Prodigy scanner. Control scans were performed on 40 volunteers, who had not received any radioactive tracer. In both phantom and patient measurements, we found a significant dose-related decrease in fat mass and BMD and a corresponding increase in fat-free mass (p < 0.001). Based on the linear regression analysis, we suggest upper dose limits for the measurement of BMD at 0.77 MUSv/h and body composition at 0.21 MUSv/h (dose rate measured at a distance of 1m from the patient). Caution should be taken when interpreting the results of DXA scans performed in close temporal proximity to procedures involving the administration of 99mTc. PMID- 22832037 TI - In vitro and in vivo entrapment of bupivacaine by lipid dispersions. AB - Intravenous lipid emulsion is recommended as treatment for local anesthetic intoxication based on the hypothesis that the lipophilic drug is entrapped by the lipid phase created in plasma. We compared a 15.6 mM 80/20 mol% phosphatidyl choline (PC)/phosphatidyl glycerol (PG)-based liposome dispersion with the commercially available Intralipid(r) emulsion in a pig model of local anesthetic intoxication. Bupivacaine-lipid interactions were studied by electrokinetic capillary chromatography. Multilamellar vesicles were used in the first in vivo experiment series. This series was interrupted when the liposome dispersion was discovered to cause cardiovascular collapse. The toxicity was decreased by an optimized sonication of the 50% diluted liposome dispersion (7.8 mM). Twenty anesthetized pigs were then infused with either sonicated PC/PG liposome dispersion or Intralipid(r), following infusion of a toxic dose of bupivacaine which decreased the mean arterial pressure by 50% from baseline. Bupivacaine concentrations were quantified in blood samples using liquid chromatography/mass spectrometry. No significant difference in the context-sensitive plasma half-life of bupivacaine was detected (p=0.932). After 30 min of lipid infusion, the bupivacaine concentration was 8.2+/-1.5 mg/L in the PC/PG group and 7.8+/-1.8 mg/L in the Intralipid(r) group, with no difference between groups (p=0.591). No difference in hemodynamic recovery was detected between groups (p > 0.05). PMID- 22832038 TI - High-resolution optical imaging of zebrafish larval ribbon synapse protein RIBEYE, RIM2, and CaV 1.4 by stimulation emission depletion microscopy. AB - The synaptic ribbon is a unique presynaptic structure with an intricate morphology in photoreceptors. Because of the resolution limit in conventional fluorescence microscopy, investigating ribbon protein locations has been challenging, especially in the early development stages of model animals. Here, we used stimulated emission depletion microscopy, a super-resolution imaging technique, to look at retina sections in 4 days post-fertilization (dpf) zebrafish. We observed that in photoreceptor cells, RIBEYE and RIM2 are expressed along the synaptic ribbon, with RIM2 consistently located inside of the horseshoe shaped synaptic ribbon structure with RIBEYE located on the outside. The L-type calcium channel subunit, CACNA1F, exhibited small spot-like staining beneath the RIM2 and RIBEYE structures. Using morpholino antisense oligonucleotides to knock down RIBEYE expression, we observed fewer and shorter ribbons in the photoreceptor outer plexiform layers of 4 dpf fish retina as well as a reduction in RIM2 expression. The clustering of CACNA1F in these blind fish was no longer observed, but instead showed a diffuse expression in the photoreceptor terminal. PMID- 22832039 TI - Adipokine adipsin is associated with the degree of lung fibrosis in asbestos exposed workers. AB - OBJECTIVES: Asbestos-exposure causes an inflammatory response driven by alveolar macrophages that can lead to pulmonary fibrosis. In addition to classical inflammatory cytokines, macrophages produce adipokines which regulate the inflammatory response. We studied if adipokines are related to the degree of parenchymal fibrosis, impaired lung function and inflammation in asbestos-exposed subjects. METHODS: Eighty-five males with moderate to heavy occupational exposure to asbestos and unexposed controls were studied. We measured plasma levels of adipokines adiponectin, adipsin, leptin and resistin, IL-6, IL-8, erythrocyte sedimentation rate (ERS), spirometry and D(L,CO). Degree of interstitial lung fibrosis (septal thickening, subpleural lines, parenchymal bands or honeycombing) was scored in classes 0-5 according to a validated scoring system. The subjects were divided into three groups: normal parenchymal finding (fibrosis class 0), borderline changes (classes 0.5-1.5) and fibrosis (i.e. asbestosis; classes 2-5). RESULTS: Adipsin correlated positively with parenchymal fibrosis (rho=0.412, p<0.001) and there was a linear increasing trend of mean plasma adipsin levels among the three groups of asbestos-exposed subjects (from normal parenchymal finding to borderline changes and to fibrosis) (p<0.0001). Accordingly, plasma adipsin levels correlated positively with the extent of pleural plaques (r=0.245, p=0.043), and negatively with D(L,CO) (r=-0.246, p=0.023). Also, a positive correlation was found between adipsin and inflammatory markers ESR (r=0.315, p=0.008) and IL-6 (r=0.256, p=0.018). CONCLUSIONS: Adipsin was associated with the degree of parenchymal fibrosis, impairment of pulmonary diffusing capacity and with inflammatory activity in asbestos-exposed subjects suggesting that adipsin may have a role in the pathogenesis or as a biomarker in asbestos-induced lung disease. PMID- 22832040 TI - Fast intraoperative testosterone assay confirms the location of an ovarian virilizing tumor in a young girl. AB - The detection of testosterone-producing ovarian tumors in childhood and adolescence by imaging techniques only can be difficult because of the tumors' radiological structure and sometimes diminutive size. We describe an 11.5-year old girl with a 9-month history of voice deepening, mild hirsutism, minor acne, increased growth velocity, weight gain, and clitoromegaly. Laboratory investigation revealed an extremely elevated serum testosterone level without any additional endocrine abnormalities. Abdominal ultrasound and MRI showed a sparsely noticeable solid mass in the center of the right ovary. At laparotomy, blood was selectively drawn from the right and the left ovarian veins. Rapid testosterone measurement revealed a 70-fold higher testosterone concentration in the right ovarian vein within 45 min. Based on this finding, a right salpingo oophorectomy was performed. The patient's postoperative testosterone level declined within 24 h. The histopathological diagnosis was Leydig cell tumor. In conclusion, the implementation of a fast intraoperative testosterone assay enabled the localization and curative therapy of a Leydig cell tumor. This technique seems to be a good alternative to preoperative selective venous blood sampling when body imaging does not unveil the tumor's site. PMID- 22832041 TI - [Clinical and metabolic effectiveness of a new motivational therapy for the treatment of obesity in adolescents (OBEMAT)]. AB - INTRODUCTION: The mainstay of the treatment of childhood obesity is the promotion of behavioural changes, which are especially difficult during adolescence. This paper proposes and evaluates a new motivation-based therapeutic protocol, structured in objectives, which is applicable from paediatric practice. PATIENTS AND METHODS: A total of 110 obese adolescents were studied. The therapeutic protocol consisted of 12 monthly visits, in two phases: Motivational and Interventional, in which changes were proposed and objectives were agreed, and later evaluated taking into account the difficulties and achievements. Weight and height was measured in each visit, and blood pressure, waist circumference, glucose, insulin and lipid profile were measured at the beginning and at the end. RESULTS: There was a mean decrease of 0.5 SDS in BMI z-score in the adolescents who completed the intervention (78.2%), with this decrease being 0.8 SDS in the group of patients with good response to treatment (75.6%). This group had a significantly lower total cholesterol, LDL, triglycerides, insulin and HOMA index. The main predictor of good response was the success of the motivational phase, with a positive predictive value of 95% (83-98%). CONCLUSIONS: BMI z-score decreases and the control of anthropometric and biochemical parameters, show that OBEMAT is a highly effective method compared to those published previously. The response to the motivational phase largely determines the success or failure of the intervention. PMID- 22832043 TI - Neonatal intensive care unit graduate home visit: a learning opportunity for pediatric interns. PMID- 22832044 TI - 50 years ago in the Journal of Pediatrics: the intestinal flora of infants and children with diarrhea. PMID- 22832045 TI - 50 years ago in the Journal of Pediatrics: basal oxygen consumption in the obese patient. PMID- 22832046 TI - 50 years ago in The Journal of Pediatrics: congenital abnormalities of the urinary system. III. Growth of the kidney in childhood-determination of normal weight. PMID- 22832047 TI - Severe spinal neurofibromatosis in a child. PMID- 22832056 TI - Sclerosing hemangioma of the lung manifesting as a cystic lesion with an air fluid level. PMID- 22832057 TI - Germ cell removal after induction of cryptorchidism in adult rats. AB - Cryptorchidism is associated with male infertility due to germ cell loss in response to elevated temperature. However, there is a great deal of contradictory information prevalent on the status of germ cells and their process of removal in the cryptorchid testis. In the present study, we investigate the cell removal from cryptorchid rat testis by the methods of morphology and stereology. The testis weight is reduced according to previous reports after surgical induction of cryptorchidism. Interestingly, the epididymal weight is significantly increased in 7 days after surgery, and the caput epididymis tubules show filling with countless round germ cells. We found that the elongating spermatids (steps 10-13), newborn spermatids (step 1) and the dividing spermatocytes are the most susceptible cells to elevated temperature, and are the first disappeared cells from the seminiferous tubules after surgery. Germ cell removal followed the order, starting first with elongating spermatids and newborn spermatids, followed by round spermatids and elongated spermatids and later extending to spermatocytes. PMID- 22832058 TI - A newly designed real-time RT-PCR for SAFV detects SAFV-2 and SAFV-3 in the respiratory tracts of ill children during 2011. PMID- 22832059 TI - Validation for clinical use of a novel HIV-2 plasma RNA viral load assay using the Abbott m2000 platform. AB - BACKGROUND: Optimal care of persons infected with human immunodeficiency virus type 2 (HIV-2) requires an accurate assessment of HIV-2 plasma viral load (VL), but no clinically approved quantitative HIV-2 RNA VL assay exists. OBJECTIVES: To validate a novel quantitative HIV-2 RNA assay for clinical and research use. STUDY DESIGN: The Abbott m2000sp/rt platform was adapted for quantification of HIV-2 RNA in plasma. Amplification targeted a region of the long terminal repeat conserved in Group A and B HIV-2. Electron microscopy-counted-HIV-2 standards, the WHO/NIBSC HIV-2 International Standard and clinical specimens (N=162) were used to determine the precision, sensitivity, specificity, linear range, accuracy, and clinical performance of the assay. RESULTS: The quantitative linear range of the HIV-2 RNA assay was 10-1,000,000 copies/mL (R(2)>0.99), with a limit of detection of 8 copies/mL (95% CI, 5-18 copies/mL). The assay did not cross react with HIV-1, and quantification of HIV-2 RNA was not affected by the presence of >5 log(10)HIV-1 RNA copies/mL. The total standard deviation (SD) and intra- and inter-run SD were 0.095, 0.093 and 0.162, respectively, at nominal inputs of 3.7, 1.7 and 1.0 log(10)HIV-2 RNA copies/mL. The HIV-2 WHO/NIBSC International Standard (1000 IU) was shown to contain 152 RNA copies/mL (95% CI 141-163). Overall, HIV-2 RNA was quantified at >=10 copies/mL from 86 (53%) clinical specimens (median, 2.24 log(10) copies/mL; range 10-16,870), and nine specimens (6%) had HIV-2 RNA detected at <10 copies/mL. CONCLUSIONS: We developed and validated a highly sensitive HIV-2 VL assay that is suitable for clinical and research use. PMID- 22832060 TI - Diagnostic performance of two highly multiplexed respiratory virus assays in a pediatric cohort. AB - BACKGROUND: Rapid detection of respiratory viruses is important for management and infection control in hospitalized patients. Multiplex nucleic acid tests (NATs) have begun to replace conventional methods as gold standards for respiratory virus detection. OBJECTIVE: To compare the performance of two large multiplex NATS, ResPlex II (RPII) and Respiratory Virus Surveillance kit with electrospray ionization mass spectrometry (RVS/MS) using nasopharyngeal aspirates (NPAs) from hospitalized children who had been tested previously with conventional methods. STUDY DESIGN: Stored residual NPAs (N=306) were tested concomitantly by RPII and RVS/MS. Alternate NATs were used to adjudicate discordant results. RESULTS: More viruses were detected with multiplex NATs (RPII, 110; RVS/MS, 109) than conventional assays (86); diagnostic gain was primarily for fastidious viruses (coronaviruses and enteroviruses [EVs]/human rhinoviruses [HRVs]). Total positive and negative agreement between the multiplex NATs for all viruses detected was quite high (86% positive agreement, 99% negative agreement). Most individual viruses were detected with fairly equivalent accuracy by the multiplex NATs, except for adenoviruses (RPII sensitivity 40%) and human metapneumovirus (RVS/MS sensitivity 42%). RPII had the advantage of detecting EVs and HRVs, however, it demonstrated considerable EV/HRV cross reactivity (29 HRV-positive specimens by real-time PCR were positive for EV by RPII and 21 specimens positive for HRV only by RT-PCR were dual positive for EV/HRV by RPII). RPII also had reduced sensitivity for HRV detection (in 36 specimens, HRV was detected by RT-PCR but not by RPII). CONCLUSIONS: Both multiplex NATs were promising, but had notable limitations. PMID- 22832061 TI - [Single port, NOTES: a promising future or a passing fashion]. PMID- 22832062 TI - [Evaluation of surgical skills in medical students using a virtual simulator]. AB - INTRODUCTION: The use of virtual simulators together with hospital practicals during undergraduate training can improve basic surgical skills, and may even be an important motivating focal point. The aim of this work is to determine the endoscopy skill level and its learning curve in three stages within the Medical degree (second, fourth, and sixth year) using a virtual simulator. MATERIAL AND METHODS: The Lapsim simulator with 7 basic modular exercises was used. Twenty four students (8 second, 8 fourth, and 8 sixth year) were subjected to a training program (basic test plus 3 sessions), and an examination at 30 days. A control group (n=24) from each year were subjected to 2 examinations with an interval of 30 days. RESULTS: All the groups improved significantly after training, and this was maintained in all the exercises after a "wash out" period of 30 days. All the groups achieved lower baseline scores in the "Cutting" and "Lifting and grasping" exercises, considered of intermediate level than any of the others. However, after the training process, they were the only exercises that the sixth year students demonstrated that they were clearly superior to the rest of the years: "Cutting" (94.5%+/-11 vs 81%+/-7) (P<.05), "Lifting and grasping" (88.1%+/-13 vs 68%+/-11) (P<.001). CONCLUSIONS: The virtual simulator appears to be of greater use for those students in higher years with more clinical experience, there already being a discrimination process during this period. Surgical skills during this phase should be reinforced by means of new teaching challenges, such as simulation programs in the framework of skills laboratories. PMID- 22832063 TI - Acute necrotizing encephalopathy associated with enterovirus infection. AB - Acute necrotizing encephalopathy is a rare, clinically distinct entity of acute encephalopathy triggered by acute febrile diseases, mostly viral infections. It is postulated to arise from uncontrolled cytokine release during a febrile illness, and is most often seen in East Asia. We describe a rare Saudi patient of acute necrotizing encephalopathy attributable to enterovirus in a 4 years and 6 months old girl. A work-up revealed elevations in serum and cerebrospinal fluid interleukin-6 and tumor necrosis factor-alpha. The outcome on intravenous pulse methylprednisolone was good. This case is the first, to the best of our knowledge, of acute necrotizing encephalopathy reported from Saudi Arabia with a good outcome despite severe magnetic resonance imaging findings and delay in the steroid treatment. PMID- 22832064 TI - Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in Japan. AB - Tetrahydrobiopterin (BH(4)) deficiency is a rare, congenital and lethal condition resulting in phenylalanine build-up that can lead to mental retardation and developmental defects, unless properly treated. About 1 million newborn infants in Japan undergo neonatal PKU screening every year, of which about 1 in 2 million are diagnosed with the condition. In this post-marketing surveillance study, 19 patients with BH(4) deficiency in whom BH(4) supplementation with sapropterin dihydrochloride (Biopten(r)) (hereafter referred to as 'BH(4) therapy') was initiated before the age of 4 years, were followed up for <=28 years. Patients who screened positive for BH(4) deficiency were treated with supplemental BH(4) plus L-dopa and 5-hydroxytryptophan. Data on the patients' clinical courses were collected once yearly at 10 medical centers in Japan. Seventeen patients were diagnosed with 6-pyruvoyl tetrahydropterin synthase deficiency and two with dihydropteridine reductase deficiency at an average age of 3.6 months; the mean age at end of follow-up was 14.6 years. Average duration of BH(4) therapy (mean dose, 5 mg/kg per day) was 13.2 years. Serum phenylalanine was reduced from more than 10 mg/dL at the start of drug administration to less than 2 mg/dL at end of follow-up. No abnormalities in height or weight were observed in any patients, except for one female patient with familial obesity. No unwarranted side effects were reported throughout the long-term course of treatment, even during pregnancy. BH(4) therapy can effectively maintain serum phenylalanine levels within the normal range in patients with BH(4) deficiency, and demonstrated excellent long-term safety, with no side effects. PMID- 22832065 TI - A scenario analysis for reducing organic priority pollutants in receiving water using integrated dynamic urban fate models. AB - The Water Framework Directive (WFD) has the objective of a catchment-oriented water quality protection for all European waters with the purpose of achieving a good ecological and chemical quality status by the year 2015. To that end, necessary measures should be identified and implemented, with the aim of progressively reducing pollution from priority substances. The objective of this paper is to demonstrate how a dynamic model of the integrated urban wastewater system (IUWS) can be used to test different emission reduction strategies for organic priority pollutants (PPs) in a semi-hypothetical case study on di(2 ethylhexyl)phthalate (DEHP). The IUWS is composed of coupled entities: sources, urban catchment surface (run-off/infiltration), sewer system, stormwater treatment unit, wastewater treatment plant (WWTP) including sludge handling, and receiving surface water (river). State-of-the-art dynamic fate models were selected from literature and extended with an organic pollutant fate sub-model. Dynamic DEHP release profiles were estimated using a dynamic model input generator and fed to the model to predict the fate and concentration of DEHP in each IUWS sub-system. The model was then used to test eight scenarios on environmental performance, namely (1) reduction of impervious urban area, (2) reduction of infiltration in the sewer system, (3) input reduction (excluding the main pollutant sources), (4) separating the combined sewer system, (5) treatment of stormwater by stormwater infiltration ponds (separate sewer systems), (6) placement of retention basins at main sewer junctions, (7) sand filtration of secondary effluent, and (8) pre-precipitation of phosphorous. The simulation results revealed that the most effective measure in terms of river water quality improvement for DEHP (annual average and spikiness reduction) and PP concentration in the disposed WWTP sludge, is reducing release of this substance into the environment, not surprisingly. In general, this will heavily depend on the parameterisation of the scenarios. PMID- 22832066 TI - Knowledge and injury prevention practices in homes of older adults. AB - This study aimed to describe the prevalence of preventive safety measures in homes with older, urban-dwelling adults; determine the relationship between sociodemographic variables and injury prevention measures; and describe older adults' knowledge of safety topics. Teams conducted interviews and home observations in 603 homes to confirm preventive safety measures. Households with older adults were rarely observed to have recommended smoke alarm (34%) or carbon monoxide coverage (22%). Water temperature was safe in 64% of homes. Among households headed by someone other than the older adult, odds of having a working smoke alarm on every floor were much lower than in older adult-headed households (95% confidence interval: 0.04-0.35). Few older adults interviewed about safety knowledge correctly answered several items related to fire and carbon monoxide. Effort is needed to improve knowledge and promote the lifesaving benefits of injury countermeasures so that older adults can be adequately protected. PMID- 22832068 TI - Estimating workload using EEG spectral power and ERPs in the n-back task. AB - Previous studies indicate that both electroencephalogram (EEG) spectral power (in particular the alpha and theta band) and event-related potentials (ERPs) (in particular the P300) can be used as a measure of mental work or memory load. We compare their ability to estimate workload level in a well-controlled task. In addition, we combine both types of measures in a single classification model to examine whether this results in higher classification accuracy than either one alone. Participants watched a sequence of visually presented letters and indicated whether or not the current letter was the same as the one (n instances) before. Workload was varied by varying n. We developed different classification models using ERP features, frequency power features or a combination (fusion). Training and testing of the models simulated an online workload estimation situation. All our ERP, power and fusion models provide classification accuracies between 80% and 90% when distinguishing between the highest and the lowest workload condition after 2 min. For 32 out of 35 participants, classification was significantly higher than chance level after 2.5 s (or one letter) as estimated by the fusion model. Differences between the models are rather small, though the fusion model performs better than the other models when only short data segments are available for estimating workload. PMID- 22832069 TI - Structural basis behind the interaction of Zn2+ with the protein alpha-synuclein and the Abeta peptide: a comparative analysis. AB - alpha-Synuclein (AS) aggregation is associated to neurodegeneration in Parkinson's disease (PD). At the same time, alterations in metal ion homeostasis may play a pivotal role in the progression of AS amyloid assembly and the onset of PD. Elucidation of the structural basis directing AS-metal interactions and their effect on AS aggregation constitutes a key step towards understanding the role of metal ions in AS amyloid formation and neurodegeneration. Despite of the reported evidences that link Zn(2+) with the pathophysiology of PD and the fact that this metal ion was shown to promote AS fibrillation in vitro, neither the structural characterization of the binding sites nor the identification of the amino acids involved in the interaction of Zn(2+) with the protein AS has been carried out. By using NMR spectroscopy, we have addressed here unknown structural details related to the binding of Zn(2+) to the protein AS through the design of site-directed and domain truncated mutants of AS. The binding of zinc to the Abeta peptide was also studied and discussed comparatively. Although the results of this study contribute to the understanding of the structural and molecular basis behind the acceleration of AS fibrillation mediated by Zn(2+), the low affinity that characterizes the interaction of Zn(2+) with AS contrasts strongly with the high-affinity features reported for the binding of this metal ion to other target proteins linked to human amylodosis such as Abeta peptide and the Islet Amyloid Polypeptide (IAPP), challenging the biological relevance of zinc interactions in the pathogenesis of PD. PMID- 22832070 TI - Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men. AB - BACKGROUND: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. OBJECTIVES: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. METHODS: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2 ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). RESULTS: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E(2). %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality. CONCLUSION: Our data suggest that both testosterone production and pituitary-hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites. PMID- 22832071 TI - Morphological and molecular identification of the fish-borne metacercaria of Ascocotyle (Phagicola) longa Ransom, 1920 in Mugil liza from Argentina. AB - This is the first report of Ascocotyle (Phagicola) longa Ransom, 1920 (Digenea: Heterophyidae) in Argentina confirmed by morphological and molecular studies. The metacercaria was found encysted in myotomal musculature, heart and mesentery of the mullet Mugil liza (Pisces: Mugilidae) from Samborombon bay. We provide a morphological description of the metacercaria which we identified using species specific primers for A. (Phagicola) longa and nucleotid sequence. This worldwide parasite has been reported as one of the causative agents of heterophyiosis, an emerging fish-borne disease of humans, contracted by the consumption of raw mullet. The discovery of A. (Phagicola) longa in Argentina represents a warning of the potentially great impact of this parasite on public health. PMID- 22832072 TI - Morphological evaluation of the male external urethral sphincter complex by transrectal ultrasound: feasibility study and potential clinical applications. AB - INTRODUCTION: Previous measurement of the male external urethral sphincter complex (EUSC) length by magnetic resonance imaging and urethral pressure profilometry did not consider the intraprostatic portion, although its role for urinary continence has been demonstrated. The aim of our study was to verify the feasibility of a morphological evaluation of the EUSC by transrectal ultrasound (TRUS). MATERIALS AND METHODS: Data from 52 men that underwent TRUS were prospectively collected. The EUSC was identified in the midline sagittal plane. Total and intraprostatic EUSC length and prostate volume were measured. RESULTS: EUSC appears as a hypoechoic area surrounding the urethra. The proximal end was identified between the verumontanum and the prostate apex by the net change in prostate echo patterns, while the distal end was identified by voluntary contraction of the external anal sphincter. Mean total and intraprostatic EUSC lengths were 20.17 and 3.78 mm, respectively. Total EUSC length presented a weak correlation with prostate volume (r = 0.41; p = 0.003), while the intraprostatic portion had a stronger correlation (r = 0.60; p = 0.001). CONCLUSIONS: The evaluation of the EUSC is feasible by TRUS, and length measurement should include the intraprostatic portion. Potential clinical application should be the preoperative assessment of the risk of urinary incontinence in men undergoing radical prostatectomy. PMID- 22832073 TI - Halitosis in cystinosis patients after administration of immediate-release cysteamine bitartrate compared to delayed-release cysteamine bitartrate. AB - Halitosis due to dimethylsulfide (DMS) generation is a major side effect of cysteamine in the treatment of cystinosis. Recently, an enteric coated formulation of cysteamine bitartrate (RP103) administered twice daily was demonstrated to be non-inferior for lowering WBC cystine levels compared to the non-enteric coated formulation (Cystagon(r)), administered 4 times per day. Since both formulations had different pharmacokinetic profiles, we compared DMS breath levels after administration of either RP103 or Cystagon(r) in four cystinosis patients. Although cysteamine areas under the curve (AUCs) were comparable, AUC of DMS was lower after the administration of RP103 compared to Cystagon(r). This observation is of importance in cystinosis patients, since halitosis hampers compliance with cysteamine therapy. PMID- 22832074 TI - Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism. AB - The genes MMACHC and MMADHC encode critical proteins involved in the intracellular metabolism of cobalamin. Two clinical features, homocystinuria and methylmalonic aciduria, define inborn errors of these genes. Based on disease phenotypes, MMADHC acts at a branch point for cobalamin delivery, apparently exerting its function through interaction with MMACHC that demonstrates dealkylase and decyanase activities. Here we present biophysical analyses of MMADHC to identify structural features and to further characterize its interaction with MMACHC. Two recombinant tag-less isoforms of MMADHC (MMADHCDelta1-12 and MMADHCDelta1-61) were expressed and purified. Full length MMACHC and full length MMADHC were detected in whole cell lysates of human cells; by Western blotting, their molecular masses corresponded to purified recombinant proteins. By clear-native PAGE and by dynamic light scattering, recombinant MMADHCs were stable and monodisperse. Both species were monomeric, adopting extended conformations in solution. Circular dichroism and secondary structure predictions correlated with significant regions of disorder within the N-terminal domain of MMADHC. We found no evidence that MMADHC binds cobalamin. Phage panning against MMADHC predicted four binding regions on MMACHC, two of which overlap with predicted sites on MMACHC at which it may self-associate. Specific, concentration-dependent responses were observed for MMACHC binding to itself and to both MMADHC constructs. As estimated in the sub-micromolar range, the binding of MMACHC to itself was weaker compared to its interaction with either of the MMADHC isoforms. We propose that the function of MMADHC is exerted through its structured C-terminal domain via interactions with MMACHC. PMID- 22832075 TI - Vitamin A deficiency disturbs collagen IV and laminin composition and decreases matrix metalloproteinase concentrations in rat lung. Partial reversibility by retinoic acid. AB - Vitamin A is essential for lung development and pulmonary cell differentiation. Its deficiency leads to altered lung structure and function and to basement membrane architecture and composition disturbances. Previously, we showed that lack of retinoids thickens the alveolar basement membrane and increases collagen IV, which are reversed by retinoic acid, the main biologically active vitamin A form. This study analyzed how vitamin A deficiency affects the subunit composition of collagen IV and laminin of lung basement membranes and pulmonary matrix metalloproteinase content, plus the recovering effect of all-trans retinoic acid. Male weanling pups were fed a retinol-adequate/-deficient diet until 60 days old. A subgroup of vitamin-A-deficient pups received daily intraperitoneal all-trans-retinoic acid injections for 10 days. Collagen IV and laminin chain composition were modified in vitamin-A-deficient rats. The protein and mRNA contents of chains alpha1(IV), alpha3(IV) and alpha4(IV) increased; those of chains alpha2(IV) and alpha5(IV) remained unchanged; and the protein and mRNA contents of laminin chains alpha5, beta1 and gamma1 decreased. The mRNA of laminin chains alpha2 and alpha4 also decreased. Matrix metalloproteinases 2 and 9 decreased, but the tissue inhibitors of metalloproteinases 1 and 2 did not change. Treating vitamin-A-deficient rats with retinoic acid reversed all alterations, but laminin chains alpha2, alpha4 and alpha5 and matrix metalloproteinase 2 remained low. In conclusion, vitamin A deficiency alters the subunit composition of collagen IV and laminin and the lung's proteolytic potential, which are partly reverted by retinoic acid. These alterations could contribute to impaired lung function and predispose to pulmonary disease. PMID- 22832077 TI - Prophylactic neuroprotection by blueberry-enriched diet in a rat model of light induced retinopathy. AB - The role of anthocyanins is controversial in vision health. This study investigates the impact of a blueberry-enriched diet as neuroprotectant in a rat model of light-induced retinopathy. Thirty-eight albino Wistar rats and 25 pigmented Brown-Norway rats were fed by gavage with long (7 weeks) and short (2 weeks) intervention with fortified blueberry juice (1 ml; 2.8 mg cyanidin 3 glucoside equivalents) or with a placebo solution (7 weeks) that contained the abundant nonanthocyanin blueberry phenolic, namely, chlorogenic acid, before being submitted to 2 hours of intense light regimen (1.8*10(4) lux). Retinal health was measured by fitting electroretinogram responses with the Naka-Rushton equation. The light-induced retinal damage was severe in the placebo groups, with the maximum amplitude of the electroretinogram being significantly reduced in both Wistar and Brown-Norway rats. The maximum amplitude of the electroretinogram was significantly protected from the light insult in the Wistar rats supplemented with blueberry juice for 7 or 2 weeks, and there was no significant difference between these two groups. The same dietary intervention in the Brown-Norway groups failed to protect the retina. Histological examination of retinal section confirmed the electroretinography results, showing protection of the outer nuclear layer of the retina in the Wistar rats fed with blueberries, while all placebo-fed rats and blueberry-fed Brown-Norway rats showed evidence of retinal damage concentrated in the superior hemiretina. The neuroprotective potential of anthocyanins in this particular model is discussed in terms of interaction with rhodopsin/phototransduction and in terms of antioxidative capacity. PMID- 22832076 TI - trans-10,cis-12 conjugated linoleic acid promotes bone formation by inhibiting adipogenesis by peroxisome proliferator activated receptor-gamma-dependent mechanisms and by directly enhancing osteoblastogenesis from bone marrow mesenchymal stem cells. AB - The bone undergoes continuous remodeling of osteoblastic bone formation and osteoclastic bone resorption to maintain proper bone mass. It is also reported that bone marrow adiposity has a reciprocal role in osteoblasts due to their same origin from mesenchymal stem cells. In addition, one of the key mediators of adipogenesis, peroxisome-proliferator activated receptor-gamma (PPARgamma), plays a significant role in osteoblastogenesis in bone marrow mesenchymal stem cells. One dietary component that is known to have significant impact on adiposity and bone mass is conjugated linoleic acid (CLA). However, the link between controlling adiposity to improving bone mass by CLA has not been studied intensively. Thus, the purpose of this study is to determine the role of CLA on bone marrow adiposity and bone formation using murine mesenchymal stem cells. The results confirmed that the trans-10,cis-12 CLA, but not the cis-9,trans-11 CLA isomer, significantly inhibited adipogenesis and promoted osteoblastogenesis from mesenchymal stem cells. The inhibition of adipogenesis by the trans-10,cis-12 CLA was mediated by PPARgamma; however, the trans-10,cis-12 CLA had a direct effect on osteoblastogenesis which was independent to PPARgamma in this model. The trans 10,cis-12 CLA also had significant effects on osteoclastogenesis inhibitory factor, which suggests potential influence of CLA on osteoclastogenesis. Overall, the results suggest that the trans-10,cis-12, but not the cis-9,trans-11 CLA isomer, has a positive impact on bone health by both PPARgamma mediated and independent mechanisms in mesenchymal stem cells. PMID- 22832078 TI - Dietary polyphenols and mechanisms of osteoarthritis. AB - Osteoarthritis is a condition caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and anti-inflammatory pathways. It primarily affects the articular cartilage and subchondral bone of synovial joints and results in joint failure, leading to pain upon weight bearing including walking and standing. There is no cure for osteoarthritis, as it is very difficult to restore the cartilage once it is destroyed. The goals of treatment are to relieve pain, maintain or improve joint mobility, increase the strength of the joints and minimize the disabling effects of the disease. Recent studies have shown an association between dietary polyphenols and the prevention of osteoarthritis-related musculoskeletal inflammation. This review discusses the effects of commonly consumed polyphenols, including curcumin, epigallocatechin gallate and green tea extract, resveratrol, nobiletin and citrus fruits, pomegranate, as well as genistein and soy protein, on osteoarthritis with an emphasis on molecular antiosteoarthritic mechanisms. PMID- 22832079 TI - Intrauterine undernourishment alters TH1/TH2 cytokine balance and attenuates lung allergic inflammation in wistar rats. AB - IL-4 produced by Th2 cells can block cytokine production by Th1 cells, and Th1 IFN-gamma is known to counterregulate Th2 immune response, inhibiting allergic eosinophilia. As intrauterine undernutrition can attenuate lung inflammation, we investigated the influence of intrauterine undernourishment on the Th1/Th2 cytokine balance and allergic lung inflammation. Intrauterine undernourished offspring were obtained from dams fed 50% of the nourished diet of their counterparts and were immunized at 9 weeks of age. We evaluated the cell counts and cytokine protein expression in the bronchoalveolar lavage, mucus production and collagen deposition, and cytokine gene expression and transcription factors in lung tissue 21 days after ovalbumin immunization. Intrauterine undernourishment significantly reduced inflammatory cell airway infiltration, mucus secretion and collagen deposition, in rats immunized and challenged. Intrauterine undernourished rats also exhibited an altered cytokine expression profile, including higher TNF-alpha and IL-1beta expression and lower IL-6 expression than well-nourished rats following immunization and challenge. Furthermore, the intrauterine undernourished group showed reduced ratios of the IL-4/IFN-gamma and the transcription factors GATA-3/T-Bet after immunization and challenge. We suggest that the attenuated allergic lung inflammation observed in intrauterine undernourished rats is related to an altered Th1/Th2 cytokine balance resulting from a reduced GATA-3/T-bet ratio. PMID- 22832080 TI - Evaluation of pulmonary function in European land tortoises using whole-body plethysmography. AB - The aim of this study was to evaluate the use of whole-body plethysmography as a non-invasive method to determine the respiratory parameters and profiles in two tortoise species belonging to the genus Testudo. Pulmonary functions and volumetric parameters were determined in 10 adults of Testudo hermanni and in seven Testudo marginata animals, using whole-body plethysmography. A profile pattern was regularly observed: an inspiratory flow peak, an expiratory peak, an apnoea phase and a second expiratory peak, previous to the beginning of the next respiratory cycle. Positive and significant correlation was observed between the inspiratory time, weight and length of the tortoises. Larger tortoises showed a higher time of inhalation. The peak of inspiratory flow was correlated with the sex, being longer in the females. T. marginata had an inspiratory time longer than that of T. hermanii. In T. hermanii, differences related to the sex were observed in the tidal volume, peak inspiratory flow, peak expiratory flow, expiratory flow of 50 per cent and enhanced pause, which could be related to the smaller size of males. The results suggest that additional information on new technologies currently used in pet medicine or even in human medicine should be developed and adjusted as alternative ways to support the rehabilitation of turtles and tortoises. PMID- 22832081 TI - A rare case of a male with 45, XO, SRY+, ZFY+ with short stature and mild Turner stigmata. AB - BACKGROUND: Turner syndrome is hypothesized to result from haploinsufficiency of certain genes expressed from both sex chromosomes that escape X inactivation. CASE REPORT: We present the rare case of a 4-year-old boy who was referred to the pediatric endocrinology unit for evaluation of slight growth delay. RESULTS: Standard cytogenetic analysis showed a 45,XO karyotype. Molecular studies disclosed the presence of an intact SRY homeobox region and the ZFY region sited on the Y short arm. Other Y chromosome sequences which are normally found on the short arm of chromosome Y (p) were absent and their exact location on a different chromosome remained unclear. Subsequently, FISH (fluorescent in situ hybridization) analysis failed to detect any Y sequences, while haplotype analysis indicated that the present X chromosome was of paternal origin. CONCLUSION: Phenotype-genotype correlation studies were consistent with a male patient presenting with short stature and some of the Turner's syndrome stigmata. The consequences for the patients with this chromosomal abnormality and treatment with recombinant growth hormone are also discussed. PMID- 22832083 TI - Application of electron backscatter diffraction for crystallographic characterization of tin whiskers. AB - Understanding the growth of whiskers or high aspect ratio features on substrates can be aided when the crystallography of the feature is known. This study has evaluated three methods that utilize electron backscatter diffraction (EBSD) for the determination of the crystallographic growth direction of an individual whisker. EBSD has traditionally been a technique applied to planar, polished samples, and thus the use of EBSD for out-of-surface features is somewhat more difficult and requires additional steps. One of the methods requires the whiskers to be removed from the substrate resulting in the loss of valuable physical growth relationships between the whisker and the substrate. The other two techniques do not suffer this disadvantage and provide the physical growth information as well as the crystallographic growth directions. The final choice of method depends on the information required. The accuracy and the advantages and disadvantages of each method are discussed. PMID- 22832082 TI - Evaluation of 18F-labeled targeted perfluorocarbon-filled albumin microbubbles as a probe for microUS and microPET in tumor-bearing mice. AB - OBJECTIVE: In this study, albumin-shelled, targeted MBs (tMBs) were first demonstrated with the expectation of visualization of biodistribution of albumin shelled tMBs. The actual biodistribution of albumin-shelled tMBs is of vital importance either for molecular imaging or for drug delivery. MOTIVATION: Recently, albumin microbubbles (MBs) have been studied for drug and gene delivery in vitro and in vivo through cavitation. Targeted lipid-shelled MBs have been applied for ultrasound molecular imaging and conjugated with radiolabeled antibodies for whole-body biodistribution evaluations. The novelty of the work is that, in addition to the lipid tMBs, the albumin tMBs was also applied in biodistribution detection. METHODS: Multimodality albumin-shelled, (18)F-SFB labeled VEGFR2 tMBs were synthesized, and their characteristics in mice bearing MDA-MB-231 human breast cancer were investigated with micro-positron-emission tomography (microPET) and high-frequency ultrasound (microUS). RESULTS: Albumin shelled MBs can be labeled with (18)F-SFB directly and conjugated with antibodies for dual molecular imaging. The albumin-shelled tMBs show a lifetime in 30min in the blood pool and a highly specific adherence to tumor vessels in mice bearing human breast cancer. CONCLUSIONS: From the evaluations of whole-body biodistribution, the potential of the dual molecular imaging probe for drug or gene delivery in animal experiments with albumin shelled MBs has been investigated. PMID- 22832084 TI - [Strategy in intraductal papillary mucinous neoplasm of the pancreas]. AB - Intraductal papillary mucinous neoplasm (IPMN) is a premalignant pancreatic entity characterized by papillary growth of the ductal epithelium with rich mucin production and cystic dilatation of the main pancreatic duct and/or its branches. These neoplasms are often multifocal. Preoperative distinction between benign and malignant lesions is important to select the most appropriate treatment and to improve prognosis. Early surgical resection is the treatment of choice to avoid malignant transformation when predictive factors for malignancy are present. These factors include localization, cyst greater than 3cm, nodules in the cystic wall, atypias in the cyst fluid and the presence of symptoms. The extent of resection required for adequate treatment of IPMN of the pancreas is still controversial. Patients who retain a portion of their pancreas following resection of an IPMN need to be followed up with periodic imaging to detect recurrences, signs indicating a risk of malignant transformation, and metachronous lesions. The existence of possible synchronous or metachronous lesions in other organs should also be investigated. PMID- 22832085 TI - Dietary restraint in college women: fear of an imperfect fat self is stronger than hope of a perfect thin self. AB - We predicted that the perceived likelihood of acquiring a hoped-for thin self would mediate perfectionistic strivings on dietary restraint, and that the perceived likelihood of acquiring a feared fat self would mediate perfectionistic concerns on dietary restraint. We also predicted that the mediation pathway from perfectionistic concerns to dietary restraint would have a greater impact than that from perfectionistic strivings. Participants were 222 female college students who reported their height and weight and completed measures of perfectionism, the likelihood of acquiring the feared fat and hoped-for thin selves, and dietary restraint. Statistical analyses revealed that the perceived likelihood of acquiring the feared fat self mediated both perfectionistic concerns and perfectionistic strivings on dietary restraint, and that the mediating pathway from perfectionistic concerns to dietary restraint was greater than that from perfectionistic strivings. Implications for future research and eating pathology interventions are discussed. PMID- 22832086 TI - Using Amazon's Mechanical Turk website to measure accuracy of body size estimation and body dissatisfaction. AB - This study investigated Amazon.com's website Mechanical Turk (MTurk) as a research tool for measuring body size estimation and dissatisfaction. 160 U.S. participants completed the BIAS-BD figural drawing scale and demographic questions posted on the MTurk website. The BIAS-BD consists of 17 drawings of various male and female body sizes based on anthropometric data corresponding to a range of 60% below to 140% above the average U.S. adult. Respondents selected a drawing that best reflected their current size and ideal size. Results revealed that respondents overestimated their body size by 6% and desired an ideal size 9.2% smaller than their perceived size. Findings are compared with three previous studies using the BIAS-BD scale. A general correspondence in findings between the four studies was found. We conclude that the MTurk can serve as a viable method for collecting data on the perceptual and attitudinal aspects of body image quickly and inexpensively. PMID- 22832087 TI - Method and strain rate dependence of Achilles tendon stiffness. AB - Tendon stiffness is calculated by dividing changes in tendon force by tendon elongation. For this purpose, participants are commonly asked to perform a maximal muscle contraction ("active" method). Alternatively tendon elongation can be achieved by means of a passive joint rotation ("passive" method). The purpose of this study was to compare Achilles tendon stiffness obtained from both methods across different tendon strain rates. Twenty adults performed a series of ramped maximum isometric plantarflexions of different durations. Passive ankle rotations of different angular velocities were also performed. Achilles tendon stiffness was obtained from a combination of motion analysis, isokinetic dynamometry and ultrasonography and compared across methods at three strain rates. At all strain rates, tendon stiffness obtained from the active method was 6% greater compared to the passive method. In spite of this systematic bias, there was good agreement between the methods. Intraclass correlation coefficients were greater than 0.98, and more than 95% of data points fell into the 95% confidence intervals. This agreement will be acceptable in many research contexts. We also found a linear increase in tendon stiffness with increasing strain rate, which must be taken into consideration when interpreting or reporting tendon stiffness. PMID- 22832088 TI - Earthworm bioassays and seedling emergence for monitoring toxicity, aging and bioaccumulation of anthropogenic waste indicator compounds in biosolids-amended soil. AB - Land application of biosolids (treated sewage sludge) can be an important route for introducing xenobiotic compounds into terrestrial environments. There is a paucity of available information on the effects of biosolids amendment on terrestrial organisms. In this study, the influence of biosolids and biosolids aging on earthworm (Eisenia fetida) reproduction and survival and lettuce (Lactuca sativa) seedling emergence was investigated. Earthworms were exposed to soils amended with varying quantities of biosolids (0, 1, 2, 3, or 4% dry mass). To investigate the influence of biosolids aging, the biosolids used in the study were aged for differing lengths of time (2 or 8 weeks) prior to exposure. All of the adult earthworms survived in the biosolids-amended soils at all concentrations that were aged for 2 weeks; however, only 20% of the adults survived in the soil amended with the highest concentration of biosolids and aged for 8 weeks. Reproduction as measured by mean number of juveniles and unhatched cocoons produced per treatment correlated inversely with biosolids concentration, although the effects were generally more pronounced in the 8-week aged biosolids soil samples. Latent seedling emergence and reduced seedling fitness correlated inversely with biosolids concentration, but these effects were tempered in the 8 week aged versus the 2-week aged soil-biosolids mixtures. Anthropogenic waste indicator compounds (AWIs) were measured in the biosolids, biosolids-soil mixtures, and earthworm samples. Where possible, bioaccumulation factors (BAFs) were calculated or estimated. A wide variety of AWIs were detected in the biosolids (51 AWIs) and earthworm samples (<=19 AWI). The earthworms exposed to the 8-week aged biosolids-soil mixtures tended to accumulate greater quantities of AWIs compared to the 2-week aged mixture, suggesting that the bioavailability of some AWIs was enhanced with aging. The BAFs for a given AWI varied with treatment. Notably large BAFs were determined for some AWIs. For example, the maximum BAF determined for para-cresol, methyl salicylate, bisphenol-A, and cholesterol was greater than 100 in some treatments. PMID- 22832089 TI - Determinants of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in house dust samples from four areas of the United States. AB - Determinants of levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) in dust in U.S. homes are not well characterized. We conducted a pilot study to evaluate the relationship between concentrations of PCDD/F in house dust and residential proximity to known sources, including industrial facilities and traffic. Samples from vacuum bag dust from homes of 40 residents of Detroit, Los Angeles, Seattle, or Iowa who participated in a population-based case-control study of non-Hodgkin lymphoma conducted in 1998 2000 were analyzed using high resolution gas chromatography/high resolution mass spectrometry for 7 PCDD and 10 PCDF congeners considered toxic by the U.S. Environmental Protection Agency (EPA). Locations of 10 types of PCDD/F-emitting facilities were obtained from the EPA; however only 4 types were located near study homes (non-hazardous waste cement kilns, coal-fired power plants, sewage sludge incinerators, and medical waste incinerators). Relationships between concentrations of each PCDD/F and proximity to industrial facilities, freight routes, and major roads were evaluated using separate multivariate regression models for each congener. The median (inter-quartile range [IQR]) toxic equivalence (TEQ) concentration of these congeners in the house dust was 20.3 pg/g (IQR=14.3, 32.7). Homes within 3 or 5 km of a cement kiln had 2 to 9-fold higher concentrations of 5 PCDD and 5 PCDF (p<0.1 in each model). Proximity to freight routes and major roads was associated with elevated concentrations of 1 PCDD and 8 PCDF. Higher concentrations of certain PCDD/F in homes near cement kilns, freight routes, and major roads suggest that these outdoor sources are contributing to indoor environmental exposures. Further study of the contribution of these sources and other facility types to total PCDD/F exposure in a larger number of homes is warranted. PMID- 22832090 TI - The analytic common spatial patterns method for EEG-based BCI data. AB - One of the most important stages in a brain-computer interface (BCI) system is that of extracting features that can reliably discriminate data recorded during different user states. A popular technique used for feature extraction in BCIs is the common spatial patterns (CSP) method, which provides a set of spatial filters that optimally discriminate between two classes of data in the least-squares sense. The method also yields a set of spatial patterns that are associated with the most relevant activity for distinguishing between the two classes. The high recognition rates that have been achieved with the method have led to its widespread adoption in the field. Here, a variant of the CSP method that considers EEG data in its complex form is described. By explicitly considering the amplitude and phase information in the data, the analytic CSP (ACSP) technique can provide a more comprehensive picture of the underlying activity, resulting in improved classification accuracies and more informative spatial patterns than the conventional CSP method. In this paper, we elaborate on the theoretical aspects of the ACSP algorithm and demonstrate the advantages of the method through a number of simulations and through tests on EEG data. PMID- 22832091 TI - What is the optimal therapy for patients with metastatic renal cell carcinoma who progress on an initial VEGFr-TKI? AB - Sequential treatment with targeted therapies is the current standard of care for patients with metastatic renal cell carcinoma (mRCC). Most patients are initially treated with a first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI), but will eventually develop resistance and subsequent disease progression. Patients with mRCC whose disease progresses during initial VEGFr-TKI therapy may continue treatment with a different VEGFr TKI or they may switch to treatment with a mammalian target of rapamycin (mTOR) inhibitor which has a different mechanism of action. Based on positive results of the phase III RECORD-1 trial, clinical guidelines in the United States and Europe recommend use of everolimus, an mTOR inhibitor, in patients with VEGFr-TKI refractory mRCC. Positive results of the phase III AXIS trial led to recent approval in the United States of the VEGFr-TKI axitinib for use in patients with mRCC who failed one previous therapy. VEGFr-TKIs and mTOR inhibitors have distinct clinical effects with differing safety profiles, but to date, no head-to head comparisons in the post-VEGFr-TKI second-line setting are available. This review discusses multiple factors that should be considered when selecting a second-line therapy for patients with VEGFr-TKI-refractory mRCC, including evidence-based guidelines, efficacy, safety, patient profile, and clinician familiarity with available agents. PMID- 22832092 TI - Effect of imidafenacin on nocturia and sleep disorder in patients with overactive bladder. AB - OBJECTIVE: To evaluate the efficacy of imidafenacin on nocturia and sleep disorder in patients with overactive bladder (OAB). PATIENTS AND METHODS: A prospective multicenter study of imidafenacin 0.1 mg twice daily for patients with OAB and nocturia was conducted. At baseline and at week 4 and 8, patients were assessed using the overactive bladder symptom score (OABSS), frequency volume charts (FVC) and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Treatment with imidafenacin significantly improved OAB symptoms. Imidafenacin also improved PSQI, especially subjective sleep quality, sleep latency and daytime dysfunction. In FVC, the number of daytime voids and nighttime voids significantly decreased and average voided volume significantly increased after imidafenacin. Subanalysis of FVC based on the patients' age revealed that nocturnal polyuria was more often found in patients aged 75 years or over than in those aged under 75 years (79 vs. 55%, p < 0.05). Treatment with imidafenacin significantly reduced the nocturnal polyuria index only in patients aged 75 years or over. CONCLUSIONS: Imidafenacin can improve nocturia and sleep disorder in patients with OAB. The efficacy of imidafenacin on nocturia is attributable to an increase in bladder capacity and a decrease in nocturnal urine volume. We conclude that imidafenacin is an effective and safe drug for nocturia in patients with OAB. PMID- 22832093 TI - Removal of phosphate from solution by adsorption and precipitation of calcium phosphate onto monohydrocalcite. AB - The sorption behavior and mechanism of phosphate on monohydrocalcite (CaCO(3).H(2)O: MHC) were examined using batch sorption experiments as a function of phosphate concentrations, ionic strengths, temperatures, and reaction times. The mode of PO(4) sorption is divisible into three processes depending on the phosphate loading. At low phosphate concentrations, phosphate is removed by coprecipitation of phosphate during the transformation of MHC to calcite. The sorption mode at the low-to-moderate phosphate concentrations is most likely an adsorption process because the sorption isotherm at the conditions can be fitted reasonably with the Langmuir equation. The rapid sorption kinetics at the conditions is also consistent with the adsorption reaction. The adsorption of phosphate on MHC depends strongly on ionic strength, but slightly on temperature. The maximum adsorption capacities of MHC obtained from the regression of the experimental data to the Langmuir equation are higher than those reported for stable calcium carbonate (calcite or aragonite) in any conditions. At high phosphate concentrations, the amount of sorption deviates from the Langmuir isotherm, which can fit the low-to-moderate phosphate concentrations. Speciation saturation analyses of the reacted solutions at the conditions indicated that the solution compositions which deviate from the Langmuir equation are supersaturated with respect to a certain calcium phosphate. The obtained calcium phosphate is most likely amorphous calcium phosphate (Ca(3)(PO(4))(2).xH(2)O). The formation of the calcium phosphate depends strongly on ionic strength, temperature, and reaction times. The solubility of MHC is higher than calcite and aragonite because of its metastability. Therefore, the higher solubility of MHC facilitates the formation of the calcium phosphates more than with calcite and aragonite. PMID- 22832094 TI - Insulin complexes with PEGylated basic oligopeptides. AB - Biodegradable oligolysine and oligoarginine-type homopeptides functionalized with PEG of two different molecular weights interact with insulin, at physiological pH, affording complexes studied by dynamic light scattering, zeta-potential, circular dichroism, FTIR spectroscopy, and isothermal titration calorimetry (ITC). High levels of insulin complexation efficiencies (>99.5%) were determined for all derivatives. FTIR spectra suggest that the positively charged homo oligopeptide derivatives interact with B chain C-terminus of insulin leading to the formation of nanoparticles than can be traced even at low oligopeptide/insulin molar ratios. The ITC profiles are complex, displaying significant endothermic and exothermic contributions. Oligoarginine-type derivatives exhibit the strongest interactions, while PEGylation of either oligopeptide with the high molecular weight chains significantly affects the ITC profiles and leads to larger enthalpy changes. This may be attributed to PEG induced aggregation of insulin due to the depletion attraction effect leading to the formation of stable nanocomplexes. Stabilization of complexed insulin against enzymatic degradation by trypsin and alpha-chymotrypsin is observed especially for the high molecular weight PEGylated arginine-based derivative. Insulin release rates in simulated intestinal fluid are controlled by the length of PEG chains and the presence of arginine end-groups. Released insulin retains its secondary structure as established by circular dichroism spectroscopy. PMID- 22832095 TI - Formation of liquid marbles and wetting transitions. AB - The formation of liquid marbles was studied in the situation where hydrophobic particles coating the marbles "come from air". Droplets of water/ethanol solutions of various concentrations were coated with three kinds of powders: polytetrafluoroethylene, polyvinylidene fluoride and polyethylene. We established that there exists a critical concentration of ethanol, and correspondingly a critical surface tension of the water/ethanol solution allowing formation of liquid marbles. A critical surface tension depends on the kind of the powder. In parallel, wetting transitions of water/ethanol solutions were studied on the layers of the same polymer powders. The onset of wetting transitions on the powders took place at the concentrations of ethanol coinciding with those enabling the formation of liquid marbles. Wetting transitions stipulate the formation of liquid marbles when a droplet is deposited on a layer of hydrophobic powder. This assumption was validated by the experiments performed with di iodomethane and glycerol. PMID- 22832096 TI - Surface complexation reactions of inorganic anions on hydrotalcite-like compounds. AB - Complexation reactions of environmentally important inorganic anions such as nitrate, chloride, sulfate, arsenate, and phosphate on the surface of hydrotalcite-like compounds (HT) were investigated to understand the role of HT in the immobilization of hazardous anions in an alkaline environment. The effects of surface complexation reactions on the solid state properties of HT were also evaluated to understand their stability. Synthetic HT was used for the adsorption and post-adsorption experiments. The obtained adsorption isotherms showed that the order of selectivity of HT for anions was NO(3)= 1.4-fold difference from baseline to after SHC, were detected in 95% of patients. VS findings guided successful surgery in 77% of SHC cases and 90% of super-selective VS cases; the peak gradient site was concordant with operative findings in 46% of SHC cases and 80% of super-selective VS cases. Avoidance of super-selective sampling decreased mean fluoroscopy time from 91 minutes to 33 minutes and decreased contrast material administered from 204 mL to 63 mL (both P < .0001). CONCLUSIONS: The SHC protocol to enable non-super-selective VS in patients with persistent PHPT had the same ability as super-selective VS to detect a positive (>= 1.4-fold) PTH gradient, was associated with decreased accuracy in identifying the site of the adenoma compared with super-selective VS, and significantly decreased contrast material used and fluoroscopy time. PMID- 22832138 TI - Staff doses in interventional radiology: a national survey. AB - PURPOSE: To present the results of occupational radiation doses investigated through a national survey promoted by the National Society of Interventional Radiology in Spain. MATERIALS AND METHODS: The monthly dosimetric records of 28 interventional radiologists from 10 hospitals were analyzed and filtered to remove inconsistent dosimeter readings. The evaluation of the results includes different workloads as well as different radiation protection habits. RESULTS: Poor use of personal dosimetry by some interventional radiologists was brought to light. Most professionals do not use an over-apron dosimeter as recommended by the International Commission on Radiological Protection. Ceiling-suspended protective screens are used irregularly in many cases. All interventionalists perform digital subtraction angiographic imaging from a control room in more than 80% of procedures. The maximum monthly doses recorded were 3.8 mSv under the apron, 20.2 mSv over the apron, and 63.1 mSv to the hands. CONCLUSIONS: For under apron and hand readings, extrapolated median values were below 30% of annual dose limits, but in the case of over-apron readings, the extrapolated median dose was higher than the newly recommended limit for the eye lens of 20 mSv per year. This study mainly highlights the need to use radiation protection tools and personal dosimeters to protect staff and monitor eye lens doses. PMID- 22832139 TI - Efficacy of balloon-occluded retrograde transvenous obliteration of large spontaneous lienorenal shunt in patients with severe recurrent hepatic encephalopathy with foam sclerotherapy: initial experience. AB - PURPOSE: Balloon-occluded retrograde transvenous obliteration (BRTO) is a widely accepted treatment for gastric varices, but data are limited in regard to its role in the management of hepatic encephalopathy (HE). This study evaluated the efficacy of BRTO with foam sclerotherapy in the management of HE arising as a result of spontaneous large portosystemic shunts. MATERIALS AND METHODS: Eight sessions of BRTO with sodium tetradecyl sulfate foam were performed in seven patients with cirrhosis complicated by HE. All patients had portosystemic communication (ie, gastro-/lienorenal shunt) on preprocedure computed tomography. Clinical and laboratory parameters including arterial ammonia level were evaluated in all patients before and after the procedure. RESULTS: Technical success rates were 86% (six of seven) for the first BRTO session and 100% (one of one) for the second. Follow-up imaging revealed complete obliteration of the varices in five of seven patients (71%) and partial obliteration in the remaining two. Immediate clinical improvement of HE was observed in six of seven patients (86%), with postprocedural decrease in arterial ammonia levels; one patient showed delayed improvement. Procedure-related complications (eg, abnormal liver function test results, acute kidney injury with leukocytosis) were encountered in two patients. All patients showed clinical and symptomatic improvement at the time of discharge and during a follow-up of 4 months (with visits at 1 mo and 3 mo later). CONCLUSIONS: Initial experience suggests that BRTO is an effective procedure in the management of HE arising as a result of large portosystemic shunts. PMID- 22832140 TI - Hypertrophic inferior phrenic artery embolization. PMID- 22832141 TI - Antegrade superficial femoral artery versus common femoral artery punctures for infrainguinal occlusive disease. AB - PURPOSE: To compare the outcomes of planned superficial femoral artery (SFA) and common femoral artery (CFA) antegrade punctures in patients undergoing endovascular interventions for infrainguinal occlusive arterial disease in a single center. MATERIALS AND METHODS: Between August 2010 and July 2011, consecutive patients who underwent antegrade puncture of CFA or SFA for infrainguinal occlusive disease were studied. Data including sheath size, rate of closure device usage, and complications relating to the arterial puncture were classified according to Society of Interventional Radiology (SIR) classification and analyzed retrospectively. RESULTS: There were 199 antegrade arterial punctures, of which 28 (14%) were planned SFA punctures, performed in 184 patients. All patients had ultrasound-guided puncture. The sheath size ranged from 4 F to 8 F. In 2 of 28 (7%) SFA punctures, a closure device was deployed compared with 43 of 171 (25%) CFA punctures. Six bleeding complications were noted in the CFA puncture group (6 of 171 [3.5%]), of which 2 required urgent operations (repair of a pseudoaneurysm and evacuation of retroperitoneal hematoma). In comparison, only one minor groin hematoma was noted in the SFA puncture group; this did not require any further treatment. No thromboembolic complications were associated with SFA puncture. CONCLUSIONS: Planned antegrade SFA puncture under ultrasound guidance can be performed safely in selected cases with no added morbidity. Interventionalists should have a low threshold for considering antegrade SFA puncture as a first-line access site, especially in patients with a hostile groin. PMID- 22832142 TI - Hemodynamic changes after balloon occlusion of the splenic artery during balloon occluded retrograde transvenous obliteration for gastric varices. AB - PURPOSE: To elucidate changes in hemodynamics after balloon occlusion of the splenic artery during balloon-occluded retrograde transvenous obliteration (B RTO). MATERIALS AND METHODS: In eight patients who had B-RTO for a gastric varix, the balloon-occluded venous pressure of the drainage vein was measured, and balloon-occluded retrograde venography (B-RTV) was performed with and without occlusion of the splenic artery during B-RTO. The pressure and the degrees of the variceal complex visualized on B-RTV were compared between those with and without occlusion of the splenic artery. RESULTS: In seven of the eight patients, balloon occluded venous pressure of the drainage vein decreased after balloon occlusion of the splenic artery. A paired t test showed that the mean decrease from 21.88 mm Hg to 18.38 mm Hg was statistically significant (P = .0033). From findings of B-RTV, the variceal complex was more extensively visualized after occlusion of the splenic artery in seven of the eight patients. CONCLUSIONS: Balloon occlusion of the splenic artery during B-RTO for gastric varices can produce changes in hemodynamics related to gastric varices and has the potential to prompt the sclerosing agent to distribute more extensively and evenly in the gastric varix. PMID- 22832143 TI - Multimodal visibility of a modified polyzene-F-coated spherical embolic agent for liver embolization: feasibility study in a porcine model. AB - PURPOSE: To evaluate multimodal visibility of modified currently available microspheres on radiography, magnetic resonance (MR) imaging, and computed tomography (CT) in a porcine liver model. MATERIALS AND METHODS: Livers of four pigs were embolized with two sizes (100 MUm +/- 25 and 700 MUm +/- 50) of modified Embozene Microspheres embedded with different densities of barium sulfate and iodine as radiopaque materials (intensity groups A-C, with increasing intensity from A to C for 100 MUm and intensities A and C for 700 MUm) and iron oxide as magnetic substance for MR imaging visibility. Pigs embolized with currently available Embozene Microspheres served as control groups. Pre- and postinterventional MR imaging (T1- and T2-weighted) and CT were performed. Qualitative and quantitative (ie, determination of signal-to-noise ratio [SNR]) particle visibility was evaluated on radiography, MR imaging, and CT. RESULTS: Modified particles of both sizes were visible on radiography, MR imaging, and CT. Particles in the control group were not visible. For modified particles of both sizes, SNRs measured on MR imaging decreased significantly after embolization (eg, cluster analysis of group A, 100 MUm +/- 50 particles, T1-weighted, -74.6% +/- 3.4; P = .03). For modified particles of both sizes, SNR measured on CT increased significantly after embolization (eg, cluster analysis of group A, 700 MUm +/- 25 particles, +54.3% +/- 13.5; P = .03). CONCLUSIONS: Modification of currently available Embozene Microspheres was successful, with multimodal visibility on radiography, MR imaging, and CT in porcine liver. In the future, this might improve procedure accuracy and allow monitoring, control, and improvement of embolotherapy during and after the procedure. PMID- 22832144 TI - Comparison of 3D and 2D FSE T2-weighted MRI in the diagnosis of deep pelvic endometriosis: preliminary results. AB - AIM: To evaluate image quality and diagnostic accuracy of two- (2D) and three dimensional (3D) T2-weighted magnetic resonance imaging (MRI) for the evaluation of deep infiltrating endometriosis (DIE). MATERIALS AND METHODS: One hundred and ten consecutive patients with suspicion of endometriosis were recruited at two institutions over a 5-month period. Twenty-three women underwent surgery, 18 had DIE at histology. Two readers independently evaluated 3D and 2D MRI for image quality and diagnosis of DIE. Descriptive analysis, chi-square test for categorical or nominal variables, McNemar test for comparison between 3D and 2D T2-weighted MRI, and weighted "statistics" for intra- and interobserver agreement were used for statistical analysis. RESULTS: Both readers found that 3D yielded significantly lower image quality than 2D MRI (p < 0.0001). Acquisition time for 3D was significantly shorter than 2D MRI (p < 0.01). 3D offered similar accuracy to diagnose DIE compared to 2D MRI. For all locations of endometriosis, a high or variable intra-observer agreement was observed for reader 1 and 2, respectively. CONCLUSIONS: Despite a lower overall image quality, 3D provides significant time saving and similar accuracy than multiplanar 2D MRI in the diagnosis of specific DIE locations. PMID- 22832145 TI - Ultrasound of penetrating ocular injury in a combat environment. AB - Penetrating eye injuries are uncommon in a civilian environment, but unfortunately, very common in a military emergency department. Ultrasound of the eye is quick, reliable, accurate, and easy to learn. This review aims to demonstrate normal anatomy and penetrating injuries of the anterior and posterior compartments of the eye. PMID- 22832146 TI - Incidence of induced abortion by age and state, Mexico, 2009: new estimates using a modified methodology. AB - CONTEXT: Because abortion laws in Mexico, which are generally highly restrictive, are determined by individual states, state-level data are essential for policymakers to make informed decisions. In addition, age-specific abortion estimates are needed, given societal concern about young women's risk for unwanted pregnancy and abortion. METHODS: The Abortion Incidence Complications Method, an established approach designed to obtain national and broad regional estimates, was extended to produce for the first time estimates for age-groups and states. Data included government statistics on postabortion patients and health professionals' estimates concerning abortion complications. States were classified into six regions according to level of development. RESULTS: In 2009, the abortion rate in Mexico was 38 per 1,000 women aged 15-44. The rate was 54 per 1,000 in Region 1 (Mexico City), the most developed region; 35-41 per 1,000 in Regions 2, 3 and 4, which are moderately developed; and 26-27 in Regions 5 and 6, which are the least developed. States' rates of abortion incidence and treatment for induced abortion complications were generally consistent with development level, although exceptions emerged. Age-specific abortion rates peaked among women aged 20-24 and then steadily declined with age; this pattern was observed nationally, regionally and in most states. CONCLUSION: Extension of the Abortion Incidence Complications Method to obtain state- and age-specific data is feasible. Unsafe abortion is common in all states of Mexico, especially among women aged 15-24, suggesting a need for improved family planning and postabortion services. PMID- 22832147 TI - Increasing postpartum contraception in rural India: evaluation of a community based behavior change communication intervention. AB - CONTEXT: The Indian family planning program, though successful in increasing contraceptive use among couples who have achieved their desired family size, has not been equally successful in educating couples about the use of contraceptive methods for birth spacing. METHODS: An evaluation was conducted of a behavior change communication intervention integrated into the existing government program to increase knowledge and use of the lactational amenorrhea method and postpartum contraception through counseling by community workers. The intervention, which ran between September 2006 and January 2007, was conducted among 959 pregnant women aged 15-24 who lived in Uttar Pradesh, India. The evaluation used logistic regression analyses to measure differences in knowledge and contraceptive use between baseline and the four- and nine-month postpartum follow-up surveys within and between the intervention and comparison groups. RESULTS: The follow-up data show increases in knowledge of the lactational amenorrhea method and spacing methods and in use of spacing methods. At four months postpartum, women in the intervention group were more likely to know the healthy spacing messages than those in the comparison group (odds ratio, 2.1). At nine months postpartum, women in the intervention group, those with higher knowledge of healthy spacing practices and those with correct knowledge of two or more spacing methods were more likely than others to be using a contraceptive method (1.5-3.5). Use of modern contraceptives for spacing at nine months postpartum was 57% in the intervention group versus 30% in the comparison group. CONCLUSIONS: Targeted behavior change communication using community workers is an effective and feasible strategy for promoting postpartum contraception. PMID- 22832148 TI - Women's empowerment and ideal family size: an examination of DHS empowerment measures in Sub-Saharan Africa. AB - CONTEXT: The Demographic and Health Survey (DHS) program collects data on women's empowerment, but little is known about how these measures perform in Sub-Saharan African countries. It is important to understand whether women's empowerment is associated with their ideal number of children and ability to limit fertility to that ideal number in the Sub-Saharan African context. METHODS: The analysis used couples data from DHS surveys in four Sub-Saharan African countries: Guinea, Mali, Namibia and Zambia. Women's empowerment was measured by participation in household decision making, attitudes toward wife beating and attitudes toward refusing sex with one's husband. Multivariable linear regression was used to model women's ideal number of children, and multivariable logistic regression was used to model women's odds of having more children than their ideal. RESULTS: In Guinea and Zambia, negative attitudes toward wife beating were associated with having a smaller ideal number of children (beta coefficients, -0.5 and -0.3, respectively). Greater household decision making was associated with a smaller ideal number of children only in Guinea (beta coefficient, -0.3). Additionally, household decision making and positive attitudes toward women's right to refuse sex were associated with elevated odds of having more children than desired in Namibia and Zambia, respectively (odds ratios, 2.3 and 1.4); negative attitudes toward wife beating were associated with reduced odds of the outcome in Mali (0.4). CONCLUSIONS: Women's empowerment--as assessed using currently available measures--is not consistently associated with a desire for smaller families or the ability to achieve desired fertility in these Sub-Saharan African countries. Further research is needed to determine what measures are most applicable for these contexts. PMID- 22832149 TI - Treatment-seeking for symptoms of reproductive tract infections among young women in India. AB - CONTEXT: Small proportions of Indian women report seeking treatment for symptoms suggestive of reproductive tract infections (RTIs). Most studies on treatment seeking have focused broadly on women of reproductive age, and little is known about the experiences of adolescent girls and young women, particularly the unmarried. METHODS: Data from 2,742 married and 2,108 unmarried women aged 15-24 who reported at least one symptom of an RTI in the past three months were drawn from a subnationally representative survey of youth in India in 2006-2008. Multivariate logistic regression analysis was conducted to identify associations between respondents' characteristics and treatment-seeking from a formal medical provider. In addition, among those who had used such providers, associations between characteristics and use of private rather than public providers were identified. RESULTS: About two-fifths of married and one-third of unmarried women had sought treatment from formal medical providers for their RTI symptoms. While married women's experience of intimate partner violence was negatively associated with seeking treatment from a formal provider (odds ratio, 0.8), their perceived access to sexual and reproductive health services and their awareness of STI symptoms were positively associated with such treatment (1.3-1.4). Both married and unmarried women were more likely to seek treatment from private than from public providers, and two indicators of women's autonomy were positively correlated with using private providers (1.6-2.8). CONCLUSIONS: Limited treatment seeking for RTI symptoms by young women underscores the need to address power imbalances within marriage and to encourage health care providers to develop appropriate strategies to reach younger, as well as unmarried, women. PMID- 22832150 TI - Ethnic inequality in Guatemalan women's use of modern reproductive health care. AB - CONTEXT: Guatemala has some of the poorest reproductive health indices and largest disparities in health in Latin America, particularly between indigenous and ladina women. To reduce these disparities, it is necessary to understand how indigenous women's disadvantages in linguistic, socioeconomic or residential characteristics relate to their underutilization of reproductive health services. METHODS: Logistic regression analyses of a nationally representative sample of women aged 15-49 from the 2008-2009 National Survey of Maternal and Infant Health were used to estimate ethnic disparities in women's use of institutional prenatal care and delivery, and in met demand for modern contraceptives. Using predicted probabilities, we estimated the extent to which these disparities were attributable to a language barrier among indigenous women and to their disadvantage in selected socioeconomic and residential characteristics. RESULTS: The ethnic difference in use of institutional prenatal care was small; however, institutional delivery was far less common among indigenous women than among ladina women (36% vs. 73%), as was met need for modern contraceptives (49% vs. 72%). Not speaking Spanish accounted for the largest portion of these ethnic differentials. Indigenous women's poor education and rural residence made up smaller portions of the ethnic differential in modern contraceptive use than did their economic disadvantage. CONCLUSION: The large proportion of indigenous women who use institutional prenatal care suggests that further integrating the three services may increase their use of institutional delivery and modern contraceptives. Adding speakers of local Mayan languages to the staff of health facilities could also help increase use. PMID- 22832151 TI - ST peak during primary percutaneous coronary intervention predicts final infarct size, left ventricular function, and clinical outcome. AB - BACKGROUND AND PURPOSE: One third of patients treated with primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction develop a secondary increase in electrocardiographic ST segment (ST peak) during reperfusion. The purpose was to determine the clinical importance of ST peak during primary PCI. METHODS: A total of 363 patients with ST-elevation myocardial infarction were stratified to no ST peak or ST peak. Final infarct size and ejection fraction (EF) were assessed by cardiovascular magnetic resonance. RESULTS: Patients with ST peak had a larger infarct size (14% vs 10%; P = .003) and lower EF (53% vs 57%; P = .022). Rates of cardiac mortality (8% vs 3%; P = .047) and cardiac events (cardiac mortality and admission for heart failure; 19% vs 10%; P = .018) were higher among patients with ST peak, but not all-cause mortality (8% vs 5%; P = .46). In a multivariable Cox regression analysis, ST peak remained significantly associated with cardiac events (adjusted hazard ratio, 2.03 [1.08-3.82]). CONCLUSION: ST peak during primary PCI is related to larger final infarct size, a reduced EF, and adverse cardiac clinical outcome. PMID- 22832152 TI - Development and application of a longitudinal electrocardiogram repository: the Framingham Heart Study. AB - The electrocardiogram (ECG) has widespread use in clinical care and research. Despite its extensive use and study, important gaps remain in examining prospective, repeated longitudinal ECG measures, and their association with cardiovascular outcomes. The Framingham Heart Study (FHS) is a community-based study designed to examine risk factors and outcomes associated with cardiovascular disease. Here, we describe a novel effort in the FHS to develop a unique resource: serial ECGs conducted on 3 generations of study participants spanning multiple decades (1986 to the present). We describe the FHS and the role the ECG has had in conducting cardiovascular epidemiology in the FHS. We then describe potential applications for a longitudinal ECG repository. We expect the Framingham ECG repository to enhance cardiovascular research and epidemiologic study. Such a resource will complement the phenotypic and genotypic characterization of FHS, facilitating novel investigations of cardiovascular epidemiology. PMID- 22832153 TI - A complete right bundle-branch block masking Brugada syndrome. AB - A 69-year-old man without structural heart disease was admitted for syncope. His electrocardiogram displayed complete right bundle branch (CRBBB). A coved type ST elevation was observed with transient normalization of CRBBB giving rise to a normal QRS. These findings suggest that Brugada syndrome can be masked by CRBBB. PMID- 22832154 TI - Associations of relative weight with subsequent changes over time in insomnia symptoms: a follow-up study among middle-aged women and men. AB - BACKGROUND: Obese people tend to report more insomnia symptoms than their normal weight counterparts. However, longitudinal studies are sparse. We aimed to examine whether relative weight is associated with changes over time in insomnia symptoms. METHODS: The data were derived from the prospective Helsinki Health Study cohort among 40-60-year-old employees of the City of Helsinki. Baseline survey data were collected in 2000-2002 (n=8960, response rate 67%) and follow-up data in 2007 (n=7332, response rate 83%). Body mass index (BMI) was calculated from self-reported height and weight. Insomnia symptoms were measured at baseline and follow-up. Multinomial logistic regression analysis was used. RESULTS: 45% of women and 59% of men were overweight or obese at baseline. Most participants reported at least occasional or transient insomnia symptoms, with 29% of women and 34% of men reporting no or rare symptoms at both time points. Adjusting for age, baseline BMI was strongly associated with persistent and increasing insomnia symptoms. The associations mainly remained after adjustments for marital status, occupational class, alcohol consumption, physical inactivity, common mental disorders, physical health, and employment status. CONCLUSION: BMI is a strong determinant of persistent and increasing insomnia symptoms. Successful maintenance of a healthy body weight probably helps prevent insomnia symptoms, and their increase and persistence, among both women and men. PMID- 22832155 TI - L1-penalized N-way PLS for subset of electrodes selection in BCI experiments. AB - Recently, the N-way partial least squares (NPLS) approach was reported as an effective tool for neuronal signal decoding and brain-computer interface (BCI) system calibration. This method simultaneously analyzes data in several domains. It combines the projection of a data tensor to a low dimensional space with linear regression. In this paper the L1-Penalized NPLS is proposed for sparse BCI system calibration, allowing uniting the projection technique with an effective selection of subset of features. The L1-Penalized NPLS was applied for the binary self-paced BCI system calibration, providing selection of electrodes subset. Our BCI system is designed for animal research, in particular for research in non human primates. PMID- 22832156 TI - Calcium-sensing receptor activation increases cell-cell adhesion and beta-cell function. AB - BACKGROUND/AIMS: The extracellular calcium-sensing receptor (CaR) is expressed in pancreatic beta-cells where it is thought to facilitate cell-to-cell communication and augment insulin secretion. However, it is unknown how CaR activation improves beta-cell function. METHODS: Immunocytochemistry and western blotting confirmed the expression of CaR in MIN6 beta-cell line. The calcimimetic R568 (1uM) was used to increase the affinity of the CaR and specifically activate the receptor at a physiologically appropriate extracellular calcium concentration. Incorporation of 5-bromo-2'-deoxyuridine (BrdU) was used to measure cell proliferation, whilst changes in non-nutrient-evoked cytosolic calcium were assessed using fura-2-microfluorimetry. AFM-single-cell-force spectroscopy related CaR-evoked changes in epithelial (E)-cadherin expression to improved functional tethering between coupled cells. RESULTS: Activation of the CaR over 48hr doubled the expression of E-cadherin (206+/-41%) and increased L type voltage-dependent calcium channel expression by 70% compared to control. These changes produced a 30% increase in cell-cell tethering and elevated the basal-to-peak amplitude of ATP (50uM) and tolbutamide (100uM)-evoked changes in cytosolic calcium. Activation of the receptor also increased PD98059 (1-100uM) and SU1498 (1-100uM)-dependent beta-cell proliferation. CONCLUSION: Our data suggest that activation of the CaR increases E-cadherin mediated functional tethering between beta-cells and increases expression of L-type VDCC and secretagogue-evoked changes in [Ca(2+)](i). These findings could explain how local changes in calcium, co-released with insulin, activate the CaR on neighbouring cells to help ensure efficient and appropriate secretory function. PMID- 22832157 TI - Elevated serum IL-6, IL-8, MCP-1, CRP, and IFN-gamma levels in 10- to 11-year-old boys with increased BMI. AB - BACKGROUND/AIMS: Many inflammation parameters are associated with obesity, but few comparable data are found in youth. This study aims to characterize the differences in serum levels of 13 biochemical inflammatory markers between boys with increased BMI and boys with normal BMI, and examine the relationships between inflammation markers, skinfold thicknesses, and body composition. PARTICIPANTS/METHODS: The participants were 38 boys (BMI above 85th percentile) and 38 boys (normal BMI) at the age of 10-11 years. Measurements included BMI, 9 skinfold thicknesses, waist and hip circumferences, and total body and trunk fat mass and percentage as indices of obesity, fasting insulin, glucose, and serum concentrations of IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFN-gamma, TNF-alpha, IL 1alpha, IL-1beta, monocyte chemoattractant protein-1 (MCP-1), epidermal growth factor, and CRP. RESULTS: Overweight boys (OWB) were taller and more frequently in puberty than normal-weight boys (NWB). Skinfold thicknesses and body composition parameters were higher in OWB. They had significantly higher serum IL 6, IL-8, IFN-gamma, MCP-1, and CRP values compared to NWB. CONCLUSIONS: Six of 13 measured biochemical markers were significantly increased in OWB, indicating that many low-grade inflammatory processes are already involved in the development of obesity in childhood. PMID- 22832158 TI - All for one and one for all! Disparity between overall crew's and individual rowers' pacing strategies during rowing. AB - PURPOSE: This study examined individual contributions to overall pacing strategy during 2- and 5-km rowing trials in a coxless-4 boat. METHODS: A crew of 4 male rowers performed maximal-effort on-water trials over 2 and 5 km, and power output during every individual stroke was measured for each crew member. Mean overall boat and individual rower stroke power were calculated for each 25% epoch (25% of total strokes taken), and power for each individual epoch was calculated as a percentage of mean power maintained over the entire distance. The coefficient of variation was used to determine stroke-to-stroke and epoch-to-epoch variability for individual rowers and the overall boat. RESULTS: In both trials, the overall pacing strategy consisted of a high power output in the initial 25% that decreased in the middle 50% and increased again in the final 25%. However, individual rower data indicate wide variation in individual power profiles that did not always mimic the overall boat profile. CONCLUSIONS: This study demonstrates that overall boat power profiles during 2- and 5-km rowing trials are similar to velocity profiles previously reported for individual ergometry and on-water racing events. However, this overall profile is achieved despite considerable variation in individual rower profiles. Further research is warranted to determine the mechanisms through which individual contributions to overall pacing strategy are regulated and the effectiveness or otherwise of seemingly disparate individual strategies on overall performance. PMID- 22832159 TI - Long telomeres bypass the requirement for telomere maintenance in human tumorigenesis. AB - Despite the importance of telomere maintenance in cancer cell survival via the elongation of telomeres by telomerase reverse transcriptase (TERT) or alternative lengthening of telomeres (ALT), it had not been tested directly whether telomere maintenance is dispensable for human tumorigenesis. We engineered human tumor cells containing loxP-flanked hTERT to enable extensive telomere elongation prior to complete hTERT excision. Despite unabated telomere erosion, hTERT-excised cells formed tumors in mice and proliferated in vitro for up to 1 year. Telomerase reactivation or ALT was not observed, and the eventual loss of telomeric signal coincided with loss of tumorigenic potential and cell viability. Crisis was averted via the reintroduction of active but not inactive hTERT. Thus, telomere maintenance is dispensable for human tumorigenesis when telomere reserves are long. Yet, despite telomere instability and the presence of oncogenic RAS, human tumors remain susceptible to crisis induced by critically short telomeres. PMID- 22832160 TI - Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency. AB - Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes. PMID- 22832161 TI - Frequent recent origination of brain genes shaped the evolution of foraging behavior in Drosophila. AB - The evolution of the brain and behavior are coupled puzzles. The genetic bases for brain evolution are widely debated, yet whether newly evolved genes impact the evolution of the brain and behavior is vaguely understood. Here, we show that during recent evolution in Drosophila, new genes have frequently acquired neuronal expression, particularly in the mushroom bodies. Evolutionary signatures combined with expression profiling showed that natural selection influenced the evolution of young genes expressed in the brain, notably in mushroom bodies. Case analyses showed that two young retrogenes are expressed in the olfactory circuit and facilitate foraging behavior. Comparative behavioral analysis revealed divergence in foraging behavior between species. Our data suggest that during adaptive evolution, new genes gain expression in specific brain structures and evolve new functions in neural circuits, which might contribute to the phenotypic evolution of animal behavior. PMID- 22832162 TI - Optimization of gene expression through divergent mutational paths. AB - Adaptation under similar selective pressure often leads to comparable phenotypes. A longstanding question is whether such phenotypic repeatability entails similar (parallelism) or different genotypic changes (convergence). To better understand this, we characterized mutations that optimized expression of a plasmid-borne metabolic pathway during laboratory evolution of a bacterium. Expressing these pathway genes was essential for growth but came with substantial costs. Starting from overexpression, replicate populations founded by this bacterium all evolved to reduce expression. Despite this phenotypic repetitiveness, the underlying mutational spectrum was highly diverse. Analysis of these plasmid mutations identified three distinct means to modulate gene expression: (1) reducing the gene copy number, (2) lowering transcript stability, and (3) integration of the pathway-bearing plasmid into the host genome. Our study revealed diverse molecular changes beneath convergence to a simple phenotype. This complex genotype-phenotype mapping presents a challenge to inferring genetic evolution based solely on phenotypic changes. PMID- 22832163 TI - miR-511-3p modulates genetic programs of tumor-associated macrophages. AB - Expression of the mannose receptor (MRC1/CD206) identifies macrophage subtypes, such as alternatively activated macrophages (AAMs) and M2-polarized tumor associated macrophages (TAMs), which are endowed with tissue-remodeling, proangiogenic, and protumoral activity. However, the significance of MRC1 expression for TAM's protumoral activity is unclear. Here, we describe and characterize miR-511-3p, an intronic microRNA (miRNA) encoded by both mouse and human MRC1 genes. By using sensitive miRNA reporter vectors, we demonstrate robust expression and bioactivity of miR-511-3p in MRC1(+) AAMs and TAMs. Unexpectedly, enforced expression of miR-511-3p tuned down the protumoral gene signature of MRC1(+) TAMs and inhibited tumor growth. Our findings suggest that transcriptional activation of Mrc1 in TAMs evokes a genetic program orchestrated by miR-511-3p, which limits rather than enhances their protumoral functions. Besides uncovering a role for MRC1 as gatekeeper of TAM's protumoral genetic programs, these observations suggest that endogenous miRNAs may operate to establish thresholds for inflammatory cell activation in tumors. PMID- 22832164 TI - The mechanisms of repetitive spike generation in an axonless retinal interneuron. AB - Several types of retinal interneurons exhibit spikes but lack axons. One such neuron is the AII amacrine cell, in which spikes recorded at the soma exhibit small amplitudes (<10 mV) and broad time courses (>5 ms). Here, we used electrophysiological recordings and computational analysis to examine the mechanisms underlying this atypical spiking. We found that somatic spikes likely represent large, brief action potential-like events initiated in a single, electrotonically distal dendritic compartment. In this same compartment, spiking undergoes slow modulation, likely by an M-type K conductance. The structural correlate of this compartment is a thin neurite that extends from the primary dendritic tree: local application of TTX to this neurite, or excision of it, eliminates spiking. Thus, the physiology of the axonless AII is much more complex than would be anticipated from morphological descriptions and somatic recordings; in particular, the AII possesses a single dendritic structure that controls its firing pattern. PMID- 22832165 TI - An unbiased analysis method to quantify mRNA localization reveals its correlation with cell motility. AB - Localization of mRNA is a critical mechanism used by a large fraction of transcripts to restrict its translation to specific cellular regions. Although current high-resolution imaging techniques provide ample information, the analysis methods for localization have either been qualitative or employed quantification in nonrandomly selected regions of interest. Here, we describe an analytical method for objective quantification of mRNA localization using a combination of two characteristics of its molecular distribution, polarization and dispersion. The validity of the method is demonstrated using single-molecule FISH images of budding yeast and fibroblasts. Live-cell analysis of endogenous beta-actin mRNA in mouse fibroblasts reveals that mRNA polarization has a half life of ~16 min and is cross-correlated with directed cell migration. This novel approach provides insights into the dynamic regulation of mRNA localization and its physiological roles. PMID- 22832166 TI - Changes in object recognition and anxiety-like behaviour in mice expressing a Cx47 mutation that causes Pelizaeus-Merzbacher-like disease. AB - Pelizaeus-Merzbacher-like disease is characterized by impaired psychomotor development, ataxia, progressive spasticity and mental retardation. It is induced by mutations in the gap junction gene GJC2 that encodes for the gap junction protein connexin 47. Mice bearing a human Cx47M283T missense mutation have been generated as a transgenic mouse model of Pelizaeus-Merzbacher-like disease. Homozygous expression of the mutant connexin 47 gene in oligodendrocytes resulted in a complex and variable neuropathologic phenotype, which was associated with impairments in motor coordination in juvenile, but not adult mice. In the present study, we have investigated anxiety-like behaviour and spatial working memory in juvenile (P23) and adult (3-month-old) Cx47M282T mutant mice. Adult Cx47M282T mice were also evaluated in terms of neuromotor functions and in the novel object recognition test. Juvenile Cx47M282T mutant mice exhibited an increase in anxiety like behaviour in the open field test, but no changes in spatial working memory performance. No significant changes in anxiety-like behaviour, spatial working memory or neuromotor functions were observed in the adult Cx47M282T mutant mice. However, novel object recognition was significantly impaired in adult Cx47M282T mice. Our results suggest that the expression of the human Cx47M282T mutation in the mouse causes changes in anxiety-like behaviour in juvenile and novel object recognition impairments in adult mice. It appears that the distortion of panglial gap junction coupling in white and grey matter tissue in the Cx47M282T mice is associated with a complex age-dependent behavioural phenotype including changes in psychomotor, emotional and memory functions. PMID- 22832168 TI - Quantitative evaluation of periprosthetic infection by real-time polymerase chain reaction: a comparison with conventional methods. AB - Several recent studies have demonstrated the limited accuracy of conventional culture methods for diagnosing periprosthetic infections. We have applied real time polymerase chain reaction (PCR) assays for the rapid identification of bacteria around implants and reported its utility. However, the capability of quantification is also a useful feature of this type of assay. The aim of our study was to validate the usefulness of quantitative analyses using real-time PCR of cases with clinical periprosthetic infections in comparison with more established tests, such as C-reactive protein (CRP) levels, microbiologic cultures, and histopathology. Fifty-six joints with suspected infections were reviewed retrospectively. A universal PCR assay was used to perform the quantitative analyses. The differences in the threshold cycles between clinical samples and a negative control (?Ct) in each case were calculated. The results of the quantitative PCR assay were compared with CRP levels, microbiologic cultures, and histopathology. There was a significant correlation found between the CRP and ?Ct values. There were also significant differences found in the ?Ct values according to CRP levels, with higher CRP levels showing higher ?Ct values. Similarly, there were significant differences in the ?Ct measurements in our culture results and among our pathologic evaluations. We confirmed that quantification by universal PCR based on the ?Ct correlated with preoperative CRP levels and was associated with the microbiologic culture results and pathologic severity. This quantification method may be valuable for assessing infection severity. PMID- 22832167 TI - [Development of an instrument for the assessment of chronic care models]. AB - OBJECTIVE: To present the context, aim and process of designing the Instrument for the Assessment of Chronic Care Models (Instrumento de Evaluacion de Modelos de Atencion ante la Cronicidad [IEMAC]), which was developed to make the conceptual framework of the chronic care model operational in the Spanish national health system. METHODS: The IEMAC was developed by a series of national experts with distinct profiles of expertise using qualitative research techniques. A matrix was built with the dimensions selected as basic for the new model. In each dimension, actions were identified and categorized, creating a taxonomy of components and interventions. The clarity and appropriateness of each intervention, and the degree of evidence to support it, were assessed. The resulting questionnaire was validated by other experts from diverse disciplines and settings. Finally, the IEMAC 1.0 was piloted at macro, meso and micro levels. RESULTS: The IEMAC is a tool to be self-administered by health organizations at macro, meso and micro levels. This instrument is composed of six dimensions, 27 components and 80 interventions, whose implementation is assessed with the aid of a scale that combines deployment, systematic evaluation, and orientation improvement. The IEMAC uses a systemic, population-based approach and integrates promotion, prevention, and coordination with social services. CONCLUSIONS: The IEMAC contains a set of interventions that can be used as a road map by decision makers, managers and clinicians interested in building a state-of-the-art chronic care model. At the same time, the IEMAC allows healthcare organizations to identify their baseline score and the progress achieved after improvement interventions. PMID- 22832169 TI - The relationship between adult separation anxiety disorder and complicated grief in a cohort of 454 outpatients with mood and anxiety disorders. AB - BACKGROUND: Recent epidemiological studies indicate that separation anxiety disorder occurs more frequently in adults than children. Data from literature suggest that Adult Separation Anxiety Disorder (ASAD) may develop after a bereavement or threat of loss. Research has demonstrated that bereaved persons may present a clinically significant grief reaction, defined as Complicated Grief (CG) that causes a severe impairment in the quality of life. The aim of this study was to evaluate the relationship between ASAD and CG in a large cohort of outpatients with mood and anxiety disorders. METHODS: Study participants comprised 454 adult psychiatric outpatients with DSM-IV mood or anxiety disorders diagnoses. Diagnostic assessments were performed using the SCID-I; ASAD was assessed using an adapted version of the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-adult). Complicated grief symptoms were assessed by the Inventory of Complicated Grief (ICG). Social and work impairments were evaluated using the Sheehan Disability Scale (SDS). Adult attachment styles were assessed by the Relationship Questionnaire (RQ). RESULTS: The overall frequency of ASAD in our sample was 43% and that of CG was 23%. Individuals with CG had a greater frequency of ASAD (56%) with respect to those without CG (40%). Subjects with CG plus ASAD reported higher scores on ICG and greater impairment on quality of life, as measured with SDS, than CG patients without ASAD. CONCLUSIONS: Adult separation anxiety disorder occurs in a high proportion of adult psychiatric outpatients with complicated grief. The association between these two conditions should be further investigated in light of their clinical implications. PMID- 22832170 TI - Residual memory dysfunction in recurrent major depressive disorder--a longitudinal study from Juntendo University Mood Disorder Project. AB - BACKGROUND: Depression may increase the risk of developing Alzheimer's disease. Large cohort studies have shown that recurrent depression is associated with a risk of developing dementia. Other studies have documented smaller hippocampal volume in patients with recurrent depression. It is speculative that a greater risk of developing dementia may result from a higher number of previous depressive episodes. This study compared patients with recurrent and single episode depression in the remitted stage, and healthy controls to elucidate the impact of the number of depressive episodes on memory. METHODS: Logical memory and visual reproduction subtests of the Wechsler Memory Scale-Revised were given to 68 patients with major depressive disorder (MDD) (30 patients with a single episode and residual 38 patients with recurrent multiple episodes) and 57 healthy controls. The patients with MDD received memory assessment at the time of initial remission and at the follow-up period 3 years after remission. RESULTS: At the time of initial remission, scores of both logical memory and visual reproduction subtests were significantly lower in both patient groups compared with healthy controls. At follow-up, memory dysfunction of the single-episode group disappeared, whereas scores in the recurrent group remained significantly lower than those of the single-episode group and controls. LIMITATIONS: All patients in the present study were on antidepressant medications. CONCLUSIONS: Patients with recurrent MDD with multiple depressive episodes showed residual memory dysfunction even after 3 years of remission. Persistence of memory deficits in the recurrent depression may be a risk factor for developing dementia. PMID- 22832171 TI - Changes in saccadic eye movement (SEM) and quantitative EEG parameter in bipolar patients. AB - BACKGROUND: There is increasing evidence that neurocognitive dysfunction is associated with the different states in Bipolar Disorder. Gamma coherence is strongly related to cognitive processes and cortico-cortical communication. This paper aims at shedding light on the relationship between cortical gamma coherence within bipolar patients and a control group during a prosaccadic attention task. We hypothesized that gamma coherence oscillations act as a main neural mechanism underlying information processing which changes in bipolar patients. METHOD: Thirty-two (12 healthy controls and 20 bipolar patients) subjects were enrolled in this study. The subjects performed a prosaccadic attention task while their brain activity pattern was recorded using quantitative electroencephalography (20 channels). RESULTS: We observed that the maniac group presented lower saccade latency when compared to depression and control groups. The main finding was a greater gamma coherence for control group in the right hemisphere of both frontal and motor cortices caused by the execution of a prosaccadic attention task. LIMITATIONS: The findings need to be confirmed in larger samples and in bipolar patients before start the pharmacological treatment. CONCLUSIONS: Our findings suggest a disrupted connection of the brain's entire functioning of maniac patients and represent a deregulation in cortical inhibitory mechanism. Thus, our results reinforce our hypothesis that greater gamma coherence in the right and left frontal cortices for the maniac group produces a "noise" during information processing and highlights that gamma coherence might be a biomarker for cognitive dysfunction during the manic state. PMID- 22832172 TI - The effects of psychotherapy for adult depression on suicidality and hopelessness: a systematic review and meta-analysis. AB - BACKGROUND: Although treatment guidelines suggest that suicidal patients with depression should be treated for depression with psychotherapy, it is not clear whether these psychological treatments actually reduce suicidal ideation or suicide risk. METHODS: We conducted a systematic review and meta-analysis of studies on psychotherapy for depression in which outcomes on suicidality were reported. We also focused on outcomes on hopelessness because this is strongly associated with suicidal behavior in depression. RESULTS: Thirteen studies (with 616 patients) were included, three of which examined the effects of psychotherapy for depression on suicidal ideation and suicide risk, and eleven on hopelessness. No studies were found with suicide attempts or completed suicides as the outcome variables. The effects on suicidal ideation and suicide risk were small (g=0.12; 95% CI: -0.20-0.44) and not statistically significant. A power calculation showed that these studies only had sufficient power to find an effect size of g=0.47. The effects on hopelessness were large (g=1.10; 95% CI: 0.72-1.48) and significant, although heterogeneity was very high. Furthermore, significant publication bias was found. After adjustment of publication bias the effect size was reduced to g=0.60. DISCUSSION: At this point, there is insufficient evidence for the assumption that suicidality in depressed patients can be reduced with psychotherapy for depression. Although psychotherapy of depression may have small positive effects on suicidality, available data suggest that psychotherapy for depression cannot be considered to be a sufficient treatment. The effects on hopelessness are probably higher. PMID- 22832173 TI - New materials from proteins and peptides. AB - In this review we highlight recent accomplishments in the design of materials from proteins and peptides. Examples include hydrogels made from aggregating designed beta-hairpin peptides, whose physical properties respond to small changes in the amino acid composition of the peptide; materials that combine different segments of natural elastomeric proteins - such as elastin, resilin, silk fibroin whose bulk properties are dictated in unanticipated ways by their composition; and hydrogels formed by strings or arrays of protein modules, which are cross-linked by multivalent versions of their peptide ligands, and which may exhibit exquisite stimuli-responsive behavior. The suitability of the unique properties of such new materials for practical applications is also considered. PMID- 22832174 TI - Squaring theory with practice in RNA design. AB - Ribonucleic acid (RNA) design offers unique opportunities for engineering genetic networks and nanostructures that self-assemble within living cells. Recent years have seen the creation of increasingly complex RNA devices, including proof-of concept applications for in vivo three-dimensional scaffolding, imaging, computing, and control of biological behaviors. Expert intuition and simple design rules--the stability of double helices, the modularity of noncanonical RNA motifs, and geometric closure--have enabled these successful applications. Going beyond heuristics, emerging algorithms may enable automated design of RNAs with nucleotide-level accuracy but, as illustrated on a recent RNA square design, are not yet fully predictive. Looking ahead, technological advances in RNA synthesis and interrogation are poised to radically accelerate the discovery and stringent testing of design methods. PMID- 22832175 TI - Intravenous tissue plasminogen activator therapy for an acute ischemic stroke patient with later diagnosed unilateral moyamoya syndrome. AB - We report the use of intravenous tissue plasminogen activator (t-PA) therapy in a 38-year-old patient who was later diagnosed with unilateral moyamoya syndrome. The patient had a sudden onset of unconsciousness, vomiting, dysarthria, and tetraparesis. A neurologic examination revealed consciousness disturbance, right central facial nerve palsy, dysarthria, and tetraparesis with bilateral exotropia and horizontal gaze palsy. A magnetic resonance imaging scan on admission did not reveal fresh cerebral infarction or hemorrhage, but magnetic resonance angiography revealed severe stenosis at the terminal portion of left internal carotid artery, the anterior cerebral arteries, and the right vertebral artery. We suspected infarction of brain stem. The patient was treated with intravenous t PA approximately 2.5 hours after onset, and the patient demonstrated a remarkable recovery 1 day after onset and had only a minimal deficit at discharge (12 days after onset). Cerebral angiography 7 days after onset confirmed the diagnosis of moyamoya disease. The present case suggests that therapeutic intravenous t-PA may be applicable for an acute ischemic stroke patient coexisting with moyamoya disease after careful evaluation and discussion with patient and family. PMID- 22832176 TI - Staining characteristics of Lonchocarpus cyanescens leaf extract on the testis of Sprague-Dawley rats. AB - The use of nonallergic, nontoxic, and eco-friendly natural dyes has become a matter of significant importance due to increased environmental awareness on the need to avoid hazardous synthetic dyes. This study was to determine the staining properties of the dye extract of Lonchocarpus cyanescens on histomorphology of the testis. Freshly cut leaves of L. cyanescens obtained from Akpan Ifia Inan village in Ikono local government area of Akwa Ibom state (latitude 5 degrees 10' 12" N; longitude 7 degrees 48' 0" E) were put into a plastic jar and boiling water was poured to cover the leaves. It was covered and left for an hour. The liquid was strained and potassium hydroxide was added to the dye water mixture to reach a pH of 9. A whisk was used to mix air into the liquid, and the mixuture was then allowed to sit until the blue indigo had settled to the bottom of the container. The dye was diluted with 70% ethanol to a concentration of 0.1 g/mL and was used to stain sections of testes. Its potential for use as a counterstain was also investigated. The testes sections were stained in shades of blue. The dye overshadowed the colors of haematoxylin and eosin. Preliminary phytochemical screening of L. cyanescens revealed that it contains alkaloids, saponins, flavonoids, and tannins. PMID- 22832177 TI - Hoping for more: the influence of outcome desirability on information seeking and predictions about relative quantities. AB - People must often engage in sequential sampling in order to make predictions about the relative quantities of two options. We investigated how directional motives influence sampling selections and resulting predictions in such cases. We used a paradigm in which participants had limited time to sample items and make predictions about which side of the screen contained more of a critical item. Sampling selections were biased by monetary desirability manipulations, and participants exhibited a desirability bias for both dichotomous and continuous predictions. PMID- 22832178 TI - The role of memory consolidation in generalisation of new linguistic information. AB - Accounts of memory that postulate complementary learning systems (CLS) have become increasingly influential in the field of language learning. These accounts predict that generalisation of newly learnt linguistic information to untrained contexts requires offline memory consolidation. Such generalisation should not be observed immediately after training, as these accounts claim unconsolidated representations are context and hippocampus-dependent and gain contextual and hippocampal independence only after consolidation. We trained participants on new affixes (e.g., -nule) attached to familiar word stems (e.g., buildnule), testing them immediately or 2days later. Participants showed an immediate advantage for trained affixes in a speeded shadowing task as long as these affixes occurred in the stem contexts in which they were learnt (e.g., buildnule). This learning effect generalised to words with untrained stems (e.g., sailnule) only in the delayed test condition. By contrast, a non-speeded definition selection task showed immediate generalisation. We propose that generalisation can be supported by initial context-dependent memories given sufficient processing time, but that context-independent lexical representations emerge only following consolidation, as predicted by CLS accounts. PMID- 22832179 TI - How framing statistical statements affects subjective veracity: validation and application of a multinomial model for judgments of truth. AB - Extending the well-established negativity bias in human cognition to truth judgments, it was recently shown that negatively framed statistical statements are more likely to be considered true than formally equivalent statements framed positively. However, the underlying processes responsible for this effect are insufficiently understood. Therefore, a multinomial processing tree model is herein proposed to distinguish between differences in (a) knowledge or (b) response bias that may account for the framing effect. Three model validation experiments supported the psychological interpretability of model parameters. Model application revealed that the framing effect can be considered a bias: Given insufficient knowledge, individuals more likely guessed "true" when faced with a negatively framed statistical statement. The probability of conclusive knowledge, however, remained constant across frames. In summary, this article puts forwards and validates a formal model that can be used more generally to investigate processes underlying truth judgments. Based on this model, it is herein shown that one particular phenomenon - framing effects observed for statistical statements - can be considered a response bias, rather than the upshot of differential knowledge. PMID- 22832180 TI - [Control of bronchial asthma in children seen in a primary care centre]. AB - OBJECTIVES: This study aimed to assess the level of asthma control in children aged 6 to 14 years old in a Primary Care Centre. METHODOLOGY: A cross-sectional descriptive study was conducted on asthmatic children aged 6 to 14 years old followed up in a Primary Health Care Centre in a metropolitan area of Barcelona. The Asthma Control Test (ACT) was the tool used to measure asthma control. Asthma was considered to be well controlled with an ACT score >20. Demographic and disease specific data were also collected. RESULTS: A total of 46 patients (45% girls, 55% boys) completed the ACT. Their mean age was 8,9 years (SD 2.8). The prevalence of poorly controlled asthma was 41.3%. A family history of asthma was found in 36% of the children, and 43% of them declared to have activity limitations. CONCLUSIONS: The high percentage of poorly controlled asthma in children raises the need for reviewing the effectiveness in the processes to improve asthma control in these patients. PMID- 22832181 TI - The veil of ignorance and health resource allocation. AB - Some authors view the veil of ignorance as a preferred method for allocating resources because it imposes impartiality by stripping deliberators of knowledge of their personal identity. Using some prominent examples of such reasoning in the health care sector, I will argue for the following claims. First, choice behind a veil of ignorance often fails to provide clear guidance regarding resource allocation. Second, regardless of whether definite results could be derived from the veil, these results do not in themselves have important moral standing. This is partly because the veil does not determine which features are morally relevant for a given distributive problem. Third, even when we have settled the question of what features to count, choice behind a veil of ignorance arguably fails to take persons seriously. Ultimately, we do not need the veil to solve distributive problems, and we have good reason to appeal to some other distributive model. PMID- 22832182 TI - Design considerations in developing a text messaging program aimed at smoking cessation. AB - BACKGROUND: Cell phone text messaging is gaining increasing recognition as an important tool that can be harnessed for prevention and intervention programs across a wide variety of health research applications. Despite the growing body of literature reporting positive outcomes, very little is available about the design decisions that scaffold the development of text messaging-based health interventions. What seems to be missing is documentation of the thought process of investigators in the initial stages of protocol and content development. This omission is of particular concern because many researchers seem to view text messaging as the intervention itself instead of simply a delivery mechanism. Certainly, aspects of this technology may increase participant engagement. Like other interventions, however, the content is a central driver of the behavior change. OBJECTIVE: To address this noted gap in the literature, we discuss the protocol decisions and content development for SMS Turkey (or Cebiniz birakin diyor in Turkish), a smoking cessation text messaging program for adult smokers in Turkey. METHODS: Content was developed in English and translated into Turkish. Efforts were made to ensure that the protocol and content were grounded in evidence-based smoking cessation theory, while also reflective of the cultural aspects of smoking and quitting in Turkey. RESULTS: Methodological considerations included whether to provide cell phones and whether to reimburse participants for texting costs; whether to include supplementary intervention resources (eg, personal contact); and whether to utilize unidirectional versus bidirectional messaging. Program design considerations included how messages were tailored to the quitting curve and one's smoking status after one's quit date, the number of messages participants received per day, and over what period of time the intervention lasted. CONCLUSION: The content and methods of effective smoking cessation quitline programs were a useful guide in developing SMS Turkey. Proposed guidelines in developing text messaging-based behavior change programs are offered. PMID- 22832183 TI - Companions reverse stressor-induced decreases in neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in dentate gyrus. AB - The presence of companions can reverse the stressor-induced decrease in neurogenesis in mouse dentate gyrus (DG). In this study, we decided to study the underlying mechanisms of the companions' protective effect and to assess whether two DG neurogenesis-related memories, cocaine-induced conditioned place preference (CPP) and spatial memory, can be affected by our stressor and companions. Neurotrophin levels in DG were measured, in this regard, to reveal their roles in mediating the stressors' and companions' effect. We found that the stressor did not affect NT-3 but acutely decreased NGF and BDNF levels in DG. The presence of companions abolished these stressor-decreased NGF and BDNF levels. Neither the stressor nor the presence of companions affected TrkA, TrkB or TrkC expression in DG. Pre-exposure to the stressor rendered deficits in cocaine induced CPP and spatial memory, while companions reversed the stressor-decreased cocaine-induced CPP. Intra-ventricular infusion with K252a, a mixed TrkA and TrkB antagonist, did not affect the protective effects of companions on local NGF, BDNF levels in DG, but abolished the companions' protective effects against the stressor-decreased DG neurogenesis and cocaine-induced CPP. Systemic pretreatment with 7,8-dihydroxyflavone (DHF), a selective TrkB agonist, did not affect baseline, the stressor-stimulated corticosterone (CORT) secretion or local NGF, BDNF levels in DG, but in part mimicked companions' protective effects. These results, taken together, indicate that stressor-decreased NGF and BDNF levels in DG could be involved in the stressor-decreased DG neurogenesis and cocaine conditioning. The presence of companions reverses the stressor-decreased DG neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in DG. PMID- 22832184 TI - Maternal stress alters the developmental program of embryonic hippocampal neurons growing in vitro. AB - Maternal stress results in behavioral and anatomical alterations that persist during adult life. Here we demonstrate that hippocampal neurons cultured from embryos of stressed mothers exhibit faster development of their soma and neuritic arbor with an increase in the number of presynaptic terminals compared to cultured neurons from embryos of non-stressed mothers. Therefore, the impact of maternal stress on developing neurons is maintained even when these cells are dissociated from the brain and differentiated in vitro. PMID- 22832185 TI - Cone beam CT evaluation of maxillary sinus septa prevalence, height, location and morphology in children and an adult population. AB - OBJECTIVE: The purpose of this study was to determine the prevalence, height, location and morphology of maxillary sinus septa in dentate, partially dentate and edentulous adults as well as in mixed dentition children using cone beam computed tomography (CBCT) for maxillary sinus surgical interventions. SUBJECTS AND METHODS: Five hundred and fifty-four sides in the CBCT scans of 272 patients (30 children and 242 adults) were retrospectively analyzed. The prevalence, location and morphology were assessed in axial, sagittal, cross-sectional and panoramic 3-dimensional images. The height of septa was measured with the angle between the direction of the septum and median palatine suture. The differences among age, localization and measurements were statistically analyzed. RESULTS: The prevalence of maxillary sinus segments with septa was 58%. There were a total of 13 (3.2%) septa of completely edentulous (CE), 198 (53.9%) septa of edentate and 14 (3.8%) septa of the mixed dentition maxillary segments. The location of septa observed in all study groups demonstrated a greater prevalence (69.1%) in the middle region than in the anterior and posterior regions. No statistically significant differences were observed with regard to gender or age, for septum height (p > 0.05). However, maxillary sinus septa are higher in partially edentulous patients than edentate and CE ones (p < 0.05). CONCLUSION: Septa of various heights and courses developed in all parts of the maxillary sinus, therefore to prevent possible complications during sinus surgery, extensive evaluation with an appropriate radiographic technique was indispensable. PMID- 22832186 TI - Persistent organic pollutants in the Scheldt estuary: environmental distribution and bioaccumulation. AB - Levels of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs) were determined in the sediment and several species (European flounder, Platichthys flesus; common sole, Solea solea; Chinese mitten crab, Eriocheir sinensis; shore crab, Carcinus maenas; brown shrimp, Crangon crangon; blue mussel, Mytilus edulis and bristle worms, Polychaeta) from 7 locations in the Scheldt estuary (SE, the Netherlands Belgium). Overall POP levels in the sediment were low. The average PCB and PBDE concentrations were respectively 31.5 and 115 ng/g dry weight (dw). Highest sediment loads were measured in the vicinity of Antwerp (368 ng PCBs/g dw), a location with intense harbor and industrial activities. Pollution concentrations in the tissues of biota were species-specific. Blue mussels contained the highest lipid concentrations (2.74+/-0.55%) and reached the highest contamination levels (from 287 to 1688 ng PCBs/g ww, from 2.09 to 12.4 ng PBDEs/g ww). Lowest tissue loads were measured in brown shrimp (from 3.27 to 39.9 ng PCBs/g ww, from 0.05 to 0.47 ng PBDEs/g ww). The PCB congener profile in most of the species was similar with the pattern found in the sediment. PCB 153 was the most abundant congener (16.5-25.7% in biota, 10.4% in sediment). In the sediment, the total amount of PBDEs consisted for more than 99% of BDE 209. Congener BDE 47 had the highest concentrations in all sampled species (38.5-70.1%). Sediment POP loadings and tissue concentrations were poorly correlated, indicating that a simple linear or non-linear relationship is insufficient to describe this relationship, possible caused by the complexity of the bioaccumulation processes and the variability in exposure. Because of the high PCB levels, regular consumption of fish and seafood, especially mussels, from the Scheldt estuary should be avoided. PMID- 22832187 TI - Drugs of abuse in wastewater and suspended particulate matter--further developments in sewage epidemiology. AB - This manuscript reports, for the first time, a monitoring study analysing wastewater and associated suspended particulate matter (SPM) to determine the concentration of drugs of abuse and metabolites in wastewater influent. The monitoring of SPM is crucial for target analytes because, depending on their physico-chemical properties, they may partition to particulates; thus, analysis of wastewater only will result in under-reporting of the concentration of target analytes in the sample. A daily one week monitoring study was carried out at a WWTP serving one of the largest cities in the Czech Republic; representing the first comprehensive application of the sewage epidemiology approach in the Czech Republic. In total, 60 analytes were targeted in the monitoring programme including stimulants, opioid and morphine derivatives, benzodiazepines, antidepressants, dissociative anaesthetics, drug precursors and their metabolites. Analysis of SPM determined that significant proportions of some compounds were present on the solids. For example, 21.0-49.8% of the total concentration of EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) in the sample was determined on SPM and 11.2-19.6% of methadone. The highest proportion on SPM was determined for fluoxetine in the range 68.1-79.6%, norfluoxetine 46.6 61.9% and amitriptyline 21.8-51.2%. In contrast, some compounds presented very little partitioning to SPM. Less than 5% was determined partitioned to SPM over the week period for analytes including cocaine, benzoylecgonine, cocaethylene, amphetamine, methamphetamine, MDMA (3,4-methylenedioxymethamphetamine), codeine, dihydrocodeine, tramadol, nortramadol, oxazepam and ephedrine. Determined concentrations in wastewater influent were subsequently utilised in the sewage epidemiology approach to estimate drug consumption, in the community from which the wastewater was derived. This back-calculation was updated for the first time to include the concentration of analytes present on SPM. The consumption of methamphetamine and MDMA was determined to be especially high in the studied community in relation to other European countries, while cocaine and methadone consumption was relatively low. This manuscript shows that in order to apply the sewage epidemiology approach, SPM analysis is required for some compounds; whereas for others the partitioning is small and one may regard this as negligible. PMID- 22832188 TI - Alterations in the infrared spectral signature of avian feathers reflect potential chemical exposure: a pilot study comparing two sites in Pakistan. AB - Chemical contamination of ecosystems is a global issue with evidence that pollutants impact on living organisms in a harmful fashion. Developing sensor approaches that would allow the derivation of biomarkers or signatures of effect in target sentinel organisms and monitor environmental chemical contamination in a high throughput manner is of utmost importance. As biomolecules absorb infrared (IR), signature vibrational spectra related to structure and function can be derived. In light of this, we tested the notion that IR spectra of bird feathers might reflect environmental chemical contaminant exposure patterns. Feathers were collected from monospecific heronries of cattle egret based in two independent locations (Trimu vs. Mailsi) in the Punjab province of Pakistan; these sites were found to differ in their chemical contamination patterns. Feather samples were chemically analyzed for polychlorinated biphenyls, polybrominated diphenyl ethers, organochlorines and heavy metals. Attenuated total reflection Fourier transform IR (ATR-FTIR) spectroscopy was employed to derive a spectral signature of individual feathers. Resultant IR spectra were then subjected to canonical correspondence analysis (CAA) to determine whether feather spectral signatures correlate to chemical exposure. Additionally, we explored if principal component analysis (PCA) and linear discriminant analysis (LDA) could be applied to distinguish site-specific differences; linear discriminant function (LDF) was also applied to classify sites. The sampled feathers varied in their chemical exposure patterns depending on whether they were sourced from one site associated with heavy metal exposure or the other which suggested high organic pollutant exposures. CCA of chemical and spectral data showed a correlation between spectral signatures and chemical exposure. PCA-LDA readily distinguished feathers from the two different sites. Discriminating alterations were identified and these were associated with protein and lipid regions in IR spectra. Additionally, LDF showed that the classification rate of spectral categories correlated well with the two chemical exposure patterns (93.6% for Trimu feathers and 91.77% for Mailsi feathers). This pilot study suggests that IR spectra derived from feathers reflect background chemical exposure and points to a novel monitoring tool for contamination. PMID- 22832189 TI - Vertebral choristoma in lipomyelomeningocele: a case report. AB - Lipomeningocele is a type of occult spinal dysraphism characterized by a subcutaneous lipomatous mass that protrudes through a midline bony defect. We report a rare presentation of this condition--a vertebral choristoma wherein the lipomatous mass displaced the normally formed posterior elements--lamina and spinous process of L4 vertebra dorsally to an abnormal location in the absence of a bony defect. PMID- 22832190 TI - Immunochemical analysis of mutant CFTR in lung explants. AB - BACKGROUND/AIMS: Knowledge about the abundance and distribution of CFTR protein glycoforms in native lung tissue is scarce. For upcoming studies with correctors and potentiators for CFTR it is important to get more information about mutant CFTR protein biochemistry. Target for novel treatment is the most afflicted organ in cystic fibrosis (CF), the lung. METHODS: Lung tissue sampled from patients with CF and non-CF donors prior to lung transplantation was examined for CFTR immunoreactive signals by immunoblot. Quantitation of the immunoreactive signals was carried out by densitometry. RESULTS: The complex-glycosylated and mannose rich CFTR isoforms were present in all non-CF specimens, whereas no or only the immature CFTR isoform was visible in CF samples. Whereas some complex glycosylated CFTR was often present in rectal biopsies of F508del homozygous subjects, no mature CFTR was detectable in CF lungs at the stage of terminal respiratory insufficiency. CONCLUSION: Immunoblot analysis of CFTR in lung tissue is feasible, but in context of the upcoming studies of CFTR correctors and potentiators rectal biopsies seem to be a more appropriate choice because of their safe and repeatable excision. PMID- 22832191 TI - Neuroimaging of ventriculomegaly in the fetal period. AB - Fetal cerebral ventriculomegaly (VM) is defined as an enlargement of the lateral ventricles of the developing fetal brain. It is diagnosed when the width of one or both lateral ventricles, measured at the level of the atrium, is >=10 mm. VM is defined as mild when the atrial width is 10-15 mm and severe when >15 mm. VM is a non-specific sonographic sign which is common to various pathological conditions. It is frequently associated with neural and extraneural anomalies. The rate of associated malformations is higher (>=60%) in severe VM and lower (about 40%) in cases of mild VM. When an abnormality is associated with severe VM the incidence of aneuploidies is high (>15%); in isolated mild VM the mean value of aneuploidy is 2.7%. The rate of infections in severe VM is 10-20%, in mild forms 1-5%. Since the prognosis in cases of VM depends mainly on the associated anomalies, a careful examination of the fetus, particularly of the brain, is mandatory. Magnetic resonance imaging can be a useful diagnostic tool complementary to ultrasound in order to recognize subtle brain anomalies, such as neuronal migration and proliferation disorders. PMID- 22832192 TI - The X-ray crystal structure of full-length human plasminogen. AB - Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change. PMID- 22832193 TI - VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. AB - Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen (OVA), VEGF-C protected tumors against preexisting antitumor immunity and promoted local deletion of OVA-specific CD8(+) T cells. Naive OVA specific CD8(+) T cells, transferred into tumor-bearing mice, were dysfunctionally activated and apoptotic. Lymphatic endothelial cells (LECs) in dLNs cross-presented OVA, and naive LECs scavenge and cross-present OVA in vitro. Cross-presenting LECs drove the proliferation and apoptosis of OVA-specific CD8(+) T cells ex vivo. Our findings introduce a tumor-promoting role for lymphatics in the tumor and dLN and suggest that lymphatic endothelium in the local microenvironment may be a target for immunomodulation. PMID- 22832194 TI - Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9. AB - Activation of the complement system results in formation of membrane attack complexes (MACs), pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational changes, distinct from those observed in the homologous C3 to-C3b transition. C6 captures this conformation, which is preserved in the larger sC5b9 assembly. Together with antibody labeling, these structures reveal that complement components associate through sideways alignment of the central MAC-perforin (MACPF) domains, resulting in a C5b6-C7-C8beta-C8alpha-C9 arc. Soluble regulatory proteins below the arc indicate a potential dual mechanism in protection from pore formation. These results provide a structural framework for understanding MAC pore formation and regulation, processes important for fighting infections and preventing complement-mediated tissue damage. PMID- 22832195 TI - Transient noise amplification and gene expression synchronization in a bistable mammalian cell-fate switch. AB - Progenitor cells within a clonal population show variable proclivity toward lineage commitment and differentiation. This cell-to-cell variability has been attributed to transcriptome-wide gene expression noise generated by fluctuations in the amount of cellular machinery and stochasticity in the biochemical reactions involved in protein synthesis. It therefore remains unclear how a signaling network, in the presence of such noise, can execute unequivocal cell fate decisions from external cues. Here, we use mathematical modeling and model guided experiments to reveal functional interplay between instructive signaling and noise in erythropoiesis. We present evidence that positive transcriptional feedback loops in a lineage-specific receptor signaling pathway can generate ligand-induced memory to engender robust, switch-like responses. These same feedback loops can also transiently amplify gene expression noise in the signaling network, suggesting that external cues can actually bias seemingly stochastic decisions during cell-fate specification. Gene expression levels among key effectors in the signaling pathway are uncorrelated in the initial population of progenitor cells but become synchronized after addition of ligand, which activates the transcriptional feedback loops. Finally, we show that this transient noise amplification and gene expression synchronization induced by ligand can directly influence cell survival and differentiation kinetics within the population. PMID- 22832197 TI - DnaK functions as a central hub in the E. coli chaperone network. AB - Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity. Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL. Quantitative proteomics revealed that DnaK interacts with at least ~700 mostly cytosolic proteins, including ~180 relatively aggregation-prone proteins that utilize DnaK extensively during and after initial folding. Upon deletion of TF, DnaK interacts increasingly with ribosomal and other small, basic proteins, while its association with large multidomain proteins is reduced. DnaK also functions prominently in stabilizing proteins for subsequent folding by GroEL. These proteins accumulate on DnaK upon GroEL depletion and are then degraded, thus defining DnaK as a central organizer of the chaperone network. Combined loss of DnaK and TF causes proteostasis collapse with disruption of GroEL function, defective ribosomal biogenesis, and extensive aggregation of large proteins. PMID- 22832198 TI - Possession is not always the law: with age, preschoolers increasingly use verbal information to identify who owns what. AB - Children can identify owners either by seeing a person in possession of an object (a visual cue) and inferring that they are the owner or by hearing testimony about a claim of ownership (a verbal cue). A total of 391 children between 2.5 and 6 years of age were tested in three experiments assessing how children identify owners when these two cues are in conflict. Children were presented with stories using two dolls and a toy. One doll possessed the toy, and children were told that the toy was either the possessor's or the nonpossessor's. Two forms of ownership statement were used: a third-person statement, "That is Billy's ball", and a first-person statement by one of the dolls, "That is my ball". The results show that by 4 years of age, children prioritize the verbal statements as a more reliable cue to ownership than physical possession. Younger children did not prioritize possession over the verbal cue to ownership but rather gave mixed responses. These results are discussed in terms of children's social experience outside of the home and their acceptance of testimony in other domains. PMID- 22832199 TI - Competence with fractions predicts gains in mathematics achievement. AB - Competence with fractions predicts later mathematics achievement, but the codevelopmental pattern between fractions knowledge and mathematics achievement is not well understood. We assessed this codevelopment through examination of the cross-lagged relation between a measure of conceptual knowledge of fractions and mathematics achievement in sixth and seventh grades (N=212). The cross-lagged effects indicated that performance on the sixth grade fractions concepts measure predicted 1-year gains in mathematics achievement (beta=.14, p<.01), controlling for the central executive component of working memory and intelligence, but sixth grade mathematics achievement did not predict gains on the fractions concepts measure (beta=.03, p>.50). In a follow-up assessment, we demonstrated that measures of fluency with computational fractions significantly predicted seventh grade mathematics achievement above and beyond the influence of fluency in computational whole number arithmetic, performance on number fluency and number line tasks, central executive span, and intelligence. Results provide empirical support for the hypothesis that competence with fractions underlies, in part, subsequent gains in mathematics achievement. PMID- 22832196 TI - Mechanoprotection by polycystins against apoptosis is mediated through the opening of stretch-activated K(2P) channels. AB - How renal epithelial cells respond to increased pressure and the link with kidney disease states remain poorly understood. Pkd1 knockout or expression of a PC2 pathogenic mutant, mimicking the autosomal dominant polycystic kidney disease, dramatically enhances mechanical stress-induced tubular apoptotic cell death. We show the presence of a stretch-activated K(+) channel dependent on the TREK-2 K(2P) subunit in proximal convoluted tubule epithelial cells. Our findings further demonstrate that polycystins protect renal epithelial cells against apoptosis in response to mechanical stress, and this function is mediated through the opening of stretch-activated K(2P) channels. Thus, to our knowledge, we establish for the first time, both in vitro and in vivo, a functional relationship between mechanotransduction and mechanoprotection. We propose that this mechanism is at play in other important pathologies associated with apoptosis and in which pressure or flow stimulation is altered, including heart failure or atherosclerosis. PMID- 22832200 TI - Metabolic imaging using two-photon excited NADH intensity and fluorescence lifetime imaging. AB - Metabolism and mitochondrial dysfunction are known to be involved in many different disease states. We have employed two-photon fluorescence imaging of intrinsic mitochondrial reduced nicotinamide adenine dinucleotide (NADH) to quantify the metabolic state of several cultured cell lines, multicell tumor spheroids, and the intact mouse organ of Corti. Historically, fluorescence intensity has commonly been used as an indicator of the NADH concentration in cells and tissues. More recently, fluorescence lifetime imaging has revealed that changes in metabolism produce not only changes in fluorescence intensity, but also significant changes in the lifetimes and concentrations of free and enzyme bound pools of NADH. Since NADH binding changes with metabolic state, this approach presents a new opportunity to track the cellular metabolic state. PMID- 22832201 TI - Muscle strength, body composition, and performance of an elite shot-putter. AB - PURPOSE: Although muscle mass and strength are thought to be closely related to throwing performance, there are few scientific data about these parameters in elite shot-putters. The purpose of this case report was to present longitudinal data for muscle strength and body composition in relation to performance of an elite male shot-putter. METHODS: A male national champion with the best rotational shot-put performance of 20.36 m (in 2010) was followed from 2003 to 2011 (current age: 29 y). Data regarding body composition (dual X-ray absorptiometry), as well as 1-repetition-maximum muscle strength (bench press, squat, snatch) and rotational shot-put performance, were collected every February for the last 9 y, 4 wk before the national indoor championship event. RESULTS: The athlete's personal-best performances in squat, bench press, and snatch were 175 kg, 210 kg, and 112.5 kg, respectively. His peak total lean body mass was 92.4 kg, bone mineral density 1.55 g/cm2, and lowest body fat 12.9%. His shot-put performance over these 9 years was significantly correlated with 1-repetition maximum squat strength (r = .93, P < .01), bench press (r = .87, P < .01), and snatch (r = .92, P < .01). In contrast, shot-put performance was not significantly correlated with any of the body-composition parameters. CONCLUSIONS: The results of this case study suggest that elite rotational shot put performance may not be directly correlated with lean body mass. Instead, it seems that it is closely related with measures of muscle strength. PMID- 22832202 TI - A double-blind placebo-controlled study to evaluate endometrial safety and gynaecological symptoms in women treated for up to 5 years with tamoxifen or placebo - a substudy for IBIS I Breast Cancer Prevention Trial. AB - AIMS OF THE STUDY: This prospective study was performed to investigate the effects of 5-year's use of tamoxifen in preventive setting on endometrium and gynaecological symptoms. MATERIAL AND METHODS: Altogether 96 women were treated either with tamoxifen (TAM, n=45) or placebo (PLA, n=51) for up to 5 years in a randomised, double-blind IBIS I breast cancer prevention trial, clinically followed-up for an additional year and for the occurrence of malignancies at least 9 years between 2/1995 and 7/2009 in Finland. The gynaecological follow-up with trans-vaginal ultrasound and endometrial biopsies were performed at baseline, at 2.5 and 5 years and at the 6 years follow-up visit. RESULTS: Women in the TAM group discontinued the treatment significantly more often (44% versus 22%; p=0.017) and earlier (at 15 versus 30 months; p=0.044), than those in the PLA group. In postmenopausal women the median endometrial thickness was significantly increased at five years in the TAM group (median 4.3 versus 2.0mm, p=0.011), but there was no difference between the groups at one year after the treatment. There were also statistically significantly more referrals to hospitals due to gynaecological findings in the TAM group (risk rates (RR) 3.15; 95% confidence intervals (CI) 1.12-10.10), but no differences in hysterectomy rates or other serious adverse event rates were observed. CONCLUSIONS: The discontinuation rate in the TAM group was high, and the discontinuations also occurred early. Even though there were significantly more non-serious gynaecological events during the TAM treatment, routine gynaecological follow-up cannot be recommended. PMID- 22832203 TI - Effects of levonorgestrel-releasing intrauterine system and T380A intrauterine copper device on dysmenorrhea and days of bleeding in women with and without adenomyosis. AB - BACKGROUND: The study was conducted to compare the levonorgestrel intrauterine system (LNG-IUS) and Copper T380A intrauterine device (IUD) in women with and without adenomyosis and to investigate the effects on menstruation and dysmenorrhea. STUDY DESIGN: Women diagnosed as having adenomyosis on transvaginal ultrasound were assigned to receive LNG-IUS (Group 1, n=23), and women seeking contraception were assigned to receive either LNG-IUS (Group 2, n=25) or Copper T380A IUD (Group 3, n=26) for 12 months. RESULTS: The LNG-IUS significantly improved the duration of menstrual bleeding, dysmenorrhea and hemoglobin levels at the 1st and 12th month of the treatment in Group 1 and Group 2 as compared to Group 3. Moreover, LNG-IUS had similar efficacy but significantly lower side effects when compared to Copper T380A regarding contraception. However, acne was significantly increased after insertion in women using LNG-IUS. CONCLUSIONS: The LNG-IUS results in significant improvements in adenomyosis-associated heavy menstrual bleeding and dysmenorrhea. Moreover, this study also shows that it is an effective contraceptive method with significantly lower side effects compared to CuT 380A IUD except for acne. PMID- 22832204 TI - Time-dependent approach for single trial classification of covert visuospatial attention. AB - Recently, several studies have started to explore covert visuospatial attention as a control signal for brain-computer interfaces (BCIs). Covert visuospatial attention represents the ability to change the focus of attention from one point in the space without overt eye movements. Nevertheless, the full potential and possible applications of this paradigm remain relatively unexplored. Voluntary covert visuospatial attention might allow a more natural and intuitive interaction with real environments as neither stimulation nor gazing is required. In order to identify brain correlates of covert visuospatial attention, classical approaches usually rely on the whole alpha-band over long time intervals. In this work, we propose a more detailed analysis in the frequency and time domains to enhance classification performance. In particular, we investigate the contribution of alpha sub-bands and the role of time intervals in carrying information about visual attention. Previous neurophysiological studies have already highlighted the role of temporal dynamics in attention mechanisms. However, these important aspects are not yet exploited in BCI. In this work, we studied different methods that explicitly cope with the natural brain dynamics during visuospatial attention tasks in order to enhance BCI robustness and classification performances. Results with ten healthy subjects demonstrate that our approach identifies spectro-temporal patterns that outperform the state-of the-art classification method. On average, our time-dependent classification reaches 0.74 +/- 0.03 of the area under the ROC (receiver operating characteristic) curve (AUC) value with an increase of 12.3% with respect to standard methods (0.65 +/- 0.4). In addition, the proposed approach allows faster classification (<1 instead of 3 s), without compromising performances. Finally, our analysis highlights the fact that discriminant patterns are not stable for the whole trial period but are changing over short time intervals. These results support the hypothesis that visual attention information is actually indexed by subject-specific alpha sub-bands and is time dependent. PMID- 22832205 TI - Relationship between the head deviation angle and hemineglect in patients with right hemisphere stroke. AB - BACKGROUND: Patients with hemineglect have been reported to have abnormal head posture. We attempted to determine the extent to which the angles are correlated with the severity of hemineglect. METHODS: In a prospective, single-center, cross sectional study on 40 patients with single right hemisphere stroke, we evaluated left hemineglect severity using the line bisection and line cancellation tests. Head deviation angles were measured at admission and discharge using a head device containing 3 graduated discs that determined the angles of head deviation in the sagittal, coronal and transverse planes. RESULTS: Head angles in the transverse and coronal planes differed significantly between the left hemineglect and non-hemineglect groups. Scores obtained from the line bisection and line cancellation tests correlated with these angles. Furthermore, improvement in left hemineglect after rehabilitation training corresponded to a reduction in the angles. CONCLUSION: Stroke patients with hemineglect exhibited significant head deviations in the transverse and coronal planes. Deviation angles correlated with hemineglect test scores. PMID- 22832207 TI - SOX2 autoantibodies as noninvasive serum biomarker for breast carcinoma. AB - BACKGROUND: A clear association has been established between antibodies to the transcription factor sex-determining region Y (SRY)-box 2 (SOX2) and small cell lung cancer. In light of the pathologic role of SOX2 and its aberrant expression in breast cancer, we measured serum SOX2 autoantibodies (SOX2-Abs) in breast cancer patients. METHODS: The presence of SOX2-Abs was determined by an indirect enzyme-linked immunosorbent assay (ELISA) in sera from 282 patients with breast cancer, 78 patients with benign breast disease, and 194 healthy women. RESULTS: SOX2-Abs were more prevalent in patients with breast cancer (18.4%) compared with healthy women (2.6%, P < 0.0001), and patients with benign breast disease (6.4%, P = 0.011). The concentrations of circulating SOX2-Abs were found to discriminate between breast cancer patients and healthy controls (P < 0.001) and between breast cancer patients and those with benign breast disease (P < 0.001). In addition, measurement of SOX2-Abs was more effective than assays of serum tissue polypeptide-specific antigen, carcinoembryonic antigen, carbohydrate antigen (CA) 125, and CA 15-3 in distinguishing between malignant and benign breast disease. In breast cancer patients, the prevalence of SOX2-Abs was associated with a higher tumor grade (P = 0.021) and positive nodal status (P = 0.021). CONCLUSION: The presence of SOX2-Abs in breast cancer may be of clinical value. IMPACT: This study provides the first evidence for the presence of circulating SOX2-Abs in breast cancer and shows their potential clinical application. PMID- 22832206 TI - Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study. AB - BACKGROUND: Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today. METHODS: Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users [RR, 1.60; 95% confidence interval (CI), 1.13 2.26 and RR, 2.11; 95% CI, 1.41-3.15 for <20 and >=20 g/d of alcohol], with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3 to 4 years before completing the follow up questionnaire or in the more distant past. Results were similar for estrogen receptor positive (ER+) and ER+PR+ progesterone receptors positive (PR+) tumors; while power was limited, no increase in risk was observed for ER- tumors. CONCLUSIONS: Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a nonsignificant increased risk was observed among women who never used HT. IMPACT: Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced. PMID- 22832208 TI - Animated graphics for comparing two risks: a cautionary tale. AB - BACKGROUND: The increasing use of computer-administered risk communications affords the potential to replace static risk graphics with animations that use motion cues to reinforce key risk messages. Research on the use of animated graphics, however, has yielded mixed findings, and little research exists to identify the specific animations that might improve risk knowledge and patients' decision making. OBJECTIVE: To test whether viewing animated forms of standard pictograph (icon array) risk graphics displaying risks of side effects would improve people's ability to select the treatment with the lowest risk profile, as compared with viewing static images of the same risks. METHODS: A total of 4198 members of a demographically diverse Internet panel read a scenario about two hypothetical treatments for thyroid cancer. Each treatment was described as equally effective but varied in side effects (with one option slightly better than the other). Participants were randomly assigned to receive all risk information in 1 of 10 pictograph formats in a quasi-factorial design. We compared a control condition of static grouped icons with a static scattered icon display and with 8 Flash-based animated versions that incorporated different combinations of (1) building the risk 1 icon at a time, (2) having scattered risk icons settle into a group, or (3) having scattered risk icons shuffle themselves (either automatically or by user control). We assessed participants' ability to choose the better treatment (choice accuracy), their gist knowledge of side effects (knowledge accuracy), and their graph evaluation ratings, controlling for subjective numeracy and need for cognition. RESULTS: When compared against static grouped-icon arrays, no animations significantly improved any outcomes, and most showed significant performance degradations. However, participants who received animations of grouped icons in which at-risk icons appeared 1 at a time performed as well on all outcomes as the static grouped-icon control group. Displays with scattered icons (static or animated) performed particularly poorly unless they included the settle animation that allowed users to view event icons grouped. CONCLUSIONS: Many combinations of animation, especially those with scattered icons that shuffle randomly, appear to inhibit knowledge accuracy in this context. Static pictographs that group risk icons, however, perform very well on measures of knowledge and choice accuracy. These findings parallel recent evidence in other data communication contexts that less can be more-that is, that simpler, more focused information presentation can result in improved understanding. Decision aid designers and health educators should proceed with caution when considering the use of animated risk graphics to compare two risks, given that evidence-based, static risk graphics appear optimal. PMID- 22832209 TI - Endoscopic choroid plexus coagulation in infants with hydranencephaly or hydrocephalus with a minimal cortical mantle. AB - BACKGROUND/AIMS: This study evaluates endoscopic choroid plexus coagulation, in conjunction with third ventriculostomy when technically feasible, as a strategy to treat patients with hydranencephaly or hydrocephalus with a minimal cortical mantle. METHODS: We retrospectively reviewed patients with hydranencephaly (n = 4) or hydrocephalus with the cortical mantle <1 cm in maximal thickness (n = 4) who underwent endoscopic choroid plexus coagulation from 2007 to 2010. Endoscopic third ventriculostomy was performed simultaneously when technically feasible (in 3 of 8 patients). Endoscopic management was considered successful if a shunt was not subsequently required. RESULTS: Endoscopic management was successful in 4 of 8 patients (50%) who did not require a shunt over a median follow-up period of 15 months (range 2.5-24). Four patients (50%) failed endoscopic management and required a shunt 1 month to 11 weeks after endoscopic surgery. One patient died 4 days after shunt placement due to pneumonia and renal failure. Three of 4 patients who had a successful endoscopic procedure ultimately died of causes that were likely unrelated to hydrocephalus (pneumonia in 2 patients and sudden infant death syndrome in 1 patient). Besides failure to control hydrocephalus adequately in 4 patients, there were no additional complications noted after endoscopic surgeries. CONCLUSION: Endoscopic choroid plexus coagulation can enable some infants with hydranencephaly or massive hydrocephalus to avoid a ventriculoperitoneal shunt. PMID- 22832210 TI - Gender differences in stem cell population are induced by pregnancy. AB - Gender differences in stem cell population have recently been identified. Blood and tissue samples from women showed consistent elevation of hematopoietic stem cell populations, mesenchymal stem cell populations and endothelial progenitor cells compared to men of similar ages. We and others have shown an increase in hematopoietic stem cell population in pregnant and multiparous women compared to nulliparous women. We propose that pregnancy exposes women to increased levels of stem cells from many sources not available for nulliparous women or for men. During pregnancy, maternal fetal microchimerism results from trafficking of fetal and maternal blood across the placenta. Physiological changes in the maternal blood cellular milieu are also recognized during pregnancy and in the early post partum due to the presence of unique pregnancy associated tissues and hormones. These include the placenta, the amniotic fluid and cord blood. These tissues are highly enriched for different populations of stem cells including hematopoietic stem cells, mesenchymal stem cells and endothelial progenitor cells. Recent studies showed accelerated healing in women affected by cardiovascular insults and stroke, in part due to faster tissue regeneration and stem cell activity. We propose that gender differences in stem cell population are caused in part due to maternal exposure to fetal and unique pregnancy associated tissues, which are significantly enriched in different stem cell populations. PMID- 22832211 TI - Is it possible to overcome antiapoptotic API2/MALT1 events in tumor B-cells by influencing Tregs in MALT lymphoma? AB - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises approximately 50% of primary gastric lymphoma. Proliferation of tumor cells infected with Helicobacter pylori is facilitated by the presence of T cells activated by H. pylori antigens. Unlike the majority of MALT lymphomas, tumors bearing the t(11;18)(q21;q21) resulting in production of a chimeric protein API2/MALT1 are often resistant to H. pylori eradication therapy, and require more aggressive therapeutic approach including chemotherapy. The authors hypothesize that a subset of patients with translocation-positive MALT lymphoma might benefit from a novel therapeutic approach that would address intercellular communication pathways between various cell types in the tumor microenvironment. A subset of T cells called regulatory T cells (Tregs) are one of the major immunomodulators of antitumor response mechanisms. There are several potential tools that could have a substantial impact on this particular T cell population, such as interleukin (IL)-15, indoleamine 2,3-dioxigenase (IDO), anti CD25 antibodies. Introducing some of these components into treatment protocols for patients with API2/MALT1 translocation-positive MALT lymphomas might also prove to be benefitial for other lymphomas with increased number of intratumoral Tregs. PMID- 22832212 TI - Personality disorders disturbances of the physical brain. AB - How can physical systems of the brain, explain a psychological phenomenon such as personality? Personality is an emergent property of the brain as such it requires interacting elements that generate a whole. Per definition a physical system is a compound whole made of interacting interdependent elements. The brain is composed of multiple levels of elements ranging from single neurons interconnected by axons dendrites and synapses, up to brain regions and neural network ensembles connected by multiple modalities, from direct physical pathways to synchronized functional connectivity. Today we know that the brain develops and wires according to the influences of its environment, this is called "experience dependent plasticity" and follows Hebbian-like algorithms. Such process "embeds" into the brain internal representations in the form of physical attractor configurations distributed within the brain neural-networks. Development entails formation of personal individual-specific network configurations found recently as resting-state networks or "default-mode networks." These internal configurations represent the outer world to us and determine the way we perceive it and react to it. In other words these internal configurations determine our personality styles. The internal representations continuously adapt to the changing worlds offering good adaptability and effective functionality in our changing environments. Personality disorders are reconceptualized in terms of altered disturbed mal-developed default-mode-networks, such that the internal representations are biased, limited, fixated and non-adaptive. In this context therapy of personality disorders can be reconceptualized as experience-depended plasticity therapy. PMID- 22832213 TI - Prognostic significance of serum beta-d-glucan levels in 78 patients with Trichosporon fungemia. PMID- 22832214 TI - Which body for embodied cognition? Affordance and language within actual and perceived reaching space. AB - The mental representation of one's own body does not necessarily correspond to the physical body. For instance, a dissociation between perceived and actual reach-ability has been shown, that is, individuals perceive that they can reach objects that are out of grasp. We presented participants with 3D pictures of objects located at four different distances, namely near-reaching space, actual reaching space, perceived-reaching space and non-reaching space. Immediately after they were presented with function, manipulation, observation or pointing verbs and were required to judge if the verb was compatible with the object. Participants were faster with function and manipulation verbs than with observation and pointing verbs. Strikingly, with both function and manipulation verbs participants were faster when objects were presented in actual than the perceived reaching space. These findings suggest that our knowledge of the world is implicitly built online through behaviour, and is not necessarily reflected in explicit estimates or conscious representations. PMID- 22832215 TI - I feel who I see: visual body identity affects visual-tactile integration in peripersonal space. AB - Recent studies have shown the importance of integrating multisensory information in the body representation for constituting self-consciousness. However, one idea that has received only scant attention is that our body representation is also constituted by knowledge of bodily visual characteristics (i.e. 'what I look like'). Here in two experiments we used a full body crossmodal congruency task in which visual distractors were presented on a photograph of the participant, another person, who was either familiar or unfamiliar, or an object. Results revealed that during the 'self-condition' CCEs were enhanced compared to the 'other condition'. The CCE was similar for unfamiliar and familiar others. CCEs for the object condition were significantly smaller. The results show that presentation of an irrelevant image of a body affects multimodal processing and that the effect is enhanced when that image is of the self. The results hold intriguing implications for body representation in social situations. PMID- 22832216 TI - Biodistribution of ultra small gadolinium-based nanoparticles as theranostic agent: application to brain tumors. AB - Gadolinium-based nanoparticles are novel objects with interesting physical properties, allowing their use for diagnostic and therapeutic applications. Gadolinium-based nanoparticles were imaged following intravenous injection in healthy rats and rats grafted with 9L gliosarcoma tumors using magnetic resonance imaging and scintigraphic imaging. Quantitative biodistribution using gamma counting of each sampled organ confirmed that these nanoparticles were rapidly cleared essentially by renal excretion. Accumulation of these nanoparticles in 9L gliosarcoma tumors implanted in the rat brain was quantitated. This passive and long-duration accumulation of gadolinium-based nanoparticles in tumor, which is related to disruption of the blood-brain barrier, is in good agreement with the use of these nanoparticles as radiosensitizers for brain tumors. PMID- 22832217 TI - The effect of shear on in vitro platelet and leukocyte material-induced activation. AB - The failure to understand the mechanisms of biomaterial-associated thrombosis prevents us from improving the blood compatibility of stents and mechanical heart valves. Blood-material interactions trigger a complex series of events and anticoagulant and anti-platelet therapies are needed to reduce the risks of thrombotic complications with most cardiovascular materials. While material interaction with platelets has been widely studied, little is currently known on material-induced leukocyte activation in the presence of shear. In vitro experiments were performed to assess the effect of flow on blood cell activation induced by medical grade metals, ST316L and TiAl6V4. Blood was circulated in flow chambers preloaded with or without metal wires at shear rates of 100, 500, and 1500 s-1. Platelet and leukocyte activation, leukocyte-platelet aggregation, and tissue factor expression on monocytes were measured by flow cytometry. Metal surfaces were characterized by scanning electron microscopy. Under physiological shear rates, no significant platelet microparticle formation was observed. However, significant CD11b up-regulation, leukocyte-platelet aggregates, and tissue factor expression were observed at 100 s-1. As shear rate increased to 1500 s-1, leukocyte activation reduced to control values. TiAl6V4-induced leukocyte activation was generally lower than that of ST316L. Adhesion significantly decreased with increasing shear rate to 1500 s-1. In blood, increase within physiological shear rates led to a significant reduction in in vitro material-induced leukocyte activation, suggesting that difference between material biocompatibility may be better identified at low shear rates or under pathological shear conditions. PMID- 22832218 TI - Protein polymer hydrogels: effects of endotoxin on biocompatibility. AB - Protein polymer-based hydrogels have shown potential for tissue engineering applications, but require biocompatibility testing for in vivo use. Enzymatically crosslinked protein polymer-based hydrogels were tested in vitro and in vivo to evaluate their biocompatibility. Endotoxins present in the hydrogel were removed by Trition X-114 phase separation. The reduction of endotoxins decreased TNF alpha production by a macrophage cell line in vitro; however, significant inflammatory response was still present compared to collagen control gels. A branched PEG molecule and dexamethasone were added to the hydrogel to reduce the response. In vitro testing showed a decrease in the TNF-alpha levels with the addition of dexamethasone. In vivo implantations into the epididymal fat pad of C57/BL6 mice, however, indicated a decreased inflammatory mediated immune response with a hydrogel treated with both PEGylation and endotoxin reduction. This study demonstrates the importance of endotoxin testing and removal in determining the biocompatibility of biomaterials. PMID- 22832219 TI - Structural, physicochemical and microbial properties of flocs and biofilms in integrated fixed-film activated sludge (IFFAS) systems. AB - Integrated fixed-film activated sludge systems (IFFAS) may achieve year-round nitrification or gain additional treatment capacity due to the presence of both flocs and biofilms, and the potential for multiple redox states and long solids retention time. Flocs and biofilms are distinctive microbial structures and characterization of the physicochemical and structural properties of these may provide insight into their respective roles in wastewater treatment and contaminant removal in IFFAS. Flocs and biofilms were examined from five different pilot media systems being evaluated for potential full scale implementation at a large municipal wastewater treatment plant. Flocs and biofilms within the same system possessed different surface characteristics; flocs were found to have a higher negative surface charge (-0.35 to -0.65 meq./g VSS) and are more hydrophobic (60%-75%) than biofilms (-0.05 to -0.07 meq/g VSS; 19-34%). The EPS content of flocs was significantly higher (range of 2.1-4.5 folds) than that of biofilms. In floc-derived extracellular polymeric substances (EPS), protein (PN) was clearly dominant; whereas in biofilm-derived EPS, PN and polysaccharide (PS) were present in approximately equal proportions. Biofilm EPS had a higher proportion of DNA when compared to flocs. Biofilm growth was preferential on the protected internal surfaces of the media. Colonization of the external surfaces of the media was evident by the presence of small microcolonies. The structural heterogeneity of the biofilms examined was supported by observed differences in biomass content, thickness and roughness of biofilm surface. The biofilm on the interior surface of media was found to be patchy with clusters of cells connected by an irregular arrangement of interconnecting EPS projections. Biofilm thickness ranged between 139 MUm and 253 MUm. The pattern of oxygen penetration is expected to be complex. Nitrifiers and denitrifiers were predominantly associated with the biofilms, and the latter were found to be dispersed throughout the film and arranged in micro-clusters, suggesting partial oxygen penetration. PMID- 22832220 TI - Practical approach to emergencies in lung transplant recipients: how we do it. AB - Lung transplant recipients (LTRs) are prone to medical complications and emergencies due to the transplanted organ being in constant direct contact with the environment and the need for life-long profound immunosuppression (IS). As a result of these specific circumstances, the medical and surgical management of LTRs frequently differs from usual standard care. Therefore, we outline here some of the principles we take into account when dealing with the most frequent medical emergencies encountered in our lung transplant cohort in Zurich. The main topics dealt with are: diagnostics and treatment of infections, gastrointestinal emergencies, IS and other medication issues as well as work-up of unclear inflammatory signs and peri-operative precautions in LTRs. Early post-operative transplant complications, rare medical emergencies and surgical problems are not covered. Our report is intended to help internists and pulmonologists new to the field to obtain a better understanding of the peculiarities of LTRs and their management. PMID- 22832221 TI - Dynamic coregulatory complex containing BRCA1, E2F1 and CtIP controls ATM transcription. AB - Chromosomal instability is a key feature in cancer progression. Recently we have reported that BRCA1 regulates the transcription of several genes in prostate cancer, including ATM (ataxia telangiectasia mutated). Although it is well accepted that ATM is a pivotal mediator in genotoxic stress, it is unknown whether ATM transcription is regulated during the molecular response to DNA damage. Here we investigate ATM transcription regulation in human prostate tumor PC3 cell line. We have found that doxorubicin and mitoxantrone repress ATM transcription in PC3 cells but etoposide and methotrexate do not affect ATM expression. We have demonstrated that BRCA1 binds to ATM promoter and after doxorubicin exposure, it is released. BRCA1 overexpression increases ATM transcription and this enhancement is abolished by BRCA1 depletion. Moreover, BRCA1-BRCT domain loss impairs the ability of BRCA1 to regulate ATM promoter activity, strongly suggesting that BRCT domain is essential for ATM regulation by BRCA1. BRCA1-overexpressing PC3 cells exposed to KU55933 ATM kinase inhibitor showed significant decreased ATM promoter activity compared to untreated cells, suggesting that ATM transcriptional regulation by BRCA1 is partially mediated by the ATM kinase activity. In addition, we have demonstrated E2F1 binding to ATM promoter before and after doxorubicin exposure. E2F1 overexpression diminishes ATM transcription after doxorubicin exposure which is impaired by E2F1 dominant negative mutants. Finally, the co-regulator of transcription CtIP increases ATM transcription. CtIP increases ATM transcription. Altogether, BRCA1/E2F1/CtIP binding to ATM promoter activates ATM transcription. Doxorubicin exposure releases BRCA1 and CtIP from ATM promoter still keeping E2F1 recruited and, in turn, represses ATM expression. PMID- 22832222 TI - Visualization of subunit-specific delivery of glutamate receptors to postsynaptic membrane during hippocampal long-term potentiation. AB - An increase in the number of AMPA-type glutamate receptors (AMPARs) is critical for long-term potentiation (LTP), synaptic plasticity regarded as a basal mechanism of learning and memory. However, when and how each type of AMPAR reaches the postsynaptic membrane remain unclear. We have developed experimental methods to form postsynaptic-like membrane (PSLM) on a glass surface to precisely visualize the location and movement of receptors. We observed fluorescence labeled AMPAR subunits (GluA1-3) around PSLM with total internal reflection fluorescence microscopy. The increases of GluA1, 2, and 3 in PSLM showed different time courses after LTP induction. GluA1 increased first, and was exocytosed to the periphery of PSLM soon after LTP induction. GluA2 and GluA3 initially decreased, and then increased. Exocytosis of GluA2 and GluA3 occurred primarily in non-PSLM, and later than exocytosis of GluA1. Thus, GluA1-3 appear to increase in the postsynaptic membrane through distinct pathways during LTP. PMID- 22832223 TI - RBMX: a regulator for maintenance and centromeric protection of sister chromatid cohesion. AB - Cohesion is essential for the identification of sister chromatids and for the biorientation of chromosomes until their segregation. Here, we have demonstrated that an RNA-binding motif protein encoded on the X chromosome (RBMX) plays an essential role in chromosome morphogenesis through its association with chromatin, but not with RNA. Depletion of RBMX by RNA interference (RNAi) causes the loss of cohesin from the centromeric regions before anaphase, resulting in premature chromatid separation accompanied by delocalization of the shugoshin complex and outer kinetochore proteins. Cohesion defects caused by RBMX depletion can be detected as early as the G2 phase. Moreover, RBMX associates with the cohesin subunits, Scc1 and Smc3, and with the cohesion regulator, Wapl. RBMX is required for cohesion only in the presence of Wapl, suggesting that RBMX is an inhibitor of Wapl. We propose that RBMX is a cohesion regulator that maintains the proper cohesion of sister chromatids. PMID- 22832224 TI - A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. AB - Inhibition of NEDD8-activating enzyme (NAE) has emerged as a highly promising approach to treat cancer through the adenosine sulfamate analog MLN4924. Here, we show that selective pressure results in HCT116 colorectal carcinoma cells with decreased MLN4924 sensitivity and identify a single-nucleotide transition that changes alanine 171 to threonine (A171T) of the NAE subunit UBA3. This reduces the enzyme's affinity for MLN4924 and ATP while increasing NEDD8 activation at physiological ATP concentrations. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death. Our data suggest that the on target potency of MLN4924 selects for a point mutation in NAE that overcomes the molecule's inhibitory effects, allowing cancer cell survival. PMID- 22832225 TI - IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. AB - Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation. PMID- 22832226 TI - Rhythmic nucleotide synthesis in the liver: temporal segregation of metabolites. AB - The synthesis of nucleotides in the body is centrally controlled by the liver, via salvage or de novo synthesis. We reveal a pervasive circadian influence on hepatic nucleotide metabolism, from rhythmic gene expression of rate-limiting enzymes to oscillating nucleotide metabolome in wild-type (WT) mice. Genetic disruption of the hepatic clock leads to aberrant expression of these enzymes, together with anomalous nucleotide rhythms, such as constant low levels of ATP with an excess in uric acid, the degradation product of purines. These results clearly demonstrate that the hepatic circadian clock orchestrates nucleotide synthesis and degradation. This circadian metabolome timetable, obtained using state-of-the-art capillary electrophoresis time-of-flight mass spectrometry, will guide further investigations in nucleotide metabolism-related disorders. PMID- 22832227 TI - PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. AB - The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferation of CD4(+) T cells upon stimulation through TCR and CD28. Here, we demonstrate that the suppression of this axis by deletion of p85alpha or PI3K/mTORC1 inhibitors as well as T cell-specific deletion of raptor, an essential component of mTORC1, impairs Th17 differentiation in vitro and in vivo in a S6K1/2-dependent fashion. Inhibition of PI3K-Akt-mTORC1-S6K1 axis impairs the downregulation of Gfi1, a negative regulator of Th17 differentiation. Furthermore, we demonstrate that S6K2, a nuclear counterpart of S6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORgamma, and carries RORgamma to the nucleus. These results point toward a pivotal role of PI3K-Akt-mTORC1-S6K1/2 axis in Th17 differentiation. PMID- 22832228 TI - Spatial representation of odorant valence in an insect brain. AB - Brains have to decide whether and how to respond to detected stimuli based on complex sensory input. The vinegar fly Drosophila melanogaster evaluates food sources based on olfactory cues. Here, we performed a behavioral screen using the vinegar fly and established the innate valence of 110 odorants. Our analysis of neuronal activation patterns evoked by attractive and aversive odorants suggests that even though the identity of odorants is coded by the set of activated receptors, the main representation of odorant valence is formed at the output level of the antennal lobe. The topographic clustering within the antennal lobe of valence-specific output neurons resembles a corresponding domain in the olfactory bulb of mice. The basal anatomical structure of the olfactory circuit between insects and vertebrates is known to be similar; our study suggests that the representation of odorant valence is as well. PMID- 22832229 TI - Mixed pharmaceutical wastewater treatment by integrated membrane-aerated biofilm reactor (MABR) system--a pilot-scale study. AB - A pilot-scale integrated membrane-aerated biofilm reactor (MABR) system, consisted of hydrolysis/acidification pretreatment, MABR process and activated carbon adsorption post-processing, was designed to treat the high-loading mixed pharmaceutical wastewater. A study of MABR process was conducted to investigate the effect of aeration condition, circulation flow rate and water quality on performance over 260 days. The performances of these processes were evaluated by the removal efficiency of COD, BOD(5), turbidity, NH(4)(+)-N and TN. MABR process could effectively remove above 90% of COD and 98% of ammonia. The capacities per unit volume of MABR could reach up to 1311 gCOD/m(3)d and 48.2 gNH(4)(+)-N/m(3)d with single membrane aeration, and the oxygen utilization rate could be as high as 45%. After post-processing, the effluent of integrated treatment MABR system kept stable with COD below 200 mg/L and NH(4)(+)-N below 3 mg/L. PMID- 22832230 TI - Preface--Fukushima II. PMID- 22832231 TI - Distribution and transport of radionuclides in a boreal mire--assessing past, present and future accumulation of uranium, thorium and radium. AB - The spatial distribution of (238)U, (226)Ra, (40)K and the daughters of (232)Th, (228)Ra and (228)Th, were measured in a small mire in northern Sweden. High activity concentrations of (238)U and (232)Th (up to 41 Bq (238)U kg(-1)) were observed in parts of the mire with a historical or current inflow of groundwater from the surrounding till soils, but the activities declined rapidly further out in the mire. Near the outlet and in the central parts of the mire the activity concentrations were low, indicating that uranium and thorium are immobilized rapidly upon their entering the peat. The (226)Ra was found to be more mobile with high activity concentrations further out into the mire (up to 24 Bq kg(-1)), although the central parts and the area near the outlet of the mire still had low activity concentrations. Based on the fluxes to and from the mire, it was estimated that approximately 60-70% of the uranium and thorium entering the mire currently is retained within it. The current accumulation rates were found to be consistent with the historical accumulation, but possibly lower. Since much of the accumulation still is concentrated to the edges of the mire and the activities are low compared to other measurements of these radionuclides in peat, there are no indications that the mire will be saturated with respect to radionuclides like uranium, thorium and radium in the foreseen future. On the contrary, normal peat growth rates for the region suggest that the average activity concentrations of the peat currently may be decreasing, since peat growth may be faster than the accumulation of radionuclides. In order to assess the total potential for accumulation of radionuclides more thoroughly it would, however, be necessary to also investigate the behaviour of other organophilic elements like aluminium, which are likely to compete for binding sites on the organic material. Measurements of the redox potential and other redox indicators demonstrate that uranium possibly could be reduced in parts of the mire. The results of the study suggest that this mire currently is, and historically has been, an important sink for radionuclides and that it most likely will continue to be so for a long time to come. PMID- 22832233 TI - Control of the immune system by oxysterols and cancer development. AB - Oxysterols/oxysterol receptors have been shown to modulate several immune cell subsets, such as macrophages, T-cells and B-cells, neutrophils and dendritic cells (DCs). They participate in the control of several pathologic processes, that is, infectious diseases, atherosclerosis and autoimmunity. Moreover, some oxysterols have also been shown to favor tumor progression by dampening the antitumor immune response. The cellular responses generated by oxysterols depend on the engagement of Liver X Receptor (LXR) alpha and/or beta isoforms, which induce activation of target genes or trans-repression of pro-inflammatory gene transcription. Recently, some reports have described a different mechanism of action of oxysterols, mediated by the engagement of G-Protein Coupled Receptors. Here, we summarize LXR-dependent and LXR-independent responses of oxysterols on immune cells with possible effects on tumor development. PMID- 22832232 TI - Cholesterol and its derivatives in Sonic Hedgehog signaling and cancer. AB - The connection between the Hedgehog (HH) pathway and cholesterol has been recognized since the early days that shaped our current understanding of this unique pathway. Cholesterol and related lipids are intricately linked to HH signaling: from the role of cholesterol in HH biosynthesis to the modulation of HH signal reception and transduction by other sterols, passing by the phylogenetic relationships among many components of the HH pathway that resemble or contain lipid-binding domains. Here I review the connections between HH signaling, cholesterol and its derivatives and analyze the potential implications for HH-dependent cancers. PMID- 22832234 TI - Overcoming the challenges to developing new antibiotics. AB - In order to meet the challenges of our current medical need to address infections caused by highly resistant pathogens, we propose the use of superiority trial designs. The proposed trials may or may not be statistically powered. All require extensive preclinical justification. The designs could use either historical or active controls. For historically controlled trials we propose two approaches for defining the control response rate to therapy; (1) the use of pharmacometrics from modern trials and (2) the use of a concurrent observational study. Designs for active controlled trials could be (1) standard of care+test vs. standard of care alone or (2) standard of care vs. test article. The second approach requires extensive justification to show that the test article will be of sufficient efficacy to allow ethical use as a single agent. PMID- 22832235 TI - Physical activity levels of older adults receiving a home care service. AB - The 3 study objectives were to compare the activity levels of older people who had received a restorative home care service with those of people who had received "usual" home care, explore the predictors of physical activity in these 2 groups, and determine whether either group met the minimum recommended activity levels for their age group. A questionnaire was posted to 1,490 clients who had been referred for a home care service between 2006 and 2009. Older people who had received a restorative care service were more active than those who had received usual care (p = .049), but service group did not predict activity levels when other variables were adjusted for in a multiple regression. Younger individuals who were in better physical condition, with good mobility and no diagnosis of depression, were more likely to be active. Investigation of alternatives to the current exercise component of the restorative program is needed. PMID- 22832236 TI - Cholinergic deficit and response to donepezil therapy in Parkinson's disease with dementia. AB - BACKGROUND: Although donepezil, an acetylcholinesterase inhibitor, has been proved to be effective in ameliorating cognitive impairment in Parkinson's disease with dementia (PDD), the responsiveness of patients to donepezil therapy varies. [5-(11)C-methoxy]donepezil, the radiolabeled form of donepezil, is a ligand for positron emission tomography (PET), which can be exploited for the quantitative analysis of donepezil binding to acetylcholinesterase and for cholinergic imaging. OBJECTIVES: To investigate the deficits of the cholinergic system in the brain in PDD and its association with response to donepezil therapy. METHODS: Twelve patients with PDD and 13 normal control subjects underwent [5-(11)C-methoxy]donepezil-PET imaging. For patients with PDD, daily administration of donepezil was started after [5-(11)C-methoxy]donepezil-PET imaging and continued for 3 months. RESULTS: In the PDD group, the mean total distribution volume of the cerebral cortices was 22.7% lower than that of the normal control group. The mean total distribution volume of the patients with PDD was significantly correlated with improvement of visuoperceptual function after 3 months of donepezil therapy. CONCLUSION: The results suggest that donepezil therapy is more effective in patients with less decrease in acetylcholinesterase, a binding site of donepezil, at least in the specific cognitive domain. PMID- 22832237 TI - Prenatal immune stress in rats dampens fever during adulthood. AB - Fever is a major component of the host's defense against infection. Inadequate febrile response can predispose an individual to the deleterious effects of infection. Neonatal exposure to infectious agents such as bacterial lipopolysaccharide (LPS) permanently dampens the adult febrile response. Whether prenatal immune challenge alters febrile response during adulthood is still not known. In the present study, LPS (100 ug/kg, i.p.) or pyrogen-free saline was administered to pregnant rats on either gestation day (GD) 12, 15 or 19 and the febrile response of their respective adult offspring was monitored. During adulthood (>70 days old), the rats born to LPS-injected dams on GD15 displayed a significantly attenuated febrile response to LPS (50 ug/kg, i.p.) compared to their control counterparts born to dams given saline on GD15. Immune challenge during either early (GD12) or late (GD19) pregnancy did not have a significant impact on fever in the adult offspring. Immune challenge on GD15, but not on GD12 or 19, heightened the plasma corticosterone response to a subsequent LPS injection to the adult offspring but did not have a significant effect on their basal plasma corticosterone levels. Finally, LPS-induced COX-2 in the fever controlling regions of the hypothalamus was significantly reduced in the adult rats born to dams given LPS on GD15 compared to their counterparts born to dams given saline on GD15. Such COX-2 reduction was not observed in the adult offspring born to dams given LPS on either GD12 or 19. Taken together, these data suggest that a single immune challenge during a critical window of pregnancy alters the neuroimmune response in adult offspring. PMID- 22832238 TI - Syntax in a pianist's hand: ERP signatures of "embodied" syntax processing in music. AB - Syntactic operations in language and music are well established and known to be linked in cognitive and neuroanatomical terms. What remains a matter of debate is whether the notion of syntax also applies to human actions and how those may be linked to syntax in language and music. The present electroencephalography (EEG) study explored syntactic processes during the observation, motor programming, and execution of musical actions. Therefore, expert pianists watched and imitated silent videos of a hand playing 5-chord sequences in which the last chord was syntactically congruent or incongruent with the preceding harmonic context. 2 chord sequences that diluted the syntactic predictability of the last chord (by reducing the harmonic context) served as a control condition. We assumed that behavioural and event-related potential (ERP) effects (i.e., differences between congruent and incongruent trials) that were significantly stronger in the 5-chord compared to the 2-chord sequences are related to syntactic processing. According to this criterion, the present results show an influence of syntactic context on ERPs related to (i) action observation and (ii) the motor programming for action imitation, as well as (iii) participants' execution times and accuracy. In particular, the occurrence of electrophysiological indices of action inhibition and reprogramming when an incongruent chord had to be imitated implies that the pianist's motor system anticipated (and revoked) the congruent chord during action observation. Notably, this well-known anticipatory potential of the motor system seems to be strongly based upon the observer's music-syntactic knowledge, thus suggesting the "embodied" processing of musical syntax. The combined behavioural and electrophysiological data show that the notion of musical syntax not only applies to the auditory modality but transfers--in trained musicians--to a "grammar of musical action". PMID- 22832239 TI - Acute mastoiditis in children aged 0-16 years--a national study of 678 cases in Sweden comparing different age groups. AB - OBJECTIVE: To compare the characteristics of acute mastoiditis in children in different age groups in order to identify risk groups and risk factors for acute mastoiditis. METHODS: Records for all children aged 0-16 years treated for acute mastoiditis during 1993-2007 at 33 Ear, Nose and Throat departments in Sweden were reviewed retrospectively according to defined criteria for acute mastoiditis. RESULTS: A total of 678 cases fulfilled the inclusion criteria. Acute mastoiditis was most common in children younger than two years of age and this group was characterized by less prior history of other diseases and ear diseases, fewer visits to health care centers and less antibiotic treatment before admission, shorter duration of symptoms before admission, hospitalization for fewer days and lower frequency of complications and mastoidectomies. These children also showed a higher incidence of clinical findings, increased inflammatory markers such as fever and heightened counts of C-reactive protein and white blood cells compared with older children. They also tested positive for significantly more samples of Streptococcus pneumoniae while the older children more often exhibited growth of Streptococcus pyogenes or Pseudomonas aeruginosa or no microbial growth. CONCLUSIONS: The characteristics of pediatric acute mastoiditis differed significantly between age groups. Acute mastoiditis was most common in children younger than two years of age. They showed more rapid progress of symptoms and more distinct signs of acute mastoiditis. This is probably the reason why parents rapidly seek medical care for small children and hospital treatment thus starts earlier in the youngest children, which may in turn explain the excellent outcome. This study showed that younger children have neither more severe acute mastoiditis nor more complications than older ones. The differences between age groups suggest that there are distinctions in the pathophysiology behind the onset and course of acute mastoiditis in younger and older children. PMID- 22832240 TI - Endoscopic assisted sublabial and buccolabial incision approach for juvenile nasopharyngeal angiofibroma with extensive infratemporal fossa extension. AB - OBJECTIVE: The aim of this study is to evaluate endoscopic assisted sublabial and buccolabial incision approach as treatment option for Juvenile nasopharyngeal angiofibroma (JNA) with extensive infratemporal fossa (ITF) extension. METHODS: Seven patients diagnosed as JNA with extensive ITF extension and underwent surgery at our department between 2006 and 2010 were retrospectively reviewed. All patients underwent diagnostic arteriography followed by embolization preoperatively and intratumor injection with N-butyl cyanoacrylate (NBCA). Endoscopic assisted sublabial and buccolabial incision approach was used to remove the tumors. RESULTS: Complete resections of the tumors were achieved in all patients. Mean blood loss was 700 ml. The follow-up period ranged from 9 to 20 months, with a mean of 14.3 months. One patient had a recurrent tumor six months after operation. CONCLUSIONS: Endoscopic assisted sublabial and buccolabial incision is an optional approach to remove JNA with extensive ITF extension. PMID- 22832241 TI - Increased shedding of microvesicles from intimal smooth muscle cells in athero prone areas of the human aorta: implications for understanding of the predisease stage. AB - OBJECTIVE: This study evaluated whether a change in the content of matrix microvesicles might occur at the preatherosclerotic stage. METHODS: Applying quantitative electron microscopic and immunohistochemical analyses, two areas of grossly normal segments of the thoracic aorta were compared: atherosclerosis prone (AP) areas, situated at the dorsal aspect of the aorta along the rows of intercostal branch origins, and atherosclerosis-resistant (AR) areas, situated at the corresponding sites of the ventral aspect of the aorta. RESULTS: The electron microscopic analysis showed that there were 1.4 times more microvesicles in AP areas than AR areas (p = 0.019). It was found that matrix microvesicles originated as a result of blebbing and shedding of surface membranes of smooth muscle cells. A quantitative analysis of the expression of ADP-ribosylation factor 6 (ARF6), which is known to be involved in membrane trafficking and microvesicle formation, showed that ARF6 expression was 1.3 times higher in AP areas than that in AR areas (p = 0.006). There was a positive correlation between the content of matrix microparticles and the expression of ARF6 by intimal smooth muscle cells (r = 0.61; p < 0.0001). CONCLUSION: The present study supports the concept that alterations of the arterial intima occur at the predisease stage. PMID- 22832242 TI - A comparison of classification techniques for a gaze-independent P300-based brain computer interface. AB - This off-line study aims to assess the performance of five classifiers commonly used in the brain-computer interface (BCI) community, when applied to a gaze independent P300-based BCI. In particular, we compared the results of four linear classifiers and one nonlinear: Fisher's linear discriminant analysis (LDA), stepwise linear discriminant analysis (SWLDA), Bayesian linear discriminant analysis (BLDA), linear support vector machine (LSVM) and Gaussian supported vector machine (GSVM). Moreover, different values for the decimation of the training dataset were tested. The results were evaluated both in terms of accuracy and written symbol rate with the data of 19 healthy subjects. No significant differences among the considered classifiers were found. The optimal decimation factor spanned a range from 3 to 24 (12 to 94 ms long bins). Nevertheless, performance on individually optimized classification parameters is not significantly different from a classification with general parameters (i.e. using an LDA classifier, about 48 ms long bins). PMID- 22832243 TI - [Umbilical cord prolapse: a case study over 23 years]. AB - AIM: To determine the incidence of umbilical cord prolapse, the characteristics of the population, and to evaluate its management and the neonatal prognosis. MATERIAL AND METHODS: Ninety-three cases of cord prolapse that occurred between January 1986 and December 2009 at our level III labour ward were studied retrospectively. RESULTS: The incidence of cord prolapse was 0.18%. It occurred in 66.7% of cases in multiparous patients, in 19.4% of cases in twin pregnancies, and in 41.9% of cases in breech presentations. In 34.4% of cases, the gestational age was less than 37 weeks. Birth occurred vaginally in 33.3% of cases with a delivery time interval significantly less than for caesarean sections (P<0.001). At complete cervical dilation, more than three quarter of patients delivered vaginally. Vaginal birth was significantly more frequent in case of breech (P=0.009) and second twin (P=0.03). Parity did not influence birth route. Neonates with a birth weight less than 2500 g (30.1%) had significantly more frequently an Apgar score less than 7 at 5 min (P=0.02), a higher rate of transfer to intensive care (P<0.001) and a longer hospital stay (P=0.002). We report six neonatal deaths (6.5%). Neonatal status was not influenced by the time interval for delivery. CONCLUSION: Umbilical cord prolapse is still nowadays a serious complication of pregnancy, responsible for a significant rate of neonatal mortality. The aim in case of cord prolapse is to obtain fetal delivery the quickest way possible so as to improve the neonatal outcome. In some particular obstetrical situations such as breech presentations and second twin deliveries, birth occurs faster if performed vaginally as shown by our case study. PMID- 22832244 TI - alpha,omega-Dihexylsexithiophene self-assembled nanostructures on mica: atomic force microscopy study. AB - Self-assembled nanostructures of alpha,omega-dihexylsexithiophene (DH6T) formed by spreading DH6T solutions onto freshly cleaved mica surface were studied by atomic force microscopy. The effects of solvent and concentration on the nanostructures of DH6T molecules were studied. Flat, well-ordered, and platelet like domains were observed on mica surfaces after treatment with various polar solvent solutions of DH6T. These domains form a uniform film with height of 2.4 +/- 0.2 nm, which is consistent with a 45 degrees tilt in the molecular conformation of DH6T on mica surfaces. The formation mechanism of these multilayers is discussed in detail. PMID- 22832245 TI - The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1). AB - Preeclampsia is a pregnancy-specific syndrome mainly characterized by hypertensive disorder and proteinuria after gestational weeks 20. So far the etiology of preeclampsia remains unclear. We previously reported that preeclamptic placentas exhibited decreased mRNA expression and hypermethylation in promoter region of the paternally imprinted H19 gene compared with normal placentas. H19 has recently been identified to encode the precursor of miR-675, indicating a possible novel functional pathway of the imprinting gene. The aim of the present study was to identify the roles of H19 gene via miR-675 pathway in human trophoblast cells, and to figure out the involvement of this pathway in pathogenesis of preeclampsia. Knockdown of H19 gene or inhibition of miR-675 exhibited similar proliferation-promoting effect in human trophoblastic JEG-3 cells. Target gene prediction in combination with luciferase assay revealed that miR-675 could directly downregulate Nodal Modulator 1 (NOMO1) protein expression by binding to 3'-UTR sequence of NOMO1. Overexpression of NOMO1 in JEG-3 cells could rescue miR-675-surppressed cell proliferation and phosphorylation of Smad2, while Nodal had additive effect with miR-675 in suppression cell proliferation and activation of Smad2. In early-onset preeclamptic placentas, expression levels of H19 gene and miR-675 were appreciably lower, while NOMO1 protein level was higher than those in normal placentas. Taken together, our data suggested that H19 gene could inhibit human trophoblast cell proliferation via encoding miR-675 that targeted NOMO1, and aberrantly lowered expression of H19 in placenta may participate in the excessive proliferation of trophoblast cells observed in early onset severe preeclampsia by downregulating miR-675 which targets NOMO1 and interferes with Nodal signaling. PMID- 22832246 TI - Comprehensive characterization of viral miRNAs involved in white spot syndrome virus (WSSV) infection. AB - Guided by miRNAs, RNAi plays an important role in virus-host interactions by fine tuning gene expression. Many viral and cellular miRNAs are involved in virus infection, though no comprehensive general model for miRNAs derived from invertebrate DNA viruses exists for their function in eukaryotic systems, despite extensive research on miRNAs. To address this issue, the miRNAs from shrimp white spot syndrome virus (WSSV), a DNA virus with a 305 kb double-stranded circular DNA genome, were characterized. Based on WSSV miRNA microarray and northern blot analyses, WSSV was shown to possess the capacity to encode 40 distinct viral miRNAs, a miRNA content roughly 360 times greater than that of humans. These findings suggested that the high content of viral miRNAs might greatly contribute to viral variability in response selective pressures in the host environment. Transcription analysis revealed that 80% of WSSV miRNAs were expressed during early stages of viral infection, indicating their importance in initial infective processes. Additionally, biogenesis of viral miRNAs was demonstrated to be dependent on host Drosha and Dicer 1, mediated by Ago 1, and viral miRNAs, including WSSV-miR211 and WSSV-miR212, were required for successful WSSV infection. During WSSV infection, numerous viral genes were likely targeted by WSSV miRNAs. The current study presented the first comprehensive view of viral miRNAs encoded by an invertebrate DNA virus, providing insight into the molecular events of virus-host interactions. PMID- 22832248 TI - Blood product and host: A potentially inflamed relationship? (corrected). PMID- 22832247 TI - Translational infidelity-induced protein stress results from a deficiency in Trm9 catalyzed tRNA modifications. AB - Correct codon-anticodon pairing promotes translational fidelity, with these interactions greatly facilitated by modified nucleosides found in tRNA. We hypothesized that wobble uridine modifications catalyzed by tRNA methyltransferase 9 (Trm9) are essential for translational fidelity. In support, we have used phenotypic, reporter and protein-based assays to demonstrate increased translational infidelity in trm9Delta Saccharomyces cerevisiae cells. Codon reengineering studies suggest that Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific genes, those rich in arginine and glutamic acid codons from mixed boxes. Using quantitative tRNA modification analysis, we determined that trm9Delta cells are only deficient in 2 of 23 tRNA modifications, with those 2, 5-methoxycarbonylmethyluridine (mcm ( 5) U) and 5 methoxycarbonylmethyl-2-thiouridine (mcm ( 5) s ( 2) U), classified as key determinants of translational fidelity. We also show that in the absence of mcm ( 5) U and mcm ( 5) s ( 2) U, the resulting translational infidelity promotes protein errors and activation of unfolded protein and heat shock responses. These data support a model in which Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific transcripts, with decreased wobble base modification leading to translational infidelity, protein errors and activation of protein stress response pathways. PMID- 22832251 TI - A lucky career in bacterial vaccines. PMID- 22832252 TI - MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine. AB - The inclusion of a potent TLR4 immune potentiator to a recombinant antigen vaccine formulation enhances both the magnitude and the breadth of the engendered immune response. One such immune potentiator (TLR4 agonist E6020) was evaluated with recombinant Men B antigens delivered in MF59 sub-micron adjuvant emulsion. The ability of this formulation to enhance serum antibody and bactercidal titers was investigated. The co-delivery of E6020 within MF59 enhanced both the serum and bactericidal titers for Men B antigens and for Men B antigens combined with Men ACWY-CRM conjugate vaccine. The delivery of TLR4 agonist within MF59 emulsion oil droplets leads to a more potent response in comparison to the TLR4 when admixed with MF59 emulsion. PMID- 22832253 TI - Two years of Provenge. PMID- 22832254 TI - Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. AB - Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others cancers with defined cell surface markers. In summary, the approval of Sip-T based on a survival benefit and very tolerable safety profile will 1) enhance our ability to care for men with advanced prostate cancer, 2) allow for further investigations of this approach in combination with others therapies with different mechanisms of action and non-overlapping toxicities, and 3) allow further investigations earlier in the course of the disease. PMID- 22832255 TI - Mathematical models of the interplay between individual vaccinating decisions and disease dynamics: a need for closer integration of models and data. AB - In non-mandatory vaccination policies, individual choice can be a major driver of vaccine uptake. Choice thereby influences whether public health targets can be achieved. Individual vaccinating decisions can be influenced by perceptions of vaccine risks or infection risks. There is also the potential for non-vaccinators to strategically 'free-ride' on herd immunity provided by vaccinators. This strategic interaction between individuals generates a social dilemma--a conflict between self-interest and what is best for the group as a whole. Game theory and related mathematical approaches that couple mechanistic models of vaccinating decisions with mechanistic models of disease spread can capture this social dilemma and address relevant questions. The past decade has seen significant growth in the theoretical literature developing and analyzing such models. Here, we argue that using these models to address specific public health challenges will require more work that integrates information from empirical studies into the development and validation of such models, as well as more collaboration between mathematical modelers, psychologists, economists and public health experts. PMID- 22832256 TI - Successful combination: existing drugs boost cancer vaccine responses. PMID- 22832257 TI - Fifth Vaccine Renaissance introduction. PMID- 22832258 TI - Letter from the editor. PMID- 22832259 TI - Assessing the interest to participate in a dengue vaccine efficacy trial among residents of Puerto Rico. AB - Dengue, endemic in Puerto Rico, is a major public health problem. Vaccines are thought the best means to prevent dengue because vector control alone has been largely ineffective. We implemented qualitative studies in 2006 and 2010 to determine the acceptability of conducting placebo-controlled dengue vaccine efficacy trials in Puerto Rican children. Key informant interviews and focus groups with parents and children were conducted in municipalities with high dengue incidence. We used structured open-ended questions to determine motivators and attitudes regarding vaccine trial participation. Knowledge about dengue risk and prevention, and knowledge, attitudes, and beliefs regarding vaccines and vaccine trials were assessed. Using grounded theory, we conducted content analysis and established categories and sub-categories of participant responses. All participants were knowledgeable about dengue prevention and perceived children as most affected age groups. Participants were aware of vaccines benefits and they thought a vaccine could prevent dengue. However, most would not allow their children to participate in a placebo-controlled vaccine trial. Barriers included lack of trust in new vaccines and vaccine trial procedures; fear of developing dengue or side effects from the vaccine and lack of information about candidate dengue vaccines. Participants thought information, including results of previous trials might overcome barriers to participation. Motivators for participation were altruism, protection from dengue, free medical attention, and compensation for transportation and participation. Parents would consider children participation if accurate vaccine trial information is provided. PMID- 22832260 TI - A phase 1, randomized, open-label, active-controlled trial to assess the safety of a meningococcal serogroup B bivalent rLP2086 vaccine in healthy adults. AB - Neisseria meningitidis serogroup B (MnB) is a significant cause of invasive meningococcal disease, but no broadly protective vaccine is yet approved. We assessed the safety and immunogenicity of a bivalent MnB vaccine composed of lipidated subfamily A and B variants of recombinant LP2086 (rLP2086, also known as factor H binding protein, fHBP). Forty-eight adults, ages 18-40 y, were randomized to receive 60, 120 or 200 MUg of the bivalent rLP2086 vaccine or control at 0, 2 and 6 mo. Immunogenicity was assessed by rLP2086-specific immunoglobulin G (IgG) geometric mean titers for subfamily A and B proteins. Safety was determined by laboratory assessments of blood and urine and by reporting of solicited and unsolicited adverse events (AEs). The bivalent rLP2086 vaccine elicited high IgG titers following the second and third vaccination at all dose levels. In each of the four study arms, 11 of the 12 participating subjects reported >= 1 AE, and no serious AEs were reported. Local and systemic reactions were mainly mild to moderate. Laboratory abnormalities (including increased sodium, decreased neutrophils, and proteinuria) were not associated with clinical events and were not considered to be related to the study vaccine. Vaccinations were generally well-tolerated. Strong IgG antibody responses and the absence of clinically significant laboratory abnormalities support further development of the bivalent rLP2086 vaccine (www.clinicaltrials.gov; identifier: NCT00879814). PMID- 22832261 TI - Phase 4 randomized trial of intradermal low-antigen-content inactivated influenza vaccine versus standard-dose intramuscular vaccine in HIV-1-infected adults. AB - This study evaluated safety, tolerability and immunogenicity of intradermal (ID) trivalent inactivated split influenza vaccine, with a lower antigen content (9 mcg HA per strain) than the conventional intramuscular one (15 mcg), in HIV-1 infected adults younger than 60 years. A total of 54 HIV-1-positive participants were enrolled and randomly assigned to receive a single dose of either ID administered low-antigen-content split inactivated vaccine or intramuscularly administered (IM) standard-dose inactivated split vaccine. Subjects were provided with a diary to monitor any local and/or systemic reactions to the vaccine for 7 days following vaccination. Serum samples were collected before, 28 days and 90 days after immunization. The plasma HIV-RNA and CD4+ T-lymphocyte count were checked at day 0 and day 90. Serum hemagglutination-inhibition (HI) activity for the three influenza strains included in the vaccine composition was measured to assess the antibody response at one month and 3 months after vaccination. Both vaccines showed optimal safety and tolerability profiles. All the three Committee for Medicinal Products for Human Use immunogenicity criteria for vaccine approval in adults younger than 60 were met by both vaccines against A(H1N1) and A(H3N2) viruses. Both vaccines met mean-fold-increase and seroprotection criteria but failed seroconversion criteria against B virus. No difference in terms of post vaccination geometric mean titers, mean fold increase, seroprotection and seroconversion rates were found comparing ID and IM vaccines. In conclusion, the recently available low-antigen-content ID vaccine is safe, well-tolerated and as immunogenic as IM standard-dose influenza vaccine. PMID- 22832262 TI - Superficial venous thrombosis and compression ultrasound imaging. AB - BACKGROUND: A current debate concerning suspected superficial vein thrombosis (SVT) focuses on the need of performing a compression ultrasound (CUS) exploration for confirming the diagnosis of SVT. This study was conducted to determine the clinical relevance and optimal CUS exploration in patients with symptomatic SVT. METHODS: We analyzed the characteristics of SVT and concomitant deep vein thrombosis (DVT) in patients included in the Prospective Observational Superficial Thrombophlebitis (POST) multicenter, observational prospective study. All patients underwent complete bilateral lower limb CUS, exploring both the superficial and deep venous systems. RESULTS: A total of 844 patients with clinical symptoms of SVT were recruited, of which 99 isolated SVTs (21.4%) had saphenofemoral/popliteal junction involvement, and 198 (23.5%) had a concomitant DVT, with 41.8% of them proximal DVTs. In 83 patients (41.9%), DVT and SVT were not contiguous. Five of 639 patients (1%) had an isolated contralateral DVT (ie, not bilateral). Age >= 75 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.4), inpatient status (OR, 5.4; 95% CI, 3.4-8.7), a personal history of DVT or pulmonary embolism (OR, 1.8; 95% CI, 1.2-2.8), and SVT on nonvaricose veins (OR, 3.3; 95% CI, 2.1-5.0) were significantly and independently associated with an increased risk of concomitant DVT. Half of the patients exhibited none of these risk factors, and the prevalence of concomitant DVT dropped to 11%. CONCLUSIONS: In patients with symptomatic SVT, a CUS exploration screening the whole venous system of the affected limb is useful because it provides information that has important consequences for the management of these patients. PMID- 22832263 TI - Impact of screening versus symptomatic measurement of deep vein thrombosis in a national quality improvement registry. AB - BACKGROUND: Deep vein thrombosis (DVT) is a quality measure recorded by initiatives such as the National Surgical Quality Improvement Program (NSQIP). However, because surveillance-detected DVT rates may be higher than symptomatic DVT rates, we examined how differences in the method of DVT detection may affect the use of this quality measure. METHODS: Using the NSQIP database (2007-2009), we compared DVT rates of vascular (amputation, open aortic procedures, and lower extremity bypass) and nonvascular (prostatectomy, gastric bypass [GBP], and hip arthroplasty) operations. Using a predefined literature search strategy, we compared the incidence of DVT in NSQIP to the incidence of DVT reported in published literature, diagnosed by symptomatic status or by surveillance studies. RESULTS: Within NSQIP, the overall incidence of postoperative DVT was 0.7%. This varied from 0.3% after GBP to 1.8% after open aortic surgery. Across all procedures except amputation, the incidence of DVT in NSQIP was similar to the incidence of DVT reported in our literature survey of "symptomatic" DVTs. The relative rate (RR) of literature-derived symptomatic DVTs to NSQIP ranged from 0.7 for aortic cases (95% confidence interval [CI], 0.3-1.7) to 1.4 (95% CI, .7 3.1) for GBP. Overall, surveillance studies had 11.6 higher RR of DVT compared to NSQIP (95% CI, 10.5-13), ranging from 2.6 for GBP (95% CI, 1.4-5) to 14 .5 for hip arthroplasty (95% CI, 10.5-20). CONCLUSIONS: The incidence of DVT reported in NSQIP is similar to the reported incidence of symptomatic DVT for many high-risk procedures but is much lower than rates of DVT reported in surveillance studies. Clear delineation of symptomatic vs surveillance detection of DVT would improve the usefulness of this measurement in quality improvement registries. PMID- 22832265 TI - Suprarenal stent perforation after endovascular abdominal aortic aneurysm repair. AB - A 66-year-old man with an abdominal aortic aneurysm previously repaired with an endovascular stent graft presented to our facility with worsening midabdominal and back pain. Previous postoperative surveillance computed tomography scans were unremarkable, showing excellent stent-wall apposition and a shrinking aneurysm sac; however, imaging done on his arrival identified a contained rupture at the level of the celiac artery containing a perforating suprarenal stent. We repaired this rupture with a surgeon-modified fenestrated stent graft. To our knowledge, this is the first reported case of penetration of the native aorta by a suprarenal stent in the absence of infection or trauma. PMID- 22832264 TI - No increased mortality with early aortic aneurysm disease. AB - OBJECTIVE: In addition to increased risks for aneurysm-related death, previous studies have determined that all-cause mortality in abdominal aortic aneurysm (AAA) patients is excessive and equivalent to that associated with coronary heart disease. These studies largely preceded the current era of coronary heart disease risk factor management, however, and no recent study has examined contemporary mortality associated with early AAA disease (aneurysm diameter between 3 and 5 cm). As part of an ongoing natural history study of AAA, we report the mortality risk associated with presence of early disease. METHODS: Participants were recruited from three distinct health care systems in Northern California between 2006 and 2011. Aneurysm diameter, demographic information, comorbidities, medication history, and plasma for biomarker analysis were collected at study entry. Survival status was determined at follow-up. Data were analyzed with t tests or chi(2) tests where appropriate. Freedom from death was calculated via Cox proportional hazards modeling; the relevance of individual predictors on mortality was determined by log-rank test. RESULTS: The study enrolled 634 AAA patients; age 76.4 +/- 8.0 years, aortic diameter 3.86 +/- 0.7 cm. Participants were mostly male (88.8%), not current smokers (81.6%), and taking statins (76.7%). Mean follow-up was 2.1 +/- 1.0 years. Estimated 1- and 3-year survival was 98.2% and 90.9%, respectively. Factors independently associated with mortality included larger aneurysm size (hazard ratio, 2.12; 95% confidence interval, 1.26-3.57 for diameter >4.0 cm) and diabetes (hazard ratio, 2.24; 95% confidence interval, 1.12-4.47). After adjusting for patient-level factors, health care system independently predicted mortality. CONCLUSIONS: Contemporary all-cause mortality for patients with early AAA disease is lower than that previously reported. Further research is warranted to determine important factors that contribute to improved survival in early AAA disease. PMID- 22832266 TI - Attenuation of spinal cord ischemia-reperfusion injury by specific alpha-2a receptor activation with dexmedetomidine. AB - BACKGROUND: Despite surgical adjuncts, paralysis remains a devastating complication after thoracoabdominal aortic interventions. Dexmedetomidine, a selective alpha-2a agonist commonly used for sedation in the critical care setting, has been shown to have protective effects against ischemia-reperfusion injuries in multiple organ systems. We hypothesized that treatment with dexmedetomidine would attenuate spinal cord ischemia-reperfusion injury via alpha 2a receptor activation. METHODS: Adult C57BL/6 mice underwent sternotomy, followed by occlusion of the aortic arch for 4 minutes. Eight experimental mice received pretreatment with intraperitoneal dexmedetomidine (25 MUg/kg) and at 12 hour intervals after reperfusion. Eight control mice received an equivalent amount of 0.9% normal saline. Five mice underwent the same procedure with dexmedetomidine (25 MUg/kg) and atipamezole (250 MUg/kg), an alpha-2a receptor antagonist. Functional analysis of the mice was obtained at 12-hour intervals and scored using the Basso Mouse Scale for Locomotion until 60 hours. All mice were euthanized at 60 hours. Their spinal cords were removed en bloc and were stained with hematoxylin and eosin to assess cytoarchitecture and neuronal viability. RESULTS: Mice treated with the alpha-2a agonist demonstrated preserved motor function compared with ischemic controls and with mice treated with the alpha-2a antagonist in addition to the agonist. Functional differences in the dexmedetomidine group were statistically significant from 24 hours through the remainder of the experiment (P < .05). In addition, the treated mice had preserved cytoarchitecture, decreased vacuolization, and improved neuronal viability compared with ischemic control mice and mice concurrently treated with atipamezole, the dexmedetomidine alpha-2a antagonist. CONCLUSIONS: Treatment of mice with the alpha-2a agonist dexmedetomidine preserves motor function and neuronal viability after aortic cross-clamping. In addition, mice exhibited almost complete reversal of the protective effect with the administration of the alpha-2a receptor antagonist atipamezole. Dexmedetomidine appears to attenuate spinal cord ischemia-reperfusion injury via alpha-2a receptor-mediated agonism. CLINICAL RELEVANCE: There remains a significant risk of paraplegia after thoracoabdominal aortic interventions. This complication is devastating to the patient and the health care system. Pharmacologic adjuncts to further decrease this complication have been studied; however, few viable options exist. The alpha 2a agonists have been shown to improve outcomes after strokes but have not been studied in spinal cord ischemia. We show that dexmedetomidine, a commonly used alpha-2a agonist in the operating room, can preserve neurologic function in mice after aortic cross-clamping. Although the protective mechanism of dexmedetomidine remains unknown, it might prove to be beneficial in reducing the incidence of paraplegia after aortic interventions. PMID- 22832267 TI - Pivotal results for the Medtronic Valiant Thoracic Stent Graft System in the VALOR II trial. AB - OBJECTIVE: We report 30-day and 12-month results of endovascular treatment with the Valiant Thoracic Stent Graft System (Medtronic Vascular, Santa Rosa, Calif) in patients with descending thoracic aortic aneurysms of degenerative etiology. The Valiant stent graft is an evolution of the Talent thoracic stent graft (Medtronic Vascular). METHODS: The VALOR II (Evaluation of the Clinical Performance of the Valiant Thoracic Stent Graft System in the Treatment of Descending Thoracic Aneurysms of Degenerative Etiology in Subjects Who Are Candidates for Endovascular Repair) was a prospective, nonrandomized, pivotal trial conducted at 24 U.S. sites with enrollment between December 2006 and September 2009. Standard follow-up examinations, including physical examination, computed tomography, and chest radiography, were at 1, 6, and 12 months, and annually through 5 years. VALOR II outcomes were compared with those from the pivotal VALOR (Evaluation of the Medtronic Vascular Talent Thoracic Stent Graft System for the Treatment of Thoracic Aortic Aneurysms) trial of the Talent stent graft, which enrolled 195 patients with similar enrollment criteria. RESULTS: VALOR II enrolled 160 patients. Compared with VALOR patients, VALOR II patients had similar age and sex distribution but higher rates of cardiovascular risk factors and significantly more severe modified Society for Vascular Surgery/American Association for Vascular Surgery risk scores. Stent graft delivery and deployment were successful in 154 patients (96.3%). Outcomes at 30 days in VALOR II were perioperative mortality, 3.1%; major adverse events, 38.1%; paraplegia, 0.6%; paraparesis, 1.9%; and stroke, 2.5%. At 12 months, after the minimum sample size was reached, 151 patients were evaluated: aneurysm-related mortality was 4.0%, stent graft migration was 2.9%, and endoleak was 13.0%. Through 12 months, there were no ruptures, conversions to open surgery, secondary procedures due to endoleak >30 days, or loss of stent graft patency. The Valiant stent graft was statistically noninferior to the Talent stent graft in 12-month all-cause mortality (12.6% vs 16.1%) and exceeded the primary effectiveness goal of 12-month successful aneurysm treatment, defined as absence of aneurysm growth >5 mm and of secondary procedures for type I/III endoleak (97.4% vs 80.0%). CONCLUSIONS: The VALOR II 12-month results demonstrate that the Medtronic Valiant thoracic stent graft is a safe and effective treatment for patients with descending thoracic aortic aneurysms of degenerative etiology. PMID- 22832268 TI - Staged hybrid approach using proximal thoracic endovascular aneurysm repair and distal open repair for the treatment of extensive thoracoabdominal aortic aneurysms. AB - OBJECTIVE: Repair of patients with extent I and II thoracoabdominal aortic aneurysms (TAAAs) is associated with significant morbidity and mortality, whereas repair of more distal extent III and IV TAAAs has a lower risk of paraplegia and death. Therefore, we describe an approach using thoracic endovascular aneurysm repair (TEVAR) as the index operation to convert extent I and II TAAAs to extent III and IV TAAAs amenable to subsequent open aortic repair to minimize patient risk. METHODS: Between July 2007 and March 2012, 10 staged hybrid operations were performed to treat one extent I and nine extent II TAAAs. Aortic aneurysm pathology included five chronic type B dissections, three acute type B dissections, and two penetrating aortic ulcers. Initially, the proximal descending thoracic aorta was repaired with TEVAR for coverage of the most proximal fenestration or penetrating ulcer, with seven elective and three emergent repairs. Interval open distal aortic replacement was performed in a short-term planned setting or for progressive dilation of the distal aortic segment. In the open repair, the proximal end of the graft was sewn directly to the distal end of the TEVAR and outer wall of the aorta. RESULTS: Average patient age was 48 years, and 60% were men. Risk factors included hypertension (80%), current tobacco use (50%), and Marfan syndrome (30%). Complications after TEVAR included type IA (n=1) and type II (n=3) endoleaks, pleural effusions (n=3), and acute kidney injury (n=1). Three patients required endovascular reinterventions. In patients with dissection, persistent filling of the false lumen was common and associated with distal thoracic aortic dilation. Complications of open repair included acute kidney injury in two patients, but no cardiac, pulmonary, or neurologic morbidity. Median time between TEVAR and open repair was 14 weeks. Most importantly, no deaths or neurologic deficits occurred after either procedure during a median follow-up of 35 weeks. CONCLUSIONS: A staged hybrid approach to extensive TAAAs combining proximal TEVAR, followed by interval open distal TAAA repair, is safe and appears to be an effective alternative to traditional open repair. This approach may decrease the significant morbidity associated with single-stage open extent I and II TAAA repairs and may be applicable to multiple TAAA etiologies. PMID- 22832269 TI - Activity of 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines to Tetrahymena. AB - A series 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines (43 compounds), some of which are epidermal growth factor tyrosine kinase inhibitors, were tested for their protozoal toxicity using an environmental Tetrahymena strain as model organism. The protozoacidal activity of the analogues was found to be highly dependent on a 4-hydroxyl group at the 6-aryl ring, and a chiral 1-phenylethanamine substituent in position 4. Further, the potency was affected by the aromatic substitution pattern of the phenylethanamine: the unsubstituted, the meta-fluoro and the para bromo substituted derivatives had the lowest minimum protozoacidal concentrations (8-16 MUg/mL). Surprisingly, both enantiomers were found to have high potency suggesting that this compound class could have several modes of action. No correlation was found between the compounds protozoacidal activity and the in vitro epidermal growth factor receptor tyrosine kinase inhibitory potency. This suggests that the observed antimicrobial effects are related to other targets. Testing towards a panel of kinases indicated several alternative modes of action. PMID- 22832270 TI - The functional antagonism between Eg5 and dynein in spindle bipolarization is not compatible with a simple push-pull model. AB - During cell division, the molecular motor Eg5 crosslinks overlapping antiparallel microtubules and pushes them apart to separate mitotic spindle poles. Dynein has been proposed as a direct antagonist of Eg5 at the spindle equator, pulling on antiparallel microtubules and favoring spindle collapse. Some of the experiments supporting this hypothesis relied on endpoint quantifications of spindle phenotypes rather than following individual cell fates over time. Here, we present a mathematical model and proof-of-principle experiments to demonstrate that endpoint quantifications can be fundamentally misleading because they overestimate defective phenotypes. Indeed, live-cell imaging reveals that, while depletion of dynein or the dynein binding protein Lis1 enables spindle formation in presence of an Eg5 inhibitor, the activities of dynein and Eg5 cannot be titrated against each other. Thus, dynein most likely antagonizes Eg5 indirectly by exerting force at different spindle locations rather than through a simple push-pull mechanism at the spindle equator. PMID- 22832271 TI - Crucial role for membrane fluidity in proliferation of primitive cells. AB - The cell wall is a defining structural feature of the bacterial subkingdom. However, most bacteria are capable of mutating into a cell-wall-deficient "L form" state, requiring remarkable physiological and structural adaptations. L forms proliferate by an unusual membrane deformation and scission process that is independent of the conserved and normally essential FtsZ based division machinery, and which may provide a model for the replication of primitive cells. Candidate gene screening revealed no requirement for the cytoskeletal systems that might actively drive membrane deformation or scission. Instead, we uncovered a crucial role for branched-chain fatty acid (BCFA) synthesis. BCFA-deficient mutants grow and undergo pulsating shape changes, but membrane scission fails, abolishing the separation of progeny cells. The failure in scission is associated with a reduction in membrane fluidity. The results identify a step in L-form proliferation and demonstrate that purely biophysical processes may have been sufficient for proliferation of primitive cells. PMID- 22832272 TI - CD8(+) T cells from mice transnuclear for a TCR that recognizes a single H-2K(b) restricted MHV68 epitope derived from gB-ORF8 help control infection. AB - To study the CD8(+) T cell response against a mouse gamma-herpes virus, we generated K(b)-MHV-68-ORF8(604-612)RAG(-/-) CD8(+) T cell receptor transnuclear (TN) mice as a source of virus-specific CD8(+) T cells. K(b)-ORF8-Tet(+) CD8(+) T cells, expanded in the course of a resolving MHV-68 infection, served as a source of nucleus donors. Various in vivo and ex vivo assay criteria demonstrated the fine specificity and functionality of TN cells. TN cells proliferated extensively in response to viral infection, helped control viral burden, and exhibited a phenotype similar to that of endogenous K(b)-ORF8-Tet(+) cells. When compared to OT-1 cells, TN cells displayed distinct properties in response to lymphopenia and cognate antigen stimulation, which may be attributable to the affinity of the TCR expressed by the TN cells. The availability of MHV-68-specific CD8(+) TCR TN mice provides a new tool for investigating aspects of host-pathogen interactions unique to gamma-herpes viruses. PMID- 22832273 TI - Scp160-dependent mRNA trafficking mediates pheromone gradient sensing and chemotropism in yeast. AB - mRNAs encoding polarity and secretion factors (POLs) target the incipient bud site in yeast for localized translation during division. In pheromone-treated cells we now find that these mRNAs are also localized to the yeast-mating projection (shmoo) tip. However, in contrast to the budding program, neither the She2 nor She3 proteins are involved. Instead, the Scp160 RNA-binding protein binds POL and mating pathway mRNAs and regulates their spatial distribution in a Myo4- and cortical ER-dependent fashion. RNA binding by Scp160 is stimulated by activation of Gpa1, the G protein alpha subunit regulated by the pheromone receptor, and is required for pheromone gradient sensing, as well as subsequent chemotropic growth and cell-cell mating. These effects are incurred independently of obvious changes in translation; thus, mRNA trafficking is required for chemotropism and completion of the mating program. This is, to our knowledge, the first demonstration of ligand-activated RNA targeting in the development of a simple eukaryote. PMID- 22832274 TI - Backpropagating action potentials enable detection of extrasynaptic glutamate by NMDA receptors. AB - Synaptic NMDA receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, back-propagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are "protected," under baseline conditions, from such glutamate influences by peri-synaptic transporters: we detect bAP-evoked Ca(2+) entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca(2+) entry either downregulates or upregulates an h-channel conductance (G(h)) of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of G(h) plasticity. G(h) plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation. PMID- 22832275 TI - ATP4a is required for Wnt-dependent Foxj1 expression and leftward flow in Xenopus left-right development. AB - Most vertebrate embryos break symmetry by a cilia-driven leftward flow during neurulation. In the frog Xenopus asymmetric expression of the ion pump ATP4a was reported at the 4-cell stage. The "ion-flux" model postulates that symmetry is broken flow-independently through an ATP4-generated asymmetric voltage gradient that drives serotonin through gap junctions to one side of the embryo. Here, we show that ATP4a is symmetrically expressed. Gene knockdown or pharmacological inhibition compromised organ situs, asymmetric marker gene expression, and leftward flow. The gastrocoel roof plate (GRP), where flow in frog occurs, revealed fewer, shortened, and misaligned cilia. Foxj1, a master control gene of motile cilia, was downregulated in the superficial mesoderm, from which the GRP develops. Specifically, ATP4 was required for Wnt/beta-catenin-regulated Foxj1 induction and Wnt/PCP-dependent cilia polarization. Our work argues for evolutionary conservation of symmetry breakage in the vertebrates. PMID- 22832276 TI - Epigenetically heritable alteration of fly development in response to toxic challenge. AB - Developing organisms have evolved a wide range of mechanisms for coping with recurrent environmental challenges. How they cope with rare or unforeseen challenges is, however, unclear as are the implications to their unchallenged offspring. Here, we investigate these questions by confronting the development of the fly, D. melanogaster, with artificial tissue distributions of toxic stress that are not expected to occur during fly development. We show that under a wide range of toxic scenarios, this challenge can lead to modified development that may coincide with increased tolerance to an otherwise lethal condition. Part of this response was mediated by suppression of Polycomb group genes, which in turn leads to derepression of developmental regulators and their expression in new domains. Importantly, some of the developmental alterations were epigenetically inherited by subsequent generations of unchallenged offspring. These results show that the environment can induce alternative patterns of development that are stable across multiple generations. PMID- 22832277 TI - Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. AB - During evolution segments of homeothermic genomes underwent a GC content increase. Our analyses reveal that two exon-intron architectures have evolved from an ancestral state of low GC content exons flanked by short introns with a lower GC content. One group underwent a GC content elevation that abolished the differential exon-intron GC content, with introns remaining short. The other group retained the overall low GC content as well as the differential exon-intron GC content, and is associated with longer introns. We show that differential exon intron GC content regulates exon inclusion level in this group, in which disease associated mutations often lead to exon skipping. This group's exons also display higher nucleosome occupancy compared to flanking introns and exons of the other group, thus "marking" them for spliceosomal recognition. Collectively, our results reveal that differential exon-intron GC content is a previously unidentified determinant of exon selection and argue that the two GC content architectures reflect the two mechanisms by which splicing signals are recognized: exon definition and intron definition. PMID- 22832278 TI - Expression profiling of breast tumors based on human epidermal growth factor receptor 2 status defines migration-related genes. AB - OBJECTIVE: Breast cancer is a heterogeneous neoplasm. Distinct subtypes of breast cancer have been defined, suggesting the existence of molecular differences contributing to their clinical outcomes. However, the molecular differences between human epidermal growth factor receptor 2 (HER2)-positive and HER2 negative breast cancer tumors remain unclear. The aim of this study was to identify a gene expression profile for breast tumors based on their HER2 status. METHODS: The HER2 status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 54 breast tumor samples. Using Affymetrix microarray data from these breast tumors, we established the expression profiling of breast cancer based on HER2 IHC and FISH results. To validate microarray experiment data, real-time quantitative reverse transcription PCR was performed. RESULTS: We found significant differences between the HER2 positive and HER2-negative breast tumor samples, which included overexpression of HER2, other genes located on 17q12 and genes functionally related to migration. CONCLUSION: Our study shows the potential of integrated genomic profiling to shed light on the molecular knowledge of HER2-positive breast tumors. PMID- 22832279 TI - Estimation of absolute sound pressure in a small-sized sonochemical reactor. AB - A small-sized sonochemical reactor in which the absolute value of the sound pressure amplitude can be estimated from the vibration velocity of the transducer was investigated. The sound pressure distribution in the reactor and the relationship between the vibration velocity and the sound pressure amplitude were derived through Helmholtz wave equation. The reactor consists of a bolt-clamped Langevin transducer and a rectangular cell with a tungsten reflector. A 3lambda/4 standing-wave-field was generated in the reactor to simplify the sound pressure distribution. The sound pressure distribution was measured from the optical refractive index change of water using a laser interferometer. The experimental and theoretical results showed a good agreement in the absolute value of the sound pressure amplitude, and it was confirmed that the sound pressure in the sonochemical reactor can be estimated from the input current of the vibrator. PMID- 22832280 TI - UV-B affects photosynthesis, ROS production and motility of the freshwater flagellate, Euglena agilis Carter. AB - The effects of ultraviolet B (UV-B; 295-320 nm) radiation on certain vital physiological (photosynthesis), biochemical (production of reactive oxygen species - ROS) and behavioral (motility and orientation) characteristics were investigated in the unicellular photoautotroph, Euglena agilis Carter. The photosynthetic performance of E. agilis was recorded after exposure of between 15 and 60 min followed by a period of recovery lasting 6-24h under dim light (5-10 MUmol photons m(-2) s(-1)). The maximum quantum yield of PS II (F(v)/F(m)) was reduced to 65% and 14% of initial values immediately following 15 and 30 min UV-B exposure, but recovered to 100 and 86% of the initials, respectively. Values of rETR(max) in E. agilis exposed to 15 min UV-B were similar to those of the initials, but a 30 min UV exposure resulted in 75% reduction of rETR(max) with only a 43% recovery as compared with the initial after 24h recovery. After a 60 min UV-B exposure, there were no Chl a fluorescence signals, and hence no F(v)/F(m) or rETR(max). A UV dose-dependent increase in DCFH-DA fluorescence was found in E. agilis cells, reflecting an increase in ROS production. After exposures to UV-B for between 15 and 60 min, the percentages of motile cells in the population decreased to 76, 39 and 15%, respectively. Following 24h in dim light, the percentage of motile cells increased to between 66% and 95% of the initial value. The velocity of non-irradiated cells was 60 MUm s(-1), which decreased to 16-35 MUm s(-1) immediately following exposure for 15-60 min. After periods of time in dim light (6, 12 and 24h) velocities had recovered to between 44 and 81% of the initial value. In untreated controls, the r-value was 0.23, indicating random movement of E. agilis, but it increased to 0.35 and 0.72 after exposure to UV-B for 30 and 60 min, respectively. There was a tendency towards vertical downward movement of cells proportional to the duration of exposure. The compactness of E. agilis decreased from 2.9 in controls to 1.8-2.3 in cells treated with UV-B although significant recovery followed. UV-B dose-dependent interaction between photosynthetic activity, ROS production and movement is discussed in terms of a UV-protective mechanism in E. agilis. PMID- 22832281 TI - Effects of propranolol on heart rate and development in Japanese medaka (Oryzias latipes) and zebrafish (Danio rerio). AB - Propranolol is a beta-adrenergic receptor antagonist (beta-blocker) that is frequently used to treat hypertension and other cardiovascular conditions in humans. Detected in surface waters due to discharge of domestic wastewater, propranolol has demonstrated significant species differences in toxicity between fish. The aim of this study was to investigate the effects of propranolol on heart rate and development in embryos of two species of fish; Japanese medaka (JM) Oryzias latipes and zebrafish (ZF) Danio rerio. Parents and fertilized embryos of each species were exposed to nominal (measured) concentrations of 0.1 (0.09), 1 (1.1) and 10 (8.3) MUg/L of propranolol. Heart rate was monitored during subsequent exposure in embryos at incremental developmental periods (44, 54, 64 h post-fertilization (hpf) for ZF and 68, 116, 164 hpf for JM). Heart development and morphology was examined using whole mount immunostaining with distance measurements between the sinus venosus (SV) and bulbus arteriosis (BV). Morphological measurements were made at 44 hpf for ZF and 164 hpf for JM. In ZF, a significant reduction in heart rate was observed at 0.08 MUg/L propranolol, along with an increase in the SV-BA distance at 44 hpf. Significant reductions in heart rate were also observed in ZF at 54 and 64 hpf at all concentrations of propranolol. For JM, heart rates generally decreased at all developmental timepoints (68, 116 and 164 hpf) after propranolol treatment, with concentration dependent decreases observed at 164 hpf and a lowest observed effect concentration (LOEC) of 0.09 MUg/L propranolol at each timepoint. However, significant alterations in cardiac morphology were not observed in JM at 164 hpf. In contrast, heart rates and morphology in ZF were affected with a non-monotonic concentration response in morphology and a LOEC of 0.09 MUg/L propranolol for morphological alterations at 44 hpf and for heart rate at each timepoint. These data indicated unique developmental stages of susceptibility between species and that combined parental and embryo exposures may lead to greater impairment of cardiac development and function in offspring than separate exposures of adults and embryos. PMID- 22832283 TI - Stab injury and device implantation within the brain results in inversely multiphasic neuroinflammatory and neurodegenerative responses. AB - An estimated 25 million people in the US alone rely on implanted medical devices, ~2.5 million implanted within the nervous system. Even though many devices perform adequately for years, the host response to medical devices often severely limits tissue integration and long-term performance. This host response is believed to be particularly limiting in the case of intracortical microelectrodes, where it has been shown that glial cell encapsulation and localized neuronal cell loss accompany intracortical microelectrode implantation. Since neuronal ensembles must be within ~50 um of the electrode to obtain neuronal spikes and local field potentials, developing a better understanding of the molecular and cellular environment at the device-tissue interface has been the subject of significant research. Unfortunately, immunohistochemical studies of scar maturation in correlation to device function have been inconclusive. Therefore, here we present a detailed quantitative study of the cellular events and the stability of the blood-brain barrier (BBB) following intracortical microelectrode implantation and cortical stab injury in a chronic survival model. We found two distinctly inverse multiphasic profiles for neuronal survival in device-implanted tissue compared to stab-injured animals. For chronically implanted animals, we observed a biphasic paradigm between blood-derived/trauma induced and CNS-derived inflammatory markers driving neurodegeneration at the interface. In contrast, stab injured animals demonstrated a CNS-mediated neurodegenerative environment. Collectively these data provide valuable insight to the possibility of multiple roles of chronic neuroinflammatory events on BBB disruption and localized neurodegeneration, while also suggesting the importance to consider multiphasic neuroinflammatory kinetics in the design of therapeutic strategies for stabilizing neural interfaces. PMID- 22832282 TI - Changes in ambient temperature differentially alter the thermoregulatory, cardiac and locomotor stimulant effects of 4-methylmethcathinone (mephedrone). AB - BACKGROUND: The substituted cathinone compound known as mephedrone (4 methylmethcathinone; 4-MMC) has become popular with recreational users of psychomotor-stimulant compounds. Only recently have the first preclinical studies provided information about this drug in the scientific literature; nevertheless, media reports have led to drug control actions in the UK and across several US states. Rodent studies indicate that 4-MMC exhibits neuropharmacological similarity to 3,4-methylenedioxymethamphetamine (MDMA) and prompt investigation of the thermoregulatory, cardiac and locomotor effects of 4-MMC. This study focuses on the role of ambient temperature, which has been shown to shift the effects of MDMA from hyperthermic to hypothermic. METHODS: Male Sprague-Dawley rats were monitored after subcutaneous administration of 4-MMC (1.0-5.6 mg/kg) using an implantable radiotelemetry system under conditions of low (20 degrees C) and high (30 degrees C) ambient temperature. RESULTS: A pharmacokinetic study found a T(max) of 0.25 h and a C(max) of 1206 ng/ml after 5.6 mg/kg 4-MMC. A dose dependent reduction of body temperature was produced by 4-MMC at 20 degrees C but there was no temperature change at 30 degrees C. Increased locomotor activity was observed after 4-MMC administration under both ambient temperatures, however, significantly more activity was observed at 30 degrees C. Heart rate was slowed by 1.0 and 5.6 mg/kg 4-MMC at 20 degrees C, and was slower in the 30 degrees C vs. 20 degrees C condition across all treatments. CONCLUSION: These results show that the cathinone analog 4-MMC exhibits in vivo thermoregulatory properties that are distinct from those produced by MDMA. PMID- 22832284 TI - Chronic subdural hematoma associated with an arachnoid cyst in a juvenile taekwondo athlete: a case report and review of the literature. AB - Both chronic subdural hematoma and arachnoid cysts are common lesions in neurosurgical practice. Arachnoid cysts are a well-known predisposing factor for chronic subdural hematoma. Here, we present a 12-year-old taekwondo athlete with chronic subdural hematoma associated with arachnoid cysts. The chronic subdural hematoma was evacuated through 2 burr holes and the patient was discharged in good condition. To our knowledge, this is the first case of chronic subdural hematoma with associated arachnoid cysts in a taekwondo athlete. We also review the literature on sports-related chronic subdural hematomas associated with arachnoid cysts in children. PMID- 22832285 TI - Women are from venus, men are from Mars: do gender differences also apply to rheumatoid arthritis activity and treatment responses? PMID- 22832286 TI - Methotrexate is an option for patients with refractory calcium pyrophosphate crystal arthritis. AB - BACKGROUND: Patients with calcium pyrophosphate deposition disease sometimes require a continuous therapy. Nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids are commonly used with good results, but occasionally, these are ineffective, contraindicated, or not tolerated. We present our experience with methotrexate (MTX) in refractory CPP arthritis. METHODS: An observational study to describe and evaluate the use of MTX in refractory calcium pyrophosphate deposition disease was undertaken. Ten patients were included. Treatment response was evaluated by the physician (excellent, good, medium, poor, or absent response) and the patient as measured on a 10-cm visual analog scale (0 = no effect; 10 = complete resolution of symptoms). Adverse effects were recorded on all patients. RESULTS: Five patients presented a persistent polyarthritis, 3 presented a persistent oligoarthritis, and 2 presented a very frequently recurring monoarthritis. Median MTX evaluation by patients on visual analog scale was 7.4, and physicians considered excellent (n = 2), good (n = 5), or medium (n = 3). The safety profile was generally good, but MTX was discontinued in 2 patients because of adverse effects (transient bone marrow aplasia and elevation of liver enzymes). CONCLUSIONS: Methotrexate could be an effective and safe option for patients with refractory CPP arthritis, but additional studies are necessary to determine to what extent and for which patients MTX is effective. PMID- 22832287 TI - Knowledge, attitudes, and clinical practice of rheumatologists in vaccination of the at-risk rheumatology patient population. AB - BACKGROUND: Patients with inflammatory arthritis are at increased risk of infection. Much of the burden of infection in this population is vaccine preventable. A number of international rheumatology organizations have published expert recommendations for vaccination in adult patients. Despite this, reported vaccination rates remain low among patients with inflammatory arthritis. OBJECTIVES: We sought to establish the knowledge, attitudes, and clinical practice of rheumatologists with respect to vaccination. METHODS: Rheumatologists practicing in Ireland in 2009 were surveyed by postal questionnaire. Data collected was entered into Microsoft Excel and statistical analysis was carried out using SPSS18 software. RESULTS: Eighty (100%) practicing rheumatologists were surveyed. Response rate was 55% (44/80). Of those surveyed, 57% (25/44) had no written departmental vaccination guidelines. Although 90% of those surveyed agreed that the responsibility for ensuring vaccine compliance rests with health professionals, only 5% considered that the rheumatology clinic was the best setting in which to accomplish this. Half (50%, n = 22) of practicing rheumatologists do not inquire about vaccination history in the clinic, with a minority (9%, n = 4) recording vaccination history in their clinical notes. A significant percentage of rheumatologists do not perform screening about prior vaccination before initiation of either anti-tumor necrosis factor (34%) or disease-modifying antirheumatic disease (42%) therapy. Moreover, 57% (n = 25) considered the responsibility for vaccination the domain of the patients' general practitioners with the favored strategy to improve vaccine compliance being led by the primary care physicians (48%, n = 21). CONCLUSIONS: The practice of Irish rheumatologists with regard to vaccination in this survey was suboptimal. Most neither recommend nor record vaccination history in their clinical notes, with the majority feeling that the rheumatology clinic is not the appropriate setting in which to target strategies to improve vaccine compliance. Although a more proactive role needs to be taken by rheumatologists as the principal prescribers of immunosuppressive therapy on this issue, our survey respondents suggest that strategies to improve vaccine uptake should be developed outside the rheumatology clinic and, in particular, involve primary care. The circulation of currently available international guidelines on vaccination specific for rheumatology patients to primary care physicians should be used to inform practices to ensure improved vaccine compliance. PMID- 22832288 TI - High-resolution computed tomographic findings in systemic sclerosis-associated interstitial lung disease: comparison between diffuse and limited systemic sclerosis. AB - OBJECTIVE: This study aimed to compare the high-resolution computed tomographic (HRCT) findings between patients with diffuse cutaneous systemic sclerosis (DcSSc) and limited cutaneous systemic sclerosis (LcSSc) as well as to correlate the HRCT scores and the other variables. METHODS: The medical records of all patients with SSc who presented at the Rheumatology Clinic, Chiang Mai University Hospital, from March 2005 to 2010 and underwent HRCT of the chest for the presence of interstitial lung disease were retrospectively reviewed. The extent of ground glass, lung fibrosis, and honeycombing was scored. All scores were aggregated to produce a total CT perfusion score. The widest coronal esophageal diameter (WED), the maximum diameter of the main pulmonary artery (MPAD), and ascending aortic diameter (AD) were measured. The ratio of MPAD to AD (MPAD/AD) was calculated. RESULTS: Of the 71 patients with SSc, mean (SD) age and disease duration were 54.8 (11.8) and 3.9 (4.2) years, respectively. Of them, 69.0% were female and 67.6% were classified as having DcSSc. There were no significant differences between patients with DcSSc and LcSSc with respect to age, disease duration, New York Heart Association Functional Classification, the calculated HRCT scores, WED, and MPAD. The lung fibrosis and total CT perfusion score correlated inversely with the SpO2 (r = -0.47, P < 0.01). The honeycombing correlated positively with the New York Heart Association Functional Classification and the WED (r = 0.29 and r = 0.32, respectively, P < 0.05). CONCLUSIONS: The HRCT scores of these patients were comparable in both subtypes of SSc. Careful evaluation of lungs and esophageal involvement should be performed irrespective of SSc subtypes. The calculated HRCT scores may be useful to assess the severity of the interstitial lung disease in SSc. PMID- 22832289 TI - Interleukin 1beta blockade improves signs and symptoms of chronic calcium pyrophosphate crystal arthritis resistant to treatment. AB - A 54-year-old woman with recurrent episodes of bilateral knee arthritis was admitted several times to the Department of Rheumatology. She was diagnosed to have chronic calcium pyrophosphate crystal arthritis. Interleukin 1beta (IL 1beta) plays a central role in the pathogenesis of inflammation induced by calcium pyrophosphate crystals, and IL-1beta blockade may be an effective treatment in patients with severe chronic calcium pyrophosphate crystal arthritis. Because of the short effect of treatment with corticosteroids and the frequent attacks of arthritis, the patient was treated with the IL-1 receptor antagonist anakinra. She responded well after 1 week with normalization of inflammation. Eight months after the initiation of treatment, the patient has had no relapses, although we were unable to withdraw the anakinra. PMID- 22832290 TI - Reactive arthritis after Shigella gastroenteritis in American military in Afghanistan. AB - In Afghanistan in mid June 2011, 2 US Marines developed reactive arthritis manifested by conjunctivitis, urethritis, arthritis, and circinate balanitis. Their symptoms were preceded by an outbreak in their unit of gastroenteritis caused by Shigella species after ingesting contaminated chicken. Gastroenteritis has plagued military operations for millennia. This report emphasizes that personnel can develop reactive arthritis after bouts of gastrointestinal infections that are common in deployed environments. It is highly recommended to maintain vigilance in keeping reactive arthritis on the differential diagnosis in deployed personnel after bouts of gastroenteritis. PMID- 22832291 TI - Pachydermodactyly in a 16-year-old adolescent boy. AB - Pachydermodactyly is a superficial benign fibromatosis of unknown etiology; it is rare, more frequent in adolescent males, and characterized by painless swelling of the proximal interphalangeal joints(PIP) of the hands. Histologic examination of the skin shows epidermal hyperplasia and increased number of dermal fibroblasts and collagen fibers.We report the case of a 16-year-old adolescent boy who presented swelling of the lateral and dorsal regions of all the metacarpophalangeal and PIP joints of the left hand and PIP and metacarpophalangeal joints of the second and fifth fingers of the right hand, with 3 years of evolution and no arthritis or functional impairment. Results of complementary diagnostic examinations were normal, with the exception of hand ultra sound that showed skin thickening, without synovial proliferation or joint effusion. Skin biopsy confirmed pachydermodactyly. The patient under went aesthetic surgery with good outcome, without recurrence.This rare condition should be distinguished from idiopathic juvenile arthritis and other entities such as knuckle pads syndrome. PMID- 22832292 TI - Basic science for the clinician 57: transforming growth factor beta. AB - As is so often the case, a molecule gets named for its first identified activity or apparent role and then that initial name sticks, even as new and perhaps fundamentally different activities emerge from later studies. It is the special power of evolution that takes a certain activity and then uses it over and over again in pursuit of apparently disparate goals in a maturing or mature organism. In general terms, transforming growth factor beta (TGF-beta) is intimately involved in a variety of differentiation and growth inhibition processes, in apoptosis, and in deposition of the extracellular matrix. Initially identified in its role in oncogenesis, TGF-beta is now implicated in a number of vascular and rheumatologic disorders, perhaps most notably the scleroderma. TGF-beta has been identified as a powerful influence in angiogenesis, wound healing, joint inflammation, tumor growth and metastasis, and, of course, immunoregulation. So "what is in a name?" A rose by any other name would smell as sweet and would still be immunologically active, even if the name is "misleading." PMID- 22832293 TI - Central nervous system involvement including visual loss in a patient with systemic lupus erythematosus with posterior reversible leukoencephalopathy syndrome. PMID- 22832294 TI - Cyclophosphamide without corticosteroids for treatment of severe systemic necrotizing vasculitis. PMID- 22832296 TI - A rare case of mixed connective tissue disease complicated with neuromyelitis optica. PMID- 22832297 TI - Muscular polyarteritis nodosa. AB - We present an unusual case of a 26-year-old man with muscular polyarteritis nodosa (PAN) with severe calf pain and gait disturbance. Magnetic resonance imaging of the lower limbs demonstrated highly increased signal intensity in both soleus muscles and the lateral head of the left gastrocnemius muscle. Biopsies of the soleus muscle showed acute necrotizing arteritis. The calf pain and limited range of motion of ankle dorsiflexion subsided from day 1 on administration of oral corticosteroid at high dosage and were completely resolved by 4 months. After tapering corticosteroid to 10 mg, symptoms recurred. A combined regimen of immunosuppressants was found to maintain symptomatic relief.Muscular PAN should be included in the differential diagnosis of a patient presenting with symptoms of acute or subacute calf pain. Although this muscular PAN was so far been benign, complete remission of the underlying process may be difficult to achieve. PMID- 22832298 TI - Fatal Henoch-Schonlein purpura in an adult with Dieulafoy lesions. AB - Henoch-Schonlein purpura (HSP) is considered a benign disease of children. We report a severe case of HSP in an adult causing renal failure and gastrointestinal (GI) hemorrhage. Despite aggressive treatment with corticosteroids, cyclophosphamide, and plasmapheresis, the patient developed massive GI bleeding from 2 Dieulafoy lesions and died weeks after bowel resection. Although uncommon, when massive GI hemorrhage occurs, actively bleeding Dieulafoy lesions, although uncommon, should be suspected and evaluated early. PMID- 22832299 TI - Pigmented villonodular synovitis of the lumbar spine. PMID- 22832300 TI - Elevated anti-neutrophil cytoplasmic antibodies without vasculitis after influenza vaccination. PMID- 22832301 TI - Occult erosions in Jaccoud arthropathy. PMID- 22832303 TI - Histoplasmosis mimicking felty syndrome. PMID- 22832302 TI - Intestinal vasculitis and renal infarction in a lupus patient with antiphospholipid syndrome. PMID- 22832304 TI - LE cells in pleural fluid. PMID- 22832306 TI - Female gout: age and duration of the disease determine clinical presentation. AB - OBJECTIVE: This study aimed to compare data and associated diseases between women and men with gout paired for age and duration of the disease. METHODS: Consecutive patients from outpatient gout clinics of 2 rheumatology departments were included in this case-control study. We identified 37 women with gout diagnosis and paired them by age and duration of the disease with 37 men with gout (American College of Rheumatology criteria). Variables were clinical data, associated diseases, and renal function evaluated by 3 methods: creatinine clearance, modification of diet in renal disease, and Cockcroft-Gault. RESULTS: Mean (SD) age was 54.47 (15.13) years in women versus 53.52 (15.23) years in males, and mean (SD) age at onset 46.77 (16.63) years versus 45.62 (16.16) years in women and men, respectively. Hypertension was found in 26 (73%) of 37 women and in 27 (70%) of 37 men, previous diuretics was found in only 1 man, and no significant differences were found between women and men in gout or associated metabolic diseases. Females had lower creatinine clearance than males did (49.8 [29.7] vs. 67.1 [35.5] mL/min, P = 0.039). But, when it was calculated by methods considering sex, there were no significant differences (Cockcroft-Gault 66.4 [37.6] vs. 78.8 [43.8] mL/min [P = 0.2] and modification of diet in renal disease 73.8 [64.6] vs. 73.1 [35.0] mL/min [P = 0.9], females vs. males, respectively). Thirteen women (35%) were premenopausal at onset, 2 had familial history of gout, and 2 had history of lithiasis; other variables were not different from postmenopausal women. CONCLUSIONS: Factors previously associated to female gout seem to be more related to age than to sex or to the disease itself. In our country, patients with gout (males and females) are younger at onset. Gender should be considered to evaluate renal function in females with gout. One third of our female patients with gout were premenopausal and had unexpected higher frequency of lithiasis; no other differences with postmenopausal women were found. PMID- 22832308 TI - Design and synthesis of photolabile caged cytokinin. AB - Cytokinins are phytohormones that regulate diverse developmental processes throughout the life of a plant. trans-Zeatin, kinetin, benzyladenine and dihydrozeatin are adenine-type cytokinins that are perceived by the AHK cytokinin receptors. Endogenous cytokinin levels are critical for regulating plant development. To manipulate intracellular cytokinin levels, caged cytokinins were designed on the basis of the crystal structure of the AHK4 cytokinin receptor. The caged cytokinin was photolyzed to release the cytokinin molecule inside the cells and induce cytokinin-responsive gene expression. The uncaging of intracellular caged cytokinins demonstrated that cytokinin-induced root growth inhibition can be manipulated with photo-irradiation. This caged cytokinin system could be a powerful tool for cytokinin biology. PMID- 22832309 TI - Metronidazole thiosalicylate conjugates: synthesis, crystal structure, docking studies and antiamoebic activity. AB - Metronidazole thiosalicylate conjugates were synthesized and crystallised in order to discover new molecules having better efficacy than therapeutically administered drug metronidazole, used against Entamoeba histolytica. The three compounds (4-6) showed lower IC(50) values than metronidazole on HM1:IMSS strain of E. histolytica and displayed low cytotoxicity on MCF-7 cell line. In order to get an insight into the mechanisms of action of these compounds, a homology model of E. histolytica thioredoxin reductase (EhTHRase) was constructed and molecular docking was performed into the binding pocket to identify the nature of interactions. The docking studies suggest that the improved inhibitory activity of the newly synthesised metronidazole analogues could be due to involvement of the additional hydrophobic interactions in the binding mode. The result of the present study indicates the molecular fragments that play an essential role in improving the antiamoebic activity. PMID- 22832310 TI - Synthesis of N-(1-methyl-1H-indol-3-yl)methyleneamines and 3,3-diaryl-4-(1-methyl 1H-indol-3-yl)azetidin-2-ones as potential antileishmanial agents. AB - A series of N-(1-methyl-1H-indol-3-yl)methyleneamines and eight new 3,3-diaryl-4 (1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized and screened for their antileishmanial activity against Leishmania major. 3,3-Diaryl-4-(1-methyl 1H-indol-3-yl)azetidin-2-ones have been synthesized by the Staudinger's ketene imine cycloaddition employing two 2-diazo-1,2-diarylethanones as the precursors of diarylketenes. A marked improvement in anti-parasitic activity is observed by transformation of the methyleneamines to azetidin-2-ones in seven out of eight compounds. Two compounds displayed antileishmanial activity comparable to that of the clinically used antileshmanial drug, amphotericine B. PMID- 22832311 TI - N-Aryl pyrrolidinonyl oxadiazoles as potent mGluR5 positive allosteric modulators. AB - A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug like properties. PMID- 22832312 TI - Green synthesis and anti-infective activities of fluorinated pyrazoline derivatives. AB - A new series of fluorinated pyrazoles, 4a-e, were synthesized in good to excellent overall yields (65-82%) from the corresponding chalcones, 3a-e, by ultrasonic irradiation. The newly synthesized compounds were characterized and screened for their in vitro anti-bacterial, anti-fungal, and anti-tubercular activities against Mycobacterium tuberculosis H(37)Rv. PMID- 22832313 TI - The antioxidant effect of imine resveratrol analogues. AB - Twenty five Imine resveratrol analogues (IRAs) were synthesized, replacing the C=C bond in resveratrol with CN bond, as well as substitution modifications on aromatic rings. Radical scavenging activities against DPPH, along with singlet oxygen quenching capacities were evaluated, and further confirmed using density functional theory calculations (DFT). It was found that IRAs bearing ortho-OH on B ring have better radical scavenging activities against DPPH than resveratrol, these compounds were also found to be effective (1)O(2) quenchers. Theoretical studies on the reaction mechanism of these compounds with (1)O(2) suggest that the 1,3-addition to a double bond with a -OH group with the formation of allylic hydroperoxide is the most probable reaction route. PMID- 22832314 TI - A Co(III) complex cleaving soluble oligomers of h-IAPP in the presence of polymeric aggregates of h-IAPP. AB - Soluble oligomers of human islet amyloid polypeptide (h-IAPP) are believed to be the pathogenic species for type 2 diabetes mellitus. In search of the peptide cleavage agent cleaving oligomers of h-IAPP with low affinity for polymeric aggregates of h-IAPP, a chemical library was constructed by using the Ugi condensation. From the library, a Co(III) complex was discovered to cleave soluble oligomers of h-IAPP in the presence of polymeric aggregates of h-IAPP without being captured by the aggregates considerably. The peptide-cleavage agent inhibited apoptosis of INS-1 cell by h-IAPP even in the presence of preformed polymeric aggregates of h-IAPP. This suggests that target-selective peptide cleavage agents may be applied clinically not only to diabetes but also to various other amyloid diseases. PMID- 22832315 TI - Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers. AB - Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model. PMID- 22832316 TI - Anti-androgen receptor activity of apoptotic CK2 inhibitor CX4945 in human prostate cancer LNCap cells. AB - Androgen receptor (AR) is crucial for transcriptional signaling in prostate cancers. The anti-cancer activity of protein kinase CK2 (formerly called casein kinase 2)-specific small molecule inhibitors have been reported in several cancers including prostate cancers. The orally available CX4945, a potent and selective small molecule inhibitor of CK2, has advanced into human clinical trials and has exhibited strong anti-tumor activity. The inhibition of CK2 leads to a down-regulation of the AR-dependent transcription, but the functional relevance of CX4945 to AR-dependent transcription in AR-positive LNCap cells has not been studied yet. Our observation of inhibitory effects of CX4945 on the expression or phosphorylation levels of CK2alpha, Akt and anti-apoptotic molecules including IAP family members agreed with a previous study showing the effect of CK2 inhibition in cancer cells. This study also provides novel information on the impact of CX4945 in the inhibition of AR-dependent transcriptional activation in LNCap cells via its down-regulation. Pharmacologic inhibition experiment revealed that CX4945 could exhibit its anti-cancer activity in LNCap cells via the independent inhibitions of AR and Akt-survivin signalings. PMID- 22832317 TI - Design, synthesis and biological evaluation of simplified side chains of the macrolide antibiotic etnangien. AB - Novel simplified side chains of the potent RNA polymerase inhibitor etnangien were designed, synthesized and evaluated for antibacterial activity against Gram positive bacteria and one Gram-negative bacterium. PMID- 22832318 TI - Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability. AB - Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor's stability in mouse liver microsomes indicated that they were rapidly degraded. A structure-activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., alpha-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3 c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies. PMID- 22832319 TI - Synthesis and biological evaluation of novel oxindole derivatives for imaging neurofibrillary tangles in Alzheimer's disease. AB - This letter describes the synthesis and biological evaluation of a novel series of radioiodinated oxindole (OI) derivatives for detecting neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer's disease (AD). In binding experiments in vitro, 2-oxindole (2-OI) and 3-oxindole (3-OI) derivatives showed affinity for tau aggregates. The 3-OI derivative 14 showed the highest affinity of these derivatives. In biodistribution experiments using normal mice, the OI derivatives displayed good uptake (2.4-2.5%ID/g at 2 min) and clearance from the brain with time (0.6-1.4%ID/g at 30 min). In fluorescence staining experiments using AD brain sections, 14 clearly stained NFTs. 3-OI may serve as a new molecular scaffold for developing novel NFT imaging agents. PMID- 22832320 TI - Antitrypanosomal and antioxidant properties of 4-hydroxycoumarins derivatives. AB - In the present communication we prepared a series of six 4-hydroxycoumarin derivatives, isosters of quercetin, recognized as an antioxidant natural compound, with the aim of evaluating the antitrypanosomal activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, and the antioxidant properties. We have used the 4-hydroxycoumarin moiety (compound 1) as the molecular template for the synthesis of compounds 2-7. These derivates have shown moderate trypanocidal activity. However they have been proved to be good antioxidants. In particular compound 7 is the most active antioxidant and it is, therefore, a potential candidate for a successful employment in conditions characterized by free radicals overproduction. PMID- 22832321 TI - Design and synthesis of Pictet-Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death. AB - A series of Pictet-Spengler condensation derivatives (tetrahydro-beta-carbolines) was designed, synthesized and evaluated for lethality against a panel of seven cancer cell lines. Seven compounds (2a, 13, 20, 21, 27, 29 and 34) showed lethality in at least five cell lines. Among these, compound 27 showed a unique selectivity towards oncogenic-RAS expressing BJ-TERT/LT/ST/RAS(V12) tumor cells, compared to non-transformed BJ-TERT cells. Further investigation revealed that 27 induces cell death without activation of caspases. This represents a useful new probe of non-apoptotic cell death and oncogenic-RAS synthetic lethality. PMID- 22832322 TI - Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold. AB - Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL). PMID- 22832323 TI - Challenges of disorders of sex development: diverse perceptions across stakeholders. AB - BACKGROUND/AIMS: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. Optimal management is patient- and family-centered and delivered by interdisciplinary teams. The present pilot study elicits concerns held by important stakeholders on issues affecting young patients with DSD and their families. METHODS: Content from focus groups with expert clinicians (pediatric urologists (n = 7), pediatric endocrinologists (n = 10), mental health professionals (n = 4), DSD patient advocates (n = 4), and interviews with parents of DSD-affected children (newborn to 6 years; n = 11) was coded and content-analyzed to identify health-related quality of life issues. RESULTS: Key stressors varied across stakeholder groups. In general, family-centered issues were noted more than child-centered. In the child-centered domain, providers worried more about physical functioning; family and advocates emphasized gender concerns and body image. In the family-centered domain, parental concerns about medication management outweighed those of providers. Advocates reported more stressors regarding communication/information than other stakeholders. CONCLUSION: Variability exists across stakeholder groups in the key concerns affecting young children/families with DSD. Interdisciplinary DSD healthcare team development should account for varying perspectives when counseling families and planning treatment. PMID- 22832324 TI - Gender-based violence and HIV sexual risk behavior: alcohol use and mental health problems as mediators among women in drinking venues, Cape Town. AB - Gender-based violence is a key determinant of HIV infection among women in South Africa as elsewhere. However, research has not examined potential mediating processes to explain the link between experiencing abuse and engaging in HIV sexual risk behavior. Previous studies suggest that alcohol use and mental health problems may explain how gender-based violence predicts sexual risk. In a prospective study, we examined whether lifetime history of gender-based violence indirectly affects future sexual risk behavior through alcohol use, depression and post-traumatic stress disorder (PTSD) in a high-risk socio-environmental context. We recruited a cohort of 560 women from alcohol drinking venues in a Cape Town, South African township. Participants completed computerized interviews at baseline and 4 months later. We tested prospective mediating associations between gender-based violence, alcohol use, depression, PTSD, and sexual risk behavior. There was a significant indirect effect of gender-based violence on sexual risk behavior through alcohol use, but not mental health problems. Women who were physically and sexually abused drank more, which in turn predicted more unprotected sex. We did not find a mediated relationship between alcohol use and sexual risk behavior through the experience of recent abuse or mental health problems. Alcohol use explains the link between gender-based violence and sexual risk behavior among women attending drinking venues in Cape Town, South Africa. Efforts to reduce HIV risk in South Africa by addressing gender-based violence must also address alcohol use. PMID- 22832326 TI - Bruns syndrome and cysticercosis. PMID- 22832325 TI - Unique sleep disorders profile of a population-based sample of 747 Hmong immigrants in Wisconsin. AB - Concerns regarding sleep disorders in Hmong immigrants in the US emerged when an astonishingly high mortality rate of Sudden Unexplained Nocturnal Death Syndrome (SUNDS) was documented in Hmong men. Stress, genetics, and cardiac abnormalities interacting with disordered sleep were hypothesized as contributing factors to SUNDS. Most recently, sleep apnea has been implicated in nighttime deaths of Brugada Syndrome. This syndrome is thought to comprise a spectrum of sudden cardiac death disorders, including SUNDS. However, little research since has placed SUNDS in its context of Hmong cultural beliefs, health, or the prevalence of other sleep disorders. Because the epidemiology of sleep disorders and terrifying nighttime experiences in Hmong is poorly documented, we investigated the prevalence and correlates of sleep apnea, rapid eye movement (REM) sleep stage related disorders, and insomnia in 3 population-based samples (collected from 1996 to 2001) comprising 747 Hmong immigrants in Wisconsin. Participants were questioned on sleep problems, cultural beliefs, health, and other factors. A random subsample (n = 37) underwent in-home polysomnography to investigate sleep apnea prevalence. Self-report and laboratory findings were compared with similarly collected data from the Wisconsin Sleep Cohort (WSC) study (n = 1170), a population-based longitudinal study of sleep. The results inform a unique Hmong sleep disorder profile of a high prevalence of sleep apnea, sleep paralysis, and other REM-related sleep abnormalities as well the interaction of culturally related nighttime stressors with these sleep problems. For example, experiences of dab tsog (frightening night spirit pressing on chest) was prevalent and related to sleep apnea indicators, sleep paralysis, nightmares, hypnogogic hallucinations, and insomnia. Understanding the role of sleep disorders and the cultural mechanisms that may trigger or condition response to them could ultimately provide a basis for screening and intervention to reduce the adverse health and emotional consequences of these conditions in Hmong. PMID- 22832327 TI - Ketamine inhibits lipopolysaccharide-induced astrocytes activation by suppressing TLR4/NF-KB pathway. AB - BACKGROUND/AIMS: Ketamine has been reported to exert anti-inflammatory effects on astrocytes stimulated by lipopolysaccharide (LPS) in vitro and in vivo. However, the mechanism has not been elicited clearly. The aim of this study was to investigate the effects of ketamine on TLR4 expression and NF-KB-p65 phosphorylation, as well as the production of proinflammatory cytokines in LPS challenged astrocytes. METHODS: Astrocytes were stimulated with LPS (1ug/ ml) in the absence and presence of various concentrations of ketamine (10, 100, 1000uM). The concentrations of IL-1beta, IL-6 and TNF-alpha were measured by ELISA, the expression of glial fibrillary acidic protein (GFAP) in astrocytes was detected by immunofluorescence staining, the level of phosphorylated NF-KB p65 and the expression of TLR4 were detected by western blotting. RESULTS: LPS increased TLR4 expression and the phosphorylation of NF-KB p65 subunit as well as GFAP expression and the production of IL-1beta, IL-6 and TNF-alpha in cultured astrocytes. Ketamine (100 and 1000 uM) reduced the expression of GFAP and the production of these proinflammatory cytokines, inhibited the expression of TLR4 and attenuated the phosphorylation of NF-KB p65 in astrocytes challenged by LPS. CONCLUSION: The inhibitory effects of ketamine on LPS-induced astrocytes activation and inflammation response may be mediated by suppressing NF-KB activation through reducing the expression of TLR4. PMID- 22832328 TI - Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. AB - OBJECTIVE: The purpose of this study was to investigate the expression of metabolism-related proteins such as Glut-1 and carbonic anhydrase IX (CAIX) according to breast cancer molecular subtype. METHODS: We generated a tissue microarray of 276 breast cancer patients and performed immunohistochemical staining for known metabolism-related proteins, which were evaluated according to the molecular subtype. RESULTS: The expression of IGF-1, MIF, and HIF-1alpha was correlated with the HER-2 type (p < 0.05). Glut-1 overexpression and CAIX expression were associated with TNBC type, especially with basal-like type, high histologic grade, estrogen receptor negativity, and progesterone receptor negativity (p < 0.05). The expression of Glut-1 and CAIX was correlated with statistical significance (p < 0.001). CONCLUSION: We identified different patterns of expression of metabolism-related proteins according to the molecular subtypes of breast cancer defined by surrogate immunohistochemistry. Increased expression of HIF-1alpha, IGF-1, and MIF was noted in HER-2 type breast cancer and increased expression of Glut-1 and CAIX was noted in TNBC type breast cancer, especially in the basal-like subtype, which exhibited a glycolytic and acid resistant tumor phenotype. PMID- 22832329 TI - A comparison of the central nervous system effects of alcohol at pseudo-steady state in Caucasian and expatriate Japanese healthy male volunteers. AB - In general, Japanese and Caucasians differ in their response to alcohol. To investigate these differences the alcohol clamping method can be used. This strictly controlled infusion regimen provides a reliable tool to study contrasts in central nervous system (CNS) effects and/or alcohol disposition. In this study, twelve Japanese and twelve Caucasian healthy volunteers received two concentrations of intravenous alcohol or placebo using the alcohol clamp. Infusion rates during the steady state phase were used to compare alcohol clearance between the subgroups. Central nervous system (CNS) effects were frequently measured throughout the clamp. On average, significantly lower amounts of alcohol were needed to maintain similar stable concentrations in the Japanese group. However, these differences disappeared when values were corrected for lean body mass. The most pronounced pharmacodynamic differences between the groups were observed on body sway and on the visual analogue scale for subjective alcohol effects, mainly at the highest dose level. The alcohol clamp seems a useful method to compare differences in alcohol metabolism between groups. Some CNS effects of alcohol differed clearly between Japanese and Caucasians, but others did not, even though alcohol levels were stable and similar between the two groups. PMID- 22832330 TI - Relationships between aging of PAHs and soil properties. AB - Sequestration and diffusion of three polycyclic aromatic hydrocarbons (PAHs) in seven Chinese soils were investigated for up to 200 days in sterile soil microcosms as functions of soil property and aging time. The aging of the PAHs, assessed using a mild extractant that removes primarily the labile fraction, showed a biphasic behavior. The rapid diffusion from labile to nonlabile domains was mainly dependent upon the distribution of meso- and micropore fraction and total organic carbon content. Meanwhile, the slow diffusion was found to decrease with the increase of the content of soil organic carbon, particularly of hard organic carbon (p < 0.01) and the meso- and micropore fraction, as well as with the increasing molecular size of PAHs. This work offers evidence that analyses of organic carbon fractionation and porosity are important to adequately assess the mechanistic basis of sequestration and diffusion of organic contaminants in soils. PMID- 22832331 TI - The fractional patterns of polybrominated diphenyl ethers in the soil of the central Tibetan Plateau, China: the influence of soil components. AB - Sixteen soil samples were collected from the central Tibetan Plateau (CTP). The soil concentrations of polybrominated diphenyl ethers (PBDEs) in CTP were analyzed. The detected 42 congeners were divided into light, intermediate and heavy fractions. In addition to the various minerals, other soil properties were also characterized, including the content of soil organic carbon (SOC) and the particle size distribution. The clay content is positively related to the intermediate fraction of the PBDEs and negatively related to the light and heavy fractions. Similar correlations were observed for SOC and the fine-particle fraction (size < 2 MUm). The coefficient of determination (r(2)) associated with a linear regression indicated that the clays were more highly correlated with the fractional pattern of the PBDEs than with the other properties, such as SOC and the fine-particle fraction. The values of r(2) between clays and three fractions of PBDEs are 0.70, 0.69 and 0.58. PMID- 22832332 TI - Physiological responses of lichens to factorial fumigations with nitric acid and ozone. AB - This paper addresses the effects of gaseous nitric acid (HNO(3)) and ozone (O(3)), two important air pollutants, on six lichen species with different morphological, ecological, and biological characteristics. The treatment chambers were set up in a factorial design consisting of control chambers, chambers fumigated with HNO(3), with O(3), and with HNO(3) and O(3), together. Each species showed a different sensitivity to the fumigations, reflecting the physiological variation among species. Our results clearly indicate that HNO(3) is a strong phytotoxin to many lichens, and that O(3) alone has little effect on the measured parameters. The combined fumigation effects of HNO(3) and O(3) were not significantly different from HNO(3) alone. PMID- 22832333 TI - Recommendations for aerobic endurance training based on subjective ratings of perceived exertion in healthy seniors. AB - The study investigated physiological responses during 2-km walking at a certain intensity of a previously performed maximal exercise test where moderate perceived exertion was reported. Twenty seniors were examined by an incremental walking treadmill test to obtain maximal oxygen uptake (VO2max). A submaximal 2 km walking test was applied 1 wk later. The corresponding moderate perceived exertion (4 on the CR-10 scale) during the VO2max test was applied to the 2-km treadmill test. Moderate exertion (mean rating of perceived exertion [RPE]: 4 +/- 1) led to 76% +/- 8% of VO2max and 79% +/- 6% of maximal heart rate. RPE values drifted with a significant time effect (p = .001, eta(p) = .58) during the 2-km test from 3 +/- 0.7 to 4.6 +/- 0.8. Total energy expenditure (EE) was 3.3 +/- 0.5 kcal/kg. No gender differences in ventilatory, heart-rate, or EE data occurred. Brisk walking at moderate RPE of 3-5 would lead to a beneficial physiological response during endurance training and a weekly EE of nearly 1,200 kcal when exercising 5 times/wk for 30 min. PMID- 22832334 TI - Antenatal care use in Brazil and India: scale, outreach and socioeconomic inequality. AB - This paper investigates the extent of socioeconomic inequalities in antenatal care use and related medical procedures in Brazil and India, which represent transition economies with contrasting geographical and sociocultural composition and health care provision. Concentration indices and regression analyses applied on recent Demographic Health Survey data reveal high and proportionate distribution of antenatal coverage in Brazil, whereas the Indian case present problems of both scale and equity. Inequalities in access to four or more antenatal visits are significantly pronounced in India, and in Brazil the differences are significant only for those who had six or more visits. Brazil's universal healthcare model which proved effective in promoting equitable distribution of antenatal care could be implemented in India. Future interventions should emphasis quality of care in monitoring essential antenatal services especially targeting the poor and deprived communities. PMID- 22832335 TI - Monitoring of equine health in Denmark: a survey of the attitudes and concerns of potential database participants. AB - At present Denmark has no central database holding records of equine health and disease. Nor have attitudes to the establishment of a national database, and the concerns it raises, been investigated in a systematic way. The objective of the present study was to assess the attitudes and concerns of potential database stakeholders. Attitudes to participation, and the location, financing and management of the proposed database, together with any concerns it raises, were investigated in a questionnaire study of 13 potential stakeholder groups in Denmark (in total, 1581 questionnaire recipients and 717 respondents): equine veterinarians, researchers, veterinary students, animal welfare organization representatives, horse owners, trainers, farriers, representatives from authorities, ordinary citizens, and representatives of laboratories, and insurance, medical equipment and pharmaceutical companies. Proportions were calculated for pre-categorised responses, and supplementary attitudes were extracted from qualitative responses. Eighty-six percent of respondents stated a positive interest in providing data for the database; the percentage for veterinarians was 90%. Data contribution was regarded as feasible by many of the stakeholder groups; this willingness to provide data, however, depended on the implementation of a very user-friendly system. Requirements included an electronic, simple, and time-efficient data reporting system. Most respondents felt the database should be financed via horse owners through mandatory contributions linked to each horse. Disagreement appeared to arise over data ownership, accessibility, and location. These and other issues need further elaboration in order to find a solution that is acceptable for all stakeholders. It may be advisable to collect and store data in more than one database. PMID- 22832336 TI - Different photolysis kinetics and photooxidation reactivities of neutral and anionic hydroxylated polybrominated diphenyl ethers. AB - Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) pose potential ecological risks due to their endocrine disrupting effects and extensive sources. It is of great importance to know their environmental transformation for the purpose of ecological risk assessment. Photodegradation is an important transformation pathway of HO-PBDEs. As HO-PBDEs ionize in natural waters, the photochemical reactivities of both neutral and anionic HO-PBDEs need to be unveiled. In this study, six HO-PBDEs were selected as model compounds. Their direct photolysis rate constants (k(d)), quantum yields (Phi), light absorptions (A), second-order reaction rate constants with (1)O(2) (k(1O2)) and (.)OH (k(OH)) at different pH were determined, as well as these parameters for the neutral and anionic HO PBDEs. The k(d), Phi, A, k(1O2) and k(OH) for the anions are much higher than those for the neutral molecules and vary with the bromination degree. Molecular parameters computed with the density functional theory (DFT) were employed to construct structure-reactivity equations. The ether bond strength, the frontier molecular orbital energy and the charge distribution were found to be the intrinsic structural characters governing the photochemical reactivities. The half-lives range from 0.7 to 60.1h for the photodegradation including the direct photolysis and the reactions with (1)O(2) and ()OH in surface waters at 45 degrees N latitude under the continuous solar irradiation of sunny noon on 15 July. Direct photolysis is the dominant pathway. The photochemical reactivities of other HO-PBDEs at a given pH can also be estimated based on the structure reactivity equations, which is important for the ecological risk assessment of HO PBDEs. PMID- 22832337 TI - Chlorpyrifos acute exposure induces hyperglycemia and hyperlipidemia in rats. AB - In this study we evaluated the hyperglycemic and hyperlipidemic effects of chlorpyrifos (CPF) after an acute exposure in rats. The mechanisms involved in hyperglycemia induced by CPF were studied. A single dose of CPF (50 mg kg(-1), subcutaneous, s.c.) was administered to overnight-fasted rats. Glucose and corticosterone levels, lipid status and paraoxonase (PON1) activity were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels, tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was also determined. CPF caused an increase in glucose and glycogen levels as well as in TAT and G6Pase activities. The CPF exposure caused an increase in corticosterone levels, an inhibition of AChE activity and a reduction of PON1 activity. Regarding the lipid status, CPF induced an increase in triglycerides (TG) and low-density lipoprotein-cholesterol (LDL) levels and a decrease in high-density lipoprotein (HDL) levels associated with an increase of cardiovascular risk factors and the atherogenic index. The present study demonstrated that a single CPF administration caused hyperglycemia and hyperlipidemia in rats. The activation of the gluconeogenesis pathway, probably elicited by hypercorticosteronemia, is involved in the hyperglycemic effect of CPF in rats. PMID- 22832338 TI - Effect of vegetation in pilot-scale horizontal subsurface flow constructed wetlands treating sulphate rich groundwater contaminated with a low and high chlorinated hydrocarbon. AB - In order to characterize the effect of vegetation on performance of constructed wetlands (CWs) treating low and high chlorinated hydrocarbon, two pilot-scale horizontal subsurface flow (HSSF) CWs (planted with Phragmites australis and unplanted) treating sulphate rich groundwater contaminated with MCB (monochlorobenzene, as a low chlorinated hydrocarbon), (about 10 mg L(-1)), and PCE (perchloroethylene, as a high chlorinated hydrocarbon), (about 2 mg L(-1)), were examined. With mean MCB inflow load of 299 mg m(-2) d(-1), the removal rate was 58 and 208 mg m(-2) d(-1) in the unplanted and planted wetland, respectively, after 4 m from the inlet. PCE was almost completely removed in both wetlands with mean inflow load of 49 mg m(-2) d(-1). However, toxic metabolites cis-1,2-DCE (dichloroethene) and VC (vinyl chloride) accumulated in the unplanted wetland; up to 70% and 25% of PCE was dechlorinated to cis-1,2-DCE and VC after 4 m from the inlet, respectively. Because of high sulphate concentration (around 850 mg L(-1)) in the groundwater, the plant derived organic carbon caused sulphide formation (up to 15 mg L(-1)) in the planted wetland, which impaired the MCB removal but not statistically significant. The results showed significant enhancement of vegetation on the removal of the low chlorinated hydrocarbon MCB, which is probably due to the fact that aerobic MCB degraders are benefited from the oxygen released by plant roots. Vegetation also stimulated completely dechlorination of PCE due to plant derived organic carbon, which is potentially to provide electron donor for dechlorination process. The plant derived organic carbon also stimulated dissimilatory sulphate reduction, which subsequently have negative effect on MCB removal. PMID- 22832339 TI - Identifying the cause of sediment toxicity in agricultural sediments: the role of pyrethroids and nine seldom-measured hydrophobic pesticides. AB - Few currently used agricultural pesticides are routinely monitored for in the environment. Even if concentrations are known, sediment LC(50) values are often lacking for common sediment toxicity testing species. To help fill this data gap, sediments in California's Central Valley were tested for nine hydrophobic pesticides seldom analyzed: abamectin, diazinon, dicofol, fenpropathrin, indoxacarb, methyl parathion, oxyfluorfen, propargite, and pyraclostrobin. Most were detected, but rarely at concentrations acutely toxic to Hyalella azteca or Chironomus dilutus. Only abamectin, fenpropathrin, and methyl parathion were found at concentrations of potential concern, and only in one or two samples. One quarter of over 100 samples from agriculture-affected waterways exhibited toxicity, and in three-fourths of the toxic samples, pyrethroids exceeded concentrations expected to cause toxicity. The pyrethroid Bi-fen-thrin in particular, as well as lambda-cyhalothrin, cypermethrin, esfenvalerate, permethrin, and the organophosphate chlorpyrifos, were primarily responsible for the observed toxicity, rather than the more novel analytes, despite the fact that much of the sampling targeted areas of greatest use of the novel pesticides. PMID- 22832340 TI - Antioxidant system efficiently protects goldfish gills from Ni(2+)-induced oxidative stress. AB - Fish gills are target organs for waterborne metal ions and this work aimed to investigate the effects of waterborne Ni(2+) (10, 25 and 50 mg L(-1)) on goldfish gills. A special focus was on the relationship between Ni uptake and the homeostasis of reactive oxygen species (ROS) in the gills, the tissue, in direct contact with the metal pollutant. Ni-accumulation in the gills occurred as a function of exposure concentration (R(2)=0.98). The main indices of oxidative stress, namely carbonyl proteins (CP) and lipid peroxides (LOOH), decreased by 21 33% and 21-24%, as well as the activities of principal antioxidant enzymes superoxide dismutase and glutathione-dependent peroxidase, by 29-47% and 41-46%, respectively, in gills of Ni-exposed fish. One of the main players in the antioxidant defense of gills seems to be catalase, which increased by 23-53% in Ni-treated fish, and low molecular mass thiol-containing compounds (L-SH), exceeding untreated controls by 73-105% after fish exposure to 10-50 mg L(-1) of Ni(2+). The increased level of L-SH, mainly represented by reduced glutathione, was supported by enhanced activities of glutathione reductase (by 27-38%), glutathione-S-transferase (56-141%) and glucose-6-phosphate dehydrogenase (by 96 117%) and demonstrates the ability of the antioxidant system of gills to resist Ni-induced oxidative stress. PMID- 22832341 TI - MELAS-like encephalomyopathy caused by a new pathogenic mutation in the mitochondrial DNA encoded cytochrome c oxidase subunit I. AB - We report a 35-year-old woman presenting a stroke-like episode with transitory aphasia followed by generalized tonic-clonic seizures. She had severe hearing loss and suffered from frequent episodes of migraine. Although a brain MRI disclosed a T2-hyperintense lesion in the left parietal lobe, she had hardly any long-term sequela. Exercise intolerance, myalgias and limb-girdle muscle weakness indicated a slowly progressive myopathy. Extra-neurological features included short stature, and secondary amenorrhea with low gonadotropin levels, indicating secondary hypogonadism. However, she had three mutation-free, healthy children by ovarian stimulation. A muscle biopsy showed ragged-red, cytochrome c oxidase negative fibers, and an isolated defect of cytochrome c oxidase activity in muscle mitochondria. Sequence analysis of muscle mtDNA revealed a previously unreported heteroplasmic m.6597C>A transversion in the MTCOI gene, encoding subunit I of cytochrome c oxidase, corresponding to p.Q232K aminoacid change. Analysis on transmitochondrial cybrids demonstrated that the mutation is indeed associated with COX deficiency, i.e. pathogenic. PMID- 22832342 TI - Observational study of caloric and nutrient intake, bone density, and body composition in infants and children with spinal muscular atrophy type I. AB - Clinical experience supports a critical role for nutrition in patients with spinal muscular atrophy (SMA). Three-day dietary intake records were analyzed for 156 visits in 47 SMA type I patients, 25 males and 22 females, ages 1month to 13years (median 9.8months) and compared to dietary reference intakes for gender and age along with anthropometric measures and dual-energy X-ray absorptiometry (DEXA) data. Using standardized growth curves, twelve patients met criteria for failure to thrive (FTT) with weight for age <3rd percentile; eight met criteria based on weight for height. Percentage of body fat mass was not correlated with weight for height and weight for age across percentile categories. DEXA analysis further demonstrated that SMA type I children have higher fat mass and lower fat free mass than healthy peers (p<0.001). DEXA and dietary analysis indicates a strong correlation with magnesium intake and bone mineral density (r=0.65, p<0.001). Average caloric intake for 1-3years old was 68.8+/-15.8kcal/kg - 67% of peers' recommended intake. Children with SMA type I may have lower caloric requirements than healthy age-matched peers, increasing risk for over and undernourished states and deficiencies of critical nutrients. Standardized growth charts may overestimate FTT status in SMA type I. PMID- 22832343 TI - Mutations in TPM2 and congenital fibre type disproportion. AB - The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small 'caps' were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis. PMID- 22832346 TI - Achieving temperature-size changes in a unicellular organism. AB - The temperature-size rule (TSR) is an intraspecific phenomenon describing the phenotypic plastic response of an organism size to the temperature: individuals reared at cooler temperatures mature to be larger adults than those reared at warmer temperatures. The TSR is ubiquitous, affecting >80% species including uni- and multicellular groups. How the TSR is established has received attention in multicellular organisms, but not in unicells. Further, conceptual models suggest the mechanism of size change to be different in these two groups. Here, we test these theories using the protist Cyclidium glaucoma. We measure cell sizes, along with population growth during temperature acclimation, to determine how and when the temperature-size changes are achieved. We show that mother and daughter sizes become temporarily decoupled from the ratio 2:1 during acclimation, but these return to their coupled state (where daughter cells are half the size of the mother cell) once acclimated. Thermal acclimation is rapid, being completed within approximately a single generation. Further, we examine the impact of increased temperatures on carrying capacity and total biomass, to investigate potential adaptive strategies of size change. We demonstrate no temperature effect on carrying capacity, but maximum supported biomass to decrease with increasing temperature. PMID- 22832347 TI - Shape and evolution of the fundamental niche in marine Vibrio. AB - Hutchinson's fundamental niche, defined by the physical and biological environments in which an organism can thrive in the absence of inter-species interactions, is an important theoretical concept in ecology. However, little is known about the overlap between the fundamental niche and the set of conditions species inhabit in nature, and about natural variation in fundamental niche shape and its change as species adapt to their environment. Here, we develop a custom made dual gradient apparatus to map a cross-section of the fundamental niche for several marine bacterial species within the genus Vibrio based on their temperature and salinity tolerance, and compare tolerance limits to the environment where these species commonly occur. We interpret these niche shapes in light of a conceptual model comprising five basic niche shapes. We find that the fundamental niche encompasses a much wider set of conditions than those strains typically inhabit, especially for salinity. Moreover, though the conditions that strains typically inhabit agree well with the strains' temperature tolerance, they are negatively correlated with the strains' salinity tolerance. Such relationships can arise when the physiological response to different stressors is coupled, and we present evidence for such a coupling between temperature and salinity tolerance. Finally, comparison with well documented ecological range in V. vulnificus suggests that biotic interactions limit the occurrence of this species at low-temperature-high-salinity conditions. Our findings highlight the complex interplay between the ecological, physiological and evolutionary determinants of niche morphology, and caution against making inferences based on a single ecological factor. PMID- 22832345 TI - Metaproteogenomic insights beyond bacterial response to naphthalene exposure and bio-stimulation. AB - Microbial metabolism in aromatic-contaminated environments has important ecological implications, and obtaining a complete understanding of this process remains a relevant goal. To understand the roles of biodiversity and aromatic mediated genetic and metabolic rearrangements, we conducted 'OMIC' investigations in an anthropogenically influenced and polyaromatic hydrocarbon (PAH) contaminated soil with (Nbs) or without (N) bio-stimulation with calcium ammonia nitrate, NH(4)NO(3) and KH(2)PO(4) and the commercial surfactant Iveysol, plus two naphthalene-enriched communities derived from both soils (CN2 and CN1, respectively). Using a metagenomic approach, a total of 52, 53, 14 and 12 distinct species (according to operational phylogenetic units (OPU) in our work equivalent to taxonomic species) were identified in the N, Nbs, CN1 and CN2 communities, respectively. Approximately 10 out of 95 distinct species and 238 out of 3293 clusters of orthologous groups (COGs) protein families identified were clearly stimulated under the assayed conditions, whereas only two species and 1465 COGs conformed to the common set in all of the mesocosms. Results indicated distinct biodegradation capabilities for the utilisation of potential growth-supporting aromatics, which results in bio-stimulated communities being extremely fit to naphthalene utilisation and non-stimulated communities exhibiting a greater metabolic window than previously predicted. On the basis of comparing protein expression profiles and metagenome data sets, inter-alia interactions among members were hypothesised. The utilisation of curated databases is discussed and used for first time to reconstruct 'presumptive' degradation networks for complex microbial communities. PMID- 22832348 TI - Dispersal of thermophilic Desulfotomaculum endospores into Baltic Sea sediments over thousands of years. AB - Patterns of microbial biogeography result from a combination of dispersal, speciation and extinction, yet individual contributions exerted by each of these mechanisms are difficult to isolate and distinguish. The influx of endospores of thermophilic microorganisms to cold marine sediments offers a natural model for investigating passive dispersal in the ocean. We investigated the activity, diversity and abundance of thermophilic endospore-forming sulfate-reducing bacteria (SRB) in Aarhus Bay by incubating pasteurized sediment between 28 and 85 degrees C, and by subsequent molecular diversity analyses of 16S rRNA and of the dissimilatory (bi)sulfite reductase (dsrAB) genes within the endospore-forming SRB genus Desulfotomaculum. The thermophilic Desulfotomaculum community in Aarhus Bay sediments consisted of at least 23 species-level 16S rRNA sequence phylotypes. In two cases, pairs of identical 16S rRNA and dsrAB sequences in Arctic surface sediment 3000 km away showed that the same phylotypes are present in both locations. Radiotracer-enhanced most probable number analysis revealed that the abundance of endospores of thermophilic SRB in Aarhus Bay sediment was ca. 10(4) per cm(3) at the surface and decreased exponentially to 10(0) per cm(3) at 6.5 m depth, corresponding to 4500 years of sediment age. Thus, a half-life of ca. 300 years was estimated for the thermophilic SRB endospores deposited in Aarhus Bay sediments. These endospores were similarly detected in the overlying water column, indicative of passive dispersal in water masses preceding sedimentation. The sources of these thermophiles remain enigmatic, but at least one source may be common to both Aarhus Bay and Arctic sediments. PMID- 22832344 TI - Phylogenetic stratigraphy in the Guerrero Negro hypersaline microbial mat. AB - The microbial mats of Guerrero Negro (GN), Baja California Sur, Mexico historically were considered a simple environment, dominated by cyanobacteria and sulfate-reducing bacteria. Culture-independent rRNA community profiling instead revealed these microbial mats as among the most phylogenetically diverse environments known. A preliminary molecular survey of the GN mat based on only ~1500 small subunit rRNA gene sequences discovered several new phylum-level groups in the bacterial phylogenetic domain and many previously undetected lower level taxa. We determined an additional ~119,000 nearly full-length sequences and 28,000 >200 nucleotide 454 reads from a 10-layer depth profile of the GN mat. With this unprecedented coverage of long sequences from one environment, we confirm the mat is phylogenetically stratified, presumably corresponding to light and geochemical gradients throughout the depth of the mat. Previous shotgun metagenomic data from the same depth profile show the same stratified pattern and suggest that metagenome properties may be predictable from rRNA gene sequences. We verify previously identified novel lineages and identify new phylogenetic diversity at lower taxonomic levels, for example, thousands of operational taxonomic units at the family-genus levels differ considerably from known sequences. The new sequences populate parts of the bacterial phylogenetic tree that previously were poorly described, but indicate that any comprehensive survey of GN diversity has only begun. Finally, we show that taxonomic conclusions are generally congruent between Sanger and 454 sequencing technologies, with the taxonomic resolution achieved dependent on the abundance of reference sequences in the relevant region of the rRNA tree of life. PMID- 22832349 TI - Metabolome in progression to Alzheimer's disease. AB - Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues. PMID- 22832350 TI - Metabolite profiling of antidepressant drug action reveals novel drug targets beyond monoamine elevation. AB - Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery. PMID- 22832351 TI - Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. AB - Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic-pituitary-adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1(F) NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 * 10(-8), 5.18 * 10(-7) and 1.25 * 10( 9), respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology. PMID- 22832353 TI - Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice. AB - Stem cell-based regenerative therapy is considered a promising cellular therapeutic approach for the patients with incurable brain diseases. Mesenchymal stem cells (MSCs) represent an attractive cell source for regenerative medicine strategies for the treatment of the diseased brain. Previous studies have shown that these cells improve behavioral deficits in animal models of neurological disorders such as Parkinson's and Huntington's diseases. In the current study, we examined the capability of intracerebral human MSCs transplantation (medial pre frontal cortex) to prevent the social impairment displayed by mice after withdrawal from daily phencyclidine (PCP) administration (10 mg kg(-1) daily for 14 days). Our results show that MSCs transplantation significantly prevented the PCP-induced social deficit, as assessed by the social preference test. In contrast, the PCP-induced social impairment was not modified by daily clozapine treatment. Tissue analysis revealed that the human MSCs survived in the mouse brain throughout the course of the experiment (23 days). Significantly increased cortical brain-derived neurotrophic factor levels were observed in the MSCs treated group as compared with sham-operated controls. Furthermore, western blot analysis revealed that the ratio of phosphorylated Akt to Akt was significantly elevated in the MSCs-treated mice compared with the sham controls. Our results demonstrate that intracerebral transplantation of MSCs is beneficial in attenuating the social deficits induced by sub-chronic PCP administration. We suggest a novel therapeutic approach for the treatment of schizophrenia-like negative symptoms in animal models of the disorder. PMID- 22832354 TI - A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. AB - Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ~0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system. PMID- 22832355 TI - Identification of autoimmune gene signatures in autism. AB - The role of the immune system in neuropsychiatric diseases, including autism spectrum disorder (ASD), has long been hypothesized. This hypothesis has mainly been supported by family cohort studies and the immunological abnormalities found in ASD patients, but had limited findings in genetic association testing. Two cross-disorder genetic association tests were performed on the genome-wide data sets of ASD and six autoimmune disorders. In the polygenic score test, we examined whether ASD risk alleles with low effect sizes work collectively in specific autoimmune disorders and show significant association statistics. In the genetic variation score test, we tested whether allele-specific associations between ASD and autoimmune disorders can be found using nominally significant single-nucleotide polymorphisms. In both tests, we found that ASD is probabilistically linked to ankylosing spondylitis (AS) and multiple sclerosis (MS). Association coefficients showed that ASD and AS were positively associated, meaning that autism susceptibility alleles may have a similar collective effect in AS. The association coefficients were negative between ASD and MS. Significant associations between ASD and two autoimmune disorders were identified. This genetic association supports the idea that specific immunological abnormalities may underlie the etiology of autism, at least in a number of cases. PMID- 22832357 TI - Segmental testicular infarction: partial orchiectomy in a very rare pathology. AB - Segmental testicular infarctions are a rare disease with a low prevalence and few cases have been reported in the literature. We present a 26-year-old male without any relevant medical history who consulted at the Urology Department due to mild pain in the right testicle over the last month. He had no previous trauma or acute testicular pain. Partial orchiectomy was performed through an inguinal incision with removal of lesions and reconstruction of the testicular parenchyma. Histological examination revealed testicular infarction with no presence of neoplastic cells. PMID- 22832356 TI - Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. AB - Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders. PMID- 22832358 TI - Neuromedin S increases L-type Ca(2+) channel currents through G(i)alpha-protein and phospholipase C-dependent novel protein kinase C delta pathway in adult rat ventricular myocytes. AB - Neuromedin S (NMS), a peptide structurally related to NMU, has been identified in the mammalian heart tissues. However to date, any role of NMS in cardiomyocytes and the relevant mechanisms still remain unknown. In this study, we identified a novel functional role of NMS in modulating L-type Ca(2+) channels in adult rat ventricular myocytes, in which NMU type 2 receptors (NMUR2), but not NMUR1, are endogenously expressed. We found that NMS at 0.1 uM reversibly increased I(Ba) by ~29.7%. Intracellular infusion of GDP-beta-S or a selective antibody raised against the G(i)-protein blocked the stimulatory effects of NMS. The classical and novel protein kinase C (nPKC) antagonist calphostin C or chelerythrine chloride, as well as the phospholipase C (PLC) inhibitor U73122, abolished NMS responses, whereas a classical PKC antagonist Go6976 or a PKA antagonist PKI 5-24 had no such effects. Pretreatment of cells with PKC-delta specific inhibitor rottlerin or intracellular application of a PKC-delta-derived inhibitory peptide, deltaV1-1, abolished NMS responses, while an inactive control peptide had no effects. In summary, NMS acting through NMUR2 increases I(Ba) via a G(i)alpha protein-dependent PKC-delta pathway in rat ventricular myocytes. PMID- 22832359 TI - Endobronchial ultrasound-guided transbronchial biopsy of peripheral pulmonary lesions: how many specimens are necessary? AB - BACKGROUND: Although endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) has been shown to increase the diagnostic yield over conventional bronchoscopic techniques, an important issue regarding the optimal number of biopsy specimens required has not been thoroughly investigated. OBJECTIVES: We sought to examine whether the number of biopsy specimens taken was associated with the diagnostic yield of EBUS-guided TBB and, if this was the case, to determine the optimal number of specimens required for the maximum diagnostic yield in peripheral pulmonary lesions. METHODS: The medical records of patients undergoing EBUS-guided TBB for the diagnosis of peripheral pulmonary lesions from 2008 to 2010 were retrospectively reviewed. The association of clinical and radiological features, including the number of biopsy specimens, with the diagnostic yield was analysed. RESULTS: A total of 384 patients were included for analysis. The overall diagnostic yield of EBUS-guided TBB was 73%, and the only factor influencing the diagnostic yield was the position of the probe. Patients in which the EBUS probe was placed within the lesions had a significantly higher yield (85%) than those in which the probe was adjacent to or outside the lesions (38%; p < 0.001). When the number of biopsy specimens was determined based on their adequacy, it was an insignificant factor in predicting the diagnostic yield. CONCLUSIONS: Probe position independently predicts the diagnostic yield of EBUS-guided TBB. In real-world practice, the optimal number of biopsy specimens should be decided on a case-by-case basis. PMID- 22832360 TI - Do 'passive' medical titanium surfaces deteriorate in service in the absence of wear? AB - Globally, more than 1000 tonnes of titanium (Ti) is implanted into patients in the form of biomedical devices on an annual basis. Ti is perceived to be 'biocompatible' owing to the presence of a robust passive oxide film (approx. 4 nm thick) at the metal surface. However, surface deterioration can lead to the release of Ti ions, and particles can arise as the result of wear and/or corrosion processes. This surface deterioration can result in peri-implant inflammation, leading to the premature loss of the implanted device or the requirement for surgical revision. Soft tissues surrounding commercially pure cranial anchorage devices (bone-anchored hearing aid) were investigated using synchrotron X-ray micro-fluorescence spectroscopy and X-ray absorption near edge structure. Here, we present the first experimental evidence that minimal load bearing Ti implants, which are not subjected to macroscopic wear processes, can release Ti debris into the surrounding soft tissue. As such debris has been shown to be pro-inflammatory, we propose that such distributions of Ti are likely to effect to the service life of the device. PMID- 22832361 TI - Probabilistic patterns of interaction: the effects of link-strength variability on food web structure. AB - Patterns of species interactions affect the dynamics of food webs. An important component of species interactions that is rarely considered with respect to food webs is the strengths of interactions, which may affect both structure and dynamics. In natural systems, these strengths are variable, and can be quantified as probability distributions. We examined how variation in strengths of interactions can be described hierarchically, and how this variation impacts the structure of species interactions in predator-prey networks, both of which are important components of ecological food webs. The stable isotope ratios of predator and prey species may be particularly useful for quantifying this variability, and we show how these data can be used to build probabilistic predator-prey networks. Moreover, the distribution of variation in strengths among interactions can be estimated from a limited number of observations. This distribution informs network structure, especially the key role of dietary specialization, which may be useful for predicting structural properties in systems that are difficult to observe. Finally, using three mammalian predator prey networks (two African and one Canadian) quantified from stable isotope data, we show that exclusion of link-strength variability results in biased estimates of nestedness and modularity within food webs, whereas the inclusion of body size constraints only marginally increases the predictive accuracy of the isotope based network. We find that modularity is the consequence of strong link strengths in both African systems, while nestedness is not significantly present in any of the three predator-prey networks. PMID- 22832362 TI - Variation in carotenoid-protein interaction in bird feathers produces novel plumage coloration. AB - Light absorption by carotenoids is known to vary substantially with the shape or conformation of the pigment molecule induced by the molecular environment, but the role of interactions between carotenoid pigments and the proteins to which they are bound, and the resulting impact on organismal coloration, remain unclear. Here, we present a spectroscopic investigation of feathers from the brilliant red scarlet ibis (Eudocimus ruber, Threskiornithidae), the orange-red summer tanager (Piranga rubra, Cardinalidae) and the violet-purple feathers of the white-browed purpletuft (Iodopleura isabellae, Tityridae). Despite their striking differences in colour, all three of these feathers contain canthaxanthin (beta,beta-carotene-4,4'-dione) as their primary pigment. Reflectance and resonance Raman (rR) spectroscopy were used to investigate the induced molecular structural changes and carotenoid-protein interactions responsible for the different coloration in these plumage samples. The results demonstrate a significant variation between species in the peak frequency of the strong ethylenic vibration (nu(1)) peak in the rR spectra, the most significant of which is found in I. isabellae feathers and is correlated with a red-shift in canthaxanthin absorption that results in violet reflectance. Neither polarizability of the protein environment nor planarization of the molecule upon binding can entirely account for the full extent of the colour shift. Therefore, we suggest that head-to-tail molecular alignment (i.e. J-aggregation) of the protein-bound carotenoid molecules is an additional factor. PMID- 22832363 TI - Collective cell migration: leadership, invasion and segregation. AB - A number of biological processes, such as embryo development, cancer metastasis or wound healing, rely on cells moving in concert. The mechanisms leading to the emergence of coordinated motion remain however largely unexplored. Although biomolecular signalling is known to be involved in most occurrences of collective migration, the role of physical and mechanical interactions has only been recently investigated. In this study, a versatile framework for cell motility is implemented in silico in order to study the minimal requirements for the coordination of a group of epithelial cells. We find that cell motility and cell cell mechanical interactions are sufficient to generate a broad array of behaviours commonly observed in vitro and in vivo. Cell streaming, sheet migration and susceptibility to leader cells are examples of behaviours spontaneously emerging from these simple assumptions, which might explain why collective effects are so ubiquitous in nature. The size of the population and its confinement appear, in particular, to play an important role in the coordination process. In all cases, the complex response of the population can be predicted from the knowledge of the correlation length of the velocity field measured in the bulk of the epithelial layer. This analysis provides also new insights into cancer metastasis and cell sorting, suggesting, in particular, that collective invasion might result from an emerging coordination in a system where single cells are mechanically unable to invade. PMID- 22832364 TI - Evolution of the most common English words and phrases over the centuries. AB - By determining the most common English words and phrases since the beginning of the sixteenth century, we obtain a unique large-scale view of the evolution of written text. We find that the most common words and phrases in any given year had a much shorter popularity lifespan in the sixteenth century than they had in the twentieth century. By measuring how their usage propagated across the years, we show that for the past two centuries, the process has been governed by linear preferential attachment. Along with the steady growth of the English lexicon, this provides an empirical explanation for the ubiquity of Zipf's law in language statistics and confirms that writing, although undoubtedly an expression of art and skill, is not immune to the same influences of self-organization that are known to regulate processes as diverse as the making of new friends and World Wide Web growth. PMID- 22832365 TI - Decompressive surgery for malignant middle cerebral artery infarcts: the results of randomized trials can be reproduced in daily practice. AB - BACKGROUND: In clinical randomized controlled trials (RCTs), decompressive surgery (DS) for malignant middle cerebral artery (MMCA) infarcts leads to a 50% absolute risk reduction in mortality, and improves the 1-year functional outcome. The reproducibility of these results in routine practice has never been evaluated. The purpose of this study was to test the hypothesis that the results of DS for MMCA in practice are similar to those observed in the surgical group of RCTs. METHODS: We prospectively included the first 31 patients who underwent DS for MMCA. They were screened based on similar criteria as in the meta-analysis. The primary outcome was a modified Rankin Scale (mRS) score of <=4, and secondary outcomes were mRS of <=3 and death at 1 year. RESULTS: Thirty-one patients underwent DS for MMCA. The 1-year mRS was <=4 in 22 patients (71.0%) and <=3 in 16 (51.6%). Seven patients died (22.6%). CONCLUSION: This observational study showed that DS for MMCA in a center without previous experience provides similar results as those obtained in the surgical arm of RCTs. PMID- 22832366 TI - Early onset inflammation in pre-insulin-resistant diet-induced obese rats does not affect the vasoreactivity of isolated small mesenteric arteries. AB - BACKGROUND: Obesity is an increasing burden affecting developed and emerging societies since it is associated with an increased risk of diabetes and consequent cardiovascular complications. Increasing evidence points towards a pivotal role of inflammation in the etiology of vascular dysfunction. Our study aimed to investigate signs of inflammation and their relation to vascular dysfunction in rats receiving a high fat diet. METHODS: Diet-induced obese (DIO) rats were used as a model since these rats exhibit a human pre-diabetic pathology. Oral glucose and insulin tolerance tests were conducted on DIO rats and their controls prior to the development of insulin resistance. Furthermore, the plasma contents of selected cytokines [macrophage chemoattractant protein (MCP-1), interleukin-6 (IL-6), and interleukin-1 (IL-1)] and the concentration of adiponectin were measured. Using wire myography, we tested the vascular function of isolated small mesenteric arteries. RESULTS: DIO animals had significantly (p < 0.05) increased body weight (721.2 +/- 6.3 g) compared to age- and sex-matched controls (643.4 +/- 14.6 g), as well as a significant increase (p < 0.01) in body fat percentage (29.7 +/- 1.7% and 22.7 +/- 0.97%, respectively). No significant difference in fasting plasma insulin levels could be detected between the two groups (chow-fed group 141.5 +/- 15.1 pmol/l; high fat-fed group 125.9 +/- 18.8 pmol/l). However, the levels of MCP-1 (89.7 +/- 4.2 pg/ml vs. 60.8 +/- 7.7 pg/ml) and IL-6 (61.6 +/- 3.1 pg/ml vs. 41.6 +/- 7.4 pg/ml) were significantly elevated in DIO animals (p < 0.05) as compared to controls. Adiponectin levels were also significantly increased (p < 0.01) in DIO rats (10.8 +/- 0.7 ng/ml) versus controls (6.9 +/- 0.5 ng/ml). No difference in vascular or endothelial function was evident as determined by responses to acetylcholine, sodium nitroprusside, endothelin-1, and calcitonin gene-related peptide. CONCLUSION: In DIO rats, which have not yet developed hyperinsulinaemia or glucose intolerance, the levels of inflammatory mediators MCP-1 and Il-6 are significantly increased without concomitant vascular dysfunction. The results show that inflammation and obesity are tightly associated, and that inflammation is manifested prior to significant insulin resistance and vascular dysfunction. PMID- 22832367 TI - Scapular positioning assessment: is side-to-side comparison clinically acceptable? AB - Clinicians routinely assess scapular position and motion of the symptomatic shoulder taking as reference for the contralateral asymptomatic side. A different positioning between sides (scapular asymmetry) is often assumed as pathological, however, the symmetry of scapular kinematics in healthy individuals is yet to be demonstrated. This study tested the hypothesis of scapular symmetry during arm elevation. The 3-dimensional scapular positioning of the dominant and non dominant shoulders of fourteen healthy young adults was simultaneously measured by a 6 degrees of freedom electromagnetic tracking device at three positions of arm elevation: rest, hands on hips, and 90 degrees of shoulder abduction with internal rotation. The scapula on the dominant shoulder showed greater retraction (P < 0.001; eta(2)(p) = 0.68) and upward rotation (P < 0.001; eta(2)(p) = 0.70) at all positions of arm elevation. From rest to 90 degrees of shoulder abduction, the mean (+/-SD) amount of scapular angular displacement was, respectively for dominant and non-dominant shoulders, 7.2 degrees (+/-7.8 degrees ) and 7.2 degrees (+/-4.4 degrees ) for retraction, 17.4 degrees (+/ 5.1 degrees ) and 17.8 degrees (+/-6.4 degrees ) for upward rotation, and 3.8 degrees (+/-3.6 degrees ) and 0.9 degrees (+/-3.6 degrees ) for posterior tilting. These findings suggest that scapular positioning on the thorax are not the same despite the observation of an identical kinematic pattern during arm elevation. This should be taken into consideration when comparing scapular position and motion of symptomatic and contralateral shoulders. PMID- 22832368 TI - T cell exhaustion in protozoan disease. AB - Protozoan parasites cause severe morbidity and mortality in humans worldwide, especially in developing countries where access to chemotherapeutic agents is limited. Although parasites initially evoke a robust immune response, subsequent immunity fails to clear infection, ultimately leading to the chronic stage. This enigmatic situation was initially addressed in chronic viral models, where T cells lose their function, a phenomenon referred to as 'exhaustion'. However, recent studies demonstrate that this paradigm can be extended to protozoan diseases as well, although with notable differences. These studies have revealed that T cell responses generated against Toxoplasma gondii, Plasmodium sp., and Leishmania sp. can become dysfunctional. This review discusses T cell exhaustion in parasitic infection, mechanisms of development, and a possible role in disease outcome. PMID- 22832369 TI - Centrum semiovale and corpus callosum integrity in relation to information processing speed in patients with severe traumatic brain injury. AB - OBJECTIVES: This study investigated white matter alterations in the corpus callosum (CC) and centrum semiovale (CSO), using diffusion tensor imaging and magnetization transfer imaging, in participants with severe traumatic brain injury (TBI) and related these changes to processing speed measures. PARTICIPANTS AND METHODS: Fourteen adult participants with severe TBI underwent neuroimaging and assessment, using the Symbol Digit Modalities Test and Trail-Making Test, Part B, at approximately 6 months postinjury. Thirteen demographically similar, neurologically intact adults were imaged for comparison. RESULTS: The TBI group demonstrated lower fractional anisotropy (FA) for the right CSO and higher apparent diffusion coefficient (ADC) for the CSO bilaterally than the control group. Lower FA and higher ADC were noted in all CC regions. Magnetization transfer imaging revealed smaller magnetization transfer ratios (MTRs) in the right and left CSO and CC genu and splenium. Written Symbol Digit Modalities Test performance was related to right CSO FA, bilateral CSO ADC, CC FA, and right CSO MTR, whereas oral Symbol Digit Modalities Test was related to right CSO FA, ADC, and MTR. Trail-Making Test, Part B, was related to right CSO FA and MTR. CONCLUSIONS: Advanced neuroimaging modalities such as diffusion tensor imaging and magnetization transfer imaging demonstrate significant alterations in white matter, which are related to processing speed. These techniques may be useful in quantifying the extent of injury even in normal appearing white matter after TBI. PMID- 22832370 TI - Treatment of metaphor interpretation deficits subsequent to traumatic brain injury. AB - OBJECTIVE: To improve oral interpretation of metaphors by patients with traumatic brain injury (TBI). DESIGN: Both single subject experimental design and group analysis. SETTING: Patients' homes. PARTICIPANTS: Eight adult patients with moderate to severe traumatic brain injury sustained 3 to 20 years before testing. INTERVENTION: The Metaphor Training Program consisted typically of 10 baseline sessions, 3 to 9 1-hour sessions of structured intervention, and 10 posttraining baseline sessions. Training used extensive practice with simple graphic displays to illustrate semantic associations. MAIN OUTCOME MEASURES: Quality of orally produced metaphor interpretation and accuracy of line orientation judgments served as dependent measures obtained during baseline, training, posttraining, and at a 3- to 4-month follow-up. Untrained line orientation judgments provided a control measure. RESULTS: Group data showed significant improvement in metaphor interpretation but not in line orientation. Six of 8 patients individually demonstrated significant improvement in metaphor interpretation. Gains persisted for 3 of the 6 patients at the 3- to 4-month follow-up. CONCLUSION: The Metaphor Training Program can improve cognitive-communication performance for individuals with moderate to severe traumatic brain injury. Results support the potential for treating patients' residual cognitive-linguistic deficits. PMID- 22832371 TI - The impact of neurobehavioral impairment on family functioning and the psychological well-being of male versus female caregivers of relatives with severe traumatic brain injury: multigroup analysis. AB - OBJECTIVE: To examine the differential effect of neurobehavioral impairments (cognitive, behavioral, and social) on family functioning, family roles, and psychological distress in male versus female caregivers of relatives with severe traumatic brain injury (TBI). DESIGN: Structural equation modeling with multigroup analysis conducted in a cross-sectional sample to test an established theoretical model. PARTICIPANTS: An aggregated sample of 122 caregivers (46 male, 76 female) of people with severe TBI. The sample comprised 64 spouses and 58 parents (29 parental couples) of 93 persons with TBI. MEASURES: Neurobehavioral Problem Checklist; Family Assessment Device; and Brief Symptom Inventory. RESULTS: Structural equation modeling showed that the proposed model had acceptable fit indices for the combined sample. Multigroup analysis indicated that both male and female caregivers (i) responded similarly to the neurobehavioral impairments experienced by the injured relative and (ii) reported behavior having a direct effect on family functioning, which, in turn, increased psychological distress. However, the effect of disrupted family functioning was more influential on the level of distress in male caregivers than in female caregivers. CONCLUSION: Evidence was found for gender-specific pathways underlying the psychological distress of male versus female caregivers. Such findings can assist in tailoring family support strategies so that they cater for caregivers of both genders. PMID- 22832372 TI - Does isolated traumatic subarachnoid hemorrhage affect outcome in patients with mild traumatic brain injury? AB - BACKGROUND: The importance of isolated traumatic subarachnoid hemorrhage (SAH) in relation to functional outcome in patients with mild traumatic brain injury (TBI) has not been frequently studied. The aim of this study was to compare the impact of isolated SAH with normal computed tomographic (CT) scan on outcome of patients with mild TBI. METHODS: This is a retrospective study of clinical records and CT scans of all patients with mild TBI (Glasgow Coma Scale score >=13) evaluated from January 1, 2010, to March 15, 2010, at our institution. The patients were divided into 2 groups: isolated SAH and normal CT scan. The telephonic Glasgow Outcome Scale-Extended, Rivermead Post-Concussion Symptoms Questionnaire (RPCSQ), and Rivermead Head Injury Follow-up Questionnaire (RHFUQ) scores were used to assess outcome after 1 year of injury. Independent sample t test in SPSS was used to assess difference in outcome. RESULTS: A total of 1149 patients with mild TBI were evaluated during study period. Among them, 34 (2.9%) patients had isolated SAH. Twenty-eight patients were male and 6 were female, with a mean age of 36.5 years. Subarachnoid hemorrhage was cortical in 19 (55.9%) patients, interhemispheric in 3 (8.8%) patients, Sylvian fissure in 2 (5.9%) patients, and basal cisternal in 1 (2.9%) patient. Nine (26.5%) patients had SAH at multiple locations. The mean RPCSQ and RHFUQ scores for patients with isolated SAH were 1.38 +/- 2.40 and 1.11 +/-3.305, respectively. The mean RPCSQ and RHFUQ scores for patients with normal CT scans were 0.40 +/- 1.549 and 0.533 +/- 1.59, respectively. There was no significant difference in the outcome scores between the SAH and the normal CT scan groups (RHFUQ, P = .45; RPCSQ, P = .248). CONCLUSION: In our study sample of patients with mild TBI, there is no difference in outcome of patients with isolated SAH compared with those with normal CT scans 1 year after injury. PMID- 22832373 TI - Oral immunization of wild boar and domestic pigs with attenuated live vaccine protects against Pseudorabies virus infection. AB - In domestic pigs strict control measures and the use of gene-deleted marker vaccines resulted in the elimination of pseudorabies virus (PrV) infections in many parts of Europe and North America. In free-roaming feral pigs and wild boar populations, however, serological surveys and monitoring in The Americas, Europe and North Africa provided serological and virological evidence that PrV is more widely distributed than previously assumed. Thus, there is a constant risk of spillover of PrV infection from wild pig populations to domestic animals which could require intervention to limit the infection in wild pigs. To investigate whether oral immunization of wild boar by live-attenuated PrV could be an option, wild boar and domestic pigs were orally immunized with 2*10(6) TCID(50) of the attenuated live PrV vaccine strain Bartha supplied either with a syringe or within a blister, and subsequently intranasally challenged with 10(6) TCID(50) of the highly virulent PrV strain NIA-3. Oral immunization with live-attenuated PrV was able to confer protection against clinical signs in wild boar and against transmission of challenge virus to naive contact animals. Only two vaccinated domestic pigs developed neurological signs after challenge infection. Our results demonstrate that oral immunization against PrV infection in wild boar is possible. In case increasing PrV infection rates in wild boar may enhance the risk for spillover into domestic pig populations, oral immunization of wild boar against PrV in endemic areas might be a feasible control strategy. PMID- 22832374 TI - Efficacy of a high-yield attenuated vaccine strain wholly derived from avian influenza viruses by use of reverse genetics. AB - The preparation of high-yield influenza H5N1 vaccine strains is challenging for researchers and manufacturers. Here, we used reverse genetics to generate a high yield avian influenza vaccine strain based on a novel avian influenza virus. A high-yield attenuated recombinant H5N3 virus (rH5N3-DL) was prepared from the HA gene of A/Goose/Anhui/08 (H5N1), modified by deletion of the multiple basic amino acids at the cleavage site, the NA gene from A/Duck/Germany/1215/73 (H2N3), and the six internal genes from the high-yield A/Goose/Dalian/3/01 (H9N2) virus. rH5N3-DL grew to high HA titers (1:2048) in eggs, eight times those of the parental H5N1 virus, and four times higher than that of rH5N3-PR8 (six internal genes from the high-yield PR8). Infection tests demonstrated that rH5N3-DL was avirulent in chickens, chicken embryos, and mice. rH5N3-DL-vaccinated chickens were fully protected against the morbidity and mortality of a lethal challenge with homologous A/Goose/Anhui/08, but only 80% of chickens were protected after challenge with heterologous A/Goose/Guangdong/1/96. The N3 neuraminidase marker distinguishes rH5N3-DL-vaccinated from H5N1-infected animals. rH5N3-DL is thus a promising vaccine candidate to combat highly pathogenic avian influenza virus infections. The A/Goose/Dalian/3/01 virus could be a promising candidate as providing internal genes donors with high-yield properties in reverse-genetics system and might be applicable for future avian influenza vaccine development. PMID- 22832375 TI - Does habitual physical activity prevent insomnia? A cross-sectional and longitudinal study of elderly Japanese. AB - Few epidemiological studies have examined the potential protective effects of physical activity on insomnia. The authors thus evaluated the association between physical activity and insomnia in a large population-based study in Shizuoka, Japan. Individual data were obtained from participants in an ongoing cohort study. A total of 14,001 older residents who completed questionnaires were followed for 3 yr. Of these, 10,211 and 3,697 participants were eligible for the cross-sectional and longitudinal analyses, respectively. The authors obtained information about the frequency of physical activity and insomnia. Then, the adjusted odds ratios and 95% confidence intervals between physical activity and insomnia were estimated. Habitual physical activity was related to lower prevalence of insomnia. Frequent physical activity also reduced the incidence of insomnia, especially difficulty maintaining sleep. For elderly people with sufficient mobility and no preexisting disease, high-frequency physical activity (e.g., 5 or more days/wk) may help reduce insomnia. PMID- 22832376 TI - Unraveling the puzzle of dementia risk in diabetes. PMID- 22832378 TI - Inflammatory myopathy presenting as head drop. PMID- 22832377 TI - Post-admission glucose levels are associated with healthcare-associated bloodstream infections and pneumonia in hospitalized patients with diabetes. AB - OBJECTIVE: We conducted a case-control study to examine if short-term glucose control is related to healthcare-associated bloodstream infections (BSI), urinary tract infections (UTI), and pneumonia in hospitalized adults with diabetes. SETTING AND PATIENTS: We analyzed 205 BSI, 510 UTI, and 109 pneumonia cases and 989, 2463, and 543 controls matched by age, sex and hospital stay seen at a large healthcare system in Manhattan from 2006 to 2008. METHODS: We examined whether infection risk was associated with serum glucose measured at admission and within 2 days to infection, using conditional logistic regression. Co-morbidities, immunosuppressive medications, prior hospitalizations, and insertion of indwelling devices were considered as potential confounders. RESULTS: Admission glucose level was not associated with infection. Glucose levels of >= 110 mg/dL measured within 2 days to infection were associated with BSI (Odds ratios from 2.04 to 2.67). Glucose level of >= 180 mg/dL was associated with pneumonia (Odds ratio=2.30). Decrease in glucose levels from admission to the infection was greater for controls than for infected cases. CONCLUSION: Healthcare-associated BSI and pneumonia were associated with glucose levels prior to infection diagnosis, but not with glucose levels at admission. Persistently high glucose level could be an indication of an underlying undiagnosed infection. PMID- 22832379 TI - 'Do Not Attempt Resuscitation' (DNAR) decisions in patients with femoral fractures: modification, clinical management and outcome. AB - BACKGROUND: increased provision of orthogeriatric expertise for patients with femoral fractures has led to implementation of 'Do Not Attempt Resuscitation' (DNAR) decisions prior to anaesthesia and surgery for fixation of their fractures. Review and modification of the DNAR decision by the medical team is necessary before surgery and is recommended by guidelines from the Association of Anaesthetists of Great Britain and Ireland (AAGBI) and the General Medical Council. METHODS: over a 17-month period, DNAR decisions were already present or were implemented for the first time in 22 patients prior to scheduled surgical fixation of their femoral fractures. Data were collected prospectively on each patient's management, including modification of their DNAR decision, and outcome at 30 days and 1 year. RESULTS: two patients died prior to surgery. In eight of the 20 patients who underwent surgical fixation, there was no documentation regarding the status of the DNAR decision in the perioperative period. The 30-day mortality rate for those undergoing surgery was 15% (3/20). At 1 year, eight patients survived with six living in their own homes. CONCLUSIONS: despite the favourable outcomes for hip fracture patients with pre-existing DNAR decisions, this audit showed inadequate review and documentation of the DNAR decision in advance of surgery. PMID- 22832380 TI - Potentially inappropriate prescribing in older residents in Irish nursing homes. AB - BACKGROUND: STOPP/START was formulated to identify potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) in older people. The purpose of this study was to determine the prevalence of PIP and PPO in older Irish patients in residential care using STOPP/START. METHODS: data were collected prospectively from seven publicly funded nursing homes within the Munster Region of Ireland over 3 weeks. Data recorded included: current medication, current medical conditions, previous medical conditions, biochemistry, sex and age. STOPP/START was applied to each patient record. RESULTS: of the 313 patients recruited, 74.4% (233) were female, mean age (+/- SD) 84.4 (+/- 7.5) years. The total number of medicines prescribed was 2,555 [range: 1-16; median: 8 (IQR 6-10 )]. STOPP identified 329 instances of PIP in 187 (59.8%) patients and START identified 199 PPOs in 132 (42.2%) patients. The number of medicines prescribed was positively associated with PIP identified by STOPP (rs = 0.303, P < 0.01). Age, sex and the number of medicines prescribed were not associated with prescribing omissions using START. CONCLUSIONS: a high proportion of patients recruited were prescribed at least one potentially inappropriate medicine, or had an omission of a clinically indicated medicine. Incorporating these tools into every-day practice could play a pivotal role in improving prescribing in this cohort. PMID- 22832381 TI - Infective coronary arteritis: a pathological analysis at autopsy. AB - Coronary artery disease, one of the leading causes of worldwide adult mortality, is most commonly atherosclerotic in pathogenesis. Nonatherosclerotic etiologies are quite rare. In the latter category, infective arteritis or infective vasculitis of the coronary arteries is a very rare but well-recognized subtype, usually discovered at autopsy. In this article, we present the clinicopathologic necropsy data of 10 patients in whom infective coronary arteritis was the leading cause of death. Among the 10 cases, the male/female ratio was 6:4, and with the exception of a 2-year-old female child, all the other patients were adults with an age range of 26 to 59 years. Of the 10 cases, 6 had infective endocarditis along with history of rheumatic heart disease in 3 patients, whereas 2 other patients had strong clinical suspicion of bacteremia or septicemia. The remaining 2 cases had preexisting coronary atherosclerosis with a history of stent placement in 1 of them. All our cases showed on histopathology acute obliterative inflammatory infiltrate consisting mainly of neutrophils along with bacterial colonies (in most of them) involving the epicardial and intramural coronary arteries. To the best of our knowledge, this is the largest series of infective coronary arteritis to be reported in the world. PMID- 22832382 TI - Effect of exercise on the vital signs and inflammatory biomarkers: scientific views. PMID- 22832383 TI - Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells. AB - BACKGROUND: Matrine is one of the major alkaloids extracted from Sophora flavescens and has been used clinically for breast cancer with notable therapeutic efficacy in China. However, the mechanisms are still largely unknown. METHODS: Cell viability was analyzed by MTT assay. After MCF-7 cells were treated with matrine for 48h, apoptosis was detected by flow cytometry, TUNEL assay and transmission electron microscopy, and the cell cycle distribution was also analyzed by flow cytometry. Further, the expression of PTEN, pAkt, Akt, pBad, Bad, p21(/WAF1/CIP1), and p27(/KIP1) was determined by Western blot. Changes of miR-21 level were quantified by real-time RT-PCR. After miR-21 was transfected in MCF-7 cells, PTEN protein level was measured by Western blot. RESULTS: Matrine inhibited MCF-7 cell growth in a concentration-and time-dependent manner, by inducing apoptosis and cell cycle arrest at G(1)/S phase. Matrine up-regulated PTEN by downregulating miR-21 which in turn dephosphorylated Akt, resulting in accumulation of Bad, p21(/WAF1/CIP1) and p27(/KIP1). CONCLUSION: Our study unraveled, for the first time, the ability of matrine to suppress breast cancer growth and elucidated the miR-21/PTEN/Akt pathway as a signaling mechanism for the anti-cancer action of matrine. Our findings also reinforce the notion that miRNAs can act as mediators of the therapeutic efficacy of natural medicines. PMID- 22832384 TI - Genetic variants at 5p12 and risk of breast cancer in Han Chinese. AB - A genome-wide association study, conducted among women of European ancestry, has identified two single-nucleotide polymorphisms (SNPs) rs4415084 (T>C) and rs10941679 (A>G) at chromosome 5p12 were associated with risk of breast cancer, suggesting that genetic variants in this region may have a role in the development of breast cancer. To investigate the associations between SNPs at 5p12 and risk of breast cancer in the Chinese population, we conducted a fine mapping in 5p12 using a haplotype-tagging SNP approach and genotyped these SNPs with a case-control study consisting of 878 cases and 900 controls. We found that the two risk SNPs reported in the European population were neither associated with breast cancer risk in our Chinese population, nor did the fine-mapping SNPs after controlling multiple comparison. PMID- 22832385 TI - Admixture and population structure in Mexican-Mestizos based on paternal lineages. AB - In the nonrecombining region of the Y-chromosome, there are single-nucleotide polymorphisms (Y-SNPs) that establish haplogroups with particular geographical origins (European, African, Native American, etc.). The complex process of admixture that gave rise to the majority of the current Mexican population (~93%), known as Mestizos, can be examined with Y-SNPs to establish their paternal ancestry and population structure. We analyzed 18 Y-SNPs in 659 individuals from 10 Mexican-Mestizo populations from different regions of the country. In the total population sample, paternal ancestry was predominately European (64.9%), followed by Native American (30.8%) and African (4.2%). However, the European ancestry was prevalent in the north and west (66.7-95%) and, conversely, Native American ancestry increased in the center and southeast (37-50%), whereas the African ancestry was low and relatively homogeneous (0 8.8%). Although this paternal landscape concurs with previous studies based on genome-wide SNPs and autosomal short tandem repeats (STRs), this pattern contrasts with the maternal ancestry, mainly of Native American origin, based on maternal lineages haplogroups. In agreement with historical records, these results confirm a strong gender-biased admixture history between European males and Native American females that gave rise to Mexican-Mestizos. Finally, pairwise comparisons and analysis of molecular variance tests demonstrated significant population structure (F(ST)=4.68%; P<0.00005), delimiting clusters that were geographically defined as the following: north-west, center-south and southeast. PMID- 22832386 TI - Novel PNPLA2 gene mutations in Chinese Han patients causing neutral lipid storage disease with myopathy. AB - Neutral lipid storage disease with myopathy (NLSDM) referred to those neutral lipid storage disease (NLSD) patients with myopathy but without ichthyosis. Recently, NLSDM has been attributed to mutations in the PNPLA2 gene. Until now, 19 patients with PNPLA2 mutations have been reported. In the present study, we describe the clinical and genetic findings in three Chinese patients with NLSDM. Sequence analysis of PNPLA2 gene was performed. In our patients we identified four novel mutations in the PNPLA2 gene including two splicing mutations. The identification and study of mutations found in PNPLA2 is also particularly important to define the clinical spectrum and genotype-phenotype correlations of the PNPLA2 gene. PMID- 22832387 TI - Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders. AB - Traditional approaches for gene mapping from candidate gene studies to positional cloning strategies have been applied for Mendelian disorders. Since 2005, next generation sequencing (NGS) technologies are improving as rapid, high-throughput and cost-effective approaches to fulfill medical sciences and research demands. Using NGS, the underlying causative genes are directly distinguished via a systematic filtering, in which the identified gene variants are checked for novelty and functionality. During the past 2 years, the role of more than 100 genes has been distinguished in rare Mendelian disorders by means of whole-exome sequencing (WES). Combination of WES with traditional approaches, consistent with linkage analysis, has had the greatest impact on those disorders following autosomal mode of inheritance; in more than 60 identified genes, the causal variants have been transmitted at homozygous or compound heterozygous state. Recent literatures focusing on identified new causal genes in Mendelian disorders using WES are reviewed in the present survey. PMID- 22832388 TI - Degree of musical expertise modulates higher order brain functioning. AB - Using functional magnetic resonance imaging, we show for the first time that levels of musical expertise stepwise modulate higher order brain functioning. This suggests that degree of training intensity drives such cerebral plasticity. Participants (non-musicians, amateurs, and expert musicians) listened to a comprehensive set of specifically composed string quartets with hierarchically manipulated endings. In particular, we implemented 2 irregularities at musical closure that differed in salience but were both within the tonality of the piece (in-key). Behavioral sensitivity scores (d') of both transgressions perfectly separated participants according to their level of musical expertise. By contrasting brain responses to harmonic transgressions against regular endings, functional brain imaging data showed compelling evidence for stepwise modulation of brain responses by both violation strength and expertise level in a fronto temporal network hosting universal functions of working memory and attention. Additional independent testing evidenced an advantage in visual working memory for the professionals, which could be predicted by musical training intensity. The here introduced findings of brain plasticity demonstrate the progressive impact of musical training on cognitive brain functions that may manifest well beyond the field of music processing. PMID- 22832389 TI - Translational Psychiatry: leading the transition from the cesspool of devastation to a place where the grass is really greener. PMID- 22832390 TI - A bridge to somewhere. PMID- 22832391 TI - Vasopressin modulates social recognition-related activity in the left temporoparietal junction in humans. AB - The neuropeptide vasopressin is a key molecular mediator of social behavior in animals and humans, implicated in anxiety and autism. Social recognition, the ability to assess the familiarity of others, is essential for appropriate social interactions and enhanced by vasopressin; however, the neural mechanisms mediating this effect in humans are unknown. Using functional magnetic resonance imaging (fMRI) and an implicit social recognition matching task, we employed a double-blinded procedure in which 20 healthy male volunteers self-administered 40 UI of vasopressin or placebo intranasally, 45 min before performing the matching task in the scanner. In a random-effects fMRI analysis, we show that vasopressin induces a regionally specific alteration in a key node of the theory of mind network, the left temporoparietal junction, identifying a neurobiological mechanism for prosocial neuropeptide effects in humans that suggests novel treatment strategies. PMID- 22832393 TI - Is medical thoracoscopy efficient in the management of multiloculated and organized thoracic empyema?. AB - BACKGROUND: Pleural empyema can be subdivided into 3 stages: exudative, multiloculated, and organizing. In the absence of clear septation, antibiotics plus simple drainage of pleural fluid is often sufficient treatment, whereas clear septation often requires more invasive treatment. OBJECTIVES: The aim of this study was to report our experience and analyze the safety and efficacy of medical thoracoscopy in patients with multiloculated and organizing empyema. METHODS: We performed a retrospective study reviewing the files of patients referred for empyema and treated by medical thoracoscopy at our department from July 2005 to February 2011. RESULTS: A total of 41 patients with empyema were treated by medical thoracoscopy; empyema was free flowing in 9 patients (22%), multiloculated in 24 patients (58.5%), and organized in 8 patients (19.5%). Medical thoracoscopy was considered successful without further intervention in 35 of 41 patients (85.4%): all of the 9 patients with free-flowing fluid, 22 of the 24 patients with multiloculated empyema (91.7%), and only 4 of the 8 patients with organizing effusion (50%). CONCLUSIONS: Our study confirms that multiloculated pleural empyema could safely and successfully be treated with medical thoracoscopy while organizing empyema can be resistant to drainage with medical thoracoscopy, requiring video-assisted thoracic surgery or open surgical decortications; among this population, the presence of separate 'pockets' not in apparent communication with each other often leads to a surgical approach. PMID- 22832394 TI - Thymic carcinoid associated with multiple endocrine neoplasia syndrome type I. AB - Thymic carcinoids are a rare entity that may be associated with endocrine diseases like Cushing's syndrome or multiple endocrine neoplasia syndrome type I (MEN1). These tumors represent 4% of anterior mediastinal tumors and are characterized by their very aggressive behavior. We present the case of a patient with a previous MEN 1 diagnosis in whom, during the follow up of his disease, a thoracic image compatible with thymic carcinoid was detected. After an extended thymectomy that included peri-thymic fat resection, the clinical diagnosis was confirmed. A follow up examination 14 months later revealed a suspicious lesion that suggested local recurrence, therefore the patient was reoperated on. The pathology report of this surgery indicated post-radiation fibrosis. Likewise, we present a review of the current diagnostic and therapeutic management of patients with MEN1 syndrome who are diagnosed with thymic carcinoid. PMID- 22832395 TI - Incomplete healing of the uterine incision after cesarean section: is it preventable by intraoperative digital dilatation of the internal cervical ostium?. AB - BACKGROUND/AIMS: It was the aim of this study to determine if intraoperative digital dilatation of the closed internal cervical ostium affects the healing of the uterine scar after a cesarean section (CS). METHODS: In this randomized, prospective study, 94 term pregnant patients who elected to have a CS were assigned to two groups: intraoperative digital dilatation of the internal cervical ostium (group I, n = 48) or no dilatation (group II, n = 46). Vaginal ultrasound was used to check the integrity of the cesarean scar at the uterine incision site 40-42 days after the operation. We calculated the healing ratio based on ultrasonographic results and compared the groups as to the amount of incomplete healing. RESULTS: The frequency of abnormal scarring was significantly higher in group II (14.3 vs. 40.6%; p < 0.05). The mean healing ratio was significantly higher in group I (0.95 +/- 0.12) than in group II (0.87 +/- 0.1; p < 0.05). In the multiple logistic regression model, digital dilatation remained the most significant factor affecting abnormal scar formation (odds ratio = 7.7). CONCLUSION: Digital dilatation of a closed cervix in elective CS might lower the incidence of abnormal scarring of the uterine incision. PMID- 22832396 TI - Cognitive dysfunction with complex visual hallucinations due to focal nonconvulsive status epilepticus: a neuropsychological study and SISCOM. AB - A 74-year-old woman with left hemiparesis due to a previous stroke presented with the sudden development of cognitive impairment and episodic complex visual hallucinations as manifestations of nonconvulsive status epilepticus (NCSE). Neuropsychological tests performed during NCSE demonstrated deficits encompassing several cognitive domains. The short-lasting complex visual hallucinations were stereotypical, vivid, and accompanied by intense fear. The seizure activity in the right temporo-parieto-occipital region, as documented by SISCOM and electroencephalogram (EEG) recording, was thought to be due to an unusual clinical presentation of NCSE. Subcortical cerebromalacia likely blocked the propagation route, restricting the ictal activities within this area. PMID- 22832397 TI - Economics of medically unexplained symptoms: a systematic review of the literature. AB - OBJECTIVE: To review cost-of-illness studies (COI) and economic evaluations (EE) conducted for medically unexplained symptoms and to analyze their methods and results. METHODS: We searched the databases PubMed, PsycINFO and National Health Service Economic Evaluations Database of the University of York. Cost data were inflated to 2006 using country-specific gross domestic product inflators and converted to 2006 USD purchasing power parities. RESULTS: We identified 5 COI and 8 EE, of which 6 were cost-minimization analyses and 2 were cost-effectiveness analyses. All studies used patient level data collected between 1980 and 2004 and were predominantly conducted in the USA (n = 10). COI found annual excess health care costs of somatizing patients between 432 and 5,353 USD in 2006 values. Indirect costs were estimated by only one EE and added up to about 18,000 USD per year. In EE, educational interventions for physicians as well as cognitive behavioral therapy approaches for patients were evaluated. For both types of interventions, effectiveness was either shown within EE or by previous studies. Most EE found (often insignificant) cost reductions resulting from the interventions, but only two studies explicitly combined changes in costs with data on effectiveness to cost-effectiveness ratios (ratio of additional costs to additional effects). CONCLUSIONS: Medically unexplained symptoms cause relevant annual excess costs in health care that are comparable to mental health problems like depression or anxiety disorders and which may be reduced by interventions targeting physicians as well as patients. More extensive research on indirect costs and cost-effectiveness is needed. PMID- 22832398 TI - Developmental validation of DogFiler, a novel multiplex for canine DNA profiling in forensic casework. AB - While the analysis of human DNA has been the focus of large-scale collaborative endeavors, non-human forensic DNA analysis has not benefited from the same funding streams and coordination of effort. Consequently, the development of standard marker panels, allelic ladders and allele-specific sequence data comparable to those established for human forensic genetics has lagged. To meet that need for domestic dogs, we investigated sequence data provided by the published 7.6X dog genome for novel short tandem repeat markers that met our criteria for sensitivity, stability, robustness, polymorphic information content, and ease of scoring. Fifteen unlinked tetranucleotide repeat markers were selected from a pool of 3113 candidate markers and assembled with a sex-linked marker into a multiplex capable of generating a full profile with as little as 60pg of nuclear DNA. An accompanying allelic ladder was assembled and sequenced to obtain detailed repeat motif data. Validation was carried out according to SWGDAM guidelines, and the DogFiler panel has been integrated into forensic casework and accepted in courts across the U.S. Applying various formulae for calculating random match probabilities for inbred populations, estimates for this panel of markers have proven to be comparable to those obtained in human forensic genetics. The DogFiler panel and the associated allelic ladder represent the first published non-human profiling system to fully address all SWGDAM recommendations. PMID- 22832392 TI - Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism. AB - Omega-3 fatty acids have been proposed as an adjuvant treatment option in psychiatric disorders. Given their other health benefits and their relative lack of toxicity, teratogenicity and side effects, they may be particularly useful in children and in females of child-bearing age, especially during pregnancy and postpartum. A comprehensive mechanistic understanding of their effects is needed. Here we report translational studies demonstrating the phenotypic normalization and gene expression effects of dietary omega-3 fatty acids, specifically docosahexaenoic acid (DHA), in a stress-reactive knockout mouse model of bipolar disorder and co-morbid alcoholism, using a bioinformatic convergent functional genomics approach integrating animal model and human data to prioritize disease relevant genes. Additionally, to validate at a behavioral level the novel observed effects on decreasing alcohol consumption, we also tested the effects of DHA in an independent animal model, alcohol-preferring (P) rats, a well established animal model of alcoholism. Our studies uncover sex differences, brain region-specific effects and blood biomarkers that may underpin the effects of DHA. Of note, DHA modulates some of the same genes targeted by current psychotropic medications, as well as increases myelin-related gene expression. Myelin-related gene expression decrease is a common, if nonspecific, denominator of neuropsychiatric disorders. In conclusion, our work supports the potential utility of omega-3 fatty acids, specifically DHA, for a spectrum of psychiatric disorders such as stress disorders, bipolar disorder, alcoholism and beyond. PMID- 22832399 TI - PCLO rs2522833 impacts HPA system activity in healthy young adults. AB - Recent genetic studies showed evidence for a role of the single-nucleotide polymorphism rs2522833 within the PCLO gene in the etiology of major depression, and rs2522833 has been shown to modulate hypothalamic pituitary adrenal (HPA) axis activity during antidepressant treatment. Monoaminergic modulation of the HPA system may be one possible pathomechanism by which PCLO exerts its effect on depression. In the present study, we investigated the effect of rs2522833 on the cortisol awakening response (CAR) in healthy young adults. A total of 66 healthy volunteers from the community (36 men and 30 women) aged 18-25 years without individual or family history of affective disorders and schizophrenia collected saliva cortisol samples at 0, 30, 45 and 60 min after awakening on two consecutive working days. We identified a blunted CAR (AUCinc) in rs2522833 risk allele (C) carriers, possibly indicating exhausted regulatory mechanisms underlying the HPA system. We also identified higher neuroticism scores in rs2522833 risk-allele carriers but no phenotypic correlation between the CAR (AUCinc) and neuroticism. These findings suggest that the rs2522833 risk variant might increase vulnerability to depression both by physiological and behavioral pathways, which appear, however, not to be substantially overlapped. Replication with larger samples is warranted. PMID- 22832401 TI - Pharmacogenomic testing and outcome among depressed patients in a tertiary care outpatient psychiatric consultation practice. AB - The authors tested the hypothesis that pharmacogenomic genotype knowledge is associated with better clinical and cost outcomes in depressed patients, after controlling for other factors that might differentiate tested and non-tested patients. Medical records of 251 patients, seen in the Mayo Clinic Rochester outpatient psychiatric practice, who had patient health questionnaire-9 (PHQ-9) scores before and after consultation, were reviewed. Comparisons of differences in pre-consultation and post-consultation depression scores and slopes between tested and non-tested patients and between genotype categories of tested patients, were evaluated, along with healthcare cost and utilization comparisons between tested and non-tested patients, using Kruskal-Wallis tests, Wilcoxon rank sum tests and group mean comparisons, controlling for significant univariate demographic and clinical differences. Tested patients had significantly higher depression diagnosis frequency, baseline PHQ-9 scores, family history of depression, psychiatric hospitalization history, and higher numbers of antidepressant, mood stabilizer and antipsychotic medication trials. After controlling for these differences, there were no differences between tested and non-tested patients in post-baseline depression scores or slopes for CYP genotype categories. For patients with 5-HTTLPR testing, there was significantly more depression score improvement for patients with the long/long genotype at time 4 (N=55, chi(2)-value=8.0492, P=0.018) and at time 5 (N=44, chi(2)-value=6.1492, P=0.046). For a subgroup (n=46) with >=two pre- and >=two post-baseline PHQ-9 scores, the mean difference between pre-baseline and post-baseline PHQ-9 score slopes for tested patients was -0.08 (median -0.01; range -1.20 to 0.15) compared with 0.13 (median 0.02; range -0.18 to 2.16) for non-tested patients (P=0.03). Among genotype categories, mean differences between pre-consultation and post consultation slopes were significantly better for poor CYP2D6 metabolizers than intermediate or extensive metabolizers (P=0.04); there was a trend for slope differences to be better for 5-HTTLPR long/long genotype patients (P=0.06). Subsets of local tested and consultant-adjusted non-tested controls (n=19), who had 8 years of longitudinal care within the health system, had similar overall mean healthcare costs before and after testing; however, tested patients on average had significantly fewer time-adjusted post-baseline psychiatric admissions (0.8 vs 3.8, P=0.04) and fewer time-adjusted psychiatric consultations and comprehensive mental health-specialty evaluations (4.2 vs 9.9, P=0.03). Prospective study is indicated as to whether and how pharmacogenomic testing in a psychiatric consultation practice may improve clinical and cost outcomes. PMID- 22832403 TI - Increased expression of receptor phosphotyrosine phosphatase-beta/zeta is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes. AB - Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-beta/zeta (RPTP beta/zeta) and that the gene encoding RPTPbeta/zeta (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPbeta/zeta in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPbeta/zeta (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTPbeta/zeta signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPbeta/zeta as a therapeutic target in schizophrenia. PMID- 22832405 TI - The surface-enhanced Raman spectra of aflatoxins: spectral analysis, density functional theory calculation, detection and differentiation. AB - High-quality surface-enhanced Raman scattering (SERS) spectra of aflatoxin (AF) B(1), B(2), G(1) and G(2) have been acquired using silver nanorod (AgNR) array substrates fabricated by oblique angle deposition method. Significant vibrational peaks are identified on the argon plasma-cleaned substrates, and those peaks agree very well with the Raman spectra calculated by density function theory (DFT). The concentration-dependent SERS detection is also explored. The relationship between the concentration (C) of different AFs and the SERS intensity (I) of the Raman peak at Deltanu = 1592 cm(-1) is found to follow the general relationship I = AC(alpha), with alpha ranging from 0.32 to 0.46 for the four AFs. The limits of detection (LODs) reach 5 * 10(-5) mol L(-1) for AFB(1), 1 * 10(-4) mol L(-1) for AFB(2), and 5 * 10(-6) mol L(-1) for both AFG(1) and AFG(2) in bulk solution, or 6.17 * 10(-16) mol/1.93 * 10(-4) ng of AFB(1), 1.23 * 10(-15) mol/3.88 * 10(-4) ng for AFB(2), 6.17 * 10(-17) mol/2.03 * 10(-5) ng for AFG(1), and 6.17 * 10(-17) mol/2.04 * 10(-5) ng for AFG(2) per laser spot. Principal component analysis (PCA) is used to successfully differentiate these four different kinds of AFs at different concentrations up to their detection limits. The LODs obtained from PCA agree with the LODs obtained by using peak fitting method. With such a low detection limit and outstanding differentiation ability, we prove the possibility of utilizing the SERS detection system as a platform for highly sensitive mycotoxin detection. PMID- 22832400 TI - Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy. AB - Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive-compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1-8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative-limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative-limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology. PMID- 22832406 TI - Transformational leadership: visibility, accessibility, and communication. AB - The chief nursing officer of a Magnet(r) organization is a dynamic, transformational leader who develops and communicates a strong vision for nursing excellence and creates a foundation for exemplary nursing practice and excellent patient care. Transformational leadership is a core component of the Magnet Model(r). The 3rd subcomponent--visibility, accessibility, and communication--is the focus of this article. PMID- 22832407 TI - The future of nursing: community health's network approach. AB - This bimonthly department, sponsored by the American Organization of Nurse Executives (AONE), presents information to assist nurse leaders in shaping the future of healthcare through creative and innovative leadership. The strategic priorities of AONE anchor the editorial content. They reflect contemporary healthcare and nursing practice issues that challenge nurse executives as they strive to meet the needs of patients. PMID- 22832404 TI - Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms. AB - Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug- yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain. PMID- 22832408 TI - Implementing evidence-based practice during an economic downturn. AB - Building a sustainable evidence-based practice (EBP) infrastructure during times of financial constraints poses challenges for nurse leaders. To be successful, plans need to be creative and adaptive, while mindful of limited resources. This commentary describes change management strategies used to implement an EBP infrastructure at a hospital after organizational restructuring occurred. PMID- 22832409 TI - Measuring return on investment in complex healthcare systems. PMID- 22832410 TI - The national AgeWISE pilot. AB - AgeWISE is a 6-month nurse residency program designed to prepare hospital nurses to meet the needs of older adults, a population that comprises nearly 50% of all US hospital admissions. The goal of AgeWISE, now being piloted in 12 hospitals in the United States, is to produce a tested and refined national model for building geropalliative care capacity among hospital nurses. PMID- 22832411 TI - The role of nursing surveillance in keeping patients safe. AB - The most frequently reported threats to patient safety take place in hospitals, with the majority of errors and adverse events occurring during the course of routine care. Nursing surveillance has been proposed as an intervention to reduce adverse patient events. This article presents an overview and analysis of nursing surveillance with emphasis on the defining characteristics, antecedents, and consequences. PMID- 22832412 TI - Creating staff confidence in distinguishing between performance improvement and research studies: a user-friendly worksheet. AB - In an era when emphasis is placed on implementing quality improvement and research initiatives promoting quality patient care, confusion often exists about the differences between research and performance improvement. The authors discuss the construction of a performance improvement/research differentiation form, a decision-making tool designed to assist nurses distinguish between these processes and inform them about the regulatory requirements to protect the rights and interests of patients. PMID- 22832413 TI - Involving nurses in decisions: improving both nurse and patient outcomes. AB - OBJECTIVE: The objective of this study was to determine the relationship between nurse involvement in decisions and nurse-patient outcomes. BACKGROUND: Evidence demonstrates that nurse involvement is associated with satisfaction, but little evidence exists about patient effects. Because of significant resource expenditure, evidence about expected outcomes is needed. METHODS: Outcomes classified as patient satisfaction, nurse satisfaction, infections, and adverse events were compared between units with high and low levels of involvement from 9 hospitals in Colorado. RESULTS: Involving nurses in outcomes evaluation was associated with better patient outcomes. High involvement units had fewer infections and pressure ulcers. CONCLUSIONS: A formal structure was not required to involve nurses in decisions and is related to nurse and patient satisfaction demonstrating a reduction in adverse events. PMID- 22832414 TI - Who will be our nursing leaders in the future? The role of succession planning. AB - As nursing leaders retire and leave the profession, who will take their place? The question is not just about the number of nurses who will take on leadership roles; it is about the preparation required to be successful. Formal succession planning is a crucial part of strategy to ensure that nursing leadership positions, at all levels, are filled with qualified candidates. PMID- 22832415 TI - Nursing research in a nonacademic health system: measuring knowledge, attitudes, and behaviors. AB - OBJECTIVE: The objective of this study was to evaluate nurses' knowledge, attitudes, and use of research in a large nonacademic health system prior to and following a 6-month intervention. BACKGROUND: Many organizations have begun to implement a variety of research-oriented activities to build interest in and support of nursing research. METHODS: Nurses were surveyed to measure attitudes, knowledge, and behaviors related to nursing research and familiarity with available resources. Barriers to conducting research were identified. RESULTS: Nurses with a baccalaureate degree or higher reported a greater degree of support and knowledge and higher level of familiarity with resources than did diploma/associate degree nurses. CONCLUSIONS: Outcomes suggest that implementation of the components of a typical nursing research program may help to improve nurses' attitudes and knowledge of research. Affecting behaviors requires a more targeted approach. PMID- 22832416 TI - Ionothermal syntheses, crystal structures and properties of three-dimensional rare earth metal-organic frameworks with 1,4-naphthalenedicarboxylic acid. AB - Twelve isostructural rare earth metal-organic frameworks, namely, [Hmim][RE(2)Cl(1,4-NDC)(3)] (RE = La (1), Ce (2), Pr (3), Nd (4), Sm (5), Eu (6), Gd (7), Tb (8), Dy (9), Ho (10), Er (11), Y (12), Hmim = 1-hexyl-3 methylimidazolium, 1,4-NDCH(2) = 1,4-naphthalenedicarboxylic acid), have been ionothermally synthesized and structurally characterized. The structures feature three-dimensionally anionic frameworks of [RE(2)Cl(1,4-NDC)(3)](n)(n-) with channels in which the Hmim(+) cations are located. The current results are the first ionothermal synthesis of rare earth metal-organic frameworks based on 1,4 NDCH(2) which possess a previously unknown (4,7)-connected 3-nodal network with the Schlafli symbol of (3(2).4(2).5(2))(3(2).4(9).5(2).6(8))(2)(4(3).6(3))(2). Luminescent and magnetic properties of some of the title compounds have been studied. Thermogravimetric analyses indicated that all these compounds were thermally stable up to ca. 250 degrees C. PMID- 22832417 TI - The effects of age and estrogen on stress responsivity in older women. AB - OBJECTIVE: The current study examined whether age after menopause impacted the effect of estradiol (E2) on mood after a psychosocial stress manipulation. BACKGROUND: Previous studies have shown that E2 improves mood in women around the menopause transition but does not improve mood for older postmenopausal women. We have previously shown that E2 treatment in nondepressed women resulted in increased negative mood after psychosocial stress. DESIGN: Participants were 22 postmenopausal women placed on either oral placebo or 17beta-estradiol (1 mg/day for 1 month, then 2 mg/day for 2 months). METHOD: At the end of the 3-month treatment phase, the participants performed the Trier Social Stress Test followed by mood ratings. To examine the effects of age on the estrogen-stress interaction, we performed a median split on age and created four groups of participants: younger-placebo (mean age: 55.5 years), younger-E2 (mean age: 55.5 years), older-placebo (mean age: 73.0 years), and older-E2 (mean age: 76.8 years). RESULTS: : The results showed that both older and younger E2-treated participants exhibited a significant and similar increase in negative mood after psychosocial stress compared with placebo-treated women. CONCLUSIONS: These results suggest that E2 may play a significant role in modulating emotional reactivity to stressful events and that this effect persists in older women. Furthermore, responsivity to E2 effects on emotional processing appears to be intact even years after menopause in contrast with other cognitive and behavioral effects of E2, which may be limited to the early postmenopausal years. PMID- 22832419 TI - Traditional versus functional strength training: effects on muscle strength and power in the elderly. AB - The aim was to determine whether strength training with machines vs. functional strength training at 80% of one-repetition maximum improves muscle strength and power among the elderly. Sixty-three subjects (69.9 +/- 4.1 yr) were randomized to a high-power strength group (HPSG), a functional strength group (FSG), or a nonrandomized control group (CG). Data were collected using a force platform and linear encoder. The training dose was 2 times/wk, 3 sets * 8 reps, for 11 wk. There were no differences in effect between HPSG and FSG concerning sit-to-stand power, box-lift power, and bench-press maximum force. Leg-press maximum force improved in HPSG (19.8%) and FSG (19.7%) compared with CG (4.3%; p = .026). Bench press power improved in HPSG (25.1%) compared with FSG (0.5%, p = .02) and CG (2%, p = .04). Except for bench-press power there were no differences in the effect of the training interventions on functional power and maximal body strength. PMID- 22832421 TI - Adenomyosis reduces pregnancy rates in infertile women undergoing IVF. AB - High-resolution transvaginal ultrasound has facilitated the diagnosis of adenomyosis. This study determined the prevalence of this finding in infertile women and its effect on the outcome of IVF/intracytoplasmic sperm injection (ICSI). This prospective study evaluated 275 consecutive women, commencing IVF/ICSI for the first time. Inclusion criteria were adequate ovarian reserve. Women with fibroids or a previous myomectomy were excluded. All women were screened for adenomyosis by transvaginal ultrasound on three separate occasions. The control group included 256 women and the adenomyosis group included 19 women. There was no significant difference in the ages of women, FSH, cause of infertility, body mass index, total dose of gonadotrophin used and number of oocytes collected between the two groups. However, women with adenomyosis had a higher mean antral follicle count (P=0.006). The clinical pregnancy rate (22.2% versus 47.2%) and ongoing pregnancy rate (11.1% versus 45.9%) were significantly lower in women with adenomyosis and the miscarriage rate (50.0% versus 2.8%) was significantly higher in women with adenomyosis (all P<0.001). Ultrasound evidence of adenomyosis is found in a significant number of women presenting with infertility and has a negative impact on the outcome of IVF/ICSI. This paper suggests that a common condition known as adenomyosis is associated with a reduced success following fertility treatment such as IVF. The diagnosis of adenomyosis has been greatly facilitated by the advent of high-resolution transvaginal ultrasound. This was a study including 275 consecutive women who were commencing IVF for the first time. Comparing women who did not have adenomyosis and those that did, the clinical and ongoing pregnancy rates were both lower in women with adenomyosis (22.2% versus 47.2% and 11.1% versus 45.9%, respectively). So, fewer women with adenomyosis became pregnant and had an ongoing pregnancy. The miscarriage rate was higher in women with adenomyosis compared with those without (50.0% versus 2.8%). We conclude that ultrasound evidence of adenomyosis is found in a significant number of women presenting with infertility and has a negative impact on the outcome of IVF. PMID- 22832422 TI - Nonallergic drug hypersensitivity reactions. AB - BACKGROUND: Nonallergic drug hypersensitivities, also referred to as pseudoallergic or anaphylactoid reactions, have clinical manifestations that are often indistinguishable from allergic reactions. METHODS: We performed a PubMed search using the terms 'drug allergy, drug hypersensitivity, pseudoallergies, anaphylaxis and nonallergic drug reactions' and reviewed 511 publications dated between 1970 and 2012. A total of 160 papers that were relevant to the most common nonallergic drug hypersensitivity reactions were selected for discussion. RESULTS: Nonallergic drug hypersensitivities do not involve either IgE-mediated (type 1) or delayed (type 4) hypersensitivity. Nonallergic hypersensitivities are commonly referred to as pseudoallergic or idiosyncratic reactions. The common nonallergic drug hypersensitivities are secondary to chemotherapeutic drugs, radiocontrast agents, vancomycin, nonsteroidal anti-inflammatory agents, local anesthetic reactions and opiates. Protocols for skin testing of radiocontrast, nonsteroidal anti-inflammatory agents, local anesthetics and chemotherapeutic agents have been developed, though most have not been validated or standardized. Other diagnostic tests include in vitro-specific IgE tests, and the current 'gold' standard is usually an oral challenge or bronchoprovocation test. In the case of aspirin, even though it is not believed to be IgE-mediated, a 'desensitization' protocol has been developed and utilized successfully, although the mechanism of this desensitization is unclear. CONCLUSIONS: Diagnostic methods exist to distinguish allergic from nonallergic drug hypersensitivity reactions. The best option in nonallergic drug hypersensitivity is avoidance. If that is not possible, premedication protocols have been developed, although the success of premedication varies amongst drugs and patients. PMID- 22832423 TI - Transthoracic ultrasonography for the respiratory physician. AB - Transthoracic ultrasonography is still not utilized to its full potential by respiratory physicians, despite being a well-established and validated imaging modality. It allows for an immediate and mobile assessment that can potentially augment the physical examination of the chest. Ultrasound (US)-assisted procedures can be performed by a single clinician with no sedation and with minimal monitoring, even outside of theatre. The main indications for the use of transthoracic US are: the qualitative and quantitative description of pleural effusions, pleural thickening, diaphragmatic dysfunction and chest-wall and pleural tumours. It may also be used to visualise lung tumours and other parenchymal pulmonary processes provided they abut the pleura. It is at least as sensitive as chest radiographs as far as the detection of a pneumothorax is concerned. It is the ideal tool to assist with thoracocentesis and drainage of effusions. The US-assisted fine-needle aspiration and/or cutting-needle biopsy of extrathoracic lymph nodes, lesions arising from the chest wall, pleura, peripheral lung and mediastinum, are safe and have a high yield in the hands of chest physicians. US may also guide the aspiration and biopsy of diffuse pulmonary infiltrates, consolidations and lung abscesses, provided the chest wall is abutted. Advanced applications of transthoracic US include the diagnosis of pulmonary embolism. PMID- 22832424 TI - A meta-analysis of randomized controlled trials appraising the efficacy and safety of cilostazol after coronary artery stent implantation. AB - OBJECTIVES: To evaluate the impact of cilostazol on the angiographic and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) with stents and treated with aspirin and thienopyridine. METHODS: A total of 11 randomized controlled trials including 8,525 patients comparing triple antiplatelet therapy (aspirin, thienopyridine and cilostazol) with standard dual antiplatelet therapy were included in the analysis. The primary end points were in-segment late loss and angiographic restenosis at angiographic follow-up. Secondary end points included mortality, stent thrombosis, target lesion revascularization (TLR) and major adverse cardiac events (MACE). RESULTS: Triple antiplatelet therapy was associated with a significant reduction in late loss [weighted mean difference 0.14, 95% confidence interval (CI) 0.08-0.20; p < 0.001] and angiographic restenosis [odds ratio (OR) 0.58, 95% CI 0.48-0.71; p < 0.001]. Addition of cilostazol to dual antiplatelet therapy was associated with a significant reduction in TLR (OR 0.56, 95% CI 0.41-0.77; p < 0.001) and MACE (OR 0.72, 95% CI 0.60-0.86; p < 0.001) with no differences in mortality (p = 0.29), stent thrombosis (p = 0.60) or bleeding episodes (p = 0.77). CONCLUSIONS: Cilostazol in addition to dual antiplatelet therapy appears to be effective in reducing the risk of restenosis and repeat revascularization after PCI without any significant benefits for mortality or stent thrombosis. PMID- 22832425 TI - Cognitive impairment in systemic lupus erythematosus women with elevated autoantibodies and normal single photon emission computerized tomography. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is known to induce psychiatric disorders, from psychoses to maladaptive coping. Brain autoantibodies were proposed to explain SLE neuropsychiatric disorders and found to be elevated before the onset of clinical symptoms. We assessed cognition in Caucasian SLE women with elevated autoantibodies without overt neuropsychiatric syndromes, in conjunction with single photon emission computerized tomography (SPECT). METHODS: 31 women meeting SLE criteria of the American College of Rheumatology (ACR) were included. Patients who met the ACR neuropsychiatric definition were excluded. Matched controls were 23 healthy women from the Champagne-Ardenne region, France. Participants completed neuropsychological and autoantibodies measurements, and 19 completed SPECT. RESULTS: 61% (19/31) of women with SLE and 53% (9/17) of those with normal SPECT had significant global cognitive impairment defined as 4 T scores <40 in cognitive tests, compared to 0% (0/23) of controls. SLE women also had significantly greater cognitive dysfunction (mean T-score) on the Wechsler Adult Intelligence Scale (WAIS) visual backspan, Trail Making Test A and B, WAIS Digit Symbol Substitution Test and Stroop Interference, compared to controls. Elevated antinuclear antibody correlated with impairment in the WAIS visual span, WAIS visual backspan, and cancellation task; elevated anti-double-stranded DNA antibody and anticardiolipin correlated respectively with impairment in the Trail Making Test A and WAIS auditive backspan. Two SLE women had abnormal SPECT. CONCLUSIONS: A high prevalence of cognitive deficits was found in Caucasian SLE women compared to normal women, which included impairment in cognitive domains important for daily activities. Elevated autoantibodies tended to correlate with cognitive dysfunction. PMID- 22832426 TI - Enhanced exhalation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with COPD exacerbation: a prospective study. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) and its inhibitor tissue inhibitor of metalloproteinase-1 (TIMP-1) are involved in the pathogenesis of airway inflammation in patients with chronic obstructive pulmonary disease (COPD). However, no study so far has addressed their value as noninvasive biomarkers of airways inflammation. OBJECTIVE: To evaluate MMP-9 and TIMP-1 concentrations in the exhaled breath condensate (EBC) of patients with stable COPD and also during the exacerbation episode. METHODS: EBC and serum samples were collected in 17 stable-phase COPD patients who were current smokers as well as during their first exacerbation episode, and in 22 asymptomatic smokers. EBC and serum levels of MMP 9 and TIMP-1 were measured with ELISA kit. RESULTS: Mean EBC MMP-9 and TIMP-1 levels were higher in patients with stable COPD than in asymptomatic smokers. Exacerbation of COPD increased 2-fold the exhalation of MMP-9 (18.5 +/- 10.1 ng/ml vs. 8.9 +/- 6.2 ng/ml, p = 0.01) and TIMP-1 (to 41.1 +/- 20.4 ng/ml vs. 16.4 +/- 6.8 ng/ml, p < 0.001). Both, MMP-9 and TIMP-1 in EBC correlated negatively with FEV(1) (% predicted) at baseline (r = -0.78, p < 0.001 and r = 0.73, p < 0.001) and during the exacerbation episode (r = -0.57, p = 0.02 and r = -0.65, p = 0.005). Similar negative correlations were noted with FVC (% predicted), except for MMP-9 in EBC at exacerbation. Exhaled MMP-9 and TIMP-1 did not correlate with serum concentrations in COPD patients, either at baseline or during exacerbation. CONCLUSION: Exhaled MMP-9 and TIMP-1 increased during COPD exacerbation and was negatively correlated with spirometric variables, which suggests the usefulness of their measurement in EBC for the monitoring of airways inflammation. However, to better assess their diagnostic or prognostic value larger studies are necessary. PMID- 22832427 TI - Hostility in adolescents and adults: a genome-wide association study of the Young Finns. AB - Hostility is a multidimensional personality trait with changing expression over the life course. We performed a genome-wide association study (GWAS) of the components of hostility in a population-based sample of Finnish men and women for whom a total of 2.5 million single-nucleotide polymorphisms (SNPs) were available through direct or in silico genotyping. Hostility dimensions (anger, cynicism and paranoia) were assessed at four time points over a 15-year interval (age range 15 30 years at phase 1 and 30-45 years at phase 4) in 982-1780 participants depending on the hostility measure. Few promising areas from chromosome 14 at 99 cM (top SNPs rs3783337, rs7158754, rs3783332, rs2181102, rs7159195, rs11160570, rs941898, P values <3.9 * 10(-8) with nearest gene Enah/Vasp-like (EVL)) were found suggestively to be related to paranoia and from chromosome 7 at 86 cM (top SNPs rs802047, rs802028, rs802030, rs802026, rs802036, rs802025, rs802024, rs802032, rs802049, rs802051, P values <6.9 * 10(-7) with nearest gene CROT (carnitine O-octanoyltransferase)) to cynicism, respectively. Some shared suggestive genetic influence for both paranoia and cynicism was also found from chromosome 17 at 2.8 cM (SNPs rs12936442, rs894664, rs6502671, rs7216028) and chromosome 22 at 43 cM (SNPs rs7510759, rs7510924, rs7290560), with nearest genes RAP1 GTPase activating protein 2 (RAP1GAP2) and KIAA1644, respectively. These suggestive associations did not replicate across all measurement times, which warrants further study on these SNPs in other populations. PMID- 22832428 TI - Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction. AB - Exposure therapy for anxiety disorders relies on the principle of confronting a patient with the triggers of his fears, allowing him to make the unexpected safety experience that his fears are unfounded and resulting in the extinction of fear responses. In the laboratory, fear extinction is modeled by repeatedly presenting a fear-conditioned stimulus (CS) in the absence of the aversive unconditioned stimulus (UCS) to which it had previously been associated. Classical associative learning theory considers extinction to be driven by an aversive prediction error signal that expresses the expectation violation when not receiving an expected UCS and establishes a prediction of CS non-occurrence. Insufficiencies of this account in explaining various extinction-related phenomena could be resolved by assuming that extinction is an opponent appetitive like learning process that would be mediated by the mesostriatal dopamine (DA) system. In accordance with this idea, we find that a functional polymorphism in the DA transporter gene, DAT1, which is predominantly expressed in the striatum, significantly affects extinction learning rates. Carriers of the 9-repeat (9R) allele, thought to confer enhanced phasic DA release, had higher learning rates. Further, functional magnetic resonance imaging revealed stronger hemodynamic appetitive prediction error signals in the ventral striatum in 9R carriers. Our results provide a first hint that extinction learning might indeed be conceptualized as an appetitive-like learning process and suggest DA as a new candidate neurotransmitter for human fear extinction. They open up perspectives for neurobiological therapy augmentation. PMID- 22832430 TI - Decanalization, brain development and risk of schizophrenia. AB - Waddington's original description of canalization refers to the ability of an organism to maintain phenotypic fidelity in the face of environmental and/or genetic perturbation. Development of the human brain requires exposure to a 'wild type' environment-one that supports the optimal set of instructions for development. Recently derived brain structures in our species, such as the expanded neocortex, may be more vulnerable to decanalization because there has been insufficient time to evolve buffering capacity. On the basis of modern notions of decanalization, we provide perspectives on selected environmental and genetic risk factors for schizophrenia, and we discuss strengths and weaknesses of this conceptual framework. We argue that if we are to build a solid foundation for translational psychiatry, we must explore models that attempt to capture the complexity of the interaction between genetic and non-genetic risk factors in mediating and modulating brain development. PMID- 22832429 TI - Gene expression biomarkers of response to citalopram treatment in major depressive disorder. AB - There is significant variability in antidepressant treatment outcome, with ~30 40% of patients with major depressive disorder (MDD) not presenting with adequate response even following several trials. To identify potential biomarkers of response, we investigated peripheral gene expression patterns of response to antidepressant treatment in MDD. We did this using Affymetrix HG-U133 Plus2 microarrays in blood samples, from untreated individuals with MDD (N=63) ascertained at a community outpatient clinic, pre and post 8-week treatment with citalopram, and used a regression model to assess the impact of gene expression differences on antidepressant response. We carried out technical validation of significant probesets by quantitative reverse transcriptase PCR and conducted central nervous system follow-up of the most significant result in post-mortem brain samples from 15 subjects who died during a current MDD episode and 11 sudden-death controls. A total of 32 probesets were differentially expressed according to response to citalopram treatment following false discovery rate correction. Interferon regulatory factor 7 (IRF7) was the most significant differentially expressed gene and its expression was upregulated by citalopram treatment in individuals who responded to treatment. We found these results to be concordant with our observation of decreased expression of IRF7 in the prefrontal cortex of MDDs with negative toxicological evidence for antidepressant treatment at the time of death. These findings point to IRF7 as a gene of interest in studies investigating genomic factors associated with antidepressant response. PMID- 22832431 TI - Patient variables which may predict length of stay and hospital costs in elderly patients with hip fracture. AB - OBJECTIVES: To investigate what factors contribute to increased length of stay (LOS) and increased costs in treatment of elderly patients with hip fractures. DESIGN: Retrospective chart review. SETTING: All patients who presented to a large tertiary care center between January 2000 and December 31, 2009. PARTICIPANTS: Charts for all patients older than 60 years who presented with isolated low-energy hip fractures were reviewed. Of the 719 patients identified, 660 were included. INTERVENTION: Patients who underwent operative fixation or hemiarthroplasty secondary to hip fracture were identified using a search of Current Procedural Terminology (CPT) codes search. MAIN OUTCOME MEASUREMENTS: Gender, height, weight, body mass index, length of procedure, American Society of Anesthesiologists (ASA) classification, and medical comorbidities were gathered and compared with LOS and direct daily inpatient hospital cost. RESULTS: No correlation existed between body mass index or specific comorbidities and LOS, but ASA classification was a predictor. For each ASA increase of 1, average LOS increased 2.053 days (P < 0.001). Given total daily cost to the hospital for these patients was $4530, each increase in ASA classification translated to an increase of $9300. CONCLUSIONS: ASA classification proved useful in estimating LOS and cost for patients undergoing operative fixation of hip fractures. Because ASA classification and cost are universally collected, this method can be employed in almost any hospital. This highlights a role for ASA classification in preoperative estimation of the elderly patient's cost and a potential advantage for incorporating patient factors in the development of tiered reimbursement models. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22832432 TI - Factors affecting revenue from the management of pelvis and acetabulum fractures. AB - OBJECTIVES: The purpose was to define charges and reimbursement in the management of pelvis and acetabulum fractures and to identify opportunities for revenue enhancement. DESIGN: Retrospective review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Four hundred sixty-five patients with 210 pelvic ring injuries and 285 acetabulum fractures. INTERVENTION: All fractures were treated surgically. MAIN OUTCOME MEASUREMENTS: Professional and facility charges and collections were determined for each patient. Costs of care and profitability were calculated for patients with isolated pelvis or acetabulum fractures. RESULTS: : Definitive fixation was <= 24 hours of injury in 35% and >72 hours in 24%. Mean hospital length of stay (LOS) was 9.2 days, with mean 3.1 days in the intensive care unit (ICU). Mean facility charges were $51,069 with collections of $22,702 (44%). Mean orthopaedic professional charges were $20,184 with collections of $4629 (23%). Combined pelvis and acetabulum fractures had the highest facility collection rates (49%) with lower professional collections (21%) versus isolated fractures (25%, P = 0.03). The payer mix had significantly more commercial (27%), managed care (27%), and Bureau of Worker's Compensation (10%) versus the entire hospital, despite progressively more patients with Medicaid or no insurance during the study. Uninsured patients were significantly younger with lower injury severity score. Fractures managed definitively <= 24 hours had shorter LOS, shorter ICU stay, and fewer complications, with mean net facility revenue over costs of $2376. Longer LOS due to complications increased initial hospital costs by a mean of $14,829. CONCLUSIONS: Patients with multiple injuries generated higher facility charges and collection rates. Professional collection rates were lower in patients with more than 1 surgical procedure in the same setting. Trauma patients were more likely to have commercial, managed care, and Bureau of Worker's Compensation insurance versus the entire hospital. Fractures managed definitively within 24 hours were associated with shorter LOS, shorter ICU stay, and fewer complications, resulting in lower treatment expenses. Fracture care was profitable to the hospital when definitively completed within 72 hours. Prolonged LOS and complications were associated with larger costs of care. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22832434 TI - Radial head replacement for radial head fractures. AB - OBJECTIVE: This study aimed to analyze the clinical results after treatment of complex elbow injuries with modular anatomic radial head prosthesis (MARHP), along with ligament repair and fracture fixation. DESIGN: Retrospective. SETTING: District teaching hospital. PATIENTS/PARTICIPANTS: The inclusion criteria were all patients with traumatic elbow instability after acute fracture or fracture dislocation, where the radial head was comminuted and irreparable at the time of surgery (Mason type III) and there was associated valgus laxity of the elbow. Of 14 patients, 12 with radial head prosthesis were available for the study. INTERVENTION: MARHP (Acumed, Hillsboro, OR) was used to replace irreparable and comminuted radial head fractures when it was associated with valgus instability. MAIN OUTCOME MEASUREMENTS: All patients were evaluated clinically and radiographically for a mean follow-up of 42 months (range, 22-58 months). RESULTS: Patients recovered a similar range of motion between affected and unaffected elbows. Stability was restored to all 12 elbows, and all patients had a good or excellent result according to Mayo Elbow Performance Index and a disability of the arm, shoulder, and hand survey. Radiographic measurement revealed a congruent elbow joint. CONCLUSION: The MARHP is effectively restoring stability and congruency to the elbow joint. There was no evidence of arthritic radiocapitellar joint, capitellar osteopenia, significant proximal radial migration of the implant, or any major complications. Outcomes were optimized by recognition and addressing the associated injuries. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22832433 TI - Incidence and severity of infections after closed reduction and external fixation of proximal humeral fractures. AB - OBJECTIVES: This study aimed to evaluate the incidence and severity of pin tract infections in a series of patients treated by Closed reduction external fixation (CREF) for proximal humeral fractures. DESIGN: Retrospective review of medical charts and radiographs. SETTING: Academic level-1 trauma center. PATIENTS: Forty six consecutive patients (20 males, 26 females, mean age 50 years (range 20-90 years) with proximal humeral fractures treated by CREF were enrolled into the study based on data retrieved from medical charts and radiographs. INTERVENTION: None. MAIN OUTCOME MEASURE: Evaluation of the incidence and severity of post-CREF pin tract infections. RESULTS: All 46 fractures healed after an average of 4 weeks. There were 18 (39.1%) cases of pin tract infections whose most common bacteria colonization was gram-positive. Pin tract infections were significantly higher among patients with multiple fragment fractures and multiple pins. Treatment consisting of oral or intravenous antibiotics was effective in all cases, and the infection was resolved within 2 weeks at most. CONCLUSIONS: Most pin tract infections were managed with systemic antibiotics with good results. The occurrence of pin tract infection did not require a change of the stabilization method and none of the patients required revision of their CREF. PMID- 22832435 TI - Pediatric displaced fractures of the lateral condyle of the humerus treated using high strength, bioactive, bioresorbable F-u-HA/PLLA pins: a case report of 8 patients with at least 3 years of follow-up. AB - OBJECTIVES: The purpose of this report is to present our surgical technique using forged composites of unsintered hydroxyapatite particles/poly-L-lactide (F-u HA/PLLA) pins for pediatric displaced fractures of the lateral condyle of the humerus, to retrospectively evaluate clinical outcomes, and to verify the advantages of this device by using postoperative radiographs. DESIGN: Retrospective (level IV) case series. SETTING: Academic medical center. PATIENTS: From October 2004 to September 2006, 8 pediatric displaced closed fractures of the lateral condyle of the humerus (AO/OTA 13-B1) were treated. INTERVENTION: Lateral condyle fractures were fixed using 2 threaded pins. All the patients were placed in a long arm cast for 4 weeks after surgery. MAIN OUTCOME MEASUREMENTS: Radiographic and clinical outcomes and postoperative complications were evaluated. RESULTS: The average follow-up period was 52.5 months. All fractures were successfully united. All shadows of pins were observed, and there were no radiolucent zones around the pins at the final radiographic follow-up. No patients experienced pain or cosmetic deformity at the most recent follow-up. Loss of reduction, malunion, deep infection, implant failure, osteolysis, skin ulcer, and foreign body reaction were not observed postoperatively. No patient required secondary operation. CONCLUSIONS: Radioopacity of F-u-HA/PLLA devices is a major advantage of this device. No radiolucent zones were present around the pins, no osteolysis was observed on postoperative radiographs, and there were no postoperative complications. Reoperation for removal was unnecessary. Open reduction, internal fixation using F-u-HA/PLLA pins offers several advantages in treating pediatric displaced fractures of the lateral condyle of the humerus. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22832436 TI - Controllable synthesis of monodisperse ultrathin SnO2 nanorods on nitrogen-doped graphene and its ultrahigh lithium storage properties. AB - Monodisperse ultrathin SnO2 nanorods on nitrogen-doped graphene were firstly synthesized by a facile one-step hydrothermal strategy. The uniformed composites with high nitrogen content and ultrathin SnO2 nanorods of 2.5-4.0 nm in diameter and 10-15 nm in length show a high reversible specific capacity, superior rate capability and outstanding cycling stability (803 mA h g-1) as anode materials for lithium ion batteries, owing to the synergistic effect between GS and SnO2 and nitrogen-doping, which can greatly decrease the energy barrier for Li penetrating the pyridinic defects and improve the electronic structures. This work opens the door to prepare metal oxide/GS-N composites with superior lithium storage properties and engineering of graphene composites for advanced energy storage. PMID- 22832437 TI - Having the courage to change. AB - The ANA votes in new bylaws but falls short of transformation. PMID- 22832440 TI - We silence our profession when we fail to identify ourselves as nurses. AB - The approach of health care publications to author credentials remains inconsistent. PMID- 22832441 TI - The ANA House of Delegates closes its doors. AB - Bylaws changes move the association toward leaner governance. PMID- 22832443 TI - ED visits from battery injuries on the rise in children. PMID- 22832448 TI - Patient satisfaction metrics: customer service or quality care? AB - Nurses support better quality care but balk at using scripts to get there. PMID- 22832449 TI - Emergency contraception. PMID- 22832451 TI - Caring for those with disabilities. PMID- 22832450 TI - Simvastatin administration. PMID- 22832452 TI - Caring for those with disabilities. PMID- 22832453 TI - Bias and mental illness. PMID- 22832458 TI - My grandfather's unpublished manuscript. AB - A glimpse into nursing's past may provide a prescription for its future. PMID- 22832459 TI - Continuing education for patient care technicians: a unit-based, RN-led initiative. AB - Unlicensed assistive personnel get an upgrade--and everyone benefits. PMID- 22832464 TI - The Korean Nurses Association in New England. AB - Forging new ground for minority nurses in the community. PMID- 22832465 TI - Acute infectious diarrhea. PMID- 22832467 TI - A man of few words. PMID- 22832468 TI - Gait parameter risk factors for falls under simple and dual task conditions in cognitively impaired older people. AB - Impaired gait may contribute to the increased rate of falls in cognitively impaired older people. We investigated whether gait under simple and dual task conditions could predict falls in this group. The study sample consisted of 64 community dwelling older people with mild to moderate cognitive impairment. Participants walked at their preferred speed under three conditions: (a) simple walking, (b) walking while carrying a glass of water and (c) walking while counting backwards from 30. Spatiotemporal gait parameters were measured using the GAITRite((r)) mat. Falls were recorded prospectively for 12months with the assistance of carers. Twenty-two (35%) people fell two or more times in the 12month follow-up period. There was a significant main effect of gait condition and a significant main effect of faller status for mean value measures (velocity, stride length, double support time and stride width) and for variability measures (swing time variability and stride length variability). Examination of individual gait parameters indicated that the multiple fallers walked more slowly, had shorter stride length, spent longer time in double support, had a wider support width and showed more variability in stride length and swing time (p<0.05). There was no significant interaction between gait condition and faller status for any of the gait variables. In conclusion, dual task activities adversely affect gait in cognitively impaired older people. Multiple fallers performed worse in each gait condition but the addition of a functional or cognitive secondary task provided no added benefit in discriminating fallers from non-fallers with cognitive impairment. PMID- 22832469 TI - Postural stability and history of falls in cognitively able older adults: the Canton Ticino study. AB - Falls are common events in the elderly and represent the main risk factor for fractures and other injuries. Strategies for fall prevention rely on the multifactorial assessment of the risk of falling. The contribution of instrumented balance assessment to the prediction of falls remains unclear in the literature. In this study, we analyzed the association between the fall-history of a wide sample of older people without dementia and the values of a set of posturographic parameters acquired in different visual, proprioceptive and mental conditions. A consecutive sample of 130 cognitively able elderly subjects, age>=70 years, was analyzed. Based on their fall-history in the last year, subjects were categorized into non-fallers (NF), fallers (F) and recurrent fallers (RF>2 falls). Each subject was assessed by measurements of cognition and functional ability. Static posturography tests were performed in five conditions: with eyes open/close (EO/EC) on a firm/compliant (FS/CS) surface and while performing a cognitive task. The center of pressure (COP) mean position referred to the mid-point of the heels, area of the 95% confidence ellipse, sway mean velocities and RMS displacements in the antero-posterior (AP) and medio-lateral (ML) directions were computed and their association with the fall-history was assessed. The mean position of the COP in the AP direction and the confidence ellipse area were associated with the fall-history in the EOFS, ECFS and EOCS conditions (P<0.05). RMS displacements were also associated with the fall-history in the EOCS condition (P<0.05). Significant group differences (P<0.05) were found in the EOCS conditions, which greatly enhanced the differences among NF, F and RF. The ability to control balance while standing with eyes open on a compliant surface showed a high degree of association with the fall-history of older people with no or mild cognitive impairment. PMID- 22832470 TI - Effect of robotic performance-based error-augmentation versus error-reduction training on the gait of healthy individuals. AB - Effective locomotion training with robotic exoskeletons requires identification of optimal control algorithms to better facilitate motor learning. Two commonly employed training protocols emphasize use of training stimuli that either augment or reduce performance errors. The current study sought to identify which of these training strategies promote better short-term modification of a typical gait pattern in healthy individuals as a framework for future application to neurologically impaired individuals. Ten subjects were assigned to each of a performance-based error-augmentation or error-reduction training group. All subjects completed a 45-min session of treadmill walking at their preferred speed with a robotic exoskeleton. Target templates prescribed an ankle path for training that corresponded to an increased step height. When subjects' instantaneous ankle positions fell below the inferior virtual wall of the target ankle path, robotic forces were applied that either decreased (error-reduction) or increased (error-augmentation) the deviation from the target path. When the force field was turned on, both groups walked with ankle paths better approximating the target template compared to baseline. When the force field was removed unexpectedly during catch and post-training trials, only the error augmentation group maintained an ankle path close to the target ankle path. Further investigation is required to determine if a similar training advantage is provided for neurologically impaired individuals. PMID- 22832471 TI - Kinematic and kinetic analysis of planned and unplanned gait termination in children. AB - Gait termination is a task which requires people to alter momentum and stabilize the body. To date, many of the kinematic and kinetic characteristics of gait termination have not been reported, making it difficult for clinicians to design interventions to improve the ability to terminate gait quickly and efficiently. Therefore, the purpose of this study was to describe the lower body mechanics of healthy children as they performed walking trials, planned stopping trials, and unplanned stopping trials. Kinematic and kinetic data were collected from 15 healthy children between the ages of 11 and 17 years (14.3+/-2.1 years). The timing and magnitude of peak sagittal plane joint angles and moments were compared across the three conditions for the leg that led the stop step. Most differences were found when comparing unplanned stopping to both walking and planned stopping. During unplanned stopping, most subjects used either a hip/knee extension strategy or hip/knee flexion strategy to stabilize and perform the stopping task. The magnitudes of the peak hip extension moment and peak knee flexion angle were significantly greater, while the peak plantarflexion moment was significantly smaller during unplanned stopping than walking and planned stopping. The peak plantarflexion moment occurred significantly earlier during the stop stance phase of planned and unplanned stopping than during walking. This suggests that the ability to create sufficient joint moments in a short period of time is essential to be able to stop quickly and safely. Therefore, possible treatments/interventions should focus on ensuring that patients have appropriate strength, power, and range of motion. PMID- 22832472 TI - Effects of prosthetic mass distribution on the spatiotemporal characteristics and knee kinematics of transfemoral amputee locomotion. AB - This study was designed to investigate the effect of changing the location of the center of mass (COM) of transfemoral prostheses on the spatiotemporal and kinematical characteristics of the amputee gait, while maintaining the prosthetic mass fixed. Ten men with unilateral traumatic transfemoral amputation participated in gait analysis, 2-min walk and subject preference tests. Weights were added to the original prosthetic legs in three conditions: 600g added to the ankle, 600g added at 10cm distal to the prosthetic knee, and 300g added to the ankle, and 300g at 10cm distal to the knee. For each prosthetic mass condition, the stride and step lengths, stepping speed, stance, swing and gait cycle durations, self-selected walking speed, cadence, and knee flexion angle, were measured. We found no significant change in the spatiotemporal variables and the knee kinematics with alteration of the prosthetic COM, for both the prosthetic and the intact limbs. With the mass added to the ankle, the stepping speed, and the step and stride lengths of the prosthetic limb were significantly larger than those of the intact limb. Subject's preference revealed that 8 of 10 preferred their original no-added mass prostheses or mass added prostheses with minimal change of the COM. It was concluded that a short-term intervention with changed prosthetic mass distribution has no significant effect on the spatiotemporal and knee kinematical characteristics of the transfemoral amputee gait, although it can affect the spatiotemporal symmetry of locomotion. PMID- 22832473 TI - Relationship between strength, balance and mobility in children aged 7-10 years. AB - The purpose of this study was to investigate the association between variables of lower extremity muscle strength, balance, and mobility assessed under various task conditions. Twenty-one healthy children (mean age: 9+/-1 years) were tested for their isometric and dynamic strength as well as for their steady-state, proactive, and reactive balance and mobility. Balance and mobility tests were conducted under single and dual task conditions. Significant positive correlations were detected between measures of isometric and dynamic leg muscle strength. Hardly any significant associations were observed between variables of strength and balance/mobility and between measures of steady-state, proactive, and reactive balance. Additionally, no significant correlations were detected between balance/mobility tests performed under single and dual task conditions. The predominately non-significant correlations between different balance components and mobility imply that balance and mobility performance is task specific. Further, strength and balance/mobility as well as balance under single and dual task conditions seem to be independent of each other and may have to be tested and trained complementarily. PMID- 22832474 TI - Functionalization of poly-SNS-anchored carboxylic acid with Lys and PAMAM: surface modifications for biomolecule immobilization/stabilization and bio sensing applications. AB - Poly(2-(2,5-di(thiophen-2-yl)-1H-pyrrol-1-yl) (SNS) acetic acid) was electrochemically deposited on graphite electrodes and functionalized with lysine (Lys) amino acid and poly(amidoamine) derivatives (PAMAM G2 and PAMAM G4) to investigate their matrix properties for biosensor applications. Glucose oxidase (GOx) was immobilized onto the modified surface as the model enzyme. X-Ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) were used to report the surface properties of the matrices in each step of the biosensor construction. The biosensors were characterized in terms of their operational and storage stabilities and the kinetic parameters (K(app)(m) and I(max)). Three new glucose biosensors revealed good stability, featuring low detection limits (19.0 MUM, 3.47 MUM and 2.93 MUM for lysine-, PAMAM G2- and PAMAM G4-functionalized electrodes, respectively) and prolonged the shelf lives (4, 5, and 6 weeks for Lys-, PAMAM G2- and PAMAM G4-modified electrodes, respectively). The proposed biosensors were tested for glucose detection on real human blood serum samples. PMID- 22832475 TI - Perceived barriers, benefits, and motives for physical activity: two primary-care physical activity prescription programs. AB - This study examined whether perceived barriers, benefits, and motives for physical activity differed based on allocation to 2 different types of primary care activity-prescription programs (pedometer-based vs. time-based Green Prescription). Eighty participants from the Healthy Steps study completed a questionnaire that assessed their perceived barriers, benefits, and motives for physical activity. Factor analysis was carried out to identify common themes of barriers, benefits, and motives for physical activity. Factor scores were then used to explore between-groups differences for perceived barriers, benefits, and motives based on group allocation and demographic variables. No significant differences were found in factor scores based on allocation. Demographic variables relating to the existence of chronic health conditions, weight status, and older age were found to significantly influence perceived barriers, benefits, and motives for physical activity. Findings suggest that the addition of a pedometer to the standard Green Prescription does not appear to increase perceived motives or benefits or decrease perceived barriers for physical activity in low-active older adults. PMID- 22832476 TI - Electronic circular dichroism in the 4f-4f transitions of a series of cesium tetrakis (+)-3-heptafluorobutyrylcamphorate Ln(III) complexes. AB - For electronic circular dichroism in the 4f-4f transitions (4f-4f CD) of a series of nine tetrakis ((+)-3-heptafluorobutyrylcamphorato) Ln(III) complexes, Delta SAPR-8-C(4)(llll) Cs[Ln((+)-hfbc)(4)].H(2)O (Cs-Ln = Cs-Pr, -Nd, -Sm, -Eu, -Dy, Ho, -Er, -Tm, -Yb), the spectroscopic observables such as the dissymmetry factor g = Deltaepsilon/epsilon values with the intensities (Deltaepsilon) of the CD components and the molar absorption intensities (epsilon) in the 4f-4f transitions between the (2S+1)L(J) levels are compared with each other to test the classification of the CD components in the relative order of the observables predicted in terms of the selection rule for 4f-4f transitions. The 4f-4f CD based chiroptical spectra-structural relationship across the series of Delta-SAPR 8-C(4)(llll) lanthanide(III) complexes is proposed: the signs of the 4f-4f CD or CPL in the hypersensitive transitions are related to the absolute configuration; Ln complexes with a negative CD component have the Delta-configuration around Ln(III) and vice versa. PMID- 22832477 TI - Successful emergency double valve repair operation during acute aortic dissection type A. AB - Reconstructive valve surgery in acute aortic dissection type A (AADTA) remains challenging. We describe a case of successful combined repair of the aortic and mitral valves, and replacement of the ascending aorta after AADTA with aortic and mitral insufficiency. Mitral valve repair was achieved by quadrangular resection of the posterior leaflet, combined with ring annuloplasty. Aortic valve repair was achieved by Cabrol commissural sutures with resuspension of the annulus. The postoperative clinical course was uneventful and an echocardiogram revealed competent mitral and aortic valves. Mitral and aortic valve repair is an option in AADTA with mitral and aortic valve insufficiency. PMID- 22832478 TI - Dilated cardiomyopathy secondary to coarctation of the aorta was completely resolved after stent implantation. AB - Although rare in adults, coarctation of the aorta can present as an occult cause of cardiomyopathy. In this case report, we describe a 55-year-old man who presented to our clinic with new-onset symptoms of heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed systolic function. Cardiac catheterisation showed no critical coronary artery disease but a severe aortic coarctation just distal to the origin of the left subclavian artery, with a peak-to-peak systolic pressure gradient of 40 mmHg. We successfully implanted a balloon-expandable stent with good angiographic results. The procedure resulted in immediate clinical improvement. Six-months after stent implantation, the patient was free of symptoms and an echocardiographic examination showed completely normalised cardiac size and systolic function. PMID- 22832479 TI - A rare case of spontaneous rectus sheath haematoma in a patient with mechanical prosthetic aortic and mitral valves. AB - Every year nearly 300 000 patients have heart valve operations and mostly prosthetic valves are inserted. Coumadin is the mainstay of therapy in these individuals but it has many side effects, mostly related to its anticoagulant effect. Rectus sheath haematoma (RSH) is a rare complication of abdominal trauma, surgery and excessive strain, however, anticoagulant agents may predispose to this condition without any precipitating event. Reversal of anticoagulation and resuscitation with fluids and blood products are necessary but anticoagulation is crucial in patients with prosthetic valves, as they have acquired thrombotic diathesis. Herein we report on a case of spontaneous RSH in a patient with prosthetic mitral and aortic valves and a history of prosthetic valve thrombosis. He was successfully managed medically. PMID- 22832480 TI - Sustained idiopathic ventricular tachycardia originating from the posteroseptal tricuspid annulus. AB - Tricuspid annular ventricular tachycardia (VT) is a rarely encountered entity. Despite abundant data on idiopathic VTs, the prevalence and clinical characteristics of this infrequent form are not well defined and the efficacy of radiofrequency (RF) catheter ablation treatment remains unknown. We report on a case of a 44-year-old male presenting with symptomatic sustained idiopathic VT originating from the posteroseptal tricuspid annulus. PMID- 22832481 TI - LEOPARD syndrome. AB - LEOPARD syndrome (LS) is a rare hereditary disorder, characterised mainly by skin, facial and cardiac abnormalities. We report on the case of a six-year-old Djiboutian with typical features of LS. Multiple cardiovascular problems are described, including pulmonary infundibular, valvular and supra-valvular stenosis. A favourable course was observed after successful cardiac surgery. This is the first reported case of LS from the horn of Africa. PMID- 22832482 TI - Prenatal and early sucking influences on dietary preference in newborn, weaning, and young adult cats. AB - Early experiences are of potential importance in shaping long-term behavior. This study examined the relative influence of prenatal and/or early postnatal experience of chemosensory stimuli on subsequent olfactory and dietary preferences of cats as newborns, at 9-10 weeks, and at 6 months. Cats were exposed to vanillin or 4-ethylguaiacol via their mother's diet either prenatally, postnatally, perinatally (prenatal and postnatal), or experienced no exposure to the stimuli (control). Newborns were given a two-choice olfactory test between the familiar "odor" and no odor; 9-10 week olds were tested for their preference between two food treats, one flavored with the familiar stimulus and the other unflavored; at 6 months, cats were given a choice of two bowls of food, one flavored with the familiar stimulus and the other unflavored. At all ages, cats preferred the familiar, and avoided the unfamiliar, stimulus. Perinatal exposure exerted the strongest influence on preference. Prenatal exposure influenced preference at all ages and postnatal exposure exerted a stronger effect as the cat aged. We conclude that long-term chemosensory and dietary preferences of cats are influenced by prenatal and early (nursing) postnatal experience, supporting a natural and biologically relevant mechanism for the safe transmission of diet from mother to young. PMID- 22832484 TI - Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts. AB - Systemic sclerosis (SSc) is characterized by excess collagen deposition in the skin, due to intrinsic transforming growth factor-beta (TGF-beta) activation. We tried to determine the expression and the role of discoidin domain receptor 2 (DDR2) in SSc. The expression of DDR2 mRNA and protein was significantly decreased in SSc dermal fibroblasts, which was recovered by knocking down TGF beta. The knockdown of DDR2 in normal fibroblasts induced microRNA-196a expression, which led to type I collagen downregulation, indicating that DDR2 itself has a negative effect on microRNA-196a expression and inducible effect on collagen expression. In SSc fibroblasts, however, the DDR2 knockdown did not affect TGF-beta signaling and microRNA-196a expression. The microRNA-196a levels were significantly decreased in normal fibroblasts treated with TGF-beta and in SSc fibroblasts. Taken together our data indicate that, in SSc fibroblasts, intrinsic TGF-beta stimulation induces type I collagen expression, and also downregulates DDR2 expression. This probably acts as a negative feedback mechanism against excess collagen expression, as a decreased DDR2 expression is supposed to stimulate the microRNA-196a expression and further change the collagen expression. However, in SSc fibroblasts the microRNA-196a expression was downregulated by TGF-beta signaling. DDR2-microRNA-196a pathway may be a previously unreported negative feedback system, and its impairment may be involved in the pathogenesis of SSc. PMID- 22832485 TI - Digenic inheritance in epidermolysis bullosa simplex. PMID- 22832486 TI - TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. AB - Atopic dermatitis often precedes the development of asthma, a phenomenon known as "atopic march". An important role of allergen sensitization developed through barrier-defective skin has been recognized in the onset of atopic march; however, the underlying mechanism remains poorly understood. In this study, we use an experimental atopic march mouse model, in which the sensitization to allergen is achieved through barrier-impaired skin, followed by allergen challenge in the airway. By using thymic stromal lymphopoietin (TSLP)(iep-/-) mice in which the cytokine TSLP is selectively and inducibly ablated in epidermal keratinocytes, we demonstrate that keratinocytic TSLP, the expression of which is induced by skin barrier impairment, is essential for generating skin allergic inflammation and allergen-induced T helper type 2 response, for developing sensitization to allergen, and for triggering a subsequent allergic asthma. Furthermore, using TSLP(over) mice in which overexpression of keratinocytic TSLP is induced by skin topical application of MC903 (a vitamin D3 analog) in a dose-dependent manner, we show that keratinocytic TSLP levels are correlated with skin sensitization strength and asthma severity. Taken together, our study uncovers a crucial role of keratinocytic TSLP in the "atopic march" by promoting allergen sensitization occurring in barrier-impaired skin, which ultimately leads to allergic asthma. PMID- 22832487 TI - NGF sensitizes nociceptors for cowhage- but not histamine-induced itch in human skin. PMID- 22832483 TI - Olfaction under metabolic influences. AB - Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis. PMID- 22832488 TI - CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and beta1-integrin signaling pathways. AB - The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased beta1-integrin and inhibited pJNK induction by tumor necrosis factor-alpha or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and beta1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma. PMID- 22832489 TI - Prospective registration and outcome-reporting bias in randomized controlled trials of eczema treatments: a systematic review. AB - We assessed completeness of trial registration and the extent of outcome reporting bias in published randomized controlled trials (RCTs) of eczema (atopic dermatitis) treatments by surveying all relevant RCTs published from January 2007 to July 2011 located in a database called the Global Resource of Eczema Trials (GREAT). The GREAT database is compiled by searching six bibliographic databases, including EMBASE and MEDLINE. Out of 109 identified RCTs, only 37 (34%) had been registered on an approved trial register. Only 18 out of 109 trials (17%) had been registered "properly" in terms of submitting the registration before the trial end date and nominating a primary outcome. The proportion of "any registered" and "properly registered" RCTs increased from 19% and 10% in 2007 to 57% and 36% in 2011, respectively. Assessment of selective outcome-reporting bias was difficult even among the properly registered trials owing to unclear primary outcome description especially with regard to timing. Only 5 out of the 109 trials (5%) provided enough information for us to be confident that the outcomes reported in the published trial were consistent with the original registration. Adequate trial registration and description of primary outcomes for eczema RCTs is currently poor. PMID- 22832490 TI - TGFbeta1 overexpression by keratinocytes alters skin dendritic cell homeostasis and enhances contact hypersensitivity. AB - Overexpression of transforming growth factor beta-1 (TGFbeta1) in mouse epidermis causes cutaneous inflammation and keratinocyte hyperproliferation. Here we examined acute effects of TGFbeta1 overproduction by keratinocytes on skin dendritic cells (DCs). TGFbeta1 induction for 2 and 4 days increased the numbers and CD86 expression of B220(+) plasmacytoid DCs (pDCs) and CD207(+)CD103(+), CD207(-)CD103(-)CD11b(+), and CD207(-)CD103(-)CD11b(-) dermal DCs (dDCs) in skin draining lymph nodes (SDLNs). The dermis of TGFbeta1-overexpressing mice had significantly more pDCs, CD207(+)CD103(+) dDCs, and CD207(-)CD11b(+) dDCs in the absence of increased dermal proliferation. Application of dye, tetramethyl rhodamine iso-thiocyanate (TRITC), in dibutylpthalate (DBP) solution after TGFbeta1 induction increased the numbers of TRITC(+)CD207(-) dDCs in SDLNs, and augmented TRITC/DBP-induced Langerhans cell (LC) migration 72 hours post TRITC treatment. Consistent with this, LC migration was increased in vitro by TGFbeta1 overexpression in skin explants and by exogenous TGFbeta1 in culture media. Transient TGFbeta1 induction during DNFB sensitization increased contact hypersensitivity responses by 1.5-fold. Thus, elevated epidermal TGFbeta1 alone is sufficient to alter homeostasis of multiple cutaneous DC subsets, and enhance DC migration and immune responses to contact sensitizers. These results highlight a role for keratinocyte-derived TGFbeta1 in DC trafficking and in the initiation of skin inflammation. PMID- 22832491 TI - Aurora kinase-A deficiency during skin development impairs cell division and stratification. AB - Aurora kinase-A (Aurora-A) promotes timely entry into mitosis, centrosome maturation, and formation of bipolar spindles. To address the role of Aurora-A in skin development and homeostasis, we interbred a floxed Aurora-A (Aurora-A(fl)) mouse with the Cre-deleter strain, K14.Cre. Aurora-A(fl/fl);Krt14.Cre (Aurora-A( /-)) mice died shortly after birth. These mice had translucent skin, and histological evaluation showed that the dorsal skin was very thin and fragile with frank erosions. Although the expression of the basal layer marker keratin 14 and the differentiation marker keratin 1 was evident in Aurora-A(-/-) epidermis, there was a marked reduction in the number of suprabasal layers and basal keratinocytes. Dye exclusion assays also showed defects in barrier function. Unlike wild-type cells, Aurora-A(-/-) basal progenitors were delayed in forming two layers at embryonic day (E)13.5 when embryonic skin begins to stratify. Increased numbers of mitotic cells, apoptotic bodies, and polyploid keratinocytes were evident in Aurora-A(-/-) epidermis, indicating that a deficiency in Aurora-A promotes aberrant mitosis, mitotic slippage, and cell death. Finally, Aurora-A(-/ ) keratinocytes displayed centrosomal abnormalities that included centrosomes located at nonapical sites in basal cells. Thus, the deletion of Aurora-A in the developing epidermis alters centrosome function of basal keratinocytes and markedly impairs their ability to divide and stratify. PMID- 22832492 TI - Inhibition of CRM1-mediated nucleocytoplasmic transport: triggering human melanoma cell apoptosis by perturbing multiple cellular pathways. AB - Development of multiple drug resistance mechanisms in melanomas necessitates the identification of new drug targets, which when inhibited could impact multiple cellular pathways, thus circumventing potential resistance. By performing complementary DNA microarray analysis, we identified four key components of the nucleocytoplasmic transport machinery-CRM1, RAN (RAN-GTPase), RANGAP1, and RANBP1 to be overexpressed in human melanoma metastases. Chromosome region maintenance 1 (CRM1) inhibition induced a marked depletion of prosurvival/cytoplasmic extracellular signal-regulated kinase 1/2 (Erk1/2) and p90 ribosomal S6 kinase1 and elicited persistent Erk-signaling hyperactivation. Consistently, CRM1 inhibition inflicted extensive apoptosis in melanoma cells while sparing nontransformed melanocytes and primary lung fibroblasts. Apoptosis required both the intrinsic and extrinsic apoptotic pathways and was associated with a nuclear entrapment and downregulation of the antiapoptotic CRM1 target protein, Survivin. Apoptosis was preceded by a G1 cell-cycle arrest, and even though CRM1 inhibition mediated marked p53 and p21 induction in wild-type p53 melanoma cells, the latter's silencing or inactivation failed to alleviate apoptosis. Notably, CRM1 inhibition induced cell line-specific, G1 to S progression-retarding changes in the expression of multiple cell-cycle regulatory proteins, thus potentially explaining p53 dispensability. We propose CRM1 as a potential therapeutic target in human melanoma, whose inhibition induces loss of prosurvival/cytoplasmic Erk1/2, mediates persistent Erk hyperactivation, and initiates a multitude of cell context-dependent molecular events to trigger G1 arrest followed by massive apoptosis. PMID- 22832493 TI - Adenovirus-mediated Wnt10b overexpression induces hair follicle regeneration. AB - Hair follicles periodically undergo regeneration. The balance between activators and inhibitors may determine the time required for telogen hair follicles to reenter anagen. We previously reported that Wnt10b (wingless-type mouse mammary tumor virus integration site family member 10b) could promote the growth of hair follicles in vitro. To unveil the roles of Wnt10b in hair follicle regeneration, we established an in vivo mouse model using intradermal injection. On the basis of this model, we found that Wnt10b could induce the biological switch of hair follicles from telogen to anagen when overexpressed in the skin. The induced hair follicles expressed structure markers and could cycle normally into catagen. Conversely, anagen onset was abrogated by the knockdown of Wnt10b with small interfering RNA (siRNA). The Wnt10b aberrant expression data suggest that it is one of the activators of hair follicle regeneration. The beta-catenin protein is translocated to the nucleus in Wnt10b-induced hair follicles. The biological effects of Wnt10b were abrogated when beta-catenin expression was downregulated with siRNA. These data revealed that Wnt10b might induce hair follicle regeneration in vivo via the enhanced activation of the canonical Wnt signaling pathway. To our knowledge, our data provide previously unreported insights into the regulation of hair follicle cycling and provide potential therapeutic targets for hair follicle-related diseases. PMID- 22832494 TI - A transposon-based analysis of gene mutations related to skin cancer development. AB - Nonmelanoma skin cancer (NMSC) is by far the most frequent type of cancer in humans. NMSC includes several types of malignancies with different clinical outcomes, the most frequent being basal and squamous cell carcinomas. We have used the Sleeping Beauty transposon/transposase system to identify somatic mutations associated with NMSC. Transgenic mice bearing multiple copies of a mutagenic Sleeping Beauty transposon T2Onc2 and expressing the SB11 transposase under the transcriptional control of regulatory elements from the keratin K5 promoter were treated with TPA, either in wild-type or Ha-ras mutated backgrounds. After several weeks of treatment, mice with transposition developed more malignant tumors with decreased latency compared with control mice. Transposon/transposase animals also developed basal cell carcinomas. Genetic analysis of the transposon integration sites in the tumors identified several genes recurrently mutated in different tumor samples, which may represent novel candidate cancer genes. We observed alterations in the expression levels of some of these genes in human tumors. Our results show that inactivating mutations in Notch1 and Nsd1, among others, may have an important role in skin carcinogenesis. PMID- 22832496 TI - Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation. AB - Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway. PMID- 22832495 TI - A peptide derived from the highly conserved protein GAPDH is involved in tissue protection by different antifungal strategies and epithelial immunomodulation. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an important role not only in glycolysis but also in nonmetabolic processes, including transcription activation and apoptosis. We report the isolation of a human GAPDH (hGAPDH) (2 32) fragment peptide from human placental tissue exhibiting antimicrobial activity. The peptide was internalized by cells of the pathogenic yeast Candida albicans and initiated a rapid apoptotic mechanism, leading to killing of the fungus. Killing was dose-dependent, with 10 MUg ml (3.1 MUM) and 100 MUg ml hGAPDH (2-32) depolarizing 45% and 90% of the fungal cells in a population, respectively. Experimental C. albicans infection induced epithelial hGAPDH (2-32) expression. Addition of the peptide significantly reduced the tissue damage as compared with untreated experimental infection. Secreted aspartic proteinase (Sap) activity of C. albicans was inhibited by the fragment at higher concentrations, with a median effective dose of 160 mg l(-1) (50 MUM) for Sap1p and 200 mg l(-1) (63 MUM) for Sap2p, whereas Sap3 was not inhibited at all. Interestingly, hGAPDH (2-32) induced significant epithelial IL-8 and GM-CSF secretion and stimulated Toll-like receptor 4 expression at low concentrations independently of the presence of C. albicans, without any toxic mucosal effects. In the future, the combination of different antifungal strategies, e.g., a conventional fungicidal with immunomodulatory effects and the inhibition of fungal virulence factors, might be a promising treatment option. PMID- 22832497 TI - Field performance of the Skindex-17 quality of life questionnaire: a comparison with the Skindex-29 in a large sample of dermatological outpatients. AB - The utilization of health-related quality of life (HRQoL) questionnaires in routine clinical practice is hampered by several factors, including their length and thus the time needed to complete and score them. For this reason, growing efforts are devoted both to create short questionnaires and to shorten existing ones. The Skindex-17 is a dermatological HRQoL instrument that was derived from the Skindex-29 using Rasch analysis. It consists of 17 items instead of 29, and answers are given on a three-point scale instead of a five-point scale. The aim of this study was to compare information obtained by the Skindex-29 and the Skindex-17 in a large sample of dermatological outpatients. We compared the Skindex-29 with the Skindex-17 scores in 2,487 patients with several dermatological conditions, using intraclass correlation coefficients. The overall correlation was 0.957 for the symptoms scale and 0.940 for the psychosocial scale. The values were very similar for all diseases. The concordance between the levels of severity of the Skindex subscales in the two instruments was also very high. In conclusion, the Skindex-17 provided very similar information compared with the Skindex-29, with the advantage of being shorter and including some important psychometric properties. PMID- 22832498 TI - Skeletal muscle-specific overproduction of constitutively activated c-Jun N terminal kinase (JNK) induces insulin resistance in mice. AB - AIMS/HYPOTHESIS: Although skeletal muscle insulin resistance has been associated with activation of c-Jun N-terminal kinase (JNK), whether increased JNK activity causes insulin resistance in this organ is not clear. In this study we examined the metabolic consequences of isolated JNK phosphorylation in muscle tissue. METHODS: Plasmids containing genes encoding a wild-type JNK1 (WT-JNK) or a JNK1/JNKK2 fusion protein (rendering JNK constitutively active; CA-Jnk) were electroporated into one tibialis anterior (TA) muscle of C57Bl/6 mice, with the contralateral TA injected with an empty vector (CON) to serve as a within-animal control. RESULTS: Overproduction of WT-JNK resulted in a modest (~25%) increase in phosphorylation (Thr(183)/Tyr(185)) of JNK, but no differences were observed in Ser(307) phosphorylation of insulin receptor substrate 1 (IRS-1) or total IRS 1 protein, nor in insulin-stimulated glucose clearance into the TA muscle when comparing WT-JNK with CON. By contrast, overexpression of CA-Jnk, which markedly increased the phosphorylation of CA-JNK, also increased serine phosphorylation of IRS-1, markedly decreased total IRS-1 protein, and decreased insulin-stimulated phosphorylation of the insulin receptor (Tyr(1361)) and phosphorylation of Akt at (Ser(473) and Thr(308)) compared with CON. Moreover, overexpression of CA-Jnk decreased insulin-stimulated glucose clearance into the TA muscle compared with CON and these effects were observed without changes in intramuscular lipid species. CONCLUSIONS/INTERPRETATION: Constitutive activation of JNK in skeletal muscle impairs insulin signalling at the level of IRS-1 and Akt, a process which results in the disruption of normal glucose clearance into the muscle. PMID- 22832499 TI - Bronchoscopic treatment of emphysema: state of the art. AB - In recent years, different bronchoscopic techniques have been proposed for the treatment of emphysema, with the aim of obtaining the same clinical and functional advantages of lung volume reduction surgical techniques while reducing risks and costs. Such techniques can be classified into: methods employing devices that block the airways (e.g. spigots and unidirectional valves), methods that have a direct effect on the lung parenchyma (polymeric lung volume reduction, coils and thermal vapor ablation) and procedures that facilitate the expiration of trapped air from the emphysematous lung (airway bypass). This review aimed to evaluate the indications, outcomes and safety of the different techniques, based on the evidence from the available literature. Results obtained by these methods are encouraging, but they are still based mainly on studies with small groups of patients. However, several trials are ongoing and in the near future we will acquire more knowledge which should lead to a better optimization of these procedures. Meanwhile, the bronchoscopic treatment of emphysema cannot yet be considered a standard of care and patients should be treated in the context of clinical trials or controlled registries, with well-defined programs of evaluation and follow-up. PMID- 22832500 TI - Adverse effects of antiepileptic drugs. AB - More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects. PMID- 22832501 TI - Effect of aggressively driven intravenous iron therapy on infectious complications in end-stage renal disease patients on maintenance hemodialysis. AB - For treating end-stage renal disease-associated anemia, various strategies to achieve optimal hemoglobin levels with lower erythropoiesis stimulating agent doses are being tried. One of these involves the use of a high dose [transferrin saturation (TSAT) >30%] of intravenous (IV) iron supplementation. However, due to in vitro effects of iron on stimulating bacterial growth, there are concerns of increased risk of infection. The safety of higher iron targets with respect to infectious complications (bacteremias, pneumonias, soft tissue infections, and osteomyelitis) is unknown. This was a retrospective study of patients on maintenance hemodialysis from a single, urban dialysis center to assess the long term impact of the higher cumulative use of IV iron, on the incidence of clinically important infections. Our iron protocol was modified in June 2010 to aim for TSAT >30% unless serum ferritin levels were >1200 ng/mL. Data from only those patients who had been on dialysis for the whole duration between June 2009 and May 2011 were included. A total of 140 patients with end-stage renal disease on hemodialysis patients were found to be eligible for the study. There was a statistically significant increase in the mean TSAT and mean serum ferritin with the new anemia management protocol with a significant decrease in the mean erythropoiesis stimulating agent dose requirement. There was no statistically significant increase in the incidence of infectious complications. Although in vitro effects of iron are known to stimulate bacterial growth, a higher IV dose of iron may not increase the risk of infection in such patients. PMID- 22832502 TI - [New clinical aspects of cardiac myxomas: a clinical and pathological reappraisal]. AB - Easy access to echocardiography and its extensive and repeated use (as is the case in Portugal) now facilitates the early diagnosis of cardiac myxoma (CM). OBJECTIVE: To re-evaluate the clinical and pathological profile of CM under current diagnostic conditions. METHODS: We performed a retrospective study of 40 patients consecutively referred for surgery (between January 2003 and January 2010) with a histologically-confirmed diagnosis of CM - 26 female (F) and 14 male (M), with a mean age of 64+/-12 years (range 12-81; 53% over 65, 43% over 70); 39 patients were operated (one was not operable due to major neurological deficit). Clinical characteristics, surgical protocols, follow-up records of survivors (range 1-76 months, with serial echocardiograms), and histological data were reviewed. RESULTS: The apparent incidence was 2.6 cases/million/year; the overall F/M ratio was 1.9:1 (1.3:1 in those aged over 65, similar to the general population). The CM was located in the left atrium (LA) in 92.5%, with insertion in the fossa ovalis of the interatrial septum (IAS) in 53% (only 57% of LA myxomas), and outside the IAS in 30%. The mean size was 4.6 x 3.7cm. Asymptomatic tumors occurred in 48% of the total population (sessile and/or atypically inserted in 74%; 63% of large size, over 3 x 3cm), 61% were in patients referred in the last 25 months of the study; 23% of patients showed constitutional symptoms (all with very large CMs - mean 6.7 x 5.1cm), 35% had hemodynamic/obstructive symptoms, and 15% presented with embolic events. There was evidence of CM-related mitral valve (MV) disease in 20% of patients, resulting in moderate to severe mitral regurgitation requiring associated MV surgery in 13%. Significant comorbidities were present in 69%. Surgical procedures included simple excision in 74%; septoplasty/atrioplasty associated with extensive resection of the insertion site in 26%; and combined surgery (CM excision plus other procedures) in 28%. There were significant postoperative complications in 38%. In-hospital mortality was 10%; postoperative mortality was 7.7%. Mean follow-up was 30 months (100% of survivors, 44% for >2 years); late mortality was 5.6% and no CM recurrences were observed. CONCLUSIONS: (1) CM has a higher incidence than described in the literature and mainly affects patients aged over 65; the reported predominance of female patients disappears after the age of 65. (2) Most CM cases are now asymptomatic at presentation as a result of earlier diagnosis. (3) CM is the cause of MV disease requiring surgical correction in more than 10% of cases, and is associated with significant postoperative mortality, mainly due to the presence of comorbidities. PMID- 22832503 TI - Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. AB - BACKGROUND: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell mediated immune (CMI) responses between depression and ME/CFS. METHODS: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. RESULTS: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-alpha were significantly greater in depression than in ME/CFS. CONCLUSIONS: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared 'pathway phenotype', i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks. PMID- 22832505 TI - Plant food allergy in patients with pollinosis from the Mediterranean area. AB - BACKGROUND: Patients with pollinosis develop symptoms after intake of plant food more often than the general population. In order to study the prevalence of the presentation of allergic symptoms to plant foods in pollinosis, we selected a representative sample of the population from our Mediterranean area. METHODS: All patients completed a questionnaire, provided a blood sample and underwent a battery of skin and other complementary tests (prick-prick, oral challenge test) when necessary. The pollen counts were obtained from the Elche pollen station. In addition, sera from a subgroup of patients were checked with an allergen molecule panel on an Advia Centaur XP platform. RESULTS: Of the final sample (n = 233), 39.9% of the patients with pollinosis were sensitized and 30.9% had clinical allergy to at least one of the plant foods studied. Regression analysis showed that age and sensitization to the extracts of Platanus acerifolia and Artemisia vulgaris were the most important variables for discriminating between groups. Patients with pollinosis at a risk of allergy to plant foods had significantly higher Pru p 3 values [odds ratio (OR) 3.3; 95% confidence interval (95% CI) 2.3 4.8], and the value increased according to the number of plant food sensitizations. CONCLUSION: Plant food allergy is more common in patients with pollinosis than in the general population. The use of the London plain tree (P. acerifolia) and mugwort (A. vulgaris) in the skin tests may help identify such patients in our Mediterranean area, but determination of rPru p 3 could also be very useful in patients suspected of having plant food allergy. PMID- 22832506 TI - Ticagrelor FDA approval issues revisited. AB - CONTEXT: On July 20, 2011, the Food and Drug Administration (FDA) approved ticagrelor (BrilintaTM) for use during acute coronary syndromes. The drug labeling includes a 'black box' warning for bleeding risks, conventional for antithrombotics, and a unique warning that higher than 100 mg/daily maintenance treatment with aspirin may reduce ticagrelor effectiveness. The approval was granted following ticagrelor secondary reviews, and review of complete response by FDA officials. OBJECTIVE: To summarize the recommendations of different FDA reviewers, and their impact on drug approval. DESIGN, SETTING, AND PATIENTS: Review of the Platelet Inhibition and Clinical Outcomes (PLATO) trial comparing the efficacy of ticagrelor versus standard care treatment with clopidogrel. Patients (n = 18,624) with moderate- to high-risk acute coronary syndromes undergoing coronary intervention or being medically managed were randomized to ticagrelor (180-mg loading dose followed by 90 mg twice daily thereafter) or clopidogrel (300-600-mg loading dose followed by 75 mg once daily) for 6-12 months. RESULTS: The facts outlined in official reviews suggest that ticagrelor has been approved despite objections from both clinical primary reviewers assessing drug efficacy and safety. In addition, the statistical reviewer and cross-discipline team leader also recommended against approval. The putative grounds for their concerns were retrieved from the public FDA records and are briefly outlined here. PMID- 22832507 TI - A new strategy for the detection of adenosine triphosphate by aptamer/quantum dot biosensor based on chemiluminescence resonance energy transfer. AB - We designed an aptasensor for the detection of adenosine triphosphate (ATP) based on chemiluminescence resonance energy transfer (CRET). An adenosine aptamer was cut into two pieces of ssDNA, which were attached to quantum dots (QDs) and horse radish peroxidase (HRP), respectively. They could reassemble into specific structures in the presence of ATP and then decrease the distance of HRP and QDs. ATP detection can be easily realized according to the fluorescent intensity of QDs, which is excited by CRET between luminol and QDs. Results show that the concentration of ATP is linear relation with the fluorescent intensity of the peak of QDs emission and the linear range for the linear equation is from 50 MUM to 231 MUM and the detection limit was 185 nM. When the concentration of ATP was 2 mM, the efficiency of CRET is 13.6%. Good specificity for ATP had been demonstrated compared to thymidine triphosphate (TTP), cytidine triphosphate (CTP) and guanosine triphosphate (GTP), when 1 mM of each was added, respectively. This method needs no external light source and can avoid autofluorescence and photobleaching, and ATP can be detected selectively, specifically, and sensitively in a low micromolar range, which means that the strategy reported here can be applicable to the detection of several other target molecules. PMID- 22832508 TI - High-resolution gene expression atlases for adult and developing mouse brain and spinal cord. AB - Knowledge of the structure, genetics, circuits, and physiological properties of the mammalian brain in both normal and pathological states is ever increasing as research labs worldwide probe the various aspects of brain function. Until recently, however, comprehensive cataloging of gene expression across the central nervous system has been lacking. The Allen Institute for Brain Science, as part of its mission to propel neuroscience research, has completed several large gene mapping projects in mouse, nonhuman primate, and human brain, producing informative online public resources and tools. Here we present the Allen Mouse Brain Atlas, covering ~20,000 genes throughout the adult mouse brain; the Allen Developing Mouse Brain Atlas, detailing expression of approximately 2,000 important developmental genes across seven embryonic and postnatal stages of brain growth; and the Allen Spinal Cord Atlas, revealing expression for ~20,000 genes in the adult and neonatal mouse spinal cords. Integrated data-mining tools, including reference atlases, informatics analyses, and 3-D viewers, are described. For these massive-scale projects, high-throughput industrial techniques were developed to standardize and reliably repeat experimental goals. To verify consistency and accuracy, a detailed analysis of the 1,000 most viewed genes for the adult mouse brain (according to website page views) was performed by comparing our data with peer-reviewed literature and other databases. We show that our data are highly consistent with independent sources and provide a comprehensive compendium of information and tools used by thousands of researchers each month. All data and tools are freely available via the Allen Brain Atlas portal (www.brain-map.org). PMID- 22832509 TI - Delayed identification of proximal tracheoesophageal fistula. PMID- 22832510 TI - Vitamin and mineral status in patients with inflammatory bowel disease. AB - OBJECTIVES: Patients with inflammatory bowel disease (IBD) are at risk for vitamin and mineral deficiencies because of long-term inflammation in the gut mucosa and decreased oral intake. The aim of the study is to investigate the prevalence of vitamin and zinc deficiencies in patients with newly diagnosed IBD compared with a control group. METHODS: This is a retrospective chart review of all of the patients diagnosed as having IBD from 2006 to 2010, ages 1 to 18 years. Patients who had fat- and water-soluble vitamins (A, E, D 25-OH, folate, and B(12)) and zinc levels obtained at time of diagnosis were included in the study. A total of 61 patients with IBD and 61 age- and sex-matched controls were included. RESULTS: None of the 61 patients with IBD had folate or vitamin B12 deficiency. Vitamin D deficiency was found in 62% of the patients, vitamin A deficiency in 16%, vitamin E deficiency in 5%, and zinc deficiency in 40%. The control group had vitamin D and E and zinc deficiency in 75%, 8%, and 19% patients, respectively. CONCLUSIONS: We conclude that vitamin B12 and folate deficiencies are rare in children with newly diagnosed IBD in the United States and we question whether routine monitoring is warranted. Vitamin A and zinc deficiency are common in patients with newly diagnosed IBD and levels should be assessed at the time of diagnosis so that enteral repletion can commence. Vitamin D deficiency is common in all of the children in the Buffalo, NY, area, and routine screening for this deficiency is warranted. PMID- 22832511 TI - Detection of low-concentration host mRNA transcripts in Malawian children at risk for environmental enteropathy. AB - BACKGROUND AND OBJECTIVE: Transcriptomic analysis of fecal samples is an emerging method for the diagnosis of gastrointestinal pathology because it is noninvasive and requires minute volumes of analyte; however, detection of mRNA in low copy numbers in human stool is challenging. Our objective was to develop a method for detecting human mRNA suggestive of environmental enteropathy (EE) in feces. METHODS: Stool samples from 70 Malawian children, 34 without EE and 36 with EE, as defined by dual sugar absorption, were used to develop the methodology for mRNA detection. Multiple RNA isolation techniques and polymerase chain reaction formats were tested to detect 38 potential mRNA biomarkers suggestive of EE, and the results compared. RESULTS: RNA isolation using magnetic bead extraction best recovered host mRNA in stool, and digital droplet polymerase chain reaction was the most sensitive format to detect low copy numbers of mRNA. In all of the 70 samples, >20 copies of glyceraldehyde-3-phosphate dehydrogenase/200 mg of stool were detected. Copy numbers of potential biomarkers were normalized to glyceraldehyde-3-phosphate dehydrogenase, to account for interspecimen differences in concentration of human mRNA. Of the 38 transcripts chosen for initial evaluation, 24 had copy numbers >10 in all of the samples tested. Of the 6 potential markers measured in all of the 70 samples, REG4 best differentiated children with and without EE. CONCLUSIONS: A reproducible and reliable method to quantify human mRNA in stool present in low copy numbers has been developed, and may prove useful in investigations of EE and possibly other inflammatory gut conditions. PMID- 22832512 TI - Should intussusception in children prompt screening for celiac disease? AB - OBJECTIVES: An association between adult celiac disease (CD) and intussusceptions (ISs) has been described. Although more common among children, intussusception has not been linked with childhood CD aside from isolated case reports. Our aim was to investigate the frequency of IS among children with CD. METHODS: A patient database containing children with biopsy-proven CD was reviewed, in addition to radiology records contained in a hospital-maintained clinical data repository. RESULTS: Of 254 children with biopsy-proven CD and complete records available for review, abdominal imaging was performed in 21%, mainly because of abdominal pain. Among children with CD, 1.2% experienced an IS <9 months before their diagnosis with CD. Among children seen at our institution in the same time period, 0.07% experienced an IS. The majority of those children with CD who were found to have IS had no evidence of nutritional deficit at the time of IS. IS was not identified in any children with CD who had been treated with a gluten-free diet. CONCLUSIONS: IS was far more common among children in our cohort with untreated CD than in the general pediatric population simultaneously seen at our center. The diagnosis of CD should be considered in children with IS, even in the absence of signs of nutritional compromise. PMID- 22832513 TI - Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. AB - Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the nonmuscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants. PMID- 22832514 TI - Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention. AB - Patients with a moderately reduced glomerular filtration rate (GFR) typically have no metabolic acidosis and a urine net acid excretion comparable to those with normal GFR, supporting greater per nephron acidification with moderately reduced GFR. We modeled such patients using rats with a surgical reduction of 2/3 kidney mass, yielding animals with reduced GFR without metabolic acidosis. We then tested the hypothesis that reduction of nephron mass augments distal nephron acidification in remnant nephrons mediated by increased angiotensin II activity, and that the latter is induced by underlying acid retention. Nephron mass reduction yielded lower GFR than controls (sham operation), higher acid retention (measured by microdialysis of kidney cortex), higher distal nephron acidification, and higher plasma and kidney levels of angiotensin II, but plasma total CO(2) and urine net acid excretion were not different. Angiotensin II receptor antagonism reduced distal nephron acidification to levels similar to control. Dietary alkali that lowered acid retention to that of control also reduced plasma and kidney levels of angiotensin II and reduced distal nephron acidification to control. Angiotensin II receptor antagonism with dietary alkali had no significant added effect on distal nephron acidification. Thus, nephron reduction that moderately reduced GFR with no metabolic acidosis is characterized by increased angiotensin II activity. This mediates increased distal nephron acidification and is induced by acid retention. PMID- 22832516 TI - Barriers facing patients referred for kidney transplant cause loss to follow-up. AB - End-stage renal disease affects many Americans; however, transplant is the best treatment option increasing life years and offering a higher quality of life than possible with dialysis. Ironically, many who are eligible for transplant do not follow through on the complex workup protocols required to be placed on the transplant waiting list. Here we surveyed vascular access clinic patients at an academic medical center referred for transplant, who did not follow up on the needed workup to be added to the national transplant waiting list. The most frequent responses of 83 patients for not pursuing transplantation were that the patients did not think they would pass the medical tests, they were scared of getting a transplant, and they could not afford the medicine or the transplantation. These impediments may result from unclear provider communication, misinformation received from peers or other sources, misperceptions related to transplant surgery, or limited health literacy/health decision-making capacity. Thus, patients with end-stage renal disease lost to follow-up after referral for kidney transplant faced both real and perceived barriers pursuing transplantation. PMID- 22832515 TI - The C5a receptor has a key role in immune complex glomerulonephritis in complement factor H-deficient mice. AB - Chronic serum sickness leads to the formation of glomerular immune complexes; however, C57BL/6 mice do not develop glomerulonephritis unless complement factor H (CFH) is absent from the plasma. Here we studied the role for C5a receptor (R) in this setting. The exaggerated humoral immune response in CFH(-/-) mice was normalized in CFH(-/-)C5aR(-/-) double knockout mice, highlighting the C5aR dependence. The CFH knockout mice developed proliferative glomerulonephritis with endocapillary F4/80+ macrophage infiltration, a process reduced in the double knockout mice. There was no interstitial inflammation by histologic criteria or flow cytometry for F4/80+ Ly6C(hi)CCR2(hi) inflammatory macrophages. There were, however, more interstitial CD3+ CD4+ T lymphocytes in CFH knockout mice with chronic serum sickness, while double knockout mice had greater than 5-fold more Ly6C(lo)CCR2(lo) anti-inflammatory macrophages compared to the CFH knockout mice. Mice lacking C5aR were significantly protected from functional renal disease as assessed by blood urea nitrogen levels. Thus, IgG- and iC3b-containing immune complexes are not inflammatory in C57BL/6 mice. Yet when these mice lack CFH, sufficient C3b persists in glomeruli to generate C5a and activate C5aR. PMID- 22832517 TI - Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics. AB - Pleckstrin homology domain-containing, family H (with MyTH4 domain), member 2 (Plekhh2) is a 1491-residue intracellular protein highly enriched in renal glomerular podocytes for which no function has been ascribed. Analysis of renal biopsies from patients with focal segmental glomerulosclerosis revealed a significant reduction in total podocyte Plekhh2 expression compared to controls. Sequence analysis indicated a putative alpha-helical coiled-coil segment as the only recognizable domain within the N-terminal half of the polypeptide, while the C-terminal half contains two PH, a MyTH4, and a FERM domain. We identified a phosphatidylinositol-3-phosphate consensus-binding site in the PH1 domain required for Plekhh2 localization to peripheral regions of cell lamellipodia. The N-terminal half of Plekkh2 is not necessary for lamellipodial targeting but mediates self-association. Yeast two-hybrid screening showed that Plekhh2 directly interacts through its FERM domain with the focal adhesion protein Hic-5 and actin. Plekhh2 and Hic-5 coprecipitated and colocalized at the soles of podocyte foot processes in situ and Hic-5 partially relocated from focal adhesions to lamellipodia in Plekhh2-expressing podocytes. In addition, Plekhh2 stabilizes the cortical actin cytoskeleton by attenuating actin depolymerization. Our findings suggest a structural and functional role for Plekhh2 in the podocyte foot processes. PMID- 22832518 TI - Prefrontal dopamine and the dynamic control of human long-term memory. AB - Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test-a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism. The COMT Val(108/158)Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories. PMID- 22832519 TI - A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome. AB - The severity of attention-deficit/hyperactivity disorder (ADHD) symptoms is a major predictor of long-term ADHD outcome. To investigate if two-locus interactions might predict ADHD severity, we studied a sample of 1341 individuals from families clustering ADHD, using the Vanderbilt Assessment Scale for Parents. Latent class cluster analysis was used to construct symptom profiles and classify ADHD severity. Single nucleotide polymorphisms (SNPs) spanning ADHD-linked chromosomal regions on chromosomes 4, 5, 10, 11, 12 and 17 were genotyped. SNPs associated with ADHD severity were identified and potential two-locus genetic interactions were tested. We found that SNPs within the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 not only to increase the risk of developing ADHD but also to increase ADHD severity. All these genes are identified to have a major role in shaping both brain development and function. These findings demonstrate that genetic interactions may predict the severity of ADHD, which in turn may predict long-term ADHD outcome. PMID- 22832521 TI - A novel functional brain imaging endophenotype of autism: the neural response to facial expression of emotion. AB - Siblings of individuals with autism have over 20 times the population risk of autism. Evidence of comparable, but less marked, cognitive and social communication deficits in siblings suggests a role for these traits in the search for biomarkers of familial risk. However, no neuroimaging biomarkers of familial risk have been identified to date. Here we show, for the first time, that the neural response to facial expression of emotion differs between unaffected siblings and healthy controls with no family history of autism. Strikingly, the functional magnetic resonance imaging (fMRI) response to happy versus neutral faces was significantly reduced in unaffected siblings compared with controls within a number of brain areas implicated in empathy and face processing. The response in unaffected siblings did not differ significantly from the response in autism. Furthermore, investigation of the response to faces versus fixation crosses suggested that, within the context of this study, an atypical response specifically to happy faces, rather than to faces in general, accounts for the observed sibling versus controls difference and is a clear biomarker of familial risk. Our findings suggest that an atypical implicit response to facial expression of emotion may form the basis of impaired emotional reactivity in autism and in the broader autism phenotype in relatives. These results demonstrate that the fMRI response to facial expression of emotion is a candidate neuroimaging endophenotype for autism, and may offer far-reaching insights into the etiology of autism. PMID- 22832522 TI - Tetrahydrohyperforin prevents cognitive deficit, Abeta deposition, tau phosphorylation and synaptotoxicity in the APPswe/PSEN1DeltaE9 model of Alzheimer's disease: a possible effect on APP processing. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-beta peptide (Abeta) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Abeta neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1DeltaE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Abeta were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Abeta peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment. PMID- 22832523 TI - Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. AB - Prenatal exposure to maternal stress can have lifelong implications for psychological function, such as behavioral problems and even the development of mental illness. Previous research suggests that this is due to transgenerational epigenetic programming of genes operating in the hypothalamic-pituitary-adrenal axis, such as the glucocorticoid receptor (GR). However, it is not known whether intrauterine exposure to maternal stress affects the epigenetic state of these genes beyond infancy. Here, we analyze the methylation status of the GR gene in mothers and their children, at 10-19 years after birth. We combine these data with a retrospective evaluation of maternal exposure to intimate partner violence (IPV). Methylation of the mother's GR gene was not affected by IPV. For the first time, we show that methylation status of the GR gene of adolescent children is influenced by their mother's experience of IPV during pregnancy. As these sustained epigenetic modifications are established in utero, we consider this to be a plausible mechanism by which prenatal stress may program adult psychosocial function. PMID- 22832524 TI - Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology. AB - We report an association of single-nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in a sample of patients with Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnoses of schizophrenia, compared with healthy controls. Moreover, VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. The VSNL1 gene product, Visinin-like-protein-1 (VILIP-1), is a member of the neuronal EF-hand Ca(2+) sensor protein family. Previously, VILIP-1 mRNA and protein expression were shown to be altered in animal models and in schizophrenia patients. VILIP-1 influences cytosolic cyclic adenosine mono phosphate (cAMP) levels, cell migration, exocytotic processes and differentiation in the periphery. This raises the question, whether, similar to other potential schizophrenia susceptibility genes such as Disc1, PDE4B and Akt, VSNL1 may affect cAMP signaling and neurite outgrowth in neurons. In dissociated rat hippocampal neurons, VILIP-1 small interfering RNA knockdown decreased cAMP levels and reduced dendrite branching, compared with control-transfected cells. In contrast, VILIP-1 overexpression had the opposite effect. Similar results have been obtained in the human dopaminergic neuronal cell line SH-SY5Y, where the effect on neurite branching and length was attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and the protein kinase A inhibitor KT5720. These results show that the association of VSNL1 SNPs with the disease and cognitive impairments, together with previously observed pathological changes in VILIP-1 protein expression, possibly occurring during brain development, may contribute to the morphological and functional deficits observed in schizophrenia. PMID- 22832525 TI - Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. AB - Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, alpha-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia. PMID- 22832526 TI - Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins. AB - Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case-control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology. PMID- 22832530 TI - Identification of a novel heterozygous IGF1 splicing mutation in a large kindred with familial short stature. AB - BACKGROUND/AIMS: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. CASE/METHOD: A young male presented with postnatal growth retardation (-4.0 height SDS). His serum IGF-I concentration was low (115 ug/l, -2.21 SDS) and increased minimally to 130 ug/l (-1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations. RESULTS: From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation. CONCLUSIONS: A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest. PMID- 22832529 TI - Decreased neuroautonomic complexity in men during an acute major depressive episode: analysis of heart rate dynamics. AB - Major depression affects multiple physiologic systems. Therefore, analysis of signals that reflect integrated function may be useful in probing dynamical changes in this syndrome. Increasing evidence supports the conceptual framework that complex variability is a marker of healthy, adaptive control mechanisms and that dynamical complexity decreases with aging and disease. We tested the hypothesis that heart rate (HR) dynamics in non-medicated, young to middle-aged males during an acute major depressive episode would exhibit lower complexity compared with healthy counterparts. We analyzed HR time series, a neuroautonomically regulated signal, during sleep, using the multiscale entropy method. Our results show that the complexity of the HR dynamics is significantly lower for depressed than for non-depressed subjects for the entire night (P<0.02) and combined sleep stages 1 and 2 (P<0.02). These findings raise the possibility of using the complexity of physiologic signals as the basis of novel dynamical biomarkers of depression. PMID- 22832527 TI - Genetic regulation of Nrxn1 [corrected] expression: an integrative cross-species analysis of schizophrenia candidate genes. AB - Neurexin 1 (NRXN1) is a large presynaptic transmembrane protein that has complex and variable patterns of expression in the brain. Sequence variants in NRXN1 are associated with differences in cognition, and with schizophrenia and autism. The murine Nrxn1 gene is also highly polymorphic and is associated with significant variation in expression that is under strong genetic control. Here, we use co expression analysis, high coverage genomic sequence, and expression quantitative trait locus (eQTL) mapping to study the regulation of this gene in the brain. We profiled a family of 72 isogenic progeny strains of a cross between C57BL/6J and DBA/2J (the BXD family) using exon arrays and massively parallel RNA sequencing. Expression of most Nrxn1 exons have high genetic correlation (r>0.6) because of the segregation of a common trans eQTL on chromosome (Chr) 8 and a common cis eQTL on Chr 17. These two loci are also linked to murine phenotypes relevant to schizophrenia and to a novel human schizophrenia candidate gene with high neuronal expression (Pleckstrin and Sec7 domain containing 3). In both human and mice, NRXN1 is co-expressed with numerous synaptic and cell signaling genes, and known schizophrenia candidates. Cross-species co-expression and protein interaction network analyses identified glycogen synthase kinase 3 beta (GSK3B) as one of the most consistent and conserved covariates of NRXN1. By using the Molecular Genetics of Schizophrenia data set, we were able to test and confirm that markers in NRXN1 and GSK3B have epistatic interactions in human populations that can jointly modulate risk of schizophrenia. PMID- 22832531 TI - Effect on corneal endothelial cell loss during phacoemulsification: fortified balanced salt solution versus Ringer lactate. AB - PURPOSE: To compare the effect of phacoemulsification on the corneal endothelium using fortified balanced salt solution (BSS Plus) and Ringer lactate as the intraocular irrigating solution. SETTING: P.D. Hinduja Hospital, Mumbai, India. DESIGN: Prospective randomized controlled double-blinded clinical study. METHODS: Patients with senile cataract up to nuclear grade III were randomized to have phacoemulsification with posterior chamber intraocular lens implantation performed using fortified balanced salt solution (Group A) or Ringer lactate (Group B) as the intraocular irrigating solution. The corneal endothelial cell density (primary outcome) and pachymetry were measured preoperatively and 1 week and 1 and 6 months postoperatively. RESULTS: Each group comprised 35 eyes (35 patients). The postoperative percentage of endothelial cell loss was not significantly different between the 2 groups at 1 week (P=.582), 1 month (P=.668), or 6 months (5.03% and 8.35% in Group A and Group B, respectively) (P=.483) and was within the limits reported in the literature. The postoperative percentage change in pachymetry was not significantly different between the 2 groups at 1 week (P=.179) or 1 month (P=.170) but was significant at 6 months (P<.001) (-1.59% and 0.54% in Group A and Group B, respectively); however, the mean pachymetry value was near baseline in both groups at 6 months. CONCLUSION: Corneal endothelial cell loss after phacoemulsification with Ringer lactate was similar to that with fortified balanced salt solution over the long term. PMID- 22832532 TI - Timing of ischemic insult alters fetal growth trajectory, maternal angiogenic balance, and markers of renal oxidative stress in the pregnant rat. AB - Increased uterine artery resistance and angiogenic imbalance characterized by increased soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased free vascular endothelial growth factor (VEGF) are often associated with placental insufficiency and preeclampsia but not synonymous with hypertension. We hypothesized chronic reductions in utero-placental perfusion (RUPP) for 5 days (d) during either mid- (d12-d17) or late (d14-d19) gestation would have disparate effects on plasma sFlt-1 and VEGF levels and blood pressure. Five days of chronic RUPP was achieved by placement of silver clips on the abdominal aorta and ovarian arteries on either gestational d12 or d14. Arterial pressure was increased (P < 0.05) in RUPP vs. normal pregnant (NP) in both d17 (10%) and d19 (25%) groups, respectively. Circulating free VEGF was decreased (P < 0.05) and sFlt-1:VEGF ratio increased (P < 0.05) after 5 days of RUPP ending on d19 but not d17 compared with NP controls. Angiogenic imbalance, measured by an endothelial tube formation assay, was present in the d19 RUPP but not the d17 RUPP compared with age-matched NP rats. Five days of RUPP from days 14 to 19 decreased fetal and placental weights 10% (P < 0.01) compared with d19 NP controls. After 5 days of RUPP, from days 12 to 17 of pregnancy, fetal weights were 21% lighter (P < 0.01) compared with d17 NP controls, but placental weight was unchanged. These findings suggest that the timing during which placental insufficiency occurs may play an important role in determining the extent of alterations in angiogenic balance, fetal growth restriction, and the severity of placental ischemia-induced hypertension. PMID- 22832533 TI - Influence of estradiol supplementation on neuropeptide Y neurotransmission in skeletal muscle arterioles of F344 rats. AB - The effects of estradiol on neuropeptide Y (NPY) neurotransmission in skeletal muscle resistance vessels have not been described. The purpose of this study was to determine the effects of long-term estradiol supplementation on NPY overflow, degradation, and vasoconstriction in gastrocnemius first-order arterioles of adult female rats. Female rats (4 mo; n = 34) were ovariectomized (OVX) with a subset (n = 17) receiving an estradiol pellet (OVE; 17beta-estradiol, 4 MUg/day). After conclusion of the treatment phase (8 wk), arterioles were excised, placed in a physiological saline solution (PSS) bath, and cannulated with micropipettes connected to albumin reservoirs. NPY-mediated vasoconstriction via a Y(1)-agonist [Leu31Pro34]NPY decreased vessel diameter 44.54 +/- 3.95% compared with baseline; however, there were no group differences in EC(50) (OVE: -8.75 +/- 0.18; OVX: 8.63 +/- 0.10 log M [Leu31Pro34]NPY) or slope (OVE: -1.11 +/- 0.25; OVX: -1.65 +/ 0.34% baseline/log M [Leu31Pro34]NPY). NPY did not potentiate norepinephrine mediated vasoconstriction. NPY overflow experienced a slight increase following field stimulation and significantly increased (P < 0.05) over control conditions in the presence of a DPPIV inhibitor (diprotin A). Estradiol status did not affect DPPIV activity. These data suggest that NPY can induce a moderate decrease in vessel diameter in skeletal muscle first-order arterioles, and DPPIV is active in mitigating NPY overflow in young adult female rats. Long-term estradiol supplementation did not influence NPY vasoconstriction, overflow, or its enzymatic breakdown in skeletal muscle first-order arterioles. PMID- 22832534 TI - Impact of maternal dexamethasone on coronary PGE(2) production and prostaglandin dependent coronary reactivity. AB - Intrauterine growth restriction is associated with increased fetal glucocorticoid exposure and an increased risk of adult coronary artery disease. Coronary arteries from sheep exposed to early gestation dexamethasone (Dex) have increased constriction to angiotensin II (ANG II). Prostaglandin E(2) (PGE(2)) helps maintain coronary dilation, but PGE(2) production is acutely decreased by Dex administration. We hypothesized early gestation Dex exposure impairs adult coronary PGE(2) production with subsequent increases in coronary reactivity. Dex was administered to ewes at 27-28 days gestation (term 145 days). Coronary reactivity was assessed by wire myography in offspring at 4 mo of age (N = 5 to 7). Coronary smooth muscle cells were cultured and prostaglandin production was measured after 90 min incubation with radiolabeled arachidonate. Coronary myocytes from Dex-exposed lambs had a significant decrease in PGE(2) production that was reversed with ANG II incubation. Dex-exposed coronary arteries had increased constriction to ANG II and attenuated dilatation to arachidonic acid, with the greatest difference seen after the endothelium was inactivated by rubbing. Preincubation with the cyclooxygenase (COX) inhibitor indomethacin altered control responses and recapitulated the heightened coronary tone seen following Dex exposure. We conclude that impaired coronary smooth muscle COX mediated PGE(2) production contributes to the coronary dysfunction elicited by early gestation Dex. Programmed inhibition of vasodilatory prostanoid production may link an adverse intrauterine environment with adult coronary artery disease. PMID- 22832535 TI - Amylin blunts hyperphagia and reduces weight and fat gain during recovery in socially stressed rats. AB - During recovery from social stress in a visible burrow system (VBS), during which a dominance hierarchy is formed among the males, rats display hyperphagia and gain weight preferentially as visceral adipose tissue. By proportionally increasing visceral adiposity, social stress may contribute to the establishment of metabolic disorder. Amylin was administered to rats fed ad libitum during recovery from VBS stress in an attempt to prevent hyperphagia and the resultant gain in body weight and fat mass. Amylin treatment reduced food intake, weight gain, and accumulation of fat mass in male burrow rats, but not in male controls that spent time housed with a single female rather than in the VBS. Amylin did not alter neuropeptide Y (NPY), agouti-related peptide (AgRP), or proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of the hypothalamus as measured at the end of the recovery period, nor did it affect plasma corticosterone or leptin. Amylin exerted most of its effect on food intake during the first few days of recovery, possibly through antagonism of NPY and/or increasing leptin sensitivity. The potential for chronic social stress to contribute to metabolic disorder is diminished by amylin treatment, though the neuroendocrine mechanisms behind this effect remain elusive. PMID- 22832536 TI - Increased muscle size and strength from slow-movement, low-intensity resistance exercise and tonic force generation. AB - The authors investigated the effects of low-intensity resistance training on muscle size and strength in older men and women. Thirty-five participants (age 59 76 yr) were randomly assigned to 2 groups and performed low-intensity (50% of 1 repetition maximum) knee-extension and -flexion exercises with either slow movement and tonic force generation (LST; 3-s eccentric, 3-s concentric, and 1-s isometric actions with no rest between repetitions) or normal speed (LN; 1-s concentric and 1-s eccentric actions with 1-s rests between repetitions) twice a week for 12 wk (2-wk preparation and 10-wk intervention). The LST significantly increased thigh-muscle thickness, as well as isometric knee-extension and flexion strength. The LN significantly improved strength, but its hypertrophic effect was limited. These results indicate that even for older individuals, the LST can be an effective method for gaining muscle mass and strength. PMID- 22832537 TI - Pediatric robotic assisted laparoscopy for paraureteral bladder diverticulum excision with ureteral reimplantation. AB - We describe pediatric robotic assisted laparoscopic bladder diverticulectomy with a ureteral reimplantation in a 9-year-old male for a symptomatic paraureteral diverticulum. PMID- 22832538 TI - Retroperitoneal laparoscopic approach for renal hydatid cyst in children. A technical report. AB - Renal hydatid disease is a rare pathological condition in children. Hydatid cyst of the kidney corresponds to 2-4% of all hydatid disease cases. Minimally invasive techniques have been used in the treatment of renal hydatid cysts but surgical experience is limited. We report a 10-year-old patient with a left renal hydatid cyst treated using a retroperitoneal laparoscopic technique. PMID- 22832539 TI - The effect of the number of carbohydrate moieties on the azaphthalocyanine properties. AB - A series of azaphthalocyanines (AzaPc) bearing one, two, four or eight isopropylidene-protected galactosyl units was prepared by azide-alkyne click reaction or by classical Pc template cyclotetramerization of the corresponding dicyanopyrazine and AzaPc properties important for photodynamic therapy were compared. All compounds absorbed at long wavelengths (above 650 nm) and belonged to strong singlet oxygen producers (Phi(Delta) = 0.58-0.64) retaining significant fluorescence emission (Phi(F) = 0.026-0.23). The only exception was the compound with four isopropyliden-protected galactosyl units where partial aggregation was observed. Removal of protecting groups increased the polar character of all AzaPc. However, only AzaPc bearing eight galactoses was found to be water-soluble (105 mg mL(-1)) but noticeably aggregated in water as well as in organic solvents (DMF, DMSO). Amphiphilic AzaPc bearing one deprotected galactose was incorporated into the lipidic bilayer of liposomes in a nonaggregated form. Liposomes may therefore be a suitable delivery system for this amphiphilic photosensitizer. PMID- 22832541 TI - Diagnostic and prognostic characteristics of phytotoxicity caused by fluoride on Spondias dulcis Forst. F. (Anacardiaceae). AB - The goal of this study was to determine the symptoms and microscopic damage caused by fluoride on Spondias dulcis, a fluoride-sensitive species. The plants were exposed to simulated fog with fluoride (0, 5, 10, 15 and 20 mg L(-1)) for 20 min daily during four consecutive days. Samples from leaflets without any apparent fluoride injury were collected to microscopic analysis. The percentage of necrosed leaf area was measured, and the level of pollutant in the dry matter from the basal and apical portions of the plant was determined. The necroses began 24 h after the first simulation mainly from the base of the leaflets. A higher level of necrosis was observed at the apical portion of the plants, a region of higher fluoride accumulation. The damage on the surface of the leaflets was characterized as plasmolysis, erosion of the epicuticular waxes and epidermal rupture. Structurally, the noticeable accumulation of granules and droplets green stained by toluidine blue in the spongy parenchima and the boundaries of ending veinlets was observed. The limb thickness reduction occurred due to plasmolysis in the mesophyll, showing an apparent correlation with the damage observed on the surface. The parameters observed in the laboratory are promising for field biomonitoring studies. PMID- 22832540 TI - Mindfulness-based cognitive therapy improves polysomnographic and subjective sleep profiles in antidepressant users with sleep complaints. AB - BACKGROUND: Many antidepressant medications (ADM) are associated with disruptions in sleep continuity that can compromise medication adherence and impede successful treatment. The present study investigated whether mindfulness meditation (MM) training could improve self-reported and objectively measured polysomnographic (PSG) sleep profiles in depressed individuals who had achieved at least partial remission with ADM, but still had residual sleep complaints. METHODS: Twenty-three ADM users with sleep complaints were randomized into an 8 week Mindfulness-Based Cognitive Therapy (MBCT) course or a waitlist control condition. Pre-post measurements included PSG sleep studies and subjectively reported sleep, residual depression symptoms. RESULTS: Compared to controls, the MBCT participants improved on both PSG and subjective measures of sleep. They showed a pattern of decreased wake time and increased sleep efficiency. Sleep depth, as measured by stage 1 and slow-wave sleep, did not change as a result of mindfulness training. CONCLUSIONS: MM is associated with increases in both objectively and subjectively measured sleep continuity in ADM users. MM training may serve as more desirable and cost-effective alternative to discontinuation or supplementation with hypnotics, and may contribute to a more sustainable recovery from depression. PMID- 22832542 TI - Spatial distribution of pollen grains and spores in surface sediments of Guanabara Bay, Rio de Janeiro, Brazil. AB - Aiming to investigate the deposition of pollen grains and spores in Guanabara Bay, Rio de Janeiro State, 61 surface sediment samples were analyzed. The results showed that the current deposition of palynomorphs in surface sediments of Guanabara Bay represents the regional vegetation of this hydrographic basin. The differential distribution of palynomorphs followed a pattern influenced by bathymetry, tidal currents speed, discharge of numerous rivers, and by human activity. The dominance of representatives of Field Vegetation reflects the changes of the original flora caused by intense human activities in the region. The continued presence and richness of pollen types of rain forest in the samples indicates that their source area might be the vegetation from riparian border of rivers in the western sector of the Bay, where the mangrove vegetation is being preserved. The large amount of damaged palynomorphs may be related to abrasion that occurs during river transport, indicating removal or reworking from their areas of origin. PMID- 22832543 TI - Characterization of the myenteric neuronal population and subpopulation of the duodenum of adult wistar rat fed with hypoproteic chow. AB - The effects of severe protein malnutrition (4%) on myenteric neurons of Wistar rat duodenum, in relation to a standard 22%-protein diet for rodents, were assessed in this study. Segments of the duodenum from 10 rats from each nutritional group were submitted to the elaboration of whole mounts - 5 stained with Giemsa to determine the total population of myenteric neurons and the others stained by a histochemical method to detect nervous cells through the NADPH diaphorase enzyme activity for studying the subpopulation of nitrergic neurons. The area of 100 neurons per animal, totalizing 2,000 neurons, were randomly measured by using the Image Pro-Plus((r))software. Malnourished rats presented 34.38% lower body weight and 10.60% duodenum length reduction when compared to the control group. Quantitative analysis demonstrated no significant differences between control and malnourished group by using Giemsa; however, as the organ reduction was not followed by an increase inversely proportional to the density of neurons, the condition imposed suggests the loss of neurons from the total population. Nevertheless, through NADPH-d histochemistry, there was a neuronal density increase for the malnourished group. There was no significant difference between the groups for both techniques with respect to the morphometric analysis of the body cell. PMID- 22832544 TI - Honey physicochemical properties of three species of the Brazilian Melipona. AB - Physicochemical analyses were carried out to evaluate 27 samples of honeys from three species of the Brazilian genus Melipona (M. capixaba, M. rufiventris and M. mondury) from Espirito Santo and Minas Gerais States. The parameters water activity (Aw), percentage of soluble solids (Brix %), pH, acidity (meq/Kg) and moisture (%) were evaluated. The honey characteristics obtained from these samples were very similar to the ones from other Melipona species. However, regarding the honey from Apis (honey bee), only the pH values were similar. The low pH value and the high acidity detected in Melipona honey are potential factors for increasing the honey shelf life because they do not provide favorable conditions for the microbial development. On the other hand, the high level of water activity favors the growth of microorganisms, especially yeast, which demands a more careful handled and storage. The observed differences between Melipona and Apis honey reinforce the need for specific quality settings for stingless bee honey. PMID- 22832545 TI - Myenteric neuronal plasticity induced by Toxoplasma gondii (genotype III) on the duodenum of rats. AB - The effects of acute and chronic infection caused by Toxoplasma gondii on duodenal myenteric neurons were analyzed. Eighteen rats were assigned into four groups: Acute Control Group (ACG, n=4); Acute Experimental Group (AEG, n=4); Chronic Control Group (CCG, n=5); and Chronic Experimental Group (CEG, n=5). Rats from the AEG and CEG were inoculated orally with 105 genotype III (BTU-II strain) tachyzoites of T. gondii isolated from a dog with neurological signs. Acute groups were killed after 24 hours after the inoculation and the chronic groups after 30 days. Whole-mount from the duodenum were stained with Giemsa. The population density of myenteric neurons, as well the body cell, nuclear and cytoplasmic area were analyzed. Both acute and chronic toxoplasmic infection did not provoke neuronal loss. On the other hand, plastic alterations were observed: decreasing of the nuclear and cytoplasmic area during the acute phase and neuronal hypertrophy during the chronic phase. PMID- 22832546 TI - Effects of medical nutrition therapy on body fat and metabolic syndrome components in premenopausal overweight women. AB - BACKGROUND/AIMS: To evaluate the effects of medical nutrition therapy (MNT) on body composition and metabolic syndrome (MetS) components in premenopausal Korean women with a body mass index >=23. METHODS: Participants (n = 160) were classified into MetS (n = 44) or non-MetS (n = 116) groups based on the criteria proposed by the revised National Cholesterol Education Program-Adult Treatment Panel III and the International Diabetes Federation classification. Anthropometric and dietary assessments and blood analyses were performed for all participants prior to and following 12 weeks of MNT. RESULTS: Following MNT, body fat decreased in both groups by roughly 11% (p < 0.001), and the number of participants meeting the criteria for MetS thus decreased from 44 to 19 (56.8%). Mean waist circumference (WC), blood pressure (BP), plasma triglyceride (TG) and blood glucose levels decreased in the MetS group (p < 0.001). Body fat reduction in the MetS group was correlated with changes in WC (r = 0.584), systolic BP (r = 0.451), diastolic BP (r = 0.429) and plasma TG (r = 0.488) levels after adjusting for covariates (p < 0.05). CONCLUSIONS: Body fat reduction and MetS component improvement was achieved by MNT in overweight women. Changes in MetS components appear to be related to body fat reduction. MNT should focus on body fat reduction when used as a primary prevention for MetS. PMID- 22832547 TI - Validation of a stability-indicating RP-LC method for the determination of tigecycline in lyophilized powder. AB - A reversed-phase liquid chromatography (RP-LC) method was validated for the determination of tigecycline in lyophilized powder. The LC method was conducted on a Luna C18 column (250 * 4.6 mm i.d.), maintained at room temperature. The mobile phase consisted of buffer containing sodium phosphate monobasic (0.015M) and oxalic acid (0.015M) (pH 7.0)-acetonitrile (75:25, v/v), run at a flow rate of 1.0 mL/min and using ultraviolet detection at 280 nm. The chromatographic separation was obtained with a retention time of 8.6 min, and was linear in the range of 40-100 ug/mL (r(2) = 0.9997). The specificity and stability-indicating capability of the method was proven through forced degradation studies, which also showed no interference of the excipients. The accuracy was 99.01% with a bias lower than 1.81%. The limits of detection and quantitation were 1.67 and 5.05 ug/mL, respectively. Moreover, method validation demonstrated satisfactory results for precision and robustness. The proposed method was applied for the analysis of the lyophilized powder formulation, contributing to improve the quality control and to assure the therapeutic efficacy. PMID- 22832548 TI - Plasma surface modification of electrospun fibers for adhesion-based cancer cell sorting. AB - Personalized cancer therapies drive the need for devices that rapidly and accurately segregate cancer cells from solid tumors. One potential sorting strategy is to segregate populations of cells based on their relative strength of adhesion. To investigate the effect of surface hydrophilicity and cell phenotype on adhesion, primary human breast skin fibroblasts and keratinocytes and MCF-7 breast cancer cells were seeded onto air and CF(4) plasma-treated nanofibers followed by exposure to three shear stresses (200, 275 and 350 dynes per cm(2)) 1 hour after inoculation. No difference in strength of adhesion was measured in either fibroblasts or keratinocytes on either plasma treated-surface: all exhibited >60% of the initial cell count after a 5 minute exposure to 350 dynes per cm(2) of shear stress. In contrast, a significant difference between relative strength of adhesion on air versus CF(4) plasma-treated surfaces was observed for MCF-7 cells: 26% and 6.6% of cells remained on the air and CF(4) plasma-treated surfaces, respectively. The ability to sort this cancer cell line from two non cancerous primary human cells was evaluated by inoculating a mixture of all three cell types simultaneously onto CF(4) treated nanofibers followed by 1 hour of culture and exposure to 350 dynes per cm(2) shear stress. The majority of MCF-7 cells were removed (0.7% remained) while a majority of fibroblasts and keratinocytes remained adhered (74 and 57%). Post-sorted MCF-7 viability and morphology remained unchanged, preserving the possibility of post-separation and analysis. These data suggest that the plasma treatment of electrospun scaffolds provides a tool useful in sorting cancer cells from a mixed cell population based on adhesion strength. PMID- 22832550 TI - EOT or Kretschmann configuration? Comparative study of the plasmonic modes in gold nanohole arrays. AB - The debate is still ongoing on the optimal mode of interrogation for surface plasmon resonance (SPR) sensors. Comparative studies previously demonstrated that nanoparticles exhibiting a localized SPR (LSPR) have superior sensitivity to molecular adsorption processes while thin Au film-based propagating SPR is more sensitive to bulk refractive index. In this paper, it is demonstrated that nanohole arrays (1000 nm periodicity, 600 nm diameter and 125 nm depth), which support both LSPR and propagating SPR modes, exhibited superior sensitivity to bulk refractive index and improved detection limits for IgG sensing by using the Kretschmann configuration. The greater sensitivity to IgG detection in the Kretschmann configuration was obtained despite the shorter penetration depth of nanohole arrays excited in the enhanced optical transmission (EOT) configuration. The decay length of the electromagnetic field in EOT mode was estimated to be approximately 140 nm using a layer-by-layer deposition technique of polyelectrolytes (PAH and PSS) and was confirmed with 3D FDTD simulations, which was lengthen by almost a factor of two in the Kretschmann configuration. Spectroscopic data and field depth were correlated with RCWA and FDTD simulations, which were in good agreement with the experimental results. Considering these analytical parameters, it is advantageous to develop sensors based on nanohole arrays in the Kretschmann configuration of SPR. PMID- 22832549 TI - Palladium-catalyzed, pyrrolidine-mediated arylmethylation of ketones and aldehydes with coumarinyl(methyl) acetates. AB - We report the palladium-catalyzed, pyrrolidine-mediated alpha-benzylation of enamines generated from aldehydes and ketones. The method allows for direct coupling of medicinally relevant coumarin moieties with aldehydes and ketones in good yield under mild conditions. The reaction is believed to proceed via a Pd-pi benzyl complex generated from (coumarinyl)methyl acetates. PMID- 22832551 TI - Effect of lamina open angles in expansion open-door laminoplasty on the clinical results in treating cervical spondylotic myelopathy. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate and compare the relation of the efficacy and clinical results of expansion open-door laminoplasty (EOLP) with different angles in lamina open-door. SUMMARY OF BACKGROUND DATA: EOLP is currently the most widely adopted surgical treatment for cervical spondylotic myelopathy. Although many long-term clinical follow-up studies have reported that most patients recover satisfactorily after EOLP, there have been numerous reports regarding postoperative complications, such as stubborn axial symptoms (AS) and C5 palsy. The lamina open-door angles in EOLP play a decisive role in determining the openness of the door that affects clinical outcomes. Nonetheless, no thorough studies on different angles in EOLP have been published. METHOD: A total of 198 cervical spondylotic myelopathy patients who underwent posterior cervical EOLP and at least 24 months follow-up treatment between July 2006 and January 2009 were selected as case studies. Among the 198 cases used, there were 39 double-segment cases with the location being C3-C5 in 11 cases and C4-C6 in 28 cases, 97 three-segments (C4-C7) and 62 four segments (C3-C7). All of the patients underwent x-ray, computed tomography, and magnetic resonance imaging images for evaluation of the cervical spine. According to different opening angles, measured by computed tomography scan after operation 1 week, the patients were divided into 2 groups, group A (>30 degrees, 76 patients including 44 males and 32 females) and group B (15-30 degrees, 122 patients including 71 males and 51 females). All patients were followed up for over 24 months, clinical results including operative duration, intraoperative bleeding volume, postoperative complications, C2-C7 Cobb angle, cervical curvature index (CI), range of motion (ROM), and values after the spinal cord backward shift were analyzed statistically, evaluating the neurological function at final follow-up and calculating the improvement rate of nerve function recovery. RESULTS: There was no statistically significant difference (P>0.05) between the 2 groups in the following areas: the Japanese Orthopedic Association scores, C2-C7 Cobb angle, cervical CI, and ROM. In addition, operative duration and intraoperative bleeding volume between A group and B group showed no significant differences (P>0.05). After surgery, 51 patients (67.1%) in group A had AS, 8 patients (10.4%) had C5 palsy, and 1 patient had mild cervical kyphosis. Whereas postoperatively group B contained 37 cases (10.5%) with AS, 3 (2.4%) with C5 palsy, and in 4 cases (3.28%) the lamina open-door had reclosed. The rate of patients with AS and C5 palsy in group A was higher than group B. The incidence of postoperative complications between the 2 groups have a significant difference (P<0.05). The rate of improvement of Japanese Orthopedic Association scores in last follow-up between group A and group B did not reach statistical significance (P>0.05). At the 1-month follow-up the range of the value of spinal cord backward shift was 0 7.95 mm with the average being 2.41+/-0.46 mm. C2-C7 Cobb angle, CI, and ROM between the 2 groups revealed no statistical significance (P>0.05). ROM comparisons preoperatively and postoperatively between the 2 groups were significantly different (P<0.05). CONCLUSIONS: In different angles of lamina open door, the improvement rate of neurological function after surgery had no statistically significant difference between 2 groups. When the open-door angle is maintained between 15 and 30 degrees, it can reduce the incidence of C5 palsy in the hinge side and AS, but we should prevent reclosure of the lamina open door. PMID- 22832552 TI - Long-term sequelae of patients with retained drains in spine surgery. AB - STUDY DESIGN: Case series. OBJECTIVE: To assess sequelae of retained surgical drains in patients undergoing spine surgery. SUMMARY OF BACKGROUND DATA: Although a rare event, surgical drains may break either before or during removal attempts. In cases of retained surgical drains, the patient and surgeon are left with a decision of either surgically removing the drain fragment, or leaving it in situ. There is a paucity of literature that pertains to this unusual complication of spine surgery and its effect on long-term outcome. METHODS: Cases of retained drain fragments that occurred at the spine service of a single institution between January 1, 1990 and December 31, 2008 were identified using the institutional electronic billing system, International Classification of Diseases and Related Health Problems-9 codes, and surgeons' records. RESULTS: Seven cases of retained drains were identified to have occurred during the study period. Five of the patients underwent a subsequent operation for drain removal without complications, whereas 2 patients elected to leave the drain in situ. At a minimum of 2-year follow-up, neither of the patients in which the drain fragment had been left in situ reported complications or sequelae related to the drain fragment, and radiographic imaging showed no distinct migration of the fragment within the soft tissue. CONCLUSIONS: The 2 reported cases with a retained drain fragment left in situ support published and anecdotal opinions on retained soft tissue drains not adversely affecting long-term patient outcome. In cases of asymptomatic patients with retained drains within soft tissue, leaving the fragment in situ is a treatment option that deserves consideration. PMID- 22832553 TI - Inflammatory cytokines induce fibrosis and ossification of human ligamentum flavum cells. AB - STUDY DESIGN: In vitro experiment using degenerated human ligamentum flavum (LF) and various inflammatory cytokines. OBJECTIVES: To examine the effect of inflammatory cytokines on LF cells and to identify their roles in the pathogenesis of LF hypertrophy and ossification. SUMMARY OF BACKGROUND DATA: Spinal stenosis is caused, in part, by hypertrophy and ossification of the LF, which are induced by the degenerative processes (ie, increased collagen synthesis and chondroid metaplasia) of ligament fibroblasts. Degenerated intervertebral disk spontaneously produces inflammatory cytokines, which might affect the adjacent LF through local milieu of the spinal canal. METHODS: The interlaminar portion of the LF was collected during surgical spinal procedures in 15 patients (age range, 49-78 y) with lumbar spinal stenosis. LF fibroblasts were isolated by enzymatic digestion of LF tissue. LF cell cultures were treated with various inflammatory cytokines: interleukin (IL)-1alpha, IL-6, tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), and nitric oxide (NO). Cytotoxicity was analyzed by MTT assays. DNA synthesis was measured with H-thymidine incorporation, and mRNA expression of types I, III, V, and XI collagen and osteocalcin were performed by reverse transcription-polymerase chain reaction. Histochemical stains such as Von Kossa were also performed to detect bone nodule formation. RESULTS: There was no cytotoxicity in the LF cells treated with each cytokine. There were significant increases in DNA synthesis and upregulated mRNA expression of types I, V, XI collagen and osteocalcin in LF cultures treated with various cytokines. LF cultures treated with IL-6, TNF-alpha, PGE2, and NO showed positive Von Kossa staining, indicating bone nodule formation from LF cells. CONCLUSIONS: Inflammatory cytokines (IL-6, TNF-alpha, PGE2, and NO) seem to play a crucial role in hypertrophy and ossification of LF. Degenerated, herniated intervertebral disks, and facet arthrosis may influence LF through inflammatory cytokines and cause hypertrophy and ossification of LF. PMID- 22832554 TI - Bacteriology of degenerated lumbar intervertebral disks. AB - STUDY DESIGN: A prospective microbiological analysis of intervertebral disk material in surgically treated patients presenting lumbar disk degeneration. OBJECTIVE: To determine the prevalence and species of bacteria in degenerated lumbar disks, their eventual role in the pathophysiology, and the possible influence of risk factors. SUMMARY OF BACKGROUND DATA: Intervertebral disk degeneration results from biochemical, mechanical, genetic, and toxic factors. The hypothesis of low-grade infection has been raised but not elucidated to date. METHODS: Eighty-three patients (34 males, 49 females, 41 y) were treated by lumbar disk replacement at L3-L4, L4-L5, or L5-S1. An intraoperative biopsy and microbiological culture were performed for each disk to determine if intradiskal bacteria were present. Magnetic resonance stages were Pfirrmann IV or V, with Modic I in 32, and Modic II in 25 cases. A preoperative discography was performed in 49 patients, 24 had previous nucleotomy. RESULTS: Bacteria were found in 40 disks, 43 cultures were sterile. The following bacteria were evidenced: Propionibacterium acnes 18, coagulase-negative staphylococci 16, gram-negative bacilli 3, Micrococcus 3, Corynebacterium 3, others 5. Ten biopsies presented 2 different species. Multinucleated cells were evidenced histologically in 33% of positive biopsies. Bacteria were predominantly found in males (P=0.012). The mostly positive level was L4-L5 (P=0.075). There was no significant relationship between bacterial evidence and Modic sign. A preoperative discography or previous nucleotomy did not represent significant contamination sources. None of the patients presented infectious symptoms. CONCLUSIONS: Although the hypothesis of biopsy contamination cannot be excluded, intradiskal bacteria might play a role in the pathophysiology of disk degeneration. However, the histologic presence of multinucleated cells may indicate an inflammatory process that could sustain the hypothesis of low-grade spondylodiscitis at 1 stage of the cascade of lumbar disk degeneration. These microbiological and histologic findings would need to be compared with nondegenerated disks. LEVEL OF EVIDENCE: : Diagnostic level III. PMID- 22832555 TI - Cervical Disk Replacement Combined With Cage Fusion for the Treatment of Multilevel Cervical Disk Herniation. AB - STUDY DESIGN: This is a prospective study of artificial disk replacement combined with cage fusion for the treatment of multilevel cervical disk herniation. OBJECTIVE: To evaluate the clinical outcome of Bryan cervical disk replacement combined with adjacent segment cage fusion in the treatment of patients with multilevel cervical disk herniation. To observe neurological improvement and interpret the radiographic findings. SUMMARY OF BACKGROUND DATA: It is generally considered that 1-level cervical disk replacement had an excellent intermediate clinical outcome. There was no final conclusion about the disk replacement for the treatment of multilevel cervical disk disease. The negative factors include possible complication, high cost, and contraindication for disk replacement at one of the multisegments. Disk replacement combined with adjacent segment cage fusion may be an option for the treatment of multilevel cervical disk disease for certain patients. METHODS: There were 26 patients with multilevel cervical disk herniation who underwent 1-level disk replacement and adjacent segment cage fusion. Of the patients, there were 17 male and 9 female, aged between 35 and 63 (mean age 47 y). The herniated disk was located at C3-C4, C4-C5 in 1 case, C4-C5, C5-C6 in 11cases, C5-C6, C6-C7 in 7 cases, C4-C5, C6-C7 in 3 cases, and C4-C5, C5 C6, C6-C7 in 4 cases. There were 12 cases with myelopathy and 14 patients with radiculopathy. The stabilization and the range of motion of implanted disk, the fusion of cage, and the displacement of cage were observed on dynamic radiograph postoperatively. The clinical symptoms and the neurological functions were evaluated based on the Japanese Orthopaedic Association Scale score (17 points), neck disability index score, and Odom's Criteria. RESULTS: All patients underwent 1-level Bryan disk replacement and cage fusion on adjacent segment. The replacement segment and fusion segment were located next to each other among 23 patients. They were not next to each other in 3 cases. The follow-up was 24 to 47 months. Definite stabilization was achieved for all Bryan disks. The average range of motion at replaced level was 9.5 degrees postoperatively. Solid fusion was achieved in all cages. There was no subsidence or displacement of cage. The Japanese Orthopaedic Association Scale score (17 points) rose from 9.2 to 13.5 at final follow-up. The neck disability index was reduced from 40.8 to 28.5 at final follow-up. The clinical success (excellent/good/fair) based on Odom's Criteria were 84.6%. CONCLUSIONS: Definite stabilization and satisfactory mobility were achieved after cervical disk replacement and cage fusion. This provides an effective option for the treatment of multilevel cervical disk herniation. The evaluation of high fusion rate of cage may need to accumulate more clinical cases. PMID- 22832556 TI - Lumbar facet joint effusion on MRI as a sign of unstable degenerative spondylolisthesis: should it influence the treatment decision? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To examine whether the outcomes of decompression alone (D) or decompression with fusion (D&F) differed depending on the presence or absence of the facet effusion sign in degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: There is ongoing discussion as to whether D&F is superior to D in the surgical treatment of patients with lumbar degenerative spondylolisthesis (LDS) and symptoms of spinal or radicular claudication. Previous studies have shown that a positive facet joint effusion sign on magnetic resonance imaging correlates with the spontaneous reduction of slip when comparing upright and supine postures and might represent a sign of instability, guiding treatment decisions. PATIENTS AND METHODS: One hundred sixty patients [age 69 (SD 10) y; 119 women, 41 men] with a diagnosis of LDS were identified retrospectively from our Spine Center Registry (linked to the Eurospine, Spine Society of Europe Spine Tango Registry). They were categorized based on the presence/absence of the facet effusion sign and the type of treatment received. Forty-four patients had effusion and underwent D; 76 effusion and D&F; 19 no effusion and D; and 21 no effusion and D&F. Before surgery and 3, 12, and 24 months after surgery, patients completed the multidimensional Core Outcome Measures Index questionnaire. At follow-up, they rated the global treatment outcomes (1-5 scale). Multiple regression analyses evaluated the factors influencing the outcomes. RESULTS: When age and sex was controlled for, there was no significant difference in outcomes dependent on the presence of the facet effusion sign and/or the treatment received (D vs. D&F). CONCLUSIONS: Although mindful of the limitations of this retrospective study, we conclude that the effusion sign alone does not seem to be an indication for adding fusion to decompression in the treatment of LDS. Hence, the presence of the facet effusion sign should not, in itself, deter the surgeon from performing decompression alone. However, the phenomenon should be investigated in larger samples of patients, ideally within a randomized trial. PMID- 22832557 TI - Minimally invasive transpsoas L2 corpectomy and percutaneous pedicle screw fixation for osteoporotic burst fracture in the elderly: a technical report. AB - BACKGROUND AND IMPORTANCE: Osteoporotic vertebral burst fractures are an increasingly common cause of pain and severe functional disability in the elderly. Although anterior-posterior surgical stabilization offers an efficacious and durable treatment, the associated high blood loss, long durations of surgery, and prolonged hospitalization are often not tolerable for elderly patients, who are most often medically frail with multiple comorbidities. CLINICAL PRESENTATION: We report a case of an L2 osteoporotic burst fracture in an elderly patient with significant comorbidities treated with a minimally invasive tubular direct lateral transpsoas approach for L2 vertebrectomy and anterior cage placement. The construct was supplemented by a percutaneous pedicle screw construct and adjacent level vertebroplasty. Duration of surgery was 3.5 hours with a total of 35 mL blood loss. The patient was discharged ambulating 36 hours after surgery and reported marked improvement in pain, disability, and quality of life measures at 6 weeks postoperatively. CONCLUSIONS: L2 vertebrectomy by direct lateral transpsoas tube systems supplemented by percutaneous pedicle screws can be performed safely and may allow for anterior column decompression and reconstruction in elderly or comorbid patients not otherwise able to tolerate traditional stabilization procedures. PMID- 22832558 TI - Would CoCr rods provide better correctional forces than stainless steel or titanium for rigid scoliosis curves? AB - STUDY DESIGN: Comparative in vitro, biomechanical study. OBJECTIVE: Compare the effect of rod curvature and material properties on rod flattening and correctional forces. SUMMARY OF BACKGROUND DATA: Traditional methods of correction for large progressive deformities involve 3-dimensional correction, performed with an attempt to reach a balanced correction in all planes, spinal instrumentation, and fusion. Increasing attention to the transverse plane correction has developed after the introduction of segmental pedicle screws into the treatment of idiopathic scoliosis. Approximation of the spine (pedicle screws or hooks) to the rods remains the heart of many deformity procedures. Therefore, it is crucial that the instrumentation used provide and maintain the initial correction of the spinal deformity while minimizing potential intraoperative failures. METHODS: Two experiments were performed using 80 rods made from 4 different materials namely: stainless steel (SS), titanium (Ti), cobalt chromium (CoCr), and ultrahigh strength stainless steel (UHSS). Half of the rods were contoured to 20 degrees, whereas the reaming contoured to 30 degrees. Half of the rods were approximated to a synthetic spine models to measure the flattening of the rods when approximated to highly rigid spine. The other half was used to measure the correctional forces produced by each rod type and curvature. RESULTS: For the 20-degree pre-bend rods, Ti was the best in maintaining its original shape followed by UHSS, SS, and CoCr of 90%, 77%, 62.5%, and 54.4%, respectively. The 30-degree pre-bend showed exactly a similar trend with 80.7% for Ti, 71% for UHSS, 54.6% for SS, and 48.1% for the CoCr rods. For 30-degree pre-bend CoCr and UHSS rods, the intraoperative reduction forces were almost 42% and 10% higher than the Ti and SS rods, respectively. The correctional force produced by the Ti 30-degree pre-bend rod was approximately 67% that of a CoCr and UHSS rods. CONCLUSIONS: CoCr and UHSS rods have the ability to produce the highest correction forces, however, both can plastically deform in a very rigid curves. Therefore, it is critical to have sense of the quality of the bone fixation as well as the curve flexibility when selecting for appropriate rod size material and contouring the rod to the desired shape. PMID- 22832559 TI - Clinical and radiographic analysis of c5 palsy after anterior cervical decompression and fusion for cervical degenerative disease. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: To present the cases of 6 patients who developed C5 palsy after anterior decompression and discuss the mechanism of C5 palsy development, especially with respect to radiographic change. SUMMARY OF BACKGROUND DATA: C5 palsy has been reported to be a major complication of both anterior and posterior decompression procedures. Although several mechanisms of injury have been proposed, few reports have been issued on C5 palsy after anterior decompression surgery. METHODS: A retrospective medical record review was performed on 134 patients who underwent anterior decompression and fusion in our hospital from 2008 to 2011. C5 paralysis was defined as deterioration in muscle power of the deltoid or biceps brachii by at least 1 grade by manual muscle testing. Clinical features and radiologic parameters were evaluated to identify predisposing factors. RESULTS: Six patients (4.3%) suffered postoperative paralysis in the upper extremities (C5 radiculopathy). C5 palsy did not occur in 30 patients with radiculopathy. Excluding patients with cervical radiculopathy, the rate of C5 palsies was 5.8% for myelopathy patients. Three of 76 (3.95'%) cervical spondylotic myelopathy cases, one of 6 (16.7%) cervical spondylotic radiculomyelopathy patients, and 2 of 22 (9%) patients with ossification of the posterior longitudinal ligament showed C5 palsy. In 2 of the 6, C5 palsy developed after anterior cervical corpectomy, in 3 patients after anterior cervical discectomy and plate fusion, and in 1 after a standalone cage. Two patients underwent reoperation for foraminal decompression. Of the 4 treated conservatively, 3 fully recovered and the other almost fully improved (grade 4). Of 2 patients treated surgically, 1 showed full improvements. The other had no improvement. Radiographic measurements of these 6 patients showed that lordosis at operated segments increased postoperatively (mean, 6 degrees), and that overall sagittal alignments of the cervical spine (C3-C7) also increased (mean, 8.2 degrees). CONCLUSIONS: This study suggests that improved lordosis of the cervical spinal column can result in traction injury to the spinal cord and C5 nerve roots and that reoperation does not always produce good results. Methods of preventing and treating C5 palsy after anterior decompression and fusion require more evaluation. PMID- 22832560 TI - Temporary endobronchial embolization with silicone spigots for moderate hemoptysis: a retrospective study. AB - BACKGROUND: The management of airway bleeding is generally performed in an emergency to prevent hypoxemia and lung flooding. When the bleeding arises from peripheral lesions that are not visible endoscopically, bronchoscopic options have limited curative intents. Endobronchial embolization using silicone spigots (EESS) is a novel approach. OBJECTIVES: We analyzed the efficacy and safety of EESS in a retrospective study. METHODS: We retrospectively reviewed charts of patients referred to our center for moderate hemoptysis (MH) who underwent EESS. Successful management is defined as immediate bleeding cessation. RESULTS: From December 2008 to January 2012, 9 patients were treated with EESS in our endoscopy unit. The MH originated from the left upper lobe in 4 cases, the right upper lobe in 3 cases and the right middle lobe and left lower lobe in 1 case each. Thirteen spigots were inserted. The success rate was 78%. Of the 9 patients, 7 were referred to interventional radiology for bronchial artery embolization, with a success rate of 86%, and 2 were referred for thoracic surgery. One patient had EESS as definitive treatment; the silicone spigots were bronchoscopically removed after a median of 4 days in 6 of the remaining 8 patients. Only 2 patients had hemoptysis recurrence after a median follow-up of 107 days (ranging from 13 to 1,017 days). None of the patients died from hemoptysis. CONCLUSION: EESS is an original, temporary technique that requires only a flexible bronchoscope and biopsy forceps for placement and removal. EESS ensures airway protection while waiting for definitive management. PMID- 22832561 TI - Cilostazol-based triple antiplatelet therapy compared to dual antiplatelet therapy in patients with coronary stent implantation: a meta-analysis of 5,821 patients. AB - BACKGROUND: Uncertainties still remain in terms of what kinds of patients benefit most from cilostazol-based triple antiplatelet therapy (TAT) after coronary stenting. METHODS: We performed a meta-analysis of all relevant randomized controlled trials (RCTs) to investigate the effect of TAT versus dual antiplatelet therapy (DAT) in terms of major adverse cardiovascular events (MACEs) in patients undergoing coronary stenting. RESULTS: Fourteen RCTs with 5,821 patients were included in this study. TAT was associated with a significant reduction in the risk of MACEs compared to DAT [9.2 vs. 13.4%; odds ratio 0.59 (0.46, 0.76)] with consistent benefits among patients with diabetes, long lesions and small vessels. There were no significant between-group differences in the risk of cardiac death, myocardial infarction, stent thrombosis and bleeding events; however, the risk of target lesion revascularization was significantly lower in the TAT group. TAT resulted in borderline significant reduction in the risk of cardiovascular thrombotic events in unselected patients and significant decrease in patients with acute coronary syndrome [odds ratio 0.51 (0.27, 0.94)]. CONCLUSION: Under the treatment of standard DAT, the addition of cilostazol is an effective and relatively safe strategy in preventing MACEs after coronary stenting, especially for patients at high risk of restenosis or clinical events. PMID- 22832562 TI - Different spatial frequency bands selectively signal for natural image statistics in the early visual system. AB - Early visual evoked potentials (VEPs) measured in humans have recently been observed to be modulated by the image statistics of natural scene imagery. Specifically, the early VEP is dominated by a strong positivity when participants view minimally complex natural scene imagery, with the magnitude of that component being modulated by luminance contrast differences across spatial frequency (i.e., the slope of the amplitude spectrum). For scenes high in structural complexity, the early VEP is dominated by a prominent negativity that exhibits little dependency on luminance contrast. However, since natural scene imagery is broad band in terms of spatial frequency, it is not known whether the above-mentioned modulation results from a complex interaction within or between the early neural processes tuned to different bands of spatial frequency. Here, we sought to address this question by measuring early VEPs (specifically, the C1, P1, and N1 components) while human participants viewed natural scene imagery that was filtered to contain specific bands of spatial frequency information. The results show that the C1 component is largely unmodulated by the luminance statistics of natural scene imagery (being only measurable when such stimuli were made to contain high spatial frequencies). The P1 and N1, on the other hand, were observed to exhibit strong spatial frequency-dependent modulation to the luminance statistics of natural scene imagery. The results therefore suggest that the dependency of early VEPs on natural image statistics results from an interaction between the early neural processes tuned to different bands of spatial frequency. PMID- 22832563 TI - External urethral sphincter motor unit recruitment patterns during micturition in the spinally intact and transected adult rat. AB - In the rat, external urethral sphincter (EUS) activation during micturition consists of three sequential phases: 1) an increase in tonic EUS activity during passive filling and active contraction of the bladder (guarding reflex), 2) synchronized phasic activity (EUS bursting) associated with voiding, and 3) sustained tonic EUS activity that persists after bladder contraction. These phases are perturbed following spinal cord injury. The purpose of the present study was to characterize individual EUS motor unit (MU) patterns during micturition in the spinally intact and transected adult rat. EUS MU activity was recorded from either the L5 or L6 ventral root (intact) or EUS muscle (transected) during continuous flow cystometry in urethane-anesthetized adult female Sprague-Dawley rats. With the use of bladder pressure threshold and timing of activation, four distinct patterns of EUS MU activity were identified in the intact rat: low threshold sustained, medium/high threshold sustained, medium/high threshold not sustained, and burst only. In general, these MUs displayed little frequency modulation during active contraction, generated high-frequency bursts of action potentials during EUS bursting, and varied in terms of the duration of sustained tonic activity. In contrast, three general patterns of EUS MU activity were identified in the transected rat: low threshold, medium threshold, and high threshold. These MUs exhibited considerable frequency modulation during active contraction of the bladder, no bursting behavior and little to no sustained firing. The prominent frequency modulation of EUS MUs is likely due to the enhanced guarding reflex seen in EUS whole muscle electromyogram recordings in transected rats (D'Amico SC, Schuster IP, Collins WF 3rd. Exp Neurol 228: 59-68, 2011). In addition, EUS MU recruitment in transected rats more closely followed predictions by the size principle than in intact rats. This may reflect the influence of local synaptic circuits or intrinsic properties of EUS motoneurons that are active in intact rats but attenuated or absent in transected rats. PMID- 22832564 TI - Postnatal emergence of serotonin-induced plateau potentials in commissural interneurons of the mouse spinal cord. AB - Most studies of the mouse hindlimb locomotor network have used neonatal (P0-5) mice. In this study, we examine the postnatal development of intrinsic properties and serotonergic modulation of intersegmental commissural interneurons (CINs) from the neonatal period (P0-3) to the time the animals bear weight (P8-10) and begin to show adult walking (P14-16). CINs show an increase in excitability with age, associated with a decrease in action potential halfwidth and appearance of a fast component to the afterhyperpolarization at P14-16. Serotonin (5-HT) depolarizes and increases the excitability of most CINs at all ages. The major developmental difference is that serotonin can induce plateau potential capability in P14-16 CINs, but not at younger ages. These plateau potentials are abolished by nifedipine, suggesting that they are mediated by an L-type calcium current, I(Ca(L)). Voltage-clamp analysis demonstrates that 5-HT increases a nifedipine-sensitive voltage-activated calcium current, I(Ca(V)), in P14-16 CINs but does not increase I(Ca(V)) in P8-10 CINs. These results, together with earlier work on 5-HT effects on neonatal CINs, suggest that 5-HT increases the excitability of CINs at all ages studied, but by opposite effects on calcium currents, decreasing N- and P/Q-type calcium currents and, indirectly, calcium activated potassium current, at P0-3 but increasing I(Ca(L)) at P14-16. PMID- 22832565 TI - Biomechanical constraints on the feedforward regulation of endpoint stiffness. AB - Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed. PMID- 22832567 TI - Self-motion leads to mandatory cue fusion across sensory modalities. AB - When perceiving properties of the world, we effortlessly combine multiple sensory cues into optimal estimates. Estimates derived from the individual cues are generally retained once the multisensory estimate is produced and discarded only if the cues stem from the same sensory modality (i.e., mandatory fusion). Does multisensory integration differ in that respect when the object of perception is one's own body, rather than an external variable? We quantified how humans combine visual and vestibular information for perceiving own-body rotations and specifically tested whether such idiothetic cues are subjected to mandatory fusion. Participants made extensive size comparisons between successive whole body rotations using only visual, only vestibular, and both senses together. Probabilistic descriptions of the subjects' perceptual estimates were compared with a Bayes-optimal integration model. Similarity between model predictions and experimental data echoed a statistically optimal mechanism of multisensory integration. Most importantly, size discrimination data for rotations composed of both stimuli was best accounted for by a model in which only the bimodal estimator is accessible for perceptual judgments as opposed to an independent or additive use of all three estimators (visual, vestibular, and bimodal). Indeed, subjects' thresholds for detecting two multisensory rotations as different from one another were, in pertinent cases, larger than those measured using either single-cue estimate alone. Rotations different in terms of the individual visual and vestibular inputs but quasi-identical in terms of the integrated bimodal estimate became perceptual metamers. This reveals an exceptional case of mandatory fusion of cues stemming from two different sensory modalities. PMID- 22832566 TI - The organization of the human striatum estimated by intrinsic functional connectivity. AB - The striatum is connected to the cerebral cortex through multiple anatomical loops that process sensory, limbic, and heteromodal information. Tract-tracing studies in the monkey reveal that these corticostriatal connections form stereotyped patterns in the striatum. Here the organization of the striatum was explored in the human with resting-state functional connectivity MRI (fcMRI). Data from 1,000 subjects were registered with nonlinear deformation of the striatum in combination with surface-based alignment of the cerebral cortex. fcMRI maps derived from seed regions placed in the foot and tongue representations of the motor cortex yielded the expected inverted somatotopy in the putamen. fcMRI maps derived from the supplementary motor area were located medially to the primary motor representation, also consistent with anatomical studies. The topography of the complete striatum was estimated and replicated by assigning each voxel in the striatum to its most strongly correlated cortical network in two independent groups of 500 subjects. The results revealed at least five cortical zones in the striatum linked to sensorimotor, premotor, limbic, and two association networks with a topography globally consistent with monkey anatomical studies. The majority of the human striatum was coupled to cortical association networks. Examining these association networks further revealed details that fractionated the five major networks. The resulting estimates of striatal organization provide a reference for exploring how the striatum contributes to processing motor, limbic, and heteromodal information through multiple large-scale corticostriatal circuits. PMID- 22832568 TI - Learning about gravity: segmental assessment of upright control as infants develop independent sitting. AB - The question of how infants attain upright sitting is at the core of understanding the development of most functional abilities. Our simple, practical method of securing the hips and different trunk segments while evaluating the infant's ability to vertically align and stabilize the trunk in space contributes a useful method and new insights into the development of upright control. Previous studies have considered the trunk to develop as a single segment. The goal of the present study was to examine how postural control changes across multiple trunk segments during typical development (TD) of sitting balance. For this purpose, electromyography (EMG) and kinematic data were collected at four levels of trunk support (axillae, midribs, waist, hips), in a longitudinal study of eight TD infants (3-9 mo of age). We found that developmental changes in stability were specific to the region of the trunk being investigated, changes in antagonistic muscle activity differed for the anterior-posterior versus the medial-lateral axis, and the relationship between muscle activation and movement changed from erratic attempts to gain upright position to anticipatory graded responses as infants developed upright control through a four-stage behavioral process. This information can be used by researchers to further refine hypotheses regarding this developmental process and by clinicians who wish to develop and test more specific treatment programs for children with postural dysfunction. PMID- 22832570 TI - Molecular identity, ontogeny, and cAMP modulation of the hyperpolarization activated current in vestibular ganglion neurons. AB - Properties, developmental regulation, and cAMP modulation of the hyperpolarization-activated current (I(h)) were investigated by the whole cell patch-clamp technique in vestibular ganglion neurons of the rat at two postnatal stages (P7-10 and P25-28). In addition, by RT-PCR and immunohistochemistry the identity and distribution of hyperpolarization-activated and cyclic nucleotide gated channel (HCN) isoforms that generate I(h) were investigated. I(h) current density was larger in P25-28 than P7-10 rats, increasing 410% for small cells (<30 pF) and 200% for larger cells (>30 pF). The half-maximum activation voltage (V(1/2)) of I(h) was -102 mV in P7-10 rats and in P25-28 rats shifted 7 mV toward positive voltages. At both ages, intracellular cAMP increased I(h) current density, decreased its activation time constant (tau), and resulted in a rightward shift of V(1/2) by 9 mV. Perfusion of 8-BrcAMP increased I(h) amplitude and speed up its activation kinetics. I(h) was blocked by Cs(+), zatebradine, and ZD7288. As expected, these drugs also reduced the voltage sag caused with hyperpolarizing pulses and prevented the postpulse action potential generation without changes in the resting potential. RT-PCR analysis showed that HCN1 and HCN2 subunits were predominantly amplified in vestibular ganglia and end organs and HCN3 and HCN4 to a lesser extent. Immunohistochemistry showed that the four HCN subunits were differentially expressed (HCN1 > HCN2 > HCN3 >= HCN4) in ganglion slices and in cultured neurons at both P7-10 and P25-28 stages. Developmental changes shifted V(1/2) of I(h) closer to the resting membrane potential, increasing its functional role. Modulation of I(h) by cAMP-mediated signaling pathway constitutes a potentially relevant control mechanism for the modulation of afferent neuron discharge. PMID- 22832569 TI - Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons. AB - Previous work demonstrated that hyperthermia (43 degrees C for 2 h) results in delayed, apoptotic-like death in striatal neuronal cultures. We investigated early changes in mitochondrial function induced by this heat stress. Partial depolarization of the mitochondrial membrane potential (DeltaPsi(m)) began about 1 h after the onset of hyperthermia and increased as the stress continued. When the heat stress ended, there was a partial recovery of DeltaPsi(m), followed hours later by a progressive, irreversible depolarization of DeltaPsi(m). During the heat stress, O(2) consumption initially increased but after 20-30 min began a progressive, irreversible decline to about one-half the initial rate by the end of the stress. The percentage of oligomycin-insensitive respiration increased during the heat stress, suggesting an increased mitochondrial leak conductance. Analysis using inhibitors and substrates for specific respiratory chain complexes indicated hyperthermia-induced dysfunction at or upstream of complex I. ATP levels remained near normal for ~4 h after the heat stress. Mitochondrial movement along neurites was markedly slowed during and just after the heat stress. The early, persisting mitochondrial dysfunction described here likely contributes to the later (>10 h) caspase activation and neuronal death produced by this heat stress. Consistent with this idea, proton carrier-induced DeltaPsi(m) depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress DeltaPsi(m) depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL. PMID- 22832572 TI - Active movement restores veridical event-timing after tactile adaptation. AB - Growing evidence suggests that time in the subsecond range is tightly linked to sensory processing. Event-time can be distorted by sensory adaptation, and many temporal illusions can accompany action execution. In this study, we show that adaptation to tactile motion causes a strong contraction of the apparent duration of tactile stimuli. However, when subjects make a voluntary motor act before judging the duration, it annuls the adaptation-induced temporal distortion, reestablishing veridical event-time. The movement needs to be performed actively by the subject: passive movement of similar magnitude and dynamics has no effect on adaptation, showing that it is the motor commands themselves, rather than reafferent signals from body movement, which reset the adaptation for tactile duration. No other concomitant perceptual changes were reported (such as apparent speed or enhanced temporal discrimination), ruling out a generalized effect of body movement on somatosensory processing. We suggest that active movement resets timing mechanisms in preparation for the new scenario that the movement will cause, eliminating inappropriate biases in perceived time. Our brain seems to utilize the intention-to-move signals to retune its perceptual machinery appropriately, to prepare to extract new temporal information. PMID- 22832571 TI - Sweet-bitter and umami-bitter taste interactions in single parabrachial neurons in C57BL/6J mice. AB - We investigated sweet-bitter and umami-bitter mixture taste interactions by presenting sucrose or umami stimuli mixed with quinine hydrochloride (QHCl) while recording single-unit activity of neurons in the parabrachial nucleus (PbN) of urethane-anesthetized C57BL/6J mice. A total of 70 taste-responsive neurons were classified according to which stimulus evoked the greatest net response (36 sucrose-best, 19 NaCl-best, 6 citric acid-best, and 9 QHCl-best). Although no neurons responded best to monopotassium glutamate (MPG) or inosine 5' monophosphate (IMP), the combination of these two stimuli evoked a synergistic response (i.e., response > 120% of the sum of the component responses) in all sucrose-best and some NaCl-best neurons (n = 43). Adding QHCl to sucrose or MPG + IMP resulted in suppression of the response (responses to mixture < responses to the more effective component) in 41 of 43 synergistic neurons. Neurons showing QHCl suppression were classified into two types: an "MS1" type (n = 27) with suppressed responses both to sucrose and MPG + IMP and an "MS2" type (n = 14) that showed suppressed responses only to sucrose. No neuron displayed suppressed responses to MPG or IMP alone. The suppression ratio (1 - mixture response/sucrose or MPG + IMP response) of sucrose and MPG + IMP in MS1 neurons had a weak positive correlation (r = 0.36). The pattern of reconstructed recording sites of neuron types suggested chemotopic organization in the PbN. Although a peripheral basis for QHCl suppression has been demonstrated, our results suggest that convergence in the PbN plays a role in shaping responses to taste mixtures. PMID- 22832573 TI - Intermittent stimulus presentation stabilizes neuronal responses in macaque area MT. AB - Repeated stimulation impacts neuronal responses. Here we show how response characteristics of sensory neurons in macaque visual cortex are influenced by the duration of the interruptions during intermittent stimulus presentation. Besides effects on response magnitude consistent with neuronal adaptation, the response variability was also systematically influenced. Spike rate variability in motion sensitive area MT decreased when interruption durations were systematically increased from 250 to 2,000 ms. Activity fluctuations between subsequent trials and Fano factors over full response sequences were both lower with longer interruptions, while spike timing patterns became more regular. These variability changes partially depended on the response magnitude, but another significant effect that was uncorrelated with adaptation-induced changes in response magnitude was also present. Reduced response variability was furthermore accompanied by changes in spike-field coherence, pointing to the possibility that reduced spiking variability results from interactions in the local cortical network. While neuronal response stabilization may be a general effect of repeated sensory stimulation, we discuss its potential link with the phenomenon of perceptual stabilization of ambiguous stimuli as a result of interrupted presentation. PMID- 22832575 TI - Anatomical left ventricular lead location and clinical outcome: not a one size fit all strategy. PMID- 22832574 TI - Circulating tumor-derived mutant mitochondrial DNA: a predictive biomarker of clinical prognosis in human squamous cell carcinoma. AB - While circulating tumor-derived molecules have been identified in a variety of malignant tumors, it is sometimes difficult to detect the molecular targets due to the lower serum concentration. We report that evaluation of circulating tumor derived mitochondrial DNA (mtDNA) seems to have novel efficiency for detecting tumoral micrometastasis. In murine xenografting human oral cancer cells, human mtDNAs could be quantitatively detected from multiple organs and blood samples whereas human nucleic DNAs could not. We also determined if this mtDNA blood test was relevant for patients with oral cancer with no histologic evidence of tumoral cells in their surgical margins. For this, mtDNA from normal and tumorous tissues and serum mtDNA obtained pre and postoperatively was examined at three different regions including the displacement loop, 12S-rRNA, and 16S-rRNA. All non recurring patients had significantly higher amounts of mutant mtDNAs in the tumoral tissues compared with the non-recurring group. More importantly, on the blood test with the cut-off point by receiver operating characteristic (ROC) curve analysis, while the vast majority of serum mtDNA samples obtained postoperatively in the recurring cases maintained significantly higher amounts of mutant mtDNAs, the non-recurring cases did not, and they showed good prognosis. This is the first report of this approach for managing patients after resection of oral tumors, and may have substantial diagnostic potential for other tumoral types. PMID- 22832576 TI - Current practice in out-of-hospital cardiac arrest management: a European heart rhythm association EP network survey. AB - AIMS: The purpose of this EP wire is to examine clinical practice in the field of out-of-hospital cardiac arrest (OHCA) management, with special focus on in hospital diagnostic and therapeutic strategies. METHODS AND RESULTS: Fifty-three European centres, all members of the EHRA-EP Research network, completed the questions of the survey. A dedicated strategy for OHCA management is active in 85% of the centres. Shockable tachyarrhythmias such as initial OHCA rhythm are reported in >70% of the patients in 64% of the centres. In-hospital therapeutic hypothermia was applied in >50% of the patients in 53% of the centres and in <50% in 47% of the centres. In the year 2011 90% of the centres performed >10 primary percutaneous coronary angioplasties (PCI) in OHCA patients. The survival rate, when the initial documented rhythm was shockable, was >30% in 42% of the centres, and conversely, was significantly lower when asystole or pulseless electrical activity was the initial rhythm. A favourable neurological recovery was reported in >50% of the patients in 13 (26%) centres and in 21-50% of the patients in 21 (44%). CONCLUSIONS: This EP wire survey demonstrates a favourable implementation in OHCA of an invasive management strategy, including coronary angiography/PCI and implantable cardioverter defibrillator therapy, while therapeutic hypothermia appears to be underused. PMID- 22832578 TI - Quantum optics: Strongly interacting photons. PMID- 22832579 TI - A transitional snake from the Late Cretaceous period of North America. AB - Snakes are the most diverse group of lizards, but their origins and early evolution remain poorly understood owing to a lack of transitional forms. Several major issues remain outstanding, such as whether snakes originated in a marine or terrestrial environment and how their unique feeding mechanism evolved. The Cretaceous Coniophis precedens was among the first Mesozoic snakes discovered, but until now only an isolated vertebra has been described and it has therefore been overlooked in discussions of snake evolution. Here we report on previously undescribed material from this ancient snake, including the maxilla, dentary and additional vertebrae. Coniophis is not an anilioid as previously thought a revised phylogenetic analysis of Ophidia shows that it instead represents the most primitive known snake. Accordingly, its morphology and ecology are critical to understanding snake evolution. Coniophis occurs in a continental floodplain environment, consistent with a terrestrial rather than a marine origin; furthermore, its small size and reduced neural spines indicate fossorial habits, suggesting that snakes evolved from burrowing lizards. The skull is intermediate between that of lizards and snakes. Hooked teeth and an intramandibular joint indicate that Coniophis fed on relatively large, soft-bodied prey. However, the maxilla is firmly united with the skull, indicating an akinetic rostrum. Coniophis therefore represents a transitional snake, combining a snake-like body and a lizard-like head. Subsequent to the evolution of a serpentine body and carnivory, snakes evolved a highly specialized, kinetic skull, which was followed by a major adaptive radiation in the Early Cretaceous period. This pattern suggests that the kinetic skull was a key innovation that permitted the diversification of snakes. PMID- 22832581 TI - Subgroup-specific structural variation across 1,000 medulloblastoma genomes. AB - Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappaB signalling in Group 4, suggest future avenues for rational, targeted therapy. PMID- 22832584 TI - Quantum nonlinear optics with single photons enabled by strongly interacting atoms. AB - The realization of strong nonlinear interactions between individual light quanta (photons) is a long-standing goal in optical science and engineering, being of both fundamental and technological significance. In conventional optical materials, the nonlinearity at light powers corresponding to single photons is negligibly weak. Here we demonstrate a medium that is nonlinear at the level of individual quanta, exhibiting strong absorption of photon pairs while remaining transparent to single photons. The quantum nonlinearity is obtained by coherently coupling slowly propagating photons to strongly interacting atomic Rydberg states in a cold, dense atomic gas. Our approach paves the way for quantum-by-quantum control of light fields, including single-photon switching, all-optical deterministic quantum logic and the realization of strongly correlated many-body states of light. PMID- 22832585 TI - Quality of life after traumatic injury: a latent trajectory modeling approach. AB - BACKGROUND: It is largely unknown how quality of life (QoL) changes following accidental injuries. Equally, the mechanisms underlying such changes have not yet been identified in detail. This study of injured accident survivors aimed to: (1) detect a model of change which best explains the observed course of QoL, and (2) identify potential predictor variables. METHODS: 323 injured accident survivors were interviewed within 2 weeks of the trauma, and followed up at 6 and 12 months. Latent trajectory modeling was used to analyze the fit of three potential trajectories regarding the observed course of general QoL as measured by the Questions on Life Satisfaction questionnaire. RESULTS: The trajectory model adopting a negative square-root change fitted the observed data best, meaning that shortly after the accident, general QoL decreased strongly with diminishing negative changes occurring later on. Early and prolonged QoL impairment was largely attributable to the initial level of posttraumatic stress as measured by the Clinician-Administered PTSD Scale. To a lesser extent, depressive symptoms also predicted change in subjective QoL, while injury severity showed no direct effect; rather, its impact on QoL was mediated by initial posttraumatic stress. By contrast, reduced occupational functioning was attributable to injury severity rather than psychopathology. CONCLUSIONS: When treating injured accident survivors, clinicians should consider symptoms of posttraumatic stress and comorbid depression in order to prevent or mitigate negative changes in QoL. PMID- 22832582 TI - Averting biodiversity collapse in tropical forest protected areas. AB - The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world's major tropical regions. Our analysis reveals great variation in reserve 'health': about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines. PMID- 22832586 TI - [Radiofrequency ablation in spinal osteoid osteoma. Options and limits]. AB - Osteoid osteoma was first described by Jaffe in 1935 as a benign bone neoplasm mainly located in the diaphyseal areas of long bones: 10% are located in the spine, mainly in the lumbar and thoracic posterior elements. Therapy is required due to nocturnal pain independent of the physical load and responds especially well to anti-inflammatory drugs due to the excessive production of prostaglandins in the nidus. Diagnosis is confirmed by multi-slice computed tomography (CT), magnetic resonance imaging (MRI) and skeletal scintigraphy scans. In cases with typical symptoms and imaging, open biopsies are rarely needed. Although CT-guided radiofrequency ablation is accepted as the gold standard treatment option for osteoid osteoma in the extremities, this technique is limited in spinal applications due to the risk of thermal damage to adjacent neurovascular structures. Technical advances in the administration of radiofrequency ablation have, however, resulted in new and expanded indications in the spine so that the necessity for open surgical excision of spinal osteoid osteoma is becoming less. PMID- 22832583 TI - Dissecting the genomic complexity underlying medulloblastoma. AB - Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients. PMID- 22832587 TI - Does increasing the nodal yield improve outcomes in patients without nodal metastasis at radical cystectomy? AB - PURPOSE: To determine whether the number of lymph nodes (LNs) examined is associated with outcomes in patients without nodal metastasis after radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively analyzed data from 4,188 patients treated at 12 centers with RC and pelvic lymphadenectomy without neo-adjuvant chemotherapy for urothelial carcinoma of the bladder (UCB). Outcomes of patients without LN metastasis (n = 3,088) were examined according to the LN yield analyzed as continuous variable, tertiles, and using the cutoffs of >= 9 and >= 20. RESULTS: The median nodal yield was 18 (range 1-123; IQR:20). A total of 2591 (84 %) and 1445 (47 %) patients had a LN yield >= 9 and >= 20, respectively. Median follow-up was 47 months (IQR:70). In multivariable analyses that adjusted for the standard clinicopathologic factors, higher LN yield was associated with a decreased risk of disease recurrence (continuous: HR = 0.996, p = 0.05; 3rd vs 1st tertile: HR = 0.853, p = 0.048; cutoff >= 20: HR = 0.851, p = 0.032). In the subgroups of patients with muscle-invasive UCB or those with >= 9 LN removed, LN yield was not associated with outcomes (p values >0.05). CONCLUSIONS: In this large multicenter cohort of patients with node-negative UCB, higher nodal yield improved recurrence-free survival when all patients were analyzed. Patients with a high LN yield (>= 20 LN removed or 3rd tertile) had the largest benefit. The lack of prognostic significance of LN yield in patients with muscle-invasive UCB or those stratified by 9 LNs removed suggests that this effect is weak. Further prospective studies are needed to help identify preoperatively the optimal template for each patient. PMID- 22832588 TI - Feasibility of radical cystectomy in exclusive spinal and/or epidural anaesthesia. AB - PURPOSE: Muscle invasive bladder cancer can be found predominantly in elderly people with a high likelihood of suffering from concomitant diseases; especially in these patients, the risks associated with general anaesthesia during radical cystectomy can be the limiting factor of performing an otherwise indicated radical operation. To overcome this limitation, we analysed the feasibility of performing radical cystectomy in exclusive spinal and/or epidural anaesthesia. METHODS: Between March and June 2010, nine patients underwent radical cystectomy in exclusive spinal and/or epidural anaesthesia. These patients were either not willing or unfit to undergo radical cystectomy in general anaesthesia. A continent urinary diversion (ileum neobladder) and an ileum-conduit were performed in five patients and four patients, respectively. The feasibility of radical cystectomy in regional anaesthesia was tested using a variety of parameters. RESULTS: All nine procedures could be performed under strict regional anaesthesia. Mean operation time was 206 min (range 146-265 min), mean intraoperative blood loss was 622 ml (range 200-1,500 ml), mean postoperative time at intermediate care was 1 day (range 0-3 days) and mean length of hospital stay was 21.8 days (range 17-26 days). Analgesics of the WHO class I, II and III were applied for 5.7, 1.2 and 2.8 days mean, respectively. CONCLUSION: Performance of radical cystectomy in exclusive spinal and/or epidural anaesthesia is feasible and can be considered particularly in those patients who would be otherwise unfit to undergo radical cystectomy in general anaesthesia. This new operative and anaesthesiological concept could also play an important role in new fast track regimens. PMID- 22832590 TI - Fasting hypoglycaemia and postprandial hyperglycaemia as a prodrome of type 1 diabetes mellitus. AB - The pathophysiology of type 1 diabetes mellitus (DM) involves the selective autoimmune destruction of the pancreatic beta-cells [Pihoker et al.: Diabetes 2005;54(suppl 2):S52-S61]. The onset of type 1 DM is characterised by hyperglycaemia. Islet cell antibody (ICA), anti-insulin, anti-glutamic acid decarboxylase and the antibody against tyrosine phosphatase-like protein known as ICA-512 (IA-2) usually appear before the clinical onset of DM and are markers of the autoimmune process. Hypoglycaemia in type 1 DM is a common complication and a result of the interaction between excess insulin administration and a compromised glucose counterregulatory hormonal response [Cryer: Endocrinol Metab Clin North Am 2010;39:641-654]. Spontaneous fasting hypoglycaemia alternating with hyperglycaemia prior to the onset of antibody-positive type 1 DM has not been described before. PMID- 22832589 TI - Standardization of isothermal microcalorimetry in urinary tract infection detection by using artificial urine. AB - PURPOSE: Isothermal microcalorimetry (IMC) has recently been reported as a new method to rapidly detect urinary tract pathogens (UTP). However, further application of microcalorimetry in the clinical setting requires a standardized procedure. An important step toward such standardization is to use a reproducible growth medium. In this study, we investigated the potential of artificial urine in combination with microcalorimetry for detection of common UTP. METHODS: A microcalorimeter equipped with 48 channels was used. Detection was accomplished, and growth was monitored for four bacterial strains in artificial urine at 37 degrees C by measuring metabolic heat flow (MUW = MUJ/s) as a function of time. The strains were Escherichia coli, Proteus mirabilis, Enterococcus faecalis, and Staphylococcus aureus. RESULT: Bacterial growth was detected after 3-32 h with decreasing inoculums down to 1 CFU. The gram-negative strains grew and were detected faster than their gram-positive counterparts. The growth rates the different strains were 0.75 +/- 0.11 for E. coli, 0.74 +/- 0.10 for E. faecalis, 1.31 +/- 0.04 for P. mirabilis, and 0.56 +/- 0.20 for S. aureus. The shape of individual heat flow curves was characteristic for each species independent of its initial concentration. CONCLUSIONS: IMC allows rapid detection of UTP in artificial urine. Clearly, different heat flow patterns enable accurate pathogen differentiation. UTP detection after only 4 h is realistic. The rapid detection of UTP tested in standardized artificial urine proves the diagnostic potential of IMC and warrants further microcalorimetric studies in the clinical setting of urinary tract infections. PMID- 22832591 TI - Doing the E-Delphi: using online survey tools. PMID- 22832592 TI - Observing the landscape, reading the tea leaves: hospitals and health information exchange. PMID- 22832594 TI - Unique and cross-reactive T cell epitope peptides of the major Bahia grass pollen allergen, Pas n 1. AB - BACKGROUND: Bahia grass pollen (BaGP) is a major cause of allergic rhinitis. Subcutaneous allergen-specific immunotherapy is effective for grass pollen allergy, but is unsuitable for patients with moderate to severe asthma due to the risk of anaphylaxis. T cell-reactive but IgE nonreactive peptides provide a safer treatment option. This study aimed to identify and characterize dominant CD4(+) T cell epitope peptides of the major BaGP allergen, Pas n 1. METHODS: Pas n 1 specific T cell lines generated from the peripheral blood of BaGP-allergic subjects were tested for proliferative and cytokine response to overlapping 20 mer Pas n 1 peptides. Cross-reactivity to homologous peptides from Lol p 1 and Cyn d 1 of Ryegrass and Bermuda grass pollen, respectively, was assessed using Pas n 1 peptide-specific T cell clones. MHC class II restriction of Pas n 1 peptide T cell recognition was determined by HLA blocking assays and peptide IgE reactivity tested by dot blotting. RESULTS: Three Pas n 1 peptides showed dominant T cell reactivity; 15 of 18 (83%) patients responded to one or more of these peptides. T cell clones specific for dominant Pas n 1 peptides showed evidence of species-specific T cell reactivity as well as cross-reactivity with other group 1 grass pollen allergens. The dominant Pas n 1 T cell epitope peptides showed HLA binding diversity and were non-IgE reactive. CONCLUSIONS: The immunodominant T cell-reactive Pas n 1 peptides are candidates for safe immunotherapy for individuals, including those with asthma, who are allergic to Bahia and possibly other grass pollens. PMID- 22832595 TI - Recognizing the translocation signals of individual peptide-oligonucleotide conjugates using an alpha-hemolysin nanopore. AB - Two peptide-oligonucleotide conjugates are studied using an alpha-hemolysin nanopore to investigate their structural properties at the single-molecule level. PMID- 22832596 TI - Immune stimulating photoactive hybrid nanoparticles for metastatic breast cancer. AB - A therapeutic technology that combines the phototoxic and immune-stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system can be very promising to treat metastatic breast cancer. We speculated that the knowledge of molecular mechanisms of existing multi-component therapies could provide clues to aid the discovery of new combinations of an immunostimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform. Therapeutic challenges when administering therapeutic combinations include the choice of dosages to reduce side effects, the definitive delivery of the correct drug ratio, and exposure to the targets of interest. These factors are very difficult to achieve when drugs are individually administered. By combining controlled release polymer-based NP drug delivery approaches, we were able to differentially deliver zinc phthalocyanine (ZnPc) based PS to metastatic breast cancer cells along with CpG-ODN, a single-stranded DNA that is a known immunostimulant to manage the distant tumors in a temporally regulated manner. We encapsulated ZnPc which is a long-wavelength absorbing PS within a polymeric NP core made up of poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b PEG). After coating the outside of the polymeric core with gold NPs (AuNPs), we further modified the AuNP surface with CpG-ODN. In vitro cytotoxicity using 4T1 metastatic mouse breast carcinoma cells shows significant photocytotoxicity of the hybrid NPs containing both ZnPc and CpG-ODN after irradiation with a 660 nm LASER light and this activity was remarkably better than either treatment alone. Treatment of mouse bone marrow derived dendritic cells with the PDT-killed 4T1 cell lysate shows that the combination of PDT with a synergistic immunostimulant in a single NP system results in significant immune response, which can be used for the treatment of metastatic cancer. PMID- 22832597 TI - Effects of xylitol on blood glucose, glucose tolerance, serum insulin and lipid profile in a type 2 diabetes model of rats. AB - BACKGROUND/AIMS: The present study was conducted to examine the antidiabetic effects of xylitol in a type 2 diabetes rat model. METHODS: Six-week-old male Sprague-Dawley rats were randomly divided into 3 groups: normal control (NC), diabetic control (DBC) and xylitol (XYL). Diabetes was induced only in the DBC and XYL animal groups by feeding them a 10% fructose solution for 2 weeks followed by an injection (i.p.) of streptozotocin (40 mg/kg body weight). One week after the streptozotocin injection, the animals with a nonfasting blood glucose level of >300 mg/dl were considered to be diabetic. The XYL group was fed further with a 10% xylitol solution, whereas the NC and DBC groups were supplied with normal drinking water. RESULTS: After 5 weeks of intervention, food and fluid intake, body weight, blood glucose, serum fructosamine and most of the serum lipids were significantly decreased, and serum insulin concentration and glucose tolerance ability was significantly increased in the XYL group compared to the DBC group. Liver weight, liver glycogen and serum triglycerides were not influenced by feeding with xylitol. CONCLUSION: The data of this study suggest that xylitol can be used not only as a sugar substitute but also as a supplement to antidiabetic food and other food products. PMID- 22832598 TI - [XIm][FeI(CO)3(SnI3)2] (XIm: EMIm, EHIm, PMIm) containing a barbell-shaped FeSn2 carbonyl complex. AB - By reacting Fe(CO)(5) and SnI(4) in the ionic liquids [XIm][NTf(2)] (XIm: 1-ethyl 3-methylimidazolium/EMIm, 1-ethyl-imidazolium/EHIm, 1-propyl-3 methylimidazolium/PMIm; NTf(2): bistrifluoridomethansulfonimide), the compounds [XIm][FeI(CO)(3)(SnI(3))(2)] are obtained as transparent, dark red crystals. According to single-crystal structure analysis, the title compounds crystallize monoclinically and contain the anionic carbonyl complex [FeI(CO)(3)(SnI(3))(2)]( ) as well as [EMIm](+), [EHIm](+) or [PMIm](+) cations. The anionic carbonyl is composed of a Sn-Fe-Sn barbell-shaped building unit with Fe-Sn distances of 252.0(1) pm. Herein, tin is coordinated distorted tetrahedrally by iodine; iron is coordinated pseudo-octahedrally by three carbonyl ligands, one iodine atom and two tin atoms. Bonding situation and valence state are investigated in detail for [EMIm][FeI(CO)(3)(SnI(3))(2)] based on bond-lengths considerations, infrared spectroscopy, Mossbauer spectroscopy, density functional theory and DFT-based Mulliken population analysis. Hence, the formal oxidation state of the metal atoms can be concluded to Fe(+/-0) and Sn(3+). PMID- 22832599 TI - Serial monitoring of soluble interleukin family member ST2 in patients with acutely decompensated heart failure. AB - OBJECTIVES: To determine whether serial measures of the interleukin receptor family member soluble ST2 (sST2) provide additional prognostic information to baseline measures for long-term risk stratification of acutely decompensated heart failure (ADHF) patients. METHODS: We prospectively enrolled 72 ADHF patients. Blood samples were collected to measure sST2 concentrations at presentation and on day 4 of hospitalization. All patients were clinically followed, and vital status was registered. RESULTS: Between presentation and day 4, sST2 concentrations decreased from 62 ng/ml (interquartile range 38-105) to 44 ng/ml (interquartile range 26-72; p < 0.001). Both sST2 concentrations at presentation [hazard ratio (HR) 1.011, 95% confidence interval (CI) 1.005-1.016; p < 0.001] and on day 4 (HR 1.015, 95% CI 1.005-1.024; p = 0.003) were independent predictors of mortality. Patients with sST2 <= 76 ng/ml at presentation and <= 46 ng/ml on day 4 had the lowest mortality rates (3%), whereas those with both sST2 values above these cutoff points had the highest mortality (50%). C index and reclassification analyses demonstrated that the use of serial sST2 measures resulted in an improvement in the accuracy of mortality prediction. CONCLUSIONS: Among ADHF patients, sST2 concentrations tend to decrease following initiation of treatment and are prognostic both at presentation and during hospitalization. Serial sampling of sST2 adds prognostic information and may provide a basis for enhanced clinical decision making. PMID- 22832600 TI - Effect of the 5-HT4 receptor and serotonin transporter on visceral hypersensitivity in rats. AB - Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT(4) receptor and the serotonin transporter (SERT) as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times) between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT(4) receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5 HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 +/- 0.038 vs 0.634 +/- 0.200, P < 0.05) and increased 5-HT(4) receptor expression (0.308 +/- 0.017 vs 0.298 +/- 0.021, P < 0.05). Treatment with fluoxetine (10 mg . kg(-1) . day(-1), days 36-42), tegaserod (1 mg . kg(-1) . day(-1), day 43), or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT(4) receptor expression (0.322 +/- 0.020 vs 0.308 +/- 0.017, P < 0.01) but not SERT expression (0.219 +/- 0.039 vs 0.298 +/- 0.038, P = 0.654). These results indicate that both the 5-HT(4) receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT level. PMID- 22832601 TI - The role of Ca2+/calmodulin-dependent protein kinase II and calcineurin in TNF alpha-induced myocardial hypertrophy. AB - We investigated whether Ca2+/calmodulin-dependent kinase II (CaMKII) and calcineurin (CaN) are involved in myocardial hypertrophy induced by tumor necrosis factor alpha (TNF-alpha). The cardiomyocytes of neonatal Wistar rats (1 2 days old) were cultured and stimulated by TNF-alpha (100 MUg/L), and Ca2+ signal transduction was blocked by several antagonists, including BAPTA (4 uM), KN-93 (0.2 uM) and cyclosporin A (CsA, 0.2 uM). Protein content, protein synthesis, cardiomyocyte volumes, [Ca2+]i transients, CaMKIIdeltaB and CaN were evaluated by the Lowry method, [3H]-leucine incorporation, a computerized image analysis system, a Till imaging system, and Western blot analysis, respectively. TNF-alpha induced a significant increase in protein content in a dose-dependent manner from 10 ug/L (53.56 ug protein/well) to 100 MUg/L (72.18 ug protein/well), and in a time-dependent manner from 12 h (37.42 ug protein/well) to 72 h (42.81 ug protein/well). TNF-alpha (100 MUg/L) significantly increased the amplitude of spontaneous [Ca2+]i transients, the total protein content, cell size, and [3H] leucine incorporation in cultured cardiomyocytes, which was abolished by 4 uM BAPTA, an intracellular Ca2+ chelator. The increases in protein content, cell size and [3H]-leucine incorporation were abolished by 0.2 uM KN-93 or 0.2 uM CsA. TNF-alpha increased the expression of CaMKIIdeltaB by 35.21% and that of CaN by 22.22% compared to control. These effects were abolished by 4 uM BAPTA, which itself had no effect. These results suggest that TNF-alpha induces increases in [Ca2+]i, CaMKIIdeltaB and CaN and promotes cardiac hypertrophy. Therefore, we hypothesize that the Ca2+/CaMKII- and CaN-dependent signaling pathways are involved in myocardial hypertrophy induced by TNF-alpha. PMID- 22832602 TI - Decreased cerebral blood flow in the limbic and prefrontal cortex using SPECT imaging in a cohort of completed suicides. AB - Suicide has a high comorbidity with impulsivity and depression, and finding imaging biomarkers indicative of patients at high risk for suicidal behavior is invaluable to the clinician. Using single-photon emission computed tomography (SPECT) imaging, we have previously reported regional cerebral blood flow (rCBF) decreases in the medial prefrontal cortex, ventral tegmental area and subgenual cingulate cortex (Brodmann area 25 (BA 25)), a region found to be hypoperfused with treatment-resistant depression. From 2007 to 2010, we have extended our analysis to include nine additional completed suicides. In all, 27 healthy, age- and gender-matched subjects from a previously acquired healthy brain study served as controls to our 21 completed suicides. All 21 suicides had been previously diagnosed with depression according to Diagnostic and Statistical Manual of Mental Disorder-IV criterion. Voxel-by-voxel analyses were performed using statistical parametric mapping to compare the differences in technetium-99m hexamethylpropylene amine oxime brain uptake between the groups. Factor analysis of the data identified the top 10 regions of hypoperfusion in the suicidal group, including the bilateral superior frontal lobes, the right precuneus, the rolandic operculum, postcentral gyrus, left caudate and insular cortex. We also demonstrate more focal decreases in rCBF in the subgenual cingulate cortex (BA 25) in 18 subjects, supporting our previous hypothesis that hypoperfusion of BA 25 may be a risk factor for suicide in depressed patients. This work suggests that SPECT might be useful in predicting risk for suicide completion in subjects with depression or treatment-resistant depression. Further investigation of this work is necessary to better understand the predictive value of this finding. PMID- 22832603 TI - Intravenous injection of neural progenitor cells improved depression-like behavior after cerebral ischemia. AB - Poststroke depression (PSD) occurs in approximately one-third of stroke survivors and is one of the serious sequelae of stroke. The onset of PSD causes delayed functional recovery by rehabilitation and also increases cognitive impairment. However, appropriate strategies for the therapy against ischemia-induced depression-like behaviors still remain to be developed. Such behaviors have been associated with a reduced level of brain-derived neurotrophic factor (BDNF). In addition, accumulating evidence indicates the ability of stem cells to improve cerebral ischemia-induced brain injuries. However, it remains to be clarified as to the effect of neural progenitor cells (NPCs) on PSD and the association between BDNF level and PSD. Using NPCs, we investigated the effect of intravenous injection of NPCs on PSD. We showed that injection of NPCs improved ischemia induced depression-like behaviors in the forced-swimming test and sucrose preference test without having any effect on the viable area between vehicle- and NPC-injected ischemic rats. The injection of NPCs prevented the decrease in the level of BDNF in the ipsilateral hemisphere. The levels of phosphorylated CREB, ERK and Akt, which have been implicated in events downstream of BDNF signaling, were also decreased after cerebral ischemia. NPC injection inhibited these decreases in the phosphorylation of CREB and ERK, but not that of Akt. Our findings provide evidence that injection of NPCs may have therapeutic potential for the improvement of depression-like behaviors after cerebral ischemia and that these effects might be associated with restoring BDNF-ERK-CREB signaling. PMID- 22832604 TI - Interactions of human truncated DISC1 proteins: implications for schizophrenia. AB - Numerous genetic linkage and association reports have implicated the Disrupted-in Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3beta and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants LDelta78, LDelta3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3beta. The temporal expression pattern of GSK3beta in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function. PMID- 22832606 TI - Simultaneous genotyping of multiple polymorphisms in human serotonin transporter gene and detection of novel allelic variants. AB - The serotonin transporter, called SLC6A4, SERT or 5-HTT, modulates neurotransmission by removal of serotonin from the synapse of serotonergic neurons, facilitating serotonin reuptake into the presynaptic terminus. Selective serotonin reuptake inhibitors block the action of the serotonin transporter and are used to treat depression and other neuropsychiatric disorders. Three polymorphisms in the 5-HTT gene have been implicated in treatment response and neuropsychiatric disorders. A 44-bp promoter ins/del polymorphism (5-HTTLPR) produces primarily long and/or short alleles due to either 14 (short) or 16 (long) repeats of variably conserved 20-23 bp units. Also implicated, a 17-18 bp variable number tandem repeat found in intron2 (StIn2) is expressed as triallelic content with 9, 10, or 12 repeats (StIn2.9, StIn2.10 or StIn2.12). Finally, a single nucleotide polymorphism rs25531 located within the promoter polymorphic linked region alters the function of the long promoter allele. We developed a PCR based fragment analysis assay, which is analyzed on an ABI sequencer, whereby we are able to detect all three genotypes simultaneously. Using this technique, we identified novel sequences, which demonstrate promoter repeat regions containing (1) a 17 repeat with rs25531 A/G polymorphism, (2) two with 18-repeat units, (3) one with 20-repeat units and (4) a 24-repeat sequence. The novel repeats were confirmed by direct sequencing of gel-purified amplicons. PMID- 22832605 TI - Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer's disease brain. AB - Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A recent positron emission tomography imaging study demonstrated upregulated brain arachidonic acid (AA) metabolism in AD patients. Further, a mouse model of AD shows an increase in AA-releasing cytosolic phospholipase A(2) (cPLA(2)) in brain, and a reduction in cPLA(2) activity ameliorated cognitive deficits. These observations led us to hypothesize that there is an upregulation of AA cascade and neuroinflammatory markers in the brain of AD patients. To test this hypothesis, we measured protein and mRNA levels of AA cascade, neuroinflammatory and synaptic markers in postmortem frontal cortex from 10 AD patients and 10 age-matched controls. Consistent with our hypothesis, AD frontal cortex showed significant increases in protein and mRNA levels of cPLA(2)-IVA, secretory sPLA(2)-IIA, cyclooxygenase-1 and -2, membrane prostaglandin (PG) synthase-1 and lipoxygenase-12 and -15. Calcium independent iPLA(2)-VIA and cytosolic PGE(2) synthase were decreased. In addition, interleukin-1beta, tumor necrosis factor-alpha, glial fibrillary acidic protein and CD11b were increased. AD postmortem brain also showed signs of cellular injury, including decreased synaptophysin and drebrin, pre- and postsynaptic markers. These results indicate that increased AA cascade and inflammatory markers could contribute to AD pathology. Altered brain AA cascade enzymes could be considered therapeutic targets for future drug development. PMID- 22832607 TI - Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo. AB - Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5 HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5 HT(2A)-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4 iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene- a rare structural variant associated with schizophrenia--is not only pro psychotic but also attenuates atypical antipsychotic drug actions. PMID- 22832608 TI - Increased de novo copy number variants in the offspring of older males. AB - The offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. In light of the evidence implicating copy number variants (CNVs) with schizophrenia and autism, we used a mouse model to explore the hypothesis that the offspring of older males have an increased risk of de novo CNVs. C57BL/6J sires that were 3- and 12-16-months old were mated with 3-month-old dams to create control offspring and offspring of old sires, respectively. Applying genome-wide microarray screening technology, 7 distinct CNVs were identified in a set of 12 offspring and their parents. Competitive quantitative PCR confirmed these CNVs in the original set and also established their frequency in an independent set of 77 offspring and their parents. On the basis of the combined samples, six de novo CNVs were detected in the offspring of older sires, whereas none were detected in the control group. Two of the CNVs were associated with behavioral and/or neuroanatomical phenotypic features. One of the de novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism and brain development. This is the first experimental demonstration that the offspring of older males have an increased risk of de novo CNVs. Our results support the hypothesis that the offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism by generation of de novo CNVs in the male germline. PMID- 22832609 TI - Impact of early adverse experience on complexity of adult-generated neurons. AB - New neurons continue to be generated in the dentate gyrus (DG) region of the hippocampus throughout adulthood, and abnormal regulation of this process has emerged as an endophenotype common to several psychiatric disorders. Previous research shows that genetic risk factors associated with schizophrenia alter the maturation of adult-generated neurons. Here, we investigate whether early adversity, a potential environmental risk factor, similarly influences adult neurogenesis. During the first 2 weeks of postnatal life, mice were subject to repeated and unpredictable periods of separation from their mothers. When the mice reached adulthood, pharmacological and retroviral labelling techniques were used to assess the generation and maturation of new neurons. We found that adult mice that were repeatedly separated from their mothers early in life had similar rates of proliferation in the DG, but had fewer numbers of cells that survived and differentiated into neurons. Furthermore, neurons generated in adulthood had less complex dendritic arborization and fewer dendritic spines. These findings indicate that early adverse experience has a long-lasting impact on both the number and the complexity of adult-generated neurons in the hippocampus, suggesting that the abnormal regulation of adult neurogenesis associated with psychiatric disorders could arise from environmental influence alone, or from complex interactions of environmental factors with genetic predisposition. PMID- 22832610 TI - Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. AB - Low-grade peripheral inflammation is often present in psychotic patients. Toll like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24 h. Cell supernatants were analysed using a multiplex enzyme linked immunosorbent assay approach to measure IL-1beta, IL-6, IL-8 and tumour necrosis factor-alpha (TNFalpha). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1beta, IL-6, IL-8 and TNFalpha) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1beta, IL-6 and TNFalpha following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1beta for both disorders coupled with TNFalpha increases for bipolar patients were observed. TLR8-induced increases in IL-1beta for both disorders as well as IL-6 and TNFalpha increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNFalpha levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders. PMID- 22832611 TI - How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure. AB - The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [(11)C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment. PMID- 22832612 TI - Non-synaptic mechanisms that could be responsible for potential antiepileptic effects of omega-3 fatty acids. PMID- 22832613 TI - Solvent-free double aza-Michael under ultrasound irradiation: diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids analogues. AB - Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical double Michael acceptors. The key step rested on an aza Michael addition of primary alkylamines to bis-enones. Competitive Rauhut-Currier and aza-Michael reactions have been highlighted in protic solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences. PMID- 22832614 TI - Remembering visionaries in nursing practice. PMID- 22832615 TI - Tattoo acceptance. PMID- 22832618 TI - Plan for a successful research day! PMID- 22832621 TI - Cracking the code: Successful strategies for studying. PMID- 22832623 TI - Breaking sterility: Dealing with procedural violations in healthcare. PMID- 22832625 TI - Time for Mrs. M. PMID- 22832627 TI - Peripheral arterial disease. PMID- 22832628 TI - Beyond "baby blues": Recognizing postpartum psychosis. PMID- 22832629 TI - When do (or don't) you administer drugs to patients on hemodialysis? PMID- 22832630 TI - Detecting and treating hypoglycemia in patients with diabetes. PMID- 22832631 TI - CNLs make a difference! PMID- 22832633 TI - Online resources for stroke prevention. PMID- 22832632 TI - What your patient needs to know about CAM. PMID- 22832634 TI - Understanding sickle cell disease. PMID- 22832635 TI - How substance abuse impacts pain management in acute care. PMID- 22832636 TI - Avulsed tooth. PMID- 22832637 TI - Effect of a multifactorial fall-and-fracture risk assessment and management program on gait and balance performances and disability in hospitalized older adults: a controlled study. AB - This controlled intervention study in hospitalized oldest old adults showed that a multifactorial fall-and-fracture risk assessment and management program, applied in a dedicated geriatric hospital unit, was effective in improving fall related physical and functional performances and the level of independence in activities of daily living in high-risk patients. INTRODUCTION: Hospitalization affords a major opportunity for interdisciplinary cooperation to manage fall-and fracture risk factors in older adults. This study aimed at assessing the effects on physical performances and the level of independence in activities of daily living (ADL) of a multifactorial fall-and-fracture risk assessment and management program applied in a geriatric hospital setting. METHODS: A controlled intervention study was conducted among 122 geriatric inpatients (mean +/- SD age, 84 +/- 7 years) admitted with a fall-related diagnosis. Among them, 92 were admitted to a dedicated unit and enrolled into a multifactorial intervention program, including intensive targeted exercise. Thirty patients who received standard usual care in a general geriatric unit formed the control group. Primary outcomes included gait and balance performances and the level of independence in ADL measured 12 +/- 6 days apart. Secondary outcomes included length of stay, incidence of in-hospital falls, hospital readmission, and mortality rates. RESULTS: Compared to the usual care group, the intervention group had significant improvements in Timed Up and Go (adjusted mean difference [AMD] = -3.7s; 95 % CI = -6.8 to -0.7; P = 0.017), Tinetti (AMD = -1.4; 95 % CI = -2.1 to -0.8; P < 0.001), and Functional Independence Measure (AMD = 6.5; 95 %CI = 0.7-12.3; P = 0.027) test performances, as well as in several gait parameters (P < 0.05). Furthermore, this program favorably impacted adverse outcomes including hospital readmission (hazard ratio = 0.3; 95 % CI = 0.1-0.9; P = 0.02). CONCLUSIONS: A multifactorial fall-and-fracture risk-based intervention program, applied in a dedicated geriatric hospital unit, was effective and more beneficial than usual care in improving physical parameters related to the risk of fall and disability among high-risk oldest old patients. PMID- 22832638 TI - Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis. AB - Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis. INTRODUCTION: This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials. METHODS: Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents. RESULTS: Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures. CONCLUSIONS: The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis. PMID- 22832639 TI - Robotic assisted radical cystectomy: oncological safety. AB - OBJECTIVES: To describe the quality parameters established based on surgical and pathological aspects of bladder carcinoma treatment in the study published by the Bladder Cancer Collaborative Group (BCCG) and compare them against the publications of the International Robotic Cystectomy Consortium (IRCC). METHODS: A MEDLINE database search for articles published by BCCG and IRCC and description of them. RESULTS: Margins: IRCC work globally presented 6.8% of positive margins, a result close to the 6.5% of BCCG. The margins were similar in patients with organ-confined disease (<= pT2) and those with extravesical disease (pT3-pT4), IRCC work showed a 4.6% positive margin compared to open surgery. In those who had lymph node involvement, negative margins were 6% higher for conventional surgery(BCCG: 14% vs. IRCC: 20%). The impact of learning curve in surgical margins in robotic surgery was not significant. Lymphadenectomy: In BCCG's work, 11% of patients did not have a lymphadenectomy performed, 9% underwent an LL, 67% SL and 13% EL. The mean number of lymph nodes collected was 12.5, with a median of 11. In the IRCC, 82.9% of patients underwent lymphadenectomy (defined as with more than 10 lymph nodes removed), of which 43% had more than 20 nodes removed. The median of the entire series was 17 nodes (range 0-68). CONCLUSIONS: The robotic assisted laparoscopic radical cystectomy (RALRC) is a technique with similar results to conventional surgery in terms of surgical margins and enables the performance of an adequate pelvic lymphadenectomy. Long term results are pending of a longer follow-up of patients operated to date. PMID- 22832640 TI - [Editorial comment: robotic assisted radical cystectomy: oncological safety]. PMID- 22832641 TI - High-sensitivity C-reactive protein as a predictor of locally advanced renal cell carcinoma. AB - OBJECTIVES: To determine if elevated levels of high-sensitivity C-reactive protein (CRP) in plasma are associated with locally advanced renal cell carcinoma (LARCC) after surgery. METHODS: Retrospective cross-sectional study conducted from May 2009 to January 2011. Altogether, 192 patients with non-disseminated disease and with preoperative quantitative determination of the CRP were evaluated. We evaluated the relation between age, gender, history of smoking, symptoms and CRP higher than 10 mg/L, with LARCC. The chi-square and Fisher's tests were used to compare categorical variables. For the multivariate analysis, we used logistic regression methods. RESULTS: The median age was 62 years (r=23 85), 72.4% were males. The median CRP was 2.40 mg/L (r=0.1-173). Of all the patients, 43.2% had a history of smoking and 81.8% were asymptomatic. As for the tumors, 77.1%were clear cell carcinoma, 14.6% chromophobe, 4.7% papillary, 2.6% oncocytomas, and 1% other varieties of renal cell carcinoma. As for the TNM classification, 45.8% corresponded to stage pT1a, 27.6% pT1b, 13% pT2, and 13.5% pT3, pT4 was not found. In the multivariate analysis, the presence of symptoms (p=0.002, OR=3.1) and the presence of CRP higher than 10 mg/L (p=0.006, OR=4) remained as the only prognostic variables of LARCC. CONCLUSIONS: Values of CRP higher than 10 mg/L increase 4 times the possibilities of finding LARCC in the pathological study of the surgical specimen. This variable should be taken into account when deciding what is the best surgical option. PMID- 22832642 TI - Paratesticular tumors. Description of our case series through a period of 25 years. AB - INTRODUCTION: Paratesticular tumors are masses of slow and indolent growth and in most cases of benign nature (70 %), being that the case, the treatment of choice is simple extirpation of the lesion and follow-up, based on observation only. On those identified as malignant (30 %), treatment is more complex, consisting in radical orchiectomy with adjuvant chemotherapy or radiotherapy. This work tries to describe our case series of paratesticular tumors over the last 25 years and to make a comparative analysis with the information published in the world literature. OBJECTIVE: To describe our experience with paratesticular tumors, their incidence, demographic data and treatment over a period of 25 years. METHODS: Descriptive study where we analyzed clinical data of 16 patients with the diagnosis of paratesticular tumor treated at Mostoles Hospital between 1984 and 2010 analyzing the age, type of tumor, treatment and follow-up. RESULTS: Mean age was 50 years (range: 16-88), benign tumors were detected in 76 % of the cases and malignant in 24%. The tumor more frequently found in our series was leiomyoma (23.5%), with slight predominance of the right side (53 %); the most frequent location was the epididymis (50%) and mean size was 4.9 cm of diameter. The mean follow up was 34 months without complications or tumor relapse in any patient. CONCLUSIONS: Despite only three-quarters of paratesticular tumors are non-malignant, it is always advisable to do intraoperative pathological analysis of all this masses. Having a non-malignant diagnosis, the treatment of choice is simple extirpation of the mass. In our study the majority of the tumors were diagnosed in adult age (average 51 years), the most frequent was leiomyoma and the most common location was the epididymis. PMID- 22832643 TI - Surgical treatment of vaginal prolapse with Prolift(r) mesh in patients with risk of recurrence. AB - OBJECTIVE: The aim of this paper is to analyze the results obtained in pelvic floor surgery using a non-absorbable mesh in selected patients with risk factors of recurrent prolapse. METHODS: Case series including a total of 76 patients who were surgically treated for severe genital prolapse from July 2005 to December 2009, with risk factors for recurrence of genital prolapse. RESULTS: We detected 3 cases (6.8%) of symptomatic prolapse recurrence and 6 cases (13.6%) of prolapse of another compartment in the anterior Prolift(r) group. In the posterior Prolift(r) group there were no recurrences but there were 2 cases (10.52%) of prolapse of another compartment. In the total Prolift(r) group, there were 2 cases (16.6%) of symptomatic prolapse recurrence. As for de novo urgency, there were a total of 4 cases (5.33%), 3 in the anterior Prolift(r) group and 1 in the total Prolift(r) group. We did not detect any case of severe pain in the pelvis or mesh insertion points that required reoperation due to persistence. CONCLUSIONS: The use of mesh in pelvic floor reconstructive surgery in selected patients with risk factors for recurrence is a good treatment option to prevent or attempt to reduce the recurrence or reoperation rates currently described. PMID- 22832644 TI - Bladder hemangioma: case report. AB - OBJECTIVE: Bladder hemangioma is a benign rare lesion. There are no pathognomonic clinical signs and management is controversial due to the bleeding risk. We report a bladder cavernous hemangioma resolved using bipolar transurethral resection. METHODS: We review the case of a female patient who presented with asymptomatic hematuria. On cystoscopy we discovered a reddish sessile lesion compatible with bladder hemangioma. We describe the diagnostic work up, surgical management and review other therapeutic alternatives for these lesions. RESULTS: Fifty five year old healthy female patient consulting for total painless hematuria. Cystoscopic evaluation revealed a 1 cm diameter sessile reddish elevated lesion near the bladder neck. We performed a transurethral endoscopic resection using the Gyrus Bipolar resectoscope(r). Pathologic report concluded cavernous angioma. CONCLUSION: Bladder hemangiomas are benign and rare lesions. Clinical presentation has no pathognomonic signs although gross painless hematuria is the most frequent complain. Management is controversial due to the bleeding risk of this highly vascularized lesion. However, it appears that small lesions could be treated using transurethral resection. Although they have a benign course, follow up is mandatory to detect recurrence or residual disease. PMID- 22832645 TI - Late migration of a toothpick into the bladder: initial presentation with urosepsis and hydronephrosis. AB - OBJECTIVE: Migration of objects into the urinary tract from the digestive tract has been described. Our objective is to report the case of a patient with urosepsis and late migration of toothpick from the gastrointestinal tract into the bladder. METHODS: A 78 y/o male patient with uro-sepsis and hydronephrosis was admitted. The initial suspected etiological cause was obstructive ureteral lithiasis. CT scan showed hydronephrosis and a possible ureteral stone. However, a femoral catheter was in place near the toothpick location, which jeopardized the detection of the foreign body. Antibiotic therapy and placement of a ureteral stent were performed. Once infection subsided, ureteroscopy was carried out showing a slight extrinsic compression of the distal ureter. The patient was readmitted with urinary infection. New imaging studies showed a foreign body in the bladder, which was not evident previously. Cystoscopy showed a toothpick penetrating the bladder and it was removed. RESULTS: Retrospectively, we interpreted that the foreign body perforated the gastrointestinal tract, migrated to the retroperitoneum and caused upper urinary tract obstruction by inflammatory reaction in the periureteral tissues. Once infection was solved, ureteral manipulation by ureteroscopy may have caused the toothpick migration into the bladder. CONCLUSIONS: Migration of foreign bodies from the gastrointestinal tract into the bladder occurs rarely. They clinically present as a complicated urinary tract infection. Imaging studies make the diagnosis, and a high level of suspicion is required. PMID- 22832646 TI - Bilateral kidney pseudotumor due to sarcoidosis: a radiological study case. AB - OBJECTIVE: To report one case of bilateral kidney pseudotumor due to sarcoidosis in a 75 year-old man with prostatic carcinoma and hypertrophic pachymeningitis. METHODS: Renal Doppler, body CT, CT-guided renal biopsy, blood analysis including angiotensin converting enzyme (ACE), blood levels and test-treatment (corticosteroid response) were performed. RESULTS: The radiological studies performed showed bilateral kidney masses and pulmonary calcified hilar adenopathies. Blood analysis showed renal failure and increased ACE levels. Renal biopsy showed non-caseating granulomas. Neurological symptoms and renal failure improved with corticosteroid therapy. CONCLUSION: Bilateral kidney pseudotumor due to sarcoidosis is a rare pathology. Sarcoidosis must be included in the differential diagnosis work up of patients with inflammatory or autoimmune disease and bilateral kidney pseudotumors. Radiological findings of kidney sarcoidosis are quite unspecific. Histological diagnosis with CT guided biopsy or US guided biopsy of kidney masses may be performed. PMID- 22832647 TI - Right hypochondrium pain and giant mass. AB - OBJECTIVE: To report a case of a right hypochondrium giant mass in a 40-year-old patient. METHODS: We report the case of a 40 year-old male referred to our Department because of right hypochondrium pain and increased abdominal perimeter. Radiological examination showed a 30 * 24 * 20 cm retroperitoneal mass, dependent on the upper pole of the right kidney. RESULTS: We performed radical nephrectomy through a mid line laparotomy. The pathological analysis described it as a clear cell renal carcinoma pT2bN0M0. CONCLUSION: There are few reported cases of renal carcinomas with intraparenchymal bleeding exceeding 20 cm, the largest one exceeding 10 kg, and they usually show a good prognosis. PMID- 22832648 TI - Hutch bladder diverticula: a very uncommon entity in adults. AB - OBJECTIVE: We present the case of an adult patient diagnosed with Hutch diverticula after examination. Indications were of a type of congenital bladder diverticula very rare in children and unusual in adults, as very few cases in adults are addressed in the literature. METHODS: Intravenous Urography and Voiding Cystourethrogram (VCUG) were realized RESULTS: The intravenous urography revealed ureterohydronephrosis in the excretory phase that did not have repletion defects suggesting lithiasis at distal urethra. On the other hand, a narrowing of the urethra was observed at the point of bladder entry due to the presence of a juxtameatal bladder diverticulum. Next a retrograde cystography was performed which ruled out vesicourethral reflux and revealed that the diverticulum presented elevated residuals after urination. As a result of our patient's clinical characteristics and the absence of vesico-urethral reflux, we decided to perform an endoscopic surgical opening of the diverticula's neck. CONCLUSIONS Hutch paraurethral diverticula is an very uncommon entity, even in infancy. The Voiding Cystourethrogram (VCUG) is especially useful in diagnosing these patients. In symptomatic cases surgical correction of the diverticula is required. PMID- 22832649 TI - Urinary tract tuberculosis. "fading flower" image. PMID- 22832650 TI - Right orchiectomy: inflammatory testicular pseudotumor. PMID- 22832651 TI - [Polyorchidism. Review of the Spanish literature (1965-2012)]. PMID- 22832652 TI - [Necrology of Juan Manuel Ghirlanda]. PMID- 22832654 TI - Myxopapillary ependymoma of the sacrococcygeal region presenting as a pilonidal sinus. PMID- 22832656 TI - Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. AB - Promoter IV-driven expression of brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is implicated in the pathophysiology of major depression. We previously reported that mice lacking expression of BDNF through promoter IV (BDNF-KIV mice) exhibit a depression-like phenotype. Here, we examined whether the depression-like phenotype and decreased levels of BDNF because of promoter IV deficit could be rescued by enriched environment (EE) treatment, a potential antidepressant intervention. Three weeks of EE treatment rescued depression-like behavior of BDNF-KIV mice as assessed by the tail suspension test, open-field test and sucrose preference test. EE treatment also increased BDNF transcripts driven by multiple endogenous promoters and restored BDNF protein levels in the hippocampus (HIP) of BDNF-KIV mice. Further, we investigated adult hippocampal neurogenesis as a possible cellular mechanism underlying the depression-like behavior and its recovery in BDNF-KIV mice. We found that the number of surviving progenitors and their dendritic length in the dentate gyrus of the HIP were reduced in BDNF-KIV mice compared with the control wild-type mice. EE treatment restored the reduction in cell survival and dendritic length and increased cell proliferation in BDNF-KIV mice. In conclusion, this study demonstrated that EE rescued depression-like behavior, decreased BDNF levels and defective neurogenesis in the HIP caused by lack of promoter IV-driven BDNF expression. These results suggest that decreased BDNF levels because of one impaired promoter can be compensated by other BDNF promoters and that BDNF levels may be one of the key factors regulating depression and antidepressant effects through hippocampal neurogenesis. PMID- 22832657 TI - A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment. AB - Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further. PMID- 22832658 TI - Resilient emotionality and molecular compensation in mice lacking the oligodendrocyte-specific gene Cnp1. AB - Altered oligodendrocyte structure and function is implicated in major psychiatric illnesses, including low cell number and reduced oligodendrocyte-specific gene expression in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) rodent model of the illness, suggesting that they are consequential to environmental precipitants; however, whether oligodendrocyte changes contribute causally to low emotionality is unknown. Focusing on 2'-3'-cyclic nucleotide 3'-phosphodiesterase (Cnp1), a crucial component of axoglial communication dysregulated in the amygdala of MDD subjects and UCMS-exposed mice, we show that altered oligodendrocyte integrity can have an unexpected functional role in affect regulation. Mice lacking Cnp1 (knockout, KO) displayed decreased anxiety- and depressive-like symptoms (i.e., low emotionality) compared with wild-type animals, a phenotypic difference that increased with age (3-9 months). This phenotype was accompanied by increased motor activity, but was evident before neurodegenerative-associated motor coordination deficits (<= 9-12 months). Notably, Cnp1(KO) mice were less vulnerable to developing a depressive-like syndrome after either UCMS or chronic corticosterone exposure. Cnp1(KO) mice also displayed reduced fear expression during extinction, despite normal amygdala c-Fos induction after acute stress, together implicating dysfunction of an amygdala-related neural network, and consistent with proposed mechanisms for stress resiliency. However, the Cnp1(KO) behavioral phenotype was also accompanied by massive upregulation of oligodendrocyte- and immune-related genes in the basolateral amygdala, suggesting an attempt at functional compensation. Together, we demonstrate that the lack of oligodendrocyte-specific Cnp1 leads to resilient emotionality. However, combined with substantial molecular changes and late-onset neurodegeneration, these results suggest the low Cnp1 seen in MDD may cause unsustainable and maladaptive molecular compensations contributing to the disease pathophysiology. PMID- 22832659 TI - Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1. AB - Disrupted-in-Schizophrenia-1 (DISC1) is a genetic susceptibility locus for major mental illness, including schizophrenia and depression. The Disc1 protein was recently shown to interact with the Wnt signaling protein, DIX domain containing 1 (Dixdc1). Both proteins participate in neural progenitor proliferation dependent on Wnt signaling, and in neural migration independently of Wnt signaling. Interestingly, their effect on neural progenitor proliferation is additive. By analogy to Disc1, mutations in Dixdc1 may lead to abnormal behavior in mice, and to schizophrenia or depression in humans. To explore this hypothesis further, we generated mice mutant at the Dixdc1 locus and analyzed their behavior. Dixdc1(-/-) mice had normal prepulse inhibition, but displayed decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity. Our results suggest that Dixdc1(-/-) mice will be a useful tool to elucidate molecular pathophysiology involving Disc1 in major mental illnesses. PMID- 22832661 TI - Symptoms before and after posterior fossa surgery in pediatric patients. AB - The posterior fossa syndrome (PFS) is common after cerebellar tumor resection in pediatric patients. It is characterized by postoperative mutism and ataxia and associated with persistent abnormalities in mood and cognition. METHOD: A 2-year prospective study of children and adolescents with cerebellar tumors identified by neuroimaging was performed at the Children's Hospital Los Angeles. RESULTS: There were 8 girls and 14 boys in the study, aged 14 months to 17 years. The tumor sizes ranged from 2 to 6.5 cm in diameter. The patients presented with ataxia, headache, vomiting, depressed or irritable mood and inattention. Symptoms of PFS were present postoperatively in all except for the 2 patients with lateral tumors. The symptoms began before resection, were most prominent immediately after surgery, and improved over time. Neuropsychological assessment of 10 patients documented a persistent cognitive decrement. CONCLUSION: This small, descriptive study provides information on the natural history of pediatric posterior fossa tumors from before surgery through the postoperative period. PMID- 22832663 TI - Congenital Frey's syndrome associated with nontraumatic bilateral trifid mandibular condyle. AB - Congenital Frey's syndrome and bilateral trifid mandibular condyle are two different entities. The occurrence of both together is rare and has not been reported in the literature. This article describes the case of a 17-year-old male patient who complained of bilateral warmness, flushing and sweating in the preauricular area after eating spicy and sour foods since childhood. He had no complaint related to the functions of the temporomandibular joint and had no history of facial trauma. The patient was treated with injections of botulinum toxin A and the signs and symptoms of Frey's syndrome improved significantly. PMID- 22832662 TI - What is the most fearful intervention in ambulatory oral surgery? Analysis of an outpatient clinic. AB - The aim of this study was to evaluate the levels of fear and anxiety in patients undergoing different types of minor oral surgery procedures by using conventional rating scales adjusted to the population characteristics. A demographic form and translated versions of the Modified Dental Anxiety Scale (MDAS) and Dental Fear Survey (DFS) were completed by 500 patients having hard or soft tissue pathologies, third molar removal, implant placement, tooth extraction procedures and 200 non-clinical participants. MDAS and DFS were highly correlated (r = 0.79; P < 0.05). The structural properties of the MDAS were similar to the original, but the DFS required substantive changes to achieve comparable measurement properties. Anxiety levels decreased with age and were greater in females, those with higher education and following a previous unpleasant experience (P < 0.05 for all). The third molar group scored higher than most of the surgical categories in both questionnaires (P < 0.05 for each). DFS showed they tended to avoid surgical procedures and were more susceptible to environmental and chair side effects (P<0.05 for all). Regarding oral surgery, third molar patients should be targeted to increase overall comfort of the treatment. Assessments should be adjusted to cultural differences. PMID- 22832660 TI - Tolfenamic acid suppresses cytochrome P450 2E1 expression in mouse liver. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) play a significant role in the chemoprevention of cancer. We recently showed the chemopreventive response of a NSAID, 2-[(3-chloro-2-methylphenyl)amino]benzoic acid) known as tolfenamic acid (TA) in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in rats. Pre clinical studies showed that TA inhibits Specificity protein (Sp) transcription factors and acts as an anti-cancer agent in several cancer models; however the pertinent mechanisms associated with its chemopreventive response in esophageal cancer are not known. Since the bioactivation of carcinogens through cytochrome P450 (CYP) is critical for the induction of cancer, we have studied the effect of TA on critical CYP isozymes in mouse liver samples. Athymic nude mice were treated with vehicle (corn oil) or TA (50 mg kg(-1), 3 times per week) for 4 weeks. Protein extracts (whole cell lysates and microsomal fractions) were prepared from liver tissue and the expression of various CYP isozymes was determined by Western blot analysis. Rat (Sprague-Dawley) livers were harvested and primary hepatocyte cultures were treated with vehicle (DMSO) or TA (50 MUM) and cell viability was assessed at 2 and 5 days post-treatment. TA caused remarkable decrease in the expression of CYP2E1 in both liver lysates and sub cellular fraction, while its response on other tested isozymes was marginal. TA did not affect the body weight of animals (mice) and viability of rat hepatocytes. These results demonstrate that TA modulates the expression of CYP2E1 which is associated with the bioactivation of carcinogens without causing apparent toxicity. These data suggest that TA-induced inhibition of CYP2E1 attenuates the bioactivation of carcinogens potentially leading to the chemoprevention of NMBA-induced esophageal tumorigenesis in rats. PMID- 22832664 TI - Surgical treatment of frontal sinus fractures: the simple percutaneous reduction revised. AB - Frontal sinus fractures are common fractures in high-energetic trauma. Different treatments options are available for different types of frontal sinus fractures. A fracture that consists only of the anterior wall is most commonly reduced with the coronal approach. This approach is invasive and produces a large scar on the scalp, which can result in an unfavourable situation in patients with alopecia and in balding men. To avoid this, a percutaneous reduction method can be used to treat patients with simple anterior wall fractures. This approach is less invasive and does not result in a conspicuous scar. The disadvantages of this procedure are the absence of direct vision and less control of the fracture, which can reduce the chances of complete reduction. This paper provides an overview of anterior wall fractures of the frontal sinus and elaborates on the simple percutaneous reduction technique. PMID- 22832665 TI - Growth trajectory of children and adolescents with isolated cleft lip and/or palate through the first two decades of life. AB - A wide body of evidence shows that patients with clefts exhibit decreased growth in their early years. Less evidence regarding their growth trajectory, specifically their body mass indices (BMIs), in later years is available. This study analyzes BMIs of patients with isolated clefts and/or palate over time using age-adjusted BMI z-scores based on the CDC 2000 references for height and weight for age. At least two height and weight measurements were obtained during 2-10 years and at least two height and weight measurements were obtained during 10-20 years. Mean BMI z-score for all patients was 0.117. Males had a mean z score of 0.087 and females a mean of 0.160 (p=0.407). Patients under 10 years of age had a mean z-score of 0.208, while patients older than 10 years had a mean z score of -0.028 (p=0.223). While significance was not achieved in the statistical analysis, the results suggest that overall, the cleft population maintains a mean BMI that is similar to that of the general population during childhood and adolescence. A larger analysis is warranted to investigate this phenomenon further and to investigate specifically the rate of obesity within this group. PMID- 22832666 TI - Synthesis of Fischer type-carbene complexes containing a coordinated thioimidate structural motif. AB - This paper describes a tandem strategy to synthesize a series of new Fischer carbene complexes [(CO)(4)M=C[N-(CH(2))(4)-]CH=C(NRR')(SR'); M = Cr, W; R = Ar, R' = Me, -(CH(2))(2)-] with a thioimide or thiazoline fragment, in which the sulfur or nitrogen atom is coordinated to a metal center, depending on the nature of alkylating groups included as R'. We have trapped by protonation the proposed intermediate as the thioamide 12 [(CO)(5)W=[N-(CH(2))(4)-]CH(2)C(S)NHPh], which reveals the pathway of this reaction. PMID- 22832667 TI - Quality of life in children with end-stage renal disease based on a PedsQL ESRD module. AB - BACKGROUND: Health-related quality of life (HRQOL) is an essential subject for children with end-stage renal disease (ESRD) and their families. METHODS: We performed a cross-sectional investigation of HRQOL in children undergoing renal replacement therapies, such as dialysis and renal transplantation, using the 34 item Pediatric Quality of Life Inventory 3.0 End-Stage Renal Disease (PedsQL 3.0 ESRD) module. We assessed 92 ESRD patients aged 2-18 from four Korean university hospitals. RESULTS: The male:female ratio was 44:48, and the most common cause of ESRD was chronic glomerulonephritis. Fifty-five children were treated by dialysis, and 37 received renal transplantation. Transplant patients had better HRQOL than dialysis patients in two domains in parent proxy reports: "About my kidney disease" and "Worry." In child self-reports, transplant patients had better HRQOL than dialysis patients in one domain: Treatment problems. However, there were no significant differences in total QOL scores between peritoneal dialysis (PD) and transplant patients in child self-reports. In addition, there were differences in the ESRD module scores between child self- and parent proxy reports. Children usually reported better QOL than their parents. Child self reports showed significantly higher QOL scores than parent proxy reports in the domains of General fatigue, Family & peer interaction, and Worry. Children on PD self-reported a significantly higher QOL than children on hemodialysis (HD). CONCLUSIONS: The PedsQL 3.0 ESRD module may be useful as an ESRD-specific instrument to evaluate HRQOL in children; however, a larger, longitudinal prospective study is warranted. PMID- 22832669 TI - Assessment of near-infrared densitometry for in situ determination of the total stratum corneum thickness on pig skin: influence of storage time. AB - To perform accurate tape-stripping measurements and to control for site-specific and interindividual differences the amount of stratum corneum (SC) removed by each tape and the total SC thickness must be known. The purpose of this study was to evaluate the use of near-infrared (NIR) densitometry at lambda = 850 nm for in situ determination of the total SC thickness. Quantitative tape stripping was performed on pig ear skin. The amount of SC removed by each tape was measured by NIR densitometry and by microprotein assay. Derived from the linear correlation between both measurements, a conversion factor was calculated that relates the individual NIR densitometry readings to the thickness of the SC on the corresponding tape (l(SC-tape) [um] = (abs.(850) - abs.(850)(blank))/23.9). The total SC thickness was determined based on the accumulated values of all tapes applied in quantitative tape stripping and compared to the values obtained from microscopic cross sections of biopsies. The total SC thickness was correctly determined by infrared densitometry independent of storage time and conditions (4 degrees C up to 24 h; -21 degrees C up to 3 months) in comparison with the standard histological evaluation. PMID- 22832668 TI - Renal function and systolic blood pressure in very-low-birth-weight infants 1-3 years of age. AB - BACKGROUND: Preterm very-low-birth-weight (PT-VLBW) infants are at risk of an elevated systolic blood pressure (SBP) in infancy and adulthood; however, the pathogenesis remains unclear. Altered renal development or function may be associated with increased SBP, but their contribution in PT-VLBW is unknown. METHODS: We determined renal function and its relationship to SBP in three groups of PT-VLBW at 1, 2, and 3 years of age, using serum cystatin-C to calculate the estimated glomerular filtration rate (eGFR). RESULTS: Cystatin-C levels decreased from 0.84 +/- 0.2 (SD) within the 1-year group to 0.70 +/- 0.1 mg/l (+/-SD; P < 0.001) at 3 years and were unrelated to gender, fetal growth, and neonatal indomethacin exposure. eGFR rose from 121 +/- 59 in the 1-year group to 138 +/- 21 ml/min . 1.73 m(2) (P < 0.001) at 3 years. At 1 year, cystatin-C levels decreased with increasing SBP (P < 0.007), and infants with SBP >= 90 th% had lower cystatin-C and higher eGFR (P < 0.05). At 3 years, infants with lower birth weight (P < 0.03) and gestational age (P = 0.06) had reduced eGFR. CONCLUSIONS: Preterm very-low-birth-weight infants demonstrate increasing renal function with advancing age. An elevated SBP and eGFR at 1 year suggests dysfunctional renal autoregulation and hyperfiltration, which may alter subsequent renal function and contribute to the lower eGFR seen at 3 years in infants with the lowest birth weight and gestational age. PMID- 22832670 TI - Prevalence, awareness, treatment and control of hypertension in adults with chronic kidney disease in Turkey: results from the CREDIT study. AB - BACKGROUND: In the Chronic REnal Disease in Turkey-CREDIT Study, a large populationbased study on 10,748 adults, the prevalence of chronic kidney disease (CKD) and relationship between CKD and other cardiovascular risk factors had been studied. METHODS: This report presents the results of CREDIT study on the prevalence, awareness, treatment, and control of hypertension among CKD patients. RESULTS: The prevalence and awareness of hypertension in CREDIT population was 32.7% and 48.6%, respectively. Of the patients with hypertension, 31.5% were under treatment, and 16.4% had hypertension under control. Prevalence of CKD was 25.3% in patients with hypertension. Among CKD patients (15.7% of the CREDIT study population), 56.3% had hypertension. The prevalence of hypertension was 34.8% at stage 1, 79.8% at stage 3, and 92.3% at stage 5 CKD. Only 13.4% of patients with CKD have optimal blood pressure. Among CKD patients, 61.9% were aware of hypertension, and 44.2% were under treatment. Overall control rate of hypertension in subjects with CKD was 16.3% with the lowest rate at stage 1 (12.3%) and highest rate at stage 4 (40%). The control rate increased to 28.8% for CKD patients under treatment for hypertension. CONCLUSION: As a conclusion, hypertension is highly prevalent in subjects with CKD in Turkey with suboptimal awareness, treatment, and control rates. Appropriate health strategies should be implicated to improve prevention, early diagnosis, and treatment of hypertension, which is one of the leading causes of CKD. PMID- 22832671 TI - Ionic liquids supported on magnetic nanoparticles as a sorbent preconcentration material for sulfonylurea herbicides prior to their determination by capillary liquid chromatography. AB - A magnetic material based on N-methylimidazolium ionic liquid and Fe(3)O(4) magnetic nanoparticles incorporated in a silica matrix has been used to extract and preconcentrate sulfonylurea herbicides, such as thifensulfuron methyl (TSM), metsulfuron methyl (MSM), triasulfuron (TS), tribenuron methyl (TBM) and primisulfuron methyl (PSM) from polluted water samples, prior to their analysis by capillary liquid chromatography with a diode array detector (DAD). Under the optimum conditions, this method allows the determination of TSM, MSM, TS, TBM and PSM in a linear range between 5 and 100 ng mL(-1), with relative standard deviation values lower than 5.3% (n = 10), in all cases. Detection limits ranging between 1.13 and 2.95 ng mL(-1) were achieved. The usefulness of the proposed method was demonstrated by the analysis of river water samples, obtaining recoveries higher than 91%. PMID- 22832672 TI - Multichromophoric dye-sensitized solar cells based on supramolecular zinc porphyrin...perylene-imide dyads. AB - Multichromophoric dye-sensitized solar cells (DSCs) based on self-assembled zinc porphyrin...peryleneimide dyads on TiO(2) films display more efficient light-to electrical energy conversion than DSCs based on individual dyes. Higher efficiency of multichromophoric dyes can be attributed to co-sensitization as well as vectorial electron transfer that lead to better electron-hole separation in the device. PMID- 22832673 TI - Benefits of endocardial and multisite pacing are dependent on the type of left ventricular electric activation pattern and presence of ischemic heart disease: insights from electroanatomic mapping. AB - BACKGROUND: There is considerable heterogeneity in the myocardial substrate of patients undergoing cardiac resynchronization therapy (CRT), in particular in the etiology of heart failure and in the location of conduction block within the heart. This may account for variability in response to CRT. New approaches, including endocardial and multisite left ventricular (LV) stimulation, may improve CRT response. We sought to evaluate these approaches using noncontact mapping to understand the underlying mechanisms. METHODS AND RESULTS: Ten patients (8 men and 2 women; mean [SD] age 63 [12] years; LV ejection fraction 246%; QRS duration 161 [24] ms) fulfilling conventional CRT criteria underwent an electrophysiological study, with assessment of acute hemodynamic response to conventional CRT as well as LV endocardial and multisite pacing. LV activation pattern was assessed using noncontact mapping. LV endocardial pacing gave a superior acute hemodynamic response compared with conventional CRT (26% versus 37% increase in LV dP/dt(max), respectively; P<0.0005). There was a trend toward further incremental benefit from multisite LV stimulation, although this did not reach statistical significance (P=0.08). The majority (71%) of patients with nonischemic heart failure etiology or functional block responded to conventional CRT, whereas those with myocardial scar or absence of functional block often required endocardial or multisite pacing to achieve CRT response. CONCLUSIONS: Endocardial or multisite pacing may be required in certain subsets of patients undergoing CRT. Patients with ischemic cardiomyopathy and those with narrower QRS, in particular, may stand to benefit. PMID- 22832674 TI - Novel assessment of temporal variation in fractionated electrograms using histogram analysis of local fractionation interval in patients with persistent atrial fibrillation. AB - BACKGROUND: The characteristics of atrial electrograms associated with atrial fibrillation (AF) termination are controversial. We investigated the electrogram characteristics that indicate procedural AF termination during continuous complex fractionated electrogram ablation. METHODS AND RESULTS: Fifty-two consecutive patients with persistent AF (47 men; aged 54 +/- 9 years), who underwent electrogram-based catheter ablation in the left atrium and coronary sinus after pulmonary vein isolation, were enrolled. The intracardiac bipolar atrial electrogram recordings were characterized by (1) fractionation interval (FI) analysis (>6 seconds), (2) kurtosis (shape of the FI histogram), and (3) skewness (asymmetry of the FI histogram). Sites showing complex, fractionated electrograms (mean FI <= 60 ms) were targeted, and AF was terminated in 20 patients (38%) after the pulmonary vein isolation. The conventional complex fractionated electrogram sites (mean <= 120 ms) in patients with AF termination exhibited higher median kurtosis (2.69 [interquartile range, 2.03-3.46] versus 2.35 [interquartile range, 1.79-2.48]; P=0.024) and higher complex fractionated electrogram-mean interval (102.7 +/- 19.8 versus 87.7 +/- 15.0; P=0.008) than patients without AF termination. Furthermore, AF termination sites had higher median kurtosis than targeted sites without AF termination (5.13 [interquartile range, 3.51-6.47] versus 4.18 [interquartile range, 2.91-5.34]; P<0.01) in patients with procedural termination. In addition, patients with AF termination had a higher sinus rhythm maintenance rate after a single procedure than patients without AF termination (log-rank test, P=0.007). CONCLUSIONS: A kurtosis analysis using the FI histogram may be a useful tool in identifying the critical substrate for persistent AF and potential responders to catheter ablation. PMID- 22832675 TI - Sustained vowels and continuous speech in the auditory-perceptual evaluation of dysphonia severity. AB - PURPOSE: Auditory-perceptual evaluation of dysphonia may be influenced by the type of speech/voice task used to render judgements during the clinical evaluation, i.e., sustained vowels versus continuous speech. This study explored (a) differences in listener dysphonia severity ratings on the basis of speech/voice tasks, (b) the influence of speech/voice task on dysphonia severity ratings of stimuli that combined sustained vowels and continuous speech, and (c) the differences in inter-rater reliability of dysphonia severity ratings between both speech tasks. METHODS: Five experienced listeners rated overall dysphonia severity in sustained vowels, continuous speech and concatenated speech samples elicited by 39 subjects with various voice disorders and degrees of hoarseness. RESULTS: Data confirmed that sustained vowels are rated significantly more dysphonic than continuous speech. Furthermore, dysphonia severity in concatenated speech samples is least determined by the sustained vowel. Finally, no significant difference was found in inter-rater reliability between dysphonia severity ratings of sustained vowels versus continuous speech. CONCLUSION: Based upon the results, both types of speech/voice tasks (i.e., sustained vowel and continuous speech) should be elicited and judged by clinicians in the auditory perceptual rating of dysphonia severity. PMID- 22832676 TI - Perceived dysphonia by the clinician's and patient's viewpoint. AB - PURPOSE: To verify the relationship between the clinician's vocal evaluation and vocal self-assessment and voice-related quality of life. METHODS: Participants were 96 individuals: 48 with vocal complaints and voice deviation (VCG), mean age of 51 years, with diagnosis and indication of voice therapy; and 48 with no vocal complaints and healthy voices (NVCG), mean age of 46 years. All participants answered the Voice-Related Quality of Life (V-RQOL) questionnaire, performed a vocal self-assessment and were submitted to auditory-perceptual analysis of voice. RESULTS: Mean V-RQOL scores were different between groups for all domains. Self-assessment results also showed differences between groups, which was not the case in the auditory-perceptual analysis of sustained vowel and connected speech, showing that the patient's perception was worse than the clinician's. There was correlation between the V-RQOL domains (Socio-emotional and Physical: 76.8%; Socio-emotional and Total: 90.8%; Physical and Total: 95.8%), as well as between the Socio-emotional (-52.9%), Physical (-43.1%) and Total (-52.2%) domains and the self-assessment. However, no correlation was found between auditory perceptual analysis and self-assessment measures, except for a weak correlation between vocal self-assessment and auditory-perceptual analysis of the sustained vowel (33.3%). CONCLUSION: The clinician's perception does correspond to the individual's self-perception of his/her vocal quality and the impact of a voice deviation on his/her quality of life, but not directly. The individual's perception about his/her vocal quality and voice-related quality of life complements the clinician's perception regarding the overall degree of the voice deviation. PMID- 22832677 TI - Evaluation of oral functions of the stomatognathic system according to the levels of asthma severity. AB - PURPOSE: To compare the orofacial functions (chewing, swallowing and speech) in children with asthma and healthy children. METHODS: A cross sectional study including 54 children of both genders with ages between 7 and 10 years was conducted. Twenty-seven of these subjects composed the experimental group, and were subdivided into two severity levels of asthma: Group I - mild intermittent and persistent asthma; Group II - persistent moderate to severe asthma. Twenty seven healthy children were included in the control group (Group III). Speech language pathology evaluation used the adapted Orofacial Myofunctional Assessment Protocol. Adaptation consisted in the exclusion of the structural part of the test, since this was not the aim of the study. The structural part was excluded because it was not the aim of this study. RESULTS: It was found alterations in oral functions, with significant differences between the three groups. These alterations showed no correlation with asthma severity, since the highest rate of alterations was found in Group I (mild asthma). CONCLUSION: Regardless of the severity level, children with asthma have altered patterns of chewing, swallowing and speech. PMID- 22832678 TI - Postural evaluation in children with atypical swallowing: radiographic study. AB - PURPOSE: To evaluate the cranial posture on lateral teleradiographs of children with atypical swallowing in mixed dentition. METHODS: By using cephalometric analysis on lateral teleradiographs, the angles between the odontoid process and cranial base (CC1) and the odontoid process and Frankfurt plane (CC2) were measured in two groups: 55 teleradiographs from the experimental group (with atypical swallowing), and 55 lateral teleradiographs from the control group (normal swallowing). These angular measurements were subjected to statistical analysis. RESULTS: The means of the variable CC1 were 99.95 degrees in the experimental group and 96.42 degrees in the control group, with significant difference between them. The means of the variable CC2 were 90.60 degrees in the experimental group and 86.35 degrees in the control group, which was also statistically significant. CONCLUSION: The angles CC1 and CC2 are increased in the group with atypical swallowing. PMID- 22832679 TI - Chewing time and chewing strokes in different dentofacial deformities. AB - PURPOSE: To verify whether the number of chewing strokes and the chewing time are influenced by dentofacial deformities in habitual free mastication. METHODS: Participants were 15 patients with diagnosis of class II dentofacial deformity (GII), 15 with class III (GIII), and 15 healthy control individuals with no deformity (CG). Free habitual mastication of a cornstarch cookie was analyzed, considering the number of chewing strokes and the time needed to complete two mastications. Strokes were counted by considering the opening and closing movements of the mandible. The time needed to consume each bite was determined using a digital chronometer, started after the placement of the food in the oral cavity and stopped when each portion was swallowed. RESULTS: There were no differences between groups regarding both the number of strokes and the chewing time. However, with regards to the number of strokes, CG and GII presented a significant concordance between the first and the second chewing situation, which was not observed in GIII. The analysis of time showed significant concordance between the first and second chewing situation in CG, reasonable concordance in GII, and discordance in GIII. CONCLUSION: Dentofacial deformities do not influence the number of chewing strokes or the chewing time. However, class III individuals do not show uniformity regarding these aspects. PMID- 22832680 TI - Cervical spine dysfunction signs and symptoms in individuals with temporomandibular disorder. AB - PURPOSE: To study the frequency of cervical spine dysfunction (CCD) signs and symptoms in subjects with and without temporomandibular disorder (TMD) and to assess the craniocervical posture influence on TMD and CCD coexistence. METHODS: Participants were 71 women (19 to 35 years), assessed about TMD presence; 34 constituted the TMD group (G1) and 37 comprised the group without TMD (G2). The CCD was evaluated through the Craniocervical Dysfunction Index and the Cervical Mobility Index. Subjects were also questioned about cervical pain. Craniocervical posture was assessed by cephalometric analysis. RESULTS: There was no difference in the craniocervical posture between groups. G2 presented more mild CCD frequency and less moderate and severe CCD frequency (p=0.01). G1 presented higher percentage of pain during movements (p=0.03) and pain during cervical muscles palpation (p=0.01) compared to G2. Most of the TMD patients (88.24%) related cervical pain with significant difference when compared to G2 (p=0.00). CONCLUSION: Craniocervical posture assessment showed no difference between groups, suggesting that postural alterations could be more related to the CCD. Presence of TMD resulted in higher frequency of cervical pain symptom. Thus the coexistence of CCD and TMD signs and symptoms appear to be more related to the common innervations of the trigeminocervical complex and hyperalgesia of the TMD patients than to craniocervical posture deviations. PMID- 22832681 TI - Social cognitive performance and different communication settings in groups of children with different disorders. AB - PURPOSE: To investigate the social-cognitive performance of children with diagnostics of autism spectrum disorder (ASD), mental disability (MD) and hearing impairment (HI) in two different communicative situations. METHODS: Participated in this study 30 children ages between 3 and 12 years starting speech language therapy processes, divided in three groups: Group 1 - ten children with diagnoses included in the Autism Spectrum Disorders (ASD); Group 2: ten children diagnosed with mental disabilities (MD) and Group 3: ten children diagnosed with hearing impairment (HI). The subjects were assessed in two different communicative situations (group and individual therapy situation) for 12 months. RESULTS: Data regarding the performance of the three groups in the two situations show that G3 had better absolute performance when compared with other groups, with the variable symbolic play as an important differential criterion for the three groups. CONCLUSION: We conclude that the social-cognitive performance can be used as an auxiliary tool for intervention, helping the identification of variables that could interfere in the communicative performance. PMID- 22832682 TI - Brazilian version of the Overall Assessment of the Speaker's Experience of Stuttering - Adults protocol (OASES-A). AB - PURPOSE: To verify the applicability of the protocol Overall Assessment of the Speaker's Experience of Stuttering - Adults (OASES-A), translated into Brazilian Portuguese, in a sample of adults who stutter. METHODS: The Brazilian Portuguese version of the OASES-A protocol was individually applied to 18 people who stutter. The classification of stuttering severity was based on the Stuttering Severity Instrument for Children and Adults (SSI-3) protocol. Translation and back-translation processes were carried out by specialists, considering semantic, conceptual, cultural, and idiomatic equivalences. RESULTS: There was no correlation between the severity degrees of stuttering assessed by the SSI-3 protocol and the self-assessment performed using the OASES-A. Subjects reported impairments in perceived fluency; speech ability; level of knowledge about stuttering and treatment options; use of confrontational techniques; quality of life. They also mentioned having difficulty coping with emotional states such as anxiety and embarrassment, and with communication in daily situations. CONCLUSION: The OASES-A protocol is useful in the assessment and treatment of stutterers, as it provides specialized speech-language pathologists with sutterers' self-perception regarding their communication difficulties and the impact of stuttering on their quality of life. PMID- 22832683 TI - The complexity of narrative interferes in the use of conjunctions in children with specific language impairment. AB - PURPOSE: To verify the use of conjunctions in narratives, and to investigate the influence of stimuli's complexity over the type of conjunctions used by children with specific language impairment (SLI) and children with typical language development. METHODS: Participants were 40 children (20 with typical language development and 20 with SLI) with ages between 7 and 10 years, paired by age range. Fifteen stories with increasing of complexity were used to obtain the narratives; stories were classified into mechanical, behavioral and intentional, and each of them was represented by four scenes. Narratives were analyzed according to occurrence and classification of conjunctions. RESULTS: Both groups used more coordinative than subordinate conjunctions, with significant decrease in the use of conjunctions in the discourse of SLI children. The use of conjunctions varied according to the type of narrative: for coordinative conjunctions, both groups differed only between intentional and behavioral narratives, with higher occurrence in behavioral ones; for subordinate conjunctions, typically developing children's performance did not show differences between narratives, while SLI children presented fewer occurrences in intentional narratives, which was different from other narratives. CONCLUSION: Both groups used more coordinative than subordinate conjunctions; however, typically developing children presented more conjunctions than SLI children. The production of children with SLI was influenced by stimulus, since more complex narratives has less use of subordinate conjunctions. PMID- 22832684 TI - The relation between auditory discrimination and phonological disorder. AB - PURPOSE: To determine the most frequent errors of children with phonological disorders in an auditory discrimination test, and to correlate their performance with age, gender and severity of phonological disorder. METHODS: The sample consisted of 82 children with phonological disorders, of both gender, with ages between 4 years and 7 years and 11 months. All subjects were submitted to the Phonological Assessment of Child (Avaliacao Fonologica da Crianca) in order to establish the severity of phonological disorder, and to the auditory discrimination test. Data were statistically analyzed. RESULTS: It was found that 38% of the subjects had poor results on the test, and the most frequent errors were: posteriorization, devoicing of stops, and semivocalization of liquid consonants. Moreover, it was observed that auditory discrimination difficulties were less frequent in older subjects, and more severe according to the severity of the phonological disorder. CONCLUSION: Great part of the children with phonological disorders has difficulties in auditory discrimination. However, these difficulties were less frequent in older subjects and more severe according to the severity of the disorder. Male subjects seem to have more difficulty in discriminating speech sounds. PMID- 22832685 TI - Electrophysiological study of hearing in full-term small-for-gestational-age newborns. AB - PURPOSE: To describe the Brainstem Auditory Evoked Potential (BAEP) results of full-term small-for-gestational-age newborns, comparing them to the results of full-term appropriate-for-gestational-age newborns, in order to verify whether the small-for-gestational-age condition is a risk indicator for retrocochlear hearing impairment. METHODS: This multicentric prospective cross-sectional study assessed 86 full-term newborns - 47 small- (Study Group) and 39 appropriate-for gestational-age (Control Group - of both genders, with ages between 2 and 12 days. Newborns with presence of transient evoked otoacoustic emissions and type A tympanometry were included in the study. Quantitative analysis was based on the mean and standard deviation of the absolute latencies of waves I, III and V and interpeak intervals I-III, III-V and I-V, for each group. For qualitative analysis, the BAEP results were classified as normal or altered by analyzing these data considering the age range of the newborn at the time of testing. RESULTS: In the Study Group, nine of the 18 (38%) subjects with altered BAEP results had the condition of small-for-gestational-age as the only risk factor for hearing impairments. In the Control Group, seven (18%) had altered results. Female subjects from the Study Group tended to present more central alterations. In the Control Group, the male group tended to have more alterations. CONCLUSION: Full-term children born small or appropriate for gestational age might present transitory or permanent central hearing impairments, regardless of the presence of risk indicators. PMID- 22832686 TI - Temporal resolution with click and pure tone stimuli in youngsters with normal hearing sensitivity. AB - PURPOSE: To assess the auditory ability of temporal resolution and to compare the random gap detection test (RGDT) versions with pure tone and clicks stimuli. METHODS: Participants were 40 young individuals of both genders with ages between 18 and 25 years, and normal hearing thresholds for the sound frequencies of 250 Hz to 8 kHz. Initially, participants were submitted to the basic audiological evaluation. Then they underwent the RGDT with pure tone and clicks stimuli. Finally, we obtained the temporal acuity threshold, which corresponds to the shorter silence interval in which the patient perceives two sounds, for each type of stimulus, called final temporal acuity threshold for pure tones (mean of the thresholds obtained for 500 Hz, 1k, 2k and 4 kHz), and temporal acuity threshold for clicks. RESULTS: The mean temporal acuity threshold for the sound frequency of 500 Hz was 7.25 ms; for the frequency of 1 kHz was 7.25 ms; for 2 kHz was 6.73 ms; for the frequency of 4 kHz was 6.03 ms. The final temporal acuity threshold was 6.72 ms. The mean temporal acuity threshold for clicks was 6.43 ms. No difference was found between the temporal acuity thresholds obtained with pure tone and clicks stimuli. CONCLUSION: There is no difference in the performance of individuals on the auditory ability of temporal resolution, regardless of the auditory stimulus used. PMID- 22832687 TI - Temporal auditory processing in rural workers exposed to pesticide. AB - PURPOSE: The objective of this research was to assess the ordering and temporal resolution auditory abilities in rural workers exposed to pesticides and compare them with laborers exposure index. METHODS: A sectional study assessed 33 individuals of both genders, aged 18-59 years, who were exposed to pesticides during their daily routine. The procedures were: questionnaire, meatoscopy, basic audiological evaluation and Temporal Auditory Processing tests: pattern test duration and Gaps-in-Noise. In order to analyse the results, a variable called 'index of exposure' was set up through a simple sum of variables present in the questionnaire. The tests' results on Temporal Auditory Processing were categorized according to the tercis of distribution, based on the results observed - in this study, tertile 1, tertile 2, and tertile 3 - and then compared with the exposure index. RESULTS: Difference was verified in all tertiles, with a dose-response relationship, i.e. increased average exposure was associated to worse performance on pattern test duration (p=0.001) and Gaps-in-Noise (p=0.001) in all tertiles. The highest correlation was observed between tertiles 3 and 1. CONCLUSION: Workers exposed to pesticide performed bellow average on Temporal Auditory Processing tests. There was association between the index of exposure to pesticides and worse performance in Temporal Auditory Processing tests, suggesting that the pesticides may be harmful to central auditory pathways. PMID- 22832688 TI - Auditory and communicative abilities in the auditory neuropathy spectrum disorder and mutation in the Otoferlin gene: clinical cases study. AB - This study had the aim to investigate the auditory and communicative abilities of children diagnosed with Auditory Neuropathy Spectrum Disorder due to mutation in the Otoferlin gene. It is a descriptive and qualitative study in which two siblings with this diagnosis were assessed. The procedures conducted were: speech perception tests for children with profound hearing loss, and assessment of communication abilities using the Behavioral Observation Protocol. Because they were siblings, the subjects in the study shared family and communicative context. However, they developed different communication abilities, especially regarding the use of oral language. The study showed that the Auditory Neuropathy Spectrum Disorder is a heterogeneous condition in all its aspects, and it is not possible to make generalizations or assume that cases with similar clinical features will develop similar auditory and communicative abilities, even when they are siblings. It is concluded that the acquisition of communicative abilities involves subjective factors, which should be investigated based on the uniqueness of each case. PMID- 22832689 TI - Hearing loss and acquired immune deficiency syndrome: systematic review. AB - PURPOSE: To investigate the occurrence of hearing loss in individuals with HIV/AIDS and their characterization regarding type and degree. RESEARCH STRATEGY: It was conducted a systematic review of the literature found on the electronic databases PubMed, EMBASE, ADOLEC, IBECS, Web of Science, Scopus, Lilacs and SciELO. SELECTION CRITERIA: The search strategy was directed by a specific question: "Is hearing loss part of the framework of HIV/AIDS manifestations?", and the selection criteria of the studies involved coherence with the proposed theme, evidence levels 1, 2 or 3, and language (Portuguese, English and Spanish). DATA ANALYSIS: We found 698 studies. After an analysis of the title and abstract, 91 were selected for full reading. Out of these, 38 met the proposed criteria and were included on the review. RESULTS: The studies reported presence of conductive, sensorineural, and mixed hearing loss, of variable degrees and audiometric configurations, in addition to tinnitus and vestibular disorders. The etiology can be attributed to opportunistic infections, ototoxic drugs or to the action of virus itself. The auditory evoked potentials have been used as markers of neurological alterations, even in patients with normal hearing. CONCLUSION: HIV/AIDS patients may present hearing loss. Thus, programs for prevention and treatment of AIDS must involve actions aimed at auditory health. PMID- 22832690 TI - Visual stimuli and written production of deaf signers. AB - PURPOSE: To verify the interference of visual stimuli in written production of deaf signers with no complaints regarding reading and writing. METHODS: The research group consisted of 12 students with education between the 4th and 5th grade of elementary school, with severe or profound sensorineural hearing loss, users of LIBRAS and with alphabetical writing level. The evaluation was performed with pictures in a logical sequence and an action picture. The analysis used the communicative competence criteria. RESULTS: There were no differences in the writing production of the subjects for both stimuli. In all texts there was no title and punctuation, verbs were in the infinitive mode, there was lack of cohesive links and inclusion of created words. CONCLUSION: The different visual stimuli did not affect the production of texts. PMID- 22832691 TI - Editorial. Speech-language evaluation. PMID- 22832693 TI - The Fear Avoidance model of chronic pain: examination for pediatric application. AB - The current study examined the Fear Avoidance (FA) model of chronic pain in pediatric chronic pain patients. Multiple structural equation models were tested in the current study with pairwise parameter comparisons made between younger children (8-12 years) and adolescents (13-17 years). Within a sample of 350 children and adolescents, we examined functional disability and depressive symptoms in separate models with the following predictor variables-pain, pain catastrophizing, fear of pain, and avoidance of activities-after controlling for duration of pain. For a subset of patients (n = 151), we also tested a brief prospective outcome model with baseline predictor variables and functional disability at 1-month follow-up. The FA models predicting functional disability concurrently and prospectively were an excellent fit to the data. The theorized FA model for depression was a poor fit. When the model was modified to include direct pathways from the cognitive processes of pain catastrophizing and fear of pain to depressive symptoms, the model fit was significantly improved. In the examination of developmental differences between younger children and adolescent patients, duration of pain contributed to the model for younger children, whereas pain-related fears were more influential for adolescent patients. PERSPECTIVE: The FA model of chronic pain appears to be applicable for pediatric patients with some modification to account for developmental differences across childhood. We discuss the developmental, theoretical, and clinical implications of these results. PMID- 22832694 TI - Factors associated with adolescent chronic non-specific pain, chronic multisite pain, and chronic pain with high disability: the Young-HUNT Study 2008. AB - The aim of this study was to assess the association of chronic pain with different lifestyle factors and psychological symptoms in a large, unselected adolescent population. Pain was evaluated as chronic non-specific pain, chronic multisite pain, and in additional analyses, chronic pain with high disability. The study was performed during 2006 to 2008 in Nord-Trondelag County, Norway. Adolescents aged 13 to 18 years were invited to participate. The response rate was 78%. The final study population consisted of 7,373. Sedentary behavior and pain were associated only in girls. In both sexes, overweight and obesity were associated with increased odds of pain. Whereas both smoking and alcohol intoxication showed strong associations with pain, the associations were attenuated after adjustments for psychosocial factors. Symptoms of anxiety and depression showed the strongest associations with pain (odds ratio 4.1 in girls and 3.7 in boys). The odds of pain increased gradually by number of unfavorable lifestyle factors reported. This study revealed consistent associations between lifestyle factors, anxiety and depression, and chronic pain, including multisite pain and pain with high disability. The consistency across the different pain categories suggests common underlying explanatory mechanisms, and despite the cross-sectional design, the study indicates several modifiable targets in the management of adolescent chronic pain. PERSPECTIVE: This study showed a clear and consistent relation between different lifestyle factors, anxiety and depression, and the pain categories chronic non-specific pain, multisite pain, and also pain with high disability. Independent of causality, it underlines the importance of a broad perspective when studying, preventing, and treating chronic pain in adolescents. PMID- 22832696 TI - Anal manometry in the investigation of fecal incontinence: totum pro parte, not pars pro toto. PMID- 22832697 TI - Accurate long-term prediction of height during the first four years of growth hormone treatment in prepubertal children with growth hormone deficiency or Turner Syndrome. AB - BACKGROUND/AIMS: The study aim was to develop and validate models for long-term prediction of growth in prepubertal children with idiopathic growth hormone deficiency (GHD) or Turner syndrome (TS) for optimal, cost-effective growth hormone (GH) therapy. METHODS: Height was predicted by sequential application of annual prediction algorithms for height velocity in cohorts of GHD (n = 664) and TS (n = 607) as documented within KIGS (Pfizer International Growth Database). As height prediction models also require an estimate of weight, new algorithms for weight increase during the first to fourth prepubertal years on GH were developed. RESULTS: When height was predicted from the start of GH treatment, the predicted and observed mean (SD) gain over 4 years was 30.4 (3.4) cm and 30.1 (4.9) cm, respectively, in GHD patients, and 27.2 (2.2) cm and 26.6 (3.5) cm, respectively, in TS patients. For all 4 years, gains of weight SD scores (SDS) were accurately described as a function of weight SDS and observed gain in height SDS (R(2) > 0.89). CONCLUSION: In GHD and TS patients treated with GH, an accurate prepubertal long-term prediction of height development in groups is possible. Based on this, an optimal individual height outcome could be simulated. PMID- 22832698 TI - A supramolecular route towards core-shell polymeric microspheres in water via cucurbit[8]uril complexation. AB - Core-shell polymeric microspheres with a cleavable shell were prepared in water using cucurbit[8]uril to bring together functional polymeric microspheres and functional polymers. This supramolecular approach was employed to switch the cytotoxicity of the polymeric microspheres, leading to potential applications in the eradication of cancer cells. PMID- 22832699 TI - Ventricular access devices are safe and effective in the treatment of posthemorrhagic ventricular dilatation prior to shunt placement. AB - Intraventricular hemorrhage of prematurity (IVH) is a diagnosis that has become more frequent in recent years. Advances in medical care have led to survival of increasingly premature infants, as well as infants with more complex medical conditions. Treatment with a ventricular access device (VAD) was reported almost 3 decades ago; however, it is unclear how effective this treatment is in the current population of premature infants. At our institution (from 2004 to present), we treat posthemorrhagic hydrocephalus (PHH) with a VAD. In order to look at safety and efficacy, we retrospectively combed the medical records of premature children, admitted to Lucile Packard Children's Hospital from January 2005 to December 2009, and identified 310 premature children with IVH. Of these, 28 children required treatment for PHH with a VAD. There were no infections associated with placement of these devices and a very low rate of other complications, such as need for repositioning (7.41%) or replacement (3.75%). Our data show that treatment with a VAD is very safe, with few complications and can be used to treat PHH in this very complex infant population. PMID- 22832700 TI - Gait characteristics of younger-old and older-old adults walking overground and on a compliant surface. AB - BACKGROUND: Walking across unstable surfaces disturbs normal stability and efficient strategies must be used to avoid falls. This study identified age related changes in gait during unstable surface walking. METHOD: Eight healthy younger-old adults (YOG, mean age, 68.6 years) and eight healthy older-old adults (OOG, mean age, 82.1 years) were assessed. Both groups performed the Timed Up and Go Test (TUG) and walked on a rigid and on a compliant surface while kinematic data were obtained. RESULTS: The OOG needed more time to complete the TUG test compared to YOG (F1,14=5.18; p=0.04). The gait speed, stride length and vertical displacement of the foot were similar for both groups, but they were slower (F1,14=5.64; p=0.03) when walking on the compliant surface. The knee and hip range of motion on the sagittal plane (F1,14=191.9; p<0.001 and F1,14=36.4, p<0,001, respectively) increased on the complaint surface but no group effect was found. The displacement of upper trunk on the frontal plane was similar between groups (F1,14=2.43; p=0.14) and conditions (F1,14=1.15; p=0.3). The OOG had greater displacement of the pelvic segment on the frontal plane than the YOG (F1,14=4.9; p=0.04) mainly for the complaint surface. CONCLUSIONS: Older-old individuals have slower TUG test and greater displacement of the pelvic segment on a compliant surface. More challenging tasks and/or environment should be used for gait assessment and intervention of older adults with risk of falls. PMID- 22832701 TI - Metabolic and clinical comparative analysis of treadmill six-minute walking test and cardiopulmonary exercise testing in obese and eutrophic women. AB - BACKGROUND: Impaired exercise tolerance is directly linked to decreased functional capacity as a consequence of obesity. OBJECTIVES: To analyze and compare the cardiopulmonary, metabolic, and perceptual responses during a cardiopulmonary exercise test (CPX) and a treadmill six-minute walking test (tread6MWT) in obese and eutrophic women. METHOD: Twenty-nine female participants, aged 20-45 years were included. Fourteen were allocated to the obese group and 15 to the eutrophic group. Anthropometric measurements and body composition assessment were performed. RESULTS: In both tests, obese women presented with significantly higher absolute oxygen uptake, minute ventilation, and systolic and diastolic blood pressure; they also presented with lower speed, distance walked, and oxygen uptake corrected by the weight compared to eutrophics. During the maximal exercise test, perceived dyspnea was greater and the respiratory exchange ratio was lower in obese subjects compared to eutrophics. During the submaximal test, carbon dioxide production, tidal volume, and heart rate were higher in obese subjects compared to eutrophic women. When analyzing possible correlations between the CPX and the tread6MWT at peak, there was a strong correlation for the variable heart rate and a moderate correlation for the variable oxygen uptake. The heart rate obtained in the submaximal test was able to predict the one obtained in the maximal test. Bland-Altman plots demonstrated the agreement between both tests to identify metabolic and physiological parameters at peak exercise. CONCLUSIONS: The six-minute walking test induced ventilatory, metabolic, and cardiovascular responses in agreement with the maximal testing. Thus, the six-minute walking test proves to be important for functional evaluation in the physical therapy routine. PMID- 22832702 TI - Low pressure support changes the rapid shallow breathing index (RSBI) in critically ill patients on mechanical ventilation. AB - BACKGROUND: The rapid shallow breathing index (RSBI) is the most widely used index within intensive care units as a predictor of the outcome of weaning, but differences in measurement techniques have generated doubts about its predictive value. OBJECTIVE: To investigate the influence of low levels of pressure support (PS) on the RSBI value of ill patients. METHOD: Prospective study including 30 patients on mechanical ventilation (MV) for 72 hours or more, ready for extubation. Prior to extubation, the RSBI was measured with the patient connected to the ventilator (DragerTM Evita XL) and receiving pressure support ventilation (PSV) and 5 cmH2O of positive end expiratory pressure or PEEP (RSBI_MIN) and then disconnected from the VM and connected to a Wright spirometer in which respiratory rate and exhaled tidal volume were recorded for 1 min (RSBI_ESP). Patients were divided into groups according to the outcome: successful extubation group (SG) and failed extubation group (FG). RESULTS: Of the 30 patients, 11 (37%) failed the extubation process. In the within-group comparison (RSBI_MIN versus RSBI_ESP), the values for RSBI_MIN were lower in both groups: SG (34.79+/ 4.67 and 60.95+/-24.64) and FG (38.64+/-12.31 and 80.09+/-20.71; p<0.05). In the between-group comparison, there was no difference in RSBI_MIN (34.79+/-14.67 and 38.64+/-12.31), however RSBI_ESP was higher in patients with extubation failure: SG (60.95+/-24.64) and FG (80.09+/-20.71; p<0.05). CONCLUSIONS: In critically ill patients on MV for more than 72h, low levels of PS overestimate the RSBI, and the index needs to be measured with the patient breathing spontaneously without the aid of pressure support. PMID- 22832703 TI - Concurrent validity of the pressure biofeedback unit and surface electromyography in measuring transversus abdominis muscle activity in patients with chronic nonspecific low back pain. AB - BACKGROUND: The Pressure biofeedback unit (PBU) is an assessment tool used in clinical practice and research aimed to indirectly analyze the transversus abdominis (TrA) muscle activity. The concurrent validity of the PBU in a clinically relevant sample is still unclear. OBJECTIVE: The purpose of this study was to evaluate the concurrent validity and diagnostic accuracy of the PBU in measuring TrA muscle activity in patients with chronic nonspecific low back pain. METHOD: This study was performed using a validation, cross-sectional design. Fifty patients with chronic nonspecific low back pain were recruited for this study. To test the concurrent validity both PBU measures (index test) and superficial electromyographic measures (reference-standard test) were compared and collected by a physical therapist in a series of voluntary contraction maneuvers of TrA muscle. RESULTS: Participants were on average 22 years old, weighed 63.7 kilos, 1.70 meters height and mean low back pain duration was 1.9 years. It was observed a weak and non-significant Phi coefficient (r=0.2, p<0.20). With regards to diagnostic accuracy tests, our results suggest a low sensitivity (60%) and specificity (60%) of the PBU. The positive predictive value was high (0.8) and negative predictive value was low (0.2). CONCLUSIONS: Concurrent validity of the PBU in measuring TrA muscle activity in patients with chronic nonspecific low back pain is poor given the low correlation and diagnostic accuracy with superficial EMG. PMID- 22832704 TI - A novel transdermal fomulation of 18beta-glycyrrhetic acid with lysine for improving bioavailability and efficacy. AB - The aim of this study was to develop a novel topical liposomal system entrapping 18beta-glycyrrhetic acid (GA) for the treatment of chronic allergic dermatitis. A novel liposomal system with molar ratios of GA to lysine from 1:1 to 1:3 was prepared by high-pressure homogenization. The liposomes at the optimized molar ratio of GA to lysine of 1:2 significantly improved GA loading (1.2%) and penetration in vitro. Liposomal gels containing GA 0.3, 0.6 and 0.9% were prepared to investigate the dosage effect on transdermal delivery and anti inflammatory activity. In vivo pharmacokinetic studies were carried out by nonocclusive application of GA liposomal gels to ICR mouse ears. GA concentrations in skin and plasma increased proportionally with dose over the dose range of 0.3-0.9%. A 2,4-dinitrofluorobenzene-induced contact dermatitis mouse model was made up to evaluate the pharmacodynamics of GA liposomal gels. The liposomal gel with GA 0.9% showed a stronger anti-inflammatory activity than triamcinolone acetonide and econazole nitrate cream, while few side effects were observed in the present model. The topical administration of gel containing novel elastic liposomes of GA was safe and effective in the treatment of chronic allergic dermatitis. PMID- 22832705 TI - Mechanics of blast loading on the head models in the study of traumatic brain injury using experimental and computational approaches. AB - Blast waves generated by improvised explosive devices can cause mild, moderate to severe traumatic brain injury in soldiers and civilians. To understand the interactions of blast waves on the head and brain and to identify the mechanisms of injury, compression-driven air shock tubes are extensively used in laboratory settings to simulate the field conditions. The overall goal of this effort is to understand the mechanics of blast wave-head interactions as the blast wave traverses the head/brain continuum. Toward this goal, surrogate head model is subjected to well-controlled blast wave profile in the shock tube environment, and the results are analyzed using combined experimental and numerical approaches. The validated numerical models are then used to investigate the spatiotemporal distribution of stresses and pressure in the human skull and brain. By detailing the results from a series of careful experiments and numerical simulations, this paper demonstrates that: (1) Geometry of the head governs the flow dynamics around the head which in turn determines the net mechanical load on the head. (2) Biomechanical loading of the brain is governed by direct wave transmission, structural deformations, and wave reflections from tissue-material interfaces. (3) Deformation and stress analysis of the skull and brain show that skull flexure and tissue cavitation are possible mechanisms of blast-induced traumatic brain injury. PMID- 22832706 TI - Effect of intramolecular charge transfer on fluorescence and singlet oxygen production of phthalocyanine analogues. AB - Intramolecular charge transfer (ICT) was studied on a series of magnesium, metal free and zinc complexes of unsymmetrical tetrapyrazinoporphyrazines and tribenzopyrazinoporphyrazines bearing two dialkylamino substituents (donors) and six alkylsulfanyl or aryloxy substituents (non-donors). The dialkylamino substituents were responsible for ICT that deactivated excited states and led to considerable decrease of fluorescence and singlet oxygen quantum yields. Photophysical and photochemical properties were compared to corresponding macrocycles that do not bear any donor centers. The data showed high feasibility of ICT in the tetrapyrazinoporphyrazine macrocycle and significantly lower efficiency of this deactivation process in the tribenzopyrazinoporphyrazine type molecules. Considerable effect of non-donor peripheral substituents on ICT was also described. The results imply that tetrapyrazinoporphyrazines may be more suitable for development of new molecules investigated in applications based on ICT. PMID- 22832707 TI - Hypobilirubinemia might be a possible risk factor of end-stage kidney disease independently of estimated glomerular filtration rate. AB - BACKGROUND/AIMS: The relationship between serum total bilirubin (TB) and estimated glomerular filtration rate (eGFR) is controversial and there is no report on the association between TB and end-stage kidney disease (ESKD). METHODS: We examined the cross-sectional association between TB and eGFR and investigated whether TB can predict ESKD with multivariable logistic regression adjusted for age, sex, and baseline eGFR using hospital-based data. RESULTS: The geometric mean TB of patients with eGFR >= 90 mL/min/1.73 m2 (S1), 8960 mL/min/1.73 m2 (S2), 59-30 mL/min/1.73 m2 (S3), 29-15 mL/min/1.73 m2 (S4), and < 15 mL/min/1.73 m2 (S5 = ESKD) was 0.55 mg/dL, 0.59 mg/dL, 0.56 mg/dL, 0.47 mg/dL, and 0.36 mg/dL (all p<0.0001 except for S1 vs. S3 where p=0.3726), respectively excluding patients with hyperbilirubinemia (TB > 1.24 mg/dL). The odds ratio (95% confidence interval) of incident ESKD for each 0.1 mg/dL increase in TB and hypobilirubinemia defined as TB <= 0.34 mg/dL were 0.92 (0.80-1.07) (p=0.2804) and 3.51 (1.56-7.88) (p=0.0023), respectively in patients with baseline eGFR >= 15 mL/min/1.73 m2 and 0.59 (0.37-0.95) (p=0.0283) and 6.03 (1.63-22.30) (p=0.0071), respectively in patients with baseline eGFR 29-15 mL/min/1.73 m2. CONCLUSIONS: Hypobilirubinemia might be a possible risk factor of ESKD. PMID- 22832708 TI - Clinical studies with chemokine receptor-5 (CCR5)-inhibitors. AB - PURPOSE OF REVIEW: To summarise recently published clinical studies of chemokine receptor-5 (CCR5)-blockers, including the small-molecule blocker, maraviroc (MVC) and CCR5-monoclonal antibodies for HIV. MVC may have immunomodulating properties through CCR5-blockade. MVC appears well tolerated and penetrates the central nervous system. For these reasons, MVC is being investigated in immunodiscordance, prevention of IRIS and in HCV-HIV co-infection. Novel techniques allow tropism assignment via sequencing of proviral DNA; this testing platform is being utilised in MVC switch studies in those with HIV viraemia below the level of quantification. MVC is being utilised in regimen intensification studies for HIV associated neurocognitive disease. RECENT FINDINGS: MVC has no anti-inflammatory activity in rheumatoid arthritis. MVC appears well tolerated in hepatitis virus co-infected patients and MVC-intensification in HCV-HIV co infection suggests a favourable impact on liver fibrosis. Early pilot data suggests MVC intensification may have functional benefit in the CNS. There is a growing body of data on tropism testing using proviral DNA; this technology is being utilised in MVC switch studies. CCR5-monoclonal antibodies administered subcutaneously are promising in Phase II development. SUMMARY: The place of MVC as an anti-HIV drug in the switch setting and as an immunomodulator is yet to be fully determined. PMID- 22832709 TI - Coreceptor usage in different reservoirs. AB - PURPOSE OF REVIEW: HIV-1 infects tissue macrophages, microglia and other mononuclear phagocytes which represent an important cellular reservoir for viral replication and persistence in macrophage-rich tissue. This compartmentalization allows the virus to exist as genetically distinct quasi-species that can have capacities to use different coreceptors for cell entry. This review assesses the tropism of HIV-1 in different human compartments. RECENT FINDINGS: The majority of HIV infection occurs with R5-tropic viruses probably due to the selective expression of the R5 cell-surface protein on the target cells in the genital muscosa. There is a large concordance of tropism use between blood cell associated proviral DNA and RNA plasma viruses, allowing the use of CC chemokine receptor 5 (CCR5) antagonists in patients who have undetectable viral load and for whom HIV tropism was determined in DNA. Most of HIV strains in central nervous system remain R5-tropic allowing the use of CCR5 antagonists. SUMMARY: There are many clinical situations in which the use of CCR5 antagonists can be used and several ways to determine HIV tropism in most of the compartments. PMID- 22832710 TI - Next-generation sequencing to assess HIV tropism. AB - PURPOSE OF REVIEW: Deep sequencing of the V3 region of the HIV envelope gene can detect minority non-R5 variants in patients with high sensitivity and specificity. As next-generation sequencing approaches have matured, the clinical utility of deep sequencing for HIV tropism has entered the clinic. Accurate and sensitive tropism testing is essential for successful treatment with the CCR5 antagonist class of antiretrovirals. RECENT FINDINGS: This review will focus on five aspects of next-generation sequencing for assessing HIV tropism: some background on the necessity of deep sequencing versus other tropism methods; the methodological process of 454 sequencing and analysis; other next-generation sequencing technologies; the diagnostic performance of deep sequencing relative to other tropism assays; and the use of deep sequencing in clinical practice. SUMMARY: This method has emerged quickly as both a research and clinical tool because of its high concordance with commonly used phenotypic tropism assays and its ability to predict virological response to CCR5 antagonist-containing regimens. PMID- 22832711 TI - HIV population genotypic tropism testing and its clinical significance. AB - PURPOSE OF REVIEW: HIV co-receptor tropism testing is recommended before therapy when the C-C chemokine receptor type 5 antagonist maraviroc is initiated. This review addresses the use of population genotypic tropism testing in relation to clinical practice. RECENT FINDINGS: Genotypic tropism tests predict viral co receptor tropism based on the sequence of the V3 loop of the viral envelope. HIV occurs in a swarm of variants in the patient's body, called quasispecies. As next generation sequencing techniques are not generally accessible to date, triplicate testing is often performed to improve sensitivity of population-based approaches, but no prospective studies assessing the performance of single and triplicate procedures related to clinical outcome have been performed yet. For interpretation of the genotype several web-based algorithms have been developed. Varying the cut-off of the commonly used geno2pheno[co-receptor] algorithm changes the sensitivity and specificity of the tropism prediction. In retrospective analyses of clinical studies and cohorts genotypic population tropism testing demonstrated equal correlation with clinical outcome on maraviroc compared with phenotypic assays.In patients with suppressed viraemia, proviral DNA testing is a well tolerated alternative to HIV-RNA testing. SUMMARY: Population genotypic methods have greater accessibility, lower cost, and faster turnaround time than other methods. Despite limited sensitivity for minority variants HIV genotypic population tropism testing showed good correlation with clinical outcome. PMID- 22832712 TI - Phenotyping methods for determining HIV tropism and applications in clinical settings. AB - PURPOSE OF REVIEW: HIV-1 enters CD4-expressing cells via one or both of the chemokine receptors CCR5 and CXCR4. Specific CCR5 antagonists are now in clinical use, but only for CCR5-tropic viruses. Hence, several methods have been developed for assessing HIV-1 tropism in patients who are candidates for CCR5 antagonists. This article reviews current data on phenotypic assays of tropism. RECENT FINDINGS: Phenotypic assays are still used as reference, although genotypic methods have improved. The main advantages of phenotypic assays are their great sensitivity for detecting minor CXCR4-using variants and their capacity to assess non-B subtypes of HIV-1. Clinical trials of maraviroc have, thus, relied on the phenotypic determination of HIV-1 tropism. However, new genotypic approaches that are more sensitive for minor CXCR4-using variants, notably ultra-deep pyrosequencing, are now challenging phenotypic assays. Nevertheless, phenotypic assays are essential for improving genotypic algorithms for determining HIV-1 tropism as well as for assessing the resistance of R5-tropic viruses to CCR5 antagonists. SUMMARY: HIV-1 tropism should be determined before using CCR5 antagonists. Phenotypic recombinant assays are still the benchmark tests for characterizing HIV-1 tropism as their great sensitivity enables them to detect minor CXCR4-using variants of both B and non-B HIV-1 subtypes. PMID- 22832713 TI - Global end-diastolic volume is associated with the occurrence of delayed cerebral ischemia and pulmonary edema after subarachnoid hemorrhage. AB - Predictive variables of delayed cerebral ischemia (DCI) and pulmonary edema following subarachnoid hemorrhage (SAH) remain unknown. We aimed to determine associations between transpulmonary thermodilution-derived variables and DCI and pulmonary edema occurrence after SAH. We reviewed 34 consecutive SAH patients monitored by the PiCCO system. Six patients developed DCI at 7 days after SAH on average; 28 did not (non-DCI). We compared the variable measures for 1 day before DCI occurred (DCI day -1) in the DCI group and 6 days after SAH (non-DCI day -1) in the non-DCI group for control. The mean value of the global end-diastolic volume index (GEDI) for DCI day -1 was lower than that for non-DCI day -1 (676 +/ 65 vs. 872 +/- 85 mL/m, P = 0.04). Central venous pressure (CVP) was not significantly different (7.8 +/- 3.1 vs. 9.4 +/- 1.9 cm H2O, P = 0.45). At day -1 for both DCI and non-DCI, 11 patients (32%) had pulmonary edema. Global end diastolic volume index was significantly higher in patients with pulmonary edema than in those without this condition (947 +/- 126 vs. 766 +/- 81 mL/m, P = 0.02); CVP was not significantly different (8.7 +/- 2.8 vs. 9.2 +/- 2.1 cm H2O, P = 0.78). Although significant correlation was found between extravascular lung water (EVLW) measures and GEDI (r = 0.58, P = 0.001), EVLW and CVP were not correlated (r = 0.03, P = 0.88). Thus, GEDI might be associated with DCI occurrence and EVLW accumulation after SAH. PMID- 22832715 TI - Isolation and characterisation of a novel Bohle-like virus from two frog species in the Darwin rural area, Australia. AB - Twelve captive magnificent tree frogs Litoria splendida and 2 green tree frogs L. caerulea on a property in the Darwin rural area (Northern Territory, Australia) either died or were euthanased after becoming lethargic or developing skin lesions. Samples from both species of frog were submitted for histopathology and virus isolation. An irido-like virus was cultured from tissue samples taken from both species and was characterised using electron microscopy, restriction enzyme digests and nucleic acid amplification and sequencing. The isolates were determined to belong to the genus Ranavirus, were indistinguishable from each other and shared a 98.62% nucleotide similarity and a 97.32% deduced amino acid homology with the Bohle iridovirus over a 1161 bp region of the major capsid gene. This is the first isolation of a ranavirus from amphibians in the Northern Territory and the first report of natural infection in these 2 species of native frog. The virus is tentatively named Mahaffey Road virus (MHRV). PMID- 22832716 TI - New genotypes of white spot syndrome virus (WSSV) and Taura syndrome virus (TSV) from the Kingdom of Saudi Arabia. AB - White spot syndrome virus (WSSV) and Taura syndrome virus (TSV) are highly pathogenic to penaeid shrimp and have caused significant economic losses in the shrimp culture industry around the world. During 2010 and 2011, both WSSV and TSV were found in Saudi Arabia, where they caused severe mortalities in cultured Indian white shrimp Penaeus indicus. Most outbreaks of shrimp viruses in production facilities can be traced to the importation of infected stocks or commodity shrimp. In an attempt to determine the origins of these viral outbreaks in Saudi Arabia, we performed variable number of tandem repeat (VNTR) analyses for WSSV isolates and a phylogenetic analysis for TSV isolates. From the WSSV genome, the VNTR in open reading frames (ORFs) 125 and 94 were investigated with PCR followed by DNA sequence analysis. The genotypes were categorized as {N125, N94} where N is the number of repeat units in a specific ORF, and the subscript indicates the ORF (i.e. ORFs 125 and 94 in this case). From 15 Saudi Arabia WSSV isolates, we detected 3 genotypes: {6125, 794}, {7125, del94}, and {8125, 1394}. The WSSV genotype of {7125, del94} appears to be a new variant with a 1522 bp deletion encompassing complete coding regions of ORF 94 and ORF 95 and the first 82 bp of ORF 93. For TSV genotyping, we used a phylogenetic analysis based on the amino acid sequence of TSV capsid protein 2 (CP2). We analyzed 8 Saudi Arabian isolates in addition to 36 isolates from other areas: SE Asia, Mexico, Venezuela and Belize. The Saudi Arabian TSV clustered into a new, distinct group. Based on these genotyping analyses, new WSSV and TSV genotypes were found in Saudi Arabia. The data suggest that they have come from wild shrimp Penaeus indicus from the Red Sea that are used for broodstock. PMID- 22832717 TI - Sodium alginate from Sargassum wightii retards mortalities in Penaeus monodon postlarvae challenged with white spot syndrome virus. AB - Sodium alginate extracted from brown seaweed Sargassum wightii (16.35 +/- 1.42%, mean [+/-SD] yield from 5 extractions) was prepared as a powder or beads and used to enrich Artemia nauplii at concentrations of 100, 200, 300 and 400 mg l-1. The alginate-enriched nauplii were fed to Penaeus monodon shrimp postlarvae (PL) stage 15 (PL15, i.e. 15 d old) for 20 d. Mean weight gain and specific growth rate over this period were 0.24 g and 15.8%, respectively, in PL groups not fed alginate, and 0.20-0.28 g and 14.7-16.5%, respectively, in PL groups fed alginate. Amongst PL35 then challenged with white spot syndrome virus (WSSV) by immersion, all PL not fed alginate died within 9 d. However, amongst PL fed the 4 concentrations of alginate powder or beads, mortality rates reduced with increasing alginate concentration, and between 25 and 32% PL remained alive when the bioassay was terminated on Day 21. Amongst alginate-fed PL groups compared with the control group, mortality was reduced by 26.5 to 58.4%. Nested PCR detection of WSSV revealed sodium alginate concentration-dependent reductions in infection loads. The data indicate that sodium alginate extracted from brown seaweed and fed to P. monodon can retard progression of WSSV disease. PMID- 22832718 TI - Monoclonal antibodies against extra small virus show that it co-localizes with Macrobrachium rosenbergii nodavirus. AB - The capsid protein (CP) gene of extra small virus (XSV) expressed in Escherichia coli as a 42 kDa glutathione S-transferase (GST)-fusion protein (GST-XCP) or a 20 kDa His6-fusion protein (His6-XCP) were purified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), combined, and used to immunize Swiss mice to produce monoclonal antibodies (MAbs). Using dot blot, Western blot, and immunohistochemistry (IHC) methods, 4 MAbs specific to the XSV CP detected XSV in the freshwater prawn Macrobrachium rosenbergii without cross-reaction to host proteins or to proteins of Macrobrachium rosenbergii nodavirus (MrNV) or 5 of the most pathogenic viruses of penaeid shrimp. In dot blots, the combined MAbs could detect down to ~10 to 20 fmol ul-1 of purified GST-XCP protein, which was somewhat more sensitive compared to any single MAb. Used in conjunction with an MrNV-specific MAb, white tail disease (WTD) was diagnosed more effectively. However, the sensitivity at which the combined 4 MAbs detected XSV CP was 1000 fold lower than XSV RNA detected by RT-PCR. IHC analysis of M. rosenbergii tissue sections using the MAbs showed XSV infection to co-localize at variable loads with MrNV infection in heart and muscle cells as well as cells of connective tissues in the hepatopancreas. Since XSV histopathology remained prominent in tissues of some prawns in which MAb reactivity for MrNV was low compared to MAb reactivity for XSV, XSV might play some role in WTD severity. PMID- 22832720 TI - Development of real-time PCR assays for discrimination and quantification of two Perkinsus spp. in the Manila clam Ruditapes philippinarum. AB - The Manila clam Ruditapes philippinarum is infected with 2 Perkinsus species, Perkinsus olseni and P. honshuensis, in Japan. The latter was described as a new species in Mie Prefecture, Japan, in 2006. Ray's Fluid Thioglycollate Medium (RFTM) assay has been most commonly used to quantify Perkinsus infection. However, this assay cannot discriminate between species that resemble one another morphologically. We developed real-time PCR assays for the specific quantification of P. olseni and P. honshuensis. DNA was extracted using Chelex resin. Cultured P. olseni and P. honshuensis cells were counted and spiked into uninfected clam gill tissue prior to DNA extraction to generate standard curves, which allowed quantification based on the PCR cycle threshold values. We compared the RFTM assay with both real-time PCR assays by quantifying Perkinsus spp. in gill tissue samples from the same individual clams obtained from various localities in Japan. Infection intensities estimated by both assays were significantly correlated (r2 = 0.70). Our results suggest that the prevalence and infection intensity of P. honshuensis are much lower than for P. olseni in Manila clams. PMID- 22832719 TI - Gibel carp Carassius auratus gut microbiota after oral administration of trimethoprim/ sulfamethoxazole. AB - Trimethoprim/sulfamethoxazole is widely used in the treatment of infectious diseases caused by bacterial pathogens in aquaculture. However, the practice of antibiotic administration can promote the emergence of resistant strains of bacteria and result in a wane in efficacy over time. The objective of this study was to assess the effect of oral treatment with trimethoprim/sulfamethoxazole on the gastrointestinal (GI) microbiota of healthy gibel carp and those affected with bacterial enteritis. By using denaturing gradient gel electrophoresis (DGGE), the changes in the predominant bacterial communities were directly depicted for the first time. The main findings were (1) Actinobacteria, Firmicutes and Proteobacteria were the predominant phyla in the healthy gibel carp intestine; (2) administration of antibiotics had a more profound impact on the intestinal microflora of healthy fish than of the diseased ones; and (3) Enterobacteriaceae might be one of the major drug-resistant bacteria in the gibel carp intestine. This study provides an insight into the effect of antibiotic treatment on the establishment and colonization of fish GI microbiota and speculates on some possible drug-resistant bacteria. PMID- 22832721 TI - Gastrointestinal helminth community of loggerhead sea turtle Caretta caretta in the Adriatic Sea. AB - We analysed the intestinal helminth community of 70 loggerhead sea turtles Caretta caretta with a curved carapace length ranging from 25 to 85.4 cm, recovered dead in neritic foraging habitats in the Adriatic Sea in 1995 to 2004. The overall prevalence of infection was high (70.0%), with a mean abundance of 36.8 helminth parasites per turtle. Helminth fauna comprised 5 trematodes (Calycodes anthos, Enodiotrema megachondrus, Orchidasma amphiorchis, Pachypsolus irroratus, Rhytidodes gelatinosus) and 3 nematodes (Sulcascaris sulcata, Anisakis spp., Hysterothylacium sp.), with 6 taxa specific for marine turtles. In terms of infection intensity and parasite abundance, O. amphiorchis was the dominant species (mean intensity: 49.8; mean abundance: 12.8), followed by R. gelatinosus (30.5 and 8.3, respectively) and P. irroratus (23.5 and 7.0, respectively), while larval Anisakis spp. exhibited the highest prevalence (34.3%). The intensity of helminth infection ranged from 1 to 302 (mean: 52.6 +/- 69.1) and was not correlated with the size of turtles; this relationship held for all species, except R. gelatinosus (rS = 0.556, p < 0.05). In comparison to other marine habitats, the helminth community of Adriatic loggerheads is characterised by higher species diversity (Shannon-Wiener H' = 1.58) and evenness (E = 0.76), and lower dominance values (Berger-Parker d = 0.35), which can be attributed to the life history and feeding ecology of sea turtles in recruited neritic grounds and the diversity of their benthic prey. PMID- 22832722 TI - Thirty year retrospective evaluation of pneumonia in a bottlenose dolphin Tursiops truncatus population. AB - Pneumonia is one of the most common causes of morbidity in bottlenose dolphins Tursiops truncatus. To better understand associations of pneumonia with demographics, microbiology, pathology, and histopathology, a retrospective study on 42 dolphins from the US Navy Marine Mammal Program dolphin population was conducted (1980 to 2010). A total of 21 (50%) of the dolphins evaluated had pneumonia confirmed by histopathology. Bacterial and fungal pneumonia was present in 42.9 and 28.6% of cases (9 and 6 cases), respectively, with Staphylococcus aureus as the most common confirmed pathogen (4 cases, 19%). Other pathogens identified as the cause of pneumonia were Cryptococcus neoformans, Erysipelothrix rhusiopathiae, Histoplasma capsulatum, parainfluenza virus, Proteus species, Pseudomonas aeruginosa, and Streptococcus zooepidemicus. Neither sex nor age was a predictor of pneumonia. While many of the infections involved disseminated disease, lungs were consistently the most severely affected organs. The present study demonstrates the high susceptibility of dolphins to respiratory infections. Areas that warrant further investigation include eosinophilic pneumonia, chronic infections, co-infections, and metabolic or iron-storage diseases. There is a continuing need to improve the early diagnosis and effective treatment of pneumonia in dolphins. PMID- 22832723 TI - Treatment of chytridiomycosis with reduced-dose itraconazole. AB - Effective treatment methods to eliminate infection with Batrachochytrium dendrobatidis (Bd) are required for development of sustainable captive survival assurance populations of amphibians and to reduce the risk of introducing Bd to new locations as part of amphibian trade or reintroduction programs. Treatment with itraconazole baths at 100 mg l-1 is commonly used in captive amphibians, but side effects are observed in some amphibian species and life stages. Naturally occurring outbreaks of chytridiomycosis in Wyoming toads Anaxyrus baxteri and White's tree frogs Litoria caerulea were treated with lower-dose itraconazole baths (e.g. 50 mg l-1 for White's tree frogs) and followed post-treatment with serial Taqman PCR testing to confirm elimination of Bd infection. Post-treatment PCR tests were consistently negative for the presence of Bd and treatment was deemed successful. Although this was not a controlled clinical trial, results suggest that lower doses of itraconazole may be effective for treatment of chytridiomycosis with resulting cost savings to amphibian conservation programs and a potential for a reduction in dose-related side effects from itraconazole treatment. Prospective clinical trials of alternative itraconazole treatment protocols are encouraged. PMID- 22832724 TI - Effective penile block for circumcision in adults. AB - BACKGROUND: The dorsal nerve block of the penis during circumcision has not been standardized and the effectiveness of the block can be changeable. The aim of this study was to determine which technique is more suitable for blocking sensory innervations of penis. METHODS: This prospective study was done on adults who voluntarily applied to be circumcised. Patients were randomized into three distinctive groups; first, just circular infiltration; second, circular plus dorsal penile infiltration; and third, circular plus ventral upward infiltration. Sensation was tested using pinprick sensory testing before and after infiltration. The total duration of the procedure was recorded. RESULTS: In total, 89 adult uncircumcised men were included into the study. The average age of men was 21.4 (min: 20; max: 25). The average operation time in the third group was significantly shorter. The sensation distribution, especially around the frenulum sensitivity results were in the first minute 100, 81.3, 72.4 %; in the third minute 85.7, 37.5, 20.7 %; and in the fifth minute 57.1, 18.8, and 0 % for the first, second, and third group, respectively. In the fifth minute, there was no sensitivity for any patients in the third group and it was significant. CONCLUSION: Circular plus ventral upward anesthesia is an easy and feasible technique for local anesthesia in circumcision. PMID- 22832725 TI - Methods in pharmacoepidemiology: a review of statistical analyses and data reporting in pediatric drug utilization studies. AB - PURPOSE: To evaluate the quality of data reporting and statistical methods performed in drug utilization studies in the pediatric population. METHODS: Drug utilization studies evaluating all drug prescriptions to children and adolescents published between January 1994 and December 2011 were retrieved and analyzed. For each study, information on measures of exposure/consumption, the covariates considered, descriptive and inferential analyses, statistical tests, and methods of data reporting was extracted. An overall quality score was created for each study using a 12-item checklist that took into account the presence of outcome measures, covariates of measures, descriptive measures, statistical tests, and graphical representation. RESULTS: A total of 22 studies were reviewed and analyzed. Of these, 20 studies reported at least one descriptive measure. The mean was the most commonly used measure (18 studies), but only five of these also reported the standard deviation. Statistical analyses were performed in 12 studies, with the chi-square test being the most commonly performed test. Graphs were presented in 14 papers. Sixteen papers reported the number of drug prescriptions and/or packages, and ten reported the prevalence of the drug prescription. The mean quality score was 8 (median 9). Only seven of the 22 studies received a score of >=10, while four studies received a score of <6. CONCLUSIONS: Our findings document that only a few of the studies reviewed applied statistical methods and reported data in a satisfactory manner. We therefore conclude that the methodology of drug utilization studies needs to be improved. PMID- 22832726 TI - Cytotoxicity analysis of water disinfection byproducts with a micro-pillar microfluidic device. AB - Water disinfection byproducts (DBPs) are a class of chemicals that are produced when chemical disinfectants react with organic materials in untreated water. Cytotoxicity and genotoxicity of DBPs have been systematically evaluated to compile a comparative, quantitative database of in vitro mammalian cell toxicity of DBPs. However, one of the most challenging limitations for current DBP cytotoxicity assessment assays is sample availability. Although our current cytotoxicity assay using a 96-well microplate has been designed to reduce sample consumption, further minimization of the size of the test system would allow us to explore various possibilities for point-of-care applications. We have developed a microfluidic device with micro-pillars that shows high uniformity in distribution of cells across all chambers with low cell count. We compare the performance between the 96-well microplate and the microfluidic device by running 72-hour standalone-on-chip cell culture and cytotoxicity analysis experiments, using dimethyl sulfoxide (DMSO) and ethanol as model toxic agents, and bromoacetic acid (BAA) as a representative DBP. The results show close agreement between the two systems. The measured LC(50) values for the 96-well microplate and the microfluidic device are 1.54% v/v and 1.27% v/v for DMSO, 1.44% v/v and 2.92% v/v for ethanol, and 17.6 MUM and 8.20 MUM for BAA, respectively. The micro pillar microfluidic device offers a great reduction in sample consumption while maintaining the accuracy of the cytotoxicity analyses of water disinfection byproducts. PMID- 22832727 TI - Plasma biomarkers of depressive symptoms in older adults. AB - The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) tau and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (~80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches. PMID- 22832729 TI - NMDA receptor genotypes associated with the vulnerability to develop dyskinesia. AB - Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl-D-aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism. PMID- 22832728 TI - Serotonin 1A receptor-mediated signaling through ERK and PKCalpha is essential for normal synaptogenesis in neonatal mouse hippocampus. AB - Aberrant expression of the presynaptic serotonin 1A receptor (5-HT(1A)-R) because of a polymorphism in the 5-HT(1A)-R gene is associated with severe depression in human, whereas its absence up to postnatal day 21 (P21) in the forebrain of mice results in heightened anxiety in adulthood. These observations collectively indicate that the 5-HT(1A)-R has a crucial role in brain development. To understand the mechanistic underpinnings of this phenomenon, we used organotypic slice cultures of hippocampi from C57BL6 mice (C57) at P15, which coincides with the peak of neonatal synaptogenesis. Stimulation of the hippocampal 5-HT(1A)-R caused a dramatic increase in PSD95 expression and dendritic spine and synapse formation through sequential activation of the mitogen-activated protein kinase isozymes Erk1/2 and protein kinase C (PKC). Intrahippocampal infusion of 5-HT(1A) R agonists and signaling inhibitors at P15 revealed that the same pathway through PKCalpha augments PSD95 expression and synaptogenesis in vivo in 24 h in both C57 as well as Swiss Webster mice. Furthermore, intrahippocampal infusion of the antidepressant fluoxetine, a serotonin reuptake inhibitor, also augmented PSD95 expression and synaptogenesis through the same pathway. This increased synaptogenesis was observed even 5 days after treatment. Finally, compared with the wild type, the 5-HT(1A)-R(-/-) mice harbor significantly less synapses in the hippocampus, but infusion of the PKC-stimulator and Alzheimer drug bryostatin into the 5-HT(1A)-R(-/-) mice to bypass the non-existent 5-HT(1A)-R boosted PSD95 expression and synaptogenesis. The elucidated signaling cascade explains how 5 HT(1A)-R regulates hippocampal sculpting and function, which may determine the affective phenotype of an adult. PMID- 22832730 TI - Elevated body mass in National Football League players linked to cognitive impairment and decreased prefrontal cortex and temporal pole activity. AB - Obesity is a risk factor for neurodegenerative disease and has been shown to adversely affect cognitive function. Professional athletes who participate in sports, which expose them to repetitive concussions, may be at heightened risk for cognitive impairment. Here, we investigated the effects of body mass as measured by waist-to-height ratio (WHtR) on regional cerebral blood flow using single-photon emission computed tomography imaging in 38 healthy weight (WHtR mean 49.34 +/- 2.8; age 58 +/- 9.6) and 38 overweight (WHtR mean 58.7 +/- 4.7; age 58 +/- 13.3) retired National Football League football players. After matching for age and position, we used a two sample t-test to determine the differences in blood flow in healthy versus overweight subjects. Statistical parametric mapping revealed a higher WHtR ratio is associated with decreased blood flow in Brodmann areas 8, 9 and 10, brain regions involved in attention, reasoning and executive function (P<0.05, family-wise error) along with deficits in the temporal pole. Moreover, overweight athletes had significant decrease in attention (P = 0.01326), general cognitive proficiency (P = 0.012; Microcog: Assessment of Cognitive Functioning) and memory (P=0.005; Mild Cognitive Impairment Screen). The association between elevated WHtR percentage and decreased blood flow in the prefrontal cortex and temporal pole may be correlated with the decreased performance on tests of attention and memory. These findings suggest that a weight management program may be critical to the health of athletes who have been exposed to mild brain trauma during their careers. PMID- 22832731 TI - Age-related change in brain metabolite abnormalities in autism: a meta-analysis of proton magnetic resonance spectroscopy studies. AB - Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of (1)H-magnetic resonance spectroscopy ((1)H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of (1)H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation. PMID- 22832732 TI - Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry. AB - Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders. PMID- 22832733 TI - Cardiometabolic risk and the MTHFR C677T variant in children treated with second generation antipsychotics. AB - Second-generation antipsychotics (SGAs) are increasingly being used to treat children with a variety of psychiatric illnesses. Metabolic syndrome (MetS), a risk factor for cardiovascular disease, is a side-effect of SGA-treatment. We conducted a cross-sectional study and assessed the association of the methylenetetrahydrofolate reductase (MTHFR) C677T variant with features of MetS in SGA-treated (n=105) and SGA-naive (n=112) children. We targeted the MTHFR C677T variant, because it is associated with risk for cardiovascular disease, and features of MetS in adults without psychiatric illness. MetS in children is based on the presence of any three of the following: waist circumference >= 90th percentile for age and sex; plasma triglyceride >= 1.24 mmol l(-1); plasma high density lipoprotein-cholesterol <= 1.03 mmol l(-1); systolic or diastolic blood pressure >= 90th percentile for age, sex, and height; and fasting glucose >= 5.6 mmol l(-1). We found that 15% of SGA-treated children had MetS compared with 2% of SGA-naive children (OR 8.113, P<0.05). No effect of the MTHFR C677T variant on psychiatric diagnosis was observed. The MTHFR 677T allele was associated (P<0.05) with MetS (OR 5.75, 95% CI= 1.18-28.12) in SGA-treated children. Models adjusted for duration of SGA treatment, ethnicity, sex, age and use of other medications revealed a positive relationship between the MTHFR 677T allele and diastolic blood pressure Z-scores (P=0.001) and fasting plasma glucose (P<0.05) in SGA treated children. These findings illustrate the high prevalence of MetS in SGA treated children and suggest metabolic alterations associated with the MTHFR C677T variant may have a role in the development of MetS features in SGA-treated children. PMID- 22832734 TI - Activation of latent precursors in the hippocampus is dependent on long-term potentiation. AB - The recent discovery of a large latent population of precursor cells in the dentate gyrus of adult mice led us to investigate whether activation of this population is regulated by synaptic activity, thereby explaining the observation that environmental signals can affect neurogenesis. Using a variety of stimulation protocols, we found that only a long-term potentiation (LTP)-inducing protocol activated the latent precursor pool, leading to increased neurogenesis in the dentate gyrus. LTP induced by high-frequency stimulation (HFS) of the perforant pathway in vivo produced a two-fold increase in the number of neurospheres cultured from the stimulated hippocampus, compared with the unstimulated hippocampus. No increase in neurosphere number or neurogenesis was observed when the HFS failed to induce LTP. These results show that LTP can activate latent neural precursor cells in the adult mouse dentate gyrus, thereby providing a direct mechanism for regulating activity-driven neurogenesis. In the future, it may be possible to utilize such learning- or stimulation-induced neurogenesis to overcome disorders characterized by neuronal loss. PMID- 22832735 TI - A promoter polymorphism in the Per3 gene is associated with alcohol and stress response. AB - The period homolog genes Per1, Per2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol. PMID- 22832736 TI - BDNF val66met affects hippocampal volume and emotion-related hippocampal memory activity. AB - The val(66)met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life stress, such as childhood abuse, and psychiatric status. Using structural and functional MRI, we therefore investigated in 126 depressed and/or anxious patients and 31 healthy control subjects the effects of val(66)met on hippocampal volume and encoding activity of neutral, positive and negative words, while taking into account childhood abuse and psychiatric status. Our results show slightly lower hippocampal volumes in carriers of a met allele (n=54) relative to val/val homozygotes (n=103) (P=0.02, effect size (Cohen's d)=0.37), which appeared to be independent of childhood abuse and psychiatric status. For hippocampal encoding activity, we found a val(66)met-word valence interaction (P=0.02) such that carriers of a met allele showed increased levels of activation in response to negative words relative to activation in the neutral word condition and relative to val/val homozygotes. This, however, was only evident in the absence of childhood abuse, as abused val/val homozygotes showed hippocampal encoding activity for negative words that was comparable to that of carriers of a met allele. Neither psychiatric status nor memory accuracy did account for these associations. In conclusion, BDNF val(66)met has a significant impact on hippocampal volume independently of childhood abuse and psychiatric status. Furthermore, early adverse experiences such as childhood abuse account for individual differences in hippocampal encoding activity of negative stimuli but this effect manifests differently as a function of val(66)met. PMID- 22832737 TI - Fatty-acid amide hydrolase polymorphisms and post-traumatic stress disorder after penetrating brain injury. AB - The past few years have seen an increase in the clinical awareness of post traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition. PMID- 22832738 TI - Psychosis, C9ORF72 and dementia with Lewy bodies. PMID- 22832739 TI - Internet teleneurology. PMID- 22832741 TI - Aspirin for acute migraine headaches in adults. PMID- 22832740 TI - Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. AB - BACKGROUND: Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. METHODS: We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. RESULTS: All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype-phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. CONCLUSION: Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea. PMID- 22832742 TI - Enantio- and diastereocontrolled conversion of chiral epoxides to trans cyclopropane carboxylates: application to the synthesis of cascarillic acid, grenadamide and L-(-)-CCG-II. AB - An efficient high yielding improved method for the enantio- and diastereoselective cyclopropanation of chiral epoxides using triethylphosphonoacetate and base (Wadsworth-Emmons cyclopropanation) is reported. The utility of this protocol is illustrated by concise and practical synthesis of cascarillic acid, grenadamide and L-(-)-CCG-II, a cyclopropane containing natural products. PMID- 22832743 TI - Bottom-up optimization of SERS hot-spots. AB - The bottom-up optimization of signal-to-noise ratios for SERS tags employing SAMSA fluorescein as the reporter was achieved using a bifunctional linker with low Raman cross section. By holding the nanoparticles at subnanometer separation, the linker allowed us to optimize the hot-spot thereby significantly reducing the fluorescence background. PMID- 22832744 TI - In vitro cultivation of Anaplasma marginale and A. phagocytophilum in tick cell lines: a review. AB - Continuous cell lines have been established from several ixodid and argasid tick species, representing an excellent tool suitable for the isolation of pathogens and their subsequent propagation, which in turn allows the production of antigenic material for diagnostic tests, antibody and vaccine production, and also for studies on host-vector-pathogen relationships. This paper reviews the use of tick cells for culture initiation and maintenance of two obligate intracellular bacterial pathogens, Anaplasma marginale and Anaplasma phagocytophilum. These in vitro cultivation systems have been used in a wide range of studies, covering morphological ultrastructural analysis, genetics, proteomics and biological differences between strains, including genome transcriptional and protein expression approaches, enabling comparisons between host and vector cells. Thus, such systems open a new window for a better understanding of interactions between pathogens and tick cells. Last but not least, such systems contribute to the reduction in usage of animals for experimental research, as antigenic material can be produced in reasonably large quantities without the use of in vivo species-specific systems. PMID- 22832745 TI - Gastrointestinal helminths in calves and cows in an organic milk production system. AB - The main aim of this study was to determine the distribution of populations of gastrointestinal helminths in lactating crossbred cows and calves during the grazing season in an organic milk production system. In addition, the potential importance of the peripartum in relation to the parasite load was examined. Between January 2007 and December 2008, parasitological fecal examinations were performed on cattle belonging to the Integrated Animal Production Program of Embrapa Agrobiology. The cows' parasite load remained low during the study period, and there were no statistical differences (p > 0.05) in comparisons between the seasons. The average egg count showed a positive correlation (0.80) with the peripartum, such that egg elimination per gram (p < 0.05) was higher during the week of labor than during the pre and postpartum periods. Calves showed low parasite loads, with significantly higher egg elimination (p < 0.05) during the winter. The study indicated that infection with gastrointestinal helminths was not a limiting factor for milk production in the organic system. Specifically, it was concluded that the nematode load can be maintained at moderate levels throughout the production system, even in the absence of anthelmintic treatment. PMID- 22832746 TI - Risk factors relating to helminth infections in cows during the peripartum. AB - The aim of this study was to investigate whether season, lactation number, breed standard and milk production were risk factors relating to occurrences of gastrointestinal nematodes in dairy cows during the peripartum period. Eighty four cows were randomly selected through proportional stratified sampling. In order to analyze the fecal egg per gram (EPG) count, the data were subjected to the Spearman test, Kruskal-Wallis test at 5% significance and linear regression. At the time of calving, the cows showed high EPG counts in relation to all variables analyzed. Among the animals studied, we observed that purebred Holstein cows at their first lactation and with high milk production showed high EPG counts (600) and comprised the group most at risk within the herd studied. In this group, the animals showed moderate EPG during the prepartum period (300) and a significant increase (p < 0.01) in EPG count from the time of calving (900), i.e. an increase of the order of 300%. Selection of animals for milk production in tropical countries should be based not only on productive potential, but also on adaptive features. PMID- 22832747 TI - Acute phase proteins: a potential approach for diagnosing chronic infection by Trypanosoma vivax. AB - The present study aimed to assess potential changes in acute phase proteins in sheep experimentally infected with Trypanosoma vivax. There were studied eight male sheep, four used as controls and four infected with 10(5) T. vivax trypomastigotes. Blood samples were collected at two points times before infection and then at 5,7, 9, 11, 13, 15, 20, 30, 45, 60, 75, 90, 105 and 120 days post-infection (dpi). Blood samples were centrifuged and allotted, and acute phase proteins were then separated by electrophoresis on acrylamide gel containing sodium dodecyl sulfate. Protein concentrations were determined by computer-assisted densitometry. Total protein was determined by colorimetric biuret method. Trypanosomes were counted daily using a 5 mL aliquot of blood smear on a glass slide under a 22 * 22 mm coverslip. Parasites were counted in 100 microscopic fields (40* magnification), and then multiplied by a correction factor. The results were expressed as parasites per mL of blood. For statistical analyses, we used the Wilcoxon test at 5% significance level. There was found a reduction in several acute phase proteins and increase in antitrypsin and transferrin. This finding can be used for the diagnosis of T. vivax infection, especially in chronic infection. PMID- 22832748 TI - Dog parasite incidence and risk factors, from sampling after one-year interval, in Pinhais, Brazil. AB - Domestic animals in urban areas may serve as reservoirs for parasitic zoonoses. The aim of this study was to monitor the parasitic status of household dogs in an urban area of Pinhais, in the metropolitan region of Curitiba, Parana State, Brazil, after a one-year period. In May 2009, fecal samples, skin scrapings and ticks were collected from 171 dogs. Questionnaires were applied to the owners (sex, age, environment and anthelmintic use). In May 2010, 26.3% (45/171) of the dogs were fecal samples re-analysed. From the fecal samples, 33.3% (57/171) in 2009 and 64.4% (29/45) in 2010 were positive. The parasite species most observed were, respectively in 2009 and 2010, Ancylostoma sp., 66.7 and 44.8%, and Strongyloides stercoralis, 26.3 and 3.4%. All the skin scrapings were negative, and no ticks or protozoa were found. There was no statistical association (p > 0.05) between positive fecal tests and age, sex or environment. In 2009 alone, dogs with a history of antiparasitic drug administration were 2.3 times more likely to be negative. A great number of replacement dogs was noticed one year later. Therefore, isolated antiparasitic treatment strategies may have no impact on parasite control, given the risk of introduction of new agents, thereby limiting the prevention strategies. PMID- 22832749 TI - Occurrence of anti-Toxoplasma gondii and anti-Neospora caninum antibodies in cats with outdoor access in Sao Luis, Maranhao, Brazil. AB - The present study aimed to investigate the frequency of anti-Toxoplasma gondii and anti-Neospora caninum antibodies in cats with outdoor access in Sao Luis, Maranhao, Brazil. The presence of IgG anti-T. gondii and anti-N. caninum antibodies was tested using the Indirect Immunofluorescent Antibody Test (IFAT). IgG anti-T. gondii and anti-N. caninum antibodies were detected in 101 (50.5%) and 54 (27%) sampled cats, respectively. The titers of anti-T. gondii antibodies ranged from 40 (cut-off) to 2560. On the other hand, the titers of anti-N. caninum antibodies ranged from 25 (cut-off) to 400. Twenty-seven cats (13.5%) were shown to be seropositive for both parasites. Seventy-four cats (34%) were seropositive only for T. gondii. Twenty-two cats (11%) were seropositive only for N. caninum. The present study showed that cats with outdoor access in Sao Luis, Maranhao, are exposed to T. gondii and N. caninum. PMID- 22832750 TI - Evaluating the effectiveness of an inactivated vaccine from Anaplasma marginale derived from tick cell culture. AB - The protective efficacy of an inactivated vaccine from Anaplasma marginale that was cultured in tick cells (IDE8) for use against bovine anaplasmosis was evaluated. Five calves (Group 1) were inoculated subcutaneously, at 21-day intervals, with three doses of vaccine containing 3 * 10(9) A. marginale initial bodies. Five control calves received saline solution alone (Group 2). Thirty-two days after the final inoculation, all the calves were challenged with approximately 3 * 10(5) erythrocytes infected with A. marginale high-virulence isolate (UFMG2). The Group 1 calves seroconverted 14 days after the second dose of vaccine. After the challenge, all the animals showed patent rickettsemia. There was no significant difference (p > 0.05) between the Group 1 and 2 calves during the incubation period, patency period or convalescence period. All the animals required treatment to prevent death. The results suggest that the inactivated vaccine from A. marginale produced in IDE8 induced seroconversion in calves, but was not effective for preventing anaplasmosis induced by the UFMG2 isolate under the conditions of this experiment. PMID- 22832751 TI - First report of Trypanosoma vivax outbreak in dairy cattle in Sao Paulo state, Brazil. AB - This is the first description of a Trypanosoma vivax outbreak in the state of Sao Paulo (municipality of Lins). Fever, jaundice, decreased milk production, weight loss, profuse diarrhea, abortion, anemia, leukocytosis and hyperfibrinogenemia were observed in the affected animals. Thirty-one cows and calves died out of a total of 1080 in the herd. Three cows showed neurological symptoms like dysmetria, ataxia, muscle weakness, ptyalism, lymph node enlargement and submandibular edema. Flagellated hemoparasites were observed in blood smears. The species was diagnosed as T. vivax by means of PCR. This T.vivax strain showed resistance to diaminazene aceturate and the infection spread quickly at the herd. From the ELISA test, 599 serum samples (98.36%) were positive for anti-T.vivax IgG antibodies. This outbreak occurred during a very dry period, which indicates that other factors were involved in the outbreak, such as absence of tabanids and large populations of Haematobia irritans and Stomoxys calcitrans. The increases in these populations may have been due to the use of biosolid waste from sugar and ethanol plants in the sugarcane plantations surrounding the dairy farm. PMID- 22832752 TI - Susceptibility of the horn fly, Haematobia irritans irritans (Diptera: Muscidae), to insecticides in Brazil. AB - Since horn fly populations became established throughout Brazil, complaints regarding control failure have increased around the country. A broad survey to evaluate the susceptibility of horn flies to both organophosphate (OP) and pyrethroid insecticides was conducted from October 2000 to April 2003. Bioassays using filter papers impregnated with cypermethrin, permethrin or diazinon were conducted on 154 horn fly populations in 14 states and 78 municipalities. Resistance to cypermethrin, the active ingredient present in most insecticide products for horn fly control in Brazil, was detected in 98.46% of the populations, with resistance ratios (RR) ranging from 2.5 to 719.9. Resistance to permethrin (RRs < 6.3) was found in 96.67% of the populations, despite its lack of use. In general, pyrethroid resistance was detected in 97.18% of the horn fly populations, with frequencies greater than 87% in all regions of the country. The status of susceptibility of horn fly populations in Brazil to insecticides can be characterized by high susceptibility to OPs and widespread resistance to pyrethroids, potentially compromising the efficacy of pyrethroid products in most cases. Although some partial results have previously been presented, a general picture of horn fly susceptibility in Brazil is presented here for the first time. PMID- 22832753 TI - Resistance to cypermethrin and amitraz in Rhipicephalus (Boophilus) microplus on the Santa Catarina Plateau, Brazil. AB - With the objective of evaluating Rhipicephalus (Boophilus) microplus resistance to cipermetrina and amitraz, were collected engorged tick females from cattle on 20 farms on the Santa Catarina Plateau, in southern Brazil, between January of 2004 and May of 2006. Were also received 20 groups of engorged R. (B.) microplus females, collected by cattle farmers requesting acaricidal efficacy (AE) testing. Were performed in vitro tests, which consisted of immersing engorged females in cypermethrin (0.015%) and in amitraz (0.025%). An AE >95% was considered indicative of effectiveness. Of the 20 collected groups, 18 (90%) showed cypermethrin resistance and 1 (5%) showed amitraz resistance. Of the 20 received groups, 19 (95%) showed cypermethrin resistance and 2 (10%) showed amitraz resistance. The AE of cypermethrin was found to be >95%, 85-94%, and 55-64%, respectively, in 4 (57.1%), 2 (28.6%), and 1 (14.3%) of 7 reference groups, collected in the 1997-2001 period. The AE of amitraz was >95% in all of those groups. Among the groups of specimens received for analysis in that period, the AE of amitraz was >95% in 6 (85.71%) and 75-84% in 1 (14.28%). R. (B.) microplus resistance to acaricides is increasing on the Santa Catarina Plateau. PMID- 22832754 TI - Detection and molecular characterization of piroplasms species from naturally infected dogs in southeast Brazil. AB - Rangelia vitalii is a protozoon described from dogs in the south and southeast regions of Brazil. It is phylogenetically related to Babesia spp. that infects dogs, but data on this enigmatic parasite is still limited. The aim of this work was to detect piroplasm species in dogs in the state of Rio de Janeiro, Brazil, by 18S rRNA gene-based PCR assay, restriction fragment length polymorphism (RFLP) and sequence analyses. Of 103 dogs examined, seven (6.8%) were positive for Babesia spp. by PCR. The amplified products were digested by restriction enzymes to differentiate the Babesia species, and one sample was identified as Babesia vogeli. The pattern observed for the other six amplification products did not match with pattern described for large Babesia infecting dogs. Sequencing analysis confirmed these six samples as R. vitalii, with high homologies (99 100%) with a sequence from south Brazil. This study confirms the presence of Babesia vogeli and Rangelia vitalii circulate in domestic dogs in Teresopolis, Rio de Janeiro, Brazil. PMID- 22832755 TI - Contracaecumovale (Nematoda: Anisakidae) from Rollandia rolland Quoy & Gaimard 1824 (Aves, Podicipedidae) in Argentina. AB - Necropsy on 15 specimens of white-tufted grebe, Rollandiarolland, caught in the Mar Chiquita and Chascomus lagoons (Buenos Aires province), revealed the presence of Contracaecumovale (Linstow, 1907). This nematode shows a marked specificity for podicipediform birds. The specimens were identified from morphological study on features such as cephalic and esophageal structures and caudal papillae, using both optical and scanning electron microscopy. This is the first record of C. ovale parasitizing R. rolland in Argentina. PMID- 22832756 TI - Gastrointestinal parasites in goats from Monte Castelo, Santa Catarina, Brazil. AB - This study was carried out with the aim of estimating the degree of gastrointestinal helminth infection in goats on the Northern Plateau of Santa Catarina. Twelve young females and 11 adult females were used. Every 28 days, feces samples were taken to quantify the nematode eggs per gram of feces (EPG). Larval culturing was performed on a pool of positive samples from the same group. The fecal egg counts (FECs) ranged from zero to 10,400 EPG in the young group and zero to 7,600 EPG in the adult group. The mean FECs were between 583.3 and 4441.7 in the young group and between 418.2 and 2181.8 in the adult group. Eggs of the order Strongylida and genera Moniezia and Toxocara, and oocysts of Coccidia, were observed. The young animals were more affected and Haemonchus was the most prevalent genus in the samples. PMID- 22832757 TI - Hematological alterations during experimental canine infection by Trypanosoma cruzi. AB - To confirm that Beagle dogs are a good experimental model for Chagas disease, we evaluated hematological alterations during the acute and chronic phases in Beagle dogs infected with the Y, Berenice-78 (Be-78) and ABC strains of Trypanosomacruzi, correlating clinical signs with the parasitemia curve. We demonstrate that the acute phase of infection was marked by lethargy and loss of appetite. Simultaneously, we observed anemia, leukocytosis and lymphocytosis. Also,we describe hematological alterations and clinical signs that were positively correlated with the parasitemia during the experimental infection with the three strains of T.cruzi, and demonstrate that experimental infection of Beagle is a trustworthy model for Chagas disease. PMID- 22832758 TI - Control of Strongyloides westeri by nematophagous fungi after passage through the gastrointestinal tract of donkeys. AB - Strongyloides westeri is the most prevalent nematode among equines aged up to four months and causes gastrointestinal disorders. The objective of this study was to observe the control of infective S. westeri larvae (L3) by the nematophagous fungi Duddingtonia flagrans (AC001) and Monacrosporium thaumasium (NF34) after passage through the gastrointestinal tract of female donkeys. Twelve dewormed female donkeys that were kept in stables were used. Two treatment groups each comprising four animals received orally 100 g of pellets made of sodium alginate matrix containing a mycelial mass of either D. flagrans (AC001) or M. thaumasium (NF34). The control group consisted of four animals that received pellets without fungus. Feces samples were then collected from the animal groups at different times (after 12, 24, 48 and 72 hours). These feces were placed in Petri dishes containing 2% water-agar medium and 1000 L3 of S. westeri. AC001 and NF34 isolates showed the ability to destroy the L3, after gastrointestinal transit, thus demonstrating their viability and predatory activity. PMID- 22832759 TI - Occurrence of anti-Neospora caninum antibodies in dogs in rural areas in Minas Gerais, Brazil. AB - The aim of this study was to determine the frequency of anti-Neospora caninum antibodies and risk factors associated with seropositivity in 240 dogs from rural areas of the Lavras, Belo Horizonte and Nanuque regions, state of Minas Gerais, Brazil. The indirect fluorescence antibody test (IFAT) with a cutoff of 50 was used to assess the frequency of seropositive dogs. The risk factor analysis was performed using the Chi-square test (chi2) and multiple logistic regression. The frequency of seropositivity for N. caninum was 15% of the dogs (36/240). Presence of dogs without defined breed (p = 0.018; OR = 5.9) and presence of cattle on the farm (p = 0.053, OR = 4.3) were associated with N. caninum seropositivity. Dogs in the Nanuque region had higher seropositivity for N. caninum (29.9%) than did those in the Lavras (6.2%) and Belo Horizonte (2.2%) regions (p < 0.05). The presence of seropositive dogs in rural areas of Minas Gerais demonstrates the potential risk of horizontal transmission of N. caninum to cattle, especially from dogs without defined breed, which were four times more likely to be seropositive than purebred dogs were. PMID- 22832760 TI - Nematodes in Hoplerytrinus unitaeniatus, Hoplias malabaricus and Pygocentrus nattereri (pisces characiformes) in Marajo Island, Brazil. AB - The aim of this study was to evaluate the tegument, musculature and mesentery of 102 specimens of Hoplerytrinus unitaeniatus, 104 of Hoplias malabaricus and 101 of Pygocentrus nattereri, from Arari Lake, Marajo Island, State of Para, Brazil. Were identified the nematodes Contracaecum sp., Eustrongylides sp. and Procamallanus sp. Contracaecum sp. was the most prevalent, with rates of 84.31% (H. unitaeniatus), 95.19% (H. malabaricus), and 89.11% (P. nattereri). The highest prevalences of Eustrongylides sp. occurred in H. unitaeniatus (56.86%) and H. malabaricus (53.84%). Procamallanus sp. was only collected in the mesentery. Specimens of Eustrongylides sp. collected from the musculature were 91.9% of its population. Among the nematodes found in the mesentery, 98.34% were Contracaecum sp. with a mean intensity (MI) of 7.92 +/- 8.11 (H. unitaeniatus), 8.49 +/- 8.34 (H. malabaricus) and 7 +/- 6.40 (P. nattereri). Contracaecum sp. presented the highest MI (8.49 +/- 8.34) and mean abundance (8.09 +/- 8.34). The highest MI values were observed in the mesentery. Eustrongylides sp. presented MI of 2.65 +/- 3.21 (H. unitaeniatus), 3.41 +/- 3.27 (H. malabaricus) and 2.17 +/- 1.18 (P. nattereri). Nematodes with zoonotic potential that were found with high prevalence, shows the importance of actions by the health authorities. PMID- 22832761 TI - Occurrences of Eimeria spp. and gastrointestinal nematodes in dairy calves in southern Minas Gerais, Brazil. AB - The aim of this cross-sectional observational study was to determine the frequency and factors associated with infection by Eimeria spp. and gastrointestinal nematodes in 356 calves on 20 dairy farms located in southern Minas Gerais, Brazil. Ten species of Eimeria spp. were identified, of which E. bovis (37.6%) and E. zuernii (17.9%) were the most frequent. From fecal cultures, four genera of gastrointestinal nematodes were recovered, of which Cooperia spp. (74.6%) and Haemonchus (19.4%) were the most frequent. Variables relating to higher levels of technology used on dairy farms showed a significant association (p < 0.05) with higher OPG and EPG counts, and are discussed in this study. PMID- 22832762 TI - Calyptospora sp. in Brachyplatystoma vaillantii trapped at the Vigia, State of Para, Brazil. AB - The article describes the first occurrence of hepatic coccidiosis in catfish of the species Brachyplatystoma vaillantii, captured in the coastal region of the Vigia city, state of Para, Brazil, caused by species of the genus Calyptospora, family Calyptosporidae. Thirty specimens of piramutabas were examined where 60% were infected with liver location, featuring numerous mature and immature oocysts, grouped or isolated, with four sporocysts in pyriform shape. They were described on their morphology and dimensions of the oocysts and sporocysts, obtained from light microscopy and differential interference contrast. PMID- 22832764 TI - Starting the year 2012. PMID- 22832763 TI - Ectoparasites of dogs in home environments on the Caribbean slope of Costa Rica. AB - Reports on ectoparasites on dogs in Central America are scarce. The aim of this study was to identify flea, louse and tick species infesting dogs in home environments on the Caribbean slope of Costa Rica, and determine their frequency and coexistence. Ectoparasites were collected from dogs in 83 rural homes at five study sites. Specimens were identified and separated according to species. Fleas were the most common ectoparasite (G = 22,217, DF = 8, p = 0.004). Ctenocephalides felis and Pulex simulans were found in 83% and 55% of the homes with ectoparasites, respectively. Trichodectes canis (13%), Heterodoxus spiniger (10%), Rhipicephalus sanguineus (18%), Rhipicephalus (Boophilus) microplus (5%) and Amblyomma ovale (8%) were also present. More than one species was collected in most cases (66%), and the most common combination was C. felis and P. simulans (59% of homes with fleas). The high frequency of P. simulans emphasizes the need for adequate identification. This was the first study involving different ectoparasites of dogs in Costa Rica, as well as the first report of T. canis in this country. The relative frequency and coexistence of these ectoparasites in the home environment may have implications for animal and human health. PMID- 22832765 TI - The use of contrast-enhanced ultrasound for the evaluation of solid abdominal organ injury in patients with blunt abdominal trauma. AB - BACKGROUND: The evaluation and management of blunt abdominal trauma is primarily nonoperative. Previous attempts to identify parenchymal solid-organ injury with sonography have been unsatisfactory. The use of Perflutren Lipid Microsphere (Definity) contrast-enhanced ultrasound (DUS) may provide an additional modality for evaluation of solid-organ injury with decreased risk of radiation exposure and contrast-related complications. METHODS: Injured patients admitted to a state designated Level I trauma center (January 2008 to July 2009), who showed evidence of solid-organ injury after blunt abdominal trauma on initial computed tomography (CT) were eligible for entry into the study. Patients underwent DUS examinations within 12 hours of initial CT. Ultrasound images were then compared with findings of CT for organ location, size, and grade of injury. RESULTS: Twenty patients with evidence of solid-organ injury on CT were evaluated with DUS. DUS correctly identified five of eight liver lesions, with a sensitivity of 62.5%. DUS correctly identified all nine splenic lesions demonstrating a sensitivity of 100%. DUS correctly identified one of two kidney injuries, demonstrating a sensitivity of 50%. Overall, the positive predictive value for all solid-organ injuries was 100%, with negative predictive value of 20%. The overall sensitivity for DUS was 79% (15 of 19 patients), and specificity was 100% (15 of 15 patients). CONCLUSION: Contrast-enhanced sonography is a potential new modality for the evaluation of solid-organ injury for patients with blunt abdominal trauma. With further research, DUS may provide a safe and accurate alternative to CT. LEVEL OF EVIDENCE: Diagnostic study, level IV. PMID- 22832766 TI - A biomimetic porous hydrogel of gelatin and glycosaminoglycans cross-linked with transglutaminase and its application in the culture of hepatocytes. AB - The development of blended gelatin and glycosaminoglycan (GAG) scaffolds can potentially be used in many soft tissue engineering applications since these scaffolds mimic the structure and biological function of native extracellular matrix (ECM). In this study, we were able to obtain a gelatin-GAG scaffold by using a concentrated emulsion templating technique known as high internal phase emulsion (HIPE), in which a prevailing in volume organic phase is dispersed in the form of discrete droplets inside an aqueous solution of three biopolymers represented by gelatin, hyaluronic acid (HA) and chondroitin sulfate (CS) in the presence of a suitable surfactant. In order to preserve the bioactive potential of the biopolymers employed, the cross-linking procedure involved the use of transglutaminase (MTGase) that catalyzes the formation of covalent N-epsilon (gamma-glutamyl) lysine amide bonds. Since neither HA nor CS possess the necessary primary amino groups toward which MTGase is active, they were functionalized with the dipeptide glycine-lysine (GK). In this way the introduction of foreign cross-linking bridging units with an unpredictable biocompatibility was avoided. These enzymatic cross-linked gelatin-GAG scaffolds were tested in the culture of primary rat and C3A hepatocytes. Results underlined the good performance of this novel support in maintaining and promoting hepatocyte functions in vitro. PMID- 22832767 TI - Usefulness of the tendon reflex for assessing spasticity after botulinum toxin-a injection in children with cerebral palsy. AB - This study sought to investigate the relationships between clinical and neurophysiologic assessments of spasticity after injection of botulinum toxin-A in children with cerebral palsy. A total of 40 children were recruited. Clinical assessments included the modified Ashworth scale and modified Tardieu scale parameters R1, R2, and D. Neurophysiologic assessment included compound motor action potential, Hoffmann, and tendon reflex. Children showed significant decreases in modified Ashworth scale, R1, and R2 at 2, 4, and 12 weeks and in D at 2 and 4 weeks. Amplitude of compound motor action potential decreased at 2 weeks, Hoffmann reflex amplitude decreased at 4 weeks, and tendon reflex amplitude decreased at 2 and 4 weeks. At 12 weeks, none of the neurophysiologic parameters differed from baseline. The correlations among R2, D, and the amplitude of tendon reflex were significant. Neurophysiologic tests could be used to evaluate reduced spasticity after botulinum toxin-A injection. The amplitude of tendon reflex showed the highest correlation with severity of spasticity. PMID- 22832768 TI - Declining use of the Hallervorden-Spatz disease eponym in the last two decades. AB - There has been a movement to rename Hallervorden-Spatz disease to pantothenate kinase-associated neurodegeneration given Hallervorden and Spatz's complicity in murderous Nazi programs. Similar controversy surrounds Reiter syndrome, and 2 studies demonstrated decreased unqualified use of that eponym in the literature, but not in textbooks. There have been no similar studies regarding Hallervorden Spatz disease. The authors performed a MEDLINE search (1990-2010) looking for unqualified use of Hallervorden-Spatz disease and performed statistical analysis. They defined "unqualified" as having no reference to the eponym's disfavored use. They then looked in 6 neurology textbooks. The authors identified 156 of 278 articles (56.1%) containing unqualified use of Hallervorden-Spatz disease. But there was a declining trend (P = .000), with 70/80 (87.5%) of articles from 1990 to 1999 and 86/198 (43.4%) from 2000 to 2010. There was also decreased unqualified use of the eponyms in textbooks, with all recent editions using pantothenate kinase-associated neurodegeneration instead. The significant decrease in unqualified use of Hallervorden-Spatz disease is reassuring. PMID- 22832769 TI - Trends, correlates, and disease patterns of antidepressant use among children and adolescents in Taiwan. AB - The authors used a population-based database to investigate antidepressant use among children and adolescents in Taiwan. The National Health Research Institutes provided a database of 1 000 000 random subjects for study. The authors adopted this sample of subjects who were younger than 18 years during 1997 to 2005. Subjects with at least 1 antidepressant prescription were identified. Trends, prevalence, associated factors, and disease patterns of antidepressant use were detected. The 1-year prevalence of pediatric antidepressant use increased from 0.27% in 1997 to 0.47% in 2005. The 1-year prevalence of tricyclic antidepressant, selective serotonin reuptake inhibitor, and other antidepressant use among pediatric population was 0.23%, 0.20%, and 0.08%, respectively, in 2005. The prevalence of pediatric antidepressant use increased from 1997 to 2005. Among pediatric subjects with antidepressant use, selective serotonin reuptake inhibitors, and other antidepressants were used the most for psychiatric disorders, whereas tricyclic antidepressant was used the most for nonpsychiatric disorders. PMID- 22832770 TI - Unusual manifestations of pediatric neuromyelitis optica. AB - Neuromyelitis optica is a rare, severe idiopathic disease that predominantly involves optic nerves and spinal cord. Main clinical features of neuromyelitis optica are visual loss, paraparesis or tetraparesis, sensory loss, and sphincter dysfunction. A 13-year-old girl with vision loss and behavioral change was admitted. Her behavioral changes concerned demanding everything, eating cacik (a kind of meal prepared by yogurt) continuously, calling everyone "father," and self-throttling during the last 1 month, and blurred vision started 15 days ago. On cranial magnetic resonance imaging (MRI), multiple lesions were seen. The patient was admitted 40 days later with walking difficulty. There were lesions in the medulla and cervical spinal cord on MRI. Neuromyelitis optica was diagnosed. Vomiting was the beginning complaint in 2 of 5 hospitalizations later. We conclude that neuromyelitis optica may involve atypical symptoms such as behavioral change and vomiting. Atypical presentations may delay diagnosis. Vomiting may be a recurrence messenger. PMID- 22832771 TI - Autoimmune basal ganglia disorders. AB - The basal ganglia are deep nuclei in the brain that include the caudate, putamen, globus pallidus, and substantia nigra. Pathological processes involving the basal ganglia often result in disorders of movement and behavior. A number of different autoimmune disorders predominantly involve the basal ganglia and can result in movement and psychiatric disorders. The classic basal ganglia autoimmune disorder is Sydenham chorea, a poststreptococcal neuropsychiatric disorder. Resurgence in the interest in Sydenham chorea is the result of the descriptions of other poststreptococcal neuropsychiatric disorders including tics and obsessive compulsive disorder, broadly termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Encephalitic processes affecting the basal ganglia are also described including the syndromes basal ganglia encephalitis, encephalitis lethargica, and bilateral striatal necrosis. Last, systemic autoimmune disorders such as systemic lupus erythematosus and antiphospholipid syndrome can result in chorea or parkinsonism. Using paradigms learned from other autoantibody associated disorders, the authors discuss the autoantibody hypothesis and the role of systemic inflammation in autoimmune basal ganglia disorders. Identification of these entities is important as the clinician has an increasing therapeutic repertoire to modulate or suppress the aberrant immune system. PMID- 22832772 TI - Moebius syndrome and hydrosyringomyelia: description of a new association. AB - The diagnosis of Moebius syndrome, a rare congenital disorder, is primarily based on congenital facial and abducent nerve palsy. Involvement of other cranial nerves is also common. Occasionally the V, X, XI, and XII cranial nerves are involved, resulting in a difficulty to chew, swallow, and cough, which often leads to respiratory complications. Mental retardation and autism have been reported in some cases. Moebius syndrome can be associated with orofacial anomalies and limb malformations. The authors describe a patient with a confirmed diagnosis of Moebius syndrome associated with hydrosyringomyelia. No case of Moebius syndrome involving primarily the spinal cord has been reported so far. This patient did not present with other factors directly linked to syringomyelia. PMID- 22832773 TI - Resistance (weight lifting) training in an adolescent with McArdle disease. AB - Owing to the risk of severe rhabdomyolysis, clinicians advise McArdle disease patients to refrain from strenuous exercise, particularly weight lifting. A 15 year-old male McArdle disease patient performed a 6-week, supervised, light- to moderate-intensity (~65-70% of one-repetition-maximum) resistance (weight lifting) training program (2 sessions/week). Training resulted in ~27% and ~6% increase in one-repetition-maximum bench press and multipower squat performance while inducing no myoglobinuria. The patient changed to a lower disease severity class, that is, he became virtually asymptomatic in terms of exercise limitations. The authors' preliminary data suggest that supervised, light to moderate resistance training is feasible in children with McArdle disease and has potential clinical benefits. PMID- 22832774 TI - The effect of diagnosis, age, and symptom severity on cortical surface area in the cingulate cortex and insula in autism spectrum disorders. AB - Functional activity in the anterior cingulate cortex and insula has been reported to be abnormal during social tasks in autism spectrum disorders. However, few studies have examined surface morphometry in these regions and how this may be related to autism spectrum disorder symptomatology. In this study, 27 individuals with autism spectrum disorders and 25 controls between the ages of 7 to 39 years underwent structural magnetic resonance imaging. Our primary analysis examined differences in surface area in the cingulate and insula, between individuals with and without autism spectrum disorders, as well as age-related changes and associations with social impairments. Surface area in the right cingulate was significantly different between groups and decreased more rapidly with age in autism spectrum disorder participants. In addition, greater surface area in the insula and isthmus was associated with poorer social behaviors. Results suggest atypical surface morphometry in brain regions involved in social function, which appeared to be related to poorer social ability scores. PMID- 22832775 TI - CDKL5 mutations as a cause of severe epilepsy in infancy: clinical and electroencephalographic long-term course in 4 patients. AB - CDKL5 mutations cause severe epilepsy in infancy with subsequent epileptic encephalopathy. As yet, few studies report on long-term observations in patients with CDKL5-related epileptic encephalopathy. In this study, we describe the evolution of the epilepsy phenotype and the electroencephalographic (EEG) features in 4 patients during a maximum observation period of 22 years. All 4 patients had epilepsy starting with focal seizures in the first 3 months of life, evolving to epileptic spasms between the ages of 2 and 6 years and later on to tonic seizures. In 3 patients, epilepsy was resistant to antiepileptic therapy. Although there was no common EEG pattern in all patients, late hypsarrhythmia until the age of 9 years was observed in 2 patients. CDKL5-related epileptic encephalopathies are a group of refractory seizure disorders starting in early infancy. The phenomenon of late hypsarrhythmia may help define a subgroup of patients with severe and adverse outcomes. PMID- 22832777 TI - Sturge-Weber syndrome: clinical spectrum, disease course, and outcome of 30 patients. AB - Sturge-Weber syndrome is a heterogeneous neurocutaneous syndrome with facial and leptomeningeal angiomas, glaucoma, seizures, stroke-like episodes, and mental retardation. The authors critically evaluated the clinical manifestations, outcome, and natural history in 30 patients with Sturge-Weber syndrome followed up from January 1985 to May 2010. Of the patients, 15 were males, age at diagnosis ranged from 1 month to 43 years. Typical port-wine stain nevus occurred in 26 (86%), it was bilateral in 2 (8%), and it was absent in 4 (4%). Nine patients had glaucoma (30%), 3 required surgery. Four had transient hemiparesis. All patients had seizures; they were well controlled in 22 (73.3%); in 8 they remained drug resistant. Three patients underwent surgery and became seizure free. Of the 17 who had mental subnormality, 14 (82.4%) had seizure onset before 2 years. An early age at seizure onset and those with drug-resistant seizures had more severe degree of mental subnormality. Uncontrolled seizures, mental subnormality, visual handicap, and cosmetic disfiguration were the major impediments in life. PMID- 22832776 TI - Unanswered questions in Friedreich ataxia. AB - During the past 15 years, the pace of research advancement in Friedreich ataxia has been rapid. The abnormal gene has been discovered and its gene product characterized, leading to the development of new evidence-based therapies. Still, various unsettled issues remain that affect clinical trials. These include the level of frataxin deficiency needed to cause disease, the mechanism by which frataxin-deficient mitochondrial dysfunction leads to symptomatology, and the reason selected cells are most affected in Friedreich ataxia. In this review, we summarize these questions and propose testable hypotheses for their resolution. PMID- 22832778 TI - Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. AB - Late infantile neuronal ceroid lipofuscinosis (Jansky-Bielchowsky disease) is a rare disease caused by mutations in the CLN2 gene. The authors report the clinical outcome and correlate with genotype in 12 Spanish patients with this disease. Psychomotor regression, epilepsy, and other clinical symptoms/signs were assessed. Age at onset of clinical symptoms ranged from 18 months to 3.7 years, and they included delayed speech and simple febrile seizures followed by epilepsy. Partial seizures and myoclonic jerks occurred at an earlier age (median 3.4 and 3.7 years, respectively) than ataxia and cognitive decline (median 4 years). Clinical regression was initiated by loss of sentences (median 3.7 years) followed by loss of walking ability and absence of language (median 4.5 years). Patients showed blindness and lost sitting ability at similar age (median 5 years). The authors report 4 novel mutations in the CLN2 gene. This study provides detailed information about the natural history of this disease. PMID- 22832779 TI - Infantile spasms (West syndrome) in children with inborn errors of metabolism: a review of the literature. AB - West syndrome (infantile spasms) is an epileptic encephalopathy that includes psychomotor deterioration. In rare cases, it is due to an inherited, progressive metabolic disease. More than 25 inborn errors of metabolism have been considered etiologic or predisposing factors for infantile spasms. This is a review of the literature on reported cases of children diagnosed with a metabolic disease who developed infantile spasms. This article presents in brief the most frequent inborn errors of metabolism that have been associated with West syndrome and also illustrates the importance of screening for inborn errors of metabolism in infantile spasms. PMID- 22832780 TI - Spectrum and prevalence of vasculopathy in pediatric neurofibromatosis type 1. AB - To describe the spectrum and associated clinical features of peripheral and cerebral vasculopathy in pediatric patients with neurofibromatosis type 1, children seen at a single center from 2000 to 2010 with appropriate imaging studies were identified. Scans were assessed for vascular disease by 2 pediatric neuroradiologists. Of 181 children, 80 had pertinent imaging studies: 77 had brain imaging, 6 had peripheral imaging, and 3 had both. Vasculopathy was identified in 14/80 children (18%, minimum prevalence of 14/181; 8%). Of those with vascular abnormalities, 2/14 had peripheral vasculopathy (1% minimum prevalence) and 12/14 had cerebrovascular abnormalities (7% minimum prevalence). No associations were found between vasculopathy and common clinical features of neurofibromatosis type 1, including optic pathway glioma, plexiform neurofibroma, skeletal abnormalities, attention-deficit hyperactivity disorder (ADHD), or suspected learning disability. Both peripheral and cerebral vasculopathy are important complications of pediatric neurofibromatosis type 1 and should be considered in the management of this complex disease. PMID- 22832781 TI - Accuracy of anorectal manometry in patients with fecal incontinence. AB - BACKGROUND/AIM: Patients with fecal incontinence (FI) have lower anal resting (MRP) and squeeze (MSP) pressure and an impaired sensitivity compared to healthy people. However, whether anorectal manometry (ARM) can separate precisely between health and disease is discussed controversially. The aim was to evaluate the accuracy of ARM in a huge cohort of patients and controls. METHODS: ARM was obtained in 144 controls and in 559 FI patients. MRP, MSP, and balloon volume at first perception (BVP) and urge sensation (BVU) were determined. Receiver operating curve analysis was used to determine optimal cut-offs and sensitivity, specificity and accuracy calculated. RESULTS: FI patients showed lower MRP, MSP, BVU (p < 0.001) and a higher BVP (p = 0.007). Deterioration of the ARM parameter increased with FI severity. ARM demonstrated an excellent sensitivity (91.4%) and accuracy (85.8%), but only a moderate specificity (62.5%). The sensitivity of ARM rose with FI severity. The pressure data showed higher sensitivity and accuracy than the sensory data despite comparable specificity. CONCLUSIONS: Sensitivity and accuracy of single ARM parameters is only moderate for the pressure data and poor for the sensory data. In contrast, ARM demonstrated an excellent sensitivity, a moderate specificity, and a convincing accuracy justifying its use in clinical routine. PMID- 22832783 TI - Identification of two DNA helicases UvrD and DinG as suppressors for lethality caused by mutant cspA mRNAs. AB - CspA is a major cold shock-inducible protein (70 aa), and its major role in the cold shock response was shown to be as an RNA chaperone destabilizing secondary structure of mRNAs at low temperature. Previously, we showed that the overexpression of mutant cspA containing premature non-sense codons at various positions led to stalled ribosomes on mutant cspA transcripts, ultimately leading to cell death. This lethality is primarily due to the highly translatable cspA 5' UTR that recruits most of the ribosomes from other mRNAs, which are then stalled at the abnormal stop codon. This was called the 'LACE' effect. We show here that non-sense mutation even at the 67th position as well as substitutions of aromatic amino acid residues present on the RNA-binding surface of CspA protein to alanine caused the LACE effect by trapping a substantial amount of ribosomes on cspA mRNAs. In an attempt to identify a suppressor(s), which may help the cells to recover from the inhibitory LACE effect, genetic screening of an Escherichia coli genomic library was performed. We isolated suppressors that contained the genomic fragments encoding uvrD and dinG, respectively, whose gene products are ATP dependent DNA helicases. The nucleic acid-binding and ATPase activities of these two helicases were found to be essential for their suppression activity. This genomic screening offers an approach to shed light on the mechanistic of 5'-UTR of cspA mRNA and novel roles of E. coli helicases that function in DNA repair. PMID- 22832784 TI - Determinants and prognostic significance of exercise pulmonary hypertension in asymptomatic severe aortic stenosis. AB - BACKGROUND: Recent studies emphasized the usefulness of exercise stress echocardiography in asymptomatic patients with aortic stenosis. Nevertheless, the additive value of exercise pulmonary hypertension (Ex-PHT) in such patients remains unexplored. We therefore aimed to identify the determinants and to test the impact on outcome of Ex-PHT in asymptomatic patients with severe aortic stenosis. METHOD AND RESULTS: Asymptomatic patients with severe aortic stenosis (n=105; aortic valve area <0.6 cm(2)/m(2); age, 71+/-9 years; male, 59%) and preserved left ventricular systolic function (ejection fraction >=55%) were prospectively submitted to exercise stress echocardiography. Resting PHT and Ex PHT were defined as a systolic pulmonary arterial pressure >50 and >60 mm Hg, respectively. Ex-PHT was more frequent than resting PHT (55% versus 6%; P<0.0001). On multivariable logistic regression, the independent predictors of Ex PHT were male sex (odds ratio, 4.3; P=0.002), resting systolic pulmonary arterial pressure (odds ratio, 1.16; P=0.002), exercise indexed left ventricular end diastolic volume (odds ratio, 1.04; P=0.026), exercise e'-wave velocity (odds ratio, 1.35; P=0.047), and exercise-induced changes in indexed left atrial area (odds ratio, 1.36; P=0.006). Ex-PHT was associated with reduced cardiac event free survival (at 3 years, 22+/-7% versus 55+/-9%; P=0.014). In a multivariable Cox proportional hazards model, Ex-PHT was identified as an independent predictor of cardiac events (hazard ratio, 1.8; 95% confidence interval, 1.0-3.3; P=0.047). When exercise-induced changes in mean aortic pressure gradient were added to the multivariable model, Ex-PHT remained independently associated with reduced cardiac event-free survival (hazard ratio, 2.0; 95% confidence interval, 1.1-3.6; P=0.025). CONCLUSIONS: In asymptomatic patients with severe aortic stenosis, the main determinants of Ex-PHT are male sex, resting systolic pulmonary arterial pressure, and exercise parameters of diastolic burden. Moreover, Ex-PHT is associated with a 2-fold increased risk of cardiac events. These results strongly support the use of exercise stress echocardiography in asymptomatic aortic stenosis. PMID- 22832785 TI - Exercise hemodynamics and risk assessment in asymptomatic aortic stenosis. PMID- 22832788 TI - Endoscopic large balloon dilation versus endoscopic sphincterotomy in patients with choledocholithiasis. PMID- 22832786 TI - Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. AB - BACKGROUND: Beyond their role as innate immune effectors, natural killer (NK) cells are emerging as important regulators of angiogenesis and vascular remodeling. Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling and has long been associated with immune dysfunction. Despite this association, a role for NK cells in disease pathology has not yet been described. METHODS AND RESULTS: Analysis of whole blood lymphocytes and isolated NK cells from PAH patients revealed an expansion of the functionally defective CD56(-)/CD16(+) NK subset that was not observed in patients with chronic thromboembolic pulmonary hypertension. NK cells from PAH patients also displayed decreased levels of the activating receptor NKp46 and the killer immunoglobulin-like receptors 2DL1/S1 and 3DL1, reduced secretion of the cytokine macrophage inflammatory protein-1beta, and a significant impairment in cytolytic function associated with decreased killer immunoglobulin-like receptor 3DL1 expression. Genotyping patients (n=222) and controls (n=191) for killer immunoglobulin-like receptor gene polymorphisms did not explain these observations. Rather, we show that NK cells from PAH patients exhibit increased responsiveness to transforming growth factor-beta, which specifically downregulates disease-associated killer immunoglobulin-like receptors. NK cell number and cytotoxicity were similarly decreased in the monocrotaline rat and chronic hypoxia mouse models of PAH, accompanied by reduced production of interferon-gamma in NK cells from hypoxic mice. NK cells from PAH patients also produced elevated quantities of matrix metalloproteinase 9, consistent with a capacity to influence vascular remodeling. CONCLUSIONS: Our work is the first to identify an impairment of NK cells in PAH and suggests a novel and substantive role for innate immunity in the pathobiology of this disease. PMID- 22832790 TI - Pediatric crushing head injury: biomechanics and clinical features of an uncommon type of craniocerebral trauma. AB - BACKGROUND: Head injuries constitute one of the leading causes of pediatric morbidity and mortality. Most injuries result from accidents involving an acceleration/deceleration mechanism. However, a special type of head injury occurs when the children sustain a traumatism whose main component is a static load in relation to a crushing mechanism with the head relatively immobile. PATIENTS AND METHODS: We report a series of children who sustained a craniocerebral injury of variable severity produced by head crushing. We also analyze epidemiological and clinical data, and biomechanics in these injuries. RESULTS: Mean age of the group (13 boys/6 girls) was 4.1 years. All patients showed external lesions (scalp wounds or hemorrhage from the nose, ears, or throat). Eleven children were initially unconscious. Six children presented cranial nerve deficits in addition to impaired hearing. Skull base fractures were seen in most cases with extension to the vault in 11 instances. Fourteen patients had an associated intracranial lesion, including two with diffuse axonal injury. Surgery was performed in three instances. Only seven patients were left with sequelae. DISCUSSION AND CONCLUSIONS: The observed skull, brain, and cranial nerve lesions corresponded to a mechanism of bilateral compression of the children's heads mainly occasioned by a static load, although an associated component of dynamic forces was also involved. The skull and its covering and the cranial nerves were the most severely affected structures while the brain seemed to be relatively well preserved. Most crush injuries appear to be preventable by the appropriate supervision of the children. PMID- 22832791 TI - An approach to aliphatic 1,8-stereocontrol: diastereoselective syntheses of (+/-) patulolide C and (+/-)-epipatulolide C. AB - The tin(iv) bromide promoted reaction of 7-hydroxy-7-phenylhept-2 enyl(tributyl)stannane 11 with benzaldehyde gave a mixture of the epimeric 1,8 diphenyloct-3-ene-1,8-diols 12 and so indirect methods were developed for aliphatic 1,8-stereocontrol to complete diastereoselective syntheses of (+/-) patulolide C 1 and (+/-)-epipatulolide C 40. (5Z)-3,7-syn-7-(2 Trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was prepared from the tin(iv) chloride promoted reaction of 4-(2-trimethylsilylethoxy)methoxypent-2 enyl(tributyl)stannane 16 with acrolein (1,5-syn : 1,5-anti = 96 : 4). An Ireland Claisen rearrangement of the corresponding benzoyloxyacetate 21 with in situ esterification of the resulting acid using trimethylsilyldiazomethane gave methyl (4E,7Z)-2,9-anti-2-benzyloxy-9-(2-trimethylsilylethoxy)methoxydeca-4,7-dienoate 22 together with 10-15% of its 2,9-syn-epimer 26, the 2,9-syn- : 2,9-anti-ratio depending on the conditions used. An 88 : 12 mixture of esters was taken through to the tert-butyldiphenylsilyl ether 38 of (+/-)-patulolide C 1 together with 6% of its epimer 39, by reduction, a Wittig homologation and deprotection/macrocyclisation. Following separation of the epimeric silyl ethers, deprotection of the major epimer 38 gave (+/-)-patulolide C 1. The success of 2,3 Wittig rearrangements of allyl ethers prepared from (5Z)-3,7-syn-7-(2 trimethylsilylethoxy)methoxyocta-1,5-dien-3-ol 17 was dependent on the substituents on the allyl ether. Best results were obtained using the pentadienyl ether 56 and the cinnamyl ether 49 that rearranged with >90 : 10 stereoselectivity in favour of (1E,5E,8Z)-3,10-syn-1-phenyl-10-(2 trimethylsilylethoxy)methoxyundeca-1,5,8-trien-3-ol 50. This product was taken through to the separable silyl ethers 38 and 39, ratio 7 : 93 by regioselective epoxidation and alkene reduction using diimide, followed by deoxygenation, ozonolysis, a Wittig homologation and selective deprotection/macrocyclisation. Deprotection of the major epimer 39 gave (+/-)-epipatulolide C 40. PMID- 22832792 TI - Magnetically-actuated blood filter unit attachable to pre-made biochips. AB - We present a novel blood filter unit that is designed to separate blood plasma from whole blood by simple magnetic actuation. A non-diluted blood sample is dropped into the filter unit and magnetic attraction is applied to squeeze out only blood plasma while blood particles are filtered by membranes stacked in the filter unit. The new filter device yields good filtering performance with nearly perfect filtering efficiency (~99.999%), high plasma recovery (~30%), low blood consumption (<50 MUl), and fast operation (~1 min). Because it is simple to operate and is attachable to any kind of pre-made biochip, it has commercial potential in various lab-on-a-chip applications for blood tests. PMID- 22832794 TI - [Eosinophilic esophagitis: update 2012]. AB - Eosinophilic esophagitis (EoE) with adults, as a new disease emerging during the last decade, is a clinicopathologic disorder of the esophagus characterized by a dense esophageal eosinophilic infiltration and typical esophageal symptoms. As numerous studies about EoE had been reported during last several years, updated consensus of EoE was reported in July 2011. The conceptual definition of EoE is coming. EoE is defined as a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominat inflammation. Other important addition is genotyping feature that implicates thymic stromal lymphopoietin genes or filagrrin as EoE susceptibility genes. The majority of patients has the concurrent allergic disease, especially food or aeroallergen sensitization. Main therapeutic options include topical steroids and dietary modification. Recent issues of EoE include a new concept for proton pump inhibitor-responsive esophageal eosinophilia that it should be excluded to diagnose EoE. PMID- 22832793 TI - Inhibition of acetylcholinesterase activity in brain and behavioral analysis in adult rats after chronic administration of fenproporex. AB - Fenproporex is an amphetamine-based anorectic and it is rapidly converted in vivo into amphetamine. It elevates the levels of extracellular dopamine in the brain. Acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine. Thus, we investigated whether the effects of chronic administration of fenproporex in adult rats alters acquisition and retention of avoidance memory and acetylcholinesterase activity. Adult male Wistar rats received repeated (14 days) intraperitoneal injection of vehicle or fenproporex (6.25, 12.5 or 25 mg/kg i.p.). For behavioral assessment, animals were submitted to inhibitory avoidance (IA) tasks and continuous multiple trials step-down inhibitory avoidance (CMIA). Acetylcholinesterase activity was measured in the prefrontal cortex, hippocampus, hypothalamus and striatum. The administration of fenproporex (6.25, 12.5 and 25 mg/kg) did not induce impairment in short and long-term IA or CMIA retention memory in rats. In addition, longer periods of exposure to fenproporex administration decreased acetylcholinesterase activity in prefrontal cortex and striatum of rats, but no alteration was verified in the hippocampus and hypothalamus. In conclusion, the present study showed that chronic fenproporex administration decreased acetylcholinesterase activity in the rat brain. However, longer periods of exposure to fenproporex did not produce impairment in short and long-term IA or CMIA retention memory in rats. PMID- 22832795 TI - Incidence and risk factors of irritable bowel syndrome in community subjects with culture-proven bacterial gastroenteritis. AB - BACKGROUND/AIMS: The aim of this study was to investigate the incidence and risk factors of irritable bowel syndrome (IBS) in community subjects with culture proven bacterial gastroenteritis. METHODS: This was a prospective, community based, cohort study, which followed patients with a recent history of culture proven bacterial gastroenteritis. IBS was diagnosed with the use of the Rome II criteria at 3 and 6 months after bacterial dysentery. RESULTS: Sixty five cases were included and completed the 6 month follow-up. Thirty four cases (52.3%) were female. Salmonella was the pathogen most frequently identified and seen in 41 patients (63.1%). The cumulative incidence of IBS among patients with microbiologically proven bacterial gastroenteritis within a community was 9.2% and 12.3% at 3 and 6 months of follow-up, respectively. The duration of initial diarrhea (>= 7 days) was associated with an increased risk for the development of IBS (aOR, 14.50 [95% CI, 1.38-152.72]; p=0.022). CONCLUSIONS: Our study suggests that the incidence of IBS among patients with culture-proven bacterial gastroenteritis within a community is similar to that reported among Western populations. A large, prospective study is encouraged to confirm our results and to evaluate the influence of the microbial species on the epidemiology of IBS in Asian populations. PMID- 22832796 TI - [Clinical outcomes in ischemic colitis: according to the colonoscopic extent and feature]. AB - BACKGROUND/AIMS: Ischemic colitis (IC) usually occurs in the elderly population and has a various clinical presentations from mild to severe forms. The aim of this study was to investigate the clinical outcomes according to the involved sites and colonoscopic findings in IC. METHODS: We retrospectively analyzed the medical records of 77 patients who had diagnosed with IC between January 2000 and July 2010. The clinical outcomes were compared according to numbers of the involved segments, location and endoscopic findings. RESULTS: Mean age of the patients was 70+/-11 years and male to female ratio was 1 : 1.26. Hematochezia (67.5%) and abdominal pain (63.6%) were the most common associated symptoms. The colonoscopic examination was performed at mean 4.6+/-3.7 days after the symptom onset. The most common involved segment was the sigmoid colon (72.7%). Duration of fasting, antibiotics therapy, hospital stay and mortality were significantly increased in the patients group with more involved segments (p<0.001, p=0.004, p<0.001, p<0.001, respectively). Duration of antibiotics therapy and hospital stay were significantly longer in the right colon involvement group (p=0.038, p=0.002, respectively). The time taken until the alleviation of symptoms and the white blood cells count were significantly longer and higher in the ulcer or gangrenous group (p=0.001, p=0.022, respectively). CONCLUSIONS: Evaluating the involved sites, the degree and severity of mucosal damage by colonoscopy may be important in predicting the clinical course and prognosis of the patients with IC. Early detection, careful monitoring and prompt treatment are crucial especially in the patients with ulcer or necrosis in colonscopic findings. PMID- 22832797 TI - [A Korean national survey for colorectal cancer screening and polyp diagnosis methods using web-based survey]. AB - BACKGROUND/AIMS: There is a paucity of national guideline for colorectal cancer screening and polyp diagnosis in Korea. Thus, we investigated the present state of colorectal cancer screening and polyp diagnosis methods using web-based survey to use as reference data for developing a guideline. METHODS: A multiple choice questionnaires of screening recommendations was sent via e-mail to members of the Korean Association for the Study of Intestinal Diseases and primary care physicians who participated in the national colonoscopy surveillance program. Among 425 colonoscopists, a total 263 colonoscopists replied (response rate, 61.9%). RESULTS: The most commonly recommended starting age for colorectal cancer screening and polyp diagnosis was 50 years old in the average risk group, and 40 years old in groups who had a family history of colon cancer (64.3% and 65.0% respectively). Surgeons had a tendency to recommend screening in younger people than internist do. Ninety-eight percent of physicians recommended screening colonoscopy to asymptomatic, average-risk patients as a first choice. Only 2% of physicians chose sigmoidoscopy as a screening tool. When the initial colonoscopy showed a negative finding, over 60% of internists repeated the exam 5 years later, whereas 62% of surgeons did so within 3 years. CONCLUSIONS: The starting age of colorectal cancer screening and the interval of the colorectal polyp examination are not uniform in various medical environments, and there is a discrepancy between the practical recommendations and western guidelines. Thus, a new evidence-based national practice guideline for colorectal cancer screening and polyp diagnosis should be developed. PMID- 22832798 TI - [The effects of family history of colorectal cancer on the development of colorectal adenoma]. AB - BACKGROUND/AIMS: Early detection of polyp is important for the prevention of colorectal cancer (CRC). There have been few studies to investigate the relationship between colorectal adenoma and family history of CRC (FHCRC) in Korea. The aim of this study was to identify the relationship between colorectal adenoma and FHCRC. METHODS: Between March 2009 and September 2010, 225 patients with adenomatous polyps were included. Their medical records with clinical history and size, numbers, histology of polyps were reviewed. Immunohistochemical staining using Bcl-2, Bax, p-AKT, NF-kappaB, and beta-catenin antibodies were performed. We compared the histology of adenoma and expression of immunohistochemical staining according to the existence of FHCRC. RESULTS: The incidence of colorectal adenoma increased in case of FHCRC (p=0.029). In patients with FHCRC, the mean age of patients was 49 years old and younger than patients without FHCRC. In addition in patients with FHCRC, the incidence of advanced adenoma was significantly higher than in patients without FHCRC (p=0.001). The expression of Bax was significantly lower in patients with FHCRC than without FHCRC (p=0.046). CONCLUSIONS: There was a tendency for polyp to develop in their younger ages and to be more advanced adenomas in patients with FHCRC. The low expression of Bax, tumor suppressor gene, might be associated with the development of polyps in patient with FHCRC. Therefore, patients with FHCRC may be better to start screening colonoscopy earlier than patient without FHCRC. PMID- 22832799 TI - [A case of gastric adenocarcinoma presenting as portal hypertension]. AB - Portal vein thrombus has been detected in patients with liver cirrhosis, pancreatitis, ulcerative colitis, septicemia, myeloproliferative disorder, and neoplasm. The formation of portal tumor thrombus by hepatocellular carcinoma is well recognized, because of its high incidence, and subsequent development of portal hypertension such as rupture of varices, ascites and liver failure indicates the poor prognosis. In gastric cancer, portal hypertension as an initial presentation is extremely rare. Herein we report a case presenting as portal hypertension caused by tumor thrombus without invasion of liver parenchyma. It is presumed to be intraluminal tumor thrombus originating from primary foci of gastric adenocarcinoma. Tumor thrombus in the portal vein is demonstrated on the PET-CT. PMID- 22832800 TI - Polysplenia syndrome with congenital agenesis of dorsal pancreas presenting as acute pancreatitis and the role of endoscopic ultrasonography in its diagnosis. AB - A 49-year-old female was admitted to our hospital for acute pancreatitis. The abdomen CT scan incidentally showed midline liver with hepatomegaly, centrally located gallbladder, pancreas truncation, right sided small bowel, left sided large bowel, interruption of the inferior vena cava with azygos continuation, preduodenal portal vein, and multiple spleens in the left upper quadrant. In MRCP, the head of pancreas was enlarged and short main pancreatic duct without accessory duct was showed. EUS revealed enlarged ventral pancreas with a main pancreatic duct of normal caliber, absence of the accessory pancreatic duct and the dorsal pancreas. She was diagnosed as polysplenia syndrome with agenesis of dorsal pancreas. It is a rare congenital anomaly frequently associated with various visceral anomalies including multiple spleens, impaired visceral lateralization, congenital heart diseases, gastrointestinal abnormalities and azygos continuation of the inferior vena cava. We report a case of polysplenia syndrome with agenesis of dorsal pancreas presenting acute pancreatitis. PMID- 22832801 TI - Two cases of portal annular pancreas. AB - Portal annular pancreas is one of the pancreatic fusion anomalies in which the uncinate process of the pancreas extends to fuse with the dorsal pancreas by encircling the portal vein or superior mesenteric vein. We report two consecutive patients with portal annular pancreas. The first case is a 71-year-old male patient who underwent a pancreaticoduodenectomy for intraductal papillary mucinous neoplasm in the head of pancreas. His preoperative computed tomography scan showed the suprasplenic type portal annular pancreas. The second case is a 74-year-old female patient who underwent a laparoscopic anterior radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic body cancer. In operative finding, portal confluence (superior mesenteric vein-splenic vein portal vein) was encased with the uncinate process of pancreas in both cases. Therefore, they required pancreatic division at the pancreatic neck portion twice. During the postoperative period, grade B and A, respectively, postoperative pancreatic fistulas occurred and were controlled by conservative management. Surgeons need to know about this rare pancreatic condition prior to surgical intervention to avoid complications, and to provide patients with well designed, case-specific pancreatic surgery. PMID- 22832802 TI - [A case of mantle cell lymphoma with meningioma]. AB - Mantle cell lymphoma (MCL) is an uncommon type of gastrointestinal lymphoma. MCL is a distinct subtype of B-cell non-Hodgkin lymphomas. The major subtype of MCL is characterized by the presence of multiple lymphomatous polyposis (MLP), in which multiple polyps are observed along the gastrointestinal tract. The malignant cells express pan B-cell marker and the T-cell marker cluster of differentiation 5. The chromosomal translocation t(11;14)(q13;q32) that causes cyclin D1 overexpression is commonly observed on the cytogenetic analysis of MCL. Survival improvement has recently been achieved for patient with MCL by the successful introduction of monoclonal antibodies and dose-intensified approaches for treatment, including autologous stem cell transplantation strategies. Some reports suggest that there is an increased incidence of second malignancies in patients with MCL or lymphoma. We report a case of MCL involving the colon; the patient was a 60-year-old man who complained of low abdominal discomfort during defecation. During the workup, a meningioma was unexpectedly discovered. On analysis, the tumor was found to be a t(11;14)-negative and non-MLP-type MCL. PMID- 22832803 TI - A phase I pharmacokinetic study of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer. AB - Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6 months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600 mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %) patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose. PMID- 22832804 TI - [Magnitude, time trends and factors associate with anemia in children in the state of Paraiba, Brazil]. AB - OBJECTIVE: To estimate the magnitude of the anemia, to analyze the time trends and investigate the factors associated with this disturbance in children in the state of Paraiba, Brazil. METHODS: A cross-sectional survey, of population-based, with 1108 children, aged 6 to 59 months, both sexes in the state of Paraiba. Hemoglobin (Hb) in venous blood was analyzed with an automatic counter. The social-economic and demographic characteristics of children were obtained by questionnaire. Proportions were compared by Pearson's chi-squared test, and the association between hemoglobin concentrations and potential risk factors was tested by regression model Poisson. The time trend of anemia was assessed by the increase/decreased in the prevalence of anemia, using as comparison the prevalence observed in the years 1982, 1992 and 2007. RESULTS: The prevalence of anemia (Hb < 11.0 g/dl) in the state of Paraiba was 36.5% (CI95% 33.7 to 39.3). It was observed that 1.3% (CI95% 0.7 to 1.8) were in severe form (Hb <7.0 g/dl), 11% (CI95% 9.4 to 13.5) in a moderate form and 87.6% (CI95% 79.1 to 91.2) in the mild form. There was an increase 88.5% in cases of anemia between the years 1982 1992 and stabilization in the prevalence between the years 1992-2007. The analysis adjusted Poisson model showed a greater susceptibility to anemia in children 6 to 24 months of age, those breastfed for six months or more, who co inhabited with more than 04 people in the same household and lived in houses with less than 05 rooms. CONCLUSIONS: The results revealed that anemia remains an important public health problem in the state of Paraiba and despite having been shown an stabilization in the prevalence of anemia between 1992-2007, differently the prevalence observed between 1982-1992, this deficiency presents in high level, witch requires more effective measures of prevention and control. PMID- 22832805 TI - [Breastfeeding among children of women workers]. AB - OBJECTIVE: To analyze employment benefits and factors associated with the maintenance of breastfeeding indexes among working mothers. METHODS: The sample was constituted by 200 formal women workers who returned to work before the child had reached six months of life, in the city of Piracicaba (Southeastern Brazil). Among the participants, 100 mother-infant dyads received guidance and support for the practice of breastfeeding within an oral health prevention program, and the other 100 dyads were addressed in a child vaccination campaign. Multiple logistic regression analysis was carried out to identify variables related to weaning in the fourth month of life. RESULTS: The majority of the participants were primiparous women who underwent cesarean section, initiated breastfeeding within four hours after birth and stayed with their child in the room. The following women had higher odds of stopping breastfeeding: mothers not participating in the incentive program (OR = 3.04 [95%CI: 1.35;6.85]), mothers who did not have a 30 minute break during the working hours (OR = 4.10 [95%CI: 1.81;9.26]), and mothers whose children used pacifiers (OR = 2.68 [95%CI: 1.23;5.83]) or bottles (OR = 14.47 [95%CI: 1.85;113.24]. CONCLUSIONS: The mothers who participated in the breastfeeding incentive group, who did not offer pacifiers and bottles to their babies and who had a break during the working hours stopped breastfeeding after the fourth month. Support and information on lactation management and on their rights guaranteed by law, together with the increase in the length of maternity leave, may play an important role in maintaining breastfeeding. PMID- 22832806 TI - Impact of urban atmospheric environment on hospital admissions in the elderly. AB - OBJECTIVE: To analyze the impact of intra-urban atmospheric conditions on circulatory and respiratory diseases in elder adults. METHODS: Cross-sectional study based on data from 33,212 hospital admissions in adults over 60 years in the city of Sao Paulo, southeastern Brazil, from 2003 to 2007. The association between atmospheric variables from Congonhas airport and bioclimatic index, Physiological Equivalent Temperature, was analyzed according to the district's socioenvironmental profile. Descriptive statistical analysis and regression models were used. RESULTS: There was an increase in hospital admissions due to circulatory diseases as average and lowest temperatures decreased. The likelihood of being admitted to the hospital increased by 12% with 1oC decrease in the bioclimatic index and with 1oC increase in the highest temperatures in the group with lower socioenvironmental conditions. The risk of admission due to respiratory diseases increased with inadequate air quality in districts with higher socioenvironmental conditions. CONCLUSIONS: The associations between morbidity and climate variables and the comfort index varied in different groups and diseases. Lower and higher temperatures increased the risk of hospital admission in the elderly. Districts with lower socioenvironmental conditions showed greater adverse health impacts. PMID- 22832807 TI - [Ischemic heart disease and correlates in adults from Ribeirao Preto, Brazil]. AB - OBJECTIVE: To identify the prevalence of ischemic heart disease (IHD) and correlates in an adult population. METHODS: Cross-sectional population-based epidemiological study including a weighted sample of 2,471 adults of both sexes and with age 30 years or older residing in Ribeirao Preto, Southeastern Brazil, in 2007. The Rose Questionnaire was administered, and IHD prevalence was calculated with point estimates and 95% confidence intervals. To identify correlates (sociodemographic, cardiovascular risk factors, and those related to access to health services and to physical activity level), crude and adjusted prevalence ratios were estimated using Poisson regression. RESULTS: IHD prevalence was higher in females than males at all age strata. In the final model, the following variables were independently associated with IHD: work status (PR= 0.54 [0.37;0.78]); family history of IHD (PR=1.55 [1.12;2.13]); hypertension (PR= 1.70 [1.18;2.46]); self-reported health status (PR=2.15 [1.40;3.31]); smoking duration (third tertile) (PR= 1.73 [1.08;2.76]); adjusted waist circumference (PR=1.79 [1.21;2.65]) and hypertriglyceridemia (PR=1.48 [1.05;2.10]). Linear trend test of PR across self-reported health status categories was statistically significant (p<0.05). CONCLUSIONS: A high prevalence of IHD was found, and the factors associated with the outcome are almost all modifiable and potentially influenced by public policy interventions. PMID- 22832808 TI - [Adverse outcome screening in hospitalizations of the Brazilian Unified Health System]. AB - OBJECTIVE: To assess the frequency of screening for potential adverse outcomes in hospitalizations of the Brazilian Unified Health System. METHODS: A retrospective study, including all hospital admissions of adults in medical clinics (n = 3,565,811) and surgical clinics (n = 2,614,048) in Brazil in 2007. The Hospital Information System was used as a source of information. The measurement of adverse events was based on screening for eleven clinical conditions, as defined by previous international studies, recorded in the secondary diagnosis field. We performed bivariate and multivariate analysis to investigate associations between adverse events, death (dependent variable) and other variables such as age, use of the intensive care unit and performance of surgery. RESULTS: The frequency obtained for both clinic types was 3.6 potential adverse events per 1,000 admissions, with a greater frequency in medical clinics (5.3 per 1,000) than in surgery clinics (1.3 per 1,000). There were differences in the profile of hospital admissions between the two clinics: medical clinics were characterized by a predominance of older adults, longer average length of stay, higher mortality rate and lower total cost of hospitalization. The most common potential adverse outcome was hospital-acquired pneumonia. Cardiac arrest had a higher risk of death (OR= 5.76) compared to other potential adverse outcomes. Increased cost for hospitalizations was associated with sepsis. The conditions used as the screening criteria were associated with greater odds of death even after the introduction of variables such as use of intensive care and surgery. CONCLUSIONS: The high frequency of adverse outcomes in hospital admissions indicates a need to develop monitoring strategies and to improve quality of care for improved patient safety. PMID- 22832809 TI - MTA-enriched nanocomposite TiO(2)-polymeric powder coatings support human mesenchymal cell attachment and growth. AB - The objective of the study described in this paper was the development of novel polymer/ceramic nanocomposite coatings for implants through the application of ultrafine powder coating technology. Polyester resins were combined with um-sized TiO(2) (25%) as the biocompatibility agent, nTiO(2) (0.5%) as the flow additive and mineral trioxide aggregates (ProRoot(r) MTA, 5%) as bioactive ceramics. Ultrafine powders were prepared and applied to titanium to create continuous polymeric powder coatings (PPCs) through the application of electrostatic ultrafine powder coating technology. Energy dispersive x-ray analysis confirmed that MTA had been incorporated into the PPCs, and elemental mapping showed that it had formed small clusters that were evenly distributed across the surface. Scanning electron microscopy (SEM) revealed continuous and smooth, but highly textured surface coatings that contrasted with the scalloped appearance of commercially pure titanium (cpTi) controls. Atomic force microscopy revealed intricate nano-topographies with an abundance of submicron-sized pits and nano projections, evenly dispersed across their surfaces. Inverted fluorescence microscopy, SEM and cell counts showed that human embryonic palatal mesenchymal cells attached and spread out onto PPC and MTA-enriched PPCs within 24 h. Mitochondrial enzyme activity measured viable and metabolically active cells on all of the surfaces. After 72 h of growth, cell counts and metabolic activity were significantly higher (P < 0.05) on the grey-MTA enriched PPC surfaces, than on unmodified PPC and cpTi. The novel polymer/ceramic nanocomposites that were created with ultrafine powder coating technology were continuous, homogenous and nano-rough coatings that enhanced human mesenchymal cell attachment and growth. PMID- 22832811 TI - Randomized controlled trial of laxative use in postcolostomy surgery patients. AB - PURPOSE: We compared a standardized postoperative laxative protocol to laxatives provided on an ad hoc basis by the surgical team. SUBJECTS AND SETTING: Forty five patients who underwent colostomy surgery participated in the study. The research setting was 2 acute care facilities in south-eastern Sydney, New South Wales, Australia. METHODS: A randomized controlled trial was conducted. The intervention group (n 5 19) received a standardized laxative protocol postsurgery. Two types of laxatives were selected for first-line treatment: sterculia and frangula bark (Normacol Plus), a bulking agent and stimulant; and liquid paraffin (Agarol), a stool softener. An iso-osmotic polyethylene glycol macrogel (Movicol) was chosen as second-line treatment. The comparison group (n = 26) received laxative intervention(s) as preferred by the surgical team. Constipation, measured as fecal loading on plain abdominal film, stomal therapy nurse activity, patient comfort, and length of hospital stay were compared between intervention and control groups. RESULTS: The presence of fecal loading favored the intervention group (1 episode in the treatment group vs 7 episodes in the comparison group; chi5 = 3.8; P = .05). This finding suggests that the laxative protocol given to the treatment group was more likely to prevent fecal loading/constipation when compared to the ad hoc laxative group. Stomal therapy nurse activity in terms of the number of empty bag changes was significantly higher in the comparison group (F 5 4.8; P 5 .03). CONCLUSION: The findings of this study support the benefits of a standardized laxative protocol for prevention of constipation. Data collection was discontinued after 3 years due to a contamination effect developing, because our surgeons observed the utility of the laxative protocol and incorporated it into their routine practice. Further experimental research is needed to explore the best constipation prevention approaches for postcolostomy surgery patients. PMID- 22832812 TI - Effective improvement of D-phenylglycine aminotransferase solubility by protein crystal contact engineering. AB - Structure-guided genetic engineering of D-phenylglycine aminotransferase (D PhgAT) aimed at increasing protein solubility was attempted. In silico analyses predicted the Asn439 and Gln444 as highly solvent-exposed beta-turn residues involved with protein crystal contact (CC) potential candidates for solubility improving mutations. They were replaced with Asp and Glu creating the N439D and Q444E single mutants, and N439D/Q444E double mutant with 2.5-, 3.3- and 5.9-fold increases in solubility, respectively. The protein CC prevention effect rather than the net charge effect accounted for the dramatically improved solubility since the N439D, Q444E and N439D/Q444E mutations altered the isoelectric point of D-PhgAT by only 0.1, 0.1 and 0.3 units, respectively. Examination of the D-PhgAT structural model revealed that the N439D mutation weakened the CC attraction force and the Q444E mutation created electrostatic repulsion at the CC point. Analysis of circular dichroism spectra, melting temperature, and D-PhgAT-specific activity showed that the mutations posed no unfavorable effect on the conformational stability and catalytic performance of the enzyme. The protein solubility-improving strategy employed on D-PhgAT in this study was successful with minimal protein structure modification required. It should be applicable with a high chance of success for other proteins, especially those with 3-D structural models available. PMID- 22832813 TI - Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes. AB - Fear memory persistence, central for the development and maintenance of anxiety disorders, is partially genetically controlled. Recently, consolidation and reconsolidation processes have been reported to affect fear memory stability and integrity. This study explored the impact of reconsolidation processes and genetic make-up on fear reacquisition by manipulating reconsolidation, using extinction performed outside or inside a reconsolidation interval. Reacquisition measured by skin conductance responses was stronger in individuals that extinguished outside (6 h) than inside (10 min) the reconsolidation interval. However, the effect was predominantly present in val/val homozygotes of the functional val158met polymorphism of the catechol O-methyltransferase (COMT) enzyme and in short-allele carriers of the serotonin-transporter length 5-HTTLPR polymorphism. These results demonstrate that reconsolidation of human fear memory is influenced by dopamine and serotonin-related genes. PMID- 22832814 TI - Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells. AB - The human serotonin transporter (SERT) gene possesses a 43-base pair (bp) insertion-deletion promoter polymorphism, the h5-HTTLPR. Genotype at this locus correlates with variation in anxiety-related personality traits and risk for major depressive disorder in many studies. Yet, the complex effects of the h5 HTTLPR, in combination with closely associated single-nucleotide polymorphisms (SNPs), continue to be debated. Moreover, although SERT is of high clinical significance, transporter function in vivo remains difficult to assess. Rhesus express a promoter polymorphism related to the h5-HTTLPR. The rh5-HTTLPR has been linked to differences in stress-related behavior and cognitive flexibility, although allelic variations in serotonin uptake have not been investigated. We studied the serotonin system as it relates to the 5-HTTLPR in rhesus peripheral blood cells. Sequencing of the rh5-HTTLPR revealed a 23-bp insertion, which is somewhat longer than originally reported. Consistent with previous reports, no SNPs in the rh5-HTTLPR and surrounding genomic regions were detected in the individuals studied. Reductions in serotonin uptake rates, cell surface SERT binding, and 5-hydroxyindoleacetic acid/serotonin ratios, but not SERT mRNA levels, were associated with the rh5-HTTLPR short allele. Thus, serotonin uptake rates are differentiable with respect to the 5-HTTLPR in an easily accessible native peripheral tissue. In light of these findings, we foresee that primary blood cells, in combination with high sensitivity functional measurements enabled by chronoamperometry, will be important for investigating alterations in serotonin uptake associated with genetic variability and antidepressant responsiveness in humans. PMID- 22832815 TI - Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFkappaB pathway. AB - Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post traumatic consequences in stressed mice. Suggesting involvement of NFkappaB mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1beta increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFkappaB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFkappaB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1beta increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFkappaB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9-/- mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety. PMID- 22832816 TI - Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. AB - Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18-65 years) with a current (N = 1132) or remitted (N = 789) depressive disorder according to DSM-IV criteria and healthy controls (N = 494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL 6), tumor necrosis factor-alpha (TNF-alpha)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l(-1), P<0.001, Cohen's d = 0.32) and IL-6 (0.88 versus 0.72 pg ml(-1), P = 0.01, Cohen's d = 0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators- especially body mass index--but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-alpha). Furthermore, inflammation was increased in men using serotonin-norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation. PMID- 22832817 TI - Effects of methamphetamine abuse and serotonin transporter gene variants on aggression and emotion-processing neurocircuitry. AB - Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates. PMID- 22832819 TI - Identification of blood-based molecular signatures for prediction of response and relapse in schizophrenia patients. AB - The current inability of psychiatric medicine to objectively select the most appropriate treatment or to predict imminent relapse are major factors contributing to the severity and clinical burden of schizophrenia. We have previously used multiplexed immunoassays to show that schizophrenia patients have a distinctive molecular signature in serum compared with healthy control subjects. In the present study, we used the same approach to measure biomarkers in a population of 77 schizophrenia patients who were followed up over 25 months with four aims: (1) to identify molecules associated with symptom severity in antipsychotic naive and unmedicated patients, (2) to determine biomarker signatures that could predict response over a 6-week treatment period, (3) to identify molecular panels that could predict the time to relapse in a cross sectional population of patients in remission and (4) to investigate how the biological relapse signature changed throughout the treatment course. This led to identification of molecular signatures that could predict symptom improvement over the first 6 weeks of treatment as well as predict time to relapse in a subset of 18 patients who experienced recurrence of symptoms. This study provides the groundwork for the development of novel objective clinical tests that can help psychiatrists in the clinical management of schizophrenia. PMID- 22832818 TI - Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models. AB - The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start. PMID- 22832821 TI - Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development. AB - A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development. PMID- 22832822 TI - Neonatal lupus: advances in understanding pathogenesis and identifying treatments of cardiac disease. AB - PURPOSE OF REVIEW: Cardiac manifestations of neonatal lupus include anti-SSA/Ro SSB/La-mediated conduction system disease and endocardial/myocardial damage resulting in cardiomyopathy. This review will focus on recent data regarding updates on the proposed pathogenesis of disease, morbidity and mortality, and preventive and treatment therapies. RECENT FINDINGS: Evidence from animal models suggests that reactivity to the p200 region of the Ro52 protein, as well as antibody targeting of L-type calcium channels may be important in the development of cardiac neonatal lupus. In-vitro studies support a protective role of beta-2 glycoprotein 1 (prevents anti-Ro binding to apoptotic cells) and pathologic roles of the urokinase-plasminogen activator/receptor system (leads to activation of TGF-beta), and endothelin-1 secretion by macrophages in mediating tissue injury. Genetic studies highlight the fetal major histocompatibility complex in the development of disease, and a multigenerational study demonstrates that mothers of neonatal lupus children accumulate genetic risk factors preferentially from the neonatal lupus child's grandparents. Retrospective studies identify demographic and echocardiographic risk factors for morbidity and mortality and address the role of fluorinated steroids, intravenous immunoglobulin and hydroxychloroquine for prevention and treatment of disease. SUMMARY: Animal studies, in-vitro experiments, genetic analysis and clinical-translational research in cardiac neonatal lupus reveal novel insights and targets for therapy in this often devastating disease. PMID- 22832824 TI - Monogenic causes of inflammatory disease in rheumatology. AB - PURPOSE OF REVIEW: To review the single-gene defects that can mimic rheumatologic diseases. RECENT FINDINGS: Monogenic disorders can cause a variety of diseases that may be seen by a rheumatologist. Many of these illnesses present with recurrent episodes of arthritis, rash, fever and inflammation, and serositis. Recent discoveries have defined inflammatory diseases due to mutations in the IL 1 and IL-36 receptor antagonists, as well as the immunoproteosome. Further study of well defined monogenic causes of inflammatory diseases, such as FMF, PAPA, TRAPS, and HIDS, has elucidated the pathophysiology of these diseases leading to targeted immunotherapy with anticytokine biological medications. SUMMARY: A rheumatologist should be aware of the genetic causes of inflammatory disease mimics. This will not only help with the prognosis of these diseases, but also help to guide therapy to prevent long-term complications associated with these disorders. PMID- 22832823 TI - Type I IFN system in the development and manifestations of SLE. AB - PURPOSE OF REVIEW: Type I interferon (IFN-I) is strongly implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we focus on new developments in pathways of IFN-I stimulation, the role of IFN-I in syndromes associated with lupus-like diseases, the utility of IFN-I signatures as biomarkers, and the progress of therapeutic agents targeting IFN-I pathways in SLE. RECENT FINDINGS: Immune complexesimmune complex are a dominant driver of IFN I production by activating toll-like receptors (TLRs) in plasmacytoid dendritic cells (pDC) in SLE. The level of IFN-I production is attenuated by C1q in immune complexes and enhanced by natural killer (NK) cells as well as by activated platelets that express CD40L. In addition to immune complexs, cell-intrinsic activation pathways utilize recently described non-TLR RNA and DNA sensors. Some modules or clusters of IFN-I stimulated genes or proteins correlate with disease activity, whereas IFN-I biomarkers of disease flare or specific clinical manifestations need further study. IFN-I blocking studies have reached phase II clinical trials. SUMMARY: Significant progress has been made in defining both TLR as well as non-TLR mediated stimulation of IFN-I. This has helped elucidate the mechanisms of several mutations and common genetic variations in predisposing to SLE. Challenges remain in the establishing the utility of biomarkers and the role of IFN-I blockade in the clinical management of patients with this disease. PMID- 22832825 TI - Inflammatory diseases and bone health in children. AB - PURPOSE OF REVIEW: Chronic pediatric inflammatory diseases are associated with low bone mass and fractures during childhood, and may hasten the onset of osteoporosis later in life. Proinflammatory cytokines and glucocorticoid therapy are likely key factors that impair bone accrual, along with downstream effects including malnutrition, pubertal delay, low muscle mass and physical inactivity. RECENT FINDINGS: Studies have used advanced imaging to characterize deficits in trabecular and cortical bone and have evaluated the 'functional muscle-bone unit'. In general, bone strength in the appendicular skeleton is compromised because of thinner cortical bone, with a low periosteal circumference and a normal or expanded endosteal circumference. Low muscle mass likely contributes to, but does not fully account for bone deficits. Systematic efforts to define the incidence and prevalence of bone fragility in children with inflammatory conditions demonstrated that vertebral fractures occur in a significant minority of patients in association with high disease activity, glucocorticoid use, and weight gain. Lumbar spine dual X-ray absorptiometry does not consistently distinguish children with and without vertebral fractures. SUMMARY: In children with inflammatory diseases, the documented elevated fracture risk and bone structural abnormalities highlight the need for additional research to better define methods for the assessment and prevention of bone fragility. PMID- 22832826 TI - Mechanical stimuli and bone health: what is the evidence? AB - PURPOSE OF REVIEW: With the recent emergence of associations of bisphosphonate therapy with atypical fractures and osteonecrosis of the jaw, there is renewed interest among clinicians and patients for nonpharmacological approaches to bone health. Here, we review the new studies published in the past year or two that advance our knowledge of the effect of mechanical stimuli on bone health. RECENT FINDINGS: Physical activity is associated with serum sclerostin levels; the most physically active individuals have the lowest serum sclerostin levels. Observational trials suggest that physical activity participation results in higher bone mass, but clinical trials suggest that the effects of exercise on areal bone mineral density are small, and vary with the site measured and the type of exercise. Based on current data, it may be best to combine progressive resistance training with interventions such as walking or aerobic dancing if the desire is to improve both spine and hip in postmenopausal women. Low-magnitude high-frequency whole body vibration does not improve bone mineral density and bone structure in postmenopausal women. SUMMARY: Physical activity and exercise are important for the maintenance of musculoskeletal health as we age. Future studies need to investigate the effects of exercise in older populations with rheumatological diseases and those with a history of fragility fractures. PMID- 22832827 TI - A simple microfluidic probe of nanoparticle suspension stability. AB - We describe a simple experimental tool that enables stability of multicomponent nanoparticle suspensions to be readily assessed by establishing a confinement imposed chemical discontinuity at the interface between co-flowing laminar streams in a microchannel. When applied to examine Al(2)O(3) nanoparticle suspensions, this method readily reveals compositions that are susceptible to aggregation even when conventional bulk measurements (zeta potential, dynamic light scattering, bulk viscosity) suggest only subtle differences between formulations. This microfluidic stability test enables simple and rapid assessment of quality and variability in complex multicomponent mixtures for which few, if any, comparable data exist. The paradoxical ease at which localized aggregation can be triggered in suspensions that would otherwise appear stable also serves as a caution to researchers undertaking tracer-based studies of nanomaterial suspensions. PMID- 22832828 TI - Neighborhood socio-environmental vulnerability and infant mortality in Hermosillo, Sonora. AB - OBJECTIVE: This paper explores the impact of contextual variables at the neighborhood level on a health marker in the city of Hermosillo, Mexico and discusses the importance of collaboration between planners and health professional to minimize the negative effect of contextual factors on urban health. MATERIALS AND METHODS: Few studies in Mexico have assessed health outcomes at the intra-urban scale and their interaction with neighborhood-level contextual variables. Using spatial analysis and geographical information systems, the paper explores the association between infant mortality and an index of socio-environmental vulnerability used to measure urban contextual factors. RESULTS: Two high infant mortality clusters were detected within neighborhoods characterized by relatively good environmental conditions and one in a neighborhood with a poor environment. CONCLUSIONS: Our results show the clustering of high infant mortality areas and some association with built environment factors in Hermosillo. The results support the need to reconnect public health and urban planning as a way to create healthier environments in Mexican cities. PMID- 22832830 TI - [Children exposure to lead in contaminated sites]. AB - OBJECTIVE: To assess the exposure to lead in children living in various types of contaminated sites. MATERIALS AND METHODS: The study was conducted from June 2008 to December 2009 at four sites in Mexico: Avalos metallurgical, Chihuahua; Morales metallurgical, San Luis Potosi (SLP); Trinidad pottery area, Tlaxcala and Cedral mine site, SLP. These sites contain different sources of lead. The metal levels were quantified in outdoor dust and in peripheral blood of children. RESULTS: Lead dust concentrations exceed the National Guidelines for residential soils (400 mg/kg) in a range of values for the four sites from 62 to 5 187 mg/kg. Regarding biological monitoring, the studied children showed maximum lead blood levels of 22 ug/dL in Cedral, 31 ug/dL in Morales, 32 ug/dL in Avalos, and 52 ug/dL in Trinidad. It is important to mention that in all the studied sites, a significative positive correlation was found between blood lead levels and the lead concentrations in dust. CONCLUSION: These sites are an example of the health risks related to lead exposure in Mexico; therefore, there is an urgent need for a national public health program aimed at reducing lead exposure in vulnerable populations. PMID- 22832829 TI - Evaluation of the psychometric performance of the SCOFF questionnaire in a Mexican young adult sample. AB - OBJECTIVE: To examine the psychometric performance of the SCOFF, a brief screening instrument for eating disorders (ED). MATERIALS AND METHODS: Mexican university applicants (n= 3594, 55.7% female, M age= 18.1 years) completed self report measures and a health screen. RESULTS: Confirmatory factor analyses revealed one factor for females. However a bifactor model fits better for males and females. Reliability was lower for females (KR20 = .49) than males (KR20 = .59). More females (24.2%) presented risk for ED (SCOFF > 2) than males (11.2%). Nomological validity indicated that risk for ED in young women was associated with demographic (e.g., parental education), psychological (e.g., depression, weight management efficacy), physical (e.g., BMI), and social (e.g., family conflict) indicators in conceptually coherent ways. Fewer variables were significant for males. CONCLUSION: Although the SCOFF may be a useful ED screen in Mexico, further research must examine its criterion validity, sensitivity, and specificity. PMID- 22832831 TI - [Underreporting of deaths in children and birth certification in a representative sample of the 101 municipalities with lowest human development index in Mexico]. AB - OBJECTIVE: To measure the underregistry of mortality in children under five years old, and the coverage of the Birth Certificate (BC) in municipalities with very low human development index (HDI) in Mexico. MATERIALS AND METHODS: We studied all deaths of children under five years old occurred in 2007 and all births occurred in 2007 and 2008 in a sample of 20 municipalities with very low HDI in Mexico. We conducted an intentional search of births and deaths. RESULTS: We identified 12 additional deaths not included in official registries, for an underregistration of 22.6%, and 68.1% of births did not have a BC. Lack of BC was more frequent if the mother did not speak Spanish, if she did not have Seguro Popular if the birth was attended by a traditional midwife. Conclusions. It is necessary to strengthen the registry of deaths and births in municipalities with very low HDI. PMID- 22832832 TI - [Factors associated with the seeking of legal induced abortion services in Mexico City in 2010]. AB - OBJECTIVE: To identify factors associated with the seeking of the legal interruption-pregnancy (LIP) services in Mexico City. MATERIALS AND METHODS: We used a case-control design. Users who utilized the LIP were defined as cases, while users of the antenatal care service with gestational age 13 or more weeks and who reported having an unwanted pregnancy were defined as controls. Logistic regressions were fitted to estimate odds ratios. RESULTS: Higher level of education (OR=1.47, 95% CI:1.04-2.07), women's occupation (being student OR=7.31, 95% CI:1.58-33.95; worker OR=13.43, 95% CI:2.04-88.54), and number of previous abortions (OR=11.41, 95% CI:1.65-79.07) were identified as factors associated with the lookup of LIP. CONCLUSIONS: In Mexico City context, empowered women with a higher level of education, or having a work activity are the users of LIP services. Strategies for improving access of women with low empowerment conditions are needed. PMID- 22832833 TI - Youth who neither study nor work: mental health, education and employment. AB - OBJECTIVE: Limited educational and job opportunities for youth has led to a phenomenon termed NEET (not in education, employment or training). The objective is to estimate the prevalence of psychiatric disorders, substance use and suicidal behavior in youth classified as NEET and to compare with those who study only, work only or do both. MATERIAL AND METHODS: 3 005 12-to-17 year-olds in Mexico City were evaluated in 2005 with the Composite International Diagnostic Interview. Descriptive and logistic regression analyses considered the multistage weighted sample design. RESULTS: NEET youth as well as those who work only or study and work simultaneously have greater odds of psychiatric disorder, substance use and suicidal behavior compared to those who study exclusively even after controlling for social disadvantage. CONCLUSION: Vulnerability is not circumscribed to NEET adolescents, but to all teens who are not exclusive students. Supporting youth to continue studying exclusively may buffer negative mental health outcomes. PMID- 22832834 TI - [Inverse association between asthma and neural tube defects: a binational ecological study]. AB - OBJECTIVE: Dietary intake of methyl donors such as folic acid prevents neural tube defects (NTD), but recent studies showed that it might also favor the development of asthma. In this work a possible ecological association between NTD and asthma was explored. MATERIAL AND METHODS: Data bases from Mexico and the United States (US) were reviewed to obtain information about geographical distribution (by state) and temporal trends (by year) of NTD and asthma. RESULTS: Those states with the lowest frequency of NTD had the highest frequency of asthma, both in Mexico (rS=-0.48, p=0.005) and US (rS=-0.39, p=0.005). Temporal trends also showed an inverse correlation in Mexico (1997-2007, rS=-0.73, p=0.01) and US (1979-1998, rS=-0.91, p<0.001). CONCLUSIONS: In both countries the frequency of asthma inversely correlated with the frequency of NTD, both in geographical distribution and annual trends, giving support to the possibility that methyl donors intake in diet or supplements is influencing the asthma frequency. PMID- 22832835 TI - [Adult asthma in Mexico City: a population-based study]. AB - OBJECTIVES: To determine the prevalence of asthma and the association between sociodemographic characteristics, spirometry, respiratory symptoms, quality of life and sleep in adults > 40 years. MATERIALS AND METHODS: This report is part of our study (Latin American Research Project Obstructive Pulmonary), held in Mexico City and the metropolitan area in 2003. We used logistic regression models adjusted for study design, where asthma was the dependent and independent variable respiratory symptoms, sociodemographic and clinical characteristics among others. RESULTS: The prevalence of physician-diagnosed asthma was: 3.3% in men and 6.2% in women. Decreased lung function in asthmatics was observed. In multivariate analysis, after adjusting for potential confounders, asthmatics had a higher risk of excessive daytime sleepiness more snoring [OR = 3.2 (95% CI 1.4 7.4), p= 0.008], and more frequent work absences due to respiratory problems [OR = 5.1 (95% CI 2.5-10.4), p<0.0001]. CONCLUSIONS: The prevalence of asthma was 5%. Asthmatics showed lower quality of life and lung function. PMID- 22832836 TI - The effects of social networks on tobacco use among high-school adolescents in Mexico. AB - OBJECTIVE: To identify the effect of centrality in social network positions on tobacco-use among high-school adolescents in Tonala, Jalisco, Mexico. MATERIALS AND METHODS: Longitudinal sociometric social network data were collected among 486 high-school adolescents in 2003 and 399 in 2004. The survey included: social network components, smoking and sociodemographic characteristics. Social network measures of centrality were calculated and multivariate logistic regression was used. RESULTS: Ever used tobacco (OR= 44.98), marginalized-low stratum (OR= 2.16) and in-degree (OR=1.10) predicted tobacco use. Out-degree (OR= 0 .89) and out-in degree (OR= 0.90) protected against tobacco use. CONCLUSION: Nominating more friends rather than receiving such nominations was protective for tobacco use. Popular students, those receiving many nominations, were at higher risk for tobacco use. Involvement of leaders with capacity to influence might be an efficient strategy for dissemination of preventive messages. PMID- 22832838 TI - Spontaneous splenic vein bleeding during pregnancy: consequences of a missed diagnosis. PMID- 22832839 TI - Stress and ano-colorectal surgery in newborn/infant: role of anesthesia. AB - PURPOSE: The best anesthesia for newborns/infants necessitating colorectal surgery remains questionable. Endovenous and locoregional anesthesiological approaches were compared to determine the influence on stress response. METHODS: Patients with anorectal malformations or Hirschsprung's disease were randomized to inhalatory/epidural anesthesia (IPA) or inhalatory/endovenous anesthesia (IEA). Heart rate, blood pressure, oxygen saturation, serum concentrations of dehydroepiandrosterone, cortisol, and glucose were recorded 24 h before operation (T0), after tracheal intubation (T1), 120 min after skin incision (T2), 60 min (T3) and 24 h after operation (T4). RESULTS: Seventeen patients were enrolled in the study, 8 receiving IPA, and 9 IEA. Heart rate, blood pressure, oxygen saturation remained stable and normal, without statistical differences between the two groups, during the study period. Similar cortisol and glucose levels showed no statistical differences between groups. Dehydroepiandrosterone values were significantly higher in IEA during anesthesia (T1-T3) compared with IPA (T1: 494.0 vs. 266.5, p < 0.05; T2: 444.0 vs. 201.0, p < 0.05; T3: 385.0 vs. 305.0, p < 0.05). CONCLUSION: This study suggests that epidural and endovenous anesthesia are both effective in intra- and postoperative period. This preliminary report suggests that IPA is more efficient compared to IEA in controlling stress reaction related to surgery. Further larger studies are needed to confirm these findings. PMID- 22832840 TI - Synthesis of biotin labelled cap analogue--incorporable into mRNA transcripts and promoting cap-dependent translation. AB - Analogues of the eukaryotic messenger RNA 5' end (m(7)G cap) are useful tools for studying mRNA fate and serve as reagents for in vitro preparation of 5' capped mRNAs. We designed a biotin-labeled dinucleotide cap analogue that can be incorporated into transcripts to produce 5'-capped and biotinylated mRNAs which retain their biological functionality and may be employed for biotin (strept)avidin technologies. PMID- 22832841 TI - Imino-chitosan biodynamers. AB - The imine-bond formation on chitosan backbones occurs with very low yields in aqueous solutions and is significantly improved in hydrogels or in solid state films. The dynamic exchanges of imino-R groups and colour transfer can occur at the interfaces between various hydrogels and solid state films. PMID- 22832843 TI - Sensitivity analysis of TOPSIS method in water quality assessment II: sensitivity to the index input data. AB - This is the second part of the study on sensitivity analysis of the technique for order preference by similarity to ideal solution (TOPSIS) method in water quality assessment. In the present study, the sensitivity of the TOPSIS method to the index input data was investigated. The sensitivity was first theoretically analyzed under two major assumptions. One assumption was that one index or more of the samples were perturbed with the same ratio while other indices kept unchanged. The other one was that all indices of a given sample were changed simultaneously with the same ratio, while the indices of other samples were unchanged. Furthermore, a case study under assumption 2 was also carried out in this paper. When the same indices of different water samples are changed simultaneously with the same variation ratio, the final water quality assessment results will not be influenced at all. When the input data of all indices of a given sample are perturbed with the same variation ratio, the assessment values of all samples will be influenced theoretically. However, the case study shows that only the perturbed sample is sensitive to the variation, and a simple linear equation representing the relation between the closeness coefficient (CC) values of the perturbed sample and variation ratios can be derived under the assumption 2. This linear equation can be used for determining the sample orders under various variation ratios. PMID- 22832844 TI - Assessment of physicochemical parameters of wastewater samples. AB - Water samples from selected locations of Nullah Lai and Koh-e-Noor textile mill in the metropolitan city of Rawalpindi and Islamabad, Pakistan, were collected. Physicochemical parameters and heavy metals were determined using standard analytical procedures in comparison with sites, locations and subsequent interval of 3 months. The results of the physicochemical analysis at different locations of Nullah Lai and Koh-e-Noor textile mill with an interval of 3 months were obtained in the following range: pH (7.16-8.29), temperature (17.8-28.8 degrees C), conductivity (1,005-3,347 MUS/m), TDS (754.3-2,519.5 mg/L), turbidity (272.8 487.05 NTU), total hardness (300-452 mg/L), nitrates (10.11-22.95 ppm), calcium (74.31-139.2 ppm), chloride (127.72-396.16 ppm), sulphate (15.97-87.38 ppm), NaCl (210.5-631.1 ppm), Ni (0.30-0.72 ppm), Cd (0.005-0.03 ppm), Cr (0.2-7.4 ppm), Pb (0.12-0.73 ppm), Zn (0.03-0.08 ppm) and Cu (0.01-0.06 ppm). The highest value of physicochemical parameters (compared with Nullah Lai) was obtained in locations of Koh-e-Noor textile mill. The results obtained exceeded the maximum allowable limit set by the World Health Organization for drinking purpose but can be used for irrigation purposes after suitable treatment and purification. PMID- 22832845 TI - Ecosystem classifications based on summer and winter conditions. AB - Ecosystem classifications map an area into relatively homogenous units for environmental research, monitoring, and management. However, their effectiveness is rarely tested. Here, three classifications are (1) defined and characterized for Canada along summertime productivity (moderate-resolution imaging spectrometer fraction of absorbed photosynthetically active radiation) and wintertime snow conditions (special sensor microwave/imager snow water equivalent), independently and in combination, and (2) comparatively evaluated to determine the ability of each classification to represent the spatial and environmental patterns of alternative schemes, including the Canadian ecozone framework. All classifications depicted similar patterns across Canada, but detailed class distributions differed. Class spatial characteristics varied with environmental conditions within classifications, but were comparable between classifications. There was moderate correspondence between classifications. The strongest association was between productivity classes and ecozones. The classification along both productivity and snow balanced these two sets of variables, yielding intermediate levels of association in all pairwise comparisons. Despite relatively low spatial agreement between classifications, they successfully captured patterns of the environmental conditions underlying alternate schemes (e.g., snow classes explained variation in productivity and vice versa). The performance of ecosystem classifications and the relevance of their input variables depend on the environmental patterns and processes used for applications and evaluation. Productivity or snow regimes, as constructed here, may be desirable when summarizing patterns controlled by summer- or wintertime conditions, respectively, or of climate change responses. General purpose ecosystem classifications should include both sets of drivers. Classifications should be carefully, quantitatively, and comparatively evaluated relative to a particular application prior to their implementation as monitoring and assessment frameworks. PMID- 22832846 TI - Dynamics of harmful dinoflagellates driven by temperature and salinity in a northeastern Mediterranean lagoon. AB - To attempt to determine the effects of temperature and salinity on the dynamics of the dinoflagellate community, a monthly sampling was carried out from October 2008 to March 2009 at eight sampling stations in Ghar El Melh Lagoon (GML; Mediterranean Sea, Northern Tunisia). Dinoflagellates were dominant among plankton, accounting for 73.9 % of the lagoon's overall plankton community, and were comprised of 25 different species among which 17 were reported in the literature as harmful. While no significant difference was found in the distribution of dinoflagellates among the stations, a strong monthly difference was observed. This temporal variability was due to an increase in the abundance of Prorocentrum micans from December to February, leading to a strong decrease in the Shannon diversity index from station to station. At the onset of P. micans development, dinoflagellate abundances reached 1.26.10(5) cells l(-1). A redundance analysis indicates that both temperature and salinity have a significant effect on the dynamics of the dinoflagellate community. Using a generalized additive model, both temperature and salinity appear to have significant nonlinear relationships with P. micans abundances. Model predictions indicate that outbreaks of P. micans may occur at a temperature below 22.5 degrees C and with salinity above 32.5. We discuss our results against a backdrop of climate change which, by affecting temperature and salinity, is likely to have an antagonistic impact on P. micans development and subsequently on the dinoflagellate dynamics in GML. PMID- 22832847 TI - Patterns of tooth agenesis in Japanese subjects with bilateral agenesis of mandibular second premolars. AB - The aim of this study was to explore the patterns of tooth agenesis in Japanese orthodontic patients with bilateral agenesis of mandibular second premolars. A total of 80 Japanese orthodontic patients with 2 congenitally missing mandibular second premolars were selected as the subjects of this study (experimental group). Another 80 individuals without bilateral agenesis of mandibular second premolars were collected for comparison (control group). The 2 groups were matched with regard to sex. Radiographs, dental casts and records of medical and/or dental treatment were used to identify tooth agenesis. The Chi-square test, odds ratio, and test for equality were used to make statistical comparisons. The prevalence rates of other types of tooth agenesis were significantly higher in the experimental group than in the control group. The occurrence of agenesis of maxillary and mandibular lateral incisors and third molars, and maxillary second premolars was also significantly higher in the experimental group than in the control group. Significantly increased prevalence rates of symmetrical tooth agenesis, with third molars included, and oligodontia were observed in the experimental group. Japanese subjects with bilateral agenesis of mandibular second premolars are at significantly high risk of agenesis of other types of permanent teeth, symmetrical tooth agenesis and oligodontia. PMID- 22832848 TI - Alpha-mangostin suppresses MMP-2 and MMP-9 expression in head and neck squamous carcinoma cells. AB - The purpose of this study was to investigate the effect of alpha-mangostin on matrix metalloproteinase (MMP)-2 and MMP-9 expression in head and neck squamous cell carcinoma (HNSCC). The human HNSCC cell lines were treated with alpha mangostin and the cytotoxicity of alpha-mangostin in HNSCC was determined using the MTS assay. To determine the effect of alpha-mangostin on the expression of MMP-2 and MMP-9 in HNSCC, gelatin zymography and RT-PCR were performed. The results showed that alpha-mangostin increased in growth inhibition of HNSCC cell lines in a concentration-dependent manner. Treatment with alpha-mangostin decreased MMP-2 and MMP-9 expression in a concentration-dependent manner in all cell lines. These findings suggested that alpha-mangostin might be a potential therapeutic agent for HNSCC. PMID- 22832849 TI - Physical activity in multiple sclerosis: a comparative study of vitamin D, brain derived neurotrophic factor and regulatory T cell populations. AB - BACKGROUND: Previous studies suggest beneficial effects of exercise in multiple sclerosis (MS). However, knowledge on the effects of physical activity on the immune system is limited. OBJECTIVE: To assess potential relationships between cardiorespiratory fitness, cognitive function, and immune parameters in physically active and inactive MS patients. METHODS: We identified 83 patients with relapsing-remitting disease, an unrestricted walking range, and stable interferon-beta treatment from our data base. Based on the subjective report of physical activity, the lower/inactive (n = 21) and upper/active quartiles (n = 21) of patients were selected. We assessed the frequency of T cells, B cells, NK cells, monocytes and regulatory T cell populations by flow cytometry, measured brain-derived neurotrophic factor and vitamin D serum levels by ELISA, and conducted spiroergometry and transcranial sonography. RESULTS: Physical activity and cardiorespiratory fitness were not associated with brain-derived neurotrophic factor, frequency of T regulatory cells or any other immune cell subpopulation. However, we found a positive correlation of vitamin D serum levels with cardiorespiratory fitness. CONCLUSION: Overall, we found no negative effect of physical activity on the immune system. The association between vitamin D and cardiorespiratory fitness most likely reflects longer hours of sunlight exposure in active patients, suggesting a desirable 'side- effect' of physical activity. PMID- 22832850 TI - Prenatal exposure to cigarette smoke or alcohol and cerebellum volume in attention-deficit/hyperactivity disorder and typical development. AB - Prenatal exposure to teratogenic substances, such as nicotine or alcohol, increases the risk of developing attention-deficit/hyperactivity disorder (ADHD). To date, studies examining this relationship have used symptom scales as outcome measures to assess the effect of prenatal exposure, and have not investigated the neurobiological pathways involved. This study explores the effect of prenatal exposure to cigarettes or alcohol on brain volume in children with ADHD and typically developing controls. Children with ADHD who had been exposed prenatally to either substance were individually matched to children with and without ADHD who had not been. Controls who had been exposed prenatally were also individually matched to controls who had not been. For prenatal exposure to both smoking and alcohol, we found a pattern where subjects with ADHD who had been exposed had the smallest brain volumes and unexposed controls had the largest, with intermediate volumes for unexposed subjects with ADHD. This effect was most pronounced for cerebellum. A similar reduction fell short of significance for controls who had been exposed to cigarettes, but not alcohol. Our results are consistent with an additive effect of prenatal exposure and ADHD on brain volume, with the effects most pronounced for cerebellum. PMID- 22832851 TI - Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability. AB - Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [(11)C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction. PMID- 22832852 TI - Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients. AB - Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles. PMID- 22832853 TI - Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder. AB - Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response. PMID- 22832854 TI - PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis. AB - Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy) 4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl-D-aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP. PMID- 22832855 TI - Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation. AB - Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=-0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation. PMID- 22832856 TI - A novel blood-based biomarker for detection of autism spectrum disorders. AB - Autism spectrum disorders (ASD) are classified as neurological developmental disorders. Several studies have been carried out to find a candidate biomarker linked to the development of these disorders, but up to date no reliable biomarker is available. Mass spectrometry techniques have been used for protein profiling of blood plasma of children with such disorders in order to identify proteins/peptides that may be used as biomarkers for detection of the disorders. Three differentially expressed peptides with mass-charge (m/z) values of 2020 +/- 1, 1864 +/- 1 and 1978 +/- 1 Da in the heparin plasma of children with ASD that were significantly changed as compared with the peptide pattern of the non-ASD control group are reported here. This novel set of biomarkers allows for a reliable blood-based diagnostic tool that may be used in diagnosis and potentially, in prognosis of ASD. PMID- 22832858 TI - Carbamazepine inhibits angiotensin I-converting enzyme, linking it to the pathogenesis of temporal lobe epilepsy. AB - We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems. PMID- 22832857 TI - The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models. AB - A compelling association has been observed between cardiovascular disease (CVD) and depression, suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality. Systemic immune activation, hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship. Although a differential epidemiological association between CVD and depression subtypes is evident, it has not been determined if this indicates subtype specific biological mechanisms. A comprehensive systematic literature search was conducted using PubMed and PsycINFO databases yielding 147 articles for this review. A complex pattern of systemic immune activation, endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes. The findings of this review suggest that diagnostic subtypes rather than a unifying model of depression should be considered when investigating the bidirectional biological relationship between CVD and depression. The suggested model of a subtype-specific biological relationship between depression and CVDs has implications for future research and possibly for diagnostic and therapeutic processes. PMID- 22832861 TI - Effects of sports participation on psychiatric symptoms and brain activations during sports observation in schizophrenia. AB - Weight gain has been identified as being responsible for increased morbidity and mortality rates of schizophrenia patients. For the management of weight gain, exercise is one of the most acknowledged interventions. At the same time, exercise and sports have been recognized for their positive impact on psychiatric symptoms of schizophrenia. However, the neurobiological basis for this remains poorly understood. We aimed to examine the effect of sports participation on weight gain, psychiatric symptoms and brain activation during sports observation in schizophrenia patients. Thirteen schizophrenia patients who participated in a 3-month program, including sports participation and 10 control schizophrenia patients were studied. In both groups, body mass index (BMI), Positive and Negative Syndrome Scale (PANSS), and brain activation during observation of sports-related actions measured by functional magnetic resonance imaging were accessed before and after a 3-month interval. BMI and general psychopathology scale of PANSS were significantly reduced in the program group but not in the control group after a 3-month interval. Compared with baseline, activation of the body-selective extrastriate body area (EBA) in the posterior temporal-occipital cortex during observation of sports-related actions was increased in the program group. In this group, increase in EBA activation was associated with improvement in the general psychopathology scale of PANSS. Sports participation had a positive effect not only on weight gain but also on psychiatric symptoms in schizophrenia. EBA might mediate these beneficial effects of sports participation. Our findings merit further investigation of neurobiological mechanisms underlying the therapeutic effect of sports for schizophrenia. PMID- 22832859 TI - Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. AB - Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia. PMID- 22832863 TI - MRI of the wrist in juvenile idiopathic arthritis: proposal of a paediatric synovitis score by a consensus of an international working group. Results of a multicentre reliability study. AB - BACKGROUND: MRI is a sensitive tool for the evaluation of synovitis in juvenile idiopathic arthritis (JIA). OBJECTIVE: The purpose of this study was to introduce a novel MRI-based score for synovitis in children and to examine its inter- and intraobserver variability in a multi-centre study. MATERIALS AND METHODS: Wrist MRI was performed in 76 children with JIA. On postcontrast 3-D spoiled gradient echo and fat-suppressed T2-weighted spin-echo images, joint recesses were scored for the degree of synovial enhancement, effusion and overall inflammation independently by two paediatric radiologists. Total-enhancement and inflammation synovitis scores were calculated. RESULTS: Interobserver agreement was poor to moderate for enhancement and inflammation in all recesses, except in the radioulnar and radiocarpal joints. Intraobserver agreement was good to excellent. For enhancement and inflammation scores, mean differences (95 % CI) between observers were -1.18 (-4.79 to 2.42) and -2.11 (-6.06 to 1.83). Intraobserver variability (reader 1) was 0 (-1.65 to 1.65) and 0.02 (-1.39 to 1.44). CONCLUSION: Intraobserver agreement was good. Except for the radioulnar and radiocarpal joints, interobserver agreement was not acceptable. Therefore, the proposed scoring system requires further refinement. PMID- 22832865 TI - Treatment of corneal neovascularization by topical application of ascorbic acid in the rabbit model. AB - PURPOSE: To determine the efficacy of the topical application of ascorbic acid for the treatment of corneal neovascularization. METHODS: Corneal neovascularization was induced in 16 rabbits with a silk suture in the corneal stroma (32 eyes). At 1 week after suturing, 15 rabbits were divided into 3 groups and were treated with topical ascorbic acid at 3 different concentrations: 10 mg/mL (group 1), 1 mg/mL (group 2), and 0.5 mg/mL (group 3). All treatments were added in the right eye twice a day. All left eyes (15 eyes) and both eyes of the 16th rabbit were used as experimental controls and a normal control, respectively. The area of corneal neovascularization was measured using light microscopy. The concentrations of vascular endothelial growth factor and matrix metalloproteinase-9 in the corneal tissue were measured. RESULTS: The neovascularized area was decreased in the treated groups compared with the control group. There was a significant difference in the neovascularized areas between the control and groups 1 and 2. No significant difference was observed between the control and group 3. The concentration of vascular endothelial growth factor was significantly lower in the treated groups than in the control group, but there was no difference between the treated groups. The concentration of matrix metalloproteinase-9 showed a significant difference between the control and treated groups, but no difference between the treated groups. CONCLUSIONS: Topical administration of ascorbic acid may be useful for the treatment of corneal neovascularization. PMID- 22832864 TI - Localized hypertrophic neuropathy of the sciatic nerve in children: MRI findings. AB - BACKGROUND: Localized hypertrophic neuropathy (LHN) of the sciatic nerve in children is a rare condition characterized by a painless neurological deficit in the sciatic nerve territory. OBJECTIVE: To demonstrate the role of MRI using a specific protocol and describe the primary findings in LHN. MATERIALS AND METHODS: Imaging in four children (age 2 years to 12 years) is presented. All children presented with lower limb asymmetry. Three had a steppage gait. LHN was confirmed by electrophysiological studies and by MRI of the whole sciatic nerve with a dedicated protocol covering the lumbar spine and the lower limb. RESULTS: There were four direct MRI findings: (1) linear and focal hypertrophy with progressive enlargement of a peripheral nerve or plexus diameter, (2) abnormal hyperintensity of the nerve on T2-weighted images, (3) preserved fascicular configuration, and (4) variable enhancement after intravenous gadolinium administration. In addition there were atrophy and fatty infiltration of innervated muscles. MRI was helpful for determining the extent of lesions and in excluding peripheral nerve compression or tumour. CONCLUSION: MRI of the whole sciatic nerve is the method of choice for diagnosing LHN of the sciatic nerve. PMID- 22832862 TI - TRIB1 constitutes a molecular link between regulation of sleep and lipid metabolism in humans. AB - Epidemiological studies show association between sleep duration and lipid metabolism. In addition, inactivation of circadian genes induces insulin resistance and hyperlipidemia. We hypothesized that sleep length and lipid metabolism are partially controlled by the same genes. We studied the association of total sleep time (TST) with 60 genetic variants that had previously been associated with lipids. The analyses were performed in a Finnish population-based sample (N = 6334) and replicated in 2189 twins. Finally, RNA expression from mononuclear leucocytes was measured in 10 healthy volunteers before and after sleep restriction. The genetic analysis identified two variants near TRIB1 gene that independently contributed to both blood lipid levels and to TST (rs17321515, P = 8.92(*)10(-5), Bonferroni corrected P = 0.0053, beta = 0.081 h per allele; rs2954029, P = 0.00025, corrected P = 0.015, beta = 0.076; P<0.001 for both variants after adjusting for blood lipid levels or body mass index). The finding was replicated in the twin sample (rs17321515, P = 0.022, beta = 0.063; meta analysis of both samples P = 8.1(*)10(-6), beta = 0.073). After the experimentally induced sleep restriction period TRIB1 expression increased 1.6 fold and decreased in recovery phase (P = 0.006). In addition, a negative correlation between TRIB1 expression and slow wave sleep was observed in recovery from sleep restriction. These results show that allelic variants of TRIB1 are independently involved in regulation of lipid metabolism and sleep. The findings give evidence for the pleiotropic nature of TRIB1 and may reflect the shared roots of sleep and metabolism. The shared genetic background may at least partially explain the mechanism behind the well-established connection between diseases with disrupted metabolism and sleep. PMID- 22832867 TI - Corneal sensitivity, blink rate, and corneal nerve density in progressive supranuclear palsy and Parkinson disease. AB - PURPOSE: Patients with progressive supranuclear palsy (PSP) and patients with Parkinson disease frequently manifest signs of dry eyes, yet many remain asymptomatic. In this study, we established the relationships between blink rate, corneal sensitivity, and corneal nerve density in patients with ocular surface disease associated with PSP and Parkinson disease. METHODS: Fourteen eyes of 7 patients with PSP, 8 eyes of 4 patients with Parkinson disease, and 10 eyes of 5 age-matched controls were examined for meibomian dysfunction, ocular surface staining, and blink rate. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer, and corneal subbasal nerve density was measured by using confocal microscopy in vivo. Comparisons between variables were assessed by using generalized estimating equation models to account for possible correlation between fellow eyes of the same subject. RESULTS: Abnormal ocular surface staining and meibomian disease were present in most subjects with PSP and Parkinson disease, but in none of the controls. Patients with PSP and Parkinson disease had lower blink rates (P < 0.001) and decreased corneal sensitivity (P < 0.001) compared with controls, whereas subbasal nerve density did not differ between groups. Blink rate was correlated with corneal sensitivity (r = 0.83, P < 0.001), but corneal sensitivity was not correlated with subbasal nerve density (r = -0.16, P = 0.78). CONCLUSIONS: Patients with ocular surface disease associated with PSP and Parkinson disease might be asymptomatic because of decreased corneal sensitivity. Decreased corneal sensitivity was not explained by loss of corneal nerves but was associated with decreased blink rate. PMID- 22832868 TI - Diverted organic synthesis (DOS): accessing a new, natural product inspired, neurotrophically active scaffold through an intramolecular Pauson-Khand reaction. AB - Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads. PMID- 22832869 TI - Computational study of ethanol adsorption and reaction over rutile TiO2 (110) surfaces. AB - Studies of the modes of adsorption and the associated changes in electronic structures of renewable organic compounds are needed in order to understand the fundamentals behind surface reactions of catalysts for future energies. Using planewave density functional theory (DFT) calculations, the adsorption of ethanol on perfect and O-defected TiO(2) rutile (110) surfaces was examined. On both surfaces the dissociative adsorption mode on five-fold coordinated Ti cations (Ti(4+)(5c)) was found to be more favourable than the molecular adsorption mode. On the stoichiometric surface E(ads) was found to be equal to 0.85 eV for the ethoxide mode and equal to 0.76 eV for the molecular mode. These energies slightly increased when adsorption occurred on the Ti(4+)(5c) closest to the O defected site. However, both considerably increased when adsorption occurred at the removed bridging surface O; interacting with Ti(3+) cations. In this case the dissociative adsorption becomes strongly favoured (E(ads) = 1.28 eV for molecular adsorption and 2.27 eV for dissociative adsorption). Geometry and electronic structures of adsorbed ethanol were analysed in detail on the stoichiometric surface. Ethanol does not undergo major changes in its structure upon adsorption with its C-O bond rotating nearly freely on the surface. Bonding to surface Ti atoms is a sigma type transfer from the O2p of the ethanol-ethoxide species. Both ethanol and ethoxide present potential hole traps on O lone pairs. Charge density and work function analyses also suggest charge transfer from the adsorbate to the surface, in which the dissociative adsorptions show a larger charge transfer than the molecular adsorption mode. PMID- 22832870 TI - Metallostasis and amyloid beta-degrading enzymes. AB - Amyloid-Beta (Abeta) is a major constituent of senile plaques and one of the principle hallmarks of Alzheimer's disease (AD). The peptide is produced by proteolytic cleavage of the larger amyloid precursor protein (APP). Increased production and aggregation of the peptide are associated with pathology. Emerging evidence suggests that the steady-state levels of Abeta are determined by the balance between its production and degradation. For this reason, the tuning of the activity of enzymes that degrade Abeta may be a promising approach in the development of novel therapeutics aimed at reducing Abeta concentration by enhancing its removal. A great part of Abeta degrading enzymes are known to be metalloproteases. In the last decade increasing evidence supported the idea that metal ion homeostasis is affected in several regions of AD brain and metals play an important role in tuning enzyme activity. There are three main different pathways by which metal ions can affect the proteolytic enzymes responsible for Abeta peptides degradation, as metal ions can: (i) form complexes with Abeta peptides that are not easily degraded; (ii) directly bind to degradative enzymes; (iii) produce signalling cascades that alter enzymes activity involved in Abeta catabolism. In the current literature the three points mentioned above are very often puzzled, resulting in a quite fragmentary scenario. The aim of this work is to find a link between metal ion homeostasis and Abeta degradation by separating and analysing the three different pathways proposed. PMID- 22832871 TI - Survival analysis of Down syndrome cohort in a tertiary health care center in India. AB - OBJECTIVE: To identify the major causes of death in Down Syndrome (DS), the ages at which mortality rates are the highest and recognize factors associated with it. METHODS: The prospective cohort-based study was carried out in a tertiary health care center. Children with DS (n = 543) counseled at the Center of Medical Genetics, Sir Ganga Ram Hospital from 2005 through 2009 were followed up in year 2010. Survival curves and Cox's proportional hazards regression analysis were used to determine the effect of different variables on survival. RESULTS: Total mortality was 13 %, of which 80.3 % was in children less than 2 y of age. Presence of congenital heart disease (CHD) increased the risk of mortality by 5.7 folds (p = 0.001). A definitive survival benefit after cardiac intervention was noted, although it differed with the type of CHD. Sex, maternal age at time of birth and karyotypes did not show a significant correlation with survival. CONCLUSIONS: The higher DS infant mortality observed in the present study could be attributed to financial constraints of the families and misconceptions amongst health professionals. It is recommended that a nation-wide DS registry be created to study the morbidity and mortality in Down syndrome from birth. The findings of this study will help clinicians in making management decisions and enable better counseling. PMID- 22832872 TI - Balloon kyphoplasty versus percutaneous vertebroplasty in treating osteoporotic vertebral compression fracture: grading the evidence through a systematic review and meta-analysis. AB - OBJECTIVE: To assess the safety and efficacy of balloon kyphoplasty (KP) compared with percutaneous vertebroplasty (VP) and provide recommendations for using these procedures to treat osteoporotic vertebral compression fractures (OVCF). METHODS: A systematic search of all studies published through March 2012 was conducted using the MEDLINE, EMBASE, OVID, ScienceDirect and Cochrane CENTRAL databases. The randomized controlled trials (RCTs) and non-randomized controlled trials that compared KP to VP and provided data on safety and clinical effects were identified. Demographic characteristics, adverse events and clinical outcomes were manually extracted from all of the selected studies. The evidence quality levels and recommendations were assessed using the GRADE system. RESULTS: Twelve studies encompassing 1,081 patients met the inclusion criteria. Subgroup meta analyses were performed according to the study design. In the RCT subgroup, there were significant differences between the two procedures in short-term visual analog scale (VAS), long-term kyphosis angles, operative times and anterior vertebrae heights. In the cohort study subgroup, there were significant differences between the two procedures in short- and long-term VAS, short- and long-term Oswestry Disability Index (ODI), cement leakage rates, short- and long term kyphosis angles, operative times and anterior vertebrae heights. However, there were no significant differences in long-term VAS or adjacent vertebral fracture rates in the RCT subgroup. There were no significant differences in short- or long-term VAS, short- or long-term ODI, cement leakage rates, adjacent vertebral fracture rates, short- or long-term kyphosis angles or anterior vertebrae heights in the CCT subgroup, and the adjacent vertebral fracture rates did not differ significantly in the cohort study subgroup. The overall GRADE system evidence quality was very low, which lowers our confidence in their recommendations. CONCLUSIONS: KP and VP are both safe and effective surgical procedures for treating OVCF. KP may be superior to VP in patients with large kyphosis angles, vertebral fissures, fractures in the posterior edge of the vertebral body or significant height loss in the fractured vertebrae. Due to the poor quality of the evidence currently available, high-quality RCTs are required. PMID- 22832873 TI - Heme oxygenase-1 modulates degeneration of the intervertebral disc after puncture in Bach 1 deficient mice. AB - PURPOSE: Intervertebral disc degeneration is considered to be a major feature of low back pain. Furthermore, oxidative stress has been shown to be an important factor in degenerative diseases such as osteoarthritis and is considered a cause of intervertebral disc degeneration. The purpose of this study was to clarify the correlation between oxidative stress and intervertebral disc degeneration using Broad complex-Tramtrack-Bric-a-brac and cap'n'collar homology 1 deficient (Bach 1 /-) mice which highly express heme oxygenase-1 (HO-1). HO-1 protects cells from oxidative stress. METHODS: Caudal discs of 12-week-old and 1-year-old mice were evaluated as age-related models. Each group and period, 5 mice (a total of 20 mice, a total of 20 discs) were evaluated as age-related model. C9-C10 caudal discs in 12-week-old Bach 1-/- and wild-type mice were punctured using a 29-gauge needle as annulus puncture model. Each group and period, 5 mice (a total of 60 mice, a total of 60 discs) were evaluated. The progress of disc degeneration was evaluated at pre-puncture, 1, 2, 4, 8 and 12 weeks post-puncture. Radiographic, histologic and immunohistologic analysis were performed to compare between Bach 1 /- and wild-type mice. RESULTS: In the age-related model, there were no significant differences between Bach 1-/- and wild-type mice radiologically and histologically. However, in the annulus puncture model, histological scoring revealed significant difference at 8 and 12 weeks post-puncture. The number of HO 1 positive cells was significantly greater in Bach 1-/- mice at every period. The apoptosis rate was significantly lower at 1 and 2 weeks post-puncture in Bach 1-/ mice. CONCLUSIONS: Oxidative stress prevention may avoid the degenerative process of the intervertebral disc after puncture, reducing the number of apoptosis cells. High HO-1 expression may also inhibit oxidative stress and delay the process of intervertebral disc degeneration. PMID- 22832874 TI - Steiger et al. 2011: relationships and specificity in CLBP rehabilitation through exercise. PMID- 22832875 TI - Synthesis of 9,9'-[1,2-ethanediylbis(oxymethylene)]bis-2-amino-1,9-dihydro-6H purin-6-one, an impurity of acyclovir. AB - The synthesis of 9,9'-[1,2-ethanediylbis(oxymethylene)]bis-2-amino-1,9-dihydro-6H purin-6-one, a minor impurity of acyclovir, is described. Starting with commercial N-(9-acetyl-6-oxo-1H-purin-2-yl)acetamide, the process uses an acid catalysed phase transfer catalysis (PTC) process to produce the selective alkylation at the 9 position of the guanine ring. PMID- 22832876 TI - Negative-pressure cavitation extraction of four main vinca alkaloids from Catharanthus roseus leaves. AB - In the present study, an improved method termed negative-pressure cavitation extraction (NPCE) followed by reverse phase high-performance liquid chromatography (RP-HPLC) was developed for the extraction and quantification of vindoline (VDL), catharanthine (CTR), vincristine (VCR) and vinblastine (VLB) from Catharanthus roseus leaves. The optimized method employed 60-mesh particles, 80% ethanol, a negative pressure of -0.075 MPa, a solid to liquid ratio of 1:20, 30 min of extraction and three extraction cycles. Under these optimized conditions, the extraction yields of VDL, CTR, VCR and VLB are 0.5783, 0.2843, 0.018 and 0.126 mg/g DW, respectively. These extraction yields are equivalent to those from the well-known ultrasonic extraction method and higher than the yields from maceration extraction and heating reflux extraction. Our results suggest that NPCE-RP-HPLC represents an excellent alternative for the extraction and quantification of vinca alkaloids for pilot- and industrial-scale applications. PMID- 22832877 TI - Optimization of enzymatic process for vanillin extraction using response surface methodology. AB - Vanillin was extracted from vanilla beans using pretreatment with cellulase to produce enzymatic hydrolysis, and response surface methodology (RSM) was applied to optimize the processing parameters of this extraction. The effects of heating time, enzyme quantity and temperature on enzymatic extraction of vanillin were evaluated. Extraction yield (mg/g) was used as the response value. The results revealed that the increase in heating time and the increase in enzyme quantity (within certain ranges) were associated with an enhancement of extraction yield, and that the optimal conditions for vanillin extraction were: Heating time 6 h, temperature 60 degrees C and enzyme quantity 33.5 mL. Calculated from the final polynomial functions, the optimal response of vanillin extraction yield was 7.62 mg/g. The predicted results for optimal reaction conditions were in good agreement with experimental values. PMID- 22832878 TI - Synthesis and cytotoxicity testing of new amido-substituted triazolopyrrolo[2,1 c][1,4]benzodiazepine (PBDT) derivatives. AB - A series of amido-substituted triazolopyrrolo[2,1-c][1,4]benzodiazepine (PBDT) derivatives was synthesized from isatoic anhydride, and their cytotoxicity against the MRC-5 and Mahlavu cell lines was evaluated. The results suggest that compound PBDT-7i with the meta-trifluoromethylbenzoyl substituent can selectively inhibit the growth of Mahlavu cells and has low toxicity towards MRC-5 cells. PMID- 22832879 TI - Two new compounds isolated from Liriope muscari. AB - Two new compounds, (2S,3R)-methyl 7-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-3 (hydroxymethyl)-2,3-dihydrobenzofuran-5-carboxylate (1) and (4R,5S)-5-(3-hydroxy 2,6-dimethylphenyl)-4-isopropyldihydrofuran-2-one (2), tentatively named norcurlignan and limlactone, respectively, were isolated from Liriope muscari, together with the known compound (-)-pinoresinol (3). The structures of these compounds were elucidated and characterized on the basis of 1D NMR, 2D NMR, CD and MS data. The in vitro antioxidant activities of compounds 1-3 were assessed by the DPPH and ABTS scavenging methods. PMID- 22832880 TI - Investigation of non-enzymatic glycosylation of human serum albumin using ion trap-time of flight mass spectrometry. AB - Non-enzymatic glycosylation or glycation involves covalent attachment of reducing sugar residues to proteins without enzyme participation. Glycation of glucose to human serum albumin in vivo is related to diabetes and many other diseases. We present an approach using liquid chromatography coupled to an electrospray ionization source of a hybrid ion trap-time of flight (IT-TOF-MS/MS) tandem mass spectrometer to identify the glycation sites on serum albumin from both a healthy person and a diabetic patient. The MetID software, which is commonly used for screening metabolites, is adapted for peptide fingerprinting based on both m/z values and isotopic distribution profiles. A total of 21 glycation sites from the healthy person and 16 glycation sites from the diabetic patient were identified successfully. We also demonstrate the use of matrix assisted laser desorption ionization-time of flight mass spectrometry to estimate the incorporation ratio of glucose to albumin during glycation. Results from this study show that the glycation in healthy person is more complicated than previously thought. Further analysis of incorporation ratio distribution may be necessary to accurately reflect the change of serum albumin glycation in diabetic patients. PMID- 22832881 TI - On the reaction of 1,3-diphenylisobenzofuran and (2-iodoethynyl)(phenyl)iodonium triflate. A unique case of oxygen transfer from the Diels-Alder adduct to the diene. AB - Reaction of 1,3-diphenylisobenzofuran (DPIBF) with 2-(iodoethynyl)(phenyl) iodonium triflate at room temperature gave the expected Diels-Alder adduct, but using an excess of DFIBF (2 equiv.) and performing the reaction at 55 degrees C or heating at this temperature during the concentration stage, the initial orange solution or product mixture became dark brown and the products 1,2-phenylene-1,2 bis(phenylmethanone) and 2-(3-iodo-1,4-diphenylnaphthyl)(phenyl)iodonium triflate were obtained, which suggests an oxygen transfer between DPIBF and the initial adduct. PMID- 22832882 TI - Comparison on phenolic compounds and antioxidant properties of cabernet sauvignon and merlot wines from four wine grape-growing regions in China. AB - The antioxidant activities in the Cabernet Sauvignon and Merlot wines from four wine grape-growing regions in China were measured by different analytical assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH.), cupric reducing antioxidant capacity (CUPRAC), superoxide radical-scavenging activity (SRSA) and the contents of total phenols, total flavonoids, total flavanols and total anthocyanins were determined. The results showed that the contents of phenolic compounds and the levels of antioxidant activity in the wine samples greatly varied with cultivar and environmental factors of vine growth. The contents of phenolic compounds and antioxidant activities in Cabernet Sauvignon and Merlot wines from the Yuquanying region of Ningxia were significantly higher than other three regions, followed by the wines from Shacheng region of Hebei, and these parameters were the lowest in Cabernet Sauvignon and Merlot wines from the Changli regions of Hebei and Xiangning region of Shanxi. Taken together, a close relationship between phenolic subclasses and antioxidant activity was observed for the wine samples. Moreover, there were significant discrepancies in the individual phenolic composition and content of four regional Cabernet Sauvignon and Merlot wines, among which the individual phenolic compounds (catechin, epicatechin, cinnamic acid, quercetin-3 O-glucuronide, quercetin-3-O-glucoside, laricitrin-3-O-glucoside and isorhamnetin 3-O-glucoside) revealed a significant correlation (p < 0.05) with the antioxidant capacity in present study, especially for catechin and epicatechin. PMID- 22832883 TI - Synthesis of some novel biologically active disperse dyes derived from 4-methyl 2,6-dioxo-1-propyl-1,2,5,6-tetrahydro-pyridine-3-carbonitrile as coupling component and their colour assessment on polyester fabrics. AB - A series of novel azo-disperse dyes containing alkylhydrazonopyridinone structures were synthesized. 4-Methyl-2,6-dioxo-1-propyl-1,2,5,6 tetrahydropyridine-3-carbonitrile (8) is synthesized by one-pot synthesis using ethyl cyanoacetate, propylamine, and ethyl acetoacetate. Compound 8 is then coupled with aromatic and heteroaromatic diazonium salts to afford the corresponding aryl- and heteroaryl-4-methyl-2,6-dioxo-1-propyl-1,2,5,6 tetrahydropyridine-3-carbonitriles 12a,b and 13a-c. Structural assignments to the dyes were made using NMR spectroscopic methods. A high temperature dyeing method was employed to apply these dyes to polyester fabrics. Most of the dyed fabrics tested displayed very good light fastness levels and good wash fastness. Finally, the biological activity of the prepared dyes against Gram positive bacteria and Gram negative bacteria were evaluated. PMID- 22832884 TI - Synthesis and biological activity of 23-hydroxybetulinic acid C-28 ester derivatives as antitumor agent candidates. AB - 23-Hydroxybetulinic acid (1) served as the precursor for the synthesis of C-28 ester derivatives. The target compounds were evaluated in vitro for their antitumor activities against five cell lines (A549, BEL-7402, SF-763, B16 and HL 60). Among the obtained compounds, 6i had the most potent antitumor activity, with the IC(50 values of 8.35 uM in HL-60 cells and showed similar antitumor activity as cyclophosphamide in H22 liver tumor and as 5-fluorouracil in B16 melanoma in vivo. PMID- 22832885 TI - Anti-inflammatory and analgesic activity of total flavone of Cunninghamia lanceolata. AB - The present study was undertaken to investigate the anti-inflammatory and analgesic activity of total flavone of branches and leaves of Cunninghamia lanceolata (TFC) to provide a scientific basis for its clinical use and resource development. TFC was evaluated for anti-inflammatory and analgesic activity in mice or rats using chemical and thermal models of nociception, including acetic acid-induced writhing test, hot plate latency test, formalin test and carrageenan induced paw oedema test. Results showed that TFC given orally can significantly attenuate acetic acid-induced writhing in mice in a dose-dependent manner. In the hot plate latency test, TFC showed common activity in prolonging duration time only at the highest dose (400 mg/kg). Each dose of TFC could not significantly inhibit the first phase but was active in the later phase of formalin-induced pain, whereas morphine showed notable activity in the two phases. In the carrageenan-induced paw oedema model, TFC could significantly and dose dependently reduce the carrageenan-induced paw edema at the third and fifth hour, and decrease the content of PEG(2) in paw edema tissue and that of COX-2 in blood serum. It may be concluded that TFC showed both anti-inflammatory and analgesic effects, showing that it can be of importance in drug development, especially in the field of pain and inflammation. PMID- 22832886 TI - An ent-kaurane-type diterpene in Croton antisyphiliticus mart. AB - Croton antisyphiliticus is a medicinal plant widely used in the treatment of microbial infections, especially those affecting the genital tract. Crude extract, fractions and pure compound isolated from roots of this species were investigated to validate their antimicrobial activity against Escherichia coli and Staphylococcus aureus. The compound ent-kaur-16-en-18-oic acid was isolated as a major component (0.7% of crude extract), and its MIC value determined against S. aureus (ATCC 6538) was 250 MUg/mL. This is the first phytochemical work on the species monitored with antimicrobial assay. PMID- 22832887 TI - Sling compared with plate osteosynthesis for treatment of displaced midshaft clavicular fractures: a randomized clinical trial. AB - BACKGROUND: Few randomized controlled trials have compared operative with nonoperative treatment of clavicular fractures. METHODS: Patients with displaced midshaft clavicular fractures were randomized either to nonoperative treatment with a sling or to operative treatment with a stainless steel 3.5-mm reconstruction plate. Outcome measures were the Constant shoulder score, DASH (Disabilities of the Arm, Shoulder and Hand) score, pain, fracture-healing, and complications. The null hypothesis was that the Constant and DASH scores would not differ between the groups at the one-year follow-up evaluation. RESULTS: In accordance with the power analysis, we included sixty patients in the study; thirty-two were randomized to the nonoperative group and twenty-eight to the operative group. We found no difference in the Constant score (p = 0.75), the DASH score (p = 0.89), or pain (p = 0.98) between the groups at the one-year follow-up evaluation. All fractures in the operative group healed, but six nonunions (24%) occurred in the nonoperative group. CONCLUSIONS: One year after a displaced midshaft clavicular fracture, nonoperative treatment resulted in a higher nonunion rate but similar function and disability compared with operative treatment. PMID- 22832888 TI - Comparison of how well conscious cats tolerate blood pressure measurement from the radial and coccygeal arteries. AB - Hypertension is a common condition of older cats and acquiring clinically relevant and repeatable blood pressure (BP) measurements in conscious cats is important in its diagnosis and management. The most common sites for indirect BP measurement in the cat are the radial artery (RA) and the coccygeal artery (CA) but, to date, there are no published data comparing how conscious cats tolerate BP measurements from these sites. A high-definition oscillometric BP monitor was used to measure BP in 30 cats admitted to a cat-only veterinary clinic for reasons other than hypertension. Systolic arterial pressure (SAP), mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were measured using the RA and CA, alternating which site was used first. The number of failed attempts and total time to achieve six measurements was recorded. Measurement of BP using the CA was better tolerated than the RA, resulting in fewer failures and shorter total time required. SAP measurements were slightly higher from the CA compared with the RA, irrespective of which site was used first. There were no significant differences in MAP and DAP. The coccygeal artery appears to be the more appropriate site to use when measuring BP in conscious cats using this oscillometric machine. Further studies are required using alternative BP monitors, including Doppler machines, to establish whether this is a consistent finding. When measuring BP in cats the site used should be recorded and the same site used for all subsequent measurements from the same cat. PMID- 22832889 TI - Roles of sulfite oxidoreductase and sulfite reductase in improving desulfurization by Rhodococcus erythropolis. AB - Rhodococcus erythropolis has been widely studied for desulfurization. However, activity levels required for commercial application have not been achieved. A major limitation of the current work in biodesulfurization is inadequate information regarding sulfur metabolism generally, and in particular the metabolism of the sulfur obtained from dibenzothiophene (DBT) metabolism via the 4S pathway. In this work, we have investigated the possible routes taken by the sulfur from DBT to convert into biomass or other metabolites. We propose two alternate hypotheses. In the first, we hypothesize that the cell can convert via sulfite reductase (SR) the sulfite from the metabolism of DBT into sulfide that can be assimilated into biomass. However, in the process, it may convert any excess sulfite into extracellular sulfate via sulfite oxidoreductase (SOR) to avoid the toxic effects of sulfite. In the second, we speculate that the cell cannot assimilate the sulfite directly into biomass via SR. It must first use SOR to produce extracellular sulfate, and then recapture that sulfate into biomass via SR. Thus, either way, we propose that SOR and SR activities, in addition to dsz genes and cofactors, may be critical in increasing desulfurization levels significantly. In particular, we suggest that the simultaneous increase in SOR activity and decrease in SR activity can enable increased desulfurization activity. PMID- 22832891 TI - Newly isolated and characterized bacteria with great application potential for decomposition of lignocellulosic biomass. AB - This study focuses on the isolation and characterization of bacteria from municipal waste and peat to determine those bacteria with good potential for modification and decomposition of lignocellulosic biomass for industrial application. Twenty cellulase-producing bacteria belonging to four major phyla - Firmicutes, Actinobacteria, Proteobacteria and Bacteroidetes - were found when screened on carboxymethyl cellulose-containing agar. Six isolates also exhibited activities towards filter paper as the sole carbon source in salt media, while 12 exhibited activities towards xylan when screened on xylan-containing plates. Moreover, 5 isolates survived in and increased the absorbance of 1% black liquor in salt media by an average of 2.07-fold after 21 days of incubation. Similarly, these 5 isolates increased the absorbance of 0.1% pure lignin at 280 nm in salt media, indicating modification of lignin. Additionally, the Fourier transform infrared spectroscopy analysis of 1% barley straw treated for 21 days with these 5 strains showed a preference for consumption of hemicelluloses over lignin; however, a change in lignin was observed. A Bacillus strain (55S5) and a Pseudomonas strain (AS1) displayed the greatest potential for lignocellulose decomposition due to a variety of cellulase activities, as well as xylanase activity and modification of lignin. Several of these isolates have good potential for industrial use in the degradation of lignocellulosic biomass. PMID- 22832890 TI - The relationship between sensory sensitivity and autistic traits in the general population. AB - Individuals with Autism Spectrum Disorders (ASDs) tend to have sensory processing difficulties (Baranek et al. in J Child Psychol Psychiatry 47:591-601, 2006). These difficulties include over- and under-responsiveness to sensory stimuli, and problems modulating sensory input (Ben-Sasson et al. in J Autism Dev Disorders 39:1-11, 2009). As those with ASD exist at the extreme end of a continuum of autistic traits that is also evident in the general population, we investigated the link between ASD and sensory sensitivity in the general population by administering two questionnaires online to 212 adult participants. Results showed a highly significant positive correlation (r = .775, p < .001) between number of autistic traits and the frequency of sensory processing problems. These data suggest a strong link between sensory processing and autistic traits in the general population, which in turn potentially implicates sensory processing problems in social interaction difficulties. PMID- 22832892 TI - Production and characterization of a monoclonal antibody against putative T lymphocytes of Catla catla. AB - Catla catla is the fastest growing Indian major carp and one of the major aquaculture species in South Asia. A monoclonal antibody (MAb) designated B8 MAb was produced against nylon wool-enriched thymus mononuclear cells of C. catla. This MAb did not show reactivity with macrophage and epithelial cell lines derived from catla thymus in cellular ELISA. In flow cytometric analysis of gated lymphocytes, the percentage of B8 positive (B8+) cells in thymus (n = 10, 500-600 g) was determined to be 77.7 %. Similarly, the percentage of B8+ cells in kidney, spleen and blood (n = 5) was 15.08, 1.1 and 32.17 %, respectively. Western blotting of reduced membrane proteins showed that B8 MAb reacted with a polypeptide having a molecular weight of 168.2 kDa. In indirect immunoperoxidase test, B8+ cells appeared to be lymphoid cells with a high nucleus to cytoplasmic ratio. B8 reactive cells were densely packed in central region of thymus whereas, a few cells were found to be positive in kidney and spleen sections. B8 MAb also reacted with a significant population of lymphocytes in blood smears. Considering the economic importance of C. catla, this MAb should be a useful tool for studying immune response of this fish species. PMID- 22832893 TI - Spatial distribution of wall shear stress in common carotid artery by color Doppler flow imaging. AB - The purpose of this study is to provide a novel approach for measuring the spatial distribution of wall shear stress (WSS) in common carotid artery in vivo. WSS distributions were determined by digital image processing from color Doppler flow imaging (CDFI) in 50 healthy volunteers. In order to evaluate the feasibility of the spatial distribution, the mean values of WSS distribution were compared to the results of conventional WSS calculating method (Hagen-Poiseuille formula). In our study, the mean value of WSS distribution from 50 healthy volunteers was (6.91 +/- 1.20) dyne/cm(2), while it was (7.13 +/- 1.24) dyne/cm(2) by Hagen-Poiseuille approach. The difference was not statistically significant (t = -0.864, p = 0.604). Hence, the feasibility of the spatial distribution of WSS was proved. Moreover, this novel approach could provide three dimensional distribution of shear stress and fusion image of shear stress with ultrasonic image for each volunteer, which made WSS "visible". In conclusion, the spatial distribution of WSS could be used for WSS calculation in vivo. Moreover, it could provide more detailed values of WSS distribution than those of Hagen Poiseuille formula. PMID- 22832894 TI - UMMPerfusion: an open source software tool towards quantitative MRI perfusion analysis in clinical routine. AB - To develop a generic Open Source MRI perfusion analysis tool for quantitative parameter mapping to be used in a clinical workflow and methods for quality management of perfusion data. We implemented a classic, pixel-by-pixel deconvolution approach to quantify T1-weighted contrast-enhanced dynamic MR imaging (DCE-MRI) perfusion data as an OsiriX plug-in. It features parallel computing capabilities and an automated reporting scheme for quality management. Furthermore, by our implementation design, it could be easily extendable to other perfusion algorithms. Obtained results are saved as DICOM objects and directly added to the patient study. The plug-in was evaluated on ten MR perfusion data sets of the prostate and a calibration data set by comparing obtained parametric maps (plasma flow, volume of distribution, and mean transit time) to a widely used reference implementation in IDL. For all data, parametric maps could be calculated and the plug-in worked correctly and stable. On average, a deviation of 0.032 +/- 0.02 ml/100 ml/min for the plasma flow, 0.004 +/- 0.0007 ml/100 ml for the volume of distribution, and 0.037 +/- 0.03 s for the mean transit time between our implementation and a reference implementation was observed. By using computer hardware with eight CPU cores, calculation time could be reduced by a factor of 2.5. We developed successfully an Open Source OsiriX plug-in for T1-DCE MRI perfusion analysis in a routine quality managed clinical environment. Using model-free deconvolution, it allows for perfusion analysis in various clinical applications. By our plug-in, information about measured physiological processes can be obtained and transferred into clinical practice. PMID- 22832895 TI - Application of morphological bit planes in retinal blood vessel extraction. AB - The appearance of the retinal blood vessels is an important diagnostic indicator of various clinical disorders of the eye and the body. Retinal blood vessels have been shown to provide evidence in terms of change in diameter, branching angles, or tortuosity, as a result of ophthalmic disease. This paper reports the development for an automated method for segmentation of blood vessels in retinal images. A unique combination of methods for retinal blood vessel skeleton detection and multidirectional morphological bit plane slicing is presented to extract the blood vessels from the color retinal images. The skeleton of main vessels is extracted by the application of directional differential operators and then evaluation of combination of derivative signs and average derivative values. Mathematical morphology has been materialized as a proficient technique for quantifying the retinal vasculature in ocular fundus images. A multidirectional top-hat operator with rotating structuring elements is used to emphasize the vessels in a particular direction, and information is extracted using bit plane slicing. An iterative region growing method is applied to integrate the main skeleton and the images resulting from bit plane slicing of vessel direction dependent morphological filters. The approach is tested on two publicly available databases DRIVE and STARE. Average accuracy achieved by the proposed method is 0.9423 for both the databases with significant values of sensitivity and specificity also; the algorithm outperforms the second human observer in terms of precision of segmented vessel tree. PMID- 22832896 TI - An improved tamper detection and localization scheme for volumetric DICOM images. AB - The development of teleradiology brings the convenience of global medical record access along with the concerns over the security of medical images transmitted over the open network. With the prevailing adoption of three-dimensional (3-D) imaging modalities, it is vital to develop a security mechanism to provide large volumes of medical images with privacy and reliability. This paper presents the development of a new and improved method of implementing tamper detection and localization based on a fully reversible digital watermarking scheme for the protection of volumetric DICOM images. This tamper detection and localization method utilizes the 3-D property of volumetric data to achieve much faster processing time at both sender and receiver sides without compromising tamper localization accuracy. The performance of the proposed scheme was evaluated by using sample volumetric DICOM images. Results show that the scheme achieved on average about 65 % and 72 % reduction in watermarking and dewatermarking processing time, respectively. For cases where the images had been tampered, it is possible to detect and localize the tampered areas with improved localization resolution in the images using the scheme. PMID- 22832897 TI - A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. AB - Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, was evaluated for treatment of patients with recurrent glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16 GB patients, all previously treated with surgery, radiotherapy, and temozolomide, were enrolled in a prospective phase II study at either first or second relapse. Patients were treated with daily sunitinib for 4 consecutive weeks, followed by a 2-week break. For AA patients, the most common side effects were fatigue (86 %), diarrhea (43 %), hand-foot syndrome (36 %), neutropenia (36 %), thrombocytopenia (36 %), and nausea (29 %). In the GB cohort, the most common side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and thrombocytopenia (25 %). Six of 14 (43 %) AA and 5 of 16 (31 %) GB patients experienced grade 3 or greater toxicities. Five patients discontinued study due to drug toxicities. There were no partial or complete responses in either cohort; 8/14 (57 %) AA and 5/16 (31 %) GB patients had stable disease at the first planned assessment. Progression-free survival at 6 months was 21.5 % (AA) and 16.7 % (GB). Median overall survival was 12.1 months (AA) and 12.6 months (GB). These results are comparable to those reported in the literature in patients treated with standard cytotoxic therapies. This is the largest reported trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate significant anti-glioma activity in patients with recurrent malignant astrocytic gliomas. PMID- 22832898 TI - Multidrug resistance proteins expression in glioma patients with epilepsy. AB - Epilepsy occurs in glioma, especially in low-grade glioma (LGG), but also in glioblastoma (GBM). In about 20 % of patients pharmacological treatment with anti epileptic drugs (AEDs) fails. Refractory epilepsy is a multifactorial phenomenon not yet completely understood. The multidrug resistance phenotype was initially associated to P-glycoprotein (Pgp), an ATP-dependent transporter belonging to the same superfamily of multidrug resistance-associated proteins (MRPs). Glutathione S-transferase-pi (GST-pi) is also involved in refractory epilepsy. In the present work we investigated the expression of Pgp, MRP1, MRP3 and GST-pi in surgical specimens obtained from 35 patients with glioma and epilepsy. We observed MRP1 expression in tumor and endothelial cells (EC), MRP3 and Pgp expression mainly in ECs and GST-pi predominantly in tumor cells (TC). MRP1 and MRP3 were more expressed in high grade glioma (HGG) than in LGG. In 6 cases we could compare tumor and periphery detecting the same MRP1 and Pgp expression, while MRP3 was mainly expressed in the tumor. We observed a trend of a better outcome in seizure control associated with a lower expression of MRP1 and MRP3. MRP3 was statistically more expressed in TCs of HGG than LGG (p = 0.0401) and more expressed in tumor than in periphery, in agreement with recent works that identify MRP3 as a potential target in GBM. Moreover, MRP3 was investigated in association with refractory epilepsy for the first time in our study and it was less expressed in patients with complete response to AEDs (p = 0.0550). Our preliminary data show an association between multidrug resistance transporters and refractory epilepsy in glioma. PMID- 22832900 TI - Use of machine learning to shorten observation-based screening and diagnosis of autism. AB - The Autism Diagnostic Observation Schedule-Generic (ADOS) is one of the most widely used instruments for behavioral evaluation of autism spectrum disorders. It is composed of four modules, each tailored for a specific group of individuals based on their language and developmental level. On average, a module takes between 30 and 60 min to deliver. We used a series of machine-learning algorithms to study the complete set of scores from Module 1 of the ADOS available at the Autism Genetic Resource Exchange (AGRE) for 612 individuals with a classification of autism and 15 non-spectrum individuals from both AGRE and the Boston Autism Consortium (AC). Our analysis indicated that 8 of the 29 items contained in Module 1 of the ADOS were sufficient to classify autism with 100% accuracy. We further validated the accuracy of this eight-item classifier against complete sets of scores from two independent sources, a collection of 110 individuals with autism from AC and a collection of 336 individuals with autism from the Simons Foundation. In both cases, our classifier performed with nearly 100% sensitivity, correctly classifying all but two of the individuals from these two resources with a diagnosis of autism, and with 94% specificity on a collection of observed and simulated non-spectrum controls. The classifier contained several elements found in the ADOS algorithm, demonstrating high test validity, and also resulted in a quantitative score that measures classification confidence and extremeness of the phenotype. With incidence rates rising, the ability to classify autism effectively and quickly requires careful design of assessment and diagnostic tools. Given the brevity, accuracy and quantitative nature of the classifier, results from this study may prove valuable in the development of mobile tools for preliminary evaluation and clinical prioritization-in particular those focused on assessment of short home videos of children--that speed the pace of initial evaluation and broaden the reach to a significantly larger percentage of the population at risk. PMID- 22832899 TI - Dietary folic acid intake differentially affects methionine metabolism markers and hippocampus morphology in aged rats. AB - PURPOSE: Folic acid (FA) is an emerging nutritional factor in the pathogenesis of diverse neurodegenerative disorders by still unknown mechanisms. The hippocampus is altered during the loss of cognitive abilities in humans and selectively affected when homocysteine increases. The aim was to evaluate the potential protective role of folic acid in the maintenance of biochemical markers related to the methionine cycle, as well as the integrity of the hippocampus as part of the brain in aged rats. METHODS: Male Sprague-Dawley rats (18 months old) were assigned to four different folic acid groups (0 mg FA/kg diet, deficient; 2 mg FA/kg diet, control; 8 mg FA/kg diet, moderate supplementation; 40 mg FA/kg diet, extra supplementation) for 30 days. We evaluated several parameters related to the methionine cycle. In addition, hippocampus areas were immunostained for specific neuronal markers and astrocytes. RESULTS: Serum folate levels increased according to FA dietary level (p < 0.01). There was a significant increase in the serum homocysteine concentrations in the folic acid-deficient diet group (p < 0.01). However, brain S-adenosylmethionine and S-adenosylhomocysteine did not differ significantly between the folic acid groups. Consequently, the methylation ratio was also unchanged. The morphometric analysis did not show any differences in the number of neurons and astrocytes between groups, except when comparing the folic acid-deficient diet versus folic acid-supplemented diet in the striatum of the hippocampus. CONCLUSIONS: Clearly, the dietary FA deficiency negatively affects the methionine metabolism biomarkers, while excessive supplementation seems to be unnecessary for optimal maintenance of the methylation cycle and hippocampus integrity. PMID- 22832901 TI - Discovery of blood transcriptomic markers for depression in animal models and pilot validation in subjects with early-onset major depression. AB - Early-onset major depressive disorder (MDD) is a serious and prevalent psychiatric illness in adolescents and young adults. Current treatments are not optimally effective. Biological markers of early-onset MDD could increase diagnostic specificity, but no such biomarker exists. Our innovative approach to biomarker discovery for early-onset MDD combined results from genome-wide transcriptomic profiles in the blood of two animal models of depression, representing the genetic and the environmental, stress-related, etiology of MDD. We carried out unbiased analyses of this combined set of 26 candidate blood transcriptomic markers in a sample of 15-19-year-old subjects with MDD (N=14) and subjects with no disorder (ND, N=14). A panel of 11 blood markers differentiated participants with early-onset MDD from the ND group. Additionally, a separate but partially overlapping panel of 18 transcripts distinguished subjects with MDD with or without comorbid anxiety. Four transcripts, discovered from the chronic stress animal model, correlated with maltreatment scores in youths. These pilot data suggest that our approach can lead to clinically valid diagnostic panels of blood transcripts for early-onset MDD, which could reduce diagnostic heterogeneity in this population and has the potential to advance individualized treatment strategies. PMID- 22832902 TI - Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion. AB - The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<~2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ~12,000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e. = 0.03) for neuroticism and 0.12 (s.e. = 0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ~45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called 'missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors. PMID- 22832903 TI - Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study. AB - Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD. PMID- 22832904 TI - Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. AB - Excitement and controversy have followed neuregulin (NRG1) since its discovery as a putative schizophrenia susceptibility gene; however, the mechanism of action of the associated risk haplotype (HapICE) has not been identified, and specific genetic variations, which may increase risk to schizophrenia have remained elusive. Using a postmortem brain cohort from 37 schizophrenia cases and 37 controls, we resequenced upstream of the type I-IV promoters, and the HapICE repeat regions in intron 1. Relative abundance of seven NRG1 mRNA transcripts in the prefrontal cortex were determined and compared across diagnostic and genotypic groups. We identified 26 novel DNA variants and showed an increased novel variant load in cases compared with controls (chi(2)=7.815; P=0.05). The average nucleotide diversity (theta = 10.0 * 10(-4)) was approximately twofold higher than that previously reported for BDNF, indicating that NRG1 may be particularly prone to genetic change. A greater nucleotide diversity was observed in the HapICE linkage disequilibrium block in schizophrenia cases (theta((case)) = 13.2 * 10(-4); theta((control)) = 10.0 * 10(-4)). The specific HapICE risk haplotype was associated with increased type III mRNA (F = 3.76, P = 0.028), which in turn, was correlated with an earlier age of onset (r = -0.343, P = 0.038). We found a novel intronic five-SNP haplotype ~730 kb upstream of the type I promoter and determined that this region functions as transcriptional enhancer that is suppressed by SRY. We propose that the HapICE risk haplotype increases expression of the most brain-abundant form of NRG1, which in turn, elicits an earlier clinical presentation, thus providing a novel mechanism through which this genetic association may increase risk of schizophrenia. PMID- 22832905 TI - Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome. AB - Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects. PMID- 22832906 TI - Evidence for biological roots in the transgenerational transmission of intimate partner violence. AB - Intimate partner violence is a ubiquitous and devastating phenomenon for which effective interventions and a clear etiological understanding are still lacking. A major risk factor for violence perpetration is childhood exposure to violence, prompting the proposal that social learning is a major contributor to the transgenerational transmission of violence. Using an animal model devoid of human cultural factors, we showed that male rats became highly aggressive against their female partners as adults after exposure to non-social stressful experiences in their youth. Their offspring also showed increased aggression toward females in the absence of postnatal father-offspring interaction or any other exposure to violence. Both the females that cohabited with the stressed males and those that cohabited with their male offspring showed behavioral (including anxiety- and depression-like behaviors), physiological (decreased body weight and basal corticosterone levels) and neurobiological symptoms (increased activity in dorsal raphe serotonergic neurons in response to an unfamiliar male) resembling the alterations described in abused and depressed women. With the caution required when translating animal work to humans, our findings extend current psychosocial explanations of the transgenerational transmission of intimate partner violence by strongly suggesting an important role for biological factors. PMID- 22832907 TI - Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention. AB - Age-related increases in prevalent dementia over the next 30-40 years risk collapsing medical resources or radically altering the way we treat patients. Better prevention of dementia therefore needs to be one of our highest medical priorities. We propose a perspective on the pathological basis of dementia based on a cerebrovascular-Alzheimer disease spectrum that provides a more powerful explanatory framework when considering the impact of possible public health interventions. With this in mind, a synthesis of evidence from basic, clinical and epidemiological studies indeed suggests that the enhanced treatment of hypertension could be effective for the primary prevention of dementia of either Alzheimer or vascular etiology. In particular, we focus on candidate preventative mechanisms, including reduced cerebrovascular disease, disruption of hypoxia dependent amyloidogenesis and the potential neuroprotective properties of calcium channel blockers. Following the successful translation of large, long-term and resource-intense trials in cardiology into improved vascular health outcomes in many countries, new multinational prevention trials with dementia-related primary outcomes are now urgently required. PMID- 22832908 TI - Effects of maternal immune activation on gene expression patterns in the fetal brain. AB - We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the alpha, beta and gamma crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism. PMID- 22832910 TI - STIM-ulation for the big trial. PMID- 22832911 TI - Evolving patterns of ventricular tachycardia modifying our mapping techniques. PMID- 22832909 TI - Piccolo genotype modulates neural correlates of emotion processing but not executive functioning. AB - Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene--involved in monoaminergic neurotransmission--as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD. PMID- 22832912 TI - Epicardial access for the treatment of cardiac arrhythmias. AB - Since the introduction of percutaneous epicardial access for the purpose of mapping and ablation of cardiac arrhythmias, this technique has become an important adjunct and at times the preferred approach to treat certain cardiac arrhythmias. In addition, this approach is currently also being considered for a number of other cardiovascular applications such as epicardial pacing, left atrial appendage ligature occlusion, etc. The focus of this review is to discuss relevant aspects of pericardial anatomy, and various methods of epicardial access. PMID- 22832913 TI - The utility of manually controlled steerable sheath in epicardial mapping and ablation procedure in patients with ventricular tachycardia. AB - AIMS: The aim of this study is to evaluate the benefit of manually controlled steerable sheath, which provides greater flexibility and stability, in mapping and ablation procedure of ventricular tachycardia. METHODS AND RESULTS: We retrospectively reviewed 40 patients who underwent epicardial mapping and conclusive ablation. The first attempt to reach the primary endpoint defined as successful creation of detailed map of entire epicardial space and was achieved in 16 patients. Among the remaining 24 patients, we used the steerable sheath and achieved further success to create an entire map in all patients. After the delivery of RF energy, final procedural success was defined as complete abolishment of late potential and no more induction of any VT, and that was obtained in 10 out of 16 patients mapped with conventional sheath and 21 out of 24 patients with steerable sheath. The advantage of the steerable sheath seemed to be consistent, regardless of the site of ablation. There was no procedure related adverse event. CONCLUSIONS: The manually controlled steerable sheath was safe and effective to achieve procedural success in patients with epicardial VT. PMID- 22832914 TI - Enhancement of intracardiac navigation by new GPS-guided location system (MediGuide Technologies). PMID- 22832915 TI - The role of percutaneous left ventricular assist devices during ventricular tachycardia ablation. AB - Ventricular tachycardia (VT) is a common but serious arrhythmia that significantly adds to the morbidity and mortality of patients with structural heart disease. Percutaneous catheter ablation has evolved to be standard therapy to prevent recurrent implantable cardioverter defibrillator shocks from VT in patients on antiarrhythmia medications. Procedural outcomes in patients with structural heart disease are often limited by haemodynamically unstable VT. Although substrate- and pace-mapping techniques have become increasingly popular for VT ablation, these approaches can often times may not address inducible clinical and non-clinical VTs. Activation and entrainment mapping can help the operator target VT exit sites in a precise fashion minimizing the amount of radiofrequency ablation needed for a successful ablation. An evolving alternative strategy that allows induction and mapping of VT in the setting of severe cardiomyopathy and haemodynamic instability is through maintaining perfusion with a percutaneous ventricular assist device (pVAD). This review will discuss these pVAD technologies, distinguish technical applications of use, highlight the published clinical experience, provide a clinical approach for support device selection, and discuss use of these technologies with current mapping and navigational systems. PMID- 22832916 TI - Changes in the propagation pattern within the conduction channel during sinus rhythm and ventricular tachycardia demonstrated by non-contact mapping: role of late potential activity. AB - Sustained monomorphic ventricular tachycardia (VT) in patients with a previous myocardial infarction is due to re-entry mechanism in areas of slow conduction. The recognition of the pathogenic mechanism and the characterization of the activation pathway are usually obtained by indirect measures with entrainment mapping and pacing manoeuvres. We studied a 61-years-old patient with a history of previous inferior myocardial infarction and we provided the in vivo direct visualization of the critical components of re-entry circuit by non-contact mapping. VT circuit entrance, central pathway, and exit were characterized during the same beat by virtual electrodes and visualized on a three-dimensional map both during sinus rhythm, ongoing VT, and pacemapping. The analysis demonstrated an activation of the conductive channel in opposite directions during the sinus rhythm and ventricular tachycardia. Late potentials during sinus rhythm turned into mid-diastolic activity during VT; non-contact mapping allowed the ablation procedure to be performed in sinus rhythm, targeting the central pathway of the conducting channel and the abolition of VT inducibility. PMID- 22832917 TI - Multielectrode contact mapping to assess scar modification in post-myocardial infarction ventricular tachycardia patients. AB - Substrate-based approaches for ablation of unmappable ventricular tachycardia (VT) are strictly dependent on high-density mapping of the scar. Ultra-high density mapping with multielectrode catheters facilitates an accurate and faster definition of sites critical for re-entry, due to the possibility of simultaneous recordings of local potential from different pairs of electrodes. Multipolar catheters can be advanced to map the endocardial or the epicardial surface. A strong correlation between the scar area determined by electroanatomical mapping and the histopathological scar size has been demonstrated. A double-transeptal technique allows for an accurate definition of target sites. The complex scar architecture has been investigated by ultra-high-density mapping, let the identification of islets of heterogeneity where electrograms adjacent to the preserved myocardium have an higher incidence of late potentials. Pacing manoeuvres can easily be performed from any pair of electrode, to demonstrate the involvement of late potentials into the VT circuit. This strategy allows for a clear-cut validation of late potential abolishment, and may offer advantages to shorten procedural and fluoroscopy times. Large series are necessary to definitively assess the potential role of multielectrode mapping as a guide for the substrate ablation approach in post-myocardial infarction VT patients. PMID- 22832918 TI - Taking a historical turn: possible points of connection between social pyschology and history. AB - The article confronts methodological differences between (and among) social psychologists and historians about how far the social psychologist should be interested only in contemporary or very recent history and how far general conclusions can be drawn about human behaviour across time and space. The article suggests that social psychology need not be present-centric and might take different forms of a 'historical turn'. In turn, it is suggested, historians can benefit from approaches developed by social psychologists. Seven possible points of connection with the discipline of history are put forward in the hope of fostering future collaborations. These are: the nature of modernity; collective memory and the uses of the past; political discourse and ideologies; partisanship; the public sphere; stereotypes; and languages and images. Indeed, just as they can encourage closer collaboration between historians and social psychologists, these themes might also open a wider inter-disciplinary discussion with anthropologists, sociologists, literary scholars, art historians and scholars of political discourse. PMID- 22832919 TI - Temporal patterns in appearance of sooty blotch and flyspeck fungi on apples. AB - Sooty blotch and flyspeck (SBFS) is a complex of about 80 fungal species that blemish the surface of apple fruit in humid regions worldwide. The dark colonies become visible in mid- to late summer, reducing the value of fresh fruit. Although many SBFS species can co-occur in the same orchard and even on the same apple, little is known about temporal patterns of these species, including the timing of colony appearance. To test the hypothesis that colonies of SBFS species appear on apples at characteristic times during the growing season, 50 apples were monitored weekly at three Iowa orchards in 2006 and six orchards in 2007 and 2008. However, a mean of 24.3 apples per orchard was assessed at harvest because of apple drop throughout the season. Colonies were marked with colored pens as they appeared. After harvest and after storage of apples at 2 degrees C for 3 months, SBFS colonies on each fruit were counted and classified by morphology, and a representative subset of colonies was excised from the fruit and preserved on dried peels for species identification using rDNA. Seventeen species were identified. Stomiopeltis spp. RS1 and RS2 appeared on apples 10 to 14 days before other SBFS taxa. Dissoconium aciculare was generally the last species to appear on apple fruit, and it continued to appear during postharvest storage. The most prevalent taxa in Iowa orchards were also the most abundant. Diversity of SBFS fungi in an orchard was positively correlated with cumulative hours of surface wetness hours due to rainfall or dew, which is believed to favor growth of SBFS fungi. Species-specific information about temporal patterns of appearance on apple fruit may lead to improved SBFS management strategies. PMID- 22832920 TI - Detrital floc and surface soil microbial biomarker responses to active management of the nutrient impacted Florida everglades. AB - Alterations in microbial community composition, biomass, and function in the Florida Everglades impacted by cultural eutrophication reflect a new physicochemical environment associated with monotypic stands of Typha domingensis. Phospholipid fatty acid (PLFA) biomarkers were used to quantify microbial responses in detritus and surface soils in an active management experiment in the eutrophic Everglades. Creation of open plots through removal of Typha altered the physical and chemical characteristics of the region. Mass of PLFA biomarkers increased in open plots, but magnitude of changes differed among microbial groups. Biomarkers indicative of Gram-negative bacteria and fungi were significantly greater in open plots, reflective of the improved oxic environment. Reduction in the proportion of cyclopropyl lipids and the ratio of Gram-positive to Gram-negative bacteria in open plots further suggested an altered oxygen environment and conditions for the rapid growth of Gram-negative bacteria. Changes in the PLFA composition were greater in floc relative to soils, reflective of rapid inputs of new organic matter and direct interaction with the new physicochemical environment. Created open plot microbial mass and composition were significantly different from the oligotrophic Everglades due to differences in phosphorus availability, plant community structure, and a shift to organic peat from marl-peat soils. PLFA analysis also captured the dynamic inter-annual hydrologic variability, notably in PLFA concentrations, but to a lesser degree content. Recently, use of concentration has been advocated over content in studies of soil biogeochemistry, and our results highlight the differential response of these two quantitative measures to similar pressures. PMID- 22832923 TI - Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice. AB - Saposin D-deficient (Sap-D(-/-)) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino d-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D(-/-) mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10~12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-mo-long water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D(-/-) mice. PMID- 22832922 TI - In vivo contribution of serine proteases to the proteolytic activation of gammaENaC in aldosterone-infused rats. AB - Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of alpha-, beta-, and gamma-subunits. Aldosterone induces a molecular weight shift of gammaENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of gammaENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans. PMID- 22832921 TI - Inhibition of alphaENaC expression and ENaC activity following blockade of the circadian clock-regulatory kinases CK1delta/epsilon. AB - Increasing evidence suggests that the circadian clock plays an important role in the control of renal function and blood pressure. We previously showed that the circadian clock protein Period (Per)1, positively regulates the expression of the rate limiting subunit of the renal epithelial sodium channel (alphaENaC), which contributes to blood pressure regulation. Casein kinases 1delta and 1epsilon (CK1delta/epsilon) are critical regulators of clock proteins. CK1delta/epsilon must phosphorylate the circadian clock protein Per1 in order for the latter to enter the nucleus. We used a commercially available CK1delta/epsilon inhibitor, PF670462, to test the effect of CK1delta/epsilon blockade and inhibited Per1 nuclear entry on alphaENaC in a model of the renal cortical collecting duct (mpkCCD(c14) cells). CK1delta/epsilon blockade prevented Per1 and Clock from interacting with an E-box from the alphaENaC promoter. CK1delta/epsilon inhibition reduced alphaENaC mRNA levels by <60%. A similar decrease in alphaENaC mRNA was observed following siRNA-mediated CK1delta/epsilon knock-down. Inhibition of CK1delta/epsilon effectively prevented the transcriptional response of alphaENaC to aldosterone, suggesting an interaction between the circadian clock and aldosterone-mediated regulation of alphaENaC. CK1delta/epsilon inhibition significantly reduced alphaENaC but increased Caveolin-1 membrane protein levels; transepithelial current, a measure of ENaC activity, was decreased. Importantly, single channel analysis in amphibian renal cells demonstrated a dramatic decrease in the number of patches with observable ENaC current following CK1delta/epsilon inhibition. The present study shows for the first time that CK1delta/epsilon inhibition and impaired Per1 nuclear entry results in decreased alphaENaC expression and ENaC activity, providing further support for direct control of ENaC by the circadian clock. PMID- 22832924 TI - Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. AB - Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na(+) reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP 1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na(+) excretion, and renal membrane expression of the Na(+)/H(+) exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP 1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na(+) reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes. PMID- 22832925 TI - 3D spheroid defects in NPHP knockdown cells are rescued by the somatostatin receptor agonist octreotide. AB - Ciliopathies are a heterogeneous group of diseases that exhibit broad clinical phenotypes, including renal cysts, retinal degeneration, and cerebellar vermis aplasia. Nephronophthisis (NPHP) is a renal ciliopathy that causes chronic kidney disease and is characterized by kidney cysts at the cortico-medullary border. Among the 10 different disease-causing genes (NPHP1-NPHP10), mutations in NPHP3, NPHP6, or NPHP8 cause the most severe ciliopathy variants of NPHP, Joubert syndrome, and Meckel Syndrome. In this study, we tested the hypothesis that loss of function of these three most severe disease-associated genes leads to morphological defects in a three-dimensional (3D) renal cell culture [murine (m) inner medullary collecting duct (IMCD) 3] model by either lack of cilia formation and/or cell polarity defects. Stable knockdown cell lines were examined in 3D spheroid culture followed by rhodamine-phalloidin staining to assess spheroid architecture. We observed significantly higher percentages of abnormal spheroids for all three stable cell lines compared with control short-hairpin RNA cells. In addition, stable knockdown of Nphp3, Nphp6, and Nphp8 results in reduced cilia numbers and elevated cAMP levels in mIMCD3 cells. We demonstrate that, following gene knockdown of Nphp3, Nphp6, or Nphp8, treatment with the somatostatin agonist octreotide (2 MUM) reduces the percentage of abnormal spheroids compared with control. This study reveals that the loss of Nphp3, Nphp6, or Nphp8 leads to cilia abnormalities and cell polarity defects, resulting in spheroid abnormalities, which can be rescued by inhibiting cAMP levels with octreotide treatment. PMID- 22832926 TI - Effect of a serine protease inhibitor on the progression of chronic renal failure. AB - The number of the chronic renal failure (CRF) patients is increasing explosively. Hypertension, proteinuria, inflammation, fibrosis, and oxidative stress are intertwined in a complicated manner that leads to the progression of CRF. However, the therapeutic strategies to delay its progression are limited. Since serine proteases are involved in many processes that contribute to these risk factors, we investigated the effects of a synthetic serine protease inhibitor, camostat mesilate (CM), on the progression of CRF in 5/6 nephrectomized (Nx) rats. Eighteen male Sprague-Dawley rats were divided into three groups: a sham operated group (n = 6), a vehicle-treated Nx group (n = 6), and a CM-treated Nx group (n = 6). Following the 9-wk study period, both proteinuria and serum creatinine levels were substantially increased in the vehicle-treated Nx group, and treatment with CM significantly reduced proteinuria and serum creatinine levels. The levels of podocyte-associated proteins in glomeruli, such as nephrin and synaptopodin, were markedly decreased by 5/6 nephrectomy, and this was significantly ameliorated by CM. CM also suppressed the levels of inflammatory and fibrotic marker mRNAs including transforming growth factor-beta1, TNF-alpha, collagen types I, III, and IV, and reduced glomerulosclerosis, glomerular hypertrophy, and interstitial fibrosis in histological studies. Furthermore, CM decreased the expression of NADPH oxidase component mRNAs, as well as reactive oxygen species generation and advanced oxidative protein product levels. Our present results strongly suggest the possibility that CM could be a useful therapeutic agent against the progression of CRF. PMID- 22832927 TI - Dietary protein affects urea transport across rat urothelia. AB - Recent evidence suggests that regulated solute transport occurs across mammalian lower urinary tract epithelia (urothelia). To study the effects of dietary protein on net urothelial transport of urea, creatinine, and water, we used an in vivo rat bladder model designed to mimic physiological conditions. We placed groups of rats on 3-wk diets differing only by protein content (40, 18, 6, and 2%) and instilled 0.3 ml of collected urine in the isolated bladder of anesthetized rats. After 1 h dwell, retrieved urine volumes were unchanged, but mean urea nitrogen (UN) and creatinine concentrations fell 17 and 4%, respectively, indicating transurothelial urea and creatinine reabsorption. The fall in UN (but not creatinine) concentration was greatest in high protein (40%) rats, 584 mg/dl, and progressively less in rats receiving lower protein content: 18% diet, 224 mg/dl; 6% diet, 135 mg/dl; and 2% diet, 87 mg/dl. The quantity of urea reabsorbed was directly related to a urine factor, likely the concentration of urea in the instilled urine. In contrast, the percentage of instilled urea reabsorbed was greater in the two dietary groups receiving the lowest protein (26 and 23%) than in those receiving higher protein (11 and 9%), suggesting the possibility that a bladder/urothelial factor, also affected by dietary protein, may have altered bladder permeability. These findings demonstrate significant regulated urea transport across the urothelium, resulting in alteration of urine excreted by the kidneys, and add to the growing evidence that the lower urinary tract may play an unappreciated role in mammalian solute homeostasis. PMID- 22832928 TI - Case of isolated lateral lymph node recurrence occurring after TME for T1 lower rectal cancer treated with lateral lymph node dissection: report of a case. AB - We experienced a rare case of isolated lateral lymph node (LLN) recurrence after laparoscopic intersphincteric resection with total mesorectal excision for T1 lower rectal cancer that was successfully treated using LLN dissection with en bloc resection of the left superior vesical artery, the left ovary and the left obturator nerve, artery and vein. There are no guidelines for treating patients with isolated LLN recurrence because isolated LLN recurrence is rare, especially in patients with T1 rectal cancer. However, in patients with pT1N0 lower rectal cancer, follow-up examinations of the pelvis should be performed periodically. Patients with isolated LLN recurrence treated with surgery might have good long term prognoses. Therefore, for such patients, surgical resection should be considered as a curative treatment only. PMID- 22832932 TI - Ursolic acid inhibits growth and metastasis of human colorectal cancer in an orthotopic nude mouse model by targeting multiple cell signaling pathways: chemosensitization with capecitabine. AB - PURPOSE: Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid, a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated. EXPERIMENTAL DESIGN: The effect of ursolic acid on proliferation of CRC cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kappaB activation by DNA-binding assay, and protein expression by Western blot. The effect of ursolic acid on the growth and chemosensitization was also examined in orthotopically implanted CRC in nude mice. RESULTS: We found that ursolic acid inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-kappaB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, and survivin), proliferative (cyclin D1), and metastatic (MMP-9, VEGF, and ICAM-1) proteins. When examined in an orthotopic nude mouse model, ursolic acid significantly inhibited tumor volume, ascites formation, and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that ursolic acid downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-kappaB, STAT3, and beta-catenin. In addition, ursolic acid suppressed EGF receptor (EGFR) and induced p53 and p21 expression. We also observed bioavailability of ursolic acid in the serum and tissue of animals. CONCLUSION: Overall, our results show that ursolic acid can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through the suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis. PMID- 22832935 TI - Progress toward prevention and control of hepatitis C virus infection--Egypt, 2001-2012. AB - Worldwide, 130-170 million persons are living with chronic hepatitis C virus (HCV) infection, which, if left untreated, can result in cirrhosis and liver cancer. Egypt has the largest burden of HCV infection in the world, with a 10% prevalence of chronic HCV infection among persons aged 15-59 years. HCV transmission in Egypt is associated primarily with inadequate infection control during medical and dental care procedures. In response, the Egyptian Ministry of Health and Population (MOHP) in 2001 implemented a program to reduce health-care associated HCV transmission and in 2008 launched a program to provide care and treatment. This report describes the progress of these programs, identifies deficiencies, and recommends enhancements, including the establishment of a comprehensive national viral hepatitis control program. Infection control programs implemented in 2001 at MOHP facilities resulted in improvements in infection control practices and a decrease in the annual incidence of HCV infection among dialysis patients from 28% to 6%. Through June 2012, a total of 23 hepatitis treatment facilities had been established in Egypt, providing care and treatment to nearly 190,000 persons with chronic HCV infection. Despite these programs, Egypt continues to face an ongoing hepatitis C epidemic. A comprehensive plan is needed to prevent and control hepatitis C in Egypt. This plan should address increasing community awareness and education, preventing of HCV infection in health-care settings, ensuring a safe blood supply, establishing surveillance and monitoring to track the effectiveness of control programs, and providing care and treatment. PMID- 22832934 TI - Cell-penetrating nitroxides as molecular sensors for imaging of cancer in vivo, based on tissue redox activity. AB - The present study shows that hydrophobic and cell-penetrating piperidine-type nitroxide radicals SLENU and TEMPOL, but not hydrophilic and partially penetrating or non-penetrating pyrrolidine-type nitroxides carbamoyl-PROXYL and carboxy-PROXYL, are appropriate contrast agents for magnetic resonance imaging (MRI) of cancer, based on its functionality - tissue redox activity. The experiments were conducted on anesthetized mice: healthy and neuroblastoma bearing in a moderate stage of cancer development. The method is based on the nitroxide redox cycle, coupled with appearance or disappearance of the MRI signal. The half-life (tau(1/2)) of a nitroxide-enhanced MRI signal in the respective tissue was used as a marker to assess tissue redox activity to the nitroxide radical. In the case of SLENU and TEMPOL, there were large differences in the histograms between control and cancer-bearing mice. All tissues (cancer and non-cancer) of cancer-bearing organisms were characterized by a long-lived MRI signal (tau(1/2) > 14 min), indicating a high oxidative activity. The tissues of healthy organisms were characterized by a short-lived MRI signal (tau(1/2) = 1 3 min), indicating a high reducing activity. In the case of carbamoyl-PROXYL and carboxy-PROXYL, there was no difference in the histograms between control and cancer-bearing mice. The data show that the penetration of nitroxide in cells and tissues is obligatory for imaging of cancer, based on its redox activity. The principle of the method is applicable also to biopsy specimens, using MRI or EPR spectroscopy. We provide direct evidence that the nitroxide redox cycle could be used as a sensing platform for functional imaging of different pathologies, based on changes in cellular and tissue redox activity, as in the case of cancer. PMID- 22832933 TI - Validation of a radiosensitivity molecular signature in breast cancer. AB - PURPOSE: Previously, we developed a radiosensitivity molecular signature [radiosensitivity index (RSI)] that was clinically validated in 3 independent datasets (rectal, esophageal, and head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT)-treated breast cancer patients. EXPERIMENTAL DESIGN: RSI was tested in 2 previously published breast cancer datasets. Patients were treated at the Karolinska University Hospital (n = 159) and Erasmus Medical Center (n = 344). RSI was applied as previously described. RESULTS: We tested RSI in RT-treated patients (Karolinska). Patients predicted to be radiosensitive (RS) had an improved 5-year relapse-free survival when compared with radioresistant (RR) patients (95% vs. 75%, P = 0.0212), but there was no difference between RS/RR patients treated without RT (71% vs. 77%, P = 0.6744), consistent with RSI being RT-specific (interaction term RSI * RT, P = 0.05). Similarly, in the Erasmus dataset, RT-treated RS patients had an improved 5-year distant metastasis free survival over RR patients (77% vs. 64%, P = 0.0409), but no difference was observed in patients treated without RT (RS vs. RR, 80% vs. 81%, P = 0.9425). Multivariable analysis showed RSI is the strongest variable in RT-treated patients (Karolinska, HR = 5.53, P = 0.0987, Erasmus, HR = 1.64, P = 0.0758) and in backward selection (removal alpha of 0.10), RSI was the only variable remaining in the final model. Finally, RSI is an independent predictor of outcome in RT-treated ER(+) patients (Erasmus, multivariable analysis, HR = 2.64, P = 0.0085). CONCLUSIONS: RSI is validated in 2 independent breast cancer datasets totaling 503 patients. Including prior data, RSI is validated in 5 independent cohorts (621 patients) and represents, to our knowledge, the most extensively validated molecular signature in radiation oncology. PMID- 22832936 TI - Preconception health indicators among women--Texas, 2002-2010. AB - The first few weeks after conception are the most critical for fetal development; because most women are not aware that they are pregnant until after this critical period, health-care interventions should begin before conception. Promoting preconception health is an essential component of any broad strategy to prevent adverse pregnancy outcomes. Women who are planning pregnancy or could become pregnant should have a preconception health evaluation and adopt appropriate health behaviors. The Pregnancy Risk Assessment Monitoring System (PRAMS) tracks maternal behaviors, experiences, and health conditions, including preconception health. PRAMS is a state-specific, population-based surveillance system. The Texas Department of State Health Services analyzed PRAMS responses regarding preconception health of Texas women who delivered a live-born infant during 2002 2010. Among women who responded, 48% had no health-care insurance coverage before pregnancy and 46% reported an unintended pregnancy. In addition, 45% of the women reported consuming alcohol during the 3 months before pregnancy, and 18% reported binge drinking. Differences in demographic and socioeconomic variables were observed for the majority of preconception health indicators. Compared with non Hispanic white women, non-Hispanic black and Hispanic women reported a 20% higher prevalence of not consuming a daily multivitamin and of being physically inactive, and approximately twice the prevalence of prepregnancy diabetes. Women without health-care coverage (public or private) before pregnancy generally were more likely to report unfavorable behavioral characteristics and health conditions compared with women with health-care coverage, regardless of whether the pregnancy was planned or not. Targeted public health interventions addressing the observed disparities in the preconception health and health care of women in Texas are needed. PMID- 22832937 TI - Trends in HIV-related risk behaviors among high school students--United States, 1991-2011. AB - One of the three primary goals of the National HIV/AIDS Strategy for the United States is to reduce the number of persons who become infected with human immunodeficiency virus (HIV). In 2009, persons aged 15-29 years comprised 21% of the U.S. population but accounted for 39% of all new HIV infections. Sexual intercourse, sexual intercourse with multiple partners, sexual intercourse without using a condom, and injection drug use are behaviors that increase risk for HIV infection. To describe trends in the prevalence of HIV-related risk behaviors among high school students, CDC analyzed data from the biennial national Youth Risk Behavior Survey (YRBS) for the period 1991-2011. The results of that analysis indicated that, although the percentage of students overall who had ever had sexual intercourse decreased significantly from 54.1% in 1991 to 47.4% in 2011, the prevalence of ever having had sexual intercourse did not change significantly after reaching 45.6% in 2001. Similarly, although the percentage of students who had four or more sex partners decreased significantly from 18.7% in 1991 to 15.3% in 2011, the prevalence of having four or more sex partners did not change significantly after reaching 14.2% in 2001. Condom use at most recent sexual intercourse among students currently having sexual intercourse increased from 46.2% in 1991 to 60.2% in 2011. However, the prevalence of condom use did not change significantly beginning in 2003 (63.0%). The prevalence of injection drug use among students overall did not change significantly from 1995 (2.1%) to 2011 (2.3%). The results suggest that progress in reducing some HIV related risk behaviors among high school students overall and in certain populations did not change significantly in the past decade. To reduce the number of young persons who become infected with HIV, renewed educational efforts and other risk reduction interventions are warranted. PMID- 22832938 TI - Notes from the field: Outbreak of influenza A (H3N2) virus among persons and swine at a county fair--Indiana, July 2012. AB - During July 12-16, 2012, the Indiana State Department of Health and the Indiana Board of Animal Health identified respiratory illness among swine and persons at a county fair held July 8-14. On July 16, specimens were collected from four persons with respiratory illness; two had become ill on July 12 and sought care at an emergency department, and two were identified as part of the subsequent public health investigation. All four persons were swine exhibitors or family members of swine exhibitors and had close contact with swine. On July 18, reverse transcription-polymerase chain reaction testing at the Indiana State Department of Health laboratory identified suspected influenza A (H3N2) variant (H3N2v) virus* in all four specimens. On July 21, partial genome sequencing at CDC confirmed H3N2v virus with the influenza A (H1N1)pdm09 virus M gene; the viruses detected in the four specimens are similar to 12 viruses detected in 2011 and one detected earlier this year. None of the four persons were hospitalized, and all have fully recovered. PMID- 22832939 TI - Molecular properties and extracellular processing of the lipase of Staphylococcus warneri M. AB - Staphylococcus warneri M exhibited extracellular lipase activity. By zymogram analysis of extracellular proteins, multiple bands were detected and the profiles changed depending on the bacterial growth phase. N-terminal amino acid sequences of three bands (N1-N3) were determined. From the genome library of S. warneri M whole DNA, the gene-directing lipase activity (named gehC(WM)) was cloned and characterized. The gehC(WM )gene encoded a protein (GehC(WM)), whose calculated molecular mass was 83.4 kDa, and the sequence was similar to the other staphylococcal lipases. Though two lipases have been known from S. warneri 863, GehC(WM) differs from both of them, indicating that this enzyme is the third extracellular lipase of the S. warneri strain. The N-terminal sequences of the N1 N3 polypeptides completely coincided with the deduced amino acid sequences in GehC(WM). GehC(WM) was predicted to be a prepro-protein. In vitro processing and protein sequencing suggested that pro-GehC(WM) is possibly processed by extracellular glutamyl endopeptidase, PROM. Inductively coupled plasma-atomic emission spectrometer analysis showed that purified his-tagged mature GehC(WM) possessed zinc ion. A gehC(WM) knockout mutant was constructed by insertion of an erythromycin resistance gene into the gehC(WM). Zymogram and immunoblot analyses of the gehC(WM )mutant indicated that GehC(WM) was a major extracellular lipase of S. warneri M. PMID- 22832940 TI - Comparison of intrafollicular sperm injection and intrauterine insemination in the treatment of subfertility. AB - PURPOSE: To compare the efficacy of intrafollicular sperm injection (IFI) versus intrauterine insemination (IUI) in the treatment of subfertility. METHODS: 38 couples suffering primary or secondary subfertility contributed a total of 47 IUI or IFI cycles, 26 by IUI and 21 by IFI. Folliculogenesis, ovulation triggering, and IUI or IFI were performed. Motile spermatozoa were inseminated into the uterine cavity for IUI or injected into pre-ovulatory follicles for IFI. The rate of biochemical and clinical pregnancy was assessed. RESULTS: The rate of biochemical pregnancy/cycle for IUI was 11 % as compared to 38 % for IFI (p = 0.04). The rate of clinical pregnancy/cycle for IUI was 11 % as compared to 29 % for IFI (p = 0.26). The rate of twin pregnancy and miscarriage was low and no high order multiple gestation was observed. The rate of ectopic tubal pregnancy/cycle for IUI was 0 % as compared to 9 % for IFI (p = 0.19); no ovarian pregnancy was observed. When the analysis was confined to IFI cycles in which 2.68-6.65 million motile spermatozoa were injected/follicle (n = 10), a rate of 60 % clinical pregnancy/cycle was observed, of which 2 were ectopic. CONCLUSION: Under the conditions described herein, IFI was more effective than IUI at achieving pregnancy. PMID- 22832941 TI - Over-expression of tumor necrosis factor-alpha in vitiligo lesions after narrow band UVB therapy: an immunohistochemical study. AB - There is a growing evidence that cytokines are important in the depigmentation process of vitiligo, however, the exact mechanism is not fully understood. The aim of this work was to study the possible role of the tumor necrosis factor alpha (TNF-alpha) cytokine in the depigmentation process of the disease. Twenty patients with generalized vitiligo were exposed to narrow-band ultraviolet B (NB UVB) therapy thrice weekly for a total of 60 sessions. Immunohistochemical examination was done, to assess the TNF-alpha expression in lesional and perilesional skin as compared to normal control skin, before and after therapy. At baseline, positive lesional TNF-alpha expression was detected in 60 % of patients which was significantly higher as compared to perilesional skin (20 %) and negative expression in healthy control skin. Post-treatment, a statistically significant increase in TNF-alpha expression was detected in both lesional (90 %) and perilesional skin (70 %) as compared to baseline (P < 0.05). The significant increase of TNF-alpha in vitiligo lesions compared with perilesional and healthy skin suggests a possible involvement of this cytokine in the depigmentation of vitiligo. The increase in TNF-alpha expression after NB-UVB phototherapy suggests another role in repigmentation. PMID- 22832942 TI - Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb arthroplasty. AB - BACKGROUND: The oral anticoagulant rivaroxaban is recommended for venous thromboembolic prophylaxis following lower limb arthroplasty. Concerns regarding high rates of wound complications following its use have prompted this multicenter comparison with low-molecular-weight heparins. METHODS: English hospital trusts that replaced a low-molecular-weight heparin with rivaroxaban for thromboprophylaxis in lower limb arthroplasty during 2009 were identified. Prospectively collected national data for these units were analyzed to determine the thirty-day rates of wound complications and major bleeding (cerebrovascular event or gastrointestinal hemorrhage) and the ninety-day rates of symptomatic deep venous thrombosis (proximal or distal), symptomatic pulmonary embolism, and all-cause inpatient mortality before and after the change to rivaroxaban. A total of 2762 patients prescribed rivaroxaban following knee or hip arthroplasty were compared with 10,361 patients prescribed a low- molecular weight heparin. Data were analyzed with use of odds ratios (ORs). RESULTS: There were significantly fewer wound complications in the low-molecular-weight heparin group (2.81% compared with 3.85%; OR = 0.72, 95% confidence interval [CI] = 0.58 to 0.90; p = 0.005). There were no significant differences between the low-molecular-weight heparin and rivaroxaban groups in the rates of pulmonary embolism (0.55% compared with 0.36%; OR = 1.52, 95% CI = 0.78 to 2.98), major bleeding (OR = 0.73, 95% CI = 0.48 to 1.12), or all-cause mortality (OR = 0.93, 95% CI = 0.46 to 1.89). There were significantly more symptomatic deep venous thromboses in the low-molecular weight heparin group (0.91% compared with 0.36%; OR = 2.51, 95% CI = 1.31 to 4.84; p = 0.004). CONCLUSIONS: The rivaroxaban group had a higher wound complication rate and a lower deep venous thrombosis rate; there were no differences in symptomatic pulmonary embolism or all-cause mortality. Longer follow-up is needed to assess any potential relationship between wound complications and joint stiffness, latent infection, and limb consequences of deep venous thrombosis. PMID- 22832943 TI - Inhibition of acetate accumulation leads to enhanced production of (R,R)-2,3 butanediol from glycerol in Escherichia coli. AB - This work describes the production of (R,R)-2,3-butanediol in Escherichia coli using glycerol by metabolic engineering approaches. The introduction of a synthetic pathway converting pyruvate to (R,R)-2,3-butanediol into wild-type E. coli strain BW25113 led to the production of (R,R)-2,3-butanediol at a titer of 3.54 g/l and a yield of 0.131 g product/g glycerol (26.7 % of theoretical maximum) with acetate (around 3.00 g/l) as the dominant by-product. We therefore evaluated the impacts of deleting the genes ackA or/and poxB that are responsible for the major by-product, acetate. This increased production of (R,R)-2,3 butanediol to 9.54 g/l with a yield of 0.333 g product/g glycerol (68.0 % of theoretical maximum) in shake flask studies. The utilization of low-priced crude glycerol to produce value-added chemicals is of great significance to the economic viability of the biodiesel industry. PMID- 22832944 TI - Denitrification of high nitrate wastewater in a cloth strip bioreactor with immobilized sludge. AB - Denitrification of synthetic high nitrate wastewater containing 40,000 ppm NO(3) (9,032 ppm NO(3)-N) was achieved using immobilized activated sludge in a column reactor. Active anoxic sludge adsorbed onto Terry cloth was used in the denitrification of high nitrate wastewater. The operational stability of the immobilized sludge system was studied both in a batch reactor and in a continuous reactor. The immobilized sludge showed complete degradation of different concentrations of NO(3)-N (1,129, 1,693, 3,387, 6,774, and 9,032 ppm) in a batch process. The reactors were successfully run for 90 days without any loss in activity. The immobilized cell process has yielded promising results in attaining high denitrifying efficiency. PMID- 22832946 TI - Current state of computer-assisted trauma surgery. AB - Computer assisted surgery (CAS) was first used in neurosurgery. Currently, CAS has gained popularity in several surgical disciplines including urology and abdominal surgery. In trauma and orthopaedic surgery, computer assisted systems are used for fracture reduction, planning and positioning of implants as well as the accurate implantation of hip and knee prostheses. The patient's anatomy is virtualized and the surgical instruments integrated into the digitized image background, thus allowing the surgeon to navigate the surgical instruments and the bone in an improved, virtual visual environment. CAS improves overall accuracy, reducing intraoperative radiation exposure and minimizing unnecessary surgical dissection combined with increased patient and surgeon safety. However, limitations include prolonged surgical time, technical errors and cost implications. This article will outline the current state of computer assisted trauma surgery including its implications and specific challenges in orthopaedic trauma surgery. PMID- 22832945 TI - Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthritis: implications for insufficiency fracture risk. AB - OBJECTIVE: Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model. METHODS: Mice with established arthritis and expressing human tumor necrosis factor alpha (TNFalpha) transgene (Tg) and their wild-type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled-release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined. RESULTS: TNF Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF-Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity. CONCLUSION: Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture. PMID- 22832947 TI - The Acute Physiology and Chronic Health Evaluation II score is helpful in predicting the need of relaparotomies in patients with secondary peritonitis of colorectal origin. AB - BACKGROUND: Secondary peritonitis of colorectal origin has considerable morbidity and mortality. Relaparotomies are frequently necessary in the course of the disease. The objective of this study was to evaluate several scores in terms of their predictive value, i.e. whether Mannheim Peritonitis Index (MPI), Acute Physiology And Chronic Health Evaluation (APACHE) II, or Colorectal Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (CR POSSUM) scores can predict relaparotomies. METHODS: Charts of 147 patients treated for secondary peritonitis of colorectal origin were retrospectively reviewed, MPI, APACHE II, and CR-POSSUM scores were calculated, and groups of patients with or without relaparotomies were compared. RESULTS: Thirty-four percent of patients underwent one or more relaparotomies. Patients with relaparotomies showed a significantly higher APACHE II score than patients without relaparotomies (p = 0.004). MPI (p = 0.072) and CR-POSSUM score (p = 0.319) did not differ between the two groups. A high APACHE II score was also significantly associated with the need for a relaparotomy on demand (p <0.001), and for the combined outcome parameter relaparotomy and/or an interventional drainage (p = 0.046). Both other scores were not predictive for these outcomes. Overall in-hospital mortality was 21.8%. All three scores investigated were predictive for mortality. Sensitivity was 62.5%, 78.1%, and 75.0% for MPI, APACHE II score, and CR-POSSUM score, respectively. CONCLUSION: The Acute Physiology And Chronic Health Evaluation II score might be helpful in predicting the need for relaparotomies in patients with secondary peritonitis of colorectal origin. PMID- 22832948 TI - FTIR spectroscopic study of molecular organization of the antibiotic amphotericin B in aqueous solution and in DPPC lipid monolayers containing the sterols cholesterol and ergosterol. AB - Langmuir monolayers of amphotericin B (AmB) were investigated by recording pi-A isotherms under different pH conditions. To gain a better insight into antibiotic membrane interactions they were monitored by use of the ATR-FTIR spectroscopy. It was observed for AmB monolayers that the limiting molecular area was larger at high than at neutral pH. Analysis of FTIR spectra at different pH revealed substantial differences, depending on ionic state, for different orientations of AmB molecules. These results enable better understanding of the participation of functional groups in the interactions between AmB and sterol-containing DPPC membranes. AmB molecules incorporated into two-component lipid monolayers bind strongly to the ergosterol-rich membrane (maximum penetration surface pressures ca 35 mN/m). The FTIR spectra revealed that the ionic state of AmB and the presence of sterols led to changes in membrane fluidity and molecular packing of the AmB molecules in the lipid membranes. These investigations should be further investigated to discover the molecular mechanism responsible for the mode of action AmB in biological systems. PMID- 22832949 TI - Leuprolide acetate, a GnRH agonist, improves experimental autoimmune encephalomyelitis: a possible therapy for multiple sclerosis. AB - Gonadotrophin-releasing hormone (GnRH), a well known hypothalamic neuropeptide, has been reported to possess neurotrophic properties. Leuprolide acetate, a synthetic analogue of GnRH is considered to be a very safe and tolerable drug and it has been used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. The present study was designed to determine whether Leuprolide acetate administration, exerts neurotrophic effects on clinical signs, body weight gain, neurofilaments (NFs) and myelin basic protein (MBP) expression, axonal morphometry and cell infiltration in spinal cord of experimental autoimmune encephalomyelitis (EAE) rats. In this work, we have found that Leuprolide acetate treatment decreases the severity of clinical signs of locomotion, induces a significantly greater body weight gain, increases the MBP and NFs expression, axonal area and cell infiltration in EAE animals. These results suggest the use of this agonist as a potential therapeutic approach for multiple sclerosis. PMID- 22832950 TI - Neuroprotective effects of new protein kinase C activator TPPB against Abeta25-35 induced neurotoxicity in PC12 cells. AB - Alzheimer's disease (AD) is pathologically characterized by presence of senile plaques in the hippocampus, which are composed mainly of extracellular deposition of a polypeptide known as the beta amyloid, the Abeta. It has been demonstrated on numerous occasions that it was the deposition and aggregation of this Abeta peptide that cause neuronal dysfunction and even finally, the dementia. Lowering the deposition of Abeta or decreasing its neurotoxicity has long been one of the purposes of AD therapy. In previous study, we reported that protein kinase C (PKC) activator TPPB could regulate APP processing by increasing alpha-secretase activity. In this study we further investigated the potential neuroprotective effect of TPPB against Abeta(25-35)-induced neurotoxicity in PC12 cells. The results indicated that TPPB at concentration of 1 MUM could antagonize Abeta(25 35) induced cell damage as evidenced by MTT assays, LDH release and by morphological changes. Furthermore, the neuroprotection in cell viability can be blocked by inhibitors of PKC, Akt and MAPK. The experiment also indicated that TPPB could increase the phosphorylation of Akt, PKC, MARCKS and MAPK, which were inhibited by Abeta(25-35) treatment. Finally, TPPB inhibited the activation of caspase-3 induced by Abeta(25-35). Taken together, the experiment here implies that TPPB has a role against Abeta(25-35)-induced neurotoxicity in PC12 cells and may suggest its therapeutic potential in AD. PMID- 22832951 TI - Kinetic and computational evidence for an intermediate in the hydrolysis of sulfonate esters. AB - The hydrolytic reactions of sulfonate esters have previously been considered to occur by concerted mechanisms. We now report the observation of a break in a Bronsted correlation for the alkaline hydrolysis of aryl benzenesulfonates. On either side of a break-point, beta(leaving group) values of -0.27 (pK(a) < 8.5) and -0.97 (pK(a) > 8.5) are measured. These data are consistent with a two-step mechanism involving a pentavalent intermediate that is also supported by QM/MM calculations. The emerging scenario can be explained by the combined effect of a strong nucleophile with a poor leaving group that compel a usually concerted reaction to favour a stepwise process. PMID- 22832952 TI - Neurotrophic gene polymorphisms and response to psychological therapy. AB - Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR = 0.60 (0.42-0.85), P = 0.005). These effects remained even when other clinically relevant covariates were accounted for (OR = 0.62 (0.41-0.92), P = 0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions. PMID- 22832953 TI - A putative functional role for oligodendrocytes in mood regulation. AB - Altered glial structure and function is implicated in several major mental illnesses and increasing evidence specifically links changes in oligodendrocytes with disrupted mood regulation. Low density and reduced expression of oligodendrocyte-specific gene transcripts in postmortem human subjects points toward decreased oligodendrocyte function in most of the major mental illnesses. Similar features are observed in rodent models of stress-induced depressive-like phenotypes, such as the unpredictable chronic mild stress and chronic corticosterone exposure, suggesting an effect downstream from stress. However, whether oligodendrocyte changes are a causal component of psychiatric phenotypes is not known. Traditional views that identify oligodendrocytes solely as nonfunctional support cells are being challenged, and recent studies suggest a more dynamic role for oligodendrocytes in neuronal functioning than previously considered, with the region adjacent to the node of Ranvier (i.e., paranode) considered a critical region of glial-neuronal interaction. Here, we briefly review the current knowledge regarding oligodendrocyte disruptions in psychiatric disorders and related animal models, with a focus on major depression. We then highlight several rodent studies, which suggest that alterations in oligodendrocyte structure and function can produce behavioral changes that are informative of mood regulatory mechanisms. Together, these studies suggest a model, whereby impaired oligodendrocyte and possibly paranode structure and function can impact neural circuitry, leading to downstream effects related to emotionality in rodents, and potentially to mood regulation in human psychiatric disorders. PMID- 22832954 TI - Distinct neurometabolic profiles are evident in the anterior cingulate of young people with major psychiatric disorders. AB - Currently, there are no validated neurobiological methods for distinguishing different pathophysiological pathways in young patients presenting in the early phases of major psychiatric disorders. Hence, treatments are delivered simply on the basis of their possible effects on nonspecific symptom constructs such as depression, cognitive change or psychotic symptoms. In this study, the ratios (relative to creatine) of key metabolites (N-acetyl aspartate, myoinositol, glutamate and glutathione) were measured with proton magnetic resonance spectroscopy ((1)H-MRS) within the anterior cingulate cortex of 88 young persons presenting with major mood or psychotic symptoms. We derived empirically (using a cluster analytical technique) three subgroups of subjects on the basis of their patterns of in vivo brain biochemistry. The three subgroups were distinguished (from each other) by all the four metabolites, in particular, glutathione and glutamate. By contrast, the groups could not be distinguished by differences in terms of other demographic, functional or clinical measures. We propose that this (1)H-MRS-based subclassification system could be used as the basis for much more specific tests of novel intervention strategies (notably, antioxidant and glutamatergic therapies) early in the course of major psychiatric disorders. PMID- 22832955 TI - NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology. AB - Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47(phox) was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47(phox) were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations. PMID- 22832956 TI - TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders. AB - TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n = 596) and healthy controls (n = 385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment. PMID- 22832957 TI - Association between SNPs and gene expression in multiple regions of the human brain. AB - Identifying the genetic cis associations between DNA variants (single-nucleotide polymorphisms (SNPs)) and gene expression in brain tissue may be a promising approach to find functionally relevant pathways that contribute to the etiology of psychiatric disorders. In this study, we examined the association between genetic variations and gene expression in prefrontal cortex, hippocampus, temporal cortex, thalamus and cerebellum in subjects with psychiatric disorders and in normal controls. We identified cis associations between 648 transcripts and 6725 SNPs in the various brain regions. Several SNPs showed brain regional specific associations. The expression level of only one gene, PDE4DIP, was associated with a SNP, rs12124527, in all the brain regions tested here. From our data, we generated a list of brain cis expression quantitative trait loci (eQTL) genes that we compared with a list of schizophrenia candidate genes downloaded from the Schizophrenia Forum (SZgene) database (http://www.szgene.org/). Of the SZgene candidate genes, we found that the expression levels of four genes, HTR2A, PLXNA2, SRR and TCF4, were significantly associated with cis SNPs in at least one brain region tested. One gene, SRR, was also involved in a coexpression module that we found to be associated with disease status. In addition, a substantial number of cis eQTL genes were also involved in the module, suggesting eQTL analysis of brain tissue may identify more reliable susceptibility genes for schizophrenia than case-control genetic association analyses. In an attempt to facilitate the identification of genetic variations that may underlie the etiology of major psychiatric disorders, we have integrated the brain eQTL results into a public and online database, Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org). PMID- 22832958 TI - Cognitive reserve, presynaptic proteins and dementia in the elderly. AB - Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging. PMID- 22832959 TI - Hypervigilance for fear after basolateral amygdala damage in humans. AB - Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach-Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety. PMID- 22832960 TI - A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales. AB - Temperament has a strongly heritable component, yet multiple independent genome wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P<1.25 * 10( 8), with correction for testing four scales) accounting for >=0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene based tests and pathway analysis we have tested over 1.2 million single nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired. PMID- 22832961 TI - Genome-wide association study of Alzheimer's disease. AB - In addition to apolipoprotein E (APOE), recent large genome-wide association studies (GWASs) have identified nine other genes/loci (CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1 and ABCA7) for late-onset Alzheimer's disease (LOAD). However, the genetic effect attributable to known loci is about 50%, indicating that additional risk genes for LOAD remain to be identified. In this study, we have used a new GWAS data set from the University of Pittsburgh (1291 cases and 938 controls) to examine in detail the recently implicated nine new regions with Alzheimer's disease (AD) risk, and also performed a meta-analysis utilizing the top 1% GWAS single-nucleotide polymorphisms (SNPs) with P<0.01 along with four independent data sets (2727 cases and 3336 controls) for these SNPs in an effort to identify new AD loci. The new GWAS data were generated on the Illumina Omni1-Quad chip and imputed at ~2.5 million markers. As expected, several markers in the APOE regions showed genome-wide significant associations in the Pittsburg sample. While we observed nominal significant associations (P<0.05) either within or adjacent to five genes (PICALM, BIN1, ABCA7, MS4A4/MS4A6E and EPHA1), significant signals were observed 69-180 kb outside of the remaining four genes (CD33, CLU, CD2AP and CR1). Meta-analysis on the top 1% SNPs revealed a suggestive novel association in the PPP1R3B gene (top SNP rs3848140 with P = 3.05E-07). The association of this SNP with AD risk was consistent in all five samples with a meta-analysis odds ratio of 2.43. This is a potential candidate gene for AD as this is expressed in the brain and is involved in lipid metabolism. These findings need to be confirmed in additional samples. PMID- 22832962 TI - Olfactory discrimination predicts cognitive decline among community-dwelling older adults. AB - The presence of olfactory dysfunction in individuals at higher risk of Alzheimer's disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46-86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions using the Sniffin' Sticks battery indicated that, contrary to previous findings, olfactory discrimination, but not olfactory identification, significantly predicted subsequent cognitive decline (odds ratio = 0.869; P<0.05; 95% confidence interval = 0.764-0.988). The current study findings confirm previously reported associations between olfactory and cognitive functions, and indicate that impairment in olfactory discrimination can predict future cognitive decline. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia. PMID- 22832963 TI - 13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients. AB - Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-(13)C]phenylalanine breath test ((13)C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. (13)C phenylalanine (99 atom% (13)C; 100 mg) was administered orally and the breath (13)CO(2) /(12)CO(2) ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on (13)C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Delta(13)CO(2) (0/00) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Delta(13)CO(2) was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on (13)C-PBT indices in rats. Our results suggest that (13)C PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication. PMID- 22832964 TI - Genome-wide meta-analyses of smoking behaviors in African Americans. AB - The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (beta = 0.040, s.e. = 0.007, P = 1.84 * 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans. PMID- 22832965 TI - Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder. AB - The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [(11)C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time * LSAS(anx) change on D2-R-binding potential (BP(ND)) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BP(ND) and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD. PMID- 22832966 TI - Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. AB - Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20-30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2(-/-)) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2( /-) mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident-intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2(+/-) mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression. PMID- 22832967 TI - Circadian profiles in young people during the early stages of affective disorder. AB - Although disturbances of the circadian system are strongly linked to affective disorders, no known studies have examined melatonin profiles in young people in early stages of illness. In this study, 44 patients with an affective disorder underwent clinical and neuropsychological assessments. They were then rated by a psychiatrist according to a clinical staging model and were categorized as having an 'attenuated syndrome' or an 'established disorder'. During the evening, salivary melatonin was sampled under dim light conditions over an 8-h interval and for each patient, the time of melatonin onset, total area under the curve and phase angle (difference between time of melatonin onset and time of habitual sleep onset) were computed. Results showed that there was no difference in the timing of melatonin onset across illness stages. However, area under the curve analyses showed that those patients with 'established disorders' had markedly reduced levels of melatonin secretion, and shorter phase angles, relative to those with 'attenuated syndromes'. These lower levels, in turn, were related to lower subjective sleepiness, and poorer performance on neuropsychological tests of verbal memory. Overall, these results suggest that for patients with established illness, dysfunction of the circadian system relates clearly to functional features and markers of underlying neurobiological change. Although the interpretation of these results would be greatly enhanced by control data, this work has important implications for the early delivery of chronobiological interventions in young people with affective disorders. PMID- 22832971 TI - Synthesis and enhanced electrochemical performance of Li2CoPO4F cathodes under high current cycling. AB - Lithium cobalt fluorophosphate, Li(2)CoPO(4)F, is successfully synthesized by a solid state reaction under Ar flow at 700 degrees C. X-ray diffraction and scanning electron microscopic studies are utilized to analyze the structural and morphological features of the synthesized materials, respectively. The presence of fluorine is also supported by energy-dispersive X-ray spectroscopy. The electrochemical properties are evaluated by means of Li/Li(2)CoPO(4)F half-cell configurations in both potentiostatic and galvanostatic modes. The Li/Li(2)CoPO(4)F cell delivers an initial discharge capacity of 132 mA h g(-1) at a current density of 0.1 mA cm(-2) between 2.0 and 5.1 V at room temperature. Due to the higher operating potential of the Co(2+/3+) couple in the fluorophosphate matrix, this cell shows a capacity retention of only 53% after 20 cycles, still the material delivered 108 mA h g(-1) at a high current rate of 1 C. Cyclic voltammetric studies corroborate the insertion and extraction of Li(+) ions by a single phase reaction mechanism during cycling. PMID- 22832970 TI - Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory. AB - Ca(2+)-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca(2+) increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca(2+)-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca(2+) stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca(2+)-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene-environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience dependent changes in CF memory. We showed that the strength of CF memory in wild type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory. PMID- 22832973 TI - Can we simply infer mitochondrial function from PCr resynthesis after exercise in skeletal muscle? PMID- 22832975 TI - Computer-assisted surgery is not more accurate or precise than conventional arthroscopic ACL reconstruction: a prospective randomized clinical trial. AB - BACKGROUND: Accurate and precise tunnel placement is critical to the success of anterior cruciate ligament (ACL) reconstruction. A new development, computer assisted surgery, aids in placement of the ACL bone tunnels during surgery. Our hypothesis was that computer-assisted ACL reconstruction would allow more accurate and precise tunnel placement compared with conventional surgery. METHODS: In a prospective, double-blind, randomized clinical study, 100 patients eligible for ACL reconstruction with a transtibial technique were stratified by surgeon and randomized to either conventional or computer-assisted surgery. Measurement of femoral and tibial tunnel placement with use of three-dimensional computed tomography (CT) was used as the primary outcome to compare conventional ACL surgery with computer-assisted surgery. RESULTS: The placement of the femoral tunnel did not differ between groups (mean, 39.7% of the proximal-distal distance on the intracondylar axis [Blumensaat line] in the conventional group compared with 39.0% in the computer-assisted surgery group; p = 0.70). The anterior posterior positioning of the tibial tunnel on the tibial plateau also did not differ significantly (38.9% in the conventional group compared with 38.2% in the computer-assisted surgery group; p = 0.58). There was no significant difference in the precision of either the femoral or the tibial tunnel placement between the two groups. CONCLUSIONS: There was no significant difference in either the accuracy or the precision of tunnel placement between conventional and computer assisted ACL reconstruction. PMID- 22832977 TI - Is the resection of gliomas in Wernicke's area reliable? : Wernicke's area resection. AB - Wernicke's area was, for a long time, considered a non-removable area and patients affected by low-grade gliomas (LGGs) or high-grade gliomas (HGGs) in this region were considered inoperable. Several studies have demonstrated a large functional reshaping of language networks in patients affected by gliomas or acute stroke involving Wernicke's territories, and the complete resection of this region invaded by LGG has recently been reported. We report our experience in the removal of Wernicke's territories invaded by gliomas. Four patients underwent awake surgery, with neuropsychological and neurophysiological monitoring and direct cortico-subcortical bipolar stimulation, for resection of LGG (one case) and HGGs (three cases) invading Wernicke's territories. Resection rates were evaluated by means of magnetic resonance imaging (MRI) and computed tomography (CT) perfusion for LGG and HGGs, respectively. HGGs were totally resected and LGG was partially resected (67%), according to functional limits. No patients reported neurological deficit. The patient affected by LGG underwent postoperative chemotherapy. Two of the patients harbouring HGGs died 21 and 23 months after surgery and postoperative adjuvant treatment, respectively. The third one is still alive and progression-free 21 months after surgery. Awake surgery is a reliable and effective technique for resection of gliomas invading Wernicke's territories without postoperative permanent deficit. LGGs in this region can safely be removed, according to the functional subcortical boundaries, allowing postoperative adjuvant treatment, functional reshaping and multi-step surgery. HGGs, instead, can be completely removed without deficits and sometimes beyond the contrast enhancement area, allowing the best possible oncological prognosis for the patients. PMID- 22832978 TI - Microsurgical clipping of true posterior communicating artery aneurysms. AB - BACKGROUND: "True" posterior communicating artery (PCOM) aneurysms are rare variants in which the aneurysm arises solely from the PCOM rather than the junction of the internal carotid artery and the PCOM. METHODS: It is critical to note that for true PCOM aneurysms, the neck arises distal to the origin of the PCOM and therefore lies in what is traditionally an intra-operative blind spot. The PCOM must be followed posteriorly to visualise the aneurysm neck for microsurgical clipping. CONCLUSIONS: A thorough pre-operative understanding of this unique anatomy is essential in minimising morbidity associated with microsurgical clipping of this aneurysm configuration. PMID- 22832979 TI - Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion. AB - PURPOSE: One of the most important characteristics of ovarian cancer is invasion and metastasis. Matrix metalloproteinases (MMPs) are known to play an important role in cancer cell invasion by mediating the degradation of extracellular matrix (ECM). The activities of MMPs are regulated by tissue inhibitors of metalloproteinases (TIMPs). In this study, we investigated the clinical significance of MMP-2, -7 and -9 and TIMP-1, -2 and -3 expression and MMP-9 functional role in cell invasion and adhesion in ovarian cancer. METHODS: RT-PCR was used to determine mRNA expression of MMP-2, -7 and -9 and TIMP-1, -2 and -3 in ovarian tissues; ELISA was used to detect the serum level of MMP-9; RNA interference (RNAi) was performed to determine the function of MMP-9 in cell invasion and adhesion in ovarian cancer cells. RESULTS: mRNA expression of MMP-2, MMP-7, MMP-9, TIMP-2 and TIMP-3 and serum level of MMP-9 were significantly high in patients with ovarian cancer. MMP-9 expression was significantly high in patients with advanced ovarian cancer and correlated with poor prognosis. The ability of cells for invasion and adhesion was significantly reduced by treatment of cells with MMP-9 siRNA. CONCLUSIONS: Our results suggest that MMP-9 is a potential prognostic factor for ovarian cancer and could be a novel treatment target in ovarian cancer patients. PMID- 22832980 TI - Hyaluronan binding assay does not predict pregnancy rates in IUI cycles in couples with unexplained infertility. AB - PURPOSE: To investigate the relationship between hyaluronan binding (HB) assay and pregnancy rates in intrauterine insemination (IUI) cycles. METHODS: This prospective cohort study was done in Hacettepe University, a tertiary care center for reproductive medicine. Seventy-one consecutive couples who suffered from unexplained infertility and underwent controlled ovarian hyperstimulation (COH) and IUI were enrolled into the study. RESULTS: From the 71 IUI patients, the clinical pregnancy rate was 14.1% (10 of 71). HB ratio from the overall patient number was 48.6+/-25.9. The mean HB ratio in pregnant and non-pregnant groups was comparable (50.2+/-25.2 vs. 48.3+/-26.2, respectively, p>0.05). CONCLUSIONS: Hyaluronan binding assay does not predict pregnancy rates in IUI cycles in couples with unexplained infertility. PMID- 22832981 TI - Rare coexistence of placenta previa accreta and peritoneal adhesion: three-decade clinical observation. PMID- 22832982 TI - Carpal tunnel syndrome: the association with occupation at a population level. AB - The aim of this study was to examine the association of occupation and gender with the incidence and severity of carpal tunnel syndrome (CTS). We examined 884 patients of working age, diagnosed with CTS, in a specialist hand clinic that was the only provider of hand services to a health board area. We categorized occupation using the Standard Occupational Classification 2010 (SOC2010) and used local census data to calculate the incidence in each of the nine major occupational groups. The greatest incidence was in caring and leisure occupations (197 per 100 000 population per year), while the lowest incidence was in the associate professional group (37 per 100 000). Professional occupations had a high incidence of CTS, along with skilled trades and elementary occupations. Women had a higher incidence of CTS than men in managerial, professional, skilled trades, and elementary occupations (OR 2.9-3.6). The Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score varied across occupational groups (p < 0.001) and was worst in the caring and leisure group. As traditional heavy industry associated with previously described occupational risks declines, new patterns of occupational association may emerge. We recommend ongoing observational research of potential occupational risk factors to identify these new trends. PMID- 22832983 TI - A new and accurate method to quantify gap formation in tendon repairs. PMID- 22832984 TI - Division of the flexor pollicis longus tendon during open carpal tunnel release through a limited incision. PMID- 22832985 TI - Functional and structural studies of a novel cold-adapted esterase from an Arctic intertidal metagenomic library. AB - A novel cold-adapted lipolytic enzyme gene, est97, was identified from a high Arctic intertidal zone sediment metagenomic library. The deduced amino acid sequence of Est97 showed low similarity with other lipolytic enzymes, the maximum being 30 % identity with a putative lipase from Vibrio caribbenthicus. Common features of lipolytic enzymes, such as the GXSXG sequence motif, were detected. The gene product was over-expressed in Escherichia coli and purified. The recombinant Est97 (rEst97) hydrolysed various rho-nitrophenyl esters with the best substrate being rho-nitrophenyl hexanoate (K m and k cat of 39 MUM and 25.8 s(-1), respectively). This esterase activity of rEst97 was optimal at 35 degrees C and pH 7.5 and the enzyme was unstable at temperatures above 25 degrees C. The apparent melting temperature, as determined by differential scanning calorimetry was 39 degrees C, substantiating Est97 as a cold-adapted esterase. The crystal structure of rEst97 was determined by the single wavelength anomalous dispersion method to 1.6 A resolution. The protein was found to have a typical alpha/beta hydrolase fold with Ser144-His226-Asp197 as the catalytic triad. A suggested, relatively short lid domain of rEst97 is composed of residues 80-114, which form an alpha-helix and a disordered loop. The cold adaptation features seem primarily related to a high number of methionine and glycine residues and flexible loops in the high-resolution structures. PMID- 22832986 TI - Removal of pathogenic factors from 2,3-butanediol-producing Klebsiella species by inactivating virulence-related wabG gene. AB - Klebsiella species are the most extensively studied among a number of 2,3 butanediol (2,3-BDO)-producing microorganisms. The ability to metabolize a wide variety of substrates together with the ease of cultivation made this microorganisms particularly promising for the application in industrial-scale production of 2,3-BDO. However, the pathogenic characteristics of encapsulated Klebsiella species are considered to be an obstacle hindering their industrial applications. Here, we removed the virulence factors from three 2,3-BDO-producing strains, Klebsiella pneumoniae KCTC 2242, Klebsiella oxytoca KCTC1686, and K. oxytoca ATCC 43863 through site-specific recombination technique. We generated deletion mutation in wabG gene encoding glucosyltransferase which plays a key role in the synthesis of outer core lipopolysaccharides (LPS) by attaching the first outer core residue D-GalAp to the O-3 position of the L,D-HeppII residue. The morphologies and adhesion properties against epithelial cells were investigated, and the results indicated that the wabG mutant strains were devoid of the outer core LPS and lost the ability to retain capsular structure. The time profile of growth and 2,3-BDO production from K. pneumoniae KCTC 2242 and K. pneumoniae KCTC 2242 DeltawabG were analyzed in batch culture with initial glucose concentration of 70 g/l. The growth was not affected by disrupting wabG gene, but the production of 2,3-BDO decreased from 31.27 to 22.44 g/l in mutant compared with that of parental strain. However, the productions of acetoin and lactate from wabG mutant strain were negligible, whereas that from parental strain reached to ~5 g/l. PMID- 22832987 TI - Enhancing the cyclodextrin production by synchronous utilization of isoamylase and alpha-CGTase. AB - Cyclodextrins (CD) are cyclic alpha-1,4-glucans composed of glucose units, and they have multiple applications in food, pharmaceuticals, cosmetics, agriculture, chemicals, etc. CD are usually produced by cyclodextrin glycosyltransferase (CGTase) from starch. In the present study, a simultaneous conversion approach was developed to improve the yield of CD from starch by conjunction use of isoamylase with alpha-CGTase. The isoamylase of Thermobifida fusca was cloned and expressed in Escherichia coli BL21(DE3). The biochemical characterization of the enzyme showed that the optimum temperature and pH of the recombinant enzyme was 50 degrees C and 5.5, respectively, and it maintained 60 %, 85 % and 78 % relative activity at 30 degrees C, 40 degrees C and 60 degrees C, respectively. When the recombinant isoamylase and alpha-CGTase were used simultaneously to convert potato starch (15 %, w/v) into CD, the optimum conditions were found to be: 10 U of alpha-CGTase and 48 U of isoamylase per gram of substrate, with reaction temperature of 30 degrees C and pH 5.6. On the optimum condition, the total yield of CD reached 84.6 % (w/w) after 24 h, which was 31.2 % higher than transformation with alpha-CGTase alone. This is the first report of synchronous bioconversion of CD by both alpha-CGTase and isoamylase, and represents the highest efficiency of CD production reported so far. PMID- 22832988 TI - Characterization of five novel endolysins from Gram-negative infecting bacteriophages. AB - We here characterize five globular endolysins, encoded by a set of Gram-negative infecting bacteriophages: BcepC6gp22 (Burkholderia cepacia phage BcepC6B), P2gp09 (Escherichia coli phage P2), PsP3gp10 (Salmonella enterica phage PsP3), K11gp3.5 and KP32gp15 (Klebsiella pneumoniae phages K11 and KP32, respectively). In silico, BcepC6gp22, P2gp10 and PsP3gp10 are predicted to possess lytic transglycosylase activity, whereas K11gp3.5 and KP32gp15 have putative amidase activity. All five endolysins show muralytic activity on the peptidoglycan of several Gram-negative bacterial species. In vitro, Pseudomonas aeruginosa PAO1 is clearly sensitive for the antibacterial action of the five endolysins in the presence of the outer membrane permeabilizer EDTA: reductions are ranging from 1.89 to 3.08 log units dependent on the endolysin. The predicted transglycosylases BcepC6gp22, P2gp10 and PsP3gp10 have a substantially higher muralytic and in vitro antibacterial activity compared to the predicted amidases K11gp3.5 and KP32gp15, highlighting the impact of the catalytic specificity on endolysin activity. Furthermore, initial data exclude the synergistic lethal effect of a combination of the predicted transglycosylase PsP3gp10 and the predicted amidase K11gp3.5 on PAO1. As these globular endolysins show a lower enzymatic and antibacterial activity, in comparison to modular endolysins, we suggest that the latter should be favored for antibacterial applications. PMID- 22832989 TI - CDC's vision for public health surveillance in the 21st century. Introduction. PMID- 22832990 TI - Public health surveillance in the United States: evolution and challenges. AB - In its landmark 1988 report, a committee of the Institute of Medicine highlighted assessment as one of the three core functions of public health along with policy development and assurance. The committee recommended that every public health agency regularly and systematically collect, assemble, analyze, and make available information on the health of the community, including statistics on health status, community health needs, and epidemiologic and other studies of health problems. Public health surveillance, often called the cornerstone of public health practice, is an essential element of the assessment function. PMID- 22832991 TI - Lexicon, definitions, and conceptual framework for public health surveillance. AB - Public health surveillance is essential to the practice of public health and to guide prevention and control activities and evaluate outcomes of such activities. With advances in information sciences and technology, changes in methodology, data availability and data synthesis, and expanded health information needs, the question arises whether redefining public health surveillance is needed for the 21st century. The current definition is "Public health surveillance is the ongoing, systematic collection, analysis, and interpretation of health data, essential to the planning, implementation and evaluation of public health practice, closely integrated with the dissemination of these data to those who need to know and linked to prevention and control." PMID- 22832992 TI - Global health surveillance. AB - Awareness of the importance of global health surveillance increased in the latter part of the 20th century with the global emergence of human immunodeficiency virus and novel strains of influenza. In the first decade of the 21st century, several events further highlighted global shared interests in and vulnerability to infectious diseases. Bioterrorist use of anthrax spores in 2001 raised awareness of the value of public health surveillance for national security. The epidemic of severe acute respiratory syndrome (SARS) in 2003, re-emergence of a panzootic of avian influenza A H5N1 in 2005, and the sudden emergence of pandemic H1N1 in North America in 2009 all highlighted the importance of shared global responsibility for surveillance and disease control. In particular, in 2003, SARS precipitated changes in awareness of the world's collective economic vulnerability to epidemic shocks. PMID- 22832993 TI - The role of public health informatics in enhancing public health surveillance. AB - Public health surveillance has benefitted from, and has often pioneered, informatics analyses and solutions. However, the field of informatics also serves other facets of public health including emergency response, environmental health, nursing, and administration. Public health informatics has been defined as the systematic application of information and computer science and technology to public health practice, research, and learning. It is an interdisciplinary profession that applies mathematics, engineering, information science, and related social sciences (e.g., decision analysis) to important public health problems and processes. Public health informatics is a subdomain of the larger field known as biomedical or health informatics. Health informatics is not synonymous with the term health information technology (IT). Although the concept of health IT encompasses the use of technology in the field of health care, one can think of health informatics as defining the science, the how and why, behind health IT. For example, health IT professionals should be able to resolve infrastructure problems with a network connection, whereas trained public health informaticians should be able to support public health decisions by facilitating the availability of timely, relevant, and high-quality information. In other words, they should always be able to provide advice on methods for achieving a public health goal faster, better, or at a lower cost by leveraging computer science, information science, or technology. PMID- 22832994 TI - Public health surveillance workforce of the future. AB - Although electronic data systems that monitor for health threats are becoming increasingly automated, human expertise is, and always will be, critical to recognizing potential cases of disease, diagnosing disease, reporting diseases or conditions, analyzing and interpreting data, and communicating results to all stakeholders. For this reason, the nation's health professionals from all disciplines and at all levels are fundamental to sustaining and enhancing public health surveillance capacity. PMID- 22832995 TI - Public health surveillance data: legal, policy, ethical, regulatory, and practical issues. AB - In the United States, data systems are created by the ongoing, systematic collection of health, demographic, and other information through federally funded national surveys, vital statistics, public and private administrative and claims data, regulatory data, and medical records data. Certain data systems are designed to support public health surveillance and have used well-defined protocols and standard analytic methods for assessing specific health outcomes, exposures, or other endpoints. However, other data systems have been designed for a different purpose but can be used by public health programs for surveillance. Several public health surveillance programs rely substantially on others' data systems. An example of data used for surveillance purposes but collected for another reason is vital statistics data. CDC's National Center for Health Statistics (NCHS) purchases, aggregates, and disseminates vital statistics (birth and death rates) that are collected at the state level. These data are used to understand disease burden, monitor trends, and guide public health action. Administrative data also can be used for surveillance purposes (e.g., Medicare and Social Security Disability data that have been linked to survey data to monitor changes in health and health-care use over time). PMID- 22832997 TI - A peptide probe for detection of various beta-amyloid oligomers. AB - Aggregation of beta-amyloid (Abeta) is implicated in the pathology of Alzheimer's disease (AD). A considerable amount of data has identified soluble Abeta oligomers as potentially significant toxic agents. Rapid, specific and quantitative detection is preferred for accurate profiling of structurally unstable Abeta oligomers as well as for implementation of high-throughput assays for pharmaceutical applications. PG46 is an engineered Abeta variant, constructed by integrating Abeta self-recognition sequences with the conformation-sensitive biarsenical fluorescent dye, FlAsH. PG46 was found to be an effective peptide probe, which detected Abeta oligomers specifically and quantitatively within one hour. However, PG46 was highly aggregation-prone and displayed a limited repertoire of detectable Abeta oligomers. Here, we report the creation of a novel molecular probe, PG44, by C-terminal truncation of PG46. PG44 exhibited a reduced self-aggregation propensity and a different conformation when compared to PG46, and generated specific FlAsH fluorescence signals as a result of binding to various Abeta oligomers, including those not readily detectable by PG46. We also show that sensitivity of PG44 for detection of certain Abeta oligomers may be increased by lowering PG44 concentration and thus decreasing the extent of self aggregation of PG44. Our results suggest that PG44 can serve as an important molecular probe with a broadened repertoire of detectable Abeta oligomeric aggregates. We believe that detection of Abeta oligomers using our peptide probe would potentially contribute toward a better understanding of the molecular basis of Abeta oligomerization and the development of Abeta oligomer-based early diagnostics as well as therapeutic drugs targeting Abeta oligomers. PMID- 22832998 TI - Astrobiological complexity with probabilistic cellular automata. AB - The search for extraterrestrial life and intelligence constitutes one of the major endeavors in science, but has yet been quantitatively modeled only rarely and in a cursory and superficial fashion. We argue that probabilistic cellular automata (PCA) represent the best quantitative framework for modeling the astrobiological history of the Milky Way and its Galactic Habitable Zone. The relevant astrobiological parameters are to be modeled as the elements of the input probability matrix for the PCA kernel. With the underlying simplicity of the cellular automata constructs, this approach enables a quick analysis of large and ambiguous space of the input parameters. We perform a simple clustering analysis of typical astrobiological histories with "Copernican" choice of input parameters and discuss the relevant boundary conditions of practical importance for planning and guiding empirical astrobiological and SETI projects. In addition to showing how the present framework is adaptable to more complex situations and updated observational databases from current and near-future space missions, we demonstrate how numerical results could offer a cautious rationale for continuation of practical SETI searches. PMID- 22832996 TI - Analytical challenges for emerging public health surveillance. AB - The root of effective disease control and prevention is an informed understanding of the epidemiology of a particular disease based on sound scientific interpretation of evidence. Such evidence must frequently be transformed from raw data into consumable information before it can be used for making decisions, determining policy, and conducting programs. However, the work of building such evidence in public health practice--doing the right thing at the right time--is essentially hidden from view. Surveillance involves acquiring, analyzing, and interpreting data and information from several sources across various systems. Achieving the goals and objectives of surveillance investments requires attention to analytic requirements of such systems. The process requires computer programming, statistical reasoning, subject matter expertise, often modeling, and effective communication skills. PMID- 22832999 TI - Duodenal duplication cyst: a potentially malignant disease. AB - BACKGROUND: Duodenal duplication cysts constitute a rare congenital anomaly of the gastrointestinal tract. A recent meta-analysis of the literature between 1999 and 2009 reported a total of 47 cases of duodenal duplication cysts.1 These abnormalities are mostly diagnosed in infancy and childhood. In rare cases, they can remain asymptomatic until adulthood, and 38 % of patients are diagnosed after age 20 years.1 (,) 2 Duodenal duplication cysts are generally benign lesions; nevertheless, three cases of malignant tumours arising inside have been reported.3 (-) 5 METHODS: In this multimedia article, we illustrated the case of an 18 year-old female patient presenting with recurrent episodes of mild pancreatitis. MRI revealed a cystic structure measuring 2.5 cm in diameter located in the duodenal wall next to the papilla of Vater. Endoscopic ultrasound showed a cystic lesion cephalad to the papilla, protruding into the duodenal lumen. Endoscopic retrograde cholangiopancreatography was not feasible due to the dislocation of the papilla, whose macroscopic aspect was normal. To further elucidate the anatomical relations, 3D reconstruction of the MRI images was performed. There was neither dilatation of the biliary tract nor a visible communication between the common bile duct and the cystic structure. The pancreatic duct also was at distance. Those findings were suggestive of a duodenal duplication. Nevertheless, the differential diagnosis6 of a choledochocele (Todani III) could not be formally excluded. Indication for surgical resection was symptomatic disease in a context of potential malignancy. RESULTS: By right subcostal incision (video), surgical exploration revealed a soft tissue mass palpable at the second portion of the duodenum. Following duodenotomy, the mucosa was incised cephalad to the papilla of Vater, which could previously be localized by methylene blue injection by a catheter inserted into the cystic duct. The cystic structure was dissected and no communication between the cyst and the biliary tract was individualized. The final diagnosis was made by histological examination showing duodenal duplication. There was neither heterotopic gastric mucosa nor excreto-biliary epithelial layer. There were no signs of malignancy. The postoperative course was marked by hematemesis externalised by the nasogastric tube. We reintervened at postoperative day 2 to ensure hemostasis. A clot was removed from the area of duodenal mucosa without any visible active bleeding. Further recovery was uneventful; the patient was discharged at postoperative day 10 and is actually asymptomatic. DISCUSSION: The ideal treatment of duodenal duplication cysts is complete surgical resection.7 Due to proximity to the bilio-pancreatic duct, total resection sometimes requires pancreaticoduodenectomy. This major surgical procedure entails the disadvantages of high morbidity and mortality with poor quality of life. In our opinion, this procedure should remain an ultimate option. Less invasive approaches have been proposed, including partial resection or internal derivation.7 Marsupialization is a surgical approach that has been accomplished even endoscopically.1 Nevertheless, these techniques do not provide total resection and leave the risk of degenerescence. As cases of malignancy are reported, we decided to realize a complete surgical excision of the lesion. Three-dimensional reconstruction of the biliary anatomy is an innovative procedure, which allowed us to show the absence of any communication between the cyst and either the common bile duct or the pancreatic duct.8 So, the surgical approach could be specified preoperatively ensuring the integrity of the common bile duct. Duplication cysts could be connected to the pancreaticobiliary ducts in about 29 %.1 Subsequent realization of a total surgical excision combined the advantages of complete resection with minimal invasiveness. CONCLUSIONS: For relieving symptoms and preventing further complications, such as pancreatitis or malignant transformation, surgical resection of duodenal duplication cysts is indicated. In cases of difficulties to individualize the neighboring anatomical structures preoperatively, 3D reconstruction is a helpful approach to determine the surgical strategy. Enucleation allows a total excision while minimizing the adverse effects and therefore it is our treatment of choice for duodenal duplication cysts without communication. PMID- 22833000 TI - The role of heated intraperitoneal chemotherapy (HIPEC) in ovarian cancer: hope or hoax? PMID- 22833001 TI - Fear of recurrence and perceived survival benefit are primary motivators for choosing mastectomy over breast-conservation therapy regardless of age. AB - INTRODUCTION: Recent studies have reported increases in the rate of mastectomy and contralateral prophylactic mastectomy (CPM). We hypothesized that there would be different reasons for choosing mastectomy for women aged <50 compared with those aged >=50 years. METHODS: A questionnaire was administered to 332 patients who underwent unilateral or bilateral mastectomy for breast cancer from 2006 to 2010. The survey queried on demographics, surgical choices, and rationale for those choices. A retrospective chart review was performed to determine tumor characteristics. Responses and clinical characteristics were described by contingency tables and compared using Fisher exact test or chi(2) test, as appropriate. RESULTS: Of 332 patients surveyed, 310 were evaluable. Median age was 55 years, including 88 patients <50 (28 %) and 222 patients >=50 (72 %) at time of diagnosis. Forty-four percent of women <50 and 41 % of women >=50 were given the option of breast conservation and chose mastectomy (p > 0.63). The two groups did not differ in their reason for choosing mastectomy, with lower recurrence risk and improved survival cited as the two most common reasons. Younger patients were more likely to undergo reconstruction and CPM (p < 0.0001) as well as have estrogen receptor-negative tumors, undergo neoadjuvant chemotherapy, and have higher magnetic resonance imaging utilization (p < 0.05). CONCLUSIONS: Choosing mastectomy and the reasons for doing so were the same for women aged <50 and >=50 years. Prospective studies are needed to determine whether patient education regarding perceived versus actual recurrence risk and survival would alter this decision-making process. PMID- 22833003 TI - "Pelizaeus-Merzbacher-like disease" presenting as complicated hereditary spastic paraplegia. PMID- 22833004 TI - Comprehensive model of wild-type and mutant HIV-1 reverse transciptases. AB - An enhanced version of COMBINE that uses both ligand-based and structure-based alignment of ligands has been used to build a comprehensive 3-D QSAR model of wild-type HIV-1 reverse transcriptase and drug-resistant mutants. The COMBINEr model focused on 7 different RT enzymes complexed with just two HIV-RT inhibitors, niverapine (NVP) and efavirenz (EFV); therefore, 14 inhibitor/enzyme complexes comprised the training set. An external test set of chiral 2 (alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones (DABOs) was used to test predictability. The COMBINEr model MC4, although developed using only two inhibitors, predicted the experimental activities of the test set with an acceptable average absolute error of prediction (0.89 pK (i)). Most notably, the model was able to correctly predict the right eudismic ratio for two R/S pairs of DABO derivatives. The enhanced COMBINEr approach was developed using only software freely available to academics. PMID- 22833005 TI - Clinical competence of biopsychosocially trained physicians and controls. AB - OBJECTIVE: To assess and compare clinical observations and interpretations by physicians trained in biopsychosocial internal medicine (group A) and a control group (C) of physicians with no such special training. METHODS: A verbatim first interview of a 36-year old woman, seen for consultation by RHA, was presented to both groups (A, trained physicians: n = 30, and C, controls: n = 29). The patient's symptoms included: shaky knees, strange sensations in the abdomen and chest, insecurity and dizziness. The symptoms had begun before her final nursing- exam and exacerbated on her mother's 60th birthday two months later. The patient's mother is the sole caretaker for the patient's sister, who also attended the birthday party. The patient's sister is 19 and had been diagnosed with storage disease and is wheelchair-bound. The doctors were asked to record their observations and interpretations while reviewing the case report. RESULTS: Group A-physicians mentioned and interpreted the physician-patient relationship and the patient's body language as described in the case report more often (p = 0.002, Wilcoxon-Mann-Whitney rank sum test (RS)), mentioned physical symptoms more often (p = 0.0099, Fisher's exact test (FE)) and more often interpreted illness settings with respect to the patient's fear and guilt (Fisher's exact test, p = 0.007 and p = 0.015). A precise integrative diagnosis (life events leading to stress, the latter evoking fear and guilt, leading to symptoms of the fight-flight reaction) was suggested by 7 of group A and 4 of group C. Extensive laboratory work-up and requests for consultations were more frequently asked for by the C group (p = 0.048, RS). CONCLUSION: Residency training in biopsychosocial medicine in an Internal Medicine Department increased sensitivity to and interpretation of biological and psychosocial data many years after the training and decreased the extent of work-up and consultation costs. However it only tended to enhance psychosomatic conceptualisation with respect to anxiety/guilt/hyperventilation and conversion symptoms. PMID- 22833007 TI - Disease and illness. PMID- 22833008 TI - Molecularly-mediated assemblies of plasmonic nanoparticles for Surface-Enhanced Raman Spectroscopy applications. AB - In recent years, Surface-Enhanced Raman Spectroscopy (SERS) has experienced a tremendous increase of attention in the scientific community, expanding to a continuously wider range of diverse applications in nanoscience, which can mostly be attributed to significant improvements in nanofabrication techniques that paved the way for the controlled design of reliable and effective SERS nanostructures. In particular, the plasmon coupling properties of interacting nanoparticles are extremely intriguing due to the concentration of enormous electromagnetic enhancements at the interparticle gaps. Recently, great efforts have been devoted to develop new nanoparticle assembly strategies in suspension with improved control over hot-spot architecture and cluster structure, laying the foundation for the full exploitation of their exceptional potential as SERS materials in a wealth of chemical and biological sensing. In this review we summarize in an exhaustive and systematic way the state-of-art of plasmonic nanoparticle assembly in suspension specifically developed for SERS applications in the last 5 years, focusing in particular on those strategies which exploited molecular linkers to engineer interparticle gaps in a controlled manner. Importantly, the novel advances in this rather new field of nanoscience are organized into a coherent overview aimed to rationally describe the different strategies and improvements in the exploitation of colloidal nanoparticle assembly for SERS application to real problems. PMID- 22833009 TI - Hydrogeological definition and applicability of abandoned coal mines as water reservoirs. AB - Hydrogeologically, the Central Coal Basin (Asturias, Spain) is characterized by predominantly low-permeability materials that make up a multilayer aquifer with very low porosity and permeability values, where the sandstones act as limited aquifers, and wackes, mudstones, shales and coal seams act as confining levels. Preferential groundwater flow paths are open fractures and zones of decompression associated with them, so the hydraulic behaviour of the system is more associated with fracturing than lithology. Thus, abandoned and flooded mines in the area acquire an important role in the management of water resources, setting up an artificial "pseudo-karst" aquifer. This paper evaluates the potential application of the abandoned mines as underground reservoirs, both for water supply and energetic use, mainly through heat pumps and small hydropower plants. In particular, the groundwater reservoir shaped by the connected shafts Barredo and Figaredo has been chosen, and a detailed and multifaceted study has been undertaken in the area. The exposed applications fit with an integrated management of water resources and contribute to improve economic and social conditions of a traditional mining area in gradual decline due to the cessation of such activity. PMID- 22833010 TI - Fatiguing handgrip exercise alters maximal force-generating capacity of plantar flexors. AB - Exercise-induced fatigue causes changes within the central nervous system that decrease force production capacity in fatigued muscles. The impact on unrelated, non-exercised muscle performance is still unclear. The primary aim of this study was to examine the impact of a bilateral forearm muscle contraction on the motor function of the distal and unrelated ankle plantar-flexor muscles. The secondary aim was to compare the impact of maximal and submaximal forearm contractions on the non-fatigued ankle plantar-flexor muscles. Maximal voluntary contractions (MVC) of the forearm and ankle plantar-flexor muscles as well as voluntary activation (VA) and twitch torque of the ankle plantar-flexor muscles were assessed pre-fatigue and throughout a 10-min recovery period. Maximal (100 % MVC) and submaximal (30 % MVC) sustained isometric handgrip contractions caused a decreased handgrip MVC (to 49.3 +/- 15.4 and 45.4 +/- 11.4 % of the initial MVC for maximal and submaximal contraction, respectively) that remained throughout the 10-min recovery period. The fatigue protocols also caused a decreased ankle plantar-flexor MVC (to 77 +/- 8.3 and 92.4 +/- 6.2 % of pre-fatigue MVC for maximal and submaximal contraction, respectively) and VA (to 84.3 +/- 15.7 and 97.7 +/- 16.1 % of pre-fatigue VA for maximal and submaximal contraction, respectively). These results suggest central fatigue created by the fatiguing handgrip contraction translated to the performance of the non-exercised ankle muscles. Our results also show that the maximal fatigue protocol affected ankle plantar-flexor MVC and VA more severely than the submaximal protocol, highlighting the task-specificity of neuromuscular fatigue. PMID- 22833011 TI - Approaches to empiric ablation of slow pathway: results from the Canadian EP web survey. AB - AIM: Dual atrioventricular nodal physiology (DAVNP) is a frequent finding in patients with suspected or documented supraventricular tachycardia (SVT). Empiric slow pathway ablation (ESPA) is sometimes performed in patients with DAVNP without inducible SVT at the time of electrophysiological study. Evidence to guide this practice in the adult population is limited. This study was aimed to assess the practice of ESPA by adult electrophysiologists in Canada. METHODS: All Canadian interventional electrophysiologists (n = 81) were invited to complete a web-based questionnaire assessing their practice of ESPA in patients with suspected and documented SVT. Operator experience, reimbursement models, diagnostic, and treatment decisions regarding ESPA were assessed with case scenarios. RESULTS: Forty-one responses (50 %) were obtained. Ninety-five percent of the responders stated that the evidence for ESPA is lacking or limited. Responders were more likely to perform ESPA in the setting of non-inducible SVT when there was documentation of the clinical arrhythmia (64 vs. 31 % (p = 0.017)). The threshold to perform ESPA was highly variable. Longer time in practice (r = 0.38, p = 0.017) and less perceived complications with ESPA (r = 0.31, p = 0.05) were correlated with the practice of ESPA, whereas length of ablation waiting lists (r = -0.15, p = 0.38), number of procedures performed per day (r = 0.11, p = 0.51) and type of reimbursement (p = 0.24) were not associated with the practice of ESPA. The perceived complication rate with ESPA was <1 %. CONCLUSION: Variability in the practice of ESPA in cases of non-inducible SVT exists. Documentation of the clinical arrhythmia, operator experience, and perceived low complication rates positively influence this practice. PMID- 22833012 TI - Potential players in the hood. PMID- 22833013 TI - Regulated wet nursing: managed care or organized crime? AB - Wet nursing was widely practiced from antiquity. For the wealthy, it was a way to overcome the burdens of breastfeeding and increase the number of offspring. For the poor, it was an organized industry ensuring regular payment, and in some parishes the major source of income. The abuse of wet nursing, especially the taking in of several nurslings, prompted legislation which became the basis of public health laws in the second half of the 19th century. The qualifications demanded from a mercenary nurse codified by Soran in the 2nd century CE remained unchanged for 1,700 years. When artificial feeding lost its threat thanks to sewage disposal, improved plumbing, the introduction of rubber teats, cooling facilities and commercial formula, wet nursing declined towards the end of the 19th century. PMID- 22833015 TI - Understanding the structural and energetic basis of inhibitor and substrate bound to the full-length NS3/4A: insights from molecular dynamics simulation, binding free energy calculation and network analysis. AB - Hepatitis C virus (HCV) bifunctional NS3/4A is an attractive anti-HCV drug target, as both the protease and helicase functions are required for viral infection and replication. Although the first generation of NS3/4A protease inhibitors (PIs) has focused almost exclusively on the interaction with the protease domain alone, recent studies have shown that PIs also inhibit the full length NS3/4A protein. However, the detailed molecular mechanism of the interaction between protease inhibitors, as well as the peptide substance with the full-length NS3/4A protein, remains poorly understood. Herein, starting from the recently determined crystal structure of an inhibitor (inhibitor ) bound to the full-length NS3/4A protein, the structures of the full-length NS3/4A complexed with inhibitor ITMN-191 (by InterMune/Roche; Phase II) and substrate 4B5A (the viral cleavage product peptide) were built. Then, residue interaction network (RIN) analysis, molecular dynamics (MD) simulation, binding free energy calculation, decomposition of free energies on per-residue and dynamic substrate recognition pattern analysis were employed to uncover the structural and energetic basis of inhibitor and substrate binding mode in the binding cleft located at the interface of the protease and helicase domains of the full-length NS3/4A. The results from our study reveal that both the protease and helicase residues of the NS3/4A participate in the interactions with the inhibitor , ITMN 191 and 4B5A. Additional analysis of the NS3/4A substrate and inhibitor envelopes reveals the areas where the consensus inhibitor volume extended beyond the substrate envelope. These areas correspond to drug resistance mutations including Arg155, Ala156 and Asp168 at the protease active site as well as the two conserved helicase residues Gln526 and His528 that strongly interact with the inhibitors. Thus, the findings of this study will be very useful for understanding the interaction mechanism between the inhibitor (substrate) and NS3/4A and also for the rational design and development of new potent molecules targeting the full-length NS3/4A. PMID- 22833017 TI - Be sensible and cautious about criticizing tunnel placement in ACL reconstruction. PMID- 22833018 TI - The thriving chemistry of ketenimines. AB - Ketenimines are an important class of reactive species and useful synthetic intermediates. During the last two decades several practical and versatile approaches to ketenimines have been developed, leading to exhaustive investigations on ketenimine chemistry and the discovery of a variety of highly efficient reactions. Five types of reactions for ketenimines have been reported, including nucleophilic additions (ketenimines can be used as both electrophiles and nucleophiles), radical additions, cycloaddition reactions, electrocyclic ring closure reactions, and sigma rearrangements. Furthermore, numerous complex organic compounds, particularly the biologically interesting heterocycles, have been constructed using these methodologies. The review of these accomplishments is presented here. PMID- 22833016 TI - Arsenic exposure and DNA methylation among elderly men. AB - BACKGROUND: Arsenic exposure has been linked to epigenetic modifications such as DNA methylation in in-vitro and animal studies. This association has also been explored in highly exposed human populations, but studies among populations environmentally exposed to low arsenic levels are lacking. METHODS: We evaluated the association between exposure to arsenic, measured in toenails, and blood DNA methylation in Alu and Long Interspersed Nucleotide Element-1 (LINE-1) repetitive elements in elderly men environmentally exposed to low levels of arsenic. We also explored potential effect modification by plasma folate, cobalamin (vitamin B12), and pyridoxine (vitamin B6). The study population was 581 participants from the Normative Aging Study in Boston, of whom 434, 140, and 7 had 1, 2, and 3 visits, respectively, between 1999-2002 and 2006-2007. We used mixed-effects models and included interaction terms to assess potential effect modification by nutritional factors. RESULTS: There was a trend of increasing Alu and decreasing LINE-1 DNA methylation as arsenic exposure increased. In subjects with plasma folate below the median (<14.1 ng/mL), arsenic was positively associated with Alu DNA methylation (beta = 0.08 [95% confidence interval = 0.03 to 0.13] for one interquartile range [0.06 MUg/g] increase in arsenic), whereas a negative association was observed in subjects with plasma folate above the median (beta = 0.08 [-0.17 to 0.01]). CONCLUSIONS: We found an association between arsenic exposure and DNA methylation in Alu repetitive elements that varied by folate level. This suggests a potential role for nutritional factors in arsenic toxicity. PMID- 22833019 TI - Is timely endoscopy the answer for cost-effective management of acute upper gastrointestinal bleeding? PMID- 22833020 TI - Prediction scores in gastrointestinal bleeding: a systematic review and quantitative appraisal. AB - BACKGROUND AND STUDY AIMS: Several algorithms predicting outcomes in acute gastrointestinal bleeding have been developed over the past three decades. These algorithms differ substantially and therefore the aim of the current study was to conduct a systematic review to compare their predictive performance and methodological quality in gastrointestinal bleeding. METHODS: A PubMed literature search was performed up to 1 July 2011. All studies reporting prediction scores in gastrointestinal bleeding were included. Studies were analyzed for predictive performance, and a quality appraisal of these rules was performed for which a score range of 0 (lowest) to 29 (highest) was used. RESULTS: A total of 372 studies were identified, of which 16 were eligible for inclusion. The studies evaluated different outcomes: mortality (n = 5), rebleeding (n = 2), intervention required (n = 2), or a combination (n = 7). The predictive performance of the identified prediction scores varied between an area under the curve of 0.71 - 0.92 (if given). The mean overall quality rating was 17 (SD 4.0, range 9 - 25). Major methodological shortcomings were the absence of validation and absence of impact analyses. Eight of 16 scores (50 %) were determined "easy to use," and five scores (31 %) reported some type of action based on the results. CONCLUSION: Substantial heterogeneity in outcomes and results was seen in the 16 identified prediction scores. Moreover, the methodological quality was suboptimal in most studies. However, we suggest that clinicians should use the "best available" scores according to performance and quality, which are the Blatchford score to assess the need for intervention, and the scores of Villanueva et al. for poor outcome, Guglielmi et al. for rebleeding, and Chiu et al. for mortality risk. PMID- 22833021 TI - A prospective randomized study on the benefits of a new small-caliber colonoscope. AB - BACKGROUND AND STUDY AIMS: We compared the performance efficiency of a newly developed small-caliber colonoscope (PCF-PQ260 L) with passive bending, high force transmission, and an outer diameter of 9.2 mm with that of a standard colonoscope, in female and male patients, particularly with regard to passage through acute angulations or into the proximal colon. PATIENTS AND METHODS: A total of 330 patients were randomly allocated to undergo small-caliber (n = 164) or standard (n = 166) colonoscopy. The patients were assessed for pain using a visual analogue scale (0 = none, 100 = extremely painful), and for cecal intubation, withdrawal time, difficulty of colonoscopy, dosage and level of sedation used, and any complications. RESULTS: Median maximum pain and overall pain during colonoscopy were significantly lower in the small-caliber group than in the standard group in women (25 vs. 45, P < 0.001 and 15 vs. 26, P = 0.001, respectively), whereas no significant differences were seen in men (8 vs. 10, P = 0.103 and 16 vs. 20, P = 0.166, respectively). Furthermore, no significant differences were seen between groups in cecal intubation rate or time to cecum in all patients or by sex. CONCLUSIONS: Use of the small-caliber colonoscope reduced pain in female patients, but offered no advantage over standard colonoscopy in male patients. The performance of the small-caliber colonoscope was equivalent to that of the standard colonoscope in terms of cecal intubation rate and time to cecum, regardless of the sex of the patient. PMID- 22833022 TI - Percutaneous endoscopic jejunostomy in patients with gastroparesis following lung transplantation: feasibility and clinical outcome. AB - The aim of the present study was to describe success rates, complications, and outcome in patients who underwent percutaneous endoscopic jejunostomy (PEJ) because of gastroparesis due to previous lung transplantation. Between October 2008 and May 2011, 14 attempts at PEJ placement were made in 12 patients in our center. Of the 14 attempts, 11 were successful, giving a technical success rate of 78.6 %. Median duration of followup was8.5 months (2-15 months). No immediate complications were reported. Two severe complications occurred during follow up (one volvulus and one jejunocolic fistula). Jejunal nutrition was well tolerated in most of patients (9 /10). PEJ insertion is a feasible technique, which could help to provide nutritional support for patients with gastroparesis and previous lung transplantation. PMID- 22833023 TI - Successful treatment of anastomotic jejunal varices with N-butyl-2-cyanoacrylate (Histoacryl): single-center experience. AB - Obscure gastrointestinal bleeding can lead to extensive diagnostic work-up, as well as repeated episodes of hospitalizations with significant morbidity. Patients with a previous small-bowel anastomosis seem to be prone to varices at this site, even in the absence of portal hypertension. We report here five cases with varices of this type. All the anastomoses in these patients were reached using overtube-assisted single- or double-balloon enteroscopy. The bleeding varices were treated by injecting N-butyl-2-cyanoacrylate (Histoacryl). Bleeding was stopped in all five patients without any adverse events, requiring one session in four patients and a second session in one patient. PMID- 22833024 TI - Spread the experience of India in China: making endoscopy mobile. PMID- 22833025 TI - Single- versus double-balloon enteroscopy: the evidence base: Comment on Endoscopy essentials, Small-bowel endoscopy. PMID- 22833027 TI - Usefulness of tunnel dissection for upper gastrointestinal submucosal tumors. PMID- 22833031 TI - The antihypertensive actions of statins: modulation by salt intake. AB - Hydroxy methyl glutaryl CoA inhibitors (statins) are the agents most frequently used to reduce elevated serum cholesterol. In addition to their cholesterol lowering effects, statins also have nonlipid lowering pleiotropic properties. These include reducing oxidative stress, renin-angiotensin and endothelin synthesis and activity, and improving nitric oxide (NO) synthesis and availability. Thus, one would predict that statins might be able to exert an antihypertensive effect. Experimental models bear out the blood pressure lowering effects but the data from clinical trials have been inconsistent perhaps due to inappropriate experimental designs, sample size, blood pressure measurement techniques etc. Moreover, although experimental models strongly suggest a role for salt intake in the potential antihypertensive responses to statins, available clinical trials fail to report salt intake in the studied populations. The statins' antihypertensive effects remain an unsettled hypothesis and calls for a large clinical trial at a wide range of doses and a controlled salt intake. Statins meanwhile remain as a excellent option to control high cholesterol and in tissue injury prevention. PMID- 22833032 TI - Ultrastructural analysis of neuronal synapses using state-of-the-art nano-imaging techniques. AB - Neuronal synapses are functional nodes in neural circuits. Their organization and activity define an individual's level of intelligence, emotional state and mental health. Changes in the structure and efficacy of synapses are the biological basis of learning and memory. However, investigation of the molecular architecture of synapses has been impeded by the lack of efficient techniques with sufficient resolution. Recent developments in state-of-the-art nano-imaging techniques have opened up a new window for dissecting the molecular organization of neuronal synapses with unprecedented resolution. Here, we review recent technological advances in nano-imaging techniques as well as their applications to the study of synapses, emphasizing super-resolution light microscopy and 3 dimensional electron tomography. PMID- 22833033 TI - Chromophore-assisted laser inactivation in neural development. AB - Chromophore-assisted laser inactivation (CALI) is a technique that uses photochemically-generated reactive oxygen species to acutely inactivate target proteins in living cells. Neural development includes highly dynamic cellular processes such as asymmetric cell division, migration, axon and dendrite outgrowth and synaptogenesis. Although many key molecules of neural development have been identified since the past decades, their spatiotemporal contributions to these cellular events are not well understood. CALI provides an appealing tool for elucidating the precise functions of these molecules during neural development. In this review, we summarize the principles of CALI, a recent microscopic setup to perform CALI experiments, and the application of CALI to the study of growth-cone motility and neuroblast asymmetric division. PMID- 22833034 TI - Axonal bleb recording. AB - Patch-clamp recording requires direct accessibility of the cell membrane to patch pipettes and allows the investigation of ion channel properties and functions in specific cellular compartments. The cell body and relatively thick dendrites are the most accessible compartments of a neuron, due to their large diameters and therefore great membrane surface areas. However, axons are normally inaccessible to patch pipettes because of their thin structure; thus studies of axon physiology have long been hampered by the lack of axon recording methods. Recently, a new method of patch-clamp recording has been developed, enabling direct and tight-seal recording from cortical axons. These recordings are performed at the enlarged structure (axonal bleb) formed at the cut end of an axon after slicing procedures. This method has facilitated studies of the mechanisms underlying the generation and propagation of the main output signal, the action potential, and led to the finding that cortical neurons communicate not only in action potential-mediated digital mode but also in membrane potential dependent analog mode. PMID- 22833035 TI - Emerging approaches to probing ion channel structure and function. AB - Ion channels, as membrane proteins, are the sensors of the cell. They act as the first line of communication with the world beyond the plasma membrane and transduce changes in the external and internal environments into unique electrical signals to shape the responses of excitable cells. Because of their importance in cellular communication, ion channels have been intensively studied at the structural and functional levels. Here, we summarize the diverse approaches, including molecular and cellular, chemical, optical, biophysical, and computational, used to probe the structural and functional rearrangements that occur during channel activation (or sensitization), inactivation (or desensitization), and various forms of modulation. The emerging insights into the structure and function of ion channels by multidisciplinary approaches allow the development of new pharmacotherapies as well as new tools useful in controlling cellular activity. PMID- 22833037 TI - A review of functional magnetic resonance imaging for Brainnetome. AB - The functional brain network using blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has revealed the potentials for probing brain architecture, as well as for identifying clinical biomarkers for brain diseases. In the general context of Brainnetome, this review focuses on the development of approaches for modeling and analyzing functional brain networks with BOLD fMRI. The prospects for these approaches are also discussed. PMID- 22833036 TI - Diffusion magnetic resonance imaging for Brainnetome: a critical review. AB - Increasing evidence shows that the human brain is a highly self-organized system that shows attributes of small-worldness, hierarchy and modularity. The "connectome" was conceived several years ago to identify the underpinning physical connectivities of brain networks. The need for an integration of multi spatial and -temporal approaches is becoming apparent. Therefore, the "Brainnetome" (brain-net-ome) project was proposed. Diffusion magnetic resonance imaging (dMRI) is a non-invasive way to study the anatomy of brain networks. Here, we review the principles of dMRI, its methodologies, and some of its clinical applications for the Brainnetome. Future research in this field is discussed. PMID- 22833038 TI - Recent developments in multivariate pattern analysis for functional MRI. AB - Multivariate pattern analysis (MVPA) is a recently-developed approach for functional magnetic resonance imaging (fMRI) data analyses. Compared with the traditional univariate methods, MVPA is more sensitive to subtle changes in multivariate patterns in fMRI data. In this review, we introduce several significant advances in MVPA applications and summarize various combinations of algorithms and parameters in different problem settings. The limitations of MVPA and some critical questions that need to be addressed in future research are also discussed. PMID- 22833039 TI - Use of multi-electrode array recordings in studies of network synaptic plasticity in both time and space. AB - Simultaneous multisite recording using multi-electrode arrays (MEAs) in cultured and acutely-dissociated brain slices and other tissues is an emerging technique in the field of network electrophysiology. Over the past 40 years, great efforts have been made by both scientists and commercial concerns, to advance this technique. The MEA technique has been widely applied to many regions of the brain, retina, heart and smooth muscle in various studies at the network level. The present review starts from the development of MEA techniques and their uses in brain preparations, and then specifically concentrates on the use of MEA recordings in studies of synaptic plasticity at the network level in both the temporal and spatial domains. Because the MEA technique helps bridge the gap between single-cell recordings and behavioral assays, its wide application will undoubtedly shed light on the mechanisms underlying brain functions and dysfunctions at the network level that remained largely unknown due to the technical difficulties before it matured. PMID- 22833040 TI - Optogenetics in neuroscience: what we gain from studies in mammals. AB - Optogenetics is a newly-introduced technology in the life sciences and is gaining increasing attention. It refers to the combination of optical technologies and genetic methods to control the activity of specific cell groups in living tissue, during which high-resolution spatial and temporal manipulation of cells is achieved. Optogenetics has been applied to numerous regions, including cerebral cortex, hippocampus, ventral tegmental area, nucleus accumbens, striatum, spinal cord, and retina, and has revealed new directions of research in neuroscience and the treatment of related diseases. Since optogenetic tools are controllable at high spatial and temporal resolution, we discuss its applications in these regions in detail and the recent understanding of higher brain functions, such as reward-seeking, learning and memory, and sleep. Further, the possibilities of improved utility of this newly-emerging technology are discussed. We intend to provide a paradigm of the latest advances in neuroscience using optogenetics. PMID- 22833041 TI - Using optogenetics to translate the "inflammatory dialogue" between heart and brain in the context of stress. AB - Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism's survival and well-being. The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain, hypothalamus and brainstem, but is also under the control of the neuroendocrine and autonomic nervous systems. Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases. Altered glucocorticoid (GC) homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation, and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems. By the combined use of light and genetically-encoded light-sensitive proteins, optogenetics allows cell-type specific, fast (millisecond-scale) control of precisely defined events in biological systems. This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety, depression, autism and schizophrenia. Optogenetics also helps to understand the "inflammatory dialogue", the inflammatory processes in psychiatric disorders and cardiovascular diseases, shared by heart and brain in the context of stress. PMID- 22833042 TI - Resting-state fMRI studies in epilepsy. AB - Epilepsy is a disease characterized by abnormal spontaneous activity in the brain. Resting-state functional magnetic resonance imaging (RS-fMRI) is a powerful technique for exploring this activity. With good spatial and temporal resolution, RS-fMRI is a promising approach for accurate localization of the focus of seizure activity. Although simultaneous electroencephalogram-fMRI has been performed with patients in the resting state, most studies focused on activation. This mini-review focuses on RS-fMRI alone, including its computational methods and its application to epilepsy. PMID- 22833043 TI - Low-frequency fluctuation in continuous real-time feedback of finger force: a new paradigm for sustained attention. AB - OBJECTIVE: Behavioral studies have suggested a low-frequency (0.05 Hz) fluctuation of sustained attention on the basis of the intra-individual variability of reaction-time. Conventional task designs for functional magnetic resonance imaging (fMRI) studies are not appropriate for frequency analysis. The present study aimed to propose a new paradigm, real-time finger force feedback (RT-FFF), to study the brain mechanisms of sustained attention and neurofeedback. METHODS: We compared the low-frequency fluctuations in both behavioral and fMRI data from 38 healthy adults (19 males; mean age, 22.3 years). Two fMRI sessions, in RT-FFF and sham finger force feedback (S-FFF) states, were acquired (TR 2 s, Siemens Trio 3-Tesla scanner, 8 min each, counter-balanced). Behavioral data of finger force were obtained simultaneously at a sampling rate of 250 Hz. RESULTS: Frequency analysis of the behavioral data showed lower amplitude in the low frequency band (0.004-0.104 Hz) but higher amplitude in the high-frequency band (27.02-125 Hz) in the RT-FFF than the S-FFF states. The mean finger force was not significantly different between the two states. fMRI data analysis showed higher fractional amplitude of low-frequency fluctuation (fALFF) in the S-FFF than in the RT-FFF state in the visual cortex, but higher fALFF in RT-FFF than S-FFF in the middle frontal gyrus, the superior frontal gyrus, and the default mode network. CONCLUSION: The behavioral results suggest that the proposed paradigm may provide a new approach to studies of sustained attention. The fMRI results suggest that a distributed network including visual, motor, attentional, and default mode networks may be involved in sustained attention and/or real-time feedback. This paradigm may be helpful for future studies on deficits of attention, such as attention deficit hyperactivity disorder and mild traumatic brain injury. PMID- 22833044 TI - Ganglionic blockade alters behavioral and cerebral metabolic responses to corticotropin releasing factor in the rat. AB - Corticotropin releasing factor (CRF) has potent stimulating effects on behavior and cerebral metabolism. To investigate the role of altered peripheral autonomic function in central actions of CRF, we measured the effects of intracerebroventricular CRF (2 MUg) on locomotor activity and regional cerebral metabolic rates for glucose (rCMRglc) in control, saline pretreated rats and in rats pretreated with the ganglionic receptor blocker hexamethonium bromide (HEX) (5 mg/kg). Locomotor activity was assessed in a familial environment with an activity meter. rCMRglc were measured in 74 brain regions with the quantitative autoradiographic [14C]2-deoxy-D-glucose technique. In control rats, CRF increased the spontaneous locomotor activity and rCMRglc in 14 sensorimotor, limbic, hypothalamic and brainstem regions. HEX pretreatment blunted locomotor activations induced by CRF. While HEX did not affect cerebral metabolic activation by CRF in sensorimotor areas, it reduced metabolic activations in hippocampal and hypothalamic regions and increased metabolic activations in the brainstem reticular formation. These data indicate that CRF increases rCMRglc in the sensorimotor areas by direct CNS activity and in the limbic areas by indirect, autonomically mediated, activity. Autonomic activation also accounts, at least in part, for the motor activating properties of CRF. PMID- 22833045 TI - In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents, with up to 5 % affected worldwide. Twin and family studies on ADHD show its high familiality with heritability estimated around 70 %, but, to date, no specific polymorphism or gene was found to be specifically affected. Psychostimulants (amphetamine, methylphenidate) and non-psychostimulants (atomoxetine) are used successfully in ADHD therapy, but many of their mechanisms of action and their adverse effects are not yet fully understood. Therefore, both genetic findings and therapeutic interventions should be further investigated. One easy platform for such studies is in vitro analyses, which encompass neuronal cell culture studies, transfections of genetic constructs, binding and electrophysiology analyses. In this review, different methods will be referred in particular to ADHD findings, and new techniques will be mentioned for future studies of drug or genetic effects in vitro. PMID- 22833047 TI - Lin28 and HER2: two stem cell regulators conspire to drive aggressive breast cancer. PMID- 22833046 TI - Analysis of centrosome localization of BRCA1 and its activity in suppressing centrosomal aster formation. AB - BRCA1, a product of a familial breast and ovarian cancer susceptibility gene, localizes to centrosomes and physically interacts with gamma-tubulin, a key centrosomal protein for microtubule nucleation and anchoring at centrosomes. Here, we performed a rigorous analysis of centrosome localization of BRCA1, and found that BRCA1 is specifically associated with mother centrioles in unduplicated centrosomes, and daughter centrioles acquire BRCA1 prior to initiation of duplication, and thus duplicated centrosomes are both bound by BRCA1. We further found that BRCA1 suppresses centrosomal aster formation. In addition, we identified a new domain of BRCA1 critical for gamma-tubulin binding, which confers not only its localization to centrosomes, but also its activity to suppress centrosomal aster formation. PMID- 22833048 TI - Establishing the human rolling circle reaction. PMID- 22833049 TI - Effect of Lanz pressure regulating valve on self-sealing mechanism and air leakage across the tracheal tube cuffs in a benchtop model. AB - BACKGROUND: The aim of the present study was to investigate the effect of the Lanz system on air sealing by self-inflation in high volume-low pressure (HVLP) tube cuffs. METHODS: In vitro tracheal air sealing was studied in HVLP tracheal tube cuffs (internal diameter [ID] 8.0 mm) made from polyurethane ([PU] Seal Guard tracheal tube, Covidien, Athlone, Ireland) and from polyvinylchloride ([PVC] HiLo tracheal tube, Covidien) with and without Lanz pressure regulating valve. Tube cuffs were placed in a vertical 22 mm ID artificial trachea and inflated to 5, 10, 15, 20, 25, or 30 cm H2O cuff pressures. Pressure control ventilation with peak inspiratory pressures (PIPs) of 20 or 25 cm H2O was applied and air leakage was assessed spirometrically as the ratio of expiratory to inspiratory tidal volumes. Nonparametric Mann-Whitney test was applied to compare the air leakage with and without Lanz system for both cuff types at each cuff pressure and PIP (P < .05). RESULTS: The PVC tube cuffs with Lanz system resulted in significant air leakage at both 20 and 25 cm H2O PIP as compared to those without the Lanz system, especially at cuff pressures lower than the preset PIP (P < .05). Although PU tube cuffs with Lanz system showed reduced air sealing when compared with cuffs without Lanz, the difference was not statistically significant. CONCLUSION: Cuff pressure compensation with the Lanz system during cyclic respiratory pressure changes interferes with the self-sealing mechanism in HVLP tube cuffs at cuff pressures lower than PIP level. This results in larger air leak across tube cuffs particularly in tube cuffs made from PVC. PMID- 22833051 TI - Public stigma of mental illness in the United States: a systematic literature review. AB - Public stigma is a pervasive barrier that prevents many individuals in the U.S. from engaging in mental health care. This systematic literature review aims to: (1) evaluate methods used to study the public's stigma toward mental disorders, (2) summarize stigma findings focused on the public's stigmatizing beliefs and actions and attitudes toward mental health treatment for children and adults with mental illness, and (3) draw recommendations for reducing stigma towards individuals with mental disorders and advance research in this area. Public stigma of mental illness in the U.S. was widespread. Findings can inform interventions to reduce the public's stigma of mental illness. PMID- 22833052 TI - Liposomal nanoparticles control the uptake of ciprofloxacin across respiratory epithelia. AB - PURPOSE: Liposomal ciprofloxacin nanoparticles were developed to overcome the rapid clearance of antibiotics from the lungs. The formulation was evaluated for its release profile using an air interface Calu-3 cell model and further characterised for aerosol performance and antimicrobial activity. METHODS: Liposomal and free ciprofloxacin formulations were nebulised directly onto Calu-3 bronchial epithelial cells placed in an in vitro twin-stage impinger (TSI) to assess the kinetics of release. The aerosol performance of both the liposomal and free ciprofloxacin formulation was characterised using the next generation impactor. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined and compared between formulations to evaluate the antibacterial activity. RESULTS: The liposomal formulation successfully controlled the release of ciprofloxacin in the cell model and showed enhanced antibacterial activity against Pseudomonas aeruginosa. In addition, the formulation displayed a respirable aerosol fraction of 70.5 +/- 2.03% of the emitted dose. CONCLUSION: Results indicate that the in vitro TSI air interface Calu-3 model is capable of evaluating the fate of nebulised liposomal nanoparticle formulations and support the potential for inhaled liposomal ciprofloxacin to provide a promising treatment for respiratory infections. PMID- 22833050 TI - TNFSF15 Modulates Neovascularization and Inflammation. AB - Tumor necrosis factor superfamily-15 (TNFSF15; also known as VEGI or TL1A) is a unique cytokine that functions in the modulation of vascular homeostasis and inflammation. TNFSF15 is expressed abundantly in established vasculature but is down-regulated at sites of neovascularization such as in cancers and wounds. TNFSF15 inhibits endothelial cell proliferation and endothelial progenitor cell differentiation. Additionally, TNFSF15 stimulates T cell activation, Th1 cytokine production, and dendritic cell maturation. Some of the functions of TNFSF15 are mediated by death receptor-3. We review the experimental evidences on TNFSF15 activities in angiogenesis, vasculogenesis, inflammation, and immune system mobilization. PMID- 22833055 TI - Compressed sensing reconstruction of undersampled 3D NOESY spectra: application to large membrane proteins. AB - Central to structural studies of biomolecules are multidimensional experiments. These are lengthy to record due to the requirement to sample the full Nyquist grid. Time savings can be achieved through undersampling the indirectly-detected dimensions combined with non-Fourier Transform (FT) processing, provided the experimental signal-to-noise ratio is sufficient. Alternatively, resolution and signal-to-noise can be improved within a given experiment time. However, non-FT based reconstruction of undersampled spectra that encompass a wide signal dynamic range is strongly impeded by the non-linear behaviour of many methods, which further compromises the detection of weak peaks. Here we show, through an application to a larger alpha-helical membrane protein under crowded spectral conditions, the potential use of compressed sensing (CS) l (1)-norm minimization to reconstruct undersampled 3D NOESY spectra. Substantial signal overlap and low sensitivity make this a demanding application, which strongly benefits from the improvements in signal-to-noise and resolution per unit time achieved through the undersampling approach. The quality of the reconstructions is assessed under varying conditions. We show that the CS approach is robust to noise and, despite significant spectral overlap, is able to reconstruct high quality spectra from data sets recorded in far less than half the amount of time required for regular sampling. PMID- 22833053 TI - Modeling the yew tree tubulin and a comparison of its interaction with paclitaxel to human tubulin. AB - PURPOSE: To explore possible ways in which yew tree tubulin is naturally resistant to paclitaxel. While the yew produces a potent cytotoxin, paclitaxel, it is immune to paclitaxel's cytotoxic action. METHODS: Tubulin sequence data for plant species were obtained from Alberta 1000 Plants Initiative. Sequences were assembled with Trinity de novo assembly program and tubulin identified. Homology modeling using MODELLER software was done to generate structures for yew tubulin. Molecular dynamics simulations and molecular mechanics Poisson-Boltzmann calculations were performed with the Amber package to determine binding affinity of paclitaxel to yew tubulin. ClustalW2 program and PHYLIP package were used to perform phylogenetic analysis on plant tubulin sequences. RESULTS: We specifically analyzed several important regions in tubulin structure: the high affinity paclitaxel binding site, as well as the intermediate binding site and microtubule nanopores. Our analysis indicates that the high-affinity binding site contains several substitutions compared to human tubulin, all of which reduce the binding energy of paclitaxel. CONCLUSIONS: The yew has achieved a significant reduction of paclitaxel's affinity for its tubulin by utilizing several specific residue changes in the binding pocket for paclitaxel. PMID- 22833056 TI - Conformational exchange of aromatic side chains characterized by L-optimized TROSY-selected 13C CPMG relaxation dispersion. AB - Protein dynamics on the millisecond time scale commonly reflect conformational transitions between distinct functional states. NMR relaxation dispersion experiments have provided important insights into biologically relevant dynamics with site-specific resolution, primarily targeting the protein backbone and methyl-bearing side chains. Aromatic side chains represent attractive probes of protein dynamics because they are over-represented in protein binding interfaces, play critical roles in enzyme catalysis, and form an important part of the core. Here we introduce a method to characterize millisecond conformational exchange of aromatic side chains in selectively (13)C labeled proteins by means of longitudinal- and transverse-relaxation optimized CPMG relaxation dispersion. By monitoring (13)C relaxation in a spin-state selective manner, significant sensitivity enhancement can be achieved in terms of both signal intensity and the relative exchange contribution to transverse relaxation. Further signal enhancement results from optimizing the longitudinal relaxation recovery of the covalently attached (1)H spins. We validated the L-TROSY-CPMG experiment by measuring fast folding-unfolding kinetics of the small protein CspB under native conditions. The determined unfolding rate matches perfectly with previous results from stopped-flow kinetics. The CPMG-derived chemical shift differences between the folded and unfolded states are in excellent agreement with those obtained by urea-dependent chemical shift analysis. The present method enables characterization of conformational exchange involving aromatic side chains and should serve as a valuable complement to methods developed for other types of protein side chains. PMID- 22833057 TI - An intact kidney slice model to investigate vasa recta properties and function in situ. AB - BACKGROUND: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte mediated vasa recta constriction/dilation can be visualized in situ. METHODS: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in 'live' kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. RESULTS: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10-30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E(2)) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). CONCLUSIONS: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow. PMID- 22833058 TI - Necrotizing fasciitis: is the bacterial spectrum changing? AB - PURPOSE: Necrotizing fasciitis (NF) is a rare, but potentially fatal pathology. The aim of the present study was to identify the population characteristics of the NF patients, the responsible bacteria, and the differences between survivors and nonsurvivors. METHODS: In this retrospective case-control study, all patients with NF from January 1, 2005, to December 31, 2010, treated in an academic level 1 trauma center, were identified, and their medical records were reviewed. RESULTS: The mortality rate of the 24 identified patients was 20.8 %. The majority of the infections (54.2 %) (13/24) were monomicrobial. Hemolytic Streptococcus of group A (25 %) and methicillin-resistant Staphylococcus aureus (20.8 %) were the commonest germs. The mean number of comorbidities was 3.62 (standard deviation (SD) 3.58). Diabetes mellitus, cardiovascular disease, and immunosuppression were the commonest. Mean number of operations was 8.1 (SD 4.7). Five patients (20.8 %) developed a disseminated intravascular coagulation (DIC); all of them died. Nonsurvivors, who presented with deteriorated coagulation factors, developed a DIC (p < 0.001) and received more often antibiotic monotherapy (ampicillin/sulbactam) as initial empirical therapy (p < 0.001). CONCLUSIONS: The present study suggests a shift of the bacterial spectrum towards monomicrobial infections with multiresistant bacteria. The early recognition of high-risk patients and the aggressive surgical treatment with at least double schema antibiotic therapy are of outmost importance. PMID- 22833059 TI - Cytomegalovirus, aging, and HIV: a perfect storm. AB - The success of highly active antiretroviral therapy in preventing progression of HIV-infected individuals to AIDS has greatly reduced the burden of opportunistic infections. Individuals with HIV infection are living longer, but as a group are at greater risk to develop age-related disorders, such as certain cancers, cardiovascular disease, type II diabetes, and cognitive impairment, at earlier ages than non-HIV-infected persons. This premature susceptibility to age-related morbidities reflects a syndrome referred to as accelerated aging, wherein deleterious features associated with aging emerge decades earlier in the setting of chronic HIV infection. A prominent immunological feature of accelerated aging in HIV infection is inflation of cytomegalovirus-specific memory T-cell responses to levels associated with an immune risk phenotype. In the absence of HIV infection, immune risk phenotypes develop in cytomegalovirus-infected octogenarians and signify some degree of immune senescence and an elevated risk for all-cause mortality. Chronic inflammation is a probable factor in health risks conveyed by the immune risk phenotype and in putative relationships between cytomegalovirus infection and the same set of age-related disorders arising in chronic HIV infection. Most HIV-infected individuals are cytomegalovirus seropositive, both HIV and cytomegalovirus are associated with inflammation related morbidities, and HIV infection accelerates the development of cytomegalovirus-dependent immunological abnormalities. Therefore, closer investigation of the relationship between cytomegalovirus and age-related morbidities emerging in chronic HIV infection appears warranted. This review summarizes evidence that cytomegalovirus could be an important cofactor in the development of age-related morbidities in HIV infection and discusses research to address underlying mechanisms. PMID- 22833060 TI - Once-daily single-tablet regimens: a long and winding road to excellence in antiretroviral treatment. AB - Once-daily single-tablet regimens represent the paramount simplification of antiretroviral treatment achieved so far. They include drugs with favorable pharmacokinetics that allow once-daily administration, that do not need dose adjustments, have no additional toxicities, and do not require dissimilar intake conditions. Co-formulated efavirenz/tenofovir disoproxil fumarate/emtricitabine has been a gold standard of initial therapy since its approval in 2006. Galenic research and industry patent agreements may allow availability of single-tablet regimens with HIV-1 nonnucleoside reverse transcriptase inhibitors (efavirenz or rilpivirine), integrase inhibitors (cobicistat-boosted elvitegravir or dolutegravir), and protease inhibitors (cobicistat-boosted darunavir), combined with either tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The introduction of the new phamacoenhancer cobicistat as a potential substitution for ritonavir and the investigational agent GS-7340, with one-tenth the tenofovir mass, is a breakthrough in antiretroviral drug development. Many HIV-1-infected patients who are treatment-naive or treatment-experienced with susceptible virus will potentially have more options to reduce pill burden and optimize dosage schedules with one pill once-daily regimens. PMID- 22833061 TI - Proximal tubular renal dysfunction or damage in HIV-infected patients. AB - Antiretroviral-associated toxicity, especially in the case of tenofovir plus boosted protease inhibitors, could affect different functions of the proximal renal tubule. Considering the long-term use of antiretroviral therapy and the concomitant presence of other risk factors, several degrees of proximal tubular toxicity, from chronic subclinical renal dysfunction to Fanconi syndrome, could be observed in HIV-infected patients. However, the clinical significance of isolated tubular dysfunction, in the short and long term, remains unclear. In addition, primary tubular abnormalities, even severe, may be missed until they affect the glomerular function. Therefore, there is a need for new biomarkers, not only based in serum creatinine and estimated glomerular filtration rates, that might help to identify tubular cell toxicity and predict the clinical outcome in HIV-infected patients. Increased values of urinary beta-2 microglobulin and retinol-binding protein, observed in up to 70% of patients, have been associated to tenofovir-associated mitochondrial dysfunction. Together with other tubular parameters or in isolation, both biomarkers could be useful for diagnosing proximal tubular toxicity. Other molecules, such as urinary kidney injury molecule- 1, neutrophil gelatinase associated lipocalin, or N-acetyl-b-D glucosaminidase, could help to distinguish between tubular cell damage and dysfunction. Here, we review the current knowledge on tubular toxicity in HIV infected patients on antiretroviral therapy. PMID- 22833062 TI - MicroRNAs and HIV latency: a complex and promising relationship. AB - MicroRNAs are small RNA molecules of 20-22 nucleotides, initially discovered in Caenorhabditis elegans, and involved in the regulation of various biological processes in plant and mammalian systems. Essentially, they are key gene regulators as they may inhibit gene expression by mRNA degradation or inhibiting mRNA translation. The identification of microRNAs in plant and human viruses raised important questions regarding their function and potential use as antiviral targets. Reports have described microRNAs encoded by HIV and also the involvement of cellular mRNA in the course of HIV infection. This review investigates the potential use of microRNAs in therapeutic strategies against HIV infection and their role for the eradication of viral reservoirs. PMID- 22833063 TI - Update on kidney transplantation in HIV-infected recipients. AB - HIV infection has historically been a contraindication to kidney transplantation. Prior to the era of potent antiretroviral therapy, the survival of HIV-infected patients was too poor to justify transplantation. In the last 15 years there has been substantial improvement in antiretroviral medications, such that HIV positive patients are living longer and developing chronic diseases such as end stage renal disease. The improvement in survival of HIV-positive patients has resulted in transplant centers increasingly considering infected patients appropriate for kidney transplantation. Recently, the results of the first prospective multicenter trial of kidney transplantation into HIV-positive candidates were released, showing the success and challenges of transplantation into this population. In light of the multicenter findings as well as national registry data, kidney transplantation should be considered the standard-of-care renal replacement therapy for HIV-positive end-stage renal disease patients and they should be referred and evaluated for kidney transplantation accordingly. PMID- 22833064 TI - Update on clinical and methodological recommendations for genotypic determination of HIV tropism to guide the usage of CCR5 antagonists. AB - The genotypic determination of HIV tropism to guide the use of maraviroc, the first CCR5 antagonist with specific antiviral activity against CCR5 (R5)-tropic HIV variants, has been widespread in the last two years. Retrospective analyses from maraviroc clinical trials (MOTIVATE and MERIT) demonstrated that specific genotypic tools and the phenotypic assay TrofileTM are comparable in predicting virologic response to maraviroc. Moreover, recent studies performed in cohorts of patients outside clinical trials have reported overall rates of virologic response to maraviroc up to 82% in patients harboring HIV R5-tropic variants according to genotypic tools. Specific technical requirements as well as recommendations for proper HIV tropism determination in the clinical setting have been improving, according to new data reported in several studies related with this issue. This review updates clinical and methodological recommendations for genotypic determination of HIV tropism to guide therapeutic decisions using CCR5 antagonists, considering the most recently reported data. PMID- 22833066 TI - [Diagnostic guidelines for complex regional pain syndrome]. AB - The complex regional pain syndrome, a special form of neuropathic pain, develops after a minor trauma of the distal limbs. Besides the presentation of pain disproportional to the inciting event, further plus and minus symptoms in the form of sensory, vasomotor, sudomotor-oedematous and motor-trophic changes can be found. Interindividually and intraindividually, occurrence of these symptoms differs widely and single symptoms can be lacking completely. A gold standard in diagnosing CRPS has not been found yet, diagnostics are based on the patients medical history and correlating clinical signs. The International Association for the Study of Pain (IASP) compiled and later on revised operational diagnostic criteria resulting in a satisfactory sensitivity and specificity for both research and clinical needs. Additionally, diagnostic tools can support the clinical suspicion - reasonable tests are conventional X-ray examination comparing sides, magnetic resonance imaging and a 3-phase bone scintigraphy. Moreover, electrophysiological examinations can prove a nerve lesion and differentiate between CRPS type I and II. A temperature difference can be detected via infrared thermography. Furthermore, quantitative sensory testing can verify the magnitude of the sensory disturbance and can be beneficial to objectify therapeutic effects. Use of these diagnostic tools, even after achievement of normal findings, cannot exclude a CRPS and the decision for therapeutic initiation should not be influenced thereby. PMID- 22833067 TI - [Non-drug therapies for CRPS]. AB - State of the art CRPS therapy comprises medication, interventional therapies and non-pharmaceutical treatments like physiotherapy (PT), occupational therapy, PT with cognitive behavioural elements (mirror therapy, 'motor imagery', and 'graded exposure'), psychotherapeutic methods, local therapies and neurostimulation. These treatments are mostly as successful as medical or interventional treatment. These effects have been demonstrated in small but randomised controlled studies. Adjuvant therapies were shown to reduce pain and the severity of dysfunction in CRPS. Therefore, these non-drug therapies should be an essential part of any multimodal CRPS treatment. PMID- 22833068 TI - [Ulnar collateral ligament repair of the thumb with a transosseous suture technique - a retrospective analysis]. AB - BACKGROUND: This study analyses the outcome of a transosseous suture fixation for the ulnar collateral ligament (UCL) of the thumb, which is performed completely internally. METHODS: 60 patients with distal rupture of the UCL of the thumb were surgically treated with a transosseous suture technique. Patients with ligament tears surgically treated within 14 days after injury were included in Group 1 (n=33); patients with delayed surgical treatment (>14 days after injury) in Group 2 (n=13). Group 3 (n=14) contained patients with avulsion fractures. Subjective, functional, and radiological outcomes were evaluated after at least 24 months, and up to an average of 68 months after surgery. Statistical analysis was performed using the Kruskal-Wallis test, Mann-Whitney test, chi-square test, and Wilcoxon test. RESULTS: No significant differences were seen for the disability of the arm, shoulder and hand (DASH) scores among the groups. The average DASH score was 2.4+/-3 points in Group 1, 4.6+/-9 points in Group 2 and 5+/-8 points in Group 3. The visual and verbal pain analogue scales showed significant differences between Groups 1 and 2 at (p=0.02) and after exertion (p=0.03). Significant differences were seen for the flexion of the interphalangeal joint in Group 1 (p=0.004) and the radial abduction of the thumb in Group 3 (p=0.001), as compared to the contralateral hand. Furthermore, significant differences were obtained for the pinch strength between the thumb and the ring finger in Group 1 (p=0.03) and 3 (p=0.04), as well as pinch (p=0.02) and key strength (p=0.03) of the little finger in Group 1, again compared to the contralateral hand. Group 3 (p<0.001) showed significantly more radiological bony alterations at the distal UCL insertion than the other groups. CONCLUSIONS: This study shows good to very good subjective, functional, and radiological results in all 3 groups. Therefore, we recommend this transosseous suture fixation as an affordable, practicable technique for the treatment of acute rupture of the UCL of the thumb with and without avulsion fractures. PMID- 22833069 TI - [Lesions of the peripheral nerves: MR neurography as an innovative supplement to electrodiagnostics]. AB - The diagnostic work-up of peripheral neuropathies largely depends on neurophysiological investigations. Recently, progress in magnetic resonance imaging (MRI) has lead to new perspectives in the diagnostics of disorders of the peripheral nervous system (PNS). Experimental data show how MR neurography visualises axonal and demyelinating lesions of the PNS. In clinical use, difficult cases of focal nerve compression, traumatic or inflammatory lesions can be solved by the combination of MR neurography and neurophysiology. In particular, the localisation of nerve lesions can be improved by MR techniques. Furthermore, MR neurography enables new insights in the pathophysiology of neuropathies which will be shown for diabetic polyneuropathy. PMID- 22833070 TI - Differential diagnosis of rheumatoid and psoriatic arthritis at an early stage in the small hand and foot joints using magnetic resonance imaging. AB - The 2 major and clinically most important primary inflammatory rheumatic diseases which affect small hand and feet joints are rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The most important initial histopathological feature of RA is synovitis followed by chronic proliferative granulomatous pannus-tissue, which is associated with cartilage and bone destruction. Early inflammatory changes in RA also develop synchronously within the subchondral bone marrow. Enthesitis is the hallmark of SNSA, and is often seen as one of the first radiological manifestations of the diseases. As a rule inflammation within the synovial joints, histologically similar to RA, is not so pronounced. Consequently destructive changes within the synovial joints are much less with the exception of PsA in which pronounced bone destruction may develop (arthritis mutilans). Considerable overlapping in clinical and morphological manifestation of RA and PsA may be present. For evaluation of hand and feet joints and surrounding soft tissue structures in RA and PsA different imaging modalities are used, which include projection radiography, ultrasonography (US), radionuclide techniques and magnetic resonance imaging (MRI). MRI has become the imaging modality of choice for evaluation of arthritis, when conventional radiography is not conclusive. PMID- 22833071 TI - [Dupuytren's disease in children - case report and literature review]. AB - Dupuytren's disease in childhood and adolescence is extremely rare. As in adults most patients are male. We report on a girl at the age of 7 years with a cord in the palm. PMID- 22833072 TI - [Fibro-osseous pseudotumor of the hand in a 5-year old boy - a close relative to myositis ossificans]. AB - Fibro-osseous pseudotumors of the hand are rare lesions in children. Clinical and radiological presentation can be challenging and simulating a malignant neoplasm. We present the case of a 5-year-old boy with a rapidly growing soft tissue tumor of the right palm. Diagnosis was confirmed by biopsy and the patient was treated with a tissue preserving resection. There was no evidence for recurrence 1 year after the operation. PMID- 22833073 TI - [Acute and chronic calcium pyrophosphate dihydrate deposition disease in young patients]. AB - The acute calcium deposit belongs to the group of calcium pyrophosphate dihydrate deposition disease (CPPD). It occurs in adults. To our knowledge there is no report on an acute or chronic calcium deposit in children or adolescents. We report on 2 cases of acute and chronic calcium deposit in young patients. PMID- 22833074 TI - [Acute calcinosis of the hand in an infant]. AB - We report on an acute calcinosis in infants as a differential diagnosis to a trauma or an infect of the wrist. PMID- 22833076 TI - Understanding the fate of chlorogenic acids in coffee roasting using mass spectrometry based targeted and non-targeted analytical strategies. AB - Coffee is one of mankind's most popular beverages obtained from green coffee beans by roasting. Much effort has been expended towards the chemical characterisation of the components of the roasted coffee bean, frequently termed melanoidines, which are dominated byproducts formed from its most relevant secondary metabolites - chlorogenic acids. However, impeded by a lack of suitable authentic reference standards and analytical techniques sufficiently powerful for providing insight into an extraordinarily complex enigmatic material, unsurprisingly little structural and mechanistic information about the products of coffee roasting is available. Here we report on the characterisation of low molecular weight melanoidine fractions of roasted coffee using a conceptually novel combination of targeted and non-targeted mass spectrometrical techniques. We provide an unprecedented account of the chemical composition of roasted coffee beans. Using a targeted analytical approach we show for the first time, by comparison to authentic reference standards obtained by chemical synthesis, that chlorogenic acids follow four distinct reaction pathways including epimerization, acyl migration, lactonisation and dehydration. The analytical strategy employed in a non-targeted approach uses high resolution mass spectrometry to identify the most abundant molecular formulas present in roasted coffee samples and model roasts followed by van Krevelen and homologous series analysis. We identified the molecular formulas formed from reactions of chlorogenic acids, carbohydrates and proteins, both between classes of compounds and within same classes of compounds. Furthermore, we identified two new classes of compounds formed from chlorogenic acids during roasting, chlorogenic acid acetates and O-phenolic quinoyl and shikimoyl esters of chlorogenic acids. PMID- 22833077 TI - Analysis of bypass signaling in EGFR pathway and profiling of bypass genes for predicting response to anticancer EGFR tyrosine kinase inhibitors. AB - Some drugs, such as anticancer EGFR tyrosine kinase inhibitors, elicit markedly different clinical response rates due to differences in drug bypass signaling as well as genetic variations of drug target and downstream drug-resistant genes. The profiles of these bypass signaling are expected to be useful for improved drug response prediction, which have not been systematically explored previously. In this work, we searched and analyzed 16 literature-reported EGFR tyrosine kinase inhibitor bypass signaling routes in the EGFR pathway, which include 5 compensatory routes of EGFR transactivation by another receptor, and 11 alternative routes activated by another receptor. These 16 routes are reportedly regulated by 11 bypass genes. Their expression profiles together with the mutational, amplification and expression profiles of EGFR and 4 downstream drug resistant genes, were used as new sets of biomarkers for identifying 53 NSCLC cell-lines sensitive or resistant to EGFR tyrosine kinase inhibitors gefitinib, erlotinib and lapatinib. The collective profiles of all 16 genes distinguish sensitive and resistant cell-lines are better than those of individual genes and the combined EGFR and downstream drug resistant genes, and their derived cell line response rates are consistent with the reported clinical response rates of the three drugs. The usefulness of cell-line data for drug response studies was further analyzed by comparing the expression profiles of EGFR and bypass genes in NSCLC cell-lines and patient samples, and by using a machine learning feature selection method for selecting drug response biomarkers. Our study suggested that the profiles of drug bypass signaling are highly useful for improved drug response prediction. PMID- 22833078 TI - Architectural patterns of ovarian/pelvic high-grade serous carcinoma. AB - We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using chi tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum based chemotherapy. PMID- 22833079 TI - Inverse expression of cystein-rich 61 (Cyr61/CCN1) and connective tissue growth factor (CTGF/CCN2) in borderline tumors and carcinomas of the ovary. AB - Members of the CCN [cystein-rich 61 (Cyr61)/connective tissue growth factor (CTGF)/nephroblastoma (NOV)] protein family are involved in the regulation of cellular proliferation, apoptosis, and migration and are also assumed to play a role in carcinogenesis. Therefore, we performed a retrospective study to investigate the immunohistochemical expression of both Cyr61 and CTGF in 92 borderline tumors (BOTs) and 107 invasive carcinomas of the ovary (IOCs). To determine their diagnostic and prognostic value, we correlated protein expression with clinicopathologic factors including overall and disease-free survival. Cyr61 and CTGF were found to be inversely expressed in both BOTs and IOCs, with a stronger expression of Cyr61 in IOCs. Moreover, Cyr61 was found to be preferentially expressed in high-grade serous carcinomas, whereas CTGF was found more frequently in low-grade serous carcinomas. Weak Cyr61 levels correlated with both low estrogen receptor and p53 expression (P=0.038, P=0.04, respectively). However, no association was observed between CTGF, estrogen receptor, and p53 expression levels in IOCs. Regarding prognosis, Cyr61 was found to be of no value, but the loss of CTGF was found to be associated with a poor prognosis in multivariate analysis of overall (relative risk 2.8; P=0.050) and disease-free (relative risk 2.3; P=0.031) survival. Cyr61 and CTGF are inversely expressed in BOTs and IOCs, and loss of CTGF independently indicates poor prognosis in IOCs. PMID- 22833080 TI - Ki-67 labeling index as an adjunct in the diagnosis of serous tubal intraepithelial carcinoma. AB - There is mounting evidence that serous tubal intraepithelial carcinoma (STIC) may be the immediate precursor of ovarian high-grade serous carcinoma (HGSC) but the criteria for its diagnosis are not well established as highlighted in a recent study showing that interobserver reproducibility, even among expert gynecologic pathologists, was moderate at best. Given the clinical significance of a diagnosis of STIC in a patient who has no other evidence of ovarian carcinoma, this is a serious issue that we felt needed to be addressed. Although it is not clear, at this time, whether such a patient should or should not be treated, the importance of an accurate and reproducible diagnosis of precursors of ovarian carcinoma cannot be underestimated. We hypothesized that an elevated Ki-67 labeling index may aid the diagnosis of STIC. Accordingly, we compared the Ki-67 index of STIC and HGSC to normal fallopian tube epithelium (FTE) in the same patients and to a control group of patients without carcinoma, matched for age. A total of 41 STICs were analyzed, of which 35 were associated with a concurrent HGSC. In FTE, immunoreactivity for Ki-67 was restricted to a few scattered cells (mean 2.0%). No statistically significant difference was found between patients with and without HGSC (P>0.05). However, both STICs and HGSC had significantly higher Ki-67 indices than normal FTE (P<0.0001). STICs uniformly had an elevated Ki-67 labeling index that ranged from 11.7% to 71.1% (average 35.6%). There was no correlation of the Ki-67 labeling index in the STICs and the associated HGSC, as the labeling index was lower in STIC in 18/35 (51.4%) whereas it was higher in 17/35 (48.6%) (P=0.86). In conclusion, the findings in this study indicate that compared with FTE, STICs have a significantly higher Ki-67 index similar to HGSC. Accordingly, the Ki-67 index can aid the diagnosis of intraepithelial tubal proliferations suspicious for STIC. Therefore, we propose that a Ki-67 index of 10% is a useful diagnostic tool to distinguish STICs from normal FTE. PMID- 22833081 TI - Low-grade serous neoplasms of the ovary with transformation to high-grade carcinomas: a report of 3 cases. AB - Ovarian borderline tumors usually occur in young patients and are associated with good clinical outcomes. A proportion of these tumors, particularly those with micropapillary features, may progress to low-grade serous carcinomas. Evolution of low-grade serous neoplasms to high-grade carcinomas is rare and infrequently reported. In this case report, we describe 3 cases of serous borderline tumor that progressed to high-grade carcinoma. Patient ages were 22, 35, and 47 yr. Two patients were initially diagnosed with ovarian serous borderline tumor, and recurred in the pelvis 3 and 10 yr later with sarcomatoid carcinoma. The third patient presented with low-grade serous carcinoma arising in a micropapillary serous borderline tumor, and recurred with a carcinosarcoma 3 yr later. All 3 patients had an aggressive clinical course: 2 died of disease and 1 patient has disease progression on chemotherapy. Occasional low-grade serous tumors of the ovary may transform to high-grade carcinomas, which can occur many years after initial diagnosis. The presence of a high-grade component significantly worsens patient outcomes. PMID- 22833082 TI - Ovarian teratoma associated with anti-N-methyl D-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates. AB - Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a recently described severe neurological disorder predominantly affecting young women, which presents with psychosis, memory deficits, seizures, and encephalopathy, often requiring prolonged hospitalization. The condition is frequently associated with an underlying neoplasm, most often an ovarian teratoma, and in such cases appears to be a para-neoplastic, immune-mediated encephalopathy. The histologic features of the teratomas associated with anti-NMDAR encephalitis have seldom been described in detail. Therefore, in this report, we have compared ovarian teratomas (4 mature and 1 immature) from 5 patients with anti-NMDAR encephalitis with 22 sporadic control teratomas (14 mature and 8 immature) that included neuroglial elements. The encephalitis-associated tumors ranged from 0.7 to 9.5 cm diameter, and 1 case was bilateral; the second teratoma was discovered 13 mo after the first when symptoms recurred. In comparison with control teratomas, the anti NMDAR-associated tumors showed a more marked intratumoral lymphoid infiltrate that colocalized to the mature neuroglial elements. Reactive germinal centers (3 cases) and diffuse lymphoplasmacytic infiltrates within the neuroglial matrix (4 cases), and degenerative neuronal changes (2 cases), were seen only in the anti NMDAR-positive cases. Pathologists encountering ovarian teratomas with these distinctive reactive lymphoid elements should consider the possibility of anti NMDAR encephalitis, particularly because the neurological symptoms may develop after tumor resection. Careful histopathologic examination may be required to identify small, radiologically occult teratomas, and to demonstrate the presence of subtle neoplastic neuroglial components in teratomas associated with anti NMDAR encephalitis. PMID- 22833083 TI - Pulmonary tumor thrombotic microangiopathy in patients with low-grade ovarian serous neoplasm: a clinicopathologic review of 2 cases of a previously unknown association. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication occurring during tumor dissemination that can lead to severe, commonly unrecognized pulmonary hypertension, right-sided heart failure, and sudden death. Histologically, it is characterized by tumor microthrombi within small arteries and arterioles and associated fibrocellular and fibromuscular intimal proliferation. Gastric adenocarcinoma is the most common tumor type with this association. Of gynecologic malignancies, a single case of ovarian clear cell carcinoma has been linked to PTTM. We report 2 patients who underwent surgery with a preoperative diagnosis of pelvic mass. After surgery, the patients had unexplained progressive respiratory failure that led to their death. Autopsy revealed typical features of PTTM with tumor lymphangitic spread and microscopic tumor emboli within the lung arteries. In both cases, the primary tumor was an ovarian serous neoplasm of low malignant potential with widespread dissemination, 1 with microinvasion and progression to low-grade serous carcinoma. In this last case, mutational analysis for KRAS and BRAF genes was performed to confirm the association between the ovarian and the extraovarian tumor and rule out other primary tumors more commonly associated with this disease. PTTM is a distinct pathologic entity with very few cases reported in the literature, especially involving ovarian tumors. We report 2 cases of low-grade ovarian serous neoplasm, not previously reported with this association. PMID- 22833084 TI - Squamous cell carcinoma and pleomorphic sarcoma (MFH) arising in a mature cystic teratoma of the ovary. AB - Malignant transformation of a mature ovarian teratoma is a rare occurrence predominantly in the postmenopausal period. All histologic types can be seen; however, squamous cell carcinoma accounts for over 75% of cases. Sarcomatous transformation is much more uncommon, with cases of angiosarcoma, rhabdomyosarcoma, leiomyosarcoma and liposarcoma arising in a mature ovarian teratoma described in literature. We report a case of squamous cell carcinoma and pleomorphic sarcoma arising in a mature cystic teratoma of the ovary in a 58-year old woman. The tumor shows both epithelial and stromal components. The epithelial component is moderately-differentiated squamous cell carcinoma with foci of keratinization. The stromal component is significant for an abundance of giant cells, enlarged bizarre nuclei, and marked mitotic activity. This is a unique report of malignant transformation of a benign ovarian teratoma showing both epithelial and sarcomatous elements. PMID- 22833085 TI - Uterine adenosarcomas: diagnostic use of the proliferation marker Ki-67 as an adjunct to morphologic diagnosis. AB - Adenosarcoma (AS) is a rare biphasic neoplasm of the female genital tract characterized by an admixture of benign glandular and low-grade mesenchymal components. The classic low-power growth pattern is periglandular stromal proliferation accompanied by a variable degree of cytologic atypia and mitotic activity. However, as cytologic atypia is an objective criterion, and the number of mitotic figures required for diagnosis is inversely proportional to stromal cytologic atypia, there is a relatively wide variation in the decisive factors used among pathologists to diagnose an AS. Furthermore, the exact number of microscopic fields sufficient for diagnosis and/or the size of the fields adjusted to a specific microscope are not well established. These uncertainties are still an occasional source of misclassification of AS. Our study was conducted to explore the role of immunohistochemistry in the diagnosis of AS. Eight ASs were retrieved and compared with 14 endometrial polyps and 14 atypical polypoid adenomyomas. Immunohistochemical stains for Ki-67, caldesmon, smooth muscle actin, desmin, and CD10 were performed on all cases. All AS had a polypoid growth pattern with a variable increase in periglandular stromal cellularity and stromal nuclear atypia. The mitotic activity ranged from 1 to 15/10 high-power fields, and all AS demonstrated a distinct increase in Ki-67-positive nuclei in the periglandular zone compared with the adjacent stroma, regardless of the mitotic count. The Ki-67-labeling index in periglandular zones was ~20% compared with <5% in the adjacent stroma. This zonation was not observed in any case of atypical polypoid adenomyomas or endometrial polyps. None of the other stains (CD10, smooth muscle actin, desmin, and caldesmon) helped to differentiate between these entities. Thus, characteristic zonation by Ki-67-staining pattern is a helpful adjunct to the routine morphology in the diagnosis of AS, particularly in curettage specimens, which may lack some of the classic morphologic diagnostic features. PMID- 22833086 TI - Metastatic leiomyosarcoma of the uterus with heterologous differentiation to malignant mesenchymoma. AB - Heterologous differentiation in metastatic leiomyosarcomas of uterine origin is an extremely rare phenomenon. We report a remarkable case of a metastatic leiomyosarcoma from the uterus with an unusual pattern of tumor progression to malignant mesenchymoma after chemotherapy. The patient, an 80-yr-old woman with a history of metastatic leiomyosarcoma of the uterus to the lungs, presented with a large intra-abdominal mass. Histologic examination of the intraperitoneal mass demonstrated a high-grade sarcoma containing various heterologous malignant mesenchymal elements including osteosarcoma, chondrosarcoma, a liposarcoma-like area, and osteoclast-like multinucleated giant cells. Only the identification of small areas of smooth muscle differentiation revealed the true nature of the tumor as a metastatic leiomyosarcoma with aberrant sarcomatous differentiation. This unique presentation emphasizes the importance of clinicopathologic correlation in the diagnosis of tumors with unusual histology. PMID- 22833087 TI - Atypical epithelioid trophoblastic lesion with cyst and fistula formation after a cesarean section: a rare form of gestational trophoblastic disease. AB - We report 2 unusual cases of gestational trophoblastic disease from chorionic type intermediate trophoblastic cells after a Cesarean section. A 32-year-old woman presented with a 2-year history of vaginal bleeding, while a 41-year-old woman presented with a pelvic mass. Both patients had cystic lesions with a fistula formation beneath their Cesarean scars in the anterior uterine isthmus. Microscopically, both lesions were lined with multiple layers of intermediate trophoblastic cells without penetration into the surrounding myometrium, endometrium, or blood vessels. The trophoblastic cells were generally bland. However, a subset of trophoblastic cells showed large, hyperchromatic nuclei in some areas. The trophoblastic cells were p63 positive and human placental lactogen negative. The Ki67 indexes were 12.7% and 8.6%, respectively. We propose their description as atypical epithelioid trophoblastic lesions with cyst and fistula formation after a Cesarean section. PMID- 22833088 TI - Are women with endocervical adenocarcinoma at risk for lynch syndrome? Evaluation of 101 cases including unusual subtypes and lower uterine segment tumors. AB - It is well documented that endometrial and ovarian carcinoma are associated with Lynch syndrome (LS), but the association, if any, between endocervical carcinoma and LS has not been fully evaluated. The relationship between endocervical carcinoma and LS is particularly relevant, given the apparent affinity of LS associated endometrial carcinomas for the lower uterine segment and the attendant difficulties in determining tumor origin at this site. In this study, we examined mismatch repair (MMR) protein expression (MLH1, MSH2, MSH6, and PMS2) in 60 endocervical adenocarcinomas, including variants (minimal deviation adenocarcinoma, mesonephric adenocarcinoma, adenosquamous carcinoma, clear cell carcinoma) and a series of well-characterized lower-uterine segment carcinomas of known endocervical or endometrial origin (n=41). Two of the lower uterine segment tumors occurred in risk-reducing hysterectomy specimens from known LS patients. All endocervical adenocarcinomas including variants and lower uterine segment endocervical tumors (1 from a known LS patient) were proficient in all 4 MMR proteins. In contrast, 2/20 (10%) lower uterine segment endometrial cancers were deficient in at least 1 MMR (1 from a known LS patient). These data provide evidence that, unlike endometrial and ovarian adenocarcinoma, there is no association between LS and endocervical carcinoma. MMR testing is prudent in lower uterine segment tumors in women with possible LS, especially those for which definitive site of origin cannot be determined. PMID- 22833089 TI - The outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less: should we always re-excise? AB - To assess the management and outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less, examining the impact of re-excision. A retrospective cohort study with interval analysis performed between December 2000 and December 2010. Sheffield Gynaecological Cancer Centre and Jessop Wing Colposcopy Unit, Sheffield, UK. Women diagnosed with microinvasive cervical cancer with stromal invasion 1 mm or less during the allocated study period. Methods used is a retrospective cohort study. Risk of recurrence and mortality from disease; incidence of residual disease in repeat excision specimens. A total of 140 women were identified as having microinvasive cervical cancer with stromal invasion 1 mm or less. Sixty-three (45%) had a completely excised lesion; 77 (55%) had an incompletely excised lesion at first treatment. Fifty-five women underwent repeat excision. No residual disease was found in the majority (n=40; 73%). No women suffered disease recurrence or died from disease during the allocated study period. Outcome for women with microinvasive cervical cancer with stromal invasion 1 mm or less is excellent. Repeat excision is associated with very low rates of residual disease. A more conservative approach to follow-up incorporating HPV testing should be explored. PMID- 22833090 TI - HPV genotyping in north Indian women infected with HIV. AB - Investigating the prevalence of high-risk human papilloma virus (HPV) genotypes in human immunodeficiency virus (HIV)-infected women is vital to generate data for formulating guidelines for prevention/screening of cervical cancer in this vulnerable group. The study was aimed to analyze the HPV genotypes in HIV infected women. It was a prospective, hospital-based, and cross-sectional study. HIV-infected women were enrolled from the antiretroviral clinic and controls from the gynecology outpatient. The HPV genotyping array kit was used for identifying 21 HPV genotypes. Detection of HPV was confirmed by performing an HPV type specific polymerase chain reaction. A Pap smear was collected in all women. One hundred thirty HIV-infected women and 64 controls were enrolled. All women with low CD4 counts (n=97) were receiving antiretroviral therapy. Twenty-six (20%) HIV infected women and 12 (18.7%) women in the control group tested positive for high risk HPV (P=1.0). HPV 16 was the most common type, detected in 42% of HPV positive women in the HIV-infected cohort, followed by HPV 45 (15%), HPV 18/52/31/58 (11.5% each), and HPV 33 (7.6%). The corresponding figures in the control group were as follows: HPV 16 (66.6%), HPV 45/18/31 (16.6% each), and HPV 33/58/68 (8.3% each). Cervical intraepithelial neoplasia was detected in 2.3% of HIV-infected women. The prevalence of high-risk HPV in HIV-infected women (20%) was similar to the prevalence in controls (18.7%). This and the incidence of cervical intraepithelial neoplasia are lower than those in previous reports. It is plausible that administration of antiretroviral therapy contributed to the reduced prevalence. The currently available vaccine would likely be beneficial to the local HIV-infected population, as nearly half the HPV-infected women harbored genotypes 16 or 18. PMID- 22833091 TI - High immunohistochemical expression of TGF-beta1 predicts a poor prognosis in cervical cancer patients who harbor enriched endoglin microvessel density. AB - Endoglin, a coreceptor for transforming growth factor beta1 (TGF-beta1) in vascular endothelial cells, is highly upregulated in tumor vessels and therefore is a specific biomarker for angiogenesis. Some studies have suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy and radiotherapy. In this study, we attempted to analyze the immunohistochemical expression of endoglin and TGF-beta1 from 80 patients with different International Federation of Gynecology and Obstetrics (FIGO) stages of cervical cancer before they received concurrent chemoradiation and to investigate their prognostic significance. The median follow-up period was 86 months (range, 2-144 months). Endoglin staining was assessed by microvessel density (MVD), whereas TGF beta1 expression was semiquantified as negative, weakly, or strongly staining. A receiver operating characteristic curve was established for endoglin MVD in predicting survival; the optimal cutoff value was 11.125. With a Cox regression analysis, we found that an advanced FIGO stage (hazard ratio 4.66; 95% confidence interval 2.10-10.32, P<0.001) and endoglin MVD more than 11.125 (hazard ratio 12.21; 95% confidence interval 3.62-41.16, P=<0.001) were independent factors to predict survival. Interestingly, a strong TGF-beta1 expression was significantly associated with poor survival only when the endoglin MVD value was higher than 10. Our study shows that evaluation of endoglin MVD by immunochemistry can be used as an independent prognostic marker for cervical cancer patients receiving concurrent chemoradiation. TGF-beta1 also had an impact on survival only when endoglin MVD was enriched, suggesting its involvement in tumor progression in the later stage of angiogenesis. PMID- 22833092 TI - Mixed endocervical adenocarcinoma and high-grade neuroendocrine carcinoma of the cervix with ovarian metastasis of the former component: a report of 2 cases. AB - Endocervical adenocarcinomas (ECAs) uncommonly metastasize to the ovary; however, when they do they sometimes closely mimic a mucinous/endometrioid ovarian primary tumor. Here, 2 cases of mixed moderately differentiated ECA and high-grade cervical neuroendocrine carcinoma in which the ECA component metastasized to the ovary have been delineated and reported. In both cases, the primary tumor and the metastatic tumor were diffusely positive for p16 and high-risk human papillomavirus. Although similar to previously reported cases of adenocarcinoma in situ and invasive ECAs with ovarian involvement, none of the cases reported to date had concurrent neuroendocrine carcinoma with metastasis of the lower-grade component. In this respect, our cases are unique. The presence of lower uterine segment involvement in both cases and high-risk human papillomavirus positivity in the primary and metastatic tumors suggest a metastatic process, perhaps through transtubal spread, rather than independent primaries. PMID- 22833096 TI - AMP-activated protein kinase-alpha1 as an activating kinase of TGF-beta-activated kinase 1 has a key role in inflammatory signals. AB - Although previous studies have proposed plausible mechanisms of the activation of transforming growth factor-beta-activated kinase 1 (TAK1) in inflammatory signals, including Toll-like receptors (TLRs), its activating kinase still remains to be unclear. In the present study, we have provided evidences that AMP activated protein kinase (AMPK)-alpha1 has a pivotal role for activating TAK1, and thereby regulate NF-kappaB-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-alpha stimulation. AMPK-alpha1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-alpha1-knockdown (AMPK-alpha1(KD)) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-alpha1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF kappaB and thereby productions of proinflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-6. Importantly, the microarray analysis of AMPK-alpha1(KD) cells revealed a dramatic reduction in the NF-kappaB-dependent genes induced by TLR4 and TNF-alpha stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-alpha1(KD) cells are highly sensitive to the TNF-alpha-induced apoptosis, which is accompanied with dramatic reductions in the NF-kappaB-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-alpha1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-alpha. PMID- 22833095 TI - Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro. AB - Diamond-Blackfan anemia (DBA) is caused by aberrant ribosomal biogenesis due to ribosomal protein (RP) gene mutations. To develop mechanistic understanding of DBA pathogenesis, we studied CD34+ cells from peripheral blood of DBA patients carrying RPL11 and RPS19 ribosomal gene mutations and determined their ability to undergo erythroid differentiation in vitro. RPS19 mutations induced a decrease in proliferation of progenitor cells, but the terminal erythroid differentiation was normal with little or no apoptosis. This phenotype was related to a G0/G1 cell cycle arrest associated with activation of the p53 pathway. In marked contrast, RPL11 mutations led to a dramatic decrease in progenitor cell proliferation and a delayed erythroid differentiation with a marked increase in apoptosis and G0/G1 cell cycle arrest with activation of p53. Infection of cord blood CD34+ cells with specific short hairpin (sh) RNAs against RPS19 or RPL11 recapitulated the two distinct phenotypes in concordance with findings from primary cells. In both cases, the phenotype has been reverted by shRNA p53 knockdown. These results show that p53 pathway activation has an important role in pathogenesis of DBA and can be independent of the RPL11 pathway. These findings shed new insights into the pathogenesis of DBA. PMID- 22833097 TI - D(-)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53 independent. AB - We have recently found that D(-)lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by D(-)lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that D(-)lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5-3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3-2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 MUM D(-)lentiginosine, whereas apoptosis by D(-)lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs. PMID- 22833100 TI - Applications of extended X-ray absorption fine-structure spectroscopy to studies of bimetallic nanoparticle catalysts. AB - Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used to study short range order in heterometallic alloys for almost four decades. In this critical review, experimental, theoretical and data analytical approaches are revisited to examine their power, and limitations, in studies of bimetallic nanocatalysts. This article covers the basics of EXAFS experiments, data analysis, and modelling of nanoscale clusters. It demonstrates that, in the best case scenario, quantitative information about the nanocatalyst's size, shape, details of core-shell architecture, as well as static and dynamic disorder in metal-metal bond lengths can be obtained. The article also emphasizes the main challenge accompanying such insights: the need to account for the statistical nature of the EXAFS technique, and discusses corrective strategies. PMID- 22833098 TI - BCLAF1 is a radiation-induced H2AX-interacting partner involved in gammaH2AX mediated regulation of apoptosis and DNA repair. AB - H2AX, a histone H2A variant, has a key role in the cellular response to DNA double-strand breaks (DSBs). H2AX senses DSBs through rapid serine 139 phosphorylation, concurrently leading to the formation of phospho-(gamma)H2AX foci with various proteins. However, in the cells with different sensitivity to ionizing radiation (IR)-induced DSBs, still incomplete are those specific proteins selectively recruited by gammaH2AX to decide different cell fates. Because the abundance of gammaH2AX indicates the extent of DSBs, we first identified IR-induced dose-dependent H2AX-interacting partners and found that Bcl 2-associated transcription factor 1 (BCLAF1/Btf) showed enhanced association with gammaH2AX only under high-dose radiation. In acutely irradiated cells, BCLAF1 promoted apoptosis of irreparable cells through disturbing p21-mediated inhibition of Caspase/cyclin E-dependent, mitochondrial-mediated pathways. Meanwhile, BCLAF1 co-localized with gammaH2AX foci in nuclei and stabilized the Ku70/DNA-PKcs complex therein, facilitating non-homologous end joining (NHEJ) based DSB repair in surviving cells. In tumor cells, BCLAF1 was intrinsically suppressed, leading to formation of anti-apoptotic Ku70-Bax complexes and disruption of Ku70/DNA-PKcs complexes, all of which contribute to tumor associated apoptotic resistance and cell survival with defective NHEJ DNA repair. For the first time, our studies reveal that, based on the extent of DNA damage, BCLAF1 is involved in the gammaH2AX-mediated regulation of apoptosis and DNA repair, and is a gammaH2AX-interacting tumor suppressor. PMID- 22833099 TI - Prevalence of Ehrlichia ruminantium in adult Amblyomma variegatum collected from cattle in Cameroon. AB - Ehrlichia ruminantium, the etiologic agent of the economically important disease heartwater, is an obligate intracellular bacterium transmitted by ticks of the genus Amblyomma, particularly A. hebraeum and A. variegatum. Although serologic and microscopic evidence of the presence of heartwater have been reported in ruminants in Cameroon, knowledge of E. ruminantium infection in the tick vector, A. variegatum, is lacking. In order to determine the infectivity of A. variegatum ticks by E. ruminantium, we analysed 500 un-engorged A. variegatum ticks collected by hand-picking from predilection sites from 182 cattle [115 ticks from 82 cattle at Societe de Developpement et d'Exploitation des Productions Animales (SODEPA) Dumbo ranch (SDR) and 385 ticks from 100 cattle at the Upper Farms ranch (UFR)] by amplification of the open reading frame (ORF) 2 of the pCS20 region of E. ruminantium. PCR amplification of the 279 bp fragment of the pCS20 region detected E. ruminantium DNA in 142 (28.4 %) of the 500 ticks with a higher infection rate (47/115; 40.9 %) observed in ticks from SDR and 24.7 % (95/385) of ticks collected from cattle at UFR. Twenty five randomly selected PCR products were sequenced and results indicated that some of the isolates shared homology with one another and to sequences of E. ruminantium in the GenBank. This report represents the first molecular evidence of E. ruminantium infection in A. variegatum ticks in Cameroon and suggests possible exposure of cattle to this pathogen in our environment. PMID- 22833101 TI - Genomic and serological detection of bat coronavirus from bats in the Philippines. AB - Bat coronavirus (BtCoV) is assumed to be a progenitor of severe acute respiratory syndrome (SARS)-related coronaviruses. To explore the distribution of BtCoVs in the Philippines, we collected 179 bats and detected viral RNA from intestinal or fecal samples by RT-PCR. The overall prevalence of BtCoVs among bats was 29.6 %. Phylogenetic analysis of the partial RNA-dependent RNA polymerase gene suggested that one of the detected BtCoVs was a novel alphacoronavirus, while the others belonged to the genus Betacoronavirus. Western blotting revealed that 66.5 % of bat sera had antibodies to BtCoV. These surveys suggested the endemic presence of BtCoVs in the Philippines. PMID- 22833102 TI - The nucleoprotein is responsible for intracerebral pathogenicity of A/duck/Mongolia/47/2001 (H7N1) in chicks. AB - Avian influenza viruses A/duck/Mongolia/47/2001 (H7N1) (47/01) and A/duck/Mongolia/867/2002 (H7N1) (867/02) were defined as low-pathogenic avian influenza viruses (LPAIVs) using an intravenous pathogenicity test in chickens. On the other hand, the intracerebral pathogenicity indices of 47/01 and 867/02 were 1.30 and 0.00, respectively. A series of reassortant viruses were generated between 47/01 and 867/02, and their intracerebral pathogenicity was compared in one-day-old chicks to identify the protein(s) responsible for the intracerebral pathogenicity of 47/01. The results indicate that the amino acids at positions 50 and 98 of the nucleoprotein are related to the pathogenicity of 47/01 in chicks by intracerebral inoculation. A significant association was found between mortality of the chicks inoculated intracerebrally with 47/01 and virus replication in the lungs and/or brain. These results indicate that the NP of avian influenza viruses may be responsible for intracerebral pathogenicity in the host. PMID- 22833103 TI - Injury-induced asymmetric cell death as a driving force for head regeneration in Hydra. AB - The freshwater Hydra polyp provides a unique model system to decipher the mechanisms underlying adult regeneration. Indeed, a single cut initiates two distinct regenerative processes, foot regeneration on one side and head regeneration on the other side, the latter relying on the rapid formation of a local head organizer. Two aspects are discussed here: the asymmetric cellular remodeling induced by mid-gastric bisection and the signaling events that trigger head organizer formation. In head-regenerating tips (but not in foot ones), a wave of cell death takes place immediately, leading the apoptotic cells to transiently release Wnt3 and activate the beta-catenin pathway in the neighboring cycling cells to push them through mitosis. This process, which mimics the apoptosis-induced compensatory proliferation process deciphered in Drosophila larvae regenerating their discs, likely corresponds to an evolutionarily conserved mechanism, also at work in Xenopus tadpoles regenerating their tail or mice regenerating their skin or liver. How is this process generated in Hydra? Several studies pointed to the necessary activation of the extracellular signal regulated kinase (ERK) 1-2 and mitogen-activated protein kinase (MAPK) pathways during early head regeneration. Indeed inhibition of ERK 1-2 or knockdown of RSK, cAMP response element-binding protein (CREB), and CREB-binding protein (CBP) prevent injury-induced apoptosis and head regeneration. The current scenario involves an asymmetric activation of the MAPK/CREB pathway to trigger injury induced apoptosis in the interstitial cells and in the epithelial cells a CREB/CBP-dependent transcriptional activation of early genes essential for head organizing activity as wnt3, HyBra1, and prdl-a. The question now is how bisection in the rather uniform central region of the polyp can generate this immediately asymmetric signaling. PMID- 22833104 TI - Implication of the beta2-microglobulin gene in the generation of tumor escape phenotypes. AB - Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8(+) cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, beta2-microglobulin (beta2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that beta2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single beta2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of beta2m loss in both tumor types. It also summarizes recent studies that point to an acquired beta2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy. PMID- 22833105 TI - Patient experiences of a theory-based lifestyle-focused group treatment in the prevention of cardiovascular diseases and type 2 diabetes. AB - BACKGROUND: Cardiovascular disease and type 2 diabetes are two of the most common public health diseases, and up to 80 % of the cases may be prevented by lifestyle modification. The physiological effects of lifestyle-focused treatment are relatively well studied, but how patients actually experience such treatments is still rather unclear. PURPOSE: The aim of this study was to explore how patients experience lifestyle-focused group treatment in primary and secondary prevention of cardiovascular disease and type 2 diabetes. METHOD: Qualitative interviews were conducted with 19 patients attending lifestyle-focused group treatment based on social cognitive theory at a behavioral medicine clinic in northern Sweden. The interviews were transcribed verbatim and analyzed according to Malterud's systematic text condensation. RESULTS: The study shows that patients participating in this kind of group-based lifestyle treatment went through a process of self-development which deepened their understanding of own responsibility for health and improved their skills in finding support in others. The process could be tracked through three different themes (the holistic view, personal responsibility, and group treatment) which together reflected the most essential parts of the informants' experience and showed the patient as an active decision maker struggling to adopt the principles of behavioral change. CONCLUSION: Lifestyle-focused group treatment, based on social cognitive theory, was shown to stimulate different components that strengthen patients' self efficacy for long-term behavioral change. PMID- 22833106 TI - [Update impact factor 2011 of the journal]. PMID- 22833107 TI - Design of protein congeners containing beta-cyclopropylalanine. AB - The non-canonical amino acid (ncAA) analogue of methionine (Met), beta cyclopropylalanine (Cpa), was successfully incorporated into recombinant proteins expressed in Escherichia coli in a residue-specific manner. Proteins substituted in this way are congeners because they derive from the same gene sequence as the parent protein but contain a fraction of ncAAs. We have expressed congeners using parent and mutant gene sequences of various proteins (lipase, annexin A5, enhanced green fluorescent protein, and barstar) and found that Cpa incorporation is highly dependent on the protein sequence composition. These results indicate that the global amino acid composition of proteins might be a crucial parameter that influences the outcome of unnatural translation. In addition, we could also demonstrate that the chemical nature of the second residue could be essential for successful ncAA incorporation. PMID- 22833108 TI - Psychometrics and utility of Psycho-Educational Profile-Revised as a developmental quotient measure among children with the dual disability of intellectual disability and autism. AB - There is no agreement about the measure to quantify the intellectual/developmental level in children with the dual disability of intellectual disability and autism. Therefore, we studied the psychometric properties and utility of Psycho-Educational Profile-Revised (PEP-R) as a developmental test in this population. We identified 116 children with dual disability from the day care and inpatient database of a specialised Autism Clinic. Scale and domain level scores of PEP-R were collected and analyzed. We examined the internal consistency, domain-total correlation of PEP-R and concurrent validity of PEP-R against Gesell's Developmental Schedule, inter-rater and test-retest reliability and utility of PEP-R among children with dual disability in different ages, functional level and severity of autism. Besides the adequate face and content validity, PEP-R demonstrates a good internal consistency (Cronbach's alpha ranging from 0.91 to 0.93) and domain-total correlation (ranging from 0.75 to 0.90). The inter-rater reliability (intraclass correlation coefficient, ICC = 0.96) and test-retest reliability (ICC = 0.87) for PEP-R is good. There is moderate-to-high concurrent validity with GDS (r ranging from 0.61 to 0.82; all Ps = 0.001). The utility of PEP-R as a developmental measure was good with infants, toddlers, pre-school and primary school children. The ability of PEP-R to measure the developmental age was good, irrespective of the severity of autism but was better with high-functioning children. The PEP-R as an intellectual/developmental test has strong psychometric properties in children with dual disability. It could be used in children with different age groups and severity of autism. PEP-R should be used with caution as a developmental test in children with dual disability who are low functioning. PMID- 22833109 TI - Desiccation-induced non-radiative dissipation in isolated green lichen algae. AB - Lichens are able to tolerate almost complete desiccation and can quickly resume metabolic activity after rehydration. In the desiccated state, photosynthesis is completely blocked and absorbed excitation energy cannot be used for electron transport, leading to a potential strong vulnerability for high light damage. Although desiccation and high insolation often occur simultaneously and many lichens colonize exposed habitats, these organisms show surprisingly little photodamage. In the desiccated state, variable chlorophyll fluorescence is lost, indicating a suspension of charge separation in photosystem II. At the same time, basal fluorescence (F (0)) is strongly quenched, which has been interpreted as an indication for high photoprotective non-radiative dissipation (NRD) of absorbed excitation energy. In an attempt to provide evidence for a photoprotective function of NRD in the desiccated state, isolated green lichen algae of the species Coccomyxa sp. and Trebouxia asymmetrica were used as experimental system. In contrast to experiments with intact lichens this system provided high reproducibility of the data without major optical artifacts on desiccation. The presence of 5 mM trehalose during desiccation had no effect but culture of the algae in seawater enhanced F (0) quenching in T. asymmetrica together with a reduced depression of F (V)/F (M) after high light treatment. While this effect could not be induced using artificial seawater medium lacking trace elements, the addition of ZnCl(2) and NaI in small amounts to the normal growth medium led to qualitatively and quantitatively identical results as with pure seawater. It is concluded that NRD indicated by F (0) quenching is photoprotective. The formation of NRD in lichen algae is apparently partially dependent on the presence of specific micronutrients. PMID- 22833110 TI - Hyperglycemia and methylprednisolone: comment on the article by den Uyl et al. PMID- 22833112 TI - 1-(Hydroxyacetyl)pyrene a new fluorescent phototrigger for cell imaging and caging of alcohols, phenol and adenosine. AB - 1-(Hydroxyacetyl)pyrene has been introduced as a new fluorescent phototrigger for alcohols and phenols. Alcohols and phenols were protected as their corresponding carbonate esters by coupling with fluorescent phototrigger, 1 (hydroxyacetyl)pyrene. Photophysical studies of caged carbonates showed that they all exhibited strong fluorescence properties. Irradiation of the caged carbonates by visible light (>=410 nm) in aqueous acetonitrile released the corresponding alcohols or phenols in high chemical (95-97%) and quantum (0.17-0.21) yields. The mechanism for the photorelease was proposed based on Stern-Volmer quenching experiments and solvent effect studies. Importantly, 1-(hydroxyacetyl)pyrene showed as a phototrigger for rapid photorelease of the biologically active molecule adenosine. In vitro biological studies revealed that 1 (hydroxyacetyl)pyrene has good biocompatibility, cellular uptake property and cell imaging ability. PMID- 22833116 TI - A new, higher yielding synthetic route towards dodecaphenyl cage silsesquioxanes: synthesis and mechanistic insights. AB - Cage dodecaphenylsilsesquioxane (T12-Phenyl) was synthesized in a one batch, mildly basic aqueous solution under room temperature conditions using a trialkoxysilane precursor. Significant improvements in synthetic yield (>95%) were observed compared with previous reports. Kinetic studies of the hydrolysis of phenyltrimethoxysilane were conducted and the condensation was monitored by (29)Si NMR which revealed the presence of a transient, intermediary T1 species as the pathway to dodecaphenylsilsesquioxane spherulites, and the tendency for T12 structures over T8, T10, and other substructures was explained through MM2 simulations. PMID- 22833114 TI - Stimulatory effects of the flavanol (-)-epicatechin on cardiac angiogenesis: additive effects with exercise. AB - The consumption of moderate amounts of cocoa products has been associated with reductions in the incidence of cardiovascular diseases. In animal studies, the flavanol (-)-epicatechin (Epi) yields cardioprotection. The effects may be partly due to its capacity to stimulate endothelial nitric oxide synthase (eNOS). The sustained activation of eNOS, as observed with exercise, can serve as a trigger of muscle angiogenesis via the activation of vascular endothelial growth factor (VEGF)-related events. Experiments were pursued to examine the potential of Epi to stimulate myocardial angiogenesis and determine the effects that its combined use with exercise (Ex) may trigger. Hearts obtained from a previous study were used for this purpose. Animals received 1 mg/kg of Epi or water (vehicle) via oral gavage (twice daily). Epi and/or Ex (by treadmill) was provided for 15 days. Results indicate that Ex or Epi significantly stimulate myocardial angiogenesis by ~30% above control levels. The use of Epi-Ex lead to further significant increases (to ~50%). Effects were associated with increases in protein levels and/or activation of canonical angiogenesis pathway associated events (HIF1a, VEGF, VEGFR2, PI3K, PDK, AKT, eNOS, NO, cGMP, MMP-2/-9, Src-1, and CD31). Thus, the use of Epi may represent a safe and novel means to stimulate myocardial angiogenesis. PMID- 22833118 TI - Tolerance to MHC class II disparate allografts through genetic modification of bone marrow. AB - Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here, we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-A(b) (I-A(b)) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow-derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction. PMID- 22833119 TI - Expression analyses of Brachiaria brizantha genes encoding ribosomal proteins BbrizRPS8, BbrizRPS15a, and BbrizRPL41 during development of ovaries and anthers. AB - Brachiaria brizantha is a forage grass of the Poaceae family. Introduced from Africa, it is largely used for beef cattle production in Brazil. Brachiaria reproduces sexually or asexually by apomixis, and development of biotechnological tools for gene transfer is being researched to support the breeding programs. The molecular bases of reproduction have not yet been fully elucidated; it is known that gametophyte formation and main reproductive events occur inside the anthers and ovaries. There is therefore much interest in identifying genes expressed in these organs and their corresponding upstream regulatory sequences. In this work we characterized three cDNA from ovaries of B. brizantha plants (CL 09, CL10, and CL21) which show similarity in databases with genes encoding ribosomal proteins S8, S15a, and L41 and were named BbrizRPS8, BbrizRPS15a, and BbrizRPL41, respectively. These clones show higher expression in ovaries, anthers and roots, mitotically active tissues, when compared to leaves of B. brizantha. Localization of transcripts of BbrizRPS8, BbrizRPS15a, and BbrizRPL41 was investigated in the reproductive organs, ovaries, and anthers, from the beginning of development up to maturity. Their activity was higher in early stages of anther development, while expression was detected in all developmental stages in the ovaries, except for BbrizS15a, which was detected only in synergids of apomictic plants. PMID- 22833120 TI - Drosophila male-sterile mutation emmenthal specifically affects the mitochondrial morphogenesis. AB - Proper mitochondrial morphogenesis is crucial for successful development of motile sperm. It was known that recessive Drosophila melanogaster mutation emm caused anomalies in the formation of a mitochondrial derivative--nebenkern and led to male sterility. Here we identified primary mutation effect and showed that emm is required for the formation and maintenance of inner mitochondrial structure starting from early spermatocytes. Abnormal mitochondria structure affects subsequent cellular processes in spermatogenesis such as meiotic cytokinesis and spermatid elongation. PMID- 22833122 TI - AP2-type transcription factors determine stem cell identity in the moss Physcomitrella patens. AB - Stem cells are formed at particular times and positions during the development of multicellular organisms. Whereas flowering plants form stem cells only in the sporophyte generation, non-seed plants form stem cells in both the sporophyte and gametophyte generations. Although the molecular mechanisms underlying stem cell formation in the sporophyte generation have been extensively studied, only a few transcription factors involved in the regulation of gametophyte stem cell formation have been reported. The moss Physcomitrella patens forms a hypha-like body (protonema) and a shoot-like body (gametophore) from a protonema apical cell and a gametophore apical cell, respectively. These apical cells have stem cell characteristics and are formed as side branches of differentiated protonema cells. Here, we show that four AP2-type transcription factors orthologous to Arabidopsis thaliana AINTEGUMENTA, PLETHORA and BABY BOOM (APB) are indispensable for the formation of gametophore apical cells from protonema cells. Quadruple disruption of all APB genes blocked gametophore formation, even in the presence of cytokinin, which enhances gametophore apical cell formation in the wild type. All APB genes were expressed in emerging gametophore apical cells, but not in protonema apical cells. Heat-shock induction of an APB4 transgene driven by a heat-shock promoter increased the number of gametophores. Expression of all APB genes was induced by auxin but not by cytokinin. Thus, the APB genes function synergistically with cytokinin signaling to determine the identity of the two types of stem cells. PMID- 22833121 TI - Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE(-/-) mice. AB - AIM: The severity of atherosclerosis is primarily determined by overall lipid metabolism and the degree of inflammation present within the vessel wall. We evaluated the effects of T-0901317, a liver X receptor agonist, on the atherosclerosis process, and especially on the endothelial function in ApoE(-/-) mice. METHODS AND RESULTS: ApoE(-/-) mice were treated with LXR agonist T-0901317 (1 MUmol/L) for 6 weeks. ApoE(-/-) mice receiving T-0901317 were found to have markedly improved overall serum lipid profiles, albeit increased serum triglycerides. MRI imaging demonstrated that T-0901317 attenuated the atherosclerotic plaque burden in the aorta of ApoE(-/-) mice. Transmission electron microscopy and immunohistochemistry revealed attenuated ultrastructural changes as well as enhanced expression of the ATP-binding cassette transporter ABCA1. In addition, treatment with the LXR agonist improved the vasomotor function of atherosclerotic arteries, as assessed by KCl/norepinephrine-induced vasoconstrictive and acetylcholine-induced vasorelaxation functional assays. In vitro studies showed increased ABCG1, phospho-Akt and phospho-eNOS expression in ApoE(-/-) mice aorta endothelial cells (ECs) after T0901317 treatment. CONCLUSION: The present study suggest that LXR agonists protect the endothelium against atherosclerotic insults by increasing ABCA1 and ABCG1 expression, and improve the endothelial-dependent vasomotor function probably by promoting Akt and eNOS phosphorylation. PMID- 22833123 TI - Electrosensory ampullary organs are derived from lateral line placodes in cartilaginous fishes. AB - Ampullary organ electroreceptors excited by weak cathodal electric fields are used for hunting by both cartilaginous and non-teleost bony fishes. Despite similarities of neurophysiology and innervation, their embryonic origins remain controversial: bony fish ampullary organs are derived from lateral line placodes, whereas a neural crest origin has been proposed for cartilaginous fish electroreceptors. This calls into question the homology of electroreceptors and ampullary organs in the two lineages of jawed vertebrates. Here, we test the hypothesis that lateral line placodes form electroreceptors in cartilaginous fishes by undertaking the first long-term in vivo fate-mapping study in any cartilaginous fish. Using DiI tracing for up to 70 days in the little skate, Leucoraja erinacea, we show that lateral line placodes form both ampullary electroreceptors and mechanosensory neuromasts. These data confirm the homology of electroreceptors and ampullary organs in cartilaginous and non-teleost bony fishes, and indicate that jawed vertebrates primitively possessed a lateral line placode-derived system of electrosensory ampullary organs and mechanosensory neuromasts. PMID- 22833124 TI - Fgfr-Ras-MAPK signaling is required for apical constriction via apical positioning of Rho-associated kinase during mechanosensory organ formation. AB - Many morphogenetic movements during development require the formation of transient intermediates called rosettes. Within rosettes, cells are polarized with apical ends constricted towards the rosette center and nuclei basally displaced. Whereas the polarity and cytoskeletal machinery establishing these structures has been extensively studied, the extracellular cues and intracellular signaling cascades that promote their formation are not well understood. We examined how extracellular Fibroblast growth factor (Fgf) signals regulate rosette formation in the zebrafish posterior lateral line primordium (pLLp), a group of ~100 cells that migrates along the trunk during embryonic development to form the lateral line mechanosensory system. During migration, the pLLp deposits rosettes from the trailing edge, while cells are polarized and incorporated into nascent rosettes in the leading region. Fgf signaling was previously shown to be crucial for rosette formation in the pLLp. We demonstrate that activation of Fgf receptor (Fgfr) induces intracellular Ras-MAPK, which is required for apical constriction and rosette formation in the pLLp. Inhibiting Fgfr-Ras-MAPK leads to loss of apically localized Rho-associated kinase (Rock) 2a, which results in failed actomyosin cytoskeleton activation. Using mosaic analyses, we show that a cell-autonomous Ras-MAPK signal is required for apical constriction and Rock2a localization. We propose a model whereby activated Fgfr signals through Ras-MAPK to induce apical localization of Rock2a in a cell-autonomous manner, activating the actomyosin network to promote apical constriction and rosette formation in the pLLp. This mechanism presents a novel cellular strategy for driving cell shape changes. PMID- 22833125 TI - Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling. AB - Uncovering the origin and nature of phenotypic variation within species is the first step in understanding variation between species. Mouse models with altered activities of crucial signal pathways have highlighted many important genes and signal networks regulating the morphogenesis of complex structures, such as teeth. The detailed analyses of these models have indicated that the balanced actions of a few pathways regulating cell behavior modulate the shape and number of teeth. Currently, however, most mouse models studied have had gross alteration of morphology, whereas analyses of more subtle modification of morphology are required to link developmental studies to evolutionary change. Here, we have analyzed a signaling network involving ectodysplasin (Eda) and fibroblast growth factor 20 (Fgf20) that subtly affects tooth morphogenesis. We found that Fgf20 is a major downstream effector of Eda and affects Eda-regulated characteristics of tooth morphogenesis, including the number, size and shape of teeth. Fgf20 function is compensated for by other Fgfs, in particular Fgf9 and Fgf4, and is part of an Fgf signaling loop between epithelium and mesenchyme. We showed that removal of Fgf20 in an Eda gain-of-function mouse model results in an Eda loss-of function phenotype in terms of reduced tooth complexity and third molar appearance. However, the extra anterior molar, a structure lost during rodent evolution 50 million years ago, was stabilized in these mice. PMID- 22833126 TI - Canonical Wnt signaling regulates smooth muscle precursor development in the mouse ureter. AB - Smooth muscle cells (SMCs) are a key component of many visceral organs, including the ureter, yet the molecular pathways that regulate their development from mesenchymal precursors are insufficiently understood. Here, we identified epithelial Wnt7b and Wnt9b as possible ligands of Fzd1-mediated beta-catenin (Ctnnb1)-dependent (canonical) Wnt signaling in the adjacent undifferentiated ureteric mesenchyme. Mice with a conditional deletion of Ctnnb1 in the ureteric mesenchyme exhibited hydroureter and hydronephrosis at newborn stages due to functional obstruction of the ureter. Histological analysis revealed that the layer of undifferentiated mesenchymal cells directly adjacent to the ureteric epithelium did not undergo characteristic cell shape changes, exhibited reduced proliferation and failed to differentiate into SMCs. Molecular markers for prospective SMCs were lost, whereas markers of the outer layer of the ureteric mesenchyme fated to become adventitial fibroblasts were expanded to the inner layer. Conditional misexpression of a stabilized form of Ctnnb1 in the prospective ureteric mesenchyme resulted in the formation of a large domain of cells that exhibited histological and molecular features of prospective SMCs and differentiated along this lineage. Our analysis suggests that Wnt signals from the ureteric epithelium pattern the ureteric mesenchyme in a radial fashion by suppressing adventitial fibroblast differentiation and initiating smooth muscle precursor development in the innermost layer of mesenchymal cells. PMID- 22833127 TI - Integrating force-sensing and signaling pathways in a model for the regulation of wing imaginal disc size. AB - The regulation of organ size constitutes a major unsolved question in developmental biology. The wing imaginal disc of Drosophila serves as a widely used model system to study this question. Several mechanisms have been proposed to have an impact on final size, but they are either contradicted by experimental data or they cannot explain a number of key experimental observations and may thus be missing crucial elements. We have modeled a regulatory network that integrates the experimentally confirmed molecular interactions underlying other available models. Furthermore, the network includes hypothetical interactions between mechanical forces and specific growth regulators, leading to a size regulation mechanism that conceptually combines elements of existing models, and can be understood in terms of a compression gradient model. According to this model, compression increases in the center of the disc during growth. Growth stops once compression levels in the disc center reach a certain threshold and the compression gradient drops below a certain level in the rest of the disc. Our model can account for growth termination as well as for the paradoxical observation that growth occurs uniformly in the presence of a growth factor gradient and non-uniformly in the presence of a uniform growth factor distribution. Furthermore, it can account for other experimental observations that argue either in favor or against other models. The model also makes specific predictions about the distribution of cell shape and size in the developing disc, which we were able to confirm experimentally. PMID- 22833128 TI - Eukaryotic initiation factor 4E-3 is essential for meiotic chromosome segregation, cytokinesis and male fertility in Drosophila. AB - Gene expression is translationally regulated during many cellular and developmental processes. Translation can be modulated by affecting the recruitment of mRNAs to the ribosome, which involves recognition of the 5' cap structure by the cap-binding protein eIF4E. Drosophila has several genes encoding eIF4E-related proteins, but the biological role of most of them remains unknown. Here, we report that Drosophila eIF4E-3 is required specifically during spermatogenesis. Males lacking eIF4E-3 are sterile, showing defects in meiotic chromosome segregation, cytokinesis, nuclear shaping and individualization. We show that eIF4E-3 physically interacts with both eIF4G and eIF4G-2, the latter being a factor crucial for spermatocyte meiosis. In eIF4E-3 mutant testes, many proteins are present at different levels than in wild type, suggesting widespread effects on translation. Our results imply that eIF4E-3 forms specific eIF4F complexes that are essential for spermatogenesis. PMID- 22833129 TI - SnoN regulates mammary gland alveologenesis and onset of lactation by promoting prolactin/Stat5 signaling. AB - Mammary epithelial cells undergo structural and functional differentiation at late pregnancy and parturition to produce and secrete milk. Both TGF-beta and prolactin pathways are crucial regulators of this process. However, how the activities of these two antagonistic pathways are orchestrated to initiate lactation has not been well defined. Here, we show that SnoN, a negative regulator of TGF-beta signaling, coordinates TGF-beta and prolactin signaling to control alveologenesis and lactogenesis. SnoN expression is induced at late pregnancy by the coordinated actions of TGF-beta and prolactin. The elevated SnoN promotes Stat5 signaling by enhancing its stability, thereby sharply increasing the activity of prolactin signaling at the onset of lactation. SnoN-/- mice display severe defects in alveologenesis and lactogenesis, and mammary epithelial cells from these mice fail to undergo proper morphogenesis. These defects can be rescued by an active Stat5. Thus, our study has identified a new player in the regulation of milk production and revealed a novel function of SnoN in mammary alveologenesis and lactogenesis in vivo through promotion of Stat5 signaling. PMID- 22833131 TI - [Ophthalmopathology]. PMID- 22833130 TI - Onecut transcription factors act upstream of Isl1 to regulate spinal motoneuron diversification. AB - During development, spinal motoneurons (MNs) diversify into a variety of subtypes that are specifically dedicated to the motor control of particular sets of skeletal muscles or visceral organs. MN diversification depends on the coordinated action of several transcriptional regulators including the LIM-HD factor Isl1, which is crucial for MN survival and fate determination. However, how these regulators cooperate to establish each MN subtype remains poorly understood. Here, using phenotypic analyses of single or compound mutant mouse embryos combined with gain-of-function experiments in chick embryonic spinal cord, we demonstrate that the transcriptional activators of the Onecut family critically regulate MN subtype diversification during spinal cord development. We provide evidence that Onecut factors directly stimulate Isl1 expression in specific MN subtypes and are therefore required to maintain Isl1 production at the time of MN diversification. In the absence of Onecut factors, we observed major alterations in MN fate decision characterized by the conversion of somatic to visceral MNs at the thoracic levels of the spinal cord and of medial to lateral MNs in the motor columns that innervate the limbs. Furthermore, we identify Sip1 (Zeb2) as a novel developmental regulator of visceral MN differentiation. Taken together, these data elucidate a comprehensive model wherein Onecut factors control multiple aspects of MN subtype diversification. They also shed light on the late roles of Isl1 in MN fate decision. PMID- 22833132 TI - [Clinical and histopathological correlations of eyelid and anterior segment diseases]. AB - In this article we present the histopathological picture of common eyelid and anterior segment diseases, and directly compare histological and correlating clinical features for each disease. In addition to common benign eyelid tumours and cysts, malignant tumours of the lid are shown. For example, in such cases the histopathological characteristics can illustrate why certain tumours require a closer follow-up. Slit-lamp examination results are compared to the histological picture of relevant corneal diseases, followed by affections of the iris and anterior chamber. PMID- 22833133 TI - [In vivo confocal microscopy--correlation to histology]. AB - In vivo confocal microcopy is a fascinating technique to obtain rapidly and non invasively histological/cytological sections of the ocular surface, and observe long-term changes. It allows classification of corneal findings, facilitates the diagnosis of conjunctival lesions, and has broadened our understanding of lid margin disease. To correctly interpret in vivo confocal scans, profound knowledge of microscopic anatomy and histopathology are crucial. To reduce inter-observer variability and allow comparison of scientific studies, in vivo confocal histopathological correlations have to be investigated, and standards for the interpretation of in vivo confocal microscopic findings must be established. In suspicious lesions of the ocular surface an excisional biopsy and histopathological examination are still the gold standard. PMID- 22833134 TI - [Clinico-pathological correlations: posterior compartment of the eye and orbit]. AB - Diseases of the posterior compartment and the orbit are characterised by histological findings, most of which can be reproduced clinically. Examples are the examination of calcifications in retinoblastoma by ultrasonography. In the present review, histological findings of tumour and other diseases of the posterior ocular compartment and the orbit are presented and correlated with the clinical pictures and imaging techniques: uveal melanoma, choroidal nevus, choroidal metastases, choroidal hemangioma, retinoblastoma, Coat's disease, sympathetic ophthalmia, pleomorphic adenoma (benign mixed tumour) of the lacrimal gland, dacryoadenitis, lymphoma, rhabdomyosarcoma, Langerhans cell histiocytosis, orbital metastases, and phthisical eyes. Histopathology is usually the gold standard for a definitive diagnosis. It is very important for residents and those in training to become familiar with clinico-pathological correlations as these provide insight in pathophysiological processes. Regarding ophthalmic surgery, ophthalmic pathology offers the possibility to study wound healing and complications. A close collaboration between clinicians and ocular pathologists allows for an optimised processing of the submitted tissue and diagnosis. Thus, pre- and postoperative care can also be improved. This outstanding knowledge that ophthalmologists have gained over the last decades and beyond, should be preserved and passed on to the next generations in order to maintain a high standard in ophthalmological care. PMID- 22833135 TI - [Retinal detachment. Part 2: therapeutic procedure]. PMID- 22833136 TI - Impact on perioperative outcomes of concomitant hiatal hernia repair with laparoscopic gastric bypass. AB - BACKGROUND: The role of laparoscopic hiatal hernia repair (LHHR) at the time of laparoscopic Roux-en-y gastric bypass (LRYGB) is still debatable. This study aims to assess the safety of concomitant LHHR with LRYGB. METHODS: This study is a multi-center, retrospective analysis of a large administrative database. The University Health System Consortium (UHC) is a group of 112 academic medical centers and 256 of their affiliated hospitals. The UHC database was queried using International Classification of Diseases-9 codes and main outcome measures were analyzed. RESULTS: From October 2006 to January 2010, we found 33,717 patients who underwent LRYGB and did not have a hiatal hernia. In this same time period, 644 patients underwent concomitant LRYGB and LHHR, while 1,589 patients underwent LRYGB without repair of their hiatal hernias. On comparison of patients undergoing LRYGB with simultaneous LHHR with those who underwent LRYGB without a diagnosis of HH, there was no significant difference in mortality, morbidity, length of stay (LOS), 30-day readmission, or cost shown. On comparison of patients with HH who underwent LRYGB and simultaneous LHHR with those who had LRYGB without LHHR, no significant difference with regards to all the outcome measures was also shown. CONCLUSIONS: In conclusion, concomitant hiatal hernia repair with LRYGB appears to be safe and feasible. These patients did not have any significant differences in morbidity, mortality, LOS, readmission rate, or cost. Randomized controlled studies should further look into the benefit of hiatal hernia repair in regards to reflux symptoms and weight loss for LRYGB patients. PMID- 22833137 TI - What is the actual fate of super-morbid-obese patients who undergo laparoscopic sleeve gastrectomy as the first step of a two-stage weight-reduction operative strategy? AB - The overall success-rate of the two-stage treatment plan for the treatment of super-morbid obesity has not yet been assessed. We reviewed the long-term results of 41 treated super-morbid-obese patients. Mean initial BMI was 59.5 +/- 3.5 kg/m(2). Twelve patients (29.3 %) achieved after only LSG a BMI <35 kg/m(2) (mean 31.9 +/- 2). They have lost 78.7 +/- 11.8 % of excess body weight (EBW). The remaining 28 patients lost 48.1 +/- 11.9 % of EBW and achieved a mean BMI of 44.2 +/- 4.3 kg/m(2), thus requiring the second stage. Ten of them (24.4 % of the total or 35.7 % of those in need), were submitted to laparoscopic Roux-en-Y gastric bypass (LRYGBP). They lost 71.9 +/- 4.3 % of EBW and have a mean BMI of 33.6 +/- 2.7 kg/m(2). The 18 remaining patients have a BMI of 42 +/- 3.6 kg/m(2) and they still suffer from morbid obesity. They have lost 48.5 +/- 8.7 % of EBW. The mean rate of EBW loss for all the available 39 patients after either LSG or both LSG and LRYGBP has been 63.2 +/- 16.5 % after a mean follow-up of 42.8 +/- 19.5 months. Out of 41 patients, 1 died, 1 was lost to follow-up, 21 (51.2 %) achieved "healthy" BMIs and 18 (44 %) still require LRYGBP. The rate of cure of morbid obesity was 51.2 %. A remaining 44 % of super-morbid obese patients still need the completion LRYGBP but have not undergone it. Half of these patients have lost >50 % of their EBW. The two-stage strategy is an effective treatment plan for super-morbid obesity. A less patient-dependent strategy may be needed for a subset of patients. PMID- 22833138 TI - Perioperative management of the severely obese patient: a selective pathophysiological review. AB - PURPOSE: Obesity is widespread, yet it is often understood primarily as a disorder of body structure. This article provides anesthesiologists with a synopsis of recent research into the complex pathophysiology of obesity. It emphasizes the importance of this information for the perioperative planning and management of this patient group and for reviewing some of the major perioperative challenges. PRINCIPAL FINDINGS: Obesity is a multisystem chronic pro-inflammatory disorder associated with increased morbidity and mortality. Adipocytes are far more than storage vessels for lipids. They secrete a large number of physiologically active substances called adipokines that lead to inflammation, vascular and cardiac remodelling, airway inflammation, and altered microvascular flow patterns. They contribute to linked abnormalities, such as insulin resistance and the metabolic syndrome, and they attract and activate inflammatory cells such as macrophages. These changes can lead ultimately to organ dysfunction, especially cardiovascular and pulmonary issues. In the respiratory system, anesthesiologists should be familiar not just with screening tools for obstructive sleep apnea but also with obesity hypoventilation syndrome, which is less well appreciated and carries a significant outcome disadvantage. Perioperative management is challenging. It is centred around cardiorespiratory and metabolic optimization, minimizing adverse effects of both pain and systemic opioids, effective use of regional anesthesia, and an emphasis on mobilization and nutrition - given the prevalence of micronutrient deficiencies in the severely obese. There is a risk of incorrect drug dosing in obesity, which requires an understanding of the appropriate dosing weights for perioperative medications. CONCLUSION: The literature clearly highlights the complexity of severe obesity as a multisystem disease, and anesthesiologists caring for these patients perioperatively must have a sound understanding of the changes in order to offer the highest quality care to these patients. PMID- 22833139 TI - Dynamic-definition male pectoral reshaping and enhancement in slim, athletic, obese, and gynecomastic patients through selective fat removal and grafting. AB - BACKGROUND: One of the most appealing characteristics of an athletic male body is a well-defined pectoral area. For decades, implants have been the gold standard method for the treatment of this area, but it is not suitable for every case. The goal was to design a mixed technique combining autologous fat extraction and grafting in an anatomically guided fashion to produce a highly athletic contour in the male pectoral. METHODS: The patient criteria included a body mass index (BMI) lower than 30 kg/m(2), adequate skin tone, and general good health. A three phase procedure was performed, beginning with infiltration of tumescent solution and followed by fragmentation of extra fat in an anatomic fashion using internal third-generation ultrasound; extraction that blends deep, intermediate, and superficial fat removal; and multilayer fat grafting in the pectoral area. In the presence of gynecomastia, a selective pull-through technique was used in an anatomic manner. RESULTS: In a series of 154 consecutive male patients, the minor complications (n = 15) included asymmetries (n = 10) and residual gynecomastia (n = 5). The major complications (n = 3) included unilateral hematoma (n = 2), and abscess that required sonographic-guided removal (n = 1). An appealing muscular contour was produced in most patients, and the satisfaction rate was very high. CONCLUSION: Implants are no longer the only option for defining and augmenting the male chest. Combining fat grafting in a multilayer fashion with precise anatomic fat and gland removal achieved a contoured and athletic male pectoral in a safe and reproducible manner. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. PMID- 22833140 TI - Soft versus hard implants in dorsal nasal augmentation: a comparative clinical study. AB - BACKGROUND: Dorsal nasal augmentation plays an important role in cosmetic and reconstructive rhinoplasties performed to achieve an aesthetically pleasing result while creating facial harmony. Although it is known that the ideal implant should be biocompatible, biointegrated, nonabsorbable, and without inflammatory response, the selection of an ideal implant still remains controversial as to whether it should be biologic or synthetic. This study introduces a new question: ''What is better for the nasal dorsum, a soft or a hard implant?''. METHODS: In this study, 21 women and 7 men with a mean age of 23.5 years underwent augmentation rhinoplasty between December 2007 and July 2011. Conchal and septal cartilage grafts and Medpor were categorized as hard implants and applied for 15 patients. Soft implants, inserted in 13 patients, included diced auricular cartilage wrapped in Surgicel sheets, dermofat blocks, and rolls of Prolene mesh. RESULTS: Patient satisfaction was assessed through simple postoperative questionnaires. The satisfaction rate in the soft implant group was 100 %, whereas the overall satisfaction rate was 82.2 %. Unsatisfactory results and complications were recorded in the hard implant group, which had a dissatisfaction rate of 33.3 %, contributing to a general dissatisfaction rate of 17.8 % in the whole series. CONCLUSION: The authors recommend soft implants for both aesthetic and reconstructive surgeries because of their better ability to achieve a dorsum with a smoother contour and pad. Soft implants have fewer complications and higher satisfaction rates and can be applied for most indications using both closed and open methods. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. PMID- 22833141 TI - Is topical vitamin C an effective post-Fraxel laser regimen for asians? AB - The Fraxel laser has been a useful method for skin resurfacing. According to recent reports, vitamin C has beneficial effects for the skin. However, there is a paucity of data about the effect of vitamin C associated with the Fraxel laser. This study aimed to assess the effect of topical vitamin C as a post-Fraxel regimen. The study involved 44 Koreans, who wished to improve their facial skin aesthetics. All the patients were treated by Fraxel laser twice, with a 4-week interval between treatments. Beginning on day 1, the treatment group used a topical vitamin C agent as a post-Fraxel regimen for 12 weeks. The control group was told not to apply any topical agents. At every visit (0, 4, 8, and 12 weeks after the first Fraxel), colorimetric status, stratum corneum hydration, skin surface lipids, skin pH, and transepidermal water loss (TEWL) were measured. The parameters showing significant differences were TEWL and pH. Stratum corneum hydration, skin surface lipids, and colorimetric status showed no statistically significant differences between the two groups. Topical vitamin C application reduces the injury of the skin's surface barrier after Fraxel laser and promotes restoration of skin pH. However, there is a limit with increasing skin lightness or decreasing skin redness. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. PMID- 22833142 TI - Measuring volumetric change after augmentation mammaplasty using a three dimensional scanning technique: an innovative method. AB - BACKGROUND: Measurement of volumetric change after augmentation mammaplasty is of great significance to plastic surgeons. This study aimed to introduce a new method using a three-dimensional (3D) scanning technique to measure volumetric change after augmentation mammaplasty. METHODS: Preoperative 3D scans of 10 breasts were included in the study. A simulated postoperative breast scan was constructed using software. The true value of volumetric change was calculated. Volumetric change was measured and repeated 10 times by the traditional method and the new method. One investigator used the traditional method, and two investigators used the new method. The difference from the true value between the two methods and the intraclass coefficient (ICC) for each method was evaluated. Comparison of agreement with the true value and comparison of agreement using the new method between the two investigators were made using a Bland-Altman analysis. RESULTS: The mean breast volumetric change was 256.1 +/- 61.1 ml for the new method, 281.9 +/- 73.7 ml for the traditional method, and 256.0 +/- 61.0 ml for the true value. The difference from the true value for the traditional method was significantly greater than for the new method. The ICC was 0.9999 for the new method and 0.993 for the traditional method. Bland-Altman analysis showed a 95 % confidence interval (CI) of -40.9 to 92.7 ml for the traditional method and -0.9 to 1.2 ml for the new method. Comparison of agreement between investigators 1 and 2 showed a 95 % CI of -0.9 to 1.0 ml. The limits of agreement were +/-1.0 ml. CONCLUSIONS: The proposed new method can provide excellent accuracy, repeatability, and reproducibility in measuring volumetric change after augmentation mammaplasty using a 3D scanning technique. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. PMID- 22833144 TI - Evaluation of physical sampling efficiency for cyclone-based personal bioaerosol samplers in moving air environments. AB - The need to determine occupational exposure to bioaerosols has notably increased in the past decade, especially for microbiology-related workplaces and laboratories. Recently, two new cyclone-based personal bioaerosol samplers were developed by the National Institute for Occupational Safety and Health (NIOSH) in the USA and the Research Center for Toxicology and Hygienic Regulation of Biopreparations (RCT & HRB) in Russia to monitor bioaerosol exposure in the workplace. Here, a series of wind tunnel experiments were carried out to evaluate the physical sampling performance of these two samplers in moving air conditions, which could provide information for personal biological monitoring in a moving air environment. The experiments were conducted in a small wind tunnel facility using three wind speeds (0.5, 1.0 and 2.0 m s(-1)) and three sampling orientations (0 degrees , 90 degrees , and 180 degrees ) with respect to the wind direction. Monodispersed particles ranging from 0.5 to 10 MUm were employed as the test aerosols. The evaluation of the physical sampling performance was focused on the aspiration efficiency and capture efficiency of the two samplers. The test results showed that the orientation-averaged aspiration efficiencies of the two samplers closely agreed with the American Conference of Governmental Industrial Hygienists (ACGIH) inhalable convention within the particle sizes used in the evaluation tests, and the effect of the wind speed on the aspiration efficiency was found negligible. The capture efficiencies of these two samplers ranged from 70% to 80%. These data offer important information on the insight into the physical sampling characteristics of the two test samplers. PMID- 22833145 TI - Direct, nucleophilic radiosynthesis of [18F]trifluoroalkyl tosylates: improved labelling procedures. AB - A rapid and efficient protocol to afford the title compound 2-[(18)F]-fluoro-2,2 difluoroethyl tosylate ([(18)F]7b) is described. Starting from [(18)F]fluoride ion, labelling reagent 7b was obtained in good yields and a high specific radioactivity. Compound ([(18)F]7b) was then used to synthesise a prospective radiotracer for PET-imaging in dementia. PMID- 22833146 TI - Cardioprotection at a distance - remote conditioning takes the stage. PMID- 22833147 TI - Pancreatic beta-cell: the beauty of being plastic. PMID- 22833148 TI - Effect of Massachusetts health insurance reform on mammography use and breast cancer stage at diagnosis. AB - BACKGROUND: Massachusetts law requires all residents to maintain a minimum level of health insurance, and rates of uninsurance in that state decreased from 6.4% in 2006 to 1.9% in 2010. The authors of this report assessed whether health insurance expansion was associated with use of mammography and earlier stage at breast cancer diagnosis. METHODS: By using a prereform/postreform design with a concurrent control (California), mammography rates in the last year were assessed using the Behavioral Risk Factor Surveillance System survey and the diagnosis of stage I (vs II/III/IV) breast cancers based on cancer registry data among women ages 41 to 64. Propensity score analyses were used to compare California women who were most similar to women in Massachusetts with Massachusetts women. RESULTS: Among propensity-weighted cohorts, adjusted mammography rates in Massachusetts were 69.2% in 2006, 69.5% in 2008, and 69.0% in 2010. In California, the rates were 59% in 2006, 60.3% in 2008, and 56.2% in 2010 (P = .89 for interaction by state for 2010 vs 2006). Among propensity-weighted cohorts, adjusted rates of diagnosis with stage I cancers were 52.2% in 2006, 53.5% in 2007, and 52.4% in 2008 in Massachusetts versus 46.4% in 2006, 46.3% in 2007, and 45.7% in 2008 in California (P = .58 for interaction by state for 2010 vs 2006). CONCLUSIONS: Health insurance reform in Massachusetts was not associated with increased rates of mammography or earlier stage at diagnosis compared with California, possibly because of insurance and mammography rates that already were high. Additional research is needed to assess the impact of insurance expansions in other populations, especially those with higher uninsurance rates. PMID- 22833149 TI - Lasso peptides: structure, function, biosynthesis, and engineering. AB - Lasso peptides are a class of ribosomally-synthesized and posttranslationally modified natural products with diverse bioactivities. This review describes the structure and function of all known lasso peptides (as of mid-2012) and covers our current knowledge about the biosynthesis of those molecules. The isolation and characterization of lasso peptides are also covered as are bioinformatics strategies for the discovery of new lasso peptides from genomic sequence data. Several studies on the engineering of new or improved function into lasso peptides are highlighted, and unanswered questions in the field are also described. PMID- 22833143 TI - Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-kappaB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-kappaB pathway. METHODS: We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. CONCLUSION: Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis. PMID- 22833150 TI - Growth inhibitory effect of dihydroartemisinin on Bcr/Abl+ chronic myeloid leukemia K562 cells involve AKT, ERK and NF-kappaB modulation. AB - PURPOSE: In our previous publication, we have shown that dihydroartemisinin could significantly inhibit the growth of CML K562 cells by its anti-proliferative and inducing apoptotic effects. Given the pivotal effect of Bcr/Abl tyrosine kinase and its downstream signal factors on CML cell proliferation and survival, we extend our study to investigate the effect of DHA on Bcr/Abl and related signal factors to further illuminate the possible mechanisms of the effect of DHA on CML cells. METHODS: The expression of Bcr/Abl was analyzed with PCR and Western blotting methods at both mRNA and protein levels. Measurement of protein expression and tyrosine phosphorylation activity of Bcr/Abl, AKT, ERK1/2, NF kappaB and cytochrome c were performed with Western blotting and immunoprecipitation methods. Using the activity kits analyzed the activity of caspase 9 and caspase 3. RESULTS: The treatment with DHA results in a significant suppression on Bcr/Abl expression and leads to a concentration-dependent reduction on the Bcr/Abl tyrosine activity. Moreover, it also results in a strong influence on the downstream signal factors of Bcr/Abl, which includes inhibition of tyrosine kinase activity of AKT and ERK1/2, suppression of NF-kappaB protein expression, promotion of the cytochrome c release and the consequential activation of caspase 3/9 in CML K562 cells. CONCLUSIONS: Together with our previous report, our data show that the growth inhibitory effect of DHA on CML cells might be due to the influence on Bcr/Abl expression and its downstream signal factors. DHA might be a potential novel anti-CML drug candidate and worthy of further study. PMID- 22833151 TI - Photoinduced electron transfers in zeolites: impact of the aluminum content on the activation energies. AB - We report the activation energy determination corresponding to the recombination of the radical cation electron moiety created through photoionization of the 1,6 diphenyl-1,3,5-hexatriene molecule incorporated in ZSM-5 zeolite channels. We demonstrate that the charge separated state stabilization in zeolite does not depend only on the Al content but also on the Al repartition. PMID- 22833152 TI - The Hearing Handicap Inventory for Elderly-Screening (HHIE-S) versus a single question: reliability, validity, and relations with quality of life measures in the elderly community, Japan. AB - PURPOSE: Little is known about the usefulness of the Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) and a single question (SQ) in assessing hearing impairment (HI) and the impact of HI on quality of life (QOL). The objective of this study was to examine the reliability, validity, and associations with QOL measures (i.e., subjective well-being, depressive symptoms, subjective loneliness, and physical functioning) of the HHIE-S and the SQ in the elderly community. METHODS: A self-report questionnaire including HHIE-S, SQ, Philadelphia Geriatric Center Morale Scale, Geriatric Depression Scale, UCLA Loneliness Scale, and the Tokyo Metropolitan Institute of Gerontology Index of Competence was administered to community elderly (781 males and 950 females). Among them, 97 males and 100 females also responded voluntarily to a request for test-retest and auditory tests. The criterion validity was tested by using pure tone averages. RESULTS: Regarding the reliability of HHIE-S, Cronbach's alpha coefficient was 0.91, Spearman-Brown coefficient was 0.90, and intra-class correlation coefficient was 0.85. Regarding the test-retest reliability of SQ, kappa coefficient was 0.65. HHIE-S had significantly lower sensitivity in identifying >25-dB HI, but significantly higher specificity for the detection of >40-dB HI than SQ. HHIE-S had stronger associations with QOL measures than did SQ. CONCLUSIONS: HHIE-S had high reliability, while SQ had insufficient reliability. HHIE-S was more specific in detecting HI and more sensitive in assessing the impact of HI on QOL than SQ. HHIE-S is a more effective instrument for assessing HI and QOL research than SQ in the elderly community. PMID- 22833153 TI - Bubble Jet agent release cartridge for chemical single cell stimulation. AB - We present a new method for the distinct specific chemical stimulation of single cells and small cell clusters within their natural environment. By single-drop release of chemical agents with droplets in size of typical cell diameters (d <30 MUm) on-demand micro gradients can be generated for the specific manipulation of single cells. A single channel and a double channel agent release cartridge with integrated fluidic structures and integrated agent reservoirs are shown, tested, and compared in this publication. The single channel setup features a fluidic structure fabricated by anisotropic etching of silicon. To allow for simultaneous release of different agents even though maintaining the same device size, the second type comprises a double channel fluidic structure, fabricated by photolithographic patterning of TMMF. Dispensed droplet volumes are V = 15 pl and V = 10 pl for the silicon and the TMMF based setups, respectively. Utilizing the agent release cartridges, the application in biological assays was demonstrated by hormone-stimulated premature bud formation in Physcomitrella patens and the individual staining of one single L 929 cell within a confluent grown cell culture. PMID- 22833154 TI - A high-speed, high-performance on-chip integrated reverse transcription (RT) microchip. AB - This report introduces an on-chip integrated reverse transcription (RT) microchip, which includes two genetic functionalities of RNA extraction and cDNA synthesis. In the RNA extraction compartment, RNA is extracted from peripheral blood lysate within 1 min, by lateral magnetophoresis using magnetic oligo-dT beads. The extracted RNA is then collected and used directly to produce cDNA in the cDNA synthesis microchamber, which is monolithically integrated with the RNA extraction compartment. To verify the superiority of the proposed RT-microchip, RT-PCR amplification was performed using cDNA harvested from the RT-microchip, and the results were compared with those obtained using typical RNA extraction methods such as a silica matrix column and magnetic oligo-dT beads. The RT-PCR amplification results using 100 MUl of blood showed that the intensity of the bands in gel electrophoresis of the RT-microchip was 2-fold stronger than that of the silica matrix column and 2.65-fold stronger than that of the magnetic oligo dT beads. The results demonstrate that the RT-microchip technique is the most sensitive of the tested methods. PMID- 22833155 TI - An optimized hollow microneedle for minimally invasive blood extraction. AB - The healthcare system relies widely on biochemical information obtained from blood sample extracted via hypodermic needles, despite the invasiveness and pain associated with this procedure. Therefore, an alternative micro-scale needle for minimally invasive blood sampling is highly desirable. Traditional fabrication techniques to create microneedles do not generate needles with the combined features of a sharp tip, long length, and hollow structure concurrently. Here, we report the fabrication of a microneedle long enough to reach blood vessels and sharp enough to minimize nerve contact for minimally invasive blood extraction. The microneedle structure was precisely controlled using a drawing lithography technique, and a sharp tip angle was introduced using a laser-cutting system. We investigated the characteristics of a microneedle with a length of 1,800 MUm length, an inner diameter of 60 MUm, a tip diameter of 120 MUm, and a 15 degrees bevel angle through in-vitro liquid extraction and mechanical strength analysis. We demonstrated that the proposed structure results in blood extraction at a reasonable rate, and that a microneedle with this geometry can reliably penetrate skin without breaking. We integrated this microneedle into a blood extraction device to extract a 20 MUl volume of mouse blood in-vivo. Our optimized, hollow microneedle can potentially be incorporated with other cutting-edge technologies such as microactuators, biosensors, and microfluidic chips to create blood analysis systems for point-of-care diagnostics. PMID- 22833156 TI - A MEMS electrochemical bellows actuator for fluid metering applications. AB - We present a high efficiency wireless MEMS electrochemical bellows actuator capable of rapid and repeatable delivery of boluses for fluid metering and drug delivery applications. Nafion(r)-coated Pt electrodes were combined with Parylene bellows filled with DI water to form the electrolysis-based actuator. The performance of actuators with several bellows configurations was compared for a range of applied currents (1-10 mA). Up to 75 boluses were delivered with an average pumping flow rate of 114.40 +/- 1.63 MUL/min. Recombination of gases into water, an important factor in repeatable and reliable actuation, was studied for uncoated and Nafion(r)-coated actuators. Real-time pressure measurements were conducted and the effects of temperature, physiological back pressure, and drug viscosity on delivery performance were investigated. Lastly, we present wireless powering of the actuator using a class D inductive powering system that allowed for repeatable delivery with less than 2 % variation in flow rate values. PMID- 22833157 TI - Synthesis of new poly(ether-urethane-urea)s based on amino acid cyclopeptide and PEG: study of their environmental degradation. AB - Conventional polyurethanes (PUs) are among biomaterials not intended to degrade but are susceptible to hydrolytic, oxidative and enzymatic degradation in vivo. Biodegradable PUs are typically prepared from polyester polyols, aliphatic diisocyanates and chain extenders. In this work we have developed a degradable monomer based on alpha-amino acid to accelerate hard segment degradation. Thus a new class of degradable poly(ether-urethane-urea)s (PEUUs) was synthesized via direct reaction of 4,4'-methylene-bis(4-phenylisocyanate) (MDI), L-leucine anhydride (LA) and polyethylene glycol with molecular weight of 1,000 (PEG-1000) as polyether soft segment. The resulting polymers are environmentally biodegradable and thermally stable. Decomposition temperatures for 5 % weight loss occurred above 300 degrees C by TGA in nitrogen atmospheres. Some structural characterization and physical properties of these polymers before and after degradation in soil, river water and sludge are reported. The environmental degradation of the polymer films was investigated by SEM, FTIR, TGA, DSC, GPC and XRD techniques. A significant rate of degradation occurred in PEUU samples under river water and sludge condition. The polymeric films were not toxic to E. coli (Gram negative), Staphylococcus aureus and Micrococcus (Gram positive) bacteria and showed good biofilm formation on polymer surface. Our results show that hard segment degraded selectively as much as soft segment and these polymers are susceptible to degradation in soil and water. Thus our study shows that new environment-friendly polyurethane, which can degrade in soil, river water and sludge, is synthesized. PMID- 22833158 TI - Evaluation of a technetium-99m labeled bombesin homodimer for GRPR imaging in prostate cancer. AB - Multimerization of peptides can improve the binding characteristics of the tracer by increasing local ligand concentration and decreasing dissociation kinetics. In this study, a new bombesin homodimer was developed based on an epsilon aminocaproic acid-bombesin(7-14) (Aca-bombesin(7-14)) fragment, which has been studied for targeting the gastrin-releasing peptide receptor (GRPR) in prostate cancer. The bombesin homodimer was conjugated to 6-hydrazinopyridine-3-carboxylic acid (HYNIC) and labeled with (99m)Tc for SPECT imaging. The in vitro binding affinity to GRPR, cell uptake, internalization and efflux kinetics of the radiolabeled bombesin dimer were investigated in the GRPR-expressing human prostate cancer cell line PC-3. Biodistribution and the GRPR-targeting potential were evaluated in PC-3 tumor-bearing athymic nude mice. When compared with the bombesin monomer, the binding affinity of the bombesin dimer is about ten times lower. However, the (99m)Tc labeled bombesin dimer showed a three times higher cellular uptake at 4 h after incubation, but similar internalization and efflux characters in vitro. Tumor uptake and in vivo pharmacokinetics in PC-3 tumor bearing mice were comparable. The tumor was visible on the dynamic images in the first hour and could be clearly distinguished from non-targeted tissues on the static images after 4 h. The GRPR-targeting ability of the (99m)Tc labeled bombesin dimer was proven in vitro and in vivo. This bombesin homodimer provides a good starting point for further studies on enhancing the tumor targeting activity of bombesin multimers. PMID- 22833159 TI - Comparison of arterial stiffness indices measured by the Colins and SphygmoCor systems. AB - Arterial stiffness is a known independent predictor of cardiovascular mortality. The Colins system is an easy device and has gained widespread use, but the cutoff value for high-risk central arterial stiffness is not well established. We investigated the correlation between arterial stiffness measured by the Colins system with conventional measurements from the SphygmoCor system. Arterial pulse wave velocity (PWV) and augmentation indices (AIs) were measured on a single visit using two different devices in 948 patients with hypertension or coronary artery disease. Strong positive correlations were observed for PWV values measured by the SphygmoCor and Colins systems. The Colins system measurements accurately predicted high-risk central arterial stiffness, defined as carotid femoral PWV>=12 m s(-1), with an area under the receiver-operating characteristic curve (AUC) of 0.884 (heart-femoral PWV, hfPWV) and 0.830 (brachial-ankle PWV, baPWV) in the training set (N=664). The cutoff values, 11.18 (hfPWV) and 16.17 m s(-1) (baPWV), showed good discrimination in the validation set (N=284), with sensitivity of 83.3 (hfPWV) and 76.0% (baPWV), and specificity of 74.9 (hfPWV) and 82.6% (baPWV). The SphygmoCor and Colins AI systems also showed moderate positive correlation. The Colins AI system better predicted high-risk central pulse pressure as defined by pulse pressure>=50 mm Hg (AUC: Colins, 0.765; SphygmoCor, 0.692; P=0.011). Arterial stiffness measured by the Colins system showed strong positive correlation and agreement with the SphygmoCor system measurement. Cutoff values for high-risk central arterial stiffness in the Colins system need further validation in a prospective study. PMID- 22833160 TI - Response to Fujisawa: elevated blood pressure in different populations: the role of dietary salt consumption. PMID- 22833161 TI - Low daily salt intake is correlated with albuminuria in patients with type 2 diabetes. AB - Both high and low salt intakes have been reported to be associated with an increased risk of cardiovascular events. The aim of this study was to investigate the relationship between daily salt intake and albuminuria, a marker of diabetic nephropathy and cardiovascular disease, in patients with type 2 diabetes. We classified 270 patients with type 2 diabetes, who were not receiving antihypertensive medication into four groups according to their daily salt intake (<8, 8-10, 10-12 and >12 g per day). We investigated the relationship between daily salt intake and the logarithm of urinary albumin excretion (UAE). A multivariate linear regression analysis was used to evaluate whether daily salt intake independently correlated with the logarithm of UAE. In addition, we assessed the contribution of the variables, including age, sex, duration of diabetes, body mass index, systolic blood pressure, hemoglobin A(1C), low-density lipoprotein cholesterol, triglycerides, serum creatinine, alcohol intake, smoking status and square of (daily salt intake-10) on albuminuria, defined as a UAE>30 mg g(-1) of creatinine, using a multiple logistic regression analysis. The logarithm of the UAE was lowest in the third quartile of daily salt intake. The multivariate linear regression analysis demonstrated that the logarithm of the UAE was significantly correlated with the quadratic term of daily salt intake centered at 10 g per day (beta=0.170, P=0.008). The multivariate logistic regression analysis demonstrated that the odds ratio (95% confidence interval) of albuminuria was 3.996 (1.295-12.327; P=0.016) in patients whose daily salt intake was less than 8 g per day compared with patients whose daily salt intake was 10 12 g per day. In conclusion, low daily salt intake was correlated with albuminuria in patients with type 2 diabetes, who were not receiving antihypertensive medication. PMID- 22833162 TI - Syntheses, structure, and magnetic properties of hexanuclear Mn(III)(2)M(III)(4) (M = Y, Gd, Tb, Dy) complexes. AB - The synthesis and characterizations of a family of isomorphous [Mn(III)(2)M(III)(4)L(2)(MU(4) O)(2)(N(3))(2)(CH(3)O)(2)(CH(3)OH)(4)(NO(3))(2)].2H(2)O (M = Y(1), Gd(2), Tb(3), Dy(4)) are reported, where H(4)L = N,N'-dihydroxyethyl-N,N'-(2-hydroxy-4,5 dimethylbenzyl)ethylenediamine. They were obtained from the reactions of H(4)L with M(NO(3))(3).6H(2)O, Mn(ClO(4))(2).6H(2)O, NaN(3) and NEt(3) in a 1:1:1:2:2 molar ratio. The core structure consists of a Mn(2)M(4) unit. The four M(III) ions that are held together by two MU(4)-bridging oxygen atoms form a butterfly M(4) moiety. The M(4) core is further connected to the two five-coordinate trigonal-bipyramidal Mn(III) ions via one MU(4)-O(2-), two alkyloxo and one methoxo triple bridges. Magnetic susceptibility measurements indicate the presence of intramolecular antiferromagnetic interactions in complex 2, and overall intramolecular ferromagnetic interactions in complexes 3 and 4. The alternating current (AC) magnetic susceptibility studies revealed that complexes 3 and 4 showed frequency-dependent out-of-phase signals, which indicates that they exhibit slow relaxation of the magnetization. PMID- 22833163 TI - [Hereditary macular dystrophies in differential diagnosis of AMD]. AB - The onset of hereditary macular dystrophies may occur at all ages and may be the origin of visual disturbances even after the age of 50 years. During the disease course, many macular dystrophies change their fundus appearance, finally leading to a geographic chorioretinal atrophy making it difficult to distinguish the disease form dry AMD. Furthermore, a macular dystrophy associated CNV may be misleading to the diagnosis of wet AMD. Additional fundus autofluorescence and optical coherence tomography imaging are very valuable for delineating macular dystrophies from AMD. In this paper we provide an overview of the important hereditary macular dystrophies which should be considered as differential diagnoses for AMD. PMID- 22833164 TI - [Polypoidal choroidal vasculopathy]. AB - Polypoidal choroidal vasculopathy (PCV) is a disease that was first described almost 30 years ago. The disease is characterised by alterations of the posterior pole such as serous or serosanguineous detachments of the retina or the retinal pigment epithelium (RPE) around the optic nerve or in the central macula. The optimal therapeutic regime remains unclear. There are several studies suggesting that patients who do not respond satisfactorily to intravitreal anti-VEGF treatment are suffering from PCV which can be detected by indocyanine green angiography. Alternative therapeutic options consist of photodynamic therapy or laser photocoagulation for extrafoveal lesions. PMID- 22833165 TI - Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with systemic lupus erythematosus and Behcets disease. AB - PURPOSE: The aim of the present study was to investigate plasma concentrations of Gas6 and its soluble tyrosine kinase receptor sAxl in Systemic lupus erythematosus (SLE) and Behcets disease (BD) patients and to correlate those levels with clinical and laboratory manifestations of the diseases. METHODS: The study included 89 female SLE and 49 male BD patients. Twenty-seven age and sex matched healthy volunteers served as controls. All patients were subjected to full clinical examination, laboratory investigations and assessment of disease activity. Plasma concentrations of Gas6 and sAxl were quantified using ELISA technique. RESULTS: The level of Gas6 and Axl were significantly altered in the SLE patients (p < 0.001) and in the BD patients (p 0.001 and 0.04 respectively) compared to those of the control. In SLE, the Gas6 was remarkably lower in those with class 1 lupus nephritis and in those with neuropsychiatric manifestations. In the BD patients, the level of Axl was significantly increased in those with neurological disease activity. The number of lymphocytes significantly negatively correlated with the gas6 and Axl levels significantly correlated with the number of neutrophils and negatively with the lymphocytic count in the BD patients. CONCLUSION: The plasma concentrations of Gas6 and Axl were significantly altered in SLE and BD patients, suggesting that the Axl receptor shedding is an active process affected by and influences Gas6-mediated Axl-signaling in both diseases. Special attention is required in SLE patients with early lupus nephritis and neuropsychiatric manifestations and BD patients presenting with neurological disease activity. The relation with lymphocytes and neutrophils in BD throws light on the role of gas6 and Axl on their known resistance to cell death. Although the mechanisms responsible for the initiation of BD remain to be clarified, the role of the apoptotic process seems critical throughout the disease. PMID- 22833166 TI - Mannose-binding lectin levels and variation during invasive candidiasis. AB - The high morbi-mortality associated with invasive candidiasis (IC) is a persistent problem in hospitals. Mannose-binding lectin (MBL) plays a role in innate immunity through its interaction with mannosylated molecules of Candida albicans. A correlation between MBL deficiency and vulvovaginal candidiasis or peritonitis has been reported. We investigated circulating MBL levels and their evolution during the course of IC. Sixty-eight patients with proven IC, 82 hospitalized patients (HP) without evidence of infection, and 70 healthy subjects (HS) were studied in order to examine the relationship between serum MBL and IC. Serum MBL levels were measured by enzyme-linked immunosorbent assay (ELISA). MBL levels were significantly higher in IC patients than in HP and HS (p < 0.0001, p < 0.0055, respectively). A change in MBL concentrations was observed during the course of IC, with a dramatic decrease during the 2 days before positive blood culture sampling. This decrease was concomitant with the presence of high levels of circulating mannan (Mn). Like MBL levels, anti-mannan antibodies (AMn) increased after the mannanemia/blood culture period. These findings suggest a possible role of MBL during the early stage of IC. The mechanisms that regulate these observations in terms of effect and consequences on innate and adaptive immunity and the prognosis of IC require further investigation. PMID- 22833167 TI - Potential roles of interleukin-17A in the development of skin fibrosis in mice. AB - OBJECTIVE: Although transforming growth factor beta (TGFbeta) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of skin fibrosis. METHODS: To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-gamma (IFNgamma), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice. RESULTS: The loss of IL-17A significantly attenuated bleomycin-induced skin fibrosis, whereas a deficiency of IFNgamma or IL-4 did not. Leukocyte infiltration and the expression of TGFbeta and CTGF messenger RNA in bleomycin-injected skin were significantly reduced in IL-17A-deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a skin fibroblast cell line expressed increased TGFbeta, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated skin thickness in TSK-1 mice. CONCLUSION: This study demonstrates that IL-17A contributes to skin fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic skin disorders such as SSc. PMID- 22833168 TI - Recent advances in the development of new transgenic animal technology. AB - Transgenic animal technology is one of the fastest growing biotechnology areas. It is used to integrate exogenous genes into the animal genome by genetic engineering technology so that these genes can be inherited and expressed by offspring. The transgenic efficiency and precise control of gene expression are the key limiting factors in the production of transgenic animals. A variety of transgenic technologies are available. Each has its own advantages and disadvantages and needs further study because of unresolved technical and safety issues. Further studies will allow transgenic technology to explore gene function, animal genetic improvement, bioreactors, animal disease models, and organ transplantation. This article reviews the recently developed animal transgenic technologies, including the germ line stem cell-mediated method to improve efficiency, gene targeting to improve accuracy, RNA interference-mediated gene silencing technology, zinc-finger nuclease gene targeting technology and induced pluripotent stem cell technology. These new transgenic techniques can provide a better platform to develop transgenic animals for breeding new animal varieties and promote the development of medical sciences, livestock production, and other fields. PMID- 22833169 TI - Vascular endothelial growth factor signaling in acute myeloid leukemia. AB - This review is designed to provide an overview of the current literature concerning vascular endothelial growth factor signaling (VEGF) in acute myeloid leukemia (AML). Aberrant VEGF signaling operates in the bone marrow of AML patients and is related to a poor prognosis. The altered signaling pathway demonstrated to interfere in several autocrine and paracrine signaling pathways. VEGF signaling promotes autocrine AML blast cell proliferation, survival, and chemotherapy resistance. In addition, VEGF signaling can mediate paracrine vascular endothelial cell-controlled angiogenesis in AML. Both effects presumably explain the association of high VEGF levels and poor therapeutic outcome. More recently, researches focusing on bone marrow stem cell niches demonstrate a role for VEGF signaling in the preservation of several cell types within these niches. The bone marrow niches are proposed to be a protective microenvironment for AML cells that could be responsible for relapses in AML patients. This implies the need of sophisticated VEGF-targeted therapeutics in AML therapy strategies. This review highlights our current understanding of aberrant VEGF signaling in AML, appoints the interference of VEGF signaling in the AML-associated microenvironment, and reflects the novelty of current VEGF-targeted therapeutics used in clinical trails for the treatment of AML. PMID- 22833170 TI - Molecular mechanisms of desiccation tolerance in resurrection plants. AB - Resurrection plants are a small but diverse group of land plants characterized by their tolerance to extreme drought or desiccation. They have the unique ability to survive months to years without water, lose most of the free water in their vegetative tissues, fall into anabiosis, and, upon rewatering, quickly regain normal activity. Thus, they are fundamentally different from other drought surviving plants such as succulents or ephemerals, which cope with drought by maintaining higher steady state water potential or via a short life cycle, respectively. This review describes the unique physiological and molecular adaptations of resurrection plants enabling them to withstand long periods of desiccation. The recent transcriptome analysis of Craterostigma plantagineum and Haberlea rhodopensis under drought, desiccation, and subsequent rehydration revealed common genetic pathways with other desiccation-tolerant species as well as unique genes that might contribute to the outstanding desiccation tolerance of the two resurrection species. While some of the molecular responses appear to be common for both drought stress and desiccation, resurrection plants also possess genes that are highly induced or repressed during desiccation with no apparent sequence homologies to genes of other species. Thus, resurrection plants are potential sources for gene discovery. Further proteome and metabolome analyses of the resurrection plants contributed to a better understanding of molecular mechanisms that are involved in surviving severe water loss. Understanding the cellular mechanisms of desiccation tolerance in this unique group of plants may enable future molecular improvement of drought tolerance in crop plants. PMID- 22833171 TI - Species difference of esterase expression and hydrolase activity in plasma. AB - Differences in esterase expression among human, rhesus monkey, cynomolgus monkey, dog, minipig, rabbit, rat, and mouse plasma were identified using native polyacrylamide gel electrophoresis. Paraoxonase (PON) and butyrylcholinesterase (BChE) were ubiquitous in all species, but were highly expressed in primates and dogs, whereas carboxylesterase (CES) was only abundant in rabbits, mice, and rats. Several unknown esterases were observed in minipig and mouse plasma. These differences in plasma esterases and their expression levels result in species differences with respect to hydrolase activity. These differences were characterized using several different substrates. In contrast to the high hydrolase activity found for p-nitrophenylacetate (PNPA), a substrate of several hydrolase enzymes, irinotecan, a carbamate compound, was resistant to all plasma esterases. Oseltamivir, temocapril, and propranolol (PL) derivatives were rapidly hydrolyzed in mouse and rat plasma by their highly active CES enzyme, but rabbit plasma CES hydrolyzed only the PL derivatives. Interestingly, PL derivatives were highly hydrolyzed by monkey plasma BChE, whereas BChE from human, dog, and minipig plasma showed negligible activity. In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma. These differences should be considered when selecting model animals for preclinical studies. PMID- 22833173 TI - Quality improvement guidelines for imaging detection and treatment of endoleaks following endovascular aneurysm repair (EVAR). AB - Major concerns after aortic aneurysm repair are caused by the presence of endoleaks, which are defined as persistent perigraft flow within the aortic aneurysm sac. Diagnosis of endoleaks can be performed with various imaging modalities, and indications for treatment are based on further subclassifications. Early detection and correct classification of endoleaks are crucial for planning patient management. The vast majority of endoleaks can be treated successfully by interventional means. Guidelines for Imaging Detection and Treatment of endoleaks are described in this article. PMID- 22833174 TI - Inactivation of bacteria in plasma. AB - The photo-inactivation rate of bacteria by methylene blue, MB, was found to be significantly lower in plasma than in water, saline, and PBS solutions. The spectroscopic data and ultrafast time resolved transient spectra and kinetics presented show that methylene blue photo-bleaches faster and to a larger degree in plasma and the MB excited singlet and triplet state populations in plasma are much lower in plasma than in water and PBS solutions. The optical density, OD, of MB in plasma was found to decrease by ~50% after a minute of illumination with 661 nm light, while under identical conditions the OD in PBS solution decreased by only 1%. Based on these data and the effect of the plasma proteins on MB photochemistry, a mechanism is proposed that accounts for the low inactivation rate of bacteria in plasma. PMID- 22833175 TI - Peripheral microcirculation is affected during therapeutic hypothermia in newborns. AB - BACKGROUND: Hypothermia is becoming a common treatment for newborns with hypoxic ischaemic encephalopathy. Cerebral metabolic effects have been studied extensively. However, acute effects on peripheral microcirculation are unknown. The effects of therapeutic hypothermia on peripheral microcirculation assessed by side-stream dark field (SDF) imaging technique are presented. METHODS: Peripheral microcirculation was assessed in seven newborns undergoing selective head-cooling treatment with SDF imaging video recordings during core temperature 34 degrees C, and then after re-warming at 37 degrees C, and also in seven control patients with rectal temperature 37 degrees C. Microvascular flow index (MFI) and per cent of vessels with sluggish flow were determined by using appropriate software. RESULTS: Sluggish microcirculation was observed during hypothermia compared with controls. MFI and per cent of vessels with sluggish flow returned to normal after re-warming. CONCLUSIONS: The results of this small group of newborns going through therapeutic hypothermia suggests that microcirculation is effected with this treatment. Whether this finding has other clinical impacts requires further research. PMID- 22833172 TI - Effects of omega-3 fatty acids on progestin stimulation of invasive properties in breast cancer. AB - Clinical studies have shown that progestins increase breast cancer risk in hormone replacement therapy, while we and others have previously reported that progestins stimulate invasive properties in progesterone receptor (PR)-rich human breast cancer cell lines. Based on others' reports that omega-3 fatty acids inhibit metastatic properties of breast cancer, we have reviewed the literature for possible connections between omega-3 fatty-acid-driven pathways and progestin stimulated pathways in an attempt to suggest theoretical mechanisms for possible omega-3 fatty acid inhibition of progestin stimulation of breast cancer invasion. We also present some data suggesting that fatty acids regulate progestin stimulation of invasive properties in PR-rich T47D human breast cancer cells, and that an appropriate concentration of the omega-3 fatty acid eicosapentaenoic acid inhibits progestin stimulation of invasive properties. It is hoped that focus on the inter-relationship between pathways by which omega-3 fatty acids inhibit and progestins stimulate breast cancer invasive properties will lead to further in vitro, in vivo, and clinical studies testing the hypothesis that omega-3 fatty acids can inhibit progestin stimulation of invasive properties in breast cancer, and ameliorate harmful effects of progestins which occur in combined progestin estrogen hormone replacement therapy. PMID- 22833176 TI - Essential oil components from Asarum sieboldii Miquel are toxic to the house dust mite Dermatophagoides farinae. AB - In our effort to develop novel plant-derived acaricides, we examined the contact and fumigant toxicity of Asarum heterotropoides (Asarum sieboldii Miquel) essential oil constituents to the house dust mite Dermatophagoides farinae (Acari: Pyroglyphidae). Ten constituents, including methyl eugenol (relative amount 42.18 %), were identified by gas chromatography-mass spectroscopy (GC-MS) in the A. sieboldii Miq. essential oil. In contact toxicity tests, methyl eugenol (4.2 MUg/cm(2), 24 h LD50) was most toxic to D. farinae, followed by benzyl benzoate (9.1 MUg/cm(2)), A. sieboldii Miq. essential oil (37.7 MUg/cm(2)), and dibutyl phthalate (DBP 57.9 MUg/cm(2)). The potency of methyl eugenol and A. sieboldii Miq. essential oil was higher than benzyl benzoate and DBP, with mortalities of 100, 100, 94.6, and 13.2 %, respectively, after 2.5 h of exposure. In the vapor phase mortality bioassay, methyl eugenol and A. sieboldii Miq. essential oil resulted in 100 % mortality in closed containers after 24-h exposure, but only 4.7 and 7.9 %, respectively, in open containers, indicating that the toxicity in these tests was largely due to the vapor phase. Methyl eugenol and A. sieboldii Miq. essential oil merit further study as potential D. farinae control compounds. PMID- 22833177 TI - Toxicity of methyl tertiary-butyl ether (MTBE) following exposure of Wistar Rats for 13 weeks or one year via drinking water. AB - Thirteen-week and one-year toxicity studies of methyl tertiary-butyl ether (MTBE) administered in drinking water to Wistar rats were conducted. Male and female rats were exposed to MTBE in drinking water at 0.5, 3, 7.5 and 15 mg ml(-1) for 13 weeks and at 0.5, 3 and 7.5 (males) or 0.5, 3 and 15 mg ml(-1) (females) for 1 year. Body weights were reduced only in males following 13 weeks of exposure. Reduced water consumption and urine output were observed in males and females exposed to MTBE. Kidney cell replication and alpha(2u)-globulin levels in males were increased at 1 and 4 weeks of MTBE exposure and tubular cell regeneration was increased in male kidneys exposed to MTBE concentrations of 7.5 mg ml(-1) or greater for 13 weeks. Wet weights of male kidneys were increased following 13 weeks, 6 months and 1 year of exposure to MTBE concentrations of 7.5 mg ml(-1) or greater. Kidney wet weights were increased in females at MTBE concentrations of 15 mg ml(-1) for 13 weeks. Tertiary-butyl alcohol blood levels increased linearly with dose in males and females following 1 year of exposure. Chronic progressive nephropathy (CPN), of minimal to mild severity, increased in males, but not females, with 1 year of MTBE exposure. In summary, exposure of Wistar rats to MTBE in the drinking water resulted in minimal exposure-related effects including limited renal changes in male rats suggestive of alpha(2u)-globulin nephropathy following 13 weeks of exposure and an exacerbation of CPN in males at the end of 1 year of exposure. PMID- 22833178 TI - Sjogren-Larsson syndrome in clinical practice. AB - This review article gives a state-of-the-art synopsis of current pathophysiological concepts in Sjogren-Larsson syndrome (SLS) mainly based upon original research data of the authors in one of the world's largest clinical SLS study cohorts. Clinical features are discussed in order of appearance, and diagnostic tests are set out to guide the clinician toward the diagnosis SLS. Furthermore, current and future treatment strategies are discussed to render a comprehensive review of the topic. PMID- 22833179 TI - Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. AB - BACKGROUND: The efficacy and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single-arm, open-label, multicenter trial. METHODS: Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received <= 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression-free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed. RESULTS: Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child-Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression-free rate at 16 weeks was 31.8% (34.2% for patients with Child-Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child-Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child Pugh class A hepatic function). The most common linifanib-related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib-related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome. CONCLUSIONS: Single-agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. PMID- 22833180 TI - Monitoring the microcirculation. AB - One of the main goals of hemodynamic support is to preserve tissue perfusion. However issue perfusion is related more to microvascular perfusion than aortic blood flow. Monitoring the microcirculation has long been difficult. Recent technologic advances have made feasible monitoring of the microcirculation at bedside of critically ill patients. In this review, we will discuss the relevance of the various tools available to monitor the microcirculation. Videomicroscopic devices such as sidestream darkfield imaging are the most appropriate techniques to evaluate the microcirculation, taking into account the heterogeneous aspect of diseased microcirculation, as in sepsis. The microcirculation can also be indirectly assessed by measuring tissue PCO2. Transcutaneous PCO2 measurement at ear lobe is particularly promising. Finally, near infrared spectroscopy can also provide interesting information, especially using vascular occlusion tests which reactivity of the microcirculation to a transient hypoxic insult. These different devices have provided important data helping us to better understand the pathophysiology of sepsis and multiple organ failure. PMID- 22833181 TI - Colloidal graphenes as heterogeneous additives to enhance protein crystal yield. AB - In the structural analysis of proteins via X-ray diffraction, a rate-limiting step is in favourable nucleation, a problematic obstacle in successful generation of protein crystals. Here graphene and graphene oxide were applied to protein crystallisation trials, offering improvements in crystalline output and nucleation. PMID- 22833182 TI - Myocardial infarction changes sphingolipid metabolism in the uninfarcted ventricular wall of the rat. AB - It is known that the ratio, the level of sphingosine-1-phosphate (S1P)/the level of ceramide (CER) determines survival of the cells. The aim of the present study was to examine the effect of myocardial infarction on the level of different sphingolipids in the uninfarcted area. The experiments were carried out on male Wistar rats: 1, control; 2, after ligation of the left coronary artery (infarct) and 3, sham operated. Samples of the uninfarcted area of the left ventricle were taken in 1, 6 and 24 h after the surgery. The level of sphingolipids, S1P, CER, sphingosine (SPH), sphinganine-1-phosphate (SPA1P) and sphinganine (SPA) was determined. The control values were (ng/mg), S1P-0.33 +/- 0.03, SPH-1.02 +/- 0.13, SPA1P-0.11 +/- 0.01, SPA-0.28 +/- 0.04, total CER-20.3 +/- 1.8. In infarct, the level of S1P in the uninfarcted area was reduced by ~3 times in 1 and 6 h and decreased further in 24 h. The level of SPH decreased in 1 h and returned to the control thereafter. The total level of CER decreased in 6 h after the infarction. Sham surgery also produced changes in the level of certain sphingolipids. The ratio, the level of S1P/the level of CER was markedly reduced at each time point after the infarction. It is concluded that the reduction in the S1P/CER ratio could be responsible for increased apoptosis in the uninfarcted area after the myocardial infarction in the rat. PMID- 22833183 TI - Abnormal endothelial function in ED patients with normal nocturnal penile tumescence and rigidity: is it the role of psychogenic factors? AB - Underlying endothelial dysfunction (EnD) may present in the early stage of ED or psychogenic ED. We retrospectively evaluated 191 ED patients with effective nocturnal penile tumescence and rigidity (NPTR) recording, including detailed medical and psychosexual history, International Index of Erectile Function-5 and vascular parameter. All patients were allocated into psychogenic and organic groups according to the NPTR test. Brachial artery flow-mediated dilation (FMD) was used to diagnose EnD, and ED patients were classified into two groups: non EnD (FMD?10) and EnD (FMD<10). General and vascular parameters were compared between psychogenic and organic groups, and non-EnD and EnD groups with ED were compared in terms of NPTR parameters. In all, 48.7% and 51.3% patients were diagnosed as psychogenic and organic ED, respectively. 73.1% of the psychogenic patients had EnD and 39.8% organic patients had normal endothelial function. In all parameters, only the FMD value showed significant difference between psychogenic and organic ED groups (8.26+/-2.57 vs 9.16+/-2.76, P=0.020). No statistical difference was founded in NPTR parameters between non-EnD and EnD groups (P>0.05). In conclusion, NPTR cannot effectively identify the underlying vasculogenic ED from psychogenic ED. Psychogenic causes may cause or aggravate EnD in these ED patients with normal NPTR. PMID- 22833184 TI - Rapid exploration of curing process design space for production of controlled release pellets. AB - Time and cost are among the most often cited hurdles limiting the rate and extent of adoption of Quality by Design (QbD) and Process Analytical Technology. In this article, we demonstrate that, with appropriate techniques, a key QbD element can be achieved with amount of resources comparable to classical development approach. To control the dissolution rate of a highly soluble drug substance from latex polymer coated pellets, we have examined the effect of key variables affecting the curing process step by an experimental design study. To explore and characterize the Design Space, we have produced and tested 62 distinct pellet samples. To achieve this in a reasonable amount of time, we have developed a scaled-down automated dissolution method that demonstrated excellent correlation to the classical method. By careful planning of experimentation, we were able to obtain all samples from just two batches of pellet cores. The curing process Design Space was explored by statistical modeling of samples obtained from the first batch. Robustness and repeatability of the Design Space at the edge of failure was preliminarily investigated by analysis of selected samples from the second batch with encouraging results. PMID- 22833185 TI - Nanoscale manganese oxide within Faujasite zeolite as an efficient and biomimetic water oxidizing catalyst. AB - Nanoscale manganese oxides within Faujasite zeolite have been synthesized with a simple method and characterized by scanning electron microscopy, X-ray diffraction spectrometry, N(2) adsorption-desorption isotherms, transmission electron microscopy, and atomic absorption spectroscopy. These oxides showed efficient water oxidizing activity in the presence of cerium(IV) ammonium nitrate as a non-oxo transfer oxidant. PMID- 22833186 TI - Effect of nonsteroidal antiinflammatory drugs on the C-reactive protein level in rheumatoid arthritis: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the effects of oral nonsteroidal antiinflammatory drugs (NSAIDs) on C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients, with a prespecified focus on the different NSAIDs. METHODS: We performed a systematic search in Medline via PubMed, the Cochrane Central Register of Controlled Trials, EMBase via OVID, the Institute for Scientific Information Web of Science, and other sources. Eligible trials were parallel group, randomized, placebo-controlled trials of oral NSAID therapy in RA patients for which there were extractable CRP data. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated from the differences in means of CRP levels between groups (active treatment minus placebo) divided by the pooled SDs. For the meta-analysis, a random-effects model was used to estimate the overall change in CRP level, and stratified analysis was used to examine differences among NSAIDs. RESULTS: We included 19 trials of 10 different NSAIDs. Overall, NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI 0.03, 0.06], P = 0.62). However, the prespecified stratified analysis indicated varying effects on the CRP level according to the different NSAIDs; lumiracoxib caused a statistically significant and consistent (I(2) = 0%) increase in the CRP level (SMD 0.13 [95% CI 0.01, 0.25], P = 0.037), whereas naproxen caused a statistically significant and consistent (I(2) = 0%) decrease in the CRP level (SMD -0.11 [95% CI -0.20, -0.02], P = 0.022). CONCLUSION: Overall, NSAIDs have no effect on the CRP level. However, the nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the cyclooxygenase 2 selective NSAID lumiracoxib was associated with a significant increase in the CRP level. This finding is interesting considering the suspected influence of NSAIDs on cardiovascular complications. PMID- 22833187 TI - Economic recession and first births in Europe: recession-induced postponement and recuperation of fertility in 14 European countries between 1970 and 2005. AB - OBJECTIVES: The economic crisis that emerged after 2008 caused speculation about further postponement of fertility and a recession-induced baby-bust in countries affected by the economic downturn. This paper aims to disentangle short-term and long-term effects of economic context on entry into parenthood and explores variation of postponement and recuperation by age, gender, educational level and welfare state context. METHODS: Random-effects complementary log-log models including macro-level indicators are used to analyse longitudinal microdata on 12,121 first births to 20,736 individuals observed between 1970 and 2005. RESULTS: Adverse economic conditions and high unemployment significantly reduce first birth hazards among men and women below age 30, particularly among the higher educated. After age 30 economic context continues to affect first birth hazards of men, but not for women. Recuperation of fertility is further associated with access to labour markets and entry into cohabiting unions. CONCLUSIONS: The continuing postponement of first births has clear medical consequences and implications for health policies. Preventive policies should take access to labour markets for younger generations into account as an important factor driving postponement. PMID- 22833188 TI - Mosaic DCX deletion causes subcortical band heterotopia in males. AB - Subcortical band heterotopia (SBH) is a neuronal migration disorder usually described in females carrying heterozygous mutations in the X-linked doublecortin (DCX) gene. Hemizygous DCX mutations in males result in lissencephaly. Recently, exonic deletions of DCX resulting in a severer form of agyria have been reported. Nevertheless, rare male patients with SBH have been described with somatic mosaicism of point mutations. Here, we identified a somatic mosaicism for a deletion of exon 4 in the DCX gene in a male patient with SBH detected prenatally. This finding points to the possible implication of mosaic deletions in the DCX gene in unexplained forms of SBH and may allow for detection of SBH prenatally. PMID- 22833189 TI - Ethics corner--case studies made simple: it is about the story! PMID- 22833190 TI - Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect 'for better and worse'. AB - Positive affect has been implicated in the phenomenological experience of various psychiatric disorders, vulnerability to develop psychopathology and overall socio emotional functioning. However, developmental influences that may contribute to positive affect have been understudied. Here, we studied youths' 5-HTTLPR genotype and rearing environment (degree of positive and supportive parenting) to investigate the differential susceptibility hypothesis (DSH) that youth carrying short alleles of 5-HTTLPR would be more influenced and responsive to supportive and unsupportive parenting, and would exhibit higher and lower positive affect, respectively. Three independent studies tested this gene-environment interaction (GxE) in children and adolescents (age range 9-15 years; total N=1874). In study 1 (N=307; 54% girls), positive/supportive parenting was assessed via parent report, in study 2 (N=197; 58% girls) via coded observations of parent-child interactions in the laboratory and in study 3 (N=1370; 53% girls) via self report. Results from all the three studies showed that youth homozygous for the functional short allele of 5-HTTLPR were more responsive to parenting as environmental context in a 'for better and worse' manner. Specifically, the genetically susceptible youth (that is, S'S' group) who experienced unsupportive, non-positive parenting exhibited low levels of positive affect, whereas higher levels of positive affect were reported by genetically susceptible youth under supportive and positive parenting conditions. These GxE findings are consistent with the DSH and may inform etiological models and interventions in developmental psychopathology focused on positive emotion, parenting and genetic susceptibility. PMID- 22833191 TI - Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia. AB - Genotype-phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype-phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS 'top-10' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Gottingen Research Association for Schizophrenia) Data Collection. We found that the 'top 10' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups. PMID- 22833192 TI - Deficient prefrontal attentional control in late-life generalized anxiety disorder: an fMRI investigation. AB - Younger adults with anxiety disorders are known to show an attentional bias toward negative information. Little is known regarding the role of biased attention in anxious older adults, and even less is known about the neural substrates of any such bias. Functional magnetic resonance imaging (fMRI) was used to assess the mechanisms of attentional bias in late life by contrasting predictions of a top-down model emphasizing deficient prefrontal cortex (PFC) control and a bottom-up model emphasizing amygdalar hyperreactivity. In all, 16 older generalized anxiety disorder (GAD) patients (mean age=66 years) and 12 non anxious controls (NACs; mean age=67 years) completed the emotional Stroop task to assess selective attention to negative words. Task-related fMRI data were concurrently acquired. Consistent with hypotheses, GAD participants were slower to identify the color of negative words relative to neutral, whereas NACs showed the opposite bias, responding more quickly to negative words. During negative words (in comparison with neutral), the NAC group showed PFC activations, coupled with deactivation of task-irrelevant emotional processing regions such as the amygdala and hippocampus. By contrast, GAD participants showed PFC decreases during negative words and no differences in amygdalar activity across word types. Across all participants, greater attentional bias toward negative words was correlated with decreased PFC recruitment. A significant positive correlation between attentional bias and amygdala activation was also present, but this relationship was mediated by PFC activity. These results are consistent with reduced prefrontal attentional control in late-life GAD. Strategies to enhance top-down attentional control may be particularly relevant in late-life GAD treatment. PMID- 22833193 TI - Excess of serotonin affects neocortical pyramidal neuron migration. AB - The serotonin transporter (SERT) is a key molecule involved in the homeostasis of extracellular levels of serotonin and is regulated developmentally. Genetic deletion of SERT in rodents increases extracellular levels of serotonin and affects cellular processes involved in neocortical circuit assembly such as barrel cortex wiring and cortical interneuron migration. Importantly, pharmacological blockade of SERT during brain development leads to phenotypes relevant to psychiatry in rodents and to an increased risk for autism spectrum disorders in humans. Furthermore, developmental adversity interacts with genetically-driven variations of serotonin function in humans and nonhuman primates to increase the risk for a variety of stress-related phenotypes. In this study, we investigate whether an excess of serotonin affects the migration of neocortical pyramidal neurons during development. Using in utero electroporation combined with time-lapse imaging to specifically monitor pyramidal neurons during late mouse embryogenesis, we show that an excess of serotonin reversibly affects the radial migration of pyramidal neurons. We further identify that the serotonin receptor 5-HT(6) is expressed in pyramidal neuron progenitors and that 5-HT(6) receptor activation replicates the effects of serotonin stimulation. Finally, we show that the positioning of superficial layer pyramidal neurons is altered in vivo in SERT knockout mice. Taken together, these results indicate that a developmental excess of serotonin decreases the migration speed of cortical pyramidal neurons, affecting a fundamental step in the assembly of neural circuits. These findings support the hypothesis that developmental dysregulation of serotonin homeostasis has detrimental effects on neocortical circuit formation and contributes to increased vulnerability to psychiatric disorders. PMID- 22833194 TI - Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. AB - The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P=0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P=0.001) and reduced MET protein levels (P=0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation. PMID- 22833195 TI - Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking. AB - The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 * 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain expressed alpha-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders. PMID- 22833197 TI - BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals. AB - Numerous studies have indicated a link between the presence of polymorphism in brain-derived neurotrophic factor (BDNF) and cognitive and affective disorders. However, only a few have studied these effects longitudinally along with structural changes in the brain. This study was carried out to investigate whether valine-to-methionine substitution at position 66 (val66met) of pro-BDNF could be linked to alterations in the rate of decline in skilled task performance and structural changes in hippocampal volume. Participants consisted of 144 healthy Caucasian pilots (aged 40-69 years) who completed a minimum of 3 consecutive annual visits. Standardized flight simulator score (SFSS) was measured as a reliable and quantifiable indicator for skilled task performance. In addition, a subset of these individuals was assessed for hippocampal volume alterations using magnetic resonance imaging. We found that val66met substitution in BDNF correlated longitudinally with the rate of decline in SFSS. Structurally, age-dependent hippocampal volume changes were also significantly altered by this substitution. Our study suggests that val66met polymorphism in BDNF can be linked to the rate of decline in skilled task performance. Furthermore, this polymorphism could be used as a predictor of the effects of age on the structure of the hippocampus in healthy individuals. Such results have implications for understanding possible disabilities in older adults performing skilled tasks who are at a higher risk for cognitive and affective disorders.Translational Psychiatry (2011) 1, e51; doi:10.1038/tp.2011.47; published online 25 October 2011. PMID- 22833196 TI - The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data. AB - The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, ~0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other. PMID- 22833198 TI - Major bleeding in patients undergoing PCI and triple or dual antithrombotic therapy: a parallel-cohort study. AB - The combination of oral anticoagulants with dual antiplatelet therapy (DAT) in patients undergoing percutaneous coronary intervention with stent implantation (PCI-stenting) is subject to controversy due to the high risk of bleeding. In this multicenter retrospective parallel-group study, we compared the rate of adverse events in chronically anticoagulated patients who underwent PCI-stenting and were discharged on aspirin, clopidogrel and warfarin (triple antithrombotic therapy [TT] group) and were followed in Italian anticoagulation centers, with a parallel cohort of patients who underwent PCI-stenting and were discharged on DAT group. The primary endpoint was the incidence of major bleeding while the patients were in TT and DAT. A secondary endpoint was the occurrence of major ischemic adverse events (MACEs). The final cohort consisted of 229 TT patients and 231 DAT patients followed up for 6 and 7 months, respectively. There were 11 (4.8%; 9.1% patient/years) major bleeding events in the TT group (1 was fatal) as compared to 1 (0.4%; 0.7% patient/years) event in the DAT group (p = 0.003). Of the 28 (6.1%) MACE recorded during the follow-up, 12 (5.2%) occurred in the TT group and 16 (6.9%) in the DAT group. In conclusion, despite close monitoring of anticoagulated patients in dedicated centers, the major bleeding incidence remains high among unselected patients undergoing PCI-stenting and treated with TT. Any efforts to minimize these events should be pursued. PMID- 22833199 TI - Stage-specific breast cancer incidence rates among participants and non participants of a population-based mammographic screening program. AB - The Norwegian Breast Cancer Screening Program was rolled out county by county over the course of a decade, from 1996 to 2005, and now encompasses all Norwegian women aged 50-69 years. We aim to compare DCIS and stage-specific invasive breast cancer incidence rates among participants, non-participants, and women not yet invited to the screening program over this entire implementation period. We estimate stage-specific breast tumor incidence rates for 640,347 women 50-69 years of age invited to the screening program between 1996 and 2007. We compare incidence rates and stage distribution among women diagnosed with breast cancer who were invited and participated, invited but not participated, and women not yet invited to the screening program using two-sided Chi-squared tests to determine statistical significance between groups. The incidence of ductal carcinoma in situ (DCIS) was 3.0 times higher and invasive breast cancer was 1.5 times higher for invited participants compared to invited non-participants (p < 0.001). While the incidence of Stage I cancer was two times higher among participants compared to non-participants (p < 0.001), the incidences of Stages III and IV cancer were two and three times lower, respectively, among participants compared to non-participants (p < 0.001 for both). No significant differences in stage-specific incidence or treatment utilization rates were observed between invited non-participants and not yet invited women, except for stage IV cancers, which were detected at a higher rate among women who were not yet invited (7.5 vs. 4.6 %, p = 0.001). Compared with women invited who did not participate, participants in the screening program are more likely to be diagnosed with DCIS and early stage invasive breast cancer and are less likely to be diagnosed with advanced stage breast cancer. More research is required to determine whether these differences in stage-specific incidences among invited participants and non-participants are associated with differences in mortality rates. PMID- 22833200 TI - Feature extraction via composite scoring and voting in breast cancer. AB - Identification and characterization of tumor subtypes using gene expression profiles of triple negative breast cancer patients. Microarray data of four breast cancer studies were pooled and evaluated. Molecular subtype classification was performed using random forest and a novel algorithm for feature extraction via composite scoring and voting. Biological and clinical properties were evaluated via GSEA, functional annotation clustering and clinical endpoint analysis. The subtype signatures are highly predictive for distant metastasis free survival of tamoxifen-treated patients. Consensus clustering and the novel algorithm proposed three triple negative subtypes. One subtype shows low E2F4 gene expression and is predictive for survival of ER negative breast cancer patients. The other two subtypes share commonalities with luminal B tumors. Classification of breast cancer expression profiles may reveal novel tumor subtypes, possessing clinical impact. Furthermore, subtype characterizing gene signatures might hold potential for novel strategies in cancer therapy. PMID- 22833201 TI - The potential of neurosonography in neurological emergency and intensive care medicine: monitoring of increased intracranial pressure, brain death diagnostics, and cerebral autoregulation- part 2. AB - Transcranial B-mode sonography is an easy to use bedside imaging modality to monitor significant changes of the brain parenchyma such as in malignant middle cerebral infarction or intracerebral hemorrhage. The elevation of intracranial pressure can be followed with various neurosonographical techniques: Measurements of the ventricular width, midline shift, arterial resistance, and optic nerve sheath diameter. They should be viewed as complementary to each other and to other imaging modalities. Repeated cCT and MRI may be avoided in unstable patients by bedside neurosonography in the hands of an experienced physician. Monitoring of evolving hydrocephalus using serial measurements of the third and lateral ventricles can be used to guide therapeutic decisions such as the removal of a ventricular drainage. The cessation of cerebral blood flow in the case of intracranial pressure exceeding systemic arterial pressure is an important part of brain death diagnostics. Early demonstration of a sufficient temporal bone window is needed in patients in whom brain death may be expected. Cerebrovascular autoregulation is an integer component of the brain's blood supply and is compromised in a variety of neurological diseases. In neurological/neurosurgical patients in the intensive care unit, its assessment allows for extended neuromonitoring and control of therapeutic procedures. PMID- 22833202 TI - Hepatic elastography for the assessment of liver fibrosis--present and future. AB - Liver Biopsy was considered the "gold standard" for severity assessment in chronic hepatitis for a very long time. In recent years, non invasive methods were developed in order to replace it. Among them ultrasound based elastographic methods: Transient Elastography (already validated and replacing liver biopsy in some countries), Real Time Tissue Elastography and Acoustic Radiation Force Impulse Elastography (currently under evaluation) and Shear Wave Elastography (the newest one). As an alternative to liver biopsy, the development of all these non invasive methods for dynamic evaluation of liver fibrosis will decrease the need for LB, making clinical care safer and more convenient for patients with liver diseases. PMID- 22833203 TI - Thermal Effects of Diagnostic Ultrasound in an Anthropomorphic Skull Model. PMID- 22833204 TI - A long-term experimental test of the dynamic equilibrium model of species diversity. AB - The dynamic equilibrium model of species diversity predicts that ecosystem productivity interacts with disturbance to determine how many species coexist. However, a robust test of this model requires manipulations of productivity and disturbance over a sufficient timescale to allow competitive exclusion, and such long-term experimental tests of this hypothesis are rare. Here we use long-term (27 years), large-scale (8 * 50-m plots), factorial manipulations of soil resource availability and sheep grazing intensity (disturbance) in grasslands to test the dynamic equilibrium model. As predicted by the model, increased productivity not only reduced plant species richness, but also moderated the effects of grazing intensity, shifting them from negative to neutral with increasing productivity. Reductions in species richness with productivity were associated with dominance by faster growing (i.e. high specific leaf area) and taller plants. Conversely, grazing favoured shorter plants and this effect became stronger with greater productivity, consistent with the view that grazing can lead to weaker asymmetric competition for light. Our study shows that the dynamic equilibrium model can help to explain changes in plant species richness following long-term increases in soil resource availability and grazing pressure, two fundamental drivers of change in grasslands worldwide. PMID- 22833206 TI - Strategies for overcoming EGFR resistance in the treatment of advanced-stage NSCLC. AB - OPINION STATEMENT: Patients whose tumors harbor somatic-activating mutations within the epidermal growth factor receptor (EGFR) gene define a clinically distinct molecular cohort of lung cancers with increased sensitivity to the EGFR tyrosine kinase inhibitors (TKIs), including the "first-generation" reversible inhibitors, erlotinib and gefitinib, and the "second-generation" irreversible inhibitors, afatinib and dacomitinib. Several, large, phase III studies have shown already that patients with EGFR-mutant tumors display radiographic response rates of >60 % and improved progression free survival (PFS) when treated with an EGFR TKI compared with chemotherapy. Unfortunately, despite these initial responses, patients inevitably develop progressive disease, a concept referred to clinically as acquired resistance. Novel strategies are needed to delay or overcome acquired resistance to EGFR TKIs. These strategies include second generation EGFR inhibitors, rationale combinations of targeted small molecule inhibitors and/or monoclonal antibodies, and addition of traditional cytotoxic chemotherapy to EGFR TKI therapy at the time of progression. Unfortunately, to date, there is no genotype-specific standard of care, and enrollment of patients with acquired resistance to EGFR TKIs into clinical trials specifically addressed at overcoming resistance is paramount to continue to advance the field and to improve outcomes for these patients. PMID- 22833205 TI - Cost analysis of a patient navigation system to increase screening colonoscopy adherence among urban minorities. AB - BACKGROUND: Patient navigation (PN) is being used increasingly to help patients complete screening colonoscopy (SC) to prevent colorectal cancer. At their large, urban academic medical center with an open-access endoscopy system, the authors previously demonstrated that PN programs produced a colonoscopy completion rate of 78.5% in a cohort of 503 patients (predominantly African Americans and Latinos with public health insurance). Very little is known about the direct costs of implementing PN programs. The objective of the current study was to perform a detailed cost analysis of PN programs at the authors' institution from an institutional perspective. METHODS: In 2 randomized controlled trials, average risk patients who were referred for SC by primary care providers were recruited for PN between May 2008 and May 2010. Patients were randomized to 1 of 4 PN groups. The cost of PN and net income to the institution were determined in a cost analysis. RESULTS: Among 395 patients who completed colonoscopy, 53.4% underwent SC alone, 30.1% underwent colonoscopy with biopsy, and 16.5% underwent snare polypectomy. Accounting for the average contribution margins of each procedure type, the total revenue was $95,266.00. The total cost of PN was $14,027.30. Net income was $81,238.70. In a model sample of 1000 patients, net incomes for the institutional completion rate (approximately 80%), the historic PN program (approximately 65%), and the national average (approximately 50%) were compared. The current PN program generated additional net incomes of $35,035.50 and $44,956.00, respectively. CONCLUSIONS: PN among minority patients with mostly public health insurance generated additional income to the institution, mainly because of increased colonoscopy completion rates. PMID- 22833207 TI - Clinical effectiveness of unilateral deep brain stimulation in Tourette syndrome. AB - Dysfunctional basal ganglia loops are thought to underlie the clinical picture of Tourette syndrome (TS). By altering dopaminergic activity in the affected neural structures, bilateral deep brain stimulation is assumed to have a modulatory effect on dopamine transmission resulting in an amelioration of tics. While the majority of published case reports deals with the application of bilateral stimulation, the present study aims at informing about the high effectiveness of unilateral stimulation of pallidal and nigral thalamic territories in TS. Potential implications and gains of the unilateral approach are discussed. PMID- 22833208 TI - The neural basis of video gaming. AB - Video game playing is a frequent recreational activity. Previous studies have reported an involvement of dopamine-related ventral striatum. However, structural brain correlates of video game playing have not been investigated. On magnetic resonance imaging scans of 154 14-year-olds, we computed voxel-based morphometry to explore differences between frequent and infrequent video game players. Moreover, we assessed the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging and the Cambridge Gambling Task (CGT). We found higher left striatal grey matter volume when comparing frequent against infrequent video game players that was negatively correlated with deliberation time in CGT. Within the same region, we found an activity difference in MID task: frequent compared with infrequent video game players showed enhanced activity during feedback of loss compared with no loss. This activity was likewise negatively correlated with deliberation time. The association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity. PMID- 22833209 TI - Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment. AB - Alzheimer's disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with the rate of progression in 822 Caucasian subjects of amnestic mild cognitive impairment (MCI). There was no significant association with disease progress for any of the recently identified disease susceptibility variants in CLU, CR1, PICALM, BIN1, EPHA1, MS4A6A, MS4A4E or CD33 following multiple testing correction. We did, however, identify multiple novel loci that reached genome-wide significance at the 0.01 level. These top variants (rs7840202 at chr8 in UBR5: P=4.27 * 10(-14); rs11637611 with a cluster of SNPs at chr15q23 close to the Tay-Sachs disease locus: P=1.07 * 10(-15); and rs12752888 at chr1: P=3.08 * 10(-11)) were also associated with a significant decline in cognition as well as the conversion of subjects with MCI to a diagnosis of AD. Taken together, these variants define approximately 16.6% of the MCI sub-population with a faster rate of decline independent of the other known disease risk factors. In addition to providing new insights into protein pathways that may be involved with the progress to AD in MCI subjects, these variants if further validated may enable the identification of a more homogeneous population of subjects at an earlier stage of disease for testing novel hypotheses and/or therapies in the clinical setting. PMID- 22833211 TI - Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16. AB - Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100beta, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders. PMID- 22833210 TI - Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. AB - Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function. PMID- 22833213 TI - A comparative study of PDGFR inhibition with imatinib on radiolabeled antibody targeting and clearance in two pathologically distinct models of colon adenocarcinoma. AB - The potential of radioimmunotherapy to selectively kill tumour cells is well established. However, optimisation is required with regards to increasing tumour localisation of antibodies. We used the PDGF-receptor inhibitor imatinib mesylate to improve tumour-specific antibody localisation in two models of colorectal adenocarcinoma and correlated antibody localisation with changes to tumour microvasculature. Mice bearing human colorectal xenografts (LS174T or SW1222) were treated with imatinib prior to administration of radiolabeled anti-CEA antibodies ((125)I-A5B7). Whole tumour and regional localisation of radiolabeled antibodies were measured. Microvessel density and pericyte coverage were quantified in whole tumours and correlated with (125)I-A5B7 localisation. Imatinib increased uptake of (125)I-A5B7 in LS174T but not SW1222 tumours after 48 h (p < 0.05). Imatinib reduced microvessel density in both models (p < 0.05) but reduced pericyte attachment to endothelial cells only in SW1222 xenografts (p < 0.05). Imatinib increases antibody distribution in LS174T tumours but not SW1222 tumours, and this correlated to changes in tumour microvessels. Accelerated clearance of radiolabeled antibody from normal tissues in both models resulted in enhanced tumour to normal tissue ratios. This improvement in tumour/normal tissue ratio has potential clinical benefit from a therapy and imaging perspective, and merits further investigation. PMID- 22833212 TI - Expression of P120 catenin, Kaiso, and metastasis tumor antigen-2 in thymomas. AB - Thymomas of the same histological subtype sometimes manifest different biological behaviors. Metastasis Tumor Antigen-2 (MTA2) is targeted by the transcriptional repressor Kaiso, the distribution which is thought to be modulated by p120catenin (p120ctn). It is currently unclear if expression of p120ctn, Kaiso, and MTA2 relates to the biological behavior of thymoma. P120ctn, Kaiso, and MTA2 expression were examined in 137 cases of thymoma, three cases of thymic carcinoma, and 18 paired autologous normal thymic tissues using immunohistochemistry, and correlation of these proteins with histological subtypes and clinical stages were analyzed. In normal thymic epithelial cells, p120ctn was expressed on the cell membrane but Kaiso and MTA2 were not detected. Membranous p120ctn expression was reduced in thymoma epithelial cells, while ectopic cytoplasmic expression was observed in 76.6 % (105/137) of the cases. Cytoplasmic Kaiso was detected in 69.3 % (95/137) and nuclear MTA2 was detected in 70.8 % (97/137) of the thymomas. There were good consistencies (Kappa = 0.559, 0.512, 0.652; all P < 0.001) and correlations (r = 0.733, 0.652, 0.708; all P < 0.001) between cytoplasmic p120ctn, cytoplasmic Kaiso, and nuclear MTA2 expression in thymomas. All three protein factors correlated with histological type and clinical stage in thymoma (P < 0.05). Specifically, cytoplasmic p120ctn and Kaiso expression and nuclear MTA2 expression were higher in high-risk (types B2 and B3) thymomas and Masaoka stage III/IV thymomas than low-risk (types A, AB, and B1) and stage I/II thymomas (both P < 0.001), respectively. Cytoplasmic p120ctn, cytoplasmic Kaiso, and nuclear MTA2 expression correlated directly with histological type and Masaoka stage and may thus be used as potential biomarkers to predict biological behavior of thymoma. PMID- 22833214 TI - Evaluation of water uptake and mechanical properties of blended polymer films for preparing gas-generated multiple-unit floating drug delivery systems. AB - Among various strategies of gastroretentive drug delivery systems (DDSs) developed to prolong the gastric residence time and to increase the overall bioavailability, effervescent multiple-unit floating DDSs (muFDDSs) were studied here. These systems consist of drug (losartan)- and effervescent (sodium bicarbonate)-containing pellets coated with a blended polymeric membrane, which was a mixture of gastrointestinal tract (GIT)-soluble and GIT-insoluble polymers. The addition of GIT-soluble polymers, such as hydroxypropyl methylcellulose, polyethylene glycol (PEG) 6000, PEG 600, and Kollicoat(r) IR, greatly increased the water uptake ability of the GIT-insoluble polymers (Eudragit(r) NE, RS, and RL; Surelease(r); and Kollicoat(r) SR) and caused them to immediately initiate the effervescent reaction and float, but the hydrated films should also be impermeable to the generated CO(2) to maintain floatation and sufficiently flexible to withstand the pressure of carbon dioxide to avoid rupturing. The study demonstrated that the water uptake ability and mechanical properties could be applied as screening tools during the development of effervescent muFDDSs. The optimized system of SRT(5)P600(5) (i.e., a mixture of 5% Kollicoat(r) SR and 5% PEG 600) with a 20% coating level began to completely float within 15 min and maintained its buoyancy over a period of 12 h with a sustained-release effect. PMID- 22833215 TI - Narrow diameter distributions of metallic arc discharge single-walled carbon nanotubes via dual-iteration density gradient ultracentrifugation. PMID- 22833216 TI - Facile fabrication of NH4CoPO4.H2O nano/microstructures and their primarily application as electrochemical supercapacitor. AB - Various NH(4)CoPO(4).H(2)O nano/microstructures (oblong plate, microplate, microflower, hierarchical architectures) have been synthesized through a facile chemical precipitation method without surfactants and templates. More importantly, the supercapacitive performances of NH(4)CoPO(4).H(2)O nano/microstructures were firstly studied using cyclic voltammetry, galvanostatic charge/discharge measurements, and electrochemical impedance spectroscopy methods in 3.0 M KOH solution. These results indicated that NH(4)CoPO(4).H(2)O hierarchical architectures electrodes exhibit effective supercapacitive characteristics in aqueous KOH electrolyte. The specific capacitance of NH(4)CoPO(4).H(2)O electrode is up to 369.4 F g(-1) at a current density of 0.625 A g(-1) and the material has a long cycle life which can maintain 99.7% of initial specific capacitance after 400 cycles. PMID- 22833217 TI - Both "naked-eye" and fluorescent sensor for Hg2+ based upon 8-hydroxyquinoline. AB - A chemosensor, 2,2'-(1,4-phenylenedivinylene)bis-8-acetoxyquinoline (1), its fluorescent sensing behavior toward representative alkali ions (Na(+), K(+)), alkaline earth ions (Mg(2+), Ca(2+)), and transition-metal ions (Ni(2+), Cu(2+), Zn(2+), Hg(2+), Pb(2+), Cd(2+)) was intensively investigated. The compound (1) exhibited pronounced Hg(2+) selective on-off-type fluoroionophoric properties among the representative ions in DMF/ethanol (1:9, v/v) solution. Moreover, the highly Hg(2+)-selective fluorescence quenching property in conjunction with a visible colorimetric change from colorless to light yellow can be observed, leading to potential fabrication of both "naked-eye" and fluorescent detection of Hg(2+). PMID- 22833218 TI - Studies on the chemical modification of goat liver cystatin and the effect on its anti-papain inhibitory activity. AB - Goat liver cystatin was subjected to various chemical modifications in order to ascertain the amino acid residues responsible for its structural and functional integrity. Modification of tryptophan by HNBB led to the complete inactivation of the protein. The inactivation was also accompanied by the complete loss of tryptophan fluorescence at 340 nm. The reaction of liver cystatin with HNBB yielded a characteristic decrease in absorbance at 280 nm. Acetylation of the amino groups of liver cystatin was carried out in the presence of acetic anhydride. The acetylated cystatin showed a decrease in fluorescence intensity at 335 nm which could be attributed to the modification of tyrosine residue due to side reaction. PMID- 22833220 TI - Hollow fiber-based liquid membrane microextraction combined with high-performance liquid chromatography for extraction and determination of trimetazidine in human plasma. AB - A hollow fiber-based liquid phase microextraction strategy combined with high performance liquid chromatography was evaluated for the quantitative determination of trimetazidine in human plasma. Trimetazidine was extracted from a 2.1 mL basified plasma sample (donor phase) into the organic solvent (n octanol) impregnated in the pores of a hollow fiber and then extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fiber. The result showed that transport of drugs from alkaline sample solution into 0.5 m HCl occurred efficiently when 25 MUL of 250 mm sodium 1-octanesulfonate was added into the donor phase. Several parameters influencing the efficiency of the method, such as the nature of organic solvent used to impregnate the membrane, compositions of donor phase and acceptor phase, type and concentration of carrier, extraction time, stirring rate and salt concentration, were investigated and optimized. Under the optimal conditions, the calibration curves were obtained in the range of 5-200 ng/mL with reasonable linearity (r > 0.9980). The method was successfully applied to determine the concentration of trimetazidine in human plasma. PMID- 22833219 TI - Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. AB - OBJECTIVE: Fibroblast growth factor (FGF) family members are involved in the regulation of articular cartilage homeostasis. The aim of this study was to investigate the function of FGF receptor 1 (FGFR-1) in the development of osteoarthritis (OA) and its underlying mechanisms. METHODS: FGFR-1 was deleted from the articular chondrocytes of adult mice in a cartilage-specific and tamoxifen-inducible manner. Two OA models (aging-associated spontaneous OA, and destabilization-induced OA), as well as an antigen-induced arthritis (AIA) model, were established and tested in Fgfr1-deficient and wild-type (WT) mice. Alterations in cartilage structure and the loss of proteoglycan were assessed in the knee joints of mice of either genotype, using these 3 arthritis models. Primary chondrocytes were isolated and the expression of key regulatory molecules was assessed quantitatively. In addition, the effect of an FGFR-1 inhibitor on human articular chondrocytes was examined. RESULTS: The gross morphologic features of Fgfr1-deficient mice were comparable with those of WT mice at both the postnatal and adult stages. The articular cartilage of 12-month-old Fgfr1 deficient mice displayed greater aggrecan staining compared to 12-month-old WT mice. Fgfr1 deficiency conferred resistance to the proteoglycan loss induced by AIA and attenuated the development of cartilage destruction after surgically induced destabilization of the knee joint. The chondroprotective effect of FGFR-1 inhibition was largely associated with decreased expression of matrix metalloproteinase 13 (MMP-13) and up-regulation of FGFR-3 in mouse and human articular chondrocytes. CONCLUSION: Disruption of FGFR-1 in adult mouse articular chondrocytes inhibits the progression of cartilage degeneration. Down-regulation of MMP-13 expression and up-regulation of FGFR-3 levels may contribute to the phenotypic changes observed in Fgfr1-deficient mice. PMID- 22833221 TI - Preparation and biological evaluation of chitosan-collagen-icariin composite scaffolds for neuronal regeneration. AB - In this study the chitosan/collagen/icariin composite scaffolds for nerve regeneration were produced by blending and crosslinking chitosan with collagen and icariin. The microstructure of the composite scaffolds was observed by scanning electron microscopy. 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide and attachment assays were conducted, respectively, to investigate the biocompatibility of the scaffolds. Cell cultural tests showed that the channel-structured porous scaffolds acted as a positive factor to support connective nerve cell growth. After culture, cells showed a clear flow trend to move close to the composite scaffolds in culture solution, arranging in spiral-like, and aligned parallel to the orientation of the channel structure on the surface of scaffolds. When compared to pure chitosan and chitosan/collagen scaffolds, Schwann cells and PC12 cells on the chitosan/collagen/icariin composite scaffolds exhibited the greatest proliferation and longest average neurite length. These results suggested that the chitosan/collagen/icariin composite scaffolds are potential cell carriers in nerve tissue engineering. PMID- 22833222 TI - Transformation and conjugal transfer of foreign genes into the filamentous multicellular cyanobacteria (subsection V) Fischerella and Chlorogloeopsis. AB - Cyanobacteria of subsection V grow as filaments with asymmetrical cell divisions that can generate a true-branching phenotype. Members of the genera Fischerella and Chlorogloeopsis furthermore differentiate akinetes (spore-like resting stages), heterocysts (specialized in nitrogen fixation) and hormogonia (cell aggregates with gliding motility for colonization and dispersal). Genetic approaches to studying the complex morphology and differentiations of these prokaryotes require transformation techniques. For Fischerella and Chlorogloeopsis reliable protocols for introducing foreign genes are lacking. Here, we explored conjugation, electroporation, and biolistic DNA transfer methods in Fischerella and Chlorogloeopsis, using the cyanobacterial replicon pRL25C as a marker. We successfully transformed Fischerella muscicola PCC 7414 and Chlorogloeopsis fritschii PCC 6912 and were able to express the GFP reporter protein under two different promoters: the nitrogen regulated (p) glnA and the strong E. coli hybrid (p) trc. For Fischerella all methods worked, for Chlorogloeopsis electroporation was unsuccessful. For both strains conjugation delivered the most reproducible results, whereby partial removal of the exopolysaccharide sheath by salt washing was a critical step. PMID- 22833224 TI - Incidence of occult cervical metastasis in head and neck carcinomas: development over time. AB - BACKGROUND: With the development of imaging techniques in diagnostics of head and neck carcinomas, especially computed tomography and ultrasonogaphy, one might expect that the incidence of occult metastases would be reduced. The aim of this study was to determine the rate of occult metastases in a large population cohort and explore its changes with improvement of imaging techniques over the last 30 years. METHODS: All patients between 1980 and 2010 with head and neck carcinoma and cN0 neck status were retrospectively evaluated. Six hundred thirty-six patients with cN0 neck who received an elective neck dissection as part of a definitive surgical treatment were included. RESULTS: The overall rate of occult metastases was 24.8% (158/636). The rate was 26.5% (80/302) between 1980 and 1995 and 23.4% (78/334) between 1995 and 2010. Only pT1-2 glottic carcinomas had an occult metastases rate of less than 10%. All other pT1-2 carcinomas had an incidence of occult metastases between 19.1% and 42.5%. pT3-4 tumors showed an occult metastases rate of 24.5-53.3%. CONCLUSION: The occult metastases rate showed only a marginal improvement over the last 30 years and is still above the 20% margin. All but pT1-2 glottic carcinomas should be considered for elective treatment of the neck. PMID- 22833223 TI - Decoding plant and animal genome plasticity from differential paleo-evolutionary patterns and processes. AB - Continuing advances in genome sequencing technologies and computational methods for comparative genomics currently allow inferring the evolutionary history of entire plant and animal genomes. Based on the comparison of the plant and animal genome paleohistory, major differences are unveiled in 1) evolutionary mechanisms (i.e., polyploidization versus diploidization processes), 2) genome conservation (i.e., coding versus noncoding sequence maintenance), and 3) modern genome architecture (i.e., genome organization including repeats expansion versus contraction phenomena). This article discusses how extant animal and plant genomes are the result of inherently different rates and modes of genome evolution resulting in relatively stable animal and much more dynamic and plastic plant genomes. PMID- 22833225 TI - Efficient conversion of high concentration of glycerol to Monacolin K by solid state fermentation of Monascus purpureus using bagasse as carrier. AB - High concentration of glycerol was used as the sole carbon source for efficient production of Monacolin K (MK) by solid-state fermentation (SSF) of Monascus purpureus 9901 using agricultural residue (bagasse), as an inert carrier. A comparative study showed that MK production in SSF was about 5.5 times higher than that of submerged fermentation when 26 % of glycerol was used, which may be due to the formation of glycerol concentration gradients in the inert carrier and less catabolite repression in SSF. For enhancement of MK yield in SSF, the effects of different influential variables, such as glycerol concentration, nitrogen source and its concentration, initial moisture content, inoculum size and particle size of bagasse, were systematically examined. All the factors mentioned above had an effect on the MK production in SSF to some extent. The maximal yield of MK (12.9 mg/g) was achieved with 26 % glycerol, 5 % soybean meal, 51 % initial moisture content, 20 % inoculum size and 1 mm particle size of bagasse. The results in this study may expand our understanding on the application of SSF using agricultural residue as carrier for production of useful microbial metabolites, especially the efficient conversion of high concentration of glycerol to MK by Monascus purpureus. PMID- 22833226 TI - Lipase from marine strain using cooked sunflower oil waste: production optimization and application for hydrolysis and thermodynamic studies. AB - The marine strain Pseudomonas otitidis was isolated to hydrolyze the cooked sunflower oil (CSO) followed by the production of lipase. The optimum culture conditions for the maximum lipase production were determined using Plackett Burman design and response surface methodology. The maximum lipase production, 1,980 U/ml was achieved at the optimum culture conditions. After purification, an 8.4-fold purity of lipase with specific activity of 5,647 U/mg protein and molecular mass of 39 kDa was obtained. The purified lipase was stable at pH 5.0 9.0 and temperature 30-80 degrees C. Ca(2+) and Triton X-100 showed stimulatory effect on the lipase activity. The purified lipase was highly stable in the non polar solvents. The functional groups of the lipase were determined by Fourier transform-infrared (FT-IR) spectroscopy. The purified lipase showed higher hydrolytic activity towards CSO over the other cooked oil wastes. About 92.3 % of the CSO hydrolysis was observed by the lipase at the optimum time 3 h, pH 7.5 and temperature 35 degrees C. The hydrolysis of CSO obeyed pseudo first order rate kinetic model. The thermodynamic properties of the lipase hydrolysis were studied using the classical Van't Hoff equation. The hydrolysis of CSO was confirmed by FT-IR studies. PMID- 22833227 TI - Expression, reconstruction and characterization of codon-optimized carbonic anhydrase from Hahella chejuensis for CO2 sequestration application. AB - The high production of functional carbonic anhydrase (CA) is required for practical CO2 sequestration application mediated by CA. Here, the synthetic gene based on Escherichia coli codon usage of new alpha-type CA (HC-aCA) of Hahella chejuensis, a Korea marine microorganism, was highly expressed in E. coli. We obtained a high yield of functional HC-aCA by denaturing/refolding process and incorporating zinc ion into its active site. The refolded HC-aCA displayed a half deactivation temperature of 60 degrees C with maximal activity at 50 degrees C, and had high pH stability in alkali condition with maximal activity at pH 10.0. The esterase activity of HC-aCA almost doubled at high salt concentration ranging from 0.67 to 2.0 M NaCl. HC-aCA catalyzed the conversion of CO2 to CaCO3 as calcites form in the presence of Ca(2+). The refolded HC-aCA could be a promising candidate for the development of efficient CA-based CO2 sequestration processes. PMID- 22833228 TI - Insights into cancer metastasis from a clinicopathologic perspective: Epithelial Mesenchymal Transition is not a necessary step. AB - Epithelial-mesenchymal transition (EMT) has been implicated as the critical event initiating cancer invasion and metastasis. After disseminating through the circulation, the malignant cells have been proposed to undergo subsequent mesenchymal-epithelial transition (MET) to form secondary tumors. However, strong evidence from human tumor specimens for this paradigm is lacking. In carcinomas, cancers derived from epithelial tissues, epithelial morphology and gene expression are always retained to some degree. While mesenchymal transdifferentiation may be involved in the pathogenesis of carcinosarcomas, even in these neoplasms, as well as in germ cell tumors capable of multilineage differentiation, the mesenchymal phenotype does not facilitate metastatic progression. Indeed, most cancers invade and travel through lymphatic and blood vessels via cohesive epithelial migration, rather than going through the EMT-MET sequence. EMT gene expression is also consistently associated with high histologic grade and while the transcription factors, Snail, Slug and Twist have traditionally been thought of as inducers of EMT, under certain conditions, they also mediate dedifferentiation and maintenance of the stem cell state. In various malignancies, including basal-like breast cancer and colorectal cancer, the genetically unstable, undifferentiated phenotype predicts early metastatic spread and poor prognosis. This article discusses some of the controversies surrounding differentiation and metastasis from a clinicopathologic perspective and presents evidence that the epithelial phenotype is maintained throughout the process of cancer metastasis. PMID- 22833229 TI - Including shared peptides for estimating protein abundances: a significant improvement for quantitative proteomics. AB - Inferring protein abundances from peptide intensities is the key step in quantitative proteomics. The inference is necessarily more accurate when many peptides are taken into account for a given protein. Yet, the information brought by the peptides shared by different proteins is commonly discarded. We propose a statistical framework based on a hierarchical modeling to include that information. Our methodology, based on a simultaneous analysis of all the quantified peptides, handles the biological and technical errors as well as the peptide effect. In addition, we propose a practical implementation suitable for analyzing large data sets. Compared to a method based on the analysis of one protein at a time (that does not include shared peptides), our methodology proved to be far more reliable for estimating protein abundances and testing abundance changes. The source codes are available at http://pappso.inra.fr/bioinfo/all_p/. PMID- 22833230 TI - Enhancing family communication about genetics: ethical and professional dilemmas. AB - When a new genetic condition is diagnosed within a family, genetic counselors often describe a sense of responsibility towards other at risk family members to be appropriately informed about their status. Successful communication of genetic information in families is contingent on many factors. While a small number of probands directly state their intention not to inform their relatives, many who do intend to communicate this information appear to be unsuccessful for a wide range of reasons and may benefit from follow up support from a genetic counselor. Drawing on the reciprocal-engagement model (REM) of genetic counseling practice we explore how enhancing family communication about genetics raises a number of ethical and professional challenges for counselors-and describe how we resolved these. A subsequent manuscript will describe the counseling framework we have developed to enhance family communication about genetics. PMID- 22833231 TI - 22q11.2 deletion syndrome: attitudes towards disclosing the risk of psychiatric illness. AB - 22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with multisystem features. There is a strong association with psychiatric disorders. One in every four to five patients develop schizophrenia. Despite studies showing that early diagnosis and treatment are likely to lead to improved outcome, genetic counselors may be reluctant to discuss the risk of psychiatric illness. The aim of this research was to explore parental attitudes and genetic counselors' perspectives and practice regarding disclosure of the clinical manifestations of 22q11.2DS, particularly the risk of psychiatric illness. We delivered a questionnaire to genetic counselors via established list-serves, 54 of which were completed. We also conducted interviews with four parents of adults with 22q11.2DS and schizophrenia. The majority of counselors and parents felt that the increased risk to develop a psychiatric illness is important to disclose. However, in the initial counseling session when the diagnosis was made in infancy genetic counselors were significantly less likely to discuss the risk of psychiatric disorders compared to other later onset features such as hypothyroidism (41 % vs. 83 %, p = 0.001). When the diagnosis of 22q11.2DS was made in infancy, counselors' responses in regard to timing of disclosure about psychiatric illnesses were fairly evenly divided between infancy, childhood and adolescence. In contrast, for other major features of 22q11.2DS, disclosure would predominantly be in infancy. The respondents reported that the discussion of psychiatric issues with parents was challenging due to the stigma associated with mental illness. Some also noted limited knowledge about psychiatric illness and treatment. These results suggest that genetic counselors could benefit from further education regarding psychiatric illness in 22q11.2DS and best strategies for discussing this important subject with parents and patients. PMID- 22833232 TI - Mechanical properties of polygonal carbon nanotubes. AB - A group of polygonal carbon nanotubes (P-CNTs) have been designed and their mechanical behavior was investigated by classical molecular dynamics simulations. The research aimed at exploring the effects of structure, temperature, and strain rate on the mechanical properties. The results indicate that the Young's modulus of P-CNTs is lower than those of circumcircle carbon nanotubes (C-CNT). Moreover, with an increase in the number of sides to the polygons, the Young's modulus increases and is much closer to that of C-CNT. The effects of temperature and strain rate on the mechanical properties of P-CNTs show that the higher temperature and slower strain rate result in a lower critical strain and weaker tensile strength. In addition, it was found that the critical strains of P-CNTs are dependent on the tube size. Finally, we used the transition-state theory model to predict the critical strain of P-CNTs at given experimental conditions. It is expected that this work could provide feasible means to manipulate the mechanical properties of novel P-CNTs and facilitate the mechanical application of nanostructures as potential electronic devices. PMID- 22833233 TI - Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis. AB - OBJECTIVE: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). METHODS: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. RESULTS: Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1. CONCLUSION: This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR. PMID- 22833235 TI - Application of parallel hybrid algorithm in massively parallel GPGPU--the improved effective and efficient method for calculating Coulombic interactions in simulations of many ions with SIMION. AB - In our previous study, we introduced a new hybrid approach to effectively approximate the total force on each ion during a trajectory calculation in mass spectrometry device simulations, and the algorithm worked successfully with SIMION. We took one step further and applied the method in massively parallel general-purpose computing with GPU (GPGPU) to test its performance in simulations with thousands to over a million ions. We took extra care to minimize the barrier synchronization and data transfer between the host (CPU) and the device (GPU) memory, and took full advantage of the latency hiding. Parallel codes were written in CUDA C++ and implemented to SIMION via the user-defined Lua program. In this study, we tested the parallel hybrid algorithm with a couple of basic models and analyzed the performance by comparing it to that of the original, fully-explicit method written in serial code. The Coulomb explosion simulation with 128,000 ions was completed in 309 s, over 700 times faster than the 63 h taken by the original explicit method in which we evaluated two-body Coulomb interactions explicitly on one ion with each of all the other ions. The simulation of 1,024,000 ions was completed in 2650 s. In another example, we applied the hybrid method on a simulation of ions in a simple quadrupole ion storage model with 100,000 ions, and it only took less than 10 d. Based on our estimate, the same simulation is expected to take 5-7 y by the explicit method in serial code. PMID- 22833234 TI - A comparison of the effects of amide and acid groups at the C-terminus on the collision-induced dissociation of deprotonated peptides. AB - The dissociative behavior of peptide amides and free acids was explored using low energy collision-induced dissociation and high level computational theory. Both positive and negative ion modes were utilized, but the most profound differences were observed for the deprotonated species. Deprotonated peptide amides produce a characteristic c(m-2)(-) product ion (where m is the number of residues in the peptide) that is either absent or in low abundance in the analogous peptide acid spectrum. Peptide acids show an enhanced formation of c(m-3)(-); however, this is not generally as pronounced as c(m-2)(-) production from amides. The most notable occurrence of an amide-specific product ion is for laminin amide (YIGSR-NH(2)) and this case was investigated using several modified peptides. Mechanisms involving 6- and 9-membered ring formation were proposed, and their energetic properties were investigated using G3(MP2) molecular orbital theory calculations. For example, with C-terminal deprotonation of pentaglycine amide, formation of c(m-2)(-) and a 6-membered ring diketopiperazine neutral requires >31.6 kcal/mol, which is 26.1 kcal/mol less than the analogous process involving the peptide acid. The end group specific fragmentation of peptide amides in the negative ion mode may be useful for identifying such groups in proteomic applications. PMID- 22833237 TI - Remotely controllable liquid marbles. PMID- 22833236 TI - Mediators of the effect of neighborhood poverty on physical functioning among breast cancer survivors: a longitudinal study. AB - PURPOSE: Female breast cancer survivors, a large and growing population, experience impaired physical functioning after treatment. Survivors living in impoverished neighborhoods may suffer even greater impairment, but the mechanisms linking neighborhood poverty and individual outcomes are poorly understood. This study sought to identify mediators of the effect of neighborhood poverty on physical functioning using longitudinal data from a Missouri cancer registry based sample of 909 female breast cancer survivors. METHODS: Survivors were recruited 1 year after diagnosis (Y1) and completed two telephone interviews, at Y1 and 1 year later (Y2). The association between census-tract-level poverty and physical functioning (RAND SF-36) was tested using a multilevel a priori path model with 19 hypothesized mediators, demographic and socioeconomic confounders, and covariates. Hypothesized mediators included clinical and treatment variables, psychosocial factors (depression, stress, social support), perceived neighborhood characteristics, behavioral risk factors (physical activity, smoking, body mass index, alcohol use), and comorbidity. RESULTS: In unadjusted analysis, women living in neighborhoods with higher poverty were more likely to report lower physical functioning at Y2 (beta = -.19, p < .001). The final mediated model fit the data well (chi(2)(8) = 12.25, p = 0.14; CFI = .996; RMSEA = .024). The effect of neighborhood poverty on physical functioning was fully mediated by physical activity and body mass index. CONCLUSIONS: Breast cancer survivors living in neighborhoods with greater poverty reported lower physical functioning, but this effect was fully explained by physical activity and body mass index. Community based lifestyle interventions sensitive to the unique challenges faced by cancer survivors and the challenges of living in a high-poverty neighborhood are needed to ameliorate neighborhood socioeconomic disparities in physical functioning. PMID- 22833238 TI - Assessment of efficacy of pamidronate in undifferentiated spondyloarthropathy (uSpA): a molecular mechanism. PMID- 22833240 TI - The prevalence of rheumatoid arthritis in Estonia: an estimate based on rheumatology patients' database. AB - Sound epidemiological data are a basic requirement for decision making on the allocation of health care resources. Unfortunately, this is not the case in Estonia, where the paucity of epidemiological data has impeded health care planning for rheumatic conditions. The current paper presents the first effort to explore the epidemiology of rheumatoid arthritis (RA) in Estonia. Electronic databases of all rheumatology units of Harju County, three national and one private, were searched for the records of RA (ICD-10 diagnoses M05 and M06.0) patients who had visited a rheumatologist during 2006 or 2007. Prevalence of RA was calculated for the age 20 years and older and for subsets according to age and gender, using the numbers from the patients' database in the numerator and the corresponding population numbers in the denominator. The total number of prevalent RA cases was 1,897, of which 85 % (n = 1,605) were women. The overall crude period prevalence 2006-2007 of RA in Harju County for the age group 20 years and older was 0.46 %. RA prevalence for both sexes increased with age until the age of 70-79 years and decreased subsequently. Prevalence of RA was significantly higher for women compared with men in all age groups. The prevalence of RA among women and men 20 years and older was 0.70 % (6.68-7.37) and 0.16 % (1.42, 1.79), respectively. Age-standardized (European population) prevalence rate was 0.44 %. The results are concordant with epidemiological data on RA prevalence derived recently in other European countries. PMID- 22833239 TI - Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis-related pulmonary artery hypertension and cutaneous vascular complications. AB - Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6 min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers. PMID- 22833241 TI - In vivo measurements of blood flow and bone metabolism in osteoarthritis. AB - With increasing age, there may be a decrease in femoral blood flow. In some patients, this may result in local ischaemia, which subsequently may lead to local degenerative changes. Consequently, bone blood flow may play an important role in the aetiology of osteoarthritis of the hip. Little is known about bone blood flow in the femoral head of patients with advanced hip osteoarthritis. The purpose of this study was to evaluate bone blood flow and metabolism in vivo in patients with osteoarthritis of the hip. Ten patients with symptomatic osteoarthritis of the hip were enrolled prospectively. Femoral bone blood flow and metabolism were measured using positron emission tomography together with H2(15)O and [(18)F]fluoride, respectively. Blood flow was 0.054 +/- 0.032 mL cm( 3) min(-1) and 0.041 +/- 0.012 mL cm(-3) min(-1) in symptomatic and contralateral femoral heads, respectively (p = 0.435). The net flux of fluoride from plasma to bone mineral (K i ) was significantly (p = 0.027) higher in the femoral head of the osteoarthritic hip (0.022 +/- 0.012 mL cm(-3) min(-1)) than in that of the contralateral hip (0.007 +/- 0.005 mL cm(-3) min(-1)). This study showed significant increase in bone metabolism in the proximal femur of patients with symptomatic osteoarthritis of the hip joint. There was no evidence of decreased blood flow. PMID- 22833242 TI - The incidence and associations of malignancy in a large cohort of patients with biopsy-determined idiopathic inflammatory myositis. AB - The South Australian (SA) myositis database has registered all patients with biopsy-proven inflammatory myositis in SA from 1980 to 2009. We determined the incidence and associations of malignancy in myositis by linking this database with the SA cancer registry. Standardized incidence ratios (SIR) for malignancy were determined using the total SA population over the same time period, stratified by age and gender. The SIR for cancer in the myositis population (n = 373) was 1.39, p = 0.047. There was a trend towards an increased SIR in dermatomyositis but no increased risk of malignancy in polymyositis or inclusion body myositis. Malignancies of the lung and prostate were the commonest and 28 % of malignancies occurred within one year of IIM diagnosis. The odds of developing cancer were significantly raised in the presence of a shawl sign, male gender, and in patients with overlap syndrome or rheumatoid arthritis whilst myalgia was a significant protective factor. HLA-A28 allele was overrepresented in patients with malignancy (11 vs 2 %, p = 0.006). Patients in SA with myositis are at modestly increased risk for malignancy. We report clinical and genetic risk factors allowing the identification of patients at greatest risk for malignancy. PMID- 22833243 TI - Antiphospholipid syndrome and polyarteritis nodosa: a diagnostic and therapeutic challenge. PMID- 22833244 TI - Evaluation of interferon-gamma release assays for the diagnosis of tuberculosis: an updated meta-analysis. AB - The objective of this investigation was to systematically evaluate the diagnostic accuracy of interferon-gamma release assays (IGRAs) for tuberculosis disease. Both English and Chinese databases were searched for relevant articles through January 2012. We included studies that were restricted to diagnostic applications of IGRAs in patients with active tuberculosis and excluded studies performed in the immune-compromised population. We used Meta-DiSc software to handle the data. We calculated the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and 95 % confidence interval (CI) for each study. We also calculated the pooled sensitivity, specificity, PLR, NLR, DOR, and produced forest plots and summary receiver operating characteristic (SROC) curves. A total of 61 papers (73 studies) were eligible for meta-analysis, including 36 published in English and 25 published in the Chinese language. The overall sensitivity, specificity, PLR, NLR, DOR, and 95 % CI of IGRAs were 0.85 (95 % CI: 0.84-0.86), 0.84 (95 % CI: 0.83-0.85), 7.82 (95 % CI: 6.01-10.19), 0.17 (95 % CI: 0.14-0.21), and 59.27 (95 % CI: 40.19-87.42), respectively. For ten studies evaluating T-SPOT.TB in China, the combined sensitivity, specificity, PLR, NLR, DOR, and 95 % CI were 0.88 (95 % CI: 0.86 0.91), 0.89 (95 % CI: 0.86-0.92), 8.86 (95 % CI: 5.42-14.46), 0.13 (95 % CI: 0.10 0.17), and 88.15 (95 % CI: 41.76-186.07), respectively. The SROC area under the curve (AUC) was 0.9548 (95 % CI: 0.9323-0.9773). Though IGRAs showed good sensitivity and specificity for the detection of tuberculosis in this meta analysis, the decision to use an IGRA should be based on the local prevalence of the disease and the country guidelines, as well as resources and logistical considerations. PMID- 22833245 TI - Clinical significance of Staphylococcus aureus bacteremia in patients with liver cirrhosis. AB - Patients with liver cirrhosis (LC) have impaired immunity and thus are predisposed to infections. Few studies have attempted to evaluate Staphylococcus aureus bacteremia (SAB) in LC patients. Therefore, this study prospectively evaluated the clinical characteristics and outcomes of 642 episodes of SAB from August 1, 2008 to September 31, 2010. Of 642 patients with SAB, 109 (17.0 %) were classified as LC patients whereas the remaining 533 (83.0 %) were classified as non-LC patients. The 30-day mortality rate of LC patients was significantly higher than that of patients with other diseases (32 % vs. 22 %, respectively; P = 0.047). The 30-day mortality rates of patients with MSSA bacteremia and MRSA bacteremia were not significantly different among LC patients (35.1 % with MSSA vs. 26.9 % with MRSA; P = 0.41). A univariate analysis of the 30-day mortality rate of LC patients with SAB for survivors and non-survivors showed that rapidly fatal or ultimately fatal according to the criteria of McCabe and Jackson (OR 5.0; 95 % CI 1.60-15.65), septic shock at initial presentation (OR 3.5; 95 % CI 1.18-10.39) and Child-Pugh class C (OR 2.8; 95 % CI 1.20-6.59) were associated with increased mortality. In contrast, the removal of the eradicable focus was associated with decreased mortality (OR 0.14; 95 % CI 0.04-0.52). Disease severity and liver dysfunction may be useful for predicting the prognosis of SAB in LC patients. PMID- 22833246 TI - Cefazolin plasma protein binding and its covariates in neonates. AB - Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs. PMID- 22833248 TI - G-protein alpha subunits distribution in the cyprid of Balanus amphitrite (=Amphibalanus amphitrite) (Cirripedia, Crustacea). AB - The acorn barnacle Balanus amphitrite is a marine crustacean with six nauplius and one cyprid larval stages and a sessile adult, that represent one of the main constituents of sea biofouling. The cyprid is the last larval stage, specialized for settlement, and the study of its biology is interesting also in the frame of antifouling strategies. In this study, a novel approach to the neurobiology of B. amphitrite cyprid has undertaken, studying immunohistochemically the distribution of some G-protein alpha subunits (Galphas, Galphao Galphai, and Galphaq) on B. amphitrite cyprid. Galphas-like immunoreactivity was observed in the intestinal mucosa, oral cone, epithelial cells along the outer face of the mantle and thorax; Galphao into the fibers of the neuropile of the central nervous system; Galphai in oil cells, epithelial cells, and limbs and thorax muscles; Galphaq was not detected. The results suggest the involvement of the G-protein alpha subunits in different tissues and functions that seem to be in agreement with the distribution of the ones from the same class of G-proteins in vertebrates. PMID- 22833247 TI - Prevalence of isolates with reduced glycopeptide susceptibility in orthopedic device-related infections due to methicillin-resistant Staphylococcus aureus. AB - We evaluated, by an improved susceptibility testing method, the prevalence and significance of low-level glycopeptide resistance in methicillin-resistant Staphylococcus aureus (MRSA) isolates, which belonged to a previously described, retrospective cohort of patients treated for orthopedic device-related infections (ODRI) at the Geneva University Hospital between 2000 and 2008. Fifty-seven individual or multiple isolates were retrieved from 41 ODRI patients for glycopeptide susceptibility and clonality studies, including 20 patients with prosthetic joint (PJ) and 21 with osteosynthesis (OS) MRSA infections. Low-level glycopeptide resistance was detected by elevated teicoplanin or/and vancomycin minimum inhibitory concentrations (MICs >= 4 mg/L), as determined by a previously validated combination of macrodilution and agar dilution assays of improved sensitivity. MRSA isolates with elevated teicoplanin MICs were detected in 20/41 (49 %) ODRI patients at the onset or during the course of glycopeptide therapy, namely, in 10 of 20 patients with PJ and 10 of 21 patients with OS infections. Only one isolate developed a concomitant increase in vancomycin MIC during therapy. 13/20 (65 %) glycopeptide-intermediate S. aureus (GISA)-infected patients, including 7/10 (70 %) with PJ and 6/10 (60 %) with OS, experienced treatment failure. In contrast, therapy failed in only 5/21 (24 %) ODRI patients with non-GISA isolates (p = 0.012), including 2/10 (20 %) with PJ and 3/11 (27 %) with OS infections. The emergence of low-level teicoplanin resistance could not be explained by teicoplanin administration, since only four patients received teicoplanin. The evaluation of low-level teicoplanin resistance may improve the detection of GISA isolates. Further studies are warranted to evaluate the impact of low-level teicoplanin resistance on the outcome of glycopeptide therapy. PMID- 22833249 TI - Exploring beyond cirrhosis. PMID- 22833250 TI - Closing the gap on drug-induced liver injury. PMID- 22833252 TI - A comparison of nutrient losses from two simulated pastureland management scenarios. AB - Fecal deposits by grazing animals on pasturelands have the potential to leach nutrients to runoff during rainfall events. Unlike croplands, grazing systems such as pasturelands or rangelands have little opportunity to ameliorate nutrient runoff through in-field or edge-of-field management practices. Thus, we investigated the amounts and concentrations of nutrients in overland flow from simulated grazing lands. Two grazing management scenarios were simulated: continuous grazing represented by two sparsely vegetated (SV) plots and rotational grazing represented by two densely vegetated (DV) plots. In addition, there were two control plots. The plots were treated with standard cowpats and rainfall was simulated until overland flow at the edge of the plots reached steady-state. Higher runoff was observed from DV plots (9.97 mm) than SV plots (7.05 mm), but the average total suspended solids concentration in runoff from SV plots was approximately 17 times the concentration observed in runoff from the DV plots. The average total phosphorus (TP) concentrations were highest in plots simulating continuous grazing (5.91 mg L(-1)). In both DV and SV plots at least 83% of the TP was found to be in the dissolved form. The average total Kjeldhal nitrogen (TKN) and total nitrogen concentrations observed in runoff samples from SV plots were 1.25 and 1.46 mg L(-1), respectively. Organic nitrogen comprised 95% of the TKN observed in runoff samples from SV plots. The SV plots have relatively higher loads for those nutrients in the particle associated form compared to DV plots, whereas DV plots had higher loads for those nutrients in the dissolved form. Grazing lands without any additional manure applications were found to release nutrients in high levels and vegetation did not show any effect on removing dissolved nutrients from runoff. These results are useful to inform selection of appropriate management practices to reduce nutrient transport to surface waters in watersheds dominated by grazed lands. PMID- 22833251 TI - Time for new methods for avoidance of house dust mite and other allergens. AB - Asthma is a common disease in which environmental exposures and lifestyle factors play critical roles in expression and symptoms. Recommended methods for reducing exposure to domestic allergens as a component of asthma and rhinitis management have changed little over the last 30 years. The data that implementation of these provides clinical benefit are inconsistent. We contend that current methods are ineffective at reducing chronic personal exposure. More effective strategies can be developed based on understanding when people are exposed, the sources of this exposure and the activities associated with this exposure. Developing new methods should be founded on understanding the aerodynamic behavior of particles, their aerosolization, removal from surfaces, and the complex relationships between exposures and clinical outcomes. It will also require developing better proxy measures of chronic exposure, identifying markers for the sub-set of people who benefit, and integrating this with strategies addressing other domestic exposures and lifestyle factors. PMID- 22833253 TI - Comparison between steroid pulse therapy alone and in combination with tonsillectomy for IgA nephropathy. AB - PURPOSE: To the best of our knowledge, no study has compared intermittent steroid pulse therapy, according to Pozzi's regimen, with versus without tonsillectomy. METHODS: In this retrospective cohort analysis, we compared clinical findings, histological findings according to the Oxford classification, and complete remission rates (RR), defined in terms of urinary protein excretion (U-Prot <0.3 g/g creatinine) and urinary red blood cell count (U-RBC <5/high-power field), after 1 year of treatment in patients with IgA nephropathy (IgAN), who received tonsillectomy with steroid pulse therapy (TSP group, n = 26) or steroid pulse therapy alone (SP group, n = 15). RESULTS: The baseline clinical and histological characteristics did not differ between the two groups. The RR for U-Prot analyzed by the Kaplan-Meier method did not differ between the groups (76.9 vs. 53.3 %). However, the RR for U-RBC was significantly higher in the TSP than in the SP group (88.4 vs. 33.3 %, log-rank test; P = 0.0008). The RRs for U-Prot and U-RBC were significantly higher in the TSP group than in the SP group (69.2 vs. 13.3 %, log-rank test; P = 0.0019). Cox's regression analysis showed that combination therapy was associated with higher RR (odds ratio, 12.5; 95 % confidence interval, 2.91-86.7; P = 0.0002). CONCLUSIONS: Tonsillectomy combined with steroid pulse therapy achieved higher RR after 1 year of treatment, compared with steroid pulse monotherapy in patients with IgAN. The long-term effects on renal survival should be analyzed in further studies. PMID- 22833254 TI - Transurethral resection of ejaculatory duct in infertile men: outcome and predictors of success. AB - OBJECTIVES: To evaluate the outcome of transurethral resection of the ejaculatory duct (TURED) in the treatment for ejaculatory duct obstruction (EDO) and define predictors of success. MATERIALS AND METHODS: We retrospectively evaluated 23 infertile men between 2006 and 20011, who were diagnosed as having EDO. Inclusion criteria were azoospermia or oligozoospermia, low ejaculate volume, low ejaculate PH, little or no fructose in seminal plasma with normal serum levels of gonadotropins and testosterone and evidence of obstruction on transrectal ultrasonography (TRUS) or magnetic resonance images (MRI). Seventeen patients were diagnosed as complete EDO, and the remaining 6 were considered as having partial EDO. All patients were treated by TURED. RESULTS: Midline cysts were diagnosed in seven cases, and the remaining 16 patients had postinflammatory obstruction of ejaculatory ducts (ED). Overall, a significant improvement of semen quality was achieved after surgery. All patients with partial EDO showed improvements in semen parameters after TURED compared to 23.5% (4/17) in those with complete EDO. Improvement in sperm count was 71.5% and 31% for patients with midline cysts and patients with non-cystic causes of EDO, respectively. Six (26%) patients developed complications including epididymo-orchitis in 2, watery ejaculate in 3 and conversion to azoospermia in 1. Spontaneous pregnancies were achieved in 3 (13%) cases: 2 (33.3%) men with partial and 1 (5.9%) with complete obstruction. CONCLUSION: Partial EDO, whatever the etiology, has an excellent outcome after TURED. Complete EDO due to cysts appears to respond better than postinflammatory obstruction to TURED. PMID- 22833255 TI - Proteomic analysis from the mineralized radular teeth of the giant Pacific chiton, Cryptochiton stelleri (Mollusca). AB - The biomineralized radular teeth of chitons are known to consist of iron-based magnetic crystals, associated with the maximum hardness and stiffness of any biomineral. Based on our transmission electron microscopy analysis of partially mineralized teeth, we suggest that the organic matrix within the teeth controls the iron oxide nucleation. Thus, we used Nano-LC-MS to perform a proteomic analysis of the organic matrix in radular teeth of the chiton Cryptochiton stelleri in order to identify the proteins involved in the biomineralization process. Since the genome sequence of C. stelleri is not available, cross-species similarity searching and de novo peptide sequencing were used to screen the proteins. Our results indicate that several proteins were dominant in the mineralized part of the radular teeth, amongst which, myoglobin and a highly acidic peptide were identified as possibly involved in the biomineralization process. PMID- 22833256 TI - Incidence of type 2 diabetes by place of birth in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - Incidence of diabetes among US foreign-born individuals is not well studied. Data were from the Multi Ethnic Study of Atherosclerosis. Cox proportional hazards regression was used to examine diabetes risk by race/ethnicity, place of birth, and duration of residence among foreign-born. Foreign-born Latinos had a higher risk of incident diabetes compared to US-born Latinos (hazard ratio (HR) 1.79 [95 % confidence interval (CI) 1.00-3.21]). Latinos born in Mexico (HR, 2.26 [95 % CI, 1.18-4.33]) had higher risk of incident diabetes compared to US-born Latinos. Foreign-born living in the US >=20 years had a higher adjusted risk of incident diabetes compared to those in the US for <20 years (HR, 1.60 [95 % CI, 1.05 2.55]). Incident diabetes may be higher among foreign-born compared to native born; incident diabetes may also be higher among those immigrants who have lived in the US for longer periods of time. Future studies should characterize individuals by race/ethnicity and place of birth to account for differences in biology and time spent in the US. PMID- 22833257 TI - Engaging Latino farmworkers in the development of symbols to improve pesticide safety and health education and risk communication. AB - The working and living environments of farmworkers put them and their families at risk for pesticide exposure and, consequently, immediate and long-term health effects. In this study, visual materials for a pesticide toxicology safety and health curriculum were constructed by engaging farmworkers in various stages of symbol development. Twenty-seven farmworkers in two states participated in this descriptive case study through focused small group discussions and interviews. Our findings support the importance of vivid and realistic symbols, the effectiveness of a traffic-light symbol in communicating technical information to farmworkers, and the need to engage low-literacy end-users in the production of educational materials. This work informs the development of curricula for other vulnerable populations pertaining to a variety of health-related topics, as well as discussions surrounding regulatory proposals to revise the United States Worker Protection Standard. PMID- 22833258 TI - Socio-medical challenges of asylum seekers prior and after coming to the US. AB - Refugee asylum seekers face complex social and medical challenges. We evaluated 30 consecutive asylees in New York for socio-demographic and health backgrounds, characteristics of torture, presentations and medico legal path. RESULTS: Majority was male, young, educated from sub-Saharan Africa. In home countries, all had employment; 58 % had fair or good access to healthcare; 36 % used traditional medicine; and 14 % had insurance. In the US, social support and accommodations were provided by countrymen; overwhelmingly they were unemployed; none had insurance; and 57 % never had any contact with healthcare system. Sixty nine percent had PTSD and 69 % depression. Almost all had scars with significant sequelae. Eighty eight percent were granted asylum. Ironically, asylees had better access to social and health services in home countries than the US. We recommend better recognition of, and addressing asylees' social and health needs through a multidisciplinary approach drawing on other countries' experience, and expanding existent programs for refugees to cover asylees. PMID- 22833259 TI - Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF-beta signal. AB - BACKGROUND AND OBJECTIVES: Sorafenib has been shown to improve survival rate of hepatocellular carcinoma (HCC) patients significantly. Decline of tumor infiltrated regulatory T cells (TITs) may account for the activity of sorafenib partially. In this study, the underlying mechanism of sorafenib reducing TITs was investigated. METHODS: Tumor infiltrated mononuclear cells (TIMs), which were isolated form 19 HCC patients with or without sorafenib therapy, were analyzed by flow cytometry. TGF-beta signal pathways were analyzed by immunoblotting. In vitro test, naive T cells were induced to regulatory T cells (Tregs) with or without sorafenib. After 3 days of culture, percentage of Tregs from CD4+ cells and TGF-beta signal pathways were analyzed. Meanwhile, TIMs from HCC patients without sorafenib treatment were cultured in the presence of sorafenib, and then the percentage of Foxp3 expressing cells from TIMs was analyzed. RESULTS: TITs were increased in HCC patients compared with controls. However, after sorafenib therapy, TITs were decreased significantly and TGF-beta signal pathways were down regulated. Additionally, in the presence of sorafenib, induction of Tregs was inhibited and TGF-beta signal pathways in resulting cells were down-regulated. However, sorafenib treatment did not affect the percentage of Foxp3 expressing cells from TIMs in vitro. CONCLUSIONS: Sorafenib reducing TITs in HCC patients are associated with down-regulation of TGF-beta signal. This finding may help us for better understanding the activity of sorafenib in HCC patients. PMID- 22833260 TI - Concurrent pleural infiltration by chronic lymphocytic leukemia and adenocarcinoma of unknown primary site diagnosed by effusion cytology. AB - Synchronous malignancies in a pleural effusion are rare. A case of concurrent pleural infiltration by adenocarcinoma of unknown primary site and chronic lymphocytic leukemia (CLL) is presented in this case study, which was diagnosed by effusion cytology. Pleural effusion is not an uncommon complication in patients with B-CLL. Even in a pleural effusion rich in monoclonal lymphocytes, the presence of a second cancer must be excluded because this can be the main cause of mortality. The role of cytology in such cases is of paramount importance. PMID- 22833261 TI - A case-controlled matched-pair cohort study of single-incision and conventional laparoscopic gastric band patients in a single US center with 1-year follow-up. AB - INTRODUCTION: Single-incision laparoscopic gastric banding has been reported to be safe and feasible. This matched case-control study is the first to compare the outcome in terms of weight loss and comorbidity improvement and band positioning of single-incision versus conventional laparoscopic gastric banding with 1-year follow-up. PATIENTS AND METHODS: Patients undergoing gastric banding surgery by one surgeon (S.V.) were prospectively entered into a database. Data collected included basic demographics, perioperative parameters, early and late postoperative (PO) morbidity, weight loss, and phi angle. Ten patients who underwent a single-incision gastric banding procedure were matched one-to-two with 20 patients undergoing conventional gastric banding from a database of 151 patients. Match was obtained according to gender, body mass index (BMI) +/- 4 kg/m(2), age +/- 8 years, and presence of at least one comorbidity in common. Generalized linear mixed models were used for statistical analysis. RESULTS: Patients' initial characteristics were similar: SIL and conventional, respectively: sex (female:male) 9:10 and 18:20; age (years): 36.5 +/- 10 and 37.5 +/- 9; preoperative BMI (kg/m(2)): 41.8 +/- 4 and 42.4 +/- 3; weight (kg): 110.2 +/- 13 and 117.9 +/- 13; hospital stay (days): 1 and 1; operative time (min): 106.6 +/- 24 and 100.9 +/- 22. No significant differences were found in patients' BMI or excess weight loss during 1-year follow-up. The phi angles of the bands varied in a comparable range: PO day 1 (degrees): 62 +/- 13 and 59 +/- 15; PO week 6: 55 +/- 9 and 54 +/- 11, for SIL and conventional, respectively. CONCLUSIONS: In this matched case-controlled study, single-incision laparoscopic adjustable gastric banding surgery outcomes were similar to those of the conventional multi-trocar laparoscopic operation. Band position as described by phi angle was also similar in the two groups. These results suggest that use of a single-incision approach does not compromise the results or band positioning of gastric banding surgery. PMID- 22833262 TI - Benchtop evaluation of pressure barrier insufflator and standard insufflator systems. AB - BACKGROUND: Previous experimental research has reported minimal differences in pressure maintenance between different versions of standard insufflators (SI). However, a recent report identified potential clinical benefits with a valveless pressure barrier insufflator (PBI). We sought to perform a benchtop objective evaluation of SI and PBI systems. METHODS: A rigid box system with continuous pressure manometry was used to evaluate a PBI (Surgiquest Airseal) and two SIs (SI1 = Stryker PneumoSure High Flow Insufflator and SI2 = Storz SCB Thermoflator). Pressure maintenance of 15 mmHg was evaluated during experimental conditions of leakage from a 5 mm port site, leakage from a 12 mm port site, and continuous suction. RESULTS: With leakage from the 5 mm port site, the PBI maintained pressure of >13 mmHg whereas the pressures dropped moderately with the SI1 (7-13 mmHg) and SI2 insufflators (3-7 mmHg) and did not regain goal pressure until leakage was stopped. With leakage from 12 mm port site, the PBI pressure decreased to 9-11 mmHg, whereas the SI1 and SI2 lost insufflation pressures completely. The PBI maintained pressure of >11 mmHg during continuous suction while the SI1 and SI2 lost pressure entirely, and actually showed negative pressure from air suction into the rigid box system. When evaluated statistically with the mixed model repeated measures ANOVA, the SI1 and SI2 performed similarly while the PBI maintained increased pressure. CONCLUSIONS: In the experimental rigid box system, the PBI more successfully maintained pressure in response to leakage and suction than SIs. PMID- 22833263 TI - Integration of transanal specimen extraction into laparoscopic anterior resection with total mesorectal excision for rectal cancer: a consecutive series of 179 patients. AB - BACKGROUND AND OBJECTIVES: This prospective study focused on patients with rectal cancer who underwent transanal specimen extraction after laparoscopic anterior resection with total mesorectal excision and specifically aims to investigate whether the transanal approach can be accepted as a safe and effective method for extracting the malignant specimen from the peritoneal cavity. PATIENTS AND METHODS: A prospectively designed database of a consecutive series of patients undergoing laparoscopic low anterior resection for rectal malignancy with various tumor-node-metastasis (TNM) classifications from April 1991 to May 2011 at the Texas Endosurgery Institute was analyzed. Patient selection for transanal specimen extraction and intracorporeal anastomosis was made on the basis of size of the pathology and distance of rectal lesions from the anal verge. RESULTS: 179 anterior resections were completed laparoscopically with intracorporeal anastomosis and transanal specimen extraction. The operating time for the entire procedures including resection, anastomosis, and specimen extraction was 170.9 +/ 51.2 min, blood loss during the procedures was 86.4 +/- 37.7 ml, and distance of the lower edge of the lesion from the anal verge was measured to be 11.3 +/- 7.3 cm. Postoperatively, three patients developed anastomotic leakage with a leak rate of 1.7%, and the overall major complication rate after the procedures was 5.0%. Length of hospital stay was 6.9 +/- 2.8 days. Two-year follow-up showed development of anal stenosis in three patients (2.0%) and erectile dysfunction in one patient (0.36%) after surgery. Finally, 9 out of 179 patients who underwent laparoscopic anterior resection with transanal specimen extraction were confirmed to have cancer recurrence, with 2-year local recurrence rate of 5.0%. CONCLUSIONS: Transanal specimen extraction in laparoscopic rectal cancer resection is a safe and effective approach with comparable local cancer recurrence rate and postoperative complication rates, suggesting it can be integrated into laparoscopic anterior resection for rectal cancer. PMID- 22833264 TI - Surgeons blinded by enhanced navigation: the effect of augmented reality on attention. AB - BACKGROUND: Advanced image-guidance systems allowing presentation of three dimensional navigational data in real time are being developed enthusiastically for many medical procedures. Other industries, including aviation and the military, have noted that shifting attention toward such compelling assistance has detrimental effects. Using the detection rate of unexpected findings, we assess whether inattentional blindness is significant in a surgical context and evaluate the impact of on-screen navigational cuing with augmented reality. METHODS: Surgeons and trainees performed an endoscopic navigation exercise on a cadaveric specimen. The subjects were randomized to either a standard endoscopic view (control) or an AR view consisting of an endoscopic video fused with anatomic contours. Two unexpected findings were presented in close proximity to the target point: one critical complication and one foreign body (screw). Task completion time, accuracy, and recognition of findings were recorded. RESULTS: Detection of the complication was 0/15 in the AR group versus 7/17 in the control group (p = 0.008). Detection of the screw was 1/15 (AR) and 7/17 (control) (p = 0.041). Recognition of either finding was 12/17 for the control group and 1/15 for the AR group (p < 0.001). Accuracy was greater for the AR group than for the control group, with the median distance from the target point measuring respectively 2.10 mm (interquartile range [IQR], 1.29-2.37) and 4.13 (IQR, 3.11 7.39) (p < 0.001). CONCLUSION: Inattentional blindness was evident in both groups. Although more accurate, the AR group was less likely to identify significant unexpected findings clearly within view. Advanced navigational displays may increase precision, but strategies to mitigate attentional costs need further investigation to allow safe implementation. PMID- 22833266 TI - Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis. AB - OBJECTIVE: Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression. METHODS: Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice. RESULTS: We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-kappaB signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice. CONCLUSION: This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-kappaB signaling pathways, skeletal muscle-related genes, and induction and/or progression of OA. PMID- 22833267 TI - Growth and properties of coherent twinning superlattice nanowires. AB - Although coherent twin boundaries require little energy to form in nanoscale single crystals, their influence on properties can be dramatic. In recent years, some important steps forward have been made in understanding and controlling twinning processes at the nanoscale, making possible the fabrication of nanoengineered twinning superlattices in crystalline nanowires. These advances have opened new possibilities for properties and functionalities at the atomic and quantum scales by modulating twin densities. This article presents a brief overview of recent theoretical and experimental progress in growth mechanisms and promising properties of coherent twinning superlattice nanowires with special emphasis toward cubic systems in semiconductor and metallic materials. In particular, we show how nanoscale growth twins can considerably enhance bandgap engineering and mechanical behaviour in quasi-one-dimensional materials. Opportunities for future research in this emerging area are also discussed. PMID- 22833265 TI - Frizzled homolog proteins, microRNAs and Wnt signaling in cancer. AB - Wnt signaling pathways play important roles in tumorigenesis and are initiated by binding of Wnt to various receptors including frizzleds (FZDs). FZDs are one of several families of receptors comprised of FZD/LRP/ROR2/RYK in the Wnt signaling pathway. Expression of some FZD receptors are up regulated, thereby activating the Wnt signaling pathway and is correlated with cancer malignancy and patient outcomes (recurrence and survival) in many cancers. The FZD family contains ten genes in humans and their function has not been completely examined including the regulatory mechanisms of FZD genes in cancer. Knockdown of FZDs may suppress the Wnt signaling pathway resulting in decreased cell growth, invasion, motility and metastasis of cancer cells. Recently a number of microRNAs (miRNAs) have been identified and reported to be important in several cancers. MiRNAs regulate target gene expression at both the transcription and translation levels. The study of miRNA is a newly emerging field and promises to be helpful in understanding the pathogenesis of FZDs in cancer. In addition, miRNAs may be useful in regulating FZDs in cancer cells. Therefore, the aim of this review is to discuss current knowledge of the functional mechanisms of FZDs in cancer, including regulation by miRNAs and the potential for possible use of miRNAs and FZDs in future clinical applications. PMID- 22833268 TI - Adolescent fertility and risky environments: a population-level perspective across the lifespan. AB - Timing of first reproduction is a key life-history variable with important implications for global economic development and health. Life-history theory predicts that human reproductive strategies are shaped by mortality regimes. This study provides the first test of the relationship between population-level adolescent fertility (AF) and extrinsic risk at two time points. Data are from United Nations database and were analysed using mediation and moderation techniques. The goals were to determine whether (i) early risk has a stronger impact on fertility than current risk; (ii) current risk mediates the relationship between early risk and fertility outcomes; and (iii) different levels of early risk influence the relationship between current risk and fertility. Results indicated that current risk partially mediated the relationship between early risk and fertility, with early risk having the strongest impact on reproduction. Measures for early and current mortality did not show significant interaction effects. However, a series of separate regression analyses using a quantile split of early risk indicated that high levels of early risk strengthened the relationship between current risk and AF. Overall, these findings demonstrate that reproductive strategies are significantly influenced by fluctuations of early mortality as well as current environmental cues of harshness. PMID- 22833269 TI - Variability in solar radiation and temperature explains observed patterns and trends in tree growth rates across four tropical forests. AB - The response of tropical forests to global climate variability and change remains poorly understood. Results from long-term studies of permanent forest plots have reported different, and in some cases opposing trends in tropical forest dynamics. In this study, we examined changes in tree growth rates at four long term permanent tropical forest research plots in relation to variation in solar radiation, temperature and precipitation. Temporal variation in the stand-level growth rates measured at five-year intervals was found to be positively correlated with variation in incoming solar radiation and negatively related to temporal variation in night-time temperatures. Taken alone, neither solar radiation variability nor the effects of night-time temperatures can account for the observed temporal variation in tree growth rates across sites, but when considered together, these two climate variables account for most of the observed temporal variability in tree growth rates. Further analysis indicates that the stand-level response is primarily driven by the responses of smaller-sized trees (less than 20 cm in diameter). The combined temperature and radiation responses identified in this study provide a potential explanation for the conflicting patterns in tree growth rates found in previous studies. PMID- 22833270 TI - Maternal effects in disease resistance: poor maternal environment increases offspring resistance to an insect virus. AB - Maternal effects can be adaptive and because of their intrinsic time delays may have important effects on population dynamics. In vertebrates, and increasingly invertebrates, it is well established that offspring defence is in part determined by maternal parasite exposure. It has also been suggested that there may be indirect maternal effects on immunity mediated by other components of the maternal environment, including density and resource availability. Here, we examine the effect maternal resource availability has on the immunity of offspring in an insect-virus system. We use five different maternal resource levels and examine immunity in the offspring both directly, by challenge with a virus, and by measuring a major component of the immune system, across three offspring environments. Both the direct infection assay and the measure of immunocompetence show clearly that offspring from mothers in poor environments are more resistant to parasites. This may result from life-history optimization of mothers in poor environments, or because the poor environment acts as a cue for higher disease risk in the next generation. This emphasizes the importance of maternal effects on disease resistance, mediated through indirect environmental factors that will have important implications to both the ecological and evolutionary dynamics of host-parasite interactions. PMID- 22833271 TI - How does adaptation sweep through the genome? Insights from long-term selection experiments. AB - A major goal in evolutionary biology is to understand the origins and fates of adaptive mutations. Natural selection may act to increase the frequency of de novo beneficial mutations, or those already present in the population as standing genetic variation. These beneficial mutations may ultimately reach fixation in a population, or they may stop increasing in frequency once a particular phenotypic state has been achieved. It is not yet well understood how different features of population biology, and/or different environmental circumstances affect these adaptive processes. Experimental evolution is a promising technique for studying the dynamics of beneficial alleles, as populations evolving in the laboratory experience natural selection in a replicated, controlled manner. Whole-genome sequencing, regularly obtained over the course of sustained laboratory selection, could potentially reveal insights into the mutational dynamics that most likely occur in natural populations under similar circumstances. To date, only a few evolution experiments for which whole-genome data are available exist. This review describes results from these resequenced laboratory-selected populations, in systems with and without sexual recombination. In asexual systems, adaptation from new mutations can be studied, and results to date suggest that the complete, unimpeded fixation of these mutations is not always observed. In sexual systems, adaptation from standing genetic variation can be studied, and in the admittedly few examples we have, the complete fixation of standing variants is not always observed. To date, the relative frequency of adaptation from new mutations versus standing variation has not been tested using a single experimental system, but recent studies using Caenorhabditis elegans and Saccharomyces cerevisiae suggest that this a realistic future goal. PMID- 22833274 TI - Supportive care and palliative care: a time for unity in diversity. PMID- 22833272 TI - Abdicating power for control: a precision timing strategy to modulate function of flight power muscles. AB - Muscles driving rhythmic locomotion typically show strong dependence of power on the timing or phase of activation. This is particularly true in insects' main flight muscles, canonical examples of muscles thought to have a dedicated power function. However, in the moth (Manduca sexta), these muscles normally activate at a phase where the instantaneous slope of the power-phase curve is steep and well below maximum power. We provide four lines of evidence demonstrating that, contrary to the current paradigm, the moth's nervous system establishes significant control authority in these muscles through precise timing modulation: (i) left-right pairs of flight muscles normally fire precisely, within 0.5-0.6 ms of each other; (ii) during a yawing optomotor response, left-right muscle timing differences shift throughout a wider 8 ms timing window, enabling at least a 50 per cent left-right power differential; (iii) timing differences correlate with turning torque; and (iv) the downstroke power muscles alone causally account for 47 per cent of turning torque. To establish (iv), we altered muscle activation during intact behaviour by stimulating individual muscle potentials to impose left-right timing differences. Because many organisms also have muscles operating with high power-phase gains (Delta(power)/Delta(phase)), this motor control strategy may be ubiquitous in locomotor systems. PMID- 22833275 TI - Advanced pleomorphic liposarcomas: clinical outcome and impact of chemotherapy. PMID- 22833276 TI - Expression of a nematode symbiotic bacterium-derived protease inhibitor protein in tobacco enhanced tolerance against Myzus persicae. AB - Fusion proteins of a protease inhibitor from an entomopathogenic nematode symbiotic bacterium (PIN1) and green fluorescent protein (GFP) were expressed in tobacco (Nicotiana tobacum cv. Samsun NN). The PIN1-GFP protein expressed under the control of the CaMV-35S promoter was detected in leaves of transgenic tobacco plants. The effect of PIN1 on anti-pest activity for Myzus persicae was tested by feeding neonate aphids on three independent homozygous lines. For nymphs fed on PIN1-GFP-expressing plants, no effects on insect survival were observed but average insect weight and fecundity were significantly reduced. The aphid biomass was decreased by 30-35 % compared to those reared on control plants. The effects of PIN1 on M. persicae were correlated with the decrease of the leucine aminopeptidase and total protease activities of whole insect extracts. Furthermore, an increase in polyphenoloxidase activity was observed in PIN1-GFP expressing plants. These results revealed that the transgenic expression of PIN1 in tobacco enhanced tolerance against aphids. Key message This study suggests that entomopathogenic nematode symbiotic bacterium is another valuable resource of protease inhibitors which can be engineered into plants for insect pest management. PMID- 22833277 TI - Histological and cytological characterization of adult plant resistance to wheat stripe rust. AB - Wheat cultivar Xingzi 9104 (XZ) possesses adult plant resistance (APR) to stripe rust caused by Puccinia striiformis f. sp. tritici (Pst). In this study, histological and cytological experiments were conducted to elucidate the mechanisms of APR in XZ. The results of leaf inoculation experiments indicated that APR was initiated at the tillering stage, gradually increased as the plant aged and highly expressed after boot stage. The histology and oxidative burst in infected leaves of plants at seedling, tillering and boot stages were examined using light microscopic and histochemical methods. Subcellular changes in the host-pathogen interactions during the seedling and boot stages were analyzed by transmission electron microscopy. The results showed that haustorium formation was retarded in the adult plants and that the differentiation of secondary intercellular hyphae was significantly inhibited, which decreased the development of microcolonies in the adult plants, especially in plants of boot stage. The expression of APR to stipe rust during wheat development was clearly associated with extensive hypersensitive cell death of host cells and localized production of reactive oxygen species, which coincided with the restriction of fungal growth in infection sites in adult plants. At the same time, cell wall-related resistance in adult plants prevented ingression of haustorial mother cells into plant cells. Haustorium encasement was coincident with malformation or death of haustoria. The results provide useful information for further determination of mechanisms of wheat APR to stripe rust. KEY MESSAGE: The expression of APR to stipe rust in wheat cultivar Xingzi 9104 (XZ) was clearly associated with extensive hypersensitive cell death of host cells and the localized production of reactive oxygen species. PMID- 22833278 TI - Explaining the fibroblast growth factor paradox in osteoarthritis: lessons from conditional knockout mice. PMID- 22833279 TI - The role of FOXP3 in the development and metastatic spread of breast cancer. AB - The transcription factor FOXP3 is widely known for its role in the development and function of immunoregulatory T cells. However, it has been discovered recently that FOXP3 is also expressed in epithelial cells of the normal human breast, ovary and prostate. Aggressive cancer of these epithelial tissues often correlates with abnormal expression of FOXP3, which can be either absent or underexpressed at transcript or protein levels. It is becoming clear that this failure of normal FOXP3 expression can result in dysregulation of the expression of a range of oncogenes which have been implicated in the development and metastasis of cancer. Recent evidence suggests that FOXP3 might also regulate chemokine receptor expression, providing a possible explanation for the chemokine driven, tissue-specific spread that is characteristic of many cancers. This review first summarises the general structure, function and properties of FOXP3. This is followed by an analysis of the tumour-suppressive properties of this transcription factor, with particular reference to the development and chemokine mediated spread of human breast cancer. A final section focuses on potential applications of this new knowledge for therapeutic intervention. PMID- 22833281 TI - Cross-sensory correspondences and cross talk between dimensions of connotative meaning: visual angularity is hard, high-pitched, and bright. AB - Higher-pitched sounds are judged to be, among other things, sharper, harder, and brighter than lower-pitched sounds. Following Karwoski, Odbert, and Osgood (Journal of General Psychology 26:199-222, 1942), such cross-sensory correspondences are proposed to have a semantic basis, reflecting extensive bidirectional cross-activation among dimensions of connotative meaning. On this basis, the same core set of correspondences should emerge whichever sensory feature is used to probe it. More angular (sharper) shapes should, for example, be higher-pitched and have the same cross-sensory features as higher-pitched sounds. Experiments 1-3 employed a speeded classification task designed to reveal cross-sensory correspondences having a semantic basis. With words as to-be classified stimuli and with shapes varying in angularity as concurrent incidental stimuli, congruity effects between angularity and each of hardness, pitch, and brightness were confirmed. Correspondences with a semantic basis need not be cross-modality in nature. Experiment 4 confirmed this by reproducing the brightness-angularity congruity effect when contrasting values for both features were encoded nonverbally within the visual modality. The varying nature and origins of cross-sensory correspondences and the basis on which they induce congruity effects in speeded classification are explored. PMID- 22833282 TI - Optically tunable amino-functionalized graphene quantum dots. AB - Amino-functionalized graphene quantum dots (af-GQDs) with discrete molecular weights and specific edges were self-limitedly extracted from oxidized graphene sheet. Their optical properties can be precisely controlled only by the selective and quantitative functionalization at the edge sites. The af-GQDS exhibit bright colorful fluorescence under a single-wavelength excitation. PMID- 22833280 TI - Novel mechanisms of abdominal aortic aneurysms. AB - Abdominal aortic aneurysms (AAAs) are a common but asymptomatic disease that has high susceptibility to rupture. Current therapeutic options are limited to surgical procedures because no pharmacological approaches have been proven to decrease either expansion or rupture of human AAAs. The current dearth of effective medical treatment is attributed to insufficient understanding of the mechanisms underlying the initiation, propagation and rupture of AAAs. This review will emphasize recent advances in mechanistic studies that may provide insights into potential pharmacological treatments for this disease. While we primarily focus on recent salient findings, we also discuss mechanisms that continue to be controversial depending on models under study. Despite the progress on exploring mechanisms of experimental AAAs, ultimate validation of mechanisms will require completion of prospective double-blinded clinical trials. In addition, we advocate increased emphasis of collaborative studies using animal models and human tissues for determination of mechanisms that explore expansion and rupture of existing AAAs. PMID- 22833283 TI - Monomorphic region of the serotonin transporter promoter gene in New World monkeys. AB - Genetic variation in the human serotonin system has long been studied because of its functional consequences and links to various neuropsychiatric and behavior related disorders. Among non-human primates, the common marmosets (Callithrix jacchus) and tufted capuchins monkeys (Cebus apella) are becoming increasingly used as models to study the effects of genes, environments, and their interaction on physiology and complex behavior. In order to investigate the independent functions of and potential interactions between serotonin-related genes, anxiety and neuropsychiatric disorders, we analyzed the presence and variability of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in marmoset and capuchin monkeys. By PCR and using heterologous primers from the human sequence, we amplified and then sequenced the corresponding 5-HTT region in marmosets and capuchins. The resulting data revealed the presence of a tandem repeat sequence similar to that described in humans, but unlike humans and other Old World primates, no variable length alleles were detected in these New World monkeys, suggesting that if serotonin transporter is involved in modulating behavior in these animals it does so through different molecular mechanisms. PMID- 22833284 TI - Identification of parasites in Puffinus puffinus (Birds, Procellariiformes) from Northeastern Brazil. AB - Studies on the parasitic fauna of migratory sea birds of the Puffinus genus are scarce. Therefore, the aim of this study was to identify parasites of 16 specimens of Puffinus puffinus (Procellariiformes, Procellariidae) that died during the period of June 2011 to December 2011 at the Wildlife Screening Center (CETAS) of the Brazilian Institute of Environment and Natural Resources (IBAMA) in Cabedelo, Paraiba. During necropsy, biting lice and/or gastrointestinal helminths were collected in seven (43.7 %) birds. Lice were collected in five (31.2 %) birds, and the species identified were Halipeurus diversus, Trabeculus aviator, Austromenopon paululum), Saemundssonia sp. and Naubates sp. The prevalence of helminths was also 31.2 %. The nematodes species were Seuratia shipleyi and Contracaecum sp., and cestodes were Tetrabothrius sp. This is the first record in Brazil of Naubates sp., Seuratia shipleyi, Contracaecum sp., and Tetrabothrius sp. in Puffinus puffinus. PMID- 22833285 TI - Differential phosphorylation of thylakoid proteins in mesophyll and bundle sheath chloroplasts from maize plants grown under low or high light. AB - In C4 plants, such as maize, the photosynthetic apparatus is partitioned over two cell types called mesophyll (M) and bundle sheath (BS), which have different structure and specialization of the photosynthetic thylakoid membranes. We characterized protein phosphorylation in thylakoids of the two cell types from maize grown under either low or high light. Western blotting with phosphothreonine antibodies and ProQ phosphostaining detected light-dependent changes in the protein phosphorylation patterns. LC-MS/MS with alternating CID and electron transfer dissociation sequencing of peptide ions mapped 15 protein phosphorylation sites. Phosphorylated D2, CP29, CP26, Lhcb2 proteins, and ATPsynthase were found only in M membranes. A previously unknown phosphorylation site was mapped in phosphoenolpyruvate carboxykinase from the BS cells. Phosphorylation stoichiometry was calculated from the ratios of normalized ion currents for phosphorylated to nonphosphorylated peptide pairs from the D1, D2, CP43, and PbsH proteins of photosystem II (PSII). Every PSII in M thylakoids contained on average 1.5 +/- 0.1 or 2.3 +/- 0.2 phosphoryl groups in plants grown under either low or high light, while in BS membranes the corresponding numbers were 0.25 +/- 0.1 or 0.7 +/- 0.2, respectively. It is suggested that the phosphorylation level, as well as turnover of PSII depend on the structure of thylakoids. PMID- 22833286 TI - Treatment-related morbidity and toxicity of CRS and oxaliplatin-based HIPEC compared to a mitomycin and doxorubicin-based HIPEC protocol in patients with peritoneal carcinomatosis: a matched-pair analysis. AB - INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option for selected patients with peritoneal carcinomatosis. The use of intraperitoneal oxaliplatin seems to further improve the efficacy of the combined treatment concept. Nevertheless, additional toxicity might be expected. PATIENTS AND METHODS: Between 03/2004 and 08/2010 307 patients underwent CRS and HIPEC at the University Medical Center Regensburg. Forty of these patients received oxaliplatin-based HIPEC. A matched pair analysis was performed to compare IP oxaliplatin to our former standard HIPEC protocol with mitomycin C (MMC) and doxorubicin. RESULTS: The mean operating time in the OX and the MMC group was 315 and 313 min, respectively. Median hospital stay was 15.5 days in the OX group and 17 days in the MMC group. The grade 3/4 morbidity rate according to CTCAEv3.0 was 42.5% versus 37.5% (P = 0.648). Perioperative mortality was 2.5% versus 0%. CONCLUSION: Our data suggest that the use of IP oxaliplatin in the context of CRS and HIPEC does not significantly increase perioperative morbidity and/or mortality rates. Nevertheless, randomized controlled trials are required to determine the optimal intraperitoneal chemotherapeutic regimen regarding toxicity, postoperative complications, and oncological outcome. PMID- 22833287 TI - The effect of Er:YAG laser irradiation on hydroxyapatite-coated implants and fluoride-modified TiO2-blasted implant surfaces: a microstructural analysis. AB - The purpose of this study was to evaluate the microscopic changes and surface roughness on hydroxyapatite (HA)-coated implants following exposure to different powers and durations of Er:YAG laser irradiation in order to determine the proper pulse energy level and irradiation time. Ten HA-coated implants and ten fluoride modified TiO2 implants were used. The implants were divided into a control (one implant) and test group (nine implants) for each implant type. Implants in the test groups were sub-divided into three groups (three implants per group) based on the applied laser pulse energy and irradiation time. The measurement of surface roughness was performed on all implants in the test groups using a white light interferometer before and after laser irradiation. R a values were recorded and compared in order to evaluate changes in surface roughness. For HA-coated implants, the R a values increased in all test groups after laser irradiation. However, mean R a values in the fluoride-modified TiO2-blasted implant test group were decreased after irradiation. There was no statistical difference. Scanning electron microscope analysis revealed surface alterations in both the HA-coated and fluoridated TiO2-blasted implants irradiated for 1.5 min at 100 mJ/pulse, 10 Hz. When the pulse energy and irradiation time increased, greater surface alterations, including surface flattening and microfractures, were observed. In conclusion, the results of the current study suggest that no changes could be observed in both HA-coated implants and fluoride-modified TiO2-blasted implants after irradiation at an intensity of 100 mJ/pulse, 10 Hz for 1 min performed to achieve surface detoxification. PMID- 22833289 TI - Cytochemistry of fat body trophocytes and ovaries of workers and queens of Melipona quadrifasciata anthidioides (Hymenoptera: Apidae: Meliponini) during vitellogenesis. AB - The fat body (FB) of insects is where yolk proteins are synthesized. Therefore, relationships between the FB and oogenesis were studied in nurse workers, virgins, and physogastric queens of Melipona quadrifasciata anthidioides, a stingless bee in which the workers produce and lay eggs while provisioning brood cells. The relationships between FB and oogenesis, as well as the routes of materials from hemolymph to the oocytes, were studied through the cytochemical detection of lipids by osmium imidazole (OI), carbohydrates by ruthenium red (RR) and basic proteins by ammoniacal silver (AS). The results show differences in the presence of the studied materials in FB trophocytes and ovary of the classes of females studied and oogenesis phases. Material that tested positive for the treatments was detected among the classes of individuals studied in both, trophocytes and oocytes, and in the route of those materials from hemolymph to the oocytes. The differences found among the individual classes indicate relationships with the nutrition and adaptation to the parsimonious use of nutrients in the metabolism of reproduction. PMID- 22833288 TI - The efficacy of the use of IR laser phototherapy associated to biphasic ceramic graft and guided bone regeneration on surgical fractures treated with wire osteosynthesis: a comparative laser fluorescence and Raman spectral study on rabbits. AB - The aim of the present study was to assess, by Raman spectroscopy and laser fluorescence, the repair of surgical fractures fixed with wire osteosynthesis treated or not with infrared laser (lambda780 nm, 50 mW, 4 * 4 J/cm(2) =16 J/cm(2), phi=0.5 cm(2), CW) associated or not to the use of hydroxyapatite and guided bone regeneration. Surgical tibial fractures were created under general anesthesia on 15 rabbits that were divided into five groups, maintained on individual cages, at day/night cycle, fed with solid laboratory pelted diet, and had water ad libitum. The fractures in groups II, III, IV, and V were fixed with wires. Animals in groups III and V were grafted with hydroxyapatite (HA) and guided bone regeneration (GBR) technique used. Animals in groups IV and V were irradiated at every other day during 2 weeks (4 * 4 J/cm(2), 16 J/cm(2) =112 J/cm(2)). Observation time was that of 30 days. After animal death, specimens were taken and kept in liquid nitrogen and used for Raman spectroscopy. The Raman results showed basal readings of 1,234.38 +/- 220. Groups WO+B+L showed higher readings (1,680.22 +/- 822) and group WO+B the lowest (501.425 +/- 328). Fluorescence data showed basal readings of 5.83333 +/- 0.7. Groups WO showed higher readings (6.91667 +/- 0.9) and group WO+B+L the lowest (1.66667 +/- 0.5). There were significant differences between groups on both cases (p<0.05). Pearson correlation was negative and significant (R (2) = -0.60; p<0.001), and it was indicative that, when the Raman peaks of calcium hydroxyapatite (CHA) are increased, the level of fluorescence is reduced. It is concluded that the use of near-infrared lasertherapy associated to HA graft and GBR was effective in improving bone healing on fractured bones as a result of the increasing deposition of CHA measured by Raman spectroscopy and decrease of the organic components as shown by the fluorescence readings. PMID- 22833290 TI - Cytomorphologic features of metastatic urothelial carcinoma in serous effusions. AB - Metastatic urothelial carcinoma (UC) to serous effusion (SE) is extremely rare and its cytomorphological features have only been described in case reports. In this study, we searched the pathology database at University of Michigan for SEs due to metastatic UC in the last 20 years. A total of 25 cases from 20 patients with clinically and pathologically confirmed metastatic UC in SEs were retrieved. The specimens consisted of 15 pleural, 8 peritoneal, and 2 pericardial effusions. Smears were reviewed and evaluated for the following features: cellularity, single cells, cell clusters or short cords, cell wrapping, "windows" between the cells, two-tone cytoplasm, cytoplasmic vacuoles, signet ring cells, nuclear to cytoplasmic (N/C) ratio, nuclear hyperchromasia, irregular nuclear membrane, nuclear centricity, double or multiple nuclei, nucleoli, anaplastic cells and mitosis. Our results showed that UC manifested in SEs predominantly as a single cell population with or without clusters or short cords, and frequently exhibited the "cell wrapping" of two or more cells. Individual UC cell in SEs exhibited nuclear enlargement with increased N/C ratio, irregular nuclear membranes, hyperchromatic coarse chromatin and frequently prominent nucleoli. Double or multinucleated cells, cells with vacuolated cytoplasm or signet ring appearance were also frequently present. Our results demonstrated that while certain features could suggest the diagnosis of UC, the cytomorphological features are not specific and often overlap with those of reactive mesothelium, mesothelioma, metastatic adenocarcinoma, or squamous cell carcinoma in SEs. Accurate diagnosis of UC rests on the combination of clinical history, cytomorphologic features and appropriate immunohistochemical panel. PMID- 22833292 TI - Retraction. Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B. PMID- 22833293 TI - Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5'fluoruracil-based adjuvant chemotherapy. AB - Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high-risk patients. This study was aimed to identify a gene-expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5'fluoruracil (5FU)-based adjuvant chemotherapy. Two-hundred and twenty-eight patients diagnosed with Stages II-III colon cancer and treated with surgical resection and 5FU-based adjuvant chemotherapy were included. RNA was extracted from formalin-fixed, paraffin-embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT-qPCR. A tumor recurrence predicting model, including clinico-pathological variables and gene-expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71-4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12-6.42; p = 0.03). Identification of a new gene-expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU-based chemotherapy, and its combination in a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies. PMID- 22833291 TI - Classical and desmosomal cadherins at a glance. PMID- 22833299 TI - Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations. AB - Inflammatory bowel disease (IBD) comprising of ulcerative colitis (UC) and Crohn's disease (CD) is a major ailment affecting the small and large bowel. In clinics, IBD is treated using 5-amninosalicylates, antibiotics, the steroids and immunomodulators. Unfortunately, the long term usages of these agents are associated with undue side effects and compromise the therapeutic advantage. Accordingly, there is a need for novel agents that are effective, acceptable and non toxic to humans. Preclinical studies in experimental animals have shown that curcumin, an active principle of the Indian spice turmeric (Curcuma longa Linn) is effective in preventing or ameliorating UC and inflammation. Over the last few decades there has been increasing interest in the possible role of curcumin in IBD and several studies with various experimental models of IBD have shown it to be effective in mediating the inhibitory effects by scavenging free radicals, increasing antioxidants, influencing multiple signaling pathways, especially the kinases (MAPK, ERK), inhibiting myeloperoxidase, COX-1, COX-2, LOX, TNF-alpha, IFN-gamma, iNOS; inhibiting the transcription factor NF-kappaB. Clinical studies have also shown that co-administration of curcumin with conventional drugs was effective, to be well-tolerated and treated as a safe medication for maintaining remission, to prevent relapse and improve clinical activity index. Large randomized controlled clinical investigations are required to fully understand the potential of oral curcumin for treating IBD. PMID- 22833300 TI - Limbus vertebra. PMID- 22833301 TI - Device therapy to modulate the autonomic nervous system to treat heart failure. AB - Heart failure is the final common pathway in many forms of heart disease, and is associated with excessive morbidity and mortality. Pathophysiologic alterations in the interaction between the heart and the autonomic nervous system in advanced heart failure have been noted for decades. Over the last decade, great advances have been made in the medical and surgical treatment of heart failure - and some of these modalities target the neuro-cardiac axis. Despite these advances, many patients progress to end-stage heart failure and death. Recently, device-based therapy targeting the neuro-cardiac axis with various forms of neuromodulatory stimuli has been shown to improve heart function in experimental heart failure models. These include spinal cord stimulation, vagal nerve stimulation, and baroreflex modulation. Human trials are now underway to evaluate the safety and efficacy of these device-based neuromodulatory modalities in the heart failure population. PMID- 22833302 TI - Robotic-assisted angioplasty: current status and future possibilities. AB - Percutaneous coronary intervention (PCI) has seen steady technological progress over the past 3 decades. Despite improved patient safety and efficacy, modern interventionalists continue to face significant occupational hazards, including radiation exposure, cataracts, and orthopedic injuries. Robotic remote navigation systems have been developed to address risks and procedural challenges associated with conventional PCI. The first in-human experience using a modern robotic system for PCI yielded excellent results, with an overall technical success rate of 97.9 %. A larger multicenter prospective registry with this system is currently underway. Robotic PCI technology holds promise to reduce operator radiation exposure and musculoskeletal complaints. Postulated benefits to patients include more accurate lesion length calculations, precise stent placement, and reductions in radiation exposure and contrast-media delivery. The development of novel robotic remote control navigation systems represents the dawn of a new era of interventional cardiology. PMID- 22833304 TI - Standardizing the power of the Hosmer-Lemeshow goodness of fit test in large data sets. AB - The Hosmer-Lemeshow test is a commonly used procedure for assessing goodness of fit in logistic regression. It has, for example, been widely used for evaluation of risk-scoring models. As with any statistical test, the power increases with sample size; this can be undesirable for goodness of fit tests because in very large data sets, small departures from the proposed model will be considered significant. By considering the dependence of power on the number of groups used in the Hosmer-Lemeshow test, we show how the power may be standardized across different sample sizes in a wide range of models. We provide and confirm mathematical derivations through simulation and analysis of data on 31,713 children from the Collaborative Perinatal Project. We make recommendations on how to choose the number of groups in the Hosmer-Lemeshow test based on sample size and provide example applications of the recommendations. PMID- 22833303 TI - Monitoring therapeutic effects in experimental stroke by serial USPIO-enhanced MRI. AB - OBJECTIVES: This study sought to evaluate whether the therapeutic effects of an anti-inflammatory drug such as minocycline could be monitored by serial ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI in experimental stroke. METHODS: Mice received a three-dose minocycline treatment (n = 12) or vehicle (n = 12) after permanent middle cerebral artery occlusion. USPIOs were administered 5 h post-surgery. MRI was performed before, 24 h and 48 h post-USPIO administration. MRI endpoints were the extent of signal abnormalities on R2 maps (=1/T2) and quantitative R2 changes over time (?R2). Post-mortem brains were prepared either for immunohistology (n = 16) or for iron dosage (n = 8). RESULTS: As expected, treatment with minocycline significantly reduced infarct size, blood-brain barrier permeability and F4/80 immunostaining for microglia/macrophages. Areas of R2 maps > 35 ms(-1) also appeared significantly decreased in minocycline-treated mice (ANOVA for repeated measures, P = 0.017). There was a fair correlation between these areas and the amount of iron in the brain (R(2) = 0.69, P = 0.010), but no significant difference in ?R2 was found between the two groups. CONCLUSIONS: This study showed that the extent of signal abnormalities on R2 maps can be used as a surrogate marker to detect minocycline effects in a murine experimental model of stroke. PMID- 22833305 TI - Should intranasal splints be used after nasal septal surgery? PMID- 22833306 TI - Prospective testing of mucoepidermoid carcinoma for the MAML2 translocation: clinical implications. AB - OBJECTIVES/HYPOTHESIS: Mucoepidermoid carcinoma (MEC) with MAML2 translocation is believed to be associated with lower clinical stage, lower histologic grade, and better outcome. We summarized our prospective experience testing MEC for the MAML2 translocation. STUDY DESIGN: Prospective cohort study. METHODS: One hundred eighteen head and neck tumors (55 MECs and 63 mimics) were prospectively tested for MAML2 translocation by fluorescence in situ hybridization as part of clinical care during a 36-month period. RESULTS: MAML2 translocation was identified in 41 of 55 (75%) cases diagnosed as MEC. Translocation status did not correlate significantly with histologic grade, age, gender, tumor site, or T stage. CONCLUSIONS: Routine testing for MAML2 translocation by fluorescence in situ hybridization is feasible and useful in confirming the diagnosis of MEC. The lack of significant correlation with histologic grade or pathologic stage implies that the previously reported prognostic value of the MAML2 translocation may be an artifact of misclassification of MEC as other tumors. PMID- 22833307 TI - Toxicity, quality of life, and functional outcomes of 176 hypopharyngeal cancer patients treated by (chemo)radiation: the impact of treatment modality and radiation technique. AB - OBJECTIVES/HYPOTHESIS: The main goal of the current study was to comprehensively address the impact of chemoradiation and radiation techniques on toxicity, quality of life (QoL), and functional outcome. STUDY DESIGN: Retrospective analysis of toxicity and functional outcome and prospective QoL assessment. METHODS: From 1996 to 2010, 176 consecutive patients with hypopharyngeal cancer (HPC) were treated with (chemo)radiotherapy. End points were acute and late toxicity, QoL assessment, and functional outcome using laryngoesophageal dysfunction-free survival (LED-FS) defined by the Laryngeal Preservation Consensus Panel. RESULTS: Chemoradiation significantly increased grade 3 acute toxicity compared to radiotherapy alone (71% vs. 55%, P = .02). The 3-year grade >=2 late toxicity was 32%. Intensity-modulated radiotherapy (IMRT) significantly reduced late toxicity compared to three-dimensional conformal radiotherapy (3DCRT) (24% vs. 44%, P = .007). Slight deterioration in QoL scores was observed on almost all scales, and was more pronounced in patients treated with chemoradiation, albeit not statistically significant except for xerostomia. Chemoradiation, compared to radiotherapy alone, improved LED-FS at 3 years (51% vs. 24% for the entire group and 83% vs. 63% for the 78 living patients at last follow-up, respectively [P = .05]). CONCLUSIONS: Compared to radiotherapy alone, chemoradiation significantly improved functional outcome, increased acute toxicity, but without significant increase in late radiation-induced side effects. Statistically significant deterioration in QoL scores was reported only for xerostomia. IMRT, compared to 3DCRT, reduced the incidence and severity of acute and late toxicity, thereby broadening the therapeutic window, and may allow dose escalation for further improvement of outcomes of laryngeal preservation protocols. PMID- 22833308 TI - Electrogenerated chemiluminescence of metal-organic complex nanowires: reduced graphene oxide enhancement and biosensing application. PMID- 22833309 TI - Reduced prefrontal hemodynamic response in pediatric obsessive-compulsive disorder as measured by near-infrared spectroscopy. AB - Recent developments in near-infrared spectroscopy (NIRS) have enabled non invasive clarification of brain functions in psychiatric disorders. Functional neuroimaging studies of patients with obsessive-compulsive disorder (OCD) have suggested that the frontal cortex and subcortical structures may play a role in the pathophysiology of the disorder. Twelve treatment-naive children with OCD and 12 age- and sex-matched healthy control subjects participated in the present study after giving consent. The relative concentrations of oxyhemoglobin (oxy-Hb) were measured with prefrontal probes every 0.1 s during the Stroop color-word task, using 24-channel NIRS machines. During the Stroop color-word task, the oxy Hb changes in the OCD group were significantly smaller than those in the control group in the prefrontal cortex, especially in the frontopolar cortex. The present study suggests that children with OCD have reduced prefrontal hemodynamic response as measured by NIRS. PMID- 22833310 TI - Persistence of sleep problems in children with anxiety and attention deficit hyperactivity disorders. AB - This study examines the persistence of sleep problems over 18 months in 76 referred children with anxiety disorders and/or attention deficit hyperactivity disorders (ADHD) and 31 nonreferred controls, and explores predictors of sleep problems at follow-up (T2) in the referred children. Diagnoses were assessed at initial assessment (T1) using the semi-structured interview Kaufman Schedule for Affective Disorders and Schizophrenia. Sleep problems were assessed using the Children's Sleep Habit Questionnaire at T1 and at T2. Persistence rate of total sleep problems in the clinical range was 72.4 % in referred children, and did not differ significantly between children with a T1 diagnosis of anxiety disorder (76.0 %), ADHD (70.6 %), anxiety disorder and ADHD (68.8 %) or nonreferred controls (50.0 %) The total sleep problems score at T1 significantly predicted the total sleep problems score at T2, whereas age, sex, parent education level and total number of life events did not. PMID- 22833311 TI - Patient Satisfaction Influenced by interpersonal treatment and communication for African American men: the North Carolina-Louisiana Prostate Cancer Project (PCaP). AB - The purpose of this study was to determine if a particular set of health behaviors of health care providers and African American men (AAM) influence patient satisfaction from the AAM's perspective. This descriptive, correlational study consisted of 505 AAM in North Carolina diagnosed with prostate cancer and enrolled in the North Carolina-Louisiana Prostate Cancer Project (PCaP). Analyses consisted of bivariate analyses and multiple regression. Patient-to-provider communication, interpersonal treatment, and provider-to-patient communication accounted for 45% (p <= .0001) of the variability in patient satisfaction. Interpersonal treatment (provider focusing on the patient) explained the greatest amount (F = 313.53, R2 = .39) of patient satisfaction. Since interpersonal treatment focuses on the patient and demonstrated to be the strongest predictor in patient satisfaction, it is noteworthy to consider the emphasis that should be placed on patient-centered care. In addition, knowing important variables positively affecting patient satisfaction provides useful information for developing appropriate interventions to improve AAM health care experiences. PMID- 22833312 TI - MS Data Miner: a web-based software tool to analyze, compare, and share mass spectrometry protein identifications. AB - Data processing and analysis of proteomics data are challenging and time consuming. In this paper, we present MS Data Miner (MDM) (http://sourceforge.net/p/msdataminer), a freely available web-based software solution aimed at minimizing the time required for the analysis, validation, data comparison, and presentation of data files generated in MS software, including Mascot (Matrix Science), Mascot Distiller (Matrix Science), and ProteinPilot (AB Sciex). The program was developed to significantly decrease the time required to process large proteomic data sets for publication. This open sourced system includes a spectra validation system and an automatic screenshot generation tool for Mascot-assigned spectra. In addition, a Gene Ontology term analysis function and a tool for generating comparative Excel data reports are included. We illustrate the benefits of MDM during a proteomics study comprised of more than 200 LC-MS/MS analyses recorded on an AB Sciex TripleTOF 5600, identifying more than 3000 unique proteins and 3.5 million peptides. PMID- 22833313 TI - Characterization of the CDP-D-mannitol biosynthetic pathway in Streptococcus pneumoniae 35A. AB - Streptococcus pneumoniae is a major human pathogen associated with diseases worldwide. The capsular polysaccharides (CPSs) are considered a major virulence factor and are targets for a vaccine. d-Mannitol was found to be present in the CPS of several S. pneumoniae serotypes. Two genes, mnp1 and mnp2, which are located in the CPS gene cluster, were proposed to be responsible for the synthesis of NDP-d-mannitol (the nucleotide activated form of d-mannitol). However, the pathway has never been identified by experimental methods and we aimed to characterize it in the present study. To achieve this, the two genes, mnp1 and mnp2, were cloned and the gene products were overexpressed, purified, and analyzed in vitro for their respective enzymatic activities. Products of reactions catalyzed by Mnp1 and Mnp2 were detected by capillary electrophoresis and validated using electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. We show that Mnp1 is responsible for the transfer of CMP from CTP to d-fructose-6-phosphate (Fru-6-P) to form CDP-d fructose, whereas Mnp2 catalyzed the conversion of CDP-d-fructose to CDP-d mannitol. Therefore, Mnp1 (renamed as mnpA) was identified as Fru-6-P cytidylyltransferase-encoding gene, and mnp2 (renamed as mnpB) as a CDP-d fructose reductase-encoding gene. The kinetics of Mnp1 for the substrate (Fru-6-P and CTP) and of Mnp2 for the substrate (CDP-d-fructose) and the cofactor NADH or NADPH fitted the Michaelis-Menten model. The effects of temperature, pH and cations on the two enzymes were analyzed. This is the first time that the biosynthetic pathway of CDP-d-mannitol has been identified biochemically. PMID- 22833314 TI - Glycosphingolipid composition of epithelial cells isolated along the villus axis of small intestine of a single human individual. AB - A 6-cm fresh proximal ileum surgical specimen from a blood group A(1)Le(a-b+) secretor individual was used for stepwise isolation of epithelial cells from villus tip to crypt bottom by gentle washing with ethylenediaminetetraacetic acid containing buffer. Acid and non-acid sphingolipids were prepared from the epithelial cell fractions and the non-epithelial intestinal residue. Molecular information on the sphingolipid composition was obtained without further isolation of individual species by applying thin-layer chromatography using chemical and biological (monoclonal antibodies, cholera toxin, Escherichia coli) detection reagents, mass spectrometry and proton NMR spectroscopy of derivatized glycolipids. In this way, the structure of major and minor saccharides, ceramide components and their relative amounts were obtained. Epithelial cells and non epithelial residue were distinctly different in their sphingolipid composition. Sphingomyelin was the major single component in both compartments. Characteristic for epithelial cells was the dominance of monoglycosylceramides, sulphatides and blood group fucolipids (mainly Le(b) hexaglycosylceramides and ALe(b) heptaglycosylceramides). The non-epithelial residue had about five times less glycolipids mainly mono-, di-, tri- and tetra-glycosylceramides and gangliosides, including the GM1 ganglioside. The ceramides were more hydroxylated (1-2 additional hydroxyls) in epithelial cell glycolipids compared with the non epithelial residue. Combined with a separate detailed study on the glycoproteins of the same epithelial cell preparation, this human intestinal sample is the only epithelial cell preparation where both protein- and lipid-linked saccharides are characterized in detail. PMID- 22833316 TI - Comparative structural analysis of the glycosylation of salivary and buccal cell proteins: innate protection against infection by Candida albicans. AB - Mucosal epithelial surfaces, such as line the oral cavity, are common sites of microbial colonization by bacteria, yeast and fungi. The microbial interactions involve adherence between the glycans on the host cells and the carbohydrate binding proteins of the pathogen. Saliva constantly bathes the buccal cells of the epithelial surface of the mouth and we postulate that the sugars on the salivary glycoproteins provide an innate host immune mechanism against infection by competitively inhibiting pathogen binding to the cell membranes. The structures of the N- and O-linked oligosaccharides on the glycoproteins of saliva and buccal cell membranes were analyzed using capillary carbon liquid chromatography-electrospray ionization MS/MS. The 190 glycan structures that were characterized were qualitatively similar, but differed quantitatively, between saliva and epithelial buccal cell membrane proteins. The similar relative abundance of the terminal glycan epitope structures (e.g. ABO(H) blood group, sialylation and Lewis-type antigens) on saliva and buccal cell membrane glycoproteins indicated that the terminal N- and O-linked glycan substructures in saliva could be acting as decoy-binding receptors to competitively inhibit the attachment of pathogens to the surface of the oral mucosa. A flow cytometry-based binding assay quantified the interaction between buccal cells and the commensal oral pathogen Candida albicans. Whole saliva and released glycans from salivary proteins inhibited the interaction of C. albicans with buccal epithelial cells, confirming the protective role of the glycans on salivary glycoproteins against pathogen infection. PMID- 22833315 TI - Amino acid residues important for CMP-sialic acid recognition by the CMP-sialic acid transporter: analysis of the substrate specificity of UDP-galactose/CMP sialic acid transporter chimeras. AB - In our previous studies, we demonstrated that chimeric molecules of the CMP sialic acid (CMP-Sia) transporter (CST) and the UDP-galactose (Gal) transporter (UGT) in which the seventh transmembrane helix-containing segment was derived from the CST could transport both CMP-Sia and UDP-Gal and that the CST-derived seventh transmembrane helix segment was sufficient for the chimera to recognize CMP-Sia in the otherwise UGT context. In this study, we continued to more precisely define the submolecular region that is necessary for CMP-Sia recognition, and we demonstrated that the N-terminal half of the seventh transmembrane helix of CST is essential for the CMP-Sia transport mediated by the chimeric transporters. We further showed that Tyr214Gly and Ser216Phe mutations of a chimeric transporter that was capable of transporting both CMP-Sia and UDP Gal led to the selective loss of CMP-Sia transport activity without affecting UDP Gal transport activity. Conversely, when a residue in a chimeric transporter that was active for UDP-Gal transport but not CMP-Sia transport was replaced by Tyr, so that Tyr occupied the same position as in the CMP-Sia transporter, the resulting mutant chimera acquired the ability to transport CMP-Sia. These results demonstrated that Tyr214 and Ser216, located in the seventh transmembrane helix of the human CST, are critically important for the recognition of CMP-Sia as a transport substrate. Identification of determinants critical for the discrimination between relevant and irrelevant substrates will advance our understanding of the mechanisms of substrate recognition by nucleotide sugar transporters. PMID- 22833317 TI - Identification of relevant cancer related-genes in the flat oyster Ostrea edulis affected by disseminated neoplasia. AB - Disseminated neoplasia (DN), an oyster disease resembling leukaemia, has been reported in a number of species of marine bivalve molluscs. The disease is characterised by a proliferation of abnormal circulating cells of unknown origin resulting in the invasion of tissues and organs, frequently with a fatal end of the affected individuals. To obtain a more comprehensive view of bivalve cancer processes, suppressive subtracted hybridisation (SSH) and quantitative RT-PCR (q PCR) approaches were combined to investigate changes in the transcriptome of Ostrea edulis haemolymph cells associated to DN. Two SSH libraries were constructed and 587 expressed sequence tags (ESTs) were sequenced, obtaining 329 ESTs which showed expression changes in neoplastic process. Transcription expression analyses (q-PCR) were done for a total of 24 genes that could be relevant in neoplastic process, including genes with role in the regulation of cell cycle, apoptosis or chromosomal defects. Most of those genes had not been reported in association with cancer in non-vertebrate organisms. The over expression and under-expression of some of those genes in DN-affected oysters was in agreement with observations in vertebrate cancer. The results herein reported contribute to cancer understanding in bivalve molluscs. PMID- 22833318 TI - Comparison study and thoron interference test of different radon monitors. AB - A comparison study and thoron interference test for different continuous radon monitors were carried out. The comparison study includes three passive diffusion monitors [one pulse ionisation chamber based-Alpha Guard and two silicon semi conductor based-Radon Scout Plus (RSP)] and one silicon semi-conductor-based active radon thoron discriminating monitor--RAD 7. Radon emanation standard, supplied by National Institute of Science and Technology, has been utilised for the comparison study to qualify the calibration of the continuous radon monitors. All the instruments showed good agreement with the estimated radon concentration using (226)Ra/(222)Rn emanation standard. It was found that the active radon monitoring system is having a higher initial response towards the transient radon concentration than the passive radon monitors studied. The instruments measuring radon concentration without energy discrimination are likely to have some sensitivity towards the thoron concentration. Thus, thoron interference study was carried out in the above monitors. Nine percent interference in measured radon concentration in the Alpha Guard monitor and 4 % interference in the semi conductor-based RSP monitors was observed. Study indicates that the interference of thoron in radon monitors depends on the area of diffusion of gas, volume of detection and sensitivity factor. PMID- 22833319 TI - Application of RFID technology in patient tracking and medication traceability in emergency care. AB - One of the most important factors that directly affects the quality of health care is patient safety. Minimize the occurrence of adverse events is one of the main challenges for health professionals. This requires continuous tracking of the patient by different areas and services, a process known as traceability and proper patient identification and medication prescribed. This article presents an information system for patient tracking and drugs developed for the Emergency Department of Hospital A Coruna. The systems use RFID technology to perform various tasks: (1) locate patients in different areas; (2) measure patient care times and waiting times; (3) identify unitary doses of medication; and (4) ensure the correct matching between the patient and the medication prescribed by the doctor. The hardware infrastructure as well as the optimal configuration of devices interconnected via a wireless network was determined by conducting a detailed coverage study. To support all the functionality needed, specific tools were designed and integrated with proprietary software applications. The RFID system was evaluated positively by staff from different professional profiles involved in its development or subsequent implementation. PMID- 22833320 TI - A silviculture application of the glyphosate-based herbicide VisionMAX to wetlands has limited direct effects on amphibian larvae. AB - Herbicides are commonly used in agriculture and silviculture to reduce interspecific competition among plants and thereby enhance crop growth, quality, and volume. Internationally, glyphosate-based herbicides are the most widely used herbicides in both of these sectors. Laboratory and mesocosm studies have demonstrated that some formulations are toxic to amphibian larvae below concentrations that approximate predicted maximal or "worst-case" exposure scenarios. However, field studies have not found evidence of toxicity at these concentrations. The authors conducted a replicated field experiment involving 10 naturalized wetlands split in half with an impermeable plastic barrier to assess the direct toxicity of a glyphosate formulation commonly used in silviculture (VisionMAXTM). The herbicide formulation was applied directly to the surface of one side of each wetland at one of two target aqueous exposure rates (high = 2,880, low = 550 ug acid equivalents [a.e.]/L), and the other side was left as an untreated control. The survival and growth of green frog larvae (Lithobates clamitans) were assessed for two years following herbicide treatment. The herbicide did not have a negative impact on survival or growth of L. clamitans larvae at either treatment level. In fact, mean larval abundance was typically greater in the treated sides than in control sides within the year of herbicide application. These results indicate that typical silviculture use of VisionMAX poses negligible risk to larval amphibians, likely because the combined effects of sorption and degradation in natural wetlands limit the exposure magnitude and duration. PMID- 22833321 TI - Emotional cues do not increase the likelihood of tip-of-the-tongue states. AB - In a recent article, Schwartz (Psychonomic Bulletin & Review 17:82-87, 2010) reported the effects of emotion on tip-of-the-tongue states (TOTs). He found increased TOTs for emotion-inducing questions, as well as a carryover effect in which high TOT rates were observed following emotion-inducing questions. In the present study, we sought to replicate these findings while controlling for word frequency, but we found an increased TOT rate neither for emotion-inducing questions nor following emotion-inducing questions. We report three attempts to replicate Schwartz's (Psychonomic Bulletin & Review 17:82-87, 2010) effect that focused on systematic differences in word frequency between stimulus sets in the original study; none of the key findings reported by Schwartz (Psychonomic Bulletin & Review 17:82-87, 2010) were found in any of the experiments. These results fail to support prior claims concerning the effects of emotion on TOTs Schwartz (Psychonomic Bulletin & Review 17:82-87, 2010). The discussion focuses on the importance of controlling for systematic differences in word characteristics between groups of items. PMID- 22833322 TI - Stem cell educator therapy and induction of immune balance. AB - Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes the deficit of pancreatic islet beta cells. A true cure has proven elusive despite intensive research pressure by using conventional approaches over the past 25 years. The situation highlights the challenges we face in conquering this disease. Alternative approaches are needed. Increasing evidence demonstrates that stem cells possess the function of immune modulation. We established the Stem Cell Educator therapy by using cord blood-derived multipotent stem cells (CB SCs). A closed-loop system that circulates a patient's blood through a blood cell separator, briefly co-cultures the patient's lymphocytes with adherent CB-SCs in vitro, and returns the educated lymphocytes (but not the CB-SCs) to the patient's circulation. Our clinical trial reveals that a single treatment with the Stem Cell Educator provides lasting reversal of autoimmunity that allows regeneration of islet beta cells and improvement of metabolic control in subjects with long standing T1D. PMID- 22833323 TI - Evaluation of [18F]Mefway biodistribution and dosimetry based on whole-body PET imaging of mice. AB - PURPOSE: [(18)F]Mefway is a novel radiotracer specific to the serotonin 5-HT1A receptor class. In preparation for using this tracer in humans, we have performed whole-body PET studies in mice to evaluate the biodistribution and dosimetry of [(18)F]Mefway. METHODS: Six mice (three females and three males) received IV injections of [(18)F]Mefway and were scanned for 2 h in an Inveon-dedicated PET scanner. Each animal also received a high-resolution CT scan using an Inveon CT. The CT images were used to draw volume of interest on the following organs: the brain, large intestine, stomach, heart, kidneys, liver, lungs, pancreas, bone, spleen, testes, thymus, gallbladder, uterus, and urinary bladder. All organ time activity curves without decay correction were normalized to the injected activity. The area under the normalized curves was then used to compute the residence times in each organ. Data were analyzed using PMOD and Matlab software. The absorbed doses in mouse organs were computed using the RAdiation Dose Assessment Resource animal models for dose assessment. The residence times in mouse organs were converted to human values using scale factors based on differences between organ and body weights. OLINDA/EXM 1.1 software was used to compute the absorbed human doses in multiple organs for both female and male phantoms. RESULTS: The highest mouse residence times were found in the liver, urinary bladder, and kidneys. The largest doses in mice were found in the urinary bladder (critical organ), kidney, and liver for both females and males, indicating primary elimination via urinary system. The projected human effective doses were 1.21E - 02 mSv/MBq for the adult female model and 1.13E - 02 mSv/MBq for the adult male model. The estimated human biodistribution of [(18)F]Mefway was similar to that of [(11)C]WAY 100,635, a 5-HT1A tracer for which dosimetry has been evaluated in humans. CONCLUSIONS: The elimination of radiotracer was primarily via the kidney and urinary bladder with the urinary bladder being the critical organ. Whole-body mouse imaging can be used as a preclinical tool to provide initial estimates of the absorbed doses of [(18)F]Mefway in humans. PMID- 22833325 TI - There's a fever in healthcare called physician acquisition. AB - Some of you may remember the Donna Reed television show from the early 1960s. Donna played wife (and sometimes nurse) to her TV husband, Dr. Alex Stone. He was a pediatrician whose office was nearby, enabling Dr. Stone to come home for lunch. For those of you too young to know or remember this television program, Dr. Stone's practice of medicine was seemingly uncomplicated, and discussion at the dinner table was never centered on concerns of the practice. It is highly unlikely the same can be said for today's practicing physicians. PMID- 22833326 TI - Disclosure and documentation of reported unanticipated medical events or outcomes: need for healthcare provider education. AB - In 2001 the Joint Commission on Accreditation of Healthcare Organizations added "requirement to disclose unanticipated outcomes" to accreditation standards. Full disclosure increases patient satisfaction and trust in physicians. Though studies suggest elements of complete disclosure, there are no national standards. PMID- 22833327 TI - The A to Z of healthcare data breaches. AB - There currently exists a myriad of privacy laws that impact a healthcare entity, including more than 47 notification laws that require notification when a data breach occurs, as well as the breach notification requirements of the Health Information Technology for Economic and Clinical Health Act. Given the plethora of issues a healthcare entity faces, there are certain principles that can be built into an organization's philosophy that will comply with the law and help protect it from reputational harm. PMID- 22833328 TI - Stop the escalation before it begins by using the pediatric Behavior Response Team protocol. AB - In today's world, clinicians need to be prepared to care for challenging patients and families that are struggling with the stress of illness and hospitalization and have inadequate coping skills. The University of Michigan Health System (UMHS) has developed a protocol identifying a team with representatives from psychiatry, security, and risk management to provide a rapid response in situations that historically have resulted in, at worst, sentinel/adverse events and at best, service disasters. The pediatric BRT protocol formalizes the purpose of the team, how staff should access them, and the expectation for involved staff to debrief about the interventions at identified times. It has proven to be an effective intervention and allows clinicians to provide needed care to the patients. PMID- 22833330 TI - No duty of care arose from telephone call to emergency department. Estate of Kundert v. Illinois Valley Community Hospital, No. 3-11-0007 (Ct App Ill January 10, 2012). PMID- 22833329 TI - Differences among nursing homes in outcomes of a safe resident handling program. AB - A large nursing home corporation implemented a safe resident handling program (SRHP) in 2004-2007. We evaluated its efficacy over a 2-year period by examining differences among 5 centers in program outcomes and potential predictors of those differences. We observed nursing assistants (NAs), recording activities and body postures at 60-second intervals on personal digital assistants at baseline and at 3-month, 12-month, and 24-month follow-ups. The two outcomes computed were change in equipment use during resident handling and change in a physical workload index that estimated spinal loading due to body postures and handled loads. Potential explanatory factors were extracted from post-observation interviews, investigator surveys of the workforce, from administrative data, and employee satisfaction surveys. The facility with the most positive outcome measures was associated with many positive changes in explanatory factors and the facility with the fewest positive outcome measures experienced negative changes in the same factors. These findings suggest greater SRHP benefits where there was lower NA turnover and agency staffing; less time pressure; and better teamwork, staff communication, and supervisory support. PMID- 22833331 TI - Modulation of cell attachment and collagen production of anterior cruciate ligament cells via submicron grooves/ridges structures with different cell affinity. AB - This study aimed to investigate the effects of submicron-grooved topography and surface cell affinity on the attachment, proliferation and collagen synthesis of anterior cruciate ligament (ACL) cells. Two grooved polystyrene (PS) surfaces (equal groove/ridge width of 800 nm) with a groove depth of 100 or 700 nm were fabricated and modified by oxygen plasma treatment, dopamine deposition and conjugation of RGD-containing peptides to enhance cell affinity. The elongation and alignment of ACL cells was enhanced by grooved structures with increasing groove depths regardless of surface chemistry. On the other hand, cell spreading and proliferation mainly depended on surface chemistry, in accordance with surface cell affinity: O(2) plasma < dopamine deposition < RGD conjugation. The synthesis of type I collagen was the highest by the ACL cells cultured on the 700 nm grooved surface conjugated with RGD peptides, indicating that both surface grooved topography and chemistry play a role in modulating collagen production of ACL cells. Furthermore, the type I collagen deposited on the 700 nm PS surface was aligned with grooves/ridges. Our results indicated that both ligand presentation and cell alignment are important in the physiological activities of ACL fibroblasts. Such information is critical for design of biomaterials for ACL tissue engineering. PMID- 22833332 TI - Nodal marginal zone B-cell lymphoma showing prominent plasma cell differentiation in the pleural effusion: a case report. PMID- 22833333 TI - Maternal depressive symptoms and the risk of overweight in their children. AB - To examine the association between maternal depressive symptoms during early childhood of their offspring and later overweight in the children. Only children (n = 1,090) whose weights and heights were measured at least once for three time points (grades one, three and six) from the National Institute of Child Health and Human Development Study were included. Maternal depressive symptoms, defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of 16 or greater, were assessed using CES-D when the child was 1, 24, and 36 months. Childhood overweight was based on standardized height and weight measures taken during the interviews, and was defined according to appropriate CDC age- and sex specific BMI percentiles. Generalized estimating equation was used to examine the impact of maternal depressive symptoms on the childhood overweight after adjusting for covariates. Compared to children of mothers without depression at any of the three time points, when children were one, 24 and 36 months of age, children of mothers with depression at all three time points were 1.695 times more likely to be overweight after adjusting for other child characteristics (95 % CI = 1.001-2.869). When further adjusted for maternal characteristics, children of mothers with depression at all three time points were 2.13 times more likely to be overweight (95 % CI = 1.05-4.31). Persistent maternal depressive symptoms may be associated with an increased risk of childhood overweight in their offspring. Children of mothers with depression may benefit from special attention in terms of obesity prevention. PMID- 22833334 TI - Promoting active lifestyles in young children: investigating mothers' decisions about their child's physical activity and screen time behaviours. AB - Given increasing trends of obesity being noted from early in life and that active lifestyles track across time, it is important that children at a very young age be active to combat a foundation of unhealthy behaviours forming. This study investigated, within a theory of planned behaviour (TPB) framework, factors which influence mothers' decisions about their child's (1) adequate physical activity (PA) and (2) limited screen time behaviours. Mothers (N = 162) completed a main questionnaire, via on-line or paper-based administration, which comprised standard TPB items in addition to measures of planning and background demographic variables. One week later, consenting mothers completed a follow-up telephone questionnaire which assessed the decisions they had made regarding their child's PA and screen time behaviours during the previous week. Hierarchical multiple regression analyses revealed support for the predictive model, explaining an overall 73 and 78 % of the variance in mothers' intention and 38 and 53 % of the variance in mothers' decisions to ensure their child engages in adequate PA and limited screen time, respectively. Attitude and subjective norms predicted intention in both target behaviours, as did intentions with behaviour. Contrary to predictions, perceived behavioural control (PBC) in PA behaviour and planning in screen time behaviour were not significant predictors of intention, neither was PBC a predictor of either behaviour. The findings illustrate the various roles that psycho-social factors play in mothers' decisions to ensure their child engages in active lifestyle behaviours which can help to inform future intervention programs aimed at combating very young children's inactivity. PMID- 22833335 TI - Allostatic load and birth outcomes among white and black women in New Orleans. AB - As a marker of chronic stress, allostatic load has been theoretically recognized as a potential contributor to racial disparities in birth outcomes. The purpose of this investigation was to identify associations between allostatic load and birth outcomes and to assess differences in allostatic load and its relation to birth outcomes between white and black women. Blood samples from 123 women at 26 28 weeks gestation were assayed for cholesterol, glycosylated hemoglobin, dehydroepiandrosterone-sulfate, and cortisol, with 42 women having complete data on all biomarkers and birth outcomes. Together with systolic blood pressure, these biomarkers were combined to create an allostatic load index. Multiple linear regression models were used to evaluate associations between allostatic load index and gestational age, birth weight, birth weight ratio, birth length, and head circumference. Black women had a significantly lower allostatic load index than white women (P < 0.05). Gestational age was the only outcome significantly associated with allostatic load in both unadjusted and adjusted models (P < 0.05). Gestational age decreased significantly with increasing allostatic load (adjusted beta -0.18, 95 % CI -0.35, 0.00). A significant interaction with age indicated that the effect was less strong at higher maternal ages (adjusted interaction beta 0.04, 95 % CI 0.00, 0.08). There was no racial difference in the effect of allostatic load on birth outcomes. These findings represent possible evidence of the effect of stress age on gestational age. As a measure of cumulative disadvantage, allostatic load may prove to be a contributor to the racial disparities in birth outcomes. PMID- 22833336 TI - Infant mortality and the risk of small size for gestational age in the subsequent pregnancy: a retrospective cohort study. AB - To examine the association between prior infant mortality and subsequent risk for small for gestational age (SGA). This population-based, retrospective cohort study used the Missouri maternally linked, longitudinal dataset (1989-2005). Analyses were restricted to women who had two singleton pregnancies during the study period. Logistic regression was conducted to obtain adjusted odds ratios (AOR) and 95 % confidence intervals (CI) for the association between infant mortality in the first pregnancy and SGA in the second pregnancy. Women with a prior occurrence of infant death were more likely to be black and obese and had lower educational levels and had higher rates of pregnancy-related complications (p < 0.01). White women with previous infant mortality were at 1.46 times greater risk for SGA in the subsequent pregnancy (AOR = 1.46, 95 % CI = 1.24-1.71). For black women with prior infant death, the risk for SGA increased to 2.77 times (AOR = 2.77, 95 % CI = 2.19-3.51). White mothers who experienced infant mortality coupled with SGA in the first pregnancy had a nearly threefold heightened risk for SGA in the second pregnancy (AOR = 2.89, 95 % CI = 2.21-3.78), whereas black women with this history were more than four times as likely to have an infant with SGA (AOR = 4.60 95 % CI = 3.05-6.96). Prior occurrence of infant mortality is associated with increased risk for subsequent SGA. This finding has important implications for health professionals, as targeted inter-conception strategies for women who have experienced infant death, as well as SGA, may be warranted. PMID- 22833337 TI - Immigrants and preterm births: a nationwide epidemiological study in Sweden. AB - To examine, nationwide, if there is an association between country of birth in mothers and preterm birth and to study whether any such association remains in second-generation immigrant women. In this follow-up study, a nationwide research database located at Lund University, Sweden, was used to identify all preterm born singletons in Sweden between January 1, 1982, and December 31, 2006. Incidence ratios were standardized with regard to maternal age at birth, marital status, geographical region, body height, and smoking history as well as period of birth, family income, and gender of the infant. Singletons of mothers born in Sweden were used as the reference group. There were 2,192,843 records for singletons over the study period, of whom 4.9 % were preterm births and 0.8 % were very preterm births. Increased risk of preterm birth was observed for mothers from Austria, Yugoslavia, Romania, Central Europe, and Asia. Increased risk of very preterm birth was observed for mothers from Eastern Europe, Central Europe, Africa, and Asia; these increased risk disappeared, however, in the second-generation female immigrants. Country of birth in mothers affected the risk of preterm birth; maternity care should pay special attention to women from certain population groups. PMID- 22833338 TI - Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. AB - Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 MUM, trypan blue exclusion assay). At a lower range (25 MUM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 MUM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target. PMID- 22833340 TI - Readability assessment of internet-based patient education materials related to facial fractures. AB - OBJECTIVE/HYPOTHESIS: Various professional societies, clinical practices, hospitals, and health care-related Web sites provide Internet-based patient education material (IPEMs) to the general public. However, this information may be written above the 6th-grade reading level recommended by the US Department of Health and Human Services. The purpose of this study is to assess the readability of facial fracture (FF)-related IPEMs and compare readability levels of IPEMs provided by four sources: professional societies, clinical practices, hospitals, and miscellaneous sources. STUDY DESIGN: Analysis of IPEMs on FFs available on Google.com. METHODS: The readability of 41 FF-related IPEMs was assessed with four readability indices: Flesch-Kincaid Grade Level (FKGL), Flesch Reading Ease Score (FRES), Simple Measure of Gobbledygook (SMOG), and Gunning Frequency of Gobbledygook (Gunning FOG). Averages were evaluated against national recommendations and between each source using analysis of variance and t tests. RESULTS: Only 4.9% of IPEMs were written at or below the 6th-grade reading level, based on FKGL. The mean readability scores were: FRES 54.10, FKGL 9.89, SMOG 12.73, and Gunning FOG 12.98, translating into FF-related IPEMs being written at a "difficult" writing level, which is above the level of reading understanding of the average American adult. CONCLUSIONS: IPEMs related to FFs are written above the recommended 6th-grade reading level. Consequently, this information would be difficult to understand by the average US patient. PMID- 22833339 TI - Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis. AB - OBJECTIVE: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes a chronic debilitating polyarthralgia/polyarthritis, for which current treatments are often inadequate. To assess whether new drugs being developed for rheumatoid arthritis (RA) might find utility in the treatment of alphaviral arthritides, we sought to determine whether the inflammatory gene expression signature of CHIKV arthritis shows any similarities with RA or collagen-induced arthritis (CIA), a mouse model of RA. METHODS: Using a recently developed animal model of CHIKV arthritis in adult wild-type mice, we generated a consensus CHIKV arthritis gene expression signature, which was used to interrogate publicly available microarray studies of RA and CIA. Pathway analyses were then performed using the overlapping gene signatures. RESULTS: Gene set enrichment analysis showed that there was a highly significant overlap in the differentially expressed genes in the CHIKV arthritis model and in RA. This concordance also increased with the severity of RA, as measured by the inflammation score. A highly significant overlap was also seen between CHIKV arthritis and CIA. Pathway analysis revealed that the overlap between these arthritides was spread over a range of different inflammatory processes. Involvement of T cells and interferon-gamma (IFNgamma) in CHIKV arthritis was confirmed in studies of MHCII-deficient mice and IFNgamma-deficient mice, respectively. CONCLUSION: These results suggest that RA, a chronic autoimmune arthritis, and CHIKV disease, usually a self-limiting viral arthropathy, share multiple inflammatory processes. New drugs and biologic therapies being developed for RA may thus find application in the treatment of alphaviral arthritides. PMID- 22833341 TI - Familiarity is related to conceptual implicit memory: an examination of individual differences. AB - Explicit memory is thought to be distinct from implicit memory. However, growing evidence has indicated that explicit familiarity-based recognition memory judgments rely on the same process that supports conceptual implicit memory. We tested this hypothesis by examining individual differences using a paradigm wherein we measured both familiarity and conceptual implicit memory within the same participants. In Experiments 1a and 1b, we examined recognition memory confidence ROCs and remember/know responses, respectively, to estimate recollection and familiarity, and used a free association task to measure conceptual implicit memory. The results demonstrated that, across participants, familiarity, but not recollection, was significantly correlated with conceptual priming. In contrast, in Experiment 2, utilizing a similar paradigm, a comparison of recognition memory ROCs and explicit associative cued-recall performance indicated that cued recall was related to both recollection and familiarity. These results are consistent with models assuming that familiarity-based recognition and conceptual implicit memory rely on similar underlying processes. PMID- 22833342 TI - The impact of emotion on prospective memory and monitoring: no pain, big gain. AB - The emotionally enhanced memory effect is robust across studies of retrospective memory, with heightened recall for items with emotional content (e.g., words like "murder") relative to neutral items (e.g., words like "envelope"). Only a handful of studies have examined the influence of emotion on prospective memory (PM), with mixed results. In some cases emotion enhances PM, and in others it impairs PM. Interpretation of these findings is clouded by methodological differences across studies and by the fact that, to date, no study has examined the impact of emotion on PM monitoring. In our study, we assessed PM performance when PM targets were neutral, negative, and positive, and also investigated monitoring across these different PM target types. Participants showed heightened PM performance for positive and negative relative to neutral targets, yet there was no evidence of additional monitoring for emotional targets. In fact, measures of monitoring were significantly reduced when the PM targets were emotional rather than neutral. Our findings suggest that it is possible to boost PM performance in a focal task using emotional cues, and that the use of emotional cues reduces the need for monitoring. PMID- 22833344 TI - A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study). AB - BACKGROUND: The outcome in patients with human epidermal growth factor receptor-2 (HER-2)-positive locally advanced breast cancer may be improved by integrating trastuzumab with primary systemic therapy (PST). METHODS: The efficacy and safety of PST comprising EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), four cycles every 3 weeks) followed by docetaxel (75 mg/m(2), four cycles every 3 weeks) and concurrent trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg, 12 cycles every week) was investigated in a multicenter, prospective, phase II study in patients with HER-2-positive stage IIIB/IIIC/IV breast cancer. The primary endpoint was pathologic complete response (pCR) including the tumor intraductal component confirmed by central pathologic review. RESULTS: In total, 38 patients were enrolled (stage IIIB, 63.2 %; IIIC, 23.7 %; IV, 13.2 %; estrogen receptor- and/or progesterone receptor-positive, 47.4 %). The pCR rate was 16.2 % in the primary tumor (six of 37 patients in the Full Analysis Set) and 56.8 % (21/37) in the ipsilateral axillary lymph nodes. Treatment was given according to protocol in 28 of 37 patients; six of 28 in the Per-Protocol Set achieved pCR (21.4 %). The clinical response rate was 67.6 % (25/37 patients; complete response, 13.5 %; partial response, 54.1 %). No patients developed congestive heart failure; however, three patients had a non-symptomatic decrease of >10 % of left ventricular ejection fraction. CONCLUSIONS: PST including concurrent use of trastuzumab combined with docetaxel is effective and well-tolerated in HER-2 positive advanced breast cancer patients, including those patients requiring mastectomy for local control. PMID- 22833345 TI - Attenuation of reactive oxygen species by antioxidants suppresses hypoxia-induced epithelial-mesenchymal transition and metastasis of pancreatic cancer cells. AB - Hypoxia has been shown to promote metastasis of cancer cells through induction of epithelial-mesenchymal transition (EMT). It is also known to cause generation of reactive oxygen species (ROS). We investigated here the role of ROS in hypoxia induced EMT and whether attenuation of ROS by antioxidants suppresses hypoxia induced EMT and metastasis of human pancreatic cancer cells in a xenograft nude mouse model. PANC-1 and MiaPaCa-2 cells exposed to hypoxia (1 % O(2)) showed increased ROS generation and characteristic changes of EMT such as morphological changes, enhanced invasiveness, and upregulation of EMT regulators, SLUG, SNAI1 and TWIST. The antioxidants N-acetylcysteine (NAC) and ebselen significantly suppressed EMT and the expression of EMT regulators during hypoxia. NAC abrogated activation of HIF-1alpha and NF-kappaB, both of which were found to play an active role in hypoxia-induced EMT. Administration of NAC to nude mice with orthotopic tumors suppressed the expression of EMT regulators in hypoxic areas and significantly inhibited hepatic metastasis. Together, the present findings demonstrate that attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastatic phenotype, suggesting that antioxidants may be of therapeutic value in treating pancreatic cancers. PMID- 22833346 TI - Patient preferences and experiences of CPAP and oral appliances for the treatment of obstructive sleep apnea: a qualitative analysis. AB - OBJECTIVES: The aim of this study is to better understand patients' perspectives and preferences about treatment with continuous positive airway pressure (CPAP) and oral appliance (OA) devices for obstructive sleep apnea. METHODS: The current study used qualitative analysis of four focus group sessions with current CPAP and OA users. Twenty-two participants with OSA who currently use either CPAP or OA participated in the sessions at the University of British Columbia. RESULTS: Five topics from the focus group sessions were descriptively analyzed using NVivo software: goals and expectations of treatment, benefits of treatment for bed partners, side effects and inconveniences of CPAP, side effects and inconveniences of OA, and factors impacting treatment choice. In order of most to least frequently mentioned, patients expressed six expectations of treatment: improved health, apnea elimination, improved sleep, reduced fatigue, reduced snoring, and bed-partner benefits. The most to least mentioned factors impacting treatment choice were device effectiveness, transportability, embarrassment, and cost. CONCLUSIONS: This qualitative study showed that many factors impact patients' experience with their treatment device and that their treatment needs are not only physical but also relate to their lifestyle. This preliminary study provides treatment characteristics and attributes necessary to develop a quantitative questionnaire study, to assist in the selection of therapy, weighing the relative importance of patient and OSA treatment characteristics on treatment preference and adherence. Matching therapy to patient preferences may help identify the most appropriate treatment, and this may achieve greater likelihood of adherence. PMID- 22833347 TI - Quantitative measurement of sleep quality using cardiopulmonary coupling analysis: a retrospective comparison of individuals with and without primary insomnia. AB - OBJECTIVE: The purpose of this study was to determine the utility of a new operator-independent, automated measure of sleep physiology based on cardiopulmonary coupling (CPC) analysis in subjects with primary insomnia vs. good sleepers. PATIENTS/METHODS: The polysomnograms of 50 subjects with primary insomnia and 36 good sleepers were summarized and analyzed from a consecutive two night protocol. The electrocardiograms (ECG) from adaptation and baseline night polysomnograms were analyzed using CPC analysis. This Fourier-based technique uses heart rate variability and ECG R wave amplitude fluctuations associated with respiration to generate frequency maps of coupled autonomic-respiratory oscillations. The resulting sleep spectrogram is able to categorize sleep as "stable" (high-frequency coupling [HFC], 0.1-0.4 Hz) and "unstable" (low frequency coupling [LFC], 0.1-0.01 Hz), independent of standard sleep stages. Wake and rapid eye movement sleep exhibit very low-frequency coupling (VLFC, 0.0039-0.01 Hz). Elevated LFC (e-LFC) is a subset of LFC that is associated with fragmented sleep of various etiologies. RESULTS: CPC variables showed a significant multivariate analysis of variance group, night, and group * night main effect, except for HFC by night. Relative to good sleepers, primary insomnia patients on adaptation night had lower HFC, a putative biomarker of stable sleep, and HFC/LFC ratio, an indicator of sleep quality. The primary insomnia group also had higher LFC, an index of unstable sleep, and an increase in VLFC and e-LFC compared to good sleepers on adaptation night. On baseline night, the primary insomnia group had increased LFC, VLFC, and e-LFC and a lower HFC/LFC ratio. Except for HFC, good sleepers had larger CPC variable differences between adaptation and baseline nights compared to the primary insomnia group. CONCLUSION: Primary insomnia subjects have a marked worsening of sleep quality on the adaptation night, which is well captured by both conventional and ECG-derived sleep spectrogram techniques. The larger improvement of sleep quality was found among good sleepers and captured only by CPC analysis. The operator-independent, automated measure of sleep physiology demonstrated functionality to differentiate and objectively quantify sleep quality. PMID- 22833348 TI - Metal oxide nanoparticles as an electron-transport layer in high-performance and stable inverted polymer solar cells. PMID- 22833349 TI - Membrane affinity and antibacterial properties of cationic polyelectrolytes with different hydrophobicity. AB - The antibacterial behavior of cationic polyelectrolytes is studied using model membrane experiments and in vitro bacterial investigations. The molecular interaction with lipid films is evaluated by the degree of penetration of the polymers into Langmuir monolayers of neutral or negatively charged lipids. The polymer/lipid interaction results in structural changes of the penetrated lipid layer visualized using AFM. The polymers are found to be effective in inhibiting the proliferation of E. coli, B. subtilis and S. aureus. The influence of the chemical structure on the functional behavior is related to the conformational properties. An optimum structure is identified on the basis of antibacterial and hemolytic tests as well as membrane-destroying efficacy of the antimicrobial polymers. PMID- 22833350 TI - Distribution and sources of polybrominated diphenyl ethers in the Southern California Bight. AB - Polybrominated diphenyl ethers (PBDEs) were measured in surface sediments from 121 locations within the Southern California Bight. Site selection was based on a probabilistic approach to determine the spatial extent and magnitude of PBDE concentrations with known confidence intervals. Coastal embayments (including estuaries, marinas, ports, and bays) and the continental shelf out to the lower slope were sampled. Thirteen PBDEs were detected at 92 of the sites, with a geometric mean and maximum of 4.7 and 560 ng/g dry weight (sum of 13 congeners), respectively. The PBDE concentrations were higher in coastal embayments than in offshore locations. Embayments had an area-weighted geometric mean total PBDE concentration of 12 (95% confidence interval, 8.0-17) ng/g dry weight and a total PBDE mass of 110 (77-160) kg. The offshore stratum, which is 99% of the total area, had an area-weighted geometric mean total PBDE concentration of 2.0 (1.6 2.5) ng/g dry weight and a total PBDE mass of 860 (700-1,100) kg. The five highest PBDE concentrations were associated with the mouths of urban rivers, indicating that urban runoff is likely a major input of PBDEs to these coastal marine waters. The outfalls of wastewater treatment plants were not observed to be major sources. PMID- 22833352 TI - On-demand killing of adherent cells on photo-acid-generating culture substrates. AB - As a powerful tool of cell screening and cell purification, we developed a novel method to kill adherent cells as cultured on a substrate by micro-projection of incoherent visible light. To kill the cells by the mild light irradiated by electrically controllable micro-projection systems currently available, we introduced the assist of the photo-responsive culture substrates functionalized with a photo-acid-generating polymer. In clear contrast to the existing laser based methods requiring point scanning, areal micro-projection of blue light with the wavelength 436 nm killed many CHO-K1 cells at a time in the irradiated area on the substrate. The effect of the photo-generated acid was so confined that selective killing of targeted cells was achieved without critical damage to the neighboring cells. Further, we demonstrated the photo-selective killing of the adherent cells after preliminarily patterning through the photo-induced removal of cell adhesion-inhibiting polymer. PMID- 22833351 TI - Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B cell lymphoma? AB - Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma." Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called "anaplastic large-cell lymphoma Hodgkin-like," and their outcome with standard approaches was poor, with short overall survivals. In this review-following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS-we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically. PMID- 22833353 TI - Validating an interlingual metanorm for emotional analysis of texts. AB - In this article, we present a set of 12 norms that characterize emotional terms in French, English, German, Spanish, Italian, and Finnish. The high correlation between the norm values in the two emotional dimensions of valence and arousal suggests an interlingual homogeneity of emotional representations and allows a significant metanorm-EMONORM-to be established with 6,383 terms characterized in valence and 4,345 terms characterized in arousal. This metanorm is a resource for creating experimental materials in studies on language and emotions. Furthermore, we perform three tests using EMONORM, with the objectives of (1) identifying basic emotions from their valence and arousal values, (2) determining the orientation of texts referring to positive and negative emotions, and (3) evaluating the intensity of emotions expressed in texts. The results are highly similar to those for human judgments. Finally, we present EMOVAL/SEMOTEX, a Web application for static and dynamic valence and arousal emotional analysis of texts using EMONORM ( http://www.semotex.fr ). PMID- 22833354 TI - A system for tracking braille readers using a Wii Remote and a refreshable braille display. AB - This article describes a cheap and easy-to-use finger-tracking system for studying braille reading. It provides improved spatial and temporal resolution over the current available solutions and can be used with either a refreshable braille display or braille-embossed paper. In conjunction with a refreshable braille display, the tracking system has the unique capacity to implement display change paradigms derived from sighted reading research. This will allow researchers to probe skilled braille reading in significantly more depth than has heretofore been possible. PMID- 22833355 TI - CINtec(r) PLUS dual immunostain: a triage tool for cervical pap smears with atypical squamous cells of undetermined significance and low grade squamous intraepithelial lesion. AB - ASC and LSIL comprise the majority of abnormal Pap smears. Currently, high-risk human papillomavirus testing is utilized to triage women with ASC for colposcopy; however, no cost effective triage method is available for LSIL. p16 and Ki-67 have each been shown to be good biomarkers for high grade cervical intraepithelial neoplasia (HG CIN).We evaluated the role of the CINtec(r) PLUS p16/Ki-67 dual immunostain as a marker for underlying (U) or subsequent (S) HG CIN. One hundred and eighty eight cervical SurePath Pap smears with histological and/or cytological follow-up were retrieved from our departmental files. The Pap stained slides were destained and then immunostained utilizing the CINtec(r) PLUS dual staining reagent kit. Results of the dual stain were correlated with follow up diagnoses. Sensitivity, specificity, and positive and negative predictive values of CINtec(r) PLUS for U or S HG CIN were compared with those of HR HPV testing and with p16 and Ki-67 immunostaining alone. The sensitivity of CINtec(r) PLUS for U or S HG CIN was 91% in the ASC group and 100% in the LSIL group, while the corresponding specificities were 61 and 43%, respectively. The sensitivity and specificity of CINtec(r) PLUS for U or S HG CIN in both groups combined were 97 and 53%, respectively. CINtec(r) PLUS was more specific than HR HPV testing and Ki-67 and p16 immunostains alone in detecting an U or S HG CIN. CINtec(r) PLUS is a helpful adjunct in identifying U or S HG CIN when applied to SurePath Pap smears with ASC or LSIL. PMID- 22833356 TI - Extraction of cupric ions with ionic liquids containing polypyridine-type small molecules or peripherally pyridine-modified dendrimers. AB - The hydrophobic ionic liquid N-butyl-N-methylpyrrolidinium bis((trifluoromethyl)sulfonyl)amide (BMP-TFSA IL), which contains a series of flexible ionophores of polypyridine-type small molecules or two rigid ionophores of peripherally pyridine-modified PAMAM dendrimers, was used to extract cupric ions from aqueous solutions. The polypyridine-type ionophores show good selectivity toward cupric ions at pH 2. The selectivity is affected by the spacing between the two amino groups. However, the pyridine-modified dendrimers showed poor selectivity, although their extraction efficiency still depended on the pH of the aqueous solution. The ionic liquids that contained small molecular ionophores and their dendrimer analogs were reused after acid washing or electrochemical reduction. During acid washing, the nitrogen atoms of the ionophores were protonated to release the cupric ions into the aqueous phase, and the copper atoms were deposited onto the electrode surface during the electrochemical reduction accompanied by the regeneration of the ionophores. PMID- 22833358 TI - Establishment and cytogenetic characterization of a cell line from a pulmonary metastasis of osteosarcoma. AB - Osteosarcoma (OS) is the most frequent malignant bone tumour in children and adolescents. In metastatic patients, the most common site of metastasis is the lung. There are relatively few cell lines of metastatic OS reported in the literature and the cytogenetic aspects of OS metastases are still controversial and inconclusive. Here we describe the establishment of a new OS cell line, M-OS, from a pulmonary metastasis of a typical osteoblastic OS of an 11-year-old boy with metastatic OS at diagnosis. M-OS cells have been maintained in culture for over 50 passages for more than 1 year. M-OS was characterized by immunohistochemistry, conventional cytogenetics and fluorescence in situ hybridization (FISH). In order to evaluate in vitro cell modification, the immunohistochemical analysis was performed in three different moments of the cell line: 10th, 30th and 50th passages. The conventional cytogenetic analysis revealed the ploidy of M-OS cell line as near-diploid, with most metaphases hyperdiploid and tetraploid. We found a copy number gain of MDM2 gene as the most frequent alteration in the FISH analysis. The immunohistochemical analysis confirmed that M-OS cell line maintained the osteogenic nature even after all passages for the cell line establishment in vitro. PMID- 22833357 TI - Intestinal myofibroblasts produce nitric oxide in response to combinatorial cytokine stimulation. AB - Inflammatory bowel disease (IBD) patients display elevated levels of intraluminal nitric oxide (NO). NO can react with other molecules to form toxic compounds, which has led to the idea that NO may be an important mediator of IBD. However, the cellular source of NO and how its production is regulated in the intestine are unclear. In this study we aimed to determine if intestinal myofibroblasts produce NO in response to the IBD-associated cytokines IL-1beta, TNFalpha, and IFNgamma. Intestinal myofibroblasts were isolated from mice and found to express inducible nitric oxide synthase (iNOS) mRNA, but not endothelial NOS or neuronal NOS. Individual treatment of myofibroblasts with IL-1beta, TNFalpha, or IFNgamma had no effect on NO production, but stimulation with combinations of these cytokines synergistically increased iNOS mRNA and protein expression. Treatment with TNFalpha or IFNgamma increased cell surface expression of IFNgammaRI or TNFRII, respectively, suggesting that these cytokines act in concert to prime NO production by myofibroblasts. Impairment of NF-kappaB activity with a small molecule inhibitor was sufficient to prevent increased expression of IFNgammaRI or TNFRII, and inhibition of Akt, JAK/STAT, or NF-kappaB blocked nearly all NO production induced by combinatorial cytokine treatment. These data indicate that intestinal myofibroblasts require stimulation by multiple cytokines to produce NO and that these cytokines act through a novel pathway involving reciprocal cytokine receptor regulation and signaling by Akt, JAK/STAT, and NF-kappaB. PMID- 22833359 TI - miR-210 activates notch signaling pathway in angiogenesis induced by cerebral ischemia. AB - The compensatory angiogenesis that occurs after cerebral ischemia increases blood flow to the injured area and limits extension of the ischemic penumbra. In this way, it improves the local blood supply. Fostering compensatory angiogenesis is an effective treatment for ischemic cerebrovascular disease. However, angiogenesis in the adult organism is a complex, multi-step process, and the mechanisms underlying the regulation of angiogenesis are not well understood. Although Notch signaling reportedly regulates the vascularization process that occurs in ischemic tissues, little is known about the role of Notch signaling in the regulation of ischemia-induced angiogenesis after ischemic stroke. Recent research has indicated that miR-210, a hypoxia-induced microRNA, plays a crucial role in regulating the biological processes that occur in blood vessel endothelial cells under hypoxic conditions. This study was undertaken to investigate the role of miR-210 in regulating angiogenesis in response to brain ischemia injury and the role of the Notch pathway in the body's response. We found miR-210 to be significantly up-regulated in adult rat ischemic brain cortexes in which the expression of Notch1 signaling molecules was also increased. Hypoxic models of human umbilical vein endothelial cells (HUVE-12) were used to assess changes in miR-210 and Notch1 expression in endothelial cells. Results were consistent with in vivo findings. To determine the molecular mechanisms behind these phenomena, we transfected HUVE-12 cells with miR-210 recombinant lentiviral vectors. We found that miR-210 overexpression caused up regulation of Notch1 signaling molecules and induced endothelial cells to migrate and form capillary-like structures on Matrigel. These data suggest that miR-210 is involved in the regulation of angiogenesis in response to ischemic injury to the brain. Up-regulation of miR-210 can activate the Notch signaling pathway, which may contribute to angiogenesis after cerebral ischemia. PMID- 22833360 TI - Effects of cinacalcet on bone mineral density and bone markers in hemodialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: Cinacalcet markedly reduces the serum intact parathyroid hormone (PTH) level of hemodialysis (HD) patients with secondary hyperparathyroidism. Parathyroidectomy also reduces the serum intact PTH level of HD patients and it increases their bone mineral density (BMD). However, there is little information about the effect of cinacalcet on BMD or on the associations between bone markers and BMD in HD patients. METHODS: We performed a 1-year cohort study of 25 HD patients who had a serum intact PTH level above 300 pg/ml during treatment by conventional therapies, such as with active vitamin D, and cinacalcet was prescribed for 14 of them. BMD of the femoral neck and the serum levels of two circulating bone markers, alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BSAP), were measured before and after treatment. The other 11 HD patients without cinacalcet treatment were defined as control group. RESULTS: BMD significantly increased by 7.3 % during the 1 year of treatment in the cinacalcet group and decreased by 6.2 % during the same period in the control group, and cinacalcet therapy was independently associated with the changes in BMD after multiple regression analysis that included intact PTH (beta = 7.57, P < 0.01). In the cinacalcet group, the serum ALP levels (R(2) = 0.315, P < 0.05) and BSAP levels (R(2) = 0.682, P < 0.01) levels were significantly negatively correlated with the changes in BMD, but the serum intact PTH levels were not significantly associated with the changes in BMD (R(2) = 0.011, P = 0.72). CONCLUSIONS: One year of treatment with cinacalcet increased the BMD of the femoral neck in the HD cohort, especially in the patients who had higher serum ALP and BSAP levels at baseline. PMID- 22833361 TI - Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae. AB - The aim of the present study was to investigate the acute developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs) in zebrafish larvae. From 2 to 120 h postfertilization zebrafish embryos were exposed to DE-71 (0, 31.0, 68.7, and 227.6 ug/L). The authors studied the locomotor behavior of larvae, involvement of the cholinergic system, and selected gene and protein expressions in the central nervous system. The results showed that low DE-71 concentration caused hyperactivity, whereas higher concentrations decreased activity during the dark period. During the light period, larval activity was significantly reduced in a concentration-dependent manner. In the cholinergic system, acetylcholinesterase activity significantly increased (10.7 and 12.4%) in the 68.7 and 227.6 ug/L exposure groups, respectively, and acetylcholine concentration accordingly decreased (60.5%) in the 227.6 ug/L exposure group. The mRNA expressions of genes encoding myelin basic protein, neuron microtubule protein (alpha1-tubulin), and sonic hedgehog a were significantly downregulated. Western blotting assay demonstrated that the protein concentration of alpha1 tubulin was also decreased. Overall, the present study demonstrated that acute exposure to PBDEs can disrupt the neurobehavior of zebrafish larvae and affect cholinergic neurotransmission and neuron development. PMID- 22833362 TI - Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: results of a phase I, placebo-controlled, double-blind, dose escalation study. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)-regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNalpha, were assessed in a phase I dose-escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN-inducible proteins, and autoantibodies. METHODS: Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN-inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab. RESULTS: An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose-limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN-inducible proteins or levels of anti-double-stranded DNA and anti-extractable nuclear antigen autoantibodies following treatment with rontalizumab. CONCLUSION: The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE. PMID- 22833363 TI - The preparation of a complex of insulin-phospholipids and their interaction mechanism. AB - Subcutaneous injections of insulin remain the standard treatment for insulin dependent diabetic patients, and noninvasive routes are studied but with little success. One of the reasons is that insulin is a hydrophilic compounds and is difficult to cross the mucosa barrier. In this paper, we developed a novel technique to fabricate the insulin-phospholipids complex by a solvent evaporation method with the aim of improving the lipophilicity of insulin. A systematic study on the preparation conditions of the insulin-phospholipids complex is reported in the present work. The formation mechanism and the physicochemical properties of the complex are studied. The associated efficiency of the phospholipids and insulin can be up to 100% when their mass ratio is 7.5 : 1 or more, and the solubility of the complex is improved more than 40 000 times compared with that of insulin alone in the n-octyl alcohol. The results of the insulin content in the complex and hypoglycemic effects in diabetic mice indicated that insulin was able to withstand the preparation procedure. The stability results showed that the complex was stable for 1 year at -20 degrees C. The interaction mechanism of this formation is that the peptide bonds of insulin interact with the water soluble head of phospholipids, forming a reverse micelle-like structure. This novel complex will be of great importance in the drug delivery system for insulin via noninvasive routes. This method is cost effective, scalable, and can be used in many other peptide drugs. PMID- 22833364 TI - Wettability influences cell behavior on superhydrophobic surfaces with different topographies. AB - Surface wettability and topography are recognized as critical factors influencing cell behavior on biomaterials. So far only few works have reported cell responses on surfaces exhibiting extreme wettability in combination with surface topography. The goal of this work is to study whether cell behavior on superhydrophobic surfaces is influenced by surface topography and polymer type. Biomimetic superhydrophobic rough surfaces of polystyrene and poly(L-lactic acid) with different micro/nanotopographies were obtained from smooth surfaces using a simple phase-separation based method. Total protein was quantified and showed a less adsorption of bovine serum albumin onto rough surfaces as compared to smooth surfaces of the same material. The mouse osteoblastic MC3T3-E1 cell line and primary bovine articular chondrocytes were used to study cell attachment and proliferation. Cells attached and proliferate better in the smooth surfaces. The superhydrophobic surfaces allowed cells to adhere but inhibited their proliferation. This study indicates that surface wettability, rather than polymer type or the topography of the superhydrophobic surfaces, is a critical factor in determining cell behavior. PMID- 22833365 TI - Sex and dose-related differences in methylphenidate adolescent locomotor sensitization and effects on brain-derived neurotrophic factor. AB - This study analyzed repeated methylphenidate (MPH) administration and its effects on brain-derived neurotrophic factor (BDNF) in the dorsal striatum and nucleus accumbens of male and female adolescent rats. In Experiment 1, rats were administered intraperitoneal (ip) saline, 1, 3, or 5 mg/kg dose of MPH every second day from postnatal day (P)33-P49. Locomotor activity was analyzed for 10 min after each administration. Results revealed that the 1 mg/kg dose of MPH produced locomotor suppression, however, the 5 mg/kg dose of MPH produced locomotor sensitization and robust behavioral activation in females as compared to males. In Experiment 2, animals were administered ip saline or the 5 mg/kg dose of MPH using an identical regimen but a 30 min behavioral test was employed. Dorsal striatum and nucleus accumbens tissue was assayed for BDNF at P50. Females demonstrated sensitization to MPH and increased locomotor activation compared to males. Interestingly, females given MPH demonstrated a significant 42% decrease of striatal BDNF whereas males administered MPH demonstrated a significant 50.4% increase of striatal BDNF compared to controls. There were no effects on accumbal BDNF. This report demonstrates robust sex differences in the behavioral response, but sex-dependent changes in striatal BDNF in response to MPH in adolescence. PMID- 22833366 TI - Coblation tonsillectomy in children: incidence of bleeding. AB - OBJECTIVES/HYPOTHESIS: To evaluate the intraoperative and postoperative bleeding rate utilizing the Coblation device for total tonsillectomy in children. STUDY DESIGN: Prospectively designed clinical study. METHODS: Institutional review board approval was obtained to study patients undergoing Coblation tonsillectomy. Records of all children 1 to 18 years of age undergoing tonsillectomy or adenotonsillectomy from April 2003 to April 2010 were reviewed. All children underwent total tonsillectomy utilizing the Coblation device, and the intraoperative and postoperative bleeding complications were analyzed. The data were also analyzed to determine whether surgeon experience with the technique influenced the bleeding rate. RESULTS: A total of 1,918 patients were evaluated. Intraoperative blood loss was <5 mL in >90% of the patients, with no patients experiencing >20 mL of blood loss. The postoperative bleeding rate was consistent with the literature (n = 87, 4.5%). Of the patients with bleeding following surgery, five (5.7%) experienced primary bleeding and 82 (94.3%) secondary bleeding. Postoperative bleeding that ceased spontaneously and did not require intervention was present in 56 (2.9%). The number of patients who actually required intervention to control postoperative bleeding was 31 (1.6%). The majority of bleeding occurred by postoperative day 7. There was no statistically significant difference in bleeding rates by age, and there was no evidence found to support a surgeon learning curve for performing Coblation tonsillectomy. CONCLUSIONS: This study provides further support that Coblation total tonsillectomy in children is a reliable and safe procedure with a relatively low incidence of intraoperative and postoperative bleeding. PMID- 22833367 TI - Timing and efficacy of alternative methods of sympathetic blockade. AB - Despite the presence of seven different antihypertensive drug classes and over 120 different antihypertensive medications, about 48 % of the 75 million people with hypertension are not reaching their target blood pressure goals. One of the reasons for this lack of control is the failure to adequately inhibit the sympathetic nervous system. Consequently, alternative therapies have been attracting interest. Recent technical advances targeting the sympathetic over activity of the carotid sinuses (baroreflex activation therapy, BAT) and the renal sympathetic nerves (renal denervation therapy, RDT) have renewed interest in invasive therapies for the treatment of drug-resistant hypertension. Encouraging results from the recent Rheos Pivotal and Symplicity HTN-2 trials on the safety and efficacy of BAT and RDT, respectively, indicate that invasive approaches can safely reduce blood pressure in patients with resistant/refractory hypertension. These approaches, while still experimental in the US, are appropriate for those on more than three fully tolerated doses of antihypertensive medications whose blood pressure is not at goal, i.e. <140/90 mmHg. The present review is focused on the clinical implications of these two technics and when they are appropriate. PMID- 22833368 TI - Segmental modeling of viral load changes for HIV longitudinal data with skewness and detection limits. AB - Although it is a common practice to analyze complex HIV longitudinal data using nonlinear mixed-effects or nonparametric mixed-effects models in literature, the following issues may standout. (i) In clinical practice, the profile of each subject's viral response may follow a 'broken-stick'-like trajectory, indicating multiple phases of decline and increase in response. Such multiple phases (change points) may be an important indicator to help quantify treatment effect and improve management of patient care. To estimate change points, nonlinear mixed effects or nonparametric mixed-effects models become a challenge because of complicated structures of model formulations. (ii) The commonly assumed distribution for model random errors is normal, but this assumption may unrealistically obscure important features of subject variations. (iii) The response observations (viral load) may be subject to left censoring due to a limit of detection. Inferential procedures can be complicated dramatically when data with asymmetric (skewed) characteristics and left censoring are observed in conjunction with change points as unknown parameters into models. There is relatively little work concerning all these features simultaneously. This article proposes segmental mixed-effects models with skew distributions for the response process (with left censoring) under a Bayesian framework. A real data example is used to illustrate the proposed methods. PMID- 22833369 TI - Simultaneous Clostridial fermentation, lipase-catalyzed esterification, and ester extraction to enrich diesel with butyl butyrate. AB - The recovery of 1-butanol from fermentation broth is energy-intensive since typical concentrations in fermentation broth are below 20 g L(-1). To prevent butanol inhibition and high downstream processing costs, we aimed at producing butyl esters instead of 1-butanol. It is shown that it is possible to perform simultaneously clostridial fermentation, esterification of the formed butanol to butyl butyrate, and extraction of this ester by hexadecane. The very high partition coefficient of butyl butyrate pulls the esterification towards the product side even at fermentation pH and relatively low butanol concentrations. The hexadecane extractant is a model diesel compound and is nontoxic to the cells. If butyl butyrate enriched diesel can directly be used as car fuel, no product recovery is required. A proof-of-principle experiment for the one-pot bio ester production from glucose led to 5 g L(-1) butyl butyrate in the hexadecane phase. The principle may be extended to a wide range of esters, especially to longer chain ones. PMID- 22833371 TI - CdS-polymer nanocomposites and light-emitting fibers by in situ electron-beam synthesis and lithography. AB - A straightforward, electron-beam induced synthesis and patterning approach to the in situ generation of CdS nanocrystals in nanocomposite films and light-emitting electrospun nanofibers is used. Smartly combining room-temperature nanoimprinting, electrospinning, and electron-beam decomposition of nanocrystal precursors and subsequent nucleation of nanoparticles in a polymer matrix allows exploitation of the most favorable flow conditions of organics to produce various nanocomposite nanostructures. PMID- 22833370 TI - Investigation of environmental contamination of mono-isopropylnaphthalene, di isopropylnaphthalene and tri-isopropylnaphthalene in Hyogo in Japan. AB - Di-isopropylnaphthalene (DIPN) has highly persistent and bioaccumulative properties, and a large amount of DIPN is used as a PCB substitute in Japan. However, DIPN in the environment has not been thoroughly investigated. In addition, mono-isopropylnaphthalene (MIPN) and tri-isopropylnaphthalene (TIPN), which are the homologues of DIPN, have similar properties to DIPN. In this study, simultaneous analytical methods for MIPN, DIPN, and TIPN for air, environmental water, sediment, and biological samples were developed, and the resultant contamination caused by each in the environment was investigated. DIPN was detected at 1.1 +/- 0.38 ng/m(3) in air and between < 1.9 and 9.8 ng/L in river water, but MIPN and TIPN were not. In Lateolabrax japonicas (Japanese sea perch), TIPN was detected from only females at between 0.65 and 1.4 ng/g-wet. DIPN was detected from all perches at between 1.2 and 3.4 ng/g-wet. DIPN and TIPN isomer fingerprints in females were different from those in the reference standard stock solution ones. In sediments, MIPN, DIPN, and TIPN were detected at between < 0.16 and 8.6 ng/g-dry, between < 1.1 and 4400 ng/g-dry, and between < 0.83 and 500 ng/g-dry, respectively. The contamination trend of DIPN in the sediments was similar to that of PCBs. PMID- 22833372 TI - Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. AB - OBJECTIVES: Better therapies are needed for inflammatory pain. In arthritis the relationship between joint pain, inflammation and damage is unclear. Granulocyte macrophage colony-stimulating factor (GM-CSF) is important for the progression of a number of inflammatory/autoimmune conditions including arthritis; clinical trials targeting its action in rheumatoid arthritis are underway. However, its contribution to inflammatory and arthritic pain is unknown. The aims of this study were to determine whether GM-CSF controls inflammatory and/or arthritic pain. METHODS: A model of inflammatory pain (complete Freund's adjuvant footpad), as well as two inflammatory arthritis models, were induced in GM-CSF(-/-) mice and development of pain (assessment of weight distribution) and arthritic disease (histology) was assessed. Pain was further assessed in a GM-CSF-driven arthritis (methylated bovine serum albumin/GM-CSF) model and the cyclooxygenase-dependence determined using indomethacin. RESULTS: GM-CSF was absolutely required for pain development in both the inflammatory pain and arthritis models, including for IL 1-dependent arthritic pain. Pain in a GM-CSF-driven arthritis model, but not the disease itself, was abolished by the cyclooxygenase inhibitor, indomethacin, indicating separate pathways downstream of GM-CSF for pain and arthritis control. CONCLUSIONS: GM-CSF is key to the development of inflammatory and arthritic pain, suggesting that pain alleviation could result from trials evaluating its role in inflammatory/autoimmune conditions. PMID- 22833373 TI - Rituximab in psoriatic arthritis: an exploratory evaluation. AB - BACKGROUND/OBJECTIVE: Current therapies for psoriatic arthritis (PsA) comprise synthetic drugs and tumour necrosis factor inhibitors. In contrast, other biologicals including rituximab (RTX) are available for treating rheumatoid arthritis (RA). RTX is effective in autoantibody positive RA patients, although some efficacy has been reported in seronegative individuals. RTX has not yet been assessed in PsA. Therefore, an open label study of RTX in PsA was performed. PATIENTS AND METHODS: Nine patients with PsA and 14 with RA received RTX at 1000 mg twice within 14 days and were evaluated over 6 months. RESULTS: A PsA response criteria response was attained in 56% of patients. DAS28 improved from 6.2 to 4.9 (medians) in PsA and 6.4 to 5.2 in RA, and Health Assessment Questionnaire from 1.5 to 1.0 and from 2.1 to 1.4, respectively (all p<=0.05). Disease Activity index for PSoriatic Arthritis changed from 52.0 to 32.5 (p<0.05); C reactive protein and Psoriasis Area and Severity Index did not change significantly. RTX was tolerated well. CONCLUSIONS: In this exploratory open study, RTX exhibited significant efficacy in PsA patients with long-standing disease. Thus, RTX may have efficacy in PsA warranting a randomised controlled clinical trial. PMID- 22833375 TI - Retroperitoneal recurrence of a stage 1 renal cell carcinoma 4 years following core biopsy and fine needle aspiration: possible needle tract seeding. PMID- 22833374 TI - Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case-control study. AB - OBJECTIVE: Environmental factors may play a role in the development of rheumatoid arthritis (RA). We examined whether long-term exposures to air pollution were associated with the risk of RA in the Swedish Epidemiological Investigation of Rheumatoid Arthritis Study. METHODS: We studied 1497 incident RA cases and 2536 controls. Local levels of particulate matter (PM10) and gaseous pollutants (sulphur dioxide (SO2) and nitrogen dioxide (NO2)) from traffic and home heating were predicted for all residential addresses. We examined the association of an IQR increase (2 ug/m3 for PM10, 8 ug/m3 for SO2 and 9 ug/m3 for NO2) in each pollutant at different time points before symptom onset and average exposure with the risk of all RA and the risk of the rheumatoid factor and anti-citrullinated protein antibody (ACPA) RA phenotypes. RESULTS: There was no evidence of an increased risk of RA with PM10. Total RA risks were modestly elevated for the gaseous pollutants, but were not statistically significant after adjustment for smoking and education (OR 1.18, 95% CI 0.97 to 1.43 and OR 1.09, 95% CI 0.99 to 1.19 for SO2 and NO2 in the 10th year before onset). Stronger elevated risks were observed for individuals with less than a university education and with the ACPA negative RA phenotype. CONCLUSIONS: No consistent overall associations between air pollution in the Stockholm area and the risk of RA were observed. However, there was a suggestion of increased risks of RA incidence with increases in NO2 from local traffic and SO2 from home heating sources with stronger associations for the ACPA-negative phenotype. PMID- 22833376 TI - Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a phase I study. AB - OBJECTIVE: The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. METHODS: This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues. RESULTS: Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set. CONCLUSION: Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis. PMID- 22833378 TI - alpha,alpha'-Diarylacenaphtho[1,2-c]phosphole P-oxides: divergent synthesis and application to cathode buffer layers in organic photovoltaics. AB - A divergent method for the synthesis of alpha,alpha'-diarylacenaphtho[1,2 c]phosphole P-oxides has been established; alpha,alpha' dibromoacenaphtho[c]phosphole P-oxide, which was prepared through a Ti(II) mediated cyclization of 1,8-bis(trimethylsilylethynyl)naphthalene, underwent a Stille coupling with three different kinds of aryltributylstannanes to afford the alpha,alpha'-diarylacenaphtho[c]phosphole P-oxides in moderate to good yields. X ray crystallographic analyses and UV/Vis absorption/fluorescence measurements have revealed that the degree of pi-conjugation, the packing motif, the electron accepting ability, and the thermal stability of the acenaphtho[c]phosphole pi systems are finely tunable with the alpha-aryl substituents. All the P=O and P=S derivatives exhibited high stability in their electrochemically reduced state. To use this class of arene-fused phosphole pi-systems as n-type semiconducting materials, we evaluated device performances of the bulk heterojunction organic photovoltaics (OPV) that consist of poly(3-hexylthiophene), an indene-C(70) bisadduct, and a cathode buffer layer. The insertion of the diarylacenaphtho[c]phosphole P-oxides as the buffer layer was found to improve the power conversion efficiency of the polymer-based OPV devices. PMID- 22833380 TI - How are trace elements mobilized during the postweaning fast in Northern elephant seals? AB - Northern elephant seal (Mirounga angustirostris) pups undergo a substantial intertissue reorganization of protein, minerals, and other cellular components during their postweaning development, which might entail the mobilization of associated contaminants. The authors investigated the changes in concentrations of 11 elements (Ca, Cd, Cr, Cu, Fe, Hg, Ni, Pb, Se, V, and Zn) in a longitudinal study on 22 northern elephant seal pups during the postweaning fast. Slight changes in most element concentrations were observed in blood throughout the fast. Circulating levels of Hg, Se, and Cu appeared less altered during the postweaning fast than measured during suckling. Despite the considerable fat utilization, element concentrations, except Fe, in blubber remained stable throughout the fast, which suggests that elements are mobilized from blubber as efficiently as lipids. As indicators of the placental transfer, concentrations in lanugo hair revealed the existence of maternal transfer and accumulation of all assayed trace elements during fetal development. In addition, the new pelage, rapidly produced after weaning, appeared to be an important elimination route for toxic metals such as Hg, Cd, and Pb. The high mineral content detected in pup hair suggests that this species would be more exposed to trace elements than other phocids (except Cd and Pb). Nevertheless, this statement needs further monitoring and toxicological studies to determine better the exposition to trace elements and its potential impact on the health of the northern elephant seal. PMID- 22833377 TI - Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo controlled trial. AB - OBJECTIVES: To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone. METHODS: In this multicenter, double blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups. RESULTS: The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred. CONCLUSION: The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile. PMID- 22833381 TI - Non-anesthesiologist administered propofol with or without midazolam for moderate sedation-the problem is not "which regimen" but "who's regimen". PMID- 22833382 TI - Single- versus double-balloon-assisted colonoscopy after previous incomplete standard colonoscopy. PMID- 22833383 TI - A great masquerader: acute syphilitic hepatitis. PMID- 22833384 TI - GNAS1 and PHD2 short-interfering RNA support bone regeneration in vitro and in an in vivo sheep model. AB - BACKGROUND: Our ability to guide cells in biomaterials for in vivo bone repair is limited and requires novel strategies. Short-interfering RNA (siRNA) allows the regulation of multiple cellular pathways. Core binding factor alpha 1 (Cbfa1) and hypoxia-inducible factor 1 (HIF-1) pathways can be modulated to direct bone formation via siRNA against guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 (siGNAS1) and prolyl hydroxylase domain-containing protein 2 (siPHD2), respectively. QUESTIONS/PURPOSES: We determined whether the administration of siGNAS1 and siPHD2 in mesenchymal stem cells (MSCs) promotes osteogenic phenotype, the dose-dependent effects of siGNAS1 on MSC differentiation to osteogenic phenotype, and whether the two siRNAs promote bone formation in vivo. METHODS: siRNAs were administered to MSCs at Day 0, and protein expression of bone-specific markers was assessed at Days 1, 2, and 4 (n = 3/group/time point). In an in vivo model using seven sheep, chambers containing silk fibroin-chitosan (SFCS) scaffolds with siRNA were implanted over the periosteum and harvested at Days 7, 21, 36, and 70 (n = 4/group/time point, except at Day 70 [n = 2]) to assess bone formation. RESULTS: siGNAS1 promoted collagen I and osteopontin expression, whereas siPHD2 had no effect in vitro. Dose-dependent effects of siGNAS1 on ALP expression were maximal at Day 1 for 10 MUg/mL and Day 4 for 100 MUg/mL. In vivo, by Day 70, mean bone volume increased compared to Day 7 for siGNAS1-SFCS (47.8 versus 1.8 mg/mL) and siPHD2-SFCS (61.3 versus 1.5 mg/mL). CONCLUSIONS: Both siPHD2 and siGNAS1 support bone regeneration in vivo, whereas only siGNAS1 regulates bone phenotype in MSCs in vitro. PMID- 22833385 TI - Roflumilast--a phosphodiesterase-4 inhibitor licensed for add-on therapy in severe COPD. AB - Roflumilast is a selective phosphodiesterase 4 inhibitor which has been licensed in the European Union since 2010 and in Switzerland since November 2011 as an add on treatment for patients with chronic obstructive pulmonary disease (COPD) in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages 3 and 4 (FEV(1) <50% predicted after bronchodilatation) and frequent exacerbations despite correctly-dosed therapy with a long-acting bronchodilator. Roflumilast is designed to target both the systemic and pulmonary inflammation associated with COPD. In this review roflumilast's chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy, safety and tolerability and the current ongoing clinical trials involving roflumilast are outlined. Information has been sourced from the Swiss and US product information monographs, peer-reviewed published literature (identified from a PubMed MEDLINE search 1966 - March 2012 using the term "roflumilast"), the COPD GOLD international guidelines for the management of COPD (Revised 2011) and an independent analysis of phase 3 clinical trial data by FDA staff physicians. Clinical efficacy in terms of a modest gain in FEV(1)% and a reduction in exacerbation rate has been demonstrated in phase 3 clinical trials and roflumilast has been recently incorporated into international treatment guidelines. However data examining roflumilast as add-on therapy to long-acting bronchodilators and ICS (standard therapy) is currently awaited and phase 4 post marketing studies are required to determine the incidence and severity of adverse events and the long-term beneficial effects of roflumilast as a maintenance therapy for COPD in every-day clinical practice. PMID- 22833386 TI - Thrombin induces slug-mediated E-cadherin transcriptional repression and the parallel up-regulation of N-cadherin by a transcription-independent mechanism in RPE cells. AB - The proliferation, directional migration to the vitreous and epithelial mesenchymal transition (EMT) of quiescent, differentiated retinal pigment epithelium (RPE) cells is a major feature in the development of proliferative vitreoretinopathy (PVR) following exposure of the immuno-privileged eye niche to serum components, thrombin among them. We have previously documented thrombin induction of RPE cell proliferation and migration. We here analyzed the effect of thrombin on the E/N cadherin switch, a hallmark of EMT. Results show that thrombin induces the specific repression of epithelial E-cadherin gene transcription, alongside with the up-regulation of mesenchymal N-cadherin protein in RPE cells. We demonstrate, for the first time, that thrombin induces E cadherin repression by stimulating snail-2 (SLUG) transcription factor expression, and the concomitant up-regulation of N-cadherin through the transcription-independent increase in protein translation promoted by PI3K/PKC zeta/mTOR signaling. Our present findings suggest that the activation of protease activated receptor-1 (PAR-1) by thrombin induces EMT of RPE cells, further supporting a central role for thrombin in PVR pathogenesis. PMID- 22833387 TI - A slow gradient approach for the purification of synthetic polypeptides by reversed phase high performance liquid chromatography. AB - Unquestionably, the purification of polypeptides by chromatographic methods is a considerable bottleneck in their preparation. Peptides synthesised by solid phase synthesis typically contain chromatographically similar impurities that complicate purification by reversed phase high performance liquid chromatography (HPLC) techniques. We report on the application of a slow gradient HPLC protocol that allows, in a single chromatographic step, the purification of hundreds of milligrammes of material. This technique was applied to an extensive collection of synthetic polypeptides some incorporating non-proteinogenic functionality. In all cases examined, the peptides were not only obtained in high purity peptides but were also recovered in multi-milligramme amounts. PMID- 22833388 TI - Penalized likelihood estimation for semiparametric mixed models, with application to alcohol treatment research. AB - In this article, we implement a practical computational method for various semiparametric mixed effects models, estimating nonlinear functions by penalized splines. We approximate the integration of the penalized likelihood with respect to random effects with the use of adaptive Gaussian quadrature, which we can conveniently implement in SAS procedure NLMIXED. We carry out the selection of smoothing parameters through approximated generalized cross-validation scores. Our method has two advantages: (1) the estimation is more accurate than the current available quasi-likelihood method for sparse data, for example, binary data; and (2) it can be used in fitting more sophisticated models. We show the performance of our approach in simulation studies with longitudinal outcomes from three settings: binary, normal data after Box-Cox transformation, and count data with log-Gamma random effects. We also develop an estimation method for a longitudinal two-part nonparametric random effects model and apply it to analyze repeated measures of semicontinuous daily drinking records in a randomized controlled trial of topiramate. PMID- 22833389 TI - Increased diagnostic yield of endoscopic ultrasound-guided fine needle aspirates with flow cytometry and immunohistochemistry. AB - Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most sensitive and specific test for establishing a tissue diagnosis for many gastrointestinal malignancies; however, cytologic morphology alone may not be definitive for subsets of tumors. Our aim was to quantify the impact of the broad application of flow cytometry (FC) and immunohistochemistry (IHC) on EUS-FNA diagnostic yield. A retrospective chart review was performed on EUS procedures at a tertiary referral, academic medical center. All EUS-FNA cases performed over a 21-month period were examined. Of 606 EUS procedures reviewed during the period of study, 264 utilized FNA. After pancreatic cyst cases were excluded, 235 EUS FNA cases for 221 patients were selected for analysis. For cases with subsequent histological evaluation, including the subset utilizing FC/IHC, the sensitivity of EUS-FNA was 89%, specificity was 100%, and accuracy was 91%. One quarter (58/235, 25%) of the tissue specimens underwent further testing by FC/IHC. There were 48 definitive diagnoses made in the subset utilizing FC/IHC. In 20 of the 48 diagnoses (42%), FC/IHC was deemed critical to the diagnosis, and without FC/IHC testing in those cases, the overall sensitivity and accuracy of EUS-FNA would be reduced to 74 and 77%, respectively. FC/IHC allowed for six diagnoses rarely or not previously described by EUS-FNA. Application of FC/IHC improves characterization predominantly for nonadenocarcinoma tumor subtypes and may lead to a diagnostic result for tumors not previously characterized by EUS-FNA. With an adequate tissue sample, broad application of FC/IHC increases the diagnostic yield of EUS-FNA. PMID- 22833390 TI - Algal swimming velocities signal fatty acid accumulation. AB - The use of microalgae for biofuel production will be beneficial to society if we can produce biofuels at large scales with minimal mechanical energy input in the production process. Understanding micro-algal physiological responses under variable environmental conditions in bioreactors is essential for the optimization of biofuel production. We demonstrate that measuring micro-algal swimming speed provides information on culture health and total fatty acid accumulation. Three strains of Chlamydomonas reinhardtii were grown heterotrophically on acetate and subjected to various levels of nitrogen starvation. Other nutrient levels were explored to determine their effect on micro-algal kinetics. Swimming velocities were measured with two-dimensional micro-particle tracking velocimetry. The results show an inverse linear relationship between normalized total fatty acid mass versus swimming speed of micro-algal cells. Analysis of RNA sequencing data confirms these results by demonstrating that the biological processes of cell motion and the generation of energy precursors are significantly down-regulated. Experiments demonstrate that changes in nutrient concentration in the surrounding media also affect swimming speed. The findings have the potential for the in situ and indirect assessment of lipid content by measuring micro-algal swimming kinetics. PMID- 22833391 TI - A continuous-flow, high-throughput, high-pressure parahydrogen converter for hyperpolarization in a clinical setting. AB - Pure parahydrogen (pH(2) ) is the prerequisite for optimal pH(2) -based hyperpolarization experiments, promising approaches to access the hidden orders of magnitude of MR signals. pH(2) production on-site in medical research centers is vital for the proliferation of these technologies in the life sciences. However, previously suggested designs do not meet our requirements for safety or production performance (flow rate, pressure or enrichment). In this article, we present the safety concept, design and installation of a pH(2) converter, operated in a clinical setting. The apparatus produces a continuous flow of four standard liters per minute of ~98% enriched pH(2) at a pressure maximum of 50 bar. The entire production cycle, including cleaning and cooling to 25 K, takes less than 5 h, only ~45 min of which are required for actual pH(2) conversion. A fast and simple quantification procedure is described. The lifetimes of pH(2) in a glass vial and aluminum storage cylinder are measured to be T(1C) (glass vial) =822 +/- 29 min and T(1C) (Al cylinder) =129 +/- 36 days, thus providing sufficiently long storage intervals and allowing the application of pH(2) on demand. A dependence of line width on pH(2) enrichment is observed. As examples, (1) H hyperpolarization of pyridine and (13) C hyperpolarization of hydroxyethylpropionate are presented. PMID- 22833392 TI - Expression pattern of IQGAP1 in sinonasal inverted papillomas and squamous cell carcinomas. AB - OBJECTIVES/HYPOTHESIS: The scaffold protein IQGAP1 is a ubiquitously expressed 190 kDa protein that participates in protein-protein interactions, integrating diverse signaling pathways. In this study, we examined the expression of IQGAP1 in sinonasal inverted papillomas (IP) and sinonasal squamous cell carcinomas (SCC), which include IP with SCC (IPcSCC) and SCC alone. We also tried to elucidate whether the amount of IQGAP1 expression is related with any clinicopathologic features of sinonasal SCCs. STUDY DESIGN: This was a retrospective study. METHODS: The expression of IQGAP1 was analyzed by means of immunohistochemistry. The degrees of IQGAP1 expression and subcellular localization (rim formation) were analyzed with respect to the following clinicopathologic variables: age, gender, T stage, histologic differentiation, local recurrence, and distant metastasis. RESULTS: The expression of IQGAP1 was significantly higher in patients with IPcSCC (3.62 +/- 0.14), and SCC (2.93 +/- 0.34) compared with IP (1.43 +/- 0.26). The rim formation scale was significantly higher in IPcSCC (2.39 +/- 0.24) compared with IP (1.68 +/- 0.15). Distant metastasis in patients with SCC significantly correlated with an increased IQGAP1 rim formation (p = 0.011). Histologic differentiation was also significantly correlated with a positive staining scale for IQGAP1 in IPcSCCs (p = 0.038). CONCLUSION: These results indicated that IQGAP1 expression is associated with both the histologic differentiation of IPcSCCs and is present in SCC cases where distant metastasis has occurred. PMID- 22833393 TI - Hypothesis-free analysis of ATG16L1 demonstrates gene-wide extent of association with Crohn's disease susceptibility. PMID- 22833395 TI - Need for improved societal effort to keep inflammatory bowel disease patients in the labour market? PMID- 22833394 TI - MTG16 contributes to colonic epithelial integrity in experimental colitis. AB - OBJECTIVE: The myeloid translocation genes (MTGs) are transcriptional corepressors with both Mtg8(-/-) and Mtgr1(-/-) mice showing developmental and/or differentiation defects in the intestine. We sought to determine the role of MTG16 in intestinal integrity. METHODS: Baseline and stress induced colonic phenotypes were examined in Mtg16(-/-) mice. To unmask phenotypes, we treated Mtg16(-/-) mice with dextran sodium sulphate (DSS) or infected them with Citrobacter rodentium and the colons were examined for ulceration and for changes in proliferation, apoptosis and inflammation. RESULTS: Mtg16(-/-) mice have altered immune subsets, suggesting priming towards Th1 responses. Mtg16(-/-) mice developed increased weight loss, diarrhoea, mortality and histological colitis and there were increased innate (Gr1(+), F4/80(+), CD11c(+) and MHCII(+); CD11c(+)) and Th1 adaptive (CD4) immune cells in Mtg16(-/-) colons after DSS treatment. Additionally, there was increased apoptosis and a compensatory increased proliferation in Mtg16(-/-) colons. Compared with wild-type mice, Mtg16(-/-) mice exhibited increased colonic CD4;IFN-gamma cells in vehicle treated and DSS-treated mice. Adoptive transfer of wild-type marrow into Mtg16(-/ ) recipients did not rescue the Mtg16(-/-) injury phenotype. Isolated colonic epithelial cells from DSS-treated Mtg16(-/-) mice exhibited increased KC (Cxcl1) mRNA expression when compared with wild-type mice. Mtg16(-/-) mice infected with C rodentium had more severe colitis and greater bacterial colonisation. Last, MTG16 mRNA levels were reduced in human ulcerative colitis versus normal colon tissues. CONCLUSIONS: These observations indicate that MTG16 is critical for colonocyte survival and regeneration in response to intestinal injury and provide evidence that this transcriptional corepressor regulates inflammatory recruitment in response to injury. PMID- 22833396 TI - Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia. AB - OBJECTIVE: Increased faecal butyrate levels have been reported in irritable bowel syndrome. Rectal instillation of sodium butyrate (NaB) increases visceral sensitivity in rats by an unknown mechanism. We seek to examine the signal transduction pathways responsible for the enhanced neuronal excitability in the dorsal root ganglion (DRG) following NaB enemas and demonstrate that this is responsible for the colonic hypersensitivity reported in this animal model. DESIGN: Colorectal distention (CRD) studies were performed in rats treated with NaB rectal instillation with/without intrathecal or intravenous administration of mitogen-activated protein (MAP) kinase kinase inhibitor U0126. Western blot analysis and immunocytochemistry studies elucidated intracellular signalling pathways that modulate IA. Patch-clamp recordings were performed on isolated DRG neurons treated with NaB, with/without U0126. RESULTS: Visceromotor responses (VMR) were markedly enhanced in NaB-treated rats. Western blot analysis of DRG neurons from NaB-treated rats showed a 2.2-fold increase in phosphorylated ERK1/2 (pEKR1/2) and 1.9-fold increase in phosphorylated voltage-gated potassium channel subunit 4.2 (pKv4.2). Intrathecal or intravenous administration of U0126 reduced VMR to CRD in NaB-treated rats and prevented increases in pERK1/2 and pKv4.2. Patch-clamp recordings of isolated DRG neurons showed that NaB caused a reduction in IA to 48.9%+/-1.4% of control and an increase in neuronal excitability, accompanied by a twofold increase in pERK1/2 and pKv4.2. Concurrent U0126 administration prevented these changes. CONCLUSIONS: Visceral hypersensitivity induced by colonic NaB treatment is mediated by activation of the MAP kinase ERK1/2 pathway, which phosphorylates Kv4.2. This results in a reduction in IA and an enhancement of DRG neuronal excitability. PMID- 22833397 TI - Emergency ABO-incompatible liver transplant secondary to fulminant hepatic failure: outcome, role of TPE and review of the literature. AB - The increasing demand for solid organ transplants has brought to light the need to utilize organs in critical situations despite ABO-incompatibility. However, these transplantations are complicated by pre-existing ABO antibodies which may be potentially dangerous and makes the transplantation prone to failure due to rejection with resulting necrosis or intrahepatic biliary complications. We report the clinical outcome of an emergency ABO-incompatible liver transplant (due to fulminant hepatic failure with sudden and rapidly deteriorating mental status) using a modified therapeutic plasma exchange (TPE) protocol. The recipient was O-positive with an initial anti-B titer of 64 and the cadaveric organ was from a B-positive donor. The patient underwent initial TPE during the peri-operative period, followed by a series of postoperative daily TPE, and later a third series of TPE for presumptive antibody-mediated rejection. The latter two were performed in conjunction with the use of IVIg and rituximab. The recipient's anti-B titer was reduced and maintained at 8 or less 8 months post-op. However, an elevation of transaminases 3 months post-transplant triggered a biopsy which was consistent with cellular rejection and with weak C4d positive staining suggestive of antibody mediated rejection. Additional plasma exchange procedures were performed. The patient improved rapidly after modification of her immunosuppression regimen and treatment with plasma exchange. This case illustrates that prompt and aggressive plasma exchange, in conjunction with immunosuppression, is a viable approach to prevent and treat antibody mediated transplant rejection in emergency ABO-incompatible liver transplant. PMID- 22833398 TI - Reassessing classification criteria for Takayasu arteritis: comment on the article by Lee et al. PMID- 22833399 TI - Solvent-free palladium-catalyzed direct arylation of heteroaromatics with aryl bromides. AB - Solvent is one of the major sources of waste in the course of catalyzed direct arylations. Some palladium-catalyzed direct arylations of heteroaromatics can be advantageously performed without any solvent. In the presence of palladium catalysts (1 mol %) and potassium acetate as the base, the direct 5-arylation of some thiazoles, thiophenes, furans, or pyrroles with aryl bromides as coupling partners proceeds highly regioselectively and in moderate to high yields. However, the use of these solvent-free conditions is limited to electron deficient aryl bromides. PMID- 22833400 TI - Mixture distributions in multi-state modelling: some considerations in a study of psoriatic arthritis. AB - In many studies, interest lies in determining whether members of the study population will undergo a particular event of interest. Such scenarios are often termed 'mover-stayer' scenarios, and interest lies in modelling two sub populations of 'movers' (those who have a propensity to undergo the event of interest) and 'stayers' (those who do not). In general, mover-stayer scenarios within data sets are accounted for through the use of mixture distributions, and in this paper, we investigate the use of various random effects distributions for this purpose. Using data from the University of Toronto psoriatic arthritis clinic, we present a multi-state model to describe the progression of clinical damage in hand joints of patients with psoriatic arthritis. We consider the use of mover-stayer gamma, inverse Gaussian and compound Poisson distributions to account for both the correlation amongst joint locations and the possible mover stayer situation with regard to clinical hand joint damage. We compare the fits obtained from these models and discuss the extent to which a mover-stayer scenario exists in these data. Furthermore, we fit a mover-stayer model that allows a dependence of the probability of a patient being a stayer on a patient level explanatory variable. PMID- 22833401 TI - Cloning, sequencing, and expression of nitrile hydratase gene of mutant 4D strain of Rhodococcus rhodochrous PA 34 in E. coli. AB - The NHase encoding gene of mutant 4D was isolated by PCR amplification. The NHase gene of mutant 4D was successfully cloned and expressed in Escherichia coli by using Ek/LIC Duet cloning kits (Novagen). For the active expression of the NHase gene, the co-expression of small cobalt transporter gene (P-protein gene) has also been co-expressed with NHase gene E. coli. The nucleotide sequence of this NHase gene revealed high homology with the H-NHase of Rhodococcus rhodochrous J1. The recombinant E. coli cells showed higher NHase activity (5.9 U/mg dcw) as compared to the wild (4.1 U/mg dcw) whereas it is less than the mutant strain (8.4 U/mg dcw). Addition of cobalt ion in Luria-Bertani medium is needed up to a very small concentration (0.4 mM) for NHase activity. The recombinant E. coli exhibited maximum NHase activity at 6 h of incubation and was purified with a yield of 56 % with specific activity of 37.1 U/mg protein. PMID- 22833402 TI - Production of mixed-linkage beta-oligosaccharides from lichenan using immobilized Bacillus licheniformis UEB CF lichenase. AB - Lichenase from Bacillus licheniformis UEB CF was immobilized on Amberlite IR120 H. The immobilization yield and lichenase activity were 87 and 92.81 % of initial activity, respectively. The immobilized enzyme exhibited a shift in the optimal pH from 5.0 to 3.0, but the activity optimal temperature was not affected. The immobilized enzyme showed a residual activity of 50 % after five uses. It also exhibited high storage stability and retained 50 % of its initial activity after 120 days at 4 degrees C. The main hydrolysis products yielded from lichenan were trisaccharide and tetrasaccharide. The resulting mixed-linkage beta oligosaccharides could be used as a special nutriment for lactic bacteria. PMID- 22833403 TI - Directed evolution of Penicillium janczewskii zalesk alpha-galactosidase toward enhanced activity and expression in Pichia pastoris. AB - In this study, the activity of an alpha-galactosidase obtained from Penicillium janczewskii zalesk was improved via modifying its gene by error-prone PCR and DNA shuffling. The mutated DNA was ligated to pBGP1, an autonomous-replicating vector, which was subsequently transformed into Pichia pastoris X-33. The expressed enzyme activities were measured after single colonies were cultured in yeast-peptone-dextrose medium in deep-well plates. After two rounds of screening, two mutants with higher activity were obtained. By PCR analysis, four mutation sites (S167G, P455L, N637S, and P490L/P490H) were found in these two variants (mutant-59 and mutant-8). Mutant-59 showed the highest activity at pH 5.0 and 40 degrees C with an increased V(max) value of 769 MUmol/min and the specific activity of 667 U/mg against p-nitrophenyl alpha-D-galactopyranoside. The two mutant enzymes also showed similar resistance to the metal ions of Cu(2+), Fe(2+), and Zn(2+). In a 10-L fermenter, the supernatant enzyme activity reached the maximum of 550.2 U/mL upon the methanol induction for 96 h. This fermentation activity of the mutant was improved approximately two more folds than the wild type alpha-galactosidase. This mutant of alpha-galactosidase is prospective in feed manufacturing as feed additives to improve nutrient digestibility in monogastric animals. PMID- 22833404 TI - The unsatisfactory ThinPrep(r) Pap TestTM: analysis of technical aspects, most common causes, and recommendations for improvement. AB - ThinPrep(r) preparation is a widely-used method for processing gynecologic specimens due to the many advantages of the technique. However, the presence of blood, inflammation, and lubricant, among other factors, can significantly interfere with specimen adequacy. The aim of this study was to identify and overcome the most common reasons for unsatisfactory ThinPrep(r) Pap TestTM results in our laboratory. From October 2010 to January 2011, we reprocessed cases categorized as "unsatisfactory for evaluation" to determine whether reprocessing these specimens would impact the unsatisfactory rate. Reasons for unsatisfactory results were classified as: technical reasons, scant cellularity, and complete obscuring factors. Two hundred fifty-three cases were initially classified as unsatisfactory. Of these, 226 cases were reprocessed. Ninety cases became satisfactory after reprocessing with an overall improvement of 40%. The most common reasons for unsatisfactory results were the presence of lubricant (96 cases), presence of blood (64 cases), and technical problems (33 cases). Cases affected by blood or technical issues showed a significant improvement after reprocessing (56.2% and 90.9%, respectively). However, unsatisfactory cases owed to the presence of lubricant showed a relatively low percentage of improvement (16.6%). The main reasons for unsatisfactory results, the presence of blood and lubricant, can be avoided in many cases if sampling is not performed during bleeding and if the use of lubricants is limited during sample collection. Our study showed that reprocessing of selected cases can improve the overall unsatisfactory rate and can potentially reduce the risk of missing significant lesions. PMID- 22833405 TI - Sustained improvement in left ventricular function after bone marrow derived cell therapy in patients with acute ST elevation myocardial infarction. A 5-year follow-up from the Stem Cell Transplantation in Ischaemic Myocardium Study. AB - BACKGROUND: Intracoronary injection of autologous bone marrow-derived mononucleated cells (BM-MNC) may improve LV function shortly after acute ST elevation myocardial infarction (STEMI), but little is known about the long-term durability of the treatment effect. METHODS: In a single-centre trial a total of 60 patients with acute anterior STEMI, successful reperfusion therapy and a left ventricular ejection fraction (LVEF) of <50% were screened for the study. 23 patients were actively treated with intracoronary infusion of BM-MNC within a median of 3 days. The open-label control group consisted of 19 patients who did not consent to undergo BM-MNC treatment but agreed to undergo regular clinical and echocardiographic follow-up for up to 5 years after AMI. RESULTS: Whereas at 4 months there was no significant difference between the increase in LVEF in the BM-MNC group and the control group (+7.0%, 95%CI 3.6; 10.4) vs. +3.9%, 95%CI 2.1; 10), the absolute increase at 5 years remained stable in the BM-MNC but not in the control group (+7.95%, 95%CI 3.5; 12.4 vs. -0.5%, 95%CI -5.4; 4.4; p for interaction between groups = 0.035). DISCUSSION: In this single-centre, open labelled study, intracoronary administration of BM-MNC is feasible and safe in the short term. It is also associated with sustained improvement of left ventricular function in patients with acute myocardial infarction, encouraging phase III studies to examine the potential BM-MNC effect on clinical outcome. PMID- 22833406 TI - Vasorelaxant effects on rat aortic artery by two types of indole alkaloids, naucline and cadamine. AB - Two indole alkaloids, naucline from Nauclea officinalis and cadamine from Ochreinauclea maingayii, were individually evaluated for vasorelaxant effects on phenylephrine-precontracted aortic rings. Naucline induced concentration dependent relaxation in aortic rings. Respective EC50 values of naucline on aorta rings with/without endothelium did not show a significant difference, indicating that naucline-induced relaxation was independent of the endothelium. In further experiments with various inhibitors, naucline was found to possess inhibitory effects on both voltage-dependent Ca(2+) channel (VDC)- and receptor-operated Ca(2+) channel (ROC)-dependent Ca(2+) influx in smooth muscle. Cadamine showed concentration-dependent relaxation in endothelium-intact aortic rings, which was inhibited by addition of L-NMMA, NOS inhibitor. These results suggested that the vasorelaxant effect of cadamine is partly mediated through the increased release of NO from endothelial cells. In addition to NO involvement, vasorelaxation induced by cadamine was also attributed to inhibition of both VDC- and ROC dependent Ca(2+) influx. PMID- 22833408 TI - Medication use in normal weight and overweight children in a nationally representative sample of Canadian children. AB - BACKGROUND: As overweight and obese children are more likely to develop serious medical conditions, they incur higher doctor and hospital costs compared to their normal weight counterparts. Consequently, the differential healthcare costs between obese and normal weight children may be even greater if medication use is considered. OBJECTIVE: To compare medication use between normal weight and overweight children in a nationally representative sample from Canada. METHODS: Data from the Canadian Health Measures Survey 2007/2009, a cross-sectional survey assessing indicators of health and wellness in Canadians, was used in the current study. The analysis included 2087 children and adolescents between 6-19 years of age with valid measures of body mass index (BMI). Poisson/negative binomial regression was used to examine the association between weight status and the number of medications taken in the last month. RESULT: For 6-11 year olds, the frequency of prescription, over-the-counter and natural health product (NHP) medication use did not differ between normal weight and overweight/obese children. For 12-19 year olds, overweight/obese children used prescription medication significantly more often than their normal weight peers (adjusted incidence rate ratio (IRR), 1.59; 95% CI 1.19 to 2.14), whereas for NHP the opposite was the case (adjusted IRR, 0.52; 95% CI 0.32 to 0.82). These children also used nervous system and respiratory medications more frequently than their normal weight peers. CONCLUSION: The findings of the present study suggest that the differential usage of prescription drugs among overweight/obese children underline the need to develop effective obesity prevention programmes and policies that may reduce the health and economic burden of childhood obesity. PMID- 22833407 TI - Puberty is associated with increased deterioration of renal function in patients with CKD: data from the ItalKid Project. AB - OBJECTIVE: To analyse the timing of end stage renal disease in children with chronic kidney disease (CKD). DESIGN: A population-based cohort study. SETTING: A nationwide registry (ItalKid Project) collecting information on all patients with CKD aged <20 years. PATIENTS: 935 children with CKD secondary to renal hypodysplasia with or without urologic malformation. In a subgroup of patients (n=40) detailed pubertal staging was analysed in relation to CKD progression. MAIN OUTCOME MEASURES: Kidney survival (KS) was estimated using renal replacement therapy (RRT) as the end-point. Puberty was staged by identifying the pubertal growth spurt. RESULTS: A non-linear decline in the probability of KS was observed, with a steep decrease during puberty: the probability of RRT was estimated to be 9.4% and 51.8% during the first and second decades of life, respectively. A break-point in the KS curve was identified at 11.6 and 10.9 years of age in male and female patients, respectively. CONCLUSIONS: The present analysis suggests that puberty is associated with increased deterioration of renal function in CKD. The mechanism(s) underlying this unique and specific (to children) pattern of progression have not yet been identified, but it may be that sex hormones play a role in this puberty-related progression of CKD. PMID- 22833412 TI - Catalytic asymmetric [4+2] annulation initiated by an aza-Rauhut-Currier reaction: facile entry to highly functionalized tetrahydropyridines. AB - Under control: The first example of chiral amino phosphine catalysts for the title reaction between vinyl ketones and N-sulfonyl-1-aza-1,3-dienes has been developed. Under ambient conditions, this protocol provides straightforward access to densely functionalized, enantioenriched tetrahydropyridines with high levels of sterecontrol in good to excellent yields. PMID- 22833415 TI - Evaluating four mathematical models for nitrous oxide production by autotrophic ammonia-oxidizing bacteria. AB - There is increasing evidence showing that ammonia-oxidizing bacteria (AOB) are major contributors to N(2)O emissions from wastewater treatment plants (WWTPs). Although the fundamental metabolic pathways for N(2)O production by AOB are now coming to light, the mechanisms responsible for N(2)O production by AOB in WWTP are not fully understood. Mathematical modeling provides a means for testing hypotheses related to mechanisms and triggers for N(2)O emissions in WWTP, and can then also become a tool to support the development of mitigation strategies. This study examined the ability of four mathematical model structures to describe two distinct mechanisms of N(2)O production by AOB. The production mechanisms evaluated are (1) N(2)O as the final product of nitrifier denitrification with NO(2)- as the terminal electron acceptor and (2) N(2)O as a byproduct of incomplete oxidation of hydroxylamine (NH(2)OH) to NO(2)-. The four models were compared based on their ability to predict N(2)O dynamics observed in three mixed culture studies. Short-term batch experimental data were employed to examine model assumptions related to the effects of (1) NH4+ concentration variations, (2) dissolved oxygen (DO) variations, (3) NO(2)- accumulations and (4) NH(2OH as an externally provided substrate. The modeling results demonstrate that all these models can generally describe the NH4+, NO(2)-, and NO(3)- data. However, none of these models were able to reproduce all measured N(2)O data. The results suggest that both the denitrification and NH(2)OH pathways may be involved in N(2)O production and could be kinetically linked by a competition for intracellular reducing equivalents. A unified model capturing both mechanisms and their potential interactions needs to be developed with consideration of physiological complexity. PMID- 22833409 TI - Electrophysiological evidence for the presence of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse sperm. AB - Mammalian sperm must undergo a maturational process, named capacitation, in the female reproductive tract to fertilize the egg. Sperm capacitation is regulated by a cAMP/protein kinase A (PKA) pathway and involves increases in intracellular Ca(2+), pH, Cl(-), protein tyrosine phosphorylation, and in mouse and some other mammals a membrane potential hyperpolarization. The cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) channel modulated by cAMP/PKA and ATP, was detected in mammalian sperm and proposed to modulate capacitation. Our whole-cell patch-clamp recordings from testicular mouse sperm now reveal a Cl(-) selective component to membrane current that is ATP-dependent, stimulated by cAMP, cGMP, and genistein (a CFTR agonist, at low concentrations), and inhibited by DPC and CFTR(inh) -172, two well-known CFTR antagonists. Furthermore, the Cl(-) current component activated by cAMP and inhibited by CFTR(inh) -172 is absent in recordings on testicular sperm from mice possessing the CFTR DeltaF508 loss-of function mutation, indicating that CFTR is responsible for this component. A Cl( ) selective like current component displaying CFTR characteristics was also found in wild type epididymal sperm bearing the cytoplasmatic droplet. Capacitated sperm treated with CFTR(inh) -172 undergo a shape change, suggesting that CFTR is involved in cell volume regulation. These findings indicate that functional CFTR channels are present in mouse sperm and their biophysical properties are consistent with their proposed participation in capacitation. PMID- 22833416 TI - Endocrine changes in harbor seal (Phoca vitulina) pups undergoing rehabilitation. AB - Rehabilitating pinniped pups are often admitted to care centers as neonates and generally lack maternal investment and are in poor body condition. Upon admittance to a rehabilitation facility, pups are typically fed a milk replacement formula via gavage, which is switched to frozen fish upon weaning. While rehabilitation has been successful in terms of recovery and release, preweaning growth rates in captivity are consistently lower than in the wild. Indicators of stress (cortisol and total thyroxine; TT4), and standard morphometrics, of harbor seal pups in rehabilitation (n = 20) were determined for both preweaned and weaned pups. Hormone concentrations and standard morphometrics from pups in care were compared with free-ranging harbor seal pups (n = 59). Pups in rehabilitation gained mass on both milk and fish diets. Preweaned pups had greater mean serum cortisol and similar TT4 concentrations than weaned pups. Free ranging harbor seal pups were heavier and longer than preweaned and weaned pups in rehabilitation. The free-ranging pups had the lowest cortisol and highest TT4 concentrations of any of the pups. These results suggest that weaned pups that have undergone rehabilitation are not physiologically equivalent to free-ranging weaned pups. Additional research is needed regarding physiological changes in endocrine values during early development under captive care conditions. This information should be useful to marine mammal rehabilitation centers in their development of care protocols and release criteria for rehabilitating harbor seal pups. PMID- 22833417 TI - In reference to wire grill brush bristle as an unusual foreign body: report of two pediatric cases. PMID- 22833418 TI - Hole in the elbow of a patient with rheumatoid arthritis. PMID- 22833419 TI - Knockdown of IKK1/2 promotes differentiation of mouse embryonic stem cells into neuroectoderm at the expense of mesoderm. AB - Activation of nuclear factor kappa B (NF-kappaB) is accomplished by a specific kinase complex (IKK-complex), phosphorylating inhibitors of NF-kappaB (IkappaB). In embryonic stem cells (ESCs), NF-kappaB signaling causes loss of pluripotency and promotes differentiation towards a mesodermal phenotype. Here we show that NF kappaB signaling is involved in cell fate determination during retinoic acid (RA) mediated differentiation of ESCs. Knockdown of IKK1 and IKK2 promotes differentiation of ESCs into neuroectoderm at the expense of neural crest derived myofibroblasts. Our data indicate that RA is not only able to induce neuronal differentiation in vitro but also drives ESCs into a neural crest cell lineage represented by differentiation towards peripheral neurons and myofibroblasts. The NC is a transiently existing, highly multipotent embryonic cell population generating a wide range of different cell types. During embryonic development the NC gives rise to distinct precursor lineages along the anterior-posterior axis determining differentiation towards specific derivates. Retinoic acid (RA) signaling provides essential instructive cues for patterning the neuroectoderm along the anterior-posterior axis. The demonstration of RA as a sufficient instructive signal for the differentiation of pluripotent cells towards NC and the involvement of NF-kappaB during this process provides useful information for the generation of specific NC-lineages, which are valuable for studying NC development or disease modeling. PMID- 22833420 TI - Epidermal growth factor receptor and Kras gene expression: reliability of mutational analysis on cytological samples. AB - Epidermal growth factor receptor (EGFR) and Kras gene mutations are crucial for discriminating patients responsive to anti-EGFR drugs in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), respectively. The majority of NSCLCs come to clinical attention at an advanced stage when surgery is no longer recommended and a considerable number of them are diagnosed by cytology only. A large number of metastatic CRCs are also diagnosed by imaging and minimally invasive techniques such as fine-needle aspiration biopsy. Here, we report our experience in the mutation analysis of EGFR and Kras on cytological material obtained from superficial and deep lesions of NSCLC and CRC. Our series included 63 cytological specimens from primary or metastatic lesions of 42 NSCLCs and 21 CRCs. The cytological material was adequate for the mutation analysis in 39/42 (93%) NSCLCs and in 20/21(95%) CRCs. EGFR and Kras mutations were found in 9 (23%) and 9 (23%) NSCLC cases, respectively. Kras mutations were found in 9/20 (45%) CRC specimens. Histological samples from the primary tumors were available in 9/42 NSCLCs and in 17/21 CRCs. The agreement of EGFR and Kras mutational status in cytological vs. histological samples was 100% for NSCLC and 88% for CRC. Our results suggest that standard cytology provides adequate material for the assessment of EGFR and Kras mutational status in NSCLC and CRC patients and could be specifically indicated in patients not eligible for surgery but candidate to anti-EGFR therapy. PMID- 22833421 TI - Efficient analysis of case-control studies with sample weights. AB - Analysis of population-based case-control studies with complex sampling designs is challenging because the sample selection probabilities (and, therefore, the sample weights) depend on the response variable and covariates. Commonly, the design-consistent (weighted) estimators of the parameters of the population regression model are obtained by solving (sample) weighted estimating equations. Weighted estimators, however, are known to be inefficient when the weights are highly variable as is typical for case-control designs. In this paper, we propose two alternative estimators that have higher efficiency and smaller finite sample bias compared with the weighted estimator. Both methods incorporate the information included in the sample weights by modeling the sample expectation of the weights conditional on design variables. We discuss benefits and limitations of each of the two proposed estimators emphasizing efficiency and robustness. We compare the finite sample properties of the two new estimators and traditionally used weighted estimators with the use of simulated data under various sampling scenarios. We apply the methods to the U.S. Kidney Cancer Case-Control Study to identify risk factors. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID- 22833422 TI - In Situ fuel processing in a microbial fuel cell. AB - A microbial fuel cell (MFC) was designed in which fuel is generated in the cell by the enzyme glucoamylase, which is displayed on the surface of yeast. The enzyme digests starch specifically into monomeric glucose units and as a consequence enables further glucose oxidation by microorganisms present in the MFC anode. The oxidative enzyme glucose oxidase was coupled to the glucoamylase digestive enzyme. When both enzymes were displayed on the surface of yeast cells in a mixed culture, superior fuel-cell performance was observed in comparison with other combinations of yeast cells, unmodified yeast, or pure enzymes. The feasibility of the use of the green macroalgae Ulva lactuca in such a genetically modified MFC was also demonstrated. Herein, we report the performance of such fuel cells as a proof of concept for the enzymatic digestion of complex organic fuels in the anode of MFCs to render the fuel more available to microorganisms. PMID- 22833423 TI - Controlled ring-opening polymerization of substituted episulfides for side-chain functional polysulfide-based amphiphiles. AB - We used initiation solutions of DBU and different thiols for the controlled ring opening homo- and copolymerization of ethoxy ethyl thio glycidyl ether (EETGE) and allyl thio glycidyl ether (ATGE) to side-chain multifunctional polysulfides. Optimized preparation conditions allow the syntheses of monomodal homopolysulfides and monomodal polysulfide-block-mPEG copolymers. Furthermore, copolymers of EETGE and mPEG are firstly synthesized, characterized, and finally deprotected to yield intact poly(thio glycidol)-block-poly(ethylene glycol) copolymers. These amphiphiles are suitable to form particles in aqueous solutions as confirmed by DLS and cryo-SEM measurements. PMID- 22833424 TI - Persistent neuroinflammatory effects of serial exposure to stress and methamphetamine on the blood-brain barrier. AB - Studies of methamphetamine (Meth)-induced neurotoxicity have traditionally focused on monoaminergic terminal damage while more recent studies have found that stress exacerbates these damaging effects of Meth. Similarities that exist between the mechanisms that cause monoaminergic terminal damage in response to stress and Meth and those capable of producing a disruption of the blood-brain barrier (BBB) suggest that the well-known high co-morbidity of stress and Meth could produce long-lasting structural and functional BBB disruption. The current studies examined the role of neuroinflammation in mediating the effects of exposure to chronic stress and/or Meth on BBB structure and function. Rats were pre-exposed to chronic unpredictable stress (CUS) and/or challenged with Meth. Twenty-four hours after the treatment of Meth in rats pre-exposed to CUS, occludin and claudin-5 immunoreactivity were decreased while truncation of beta dystroglycan, as well as FITC-dextran and water extravasation was increased. All changes other than beta-dystroglycan and edema persisted 7 days later, occurred with increases in GFAP and COX-2, and were blocked by ketoprofen after Meth treatment. In addition, persistent increases in FITC-dextran extravasation were prevented by treatment with an EP1 receptor antagonist after Meth exposure. The results indicate that CUS and Meth synergize to produce long-lasting structural and functional BBB disruptions that are mediated by cyclooxygenase and protracted increases in inflammation. These results suggest that stress and Meth can synergize to produce a long-lasting vulnerability of the brain to subsequent environmental insults resulting from the persistent breach of the BBB. PMID- 22833426 TI - AKT as locus of cancer positive feedback loops and extreme robustness. AB - A positive feedback loops induce extreme robustness in metastatic cancer, relapsed leukemia, myeloma or lymphoma. The loops are generated by the signaling interactome networks of autocrine and paracrine elements from cancer hypoxic microenvironment. The elements of the networks are signaling proteins synthesized in hypoxic microenvironment such as the vascular endothelial growth factor, HIF 1alpha, hepatocyte growth factor, and molecules nitric oxide and H(2)O(2). The signals from upstream or rebound downstream pathways are amplified by the short or wide positive feedback loops, hyperstimulating AKT-inducing cancer extreme robustness. Targeting the phosphorylated AKT locus by an oxidant/antioxidant modulation induces collapse of positive feedback loops and establishment of negative feedback loops leading to stability of the system and disappearance of cancer extreme robustness. This is a new principle for the conversion of cancer positive loops into negative feedback loops by the locus chemotherapy. PMID- 22833425 TI - Leptin exacerbates collagen-induced arthritis via enhancement of Th17 cell response. AB - OBJECTIVE: To determine the role of leptin in modulating Th17 cell response and joint inflammation in mice with collagen-induced arthritis (CIA). METHODS: Leptin receptor expression on T cells was examined by polymerase chain reaction (PCR) analysis, immunofluorescence microscopy, and flow cytometry. Effects of leptin on Th17 cell differentiation and proliferation were evaluated by quantitative PCR, carboxyfluorescein diacetate succinimidyl ester proliferation assay, and flow cytometry. Dynamic changes in leptin concentrations in the joint tissue and synovial fluid of mice with CIA were determined by immunohistochemistry analysis and enzyme-linked immunosorbent assay (ELISA). Arthritis symptoms and joint pathology in mice with CIA were assessed after injection of leptin into the knee joint. Th1 and Th17 cell populations in the spleen, draining lymph nodes, and joint tissue were analyzed by flow cytometry and enzyme-linked immunospot assay. Interleukin-17 messenger RNA and protein levels in the joint tissue were measured by PCR analysis and ELISA. RESULTS: In culture, leptin treatment significantly increased Th17 cell generation from naive CD4+ T cells. During CIA development, markedly elevated levels of leptin were detected in the joint tissue and synovial fluid. Moreover, injection of leptin into the knee joint of collagen-immunized mice resulted in an early onset of arthritis and substantially increased the severity of clinical symptoms, accompanied by more pronounced synovial hyperplasia and joint damage. Further examination by immunofluorescence microscopy confirmed the presence of significantly increased numbers of Th17 cells in the joint tissue and draining lymph nodes of leptin-treated mice with CIA. CONCLUSION: The results of this study identify a previously undescribed function of leptin in enhancing Th17 cell response and exacerbating joint inflammation in mice with CIA. PMID- 22833427 TI - Functional heterogeneity and heritability in CHO cell populations. AB - In this study, we address the hypothesis that it is possible to exploit genetic/functional variation in parental Chinese hamster ovary (CHO) cell populations to isolate clonal derivatives that exhibit superior, heritable attributes for biomanufacturing--new parental cell lines which are inherently more "fit for purpose." One-hundred and ninety-nine CHOK1SV clones were isolated from a donor CHOK1SV parental population by limiting dilution cloning and microplate image analysis, followed by primary analysis of variation in cell specific proliferation rate during extended deep-well microplate suspension culture of individual clones to accelerate genetic drift in isolated cultures. A subset of 100 clones were comparatively evaluated for transient production of a recombinant monoclonal antibody (Mab) and green fluorescent protein following transfection of a plasmid vector encoding both genes. The heritability of both cell-specific proliferation rate and Mab production was further assessed using a subset of 23 clones varying in functional capability that were subjected to cell culture regimes involving both cryopreservation and extended sub-culture. These data showed that whilst differences in transient Mab production capability were not heritable per se, clones exhibiting heritable variation in specific proliferation rate, endocytotic transfectability and N-glycan processing were identified. Finally, for clonal populations most "evolved" by extended sub culture in vitro we investigated the relationship between cellular protein biomass content, specific proliferation rate and cell surface N-glycosylation. Rapid-specific proliferation rate was inversely correlated to CHO cell size and protein content, and positively correlated to cell surface glycan content, although substantial clone-specific variation in ability to accumulate cell biomass was evident. Taken together, our data reveal the dynamic nature of the CHO cell functional genome and the potential to evolve and isolate CHO cell variants with improved functional properties in vitro. PMID- 22833428 TI - The use of the h-index in academic otolaryngology. AB - OBJECTIVE/HYPOTHESIS: The h-index is an objective and easily calculable measure that can be used to evaluate both the relevance and amount of scientific contributions of an individual author. Our objective was to examine how the h index of academic otolaryngologists relates with academic rank. STUDY DESIGN: A descriptive and correlational design was used for analysis of academic otolaryngologists' h-indices using the Scopus database. METHODS: H-indices of faculty members from 50 otolaryngology residency programs were calculated using the Scopus database, and data was organized by academic rank. Additionally, an analysis of the h-indices of departmental chairpersons among different specialties was performed. RESULTS: H-index values of academic otolaryngologists were higher with increased academic rank among the levels of assistant professor, associate professor, and professor. There was no significant difference between the h-indices of professors and department chairpersons within otolaryngology. H indices of chairpersons in different academic specialties were compared and were significantly different, suggesting that the use of this metric may not be appropriate for comparing different fields. CONCLUSIONS: The h-index is a reliable tool for quantifying academic productivity within otolaryngology. This measure is easily calculable and may be useful when evaluating decisions regarding advancement within academic otolaryngology departments. Comparison of this metric among faculty members from different fields, however, may not be reliable. PMID- 22833430 TI - Nerve growth factor, D2 receptor isoforms, and pituitary tumors. PMID- 22833431 TI - Renaissance of acromegaly after bariatric surgery. PMID- 22833429 TI - Intraoperative magnetic resonance imaging during surgery for pituitary adenomas: pros and cons. AB - Surgery for pituitary adenomas still remains a mainstay in their treatment, despite all advances in sophisticated medical treatments and radiotherapy. Total tumor excision is often attempted, but there are limitations in the intraoperative assessment of the radicalism of tumor resection by the neurosurgeon. Standard postoperative imaging is usually performed with a few months delay from the surgical intervention. The purpose of this report is to review briefly the facilities and kinds of intraoperative magnetic resonance imaging for all physician and surgeons involved in the management of pituitary adenomas on the basis of current literature. To date, there are several low- and high-field magnetic resonance imaging systems available for intraoperative use and depiction of the extent of tumor removal during surgery. Recovery of vision and the morphological result of surgery can be largely predicted from the intraoperative images. A variety of studies document that depiction of residual tumor allows targeted attack of the remnant and extent the resection. Intraoperative magnetic resonance imaging offers an immediate feedback to the surgeon and is a perfect quality control for pituitary surgery. It is also used as a basis of datasets for intraoperative navigation which is particularly useful in any kind of anatomical variations and repeat operations in which primary surgery has distorted the normal anatomy. However, setting up the technology is expensive and some systems even require extensive remodeling of the operation theatre. Intraoperative imaging prolongs the operation, but may also depict evolving problems, such as hematomas in the tumor cavity. There are several artifacts in intraoperative MR images possible that must be considered. The procedures are not associated with an increased complication rate. PMID- 22833432 TI - Parkinson's disease and other neurodegenerative disorders among welders: a Danish cohort study. AB - It has been hypothesized that welders are at increased risk for neurological disorders, including Parkinson's disease, but few well-designed cohort studies have been conducted. The risk for Parkinson's disease and other neurodegenerative disorders was examined in an updated follow-up study based on a previous cohort of 5867 Danish welders and 1735 nonwelding metal workers exposed to welding fume. Occupational history and information on smoking were obtained from questionnaires, supplemented by information from the compulsory Danish Supplementary Pension Fund. Hospital contacts, including outpatient data from 1994, for Parkinson's disease and other neurological disorders were ascertained from the Danish National Hospital Register. Based on first-time hospital contacts, standardized hospitalization ratios (SHRs) were calculated for the entire cohort and for welders, metal workers, and nonresponders separately and for the general Danish population in 1987-2008. In an internal analysis of welders, Cox proportional hazard models were used to estimate hospitalization rate ratios (HRRs) for Parkinson's disease associated with lifelong exposure to welding. Overall, 45 cohort members had a hospital contact for Parkinson's disease (SHR, 1.12; 95% confidence interval [CI], 0.82-1.50), of whom 25 were welders (standardized incidence rate ratio, 1.05; 95% CI, 0.68-1.55). When duration of welding was compared among 5736 welders, the HRR was 0.83 (95% CI, 0.59-1.16) per 10 years' welding, after adjustment for smoking. The results of this study do not support the hypothesis that welders are at increased risk for Parkinson's disease; these findings are consistent with those of our previously published analysis. (c) 2012 Movement Disorder Society. PMID- 22833433 TI - Enantioselective allylic thioetherification: the effect of phosphoric acid diester on iridium-catalyzed enantioconvergent transformations. AB - You'll take the high road and I'll take the low road: Enantioenriched allylic thioethers have been synthesized from chiral racemic allylic alcohols. The combination of an Ir-(P,alkene) complex and dibutyl phosphoric acid are required to attain high selectivities. Mechanistic studies uncover an enantioconvergent transformation in which substrate enantiomers react along different pathways to give the same product (see scheme; cod=1,5-cyclooctadiene). PMID- 22833434 TI - A general framework of marker design with optimal allocation to assess clinical utility. AB - This paper proposes a general framework of marker validation designs, which includes most of existing validation designs. The sample size calculation formulas for the proposed general design are derived on the basis of the optimal allocation that minimizes the expected number of treatment failures. The optimal allocation is especially important in the targeted design which is often motivated by preliminary evidence that marker-positive patients respond to one treatment better than the other. Our sample size calculation also takes into account the classification error of a marker. The numerical studies are conducted to investigate the expected reduction on the treatment failures and the relative efficiency between the targeted design and the traditional design based on the optimal ratios. We illustrate the calculation of the optimal allocation and sample sizes through a hypothetical stage II colon cancer trial. PMID- 22833436 TI - Acute onset of systemic lupus erythematosus with extensive gastrointestinal and genitourinary involvement. AB - Lupus enteritis may occur as an acute presentation of systemic lupus erythematosus (SLE), and is not uncommonly associated with acute uretero-cystitis and/or hydronephrosis. Extensive involvement of the gastrointestinal tract from the stomach to the rectum in acute SLE is uncommon. We describe a 22-year-old Chinese female who presented with acute extensive gastrointestinal and genitourinary involvement who recovered following pulse intravenous methylprednisolone and cyclophosphamide. A high index of clinical suspicion is required to arrive at the diagnosis of SLE where only acute gastrointestinal and genitourinary manifestations are predominant, and other clinical, haematological and biochemical features of SLE are absent. PMID- 22833435 TI - Juvenile onset systemic lupus erythematosus: a possible role for vitamin D in disease status and bone health. AB - PURPOSE: In juvenile onset systemic lupus erythematosus (JoSLE), evidence for the association between vitamin D status, lupus activity, and bone health is very limited and not conclusive. The aim of this study was, therefore, to assess in JoSLE patients the possible relevance of vitamin D deficiency in disease and bone parameters. METHODS: Fifty-seven JoSLE patients were initially compared to 37 age, race and body mass index (BMI) -matched healthy controls. The serum concentration of 25 hydroxyvitamin D (25OHD) was determined by radioimmunoassay. Patients with 25OHD deficiency (<=20 ng/mL) were compared to those with levels >20 ng/mL. Disease activity was evaluated by SLE Disease Activity Index (SLEDAI). Bone mineral density (BMD) and body composition (BC) were measured using dual energy X-ray absorptiometry (DXA). RESULTS: 25OHD levels were similar in patients and controls (21.44 +/- 7.91 vs 22.54 +/- 8.25 ng/mL, p = 0.519), regardless of supplementation (65% of patients and none in controls). Thirty-one patients with 25OHD deficiency (<=20 ng/mL) were further compared to the 26 JoSLE patients with levels >20 ng/mL. These two groups were well-balanced regarding vitamin D confounding variables: age (p = 0.100), ethnicity (p = 1.000), BMI (p = 0.911), season (p = 0.502), frequency of vitamin D supplementation (p = 0.587), creatinine (p = 0.751), renal involvement (p = 0.597), fat mass (p = 0.764), lean mass (p = 0.549), previous/current use of glucocorticoids(GC) (p = 1.0), immunosuppressors (p = 0.765), and mean current daily dose of GC (p = 0.345). Patients with vitamin D deficiency had higher SLEDAI (3.35 +/- 4.35 vs 1.00 +/- 2.48, p = 0.018), lower C4 levels (12.79 +/- 6.78 vs 18.38 +/- 12.24 mg/dL, p = 0.038), lower spine BMD (0.798 +/- 0.148 vs 0.880 +/- 0.127 g/cm(2), p = 0.037) and whole body BMD (0.962 +/- 0.109 vs 1.027 +/- 0.098 g/cm(2), p = 0.024). CONCLUSION: JoSLE vitamin D deficiency, in spite of conventional vitamin D supplementation, affects bone and disease activity status independent of therapy and fat mass reinforcing the recommendation to achieve adequate levels. PMID- 22833437 TI - The prevalence of oral mucosal lesions and related factors in 188 patients with systemic lupus erythematosus. AB - BACKGROUND: One of the most important concerns about systemic lupus erythematosus (SLE) is the presence of oral lesions, which in turn is one of the diagnostic criteria for SLE. Regarding the wide range of oral lesions and the absence of comprehensive data in Iran, this study aimed to evaluate the prevalence of oral mucosal lesions and related factors in patients with SLE at three rheumatology clinics in Tehran. METHODS: This descriptive study was performed on 188 patients by observation, clinical examination, completing questionnaire and also evaluating patients' medical records. The lesions explored were ulcer, erythema, erythematous center with white striae or spots, and white plaques. Related factors taken into consideration were age, sex, smoking, frequency of pregnancy, oral health status, duration of disease, medications taken daily dosage of corticosteroid drugs, and the state of disease control. Sampling was done by the continuous method and data obtained were analyzed by SPSS version 16.0 and ordinal regression tests. FINDINGS: Out of 188 patients, 102 (54.3%) patients had oral mucosal lesions. The most prevalent lesion was ulcer (28.1%) and the most common region involved was the buccal and labial mucosa. CONCLUSION: With regard to the high prevalence of oral mucosal lesions in patients with SLE, it is of paramount importance to emphasize early detection of these lesions as a mean of diagnosis of disease and faster initiation of treatment. PMID- 22833438 TI - Cytologic features of triple-negative breast carcinoma. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is distinct from other breast cancers, because the tumor cells lack estrogen and progesterone receptors (hormone receptors) and also are negative for human epidermal growth factor receptor 2 (HER2). They comprise a heterogeneous group of tumors with various histologic features and clinical behaviors. High-grade, invasive ductal carcinoma not otherwise specified is the most frequent type, and a substantial fraction of TNBCs belongs to the basal-like tumor type. The purpose of this study was to determine whether some cytologic features could predict the triple phenotype of breast carcinoma. METHODS: Fine-needle aspiration cytology samples of 62 TNBCs were compared with samples of 82 hormone receptor-positive, high-grade, invasive carcinomas (HRBC) and with samples of 33 hormone receptor-negative, HER2 positive, invasive carcinomas (HER2BC) for the following cytomorphologic features: cellularity, necrosis, lymphocytes, syncytial clusters, tubular/ductal like clusters, large bare nuclei, streaming within the clusters, and calcifications. Moreover, single cell features, such as cellular borders, cytoplasm, cytoplasmic vacuoles, nuclear pleomorphism, nucleoli, and type of chromatin pattern, were evaluated. Descriptive analyses and 2 multivariate regression models were performed to compare TNBC, HRBC, and HER2BC and to identify the cytologic factors that were associated with tumor type. RESULTS: TNBCs were more likely to have an abundant necrotic background, many lymphocytes, many syncytial clusters, and ill defined cell borders than non-TNBCs. A tubular/ductal pattern was observed only rarely in TNBCs. Multivariate logistic analysis indicated a 90.8% probability of identifying TNBC versus HRBC by the following cytologic variables: lymphocytes, ill defined cell borders and syncytial clusters, tubular/ductal clusters, cytoplasmic vacuoles, and cellular pleomorphism; whereas there was a 77.5% probability of identifying TNBC rather than HER2BC by the following variables: cellularity, ill defined cellular borders and syncytial clusters, and tubular/ductal clusters. CONCLUSIONS: Although TNBCs embrace a heterogeneous group of tumors, in this study, they exhibited some common cytologic features that can help to distinguish them from other high-grade breast carcinomas in daily practice. PMID- 22833439 TI - Concurrent chemoradiotherapy followed by metastasectomy converts to survival benefit in stage IV rectum cancer. AB - BACKGROUND: To investigate the impact of concurrent chemoradiotherapy (CCRT) on stage IV rectum cancer. METHODS: Between 2000 and 2011, 297 consecutive patients diagnosed with stage IV rectum cancer (synchronous metastasis) were enrolled. Cox proportional hazard analyses were used for prognostic factors determination, and the Kaplan-Meier method was used for survival analyses. Propensity scores with the one-to-one nearest-neighbor matching model were used to select matched patients for validation studies. RESULTS: In total, 63 patients received CCRT and 234 did not. The patients in the CCRT group were younger, had more low-lying lesions, and had more T4 lesions, lung metastases, metastasectomies, and oxaliplatin-based upfront chemotherapy. Before propensity-score matching, a younger age (HR = 0.662, P = 0.016), lower carcinoembryonic antigen (CEA) level (<=20 ng/ml) (HR = 0.531, P = 0.001), no metastasectomy (HR = 3.214, P < 0.001), and no CCRT (HR = 1.844, P = 0.019) were independent prognostic factors after controlling for other confounding factors. After matching, only CEA and metastasectomy, but not CCRT, were independent prognostic factors. The survival benefit of CCRT was restricted to patients who undergo subsequent metastasectomy. CONCLUSIONS: Upfront CCRT only provided a survival benefit in patients with stage IV rectum cancer who undergo subsequent metastasectomy. PMID- 22833441 TI - Response to "Long term outcomes following surgery for colorectal cancers in octogenarians: a single institution's experience of 204 patients". PMID- 22833440 TI - Ultrasonic scalpel for gastric cancer surgery: a prospective randomized study. AB - BACKGROUND: The aim of the study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in gastric cancer surgery. METHODS: Patients with resectable adenocarcinoma of the stomach were randomly assigned to ultrasonic scalpel or conventional technique. We used the HARMONIC FOCUS (Ethicon Endo-Surgery, Inc.) as ultrasonic scalpel. RESULTS: Between February 2010 and December 2010, 60 patients with resectable gastric cancer were enrolled into the study. Operative time was significantly shorter with the ultrasonic arm than with the conventional arm (median 238.5 vs. 300.5 min; P = 0.0004). Blood loss was also significantly lower in the ultrasonic arm than in the conventional arm (median 351.0 vs. 569.5 ml; P = 0.016). Clavien Dindo grades of postoperative complications were similar in the two groups. From a questionnaire survey of operators, the ultrasonic scalpel significantly reduced the stress of lymph node dissection (3.67 vs. 2.87; P = 0.0006). However, in assisting surgeons, the contributions to surgery, study, and technical improvement of the ultrasonic group were lower than in the conventional group. CONCLUSIONS: This study shows that the ultrasonic scalpel is a reliable and safe tool for open gastric cancer surgery. PMID- 22833442 TI - High detection rate of clinically relevant genomic abnormalities in plasma cells enriched from patients with multiple myeloma. AB - Multiple myeloma is a heterogeneous disease, which is characterized by the occurrence of specific genomic abnormalities that are both of diagnostic and prognostic relevance. Since the detection of these abnormalities through molecular-genetic techniques is hampered by the overall low percentage of plasma cells present in primary bone marrow aspirates, we assessed the efficacy of these techniques in enriched plasma cell fractions from 61 multiple myeloma patients. Using interphase FISH, genomic abnormalities could be detected in 96% of the enriched samples as compared to 61% in the cultured whole bone marrow samples. We also found that microarray-based genomic profiling of enriched plasma samples facilitates the detection of additional, possibly clinically relevant, genomic abnormalities. We conclude that the genomic delineation of enriched plasma cells from multiple myeloma patients results in a significantly increased detection rate of clinically relevant genomic abnormalities. In order to facilitate molecular-genetic data interpretation, we recommend morphological assessment of plasma cell purity after enrichment. PMID- 22833443 TI - Bullying in classrooms: participant roles from a social network perspective. AB - The aim of this research was to investigate if and how the group process of bullying can be examined using a social network perspective. In two studies, bullying was investigated using a social network version of the participant-role questionnaire. Study 1 explored the social network structure of one classroom in detail. The findings provide evidence that ingroup and outgroup effects are important in explaining the group process of bullying, and shed new light on defending, suggesting that not only victims are defended. In line with Study 1, Study 2, using data from 494 children in 25 elementary school classes (M age = 10.5), revealed that victims as well as bullies were defended by their ingroup members. The social network perspective can be integrated in antibullying interventions by using it to inform teachers about the positive and negative relations among students, and the group structure of the classroom. PMID- 22833444 TI - Regulation of motility, invasion, and metastatic potential of squamous cell carcinoma by 1alpha,25-dihydroxycholecalciferol. AB - BACKGROUND: The active metabolite of vitamin D 1alpha,25-dihydroxycholecalciferol (1,25D(3) ) has exhibited broad-spectrum antitumor activity in xenograft animal models. However, its activity against metastatic disease has not been extensively investigated. METHODS: Squamous cell carcinoma (SCC) or 1,25D(3) -resistant variant SCC-DR cells were treated with 1,25D(3) . Actin organization was examined by immunofluorescence assay. Cell migration was assessed by "wound" healing and chemotactic migration assays. Cell invasion was assessed by a Matrigel-based invasion assay and in situ zymography. Matrix metalloproteinase 2 (MMP-2) and MMP 9 expression and secretion were examined by immunoblot analysis and an enzyme linked immunosorbent assay, respectively. E-cadherin expression was assessed by flow cytometry, immunoblot analysis, and immunohistochemistry. Knockdown of E cadherin was achieved by small interfering RNA. An experimental metastasis mouse model was created by intravenous injection of tumor cells; and lung tumor development in the mice was assessed by magnetic resonance imaging, gross observation, and histology. RESULTS: SCC cellular morphology and actin organization were altered by 10 nM 1,25D(3) . 1,25D(3) inhibited SCC cell motility and invasion, which were associated with reduced expression and secretion of MMP-2 and MMP-9, and 1,25D(3) promoted the expression of E-cadherin. These findings were not observed in SCC-DR cells. Knock down of E-cadherin rescued 1,25D(3) -inhibited cell migration. Intravenous injection of SCC or SCC DR cells resulted in the establishment of extensive pulmonary lesions in saline treated C3H mice. Treatment with 1,25D(3) resulted in a marked reduction in the formation of lung tumor colonies in mice that were injected with SCC cells, but not in mice that were injected with SCC-DR cells. CONCLUSIONS: 1,25D(3) suppressed SCC cell motility, invasion, and metastasis, partially through the promotion of E-cadherin-mediated cell-cell adhesion. PMID- 22833445 TI - Characteristics and sequelae of intracranial hypertension after intracerebral hemorrhage. AB - INTRODUCTION: The characteristics and sequelae of intracranial hypertension after ICH are unclear. METHODS: In a cohort of patients with spontaneous ICH, we obtained ICP values from nursing documentation of hourly vital signs and reviewed charts to rule out spurious ICP recordings. We used multiple logistic regression to explore factors associated with intracranial hypertension, and ordinal logistic regression controlling for the ICH score to examine the relationship between intracranial hypertension and the mRS score at 12 months. RESULTS: Among 243 patients, 57 (24 %) underwent ICP monitoring, of whom 40 (70 %; 95 % CI 57-82 %) had an episode of ICP > 20 mmHg. Intracranial hypertension was less likely in older patients (OR per decade 0.6, 95 % CI 0.3-0.9) and after infratentorial hemorrhage (OR 0.1, 95 % CI 0-0.7). Intracranial hypertension was not independently associated with mRS scores (OR 0.8, 95 % CI 0.3-2.3); this remained true for a threshold of >25 mmHg (OR 0.5, 95 % CI 0.2-1.5), number of elevations (OR 0.98 per elevation, 95 % CI 0.96-1.00), or area under the curve (OR 1.00 per mmHg * h, 95 % CI 0.99-1.01). Among patients with intracranial hypertension, seven (18 %) were functionally independent (mRS 0-2) at 12 months. Our results were not significantly changed after excluding patients with early DNR orders. CONCLUSION: Intracranial hypertension is common after ICH, especially in younger patients with supratentorial hemorrhage. Given active treatment of elevated ICP, intracranial hypertension does not appear associated with long-term outcomes, suggesting that ICP elevations should not necessarily be taken to signify a poor prognosis. PMID- 22833446 TI - In vivo bone-specific EphB4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis. AB - OBJECTIVE: In vitro activation of the receptor EphB4 positively affects human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone-specific EphB4 overexpression on OA pathophysiology. METHODS: Morphometric, morphologic, and radiologic evaluations were performed on postnatal day 5 (P5) mice and on 10-week-old mice. Knee OA was induced surgically by destabilization of the medial meniscus (DMM) in 10-week-old male EphB4 homozygous transgenic (EphB4-Tg) and wild-type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and evaluations of subchondral bone using histomorphometry, osteoclast staining, and micro-computed tomography. RESULTS: There was no obvious phenotype difference in skeletal development between EphB4-Tg mice and WT mice at P5 or at 10 weeks. At 8 and 12 weeks post-DMM, the EphB4-Tg mice demonstrated significantly less cartilage alteration in the medial tibial plateau and the femoral condyle than did the WT mice. This was associated with a significant reduction of aggrecan and type II collagen degradation products, type X collagen, and collagen fibril disorganization in the operated EphB4-Tg mice. The medial tibial subchondral bone demonstrated a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate-resistant acid phosphatase-positive osteoclasts at both times assessed post-DMM in the EphB4-Tg mice than in the WT mice. CONCLUSION: This is the first in vivo evidence that bone-specific EphB4 overexpression exerts a protective effect on OA joint structural changes. The findings of this study stress the in vivo importance of subchondral bone biology in cartilage integrity. PMID- 22833447 TI - Mental health training with soldiers four months after returning from Iraq: randomization by platoon. AB - Military personnel report significant and increasing mental health problems in the months following return from combat. Nevertheless, studies have not assessed the impact of mental health training with this at-risk population. The present study evaluated the efficacy of a prototype mental health training module designed for U.S. soldiers 3-6 months after returning from combat; the module was a component of the Battlemind Training system. Soldiers (N = 1,645) were randomly assigned by platoon to 1 hour of training or a survey-only control group. Baseline surveys were conducted immediately before training; a training satisfaction survey was administered immediately after training, and a follow-up survey was administered 6 months later. Immediate postsession surveys were conducted with 681 subjects, and follow-up surveys were conducted with 542 soldiers. The Battlemind Training module received positive ratings from participants, and those who received it reported significantly better adjustment in terms of posttraumatic stress disorder symptoms, depression, and life satisfaction at follow-up compared to those in the survey-only control group. Changes in attitudes about the stigma of seeking mental health care were found immediately posttraining, but not at follow-up. The findings demonstrate that brief mental health training can be effective in reducing mental health systems with at-risk occupational groups. PMID- 22833448 TI - Transition-metal-free trifluoromethylaminoxylation of alkenes. PMID- 22833449 TI - Doubly robust testing and estimation of model-adjusted effect-measure modification with complex survey data. AB - Model-based standardization enables adjustment for confounding of a population averaged exposure effect on an outcome. It requires either a model for the probability of the exposure conditional on the confounders (an exposure model) or a model for the expectation of the outcome conditional on the exposure and the confounders (an outcome model). The methodology can also be applied to estimate averaged exposure effects within categories of an effect modifier and to test whether these effects differ or not. Recently, we extended that methodology for use with complex survey data, to estimate the effects of disability status on cost barriers to health care within three age categories and to test for differences. We applied the methodology to data from the 2007 Florida Behavioral Risk Factor Surveillance System Survey (BRFSS). The exposure modeling and outcome modeling approaches yielded two contrasting sets of results. In the present paper, we develop and apply to the BRFSS example two doubly robust approaches to testing and estimating effect modification with complex survey data; these approaches require that only one of these two models be correctly specified. Furthermore, assuming that at least one of the models is correctly specified, we can use the doubly robust approaches to develop and apply goodness-of-fit tests for the exposure and outcome models. We compare the exposure modeling, outcome modeling, and doubly robust approaches in terms of a simulation study and the BRFSS example. PMID- 22833450 TI - 5'-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells. AB - Glioblastoma multiforme (GBM) cells are characterised by their extreme chemoresistance. The activity of multiple-drug resistance (MDR) transporters that extrude antitumor drugs from cells plays the most important role in this phenomenon. To date, the mechanism controlling the expression and activity of MDR transporters is poorly understood. Activity of the enzyme ecto-5'-nucleotidase (CD73) in tumor cells, which hydrolyses AMP to adenosine, has been linked to immunosuppression and prometastatic effects in breast cancer and to the proliferation of glioma cells. In this study, we identify a high expression of CD73 in surgically resected samples of human GBM. In primary cultures of GBM, inhibition of CD73 activity or knocking down its expression by siRNA reversed the MDR phenotype and cell viability was decreased up to 60% on exposure to the antitumoral drug vincristine. This GBM chemosensitization was caused by a decrease in the expression and activity of the multiple drug associated protein 1 (Mrp1), the most important transporter conferring multiple drug resistance in these cells. Using pharmacological modulators, we have recognized the adenosine A(3) receptor subtype in mediation of the chemoresistant phenotype in these cells. In conclusion, we have determined that the activity of CD73 to trigger adenosine signaling sustains chemoresistant phenotype in GBM cells. PMID- 22833451 TI - Spatial spectral imaging as an adjunct to the Bethesda classification of thyroid fine-needle aspiration specimens. AB - BACKGROUND: Thyroid fine-needle aspiration (FNA) biopsy, the preoperative diagnostic standard of care for patients with thyroid nodules, has limitations. Spectral imaging captures visible light information that is beyond the capability of the human eye, potentially increasing the accuracy of FNA biopsy. In the current study, the authors demonstrated the feasibility of using spectral imaging in combination with automated spatial analysis based on trainable pattern recognition as an adjunct test for thyroid FNA classification by developing an algorithm that distinguishes between images of papillary thyroid carcinoma (PTC) and benign goiter (BG). METHODS: A multispectral camera was used to capture spectral images representing 100 cases of PTC and BG. Used in conjunction with commercial software, 10 cases were used as a training set to develop a "classifier," a classification algorithm that segments digitized multispectral images into regions of PTC, BG, and "nonfeature." This algorithm was used to generate a screening test and a diagnostic test that were validated on an independent set of images representing 30 cases of PTC and 30 cases of BG. RESULTS: The area under the receiver operating characteristic for the PTC/BG classifier was 0.90. The screening test had a sensitivity of 0.93 and a specificity of 0.73. The diagnostic test had a sensitivity of 0.70 and a specificity of 0.90. CONCLUSIONS: The authors developed image classification tests that distinguish between FNAs of PTC and BG, demonstrating the potential value of spatial spectral imaging as an adjunct test for the classification of thyroid FNA samples. The data support prospective testing to determine the value of the PTC/BG classifier in routine clinical use. PMID- 22833452 TI - New estimates of gaps and transitions in health insurance. AB - Changes in individual or family circumstances cause many Americans to experience gaps and transitions in public and private health insurance. Using data from the 2004-2007 Survey of Income and Program Participation, this article updates earlier analyses of insurance gaps and transitions. Eighty-nine million people (one third of nonelderly Americans) were uninsured for at least 1 month during those 4 years. Approximately 23 million lost insurance more than once. The analyses call attention to the continuing instability and insecurity of health insurance, can inform implementation of national reforms, and establish a recent baseline that will be helpful in evaluating the reforms' effects on coverage stability. PMID- 22833453 TI - Functional analysis of promoter variants in KU70 and their role in cancer susceptibility. AB - KU70 is involved in the DNA double-strand break repair pathway, which plays a critical role in maintaining genomic stability and preventing cancer. Genetic variation within the KU70 gene has been shown to be associated with increased risk of several types of cancers including breast cancer. Here, we used gene reporter and gel shift assays combined with site-directed mutagenesis to characterize genetic variation within the KU70 proximal promoter region and investigate the putative functional role of regulatory variation and altered KU70 expression in modulating an individual's susceptibility to disease. We show that the variant rs2267437C>G significantly influences KU70 transcriptional activity in an allele- specific manner and alters DNA-protein complex formation in breast cancer cell lines. Our data provide a possible molecular explanation for the associations observed between the KU70 regulatory variant rs2267437 and breast cancer risk. PMID- 22833454 TI - Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells. AB - BACKGROUND: Aberrant methylation of tumor-related genes has been reported in Epstein-Barr virus (EBV)-associated gastric cancers. This study sought to profile EBV-driven hypermethylation in EBV-infected cells. METHODS: The EBV-positive AGS gastric cancer cell line (AGS-EBV) and EBV-negative AGS cells were used in this study. DNA methyltransferase-3b (DNMT3b) activity was assessed by EpiQuick activity assay, and genome-wide DNA methylation profiles were assessed by methyl DNA immunoprecipitation microarray assay. RESULTS: EBV infection was confirmed in AGS-EBV cells by EBV-encoded RNA in situ hybridization. Expression and activity of DNA methyltransferase-3b (DNMT3b) was significantly increased in AGS-EBV compared to AGS. Ectopic expression of LMP2A (latent membrane protein 2A) in AGS increased activity of DNMT3b. A total of 1065 genes were differentially methylated by EBV infection (fold-changes >= 2, P < .05) in AGS-EBV compared to AGS cells. The majority of the differentially methylated genes (83.2%, 886 of 1065 genes) had cytosine-guanine dinucleotide (CpG) hypermethylation in AGS-EBV (fold-changes 2.43~65.2) versus that found in AGS cells. Gene ontology analysis revealed that hypermethylated genes were enriched in the important cancer pathways (>= 10 genes each, P <= .05) including mitogen-activated protein kinase signaling, cell adhesion molecules, wnt signaling pathway, and so forth. Six novel hypermethylated candidates (IL15RA, REC8, SSTR1, EPHB6, MDGA2, and SCARF2) were further validated. Higher levels of DNA methylation were confirmed for all these genes in AGS-EBV cells by bisulfite genomic sequencing. Furthermore, these candidates were silenced or down-regulated in AGS-EBV cells, but can be restored by demethylation treatment. CONCLUSIONS: EBV infection in AGS cells induced aberrant CpG hypermethylation of 886 genes involving in important cancer-related pathways. Induction of promoter methylation by EBV is regulated by up-regulation of DNMT3b through LMP2A. PMID- 22833455 TI - The impact of intimate partner violence and additional traumatic events on trauma symptoms and PTSD in preschool-aged children. AB - Children exposed to intimate partner violence (IPV) are at increased risk for developing traumatic stress symptoms and posttraumatic stress disorder (PTSD). Unfortunately, children who witness IPV are often exposed to additional traumatic events. Previous research has indicated that approximately one third of children experience 2 or more direct victimizations each year, and that exposure to one type of victimization places children at risk for exposure to additional types of victimization. Yet little is known about the impact of these additional traumas on children's functioning. For a sample of 120 preschool children (age 4-6 years) exposed to IPV in the past 2 years, 38% were exposed to additional traumatic events, including sexual assaults by family members, physical assaults, serious accidents, and/or life-threatening illnesses. Those exposed to both IPV and additional traumatic events had higher rates of PTSD diagnoses, traumatic stress symptoms (d = 0.96), and internalizing (d = 0.86) and externalizing behavior (d = 0.47) problems, than those exposed to IPV alone. We also compared DSM-IV diagnostic criteria to proposed criteria for evaluating traumatic stress in preschool-aged children. Results revealed the importance of conducting a complete assessment of traumatic events prior to treating children exposed to IPV. PMID- 22833456 TI - Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. AB - Ubiquitin-positive inclusion containing Fused in Sarcoma (FUS) defines a new subtype of frontotemporal lobar degeneration (FTLD). FTLD is characterized by progressive alteration in cognitions and it preferentially affects the superficial layers of frontotemporal cortex. Mutation of FUS is linked to amyotrophic lateral sclerosis and to motor neuron disease with FTLD. To examine FUS pathology in FTLD, we developed the first mammalian animal model expressing human FUS with pathogenic mutation and developing progressive loss of memory. In FUS transgenic rats, ubiquitin aggregation and FUS mislocalization were developed primarily in the entorhinal cortex of temporal lobe, particularly in the superficial layers of affected cortex. Overexpression of mutant FUS led to Golgi fragmentation and mitochondrion aggregation. Intriguingly, aggregated ubiquitin was not colocalized with either fragmented Golgi or aggregated mitochondria, and neurons with ubiquitin aggregates were deprived of endogenous TDP-43. Agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma) possess anti-glial inflammation effects and are also shown to preserve the dendrite and dendritic spines of cortical neurons in culture. Here we show that rosiglitazone, a PPAR gamma agonist, rescued the dendrites and dendritic spines of neurons from FUS toxicity and preserved rats' spatial memory. Our FUS transgenic rats would be useful to the mechanistic study of cortical dementia in FTLD. As rosiglitazone is clinically used to treat diabetes, our results would encourage immediate application of PPAR-gamma agonists in treating patients with cortical dementia. PMID- 22833457 TI - Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. AB - Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease. PMID- 22833459 TI - Measurement equivalence of the brief comprehensive effects of alcohol scale in a multiethnic sample of college students. AB - OBJECTIVES: This study examined the measurement equivalence of the Brief Comprehensive Effects of Alcohol scale (B-CEOA; Ham et al., 2005)--a measure that assesses alcohol outcome expectancies (AOE) and expectancy evaluations-across ethnic groups and genders among multiethnic college student samples. METHOD: Undergraduates provided self-report data in two multisite studies (Study 1: N = 1,536, 75.5% women, Mage = 19.6 years old, 56.4% European American, 9.8% African American, 7.6% Asian American, and 26.2% Hispanic/Latino American; Study 2: N = 7,767, 72.6% women, Mage = 19.8 years old, 63.3% European American, 7.9% African American, 14.3% Asian American, and 14.5% Hispanic/Latino American). RESULTS: Exploratory and confirmatory factor analyses supported a positive and negative 4 factor model. Positive and negative AOE and expectancy evaluations were positively associated with hazardous alcohol use. Measurement equivalence of the B-CEOA across ethnicities and genders was largely supported. CONCLUSIONS: This study provides support for the utility of the B-CEOA in college students of different ethnicities and genders in assessment and prevention. PMID- 22833460 TI - Estimation methods for marginal and association parameters for longitudinal binary data with nonignorable missing observations. AB - In longitudinal studies, missing observations occur commonly. It has been well known that biased results could be produced if missingness is not properly handled in the analysis. Authors have developed many methods with the focus on either incomplete response or missing covariate observations, but rarely on both. The complexity of modeling and computational difficulty would be the major challenges in handling missingness in both response and covariate variables. In this paper, we develop methods using the pairwise likelihood formulation to handle longitudinal binary data with missing observations present in both response and covariate variables. We propose a unified framework to accommodate various types of missing data patterns. We evaluate the performance of the methods empirically under a variety of circumstances. In particular, we investigate issues on efficiency and robustness. We analyze longitudinal data from the National Population Health Study with the use of our methods. PMID- 22833458 TI - From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer's disease. AB - The non-Mendelian sporadic Alzheimer's disease (AD) is the most frequent form of dementia diagnosed worldwide. The most important risk factor to develop sporadic AD is aging itself. Next to hyperphosphorylated Tau, intracellular amyloid beta (Abeta) oligomers are known to initiate a cascade of pathological events ranging from mitochondrial dysfunction, synaptic dysfunction, oxidative stress, and loss of calcium regulation, to inflammation. All these events are considered to play an important role in the progressive loss of neurons. The molecular mechanisms determining the balance between Abeta production and clearance during the progression of the disease are not well understood. Furthermore, there is cumulating evidence that Abeta formation impairs mitochondrial function and that mitochondrial dysfunction is an early event in the pathogenesis of AD. On the other hand, mitochondrial dysfunction, in particular increased formation of mitochondrially derived reactive oxygen species, promote Abeta formation. Here, we review these latest findings linking mitochondrial dysfunction and Abeta formation. We propose that mitochondrial dysfunction, which is well-known to increase with age, is an initial trigger for Abeta production. As Abeta itself further accelerates mitochondrial dysfunction and oxidative stress, its formation is self-stimulated. Taken together, a vicious cycle is initiated that originates from mitochondrial dysfunction, implying that AD can be viewed as an age associated mitochondrial disorder. The proposed mechanism sheds new light on the pathophysiological changes taking place during the progression of AD as well as in the aging process. PMID- 22833461 TI - Photocontrolled targeted drug delivery: photocaged biologically active folic acid as a light-responsive tumor-targeting molecule. PMID- 22833462 TI - Identification of frequent BRAF copy number gain and alterations of RAF genes in Chinese prostate cancer. AB - We recently found that TMPRSS2:ERG fusion genes and PTEN loss, which are common in Western prostate cancers are infrequent in Chinese cases. As previous studies indicated a higher frequency of RAS and BRAF mutation rates in Eastern Asian than in Western prostate cancers and fusion genes involving the RAF family genes BRAF and RAF1 were recently identified in prostate cancer in the American population, we investigated BRAF and RAF1 alterations in Chinese prostate cancer. Using fluorescence in situ hybridization, we found that BRAF was truncated in five of 200 informative Chinese cases (2.5%) and that RAF1 was truncated in three of 204 informative cases (1.5%) and genomic rearrangements of these genes were significantly correlated with high Gleason scores (>7; P < 0.01) and have a trend to appear in high clinical stage disease. A high frequency of BRAF and RAF1 copy number gain was found (29 and 15%, respectively). BRAF copy number gain in Chinese cancers was significantly higher than in UK cases (9.2%)(P < 0.001) and correlated with a number of clinical parameters. High-level expression of BRAF was found by immunohistochemistry in Chinese cancer samples compared with adjacent nonmalignant epithelial cells, which was correlated with high BRAF copy number. We also identified KRAS codon 12 mutations in three of 96 Chinese cases, no BRAF V600E mutations were observed. Our finding suggests that the activation of the RAS/RAF/MEK/ERK pathway may be frequent in Chinese prostate cancer, with RAF gene copy number gain potentially being the main contributor. PMID- 22833463 TI - CCN1 and CCN2: blood brothers in angiogenic action. AB - CCN2/connective tissue growth factor (CTGF) is a matricellular protein essential for skeletal development during embryogenesis. In adulthood, aberrant CCN2 expression is associated with many malignancies and fibrosis of virtually every organ. Despite its prominent expression in endothelial cells in the vasculature, the role of CCN2 in vessel development was unknown. In a recent study, Hall-Glenn et al. (PLoS ONE 7:e30562) have revealed the role of CCN2 in developmental angiogenesis through a detailed analysis of how CCN2 mediates the interaction between vascular endothelial cells and pericytes. In addition, CCN2 also regulates endothelial basement membrane formation during vessel formation. Here I compare the angiogenic activities of CCN2 during embryogenesis to those of its homologous family member CCN1 (CYR61), which is essential for cardiovascular development. Understanding the angiogenic actions of CCN1 and CCN2 may have implication in the development of therapeutic strategies targeting these proteins for the treatment of diseases such as cancer and fibrosis. PMID- 22833465 TI - Micro-computed tomography and scanning electron microscopy comparisons of two nickel-titanium rotary root canal instruments used with reciprocating motion. AB - The single-file root canal instrumentation technique using reciprocating motion has been gaining concern. Therefore, the purpose of this study was to compare the shaping ability of single ProTaper F2 file and WaveOne Primary file when they were used in the curved root canal with reciprocation motion and to investigate the durability of the file after use with a scanning electron microscopy (SEM). Changes in structure model index (SMI), root canal volume, curvature, surface area, and degree of transportation were measured from the cross-sectional images of the prepared canals using the micro-CT system with an isotropic resolution of 16 MUm. Results showed that there were no differences in the changes of root canal volume, surface area, and SMI between the two file groups after the preparation (p > 0.05). The ProTaper group showed a curvature straightening value of 25.45 +/- 12.51%, while the WaveOne group showed 27.30 +/- 10.91%, and there was no statistically significant difference (p > 0.05). The transportation values between the two groups showed no significant differences (p > 0.05). SEM revealed that 60% of ProTaper files showed initiation of microcracks on the surface while those were detected on the only one WaveOne file. The single-file technique using either WaveOne Primary or ProTaper F2 can be safely used under each reciprocating motion without creating an increased apical transportation in curved canals. However, the metallurgic property resists cyclic fatigue was more favorable with WaveOne under the scanning evaluation. PMID- 22833466 TI - Patterns of covariation in the masticatory apparatus of hystricognathous rodents: implications for evolution and diversification. AB - The mammalian masticatory apparatus is a highly plastic region of the skull. In this study, a quantification of shape variation, the separation of phylogeny from ecology in the genesis of shape brings new insights on the relationships between morphological changes in the cranium, mandible, and muscle architecture. Our study focuses on the Ctenohystrica, a clade that is remarkably diverse and exemplifies a rich evolutionary history in the Old and New World. Current and past rodent diversity brings out the limitations of the qualitative descriptive approach and highlights the need for using integrative quantitative methods. We present here the first descriptive comparison of the whole masticatory apparatus within the Ctenohystrica, by combining geometric morphometric approaches with a noninvasive method of dissection in 3D, iodine-enhanced microcomputed tomography. We used these methods to explore the patterns of covariation between the cranium and the mandible, and the interspecific morphological variation of the skull with regard to several factors such as phylogeny, activity period, type of habitat, and diet. Our study revealed strong phylogenetic and ecological imprints on the morphological traits associated with masticatory mechanics. We showed that, despite a high diversification of lineages, the evolutionary history of Ctenohystrica comprises only a small number of morphotypes for the skull and mandible. The position of the eye was suggested as a key factor determining morphological evolution of the masticatory apparatus by limiting the number of possible pathways and promoting convergent evolution toward new habitats and diets between different clades. PMID- 22833464 TI - Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. AB - BACKGROUND: Patients with peripheral T-cell lymphomas (PTCLs) have inferior progression-free survival (PFS) and overall survival (OS) compared with patients who have aggressive B-cell non-Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P-glycoprotein (MDR-1/P-gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single-agent activity in PTCL. METHODS: Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra-nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m(2) on days 1 through 4, etoposide 40 mg/m(2) on days 1 through 4, gemcitabine 1000 mg/m(2) on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21-day cycle for 6 cycles. RESULTS: In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T-cell lymphoma (n = 6), or other T-cell non-Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T-cell lymphoma, 25% in ALK-negative and 38% in other T-cell non-Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%-31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%-54%), and the median OS was 17 months. Immunohistochemical analysis of P-gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25). CONCLUSIONS: Overall, PEGS was well tolerated, but OS was not considered promising given the design-specified targets. These results may serve as a benchmark for future comparisons for non-CHOP regimens. PMID- 22833467 TI - Peritraumatic and persistent dissociation as predictors of PTSD symptoms in a female cohort. AB - Recent research has investigated peritraumatic and persistent dissociation as a possible predictive factor for posttraumatic stress disorder (PTSD). The current study aimed to add to this literature by examining dissociative responses in female assault survivors (N = 92 at initial assessment; n = 62 at follow-up). Dissociative symptoms experienced at 3 time points were assessed: peritraumatic dissociation (PD), persistent dissociation-initial (M = 28.2 days posttrauma) and follow-up (M = 224.9 days posttrauma), as well as initial and follow-up PTSD symptoms. We hypothesized that PD and persistent dissociative symptoms would predict chronic PTSD symptoms at the follow-up assessment with initial PTSD symptoms and assault type in the model. Hierarchical regression resulted in a significant model predicting 39% of the variance in follow-up PTSD symptom scores (p < .001). Both peritraumatic and follow-up persistent dissociative symptoms significantly and uniquely added to the variance explained in follow-up PTSD symptom score contributing 4% (p = .05) and 8% (p = .008) of the variance, respectively. Results support the predictive value of peritraumatic and persistent dissociative symptoms, and the findings suggest that persistent dissociation may contribute to the development and continuation of PTSD symptoms. We discuss the implications for assessment and possible treatment of PTSD as well as future directions. PMID- 22833468 TI - Structural characterization of backbone-expanded helices in hybrid peptides: (alphagamma)n and (alphabeta)n sequences with unconstrained beta and gamma homologues of L-Val. PMID- 22833469 TI - Assessment of SpondyloArthritis International Society criteria for axial spondyloarthritis in chronic back pain patients with a high prevalence of HLA B27. AB - OBJECTIVE: The Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (SpA) allow SpA classification of HLA-B27-positive patients if >=2 specific clinical SpA features are present. We investigated the performance of these clinical ASAS criteria in a population with a high prevalence of HLA-B27. METHODS: A total of 807 persons reporting chronic back pain (CBP) lasting for >4 weeks during a population survey underwent a clinical, laboratory, and radiologic evaluation. The ASAS criteria for axial SpA were then used to determine classification status. RESULTS: Only 332 patients (41% of all CBP patients) fulfilled the prerequisite ASAS definitions for CBP (duration of >=3 months and onset at age <45 years). In this ASAS-defined CBP cohort (51% women, CBP onset at age 27.2 years, 17% HLA-B27 positive), ASAS classification criteria for axial SpA were met by 8.4% of patients. Radiographic SpA by the modified New York criteria was present in 2.4%, while 6% fulfilled the clinical arm of the ASAS SpA criteria only. One-fifth of patients with clinical SpA developed radiographic evidence of SpA after a median of 8 years. CONCLUSION: Application of the clinical ASAS classification criteria in an area with a high prevalence of HLA-B27 leads to significant increases in the prevalence of axial SpA compared to radiologic SpA among CBP patients. This increase in the prevalence of disease is likely to have significant ramifications for patient management and health care systems. PMID- 22833470 TI - PROX1 overexpression inhibits protein kinase C beta II transcription through promoter DNA methylation. AB - Prospero-related homeobox 1 (PROX1) is important for embryonic organ formation and differentiation, and changes in PROX1 activity were recently associated with cancer. To address the PROX1 roles in tumorigenesis, we established cells stably overexpressing PROX1 using the human cervical cancer cell line, HeLa. Overexpression of PROX1 reduced cell proliferation and the rate of tumor formation as compared with controls. Comparison of gene expression profiles between PROX1-overexpressing and mock-transfected cells revealed that the expression of protein kinase C betaII (PRKCB2) is down-regulated in PROX1 overexpressing cells. A PRKCB inhibitor suppressed cell growth of control cells more than PROX1-expressing cells. Analysis of the 5'-promoter of PRKCB revealed that a region between -110 bp and the first exon contains two Sp1 binding sites and is important for transcriptional regulation of PRKCB. The inhibition of Sp1 transcription factor resulted in down-regulation of PRKCB2 protein levels. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine, restored PRKCB2 mRNA expression in PROX1-expressing cells, suggesting that the 5'-promoter of PRKCB is methylated in these cells. Actually, it was found that a CpG island in this region, in particular a CpG site overlapping with the distal Sp1 site, was hypermethylated and direct Sp1 binding to this region was inhibited in PROX1 overexpressing cells. Thus, the suppressive effect of PROX1 on cell growth and tumor formation might be partially mediated by PRKCB2 via altered methylation of its promoter. PMID- 22833472 TI - Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage. AB - Following their discovery in 1961, it was speculated that satellite cells were dormant myoblasts, held in reserve until required for skeletal muscle repair. Evidence for this accumulated over the years, until the link between satellite cells and the myoblasts that appear during muscle regeneration was finally established. Subsequently, it was demonstrated that, when grafted, satellite cells could also self-renew, conferring on them the coveted status of 'stem cell'. The emergence of other cell types with myogenic potential, however, questioned the precise role of satellite cells. Here, we review recent recombination-based studies that have furthered our understanding of satellite cell biology. The clear consensus is that skeletal muscle does not regenerate without satellite cells, confirming their pivotal and non-redundant role. PMID- 22833473 TI - The patient's use of metaphor within a palliative care setting: theory, function and efficacy. A narrative literature review. AB - BACKGROUND: The modes of communication which patients use are seen as important within the sphere of palliative care and have been the focus of much research. AIM: This literature review aims to identify and analyse one particular mode of patient expression, namely that of the figure of speech (trope) 'metaphor', and ask questions regarding metaphor's therapeutic usefulness when engaging with the life-limited patient. DATA SOURCES: The investigation revolves around a literature review of academic papers which focus on the metaphorical ways in which patients speak of their condition. RESULTS: This paper provides the theoretical foundations for the patient's metaphoric utterances. It also delineates the variety and diversity of metaphors used by patients and categorises them into broad groupings which encompass metaphors of war, journeying, personhood, the natural world and existential concepts. CONCLUSIONS: The papers reviewed suggest that metaphoric communication allows sensitive subjects to be dealt with and provides benefits for patients. The results suggest that engaging with patients at the metaphoric level enables them to create new ways of viewing their situation and opens up the possibilities of new coping strategies. Finally, some developmental trajectories emanating from the reviewed papers are suggested, which will allow the efficacy of metaphor to be explored further within a palliative care setting. PMID- 22833471 TI - Vascular instruction of pancreas development. AB - Blood vessels course through organs, providing them with essential nutrient and gaseous exchange. However, the vasculature has also been shown to provide non nutritional signals that play key roles in the control of organ growth, morphogenesis and homeostasis. Here, we examine a decade of work on the contribution of vascular paracrine signals to developing tissues, with a focus on pancreatic beta-cells. During the early stages of embryonic development, blood vessels are required for pancreas specification. Later, the vasculature constrains pancreas branching, differentiation and growth. During adult life, capillaries provide a vascular niche for the maintenance of beta-cell function and survival. We explore the possibility that the vasculature constitutes a dynamic and regionalized signaling system that carries out multiple and changing functions as it coordinately grows with the pancreatic epithelial tree. PMID- 22833474 TI - A narrative literature review of the contribution of volunteers in end-of-life care services. AB - BACKGROUND: Volunteers are integral to the history of hospices and continue to play a vital role. However, economic, policy and demographic challenges in the twenty-first century raise questions about how best to manage this essential resource. AIM: This narrative review explores the recent literature on end-of life care volunteering and reflects upon the issues pertinent to current organisational challenges and opportunities. DESIGN: The parameters of the review were set deliberately wide in order to capture some of the nuances of contemporary volunteer practices. Articles reporting on research or evaluation of adult end-of-life care services (excluding prison services) that use volunteers and were published in English between 2000 and 2011 were included. DATA SOURCES: Seven electronic databases, key journals and grey literature databases. RESULTS: Sixty-eight articles were included in the analysis. The articles were drawn from an international literature, while acknowledging that volunteer roles vary considerably by organisation and/or by country and over time. The majority of articles were small in scale and diverse in methodology, but the same topics repeatedly emerged from both the qualitative and quantitative data. The themes identified were individual volunteer factors (motivation, characteristics of volunteers, stress and coping, role boundaries and value) and organisational factors (recruiting for diversity, support and training and volunteers' place in the system). CONCLUSIONS: The tensions involved in negotiating the boundary spaces that volunteers inhabit, informality and regulation, diversity issues and the cultural specificity of community models, are suggested as topics that merit further research and could contribute to the continuing development of the volunteer workforce. PMID- 22833475 TI - AFM investigation on Ox-LDL-induced changes in cell spreading and cell-surface adhesion property of endothelial cells. AB - The integrity and adhesion properties of endothelium play vital roles during atherosclerosis. It is well known that oxidized low-density lipoprotein (Ox-LDL) influences many physiological activities or mechanical properties of endothelial cells. However, the effects of Ox-LDL on the integrity and nonspecific adhesion properties of endothelial cells are still unclear. In this study, using the topographical imaging and force measurement functions of atomic force microscopy (AFM), we found that Ox-LDL can transiently weaken the integrity of endothelium by impairing cell spreading of endothelial cells and decrease the attachment of irrelevant blood cells to endothelium by impairing the nonspecific adhesion property of endothelial cells. The AFM-based data provide important information for understanding the effects of Ox-LDL on endothelial cells or during atherogenesis. PMID- 22833476 TI - Protein-assisted one-pot synthesis and biofunctionalization of spherical gold nanoparticles for selective targeting of cancer cells. PMID- 22833477 TI - PTSD and depression following armed robbery: patterns of appearance and impact on absenteeism and use of health care services. AB - Armed robbery is a sudden, life-threatening event affecting the victims' mental health. Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) in this population have rarely been studied. The objectives of the study were to assess the occurrence of PTSD and MDD in victims of armed robbery, and to evaluate occupational functioning and use of health care services. Eighty-six convenience store employees, victims of armed robbery, were evaluated within days after the robbery, and 1 and 3 months after. A validated diagnostic interview (SCID-I) was used. Data about sick leave, absenteeism, and use of health care services were collected. The total number of individuals who had PTSD, MDD, or both at any time during the 3 months following the robbery was 1 (2%), 4 (6%), and 5 (8%), respectively, showing that comorbid PTSD-MDD is as frequent as or even more frequent than either disorder in isolation. Individuals with PTSD (with or without comorbid MDD) reported more absenteeism (eta(2) (p) = .25) and more medical visits (eta(2) (p) = .12) following the robbery. Clinicians and management resources personnel must be alert to the possibility that both PTSD and MDD, either alone or comorbid, can develop in victims of armed robbery. PMID- 22833478 TI - Ontogeny and homology of the skeletal elements that form the sucking disc of remoras (Teleostei, Echeneoidei, Echeneidae). AB - The sucking disc of the sharksuckers of the family Echeneidae is one of the most remarkable and most highly modified skeletal structures among vertebrates. We studied the development of the sucking disc based on a series of larval, juvenile, and adult echeneids ranging from 9.3 mm to 175 mm standard length. We revisited the question of the homology of the different skeletal parts that form the disc using an ontogenetic approach. We compared the initial stages of development of the disc with early developmental stages of the spinous dorsal fin in a representative of the morphologically basal percomorph Morone. We demonstrate that the "interneural rays" of echeneids are homologous with the proximal-middle radials of Morone and other teleosts and that the "intercalary bones" of sharksuckers are homologous with the distal radials of Morone and other teleosts. The "intercalary bones" or distal radials develop a pair of large wing like lateral extensions in echeneids, not present in this form in any other teleost. Finally the "pectinated lamellae" are homologous with the fin spines of Morone and other acanthomorphs. The main part of each pectinated lamella is formed by bilateral extensions of the base of the fin spine just above its proximal tip, each of which develops a row of spinous projections, or spinules, along its posterior margin. The number of rows and the number of spinules increase with size, and they become autogenous from the body of the lamellae. We also provide a historical review of previous studies on the homology of the echeneid sucking disc and demonstrate that the most recent hypotheses, published in 2002, 2005 and 2006, are erroneous. PMID- 22833479 TI - Use of a disease risk score to compare serious infections associated with anti tumor necrosis factor therapy among high- versus lower-risk rheumatoid arthritis patients. AB - OBJECTIVE: To evaluate whether rates of serious infection with anti-tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients differ in magnitude by specific drugs and patient characteristics. METHODS: Among new nonbiologic disease-modifying antirheumatic drug users enrolled in Medicare and Medicaid or a large US commercial health plan, we created and validated a person specific infection risk score based on age, demographics, insurance type, glucocorticoid dose, and comorbidities to identify patients at high risk for hospitalized infections. We then applied this risk score to new users of infliximab, etanercept, and adalimumab and compared the observed 1-year rates of infection to one another and to the predicted infection risk score estimated in the absence of anti-TNF exposure. RESULTS: Among 11,657 RA patients initiating anti-TNF therapy, the observed 1-year rate of infection was 14.2 infections per 100 person-years in older patients (age >=65 years) and 4.8 in younger patients (age <65 years). There was a relatively constant rate difference of ~1-4 infections per 100 person-years associated with anti-TNF therapy across the range of the infection risk score. Infliximab had a significantly greater adjusted rate of infection compared to etanercept and adalimumab in both high- and lower-risk RA patients. CONCLUSION: The rate of serious infections for anti-TNF agents was incrementally increased by a fixed absolute difference irrespective of age, comorbidities, and other factors that contributed to infections. Older patients and those with high comorbidity burdens should be reassured that the magnitude of their incremental risk with anti-TNF agents is not greater than for lower-risk patients. PMID- 22833481 TI - Severe personality disorder in the secure estate: continuity and change. AB - The Response to Offender Personality Disorder Consultation was released in October 2011. For some this is a welcome step in the right direction due to its therapeutic optimism, however for practitioners operating in the secure estate there are significant challenges ahead. This aim of this article is to discuss the increasing convergence of health and criminal justice and their inherent ideological and practical difficulties. It does so with reference to the consultation on offender personality disorder pathways and in particular the implications regarding multi-disciplinary and cross agency approaches to risk, public protection and personality disorder respectfully. It concludes that before embarking on a new wave of determining and responding to those with personality disorder, offender or otherwise, a more in-depth and empirically informed critical reflection is warranted. PMID- 22833482 TI - Elder abuse. AB - Five types of elder abuse (physical, psychological, sexual, neglect and financial) are recognized. They are not new, occur worldwide and are associated with persistent morbidity and mortality. The forensic clinician has responsibilities to: (i) the patient, with competent history taking and examination, (ii) interpret findings and recognize patterns of harm and (iii) promulgate this issue in wider professional and public forums. Research into elder abuse is relatively recent; standardized terminology remains unsettled, and small-scale, local studies are hard to generalize. Cross-sectional, population based studies of elder abuse should be possible, and standardized endpoints will require forensic science contributions. PMID- 22833483 TI - A review of the scientific literature related to the adverse impact of physical restraint: gaining a clearer understanding of the physiological factors involved in cases of restraint-related death. AB - Deaths occurring during and/or in close proximity to physical restraint have been attributed to positional asphyxia, a conclusion primarily based on opinion and reviews of case studies. This review sought to identify the current scientific evidence available in regard to the aetiology of adverse events or death occurring during or in close proximity to physical restraint. A systematic search of electronic databases (SPORTDiscus, AMED, CINAHL, MEDLINE, PsycINFO) for papers published in English, between 1980 and 2011, using keywords that related to restraint, restraint position and cardiovascular function resulted in 11 experimental papers being found for review. The term positional asphyxia as a mechanism for sudden death is poorly understood. The literature shows that restraint position has the ability to impede life-maintaining physiological functions, but that the imposed impediment is not uniform across all restraint positions/techniques. Further research is required to ascertain the risks posed by struggling during restraint for more prolonged periods of time and in different positions using varied techniques of restraint. This research should seek to and rank known or future risk factors of adverse events occurring during restraint, seeking to understand the interactions and if present the cumulative effect of these risk factors. Finally, future research should focus on populations other than apparently healthy male adults. PMID- 22833484 TI - The first three years of an inpatient adolescent forensic service. AB - Bluebird House opened in February 2008. It was built to fill the gap of inpatient adolescent forensic services covering the South and South-West of England. This article describes the development of this highly specialized unit in its first three years. PMID- 22833485 TI - Theoretical value of the recommended expanded European Standard Set of STR loci for the identification of human remains. AB - We have undertaken a series of simulations to assess the effectiveness of commercially available sets of STR loci, including the loci recommended for inclusion in the expanded European Standard Set, for the purpose of human identification. A total of 9200 genotype simulations were performed using DNA . VIEW. The software was used to calculate likelihood ratios (LRs) for 23 groups of relatives, and to determine the probability of identification given scenarios that ranged between 10 and 250,000 victims. The additional loci included in the recommended expanded European Standard Set, when used in conjunction with the Identifiler((r)) kit, significantly improved the typical LRs for tested scenarios and the likely success of providing correct identifications. PMID- 22833486 TI - Auditing a court assessment and advice service for defendants with mental health difficulties: utilizing electronic patient records. AB - This study is an audit of the Somerset Court Advice and Assessment Service (CAAS) throughout its first year of implementation. It reports that the service successfully met the six desired objectives as set out in its Service Level Agreement. Further to this, it reports that the use of National Health Service electronic patient records within a court setting facilitated the provision of apposite and timely information to the court. Specific findings were that deliberate self-harm/suicidal ideation and mood disorders were the primary reasons for a person requiring CAAS involvement. Violence against the person, breach of orders and theft were the most prevalent categories of offending within this referred group. The prevalence of previous psychiatric history was significantly higher than found in comparable audits. It is likely that this is due to the efficacy of proactive and in vivo utilization of electronic patient records. Conclusions include the need to work in partnership with drug and alcohol agencies and the importance of recognizing that these services have significant clinical benefits for defendants with mental health problems, and the court system in terms of financial savings. We suggest ongoing audit is necessary to guide the development of other schemes in this pioneering service area. PMID- 22833487 TI - Lung fat embolism in a body changed by putrefaction: a hip fracture antemortem in origin. AB - Fat embolism in the lungs can unreservedly be accepted as a vital reaction even in cases of advanced putrefaction. A case is presented herein of an 80-year-old woman, found dead in her locked flat, lying on her right side on the floor. In addition to hip fracture, an external examination of the body and a forensic autopsy revealed putrefactive changes. The histological examination of frozen Sudan III-stained sections of the lungs was performed, where orange, drop, sausage- and branching-shaped fat emboli were found. Despite advanced postmortem putrefaction changes, findings of fat emboli in the lung vessels demonstrated that the hip fracture was antemortem in origin. In this case study, the utility of a lung fat embolism is highlighted as being a vital sign even in cases where the body of the deceased has been changed by advanced putrefaction. PMID- 22833491 TI - Three myths in end-of-life care. PMID- 22833490 TI - Determinants of racial/ethnic disparities in incidence of diabetes in postmenopausal women in the U.S.: The Women's Health Initiative 1993-2009. AB - OBJECTIVE: To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women's Health Initiative. RESEARCH DESIGN AND METHODS: Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993-1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed. RESULTS: Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47 1.63), 1.67 for Hispanics (1.54-1.81), and 1.86 for Asians (1.68-2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women. CONCLUSIONS: Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups. PMID- 22833492 TI - Novel frameshift mutation in the p16/INK4A tumor suppressor gene in canine breast cancer alters expression from the p16/INK4A/p14ARF locus. AB - The INK4 family of cyclin-dependent kinase inhibitors (CKI) encode important cell cycle regulators that tightly control cell cycle during G1 to S phase. These related genes are considered tumor suppressors as loss of function contributes to the malignant phenotype. Expression of CKIs p16, p14ARF, or p15 were defective in six different canine mammary tumor (CMT) cell lines compared to normal thoracic canine fibroblasts. This suggests CKI defects are frequently responsible for neoplastic transformation in canine mammary carcinomas. p16 and p14ARF are two alternatively spliced products derived from the canine p16/INK4A/p14ARF gene locus. Despite omissions in the published p16 transcript and canine genome and the presence of GC-rich repeats, we determined the complete coding sequence of canine p16 revealing a deletion and frameshift mutation in p16 exon 1alpha in CMT28 cells. In addition, we determined canine p14ARF mRNA and protein sequences. Mapping of these mutations uncovered important aspects of p16 and p14ARF expression and defects in CMT28 cells shifting the p16 reading frame into p14ARF making a fusion protein that was predicted to be truncated, unstable and devoid of structural and functional integrity. This data describes an important neoplastic mechanism in the p16/INK4A/p14ARF locus in a spontaneous canine model of breast cancer. PMID- 22833494 TI - Editorial: current progress in Bioinformatics 2012. PMID- 22833493 TI - Muscle weakness in hip osteoarthritis: a systematic review. PMID- 22833497 TI - NOTCH1 mutations in chronic lymphocytic leukemia with trisomy 12. PMID- 22833498 TI - Discordant antibiotic therapy and length of stay in children hospitalized for urinary tract infection. AB - BACKGROUND: Urinary tract infections (UTIs) are a common reason for pediatric hospitalizations. OBJECTIVE: To determine the effect of discordant antibiotic therapy (in vitro nonsusceptibility of the uropathogen to initial antibiotic) on clinical outcomes for children hospitalized for UTI. DESIGN/SETTING: Multicenter retrospective cohort study in children aged 3 days to 18 years, hospitalized at 5 children's hospitals with a laboratory-confirmed UTI. Data were obtained from medical records and the Pediatric Hospital Information System (PHIS) database. PARTICIPANTS: Patients with laboratory-confirmed UTI. MAIN EXPOSURE: Discordant antibiotic therapy. MEASUREMENTS: Length of stay and fever duration. Covariates included age, sex, insurance, race, vesicoureteral reflux, antibiotic prophylaxis, genitourinary abnormality, and chronic care conditions. RESULTS: The median age of the 216 patients was 2.46 years (interquartile range [IQR]: 0.27, 8.89) and 25% were male. The most common causative organisms were E. coli and Klebsiella species. Discordant therapy occurred in 10% of cases and most commonly in cultures positive for Klebsiella species, Enterobacter species, and mixed organisms. In adjusted analyses, discordant therapy was associated with a 1.8 day (95% confidence interval [CI]: 1.5, 2.1) longer length of stay [LOS], but not with fever duration. CONCLUSIONS: Discordant antibiotic therapy for UTI is common and associated with longer hospitalizations. Further research is needed to understand the clinical factors contributing to the increased LOS and to inform decisions for empiric antibiotic selection in children with UTIs. PMID- 22833496 TI - Mining the pharmacogenomics literature--a survey of the state of the art. AB - This article surveys efforts on text mining of the pharmacogenomics literature, mainly from the period 2008 to 2011. Pharmacogenomics (or pharmacogenetics) is the field that studies how human genetic variation impacts drug response. Therefore, publications span the intersection of research in genotypes, phenotypes and pharmacology, a topic that has increasingly become a focus of active research in recent years. This survey covers efforts dealing with the automatic recognition of relevant named entities (e.g. genes, gene variants and proteins, diseases and other pathological phenomena, drugs and other chemicals relevant for medical treatment), as well as various forms of relations between them. A wide range of text genres is considered, such as scientific publications (abstracts, as well as full texts), patent texts and clinical narratives. We also discuss infrastructure and resources needed for advanced text analytics, e.g. document corpora annotated with corresponding semantic metadata (gold standards and training data), biomedical terminologies and ontologies providing domain specific background knowledge at different levels of formality and specificity, software architectures for building complex and scalable text analytics pipelines and Web services grounded to them, as well as comprehensive ways to disseminate and interact with the typically huge amounts of semiformal knowledge structures extracted by text mining tools. Finally, we consider some of the novel applications that have already been developed in the field of pharmacogenomic text mining and point out perspectives for future research. PMID- 22833495 TI - Reverse engineering biomolecular systems using -omic data: challenges, progress and opportunities. AB - Recent advances in high-throughput biotechnologies have led to the rapid growing research interest in reverse engineering of biomolecular systems (REBMS). 'Data driven' approaches, i.e. data mining, can be used to extract patterns from large volumes of biochemical data at molecular-level resolution while 'design-driven' approaches, i.e. systems modeling, can be used to simulate emergent system properties. Consequently, both data- and design-driven approaches applied to omic data may lead to novel insights in reverse engineering biological systems that could not be expected before using low-throughput platforms. However, there exist several challenges in this fast growing field of reverse engineering biomolecular systems: (i) to integrate heterogeneous biochemical data for data mining, (ii) to combine top-down and bottom-up approaches for systems modeling and (iii) to validate system models experimentally. In addition to reviewing progress made by the community and opportunities encountered in addressing these challenges, we explore the emerging field of synthetic biology, which is an exciting approach to validate and analyze theoretical system models directly through experimental synthesis, i.e. analysis-by-synthesis. The ultimate goal is to address the present and future challenges in reverse engineering biomolecular systems (REBMS) using integrated workflow of data mining, systems modeling and synthetic biology. PMID- 22833500 TI - Maternal ascites after thoracoamniotic shunting. PMID- 22833499 TI - The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches. AB - Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche. PMID- 22833501 TI - Major infections including tuberculosis as a primary risk factor for poor outcome of lupus nephritis in Asian Indians: comment on the article by Dhir et al. PMID- 22833502 TI - Candida tenuis xylose reductase catalyzed reduction of aryl ketones for enantioselective synthesis of active oxetine derivatives. AB - Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1-phenyl-1-propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two-phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)-Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo-like kinase 1 inhibitor are discussed. PMID- 22833504 TI - Secondary telangiectasia after radiofrequency closure of saphenous vein: a result of blocked outflow of a feeding vein? PMID- 22833503 TI - Assessing the impact of cancer among Dutch non-Hodgkin lymphoma survivors compared with their American counterparts: a cross-national study. AB - PURPOSE: To understand cultural differences in the impact of cancer (IOC) by (i) performing an independent psychometric evaluation of the Dutch version of the Impact of Cancer Scale version 2 (IOCv2) in a non-Hodgkin lymphoma (NHL) sample and (ii) examining differences between Dutch and American NHL survivors in perceived IOC and identifying associations with socio-demographic and clinical characteristics. METHODS: Data collected from 491 Dutch and 738 American NHL survivors were used in this study. IOCv2 responses were obtained from all survivors; the Dutch survivors also completed the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire, which measures quality of life. RESULTS: Exploratory factor analysis of the Dutch version yielded a factor solution similar to the American structure but with some subscales merging into single factors. Internal consistency was good; Cronbach's alpha was 0.88 for the Positive and 0.94 for the Negative summary scales. Large differences were observed between survivors, whereby Dutch survivors reported fewer Positive (Delta -0.4, p < 0.001, effect size: 0.27) and more Negative (Delta 0.2, p <= 0.001, effect size: 0.13) impacts of cancer independent of socio demographic and clinical characteristics. CONCLUSION: Similar impact domains of the IOCv2 were observed in the Dutch sample, providing evidence that IOCv2 scales measure common and important survivor concerns across two different Western nations. Higher positive impacts for US survivors might be explained by more personal control and availability of supportive services. Future research should focus on determinants of the IOC in both Dutch and American survivors to gain better understanding of the factors that might improve it and suggest how health care may be modified toward that end. PMID- 22833505 TI - Healing rates following venous surgery for chronic venous leg ulcers in an independent specialist vein unit. AB - OBJECTIVES: This is a retrospective study over 12 years reporting the healing rates of leg ulcers at a specialist vein unit. All patients presented with active chronic venous leg ulcers (clinical,aetiological, anatomical and pathological elements [CEAP]: C6) and had previously been advised elsewhere that their ulcers were amenable to conservative measures only. METHOD: Seventy-two patients (84 limbs) were treated between March 1999 and June 2011. Patients were contacted in August 2011 by questionnaire and telephone. Of 72 patients,two were deceased and two had moved location at follow-up, so were not contactable. Fifty patients replied and 18 did not (response rate 74%), representing a mean follow-uptime of 3.1 years. RESULTS: Ulcer healing occurred in 85% (44 of 52 limbs) of which 52% (27) limbs were no longer confined to compression. Clinical improvement was achieved in 98% of limbs. CONCLUSIONS: This study shows that a significant proportion of ulcers currently managed conservatively can be healed by surgical intervention. PMID- 22833506 TI - Diagnostic accuracy of 16- versus 64-slice multidetector computed tomography angiography in the evaluation of coronary artery bypass grafts: a comparative study. AB - OBJECTIVES: Multidetector computed tomography (MDCT) angiography, which is used for native coronary vessels and bypass graft (CABG) imaging is a non-invasive test. Here, we aimed to compare the diagnostic accuracy of 16- and 64-slice MDCT for graft patency and stenosis. METHODS: A total of 129 consecutive patients with CABG who underwent both MDCT (58 patients with 16-slice, 71 patients with 64 slice) and invasive angiography were included. Median time interval between the two procedures was 12 days (range 3-28 days). Bypass grafts were evaluated concerning patency and presence of stenosis >= 50%. Both 16- and 64-slice MDCT results were compared with invasive angiography. RESULTS: Overall diagnostic accuracy for the detection of graft patency was 95% for 64-slice vs 92% for 16 slice MDCT. By analyzing the 173 grafts by 64-slice vs 153 grafts by 16-slice MDCT that could be evaluated, sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of the MDCT for visualization of graft patency were 90, 98, 90 and 98% vs 87, 97, 94 and 93%, respectively. The accuracy of MDCT for the detection of significant graft stenosis was relatively low (sensitivity, specificity, PPV and NPV were 67, 98.6, 50 and 98.6% with 16 slice vs 80, 98.1, 72.7 and 98.7% with 64-slice). CONCLUSIONS: This study showed that the 16-slice has a diagnostic accuracy comparable with the 64-slice system for graft patency and can still be used for this purpose if newer systems with improved performance are not available on-site. On the other hand, by the virtue of better image quality, the 64-slice MDCT demonstrates significant graft lesions with higher sensitivity. PMID- 22833507 TI - Ultrasound-guided thoracotomy for implantation of an epicardial left ventricular lead after left pneumonectomy. AB - Surgical placement of a left ventricular epicardial pacing lead is a valuable alternative to the standard approach of endovascular placement of a pacing lead in the coronary sinus for cardiac resynchronization therapy. Despite higher perioperative morbidity, surgically placed leads perform well with lower revision and dislocation rates. Moreover, surgery is the only option when an endovascular approach proves to be unsuccessful. We report a successful implantation of an epicardial left ventricular lead through an ultrasound-guided lateral left mini thoracotomy in a patient with a severely disturbed thoracic anatomy due to left pneumonectomy. PMID- 22833508 TI - Large monophasic synovial sarcoma of the mediastinum in a 15-year old boy. AB - We present the interesting case of a 15-year old boy with a monophasic synovial sarcoma (MSS) of the mediastinum, which was infiltrating the right heart chambers and the inferior vena cava (IVC). A radical excision was performed, with extensive reconstruction of the heart, under deep hypothermic circulatory arrest. Radical surgical excision is considered to be the treatment of choice for these lesions, as chemotherapy and radiotherapy have little effect. Unfortunately, the patient and his parents refused any further consultation with an oncologist and, although there was no recurrence at 12 months following the procedure, at 24 months we were informed of his death due to the tumour appearing on the left cardiac chambers with subsequent multi-organ failure. PMID- 22833509 TI - Haemodynamic goal-directed therapy in cardiac and vascular surgery. A systematic review and meta-analysis. AB - In cardiovascular surgery, reduced organ perfusion and oxygen delivery contribute to increased postoperative morbidity and prolonged intensive care unit stay. Goal directed therapy (GDT), a perioperative haemodynamic strategy aiming to increase cardiac output, is helpful in preventing postoperative complications, but studies in the context of cardiovascular surgery have produced conflicting results. The purpose of the present meta-analysis is to determine the effects of perioperative haemodynamic goal-directed therapy on mortality and morbidity in cardiac and vascular surgery. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched until July 2011. Randomized controlled trials reporting on adult cardiac or vascular surgical patients managed with perioperative GDT or according to routine haemodynamic practice were included. Primary outcome measures were mortality and morbidity. Data synthesis was obtained by using odds ratio (OR) with 95% confidence interval (CI) by a random effects model. An OR <1 favoured GDT. Statistical heterogeneity was assessed by Q and I(2) statistics. Eleven articles (five cardiac surgery and six vascular procedures), enrolling a total sample of 1179 patients, were included in the analysis. As compared with routine haemodynamic practice, perioperative GDT did not reduce mortality in either cardiac or vascular surgery (pooled OR 0.87; 95% CI 0.37-2.02; statistical power 64%). GDT significantly reduced the number of cardiac patients with complications (OR 0.34; 95% CI 0.18-0.63; P = 0.0006), but no effect was observed in vascular patients (OR, 0.84; 95% CI 0.45-1.56; P = 0.58). Perioperative GDT prevents postoperative complications in cardiac surgery patients, while it has no effect in vascular surgery. The different characteristics and comorbidities of the population enrolled could explain these conflicting results. More trials conforming to the characteristics of low-risk-of-bias studies and enrolling a larger and well-defined population of patients are needed to better clarify the effect of GDT in the specific setting of cardiovascular surgery. PMID- 22833510 TI - Repair of isolated aortic coarctation over two decades: impact of surgical approach and associated arch hypoplasia. AB - OBJECTIVES: A variety of surgical approaches and techniques are used for isolated coarctation repair. We have retrospectively reviewed our results of isolated repair of coarctation over the last 20 years, to establish whether the approach affects clinical outcome and the need for re-intervention. METHODS: Two hundred and eighty-eight patients who underwent isolated repair for coarctation of the aorta at Birmingham Children's Hospital between 1991 and 2010 were enrolled in this study. Chart review and the Departmental database were used to determine demographics, operative details and complications. RESULTS: The majority of patients (n = 237, 82%) underwent surgical repair via thoracotomy techniques, whereas median sternotomy was used in patients where there was associated arch hypoplasia (n = 51, 18%). For all 288 patients, median age at operation was 24 days (range 0-14 years). Between 1991 and 2000, ten patients (6%) underwent repair through midline sternotomy, increasing to 41 patients (36%) between 2001 and 2010. Overall early mortality was 1% and late mortality was 3%. There was a statistically higher re-intervention rate (16%) in the decade 1991-2000, compared to 5% in the period 2001-10 (P = 0.02). In patients with hypoplastic arch, the midline approach has a lower re-intervention rate than thoracotomy (P < 0.001). CONCLUSIONS: In our institution, there has been a trend in recent years towards increased use of median sternotomy to repair the aortic arch, which has been associated with a reduced rate of re-intervention. The midline sternotomy approach for coarctation with arch hypoplasia significantly reduces the risk of re-coarctation. PMID- 22833511 TI - Length of intensive care unit stay following cardiac surgery: is it impossible to find a universal prediction model? AB - OBJECTIVES: Accurate models for prediction of a prolonged intensive care unit (ICU) stay following cardiac surgery may be developed using Cox proportional hazards regression. Our aims were to develop a preoperative and intraoperative model to predict the length of the ICU stay and to compare our models with published risk models, including the EuroSCORE II. METHODS: Models were developed using data from all patients undergoing cardiac surgery at St. Olavs Hospital, Trondheim, Norway from 2000-2007 (n = 4994). Internal validation and calibration were performed by bootstrapping. Discrimination was assessed by areas under the receiver operating characteristics curves and calibration for the published logistic regression models with the Hosmer-Lemeshow test. RESULTS: Despite a diverse risk profile, 93.7% of the patients had an ICU stay <2 days, in keeping with our fast-track regimen. Our models showed good calibration and excellent discrimination for prediction of a prolonged stay of more than 2, 5 or 7 days. Discrimination by the EuroSCORE II and other published models was good, but calibration was poor (Hosmer-Lemeshow test: P < 0.0001), probably due to the short ICU stays of almost all our patients. None of the models were useful for prediction of ICU stay in individual patients because most patients in all risk categories of all models had short ICU stays (75th percentiles: 1 day). CONCLUSIONS: A universal model for prediction of ICU stay may be difficult to develop, as the distribution of length of stay may depend on both medical factors and institutional policies governing ICU discharge. PMID- 22833512 TI - Evaluation of lipid removal from animal fats for the determination of organochlorine, pesticides, and polychlorinated biphenyl indicators by gas chromatography with electron capture detector. AB - For cleanup of animal fat before GC analysis of organochlorine pesticides and polychlorinated biphenyls, freezing-lipid filtration with solid-phase extraction and matrix solid-phase dispersion were evaluated to replace the official Brazilian methodology that uses preparative alumina column chromatography. General drawbacks associated with this last technique, such as the use of large amounts of solvent, laborious and time-consuming procedure could be avoided by using these alternative approaches. Experiments were carried out to study the performance by using different combinations of sorbents and elution solvents. Efficiency of alternative extraction methods in terms of fat removal and recovery capability was monitored by gravimetry, TLC, and GC with electron capture detection. Freezing-lipid filtration with solid-phase extraction afforded better clean up efficiency with recoveries in a range of 54.5 to 103.6% with the relative standard deviation of less than 10% for all compounds under investigation. PMID- 22833514 TI - The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c). The underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen. PMID- 22833513 TI - Sex differences in assessment of obesity in rheumatoid arthritis. AB - OBJECTIVE: To determine the prevalence of obesity and how accurately standard anthropometric measures identify obesity among men and women with rheumatoid arthritis (RA). METHODS: Dual x-ray absorptiometry (DXA) was performed for 141 persons with RA (56 men and 85 women). Two anthropometric proxies of obesity (body mass index [BMI] and waist circumference [WC]) were compared to a DXA-based obesity criterion. Receiver operating characteristic curves determined optimal cut points for each anthropometric measure, relative to DXA. The association of body fat and anthropometric obesity measures with disease status and cardiovascular risk was assessed in multiple regression analyses, controlling for age and glucocorticoid use. All analyses were performed separately for men and women. RESULTS: A total of 20%, 32%, and 44% of women and 41%, 36%, and 80% of men were classified as obese by BMI, WC, and DXA, respectively. Cut points were identified for anthropometric measures to better approximate DXA estimates of percent body fat (BMI >=26.1 kg/m(2) for women and >=24.7 kg/m(2) for men; WC >=83 cm for women and >=96 cm for men). For women and men, higher percent fat was associated with poorer RA status. Anthropometric measures were more closely linked to RA status for women, but identified cardiovascular risk for both women and men. CONCLUSION: A large percentage of this RA sample was overfat; DXA defined obesity was twice as common in men as in women. Utility of revised BMI and WC cut points compared to traditional cut points remains to be examined in prospective studies, but results suggest that lower, sex-specific cut points may be warranted to better identify individuals at risk for poor RA and/or cardiovascular outcomes. PMID- 22833516 TI - Gait assessment during the initial fitting of customized selective laser sintering ankle foot orthoses in subjects with drop foot. AB - BACKGROUND: Recently, additive fabrication has been proposed as a feasible engineering method for manufacturing of customized ankle foot orthoses (AFOs). Consequently, studies on safety, comfort and effectiveness are now carried out to assess the performance of such devices. OBJECTIVE: Evaluate the clinical performance of customized (selective laser sintering) SLS-AFOs on eight subjects with unilateral drop foot gait and compare to clinically accepted (polypropylene) PP-AFOs. STUDY DESIGN: Active control trial. METHODS: For each subject two customized AFOs were fabricated: one SLS-AFO manufactured following an additive fabrication framework and one thermoplastic PP-AFO manufactured according to the traditional handcraft method. Clinical performance of both AFOs was evaluated during gait analysis. RESULTS: A significant beneficial effect of both custom moulded PP-AFO and customized SLS-AFO in terms of spatial temporal gait parameters and ankle kinematic parameters compared to barefoot gait of adults with drop foot gait are observed. No statistically significant difference between the effect of PP-AFO and of SLS-AFO was found in terms of spatial temporal gait parameters and ankle kinematic parameters. CONCLUSION: AFOs manufactured through the SLS technique show performances that are at least equivalent to the handcrafted PP-AFOs commonly prescribed in current clinical practice. Clinical relevance Manufacturing personalized AFOs with selective laser sintering (SLS) in an automated production process results in decreased production time and guarantees the consistency of shape and functional characteristics over different production time points compared to the traditional manufacturing process. Moreover, it reduces the dependency of the appliance on the experience and craftsmanship of the orthopaedic technician. PMID- 22833517 TI - Quality of life and functionality after lower limb amputations: comparison between uni- vs. bilateral amputee patients. AB - BACKGROUND: It is difficult for the lower limb amputee patients to adapt to their new lifestyles. OBJECTIVE: To compare the life quality and functionality of patients with bilateral vs. unilateral lower extremity amputations. STUDY DESIGN: Cross-sectional study. METHODS: Fifteen bilateral and 15 unilateral lower extremity amputee patients were enrolled. Demographics, cause and level of amputations, frequency and duration of prosthesis use were evaluated. SF-36, Satisfaction with Prosthesis Questionnaire (SAT-PRO), Amputee Body Image Scale. (ABIS), Houghton Scale (HS), six-minute walk test (6MWT), and 10-metre walk test (10 MWT) were performed. RESULTS: Physical function, physical and emotional role scores of SF-36 were significantly lower in the bilateral amputee group in comparison with the unilateral group. SAT-PRO and ABIS total scores were similar between the groups. There was a positive correlation between the frequency of prosthetic use and SF-36 subgroups (except pain). The unilateral amputee group had significantly better scores than the bilateral amputee group in terms of HS, 6MWT and 10 MWT. CONCLUSION: Physical capacity of bilateral lower extremity amputee patients is lower than the unilateral amputee patients; satisfaction with prosthesis and body image are not related with the amputation level; and the life quality and satisfaction with prostheses are increased in parallel with the use of the prostheses. Clinical relevance Although differences exist between the groups, in terms of quality of life and functionality, patients can reach an acceptable life standard with good rehabilitation and a suitable prosthesis. PMID- 22833515 TI - Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. AB - AIMS: In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. METHODS AND RESULTS: Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 +/- 1.3 vs. 3.4 +/- 1.2 mmHg/uL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 +/- 1.1 mmHg/uL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 +/- 3 vs. 48 +/- 8 MUL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. CONCLUSION: In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans. PMID- 22833518 TI - The effect of tuning ankle foot orthoses-footwear combination on the gait parameters of children with cerebral palsy. AB - BACKGROUND: There are a wide variety of ankle foot orthoses used in clinical practice which are characterised by their design, the material used and the stiffness of that material. Changing any of these three components will alter the effect of the ankle foot orthosis on gait. OBJECTIVES: The purpose of this article is to provide an overview on the available research on ankle foot orthosis-footwear combination tuning on the gait characteristics of children with cerebral palsy through a structured review. STUDY DESIGN: Literature review. METHODS: A thorough search of previous studies published in English was conducted within all major databases using relevant phrases without any limits for the dates. These searches were then supplemented by tracking all key references from the appropriate articles identified including hand searching of published books where relevant. RESULTS: To date, there are 947 papers in the literature pertaining to the study of ankle foot orthosis. Of these, 153 investigated the use of ankle foot orthosis for children with cerebral palsy. All the studies included in this review were of a within-subjects design and the evidence levels were generally low. CONCLUSIONS: The overall results suggested that ankle foot orthosis-footwear combination tuning has the potential to improve the kinematics and kinetics of gait in children with cerebral palsy. However, the review highlights a lack of well-designed and adequately powered studies. Clinical relevance While the research described in this article indicates an improvement in the gait of children with cerebral palsy following tuning of their ankle foot orthosis-footwear combination, there is still a paucity of research with quantitative data on the effects of kinematics and kinetics of ankle foot orthosis-footwear combination tuning, comparing untuned ankle foot orthosis footwear combinations with tuned ankle foot orthosis-footwear combination. Furthermore, current research does not identify the effect of tuning on energy efficiency. PMID- 22833519 TI - Esthetic, functional, and prosthetic outcomes with implant-retained finger prostheses. AB - BACKGROUND: Traumatic amputation of fingers results in a serious impairment of hand function and affects the psychological status of the patients. The implant retained finger prostheses are an alternative treatment. The aim of this case report is to represent the use of osseointegrated implants for retention of finger prostheses in a patient with amputated thumb and index finger. CASE DESCRIPTION AND METHODS: Dental implants were placed in the residual bone of the fingers using two-stage surgery. Custom-made attachments were used to provide retention between implants and silicone prostheses. Prosthetic fingernails were made of composite resin material. FINDINGS AND OUTCOMES: After 6 months, implants were clinically successful, and the patient was satisfied with the appearance and the function of the prostheses. The complications of broken prosthetic nail and mild discoloration were observed. CONCLUSION: Reconstruction of amputated fingers with implant-retained prosthesis is a worthwhile treatment providing esthetic, functional, and psychological benefits, although some complications might be experienced. Clinical relevance Implant-retained finger prostheses are an acceptable treatment modality for patients with amputated fingers. Evaluating implant prognosis, functional results and prosthetic results of the patients are necessary to address the benefits and complications of the treatment. PMID- 22833521 TI - Impact of perceived social support on the mental health and health-related quality of life in cancer patients: results from a nationwide, multicenter survey in South Korea. AB - OBJECTIVE: We investigated whether and how perceived social support is associated with depression and quality of life among patients with various cancer diagnoses. METHODS: Data were collected from 1930 cancer patients treated at the National Cancer Center and nine regional cancer centers across Korea. The Duke-UNC functional social support scale was used to measure the perceived social support, and the PHQ-9 and the EORTC QLQ-C30 were used to measure the cancer patients' depression levels and quality of life, respectively. RESULTS: Subjects with low perceived social support reported significantly higher levels of depression, lower scores on all functional scales, higher scores on all three symptom scales, lower global health/quality of life scale scores, and higher scores on most single items than subjects with high perceived social support. There was no interaction between potential stressors and perceived social support, supporting the main effect model as the mechanism that the perceived social support reduce the adverse psychological outcomes. CONCLUSION: Perceived social support was associated with mental health and quality of life in cancer patients, through direct effect rather than stress-buffering effect. Interventions to enhance perceived social support might be helpful for improving mental health and QOL in cancer patients. PMID- 22833520 TI - Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1. AB - The pi-class glutathione S-transferase (GSTP1) actively protect cells from carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is the most common epigenetic alteration observed in human prostate cancer. Silencing of GSTP1 can increase generation of reactive oxygen species (ROS) and DNA damage in cells. In this study we investigated whether loss of GSTP1 contributes to increased DNA damage that may predispose men to a higher risk of prostate cancer. We found significantly elevated (103%; P < 0.0001) levels of 8-oxo-2'-deoxogunosine (8-OHdG), an oxidative DNA damage marker, in adenocarcinomas, compared to benign counterparts, which positively correlated (r = 0.2) with loss of GSTP1 activity (34%; P < 0.0001). Silencing of GSTP1 using siRNA approach in normal human prostate epithelial RWPE1 cells caused increased intracellular production of ROS and higher susceptibility of cells to H2 O2 mediated oxidative stress. Additionally, human prostate carcinoma LNCaP cells, which contain a silenced GSTP1 gene, were genetically modified to constitutively express high levels of GSTP1. Induction of GSTP1 activity lowered endogenous ROS levels in LNCaP-pLPCX-GSTP1 cells, and when exposed to H2 O2 , these cells exhibited significantly reduced production of ROS and 8-OHdG levels, compared to vector control LNCaP-pLPCX cells. Furthermore, exposure of LNCaP cells to green tea polyphenols caused reexpression of GSTP1, which protected the cells from H2 O2 -mediated DNA damage through decreased ROS production compared to nonexposed cells. These results suggest that loss of GSTP1 expression in human prostate cells, a process that increases their susceptibility to oxidative stress-induced DNA damage, may be an important target for primary prevention of prostate cancer. PMID- 22833522 TI - Polyaniline-coated Fe3O4 nanoparticles: An anion exchange magnetic sorbent for solid-phase extraction. AB - In this study, the capability of the prepared polyaniline-coated Fe(3) O(4) nanoparticles for magnetic solid-phase extraction of three parabens from environmental wastewater, cream, and toothpaste samples is presented. Synthesized Fe(3) O(4) nanoparticles were coated with sulfate-doped polyaniline via polymerization of aniline in the presence of Fe(3) O(4) nanoparticles and sulfuric acid. Here, polyaniline-coated Fe(3) O(4) nanoparticles are presented as anion exchange sorbent, which extract anionic form of parabens via anion exchange with dopant of polyaniline. The experimental conditions affecting extraction efficiency were further studied and optimized. The experimental results showed that maximum extraction efficiency can be obtained at 70 mL sample solution of pH 8, extraction and desorption times of 2 and 1 min, respectively, 100 MUL of 3% (v/v) acetic acid in acetonitrile as eluent, and 100 mg of the adsorbent. Under these conditions, the linear dynamic ranges were 0.5-100 MUg/L with good correlation coefficients (0.998-0.999). The detection limits were in the range of 0.3-0.4 MUg/L and the relative standard deviations were less than 2.4 (n = 5) for the three parabens. Finally, this fast and efficient method was further employed for determination of target analytes in cream, toothpaste, and environmental wastewater samples and satisfactory results were obtained. PMID- 22833524 TI - Contact map prediction using a large-scale ensemble of rule sets and the fusion of multiple predicted structural features. AB - MOTIVATION: The prediction of a protein's contact map has become in recent years, a crucial stepping stone for the prediction of the complete 3D structure of a protein. In this article, we describe a methodology for this problem that was shown to be successful in CASP8 and CASP9. The methodology is based on (i) the fusion of the prediction of a variety of structural aspects of protein residues, (ii) an ensemble strategy used to facilitate the training process and (iii) a rule-based machine learning system from which we can extract human-readable explanations of the predictor and derive useful information about the contact map representation. RESULTS: The main part of the evaluation is the comparison against the sequence-based contact prediction methods from CASP9, where our method presented the best rank in five out of the six evaluated metrics. We also assess the impact of the size of the ensemble used in our predictor to show the trade-off between performance and training time of our method. Finally, we also study the rule sets generated by our machine learning system. From this analysis, we are able to estimate the contribution of the attributes in our representation and how these interact to derive contact predictions. AVAILABILITY: http://icos.cs.nott.ac.uk/servers/psp.html. CONTACT: natalio.krasnogor@nottingham.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22833523 TI - Cigarette smoke disrupts the integrity of airway adherens junctions through the aberrant interaction of p120-catenin with the cytoplasmic tail of MUC1. AB - Adherens junctions (AJs) containing epithelial cadherin (E-cad) bound to p120 catenin (p120ctn) and beta-catenin (beta-ctn) play a crucial role in regulating cell-cell adhesion. Cigarette smoke abrogates cell-cell adhesion between epithelial cells by disrupting E-cad, a hallmark of epithelial-mesenchymal transition (EMT), yet the underlying mechanism remains unknown. We used an organotypic culture of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk) to establish an essential role for the interaction between p120ctn and the cytoplasmic tail of MUC1 (MUC1-CT) in regulating E-cad disruption. Within the first 4 h of smoke exposure, apical MUC1 CT repositioned to the basolateral membrane of pseudo-stratified HBE cells, where it interacted with p120ctn. A time-dependent increase in MUC1-CT/p120ctn complexes occurred in conjunction with a time-dependent dissociation of p120ctn/E cad/beta-ctn complexes, as well as the coordinated degradation of p120ctn and E cad. Interestingly, Smk induced a similar interaction between MUC1-CT and beta ctn, but this occurred 44 h after MUC1-CT's initial interaction with p120ctn, and well after the AJs were destroyed. Blocking MUC1-CT's interaction with p120ctn using a MUC1-CT dominant-negative peptide, PMIP, successfully abolished Smk's disruptive effects on AJs and recovered apical-basolateral polarity of HBE cells. The MUC1-CT/p120ctn interaction was highly dependent on EGFR/Src/Jnk-mediated tyrosine phosphorylation (TyrP) of MUC1-CT. Accordingly, EGFR, Src or Jnk inhibitors (AG1478, PP2, SP600125, respectively) abrogated Smk-induced MUC1-CT TyrP, MUC1-CT/p120ctn interaction, AJ disruption, and loss of cellular polarity. Our work identified MUC1-CT and p120ctn as important regulators of epithelial polarity and cell-cell adhesion during a smoke-induced EMT-like process. Novel therapeutics designed to inhibit MUC1-CT/p120ctn complex formation may prevent EMT in the smoker's airway. PMID- 22833525 TI - RedoxDB--a curated database for experimentally verified protein oxidative modification. AB - SUMMARY: Redox regulation and signaling, which are involved in various cellular processes, have become one of the research focuses in the past decade. Cysteine thiol groups are particularly susceptible to post-translational modification, and their reversible oxidation is of critical role in redox regulation and signaling. With the tremendous improvement of techniques, hundreds of redox proteins along with their redox-sensitive cysteines have been reported, and the number is still fast growing. However, until now there is no database to accommodate the rapid accumulation of information on protein oxidative modification. Here we present RedoxDB-a manually curated database for experimentally validated redox proteins. RedoxDB (version 1.0) consists of two datasets (A and B, for proteins with or without verified modified cysteines, respectively) and includes 2157 redox proteins containing 2203 cysteine residues with oxidative modification. For each modified cysteine, the exact position, modification type and flanking sequence are provided. Additional information, including gene name, organism, sequence, literature references and links to UniProt and PDB, is also supplied. The database supports several functions including data search, blast and browsing. Bulk download of the entire dataset is also available. We expect that RedoxDB will be useful for both experimental studies and computational analyses of protein oxidative modification. AVAILABILITY: The database is freely available at: http://biocomputer.bio.cuhk.edu.hk/RedoxDB. CONTACT: djguo@cuhk.edu.hk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online. PMID- 22833526 TI - DELIMINATE--a fast and efficient method for loss-less compression of genomic sequences: sequence analysis. AB - SUMMARY: An unprecedented quantity of genome sequence data is currently being generated using next-generation sequencing platforms. This has necessitated the development of novel bioinformatics approaches and algorithms that not only facilitate a meaningful analysis of these data but also aid in efficient compression, storage, retrieval and transmission of huge volumes of the generated data. We present a novel compression algorithm (DELIMINATE) that can rapidly compress genomic sequence data in a loss-less fashion. Validation results indicate relatively higher compression efficiency of DELIMINATE when compared with popular general purpose compression algorithms, namely, gzip, bzip2 and lzma. AVAILABILITY AND IMPLEMENTATION: Linux, Windows and Mac implementations (both 32 and 64-bit) of DELIMINATE are freely available for download at: http://metagenomics.atc.tcs.com/compression/DELIMINATE. CONTACT: sharmila@atc.tcs.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22833528 TI - White-light emitting microtubes of mixed organic charge-transfer complexes. AB - Self-assembled microtubes of mixed charge-transfer (CT) complexes comprising TCNB and naphthalene can be constructed with pyrene as dopant by an etching-assisted CT-induced interaction. Highly efficient Forster resonance energy transfer (FRET) from the excited naphthalene-TCNB to pyrene-TCNB molecules is obtained in mixed CT complex microtubes. White-light emissive CT complex microtubes can be formed by adjusting the dopant concentration and serve as an active optical waveguide. PMID- 22833527 TI - Excess body weight and four-year function outcomes: comparison of African Americans and whites in a prospective study of osteoarthritis. AB - OBJECTIVE: We evaluated whether African Americans in the Osteoarthritis Initiative (OAI) have a greater risk (versus whites) of poor 4-year function outcome within strata defined by sex, body mass index (BMI), and waist circumference. METHODS: Using Western Ontario and McMaster Universities Osteoarthritis Index function, 20-meter walk, and chair stand performance, poor outcome was defined as moving into a worse function group or remaining in the 2 worst groups over 4 years. Logistic regression was used to evaluate the relationship between racial group and outcome within each stratum, adjusting for age, education, and income, and then further adjusting for BMI, comorbidity, depressive symptoms, physical activity, knee pain, and osteoarthritis (OA) severity. RESULTS: In 3,695 persons with or at higher risk for knee OA, higher BMI and large waist circumference were each associated with poor outcome. Among women with high BMI and among women with large waist circumference, African Americans were at greater risk for poor outcome by every measure, adjusting for age, education, and income. From fully adjusted models, potential explanatory factors included income, comorbidity, depressive symptoms, pain, and disease severity. Findings were less consistent for men, emerging only for the 20-meter walk or chair stand outcomes, and potentially explained by age and knee pain. CONCLUSION: Among OAI women with excess body weight, African Americans are at greater risk than whites for poor 4-year outcome. Modifiable factors that may help to explain these findings in the OAI include comorbidity, depressive symptoms, and knee pain. Targeting such factors, while supporting weight loss, may help to lessen the outcome disparity between African American and white women. PMID- 22833529 TI - Increased SCF/c-kit by hypoxia promotes autophagy of human placental chorionic plate-derived mesenchymal stem cells via regulating the phosphorylation of mTOR. AB - Hypoxia triggers physiological and pathological cellular processes, including proliferation, differentiation, and death, in several cell types. Mesenchymal stem cells (MSCs) derived from various tissues have self-renewal activity and can differentiate towards multiple lineages. Recently, it has been reported that hypoxic conditions tip the balance between survival and death by hypoxia-induced autophagy, although the underlying mechanism is not clear. The objectives of this study are to compare the effect of hypoxia on the self-renewal of bone marrow derived mesenchymal stem cells (BM-MSCs) and placental chorionic plate-derived mesenchymal stem cells (CP-MSCs) and to investigate the regulatory mechanisms of self-renewal in each MSC type during hypoxia. The expression of self-renewal markers (e.g., Oct4, Nanog, Sox2) was assessed in both cell lines. PI3K and stem cell factor (SCF) expression gradually increased in CP-MSCs but were markedly downregulated in BM-MSCs by hypoxia. The phosphorylation of ERK and mTOR was augmented by hypoxia in CP-MSCs compared to control. Also, the expression of LC3 II, a component of the autophagosome and the hoof-shaped autophagosome was detected more rapidly in CP-MSCs than in BM-MSCs under hypoxia. Hypoxia induced the expression of SCF in CP-MSCs and increased SCF/c-kit pathway promotes the self-renewal activities of CP-MSCs via an autocrine/paracrine mechanism that balances cell survival and cell death events by autophagy. These activities occur to a greater extent in CP-MSCs than in BM-MSCs through regulating the phosphorylation of mTOR. These findings will provide useful guidelines for better understanding the function of SCF/c-kit in the self-renewal and autophagy regulated mechanisms that promote of MSC survival. PMID- 22833530 TI - MeDIP real-time qPCR of maternal peripheral blood reliably identifies trisomy 21. AB - OBJECTIVE: To reevaluate the efficiency of the 12 differentially methylated regions (DMRs) used in the methylated DNA immunoprecipitation (MeDIP) real-time quantitative polymerase chain reaction (real-time qPCR) based approach, develop an improved version of the diagnostic formula and perform a larger validation study. METHODS: Twelve selected DMRs were checked for copy number variants in the Database of Genomic Variants. The DMRs located within copy number variants were excluded from the analysis. One hundred and seventy-five maternal peripheral blood samples were used to reconstruct and evaluate the new diagnostic formula and for a larger-scale blinded validation study using MeDIP real-time qPCR. RESULTS: Seven DMRs entered the final model of the prediction equation and a larger blinded validation study demonstrated 100% sensitivity and 99.2% specificity. No significant evidence for association was observed between cell free fetal DNA concentration and D value. CONCLUSION: The MeDIP real-time qPCR method for noninvasive prenatal diagnosis of trisomy 21 was confirmed and revalidated in 175 samples with satisfactory results demonstrating that it is accurate and reproducible. We are currently working towards simplification of the method to make it more robust and therefore easily, accurately, and rapidly reproduced and adopted by other laboratories. Nevertheless, larger scale validation studies are necessary before the MeDIP real-time qPCR-based method could be applied in clinical practice. PMID- 22833531 TI - Retroperitoneal recurrence of a stage 1 renal cell carcinoma 4 years following core biopsy and fine needle aspiration: possible needle tract seeding. PMID- 22833532 TI - Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis. AB - OBJECTIVE: To assess risk and risk factors for serious infections in seniors with rheumatoid arthritis (RA) using a case-control study nested within an RA cohort. METHODS: We assembled a retrospective RA cohort age >=66 years from Ontario health administrative data across 1992-2010. Nested case-control analyses were done, comparing RA patients with a primary diagnosis of infection (based on hospital or emergency department records) to matched RA controls. We assessed independent effects of drugs, adjusting for demographics, comorbidity, and markers of RA severity. RESULTS: A total of 86,039 seniors with RA experienced 20,575 infections, for a rate of 46.4 events/1,000 person-years. The most frequently occurring events included respiratory infections, herpes zoster, and skin/soft tissue infections. Factors associated with infection included higher comorbidity, rural residence, markers of disease severity, and history of previous infection. In addition, anti-tumor necrosis factor agents and disease modifying antirheumatic drugs were associated with a several-fold increase in infections, with an adjusted odds ratio (OR) ranging from 1.2-3.5. The drug category with the greatest effect estimate was glucocorticoids, which exhibited a clear dose response with an OR ranging from 4.0 at low doses to 7.6 at high doses. CONCLUSION: Seniors with RA have significant morbidity related to serious infections, which exceeds previous reports among younger RA populations. Rural residence, higher comorbidity, markers of disease severity, and previous infection were associated with serious infections in seniors with RA. Our results emphasize that many RA drugs may increase the risk of infection, but glucocorticoids appear to confer a particular risk. PMID- 22833533 TI - Promotion orientation explains why future-oriented people exercise and eat healthy: evidence from the two-factor consideration of future consequences-14 scale. AB - The authors extended research linking individual differences in consideration of future consequences (CFC) with health behaviors by (a) testing whether individual differences in regulatory focus would mediate that link and (b) highlighting the value of a revised, two-factor CFC-14 scale with subscales assessing concern with future consequences (CFC-Future) and concern with immediate consequences (CFC Immediate) proper. Exploratory and confirmatory factor analyses of the revised CFC-14 scale supported the presence of two highly reliable factors (CFC-Future and CFC-Immediate; alphas from .80 to .84). Moreover, structural equation modeling showed that those high in CFC-Future engage in exercise and healthy eating because they adopt a promotion orientation. Future use of the two-factor CFC-14 scale is encouraged to shed additional light on how concern with future and concern with immediate consequences (proper) differentially impact the way people resolve a host of intertemporal dilemmas (e.g., health, financial, and environmental behavior). PMID- 22833534 TI - Pathological assessment of mismatch repair gene variants in Lynch syndrome: past, present, and future. AB - Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and is the most prevalent hereditary colorectal cancer syndrome. A significant proportion of variants identified in MMR and other common cancer susceptibility genes are missense or noncoding changes whose consequences for pathogenicity cannot be easily interpreted. Such variants are designated as "variants of uncertain significance" (VUS). Management of LS can be significantly improved by identifying individuals who carry a pathogenic variant and thus benefit from screening, preventive, and therapeutic measures. Also, identifying family members that do not carry the variant is important so they can be released from the intensive surveillance. Determining which genetic variants are pathogenic and which are neutral is a major challenge in clinical genetics. The profound mechanistic knowledge on the genetics and biochemistry of MMR enables the development and use of targeted assays to evaluate the pathogenicity of variants found in suspected patients with LS. We describe different approaches for the functional analysis of MMR gene VUS and propose development of a validated diagnostic framework. Furthermore, we call attention to common misconceptions about functional assays and endorse development of an integrated approach comprising validated assays for diagnosis of VUS in patients suspected of LS. PMID- 22833535 TI - Successful use of bronchoscopic lung insufflation to treat left lung atelectasis. AB - We report first use of bronchoscopic lung insufflation in a child to treat acute left lung collapse. The patient is a 6-year old male asthmatic who was hospitalized with a 2-day history of cough, chest pain, and abdominal pain. He was tachypneic and hypoxemic on room air. Chest exam revealed diminished breath sounds on the left side. Chest X-ray and Chest CT showed complete left lung collapse. He underwent bronchoscopic lung insufflation procedure by injecting total of 200 ml air via flexible bronchoscope in the left upper lobe using 50cc syringe aliquots followed by similar injection of 200 ml of air in left lower lobe. After air insufflations, 6 ml of bovine surfactant (calfactant) were instilled in each lobe. Chest fluoroscopy was done immediately after procedure and showed expansion of entire left lung with no pneumothorax. The procedure was well tolerated. The patient's symptoms and hypoxemia resolved soon after procedure. However, left lower lobe atelectasis recurred next day and persisted for 6 days despite treatments with chest physical therapy, systemic steroids, oral azithromycin, nebulized dornase alpha, and endoscopic removal of secretions from left lower lobe. Bronchoscopic insufflation of left lower lobe was repeated resulting in immediate expansion of that lobe as demonstrated by intraoperative fluoroscopy. The patient was discharged home next day. This case suggests that brochoscopic lung insufflation can be safe and effective in treating acute lung collapse and in treating atelectasis which is refractory to conventional therapy. PMID- 22833537 TI - Global proteome changes in larvae of Callosobruchus maculatus Coleoptera:Chrysomelidae:Bruchinae) following ingestion of a cysteine proteinase inhibitor. AB - The seed-feeding beetle Callosobruchus maculatus is an important cowpea pest (Vigna unguiculata) as well as an interesting model to study insect digestive physiology. The larvae of C. maculatus rely on cysteine and aspartic peptidases to digest proteins in their diet. In this work, the global proteomic changes induced in the intestinal tract of larval C. maculatus challenged by the ingestion of cystatin, a cysteine peptidase inhibitor, was investigated by a nanoLC-MS/MS approach. The ingestion of cystatin caused a delay in the development of the larvae, but the mortality was not high, indicating that C. maculatus is able to adapt to this inhibitor. This proteomic strategy resulted in the identification of 752 and 550 protein groups in the midgut epithelia and midgut contents, respectively, and quantitative analyses allowed us to establish relative differences of the identified proteins. Ingestion of cystatin led to significant changes in the proteome of both the midgut epithelia and midgut contents. We have observed that proteins related to plant cell wall degradation, particularly the key glycoside hydrolases of the families GH5 (endo-beta-1,4 mannanase) and GH 28 (polygalacturonase) were overexpressed. Conversely, alpha amylases were downexpressed, indicating that an increase in hemicelluloses digestion helps the larvae to cope with the challenge of cystatin ingestion. Furthermore, a number of proteins associated with transcription/translation and antistress reactions were among the cystatin-responsive proteins, implying that a substantial rearrangement in the proteome occurred in C. maculatus exposed to the inhibitor. PMID- 22833538 TI - Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1beta. AB - Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1beta and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1beta releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation. PMID- 22833539 TI - The Nuss procedure made safer: an effective and simple sternal elevation manoeuvre. AB - The Nuss procedure requires the creation of a substernal tunnel for bar positioning. This is a manoeuvre that can be dangerous, and cardiac perforation has occurred in a few cases. Our purpose was to describe two technical modifications that enable the prevention of these fatal complications. A series of 25 patients with pectus excavatum were treated with a modification of the Nuss procedure that included the entrance in the left haemithorax first, and the use of the retractor to lift the sternum, with the consequent lowering displacement of the heart. These modified techniques have certain advantages: (i) the narrow anterior mediastinum between the sternum and the pericardial sac is expanded by pulling up the sternum; (ii) the thoracoscopic visualization of the tip of the introducer during tunnel creation is improved; (iii) the rubbing of the introducer against the pericardium is minimized; (iv) the exit path of the introducer can be guided by the surgeon's finger and (v) haemostasis and integrity of the pericardial sac can be more easily confirmed. We observed that with these manoeuvres, the risk of pericardial sac and cardiac injury can be markedly reduced. PMID- 22833540 TI - Pulmonary metastasectomy for osteogenic and soft tissue sarcoma: who really benefits from surgical treatment? AB - OBJECTIVES: Surgical resection is widely accepted as a beneficial treatment of pulmonary metastases originating from osteogenic and soft tissue sarcomas despite adequate validation. The factors associated with the selection of patients who receive pulmonary metastasectomy (PM) are controversial and not well known. In this study, we aimed to identify the prognostic factors associated with survival after treatment with PM and to disclose the candidates who profit from PM being performed on patients with osteogenic and soft tissue sarcomas. METHODS: We retrospectively reviewed the variables and survival outcomes in 52 consecutive patients who underwent PM to treat lung metastases originating from osteogenic and soft tissue malignancies from April 1996 to January 2011. Prognostic factors associated with overall survival after the first PM were evaluated using univariate and multivariate analyses. RESULTS: Fifty-eight PM procedures were performed in 52 patients as the first PM including 6 bilateral diseases. Wedge resection was the most frequently performed PM procedure (84%), and video assisted thoracic surgery was introduced in 34 (59%). The median follow-up of the patients was 33 months and the 5-year survival rate after the first PM was 50.9%. Forty-eight (92%) patients underwent complete resection during the first PM. Thirty-three patients (62%) experienced relapse after the first PM. Among those patients, 20 received redo surgeries for pulmonary relapse, and the 5-year survival rate in this group was 49.7%. According to univariate analyses, the use of complete resection, the number of metastatic nodules (one or two) and the length of the disease-free interval prior to the first PM were each found to be significant favourable factors. According to a multivariate analysis, the use of complete resection and the number of metastatic nodules were both found to be independent prognostic factors associated with overall survival. Although our cohort included 15 patients with poor prognostic factors (29%), 5 patients who underwent redo surgery survived >22 months. CONCLUSIONS: The survival of those patients with one or two pulmonary nodules and those who underwent complete resection was favourable following the treatment of osteogenic and soft tissue sarcomas with PM. Redo surgery may also provide some survival benefit in patients with poor prognostic factors. PMID- 22833541 TI - Validation of EuroSCORE II in a modern cohort of patients undergoing cardiac surgery. AB - OBJECTIVE: We aimed to validate the new EuroSCORE II risk model in a contemporary cardiac surgery practice in the United Kingdom (UK). METHODS: The original logistic EuroSCORE was compared to EuroSCORE II with regard to accuracy of predicting in-hospital mortality. Analysis was performed on isolated coronary artery bypass grafts (CABG; n = 2913), aortic valve replacement (AVR; n = 814), mitral valve surgery (MVR; n = 340), combined AVR and CABG (n = 517), aortic (n = 350) and miscellaneous procedures (n = 642), and the above cases combined (n = 5576). RESULTS: In a single-institution experience, EuroSCORE II is a reasonable risk model for in-hospital mortality from isolated CABG (C-statistic 0.79, Hosmer Lemeshow P = 0.052) and aortic procedures (C-statistic 0.81, Hosmer-Lemeshow P = 0.43), and excellent for mitral valve surgery (C-statistic 0.87, Hosmer-Lemeshow P = 0.6). EuroSCORE II is better than the original EuroSCORE, using contemporaneous data for combined AVR and CABG operations (C-statistic 0.74, Hosmer-Lemeshow P = 0.38). However, EuroSCORE II failed to improve on the original EuroSCORE model for isolated AVR (C-statistic 0.69, Hosmer-Lemeshow P = 0.07) and miscellaneous procedures (C-statistic 0.70, Hosmer-Lemeshow P = 0.99). EuroSCORE II has better calibration than the original EuroSCORE or the Society of Cardiothoracic Surgeons of Great Britain and Ireland (SCTS) modified EuroSCORE for cumulative sum survival (CUSUM) curves. CONCLUSIONS: EuroSCORE II improves on the original logistic EuroSCORE, though mainly for combined AVR and CABG cases. Concerns still exist, however, over its use for isolated AVR procedures, aortic surgery and miscellaneous procedures. There is still room for improvement in risk modelling. PMID- 22833542 TI - Defining indoor heat thresholds for health in the UK. AB - INTRODUCTION: It has been recognised that as outdoor ambient temperatures increase past a particular threshold, so do mortality/morbidity rates. However, similar thresholds for indoor temperatures have not yet been identified. Due to a warming climate, the non-sustainability of air conditioning as a solution, and the desire for more energy-efficient airtight homes, thresholds for indoor temperature should be defined as a public health issue. AIMS: The aim of this paper is to outline the need for indoor heat thresholds and to establish if they can be identified. Our objectives include: describing how indoor temperature is measured; highlighting threshold measurements and indices; describing adaptation to heat; summary of the risk of susceptible groups to heat; reviewing the current evidence on the link between sleep, heat and health; exploring current heat and health warning systems and thresholds; exploring the built environment and the risk of overheating; and identifying the gaps in current knowledge and research. METHODS: A global literature search of key databases was conducted using a pre defined set of keywords to retrieve peer-reviewed and grey literature. The paper will apply the findings to the context of the UK. RESULTS: A summary of 96 articles, reports, government documents and textbooks were analysed and a gap analysis was conducted. Evidence on the effects of indoor heat on health implies that buildings are modifiers of the effect of climate on health outcomes. Personal exposure and place-based heat studies showed the most significant correlations between indoor heat and health outcomes. However, the data are sparse and inconclusive in terms of identifying evidence-based definitions for thresholds. Further research needs to be conducted in order to provide an evidence base for threshold determination. CONCLUSIONS: Indoor and outdoor heat are related but are different in terms of language and measurement. Future collaboration between the health and building sectors is needed to develop a common language and an index for indoor heat and health thresholds in a changing climate. PMID- 22833543 TI - Abbreviated multi-breath washout for calculation of lung clearance index. AB - INTRODUCTION: Various functional residual capacity (FRC) repeatability criteria have been proposed for lung clearance index (LCI) measurement by multiple breath washout (MBW). Adult guidelines recommend three technically acceptable tests with FRC values within 10%, whilst preschool guidelines recommend two such tests. Feasibility of and need for recommendations in children is unclear. METHODS: Retrospective analysis of MBW data was undertaken in healthy control (n = 90) and cystic fibrosis (CF) subjects (n = 108) encompassing infancy, pre-school and school age ranges. Feasibility of FRC repeatability recommendations was investigated in those with three technically acceptable tests. Validity of mean LCI from the first two tests alone (vs. all three) was investigated by comparing mean data and sensitivity to detect abnormal peripheral airway function in CF. RESULTS: LCI coefficient of variation (CoV) was related to FRC CoV (P < 0.001) and disease category (P = 0.002). Application of adult repeatability criteria decreased LCI CoV (4.7 vs. 8.5%, P < 0.001), but had poor feasibility beyond infancy (62/150, 41%). Preschool recommendations increased feasibility but only to 70% overall. There was no difference in mean LCI (All three minus 1st two tests) in healthy controls [mean (95% CI) difference: 0.02 (-0.01, 0.06; P = 0.15)], this difference being statistically but not clinically significant in CF subjects [0.07 (0.00,0.13; P = 0.04)]. Sensitivity in CF subjects was unaffected. CONCLUSION: Adult FRC repeatability recommendations improved LCI repeatability in pediatric subjects, but poor feasibility limited utility. In an experienced pediatric MBW center, recent preschool recommendations can be extended to two technically acceptable tests, irrespective of FRC repeatability, without significantly affecting mean LCI or compromising sensitivity. PMID- 22833544 TI - Vitamin A deficiency alters airway resistance in children with acute upper respiratory infection. AB - OBJECTIVE: To assess whether vitamin A deficiency alters the recovery of total respiratory resistance (TRR) following acute upper respiratory tract infection (URI). METHODS: This is a case control study of children, age 4-6 years and grouped as: URI, (n = 74), URI and wheezing, (URI-wheezing, n = 52), and healthy controls (n = 51). Vitamin A and total respiratory resistance (TRR) were assessed using the modified relative dose response (MRDR) and forced oscillometry, respectively. RESULTS: Children with URI and URI-wheezing had lower retinol, 32.4 +/- 13.12 and 18.3 +/- 6.83 ug/dl respectively, compared to controls, 56.9 +/- 29.82 ug/dl (ANOVA, P < 0.001). The MRDR was elevated in children in the URI or URI-wheezing groups 0.066 +/- 0.045 and 0.021 +/- 0.021, respectively, compared to controls 0.007 +/- 0.006 (ANOVA, P < 0.0001). The TRR in the URI and URI wheezing groups differed from controls. During convalescence, the TRR failed to decline in the URI-group only when the MRDR was >0.06. In the URI-wheezing group, TRR declined independently of retinol and MRDR. CONCLUSION: Vitamin A contributes to preservation of airway function during and in recovery after upper respiratory infection in children. PMID- 22833545 TI - Secretome analysis of ionizing radiation-induced senescent cancer cells reveals that secreted RKIP plays a critical role in neighboring cell migration. AB - Cellular senescence is a physiological program of irreversible growth arrest that is considered to play an important role in tumor suppression. Recent studies demonstrated that senescent cells secrete multiple growth regulatory proteins that could alter the behavior of neighboring cells. In this study, we investigated the effect of secretory proteins from ionizing radiation (IR) induced senescent tumor cells on normal and tumor cells. Conditioned medium (CM) from IR-induced senescent MCF7 cells significantly increased cell proliferation, invasion, migration, and wound healing activity in MCF7 cells and HUVECs. Comparative proteomics analysis revealed 24 differentially secreted protein spots including Raf kinase inhibitor protein (RKIP), alpha-Enolase, AKAP9, and MARK4, and the findings were confirmed by Western blot analysis of IR-induced senescent cancer cells. We found that RKIP was secreted via the classical pathway, and the transfection of small interfering RNA against RKIP suppressed CM-induced migration in MCF7 cells. Treatment with recombinant human RKIP increased the migratory activity of MCF7 cells. Taken together, our results demonstrate that the senescence-associated secretory protein RKIP could be the principal target to prevent the potential effects of the secretome from IR-induced senescent tumor cells on neighboring cell migration. PMID- 22833546 TI - A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. AB - Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for <= 12 cycles. The primary endpoint was overall response rate (>= partial response). Secondary endpoints included clinical benefit response rate (>= minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238. PMID- 22833547 TI - Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso occlusive events in sickle cell disease mice. AB - Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-alpha-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease. PMID- 22833549 TI - Left ventricular mass predicts left atrial appendage thrombus in persistent atrial fibrillation. AB - AIMS: Atrial fibrillation (AF) can result in the development of left atrial appendage (LAA) thrombi. We sought to examine demographic and echocardiographic predictors of LAA thrombus in patients with persistent AF. METHODS AND RESULTS: One hundred and sixty-five patients in persistent AF (36 with LAA thrombus and 129 without thrombus) were studied. Demographic and cardiovascular risk factors were retrospectively examined. Transthoracic (TTE) and transoesophageal echocardiography (TOE) were performed to assess the size and function of the left ventricle (LV), left atrium (LA), LAA, and spontaneous echo contrast (SEC) in the LA and right atrium (RA). Univariate demographic predictors of LA thrombus included systolic blood pressure, ischaemic heart disease and congestive heart failure. Indexed LV mass and septal E' velocity on TTE and mean LAA emptying velocity and the presence of SEC in both the LA and RA on TOE were predictors of thrombus. In a multiple logistic regression analysis the only independent predictor of thrombus was indexed LV mass (P < 0.001). Receiver operator characteristic curve analysis also demonstrated that indexed LV mass had the highest area under the curve (AUC: 0.98). CONCLUSION: In the present study, increased LV mass was the strongest predictor of LAA thrombus in persistent AF. LA SEC and RA SEC were univariate predictors of LAA thrombus but did not add predictive value to a multivariate model including LV mass. This study highlights the importance of diagnosing and treating LV hypertrophy associated with persistent AF, which may reduce the risk of LAA thrombus and thrombo-embolic stroke. PMID- 22833548 TI - Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme replacement therapy and cytoreduction. AB - Gene therapy (GT) for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of gamma-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada(-/-)). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing gamma-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene transduced HSC, and short-term ERT after GT did not diminish the capacity of gene corrected cells to engraft and persist. PMID- 22833550 TI - Pocket-size hand-held cardiac ultrasound as an adjunct to clinical examination in the hands of medical students and junior doctors. AB - AIMS: While patient history taking and physical examination remain the cornerstones of patient evaluation in clinical practice, there has been a decline in the accuracy of the latter. Pocket-size hand-held echocardiographic (PHHE) devices have recently been introduced and could potentially improve the diagnostic accuracy of both medical students and junior doctors. The amount of training required to achieve optimal results remains a matter of debate. We hypothesized that the use of PHHE after limited training in the form of a tutorial can improve the clinical diagnosis even in the hands of medical students and inexperienced physicians. METHODS AND RESULTS: Five final-year medical students and three junior doctors without prior echocardiographic experience participated in a standardized 2 h PHHE bedside tutorial. Subsequently, they assessed 122 cardiology patients using history, physical examination, ECG and PHHE. Their final clinical diagnosis was compared against that of a consultant clinician's and also expert in echocardiography. A total of 122 PHHE were performed of which 64 (53%) by final-year medical students and 58 (47%) by junior doctors. Mean +/- SD for diagnostic accuracy after history, physical examination, and ECG interpretation was 0.49 +/- 0.22 (maximum = 1), whereas the addition of PHHE increased its value to 0.75 +/- 0.28 (Z = -7.761, P<0.001). When assessing left ventricular systolic dysfunction by means of history and physical examination, specificity was 84.9% and sensitivity only 25.9%, whereas after including findings from PHHE, these figures rose to 93.6 and 74.1%, respectively. CONCLUSION: The use of PHHE after brief bedside training in the form of a tutorial greatly improved the clinical diagnosis of medical students and junior doctors, over and above history, physical examination, and ECG findings. PMID- 22833551 TI - Clinical significance of respiratory isolates for Mycobacterium abscessus complex from pediatric patients. AB - Mycobacterium abscessus complex is the most virulent of rapidly growing mycobacteria causing invasive lung disease. To better delineate clinical pediatric experience and outcomes with M. abscessus complex, we retrospectively gathered 5-year data on M. abscessus complex infection and outcomes in a large, hospital-based pediatric pulmonary center. Patients were selected from the database of the microbiology department at Miller Children's Hospital in Long Beach, CA. Patients had at least one positive pulmonary isolate for M. abscessus complex from February 2006 to May 2011. Treatment modality data were collected and successful therapy of disease was determined as clearance of M. abscessus complex infection after antibiotics proven by culture negative respiratory isolate within at least 12 months of therapy initiation. Two cystic fibrosis patients with M. abscessus complex were identified, one with failed therapy and the other with stable pulmonary status despite persistent isolation. One primary ciliary dyskinesia patient had successful clearance of M. abscessus complex, however is now growing M. avium intracellulare. A patient with no prior medical history was successfully treated with antimycobacterial therapy. Eleven patients with neuromuscular disorders had tracheal aspirates positive for M. abscessus complex. None were treated due to stable lung status and all but two had spontaneous clearance of the mycobacteria. The two remaining persist with sporadic isolation of M. abscessus complex without clinical significance. We concluded that patients with tracheostomy associated M. abscessus complex infections do not appear to require treatment and often have spontaneous resolution. Cystic fibrosis or primary ciliary dyskinesia patients may have clinical disease warranting treatment, but current antimycobacterial therapy has not proven to be completely successful. As M. abscessus complex gains prevalence, standardized guidelines for diagnosis and therapy are needed in the pediatric population. Multicenter cohort analysis is necessary to achieve such guidelines. PMID- 22833552 TI - Can gradual dose titration of ketamine for management of neuropathic pain prevent psychotomimetic effects in patients with advanced cancer? AB - BACKGROUND: Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image. OBJECTIVE: To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer. METHODS: This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved. RESULTS: For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 +/- 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 +/- 58 and 272 +/- 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 +/- 2.0 to 3.5 +/- 2.2 after the administration of ketamine (P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase. CONCLUSION: Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer. PMID- 22833553 TI - Evaluation of atropine 1% ophthalmic solution administered sublingually for the management of terminal respiratory secretions. AB - Terminal respiratory secretions (TRS) or "death rattle" is a common symptom in the dying patient. Current practice for the prevention and treatment of TRS involves the use of oral, sublingual, transdermal, or parenteral anticholinergic medications. A retrospective chart review of patients admitted to a hospice inpatient unit for terminal care and treated with sublingual atropine 1% ophthalmic drops for TRS was conducted. A total of 19 of 22 patients treated with atropine had documented reduction or resolution of TRS. This study suggests that atropine 1% ophthalmic drops administered sublingually are a reasonable option for the management of TRS. Problematic cardiac or central nervous system symptoms were not found in the present study. Results should aid hospice programs who are seeking guidance on the management of TRS with atropine 1% ophthalmic drops. PMID- 22833554 TI - Outcome measures of spiritual care in palliative home care: a qualitative study. AB - The purpose of this study was to identify key outcome measures of spiritual care in palliative home care. A qualitative study was conducted with experts from 3 stakeholder groups (physicians, professional spiritual caregivers, and researchers) representing 2 countries (Belgium and The Netherlands). Three key outcome measures were identified: the extent to which the patient feels that he or she is being heard and taken seriously, the extent to which the patient experiences that there is a place for that which is insoluble, and the extent to which the patient experiences that there is a place for that which cannot be said. Further research is needed to implement and evaluate these new outcome measures. PMID- 22833555 TI - Assessing somatic, psychosocial, and spiritual distress of patients with advanced cancer: development of the Advanced Cancer Patients' Distress Scale. AB - OBJECTIVE: For adequate distress assessment in palliative care, we developed a screening evaluation tool. METHODS: Proven methods of scale construction led to a 53-item pilot form of the Advanced Cancer Patients' Distress Scale (ACPDS). We used Hornheide Questionnaire (HQ), Palliative Outcome Scale (POS), and Minimal Documentation System (MIDOS) for validation. Advanced cancer patients (N = 168) from 3 centers for palliative medicine (aged 23-89, 51% female) filled out the questionnaire. RESULTS: With a principal component analysis (PCA), we extracted 5 distress scales (emotional reactions/physical restrictions, communication deficits, negative social reactions, pain, and gastrointestinal symptoms). Internal consistencies varied between medium (.52) and very good (.88). Positive validity scores were found. CONCLUSIONS: Using the ACPDS may help to identify needs for palliative care interventions and enhance the quality of palliative care. PMID- 22833556 TI - Does the school food environment influence the dietary behaviours of Norwegian 11 year-olds? The HEIA study. AB - AIMS: The aim of the study is to investigate the influence of the school food environment on the dietary behaviours of 11-year-old Norwegian children in elementary schools. METHODS: Baseline data from a school-based intervention study: the Health In Adolescents study was used. A total of 1425 11-year-old children from 35 schools from the eastern part of Norway were included. School administrators provided information on the physical, political, and sociocultural school food environment and students reported their intake of fruits, vegetables, sugar-sweetened beverages (SSB), and snacks. Multilevel modelling was used to assess the school-level variance in dietary behaviours and to investigate the association of school food environmental factors with these dietary behaviours. RESULTS: After adjustment for student characteristics, the school level accounted for a small proportion (1.1%-3.0%) of the variance in the dietary behaviours investigated. None of the investigated school food environmental factors were found to be related to the children's reported intake of fruits, vegetables, snacks or SSB. CONCLUSIONS: Most of the variance in the dietary behaviours investigated was at the personal level. Thus in this sample, the investigated school-level factors do not appear to exert a strong influence on the dietary behaviours of children. Longitudinal studies using validated measures of the school food environment are needed. PMID- 22833557 TI - Mediterranean diet and familial dysmetabolism as factors influencing the development of acne. AB - AIM: To investigate the effects of adherence to the Mediterranean diet and familial dysmetabolisms on acne development. METHODS: A community-based case control study was carried out in Italy enrolling cases as acneic outpatients of a dermatological ambulatory service and controls as clinically healthy acne-free subjects. Food consumption were evaluated with a validated food-frequency questionnaire, exploring the consumption of pasta, meat, cheese, fish, fruit, vegetables, and olive oil. Adherence to the traditional Mediterranean diet was assessed by a 10-point Mediterranean diet scale that incorporated the main characteristics of this diet. A logistic regression analysis estimated the variables who predicted the odds of being case, using those variables that at the univariate analysis yielded a p-value <0.25. Results are presented as odds ratio (OR) or adjusted OR (AOR). RESULTS: The study included 93 cases (36.6% males, median age 17 years) and 200 controls (32% males, median age 16 years). The Mediterranean diet score >=6 revealed a protective effect towards acne (crude OR 0.22, 95% CI 0.08-0.64). Logistic regression analysis showed that familial hypercholesterolaemia, diabetes, and hypertension are strong risk factors for acne (AOR 8.79, 95% CI 1.67-46.22; 3.32, 95% CI 1.27-8.63; and 2.73, 95% CI 1.07 6.96, respectively), while the Mediterranean diet represents a protective factor (score >=6, AOR 0.31, 95% CI 0.11-0.89). CONCLUSIONS: The odds for familial dysmetabolisms was higher in cases than in controls, confirming their role in determining or maintaining acne. Moreover, this is the first study demonstrating a protective role of the Mediterranean diet in the pathogenesis of acne. PMID- 22833558 TI - Psychosocial risk assessment: French validation of the Copenhagen Psychosocial Questionnaire (COPSOQ). AB - AIMS: This study presents a French version of the Copenhagen Psychosocial Questionnaire (COPSOQ) and analyses its psychometric properties for the purpose of validation. The questionnaire assesses psychosocial risk factors at work. The French questionnaire (derived from the Danish short version) is composed of 32 items grouped into 17 scales measuring five domains and eight additional questions assessing aggressive behaviour at work. METHOD: The questionnaire was administered to 935 employees of a large firm in the Parisian area. RESULTS: All psychometric analyses performed (internal consistency of the scales, exploratory factor analysis, concurrent validity analysis) gave satisfactory results and demonstrated the validity of the French COPSOQ. CONCLUSIONS: A new questionnaire is now available in French. A large body of data is currently being gathered in view of comparing occupations and types of firms using this new instrument. PMID- 22833559 TI - Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA binding and degradation. AB - Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element-binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved. PMID- 22833560 TI - Placenta to cartilage: direct conversion of human placenta to chondrocytes with transformation by defined factors. AB - Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human placental cells into chondrocytes. Starting from a pool of candidate genes, we identified a combination of only five genes (5F pool)-BCL6, T (also called BRACHYURY), c-MYC, MITF, and BAF60C (also called SMARCD3)-that rapidly and efficiently convert postnatal human chorion and decidual cells into chondrocytes. The cells generated expressed multiple cartilage-specific genes, such as Collagen type II alpha1, LINK PROTEIN-1, and AGGRECAN, and exhibited characteristics of cartilage both in vivo and in vitro. Expression of the endogenous genes for T and MITF was initiated, implying that the cell conversion is due to not only the forced expression of the transgenes, but also to cellular reprogramming by the transgenes. This direct conversion system from noncartilage tissue to cartilaginous tissue is a substantial advance toward understanding cartilage development, cell-based therapy, and oncogenesis of chondrocytes. PMID- 22833561 TI - Interactions between the PDZ domains of Bazooka (Par-3) and phosphatidic acid: in vitro characterization and role in epithelial development. AB - Bazooka (Par-3) is a conserved polarity regulator that organizes molecular networks in a wide range of cell types. In epithelia, it functions as a plasma membrane landmark to organize the apical domain. Bazooka is a scaffold protein that interacts with proteins through its three PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains and other regions. In addition, Bazooka has been shown to interact with phosphoinositides. Here we show that the Bazooka PDZ domains interact with the negatively charged phospholipid phosphatidic acid immobilized on solid substrates or in liposomes. The interaction requires multiple PDZ domains, and conserved patches of positively charged amino acid residues appear to mediate the interaction. Increasing or decreasing levels of diacylglycerol kinase or phospholipase D-enzymes that produce phosphatidic acid reveal a role for phosphatidic acid in Bazooka embryonic epithelial activity but not its localization. Mutating residues implicated in phosphatidic acid binding revealed a possible role in Bazooka localization and function. These data implicate a closer connection between Bazooka and membrane lipids than previously recognized. Bazooka polarity landmarks may be conglomerates of proteins and plasma membrane lipids that modify each other's activities for an integrated effect on cell polarity. PMID- 22833562 TI - CIN85 phosphorylation is essential for EGFR ubiquitination and sorting into multivesicular bodies. AB - Ubiquitination of the epidermal growth factor receptor (EGFR) by cbl and its cognate adaptor cbl-interacting protein of 85 kDa (CIN85) is known to play an essential role in directing this receptor to the lysosome for degradation. The mechanisms by which this ubiquitin modification is regulated are not fully defined, nor is it clear where this process occurs. In this study we show that EGFR activation leads to a pronounced src-mediated tyrosine phosphorylation of CIN85 that subsequently influences EGFR ubiquitination. Of importance, phospho CIN85 interacts with the Rab5-positive endosome, where it mediates the sequestration of the ubiquitinated receptor into multivesicular bodies (MVBs) for subsequent degradation. These findings provide novel insights into how src- kinase-based regulation of a cbl adaptor regulates the fate of the EGFR. PMID- 22833563 TI - AP-3 regulates PAR1 ubiquitin-independent MVB/lysosomal sorting via an ALIX mediated pathway. AB - The sorting of signaling receptors within the endocytic system is important for appropriate cellular responses. After activation, receptors are trafficked to early endosomes and either recycled or sorted to lysosomes and degraded. Most receptors trafficked to lysosomes are modified with ubiquitin and recruited into an endosomal subdomain enriched in hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a ubiquitin-binding component of the endosomal-sorting complex required for transport (ESCRT) machinery, and then sorted into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)/lysosomes. However, not all receptors use ubiquitin or the canonical ESCRT machinery to sort to MVBs/lysosomes. This is exemplified by protease-activated receptor-1 (PAR1), a G protein-coupled receptor for thrombin, which sorts to lysosomes independent of ubiquitination and HRS. We recently showed that the adaptor protein ALIX binds to PAR1, recruits ESCRT-III, and mediates receptor sorting to ILVs of MVBs. However, the mechanism that initiates PAR1 sorting at the early endosome is not known. We now report that the adaptor protein complex-3 (AP-3) regulates PAR1 ubiquitin independent sorting to MVBs through an ALIX-dependent pathway. AP-3 binds to a PAR1 cytoplasmic tail-localized tyrosine-based motif and mediates PAR1 lysosomal degradation independent of ubiquitination. Moreover, AP-3 facilitates PAR1 interaction with ALIX, suggesting that AP-3 functions before PAR1 engagement of ALIX and MVB/lysosomal sorting. PMID- 22833564 TI - NESdb: a database of NES-containing CRM1 cargoes. AB - The leucine-rich nuclear export signal (NES) is the only known class of targeting signal that directs macromolecules out of the cell nucleus. NESs are short stretches of 8-15 amino acids with regularly spaced hydrophobic residues that bind the export karyopherin CRM1. NES-containing proteins are involved in numerous cellular and disease processes. We compiled a database named NESdb that contains 221 NES-containing CRM1 cargoes that were manually curated from the published literature. Each NESdb entry is annotated with information about sequence and structure of both the NES and the cargo protein, as well as information about experimental evidence of NES-mapping and CRM1-mediated nuclear export. NESdb will be updated regularly and will serve as an important resource for nuclear export signals. NESdb is freely available to nonprofit organizations at http://prodata.swmed.edu/LRNes. PMID- 22833565 TI - Sequence and structural analyses of nuclear export signals in the NESdb database. AB - We compiled >200 nuclear export signal (NES)-containing CRM1 cargoes in a database named NESdb. We analyzed the sequences and three-dimensional structures of natural, experimentally identified NESs and of false-positive NESs that were generated from the database in order to identify properties that might distinguish the two groups of sequences. Analyses of amino acid frequencies, sequence logos, and agreement with existing NES consensus sequences revealed strong preferences for the Phi1-X(3)-Phi2-X(2)-Phi3-X-Phi4 pattern and for negatively charged amino acids in the nonhydrophobic positions of experimentally identified NESs but not of false positives. Strong preferences against certain hydrophobic amino acids in the hydrophobic positions were also revealed. These findings led to a new and more precise NES consensus. More important, three dimensional structures are now available for 68 NESs within 56 different cargo proteins. Analyses of these structures showed that experimentally identified NESs are more likely than the false positives to adopt alpha-helical conformations that transition to loops at their C-termini and more likely to be surface accessible within their protein domains or be present in disordered or unobserved parts of the structures. Such distinguishing features for real NESs might be useful in future NES prediction efforts. Finally, we also tested CRM1-binding of 40 NESs that were found in the 56 structures. We found that 16 of the NES peptides did not bind CRM1, hence illustrating how NESs are easily misidentified. PMID- 22833566 TI - ECM stiffness primes the TGFbeta pathway to promote chondrocyte differentiation. AB - Cells encounter physical cues such as extracellular matrix (ECM) stiffness in a microenvironment replete with biochemical cues. However, the mechanisms by which cells integrate physical and biochemical cues to guide cellular decision making are not well defined. Here we investigate mechanisms by which chondrocytes generate an integrated response to ECM stiffness and transforming growth factor beta (TGFbeta), a potent agonist of chondrocyte differentiation. Primary murine chondrocytes and ATDC5 cells grown on 0.5-MPa substrates deposit more proteoglycan and express more Sox9, Col2alpha1, and aggrecan mRNA relative to cells exposed to substrates of any other stiffness. The chondroinductive effect of this discrete stiffness, which falls within the range reported for articular cartilage, requires the stiffness-sensitive induction of TGFbeta1. Smad3 phosphorylation, nuclear localization, and transcriptional activity are specifically increased in cells grown on 0.5-MPa substrates. ECM stiffness also primes cells for a synergistic response, such that the combination of ECM stiffness and exogenous TGFbeta induces chondrocyte gene expression more robustly than either cue alone through a p38 mitogen-activated protein kinase-dependent mechanism. In this way, the ECM stiffness primes the TGFbeta pathway to efficiently promote chondrocyte differentiation. This work reveals novel mechanisms by which cells integrate physical and biochemical cues to exert a coordinated response to their unique cellular microenvironment. PMID- 22833569 TI - Professional hospital violence: the pain that cannot be borne by Chinese medical practitioners. PMID- 22833567 TI - Large G3BP-induced granules trigger eIF2alpha phosphorylation. AB - Stress granules are large messenger ribonucleoprotein (mRNP) aggregates composed of translation initiation factors and mRNAs that appear when the cell encounters various stressors. Current dogma indicates that stress granules function as inert storage depots for translationally silenced mRNPs until the cell signals for renewed translation and stress granule disassembly. We used RasGAP SH3-binding protein (G3BP) overexpression to induce stress granules and study their assembly process and signaling to the translation apparatus. We found that assembly of large G3BP-induced stress granules, but not small granules, precedes phosphorylation of eIF2alpha. Using mouse embryonic fibroblasts depleted for individual eukaryotic initiation factor 2alpha (eIF2alpha) kinases, we identified protein kinase R as the principal kinase that mediates eIF2alpha phosphorylation by large G3BP-induced granules. These data indicate that increasing stress granule size is associated with a threshold or switch that must be triggered in order for eIF2alpha phosphorylation and subsequent translational repression to occur. Furthermore, these data suggest that stress granules are active in signaling to the translational machinery and may be important regulators of the innate immune response. PMID- 22833568 TI - Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons. AB - In response to neurotoxic signals, postmitotic neurons make attempts to reenter the cell cycle, which results in their death. Although several cell cycle proteins have been implicated in cell cycle-related neuronal apoptosis (CRNA), the molecular mechanisms that underlie this important event are poorly understood. Here, we demonstrate that neurotoxic agents such as beta-amyloid peptide cause aberrant activation of mitogen-activated kinase kinase (MEK) extracellular signal-regulated kinase (ERK) signaling, which promotes the entry of neurons into the cell cycle, resulting in their apoptosis. The MEK-ERK pathway regulates CRNA by elevating the levels of cyclin D1. The increase in cyclin D1 attenuates the activation of cyclin-dependent kinase 5 (cdk5) by its neuronal activator p35. The inhibition of p35-cdk5 activity results in enhanced MEK-ERK signaling, leading to CRNA. These studies highlight how neurotoxic signals reprogram and alter the neuronal signaling machinery to promote their entry into the cell cycle, which eventually leads to neuronal cell death. PMID- 22833570 TI - Nutrition, adult hippocampal neurogenesis and mental health. AB - INTRODUCTION: Over the last 8 years, emerging studies bridging the gap between nutrition and mental health have resolutely established that learning and memory abilities as well as mood can be influenced by diet. However, the mechanisms by which diet modulates mental health are still not well understood. Sources of data In this article, a review of the literature was conducted using PubMed to identify studies that provide functional implications of adult hippocampal neurogenesis (AHN) and its modulation by diet. AREAS OF AGREEMENT: One of the brain structures associated with learning and memory as well as mood is the hippocampus. Importantly, the hippocampus is one of the two structures in the adult brain where the formation of newborn neurons, or neurogenesis, persists. AREAS OF CONTROVERSY: The exact roles of these newborn neurons in learning, memory formation and mood regulation remain elusive. GROWING POINTS: Nevertheless, there has been accumulating evidence linking cognition and mood to neurogenesis occurring in the adult hippocampus. Therefore, modulation of AHN by diet emerges as a possible mechanism by which nutrition impacts on mental health. AREAS TIMELY FOR DEVELOPING RESEARCH: This area of investigation is new and needs attention because a better understanding of the neurological mechanisms by which nutrition affect mental health may lead to novel dietary approaches for disease prevention, healthier ageing and discovery of new therapeutic targets for mental illnesses. PMID- 22833571 TI - Health economic decision-making: a comparison between UK and Spain. AB - OBJECTIVE: This review examines the impact of economic evaluation in informing national or local policies within both jurisdictions. We focus on the factors that have made the economic evaluation evolves differently in both settings. AREAS OF AGREEMENT: Economic evaluation facilitates decision-making regarding the efficiency of interventions. The existence of national or local bodies regulating the process has contributed to increasing its use in decision-making and the development of its methods. AREAS OF CONTROVERSY: Cost-effectiveness approach is based on the assumption of health maximization subject to a budget constraint. Decision-makers are not only interested in health maximization alone. This may result in policy-makers failing to consider economic evaluations into their allocation decisions. AREAS TO DEVELOP RESEARCH: Methods that incorporate wider decision-makers goals (mainly local) and research to study the real impact of economic evaluation in terms of improved efficiency and equity are particularly required. PMID- 22833572 TI - Analysis of mRNA profiles after MEK1/2 inhibition in human pancreatic cancer cell lines reveals pathways involved in drug sensitivity. AB - Mutationally activated KRAS, detected in approximately 90% of pancreatic ductal adenocarcinomas (PDA), has proven an intractable pharmacologic target to date. Consequently, efforts to treat KRAS-mutated cancers are focused on targeting RAS regulated signaling pathways. In mouse models, expression of BRAF(V600E) combined with dominant-negative TP53 elicits PDA, and pharmacologic blockade of mitogen activated protein/extracellular signal-regulated kinase (MEK) inhibits proliferation of human PDA-derived cell lines. To better understand the role of RAF->MEK->ERK signaling on PDA cell proliferation, we assessed the consequences of MEK inhibition on global patterns of mRNA expression and tumor cell proliferation in a panel of human PDA-derived cell lines. This analysis revealed that RAF->MEK->ERK signaling regulates mRNAs involved in cell-cycle control as well as regulators of the immune system. Linear regression analysis of relative drug sensitivity and mRNA expression revealed mRNAs and pathways correlating with relative drug sensitivity of the cell lines. Mice carrying orthotopically implanted pancreas tumors that were treated with MEK inhibitor displayed reduced tumor growth, concomitant with a reduction of cells in S phase. Furthermore, analysis of tumor mRNA expression revealed PDA cell lines to display similar baseline and MEK inhibitor mRNA expression profiles in vitro and in vivo. Among the proteins subject to downregulation following MEK inhibition, we identified c MYC as a key driver of cell proliferation downstream of RAF->MEK->ERK signaling. Indeed, in some PDA cell lines, RNA interference-mediated silencing of c-MYC expression had antiproliferative effects similar to that of MEK inhibition, thereby highlighting the importance of c-MYC in key aspects of pancreatic cancer cell maintenance. PMID- 22833574 TI - Declaring conflicting interests. PMID- 22833573 TI - Identification of DNA repair pathways that affect the survival of ovarian cancer cells treated with a poly(ADP-ribose) polymerase inhibitor in a novel drug combination. AB - Floxuridine (5-fluorodeoxyuridine, FdUrd), a U.S. Food and Drug Administration approved drug and metabolite of 5-fluorouracil, causes DNA damage that is repaired by base excision repair (BER). Thus, poly(ADP-ribose) polymerase (PARP) inhibitors, which disrupt BER, markedly sensitize ovarian cancer cells to FdUrd, suggesting that this combination may have activity in this disease. It remains unclear, however, which DNA repair and checkpoint signaling pathways affect killing by these agents individually and in combination. Here we show that depleting ATR, BRCA1, BRCA2, or RAD51 sensitized to ABT-888 (veliparib) alone, FdUrd alone, and FdUrd + ABT-888 (F+A), suggesting that homologous recombination (HR) repair protects cells exposed to these agents. In contrast, disabling the mismatch, nucleotide excision, Fanconi anemia, nonhomologous end joining, or translesion synthesis repair pathways did not sensitize to these agents alone (including ABT-888) or in combination. Further studies demonstrated that in BRCA1 depleted cells, F+A was more effective than other chemotherapy+ABT-888 combinations. Taken together, these studies 1) identify DNA repair and checkpoint pathways that are important in ovarian cancer cells treated with FdUrd, ABT-888, and F+A, 2) show that disabling HR at the level of ATR, BRCA1, BRCA2, or RAD51, but not Chk1, ATM, PTEN, or FANCD2, sensitizes cells to ABT-888, and 3) demonstrate that even though ABT-888 sensitizes ovarian tumor cells with functional HR to FdUrd, the effects of this drug combination are more profound in tumors with HR defects, even compared with other chemotherapy + ABT-888 combinations, including cisplatin + ABT-888. PMID- 22833575 TI - Boundaries and borders. PMID- 22833576 TI - HLA-B*1502 screening in carbamazepine and lamotrigine candidates of Asian background. PMID- 22833577 TI - The experiences of Australian parents with psychosis: the second Australian National Survey of Psychosis. AB - OBJECTIVE: Being a parent is an important part of one's identity and role. Previous research outlines many challenges associated with parenting by people with severe mental illness. However, there is a limited research describing parenting experiences of mothers and fathers who have psychosis. METHOD: The second Australian national survey of psychosis recruited 1825 people living with symptoms of, or a diagnosis of, psychosis. The survey was conducted through face to-face interviews and included key clinical and demographic information, as well as parenting specific information. RESULTS: Over half of all women and a quarter of men were parents. Almost a quarter of women but only 5.5% of the men had dependent children (own and/or stepchildren) living at home with them. Of parents with dependent children, the most common diagnosis was schizophrenia (48.2% fathers, 28.9% mothers), and there were high rates of comorbidity with substance abuse/dependence (alcohol: fathers 69.2%, mothers 44.3%; cannabis: fathers 69.22%, mothers 47.8%). A substantial proportion of parents with dependent children experienced challenges including low educational attainment, unemployment, poverty, and social isolation. Although many parents living with dependent children functioned in the average range, a significant proportion was moderately to severely disabled on global independent functioning ratings (fathers 49.1%, mothers 35.7%) and some were identified as having obvious/severe impairments in their ability to care for their child(ren) (fathers 28.3%, mothers 21.3%). CONCLUSIONS: Most parents living with psychosis function well. However, a significant proportion has impairments in parenting and general functioning that could have adverse consequences for both the parent and children. This study brings into focus the need for interventions to optimise successful parenting outcomes. PMID- 22833578 TI - Some facts about alcohol consumption. PMID- 22833579 TI - Drugs of abuse and increased risk of psychosis development. AB - OBJECTIVE: There is considerable evidence to suggest that the abuse of illicit drugs, particularly cannabis and methamphetamine, has aetiological roles in the pathogenesis of psychosis and schizophrenia. Factors that may increase susceptibility to the propsychotic effects of these drugs include the age at which the abuse starts as well as family history of genetic polymorphisms relevant to the pathophysiology of this disorder. However, the neurobiological mechanisms involved in drug abuse-associated psychosis remain largely unclear. METHODS AND RESULTS: This paper presents an overview of the available evidence, including clinical, animal model, and molecular studies, with a focus on brain regions and neurotransmitters systems, such as dopamine and glutamate, previously implicated in psychosis. CONCLUSION: It is clear that further studies are urgently needed to provide a greater insight into the mechanisms that mediate the long-term and neurodevelopmental effects of cannabis and methamphetamine. A dialogue between basic science and clinical research may help to identify at-risk individuals and novel pathways for treatment and prevention. PMID- 22833580 TI - A case of sudden ankle pain. PMID- 22833581 TI - Treating cancer in older people. PMID- 22833582 TI - The dance of death. PMID- 22833583 TI - Commentary: Denmark's health reforms are part of a wider trend. PMID- 22833584 TI - Israel is accused of "blackmailing" patients from Gaza Strip who seek medical care. PMID- 22833585 TI - Surgeon is accused of manipulating data to move his patients up organ waiting list. PMID- 22833586 TI - Schore's regulation theory: maternal-infant interaction in the NICU as a mechanism for reducing the effects of allostatic load on neurodevelopment in premature infants. AB - Premature infants confront numerous physiologic and environmental stressors in the neonatal intensive care unit (NICU) that have the potential to permanently alter their neurodevelopment. Schore's regulation theory postulates that positive maternal-infant interactions can shape the infant's developmental outcomes through inducing mechanistic changes in brain structure and function. The purposes of this article are to explain the regulation of infant neurobiological processes during interactions between mothers and healthy infants in the context of Schore's theory, to identify threats to these processes for premature infants, and to propose principles of clinical practice and areas of research necessary to establish a supportive environment and prevent or reduce maladaptive consequences for these vulnerable infants. A premature birth results in the disruption of neurodevelopment at a critical time. Chronic exposure to stressors related to the NICU environment overwhelms immature physiologic and stress systems, resulting in significant allostatic load, as measured by long-term neurodevelopmental impairments in the premature infant. Positive maternal-infant interactions during NICU hospitalization and beyond have the potential to reduce neurologic deficits and maximize positive neurodevelopmental outcomes in premature infants. The quality of the maternal-infant interaction is affected not only by the infant's developing neurobiology but also by the mother's responses to the stressors surrounding a premature birth and mothering an infant in the NICU environment. Nurses can empower mothers to overcome these stressors, promote sensitive interactions with their infants, and facilitate neurodevelopment. Research is critically needed to develop and test nursing interventions directed at assisting mothers in supporting optimal neurodevelopment for their infants. PMID- 22833587 TI - To examine the effect of China's drunk driving policy, high-quality data are needed. PMID- 22833591 TI - Tissue oxygen saturation measurement in prehospital trauma patients: a pilot, feasibility study. AB - BACKGROUND: This study evaluated the feasibility of prehospital tissue oxygen saturation (StO2) in major trauma patients. METHODS: A prospective, pilot feasibility study carried out in a physician based prehospital trauma service. RESULTS: Prehospital StO2 was recorded on 13 patients. Continuous StO2 monitoring was achieved on all patients, despite intermittent failure of pulse oximetry and non-invasive blood pressure monitoring in six patients. No adverse outcomes of StO2 monitoring were reported. The specific equipment used was reported to be inconveniently bulky and heavy for use in the prehospital setting. CONCLUSIONS: Prehospital measurement and monitoring of StO2 is feasible in trauma patients undergoing prehospital anaesthesia and may be useful in the early identification of shock, triggering of transfusion protocols and guiding fluid resuscitation. PMID- 22833592 TI - Case report: use of topical tranexamic acid to stop localised bleeding. AB - A case is presented in which topical tranexamic acid was used to stop local bleeding from a nipple following piercing in a young man with haemophilia. This case, with a review of the relevant literature, highlights the use of topical tranexamic acid as part of a methodical approach to stop localised, non-massive bleeding, particularly in patients with inherited or acquired coagulopathies. PMID- 22833593 TI - Induction of a shorter compression phase is correlated with a deeper chest compression during metronome-guided cardiopulmonary resuscitation: a manikin study. AB - OBJECTIVES: Recent studies have shown that there may be an interaction between duty cycle and other factors related to the quality of chest compression. Duty cycle represents the fraction of compression phase. We aimed to investigate the effect of shorter compression phase on average chest compression depth during metronome-guided cardiopulmonary resuscitation. METHODS: Senior medical students performed 12 sets of chest compressions following the guiding sounds, with three down-stroke patterns (normal, fast and very fast) and four rates (80, 100, 120 and 140 compressions/min) in random sequence. Repeated-measures analysis of variance was used to compare the average chest compression depth and duty cycle among the trials. RESULTS: The average chest compression depth increased and the duty cycle decreased in a linear fashion as the down-stroke pattern shifted from normal to very fast (p<0.001 for both). Linear increase of average chest compression depth following the increase of the rate of chest compression was observed only with normal down-stroke pattern (p=0.004). CONCLUSIONS: Induction of a shorter compression phase is correlated with a deeper chest compression during metronome-guided cardiopulmonary resuscitation. PMID- 22833594 TI - How reliable and safe is full-body low-dose radiography (LODOX Statscan) in detecting foreign bodies ingested by adults? AB - OBJECTIVE: Foreign body ingestion is common and potentially lethal. This study evaluates the use of low-dose Statscans (LODOX) in emergency departments. DESIGN: This comparative cross-sectional study retrospectively assessed 28289 digital chest x-rays and 2301 LODOX scans performed between 2006 and 2010 at a tertiary emergency centre. The radiographic appearance, image quality and location of ingested foreign bodies were evaluated in standard digital chest and LODOX radiography. The mean irradiation (MUSv) and cumulative mean radiation dose per patient with the ingested foreign body were calculated according to literature based data, together with the sensitivity and specificity for each modality. RESULTS: A total of 62 foreign bodies were detected in 39 patients, of whom 19 were investigated with LODOX and 20 with conventional digital chest radiography. Thirty-three foreign bodies were located in the two upper abdominal quadrants, 21 in the lower quadrants-which are not visible on conventional digital chest radiography-seven in the oesophagus and one in the bronchial system. The sensitivity and specificity of digital chest radiography were 44.4% and 94.1%, respectively, and for the LODOX Statscan 90% and 100%, respectively. The calculated mean radiation dose for LODOX investigations was 184 MUS, compared with 524 MUS for digital chest radiography. CONCLUSIONS: LODOX Statscan is superior to digital chest radiography in the diagnostic work-up of ingested foreign bodies because it makes it possible to enlarge the field of view to the entire body, has higher sensitivity and specificity, and reduces the radiation dose by 65%. PMID- 22833595 TI - Transport with ongoing resuscitation: a comparison between manual and mechanical compression. AB - AIM: In special circumstances it may be necessary to transport out-of-hospital cardiac arrest patients with ongoing resuscitation to the hospital. External mechanical chest compression devices could be an alternative for these resuscitations. The study compares manual chest compression with external mechanical devices and a semiautomatic device in transport conditions using a resuscitation manikin. METHODS: Manual chest compressions were compared with LUCAS 2, AutoPulse and animax mono devices using the Ambu Man Wireless MegaCode manikin (10 series each). The measurements were performed in a standard ambulance vehicle during transport on a predefined track of 5.0 km. RESULTS: Mean compression frequencies in the manual group (117 +/- 18 min(-1)) and in the animax mono group (115 +/- 10 min(-1)) were significantly higher than in the LUCAS 2 group (100 min(-1), p=0.02) and the AutoPulse group (80 min(-1), p<0.01). Both mechanical devices worked absolutely constantly. Only the animax mono group reached with 51.2 mm the recommended compression depth. The quality of manual compressions decreased considerably during braking or change manoeuvres while the mechanical devices continued to work constantly. CONCLUSIONS: During a patient transport with ongoing resuscitation, external mechanical compression devices may be a good alternative to manual compression because they increase the safety of the rescuer and patient. Yet, in this study only animax mono reached the guideline specifications regarding chest compressions' frequency and depth. Concerning constancy, the mechanical devices work reliably and more independently from motion influences. Further studies are necessary to evaluate the effectiveness of these devices in patient transport. PMID- 22833596 TI - Delirium within the emergency care setting, occurrence and detection: a systematic review. AB - Recent recommendations from the Society for Academic Emergency Medicine and the American College of Emergency Physicians identified the detection of delirium in the emergency department (ED) as a 'high yield' research objective. This review aimed to determine the occurrence rate, and physician detection rates, of delirium within the ED. A systematic literature review was conducted and identified using online databases. Prospective cohort and cross-sectional studies from hospital EDs were interrogated. Systematic data extraction and assessments of quality were carried out. Searching yielded 723 publications, and 13 papers met inclusion criteria. Occurrence of delirium at admission to the ED ranged from 7% to 20% of patients. Physician diagnosis rates of preconfirmed delirium (using a specified tool) within the ED varied between 11.1% and 46.0%. Many studies used non-validated assessment tools to gather data. Four delirium outcome studies were conducted in the ED setting. Results vary, with several being of poor quality; however, delirium at ED presentation may have a significant effect on long-term outcomes. Delirium is a significant concern in the ED, with many delirious patients not identified by physicians. Given the scale, addressing delirium should be a priority for clinicians and researchers. To improve delirium outcomes and hospital management, measures must include mechanisms to improve detection. Finding a single validated assessment method and facilitating research in this difficult patient population would be an important progress. PMID- 22833597 TI - Patterns of abdominal injury in 37 387 disaster patients from the Wenchuan earthquake. AB - OBJECTIVES: Due to lack of sufficient data it is difficult to understand fully the pattern of abdominal injury after an earthquake. This study aimed to evaluate the pattern of abdominal injury by analysing the data of trauma patients with abdominal injury incurred during the 2008 Wenchuan earthquake. METHODS: We retrospectively reviewed the medical records of 37387 inpatients. Among them, 883 (2.36%) cases of abdominal injury were deemed eligible and enrolled for analysis. The data analysed included demographics, category of abdominal injury, associated injury type, cause of injury, treatment and clinical outcome, as well as risk factors for death. RESULTS: Abdominal injury was often accompanied with multiple injuries. Injury of the abdominal wall was the most frequent type of earthquake related abdominal injury (32%). The spleen was the most commonly injured abdominal organ (18%). Of the 883 patients evaluated, 221 cases received operations and 41 cases died. The highest death rate was found in patients with haemorrhagic shock (28/41, 68.3%) caused by intra-abdominal bleeding. CONCLUSIONS: Abdominal injuries are relatively uncommon in earthquake disasters and often present with associated injuries. A timely and complete diagnosis of both abdominal as well as associated injuries is of primary importance in the treatment of patients with abdominal injuries. Knowledge of different types of abdominal injury, and their relative proportions, prevalence of associated injuries, risk factors and final clinical outcomes observed in this study may be of valuable reference in dealing with major earthquake events in the future. PMID- 22833598 TI - Aspirin administration by emergency medical dispatchers using a protocol-driven aspirin diagnostic and instruction tool. AB - BACKGROUND: The American College of Cardiology and the American Heart Association recommend early aspirin administration to patients with symptoms of acute coronary syndrome (ACS)/acute myocardial infarction (AMI). The primary objective of this study was to determine if Emergency Medical Dispatchers (EMD) can provide chest pain/heart attack patients with standardised instructions effectively, using an aspirin diagnostic and instruction tool (ADxT) within the Medical Priority Dispatch System (MPDS) before arrival of an emergency response crew. METHODS: This retrospective study involved three dispatch centres in the UK and USA. We analysed 6 months of data involving chest pain/heart attack symptoms taken using the MPDS chest pain and heart problems/automated internal cardiac defibrillator protocols. RESULTS: The EMDs successfully completed the ADxT on 69.8% of the 44141 cases analysed. The patient's mean age was higher when the ADxT was completed, than when it was not (mean +/- SD: 53.9 +/- 19.9 and 49.9 +/- 20.2; p<0.001, respectively). The ADxT completion rate was higher for second party than first-party calls (70.3% and 69.0%; p=0.024, respectively). A higher percentage of male than female patients took aspirin (91.3% and 88.9%; p=0.001, respectively). Patients who took aspirin were significantly younger than those who did not (mean +/- SD: 61.8 +/- 17.5 and 64.7 +/- 17.9, respectively). Unavailability of aspirin was the major reason (44.4%) why eligible patients did not take aspirin when advised. CONCLUSIONS: EMDs, using a standardised protocol, can enable early aspirin therapy to treat potential ACS/AMI prior to responders' arrival. Further research is required to assess reasons for not using the protocol, and the significance of the various associations discovered. PMID- 22833599 TI - The usefulness of rapid point-of-care creatinine testing for the prevention of contrast-induced nephropathy in the emergency department. AB - BACKGROUND: Renal dysfunction is the most important factor to consider when predicting a patient's risk of developing contrast-induced nephropathy (CIN). Measurement of creatinine (Cr) via rapid point-of-care blood urea nitrogen/creatinine testing (POCT-BUN/Cr) to determine CIN risk could potentially reduce the time required to achieve an accurate diagnosis and to initiate and complete treatment in the emergency department (ED). The aim of our study was to compare the results of POCT-BUN/Cr and reference laboratory tests for BUN and serum Cr. MATERIALS AND METHODS: A retrospective analysis of suspected stroke patients who presented between November 2009 and November 2010, and had BUN and Cr levels measured by POCT-BUN/Cr, and the reference laboratory tests performed with the blood sample which was transferred to the central laboratory by an air shoot system. Two assays were conducted on the whole blood (POCT) and serum (reference) by trained technicians. The time interval from arrival at the ED to reporting of the results was assessed for both assays via a computerised physician order entry system. RESULTS: The mean standard deviation (SD) interval from arrival at the ED to reporting of the results was 11.4 (4.9) min for POCT BUN/Cr and 46.8 (38.5) min for the serum reference laboratory tests (p<0.001). Intra-class correlation coefficient (ICC) analysis demonstrated a high level of agreement (the consistency agreement) between POCT and the serum reference tests for both BUN (ICC=0.914) and Cr (ICC=0.980). CONCLUSIONS: This study suggests that POCT-BUN/Cr results correlate well with those of serum reference tests in terms of BUN and Cr levels and, in turn, predicting CIN. POCT-BUN/Cr is easily performed with a rapid turnaround time, suggesting its use in the ED may have substantial clinical benefit. PMID- 22833600 TI - Isolated analysis of one time measure: only seeing part of the picture. PMID- 22833601 TI - Optimal position for external chest compression during cardiopulmonary resuscitation: an analysis based on chest CT in patients resuscitated from cardiac arrest. AB - OBJECTIVES: This study was conducted to determine the proper hand position on the sternum for external chest compression to generate a maximal haemodynamic effect during cardiopulmonary resuscitation (CPR). METHODS: 114 patients with cardiac arrest who underwent chest CT after successful resuscitation from January 2006 to August 2009 were included in the study. To evaluate the area of the cardiac chambers subjected to external chest compression, the area of each cardiac chamber under the sternum was measured using cross-sectional CT at three different locations: the internipple line on the sternum (point A), halfway between point A and the sternoxiphoid junction (point B) and at the sternoxiphoid junction (point C). RESULTS: The widest total heart area, total ventricular area and left ventricular area (LVA) were observed most frequently at point C (58%, 85% and 78% of all cases, respectively). Few cases (six in total heart area, one in total ventricular area and one in LVA) were observed as the widest at point A. Predicted compressed areas of the right and left ventricle were wider at point C than at points A or B (right ventricular area: 366+/-536 mm(2) at point A, 961+/ 653 mm(2) at point B and 1383+/-689 mm(2) at point C, p<0.001; LVA: 65+/-236 mm(2) at point A, 365+/-506 mm(2) at point B and 1099+/-817 mm(2) at point C, p<0.001). CONCLUSIONS: Only a small proportion of the ventricle is subjected to external chest compression when CPR is performed according to the current guidelines. Compression of the sternum at the sternoxiphoid junction might be more effective to compress the ventricles. PMID- 22833602 TI - Pneumorrhachis from a thrown knife. PMID- 22833603 TI - Overdiagnosis and mistreatment of malaria among febrile patients at primary healthcare level in Afghanistan: observational study. AB - OBJECTIVE: To assess the accuracy of malaria diagnosis and treatment at primary level clinics in Afghanistan. DESIGN: Prospective observational study. SETTING: 22 clinics in two Afghan provinces, one in the north (adjoining Tajikistan) and one in the east (adjoining Pakistan); areas with seasonal transmission of Plasmodium vivax and Plasmodium falciparum. PARTICIPANTS: 2357 patients of all ages enrolled if clinicians suspected malaria. INTERVENTIONS: Established (>5 years) microscopy (12 clinics in east Afghanistan), newly established microscopy (five clinics in north Afghanistan), and no laboratory (five clinics in north Afghanistan). All clinics used the national malaria treatment guidelines. MAIN OUTCOME MEASURES: Proportion of patients positive and negative for malaria who received a malaria drug; sensitivity and specificity of clinic based diagnosis; prescriber's response to the result of the clinic slide; and proportion of patients positive and negative for malaria who were prescribed antibiotics. Outcomes were measured against a double read reference blood slide. RESULTS: In health centres using clinical diagnosis, although 413 of 414 patients were negative by the reference slide, 412 (99%) received a malaria drug and 47 (11%) received an antibiotic. In clinics using new microscopy, 37% (75/202) of patients who were negative by the reference slide received a malaria drug and 60% (103/202) received an antibiotic. In clinics using established microscopy, 50.8% (645/1269) of patients who were negative by the reference slide received a malaria drug and 27.0% (342/1269) received an antibiotic. Among the patients who tested positive for malaria, 94% (443/472) correctly received a malaria drug but only 1 of 6 cases of falciparum malaria was detected and appropriately treated. The specificity of established and new microscopy was 72.9% and 79.9%, respectively. In response to negative clinic slide results, malaria drugs were prescribed to 270/905 (28.8%) and 32/154 (21%) and antibiotics to 347/930 (37.3%) and 99/154 (64%) patients in established and new microscopy arms, respectively. Nurses were less likely to misprescribe than doctors. CONCLUSIONS: Despite a much lower incidence of malaria in Afghanistan than in Africa, fever was substantially misdiagnosed as malaria in this south Asian setting. Inaccuracy was attributable to false positive laboratory diagnoses of malaria and the clinicians' disregard of negative slide results. Rare but potentially fatal cases of falciparum malaria were not detected, emphasising the potential role of rapid diagnostic tests. Microscopy increased the proportion of patients treated with antibiotics producing a trade-off between overtreatment with malaria drugs and probable overtreatment with antibiotics. PMID- 22833604 TI - Use of risk assessment instruments to predict violence and antisocial behaviour in 73 samples involving 24 827 people: systematic review and meta-analysis. AB - OBJECTIVE: To investigate the predictive validity of tools commonly used to assess the risk of violence, sexual, and criminal behaviour. DESIGN: Systematic review and tabular meta-analysis of replication studies following PRISMA guidelines. DATA SOURCES: PsycINFO, Embase, Medline, and United States Criminal Justice Reference Service Abstracts. REVIEW METHODS: We included replication studies from 1 January 1995 to 1 January 2011 if they provided contingency data for the offending outcome that the tools were designed to predict. We calculated the diagnostic odds ratio, sensitivity, specificity, area under the curve, positive predictive value, negative predictive value, the number needed to detain to prevent one offence, as well as a novel performance indicator-the number safely discharged. We investigated potential sources of heterogeneity using metaregression and subgroup analyses. RESULTS: Risk assessments were conducted on 73 samples comprising 24,847 participants from 13 countries, of whom 5879 (23.7%) offended over an average of 49.6 months. When used to predict violent offending, risk assessment tools produced low to moderate positive predictive values (median 41%, interquartile range 27-60%) and higher negative predictive values (91%, 81 95%), and a corresponding median number needed to detain of 2 (2-4) and number safely discharged of 10 (4-18). Instruments designed to predict violent offending performed better than those aimed at predicting sexual or general crime. CONCLUSIONS: Although risk assessment tools are widely used in clinical and criminal justice settings, their predictive accuracy varies depending on how they are used. They seem to identify low risk individuals with high levels of accuracy, but their use as sole determinants of detention, sentencing, and release is not supported by the current evidence. Further research is needed to examine their contribution to treatment and management. PMID- 22833605 TI - Cutaneous melanoma attributable to sunbed use: systematic review and meta analysis. AB - OBJECTIVE: To estimate the burden of melanoma resulting from sunbed use in western Europe. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, ISI Web of Science (Science Citation Index Expanded), Embase, Pascal, Cochrane Library, LILACS, and MedCarib, along with published surveys reporting prevalence of sunbed use at national level in Europe. STUDY SELECTION: Observational studies reporting a measure of risk for skin cancer (cutaneous melanoma, squamous cell carcinoma, basal cell carcinoma) associated with ever use of sunbeds. RESULTS: Based on 27 studies ever use of sunbeds was associated with a summary relative risk of 1.20 (95% confidence interval 1.08 to 1.34). Publication bias was not evident. Restricting the analysis to cohorts and population based studies, the summary relative risk was 1.25 (1.09 to 1.43). Calculations for dose-response showed a 1.8% (95% confidence interval 0% to 3.8%) increase in risk of melanoma for each additional session of sunbed use per year. Based on 13 informative studies, first use of sunbeds before age 35 years was associated with a summary relative risk of 1.87 (1.41 to 2.48), with no indication of heterogeneity between studies. By using prevalence data from surveys and data from GLOBOCAN 2008, in 2008 in the 15 original member countries of the European Community plus three countries that were members of the European Free Trade Association, an estimated 3438 cases of melanoma could be attributable to sunbed use, most (n=2341) occurring among women. CONCLUSIONS: Sunbed use is associated with a significant increase in risk of melanoma. This risk increases with number of sunbed sessions and with initial usage at a young age (<35 years). The cancerous damage associated with sunbed use is substantial and could be avoided by strict regulations. PMID- 22833606 TI - RTL-P: a sensitive approach for detecting sites of 2'-O-methylation in RNA molecules. AB - 2'-O-methylation is present within various cellular RNAs and is essential to RNA biogenesis and functionality. Several methods have been developed for the identification and localization of 2'-O-methylated sites in RNAs; however, the detection of RNA modifications, especially in low-abundance RNAs and small non coding RNAs with a 2'-O-methylation at the 3'-end, remains a difficult task. Here, we introduce a new method to detect 2'-O-methylated sites in diverse RNA species, referred to as RTL-P [Reverse Transcription at Low deoxy-ribonucleoside triphosphate (dNTP) concentrations followed by polymerase chain reaction (PCR)] that demonstrates precise mapping and superior sensitivity compared with previous techniques. The main procedures of RTL-P include a site-specific primer extension by reverse transcriptase at a low dNTP concentration and a semi-quantitative PCR amplification step. No radiolabeled or fluorescent primers are required. By designing specific RT primers, we used RTL-P to detect both previously identified and novel 2'-O-methylated sites in human and yeast ribosomal RNAs (rRNAs), as well as mouse piwi-interacting RNAs (piRNAs). These results demonstrate the powerful application of RTL-P for the systematic analysis of fully or partially methylated residues in diverse RNA species, including low-abundance RNAs or small non-coding RNAs such as piRNAs and microRNAs (miRNAs). PMID- 22833607 TI - Residues of E. coli topoisomerase I conserved for interaction with a specific cytosine base to facilitate DNA cleavage. AB - Bacterial and archaeal topoisomerase I display selectivity for a cytosine base 4 nt upstream from the DNA cleavage site. Recently, the solved crystal structure of Escherichia coli topoisomerase I covalently linked to a single-stranded oligonucleotide revealed that R169 and R173 interact with the cytosine base at the -4 position via hydrogen bonds while the phenol ring of Y177 wedges between the bases at the -4 and the -5 position. Substituting R169 to alanine changed the selectivity of the enzyme for the base at the -4 position from a cytosine to an adenine. The R173A mutant displayed similar sequence selectivity as the wild-type enzyme, but weaker cleavage and relaxation activity. Mutation of Y177 to serine or alanine rendered the enzyme inactive. Although mutation of each of these residues led to different outcomes, R169, R173 and Y177 work together to interact with a cytosine base at the -4 position to facilitate DNA cleavage. These strictly conserved residues might act after initial substrate binding as a Molecular Ruler to form a protein-DNA complex with the scissile phosphate positioned at the active site for optimal DNA cleavage by the tyrosine hydroxyl nucleophile to facilitate DNA cleavage in the reaction pathway. PMID- 22833608 TI - Regulatory consequences of gene translocation in bacteria. AB - Gene translocations play an important role in the plasticity and evolution of bacterial genomes. In this study, we investigated the impact on gene regulation of three genome organizational features that can be altered by translocations: (i) chromosome position; (ii) gene orientation; and (iii) the distance between a target gene and its transcription factor gene ('target-TF distance'). Specifically, we quantified the effect of these features on constitutive expression, transcription factor binding and/or gene expression noise using a synthetic network in Escherichia coli composed of a transcription factor (LacI repressor) and its target gene (yfp). Here we show that gene regulation is generally robust to changes in chromosome position, gene orientation and target TF distance. The only demonstrable effect was that chromosome position alters constitutive expression, due to changes in gene copy number and local sequence effects, and that this determines maximum and minimum expression levels. The results were incorporated into a mathematical model which was used to quantitatively predict the responses of a simple gene network to gene translocations; the predictions were confirmed experimentally. In summary, gene translocation can modulate constitutive gene expression levels due to changes in chromosome position but it has minimal impact on other facets of gene regulation. PMID- 22833609 TI - Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti. AB - We have sequenced the genome of the emerging human pathogen Babesia microti and compared it with that of other protozoa. B. microti has the smallest nuclear genome among all Apicomplexan parasites sequenced to date with three chromosomes encoding ~3500 polypeptides, several of which are species specific. Genome-wide phylogenetic analyses indicate that B. microti is significantly distant from all species of Babesidae and Theileridae and defines a new clade in the phylum Apicomplexa. Furthermore, unlike all other Apicomplexa, its mitochondrial genome is circular. Genome-scale reconstruction of functional networks revealed that B. microti has the minimal metabolic requirement for intraerythrocytic protozoan parasitism. B. microti multigene families differ from those of other protozoa in both the copy number and organization. Two lateral transfer events with significant metabolic implications occurred during the evolution of this parasite. The genomic sequencing of B. microti identified several targets suitable for the development of diagnostic assays and novel therapies for human babesiosis. PMID- 22833612 TI - Results of a 2-year retrospective cohort study of newly prescribed triptan users in European nationwide practice databases. AB - OBJECTIVE: This study was conducted to characterize prescription refill patterns for triptans among European patients with new prescriptions of triptans. BACKGROUND: Persistency with prescriptions of triptan monotherapy for migraine headache among newly prescribed users in European primary-care practices has not been well described. METHODS: Using electronic medical databases in the UK (N = 3618), France (N = 2051) and Germany (N = 954), we conducted a retrospective cohort analysis to identify refill patterns over 2 years among migraineurs receiving new prescriptions of triptan monotherapy in 2006. RESULTS: Of all patients, >33% of migraineurs with new triptan prescriptions received >=1 refill of their index triptan prescriptions (UK, 44.3%; France, 34.2%; Germany, 37.7%). More than 50% never received index-triptan refill prescriptions (UK, 55.7%; France, 65.8%; Germany, 63.3%). Small proportions of patients (<7.0%) switched to alternative triptans, and even fewer switched to different prescription medication classes (UK and Germany, 2.3%; France, 4.0%). More than 48% of patients received no further prescriptions for migraine after index prescriptions (UK, 48.5%; France, 54.9%; Germany, 54.7%). After the second year, >83.0% of patients in each country had no further prescriptions for migraine medications, <14.0% remained persistent with index prescriptions, <4.0% switched to other triptans, and <3.0% switched to alternative medication classes. CONCLUSIONS: In migraine patients who received new prescriptions of triptan monotherapy from their primary-care physicians, poor triptan prescription refill frequency was observed in Europe. Although consistent with potential clinical challenges in migraine management, our findings should be interpreted with caution given certain inherent limitations associated with the database study design. Further research is warranted to confirm our findings and to identify reasons for, or predictors of, triptan discontinuation. PMID- 22833610 TI - NF45 dimerizes with NF90, Zfr and SPNR via a conserved domain that has a nucleotidyltransferase fold. AB - Nuclear factors NF90 and NF45 form a complex involved in a variety of cellular processes and are thought to affect gene expression both at the transcriptional and translational level. In addition, this complex affects the replication of several viruses through direct interactions with viral RNA. NF90 and NF45 dimerize through their common 'DZF' domain (domain associated with zinc fingers). NF90 has additional double-stranded RNA-binding domains that likely mediate its association with target RNAs. We present the crystal structure of the NF90/NF45 dimerization complex at 1.9-A resolution. The DZF domain shows structural similarity to the template-free nucleotidyltransferase family of RNA modifying enzymes. However, both NF90 and NF45 have lost critical catalytic residues during evolution and are therefore not functional enzymes. Residues on NF90 that make up its interface with NF45 are conserved in two related proteins, spermatid perinuclear RNA-binding protein (SPNR) and zinc-finger RNA-binding protein (Zfr). Using a co-immunoprecipitation assay and site-specific mutants, we demonstrate that NF45 is also able to recognize SPNR and Zfr through the same binding interface, revealing that NF45 is able to form a variety of cellular complexes with other DZF-domain proteins. PMID- 22833611 TI - The CR3 motif of Rrp44p is important for interaction with the core exosome and exosome function. AB - The 10-subunit RNA exosome is involved in a large number of diverse RNA processing and degradation events in eukaryotes. These reactions are carried out by the single catalytic subunit, Rrp44p/Dis3p, which is composed of three parts that are conserved throughout eukaryotes. The exosome is named for the 3' to 5' exoribonuclease activity provided by a large C-terminal region of the Rrp44p subunit that resembles other exoribonucleases. Rrp44p also contains an endoribonuclease domain. Finally, the very N-terminus of Rrp44p contains three Cys residues (CR3 motif) that are conserved in many eukaryotes but have no known function. These three conserved Cys residues cluster with a previously unrecognized conserved His residue in what resembles a metal-ion-binding site. Genetic and biochemical data show that this CR3 motif affects both endo- and exonuclease activity in vivo and both the nuclear and cytoplasmic exosome, as well as the ability of Rrp44p to associate with the other exosome subunits. These data provide the first direct evidence that the exosome-Rrp44p interaction is functionally important and also provides a molecular explanation for the functional defects when the conserved Cys residues are mutated. PMID- 22833613 TI - Influence of sex, estrous cycle, and estrogen on intracranial dural mast cells. AB - BACKGROUND: The frequency of migraine headaches is higher in women than in men and in susceptible women attacks are related to changes in ovarian hormone levels. Intracranial mast cells (MCs) are likely to have a role in migraine headache genesis, and changes in the dural MC population might influence headache susceptibility. The present study thus tested the hypothesis that sex and ovarian hormones influence the density and phenotypic makeup of dural MCs. METHODS: Histochemistry combined with quantitative analyses was used to investigate sex differences, estrous cycle and ovarian hormones on dural MC density, phenotype and degranulation level in male and female rats. RESULTS: Our data show that in female rats, dural MC density fluctuates during the estrous cycle and is overall higher than in males. In ovariectomized rats, estradiol, but not progesterone, promoted an increase in dural MC density. This effect was abolished by a splenectomy, suggesting estrogen-related recruitment of MCs from the spleen. Finally, our data suggest that the phenotypic make up of dural MCs, which represents the level of cellular maturity, is also governed by changes in estrogen levels. CONCLUSIONS: Given the potential role of dural MCs in triggering headache, our data suggest that estrogen-related modulation of dural MC density and phenotypic makeup could have a role in mediating the higher frequency and severity of headaches such as migraine, in women. PMID- 22833615 TI - Polio vaccination worker is shot and killed in Pakistan. PMID- 22833616 TI - The value of open-ended questions in surveys on patient experience: number of comments and perceived usefulness from a hospital perspective. AB - OBJECTIVE: To analyse the patients' inclination to comment in generic patient surveys, and to evaluate how these comments were received and used for quality improvement by the hospitals. DESIGN: The study is based on quantitative and qualitative data from four rounds of patient satisfaction surveys from 1999 to 2006. The open-ended questions and their applicability were evaluated by hospital and department management teams in a survey and by hospital employees and leaders, in semi-structured interviews. SETTING: Eight public hospitals in a Danish county (amt). PARTICIPANTS: In this study, the participants were 75 769 patients, 173 department/hospital management teams, and 24 hospital employees and leaders. INTERVENTIONS: Questionnaires with open-ended questions to patients and hospital/department management teams. Semi-structured interviews with hospital employees and leaders. Main outcome measure The number of comments from patients and the usefulness of the comments as perceived by employees and leaders. RESULTS: A total of 76% of the patients chose to add one or more comments to their questionnaires. The patients' inclination to comment increased over time. The patient's inclination to comment was highest for the most and the least satisfied patients. The comment-gathering was viewed as 'Very useful' or 'Useful' by 80.7% of the department management teams (31 responses). CONCLUSION: To gather comments and to forward these to small organizational entities seems to make patient satisfaction measurements more informative and patient-centred. The wording of the open-ended questions, the number of questions and an appeal in the cover letter appear to be important in relation to the patient's inclination to comment. PMID- 22833614 TI - Acute heart failure patient profiles, management and in-hospital outcome: results of the Italian Registry on Heart Failure Outcome. AB - AIMS: Registries and surveys improve knowledge of the 'real world'. This paper aims to describe baseline clinical profiles, management strategies, and the in hospital outcome of patients admitted to hospital for an acute heart failure (AHF) episode. METHODS AND RESULTS: IN-HF Outcome is a nationwide, prospective, multicentre, observational study conducted in 61 Cardiology Centres in Italy. Up to December 2009, 5610 patients had been enrolled, 1855 (33%) with AHF and 3755 (67%) with chronic heart failure (CHF). Baseline and in-hospital outcome data of AHF patients are presented. Mean age was 72 +/- 12 years, and 39.8% were female. Hospital admission was due to new-onset heart failure (HF) in 43% of cases. Co morbid conditions were observed more frequently in the worsening HF group, while those with de novo HF showed a higher heart rate, blood pressure, and more preserved left ventricular ejection fraction (LVEF). Electrical devices were previously implanted in 13.3% of the entire group. Inotropes were administered in 19.4% of the patients. The median duration of hospital stay was 10 days (interquartile range 7-15). All-cause in-hospital death was 6.4%, similar in worsening and de novo HF. Older age, hypotension, cardiogenic shock, pulmonary oedema, symptoms of hypoperfusion, hyponatraemia, and elevated creatinine were independent predictors of all-cause death. CONCLUSION: Our registry confirms that in-hospital mortality in AHF is still high, with a long length of stay. Pharmacological treatment seems to be practically unchanged in the last decades, and the adherence to HF guidelines concerning implantable cardioverter defibrillators/cardiac resynchronization therapy is still very low. Some AHF phenotypes are characterized by worst prognosis and need specific research projects. PMID- 22833617 TI - Quality in practice: implementation of hospital guidelines for patient identification in Malawi. AB - QUALITY PROBLEM OR ISSUE: Patient identification in a teaching hospital in Malawi. Initial assessment 34% of hospital staff recalled a misidentification event in the preceding year; less than 10% of staff described the use of unique patient identifiers other than name when taking blood samples and 98% of laboratory requests included no identifiers other than name. CHOICE OF SOLUTION: Hospital identification guidelines based on WHO guidelines to introduce identification wristbands; encourage routine use of an identifier in addition to name on laboratory requests and improve bedside identification procedures. IMPLEMENTATION: Provision of wristbands, educational materials, workshops and distribution of written materials to promote the new guidelines with regular monitoring. EVALUATION: At 5 months 65% of in-patients wore wristbands compliant with WHO identification guidelines and 55% of cross-match forms used a second identifier. Only 10% of non-cross-match forms had a second identifier. The use of recommended bedside identification procedures was rarely observed. Guidelines were welcomed by both staff and patients; identification wristbands were found useful in difficult identification situations. Lack of time, staffing and unimportance of procedures were given as reasons for not following guidelines. LESSONS LEARNED: Identification procedures can be rapidly introduced in a developing world context in a manner acceptable to patients and staff. Tangible tools such as wristbands appeared easier to implement than changing practice by education. Recommendations for wider implementation include increased engagement of patients in addition to healthcare and management staff; use of rejection criteria for inadequately labeled samples; generating further evidence about the prevalence, type and consequences of patient misidentification events. PMID- 22833618 TI - Screening for colorectal cancer and advanced colorectal neoplasia in kidney transplant recipients: cross sectional prevalence and diagnostic accuracy study of faecal immunochemical testing for haemoglobin and colonoscopy. AB - OBJECTIVE: To investigate whether screening kidney transplant recipients aged over 50 years for colorectal cancer with a faecal immunochemical test for haemoglobin might be justified, by determining the prevalence of advanced colorectal neoplasia and evaluating the diagnostic accuracy of faecal haemoglobin testing compared with colonoscopy in a population of kidney transplant recipients at otherwise average risk. DESIGN: Cross sectional prevalence and diagnostic accuracy study with index test of faecal haemoglobin and reference standard of colonoscopy. SETTING: Outpatient clinics in metropolitan and regional hospitals in South Australia. PARTICIPANTS: 229 kidney transplant recipients aged 50 years and over, who were at least 6 months (mean 9.0 (SD 8.4) years) post-transplant and otherwise at average risk of colorectal cancer, completed the study between June 2008 and October 2011. INTERVENTIONS: Faecal immunochemical testing (Enterix Insure) for human haemoglobin, followed by colonoscopy with histological evaluation of retrieved samples. MAIN OUTCOME MEASURES: Prevalence of advanced colorectal neoplasia, defined as an adenoma at least 10 mm in diameter, villous features, high grade dysplasia, or colorectal cancer; sensitivity, specificity, and predictive values of faecal haemoglobin testing for advanced neoplasia compared with colonoscopy. RESULTS: Advanced colorectal neoplasia was found in 29 (13%, 95% confidence interval 9% to 18%) participants, including 2% (n=4) with high grade dysplasia and 2% (n=5) with colorectal cancer. Faecal testing for haemoglobin was positive in 12% (n=28); sensitivity, specificity, and positive and negative predictive values for advanced neoplasia were 31.0% (15.3% to 50.8%), 90.5% (85.6% to 94.2%), 32.1% (15.9% to 52.4%), and 90.1% (85.1% to 93.8%). Colonoscopy was well tolerated, with no significant adverse outcomes. To identify one case of advanced neoplasia, 8 (6 to 12) colonoscopies were needed. CONCLUSIONS: Kidney transplant recipients aged over 50 years have a high prevalence of advanced colorectal neoplasia. Faecal haemoglobin screening for colorectal neoplasia has similar performance characteristics in transplant recipients to those reported in general population studies, with poor sensitivity but reasonable specificity. Surveillance colonoscopy might be a more appropriate approach in this population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12608000154303. PMID- 22833619 TI - Serum hepcidin-25 levels predict the progression of renal anemia in patients with non-dialysis chronic kidney disease. AB - BACKGROUND: Hepcidin is associated with iron-restricted erythropoiesis. A previous cross-sectional study showed that serum hepcidin-25 levels are negatively associated with the hemoglobin concentration in non-dialysis chronic kidney disease (CKD) patients with sufficient iron stores. This longitudinal study aimed at ascertaining the association between hepcidin-25 levels and the progression of renal anemia. METHODS: We selected 335 non-dialysis CKD patients who showed hemoglobin concentrations >10 g/dL and who were not receiving erythropoiesis-stimulating agent (ESA) therapy, from among the subjects of our previous study, who had been recruited between February and June 2007 in a previous study. The primary outcome was the start of the ESA therapy or hemoglobin concentrations remaining below 10 g/dL for >3 months, by 31 December 2010. The patients were classified into high- and low-ferritin groups depending on their median ferritin levels. The Cox proportional hazard model with restricted cubic spline curve analysis was used to determine the association between hepcidin-25 levels and the outcome for each group. RESULTS: The hepcidin 25 level was a significant predictor both for the high-ferritin group (P = 0.04, linearity = 0.02) and for the low-ferritin group (P = 0.04, linearity P = 0.02). The spline curve for the high-ferritin group showed that higher hepcidin-25 levels had a high log-relative hazard. CONCLUSIONS: Higher hepcidin-25 levels predict the progression of anemia in non-dialysis CKD patients with sufficient iron stores, indicating the involvement of hepcidin in the progression of anemia in non-dialysis CKD patients. PMID- 22833620 TI - Instrumental variable analysis. AB - The main advantage of the randomized controlled trial (RCT) is the random assignment of treatment that prevents selection by prognosis. Nevertheless, only few RCTs can be performed given their high cost and the difficulties in conducting such studies. Therefore, several analytical methods for removing the effects of selection bias in observational studies have been proposed. The first aim of this paper is to compare three of those methods: the multivariable risk adjustment method, the propensity score risk adjustment method, and the instrumental variable method. The second aim is to compare the results from observational studies using the instrumental variable method with those from RCTs aiming to answer the same study question. PMID- 22833621 TI - Increased prevalence of acute interstitial nephritis: more disease or simply more detection? PMID- 22833622 TI - Circulating cell-free DNA in hemodialysis patients predicts mortality. AB - BACKGROUND: Circulating cell-free DNA (CFD) appears following cell damage and DNA release, and increases in hemodialysis (HD) patients particularly following HD. We hypothesized that CFD is an integrative marker of tissue damage and can be an independent predictor for all-cause mortality in HD patients. METHODS: In a prospective study, CFD levels before and after HD were evaluated in 31 chronic HD patients with no acute disease, using the reported rapid non-cumbersome inexpensive fluorometric assay developed in our laboratory. Follow-up levels were assessed at 18 months in 22 patients. All-cause mortality was a primary endpoint. RESULTS: During 42 months of follow-up, 13 of the 31 (41.9%) patients died. The decedents were older than the survivors (mean age 69.9 versus 61.5 years, P = 0.06), but did not differ in end-stage renal disease (ESRD) duration, gender, albumin and hemoglobin, diabetes mellitus and weight. Post-dialysis CFD levels were significantly lower in survivors (median 688 versus 880 ng/mL, P = 0.01). The sensitivity and specificity of CFD levels of 850 ng/mL to predict 42 months (3.5 years) mortality were 73 and 75%, respectively, and the area under the receiver-operating characteristic curve was 0.77 [95% confidence interval (CI) 0.60-0.94]. The Cox proportional hazard regression model showed that CFD higher than 850 ng/mL adjusted for age, ESRD duration, weight and creatinine (stepwise model) was highly predictive of all-cause death with a hazard ratio of 8.0 (95% CI 2.3-28.5, P = 0.001). CONCLUSIONS: Post-dialysis CFD level is an independent predictor of all-cause mortality in patients undergoing HD. We propose that CFD detection is an inexpensive applicable tool for identifying patients at risk and their follow-up. PMID- 22833623 TI - Forced suction thrombectomy after carotid stenting in patients with massive thrombus and acute extracranial internal carotid artery occlusion. AB - PURPOSE: To evaluate the safety and efficacy of emergency carotid stenting and recanalization using the modified Penumbra System (PS) technique for cases of acute extracranial internal carotid artery (ICA) occlusion and massive thrombus with acute ischemic stroke symptoms. METHODS: The clinical outcomes of patients with tandem occlusion of the ICA and middle cerebral artery (MCA) who underwent recanalization by a modified PS technique after carotid artery stenting during the period December 2009 to June 2011 were reviewed. RESULTS: Five patients with tandem occlusion of the ICA and MCA were enrolled. The mean National Institute of Health Stroke Scale (NIHSS) score on admission was 13 (range 9-18). The median time from symptom onset to arrival at hospital was 260 min. The median time lag between arrival at hospital and intra-arterial administration was 70 min. Recanalization by stenting of carotid artery occlusion was successfully performed in all patients. The mean number of recanalizations using the modified PS technique for distally migrated thrombus was 3. Complete recanalization of the MCA was observed in all patients. Symptomatic hemorrhage transformation did not occur during the hospital stay in any of the subjects. At discharge, the mean NIHSS score was 2.2 (range 1-6). At the 3-month follow-up the modified Rankin Scale was excellent in three of the five patients, good in one patient and poor in one patient. CONCLUSIONS: The modified PS technique after carotid artery stenting is a safe and effective treatment for patients with a massive thrombus extending into the distal portion of the ICA and a tandem occlusion of the ICA and MCA. PMID- 22833625 TI - Metal-on-metal hip implants and the risk of cancer. PMID- 22833628 TI - Private hospital planned to delay NHS operations to boost income. PMID- 22833626 TI - Risk of cancer with metal-on-metal hip replacements: population based study. AB - OBJECTIVE: To assess the risk of cancer associated with modern primary metal-on metal hip replacements. DESIGN: Population based study. SETTING: Nationwide retrospective comparative register. PARTICIPANTS: 10,728 patients who underwent metal-on-metal total hip arthroplasty and 18,235 patients who underwent conventional metal-on-polyethylene, ceramic-on-polyethylene, and ceramic-on ceramic total hip arthroplasty (the non-metal-on-metal cohort) in the Finnish Arthroplasty Register 2001-10. Data on cancer cases up to 2010 for these cohorts were extracted from the Finnish Cancer Registry. MAIN OUTCOME MEASURES: The relative risk of cancer was expressed as the ratio of observed to expected number of cases from the Finnish population--that is, the standardised incidence ratio. The relative risk of cancer in the metal-on-metal cohort compared with the non metal-on-metal cohort was estimated with analyses of these ratios and Poisson regression. RESULTS: The overall risk of cancer in patients with metal-on-metal hip implants was similar to that in the Finnish population (378 observed v 400 expected, standardised incidence ratio 0.95, 95% confidence interval 0.85 to 1.04). The overall risk of cancer in patients with metal-on-metal hip implants was also no higher than in patients who had received non-metal-on-metal hip implants (relative risk 0.92, 0.81 to 1.05). CONCLUSIONS: Metal-on-metal hip replacements are not associated with an increased overall risk of cancer during a mean follow-up of four years. PMID- 22833629 TI - Cancer centre is nominated for Stirling prize. PMID- 22833630 TI - Beware the cost-benefit analysis. PMID- 22833631 TI - New drug combination for TB is tested in unique trial. PMID- 22833632 TI - Poor health does not preclude a happy life, though it does increase the odds against it. PMID- 22833633 TI - Detection of bowel cancer in kidney transplant recipients. PMID- 22833634 TI - Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. AB - Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL. PMID- 22833635 TI - Reduced susceptibility to chlorhexidine in staphylococci: is it increasing and does it matter? AB - Antiseptic agents are increasingly used for hand hygiene and skin decolonization as key tools for the prevention of healthcare-associated infections. Chlorhexidine, a divalent, cationic biguanide, has a broad spectrum of activity and is one of the most frequently used topical antiseptic agents. Notably, there are an increasing number of prevalence studies that report reduced levels of susceptibility to chlorhexidine. In contrast to bacterial resistance to antibiotics, using parameters such as the MIC to define resistance to antiseptics, including chlorhexidine, is not straightforward. A range of methods have been used for the detection of reduced susceptibility to chlorhexidine, but, importantly, there is no standardized method and no consensus on the definition of chlorhexidine 'resistance'. In this review we have assessed the methods available for the detection of reduced susceptibility to chlorhexidine and the prevalence of coresistance to other antimicrobial agents. We have focused on the development of reduced susceptibility to chlorhexidine and the presence of efflux mediated resistance genes in staphylococci, and have reviewed the clinical significance of this phenomenon. Lastly, we have identified unanswered questions to further our understanding of this emergent threat. We anticipate that clinical use of chlorhexidine will continue to increase, and it will be important to be alert to the possibility that this may lead to the emergence of new clones with reduced susceptibility. Indiscriminate chlorhexidine use in the absence of efficacy data should be discouraged. PMID- 22833636 TI - Applying biomarkers to clinical practice: a guide for utilizing procalcitonin assays. AB - Prudent use of antimicrobial therapies is an important component in decreasing bacterial resistance. Procalcitonin (PCT) is a novel biomarker proposed as both a diagnostic and prognostic agent for use in various severe infections. Elevated PCT levels have a high sensitivity and specificity for diagnosing infections. This biomarker has been studied as an aid to identify patients requiring antimicrobial initiation, stratify infections according to severity and guide therapy durations. Two commercially available tests are approved for use in the USA. Other biomarkers have been studied for similar indications, but are subject to elevation from chronic inflammatory conditions and medications. The advantage of PCT over other biomarkers is due to the limited disease states and drug therapies that may interfere with this assay. PCT has been studied extensively for use in patients with severe sepsis and septic shock, as well as in lower respiratory tract infections. Decreased antimicrobial utilization without an increase in patient morbidity and mortality has been illustrated through numerous studies using PCT algorithms. Determining the utility of PCT in practice requires a comprehensive evaluation of the impact this biomarker has on outcomes to the patient and healthcare system, as well as examining convenience and cost factors. PCT can be used to assist clinicians in initiating and guiding antimicrobial therapies for specific patient populations, as an adjunct to other diagnostic tools. Further studies examining long-term outcomes of PCT are needed to determine the effect of this intervention on resistance patterns and overall prescribing trends. PMID- 22833637 TI - Increase in transmitted HIV drug resistance among persons undergoing genotypic resistance testing in Ontario, Canada, 2002-09. AB - OBJECTIVES: To characterize persons undergoing HIV genotypic resistance testing (GRT) while treatment naive and to estimate the prevalence of transmitted HIV drug resistance (TDR) among HIV-positive outpatients in Ontario, Canada. METHODS: We analysed data from a multi-site cohort of persons receiving HIV care. Data were obtained from medical chart abstractions, interviews and record linkage with the Public Health Laboratories, Public Health Ontario. The analysis was restricted to 626 treatment-naive persons diagnosed in 2002-09. TDR mutations were identified using the calibrated population resistance tool. We used descriptive statistics and regression methods to characterize treatment-naive GRT test uptake and patterns of TDR. RESULTS: Overall, 53.2% (333/626) of participants had baseline GRT. The proportion increased with year of HIV diagnosis from 30.0% in 2002 to 82.6% in 2009 (P < 0.0001). Among those tested, 13.6% (CI 9.9-17.3%) had one or more drug resistance mutations, and 8.8% (CI 5.7 11.8%), 4.8% (CI 2.5-7.2%) and 2.7% (CI 1.0-4.5%) had mutations conferring resistance to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), respectively. TDR prevalence increased from 2002-07 to 2008-09 (adjusted OR 3.7, 95% CI 1.7-8.2), driven by a higher proportion with NRTI (18.2% versus 5.9%, P = 0.0009) and NNRTI mutations (11.7% versus 2.8%, P = 0.004) in the later time period. PI TDR remained unchanged. CONCLUSIONS: Baseline GRT increased dramatically since 2002, but remains below 100%. The prevalence of overall TDR tripled due to increases in NRTI and NNRTI mutations. These findings highlight the value of routine baseline GRT for TDR surveillance and patient care. PMID- 22833638 TI - In vitro susceptibility of multidrug-resistant Enterobacteriaceae clinical isolates to tigecycline. AB - OBJECTIVES: To assess the in vitro susceptibility of multidrug-resistant Enterobacteriaceae (MDRE) isolates to tigecycline. METHODS: Clinical isolates of MDRE tested in this study were obtained from 91 hospitals in Belgium during the period January 2010 to April 2010. MICs of tigecycline were determined by Vitek 2 (VTK) and by the reference broth microdilution (BMD) method, and the results were interpreted based on the 2011 MIC interpretative criteria recommended by EUCAST. RESULTS: A total of 501 non-duplicate MDRE isolates were tested. These comprised 284 isolates of Escherichia coli [255 (89.7%) were extended-spectrum beta lactamase (ESBL)-producing isolates], 72 isolates of Klebsiella pneumoniae [53 (73.6%) were ESBL-producing isolates], 72 isolates of Enterobacter aerogenes, 33 isolates of Enterobacter cloacae, 19 isolates of Klebsiella oxytoca and 21 miscellaneous others. The MIC(90) values of tigecycline for E. coli and non-E. coli ESBL-producing Enterobacteriaceae isolates were 0.5 and 2 mg/L by BMD, and 0.5 and 8 mg/L by VTK, respectively. The highest essential and categorical agreement rates between VTK and BMD results using EUCAST breakpoints were observed in E. coli isolates (97.2%), while lower and unacceptable essential and categorical agreement rates were obtained for isolates belonging to species other than E. coli (81.1% and 59.4%, respectively). CONCLUSIONS: VTK appears to be a suitable method for routine susceptibility testing of tigecycline only for E. coli isolates, while BMD should be preferred for other Enterobacteriaceae species isolates. PMID- 22833639 TI - A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. AB - OBJECTIVES: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. METHODS: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18-65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). RESULTS: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4-5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ~3 for 200 and 400 mg once daily and ~5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. CONCLUSIONS: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections. PMID- 22833640 TI - Considerations of antibiotic therapy duration in community- and hospital-acquired bacterial infections. AB - Despite the large number of suggestions available in the literature, the optimal duration of antibiotic treatment remains an individual decision mainly based on clinical criteria. Shorter but equally effective regimens would reduce the side effect rates, including both antibiotic resistance and drug expenses. Although several prospective, randomized trials and meta-analyses with the aim of comparing a standard duration with a shorter one for most bacterial infections have been published, to date most current recommendations carry little weight, as they are based on expert opinions or practical experience. This review will briefly touch upon the clinical evidence of short-course versus long-course antibiotic therapy for the most common community- and hospital-acquired bacterial infections. PMID- 22833641 TI - Comment on: Intensive care unit dissemination of multiple clones of linezolid resistant Enterococcus faecalis and Enterococcus faecium. PMID- 22833642 TI - Acquisition of clarithromycin resistance mutations in the 23S rRNA gene of Mycobacterium abscessus in the presence of inducible erm(41). AB - OBJECTIVES: Antibiotic therapy of pulmonary Mycobacterium abscessus infection is based on a combination treatment including clarithromycin. Recent data demonstrated that M. abscessus may carry a chromosomal, inducible erm gene coding for the ribosomal methylase Erm(41). The purpose of this study was to investigate whether in patients with chronic M. abscessus infection undergoing clarithromycin therapy, M. abscessus acquires clarithromycin resistance mutations in the rrl gene in addition to the presence of an inducible Erm(41) methylase. METHODS: We determined clarithromycin MICs, erm(41) and rrl sequences for 29 clinical M. abscessus subsp. abscessus isolates of five different patients. The isolates were obtained between 2007 and 2011 covering a longitudinal observation period of 2-4 years for the individual patients. RESULTS: In three out of five patients with an initial rrl wild-type isolate, follow-up isolates demonstrated acquisition of resistance mutations in the rrl gene in addition to the presence of an inducible Erm methylase. CONCLUSIONS: Our results show that in M. abscessus, clarithromycin resistance mutations in the 23S rRNA peptidyltransferase region provide an additional selective advantage independent of a functional erm(41) gene. PMID- 22833643 TI - Comment on: Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. PMID- 22833644 TI - Every workplace should have a mental health first aider, says government. PMID- 22833645 TI - Enantioselective determination of methylphenidate and ritalinic acid in whole blood from forensic cases using automated solid-phase extraction and liquid chromatography-tandem mass spectrometry. AB - A chiral liquid chromatography tandem mass spectrometry (LC-MS-MS) method was developed and validated for quantifying methylphenidate and its major metabolite ritalinic acid in blood from forensic cases. Blood samples were prepared in a fully automated system by protein precipitation followed by solid-phase extraction. The LC-MS-MS method was linear in the range of 0.5 to 500 ng/g for the enantiomers of both analytes. For concentrations above the limit of quantification, coefficients of variation were 15% or less, and the accuracy was 89 to 94%. For 12 postmortem samples in which methylphenidate was not determined to be related to the cause of death, the femoral blood concentration of d methylphenidate ranged from 5 to 58 ng/g, and from undetected to 48 ng/g for l methylphenidate (median d/l-ratio 5.9). Ritalinic acid was present at concentrations 10-20 times higher with roughly equal amounts of the d- and l forms. In blood from 10 living subjects that were not suspected of being intoxicated by methylphenidate, the concentration ranges and patterns were similar to those of the postmortem cases. Thus, methylphenidate does not appear to undergo significant postmortem redistribution. PMID- 22833646 TI - Improved detection of opioid use in chronic pain patients through monitoring of opioid glucuronides in urine. AB - When chronic pain patients are suspected of being non-compliant, their therapy can be withdrawn. Therefore, sensitive and specific confirmatory testing is important for identifying diversion and adherence. This work aimed to develop a novel liquid chromatography tandem mass spectrometry (LC-MS-MS) method to detect 14 opioids and six opioid glucuronide metabolites in urine with minimal sample preparation. Analytes included were morphine, oxymorphone, hydromorphone, oxycodone, hydrocodone, codeine, fentanyl, norfentanyl, 6-monoacetylmorphine, meperidine, normeperidine, propoxyphene, methadone, buprenorphine, morphine-3 glucuronide, morphine-6-glucuronide, oxymorphone glucuronide, hydromorphone glucuronide, codeine-6-glucuronide and norbuprenorphine glucuronide. Samples were processed by centrifugation and diluted in equal volume with a deuterated internal standard containing 14 opioids and four opioid glucuronides. The separation of all compounds was complete in nine minutes. The assay was linear between 10 and 1,000 ng/mL (fentanyl 0.25-25 ng/mL). Intra-assay imprecision (500 ng/mL, fentanyl 12.5 ng/mL) ranged from 1.0 to 8.4% coefficient of variation. Inter-assay precision ranged from 2.9 to 6.0%. Recovery was determined by spiking five patient specimens with opioid and opioid glucuronide standards at 100 ng/mL (fentanyl 2.5 ng/mL). Recoveries ranged from 82 to 107% (median 98.9%). The method correlated with our current quantitative LC-MS-MS assay for opioids, which employs different chromatography. Internal standards were not available for every analyte to critically evaluate for ion suppression. Instead, a novel approach was designed to achieve the most rigorous quality control possible, in which the recovery of each analyte was evaluated in each negative sample. PMID- 22833647 TI - Sensitive UPLC-MS-MS assay for 21 benzodiazepine drugs and metabolites, zolpidem and zopiclone in serum or plasma. AB - This paper reports an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method to quantitate 21 benzodiazepines, zolpidem and zopiclone in serum and plasma. After liquid-liquid extraction, an Acquity UPLC with a TQ Detector and BEH C18 column was used (Waters, Milford, MA). The injection-to-injection run time was 7.5 min. Forty-eight authentic serum and plasma patient specimens were analyzed and results compared to those obtained using a previously published method. Average r(2) values for linearity (1 to 1,000 ng/mL over five days) were all above 0.995, except alpha-hydroxytriazolam (0.993). Intra-day and inter-day relative standard deviation values were within +/- 15% and the percent deviation from the expected concentrations were within +/ 11%. Recovery ranged from 62 to 89%. Matrix effects ranged from -28% to +6%. The limits of detection were 1 ng/mL, except for lorazepam, nordiazepam, oxazepam and temazepam (5 ng/mL). Ion ratios were +/- 15% for all analytes. For authentic patient specimens (n = 48, 76 positive results), there was excellent correlation between the UPLC-MS-MS results and the previous method. The best least-squares fit had an equation of y = 1.0708x + 1.6521, r(2) = 0.9822. This UPLC-MS-MS method is suitable for the quantification of benzodiazepines and hypnotics in serum and plasma, and offers fast, reliable and sensitive results. PMID- 22833648 TI - Quantifying the RR of harm to self and others from substance misuse: results from a survey of clinical experts across Scotland. AB - OBJECTIVE: To produce an expert consensus hierarchy of harm to self and others from legal and illegal substance use. DESIGN: Structured questionnaire with nine scored categories of harm for 19 different commonly used substances. SETTING/PARTICIPANTS: 292 clinical experts from across Scotland. RESULTS: There was no stepped categorical distinction in harm between the different legal and illegal substances. Heroin was viewed as the most harmful, and cannabis the least harmful of the substances studied. Alcohol was ranked as the fourth most harmful substance, with alcohol, nicotine and volatile solvents being viewed as more harmful than some class A drugs. CONCLUSIONS: The harm rankings of 19 commonly used substances did not match the A, B, C classification under the Misuse of Drugs Act. The legality of a substance of misuse is not correlated with its perceived harm. These results could inform any legal review of drug misuse and help shape public health policy and practice. PMID- 22833649 TI - Physiotherapy rehabilitation following lumbar spinal fusion: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To evaluate the effectiveness of physiotherapy intervention following lumbar spinal fusion. DESIGN: Systematic review and meta-analysis. 2 independent reviewers searched information sources, assessed studies for inclusion and evaluated risk of bias. Quantitative synthesis using standardised mean differences was conducted on comparable outcomes across trials with similar interventions. INFORMATION SOURCES: Predefined terms were employed to search electronic databases. Additional studies were identified from key journals, reference lists, authors and experts. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: Randomised control trials published in English prior to 30 September 2011 investigating physiotherapy outpatient management of patients (>16 years), following lumbar spinal fusion, with measurements reported on one or more outcome of disability, function and health were included. RESULTS: 2 Randomised control trials (188 participants) from two countries were included. Both trials included a behavioural and an exercise intervention. 1 trial was evaluated as high risk of bias and one as unclear. 159 participants were incorporated in the meta-analysis. Although evidence from both trials suggested that intervention might reduce back pain short term (6 months) and long term (12 months and 2 years), and a behavioural intervention might be more beneficial than an exercise intervention, the pooled effects (0.72, 95% CI -0.25 to 1.69 at 6 months; 0.52, 95% CI -0.45 to 1.49 at 12 months and 0.75, 95% CI -0.46 to 1.96 at 2 years) did not demonstrate statistically significant effects. There was no evidence that intervention changes pain in the short (6 months) or long term (12 months and 2 years). The wide CI for pooled effects indicated that intervention could be potentially beneficial or harmful. Considerable heterogeneity was evident. CONCLUSIONS: Inconclusive, very low-quality evidence exists for the effectiveness of physiotherapy management following lumbar spinal fusion. Best practice remains unclear. Limited comparability of outcomes and retrieval of only two trials reflect a lack of research in this area that requires urgent consideration. PMID- 22833650 TI - Health Impact Assessment of increased cycling to place of work or education in Copenhagen. AB - OBJECTIVE: To quantify the effects of increased cycling on both mortality and morbidity. DESIGN: Health Impact Assessment. SETTING: Cycling to place of work or education in Copenhagen, Denmark. POPULATION: Effects were calculated based on the working-age population of Copenhagen. MAIN OUTCOME MEASURES: The primary outcome measure was change in burden of disease (measured as disability-adjusted life years (DALY)) due to changed exposure to the health determinants physical inactivity, air pollution (particulate matter <2.5 MUm) and traffic accidents. RESULTS: Obtainment of the proposed increase in cycling could reduce the burden of disease in the study population by 19.5 DALY annually. This overall effect comprised a reduction in the burden of disease from health outcomes associated with physical inactivity (76.0 DALY) and an increase in the burden of disease from outcomes associated with air pollution and traffic accidents (5.4 and 51.2 DALY, respectively). CONCLUSION: This study illustrates how quantitative Health Impact Assessment can help clarify potential effects of policies: increased cycling involves opposing effects from different outcomes but with the overall health effect being positive. This result illustrates the importance of designing policies that promote the health benefits and minimise the health risks related to cycling. PMID- 22833651 TI - Perineal resuturing versus expectant management following vaginal delivery complicated by a dehisced wound (PREVIEW): protocol for a pilot and feasibility randomised controlled trial. AB - BACKGROUND: Each year, approximately 350 000 women in the UK experience perineal suturing following childbirth. For those women whose perineal wound dehisces, the management will vary according to individual practitioner's preferences. For most women, the wound will be managed expectantly (healing by secondary intention), whereas others may be offered resuturing. However, there is limited scientific evidence and no clear guidelines to inform best practice. PREVIEW is a two-part study aiming to identify the best management strategy for dehisced perineal wounds, in terms of clinical effectiveness and women's preferences. METHODS/DESIGN: The main part of this study is a pilot and feasibility randomised controlled trial designed to provide preliminary evidence of the effectiveness of resuturing versus expectant management for dehisced perineal wounds following childbirth and to feed into the design and feasibility of a larger definitive trial. 144 participants will be randomly allocated to either intervention. The primary outcome is the proportion of women with a healed perineal wound at 6-8 weeks from the trial entry. Secondary outcomes include perineal pain, breast feeding rates, dyspareunia and women's satisfaction with the aesthetic results of the wound healing at 6 weeks, 3 months and 6 months post randomisation. Information will be collected using validated questionnaires. The second part of this study will be to conduct semistructured interviews with 12 study participants, aiming to capture information relating to their physical and psychological experiences following perineal wound dehiscence, assess the acceptability of the research plan and ensure that all outcomes relevant to women are included in the definitive trial. DISSEMINATION: The results of this study will inform a definitive randomised controlled trial that will provide conclusive evidence of what is the best management of perineal wound dehiscence. This will potentially lead to significant improvements in perineal care and will help to reduce the short- and long-term morbidity experienced by women. CLINICAL TRIALS REGISTRATION: PREVIEW is registered with the International Standard Research for Clinical Trials (no: ISRCTN05754020) and adopted as a National Institute for Health Research (NIHR) Reproductive Health and Childbirth specialty group portfolio study UKCRN ID 9098. PMID- 22833652 TI - Dietary intake of c9,t11-conjugated linoleic acid correlates with its concentration in plasma lipid fractions of men but not women. AB - The c9,t11-18:2 isomer of conjugated linoleic acid (c9,t11-CLA) represents the main dietary CLA form with putative health benefits. Whereas CLA intake influences the tissue CLA concentration, little is known about the association between dietary CLA and the CLA content of plasma lipid fractions. This study was designed to document fasting and nonfasting plasma c9,t11-CLA concentrations in a population of free-living adults (n = 94) and relate these concentrations to c9,t11-CLA intake. We also determined the c9,t11-CLA content of the primary plasma lipid fractions in a subset (n = 50) of our participants, related these to c9,t11-CLA intake, and determined whether c9,t11-CLA intake or plasma c9,t11-CLA was correlated with plasma cholesterol. Mean fasting plasma c9,t11-CLA concentrations were 0.46 +/- 0.01 and 0.54 +/- 0.01% (wt:wt) of total fatty acids for men and women, respectively (P < 0.05); nonfasting concentrations were 0.28 +/- 0.01 and 0.38 +/- 0.01% of total fatty acids, respectively (P < 0.001). All major esterified plasma lipid fractions contained c9,t11-CLA; TG had the highest percentages. In men, c9,t11-CLA intake correlated (r = 0.47; P < 0.05) with TG c9,t11-CLA content, suggesting that TG c9,t11-CLA may serve as a biomarker for c9,t11-CLA intake. In females, there were no correlations between c9,t11-CLA intake and the c9,t11-CLA content of any esterified plasma lipid fraction. In neither sex was there a relation between dietary c9,t11-CLA or plasma c9,t11-CLA concentration and circulating lipoprotein cholesterol concentration. The influence of sex on circulating c9,t11-CLA content and further validation of biomarkers of c9,t11-CLA intake warrant further investigation. PMID- 22833653 TI - Diet composition is associated with endogenous formation of N-nitroso compounds in obese men. AB - Endogenous formation of carcinogenic N-nitroso compounds (NOC) occurs in the human gut. Red meat is considered the most important dietary component linked to NOC formation, although nitrate and vitamin C (VitC) also contribute. We previously showed that high-protein weight-loss diets increased fecal NOC and this was enhanced by simultaneous carbohydrate restriction. Although previous studies have focused on the effect of either 1 or 2 dietary components on endogenous NOC formation, no study to date has investigated the combined contribution of various dietary components. The current study therefore assessed the joint impact of several known dietary contributors to the endogenous formation of NOC in obese men. It also aimed to identify further novel contributors and investigate their role in explaining shifts in endogenous formation of NOC. Three dietary trials were conducted in obese men consuming body weight maintenance or weight-loss diets, with NOC measured in fecal samples. Consumption of meat-based weight-loss diets increased (P < 0.001) fecal NOC. Red meat intake was positively correlated with the fecal log NOC concentration (r = 0.60; P < 0.001). Dietary carbohydrate and sugar were negatively correlated with the fecal log NOC concentration (r = -0.66 for both; P < 0.001). Multiple regression analysis identified several dietary components that drive endogenous NOC formation, namely, red meat, nitrate, VitC, total energy, and nonstarch polysaccharides. We present a regression model that predicts endogenous NOC formation in obese men based on their dietary intakes. This model could improve the estimation of endogenous NOC formation, currently used in epidemiological studies into diet and cancer. PMID- 22833654 TI - Measurement of acylcarnitine substrate to product ratios specific to biotin dependent carboxylases offers a combination of indicators of biotin status in humans. AB - This work describes a novel liquid chromatography tandem MS (LC-MS/MS) method for the determination of ratios of acylcarnitines arising from acyl-CoA substrates and products that reflect metabolic disturbances caused by marginal biotin deficiency. The urinary ratios reflecting reduced activities of biotin-dependent enzymes include the following: 1) the ratio of 3-hydroxyisovalerylcarnitine : 3 methylglutarylcarnitine (3HIAc : MGc) for methylcrotonyl-CoA carboxylase; 2) the ratio of propionylcarnitine:methylmalonylcarnitine (Pc : MMc) for propionyl-CoA carboxylase (PCC); and 3) the ratio of acetylcarnitine : malonylcarnitine (Ac : Mc) for acetyl-CoA carboxylase. To demonstrate the suitability of the LC-MS/MS method for biomonitoring, we measured the 3 ratios for 7 healthy adults at various time points (d 0, 14, and 28) during the induction of marginal biotin through the consumption of egg white. The mean change in the Pc : MMc ratio relative to d 0 was 5.3-fold by d 14 (P = 0.0049) and 8.5-fold by d 28 (P = 0.0042). The mean change in the 3HIAc : MGc ratio was 2.8-fold by d 14 (P = 0.0022) and 3.8-fold by d 28 (P = 0.0001). The mean change in the Ac : Mc ratio was 2.9-fold by d 14 (P = 0.03) and 4.7-fold by d 28 (P = 0.02). The results suggest that simultaneous assessment of ratios of multiple biotin-dependent pathways offers insight into the complex metabolic disturbances caused by marginal biotin deficiency. We hypothesize that one or a combination of the ratios might be more sensitive or robust with respect to other nutrient deficiencies or confounding metabolic processes. PMID- 22833655 TI - Maternal low-protein diet induces gender-dependent changes in epigenetic regulation of the glucose-6-phosphatase gene in newborn piglet liver. AB - Glucose-6-phosphatase (G6PC) plays an important role in glucose homeostasis because it catalyzes the final steps of gluconeogenesis and glycogenolysis. Maternal malnutrition during pregnancy affects G6PC activity, yet it is unknown whether epigenetic regulations of the G6PC gene are also affected. In this study, we fed primiparous, purebred Meishan sows either standard-protein (SP; 12% crude protein) or low-protein (LP; 6% crude protein) diets throughout gestation and analyzed hepatic G6PC expression in both male and female newborn piglets. The epigenetic regulation of G6PC, including DNA methylation, histone modifications, and micro RNA (miRNA), was determined to reveal potential mechanisms. Male, but not female, LP piglets had a significantly lower serum glucose concentration and greater hepatic G6PC mRNA expression and enzyme activity. Also, in LP males, glucocorticoid receptor binding to the G6PC promoter was lower compared with SP males, which was accompanied by hypomethylation of the G6PC promoter. Modifications in histones also were gender dependent; LP males had less histone H3 and histone H3 lysine 9 trimethylation and more histone H3 acetylation and histone H3 lysine 4 trimethylation on the G6PC promoter compared with the SP males, whereas LP females had more H3 and greater H3 methylation compared with their SP counterparts. Moreover, two miRNA, ssc-miR-339-5p and ssc-miR-532-3p, targeting the G6PC 3' untranslated region were significantly upregulated by the LP diet only in females. These results suggest that a maternal LP diet during pregnancy causes hepatic activation of G6PC gene expression in male piglets, which possibly contributes to adult-onset hyperglycemia. PMID- 22833656 TI - The 2008 food price crisis negatively affected household food security and dietary diversity in urban Burkina Faso. AB - Although the 2008 food price crisis presumably plunged millions of households into poverty and food insecurity, the real impact of the crisis has rarely been documented using field data. Our objective was to assess the consequences of this crisis for household food insecurity and dietary diversity in urban Burkina Faso. Two cross-sectional surveys were conducted among randomly selected households in Ouagadougou in July 2007 (n = 3017) and July 2008 (n = 3002). At each round, food insecurity assessed by the Household Food Insecurity Access Scale (HFIAS), the Dietary Diversity Score of an index-member of the household (IDDS = number of food groups consumed in the last 24 h), and food expenditure were collected. Food prices of the 17 most frequently consumed food items were recorded throughout the study area. Food prices at local markets increased considerably between 2007 and 2008, especially those of fish (113%), cereals (53%), and vegetable oil (44%), increasing the household monthly food expenditure by 18%. Thirty-three percent of households were food secure in 2007 and 22% in 2008 (P = 0.02). Individuals consumed fewer fruits and vegetables, dairy products, and meat/poultry in 2008 than in 2007 (mean IDDS = 5.7 +/- 1.7 food groups in 2007 vs. 5.2 +/- 1.5 in 2008; P < 0.0001). Differences in IDDS and HFIAS between the 2 y were even more marked after adjustment for confounding factors and food expenditure. Food security and dietary diversity significantly decreased between 2007 and 2008, whereas food prices increased. Households increased their food expenditure, but this was not sufficient to compensate the effects of the crisis. PMID- 22833657 TI - Shifts in the rumen microbiota due to the type of carbohydrate and level of protein ingested by dairy cattle are associated with changes in rumen fermentation. AB - Balancing energy and nitrogen in the rumen is a key to both profitability and environmental sustainability. Four dairy cows were used in a Latin square experimental design to investigate the effect of severe nitrogen underfeeding (110 vs. 80% of requirements) and the type of carbohydrate consumed [neutral detergent fiber rich (FIB) vs. starch rich (STA)] on the rumen ecosystem. These dietary treatments modified both rumen fermentation and microbial populations. Compared with STA diets, consumption of FIB diets increased bacterial and fungal diversity in the rumen and also increased the concentrations of cellulolytic microorganisms, including protozoa (+38%), anaerobic fungi (+59%), and methanogens (+27%). This microbial adaptation to fiber utilization led to similar digestibility values for the 2 carbohydrate sources and was accompanied by a shift in the rumen fermentation patterns; when the FIB diets were consumed, the cows had greater ruminal pH, ammonia concentrations, and molar proportions of acetate and propionate compared with when they consumed the STA diets. Certain rumen microorganisms were sensitive to a shortage of nitrogen; rumen concentrations of ammonia were 49% lower when the low-protein (LP) diets were consumed as were total bacteria (-13%), anaerobic fungi (-28%), methanogens ( 27%), protozoa (-19%), cellulolytic bacteria, and microbial diversity compared with when the high-protein (HP) diets were consumed. As a result, the digestibility of the LP diets was less than that of the HP diets. These findings demonstrated that the rumen microbial ecosystem is directly linked to the rumen fermentation pattern and, to some extent, to the efficiency of diet utilization by dairy cattle. PMID- 22833658 TI - Dietary patterns of women are associated with incident abdominal obesity but not metabolic syndrome. AB - Data on the relationship between empirical dietary patterns and metabolic syndrome (MetS) and its components in prospective study designs are limited. In addition, demographic and lifestyle determinants of MetS may modify the association between dietary patterns and the syndrome. We prospectively examined the relationship between empirically derived patterns and MetS and MetS components among 1146 women in the Framingham Offspring/Spouse cohort. They were aged 25-77 y with BMI >=18.5 kg/m(2) and free of cardiovascular disease, diabetes, cancer, and MetS at baseline, and followed for a mean of 7 y. Five dietary patterns, Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calorie, were previously identified using cluster analysis from food intake collected using a FFQ. After adjusting for potential confounders, we observed lower odds for abdominal obesity for Higher Fat [OR = 0.48 (95% CI: 0.25, 0.91)] and Wine and Moderate Eating clusters [OR = 0.28 (95% CI: 0.11, 0.72)] compared with the Empty Calorie cluster. Additional adjustment for BMI somewhat attenuated these OR [Higher Fat OR = 0.52 (95% CI: 0.27, 1.00); Wine and Moderate Eating OR = 0.34 (95% CI: 0.13, 0.89)]. None of the clusters was associated with MetS or other MetS components. Baseline smoking status and age did not modify the relation between dietary patterns and MetS. The Higher Fat and Wine and Moderate Eating patterns showed an inverse association with abdominal obesity; certain foods might be targeted in these habitual patterns to achieve optimal dietary patterns for MetS prevention. PMID- 22833660 TI - Attributable risk analysis reveals potential healthcare savings from increased consumption of dairy products. AB - With rising burdens of obesity and chronic disease, the role of diet as a modifiable risk factor is of increasing public health interest. There is a growing body of evidence that low consumption of dairy products is associated with elevated risk of chronic metabolic and cardiovascular disorders. Surveys also suggest that dairy product consumption falls well below recommended targets for much of the population in many countries, including the USA, UK, and Australia. We reviewed the scientific literature on the health effects of dairy product consumption (both positive and negative) and used the best available evidence to estimate the direct healthcare expenditure and burden of disease [disability-adjusted life years (DALY)] attributable to low consumption of dairy products in Australia. We implemented a novel technique for estimating population attributable risk developed for application in nutrition and other areas in which exposure to risk is a continuous variable. We found that in the 2010-2011 financial year, AUD$2.0 billion (USD$2.1 billion, ?1.6 billion, or ~1.7% of direct healthcare expenditure) and the loss of 75,012 DALY were attributable to low dairy product consumption. In sensitivity analyses, varying core assumptions yielded corresponding estimates of AUD$1.1-3.8 billion (0.9-3.3%) and 38,299 151,061 DALY lost. The estimated healthcare cost attributable to low dairy product consumption is comparable with total spending on public health in Australia (AUD$2.0 billion in 2009-2010). These findings justify the development and evaluation of cost-effective interventions that use dairy products as a vector for reducing the costs of diet-related disease. PMID- 22833659 TI - Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults. AB - Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B 12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender * MTHFR (rs1801131; P = 0.012), gender * CRBP2 (rs2118981; P = 0.011), and gender * SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy. PMID- 22833661 TI - Changes in vitamin D supplement use and baseline plasma 25-hydroxyvitamin D concentration predict 5-y change in concentration in postmenopausal women. AB - Few studies have prospectively examined predictors of change in plasma concentrations of 25-hydroxyvitamin D [25(OH)D]. We sought to determine the predictors of 5-y change in 25(OH)D. Plasma 25(OH)D concentrations were assessed at baseline (1997-2000) and 5 y later (2002-2005) in 668 postmenopausal women enrolled in the Osteoporosis and Periodontal Disease Study. Baseline and changes in demographic, dietary, lifestyle, and health-related factors were tested as predictors of change in 25(OH)D concentrations by using multivariable linear regression. The mean 5-y change in 25(OH)D (mean +/- SD) was 7.7 +/- 0.7 nmol/L (P < 0.001). In our predictive model (n = 643), predictors explained 31% of the variance in change in 25(OH)D concentrations and included baseline 25(OH)D, baseline and change in vitamin D supplementation and physical activity, change in season of blood draw, BMI, whole-body T score, and baseline hormone therapy use. Baseline 25(OH)D and change in vitamin D supplementation explained the most variation (25%) in 25(OH)D. Exploratory analyses showed a borderline significant interaction between tertiles of baseline 25(OH)D and change in vitamin D supplementation over time (P = 0.06). The greatest mean increase in 25(OH)D (22.9 +/- 16.8 nmol/L), with adjustment for other statistically significant predictors, occurred in women whose baseline 25(OH)D concentration was <=51.0 nmol/L (tertile 1) and who increased supplementation use over time. These results confirm the importance of supplementation in increasing 25(OH)D concentrations in aging women, even after other statistically significant predictors are controlled for. These data also suggest that this is especially true among aging women with inadequate 25(OH)D (e.g., <50 nmol/L). PMID- 22833662 TI - Barley cultivar, kernel composition, and processing affect the glycemic index. AB - Barley has a low glycemic index (GI), but it is unknown whether its GI is affected by variation in carbohydrate composition in different cultivars and by food processing and food form. To examine the effect of these factors on GI, 9 barley cultivars varying in amylose and beta-glucan content were studied in 3 experiments in separate groups of 10 healthy participants. In Expt. 1, 3 barley cultivars underwent 2 levels of processing: hull removal [whole-grain (WG)] and bran, germ, and crease removal [white pearled (WP)]. GI varied by cultivar (CDC Fibar vs. AC Parkhill, [mean +/- SEM]: 26 +/- 3 vs. 53 +/- 4, respectively; P < 0.05) and pearling (WG vs. WP: 26 +/- 4 vs. 35 +/- 3, respectively; P < 0.05) with no cultivar * pearling interaction. In Expt. 2, the GI of 7 WG cultivars ranged from 21 +/- 4 to 36 +/- 8 (P = 0.09). In Expt. 3, WG and WP AC Parkhill and Celebrity cultivars were ground and made into wet pasta. The GI of AC Parkhill pasta (69 +/- 3) was similar to that of Celebrity pasta (64 +/- 4) but, unlike in Expt. 1, the GI of WP pasta (61 +/- 3) was less than that of WG pasta (72 +/- 4) (P < 0.05). Pooled data from Expts. 1 and 2 showed that GI was correlated with total fiber (r = -0.75, P = 0.002) but not with measures of starch characteristics. We conclude that the GI of barley is influenced by cultivar, processing, and food form but is not predicted by its content of amylose or other starch characteristics. PMID- 22833663 TI - Recovery from workplace-induced airway inflammation 1 year after cessation of exposure. AB - BACKGROUND: Bacterial single-cell protein (BSCP) constitutes of dried bacterial mass which is used as protein enrichment in animal and fish feed. In the production of BSCP, workers are exposed to organic dust containing high levels of endotoxins (arithmetic mean 390 EU/m3 in the moderate exposure and 5800-11,000 EU/m3 in the high exposure groups) and have elevated levels of sputum neutrophils and cytokines associated with exposure. OBJECTIVE: The aim of the present study was to investigate if airway inflammation among the workers had declined 1 year after cessation of exposure. METHODS: Twenty-four non-smoking production workers (age 28-52) with a work history of 2-7 years were included in the study. MEASUREMENTS: Markers of airways inflammation and innate immune function (using flow cytometry) were assessed in an exposure period and 1 year after cessation of exposure. RESULTS: Sputum neutrophil proportion and numbers were significantly decreased 1 year after cessation of exposure to BSCP (43% vs. 71%, 186 vs. 598 neutrophils/mg sputum; p<0.001) as were eNO (17 ppb vs. 21 ppb (p=0.01) and interleukin-1beta (p<0.05) and interleukin-8 (p<0.05). Neutrophils had enhanced expression of CD11b/CR3 (p<0.01) and CD16/FcgammaRIII (p<0.001) and macrophages had lower expression of CD86 (p<0.01) 1 year after cessation of exposure. CONCLUSIONS: One year after closure of the plant airway neutrophils and exhaled NO levels resolved to lower levels and cell surface phenotypes associated with innate immune function recovered to higher levels, indicating that these changes were partly reversible among workers who were no longer exposed to endotoxins in a BSCP plant. PMID- 22833664 TI - Short-term effects of air temperature on blood markers of coagulation and inflammation in potentially susceptible individuals. AB - OBJECTIVES: Changes in air temperature are associated with an increase in cardiovascular events, but the role of procoagulant and proinflammatory blood markers is still poorly understood. The authors investigated the association between air temperature and fibrinogen, plasminogen activator inhibitor type 1, interleukin-6 and high-sensitivity C reactive protein in two potentially susceptible groups. METHODS: This prospective panel study was conducted between March 2007 and December 2008 in Augsburg, Germany. The study population comprised 187 participants with type 2 diabetes mellitus or impaired glucose tolerance and 87 participants with genetic polymorphisms on the detoxification and inflammation pathways. Overall, 1766 repeated blood measurements were collected. Hourly meteorology data were available from a central measurement site. The association between temperature and blood markers was analysed with additive mixed models. RESULTS: For type 2 diabetes mellitus and impaired glucose tolerance participants, the authors observed immediate, lagged and cumulative increases in fibrinogen (range of percentage changes in geometric mean: 0.6%-0.8%) and plasminogen activator inhibitor type 1 (6.0%-10.1%) in association with a 5 degrees C temperature decrement. Participants with a body mass index above 30 kg/m(2) as well as females showed particularly strong fibrinogen effects. In participants with the special genetic background, 5 degrees C decreases in the 5 day average of temperature led to a change of 8.0% (95% CI 0.5% to 16.2%) in interleukin-6 and of -8.4% (95% CI -15.8% to -0.3%) in high-sensitivity C reactive protein, the latter driven by physically active individuals. CONCLUSIONS: The authors observed different temperature effects on blood markers in two potentially susceptible groups probably indicating varying underlying biological mechanisms. This study results might provide a link between temperature and cardiovascular events. PMID- 22833665 TI - Kinetic assays for determining in vitro APS reductase activity in plants without the use of radioactive substances. AB - Adenosine 5'-phosphosulfate (APS) reductase (APR; EC 1.8.4.9) catalyzes the two electron reduction of APS to sulfite and AMP, a key step in the sulfate assimilation pathway in higher plants. In spite of the importance of this enzyme, methods currently available for detection of APR activity rely on radioactive labeling and can only be performed in a very few specially equipped laboratories. Here we present two novel kinetic assays for detecting in vitro APR activity that do not require radioactive labeling. In the first assay, APS is used as substrate and reduced glutathione (GSH) as electron donor, while in the second assay APS is replaced by an APS-regenerating system in which ATP sulfurylase catalyzes APS in the reaction medium, which employs sulfate and ATP as substrates. Both kinetic assays rely on fuchsin colorimetric detection of sulfite, the final product of APR activity. Incubation of the desalted protein extract, prior to assay initiation, with tungstate that inhibits the oxidation of sulfite by sulfite oxidase activity, resulted in enhancement of the actual APR activity. The reliability of the two methods was confirmed by assaying leaf extract from Arabidopsis wild-type and APR mutants with impaired or overexpressed APR2 protein, the former lacking APR activity and the latter exhibiting much higher activity than the wild type. The assays were further tested on tomato leaves, which revealed a higher APR activity than Arabidopsis. The proposed APR assays are highly specific, technically simple and readily performed in any laboratory. PMID- 22833666 TI - Nitrate reductase- and nitric oxide-dependent activation of sinapoylglucose:malate sinapoyltransferase in leaves of Arabidopsis thaliana. AB - Nitrate reductase (NR) activity is necessary for the synthesis of nitric oxide (NO), a key signaling molecule in plants. Here, we investigated the effect of NR deficiency on NO production and phenylpropanoid metabolism of Arabidopsis thaliana leaves. HPLC-mass spectrometry analysis showed that the NR double mutant (nia1 nia2) is deficient in the synthesis of sinapoylmalate (SM), the main phenylpropanoid end-product in wild-type leaves, resulting in accumulation of its precursor sinapoylglucose (SG). While real-time PCR analysis revealed no significant difference at the transcript level, sinapoylglucose:malate sinapoyltransferase (SMT) activity in leaf extracts was reduced in the mutant compared with the wild type. The low levels of SM in nia1 nia2 leaves do not result from the deficient nitrogen incorporation into amino acids, since the recovery of the amino acid content of nia1 nia2 by irrigating the plants with glutamine did not change the metabolic profile of this mutant. In contrast, an increased supply of nitrate stimulated NR activity and NO production, and enhanced SM and decreased SG levels in both genotypes. Nevertheless, sinapic acid esters in nia1 nia2 were not recovered when compared with those detected in the leaves of the wild-type plant. Mutant plants grown in medium supplemented with malate and an NO donor recovered SM to the levels of wild-type leaves. Overall, the results suggest that SMT activity is dependent on the NR-dependent steady state levels of NO during plant development. PMID- 22833667 TI - Integrin alpha2beta1 mediates tyrosine phosphorylation of vascular endothelial cadherin induced by invasive breast cancer cells. AB - The molecular mechanisms that regulate the endothelial response during transendothelial migration (TEM) of invasive cancer cells remain elusive. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) has been implicated in the disruption of endothelial cell adherens junctions and in the diapedesis of metastatic cancer cells. We sought to determine the signaling mechanisms underlying the disruption of endothelial adherens junctions after the attachment of invasive breast cancer cells. Attachment of invasive breast cancer cells (MDA-MB-231) to human umbilical vein endothelial cells induced tyrosine phosphorylation of VE-cad, dissociation of beta-catenin from VE-cad, and retraction of endothelial cells. Breast cancer cell-induced tyrosine phosphorylation of VE-cad was mediated by activation of the H-Ras/Raf/MEK/ERK signaling cascade and depended on the phosphorylation of endothelial myosin light chain (MLC). The inhibition of H-Ras or MLC in endothelial cells inhibited TEM of MDA-MB-231 cells. VE-cad tyrosine phosphorylation in endothelial cells induced by the attachment of MDA-MB-231 cells was mediated by MDA-MB-231 alpha(2)beta(1) integrin. Compared with highly invasive MDA-MB-231 breast cancer cells, weakly invasive MCF-7 breast cancer cells expressed lower levels of alpha(2)beta(1) integrin. TEM of MCF-7 as well as induction of VE-cad tyrosine phosphorylation and dissociation of beta-catenin from the VE-cad complex by MCF-7 cells were lower than in MDA-MB-231 cells. These processes were restored when MCF-7 cells were treated with beta(1)-activating antibody. Moreover, the response of endothelial cells to the attachment of prostatic (PC-3) and ovarian (SKOV3) invasive cancer cells resembled the response to MDA-MB-231 cells. Our study showed that the MDA-MB-231 cell-induced disruption of endothelial adherens junction integrity is triggered by MDA-MB-231 cell alpha(2)beta(1) integrin and is mediated by H-Ras/MLC-induced tyrosine phosphorylation of VE-cad. PMID- 22833668 TI - Identification of two-pore channel 2 as a novel regulator of osteoclastogenesis. AB - Osteoclast differentiation is one of the critical steps that control bone mass levels in osteoporosis, but the molecules involved in osteoclastogenesis are still incompletely understood. Here, we show that two-pore channel 2 (TPC2) is expressed in osteoclast precursor cells, and its knockdown (TPC2-KD) in these cells suppressed RANKL-induced key events including multinucleation, enhancement of tartrate-resistant acid phosphatase (TRAP) activities, and TRAP mRNA expression levels. With respect to intracellular signaling, TPC2-KD reduced the levels of the RANKL-induced dynamic waving of Ca(2+) in RAW cells. The search for the target of TPC2 identified that nuclear localization of NFATc1 is retarded in TPC2-KD cells. Finally, TPC2-KD suppressed osteoclastic pit formation in cultures. We conclude that TPC2 is a novel critical molecule for osteoclastogenesis. PMID- 22833669 TI - Structure and catalytic mechanism of 3-ketosteroid-Delta4-(5alpha)-dehydrogenase from Rhodococcus jostii RHA1 genome. AB - 3-Ketosteroid Delta4-(5alpha)-dehydrogenases (Delta4-(5alpha)-KSTDs) are enzymes that introduce a double bond between the C4 and C5 atoms of 3-keto-(5alpha) steroids. Here we show that the ro05698 gene from Rhodococcus jostii RHA1 codes for a flavoprotein with Delta4-(5alpha)-KSTD activity. The 1.6 A resolution crystal structure of the enzyme revealed three conserved residues (Tyr-319, Tyr 466, and Ser-468) in a pocket near the isoalloxazine ring system of the FAD co factor. Site-directed mutagenesis of these residues confirmed that they are absolutely essential for catalytic activity. A crystal structure with bound product 4-androstene-3,17-dione showed that Ser-468 is in a position in which it can serve as the base abstracting the 4beta-proton from the C4 atom of the substrate. Ser-468 is assisted by Tyr-319, which possibly is involved in shuttling the proton to the solvent. Tyr-466 is at hydrogen bonding distance to the C3 oxygen atom of the substrate and can stabilize the keto-enol intermediate occurring during the reaction. Finally, the FAD N5 atom is in a position to be able to abstract the 5alpha-hydrogen of the substrate as a hydride ion. These features fully explain the reaction catalyzed by Delta4-(5alpha)-KSTDs. PMID- 22833670 TI - Silencing or amplification of endocannabinoid signaling in blastocysts via CB1 compromises trophoblast cell migration. AB - Endocannabinoid signaling plays key roles in multiple female reproductive events. Previous studies have shown an interesting phenomenon, that mice with either silenced or elevated endocannabinoid signaling via Cnr1 encoding CB(1) show similar defects in several pregnancy events, including preimplantation embryo development. To unravel the downstream signaling of this phenomenon, microarray studies were performed using RNAs collected from WT, Cnr1(-/-), and Faah(-/-) mouse blastocysts on day 4 of pregnancy. The results indicate that about 100 genes show unidirectional changes under either silenced or elevated anandamide signaling via CB(1). Functional enrichment analysis of the microarray data predicted that multiple biological functions and pathways are affected under aberrant endocannabinoid signaling. Among them, genes enriched in cell migration are suppressed in Cnr1(-/-) or Faah(-/-) blastocysts. Cell migration assays validated the prediction of functional enrichment analysis that cell mobility and spreading of either Cnr1(-/-) or Faah(-/-) trophoblast stem cells are compromised. Either silenced or elevated endocannabinoid signaling via CB(1) causes similar changes in downstream targets in preimplantation embryos and trophoblast stem cells. This study provides evidence that a tightly regulated endocannabinoid signaling is critical to normal preimplantation embryo development and migration of trophoblast stem cells. PMID- 22833671 TI - Oncogenic K-Ras regulates bioactive sphingolipids in a sphingosine kinase 1 dependent manner. AB - Sphingosine kinase 1 (SK1) is an important enzyme involved in the production of the bioactive lipid sphingosine 1-phosphate (S1P). SK1 is overexpressed in many forms of cancer, however, the contribution of SK1 to cancer progression is still unclear. One of the best characterized mutations found in several forms of human cancer is an activating point mutation in the Ras oncogene, which disrupts its GTPase activity and leads to stimulation of the MEK/ERK pathway. Because SK1 activity and subcellular localization have been shown to be regulated by ERK, we wished to investigate the effect of oncogenic Ras, a potent activator of the Raf/MEK/ERK pathway, on the activity of SK1 and sphingolipid metabolism. Using HEK293T cells transiently transfected with the K-RasG12V oncogene and both wild type and Sphk1(-/-) mouse embryonic fibroblasts stably infected with retroviral K RasG12V, we found that K-RasG12V increases the production of S1P and decreases the production of ceramide in a SK1-dependent manner. In addition, we found that expression of the K-RasG12V oncogene leads to plasma membrane localization of SK1 and a reduction in cytosolic levels of SK1. This effect is likely mediated by the Raf/MEK/ERK pathway as constitutively active B-Raf or MEK1 are able to activate SK1, but constitutively active Akt1 is not. We believe this research has important implications for how sphingolipids may be contributing to oncogenic transformation and provide some of the first evidence for oncogenes inducing specific changes in sphingolipid metabolism through SK1 regulation. PMID- 22833672 TI - Redox modulation of flavin and tyrosine determines photoinduced proton-coupled electron transfer and photoactivation of BLUF photoreceptors. AB - Photoinduced electron transfer in biological systems, especially in proteins, is a highly intriguing matter. Its mechanistic details cannot be addressed by structural data obtained by crystallography alone because this provides only static information on a given redox system. In combination with transient spectroscopy and site-directed manipulation of the protein, however, a dynamic molecular picture of the ET process may be obtained. In BLUF (blue light sensors using FAD) photoreceptors, proton-coupled electron transfer between a tyrosine and the flavin cofactor is the key reaction to switch from a dark-adapted to a light-adapted state, which corresponds to the biological signaling state. Particularly puzzling is the fact that, although the various naturally occurring BLUF domains show little difference in the amino acid composition of the flavin binding pocket, the reaction rates of the forward reaction differ quite largely from a few ps up to several hundred ps. In this study, we modified the redox potential of the flavin/tyrosine redox pair by site-directed mutagenesis close to the flavin C2 carbonyl and fluorination of the tyrosine, respectively. We provide information on how changes in the redox potential of either reaction partner significantly influence photoinduced proton-coupled electron transfer. The altered redox potentials allowed us furthermore to experimentally describe an excited state charge transfer intermediately prior to electron transfer in the BLUF photocycle. Additionally, we show that the electron transfer rate directly correlates with the quantum yield of signaling state formation. PMID- 22833673 TI - alpha-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. AB - Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of alpha-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that alpha-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that alpha synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for alpha-synuclein-mediated disruption of adult neurogenesis in Parkinson disease. PMID- 22833674 TI - Electron transfer pathways and dynamics of chloroplast NADPH-dependent thioredoxin reductase C (NTRC). AB - NADPH-dependent thioredoxin reductases (NTRs) contain a flavin cofactor and a disulfide as redox-active groups. The catalytic mechanism of standard NTR involves a large conformational change between two configurations. Oxygenic photosynthetic organisms possess a plastid-localized NTR, called NTRC, with a thioredoxin module fused at the C terminus. NTRC is an efficient reductant of 2 Cys peroxiredoxins (2-Cys Prxs) and thus is involved in the protection against oxidative stress, among other functions. Although the mechanism of electron transfer of canonical NTRs is well established, it is not yet known in NTRC. By employing stopped-flow spectroscopy, we have carried out a comparative kinetic study of the electron transfer reactions involving NTRC, the truncated NTR module of NTRC, and NTRB, a canonical plant NTR. Whereas the three NTRs maintain the conformational change associated with the reductive cycle of catalysis, NTRC intramolecular electron transfer to the thioredoxin module presents two kinetic components (k(ET) of ~2 and 0.1 s(-1)), indicating the occurrence of additional dynamic motions. Moreover, the dynamic features associated with the electron transfer to the thioredoxin module are altered in the presence of 2-Cys Prx. NTRC shows structural constraints that may locate the thioredoxin module in positions with different efficiencies for electron transfer, the presence of 2-Cys Prx shifting the conformational equilibrium of the thioredoxin module to a specific position, which is not the most efficient. PMID- 22833675 TI - Rad50 zinc hook is important for the Mre11 complex to bind chromosomal DNA double stranded breaks and initiate various DNA damage responses. AB - The Mre11-Rad50-Nbs1 (MRN) complex plays critical roles in checkpoint activation and double-stranded break (DSB) repair. The Rad50 zinc hook domain mediates zinc dependent intercomplex associations of MRN, which is important for DNA tethering. Studies in yeast suggest that the Rad50 zinc hook domain is essential for MRN functions, but its role in mammalian cells is not clear. We demonstrated that the human Rad50 hook mutants are severely defective in various DNA damage responses including ATM (Ataxia telangiectasia mutated) activation, homologous recombination, sensitivity to IR, and activation of the ATR pathway. By using live cell imaging, we observed that the Rad50 hook mutants fail to be recruited to chromosomal DSBs, suggesting a novel mechanism underlying the severe defects observed for the Rad50 hook mutants. In vitro analysis showed that Zn(2+) promotes wild type but not the hook mutant of MR to bind double-stranded DNA. In vivo, the Rad50 hook mutants are defective in being recruited to chromosomal DSBs in both H2AX-proficient and -deficient cells, suggesting that the Rad50 hook mutants are impaired in direct binding to chromosomal DSB ends. We propose that the Rad50 zinc hook domain is important for the initial binding of MRN to DSBs, leading to ATM activation to phosphorylate H2AX, which recruits more MRN to the DSB-flanking chromosomal regions. Our studies reveal a critical role for the Rad50 zinc hook domain in establishing and maintaining MRN recruitment to chromosomal DSBs and suggest an important mechanism of how the Rad50 zinc hook domain contributes to DNA repair and checkpoint activation. PMID- 22833676 TI - A disintegrin and metalloproteinase 17 (ADAM17) and epidermal growth factor receptor (EGFR) signaling drive the epithelial response to Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1). AB - Staphylococcal superantigens (SAgs), such as toxic shock syndrome toxin-1 (TSST 1), are the main cause of toxic shock syndrome (TSS). SAgs deregulate the host immune system after penetrating epithelial barriers such as the vaginal mucosa. In response to TSST-1, human vaginal epithelial cells (HVECs) produce cytokines and undergo morphological changes. The epithelial signaling mechanisms employed by SAgs remain largely unknown and are the focus of the work presented here. Analysis of published microarray data identified a network of genes up-regulated by HVECs in response to TSST-1 that includes the sheddase, a disintegrin and metalloproteinase 17 (ADAM17). Investigation revealed that the ADAM17 proteolytic targets, amphiregulin (AREG), transforming growth factor alpha (TGFalpha), syndecan-1 (SDC1), and tumor necrosis factor receptor 1 (TNFR1), are shed from HVECs in response to TSST-1. TAPI-1 (an ADAM inhibitor) completely abrogates all observed shedding and the production of the cytokine interleukin-8 (IL-8). Knock down studies show that ADAM17, but not the closely related ADAM10, is required for AREG, TGFalpha, and TNFR1 shedding. Both ADAM10 and ADAM17 contribute to SDC1 shedding and IL-8 production by HVECs in response to TSST-1. EGFR signaling is critical for up-regulation of IL-8 at the transcriptional level in response to TSST-1 and is also necessary for AREG, TGFalpha, and TNFR1 shedding. A model is proposed describing the interactions of TSST-1, ADAMs, and the EGFR that lead to establishment of a proinflammatory positive feedback loop in epithelial cells and demonstrate a role for SAgs in the initial stages of disease. PMID- 22833677 TI - Altered pattern of immunoglobulin hypermutation in mice deficient in Slip-GC protein. AB - We recently identified a novel germinal center GTPase, SLIP-GC, that localizes to replication factories in B cells and that, when reduced, induces DNA breaks in lymphoma B cell lines in an activation-induced deaminase (AID)-dependent manner. Herein, we generated mice deficient in SLIP-GC and examined the impact of SLIP-GC deficiency in immunoglobulin hypermutation and class switch recombination, both AID-dependent mechanisms. SLIP-GC-deficient mice experienced a substantial increase in mutations at G:C base pairs at the region downstream of JH4 in the immunoglobulin heavy chain locus. This change was reflected in the overall mutation frequency, and it was associated with an increase in transitions from G:C base pairs, a hallmark of AID-mediated deamination during replication. In addition, G:C transitions at non-immunoglobulin loci also increased in these mice. Given the intracellular localization of SLIP-GC to sites of replicating DNA, these results suggest that SLIP-GC protects replicating DNA from AID mediated deamination of cytosines in both strands. PMID- 22833679 TI - Identification and characterization of D-hydroxyproline dehydrogenase and Delta1 pyrroline-4-hydroxy-2-carboxylate deaminase involved in novel L-hydroxyproline metabolism of bacteria: metabolic convergent evolution. AB - L-hydroxyproline (4-hydroxyproline) mainly exists in collagen, and most bacteria cannot metabolize this hydroxyamino acid. Pseudomonas putida and Pseudomonas aeruginosa convert L-hydroxyproline to alpha-ketoglutarate via four hypothetical enzymatic steps different from known mammalian pathways, but the molecular background is rather unclear. Here, we identified and characterized for the first time two novel enzymes, D-hydroxyproline dehydrogenase and Delta(1)-pyrroline-4 hydroxy-2-carboxylate (Pyr4H2C) deaminase, involved in this hypothetical pathway. These genes were clustered together with genes encoding other catalytic enzymes on the bacterial genomes. D-hydroxyproline dehydrogenases from P. putida and P. aeruginosa were completely different from known bacterial proline dehydrogenases and showed similar high specificity for substrate (D-hydroxyproline) and some artificial electron acceptor(s). On the other hand, the former is a homomeric enzyme only containing FAD as a prosthetic group, whereas the latter is a novel heterododecameric structure consisting of three different subunits (alpha(4)beta(4)gamma(4)), and two FADs, FMN, and [2Fe-2S] iron-sulfur cluster were contained in alphabetagamma of the heterotrimeric unit. These results suggested that the L-hydroxyproline pathway clearly evolved convergently in P. putida and P. aeruginosa. Pyr4H2C deaminase is a unique member of the dihydrodipicolinate synthase/N-acetylneuraminate lyase protein family, and its activity was competitively inhibited by pyruvate, a common substrate for other dihydrodipicolinate synthase/N-acetylneuraminate lyase proteins. Furthermore, disruption of Pyr4H2C deaminase genes led to loss of growth on L-hydroxyproline (as well as D-hydroxyproline) but not L- and D-proline, indicating that this pathway is related only to L-hydroxyproline degradation, which is not linked to proline metabolism. PMID- 22833678 TI - Vps34p is required for the decline of extracellular fructose-1,6-bisphosphatase in the vacuole import and degradation pathway. AB - When Saccharomyces cerevisiae are starved of glucose for a prolonged period of time, gluconeogenic enzymes such as fructose-1,6-bisphosphatase (FBPase), malate dehydrogenase, isocitrate lyase, and phosphoenolpyruvate carboxykinase are induced. However, when glucose is added to prolonged-starved cells, these enzymes are degraded in the vacuole via the vacuole import and degradation (Vid) pathway. The Vid pathway merges with the endocytic pathway to remove intracellular and extracellular proteins simultaneously. Ultrastructural and cell extraction studies indicate that substantial amounts of FBPase were in the extracellular fraction (periplasm) during glucose starvation. FBPase levels in the extracellular fraction decreased after glucose re-feeding in wild-type cells. The decline of FBPase in the extracellular fraction was dependent on the SLA1 and ARC18 genes involved in actin polymerization and endocytosis. Moreover, the reduction of extracellular FBPase was also dependent on the VPS34 gene. VPS34 encodes the PI3 kinase and is also required for the Vid pathway. Vps34p co localized with actin patches in prolonged-starved cells. In the absence of this gene, FBPase and the Vid vesicle protein Vid24p associated with actin patches before and after the addition of glucose. Furthermore, high levels of FBPase remained in the extracellular fraction in the Deltavps34 mutant during glucose re feeding. When the Asn-736 residue of Vps34p was mutated and when the C-terminal 11 amino acids were deleted, mutant proteins failed to co-localize with actin patches, and FBPase in the extracellular fraction did not decrease as rapidly. We suggest that VPS34 plays a critical role in the decline of extracellular FBPase in response to glucose. PMID- 22833680 TI - Negative regulation of human growth hormone gene expression by insulin is dependent on hypoxia-inducible factor binding in primary non-tumor pituitary cells. AB - Insulin controls growth hormone (GH) production at multiple levels, including via a direct effect on pituitary somatotrophs. There are no data, however, on the regulation of the intact human (h) GH gene (hGH1) by insulin in non-tumor pituitary cells, but the proximal promoter region (nucleotides -496/+1) responds negatively to insulin in transfected pituitary tumor cells. A DNA-protein interaction was also induced by insulin at nucleotides -308/-235. Here, we confirmed the presence of a hypoxia-inducible factor 1 (HIF-1) binding site within these sequences (-264/-259) and investigated whether HIF-1 is associated with insulin regulation of "endogenous" hGH1. In the absence of primary human pituitary cells, transgenic mice expressing the intact hGH locus in a somatotroph specific manner were generated. A significant and dose-dependent decrease in hGH and mouse GH RNA levels was detected in primary pituitary cell cultures from these mice with insulin treatment. Increasing HIF-1alpha availability with a hypoxia mimetic significantly decreased hGH RNA levels and was accompanied by recruitment of HIF-1alpha to the hGH1 promoter in situ as seen with insulin. Both inhibition of HIF-1 DNA binding by echinomycin and RNA interference of HIF-1alpha synthesis blunted the negative effect of insulin on hGH1 but not mGH. The insulin response is also sensitive to histone deacetylase inhibition/trichostatin A and associated with a decrease in H3/H4 hyperacetylation in the proximal hGH1 promoter region. These data are consistent with HIF-1-dependent down-regulation of hGH1 by insulin via chromatin remodeling specifically in the proximal promoter region. PMID- 22833681 TI - Interaction of endogenous tau protein with synaptic proteins is regulated by N methyl-D-aspartate receptor-dependent tau phosphorylation. AB - Amyloid-beta and tau protein are the two most prominent factors in the pathology of Alzheimer disease. Recent studies indicate that phosphorylated tau might affect synaptic function. We now show that endogenous tau is found at postsynaptic sites where it interacts with the PSD95-NMDA receptor complex. NMDA receptor activation leads to a selective phosphorylation of specific sites in tau, regulating the interaction of tau with Fyn and the PSD95-NMDA receptor complex. Based on our results, we propose that the physiologically occurring phosphorylation of tau could serve as a regulatory mechanism to prevent NMDA receptor overexcitation. PMID- 22833682 TI - TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity. AB - Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key RNA viral sensors for triggering antiviral immunity. The underlying mechanisms for RLRs to trigger antiviral immunity have yet to be explored. Here we report the identification of TAPE (TBK1-associated protein in endolysosomes) as a novel regulator of the RLR pathways. TAPE functionally and physically interacts with RIG-I, MDA5, and IPS-1 to activate the IFN-beta promoter. TAPE knockdown impairs IFN-beta activation induced by RLRs but not IPS-1. TAPE-deficient cells are defective in cytokine production upon RLR ligand stimulation. During RNA virus infection, TAPE knockdown or deficiency diminishes cytokine production and antiviral responses. Our data demonstrate a critical role for TAPE in linking RLRs to antiviral immunity. PMID- 22833683 TI - Design of a Community Ownership and Preparedness Index: using data to inform the capacity development of community-based groups. AB - BACKGROUND: Community mobilisation is an important component of a participatory approach to health and development interventions. However, it is challenging to define, measure and assess community participation and ownership of a programme, especially at scale. METHODS: An iterative cross-sectional survey was designed for implementation across a representative sample of community-based groups, using a weighted index that captured both qualitative and quantitative data in a standardised form. These data were aggregated at the level of individual groups, as well as state-wide or across the whole programme. Community participation in the survey is a primary feature of the methodology and was integral to the process of designing the index and administering the survey. RESULTS: The survey provided programme management and communities with objective tools for monitoring community mobilisation across a large-scale and complex intervention covering 32 districts in India. The implementation of the survey engaged communities in an open discussion of their goals and capabilities and helped them to challenge the power dynamics between themselves and other stakeholders. CONCLUSIONS: It is possible to translate the theoretical premises of participatory development into a tool that both measures and fosters meaningful participation. The active participation of community members in the collection and analysis of data on their mobilisation suggests that monitoring of participation can be undertaken to inform a scaled-up programme and can be a useful intervention in its own right. PMID- 22833684 TI - A randomized controlled trial comparing primary tumour resection plus systemic therapy with systemic therapy alone in metastatic breast cancer (PRIM-BC): Japan Clinical Oncology Group Study JCOG1017. AB - This trial is being conducted to confirm the superiority, in terms of overall survival, of primary tumour resection plus systemic therapy to systemic therapy alone in patients with Stage IV breast cancer who are not refractory to primary systemic therapy. The inclusion criteria for the study are as follows: untreated patients with histologically confirmed invasive breast cancer with one or more measurable metastatic lesions diagnosed by radiological examination. All patients receive primary systemic therapy according to the estrogen receptor and human epidermal growth factor receptor type-2 status of the primary breast cancer after the first registration. After 3 months, the patients without disease progression are randomized to the primary tumour resection plus systemic therapy arm or the systemic therapy alone arm. The primary endpoint is the overall survival, and the secondary endpoints are proportion of patients without tumour progression at the metastatic sites, yearly local recurrence-free survival, proportion of local ulcer/local bleeding, yearly primary tumour resection-free survival, adverse events of chemotherapy, operative morbidity and serious adverse events. The patient recruitment was commenced in May 2011. Enrolment of 410 patients for randomization is planned over a 5 year recruitment period. We hereby report the details of the study. PMID- 22833686 TI - Influence of dopamine concentration and surface coverage of Au shell on the optical properties of Au, Ag, and Ag(core)Au(shell) nanoparticles. AB - Gold (Au), silver (Ag), and Ag(core)Au(shell) nanoparticles (NPs) were explored as optical sensing agents for the sensitive detection of dopamine (DA) neurotransmitters in surface-enhanced Raman scattering (SERS) measurements. In these colloidal systems, dopamine (DA) molecules played as a cross-linker between M NPs (Au or Ag NPs), allowing them to reside in the confined junctions (i.e., hot spots) between aggregated NPs. The progressive addition of DA molecules (from 1 * 10(-6) to 1 * 10(-3) M) consequently decreased a primary absorption peak attributed to the characteristic M NPs and generated a secondary absorption peak at longer wavelengths attributed to heavily aggregated M NPs formed by molecular bridging effects of DA molecules at high concentrations. The aggregation degree of M NPs was also dependent on the surface states of Au and Ag NPs, i.e., DA molecules with positive amine groups induced more aggregations of Au NPs in comparison to Ag NPs with less negative charges. As the final outcome, Au NPs demonstrated higher sensitivity in SERS detection of DA at low concentrations (1 * 10(-7) to 1 * 10(-5) M), whereas Ag NPs exhibited the stronger Raman signals of DA molecules at high concentrations (1 * 10(-4) to 1 * 10(-3) M). Besides, Ag(core)Au(shell) NPs with the lowest surface coverage of Au shell exhibited more sensitive and stronger SERS activity for DA molecules than that of singular Au NPs, probably due to the combined contribution by Ag core with strong SERS intensity and Au shell with high SERS sensitivity. PMID- 22833687 TI - Novel spirocyclic phosphazene-based epoxy resin for halogen-free fire resistance: synthesis, curing behaviors, and flammability characteristics. AB - A novel halogen-free fire resistant epoxy resin with pendent spiro cyclotriphosphazene groups was designed and synthesized via a three-step synthetic pathway. The chemical structures and compositions of spiro cyclotriphosphazene precursors and final product were confirmed by (1)H, (13)C, and (31)P NMR spectroscopy, mass spectroscopy, elemental analysis, and Fourier transform infrared spectroscopy. The thermal curing behaviors of the synthesized epoxy resin with 4,4'-diamino-diphenylmethane, 4,4'-diamino-diphenyl sulfone, and novolac as hardeners were investigated by differential scanning calorimetry (DSC), and the curing kinetics were also studied under a nonisothermal condition. The evaluation of the thermal properties demonstrated that these thermosets achieved a good thermal resistance due to their high glass transition temperatures more than 150 degrees C, and also gained high thermal stabilities with high char yields. The flammability characteristics of the spirocyclic phosphazene-based epoxy thermosets cured with these three hardeners were investigated on the basis of the results obtained from the limiting oxygen index (LOI) and UL-94 vertical burning experiments as well as the analysis of the residual chars collected from the vertical burning tests. The high LOI values and UL-94 V-0 classification of these epoxy thermosets indicated that the incorporation of phosphazene rings into the backbone chain imparts nonflammability to the epoxy resin owing to the unique combination of phosphorus and nitrogen following by a synergistic effect on flame retardancy. The epoxy resin obtained in this study is a green functional polymer and will become a potential candidate for fire- and heat-resistant applications in electronic and microelectronic fields with more safety and excellent performance. PMID- 22833685 TI - High-capacity selective uptake of cholesteryl ester from native LDL during macrophage foam cell formation. AB - Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Recent studies have demonstrated that at high concentrations associated with hypercholesterolemia, native LDL induces macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol from native LDL during foam cell formation has not been clearly defined. Previous reports have suggested that selective cholesteryl ester (CE) uptake might contribute to cholesterol uptake from LDL independently of particle endocytosis. In this study we demonstrate that the majority of macrophage LDL-derived cholesterol is acquired by selective CE uptake in excess of LDL pinocytosis and degradation. Macrophage selective CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. In contrast to CE uptake, macrophages exhibit little selective uptake of free cholesterol (FC) from LDL. Following selective uptake from LDL, CE is rapidly hydrolyzed by a novel chloroquine-sensitive pathway. FC released from LDL-derived CE hydrolysis is largely effluxed from cells but also is subject to ACAT-mediated reesterification. These results indicate that selective CE uptake plays a major role in macrophage metabolism of LDL. PMID- 22833688 TI - Tailoring highly oriented and micropatterned clay/polymer nanocomposites by applying an a.c. electric field. AB - Clay/polymer nanocomposites have recently raised much interest because of their widespread industrial applications. Nevertheless, controlling both clay platelet exfoliation and orientation during polymerization still remains challenging. Herein, we report the elaboration of clay/polymer nanocomposite hydrogels from aqueous suspensions of natural swelling clays submitted to high-frequency a.c. electric fields. X-ray scattering experiments have confirmed the complete exfoliation of the clay sheets in the polymer matrix, even after polymerization. Moreover, polarized light microscopy shows that the clay platelets were perfectly oriented by the electric field and that this field-induced alignment was frozen in by in situ photopolymerization. This procedure allowed us to not only produce uniformly aligned samples but also pattern platelet orientation, at length scales down to 20 MUm. This straightforward and cheap nanocomposite patterning technique can be easily extended to a wide range of natural or synthetic inorganic anisotropic particles. PMID- 22833689 TI - Phase-controlled synthesis of cobalt sulfides for lithium ion batteries. AB - The polyhedral CoS(2) with a narrow size distribution was synthesized by a facile solid-state assembly process in a sealed silica tube. The flux of potassium halide (KX; X = Cl, Br, I) plays a crucial role in the formation of polyhedrons and the size distribution. The S(2)(2-) groups in CoS(2) can be controllably withdrawn during heat treatment in air. The obtained phases and microstructures of CoS(2), Co(3)S(4), CoS, Co(9)S(8), and CoO depended on heating temperature and time. These cobalt materials, successfully used as the electrodes of lithium ion batteries, possessed good cycling stability in lithium ion batteries. The discharge capacities of 929.1 and 835.2 mAh g(-1) were obtained for CoS(2) and CoS respectively, and 76% and 71% of the capacities remained after 10 cycles. High capacities and good cycle performance make them promising candidates for lithium ion batteries. The approach combining solid-state assembly and heat treatment provides a simple and versatile way to prepare various metal chalcogeides for energy storage applications. PMID- 22833690 TI - Synthesis and characterization of acetalated dextran polymer and microparticles with ethanol as a degradation product. AB - In the field of drug delivery, pH-sensitive polymeric microparticles can be used to release therapeutic payloads slowly in extracellular conditions (pH 7.4) and faster in more acidic areas in vivo, such as sites of inflammation, tumors, or intracellular conditions. Our group currently uses and is further developing the pH-sensitive polymer acetalated dextran (Ac-DEX), which is a biodegradable polymer with highly tunable degradation kinetics. Ac-DEX has displayed enhanced delivery of vaccine and drug components to immune and other cells, making it an extremely desirable polymer for immune applications. Currently, one of the degradation products of Ac-DEX is methanol, which may cause toxicity issues if applied at high concentrations with repeated doses. Therefore, in this manuscript we report the first synthesis and characterization of an Ac-DEX analog which, instead of a methanol degradation product, has a much safer ethanol degradation product. We abbreviate this ethoxy acetal derivatized acetalated dextran polymer as Ace-DEX, with the 'e' to indicate an ethanol degradation product. Like Ac-DEX, Ace-DEX microparticles have tunable degradation rates at pH 5 (intracellular). These rates range from hours to several days and are controlled simply by reaction time. Ace-DEX microparticles also show minimal cytotoxicity compared to commonly used poly(lactic-co-glycolic acid) (PLGA) microparticles when incubated with macrophages. This study aims to enhance the biocompatibility of acetalated dextran-type polymers to allow their use in high volume clinical applications such as multiple dosing and tissue engineering. PMID- 22833691 TI - Juvenile growth of the tropical sea urchin Lytechinus variegatus exposed to near future ocean acidification scenarios. AB - To evaluate the effect of elevated pCO(2) exposure on the juvenile growth of the sea urchin Lytechinus variegatus, we reared individuals for three months in one of three target pCO(2) levels: ambient seawater (380 uatm) and two scenarios that are projected to occur by the middle (560 uatm) and end (800 uatm) of this century. At the end of 89 days, urchins reared at ambient pCO(2) weighed 12% more than those reared at 560 uatm and 28% more than those reared at 800 uatm. Skeletons were analyzed using scanning electron miscroscopy, revealing degradation of spines in urchins reared at elevated pCO(2) (800 uatm). Our results indicate that elevated pCO(2) levels projected to occur this century may adversely affect the development of juvenile sea urchins. Acidification-induced changes to juvenile urchin development would likely impair performance and functioning of juvenile stages with implications for adult populations. PMID- 22833692 TI - Calibration of laser ablation inductively coupled plasma mass spectrometry for quantitative measurements of lead in bone. AB - Lead accumulates in bone over many years or decades. Accordingly, the study of lead in bone is important in determining the fate of ingested lead, the potential for remobilization, and for the application of bone lead measurements as a biomarker of lead exposure. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was used to measure the spatial distribution of lead in bone on the micrometer scale. In general, LA-ICP-MS studies are somewhat limited by the lack of matrix-matched standards and/or reference materials for calibration and validation purposes. Here we describe the application of pressed pellets prepared from New York State Department of Health candidate Reference Materials for Lead in Bone (levels 1 through 4), to provide a linear calibration for (208)Pb/(43)Ca in the concentration range <1 to 30 MUg g(-1). The limit of detection was estimated as 0.2 MUg g(-1). The measured lead values for pelletized NIST SRM 1486 Bone Meal and SRM 1400 Bone Ash were in good agreement with certified reference values. Using this approach, we quantitatively measured the spatial distribution of lead in a cross-section of goat metacarpal from a lead dosed animal. The lead content was spatially variable in the range of 2 to 30 MUg g(-1) with a complex distribution. In some sections, lead appeared to be enriched in the center of the bone relative to peripheral areas, indicating preferential accumulation in trabecular (spongy) rather than cortical bone. In addition, there were discrete areas of lead enrichment, or hot spots, of 100 to 200 MUm in width. PMID- 22833693 TI - Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors. AB - Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IVReplacement of the ribose moiety of adenosine 5'-triphosphate (ATP) with a carbocyclic ring constrained in either the Northern (N) or Southern (S) conformation produces agonists with widely differing activities at P2Y receptors (Kim et al. [2002] J Med Chem 45:208-218). We have used whole cell patch clamp recording to investigate the agonist activity of these two methanocarba analogs of ATP at four different P2X receptors (P2X(1), P2X(2), P2X(3), and P2X(2/3)). On dorsal root ganglion neurons, (N) methanocarba ATP ((1'S,2'R,3'S,4'R,5'S)-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl] bicyclo[ 3.1.0]hexane-2,3-diol; MRS 2340) activated rapidly-desensitizing (P2X(3)) and slowly-desensitizing (P2X(2/3)) receptors with a similar potency to ATP. In contrast, (S) methanocarba-ATP ((+/-)-5-(6-amino-9H-purin-9-yl)-1 [triphosphoryloxymethyl] bicycle [3.1.0]hexane-2,3-diol MRS 2312) was devoid of agonist activity. On nodose ganglion neurones, that express mainly P2X(2/3) receptors, ATP evoked a slowly desensitizing inward current with an EC(50) value of 26 MUM. MRS 2340 was an effective agonist, but less potent than ATP, while MRS 2312 at concentrations up to 100 MUM produced a barely detectable response. On mammalian cell lines expressing recombinant hP2X(1) and hP2X(2) receptors, MRS 2340 evoked inward currents similar in amplitude to those produced by the same concentration of ATP or alpha,beta-mATP. In contrast, MRS 2312 failed to give a detectable response. Although the conformation of the ribose affects agonist activity at P2Y receptors, there is a strong requirement for the (N) conformation for the activation of these P2X receptors. Furthermore, the region of the agonist binding site that accommodates the ribose moiety appears to be highly conserved among different P2X receptors. Drug Dev Res 61:227-232, 2004. PMID- 22833694 TI - ? AB - This article reflects on the ten years experience of group learning processes and skills acquisition by trainees of the ethics of biomedical and psychosocial research international training program from the Interdisciplinary Center for Studies on Bioethics of the University of Chile, Fogarty Grant R25TW6056. It takes into consideration the role of bioethics in training in its transdisciplinary character. PMID- 22833695 TI - Some Memories are Odder than Others: Judgments of Episodic Oddity Violate Known Decision Rules. AB - Current decision models of recognition memory are based almost entirely on one paradigm, single item old/new judgments accompanied by confidence ratings. This task results in receiver operating characteristics (ROCs) that are well fit by both signal-detection and dual-process models. Here we examine an entirely new recognition task, the judgment of episodic oddity, whereby participants select the mnemonically odd members of triplets (e.g., a new item hidden among two studied items). Using the only two known signal-detection rules of oddity judgment derived from the sensory perception literature, the unequal variance signal-detection model predicted that an old item among two new items would be easier to discover than a new item among two old items. In contrast, four separate empirical studies demonstrated the reverse pattern: triplets with two old items were the easiest to resolve. This finding was anticipated by the dual process approach as the presence of two old items affords the greatest opportunity for recollection. Furthermore, a bootstrap-fed Monte Carlo procedure using two independent datasets demonstrated that the dual-process parameters typically observed during single item recognition correctly predict the current oddity findings, whereas unequal variance signal-detection parameters do not. Episodic oddity judgments represent a case where dual- and single-process predictions qualitatively diverge and the findings demonstrate that novelty is "odder" than familiarity. PMID- 22833696 TI - MODELING MICROBUBBLE DYNAMICS IN BIOMEDICAL APPLICATIONS(). AB - Controlling microbubble dynamics to produce desirable biomedical outcomes when and where necessary and avoid deleterious effects requires advanced knowledge, which can be achieved only through a combination of experimental and numerical/analytical techniques. The present communication presents a multi physics approach to study the dynamics combining viscous- in-viscid effects, liquid and structure dynamics, and multi bubble interaction. While complex numerical tools are developed and used, the study aims at identifying the key parameters influencing the dynamics, which need to be included in simpler models. PMID- 22833697 TI - Maturation of medical student musculoskeletal medicine knowledge and clinical confidence. AB - PURPOSE: Despite the prevalence of musculoskeletal (MSK) disorders, the degree to which medical schools are providing students the knowledge and confidence to treat these problems is unclear. This study evaluated MSK knowledge in second and fourth year medical students using a newly developed written assessment tool and examined the maturation of clinical confidence in treating core MSK disorders. METHODS: Over a 3-year period, the National Board of Medical Examiners (NBME) MSK subject examination consisting of 75 items was administered to 568 second and fourth year students at a single institution. Students were also asked to rate their confidence in treating a selection of medicine/pediatric and MSK clinical scenarios on a 5-point Likert scale. RESULTS: Participation rate was 98%. The NBME MSK assessment score was 59.2 +/- 10.6 for all second year medical students and 69.7 +/- 9.6 for all fourth year medical students. There was a significant increase in NBME scores between the second and fourth years (p<0.0001). Students were more confident in treating internal medicine/pediatric conditions than MSK medicine conditions (p=0.001). Confidence in treating MSK medicine conditions did not improve between the second and fourth years (p=0.41). CONCLUSIONS: To our knowledge, this is the first study to report increased MSK medicine knowledge as measured by a standardized examination after completing medical school core clinical rotations. Despite increased MSK knowledge, low levels of MSK clinical confidence among graduating students were noted. Further research is needed to determine the factors that influence MSK knowledge and clinical confidence in medical students. PMID- 22833698 TI - Clinical skills assessment of procedural and advanced communication skills: performance expectations of residency program directors. AB - BACKGROUND: High stakes medical licensing programs are planning to augment and adapt current examinations to be relevant for a two-decision point model for licensure: entry into supervised practice and entry into unsupervised practice. Therefore, identifying which skills should be assessed at each decision point is critical for informing examination development, and gathering input from residency program directors is important. METHODS: Using data from previously developed surveys and expert panels, a web-delivered survey was distributed to 3,443 residency program directors. For each of the 28 procedural and 18 advanced communication skills, program directors were asked which clinical skills should be assessed, by whom, when, and how. Descriptive statistics were collected, and Intraclass Correlations (ICC) were conducted to determine consistency across different specialties. RESULTS: Among 347 respondents, program directors reported that all advanced communication and some procedural tasks are important to assess. The following procedures were considered 'important' or 'extremely important' to assess: sterile technique (93.8%), advanced cardiovascular life support (ACLS) (91.1%), basic life support (BLS) (90.0%), interpretation of electrocardiogram (89.4%) and blood gas (88.7%). Program directors reported that most clinical skills should be assessed at the end of the first year of residency (or later) and not before graduation from medical school. A minority were considered important to assess prior to the start of residency training: demonstration of respectfulness (64%), sterile technique (67.2%), BLS (68.9%), ACLS (65.9%) and phlebotomy (63.5%). DISCUSSION: Results from this study support that assessing procedural skills such as cardiac resuscitation, sterile technique, and phlebotomy would be amenable to assessment at the end of medical school, but most procedural and advanced communications skills would be amenable to assessment at the end of the first year of residency training or later. CONCLUSIONS: Gathering data from residency program directors provides support for developing new assessment tools in high-stakes licensing examinations. PMID- 22833699 TI - Connectivity and resilience of coral reef metapopulations in marine protected areas: matching empirical efforts to predictive needs. AB - Design and decision-making for marine protected areas (MPAs) on coral reefs require prediction of MPA effects with population models. Modeling of MPAs has shown how the persistence of metapopulations in systems of MPAs depends on the size and spacing of MPAs, and levels of fishing outside the MPAs. However, the pattern of demographic connectivity produced by larval dispersal is a key uncertainty in those modeling studies. The information required to assess population persistence is a dispersal matrix containing the fraction of larvae traveling to each location from each location, not just the current number of larvae exchanged among locations. Recent metapopulation modeling research with hypothetical dispersal matrices has shown how the spatial scale of dispersal, degree of advection versus diffusion, total larval output, and temporal and spatial variability in dispersal influence population persistence. Recent empirical studies using population genetics, parentage analysis, and geochemical and artificial marks in calcified structures have improved the understanding of dispersal. However, many such studies report current self-recruitment (locally produced settlement/settlement from elsewhere), which is not as directly useful as local retention (locally produced settlement/total locally released), which is a component of the dispersal matrix. Modeling of biophysical circulation with larval particle tracking can provide the required elements of dispersal matrices and assess their sensitivity to flows and larval behavior, but it requires more assumptions than direct empirical methods. To make rapid progress in understanding the scales and patterns of connectivity, greater communication between empiricists and population modelers will be needed. Empiricists need to focus more on identifying the characteristics of the dispersal matrix, while population modelers need to track and assimilate evolving empirical results. PMID- 22833700 TI - Restoration of coral populations in light of genetic diversity estimates. AB - Due to the importance of preserving the genetic integrity of populations, strategies to restore damaged coral reefs should attempt to retain the allelic diversity of the disturbed population; however, genetic diversity estimates are not available for most coral populations. To provide a generalized estimate of genetic diversity (in terms of allelic richness) of scleractinian coral populations, the literature was surveyed for studies describing the genetic structure of coral populations using microsatellites. The mean number of alleles per locus across 72 surveyed scleractinian coral populations was 8.27 (+/-0.75 SE). In addition, population genetic datasets from four species (Acropora palmata, Montastraea cavernosa, Montastraea faveolata and Pocillopora damicornis) were analyzed to assess the minimum number of donor colonies required to retain specific proportions of the genetic diversity of the population. Rarefaction analysis of the population genetic datasets indicated that using 10 donor colonies randomly sampled from the original population would retain >50% of the allelic diversity, while 35 colonies would retain >90% of the original diversity. In general, scleractinian coral populations are genetically diverse and restoration methods utilizing few clonal genotypes to re-populate a reef will diminish the genetic integrity of the population. Coral restoration strategies using 10-35 randomly selected local donor colonies will retain at least 50-90% of the genetic diversity of the original population. PMID- 22833701 TI - Moderators and Mediators in Social Work Research: Toward a More Ecologically Valid Evidence Base for Practice. AB - SUMMARY: Evidence-based practice involves the consistent and critical consumption of the social work research literature. As methodologies advance, primers to guide such efforts are often needed. In the present work, common statistical methods for testing moderation and mediation are identified, summarized, and corresponding examples, drawn from the substance abuse, domestic violence, and mental health literature, are provided. FINDINGS: While methodologically complex, analyses of these third variable effects can provide an optimal fit for the complexity involved in the provision of evidence-based social work services. While a moderator may identify the trait or state requirement for a causal relationship to occur, a mediator is concerned with the transmission of that relationship. In social work practice, these are questions of "under what conditions and for whom?" and of the "how?" of behavior change. IMPLICATIONS: Implications include a need for greater attention to these methods among practitioners and evaluation researchers. With knowledge gained through the present review, social workers can benefit from a more ecologically valid evidence base for practice. PMID- 22833703 TI - Chance encounters. PMID- 22833702 TI - Cigarette Smoking and Neonatal Outcomes in Depressed and Non-Depressed Opioid Dependent Agonist-Maintained Pregnant Patients. AB - AIMS: To investigate whether cigarette smoking and/or depression contribute to neonatal abstinence syndrome (NAS) severity. DESIGN: Cohort study analyzing data from a randomized, controlled trial of methadone versus buprenorphine. SETTING: Seven study sites that randomized patients to study conditions and provided comprehensive addiction treatment to pregnant patients. PARTICIPANTS: 119 of 131 opioid-dependent pregnant patients who completed the MOTHER study. MEASUREMENTS: Smoking data and depression status were obtained from the Addiction Severity Index and Mini International Neuropsychiatric Interview, respectively. Neonatal outcomes (birth weight, preterm delivery and NAS pharmacologic treatment) were collected from the medical charts. Study site was a fixed-effect factor in all analyses. FINDINGS: Cigarette smoking was reported by 94% of participants and depression identified in 35%. Smoking was associated with low birth weight, preterm delivery, and NAS pharmacologic treatment in both depressed and non depressed participants. The association between smoking and NAS treatment differed significantly between depressed and non-depressed participants. Among non-depressed participants, adjusting for site and illicit drug use, each additional average cigarette per day (CPD) increased the odds of NAS treatment by 12% [95%CI: (1.02-1.23), p=0.02]. Among depressed participants, each additional average CPD did not statistically increase the odds of NAS treatment [OR: 0.94, 95% CI: (0.84-1.04), p=0.23]. CONCLUSIONS: These results are consistent with the hypothesis that NAS expression is influenced by many factors. The relationship between CPD and NAS pharmacologic treatment is attenuated among depressed women in this study for reasons currently unknown. Further investigations are needed to clarify the complex relationships among maternal smoking, depression, and NAS. PMID- 22833704 TI - Restoring functional status: a long-term case report of severe lung and ventilatory muscle pump dysfunction involving recurrent bacterial pneumonias. AB - BACKGROUND AND PURPOSE: Prolonged mechanical ventilation contributes to immobility and deconditioning making efforts to safely discontinue ventilator support desirable. This case report documents how implementing physical therapy treatment interventions, based on the Guide to Physical Therapist Practice, can help to restore a person's functional status even after multiple years of mechanical ventilation dependency. CASE DESCRIPTION: A patient (female; aged 63 years) with severe restrictive and obstructive ventilatory impairment has survived 34 recurrent pneumonias involving 6 bacterial pathogens while being mechanically ventilated at home. A 3-year study was approved and informed consent obtained for a home exercise program of resistive extremity and inspiratory muscle training along with exercise reconditioning. Tolerable distances walked, maximal inspiratory and expiratory pressures, hours spent on versus off mechanical ventilation, activities performed within and around her home, and community excursions taken were charted. OUTCOMES: Daily time tolerated off the ventilator improved from less than one to 12 hours, distance walked in 6 minutes increased 33%, and maximal inspiratory and expiratory pressures improved 62% and 9.6% respectively. These improvements made out-of-home social excursions possible. DISCUSSION AND CONCLUSIONS: This patient's functional status improved following multiple physical therapy interventions dictated by the evaluation of initial physical therapy examination findings according to the Guide to Physical Therapist Practice. Long term mechanical ventilator dependency in the home environment did not exclude this patient from achieving clinically significant gains in functional status even when having severe restrictive and obstructive ventilator impairment. PMID- 22833705 TI - The heart rate response to nintendo wii boxing in young adults. AB - PURPOSE: To determine if 30 minutes of Nintendo Wii Sports boxing provides cardiorespiratory benefits and contributes to the daily exercise recommendations for healthy young adults. METHODS: Twenty healthy 23- to 27-year-olds participated in two sessions to measure maximum heart rate (HR(max)) via a treadmill test and heart rate (HR) response to 30 minutes of Wii Sports boxing. Heart rate in beats per minute (bpm) was measured continuously, and exercise intensity during each minute of play was stratified as a percentage of HR(max). Mixed designs analysis of variance (ANOVA) and Pearson product moment correlations were used to analyze the data. RESULTS: Mean (SD) HR response to boxing was 143 (15) bpm or 77.5% (10.0%) of HR(max). The mean HR response for experienced participants was significantly lower than inexperienced participants, P = .007. The ANOVA revealed a significant interaction between experience and time spent at various intensities, P = .009. Experienced participants spent more time in light to vigorous intensities, inexperienced participants in moderate to very hard intensities. Fitness was not correlated with mean HR response to boxing, P = .49. CONCLUSION: Thirty minutes of Nintendo Wii Sports boxing provides a moderate to vigorous aerobic response in healthy young adults and can contribute to daily recommendations for physical activity. PMID- 22833706 TI - The Submaximal Clinical Exercise Tolerance Test (SXTT) to Establish Safe Exercise Prescription Parameters for Patients with Chronic Disease and Disability. AB - PURPOSE: To describe how to perform a Submaximal Clinical Exercise Tolerance Test (SXTT) as part of an exercise evaluation in the physical therapy clinic to determine an appropriate exercise prescription and to establish safety of exercise for physical therapy clients. SUMMARY OF KEY POINTS: Physical activity is crucial for general health maintenance. An exercise evaluation includes a comprehensive patient history, physical examination, exercise testing, and exercise prescription. The SXTT provides important clinical data that form the foundation for an effective and safe exercise prescription. Observations obtained during the exercise evaluation will identify at-risk patients who should undergo further medical evaluation before starting an exercise program. Two case examples of SXTTs administered to individuals with multiple sclerosis are presented to demonstrate the application of these principles. STATEMENT OF RECOMMENDATIONS: Due to their unique qualifications, physical therapists shall assume responsibility to design and monitor safe and effective physical activity programs for all clients and especially for individuals with chronic disease and disability. To ensure safety and efficacy of prescribed exercise interventions, physical therapists need to perform an appropriate exercise evaluation including exercise testing before starting their clients on an exercise program. PMID- 22833707 TI - The linda crane lecture professionalism & core values in physical therapy: lessons learned from linda crane. PMID- 22833708 TI - Serum amino acid profiles and their alterations in colorectal cancer. AB - Mass spectrometry-based serum metabolic profiling is a promising tool to analyse complex cancer associated metabolic alterations, which may broaden our pathophysiological understanding of the disease and may function as a source of new cancer-associated biomarkers. Highly standardized serum samples of patients suffering from colon cancer (n = 59) and controls (n = 58) were collected at the University Hospital Leipzig. We based our investigations on amino acid screening profiles using electrospray tandem-mass spectrometry. Metabolic profiles were evaluated using the Analyst 1.4.2 software. General, comparative and equivalence statistics were performed by R 2.12.2. 11 out of 26 serum amino acid concentrations were significantly different between colorectal cancer patients and healthy controls. We found a model including CEA, glycine, and tyrosine as best discriminating and superior to CEA alone with an AUROC of 0.878 (95% CI 0.815-0.941). Our serum metabolic profiling in colon cancer revealed multiple significant disease-associated alterations in the amino acid profile with promising diagnostic power. Further large-scale studies are necessary to elucidate the potential of our model also to discriminate between cancer and potential differential diagnoses. In conclusion, serum glycine and tyrosine in combination with CEA are superior to CEA for the discrimination between colorectal cancer patients and controls. PMID- 22833709 TI - MSClust: a tool for unsupervised mass spectra extraction of chromatography-mass spectrometry ion-wise aligned data. AB - Mass peak alignment (ion-wise alignment) has recently become a popular method for unsupervised data analysis in untargeted metabolic profiling. Here we present MSClust-a software tool for analysis GC-MS and LC-MS datasets derived from untargeted profiling. MSClust performs data reduction using unsupervised clustering and extraction of putative metabolite mass spectra from ion-wise chromatographic alignment data. The algorithm is based on the subtractive fuzzy clustering method that allows unsupervised determination of a number of metabolites in a data set and can deal with uncertain memberships of mass peaks in overlapping mass spectra. This approach is based purely on the actual information present in the data and does not require any prior metabolite knowledge. MSClust can be applied for both GC-MS and LC-MS alignment data sets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0368-2) contains supplementary material, which is available to authorized users. PMID- 22833710 TI - MetAlign 3.0: performance enhancement by efficient use of advances in computer hardware. AB - A new, multi-threaded version of the GC-MS and LC-MS data processing software, metAlign, has been developed which is able to utilize multiple cores on one PC. This new version was tested using three different multi-core PCs with different operating systems. The performance of noise reduction, baseline correction and peak-picking was 8-19 fold faster compared to the previous version on a single core machine from 2008. The alignment was 5-10 fold faster. Factors influencing the performance enhancement are discussed. Our observations show that performance scales with the increase in processor core numbers we currently see in consumer PC hardware development. PMID- 22833711 TI - Optimization of cold methanol quenching for quantitative metabolomics of Penicillium chrysogenum. AB - A sampling procedure for quantitative metabolomics in Penicillium chrysogenum based on cold aqueous methanol quenching was re-evaluated and optimized to reduce metabolite leakage during sample treatment. The optimization study included amino acids and intermediates of the glycolysis and the TCA-cycle. Metabolite leakage was found to be minimal for a methanol content of the quenching solution (QS) of 40% (v/v) while keeping the temperature of the quenched sample near -20 degrees C. The average metabolite recovery under these conditions was 95.7% (+/-1.1%). Several observations support the hypothesis that metabolite leakage from quenched mycelia of P. chrysogenum occurs by diffusion over the cell membrane. First, a prolonged contact time between mycelia and the QS lead to a somewhat higher extent of leakage. Second, when suboptimal quenching liquids were used, increased metabolite leakage was found to be correlated with lower molecular weight and with lower absolute net charge. The finding that lowering the methanol content of the quenching liquid reduces metabolite leakage in P. chrysogenum contrasts with recently published quenching studies for two other eukaryotic micro-organisms. This demonstrates that it is necessary to validate and, if needed, optimize the quenching conditions for each particular micro-organism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0367-3) contains supplementary material, which is available to authorized users. PMID- 22833712 TI - Measuring self-reported health in low-income countries: piloting three instruments in semi-rural Burkina Faso. AB - BACKGROUND: National surveys in low-income countries increasingly rely on self reported measures of health. The ease, speed, and economy of collecting self reports of health make such collection attractive for rapid appraisals. However, the interpretation of these measures is complicated since different cultures understand and respond to the same question in different ways. OBJECTIVE: The aim of this pilot study was to develop a culturally sensitive tool to study the self reported health (SRH) of the local adult population in Burkina Faso. DESIGN: The study was carried out in the 2009 rainy season. The sample included 27 men and 25 women aged 18 or older who live in semi-urban Nouna, Burkina Faso. Three culturally adapted instruments were tested: a SRH question, a wooden visual analogue scale (VAS), and a drawn VAS. Respondents were asked to explain their answers to each instrument. The narratives were analyzed with the content analysis technique, and the prevalence of poor SRH was estimated from the quantitative data by stratification for respondent background variables (sex, age, literacy, education, marital status, ethnicity, chronic diseases). The correlation between the instruments was tested with Spearman's correlation test. RESULTS: The SRH question showed a 38.5% prevalence of poor SRH and 44.2% prevalence with both VAS. The correlation between the VAS was 0.89, whereas the correlation between the VAS and the SRH question was 0.60-0.64. Nevertheless, the question used as the basis of each instrument was culturally sensitive and clear to all respondents. Analysis of the narratives shows that respondents clearly differentiated between the various health statuses. CONCLUSION: In this pilot, we developed and tested a new version of the SRH question that may be more culturally sensitive than its non-adapted equivalents. Additional insight into this population's understanding and reporting of health was also obtained. A larger sample is needed to further study the validity and reliability of the SRH question and the VAS and understand which instrument is best suited to study SRH in the low-income setting of semi-rural Burkina Faso. PMID- 22833713 TI - Spelling is Just a Click Away - A User-Centered Brain-Computer Interface Including Auto-Calibration and Predictive Text Entry. AB - Brain-computer interfaces (BCI) based on event-related potentials (ERP) allow for selection of characters from a visually presented character-matrix and thus provide a communication channel for users with neurodegenerative disease. Although they have been topic of research for more than 20 years and were multiply proven to be a reliable communication method, BCIs are almost exclusively used in experimental settings, handled by qualified experts. This study investigates if ERP-BCIs can be handled independently by laymen without expert support, which is inevitable for establishing BCIs in end-user's daily life situations. Furthermore we compared the classic character-by-character text entry against a predictive text entry (PTE) that directly incorporates predictive text into the character-matrix. N = 19 BCI novices handled a user-centered ERP BCI application on their own without expert support. The software individually adjusted classifier weights and control parameters in the background, invisible to the user (auto-calibration). All participants were able to operate the software on their own and to twice correctly spell a sentence with the auto calibrated classifier (once with PTE, once without). Our PTE increased spelling speed and, importantly, did not reduce accuracy. In sum, this study demonstrates feasibility of auto-calibrating ERP-BCI use, independently by laymen and the strong benefit of integrating predictive text directly into the character-matrix. PMID- 22833714 TI - Decision making in the reward and punishment variants of the iowa gambling task: evidence of "foresight" or "framing"? AB - Surface-level differences in the reward and punishment variants, specifically greater long-term decision making in the punishment variant of the Iowa Gambling Task (IGT) observed in previous studies led to the present comparison of long term decision making in the two IGT variants (n = 320, male = 160). It was contended that risk aversion triggered by a positive frame of the reward variant and risk seeking triggered by a negative frame of the punishment variant appears as long-term decision making in the two IGT variants. Apart from the frame of the variant as a within-subjects factor (variant type: reward and punishment), the order in which the frame was triggered (order type: reward-punishment or punishment-reward), and the four types of instructions that delineated motivation toward reward from that of punishment (reward, punishment, reward and punishment, and no-hint) were hypothesized to have an effect on foresighted decision making in the IGT. As expected, long-term decision making differed across the two IGT variants suggesting that the frame of the variant has an effect on long-term decision making in the IGT (p < 0.001). The order in which a variant was presented, and the type of the instructions that were used both had an effect on long-term decision making in the two IGT variants (p < 0.05). A post hoc test suggested that the instructions that differentiated between reward and punishment resulted in greater foresight than the commonly used IGT instructions that fail to distinguish between reward and punishment. As observed in previous studies, there were more number of participants (60%) who showed greater foresight in the punishment variant than in the reward variant (p < 0.001). The results suggest that foresight in IGT decision making is sensitive to reward and punishment frame in an asymmetric manner, an observation that is aligned with the behavioral decision making framework. Benefits of integrating findings from behavioral studies in decision neuroscience are discussed, and a need to investigate cultural differences in the IGT studies is pointed out. PMID- 22833715 TI - Preference Reversals in Decision Making Under Risk are Accompanied by Changes in Attention to Different Attributes. AB - Recent work has shown that visual fixations reflect and influence trial-to-trial variability in people's preferences between goods. Here we extend this principle to attribute weights during decision making under risk. We measured eye movements while people chose between two risky gambles or bid on a single gamble. Consistent with previous work, we found that people exhibited systematic preference reversals between choices and bids. For two gambles matched in expected value, people systematically chose the higher probability option but provided a higher bid for the option that offered the greater amount to win. This effect was accompanied by a shift in fixations of the two attributes, with people fixating on probabilities more during choices and on amounts more during bids. Our results suggest that the construction of value during decision making under risk depends on task context partly because the task differentially directs attention at probabilities vs. amounts. Since recent work demonstrates that neural correlates of value vary with visual fixations, our results also suggest testable hypotheses regarding how task context modulates the neural computation of value to generate preference reversals. PMID- 22833716 TI - The Expression Pattern of the Na(+) Sensor, Na(X) in the Hydromineral Homeostatic Network: A Comparative Study between the Rat and Mouse. AB - The Scn7a gene encodes for the specific sodium channel Na(X), which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the Na(X) distribution pattern and the cell types that express Na(X) in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined Na(X) immunofluorescence with fluorescent cell markers to map and identify the Na(X) expressing cell populations throughout the network involved in hydromineral homeostasis. Here, we designed an anti-Na(X) antibody targeting the interdomain 2 3 region of the Na(X) channel's alpha-subunit. In both the rat and mouse, Na(X) immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocellular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. Na(X) immunostaining was also detected in neurons of the area postrema. In addition to this common Na(X) expression pattern, several differences in Na(X) immunostaining for certain structures and cell types were found between the rat and mouse. Na(X) was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas Na(X) was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, Na(X) immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the Na(X)-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. Na(X) expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na(+) sensing are specific to each rodent species. PMID- 22833717 TI - Self-Regulated Dynamical Criticality in Human ECoG. AB - Mounting experimental and theoretical results indicate that neural systems are poised near a critical state. In human subjects, however, most evidence comes from functional MRI studies, an indirect measurement of neuronal activity with poor temporal resolution. Electrocorticography (ECoG) provides a unique window into human brain activity: each electrode records, with high temporal resolution, the activity resulting from the sum of the local field potentials of ~10(5) neurons. We show that the human brain ECoG recordings display features of self regulated dynamical criticality: dynamical modes of activation drift around the critical stability threshold, moving in and out of the unstable region and equilibrating the global dynamical state at a very fast time scale. Moreover, the analysis also reveals differences between the resting state and a motor task, associated with increased stability of a fraction of the dynamical modes. PMID- 22833719 TI - Regulation of Fear Memory by Glucocorticoid and Cholinergic Receptors within the Dorsal Striatum. PMID- 22833720 TI - Nicotinic filtering of sensory processing in auditory cortex. AB - Although it has been known for decades that the drug nicotine can improve cognitive function, the nature of its effects and the underlying mechanisms are not well understood. Nicotine activates nicotinic acetylcholine (ACh) receptors (nAChRs) that normally are activated by endogenous ACh, presumably "hijacking" the cholinergic contribution to multiple cognitive functions, notably attention. Thus, studying nicotine's effects helps to better understand a commonly used drug as well as functions of nAChRs. Moreover, nicotinic agonists are being developed to treat a variety of disorders that involve attention-related or age-related cognitive dysfunction. Studies have shown that nicotine can enhance processing of attended stimuli and/or reduce processing of distracters; that is, nicotine enhances attentional filtering. To examine potential mechanisms within sensory cortex that may contribute to cognitive functions, here we describe nicotinic actions in primary auditory cortex, where well-characterized neural "filters" frequency receptive fields-can be exploited to examine nicotinic regulation of cortical processing. Using tone-evoked current-source density (CSD) profiles, we show that nicotine produces complex, layer-dependent effects on spectral and temporal processing that, broadly speaking, enhance responses to characteristic frequency (optimal) stimuli while simultaneously suppressing responses to spectrally distant stimuli. That is, nicotine appears to narrow receptive fields and enhances processing within the narrowed receptive field. Since basic cortical circuitry and nAChR distributions are similar across neocortex, these findings may generalize to neural processing in other sensory regions, and to non-sensory regions where afferent inputs are more difficult to manipulate experimentally. Similar effects across sensory and non-sensory cortical circuits could contribute to nicotinic enhancement of cognitive functions. PMID- 22833721 TI - Neurophysiological correlates of object recognition in the dorsal subiculum. AB - The medial temporal lobe (MTL) encompasses a network of interconnected cortical areas that is considered the neural substrate for some types of memory, such as spatial, episodic, recognition, and associative memory. Within the MTL, the subiculum has been well characterized in terms of its connectivity and structure, but its functional role remains elusive. A long-held view is that the subiculum is mainly involved in spatial encoding because it exhibits spatially selective firing and receives prominent projections from the CA1 field, which is an essential substrate for spatial memory. However, the dorsal subiculum (DS) is also reciprocally connected to the perirhinal and postrhinal cortices, which are critically involved in recognition memory. This connectivity pattern suggests that DS might encode not only spatial signals but also recognition signals. Here, we examined this hypothesis by recording with multi-electrodes in DS and CA1 of freely behaving mice, as they performed the novel object recognition (NOR) task. Analysis of network oscillations revealed that theta power was significantly higher in DS when mice explored novel objects as compared to familiar objects and that this theta modulation was absent in CA1. We also found significant differences in coherence between DS and CA1, in the theta and gamma bands, depending on whether mice examined objects or engaged in spatial exploration. Furthermore, single-unit recordings revealed that DS cells did not exhibit phase locked firing to theta and differed from CA1 place cells in that they had multiple peaks of spatially selective firing. We also detected DS units that were responsive specifically to novel object exploration, indicating that a subset of DS neurons were tuned to novelty during the NOR task. We have thus identified clear neurophysiological correlates for recognition within the DS, at the network and single-unit levels, strongly suggesting that it participates in encoding recognition-related signals. PMID- 22833722 TI - Recent and past musical activity predicts cognitive aging variability: direct comparison with general lifestyle activities. AB - Studies evaluating the impact of modifiable lifestyle factors on cognition offer potential insights into sources of cognitive aging variability. Recently, we reported an association between extent of musical instrumental practice throughout the life span (greater than 10 years) on preserved cognitive functioning in advanced age. These findings raise the question of whether there are training-induced brain changes in musicians that can transfer to non-musical cognitive abilities to allow for compensation of age-related cognitive declines. However, because of the relationship between engagement in general lifestyle activities and preserved cognition, it remains unclear whether these findings are specifically driven by musical training or the types of individuals likely to engage in greater activities in general. The current study controlled for general activity level in evaluating cognition between musicians and nomusicians. Also, the timing of engagement (age of acquisition, past versus recent) was assessed in predictive models of successful cognitive aging. Seventy age and education matched older musicians (>10 years) and non-musicians (ages 59-80) were evaluated on neuropsychological tests and general lifestyle activities. Musicians scored higher on tests of phonemic fluency, verbal working memory, verbal immediate recall, visuospatial judgment, and motor dexterity, but did not differ in other general leisure activities. Partition analyses were conducted on significant cognitive measures to determine aspects of musical training predictive of enhanced cognition. The first partition analysis revealed education best predicted visuospatial functions in musicians, followed by recent musical engagement which offset low education. In the second partition analysis, early age of musical acquisition (<9 years) predicted enhanced verbal working memory in musicians, while analyses for other measures were not predictive. Recent and past musical activity, but not general lifestyle activities, predicted variability across both verbal and visuospatial domains in aging. These findings are suggestive of different use-dependent adaptation periods depending on cognitive domain. Furthermore, they imply that early age of musical acquisition, sustained and maintained during advanced age, may enhance cognitive functions and buffer age and education influences. PMID- 22833718 TI - Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources. AB - Accumulating evidence indicates integration of dopamine function with metabolic signals, highlighting a potential role for dopamine in energy balance, frequently construed as modulating reward in response to homeostatic state. Though its precise role remains controversial, the reward perspective of dopamine has dominated investigation of motivational disorders, including obesity. In the hypothesis outlined here, we suggest instead that the primary role of dopamine in behavior is to modulate activity to adapt behavioral energy expenditure to the prevailing environmental energy conditions, with the role of dopamine in reward and motivated behaviors derived from its primary role in energy balance. Dopamine has long been known to modulate activity, exemplified by psychostimulants that act via dopamine. More recently, there has been nascent investigation into the role of dopamine in modulating voluntary activity, with some investigators suggesting that dopamine may serve as a final common pathway that couples energy sensing to regulated voluntary energy expenditure. We suggest that interposed between input from both the internal and external world, dopamine modulates behavioral energy expenditure along two axes: a conserve-expend axis that regulates generalized activity and an explore-exploit axes that regulates the degree to which reward value biases the distribution of activity. In this view, increased dopamine does not promote consumption of tasty food. Instead increased dopamine promotes energy expenditure and exploration while decreased dopamine favors energy conservation and exploitation. This hypothesis provides a mechanistic interpretation to an apparent paradox: the well-established role of dopamine in food seeking and the findings that low dopaminergic functions are associated with obesity. Our hypothesis provides an alternative perspective on the role of dopamine in obesity and reinterprets the "reward deficiency hypothesis" as a perceived energy deficit. We propose that dopamine, by facilitating energy expenditure, should be protective against obesity. We suggest the apparent failure of this protective mechanism in Western societies with high prevalence of obesity arises as a consequence of sedentary lifestyles that thwart energy expenditure. PMID- 22833724 TI - betaPix is a New Player in Renal Physiology. PMID- 22833723 TI - Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. AB - Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low-density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1) is a Nrf2 regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of HO, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide, and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative, and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO 1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This suggests that a potential intervention on HO-1 or its byproducts may need to take into account any potential alteration in the status of Nrf2 activation. This article reviews the available evidence that supports the antiatherogenic role of HO-1 as well as the potential pathways and mechanisms mediating vascular protection. PMID- 22833725 TI - Genetic inactivation of mitochondria-targeted redox enzyme p66ShcA preserves neuronal viability and mitochondrial integrity in response to oxidative challenges. AB - Mitochondria are essential to neuronal viability and function due to their roles in ATP production, intracellular calcium regulation, and activation of apoptotic pathways. Accordingly, mitochondrial dysfunction has been indicated in a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD), Huntington's disease, amyotrophic lateral sclerosis, stroke, and multiple sclerosis (MS). Recent evidence points to the permeability transition pore (PTP) as a key player in mitochondrial dysfunction in these diseases, in which pathologic opening leads to mitochondrial swelling, rupture, release of cytochrome c, and neuronal death. Reactive oxygen species (ROS), which are inducers of PTP opening, have been prominently implicated in the progression of many of these neurodegenerative diseases. In this context, inactivation of a mitochondria-targeted redox enzyme p66ShcA (p66) has been recently shown to prevent the neuronal cell death leading to axonal severing in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). To further characterize the response of neurons lacking p66, we assessed their reaction to treatment with stressors implicated in neurodegenerative pathways. Specifically, p66-knockout (p66-KO) and wild-type (WT) neurons were treated with hydrogen peroxide (H(2)O(2)) and nitric oxide (NO), and assessed for cell viability and changes in mitochondrial properties, including morphology and ROS production. The results showed that p66-KO neurons had greater survival following treatment with each stressor and generated less ROS when compared to WT neurons. Correspondingly, mitochondria in p66-KO neurons showed diminished morphological changes in response to these challenges. Overall, these findings highlight the importance of developing mitochondria-targeted therapeutics for neurodegenerative disorders, and emphasize p66, mitochondrial ROS, and the PTP as key targets for maintaining mitochondrial and neuronal integrity. PMID- 22833726 TI - Neural entrainment to rhythmically presented auditory, visual, and audio-visual speech in children. AB - Auditory cortical oscillations have been proposed to play an important role in speech perception. It is suggested that the brain may take temporal "samples" of information from the speech stream at different rates, phase resetting ongoing oscillations so that they are aligned with similar frequency bands in the input ("phase locking"). Information from these frequency bands is then bound together for speech perception. To date, there are no explorations of neural phase locking and entrainment to speech input in children. However, it is clear from studies of language acquisition that infants use both visual speech information and auditory speech information in learning. In order to study neural entrainment to speech in typically developing children, we use a rhythmic entrainment paradigm (underlying 2 Hz or delta rate) based on repetition of the syllable "ba," presented in either the auditory modality alone, the visual modality alone, or as auditory-visual speech (via a "talking head"). To ensure attention to the task, children aged 13 years were asked to press a button as fast as possible when the "ba" stimulus violated the rhythm for each stream type. Rhythmic violation depended on delaying the occurrence of a "ba" in the isochronous stream. Neural entrainment was demonstrated for all stream types, and individual differences in standardized measures of language processing were related to auditory entrainment at the theta rate. Further, there was significant modulation of the preferred phase of auditory entrainment in the theta band when visual speech cues were present, indicating cross-modal phase resetting. The rhythmic entrainment paradigm developed here offers a method for exploring individual differences in oscillatory phase locking during development. In particular, a method for assessing neural entrainment and cross-modal phase resetting would be useful for exploring developmental learning difficulties thought to involve temporal sampling, such as dyslexia. PMID- 22833728 TI - Antidepressants are an Important Part of Treating Depression. PMID- 22833727 TI - Learning to represent a multi-context environment: more than detecting changes. AB - Learning an accurate representation of the environment is a difficult task for both animals and humans, because the causal structures of the environment are unobservable and must be inferred from the observable input. In this article, we argue that this difficulty is further increased by the multi-context nature of realistic learning environments. When the environment undergoes a change in context without explicit cueing, the learner must detect the change and employ a new causal model to predict upcoming observations correctly. We discuss the problems and strategies that a rational learner might adopt and existing findings that support such strategies. We advocate hierarchical models as an optimal structure for retaining causal models learned in past contexts, thereby avoiding relearning familiar contexts in the future. PMID- 22833729 TI - Evidence for arousal-biased competition in perceptual learning. AB - Arousal-biased competition theory predicts that arousal biases competition in favor of perceptually salient stimuli and against non-salient stimuli (Mather and Sutherland, 2011). The current study tested this hypothesis by having observers complete many trials in a visual search task in which the target either always was salient (a 55 degrees tilted line among 80 degrees distractors) or non salient (a 55 degrees tilted line among 50 degrees distractors). Each participant completed one session in an emotional condition, in which visual search trials were preceded by negative arousing images, and one session in a non emotional condition, in which the arousing images were replaced with neutral images (with session order counterbalanced). Test trials in which the target line had to be selected from among a set of lines with different tilts revealed that the emotional condition enhanced identification of the salient target line tilt but impaired identification of the non-salient target line tilt. Thus, arousal enhanced perceptual learning of salient stimuli but impaired perceptual learning of non-salient stimuli. PMID- 22833730 TI - Asymmetric function of theta and gamma activity in syllable processing: an intra cortical study. AB - Low-gamma (25-45 Hz) and theta (4-8 Hz) oscillations are proposed to underpin the integration of phonemic and syllabic information, respectively. How these two scales of analysis split functions across hemispheres is unclear. We analyzed cortical responses from an epileptic patient with a rare bilateral electrode implantation (stereotactic EEG) in primary (A1/BA41 and A2/BA42) and association auditory cortices (BA22). Using time-frequency analyses, we confirmed the dominance of a 5-6 Hz theta activity in right and of a low-gamma (25-45 Hz) activity in left primary auditory cortices (A1/A2), during both resting state and syllable processing. We further detected high-theta (7-8 Hz) resting activity in left primary, but also associative auditory regions. In left BA22, its phase correlated with high-gamma induced power. Such a hierarchical relationship across theta and gamma frequency bands (theta/gamma phase-amplitude coupling) could index the process by which the neural code shifts from stimulus feature- to phonological-encoding, and is associated with the transition from evoked to induced power responses. These data suggest that theta and gamma activity in right and left auditory cortices bear different functions. They support a scheme where slow parsing of the acoustic information dominates in right hemisphere at a syllabic (5-6 Hz) rate, and left auditory cortex exhibits a more complex cascade of oscillations, reflecting the possible extraction of transient acoustic cues at a fast (~25-45 Hz) rate, subsequently integrated at a slower, e.g., syllabic one. Slow oscillations could functionally participate to speech processing by structuring gamma activity in left BA22, where abstract percepts emerge. PMID- 22833732 TI - The peer model advantage in infants' imitation of familiar gestures performed by differently aged models. AB - Infants' imitation of differently aged models has been predominately investigated with object-related actions and so far has lead to mixed evidence. Whereas some studies reported an increased likelihood of imitating peer models in contrast to adult models, other studies reported the opposite pattern of results. In the present study, 14-month-old infants were presented with four familiar gestures (e.g., clapping) that were demonstrated by differently aged televised models (peer, older child, adult). Results revealed that infants were more likely to imitate the peer model than the older child or the adult. This result is discussed with respect to a social function of imitation and the mechanism of imitating familiar behavior. PMID- 22833733 TI - What galvanic vestibular stimulation actually activates. AB - In a recent paper in Frontiers Cohen et al. (2012) asked "What does galvanic vestibular stimulation actually activate?" and concluded that galvanic vestibular stimulation (GVS) causes predominantly otolithic behavioral responses. In this Perspective paper we show that such a conclusion does not follow from the evidence. The evidence from neurophysiology is very clear: galvanic stimulation activates primary otolithic neurons as well as primary semicircular canal neurons (Kim and Curthoys, 2004). Irregular neurons are activated at lower currents. The answer to what behavior is activated depends on what is measured and how it is measured, including not just technical details, such as the frame rate of video, but the exact experimental context in which the measurement took place (visual fixation vs total darkness). Both canal and otolith dependent responses are activated by GVS. PMID- 22833731 TI - Individual differences in delay discounting under acute stress: the role of trait perceived stress. AB - Delay discounting refers to the reduction of the value of a future reward as the delay to that reward increases. The rate at which individuals discount future rewards varies as a function of both individual and contextual differences, and high delay discounting rates have been linked with problematic behaviors, including drug abuse and gambling. The current study investigated the effects of acute anticipatory stress on delay discounting, while considering two important factors: individual perceptions of stress and whether the stressful situation is future-focused or present-focused. Half of the participants experienced acute stress by anticipating giving a videotaped speech. This stress was either future oriented (speech about future job) or present-oriented (speech about physical appearance). They then performed a delay discounting task, in which they chose between smaller, immediate rewards, and larger, delayed rewards. Their scores on the Perceived Stress Scale were also collected. The way in which one appraises stressful situations interacts with acute stress to influence choices; under stressful conditions, delay discounting rate was highest in individuals with low trait perceived stress and lowest for individuals with high trait perceived stress. This result might be related to individual variation in reward responsiveness under stress. Furthermore, the time orientation of the task interacted with its stressfulness to affect the individual's propensity to choose immediate rewards. These findings add to our understanding of the intermediary factors between stress and decision-making. PMID- 22833734 TI - A specific role for phosphoinositide 3-kinase and AKT in osteoblasts? AB - The phosphoinositide 3-kinase and AKT (protein kinase B) signaling pathway (PI3K/AKT) plays a central role in the control of cell survival, growth, and proliferation throughout the body. With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts. There is further data demonstrating that PI3K/AKT has the capacity to specifically cross-talk with other signaling pathways and transcriptional networks controlling bone cells' development in order to fine-tune the osteoblast phenotype. There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies. In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast. PMID- 22833736 TI - Infection of Primary Bovine Macrophages with Mycobacterium avium Subspecies paratuberculosis Suppresses Host Cell Apoptosis. AB - Mycobacterium avium subspecies paratuberculosis (MAP) is able to survive intracellularly in macrophages by preventing normal phagosome maturation processes utilized to destroy bacteria. Infected macrophages often undergo apoptotic cell death to efficiently present bacterial antigens to the host adaptive immune system in a process known as efferocytosis. Recent studies with Mycobacterium tuberculosis (MTB) showed that macrophages infected with MTB are less likely to undergo apoptosis than control, uninfected cells. It is proposed that regulation of macrophage apoptosis is an important immune evasion tactic for MTB. Based on the similarity of MAP and MTB, we hypothesized that MAP-infected macrophages would be resistant to apoptosis compared to uninfected cells within the same culture and to cells from uninfected cultures. Our results demonstrate that, indeed, populations of MAP-infected macrophages contain fewer apoptotic cells than similar populations of control cells, and that MAP infection reduces the sensitivity of infected macrophages to induction of apoptosis by H(2)O(2). We further demonstrate that MAP-infected cells contain reduced caspase activity for caspases 3/7, 8, and 9. Reduced caspase activity in MAP-infected macrophages is also maintained after H(2)O(2) induction. This reduction in caspase activity is accompanied by a pronounced reduction in transcription of caspase genes encoding caspases 3, 7, and 8, but not for caspase 9, when compared to control, uninfected cells. Furthermore, MAP infection drastically effects the expression of several host cell proteins important for regulation of apoptosis. Studies using mutant MAP strains demonstrate the importance of bacterial specific factors in the control of host macrophage apoptosis. Together these data demonstrate that MAP specific factors may prevent caspase activity and caspase gene transcription as well as apoptosis signaling protein expression, resulting in decreased spontaneous host cell apoptosis and decreased sensitivity to apoptosis inducing agents. PMID- 22833735 TI - Glutamate signaling in healthy and diseased bone. AB - Bone relies on multiple extracellular signaling systems to maintain homeostasis of its normal structure and functions. The amino acid glutamate is a fundamental extracellular messenger molecule in many tissues, and is used in bone for both neural and non-neural signaling. This review focuses on the non-neural interactions, and examines the evolutionarily ancient glutamate signaling system in the context of its application to normal bone functioning and discusses recent findings on the role of glutamate signaling as they pertain to maintaining healthy bone structure. The underlying mechanisms of glutamate signaling and the many roles glutamate plays in modulating bone physiology are featured, including those involved in osteoclast and osteoblast differentiation and mature cell functions. Moreover, the relevance of glutamate signaling systems in diseases that affect bone, such as cancer and rheumatoid arthritis, is discussed, and will highlight how the glutamate system may be exploited as a viable therapeutic target. We will identify novel areas of research where knowledge of glutamate communication mechanisms may aid in our understanding of the complex nature of bone homeostasis. By uncovering the contributions of glutamate in maintaining healthy bone, the reader will discover how this complex molecular signaling system may advance our capacity to treat bone pathologies. PMID- 22833737 TI - Direct and Indirect Costs of Dinitrogen Fixation in Crocosphaera watsonii WH8501 and Possible Implications for the Nitrogen Cycle. AB - The recent detection of heterotrophic nitrogen (N(2)) fixation in deep waters of the southern Californian and Peruvian OMZ questions our current understanding of marine N(2) fixation as a process confined to oligotrophic surface waters of the oceans. In experiments with Crocosphaera watsonii WH8501, a marine unicellular diazotrophic (N(2) fixing) cyanobacterium, we demonstrated that the presence of high nitrate concentrations (up to 800 MUM) had no inhibitory effect on growth and N(2) fixation over a period of 2 weeks. In contrast, the environmental oxygen concentration significantly influenced rates of N(2) fixation and respiration, as well as carbon and nitrogen cellular content of C. watsonii over a 24-h period. Cells grown under lowered oxygen atmosphere (5%) had a higher nitrogenase activity and respired less carbon during the dark cycle than under normal oxygen atmosphere (20%). Respiratory oxygen drawdown during the dark period could be fully explained (104%) by energetic needs due to basal metabolism and N(2) fixation at low oxygen, while at normal oxygen these two processes could only account for 40% of the measured respiration rate. Our results revealed that under normal oxygen concentration most of the energetic costs during N(2) fixation (~60%) are not derived from the process of N(2) fixation per se but rather from the indirect costs incurred for the removal of intracellular oxygen or by the reversal of oxidative damage (e.g., nitrogenase de novo synthesis). Theoretical calculations suggest a slight energetic advantage of N(2) fixation relative to assimilatory nitrate uptake, when oxygen supply is in balance with the oxygen requirement for cellular respiration (i.e., energy generation for basal metabolism and N(2) fixation). Taken together our results imply the existence of a niche for diazotrophic organisms inside oxygen minimum zones, which are predicted to further expand in the future ocean. PMID- 22833738 TI - Phage therapy: concept to cure. PMID- 22833739 TI - Application of starter cultures to table olive fermentation: an overview on the experimental studies. AB - Table olives are one of the oldest fermented foods and are considered as an important component of the Mediterranean diet, since their richness in monounsaturated fats (primarily oleic acid) and phenolic compounds may function as antioxidants in the human body; in the Western world they represent one of the most popular fermented vegetables but, despite its economic significance, table olive fermentation is still craft-based and empirical. In particular, such a type of fermentation results from the competitive activities among indigenous, contaminating microorganisms, the microbial balance depending on several intrinsic (pH, water activity, diffusion of nutrients from the drupe, and level of anti-microbial compounds) and extrinsic (temperature, oxygen availability, and salt concentration) factors. At present, to reduce the risk of spoilage and to achieve a more predictable process there is an increasing interest in developing starter cultures for table olives fermentation. Anyway, the application of starter cultures in the field of table olives is quite far from reaching the diffusion as it has in other sectors of food industry (e.g., dairy products and alcoholic beverages). This review focuses on experimental researches devoted to studying starter cultures for possible application to table olive fermentation both at artisan and industrial level. PMID- 22833740 TI - Concurrent activity of anammox and denitrifying bacteria in the Black Sea. AB - After the discovery of ANaerobic AMMonium OXidation (anammox) in the environment, the role of heterotrophic denitrification as the main marine pathway for fixed N loss has been questioned. A 3 part, 15 month time series investigating nitrite reductase (nirS) mRNA transcripts at a single location in the Black Sea was conducted in order to better understand the activity of anammox and denitrifying bacteria. Here we show that both of these groups were active, as well as being concurrent in the lower suboxic zone over this time span. Their distributions, however, differed in that only expression of denitrification-type nirS was seen in the upper suboxic zone, where geochemistry was variable. Depth profiles covering the suboxic zone showed that the four groups of anammox-type sequences were expressed consistently in the lower suboxic zone, and were consistent with anammox 16 S rDNA gene profiles. By contrast, denitrifier-type nirS sequence groups were mixed; some groups exhibited consistent expression in the lower suboxic zone, while others appeared less consistent. Co-occurrence of both anammox and denitrifier expression was common and ongoing. Both types of transcripts were also found in samples with low concentrations of sulfide (>2 MUM). Six major groups of denitrifier-type nirS transcripts were identified, and several groups of denitrifier-type nirS transcripts were closely related to sequences from the Baltic Sea. An increase in denitrifier-type nirS transcript diversity and depth range in October 2007 corresponded to a small increase in mixed layer net community productivity (NCP) as measured by O(2)/Ar gas ratios, as well as to an increase in N(2) concentrations in the suboxic zone. Taken together, the variations in expression patterns between anammox and denitrification provide one possible explanation as to how near instantaneous rate measurements, such as isotope spike experiments, may regularly detect anammox activity but underreport denitrification. PMID- 22833742 TI - Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and cryptococcus with natural dihydroxybenzaldehydes. AB - In addition to the fungal cellular membrane, the cellular antioxidant system can also be a viable target in the antifungal action of amphotericin B (AMB). Co application of certain redox-potent natural compounds with AMB actually increases efficacy of the drug through chemosensitization. Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth. Chemosensitizing activities of four redox-potent benzaldehydes were tested against clinical and reference strains of Candida albicans, C. krusei, C. tropicalis, and Cryptococcus neoformans in combination with AMB, based on assays outlined by the European Committee on Antimicrobial Susceptibility Testing. Two dihydroxybenzaldehydes (DHBAs), i.e., 2,3-DHBA and 2,5-DHBA, significantly enhanced activity of AMB against most strains, as measured by lower minimum inhibitory concentrations and/or minimum fungicidal concentrations (MFCs). A non-hydroxylated benzaldehyde, trans cinnamaldehyde, showed chemosensitizing activity through lower MFCs, only. Contrastingly, a methoxylated benzaldehyde (3,5-dimethoxybenzaldehyde) had no chemosensitizing activity, as all strains were hypertolerant to this compound. Bioassays using deletion mutants of the model yeast, Saccharomyces cerevisiae, indicated DHBAs exerted their chemosensitizing activity by targeting mitochondrial superoxide dismutase. This targeting, in turn, disrupted the ability of the yeast strains to respond to AMB-induced oxidative stress. These in vitro results indicate that certain DHBAs are potent chemosensitizing agents to AMB through co-disruption of the oxidative stress response capacity of yeasts. Such redox-potent compounds show promise for enhancing AMB-based antifungal therapy for candidiasis and cryptococcosis. PMID- 22833741 TI - Molecular dynamics simulation in virus research. AB - Virus replication in the host proceeds by chains of interactions between viral and host proteins. The interactions are deeply influenced by host immune molecules and anti-viral compounds, as well as by mutations in viral proteins. To understand how these interactions proceed mechanically and how they are influenced by mutations, one needs to know the structures and dynamics of the proteins. Molecular dynamics (MD) simulation is a powerful computational method for delineating motions of proteins at an atomic-scale via theoretical and empirical principles in physical chemistry. Recent advances in the hardware and software for biomolecular simulation have rapidly improved the precision and performance of this technique. Consequently, MD simulation is quickly extending the range of applications in biology, helping to reveal unique features of protein structures that would be hard to obtain by experimental methods alone. In this review, we summarize the recent advances in MD simulations in the study of virus-host interactions and evolution, and present future perspectives on this technique. PMID- 22833743 TI - Post-ischemic inflammation in the brain. AB - Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor (TLR) 2 and TLR4. Some endogenous TLR ligands, high mobility group box 1 (HMGB1) and peroxiredoxin family proteins, in particular, are implicated in the activation and inflammatory cytokine expression in infiltrating macrophages. Following macrophage activation, T lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL-17 producing gammadeltaT lymphocytes induced by IL-23 from macrophages promote ischemic brain injury, whereas regulatory T lymphocytes suppress the function of inflammatory mediators. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells may lead to the development of novel neuroprotective therapies. PMID- 22833744 TI - Immunomodulatory effect of mesenchymal stem cells on B cells. AB - The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches. Mesenchymal stem cells (MSC) are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field. PMID- 22833745 TI - Cross-reactive broadly neutralizing antibodies: timing is everything. AB - The recent surge of research into new broadly neutralizing antibodies in HIV-1 infection has recharged the field of HIV-1 vaccinology. In this review we discuss the currently known broadly neutralizing antibodies and focus on factors that may shape these antibodies in natural infection. We further discuss the role of these antibodies in the clinical course of the infection and consider immunological obstacles in inducing broadly neutralizing antibodies with a vaccine. PMID- 22833746 TI - Mechanical force in T cell receptor signal initiation. PMID- 22833747 TI - An overview of existing modeling tools making use of model checking in the analysis of biochemical networks. AB - Model checking is a well-established technique for automatically verifying complex systems. Recently, model checkers have appeared in computer tools for the analysis of biochemical (and gene regulatory) networks. We survey several such tools to assess the potential of model checking in computational biology. Next, our overview focuses on direct applications of existing model checkers, as well as on algorithms for biochemical network analysis influenced by model checking, such as those using binary decision diagrams (BDDs) or Boolean-satisfiability solvers. We conclude with advantages and drawbacks of model checking for the analysis of biochemical networks. PMID- 22833748 TI - Selaginella moellendorffii telomeres: conserved and unique features in an ancient land plant lineage. AB - Telomeres, the essential terminal regions of linear eukaryotic chromosomes, consist of G-rich DNA repeats bound by a plethora of associated proteins. While the general pathways of telomere maintenance are evolutionarily conserved, individual telomere complex components show remarkable variation between eukaryotic lineages and even within closely related species. The recent genome sequencing of the lycophyte Selaginella moellendorffii and the availability of an ever-increasing number of flowering plant genomes provides a unique opportunity to evaluate the molecular and functional evolution of telomere components from the early evolving non-seed plants to the more developmentally advanced angiosperms. Here we analyzed telomere sequence in S. moellendorffii and found it to consist of TTTAGGG repeats, typical of most plants. Telomere tracts in S. moellendorffii range from 1 to 5.5 kb, closely resembling Arabidopsis thaliana. We identified several S. moellendorffii genes encoding sequence homologs of proteins involved in telomere maintenance in other organisms, including CST complex components and the telomere-binding proteins, POT1 and the TRFL family. Notable sequence similarities and differences were uncovered among the telomere related genes in some of the plant lineages. Taken together, the data indicate that comparative analysis of the telomere complex in early diverging land plants such as S. moellendorffii and green algae will yield important insights into the evolution of telomeres and their protein constituents. PMID- 22833749 TI - Improving yield potential in crops under elevated CO(2): Integrating the photosynthetic and nitrogen utilization efficiencies. AB - Increasing crop productivity to meet burgeoning human food demand is challenging under changing environmental conditions. Since industrial revolution atmospheric CO(2) levels have linearly increased. Developing crop varieties with increased utilization of CO(2) for photosynthesis is an urgent requirement to cope with the irreversible rise of atmospheric CO(2) and achieve higher food production. The primary effects of elevated CO(2) levels in most crop plants, particularly C(3) plants, include increased biomass accumulation, although initial stimulation of net photosynthesis rate is only temporal and plants fail to sustain the maximal stimulation, a phenomenon known as photosynthesis acclimation. Despite this acclimation, grain yield is known to marginally increase under elevated CO(2). The yield potential of C(3) crops is limited by their capacity to exploit sufficient carbon. The "C fertilization" through elevated CO(2) levels could potentially be used for substantial yield increase. Rubisco is the rate-limiting enzyme in photosynthesis and its activity is largely affected by atmospheric CO(2) and nitrogen availability. In addition, maintenance of the C/N ratio is pivotal for various growth and development processes in plants governing yield and seed quality. For maximizing the benefits of elevated CO(2), raising plant nitrogen pools will be necessary as part of maintaining an optimal C/N balance. In this review, we discuss potential causes for the stagnation in yield increases under elevated CO(2) levels and explore possibilities to overcome this limitation by improved photosynthetic capacity and enhanced nitrogen use efficiency. Opportunities of engineering nitrogen uptake, assimilatory, and responsive genes are also discussed that could ensure optimal nitrogen allocation toward expanding source and sink tissues. This might avert photosynthetic acclimation partially or completely and drive for improved crop production under elevated CO(2) levels. PMID- 22833751 TI - MRMaid: The SRM Assay Design Tool for Arabidopsis and Other Species. AB - Selected reaction monitoring (SRM), sometimes called multiple reaction monitoring (MRM), is becoming the tool of choice for targeted quantitative proteomics in the plant science community. Key to a successful SRM experiment is prior identification of the distinct peptides for the proteins of interest and the determination of the so-called transitions that can be programmed into an LC MS/MS to monitor those peptides. The transition for a given peptide comprises the intact peptide m/z and a high intensity product ion that can be monitored at a characteristic retention time (RT). To aid the design of SRM experiments, several online tools and databases have been produced to help researchers select transitions for their proteins of interest, but many of these tools are limited to the most popular model organisms such as human, yeast, and mouse or require the experimental acquisition of local spectral libraries. In this paper we present MRMaid, a web-based SRM assay design tool whose transitions are generated by mining the millions of identified peptide spectra held in the EBI's PRIDE database. By using data from this large public repository, MRMaid is able to cover a wide range of species that can increase as the coverage of PRIDE grows. In this paper MRMaid transitions for 25 Arabidopsis thaliana proteins are evaluated experimentally, and found capable of quantifying 23 of these proteins. This performance was found to be comparable with the more time consuming approach of designing transitions using locally acquired orbitrap data, indicating that MRMaid is a valuable tool for targeted Arabidopsis proteomics. PMID- 22833750 TI - Control of sulfur partitioning between primary and secondary metabolism in Arabidopsis. AB - Sulfur is an essential nutrient for all organisms. Plants are able to take up inorganic sulfate and assimilate it into a range of bio-organic molecules either after reduction to sulfide or activation to 3'-phosphoadenosine 5' phosphosulfate. While the regulation of the reductive part of sulfate assimilation and the synthesis of cysteine has been studied extensively in the past three decades, much less attention has been paid to the control of synthesis of sulfated compounds. Only recently the genes and enzymes activating sulfate and transferring it onto suitable acceptors have been investigated in detail with emphasis on understanding the diversity of the sulfotransferase gene family and the control of partitioning of sulfur between the two branches of sulfate assimilation. Here, the recent progress in our understanding of these processes will be summarized. PMID- 22833752 TI - Moss cell walls: structure and biosynthesis. AB - The genome sequence of the moss Physcomitrella patens has stimulated new research examining the cell wall polysaccharides of mosses and the glycosyl transferases that synthesize them as a means to understand fundamental processes of cell wall biosynthesis and plant cell wall evolution. The cell walls of mosses and vascular plants are composed of the same classes of polysaccharides, but with differences in side chain composition and structure. Similarly, the genomes of P. patens and angiosperms encode the same families of cell wall glycosyl transferases, yet, in many cases these families have diversified independently in each lineage. Our understanding of land plant evolution could be enhanced by more complete knowledge of the relationships among glycosyl transferase functional diversification, cell wall structural and biochemical specialization, and the roles of cell walls in plant adaptation. As a foundation for these studies, we review the features of P. patens as an experimental system, analyses of cell wall composition in various moss species, recent studies that elucidate the structure and biosynthesis of cell wall polysaccharides in P. patens, and phylogenetic analysis of P. patens genes potentially involved in cell wall biosynthesis. PMID- 22833753 TI - Genetic variations and alternative splicing: the Glioma associated oncogene 1, GLI1. AB - Alternative splicing is a post-transcriptional regulatory process that is attaining stronger recognition as a modulator of gene expression. Alternative splicing occurs when the primary RNA transcript is differentially processed into more than one mature RNAs. This is the result of a variable definition/inclusion of the exons, the sequences that are excised from the primary RNA to form the mature RNAs. Consequently, RNA expression can generate a collection of differentially spliced RNAs, which may distinctly influence subsequent biological events, such as protein synthesis or other biomolecular interactions. Still the mechanisms that control exon definition and exon inclusion are not fully clarified. This mini-review highlights advances in this field as well as the impact of single nucleotide polymorphisms in affecting splicing decisions. The Glioma-associated oncogene 1, GLI1, is taken as an example in addressing the role of nucleotide substitutions for splicing regulation. PMID- 22833755 TI - What is Aging? PMID- 22833754 TI - Reduction of dynamical biochemical reactions networks in computational biology. AB - Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler models, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi steady state (QSS) and quasi-equilibrium approximations (QE), and provide practical recipes for model reduction of linear and non-linear networks. We also discuss the application of model reduction to the problem of parameter identification, via backward pruning machine learning techniques. PMID- 22833756 TI - Nocebo phenomena in medicine: their relevance in everyday clinical practice. AB - BACKGROUND: Nocebo phenomena are common in clinical practice and have recently become a popular topic of research and discussion among basic scientists, clinicians, and ethicists. METHODS: We selectively searched the PubMed database for articles published up to December 2011 that contained the key words "nocebo" or "nocebo effect." RESULTS: By definition, a nocebo effect is the induction of a symptom perceived as negative by sham treatment and/or by the suggestion of negative expectations. A nocebo response is a negative symptom induced by the patient's own negative expectations and/or by negative suggestions from clinical staff in the absence of any treatment. The underlying mechanisms include learning by Pavlovian conditioning and reaction to expectations induced by verbal information or suggestion. Nocebo responses may come about through unintentional negative suggestion on the part of physicians and nurses. Information about possible complications and negative expectations on the patient's part increases the likelihood of adverse effects. Adverse events under treatment with medications sometimes come about by a nocebo effect. CONCLUSION: Physicians face an ethical dilemma, as they are required not just to inform patients of the potential complications of treatment, but also to minimize the likelihood of these complications, i.e., to avoid inducing them through the potential nocebo effect of thorough patient information. Possible ways out of the dilemma include emphasizing the fact that the proposed treatment is usually well tolerated, or else getting the patient's permission to inform less than fully about its possible side effects. Communication training in medical school, residency training, and continuing medical education would be desirable so that physicians can better exploit the power of words to patients' benefit, rather than their detriment. PMID- 22833757 TI - Inpatient treatment of type 2 diabetes. AB - BACKGROUND: Type 2 diabetes is common in hospitalized patients and is often accompanied by comorbidities; it is thus reasonable to ask whether the current standard treatments for type 2 diabetes are suitable for in-hospital use. We discuss the current glucose-lowering strategies and glycemic targets and derive practical recommendations for their application in hospitalized patients. METHODS: The pertinent literature, including clinical trials, review articles, guidelines, and manufacturers' information is selectively reviewed. RESULTS: In critically ill patients with diabetes, the glucose concentration target value should be 140 to 180 mg/dL. In stable patients, the target should be less than 140 mg/dL in the fasting state and less than 180 mg/dL after meals. Hypoglycemic episodes should be strictly avoided. Temporary treatment with insulin is indicated for most hospitalized patients with diabetes, although oral antidiabetic agents may be continued if the hospitalization is expected to be brief. Intravenous insulin is advisable in certain situations, e.g., long operations or metabolic decompensation. Glucose-lowering strategies must be chosen individually for each patient, with consideration of the relevant comorbidities (e.g. coronary heart disease, congestive heart failure, cirrhosis, renal failure) and special conditions (e.g. prolonged fasting, administration of contrast agents, high-dose glucocorticoid treatment). CONCLUSION: The treatment of patients with type 2 diabetes in the hospital is very different from their treatment at home. The particular conditions and comorbidities that can arise in the hospital necessitate flexible, individualized strategies for lowering blood glucose concentration. PMID- 22833758 TI - Consider European guidelines for syncope. PMID- 22833759 TI - Unanswered questions. PMID- 22833761 TI - The indications for liver biopsy. AB - BACKGROUND: Despite improvements in serological and radiological techniques, liver biopsy remains the most reliable way to diagnose diffuse hepatic disease and hepatic nodules. The indications for this invasive technique must be weighed against the small, but not negligible, risk of a complication. METHODS: The indications for liver biopsy are summarized on the basis of a selective review of the literature, including the published recommendations and position statements of specialty societies in Germany and abroad. The conclusions are supplemented with an evaluation of the authors' own experience. RESULTS: The success of liver biopsy depends not only on the selection of the puncture method and on due attention to the relative and absolute contraindications, but also on the experience of the person carrying out the procedure. For patients with hepatitis of various etiologies, liver biopsy is used not only to establish the cause of the disorder, but also to assess the degree of inflammatory activity (grading) and the extent of fibrosis (staging). CONCLUSION: Liver biopsy enables the reliable diagnosis of hepatic lesions and is an important aid to treatment planning and prognostication. PMID- 22833762 TI - Blindness and visual impairment in Germany: a slight fall in prevalence. AB - BACKGROUND: Some 70% of all cases of blindness in Germany are due to diseases of old age. As the population at large is aging, the prevalence of blindness and visual impairment would be expected to rise. To assess this, we studied prevalence trends in Germany over the past three decades. METHODS: We calculated the age- and sex-standardized prevalence of blindness in Germany using data from the archive of the blind registry of the Rhineland Regional Council (Landschaftsverband Rheinland, LVR) for the years 1978 to 2006. We then validated the findings with the aid of data on blindness and visual impairment from the Statistics on Severe Disability (Schwerbehindertenstatistik, SBS) that are published periodically by the German Federal Statistical Office. RESULTS: The number of registered blind persons in the Rhineland increased from 10,665 in 1978 to 12,706 in 1987 and 15,766 in 1997, but it changed little thereafter, remaining at 15,725 in 2006. There was a corresponding trend in the prevalence of blindness in the Rhineland, which rose from 116.8 to 165.6 per 100,000 persons from 1978 to 1997 but was roughly the same, at 163.1 per 100,000 persons, in 2006. The SBS data on blindness and visual impairment reveal a decline in prevalence from 392 to 372 per 100,000 persons between 1987 and 2005. The standardized prevalence rates for blindness and visual impairment in Germany have been declining slowly since about 1997. DISCUSSION: Blindness and visual impairment have become slightly less common in Germany, even though the population is aging. This may be due, at least in part, to better eye health care. PMID- 22833763 TI - Imitation behavior and subsequent complications. PMID- 22833765 TI - Phosphates and behavioral abnormalities. PMID- 22833766 TI - Hypophosphatemia also increases the risk. PMID- 22833768 TI - Heat therapy--simple treatment for acute insects stings. PMID- 22833770 TI - Low vitamin d and cardiovascular risk factors in males and females from a sunny, rich country. AB - BACKGROUND: Low serum vitamin (vit) D levels are common even in sunny countries. We assessed the prevalence and relationship of low vit D with cardiovascular risk factors in Qatar. METHODS: Data were collected retrospectively from January 2008 and November 2009. In patients who had low vi t D (< 30 ng/ml ) , demographic and clinical profiles were analyzed and compared in males and females. RESULTS: The overall mean level of vit D among 547 patients was 14.4+/-11 ng/mL. Among the low vitamin D group, 56% were females (mean age 48+/-12) and 44% males (mean age 49.6+/-13). Severely low vit D levels (<10 ng/mL) were found in 231 (46%) patients with mean age of 46+/-12 years. Compared with females, males with low vitamin D were more likely to have diabetes mellitus (38 vs 22%, p=0.001), dyslipidemia (41 vs 29%, p=0.007), myocardial infarction (5.5 vs 1.5%, p=0.001) and angiographically documented coronary artery disease (CAD) (53 vs 17%, p=0.001). Multivariate logistic regression analysis showed that in the presence of low vit D, age and hypertension were independent predictors of CAD (OR 1.07;95% CI: 1.02-1.11) and OR 8.0; 95% CI: 1.67-39.82), respectively. CONCLUSIONS: Our study supports the widespread prevalence of low vit D in sunny regions. Low vit D is associated with 3 times increase in the rate of MI among males. Hypertension increases the risk of CAD 8 times in the presence of low vit D regardless of gender. PMID- 22833771 TI - Transdermal lidocaine and ketamine for neuropathic pain: a study of effectiveness and tolerability. AB - BACKGROUND: Acute neuropathic pain is a common disorder. Transdermal cream could be an alternative to oral medications. OBJECTIVE: To evaluate the effectiveness and tolerability of transdermal Lidocaine and Ketamine for acute neuropathic pain. STUDY DESIGN: Retrospective chart review SETTING: University-affiliated outpatient Physiatry clinic METHODS: ARTICIPANTS: neuropathic pain with a prescription of a transdermal cream containing Lidocaine and Ketamine. Ef fectiveness was evaluated by the number of patients with improvement divided by the total number of patients who re-ceived a prescription of the cream. RESULTS: A total of 854 patient charts were reviewed. Twenty-one patients with symptoms, signs, and/or a documented di-agnosis of neuropathic pain and had been given a prescription of a transdermal preparation containing Lidocaine and Ketamine. Four groups were identified: those with a clearly stated diagnosis of neuropathic pain and prescribed a transdermal compound containing Lidocaine and Ketamine with follow-up (Group A) or without follow-up (Group B), and those with a suggested diagnosis of neuropathic pain with (Group C) or without follow-up (Group D). Effectiveness of the cream was seven out of eight (87%) for Group A and one out of three (33%) for Group C. In total, eight out of 11 patients (73%) benefited from a cream containing Lidocaine and Ketamine. Two patients experienced skin reactions that led to discontin-uation of treatment. LIMITATIONS: This is a retrospective chart review without control group. CONCLUSION: Transdermal cream containing Ketamine and Lidocaine was effective in 73% of patients with acute neuro-pathic pain and may be a good alternative to oral medications. PMID- 22833772 TI - The use of instruments by Iranian endodontics and general practioners. AB - AIM: The current clinical practice of endodontics involves utilization of a variety of new technological advances and materials. Technologies available for use in endodontic offices today include battery or electric motors using NiTi rotary file systems, new generation of electronic apex locators (EALs), improved digital radiographic sensors, surgical microscopes, and ultrasonic units. The aim of this study was to determine the prevalence and use of newer technologies among Iranian dental practitioners. MATERIALS AND METHODS: The population under study included the dental practitioners participating in the 49th and 50(th) Congress of Dentistry, who were selected with a simple sampling method. Data was collected by questionnaires which were completed by the participants in an anonymous manner. The contingency table and chi-squared test were used for data analysis by SPSS 13.5 software. RESULTS: A total of 700 dental practitioners participated in the study; NiTi rotary systems were used by 50.1%; electronic apex locators were often employed by 46.3%; 21.7% reported that ultrasonic units were often used. Only 1.1% frequently used surgical microscopes. Males and females differed with respect to the use of newer technologies (P<0.05). CONCLUSION: Based on the results of the present study, it seems necessary for dentists to take part in continuing dental education programs related to the newer technologies to improve their knowledge and practice. PMID- 22833773 TI - Perifoveal microcirculation in macular oedema with retinal vein occlusion. PMID- 22833774 TI - Differences and Similarities in HIV Testing Among Men Who have Sex with Men and Women (MSMW) and Men Who Have Sex with Men Only (MSMO). AB - The study examined differences in HIV testing between men who have sex with men only (MSMO) (n=300) and men who have sex with men and women (MSMW) (n=105) and assessed associations with HIV testing among MSMW. A venue-based cross-sectional HIV surveillance study in 2008 (BESURE-MSM2) was examined. Prevalence of HIV testing was similar for MSMO and MSMW. One-on-one counseling (excluding counseling that is part of HIV testing) and having seen a health care provider in the past twelve months were associated with HIV testing in the past six months among MSMW in multivariate analyses. One-on-one counseling interventions may increase rates of HIV testing among MSMW. PMID- 22833775 TI - Prevalence of sexually transmitted diseases and hepatitis C in a survey of female sex workers in the north-East of Italy. AB - A key issue in the prevention and control of Sexually Transmitted Diseases (STD) is to provide access to health centres, and in diagnosing and treating STD. The present study is aimed to assess the prevalence of sexually transmitted diseases (STDs) and Hepatitis C virus (HCV) in a population of immigrant female sex workers (FSWs). We conducted a cross sectional survey of FSWs working in Verona, North-eastern Italy. Screening test included serology for STDs [including Human Immunodeficiency Virus (HIV), syphilis and Hepatitis B virus (HBV)] and hepatitis C virus (HCV).Sixteen out of 345 (4.6%) street FSWs screened during 1999-2007 resulted positive for HIV, 12 (3.5%) were positive for HBsAg, 7 (2.0%) were positive for syphilis serological test, and 3 (0.9%) were positive for HCV. Comparison of the prevalence data between women from Africa (286/345, 82.8%) and other countries showed no statistical difference for HIV infection (R.R. 1.44; 95% CI, 0.34-6.19) and for presence of HBsAg (R.R. 2.27; 95% CI, 0.30-17.24). The positivity of syphilis serologic tests had a lower prevalence among African FSWs (mostly coming from Nigeria) than among FSWs from Eastern Europe (57/345, 16.5%). This difference was statistically significant (R.R. 0.03; 95% CI, 0.00-0.28). The prevalence of HIV infection increased with age (p=0.04, by chi2 for trend analysis), but not with the time worked as sex workers in Italy. Moreover, the presence of any of the screened infections was predictable by both age and earlier time of immigration by way of logistic multivariable regression.The prevalence of HIV and HBsAg was higher in the whole analyzed cohort compared to the general population; prevalence of syphilis was significantly higher in FSWs from Eastern Europe than in FSWs from Africa. HCV prevalence remains low among non intravenous drug abuser FSWs. The data offers a starting point to address targeted intervention that would prevent FSWs acquiring and transmitting STDs. PMID- 22833776 TI - Computing Inter-Rater Reliability for Observational Data: An Overview and Tutorial. AB - Many research designs require the assessment of inter-rater reliability (IRR) to demonstrate consistency among observational ratings provided by multiple coders. However, many studies use incorrect statistical procedures, fail to fully report the information necessary to interpret their results, or do not address how IRR affects the power of their subsequent analyses for hypothesis testing. This paper provides an overview of methodological issues related to the assessment of IRR with a focus on study design, selection of appropriate statistics, and the computation, interpretation, and reporting of some commonly-used IRR statistics. Computational examples include SPSS and R syntax for computing Cohen's kappa and intra-class correlations to assess IRR. PMID- 22833777 TI - Comparative modeling of retinol-binding protein-3 and retinal S-antigen in Eales' disease and prediction of their binding sites using computational methods. AB - Retinal S-antigen and interphotoreceptor retinoid-binding protein-3 play a significant role in the etiopathogenesis of Eales' disease. Protein 3D structures are functionally very important and play a significant role in progression of the disease, hence these 3D structures are better target for further drug designing and relative studies. We developed 3D model structure of retinol-binding protein 3 and retinal S-antigen protein of human involved in Eales' disease. Functional site prediction is a very important and related step; hence, in the current course of analysis, we predicted putative functional site residues in the target proteins. Molecular models of these proteins of Eales' disease as documented in this study may provide a valuable aid for designing an inhibitor or better ligand against Eales' disease and could play a significant role in drug design. PMID- 22833778 TI - Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress. AB - Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9-20)-, mid-age (48-60)-, and >60 (62-76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H(2)O(2) toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca(2+) [Ca(2+)](c), and mitochondrial Ca(2+) [Ca(2+)](m) levels were measured using 2',7'-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (DeltaPsim) estimated using 5,5',6,6'-tetrachloro 1,1'3,3' tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to mid-age and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced DeltaPsim, decreased [Ca(2+)](c), and increased sequestration of [Ca(2+)](m) in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age related injury. PMID- 22833779 TI - A review of statistical methods for protein identification using tandem mass spectrometry. AB - Tandem mass spectrometry has emerged as a powerful tool for the characterization of complex protein samples, an increasingly important problem in biology. The effort to efficiently and accurately perform inference on data from tandem mass spectrometry experiments has resulted in several statistical methods. We use a common framework to describe the predominant methods and discuss them in detail. These methods are classified using the following categories: set cover methods, iterative methods, and Bayesian methods. For each method, we analyze and evaluate the outcome and methodology of published comparisons to other methods; we use this comparison to comment on the qualities and weaknesses, as well as the overall utility, of all methods. We discuss the similarities between these methods and suggest directions for the field that would help unify these similar assumptions in a more rigorous manner and help enable efficient and reliable protein inference. PMID- 22833781 TI - Effect of external stress on density and size of glandular trichomes in full grown Artemisia annua, the source of anti-malarial artemisinin. AB - BACKGROUND AND AIMS: Glandular trichomes (GT) of Artemisia annua produce valuable compounds for pharmaceutical and industrial uses, most notably the anti-malarial artemisinin. Our aim was to find out whether the density, number and size of GT can be manipulated to advantage by environmental stress. A range of external stress treatments, including stress response regulators, was therefore given to fully grown plants under field and greenhouse conditions. METHODOLOGY: In a field experiment (Ex1), seed-grown plants were subjected to chemical or physical stress and plants analysed after 5 weeks. In a greenhouse experiment (Ex2), three groups of clonally derived plants were stressed at weekly intervals for 5 weeks. Stress treatments included sandblasting, leaf cutting and spraying with jasmonic acid, salicylic acid, chitosan oligosaccharide (COS), H(2)O(2) (HP) and NaCl (SC)at different concentrations. Leaves from an upper and a lower position on the plants were analysed by fluorescence microscopy to determine the density and size of GT. PRINCIPAL RESULTS: Densities of GT on upper leaves of full-grown A. annua plants generally showed no response to external stress and only plants from one clone of Ex2 supported the hypothesis that increased density of GT was inducible in upper leaves by stress (significant for SC, HP and COS). The density of GT on lower leaves was not affected by stress in any experiment. Glandular trichomes were significantly smaller on the lower leaves in response to stress in Ex2, and a similar non-significant trend was observed in Ex1. CONCLUSIONS: The results indicate a dynamic system in which stress treatments of large A. annua plants had a minor promoting effect on the initiation of GT in developing leaves, and a maturing effect of GT later in the lifetime of the individual GT. The hypothesis that applying stress can induce larger GT or more numerous GT was rejected. PMID- 22833782 TI - Expert performance by athletes in the verbal estimation of spatial extents does not alter their perceptual metric of space. AB - Athletes often give more accurate estimates of egocentric distance along the ground than do non-athletes. To explore whether cognitive calibration was accompanied by perceptual change, athletes and non-athletes made verbal height and distance estimates and also did a perceptual matching task between perceived egocentric distances and frontal vertical extents. Both groups were well calibrated for height estimation for poles viewed frontally, but athletes were much better calibrated at estimating longer egocentric distances (which are systematically underestimated by non-athletes). Athletes were more likely to have learned specific units of ground distance from relevant sports contexts. Both groups reported using human height as a metric for vertical extent. For non athletes, verbal underestimation of ground distance corresponded to predictions based on perceptual matches between egocentric distances and vertical extents in conjunction with human-height-based verbal estimates of vertical extents. For athletes, the verbal scaling of egocentric distances of 10 m or more was more accurate and was not predicted by their egocentric distance matches to vertical extents. PMID- 22833780 TI - Detection of biomarkers using recombinant antibodies coupled to nanostructured platforms. AB - The utility of biomarker detection in tomorrow's personalized health care field will mean early and accurate diagnosis of many types of human physiological conditions and diseases. In the search for biomarkers, recombinant affinity reagents can be generated to candidate proteins or post-translational modifications that differ qualitatively or quantitatively between normal and diseased tissues. The use of display technologies, such as phage-display, allows for manageable selection and optimization of affinity reagents for use in biomarker detection. Here we review the use of recombinant antibody fragments, such as scFvs and Fabs, which can be affinity-selected from phage-display libraries, to bind with both high specificity and affinity to biomarkers of cancer, such as Human Epidermal growth factor Receptor 2 (HER2) and Carcinoembryonic antigen (CEA). We discuss how these recombinant antibodies can be fabricated into nanostructures, such as carbon nanotubes, nanowires, and quantum dots, for the purpose of enhancing detection of biomarkers at low concentrations (pg/mL) within complex mixtures such as serum or tissue extracts. Other sensing technologies, which take advantage of 'Surface Enhanced Raman Scattering' (gold nanoshells), frequency changes in piezoelectric crystals (quartz crystal microbalance), or electrical current generation and sensing during electrochemical reactions (electrochemical detection), can effectively provide multiplexed platforms for detection of cancer and injury biomarkers. Such devices may soon replace the traditional time consuming ELISAs and Western blots, and deliver rapid, point-of-care diagnostics to market. PMID- 22833784 TI - Current driven magnetic damping in dipolar-coupled spin system. AB - Magnetic damping of the spin, the decay rate from the initial spin state to the final state, can be controlled by the spin transfer torque. Such an active control of damping has given birth to novel phenomena like the current-driven magnetization reversal and the steady spin precession. The spintronic devices based on such phenomena generally consist of two separate spin layers, i.e., free and pinned layers. Here we report that the dipolar coupling between the two layers, which has been considered to give only marginal effects on the current driven spin dynamics, actually has a serious impact on it. The damping of the coupled spin system was greatly enhanced at a specific field, which could not be understood if the spin dynamics in each layer was considered separately. Our results give a way to control the magnetic damping of the dipolar coupled spin system through the external magnetic field. PMID- 22833783 TI - The Bcl-2 family member BIM has multiple glaucoma-relevant functions in DBA/2J mice. AB - Axonal insult induces retinal ganglion cell (RGC) death through a BAX-dependent process. The pro-apoptotic Bcl-2 family member BIM is known to induce BAX activation. BIM expression increased in RGCs after axonal injury and its induction was dependent on JUN. Partial and complete Bim deficiency delayed RGC death after mechanical optic nerve injury. However, in a mouse model of glaucoma, DBA/2J mice, Bim deficiency did not prevent RGC death in eyes with severe optic nerve degeneration. In a subset of DBA/2J mice, Bim deficiency altered disease progression resulting in less severe nerve damage. Bim deficient mice exhibited altered optic nerve head morphology and significantly lessened intraocular pressure elevation. Thus, a decrease in axonal degeneration in Bim deficient DBA/2J mice may not be caused by a direct role of Bim in RGCs. These data suggest that BIM has multiple roles in glaucoma pathophysiology, potentially affecting susceptibility to glaucoma through several mechanisms. PMID- 22833785 TI - Spin-polarized wide electron slabs in functionally graded polar oxide heterostructures. AB - We report on the high mobility wide electron slabs with enhanced correlation effects by tailoring the polarization effects in a functionally graded ZnMgO/ZnO heterostructures. The characteristics of three-dimensional (3D) spreading electrons are evidenced by the capacitance-voltage profiling and the quantization of 3D Fermi surface in magneto-transport measurements. Despite the weak spin orbit interaction, such electron slabs are spin-polarized with a large zero-field spin splitting energy, which is induced by the carrier-mediated ferromagnetism. Our results suggest that the vast majority of electrons are localized at the surface magnetic moment which does not allow spin manipulations, and only in the region visited by the itinerant carriers that the ferromagnetic exchange interactions via coupling to the surface local moments contribute to the spin transport. The host ferromagnetism is likely due to the formation of Zn cation vacancies on the surface regime induced by the stabilization mechanism and strain relaxation in ZnMgO polar ionic surface. PMID- 22833786 TI - Shifts in morphology and diet of non-native sticklebacks introduced into Japanese crater lakes. AB - An increasing number of exotic animals are causing ecological problems. Therefore, for better ecosystem management, it is important to understand how exotic species colonize and adapt to novel environments. The threespine sticklebacks (Gasterosteus aculeatus) can be a good vertebrate model system to explore the ecological and genetic mechanisms of adaptation not only in natural populations, but also in non-native populations. Although morphological changes have been documented in several introduced populations of stickleback, little is known about the dietary changes during colonization into novel environments. Here, we investigated the morphological and dietary changes of exotic threespine stickleback populations introduced into three Japanese crater lakes (Lake Towada, Lake Kussharo, and Lake Shikotsu). Sticklebacks were introduced into the crater lakes likely along with salmonids transplanted for aquaculture. The stickleback population in Lake Kussharo had multiple mitochondrial haplotypes and had larger phenotypic variances than other crater lake stickleback populations that had only one mitochondrial haplotype. Compilation of historical data on the morphology and stomach contents of the Lake Towada stickleback population showed that substantial shifts in body size and stomach contents occurred after colonization. Some of these changes may be related to an outbreak of the Schistocephalus parasite. These results suggest that sticklebacks can change their morphology and trophic ecology when they colonize novel environments. Therefore, extreme care should be taken when salmonids are transported between watersheds for aquaculture and that long-term monitoring of exotic species is essential for ecosystem management. In addition, further genetic studies on phenotypic changes in crater lake sticklebacks would help elucidate the genetic mechanisms underlying the adaptation of exotic fishes to novel environments. PMID- 22833787 TI - Fine-scale parallel patterns in diversity of small benthic Arctic charr (Salvelinus alpinus) in relation to the ecology of lava/groundwater habitats. AB - It is critical to study factors that are important for origin and maintenance of biological diversity. A comparative approach involving a large number of populations is particularly useful. We use this approach to study the relationship between ecological factors and phenotypic diversity in Icelandic Arctic charr (Salvelinus alpinus). Numerous populations of small benthic charr have evolved in lava springs in Iceland. These charr appear morphologically similar, but differ in important morphological features related to feeding. We found a clear relationship between diversity in morphology, diet, and ecological factors among populations. In particular, there were clear differences in morphology and diet between fish coming from habitats where the lava spring flowed on as a stream compared to habitats where the lava spring flowed into a pond. Our study shows that ecological factors are important for the origin and maintenance of biological diversity. The relationship between phenotype and ecological factors are observed on a fine scale, when comparing numerous populations that are phenotypically similar. This strongly suggests that for understanding, managing, and conserving biological diversity important ecological variables have to be taken into the account. PMID- 22833788 TI - Sea snakes rarely venture far from home. AB - The extent to which populations are connected by dispersal influences all aspects of their biology and informs the spatial scale of optimal conservation strategies. Obtaining direct estimates of dispersal is challenging, particularly in marine systems, with studies typically relying on indirect approaches to evaluate connectivity. To overcome this challenge, we combine information from an eight-year mark-recapture study with high-resolution genetic data to demonstrate extremely low dispersal and restricted gene flow at small spatial scales for a large, potentially mobile marine vertebrate, the turtleheaded sea snake (Emydocephalus annulatus). Our mark-recapture study indicated that adjacent bays in New Caledonia (<1.15 km apart) contain virtually separate sea snake populations. Sea snakes could easily swim between bays but rarely do so. Of 817 recaptures of marked snakes, only two snakes had moved between bays. We genotyped 136 snakes for 11 polymorphic microsatellite loci and found statistically significant genetic divergence between the two bays (F(ST)= 0.008, P < 0.01). Bayesian clustering analyses detected low mixed ancestry within bays and genetic relatedness coefficients were higher, on average, within than between bays. Our results indicate that turtleheaded sea snakes rarely venture far from home, which has strong implications for their ecology, evolution, and conservation. PMID- 22833789 TI - Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats. AB - In industrialized and/or agriculturally used landscapes, inhabiting species are exposed to a variety of anthropogenic changes in their environments. Genetic diversity may be reduced if populations encounter founder events, bottlenecks, or isolation. Conversely, genetic diversity may increase if populations adapt to changes in selective regimes in newly created habitats. With the present study, genetic variability of 918 sticklebacks from 43 samplings (21.3 +/- 3.8 per sample) at 36 locations from cultivated landscapes in Northwest Germany was analyzed at nine neutral microsatellite loci. To test if differentiation is influenced by habitat alterations, sticklebacks were collected from ancient running waters and adjacent artificial stagnant waters, from brooks with salt water inflow of anthropogenic and natural origin and adjacent freshwater sites. Overall population structure was dominated by isolation by distance (IBD), which was significant across all populations, and analysis of molecular variance (AMOVA) revealed that 10.6% of the variation was explained by river catchment area. Populations in anthropogenic modified habitats deviated from the general IBD structure and in the AMOVA, grouping by habitat type running/stagnant water explained 4.9% of variation and 1.4% of the variation was explained by salt /freshwater habitat. Sticklebacks in salt-polluted water systems seem to exhibit elevated migratory activity between fresh- and saltwater habitats, reducing IBD. In other situations, populations showed distinct signs of genetic isolation, which in some locations was attributed to mechanical migration barriers, but in others to potential anthropogenic induced bottleneck or founder effects. The present study shows that anthropogenic habitat alterations may have diverse effects on the population genetic structure of inhabiting species. Depending on the type of habitat change, increased genetic differentiation, diversification, or isolation are possible consequences. PMID- 22833790 TI - Host adaptations reduce the reproductive success of Varroa destructor in two distinct European honey bee populations. AB - Honey bee societies (Apis mellifera), the ectoparasitic mite Varroa destructor, and honey bee viruses that are vectored by the mite, form a complex system of host-parasite interactions. Coevolution by natural selection in this system has been hindered for European honey bee hosts since apicultural practices remove the mite and consequently the selective pressures required for such a process. An increasing mite population means increasing transmission opportunities for viruses that can quickly develop into severe infections, killing a bee colony. Remarkably, a few subpopulations in Europe have survived mite infestation for extended periods of over 10 years without management by beekeepers and offer the possibility to study their natural host-parasite coevolution. Our study shows that two of these "natural" honey bee populations, in Avignon, France and Gotland, Sweden, have in fact evolved resistant traits that reduce the fitness of the mite (measured as the reproductive success), thereby reducing the parasitic load within the colony to evade the development of overt viral infections. Mite reproductive success was reduced by about 30% in both populations. Detailed examinations of mite reproductive parameters suggest these geographically and genetically distinct populations favor different mechanisms of resistance, even though they have experienced similar selection pressures of mite infestation. Compared to unrelated control colonies in the same location, mites in the Avignon population had high levels of infertility while in Gotland there was a higher proportions of mites that delayed initiation of egg-laying. Possible explanations for the observed rapid coevolution are discussed. PMID- 22833791 TI - Within and between population variation in plant traits predicts ecosystem functions associated with a dominant plant species. AB - Linking intraspecific variation in plant traits to ecosystem carbon uptake may allow us to better predict how shift in populations shape ecosystem function. We investigated whether plant populations of a dominant old-field plant species (Solidago altissima) differed in carbon dynamics and if variation in plant traits among genotypes and between populations predicted carbon dynamics. We established a common garden experiment with 35 genotypes from three populations of S. altissima from either Tennessee (southern populations) or Connecticut (northern populations) to ask whether: (1) southern and northern Solidago populations will differ in aboveground productivity, leaf area, flowering time and duration, and whole ecosystem carbon uptake, (2) intraspecific trait variation (growth and reproduction) will be related to intraspecific variation in gross ecosystem CO(2) exchange (GEE) and net ecosystem CO(2) exchange (NEE) within and between northern and southern populations. GEE and NEE were 4.8* and 2* greater in southern relative to northern populations. Moreover, southern populations produced 13* more aboveground biomass and 1.4* more inflorescence mass than did northern populations. Flowering dynamics (first- and last-day flowering and flowering duration) varied significantly among genotypes in both the southern and northern populations, but plant performance and ecosystem function did not. Both productivity and inflorescence mass predicted NEE and GEE between S. altissima southern and northern populations. Taken together, our data demonstrate that variation between S. altissima populations in performance and flowering traits are strong predictors of ecosystem function in a dominant old-field species and suggest that populations of the same species might differ substantially in their response to environmental perturbations. PMID- 22833793 TI - The effect of purging on sexually selected traits through antagonistic pleiotropy with survival. AB - Sexually selected traits are expected to evolve to a point where their positive effect on reproductive success is counterbalanced by their negative effect on survival. At the genetic level, such a trade-off implies antagonistic pleiotropy between survival and the expression of sexually selected traits. Yet, the consequences of such a genetic architecture have been largely overlooked in studies examining how inbreeding influences sexually selected traits. These studies have solely interpreted their results as an effect of increased homozygosity. An alternative, however, is that purging of recessive alleles deleterious for survival when inbreeding increases can negatively affect the expression of sexually selected traits through antagonistic pleiotropy. We tested this hypothesis by analyzing the effects of inbreeding on several male ornaments and life-history traits across 20 captive populations of guppies (Poecilia reticulata) with varying levels of inbreeding. Only one ornament, orange area, decreased in its expression with an increasing level of inbreeding. This was most likely due to purging because we found no within-population relationship between orange area and the inbreeding coefficient. We further tested this hypothesis by crossing unrelated individuals from the four most inbred populations, creating a group of individuals with purged genomes but restored heterozygosity. Restoration of heterozygosity only slightly increased orange area, confirming that the decrease in orange area in the inbred populations most likely resulted from purging. These results support previous studies suggesting the existence of antagonistic pleiotropy between ornament expression and survival. PMID- 22833792 TI - Longitudinal trends in climate drive flowering time clines in North American Arabidopsis thaliana. AB - Introduced species frequently show geographic differentiation, and when differentiation mirrors the ancestral range, it is often taken as evidence of adaptive evolution. The mouse-ear cress (Arabidopsis thaliana) was introduced to North America from Eurasia 150-200 years ago, providing an opportunity to study parallel adaptation in a genetic model organism. Here, we test for clinal variation in flowering time using 199 North American (NA) accessions of A. thaliana, and evaluate the contributions of major flowering time genes FRI, FLC, and PHYC as well as potential ecological mechanisms underlying differentiation. We find evidence for substantial within population genetic variation in quantitative traits and flowering time, and putatively adaptive longitudinal differentiation, despite low levels of variation at FRI, FLC, and PHYC and genome wide reductions in population structure relative to Eurasian (EA) samples. The observed longitudinal cline in flowering time in North America is parallel to an EA cline, robust to the effects of population structure, and associated with geographic variation in winter precipitation and temperature. We detected major effects of FRI on quantitative traits associated with reproductive fitness, although the haplotype associated with higher fitness remains rare in North America. Collectively, our results suggest the evolution of parallel flowering time clines through novel genetic mechanisms. PMID- 22833794 TI - Intraspecific variability in the response of bloom-forming marine microalgae to changed climate conditions. AB - Phytoplankton populations can display high levels of genetic diversity that, when reflected by phenotypic variability, may stabilize a species response to environmental changes. We studied the effects of increased temperature and CO(2) availability as predicted consequences of global change, on 16 genetically different isolates of the diatom Skeletonema marinoi from the Adriatic Sea and the Skagerrak (North Sea), and on eight strains of the PST (paralytic shellfish toxin)-producing dinoflagellate Alexandrium ostenfeldii from the Baltic Sea. Maximum growth rates were estimated in batch cultures of acclimated isolates grown for five to 10 generations in a factorial design at 20 and 24 degrees C, and present day and next century applied atmospheric pCO(2), respectively. In both species, individual strains were affected in different ways by increased temperature and pCO(2). The strongest response variability, buffering overall effects, was detected among Adriatic S. marinoi strains. Skagerrak strains showed a more uniform response, particularly to increased temperature, with an overall positive effect on growth. Increased temperature also caused a general growth stimulation in A. ostenfeldii, despite notable variability in strain-specific response patterns. Our data revealed a significant relationship between strain specific growth rates and the impact of pCO(2) on growth-slow growing cultures were generally positively affected, while fast growing cultures showed no or negative responses to increased pCO(2). Toxin composition of A. ostenfeldii was consistently altered by elevated temperature and increased CO(2) supply in the tested strains, resulting in overall promotion of saxitoxin production by both treatments. Our findings suggest that phenotypic variability within populations plays an important role in the adaptation of phytoplankton to changing environments, potentially attenuating short-term effects and forming the basis for selection. In particular, A. ostenfeldii blooms may expand and increase in toxicity under increased water temperature and atmospheric pCO(2) conditions, with potentially severe consequences for the coastal ecosystem. PMID- 22833795 TI - The role of the Ord Arid Intrusion in the historical and contemporary genetic division of long-tailed finch subspecies in northern Australia. AB - The effect of separation by biogeographic features followed by secondary contact can blur taxonomic boundaries and produce complex genetic signatures. We analyzed population structure and gene flow across the range of the long-tailed finch (Poephila acuticauda) in northern Australia (1) to test the hypothesis that Ord Arid Intrusion acted as the causative barrier that led to divergence of P. acuticauda subspecies, (2) to determine whether genetic data support the presence of a gradual cline across the range or a sudden shift, both of which have been suggested based on morphological data, and (3) to estimate levels of contemporary gene flow within this species complex. We collected samples from 302 individuals from 10 localities. Analyses of 12 microsatellite loci and sequence data from 333 base pairs of the mitochondrial control region were used to estimate population structure and gene flow, using analysis of molecular variance (AMOVA), haplotype network analysis, frequency statistics, and clustering methods. Mitochondrial sequence data indicated the presence of three genetic groups (regions) across the range of P. acuticauda. Genetic diversity was highest in the east and lowest in the west. The Ord Arid Intrusion appears to have functioned as a biogeographic barrier in the past, according to mtDNA evidence presented here and evidence from previous studies. The absence of isolation by distance between adjacent regions and the lack of population genetic structure of mtDNA within regions indicates that genetic changes across the range of P. acuticauda subspecies are characterized by discrete breaks between regions. While microsatellite data indicate a complete absence of genetic structure across this species' range, it appears unlikely that this results from high levels of gene flow. Mitochondrial data do not support the presence of contemporary gene flow across the range of this species. PMID- 22833796 TI - Phylogeography of the prehensile-tailed skink Corucia zebrata on the Solomon Archipelago. AB - The biogeography of islands is often strongly influenced by prior geological events. Corucia zebrata (Squamata: Scincidae) is endemic to the geologically complex Solomon Archipelago in Northern Melanesia. We examined the level of divergence for different island populations of C. zebrata and discussed these patterns in light of Pleistocene land bridges, island isolation, and island age. Corucia zebrata was sampled from 14 locations across the Solomon Archipelago and sequenced at two mitochondrial genes (ND2 and ND4; 1697 bp in total) and four nuclear loci (rhodopsin, an unknown intron, AKAP9, and PTPN12). Measures of genetic divergence, analyses of genetic variation, and Bayesian phylogenetic inference were used and the data assessed in light of geological information. Populations of C. zebrata on separate islands were found to be genetically different from each other, with reciprocal monophyly on mitochondrial DNA. Populations on islands previously connected by Pleistocene land bridges were marginally less divergent from each other than from populations on other nearby but isolated islands. There are indications that C. zebrata has radiated across the eastern islands of the archipelago within the last 1-4 million years. Nuclear loci were not sufficiently informative to yield further information about the phylogeography of C. zebrata on the Solomon Archipelago. Analyses of the mitochondrial data suggest that dispersal between islands has been very limited and that there are barriers to gene flow within the major islands. Islands that have been isolated during the Pleistocene glacial cycles are somewhat divergent in their mitochondrial genotypes, however, isolation by distance (IBD) and recent colonization of isolated but geologically younger islands appear to have had stronger effects on the phylogeography of C. zebrata than the Pleistocene glacial cycles. This contrasts with patterns reported for avian taxa, and highlights the fact that biogeographic regions for island species cannot be directly extrapolated among taxa of differing dispersal ability. PMID- 22833797 TI - Plant root distributions and nitrogen uptake predicted by a hypothesis of optimal root foraging. AB - CO(2)-enrichment experiments consistently show that rooting depth increases when trees are grown at elevated CO(2) (eCO(2)), leading in some experiments to increased capture of available soil nitrogen (N) from deeper soil. However, the link between N uptake and root distributions remains poorly represented in forest ecosystem and global land-surface models. Here, this link is modeled and analyzed using a new optimization hypothesis (MaxNup) for root foraging in relation to the spatial variability of soil N, according to which a given total root mass is distributed vertically in order to maximize annual N uptake. MaxNup leads to analytical predictions for the optimal vertical profile of root biomass, maximum rooting depth, and N-uptake fraction (i.e., the proportion of plant-available soil N taken up annually by roots). We use these predictions to gain new insight into the behavior of the N-uptake fraction in trees growing at the Oak Ridge National Laboratory free-air CO(2)-enrichment experiment. We also compare MaxNup with empirical equations previously fitted to root-distribution data from all the world's plant biomes, and find that the empirical equations underestimate the capacity of root systems to take up N. PMID- 22833798 TI - Effects of adaptation, chance, and history on the evolution of the toxic dinoflagellate Alexandrium minutum under selection of increased temperature and acidification. AB - The roles of adaptation, chance, and history on evolution of the toxic dinoflagellate Alexandrium minutum Halim, under selective conditions simulating global change, have been addressed. Two toxic strains (AL1V and AL2V), previously acclimated for two years at pH 8.0 and 20 degrees C, were transferred to selective conditions: pH 7.5 to simulate acidification and 25 degrees C. Cultures under selective conditions were propagated until growth rate and toxin cell quota achieved an invariant mean value at 720 days (ca. 250 and ca. 180 generations for strains AL1V and AL2V, respectively). Historical contingencies strongly constrained the evolution of growth rate and toxin cell quota, but the forces involved in the evolution were not the same for both traits. Growth rate was 1.5 1.6 times higher than the one measured in ancestral conditions. Genetic adaptation explained two-thirds of total adaptation while one-third was a consequence of physiological adaptation. On the other hand, the evolution of toxin cell quota showed a pattern attributable to neutral mutations because the final variances were significantly higher than those measured at the start of the experiment. It has been hypothesized that harmful algal blooms will increase under the future scenario of global change. Although this study might be considered an oversimplification of the reality, it can be hypothesized that toxic blooms will increase but no predictions can be advanced about toxicity. PMID- 22833799 TI - Integrating species distribution models (SDMs) and phylogeography for two species of Alpine Primula. AB - The major intention of the present study was to investigate whether an approach combining the use of niche-based palaeodistribution modeling and phylo-geography would support or modify hypotheses about the Quaternary distributional history derived from phylogeographic methods alone. Our study system comprised two closely related species of Alpine Primula. We used species distribution models based on the extant distribution of the species and last glacial maximum (LGM) climate models to predict the distribution of the two species during the LGM. Phylogeographic data were generated using amplified fragment length polymorphisms (AFLPs). In Primula hirsuta, models of past distribution and phylogeographic data are partly congruent and support the hypothesis of widespread nunatak survival in the Central Alps. Species distribution models (SDMs) allowed us to differentiate between alpine regions that harbor potential nunatak areas and regions that have been colonized from other areas. SDMs revealed that diversity is a good indicator for nunataks, while rarity is a good indicator for peripheral relict populations that were not source for the recolonization of the inner Alps. In P. daonensis, palaeo-distribution models and phylogeographic data are incongruent. Besides the uncertainty inherent to this type of modeling approach (e.g., relatively coarse 1 km grain size), disagreement of models and data may partly be caused by shifts of ecological niche in both species. Nevertheless, we demonstrate that the combination of palaeo-distribution modeling with phylogeographical approaches provides a more differentiated picture of the distributional history of species and partly supports (P. hirsuta) and partly modifies (P. daonensis and P. hirsuta) hypotheses of Quaternary distributional history. Some of the refugial area indicated by palaeodistribution models could not have been identified with phylogeographic data. PMID- 22833800 TI - Hybridization among Arctic white-headed gulls (Larus spp.) obscures the genetic legacy of the Pleistocene. AB - We studied the influence of glacial oscillations on the genetic structure of seven species of white-headed gull that breed at high latitudes (Larus argentatus, L. canus, L. glaucescens, L. glaucoides, L. hyperboreus, L. schistisagus, and L. thayeri). We evaluated localities hypothesized as ice-free areas or glacial refugia in other Arctic vertebrates using molecular data from 11 microsatellite loci, mitochondrial DNA (mtDNA) control region, and six nuclear introns for 32 populations across the Holarctic. Moderate levels of genetic structure were observed for microsatellites (F(ST)= 0.129), introns (Phi(ST)= 0.185), and mtDNA control region (Phi(ST)= 0.461), with among-group variation maximized when populations were grouped based on subspecific classification. Two haplotype and at least two allele groups were observed across all loci. However, no haplotype/allele group was composed solely of individuals of a single species, a pattern consistent with recent divergence. Furthermore, northernmost populations were not well differentiated and among-group variation was maximized when L. argentatus and L. hyberboreus populations were grouped by locality rather than species, indicating recent hybridization. Four populations are located in putative Pleistocene glacial refugia and had larger tau estimates than the other 28 populations. However, we were unable to substantiate these putative refugia using coalescent theory, as all populations had genetic signatures of stability based on mtDNA. The extent of haplotype and allele sharing among Arctic white headed gull species is noteworthy. Studies of other Arctic taxa have generally revealed species-specific clusters as well as genetic structure within species, usually correlated with geography. Aspects of white-headed gull behavioral biology, such as colonization ability and propensity to hybridize, as well as their recent evolutionary history, have likely played a large role in the limited genetic structure observed. PMID- 22833801 TI - Regionally nested patterns of fish assemblages in floodplain lakes of the Magdalena river (Colombia). AB - We investigated if fish assemblages in neotropical floodplain lakes (cienagas) exhibit nestedness, and thus offer support to the managers of natural resources of the area for their decision making. The location was floodplain lakes of the middle section of the Magdalena river, Colombia. We applied the nested subset analysis for the series of 30 cienagas (27 connected to the main river and three isolated). All fish were identified taxonomically in the field and the matrix for presence-absence in all the lakes was used for the study of the pattern of nestedness. The most diverse order was Characiformes (20 species), followed by Siluriformes (19 species). Characidae and Loricaridae were the richest families. The species found in all the lakes studied were migratory species (17), and sedentary species (33). Two species (Caquetaia kraussii and Cyphocharax magdalenae) were widespread across the cienagas archipelago (100% of incidence). Nestedness analysis showed that the distribution of species over the spatial gradient studied (840 km) is significantly nested. The cienagas deemed the most hospitable were Simiti, El Llanito, and Canaletal. Roughly, 13 out of the 50 species caught show markedly idiosyncratic distributions. The resulting dataset showed a strong pattern of nestedness in the distribution of Magdalenese fishes, and differed significantly from random species assemblages. Out of all the measurements taken in the cienagas, only the size (area) and local richness are significantly related to the range of order of nested subset patterns (r=-0.59 and -0.90, respectively, at p < 0.01). Differential species extinction is suggested as the cause of a nested species assemblage, when the reorganized matrix of species occurring in habitat islands is correlated with the island area. Our results are consistent with this hypothesis. PMID- 22833802 TI - Outbreeding and lack of temporal genetic structure in a drone congregation of the neotropical stingless bee Scaptotrigona mexicana. AB - Drone aggregations are a widespread phenomenon in many stingless bee species (Meliponini), but the ultimate and proximate causes for their formation are still not well understood. One adaptive explanation for this phenomenon is the avoidance of inbreeding, which is especially detrimental for stingless bees due to the combined effects of the complementary sex-determining system and the small effective population size caused by eusociality and monandry. We analyzed the temporal genetic dynamics of a drone aggregation of the stingless bee Scaptotrigona mexicana with microsatellite markers over a time window of four weeks. We estimated the drones of the aggregation to originate from a total of 55 colonies using sibship re-construction. There was no detectable temporal genetic differentiation or sub-structuring in the aggregation. Most important, we could exclude all colonies in close proximity of the aggregation as origin of the drones in the aggregation, implicating that they originate from more distant colonies. We conclude that the diverse genetic composition and the distant origin of the drones of the S. mexicana drone congregation provides an effective mechanism to avoid mating among close relatives. PMID- 22833803 TI - A genetic polymorphism in the sex-linked ATP5A1 gene is associated with individual fitness in Ovenbirds (Seiurus aurocapilla). AB - While testing genetic sexing techniques in Ovenbirds (Seiurus aurocapilla), we found a genetic polymorphism in the ATP5A1 gene in 38% of individuals. The Z' allele included changes in both intronic and exonic portions of the sequenced region, but there was no evidence that this changed the resulting ATP synthase product. Males that had one or more copies of this allele had higher relative body mass (mass corrected for size) than other genotypes. This allele was unrelated to stable isotope signatures, and so was not a useful predictor of latitude within the eastern portion of the Ovenbird breeding range. Future studies are needed to determine whether this polymorphism may be a useful geographic marker. This study is the first to link polymorphisms in the sex linked ATP5A1 gene with fitness effects. PMID- 22833804 TI - Using clones and copper to resolve the genetic architecture of metal tolerance in a marine invader. AB - The global spread of invasive species may be facilitated by adaptation to the practices that humans use to manage those species. For example, marine invertebrates that adapt to metal-based antifouling biocides on ship hulls may be more likely to be introduced to and establish in metal-polluted environments. We tested this idea by studying clonal variation in tolerance to, and ability to recover from, exposure to copper in a widespread invasive marine bryozoan, Watersipora subtorquata. We cloned colonies of this organism to independently test multiple environments in a genotype by environment design, and then created a genetic variance-covariance matrix. Genotypes were exposed to a gradient of copper concentrations and growth measured during exposure and after a recovery period. There was a significant genotype * environment interaction in growth during exposure and recovery. We found clonal variation in tolerance and ability to recover from exposure to copper, with growth during exposure apparently trading off against growth after exposure. A weak genetic correlation between growth during and after exposure further indicated that they are separate traits. Overall, the genetic variation within this population indicates that there is considerable potential for adaptation to copper, but this comes at a cost to growth in unpolluted environments. PMID- 22833806 TI - Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease. AB - BACKGROUND.: In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark's identification and subsequent rapid eradication of NSF. METHODS.: NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002-11). RESULTS.: In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide's renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION.: A confluence of factors led to the development and eradication of NSF in Denmark. PMID- 22833807 TI - Biomarkers for the prediction of acute kidney injury: a narrative review on current status and future challenges. AB - Acute kidney injury (AKI) is strongly associated with increased morbidity and mortality in critically ill patients. Efforts to change its clinical course have failed because clinically available therapeutic measures are currently lacking, and early detection is impossible with serum creatinine (SCr). The demand for earlier markers has prompted the discovery of several candidates to serve this purpose. In this paper, we review available biomarker studies on the early predictive performance in developing AKI in adult critically ill patients. We make an effort to present the results from the perspective of possible clinical utility. PMID- 22833808 TI - AA amyloidosis in the renal allograft: a report of two cases and review of the literature. AB - AA amyloidosis is a disorder characterized by the abnormal formation, accumulation and systemic deposition of fibrillary material that frequently involves the kidney. Recurrent AA amyloidosis in the renal allograft has been documented in patients with tuberculosis, familial Mediterranean fever, ankylosing spondylitis, chronic pyelonephritis and rheumatoid arthritis. De novo AA amyloidosis is rarely described. We report two cases of AA amyloidosis in the renal allograft. Our first case is a 47-year-old male with a history of ankylosing spondylitis who developed end-stage renal disease reportedly from tubulointerstitial nephritis from non-steroidal anti-inflammatory agent use. A biopsy was never performed. One year after transplantation, AA amyloidosis was identified in the femoral head and 8 years post-transplantation, AA amyloidosis was identified in the renal allograft. He was treated with colchicine and adalimumab and has stable renal function at 1 year-follow-up. Our second case is a 57-year-old male with a long history of intravenous drug use and hepatitis C infection who developed end-stage kidney disease due to AA amyloidosis. Our second patient's course was complicated by renal adenovirus, pulmonary aspergillosis and hepatitis C with AA amyloidosis subsequently being identified in the allograft 2.5 years post-transplantation. Renal allograft function remains stable 4-years post-transplantation. These reports describe clinical and pathologic features of two cases of AA amyloidosis presenting with proteinuria and focal involvement of the renal allograft. PMID- 22833809 TI - Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A(2) receptor antibody-positive membranous nephropathy. AB - Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A(2) receptor (anti-PLA(2)R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA(2)R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis. PMID- 22833810 TI - Long-term haemodialysis survival. AB - Haemodialysis (HD) treatment for end-stage renal disease bears a poor prognosis. We present a case of a patient who, apart from two transplant periods lasting 8 months in all, was treated with conventional in-centre HD three times a week and who survived for 41 years. Patients should be aware that there is no theoretical upper limit for patient survival on HD. PMID- 22833811 TI - On-site production of a dialysis bath from dry salts. Results of solute concentration control by routine clinical chemistry. AB - BACKGROUND.: Dialysis bath production, at least in Europe, is currently based on pre-produced aqueous solutions of dialysis salts (concentrate), which are re handled by dialysis machines to deliver the final dialysate concentrations. Because of the logistics of aqueous solution creation, a large amount of transportation capacity is needed. Therefore, we changed this process to use pre produced dry salt containers and to undertake in-clinic dissolution of salts and concentration production. Because no preclinical control for solute concentrations is available so far using this new process, we employed routine clinical chemistry analytics. METHODS.: We report the controls of solute concentrations created by these methods for 746 samples of concentrates and 151 dissolution processes. For analysis, absolute and relative deviations from prescriptions and associations between the solute concentrations and the density controls of the concentrates were computed. RESULTS.: A total of 98% of all the concentrates were found to be within a 10% margin of error from the prescriptions. The mean relative deviation of the solute concentrations from the prescriptions was -0.635 +/- 3.83%. Among particular solutes, sodium had the highest maximum deviation of 26 mmol/L from the prescription. Calcium and magnesium (small concentration solutes) exhibited small systematic errors of 1.37 and 1.22%, respectively. Other solute concentrations showed random errors only and no associations with the mean relative deviations of all the solutes within a production batch or with the density controls. CONCLUSIONS.: Single solute concentration control by routine clinical chemistry after dry salt production of concentrates is a valuable additional tool for monitoring clinical risk with dialysate concentrates. The analytical random error of clinical chemistry exceeds the weight tolerance of production; therefore, such analytics cannot be used for precision production and control of dry salt containers. PMID- 22833812 TI - Nipping it in the bud: An inspiring mission for prevention and management of COPD. PMID- 22833813 TI - Imaging for high-precision thoracic radiotherapy. PMID- 22833814 TI - A millimeter miss is as good as a thousand miles: The role of accurate target localization in lung stereotactic body radiation therapy. PMID- 22833815 TI - CT Imaging of Solitary fibrous tumour of the pleura (SFTP): Typical Patterns and pitfalls. PMID- 22833817 TI - Anesthesia with nontracheal intubation in thoracic surgery. AB - OBJECTIVE: To study one-lung respiration during VATS wedge resection of bullae and pulmonary nodules with nontracheal intubation, and to explore the changes of vital signs when patients return to two-lung ventilation. METHODS: Twenty-two patients with normal cardiopulmonary function and absence of contraindications to epidural anesthesia were included in this study. VATS wedge resection of bullae or pulmonary nodules was performed. 0.5% Ropivacain was administrated for epidural anesthesia (T8-9), and 2 mL of 2% lidocaine was used for local anesthetic block of the intrathoracic vagus nerves. The BIS value was maintained between 50 and 70 by target-controlled infusion of propofol and remifentanil. Electrocardiogram (ECG), heart rate (HR), blood pressure (Bp), pulse oxygen saturation (SpO(2)), respiratory rate (RR), bispectral index (BIS) and urine volume were monitored. RESULTS: None patients were converted to endotracheal intubation during anesthesia. MAP and SpO(2) after wound disclosure were stable (P>0.05), level of CVP significantly elevated, HR and RR increased (P<0.05), PaCO(2) increased gradually while PaO(2) remained stable. Fifteen minutes after wound closure, MAP, RR and SpO(2) returned to their pre-anesthesia levels, PH value gradually recovered, PaCO(2) tended to decrease and returned to normal one hour after wound closure. Physical agitation occurred in one case due to inadequate epidural anesthesia during skin incision. Cough before intrathoracic vagal blockade was noted in two cases (9.1%) because of lobe traction. CONCLUSIONS: Nontracheal intubation is feasible in VATS wedge resection of bullae and pulmonary nodules. The patients are with stable intraoperative vital signs and none experiences hypoxemia; intraoperative hypercapnia is tolerable and transient, which can be improved quickly when bilateral lungs resume spontaneous respiration. PMID- 22833816 TI - Bacterial RNA induces myocyte cellular dysfunction through the activation of PKR. AB - Severe sepsis and the ensuing septic shock are serious life threatening conditions. These diseases are triggered by the host's over exuberant systemic response to the infecting pathogen. Several surveillance mechanisms have evolved to discriminate self from foreign RNA and accordingly trigger effective cellular responses to target the pathogenic threats. The RNA-dependent protein kinase (PKR) is a key component of the cytoplasmic RNA sensors involved in the recognition of viral double-stranded RNA (dsRNA). Here, we identify bacterial RNA as a distinct pathogenic pattern recognized by PKR. Our results indicate that natural RNA derived from bacteria directly binds to and activates PKR. We further show that bacterial RNA induces human cardiac myocyte apoptosis and identify the requirement for PKR in mediating this response. In addition to bacterial immunity, the results presented here may also have implications in cardiac pathophysiology. PMID- 22833818 TI - Double CT imaging can measure the respiratory movement of small pulmonary tumors during stereotactic ablative radiotherapy. AB - PURPOSE: The purpose of this study was to investigate the application of double CT imaging to measuring the respiratory movement of small pulmonary tumors during stereotactic ablative radiotherapy (SABR). METHODS: A total of 122 small pulmonary tumors were measured in 45 patients. CT scans were conducted twice in all 122 tumors, once at the end of quiet inhalation and once at the end of exhalation. CT scans were conducted three times including at the end of quiet inhalation, at the end of exhalation and at free breathing in 36 tumors of 17 patients. The displacement of the tumor center in three directions was measured. RESULTS: The 3D motion of 122 tumors was 10.10+/-7.16 mm. On average, the tumors moved 1.96+/-2.03 mm (rang, 0-9 mm) in the X direction, 5.19+/-4.69 mm (rang, 0 19 mm) in the Y direction, and 7.38+/-6.48 mm (rang, 0-26 mm) in the Z direction. The 3D motion of tumors in the lower lung (13.00+/-7.64 mm) was significantly greater than that in the upper lung (7.15+/-5.14 mm), P<0.01. The 3D motion of the lower left lung was 16.35+/-7.31 mm, which was significantly greater than that of the lower right lung (11.40+/-7.04 mm), P<0.05. Movement in the anterior lung in the Y direction was significantly larger than in the posterior lung. The motion was 7.49+/-5.43 mm and 4.04+/-3.82 mm respectively, P<0.01. CONCLUSIONS: Double CT imaging provides accurate data for determining the outline of each target area during stereotactic ablative radiotherapy plane. The location of small pulmonary tumor foci was significantly affected by respiratory and cardiac motion. PMID- 22833819 TI - Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT. AB - OBJECTIVE: To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. METHODS: A549 cells (5*10(6) mL(-1)) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. RESULTS: The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. CONCLUSIONS: The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically. PMID- 22833820 TI - Solitary fibrous tumor of the pleura: An analysis of forty patients. AB - OBJECTIVE: To study the clinical characteristics, treatment and prognosis of patients with solitary fibrous tumor of the pleura (SFTP) in order to improve the diagnostic accuracy and treatment of SFTP. METHODS: A retrospective analysis of clinical and imaging features, serum biochemical changes, pathological characteristics and treatment follow-up results was conducted for 40 SFTP patients from January 1998 to March 2010. RESULTS: A chest CT diagnosis was conducted for 63.6% of the patients; the unenhanced and contrast-enhanced CT findings were significantly different among the cohort (P<0.01). Patients lacking a uniform MRI internal signal comprised 88.9% of the group, 66.7% showed T1 isointensity, 33.3% demonstrated T1 hypointensity, 44.4% showed T2 hypointensity and 44.4% had slight hypointensity. The follow-up time was between 2 and 116.9 months, with an average of 35 months; postoperative adjuvant therapy was not administered. Currently, all the studied patients are alive, with no metastasis or recurrence. CONCLUSION: Chest CT is a valuable tool for diagnosis and surgical decisions, and the efficacy of MRI examination is comparable to chest CT. The majority of cases originated in the visceral pleural; for these, surgical resection is an effective treatment, and the prognosis is generally favorable. PMID- 22833821 TI - Whole genome sequencing for lung cancer. AB - Lung cancer is a leading cause of cancer related morbidity and mortality globally, and carries a dismal prognosis. Improved understanding of the biology of cancer is required to improve patient outcomes. Next-generation sequencing (NGS) is a powerful tool for whole genome characterisation, enabling comprehensive examination of somatic mutations that drive oncogenesis. Most NGS methods are based on polymerase chain reaction (PCR) amplification of platform specific DNA fragment libraries, which are then sequenced. These techniques are well suited to high-throughput sequencing and are able to detect the full spectrum of genomic changes present in cancer. However, they require considerable investments in time, laboratory infrastructure, computational analysis and bioinformatic support. Next-generation sequencing has been applied to studies of the whole genome, exome, transcriptome and epigenome, and is changing the paradigm of lung cancer research and patient care. The results of this new technology will transform current knowledge of oncogenic pathways and provide molecular targets of use in the diagnosis and treatment of cancer. Somatic mutations in lung cancer have already been identified by NGS, and large scale genomic studies are underway. Personalised treatment strategies will improve care for those likely to benefit from available therapies, while sparing others the expense and morbidity of futile intervention. Organisational, computational and bioinformatic challenges of NGS are driving technological advances as well as raising ethical issues relating to informed consent and data release. Differentiation between driver and passenger mutations requires careful interpretation of sequencing data. Challenges in the interpretation of results arise from the types of specimens used for DNA extraction, sample processing techniques and tumour content. Tumour heterogeneity can reduce power to detect mutations implicated in oncogenesis. Next-generation sequencing will facilitate investigation of the biological and clinical implications of such variation. These techniques can now be applied to single cells and free circulating DNA, and possibly in the future to DNA obtained from body fluids and from subpopulations of tumour. As costs reduce, and speed and processing accuracy increase, NGS technology will become increasingly accessible to researchers and clinicians, with the ultimate goal of improving the care of patients with lung cancer. PMID- 22833823 TI - Electromagnetic navigation bronchoscopy: A descriptive analysis. AB - Electromagnetic navigation bronchoscopy (ENB) is an exciting new bronchoscopic technique that promises accurate navigation to peripheral pulmonary target lesions, using technology similar to a car global positioning system (GPS) unit. Potential uses for ENB include biopsy of peripheral lung lesions, pleural dye marking of nodules for surgical wedge resection, placement of fiducial markers for stereotactic radiotherapy, and therapeutic insertion of brachytherapy catheters into malignant tissue. This article will describe the ENB procedure, review the published literature, compare ENB to existing biopsy techniques, and outline the challenges for widespread implementation of this new technology. PMID- 22833822 TI - OSA and atherosclerosis. AB - Untreated obstructive sleep apnea (OSA) is increasingly recognized as a risk factor contributing to cardiovascular morbidity and mortality. Research in recent decades has uncovered many components of the complex pathological events leading to the atherosclerotic vascular diseases in OSA, which involve heightened oxidative stress as a result of intermittent hypoxia, vascular inflammation, activation of platelet and coagulation cascades, endothelial dysfunction and ultimately the formation of atherosclerotic plagues. The close association of OSA and conventional cardiovascular risk factors including hypertension, diabetes mellitus, dyslipidemia and obesity adds to the adverse cardiovascular sequelae. Further studies are required to clarify further on the pathophysiological processes, and the effect size of OSA therapy, and other potential preventive strategies. PMID- 22833824 TI - Pleural infection-current diagnosis and management. AB - Pleural infection is a common and increasing clinical problem in thoracic medicine, resulting in significant morbidity and mortality. In recent years there has been a marked increase in interests and publications relating to evolving interventions and management options for pleural infection and empyema. Recently published research data as well as guidelines have suggested better approaches of radiological assessment, updated management algorithms for pleural infection, intrapleural adjunct therapies and re-examined the roles of biomarkers, pleural drainage techniques, and the role of surgery. This review highlights some of the recent advances and recommendations relevant to clinical care of pleural infection. PMID- 22833825 TI - Effect of sleep on breathing - Why recurrent apneas are only seen during sleep. PMID- 22833826 TI - Immunotherapy - Vaccines for allergic diseases. AB - Allergic diseases are some of the most commonly encountered problems in clinical practice. Drugs such as corticosteroids and antihistamines can provide effective symptomatic relief, but do not alter the course of the disease. Specific immunotherapy (SIT) was first used to treat pollen allergy in 1911, and has since evolved into an effective treatment for allergic rhinitis and asthma. SIT has been shown in clinical studies to reduce symptoms and medication use in patients with allergic rhinitis and asthma. Recent studies also showed that the therapeutic benefit is long-lasting after the completion of three to five years of treatment. SIT can also effectively reduce the risk of developing asthma and new allergic sensitizations in children with allergic rhinitis. PMID- 22833827 TI - Executive summary of the multicenter survey on the prevalence and risk factors of chronic respiratory diseases in patients presenting to primary care centers and emergency rooms in Syria. PMID- 22833828 TI - COPD patients' rights: Can they be won? PMID- 22833829 TI - Gene expression assays as prognostic and predictive markers in early stage non small cell lung cancer. PMID- 22833830 TI - Predicting survival of patients with resectable non-small cell lung cancer: Beyond TNM. PMID- 22833831 TI - Prognostic molecular assays on the rise for non-small cell lung cancer. PMID- 22833832 TI - EURTAC first-line phase III randomized study in advanced non-small cell lung cancer: Erlotinib works also in European population. PMID- 22833833 TI - EURTAC first line therapy for non small cell lung carcinoma in epidermal growth factor receptor mutation positive patients: A choice between two TKIs. PMID- 22833834 TI - A time to test, a time to treat. PMID- 22833835 TI - Optimal front line treatment for European patients harboring EGFR mutations: Do longitude and race make a difference? PMID- 22833836 TI - Bilateral pneumothorax after bevacizumab-containing chemotherapy in fibrosarcoma. PMID- 22833837 TI - Skeletal muscle metastasis from NSCLC. PMID- 22833838 TI - A dyspnea patient with abnormal prolonged prothrombin time and activated partial thromboplstin time, but without bleeding symptoms. AB - A patient with erythrocytosis secondary to chronic obstructive pulmonary disease (COPD) was admitted to hospital because of dyspnea. The coagulation tests revealed abnormal prolonged prothrombin time (PT) and activated partial thromboplstin time (APTT), however, it could not be explained by the patient's medical history or physical signs of coagulation disorder. High hematocrit (Hct), which leads to reduced plasma-to-anticoagulant rate and increased final plasma anticoagulant concentration, was identified as the reason for false prolongation of PT and APTT. PMID- 22833839 TI - In vitro generation of functional insulin-producing cells from human bone marrow derived stem cells, but long-term culture running risk of malignant transformation. AB - Efforts involving therapeutic islet cell transplantation have been hampered by limited islet availability and immune rejection. In vitro transdifferentiation of human bone marrow-derived stem (hBMDS) cells into functional insulin-producing cells promises to provide a tissue source for autologous cell transplantation. In this study, we isolated hBMDS cells, developed a single-cell-derived stem cell line, and induced the cells to differentiate into islet-like clusters. These islet-like cells expressed multiple genes related to islet development and beta cell function (e.g., Pdx-1, Ngn-3, Islet-1, Neuro-D, Pax4, IAPP, and insulin) and produced insulin and C-peptide within these cells. These islet-like cells demonstrated time-dependent glucose-stimulated insulin release, and the ability to ameliorate hyperglycemia in chemically induced diabetic mice. However, these transplanted differentiated cells became tumorigenic in diabetic immunocompromised mice and their spontaneous transformation was confirmed by a marked increase in growth rate and inactivation of tumor suppressor genes (P21 and P16) by promoter hypermethylation. In conclusion, while hBMDS cells can be transdifferentiated into competent insulin-producing cells, and while such cell might be a potential source for autologous cell therapy for type 1 diabetes, caution is strongly advised in view of the neoplastic propensity of hBMDS cells, especially after a long-term culture in vitro. PMID- 22833842 TI - On the evolution of sport. AB - Sports have received little attention from evolutionary biologists. I argue that sport began as a way for men to develop the skills needed in primitive hunting and warfare, then developed to act primarily as a lek where athletes display and male spectators evaluate the qualities of potential allies and rivals. This hypothesis predicts that (1) the most popular modern male sports require the skills needed for success in male-male physical competition and primitive hunting and warfare; (2) champion male athletes obtain high status and thereby reproductive opportunities in ways that parallel those gained by successful primitive hunters and warriors; (3) men pay closer attention than do women to male sports so they can evaluate potential allies and rivals; and (4) male sports became culturally more important when opportunities to evaluate potential allies and rivals declined as both the survival importance of hunting and the proportion of men who experience combat decreased. The characteristics of primitive and modern sports are more consistent with these predictions than those generated by intersexual sexual selection theories of sport. PMID- 22833840 TI - Progenitor/stem cell transplantation for repair of myocardial infarction: Hype or hope? AB - Despite significant therapeutic advances, heart failure remains the predominant cause of mortality worldwide. Currently, progenitor/stem cell biology holds great promise for a new era of cell-based therapy for salvaging the failing heart. However, the translational arm of progenitor/stem cell science is in a relatively primitive state. For the time being, the clinical trials have been both encouraging and disappointing. How to improve the engraftment, long-term survival and appropriate differentiation of transplanted progenitor/stem cell within the cardiovascular tissues may be the key issues to facilitate the transition of cardiogenic stem cell research from bench to bedside. In this review article we discuss the state-of-the-art in adult stem cell therapies for cardiovascular diseases and approaches to release cardiac regeneration potentials of progenitor/stem cells. PMID- 22833845 TI - Evolutionary psychology is compatible with equity feminism, but not with gender feminism: a reply to Eagly and Wood (2011). AB - I comment on Eagly and Wood's biosocial constructionist evolutionary theory (2011; DOI: 10.1007/s11199-011-9949-9). Although this gender feminist theory allows for evolved physical differences between men and women and evolved psychological similarities for men and women, it fails to consider evolutionary accounts of psychological sex differences. I hypothesize that gender feminists' reluctance to acknowledge that evolution has left different fingerprints on men's and women's bodies and brains stems from two common misunderstandings of evolutionary psychology: the myth of immutability and the naturalistic fallacy. I conclude that although evolutionary psychology is eminently compatible with equity feminism, evolutionary psychology and feminist psychology will conflict as long as the latter adheres to gender feminism and its unwillingness to acknowledge the evidence for evolved psychological sex differences. Gender feminism's dualistic view of evolution hinders the search for and understanding of the proximate and ultimate causes of inequality. Feminist psychology needs to evolve by embracing equity feminism, which has no a priori stance on the origin or existence of differences between the sexes. PMID- 22833848 TI - Is self-sacrificial competitive altruism primarily a male activity? AB - This study explored the basis of self-sacrificial prosocial behavior in small groups. Seventy-eight undergraduates (39M, 39F) filled out a thirty-item personality scale and then participated in a "group problem-solving study" in which the monetary success of a three-person group depended upon one of its members volunteering to endure pain (a cold stressor test) and inconvenience (being soaked in a dunk tank). There were 13 groups consisting of two females and one male, and 13 groups consisting of two males and one female. Across groups, the behavior of the altruist was judged to be more costly, challenging, and important and he/she was liked better, rewarded with more money, and preferred as a future experimental partner. Groups containing two males showed more evidence of competition to become altruists than groups containing two females, and personality traits were more effective predictors of altruistic behavior in males than in females. We conclude that competition between males and "showing off" are key factors in triggering self-sacrificial altruistic behavior. PMID- 22833849 TI - Female facial appearance and health. AB - The current study addressed whether rated femininity, attractiveness, and health in female faces are associated with numerous indices of self-reported health history (number of colds/stomach bugs/frequency of antibiotic use) in a sample of 105 females. It was predicted that all three rating variables would correlate negatively with bouts of illness (with the exception of rates of stomach infections), on the assumption that aspects of facial appearance signal mate quality. The results showed partial support for this prediction, in that there was a general trend for both facial femininity and attractiveness to correlate negatively with the reported number of colds in the preceding twelve months and with the frequency of antibiotic use in the last three years and the last twelve months. Rated facial femininity (as documented in September) was also associated with days of flu experienced in the period spanning the November-December months. However, rated health did not correlate with any of the health indices (albeit one marginal result with antibiotic use in the last twelve months). The results lend support to previous findings linking facial femininity to health and suggest that facial femininity may be linked to some aspects of disease resistance but not others. PMID- 22833850 TI - Sport participation influences perceptions of mate characteristics. AB - Sport provides a context in which mate choice can be facilitated by the display of athletic prowess. Previous work has shown that, for females, team sport athletes are more desirable as mates than individual sport athletes and non participants. In the present study, the perceptions of males and females were examined regarding potential mates based on sport participation. It was predicted that team sport athletes would be more positively perceived than individual sport athletes and non-participants by both males and females. A questionnaire, a photograph, and manipulated descriptions were used to gauge perceptual differences with respect to team sport athletes, individual sport athletes, and extra-curricular club participants for 125 females and 119 males from a Canadian university. Both team and individual sport athletes were perceived as being less lazy, more competitive, and healthier than non-participants by both males and females. Interestingly, females perceived male athletes as more promiscuous than non-athletes, which upholds predictions based on previous research indicating (a) athletes have more sexual partners than non-athletes, and (b) females find athletes more desirable as partners than non-participants. Surprisingly, only males perceived female team sport athletes as more dependable than non participants, and both team and individual sport athletes as more ambitious. This raises questions regarding the initial hypothesis that male team athletes would be perceived positively by females because of qualities such as the ability to cooperate, likeability, and the acceptance of responsibilities necessary for group functioning. Future studies should examine similar questions with a larger sample size that encompasses multiple contexts, taking into account the role of the social profile of sport in relation to mate choice and perception. PMID- 22833841 TI - Radiation-induced brain injury: A review. AB - Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects. PMID- 22833853 TI - Sex differences in in-group cooperation vary dynamically with competitive conditions and outcomes. AB - Men's but not women's investment in a public goods game varied dynamically with the presence or absence of a perceived out-group. Three hundred fifty-four (167 male) young adults participated in multiple iterations of a public goods game under intergroup and individual competition conditions. Participants received feedback about whether their investments in the group were sufficient to earn a bonus to be shared among all in-group members. Results for the first trial confirm previous research in which men's but not women's investments were higher when there was a competing out-group. We extended these findings by showing that men's investment in the in-group varied dynamically by condition depending on the outcome of the previous trial: In the group condition, men, but not women, decreased spending following a win (i.e., earning an in-group bonus). In the individual condition, men, but not women, increased spending following a win. We hypothesize that these patterns reflect a male bias to calibrate their level of in-group investment such that they sacrifice only what is necessary for their group to successfully compete against a rival group. PMID- 22833854 TI - Automatic attention towards face or body as a function of mating motivation. AB - Because women's faces and bodies carry different cues of reproductive value, men may attend to different perceptual cues as functions of their long-term versus short-term mating motivations. We tested this hypothesis in three experiments on 135 male and 132 female participants. When influenced by short-term rather than long-term mating motivations, men's attention was captured by (Study 1), was shifted to (Study 2), and was distracted by (Study 3) the waist/hip area rather than the face on photographs of attractive women. Similar effects were not found among the female participants in response to photographs of attractive men. These results support the evolutionary view that, similar to the attentional selectivity found in other domains of life, male perceptual attention has evolved to selectively capture and hold reproductive information about the opposite sex as a function of short-term versus long-term mating goals. PMID- 22833855 TI - Between-sex differences in romantic jealousy: substance or spin? A qualitative analysis. AB - An influential evolutionary account of romantic jealousy proposes that natural selection shaped a specific sexually-dimorphic psychological mechanism in response to relationship threat. However, this account has faced considerable theoretical and methodological criticism and it remains unclear whether putative sex differences in romantic jealousy actually exist and, if they do, whether they are consistent with its predictions. Given the multidimensional nature of romantic jealousy, the current study employed a qualitative design to examine these issues. We report the results of sixteen semi-structured interviews that were conducted with heterosexual men and women with the purpose of exploring the emotions, cognitions and behaviors that formed their subjective, lived experience in response to relationship threat. Interpretative phenomenological analysis revealed four super-ordinate themes ("threat appraisal", "emotional episodes", "sex-specific threat" and "forgive and forget") and unequivocal sex differences in romantic jealousy consistent with the evolutionary account. Self-esteem, particularly when conceptualized as an index of mate value, emerged as an important proximal mediator for both sexes. However, specific outcomes were dependent upon domains central to the individual's self concept that were primarily sex-specific. The findings are integrated within the context of existing self-esteem and evolutionary theory and future directions for romantic jealousy research are suggested. PMID- 22833856 TI - Recognition based hormonal 95kDa monoclonal antibody on three human cancer cell lines for developing targeted radio-immuno-imaging and therapy. AB - The present study aimed to explore the possibility of developing a immuno imaging/therapeutic agent for hCG-expressing tumors by using antibodies raised against them. Three human cancer cell lines were selected:lung adenocarcinoma (A549), glioblastoma (U87MG) and breast cancer (MCF7). Anti-beta-hCG monoclonal antibody, obtained from ascitic fluid, was purified by affinity chromatography followed by characterization and titration. Ectopic expression of hCG on these cell lines was tested by flow cytometry and in-vitro cytotoxicity with antibodies was tested by MTT assay on the cell line with the highest percentage binding. For positive and negative controls, immortalized trophoblast cells (SW71) and peripheral blood monocytes were used. Antibody was then radiolabeled with lutetium-177 ((177)Lu) and in vivo biodistribution studies were conducted in murine tumor model. Antibodies could be purified to homogeneity with a concentration 28mg/mL. Percentage receptor expression on A549, U87MG and MCF7 cells was 95%, 66% and 55% respectively. About 90% of A549 cells could be killed with antibody at 72h post-treatment. No cytotoxicity was observed on SW71 despite a high binding percentage (96%). Antibodies were radiolabeled with high efficiency (~98%). In-vivo studies using radiolabeled antibodies showed hepato biliary excretion route and significant uptake in A549 tumor. In conclusion, among the 3 cancer cell lines, lung adenocarcinoma significantly expresses beta hCG and shows dose dependent cytotoxicity with anti-beta-hCG antibody. Radiolabeling of this antibody can aid in imaging and also has the potential of enhancing its therapeutic potential. This study provides a platform for further studies for targeted radio-immuno imaging and subsequent therapy of hCG expressing cancers. PMID- 22833857 TI - Assessment of cardiac abnormalities in Duchenne's muscular dystrophy by (99m)Tc MIBI gated myocardial perfusion imaging. AB - Cardiac abnormalities in Duchenne's muscular dystrophy (DMD) are often detected in adult patients and their early detection is warranted. Studies have suggested that myocardial damage may be detected by cardiovascular magnetic resonance imaging or by echocardiography at the early stage of DMD. We aimed to identify early changes of cardiac abnormalities in children with DMD by technetium 99m methoxyisobutylisonitrile ((99m)Tc-MIBI) gated myocardial perfusion imaging (GMPI). Forty-three boys aged 3 to 14 years (mean age 8.2+/-3.6 years) with DMD and 12 age-matched normal boys as control were studied by G-MPI. These patients were at early stage according to previous studies on DMD. Uptake of (99m)Tc-MIBI in 7 regional walls and 17 segments of the left ventricle were visually analyzed. Quantitative gated single photon emission tomography (QGSSPET) analysis of myocardium was performed to evaluate left ventricular function (LVEF). Gated myocardial perfusion imaging revealed cardiac abnormalities in 81.4% of all patients. Regional perfusion decrease involving multiple walls of LV was present. Four of the patients demonstrated mild abnormalities (11.4%), 7 moderate (20.0%) and 24 severe abnormalities (68.6%). Evident LV ejection fraction (EF) decrease (42.1+/-6.4%) and dilation with globally poor perfusion were found in three patients, aged 10 to 14, which had significant difference compared with the control group (EF=58.4+/-4.7%, P=0.001). The rest cases, aged 3 to 9 years, had normal LVF. In conclusion, from the 35 cases of DMD patients (aged 3 to 14 years), regional myocardial perfusion decrease was detected in multiple walls by (99m)Tc-MIBI G-MPI at an early stage, while left ventricular function decrease (3/35, 8.6%) appeared late at about 10 years of age or older as compared with the control group in this study. PMID- 22833858 TI - Preparation and biodistribution in mice of a new radiopharmaceutical-technetium 99m labeled methotrexate, as a tumor diagnostic agent. AB - Our aim was to develop the procedure for radiolabeling of an anticancer drug e.g., methotrexate with (99m)Tc for tumors diagnosis. The study included the radiolabeling of methotrexate, in vitro stability of radiolabeled drug, in vitro binding of radiolabeled drug with plasma protein, partition coefficient and biodistribution of radiolabeled drug in mice. Results showed 98.2+/-0.5% radiolabeling of methotrexate with technetium-99m ((99m)Tc). In vitro stability was studied for 5h and 79.3+/-5% of the drug was bound with plasma proteins. Partition coefficient of the labeled drug showed that it was highly hydrophilic. Biodistribution study in tumor bearing mice exhibited high uptake in tumor cells which were further investigated by histopathological studies. In conclusion, our study indicates that technetium-99m labeled methotrexate is a potentially strong tumor diagnostic agent with low uptake in normal tissues. PMID- 22833859 TI - Effective use of a new quality and safety checklist for the steady and safe supply of fluorine-18 fluorodeoxyglucose for positron emission tomography/computed tomography. AB - Fluorine-18-fluorodeoxyglucose ((18)F-FDG ) positron emission tomography/computed tomography (PET/CT) with the in-hospital synthesis of (18)F-FDG was initiated in our hospital on April 1, 2010. We aim to perform stable supply of (18)F-FDG for patients and to avoid unnecessary radiation exposure due to mis-preparation of (18)F-FDG. Pharmacists perform quality control tests to determine whether (18)F FDG meets official regulations. After the quality control test, we give (18)F-FDG that conforms to these standards to patients to conduct (18)F-FDG PET/CT. After a quality control test is initiated, various problems can occur including leakage and staff radiation exposure. We recorded daily radiation exposure in the hot lab and calculated the average daily radiation exposure on a monthly basis for a period of one year. We developed a checklist to safely and quickly synthesize(18)F-FDG for patients. The total radiation exposure of the three pharmacists was 394, 180, and 214MUSv/y and overall lower than the occupational maximum values (<=50mSv/year and <=100mSv/5years for males). In conclusion, using the new checklist, pharmacists and the operator of the Sumitomo Heavy Industries Accelerator service Co., Ltd. were able to practice their daily work effectively during the synthesis and quality control testing of (18)F-FDG. Notably the usual radiation exposure reported in the present study was quite lower than the allowable maximum. PMID- 22833860 TI - Dopamine transporter imaging (123)I-FP-CIT (DaTSCAN) SPET in differential diagnosis of dopa-responsive dystonia and young-onset Parkinson's disease. AB - Dopa-responsive dystonia (DRD) is a genetic disorder characterized by childhood onset dystonia, dominant inheritance, diurnal symptoms fluctuation and positive levodopa response. Adult-onset DRD is frequently combined with parkinsonism and can be mistaken with young onset Parkinson's disease (YOPD). Both conditions are caused by dopamine deficiency, due to nigral cells' loss in YOPD, and due to enzymatic defects in dopamine synthesis in DRD. Single photon emission tomography (SPET) with (123)I-N--fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane ((123)I-FP-CIT)-DaTSCAN is a sensitive neuroimaging method for the assessment of nigrostriatal dopaminergic system integrity and degeneration. Our aim was to evaluate the usefulness of (123)I-FP-CIT( DaTSCAN) SPET in the differential diagnosis of DRD and YOPD in clinical practice. Brain SPET with (123)I-FP-CIT was performed in 13 patients (7 males, 6 females), age 20-58 years, with mean age of onset of their disease, 29 years, eleven patients with early onset parkinsonian symptoms and 2 with genetically proved DRD. The images were evaluated by visual and semiquantitative analyses (ROI). The ratio of specific-striatal to non specific-occipital binding was calculated. Ten out of 11 patients with YOPD had decreased accumulation of DaTSCAN in striatum, especially in putamen, that is typical findings for Parkinson's disease. In three patients DaTSCAN was normal with symmetric tracer uptake in both striata, caudate nucleus and putamen and the diagnosis of DRD was suspected. Two patients with initial dystonic symptoms and genetically proved DRD had normal DaTSCAN. In one patient after normal DaTSCAN findings the initial diagnosis of YOPD was changed to the diagnosis of DRD. Region of interest (ROI) analyses have shown significantly lower(123)I-FP-CIT binding ratios in YOPD than in DRD in all 3 regions of interest: striatum (1.95+/ 0.32) vs (2.76+/-0.10) P<0.001, putamen (1.76+/-0.25) vs (2.84+/-0.14) P<0.0001 and caudate nucleus (2.37+/-0.51) vs (3.27+/-0.14) P<0.01. In conclusion, our results indicate that DaTSCAN is an objective neuroimaging method able to distinguisch neurodegenerative disease YOPD from DRD and clarify a clinical dilemma, which is important for the treatment, prognosis and genetic counseling of patients and their families. PMID- 22833861 TI - A new role of PET/CT for target delineation for radiotherapy treatment planning for head and neck carcinomas. AB - Fluorine-18-fluorodeoxyglucose- positron emission tomography ((18)F-FDG PET) in head and neck cancer patients is useful for staging, identification of macroscopic disease, detection of invaded lymph nodes and distant metastases, delineation of radiotherapy target volume and assessment of treatment response. This brief review addresses the potential role of PET in radiotherapy planning as compared to MRI and CT scan. Positron emission tomography is considered by radiation oncologists a useful test for the identification of the specific target volume for treatment. In addition, a number of hypoxia-related PET radiopharmaceuticals such as the fluorine-18-fluoromisonidazole ((18)F-FMISO) and the fluorine-18-fluoroazomycin arabinoside ((18)F-FAZA) are now available in order to identify hypoxic tumor subvolumes helping to implement new radiotherapy techniques. Magnetic resonance imaging (MRI) has the advantage to discriminate the soft tissue contrast from the tumor, against computerized tomography (CT), but PET/CT scans have the additional advantage to incorporate the metabolic imaging for improving the delineation of variable and hypoxic tumor tissue in the head and neck region. Regardless of the method used for determining the gross tumor volume, clinical examination remains irreplaceable. In conclusion, PET/CT offers complementary information for the delineation of the primary tumor and the corresponding lymph nodes compared to the use of MRI and CT and can support the use of modern radiotherapy techniques, having fewer toxicities. PMID- 22833862 TI - Unintended consequences of US immigration policy: explaining the post-1965 surge from Latin America. AB - Immigration reforms in the United States initiated in the 1960s are widely thought to have opened the door to mass immigration from Asia and Latin America by eliminating past discriminatory policies. While this may be true for Asians, it is not the case for Latin Americans, who faced more restrictions to legal migration after 1965 than before. The boom in Latin American migration occurred in spite of rather than because of changes in US immigration law. In this article we describe how restrictions placed on the legal entry of Latin Americans, and especially Mexicans, set off a chain of events that in the ensuing decades had the paradoxical effect of producing more rather than fewer Latino immigrants. We offer an explanation for how and why Latinos in the United States, in just 40 years, increased from 9.6 million people and 5 percent of the population to 51 million people and 16 percent of the population, and why so many are now present without authorization. PMID- 22833863 TI - Son preference, sex selection, and kinship in Vietnam. AB - This article examines the recent rise in the sex ratio at birth in Vietnam and relates its emergence to kinship systems and ethnic composition using 2009 census micro-data. Presentation of the main socioeconomic and ethnic differentials in birth masculinity is followed by a review of the three intermediate factors leading to increases in the sex ratio at birth: prenatal technology, declining fertility, and gender bias. An indirect measurement of fertility behavior is used to demonstrate the close association between levels of the sex ratio at birth and the intensity of son preference. Data on household composition indicate that Vietnam is characterized by the co-existence of kinship patterns typical of East and Southeast Asia. Son preference in Vietnam is found to be related to the prevalence of more traditional patrilineal systems. The article concludes by considering the implications of the cultural dimensions of prenatal sex selection for policy responses and for the likely future change in the sex ratio at birth. PMID- 22833864 TI - The Latin American cohabitation boom, 1970-2007. AB - The article describes the rise of unmarried cohabitation in Latin American countries during the last 30 years of the twentieth century, both at the national and regional levels. It documents that this major increase occurred in regions with and without traditional forms of cohabitation alike. In addition, the striking degree of catching up of cohabitation among the better-educated population segments is illustrated. The connections between these trends and economic (periods of high inflation) and cultural (reduction of stigmas in ethical domains) factors are discussed. The conclusion is that the periods of inflation and hyperinflation may have been general catalysts, but no clear indications of correlation were found between such economic factors and the rise in cohabitation. The shift toward more tolerance for hitherto stigmatized forms of conduct (e.g., homosexuality, euthanasia, abortion, singleparent household) is in line with the rise of cohabitation in regions of Argentina, Chile, and Brazil where cohabitation used to be uncommon. Further rises in cohabitation during the first decade of the twenty-first century are expected in a number of countries (e.g., mexico) despite conditions of much lower inflation. PMID- 22833865 TI - A demographic explanation for the recent rise in European fertility. AB - Between 1998 and 2008 European countries experienced the first continent-wide increase in the period total fertility rate (TFR) since the 1960s. After discussing period and cohort influences on fertility trends, we examine the role of tempo distortions of period fertility and different methods for removing them. We highlight the usefulness of a new indicator: the tempo- and parity-adjusted total fertility rate (TFRp*). This variant of the adjusted total fertility rate proposed by Bongaarts and Feeney also controls for the parity composition of the female population and provides more stable values than the indicators proposed in the past. Finally, we estimate levels and trends in tempo and parity distribution distortions in selected countries in Europe. Our analysis of period and cohort fertility indicators in the Czech Republic, Netherlands, Spain, and Sweden shows that the new adjusted measure gives a remarkable fit with the completed fertility of women in prime childbearing years in a given period, which suggests that it provides an accurate adjustment for tempo and parity composition distortions. Using an expanded dataset for ten countries, we demonstrate that adjusted fertility as measured by TFRp* remained nearly stable since the late 1990s. This finding implies that the recent upturns in the period TFR in Europe are largely explained by a decline in the pace of fertility postponement. Other tempo adjusted fertility indicators have not indicated such a large role for the diminishing tempo effect in these TFR upturns. As countries proceed through their postponement transitions, tempo effects will decline further and eventually disappear, thus putting continued upward pressure on period fertility. However, such an upward trend may be obscured for a few years by the effects of economic recession. PMID- 22833866 TI - Potential of ordered mesoporous silica for oral delivery of poorly soluble drugs. AB - The use of ordered mesoporous silica is one of the more recent and rapidly developing formulation techniques for enhancing the solubility of poorly water soluble drugs. Their large surface area and pore volume make ordered mesoporous silica materials excellent candidates for efficient drug loading and rapid release. While this new approach offers many promising advantages, further research is still necessary to elucidate the molecular mechanisms and to improve our scientific insight into the behavior of this system. In this review, the significant developments to date are presented and research challenges highlighted. Aspects of downstream processability are discussed in view of their special bulk powder properties and unique pore architecture. Lastly, perspectives for successful oral dosage form development are presented. PMID- 22833867 TI - A conversation with Lloyd Hollingsworth Smith Jr. PMID- 22833869 TI - Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. AB - In the catabolic state with no food intake, the liver generates ketones by breaking down fatty acids. During the nocturnal fast or longer starvation periods, this protects the brain, which cannot oxidize fatty acids. In 1977, we published a study in the JCI noting the surprising realization that malonyl-CoA, the substrate of fatty acid synthesis, was also an inhibitor of fatty acid oxidation. Subsequent experiments have borne out this finding and furthered our understanding of molecular metabolism. PMID- 22833870 TI - Cold agglutinin disease with prolymphocytic leukemia. PMID- 22833871 TI - The criminalization of people with mental illness. PMID- 22833872 TI - Proceedings of the international conference "Human Biomonitoring: Political benefits-scientific challenges", September 26-28, 2010, Berlin, Germany. PMID- 22833868 TI - The molecular pathogenesis of head and neck squamous cell carcinoma. AB - Squamous cell carcinoma of the head and neck (HNSCC) is a relatively common human cancer characterized by high morbidity, high mortality, and few therapeutic options outside of surgery, standard cytotoxic chemotherapy, and radiation. Although the most important risk factors are tobacco use and alcohol consumption, the disease is also linked to infection with high-risk types of human papilloma viruses (HPVs). Recent genetic analyses have yielded new insights into the molecular pathogenesis of this disease. Overall, while somatic activating mutations within classical oncogenes including PIK3CA and RAS occur in HNSCC, they are relatively uncommon. Instead genetic data point to a contribution of multiple tumor suppressor pathways, including p53, Rb/INK4/ARF, and Notch, in tumor initiation, progression, and maintenance. The increasingly refined knowledge of HNSCC genetics, combined with ever-more-sophisticated animal models and newer drug targeting strategies, should promote novel therapeutic approaches and improved disease outcomes. PMID- 22833873 TI - Special Issue on Chromosome Dynamics in Memory of Prof. Kurt Nordstrom. PMID- 22833874 TI - Spinal anesthesia for noncardiac surgery in infants with congenital heart diseases. AB - OBJECTIVE/AIM: To compare hemodynamic parameters in infants with congenital heart disease (CHD) undergoing noncardiac surgery (NCS) under awake spinal anesthesia (SA) with controls without CHD also undergoing SA. BACKGROUND: NCS poses a twofold higher mortality risk in infants with CHD. SA might be a good alternative to general anesthesia (GA) in this setting. METHODS: The files of 84 infants were reviewed; 42 had CHD and 42 were controls without CHD. Primary outcome measures were percent decrease in mean arterial pressure (%MAP decrease) and heart rate (%HR decrease)from baseline to the lowest intraoperative value. One-way analysis of variance(ANOVA), ANOVA with repeated measures, Pearson chi-square test, Fisher's exact test, and Pearson correlation were used for statistical analysis.Time to discharge was analyzed with the nonparametric Mann-Whitney U test. RESULTS: There were no significant between-group differences in %MAP decrease and %HR decrease; no significant associations and correlations between %MAP decrease or %HR decrease and other variables; and no correlation between %MAP decrease and %HR decrease. A %MAP decrease of >20% was documented in 11 patients with CHD (26.2%) and 10 controls (23.8%); a lowest intraoperative HR of <100 b.min)1 was recorded in two study patients (4.8%) and four controls (9.5%) (P = NS for both). There were no cases of high SA or conversion to GA and no need for mechanical ventilation or inotropic support intra/postoperatively. CONCLUSIONS: These preliminary findings show that hemodynamic parameters in infants with CHD undergoing NCS under awake SA are not different from controls without CHD and that SA appears to be safe in infants with CHD. PMID- 22833875 TI - Abstracts of the Canadian Nutrition Society's 3rd Annual Scientific Meeting, May 23-25, 2012,Vancouver, Canada. PMID- 22833876 TI - [ACL reconstruction -- also brings advantages for people over age 50]. PMID- 22833877 TI - In vitro quantification of the stiffening effect of corneal cross-linking in the human cornea using radial shearing speckle pattern interferometry. AB - PURPOSE: To quantify the magnitude of the stiffening effect of corneal cross linking (CXL) by studying intact human corneas exposed to physiological pressure transients. METHODS: Nine organ-cultured human corneas mounted in artificial anterior chambers were studied. A radial shearing speckle pattern interferometer was used to measure changes in corneal strain following an increase in artificial anterior chamber pressure from 15.0 to 15.5 mmHg before and after treatment. Measurements were taken from all corneas with their epithelium intact before all underwent epithelial debridement. Three specimens were used as controls and did not receive any further treatment; three underwent riboflavin/ultraviolet A (UVA) CXL using 30 minutes of 370-nm irradiation at 3 mW/cm2 following epithelial removal and saturation with 0.1% riboflavin; and three were fixed with the cross linking agent 2.5% glutaraldehyde. Strain measurements were repeated after these treatments. Young's moduli of individual corneas were calculated by mathematical analysis. RESULTS: Mean donor age was 81.7 years. Before treatment, the mean Young's moduli of the control, riboflavin/UVA CXL, and glutaraldehyde-fixed corneas did not differ significantly: 0.46+/-0.03, 0.48+/-0.03, and 0.47+/-0.03 MPa, respectively. Following treatment these values changed to 0.46+/-0.2, 2.06+/ 0.22, and 3.48+/-0.41 MPa, respectively. In proportional terms, this was equivalent to an increase in corneal Young's modulus by a factor of 4.3 (P<.05) following riboflavin/UVA CXL and 7.3 (P<.05) after glutaraldehyde fixation. CONCLUSIONS: Riboflavin-UVA CXL increases the stiffness of organ-cultured corneas by a factor of more than four. This finding quantifies the efficacy of CXL in a physiologic configuration. PMID- 22833878 TI - Posttraumatic stress disorder comorbidity and clinical implications in patients with severe mental illness. AB - Traumatic experiences and posttraumatic stress disorder (PTSD) are more frequent in patients with serious mental illness than in the general population. This study included 102 patients with schizophrenia, bipolar disorder, and schizoaffective disorder, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Epidemiological and clinical data were collected using the Brief Psychiatric Rating Scale and Traumatic Life Events and Distressing Event questionnaires. We found a high number of traumatic experiences, and 15.1% of the patients met all criteria for PTSD. We found no differences based on diagnosis or sex, although there was a nonsignificant trend toward greater PTSD comorbidity in women. Among patients with serious mental illness and PTSD, 64.3% had made some attempt at suicide at some point in life, compared with 37.4% of patients without PTSD. PMID- 22833880 TI - Sirtuin modulators. PMID- 22833879 TI - Psychotropic marketing practices and problems: implications for DSM-5. AB - The descriptive diagnostic model since DSM-III has often led to "cookbook" diagnosis and assumptions of "chemical imbalance" for psychiatric disorders. Pharmaceutical companies have exploited this in their marketing. This includes promoting self-diagnosis with online checklists. Significant overprescribing of psychotropics has resulted. DSM-5 will provide new disorders and broader diagnostic criteria that will likely exacerbate this. Most psychotropic prescribing is done by primary care physicians, who are problematically excluded from DSM-5 field trials and are influenced by industry funded key opinion leaders who may promote diagnosis of subthreshold cases. More lax criteria will increase diagnosis of subthreshold cases. Expansion of not otherwise specified (NOS) categories can be used to justify off-label promotion. Pediatric bipolar disorder, constructed within the bipolar disorder NOS category, became an "epidemic" in the United States, fuelled by diagnostic upcoding pressures. Disruptive mood dysregulation disorder may similarly cause overdiagnosis and excessive prescribing, as will other new disorders and lower diagnostic thresholds. PMID- 22833881 TI - [The nasal valve. Part I. Anatomical and physiological nature, clinical manifestations of dysfunction and methods for its diagnostics]. AB - In this article, the critical analysis of the available publications concerning anatomical and physiological nature of the nasal valve, clinical manifestations of its dysfunction, and diagnostic methods is presented. Various diagnostic tools are considered with special reference to the anatomical features of the nasal valve and mechanisms of its disorders. The study revealed contradictory opinions as regards the causes underlying valvular insufficiency and the necessity of the objective evaluation of nasal breathing in the patients with this pathology. The need of the search for the new methods of topical diagnostics of nasal valve dysfunction is substantiated. PMID- 22833882 TI - [The nasal valve. Part II. The modern methods for the conservative and surgical treatment of its pathology]. AB - This literature review is focused on the methods for surgical correction of the nasal valve. Various surgical techniques are critically examined with reference to their application depending on the peculiar anatomical features of the nasal valve and mechanisms underlying its disorders. Conflicting opinions about the approaches to the correction of nasal valve insufficiency dictate the necessity of further search for the new methods for this purpose taking account of the peculiarities of the patients' clinical conditions and topographic level of the disorder. PMID- 22833883 TI - [Chronic rhinosinusitis: epidemiology, classification, etiology, and pathogenesis. The current view of the problem]. AB - The study of chronic rhinosinusitis is a challenging problem bearing in mind the ever-increasing morbidity and the lack of generally accepted criteria for diagnostics and treatment of this pathology. There is a great variety of factors predisposing to the development of chronic rhinosinusitis whereas its etiology remains controversial. Moreover, the pathogenetic mechanisms of chronic rhinosinusitis remain to be elucidated despite a wealth of publications devoted to this problem The results of many evidence-based investigations are different and even conflicting. Both diagnostic techniques and characteristics of chronic rhinosinusitis vary in a broad range depending on the standards adopted in different countries. PMID- 22833884 TI - [The overview of the surgical methods for the treatment of endocrine ophthalmopathy]. AB - To analyse the efficacy of various surgical methods for the treatment of endocrine ophthalmopathy and to estimate the potential of endonasal endoscopic surgery for the management of this pathology. The available literature publications concerning surgical treatment of endocrine ophthalmopathy were reviewed; their data were compared with the results of endoscopic endonasal surgery performed by the authors. Various surgical techniques including those with the use of external and endonasal transethmoidal approachers are discussed with special emphasis on the resection of the medial and inferior orbital walls. The analysis of surgical techniques, peculiarities of postoperative treatment, and its outcomes is presented. This study has demonstrated the advantages of endonasal endoscopic transethmoidal decompression of the orbit over the external surgical approach used to manage endocrine ophthalmopathy. PMID- 22833885 TI - [Clinico-immunological substantiation of bacterial lyzates use in otorinolaringology]. PMID- 22833886 TI - [The arrest]. PMID- 22833887 TI - Canadian cuts overshadow good news on cancer statistics. PMID- 22833888 TI - NICE guidance on cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. PMID- 22833889 TI - Lenalidomide maintenance for multiple myeloma. PMID- 22833890 TI - Home from Home. PMID- 22833891 TI - Nurse care manager contribution to quality of care in a dual-eligible special needs plan. AB - We evaluated the quality of care provided to older patients with complex needs in a dual-eligible, community-based Medicare Special Needs Plan that used a nurse care manager model. Care provided by physicians was substantially supplemented by nurse care managers, as measured by Assessing Care of Vulnerable Elders quality indicators. We describe selected nurse care manager activities for six geriatric conditions (falls, dementia, depression, nutrition, urinary incontinence, and end of-life care) during provision of patient care coordination and management for patients in the highest decile of clinical complexity. We identify areas of high nurse performance (i.e., falls screening, functional assessment, behavioral interventions for dementia problems, advance care planning) and areas of potential missed opportunities (i.e., follow up for new memory problems, targeted dementia counseling, nutrition, and behavioral approaches to urinary incontinence). Increasing the collaborative interaction between nurses providing care in this model and physicians has the potential to enhance nurses' contributions to primary care for vulnerable older adults. PMID- 22833892 TI - [The importance and evaluation methods of the quality of life in surgical patients]. PMID- 22833893 TI - [The hybrid operations by multilevel lesions of the brachiocephalic arteries]. PMID- 22833894 TI - [N. N. Blohin--the glorious son of Russia]. PMID- 22833895 TI - [The myocardial revascularization in patients with diabetes mellitus and the ischemic heart disease]. PMID- 22833896 TI - [The MESH-technologies in surgical treatment of hiatal hernia and gastroesophageal reflux]. PMID- 22833897 TI - [The diagnostics and prevention of the postoperative pancreatis]. PMID- 22833898 TI - Decreased blood-brain barrier expression of P-glycoprotein in Alzheimer's disease: impact on pathogenesis and brain access of therapeutic agents. PMID- 22833899 TI - Formulation and packaging design for new chemical entities: examining specific populations and product repositioning. PMID- 22833900 TI - European Commission-supported development of targeted nanomedicines: did MediTrans make a difference? AB - Nanotechnology-inspired approaches to particle design and formulation, an improved understanding of (patho) physiological processes and biological barriers to drug targeting, as well as the limited input of new chemical entities in the 'pipeline' of pharmaceutical companies, suggest a bright future for targeted nanomedicines as pharmaceuticals. There is an increased consensus to the view that a major limitation hampering the entry of targeted delivery systems into the clinic is that new concepts and innovative research ideas within academia are not being developed and exploited in close collaboration with the pharmaceutical industry. Thus, an integrated 'bench-to-clinic' approach realized within a structural collaboration between industry and academia, will facilitate and promote the progression of targeted nanomedicines towards clinical application. The MediTrans project performed under the EU Framework Program 6, was designed to contribute to this ambition. The objectives of this collaborative initiative were: to apply nanotechnology for development of innovative targeted drug delivery systems; to optimize targeted nanomedicines by using imaging guidance; to promote structural collaboration between industry and academia; and to forward targeted nanomedicines towards the clinic and the market. In this article, we will briefly address the research content, outcome and impact of the MediTrans project. PMID- 22833901 TI - Pharmaceutical development of biologics: fundamentals, challenges and recent advances. AB - The 46th Arden Conference, held in West Point, NY, USA, March 2011, focused on development of protein therapeutics, comprising preformulation, formulation, manufacturing, advanced delivery systems, protein characterization/analysis, and regulatory landscape. The sessions of preformulation and formulation development consisted of nine lectures discussing protein stability implications and characterization during purification, freeze-drying and manufacturing. The session on advanced drug delivery encompassed two new sustained-release microsphere formulations (protein microencapsulation by annealing of premade porous PLGA microspheres and aqueous-aqueous emulsion for preformulating proteins to solvent-resistant particles), two transdermal insulins (patching after thermal ablation of skin and phase-transition hydrogel microneedle patch), and a responsible hydrogel system for intra-ear delivery. The sessions on analytical technologies and regulatory landscape both focused on challenges for biosimilars. PMID- 22833902 TI - Poly(amidoamine) polymers: soluble linear amphiphilic drug-delivery systems for genes, proteins and oligonucleotides. AB - Polymer-drug and polymer-protein conjugates are emerging as a robust and well characterized class of therapeutic entity. Although there are no low-molecular weight soluble polymer conjugates in routine clinical use, there are many examples of routinely used high-molecular-weight drugs conjugated to soluble polymers (e.g., Oncospar). Advances in synthetic polymer chemistry have fostered the development of linear poly(amidoamine)s (PAA)s that impart both biodegradability, 'smart' (pH responsive) biological activity and biocompatibility. In their linear form, such as hyper-branched poly(amidoamine) (PAMAM) dendrimers, linear PAAs can be used to deliver large therapeutic entities such as peptides, proteins and genes to either the cytosol or nucleus. Furthermore, these polymers offer great potential in vivo due to their ability to either target the liver or be directed away from the liver and enter tumor mass via the enhanced permeability and retention (EPR) effect. PAAs also exhibit minimal toxicity (dependent upon backbone chemistry), relative to well characterized polymers used for gene delivery. The propensity of PAAs to modulate intracellular trafficking resulting in their cytosolic translocation has also recently been quantified in vivo and is the primary focus of this article. PMID- 22833903 TI - See, reach, treat: ultrasound-triggered image-guided drug delivery. AB - The integration of therapeutic interventions with diagnostic imaging has been recognized as one of the next technological developments that will have a major impact on medical treatments. Therapeutic applications using ultrasound, for example thermal ablation, hyperthermia or ultrasound-induced drug delivery, are examples for image-guided interventions that are currently being investigated. While thermal ablation using magnetic resonance-guided high-intensity focused ultrasound is entering the clinic, ultrasound-mediated drug delivery is still in a research phase, but holds promise to enable new applications in localized treatments. The use of ultrasound for the delivery of drugs has been demonstrated, particularly in the field of cardiology and oncology for a variety of therapeutics ranging from small-molecule drugs to biologics and nucleic acids exploiting temperature- or pressure-mediated delivery schemes. PMID- 22833904 TI - Phage therapy: delivering on the promise. AB - Bacteriophages are viruses that infect and, in many cases, destroy their bacterial targets. Within a few years of their initial discovery they were being investigated as therapeutic agents for infectious disease, an approach known as phage therapy. However, the nature of these exquisitely specific agents was not understood and much early use was both uninformed and unsuccessful. As a result they were replaced by chemical antibiotics once these became available. Although work on phage therapy continued (and continues) in Eastern Europe, this was not conducted to a standard allowing it to support clinical uses in areas regulated by the European Medicines Agency or the US FDA. To develop phage therapy for these areas requires work carried out in accordance with the requirements of these agencies, and, driven by the current crisis of antibiotic resistance, such clinical trials are now under way. The first Phase I clinical trial of safety was reported in 2005, and the results of the first Phase II clinical trial of efficacy of a bacteriophage therapeutic was published in 2009. While the delivery of these relatively large and complex agents to the site of disease can be more challenging than for conventional, small-molecule antibiotics, bacteriophages are then able to multiply locally even from an extremely low (picogram range) initial dose. This multiplication where and only where they are needed underlies the potential for bacteriophage therapeutics to become a much needed and powerful weapon against bacterial disease. PMID- 22833905 TI - Case studies with new excipients: development, implementation and regulatory approval. AB - The purpose of this article is to describe the process whereby new excipients become accepted and to describe three case studies to illustrate the process. New excipients are defined according to the 2005 FDA Guidance on Nonclinical Safety Evaluation of New Excipients. The requirements for safety data submission for new excipients used in different classes of products for different durations are outlined in the guidance. Currently, the development of new excipients is linked to the development and approval of new drug products that contain them. New excipients that are used in US-approved drug products become listed in the FDA Inactive Ingredients Guide (IIG) database. Thereafter, US Pharmacopeia monographs for the new excipients are proposed. New excipients are reviewed and become accepted in the same way in Europe and Japan, except that there is no equivalent IIG database. Therefore, the focus of this article will be on the FDA review process. Three case studies, polyoxyl 15 hydroxystearate, sulfobutyl ether cyclodextrin and silicified microcrystalline cellulose, are used to illustrate how new excipients are accepted and implemented. PMID- 22833906 TI - Exosomes and the blood-brain barrier: implications for neurological diseases. PMID- 22833907 TI - SiRNA therapeutics: chances, pitfalls and future potential. PMID- 22833908 TI - The 18th Congress of the International Society for Aerosols in Medicine. AB - The 18th biennial Congress of ISAM was held for 4 days at the De Doelen Congress Centre, Rotterdam, Netherlands, at which approximately 350 delegates, including 60 session chairs and speakers, attended. The abstracts of the 49 podium talks and the 126 posters that were presented have been published in the society's technical journal (journal of Aerosol Medicine and Pulmonary Delivery), and the detailed program can be found on the ISAM website (www.isam.org). Postgraduate courses on the topics: 'Inhalation Therapy at the Intensive Care Unit'; 'Walking the Standards Maze: Standards for Device Development, Device Performance and Regulatory Approval'; and 'Nuts and Bolts of Aerosol Delivery: Theory, Guidelines and Practice', were offered to participants prior to the Congress itself. PMID- 22833909 TI - The AAPS National Biotechnology Conference. AB - Leading off the event, specialized workshops with panels of experts were conducted that brough together students and scientists to the current advances in their specialty. Delivery of therapeutics across the blood-brain barrier for the treatment of neurological conditions such as pain, Alzheimer's and Parkinson's disease is a field of great development with an expanding aging population of patients. Manoj Rajadhyaksha, Pfizer, Inc. and Saileta Prabhu, Genentech, Inc., brought together a panel describing the anatomy of the CNS and improvements in drug delivery. The conference that followed expanded upon the current approaches. PMID- 22833910 TI - Pulmonary delivery of therapeutic compounds for treating CNS disorders. AB - Delivering therapeutic compounds via the lungs presents potential advantages relative to other routes of administration. Depending on the compound and the disease state, these advantages may include: non-invasive medication delivery, ease of administration, higher bioavailability leading to dose sparing and lower systemic toxicity, potentially greater blood-brain barrier penetration and rapid pharmacodynamic effect. The practice of inhaling drugs has been around for centuries, including both medical and recreational usage. It is only more recently that formal clinical development programs have been undertaken specifically to use medication delivery via the lung to achieve systemic blood levels for the treatment of CNS disorders. At present, there are several CNS therapies being developed for pulmonary administration, with some of those programs at or near the marketing authorization stage. While there are still regulatory hurdles before these therapies can be put into practice, the success of these programs thus far demonstrates the scientific viability of inhalation therapies for treating CNS disorders. PMID- 22833911 TI - Formulation design considerations for oral vaccines. AB - Whilst oral vaccination is a potentially preferred route in terms of patient adherence and mass vaccination, the ability to formulate effective oral vaccines remains a challenge. The primary barrier to oral vaccination is effective delivery of the vaccine through the GI tract owing to the many obstacles it presents, including low pH, enzyme degradation and bile-salt solubilization, which can result in breakdown/deactivation of a vaccine. For effective immune responses after oral administration, particulates need to be taken up bythe M cells however, these are few in number. To enhance M-cell uptake, particle characteristics can be optimized with particle size, surface charge, targeting groups and bioadhesive properties all being considerations. Yet improved uptake may not translate into enhanced immune responses and formulating particulates with inherent adjuvant properties can offer advantages. Within this article, we establish the options available for consideration when building effective oral particulate vaccines. PMID- 22833912 TI - Mesoporous bioactive glasses as drug delivery and bone tissue regeneration platforms. AB - The use of mesoporous bioactive glasses (MBG) for drug delivery and bone tissue regeneration has grown significantly over the past 5 years. In this article, we highlight recent advances made in the preparation of MBG particles, spheres, fibers and scaffolds. The advantages of MBG for drug delivery and bone scaffold applications are related to this material's well-ordered mesopore channel structure, superior bioactivity and its capability to deliver both hydrophilic and hydrophobic drugs. A brief forward-looking perspective on the potential clinical applications of MBG in regenerative medicine is also discussed. PMID- 22833913 TI - On-off pulsed oral drug-delivery systems: a possible tool for drug delivery in chronotherapy. AB - Circadian rhythms regulate most body functions and are important factors to consider when administering drugs. The existence of circadian rhythms in nature and their influences on human biological systems have given rise to the concept of chronotherapy, which is the science of delivering drugs in a synchronized manner with the rhythm-dependent circadian variation inherent in the human body. The safety and efficacy of a drug can be improved by matching the peak plasma concentration during a 24 h period of the rhythms. An on-off pulsed (pulsatile or time-controlled) release drug-delivery system offers rapid and transient release; stepwise release; and the sustained release of a certain amount of drug within a short time period after a predetermined off-release period according to the circadian rhythm of disease states. These systems deliver the drug at the right time and at an appropriate dosage and are the best approach for chronotherapy. These systems show promise for the optimal therapy of chronic diseases such as asthma, hypertension, myocardial infarction and arthritis, which show a circadian dependency. Various technologies have been adopted to mimic circadian rhythms in physiological functions and diseases. This review focuses on the basic concept of circadian rhythm, chronotherapy and recent advances in the development of on-off pulsed oral drug-delivery systems for optimal therapy. PMID- 22833914 TI - Low-dose effects of endocrine disruptors, with Laura Vandenberg. Interview by Ashley Ahearn. PMID- 22833915 TI - Erratum to: "Direct electrochemistry and electrocatalysis of myoglobin on redox active self-assembling monolayers derived from nitroaniline modified electrode." [Biosensors and Bioelectronics 22 (12) (2007) 3042-3050]. PMID- 22833917 TI - Retraction. Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes. PMID- 22833916 TI - Retraction. Pharmacological preconditioning with resveratrol: role of nitric oxide. PMID- 22833918 TI - Retraction. Targeted disruption of peroxiredoxin 6 gene renders the heart vulnerable to ischemia-reperfusion injury. PMID- 22833919 TI - Retraction. Cardioprotection with palm oil tocotrienols: comparison of different isomers. PMID- 22833920 TI - Computational models for the in silico analysis of drug delivery from drug eluting stents. PMID- 22833921 TI - The International Conference on the Freeze-Drying of Pharmaceuticals and Biologicals. AB - The stability of pharmaceuticals and biological products is a major challenge for the industry. While some preparations have adequate stability as a liquid formulation, many biological molecules must be dried in order to achieve shelf lives compatible with a commercial product. In addition, the technology for conducting freeze-drying and sample analysis is continually improving. Researchers from all relevant areas discussed critical aspects and new developments at the conference of Freeze-Drying of Pharmaceuticals and Biologicals. PMID- 22833922 TI - 17th Annual Meeting of the German Society for Gene Therapy. AB - The 17th Annual Meeting of the German Society for Gene Therapy was held at the Chemistry and Pharmacy Campus of the University of Munich in conjunction with and supported by the British Society for Gene Therapy, the Viral Vectors Study Group of the German Society for Virology, the Research Priority Program SPP1230, the Nanosystems Initiative Munich and the Helmholtz Center Munich. The German Research Foundation provided financial support for the invited international speakers. In addition to 25 invited lectures, 21 oral presentations were selected out of more than 100 submitted abstracts. State-of-the-art advances in the field of gene therapy were presented, a field that has considerably evolved within recent years. More than 200 researchers from Germany and other European countries, as well as the USA, Canada and Japan attended the meeting. Prior to the official meeting, a public day was organized, in which the interested public could participate in talks and discussions concerning gene therapy issues. Furthermore, at the 'kids workshop' young scientists aged 8-10 years were discovering cellular and genetic mechanisms and the principles of gene therapy. PMID- 22833923 TI - Enhanced delivery of lopinavir to the CNS using Compritol-based solid lipid nanoparticles. AB - BACKGROUND: Protease inhibitors such as lopinavir have negligible permeability to the CNS due to blood-brain and blood-cerebrospinal fluid interfaces. An attempt has been made to develop solid lipid nanoparticles to increase the availability of lopinavir in the CNS. RESULTS/DISCUSSION: Solid lipid nanoparticle formulations exhibited a Cmax and T(max) of 632.86 +/- 81.61 ng/ml and 25 +/- 7.75 min, respectively, with a significant increase in bioavailability in a rat model compared with a free-drug suspension. An appreciable increase in cerebrospinal fluid concentration was detected with solid lipid nanoparticle formulations. CONCLUSION: Compritol-based solid lipid nanoparticles with a poloxamer coating can be effectively absorbed through the lymphatic system, prolong the circulation of drug in blood by acting as a reservoir and can effectively target the drug to the CNS due to the combined effect of lipophilicity and surface charge. The high biocompatibility, biodegradability and nontoxicity of compritol make the compritol-based solid lipid nanoparticles an excellent carrier for enhanced CNS delivery of lopinavir. PMID- 22833924 TI - Development of advanced therapies based on viral vector-mediated overexpression of therapeutic molecules and knockdown of disease-related genes for Parkinson's disease. AB - The last decade witnessed the translation of several gene-based therapeutic approaches from experimental studies to early clinical trials. Studies targeting the treatment of Parkinson's disease (PD) were among the forefront of trials in the CNS. In this article, we overview three major strategies for the treatment of PD: the enzyme-replacement strategies are based on well-defined principles of functional restoration and are well suited for treatment of patients with advanced disease who would typically experience complications due to side effects of pharmacotherapy. Neurotrophic factor delivery, on the other hand, aims to delay the disability and eventually modifiy disease progression. Finally, we present an outlook to a completely new way of interfering with the disease process, which is taking advantage of recently discovered RNAi mechanisms in cells. Gene therapy is now becoming a reality in the clinics and developments in the next decade will help uncover the true potential of this approach for not only the treatment of PD patients, but also many other neurological disorders. PMID- 22833925 TI - Delivery of antigens by viral vectors for vaccination. AB - Viral vectors have been developed as vaccine platforms for a number of pathogens and tumors. In particular, adenovirus (Ad)-based vectors expressing genes coding for pathogen or tumor antigens have proven efficacious to induce protective immunity. Major challenges in the use of Ad vectors are the high prevalence of anti-Ad immunity and the recent observation during an Ad-based HIV vaccine trial that led to increased HIV-1 acquisition in the presence of circulating anti-Ad5 neutralizing antibodies. In this review we summarize strategies to address these challenges and focus on modifications of the Ad capsid to enhance the adjuvant effect of anti-Ad immunogenicity and to circumvent pre-existing immunity. In addition, we summarize the current status and potential of other viral vector vaccines based on adeno-associated viruses, lentiviruses and poxviruses. PMID- 22833926 TI - Therapeutic delivery opportunities, obstacles and applications for cell penetrating peptides. AB - Advancements in the development of large bioactive molecules as therapeutic agents have made drug delivery an active and important field of research. Cell penetrating peptides (CPPs) have the ability to deliver an array of molecules and even nano-size particles into cells in an efficient and non-toxic manner, both in vitro and in vivo. This review aims to give a perspective on the obstacles that CPP-mediated drug delivery is currently facing as well as the great opportunities for improvements that lie ahead. Strategies for delivery of novel gene-modulating agents and enhancing efficacy of classical drugs will be discussed, as well as methods for increasing bioavailability and tissue specificity of CPPs. The usefulness and potential of CPPs as therapeutic drug-delivery vectors will be exemplified by their use in the treatment of cancer, viral infection and muscular dystrophy. PMID- 22833927 TI - Dermal and transdermal delivery: prodrugs. AB - Attempts to deliver drugs into and through the skin (dermal and transdermal delivery) have not been very successful because the physicochemical properties of drugs are often not optimal. Prodrugs can be used to optimize those physicochemical properties of drugs and optimize their delivery by transiently masking their polar functional groups. For a drug to cross the rate-limiting barrier to delivery (the stratum corneum) it must dissolve in and cross multiple lipid and aqueous phases within the stratum corneum. Prodrugs can be designed to exhibit increased lipid and aqueous solubilities resulting in increased delivery. In order to identify the optimal prodrugs, they must be evaluated as saturated solutions where their thermodynamic activities are maximal in the solution and in the skin. If prodrugs are evaluated at concentrations less than at saturation, inaccurate conclusions about the optimal physicochemical properties may result. Prodrugs must be designed to optimize both their lipid and aqueous solubilities to optimize their delivery into and through the skin. PMID- 22833928 TI - Challenges and opportunities in the delivery of cancer therapeutics. AB - The idea that cancer is not one but many diseases has completely changed the oncology landscape and promoted the development of personalized cancer therapy. Based on a better understanding of the mechanisms of cancer cell proliferation and tumor growth, novel therapies have emerged to address unmet medical needs and effectively treat pre-identified, responsive patients. These novel therapies require specific drug-delivery strategies that depend on the type and location of cancer, as well as the type of drugs administered, that is, a small molecule, a peptide, a therapeutic protein or a monoclonal antibody. Systemic cancer drugs are administered through three major routes that show different challenges with regard to delivery: these are oral administration, intravenous infusion and subcutaneous injection. This review presents and discusses the challenges and opportunities of the drug-delivery systems for each of these administration routes. It will be shown that, for the good of the patients, every time a drug delivery system is used to administer anticancer drugs, the patients get a major benefit from that specific system: either improved efficacy, a better tolerability and toxicity profile, or even a combination of both effects. PMID- 22833929 TI - Nanosystem formulations for rectal microbicides: a call for more research. PMID- 22833930 TI - Establishing the principle of reversibility in peptide/protein and small-molecule therapy. AB - Several important pharmacological features can be integrated into injected drugs to enhance their therapeutic efficacy following administration. Short-lived peptide/protein drugs should be converted into long-lived species in vivo to avoid multiple injections. Circulating levels of anticancer agents need to be maintained within a narrow therapeutic range for prolonged period. Water insoluble drugs must be turned into soluble species and blood-brain barrier impermeable agents need to be modified to cross it following peripheral administrations. The derivatization requiring for achieving those desirable pharmacological features typically result in biologically/pharmacologically inactive products, unless those derivatizations can be carried out in a reversible fashion. PMID- 22833931 TI - Cell-based drug-delivery platforms. AB - Cell systems have recently emerged as biological drug carriers, as an interesting alternative to other systems such as micro- and nano-particles. Different cells, such as carrier erythrocytes, bacterial ghosts and genetically engineered stem and dendritic cells have been used. They provide sustained release and specific delivery of drugs, enzymatic systems and genetic material to certain organs and tissues. Cell systems have potential applications for the treatment of cancer, HIV, intracellular infections, cardiovascular diseases, Parkinson's disease or in gene therapy. Carrier erythrocytes containing enzymes such us L-asparaginase, or drugs such as corticosteroids have been successfully used in humans. Bacterial ghosts have been widely used in the field of vaccines and also with drugs such as doxorubicin. Genetically engineered stem cells have been tested for cancer treatment and dendritic cells for immunotherapeutic vaccines. Although further research and more clinical trials are necessary, cell-based platforms are a promising strategy for drug delivery. PMID- 22833932 TI - Molecular buckets: cyclodextrins for oral cancer therapy. AB - The oral route is preferred by patients for drug administration due to its convenience, resulting in improved compliance. Unfortunately, for a number of drugs (e.g., anticancer drugs), this route of administration remains a challenge. Oral chemotherapy may be an attractive option and especially appropriate for chronic treatment of cancer. However, this route of administration is particularly complicated for the administration of anticancer drugs ascribed to Class IV of the Biopharmaceutical Classification System. This group of compounds is characterized by low aqueous solubility and low intestinal permeability. This review focuses on the use of cyclodextrins alone or in combination with bioadhesive nanoparticles for oral delivery of drugs. The state-of-the-art technology and challenges in this area is also discussed. PMID- 22833933 TI - A review on comb-shaped amphiphilic polymers for hydrophobic drug solubilization. AB - Comb-shaped amphiphilic polymers are rapidly emerging as an alternative approach to amphiphilic block copolymers for hydrophobic drug solubilization. These polymers consist of a homopolymer or copolymer backbone to which hydrophobic and hydrophilic pendant groups can be grafted resulting in a comb-like architecture. The hydrophobic pendants may consist of homopolymers, copolymers and other low molecular weight hydrophobic structures. In this review, we focus on hydrophobically modified preformed homopolymers. Comb-shaped amphiphilic polymers possess reduced critical aggregation concentration values compared with traditional surfactant micelles indicating increased stability with decreased disruption experienced on dilution. They have been fabricated with diverse architectures and multifunctional properties such as site-specific targeting and external stimuli-responsive nature. The application of comb-shaped amphiphilic polymers is expanding; here we report on the progress achieved so far in hydrophobic drug solubilization for both intravenous and oral delivery. PMID- 22833934 TI - The effect of food on the oral bioavailability of drugs: a review of current developments and pharmaceutical technologies for pharmacokinetic control. AB - Here we review the mediation of the food effects on drugs by pharmaceutical technologies. The pharmacokinetics of drugs are affected by the interaction of drugs with food, which changes drug physicochemical and physiological properties (food effects). Several pharmaceutical technologies may be used to control food effects. Drugs exhibit different patterns of solubilization depending on release formulations. Formulations such as nanoparticle, solid dispersion and cyclodextrin systems, may control the solubility and release of insoluble drugs. Other controlled-release technologies, such as osmotic-controlled release or colon-specific delivery systems may also control food effects. As the structure of drug candidates becomes more complex, different methods of investigation, such as in vitro and in vivo correlation and in silico simulation will be required to predict drug characteristics and food effects. PMID- 22833935 TI - Intracranial drug delivery for subarachnoid hemorrhage. AB - Tice and colleagues pioneered site-specific, sustained-release drug delivery to the brain almost 30 years ago. Currently there is one drug approved for use in this manner. Clinical trials in subarachnoid hemorrhage have led to approval of nimodipine for oral and intravenous use, but other drugs, such as clazosentan, hydroxymethylglutaryl CoA reductase inhibitors (statins) and magnesium, have not shown consistent clinical efficacy. We propose that intracranial delivery of drugs such as nimodipine, formulated in sustained-release preparations, are good candidates for improving outcome after subarachnoid hemorrhage because they can be administered to patients that are already undergoing surgery and who have a self-limited condition from which full recovery is possible. PMID- 22833936 TI - Understanding the lipid-digestion processes in the GI tract before designing lipid-based drug-delivery systems. AB - Many of the compounds present in lipid-based drug-delivery systems are esters, such as acylglycerols, phospholipids, polyethyleneglycol mono- and di-esters and polysorbate, which can be hydrolyzed by the various lipolytic enzymes present in the GI tract. Lipolysis of these compounds, along with dietary fats, affects the solubility, dispersion and bioavailibity of poorly water-soluble drugs. Pharmaceutical scientists have been taking a new interest in fat digestion in this context, and several studies presenting in vitro gastrointestinal lipolysis models have been published. In most models, it is generally assumed that pancreatic lipase is the main enzyme involved in the gastrointestinal lipolysis of lipid formulations. It was established, however, that gastric lipase, pancreatic carboxyl ester hydrolaze and pancreatic lipase-related protein 2 are the major players involved in the lipolysis of lipid excipients containing acylglycerols and polyethyleneglycol esters. These findings have shown that the lipolysis of lipid excipients may actually start in the stomach and involve several lipolytic enzymes. These findings should therefore be taken into account when testing in vitro the dispersion and bioavailability of poorly water-soluble drugs formulated with lipids. In this review, we present the latest data available about the lipolytic enzymes involved in gastrointestinal lipolysis and suggest tracks for designing physiologically relevant in vitro digestion models. PMID- 22833937 TI - Nanoparticles and toxicity in therapeutic delivery: the ongoing debate. PMID- 22833938 TI - Targeted cancer therapy: dendritic cell metabolism. PMID- 22833939 TI - Improved otutcome of targeted delivery of chemotherapy drugs to the brain using a combined strategy of ultrasound, magnetic targeting and drug-loaded nanoparticles. PMID- 22833940 TI - Annual Inhaled Drug Delivery Conference. AB - The Annual Inhaled Drug Delivery Conference organized by Management Forum was held in London, UK, 9-10 November 2010. The meeting focused on a range of disease therapies from the pulmonary indications routinely treated with inhaled medicines (asthma, cystic firbrosis and chronic obstructive pulmonary disease) to novel applications of the inhalation route to treat systemic diseases (irritable bowel disease, schizophrenia, migraine, diabetes and obesity). PMID- 22833941 TI - The Ninth Annual European Partnerships and Latest Innovations in Drug Delivery. AB - This European meeting was organized by Informa Life Sciences and took place in Brussels at the NH Grand Sablon Hotel, 23-24 November 2010. A total of 25 attendees, most of them scientists and industrialists, from all parts of Europe, South Korea, Israel and the USA participated in this platform, which allowed all participants to learn the latest developments in drug-delivery formulations. PMID- 22833942 TI - Moving theranostics trom bench to bedside in an interdisciplinary research team. AB - The Laboratory of Molecular Imaging and Nanomedicine of the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health has been led by Xiaoyuan Chen since 2009. The Laboratory of Molecular Imaging and Nanomedicine contains three interdisciplinary, versatile groups: the Theranostic Nanomedicine; PET/Optical Imaging Probe; and Biological Molecular Imaging Sections, consisting of chemists, engineers, biologists and clinicians working together to transfer biomedical technology from bench to bedside. To find out more about our laboratory and meet our group, please visit us at www.nibib.nih.gov/Research/Intramural/xchen. PMID- 22833944 TI - Curdlan complexes as a potential food-grade delivery system: genistein case study. AB - Complexes of curdlan and genistein were prepared using four different methods. The total amount of genistein in curdlan-genistein complexes prepared at 40 degrees C (system I) was significantly higher (2.3 mg/100 mg dry matter) than that in other systems studied: curdlan-genistein complexes prepared at 60 degrees C (system II; 1.8 mg/100 mg dry matter); curdlan-genistein gel complexes (system III; 1.0 mg/100 mg dry matter); and curdlan-genistein dimethyl sulfoxide complexes (system IV; 1.8 mg/100 mg dry matter). x-ray diffraction results indicate that complexation of curdlan with genistein changes the crystalline nature of the pure components. Particle size analysis, atomic force microscopy and scanning electron microscopy imaging of curdlan-genistein complexes showed strong difference in particle size, surface and distribution in comparison with pure curdlan, confirming our assumption of a molecular interaction between curdlan and genistein and the formation of a new structure, which was revealed at the nanoscale level. All the curdlan-genistein complexes showed prolonged genistein release of up to 72 h, enhanced upon enzymatic digestion of curdlan by lyticase, thus opening the possibility of release regulation by the incorporation of lyticase in the delivery system. It is therefore suggested that the complexes could be used as a delivery system for the protection and slow release of genistein in the digestive tract. PMID- 22833943 TI - Optimization and characterization of levamisole-loaded chitosan nanoparticles by ionic gelation method using 2(3) factorial design by Minitab 15. AB - BACKGROUND: The purpose of the present study is to investigate the combined influence of three independent variables on two dependent variables for the preparation of nanoparticles. The three independent variables are the chitosan/sodium tripolyphosphate ratio, pH of sodium tripolyphosphate and levamisole concentration; while particle size and percentage drug entrapment were dependent variables. DISCUSSION: The nanoparticles were prepared by using 2(3) factorial design to obtain high entrapment efficiency and small size. The polynomial equation can be used to predict the responses. CONCLUSION: The prepared nanoparticles show busted release for the first 2 h and then show sustained release. The differential scanning calorimetry graphs indicate that drug is completely entrapped in nanoparticles and transmission electron microscopy images show that nanoparticles are spherical in shape and dense solid in nature. The mathematical model obtained by 2(3) factorial design shows good relationship between independent variables and dependent variables for prediction. PMID- 22833945 TI - Designed peptides as model self-assembling nanosystems: characterization and potential biomedical applications. AB - Synthesis of nanomaterials via 'molecular self-assembly' allows one to define the properties of the nanomaterial by rational design of the individual constituents. Use of peptides for self-assembly offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. Our work focused on the synthesis, characterization and potential biomedical applications of small self-assembled peptide-based nanosystems. We demonstrated that dipeptides containing the conformational restricting residue alpha,beta dehydrophenylalanine, self-assembled into nanovesicular and nanotubular structures. The nanosystems could encapsulate and release anticancer drugs, showed enhanced stability to proteinase K degradation, a property crucial for them to have a high in vivo half-life, and exhibited no cytotoxicity towards cultured mammalian cells. The dipeptide nanostructures were easily taken up by cells and could evade uptake by reticuloendothelial systems when injected into healthy laboratory animals. Thus, small self-assembling peptides may offer novel scaffolds for the future design of nanostructures with potential applications in the field of drug delivery. PMID- 22833946 TI - Polyethylene-glycolylated isoniazid conjugate for reduced toxicity and sustained release. AB - BACKGROUND: The antitubercular drug, isoniazid (INH), has been conjugated with a bifunctional polyethylene glycol derivative (MW 575) with the objective of designing a novel drug-delivery system that has reduced toxicity compared with the neat drug, without compromising its biological activity. The polyethylene glycol-bis(INH) conjugate was synthesized in high yield and was completely characterized by infrared, NMR and mass spectroscopies. RESULTS: This conjugate was labeled with a 99mTc radionuclide with less than 95% labeling efficiency. MTT assay revealed lower cytotoxicity of the conjugate compared with INH. Blood kinetics in rabbits and biodistribution in mice compared the blood retention of the drug and its polymer conjugate and their uptake in various organs, respectively. Biodistribution and gamma-scintigraphy in infection-induced animal models showed significantly high accumulation of the polymer-drug conjugate at the site of infection and retention for a long duration. CONCLUSION: This conjugate could prove to be a good lead molecule for infection diagnosis and therapy. PMID- 22833947 TI - Insonation frequency selection may assist detection and therapeutic delivery of targeted ultrasound contrast agents. AB - BACKGROUND: Ultrasound-targeted drug delivery relies on the unique nature of ultrasound contrast agents--they are microbubbles that respond strongly to ultrasound. Intravenously injected microbubbles are smaller than a blood cell. By increasing the ultrasound power, the bubbles can be ruptured at the targeted endothelial wall, locally releasing any molecules in the bubble shell. Furthermore, ultrasound-activated microbubbles are known to cause sonoporation- the process by which ultrasound drives molecules through cellular membranes. However, techniques are required to selectively detect and rupture only those microbubbles on target walls. METHOD: Experiments are presented on the behaviour of microbubbles on walls. For accuracy, imaging measurements are made on model microbubbles larger than contrast agents. Bubble size was varied and the resonant frequency peak determined. RESULTS: Microbubbles on walls have a shifted frequency in good agreement with theory: a 20-25% downshift from the frequency when far from walls. Effects other than the presence of the wall account for less than 5% of the shift. DISCUSSION: Theory predicts the frequency downshift should be sustained for actual contrast-agent sized bubbles. The effect of real, compliant cell walls requires investigation. An appropriate downshift in the applied ultrasound frequency could selectively tune gene or drug delivery. To make this feasible, it may be necessary to manufacture monodispersed microbubbles. PMID- 22833948 TI - Antileishmanial activity of nanocurcumin. AB - BACKGROUND: Leishmaniasis is an endemic disease having a wide spectrum ranging from visceral, cutaneous and mucocutaneous forms caused by unicellular, obligate intracellular parasites of the monocyte-macrophage system. The aim of the present study was to develop an effective, nontoxic and biodegradable polymeric drug delivery system encapsulating curcumin in its hydrophobic core for the treatment of visceral leishmaniasis. RESULTS: We have reported a co-polymeric micelle of N isopropyl acrylamide, vinyl pyrrolidone and acrylic acid in 85:10:5 M ratios through free radical polymerization. The characterization of curcumin-loaded nanoparticles (40-50 nm) was done by transmission electron microscopy, dynamic light scattering and spectroscopic methods such as NMR which ensures polymerization and formation of nanoparticles has been achieved. Nanocurcumin was evaluated as an antileishmanial agent through spleenomegaly and delayed-type hypersensitivity experiments. CONCLUSION: Nanocurcumin has shown significantly greater in vivo therapeutic efficacy than pentamidine and free curcumin in an animal model of visceral leishmaniasis. The use of nanocurcumin compared with conventional drugs and free curcumin may prove more feasible and provide a better approach towards treatment of leishmaniasis. PMID- 22833949 TI - In search of optimal scaffold for regenerative medicine and therapeutic delivery. AB - Understanding extracellular matrix (ECM) biology is imperative for tissue engineering and regenerative medicine, which seeks functionally viable cells to be delivered at the site of injury in addition to restoring tissue/organ shape through artificial scaffolds. Cells cultured by conventional methods that allow only 2D growth are not the true representatives of functional cells existing in vivo. To expect an in vivo-like cellular response, it is mandatory to recreate an ECM-mimicking microenvironment, one of the fundamental needs of which is to allow cells to grow in a 3D scaffold. A convenient, user-friendly technology that can bridge the knowledge gaps and advance our comprehension of cell-cell and cell-ECM dynamics in a 3D environment is, therefore, the need of the hour. Such technologies can provide a novel tool for therapeutic delivery as well. PMID- 22833950 TI - Naposomes: a new class of peptide-derivatized, target-selective multimodal nanoparticles for imaging and therapeutic applications. AB - Modified supramolecular aggregates for selective delivery of contrast agents and/or drugs are examined with a focus on a new class of peptide-derivatized nanoparticles: naposomes. These nanoparticles are based on the co-aggregation of two different amphiphilic monomers that give aggregates of different shapes and sizes (micelles, vesicles and liposomes) with diameters ranging between 10 and 300 nm. Structural properties and in vitro and in vivo behaviors are discussed. For the high relaxitivity values (12-19 mM(-1)s(-1)) and to detect for the presence of a surface-exposed peptide, the new peptide-derived supramolecular aggregates are very promising candidates as target-selective MRI contrast agents. The efficiency of surface-exposed peptides in homing these nanovectors to a specific target introduces promising new opportunities for the development of diagnostic and therapeutic agents with high specificity toward the biological target and reduced toxic side effects on nontarget organs. PMID- 22833951 TI - Design of submicron and nanoparticle delivery systems using supercritical carbon dioxide-mediated processes: an overview. AB - Supercritical carbon dioxide technology is an environmentally benign technique that allows precise control of particle morphology, while minimizing organic solvent use for a wide variety of biomedical and pharmaceutical applications. Supercritical carbon dioxide processes have benefits over the conventional particle formation methods in terms of improved control, flexibility and operational ease. This article gives an insight into a variety of supercritical fluid techniques relevant to drug formulation, recent advances and novel applications in the field of controlled delivery. These new methods have been designed to alleviate the scaling-up of the traditional methods for nanoparticle formulation either in the form of polymeric scaffolds, impregnation or nanoencapsules using a simple one-step process to produce micron-size particles. PMID- 22833952 TI - Personalized medicine: transforming drug development and healthcare. PMID- 22833953 TI - Biomarkers to improve the benefit/risk balance for approved therapeutics: a US FDA perspective on personalized medicine. AB - This article highlights a current US FDA perspective concerning the use of biomarker-based diagnostics for personalized medicine. Specifically, current biomarkers that have application for improving the benefit/risk profile of already approved drugs are discussed. The success of biomarkers for use in personalized medicine depends on many factors, including proper evaluation of the usefulness of the biomarker for assessing the event of interest, and the safety and effectiveness of the diagnostic device used to measure the biomarker, which includes appropriate analytical and clinical validation. These points along with the many regulatory concerns regarding co-labeling of drugs and devices and future aspects, such as co-development, will be discussed in this regulatory science focus. PMID- 22833954 TI - An innovative software solution for personalized pharmacotherapy. AB - Drug-drug and drug-gene interactions are an important issue in healthcare. In the USA, in 1994-1995, it was estimated that there were approximately 2 million severe adverse drug reactions resulting in 76,000-137,000 deaths. A more recent study published in 2004 shows that 5% of hospital admissions in the UK are directly attributable to adverse drug reactions. Moreover, adverse drug reactions in the USA contribute to significant hospital costs of between US$1.5 and 4 billion per year. Drug metabolism is one determinant of how our bodies respond to drugs. Polymorphisms of the six major cytochrome drug metabolizing genes can lead to either poor metabolism of drugs, hence, increasing probability of toxic reactions, or enhanced metabolism leading to decreased efficacy; with opposite affects for prodrugs. Also, there are the potentially increased costs due to wastage, lack of therapeutic response, repeat doctor visits and poor patient compliance. In addition, when multiple drugs are co-administered some may act as enzyme inducers or enzyme inhibitors further complicating expected drug responses. Considering today's polypharmacy, the number of over-the-counter drugs used, environmental exotoxins, which may inhibit or induce drug metabolism (cigarette smoke), nutrients and other foods, the combination of possibilities of cytochrome P450 interactions and drug-drug interactions affecting a patient response to therapy is overwhelming. A dedicated pharmaceutical decision support software solution, designed to be intuitive, informative and provide ease of use, would greatly increase the probabilities that patients could receive much more individualized treatment. The Rx Factor, through proprietary algorithms, provides the clinician with a dosage modification recommendation for all major substrate medications being prescribed or taken, by an individual. PMID- 22833955 TI - Personalized medicine: the impact on chemistry. AB - An effective strategy for personalized medicine requires a major conceptual change in the development and application of therapeutics. In this article, we argue that further advances in this field should be made with reference to another conceptual shift, that of network pharmacology. We examine the intersection of personalized medicine and network pharmacology to identify strategies for the development of personalized therapies that are fully informed by network pharmacology concepts. This provides a framework for discussion of the impact personalized medicine will have on chemistry in terms of drug discovery, formulation and delivery, the adaptations and changes in ideology required and the contribution chemistry is already making. New ways of conceptualizing chemistry's relationship with medicine will lead to new approaches to drug discovery and hold promise of delivering safer and more effective therapies. PMID- 22833956 TI - Personalizing aerosol medicine: development of delivery systems tailored to the individual. AB - Inhalation of drugs for therapeutic effects is not a recent innovation as illicit drugs have been 'smoked' for millennia. Nicotine delivery 'devices' in convenient packaged cartons of cigarettes are simple to use, inexpensive per dose and accessible to people of most ages and lung function, but of course their use leads to increased cancer, emphysema, heart disease and other medical and societal problems. In contrast, many inhalation pharmaceutical medical devices are expensive, nonportable, inconvenient, and/or are used improperly thus leading to poor therapeutic benefit. We review the current state of the art with respect to aerosol delivery, inhalation devices and the ability to personalize the treatment and management of lung disease. The confluence of many drivers will lead to more programmable and flexible devices in the future: the transition from the blockbuster model to customized therapy, technological advancements (e.g., smartphones) and cultural changes including social networking. PMID- 22833957 TI - Finding a niche with personalized generics: opportunities from systems-based therapeutic delivery in hypertension. AB - A key principle in earlier eras of drug development was to deliver medicines with clinical benefits for populations. Individual patients frequently did not benefit, or experienced adverse drug reactions, and were at risk of exposure to a prolonged series of treatment trials before effective therapies were found, if available. A personalized medicines approach offers opportunities to select drugs likely to be effective or safer, based on knowledge, for example, of differences in disease-modulating receptors, in drug metabolism, or in drug transporters into cells and across tissue boundaries. This new genetic and phenotypic knowledge allows generics to be revisited and may also help to improve medicine adherence, by reducing predictable adverse effects from unwanted accumulation of a medicine or its metabolites. This review will consider effective population delivery of therapeutics to treat hypertension in order to illustrate the potential and current place of personalizing medicines to improve effective and safe use of therapeutics. PMID- 22833958 TI - Thermosensitive liposomes for the delivery of cancer therapeutics. PMID- 22833959 TI - Targeted nanoparticulate drug-delivery systems for treatment of solid tumors: a review. AB - Technological advancements in the field of biomaterials, polymer chemistry and drug-delivery techniques have aided the development of a number of new drug delivery systems for targeting to solid tumors. Numerous research groups have explored the possibility of utilizing tumor-specific drug-delivery systems using nanoparticles. In this review we have attempted to highlight the achievements of some research groups actively involved in nanoparticulate drug delivery systems. The manuscript presents an in-depth discussion for nanoparticle systems such as micelles, liposomes, dendrimers, nanoemulsion, solid lipid nanoparticles and carbon fullerenes as chemotherapeutic options. The review reiterates the importance of the basic fundamentals of targeted drug delivery using nanoparticles and the influence of physiological parameters on their efficacy. PMID- 22833960 TI - Delivering drugs into the brain: barriers and possibilities. PMID- 22833961 TI - Peptide-based vectors for blood-brain barrier targeting and delivery of drugs to the central nervous system. PMID- 22833962 TI - Crossing barriers from blood-to-brain and academia-to-industry. PMID- 22833963 TI - The 2nd Annual Irish Drug Delivery Network Conference with UK and Ireland Controlled Release Society: advancing drug delivery. AB - This meeting was part funded by Science Foundation Ireland and by the University College Dublin Seed-Funding program, and was an opportunity for the Irish Drug Delivery Network to invite selected internationally-recognized scientists from across Europe onto a program, together with some of its own principal investigators. The meeting was co-promoted by the UK and Ireland Controlled Release Society. Topics included fluorescent dyes for stability testing of proteins, engineering of nano-containers, peptide-polymer conjugates, designing novel biomaterials, oral liquid-emulsion drug delivery systems, barrier modulation for drug delivery to the eye using siRNA, cell-specific targeting in the lungs, hot-melt extrusion and modified cyclodextrins for delivery of siRNA. The conference was attended by 85 researchers and the Irish Drug Delivery Network co-chairs were Caitriona O'Driscoll (University College Cork) and David Brayden (University College Dublin). PMID- 22833964 TI - The 3rd International Symposium on Cellular Delivery of Therapeutic Macromolecules. AB - The 3rd International Symposium on Cellular Delivery of Therapeutic Macromolecules (CDTM 2010), held on 27-29 June 2010 in Cardiff (Wales, UK), provided a comprehensive overview of the state of the art of key topics in cellular delivery of biologics. The CDTM symposium series, which is organized every 2 years by Arwyn Tomos Jones and Mark Gumbleton, is becoming an indispensable event in the calendar for many researchers interested in the field of cell delivery and an attractive opportunity to promote and transfer knowledge between research institutions and industry. This conference report will serve to summarize the proceedings presented along the 3-day symposium, which covered from the fundamental understanding of cell membranes and entrance pathways to the most innovative cell delivery vehicles and their applications. PMID- 22833966 TI - Drug penetration across the blood-brain barrier: an overview. AB - The brain is one of the most protected organs in the body. There are two key barriers that control the access of endogenous substances and xenobiotics (drugs or toxins) to the CNS. These physiological structures are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The BBB represents the main determinant of the effective delivery of drugs to the CNS. Good access through the BBB is essential if the target site is located within the CNS or, in contrast, can be a disadvantage if adverse reactions occur at central level. The development of new drugs targeted to the CNS requires a better knowledge of the factors affecting BBB permeation as well as in vitro and in silico predictive tools to optimize screening, and to reduce the attrition rate at later stages of drug development. This review discusses the particular characteristics of the biology and physiology of the BBB with respect to the permeation and distribution of drugs into the brain. The factors affecting rate, extent and distribution into the brain are discussed and a brief description of the in silico, in vitro, in situ and in vivo methods used to measure BBB transport are presented. Finally, the lastest proposals and strategies to enhance transport across the BBB of new CNS drugs are summarized. PMID- 22833965 TI - Viral vectors and delivery strategies for CNS gene therapy. AB - This review aims to provide a broad overview of the targets, challenges and potential for gene therapy in the CNS, citing specific examples. There are a broad range of therapeutic targets, with very different requirements for a suitable viral vector. By utilizing different vector tropisms, novel routes of administration and engineered promoter control, transgenes can be targeted to specific therapeutic applications. Viral vectors have proven efficacious in preclinical models for several disease applications, spurring several clinical trials. While the field has pushed the limits of existing adeno-associated virus based vectors, a next generation of vectors based on rational engineering of viral capsids should expand the application of gene therapy to be more effective in specific therapeutic applications. PMID- 22833967 TI - Drug delivery to the brain: considerations of genetic polymorphisms of blood brain barrier transporters and imaging technologies. AB - PubMed search and literature reviews summarized our latest advances regarding the impact of genetic polymorphisms of blood-brain barrier transporters on, and the application of imaging technologies to evaluate and enhance drug delivery to the brain. Although there are reports relating transporter polymorphisms to pharmacokinetics or adverse events, few studies have extended such efforts to the brain. Conceivably, simultaneous nonfunctional expressions of more than one key efflux transporters could result in devastating clinical outcomes if the dose of their substrate drug is not adjusted for the subpopulation with such a phenotype. Imaging technologies have been used to elucidate the kinetic or functional activities of blood-brain barrier transporters, with the majority focusing on P glycoprotein. Imaging technologies have been used to discover drugs for treating brain disorders, enable targeted delivery in combination with convection-enhanced delivery, assess the therapeutic effect of a treatment protocol and assess drug penetration into brain tumors. Research is limited, however, in using imaging technologies to link the genotype or phenotype of a transporter to the uptake of drug into the brain. No imaging studies have provided clear evidence of transporter polymorphisms discriminating the distribution of drug in the brain. Research efforts are needed to use imaging technologies to explore the correlation between pharmacogenetics and individual clinical outcomes, especially for the phenotype of more than one nonfunctional transporters. PMID- 22833968 TI - Development of new peptide vectors for the transport of therapeutic across the blood-brain barrier. AB - The blood-brain barrier (BBB) is formed by the special nature of the endothelial cells of the brain capillaries characterized by tight junctions between cells and a high expression of efflux pumps only allowing the brain access to nutrients necessary for cell survival and function. These properties of the BBB result in the incapacity of small and large therapeutic compounds to reach the brain at therapeutic concentrations. Various strategies are now being developed to enhance the amount and concentration of these compounds in the brain parenchyma. The development of new technologies such as peptide vectors has the potential to achieve the delivery of active agents in therapeutic concentrations across the BBB to treat brain diseases such as brain primary and metastatic cancers and neurodegenerative disorders. In this review, the design of new active peptides and development of new peptide vectors for drug brain delivery using physiological approaches will be addressed. A new chemical entity incorporating angiopep peptide in a small anticancer agent (paclitaxel) is now in clinical trials. It is the first of such designed agents to be validated for the treatment of human brain cancers and opens the door for such approaches. PMID- 22833969 TI - RNAi-mediated barrier modulation: synergies of the brain and eye. AB - Efficient drug delivery to the brain or the eye remains a key challenge for future therapies directed against neurodegenerative disorders. Indeed it has been estimated that up to 98% of clinically relevant drugs will not diffuse across the endothelial cells associated with the delicate microvasculature of the brain and inner retina. Using RNAi-based methods for suppression of claudin-5, a molecular constituent of the tight junctions associated with both the blood-brain and inner blood-retina barriers, it has been shown that these barriers can be rendered transiently and size-selectively permeable to molecules up to approximately I kDa. This review will discuss the principles upon which this technology is based and the potential therapeutic applications with regard to neurodegenerative disorders as well as common retinopathies. PMID- 22833970 TI - Transport of drugs across the blood-brain barrier in Alzheimer's disease. AB - Alzheimer's disease, a neurodegenerative disorder, is associated with various pathological alterations to the blood-brain barrier, including disruption to the inter-endothelial tight junction proteins, altered expression of transport proteins involved in drug efflux, a reduction in cerebral blood flow and a thickening of the brain capillary basement membrane. There are many conflicting reports on whether such changes alter the ability of endogenous proteins to extravasate into the brain parenchyma, and there are even fewer reports focusing on the potential impact of these changes on drug transport into the CNS. The purpose of this review is to critically evaluate how the reported changes to the blood-brain barrier in Alzheimer's disease have (or have not) resulted in altered CNS drug delivery, and to highlight the requirement for more rigorous and systematic studies in this field for the benefit of drug discovery and delivery scientists. PMID- 22833971 TI - Transdermal delivery of analgesics. PMID- 22833972 TI - Challenges of nanoparticle engineering for cancer therapeutics. PMID- 22833973 TI - Cell-based models of blood-brain barrier penetration. PMID- 22833974 TI - Radioimmunotherapy: optimizing delivery to solid tumors. AB - Radioimmunotherapy (RIT) is a cancer treatment that exploits the specific targeting capability of monoclonal antibodies to deliver cytotoxic radionuclides to antigen-expressing tumor cells or stromal targets. While this has been extremely successful in the treatment of hematologic malignancies, RIT of solid tumors has produced less prolonged effects. In our laboratory, we have developed a bench-to-bedside translational pipeline with the aim of optimizing RIT for solid tumors. We will show how preclinical models of colorectal adenocarcinoma were initially used to study reciprocal interactions between elements of the tumor microenvironment and RIT and to test novel therapeutic strategies. These studies were then used to facilitate the design of novel trials carried out in close collaboration with our clinical colleagues. PMID- 22833975 TI - Beaded plasma clot: a potent sustained-release, drug-delivery system. AB - AIM: The aim of the study was to prepare a drug-entrapped, beaded form of blood plasma for possible sustained drug delivery. METHOD: Blood plasma mixed with various drugs was enriched with CaCl2 and transferred in the form of small droplets on to a glass slide covered with parafilm. Clot formation was induced by incubation at 37 degrees C. RESULTS: Plasma-bead entrapped tetracycline, amphotericin B and daunorubicin were released gradually in vitro. Crosslinking of the beads with glutaraldehyde decreased the release rate of drugs remarkably. The plasma bead-entrapped cefotaxime administered subcutaneously in mice was released in a slow and sustained fashion and remained in circulation for a longer duration than the antibiotic administered in the free form. CONCLUSION: The plasma beads have potential for the sustained delivery of drugs in vivo, since their preparation does not require additional thrombin or other proteins and can be readily accomplished by using autologous plasma, thereby minimizing the risk of immunological complications. PMID- 22833976 TI - Chemical nanotherapy: nitroxyl radical-containing nanoparticle protects neuroblastoma SH-SY5Y cells from Abeta-induced oxidative stress. AB - BACKGROUND: Excessive accumulation of beta-amyloid (Abeta) has been proposed as a pivotal event in the pathogenesis of Alzheimer's disease. Possible mechanisms underlying Abeta-induced neuronal cytotoxicity include excess production of reactive oxygen species (ROS) and apoptosis. We have designed novel nanoparticles, nitroxyl radical-containing nanoparticles (RNPs), which possess nitroxyl radical in the core and chemically scavenges ROS. This study aimed to determine the potential neuroprotective role of RNPs on Abeta-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. METHOD: SH-SY5Y cells were preincubated with 0.1-1 mM RNP for 24 h and then incubated with 20 microM Abeta1 42, for 48 h. In every group, cell viability, apoptotic rate, ROS levels including superoxide anion radicals and hydroxyl radicals, ROS production including lipid peroxidation, protein oxidation and DNA oxidation were measured. RESULTS: SH-SY5Y cells preincubated with 0.1-2 mM RNP for 24 h were protected from Abeta-induced damage. SH-SY5Y cells preincubated with more than 2 mM RNPfor 24 h showed cytotoxicity. From the quantitative analyses, it was observed that RNPs reduced intracellular oxidative stress. RNP treatment significantly reduced the amount of oxidized lipids, proteins and DNA. It also reduced DNA fragmentations, which caused lower apoptosis levels. CONCLUSION: RNPs are promising intracellular ROS scavengers. PMID- 22833977 TI - Design and evaluation of chitosan nanoparticles as novel drug carrier for the delivery of rivastigmine to treat Alzheimer's disease. AB - AIM: The objective of the study was to develop chitosan nanoparticles of the drug rivastigmine and to study the effect of polysorbate 80 coating on its biodistribution. RESULTS: Chitosan nanoparticles containing rivastigmine were prepared by spontaneous emulsification. The mean size of the particles was 47 +/- 4 nm. Zeta potential analysis demonstrated a positive charge for the particles and coating with polysorbate 80 slightly reduced the surface charge of the particles. A biphasic release pattern was observed for the release of drug from the nanoparticles. Release of the drug from nanoparticles was diffusion controlled and the mechanism of drug release was Fickian. CONCLUSION: The biodistribution studies demonstrated that coating of nanoparticles with 1% polysorbate 80 altered the uptake of nanoparticles by different organs. PMID- 22833978 TI - Discussion of prevalence and management of discomfort when swallowing pills: orodispersible tablets expand treatment options in patients with depression. AB - Many patients experience discomfort when trying to swallow tablets and capsules, but this issue is rarely discussed between patients and physicians. Discomfort when swallowing pills is common and arises due to the morphology of the oropharynx and esophagus, which are not well suited to swallowing rigid objects of small volume. Compliance with medication is poor in patients with chronic diseases such as depression. An inability or unwillingness to swallow medication can further reduce acceptance of and compliance with medication, which has an impact on effectiveness. Recognition that patient acceptance of prescribed medication is an important component of compliance has led to the development of pill-swallowing training programs and alternative formulations. Orodispersible tablets do not need to be taken with water and can be packaged discreetly in single doses. Orodispersible tablets have been shown to be effective in a number of therapy areas including depression. PMID- 22833979 TI - Surfactants: their critical role in enhancing drug delivery to the lungs. AB - For local lung conditions and diseases, pulmonary drug delivery has been widely used for more than 50 years now. A more recent trend involves the pulmonary route as a systemic drug-delivery target. Advantages such as avoidance of the gastrointestinal environment, different enzyme content compared with the intestine, and avoidance of first-pass metabolism make the lung an alternative route for the systemic delivery of actives. However, the lung offers barriers to absorption such as a surfactant layer, epithelial surface lining fluid, epithelial monolayer, interstitium and basement membrane, and capillary endothelium. Many delivery strategies have been developed in order to overcome these limitations. The use of surfactants is one of these approaches and their role in enhancing pulmonary drug delivery is reviewed in this article. A systematic review of the literature relating to the effect of surfactants on formulations for pulmonary delivery was conducted. Specifically, research reporting enhancement of in vivo performance was focused on. The effect of the addition of surfactants such as phospholipids, bile salts, non-ionic, fatty acids, and liposomes as phospholipid-containing carriers on the enhancement of therapeutic outcomes of drugs for pulmonary delivery was compiled. The main use attributed to surfactants in pulmonary drug delivery is as absorption enhancers by mechanisms of action not yet fully understood. Furthermore, surfactants have been used to improve the delivery of inhaled drugs in various additional strategies discussed herein. PMID- 22833980 TI - Pulmonary immunization for TB with live cell-based vaccines: the importance of the delivery route. PMID- 22833981 TI - Supercritical fluid-mediated methods to encapsulate drugs: recent advances and new opportunities. AB - With the advent of the development of novel pharmaceutical products and therapies, there is a need for effective delivery of these products to patients. Dependent on whether they are small-molecular weight drugs or biologics, many new compounds may suffer from poor solubility, poor stability or require frequent administration and therefore require optimized delivery. For example, the utilization of polymorphism and the enhanced solubility in the amorphous state is being exploited to improve the dissolution of small-molecular weight poorly soluble drugs. This can be achieved by the formation of solid dispersions in water-soluble matrices. In addition, encapsulation in biodegradable polymeric materials is one potential route to reduce the frequency of administration through the formation of sustained-release formulations. This is desirable for biologics, for example, which generally require administration once or twice daily. Supercritical fluid processing can achieve both of these outcomes, and this review focuses on the use of supercritical CO2 to encapsulate active pharmaceutical ingredients to enhance solubility or achieve sustained release. Using supercritical CO2-mediated processes provides a clean and potentially solvent-free route to prepare novel drug products and is therefore an attractive alternative to conventional manufacturing technologies. PMID- 22833982 TI - Oral peptide delivery: prioritizing the leading technologies. PMID- 22833983 TI - Intestinal receptor targeting for peptide delivery: an expert's personal perspective on reasons for failure and new opportunities. AB - The technology has been available more than 25 years that would enable the oral delivery of vaccines, proteins and peptides, thus avoiding the need for injection. To this day, injection is still the mode of delivery, yet not the main mode of choice. This review focuses on several of the potential modes for oral delivery of peptides, proteins and vaccines. Additionally, the review will provide the reader with an insight into the problems and potential solutions for several of these modes of oral delivery of peptides and proteins. PMID- 22833984 TI - Oral delivery of macromolecules: rationale underpinning Gastrointestinal Permeation Enhancement Technology (GIPET). AB - Oral delivery of macromolecular drugs, particularly peptides and proteins, is the focus of many academic and industrial laboratories. Armed with an increased understanding of the structure and regulation of intestinal epithelial junctional complexes of the paracellular barrier, the development of permeation enhancement technology initially focused on the specific and reversible opening of tight junctions in order to enable oral delivery. Despite intense research, none of these specific tight junction-opening technologies has yet been approved in an oral drug product, likely because of poor efficacy. Less specific enhancer technologies with a long history of safe use in man have additional surfactant like effects on the transcellular pathway that lead to improved efficacy. These are likely to be the first to market for selected poorly permeable peptides. This review presents a summary of some approaches taken to intestinal permeation enhancement and explores in detail the oral delivery system developed by Merrion Pharmaceuticals, Gastrointestinal Permeation Enhancement Technology (GIPET). PMID- 22833985 TI - The oral delivery of proteins using interpolymer polyelectrolyte complexes. AB - In spite of the numerous barriers inherent in the oral delivery of therapeutically active proteins, research into the development of functional protein-delivery systems is still intense. The effectiveness of such oral protein delivery systems depend on their ability to protect the incorporated protein from proteolytic degradation in the GI tract and enhance its intestinal absorption without significantly compromising the bioactivity of the protein. Among these delivery systems are polyelectrolyte complexes (PECs) which are composed of polyelectrolyte polymers complexed with a protein via coulombic and other interactions. This review will focus on the current status of PECs with a particular emphasis on the potential and limitations of multi- or inter-polymer PECs used to facilitate oral protein delivery. PMID- 22833986 TI - Opportunities and challenges for oral delivery of hydrophobic versus hydrophilic peptide and protein-like drugs using lipid-based technologies. AB - Peptide and protein-like drugs are macromolecules currently produced in increasing numbers by the pharmaceutical biotechnology industry. The physicochemical properties of these molecules posebarriers to oral administration. Lipid-based drug-delivery systems have the potential to overcome these barriers and may be utilized to formulate safe, stable and efficacious oral medicines. This review outlines the design of such lipid-based technologies. The mechanisms whereby these formulations enhance the absorption of lipophilic versus hydrophilic peptide and protein-like drugs are discussed. In the case of lipophilic compounds, the advantages of lipid-based drug-delivery systems including increased solubilization, decreased intestinal efflux, decreased intracellular metabolism and possible lymphatic transport are well established as is evident from the success of Neoral and other drug products on the market. In contrast, with respect to hydrophilic compounds, the situation is more complex and, while promising formulation approaches have been studied, issues including reproducibility of response, intersubject variability and duration of response require further optimization before commercially viable products are possible. PMID- 22833987 TI - Drug shortages: your 20 step guide to survival. Medication shortages are the new normal--here's how to manage long-term. PMID- 22833988 TI - Foreword to transdermal delivery mini focus issue. AB - "With any drug-delivery technology, it is important to select the right drug molecule for the technology being used, so that there is a clear unmet therapeutic need being addressed, making it easier to get regulatory approval and generate interest and investment". PMID- 22833990 TI - Advancing transdermal drug-delivery systems past development barriers to the clinic: an industry perspective. AB - "In order to increase the quality of transdermal drug-delivery systems, it [quality] must be built into the systemic product development". PMID- 22833989 TI - Current landscape and trends in transdermal drug delivery systems. AB - "Generic pharmaceutical marketers are increasingly keen to have a presence in generic patches as they represent high-margin, high entry-barrier opportunities with a smaller field of competition". PMID- 22833991 TI - Interview with Dr. James Birchall. Interview by Laura Harvey. PMID- 22833992 TI - Transdermal delivery of methotrexate: past, present and future prospects. AB - Mehotrexate has been reported as an immunosuppressant and an antimetabolite widely used in the treatment of rheumatoid arthritis and psoriasis. However, it causes various toxicities and has low bioavailability when taken orally, thus, it is desirable that the drug be delivered transdermally. The water solubility and charged structure of methotrexate, however, limits its use via the transdermal route mainly due to the highly organized microstructure of the stratum corneum. Hence, various technologies, such as chemical enhancers, iontophoresis, electroporation, ultrasound and microneedles, either alone or in combination, are being explored to enhance its permeability by disrupting the barrier property of the skin. The present article discusses the past, present and future of transdermal delivery of methotrexate. PMID- 22833993 TI - Evaluation of acyclovir cream and gel formulations for transdermal iontophoretic delivery. AB - BACKGROUND: Efficient iontophoretic transdermal delivery of hydrophilic drug molecules requires selection of appropriate aqueous formulation. In this study, oil/water cream and gel formulations were investigated for iontophoretic transdermal delivery of acyclovir (ACV), a model hydrophilic small-drug molecule, across hairless rat skin on Franz diffusion cells. RESULTS: Iontophoresis (0.2 mA/cm2) enhanced ACV delivery from both 5% cream (pH 6.8) and 4% gel (pH II) formulations. However, sixfold higher drug levels were delivered across the skin using gel formulation (12.25 +/- 4.04 microg/cm2) as compared with cream formulation (2.03 +/- 0.05 microg/cm2). Significantly higher drug levels were delivered when iontophoresis was performed at higher current density (0.32 mA/cm2; p < 0.05). Influence of formulation co-solvents (glycerin and propylene glycol) on drug delivery was also investigated in vitro using Franz cells and in vivo in hairless rats using microdialysis. CONCLUSION: Iontophoretic transdermal delivery of ACV was feasible and dependent on the selection of formulation components and delivery parameters. PMID- 22833994 TI - An update on the application of physical technologies to enhance intradermal and transdermal drug delivery. AB - A large number of biopharmaceuticals and other macromolecules are being developed for therapeutic applications. Conventional oral delivery is not always possible due to first-pass metabolism and degradation in the GI tract. Parenteral delivery is invasive and has poor patient compliance. Transdermal delivery provides one attractive route of administration. Transdermal administration can achieve the continuous and non-invasive delivery of drugs. However, passive transdermal delivery is restricted to small lipophilic molecules. Active physical-enhancement technologies are being investigated to increase the scope of transdermal delivery to hydrophilic molecules and macromolecules. Recent developments in transdermal technologies, such as microporation, iontophoresis and sonophoresis can enable therapeutic delivery of many drug molecules, biopharmaceuticals, cosmeceuticals and vaccines. This review provides an update of recent developments in transdermal delivery focusing on physical-enhancement technologies. PMID- 22833995 TI - Microneedle delivery: clinical studies and emerging medical applications. AB - The concept of microneedle drug delivery was described three decades ago; however, effective clinical demonstration has only occurred within the past 10-15 years. Substantial progress in microneedle design and fabrication including extensive in vitro, ex vivo, and in vivo preclinical evaluation with various drugs, vaccines and other agents has transpired over the last decade. In contrast with this large volume of preclinical data, there are relatively few published microneedle clinical studies. To date, the clinical investigative focus has included testing to reduce dermal barrier properties and enhance transdermal delivery; evaluation of enhanced vaccine antigenicity, including development of the first commercial microneedle product for intradermal influenza vaccination; evaluation of altered microneedle protein pharmacokinetics and pharmacodynamics, especially for insulin; and evaluation of the pain and other perceptions associated with microneedle usage. This review summarizes the various aspects of microneedle clinical evaluation to date and identifies areas requiring further clinical evaluation. PMID- 22833996 TI - Novel methods and devices to enhance transdermal drug delivery: the importance of laser radiation in transdermal drug delivery. AB - Skin permeation-enhancement technology is a rapidly developing field, which could significantly increase the number of drugs suitable for transdermal delivery. In this review, we highlight recent advances in both 'passive' and 'active' transdermal drug-delivery technologies, as well as in the laser ablation method. This paper concludes with a brief forward-looking perspective discussing what can be expected as laser technology continues to develop in the coming years. PMID- 22833997 TI - Erythrocytes as a novel delivery vehicle for biologics: from enzymes to nucleic acid-based therapeutics. AB - Biological drugs are among the most exciting drugs of the future, offering better treatment options for patients than ever before but they need an appropriate delivery vehicle. Carrier erythrocytes are one of the most promising drug delivery systems. Application of erythrocytes as containers for various drugs minimizes toxicity, decreasing the risk of side effects and pathologic immune reactions against encapsulated agents as well as improving their efficacy, leading to better patient compliance. This review discusses the rationale for the use of erythrocytes as a vehicle for biopharmaceuticals and summarizes the categories of these new encapsulable compounds that are currently under investigation. The authors' intent is to describe the development of this delivery system to give the reader an overview of the remarkable potential of erythrocytes as naturally designed carriers and their versatility in the field of biologics for the treatment of various pathological conditions. PMID- 22833998 TI - Focused ultrasound: crossing barriers to treat Alzheimer's disease. PMID- 22833999 TI - Pharmaceutical technology, biopharmaceutics and drug delivery. AB - The 40th annual international conference of the Korean Society of Pharmaceutical Sciences and Technology on Pharmaceutical Technology, Biopharmaceutics and Drug Delivery was held on 2-3 December 2010 in Jeju Special Self-Governing Providence, Korea, to celebrate its 40th anniversary. A comprehensive review of a wide spectrum of recent topics on pharmaceutical technology, biopharmaceutics and drug delivery was presented. Invited lectures and poster presentations over 2 days were divided into six parallel sessions covering areas such as biotechnology, biopharmaceutics, drug delivery, formulation/manufacture, regulatory science and frontier science. Among these, there were two sessions related to regulatory science and biopharmaceutics that were co-sponsored by the Korea Food and Drug Administration. In fact, this conference provided an opportunity for many investigators to discuss their research, collect new information and to promote the advancement of knowledge in each pharmaceutical area. This conference report summarizes the keynote podium presentations provided by many distinguished speakers, including Gordon L Amidon of the University of Michigan. PMID- 22834000 TI - Drug delivery to the Lungs 21. AB - Drug Delivery to the Lungs 21 was focused exclusively on delivery technologies of medicines for the treatment of diseases that are 'local' to the respiratory tract or for wider 'systemic' distribution. Therefore, the range of diseases that can be treated via delivering drugs to the lungs is large and diverse. This diversity means that the delivery technologies (device and/or formulation) are also very varied. Moreover, the patient is critically involved when using drug-delivery technologies to the lungs as their inhalation and 'user' characteristics are pivotal in ensuring that the correct dose is given and reaches the appropriate part of the respiratory tract. Thus, Drug Delivery to the Lungs 21 was a wide ranging conference, ideal for an overview of current and future inhaled-delivery technologies. The conference was split into various themed sections and supported by approximately 65 posters. Furthermore, the conference was preceded by a workshop organized by the European Pharmaceutical Aerosol Group on abbreviated impactor measurement, which is a tool currently of much interest in assessing aerosol products (see separate summary). The conference initiated a number of innovations this year, including a Facebook page on which delegates and organizers could follow and 'chat' about conference proceedings. PMID- 22834001 TI - Summary of abbreviated impactor measurement workshop organized by the European Pharmaceutical Aerosol Group. AB - This year, the Drugs Delivery to the Lungs 21 conference broke new ground with the first half-day devoted to a workshop focusing on experimental aspects of the abbreviated impactor measurement concept. The workshop had the following objectives: to define what further needs to be done experimentally to establish abbreviated impactor measurement; and to identify the pathway towards adoption of existing methods into the pharmacopeias, as the next step towards what is hoped will eventually be acceptance by the key regulatory agencies in Europe, Canada and the USA. PMID- 22834002 TI - Drug delivery to the brain via the blood-brain barrier: a review of the literature and some recent patent disclosures. AB - Delivery of drugs to the brain is challenging, not only for large biopharmaceutical molecules, but also for small organics, which are effluxed from the brain capillary endothelial cells. These cells constitute, in part, the selectively permeable blood-brain barrier. Progress is being made using delivery systems comprising a vector, a linker and cargo, which are purported to enter the brain via receptors on the luminal surface of the brain capillary endothelial cells. Unfortunately, from a delivery perspective, these receptors are not expressed only on brain capillary endothelial cells; so the approaches described in this review are for enhanced delivery to the brain, not for specific brain targeting. The inventions disclosed in patents relate to technologies to screen for new blood-brain barrier receptors and to identify new vectors, or describe systems that deliver cargoes to the brain via any blood-brain barrier receptor, or define specified peptide vectors that target a specific receptor. To date, only one of the technologies has reached early clinical trials and, as always, major challenges remain to be addressed. PMID- 22834003 TI - Monoclonal antibodies: from benchtop to bedside. AB - "Medical utility of monoclonal antibodies is only limited by our imagination. It is expected that efficient and accurate delivery strategies and technologies will continuously evolve to unveil the ever-broadening medical benefits of monoclonal antibodies". PMID- 22834004 TI - Monoclonal antibody dose determination and biodistribution into solid tumors. AB - Monoclonal antibodies are increasingly being used as protein therapeutics for cancer. They offer very specific binding to target molecules on the surface of cancer cells, relatively few side effects and predictable pharmacokinetics. Tumor shrinkage is seen in some patients, and an incremental improvement in survival occurs in the group. However, due to their large size and consequent slow diffusion, antibody penetration deep into tumors may be inhomogeneous. Even if only a few cells, deep in tumors, escape therapy, they can regrow and lead to clinical relapse, limiting the significant potential of monoclonal antibody therapy. This leads to questions about optimal dosing for monoclonal antibodies. Methods to determine monoclonal antibody dose include maximum-tolerated dose studies, pharmacokinetically and pharmacodynamically guided dosing, randomized dose-ranging studies, imaging of antibody biodistribution and competitive-binding studies. Limitations of these methods, and future directions to possibly overcome these limitations will be discussed. PMID- 22834005 TI - Quantitative and specific molecular imaging of cancer with labeled engineered monoclonal antibody fragments. AB - The high target specificity of antibodies and related constructs makes them excellent scaffolds for molecular-imaging probes. Quantitative data on biodistribution and pharmacokinetics can be acquired by radiolabeling these agents. Such studies demonstrate prolonged circulation times and resulting nonspecific accumulation with high background signal using antibody-based agents. Antibody fragments demonstrate more rapid clearance, but lower tumor uptake. Optical labeling of antibodies provides a basis for developing activatable probes that can image antigens with very high specificity, potentially allowing for the simultaneous visualization of multiple targets. While radioimmunoimaging provides valuable whole-body, quantitative information, activatable optical antibody-based agents could generate real-time diagnostic and prognostic information about near surface lesions at high-spatial and temporal resolution without requiring ionizing radiation. PMID- 22834006 TI - Monoclonal antibodies: interspecies scaling with minimal preclinical information. AB - Interspecies scaling for predicting human pharmacokinetics with information from multiple animal species is an established approach for small-molecule drugs. However, in general, the strategy is not a viable approach for therapeutic monoclonal antibodies, since relevant preclinical information is often limited due to highly specific biological activity and unique disposition mechanisms of these biologic agents. Existing data from a limited database indicates that applying minimal but relevant preclinical information and an appropriate approach; for example, fixed-exponent, provides a pragmatic and reasonably accurate prediction of human pharmacokinetics. This article briefly reviews the factors that affect the disposition of monoclonal antibodies and reiterates the importance of biological similarities between animal species and humans when selecting preclinical information for interspecies scaling. The article outlines the rationalization for utilizing the one-species with fixed-exponent approach, with discussions focused on the assumptions in allometry and monoclonal antibodies disposition mechanisms, and provides specific considerations related to practically applying such an approach. PMID- 22834007 TI - Individualizing therapy of monoclonal antibodies and fusion proteins: emerging potential in the age of personalized medicine. AB - Personalized medicine is an emerging and promising alternative to standard therapy regimens with the potential to significantly influence therapeutic interventions for many diseases. An extensive literature review of studies that focused on pharmacogenomics of monoclonal antibodies (mAbs) and immunoglobulin containing fusion proteins (igFPs) was conducted. A comprehensive survey of the US FDA-approved labels revealed that pharmacogenomics information has also been incorporated into the label of some mAbs to guide therapy. In addition, treatment emergent adverse events for mAbs and igFPs were analyzed that showed an association with the drugs' individual mechanism of action as well as molecular nature. The identification of the signaling pathways linked to the specific target of each mAb or igFP may help accelerate clinical successes in predicting and managing treatment-associated severe adverse events in individual patients. Incorporating pharmacogenomics into drug development of mAbs and igFPs will improve treatment efficacy, and may allow prediction of adverse events. Thus, a promising future of personalized medicine for these therapeutics is predicted. PMID- 22834008 TI - Quality assessment of bioanalytical quantification of monoclonal antibody drugs. AB - Monoclonal antibody biotherapeutics are developed to bind to a specific target to affect the target's biological effect. Reliable measurements of monoclonal antibodies in biological fluids using ligand-binding assays are vital for understanding the pharmacokinetic and pharmacodynamic relationships for efficacy/safety evaluations and dose-regimen selection. The method should be properly characterized and demonstrate adequate assay performance to generate credible data for the right decision making at each specific stage, with considerations on the constraints of timeline, reagent availability and assay caveats. Quality assessment of the assay performance should be based on whether the method is 'fit-for-use' to meet the objectives of the study. The basic industrial requirements and recent trends in method and data quality of ligand binding assays for drug exposure studies at various development stages are discussed. PMID- 22834009 TI - Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. AB - One approach to improving activity of anticancer drugs is to conjugate them to antibodies that recognize tumor-associated, cell-surface antigens. The antibody drug conjugate concept evolved following major advances, first, in the development of humanized and fully human antibodies; second, in the discoveries of highly cytotoxic compounds ('drugs) linkable to antibodies; and finally, in the optimization of linkers that couple the drug to the antibody and provide sufficient stability of the antibody-drug conjugate in the circulation, optimal activation of the drug in the tumor, and the ability of the activated drug to overcome multidrug resistance. In this article, we will review the considerations for selecting a target antigen, the design of the conjugate, and the pre-clinical and clinical experiences with the current generation of antibody-drug conjugates. PMID- 22834010 TI - Perfectly shaped siRNA delivery. PMID- 22834011 TI - UK PharmSci 2010: the science of medicines. AB - This conference was billed as the 'premier conference for pharmaceutical scientists in the UK in 2010 and was organized by the Academy of Pharmaceutical Sciences of Great Britain (APSGB). It was, in fact, the inaugural annual conference of the APSGB and representatives of both academic and industrial institutions were organized to showcase the 'best of pharmaceutical science from the UK and around the world'. A diverse program over 3 days was split into four parallel sessions covering areas such as therapeutics, drug delivery, drug analysis, delivery technology, regenerative medicine, medicinal chemistry and quality by design. Content amounted to a total of 143 podium presentations, 54 by invited speakers and over 90 from selected abstract submissions. Daily poster sessions highlighting 300 separate pieces of original research encircled a trade exhibition by pharmaceutical companies, instrument manufacturers and professional bodies. There appeared to be a consensus that UK PharmSci 2010 was, for 3 days, a worthy forum for the 709 registered delegates based on the feedback given during, and immediately after the event. PMID- 22834012 TI - Formulation and optimization of osmotically controlled release tablets of glipizide: hot melt granulation. AB - BACKGROUND: The use of water-soluble additives in osmotic release tablets often renders the wet granulation method unsuitable. Hence, it was proposed to investigate the feasibility of preparing granules comprising of osmogen (sodium chloride), alkalizer (sodium carbonate), polyvinyl pyrroidone (Kollidon K 30) and carboxymethyl cellulose sodium (Cekol 30000) by a hot melt technique for obtaining sustained release of glipizide from tablets. MATERIALS AND METHODS: Dry powder mixture wetted with Tween 80 was sequentially exposed to 45-110 degrees C for obtaining granules. The effect of varying the quantities of osmogen, Cekol 30000 in granules and pore former in the film coating on in vitro release of glipizide was investigated. RESULTS: Glipizide release increased with an increase in the amount of hydrophilic polymer, osmogen and alkalizer and decreased with increase in the thickness of the coating membrane. Zero-order release independent of stirring rate and media pH through 16 h was observed from tablets of the optimized formulation (glipizide osmotic tablet [GOT] 12). The f2 value of 70.2 indicated similarity in release profiles from this formulation and the marketed extended-release tablet. Accelerated tests (ICH guidelines) revealed stability of GOT 12 tablets. PMID- 22834013 TI - Exploiting nutrient transporters at the blood-brain barrier to improve brain distribution of small molecules. AB - The blood-brain barrier (BBB) is a major physiological barrier for drugs that target CNS receptors or enzymes. Several methods exist by which permeability to the CNS can be increased, one of which is using native nutrient transporters to carry these drugs through the endothelial cells of the BBB. In this review, we focus on work that characterizes the use of nutrient transporters of the BBB in delivering drugs to the CNS. PMID- 22834014 TI - Controlled-release vaginal ring drug-delivery systems: a key strategy for the development of effective HIV microbicides. AB - BACKGROUND: Over half of all HIV-infected adults are women and heterosexual intercourse is a significant mode of viral transmission. This review examines the potential for using polymeric vaginal ring systems to provide controlled delivery of HIV microbicides in order to prevent heterosexual transmission of the virus. DISCUSSION: Continuous delivery of microbicides has the potential to be more effective than one-off dosing. Thus, controlled-release vaginal delivery devices are now a key area of HIV prevention research. Initial clinical trials on vaginal rings loaded with dapivirine (a candidate microbicide) have indicated that these products are safe and well tolerated by women. These devices are female initiated, robust and capable of long-term delivery of the active agent. CONCLUSIONS: Vaginal rings may offer an effective system for the controlled delivery of microbicides to prevent heterosexual transmission of HIV. Candidate vaginal ring microbicide products are now in clinical trials. PMID- 22834015 TI - Polymer nanoassemblies for cancer treatment and imaging. AB - Amphiphilic polymers represented by block copolymers self-assemble into well defined nanostructures capable of incorporating therapeutics. Polymer nanoassemblies currently developed for cancer treatment and imaging are reviewed in this article. Particular attention is paid to three representative polymer nanoassemblies: polymer micelles, polymer micellar aggregates and polymer vesicles. Rationales, design and performance of these polymer nanoassemblies are addressed, focusing on increasing the solubility and chemical stability of drugs. Also discussed are polymer nanoassembly formation, the distribution of polymer materials in the human body and applications of polymer nanoassemblies for combined therapy and imaging of cancer. Updates on tumor-targeting approaches, based on preclinical and clinical results are provided, as well as solutions for current issues that drug-delivery systems have, such as in vivo stability, tissue penetration and therapeutic efficacy. These are discussed to provide insights on the future development of more effective polymer nanoassemblies for the delivery of therapeutics in the body. PMID- 22834043 TI - Food and the body politic. AB - Americans are in the midst of a food-consciousness revival: on television, in the mouth of the First Lady, in endless articles celebrating urban agriculture can be found a sudden enthusiasm for the politically and, perhaps, spiritually curated dinner table. In this special section, writers explore the perilous state of food and food politics in America and a wide range of responses on the Left. Marion Nestle, in her essay on the farm bill, describes how the existing policy disaster came to be, along with the relationship between Reagan-era deregulation and the obesity epidemic. Mark Engler describes both the successes and coopting of the strands of left-wing responses-buying organic, eating local, and agitating for fair trade-and asks, "What's a radical to eat?" Laurie Woolever uncovers the kind of labor exploitation endemic to the elite dining experience. Karen Bakker Le Billon compares American to French school lunches, unpacking the relationship between food and citizenship. Juliana DeVries explores vegetarianism and the politics of everyday life. PMID- 22834044 TI - Utopian dream: a new farm bill. AB - In the fall of 2011, I taught a graduate food studies course at New York University devoted to the farm bill, a massive and massively opaque piece of legislation passed most recently in 2008 and up for renewal in 2012. The farm bill supports farmers, of course, but also specifies how the United States deals with such matters as conservation, forestry, energy policy, organic food production, international food aid, and domestic food assistance. My students came from programs in nutrition, food studies, public health, public policy, and law, all united in the belief that a smaller scale, more regionalized, and more sustainable food system would be healthier for people and the planet. PMID- 22834045 TI - Hijacked organic, limited local, faulty fair trade: what's a radical to eat? AB - Organic farming has been hijacked by big business. Local food can have a larger carbon footprint than products shipped in from overseas. Fair trade doesn't address the real concerns of farmers in the global South. As the food movement has moved from the countercultural fringe to become a mainstream phenomenon, organic, local, and fair trade advocates have been beset by criticism from overt foes and erstwhile allies alike. Now that Starbucks advertises fair trade coffee and Kraft owns Boca soy burgers, it's fair to ask, "What's a radical to eat?" PMID- 22834046 TI - High-end food, low-wage labor. AB - Some people work in restaurants as a lifestyle choice: they love the fast pace, the quick jokes, the often easy-flowing booze. At the height of a busy shift, if everything's going right, a team of skilled cooks and waiters can enter a kind of adrenaline-fueled flow state that's hypnotic and addictive. Some people choose it because they got burned out as grad students or software engineers or attorneys. Some people work in restaurants to make money until they graduate or get their big break in show business. It can be lucrative, especially for young, good looking, and agile waiters, working for a great employer in a big city, where customers practically fight for the chance to buy expensive wines and $50 entrees and truffle supplements from the latest hotspot. PMID- 22834047 TI - Pret-a-Manger: why the French have their cake and eat it, too. AB - Even if you weren't aware of the rising intensity of debates over food politics in recent years, the face-off between Sarah Palin and Michelle Obama probably caught your attention. One of Michelle Obama's most high profile acts as First Lady was to plant an organic food garden on the White House lawn-ironically later found to be contaminated by sewage-sludge-based fertilizer, rendering the lovingly grown vegetables off limits. The launch of the Obama Foodorama (the First Lady's foodie blog) and "Let's Move" (Obama's cause celebre child anti obesity campaign) soon followed. Palin's subsequent attacks on Obama's "interference" in personal food choices culminated in her visit to a Pennsylvania primary school, where Palin publicly proffered cookies to schoolchildren, in a presumed attempt to warn them of nanny state "food police." PMID- 22834048 TI - Making choices: ethics and vegetarianism. AB - I was seventeen and taking an elective course in Earth and Environmental Science. We were learning about farming and the food system-genetic modification, land use, organic labeling-when our teacher assigned us an article about beef. The article explained the following process: the U.S. government subsidizes corn, so we feed it to our cows, because corn is cheap and fattens the cows up quickly. Cows are biologically designed to eat grass, so their livers are unable to process the corn. The cows' livers would actually explode if they were permitted to grow to full maturity, but we slaughter them first. This, combined with their living in close quarters and wading in their own feces, causes the cows to get ill often, so we feed them a con-stant stream of antibiotics, a practice that strengthens bacterial strains such as E. coli. Roughly 78 percent of cows raised for beef undergo this process. Similarly nauseating practices are used to raise chickens, turkeys, and pigs, 99 percent, 97 percent, and 95 percent of which, respectively, come from factory farms. Nowadays, these details are less than shocking. Movies such as Food, Inc. and Super Size Me, as well as books such as The Omnivore's Dilemma and Fast Food Nation have raised consciousness, if not much action, on the topic of our food system. But, for me, it was a new story. PMID- 22834049 TI - Writing the male abuser in cultural responses to domestic violence in Spain. AB - The article analyzes the portrayal of the male perpetrator of heterosexual domestic violence in a selection of contemporary Spanish texts (novel, drama, and autobiography) that form part of a clearly discernible cultural response to the issue of intimate partner violence in Spain today. It reads the figure of the abuser in conjunction with a range of primarily Spanish studies on domestic aggression, with the aim of showing how and why the chosen authors engage with bodies of theory that address battery. The study concludes that some cultural producers devise a strategy of eliding the male aggressor in an attempt to subvert the power he wields over the female victim. PMID- 22834050 TI - Failures in children's protection in Newfoundland and Labrador: from the Hughes (1991) to Markesteyn and Day (2006) inquiries and beyond. AB - The death in 2003 of Zachary Turner, a child in receipt of children's protection services in Foxtrap, Newfoundland, sparked an independent inquiry into his death. Subsequently, other reviews were completed of children's protection services. These were not the first reviews or inquiries of this kind in Newfoundland and Labrador. In 1991, Justice Samuel Hughes had conducted a public inquiry into children's protection services. This article is a critical historical analysis of selected aspects of children's protection services. The authors uncover repeated failures by government in its child protection systems and discuss implications for future concerns. PMID- 22834051 TI - Quantitative evidence of the continuing significance of race: tableside racism in full-service restaurants. AB - Despite popular claims that racism and discrimination are no longer salient issues in contemporary society, members of racially underrepresented groups continue to experience disparate treatment in everyday public interactions. The context of full-service restaurants is one such public setting wherein African Americans, in particular, encounter racial prejudices and discriminatory treatment. To further understand the pervasiveness of such anti-Black attitudes and actions within the restaurant context, this article analyzes primary survey data derived from a community sample of servers (N = 200). Participants were asked a series of questions ascertaining information about the racial climate of their workplaces. Findings reveal substantial server negativity toward African Americans' tipping and dining behaviors. Racialized discourse and discriminatory behaviors are also shown to be quite common in the restaurant context. The anti Black attitudes and actions that the authors document in this research are illustrative of the continuing significance of race in contemporary society, and the authors encourage further research on this relatively neglected area of inquiry. PMID- 22834052 TI - Overturning anti-miscegenation laws: news media coverage of the Lovings' legal case against the state of Virginia. AB - This study fills a gap in scholarship by exploring historical news coverage of interracial relationships. It examines coverage by The New York Times, Washington Post and Times-Herald, and Chicago Tribune of the progression of the landmark civil rights case of Loving v. Virginia, in which the Supreme Court overturned Virginia's anti-miscegenation law, which prohibited marriage between any White and non-White person. An analysis of the frames and sources used in these publications' news stories about the case indicate all three publications' coverage favored the Lovings. PMID- 22834053 TI - Take precautions for your heart this holiday season. Overindulging and taking other risks can put your heart in jeopardy this winter. PMID- 22834054 TI - Greater exercise capacity leads to higher survival rates. Research shows that even sedentary older adults who improve their ability to exercise will experience a decreased mortality risk. PMID- 22834055 TI - Personality may affect heart risk, but findings are inconclusive. Research suggests that antagonistic people may increase their cardiac risks, but living a healthy lifestyle remains the best way to protect your health. PMID- 22834056 TI - Avoid no-flush niacin in favor of the prescription version. Follow certain steps to reduce the flushing effects of prescription niacin. PMID- 22834058 TI - My wife and I both take warfarin because we have atrial fibrillation. We've been told to stay away from green vegetables, because they are high in vitamin K. Is there a guideline for a "safe" amount to eat? PMID- 22834057 TI - Nonprescription Coenzyme Q10 shown to lower blood pressure. Over-the-counter supplements may also relieve statin-related leg pain. PMID- 22834059 TI - I am among the minority of people who have experienced serious side effects from using a statin. Along with healthy lifestyle choices, are there any other non statin medications that can help? PMID- 22834060 TI - I'm 66 and in relatively good health. I was diagnosed with tricuspid regurgitation. How serious is it and how will it affect my future heart health? PMID- 22834061 TI - [Current status and problems of drug-resistant bacteria, represented by those responsible for upper airway infections]. PMID- 22834062 TI - [Autopsy study of the nasal-paranasal sinuses using clinical materials--for safer and more precise surgical procedures]. PMID- 22834063 TI - Federal law could affect mobile practice. Veterinarians express concern over drug access. PMID- 22834064 TI - Conservative treatment of spinal cord injuries. PMID- 22834065 TI - Use of distributed teaching models. PMID- 22834066 TI - Change in cultural climate at US veterinary colleges since the 1960s. PMID- 22834067 TI - The "Annie hypothesis": did the death of his daughter cause Darwin to "give up Christianity"? AB - This article examines one of the most widely believed episodes in the life of Charles Darwin, that the death of his daughter Annie in 1851 caused the end of Darwin's belief in Christianity, and according to some versions, ended his attendance of church on Sundays. This hypothesis, it is argued, is commonly treated as a straightforward true account of Darwin's life, yet there is little or no supporting evidence. Furthermore, we argue, there is sufficient evidence that Darwin's loss of faith occurred before Annie's death. PMID- 22834068 TI - The dual Green Revolutions in South Korea: reforestation and agricultural revolution under the authoritarian regime. AB - In South Korea, the Green Revolution has been commonly understood as the development and dissemination of new rice varieties ('Tongil' rice) and the rapid increase of rice yield in the 1970s. However, revolutionary success in agriculture was not the only green revolution South Korea experienced; another green revolution lay in the success of reforestation projects. In the 1970s, South Korea's forest greening was closely related to its agricultural revolution in several ways. Therefore, South Korea's Green Revolution was an intrinsically linked double feature of agriculture and forestry. This two-pronged revolution was initiated by scientific research - yet accomplished by the strong administrative mobilization of President Park Chung Hee's regime. The process of setting goals and meeting them through a military-like strategy in a short time was made possible under the authoritarian regime, known as 'Yushin', though the administration failed to fully acknowledge scientific expertise in the process of pushing to achieve goals. PMID- 22834069 TI - Discourse on healthcare delivery systems involves local and particular issues for many reasons. Preface. PMID- 22834070 TI - Patient protection and Affordable Care Act; data collection to support standards related to essential health benefits; recognition of entities for the accreditation of qualified health plans. Final rule. AB - This final rule establishes data collection standards necessary to implement aspects of section 1302 of the Patient Protection and Affordable Care Act (Affordable Care Act), which directs the Secretary of Health and Human Services to define essential health benefits. This final rule outlines the data on applicable plans to be collected from certain issuers to support the definition of essential health benefits. This final rule also establishes a process for the recognition of accrediting entities for purposes of certification of qualified health plans. PMID- 22834071 TI - Expedited vocational assessment under the sequential evaluation process. Final rules. AB - We are revising our rules to give adjudicators the discretion to proceed to the fifth step of the sequential evaluation process for assessing disability when we have insufficient information about a claimant's past relevant work history to make the findings required for step 4. If an adjudicator finds at step 5 that a claimant may be unable to adjust to other work existing in the national economy, the adjudicator will return to the fourth step to develop the claimant's work history and make a finding about whether the claimant can perform his or her past relevant work. We expect that this new expedited process will not disadvantage any claimant or change the ultimate conclusion about whether a claimant is disabled, but it will promote administrative efficiency and help us make more timely disability determinations and decisions. PMID- 22834072 TI - Regulations regarding income-related monthly adjustment amounts to Medicare beneficiaries' prescription drug coverage premiums. Final rule. AB - This final rule adopts, without change, the interim final rule with request for comments we published in the Federal Register on December 7, 2010, at 75 FR 75884. The interim final rule contained the rules that we apply to determine the income-related monthly adjustment amount for Medicare prescription drug coverage (also known as Medicare Part D) premiums. This new subpart implemented changes made to the Social Security Act (Act) by the Affordable Care Act. The interim final rule allowed us to implement the provisions of the Affordable Care Act related to the income-related monthly adjustment amount for Medicare prescription drug coverage premiums when they went into effect on January 1, 2011. PMID- 22834073 TI - Delivery of siRNA into the blood-brain barrier: recent advances and future perspective. PMID- 22834074 TI - Challenges of therapeutic delivery using conducting polymers. PMID- 22834075 TI - Bioreducible polymer-delivered siRNA targeting human telomerase reverse transcriptase for human cancer gene therapy. AB - The success of siRNA therapeutics for cancer therapy largely depends on the delivery carrier that can safely and efficiently escort siRNA from the extracellular environment into the targeted human cancer cells. Over the past few years, disulfide-containing (bioreducible) cationic polymers have been designed, prepared and successfully applied as nonviral carriers for powerful gene/siRNA transfer, meanwhile displaying lower cytotoxicity as compared with their counterparts lacking the disulfide linkage, in part due to the intracellular degradation of the disulfide linkage. We have recently developed bioreducible disulfide-based polyethylenimine (SSPEI) for potent in vitro and in vivo delivery of siRNA targeting human telomerase reverse transcriptase (hTERT). It was found that SSPEI-delivered hTERT siRNA induced significant growth inhibition of different human cancer cells in vitro and also tumor growth suppression in vivo. Importantly, the SSPEI, at an appropriate dose, revealed a negligible adverse effect on cellular metabolic activity in vitro and liver and kidney function in vivo. PMID- 22834076 TI - In vitro efficacy of antimicrobial wafers against methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Lyophilized wafers have been developed as vehicles for the storage and delivery of therapeutic compounds to exuding wounds. The primary objective of this study was to incorporate a selection of antimicrobial compounds in karaya wafers and measure their efficacy against methicillin-resistant Staphylococcus aureus. METHODS: Four antimicrobial compounds, including an antibiotic, were incorporated within karaya gels and freeze-dried to a shaped-disc form suitable for in vitro testing against methicillin-resistant S. aureus. Disc diffusion and Franz diffusion methods were used to quantify the utility and efficacy of these 'antimicrobial wafers'. Flow rheology and scanning electron microscopy were also used to aid gel and wafer characterization. RESULTS: Lyophilized wafers swelled in simulated wound fluid and released the contained compounds with mixed effect. Povidine-iodine and chlorhexidine were most effective in protein-free buffer while the action of neomycin sulfate was enhanced by the presence of bovine serum albumin. Silver sulfadiazine was the least effective overall. PMID- 22834078 TI - Intracellular nucleic acid interactions facilitated by quantum dots: conceptualizing theranostics. AB - The concept of theranostics arises from the unification of both diagnostic and therapeutic applications into a single package. The implementation of nanoparticles, such as semiconductor quantum dots (QDs), to achieve theranostic applications, offers great potential for development of methods that are suitable for personalized medicine. Researchers have taken advantage of the physiochemical properties of QDs to elicit novel bioconjugation techniques that enable the attachment of multifunctional moieties on the surface of QDs. In this review, the diagnostic and therapeutic applications of QDs that feature the use of nucleic acids are highlighted with a particular emphasis on the possibility of combinatorial applications. Nucleic acid research is of particular interest for gene therapy, and is relevant to the understanding of gene regulation pathways and gene expression dynamics. Recent toxicity studies featuring multifunctional QDs are also examined. Future perspectives discussing the expected development of this field conclude the article. PMID- 22834079 TI - Liposomes for cardiovascular targeting. AB - Liposome-based pharmaceuticals used within the cardiovascular system are reviewed in this article. The delivery of diagnostic and therapeutic agents by plain liposomes and liposomes with surface-attached targeting antibodies or polyethylene glycol to prolong their circulation time and accumulation at vascular injuries, ischemic zones or sites of thrombi are also discussed. An overview of the advantages and disadvantages of liposome-mediated in vitro, ex vivo and in vivo targeting is presented, including discussion of the targeting of liposomes to pathological sites on the blood vessel wall and a description of liposomes that can be internalized by endothelial cells. Diagnostic liposomes used to target myocardial infarction and the relative importance of liposome size, targetability of immunoliposomes and prolonged circulation time on the efficiency of sealing hypoxia-induced plasma membrane damage to cardiocytes are discussed as a promising approach for therapy. The progress in the use of targeted liposomal plasmids for the transfection of hypoxic cardiomyocytes and myocardium is presented. Stent-mediated liposomal-based drug delivery is also reviewed briefly. PMID- 22834080 TI - Electrospun nanofibers in drug delivery: recent developments and perspectives. AB - In this review article, some key challenges in drug delivery are first introduced and methods that have been applied in attempts to solve them enumerated. Particularly intractable problems are highlighted: these include issues of solubility, targeting and drug degradation. The technique of electrospinning is subsequently introduced, and the influence of processing parameters on the fibers produced discussed. The potential of electrospun nanofibers in drug delivery is then explored, with examples given from the recent literature to illustrate how fibers can be used to overcome hurdles in drug solubility, degradation and targeting. Future perspectives and challenges are also considered. PMID- 22834077 TI - Size matters: gold nanoparticles in targeted cancer drug delivery. AB - Cancer is the current leading cause of death worldwide, responsible for approximately one quarter of all deaths in the USA and UK. Nanotechnologies provide tremendous opportunities for multimodal, site-specific drug delivery to these disease sites and Au nanoparticles further offer a particularly unique set of physical, chemical and photonic properties with which to do so. This review will highlight some recent advances, by our laboratory and others, in the use of Au nanoparticles for systemic drug delivery to these malignancies and will also provide insights into their rational design, synthesis, physiological properties and clinical/preclinical applications, as well as strategies and challenges toward the clinical implementation of these constructs moving forward. PMID- 22834081 TI - Hydrogels in mucosal delivery. AB - The concept of mucoadhesion and the molecular design requirements for the synthesis of mucoadhesive agents are both well understood and, as a result, hydrogel formulations that may be applied to mucosal surfaces are readily accessible. Nanosized hydrogel systems that make use of biological recognition or targeting motifs, by reacting to disease-specific environmental triggers and/or chemical signals to affect drug release, are now emerging as components of a new generation of therapeutics that promise improved residence time, faster response to stimuli and triggered release. PMID- 22834082 TI - Drug development of intranasally delivered peptides. AB - Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies. PMID- 22834083 TI - [Effects of internal working models of attachment on cognition about facial expressions]. AB - This study examined the effects of internal working models of attachment on cognition about emotion in facial expressions. Ninety-five university students participated in a survey and an experiment. The results revealed that (a) effects of internal working models of attachment emerged when there were discrepancies between facial expressions and the emotions that should be rated, (b) "anxiety" did not affect the rating scores or reaction times, and (c) participants who scored high in "avoidance" needed more time to judge the absence of emotions in facial expressions. These results indicate that the dimension of "avoidance" affects automatic information processing. PMID- 22834084 TI - [The gitaigo personality scale for description of self and others]. AB - Gitaigo is a subtype of mimetic words (onomatopoeia) in the Japanese language, which can be regarded as words that imitate actions or states. This study develops a personality scale, with six subscales, using 60 gitaigo words as items for rating the personality of the self and others. We asked 1 054 participants to rate their own personality and 905 participants to rate a close friend's personality, using 158 gitaigo words as items to describe personality. We found that a six-factor model, found in our previous study, was also applicable to the present study of ratings of participants' own personality. We also found six groups of words in the ratings of close friends' personality, although the factor structure is slightly different from the self-rating factors. We selected ten words that exhibited high loadings for each of the six factors to develop a personality scale with six subscales showing high reliability. We named those factors: cowardliness, slowness, preciseness, irritableness, candidness, and frivolousness. The average scores for self-ratings were significantly lower for two subscales (preciseness and candidness) and higher for other four subscales compared to the rating of others. PMID- 22834085 TI - [Development of a short form of the Japanese big-five scale, and a test of its reliability and validity]. AB - Personality scales based on the five-factor model, especially the big-five scale of personality trait adjectives (Wada, 1996), are commonly used in Japan. In this study a short form of the Big-Five Scale was constructed. To avoid changes in the capacity dimension caused by the decrease in the number of items, item selection was conducted after item response theory (IRT) scales were constructed for all the items. In study 1 data was collected from 2099 participants. A generalized partial credit model was applied to the IRT model, and items were selected using the slope and location parameters for each item. Cronbach's alpha showed that the short form, as well as the five sub-scales, had sufficient reliability as a personality test. In study 2, we determined correlations with the NEO-FFI and tested the concurrent validity of the short form. The results indicate that the short form of big-five scale demonstrates sufficient reliability and validity despite the reduced number of items. PMID- 22834086 TI - [Images of unemployed people: developing a scale to measure the stigma associated with the unemployed]. AB - This study investigated the images that people have of the unemployed. In study 1, general images of the unemployed were ascertained through qualitative and quantitative research. Various images, both positive and negative, were found for the unemployed in general. In study 2, a scale to measure the level of stigma associated with the unemployed was created based on the images from study 1. The results yielded four subscales for stigma associated with the unemployed. University students seemed to show more stigma for the unemployed on some sub scales than typical adults did. Working experiences, such as an internship or a part-time job during student life, would promote the reduction of the stigma associated with the unemployed. PMID- 22834087 TI - [Development of the coping scale for interpersonal stress events related to the goals of the coping]. AB - This study developed the coping scale for interpersonal stress events, and evaluated its validity. This scale is composed of the following subscales based on the goals of the coping: problem-focused coping, emotion-focused behavioral coping, and emotion-focused cognitive coping. Based on previous research, a pilot study was used to construct scale items, considering the goals of coping to reduce measurement error. In study 1 (N=348), the validity of the scale was examined using several statistical analyses. Study 2 (N=182) and study 3 (N=161) report correlations between the coping scale for interpersonal stress events and several theoretically relevant scales. Based on these results, it was concluded that the scale and subscales are valid for measuring interpersonal stress coping. PMID- 22834088 TI - [Determinants of passengers' dissatisfaction regarding disrupted train service]. AB - This research employed an extended hypothetical model that included the cognitions of attribution and importance from Oliver's (1980) expectancy disconfirmation model. The model examined factors which might mitigate the experiences of dissatisfied passengers who encountered the types of service disruption that occur frequently on city train routes. A covariance structural analysis model was applied to questionnaire data obtained from 5383 railroad users who encountered problems. The passengers' degree of discontent was most strongly influenced by their evaluation of the responsibility attributed by the railroad company. The strong influence of the passengers' impression of the impropriety of the railroad company's announcements regarding the train service make it imperative for the railroad company to take strong corrective action. The passengers' dissatisfaction will decrease greatly when there are appropriate announcements, in addition to the alleviation of discrepancies related to time, confusion, and changes. PMID- 22834089 TI - [Emotional suppression and psychological responses to a diagnosis of breast cancer]. AB - This study examined the relationship between emotional suppression and psychological distress in response to a diagnosis related to breast cancer. After their first visit, 31 patients with breast cancer and 90 with benign breast conditions completed the courtauld emotional control scale (CECS) and the profile of mood states (POMS) and were interviewed about their concerns after being diagnosed. Breast cancer and benign breast condition patients were divided into separate emotional suppression groups or emotional expression groups based on their median CECS score. The POMS scores of breast cancer patients were higher than those of benign breast condition patients; scores in the emotional suppression groups were higher than in the emotional expression groups. Breast cancer patients in the emotional suppression group expressed more negative emotions and fewer positive emotions than benign breast condition patients. Our results suggest that patients who suppressed their emotions experienced and reported more psychological distress when diagnosed with breast cancer. PMID- 22834090 TI - [Self-reference judgments and directed forgetting of trait adjectives]. AB - The influence of self-reference and emotionally valent material on list-method directed forgetting was investigated. Participants studied lists 1 and 2, both of which consisted of positive, negative, and neutral trait adjectives. Each participant was randomly assigned to one of three experimental conditions: self reference judgment, social desirability judgment, and control (no specific judgment). Half of the participants in each condition received the forget instruction telling them to forget list 1 and to remember list 2 (forget group). The other half received the remember instruction telling them to remember both lists 1 and 2 (remember group). All participants were then asked to recall all the list words, including those that they were instructed to forget. Results indicated that the directed forgetting effect disappeared in the self-reference judgment condition: in the forget group, list 1 recall was poorer than recall of list 2, and the Forget group participants recalled fewer list 1 words compared to the remember group participants. Neither the emotional valence nor self-reference of the material modulated the magnitude of this effect. It is concluded that self reference may modify directed forgetting. PMID- 22834091 TI - [Relationship between assertiveness including consideration for others and adjustment in children]. AB - The relationship between assertiveness and internal and external adjustment was investigated. Elementary school children in grades four to six (n=207) and their classroom teachers (n=8) participated in the study. Internal and external adjustments were measured by using self-ratings, and self- and other- ratings respectively. The children responded to a questionnaires inquiring about assertiveness that included two components of assessment: "self expression" and "consideration for others". Then, the children were divided into 4 groups according to their scores on these two components of assertiveness. The results indicated that children scoring high on both components of assertiveness had higher self-rating scores than those scoring low on both components. Moreover, children that scored high on "consideration for others" tended to have high external adjustment. Also, boys that scored low on "self expression" had lower external adjustment as indicated by the negative ratings of teachers. Furthermore, girls that scored high on "consideration for others" had high external adjustment as indicated by positive ratings of teachers and same-sexed classmates. PMID- 22834092 TI - [Association between normal weight obesity and diet behaviors in female students]. AB - OBJECTIVES: The association between normal weight obesity and diet behavior and physical activity in female students was investigated in this study. METHODS: The subjects were 530 female students aged 18-21 years from 6 universities in the Kyoto Prefecture, Japan. From January to July, 2010, the body fat and walk counts of these students were measured, and they answered a questionnaire. The questionnaire included questions on life environment, perception of body shape, dieting experiences, physical activities, sleeping habits, and diet behaviors. The Eating Attitude Test-26 (EAT-26) was used to evaluate diet behavior. Students with normal weight (18.5 < or = body mass index < 25 kg/m2; n = 439) were divided into high (n = 115), middle (n = 213), and low (n = 111) groups according to their percentage of body fat. Further, a comparative analysis was performed among the 3 groups. RESULTS: From the results of the questionnaire, perception of body shape, desire for a particular body shape, reason for weight loss, success or failure in dieting, and time for sleep were significantly different among the 3 groups. Differences in physical activity were not significant among the groups. Factor III (Oral control) of EAT-26 was higher in the high group than in the low group. CONCLUSION: High body fat was associated with diet behavior and a desire to lose weight in normal weight students. These results indicate that health education is necessary to establish and maintain appropriate body fat composition and dietary habits. PMID- 22834093 TI - [Relationship between pregnant women's sensitivity to cold (hiesho) and premature labor assessed using propensity scores for adjusting confounding factors]. AB - OBJECTIVES: The purpose of this study is to analyze the influence of sensitivity to cold or hiesho in pregnant Japanese women and to examine the relationship between hiesho and premature labor. METHODS: In this retrospective cohort study in Japanese women after delivery, information for the approximately 12 months between October 19, 2009 and October 8, 2010 was obtained using questionnaire surveys and medical records at 6 hospitals with obstetric and pediatric departments in the Greater Tokyo Metropolitan Area. Further, in this analysis, confounding factors were adjusted by performing analysis of covariance and stratified analysis using propensity scores. The Research Ethics Review Committee of St. Luke's College of Nursing (09-057) approved this study. RESULTS: Analysis of data from 2,810 women was performed. Regarding the correlation between hiesho and premature labor, the incidence of premature labor was 3.38 times higher (analysis of covariance) or 3.47 times higher (stratified analysis) among pregnant women with hiesho than among those without hiesho (P < 0.001). The results of this study proved the existing discussions that there is a correlation between hiesho CONCLUSION: during the latter stages of pregnancy and incidence of premature labor. PMID- 22834094 TI - [How the novel influenza (pandemic 2009) can influence the attitudes of elementary and junior high school students toward vaccination]. PMID- 22834095 TI - [Suicide due to mental diseases based on the Vital Statistics Survey Death Form]. AB - OBJECTIVES: Mental diseases such as schizophrenia and depression put patients at risk for suicide. It is extremely important to understand that one way of preventing suicide is to determine the actual mental state of the individual. The purpose of this study was to analyze the true mental state of suicide victims reported in the vital statistics. METHODS: This study investigated the vital statistics of 30,299 suicide victims in Japan in 2008. The use of these basic statistics for non-statistical purposes was approved by the Japanese Ministry of Health, Labour and Welfare. The method involved reviewing the Vital Statistics Survey Death Form at the Ministry of Health, Labour and Welfare as well as analyzing their Online Reporting of Vital Statistics. Furthermore, this study was able to validate 29,799 of the 30,299 suicides (98.3%) that occurred in 2008. Mental diseases were validated not only from the "Cause of death" section as marked on the death certificate, but also by information found in sections for "Additional items for death by external cause" and "Other special remarks." RESULTS; From the Vital Statistics Survey Death Form and Online Reporting of Vital Statistics, 2964 individuals with either a mental disease or mental disorder were identified. Of the 2964 identified individuals, 55 had dementia (of which 13 were dementia in Alzheimer's disease), 116 had alcohol dependence/psychotic disorder, 550 had schizophrenia, 101 had bipolar affective disorder, 1,913 has had a depressive episode, 13 had obsessive-compulsive disorder, 22 had adjustment disorders, 14 had eating disorders, 49 had nonorganic sleep disorders, 24 had personality disorder, and 6 had pervasive developmental disorders. In addition, 125 individuals had more than one mental disease. The national police statistics from 2008 show that 1,368 suicide victims had schizophrenia and CONCLUSION: 6,490 had depression. These figures show quite a difference between the results of this study and the police statistics. Further, there have been controversies regarding autopsies of suicide victims. Thus, further investigation into the cause of death is of great importance. PMID- 22834096 TI - [Knowledge and attitude toward simultaneous pneumococcal and influenza vaccinations and pneumococcal revaccination in elderly nursing homes]. PMID- 22834097 TI - [Clinical features of diabetic patients with pulmonary tuberculosis admitted to a university hospital]. AB - Diabetes mellitus (DM) is a risk factor of tuberculosis (TB). We studied the clinical presentation of pulmonary TB among patients with DM in comparison with patients without DM who were admitted into the hospital of the University of the Ryukyus from 2006 to 2010. The clinical data were collected from medical records retrospectively. Ten cases (25%) of hospitalized patients with pulmonary TB had DM. The DM group showed lower Body Mass Index and higher incidence of chronic heart failure and chronic renal failure. The DM group also were more likely to have cavitary lesion, had longer period of hospitalization, and higher mortality. Their causes of deaths were mainly the co-morbidities and associated complications. Further studies are warranted in order to fully elucidate the relationships between pulmonary TB and DM. PMID- 22834098 TI - [A study of genetic characteristics of Mycobacterium avium strains from patients with pulmonary M. avium disease in Japan and Korea]. AB - INTRODUCTION: To determine the characteristics of Mycobacterium avium in Japan, we compared the genetic properties of M. avium isolated in different countries. METHODS: A Mycobacterium avium tandem-repeat variable-number tandem-repeat (MATR VNTR) analysis was performed using South Korean strains (n = 119) and Japanese strains (n = 76). In addition, we compared the frequencies of a new insertion sequence, ISMav6. RESULTS: A phylogenetic analysis identified different clusters between the two countries' strains. The prevalence of ISMav6 was significantly different between them, i.e., 75.0% in Japanese strains and 59.8% in the Korean ones (P < 0.035). The frequency of strains with IS Mav6 in the Shine-Dalgarno (SD) sequence of the cfp29 gene that is involved in the interferon-gamma induction was also different, with stronger significance (Japan: 38.2%, Korea: 12.4%, P < 0.001). DISCUSSION: It is possible that M. avium strains prevalent in Japan and in Korea are genetically distinct. The analyses of the presence of ISMav6, as well as the VNTR patterns of M.avium strains from many different countries would be a promising methodology in elucidating the causes of the recent increase in cases of pulmonary MAC diseases. PMID- 22834099 TI - [Two cases of tuberculous uveitis]. AB - Uveitis has many etiologies, but tuberculous uveitis is rare. We herein report 2 cases of uveitis due to tuberculosis infection. The first case was a 28-year-old man who was showed abnormal shadows in the chest radiographic examination performed in search of the etiology of uveitis. Computed tomography (CT) of the chest revealed hilar and mediastinal lymphadenopathy, small nodules, and consolidation, with a small cavity in the right upper lobe. An ulcerated nodule in the truncus intermedius and stenosis of the right middle lobe bronchus were found on bronchoscopy. The biopsy of the nodule in the truncus intermedius showed a small granuloma containing giant cells, consistent with mycobacterial infection. The culture of bronchial washings from the right upper lobe grew Mycobacterium tuberculosis. Diagnosis of pulmonary tuberculosis, tuberculous lymphadenitis, bronchial tuberculosis, and tuberculous uveitis was made. The patient was treated with antituberculosis drugs and his disease, including uveitis, improved. The second case was a 36-year-old man who presented with right hemiparesis, dysarthria, and visual loss of the left eye. He was diagnosed with neuro-Sweet disease causing optic neuritis and visual loss. His chest CT showed a nodule with centrilobular opacities in the left lower lobe that suggested mycobacterial infection. PCR of the bronchial washing from the left lower lobe was positive for M.tuberculosis and the diagnosis of pulmonary tuberculosis was established. Treatment with antituberculosis drugs and corticosteroids was initiated and his pulmonary lesion improved. However, bilateral tuberculous uveitis developed 15 days after initiation of the treatment. The uveitis gradually deteriorated thereafter despite continuation of antituberculosis therapy. Photocoagulation finally halted the disease progression. In both patients with uveitis presented here, chest radiographs and CT scans were important in determining the etiology of the uveitis. It is difficult to find the etiology of uveitis, and general examinations including the lungs are helpful to pinpoint tuberculosis as the etiology of uveitis. As tuberculous uveitis is sometimes asymptomatic and resistant to treatment, ophthalmological examination is recommended for patients with pulmonary tuberculosis. PMID- 22834100 TI - [Nationwide survey of suitability of tuberculosis wards for in-hospital care of tuberculosis patients]. AB - PURPOSE: To clarify the situation and suitability of tuberculosis wards for in hospital tuberculosis care, with a view toward establishing a national standard for tuberculosis wards. METHODS: Data were obtained by sending questionnaires to all 321 tuberculosis wards in Japan. RESULTS: Of the hospitals to which questionnaires were sent, 69.3% returned their responses. In most of these hospitals, the total number of beds in one tuberculosis ward was either less than 20 or more than 40. In approximately two-thirds of the hospitals, tuberculosis wards were incorporated into another (non-tuberculosis) ward. In more than 70% of the hospitals, the mean hospital stay of tuberculosis patients exceeded 40 days. This relatively long hospital stay implies that amenities are a very important issue in tuberculosis wards; however, amenities were generally far from sufficient in most of the hospitals. Of all the tuberculosis beds, 18.2% were in single-occupant rooms and 19.4% had a sufficient floor area (more than 15 m2). Beds in single-occupant rooms with sufficient floor area, equipped with a toilet, bath or shower, washstand, negative-pressure control, and HEPA filter in an air exhaust duct, comprised 2.4% of all tuberculosis beds. CONCLUSION: In spite of the relatively long hospital stays, amenities were generally less than adequate. The conditions in most tuberculosis wards were far below the presumptive recommended standards. When national standards for tuberculosis wards are established, these findings should be taken into consideration. PMID- 22834102 TI - [Clinical research=design*measurements*statistical analyses]. AB - A clinical study must address true endpoints that matter for the patients and the doctors. A good clinical study starts with a good clinical question. Formulating a clinical question in the form of PECO can sharpen one's original question. In order to perform a good clinical study one must have a knowledge of study design, measurements and statistical analyses: The first is taught by epidemiology, the second by psychometrics and the third by biostatistics. PMID- 22834101 TI - [Psychiatric implications of PACAP signaling pathway]. AB - Studies on genetically modified mice for investigating the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the brain have revealed a previously uncharacterized function of this neuropeptidergic signaling in the regulation of psychomotor behaviors. In addition, recent clinical studies investigating single nucleotide polymorphisms and copy number variations in the PACAP and its receptor genes have associated the variations with major psychiatric disorders and stress-dependent mental disorders. Here, I briefly review these recent advances in the field and make this an opportunity to consider future direction of research. PMID- 22834103 TI - [How to start a neuroimaging study]. AB - In order to help researchers understand how to start a neuroimaging study, several tips are described in this paper. These include 1) Choice of an imaging modality, 2) Statistical method, and 3) Interpretation of the results. 1) There are several imaging modalities available in clinical research. Advantages and disadvantages of each modality are described. 2) Statistical Parametric Mapping, which is the most common statistical software for neuroimaging analysis, is described in terms of parameter setting in normalization and level of significance. 3) In the discussion section, the region which shows a significant difference between patients and normal controls should be discussed in relation to the neurophysiology of the disease, making reference to previous reports from neuroimaging studies in normal controls, lesion studies and animal studies. A typical pattern of discussion is described. PMID- 22834104 TI - [Essentials of neurocognitive assessment in clinical research]. AB - Schizophrenia and mood disorders are characterized by deficits of various domains of cognition, e.g. learning memory, working memory, executive function, attention, verbal fluency, and information processing. Cognitive disturbances are considered a major determinant of social outcome. Therefore, the development of pharmacotherapy to treat impaired cognition in psychiatric diseases remains one of the major unmet needs. This paper provides some of the essentials in conducting clinical research. Emphasis is placed on 1) assessments with the Brief Assessment of Cognition in Schizophrenia and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognition Battery, as well as their selection; 2) interpretation of the repeated measure effect, or so-called "practice effect"; and 3) sensitivity of cognitive assessment for predicting outcome, with a reference to measures of daily living skills and social function. PMID- 22834105 TI - [Tips on how to publish your data in English]. AB - Japanese researchers often find it difficult to write up academic reports in English, which may be associated with a perceived "language barrier." However, in fact, it is "emotional barrier" that discourages "potential" researchers from publishing their data. The plain English that we have learnt at school is sufficient to write academic articles in English. What is important is your guts, determination, and perseverance. In this article, tips on how to practically publish your data in English are presented. PMID- 22834106 TI - [Association between lithium sensitivity and GSK3beta gene polymorphisms in bipolar disorder]. AB - GSK-3beta codes for an enzyme which is a target for the action of mood stabilizers, lithium and possibly of valproic acid. The relationship between the polymorphisms (SNPs) of GSK-3beta-50T/C and -1727A/T and the effect of lithium was studied among 29 Japanese bipolar patients. It was shown that GSK-3beta-50T/C may be linked with the effect of lithium treatment. There is a significantly higher T-allele frequency in the lithium responders than non-responders (df = 1, chi2 = 6.971, 0.01 > P > 0.001; Yates' continuity correction). However, there is not a significant relationship between the polymorphisms of GSK-3beta-1727A/T and the effect of lithium treatment. PMID- 22834107 TI - Influence of GIRK channel inhibition on relapse risk in Japanese alcohol dependent inpatients. AB - We examined the influence of G-protein-activated inwardly rectifying K+ (GIRK) channel inhibition on relapse risk in Japanese alcohol-dependent inpatients. The participants included 11 patients who received GIRK inhibition treatment and 39 patients who did not receive GIRK inhibition treatment. The participants answered a questionnaire, including the Alcohol Relapse Risk Scale (ARRS) and a questionnaire about their experiences of stressful events 2 weeks after hospitalization (time 1) and completed follow-up questionnaires 45-60 days after the first rating (time 2). A significant interaction was found between group and time on positive expectancy for alcohol scores on the ARRS (F = 5.93, p = 0.02). The scores at time 2 were lower than that at time 1 in the GIRK inhibition treatment group (p = 0.004) but not in the non-GIRK inhibition treatment group. The results of the present study suggest that GIRK inhibition treatment may improve the positive expectancy for alcohol, a component of relapse risk. The present study suggests that the effects of GIRK inhibition treatment should be investigated further in future studies. PMID- 22834108 TI - [Discriminant analysis of the two-dimensional Gabor features for facial expression recognition]. PMID- 22834109 TI - [Electrosomatography as a method for auxiliary monitoring of physiotherapeutic treatment]. PMID- 22834110 TI - [Visualization of blood vessels using optical coherence tomography]. PMID- 22834111 TI - [Information analysis of radio brightness temperature fluctuations in brain tissues]. PMID- 22834112 TI - [A thermostating device for platelet-containing material storage]. PMID- 22834113 TI - [Modeling of the passband of the spatial frequency channels of the visual system]. PMID- 22834114 TI - [A limited-coherence interferometer system for examination of biological objects]. PMID- 22834115 TI - [A system for automated control of the cardiopulmonary resuscitation procedure]. PMID- 22834116 TI - [Study of the myocardium cell membrane using the Luo-Rudy model]. PMID- 22834117 TI - [Toxicological and biological safety of medical devices]. PMID- 22834118 TI - [Use of the vibrodiagnosis method for analyzing the quality of X-ray tubes with a rotating anode]. PMID- 22834119 TI - [50th anniversary of medico-technical education in Russia]. PMID- 22834120 TI - [Stress effect on haloperidol-induced catalepsy and its circadian rhythm in intact and ovariectomized female rats]. AB - Stressing reduces the intensity of haloperidol-induced catalepsy in intact female rats and increases it in ovariectomized animals. Ovarioectomy reduces the severity of haloperidol catalepsy. Circadian rhythm acrophase of the cataleptogenic haloperidol activity in female rats after ovariectomy and stress exhibits significant displacement. PMID- 22834121 TI - [Ladasten versus placebo effect self-evaluated by neurasthenia patients with different EEG alpha rhythm types]. AB - The study was focused on the clinico-pharmacological analysis of differences between subjective and objective assessment of the effects of antiasthenic drug ladasten and placebo effects in patients with neurasthenia with different individual patterns manifested in their EEG alpha rhythms and MMPI findings. It is established that, in patients with neurasthenia characterized by reduced EEG alpha activity combined with emotional lability and inertness, the therapeutic action and effectiveness of ladasten and placebo was more robust (the subjective estimation was higher) than in patients with prominent alpha rhythm and sthenic personal traits. The self-assessment of the effect of single test doses of ladasten and placebo was independent of the individual differences of EEG alpha rhythm organization and personal traits with respect to tolerability, wish to continue the treatment, activating and calming effects. In long-term treatment, higher subjective estimations of the ladasten and placebo effect appeared in patients with reduced EEG alpha rhythm, and the difference corresponded to objective indices of the psychotropic action and effectiveness of the drug. PMID- 22834122 TI - [Effects of mexidol and sulodexide on the level of specific markers of endothelial dysfunction in animals with experimental diabetes mellitus]. AB - Streptozotocin-induced diabetes leads to the development of endothelial dysfunction, as evidenced by decreased expression of endothelial nitric oxide synthase (eNOS) and increased expression of endothelin-1 as specific markers of endothelial disorders. All test substances showed endotelioprotective activity by increasing the concentration of eNOS and reducing the level of endothelin-1. With respect to the degree of impact on the eNOS and endothelin-1 levels, the compounds studied can be rated as follows: sulodexide > meksidol. PMID- 22834123 TI - [Cycloferon in the complex therapy of patients with widespread forms of pulmonary tuberculosis]. AB - Research performed at the Grodno Regional Clinical Center "Phthisiology" was aimed at studying the dynamics of IFN-gamma and IL-4 in serum of patients with widespread forms of pulmonary tuberculosis, treated by polychemotherapy with the use of cycloferon. Results of the clinical and laboratory evaluation of the effectiveness of the basic course of treatment are presented. A total of 238 patients, including 32 patients with limited forms of the pulmonary tuberculosis and 206 patients had widespread forms of pulmonary tuberculosis, were randomized into the basic group (BG) and comparison group (CG), where 95 CG patients received only polychemotherapy and 111 BG patients received polychemotherapy with the use of cycloferon. Data on the initial levels of cytokines (IFN-gamma and IL 4) in healthy persons and patients with various spread ofa tubercular inflammation in lungs are presented and compared. It is established that, in patients with widespread forms, initially low level of IFN-gamma and high concentration IL-4 (in comparison with the limited forms) shows a severe disbalance between Th1- and Th2-mediated immune response. The administration of cycloferon in the complex therapy of patients with widespread forms leads to an increase in the IFN-gamma concentration at initially low levels (below median level of this cytokine in healthy humans). Activation of the Th1-mediated immune response upon using cycloferon leads to an early elimination of clinical manifestations of the intoxication syndrome, positive roentgenological dynamics, conversion of sputum smear, and successful outcomes of treatment. PMID- 22834124 TI - [The role of nitric oxide in regulation of the erythrocyte system state in rat offspring with chronic disturbance of uteroplacental blood circulation]. AB - The effect of exogenous nitric oxide donor deponit-10 (nitroglycerin) on red cell indices in the offspring of rats with experimental disturbances of uteroplacental circulation has been investigated. It is established that fetal hypoxia facilitates the mobilization of functional reserves of the red cell system in the prenatal and early days of postnatal life of offspring in white rats, which is manifested by the growing process of erythropoiesis. Hyperfunction of the erythrocyte system in the first lifedays of pups leads eventually to a depletion of its functional capacities. The administration of an exogenous nitric oxide donor on the background of damaged uteroplacental circulation prevents the depletion and disruption of the functional reserves of the blood red cell system. PMID- 22834125 TI - [Effect of the energy metabolism regulator Yantar-Antitox on the system of energy production in rat liver during experimental pathology of beta-oxidation]. AB - Effects of the Yantar-Aantitox (succinic acid preparation) preparation on bioenergetic processes in mitochondria of rat liver during the experimental disorders of beta oxidation process evoked by 4-pentenoic acid have been studied. It is established that the course administration of Yantar-Antitox leads to normalization of disturbed bioenergetic processes in rat liver, which is due to stimulation of the rapid metabolic cluster of mitochondria. PMID- 22834126 TI - [Estimation of the hypoglycemic effect of phytoecdysteroids]. AB - A series of phytoecodysteroids, including alpha-ecdysone, 2-deoxy-alpha-ecdysone, and 2-deoxyecdysterone isolated from Silene praemixta, integristerone A and ecdysterone isolated from Rhaponticum carthamoides and 22-acetylcyasterone and turkesterone isolated from Ajuga turkestanica, exhibit a pronounced hypoglycemic effect in experiments on intact male rats. The most active compounds--ecdysteron and turkesterone--also produce an expressed hypoglycemic effect in animals with model hyperglycemia induced by the administration of glucose, adrenalin and alloxan. Phytoecdysteroids are substances possessing protein-anabolic activity and are somewhat similar to steranobols in this aspect. Phytoecdysteroids exhibit unidirectional effect and are well comparable with steranabol actionon the carbohydrate metabolism. PMID- 22834127 TI - [High-density lipoproteins as a form of daunorubicin transport in hepatoma cells of mice]. AB - The efficiency of using high-density lipoproteins (HDLPs) as the transport form of an antineoplastic drug daunorubicin (rubomycin hydrochloride, daunoxome) has been shown on the culture of HA-1 hepatoma cells of mice. The use of HDLPs in a complex with daunorubicin led to an increase in the efficiency of drug transport and cytotoxic action with respect to tumor cells in comparison with hepatocytes of healthy animals. PMID- 22834128 TI - [Comparative evaluation of the osteoprotective effects of resveratrol and resveratrol/enalapril combination in the treatment of experimental osteoporosis]. AB - The osteoprotective effect of resveratrol and a combination of resveratrol with enalapril has been investigated in white Wistar female rats with experimental osteoporosis. It is established that, in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of the osteal tissue is developed, resulting in the occurrence of osteoporosis. Resveratrol and the combination of resveratrol with enalapril prevented depression of the microcirculation level in the osteal tissue, thus preventing the thinning of osteal trabecules and preventing their microfractures. PMID- 22834129 TI - [Intraoperative correction of temperature homeostasis disturbances in children]. AB - Some features of temperature homeostasis regulation during the intraoperative period and methods of its correction with a balanced fluid therapy are described. The possibility of using infusion of antihypoxants and amino acid solutions to maintain optimum body temperature during the perioperative period is considered. The study was performed on a group of 107 children of various age, which underwent a surgery of thoracic or abdominal cavity. All operations were performed with total intravenous anesthesia and artificial pulmonary ventilation. In order to correct intraoperative hypothermia, sodium chloride 0.9% solution, mafusol, infezol-40, and reamberin were used. Results showed that reamberin produced a significant positive effect on the indices of peripheral body temperature. This allows reamberin to be recommended for widespread use in clinical practice in order to prevent and eliminate intraoperative hypothermia. PMID- 22834130 TI - [Limitation of oxidative stress as the main factor of the universal protective properties of melatonin]. AB - Natural hormone melatonin, which is produced by pineal gland and apudocytes of peripheral tissues, has unique and universal protective features against various cerebral and somatic diseases. Melatonin effects may be based on many factors. On the cellular level, the main role in the therapeutic properties of melatonin is played by the antioxidant activity. Much evidence for this hypothesis is presented and reviewed. PMID- 22834131 TI - [Main components of gene network controlling development of dorsal appendages of egg chorion in Drosophila melanogaster]. AB - The development of dorsal appendages of the chorion (specialized structures in the D. melanogaster egg which look like elastic tubes and ensure the breathing of the developing embryo) is an attractive model for the study of genetic mechanisms of the development of organs and tissues, whose generation is based on transformation of the epithelial tissue in the tubular structures. In the present review, we present information on genes and proteins that control the development of dorsal appendages of the chorion. We demonstrated that three signal pathways (EGFR, DPP, and NOTCH), which are combined together in a single gene network through a number of components, play a major role in the development of dorsal appendages of the chorion. PMID- 22834132 TI - [Morphogenesis of proximal branch leaves in mosses]. AB - The formation of deeply dissected and compound leaves at the bases of branches, their homology between different groups of mosses, and probable factors responsible for their development are considered. Previous authors differ in the interpretation of such leaves and in most cases describe them as special morphological structures named pseudoparaphyllia. It is shown, however, that this term has been applied both to whole leaves and to separate leaf parts. Among the patterns of leaf formation deviating from the basic type, a special place belongs to the Hampeella variant, where deeply dissected and compound leaves are formed due to the delayed development of branch primordia. The families representing this variant occupy a basal position in the phylogenetic tree of pleurocarpous mosses. The Leucodon variant, where splitting of leaves into lobes is apparently explained by strong stem extension, is not specific for any definite phylogenetic group and manifests itself in different families. The Hypnum variant is also not associated with certain phylogenetic lineages, but it provides an example of more profound specialization. PMID- 22834133 TI - [Stimulation in vitro of oocytes of acipenserids with progesterone and homologous gonadotropic hormone of hypophysis]. AB - We showed that the percentage of oocytes of acipenserids ovulating in vitro in Ringer solution modified for sturgeons (RMS) considerably depends on the concentration of sodium bicarbonate and the concentration of progesterone. Under optimal conditions (0.5 g/L of sodium bicarbonate and 30 ng/mL of progesterone), it can be higher than 80. Oocytes that matured and ovulated under such conditions are capable of normal development. In the best case, approximately 70% of developing embryos (of the number of ovulated oocytes) reach the stage of hatching (dead-line of observation). This method of producing offspring based on the insemination of oocytes that have matured and ovulated in vitro can be used in work with single females of rare and disappearing species of acipenserids. PMID- 22834134 TI - [Crucial stages of embryogenesis of Rana arvalis: Part 2. Development of head structures]. AB - Analysis of the dynamics of variation in developing head structures of moor frog (R. arvalis) tadpoles has made it possible to reveal periods in which the limits of variation in relevant traits are narrowed. In the course of individual development, these so-called crucial periods for certain traits are followed by such periods for other traits. However, crucial stages for some head structures have not been revealed, which can be explained by a relatively short period of development considered in the study. Analysis of individual variation at later stages may provide the possibility to identify crucial periods for these structures. PMID- 22834135 TI - [Morphogenetic consequences of partial removal of blastomere cytoplasm during early embryonic development of the loach, Misgurnus fossilis L]. AB - The development of loach embryos is successfully regulated (normalized) after partial removal of the cytoplasm from one blastomere at the two- or four-cell stage or complete removal of one or two blastomeres at the stage of 8-16 cells. Using time-lapse video imaging and morphometric analysis, it has been shown that this regulation is a two-stage process. At the first stage, the ratio between the volumes of the blastodisk and yolk sac is rapidly (within one or two cell cycles) restored almost to the initial level; at the second stage, morphogenesis of the embryo is modified according to its new structural features acquired after the operation. After several rounds of cytokinesis, the cytoplasm remaining in the operated blastomere fuses with the marginal yolk syncytium (periblast),which at the blastula stage forms a distinct extension at the operation site. This extension marks the site of embryonic shield formation. The results of morphometric analysis show that restoration of the initial blastoderm volume in operated embryos leads to a reduction of active tension at the blastoderm--yolk boundary and an increase in the ratio of blastoderm surface to its volume at the moment of epiboly initiation. As a result, the convergence of blastoderm cells to the operation site and the embryonic shield formation begin at a lesser degree of epiboly, compared to the control. PMID- 22834136 TI - [Expression of transmitter receptor genes in early development of sea urchin Paracentrotus lividus]. AB - Neurotransmitters (including serotonin and acetylcholine) perform a number of prenervous functions in early sea urchin development. To detect the particular receptor components involved in these processes, we carried out a database search and nucleotide sequences homologous to serotonin receptor type 4, and the alpha6- and alpha10-subunits of nicotinic acetylcholine receptor were found among EST clones from early Paracentrotus lividus embryos. Expression of these transcripts during early development was demonstrated using RT-PCR. These results are the first molecular biology evidence ofserotonin and acetylcholine receptor expression in sea urchin early embryogenesis. PMID- 22834137 TI - [Where and when natriuretic peptides are secreted in the heart]. AB - This review presents recent data on the structure, synthesis, and secretion of cardiac natriuretic peptides. It is known that these hormones have a broad spectrum of activity, but they remain the least studied and poorly understood link in the regulation of the water-salt homeostasis. Emphasis is placed on the problem of ontogenetic formation of the heart secretory activity during embryogenesis. We discuss the available scarce and scattered information on the paracrine and autocrine effects of the peptides on intercellular interactions, and on the division, growth and differentiation of the heart cells. These issues are hardly addressed in Russian literature. PMID- 22834138 TI - [Mesenchymal stromal cells synchronize the rhythm of protein synthesis under the effect of an exogenous signal]. AB - A comparative study was performed of dense 5-hour cultures of rat hepatocytes and equal-density cultures of mesenchymal stromal cells (MSC) isolated from human adipose tissue of rat bone marrow. The cells were grown on collagen-coated class slides in serum-free medium. Unlike in hepatocytes, no rhythm of protein synthesis was initially revealed in MSC, but such a rhythm manifested itself when the culture medium was supplemented with melatonin (2 nM, 5 min). The results of experiments with cytoplasmic calcium chelator BAPTA-AM and protein kinase inhibitor H7 indicate that the mechanism of protein synthesis synchronization in MSC consists in calcium-dependent phosphorylation of cell proteins. PMID- 22834139 TI - [COX-2 as an early diagnostic marker of virus-associated human malignant neoplasms]. AB - The review analyzes recent data and current ideas on the enzyme cyclooxygenase 2 (COX-2) as a possible biomarker of virus-associated human malignant neoplasm. Possible mechanisms of COX-2 activation in the cells infected with oncogenic human viruses, such as hepatitis B virus, Epstein-Barr virus, and human papillomavirus are considered in detail. PMID- 22834140 TI - [Interaction of influenza A and B viruses with nanodiamond-based sorbents]. AB - The paper presents data on the sorption of influenza A(H1N1), A(H1N1)v, A(H3N2) viruses, cDNA of A(H1N1)v and B viruses on nanodiamonds and furnace charge. The sorption of viruses occurred in different solutions at 4-37 degrees C during 10 20 min. The rate of sorption varied with the concentration of a sorbent in the solution and its structure, but did not with the antigenic formula of viruses or temperature. The sorption capacity of furnace charge towards influenza A and B viruses was higher than that of nanodiamonds. Nonviral proteins (bovine serum albumin and influenza virus antibodies) were found to be bound by both sorbents. Viral desorption did not take place in physiological solution at 4 and 22 degrees C for 48 hours. PMID- 22834141 TI - [Development of methodology for predictably significant evaluation of the protective efficacy of antiviral agents]. AB - The paper provides a theoretical analysis for determining whether the antiviral nonspecific drugs being tested are promising to solve biosafety problems in the treatment of exotic viral infections. The essence of the proposed concept of evaluation of protective effectiveness is to analyze the effect of a test drug on the pathogenesis of experimental infection from the fact that it is effective in adequately eliminating the animal-simulated leading syndrome of human disease. The given approaches to using adequacy criteria to select the species of animals meeting the goals of tests in terms of pathogenetic and pharmacological parameters determine a new methodology for evaluating the efficacy of protective agents. Basic requirements for a testing procedure are presented. The prognostic value of evaluation of the protective efficacy of antiviral agents for man will depend on the approximation of the pathogenetic features and external manifestation of disease in the selected animal species to human Infection. The paper also covers the comparative characteristics of the course of Ebola fever and Venezuelan equine encephalomyelitis in man and some species of monkey. PMID- 22834142 TI - [Influenza virus reproduction in the endothelial cells of human blood vessels]. AB - The current epidemic strains of the influenza subtypes Y5N1, H3N2, and H1N1 can be reproduced in the cultured human endothelial EAhy926 cells with an infective activity of 3.0-4.5 Ig TCD50. These findings were confirmed by the analysis of the autopsy material from patients who had died from influenza during the 2009 2010 epidemic, which showed influenza virus HA and NP proteins in the pulmonary blood vascular endothelium. The results obtained reflect a new aspect of the pathogenesis of influenza, which is important for the design of antiviral agents and for the development of combination therapy. PMID- 22834143 TI - [Enhancing the immunogenic activity of influvac vaccine in the use of adjuvant TI complexes modified by echinochrome A]. AB - The self-assembly of marine macrophyte glycolipids, holothurian saponin, and cholesterol gave rise to nanoscale morphological structures called tubular immunostimulating (TI) complexes. Whether the latter could be used on the basis of vaccine preparations containing the influenza virus subunit antigens was studied. There was an obvious increase in the immunogenicity of influenza virus hemagglutinin when the experimental animals were immunized with this antigen as part of TI complexes. It was shown that the adjuvant activity of the TI complex to influenza virus hemagglutinin could be enhanced by adding the known antioxidant echinochrome A from a sand-dollar (Echinarachnius parma) to the matrix of the TI complex. PMID- 22834144 TI - [Recombinant interferon-alpha suppression of Karelian fever virus replication in human blood cells]. AB - The active replication of Karelian fever virus (KFV) in human blood vessels and the protective activity of the Russian agent reaferon were first shown. KFL was highly susceptible to interferon (IFN)-alpha. In control (uninfected) cells, reaferon caused low gene expressions of the IFN-dependent enzymes dsRNA-dependent protein kinase and 2'5'-oligoadenylate synthetase, by exerting a little effect on the activity of its family genes. KFV suppressed the reaferon-induced gene expression of IFN-dependent enzymes, but IFN-alpha gene transcription was increased in the reaferon-treated infected cells. PMID- 22834145 TI - [The ability of small interfering RNA oligonucleotides to decrease the infective activity of hepatitis C virus in the cell cultures]. AB - The use of the RNA interference technique yielded data on the antiviral activity of small interfering RNA (siRNA) oligonucleotides against hepatitis C virus (HCV) infection in the pig embryo kidney (SPEV) cell cultures. The RNA interference technique is based on the specific recognition of the mRNA target by using the specially designed siRNA (19-22 bp) oligonucleotides. In particular, it was shown that siRNA added to the monolayer of HCV-infected SPEV cells resulted in the protection of the infected cells against the cytopathogenic activity of the virus. The results were confirmed in the experiments that demonstrated the ability of RNA oligonucleotides to reduce the production of infectious (cytopathogenic) HCV by infected SPEV cells in early-stage infection. PMID- 22834146 TI - [Ingavirin treatment of experimental parainfluenza pneumonia in Syrian hamsters]. AB - Parainfluenza viruses affect the upper respiratory tract in all age group patients, in children aged 6 months to 3 years in particular. The most urgent task is to design drugs to treat parainfluenza. This investigation studied the antiviral activity of Ingavirin (2-(imidazole-4-yl) ethanamide of pentandioic-1,5 acid) on a model of parainfluenza infection in Syrian hamsters. The drug was shown to restrict the infectious process in animal lung tissue. This restriction manifested itself as reductions in the infectious titer of parainfluenza virus in the lung tissue, in the degree of pulmonary edema and tissue cell infiltration, and in virus-specific lesion of bronchial epithelial cells. The in vitro experiments demonstrated the ability of Ingavirin to diminish the infective activity of viral descendants. The finding allows one to consider Ingavirin to be a promising antiviral agent that is active against parainfluenza infection in vivo. PMID- 22834147 TI - [Changes in the reproduction of tick-borne encephalitis virus in cell cultures]. AB - The currently used tick-borne encephalitis virus vaccines are based on the inactivation of tick-borne encephalitis virus (TBEV) of Far Eastern or West European genetic types from the primary cultures of chick embryo fibroblasts. Since the WHO recommends that vaccines should be designed using continuous cell cultures rather than chick embryos as a substrate, this investigation has compared the infection of continuous monolayer SPEV, Vero E6, and vaccine line Vero (B) cell cultures with TBEV strains of the Siberian and Far Eastern genetic types dominating in the endemic regions of Russia. After cell infection with Far Eastern (Sofyin and 205 strains) or Siberian (Aina, 2530, 2689, and 2703 strains) TBEV genetic types, the viable TBEV titers reached 2.8 Ig CPD50 for Vero (B) cells, 5.5 Ig CPD50 for Vero E6 cells, and up to 9 Ig CPD50 for SPEV cells. The quantitative scores of TBEV E antigen in enzyme immunoassay (EIA) and genome equivalents by reverse-transcription polymerase chain reaction (PCR), followed by real-time PCR, permitted one to estimate as high as 108 virions in 1 ml of culture fluid, which corresponded to those of the microscopic observations of CPD for SPEV cells and substantially exceeded the values for Vero E6 cells, and for Vero (B) cells in particular. The data of TBEV strain titration, EIA, and realtime reverse-transcription PCR suggest that the Russian vaccine Vero (B) cell line defined as meeting the WHO requirements, as well as Vero E6 cells may be used to design tick-borne encephalitis vaccine. PMID- 22834148 TI - [Use of the cultural variants of Coxsackie A viruses in virological practice]. AB - Coxsackie A viruses belong to the enteroviruses, the isolation of which from infectious materials and further cultivation are possible only when laboratory animals are infected. The authors could adapt the strains of 17 of 23 serotypes of these viruses to RD cell culture. The strains of 8 serotypes were additionally adapted to Vero cell culture. The cultural variants of Coxsackle A viruses were used to prepare immune sera. The Bacterial and Viral Agents Enterprise, M. P. Chumakov Institute of Poliomyelitis and Virus Encephalitides, Russian Academy of Medical Sciences, has set up the production of bacterial and viral drugs based on the cultural variants of 5 Coxsackie A virus serotypes. The cultural variants of 14 Coxsackie A virus serotypes were used to carry out a virus neutralization test. Examination of more than 600 children from Moscow and the Moscow Region showed the wide circulation of individual Coxsackie A virus serotypes. It also demonstrated a drastic reduction in Coxsackie A-7 virus circulation in the past 50 years. PMID- 22834149 TI - [The insulin regulation of metabolism of fat acids and glucose next in the realization of biologic function of locomotion]. AB - The becoming at the late stages of phylogeny of the biologic function of locomotion, insulin system and the earliest formed function of mitochondria make it possible to align all oxidized substrates in the following sequence: a) fatty acid metabolites C4 - ketone bodies; b) butyric fatty acid short-chained metabolites C6-C10; c) palmitic fatty acid with specific carrier; d) glucose. The mitochondria will begin to oxidize glucose if there will be no ketone bodies in cytosol and no remains of short-chained fatty acids and palmitic fatty acid. According to "the biologic subordination principle" philogenically late insulin can't change the functional characteristics of the phylogeny earliest mitochondria. To "force" the mitochondria starting to oxidize glucose first of all the insulin is to inhibit the biochemical reactions in all cells where releasing of polar non-etherified fatty acids and formation of their polar metabolites occurs. As in case of insulin, the same marked and prolonged hypoglycemia is induced by DL-aminocarnitine. This substance specifically inhibits both activity of carnitine-palmitoilacylaminotrsansferase and flux of acyl-KoA in mitochondria. The pronounced decrease of fatty acids content and their metabolites in matrix force mitochondria to oxidize glucose. It is possible to be validly of opinion that the same philogenically ancient principles as inhibition of activity of carnitine-palmitoilacylaminotrsansferase, decrease of formation of fatty acid metabolites C4 (ketone bodies), short-chained metabolites of palmitic fatty acid and olein mono fatty acid are applied in realization of philogenically late insulin effect. The first insulin effect in the hypoglycemia and biologic exotrophy reaction conditions is targeted to the regulation of fatty acids metabolism. Only second insulin effect is targeted to the glucose metabolic transformation. Therefore, there is a background to consider the diabetes mellitus primarily as a disorder of metabolism of unsaturated and mono fatty acids and only secondary and only then as a disorder of glucose metabolism. If insulin will not be able to decrease in cytosol the content of lipid substances of oxidation of insulin the mitochondria will not oxidize glucose. At that, a pathogenesis uniform syndrome of resistance to insulin is formed independently of etiologic factors. Under these conditions the mitochondria physiologically "don't want" to oxidize glucose a possibility exists to oxidize fatty acids and their polar metabolites. PMID- 22834150 TI - [The population study of total antioxidant activity of human blood serum and urine]. AB - Many diseases are accompanied with the development of oxidation stress. The analysis of total antioxidant activity is one of the techniques to assess the oxidation-reduction balance. In spite of availability of normative documents recommending to apply this examination the antioxidant activity analysis technique is used in practice not very often. The absence of reference values of this indicator is one of the reasons of this situation. The article presents the results of the study of total antioxidant activity of human blood serum and single portion of urine. On the basis of the results the reference limits were estimated. The correlation analysis of interrelationship between antioxidant activity analysis technique assessment and age, gender and content of substances mostly inputting into analysis results. PMID- 22834151 TI - [The alterations in fatty acids content of membranes of erythrocytes and insulin resistance syndrome under primary gout]. AB - The content of fatty acids of lipids of membranes of erythrocytes in patients with primary gout depending on presence of insulin resistance syndrome. The alterations of content of fatty acids in patients with gout and insulin resistance syndrome are characterized by increase of content of saturated fatty acids and decrease of unsaturated fatty acids. At that, in the pool of unsaturated fatty acids the content of monounsaturated acids is increased and the content of polyunsaturated acids is decreased. In the pool of polyunsaturated fatty acids the increase of content of gamma-linolenic and digomo-gamma-linolenic acids and significant decrease of arachidonic and docosapentaenic acids are noted. The shifts mentioned above can play a certain role in the formation of insulin resistance syndrome in patients with primary gout. PMID- 22834152 TI - [The oxidation stress, lipid metabolism and their relationship in patients with severe course of hypertension disease in aggregate with carotid stenosis]. AB - The experimental samplings consisted of 25 patients with severe course of hypertension disease in aggregate with atherogenic carotid stenosis before and after carotid endarterectomy and 21 donors. The study was organized to analyze in lipid profile blood serum the content of malonic dialdehyde, ceruloplasmin, alpha tocopherol, nitric oxide and angiotensin converting enzyme. The study established that in patients took place a reliably increased level of malonic dialdehyde, ceruloplasmin, alpha-tocopherol, nitric oxide and angiotensin converting enzyme. The patients with this pathology have a reliable positive correlation between the concentration of malonic dialdehydeand lipoproteids of very low density (r = 0.51), malonic dialdehyde and triglycerides (r = 0.36), malonic dialdehyde and cholesterol (r = 0.3). This data confirms the important role of peroxidation of lipids in the development of atherosclerosis. Therefore, the enhancement of oxidation stress and expressed dislipoproteidemia are established in patients with hypertension disease with carotids atherosclerosis as a background. This result testifies the pathogenic significance of these phenomena in the mechanisms of homeostasis disorders. PMID- 22834153 TI - [The activity of peroxidation of lipids in biologic samples of patients with recurrent diseases of upper respiratory tracts]. AB - The parameters of peroxidation of lipids in blood and saliva were analyzed on sampling of 60 patients with recurrent diseases of upper respiratory tracts during period of remission. It is established that the content of primary and secondary products of peroxidation of neutral lipids in blood plasma is lower as compared with healthy persons. The content of end products of peroxidation of neutral lipids and products of oxidation of phospholipids in blood plasma is higher as compared with healthy persons. The characteristics of alterations of intermediates of peroxidation of lipids in various biologic samples depend on the localization of inflammatory process. PMID- 22834154 TI - [The dynamics of biochemical markers of remodelling of bone tissue after liver transplantation]. AB - The sample of 45 recipients (30 females and 15 males) after orthotopic transplantation of liver was examined thrice in dynamics. Three groups were formed according the resulted values of T-criterion of bone mineral density in the area of lumbar vertebrae. The bone mineral density of group A was considered as osteoporosis, of group B as osteopenia and of group C as physiologic norm. In early period (1-4 months) after orthotopic transplantation of liver gross disorders of bone metabolism were established in all recipients independently of the degree of bone mass loss. In distant period (up to 32 months) after orthotopic transplantation of liver the bone losses decreased entailing full normalization of bone metabolism in 37% of recipients with osteoporosis, 82% with osteopenia and 91% with normal bone mineral density. PMID- 22834155 TI - [The metabolic predictors of depression under diabetes mellitus]. AB - The possibility to detect the depressive disorders in patients with diabetes mellitus is discussed. The comprehensive analysis was applied to the indicators of carbohydrate metabolism, lipidograms and state of system of lipids peroxidation - antioxidant defense. It is established that the development of clinically valuable medium and severe depression under diabetes mellitus is related to the decrease of level of heptane soluble products of lipids peroxidation (diene conjugate) on the background of increasing of concentration of alpha-tocopherol and total content of cholesterol in blood serum. These biochemical indicators reflected the severity of comorbid depression under diabetes mellitus. They had no dependencies of age and gender diabetes mellitus of patients, duration and type of diabetes mellitus. The most informative predictor was established the level of tokoferolemia. Its registration makes it possible to verify the clinically valuable depression under diabetes mellitus with sensitivity level of 70.5% and specificity level of 64.1%. PMID- 22834156 TI - [The clinical laboratory comparison in the assessment of treatment prognosis in patients with infiltrative tuberculosis of lungs]. AB - The comprehensive prospective examination of 66 patients with first established non-treated infiltrative tuberculosis of lungs was used to analyze the possibility of optimization of assessment of course of specific inflammatory process on the basis of levels of proteins-reactants of acute phase. The characteristics of dynamics of clinical roentgenologic data and terms of coming of abacillarization as a result of three months anti-tuberculosis therapy has been used as grouping factors. It is established that the constellation of 3 out of 12 basic (before treatment) analyzed level indicators are the most prognostic informative--haptoglobin, ceruloplasmin and blood albumin. Their combined application according the proposed decisive rule provides 90.6% of effectiveness of prognosis of the results of treatment in the discussed category of patients. PMID- 22834157 TI - [The state of homeostasis system in patients with aplastic anemia in the period of full-fledged clinical manifestation of disease]. AB - In most cases the immediate cause of lethal outcomes of aplastic anemia is increased hemorrhage. The multifactorial causality of development of hemorrhagic syndrome is to be taken into account to receive informative and accessible characteristics in assessing the state of homeostasis system in patients with aplastic anemia during acute period of disease. The comprehensive analysis of homeostasis system indicators during acute course of aplastic anemia established such characteristic alterations as the presence of signs of activation of homeostasis system, decrease of factor XIII level, inhibition of fibrinolysis system, qualitative deficiency of platelets in peripheral blood. Hence their significance in pathogenesis of hemorrhage in patients with aplastic anemia is approved. PMID- 22834158 TI - [The dynamic detection of cytokins under aplastic anemia and idiopathic thrombocytopenic purpura in the process of impact of hypoxic hypoxia]. AB - The natural hypoxic hypoxia enhances the synthesis processes and decrease the concentration balance in cytokine rets in patients with depression of hematopoiesis. It is established that the patients with aplastic anemia and idiopathic thrombocytopenic purpura, in contrast with patients with acute leucosis, chronic myelolecosis and erythroid myeloma, have quite high values of IL-2, which can be involved in the organization of full-fledgee response to antigen stimuli. The application of hypoxic hypoxia as an additional method in treatment of aplastic anemia and idiopathic thrombocytopenic purpura has no side effects and contraindications. PMID- 22834159 TI - [The monitoring of application of dabigatran as a remedy of prevention of thromboembolic complications after hip joint arthroplasty]. AB - The analysis was applied to the indicators of hemostasis system under application of new anticoagulant, dabigatran etexilat, after hip joint arthroplasty. It is established that among the coagulation methods analysis the most specific to the effect of dabigatran is the testing of thrombin and echitox time of coagulation. Considering low sensitivity of the echitox to anticoagulation effect of D-dimer the echitox test is optimal for laboratory monitoring of application of dabigatran after orthopedic intervention. PMID- 22834160 TI - [The comparative study of indicators of immunity and state of pro- and antioxidant systems in patients with chronic pyelonephritis of single kidney in active and latent stages of disease]. AB - It is established that in patients with chronic pyelonephritis of single kidney the antibacterial defense of organism and balance between pro- and antioxidant systems are disturbed both in active and latent stages of disease. The results testify the need of organization of comprehensive immunologic and biochemical examination to establish a prognosis of complications and evaluation of effectiveness of applied treatment. PMID- 22834161 TI - [The development of immune-enzyme test-systems to diagnose rubella]. AB - Two new immune-enzyme test-systems are developed to diagnose rubella using the natural antigen of rubella virus. The test-systems by their characteristics are equal with the known international models and can be recommended for large implementation in clinical diagnostic laboratories of health institutions to detect antibodies classes G, M to rubella virus both for disease diagnosis and mass serologic examination of immune status of population and evaluation of effectiveness of vaccination. PMID- 22834162 TI - [The concentrations of certain cytokins and lactoferrin in blood and supernatants of cell cultures in patients with autoimmune thyroiditis]. AB - The analysis was applied to serum and supernatants of day cultures of blood cells of patients with autoimmune thyroiditis and healthy women to determine the content of cytokins (IFN-gamma, TNF-alpha, IL-beta, IL-6, IL-10, L-17) and lactoferrin. The test-system "Cytokin-Stimul-Best" was applied. It is established that in patients with autoimmune thyroiditis the proliferative response of cells to mitogen stimulation is lowered in vitro: the levels of alpha-tumor necrosis factor interleikin-6, lactoferrin. The stimulation index of alpha-tumor necrosis factor, interleikin-6, 1beta, 10 and interferon was statistically reliably lower in supernatants of mitogen stimulated cultures of cells of patients with autoimmune thyroiditis as compared with indicators of healthy women. PMID- 22834163 TI - [The evaluation of diagnostic effectiveness of algorithm of isolation and express identification of opportunistic enterobacteria using national chromogenic growth mediums]. AB - The testing of specificity and diagnostic effectiveness was applied to new national chromogenic growth mediums. The algorithm was developed to isolate and express identify the clinically significant and sanitary demonstrative opportunistic enterobacteria using chromogenic growth mediums. PMID- 22834164 TI - [60 years of the equilibrium theory of insular biogeography: problems of testing, results of the field studies, applied importance]. AB - A review is presented of publications dealing with analysis of species richness of island biological communities and habitat islands based on the equilibrium theory of insular biogeography by MacArthur and Wilson (1963). Principal points of the theory are considered along with its shortcomings, problems and results of its testing. Also, possibilities are appraised for using recommendations elaborated on the base of the theory in nature conservation practice. The results of island and habitat island biota studies indicate that in many cases data corroborate the equilibrium theory while in many other cases they do not. In particular, for cenoses fragmented 50-250 years ago, especially for the ones formed by long living species, there have been no conspicuous effects of species relaxation detected. At that, the theory prediction of substantial reduction in species richness of fragmented communities in the long run is hardly disputed. The results of studies conducted in the field of insular biogeography are taken as a basis for recommendations on the long-term conservation of isolated communities integrity, although mostly they are of qualitative nature. PMID- 22834165 TI - [Karyotypes divergence in superspecies complex Cricetulus barabensis sensu lato and their interrelationships in natural contact zones]. AB - Interrelationships between three chromosomal forms of striped hamsters belonging to the superspecies complex Cricetulus barabensis sensu lato (Cricetidae, Rodentia), namely 'barabensis', 'pseudogriseus', and 'griseus', are examined from the standpoint of different biological/genetic species concepts. Craniometric data suggest that differences between the karyotypes are rather of subspecies level. Cytogenetic differences between the karyotypes are also not great and correspond to the level of chromosomal races within a single species. The analysis of mitochondrial gene for cytochrome b (cytb) indicates the level of differences between forms of about 2.3-4.1%. Such a level may correspond to intraspecific differences as well as to differences between allied species. Experiments on hybridization resulted in hybrid litters obtained in different mating combinations of karyotypes. Both hybrid males and females fertility was confirmed, too. In nature, there exist several zones where contact between karyotypes 'barabensis' and 'pseudogriseus' is possible. Within one of such zones, in Central Mongolia, two males with atypical karyotype were detected by use of chromosome analysis. With chromosomes number and form, this karyotype may correspond to the hybrid between second and subsequent generations. However, typing of gene cytb and the intron localized in Y-chromosome (DBY1) did not reveal any traces of recent or ancient hybridization. In the other zone where contact between the karyotypes is possible, in South Buryatia, 'barabensis' and 'pseudogriseus' populations are separated by the River Chika and the distance between them does not exceed 5 km. Nevertheless, no hamsters with non-standard karyotypes and no traces of gene flow are detected by karyological and molecular analyses of these populations. The results of Tajima's test, analysis of pairwise differences distribution and indices of nucleotide diversity obtained in the course of examining gene cytb full nucleotide sequence all suggest that both contact zones studied have formed long ago and the absence of gene flow cannot be explained by their forming in the recent past. Thus, the karyotypes studied appear to be evolutionary lines developing independently from each other. PMID- 22834166 TI - [Basic types of respiratory system structure in insect egg envelopes, and genes controlling their formation]. AB - Insects is a taxon surprisingly rich with species and varieties, and its representatives are considered as the most fitted and "evolutionary successful" living things. Insects are distinguished by diversity and abundance of adaptations to environmental conditions, representatives of this class inhabit different ecological niches, they can be found practically in every corner of the Earth and, in particular, in close adjacency to man. Among them are those who man benefits from and those who man struggles against. This determines man's interest in studying peculiarities of their development as well as adaptations formed by them in the course of evolution to become more viable. In the paper, data are presented on morphological structure of respiratory systems in insect egg envelopes that ensure respiration process of developing embryo. Variability of these systems and their dependence on environmental conditions are demonstrated for different insect species. The information about genes controlling development of respiratory systems in fruit fly eggs is brought together, and occurrence of evolutionary conservative genes participating in development of such systems in other insect species is ascertained. PMID- 22834167 TI - [Patterns of morphological variability in reintroduced populations with two beaver subspecies Castor fiber orientoeuropaeus and Castor fiber belorussicus (Castoridae, Rodentia) as an example]. AB - Taking as an example two beaver subspecies (Castor fiber orientoeuropaeus and Castor fiber belorussicus) with documented history of population formation, the patterns of morphological variability in translocated groups of mammals are studied. The variability of quantitative and qualitative traits in the formed populations is not characterized by a single direction. The main trend consists in increasing of adaptive norms diversity as related to body size. There observed a slight increase in the level of fluctuating asymmetry, reduction in polymorphism of nonmetric traits, and increase in fraction of rare aberrations. All these may be caused by inbreeding taking place during the period of prapopulations formation. The results of the study allow for considering the intraspecific differentiation as a consequence of adaptive variability (adaptatiogenesis) or subspecies hybridization. As for stochastic processes (genetic drift, founder effect), they seem to not influence the morphological variability significantly. The differences between discrete and dimensional traits are indicative of population groups' peculiarity. PMID- 22834168 TI - [Amplitude modulation in sound signals by mammals]. AB - Periodic variations in amplitude of a signal, or amplitude modulation (AM), affect the structure of communicative messages spectrum. Within the spectrum of AM-signals, side frequencies are formed both above and below the carrier frequency that is subjected to modulation. In case of harmonic signal structure they are presented near fundamental frequency as well as near harmonics. Thus, AM may by viewed as a relatively simple mechanism for controlling the spectrum of messages transmitted by mammals. Examples of AM affecting the spectrum structure of functionally different sound signals are discussed as applied to representatives of four orders of mammals: rodents (Reodentia), duplicidentates (Lagomorpha), pinnipeds (Pinnipedia), and paridigitates (Artiodactia). For the first time, the classification of AM in animals' sound signals is given. Five forms of AM are picked out in sound signals by mammals: absence of AM, continuous AM, fragmented, heterogeneous, and multilevel one. AM presence/absence is related neither with belonging to any specific order nor with some particular function of a signal. Similar forms of AM can occur in different orders of mammals in parallel. On the contrary, different forms of AM can be detected in signals meant for similar functions. The assumption is made about AM-signals facilitating information encoding and jamprotection of messages transmitted by mammals. Preliminry analysis indicates that hard-driving amplitude modulation is incompatible with hard-driving frequency modulation. PMID- 22834169 TI - Effects of nursing home stays on household portfolios. PMID- 22834171 TI - Cleanliness critical in feeding tube management. PMID- 22834170 TI - Solving the mystery. Providers are finding alternatives to antipsychotics by doing some old-fashioned detective work. PMID- 22834172 TI - Disaster preparedness refresher. PMID- 22834173 TI - Getting ready for QAPI. PMID- 22834174 TI - Healthcare reform could be a reality regardless of rulings. PMID- 22834175 TI - Federal audit findings in E/M services: a top 10 survival guide. AB - Physician practices are under intense scrutiny, led by several aggressive and pervasive federal auditing initiatives. One of the primary targets for these initiatives is the most common physician service provided: the E/M service--with the most prevalent E/M service being the basic office visit. Physicians and practice managers should be aware of the risk areas when documenting, coding, and billing E/M services. This article presents the top 10 areas of risk exposure for such services, and throws in an additional eleventh area for an added preventive measure. PMID- 22834176 TI - Competing interests in healthcare: a conflict of quality. Part I: definition, background, and evidence. AB - This policy paper investigates whether physician conflicts of interest have an effect on physicians' quality of care and whether implementation of conflict-of interest policies will ameliorate any negative effects of divergent interests. Some government regulations are discussed in a policymaking perspective. We also suggest that healthcare organizations establish specific policies guarding against potential negative outcomes related to conflicts of interest. At the pinnacle of the conflict-of-interest debate resides the patient. One of the most important effects of disclosure is providing patients with the opportunity to make informed decisions regarding their healthcare. Research supports that conflicts of interest are inherent and oftentimes unavoidable in the healthcare setting. PMID- 22834178 TI - Managing your online reputation. AB - Doctor review sites now populate the Internet. Such posts are often anonymous. Doctors cannot respond because of HIPAA. And the information rarely addresses matters such as patient safety and clinical outcomes. Nonetheless, a doctor's online reputation can positively or negatively impact a doctor's business. By following a number of rules, a doctor can proactively manage his or her reputation. PMID- 22834177 TI - What to do before the office for civil rights comes knocking: part I. AB - A comprehensive privacy and security program consists of written policies, standards, training, technical and procedure controls, risk assessment, auditing and monitoring, and the assignment of privacy- and compliance officers who are responsible for the management of the above. The privacy officer serves as the central person who is responsible for overall coordination of policies and procedures of the organization. Entities subject to HIPAA should also review their employee training programs, and determine whether it is time for updated training. The current privacy and security rules require covered entities to train workforce members as well as provide periodic security reminders. It is critical to sensitize employees to the potential consequences of improper uses or disclosures of PHI. As illustrated in this article, PHI must be handled with great care, and entities must respond to OCR inquiries adequately. Increased enforcement activity reemphasizes the need to take HIPAA compliance seriously. PMID- 22834179 TI - How outliers become superstars: what shadow coaches do. AB - Physicians who score low on patient satisfaction surveys usually don't know what they're doing (or not doing) to cause below-average ratings. Too often, the temporary improvement gained from books and seminars dissipates as providers return to overloaded schedules and variability in patient expectations. Shadow coaching has proved effective for motivated physicians seeking more patient visits, better risk management, and high marks on the payer metrics that will soon affect qualification for Accountable Care, Medical Home, and favorable reimbursement. PMID- 22834180 TI - The seven most common web site mistakes...and how to avoid them! PMID- 22834181 TI - Who's at the center of your universe? PMID- 22834182 TI - Financial Rx for physicians. AB - It's no secret that doctors are facing more financial struggles than ever before. Thanks to skyrocketing malpractice insurance premiums, slashed or stagnant reimbursement rates, and an aging population that will need more care, physicians across the country are struggling to stay financially solvent. This article outlines some simple steps that physicians can take to keep their personal and professional lives financially healthy. Not only will these suggestions help ease the difficulties of the present, but they will also help doctors plan for the future. PMID- 22834183 TI - Are you communicating what you want to say? AB - More than just words and gestures, communication is the basis of all relationships. Therefore, it is important to learn what effective communication is and how best to use it to get your message across. You want the recipient to hear you and know what you mean by what you are saying and to understand your gestures. PMID- 22834184 TI - Physician-hospital relationships: from historical failures to successful "new kids on the block". AB - Trends in healthcare reveal that increasing numbers of physicians prefer to work directly with hospitals-whether through employment models, new or revived partnership structures, or other such "deals". Meanwhile, hospital executives are vigorously seeking ways to create win-win arrangements that satisfy both parties models that will ensure medical coverage for the hospital, along with revenue gains and cost savings when possible. Add to this a competitive environment, physician shortages, and high regulatory activity and healthcare reform, and the path to clinical, operational, and financial viability in the context of a hospital/physician partnership can be a challenging one. Models such as The physician enterprise and co-management agreements are gaining popularity, each with distinct benefits. With market forces dynamically changing, along with accountable care, it is time for hospitals, health systems, and physicians to prioritize their partnering relationships, a strategy that is now key to achieving success in the future...and that's a trend that's likely to continue far into the years ahead. PMID- 22834185 TI - Use HCAHPS as a motivator to reenergize your five-star program, and make it personal. AB - For many reasons, HCAHPS, short for Hospital Consumer Assessment of Healthcare Providers and Systems, is quickly becoming the national standard on evaluating patient experience. This article shows the aligned incentives of hospitals and physicians to enhance patient perceptions of their care experience, provides an overview of the HCAHPS concept for physicians, and discusses using HCAHPS as an opportunity to further individual and group practice five-star goals. The current healthcare environment, with its focus on quality and outcomes and patient perception, provides an incentive for physicians and other healthcare professionals to make five-star service personal. PMID- 22834186 TI - The impact of scheduling policies on surgical clinical access. AB - We present a simulation model that features a single surgeon who splits his available time between a clinical office and surgery. Using a first-come, first served queuing discipline, the model allows us to investigate how clinical access responds to surgeons' time allocation policies, patients' office visit frequency, access priority rules, frequency of emergencies, surgery length, and other factors. We demonstrate through simulations that linear functions oversimplify how patients' wait times increase as demand approaches capacity. There is a critical access point at which loss of new patients occurs. Around the critical access point, patients' clinical access rises in a nonlinear fashion. This point defines the beginning of the collapse of the system. Clinical monitors of access such as third-available appointment lack the sensitivity to correctly identify the approach of the critical access point before it has been exceeded. PMID- 22834187 TI - Leverage technology to improve your revenue cycle. AB - Evaluating technology and implementing it effectively can produce major results to your bottom line. These technologies increase automation, which reduces errors and thus increases the clean claim percentage. New technology can enable the medical practice to reduce staff costs through increased productivity. Adding technology can offer medical practices new ways to run their business. Continue to learn about new technologies and the vendors and companies that offer them. Leverage technology in ways to get more money to the bottom line! PMID- 22834188 TI - Understanding your role with patients: the big picture. AB - Medical practice employees can become so engrossed in their daily administrative and clinical duties that they risk losing sight of their larger purposes and functions in the practice. Chief among these is their role with patients. It's important for every medical practice employee to remember the big picture and the vital role each member of the team plays. This article helps medical practice employees take a step back and see the medical practice landscape from a much larger and broader perspective. It explores the particular roles each member of the team plays with patients, including those who serve as the first point of contact on the phone and in person. It further explores staff roles during appointments, after appointments, and later on the telephone for administrative or clinical follow-up with patients. This article uses imaginative analogies to help medical practice employees understand and define their roles in new ways, such as that of practice host, tour guide, grand finale, and troubleshooter. Finally, this article offers 10 additional strategies to help medical practice employees further define and embrace their roles as they relate to patients. PMID- 22834189 TI - The ACO paradox impacting physicians. AB - Accountable care organizations (ACOs) would hold care providers jointly accountable for the quality and costs of care, allow consumers the freedom to choose their providers, and involve physicians and consumers in their shared decision-making. Even though the ACO model proposes physician empowerment, it also poses significant financial and change-management challenges for physicians. Furthermore, the "patient-centered" ACOs that have been established to safeguard consumer sovereignty pose the risks of concentrating healthcare markets further and exacerbating the existing disparities in healthcare. We conducted a survey study to understand physicians' perspectives of ACOs by seeking their first-hand feedback. The survey results suggest that there are significant communication gaps between physicians and healthcare administrators; and efficient communication can help improve physician-administrator alignment and help them identify opportunities that would be critical to the success of ACOs. PMID- 22834190 TI - Marketing metrics for medical practices. AB - There's a saying by John Wanamaker who pontificated, "Half the money I spend on advertising is wasted; the trouble is, I don't know which half". Today you have opportunities to determine which parts of your marketing efforts are effective and what is wasted. However, you have to measure your marketing results. This article will discuss marketing metrics and how to use them to get the best bang for your marketing buck. PMID- 22834191 TI - ICD-10-CM diagnosis coding (October 1, 2014). PMID- 22834192 TI - Oral delivery of nucleic acid-based therapeutics. PMID- 22834193 TI - Modeling and mechanistic approaches for oral absorption: quality by design in action. PMID- 22834194 TI - AUS-CRS 2011: 5th Annual Meeting of the Australian Chapter of the Controlled Release Society. AB - AUS-CRS 2011, the 5th Annual Meeting of the Australian Chapter of the Controlled Release Society was held as a satellite meeting to the Australian Peptide Conference at Hamilton Island, Queensland, Australia in October 2011. The conference provides a forum for showcasing a range of research towards improving drug delivery across Australia and New Zealand, with international visitors from beyond also participating, this year from the UK and Sweden. This year's meeting had an emphasis on peptide and protein delivery because of its association with the Australian Peptide Conference, although invited and contributed talks from a range of other fields of delivery research were also presented with excellent talks on lipid-based drug delivery, pulmonary delivery, anticancer drug delivery and drug development from a range of academic and industry speakers. PMID- 22834195 TI - Nitroxide radicals and nanoparticles: a partnership for nanomedicine radical delivery. AB - This article aims to provide a research update on nitroxide radical compounds for application of anti-oxidative stress therapy. Nitroxide compounds such as 2,2,6,6 tetramethylpyperidine-1-oxyl (TEMPO) can catalytically react with reactive oxygen species (ROS) and are anticipated as new anti-oxidant therapies for several diseases. However, low-molecular-weight nitroxide compounds pose several problems such as nonspecific dispersion in normal tissues, preferential renal clearance and rapid reduction of the nitroxide radical to the corresponding hydroxylamine. Nitroxide radical compounds are also known to show dose-related antihypertensive action accompanied by reflex tachycardia, increased skin temperature, and seizures. The author has recently designed novel nanoparticles, which possess nitroxide radicals in the core for novel bioimaging and nanotherapy. Nitroxide radical-containing nanoparticles (RNP) shows high safety, long blood circulation, magnetic resonance imaging and ESR imaging sensitive character and efficient therapeutic effects to several diseases such as cerebral and renal ischemia reperfusions, ulcerative colitis and Alzheimer's disease models. RNPs are, thus, promising as new nanotherapeutic materials. PMID- 22834197 TI - Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective. AB - Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery. PMID- 22834196 TI - The shape of things to come: importance of design in nanotechnology for drug delivery. AB - The design of nanoparticle (NP) size, shape and surface chemistry has a significant impact on their performance. While the influences of the particle size and surface chemistry on drug delivery have been studied extensively, little is known about the effect of particle shapes on nanomedicine. In this perspective article, we discuss recent progress on the design and fabrication of NPs of various shapes and their unique delivery properties. The shapes of these drug carriers play an important role in therapeutic delivery processes, such as particle adhesion, distribution and cell internalization. We envision that stimuli-responsive NPs, which actively change their shapes and other properties, might pave way to the next generation of nanomedicine. PMID- 22834198 TI - Modification of the release characteristics of estradiol encapsulated in PLGA particles via surface coating. AB - BACKGROUND: Drug-loaded poly(lactide-co-glycolide) particles (100-4500 nm in diameter) were prepared via the electrospraying method. An extensive study was then carried out to determine the parameters affecting the release profile of estradiol (the drug or active pharmaceutical ingredient) in order to facilitate minimum initial burst release of estradiol. RESULTS AND DISCUSSION: The three most important factors affecting estradiol release were identified as: particle size, coating of the particles with chitosan/gelatin and the concentration of the coating agent. It was shown that coating the particles with chitosan significantly reduced the burst and initial release without affecting the subsequent release profile. CONCLUSIONS: This work demonstrates a powerful method of generating drug-loaded polymeric particles with modified release behavior and control over the initial release phase. The surface-modified particles may be useful in controlled therapeutic delivery systems to minimize undesirable side effects. PMID- 22834199 TI - Cancer stem cell targeting: the next generation of cancer therapy and molecular imaging. AB - Cancer stem cells (CSCs) have the capacity to generate the heterogeneous lineages of all cancer cells comprising a tumor and these populations of cells are likely to be more relevant in determining prognosis. However, these cells do not operate in isolation, but instead rely upon signals co-opted from their microenvironment, making the targeting and imaging of CSCs within a cancer mass a daunting task. A better understanding of the molecular cell biology underlying CSC pathology will facilitate the development of new therapeutic targets and novel strategies for the successful eradication of cancer. In addition, the continued investigation of sensitive molecular-imaging modalities will enable more accurate staging, treatment planning and the ability to monitor the effectiveness of CSC-targeted therapies in vivo. In this review, we explore the possibilities and limitations of CSC-directed therapies and molecular imaging modalities. PMID- 22834200 TI - Delivery and biodistribution of siRNA for cancer therapy: challenges and future prospects. AB - RNAi-based approaches provide a promising therapeutic modality for the treatment of cancer. The inaccessibility of tumors in different cancer types necessitates the development of safe, specific and efficient systemic delivery systems to meet therapeutic need. The translation of siRNA-based cancer therapeutics to the clinic is hindered by several challenges associated with the cargo (siRNA) and the delivery system, including susceptibility to nucleases; insufficient circulation half-life due to phagocytosis by the reticuloendothelial system, transient and poor biodistribution in the tumor tissue; cellular uptake; inability to escape endosomes and release into the cytosolic compartment for an RNAi-mediated effect; microRNA-like unintended off-target effects; undesirable immune stimulation; and carrier-related toxicity. This review provides an overview of the pharmacokinetic and biodistribution challenges witnessed in the delivery of siRNA when administered systemically. It also describes the current delivery approaches using liposome-, polymer- and peptide-based delivery systems shown to elicit significant gene silencing and tumor growth regression in proof of-concept studies. As part of future perspectives, delivery agents that showed significant efficacy in preclinical rodent models and clinical trials are also reviewed. PMID- 22834203 TI - A virtual roundtable. Providers in the spotlight hold a frank discussion on the state of the profession today. PMID- 22834201 TI - Targeted interception of signaling reactive oxygen species in the vascular endothelium. AB - Reactive oxygen species (ROS) are implicated as injurious and as signaling agents in human maladies including inflammation, hyperoxia, ischemia-reperfusion and acute lung injury. ROS produced by the endothelium play an important role in vascular pathology. They quench, for example, nitric oxide, and mediate pro inflammatory signaling. Antioxidant interventions targeted for the vascular endothelium may help to control these mechanisms. Animal studies have demonstrated superiority of targeting ROS-quenching enzymes catalase and superoxide dismutase to endothelial cells over nontargeted formulations. A diverse arsenal of targeted antioxidant formulations devised in the last decade shows promising results for specific quenching of endothelial ROS. In addition to alleviation of toxic effects of excessive ROS, these targeted interventions suppress pro-inflammatory mechanisms, including endothelial cytokine activation and barrier disruption. These interventions may prove useful in experimental biomedicine and, perhaps, in translational medicine. PMID- 22834205 TI - Leadership strategies stick. PMID- 22834204 TI - The MDS 3.0 and its impact on bladder and bowel care. PMID- 22834202 TI - Use of lectin-functionalized particles for oral immunotherapy. AB - Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses. PMID- 22834206 TI - [The risk of cardiovascular disease in the Swedish population is decreasing. Still better control of risk factors is needed--especially in certain risk groups]. PMID- 22834207 TI - [The pandemic A/H1N1 in 2009 milder than regular seasonal influenza. Report from Uppsala County]. PMID- 22834208 TI - [Risk-adjusted mortality in intensive care. Self-analysis is needed to draw the right conclusions from the national registry]. PMID- 22834209 TI - [Guidelines for primary cardiovascular prevention are not being observed in clinical practice. EURIKA study shows European shortcomings]. PMID- 22834210 TI - [Integrated teaching of ethics of value in the medical education]. PMID- 22834211 TI - [Treatment of status epilepticus]. PMID- 22834212 TI - [Typical symptoms for tularemia without a typical medical history]. PMID- 22834213 TI - [The optic chiasm in the light of a new hand-eye hypothesis]. PMID- 22834214 TI - On the repair of the dentine barrier. AB - The overall aim of this thesis was to study some aspects of the repair of the dentine barrier, especially in conjunction with dental pulp capping. Understanding the events leading to the healing of the dentine and pulp, and hence successfully preserving the vitality and functions of the tooth, would lead to a scientific basis for a less invasive treatment of pulp exposures than performing root canal treatments. The surfaces of the body have physiological barrier functions aimed at protecting the body from external noxious agents. In the tooth, the odontoblasts, which line the outermost part of the pulp and are responsible for the formation of dentine, play a central role in the barrier function and thus in the defence mechanisms of the tooth. The micro-organisms in the caries lesion can reach the pulp via the dentinal tubules. However, the barrier function helps to prevent microbial invasion and thereby avoid deleterious inflammation and subsequent necrosis of the pulp. Dentine repair is an important part of the barrier function. There are however doubts as to whether the repair also leads to restitution of the function and the ability to withstand bacterial influx over the longer term. Pulp capping is a treatment method used when the pulp has been exposed in order to stimulate healing of the pulp and dentine. The evidence for repair of the dentine after pulp capping in humans has been studied by means of a systematic review. The focus of the literature search was studies performed in humans where hard tissue formation had been studied with the aid of a microscope. We concluded, based on the limited evidence available, that calcium hydroxide based materials but not bonding agents promote formation of a hard tissue bridge. Scientific evidence was lacking as to whether MTA was better than calcium hydroxide based materials in this regard. A gel (Emdogain Gel) containing amelogenin, known to be involved in dentinogenesis, was evaluated with regard to formation of hard tissue in a clinical study. A greater amount of hard tissue was formed after application of the gel compared to the control. Characterization of the tissue concluded it to be dentine, based on its content of type 1 collagen and dentine sialoprotein, although it was not formed as a continuous bridge covering the pulp wound. Beneath a deep caries lesion an important part of the barrier function is the odontoblasts' response to bacteria with the formation of new dentine. A cell model with odontoblasts was used to study the effects of clinical isolates from a deep carious lesion on their viability and production of type 1 collagen, the major component of the dentine in the early stages of its formation. There were bacteria that negatively affected the viability of the odontoblast-like cells and different bacteria varied in their effects on type 1 collagen production, suggesting that some bacteria may have a direct influence on the odontoblasts' ability to form dentine. In summary; Emdogain Gel initiated dentine formation, though not in a form that could constitute a barrier and there are indications that bacteria may differentially affect the odontoblasts' ability to repair the dentine barrier. PMID- 22834215 TI - Dentofacial morphology in Turner syndrome karyotypes. AB - The overall aim of this thesis was to study dentofacial morphology in Turner syndrome (TS) versus controls and the influence hereupon from karyotype. One hundred thirty two TS females (5-66 years of age), from Goteborg, Uppsala and Umea were participating. Cephalometric analysis, cast model analysis concerning palatal height, dental arch morphology and dental crown width were performed. Eighteen primary teeth were analysed in polarized light microscopy, scanning electron microscopy, microradiography and X-ray microanalysis were performed. The TS females were divided according to karyotype into: 1 45,X; 2 45,X/46,XX; 3 isochromosome; 4 other. Compared to healthy females, TS were found to have a flattened cranial base as well as small and retrognathic jaws with a posterior inclination. The maxillary dentoalveolar arch was narrower and longer, while the mandibular dental arch was wider and longer in TS compared to controls. The palatal height did not differ comparing TS and healthy females. The dental crown width was smaller in TS for both permanent and primary teeth. Aberrant elemental composition, prism pattern and lower mineral density were found in TS primary enamel compared to enamel in primary teeth from healthy girls. Turner syndrome karyotype was found having an impact on craniofacial morphology, with the mosaic 45,X/46,XX exhibiting a milder mandibular retrognathism as well as fewer cephalometric variables differing from controls compared to other karyotypes. Also for the dentoalveolar arch morphology the 45,X/46,XX group had fewer variables differing from healthy females. The isochromosome TS group exhibited the smallest dental crown width for several teeth, while 45,X/46,XX hade the largest dental crown with for some teeth and fewer teeth than both 45,X and isochromosomes that differed from controls. Thus, the mosaic 45,X/46,XX seemed to exhibit a milder phenotype, possibly due to presence of healthy 46,XX cell lines. PMID- 22834216 TI - Biosorption of lead(II) in aqueous solution by spent mushroom Tricholoma lobayense. AB - The biosorption of lead(II) ions in both simulated and real wastewater by spent mushroom Tricholoma lobayense, was studied in this work. The results show a biomass with a high potential for removing lead ions from wastewater. The optimum pH for the adsorption is 4, and the adsorption process is fast. The best sorbent mass of the biomaterial is 5 g/L with an initial lead(II) concentration of 1 mmol/L. The process follows the Langmuir isotherm model, and the biosorption capacity of lead ions reaches to 210 mg/g, which is higher than many biosorbents previously studied. The mechanism of biosorption may be mainly attributed to ion exchange. The FT-IR study identifies the functional groups responsible for this process. A scanning electron microscope showed a significant change of the sorbent surface after the biosorption process. The energy dispersive elemental analysis also confirmed the adsorption of lead(II) ions. PMID- 22834217 TI - Optimization of circular plate separators with cross flow for removal of oil droplets and solid particles. AB - A circular gravity-phase separator using coalescing medium with cross flow was developed to remove oil and suspended solids from wastewaters. Coalescence medium in the form of inclined plates promotes rising of oil droplets through coalescence and settling of solid particles through coagulation. It exhibits 22.67% higher removal of total suspended solids (TSS) compared to separators without coalescing medium. Moreover, it removed more than 70% of oil compared to conventional American Petroleum Institute separators, which exhibit an average of 33% oil removal. The flowrate required to attain an effluent oil concentration of 10 mg/L (Q(o10)) at different influent oil concentrations (C(io)) can be represented by Q(o10) x 10(-5) = -0.0012C(io) + 0.352. The flowrate required to attain an effluent TSS concentration of 50 mg/L (Q(ss50)) at different influent TSS concentrations (C(iss)) can be represented by Q(ss50) x 10(-5) = 1.0 x 10(6) C(iss)(-2.9576). The smallest removable solid particle size was 4.87 microm. PMID- 22834218 TI - Contrast of volatile fatty acid driven and inorganic acid or base driven phosphorus release and uptake in enhanced biological phosphorus removal. AB - Addition of an inorganic acid or base was detrimental to net phosphorus removals in short-term batch experiments, suggesting there might be system upset when pH changes. In contrast, addition of volatile fatty acids (VFAs) increased anaerobic phosphorus release and aerobic phosphorus uptake while maintaining or improving net phosphorus removals. The effect of pH change differed if the acid or base added was inorganic versus organic. Volatile fatty acids that resulted in poly-3 hydroxy-butyrate rather than poly-3-hydroxy-valerate resulted in greater net phosphorus removals, and this corresponded to differences in consumption of reducing equivalents. Acetic acid resulted in improved net phosphorus removal compared to sodium acetate, suggesting that acid forms of VFAs might be superior as supplemental VFAs. It is hypothesized that anaerobic phosphorus release following addition of inorganic acid is primarily a result of phosphorus and proton (H+) symport (excretion from the cell) for pH homeostasis, whereas addition of VFAs results in phosphorus and H+ release to maintain the proton motive force. PMID- 22834219 TI - Phosphorus recovery from wastewater--expert survey on present use and future potential. AB - Today, a variety of different approaches to the recovery of phosphorus from wastewater, sludge, and sludge ash exist. These approaches differ basically by the origin of the used matter (wastewater, sludge liquor, fermented or nonfermented sludge ash) and the process (precipitation, wet-chemical extraction, and thermal treatment). To rate them according to their characteristics, the latter were phrased as hypotheses and subjected to an international expert survey. The survey showed that phosphorus recovery is expected to become an established process over the next 20 years in industrialized countries for economic reasons. A decisive aspect in this regard will be the quality of the produced fertilizer. Simple technologies such as the recovery from sludge liquor seem to be preferred. If sludge is incinerated, phosphorus recycling from ash then becomes more interesting and has to be considered. Phosphorus recovery and source-separating sanitation technologies are more appropriate for industrialized countries than for developing countries. Because the growing awareness of environmental issues will prevent sludge from being used agriculturally in an increasing number of countries in the next decade, the market potential for nutrient recovery technologies will increase in the immediate future. PMID- 22834220 TI - The removal of reactive black 5 from aqueous solutions by cotton seed shell. AB - This study investigated the removal of Reactive Black 5 (RB5) textile dye from aqueous solutions using cotton (Gossypium hirsutum) seed shell (CSS) as low cost adsorbents. The data were described according to the Freundlich and Langmuir isotherm models. Of these, the Langmuir model provided the best fit for the experimental data. The highest measured adsorption density was 12.19 mg/g at pH 2. An equilibrium adsorption rate of RB5 by CSS (q(e) = 11.879 mg/g) was observed at 30 minutes. In order to evaluate the adsorption kinetic mechanisms, pseudo first and second order rate kinetic models and an intraparticle diffusion model were applied, with the pseudo second order model providing an excellent fit for the data. PMID- 22834222 TI - Healthcare facility effluents as point sources of select pharmaceuticals to municipal wastewater. AB - Effluents from four healthcare facilities were characterized for the concentration of 16 common active pharmaceutical ingredients. The sampled facilities included a hospital, nursing care, assisted living, and independent living facility located within a single municipal wastewater system in Texas. Eleven of the 16 monitored pharmaceuticals were detected in at least 1 healthcare facility effluent and 2 measured antibiotics (sulfamethoxazole and trimethoprim) were detected in all 4 facility effluents. Active pharmaceutical ingredient concentrations ranged from non-detectable levels for several corticosteroids in all facility effluents to 180 microg/L sulfamethoxazole in the nursing care wastewater effluent. The mass of active pharmaceutical ingredients discharged to the municipality's wastewater conveyance system was determined by combining individual facility concentration data and daily wastewater flow. The estimated daily mass loading of all 16 pharmaceuticals ranged from 0.16 g/day to 23 g/day in the assisted living facility and nursing wastewater effluents, respectively. The combined active pharmaceutical ingredient mass loading for all four facilities was 42.6 g/day. These findings provide source characterization data for 16 common pharmaceuticals in healthcare facility wastewater and provide a basis for risk assessment of pharmaceuticals present in healthcare facility wastewaters. PMID- 22834221 TI - Effects of long exposure to low temperatures on nitrifying biofilm and biomass in wastewater treatment. AB - Attached growth biological treatment systems are a promising solution to ammonia removal in cold-temperature climates. Environmental scanning electron microscopy (ESEM) and confocal laser scanning microscopy in combination with fluorescent in situ hybridization (FISH) was used to investigate the effects of 4 months of exposure to 4 degrees C on nitrifying biofilm and biomass. These molecular and microscopic methods were modified to minimize loss of mass and distortion of in situ perspectives. Environmental scanning electron microscopy revealed that nitrifying biofilm did not exhibit significant changes in volume with exposure to 4 degrees C. Confocal laser scanning microscopy in combination with FISH showed that the number of ammonia-oxidizing bacteria (AOB) cells present in the biofilm was statistically consistent during exposure to 4 degrees C. The RNA content of AOB cells remained sufficient for FISH enumeration. The number of nitrite oxidizing bacteria cells remained steady during exposure to 4 degrees C; however, the RNA content of the cells appeared to decrease with exposure to 4 degrees C, thereby preventing their enumeration using FISH. PMID- 22834223 TI - Microbiological and performance evaluation of sequencing batch reactor for textile wastewater treatment. AB - This study focused on laboratory-scaled and real-scaled treatment plant performances and microbiological investigations for the optimum treatment of textile industry wastewater performed with sequencing batch reactor (SBR). As a result of experimental studies of laboratory-scaled SBR treatment unit, optimum treatment efficiency was taken from 0.5 h filling to 1.5 h. reaction to 1.5 h. settlement to 0.5 h. discharge-idle periods. Average chemical oxygen demand (COD) removal efficiency of SBR of laboratory-scaled textile industry was 75%, whereas average turbidity and color removal (coloration number [RES, m(-1)] 586 nm) efficiencies were 90% and 75%, respectively. Optimum reaction and settlement periods were used in a real-scaled plant, and plant efficiency was examined for parameters such as COD, phenol, pH, mixed liquor suspended solids (MLSS) and sludge volume index (SVI). In this study, optimum reaction and settlement periods for treatment of textile industry wastewater were determined within a SBR in a laboratory-scaled plant. These reaction and settlement periods were verified with the measurement of COD, color, and turbidity parameters. Floc structure and protozoa-metazoa species of activated sludge in a SBR were also determined. Optimum reaction and settlement times were used in a real-scaled plant, and plant efficiency was examined for COD, Phenol, pH, MLSS, and SVI parameters. The corresponding values were found as appropriate, acceptable, and meaningful because of variance value of statistical analysis. Protozoa and metazoan in the activated sludge in the laboratory-scaled plant were investigated. Peranema sp., Epistylis sp., Didinium sp., Chilodonella sp., Opercularia sp., Vorticella sp. as protozoa species and Habrotrocha sp., Philodina sp. as metazoa species were determined. PMID- 22834224 TI - Process performance and polyphosphate-accumulating organism-glycogen-accumulating organism communities in an anaerobic/anoxic/oxic system operated with different carbon sources. AB - A pilot plant anaerobic/anoxic/oxic (A2/O) system fed with domestic wastewater was operated to examine the effect of varying different types of carbon source (acetic acid, propionic acid, and glucose), added as a complement to the wastewater, on the (1) process performance and (2) microbial population. The operational condition that lead to a significant removal of total nitrogen (82%) was achieved with acetic acid. When the complementary carbon source was propionic acid, an improved removal efficiency of orthophosphate (97%) was observed. Because this finding was concurrent with higher polyphosphate-accumulating organism (PAO) population fractions detected using fluorescent in situ hybridization analysis (41.9 +/- 3.0%), it suggests that members of PAO populations that were able to reduce nitrate gained importance over PAO members that could not, thus improving the denitrifying phosphorus removal. PMID- 22834225 TI - An assessment of the feasibility of employing biochemical acidogenic potential tests for characterizing anaerobic biodegradability of raw and pretreated waste activated sludge. AB - The potential to use the results of biochemical acid potential (BAP) tests to predict the ultimate digestibility of raw and pretreated waste activated sludge (WAS) was investigated. The ultimate methane production from biochemical methane potential (BMP) tests on raw and pretreated samples which spanned a range of biodegradability proved linearly related to the volatile fatty acid (VFA) and soluble chemical oxygen demand (COD) production in corresponding BAP tests. In addition, a linear relationship between NH4-N production in the BMP and BAP tests was observed. Despite the linear nature of the relationships, the ratio of the production of methane in the BMP tests to the production of VFAs in the BAP tests varied with the biodegradability of the sludge samples. Waste Activated Sludge samples with low digestibility had ultimate yields of CH4 that were greater than the VFA yields in BAP tests, whereas sludge samples with high digestibility had lower yields of CH4 than the corresponding VFA yields. This trend contrasted with the NH4 results, in which the yields in the BAP tests were consistently less than those observed in the BMP tests. It was hypothesized that the varying relationship between CH4 and VFA yields was because of the inhibition of anaerobic oxidation of long-chain fatty acids (LCFAs) in the BAP tests. Long chain fatty acids would be converted to CH4 in BMP tests but produced as digestion intermediates in the BAP tests and were not measured as part of the VFA yield. Hydrogen and acetate were identified as the two most likely intermediates that would accumulate in the BAP tests (which would cause inhibition). A stoichiometric model to facilitate the development of an improved understanding of the biodegradation processes in the BAP and BMP tests was assembled. When the model was applied to the BAP tests the anaerobic oxidation of LCFAs and propionate and methanogenesis were excluded from the model. The model was employed to estimate the extent of degradation of lipids, carbohydrates, and proteins in the batch tests as a function of the ultimate biodegradability of the sludge samples. On the basis of model fitting, it was determined that the degradation of lipids in BMP tests decreased, whereas the degradation of carbohydrates and proteins increased as the digestibility of the sludge samples increased. The varying ratio of lipid to protein and carbohydrate degradability with increasing digestibility of the sludge samples describes the relationship between VFA production and CH4 production in the BAP, and BMP tests, respectively. PMID- 22834226 TI - Trace metal accumulation in sediments and benthic macroinvertebrates before and after maintenance of a constructed wetland. AB - Stormwater best management practices (BMPs) require regular maintenance. The impact on trace metal concentrations in a constructed stormwater wetland BMP on Staten Island, New York, was investigated by analyzing sediment concentrations and tissue residues of the dominant macroinvertebrates (Tubifex tubifex) prior and subsequent to maintenance. Trace metal concentrations were assessed using standard serial extraction (for sediment) and acid digestion (for tissue burdens) techniques, followed by quantitative determination using graphite furnace atomic absorption spectrometry and inductively coupled plasma optical emission spectrometry, respectively. The results suggest that disturbance of sediment during maintenance of the BMP resulted in an increase in the most mobile fraction of trace metals, especially those associated with finer grained sediments (< 63 tm), and as a consequence, measured metal concentrations in macroinvertebrates increased. Regressions of a subset of metal concentrations (copper, lead, and zinc) in sediment and the macroinvertebrate tissue burden samples generally increased as a result of maintenance. A follow-up sampling event 9 months after maintenance demonstrated that the most readily available form of trace metal in the BMP was reduced, which supports (1) long-term sequestration of metals in the BMP and (2) that elevated bioavailability following maintenance was potentially a transient feature of the disturbance. This study suggests that in the long-term, performing sediment removal might help reduce bioavailability of trace metal concentrations in both the BMP and the receiving water to which a BMP discharges. However, alternative practices might need to be implemented to reduce trace metal bioavailability in the short-term. PMID- 22834227 TI - Of: Influence of variable precipitation on coastal water quality in southern California, R. H. Dwight, J. S. Caplan, M. V. Brinks, S. N. Catlin, G. Buescher, J. C. Semenza, 83, 2121-2130 (2011). PMID- 22834228 TI - Summary health statistics for U.S. adults: National Health Interview Survey, 2010. AB - OBJECTIVES: This report presents health statistics from the 2010 National Health Interview Survey (NHIS) for the civilian noninstitutionalized adult population, classified by sex, age, race and Hispanic origin, education, family income, poverty status, health insurance coverage, marital status, and place and region of residence. Estimates are presented for selected chronic conditions and mental health characteristics, functional limitations, health status, health behaviors, health care access and utilization, and human immunodeficiency virus testing. Percentages and percent distributions are presented in both age-adjusted and unadjusted versions. DATA SOURCE: NHIS is a household, multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics. In 2010, data were collected on 27,157 adults in the Sample Adult questionnaire. The conditional response rate was 77.3%, and the final response rate was 60.8%. The health information for adults in this report was obtained from one randomly selected adult per family. In very rare instances where the sample adult was not able to respond for himself or herself, a proxy was used. HIGHLIGHTS: In 2010, 61% of adults aged 18 years and over had excellent or very good health. Twelve percent of adults had been told by a doctor or health professional that they had heart disease, 25% had been told on two or more visits that they had hypertension, 9% had been told they had diabetes, and 22% had been told they had some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia. Twenty-one percent of adults were current smokers, and 21% were former smokers. Based on estimates of body mass index, 35% of adults were overweight and 27% were obese. PMID- 22834229 TI - Design and operation of the National Survey of Children's Health, 2007. AB - OBJECTIVES: This report presents the development, plan, and operation of the 2007 National Survey of Children's Health, a module of the State and Local Area Integrated Telephone Survey, conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics. This survey was designed to produce national and state-specific prevalence estimates for a variety of physical, emotional, and behavioral health indicators and measures of children's experiences with the health care system. The survey also includes questions about the family (for example, parents' health status, stress and coping behaviors, family activities) and about respondents' perceptions of the neighborhoods where their children live. Funding and direction for this survey was provided by the Maternal and Child Health Bureau of the Health Resources and Services Administration. METHODS: A random-digit-dialed sample of households with children under age 18 years was selected from each of the 50 states and the District of Columbia. One child was randomly selected from all children in each identified household to be the subject of the survey. The respondent was a parent or guardian who knew about the child's health and health care. RESULTS: A total of 91,642 interviews were completed from April 2007 to July 2008. Nearly 80% of the interviews were completed in 2007. Interviews were completed in 66.0% of identified households with children. The weighted overall response rate was 46.7%. A data file has been released that contains demographic information on the selected child, substantive health and well-being data for the child and his or her family, and sampling weights. Estimates based on the sampling weights generalize to the noninstitutionalized population of children in each state and nationwide. PMID- 22834230 TI - [Radio-induced maculopathy]. AB - Macula was examined using fundus photo and OCT in 115 patients with choroidal melanoma located distant from macula before and after brachytherapy. Macular changes were revealed in 24,35% of irradiated eyes. Nevertheless primary radiation-induced maculopathy after ruthenium plaque radiotherapy occurred in 9,59% only. In the rest of cases (10,43%) macular changes were present before brachytherapy. The causes of their development were choroidal melanoma (tumor associated maculopathy) and AMD. PMID- 22834231 TI - [The first experience of using OCT in diagnosis of primary and residual retinoblastoma]. AB - 21 children with retinoblastoma (32 eyes, 36 lesions) were examined using optical coherence tomography (OCT). Pathognomonic features of initial primary exophytic, endophytic and mixed retinoblastoma were revealed OCT-control allowed to estimate combined treatment efficacy (chemotherapy, brachytherapy, transpupillary thermotherapy) and to reveal signs of latent growth. Thus revealed OCT signs of primary, residual retinoblastoma, retinal scar, zones of latent growth allow early estimation of appropriateness of combined eye-preserving treatment. PMID- 22834232 TI - [Ultrasound biomicroscopy in diagnosis of uveal tumors]. AB - Detailed analysis of ultrasound biomicroscopy (UBM) scanogrammes of 232 patients (232 eyes), aged 4-78 years old, with various uveal lesions was performed including comparison with morphologic study of specimens obtained after tumor removal. Results of the study showed UBM to allow to obtain objective data on location, configuration, size and structure of lesions of iris, ciliary body and preequatorial choroid. In a number of cases UBM virtually is the only option of vital visualization of the whole tumor. PMID- 22834233 TI - [Potentials of 3D-modeling in reconstructive orbital surgery]. AB - A technique of bone reconstructive surgery of orbitofrontonasomalar region using 3D-modeling based on multispiral computer tomography data is presented. The efficacy of intraoperative templates created using 3D-modeling was showed for harvesting and modeling of bone calvarial autografts. The steps of reconstructive procedure are explained in details for repair of medial and inferior orbital fractures. PMID- 22834234 TI - [Comparative experimental study of current implant materials used in orbital surgery]. AB - Reconstructive orbital procedures are often associated with the use of different implant materials, that may sometimes cause complications resulting in surgery efficacy impairing and need of reoperation. At the present time in Russia and abroad various orbital implants are used though there are no experimental or clinical studies comparing implant materials used In this study comparative experimental morphological investigation of biointegrative characteristics of 6 current orbital implant materials was performed, tissue reactions in response to implantation is described in details in laboratory animals, recommendations for implant use in clinic are given. PMID- 22834235 TI - [Accomodation tonus in myopia and its potential prognostic value]. AB - 60 patients with different degree of myopia were examined to study habitual accomodation tonus (HAT) and accomodation rest tonus (ART). HAT was calculated as a difference between standard autorefratometer measurements before and after cycloplegia; HAT in open field (HAT-OF) was estimated using open-field autorefractometer before and after cycloplegia with a patient looking at the distant object; ART was considered as a difference between refraction in dark conditions (dark focus) and cycloplegic refraction using open-field autorefractometer Grand Seiko WR-5100K (Japan). In examined patients ART was maximal (-0,87 +/- 0,08 dpt) and HAT-OF-minimal (-0,15 +/- 0,04 dpt). The high values of accomodation tonus (both HAT and ART) were associated with higher rates of myopia progressing. For the first time dynamic refraction measured using open field autorefractometer confirmed the phenomenon of "negative" accomodation. PMID- 22834236 TI - [Nitric oxide metabolites concentration in tear fluid and its prognostic value in development of early inflammatory reactions after consecutive intraocular surgery]. AB - Dynamics of NOx concentration in tear fluid is studied before and different time after consecutive operations in various postoperative courses. Preoperative deviation of this parameters by 25-30% of control group was showed to be a risk factor of complicated postoperative course. It may be considered a prognostic criterion of early postoperative inflammatory reactions. PMID- 22834237 TI - [Ocular hemodynamic in patients with diabetic retinopathy according to ultrasound dopplerography data]. AB - Hemodynamic indices were estimated in ophthalmic artery, central retinal artery and short posterior ciliary artery using ultrasound dopplerography in patients with diabetic retinopathy receiving "Piyavit'". "Piyavit" improves hemodynamic indices in this patient group resulting in increasing of visual functions and reduction of macula edema height. PMID- 22834238 TI - [Intracapsular ring in cataract surgery in lens subluxation (15 years exrerience)]. AB - Based on literature and own experience recommendations for intracapsular ring use in cataract surgery in patients with different types of suspensory ligament deficiency were given. Operation technique and prevention of complications during ring implantation with or without retractors in different etiology of subluxation and individual degree of suspensory ligament deficiency were described for every principal step of phacoemulsification. PMID- 22834240 TI - [What is essential to know to confirm or exclude diagnosis of normal tension glaucoma?]. PMID- 22834239 TI - [The levels of neuron specific enolase and autoantibodies to it in lacrimal and intraocular fluids in patients with open-angle glaucoma (preliminary report)]. AB - The concentration of neuron specific enolase (NSE) and autoantibodies (aAB) to it were studied in lacrimal and intraocular fluids in 9 patients with open-angle glaucoma (OAG) and 17 patients without this condition using ELISA. NSE concentration in lacrimalfluid of patients with OAG was showed to be 22 times as high and aAB 2 times as high as in control group. PMID- 22834241 TI - [Conservative treatment of amblyopia]. AB - Methods of conservative treatment of amblyopia are presented in the review. The paper includes information about pleoptics, physiotherapy, pharmacotherapy and examples of combined treatment of the amblyopic eye. Analysis of literature shows that this problem is an issue of concern and further research is needed. PMID- 22834242 TI - [Small retinoblastoma: early diagnosis and combined eye-preserving treatment]. AB - The presented review devoted to early diagnosis and combined eye-preserving treatment of small retinoblastoma emphasizes significance of using optical coherence tomography and transpupillary thermotherapy in malignant retinal tumors along with other options. PMID- 22834243 TI - [Eye blood flow and its changes in patients with diabetes mellitus]. AB - The main characteristics of retinal blood flow are presented including vessel diameter blood velocity, blood flow, perfusion pressure, indices of vasoresistance. The main methods of eye blood flow and retinal circulation examination are described. Comparative estimation of different techniques for eye haemodynamics examination in patients with diabetes mellitus is presented. The impact of autoregulation on blood flow changes is discussed. PMID- 22834244 TI - How hospitals can maximize revenue from their physician networks. PMID- 22834245 TI - Measuring your technical and clinical denial rates. PMID- 22834246 TI - Payer-provider collaboration reduces denials. PMID- 22834247 TI - [Mandatory vaccination and health's right: the value of case law in the public health practice in Italy]. AB - In Italy there have been several court appeals registered, which have been driven by individual convictions or group actions or movements and were aimed at obtaining exemption from the obligation to comply with compulsory vaccinations required by law. The aim of the present paper is to provide a quick review of the sentences resulting from activating these disputes, in order to contribute to the debate on overturning compulsory vaccination. The Jurisprudence of the Italian Constitutional Court has repeatedly confirmed the judgment on the constitutionality of rules on obligation, clarifying that only where specific reasons exist that make vaccinating the individual dangerous may non-compliance with the rules on compulsory vaccination be justified. This is in contrast with the case law on enforcement of compulsory vaccination, through the temporary suspension of parental authority. Taking responsibility for promoting immunisation decisions away from Public Health Services and handing it to the courtroom is not advisable, given the very small benefit. The problem must be placed under the careful attention of the Health Service due to communicative implications, which can be serious during the transition from a compulsory system of immunisation to a voluntary one. PMID- 22834248 TI - [Hospital clinical records accuracy in traceability of healthcare associated infections]. AB - We conducted a retrospective analysis on health care records in order to validate its accuracy in the reporting of healthcare associated infections (HAIs) for the purpose of supporting epidemiological surveillance and nursing-sensitive patient outcomes studies. The health care records have been selected on the basis of the database of alert microorganisms in a teaching Hospital of North-Eastern of Italy, for the years 2005-2006-2007 in three wards (Hematology, ICU and Surgical ward). In 80/107 (74.8%) cases of alert microorganisms a written record was found in the patient's health care records, most frequently in the nursing records (64/80, 80%). In the health care records have been reported 21 diagnosis of infection (21/107, 19.6%). The presence of written symptoms was heterogeneous among the different sources considered (medical and nursing records, vital parameters and therapy sheets). The results are not completely satisfactory from the point of view of the information accuracy. The promotion of integrated clinical health care record systems (doctors/nurses), also electronics, a more accurate compilation and periodical supervision would be needed. PMID- 22834249 TI - [150 years of hygienic requirements of dwellings in Italy]. AB - In Italy Public Health legislation had, since unification of the nation in 1861, a peculiar consideration for building hygiene, with a particular focus on dwellings. The first law about these themes is the number 5849 in 1888, named Crispi-Pagliani, after the Italian prime minister of the time and the hygienist who collaborated in lawmaking. The authors of the present work describe how laws evolved during 150 years of history, passing through social, demographic, political, economical, cultural and scientific changes. In the meantime they try to explain the role of public health practitioners in this field, also in relation with administrative processes that changed in time. Everything considering how indoor environment and home in particular are fundamental determinants of health, nowadays that people in richest countries spend most of their lifetime in this particular environment. PMID- 22834250 TI - [Evidence of snakes in urban areas. Analysis of cases in the province of Cuneo and public health issues]. AB - In this paper the authors analyse the cases of intrusion of snakes into urban environments in southern Piedmont (province of Cuneo) in the years 2010-2012 (up to may). In the study period there were 83 cases of intrusions in urban and domestic areas, mostly due to native harmless species (97.6%), while in 2.4% (n=2) of the cases alien species were responsible, and in 4.8% (n=4) poisonous native species were involved (Vipera aspis). The incidence of bites after a domestic intrusion is found to be 6% (n=5). All bites have resulted in loco regional minor symptoms and occurred as a result of an accidental contact. In order to limit the risk of poisoning, the authors recommend the intrusions to be handled by properly trained personnel, since it can never be ruled out the presence of dangerous alien species on the national territory. PMID- 22834251 TI - [Experimental value of formaldehyde exposure to preserve anatomical findings]. AB - Formaldehyde, already classified as potentially carcinogen and recently as "human carcinogen" by IARC, is generally used for fixing and preserving anatomical findings. This reason causes a problem of professional exposure for the operators who use the formaldehyde for this purpose. In this work we present the results of the periodical monitoring which is done for the determination of the exposure at formaldehyde in operating theatres and surgeries, where the operator fill the special container with the anatomical findings andformaldehyde for following tests. The measurements have been done using an instrument that continuously measure the concentration of formaldehyde, based on the infrared spectrometry, in 54 rooms which are operating theatres or surgeries in 9 public hospitals in Campania (Italy). The results show that the long-term exposure limits are not exceeded and that the average of the highest values of concentration obtained during its use was 0.15 +/- 0.04 ppm, that is below the limits. It is important to point out that such a limit was never exceeded during every single measurement. Finally, analyzing statistically the data, we can infer that the probability of exceeding the short-term limit is less than 0.1%, when formaldehyde is used for the purposes mentioned above. PMID- 22834252 TI - [State of emergency plans for massive influx of injured (PEMAF) in Italian hospitals. Pilot study]. AB - Aim of this study is to assess the level of implementation of plans for the massive influx of injured (PEMAF) in Italian hospitals. An anonymous questionnaire was administered to a sample of 100 hospitals selected through the network of the Italian Society of Emergency Medicine (SIMEU). Each answer of the questionnaire was assigned a score, then reported on a scale of compliance (maximum 65 points, threshold 35 points). The average scores were analyzed by hospital's venue, level of activity and previous experience of managing a real emergency. Student's t-test was used to compare means. Thirty-two hospitals sent the questionnaire, representing 33% of those selected. Five were excluded for incomplete data. The data analyzed refers to 27 hospitals of various levels of complexity, from all around the country: 55.6% from the Northern Section, 22.2% from the Centre and 22.2% from the Southern section and the Islands; and only 55.6% are above the minimum threshold of compliance. The weakest PEMAF's area is the one related to the specific training of health workers, therefore the percentage of hospitals complying the requirements in this field is down to 37%. Ten hospitals (37%) had managed a real maxi-emergence in the past: belonging to such group of hospitals is associated with an average level of compliance significantly higher than the others (p < 0.005). Due to a limited percentage of responders, the study involved so far a too small amount of hospitals; happily, they were evenly distributed in the different sections of the Country; therefore it will be appropriate to obtain a larger compliance before reaching clear-cut conclusions, but it already appears that the most critical point is the lack of specific education to maxi-emergencies in the hospital personnel. PMID- 22834253 TI - [Assessment of the impact of cancer in the Vercelli Local Health Authority from 2002 to 2009]. AB - The object of the study is to provide an epidemiological overview of the impact of neoplasms in an area that has no cancer registry. A descriptive study was conducted within the Local Health Authority of Vercelli. To estimate the number of cases, hospital discharge documents (including passive mobility) were used and integrated with the archives of pathology. The number of cases was calculated on the basis of SIR (specific rates of the Vercelli Local Health Authority divided by age in the years 2002-2009 in comparison with new cases of cancer in the city of Turin from 2005 to 2007, used as standard population). All readings were expressed including intervals of confidence at 95%. For tumors of low lethality for males, extending the period of observation confirms the excess for bladder cancer (SIR = 1.1, 1.07 to 1.21) and lymphoma aggregate (SIR = 1.4, 1.2 to 1.6). for females: thyroid (SIR = 1.5, 1.3 to 1.65) and lymphomas (SIR = 1.25, 1.1 to 1.4). In addition to these tumors in both sexes is observed to decrease colorectal cancer but excess for leukemias and brain. The extension of the study is intended as the base for the creation of a cancer register that will be established, naturally integrating further sources of information. In all cases, data observed indicated several epidemiological peculiarities in the region, probably linked to specific characteristics of local exposure, which should be addressed in terms of Public Health. PMID- 22834254 TI - [Prevention of patient's falls in University Hospital to Sassari, Italy]. AB - The University Hospital has addressed the issue of prevention of falls in hospital with some goals: empowerment of practitioners, patients and their families, development of a tool for classification of the patient to the risk of falls, development of an instrument of signal detection and analysis ofthe fall. Were defined: (a) a scale for assessing risk falls, to be completed upon acceptance by the nurse, made up of several indicators with a score corresponding to each of them, can help to define the patient: low risk, medium risk and high risk, (b) a statement of measures to be implemented depending on the severity of the risk falls, (c) a reportingformfor all fall divided into two sections: nursing and medical (d) a brochure to be delivered at the time acceptance in the department that contains behavioral suggestions for patients and families/caregivers, useful for the prevention of falls. Experimentation of the project took place during the months of October-December 2009 in three UU.00. (Clinic Pulmonology, Neurology and Medical Clinic) with a broad membership of the personnel involved (directors, nursing coordinators, Doctors, Nurses). The results of the trial (of 287 total admissions in the three UO involved, with 90% of evaluation forms filled out, reports offalls were 19 (8%), 17 without loss (85%) and 2 with injury (15%), analyzed for both single UO, which together, have allowed the Department to evaluate the project and to act positively in April 2010 approval of the developed tools and their dissemination to all UO inpatient Company. Were analyzed all report forms received from May 2010 to December 2011. The total admissions in University Hospital, for the whole period examined, were 25,847. The U.O. occurred where the falls are 11 reported (in which the total admissions were 13,791). The reports of falls were 55 (0.40%), of which 29 (53%) from the upright position, 18 (33%) falls out of bed, of which 4 (8%) had fallen from the wheelchair seat and # 4 (8%) falls undetectable; 26 without damage (48%) and 29 with damage (53%). PMID- 22834255 TI - [Hygienic problems of hot water supply for the population]. AB - The paper reviews the literature on the current hygienic problems of centralized hot water supply for the population. It gives data on the types of domestic hot water used by the population in quantities and at temperatures. The paper considers the importance of meeting the standards for the temperature of hot water at the points of water pumping to prevent legionellosis and other diseases associated with the opportunistic microflora being in hot water. The possible negative effect of chlorinated water disinfection byproducts, present in hot water on the population's health is considered in detail. PMID- 22834256 TI - [Effect of different calcium hypochlorite concentrations on the survival of potentially pathogenic microorganisms isolated from Baikal Lake]. AB - The survival rate of bacteria of the genera Pseudomonas and Enterococcus isolated from Baikal Lake, exposed to different concentration of calcium hypochlorite used as a main agent for drinking water disinfection, was studied. Experimental studies have shown that chlorination was imperfect as this method is not always effective against Enterococci. PMID- 22834257 TI - [Effect of the increasing levels of soil radioactive pollution on the biochemical composition of plants]. AB - The study was undertaken to study a relationship between the changes of some parameters of the biochemical and mineral composition of different plants, such as rape, pods, and lentil, and the levels of soil radiation pollution, by using the conventional methods. Radioactive pollution of dark-grey forest soils was found to cause a change in the biochemical composition of plant seeds even at the level of cesium 137 (137Cs) within the present temporary permissible levels (TPL) (600 Bq/kg): there were elevated concentrations of salts of potassium, phosphorus, ammonia nitrogen, catechols, sucrose, and some amino acids. With the radioactive cesium level exceeding the TPL, biochemical changes in the seeds depended on the species of the plants: in the rape seeds, the additional formation of sucrose and amino acids continued, but less intensively than with its lower radiation; the pod beans were significantly positively correlated with the increasing amounts of catechols. PMID- 22834258 TI - [Specificity of exposure of the indigenous dwellers of coastal and inland Chukotka to dichlorodiphenyltrichloroethane]. AB - In the indigenous dwellers of coastal Chukotka, blood DDT levels are 1.5-2 times higher than those of continental areas, which is due to the higher global DDT pollution of a sea food chain. The blood levels of 4,4-DDE in the reproductive age women of coastal Chukotka are comparable to those in other Russian Arctic regions, slightly lower than in Greenland, but essentially higher than in Canada, Alaska and Scandinavian countries. Blood DDE/DDT ratio in the coastal indigenous dwellers is almost twice higher than that in the inland inhabitants, which is indicative of the "older" exposure of coastal people to DDT. There was an about equal (70-75%) decrease in 4,4-DDE and 4,4-DDT levels with a practically invariable ratio (12-15) and a nearly equal elimination half-life period (about 3.5 years) in the mothers of coastal Chukotka 5 years after the first examination. The elevated 4,4-DDE/4,4-DDT ratios in the tissues of sea mammals generally correspond to higher isomer ratios in the blood of coastal natives and relatively low 4,4-DDE/4,4-DDT ratios in the venison, fowl, and fish predetermine lower ratios in the blood of inland inhabitants. The extremely low of DDE/DDT ratio (0.4) in the washouts and scrapes from the kitchen walls of dwellings are conclusively associated with the recent application of DDT as a household insecticide. PMID- 22834259 TI - [The content of trace elements in the biosubstrates of children aged 1 to 3 years under anthropogenic load]. AB - The paper comparatively characterizes the content of Zn, Cu, Pb, and Cd in the hair of children aged 1 to 3 years, who reside in Yaroslavl and Kotlas, as well as rural communities of the Yaroslavl Region and the Republic of Komi. Differences have been found in the trace element status of children living in areas with various anthropogenic load and under climatic and geographic conditions. PMID- 22834260 TI - [Hygienic evaluation of mineral therapy conditions]. AB - Physiological and hygienic investigations conducted in the underground structures and different types of above-ground ones made of natural sylvinite have provided evidence for the modes of their maintenance and methods for correcting the internal environment to enhance therapeutic effectiveness in patients. PMID- 22834261 TI - [Priorities for health improvement in the medical personnel of phthisiatric service in the Primor'ie Territory]. AB - The authors analyze occupational morbidity rates in the medical personnel of tuberculosis facilities in the Primorsky Territory, as well as the location of the institutions (workrooms) and the influence of occupational factors on medical workers. The nature of work and working conditions in the medical workers of a tuberculosis facility where they are exposed to occupational hazards in practically 100% of cases necessitate effective measures to promote and preserve their health. The absence of standard buildings and premises for tuberculosis facilities and the low efficiency of rehabilitative sanatorium-and-spa treatment, health improvement, and the prevention of occupational diseases are one of the problems of a tuberculosis service in the Primorsky Territory. The findings serve as the basis for the development of an approach to preventing occupational diseases and recovering the health status among the medical workers who have experienced tuberculosis. PMID- 22834262 TI - [Working conditions and occupational pathology in electrolytic nickel refinery workers]. AB - The working conditions during electrolytic nickel refinery correspond to Class 3, Grade 3-4, which may give rise to health problems in workers of all occupations employed in this production. Their risk and prevalence are significantly higher in the most exposed occupational group, such as electrolysis workers (40.1% of all cases). The structure of occupational diseases is dominated by respiratory diseases (68.8%), mainly due to exposure to aerosols of nickel compounds. It is concluded that working conditions and medical prevention interventions should be improved for this group of workers. PMID- 22834263 TI - [Sanitary and hygienic characteristics of working conditions during accumulator scrap recycling]. AB - An in-depth study of the working conditions of crushers engaged in different proceduresforpreparing the used storage batteries for melting permitted a comparative assessment of working conditions and evaluation of the impact of a production process on the tension of the cardiovascular system during a shift and a week. PMID- 22834264 TI - [Early signs of the influence of harmful industrial factors on workers at present day petrochemical plants]. AB - The working conditions and health status were studied in workers from different petrochemical plants. The leading industrial factors that conferred moderate and high risks of health impairments as early signs of the combined action of harmful substances and industrial noise, as well as mild occupational diseases were identified in the workers of essential trades at the petrochemical plants. According to the results of the investigation, the authors have elaborated a package of measures to promote the health status of workers at the petrochemical plants. PMID- 22834265 TI - [Investigation of the content of carcinogenic compounds in commercial smoked fish]. AB - The authors performed investigations of the content of polycyclic aromatic hydrocarbons (PAH) (n = 17) and their nitro derivatives (n = 5) in commercial cold and hot smoked herrings and greenlings. The level of benz(a)pyrene in all fish samples was found to be well below the current sanitary and hygienic limits. The concentration of N-nitrosoamines in cold smoked fish was slightly below that in hot smoked one. The content of nitro derivatives of PAH in fish is indicative of the low significance of these compounds in the total negative potential of smoked fish. PMID- 22834266 TI - [Development of food supply quality assurance system for armed forces]. AB - To study a serviceman's satisfaction with how nutrition was organized, the author elaborated a questionnaire containing the sections "nutrition organization quality assessment" and "mess food intake condition quality assessment". Different categories of military men taking food were inquired in a mess. The affirmation "I have no after-meal heartburn" became evidence that the sample was heterogeneous. For detailed analysis, the total sample was divided into two subgroups: those who had (Subgroup 1) and had not (Subgroup 2) a burning sensation after eating. Subgroup II servicemen gave lower scores on the questions about the comfort of food intake, the quality of dishes, a general attitude towards nutrition organization in the mess than did Subgroup I. The study has verified that the developed subsistence quality assurance system is of importance. The questionnaire has provided a valid assessment of the quality of the services given by the mess and revealed a reason for low scores. PMID- 22834267 TI - [Health-preserving capacities of pedagogical technologies]. AB - The hygienic evaluation of pedagogical technology for teaching under the active sensory-developing environment and the Intellect technology showed that their implementation caused a reduction in the fatiguing effect of an educational load, by optimizing the organization of a teaching process and enhancing the functional capacities of pupils. PMID- 22834268 TI - [Parental life style as a determinant of children's health]. AB - The paper considers a family in the context of an attitude towards health. The focus of attention in children is their parental lifestyle they imitate in their behavioral model. A sociological survey of parents (n = 328) and adolescent schoolchildren (n = 344) has established that by the time of leaving school, the children form behavioral norms accepted in their families. There is devaluation of family values and lesser parenteral responsibility for children's health. The pedagogical unsoundness of the parents to cultivate healthy lifestyle (HLS) habits in children is due to their personal example, inadequate HLS motivation, and the spread of bad habits. PMID- 22834269 TI - [Influence of subject competitions on the functional state of senior pupils]. AB - The paper gives the results of an experiment comparing the morphofunctional parameters of schoolchildren participating and non-participating in a subject competition. The latter is shown to be a stress that alters the functional state of the cardiovascular system. PMID- 22834270 TI - [The functional state of the cardiovascular system and the level of physical performance in 7-8-year-old children under conditions of aerotechnogenic pollution]. AB - The aim of the study was to investigate the functional state of the cardiovascular system and the level of physical performance in 7-8-year-old children living in the urban area where air pollution caused by heavy vehicle traffic is high. The cardiovascular system and physical performance were evaluated using the conventional methods in 7-8-year-old 1097 children: a control group included 652 children (363 boys and 289 girls) and a comparison group consisted of 445 persons (239 boys and 206 girls). Under aerotechnogenic pollution, diastolic and mean blood pressures were found to be higher in both groups; the maximum oxygen consumption was lower in the boys and the girls had a decreased heart rate following 4-minute exercise. PMID- 22834271 TI - [Time budget, progress, and adaptation in school-university profile class pupils]. AB - The paper considers the hygienic aspects of optimization of daily and weekly time budgets, the formation of healthy lifestyle choices in 10th-to-11th-form pupils from the vocational guidance classes of comprehensive secondary schools during intensified school lessons and adaptation of first-year students. PMID- 22834272 TI - [Changes in the physical development of Kiev schoolchildren over a ten-year period (1996-2008)]. AB - Physical development and morphofunctional state were assessed in 2452 urban schoolchildren, by using the Ukrainian standards (intergroup regression scales). During their schooling, the Kiev schoolchildren of both sexes were shown to have significant qualitative and quantitative physical and morphofunctional worsening that was more obvious in boys. Not more than 57-59% of the Kiev children aged 6 to 17 years had normal physical development and harmonic morphofunctional state. Every six Kiev boys and every five girls had overweight and reduced chest circumference. In the period 1996-2008, there was significant weight gain without respective changes in chest circumference and height, which indicated an imbalance in growth processes and physical development in the present-day Kiev schoolchildren. Evaluation standards for schoolchildren's physical development were developed and put into practice of the state sanitary-and-epidemiological service of Ukraine. PMID- 22834273 TI - [Influence of birth weight on the physical development of children and teenagers]. AB - To study the influence of birth weight (BW) on the physical development of children and teenagers, weight, height, weight-to-height ratio, and Quetelet's and Rohrer's indices were retrospectively estimated in 699 children at 1, 7, 8, 12, 14, and 16 years of age (including 320 girls) from the tenth classes of 16 Kirov comprehensive schools. It was established that 82.1% of the examined had normal (2.6-3.9 kg) BW, 126% had high (4.0-5.1 kg) BW; and 5.3% had low (1.6-2.5 kg) BW. Moreover; gender differences were characterized only for high-weight schoolchildren, among whom there were more young men (9.2 versus 3.4%). Both the girls and the young men with high BW had higher values of weight, height, and physical development at 1, 7, 8, 12, 14, and 16 years of age than the persons of their age. This shows the specific features of their metabolism at all stages of ontogenesis. The children with low BW lagged behind their peers with normal BW in all physical development indicators by 1 year but did not differ from them at 7, 8 and 12 years of age and again fell behind at 14 and 16 years of age (in weight, weight-to-height ratio, and Quetelet's index). Hence, when evaluating the physical development of schoolchildren, it is necessary to consider their BW. PMID- 22834274 TI - [Comprehensive hygienic evaluation of the environment and health status of children and adolescents in the North administrative district of Moscow]. AB - The high environmental levels of foreign chemical substances and the inadequate intake of both essential nutrients, such as proteins, fats, carbohydrates, and micronutrients, such as minerals, vitamins, and trace elements, in half of the examined children and adolescents promoted a rise in the incidence of chronic noncommunicable diseases in 2005-2009 particularly in the districts of Dmitrovskv, Khovrino where the morbidity rates were 1.5-2 times higher than those in the whole area. PMID- 22834275 TI - [The sociomedical portrait of girls studying at a secondary special educational establishment]. AB - The purpose of this investigation was to study a social portrait in 15-17-year old girls studying at secondary specialized educational establishments and the characteristics of their families. The urban girls have better living conditions than the rural ones. The income of the families of first- and second-year students from other towns was significantly more frequently lower (63.9 and 57.5%, respectively) versus that of the urban students (14.7 and 20.8%). The urban students had more conflicts with their parents (66.1% versus 52.6%). There are also differences in the professional and educational level of their parents. The parents living in the rural areas had a lower education level and more frequently belong to a class of workers and, accordingly, had more often occupational harms and heavy working conditions than the urban dwellers. The spread of bad habits in the families of urban and rural inhabitants is rather high. Nearly one-third of the students of Moscow and other towns experienced emotional violence by the members of their families. PMID- 22834276 TI - [The individual health of male teenagers studying at secondary school]. AB - Mental health, physical development, physiological constants, somatic health and chronic case rates were studied in graduating-class schoolboys aged 16 (n = 63) and 17 (n = 82) years. The prevailing temperament in 17-year-old teenagers was hyperthymic and that in 16-year-olds was labile and introverted. The majority of the surveyed young men were extroverts, emotionally stable with a moderate useful level of situational and personal anxiety. More than 70.0% of the young men showed high social adaptation and low autonomic lability. 17-year-old young men had retarded processes as shown by moderate-low and moderate rates ofphysical development and disharmony. The most of teenagers had moderate and above-moderate levels of somatic health and a vital index that characterizes good functional, adaptive capacities of the cardiorespiratory system. PMID- 22834277 TI - [Methods in the assessment of combined effect of substances]. AB - Russian and foreign approaches to estimating the combined effect of substances are considered depending on the problems to be solved Data are given on the relationship of the type of combined effect to the mechanism of the toxic action of components and acting doses (concentrations). Various mathematical models for calculating the combined efect of mixtures are discussed There is evidence that it is necessary to study the combined effects of the mixtures of constant composition, which are used in water supply upon chronic exposure of the substances that are constituents of the mixtures. Based on their studies and the data available in the literature, the authors inferred that the nature of the combined effect of such mixtures should be investigated under the conditions suiting those of application, as well as when used at low concentrations. PMID- 22834278 TI - [Toxicological and sanitary characteristics of fullerene C60 administered to the rat gastrointestinal tract]. AB - A four-week experiment dealing with the intragastric administration of fullerene C60 dispersion to rats has established that this substance in a dose of 1 to 10 mg/kg body weight causes a number of changes in the parameters of animals, such as reductions in relative liver weight and isoform CYP 1A2 activity and increases in glutathione reductase activity, eosinophils, and neutrophils. It is concluded that fullerene can affect the animals when orally given in the doses studied. PMID- 22834279 TI - [Total intravenous and combined general anaesthesia]. AB - In this review TIVA and combined general anaesthesia are not opposed to each other, but considered as having common physiological, clinical, pharmacological, technological and methodological features. This approach will help to borrow useful qualities of each anaesthesia method. PMID- 22834280 TI - [Efficiency and controllability of esmolol (breviblock)-induced adrenergic blockade during the heart and aorta surgery]. AB - This article contains analysis of retrospective and prospective studies of use of selective ultrashort Beta-blocker esmolol during intraoperative period in cardiac surgery patients in recent years. The drug is highly effective and controlled the means for prevention and treatment of tachycardia, arising as a result of the sympathoadrenal system activation during anaesthesia induction (laryngoscopy, trachea intubation) and intraoperative period (during heart and aorta manipulations). It should be considered that the use of esmolol has dose dependent effect. For the treatment of tachycardia against the background of hypertension is recommended dose of 0.6-1.0 mg/kg, with normal blood pressure it is recommended to decrease the esmolol dose up to 0.3-0.6 mg/kg. It is possible to use esmolol-infusion in the dose of 50-200 g/kg/min prolonging adrenergic blockade during heart and aorta surgery. PMID- 22834281 TI - [Cardioprotective effects of glutamine in patients with ischemic heart disease operated under conditions of extracorporeal blood circulation]. AB - It was conducted a study of glutamine cardioptotective effects during perioperative use in patients with ischemic heart disease, operated under CB. Exclusion criteria were: left ventricular ejection fraction less than 50%, diabetes melitus, myocardial infarction less than 3 months ago, Patients of the study group (n=25) had glutamine (20% solution N(2)-L-alanine-L-glutamine ("Dipeptiven" Fresenius Kabi, Germany); 0.4 g/kg/day. Patients of control group (n=25) received placebo (0.9% NaCl solution). The main indicators were the dynamics of troponin I, as well as central hemodynamics parameters. On the 1-st day after operation the concentration of troponin I was significantly lower in the glutamine-group compared placebo-group (1.280 (0.840-2.230) 2.410 (1.060 6.600) ng/ml; p=0.035). 4 hours after CB in a glutamine-group also had significantly large indicators of cardiac index (2.58 (2.34-2.91) l/min/m2 vs 2.03 (1.76-2.32)) l/min/m2; p=0,002) and stroke index (32.8 (27.8-36.0.) ml/m2 vs 26.1 (22.6-31.8) ml/m2; p=0.023). Systemic vascular resistance index was significantly lower in glutamine-group (1942 (1828-2209) dyn x s/cm(-5)/m2 vs 2456 (2400-3265) dyn x s/cm(-5)/m2; p=0.001). Conclusion. Perioperative use of N(2)-L-alanine-L-glutamine during the first 24 hours ofperioperative period gives cardioprotective effect in patients with ischemic heart disease operated under CB. PMID- 22834282 TI - [Status of central hemodynamics in elderly patients with different types of anesthesia during laparoscopic operations for colon cancer]. AB - Comparative analysis of central hemodynamics changes in 54 elderly patients with colon cancer during laparoscopic interventions. Physical status - ASA II-III. Were used 3 methods of anesthesia maintenance. In the 1-st group applied total intravenous anesthesia (TIVA) with myoplegia and ALV in the 2nd group surgical intervention was performed under the co-epidural anesthesia with intravenous potentiation with myoplegia and ALV; the 3rd group operations were performed under combination of epidural anesthesia with sevorane potentiation with myoplegia and ALV. The best results were obtained in groups with combined types of anaesthesia - epidural anesthesia with intravenous potentiation with myoplegia and ALV and epidural anesthesia with sevorane potentiation with myoplegia and ALV. PMID- 22834283 TI - [Effect of intraoperative infusion-transfusion therapy on mortality of patients with massive blood loss]. AB - The aim of the research is to determine the influence of infusion-transfusion therapy of the volume and structure on intraoperation and hospital lethality in patients with injuries and diseases, complicated in blood loss, exceeding circulating blood volume (CBV). It was conducted a retrospective analysis of the anaesthesia flow, infusion-transfusion therapy and treatment results in 112 patients with injuries and diseases complicated in intra-abdominal bleeding, volume of more than 4 liters. It was found that the risk of death increases in low-volume infusion therapy (less than 1.5 volume of blood), use of the maximum permitted doses of colloids, high speed of infusion therapy. Adverse factors of intraoperative transfusion: the lack of intraoperative compensation erythrocytes(less than 50% of the lost), ones transfuse more than 2 standard doses of the donor's erythrocytes and large volumes of fresh frozen plasma (FFP). PMID- 22834284 TI - [Epidural analgesia in surgical treatment of scoliosis]. AB - The article provides data on the use of a two-level epidural analgesia as a component of general anesthesia and postoperative analgesia in surgical treatment of scoliosis on the front and back structures of the spine. The study included 150 patients aged from 12 to 25 years. All the patients were divided into 4 groups. The patients of the 2-nd and 3-rd groups before the main stage was carried out an epidural analgesia with 0.75% ropivacaine and sevorane-propofol general anaesthesia . In the 1-st and 4-th group carried out an propofol-fentanyl TIVA or inhalational sevorane-fentanyl one. The best result were obtained in the 3-rd group, where they carried out the infusion 0.2% ropivacaine with fentanyl (1 microg/ml) and epinephrine (2 microg/ml) via 2 epidural catheters. It was noted decreased blood loss by more than 50% in groups with epidural analgesia. PMID- 22834285 TI - [To the issue of postreperfusion syndrome predictors in orthotopic liver transplantation (OLT)]. AB - The aim of the study is revelation of postperfusion syndrome (pPS) predictors in orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Was conducted a retrospective analysis of anesthesia maintainance protocols during orthotopic liver transplantation in 261 patients aged from 6 months to 60 years. Investigated the effect of various factors on the development of PPS by the application of methods of non-parametric statistics. RESULTS: Significantly more frequent development of the PPS is noted in the age group from 3 to 18 years (up to 30% of patients). In recipients older than 18 years the frequency of the development of the PPS does not depend on age, with an average of 14%. The development of the PPS does not depend on the recipient sex, the nature of the pathology which served as an indication to the OTP, the initial severity of the state, type of OTP (living related donor or cadaveric transplantation, primary or re-transplantation), the transplant warm ischemia duration, use, or the lack of venous-venous bypass, metabolic status of the patient. The obtained results do not contradict to the data of foreign publications. Among parameters available for screening, predictor of PPS was not detected. PMID- 22834286 TI - [The thromboelastometric criteria of hemostasis disorders correction during liver transplantation]. AB - The purpose of the study. Optimum correction of hemostasis remains one of the unsolved problems in anesthesia maintenance during liver transplantation. Modern methods of coagulation monitoring (thromboelastography, thromboelastometry) allows to differ the increased bleeding reason. The clear criteria for the appointment of the blood components according to these methods have not developed so far. The aim of this study was to determine the criteria of hemostasis disorders correction during liver transplantation. MATERIALS AND METHODS: The study included all patients undergoing a liver transplantation in our clinic from January 2009 to December 2010. In certain intervals of time an intake of blood samples for the hemostasis study including koagulogramm, determination of the clotting factors and natural anticoagulants activity was performed. RESULTS: There is no significant correlation between the results of the standard coagulation tests and thromboelastometry Based on the international hemostasis correction recommendations, with the help of ROC-analysis the search for thromboelastometry data, which would have pointed to the need for this therapy was made. Concerning coagulation factors deficiency (INR>2, APTT> 1.5) CT EXTEM>80 has a sensitivity of 17% and a specificity of 97%, and CT-INTEM>240 has sensitivity of 51% and specificity of 96%. Use of A10-FIBTEM for fibrinogen deficiency diagnosis, A10-FIBTEM <9 has sensitivity of 95% and specificity of 63%. A simultaneous increase of CT-EXTEM >80 and CT-INTEM more than 300 has a sensitivity of 96% and a specificity 81% in relation to diagnose thrombocytopenia (platelet count less than 50,000 per mcl). CONCLUSION: Correction of coagulation factors deficiency indicated when CT-EXTEM>80 and CT-INTEM> 240, hypofibrinogenemia when A10-FIBTEM <9, thrombocytopenia when of CT-EXTEM >80 and CT-INTEM increase simultaneously more than 300. PMID- 22834287 TI - [Fibrinolysis system in patients with sepsis in state of myelotoxic agranulocytosis]. AB - PURPOSE: Hemostasis disorders are the part of multiple organ failure (mOF) in sepsis. This work objective is to evaluate the system parameters in septic patients. PATIENTS AND METHODS: 55 oncohaematological patients were included in study: 45 with sepsis and 10 patients in control group (no signs of infection). Septic patients were subdivided into septic patients without multiple organ failure, patient with multiple organ failure and patients with septic shock. The C-reactive protein (CRP), procalcitonine (pCT), interleukine-6 (IL-6) serum concentration and fibrinolysis parameters were measured Patients were examined daily during first 5 days, later once a week during 28 days, control group was examined one time. RESULTS: Levels of CRP IL-6 and PCT were raised since 1st day. PCT and IL-6 concentrations were higher in sepsis and MOF group and septic shock group, than in sepsis without MOF group. CRP was raised in all patients. PCT went to normal at 7th day, CRP and IL-6 have started to decrease after 7th day, but both were higher than in control group. T-PA and plasmin inhibitors were comparable to control group and haven't changed significantly. Septic shock patients and patients with MOF have shown a decrease of plasminogen activity. Patients without MOF have shown an initially decreased plasminogen activity, but after 2 days it was similar to control group. PAI-I activity was increased only in septic shock and MOF groups in first days, and was similar to control group in cases of no MOF. Exended XIIa-dependent fibrinolysis time in average was present in all septic patients since 1st day, and extended twice in MOF and septic shock groups. Clot lysis time tended to decrease starting from 8th day, but it was longer than in control group till 28th day. A raised D-dimer concentration compared to control group was present in 75% of patients, but no difference was found among subgroups. A raised D-dimer serum concentration was relevant for prognosis. CONCLUSION: The most sensitive diagnostic test in sepsis is XIIa dependent fibrinolysis. Plasminogen and PAI-I activity changes are mostly present inpatient with MOF and septic shock. The 28-day survival rate was 60% in MOF and septic shock groups and 95% in no MOF groups. A raised D-dimer concentration was found in 75% of septic patients. PMID- 22834288 TI - [Clinical signs of endothelial disorders in patients with severe sepsis]. AB - A clinical-experimental study was carried out. The objective was to find some regularities in endothelial disorder progression in patients with severe sepsis and to evaluate clinical efficacy of some methods of hepatic protection. Experimental part of work was carried out on 59 mice with induced peritonitis. Obtained data shows early emergence of lung disorders that precede changes in hepatic tissue. Clinical part of work included 181 patient with severe sepsis. It was noted that acute respiratory distress syndrome symptoms occurred earlier than hepatic dysfunction, if the latter joints, it aggravates the patients status and worsens the prognosis. Use of Heptral (Ademetionine) and Ketamine in order to protect liver is a clinically effective method which makes possible to decrease the lethality. PMID- 22834289 TI - [Prevention of stress-induced damage of the upper gastrointestinal mucosa in patients during early postoperative period]. AB - Stress-damage of upper gastro-intestinal tract (GIT) mucous membrane and gastro intestinal hemorrhage (GIH) increase the lethality of patients in the departments of reanimation and intensive care unit. The purpose of this study is to evaluate effectiveness and safety of pantoprazole use in patients with at least one risk factor of upper GIT mucosa stresses-damage and GIH. An important part of this study was examination of 24-hour intragastric pH - control results in patients during 1-st day after the surgery. MATERIALS AND METHODS: Pantoprazole antisecretory therapy conducted in 40 patients, 38 of which had at least one risk factor of upper GIT mucosa stresses-damage and GIH. If there are risk factors, in the postoperative period prescribed pantoprazole (controlok) 80 mg/day bolus intravenously, then went to 40 mg/day per os. The criteria of the preventive therapy efficiency were absence of manifest and/or clinically significant GIH symptoms, the need for emergency upper endoscopy and emergency surgery, caused by the GIH. Among the patients with risk factors were marked out 15 patients: liver cirrhosis, portal hypertension syndrome (esophagus and stomach varix), liver failure (Child-Pugh A/B), high risk of hemorrhage. Within 24 hours, a constant intragastric-Ph monitoring ws carried out. RESULTS: During observation in all patients, which were undergoing upper GIT mucosa stress-damage prevention, there was no need for emergency upper endoscopy. No patients needed to carry out emergency surgery, caused by the GIH. Lethality rate in this group was absent. CONCLUSIONS: The use of pantoprazole demonstrates its good efficiency and tolerance. PMID- 22834290 TI - [Respiratory support using multi-level lung ventilation in patients in critical state with systemic inflammatory response syndrome]. AB - PURPOSE: To prove the effectiveness of the method and improve lung gas exchange in patients with non-homogenous lung tissue damage with multi-level (3-level, MLV) ventilation. MATERIALS AND METHODS: Artificial lung ventilation (ALV) with MLV carried out in 13 patients with severe lung tissue damage (polytrauma, pneumonia and ARDS) treated at the unit of resuscitation and intensive care (for septic patients) SCH No 1 of Omsk since May 2011. The initial values of pO2 and oxygenation index were significantly reduced, the fraction of the intrapulmonary shunting - essentially increased. During the first day after the beginning of respiratory support with the use of MLV, was registered pO2, SaO2 and oxygenation index growth, there was a positive x-ray dynamics of improved lung tissue biomechanics. As a result of the ALV with MLV in 11 patients had achieved steady improvements of arterial oxygenation. The use of respiratory support with MLV in patients with severe lung damage leads to a significant improvement of the alveolar ventilation and arterial oxygenation, and to reduce the intrapulmonary shunting level. The use of this type of ventilation system versus traditional methods of respiratory therapy leads to respiratory failure solution, in reduce of duration of ALV terms and stay in the intensive care unit. PMID- 22834291 TI - [Metabolic correction of bile outflow in patients with obstructive jaundice]. AB - The purpose of research is to study the influence of infusion therapy structure on the of metabolic disorders and biliary excretion correction in patients with obstructive jaundice. MATERIALS AND METHODS: The study was carried out in 139 patients divided into 3 groups with the same volume of infusion therapy (1600 ml/day). In 1-St group (54 patients) infusion therapy included ringer's lactate and 10% glucose solution in the ratio of 1:1. In the 2nd group (37 patients) infusion therapy was sterofundine - G-5. In the 3rd group (48 patients) in infusion therapy have included remaxol with dosage of 800 ml/day. RESULTS: The inclusion of remaxol and sterofundin in infusion therapy leads to the improvement of biliary excretion in the early postoperative period versus ringer's lactate and 10% glucose solution. Remaxol has the advantage in metabolic disorders and biliary excretion correction versus sterofundine-G-5. PMID- 22834292 TI - [Methods of heparin therapy in surgical patients with thrombohemorrhagic syndrome]. AB - The results of comparative study of different heparin medications efficacy in patients with thrombohemorrhagic syndrome (THS) are presented. The study was conducted in 286 patients with THS as a result of peritonitis of various etiology (174 patients), massive hemorrhage, shock, microcirculation disorders (112 patients). Heparin therapy carried out in 249 patients (87.1%), 37 patients (12.9%) had no heparin therapy./ In "heparin" group 193 patients (77.5%) received low molecular weight heparin (LMWH), 56 patients (22.5%) took unfractionated heparin (UFH). LWMH demonstrated high efficiency with fewer hemorrhagic complications in comparison with UFH/. PMID- 22834293 TI - [Application of artificial lung respiration in intensive care units in Russia: national epidemiological research "RuVent"]. AB - The purpose of the research is to study the real use of the various modes and parameters of prolonged respiratory support in Russia. MATERIALS AND METHODS: The study included all patients from ICU with no limitation by sex and age with ALV duration more than 12 hours in the period from February 7 to 11. 2011. 470 patients, including 104 children under the age of 15 years, from 101 ICU in Russian Federation, 2 ICU in the Republic of Belarus and 1 ICU in Ukraine (total 104 centres). The collection of information performed through online forms. RESULTS: Total lethality was 35.1% (139 from 396 patients), in case of the ARDS development - 44.9%. The frequency of ARDS development - 18.7%. According to the study "Ru Vent" doctors mostly prefer managed modes of respiratory support (SIMV 45.1%, A/C 20.2%, BiPAP 12.6%) which can partly be explained by a large proportion ofpatients with Central nervous system pathology, included in the study (39.8%). Frequency of non-invasive respiratory support use amounted to 1.1%. Real respiratory volume based on ideal body weight calculation, averaged for men 8.13 (6.84-9.33) ml/kg, for women - 9.1 (7.6-10.9) ml/kg, which is above the "ideal" respiratory volume 6 ml/kg in 1.35 times (1.14-1.56) for men (n=251) and in 1.51 times (1.27 - 1.81) for women (r=161). PEEP median amounted to 5 mbar, in case ofARDS development - 6 mbar. CONCLUSION: The results of the Russian national epidemiological research of ALV use in ICU ("RuVent) showed comparable data with real international clinical practice. The used tidal volumes are slightly overestated, and the values ofthe PEEP are understated in comparison with the national and international recommendations. PMID- 22834296 TI - [Antibacterial metabolites of lactic acid bacteria: their diversity and properties]. AB - The review is devoted to literature data on antimicrobial metabolites produced by lactic acid bacteria (LAB), which have long been used for the preparation of cultured dairy products. This paper summarizes data on low-molecular-weight antimicrobial substances, which are primary products or by-products of lactic fermentation. Individual sections are devoted to a variety of antifungal agents and bacteriocins produced by LAB; their potential use as food preservatives has been discussed. The characteristics and classification of bacteriocins are presented in a greater detail; their synthesis and mechanism of action are described using the example of nisin A, which belongs to class I lantibiotics synthesized by the bacterium Lactococcus lactis subsp. lactis. The mechanism of action of class II bacteriocins has been demonstrated with lacticin. Prospective directions for using LAB antimicrobial metabolites in industry and medicine are discussed in the Conclusion. PMID- 22834295 TI - [The problem of perioperative care of patients with high risk of heart arrhythmias in oncosurgery]. AB - This review is devoted to analysis of the world experience of perioperative care in patients with high risk of development and aggravation of heart rhythm and conduction disturbances. There was given the definition of the arrhythmia, their modern classification, described the mechanisms of formation and causes of long duration. Special attention is paid to the problem of perioperative arrhythmias in oncosurgery, which is characterized by the extent and traumatic interventions in reflexogenic zones in patients with nutritive deficiency, hypovolaemia, anemia, electrolyte imbalance. The problem of interaction of antiarrhythmic drugs with anaesthetics, possible complications and ways of correction of hemodynamically significant bradycardia with the help of drugs (atropine, sympathomimetics) and drug-free (transesophageal (TEECS) and invasive cardiac stimulation) methods. Describes approaches to the diagnosis and prediction of the risk of the arrhythmia development with the help of the analysis of Holter ECG results with e of heart rhythm variability (HRV) assessment. PMID- 22834294 TI - [Are we controlling the sedation in ICU? A multicenter study results]. AB - The aim of this study is to evaluate the issues of sedation and analgesia in all purpose ICUs in Russia. To obtain that, a single-day observational survey was performed in 55 ICUs of Ural and Siberia regions. This work enabled to describe the targets, instruments of control and patterns of sedative and analgetics and sedatives prescription, as well as to make conclusions about issues in this area and possibilities of creation and necessity of analgesia and sedation standards. The study has shown a decent percentage of use of standardized scales evaluating pain in ICU and predominance of effectivae drugs and analgesia patterns, which leads to "formalization" of analgesia and decrease of it's effectiveness. Sedation indications do not satisfy the modern concept, sedation level evaluation scores are used only in 13%, schemes and drugs are traditional. The results of this study may serve as a reason for discussion of necessity of introducing of sedative and analgetic therapy in ICU standarts. PMID- 22834297 TI - The involvement of Pseudomonas bacteria in induced systemic resistance in plants (review). AB - This article reviews the most recent results of studies on the mechanism of induced systemic resistance (ISR) elicited in plants by non-pathogenic bacteria of the genus Pseudomonas. Several examples of Pseudomonas strains eliciting resistance against fungal phytopathogens in different species of crop plants are presented. Literature data dealing with bacterial elicitors and the effect of their interaction with plant receptors are quoted. Special focus is focused on the controversial issue of the correlation between the synthesis of pathogenesis related proteins (PRs) and ISR. PMID- 22834298 TI - [Antioxidant activity of hydroxy derivatives of coumarin]. AB - The inhibition efficiency (antioxidant activity) of hydroxy derivatives of coumarin, such as esculetin, dicumarol, and fraxetin, was studied in the methemalbumin-H2O2-tetramethylbenzidine (TMB) pseudoperoxidase system at 20 degrees C in a buffered physiological solution (pH 7.4) containing 6% DMF and 0.25% DMSO. The inhibitor's efficiency was quantitatively characterized by the inhibition constants (K(i), microM) and the inhibition degree (%). The K(i) values for esculetin, dicumarol, and fraxetin were 9.5, 15, and 26 microM, respectively. Esculetin and fraxetin inhibited pseudoperoxidase oxidation of TMB in a noncompetitive manner; dicumarol, in a mixed manner. The inhibiting activity ofesculetin in peroxidase-catalyzed TMB oxidation at pH 6.4 is characterized by a K(i) value equal to 1.15 microM, and the inhibition process is competitive. Esculetin was found to be the most effective antioxidant of plant origin among all derivatives previously studied in model biochemical systems. PMID- 22834299 TI - E. coli propionyl-CoA synthetase is regulated in vitro by an intramolecular disulfide bond. AB - The E. coli propionyl-CoA synthetase (PCS) was cloned, expressed, purified, and analyzed. Kinetic analyses suggested that the enzyme preferred propionate as substrate but would also use acetate. The purified, stored protein had relatively low activity but was activated up to about 10-fold by incubation with dithiothreitol (DTT). The enzyme activation by DTT was reversed by diamide. This suggests that the protein contains a regulatory disulfide bond and that the reduction to two sulfhydryl groups activates PCS while the oxidation to a disulfide leads to its inactivation. This idea was tested by sequential mutagenesis of the 9 Cys in the protein to Ala. It was revealed that the C128A and C315A mutants had wildtype enzyme activity but were no longer activated by DTT or inhibited by diamide. The data obtained indicate that two Cys residues could be involved in redox-regulated system through formation of an intramolecular disulfide bridge in PCS. PMID- 22834300 TI - [Role of polymer complexes in the formation of biofilms by corrosive bacteria on steel surfaces]. AB - The composition of exopolymer complexes (EPCs), synthesized by the monocultures Desulfovibrio sp. 10, Bacillus subtilis 36, and Pseudomonas aeruginosa 27 and by microbial associations involved in the corrosion of metal surfaces has been studied. An analysis of the monosaccharide composition of carbohydrate components, as well as the fatty acid composition of the lipid part of EPCs, was carried out by gas-liquid chromatography (GLC). It was found that bacteria in biofilms synthesized polymers; this process was dominated by glucose, while the growth of bacteria in a suspension was marked by a high rhamnose content. Hexouronic acids and hexosamine have been revealed as a part of B. subtilis 36 and P. aeruginosa 27 EPCs. Qualitative differences were revealed in the fatty acid composition ofexopolymers in biofilms and in a bacterial suspension. It was shown that the transition to a biofilm form of growth led to an increase in the unsaturation degree of fatty acids in the exopolymers of associative cultures. The results can be used to develop methods to control microbial corrosion of metal surfaces. PMID- 22834301 TI - [Role of superoxide anion radicals in the bacterial corrosion of metals]. AB - It was found that seven strains of bacteria can cause corrosion damage to aluminum, its alloys, and zinc. With respect to the studied metals, the most active bacteria were Proteus vulgaris 1212 and Pseudomonas aeruginosa 969. Superoxide anion radicals were demonstrated to play a role in the initiation of corrosive damage to aluminum and zinc, while bacterial exometabolites participate in the later stages of this process. PMID- 22834302 TI - [Effect of volatile metabolites from germinating seeds on the reproduction of the bacteria Listeria monocytogenes and Yersinia pseudotuberculosis]. AB - The biological activity of volatile metabolites of germinating seeds of cabbage (Brassica oleacia), carrot (Daukus carota), salad (Lactuca sativa), and corn (Zea mays L.) against Listeria monocytogenes and Yersinia pseudotuberculosis was studied. It was shown that volatile metabolites are transfer factors and can be the sole carbon and energy source for these bacteria. Methanol is the main substance affecting their growth and reproduction. PMID- 22834303 TI - [Auxin synthesis by the higher fungus Lentinus edodes (Berk.) Sing in the presence of low concentrations of indole compounds]. AB - The auxin formation in a submerged culture of the xylotrophic basidiomycete Lentinus edodes (Berk.) Sing (Lentinula edodes (Berk.) Pegler) (shiitake) is studied. Biologically active substances of an indole nature are identified, "the effect of small doses" of which lies in not only the stimulation of growth of the mycelium (indole-3-acetic acid, 2 x 10(-7)-2 x 10(-4) g/l), but also in the induction of tryptophan-independent paths of auxin biosynthesis. The above mentioned path is realized in the presence of exogenous indole (1 x 10(-3)-1 x 10(-4) g/l), as well as while inducing the biosynthesis of indole-3-acetic acid by its microadditives (1 x 10(-5)-1 x 10(-8) g/l), and is accompanied by the formation of anthranilic acid (up to 1.5 mg/l). Induction of the generative development stage ofshiitake by indole derivatives is revealed. It was found that among the studied compounds only indoleacetamide at a concentration of an order of x 10(-4) g/l in the culture fluid of L. edodes had a pronounced stimulatory effect on the formation of shiitake's brown mycelial film. PMID- 22834304 TI - Induction, purification and molecular characterization of sulfhydryl oxidase from an Egyptian isolates of Aspergillus niger. AB - The conditions for the sulfhydryl oxidase (SOX) production and activity from an Egyptian isolate of Aspergillus niger were optimized. Purification and determination of the kinetic properties (K(m) and V(max)) of the purified enzyme have been done. The possibility for the SOX induction using L-Cys (as a natural substrate) was studied to determine whether SOX could be produced as an inducible enzyme in addition to being a constitutive one (i.e. whether induction leads to increase SOX production and activity or not). The optimum temperature and pH for its activity were found to be 60 degrees C and 5.5, respectively. The activity of the induced intracellular SOX, was measured according to Ellman's method using the standard GSH oxidation where it reached 94% while that of non-induced one reached only 27.6%. This wide difference in activity between the induced and non induced SOX indicates the successful L-Cys-induction of the SOX production (i.e. SOX from A. niger AUMC 4947 is an inducible enzyme). Molecular characterization of the pure SOX revealed that it is constituted of two 50-55 KDa subunits. K(m) and V(max) were found to be 6.0 mM and 100 microM/min/mg respectively. PMID- 22834305 TI - Alpha-L-rhamnosidase from Aspergillus clavato-nanicus MTCC-9611 active at alkaline pH. AB - An alpha-L-rhamnosidase secreting fungal strain has been isolated and identified as Aspergillus clavato-nanicus MTCC-9611. The enzyme was purified to homogeneity from the culture filtrate of the fungus using concentration by ultrafiltration membrane and ion-exchange chromatography on CM-cellulose. The native PAGE analysis confirmed the homogeneity of the purified enzyme. The SDS-PAGE analysis of the purified enzyme revealed a single protein band corresponding to the molecular weight 82 kDa. The alpha-L-rhamnosidase activity of Aspergillus clavato nanicus MTCC-9611 had optimum at pH 10.0 and 50 degrees C. The K(m) values of the enzyme were 0.65 mM and 0.95 mM using p-nitrophenyl alpha-L-rhamnopyranoside and naringin as a substrates respectively. The enzyme transforms naringin to prunin at pH 10.0 and further hydrolysis of prunin to naringenin does not occur under these reaction conditions that makes alpha-L-rhamnosidase activity of Aspergillus clavatonanicus MTCC-9611 promising enzyme to get prunin for pharmaceutical purposes. PMID- 22834306 TI - [Biosynthesis of fumiquinazolines by the fungus Penicillium thymicola]. AB - Biosynthesis of fumiquinazolines F and G (FQs), PC-2, and pigments by the fungus P. thymicola VKM FW-869 is directly dependent on the content of carbon substrate (mannitol) in the medium. Pigment production prevailed at all of the tested mannitol concentrations. The necessary conditions for predominant FQ biosynthesis by the fungus P. thymicola are carbon source (mannitol) limitation and presence of NaCl in the cultivation medium. NaCl has a regulatory effect on the formation of secondary metabolites by enhancing FQ biosynthesis and reducing pigment formation. The maximum values of FQ biosynthesis and inhibition of pigment production are obtained at a mannitol concentration of 20 g/l and 2.5% NaCl in the medium. PMID- 22834307 TI - [Chitin-glucan complex in cell walls of the Peltigera aphthosa lichen]. AB - Cell walls and chitin-glucan complexes isolated from uneven-aged components of the thallus of the Peltigera aphthosa lichen were studied. The mass fraction of the cell wall and chitin-glucan complexes increased with age, but the content of nitrogen in these structures decreased with age. The basal area of the thallus was characterized by the largest mass fraction of the chitin-glucan complex from the dry mass of the thallus; the apical area, by the largest mass fraction of chitin in the complex. It was demonstrated that in P. aphthosa, the degree of deacetylation of chitin in the complex (depending on the age) was 33 and 54% in the apical and basal areas, respectively. The suggested method of functional analysis of chitin-glucan complexes for the presence of free amino groups in them can be used for studying other lichenified fungi. PMID- 22834308 TI - [Effect of particle size on the enzymatic hydrolysis of polysaccharides from ultrafine lignocellulose particles]. AB - The efficiency of the enzymatic hydrolysis of wood polysaccharides ground into ultrafine particles (UFPs) has been investigated. The content of reducing sugars (RS's) in powdered raw materials and the yield of sugars during enzymatic hydrolysis have been shown to depend on the particle size. Laser interference microscopy and dynamic light scattering studies have shown that increasing the grinding time from 20 to 40 min resulted in the formation of particles ranging from 2 to 200 nm in size. Enzymatic hydrolyzates of UFPs mostly contained glucose and galactose. The grinding intensity (mill rotation rate) and time had a significant effect on the extent of the enzymatic hydrolysis of wood. PMID- 22834309 TI - [Specific features in realization of the principle of minimum energy dissipation during individual development]. AB - Realization of the principle of minimum energy dissipation (Prigogine's theorem) during individual development has been analyzed. This analysis has suggested the following reformulation of this principle for living objects: when environmental conditions are constant, the living system evolves to a current steady state in such a way that the difference between entropy production and entropy flow (psi(u) function) is positive and constantly decreases near the steady state, approaching zero. In turn, the current steady state tends to a final steady state in such a way that the difference between the specific entropy productions in an organism and its environment tends to be minimal. In general, individual development completely agrees with the law of entropy increase (second law of thermodynamics). PMID- 22834310 TI - [Electron microscope analysis of cardiomyocytes in the rat left ventricle under simulation of weightlessness effects and artificial gravitation]. AB - Electron microscopic study of left ventricle cardiomyocytes and quantitative analysis of their mitochondriom was performed in rats exposed to tail-suspension, as a model of weightlessness effects, to artificial gravity produced by intermittent 2G centrifugation and a combination of these effects. It was found that the cardiomyocytes ultrastructure changed slightly after tail-suspension and after intermittent 2G influence, as well as under a combination of these effects. However, the number of intermitochondrial junctions increased significantly in the interfibrillar zone of cardiomyocytes under a combination of tail-suspension and intermittent 2G influence, which agrees with the cell hypertrophy described earlier. PMID- 22834311 TI - [Effect of gold nanoparticles on mouse spermatogenesis]. AB - The response of the mouse male germ cells exposed to gold nanoparticles (approximately 2.5 nm) was studied. Our investigation demonstrates that treatment with Au nanoparticles for four days does not impair the architecture of the spermatogenic epithelium. Cytogenetic evaluation using micronucleus assay showed that gold nanoparticles can affect the chromosomes of early primary spermatocytes. However, gold nanoparticles did not induce chromosome abnormalities in spermatogonial stem cells. Further, the cauda epididymal sperm was isolated on the 14th day after treatment and was incubated in SDS solution (Na sodium dodecyl) and then in a solution containing DTT (dithiothreitol) to induce nuclear chromatin decondensation. Observations showed that after four days of treatment of spermiogenic (postmeiotic) cells with gold nanoparticles the decondensation process had no differences from the control. On the contrary, in the experiment with the same cells and period of fixation but with a single exposure to gold nanoparticles, the number of mature gametes with totally decondensed nuclei reached 100% as opposed to 44% in the controls. PMID- 22834312 TI - [The role of serotonin in the immune system development and functioning during ontogenesis]. AB - In this study, we investigated the influence of serotonin on the development and functioning of T- and B-cell-mediated immunity during ontogenesis using the pharmacological model of serotonin depletion in rat fetuses. It has been demonstrated that prenatal serotonin deficiency resulted in a decrease in thymus and spleen weights, changes in their cellular composition, and long-lasting disturbances in cell-mediated and humoral immunity in postnatal ontogenesis. The data obtained suggest that serotonin may be considered a morphogenic factor in development of the immune system. PMID- 22834313 TI - [Changes in the proteasome function after induction of donor-specific tolerance in rats with ovarian allograft]. AB - Induction of donor-specific tolerance in a recipient is one of the methods for enhancing acceptance of the grafts of endocrine glands in the absence of immunodepressants, which interfere with hormone production. This paper describes changes in the proteasome pool in the rat liver, spleen, and graft during the development of donor-specific tolerance after intraportally infusing the recipient with donor splenocytes with subsequent allografting of ovarian tissue into the renal capsule. It has been demonstrated that the shift in the balance in the liver and graft proteasome pools towards the variants with the LMP2 subunit determines the development of immunological tolerance and graft retention. On the contrary, an increase in the forms with the LMP7 subunit induces the immune response and graft rejection. PMID- 22834314 TI - [Contribution to the study of the biology of soil-dwelling dipteran larvae (Insecta, Diptera) of the desert zone]. AB - The composition of seven dipteran families from the complex of larvae dwelling in sandy soils of the southeastern Karakum Desert, represented by both free-living soil forms and endobionts ecologically dependent mainly on herbaceous plants, is analyzed. In the surface horizons of the soil, at a depth of up to 20 cm, free living soil-dwellers form a stable complex, which includes saprophagous coleopteran larvae and their constant companions, the obligatorily predaceous dipteran larvae. Previously unknown data on the lifestyle of the larvae of five therevid genera are given. PMID- 22834315 TI - [Seasonal peculiarities of female hormonal response of females to conspecific chemical signals of the male in two species of the genus Phodopus]. AB - Changes in diestrous female blood plasma progesterone, estradiol, and cortisol in response to odors of urine and midventral gland secretion (MVGS) of conspecific males during different seasons have been studied in the desert hamster (Phodopus roborowskii and Djungarian hamster (Phodopus sungorus). In desert hamster females, a statistically significant (p < or = 0.05) increase in the plasma hormonal level was observed: for progesterone in response to conspecific male MGVS in all seasons except winter, and to conspecific male urine in spring and summer; for cortisol in response to male MVGS and urine in all seasons except spring; and for estradiol in response to male MGVS in autumn. Djungarian hamster females demonstrated a statistically significant increase in the plasma progesterone level in response to conspecific male MVGS and urine in winter and summer, and no response to the estradiol and cortisol level for both odors in all seasons. PMID- 22834316 TI - [NO and H2S brain systems of the Japanese shore crab Hemigrapsus sanguineus under conditions of anoxia]. AB - The topography and dynamics of the activity of the enzymes of the synthesis of nitric oxide (NO) and hydrogen sulfide (H2S) in the brain of the Japanese shore crab Hemigrapsus sanguineus after 1, 6, and 12 h ofanoxia was studied histochemically and immunocytochemically. Changes in the activity and number of NO- and CBS-immune-positive cells that take place due to anoxia and the intensity of which depends on the duration of the influence were revealed. The fact that the balance between the nitric oxide and hydrogen sulfide systems in the brain of the crabs H. sanguineus is preserved indicates the joint participation of those systems in the central regulation of adaptive mechanisms under the influence of anoxia and, apparently, plays an important role in the adaptation of these hydrobionts to oxygen deficit. PMID- 22834317 TI - [Multifractal analysis of the species structure of freshwater hydrobiocenoses]. AB - The principles and methods of fractal analysis of the species structure of freshwater phytoplankton, zooplankton, and macrozoobenthos communities of plain water reservoirs and urban waterbodies are discussed. The theoretical foundation and experimental verification are provided for the authors' concept of self similar (quasi-fractal) nature of the species structure of communities. According to this concept, the adequate mathematical image of species richness accumulation with growing sampling effort is quasi-monofractals, while the generalized geometric image of the species structure of the community is a multifractal spectrum. PMID- 22834318 TI - [Specific features of feeding of the Amur tiger Panthera tigris altaica (Carnivora, Felidae) in a densely populated locality (with reference to Bol'shekhekhtsirskii Reserve and its environs)]. AB - Specific features of feeding of the Amur tiger (Panthera tigris altaica) in the Bol'shekhekhtsirskii Reserve located in a densely populated locality (only 15 km to the north of it is the city of Khabarovsk) have been investigated. For a long time (1992-2000) the diet of tigers consisted 100% of wild animals, although the accessibility of domestic animals, dogs, in particular, was high. From 2000 to 2007, in their feeding, the proportion of dogs increased (up to 47%), and the proportion of wild animals decreased (50.8%). Tigers attacking dogs were physically weakened (broken fangs, wounds, inflicted by humans, diseases). Thus, even in a densely populated locality, the tiger's diet includes domestic animals only at exposure to different negative factors. PMID- 22834319 TI - [Factors determining the origin and maintenance of redundant species diversity of the soil animal population (by a case study of the Far East)]. AB - The factors determining the origin and maintenance of a high taxonomic diversity of soil communities are discussed by a case study of the key groups constituting the soil saproblock. The bulk of the species richness in the southern Far East is localized to the coniferous-deciduous forests retaining the tertiary elements in their flora and ancient relations with the Asian tropical fauna. The roles of the following factors are considered: the long-term geographic isolation in the absence of catastrophic climate changes; pyrogenic effects, enhancing formation of isolated survival sites; and abundance of mutagenesis in various pedobiont groups. The high species richness of individual taxocenes in combination with a high topic association in the distribution of closely related and ecologically similar species suggests the absence of competitive exclusion. It has been demonstrated that this phenomenon is determined, on the one hand, by rich resource reserves and their spatial differentiation in the soil-litter stratum and, on the other, by spatial-temporal segregation and dense packing of ecological niches, decreasing competition. PMID- 22834320 TI - [Dynamics of seasonal plant growth in halophytic meadows taking into account the temperature factor and soil salinity level]. AB - A mathematical model has been constructed to describe the growth dynamics of various plant communities of halophytic meadows depending on the temperature factor and degree of soil salinity. Field investigation of the yields of halophytic meadow plant communities were performed in the coastal area of Kurinka Lake in the Altaiskii district of the Republic of Khakasia in 2004 and 2006. The results of field investigations and model studies show that there is a correlation between plant growth and air temperature for plant communities growing on soils with the lowest and medium salinity levels. It was proven in model studies that for the plant communities that grow on highly saline (3.58%) soils, not only air temperature but also the salinity level of the soil should be taken into account. PMID- 22834321 TI - [Modern ways of treating female genital infections]. AB - In article various ways of increase of efficiency of treatment of is mixed the bacterial-virus infection of the bottom department of sexual ways at women by means of application in complex therapy of homologous bacteriophages, pectovit, antiviral -immunomodulation therapies and sated with oxygen (oxygenic) water solutions of antiseptic tanks are considered. The scientifically-practical urgency of this problem is represented and actual for the decision of an important social and economic problem of improvement of quality of life, decrease in number of infectious complications and perfection of the medical help to sick women with frequent recidives an infection of the bottom department of sexual ways. PMID- 22834322 TI - [The distribution of iodine-125 labeled alpha-fetoprotein in the animal organism and its accumulation in the tumor]. AB - The distribution of iodine-125 labeled human alpha-fetoprotein in mice was studied after its intravenous injection. The maximal accumulation of alpha fetoprotein in different tissues and organs of animals was observed mainly 5 hours after injection. Then the protein was gradually eliminated from the body. In the liver, intestine and blood of intact animals 125I-alpha-fetoprotein persists for at least three days. Accumulation of alpha-fetoprotein in various tissues and organs may determine the different biological effects of this protein. In the mice with transplanted lymphatic leukemia cells P388 the high level of alpha-fetoprotein accumulation was detected in the tumor tissue, reaching 6% of the injected amount per 1 g of tissue. This allows considering the radionuclide-labeled alpha-fetoprotein as a promising medical radionuclide marker for the radiological detection of malignant tumors. PMID- 22834323 TI - [Actual problems of cell therapy for cardiac diseases]. AB - This article reviews the literatury and own dates of cell therapy for cardiac diseases. The principal unresolved issues were formulated. PMID- 22834324 TI - [Role of endothelium in remodelling a myocardium left ventricular at patients on a hemodialysis]. AB - To study influence of markers of function endothelium on structurally functional indicators left ventricular at patients on a hemodialysis. 98 Patients on a hemodialysis are surveyed. To all patients defined concentration stable metabolites of oxyde nitrogen whey of blood, total cholesterol, cholesterol of low density lipoproteine, cholesterol of high density lipoproteine, triglycerides, homocysteine, Willebrand factor, spent echocardiography research. During correlation, multiple regression the analysis independent influence of indicators of function endothelium on structurally functional indicators of a myocardium left ventricular, processes of formation of dysfunction of heart reflecting parallelism and endothelium is revealed. PMID- 22834325 TI - [The registers of acute coronary syndromes--their types, characteristics and significance in clinical practice]. AB - The term registry in individual application to patients with acute coronary syndrome (ACS) is discussed in this review. The author performs a detailed analysis of literature concerning objectives and goals of registries and their significance in clinical practice. The marked differences can be found between registries and randomized clinical trials (RCT). After the example of ACS registries the author shows the influence of information received according to registries limits on the formation of recommendations on treatment of patients with ACS. PMID- 22834326 TI - [Agonist of V2 vasopressin receptor reduces depressive disorders in post-stroke patients]. AB - Poststroke depression is one of the common psychiatric complications after stroke. Thus, the research of new ways for treatment depressed mood after stroke is actual. The previous researches revealed vasopressin to be effective in patients with memory, speech and motor function disorders after stroke. The purpose of the study was to investigate influence of vasopressin on depression after stroke. Fourteen patients with affective disorders have been treated with subendocrine doses of 1-desamino-8-D-arginin-vasopressin (DDAVP) daily by intranasal application during 1,5-2 months. Vasopressin was effective in correcting both apatoadinamic and anxious depression. Treatment effect was durable, lasts for 0,5-1 year after the first course of therapy. The results of this pilot study demonstrate perspective of using selective agonist of vasopressin V2 receptors, DDAVP, in therapy of post-stroke depression. PMID- 22834327 TI - [The classification of functional disorders of brain activity in patients with brain tumors]. AB - This paper is devoted to the automatic classification of functional disorders of brain activity in patients with brain tumors on the basis of the reference groups. The test of statistical hypotheses set made crisp classification. Functional activity of the brain abnormality is assessed indicators of the frequency spectrum of the EEG. We describe the scheme of the algorithm and an analysis of the results. The publication is intended for IT-professionals and clinicians who are actively applying them in their work. PMID- 22834328 TI - [Immunocytochemical characterization H2S-positive neurons in the nuclei of bulbar cardiovascular center in the development of renovascular hypertension]. AB - Immunocytochemical method in Wistar rats in 6 nuclei of the medulla oblongata, related to the cardiovascular center, identified nerve cells (H2S-neurons) with a positive reaction to cystathionine beta-synthase (CBS)--an enzyme involved in the synthesis of hydrogen sulfide in the brain. Found that in rats with renovascular hypertension only after 6 weeks of hypertension in the neurons of the reticular nuclei observed a significant reduction of CBS, while the number of H2S-positive cells in this period does not change significantly. Only at week 12 renovascular hypertension notes marked reduction in the proportion of positive H2S-neurons in the reticular nuclei of most of the medial zone, although further reduction in the intensity of the enzymatic reaction in the neurons were observed. Between 14 16 weeks of hypertension to further reduce the proportion of neurons and H2S content of the enzyme is not observed. In a single nucleus and reticular lateral nucleus, which receive afferent impulses in the development of renovascular hypertension specify the minimum change of the indicators. PMID- 22834329 TI - [Carbohydrate metabolism abnormalities in patients with cancer of major duodenal papilla before and after pancreaticoduodenal resections]. AB - 56 Patients with cancer of major duodenal papilla were examined before and after pylorus-saving pancreaticoduodenal resection. Carbohydrate metabolism was estimated before and after the operation, impact of the operation on diabetes mellitus progression was detected. If there were no carbohydrate metabolism abnormalities in 75% before the operation, then there were 55% of such patients after the operation. After the pylorus-saving pancreaticoduodenal resection the impaired glucose tolerance was detected in 4 (7%) of patients whose carbohydrate metabolism had corresponded to norms before the operation. 7 (13%) of 17 (31%) patients had diabetes mellitus of mild severity after the pylorus-saving pancreaticoduodenal resection, the rest 10 (18%) had diabetes mellitus of moderate severity. In 7 (13%) patients after the pylorus-saving pancreaticoduodenal resection the diabetes mellitus of moderate severity was detected for the first time, at that in 4 patients diabetes mellitus of mild severity was detected, and in 3 patients--diabetes mellitus of moderate severity (everyone received insulin therapy in the long-term postoperative period) was detected. Checking protocol of the patients' carbohydrate metabolism in the perioperative period was described in detail. The possibility of prognostication of carbohydrate metabolism abnormalities in the long-term postoperative period by indications of carbohydrate metabolism before the operation and in early postoperative period was studied. Middle blood glucose level in early postoperative period is an informative indication for prognostication of carbohydrate metabolism state in the long-term postoperative period. An algorithm of patients' examination with cancer of major duodenal papilla before the operation and after it was offered; also checking protocol of carbohydrate metabolism indices and correction of the detected abnormalities in the early postoperative period were offered. PMID- 22834330 TI - [Influence of regulatory T cells on the functioning of natural killer cells during cancer immunotherapy]. AB - One of the common arguments against cancer immunotherapy based on natural killer (NK) cells activated in the presence of interleukin-2 (IL-2) is the probability of the activation of regulatory T cells (Tregs) by IL-2 besides NK cells. Thus, we have monitored numbers of FoxP3+CD4+CD25+ T cells in the samples of healthy volunteers' peripheral blood mononuclear cells (PBMCs) cultured with or without IL-2. We observed marked increase in the percentages of the CD4+CD25+ T cells in the presence of IL-2. Proportions of Foxp3+CD4+CD25+ T cells feebly increased, remained on the same level or even decreased compared to PBMCs cultured without exogenous IL-2. Based on the absence of FoxP3 expression, most of the CD4+CD25+ T cells purified from IL-2 activated PBMCs were not Tregs, but activated Th cells. Moreover, the addition of the purified supposed Tregs to samples of activated NK cells never inhibited their cytotoxic reactions. PMID- 22834331 TI - [Phylogenesis, etiology and pathogenesis of insulin resistance. Differences from type II diabetes mellitus]. AB - We believe that etiological factor of insulin resistance is phylogenetically late formation of insulin and its specific functionality, i.e., providing energy substrates for the biological function of locomotion. According to biological subordination, insulin cannot change regulation formed at the early stages of phylogenesis in all cells, including those that become insulin-dependent at the late stages of phylogenesis. This involves a) beta-oxidation of fatty acids in the mitochondria, b) synthesis of C 16:0 palmitic saturated fatty acid, c) glucose metabolism in pro- and eukaryotes, d) regulation of biochemical reactions in insulin-independent cells, e) humoral effects of mediators at the level of paracrine cell communities which are structural and functional units of all internal organs, and f) hormonal regulation at the entire organism level. Pathogenetic factors of insulin resistance are biochemical and functional disorders occurring in vivo upon activation of biological functions and reactions that formed phylogenetically earlier than insulin. During phylogenesis the insulin system has intrinsically built up over the regulatory mechanisms of mitochondria, early unicellular organisms and paracrine cell communities. Insulin functionally interacts with them all, but it cannot abolish the effects of any phylogenetically earlier humoral mediator. Insulin resistance is a pathophysiological disparity between humoral regulation of metabolism at the level of phylogenetically earlier paracrine cell communities and at the level of phylogenetically late total organism, on the one hand, and successive phylogenetic formation of passive cellular uptake of fatty acids as unesterified fatty acids and later triglycerides, on the other. If insulin resistance results from changes in the primary structure of transport proteins, in glucose storage and cellular insulin reception, it can be referred to as type II diabetes mellitus. PMID- 22834332 TI - [Novel concepts in biology of diffuse endocrine system: results and future investigations]. AB - Diffuse endocrine system is a largest part of endocrine system of vertebrates. Recend findings showed that DES-cells are not neuroectodermal but have ectodermal, mesodermal, and entodermal ontogeny. The article reviews novel concept of diffuse endocrine system anatomy and physiology, functional role of DES hormones and poorly investigated aspects like DES-cell morphology, hormones secretion in normal and pathologic conditions. Further research of diffuse endocrine system has a great significance for biochemistry, morphology, and clinical medicine. PMID- 22834334 TI - [Effects of ionotropic glutamate receptor channel blockers on the development of audiogenic seizures in Krushinski-Molodkina rats]. AB - The action of noncompetitive blockers of glutamate receptors has been investigated on Krushinski-Molodkina rats genetically-prone to audiogenic seizures. The selective blockers of NMDA receptor channels, memantine and IEM 1921, and their dicationic homologues, IEM-1925 and IEM-1754, capable of blocking in varying degrees both NMDA and Ca-permeable AMPA receptor channels, were studied. The drugs were injected intramuscularly to rats with the different time intervals (30 min, 1, 2 or 3 hours) before sound signal. The effects of the drugs on latent period of initial locomotor activity provoked by audio stimulation (8 kHz sine-wave tone, 90 dB volume), the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. Within 30 min after injection IEM-1921 at a dose of 5 mg/kg, 33% of rats manifested a complete absence of convulsive reactions to sound, and in 59% of rats audiogenic seizures occured only in the form of motor excitation without a generalized clonic-tonic convulsions. Memantine at a dose of 5 mg/kg did not cause a complete blockade of seizures, but after 1 h of injection in 50% of the rats and after 2 h in 70% of rats a weakening of the audiogenic seizures to the level of motor excitation only was observed. After 3 hrs after administration of blockers its anticonvulsive action weakened significantly (p < 0.01). Dicationic blockers that block both NMDA and AMPA/kainate receptors, IEM 1925 (in doses of 0.001-20.0 mg/kg) and IEM-1754 (0.025-50.0 mg/kg), did not affect audiogenic clonic-tonic convulsive reactions. The involvement of activation of NMDA and calcium permeable AMPA/kainate receptors in the pathogenesis of audiogenic seizures is discussed. PMID- 22834333 TI - [Preconditioning impact on coronary perfusion during ischemia and reperfusion of heart]. AB - Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms involved in the cardioprotective and vasoprotective effects of preconditioning are different. The ability of preconditioning in preventing reperfusion endothelial dysfunction is dependent upon bradykinin B2-receptor activation and not dependent upon adenosine receptor stimulation. The vasoprotective effect of preconditioning is mediated via mechanisms relying in part on activation of protein kinase C, NO-synthase, cyclooxygenase, mitochondrial K(ATP)-channel opening and an enhancement of antioxidative protection of the heart. The delayed preconditioning also exerts endothelium-protective effect. Peroxynitrite, NO* and O2* are the triggers of this effect but a possible end-effector involves endothelial NO-synthase. PMID- 22834335 TI - [Mediolateral gradient of the nucleus accumbens nitrergic activation during exploratory behavior]. AB - In Sprague-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis it has been shown that an exploratory behavior in a new environment is accompanied by a rise in extracellular levels of citrulline (an NO co-product) in the mediolateral regions of the n. accumbens with the maximum observed in the medial n. accumbens. Infusions of 7-nitroindazole (0.5 mM), a neuronal NO synthase inhibitor, into the medial n. accumbens prevented the exploration induced rise of extracellular citrulline levels in this area. The second presentation of the same chamber did not produce any significant changes of extracellular citrulline levels in the medial n. accumbens, although there was a tendency of a small increase. The presentation of a familiar chamber did not affect citrulline extracellular levels in this area. The data obtained indicate for the first time that exploratory activity in a new environment is accompanied by the nitrergic activation in the entire n. accumbens with the maximal activation in the medial part of this brain area. PMID- 22834336 TI - [The dynamics of coheren links in persons with different ability to recognise speech emotional expessions]. AB - The coherency characteristics of the brain electrical activity were studied in two groups of subjects: 1) with high and 2) low indexes of "emotional ear" (an ability to successfully recognize emotions in the speech). Comparison of the coherency links between two groups of subjects permitted the authors to make a conclusion that the persons of the first group had a much lower coherency level, especially in the alpha- and gamma-rhythms. The subjects of the second group were characterized by the opposite tendency: an increase in coherent links on the majority of frequency bands. PMID- 22834337 TI - [The influence of strabismus and monocular deprivation on the size of callosal cells in cortical areas 17 and 18 of the cat]. AB - To reveal the changes in visual cortex structure following impaired early binocular experience, the size (somatic area) of callosal cells in areas 17, 18 ofmonocularly deprived and convergent strabismic cats was measured. Horseradish peroxidase was injected into the single ocular dominance columns of areas 17, 18 and the transition zone 17/18. In both groups of impaired cats the mean size of callosal cells in area 17 was increased in comparison to intact cats. In area 18, the similar difference was found in monocularly deprived cats only. It was shown that the differences in the mean sizes of cells are due to the increase of the number of large cells. In strabismic cats, the portion of large cells (soma > 200 mkm2) in area 17 was 58% and in area 18 was 8%. The relative share of large cells in areas 17 and 18 of monocularly deprived cats was similar (28 and 26 % correspondingly). These data show that early binocular vision impairments may lead to the changes in cytoarchitecture of cortical layers where the interhemispheric connections originate. PMID- 22834338 TI - [Latent inhibition and extinction of passive avoidance in mice C57BL/6J AND DBA/2J]. AB - The study was carried out in mice C57BL/6J and DBA/2J for comparative analysis of two interference processes: latent inhibition and extinction of passive avoidance produced with an unconditioned aversive stimulus of different parameters (0.5 and 0.25 mA). With a strong training to new stimulus, impairment of extinction has been detected only in mice DBA/2J. Reduction in the strength of punishment during training was accompanied by acceleration of extinction in mice C57BL/6J and its appearance in mice DBA/2J. The learning of passive avoidance in strong and weak reinforcement was the same for both strains of mice. Interline differences were found also in the analysis of latent inhibition. With strong and weak training to conditional stimulus, lost of novelty by repeated an 8-fold pre-exposures to the experimental chamber, in DBA/2J mice, in contrast to C57BL/6J, latent inhibition was disrupted. In addition, DBA/2J mice showed impairment of extinction with weak training to non-relevant stimulus. PMID- 22834339 TI - [The role of asymmetric dimethylarginine in the regulation of nitric oxide level in rats with acute renal injury]. AB - Nitric oxide (NO) is synthesized from arginine (ARG) by NO synthase (NOS). Asymmetric dimethylarginine (ADMA), a competitive inhibitor of NOS, participates in the endogenous regulation of NO synthesis. The main amount of ADMA is enzymatically degraded by dimethylarginine dimethylaminohydrolase (DDAH) widely expressed in renal tissue. The aim of our study was to compare the changes in DDAH activity and ARG synthesis in kidneys, ADMA and ARG concentration in plasma and their urinary excretion under physiological conditions and in acute renal injury (ARI) induced by glycerol in rats. Urinary nitrite/nitrate excretion (NOx) was estimated as an indicator of whole-body NO synthesis. DDAH activity was decreased, ADMA excretion was increased and plasma ADMA did not change in ARI. Plasma ARG concentration, renal ARG synthesis and urinary NOx excretion were decreased. In conclusion, the diminished enzymatic hydrolysis of the NOS inhibitor ADMA and the reduced synthesis of the NOS substrate ARG might affect NO production in ARI. PMID- 22834340 TI - [Gram-negative bacteria influence on the ability of the arginine-vasotocin to stimulate osmotic permeability of the frog urinary bladder epithelium]. AB - The influence of endogenous gram-negative bacteria colonizing the mucosal epithelium of frog Rana temporaria L. urinary bladders (FUB) on arginine vasotocin AVT-stimulated osmotic water flow in isolated urinary bladders was investigated. 170 animals were examined and only 40% were contaminated with gram negative bacteria (about 10(3)-10(6) CFU per hemibladder). Several Enterobacteriaceae species were identified (Hafnia alvei, 36.7%, E. coli, 32.3%, Serratia marcescens, 8.8%, Citrobacter freundii, 4.4% etc.). Basal osmotic water flow level was invariable in "clean" and contaminated FUB, whereas bacterial contamination resulted in considerable decrease in AVT-stimulated water flow ("clean": 2.53 +/- 0.13, n = 59, contaminated: 1.21 +/- 0.17 me/min/cm2, n = 38, p < 0.001, within first 15 min of incubation with 5 x 10(-10)M AVT). Gentamycin protection assay revealed predominantly adhesive forms of bacteria. Thus our data indicated that the presence of gram-negative bacteria colonizing the mucosal epithelium of the urinary bladder results in decreased adility of ADH to rise osmotic water permeability which in turn could impair body osmoregulation. PMID- 22834341 TI - [Correlation relationships between rats' fronral cortex and erythrocytes lipid composition during immobilization stress]. AB - The relationship between changes in phospholipids of red blood cells and frontal cortex during repeated 5, 10, 15, 20, 30 and 45 days of immobilization (for 2 hours a day) was studied on non-linear stress-resistant and stress-unstable white male rats. We suggested a regression equation that can be used for in vivo assessment of brain lipid composition under influence of the stress. PMID- 22834342 TI - [The effect of intracerebral mesenchymal stem cells transplantation on the density of microvascular network of the pial matter of the rat brain cortex]. AB - Using a TV installation for studying the microcirculation (with 30-160-fold magnification), the density of microvascular network in the pia matter of the rat brain sensomotor cortex was determined after intracerebral transplantation of mesenchymal stem cells (MSC) or (as control) of the MSC cultivation nutrition medium, or of saline. The results have shown that intracerebral transplantation does not change density of microvascular network in the pia mater of the ipsilateral hemisphere. Transplantation of the MSC led to a 1.8-fold increase of density of the pia matter of the contralateral hemisphere as compared with control animals; the number of arterioles in the same zone was 2.5-fold higher than in intact rats. PMID- 22834343 TI - [Condition of erythron in newbord rats with disturbed sensorimotor reflexes]. AB - Early adaptation issues of newborn rats of Wistar population and August line were examined. Absence of the connection between the condition of a female during the pregnancy and the birth, and newborn rats in early postnatal period was revealed. PMID- 22834344 TI - [Apoptosis of the hypothalamus neurosecretory cells in stress and ageing: the role of immune modulators]. AB - There is assumption about active role of immune modulators in cell death process. The involvement of interferon-alpha and cycloferon in apoptosis regulation of hypothalamic neurons of mice during stress and aging was studied. We determined the expression of apoptosis markers (Bcl-2, Mcl-1, Bax) in comparison with apoptosis level. We have found that immune modulators suppress activity of nonapeptidergic neurons. Thus, interferon-alpha treatment reduces synthesis of Bcl-2; cycloferon treatment inhibits expression of Bax and Bcl-2. So the role of immune modulators in neuron apoptosis depends on the stage of ontogenesis and type of immune modulator. Cycloferon is able to reduce the level of age-dependent apoptosis of neurons in aging, but under stress condition both interferon-alpha and cycloferon act as protectors of cell death. PMID- 22834345 TI - [Demography and population models of ticks of the genus Ixodes with long-term life cycles]. AB - The most important parameters necessary for the creation of population models for threehost species with long-term life cycles are discussed with an example of ticks Ixodes persulcatus and I. ricinus. In these species, specimens of the same biological age may belong to different age cohorts and their calendar age may differ by several months or even years. Accurate estimation of the calendar age of separate individuals is dofficult; it is based on the extrapolation by its possible biological age and by belonging to the certain age cohort of a natural population. Population models that can predict simultaneous abundance of activated hungry specimens of all the three developmental stages and probability of host-finding in hyngry ticks during questing period possess the prognostic value. Daily mortality of ticks of different developmental stages and phases of each stage (questing, feeding, preparation for molting, and diapause) must also be known. The abundance of questing hungry ticks in the ecosystem is determined by the balance between recruitment of the population with new individuals, their selection by hosts, dying of ticks from starvation, and consumption of ticks by predators. At present, unfortunately, only some of these parameters are known rather sufficiently. PMID- 22834346 TI - [Host influence on the frequency of block formation in males and females of Citellophilus tesquorum altaicus Ioff, 1936 (Siphonaptera: Ceratophyllidae) and transmission the plague pathogen by these fleas]. AB - Data obtained during feeding of Citellophilus tesquorum aitaicus Ioff, 1936 infested females and males (Siphonaptera: Ceratophyllidae), the main vectors of plague in Tuva natural plague locus, on the natural host and laboratory animal was analyzed. It was found that sexual differences in fleas depended on the type of the host. Females fed more actively on the longtailed ground Citellus undulatus than on white mouse. Alimentary activity of males on these animals was similar. Higher mortality of fed females and males was noted during feeding on mice. Frequency of formation of the "block" and transmission of the pathogen in males was higher during bloodsucking on the ground squirrel; in females, during feeding on mice. Thus, differences in the transmission of the plague pathogen, revealed in laboratory on white mice, can be quite different in nature. So, extrapolation of experimental data on natural processes of interrelations between plague pathogen and ectoparasites must be performed taking into account revealed peculiarities. PMID- 22834347 TI - [Trematodes fauna of waterfowl birds in Karelia]. AB - Trematode fauna of waterfowl birds of Karelia comprises 23 species; 8 of them are described from the region for the first time. Descriptions and figures of Urogonimus macrostomus, Neoeucotyle zakharovi, Hypoderaeum conoideum, Echinostoma robustum, Orchipedum tracheicola, Prostogonimus cuneatus P. ovatus, and P. rarus are given. PMID- 22834348 TI - [Quantitative analysis of seasonal dynamics of the species structure in a component parasite community of the minnow Phoxinus phoxinus (L.) of the Pechora River]. AB - Earlier analysis of a seasonal succession of fish parasites assemblage was, as a rule, performed in May-October. At the same time, winter season can be important in seasonal dynamics of the assemblage. In the present work, quantitative analysis of complete seasonal dynamics of species structure of fish assemblage parasites with an example of the adult minnow of the river Pechora was performed. The new stable state of parasites assemblage of the minnow, corresponding to winter season of its existence, is revealed. Irrespective of population density or a biomass of parasitic assemblages of the minnow, obtained dynamic phase portraits well reflect their seasonal succession. PMID- 22834349 TI - [Helminth fauna of the wolf (Canis lupus Linnaeus, 1758) in Belorussian Polesie]. AB - The results of our own long-term helminthological investigations (1980-2010) of wolves in Belorussian Polesie are presented. 87.2% of wolves were infected by helminths according to helminthological autopsy, and 98.5% by coproscopical data. 26 species of helminths were found: 5 trematode species, 9 cestode species, 11 nematode species and 1 acanthocephalan species. The wolf is a new host for nematode Dirofilaria immitis (Leidy, 1856) in Belarus. PMID- 22834350 TI - [Strongylids (Nematoda: Strongylidae) of domestic horses in Ukraine: modern state of Fauna and structure of the parasite community]. AB - Species composition and structure of the strongylid community was studies on helminthological material collected from 162 domestic horses from 11 regions of Ukraine by the in vivo method. Animals were treated with anthelmintic drug "Univerm" (0.2% aversectin C, Russia). Faecal samples (200 g each) were collected from every horse at 24, 36, 48 and 60 hours after treatment; all nematodes expelled (90.851 specimens) were collected and identified. Thirty-three strongylid species from 12 genera (8 species of subfamily Strongylinae and 25--of Cyathostominae) were found in domestic horses in Ukraine. Cyathostominae dominated in the strongylid community; they were found in 100 % horses and composed 98.21% of community. "Core" of the strongylid community was composed by 7 cyathostome species. Decreasing of proportion of Strongylinae in the community for last 40 years was registered; strongylines were found in 37.6% of horses and composed 1.25% of community. Maximal prevalence was 20.98% (Strongylus vulgaris). Bray-Curtis cluster analysis revealed high similarity of strongylid communities in horses from various regions of Ukraine. Difference in general structure of strongylid communities of horses from different horse-keeping conditions was established. Horses from farms with stable-paddock keeping conditions had bimodal strongylid community structure; while horses from stable-pasture keeping conditions possessed multimodal community structure. PMID- 22834351 TI - [Staining of microsporidian spores with diamidine phenylindole]. AB - A number of microscopic techniques and dyes are available to diagnose microsporidian infections in invertebrate and vertebrate hosts. Among these, DNA specific fluorochrome DAPI is widely used to stain DNA in prokaryotic and eukaryotic cells, alone or in combination with other histochemical or fluorescent dyes. Moreover, this dye also binds to membraneous structures and protein complexes. In our studies, DAPI was used to stain spores of microsporidia infecting orthopteran, coleopteran, dipteran and lepidopteran insect hosts. DAPI staining of diplokarya helped to discriminate the Nosema-like microsporidian spores from spore-shaped bodies lacking this characteristic staining. It was found, moreover, that non-DNA staining occurred in many cases and other components of the spores were stained: the exospore, the cytoplasm, the extruded polar filament and the polaroplast. Staining of these structures was feeble as compared to DNA and in most cases did not interfere with nuclear apparatus staining. Feebly stained cytoplasm and exospore clearly indicated unstained zone of endospore, making it easier to diagnose both mono- and diplokaryotic spores. Staining of extruded polar filament allowed to demonstrate viability and to observe some stages of extrusion process of microsporidian spores. PMID- 22834352 TI - Looking forward. Professional organizations offer array of educational programs for professional development. PMID- 22834353 TI - Twenty-first century surgery: Have we entered uncharted waters? PMID- 22834354 TI - Health information technology, meaningful use criteria, and their effects on surgeons. PMID- 22834355 TI - Enhancing American surgical training: meeting the challenge of a globalizing world. PMID- 22834356 TI - ASSET: An effective educational experience for practicing surgeons. PMID- 22834357 TI - The clinically negative axilla: The dilemma of occult metastases in sentinel nodes. PMID- 22834358 TI - [Application of a modified stage classification in evaluating wisdom tooth eruption in a German population]. AB - The evaluation of the eruption status of the wisdom teeth constitutes a significant component of the spectrum of dental methods available for purposes of forensic age diagnostics. In the present study, the status of wisdom tooth eruption was identified in 606 conventionally created orthopantomograms of 515 female and 91 male Germans, divided by sex and tooth, using a modified classification comprising four stages. Instead of the original stage C (gingival eruption) which cannot always be reliably identified on X-ray images of suboptimal quality, stage C of the modified classification was considered reached when the erupting wisdom tooth had reached at least half the length of the crown of the adjacent second molar, without however having yet reached the occlusal plane. The new stage classification is especially recommended for age estimation based on X-ray images in which a conclusive delimitation of the gingiva is not possible. PMID- 22834359 TI - [Does a positive finding of tetrahydrocannabinol in the blood result from ingestion of Indian frankincense (Boswellia serrata)?]. AB - The exculpatory statement that a positive THC finding in the blood is due to the consumption of hemp products or passive exposure to cannabis smoke has been disproved by the monitoring of hemp products and recent passive inhalation studies conducted in social settings, which showed that these conditions are unlikely to produce a positive result in the blood. The defense that the ingestion of Indian olibanum may result in a positive THC concentration in the blood is unusual; it is based on older publications where authors had speculated on a possible association of the synthetic pathways of THC from terpenoid precursors also being present in olibanum and the biogenesis of THC in hemp. It had further been speculated whether chemical or plant-derived pathways may also occur in humans. A thorough understanding of the different pathways and recently published results have outdated these speculations. PMID- 22834360 TI - [Simon's bleedings as a vital sign of hanging--a literature review]. AB - The intervertebral haemorrhages described by Simon in 1968 as a vital sign of hanging have been verified and endorsed by other authors. They occur in 40-50 % of hanging cases, most frequently in the lumbar spine, in younger age groups, and in cases of free suspension. The haemorrhages are not unique to hanging, but may occur in particular as a result of other traumatic elongation or overextension of the spinal column (e. g. in the course of traffic accidents). In cases of decomposition of the body, "false positive" findings are relatively common. As external findings scarcely provide any reliable vital signs of hanging, there is still a high demand for autopsies. In addition to Simon's bleedings, internal findings which are diagnostically conclusive also include microscopic examinations of the lungs and the neck musculature. More recent findings such as haemorrhages in the back and auxiliary respiratory muscles as well as the intestinal wall, if confirmed, could supplement Simon's bleedings. Frei's fibre sample and evidence of histamine in the ligature mark should not be neglected. Finally, it must be emphasized that the forensic assessment of hanging cases should always be based on a criminological and forensic evaluation of all the circumstances of the offence as well as on post-mortem findings. PMID- 22834361 TI - [Fall from height--surprising autopsy diagnosis in primarily unclear initial situations]. AB - External post-mortem examination and first police assessments are often not consistent with subsequent autopsy results. This is all the more surprising the more serious the injuries found at autopsy are. Such discrepancies result especially from an absence of gross external injuries, as demonstrated by four examples. A 42-year-old, externally uninjured male was found at night time in a helpless condition in the street and died in spite of resuscitation. Autopsy showed severe polytrauma with traumatic brain injury and lesions of the thoracic and abdominal organs. A jump from the third floor was identified as the cause. At dawn, a twenty-year-old male was found dead on the grounds of the adjacent house. Because of the blood-covered head the police assumed a traumatic head injury by strike impact. The external examination revealed only abrasions on the forehead and to a minor extent on the back. At autopsy a midfacial fracture, a trauma of the thorax and abdomen and fractures of the spine and pelvis were detected. Afterwards investigations showed that the man, intoxicated by alcohol, had fallen from the flat roof of a multistoried house. A 77-year-old man was found unconscious on his terrace at day time; a cerebral seizure was assumed. He was transferred to emergency care where he died. The corpse was externally inconspicuous. Autopsy revealed serious traumatic injuries of the brain, thorax, abdomen and pelvis, which could be explained by a fall from the balcony. A 47 year-old homeless person without any external injuries was found dead in a barn. An alcohol intoxication was assumed. At autopsy severe injuries of the brain and cervical spine were found which were the result of a fall from a height of 5 m. CONCLUSION: On the basis of an external post-mortem examination alone gross blunt force trauma cannot be reliably excluded. PMID- 22834362 TI - [Analysis with the Combur-Test--special aspects in forensic trace examination]. AB - The Combur Test is a ready-made and easy-to-use pretest for blood. It is based on the oxidation of tetramethylbenzidine (TMB), which is catalysed by haemoglobin and its derivatives. Despite its high sensitivity, there are many known substances which are responsible for false positive and false negative test results. On the basis of experiments of our own, case reports and the pertinent literature special aspects of the application of the Combur Test in the forensic routine case work are discussed. PMID- 22834363 TI - [Criminal superstition, pregnancy and infants at the turn of the 19th century]. AB - Around 1900, various crimes were still caused by criminal superstition. Criminologists like Hans Gross, Albert Hellwig and August Lowenstimm were engaged in the exploration of this topic aiming at the complete explanation of criminal behaviour linked to superstition. Crimes against pregnant women and infants are particularly good examples to illustrate the problems arising from crimes motivated by superstition. When assessing superstition under scientific and legal aspects, the criminologists applied different approaches, although positivistic rationalization was the most common tendency. In the forensic and legal evaluation of crimes related to superstition the problematical questions were whether the perpetrator was criminally responsible and how the offence was to be legally qualified. In many cases, criminals motivated by superstition were treated with more lenience. PMID- 22834364 TI - Parasite transmission in complex communities: predators and alternative hosts alter pathogenic infections in amphibians. AB - While often studied in isolation, host-parasite interactions are typically embedded within complex communities. Other community members, including predators and alternative hosts, can therefore alter parasite transmission (e.g., the dilution effect), yet few studies have experimentally evaluated more than one such mechanism. Here, we used data from natural wetlands to design experiments investigating how alternative hosts and predators of parasites mediate trematode (Ribeiroia ondatrae) infection in a focal amphibian host (Pseudacris regilla). In short-term predation bioassays involving mollusks, zooplankton, fish, larval insects, or newts, four of seven tested species removed 62-93% of infectious stages. In transmission experiments, damselfly nymphs (predators) and newt larvae (alternative hosts) reduced infection in P. regilla tadpoles by -50%, whereas mosquitofish (potential predators and alternative hosts) did not significantly influence transmission. Additional bioassays indicated that predators consumed parasites even in the presence of alternative prey. In natural wetlands, newts had similar infection intensities as P. regilla, suggesting that they commonly function as alternative hosts despite their unpalatability to downstream hosts, whereas mosquitofish had substantially lower infection intensities and are unlikely to function as hosts. These results underscore the importance of studying host-parasite interactions in complex communities and of broadly linking research on predation, biodiversity loss, and infectious diseases. PMID- 22834365 TI - Community ecology of invasions: direct and indirect effects of multiple invasive species on aquatic communities. AB - With many ecosystems now supporting multiple nonnative species from different trophic levels, it can be challenging to disentangle the net effects of invaders within a community context. Here, we combined wetland surveys with a mesocosm experiment to examine the individual and combined effects of nonnative fish predators and nonnative bullfrogs on aquatic communities. Among 139 wetlands, nonnative fish (bass, sunfish, and mosquitofish) negatively influenced the probability of occupancy of Pacific treefrogs (Pseudacris regilla), but neither invader correlated strongly with occupancy by California newts (Taricha torosa), western toads (Anaxyrus boreas), or California red-legged frogs (Rana draytonii). In mesocosms, mosquitofish dramatically reduced the abundance of zooplankton and palatable amphibian larvae (P. regilla and T. torosa), leading to increases in nutrient concentrations and phytoplankton (through loss of zooplankton), and rapid growth of unpalatable toad larvae (through competitive release). Bullfrog larvae reduced the growth of native anurans but had no effect on survival. Despite strong effects on natives, invaders did not negatively influence one another, and their combined effects were additive. Our results highlight how the net effects of multiple nonnative species depend on the trophic level of each invader, the form and magnitude of invader interactions, and the traits of native community members. PMID- 22834366 TI - Invasive ecosystem engineer selects for different phenotypes of an associated native species. AB - Invasive habitat-forming ecosystem engineers modify the abiotic environment and thus represent a major perturbation to many ecosystems. Because native species often persist in these invaded habitats but have no shared history with the ecosystem engineer, the engineer may impose novel selective pressure on native species. In this study, we used a phenotypic selection framework to determine whether an invasive habitat-forming ecosystem engineer (the seaweed Caulerpa taxifolia) selects for different phenotypes of a common co-occurring native species (the bivalve Anadara trapezia). Compared to unvegetated habitat, Caulerpa habitat has lower water flow, lower dissolved oxygen, and sediments are more silty and anoxic. We determined the performance consequences of variation in key functional traits that may be affected by these abiotic changes (shell morphology, gill mass, and palp mass) for Anadara transplanted into Caulerpa and unvegetated habitat. Both linear and nonlinear performance gradients in Anadara differed between habitats, and these gradients were stronger in Caulerpa compared to unvegetated sediment. Moreover, in Caulerpa alternate phenotypes performed well, and these phenotypes were different from the dominant phenotype in unvegetated sediment. By demonstrating that phenotype-performance gradients differ between habitats, we have highlighted a role for Caulerpa as an agent of selection on native species. PMID- 22834367 TI - Trend analyses of hierarchical pin-point cover data. AB - The use of state-space models for analyzing longitudinal hierarchical pin-point plant cover data is demonstrated. The main advantages of using a state-space model are (1) that the observed variance is separated into sampling variance and the more interesting structural variance which are needed for quantifying prediction uncertainty, (2) that missing values or an unbalanced sampling design readily may be accounted for, and (3) that the structural equation easily may be expanded and made as complex as necessary for modeling longitudinal pin-point cover data, thus allowing the incorporation of the most important ecological processes in the state-space model without technical difficulties. Typically, there is considerable spatial variation in plant abundance, and this variation is modeled using the Polya-Eggenberger distribution (a generalization of the beta binomial distribution). To illustrate this method, longitudinal hierarchical pin point data of Erica tetralix in wet Danish heathlands were analyzed, including and excluding autocorrelation and an environmental covariable in the state-space model. The pin-point plant cover data showed a significant decrease in the plant cover of E. tetralix in the period from 2004 to 2009, with an annual decrease of about 10% in the logit-transformed cover. The distribution of predicted plant cover at a given site the following year was calculated, including and excluding the information of an environmental covariable. PMID- 22834368 TI - Setbacks to shoot growth are common in woody plants, so how are shoots of some species safer than others? AB - Tissue turnover is a critical facet of plant life history variation. This study quantifies losses from setbacks to growth of terminal woody shoots 1.2m long, across 83 species and seven sites in eastern Australia. Setbacks, where the leading meristem had been removed or died and a new leader had emerged, were common (median three per shoot). Shoots had lost an average of 0.25 m of lead stem length for 1.2 m net shoot-length gain. Insects like girdlers and borers were prominent causes of large setbacks. The sites spanned tropical to temperate and humid to semiarid climates, but variation in stem loss was much greater across species than across sites. We measured 17 plant functional traits related to growth form, mechanics, hydraulics, and economics. Only four traits were correlated with variation across species in stem losses: stem diameter, stem nitrogen content, bark thickness, and maximum photosynthetic rate. The correlations were weak. Stem specific gravity (wood density) showed no correlation with risk. Our results suggest a pattern similar to the growth risk trade-off known for herbaceous plants, where traits associated with fast growth increase tissue turnover and herbivory, but the weak correlations leave ample scope for other influences that remain to be identified. PMID- 22834369 TI - Plant growth rates and seed size: a re-evaluation. AB - Small-seeded plant species are often reported to have high relative growth rate or RGR. However, because RGR declines as plants grow larger, small-seeded species could achieve higher RGR simply by virtue of their small size. In contrast, size standardized growth rate or SGR factors out these size effects. Differences in SGR can thus only be due to differences in morphology, allocation, or physiology. We used nonlinear regression to calculate SGR for comparison with RGR for 10 groups of species spanning a wide range of life forms. We found that RGR was negatively correlated with seed mass in nearly all groups, but the relationship between SGR and seed mass was highly variable. We conclude that small-seeded species only sometimes possess additional adaptations for rapid growth over and above their general size advantage. PMID- 22834370 TI - Small-scale grassland assembly patterns differ above and below the soil surface. AB - The existence of deterministic assembly rules for plant communities remains an important and unresolved topic in ecology. Most studies examining community assembly have sampled aboveground species diversity and composition. However, plants also coexist belowground, and many coexistence theories invoke belowground competition as an explanation for aboveground patterns. We used next-generation sequencing that enables the identification of roots and rhizomes from mixed species samples to measure coexisting species at small scales in temperate grasslands. We used comparable data from above (conventional methods) and below (molecular techniques) the soil surface (0.1 x 0.1 x 0.1 m volume). To detect evidence for nonrandom patterns in the direction of biotic or abiotic assembly processes, we used three assembly rules tests (richness variance, guild proportionality, and species co-occurrence indices) as well as pairwise association tests. We found support for biotic assembly rules aboveground, with lower variance in species richness than expected and more negative species associations. Belowground plant communities were structured more by abiotic processes, with greater variability in richness and guild proportionality than expected. Belowground assembly is largely driven by abiotic processes, with little evidence for competition-driven assembly, and this has implications for plant coexistence theories that are based on competition for soil resources. PMID- 22834371 TI - Spatial and temporal changes in group dynamics and range use enable anti-predator responses in African buffalo. AB - The reintroduction of large predators provides a framework to investigate responses by prey species to predators. Considerable research has been directed at the impact that reintroduced wolves (Canis lupus) have on cervids, and to a lesser degree, bovids, in northern temperate regions. Generally, these impacts alter feeding, activity, and ranging behavior, or combinations of these. However, there are few studies on the response of African bovids to reintroduced predators, and thus, there is limited data to compare responses by tropical and temperate ungulates to predator reintroductions. Using the reintroduction of lion (Panthera leo) into the Addo Elephant National Park (AENP) Main Camp Section, South Africa, we show that Cape buffalo (Syncerus caffer) responses differ from northern temperate ungulates. Following lion reintroduction, buffalo herds amalgamated into larger, more defendable units; this corresponded with an increase in the survival of juvenile buffalo. Current habitat preference of buffalo breeding herds is for open habitats, especially during the night and morning, when lion are active. The increase in group size and habitat preference countered initial high levels of predation on juvenile buffalo, resulting in a return in the proportion of juveniles in breeding herds to pre-lion levels. Our results show that buffalo responses to reintroduced large predators in southern Africa differ to those of northern temperate bovids or cervids in the face of wolf predation. We predict that the nature of the prey response to predator reintroduction is likely to reflect the trade-off between the predator selection and hunting strategy of predators against the life history and foraging strategies of each prey species. PMID- 22834372 TI - A multi-event model to study stage-dependent dispersal in radio-collared hares: when hunting promotes costly transience. AB - Behavioral ecologists have often assumed that dispersal is costly mainly because of unfamiliarity with traversed habitats during dispersal and energy costs of the movement per se; thus, dispersers that have successfully settled should experience survival rates comparable to those of philopatric individuals. In this paper, we tested that hypothesis using 152 radio-collared European hares in a harvested population. We developed a multi-event capture recapture model, combining telemetry data and recoveries and separately modeling the foray probability, the settlement probability, and the permanent dispersal probability. The parameterization introduced here raises the possibility of separately testing effects on survival and dispersal probabilities at each stage of dispersal (departure, transience, and settlement). In accordance with our expectations, we reveal that dispersers incur higher mortality risks during transience and the early settlement period than philopatric individuals or settled dispersers. We also found that dispersers suffer from higher risks of being shot. Those results illustrate that unfamiliarity with the habitat during transience makes dispersal costly and that settled dispersers may enjoy survival rates comparable to those of philopatric individuals. Surprisingly, we also found that individuals have a higher probability of foraying during the hunting season. We suggest that hunting and related disturbances increase dispersal costs both by increasing mortality risk during transience and (perhaps) by increasing movement rates. We emphasize the need to take human pressures into account as factors that may drive the demographics of movements in populations. PMID- 22834373 TI - Habitat selection predicts genetic relatedness in an alpine ungulate. AB - Landscape heterogeneity plays an integral role in shaping ecological and evolutionary processes. Despite links between the two disciplines, ecologists and population geneticists have taken different approaches to evaluating habitat selection, animal movement, and gene flow across the landscape. Ecologists commonly use statistical models such as resource selection functions (RSFs) to identify habitat features disproportionately selected by animals, whereas population genetic approaches model genetic differentiation according to the distribution of habitat variables. We combined ecological and genetic approaches by using RSFs to predict genetic relatedness across a heterogeneous landscape. We constructed sex- and season-specific resistance surfaces based on RSFs estimated using data from 102 GPS (global positioning system) radio-collared mountain goats (Oreamnos americanus) in southeast Alaska, USA. Based on mountain goat ecology, we hypothesized that summer and male surfaces would be the best predictors of relatedness. All individuals were genotyped at 22 microsatellite loci, which we used to estimate genetic relatedness. Summer resistance surfaces derived from RSFs were the best predictors of genetic relatedness, and winter models the poorest. Mountain goats generally selected for areas close to escape terrain and with a high heat load (a metric related to vegetative productivity and snow depth), while avoiding valleys. Male- and female-specific surfaces were similar, except for winter, for which male habitat selection better predicted genetic relatedness. The null models of isolation-by-distance and barrier only outperformed the winter models. This study merges high-resolution individual locations through GPS telemetry and genetic data, that can be used to validate and parameterize landscape genetics models, and further elucidates the relationship between landscape heterogeneity and genetic differentiation. PMID- 22834374 TI - The roles of competition and environmental heterogeneity in the maintenance of behavioral variation and covariation. AB - Many models of selection predict that populations will lose variation in traits that affect fitness. Nonetheless, phenotypic variation is commonly observed in natural populations. We tested the influences of competition and spatial heterogeneity on behavioral variation within and among populations of Merriam's kangaroo rats (Dipodomys merriami) and tested for the differential expression of trait correlations. We found that populations of D. merriami exhibited more aggression at sites with more competition. Contrary to theoretical predictions and empirical results in other systems, the sites with the greatest spatial heterogeneity and highest levels of competition did not exhibit the most behavioral variation among individuals. However, the greatest within-individual behavioral variability in boldness (response to cues of predator presence) was exhibited where spatial heterogeneity was highest. Aggression and boldness of D. merriami were highly repeatable, that is, individuals behaved in a consistent manner over time, and the two behaviors were also highly correlated. Interestingly, the strength of this correlation was greatest where the competitive community was least diverse. These findings add to increasing evidence that natural populations of animals exhibit patterns of behavioral covariance, or personality structure, and suggest that competitive variation may act to erode personality structure. PMID- 22834375 TI - Generalists and specialists along a latitudinal transect: patterns of thermal adaptation in six species of damselflies. AB - Tropical organisms colonizing temperate environments face reduced average temperatures and dramatic thermal fluctuations. Theoretical models postulate that thermal specialization should be favored either when little environmental variation is experienced within generations or when among-generation variation is small relative to within-generation variation. To test these predictions, we studied six temperate species of damselflies differing in latitudinal distribution. We developed a computer model simulating how organisms experience environmental variation (accounting for diapause and voltinism) and performed a laboratory experiment assaying thermal sensitivities of growth rates. The computer model showed opposing latitudinal trends in among- and within-generation thermal variability: within-generation thermal variability decreased toward higher latitudes, whereas relative levels of among-generation thermal variability peaked at midlatitudes (where a shift in voltinism occurred). The growth experiment showed that low-latitude species were more thermally generalized than mid- and high-latitude species, supporting the prediction that generalists are favored under high levels of within-generation variation. Northern species had steeper, near-exponential reaction norms suggestive of thermal specialization. However, they had strikingly high thermal optima and grew very slowly over most of the thermal range they are expected to experience in the field. This observation is at present difficult to explain. These results highlight the importance of considering interactions between life history and environmental variation when deriving expectations of thermal adaptation. PMID- 22834376 TI - Climatic niche divergence or conservatism? Environmental niches and range limits in ecologically similar damselflies. AB - The factors that determine species' range limits are of central interest to biologists. One particularly interesting group comprises odonates (dragonflies and damselflies), which show large differences in secondary sexual traits and respond quickly to climatic factors, but often have minor interspecific niche differences, challenging models of niche-based species coexistence. We quantified the environmental niches at two geographic scales to understand the ecological causes of northern range limits and the coexistence of two congeneric damselflies (Calopteryx splendens and C. virgo). Using environmental niche modeling, we quantified niche divergence first across the whole geographic range in Fennoscandia, and second only in the sympatric part of this range. We found evidence for interspecific divergence along the environmental axes of temperature and precipitation across the northern range in Fennoscandia, suggesting that adaptation to colder and wetter climate might have allowed C. virgo to expand farther north than C. splendens. However, in the sympatric zone in southern Fennoscandia we found only negligible and nonsignificant niche differences. Minor niche differences in sympatry lead to frequent encounters and intense interspecific sexual interactions at the local scale of populations. Nevertheless, niche differences across Fennoscandia suggest that species differences in physiological tolerances limit range expansions northward, and that current and future climate could have large effects on the distributional ranges of these and ecologically similar insects. PMID- 22834377 TI - Spatially integrated assessment reveals widespread changes in penguin populations on the Antarctic Peninsula. AB - As important marine mesopredators and sensitive indicators of Antarctic ecosystem change, penguins have been a major focus of long-term biological research in the Antarctic. However, the vast majority of such studies have been constrained by logistics and relate mostly to the temporal dynamics of individual breeding populations from which regional trends have been inferred, often without regard for the complex spatial heterogeneity of population processes and the underlying environmental conditions. Integrating diverse census data from 70 breeding sites across 31 years in a robust, hierarchical analysis, we find that trends from intensely studied populations may poorly reflect regional dynamics and confuse interpretation of environmental drivers. Results from integrated analyses confirm that Pygoscelis adeliae (Adelie Penguins) are decreasing at almost all locations on the Antarctic Peninsula. Results also resolve previously contradictory studies and unambiguously establish that P. antarctica (Chinstrap Penguins), thought to benefit from decreasing sea ice, are instead declining regionally. In contrast, another open-water species, P. papua (Gentoo Penguin), is increasing in abundance and expanding southward. These disparate population trends accord with recent mechanistic hypotheses of biological change in the Southern Ocean and highlight limitations of the influential but oversimplified "sea ice" hypothesis. Aggregating population data at the regional scale also allows us to quantify rates of regional population change in a way not previously possible. PMID- 22834378 TI - How do dispersal costs and habitat selection influence realized population connectivity? AB - Despite the importance of dispersal for population connectivity, dispersal is often costly to the individual. A major impediment to understanding connectivity has been a lack of data combining the movement of individuals and their survival to reproduction in the new habitat (realized connectivity). Although mortality often occurs during dispersal (an immediate cost), in many organisms costs are paid after dispersal (deferred costs). It is unclear how such deferred costs influence the mismatch between dispersal and realized connectivity. Through a series of experiments in the field and laboratory, we estimated both direct and indirect deferred costs in a marine bryozoan (Bugula neritina). We then used the empirical data to parameterize a theoretical model in order to formalize predictions about how dispersal costs influence realized connectivity. Individuals were more likely to colonize poor-quality habitat after prolonged dispersal durations. Individuals that colonized poor-quality habitat performed poorly after colonization because of some property of the habitat (an indirect deferred cost) rather than from prolonged dispersal per se (a direct deferred cost). Our theoretical model predicted that indirect deferred costs could result in nonlinear mismatches between spatial patterns of potential and realized connectivity. The deferred costs of dispersal are likely to be crucial for determining how well patterns of dispersal reflect realized connectivity. Ignoring these deferred costs could lead to inaccurate predictions of spatial population dynamics. PMID- 22834379 TI - Density-dependent facilitation cascades determine epifaunal community structure in temperate Australian mangroves. AB - Co-occurring foundation species can determine biological community structure via facilitation cascades. We examined the density dependencies of facilitation cascades, including how the density of a basal foundation species influences the density of secondary foundation species, and how the density of secondary foundation species influences community structure. The system in which we assessed density dependencies was a temperate mangrove forest in which pneumatophores trap the fucoid alga Hormosira banksii and provide substrate for the oyster, Saccostrea glomerata. The alga and oyster in turn determine benthic community structure. In the field, algal biomass was positively correlated with pneumatophore density. Oysters, by contrast, were highly over-dispersed and correlated with the presence/absence of pneumatophores. Epifaunal abundance and species richness were positively correlated with algal and oyster abundance, but their effects were independent. The positive effect of pneumatophore density on epifauna was primarily an indirect effect of trapping more algae. Pneumatophores did not directly influence invertebrate communities. Experiments revealed that, at very low pneumatophore densities, algal retention was insufficient to facilitate epifauna above that found on pneumatophores alone. At higher densities, however, increasing the density of pneumatophores increased algal retention, and the density and diversity of associated invertebrates. Shading by the mangrove canopy reduced algal biomass but did not modify the density dependent nature of the cascade. Our results extend facilitation theory by showing that the density of both basal and secondary foundation species can be critical in triggering facilitation cascades. Our study also reveals that, where foundation species co-occur, multiple, independent cascades may arise from a single basal facilitator. These findings enhance our understanding of the role of density-dependent facilitation cascades in community assembly. PMID- 22834381 TI - A neighboring plant species creates associational refuge for consumer and host. AB - Examples of plant-animal and plant-plant associational defenses are common across a variety of systems, yet the potential for them to occur in concert has not been explored. In salt marshes in the Gulf of Mexico, the marsh periwinkle (Littoraria irrorata) is an abundant and conspicuous member of the community, climbing up the stems of marsh plants to remain out of the water at high tide. Though Littoraria are thought to primarily utilize stems of marsh cordgrass Spartina alterniflora as a source of food and refuge, Littoraria were more abundant in mixed assemblages of Spartina and Juncus roemerianus than in Spartina-only areas at the same tidal height. Mesocosm experiments confirmed that Juncus provided a refuge for Littoraria, with predation by Callinectes sapidus (but not Melongena corona) reduced when Juncus was present. However, Littoraria's utilization of Juncus as well as the effectiveness of Juncus as a refuge depended strongly on plant height: when Juncus was experimentally clipped to a shorter height than Spartina, snail abundance on Spartina and snail predation by crabs increased. Interestingly, this plant animal refuge led to a corresponding refuge for Spartina from Littoraria: Spartina plants lost less biomass to snail grazing when growing with Juncus in mesocosm and field experiments, and Spartina plants in natural assemblages were taller when growing with Juncus than when growing alone, even in the presence of abundant snails. This example highlights the potential importance of plant plant and plant-animal associational refuges in competitive plant assemblages. PMID- 22834380 TI - A trophic cascade triggers collapse of a salt-marsh ecosystem with intensive recreational fishing. AB - Overexploitation of predators has been linked to the collapse of a growing number of shallow-water marine ecosystems. However, salt-marsh ecosystems are often viewed and managed as systems controlled by physical processes, despite recent evidence for herbivore-driven die-off of marsh vegetation. Here we use field observations, experiments, and historical records at 14 sites to examine whether the recently reported die-off of northwestern Atlantic salt marshes is associated with the cascading effects of predator dynamics and intensive recreational fishing activity. We found that the localized depletion of top predators at sites accessible to recreational anglers has triggered the proliferation of herbivorous crabs, which in turn results in runaway consumption of marsh vegetation. This suggests that overfishing may be a general mechanism underlying the consumer driven die-off of salt marshes spreading throughout the western Atlantic. Our findings support the emerging realization that consumers play a dominant role in regulating marine plant communities and can lead to ecosystem collapse when their impacts are amplified by human activities, including recreational fishing. PMID- 22834382 TI - Warming modifies trophic cascades and eutrophication in experimental freshwater communities. AB - Climate warming is occurring in concert with other anthropogenic changes to ecosystems. However, it is unknown whether and how warming alters the importance of top-down vs. bottom-up control over community productivity and variability. We performed a 16-month factorial experimental manipulation of warming, nutrient enrichment, and predator presence in replicated freshwater pond mesocosms to test their independent and interactive impacts. Warming strengthened trophic cascades from fish to primary producers, and it decreased the impact of eutrophication on the mean and temporal variation of phytoplankton biomass. These impacts varied seasonally, with higher temperatures leading to stronger trophic cascades in winter and weaker algae blooms under eutrophication in summer. Our results suggest that higher temperatures may shift the control of primary production in freshwater ponds toward stronger top-down and weaker bottom-up effects. The dampened temporal variability of algal biomass under eutrophication at higher temperatures suggests that warming may stabilize some ecosystem processes. PMID- 22834383 TI - Inversion of plant dominance-diversity relationships along a latitudinal stress gradient. AB - Species interactions affect plant diversity through the net effects of competition and facilitation, with the latter more prevalent in physically stressful environments when plant cover ameliorates abiotic stress. One explanation for species loss in invader-dominated systems is a shift in the competition-facilitation balance, with competition intensifying in areas formerly structured by facilitation. We test this possibility with a 10-site prairie meta experiment along a 500-km latitudinal stress gradient, quantifying the relationships among abiotic stress, exotic dominance, and native plant recruitment over five years. The latitudinal gradient is inversely correlated with abiotic stress, with lower latitudes more moisture- and nutrient-limited. We observed strong negative effects by invasive dominant grasses on plant establishment, but only in northern sites with lower-stress environments. At these locations, disturbance was critical for recruitment by reducing the suppressive dominant (invasive) canopy. In more stressful environments to the south, the impacts of the dominant invaders on plant establishment became facilitative, and diversity was more limited by seed availability. Disturbance prevented recruitment because seedling survival depended on a protective plant canopy, presumably because the canopy reduced temperature or moisture stress. Seed limitation was similarly prevalent in all sites. Our work confirms the importance of facilitation as an organizing process for plants in higher-stress environments, even with transformations of species composition and dominance. It also demonstrates that the mechanisms regulating diversity, including invader impacts, can vary within the same plant community depending on environmental context. Because limits on native plant recruitment are environmentally contingent, management strategies that seek to increase diversity, including invader eradication, must account for site-level variations in the balance between biotic and abiotic constraints. PMID- 22834384 TI - Biophysical feedback mediates effects of invasive grasses on coastal dune shape. AB - Vegetation at the aquatic-terrestrial interface can alter landscape features through its growth and interactions with sediment and fluids. Even similar species may impart different effects due to variation in their interactions and feedbacks with the environment. Consequently, replacement of one engineering species by another can cause significant change in the physical environment. Here we investigate the species-specific ecological mechanisms influencing the geomorphology of U.S. Pacific Northwest coastal dunes. Over the last century, this system changed from open, shifting sand dunes with sparse vegetation (including native beach grass, Elymus mollis), to densely vegetated continuous foredune ridges resulting from the introduction and subsequent invasions of two nonnative grass species (Ammophila arenaria and Ammophila breviligulata), each of which is associated with different dune shapes and sediment supply rates along the coast. Here we propose a biophysical feedback responsible for differences in dune shape, and we investigate two, non-mutually exclusive ecological mechanisms for these differences: (1) species differ in their ability to capture sand and (2) species differ in their growth habit in response to sand deposition. To investigate sand capture, we used a moveable bed wind tunnel experiment and found that increasing tiller density increased sand capture efficiency and that, under different experimental densities, the native grass had higher sand capture efficiency compared to the Ammophila congeners. However, the greater densities of nonnative grasses under field conditions suggest that they have greater potential to capture more sand overall. We used a mesocosm experiment to look at plant growth responses to sand deposition and found that, in response to increasing sand supply rates, A. arenaria produced higher-density vertical tillers (characteristic of higher sand capture efficiency), while A. breviligulata and E. mollis responded with lower-density lateral tiller growth (characteristic of lower sand capture efficiency). Combined, these experiments provide evidence for a species-specific effect on coastal dune shape. Understanding how dominant ecosystem engineers, especially nonnative ones, differ in their interactions with abiotic factors is necessary to better parameterize coastal vulnerability models and inform management practices related to both coastal protection ecosystem services and ecosystem restoration. PMID- 22834385 TI - Seed and establishment limitation contribute to long-term native forb declines in California grasslands. AB - The effects of exotic species invasions on biodiversity vary with spatial scale, and documentation of local-scale changes in biodiversity following invasion is generally lacking. Coupling long-term observations of local community dynamics with experiments to determine the role played by exotic species in recruitment limitation of native species would inform both our understanding of exotic impacts on natives at local scales and regional-scale management efforts to promote native persistence. We used field experimentation to quantify propagule and establishment limitation in a suite of native annual forbs in a California reserve, and compared these findings to species abundance trends within the same sites over the past 48 years. Observations at 11 paired sites (inside and outside the reserve) indicated that exotic annual plants have continued to increase in abundance over the past 48 years. This trend suggests the system has not reached equilibrium > 250 years after exotic species began to spread, and 70 years after livestock grazing ceased within the reserve. Long-term monitoring observations also indicated that six native annual forb species went extinct from more local populations than were colonized. To determine the potential role of exotic species in these native plant declines, we added seed of these species into plots adjacent to monitoring sites where plant litter and live grass competition were removed. Experimental results suggest both propagule and establishment limitation have contributed to local declines observed for these native forbs. Recruitment was highest at sites that had current or historical occurrences of the seeded species, and in plots where litter was removed. Grazing history (i.e., location within or outside the reserve) interacted with exotic competition removal, such that removal of live grass competition increased recruitment in more recently grazed sites. Abundance of forbs was positively related to recruitment, while abundance of exotic forbs was negatively related. Thus, exotic competition is likely only one factor contributing to local declines of native species in invaded ecosystems, with a combination of propagule limitation, site quality, and land use history also playing important and interactive roles in native plant recruitment. PMID- 22834386 TI - Do evergreen and deciduous trees have different effects on net N mineralization in soil? AB - Evergreen and deciduous plants are widely expected to have different impacts on soil nitrogen (N) availability because of differences in leaf litter chemistry and ensuing effects on net N mineralization (N(min)). We evaluated this hypothesis by compiling published data on net N(min) rates beneath co-occurring stands of evergreen and deciduous trees. The compiled data included 35 sets of co occurring stands in temperate and boreal forests. Evergreen and deciduous stands did not have consistently divergent effects on net N(min) rates; net N(min) beneath deciduous trees was higher when comparing natural stands (19 contrasts), but equivalent to evergreens in plantations (16 contrasts). We also compared net N(min) rates beneath pairs of co-occurring genera. Most pairs of genera did not differ consistently, i.e., tree species from one genus had higher net N(min) at some sites and lower net N(min) at other sites. Moreover, several common deciduous genera (Acer, Betula, Populus) and deciduous Quercus spp. did not typically have higher net N(min) rates than common evergreen genera (Pinus, Picea). There are several reasons why tree effects on net N(min) are poorly predicted by leaf habit and phylogeny. For example, the amount of N mineralized from decomposing leaves might be less than the amount of N mineralized from organic matter pools that are less affected by leaf litter traits, such as dead roots and soil organic matter. Also, effects of plant traits and plant groups on net N(min) probably depend on site-specific factors such as stand age and soil type. PMID- 22834387 TI - Is the Mantel correlogram powerful enough to be useful in ecological analysis? A simulation study. AB - The Mantel correlogram is an elegant way to compute a correlogram for multivariate data. However, recent papers raised concerns about the power of the Mantel test itself. Hence the question: Is the Mantel correlogram powerful enough to be useful? To explore this issue, we compared the performances of the Mantel correlogram to those of other methods, using numerical simulations based on random, normally distributed data. For a single response variable, we compared it to the Moran and Geary correlograms. Type I error rates of the three methods were correct. Power of the Mantel correlogram was nearly as high as that of the univariate methods. For the multivariate case, the test of the multivariate variogram developed in the context of multiscale ordination is in fact a Mantel test, so that the power of the two methods is the same by definition. We devised an alternative permutation test based on the variance, which yielded similar results. Overall, the power of the Mantel test was high, the method successfully detecting spatial correlation at rates similar to the permutation test of the variance statistic in multivariate variograms. We conclude that the Mantel correlogram deserves its place in the ecologist's toolbox. PMID- 22834388 TI - Niche and fitness differences relate the maintenance of diversity to ecosystem function: comment. PMID- 22834389 TI - Treatment options for the maintenance of marginal bone around endosseous oral implants. Introductory remarks. PMID- 22834390 TI - Working Group on Treatment Options for the Maintenance of Marginal Bone Around Endosseous Oral Implants, Stockholm, Sweden, 8 and 9 September 2011. Methodology. AB - PURPOSE: To reach through intense interactions among a group of renowned experts a better view of the treatment options available for marginal bone maintenance and eventual inflammation and/or loss around oral implants. The working group was intended to generate guidelines useful for th clinical community at large. FORMAT: Two days of interactive presentations and discussions on the basis of review papers delivered beforehand by the participants. Each of the participants was asked to focus on a particular aspect of the global theme--maintenance of marginal bone around oral implants and treatment options while keeping a global view for further discussion. From the prepared reviews only the conclusions were presented at the meeting as an introduction for the discussions. The reviews were distributed among all participants beforehand and, if needed, the other participants could draw the attention of the author on missing aspects and references prior to the meeting. A general consensus was formulated. The consensus was amended during the two days of the meeting until a unanimous opinion was reached. Minority statements could be considered. The review papers were not required to be systematic reviews (time and means were lacking) but they were to be valuable critical analyses considering the internationally recognised expertise of the authors. PMID- 22834391 TI - Peri-implant marginal bone loss: an academic controversy or a clinical challenge? AB - PURPOSE: The aim of this narrative review was to explore and discuss marginal bone loss around transmucosal oral implants and the related incidence of this biologic complication. RESULTS: Treatment with osseointegrated implants is most often successful and improves the quality of life for the patient. At present only limited data are available to evaluate long-term technical and biological complications. When peri-implant tissue destruction occurs, little is known about the initiating process. Possible factors of relevance for the initiation and progression of peri-implantitis are discussed. Periodontitis, smoking and a variety of local factors are among the most plausible putative reported risk factors. Also, oral hygiene and the inability to clean the reconstruction were reported. The unit for reporting incidence of peri-implant bone loss varies in different studies between implants and patients. Since there seems to be a clustering effect, and implants in the same mouth cannot be considered independent from each other, it is recommended to use the patient as a unit. The different cut-off values for clinical parameters reported in different studies will exert a significant influence on the magnitude of the reported incidence of peri-implantitis. It is suggested that the composite variables including bone loss > or =2 mm, compared to initial radiographs at delivery of the prosthetic device, in combination with bleeding on probing should be interpreted as a 'red flag' for the clinician to critically evaluate if any intervention is indicated in the individual case. CONCLUSION: Until more solid scientific evidence has been made available, it is likely that the academic controversy in relation to peri implant bone loss and peri-implantitis will continue. PMID- 22834392 TI - Treatment of peri-implantitis: what interventions are effective? A Cochrane systematic review. AB - PURPOSE: To identify the most effective interventions for treating peri implantitis around osseointe-grated oral implants. MATERIALS AND METHODS: The Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE were searched up to the 9th of June 2011 for randomised controlled trials (RCTs) comparing agents or interventions for treating peri-implantitis around oral implants. Primary outcome measures were implant failure, radiographic marginal bone level change, complications and side effects, and recurrence of peri implantitis. Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. The statistical unit was the patient and not the implant unless the clustering of the implants within the patients had been taken into account. Results were expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CI). RESULTS: Fifteen eligible trials were identified, but six were excluded. The following interventions were compared in the nine included studies: different non-surgical interventions (five trials), adjunctive treatments to non-surgical interventions (one trial), and different surgical interventions (two trials) and adjunctive treatments to surgical interventions (one trial). Follow-up ranged from 3 months to 4 years. No study was judged to be at low risk of bias. Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After 4 months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% CI 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After 4 years, patients with periimplant infrabony defects >3 mm treated with Bio-Oss and resorbable barriers showed an improvement of 1.4 mm for PAL (95% CI 0.24 to 2.56) and PPD (95% CI 0.81 to 1.99) compared to patients treated with a nanocrystalline hydroxyapatite. CONCLUSIONS: There is no reliable evidence suggesting which could be the most effective interventions for treating peri-implantitis. This is not to say that currently used interventions are not effective. A single small trial at unclear risk of bias showed that the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement in PAL and PPD over a 4-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after 4 years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies, which basically consisted of simple subgingival mechanical debridement. Follow-up longer than 1 year suggested recurrence of peri-implantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-ups longer than 1 year are needed. PMID- 22834393 TI - Antibiotics in the treatment of peri-implantitis. AB - PURPOSE: To review and discuss current literature on the use of systemically administered or locally delivered antibiotics in the treatment of peri implantitis. MATERIALS AND METHODS: A literature search was conducted using MEDLINE through the PubMed database of the US National Library of Medicine using studies up to 2011. Studies on the microbiology of peri-implantitis lesions were hand selected. RESULTS AND CONCLUSIONS: Two studies on the use of systemically administered antibiotics in the treatment of peri-implantitis were identified. Both studies involved a case series without controls. Five studies on locally delivered antibiotics were found. In all cases, local antibiotics were used in conjunction with mechanical debridement and chemical disinfection with antimicrobial agents such as chlorhexidine digluconate or hydrogen peroxide. The additional effects of local antibiotics were noted in all studies but were in general moderate. This may in part be due to the selection of patients with advanced deep pockets and advanced bone loss. The current available scientific information on the use of locally or systemically administered antibiotics is insufficient to allow any firm specific recommendations for the use of these drugs. Local application of minocycline or doxycycline as an adjunct to mechanical debridement and irrigation with an antimicrobial agent may be effective in moderately deep lesions. Surgical access by full-thickness flap surgery in deeper lesions is probably necessary to halt the progression of bone loss. No sound scientific basis is available for the use of systemic antibiotics. There is an urgent need for randomised clinical trials on the use of antibiotics in the treatment of peri-implantitis. Proper periodontal infection control in dentate patients before implants are installed and frequent supportive implant care represent effective measures to reduce the risk of future infections and their complications around oral implants. PMID- 22834394 TI - The impact of genotypes and immune reactivity on peri-implant inflammation: Identification and therapeutic use of anti-inflammatory drugs and immunomodulators. AB - PURPOSE: Peri-implantitis is a growing problem because of the increasing number of patients rehabilitated with oral implants. Predictors of susceptibility to peri-implantitis and pharmacological agents for the treatment of inflammatory peri-implantitis are of significant interest to the practicing community. The goal of this paper is to review the current literature relating to the impact of genotypes and immune reactivity on peri-implant inflammation and to identify the potential use of anti-inflammatory and immunomodulatory drugs. MATERIALS AND METHODS: A MEDLINE search of the relevant literature was performed and all related articles were evaluated. RESULTS: There was little support in the literature for a specific genotype or phenotype of immune reactivity that could be reliably used as an indicator of susceptibility to peri-implant disease. Furthermore, no currently available anti-inflammatory drugs were identified that could be used long term for the treatment of inflammatory peri-implantitis. New pathways for the control of inflammation have been identified that have the potential for new pharmacologic therapies. The basis for these new discoveries is reviewed in some detail. CONCLUSIONS: While there are varying reports of associations of specific genotypes with peri-implantitis, the studies are inconsistent and generally underpowered precluding any interpretable pattern. Inflammatory peri-implantitis is associated with increased local inflammation, but no consistent systemic inflammatory markers have been identified. To date, no safe and effective anti-inflammatory therapy is known for the treatment of peri implantitis. However, a new class of molecules in development for the active regulation and resolution of inflammation shows theoretical promise for the treatment of inflammatory lesions. PMID- 22834395 TI - Surgical treatments of peri-implantitis. PMID- 22834396 TI - Mechanical, chemical and laser treatments of the implant surface in the presence of marginal bone loss around implants. AB - PURPOSE: The objective of this review was to summarise current evidence with regard to the decontamination of implant surfaces by mechanical, chemical and physical methods in the presence of marginal bone loss arising from peri-implant infections. MATERIALS AND METHODS: A PubMed search identified studies and publications dealing with 'peri-implantitis', 'treatment', 'surface decontamination', 'laser application' 'air-abrasive treatment' and 'photodynamic therapy'. Only studies in international peer-reviewed journals were selected for further evaluation; case reports were not included. RESULTS: Several therapeutic approaches were identified such as mechanical treatment, antiseptics and air abrasive treatment, photodynamic treatment, and laser applications. Since treatment of infected surfaces with air-powder +/- citric acid, gauze soaked with saline + citric acid or gauze soaked with chlorhexidine led to similar results in experimental studies, cotton pellets with saline may be adequate for cleaning micro-rough surfaces. Antimicrobial photodynamic therapy can effectively reduce the prevalence of pathogens on implant surfaces, but the clinical benefits remain unknown. The increase in temperature of the implant surface caused by the CO2 laser poses a risk. The Er:YAG laser is considered to possess the best properties for implant surface decontamination. In vivo, no single method of surface decontamination (chemical agents, air abrasives or lasers) was found to be superior. In several animal experiments, thorough cleaning of the infected implant surfaces and implantation of these previously infected devices into freshly prepared sites resulted in re-osseointegration, while currently there are no controlled clinical trials where re-osseointegration has been demonstrated in patients. CONCLUSIONS: For decontamination of the infected implant surfaces, rinsing with saline (or cleaning with cotton pellets soaked with sterile saline) and air-abrasive treatment seem to work. Laser decontamination of the surface does not improve healing results. Non-surgical therapy of implants with peri implantitis does not lead to successful treatment outcomes. PMID- 22834397 TI - The impact of the type and configuration of abutments and their (repeated) removal on the attachment level and marginal bone. AB - PURPOSE: The quality and stability of the soft tissue-implant interface is most likely of paramount importance for the preservation of marginal bone and for the long-term prognosis of oral implants. The aim of the present review was to screen existing data in the literature concerning the influence of transmucosal components' composition, type, design and disconnection on peri-implant tissues. RESULTS: The influence of the type of implant system (one-piece or soft tissue level implants versus two-piece or bone level implants) has been poorly studied in humans, and data from animal studies are controversial; both concepts demonstrated comparable long-term stability of peri-implant tissues. The chemical composition of abutments has been mostly studied in animals, with the conclusion that only a few materials (namely titanium, aluminium and zirconium oxides) allow the proper formation of a soft tissue interface. However, there is a severe lack of information about the clinical impact of this parameter, as well as of surface contamination of abutments. Mobility of transmucosal components has been shown to increase marginal bone loss in animals, while the influence of abutment disconnection is more controversial. Only one clinical study suggests that a 'one abutment-one time' technique preserves marginal bone. Studies investigating the influence of platform switching suggest that using an abutment narrower than the implant's platform could have a positive effect on the fate of marginal bone. But those studies are extremely heterogenous and their results controversial. CONCLUSION: There is still a severe lack of information about the clinical impact of implant type, of implant/abutment connection, and of abutment composition and stability on peri-implant bone remodelling. PMID- 22834398 TI - Identifying occlusal overload and how to deal with it to avoid marginal bone loss around implants. AB - BACKGROUND: Occlusal overloading is the primary cause of biomechanical implant complications, which include fracture and/or loosening of the implant fixture and/or prosthetic components. It may also disrupt the intricate bond between the implant surface and bone, leading to peri-implant bone loss and eventual implant failure. PURPOSE: This paper was aimed at identifying and evaluating clinical and radiographic parameters relevant for diagnosing occlusal overloading of oral implants. It also discusses its management in order to prevent peri-implant marginal bone loss. MATERIALS AND METHODS: An electronic literature search for relevant studies, examining the relationship between occlusal overloading and peri-implant bone loss, was conducted in the PubMed database. Clinical human studies published in English with a minimum of 10 implants were included. RESULTS: Seven articles were identified. Occlusal overloading was found to be positively associated with peri-implant marginal bone loss. CONCLUSION: Preventing occlusal overloading involves conducting comprehensive examinations, treatment planning, precise surgical and prosthetic treatment executions, and regular maintenance. If occlusal overloading occurs, management of biomechanical implant complications and preventing/treating peri-implant bone loss involves surgical and prosthetic treatment modalities. They include occlusal treatment, repair and replacement of defective prosthetic components, and surgical treatment of the bony craters. PMID- 22834399 TI - Working Group on the Treatment Options for the Maintenance of Marginal Bone Around Endosseous Oral Implants, Stockholm, Sweden, 8 and 9 September 2011. Consensus statements. PMID- 22834400 TI - Iron chelation and nanoparticle target delivery in the development of new multifunctional disease-modifying drugs for Alzheimer's disease. PMID- 22834401 TI - Location, location, location: gastrointestinal delivery site and its impact on absorption. PMID- 22834402 TI - Targeting our snacking culture to improve patient compliance. PMID- 22834403 TI - Self-assembled nanosystems as delivery vehicles for regenerative medicine. PMID- 22834404 TI - Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics. AB - Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. In this review, past and current studies on lipoproteins and similar alternative drug carriers are discussed regarding their suitability as agents to deliver drugs, primarily to cancer cells and tumors. A lipoprotein-based delivery strategy may also provide a novel platform for improving the therapeutic efficacy of drugs that have previously been judged unsuitable or had only limited application due to poor solubility. An additional, and perhaps the most important aspect of the drug-delivery process via lipoprotein-type carriers, is the receptor-mediated uptake of the payload from the lipoprotein complex. Monitoring the expression of specific receptors prior to treatment could, thus, give rise to efficient selection of optimally responsive patients, resulting in a successful personalized therapy regimen. PMID- 22834405 TI - Peptides for cancer therapy: a drug-development opportunity and a drug-delivery challenge. AB - Therapeutic peptides (TPs) are a class of peptide-based agents capable of eliciting a therapeutic response by modulation of targets within or on the surface of cells. TPs are advantageous because they are amenable to rational design, they have high specificity for their targets and can be made to target almost any protein of interest, including proteins for which we have no small molecule drugs. Owing to this versatility, TPs have a great potential for cancer therapy in an age of personalized medicine, in which we need novel drugs to target the many novel pathways being discovered as tumor drivers. However, in order to utilize TPs as drugs, many obstacles must be overcome. TPs have short half-lives in systemic circulation, are easily degraded by proteases in plasma and target cells, are often cleared by the reticuloendothelial system and can be immunogenic. This article will discuss ways of overcoming many of these hurdles by utilizing macromolecular peptide delivery systems and tumor-targeting agents. PMID- 22834406 TI - Hydroxyapatite nanoparticles as vectors for gene delivery. AB - The long-recognized promise of gene therapy to treat a broad range of currently incurable diseases remains largely unfulfilled, hindered by lack of a safe and efficient delivery vehicle. Hydroxyapatite nanoparticles are deemed a feasible candidate and possess many characteristics desired of an ideal gene vector. Current fabrication techniques can readily synthesize hydroxyapatite particles in the nanometer range; however, these particles suffer from extensive aggregation and heterogeneity, mainly in size, shape and surface charge, which render them inappropriate for gene-therapy application. There is thus a pertinent need to develop a method capable of fabricating homogenous and monodispersed hydroxyapatite nanoparticles in a rapid, efficient and cost-effective manner that can be easily upscaled. Cell transfection is impeded by several physical and biological barriers, with the vector's properties highly determinant of its ability to overcome these barriers. Fine-tuning hydroxyapatite nanoparticles' morphological and physicochemical properties, achievable through precise regulation of the reaction environment, can enhance transfection efficiencies of particles, in turn, generating safe and effective gene vectors. PMID- 22834407 TI - Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms. AB - Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation. PMID- 22834408 TI - Liposomes and inorganic nanoparticles for drug delivery and cancer imaging. AB - Recently, there have been several advancements in material sciences and nanosciences. At the moment these new techniques are slowly entering into clinical settings in drug delivery and imaging. In this review, we will look more closely at the applications that are at the forefront of this translation and examine critical aspects that are involved in the process. Nanoparticles have been increasingly used in clinical settings for drug delivery over the past two decades. Lipid-based nanoparticles are front-runners, but other innovative strategies, such as small inorganic nanoparticles, are entering into the field, particularly for imaging applications. Lipid-based nanoparticles can be metabolized and consumed by the body and are regarded as safe for clinical use. They are usually large with hydrodynamic diameters of approximately 100-200 nm; however, phospholipid-containing particles such as microbubbles with diameters as low as 10 microm in size and micelles with diameters of 10-40 nm can also be used. Hollow liposomes with a large aqueous inner cavity can carry high payloads of drugs and imaging moieties, but are easily trapped by liver kupffer cells and can result in lower tissue penetration rates. New classes of particles with hydrodynamic diameters of < 10 nm, which are cleared by the kidneys, have recently been developed. These particles have been used primarily for imaging applications since they offer only small loading capacities for drugs. However, new strategies such as surface-coupled prodrugs have been developed to facilitate drug delivery in small nanoparticles. We describe different strategies for targeted delivery, imaging and controlled release, and discuss the ability of small inorganic particles as well as larger nanoparticles to be used broadly in human diagnostics and drug delivery. PMID- 22834409 TI - Polymer-based oral peptide nanomedicines. AB - Oral peptide delivery has been one of the major challenges of pharmaceutical sciences as it could lead to a great improvement of classical therapies, such as insulin, alongside making an important number of new therapies feasible. Successful oral delivery needs to fulfill two key tasks: to protect the macromolecules from degradation in the GI tract and to shuttle them across the intestinal epithelium in a safe and efficient fashion. Over the last decade, there have been numerous approaches based on the chemical modification of peptides and on the use of permeation enhancers, enzyme inhibitors and drug delivery systems. Among the approaches developed to overcome these restrictions, the design of nanocarriers seems to be a particularly promising approach. This article is an overview on the state of the art of oral-peptide formulation strategies, with special attention to insulin delivery and the use of polymeric nanocarriers as delivery systems. PMID- 22834410 TI - Microfluidic platform for the evaluation of multi-glycan expressions on living cells using electrochemical impedance spectroscopy and optical microscope. AB - A microfluidic platform to evaluate the expression of multi-glycans on a cell surface was developed using electrochemical impedance spectroscopy (EIS) and optical microscope technique. In the microfluidic channel, four indium tin oxide (ITO) electrodes were modified with three lectins and one passivation agent, respectively, to selectively recognize the corresponding carbohydrate epitopes on the cell surface. The binding of the cells on the electrode array was monitored by the electrochemical impedance to evaluate the expression of cell surface glycans. The excellent optical transparency of ITO electrode permitted the microscopic observation of the cell binding simultaneously to substantiate the impedance measurement. Compared with the individual technology, the double-check mode increased the sensitivity and accuracy of the assay. The experimental results using these two techniques indicated that the cell binding ability decreased in the order WGA > Con A > PNA, which was consistent with the expression difference of carbohydrate epitopes on K562 cell surface. The proposed strategy was further used for facile evaluating the variations of glycan expression on living cells in response to drugs. The consumption of cell sample for each sensing interface in the whole experiments is merely 5 * 10(3) cells. This platform offers great promise for cancer-associated glycol-biomarkers screening and further helps cancer diagnosis and treatment. PMID- 22834411 TI - The alignment of barium ferrite nanoparticles from their suspensions in electric and magnetic fields. AB - The alignment of plate-like barium ferrite nanoparticles, with diameters of 10 350 nm and thicknesses of 3-10 nm, in electric and/or magnetic fields was studied. Stable suspensions were prepared in 1-butanol with dodecylbenzenesulphonic acid as a surfactant. The deposits were produced from the suspensions with classic electrophoretic deposition, electrophoretic deposition in a magnetic field, and with drying in a magnetic field. The experiments, supported by theoretical calculations, show that the alignment of the nanoplates in the deposits was determined by the interplay between the hydrodynamic, electric, and magnetic forces. The preferential alignment of the nanoplates in plane with the substrate coincided with their magnetic orientation, and it increased with the shape anisotropy of the particles. The deposits were sintered at 1150 degrees C for 5 h to obtain ceramic films, which showed a magnetic orientation up to 90%. PMID- 22834412 TI - Synthesis of optically active 2- and 3- indolylglycine derivatives and their oxygen analogues. AB - 2-Indolylglycine derivative and its oxygen analogue have been synthesized by Sonogashira coupling followed by cyclization in one pot between 2 iodoheteroarenes and ethynyloxazolidinone where 3-indolylglycine derivative and its oxygen analogue have been synthesized from silylated internal alkyne using Larock's heteroannulation as the key reaction. PMID- 22834413 TI - A mechano-electronic DNA switch. AB - We report a new kind of DNA nanomachine that, fueled by Hg(2+) binding and sequestration, couples mechanical motion to the multiply reversible switching of through-DNA charge transport. This mechano-electronic DNA switch consists of a three-way helical junction, one arm of which is a T-T mismatch containing Hg(2+) binding domain. We demonstrate, using chemical footprinting and by monitoring charge-flow-dependent guanine oxidation, that the formation of T-Hg(2+)-T base pairs in the Hg(2+)-binding domain sharply increases electron-hole transport between the other two Watson-Crick-paired stems, across the three-way junction. FRET measurements are then used to demonstrate that Hg(2+) binding/dissociation, and the concomitant increase/decrease of hole transport efficiency, are strongly linked to specific mechanical movements of the two conductive helical stems. The increase in hole transport efficiency upon Hg(2+) binding is tightly coupled to the movement of the conductive stems from a bent arrangement toward a more linear one, in which coaxial stacking is facilitated. This switch offers a paradigm wherein the performance of purely mechanical work by a nanodevice can be conveniently monitored by electronic measurement. PMID- 22834414 TI - Aggregation, dissolution, and stability of quantum dots in marine environments: importance of extracellular polymeric substances. AB - There is an increasing concern that a considerable fraction of engineered nanoparticles (ENs), including quantum dots (QDs), will eventually find their way into the marine environment and have negative impacts on plankton. As ENs enter the ocean, they will encounter extracellular polymeric substances (EPS) from microbial sources before directly interacting with plankton cells. In this study, EPS harvested from four phytoplankton species, Amphora sp., Dunaliella tertiolecta, Phaeocystis globosa, and Thalassiosira pseudonana, were examined for potential interactions with CdSe nonfunctionalized and functionalized (carboxyl- and amine-) QDs in artificial seawater. Our results show that EPS do not reduce the solubility of QDs but rather decrease their stability. The degradation rate of QDs was positively correlated to the protein composition of EPS (defined by the ratio of protein/carbohydrate). Two approaches showed significant inhibition to the degradation of carboxyl-functionalized QDs: (1) the presence of an antioxidant, such as N-acetyl cysteine, and (2) absence of light. Owing to the complexity in evaluating integrated effects of QDs intrinsic properties and the external environmental factors that control the stability of QDs, conclusions must be based on a careful consideration of all these factors when attempting to evaluate the bioavailability of QDs and other ENs in the marine environments. PMID- 22834415 TI - VFEND(r) (voriconazole)-associated hypoglycaemia without identified drug interaction. AB - To report the first case of severe hypoglycaemia episodes related to voriconazole, involving neither over dosage nor any identified interaction with hypoglycaemic drugs. A 51-year-old man developed faints without loss of consciousness, with sweating in the morning for 3-4 days and low blood glucose, about 1 month after initiating voriconazole therapy. Hypoglycaemia was diagnosed and the patient required permanent intravenous glucose solutions for 8 days after voriconazole was stopped, after which glycaemia remained normal. A hyperinsulinaemia peak was observed, which disappeared when glycaemia normalized. Hypoglycaemia is known as a less common adverse event resulting from high voriconazole concentration and hepatic dysfunction. The mechanism of hypoglycaemia may be linked to insulinemia as its serum values are similar to glycaemia. Voriconazole may induce hypoglycaemia in patients without over dosage nor drug interaction. PMID- 22834416 TI - Temporal trends and gender differentials in causes of childhood deaths at Ballabgarh, India - need for revisiting child survival strategies. AB - BACKGROUND: Relating Information on causes of deaths to implementation of health interventions provides vital information for program planning and evaluation. This paper from Ballabgarh Health and Demographic Surveillance System (HDSS) site in north India looks at temporal trends and gender differentials in the causes of death among under-five children. METHODS: Data on causes of death for 1972-74, 1982-84, 1992-94, 2002-04 were taken from existing HDSS publications and database. Physicians' assigned causes of death were based on narratives by lay health worker till 1994 and later by verbal autopsy. Cause Specific Mortality Fractions (CSMF) and Cause Specific Mortality Rates (CSMR) per 1000 live births were calculated for neonatal (<1 month) and childhood (1-59 months) period. Gender difference was estimated by calculating ratio of CSMR between girls and boys. Available information on coverage of childhood interventions in the HDSS was retrieved and compiled. RESULTS: The CSMF of prematurity and sepsis was 32% and 17.6% during neonatal period in 2002-04. The share of infections in all childhood deaths decreased from 55.2% in 1972-74 to 43.6% in 2002-04. All major causes of mortality (malnutrition, diarrhea and acute lower respiratory infection) except injuries showed a steep decline among children and seem to have plateued in last decade. Most of disease specific public health interventions were launched in mid eighties. . Girls reported significantly higher mortality rates for prematurity (RR 1.52; 95% CI 1.01-2.29); diarrhea (2.29; 1.59 - 3.29), and malnutrition (3.37; 2.05 - 5.53). CONCLUSIONS: The findings of the study point out to the need to move away from disease-specific to a comprehensive approach and to address gender inequity in child survival through socio behavioural approaches. PMID- 22834417 TI - Percutaneous estradiol/oral micronized progesterone has less-adverse effects and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. AB - Gene expression analysis of healthy postmenopausal women in a prospective clinical study indicated that genes encoding for epithelial proliferation markers Ki-67 and progesterone receptor B mRNA are differentially expressed in women using hormone therapy (HT) with natural versus synthetic estrogens. Two 28-day cycles of daily estradiol (E2) gel 1.5 mg and oral micronized progesterone (P) 200 mg/day for the last 14 days of each cycle did not significantly increase breast epithelial proliferation (Ki-67 MIB-1 positive cells) at the cell level nor at the mRNA level (MKI-67 gene). A borderline significant beneficial reduction in anti-apoptotic protein bcl-2, favouring apoptosis, was also seen followed by a slight numeric decrease of its mRNA. By contrast, two 28-day cycles of daily oral conjugated equine estrogens (CEE) 0.625 mg and oral medroxyprogesterone acetate (MPA) 5 mg for the last 14 days of each cycle significantly increased proliferation at both the cell level and at the mRNA level, and significantly enhanced mammographic breast density, an important risk factor for breast cancer. In addition, CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P. These results suggest that HT with natural estrogens affects a much smaller number of genes and has less-adverse effects on the normal breast in vivo than conventional, synthetic therapy. PMID- 22834418 TI - Ilelic acids A and B, two unusual triterpenes with a seven-membered ring from Ilex latifolia. AB - Two unusual triterpenes, ilelic acids A (1) and B (2), together with their biosynthetic related compounds ilelic acids C (3) and D (4) were isolated from the leaves of Ilex latifolia. Their structures with absolute configurations were elucidated by spectroscopic analysis and modified Mosher's method. The plausible biogenetic pathway of 1 and 2 is proposed. These triterpenes exhibited a potent inhibitory effect on MCF-7 and MDA-MB-231 cells. PMID- 22834450 TI - Fifth issue of 2012. Editorial. PMID- 22834419 TI - Molecular evolution of A-kinase anchoring protein (AKAP)-7: implications in comparative PKA compartmentalization. AB - BACKGROUND: A-Kinase Anchoring Proteins (AKAPs) are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP dependent protein kinase A (PKA), directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18) are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca2+ handling and renal water transport. RESULTS: Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction) corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7alpha, while the ancestral long form AKAP7 splice variant is AKAP7gamma. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7delta occurs with the loss of native AKAP7gamma in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7gamma is produced from an internal translation-start site that is present in the AKAP7delta cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7gamma replaces AKAP7delta at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7delta insertion-deletions (indels) that promote the production of AKAP7gamma instead of AKAP7delta. CONCLUSIONS: This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7delta, a splice variant of likely lesser importance in humans than currently described. PMID- 22834451 TI - World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. AB - These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment resistant schizophrenia. PMID- 22834452 TI - Biomarkers for attention-deficit/hyperactivity disorder (ADHD). A consensus report of the WFSBP task force on biological markers and the World Federation of ADHD. AB - OBJECTIVE: Psychiatric "nosology" is largely based on clinical phenomenology using convention-based diagnostic systems not necessarily reflecting neurobiological pathomechanisms. While progress has been made regarding its molecular biology and neuropathology, the phenotypic characterization of ADHD has not improved. Thus, validated biomarkers, more directly linked to the underlying pathology, could constitute an objective measure for the condition. METHOD: The task force on biological markers of the World Federation of Societies of Biological Psychiatry (WFSBP) and the World Federation of ADHD commissioned this paper to develop a consensus report on potential biomarkers of ADHD. The criteria for biomarker-candidate evaluation were: (1) sensitivity >80%, (2) specificity >80%, (3) the candidate is reliable, reproducible, inexpensive, non-invasive, easy to use, and (4) confirmed by at least two independent studies in peer reviewed journals conducted by qualified investigators. RESULTS: No reliable ADHD biomarker has been described to date, but some promising candidates (e.g., olfactory sensitivity, substantial echogenicity) exist. A problem in the development of ADHD markers is sample heterogeneity due to aetiological and phenotypic complexity and age-dependent co-morbidities. CONCLUSIONS: Most likely, no single ADHD biomarker can be identified. However, the use of a combination of markers may help to reduce heterogeneity and to identify homogeneous subtypes of ADHD. PMID- 22834454 TI - Pharmacokinetics after a single intravenous dose of the opioid ketobemidone in neonates. AB - BACKGROUND: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. In an earlier study, we have examined the pharmacokinetic properties in children in different age groups but have not focused on neonates. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in neonates. METHODS: Fifteen full-term neonates (eight females) from 37 gestational weeks at birth and scheduled for elective surgery were included in the trial. Their median age was 3 days (range 1-18 days). Ketobemidone hydrochloride was administered as a single intravenous bolus dose, and ketobemidone concentrations were measured by liquid chromatography-mass spectrometry over 10 h. Pharmacokinetic parameters were calculated with standard compartmental methods. RESULTS: The median (range) values for ketobemidone clearance, apparent volume of distribution, volume of central compartment, distribution half-life and elimination half-life were 0.46 (0.23-0.84) l/h/kg, 4.64 (3.50-7.31) l/kg, 1.71 (0.16-3.47) l/kg, 2.85 (1.04-10.78) min and 7.26 (3.5 11.3) h. CONCLUSION: Compared with our previous study in children older than 1 year of age, the elimination of ketobemidone appeared to be slower in full-term neonates. Despite a low pharmacokinetic variability of ketobemidone as observed in the present neonatal patient population, we recommend individualizing the dose of ketobemidone based on observations of analgesic efficacy. PMID- 22834455 TI - A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease with characteristic recurrent draining sinuses, skin abscesses and disfiguring scars, mainly involving the axilla, groin, perianal and perineal regions. While most HS cases are nonfamilial, familial cases showing autosomal dominant inheritance have been reported. Recently, loss-of-function mutations in the genes encoding gamma-secretase have been identified as a cause of familial HS in the Chinese and British populations. OBJECTIVES: To identify mutations in the genes encoding gamma-secretase in Japanese patients with familial and nonfamilial HS. METHODS: Two affected and three unaffected individuals from a Japanese family with familial HS and nine patients with nonfamilial HS were recruited. We conducted mutation analysis of the gamma-secretase genes in Japanese patients with familial and nonfamilial HS. RESULTS: A novel splice site mutation in the nicastrin gene NCSTN, one of the six key component genes encoding gamma secretase, was identified in the patients with familial HS. Neither unaffected individuals in the family nor 100 ethnically matched control alleles carry this mutation. None of the nine patients with nonfamilial HS carry nonsense, frameshift or splice site mutations in this gene. CONCLUSIONS: A novel splice site mutation, c.582+1delG, in NCSTN was identified in the familial patients with HS. We also reveal for the first time that a gamma-secretase gene mutation is not linked to the development of nonfamilial HS. These results would further pave the way to a better understanding of the contribution of gamma-secretase and other genes to the pathogenesis of HS and to the development of a new therapeutic strategy for HS. PMID- 22834457 TI - Erythema ab igne as a differential diagnosis of chronic graft versus host disease (GVHD). PMID- 22834456 TI - Social and individual risk determinants of HIV testing practices among noninjection drug users at high risk for HIV/AIDS. AB - HIV testing services and research among drug users has largely focused on injection drug users (IDUs); yet noninjection drug users (NIDUs) are also at increased risk for HIV due to high-risk sexual behaviors and overlapping networks with IDUs. This study examined drug use, sexual risk, and social network characteristics associated with recent HIV testing (testing within past year) among NIDUs. Interviewer-administered questionnaires were conducted among 418 NIDUs and log-binomial regression models were used to identify correlates of recent HIV testing. Prevalence ratios (PR) with 95% confidence intervals (CI) were reported. Nearly 97% of NIDUs reported having ever been tested for HIV and most participants (85.7%) indicated testing for HIV within the past year. Factors independently associated with recent HIV testing were higher educational attainment (PR: 1.86; 95% CI: 1.03, 3.34) and networks to discuss health and medical services (PR: 1.84; 95% CI: 1.06, 1.20). A prior positive sexually transmitted infection was associated with decreased likelihood of recent HIV test (PR: 0.43; 95% CI 0.25, 0.74). Identifying specific social network characteristics may be effective in facilitating HIV testing and prevention strategies targeting NIDUs. PMID- 22834459 TI - Bipolar disorder type II revisited. PMID- 22834460 TI - Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. AB - OBJECTIVES: Bipolar disorder (BD) is a common and highly disabling disease characterized by substantial cognitive and functional impairment. The exact neurobiological mechanisms underlying the expression of symptoms in this condition remain unknown but there is growing evidence that glutamate might play an important role. Using proton magnetic resonance spectroscopy (1H-MRS), a number of studies have examined brain glutamate/glutamine levels in patients with bipolar disorder, but they have produced conflicting results. The objective of this paper was to conduct a systematic review and meta-analysis of the literature on brain glutamate/glutamine in BD as measured by 1H-MRS. METHODS: A Medline search for the period January 1980-April 2010 was conducted to identify published studies that used 1H-MRS to measure glutamate + glutamine (Glx), the Glx/creatine (Cr) ratio, glutamate (Glu), or the Glu/Cr ratio in any brain region in adult or child/adolescent patients with BD and healthy subjects. A meta-analysis of the pooled data was conducted. RESULTS: BD patients were found to have increased Glx compared to healthy subjects when all brain areas were combined. This finding remained true in medicated and non-medicated patients, and in frontal brain areas in adults. There was a non-significant trend (p = 0.09) for an increase in whole brain Glx/Cr and Glu in patients compared with healthy subjects. No significant difference was found in Glu/Cr. CONCLUSIONS: The results of this meta-analysis suggest that brain Glx levels are elevated in BD patients and support the idea that glutamate might play an important role in the pathophysiology of BD. PMID- 22834461 TI - Differential executive functioning performance by phase of bipolar disorder. AB - OBJECTIVE: This study examined the influence of illness phase on executive functioning performance using factor-derived cognitive scores in a cross sectional design. METHODS: Healthy control (HC) subjects (n = 57), and euthymic (E-BD) (n = 117), depressed (D-BD) (n = 73), and hypomanic/mixed (HM/M-BD) (n = 26) patients with bipolar disorder (BD) were evaluated using executive functioning measures (Wisconsin Card Sorting Test, Trail Making Test-Parts A and B, Verbal Fluency, Parametric Go/No-Go, Stroop, and Digit Symbol) comprising Conceptual Reasoning and Set-Shifting (CRSS), Processing Speed with Interference Resolution (PSIR), Verbal Fluency and Processing Speed (VFPS), and Inhibitory Control (IC) factor scores. RESULTS: Two of the four executive functioning factors were significantly different between groups based upon phase of illness. The HM/M group was significantly worse than both of the other BD groups and the HC group in IC. The VFPS factor was sensitive to the active phase of BD, with the HM/M-BD and D-BD groups worse than HC. Extending our prior work, the PSIR factor, and now the CRSS factor were significantly worse in BD relative to HC, irrespective of phase of illness. CONCLUSIONS: Phase of illness had differential cognitive profiles in executive functioning factors, even after considering and excluding the impact of clinical features, illness characteristics, medications, and demographics. Consolidating executive functioning tasks into reliable factor scores provides unique information to measure and define cognitive deficiencies throughout phases of BD, and to measure intermediate phenotypes in BD, and may aid in tracking and clarifying treatment focus. PMID- 22834462 TI - Relational memory in psychotic bipolar disorder. AB - OBJECTIVES: Recent research has highlighted the phenotypic and genetic overlap of bipolar disorder and schizophrenia. Cognitive deficits in bipolar disorder parallel those seen in schizophrenia, particularly for bipolar disorder patients with a history of psychotic features. Here we explored whether relational memory deficits, which are prominent in schizophrenia, are also present in patients with psychotic bipolar disorder. METHODS: We tested 25 patients with psychotic bipolar disorder on a relational memory paradigm previously employed to quantify deficits in schizophrenia. During the training, participants learned to associate a set of faces and background scenes. During the testing, participants viewed a single background overlaid by three trained faces and were asked to recall the matching face, which was either present (Match trials) or absent (Non-Match trials). Explicit recognition and eye-movement data were collected and compared to those for 28 schizophrenia patients and 27 healthy subjects from a previously published dataset. RESULTS: Contrary to our prediction, we found psychotic bipolar disorder patients were less impaired in relational memory than schizophrenia subjects. Bipolar disorder subjects showed eye-movement behavior similar to healthy controls, whereas schizophrenia subjects were impaired relative to both groups. However, bipolar disorder patients with current delusions and/or hallucinations were more impaired than bipolar disorder patients not currently experiencing these symptoms. CONCLUSIONS: We found that patients with psychotic bipolar disorder had better relational memory performance than schizophrenia patients, indicating that a history of psychotic symptoms does not lead to a significant relational memory deficit. PMID- 22834463 TI - Non-right-handedness in adolescents and adults with bipolar disorder. PMID- 22834464 TI - Attentional set protects visual marking from visual transients. AB - When some distractors (old items) appear before others (new items) in an inefficient visual search task, the old items are excluded from the search (visual marking). Previous studies have shown that changing the shape of old items eliminates this effect, suggesting that shape identity must be maintained for successful visual marking. However, the contribution of top-down target knowledge to the maintenance of visual marking under shape change conditions has not been systematically examined. The present study tested whether the vulnerability of visual marking to shape change is contingent on observers' attentional set, by manipulating compatibility of the set and the domains in which the change occurs. The results indicated that visual marking survived shape changes when the observer's attentional set was consistent with critical features between the old and new items. This protection was observed when the set was based on explicit instructions at the beginning of the experiment, and when the task set was implicitly carried over from the previous task. These results suggest that top-down processes play a role in maintaining memory templates by enhancing the grouping and suppression processes during visual search, despite disruptive bottom-up signals. PMID- 22834466 TI - Structure and genetics of the O-antigen of Cronobacter turicensis G3882 from a new serotype, C. turicensis O2, and identification of a serotype-specific gene. AB - Lipopolysaccharides on the cell surface of Gram-negative bacteria are an important factor in pathogenicity, and the O-specific polysaccharide chain (O polysaccharide, O-antigen) defines the immunospecificity of different bacterial strains. Cronobacter turicensis is an emerging foodborne pathogen which causes severe invasive infections in neonates. In this study, a new O serotype, C. turicensis O2, was established, the structure and genetics of the O-antigen were investigated, and a serotype-specific gene was identified. Sugar and methylation analyses, and nuclear magnetic resonance spectroscopy indicated that the O polysaccharide contains D-galactose (D-Gal), N-acetyl-D-glucosamine (D-GlcNAc), L rhamnose (L-Rha) and 5,7-diacetamido-3,5,7,9-tetradeoxy-D-glycero-D-galacto-non-2 ulosonic acid (di-N-acetyllegionaminic acid, Leg5Ac7Ac). The structure of the tetrasaccharide repeat of the O-polysaccharide was established as: [Formula: see text]. The O-antigen gene cluster of C. turicensis O2 was sequenced and compared with related gene clusters from available databases. Putative genes for the synthesis of L-Rha and Leg5Ac7Ac, and genes encoding sugar transferases and O antigen processing genes (wzx and wzy) were found. The tentatively assigned functions of the O-antigen genes were in agreement with the structure of the O polysaccharide. In addition, primers based on the wzy gene were shown to be specific for C. turicensis O2 in a screen against 145 strains. PMID- 22834467 TI - Clinical implications of the transversus abdominis plane block in pediatric anesthesia. AB - Optimal perioperative analgesia for infants and children after major abdominal surgery poses a challenge when central neuraxial techniques are contraindicated. As a regional anesthesia technique, the transversus abdominis plane (TAP) block has been shown to reduce opioid consumption and improve pain scores compared to traditional perioperative pain strategies. Accordingly, TAP blocks may be considered as an alternative to central neuraxial analgesia to optimize perioperative pain control. Advancements in ultrasound technology have further improved the reliability and safety profile of this technique. Despite growing recognition of the diverse clinical scenarios where TAP blocks may be of benefit, its use among pediatric anesthesiologists remains limited. This article describes the history, anatomy, and a review of the current literature on TAP blocks with an emphasis on outcomes in pediatric patients. PMID- 22834465 TI - The role of barrier membranes for guided bone regeneration and restoration of large bone defects: current experimental and clinical evidence. AB - Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Although there are several methods for bone reconstruction, they all have specific indications and limitations. The concept of using barrier membranes for restoration of bone defects has been developed in an effort to simplify their treatment by offering a single-staged procedure. Research on this field of bone regeneration is ongoing, with evidence being mainly attained from preclinical studies. The purpose of this review is to summarize the current experimental and clinical evidence on the use of barrier membranes for restoration of bone defects in maxillofacial and orthopedic surgery. Although there are a few promising preliminary human studies, before clinical applications can be recommended, future research should aim to establish the 'ideal' barrier membrane and delineate the need for additional bone grafting materials aiming to 'mimic' or even accelerate the normal process of bone formation. Reproducible results and long-term observations with barrier membranes in animal studies, and particularly in large animal models, are required as well as well-designed clinical studies to evaluate their safety, efficacy and cost effectiveness. PMID- 22834469 TI - Case report: airway and concurrent hemodynamic management in a neonate with oculo auriculo-vertebral (Goldenhar) syndrome, severe cervical scoliosis, interrupted aortic arch, multiple ventricular septal defects, and an unstable cervical spine. AB - We report the challenging case of a 1-week-old, term, 2.4 kg neonate with Goldenhar syndrome (including microcephaly, left microtia, left facial palsy, dextro-scoliosis of the cervical spine, and cervico-thoracic levoscoliosis), multiple ventricular septal defects, a type B interrupted aortic arch, a large patent ductus arteriosis, and radiographic and clinical signs concerning for an unstable cervical spine. Our anesthesia team was consulted for perioperative management of this patient during her surgical repair. This case report describes the use of the Air-Q size 1 laryngeal airway (LA) to assist fiberoptic intubation in an ASA 4 neonate with cardiac disease, an anticipated difficult airway with the addition of an unstable cervical spine, as well as the anesthetic techniques used to maintain hemodynamic stability while the airway was secured. PMID- 22834470 TI - Delayed primary repair of giant omphalocele: anesthesia challenges. PMID- 22834471 TI - Extracorporeal membrane oxygenation in a 10-year-old girl with macrophage activation syndrome. PMID- 22834472 TI - Query for 'The air-Q in infant intubation'. PMID- 22834473 TI - Single-lung ventilation for resection of a giant bronchogenic cyst in a 5-month old patient. PMID- 22834474 TI - Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome. AB - INTRODUCTION: Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction. AREAS COVERED: This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages. EXPERT OPINION: Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown. PMID- 22834475 TI - Large granular lymphocytic leukaemia mimicking ulcer of the lower limb. PMID- 22834477 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin enhances CCl4-induced hepatotoxicity in an aryl hydrocarbon receptor-dependent manner. AB - Cytochrome P4502E1 (CYP2E1) is involved in the biotransformation of several low molecular weight chemicals and plays an important role in the metabolic activation of carcinogens and hepatotoxins such as CCl(4). Induction of CYP2E1 is exerted mainly at posttranscriptional levels through mRNA and protein stabilization, and there is little evidence of xenobiotic induction at the transcriptional level. Previously, we reported microarray analysis data suggesting a decrease in Cyp2e1 gene expression on Ahr-null livers when compared to wild-type mouse livers. The goal of the present study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased mouse CYP2E1 levels in an AhR-dependent manner and the impact on CCl(4)-induced hepatotoxicity. TCDD treatment induced CYP2E1 mRNA and protein levels in mouse liver, and this effect was aryl hydrocarbon receptor (AhR)-dependent. Moreover, TCDD pre-treatment increased the CCl(4)-induced alanine aminotransferase (ALT) activity, the extent of CCl(4)-induced necrosis, and the number of sinusoidal cells in wild-type animals, while this potentiating effect was not observed in Ahr-null mice. In conclusion, this study revealed that TCDD, probably in an AhR-dependent manner, exacerbated CCl(4)-induced hepatotoxicity through induction of CYP2E1. PMID- 22834478 TI - In vitro inhibition and induction of human cytochrome P450 enzymes by mirabegron, a potent and selective beta3-adrenoceptor agonist. AB - The potential for mirabegron, a beta(3)-adrenoceptor agonist for the treatment of overactive bladder, to cause drug-drug interactions via inhibition or induction of cytochrome P450 (CYP) enzymes was investigated in vitro. Mirabegron was shown to be a time-dependent inhibitor of CYP2D6 in the presence of NADPH as the IC(50) value in human liver microsomes decreased from 13 to 4.3 MUM after 30-min pre incubation. Further evaluation indicated that mirabegron may act partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Therefore, the potential of mirabegron to inhibit the metabolism of CYP2D6 substrates in vivo cannot be excluded. Mirabegron was predicted not to cause clinically significant metabolic drug-drug interactions via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 because the IC(50) values for these enzymes both with and without pre-incubation were >100 MUM (370 times maximum human plasma concentration [C(max)]). Whereas positive controls (100 uM omeprazole and 10 uM rifampin) caused the anticipated CYP induction, the highest concentration of mirabegron (10 uM; 37 times plasma C(max)) had minimal effect on CYP1A2 and CYP3A4/5 activity, and CYP1A2 and CYP3A4 mRNA levels in freshly isolated human hepatocytes, suggesting that mirabegron is not an inducer of these enzymes. PMID- 22834476 TI - Targeting memory processes with drugs to prevent or cure PTSD. AB - INTRODUCTION: Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. AREAS COVERED: Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. EXPERT OPINION: Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment. PMID- 22834480 TI - Ag nanoparticles: size- and surface-dependent effects on model aquatic organisms and uptake evaluation with NanoSIMS. AB - This study aims to assess the effects of Ag particles synthesised by a chemical (Ag 20, 200 nm) and biological method (Ag 23, 27 nm) in aquatic organisms: the bacterium Vibrio fischeri, the alga Desmodesmus subspicatus and the crustacean Daphnia magna. Ag particles exerted toxic effects in all organisms studied with Ag particles 23 nm being the most potent. Although soluble Ag was released in all media, the differences between the tested Ag particles still cannot be explained solely based on soluble Ag. NanoSIMS analysis performed with D. magna showed that apart from their localisation in the gut lumen, Ag 200 nm and Ag NPs 23 nm seemed to pass through the epithelial barrier as well. Ag NPs 23 nm localised in specific areas seemed to be within the ovaries. This study strengthens the argument that size, method of synthesis as well as surface chemistry may affect the uptake and toxic effects of Ag NPs. PMID- 22834481 TI - Suicide among the elderly and associated factors in South Korea. AB - With the population of the elderly increasing, suicides among elderly people present a serious problem for global societies. However, there are few studies on suicide among elderly subjects, especially in Asia. The study aimed to determine the relationship between physical health, mental health, social environmental condition, and the suicide behavior among elderly subjects in the city of Suwon, located southeast of Seoul. We analyzed 1548 Korean aged over 60 years from baseline data of a larger prospective study called the Suwon Project. The study protocol included sociodemographic variables, mental health factors, and physical health factors. In the interview, the subjects were asked about suicide ideation and history of suicide attempt. Of the total subjects, 7.42% reported suicide ideation and 1.42% reported a history of suicide attempt. A logistic regression analysis showed that physical illness, five stroke warning signs, anxiety and depression associated with suicide ideation, and depression strongly corresponded to the suicide ideation. Anxiety, depression, and stroke warning signs were associated with history of suicide attempt among the elderly. Additionally, stroke warning signs and depression are independently associated with history of suicide attempt. This study revealed that stroke warning signs have a high correlation with history of suicide attempt in the elderly, independent from the depression factors. This study suggests that there is an independent relationship between physical health status and suicide behavior in the case of elders. PMID- 22834482 TI - Interleukin-12 and interleukin-2 alone or in combination against the infection in invasive pulmonary aspergillosis mouse model. AB - Aspergillus fumigatus is an intracellular opportunistic fungus causing invasive pulmonary mycosis, characterised by hyphal invasion and destruction of pulmonary tissue. Th1 cytokines could enhance fungicidal activity. The effects from the combination of interleukin-12 (IL-12) and IL-2 are rarely known in invasive pulmonary aspergillosis infection. To assess the cleaning of A. fumigatus infection in the pulmonary tissues by IL-12 and IL-2, interferon-gamma (IFN gamma) was detected in the sera using ELISA, quantification of IFN-gamma mRNA using real-time RT-PCR and lung Colony-forming unit was assayed by cultivation. Morphology was analysed by histopathological examination. Our results showed that IL-12 and/or IL-2 could enhance the IFN-gamma expression in the pulmonary tissue, reduce the colony load in the pulmonary tissue and increase the survival rate of mouse. The combination of IL-12 and IL-2 could assist in increasing the IFN-gamma expression in the pulmonary tissue, but neither reduce colony load in the pulmonary tissue nor increase the survival rate of mouse significantly. It was demonstrated that IL-12 and IL-2 were strong immunomodulatory cytokines as a prerequisite for protecting the host from infectious agents. PMID- 22834483 TI - A taco complex derived from a bis-crown ether capable of executing molecular logic operation through reversible complexation. AB - As learned from natural systems, self-assembly and self-sorting help in interconnecting different molecular logic gates and thus achieve high-level logic functions. In this context, demonstration of important logic operations using changes in optical responses due to the formation of molecular assemblies is even more desirable for the construction of a molecular computer. Synthesis of an appropriate divalent as well as a luminescent crown ether based host 1 and paraquat derivatives, 2(PF(6))(2) and 3(PF(6))(2), as guests helped in demonstrating a reversible [3](taco complex) (1.{2(PF(6))(2)}(2) or 1.{3(PF(6))(2)}(2)) formation in nonpolar solvent. Detailed (1)H NMR studies revealed that two paraquat units were bound cooperatively by the two crown units in 1. Because of preorganization, the flexible host molecule 1 adopts a folded conformation, where each of two paraquat units remain sandwiched between the two aromatic units of each folded crown ether moiety in 1. Disassembly of the "taco" complex in the presence of KPF(6) and reassembly on subsequent addition of DB18C6 was initially demonstrated by (1)H NMR spectral studies, which were subsequently corroborated through luminescence spectral studies. Further, luminescence spectral responses as output signals with appropriate and two independent molecular inputs could be correlated to demonstrate basic logic operation like OR and YES gates, while the results of the three molecular inputs could be utilized to demonstrate important logic operation like an INHIBIT gate. PMID- 22834484 TI - Changes in bacterial community structure after exposure to silver nanoparticles in natural waters. AB - Silver nanoparticles (AgNPs) are widely used in commercial products as antibacterial agents, but AgNPs might be hazardous to the environment and natural aquatic bacterial communities. Our recent research demonstrated that AgNPs rapidly but temporarily inhibited natural bacterioplankton production. The current study investigates the mechanism for the observed bacterial reaction to AgNPs by examining how AgNPs impact bacterial abundance, metabolic activity (5 cyano-2,3-ditolyl tetrazolium chloride (CTC+) cells), and 16S rRNA community composition. Natural bacterioplankton communities were dosed with carboxy functionalized AgNPs at four concentrations (0.01-1 mg-Ag/L), incubated in triplicate, and monitored over 5 days. Ionic silver (AgNO(3)) and Milli-Q water treatments were used as a positive and negative control, respectively. Four general AgNP exposure responses, relative to the negative control, were observed: (1) intolerant, (2) impacted but recovering, (3) tolerant, and (4) stimulated phylotypes. Relationships between cell activity indicators and bacterial phylotypes, suggested that tolerant and recovering bacteria contributed the most to the community's productivity and rare bacteria phylotypes stimulated by AgNPs did not appear to contribute much to cell activity. Overall, natural bacterial communities tolerated single, low level AgNP doses and had similar activity levels to the negative control within five days of exposure, but bacterial community composition was different from that of the control. PMID- 22834485 TI - Public perception of drinking water safety in South Africa 2002-2009: a repeated cross-sectional study. AB - BACKGROUND: In low and middle income countries, public perceptions of drinking water safety are relevant to promotion of household water treatment and to household choices over drinking water sources. However, most studies of this topic have been cross-sectional and not considered temporal variation in drinking water safety perceptions. The objective of this study is to explore trends in perceived drinking water safety in South Africa and its association with disease outbreaks, water supply and household characteristics. METHODS: This repeated cross-sectional study draws on General Household Surveys from 2002-2009, a series of annual nationally representative surveys of South African households, which include a question about perceived drinking water safety. Trends in responses to this question were examined from 2002-2009 in relation to reported cholera cases. The relationship between perceived drinking water safety and organoleptic qualities of drinking water, supply characteristics, and socio-economic and demographic household characteristics was explored in 2002 and 2008 using hierarchical stepwise logistic regression. RESULTS: The results suggest that perceived drinking water safety has remained relatively stable over time in South Africa, once the expansion of improved supplies is controlled for. A large cholera outbreak in 2000-02 had no apparent effect on public perception of drinking water safety in 2002. Perceived drinking water safety is primarily related to water taste, odour, and clarity rather than socio-economic or demographic characteristics. CONCLUSION: This suggests that household perceptions of drinking water safety in South Africa follow similar patterns to those observed in studies in developed countries. The stability over time in public perception of drinking water safety is particularly surprising, given the large cholera outbreak that took place at the start of this period. PMID- 22834486 TI - Satisfaction with joint replacement in public versus private hospitals: a cohort study. AB - INTRODUCTION: In Australia, the majority of total knee and hip replacement surgeries occur in the private sector. Outcome-based research needs to be inclusive of this sector if the findings are intended to reflect the broader picture. This study compares outcomes up to 1 year post knee and hip replacement between patients treated in the public and private sectors. METHODS: A prospective, observational study was performed in four high-volume joint replacement centres: two public, two private. Experienced orthopaedic surgeons contributed via their public and private practices. Knee and hip patients were recruited preoperatively. Self-reported questionnaires were completed preoperatively and at 6 and 12 months post-operatively. The primary outcome was satisfaction with surgery. Secondary outcomes included Oxford score, and SF-36 physical and mental component summary scores. Regression modelling was performed to adjust for potential confounders. RESULTS: Three hundred and thirty-one patients (184 public, 147 private; 215 knees, 116 hips) were recruited, with 6- and 12-month follow-up rates of 95% and 89%, respectively. Satisfaction rates were high in both public and private patients (approximately 90%) at 6 and 12 months, but private patients were less likely to be satisfied after adjusting for the strong effect of patient expectation. For both hip and knee cohorts, no between-sector differences were found in either the magnitude or rate of improvement in Oxford score or quality of life post-operatively. DISCUSSION: Joint replacement outcomes are similar for patients treated in public and private hospitals. Surgeons should manage patient expectation prior to surgery, particularly in private patients. PMID- 22834487 TI - Switching the stereoselectivity: (fullero)pyrrolidines "a la carte". AB - Stereodivergent syntheses of cis/trans pyrrolidino[3,4:1,2]fullerenes and endo/exo pyrrolidines are reported with high enantioselectivity levels. Fullerenes are revealed as a useful benchmark to develop suitable catalysts to control the stereochemical outcome and to shed light on the mechanism involved in the related 1,3-dipolar cycloaddition. PMID- 22834488 TI - Refractory generalized pustular psoriasis responsive to a combination of adalimumab and acitretin. PMID- 22834536 TI - Iron-catalyzed unexpected easy access to stereodefined trimethylsilyl vinyl ketenes. AB - Stereodefined trimethylsilyl vinyl ketenes with polysubstitution have been synthesized highly regio- and stereoselectively via an iron-catalyzed reaction of 2-trimethylsilyl-2,3-allenoates with Grignard reagents in good to excellent yields. The reaction was believed to proceed via a conjugate addition and elimination mechanism. Applications of the products for the synthesis of stereodefined alpha-silyl-beta,gamma-unsaturated enones, a stereodefined triene, and polysubstituted phenols have been carefully demonstrated. PMID- 22834489 TI - CTGC motifs within the HIV core promoter specify Tat-responsive pre-initiation complexes. AB - BACKGROUND: HIV latency is an obstacle for the eradication of HIV from infected individuals. Stable post-integration latency is controlled principally at the level of transcription. The HIV trans-activating protein, Tat, plays a key function in enhancing HIV transcriptional elongation. The HIV core promoter is specifically required for Tat-mediated trans-activation of HIV transcription. In addition, the HIV core promoter has been shown to be a potential anti-HIV drug target. Despite the pivotal role of the HIV core promoter in the control of HIV gene expression, the molecular mechanisms that couple Tat function specifically to the HIV core promoter remain unknown. RESULTS: Using electrophoretic mobility shift assays (EMSAs), the TATA box and adjacent sequences of HIV essential for Tat trans-activation were shown to form specific complexes with nuclear extracts from peripheral blood mononuclear cells, as well as from HeLa cells. These complexes, termed pre-initiation complexes of HIV (PICH), were distinct in composition and DNA binding specificity from those of prototypical eukaryotic TATA box regions such as Adenovirus major late promoter (AdMLP) or the hsp70 promoter. PICH contained basal transcription factors including TATA-binding protein and TFIIA. A mutational analysis revealed that CTGC motifs flanking the HIV TATA box are required for Tat trans-activation in living cells and correct PICH formation in vitro. The binding of known core promoter binding proteins AP-4 and USF-1 was found to be dispensable for Tat function. TAR RNA prevented stable binding of PICH-2, a complex that contains the general transcription factor TFIIA, to the HIV core promoter. The impact of TAR on PICH-2 specifically required its bulge sequence that is also known to interact with Tat. CONCLUSION: Our data reveal that CTGC DNA motifs flanking the HIV TATA box are required for correct formation of specific pre-initiation complexes in vitro and that these motifs are also required for Tat trans-activation in living cells. The impact of TAR RNA on PICH-2 stability provides a mechanistic link by which pre-initiation complex dynamics could be coupled to the formation of the nascent transcript by the elongating transcription complex. Together, these findings shed new light on the mechanisms by which the HIV core promoter specifically responds to Tat to activate HIV gene expression. PMID- 22834537 TI - Forced fluid removal in critically ill patients with acute kidney injury. AB - PURPOSE: The aim was to test the feasibility of protocol-driven fluid removal with continuous renal replacement therapy (CRRT) in patients in whom standard fluid balance prescription did not result in substantial negative fluid balances. MATERIALS AND METHODS: In 10 mechanically ventilated patients with sepsis or signs of inflammation and acute kidney injury [age 65 (48-78 years; median, range), simplified acute physiology score II 66 (39-116)], fluid removal was guided by mean arterial pressure (MAP), cardiac index (CI), mixed venous oxygen saturation (SvO(2)), lactate/base excess, peripheral circulation, and filling pressures, and adjusted hourly with the goal to maximize volume removal for up to 3 days. RESULTS: Fluid removal rates during the 3 days before and during the study period [66 (36-72) h] were 11 (-30 to +36) ml/kg/day and -59 (-85 to -31) ml/kg/day, respectively (P = 0.002). In 12% of a total of 594 fluid removal rate evaluations, fluid removal had to be decreased or stopped. Most frequent reasons leading to decreasing fluid removal were (n, % of all instances, median lowest value from all patients): SvO(2) (44, 28%, 59%), MAP (36, 23%, 57 mmHg), CI (26, 17%, 2.4 l/min/m(2)), low peripheral temperature (22, 14%, 'cold'). Overall, systemic hemodynamics remained stable throughout the study period. CONCLUSIONS: In these patients, protocolized fluid removal with CRRT was associated with large negative fluid balances. PMID- 22834535 TI - Comparative molecular analysis of chemolithoautotrophic bacterial diversity and community structure from coastal saline soils, Gujarat, India. AB - BACKGROUND: Soils harbour high diversity of obligate as well as facultative chemolithoautotrophic bacteria that contribute significantly to CO2 dynamics in soil. In this study, we used culture dependent and independent methods to assess the community structure and diversity of chemolithoautotrophs in agricultural and coastal barren saline soils (low and high salinity). We studied the composition and distribution of chemolithoautotrophs by means of functional marker gene cbbL encoding large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase and a phylogenetic marker 16S rRNA gene. The cbbL form IA and IC genes associated with carbon fixation were analyzed to gain insight into metabolic potential of chemolithoautotrophs in three soil types of coastal ecosystems which had a very different salt load and sulphur content. RESULTS: In cbbL libraries, the cbbL form IA was retrieved only from high saline soil whereas form IC was found in all three soil types. The form IC cbbL was also amplified from bacterial isolates obtained from all soil types. A number of novel monophyletic lineages affiliated with form IA and IC phylogenetic trees were found. These were distantly related to the known cbbL sequences from agroecosystem, volcanic ashes and marine environments. In 16S rRNA clone libraries, the agricultural soil was dominated by chemolithoautotrophs (Betaproteobacteria) whereas photoautotrophic Chloroflexi and sulphide oxidizers dominated saline ecosystems. Environmental specificity was apparently visible at both higher taxonomic levels (phylum) and lower taxonomic levels (genus and species). The differentiation in community structure and diversity in three soil ecosystems was supported by LIBSHUFF (P = 0.001) and UniFrac. CONCLUSION: This study may provide fundamentally new insights into the role of chemolithoautotrophic and photoautotrophic bacterial diversity in biochemical carbon cycling in barren saline soils. The bacterial communities varied greatly among the three sites, probably because of differences in salinity, carbon and sulphur contents. The cbbL form IA-containing sulphide oxidizing chemolithotrophs were found only in high saline soil clone library, thus giving the indication of sulphide availability in this soil ecosystem. This is the first comparative study of the community structure and diversity of chemolithoautotrophic bacteria in coastal agricultural and saline barren soils using functional (cbbL) and phylogenetic (16S rDNA) marker genes. PMID- 22834538 TI - Biological clock dysfunction exacerbates contact hypersensitivity in mice. AB - BACKGROUND: Immediate-type skin allergic reactions, such as passive cutaneous anaphylactic reaction, are associated with circadian rhythm, but the role of circadian mechanisms on delayed-type skin allergic reactions, such as contact hypersensitivity (CHS), remains uncertain. In mice, CHS, a T-cell-mediated immune response, is a classic model of human allergic contact dermatitis. OBJECTIVES: We investigated whether biological clock dysfunction affects CHS pathogenesis in CLOCK mutant mice compared with wild-type (WT) mice. METHODS: Mice were treated with 2,4,6-trinitro-1-chlorobenzene (TNCB) on the abdominal skin on day 0 (sensitization) and then treated with TNCB on the ears on day 5 (challenge). RESULTS: We found that biological clock dysfunction resulted in severe inflammation. Ear swelling, serum immunoglobulin E level and mast cell number were significantly increased in CLOCK mutant mice compared with WT mice. These results provide evidence that CLOCK mutation promotes the T-helper type 2 immune response and exacerbates CHS. Corticosterone has a protective effect on CHS. The serum corticosterone level lost rhythmicity and showed a decreased daily level in CLOCK mutant mice compared with WT mice, supporting the exacerbating effect of CLOCK mutation on CHS. Adrenalectomy markedly worsened TNCB-induced CHS in WT mice but not in CLOCK mutant mice. In addition, dramatic dexamethasone-induced protection of CHS was observed in CLOCK mutant mice compared with WT mice. CONCLUSIONS: The present results suggest that circadian rhythm might be an important factor in the regulation of CHS via corticosterone rhythmicity and/or level. PMID- 22834539 TI - Single-cell mRNA profiling identifies progenitor subclasses in neurospheres. AB - Neurospheres are widely used to propagate and investigate neural stem cells (NSCs) and neural progenitors (NPs). However, the exact cell types present within neurospheres are still unknown. To identify cell types, we used single-cell mRNA profiling of 48 genes in 187 neurosphere cells. Using a clustering algorithm, we identified 3 discrete cell populations within neurospheres. One cell population [cluster unsorted (US) 1] expresses high Bmi1 and Hes5 and low Myc and Klf12. Cluster US2 shows intermediate expression of most of the genes analyzed. Cluster US3 expresses low Bmi1 and Hes5 and high Myc and Klf12. The mRNA profiles of these 3 cell populations correlate with a developmental timeline of early, intermediate, and late NPs, as seen in vivo from the mouse brain. We enriched the cell population for neurosphere-forming cells (NFCs) using morphological criteria of forward scatter (FSC) and side scatter (SSC). FSC/SSC(high) cells generated 2.29-fold more neurospheres than FSC/SSC(low) cells at clonal density. FSC/SSC(high) cells were enriched for NSCs and Lewis-X(+ve) cells, possessed higher phosphacan levels, and were of a larger cell size. Clustering of both FSC/SSC(high) and FSC/SSC(low) cells identified an NFC cluster. Significantly, the mRNA profile of the NFC cluster drew close resemblance to that of early NPs. Taken together, data suggest that the neurosphere culture system can be used to model central nervous system development, and that early NPs are the cell population that gives rise to neurospheres. In future work, it may be possible to further dissect the NFCs and reveal the molecular signature for NSCs. PMID- 22834540 TI - Stability of purple membranes from Halobacterium salinarum toward surfactants: inkjet printing of a retinal protein. AB - Inkjet printing is a versatile technique widely applied in biological microarray technology. Because of its photochemical and photophysical properties, bacteriorhodopsin (BR) from Halobacterium salinarum holds promise for applications in nanotechnology, and inkjet printing would simplify the transfer of BR to suitable substrates. Surfactants are essential parts of inkjet formulations tuning viscosity, rheology, and spreading behavior of the solution. However, many surfactants destabilize the structure of proteins and often cause denaturation accompanied by a complete loss of function. Inkjet printing of membrane proteins is particularly challenging and special care must be taken in the choice of the surfactant. For BR, the situation is complicated by the fact that the structural integrity of BR depends on its native membrane environment, the so-called purple membrane (PM). PM contains 10 lipid molecules per BR monomer and is very sensitive toward surfactants. In this work, we identified surfactants suitable for inkjet formulations containing PM. Initially, we screened a variety of technically relevant surfactants for compatibility with PM using the UV-vis absorption of the retinal chromophore as a natural probe. Promising candidates were selected, and their impact on the structure of PM and BR was analyzed using UV-vis spectroscopy, CD spectroscopy, and small-angle X-ray scattering (SAXS). We identified two surfactants compatible with PM and suitable for inkjet formulations. An inkjet formulation containing PM as dye component was developed. We demonstrate that the photochromic properties of BR are maintained upon inkjet printing. PMID- 22834541 TI - A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers. PMID- 22834543 TI - High-precision MRI-guided adaptive brachytherapy for cervical carcinoma. AB - Over the past 20 years advances in radiological technology have led to dramatic changes in cervical cancer management. External beam radiotherapy has evolved radically as a result of these changes. More recently, though, three-dimensional (3D) image guidance and volume-based prescribing has been adopted into cervical cancer brachytherapy. This overview covers the science and technology behind magnetic resonance imaging (MRI)-guided adaptive brachytherapy and explains why it is now considered the new international standard of care. PMID- 22834544 TI - Newcastle disease. Editorial. PMID- 22834542 TI - Availability of emergency contraception: a survey of hospital emergency department gynaecologists and emergency physicians in Piedmont, Italy. AB - OBJECTIVES: To compare the knowledge and the willingness of emergency physicians and gynaecologists caring for women in Italian emergency departments (EDs) to prescribe levonorgestrel-only emergency contraceptive pills (LNG-EC pills). METHODS: A cross-sectional survey was conducted in 2009; anonymous postal questionnaires were mailed to the medical staff working at the 30 EDs located in Piedmont (Italy). RESULTS: Emergency physicians and gynaecologists have similar knowledge of the pharmacokinetics and pharmacodynamics of LNG-EC pills, but do not feel at ease in prescribing these and consider the prescription of LNG-EC pills an inappropriate activity for ED staff. CONCLUSIONS: In Italy, unlike in most other European countries, LNG-EC pills are still prescription drugs. Thus it may be useful to further investigate the reasons why Italian ED medical staff do not feel the prescription of LNG-EC pills should be within their remit and whether women can successfully obtain the prescription from physicians working in other services that can be accessed around the clock. PMID- 22834545 TI - The long view: a selective review of 40 years of Newcastle disease research. AB - This review is written for the series celebrating the 40th year since the first issue of Avian Pathology. The aim of the authors was to cover the developments in Newcastle disease (ND) research over the last 40 years that they considered significant. During those 40 years there have been several panzootics of this serious disease in poultry and for the last 30 years there has been a continuing panzootic in domestic pigeons, which has spread to wild birds and poultry. The 40 year period began with worldwide outbreaks of severe ND, which served as an important impetus for ND research work. Although early work was concerned with controlling the disease, specifically by improving and developing new vaccines and vaccine regimens, even prior to the 1970s ND virus was seen as a useful laboratory virus for replication and virulence studies. This review covers the historical developments in the following areas: understanding the molecular basis of virulence; epidemiology and relatedness of different ND strains, both antigenically and genetically; the emergence of virulent strains and their relationship with viruses of low virulence; sequencing and understanding the viral genome and genes; the development of rapid molecular-based diagnostic tests; and the phylogeny and molecular taxonomy of ND virus. The authors suggest areas in which future research could or should be undertaken. PMID- 22834546 TI - Occurrence of avian pathogenic Escherichia coli and antimicrobial-resistant E. coli in red-legged partridges (Alectoris rufa): sanitary concerns of farming. AB - Red-legged partridges (Alectoris rufa) are a significant part of the culture, diet and income for many people in central and southern Spain. Due to declining populations in the wild, intensive farming is common and 4 million juvenile partridges are released each autumn. Intensive management and high densities result in high prevalence of enteric disease and the use of antimicrobials as preventive measures on partridge farms and prior to restocking in the wild. We determined the occurrence of avian pathogenic Escherichia coli (APEC), and screened phenotypic resistance of E. coli against enrofloxacin, gentamicin and cefotaxim in farmed, restocked and wild partridges. Prevalence of APEC in farmed and restocked red-legged partridges was significantly higher than in natural populations. Phenotypic resistance against both gentamicin and enrofloxacin was significantly more frequent in farmed (75%) and restocked (43%) partridges than in wild partridges, while most E. coli isolated from natural populations were susceptible to all three antimicrobials tested (65%). This indicates that farmed and restocked partridges carry APEC that could be a reason for disease outbreaks on farms, and that E. coli carried by farmed and restocked partridges can acquire resistance to frequently used antimicrobials, thus being a concern for the environment, wild birds and consumers. Management in farms and restocking procedures may create a hazard not only for spreading APEC, but also as a potential source of resistant E. coli in the environment. PMID- 22834547 TI - Emaciation and larval filarioid nematode infection in boreal owls (Aegolius funereus). AB - Microfilariae are considered non-pathogenic in wild birds. The objective of the current communication is to report host reactions to microfilarial infection of unusual intensity in emaciated boreal owls (Aegolius funereus). An unusually large number of boreal owls (n = 21) were submitted to the Canadian Cooperative Wildlife Health Center-Quebec Region for post-mortem examination during the winter of 2009. Nineteen out of 21 birds were considered emaciated based on atrophy of adipose tissue and pectoral muscles and suboptimal weight. A microscopic examination of a subset of nine owls revealed the presence of microfilariae in six owls. Three of the birds with a heavy parasite burden had masses of larval nematodes obstructing large vessels of the lungs. The emaciated owls are believed to have died from starvation due to a cyclic decrease in prey abundance in the boreal forest. This cycle also drives winter movements of boreal owls to urbanized areas of southern Quebec, presumably accounting for the large number of birds submitted in 2009. In the most severely infected owls, the extreme microfilarial burden might have caused an alteration in circulatory dynamics, gaseous exchanges and also probably some metabolic cost. Consequently, microfilariae could have significantly contributed to the death of some of these owls. PMID- 22834548 TI - Epigenetic modification: possible approach to reduce Salmonella enterica serovar enteritidis susceptibility under stress conditions. AB - Stressors may influence chicken susceptibility to pathogens such as Salmonella enterica. Feed withdrawal stress can cause changes in normal intestinal epithelial structure and may lead to increased attachment and colonization of Salmonella. This study aimed to investigate modulatory effects of epigenetic modification by feed restriction on S. enterica serovar Enteritidis colonization in broiler chickens subjected to feed withdrawal stress. Chicks were divided into four groups: ad libitum feeding; ad libitum feeding with 24-h feed withdrawal on day 42; 60% feed restriction on days 4, 5, and 6; and 60% feed restriction on days 4, 5, and 6 with 24-h feed withdrawal on day 42. Attachment of S. Enteritidis to ileal tissue was determined using an ex vivo ileal loop assay, and heat shock protein 70 (Hsp70) expression was evaluated using sodium dodecyl sulphate-polyacrylamide gel electrophoresis and western blotting. Feed withdrawal stress increased S. Enteritidis attachment to ileal tissue. However, following feed withdrawal the epigenetically modified chickens had significantly lower attachment of S. Enteritidis than their control counterparts. A similar trend with a very positive correlation was observed for Hsp70 expression. It appears that epigenetic modification can enhance resistance to S. Enteritidis colonization later in life in chickens under stress conditions. The underlying mechanism could be associated with the lower Hsp70 expression in the epigenetically modified chickens. PMID- 22834549 TI - Preliminary evaluation of the immunoenhancement potential of Newcastle disease vaccine formulated as a cationic liposome. AB - This study evaluates the enhancement of immune response of birds to Newcastle disease (ND) vaccine encapsulated in 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-based liposomes. The vesicles of the liposomal ND vaccine were physically characterized for shape, particle size and zeta potential. The results of the analyses showed that vesicles of the liposomal ND vaccine were spherical and tightly packed. The mean size distribution was below 100 nm. The mean zeta potential was 24 mV. Sixty experimental birds were then divided into an unvaccinated group, a liposomal ND vaccine group and a live La Sota((r)) vaccine group. Both the liposomal ND vaccine and live La Sota((r)) vaccine groups were vaccinated orally at 3 and 6 weeks of age. The mean antibody titres, total and differential white blood cell count, and blood chemistry, respectively, were assessed. Ten birds from each group were challenged by oral administration of 0.2 ml virulent Herts 33 strain at 9 weeks of age. The log(2) mean antibody titre induced by the liposomal ND vaccine after secondary immunization of the birds was 9.60+/-0.95 while that of the live La Sota( ((r)) ) vaccine was 6.00+/-0.63. Nine of the 10 challenged birds in the unvaccinated group died while none died from the liposomal ND vaccine group or the live La Sota((r)) vaccine group. After the boost vaccination, the chickens vaccinated with the liposomal ND vaccine had a higher mean antibody titre, indicating that encapsulating ND vaccine in DOTAP based liposome induced significantly higher immunity than the live La Sota((r)) vaccine. PMID- 22834550 TI - Zinc prevents Salmonella enterica serovar Typhimurium-induced loss of intestinal mucosal barrier function in broiler chickens. AB - The study was carried out to evaluate the beneficial effects of supplemental zinc (Zn) on the intestinal mucosal barrier function in Salmonella enterica serovar Typhimurium-challenged broiler chickens in a 42-day experiment. A total of 336 1 day-old male Arbor Acres broiler chicks were assigned to eight treatment groups. A 4*2 factorial arrangement of treatments was used in a completely randomized experimental design to study the effects of levels of supplemental Zn (0, 40, 80 and 120 mg/kg diet), pathogen challenge (with or without S. Typhimurium challenge), and their interactions. S. Typhimurium infection caused reduction of growth performance (P<0.05) and intestinal injury, as determined by reduced (P<0.05) villus height/crypt depth ratio and sucrase activity in the ileum, increased (P<0.05) plasma endotoxin levels, and reduced (P<0.05) claudin-1, occludin and mucin-2 mRNA expression in the ileum at day 21. Zn pre-treatment tended to improve body weight gain (P=0.072) in the starter period, to increase the activity of ileal sucrase (P=0.077), to reduce plasma endotoxin levels (P=0.080), and to significantly increase (P<0.05) the villus height/crypt depth ratio and mRNA levels of occludin and claudin-1 in the ileum at day 21. The results indicated that dietary Zn supplementation appeared to alleviate the loss of intestinal mucosal barrier function induced by S. Typhimurium challenge and the partial mechanism might be related to the increased expression of occludin and claudin-1 in broiler chickens. PMID- 22834551 TI - The effect of Artemisia annua on broiler performance, on intestinal microbiota and on the course of a Clostridium perfringens infection applying a necrotic enteritis disease model. AB - The aerial parts of the plant Artemisia annua contain essential oils having antimicrobial properties against Clostridium perfringens Type A, the causal agent for necrotic enteritis in broilers. In two experiments, the influence of increasing dietary concentrations of dried A. annua leaves (0, 5, 10 and 20 g/kg) and n-hexane extract from fresh A. annua leaves (0, 125, 250 and 500 mg/kg) on broiler performance was investigated. Dried plant material decreased feed intake and body weight in a dose-dependent manner, and 10 and 20 g/kg diet tended to improve the feed conversion ratio. The n-hexane extract also reduced feed intake, but broiler weight tended to decrease only at the highest dietary concentration. The feed conversion ratio tended to improve when birds received 250 and 500 mg/kg n-hexane extract. In a third experiment, a necrotic enteritis disease model was applied to investigate the effect of the dietary addition of dried A. annua leaves (10 g/kg on top) or n-hexane extract of A. annua (250 mg/kg) on the severity of the disease in broilers. The addition of n-hexane extract reduced the intestinal C. perfringens numbers and the severity of the disease-related small intestinal lesions. Over the infection period from day 17 to day 27, birds supplemented with the n-hexane extract gained more weight than both the challenged control birds and birds receiving dried plant material. The results indicate that n-hexane extracts derived from A. annua can modulate the course of necrotic enteritis and compensate to a certain extent for the disease-associated weight losses. PMID- 22834552 TI - Further evidence for the widespread co-circulation of lineages 4b and 7 velogenic Newcastle disease viruses in rural Nigeria. AB - Newcastle disease (ND) is an endemic disease in rural poultry of Western Africa. It may cause severe economic losses in the poultry sector and, as such, is listed as a notifiable disease by the World Organisation for Animal Health (OIE). Recently, a new genetic lineage of ND viruses was discovered in Western Africa. We determined the complete fusion (F) gene coding sequence of 12 ND viruses isolated from pigeons and rural chickens in six Nigerian states in 2007 and 2008. Phylogenetic analysis of the complete F coding sequence confirmed the circulation of genetically diverse ND isolates in a large geographic area in Nigeria. Next to isolates belonging to lineage 4b, viruses of the recently discovered lineage 7 (some of which were previously reported to escape routine real-time reverse transcriptase-polymerase chain reaction detection) were isolated in six states during the two-year period. The documented genetic variants occurred over a large geographic area, indicating an endemic circulation of these viruses. Three different velogenic fusion gene cleavage site motifs were observed. These findings confirm the endemic circulation and diversification of ND isolates in rural poultry and pigeons in Nigeria and highlight the importance of surveillance in developing countries to monitor the validity of rapid molecular diagnostic tools and of vaccination regimes. PMID- 22834553 TI - Isolation of herpesvirus and Newcastle disease virus from White Storks (Ciconia ciconia) maintained at four rehabilitation centres in northern Germany during 1983 to 2001 and failure to detect antibodies against avian influenza A viruses of subtypes H5 and H7 in these birds. AB - Herpesvirus isolations from peripheral white blood cells of 253 White Storks (Ciconia ciconia) were obtained during a long-term study (1983 to 2001). The storks lived for a few months to 20 years at four rehabilitation centres. Isolates were obtained from 83 of 253 storks. This herpesvirus is indigenous for storks and unrelated to any other avian herpesvirus. Significantly more herpesvirus isolates were obtained during spring than in autumn samplings. The intervals between the first and last virus isolation ranged from 1 to 15 years. Herpesvirus isolates were simultaneously obtained from white blood cells and from pharyngeal swabs of four of 34 storks but not from cloacal swabs. Neutralizing antibodies to stork herpesvirus were detected in 178 of 191 examined blood plasma samples. Neutralizing antibodies against stork herpesvirus did not correlate with herpesvirus viraemia. The results further substantiate the persistence of herpesvirus in White Storks and underline the previously unrecorded long periods of virus and antibody presence. Virulent avian paramyxovirus type 1 (APMV-1; Newcastle disease virus) was isolated from white blood cells during 1992 and 1993 from four healthy migrating storks, and possessed virulence markers on the cleavage site of the H and F genes. These properties resemble the NE type of APMV 1. Haemagglutination inhibition antibodies against APMV-1 were detected in 16 of 191 blood plasma samples. Avian influenza A virus was not isolated and antibodies against subtypes H5 and H7 were not detected. PMID- 22834554 TI - Fatal skull trauma in caged layer chickens associated with a moving feed hopper: diagnosis based on autopsy examination, forensic computed tomography and farm visit. AB - Investigation of unexpected mortality in caged layer chickens led to the discovery of a consistent traumatic injury to the heads of affected hens. Initial post-mortem examination found linear skin lacerations and associated fractures in the dorsal cranium of all birds examined, and 5 to 10 mm deep trauma in the underlying brain tissue. Post-mortem multidetector computed tomography (CT) scanning of two affected birds demonstrated similar obliquely orientated, linear, depressed fractures of the skulls consistent with a single, severe impact force to the head. Both skull fractures had a pattern of rounded, rostral expansion measuring approximately 3 mm in width. On inspection of the cages during a farm visit, this CT pattern corresponded with the size and shape of sheet metal lugs holding feed troughs onto the cages (on which blood stains were subsequently observed). Based on this analysis and hypothesizing that hunger was a triggering factor, a recommendation was made to reverse the shed "lights on" and feed hopper operation times with instant reduction in mortality. This case highlights the value of post-mortem CT imaging in bird death investigation where trauma is a postulated cause. PMID- 22834555 TI - Conjunctivitis, rhinitis, and sinusitis in cliff swallows (Petrochelidon pyrrhonota) found in association with Mycoplasma sturni infection and cryptosporidiosis. AB - Fledgling cliff swallows were cared for at a rehabilitation facility when clinical signs of ocular disease, characterized by conjunctivitis, epiphora, and hyperaemia of palpebrae and nictitans, were recognized. Treatment consisted of topical and oral antibiotic therapy and one topical steroid administration. However, one cliff swallow died and three were killed due to poor therapeutic response. Conjunctival swabs were obtained ante-mortem from the three cliff swallows and were submitted for mycoplasma culture and molecular diagnostics. Heads of the three birds were fixed in 10% neutral buffered formalin and submitted for histopathologic examination of oculonasal tissues. Mycoplasma cultures and molecular evaluation of isolates identified Mycoplasma sturni, but not Mycoplasma gallisepticum, from each specimen. Histopathologic examination revealed lymphoplasmacytic conjunctivitis, rhinitis and infraorbital sinusitis with follicular lymphoid hyperplasia, epithelial hyperplasia, and protozoal stages compatible with Cryptosporidium spp. arranged in and along the apical surfaces of epithelial cells. Identification of concurrent M. sturni and Cryptosporidium spp. infections in these cliff swallows demonstrates an alternative infectious condition that can produce gross and microscopic lesions comparable with those commonly observed in M. gallisepticum infections of house finches and other passerine species. Conjunctivitis associated with M. sturni and Cryptosporidium spp. in cliff swallows may represent an emerging disease risk to a naive, high-density and colonial species such as colony-nesting cliff swallows. PMID- 22834556 TI - Anticoccidial effect of supplemental dietary Galla Rhois against infection with Eimeria tenella in chickens. AB - The anticoccidial effects of Galla Rhois (GR) powder, which contains a major tannin-derived component of 52.7%, were evaluated in chickens following oral infection with Eimeria tenella. One-day-old chickens were assigned to five groups (control, unsupplemented, GR 0.5% supplemented [GRS 0.5%], GRS 1.0% [GRS 1.0%] and salinomycin supplemented [SS]). The chickens were fed a standard diet supplemented or not supplemented with GR or salinomycin for 10 days prior to infection. The birds received the supplemented diets continuously until 10 days post infection. The effects of GR on a E. tenella infection were evaluated by several parameters, including body weight gain, feed intake, oocyst excretion, bloody diarrhoea, and lesion scores. Infected chickens on the GRS and SS diets had a relatively moderate body weight loss (reduction ratio < 15%) and improved feed conversion. GRS and SS chickens produced significantly fewer faecal oocysts (P<0.05) and showed milder bloody diarrhoea compared with the E. tenella-infected control group. Furthermore, the lesion scores of both the GRS 0.5% and GRS 1.0% groups were significantly lower than the scores of the unsupplemented group on day 5 post infection. The lesion scores for the GR groups were similar to the scores for the SS group. In conclusion, this study suggests that GR appears to be as efficacious as salinomycin against E. tenella infection. GR supplementation leads to a reduction in infected chickens, although infected chickens are still affected compared with the uninfected control group. GR-based diets may be beneficial in preventing or treating coccidial infections in poultry. PMID- 22834557 TI - Cell cycle synchronization of skin fibroblast cells in four species of family Felidae. AB - This study was examined whether the species of felid affects synchronization accuracy at the G0/G1 stage of the cell cycle and the occurrence of apoptosis by different protocols, such as serum starvation, confluent and roscovitine treatment. Skin fibroblast cells were obtained from the Asian golden cat, marbled cat, leopard and Siamese cat. The cells from each animal were treated with either serum starvation for 1-5 days, cell confluency-contact inhibition for 5 days or roscovitine at various concentrations (7.5-30 MUm). Flow cytometric analysis revealed that serum starvation for 3 days provided the highest cell population arrested at the G0/G1 stage, irrespective of the felid species. In all species, 100% confluency gave a significantly higher percentage of cells arrested at the G0/G1 stage compared with the non-treated control cells. The effects of roscovitine treatment and the appropriate concentration on the rates of G0/G1 cells differed among the felid species. Serum starvation for more than 4 days in the marbled cat and Siamese cat and roscovitine treatment with 30 MUm in the Asian golden cat and leopard increased the rates of apoptosis. In conclusion, different felid species responded to different methods of cell cycle synchronization. Asian golden cat and Siamese cat fibroblast cells were successfully synchronized to G0/G1 stage using the serum starvation and roscovitine treatment, whereas only confluency-contact inhibition treatment induced cell synchronization in the leopard. Moreover, these three methods did not successfully induce cell synchronization of the marbled cat. These findings may be valuable for preparing their donor cells for somatic cell nuclear transfer in the future. PMID- 22834558 TI - Role of thin n-type metal-oxide interlayers in inverted organic solar cells. AB - We have investigated the photovoltaic properties of inverted solar cells comprising a bulk heterojunction film of poly(3-hexylthiophene) and phenyl-C(61) butyric acid methyl ester, sandwiched between an indium-tin-oxide/Al-doped zinc oxide (ZnO-Al) front, and tungsten oxide/aluminum back electrodes. The inverted solar cells convert photons to electrons at an external quantum efficiency (EQE) exceeding 70%. This is a 10-15% increase over EQEs of conventional solar cells. The increase in EQE is not fully explained by the difference in the optical transparency of electrodes, interference effects due to an optical spacer effect of the metal-oxide electrode buffer layers, or variation in charge generation profile. We propose that a large additional splitting of excited states at the ZnO-Al/polymer interface leads to the considerably large photocurrent yield in inverted cells. Our finding provides new insights into the benefits of n-type metal-oxide interlayers in bulk heterojunction solar cells, namely the splitting of excited states and conduction of free electrons simultaneously. PMID- 22834559 TI - Dependences of water permeation through cyclic octa-peptide nanotubes on channel length and membrane thickness. AB - Effects of the channel length and membrane thickness on the water permeation through the transmembrane cyclic octa-peptide nanotubes (octa-PNTs) have been studied by molecular dynamics (MD) simulations. The water osmotic permeability (p(f)) through the PNTs of k * (WL)(4)/POPE (1-palmitoyl-2-oleoyl glycerophosphoethanolamine; k = 6, 7, 8, 9, and 10) was found to decay with the channel length (L) along the axis (~L(-2.0)). Energetic analysis showed that a series of water binding sites exist in these transmembrane PNTs, with the barriers of ~3k(B)T, which elucidates the tendency of p(f) well. Water diffusion permeability (p(d)) exhibits a relationship of ~L(-1.8), which results from the novel 1-2-1-2 structure of water chain in such confined nanolumens. In the range of simulation accuracy, the ratio (p(f)/p(d)) of the water osmotic and diffusion permeability is approximately a constant. MD simulations of water permeation through the transmembrane PNTs of 8 * (WL)(4)/octane with the different octane membrane thickness revealed that the water osmotic and diffusion permeability (p(f) and p(d)) are both independent of the octane membrane thickness, confirmed by the weak and nearly same interactions between the channel water and octane membranes with the different thickness. The results may be helpful for revealing the permeation mechanisms of biological water channels and designing artificial nanochannels. PMID- 22834560 TI - Thiol derivatization for LC-MS identification of microcystins in complex matrices. AB - Microcystins are a group of cyclic heptapeptides originating from cyanobacteria. Cyanobacteria also produce a range of peptides and other compounds that can result in complex chromatograms when samples are analyzed by LC-MS. Derivatization with appropriate thiols (e.g., mercaptoethanol) of the olefin in the alpha,beta-unsaturated amide present in most microcystins was shown to simplify analysis of LC-MS chromatograms of sample extracts, making it much easier to identify peaks corresponding to candidate microcystins. Furthermore, interpretation of MS(2) spectra was facilitated by addition of the mass associated with the thiol to the alpha,beta-unsaturated amide of microcystins. Cyanotoxins containing Mdha or Dha reacted readily with thiols, whereas Mser, Ser, Mdhb, and thiol-derivatives of Mdha or Dha did not react under the conditions used. This approach therefore provides a convenient LC-MS method to obtain evidence for the presence of Mdha or Dha and can likely be used to differentiate between the isobaric amino acids Mdha and Dhb in candidate cyanotoxin peaks. When O-(2-mercaptoethyl)-O'-methyl-hexa(ethylene glycol) (MEMHEG) (M(w)t. 356) was used as the thiol, the resulting derivatives eluted in an LC-MS mass window that was largely free of interferences. This approach simplifies detection of candidate microcystin analogues even in the presence of complex mixtures of coeluting components. The method was used for qualitative analysis of a Microcystis aeruginosa culture from Lake Naivasha, Kenya, and the results were verified using precursor-ion scanning and high-resolution mass spectrometry. PMID- 22834561 TI - Epidemiologic study of dermatologic disorders among children in South Sinai, Egypt. AB - BACKGROUND: Few epidemiologic surveys have been carried out to determine the prevalence of skin diseases in the population of Egypt, particularly in the Sinai Peninsula. Thus, the necessity of such research in South Sinai is pressing. This study aimed to determine the prevalence of various skin diseases among children in South Sinai. METHODS: A community-based protocol was followed. The study included 2194 children of both genders, 18 years of age and younger, and in six different localities within South Sinai. Data were collected by taking a full history and by systemic and dermatologic clinical examination that included the site, severity, distribution, and extent of skin lesions if present. Subjects were surveyed at general morbidity consultations and campaign field visits. The study was conducted from August 2008 to August 2009. Data were tabulated and analyzed statistically using Pearson's chi-squared test. Differences were considered significant at a P-value of < 0.05. RESULTS: Findings revealed that 71.4% of the studied population had one or more skin diseases. The highest rate of prevalence applied to parasitic skin infestations (pediculosis capitis, 37.6%). Eczema or dermatitis were found in 25.8% of participants. Pityriasis alba occurred at a rate of 18.3% and seborrheic dermatitis at a rate of 6.7%. Xerosis was found in 11.8% of subjects, viral warts in 4.1%, photosensitivity in 4.1%, acne vulgaris in 2.6%, and fungal skin infections in 1.0%. Other skin diseases diagnosed in low numbers in the study children included impetigo, freckles, and scabies. Prevalences of vitiligo and psoriasis were very low (0.18% and 0.05%, respectively). CONCLUSIONS: Infective parasitic diseases are a major health problem, particularly among younger children and in subjects of low socioeconomic status. PMID- 22834562 TI - Facile, solution-based synthesis of soft, nanoscale Janus particles with tunable Janus balance. AB - We present a novel, versatile, and simple solution-based routine to produce soft, nanosized Janus particles with tunable structural and physical properties at high volume yield. This process is based on the cross-linking of compartments within precisely defined multicompartment micelles (MCMs), which are themselves formed by the self-assembly of ABC triblock terpolymers. Therein, the C blocks form the stabilizing corona emanating from B compartments, which in turn reside on an A core. Cross-linking of the B compartments allows to permanently fixate the phase separated state and dissolution in a good solvent for all blocks breaks up the MCMs into single Janus particles. They now consist of a core of cross-linked B blocks and two phase-separated hemispheres of A and C. The process gives access to unprecedented structural features such as tunable core diameter and control over the Janus balance ranging from dominant A side to equal hemispheres to dominant C side. We demonstrate that this simple one-pot approach can be extended to a range of triblock terpolymers with different block lengths and block chemistries to furnish a library of tailor-made Janus particles with widely tunable physical properties. Such a diversity and simplicity has remained unreachable with our previously developed approach using the controlled cross linking of bulk morphologies. We show that this new synthetic route can be upscaled to a high volume yield of 10 wt %, thereby enabling large-scale applications. We further demonstrate the effect of the Janus balance on colloidal self-assembly. Janus particles with a dominant hydrophobic and a small hydrophilic patch aggregate into large clusters in water, but merely di- or trimerize in chloroform. PMID- 22834563 TI - Roll-your-own tobacco use among Canadian youth: is it a bigger problem than we think? AB - BACKGROUND: Despite the apparent decline in the popularity of roll-your-own (RYO) cigarettes over the past few decades, RYO tobacco products are widely available and used by a substantial number of adult smokers. Considering research has yet to examine the prevalence of RYO tobacco use among youth populations, this manuscript examines the prevalence of RYO tobacco use and factors associated with RYO use in a nationally representative sample of youth smokers from Canada. METHODS: This study used data collected from 3,630 current smokers in grades 9 to 12 as part of the 2008-09 Canadian Youth Smoking Survey (YSS). Descriptive analyses of the sample demographic characteristics, smoking status, cigarettes per day, weekly spending money, and frequency of marijuana use were examined by RYO tobacco ever use and RYO tobacco current use. Two logistic regression models were used to examine factors associated with RYO tobacco ever use and RYO tobacco current use. RESULTS: We identified that 51.2% of current smokers were RYO ever users and 24.2% were RYO current users. The prevalence of RYO current users was highest in Atlantic Canada (40.1%) and lowest in Quebec (12.3%). RYO current users were more likely to be male (OR 1.27), to be daily smokers (OR 1.75), to use marijuana once a month or more (OR 2.74), and to smoke 11 or more cigarettes per day (OR 6.52). RYO current users were less likely to be in grade 11 (OR 0.65) or grade 12 (OR 0.40) and less likely to have between $20 to $100 (OR 0.44) or more than $100 (OR 0.45) of disposable income. CONCLUSIONS: Developing a better understanding of RYO tobacco use among youth is important for advancing population-level tobacco control prevention strategies and cessation programs. We identified that RYO tobacco use is not a negligible problem among Canadian youth. Ongoing research is needed to continue monitoring the prevalence of RYO use among youth and the factors associated with its use, but to also monitor if this more affordable tobacco product is being targeted to price sensitive youth smokers. PMID- 22834564 TI - Reliance on pollinators predicts defensive chemistry across tobacco species. AB - Defensive traits are typically studied in the context of avoiding antagonists, but may also mediate key interactions with mutualists. Plant chemical defences occur in flowers, suggesting pollinators may be agents of selection on defence. We hypothesised that floral defences would deter pollinators, and therefore, pollinators would select for lower defences in outcrossing than self-pollinating species. We measured pollinator reliance and alkaloid levels in 32 greenhouse grown Nicotiana species. Using a comparative phylogenetic approach, we found significantly lower nectar, floral and leaf nicotine concentrations in outcrossing than selfing species, with a 15-fold decrease in leaf nicotine levels. Nicotine concentrations were positively correlated across tissues, suggesting that selection against floral defences could constrain the evolution of leaf defences. Thus, pollinators could shape the evolution not only of floral defences but also of defences in other tissues where herbivores have traditionally been considered the dominant agent of selection. PMID- 22834565 TI - The effects of age, disease state, and granulocyte colony-stimulating factor on progenitor cell count and function in patients undergoing cell therapy for cardiac disease. AB - The potential of autologous bone marrow (BM)-derived progenitor/stem cell (BMSC) therapy for cardiac repair maybe limited by patient-related factors, such as age and the disease process itself. In this exploratory analysis, we assessed the impact of age, different disease states, and granulocyte colony-stimulating factor (G-CSF) therapy on progenitor cell concentration and function in patients recruited to our clinical trials of BMSC therapy for ischaemic heart failure (IHD), dilated cardiomyopathy (DCM), and acute myocardial infarction (AMI). The concentrations of CD34+ cells and endothelial progenitor cells (EPCs) were measured in the peripheral blood (PB) and BM of 201 patients. Additionally, cell mobilization following G-CSF and the functional capability of CD34+ cells (using a colony-forming unit assay) were assessed. We found that older age was associated with a lower PB CD34+ cell concentration in the whole study group as well as blunting the effect of G-CSF on BMSC mobilization in IHD patients. Nonischaemic heart failure (DCM) was associated with a significantly higher baseline PB CD34+ and EPC concentration compared to IHD. Following G-CSF treatment, the CD34+ cell concentration was greater in the BM compared to PB, however, the PB CD34+ cells appeared to have a greater and improved (compared to baseline) functional potential. Our results suggest treatment with G-CSF improves the functional potential of mobilized circulating progenitor cells compared to those in the BM. Further work is required to determine which source of cells is best for the purposes of cardiac repair following G-CSF therapy. PMID- 22834566 TI - Determinants for refusal of HIV testing among women attending for antenatal care in Gambella Region, Ethiopia. AB - BACKGROUND: In Gambella region, inhabitants owe socio-cultural factors that might favor refusal for HIV testing service utilization among Antenatal Care attendees. OBJECTIVE: To assess determinants for refusal of HIV testing service utilization among ANC attendees in Gambella Region. METHODS: A comparative cross sectional study was conducted among ANC attendees from March 2008 to May 2008 in four selected health facilities of Gambella region. Sample size of 332 participants (83 who refused HIV testing and 249 who accepted HIV testing) were taken for the study. The study was supplemented with four focus group discussions. Multivariate binary logistic regression was employed to control for confounding factors. RESULTS: When adjusted with other factors pregnant women with 2-3 live births in the past; who claimed divorce as a perceived response of their husband following HIV positive test result; who had not sought agreement from their husband for testing; disclosure of test for husband and being from certain ethnic group (E.g. Mejenger) were independent predictors for refusal of HIV testing among ANC attendees. CONCLUSION AND RECOMMENDATION: Based on the findings, the following recommendations were forwarded: Provision of innovative information and education on the pre-test session for those pregnant women having two or more children; community involvement to tackle stigma; women empowerment; designing couple friendly counseling service; and fighting harmful traditional practices related with decision of HIV testing. PMID- 22834567 TI - Rasagiline: a guide to its use in Parkinson's disease. AB - Oral rasagiline (Azilect(r)) as monotherapy or as an adjunct to levodopa provides a useful option in the symptomatic treatment of adult patients with Parkinson's disease. In patients with early Parkinson's disease, monotherapy with rasagiline 1 mg/day improved symptoms of the disease relative to placebo. As adjunctive therapy to levodopa in patients with advanced Parkinson's disease, rasagiline 0.5 or 1 mg/day significantly reduces the total daily 'off' time. Rasagiline is generally well tolerated when administered as monotherapy or as adjunctive therapy. PMID- 22834568 TI - Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy. AB - Transdermal granisetron (Sancuso(r)) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance. PMID- 22834569 TI - GiA Roots: software for the high throughput analysis of plant root system architecture. AB - BACKGROUND: Characterizing root system architecture (RSA) is essential to understanding the development and function of vascular plants. Identifying RSA associated genes also represents an underexplored opportunity for crop improvement. Software tools are needed to accelerate the pace at which quantitative traits of RSA are estimated from images of root networks. RESULTS: We have developed GiA Roots (General Image Analysis of Roots), a semi-automated software tool designed specifically for the high-throughput analysis of root system images. GiA Roots includes user-assisted algorithms to distinguish root from background and a fully automated pipeline that extracts dozens of root system phenotypes. Quantitative information on each phenotype, along with intermediate steps for full reproducibility, is returned to the end-user for downstream analysis. GiA Roots has a GUI front end and a command-line interface for interweaving the software into large-scale workflows. GiA Roots can also be extended to estimate novel phenotypes specified by the end-user. CONCLUSIONS: We demonstrate the use of GiA Roots on a set of 2393 images of rice roots representing 12 genotypes from the species Oryza sativa. We validate trait measurements against prior analyses of this image set that demonstrated that RSA traits are likely heritable and associated with genotypic differences. Moreover, we demonstrate that GiA Roots is extensible and an end-user can add functionality so that GiA Roots can estimate novel RSA traits. In summary, we show that the software can function as an efficient tool as part of a workflow to move from large numbers of root images to downstream analysis. PMID- 22834570 TI - Spectroscopic investigation of the effect of salt on binding of tartrazine with two homologous serum albumins: quantification by use of the Debye-Huckel limiting law and observation of enthalpy-entropy compensation. AB - Formation of ion pair between charged molecule and protein can lead to interesting biochemical phenomena. We report the evolution of thermodynamics of the binding of tartrazine, a negatively charged azo colorant, and serum albumins with salt. The dye binds predominantly electrostatically in low buffer strengths; however, on increasing salt concentration, affinity decreases considerably. The calculated thermodynamic parameters in high salt indicate manifestation of nonelectrostatic interactions, namely, van der Waals force and hydrogen bonding. Site-marker competitive binding studies and docking simulations indicate that the dye binds with HSA in the warfarin site and with BSA at the interface of warfarin and ibuprofen binding sites. The docked poses indicate nearby amino acid positive side chains, which are possibly responsible for electrostatic interaction. Using the Debye-Huckel interionic attraction theory for binding equilibria, it is shown that, for electrostatic binding the calculated free energy change increases linearly with square root of ionic strength. Also UV-vis, fluorescence, CD data indicate a decrease of interaction with salt concentration. This study quantitatively relates how ionic strength modulates the strength of the protein ligand electrostatic interaction. The binding enthalpy and entropy have been found to compensate one another. The enthalpy-entropy compensation (EEC), general property of weak intermolecular interactions, has been discussed. PMID- 22834571 TI - Avoidance of heat and attraction to optogenetically induced sugar sensation as operant behavior in adult Drosophila. AB - Animals have to perform adequate behavioral actions dependent on internal states and environmental situations, and adjust their behavior according to positive or negative consequences. The fruit fly Drosophila melanogaster represents a key model organism for the investigation of neuronal mechanisms underlying adaptive behavior. The authors are using a behavioral paradigm in which fruit flies attached to a manipulator can walk on a Styrofoam ball whose movements are recorded such that intended left or right turns of the flies can be registered and used to operantly control heat stimuli or optogenetic activation of distinct subsets of neurons. As proof of principle, the authors find that flies in this situation avoid heat stimuli but prefer optogenetic self-stimulation of sugar receptors. Using this setup it now should be possible to study the neuronal network underlying positive and negative value assessment of adult Drosophila in an operant setting. PMID- 22834632 TI - Continuous evaluation of neurological prognosis after cardiac arrest. AB - Post-resuscitation care has changed in the last decade, and outcome after cardiac arrest has improved, thanks to several combined measures. Induced hypothermia has shown a treatment benefit in two randomized trials, but some doubts remain. General care has improved, including the use of emergency coronary intervention. Assessment of neurological function and prognosis in comatose cardiac arrest patient is challenging, especially when treated with hypothermia. In this review, we evaluate the recent literature and discuss the available evidence for prognostication after cardiac arrest in the era of temperature management. Relevant literature was identified searching PubMed and reading published papers in the field, but no standardized search strategy was used. The complexity of predicting outcome after cardiac arrest and induced hypothermia is recognized in the literature, and no single test can predict a poor prognosis with absolute certainty. A clinical neurological examination is still the gold standard, but the results need careful interpretation because many patients are affected by sedatives and by hypothermia. Common adjuncts include neurophysiology, brain imaging and biomarkers, and a multimodal strategy is generally recommended. Current guidelines for prediction of outcome after cardiac arrest and induced hypothermia are not sufficient. Based on our expert opinion, we suggest a multimodal approach with a continuous evaluation of prognosis based on repeated neurological examinations and electroencephalography. Somatosensory-evoked potential is an established method to help determine a poor outcome and is recommended, whereas biomarkers and magnetic resonance imaging are promising adjuncts. We recommend that a decisive evaluation of prognosis is performed at 72 h after normothermia or later in a patient free of sedative and analgetic drugs. PMID- 22834633 TI - Febrile-range hyperthermia augments reversible TNF-alpha-induced hyperpermeability in human microvascular lung endothelial cells. AB - Fever commonly occurs in acute lung injury (ALI) and ALI occurs in 25% of victims of heat stroke. We have shown in mouse models of ALI that exposure to febrile range hyperthermia (FRH), 39.5 degrees C, increases non-cardiogenic pulmonary oedema. In this study we studied the direct effects of FRH on endothelial barrier integrity using human microvascular endothelial cells (HMVEC-Ls). We analysed the effect of exposure to culture temperatures between 38.5 degrees and 41 degrees C with and without tumour necrosis factor-alpha (TNF-alpha) up to 250 U/mL for 6-24 h. We found that exposure to 2.5-250 U/mL TNF-alpha increased HMVEC-L permeability by 4.1-15.8-fold at 37 degrees C. Exposure to 39.5 degrees C alone caused variable, modest, lot-specific increases in HMVEC-L permeability, however raising culture temperature to 39.5 degrees C in the presence of TNF-alpha increased permeability an additional 1.6-4.5-fold compared with cells incubated with the same TNF-alpha concentration at 37 degrees C. Permeability occurred without measurable cytotoxicity and was reversible upon removal of TNF-alpha and reduction in temperature to 37 degrees C. Exposure to 39.5 degrees C or TNF-alpha each stimulated rapid activation of p38 and ERK but the effects were not additive. Treatment with inhibitors of ERK (U0126) or p38 (SB203580) each reduced TNF-alpha-induced permeability in 39.5 degrees C monolayers to levels in 37 degrees C cells, but did not alter TNF-alpha-induced permeability in the 37 degrees C cells. These results demonstrate that FRH directly increases paracellular pathway opening through a process that requires ERK and p38 MAPKs. A better understanding of this mechanism may provide new understanding about how fever may contribute to the pathogenesis of ALI and provide new therapeutic targets to improve clinical outcomes. PMID- 22834634 TI - 18F-fluorodeoxyglucose positron emission tomography/computed tomography as an effective diagnostic workup in cervical metastasis of carcinoma from an unknown primary tumor. AB - PURPOSE: The purpose of this study is to assess the potential of 18F fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) imaging for the diagnosis of cervical metastasis of carcinoma of an unknown primary tumor (CUP) and to determine whether the maximum standardized uptake value (SUV(max)) is a prognostic factor. METHODS: Twenty-five consecutive patients with cervical metastasis of CUP were retrospectively analyzed by PET/CT between July 2007 and July 2011. RESULTS: FDG PET/CT suggested a primary tumor in 21 out of 25 patients (84.0%). The sensitivity of FDG PET/CT in detecting the primary tumor was 73.3% (11 of 15), and the positive predictive value was 52.4% (11 of 21). The median follow-up duration of survival patients was 10.4 months (range: 0-30 months). The estimated 2-year overall survival rate of all patients was 50.0%. Univariate analyses did not reveal a significant difference in overall survival between the group of 11 patients identified by pathology and the 14 patients not identified by pathology (overall survival was 57.1% and 49.1%, respectively; p=0.468). The median SUV(max) was 7.6. In the log-rank test, patients with a low SUV(max) (<= 7.0) in cervical lymph nodes had a significantly higher survival rate at 2 years (87.5% vs. 21.2%; p=0.007) than patients with a high SUV(max) (>7.0). CONCLUSIONS: Although our study was inconclusive due to the small sample size, our results suggest that FDG PET/CT may be an effective diagnostic workup in the cervical metastasis of carcinoma from an unknown primary tumor (UPT). In the present study, SUV(max) of PET/CT in the cervical lymph node may serve as a prognostic factor of cervical metastasis of carcinoma from a UPT based on the limited number of patients. Further studies are needed to confirm these findings. PMID- 22834635 TI - Water encapsulation in a polyoxapolyaza macrobicyclic compound. AB - A new heteroditopic macrobicyclic compound (t(2)pN(5)O(3)) containing two separate polyoxa and polyaza compartments was synthesized in good yield through a [1 + 1] "tripod-tripod coupling" strategy. The X-ray crystal structure of H(3)t(2)pN(5)O(3)(3+) revealed the presence of one encapsulated water molecule accepting two hydrogen bonds from two protonated secondary amines and donating a hydrogen bond to one amino group. The acid-base behavior of the compound was studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KCl. The results revealed unusual protonation behavior, namely a surprisingly low fourth protonation constant contrary to what was expected for the compound. (1)H NMR and DOSY experiments, as well as molecular modeling studies, showed that the water encapsulation and the conformation observed in the solid state are retained in solution. The strong binding of the encapsulated water molecule, reinforced by the cooperative occurrence of a trifurcated hydrogen bond at the polyether compartment of the macrobicycle, account for the very low log K(4)(H) value obtained. PMID- 22834636 TI - Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema. AB - BACKGROUND: Lipoxins are potential anti-inflammatory mediators and serve as an endogenous 'braking signal' in the inflammatory process. Accumulating evidence has indicated the efficacy of lipoxin A(4) (LXA(4) ) and its analogs in the treatment of many animal models of inflammatory diseases. OBJECTIVES: This study investigates the efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in the topical treatment of infantile eczema. PATIENTS AND METHODS: In this two-centre, double-blind, placebo-controlled, randomized, parallel-groups comparative study, 60 patients were randomly assigned to receive either the 15(R/S)-methyl-lipoxin A(4) cream, mometasone furoate (Eloson, Schering-Plough, Shanghai, China) or placebo for 10days. The efficacy was determined using the Severity Scale Score (SSS), Eczema Area and Severity Index (EASI) and the Infants' Dermatitis Quality of Life Index (IDQOL). Safety was monitored by physical examination, laboratory investigation and documentation of clinical adverse events. RESULTS: The treatment of eczema with 15(R/S)-methyl-LXA(4) cream significantly relieved the severity, induced a recovery, and improved the quality of life of the patients, as demonstrated by significantly reduced SSS, EASI and IDQOL, respectively, in a way similar to the efficacy of Eloson. All safety parameters remained within normal limits. No clinical adverse event was found in the three patient groups. CONCLUSIONS: 15(R/S)-methyl-LXA(4) was well tolerated, and significantly reduced the severity of eczema. The results of this small exploratory study suggest that 15(R/S)-methyl-LXA(4) warrants further investigation in the treatment of eczema. PMID- 22834637 TI - Potential of anti-cancer therapy based on anti-miR-155 oligonucleotides in glioma and brain tumours. AB - MicroRNAs are aberrantly expressed in many cancers and can exert tumour suppressive or oncogenic functions. As oncomirs promote growth of cancer cells and support survival during chemotherapy, thus microRNA-silencing therapies could be a valuable approach to be associated with anticancer drugs and chemotherapy treatments. miR-155 microRNA was found overexpressed in different types of cancer, such as leukaemias (PML, B-cell lymphomas), lung cancer and glioblastoma. GABA-A receptor downregulation was found correlated with glioma grading, with decreasing levels associated with higher grade of malignancies. A relationship between knock-down of miR-155 and re-expression of GABRA 1 protein in vivo was recently individuated. This finding has implication on the effectiveness of RNA silencing approaches against miR-155 with the scope to control proliferation and signalling pathways regulated by GABA-A receptor. Applying microRNAs for treatment of brain tumours poses several problems, and fields to be solved are mainly the passage of the brain-blood barrier and the targeted delivery to specific cell types. Glioblastoma multiforme cells bud off microvesicles that deliver cytoplasmic contents to nearby cells. Thus, the exploitation of these mechanisms to deliver antagomir therapeutics targeting microvescicles in the brain could take the lead in the near future in the treatment for brain cancers in substitution of invasive surgical intervention. PMID- 22834638 TI - Characterization of Mycobacterium tuberculosis isolated from cancer patients with suspected tuberculosis infection in Egypt: identification, prevalence, risk factors and resistance pattern. AB - Data are sparse on Mycobacterium tuberculosis infection among patients with cancer in Egypt. We sought to detect the presence of tuberculosis (TB) disease among patients with malignant conditions and suspected TB and to study the main risk factors. Also, we compared different diagnostic procedures and detected the antimicrobial susceptibility of M. tuberculosis isolates against rifampin and isoniazid. One hundred patients were included in this study, all of them had malignant conditions and were suspected by the clinicians of having TB. Identification of M. tuberculosis in different specimens was performed by smear microscopy, followed by Lowenstein-Jensen medium and Mycobacterium growth indicator tube (MGIT) cultures and artus((r)) real-time PCR. In addition, an indirect MGIT anti-TB susceptibility test was carried out against rifampin and isoniazid. A total of 76% of studied cases were found to be TB positive. The frequencies of TB-positive cases in the bronchogenic, haematological and solid tumour malignancy groups were 21%, 25% and 30%, respectively. Significant differences between pulmonary and extrapulmonary TB in different malignancy groups were recorded. Real-time PCR showed the highest overall diagnostic efficiency. Multidrug-resistance of M. tuberculosis to both rifampin and isoniazid was detected in 28.6% of examined isolates. Infection in cancer patients with TB was significantly more often recorded among elderly patients and those suffering from poverty. Pulmonary TB is more common than extrapulmonary TB in patients with malignancy. Real-time PCR is the most accurate and rapid method for TB diagnosis. MGIT-rifampin resistance may be used as a reliable marker for detection of multidrug-resistant TB. Diagnosis and instituting treatment course for active or latent TB infection are crucial before starting anticancer therapy. PMID- 22834639 TI - Enhanced electron extraction from template-free 3D nanoparticulate transparent conducting oxide (TCO) electrodes for dye-sensitized solar cells. AB - The semiconducting metal oxide-based photoanodes in the most efficient dye sensitized solar cells (DSSCs) desires a low doping level to promote charge separation, which, however, limits the subsequent electron extraction in the slow diffusion regime. These conflicts are mitigated in a new photoanode design that decouples the charge separation and extraction functions. A three-dimensional highly doped fluorinated SnO(2) (FTO) nanoparticulate film serves as conductive core for low-resistance and drift-assisted charge extraction while a thin, low doped conformal TiO(2) shell maintains a large resistance to recombination (and therefore long charge lifetime). EIS reveals that the electron transit time is reduced by orders of magnitude, whereas the recombination resistance remains in the range of traditional nanoparticle TiO(2) photoelectrodes. PMID- 22834640 TI - Assessment of different functional parameters of frozen-thawed buffalo spermatozoa by using cytofluorimetric determinations. AB - Flow cytometry is a useful tool that provides an accurate, objective and rapid evaluation of semen quality. The use of this technique could significantly improve the quality of buffalo semen samples used in artificial insemination. This study was carried out to evaluate, by flow cytometry, frozen-thawed buffalo spermatozoa quality parameters such as sperm viability by SYBR-14/propidium iodide staining; mitochondrial function by JC-1 potentiometric probe; sperm chromatin stability (SCSA) by acridine orange; and acrosome reaction (AR) by FITC PNA staining. Semen samples from five Italian Mediterranean buffalo bulls were used. Sperm viability was not different between bulls and ranged from 33.4% to 43.6%. A consistent rate (55.1 +/- 10.8%) of sperm cells showed high mitochondrial membrane potential (Deltapsi(high)), with no significant differences between subjects. Sperm chromatin structure assay differed significantly between the five buffalo bulls; moreover, data showed high stability within each buffalo. DNA fragmentation indexes (DFI), such as %-DFI, DFI, SD-DFI, were 11.2 +/- 8.6, 153.3 +/- 24.6 and 81.6 +/- 21.2, respectively. Regarding AR, the percentage of acrosome-reacted live (ARL) and acrosome-reacted dead (ARD) spermatozoa was 0.3 +/- 0.2 and 15.3 +/- 5.5, respectively. This functional parameter differed significantly between buffalo bulls and showed high stability. Following to Ca(2+) ionophore A23187 for 3 h, AR significantly differed between subjects and was characterized by an increase in both ARL (10.8%) and ARD population (22.0%). This study indicates that flow cytometry could be a useful tool for a quick multiparametric evaluation of sperm quality in buffalo. In particular, SCSA and AR resulted in sperm functional parameters sensitive enough for the diagnosis of frozen-thawed semen fertilizing potential. PMID- 22834641 TI - Nocturnal enuresis in children in Kinshasa, Democratic Republic of Congo. AB - AIM: To determine the prevalence of nocturnal enuresis in children of Kinshasa in Democratic Republic of Congo. METHODS: In all, 506 questionnaires were sent to parents of children aged 6-12 years randomly selected from four primary schools in Kinshasa, Democratic Republic of Congo. The questionnaire was designed to collect information about prevalence and factors associated with nocturnal enuresis. RESULTS: A total of 415 (82.0%) were correctly completed. In this series, 109 children were identified as nocturnal enuresis in which 50 boys and 56 girls (p > 0.05). Factors associated with nocturnal enuresis were deep sleep, young age and familial history of enuresis (p < 0.05). Only 11% of patients have been consulted by doctors. Twelve children (11.0%) were treated by healers traditional. In the other part, 43 children (39.4%) were frequently punished by their parents. The common self-help strategies were 79 children (72.5%) were submitted to fluid restrictions before going to sleep and 68 (62.4%) were waking the child at night to void. CONCLUSION: In Kinshasa, the prevalence of nocturnal enuresis was high to those reported in Asian and Western countries. Nocturnal enuresis remains an important clinical problem in children but only a small percentage of parents seek medical help. PMID- 22834642 TI - Abundant and stable char residues in soils: implications for soil fertility and carbon sequestration. AB - Large-scale soil application of biochar may enhance soil fertility, increasing crop production for the growing human population, while also sequestering atmospheric carbon. But reaching these beneficial outcomes requires an understanding of the relationships among biochar's structure, stability, and contribution to soil fertility. Using quantitative (13)C nuclear magnetic resonance (NMR) spectroscopy, we show that Terra Preta soils (fertile anthropogenic dark earths in Amazonia that were enriched with char >800 years ago) consist predominantly of char residues composed of ~6 fused aromatic rings substituted by COO(-) groups that significantly increase the soils' cation exchange capacity and thus the retention of plant nutrients. We also show that highly productive, grassland-derived soils in the U.S. (Mollisols) contain char (generated by presettlement fires) that is structurally comparable to char in the Terra Preta soils and much more abundant than previously thought (~40-50% of organic C). Our findings indicate that these oxidized char residues represent a particularly stable, abundant, and fertility-enhancing form of soil organic matter. PMID- 22834643 TI - Bioactive polymeric metallosomes self-assembled through block copolymer-metal complexation. AB - Spontaneous formation of polymeric metallosomes with uniform size (~100 nm) was found to occur in aqueous medium through the reaction of an anticancer agent, (1,2-diaminocyclohexane)platinum(II) (DACHPt), with a Y-shaped block copolymer of omega-cholesteroyl-poly(L-glutamic acid) and two-armed poly(ethylene glycol) (PEGasus-PLGA-Chole). Circular dichroism spectrum measurements revealed that the PLGA segment forms an alpha-helix structure within the metallosomes, suggesting that secondary-structure formation of metallocomplexed PLGA segment may drive the self-assembly of the system into vesicular structure. These metallosomes can encapsulate water-soluble fluorescent macromolecules into their inner aqueous phase and eventually deliver them selectively into tumor tissues in mice, owing to the prolonged blood circulation. Accordingly, fluorescent imaging of the tumor was successfully demonstrated along with an appreciable antitumor activity by DACHPt moieties retained in the vesicular wall of the metallosomes, indicating the potential of metallosomes as multifunctional drug carriers. PMID- 22834644 TI - Palmar filiform hyperkeratosis. PMID- 22834645 TI - Exclusive male care despite extreme female promiscuity and low paternity in a marine snail. AB - Males exhibit striking variation in the degree to which they invest in offspring, from merely provisioning females with sperm, to providing exclusive post-zygotic care. Paternity assurance is often invoked to explain this variation: the greater a male's confidence of paternity, the more he should be willing to provide care. Here, we report a striking exception to expectations based on paternity assurance: despite high levels of female promiscuity, males of a marine snail provide exclusive, and costly, care of offspring. Remarkably, genetic paternity analyses reveal cuckoldry in all broods, with fewer than 25% of offspring being sired by the caring male, although caring males sired proportionally more offspring in a given clutch than any other fathers did individually. This system presents the most extreme example of the coexistence of high levels of female promiscuity, low paternity, and costly male care, and emphasises the still unresolved roles of natural and sexual selection in the evolution of male parental care. PMID- 22834646 TI - Comparison and druggability prediction of protein-ligand binding sites from pharmacophore-annotated cavity shapes. AB - Estimating the pairwise similarity of protein-ligand binding sites is a fast and efficient way of predicting cross-reactivity and putative side effects of drug candidates. Among the many tools available, three-dimensional (3D) alignment dependent methods are usually slow and based on simplified representations of binding site atoms or surfaces. On the other hand, fast and efficient alignment free methods have recently been described but suffer from a lack of interpretability. We herewith present a novel binding site description (VolSite), coupled to an alignment and comparison tool (Shaper) combining the speed of alignment-free methods with the interpretability of alignment-dependent approaches. It is based on the comparison of negative images of binding cavities encoding both shape and pharmacophoric properties at regularly spaced grid points. Shaper approximates the resulting molecular shape with a smooth Gaussian function and aligns protein binding sites by optimizing their volume overlap. Volsite and Shaper were successfully applied to compare protein-ligand binding sites and to predict their structural druggability. PMID- 22834647 TI - Neurogenetics of slow axonal transport: from cells to animals. AB - Slow axonal transport is a multivariate phenomenon implicated in several neurodegenerative disorders. Recent reports have unraveled the molecular basis of the transport of certain slow component proteins, such as the neurofilament subunits, tubulin, and certain soluble enzymes such as Ca(2+)/calmodulin dependent protein kinase IIa (CaM kinase IIa), etc., in tissue cultured neurons. In addition, genetic analyses also implicate microtubule-dependent motors and other housekeeping proteins in this process. However, the biological relevance of this phenomenon is not so well understood. Here, the authors have discussed the possibility of adopting neurogenetic analyses in multiple model organisms to correlate molecular level measurements of the slow transport phenomenon to animal behavior, thus facilitating the investigation of its biological efficacy. PMID- 22834648 TI - A review of barriers and myths preventing the more widespread use of intrauterine contraception in nulliparous women. AB - OBJECTIVES: Intrauterine contracepives (IUCs) are highly effective and safe for use in all women, including those who are nulliparous. However, many myths and barriers prevent more widespread utilisation. The objective of this article was to explore the health care provider (HCP), health system and user issues that prevent more widespread use of IUCs, particularly among nulliparous women, and to present the evidence that supports achieving greater utilisation of these devices. METHODS: MEDLINE, PubMed and Embase were used to identify studies reporting attitudes and beliefs around IUCs, and clinical studies providing evidence of their risks and benefits. RESULTS: HCP, health system and user factors limiting use of IUCs were identified. The most widely explored barriers in published studies are those at the HCP level. User barriers are less well documented and health system barriers are mostly assessed through indirect evidence. Many, but not all, of the barriers can be reduced through greater understanding of the evidence. CONCLUSIONS: Efforts need to be made to disseminate the evidence, which shows that few contraindications exist to IUC use. Addressing HCP lack of knowledge, training and confidence with IUC insertions, particularly in nulliparous women, could make a substantial positive impact on IUC utilisation. PMID- 22834650 TI - The substance of love when encountering suffering: an interpretative research synthesis with an abductive approach. AB - AIM: This study presents the results of an interpretative research synthesis undertaken to explore the essence of love when encountering suffering. The idea of caring as an expression of love and compassion belongs with ideas that have shaped caring for hundreds of years. Love and suffering are the core concepts in caring science and thus demand a basic research approach. METHODS: The synthesis was undertaken by the interpretation of 15 articles focusing on love in different aspects, but within a caring science perspective. The research process was guided by a hermeneutical perspective with an abductive approach. RESULTS: The substance of love, when encountering suffering, reveals itself in three themes: love as a holy power, love as fundamental for being and love as an ethical act, which are to be found, respectively, within three dimensions: love as holiness, love as a communion and love as an art. Love is a holy power and encompasses everything; it is the well of strength that heals. No human can exist without love: this points to the ethical responsibility one has as a neighbour. In the ethical act, love is evident in concrete caring actions. CONCLUSIONS: The core of the substance of love within the three dimensions can be understood as agape. Agape connects and mirrors the dimensions, while at the same time it is clear that agape stems from and moves towards holiness, enabling love to be the ethical foundation when encountering suffering. Through the dimensions of love as communion and love as an art agape intertwine with eros forming caritas enabling the human being to move towards the dimension of holiness, which signifies becoming through suffering. PMID- 22834649 TI - A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. AB - INTRODUCTION: The clinical significance of low to low-normal testosterone (T) levels in men remains debated. AIM: To analyze the effects of raising serum T on lean body mass (LBM), fat mass (FM), total body mass, and health-related quality of-life (HRQoL). METHODS: Randomized, double-blind, placebo-controlled study. Men, aged 50-80 years, with serum total T<15 nmol/L and bioavailable T < 6.68 nmol/L, and a Aging Males' Symptoms (AMS) total score >36, received 6 months treatment with transdermal 1% T gel (5-7.5 mg/day; n =183) or placebo gel (n =179), followed by 12 months open-label with T in all. RESULTS: After 6 months, LBM increased in T- treated patients by 1.28 +/- 0.15 kg (mean +/- SE) and FM decreased by 1.16 +/- 0.16 kg, with minor changes with placebo (LBM +0.02 +/- 0.10 kg and FM -0.14 +/- 0.12 kg; all p < 0.001, T group vs. placebo). Changes were largely similar across subgroups of age, baseline total testosterone, and baseline BMI. Total HRQoL improved compared with placebo (p < 0.05, T group vs. placebo). CONCLUSIONS: Six months 1% T gel improved body composition and HRQoL in symptomatic men with low to low-normal T, with further improvements over the following 12 months. PMID- 22834651 TI - The circadian clock transcriptional complex: metabolic feedback intersects with epigenetic control. AB - Chromatin remodeling is a prerequisite for most nuclear functions, including transcription, silencing, and DNA replication. Accumulating evidence shows that many physiological processes require highly sophisticated events of chromatin remodeling. Recent findings have linked cellular metabolism, epigenetic state, and the circadian clock. The control of a large variety of neuronal, behavioral, and physiological responses follows diurnal rhythms. This is possible through a transcriptional regulatory network that governs a significant portion of the genome. The harmonic oscillation of gene expression is paralleled by critical events of chromatin remodeling that appear to provide specificity and plasticity in circadian regulation. Accumulating evidence shows that the circadian epigenome appears to share intimate links with cellular metabolic processes. These notions indicate that the circadian epigenome might integrate tissue specificity within biological pacemakers, bridging systems physiology to metabolic control. This review highlights several advances related to the circadian epigenome, the contribution of NAD+ as a critical signaling metabolite, and its effects on epigenetic state, followed by more recent reports on circadian metabolomics analyses. PMID- 22834652 TI - Influence of inflammatory polyarthritis on quantitative heel ultrasound measurements. AB - BACKGROUND: There are few data concerning the impact of inflammatory polyarthritis (IP) on quantitative heel ultrasound (QUS) measurements. The aims of this analysis were i) to determine the influence of IP on QUS measurements at the heel and, ii) among those with IP to determine the influence of disease related factors on these measurements. METHODS: Men and women aged 16 years and over with recent onset IP were recruited to the Norfolk Arthritis Register (NOAR). Individuals with an onset of joint symptoms between 1989 and 1999 were included in this analysis. At the baseline visit subjects underwent a standardised interview and clinical examination with blood taken for rheumatoid factor. A population-based prospective study of chronic disease (EPIC-Norfolk) independently recruited men and women aged 40 to 79 years from the same geographic area between 1993 and 1997. At a follow up assessment between 1998 and 2000 subjects in EPIC-Norfolk were invited to have quantitative ultrasound measurements of the heel (CUBA-Clinical) performed. We compared speed of sound (SOS) and broadband ultrasound attenuation (BUA), in those subjects recruited to NOAR who had ultrasound measurements performed (as part of EPIC-Norfolk) subsequent to the onset of joint symptoms with a group of age and sex matched non IP controls who had participated in EPIC-Norfolk. Fixed effect linear regression was used to explore the influence of IP on the heel ultrasound parameters (SOS and BUA) so the association could be quantified as the mean difference in BUA and SOS between cases and controls. In those with IP, linear regression was used to examine the association between these parameters and disease related factors. RESULTS: 139 men and women with IP and 278 controls (mean age 63.2 years) were studied. Among those with IP, mean BUA was 76.3 dB/MHz and SOS 1621.8 m/s. SOS was lower among those with IP than the controls (difference = -10.0; 95% confidence interval (CI) -17.4, -2.6) though BUA was similar (difference = -1.2; 95% CI -4.5, +2.1). The difference in SOS persisted after adjusting for body mass index and steroid use. Among those with IP, disease activity as determined by the number of swollen joints at baseline, was associated with a lower SOS. In addition SOS was lower in the subgroup that satisfied the 1987 ACR criteria. By contrast, disease duration, steroid use and HAQ score were not associated with either BUA or SOS. CONCLUSIONS: In this general population derived cohort of individuals with inflammatory polyarthritis there is evidence from ultrasound of a potentially adverse effect on the skeleton. The effect appears more marked in those with active disease. PMID- 22834653 TI - An evaluation of the inhibitory effects against rotavirus infection of edible plant extracts. AB - BACKGROUND: Rotaviruses are the single most important cause of severe diarrhea in young children worldwide. The developments of specific, potent and accessible antiviral treatments that restrain rotavirus infection remain important to control rotavirus disease. METHODS: 150 plant extracts with nutritional applications were screened in vitro on MA-104 cells for their antiviral activity against rhesus rotavirus (RRV). One extract (Aspalathus linearis (Burm.f.) R.Dahlgren) was also tested for its effect on the loss of transepithelial resistance (TER) of Caco-2 cells caused by simian rotavirus (SA-11) infection. RESULTS: Aqueous extracts of Nelumbo nucifera Gaertn. fruit, Urtica dioica L. root, Aspalathus linearis (Burm.f.) R.Dahlgren leaves, Glycyrrhiza glabra L. root and Olea europaea L. leaves were found to have strong significant antiviral activity with a 50% inhibitory concentration (IC50) < 300 MUg/ml. The pure compound 18beta-glycyrrhetinic acid from Glycyrrhiza glabra was found to have the strongest antiviral activity (IC50 46 MUM), followed by luteolin and vitexin from Aspalathus linearis (IC50 respectively 116 MUM and 129 MUM) and apigenin-7-O glucoside from Melissa officinalis (IC50 150 MUM). A combination of Glycyrrhiza glabra L. + Nelumbo nucifera Gaertn. and Urtica dioica L. + Nelumbo nucifera Gaertn. showed synergy in their anti-viral activities. Aspalathus linearis (Burm.f.) R.Dahlgren showed no positive effect on the maintenance of the TER. CONCLUSIONS: These results indicate that nutritional intervention with extracts of Nelumbo nucifera Gaertn., Aspalathus linearis (Burm.f.) R.Dahlgren, Urtica dioica L., Glycyrrhiza glabra L. and Olea europaea L. might be useful in the treatment of diarrhea caused by rotavirus infection. PMID- 22834654 TI - Volume transition and adhesion force of nanosized bifunctional spherical polyelectrolyte brushes observed by dynamic light scattering and atomic force microscopy. AB - Stimuli-responsive nanoparticles have attracted considerable interest due to their enormous potential applications. In this paper, nanosized bifunctional spherical polyelectrolyte brushes (BSPBs) were prepared through grafting random copolymer chains from N-isopropylacrylamide (NIPA) and acrylic acid (AA) onto polystyrene core by photoemulsion polymerization. The pH- and thermo-responses of the BSPB with different ratio of NIPA and AA were investigated by dynamic light scattering. Atomic force microscopy (AFM) was employed to in situ monitor the pH response of the morphology and surface adhesion of BSPB as well as to visualize BSPB individually or as monolayer in air and liquid. The brush-like shell was illegible in electron microscopy images but clearly observed in AFM images. The results demonstrated that AFM was a powerful tool for in situ observing the stimulus-response of brushes on the surface of nanoparticles. PMID- 22834655 TI - Radiotherapy for nasopharyngeal carcinoma and combined capecitabine and nimotuzumab treatment for lung metastases in a liver transplantation recipient: a case experience of sustained complete response. AB - The primary treatment for nasopharyngeal carcinoma (NPC) is external beam radiotherapy. However, until now, there is little experience with the management of NPC occurred after solid organ transplantation. In this report, a 60-year-old man was found to have NPC (T2N1M0; stage III) 3 years after orthotopic liver transplantation treatment for hepatocellular carcinoma. Intensity-modulated radiotherapy (IMRT) was performed for NPC. One month after IMRT, complete response of NPC was achieved. However, multiple lung metastases occurred 18 months after the IMRT with the largest lesion measuring 4.1*5.5 cm and confirmed to be originated from NPC. Combined chemo-/targeted therapy consisted of capecitabine, and nimotuzumab was administered for four cycles. One month after initiation of capecitabine plus nimotuzumab treatment, a near-complete response was achieved for lung metastases. A repeat CT scan 1 year later showed sustained resolution of the lung metastases. The patient is still alive 16 months after the combined chemo-/targeted therapy. PMID- 22834656 TI - Preliminary outcome study on assertive community treatment in Japan. AB - AIMS: The beneficial effects of assertive community treatment (ACT), which has been widely acclaimed as being successful in several foreign countries, must also be objectively evaluated with respect to the transition from inpatient to community-based mental health treatment in Japan. This was the first study that examined effects of the ACT program in Japan using pre/post design data of the pilot trial of the ACT program in Japan project. METHODS: The study included 41 subjects hospitalized at Kohnodai Hospital, National Center of Neurology and Psychiatry between May 2003 and April 2004 for severe mental illness and who met inclusion criteria for entry regarding age, diagnosis, residence, utilization of mental health services, social adjustment, and ability to function in daily activities. All subjects provided informed consent for study participation and were followed for 1 year after hospital discharge. RESULTS: Comparison of the number of days and frequency of inpatient psychiatric hospitalization and frequency of emergency psychiatric visits between the 1-year period before hospitalization and 1-year period after hospital discharge showed a significant decrease in number of days and frequency of hospitalization. Comparison at 1 year after discharge with baseline showed no change in satisfaction with overall quality of life or Brief Psychiatric Rating Scale scores, but the Global Assessment of Functioning score significantly increased, and the antipsychotic dose (chlorpromazine equivalent) significantly decreased. CONCLUSION: Despite some limitations in methodology and conclusions, this study suggests that ACT enables persons with severe mental illness to live for longer periods in the community, without worsening of symptoms, decreased social function, or deterioration in quality of life. PMID- 22834657 TI - Sex differences in risk factors for suicidality among Japanese substance use disorder patients: association with age, types of abused substances, and depression. AB - AIM: The aim of this study was to identify risk factors for suicide in Japanese substance use disorder (SUD) patients, adjusting for age and sex, and to examine sex differences in suicide risk among these patients. METHODS: A self-reporting questionnaire on age, sex, types of abused substances, current depression, and suicidality was administered to 1420 SUD patients who consecutively visited seven hospitals specializing in SUD treatment during the month of December 2009. Unadjusted/adjusted odds ratios of factors associated with suicidality were calculated for each sex. RESULTS: The multivariate analysis using the total sample identified younger age, female sex, and current depression as risk factors for severe suicidality in SUD patients. The multivariate analysis by each sex demonstrated that younger age and current depression were associated with severe suicidality in male SUD patients. Only current depression was associated with severe suicidality in female patients. CONCLUSION: Current depression is a risk factor for suicide in SUD patients common in both Western countries and Japan, although in Japanese SUD patients both younger age and female sex were more closely associated with severe suicidality than aspects of SUD. Additionally, young male SUD patients are speculated to have psychosocial features associated with suicidality in common with female SUD patients. PMID- 22834658 TI - Effects of antipsychotic polypharmacy on side-effects and concurrent use of medications in schizophrenic outpatients. AB - AIMS: Medical therapy is the cornerstone of schizophrenia, but >50% of patients do not adhere to medication regimens. In previous reports, the reasons for non adherence were assessed only by medical staff. We think that patients have specific reasons for non-adherence. We researched whether there was an association between patients' subjective opinions and the number of antipsychotics used. METHODS: A self-rating questionnaire survey was conducted on 252 outpatients with schizophrenia at five psychiatric hospitals in Japan. Based on patients' subjective opinions, we retrospectively analyzed the patients' medications: the number of antipsychotics, concurrently used agents, and dosages of antipsychotics. RESULTS: There was no significant difference regarding attitudes toward medication between monotherapy and polypharmacy. The most common reason for not taking medications was 'I sometimes forget' followed by 'side effects'. Of the latter, weight gain was the most common, and dry mouth (P < 0.05) and sexual dysfunction (P < 0.01) were significantly higher in polypharmacy. The dosages of antipsychotics (P < 0.01), concurrent use of anti Parkinsonian agents (P < 0.01), and the number of side-effects (P < 0.01) were also higher in polypharmacy. CONCLUSIONS: Patients had good attitudes toward medication but a higher prevalence of side-effects was seen in polypharmacy of antipsychotics. Hence, monotherapy may be a more appropriate prescription with respect to side-effects. By using monotherapy, patients may reduce feelings of discomfort due to side-effects. PMID- 22834659 TI - Treatment of delirium with risperidone in cancer patients. AB - AIM: Antipsychotic medications have frequently been regarded as the treatment of choice for delirium. This study examined the clinical efficacy of risperidone for the treatment of delirium in cancer patients, combined with a repeated assessment of underlying medical severity levels. METHODS: The study included consecutive referrals of 29 delirious cancer patients (mean age, 68.9 +/- 12.5 years; male, 69%) to the psychiatric consultation service. Risperidone was given orally once per day (mean dosage, 1.4 +/- 1.3 mg/day). Study participants were assessed using quantitative standardized scales of cognitive function, delirium, and physical impairment at baseline and at the end of the study (seventh day). RESULTS: Risperidone with routine clinical management was effective for the treatment of delirium: 48% of the patients responded and 38% achieved remission. The reduction of delirium severity occurred in 79% of the patients. Changes in delirium severity were unrelated to age, gender, general cognitive dysfunction, or to severity of attendant medical conditions. In addition to changes in agitation and perceptional disturbances, risperidone was also effective for other specific delirium symptoms. CONCLUSIONS: Risperidone with routine clinical management is effective in the treatment of delirium in advanced cancer patients, independent of changes in the underlying medical condition. PMID- 22834660 TI - Clinical evaluation of percutaneous endoscopic gastrostomy tube feeding in Japanese patients with dementia. AB - AIM: The aim of this study was to clinically evaluate percutaneous endoscopic gastrostomy (PEG) tube feeding of elderly Japanese patients with dementia. METHOD: The records of the 155 patients with dementia who underwent PEG in Juntendo Tokyo Koto Geriatric Medical Center were reviewed for pertinent clinical data, including diagnosis of dementia, place of stay before and after hospitalization, as well as survival rate, albumin levels, and incidence of aspiration pneumonia (AP) before and 6 months after PEG feeding. The latter three data of these patients were compared with those of 106 patients with dementia fed through a nasogastric (NG) tube. RESULTS: Alzheimer's disease and vascular dementia were predominant. Fifty-three percent of the patients were admitted from their home; the number of discharges to homes decreased to 21.2%. The mean (SD) of the albumin levels was 2.9 (0.4) g/dl before feeding and 2.9 (0.6) g/dl after 6 months. Among the patients with AP before PEG tube feeding, 51.6% had an AP recurrence. Conversely, AP occurred in 9.4% of the patients without AP before feeding. The patient survival rate was higher by 27 months when using PEG tube than when using an NG tube. CONCLUSION: PEG tube feeding in patients with dementia leads to preservation of status for a few years. Compared with NG tube feeding, PEG tube feeding did not induce AP due to impairment of intact swallowing function, and was associated with higher survival rate of approximately 2 years. However, PEG tube feeding does not seem to promote home medical care. PMID- 22834661 TI - Determinants of psychogeriatric inpatient length of stay and direct medical costs: a 6-year longitudinal study using a national database in Taiwan. AB - AIMS: This research examined factors related to the average length of hospital stay (LOS) and average direct medical costs (DMC) for 2291 psychogeriatric inpatients (aged 65 and over) admitted for the first time to a psychiatric ward in 2002. METHODS: Hospitalization claim data of these inpatients were traced for the subsequent 6 years (2002-2007) from the dataset of Taiwan's National Health Insurance program. Analysis was carried out using the t-test, chi(2) -test and zero truncated Tobit regression. RESULTS: Mean LOS and mean DMC were significantly different according to sex, psychiatric diagnosis, institution type, ownership type, and number of hospitalizations, but age was the exception. Both LOS and DMC exhibited downward U-shape for the number of hospitalizations. Factors significantly associated with longer LOS and higher DMC were: male sex; schizophrenic and delusional disorders (compared with dementia); and public institution (compared with private hospital). Compared with dementia, organic mental and anxiety disorders had significantly shorter LOS, and affective disorders had shorter LOS but higher DMC. Community and psychiatric hospitals (compared with general hospital) significantly influenced LOS but not DMC. CONCLUSION: Our results can be used as a reference for providers and policymakers to improve psychiatric care efficiency and carry out National Health Insurance financial reform for psychogeriatric inpatients. PMID- 22834662 TI - Dimensional analysis of burden in family caregivers of patients with obsessive compulsive disorder. AB - AIMS: Obsessive-compulsive disorder (OCD) also generates emotional burden in the patient's family members, but no study has evaluated the specific dimensions of burden. The objectives were to evaluate the dimensions of the Zarit Burden Interview (ZBI) and possible correlates. METHODS: This was a cross-sectional study involving 47 patients and 47 caregivers, using a sociodemographic questionnaire; the ZBI; the Self Reporting Questionnaire; the Family Accommodation Scale; and the Yale-Brown Obsessive-Compulsive Scale. The ZBI factor analysis was conducted using Varimax Rotation. RESULTS: Six factors were identified, explaining 74.2% of the total variance: factor 1, interference in the caregiver's personal life (36.6% of the variance); factor 2, perception of patient's dependence (10.8%); factor 3, feelings of irritation or intolerance (9.2%); factor 4, guilt (7.2%); factor 5, insecurity (5.6%); and factor 6, embarrassment (4.8%). The six ZBI factors were associated with greater OCD severity and with greater accommodation to the patient's symptoms, and factors 1, 2, 5 and 6 with caregiver's psychological morbidity. Caregiver's sex (female) was associated with factors 5 and 6, relationship with the patient (being a parent or son/daughter) with factor 5, higher educational level with factor 6, living with the patient with factor 3, worse self-evaluation of health with factors 1, 5 and 6, and occupational status (not working) with factors 1, 2, 5 and 6. CONCLUSION: The dimensions of burden identified indicate the most affected aspects of a caregiver's life and could guide the planning of more specific interventions. Thus, the caregiver could participate more effectively in the OCD patient's treatment, with a lower impact on his/her life. PMID- 22834663 TI - Associations between hypothalamic-pituitary-adrenal axis function and facial emotion processing in depressed and control participants. AB - AIM: The current study examined the relation between facial emotion processing accuracy and an aspect of hypothalamic-pituitary-adrenal axis function in 64 inpatients with major depression and 49 healthy controls over a 2-week period. METHODS: The Dexamethasone Suppression Test and a Facial Expression Recognition Task were completed at baseline and 10-14 days after baseline. Treatment response was determined 6 weeks after baseline by change in the Montgomery-Asberg Depression Rating Scale. RESULTS: Increased cortisol response to dexamethasone was significantly correlated with reduced ability to recognize facial expressions of anger, sadness and disgust within the total sample, but these correlations did not remain significant at 10-14 days. Surprisingly, cortisol response to dexamethasone was comparable in acutely depressed inpatients and healthy controls, and did not change over time in relation to treatment response. CONCLUSION: The study findings provide preliminary evidence that hypothalamic pituitary-adrenal axis functioning and processing threat-related facial expressions are related, perhaps through involvement of the amygdala. PMID- 22834664 TI - Association between deliberate self-harm-related Internet searches and the mental states and lifetime suicidal behaviors of Japanese young adults. AB - This study aimed to clarify the association between the experience of searching for deliberate self-harm (DSH)-related Internet content and the mental states and lifetime suicidal behaviors of Japanese young adults (n = 1000) using an online questionnaire. The results were assessed using chi(2) and t-tests, which revealed that the experience of DSH-related Internet searches may be significantly associated with lifetime suicidal behaviors (including DSH), suicidal ideation, and tendencies towards depression/anxiety. We discussed the possibility of using search engines to increase the motivation of Japanese young adults who deliberately harmed themselves with regard to seeking help. PMID- 22834665 TI - Early psychological distress among sufferers after the 2011 Northern Nagano Prefecture Earthquake. AB - We surveyed 3078 sufferers in Tsunan (Niigata), an intermediate and mountainous area of Japan, after the 2011 Northern Nagano Prefecture Earthquake. More subjects reported fear of the earthquake or related anxiety symptoms and insomnia in Tsunan than in the control group. Female sex and older age were found to be risk factors for poor psychological outcome. Those with risk factors should be carefully followed up. PMID- 22834666 TI - Platelet count alterations associated with escitalopram, venlafaxine and bupropion in depressive patients. AB - The objective of the present study was to evaluate changes in platelet counts on three different kinds of antidepressant. All subjects (n = 131) in their drug naive state had been diagnosed with depression. Escitalopram (n = 42), venlafaxine (n = 50) and bupropion (n = 39) were prescribed, and platelet count was measured before and after 1 month of treatment and compared. Decrease in platelet count on escitalopram was significant, while the others were not. These findings suggest that escitalopram may be associated with decreased platelet count, and bupropion is less likely to exert an influence on platelet count. PMID- 22834667 TI - Preferences of help regarding behavioral health problems among the Japanese general population. PMID- 22834668 TI - Progressive cerebroretinal microangiopathy with calcifications and cysts syndrome: an unusual cause of complex partial seizure. PMID- 22834669 TI - Interferon-beta-1a-induced psychosis in a patient with multiple sclerosis. PMID- 22834670 TI - Low-dose aripiprazole in the treatment of selective serotonin reuptake inhibitors induced orofacial and buccal dystonia. PMID- 22834672 TI - Valproic acid augmentation in clozapine-associated hand-washing compulsion. PMID- 22834671 TI - What is a rational antidepressant treatment for major depression in patients with Parkinson's disease? PMID- 22834673 TI - Risperidone augmentation with amisulpride: the blue-tongue sign. PMID- 22834674 TI - Successful use of olanzapine for catatonia following delirium. PMID- 22834675 TI - A model reaction assesses contribution of H-tunneling and coupled motions to enzyme catalysis. AB - To assess the contribution of physical features to enzyme catalysis, the enzymatic reaction has to be compared to a relevant uncatalyzed reaction. While such comparisons have been conducted for some hydrolytic and radical reactions, it is most challenging for biological hydride transfer and redox reactions in general. Here, the same experimental tools used to study the H-tunneling and coupled motions for enzymatic hydride transfer between two carbons were used in the study of an uncatalyzed model reaction. The enzymatic oxidations of benzyl alcohol and its substituted analogues mediated by alcohol dehydrogenases were compared to the oxidations by 9-phenylxanthylium cation (PhXn(+)). The PhXn(+) serves as an NAD(+) model, while the solvent, acetonitrile, models the protein environment. Experimental comparisons included linear free energy relations with Hammett reaction constant (rho) of zero versus -2.7; temperature-independent versus temperature-dependent primary KIEs; deflated secondary KIEs with deuteride transfer (i.e., primary-secondary coupled motion) versus no coupling between secondary KIEs and H- or D-transfer; and large versus small secondary KIEs for the enzymatic versus uncatalyzed alcohol oxidation. Some of the differences may come from differences in the order of microscopic steps between the catalyzed versus uncatalyzed reactions. However, several of these comparative experiments indicate that in contrast to the uncatalyzed reaction the transition state of the enzymatic reaction is better reorganized for H-tunneling and its H-donor is better rehybridized prior to the C-H->C transfer. These findings suggest an important role for these physical features in enzyme catalysis. PMID- 22834677 TI - Shikonin and its derivatives: a patent review. AB - INTRODUCTION: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects. AREAS COVERED: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed. EXPERT OPINION: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow. PMID- 22834676 TI - Karyotype variation is indicative of subgenomic and ecotypic differentiation in switchgrass. AB - BACKGROUND: Karyotypes can provide information about taxonomic relationships, genetic aberrations, and the evolutionary origins of species. However, differentiation of the tiny chromosomes of switchgrass (Panicum virgatum L.) and creation of a standard karyotype for this bioenergy crop has not been accomplished due to lack of distinguishing features and polyploidy. RESULTS: A cytogenetic study was conducted on a dihaploid individual (2n = 2X = 18) of switchgrass to establish a chromosome karyotype. Size differences, condensation patterns, and arm-length ratios were used as identifying features and fluorescence in-situ hybridization (FISH) assigned 5S and 45S rDNA loci to chromosomes 7 and 2 respectively. Both a maize CentC and a native switchgrass centromeric repeat (PviCentC) that shared 73% sequence identity demonstrated a strong signal on chromosome 3. However, only the PviCentC probe labeled the centromeres of all chromosomes. Unexpected PviCentC and 5S rDNA hybidization patterns were consistent with severe reduction or total deletion of these repeats in one subgenome. These patterns were maintained in tetraploid and octoploid individuals. The 45S rDNA repeat produced the expected number of loci in dihaploid, tetraploid and octoploid individuals. Differences observed at the 5S rDNA loci between the upland and lowland ecotypes of switchgrass provided a basis for distinguishing these subpopulations. CONCLUSION: Collectively, these results provide a quantitative karyotype of switchgrass chromosomes. FISH analyses indicate genetic divergence between subgenomes and allow for the classification of switchgrass plants belonging to divergent genetic pools. Furthermore, the karyotype structure and cytogenetic analysis of switchgrass provides a framework for future genetic and genomic studies. PMID- 22834678 TI - Drug-induced atrial fibrillation. AB - Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, haemodynamic instability, increased cardiovascular mortality and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug induced, AF may also be precipitated by drug therapy, although ascribing causality to drug associated AF is more difficult than with other drug-induced arrhythmias. Drug induced AF is more likely to occur in patients with risk factors and co morbidities that commonly co-exist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnoea and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine and milrinone. In addition, medications such as corticosteroids, ondansetron and antineoplastic agents such as paclitaxel, mitoxantrone and doxorubicin have been reported to induce AF. Whether bisphosphonate drugs are associated with new-onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new-onset AF. PMID- 22834680 TI - Rapid synthesis of PEGylated ultrasmall gadolinium oxide nanoparticles for cell labeling and tracking with MRI. AB - Ultrasmall paramagnetic Gd(2)O(3) nanoparticles have been developed as contrast agents for molecular and cellular preclinical MRI procedures. These small particles (mean diameter <5 nm) have the highest Gd density of all paramagnetic contrast agents. They generate strong positive contrast enhancement in T(1) weighted MRI. Signal enhancement is modulated by the interactions of water molecules with Gd, and very small particles provide the optimal surface-to-volume ratios necessary to reach high relaxivities. Conventional Gd(2)O(3) nanocrystal synthesis techniques, and subsequent polyethylene glycol (PEG) grafting procedures are usually time-consuming and recovery losses are also limitative. The present study reports on a new, fast, and efficient one-pot Gd(2)O(3) synthesis technique that provides PEGylated nanoparticles of very small size (mean diameter = 1.3 nm). Readily coated with PEG, the particles are colloidally stable in aqueous media and provide high longitudial relaxivities and small r(2)/r(1) ratios (r(1) = 14.2 mM(-1) s(-1) at 60 MHz; r(2)/r(1) = 1.20), ideal for T(1)-weighted MRI. In this study, F98 brain cancer cells (glioblastoma multiforme) were labeled with the contrast agent and implanted in vivo (mice brains). The labeled cells appeared positively contrasted at least 48 h after implantation. Each one of the implanted animals developed a brain tumor. The performance of PEG-Gd(2)O(3) was also compared with that of commercially available iron oxide nanoparticles. This study demonstrated that ultrasmall PEG Gd(2)O(3) nanoparticles provide strong positive contrast enhancement in T(1) weighted imaging, and allow the visualization of labeled cells implanted in vivo. PMID- 22834679 TI - PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer. AB - The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of concept for a synthetic lethal anti-cancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized. PMID- 22834681 TI - Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty: a randomised study. AB - BACKGROUND: In this proof-of-concept study, we investigated the effect of the predominantly sensory adductor-canal-blockade on established pain in the early post-operative period after total knee arthroplasty (TKA). We hypothesised that the adductor-canal-blockade would reduce pain during flexion of the knee (primary end point) and at rest, as well as reducing morphine consumption and morphine related side effects (secondary outcomes) compared with placebo. METHODS: We enrolled patients scheduled for elective TKA into this double-blind, placebo controlled, randomised study. During general anaesthesia, we placed a catheter in the adductor canal, and after obtaining pre-block pain scores 30 min post operatively, we injected 30 ml of ropivacaine 0.75% (n = 21) or saline (n = 20) according to randomisation. Clinicaltrials.gov Identifier: NCT01261897. RESULTS: Forty-two patients were randomised, and 41 were analysed. Mean (standard deviation) pain scores during flexion of the knee at 1 h post-operatively were 58 (22) mm and 67 (29) mm, ropivacaine and placebo group, respectively (P = 0.23) but was significantly reduced in the ropivacaine group when calculated as area under the curve for the interval 1-6 h (P = 0.02). There were no statistically significant differences regarding pain at rest (P = 0.08), morphine consumption (P = 0.06), nor morphine-related side effects, apart from nausea (P = 0.04). CONCLUSION: This proof-of-concept study shows promising results regarding the analgesic efficacy of adductor-canal-blockade in post-operative pain treatment after TKA, with a significant reduction in pain during flexion of the knee in the early post-operative period compared with placebo. However, the study was not sufficiently powered to permit final conclusions. PMID- 22834682 TI - Superior analgesic effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a multifunctional opioid peptide, compared to morphine in a rat model of neuropathic pain. AB - H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and is an extremely potent analgesic. [Dmt(1) ]DALDA is unusual in the way that the greater part of its analgesic potency appears to be produced by its actions in the spinal cord. Furthermore, [Dmt(1) ]DALDA inhibits norepinephrine re-uptake and is a mitochondria-targeted antioxidant. Such characteristics may make [Dmt(1)]DALDA particularly effective against neuropathic pain. The present study was designed to compare the effects of [Dmt(1)]DALDA and morphine on thermal hyperalgesia in an experimental neuropathic pain model. Neuropathic pain was induced in rats by surgical ligation of the L5 spinal nerve, and thermal pain thresholds were assessed by latencies of paw withdrawal to radiant heat. The increase in paw withdrawal latency was greater after the administration of [Dmt(1) ]DALDA than that of morphine in neuropathic rats at doses that were equianalgesic in naive animals. We conclude that [Dmt(1)]DALDA is more effective than morphine against thermal hyperalgesia in this experimental model of neuropathic pain. PMID- 22834683 TI - Confinement effects on the crystallization of poly(ethylene oxide) nanotubes. AB - In this work, we show the effects of nanoconfinement on the crystallization of poly(ethylene oxide) (PEO) nanotubes embedded in anodized aluminum oxide (AAO) templates. The morphological characteristics of the hollow 1D PEO nanostructures were evaluated by scanning electron microscopy (SEM). The crystallization of the PEO nanostructures and bulk was studied with differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD). The crystallization of PEO nanotubes studied by DSC is strongly influenced by the confinement showing a strong reduction in the crystallization temperature of the polymer. X-ray diffraction (XRD) experiments confirmed the isothermal crystallization results obtained by DSC, and studies carried out at low temperatures showed the absence of crystallites oriented with the extended chains perpendicular to the pore wall within the PEO nanotubes, which has been shown to be the typical crystal orientation for one-dimensional polymer nanostructures. In contrast, only planes oriented 33, 45, and 90 degrees with respect to the plane (120) are arranged parallel to the pore's main axis, indicating preferential crystal growth in the direction of the radial component. Calculations based on classical nucleation theory suggest that heterogeneous nucleation prevails in the bulk PEO whereas for the PEO nanotubes a surface nucleation mechanism is more consistent with the obtained results. PMID- 22834684 TI - Evolving pharmacological approaches in gastroesophageal reflux disease. AB - INTRODUCTION: Proton pump inhibitors (PPIs) have considerably improved quality of life in patients with gastroesophageal reflux disease (GERD). However, many patients remain symptomatic despite standard PPI therapy. AREAS COVERED: This review focuses on evolving therapeutic strategies related to the pathophysiological processes of GERD and insufficient response to PPIs. Several clinical trials evaluated new PPI formulations and newer types of acid suppressive drugs. These studies have evaluated traditional end points in GERD, but have not shown clinical superiority to current PPIs. Novel therapeutic strategies targeting underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity, are being developed for add-on therapy to PPIs. Prokinetic drugs may also have some potential in the add-on treatment of GERD with insufficient response to PPIs. Add on studies are hampered by insufficient information on optimal patient selection and lack of established end points. EXPERT OPINION: Newer drugs for symptomatic control in GERD have largely focused on improved acid suppression, without evidence of clinical superiority. Drugs targeting esophageal motility and sensitivity to be used as add-onc therapy in PPI insufficient responders have not reached Phase III trials to date, due to difficulties with patient selection, tolerability and end points. PMID- 22834685 TI - LRRC4 inhibits glioma cell growth and invasion through a miR-185-dependent pathway. AB - Leucine-rich repeat (LRR) genes encode transmembrane proteins that are essential for normal brain development and are often dysregulated in central nervous system tumors. Leucine-rich repeat C4 (LRRC4) is a member of the LRR protein superfamily and specifically expressed in brain tissue. Importantly it acts as a tumor suppressor in the pathogenesis of malignant gliomas. However, the molecular mechanisms by which LRRC4 regulates glioma tumorigenesis are largely unknown. In this report, we found that miR-185 is markedly upregulated by LRRC4. We also found that miR-185 was downregulated in glioma, and overexpression of miR-185 inhibited glioma cell invasion. Low expressions of LRRC4 and miR-185 were associated with a poor outcome in glioma patients. Further investigation revealed that LRRC4 mediated its tumor suppressor function by regulating miR-185 targets CDC42 and RhoA. LRRC4 overexpression inhibited glioma cell invasion through miR 185-mediated CDC42 and RhoA direct regulation and VEGFA indirect regulation. Together, our findings suggest that the altered expression of the tumor suppressor LRRC4 may be an important event that leads to the dysregulation of miR 185 in human gliomas. LRRC4 and miR-185 may also be good prognostic markers and therapeutic targets in glioma. PMID- 22834686 TI - Interactions between rotavirus and Suwannee River organic matter: aggregation, deposition, and adhesion force measurement. AB - Interactions between rotavirus and Suwannee River natural organic matter (NOM) were studied by time-resolved dynamic light scattering, quartz crystal microbalance, and atomic force microscopy. In NOM-containing NaCl solutions of up to 600 mM, rotavirus suspension remained stable for over 4 h. Atomic force microscopy (AFM) measurement for interaction force decay length at different ionic strengths showed that nonelectrostatic repulsive forces were mainly responsible for eliminating aggregation in NaCl solutions. Aggregation rates of rotavirus in solutions containing 20 mg C/L increased with divalent cation concentration until reaching a critical coagulation concentration of 30 mM CaCl(2) or 70 mM MgCl(2). Deposition kinetics of rotavirus on NOM-coated silica surface was studied using quartz crystal microbalance. Experimental attachment efficiencies for rotavirus adsorption to NOM-coated surface in MgCl(2) solution were lower than in CaCl(2) solution at a given divalent cation concentration. Stronger adhesion force was measured for virus-virus and virus-NOM interactions in CaCl(2) solution compared to those in MgCl(2) or NaCl solutions at the same ionic strength. This study suggested that divalent cation complexation with carboxylate groups in NOM and on virus surface was an important mechanism in the deposition and aggregation kinetics of rotavirus. PMID- 22834687 TI - The role of general practitioners in diagnosis of cutaneous melanoma: a population-based study in France. AB - BACKGROUND: Little data are available concerning the role of general practitioners (GPs) in the diagnosis of melanoma. OBJECTIVES: To evaluate the actual role of GPs in a population-based study covering five regions of France and 8.2 million inhabitants. MATERIALS AND METHODS: A survey of cancer registries and pathology laboratories, and questionnaires to practitioners were used to identify incident melanomas in 2008, and evaluate characteristics of patients (age, sex, area of residence, social isolation), tumours (Breslow, ulceration, location, histological type), and GPs (training, conditions of practice), and their influence on patterns of diagnosis and Breslow thickness. RESULTS: Among 898 melanomas, 376 (42%) were first diagnosed in a general practice setting (GP group). Breslow thickness was much higher in the GP group than in other melanomas (median: 0.95 vs. 0.61 mm, P < 0.0001). Multivariate analysis identified an older age, lower limb location, nodular subtype and Breslow thickness as factors associated with the GP group. Within this group, 52.5% of melanomas were detected by patients (median Breslow thickness: 1.30 mm) and 47.5% by GPs (median Breslow thickness: 0.80 mm, P = 0.0009), including 8% during a systematic full-body skin examination. Previous GP training on melanoma was associated with active detection by GPs. Male sex and social isolation of patients were associated with thicker melanomas, whereas active detection by GPs was associated with thinner CMs. CONCLUSIONS: GPs play a key role in melanoma diagnosis in France, but still frequently detect thick tumours. Increasing awareness and training of GPs and focusing attention on male and/or socially isolated patients should help to improve early detection of melanoma. PMID- 22834689 TI - Langerhans cell histiocytosis in children born 1982-2005 after in vitro fertilization. AB - AIM: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 1982-2005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population. METHODS: Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 1992-2001 in the Stockholm County. RESULTS: We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.4 7.3] and for children born before 2002, 5.2 [95% CI, 2.3-11.9], compared with children in Stockholm County 1992-2001. CONCLUSION: LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged. PMID- 22834688 TI - In vitro endothelialization of electrospun terpolymer scaffolds: evaluation of scaffold type and cell source. AB - A family of methacrylic terpolymer biomaterials was electrospun into three dimensional scaffolds. The glass transition temperature of the polymer correlates with the morphology of the resulting scaffold. Glassy materials produce scaffolds with discrete fibers and large pore areas (1531+/-1365 MUm(2)), while rubbery materials produce scaffolds with fused fibers and smaller pore areas (154+/-110 MUm(2)). Three different endothelial-like cell populations were seeded onto these scaffolds under static conditions: human umbilical vein endothelial cells (HUVECs), adult human peripheral blood-derived outgrowth endothelial cells, and umbilical cord blood-derived human blood outgrowth endothelial cells. Cellular behavior depended on both cell type and scaffold topography. Specifically, cord blood-derived outgrowth endothelial cells showed more robust adhesion and growth on all scaffolds in comparison to other cell types as measured by the density of adherent cells, the number of proliferative cells, and the enzymatic activity of the adherent cells. Peripheral blood-derived outgrowth cells exhibited less ability to inhabit the terpolymer interfaces in comparison to their cord blood derived counterparts. HUVECs also exhibited less of a capacity to colonize the terpolymer interfaces in comparison to the cord blood-derived cells. However, the mature endothelial cells did show scaffold-dependent behavior. Specifically, we observed an increase in their ability to populate the low-porosity scaffolds. All cells maintained an endothelial phenotype after 1 week of culture on the electrospun scaffolds. PMID- 22834690 TI - Estimation of carcinogenicity using molecular fragments tree. AB - Carcinogenicity is an important toxicological endpoint that poses high concern to drug discovery. In this study, we developed a method to extract structural alerts (SAs) and modulating factors of carcinogens on the basis of statistical analyses. First, the Gaston algorithm, a frequent subgraph mining method, was used to detect substructures that occurred at least six times. Then, a molecular fragments tree was built and pruned to select high-quality SAs. The p-value of the parent node in the tree and that of its children nodes were compared, and the nodes that had a higher statistical significance in binomial tests were retained. Finally, modulating factors that suppressed the toxic effects of SAs were extracted by three self-defining rules. The accuracy of the 77 SAs plus four SA/modulating factor pairs model for the training set, and the test set was 0.70 and 0.65, respectively. Our model has higher predictive ability than Benigni's model, especially in the test set. The results highlight that this method is preferable in terms of prediction accuracy, and the selected SAs are useful for prediction as well as interpretation. Moreover, our method is convenient to users in that it can extract SAs from a database using an automated and unbiased manner that does not rely on a priori knowledge of mechanism of action. PMID- 22834691 TI - What is the role and authority of gatekeepers in cluster randomized trials in health research? AB - This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the sixth of the questions posed, namely, what is the role and authority of gatekeepers in CRTs in health research? 'Gatekeepers' are individuals or bodies that represent the interests of cluster members, clusters, or organizations. The need for gatekeepers arose in response to the difficulties in obtaining informed consent because of cluster randomization, cluster-level interventions, and cluster size. In this paper, we call for a more restrictive understanding of the role and authority of gatekeepers.Previous papers in this series have provided solutions to the challenges posed by informed consent in CRTs without the need to invoke gatekeepers. We considered that consent to randomization is not required when cluster members are approached for consent at the earliest opportunity and before any study interventions or data-collection procedures have started. Further, when cluster-level interventions or cluster size means that obtaining informed consent is not possible, a waiver of consent may be appropriate. In this paper, we suggest that the role of gatekeepers in protecting individual interests in CRTs should be limited. Generally, gatekeepers do not have the authority to provide proxy consent for cluster members. When a municipality or other community has a legitimate political authority that is empowered to make such decisions, cluster permission may be appropriate; however, gatekeepers may usefully protect cluster interests in other ways. Cluster consultation may ensure that the CRT addresses local health needs, and is conducted in accord with local values and customs. Gatekeepers may also play an important role in protecting the interests of organizations, such as hospitals, nursing homes, general practices, and schools. In these settings, permission to access the organization relies on resource implications and adherence to institutional policies. PMID- 22834692 TI - Smoking prevalence and beliefs on smoking cessation among members of the Japanese Cancer Association in 2006 and 2010. AB - Smoking is a significant contributing factor to disease-related deaths worldwide. Members of the Japanese Cancer Association (JCA) can play a leading role in helping people to live tobacco-free through social action. In 2010, this study assessed smoking prevalence among JCA members and their attitudes toward smoking, smoking cessation, and their responsibilities. Results of the 2010 survey were compared with those of a 2006 survey. Final response rates were 60.8% in the 2006 survey and 47.4% in the 2010 survey, and the current smoking rates were 9.0% and 5.3%, respectively. Regarding concern by current smokers over smoking cessation, the percentage of smokers who were ready to quit smoking within the next month increased from 4.9% to 6.3% between 2006 and 2010. Most JCA members agreed with antismoking actions such as smoking bans in all workplaces, public places, or while walking in the street, regulation restricting the sale and distribution of tobacco to children, tobacco education at school, use of tobacco tax for health, provision of information on tobacco, and smoking cessation support. Approximately 30% of responders disagreed on actions to raise the price of tobacco, regulations restricting the sale of tobacco, health warnings on tobacco packaging, bans on tobacco advertisement, and antismoking campaigns. Barriers to smoking cessation interventions identified were physician's time required to provide interventions, resistance of patients to smoking cessation advice, and lack of education on tobacco control. Not only antismoking actions but also support of smokers by health professionals through adequate education on smoking cessation treatment is needed in the future. PMID- 22834696 TI - Conjectures on some curious connections among social status, calorie restriction, hunger, fatness, and longevity. AB - Many animal and human studies show counterintuitive effects of environmental influences on energy balance and life span. Relatively low social and/or economic status seems to be associated with and produce greater adiposity, and reduced provision (e.g., caloric restriction) of food produces greater longevity. We suggest that a unifying factor may be perceptions of the environment as "energetically insecure" and inhospitable to reproduction, which may in turn provoke adiposity-increasing and longevity-extending mechanisms. We elaborate on two main aspects of resources (or the perceptions thereof) on body weight and longevity. We first discuss the effects of social dominance on body weight regulation in human and animal models. Second, we examine models of the interactions between caloric restriction, body composition, and longevity. Finally, we put forth a relational model of the influences of differing environmental cues on body composition and longevity. PMID- 22834697 TI - Behavior of platelet activating factor in membrane-mimicking environment. Langmuir monolayer study complemented with grazing incidence X-ray diffraction and Brewster angle microscopy. AB - 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) belonging to the class of single-chained ether phospholipids is widely known from its essential biological activities. There is a growing body of evidence that some significant aspects of PAF actions are connected with its capability to direct intercalation into biomembranes' environment. Although this mechanism is of great importance in the perspective of understanding PAF implications in various physiological processes, in the literature, there is a lack of studies devoted to this subject. It is still unknown which is the exact influence of membrane composition, molecular organization, and its other properties on the PAF impact on cells and tissues. Unfortunately, the biological studies carried out on cell cultures do not provide satisfactory results, mainly because of the complexity of natural systems. In order to obtain insight into the behavior of PAF in a lipid environment at the molecular level, the application of appropriate model systems is required. Among them, Langmuir monolayers are very often applied as a simple but very efficient platform for studies of the interactions between membrane lipids. In the present paper, special attention is focused on the issue concerning the interactions between PAF and two representatives of membrane components occurring mainly in the outer leaflet of natural bilayers, namely, cholesterol and DPPC. The application of Langmuir monolayers enabled us to construct the effective model mimicking the exogenous incorporation of PAF into membrane environment. On the basis of the obtained results, a thorough discussion was carried out and the conclusions derived from the traditional thermodynamic analysis were confronted with microscopic analysis of surface domains and the GIXD results. The selection of experimental techniques enables us to obtain information regarding the miscibility and interactions in the binary mixed films as well as the molecular organization of film-forming molecules on water surface. The experiments revealed that the addition of the investigated single-chained ether phospholipid into both cholesterol and DPPC monolayers causes a considerable decrease of monolayer condensation. On the basis of thermodynamic analysis, it was found that PAF mixes and consequently interacts strongly with cholesterol, whereas its interactions with DPPC are thermodynamically unfavorable. Differences between the PAF influence on cholesterol and DPPC monolayer found its corroboration in the results obtained with the GIXD technique. Namely, the monolayer of DPPC can incorporate more PAF than the model membrane containing cholesterol. The obtained results indicate that short chained sn-2 ether phospholipid is able to modify model membrane properties in a concentration-dependent way. PMID- 22834698 TI - High carriage rate of Staphylococcus aureus and Streptococcus agalactiae in nine cases of fungus-free intertrigo of the toe cleft. PMID- 22834699 TI - Characterization of a eukaryotic translation initiation factor 5A homolog from Tamarix androssowii involved in plant abiotic stress tolerance. AB - BACKGROUND: The eukaryotic translation initiation factor 5A (eIF5A) promotes formation of the first peptide bond at the onset of protein synthesis. However, the function of eIF5A in plants is not well understood. RESULTS: In this study, we characterized the function of eIF5A (TaeIF5A1) from Tamarix androssowii. The promoter of TaeIF5A1 with 1,486 bp in length was isolated, and the cis-elements in the promoter were identified. A WRKY (TaWRKY) and RAV (TaRAV) protein can specifically bind to a W-box motif in the promoter of TaeIF5A1 and activate the expression of TaeIF5A1. Furthermore, TaeIF5A1, TaWRKY and TaRAV share very similar expression pattern and are all stress-responsive gene that functions in the abscisic acid (ABA) signaling pathway, indicating that they are components of a single regulatory pathway. Transgenic yeast and poplar expressing TaeIF5A1 showed elevated protein levels combined with improved abiotic stresses tolerance. Furthermore, TaeIF5A1-transformed plants exhibited enhanced superoxide dismutase (SOD) and peroxidase (POD) activities, lower electrolyte leakage and higher chlorophyll content under salt stress. CONCLUSIONS: These results suggested that TaeIF5A1 is involved in abiotic stress tolerance, and is likely regulated by transcription factors TaWRKY and TaRAV both of which can bind to the W-box motif. In addition, TaeIF5A1 may mediate stress tolerance by increasing protein synthesis, enhancing ROS scavenging by improving SOD and POD activities, and preventing chlorophyll loss and membrane damage. Therefore, eIF5A may play an important role in plant adaptation to changing environmental conditions. PMID- 22834700 TI - The unusual mycobacterial chaperonins: evidence for in vivo oligomerization and specialization of function. AB - The pathogen Mycobacterium tuberculosis expresses two chaperonins, one (Cpn60.1) dispensable and one (Cpn60.2) essential. These proteins have been reported not to form oligomers despite the fact that oligomerization of chaperonins is regarded as essential for their function. We show here that the Cpn60.2 homologue from Mycobacterium smegmatis also fails to oligomerize under standard conditions. However, we also show that the Cpn60.2 proteins from both organisms can replace the essential groEL gene of Escherichia coli, and that they can function with E. coli GroES cochaperonin, as well as with their cognate cochaperonin proteins, strongly implying that they form oligomers in vivo. We show that the Cpn60.1 proteins, but not the Cpn60.2 proteins, can complement for loss of the M. smegmatis cpn60.1 gene. We investigated the oligomerization of the Cpn60.2 proteins using analytical ultracentrifugation and mass spectroscopy. Both form monomers under standard conditions, but they form higher order oligomers in the presence of kosmotropes and ADP or ATP. Under these conditions, their ATPase activity is significantly enhanced. We conclude that the essential mycobacterial chaperonins, while unstable compared to many other bacterial chaperonins, do act as oligomers in vivo, and that there has been specialization of function of the mycobacterial chaperonins following gene duplication. PMID- 22834701 TI - Hyperthermia-induced DNA repair deficiency suggests novel therapeutic anti-cancer strategies. AB - Local hyperthermia is an effective treatment modality to augment radio- and chemotherapy-based anti-cancer treatments. Although the effect of hyperthermia is pleotropic, recent experiments revealed that homologous recombination, a pathway of DNA repair, is directly inhibited by hyperthermia. The hyperthermia-induced DNA repair deficiency is enhanced by inhibitors of the cellular heat-shock response. Taken together, these results provide the rationale for the development of novel anti-cancer therapies that combine hyperthermia-induced homologous recombination deficiency with the systemic administration of drugs that specifically affect the viability of homologous recombination deficient cells and/or inhibit the heat-shock response, to locally sensitise cancer cells to DNA damaging agents. PMID- 22834702 TI - Targeting STAT3 in gastric cancer. AB - INTRODUCTION: STAT3 is a key transcription factor for many regulatory factors that modulate gene transcription. Particularly important are cytokines and growth factors that maintain homeostasis by regulating immunocytes, stromal and epithelial cells. Dysregulation of STAT3 by constitutive activation plays an important role in the initiation of inflammation and cellular transformation in numerous cancers, especially of epithelial origin. This review focuses on STAT3 drive in gastric cancer initiation and progression, with emphasis on its activation by cytokines, and how targeting the primary drivers or gastric STAT3 therapeutically may prevent or slow stomach cancer development. AREAS COVERED: This review will discuss the mechanics of STAT3 signalling, how constitutive STAT3 activation promotes gastric tumourigenesis in both human adenocarcinomas and mouse models, the nature of the upstream regulators of STAT3, and their association with chronic Helicobacter pylori infection, STAT3-activated genes that promote transformation and progression, and finally the development and use of STAT3 and upstream cytokine inhibitors as therapeutics. EXPERT OPINION: Chronic STAT3 activation is a key event in gastric cancer induction and progression. Specific targeting of stomach epithelial STAT3 or blocking IL 11Ralpha/gp130 and/or EGFR signal transduction in chronic gastric inflammation and metaplasia may be therapeutically effective in preventing gastric carcinogenesis. PMID- 22834703 TI - Patient perceptions of epinephrine auto-injectors: exploring barriers to use. AB - BACKGROUND: In recent years, government initiatives have proposed that patient self-care should serve as a key resource in response to the anticipated increase in global demand for health care. However, if patients are to be empowered as self-carers, barriers to engagement must be identified and overcome. Anaphylaxis is an increasingly common life-threatening allergic reaction. Patients at risk of anaphylaxis are prescribed epinephrine auto-injectors and play a crucial role in delivering their own care and management of this condition. One key recommendation is that patients routinely carry an epinephrine auto-injector with them and deploy the device when needed. However, only a small proportion of patients that require epinephrine actually receive it. OBJECTIVE: To explore the reasons why patients who have been prescribed epinephrine auto-injectors fail to adhere to self-care and management recommendations. METHODS: In-depth interviews with 15 adults who have been prescribed epinephrine auto-injectors were carried out to explore the barriers that exist in the provision of effective self-care and management of anaphylaxis. RESULTS: Inconsistent health professional advice, perceived stigma of carrying a 'weapon-like' device, poor device design and limited patient training were identified as barriers to carriage or use. Patients were reluctant to carry devices in public because of perceived and observed stigma and suspicion. They were happy to ignore expiry dates, and some participants were confident that the emergency services would provide them with the appropriate care they needed, and therefore, did not carry the device in urban areas. CONCLUSIONS AND CLINICAL IMPLICATIONS: Improved training of patients, the public and health professionals around both the carriage and use of auto-injectors are areas for urgent attention if improved levels of self-care are to be attained. The design of epinephrine auto-injectors should also receive attention as patients often fail to carry them owing to size and aesthetics. PMID- 22834705 TI - Unexpected one-pot synthesis of highly conjugated pentacyclic diquinoid compounds. AB - A new class of pentacyclic diquinoid compounds has been synthesized with a facile one-pot reaction of two molecules of 2-hydroxynaphthoquinone and 1-bromoalkanes in the presence of ferrocene. These molecules were isolated as enol tautomers that exhibit intramolecular hydrogen bond and extended electronic conjugation as proved by the intense absorption spectrum with a broad band between 400 and 600 nm. The spectroscopic and electrochemical characterization of this new class of compounds has been performed. One of the synthesized diquinoid derivatives showed a significant cytotoxicity with IC(50) values of 25-50 MUM against Cisplatin Resistant SKOV3 and colon carcinoma SW480 cell lines. The results of our study provide a valuable tool to a one-pot synthesis of highly conjugated polyquinones, analogous to important biological systems, with significant antitumoral activity. PMID- 22834704 TI - Multivalent recognition of histone tails by the PHD fingers of CHD5. AB - The chromodomain, helicase, DNA-binding protein 5 (CHD5) is a chromatin remodeling enzyme which is implicated in tumor suppression. In this study, we demonstrate the ability of the CHD5 PHD fingers to specifically recognize the unmodified N-terminus of histone H3. We use two distinct modified peptide-library platforms (beads and glass slides) to determine the detailed histone binding preferences of PHD(1) and PHD(2) alone and the tandem PHD(1-2) construct. Both domains displayed similar binding preferences for histone H3, where modification (e.g., methylation, acetylation, and phosphorylation) at H3R2, H3K4, H3T3, H3T6, and H3S10 disrupts high-affinity binding, and the three most N-terminal amino acids (ART) are crucial for binding. The tandem CHD5-PHD(1-2) displayed similar preferences to those displayed by each PHD finger alone. Using NMR, surface plasmon resonance, and two novel biochemical assays, we demonstrate that CHD5 PHD(1-2) simultaneously engages two H3 N-termini and results in a 4-11-fold increase in affinity compared with either PHD finger alone. These studies provide biochemical evidence for the utility of tandem PHD fingers to recruit protein complexes at targeted genomic loci and provide the framework for understanding how multiple chromatin-binding modules function to interpret the combinatorial PTM capacity written in chromatin. PMID- 22834706 TI - 32P-chromic phosphate-Poly(L-Lactide) seeds of sustained release and their brachytherapy for prostate cancer with lymphatic metastasis. AB - This study aims to develop a new agent, the 32P-chromic phosphate-poly(l-lactide) (32P-CP-PLLA) seed and to explore its anticancer effect against prostate cancer (Pca) with local lymphatic metastasis in nude mice. 32P-CP-PLLA seeds of sustained release and nude mouse models of Pca with lymphatic metastasis were prepared. After 4 weeks, the tumor nude mouse models were randomly assigned into five groups. 32P-CP-PLLA seeds (3.7, 7.4, 14.8, and 0 MBq) and 32P-CP (14.8 MBq) were implanted in the tumor tissues of the nude mouse models. The following were discussed in this study: (1) the distributions of 32P-CP-PLLA, (2) the pathological and morphological changes in the tumor and regional lymph nodes, and (3) the changes in white blood cell (WBC) and platelet counts in peripheral blood for toxic reactions. The homemade 32P-CP-PLLA seed was a regular green cylinder, with an even distribution of mass and radioactivity. After implantation, single photon emission computed tomograph (SPECT) showed that 32P was mainly gathered in the tumor and regional lymph nodes. Morphological examinations revealed that necrosis and hemorrhage were around the tumor and focal lymph nodes. The tumor inhibition rates of the five groups were 70.16% +/- 5.48%, 80.18% +/- 5.84%, 84.97% +/- 4.79%, (-), and 78.81% +/- 3.13%, respectively. These values were all positive when compared with the control group. As a new homemade agent of pure beta-ray, local implantation of the agent increased the focal retention of radioactivity at the target. Moreover, effective half-life showed an obvious damage to the tumor and metastatic foci of Pca. PMID- 22834707 TI - Dose and aging effect on patients reported treatment benefit switching from the first overactive bladder therapy with tolterodine ER to fesoterodine: post-hoc analysis from an observational and retrospective study. AB - BACKGROUND: Previous randomized studies have demonstrated that fesoterodine significantly improves the Overactive Bladder (OAB) symptoms and their assessment by patients compared with tolterodine extended-release (ER). This study aimed to assess the effect of aging and dose escalation on patient-reported treatment benefit, after changing their first Overactive Bladder (OAB) therapy with tolterodine-ER to fesoterodine in daily clinical practice. METHODS: A post-hoc analysis of data from a retrospective, cross-sectional and observational study was performed in a cohort of 748 OAB adults patients (OAB-V8 score >=8), who switched to fesoterodine from their first tolterodine-ER-based therapy within the 3-4 months before study visit. Effect of fesoterodine doses (4 mg vs. 8 mg) and patient age (<65 yr vs. >=65 yr) were assessed. Patient reported treatment benefit [Treatment Benefit Scale (TBS)] and physician assessment of improvement with change [Clinical Global Impression of Improvement subscale (CGI-I)] were recorded. Treatment satisfaction, degree of worry, bother and interference with daily living activities due to urinary symptoms were also assessed. RESULTS: Improvements were not affected by age. Fesoterodine 8 mg vs. 4 mg provides significant improvements in terms of treatment benefit [TBS 97.1% vs. 88.4%, p < 0.001; CGI-I 95.8% vs. 90.8% p < 0.05)], degree of worry, bother and interference with daily-living activities related to OAB symptoms (p <0.05). CONCLUSIONS: A change from tolterodine ER therapy to fesoterodine with dose escalation to 8 mg in symptomatic OAB patients, seems to be associated with greater improvement in terms of both patient-reported-treatment benefit and clinical global impression of change. Improvement was not affected by age. PMID- 22834708 TI - Acrylic AB and ABA block copolymers based on poly(2-ethylhexyl acrylate) (PEHA) and poly(methyl methacrylate) (PMMA) via ATRP. AB - Acrylic block copolymers have several advantages over conventional styrenic block copolymers, because of the presence of a saturated backbone and polar pendant groups. This investigation reports the preparation and characterization of di- and triblock copolymers (AB and ABA types) of 2-ethylhexyl acrylate (EHA) and methyl methacrylate (MMA) via atom transfer radical polymerization (ATRP). A series of block copolymers, PEHA-block-PMMA(AB diblock) and PMMA-block-PEHA-block PMMA(ABA triblock) were prepared via ATRP at 90 degrees C using CuBr as catalyst in combination with N,N,N',N",N"-pentamethyl diethylenetriamine (PMDETA) as ligand and acetone as additive. The chemical structure of the macroinitiators and molar composition of block copolymers were characterized by (1)H NMR analysis, and molecular weights of the polymers were analyzed by GPC analysis. DSC analysis showed two glass transition temperatures (T(g)), indicating formation of two domains, which was corroborated by AFM analysis. Small-angle X-ray scattering (SAXS) analysis of AB and ABA block copolymers showed scattering behavior inside the measuring limits indicating nanophase separation. However, SAXS pattern of AB diblock copolymers indicated general phase separation only, whereas for ABA triblock copolymer an ordered or mixed morphology could be deduced, which is assumed to be the reason for the better mechanical properties achieved with ABA block copolymers than with the AB analogues. PMID- 22834709 TI - Unmet dental and orthodontic need of children with special healthcare needs in West Virginia. AB - INTRODUCTION: Of children aged 0-17 years in the USA, an estimated 11 203 616 (15.1%; 95% CI: 14.8, 15.3) are Children with Special Health Care Needs (CSHCN). The state of West Virginia, the heart of Appalachia, has a land mass which is 97.65% rural with previously identified high overall dental need and oral health disparities. It is home to an estimated 70 609 CSHCN, or 18.5% (95% CI: 17.0, 19.9) of the state's children in 2009-2010. The purpose of this study was to determine the parent/guardian's perceived unmet dental care need of CSHCN in West Virginia. METHODS: Data from the National Survey of Children with Special Health Care Needs was used to determine prevalence. A telephone survey of 59 941 parents/guardians of CSHCN (1149 from West Virginia) for the dental interview was conducted in 2009-2010. RESULTS: Nationwide, 26.7% (25.9, 27.5) of parents/guardians reported their CSHCN had dental care or orthodontia needs other than preventive care. In West Virginia, the perceived dental care or orthodontia needs other than preventive dental care need was 26.5% (22.2, 30.0). Unmet national dental care need other than preventive dental care was 5.4% (5.0, 5.9) and in West Virginia 5.0% (2.4, 7.5). CONCLUSIONS: CSHCN have significant unmet dental needs. Parents/guardians in West Virginia reported similar unmet need compared with national reporting. Policies to address the health care of CSHCN should include dental needs. The clinical implications are that CSHCN have a variety of needs, including orthodontia. The benefits of orthodontic referrals should be considered in treatment planning options for CSHCN. PMID- 22834710 TI - Design and implementation of a closed-loop control system for infusion of propofol guided by bispectral index (BIS). AB - BACKGROUND: This study describes the design of a hypnosis closed-loop control system with propofol. The controller used a proportional-integral (PI) algorithm with the bispectral index (BIS) as the feedback signal. Our hypothesis was that a PI closed-loop control could be applied in clinical practice safely keeping the BIS within a pre-determined target range. METHODS: The adjustment of the PI parameters was based on simulation. The procedure had three steps: obtaining a patient model using data from 12 patients, designing and adjusting the controller in simulation, and fine tuning the PI parameters in a pilot study (10 patients). The resulting controller was tested in 24 American Society of Anesthesiology (ASA) I-II patients. The controller directly decides the infusion rate of propofol, and no model is necessary in its online operation. The BIS target was set to 50. Remifentanil was used for analgesia. RESULTS: We evaluated the efficiency and safety of the automatic feedback system. It worked properly in all the patients. The median performance error was -1.62, and the median absolute performance error was 11.03. Average propofol-normalized consumption was 5.3 +/- 1.8 mg/kg/h. Mean percentage of BIS in the range 40-60 was 83%. Mean time to open eyes was 8 +/- 4 min. Time to extubation was 9 +/- 5 min. Hemodynamic adverse event or intraoperative awareness were not recorded. CONCLUSIONS: The closed-loop system was able to maintain the BIS within an acceptable range of levels. The control of a propofol infusion guided by the BIS is feasible without hemodynamic instability in ASA I/II patients. PMID- 22834711 TI - Evaluation of perylenediimide derivatives for potential therapeutic benefits on cancer chemotherapy. AB - Perylene derivatives, known to have potential therapeutic benefits on particular cancer types as photosensitizers, may also function as small-molecule inhibitors with promising therapeutic value for diverse diseases. This recently recognized biological activity was attributed to their capacity to modulate the function of various enzymes as biological targets in vitro. Although the inhibitory activity on glutathione transferase and Src tyrosine kinase is important in determining the anticancer potential of compounds for target-specific drug design and development, to date, there are no successful inhibitors of this kind. Moreover, there are only a few studies about the effects of perylene derivatives on glutathione transferase and various kinases. In this study, four novel perylene compounds, N,N'-disubstituted perylenediimides and their 1,7-dibromo derivatives, were synthesized and evaluated for their biological activities. Here, among the compounds analyzed, one of them was identified with strong glutathione transferase inhibition and two with dual activity for both glutathione transferase and c-src inhibition. These results revealed that perylene derivatives may be employed as potential chemosensitizers to prevent chemotherapy dependent drug resistance and identified as prospective anticancer agents with dual activity on both glutathione transferase and c-src enzymes. PMID- 22834712 TI - Combining aspirin and proton pump inhibitors: for whom the warning bell tolls? AB - Aspirin and clopidogrel are well-known antiplatelet agents that are widely used across the spectrum of cardio- and cerebrovascular disease. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, many patients are also treated with a proton pump inhibitor (PPI). PPIs exert gastroprotection by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Initially, pharmacodynamic and pharmacokinetic studies suggested a considerable drug interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it has been reported that PPIs may also attenuate the antiplatelet effect of aspirin. This is particularly interesting, because a fixed combination of aspirin and a PPI (esomeprazole) has been developed and is currently under approval. Given the large number of patients taking aspirin and PPIs, even a small attenuation of the antiplatelet effect of aspirin may have substantial clinical impact. The present editorial summarizes current evidence on this drug interaction and discusses potential clinical implications. PMID- 22834713 TI - Physical gels based on charge-driven bridging of nanoparticles by triblock copolymers. AB - We have prepared an aqueous physical gel consisting of negatively charged silica nanoparticles bridged by ABA triblock copolymers, in which the A blocks are positively charged and the B block is neutral and water-soluble. Irreversible aggregation of the silica nanoparticles was prevented by precoating them with a neutral hydrophilic polymer. Both the elastic plateau modulus and the relaxation time increase slowly as the gel ages, indicating an increase both in the number of active bridges and in the strength with which the end blocks are adsorbed. The rate of this aging process can be increased significantly by applying a small shear stress to the sample. Our results indicate that charge-driven bridging of nanoparticles by triblock copolymers is a promising strategy for thickening of aqueous particle containing materials, such as water-based coatings. PMID- 22834714 TI - Reduction of U(VI) incorporated in the structure of hematite. AB - U(VI) doped hematite was synthesized and exposed to two different organic reductants with E(0) of 0.23 and 0.70 V. A combination of HAADF-TEM and EXAFS provided evidence that uranium was incorporated in hematite in uranate, likely octahedral coordination. XPS indicated that structurally incorporated U(VI) was reduced to U(V), whereas non-incorporated U(VI) was reduced to U(IV). Specifically, the experiments indicate that U(V) was the dominant oxidation state of uranium in hematite around Eh -0.24 to -0.28 V and pH 7.7-8.6 for at least up to 5 weeks of reaction time. U(V), but not U(IV), was also detected in hematite at Eh +0.21 V (pH 7.1-7.3). The results support the hypothesis, based on previous experimental and theoretical work, that the stability field of U(V) is widened relative to U(IV) and U(VI) in uranate coordination environments where the coordination number of U is less than 8. PMID- 22834716 TI - Differentiating the scientific endeavors of research, program evaluation, and quality improvement studies. PMID- 22834717 TI - Quality patient care in labor and delivery: a call to action. PMID- 22834718 TI - A systematic review of implementing an elective labor induction policy. AB - OBJECTIVE: To evaluate the effect of implementing hospital policies aimed at reducing elective labor induction and increasing spontaneous labor rates. DATA SOURCES: PubMed, CINAHL, Cochrane Database of Systematic Reviews, and Dissertation Abstracts International. STUDY SELECTION: Observational studies published from 2000 to 2010 were the only original studies from the past 20 years that met the review criteria. These focused on elective induction, labor induction policies, pre- and postimplementation of labor induction policy outcomes, and cesarean and maternal/neonatal morbidity rates. DATA EXTRACTION: Six retrospective and three prospective observational studies regarding implementation of labor induction policies were reviewed for types of intervention guidelines implemented and outcomes on rates of induction, cesarean, and maternal/neonatal morbidity. DATA SYNTHESIS: Implementation of elective induction policies resulted in lower induction, cesarean, operative/instrumental vaginal delivery, and maternal/neonatal morbidity rates. Patients spontaneously gave birth before scheduled elective induction date after policies were implemented, thereby resulting in lower rates of elective induction. CONCLUSIONS: Elective labor induction policies should be developed and implemented in all labor and delivery units. PMID- 22834719 TI - Refining Neurobehavioral Assessment of the High-Risk Infant Using the NICU Network Neurobehavioral Scale. AB - Nurses caring for high-risk infants use advanced assessment skills to identify the nature of infant instability and to assure timely intervention. The NICU Network Neurobehavioral Scale (NNNS) is a comprehensive assessment of neurological integrity and behavioral function of infants at risk. Research evidence supports its validity and reliability for clinical and research use. The NNNS offers nurses a neurobehavioral assessment especially suited to high-risk and premature infants. PMID- 22834720 TI - A randomized controlled trial of the effect of intrapartum intravenous fluid management on breastfed newborn weight loss. AB - OBJECTIVE: To determine the effect of conservative versus usual intrapartum intravenous (IV) fluid management for low-risk women receiving epidural analgesia on weight loss in breastfed newborns. DESIGN: A randomized controlled trial. SETTING: A tertiary perinatal center in a large urban setting. SAMPLE: Women experiencing uncomplicated pregnancies who planned to have epidural analgesia and to breastfeed. METHODS: Healthy pregnant women were randomized to receive an IV epidural preload volume of <500 mLs continuing at an hourly rate of 75-100 mL/h (conservative care) or an epidural preload volume of >=500 mLs and an hourly rate >125 mL/h (usual care). The primary study outcome was breastfed newborn weight loss >7% prior to hospital discharge. Secondary study outcomes included breastfeeding exclusivity, referral to outpatient breastfeeding clinic support, and delayed discharge. Other outcomes were admission to the neonatal intensive care unit and cord blood pH <7.25. RESULTS: Two hundred women participated (100 in the conservative care and 100 in the usual care groups). Forty-eight of 100 infants in the usual care group and 44 of the 100 infants in the conservative care group lost >7% of their birth weight prior to discharge, p < 0.52 RR 0.92 [0.68-1.24]. CONCLUSION: A policy of restricted IV fluids did not affect newborn weight loss. Women and their care providers should be reassured that the volumes of IV fluid <2500 mLs are unlikely to have a clinically meaningful effect on breastfed newborn weight loss >7%. Exploratory analyses suggest that breastfed newborn weight loss increases when intrapartum volumes infused are >2500 mLs. Care providers are encouraged to consider volumes of IV fluid infused intrapartum as a factor that may have contributed to early newborn weight loss in the first 48 h of life. PMID- 22834721 TI - Effects of labor support from close female relative on labor and maternal satisfaction in a Thai setting. AB - OBJECTIVE: To evaluate the efficacy of a close female relative providing emotional and physical support during active labor and birth. DESIGN: Randomized, two-group controlled clinical trial. SETTING: Regional teaching hospital in the eastern part of Thailand with 782 beds. PARTICIPANTS: Primiparous women (N = 120) whose gestational ages were >= 36 weeks and who had uncomplicated pregnancies. METHODS: Participants were randomly assigned to receive usual care and support from a chosen close female relative from admission until 2 hours after birth or usual care only. Within 24 hours of birth, labor outcomes (length of labor & type of birth) and levels of maternal satisfaction were assessed. RESULTS: Those in the experimental group had a significantly shorter duration of active labor and were more satisfied with their childbirth experiences than those in the control group. Differences between groups with respect to incidence of spontaneous delivery were not found. CONCLUSIONS: A close female relative was effective in providing supportive care during labor and delivery. The integration of this nursing intervention for women and their families at public hospitals in Thailand is supported. PMID- 22834722 TI - Stages of change in the trajectory of postpartum weight self-management. AB - OBJECTIVE: To identify women's patterns of readiness to engage in weight self management behaviors during the postpartum period. DESIGN: Prospective, longitudinal design with repeated measures, guided by the transtheoretical model of behavior change (TTM). SETTING: A tertiary perinatal center in an urban setting in the midwestern United States with approximately 3,000 births annually. PARTICIPANTS: One hundred ninety-one (191) adult postpartum women. METHODS: Participants were surveyed in person during their postpartum hospitalizations, and by telephone at 4 and 8 weeks postpartum using the Stages of Change for Weight Management (SOCWM) and the Decisional Balance for Weight Management (DBWM) tools. RESULTS: There was a significant effect of time on stage of change for women in the postpartum period, with women in a higher stage of change at 8 weeks than during the postpartum hospitalization. There were no significant differences in stage of change at any of the three time points by prepregnant weight category or by race. Nearly one half of the sample was in the contemplation stage during the postpartum hospitalization, and more than 80% were in action or maintenance stages by 8 weeks postpartum. CONCLUSIONS: The early postpartum period is an opportune time to influence stage of change in women's weight management behaviors. Assessment of readiness to engage in or continue weight management behaviors will allow providers to use stage-matched interventions guided by the TTM to facilitate women's self-management of weight. PMID- 22834724 TI - Current resources for evidence-based practice January/February 2012. PMID- 22834723 TI - Black adolescent mothers' perspectives on sex and parenting in nonmarital relationships with the biological fathers of their children. AB - OBJECTIVE: To understand single Black adolescent mothers' perspectives on the sexual and parenting-related aspects of their relationships with the biological fathers of their children. METHODS: The study was a qualitative description of perspectives from a convenience sample of Black single (nonmarried) adolescent mothers. Data were generated through focus groups and interviews. Participants were recruited using self-referral and health provider referrals. SETTING: The study was conducted in a county public health department sexually transmitted diseases clinic in Rochester, New York. PARTICIPANTS: Single mothers (N = 31) ages 15 to 19 participated in the study. The mean age of participants was 17.5 years (SD = 1.4). FINDINGS: Four themes were identified that reflected the major characteristics of the relationships between the mothers and the biological fathers of their children: (a) You will always care about your "baby daddy" because of your child, (b) Negative behavior is tolerated to keep the family together, (c) The "baby daddy" can get sex as long as we are not on bad terms, and (d) He will always be part of our lives. CONCLUSION: Black adolescent mothers have complex relationships with the biological fathers of their children that may include ongoing sexual activity. The intersection of coparenting and sexual health needs among adolescent mothers highlights the importance of integrating sexually transmitted infections prevention with perinatal health programs. It is important to consider this unique coparenting relationship when providing risk reduction counseling to young mothers. PMID- 22834725 TI - Psychoanalytic and cognitive-behavior therapy of chronic depression: study protocol for a randomized controlled trial. AB - BACKGROUND: Despite limited effectiveness of short-term psychotherapy for chronic depression, there is a lack of trials of long-term psychotherapy. Our study is the first to determine the effectiveness of controlled long-term psychodynamic and cognitive-behavioral (CBT) treatments and to assess the effects of preferential vs. randomized assessment. METHODS/DESIGN: Patients are assigned to treatment according to their preference or randomized (if they have no clear preference). Up to 80 sessions of psychodynamic or psychoanalytically oriented treatments (PAT) or up to 60 sessions of CBT are offered during the first year in the study. After the first year, PAT can be continued according to the 'naturalistic' usual method of treating such patients within the system of German health care (normally from 240 up to 300 sessions over two to three years). CBT therapists may extend their treatment up to 80 sessions, but focus mainly maintenance and relapse prevention. We plan to recruit a total of 240 patients (60 per arm). A total of 11 assessments are conducted throughout treatment and up to three years after initiation of treatment. The primary outcome measures are the Quick Inventory of Depressive Symptoms (QIDS, independent clinician rating) and the Beck Depression Inventory (BDI) after the first year. DISCUSSION: We combine a naturalistic approach with randomized controlled trials(RCTs)to investigate how effectively chronic depression can be treated on an outpatient basis by the two forms of treatment reimbursed in the German healthcare system and we will determine the effects of treatment preference vs. randomization. TRIAL REGISTRATION: http://www.controlled-trials.com/ISRCTN91956346. PMID- 22834726 TI - Comparison of fracture-load values of cantilevered FDPs. AB - OBJECTIVE: Evaluation of the effect of different framework designs and of fatigue on the fracture-load values of cantilevered fixed dental prostheses (FDPs). The load values were compared with those for lithium disilicate ceramic and metal ceramic FDPs. MATERIALS AND METHODS: Fifty cantilevered FDPs were manufactured using a zirconia framework veneered with a feldspathic ceramic. Ten FDPs were made from a lithium disilicate ceramic and 10 were designed as metal-ceramic FDPs. All FDPs were anchored by two premolar crowns to replace a missing premolar. Twenty of the 50 zirconia FDPs were regarded as the control groups; these were divided into two groups-with and without fatigue. The other 30 zirconia FDPs were divided into three test groups with different framework designs. The load to fracture was measured and fracture sites were identified. The Kruskal-Wallis test and the Mann-Whitney U-test were used for statistical analysis. RESULTS: Most of the all-ceramic FDPs fractured within the distal wall of the terminal crown abutment. The mean fracture-load ranged between 346-493 N for the FDPs with the 0.7 mm framework. Mean values for the three zirconia test groups ranged from 529-590 N. Reinforcement of the framework resulted in significantly higher fracture-loads than for the control group. Values for lithium disilicate restorations were significantly lower than those for the test groups and the values for the metal-ceramic group were significantly higher than those for the test groups. CONCLUSION: Although reinforcement of the distal crown core might enhance the fracture resistance of all-ceramic cantilever FPDs, they cannot yet be unreservedly recommended for clinical use. PMID- 22834727 TI - Extended diagnostic value of autologous serum skin test and basophil CD63 expression assay in chronic urticaria. PMID- 22834728 TI - Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia. AB - Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long-term outcome of elderly APL patients (60-70 years) with younger patients (15-59 years) treated with all-trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non-relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease-free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206. PMID- 22834729 TI - Moving toward a generalizable application of central thalamic deep brain stimulation for support of forebrain arousal regulation in the severely injured brain. AB - This review considers the challenges ahead for developing a generalizable strategy for the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the severely injured brain. Historical efforts to apply CT/DBS to patients with severe brain injuries and a proof-of concept result from a single-subject study are discussed. Circuit and cellular mechanisms underlying the recovery of consciousness are considered for their relevance to the application of CT/DBS, to improve consciousness and cognition in nonprogressive brain injuries. Finally, directions for development, and testing of generalizable criteria for CT/DBS are suggested, which aim to identify neuronal substrates and behavioral profiles that may optimally benefit from support of arousal regulation mechanisms. PMID- 22834730 TI - Effect of an adipose-derived stem cell and nerve growth factor-incorporated hydrogel on recovery of erectile function in a rat model of cavernous nerve injury. AB - Postprostatectomy erectile dysfunction (ED) is the major problem for patients with clinically localized prostate cancer. Recently, gene and stem cell-based therapy of the corpus cavernosum has been attempted for postprostatectomy ED, but those therapies are limited by rapid blood flow and disruption of the normal architecture of the corpus cavernosum. In this study, we attempted to regenerate the damaged cavernous nerve (CN), which is the main cause of ED. We investigated the effectiveness of human adipose-derived stem cell (hADSC) and nerve growth factor-incorporated hyaluronic acid-based hydrogel (NGF-hydrogel) application on the CN in a rat model of bilateral cavernous nerve crush injury. Four weeks after the operation, erectile function was assessed by detecting the intracavernous pressure (ICP)/arterial pressure level by CN electrostimulation. The ICP was significantly increased by application of hADSC with NGF-hydrogel compared to the other experimental groups. CN and penile tissue were collected for histological examination. PKH-26 labeled hADSC colocalized with beta III tubulin were shown in CN tissue sections. hADSC/NGF-hydrogel treatment prevented smooth muscle atrophy in the corpus cavernosum. In addition, the hADSC/NGF-hydrogel group showed increased endothelial nitric oxide synthase protein expression. This study suggests that application of hADSCs with NGF-hydrogel on the CN might be a promising treatment for postprostatectomy ED. PMID- 22834731 TI - Discovery and functional characterization of two diterpene synthases for sclareol biosynthesis in Salvia sclarea (L.) and their relevance for perfume manufacture. AB - BACKGROUND: Sclareol is a diterpene natural product of high value for the fragrance industry. Its labdane carbon skeleton and its two hydroxyl groups also make it a valued starting material for semisynthesis of numerous commercial substances, including production of Ambrox(r) and related ambergris substitutes used in the formulation of high end perfumes. Most of the commercially-produced sclareol is derived from cultivated clary sage (Salvia sclarea) and extraction of the plant material. In clary sage, sclareol mainly accumulates in essential oil producing trichomes that densely cover flower calices. Manool also is a minor diterpene of this species and the main diterpene of related Salvia species. RESULTS: Based on previous general knowledge of diterpene biosynthesis in angiosperms, and based on mining of our recently published transcriptome database obtained by deep 454-sequencing of cDNA from clary sage calices, we cloned and functionally characterized two new diterpene synthase (diTPS) enzymes for the complete biosynthesis of sclareol in clary sage. A class II diTPS (SsLPPS) produced labda-13-en-8-ol diphosphate as major product from geranylgeranyl diphosphate (GGPP) with some minor quantities of its non-hydroxylated analogue, (9 S, 10 S)-copalyl diphosphate. A class I diTPS (SsSS) then transformed these intermediates into sclareol and manool, respectively. The production of sclareol was reconstructed in vitro by combining the two recombinant diTPS enzymes with the GGPP starting substrate and in vivo by co-expression of the two proteins in yeast (Saccharomyces cerevisiae). Tobacco-based transient expression assays of green fluorescent protein-fusion constructs revealed that both enzymes possess an N-terminal signal sequence that actively targets SsLPPS and SsSS to the chloroplast, a major site of GGPP and diterpene production in plants. CONCLUSIONS: SsLPPS and SsSS are two monofunctional diTPSs which, together, produce the diterpenoid specialized metabolite sclareol in a two-step process. They represent two of the first characterized hydroxylating diTPSs in angiosperms and generate the dihydroxylated labdane sclareol without requirement for additional enzymatic oxidation by activities such as cytochrome P450 monoxygenases. Yeast-based production of sclareol by co-expresssion of SsLPPS and SsSS was efficient enough to warrant the development and use of such technology for the biotechnological production of scareol and other oxygenated diterpenes. PMID- 22834733 TI - The SOX family of genes in cancer development: biological relevance and opportunities for therapy. AB - INTRODUCTION: It has been more that 20 years since the first SOX genes were discovered. Twenty SOX genes have now been identified in mammals and classified into groups with respect to protein identity. SOX family genes code for transcription factors that either activate or repress lineage-specific genes during embryonic development. Furthermore, SOX genes are altered in human genetic syndromes and malignancies, highlighting their involvement in development. AREAS COVERED: This paper reviews the role of SOX genes in embryonic development and human diseases, and describe their involvement in human cancers and possible use in cancer therapeutics. EXPERT OPINION: Since most SOX genes behave as oncogenes in many human cancers, their targeting has great therapeutic potential. However, novel specific therapies such as those recently developed against growth factor receptors based on monoclonal antibodies, small inhibitors and even small interfering RNA strategies are difficult to implement for transcriptional factors. Novel strategies are being developed to overcome some of these obstacles. Alternative approaches could indirectly tackle altered SOX genes by exploiting the related molecular networks. PMID- 22834732 TI - Disruption of phosphatidylcholine monolayers and bilayers by perfluorobutane sulfonate. AB - Perfluoroalkyl acids (PFAAs) are persistent environmental contaminants resistant to biological and chemical degradation due to the presence of carbon-fluorine bonds. These compounds exhibit developmental toxicity in vitro and in vivo. The mechanisms of toxicity may involve partitioning into lipid bilayers. We investigated the interaction between perfluorobutane sulfonate (PFBS), an emerging PFAA, and model phosphatidylcholine (PC) lipid assemblies (i.e., dimyristoyl-, dipalmitoyl- and distearoylphosphatidylcholine) using fluorescence anisotropy and Langmuir monolayer techniques. PFBS decreased the transition temperature and transition width of PC bilayers. The apparent membrane partition coefficients ranged from 4.9 * 10(2) to 8.2 * 10(2). The effects on each PC were comparable. The limiting molecular area of PC monolayers increased, and the surface pressure at collapse decreased in a concentration-dependent manner. The compressibility of all three PCs was decreased by PFBS. In summary, PFBS disrupted different model lipid assemblies, indicating potential for PFBS to be a human toxicant. However, the effects of PFBS are not as pronounced as those seen with longer chain PFAAs. PMID- 22834734 TI - Combined immunization of mice with DNA, rMVA and rAd5 expressing HIV-1 structural genes from different subtypes. AB - The objective of present paper is to study the immunogenicity of combinations of multiple vector vaccines expressing HIV-1 structural genes from different subtypes. Mice were vaccinated with DNA (B'/C) and rMVA (B'/C) vaccines expressing B'/C recombinant subtype gag-pol and env genes, DNA (B') and rAd5 (B') vaccines expressing subtype B' gag gene with different combination schemes. HIV-1 Gag-specific cellular immune responses and P24- specific IgG levels were analyzed by IFN-gamma enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) respectively. ELISPOT results indicated that the Gag specific cellular immune responses induced by combination of three vaccines were much higher than that induced by combination of two vaccines. Among the groups of mice immunized with two vaccines, the groups with rAd5 booster elicited higher cellular immune responses compared with the groups with rMVA booster. All the test groups of three vaccines in combination could induce similar level of cellular immune responses, which did not correlate with the immunization order. ELISA results showed that p24- specific IgG induced by combination of three vaccines were much higher than that induced by combination of two vaccines. It indicates that the combination scheme of multiple vector vaccines maybe a promising AIDS vaccine strategy. PMID- 22834735 TI - Structural insight into the mechanism of DNA-binding attenuation of the Neisserial adhesin repressor NadR by the small natural ligand 4 hydroxyphenylacetic acid. AB - Neisserial adhesin A (NadA) is a surface exposed trimeric protein present in most hypervirulent meningococcal strains and involved in epithelial cell adhesion and colonization. The expression of nadA is controlled by Neisserial adhesin regulator (NadR), a member of the MarR family, which binds to the nadA promoter and strongly represses the transcription of nadA. It was recently demonstrated that the DNA-binding activity of NadR was attenuated by 4-hydroxyphenylacetic acid (4-HPA), a natural molecule released in human saliva, thus leading to the de repression of nadA in vivo. To elucidate the mechanism of regulation of NadR by 4 HPA, we used hydrogen-deuterium exchange mass spectrometry in association with in silico docking and site-directed mutagenesis. We show here that 4-HPA binds at the interface between the dimerization and the DNA-binding domains and stabilizes the homodimeric state of NadR without inducing large conformational changes in the DNA-binding lobes. The residues predicted to be in contact with 4-HPA were further selected for mutagenesis to assess their in vitro and in vivo functions in 4-HPA binding. Our results indicate that Arg(40) is critical for DNA-binding and reveal that Tyr(115) plays a key role in the mechanism of regulation of NadR by 4-HPA. Altogether our data suggest that the mechanism of regulation of NadR by 4-HPA mainly involves the stabilization of the dimer in a configuration incompatible with DNA binding. PMID- 22834736 TI - Comparing evolvabilities: common errors surrounding the calculation and use of coefficients of additive genetic variation. AB - In 1992, David Houle showed that measures of additive genetic variation standardized by the trait mean, CVA (the coefficient of additive genetic variation) and its square (IA), are suitable measures of evolvability. CVA has been used widely to compare patterns of genetic variation. However, the use of CVAs for comparative purposes relies critically on the correct calculation of this parameter. We reviewed a sample of quantitative genetic studies, focusing on sire models, and found that 45% of studies use incorrect methods for calculating CVA and that practices that render these coefficients meaningless are frequent. This may have important consequences for conclusions drawn from comparative studies. Our results are suggestive of a broader problem because miscalculation of the additive genetic variance from a sire model is prevalent among the studies sampled, implying that other important quantitative genetic parameters might also often be estimated incorrectly. We discuss the most prominent issues affecting the use of CVA and IA, including scale effects, data transformation, and the comparison of traits with different dimensions. Our aim is to increase awareness of the potential mistakes surrounding the calculation and use of evolvabilities, and to compile general guidelines for calculating, reporting, and interpreting these useful measures in future studies. PMID- 22834737 TI - Fisher's geometrical model of fitness landscape and variance in fitness within a changing environment. AB - The fitness of an individual can be simply defined as the number of its offspring in the next generation. However, it is not well understood how selection on the phenotype determines fitness. In accordance with Fisher's fundamental theorem, fitness should have no or very little genetic variance, whereas empirical data suggest that is not the case. To bridge these knowledge gaps, we follow Fisher's geometrical model and assume that fitness is determined by multivariate stabilizing selection toward an optimum that may vary among generations. We assume random mating, free recombination, additive genes, and uncorrelated stabilizing selection and mutational effects on traits. In a constant environment, we find that genetic variance in fitness under mutation-selection balance is a U-shaped function of the number of traits (i.e., of the so-called "organismal complexity"). Because the variance can be high if the organism is of either low or high complexity, this suggests that complexity has little direct costs. Under a temporally varying optimum, genetic variance increases relative to a constant optimum and increasingly so when the mutation rate is small. Therefore, mutation and changing environment together can maintain high genetic variance. These results therefore lend support to Fisher's geometric model of a fitness landscape. PMID- 22834738 TI - Modeling stabilizing selection: expanding the Ornstein-Uhlenbeck model of adaptive evolution. AB - Comparative methods used to study patterns of evolutionary change in a continuous trait on a phylogeny range from Brownian motion processes to models where the trait is assumed to evolve according to an Ornstein-Uhlenbeck (OU) process. Although these models have proved useful in a variety of contexts, they still do not cover all the scenarios biologists want to examine. For models based on the OU process, model complexity is restricted in current implementations by assuming that the rate of stochastic motion and the strength of selection do not vary among selective regimes. Here, we expand the OU model of adaptive evolution to include models that variously relax the assumption of a constant rate and strength of selection. In its most general form, the methods described here can assign each selective regime a separate trait optimum, a rate of stochastic motion parameter, and a parameter for the strength of selection. We use simulations to show that our models can detect meaningful differences in the evolutionary process, especially with larger sample sizes. We also illustrate our method using an empirical example of genome size evolution within a large flowering plant clade. PMID- 22834739 TI - Response to selection on cold tolerance is constrained by inbreeding. AB - The evolutionary potential of any given population is of fundamental importance for its longer term prospects. Modern land-use practices often result in small and isolated populations, increasing the risk of extinction through reduced genetic diversity as a consequence of inbreeding or drift. Such genetic erosion may also interfere with a population's evolutionary potential. In this study, we investigate the consequences of inbreeding on evolutionary potential (the ability to increase cold resistance) in a laboratory population of the tropical butterfly Bicyclus anynana. To explore constraints on evolution, we applied artificial selection to chill-coma recovery time, starting from three levels of inbreeding (outbred control, one or two full-sibling matings). Ten generations of selection produced highly divergent phenotypes, with the lines selected for increased cold tolerance showing about 28% shorter recovery times after cold exposure relative to unselected controls. Correlated responses to selection in 10 different life history and stress-resistance traits were essentially absent. Inbred lines showed a weaker response to selection, indicating reduced evolutionary potential and thereby constraints on evolution. Inbreeding depression was still measurable in some traits after the course of selection. Traits more closely related to fitness showed a clear fitness rebound, suggesting a trait-specific impact of purging. Our findings have important implications for the longer term survival of small populations in fragmented landscapes. PMID- 22834740 TI - The prediction of adaptive evolution: empirical application of the secondary theorem of selection and comparison to the breeder's equation. AB - Adaptive evolution occurs when fitness covaries with genetic merit for a trait (or traits). The breeder's equation (BE), in both its univariate and multivariate forms, allows us to predict this process by combining estimates of selection on phenotype with estimates of genetic (co)variation. However, predictions are only valid if all factors causal for trait-fitness covariance are measured. Although this requirement will rarely (if ever) be met in practice, it can be avoided by applying Robertson's secondary theorem of selection (STS). The STS predicts evolution by directly estimating the genetic basis of trait-fitness covariation without any explicit model of selection. Here we apply the BE and STS to four morphological traits measured in Soay sheep (Ovis aries) from St. Kilda. Despite apparently positive selection on heritable size traits, sheep are not getting larger. However, although the BE predicts increasing size, the STS does not, which is a discrepancy that suggests unmeasured factors are upwardly biasing our estimates of selection on phenotype. We suggest this is likely to be a general issue, and that wider application of the STS could offer at least a partial resolution to the common discrepancy between naive expectations and observed trait dynamics in natural populations. PMID- 22834741 TI - Shared spatial effects on quantitative genetic parameters: accounting for spatial autocorrelation and home range overlap reduces estimates of heritability in wild red deer. AB - Social structure, limited dispersal, and spatial heterogeneity in resources are ubiquitous in wild vertebrate populations. As a result, relatives share environments as well as genes, and environmental and genetic sources of similarity between individuals are potentially confounded. Quantitative genetic studies in the wild therefore typically account for easily captured shared environmental effects (e.g., parent, nest, or region). Fine-scale spatial effects are likely to be just as important in wild vertebrates, but have been largely ignored. We used data from wild red deer to build "animal models" to estimate additive genetic variance and heritability in four female traits (spring and rut home range size, offspring birth weight, and lifetime breeding success). We then, separately, incorporated spatial autocorrelation and a matrix of home range overlap into these models to estimate the effect of location or shared habitat on phenotypic variation. These terms explained a substantial amount of variation in all traits and their inclusion resulted in reductions in heritability estimates, up to an order of magnitude up for home range size. Our results highlight the potential of multiple covariance matrices to dissect environmental, social, and genetic contributions to phenotypic variation, and the importance of considering fine-scale spatial processes in quantitative genetic studies. PMID- 22834742 TI - The relation between the neutrality index for mitochondrial genes and the distribution of mutational effects on fitness. AB - We explore factors affecting patterns of polymorphism and divergence (as captured by the neutrality index) at mammalian mitochondrial loci. To do this, we develop a population genetic model that incorporates a fraction of neutral amino acid sites, mutational bias, and a probability distribution of selection coefficients against new nonsynonymous mutations. We confirm, by reanalyzing publicly available datasets, that the mitochondrial cyt-b gene shows a broad range of neutrality indices across mammalian taxa, and explore the biological factors that can explain this observation. We find that observed patterns of differences in the neutrality index, polymorphism, and divergence are not caused by differences in mutational bias. They can, however, be explained by a combination of a small fraction of neutral amino acid sites, weak selection acting on most amino acid mutations, and differences in effective population size among taxa. PMID- 22834743 TI - Genetic signature of adaptive peak shift in threespine stickleback. AB - Transition of an evolving population to a new adaptive optimum is predicted to leave a signature in the distribution of effect sizes of fixed mutations. If they affect many traits (are pleiotropic), large effect mutations should contribute more when a population evolves to a farther adaptive peak than to a nearer peak. We tested this prediction in wild threespine stickleback fish (Gasterosteus aculeatus) by comparing the estimated frequency of large effect genetic changes underlying evolution as the same ancestor adapted to two lake types since the end of the ice age. A higher frequency of large effect genetic changes (quantitative trait loci) contributed to adaptive evolution in populations that adapted to lakes representing a more distant optimum than to lakes in which the optimum phenotype was nearer to the ancestral state. Our results also indicate that pleiotropy, not just optimum overshoot, contributes to this difference. These results suggest that a series of adaptive improvements to a new environment leaves a detectable mark in the genome of wild populations. Although not all assumptions of the theory are likely met in natural systems, the prediction may be robust enough to the complexities of natural environments to be useful when forecasting adaptive responses to large environmental changes. PMID- 22834744 TI - Complex patterns of multivariate selection on the ejaculate of a broadcast spawning marine invertebrate. AB - Assessing how selection operates on several, potentially interacting, components of the ejaculate is a challenging endeavor. Ejaculates can be subject to natural and/or sexual selection, which can impose both linear (directional) and nonlinear (stabilizing, disruptive, and correlational) selection on different ejaculate components. Most previous studies have examined linear selection of ejaculate components and, consequently, we know very little about patterns of nonlinear selection on the ejaculate. Even less is known about how selection acts on the ejaculate as a functionally integrated unit, despite evidence of covariance among ejaculate components. Here, we assess how selection acts on multiple ejaculate components simultaneously in the broadcast spawning sessile invertebrate Mytilus galloprovincialis using the statistical tools of multivariate selection analyses. Our analyses of relative fertilization rates revealed complex patterns of selection on sperm velocity, motility, and morphology. Interestingly, the most successful ejaculates were made up of slower swimming sperm with relatively low percentages of motile cells, and sperm with smaller head volumes that swam in highly pronounced curved swimming trajectories. These results are consistent with an emerging body of literature on fertilization kinetics in broadcast spawners, and shed light on the fundamental nature of selection acting on the ejaculate as a functionally integrated unit. PMID- 22834745 TI - The evolution of trade-offs under directional and correlational selection. AB - Using quantitative genetic theory, we develop predictions for the evolution of trade-offs in response to directional and correlational selection. We predict that directional selection favoring an increase in one trait in a trade-off will result in change in the intercept but not the slope of the trade-off function, with the mean value of the selected trait increasing and that of the correlated trait decreasing. Natural selection will generally favor an increase in some combination of trait values, which can be represented as directional selection on an index value. Such selection induces both directional and correlational selection on the component traits. Theory predicts that selection on an index value will also change the intercept but not the slope of the trade-off function but because of correlational selection, the direction of change in component traits may be in the same or opposite directions. We test these predictions using artificial selection on the well-established trade-off between fecundity and flight capability in the cricket, Gryllus firmus and compare the empirical results with a priori predictions made using genetic parameters from a separate half-sibling experiment. Our results support the predictions and illustrate the complexity of trade-off evolution when component traits are subject to both directional and correlational selection. PMID- 22834746 TI - A significant component of ageing (DNA damage) is reflected in fading breeding colors: an experimental test using innate antioxidant mimetics in painted dragon lizards. AB - A decade ahead of their time, von Schantz et al. united sexual selection and free radical biology by identifying causal links between deep-rooted physiological processes that dictate resistance to toxic waste from oxidative metabolism (reactive oxygen species, ROS), and phenotypic traits, such as ornaments. Ten years later, these ideas have still only been tested with indirect estimates of free radical levels (oxidative stress) subsequent to the action of innate and dietary antioxidants. Here, we measure net superoxide (a selection pressure for antioxidant production) and experimentally manipulate superoxide antioxidation using a synthetic mimetic of superoxide dismutase (SOD), Eukarion 134 (EUK). We then measure the toxic effect of superoxide in terms of DNA erosion and concomitant loss of male breeding coloration in the lizard, Ctenophorus pictus. Control males suffered more DNA damage than EUK males. Spectroradiometry showed that male coloration is lost in relation to superoxide and covaries with DNA erosion; in control males, these variables explained loss of color, whereas in EUK males, the fading of coloration was unaffected by superoxide and unrelated to DNA damage. Thus, EUK's powerful antioxidation removes the erosion effect of superoxide on coloration and experimentally verifies the prediction that colors reflect innate capacity for antioxidation. PMID- 22834747 TI - Origins of altruism diversity I: The diverse ecological roles of altruistic strategies and their evolutionary responses to local competition. AB - Nature abounds with a rich variety of altruistic strategies, including public resource enhancement, resource provisioning, communal foraging, alarm calling, and nest defense. Yet, despite their vastly different ecological roles, current theory typically treats diverse altruistic traits as being favored under the same general conditions. Here, we introduce greater ecological realism into social evolution theory and find evidence of at least four distinct modes of altruism. Contrary to existing theory, we find that altruistic traits contributing to "resource-enhancement" (e.g., siderophore production, provisioning, agriculture) and "resource-efficiency" (e.g., pack hunting, communication) are most strongly favored when there is strong local competition. These resource-based modes of helping are "K-strategies" that increase a social group's growth yield, and should characterize species with scarce resources and/or high local crowding caused by low mortality, high fecundity, and/or mortality occurring late in the process of resource-acquisition. The opposite conditions, namely weak local competition (abundant resource, low crowding), favor survival (e.g., nest defense) and fecundity (e.g., nurse workers) altruism, which are "r-strategies" that increase a social group's growth rate. We find that survival altruism is uniquely favored by a novel evolutionary force that we call "sunk cost selection." Sunk cost selection favors helping that prevents resources from being wasted on individuals destined to die before reproduction. Our results contribute to explaining the observed natural diversity of altruistic strategies, reveal the necessary connection between the evolution and the ecology of sociality, and correct the widespread but inaccurate view that local competition uniformly impedes the evolution of altruism. PMID- 22834749 TI - On the evolutionary dynamics of pathogens with direct and environmental transmission. AB - A number of ecologically and economically important pathogens exhibit a complex transmission dynamics that involves distinct transmission modes. In this paper, we study the evolutionary dynamics of pathogens for which transmission includes direct host-to-host as well as indirect environmental transmission. Different routes of infection spread require specific adaptations of the parasite, which may result in conflicting selection pressures. Using the framework of Adaptive dynamics, we investigate how these conflicting selection pressures are resolved in the course of evolution and determine the conditions for evolutionary diversification of pathogen strains. We show that evolutionary branching and subsequent evolution of specialist strains occurs in wide parameter regions but evolutionary bistability and evolution of generalist pathogens are possible as well. Our analysis reveals that the relative contributions of direct and environmental transmission, as well as the underlying ecological dynamics, play a crucial role in shaping the course of pathogen evolution. Our findings may explain the coexistence of high and low virulence strains observed in several pathogenic organisms using different transmission modes (e.g., influenza viruses) and highlight the importance of considering ecological dynamics in virulence management. PMID- 22834748 TI - Origins of altruism diversity II: Runaway coevolution of altruistic strategies via "reciprocal niche construction". AB - Understanding the evolution of altruism requires knowledge of both its constraints and its drivers. Here we show that, paradoxically, ecological constraints on altruism may ultimately be its strongest driver. We construct a two-trait, coevolutionary adaptive dynamics model of social evolution in a genetically structured population with local resource competition. The intensity of local resource competition, which influences the direction and strength of social selection and which is typically treated as a static parameter, is here allowed to be an evolvable trait. Evolution of survival/fecundity altruism, which requires weak local competition, increases local competition as it evolves, creating negative environmental feedback that ultimately inhibits its further evolutionary advance. Alternatively, evolution of resource-based altruism, which requires strong local competition, weakens local competition as it evolves, also ultimately causing its own evolution to stall. When evolving independently, these altruistic strategies are intrinsically self-limiting. However, the coexistence of these two altruism types transforms the negative ecoevolutionary feedback generated by each strategy on itself into positive feedback on the other, allowing the presence of one trait to drive the evolution of the other. We call this feedback conversion "reciprocal niche construction." In the absence of constraints, this process leads to runaway coevolution of altruism types. We discuss applications to the origins and evolution of eusociality, division of labor, the inordinate ecological success of eusocial species, and the interaction between technology and demography in human evolution. Our theory suggests that the evolution of extreme sociality may often be an autocatalytic process. PMID- 22834750 TI - Hosts are ahead in a marine host-parasite coevolutionary arms race: innate immune system adaptation in pipefish Syngnathus typhle against Vibrio phylotypes. AB - Microparasites have a higher evolutionary potential than their hosts due to an increased mutation rate and a shorter generation time that usually results in parasites being locally adapted to their sympatric hosts. This pattern may not apply to generalist pathogens as adaptation to sympatric host genotypes is disadvantageous due to a narrowing of the host range, in particular under strong gene flow among host populations. Under this scenario, we predict that the immune defense of hosts reveals adaptation to locally common pathogen phylotypes. This was tested in four host populations of the pipefish Syngnathus typhle and associated bacteria of the genus Vibrio. We investigated the population divergence among host and bacteria populations and verified that gene flow is higher among host populations than among parasite populations. Next, we experimentally assessed the strength of innate immune defense of pipefish hosts using in vitro assays that measured antimicrobial activity of blood plasma against sympatric and allopatric Vibrio phylotypes. Pipefish plasma displays stronger antimicrobial activity against sympatric Vibrio phylotypes compared to allopatric ones. This suggests that host defense is genetically adapted against local bacteria with a broad and unspecialized host spectrum, a situation that is typical for marine systems with weak host population structure. PMID- 22834751 TI - Virulence not only costs but also benefits the transmission of a fungal virus. AB - Current theory suggests that cost-benefit relationships govern the evolution of parasite virulence. The cost of virulence is expected to be high for fungal viruses, which are obligate parasites and completely dependent on their hosts. The majority of fungal viruses infect their hosts without any apparent symptoms. Cryphonectria hypovirus 1 (CHV-1), in contrast, is virulent and debilitates its host, Cryphonectria parasitica. However, the virulence of CHV-1 is associated with high costs for virus transmission, such as an attenuated fungal growth and reduced production of the fungal spores spreading the virus. In this study, we tested the hypothesis that virulence may not only have costs but also benefits for transmitting CHV-1 across vegetative incompatibility barriers between fungi. We investigated viruses with low, medium, and high virulence, and determined their transmission rate per host-to-host contact (transmissibility). The average transmission rate across all combinations tested was 53% for the most virulent virus, 37% for the virus with intermediate virulence, and 20% for the virus with lowest virulence. These results showed that increased virulence was strongly correlated with increased transmissibility, potentially counterbalancing virulence costs. This association of virulence and transmissibility may explain why CHV-1 spread widely and evolved higher virulence than most other fungal viruses. PMID- 22834752 TI - Phylogenetic comparison of neuron and glia densities in the primary visual cortex and hippocampus of carnivores and primates. AB - A major focus of comparative neuroanatomy has been on whether the mammalian brain evolves in a concerted or a mosaic fashion. Workers have examined variation in the volume of different brain regions across taxa to test the degree to which selection is constrained by the timing of events in neural development. Whether a conserved neurogenetic program in the mammalian brain constrains the distribution of different cell types, however, has not yet been investigated. Here we tested for evidence of evolutionary constraints on the densities of different cell types in the primary visual cortex (V1) and the hippocampus in 37 primate and 21 carnivore species. Cellular densities in V1 and the hippocampus scale isometrically with respect to one another in carnivores, as predicted by the concerted evolution hypothesis. In primates, however, cellular distributions in the hippocampus and primary visual cortex show no correlations, which supports the hypothesis of mosaic brain evolution. We therefore provide evidence for the presence of constraints controlling the adult densities of different cell types in disparate regions of the mammalian brain, but also for specializations along the primate lineage. We propose that adaptations to modularity at the cellular level may carry a deep phylogenetic signal. PMID- 22834755 TI - Dietary hardness, loading behavior, and the evolution of skull form in bats. AB - The morphology and biomechanics of the vertebrate skull reflect the physical properties of diet and behaviors used in food acquisition and processing. We use phyllostomid bats, the most diverse mammalian dietary radiation, to investigate if and how changes in dietary hardness and loading behaviors during feeding shaped the evolution of skull morphology and biomechanics. When selective regimes of food hardness are modeled, we found that species consuming harder foods have evolved skull shapes that allow for more efficient bite force production. These species have shorter skulls and a greater reliance on the temporalis muscle, both of which contribute to a higher mechanical advantage at an intermediate gape angle. The evolution of cranial morphology and biomechanics also appears to be related to loading behaviors. Evolutionary changes in skull shape and the relative role of the temporalis and masseter in generating bite force are correlated with changes in the use of torsional and bending loading behaviors. Functional equivalence appears to have evolved independently among three lineages of species that feed on liquids and are not obviously morphologically similar. These trends in cranial morphology and biomechanics provide insights into behavioral and ecological factors shaping the skull of a trophically diverse clade of mammals. PMID- 22834754 TI - Explosive radiation of a bacterial species group. AB - The current diversity of life on earth is the product of macroevolutionary processes that have shaped the dynamics of diversification. Although the tempo of diversification has been studied extensively in macroorganisms, much less is known about the rates of diversification in the exceedingly diverse and species rich microbiota. Decreases in diversification rates over time, a signature of explosive radiations, are commonly observed in plant and animal lineages. However, the few existing analyses of microbial lineages suggest that the tempo of diversification in prokaryotes may be fundamentally different. Here, we use multilocus and genomic sequence data to test hypotheses about the rate of diversification in a well-studied pathogenic bacterial lineage, Borrelia burgdorferi sensu lato (sl). Our analyses support the hypothesis that an explosive radiation of lineages occurred near the origin of the clade, followed by a sharp decay in diversification rates. These results suggest that explosive radiations may be a general feature of evolutionary history across the tree of life. PMID- 22834753 TI - Evolutionary stability in a 400-million-year-old heritable facultative mutualism. AB - Many eukaryotes interact with heritable endobacteria to satisfy diverse metabolic needs. Some of these interactions are facultative symbioses, in which one partner is not essential to the other. Facultative symbioses are expected to be transitional stages along an evolutionary trajectory toward obligate relationships. We tested this evolutionary theory prediction in Ca. Glomeribacter gigasporarum, nonessential endosymbionts of arbuscular mycorrhizal fungi (Glomeromycota). We found that heritable facultative mutualisms can be both ancient and evolutionarily stable. We detected significant patterns of codivergence between the partners that we would only expect in obligate associations. Using codiverging partner pairs and the fungal fossil record, we established that the Glomeromycota-Glomeribacter symbiosis is at least 400 million years old. Despite clear signs of codivergence, we determined that the Glomeribacter endobacteria engage in recombination and host switching, which display patterns indicating that the association is not evolving toward reciprocal dependence. We postulate that low frequency of recombination in heritable endosymbionts together with host switching stabilize facultative mutualisms over extended evolutionary times. PMID- 22834756 TI - Ecological limits on diversification of the Himalayan core Corvoidea. AB - Within regions, differences in the number of species among clades must be explained by clade age, net diversification rate, or immigration. We examine these alternatives by assessing historical causes of the low diversity of a bird parvorder in the Himalayas (the core Corvoidea, 57 species present), relative to its more species rich sister clade (the Passerida, ~400 species present), which together comprise the oscine passerines within this region. The core Corvoidea contain ecologically diverse species spanning a large range of body sizes and elevations. Despite this diversity, on the basis of ecological, morphological, and phylogenetic information, we infer that the best explanation for the low number of species within the Himalayan core Corvoidea is one in which ecology limits diversification and/or immigration. Within the core Corvoidea, body size is correlated with elevation: large species are found at high elevations, and small species at lower elevations. This contrasts with the presence of many small bodied species spanning all elevations in the Passerida and many large bodied species at low elevations in the other orders of birds (the nonpasserines). Cladogenetic events leading to ecological differences between species in body size and shape mostly occurred millions of years ago, and the rate of evolutionary change has declined toward the present. Elevational distributions have been evolutionarily more labile, but are also associated with ancient cladogenetic events. We suggest the core Corvoidea occupy a restricted volume of ecological space in competition with other bird species, and this has limited in situ diversification and/or immigration. PMID- 22834757 TI - Assessing phylogenetic signal with measurement error: a comparison of Mantel tests, Blomberg et al.'s K, and phylogenetic distograms. AB - In macroevolutionary studies, different approaches are commonly used to measure phylogenetic signal--the tendency of related taxa to resemble one another- including the K statistic and the Mantel test. The latter was recently criticized for lacking statistical power. Using new simulations, we show that the power of the Mantel test depends on the metrics used to define trait distances and phylogenetic distances between species. Increasing power is obtained by lowering variance and increasing negative skewness in interspecific distances, as obtained using Euclidean trait distances and the complement of Abouheif proximity as a phylogenetic distance. We show realistic situations involving "measurement error" due to intraspecific variability where the Mantel test is more powerful to detect a phylogenetic signal than a permutation test based on the K statistic. We highlight limitations of the K-statistic (univariate measure) and show that its application should take into account measurement errors using repeated measures per species to avoid estimation bias. Finally, we argue that phylogenetic distograms representing Euclidean trait distance as a function of the square root of patristic distance provide an insightful representation of the phylogenetic signal that can be used to assess both the impact of measurement error and the departure from a Brownian evolution model. PMID- 22834758 TI - Positive correlation between diversification rates and phenotypic evolvability can mimic punctuated equilibrium on molecular phylogenies. AB - The hypothesis of punctuated equilibrium proposes that most phenotypic evolution occurs in rapid bursts associated with speciation events. Several methods have been developed that can infer punctuated equilibrium from molecular phylogenies in the absence of paleontological data. These methods essentially test whether the variance in phenotypes among extant species is better explained by evolutionary time since common ancestry or by the number of estimated speciation events separating taxa. However, apparent "punctuational" trait change can be recovered on molecular phylogenies if the rate of phenotypic evolution is correlated with the rate of speciation. Strong support for punctuational models can arise even if the underlying mode of trait evolution is strictly gradual, so long as rates of speciation and trait evolution covary across the branches of phylogenetic trees, and provided that lineages vary in their rate of speciation. Species selection for accelerated rates of ecological or phenotypic divergence can potentially lead to the perception that most trait divergence occurs in association with speciation events. PMID- 22834759 TI - Patterns of reproductive isolation in Nolana (Chilean bellflower). AB - We examined reproductive isolating barriers at four postmating stages among 11 species from the morphologically diverse genus Nolana (Solanaceae). At least one stage was positively correlated with both genetic and geographic distance between species. Postzygotic isolation was generally stronger and faster evolving than postmating prezygotic isolation. In addition, there was no evidence for mechanical isolation, or for reproductive character displacement in floral traits that can influence pollinator isolation. In general, among the potential isolating stages examined here, postzygotic barriers appear to be more effective contributors to reducing gene flow, including between sympatric species. PMID- 22834760 TI - The precopulatory function of male genital spines in Drosophila ananassae[Doleschall] (Diptera: Drosophilidae) revealed by laser surgery. AB - That male genital morphology evolves via postcopulatory sexual selection is a widely held view. In contrast, the precopulatory sexual selection hypothesis for genital evolution has received less attention. Here, we test the hypothesis that male genital spines of Drosophila ananassae promote competitive male copulation success. Using laser surgery to manipulate trait size, we demonstrate that incremental reductions of spine length progressively reduce male copulation success: males without spines failed entirely to copulate because of an inability to couple the genitalia together, whereas males with halfway ablated and blunted spines suffered reductions in copulation success of 87% and 13%, respectively. The decrease in copulation success resulting from spine length reduction was markedly stronger in sexually competitive environments than in noncompetitive environments, and females expressed resistance behaviors similarly toward competing male treatments, demonstrating directly the role of genital spines in promoting competitive copulation success. Because these spines are widespread within Drosophila, and because genital traits with precopulatory function are being discovered in a growing number of animal taxa, precopulatory sexual selection may have a more pervasive role in genital evolution than previously recognized. PMID- 22834761 TI - Measuring the fitness benefits of male mate choice in Drosophila melanogaster. AB - It is increasingly realized that the potential for male mate choice is widespread across many taxa. However, measurements of the relative magnitude of the fitness benefits that such choice can confer are lacking. Here, we directly measured, in a comprehensive set of tests that manipulated key variables, the fitness benefits of male mate choice in Drosophila melanogaster by measuring egg production in females that were chosen or rejected by males. The results provided significant evidence for male mate choice. In absolute terms, the observed degree of choice increased male fitness by an average of only 1.59 eggs. However, using a novel technique we show that this benefit of choice represented 14.5% of the maximum potential fitness benefit of choice. The magnitude of mate choice was not significantly altered by variation in (1) mate compatibility, (2) phenotypic plasticity in male mate choice, or (3) whether choosing males were preferred or nonpreferred by females. Overall, we show that male mate choice represents a subtle but significant opportunity for sexual selection, and we offer a novel and widely applicable method for quantifying mate choice. PMID- 22834762 TI - Science, religion, and society: the problem of evolution in America. AB - American resistance to accepting evolution is uniquely high among First World countries. This is due largely to the extreme religiosity of the United States, which is much higher than that of comparably advanced nations, and to the resistance of many religious people to the facts and supposed implications of evolution. The prevalence of religious belief in the United States suggests that outreach by scientists alone will not have a huge effect in increasing the acceptance of evolution, nor will the strategy of trying to convince the faithful that evolution is compatible with their religion. Because creationism is a symptom of religion, another strategy to promote evolution involves loosening the grip of faith on America. This is easier said than done, for recent sociological surveys show that religion is highly correlated with the dysfunctionality of a society, and various measures of societal health show that the United States is one of the most socially dysfunctional First World countries. Widespread acceptance of evolution in America, then, may have to await profound social change. PMID- 22834763 TI - CAF@ZIF-8: one-step encapsulation of caffeine in MOF. AB - Two strategies for encapsulating caffeine in ZIF-8 were carried out in this work: (1) one-step, in situ encapsulation where caffeine is added to a ZIF-8 synthesis solution and the MOF structure is formed around the entrapped molecule; and (2) ex situ encapsulation whereby caffeine is put into contact with previously synthesized or purchased ZIF-8. The products obtained were analyzed with XRD, TGA, Vis-UV, GC-MS, FTIR, (13)C NMR, and N 1s XPS to compare both encapsulation methods. Chemical and structural evidence indicated that the preferential adsorption site of caffeine molecules inside the ZIF-8 structure is near the methyl and CH groups of 2-methylimidazole ligand. These two groups interact with caffeine by van der Waals forces with methyl groups and via CH...O hydrogen bonds with C?O groups, respectively. In addition, the one-step encapsulation of caffeine in ZIF-8 produced high guest loading (ca. 28 wt % in only 2 h at 25 degrees C) and controlled release (during 27 days). PMID- 22834764 TI - Effect of social support on changes in quality of life in early breast cancer patients: a longitudinal study. AB - BACKGROUND: Breast cancer diagnosis as well as diversity of the treatment process deteriorates women's quality of life (QOL). Researchers have examined social support and its relations with QOL overall, but less is known about effects of social support on changes in QOL. AIMS: The aim of this study was to examine social support received from social network and nurses within 6 months and QOL in women with breast cancer. METHODS: Women (N = 164) after breast cancer surgery were quasi-randomized to the intervention (n = 85) and control groups (n = 79). Participants completed two well-known QOL questionnaires, and the questionnaire measuring received social support from network and from nurses both 1 week and 6 months after the breast cancer surgery. Data were analysed using descriptive statistics and nonparametric tests. Logistic regression model with the enter method was employed to identify associations between social support and negative changes in QOL. RESULTS: Affect and aid from network decreased in both groups and affirmation in the intervention group within 6 months. No significant changes in received social support from nurses were found within groups. Furthermore, no statistically significant difference in the magnitude of changes over time was found between groups. Received social support had an effect on changes in sexual functioning, global QOL and health and functioning. CONCLUSIONS: Received social support decreased in both groups within 6 months. Significant effects of social support on negative changes on QOL were found. Social support tailored to women's individual needs is an essential part of the care in patients with breast cancer. For further research, longitudinal designs for longer period should be established to explore social support and its effects on QOL. PMID- 22834765 TI - Interference of low frequency magnetic fields with implantable cardioverter defibrillators. AB - OBJECTIVES: The aim of this study was to find the electromagnetic interference (EMI) thresholds for several commonly used implantable cardioverter defibrillators (ICD). DESIGN: Seventeen ICDs were exposed to magnetic fields with different intensities produced by the Helmholtz coil system. Sinusoidal, pulse, ramp, and square-waveforms with a frequency range of 2 Hz to 1 kHz were used. RESULTS: ICD malfunctions occurred in 11 of the 17 ICDs tested. The ICD malfunctions that occurred were false detections of ventricular tachycardia (6/17 ICDs) and ventricular fibrillation (3/17 ICDs), false detection of atrial tachycardia (4/6 dual chamber ICDs) and tachycardia sensing occurring during atrial or ventricular refractory periods (1/17 ICD). In most cases, no interference occurred at magnetic field levels below the occupational safety limits of the International Commission on Non-Ionizing Radiation Protection (ICNIRP). Nevertheless, some frequencies using sine, ramp or square waveforms did interfere with certain ICDs at levels below these limits. No EMI occurred with any of the ICDs below the ICNIRP limits for public exposure. CONCLUSION: Evaluation of EMI should be part of the risk assessment of an employee returning to work after an ICD implantation. The risk assessment should consider magnetic field intensities, frequencies and waveforms. PMID- 22834766 TI - Timing the onset of sulfate reduction over multiple subsurface acetate amendments by measurement and modeling of sulfur isotope fractionation. AB - Stable isotope fractionations of sulfur are reported for three consecutive years of acetate-enabled uranium bioremediation at the US Department of Energy's Rifle Integrated Field Research Challenge (IFRC) site. The data show a previously undocumented decrease in the time between acetate addition and the onset of sulfate reducing conditions over subsequent amendments, from 20 days in the 2007 experiment to 4 days in the 2009 experiment. Increased sulfide concentrations were observed at the same time as delta(34)S of sulfate enrichment in the first year, but in subsequent years elevated sulfide was detected up to 15 days after increased delta(34)S of sulfate. A biogeochemical reactive transport model is developed which explicitly incorporates the stable isotopes of sulfur to simulate fractionation during the 2007 and 2008 amendments. A model based on an initially low, uniformly distributed population of sulfate reducing bacteria that grow and become spatially variable with time reproduces measured trends in solute concentration and delta(34)S, capturing the change in onset of sulfate reduction in subsequent years. Our results demonstrate a previously unrecognized hysteretic effect in the spatial distribution of biomass growth during stimulated subsurface bioremediation. PMID- 22834767 TI - Direct renin inhibition improves parasympathetic function in diabetes. AB - AIM: The renin-angiotensin-aldosterone system (RAAS) and autonomic nervous system regulate the cardiovascular system. Blockade of the RAAS may slow the progression of end-organ damage. Direct renin inhibition offers a means for blocking the RAAS. The objective of this study was to examine the effect of direct renin inhibition on cardiovascular autonomic function. METHODS: In this double-blind, placebo-controlled trial, 60 individuals with diabetes were randomly assigned to 300 mg of aliskiren or placebo once daily for 6 weeks. The primary end point was a change in tests of cardiovascular autonomic function. Autonomic function was assessed by power spectral analysis and RR-variation during deep breathing [i.e. mean circular resultant (MCR), expiration/inspiration (E/I) ratio]. The MCR and E/I ratio assess parasympathetic function. Secondary measures included change in biochemical parameters [e.g. plasma renin activity, leptin and interleukin-6]. Change in cardiovascular autonomic function and blood analytes were analysed by a mixed effects model for repeated measures. RESULTS: Baseline characteristics were similar between treatment groups. In response to aliskiren compared with placebo, blood pressure was reduced as well as plasma renin activity [from 2.4 +/- 3.8 (mean +/- standard deviation) to 0.5 +/- 0.4 ug/l/h, p < 0.001]. There was a significant interaction (aliskiren * visit) for MCR (p = 0.003) and E/I ratio (p = 0.003) indicating improvement in MCR and E/I ratio for those on aliskiren. MCR means, baseline vs. follow-up, were 41.8 +/- 19.7 vs. 50.8 +/- 26.1 (aliskiren) and 38.2 +/- 23.6 vs. 37.5 +/- 24.1 (placebo). CONCLUSIONS: Parasympathetic function (i.e. MCR and E/I ratio) was enhanced by downregulation of the RAAS. PMID- 22834769 TI - Conformation and self-association of peptide amphiphiles based on the KTTKS collagen sequence. AB - Studying peptide amphiphiles (PAs), we investigate the influence of alkyl chain length on the aggregation behavior of the collagen-derived peptide KTTKS with applications ranging from antiwrinkle cosmetic creams to potential uses in regenerative medicine. We have studied synthetic peptides amphiphiles C(14)-KTTKS (myristoyl-Lys-Thr-Thr-Lys-Ser) and C(18)-KTTKS (stearoyl-Lys-Thr-Thr-Lys-Ser) to investigate in detail their physicochemical properties. It is presumed that the hydrophobic chain in these self-assembling peptide amphiphiles enhances peptide permeation across the skin compared to KTTKS alone. Subsequently C(n)-KTTKS should act as a prodrug and release the peptide by enzymatic cleavage. Our results should be useful in the further development of molecules with collagen stimulating activity. PMID- 22834768 TI - Duration of luteal support (DOLS) with progesterone pessaries to improve the success rates in assisted conception: study protocol for a randomized controlled trial. AB - BACKGROUND: Luteal support with progesterone is necessary for successful implantation of the embryo following egg collection and embryo transfer in an in vitro fertilization (IVF) cycle. Progesterone has been used for as little as 2 weeks and for as long as 12 weeks of gestation. The optimal length of treatment is unresolved at present and it remains unclear how long to treat women receiving luteal supplementation. DESIGN: The trial is a prospective, randomized, double blind, placebo-controlled trial to investigate the effect of the duration of luteal support with progesterone in IVF cycles. Following 2 weeks standard treatment and a positive biochemical pregnancy test, this randomized control trial will allocate women to a supplementary 8 weeks treatment with vaginal progesterone or 8 weeks placebo. Further studies would be required to investigate whether additional supplementation with progesterone is beneficial in early pregnancy. DISCUSSION: Currently at the Hewitt Centre, approximately 32.5% of women have a positive biochemical pregnancy test 2 weeks after embryo transfer. It is this population that is eligible for trial entry and randomization. Once the patient has confirmed a positive urinary pregnancy test they will be invited to join the trial. Once the consent form has been completed by the patient a trial prescription sheet will be sent to pharmacy with a stated collection time. The patient can then be randomized and the drugs dispensed according to pharmacy protocol. A blood sample will then be drawn for measurement of baseline hormone levels (progesterone, estradiol, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A, Activin A, Inhibin A and Inhibin B). The primary outcome measure is the proportion of all randomized women that continue successfully to a viable pregnancy (at least one fetus with fetal heart rate >100 beats/minute) on transabdominal/transvaginal ultrasound at 10 weeks post embryo transfer/12 weeks gestation (that is at the end of 8 weeks supplementary trial treatment). TRIAL REGISTRATION: ISRCTN05696887. PMID- 22834771 TI - Design, synthesis and fungicidal activity of novel sclerotiorin derivatives. AB - Sclerotiorin, a chlorine-containing azaphilone-type natural product, was first isolated from Penicillium sclerotiorum and has been reported to exhibit weak fungicidal activity. Optimization of the substituents at the 3- and 5-positions of the sclerotiorin framework was investigated with the aim of discovering novel fungicides with improved activity. The design of sclerotiorin analogues involved replacing the diene side chain with a phenyl group or an aromatic- or heteroaromatic-containing aliphatic side chain. The designed compounds were synthesized by cycloisomerization and subsequent oxidation of suitable 2 alkynylbenzaldehydes, in which a variety of substituents were introduced using a Sonogashira coupling reaction. The structures of these newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy, HRMS and single-crystal X-ray analysis. The antifungal activity of the synthesized compounds was evaluated against seven phytopathogenic species. Compounds 3, 9g and 9h were found to have a broad spectrum of fungicidal activity, and these structurally simpler products can be recognized as lead compounds for further optimization. PMID- 22834770 TI - Prevalence and socio-behavioral influence of early childhood caries, ECC, and feeding habits among 6-36 months old children in Uganda and Tanzania. AB - BACKGROUND: Early childhood caries (ECC) is a serious problem that has remained unexplored in sub-Saharan Africa. This study aimed to identify possible socio behavioral correlates of ECC focusing 6-36 months old children and their caretakers. METHODS: Cross sectional studies were conducted in a high fluoride rural area, Manyara, Tanzania and a low fluoride urban area, Kampala, Uganda. Totals of 1221 and 816 child - caretaker pairs attending health care facilities for growth monitoring were recruited in Manyara and Kampala, respectively. All caretakers completed face to face interviews at the health care facility. Children underwent oral clinical examination whereby ECC and Enamel hypoplasia were recorded using the dmft (WHO 1997) and the DDE index (FDI 1992). RESULTS: The prevalence of ECC was 3.7% in Manyara and 17.6% in Kampala. According to multiple logistic regression analyses, received oral health information from health worker was the strongest determinant of ECC in Manyara, adjusted OR 0.3, 95% CI 0.09 - 0.93. In Kampala, visible plaque, high sugar intake and presence of enamel hypoplasia associated with ECC, adjusted ORs 2.8 (95% CI 1.61- 4.95), 3.0 (95% CI 1.39 - 6.34) and 2.3 (95% CI 1.36 - 3.95). CONCLUSION: Oral health education aimed at caretakers of 6-36 months, including health care workers' information regarding the detrimental consequences for oral health of frequent sugar consumption and poor oral hygiene is important for prevention of ECC in Tanzania and Uganda. PMID- 22834772 TI - Modified asymmetric Strecker reaction of aldehyde with secondary amine: a protocol for the synthesis of S-clopidogrel (an antiplatelet agent). AB - A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave alpha-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-clopidogrel (an antiplatelet agent). PMID- 22834773 TI - Hair shaft abnormalities after chemotherapy and tamoxifen therapy in patients with breast cancer evaluated by optical coherence tomography. AB - BACKGROUND: Antineoplastic treatment for breast cancer is frequently associated with alopecia. Increasingly, changes in the texture and shape of regrowing hair after chemotherapy have been reported, without evaluation on a scientific basis. Optical coherence tomography (OCT) provides highly reproducible measurements of hair shaft parameters. OBJECTIVES: This study aims to evaluate hair shaft alterations using OCT in chemotherapy-induced alopecia and in patients taking tamoxifen. METHODS: The measurements of this prospective case series were performed on women aged 29-68 years, receiving either tamoxifen (n = 17) or chemotherapy (n = 17) prior to (T1) and after (T2) treatment. Each time, 20 hairs from two different sites of the scalp (frontal, occipital) were examined by OCT. The hair parameters were characterized by cross section (CS) and form factor (FF). The ratio of maximal to minimal hair diameters determined the FF. RESULTS: After chemotherapy, the CS of hairs was significantly lower compared with hairs taken at T1. The FF did not vary between T1 and T2 for the frontal area, but it did for the occipital area. In patients treated with tamoxifen, changes were observed neither in CS nor in FF. However, comparing both therapeutic groups, there were significant differences in CS and FF for T2, but not for T1. CONCLUSIONS: Reported changes in hair structure after chemotherapy may be due to reduction of hair shaft calibre and increase of FF in regrowing hair. The OCT technique is a promising method to gain more insight into chemotherapy-induced changes of hair morphology. PMID- 22834774 TI - Thyroid hormones and male sexual function. AB - The role of thyroid hormones in the control of erectile functioning has been only superficially investigated. The aim of the present study was to investigate the association between thyroid and erectile function in two different cohorts of subjects. The first one derives from the European Male Ageing Study (EMAS study), a multicentre survey performed on a sample of 3369 community-dwelling men aged 40 79 years (mean 60 +/- 11 years). The second cohort is a consecutive series of 3203 heterosexual male patients (mean age 51.8 +/- 13.0 years) attending our Andrology and Sexual Medicine Outpatient Clinic for sexual dysfunction at the University of Florence (UNIFI study). In the EMAS study all subjects were tested for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Similarly, TSH levels were checked in all patients in the UNIFI study, while FT4 only when TSH resulted outside the reference range. Overt primary hyperthyroidism (reduced TSH and elevated FT4, according to the reference range) was found in 0.3 and 0.2% of EMAS and UNIFI study respectively. In both study cohorts, suppressed TSH levels were associated with erectile dysfunction (ED). Overt hyperthyroidism was associated with an increased risk of severe erectile dysfunction (ED, hazard ratio = 14 and 16 in the EMAS and UNIFI study, respectively; both p < 0.05), after adjusting for confounding factors. These associations were confirmed in nested case-control analyses, comparing subjects with overt hyperthyroidism to age, BMI, smoking status and testosterone-matched controls. Conversely, no association between primary hypothyroidism and ED was observed. In conclusion, erectile function should be evaluated in all individuals with hyperthyroidism. Conversely, assessment of thyroid function cannot be recommended as routine practice in all ED patients. PMID- 22834777 TI - Abstracts of the British Society of Paediatric Dentistry Annual Scientific Meeting. September 18-21, 2012. Newcastle, United Kingdom. PMID- 22834775 TI - Profiling oxidative DNA damage: effects of antioxidants. AB - The goal of this research was to determine whether antioxidant usage could be correlated with changes in DNA damage levels. Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) was used to simultaneously measure five different oxidatively-induced base modifications in the DNA of WBC. Measurements of the five modifications were made before and after an 8-week trial during which participants took the SU.VI.MAX supplement. Levels of the five DNA modifications were compared among different groupings: users versus non-users of antioxidant supplements, before versus after the supplement intervention and men versus women. The statistical significance of differences between groups was most significant for pyrimidine base modifications and the observed trends reflect trends reported in epidemiological studies of antioxidant usage. A combination of modifications derived from pyrimidine bases is suggested as a superior indicator of oxidative stress. PMID- 22834779 TI - Dual guidance improves needle tip placement for peripheral nerve blocks in a porcine model. AB - BACKGROUND: The objective of the study was to evaluate whether the use of ultrasound (US) together with nerve stimulation (USNST) provides a better needle tip position for performing peripheral regional anaesthesia than the use of US or nerve stimulation (NST) alone. METHODS: Needle placements were applied at the brachial plexus and sciatic nerves in 32 anaesthetised pigs. Following needle placement near the target nerve, using either the USNST or the US or NST, a volume of 0.3 ml synthetic resin was injected mimicking a 'test-dose' injection. The primary outcome was the incidence of close needle-to-nerve placement assessed by injectate localisation in direct contact with the nerve epineurium. Secondary endpoints were the incidences of intraneural injection and haematoma formation in direct contact with the target nerve. RESULTS: A total of 611 punctures were performed. The evaluation for the criterion 'close needle placement' revealed significant differences in favour of the USNST group (98.5%) compared with the NST (90.1%) and the US group (81.6%) (P = 0.001). Significant differences were observed regarding 'intraneural needle placement' between the groups as well (USNST, 0.5%; US, 4%; NST, 2.5%; P = 0.034). The incidence of haematoma formation was significantly higher in the NST group (10.8%) than in the US group (2.5%) and in the USNST group (1.5%) (P = 0.001). CONCLUSION: These findings suggest that the USNST approach combines the benefits of the US and the NST techniques in terms of a higher rate of close needle tip placements and a lower incidence of haematoma formation. PMID- 22834778 TI - Association of cardiac and renal function with extreme N-terminal fragment pro-B type natriuretic peptide levels in elderly patients. AB - BACKGROUND: The data are inconsistent regarding whether extreme N-terminal fragment pro-B-type natriuretic peptide (NT pro-BNP) levels are associated with impaired renal function. Furthermore, the relationship between extreme NT pro-BNP levels and cardiac and renal function in elderly patients has not been reported. The aim of the present study was to examine a hypothesis that extreme NT pro-BNP levels may be associated with impaired cardiac and renal function in elderly patients. METHODS: We retrospectively analyzed the data of demographic, clinical, and echocardiographic features on 152 consecutive elderly patients aged more than 80 years old (average age, 83.65 +/- 3.58 years) with NT pro-BNP levels >= 3000 pg/ml. The participants were divided into two categories according to their NT pro-BNP levels: (1) 3000-10000 pg/mL and (2) >10000 pg /mL. RESULTS: The number of patients with impaired renal function (P = 0.019) and the mortality (P < 0.001) in the period of inpatient was higher in the group with NT pro-BNP > 10000 pg /mL. The levels of serum creatinine and creatine kinase MB (CK-MB) in the group of NT pro-BNP > 10000 pg / mL were higher than those in the group of NT pro BNP = 3000-10000 pg/mL (P = 0.001 and P = 0.023, respectively). Furthermore, no significant difference in the distribution by NYHA class in different NT pro-BNP levels was observed. Multiple linear regression analyses demonstrated that with NT pro-BNP levels as the dependent variable, NT pro-BNP levels were positively correlated with CK-MB (beta = 0.182, P = 0.024) and creatinine levels (beta = 0.281, P = 0.001). The area under the receiver-operating characteristic (ROC) curve of NT pro-BNP levels and clinical diagnosis of impaired renal function was 0.596 and reached significant difference (95%CI:0.503-0.688, P = 0.044). CONCLUSION: These data suggest that the extreme elevation of NT pro-BNP levels (>=3000 pg/ml) is mainly determined by impaired renal function in elderly patients above 80 years. Extreme NT pro-BNP levels may be useful for assessing the severity of impaired renal function. PMID- 22834781 TI - A vector-host system to fingerprint virus tropism. AB - Reporter genes are important tools for assessing vector pharmacology in vivo. Although useful, current systems are limited by (1) the need to generate a new vector for each different reporter, (2) the inability to package reporter genes in small vectors, and (3) variations in reporter gene feedback due to variations in cell-to-cell vector copy number. To circumvent these problems, we have used Cre recombinase as a "cat's paw" to activate reporter genes embedded in transgenic mice. The small Cre gene was introduced into self-complementary adeno associated viral (scAAV) vectors with limited packaging capacity. Injection of scAAV-Cre vectors into mice with loxP-inactivated luciferase enabled in vivo imaging distributions comparable to the signal observed after AAV-luciferase injection. When injected into mT/mG mice, AAV-Cre converted ubiquitous expression of red fluorescent protein (RFP) to green fluorescent protein (GFP) expression only where the vectors transduced cells. Injection into F(1) hybrid luciferase and mT/mG mice enabled simultaneous three-reporter tracking. This system was able to discriminate cell-specific transduction in all organs tested, with particular usefulness for detecting AAV serotype-specific transduction in the liver, kidney, and muscle. Given that F(1) mice bear exactly one copy of luciferase and one copy of RFP-GFP, each reporter gene is either "on" or "off" in a cell. The Cre system therefore provides a unique quantum method to quantify vector delivery that can be applied when vector capacity is limited. PMID- 22834780 TI - Ron receptor tyrosine kinase signaling as a therapeutic target. AB - INTRODUCTION: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis. AREAS COVERED: This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer. EXPERT OPINION: The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients. PMID- 22834782 TI - Radial-flow bioreactor enables uniform proliferation of human mesenchymal stem cells throughout a three-dimensional scaffold. AB - Mesenchymal stem cells (MSCs) obtained from human bone marrow are pluripotent and have been expanded and differentiated into several kinds of mesodermal tissue in vitro. To create bioartificial tissues and organs for implantation, it is necessary to induce proliferation in such cells. In this study, a radial-flow bioreactor (RFB) was used to induce three-dimensional (3D) expansion of human MSCs (hMSCs) on a large scaffold. The effect of this expansion on cellular characteristics was investigated. To produce precultured sheets, the hMSCs were first seeded onto type 1 collagen sheets and incubated for 12 h, after which they were placed in the RFB for fabrication of scaffolds. The culture medium was circulated at 3 mL/min, and the cells were dynamically cultured for 1 week at 37 degrees C. As a control, static cultivation in a culture dish was also carried out. Cellular expansion and characteristics were analyzed. Alkaline phosphatase (ALP) activity in the hMSCs was also investigated after dynamic culture in an osteogenesis induction medium to explore their potential for osteogenic differentiation. At 1 week of dynamic cultivation, a >60% increase was observed in a number of cells together with a uniform distribution throughout the scaffolds compared with under static conditions; no change in hMSC markers was observed. The hMSCs retained the ability for osteogenic differentiation after culture in the RFB. The present results indicate that 3D dynamic culture in an RFB enables uniform expansion of hMSCs with no change in cellular characteristics, suggesting the usefulness of this technique in tissue engineering. PMID- 22834784 TI - Large-scale in-vitro expansion of RBCs from hematopoietic stem cells. AB - The quest for RBCs in transfusion medicine has prompted scientists to explore the large-scale expansion of human RBCs from various sources. The successful production of RBCs in the laboratory depends on the selection of potential cell source, optimized culture, bio-physiological parameters, clinically applicable culture media that yields a scalable, contamination-free, non-reactive, non tumorogenic, stable and functional end product. The expansion protocol considering the in vivo factors involved in homeostasis can generate a cost effective and readily available cell source for transfusion. This review paper discusses several approaches used to expand RBCs from various sources of stem cells. PMID- 22834785 TI - Surface chemistry and spectroscopy of human insulin Langmuir monolayer. AB - The human insulin (HI) protein was examined to elucidate its structure at the air water interface. Optimal experimental conditions were determined to prepare a homogeneous and stable human insulin (HI) Langmuir monolayer. HI insulin Langmuir monolayer can be used to study interactions of HI with a membrane as Langmuir monolayers are used as an in vitro model of biological membranes. Surface pressure and surface potential-area isotherms were used to characterize the HI Langmuir monolayer. The compression-decompression cycles and stability measurements showed a homogeneous and stable monolayer at the air-water interface. However, higher surface pressures resulted in a higher decrease in area and less stability. In situ UV-vis and fluorescence spectroscopy were used to verify the homogeneity of the HI monolayer and to identify the chromophore residues in the HI. Domain formation was examined through epifluorescence and Brewster angle microscopies. The conformation of HI was examined by circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) in the aqueous phase and at the air-water interface by infrared reflection absorption spectroscopy (IRRAS). HI was found to exist as a monomer in 2-D. PMID- 22834783 TI - Genetics of primary intraocular tumors. AB - Primary intraocular neoplasms are tumors that originate within the eye. The most common malignant primary intraocular tumor in adults is uveal melanoma and the second is primary intraocular lymphoma or vitreoretinal (intraocular) lymphoma. The most common malignant intraocular tumor in children is retinoblastoma. Genetics plays a vital role in the diagnosis and detection of ocular tumors. In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas. The retinoblastoma gene RB1 is the prototype tumor suppressor gene-mutations in RB1 alleles lead to inactivated RB protein and the development of retinoblastoma. Immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement is observed in B-cell or T-cell primary vitreoretinal lymphoma, respectively. Other factors related to the genetics of these three common malignancies in the eye are discussed and reviewed. PMID- 22834786 TI - Role of active site histidines in the two half-reactions of the aryl-alcohol oxidase catalytic cycle. AB - The crystal structure of aryl-alcohol oxidase (AAO), a flavoenzyme involved in lignin degradation, reveals two active-site histidines, whose role in the two enzyme half-reactions was investigated. The redox state of flavin during turnover of the variants obtained show a stronger histidine involvement in the reductive than in the oxidative half-reaction. This was confirmed by the k(cat)/K(m(Al)) and reduction constants that are 2-3 orders of magnitude decreased for the His546 variants and up to 5 orders for the His502 variants, while the corresponding O(2) constants only decreased up to 1 order of magnitude. These results confirm His502 as the catalytic base in the AAO reductive half-reaction. The solvent kinetic isotope effect (KIE) revealed that hydroxyl proton abstraction is partially limiting the reaction, while the alpha-deuterated alcohol KIE showed a stereoselective hydride transfer. Concerning the oxidative half-reaction, directed mutagenesis and computational simulations indicate that only His502 is involved. Quantum mechanical/molecular mechanical (QM/MM) reveals an initial partial electron transfer from the reduced FADH(-) to O(2), without formation of a flavin-hydroperoxide intermediate. Reaction follows with a nearly barrierless His502H(+) proton transfer that decreases the triplet/singlet gap. Spin inversion and second electron transfer, concomitant with a slower proton transfer from flavin N5, yields H(2)O(2). No solvent KIE was found for O(2) reduction confirming that the His502 proton transfer does not limit the oxidative half reaction. However, the small KIE on k(cat)/K(m(Ox)), during steady-state oxidation of alpha-deuterated alcohol, suggests that the second proton transfer from N5H is partially limiting, as predicted by the QM/MM simulations. PMID- 22834787 TI - Computational studies of novel chymase inhibitors against cardiovascular and allergic diseases: mechanism and inhibition. AB - To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4-diazepane-2,5 diones ring are essential for effective binding of inhibitors at active site of enzyme. The Bayesian model with receiver operating curve statistic of 0.82 also identified arylsulfonyl and aminocarbonyl as the molecular features favoring and not favoring inhibition of chymase, respectively. Moreover, genetic function approximation was applied to construct 3D quantitative structure-activity relationships models. Two models (genetic function approximation model 1 r(2) = 0.812 and genetic function approximation model 2 r(2) = 0.783) performed better in terms of correlation coefficients and cross-validation analysis. In general, this study is used as example to illustrate how combinational use of 2D/3D quantitative structure-activity relationships modeling techniques, molecular docking, frontier molecular orbital density fields (highest occupied molecular orbital and lowest unoccupied molecular orbital), and molecular electrostatic potential analysis may be useful to gain an insight into the binding mechanism between enzyme and its inhibitors. PMID- 22834788 TI - Hsp70-2 gene polymorphism: susceptibility implication in Tunisian patients with coronary artery disease. AB - Coronary artery disease (CAD) is a multifactorial disease where genetic and environmental factors interact in complex ways to cause the disease. Heat shock protein genes are involved in the progress of CAD. This implies that genetic variants of Hsp70-2 genes might contribute to the development of the CAD. AIM OF STUDY: The aim of this study was to characterize statistical correlation of linkage between lipid profiles, polymorphism PstI site of Hsp70-2 gene and CAD. PATIENTS AND METHODS: This study was carried out on Tunisian patients with CAD recruited from Hospital of Fattouma Bourguiba of Monastir-Tunisia. Polymerase chain reaction and restriction enzymes were used to determine the genotypic distributions in 252 unrelated patients and 151 healthy control subjects. Further, ApoA-I and ApoB as well as the serum total of cholesterol, HDL, triglyceride, and hs-CRP levels were measured. RESULTS: We showed a decreased level of ApoA-I, whereas the levels of each of ApoB and hs-CRP were increased in patients with CAD compared with control group. In addition our studies of a polymorphic PstI site of Hsp70-2 gene at position 1267 of the Hsp70-2 gene have revealed that the allelic frequency of P2 was significantly more frequent in CAD patients than controls group (p=0.007, OR=1.495). The genotypic distribution showed a high incidence of P2/P2 genotype in CAD patients (0.190) compared to healthy control (0.009) with reach significant difference (p=0.006). The P2 carriers showed a significantly increased of Total-Cholesterol (CT) and C reactive protein (hs-CRP) levels in CAD patients (p=0.008 and p=0.018, respectively). CONCLUSION: The high incidence of P2-Hsp70-2 genotype in CAD patients and the significantly association of P2/P2 genotype with elevated Total Cholesterol and hs-CRP levels, supported that P2-Hsp70-2 genotype has susceptibility implication in CAD and could increased the risk of CAD in Tunisian population. PMID- 22834789 TI - Multicomponent patterning of indium tin oxide. AB - We report a versatile functionalization and pattering technique that permits multicomponent pattern-specific modification of indium tin oxide (ITO) with organic species. The method relies on a bilayered molecular system that simultaneously protects ITO from degradation and provides uniform chemical functionality suitable for further elaboration. Pattern-specific modification is achieved via specific reaction between functionality on an elastomeric stamp and functionality of cognate reactivity at the surface of a bilayered molecular substrate. We demonstrate that a single molecular system in a combination with different printing approaches can be used to immobilize multiple organic functionalities with exquisite spatial control on a single ITO surface. Our study provides the first general approach that permits patterning and functionalization of ITO with different molecules using a single set of printing conditions and materials. PMID- 22834790 TI - Permeability and micromechanical properties of silk ionomer microcapsules. AB - We studied the pH-responsive behavior of layer-by-layer (LbL) microcapsules fabricated from silk fibroin chemically modified with different poly amino acid side chains: cationic (silk-poly L-lysine, SF-PL) or anionic (silk-poly-L glutamic acid, SF-PG). We observed that stable ultrathin shell microcapsules can be assembled with a dramatic increase in swelling, thickness, and microroughness at extremely acidic (pH < 2.5) and basic (pH > 11.0) conditions without noticeable disintegration. These changes are accompanied by dramatic changes in shell permeability with a 2 orders of magnitude increase in the diffusion coefficient. Moreover, the silk ionomer shells undergo remarkable softening with a drop in Young's modulus by more than 1 order of magnitude due to the swelling, stretching, and increase in material porosity. The ability to control permeability and mechanical properties over a wide range for the silk-based microcapsules, with distinguishing stability under harsh environmental conditions, provides an important system for controlled loading and release and applications in bioengineering. PMID- 22834791 TI - Experiences of the individual placement and support approach in persons with severe mental illness. AB - BACKGROUND: Across several research studies comparing the individual placement and support (IPS) approach to traditional vocational services, the approach has achieved employment outcomes superior to comparison conditions. However, to understand the efficacy of IPS, it is equally important to consider what is more or less effective as viewed by the IPS participants. AIM: To investigate participants' experiences of IPS participation and their experiences of receiving support from an employment specialist (ES). METHOD: Interviews were conducted with 17 persons with severe mental illness. The interviews were subjected to qualitative content analysis. The principles of informed consent and the voluntary nature of participation were included as ethical considerations. RESULTS: Participation in IPS was associated with hope, meaning and an individualized support provided by the ES. The skills of the ES facilitated the relationship with the participant and the contact with the labour market. However, to make a change happen, everybody involved in IPS had to contribute. CONCLUSION: These findings have endorsed the guiding principles of IPS and emphasized the ES's role and skills during IPS as well as the participant's motivation. PMID- 22834792 TI - Cd2+ complex of a triazole-based calix[4]arene conjugate as a selective fluorescent chemosensor for Cys. AB - An N,N-Dimethylamine ethylimino-appended triazole-linked calix[4]arene conjugate, L, has been synthesized and characterized, and its Cd(2+) complex has been isolated and characterized. The structure of [CdL] was established by computational calculation using B3LYP/LANL2DZ. Time-dependent density functional theory calculations were performed to demonstrate the electronic properties of [CdL]. This highly fluorescing [CdL] has been used to recognize Cys selectively among the 20 naturally occurring amino acids. [CdL] exhibits a minimum detection limit of 58 ppb for Cys, with reusability and reversibility being imparted to the system during sensing. Thus, the sensing of Cys was well demonstrated using various techniques, viz., fluorescence, absorption, visual color change, electrospray ionization MS, (1)H NMR, and live cell imaging experiments. PMID- 22834793 TI - Editorial: chromogranin A at the crossroads of health and disease. PMID- 22834794 TI - Chromogranin A and the endothelial barrier function. AB - Chromogranin A (CgA) is an acidic glycoprotein belonging to a family of regulated secretory proteins stored in the dense core granules of many neuroendocrine cells and neurons. This protein is produced, in certain conditions also by cardiomyocytes, keratinocytes and granulocytes. Upon secretion CgA is released in the extracellular environment and then in circulation. Increased levels of circulating CgA have been detected in patients with cancer, heart failure, hypertension, atrophic gastritis, renal failure, giant cell artheritis, rheumatoid arthritis, sepsis and other inflammatory diseases. Endothelial cells, either those located in the close proximity of secretory cells or in distant tissues, may be exposed, therefore, to variable levels of CgA. In this review we discuss recent findings that implicate CgA and its fragments as a modulators of the physiology of endothelial cells in normal and in pathological conditions. In particular, we review data that suggest that CgA and its N-terminal fragment, called vasostatin-1, are important modulators of the endothelial barrier function and potent inhibitors of the endothelial cell activation caused by inflammatory and pro-angiogenic cytokines, with potential implications in angiogenesis, inflammation and cancer. PMID- 22834795 TI - Chromogranin-A: a multifaceted cardiovascular role in health and disease. AB - Chromogranin A (CgA), a major component of the chromaffin granules, is co-stored and co-released with catecholamines. It is also expressed in extra-adrenal sites, including the heart. In the rat, CgA localizes in atrial myoendocrine cells, associated with Atrial Natriuretic Peptide (ANP), and in the conduction system. In the human heart it is present in the ventricular myocardium, co-localized with B-type NP (BNP). CgA is the precursor of several biologically active peptides generated by proteolytic processing also in the heart. Two of them, vasostatin-1 (VS-1) and catestatin (Cst), inhibit cardiac contraction and relaxation, counter regulate beta-adrenergic and endothelinergic stimulation, and protect the heart against ischemia/reperfusion damages. Recently, clinical studies have suggested CgA to be involved also in cardiovascular pathologies. High plasma CgA levels were found in hypertension, chronic and acute heart failure, myocardial infarction, decompensated and hypertrophic heart, and acute coronary syndromes. These alterations correlate with those of conventional cardiovascular biomarkers, such as NP and endothelin-1 (ET-1), and have prognostic relevance, being indicative of both severity of the disease and mortality. Accordingly, the current knowledge indicates CgA as a multifaceted peptide in cardiovascular homeostasis. Whether the influence elicited by the protein on both normal and failing heart is beneficial and/or detrimental, as well as its implication in the cardiac neuroendocrine scenario is under intense investigation. This review will focus on: i) the involvement of CgA and its derived peptides in the mechanisms which sustain cardiac function and compensation, ii) CgA clinical relevance, and iii) its putative value as a clinical biomarker. PMID- 22834796 TI - Endothelium dependent cardiovascular effects of the Chromogranin A-derived peptides Vasostatin-1 and Catestatin. AB - The involvement of Chromogranin A (CgA) in the cardiovascular function regulation is attributed to its function as a prohormone. Several studies indicated that CgA derived peptides, particularly Vasostatin-1 (VS-1) and Catestatin (CST), exert signaling effects in numerous organs/systems, including the cardiovascular system. This review focuses on the recently described signaling pathways activated by VS-1 and CST, giving insights into the mechanisms at the basis of their cardiac negative inotropic action, their vasodilator effects and their cardioprotective role observed in different experimental conditions. Accumulated evidences provided convincing support for VS-1 and CST as vasoactive peptides indirectly acting on cardiomyocytes through a Ca(2+)-independent/PI3-K-dependent NO release from endothelial cells. This pathway is supposed to be triggered by the interaction of these peptides with the plasma membrane. The premise of these studies grounds on the biochemical features of VS-1 and CST, which are structurally characterized by amphipathic properties and the ability to interact with mammalian and microbial membranes. On the other hand, recent data obtained in both isolated heart and isolated cardiomyocytes suggest that the VS-1 and CST mediated cardioprotective effects are primarily direct on the myocardium, rather than endothelium-dependent. Anyway, both direct and indirect pathways seem to be characterized by the absence of specific membrane receptors on target cells, highlighting intriguing novelties in the topic of cell signaling, in particular respect to an hypothetical receptor-independent eNOS activation. PMID- 22834797 TI - Chromogranins and inositol 1,4,5-trisphosphate-dependent Ca(2+)-signaling in cardiomyopathy and heart failure. AB - Cardiomyocytes contain secretory granules in which chromogranins and several types of natriuretic peptides and growth factors are stored in addition to high Ca(2+) concentrations. Yet the expression and serum levels of chromogranins and natriuretic peptides have been closely correlated with pathological cardiac hypertrophy and heart failure. Moreover, in distinction from the physiological cardiac hypertrophy that appears not to involve inositol 1,4,5-trisphosphate (IP3) production as the primary signaling step, accumulating evidence underscores the central role of IP3-induced intracellular Ca(2+) releases in cardiomyocytes in the development of pathological cardiac hypertrophy. Consistent with this observation, chronic treatment of cardiomyocytes with G-protein coupled receptor agonists endothelin-1, angiotensin II, or phenylephrine, agents that are known to produce intracellular IP3, leads to cardiomyopathy and heart failure. In particular, the IP3-induced Ca(2+) release inside the nucleus has been suggested to initiate a series of nuclear activities, including 1) Ca(2+)-calmodulin (CaM) mediated protein kinase II (CaMKII) activation, 2) activation of transcription factors such as myocyte enhancer factor-2 (MEF-2) and nuclear factor kappaB (NF kappaB), and 3) increased production of chromogranins, natriuretic peptides, and growth factors, which eventually lead to pathological hypertrophy. Although secretory granules function as the major IP3-sensitive intracellular Ca(2+) store and the IP3-mediated Ca(2+) release from secretory granules in cardiomyocytes contributes to secretion of chromogranins and natriuretic peptides, the direct cause of pathological hypertrophy appears to be due to the IP3-induced Ca(2+) release from the small nucleoplasmic IP3-sensitive Ca(2+) store vesicles, thereby initiating the Ca(2+)-activated nuclear activities that lead to formation of more secretory granules, pathologic enlargement of cardiomyocytes, and heart failure. PMID- 22834798 TI - Cardioprotection against ischemia/reperfusion injury and chromogranin A-derived peptides. AB - Chromogranin A (CgA) is produced by cells of the sympathoadrenal system and by human ventricular myocardium. In the clinical setting CgA has been mainly used as a marker of neuroendocrine tumors, but in the last decade a plenty of data have been published on the role of CgA and its derived peptides, particularly catestatin and vasostatin, in the regulation of cardiovascular function and diseases, including heart failure and hypertension. CgA-derived peptides, namely catestatin and vasostatin, may exert negative inotropic and lusitropic effects on mammalian hearts. As such CgA and its derived peptides may be regarded as mediators of a complex feedback system able to modulate the exaggerated release of catecholamines. This system may be also interpreted as an attempt for compensatory cardioprotective response against myocardial injury in the pre and postischemic scenarios. In fact, while vasostatin can trigger cardioprotective effects akin ischemic preconditioning (protection is triggered before ischemia), catestatin is a potent cardioprotective agent in the early post-ischemic phase, acting like a postconditioning agent (protection is triggered at the onset of reperfusion). Admittedly, the exact mechanism of cardioprotection of this system is far from being fully understood. Interestingly, both vasostatin and catestatin have shown to be able to activate multiple cardioprotective pathways. In particular, these two CgA-derived peptides may induce nitric oxide dependent pathway, which may play a pivotal role in cardioprotection against ischemia/reperfusion injury. Here, we review the literature about the cardiac effects of catestatin and vasostatin, the mechanisms of myocardial injury and protection and the role of CgA derived peptides in cardioprotection. PMID- 22834799 TI - Serpinins: role in granule biogenesis, inhibition of cell death and cardiac function. AB - Serpinins are a family of peptides derived from proteolytic cleavage of the penultimate and the last pair of basic residues at the C-terminus of Chromogranin A. Three forms of naturally occurring serpinin have been found in AtT-20 pituitary cells and rat heart. They are serpinin, pyrogutaminated (pGlu) serpinin and a C-terminally extended form, serpinin-RRG. In addition pGlu serpinin has been found in brain, primarily in neurites and nerve terminals and shown to have protective effects against oxidative stress on neurons and pituitary cells. Serpinin has also been demonstrated to regulate granule biogenesis in endocrine cells by up-regulating the protease inhibitor, protease nexin-1 transcription via a cAMP-PKA-sp1 pathway. This leads to inhibition of granule protein degradation in the Golgi complex which in turn promotes granule formation. More recently, pGlu-serpinin has been demonstrated to enhance both myocardial contractility (inotropy) and relaxation (lusitropy). In the Langendorff perfused rat heart, pGlu-serpinin showed a concentration-dependent positive inotropic effect exerted through a cAMP-PKA dependent pathway. In conclusion, the serpinin peptides have profound effects at many levels that affect the endocrine and nervous systems and cardiac function. PMID- 22834800 TI - Brain excitatory/inhibitory circuits cross-talking with chromogranin A during hypertensive and hibernating states. AB - To date, many scientific attempts have been directed towards the development of experimental models for the identification of neuronal mechanisms evoking cardiovascular and hemodynamic dysfunctions. The spontaneously hypertensive rat (SHR), a genetic model of essential hypertension, has become a valuable rodent for the characterization of molecular markers in hypertensive-related diseases. Recently, growing interests have also been directed to a new experimental paradigm i.e. hibernation, a physiological state consenting the hamster (Mesocricetus auratus) to activate protective mechanisms against ischemic-like complications during the arousal phase. With this intention, the present review will focus attention on specific neurosignaling systems involved with the preservation of hemodynamic conditions in those brain areas that play a pivotal role on such a feature. It is widely known that healthy neurons conserve their structural and responsiveness properties in presence of a constant blood supply, which is assured by their coupling to microvessels and perivascular astrocytes as well as by secretory proteins such as chromogranin A (CgA). So, it will be interesting to establish if this protein alone or with the participation of excitatory/inhibitory neurosignals is capable of influencing some brain areas controlling cardiovascular conditions in both SHRs and hibernating hamsters. In this context, the present work will deliver the most important findings regarding neuronal CgA and its cross-talking ability with major inhibitory (GABA/adenosine) and/or excitatory (glutamate) neuroreceptor systems in relation to hypertensive/hypotensive states of both animal models. Indications deriving from such approaches may provide clinically useful insights regarding their role as protective factors of hemodynamic and neurological disorders. PMID- 22834801 TI - Chromogranin A-derived peptides are involved in innate immunity. AB - New endogenous antimicrobial peptides (AMPs) derived from chromogranin A (CgA) are secreted by nervous, endocrine and immune cells during stress. They display antimicrobial activities by lytic effects at micromolar range using a pore forming mechanism against Gram-positive bacteria, filamentous fungi and yeasts. These AMPs can also penetrate quickly into neutrophils (without lytic effects), where, similarly to "cell penetrating peptides", they interact with cytoplasmic calmodulin, and induce calcium influx via Store Operated Channels therefore triggering neutrophils activation. Staphylococcus aureus and Salmonella enteritis are bacteria responsible for severe infections. We investigated here the effects of S. aureus and S. enteritis bacterial proteases on CgA-derived peptides and evaluated their antimicrobial activities. We showed that the Glu-C protease produced by S. aureus V8 induces the loss of the AMPs antibacterial activities and produces new antifungal peptides. In addition, four antimicrobial CGA-derived peptides (chromofungin, procatestatin, human/bovine catestatin) are degraded when treated with bacterial supernatants from S. aureus and S. enteritis, whereas, cateslytin, the short active form of catestatin, resists to this degradation. Finally, we demonstrate that several antimicrobial CgA-derived peptides are able to act synergistically with antibiotics against bacteria and fungi indicating their roles in innate defense. PMID- 22834802 TI - Synchronous resection of the primary tumour and liver metastases? PMID- 22834803 TI - Commentary: Fast track surgery: the need for improved study design. PMID- 22834804 TI - This paper is about a rather small colorectal unit trying to come to grips with the frustration produced by the discrepancy between their perceived performance and NBOCAP performance. PMID- 22834807 TI - Physical health symptoms reported by trafficked women receiving post-trafficking support in Moldova: prevalence, severity and associated factors. AB - BACKGROUND: Many trafficked people suffer high levels of physical, sexual and psychological abuse. Yet, there has been limited research on the physical health problems associated with human trafficking or how the health needs of women in post-trafficking support settings vary according to socio-demographic or trafficking characteristics. METHODS: We analysed the prevalence and severity of 15 health symptoms reported by 120 trafficked women who had returned to Moldova between December 2007 and December 2008 and were registered with the International Organisation for Migration Assistance and Protection Programme. Women had returned to Moldova an average of 5.9 months prior to interview (range 2-12 months). RESULTS: Headaches (61.7%), stomach pain (60.9%), memory problems (44.2%), back pain (42.5%), loss of appetite (35%), and tooth pain (35%) were amongst the most commonly reported symptoms amongst both women trafficked for sexual exploitation and women trafficked for labour exploitation. The prevalence of headache and memory problems was strongly associated with duration of exploitation. CONCLUSIONS: Trafficked women who register for post-trafficking support services after returning to their country of origin are likely to have long-term physical and dental health needs and should be provided with access to comprehensive medical services. Health problems among women who register for post trafficking support services after returning to their country of origin are not limited to women trafficked for sexual exploitation but are also experienced by victims of labour exploitation. PMID- 22834808 TI - Spatial heterogeneity and kinetic regulation of arsenic dynamics in mangrove sediments: the Sundarbans, Bangladesh. AB - The biogeochemistry of arsenic (As) in sediments is regulated by multiple factors such as particle size, dissolved organic matter (DOM), iron mobilization, and sediment binding characteristics, among others. Understanding the heterogeneity of factors affecting As deposition and the kinetics of mobilization, both horizontally and vertically, across sediment depositional environments was investigated in Sundarban mangrove ecosystems, Bengal Delta, Bangladesh. Sediment cores were collected from 3 different Sundarbans locations and As concentration down the profiles were found to be more associated with elevated Fe and Mn than with organic matter (OM). At one site chosen for field monitoring, sediment cores, pore and surface water, and in situ diffusive gradients in thin films (DGT) measurements (which were used to model As sediment pore-water concentrations and resupply from the solid phase) were sampled from four different subhabitats. Coarse-textured riverbank sediment porewaters were high in As, but with a limited resupply of As from the solid phase compared to fine textured and high organic matter content forest floor sediments, where porewater As was low, but with much higher As resupply. Depositional environment (overbank verses forest floor) and biological activity (input of OM from forest biomass) considerably affected As dynamics over very short spatial distances in the mosaic of microhabitats that constitute a mangrove ecosystem. PMID- 22834809 TI - A severe familial phenotype of Ichthyosis Curth-Macklin caused by a novel mutation in the KRT1 gene. PMID- 22834810 TI - Experimental study of the effects of DNAPL distribution on mass rebound. AB - The release of stored dissolved contaminants from low permeability zones contributes to plume persistence beyond the time when dense nonaqueous phase liquid (DNAPL) has completely dissolved. This is fundamental to successfully meeting acceptable low concentrations in groundwater that are driven by site specific cleanup goals. The study goals were to assess the role of DNAPL entrapment morphology on mass storage and plume longevity. As controlled field studies are not feasible, two-dimensional (2D) test tanks were used to quantify the significance of mass loading processes from source dissolution and stored mass rebound. A simple two-layer soil domain representing a high permeable formation sand overlying a zone of lower permeability sand was used in the tests. DNAPL mass depletion through dissolution was monitored via X-ray photon attenuation, and effluent samples were used to monitor the plume. These data enabled analysis of the DNAPL distribution, the dissolved plume, and the dissolved phase distribution within the low permeability layer. Tests in an intermediate tank showed that mass storage contributes substantially to plume longevity. Detectable effluent concentrations persisted long after DNAPL depletion. The small tank results indicated that the DNAPL morphology influenced the flow field and caused distinctive transport mechanisms contributing to mass storage. Zones of high DNAPL saturation at the interface between the low and high permeability layers exhibited flow bypassing and diffusion dominated transport into the low permeability layer. In the absence of a highly saturated DNAPL zone near the soil interface the contaminant penetrated deeper into the low permeability layer caused by a combination of advection and diffusion. PMID- 22834811 TI - QSAR studies of PTP1B inhibitors: recent advances and perspectives. AB - Diabetes mellitus, a chronic condition caused by defects in insulin secretion, or action, or both, is a group of metabolic disorders, complications of which can contribute significantly to ill health, disability, poor quality of life and premature death. From the three main types of diabetes, Type 2 is by far the most common, accounting for about 90% of cases worldwide. Studies on the role of protein tyrosine phosphatase 1B (PTP1B) have clearly shown that it serves as a key negative regulator of insulin signaling and is involved in the insulin resistance associated with Type 2 diabetes. The present work aims to survey information related to PTP1B research published in the last decade. Emphasis is laid particularly on Quantitative Structure-Activity Relationships (QSAR) based studies that supported so far the design of new, potent and selective PTP1B inhibitors. Finally, the challenges and perspectives of QSAR studies in this field are discussed to show how these method can be used to design new chemical entities with enhanced PTP1B inhibition activity. PMID- 22834812 TI - Anti-tumor monoclonal antibodies in conjunction with beta-glucans: a novel anti cancer immunotherapy. AB - Monoclonal antibodies (mAbs) have greatly advanced the field of anti-cancer immunotherapy and have made a major impact in clinical medicine. While more mAbs have been approved by the FDA and entered into the clinical therapeutic arena with indications to treat various solid tumors and hematologic malignancies, extensive efforts have also been made to make mAb therapy more effective. Combination therapy of anti-tumor mAbs with chemotherapeutic drugs has been widely used in the clinical patient care. In addition, many immune stimulating agents have been specifically studied for this very purpose. One compound in particular, beta-glucan, has shown very promising and exciting results in pre clinical animal models and early phase human clinical trials. beta-Glucans are naturally occurring, abundant polysaccharides with different structures that can be extracted and purified from fungi, bacteria, oats and barley. The active components of yeast-derived beta-glucan exert their unique immune stimulating functions by binding specifically to complement receptor 3 (CR3) via lectin-like domain (LLD) and activating CR3 to promote cellular cytotoxicity of iC3b-coated cancer cells. In addition, particulate yeast-derived beta-glucan stimulates both innate and adaptive anti-tumor immune responses. This review covers the anti cancer mechanisms of anti-tumor mAbs and beta-glucans, the pre-clinical studies done with beta-glucans in conjunction with anti-tumor mAbs in human carcinoma xenograft models, and the preliminary results of human clinical trials with different beta-glucans, as well as those of phase I/II and III studies using the combination of yeast-derived soluble beta-glucan and anti-tumor mAbs. PMID- 22834813 TI - Innovative lead compounds and formulation strategies as newer kinetoplastid therapies. AB - The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B (AmBisome(r)) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia. PMID- 22834814 TI - Cellular based cancer vaccines: type 1 polarization of dendritic cells. AB - Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor-associated antigens introduced to dendritic cells (DCs) generated in vitro. This may in part result from suboptimal maturation of DCs leading to insufficient production of IL-12, a key driver of cellular immunity. Therefore, tremendous efforts have been put into the design of maturation cocktails that are able to induce IL-12 secreting type 1 polarized DCs mimicing pathogen-derived molecular activation of DCs. Correct timing and potential synergisms of clinical-grade toll-like receptor ligands, interferons (IFN) and CD40L enhance IL-12 production in DCs. However, cytokine exhaustion, predominant expression of tolerogenic molecules and activation induced dendritic cell death should be avoided. Thus, compounds such as IFN-gamma may initially induce immunity but later on tolerance. Maturation with PGE(2) obviously promotes migration via expression of CCR7 but on the down side PGE(2) limits the production of IL-12 especially following encounter with CD40L expressing cells and furthermore, PGE(2) imprints DCs for preferential interaction with tolerogenic T cells. In addition, type 1 polarized DCs matured without PGE(2) also seem to be capable of migrating in vivo, although concomitant production of CCL19 seems to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines. PMID- 22834815 TI - Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis. AB - BACKGROUND: Inflammatory bowel disease is a chronic and idiopathic gastrointestinal inflammation mediated by disregulated immune responses. Artemisinin (a chemical from a traditional Chinese herbal medicine Artemisia annua L.) and its derivatives have been proven to exhibit anti-inflammatory and immunomodulatory effects in the treatment of systemic lupus erythematosus and rheumatoid arthritis with low side-effects. This study is aimed to evaluate the potential therapeutic value of artesunate for inflammatory bowel disease. METHODS: Murine colitis was induced by either oral administration of dextran sulfate sodium salt (DSS) or intrarectal delivery of 2,4,6- trinitrobenzene sulfonic acid (TNBS) or oxazolone. Mice were treated with artesunate (150mg/kg/day). Peritoneal macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of artesunate. Changes in cytokines or proteins of interests were analyzed by enzyme-linked immunosorbent assay (ELISA) or SDS PAGE/Western blot. RESULTS: Artesunate significantly ameliorated DSS colitis and TNBS colitis (but not oxazolone colitis), including reduced weight loss and disease activity, as well as macroscopic and microscopic colonic injury. The expression of NF-kappaBp65 and p-IkappaB-alpha were reduced in artesunate treated TNBS colitis compared with untreated. The levels of IFN-gamma, IL-17, and TNF alpha were significantly decreased in artesunate treated TNBS colitis or DSS colitis. Furthermore, in vitro artesunate treatment significantly inhibited TNF alpha production by LPS-activated macrophages. CONCLUSIONS: Artesunate suppresses TNF-alpha expression in vitro and in vivo as well as T-helper (Th)1/Th17 responses in TNBS colitis model. Our data suggest a novel clinical application of artesunate as a potential therapy for Crohn's disease. PMID- 22834816 TI - Modulation of poly(A)-specific ribonuclease (PARN): current knowledge and perspectives. AB - Deadenylation is the exoribonucleolytic shortening of eukaryotic poly(A) tails. It is often the first and rate-limiting step for mRNA decay and translational silencing. The process is catalysed by a diversity of deadenylases, which provide robust and flexible means to control mRNA levels and gene expression. Poly(A) specific ribonuclease (PARN) is a major mammalian deadenylase and the only known to concurrently bind the 5' cap-structure and the 3' poly(A), thus enhancing the degradation rate and amplifying its processivity. PARN is important during oocyte maturation, embryogenesis, early development, DNA damage, and in cell-cycle progression, but also in processes beyond mRNA metabolism, such as the maturation of snoRNAs. The enzyme also participates in nonsense-mediated mRNA decay and in the regulation of cytoplasmic polyadenylation. Importantly, PARN is involved in the degradation of several cancer-related genes, while its expression is altered in cancer. Apart from the direct interaction with the cap structure, several strategies regulate PARN activity, such as phosphorylation, interaction with RNA binding proteins (RBPs), and natural nucleotides. Recent studies have focused on the regulation of its activity by synthetic nucleoside analogues with therapeutic potential. In this context, the wide repertoire of RBPs and molecules that regulate PARN activity, together with the established role of deadenylases in miRNA-mediated regulation of mRNA expression, suggest that mRNA turnover is more complex than it was previously thought and PARN holds a key role in this process. In this review, we highlight the importance of PARN during RNA's lifecycle and discuss clinical perspectives of modulating its activity. PMID- 22834817 TI - Non-viral engineering of skin precursor-derived Schwann cells for enhanced NT-3 production in adherent and microcarrier culture. AB - Genetic engineering of stem cells and their derivatives has the potential to enhance their regenerative capabilities. Here, dendrimer- and lipofection-based approaches were used for non-viral neurotrophin-3 (NT-3) over-expression in Schwann cells differentiated from skin precursors (SKP-SCs). A variety of dendrimers were first tested for transfection efficiency on HEK 293T cells, with PAMAMNH2 G4 found most effective and used subsequently for SKP-SCs transfection. Plasmid-based expression resulted in increased NT-3 release from SKP-SCs in both adherent and microcarrier-based culture. In a proof-of-concept study, the microcarrier/SKP-SCs were implanted into the injured nerve, and transfected cells were shown to detach, integrate into the nerve tissue and associate with regenerating axons. Virus-free systems for transient neurotrophin expression are a feasible and biologically safe option to increase the therapeutic value of stem cells and stem cell-derived cells in nerve repair strategies. Further work to develop bioprocesses for expansion of SKP-SCs on microcarriers in bioreactors is still needed. PMID- 22834818 TI - Highly organized self-assembled dendriplexes based on poly(propylene imine) glycodendrimer and anti-HIV oligodeoxynucleotides. AB - Dendrimers are artificial polymeric macromolecules which are widely considered to be a promising tool for future gene therapy applications. They have been used as efficient delivery vehicles for antisense oligonucleotides targeting the interior of cells. We demonstrate that dendriplexes formed from anti-HIV oligodeoxynucleotides ANTI-TAR, GEM91, and SREV in complex with generation 4 maltose (PPI-Mal G4) and maltotriose (PPI-Mal-III G4) modified poly(propylene imine) dendrimers are able to self-assemble into highly organized 1D and 3D nanostructures. The resulting nanostructures were characterized by fluorescence methods, laser Doppler electrophoresis, dynamic light scattering (DLS), atomic force microscopy (AFM) and molecular modeling. The results show that ANTI-TAR and GEM 91 dendriplexes self-assemble into fibrils with length scales up to several hundreds of nm. SREV, on the contrary, forms quadrilateral- like 3D nanostructures. A good correlation between the various experimental methods and molecular modeling indicates the formation of those nanostructures in solution. Space symmetry of the oligonucleotides and the resulting dendriplex monomeric units are probably the most important factors which influence the way of self assembling. PMID- 22834819 TI - Kinetics of amyloid and prion fibril formation in the absence and presence of dense shell sugar-decorated dendrimers. AB - The aggregation behavior of the amyloid peptide Abeta(1-28) and the prion peptide PrP(185-208) - both responsible for neurodegenerative disorders - was analyzed in the absence and in the presence of poly(propylene imine) (PPI) dendrimers at generation 5 (G5) with a dense shell of maltose and maltotriose units. Thioflavin T (ThT) fluorescence assay and circular dichroism (CD) experiments indicated that fibril formation is enhanced at low dendrimer concentration, while it is prevented at relatively high dendrimer concentrations. Computer aided EPR analysis by means of the selected spin probe 4-octyl-dimethylammonium,2,2,6,6 tetramethyl-piperidine-1-oxyl bromide (CAT8) further demonstrated this behavior, but also provided detailed information on the mechanism of fibril formation and on the different behavior of the differently decorated dendrimers. The CAT8 radicals were progressively trapped at the peptide interphase when peptide aggregates were formed, also monitoring pre-fibrillar structures. At later time, a phase separation of the CAT8 radicals monitors the formation of further supramolecular structures where the probes become squeezed among fibrillar aggregates. The addition of small amounts of dendrimers promotes the formation of peptide fibrils breaking them and providing a larger amount of ends that serve as sites of replications. Conversely, a high amount of dendrimers allows the peptides to well separate from each other such preventing their aggregation. EPR results also indicate that the perturbation played by PPI(G5)-Maltose are more effective onto PrP(185-208) than onto Abeta(1-28), while PPI(G5)-Maltotriose is less effective towards PrP(185-208) in both promoting aggregation and preventing it by changing the dendrimer concentration. These results provide useful information about the mechanism and interactions which regulate the ability of macromolecules like the dendrimers to favor, prevent or cure neurodegenerative diseases. PMID- 22834820 TI - L-type voltage-dependent calcium channels as therapeutic targets for neurodegenerative diseases. AB - Ca(2+) is a highly versatile intracellular second messenger in the central nervous system, and regulates many complicated cellular processes, including excitation, plasticity and apoptosis. Influx of Ca(2+) from the extracellular fluid is required for sustained elevation of the cytosolic Ca(2+) concentration and full activation of Ca(2+)-dependent processes. Voltage-dependent Ca(2+) channels (VDCCs) serve as the principal routes of Ca(2+) entry into electrically excitable cells such as neurons. The nervous system expresses VDCCs with unique cellular and subcellular distribution and specific functions. L-type voltage dependent Ca(2+) channels (L-VDCCs) are distributed at neuronal cell bodies, dendrites and spines, and the postsynaptic L-VDCCs regulate neuronal excitability and gene expression. Presynaptic P/Qand N-type VDCCs trigger neurotransmitter release, and T-type channels support neuronal rhythmic burst firing. Evidence from natural mutants, knockout mice, and human genetic disorders indicates a fundamental role of some VDCCs in a wide variety of neurological disorders, including vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD) and Prion disease. Amyloid beta peptides, causative factors for AD, potentiate the influx of Ca(2+) into neurons via L-VDCCs. L-VDCCs blockers prevent neurons from undergoing amyloid beta-induced apoptosis. The present review highlights some recent findings on biochemical characterizations, physiological functions, pathological roles and pharmacological applications of the L-VDCCs and their implication in neurologic diseases. PMID- 22834821 TI - Lipid-based nanocarriers as an alternative for oral delivery of poorly water- soluble drugs: peroral and mucosal routes. AB - The hydrophobic character of most drug molecules and their potential for degradation under the hostile environment of the gastrointestinal tract (GIT) constitutes the main obstacle in the development of a successful oral drug delivery system, since these are related to limitations of bioavailability and absorption processes. However, according to the advantages of the oral route, alternative ways of drug administration in the oral cavity should be considered. In this context, it is essential to have a systematic knowledge of the GIT and the oral cavity components, for a better understanding of the processes taking place during the oral administration of drugs. This review gives an overview of those anatomical and physiological features and elucidates about the current approaches employed to enhance the bioavailability of oral poorly water-soluble drugs. Strategies including the uses of lipid-based nanocarriers, such as nanoemulsions, liposomes and lipid nanoparticles are discussed, considering their ability to improve solubility, dissolution kinetics, absorption and, consequently, biopharmaceutical properties. Some toxicological concerns are also highlighted. PMID- 22834822 TI - Polymer nanoparticles--a novel strategy for administration of Paclitaxel in cancer chemotherapy. AB - The main challenge encountered while treating using Paclitaxel (PTX) is its poor solubility in aqueous solutions. The cremophor used in the formulation can cause various side effects such as hypersensitivity, myelosuppression and neurotoxicity and also leads to non-specific distribution in tumor and normal tissues. Since the structure of Paclitaxel does not possess a functional group, it is not easy to manipulate to enhance the solubility. Such limitations can be overcome by delivering Paclitaxel with the aid of drug delivery systems such as polymeric micelles, nanoparticles, hydrogels and liposomes. The review discusses various approaches of Paclitaxel delivery via polymeric nanoparticles. It focuses on the passive and active targeting of Paclitaxel. PMID- 22834823 TI - Analogous effects of recombinant human full-length amelogenin expressed by Pichia pastoris yeast and enamel matrix derivative in vitro. AB - OBJECTIVES: Amelogenins are proposed to be responsible for enamel matrix derivative (EMD)-induced periodontal regeneration; however, heterogeneity of amelogenins makes it challenging to purify the full-length proteins. This study has been carried out to express and purify a recombinant full-length human amelogenin protein (rHhAm175) in the eukaryotic yeast Pichia pastoris, and further compare biological responses of human periodontal ligament fibroblasts (PDLFs) to rHhAm175 and porcine EMD (pEMD). MATERIALS AND METHODS: Human cDNA encoding a 175-amino acid amelogenin was subcloned into the pPIC3.5K vector. The rHhAm175 expressed in P. pastoris GS115 (Mut+) was purified and characterized. We examined cell attachment, migration and proliferation responses of human PDLFs to rHhAm175 and pEMD respectively, and characterized associated changes of proliferation-related intracellular signalling molecules, including extracellular signal response kinase (ERK) and Akt kinases/protein kinase B (Akt/PKB) kinases. RESULTS: The purified rHhAm175 was confirmed to be molecular mass 22 021.13 Da, phosphorylated human amelogenin, and alone significantly promoted proliferation and migration of human PDLFs to an extent comparable to that of pEMD. Cell attachment was increased over the first 60 min incubation with rHhAm175 or pEMD. Both rHhAm175 and pEMD induced PDLF mitogenesis via extracellular signal response kinase (ERK1/2), but not by Akt kinases/protein kinase B (Akt/PKB). CONCLUSIONS: rHhAm175 modulated cell activities of human PDLFs, to a comparable extent as porcine EMD. These data suggest that rHhAm175 might be used to induce periodontal tissue regeneration. PMID- 22834824 TI - Interface of nanoparticle-coated electropolished stents. AB - Nanostructures entail a high potential for improving implant surfaces, for instance, in stent applications. The electrophoretic deposition of laser generated colloidal nanoparticles is an appropriate tool for creating large-area nanostructures on surfaces. Until now, the bonding and characteristics of the interface between deposited nanoparticles and the substrate surface has not been known. It is investigated using X-ray photoelectron spectroscopy, Auger electron spectroscopy, and transmission electron microscopy to characterize an electropolished NiTi stent surface coated by laser-generated Au and Ti nanoparticles. The deposition of elemental Au and Ti nanoparticles is observed on the total 3D surface. Ti-coated samples are composed of Ti oxide and Ti carbide because of nanoparticle fabrication and the coating process carried out in 2 propanol. The interface between nanoparticles and the electropolished surface consists of a smooth, monotone elemental depth profile. The interface depth is higher for the Ti nanoparticle coating than for the Au nanoparticle coating. This smooth depth gradient of Ti across the coating-substrate intersection and the thicker interface layer indicate the hard bonding of Ti-based nanoparticles on the surface. Accordingly, electron microscopy reveals nanoparticles adsorbed on the surface without any sorption-blocking intermediate layer. The physicomechanical stability of the bond may benefit from such smooth depth gradients and direct, ligand-free contact. This would potentially increase the coating stability during stent application. PMID- 22834825 TI - Molecular targets of FTY720 (fingolimod). AB - FTY720 is a recently approved first line therapy for relapsing forms of multiple sclerosis. In this context, FTY720 is a pro-drug, with its anti-multiple sclerosis, immunosuppressive effects largely elicited following its phosphorylation by sphingosine kinase 2 and subsequent modulation of G protein coupled sphingosine 1-phosphate (S1P) receptor 1 that induces lymphopenia by altering lymphocyte trafficking. A number of other biological effects of FTY720 have, however, been described, including considerable evidence that this drug also has anti-cancer properties. These other effects of FTY720 are independent of S1P receptors, and appear facilitated by modulation of a range of other recently described protein targets by nonphosphorylated FTY720. Here, we review the direct targets of FTY720 that contribute to its anti-cancer properties. We also discuss other recently described protein effectors that, in combination with S1P receptors, appear to contribute to its immunosuppressive effects. PMID- 22834826 TI - Fibroblast activation protein in remodeling tissues. AB - Tissue remodeling is critical during development and wound healing. It also characterizes a number of pathologic conditions, including chronic inflammation, fibrosis and cancer. It is well appreciated that reactive stromal cells play critical roles in these settings. However, understanding of the mechanisms involved in the differentiation of reactive stromal cells and their biologic activities has been hampered by the fact that they are generated from diverse progenitors, and by their phenotypic and function heterogeneity. Furthermore, molecular markers that are expressed by all reactive stromal cells and that distinguish them from all other cell types have been lacking. Fibroblast activation protein (FAP) is a serine protease that was originally discovered as a cell surface protein expressed on astrocytomas and sarcomas. Over the last two decades, FAP has attracted increasing attention as a selective marker of carcinoma-associated fibroblasts (CAFs) and more broadly, of activated fibroblasts in tissues undergoing remodeling of their extracellular matrix (ECM) due to chronic inflammation, fibrosis or wound healing. Herein we review the evidence that FAP is indeed a robust and selective marker for reactive mesenchymal stromal cells associated with pathophysiologic tissue remodeling. We also review recent insights obtained using FAP as a tool to define the relationship between subpopulations of reactive stromal cells in various settings of tissue remodeling. Furthermore, we review recent genetic and pharmacologic data indicating that FAP and FAP-expressing cells play important roles in such conditions. Finally, we discuss the potential risks and therapeutic benefits of targeting FAP and FAP-expressing cells, as well as approaches to do so. PMID- 22834828 TI - Adult neurogenesis in the olfactory system and neurodegenerative disease. AB - The olfactory system is unique in many respects-two of which include the process of adult neurogenesis which continually supplies it with newborn neurons, and the fact that neurodegenerative diseases are often accompanied by a loss of smell. A link between these two phenomena has been hypothesized, but recent evidence for the lack of robust adult neurogenesis in the human olfactory system calls into question this hypothesis. Nevertheless, model organisms continue to play a critical role in the exploration of neurodegenerative disease. In part one of this review we discuss the most promising recent technological advancements for studying adult neurogenesis in the murine olfactory system. Part two continues by looking at emerging evidence related to adult neurogenesis in neurodegenerative disease studied in model organisms and the differences between animal and human olfactory system adult neurogenesis. Hopefully, the careful application of advanced research methods to the study of neurodegenerative disease in model organisms, while taking into account the recently reported differences between the human and model organism olfactory system, will lead to a better understanding of the reasons for the susceptibility of olfaction to disease. PMID- 22834827 TI - Honokiol: a novel natural agent for cancer prevention and therapy. AB - Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,4'-diol) is a bioactive natural product derived from Magnolia spp. Recent studies have demonstrated anti inflammatory, anti-angiogenic, anti-oxidative and anticancer properties of honokiol in vitro and in preclinical models. Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-kappaB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR), which have great relevance during cancer initiation and progression. Furthermore, pharmacokinetic profile of honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials. In this review, we discuss recent data describing the molecular targets of honokiol and its anti-cancer activities against various malignancies in pre-clinical models. Evaluation of honokiol in clinical trials will be the next step towards its possible human applications. PMID- 22834829 TI - CREG: a possible candidate for both prevention and treatment of proliferative vascular disease. AB - Cellular repressor of E1A-stimulated genes (CREG), a novel cellular protein, was discovered in 1998. Accumulating evidence, mainly from our laboratory, has suggested that CREG plays critical roles in reducing neointimal hyperplasia, maintaining vascular homeostasis, and promoting endothelial restoration. The study of CREG has the potential to offer new insights into both prevention and treatment of proliferative vascular disease, and will help us understand the processes of vascular repair after injury. It will also contribute to the development of new therapeutic strategies and devices, such as anti-in-stent restenosis stents. The present review summarizes our research on the molecular identity of CREG, and reviews the biological activities of CREG in regulating cell differentiation, proliferation, migration, and apoptosis of vascular smooth muscle cells and endothelial cells. PMID- 22834831 TI - Role of pancreatic beta-cell death and cell death-associated inflammation in diabetes. AB - Pancreatic beta-cell death of various types has diverse and important roles in the pathogenesis of both type 1 (T1D) and type 2 (T2D) diabetes. The most widely recognized types of beta-cell death in diabetes are apoptosis (type 1 programmed cell death) and necrosis. Apoptosis of beta-cells is the key and final step in the development of T1D and contributes to beta-cell failure or dysfunction in T2D. In the course of natural T1D, apoptotic beta-cells undergoing secondary necrosis probably due to their defective clearance by phagocytes, may be involved in the initiation and development of the disease. Recently, autophagy (type 2 programmed cell death) is proposed as a third type of cell death and is being recognized as having certain roles in the prevention and execution of beta-cell death, depending on the cellular context. Moreover, as dying beta-cells are routinely exposed to the immune system, beta-cell death could also affect the development of diabetes through regulation of inflammation or immune response. In this review, we describe the role of various types of pancreatic beta-cell death in the development of T1D and T2D. We also discuss the role of dying beta-cells in the control of inflammation which contributes to the pathogenesis of diabetes. PMID- 22834830 TI - Therapeutic hypothermia as a neuroprotective strategy in neonatal hypoxic ischemic brain injury and traumatic brain injury. AB - Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury. PMID- 22834832 TI - Recent progress in gene therapy for Parkinson's disease. AB - Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD. PMID- 22834833 TI - Transient receptor potential channels in human platelets: expression and functional role. AB - Recent studies have demonstrated that mammalian homologues of Drosophila transient receptor potential (TRP) channels are widely expressed in human platelets. Occupation of G protein-coupled receptors by agonists results in activation of these channels, which results in Na+ and Ca2+ entry. Canonical or classic TRP (TRPC) family members have been reported to associate with different Ca2+-handling proteins, including the type II inositol 1,4,5-trisphosphate receptor, the endoplasmic reticulum Ca2+ sensor STIM1 (STromal Interaction Molecule-1) or the Ca2+ permeable channel Orai1. The dynamic interaction of TRPC channels with the above mentioned proteins has been found to be important for both store-operated and capacitative Ca2+ entry, as well as for non-capacitative Ca2+ influx. The former is a major mechanism for Ca2+ entry in human platelets. This mechanism, activated by a reduction in the concentration of free Ca2+ in the intracellular stores, results in the formation of signaling complexes involving STIM proteins, Orai1, Orai2, TRPC1 and TRPC6. There is a growing body of evidence supporting that Ca2+ signaling dysfunction plays an important role in the pathogenesis of several platelet-linked disorders, including those associated to type 2 diabetes mellitus. Abnormal Ca2+ signals in response to physiological agonists have been associated to platelet hyperactivity. The expression of several TRPCs, STIM1 and Orai1, as well as their interaction, has been reported to be altered in platelets from type 2 diabetic patients, which results in attenuated capacitative Ca2+ entry but enhanced non-capacitative Ca2+ influx; thus suggesting a role for Ca2+ handling proteins, including TRPs, in the pathomechanism of diabetic complications. PMID- 22834834 TI - Polymeric nanomedicines as a promising vehicle for solid tumor therapy and targeting. AB - Inspite of demanding research that has been undertaken for cancer treatment, cancer is a major cause of mortality. Available conventional treatment options of solid tumor are associated with serious side effects. Nanomedicines mediated fascinating approach may be effectively utilized for efficient tumor targeting by avoiding all the problems associated with conventional chemotherapy. Polymeric nanomedicines such as polymer micelles, polymeric nanoparticles, polymersomes and polymer conjugates currently developed for solid tumor treatment have proved to be efficacious cancer therapeutics. These polymeric nanostructures are able to reach tumor tissue or angiogenic endothelial cells either passively or actively. To date, more advancement in the tumor targeting field includes stimuli sensitive polymeric nanocarriers that pass through the intracellular delivery barriers and release the bioactives in response to the microenvironmental trigger of tumor cell. This review discusses the molecular aspects of solid tumor pathophysiology and its dramatic impact on research for innovative and novel therapeutic approaches linked with tumor-targeting polymeric nanomedicines. PMID- 22834836 TI - Tumor-derived microvesicles and the cancer microenvironment. AB - Tumor cells release microvesicles (MVs) that may remain in the extracellular space in proximity to the cell of origin, or that may migrate to distant sites by entering biological fluids. Increasing evidence indicates that MVs are mediators of cell-to-cell communication which are able to deliver specific signals, both within the tumor microenvironment and in the long-range. MVs are able to transfer bioactive lipids and proteins, including oncogene products and receptors, from the cell of origin to recipient cell. In addition, MVs may induce epigenetic changes in recipient cells by transferring genetic information in the form of mRNA, microRNA and oncogenes. Several changes in the phenotype and function that occur in stromal cells within the cancer microenvironment have been ascribed to tumor cell-derived MVs. In this review we discuss the various biological actions of tumor-derived MVs and their potential role in tumor biology. PMID- 22834837 TI - The Tribbles-1 protein in humans: roles and functions in health and disease. AB - This review describes the key role of the serine-threonine kinase like protein Tribbles-1 in health as well as in diverse human pathologies. Tribbles-1 is a homolog protein of the Drosophila Tribbles. In Drosophila, the Tribbles protein is involved in the cell-cycle progression during mitosis and in mammals initial data showed TRIB1 to be involved in cell proliferation. In mammals, TRIB1 lacks a catalytic domain and thus acts as an adaptor protein by interacting with several partners. The activity of TRIB1 seems to be very specific to the environment and the cells type in which it is expressed, and a role for this molecule has been mainly described in several pathological states including various cancers such as acute myeloid leukemia and ovarian cancer. Further evidence has also linked TRIB1 to the control of plasmalipid homeostasis thus indicating the role of this molecule as a risk factor for myocardial infarction. Finally, TRIB1 is shown to be up-regulated during inflammatory events such as chronic inflammation of atherosclerotic arteries or chronic antibody-mediated rejection of transplanted organs. Here we provide a review of the current state of the scientific literature for TRIB1, highlighting its role in diverse pathologies and inflammatory states. A better understanding of the role of this protein as both a target as well as a biological marker in diseases should drive the development of new therapeutic strategies. PMID- 22834838 TI - An integrated and disease-oriented growth factor-regulated signal transduction network. AB - The importance of Akt, Erk, and their downstream effectors-mediated signaling is indisputable for the proliferation of cell. Growth factor-induced activation of Akt and Erk pathways interacts with each other to regulate proliferation. However, an instructive model, wiring the crucial signaling nodes working in cellular growth and division, is still absent or controversial. Although growth factor-mediated mTORC1 regulation is defined considerably, debates still exist formTORC2. TSC1-TSC2 complex integrates both nutrient and mitogenic signals coming from growth factor receptors. Growth factor-induced PI3K/Akt- and Ras/Erk mediated TSC2 inhibition is well defined. However, the interaction between TSC complex and new molecules such as Pin1 and DAPK requires further clarifications. Furthermore, the Wnt-beta-catenin signaling pathway also intersects with the growth factor signaling at TSC1/TSC2 junction. Therefore, the aim of this perspective paper is to suggest an integrated model, linking growth factor activated crucial signaling nodes in order to supply key molecular connections to degenerative diseases. PMID- 22834839 TI - Current progress in stem cell research and its potential for islet cell transplantation. AB - Diabetes is characterized by insulin deficiency concomitant with hyperglycemia due to reduced islet cell mass and/or dysfunction. Currently, insulin replacement is the first-line treatment option for patients with type 1 and a severe form of type 2 diabetes. Treatment by insulin injection is generally effective but nonphysiological, and has the potential of producing chronic complications. On the other hand, islet transplantation can maintain normoglycemia without hypoglycemic side effects, potentially freeing diabetic patients of insulin dependence. In practice, islet transplantation remains hindered by the lack of organ donors and transplant rejection concerns. Recent advances in stem cell research and regenerative medicine, however, offer promise for the clinical application of islet cell transplantation. This review article offers a critical appraisal of current molecular induction approaches, such as directed differentiation, microenvironment induction, and genetic modification, which mimic islet cell development by inducing a variety of stem cells; they include embryonic stem cells, induced pluripotent stem cells, and various tissue-derived stem cells to become functional and transplantable insulin-producing islet cells. Despite good progress, several obstacles remain to be overcome before islet transplantation can be translated into a therapy for human patients, including, but are not limited to, immunogenicity and risk of tumorogenesis. PMID- 22834840 TI - First phase insulin secretion and type 2 diabetes. AB - Type 2 diabetes (T2D) is a metabolic disorder characterised by the inability of beta-cells to secrete enough insulin to maintain glucose homeostasis. Pancreatic beta-cells secrete insulin in a biphasic manner, first and second phase insulin secretion, and loss of first phase insulin secretion is an independent predictor of T2D onset. Restoration of first phase insulin secretion has been shown to improve blood glucose in T2D by suppressing hepatic glucose production and priming insulin sensitive tissue to more readily take up glucose and has thus prompted numerous studies into its regulation. First phase insulin secretion is initiated primarily by the classical triggering pathway, a complex system comprised of multiple stimulatory signals. Recent studies have identified a number of novel regulatory factors that are crucial for first phase insulin secretion and glucose homeostasis. These include, among others, hypoxia inducible factor 1alpha, von Hippel-Lindau, factor inhibiting HIF, nicotinamide phospho ribosyl-transferase, and the sirtuin family. This review will outline how first phase insulin secretion is initiated and detail some of the recent findings in its regulation. PMID- 22834841 TI - The influence of macrophages and the tumor microenvironment on natural killer cells. AB - Numerous reviews in the field of NK cell biology dictate the pivotal role that NK cells play in tumor rejection. Although these cell types were originally described based on their cytotoxic ability, we now know that NK cells are not naturally born to kill. Both cellular interactions and the local environment in which the NK cell resides in may influence its cytotoxic functions. Just as organ specific NK cells have distinct phenotypic and functional differences, the tumor is a unique microenvironment in itself. The NK cells originally recruited to the tumor site are able to stimulate immune responses and aid in tumor destruction but eventually become persuaded otherwise by mechanisms of immunosuppression. Here, we review potential mechanisms and players involved in NK cell immunosuppression. In particular the effects of another innate immune player, macrophages, will be addressed in augmenting immunosuppression of NK cells within tumors. Tumor-associated macrophages (TAMs) are the main regulatory population of myeloid cells in the tumor and are characterized by their ability to promote tumor cell proliferation and metastasis. In addition, they express/release immunoregulatory factors which have been shown to directly inhibit NK cell function. Understanding how these two cell types interact in the distinct tumor microenvironment will allow us to consider therapies that target TAMs to promote enhanced NK cell activity. PMID- 22834842 TI - Current and experimental antibody-based therapeutics: insights, breakthroughs, setbacks and future directions. AB - The premise of targeted therapy was born from an intimate understanding of the unique biological pathways and endpoints which are implicated in the development of different disease states and conditions. In addition, the identification of the most appropriate drugs to use for targeted drug therapy has aided in growing interest of the pharmaceutical industry to allocate more resources to monoclonal antibody (mAb) therapeutics. This being the case, it is important to understand antibody based therapeutics, some of the currently Food and Drug Administration (FDA)-approved mAbs in different disease states, as well as the future direction of mAb therapies. In this article, we will provide a critical overview, and discuss a selection of antibody based therapeutics, including their bioengineered structural and functional elements. Furthermore, a segment of the currently FDA approved mAb antibody therapies, those in research, or in investigation for disease states and conditions ranging from autoimmune disease, inflammatory response, immunosuppression, cancer, including antibody-drug conjugates, immunotherapy, and exciting prospects for antiplatelet and antithrombotic monoclonal antibody therapeutics will be reviewed. Finally, we will discuss our predictions and aspirations for the future directions of mAb-based therapeutic interventions. PMID- 22834843 TI - The cellular effects of carbon monoxide in the airway. AB - The notion of inhaled carbon monoxide (CO) being a toxic chemical under all circumstances is currently being challenged, as recent research has suggested that low concentrations of CO may have therapeutic value, especially in the airway. This review evaluates CO's effects on cellular functions that may result in beneficial outcomes in the settings of airway disease, inflammation, and injury. CO can modulate the stress response system of the cell by decreasing levels of reactive intermediates over time, produced by mitochondrial iNOS and NADPH oxidase. Intracellular stress-induced response factors (e.g., HIF-1 and HSP 70) are induced in response to CO, possibly facilitating more rapid and effective defenses, in response to subsequent stressors. CO also can trigger changes in cellular functions downstream, protecting the cells from stress associated events promoted in the airway, as a result of disease or injury, including reducing rates of apoptosis, proliferation, and inflammatory cellular infiltration, as well as preventing an imbalance in the extracellular matrix composition. CO has also been associated with maintaining homeostasis of ions essential for normal cellular functions (e.g., Na+, Fe2+,3+). CO also targets cell-specific functions of the airway, such as reduction of contractility of airway smooth muscle cells, and preservation of the innate defense mechanism of airway epithelial cells. Further understanding of CO's effects on fundamental cellular functions in the airway will likely hold significant value in future considerations of CO's role in airway therapy and health. PMID- 22834844 TI - Extranuclear localization of SIRT1 and PGC-1alpha: an insight into possible roles in diseases associated with mitochondrial dysfunction. AB - SIRT1 and PGC-1alpha are two nutrient sensing master regulators of cellular metabolism and their upregulation is often linked to increased lifespan. SIRT1 and PGC-1alpha modulate the expression of a set of nuclear genes controlling many metabolic pathways. In recent years mounting evidence has indicated the implication of these proteins in several mitochondrial diseases including neurodegenerative disorders, myopathies and Type II diabetes mellitus. Recently, these proteins have been localized in cytoplasm and mitochondria wherein they target novel substrates opening new insight into their possible function in modulating extranuclear genes and proteins. This review will firstly summarize the nuclear function of SIRT1 and PGC-1alpha. Then, data from papers demonstrating the presence of SIRT1 and PGC-1alpha in the cytoplasm and in mitochondria will be outlined so that these extranuclear forms do not remain out of sight. Finally, very recent evidence of the alteration of the pathways governed by SIRT1 and PGC-1alpha in human mitochondrial diseases will be described and the possible role of their mitochondrial forms will be briefly discussed. PMID- 22834846 TI - Public attitudes about genetic testing in the newborn period. AB - OBJECTIVE: To measure attitudes toward newborn genetic testing in our jurisdiction. DESIGN: A cross-sectional, pen-and-paper survey. SETTING: The survey was administered to the general public and prospective parents in Eastern Canada between April 2010 and December 2010. PARTICIPANTS: A total of 648 individuals completed surveys. RESULTS: Positive attitudes were found toward newborn genetic testing, regardless of whether an effective treatment existed for the disorder in question or whether the disorder developed in adulthood. A majority agreed (69%) that testing should be available for any condition to assist with future reproductive decisions. Most respondents (93%) agreed parents should provide informed consent before newborn screening (NBS) was undertaken and that parents had a fundamental right to access NBS if they so choose. CONCLUSION: Interest in NBS for genetic disorders is generally high, regardless of whether an effective treatment exists. Findings lend support to the expansion of NBS panels to include those disorders currently lacking treatment but highlight consumers' desire for informed consent before testing is undertaken. PMID- 22834845 TI - Safe sound exposure in the fetus and preterm infant. AB - Exposure to sound can have beneficial and harmful effects on the developing fetus and preterm infant. Although recommendations for safe exposure to sound have existed for more than three decades, reports indicate that these recommendations are not being followed. Recommendations are made to promote attention to the problem of unsafe exposure to sound in early development, and a multidisciplinary team, including representatives from disciplines beyond medicine and nursing, must redress safe exposure. PMID- 22834835 TI - Functions of S100 proteins. AB - The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion. PMID- 22834847 TI - Physical activity and depression symptoms among pregnant women from the National Health and Nutrition Examination Survey 2005-2006. AB - OBJECTIVE: To examine the association between objectively measured physical activity and depression symptoms among a nationally representative sample of pregnant women to provide a more accurate understanding of the relationship between physical activity and depression symptoms. DESIGN: We employed a cross sectional study design. SETTING: Data from the National Health and Nutrition Examination Survey 2005-2006 were used for this study. METHODS: One-hundred and forty-one pregnant women wore an ActiGraph accelerometer for 7 days and completed the Patient Health Questionnaire-9 to assess depression status. RESULTS: More than 19% of the participants experienced some depression symptoms, and compared to their counterparts not having depression symptoms, they were less physically active. CONCLUSION: An inverse association was found between physical activity and depression symptoms among pregnant women. When feasible, nurses are encouraged to help facilitate physical activity among pregnant women, assuming an uncomplicated pregnancy. PMID- 22834850 TI - Caring for military women and families as a nation at war. PMID- 22834848 TI - Cardiometabolic risk, knowledge, risk perception, and self-efficacy among American Indian women with previous gestational diabetes. AB - OBJECTIVE: To describe cardiometabolic risk among a sample of American Indian women with previous gestational diabetes and describe the women's knowledge, risk perception for type 2 diabetes and cardiovascular disease, and self-efficacy beliefs related to preventing these diseases. DESIGN: Mixed methods, cross sectional, exploratory, descriptive. SETTING: Four campuses within one American Indian tribal health care system in a southwestern state. PARTICIPANTS: A purposeful sample of 22 self-identified American Indian women with a history of gestational diabetes. METHODS: Qualitative interview data were subjected to content analysis, and descriptive statistics were used to analyze quantitative questionnaire data and biophysiologic data. RESULTS: The majority of participants (13 of 21) were classified as having metabolic syndrome, and 13 of 18 women were found to be insulin resistant. In general, the women had high levels of knowledge related to type 2 diabetes and cardiovascular disease and high risk perception, but low self-efficacy related to preventing cardiometabolic disease. The overarching theme from the in-depth interviews, struggling to change lifestyle behaviors while doubting prevention is possible, encompassed four categories that provided further illumination into participants' risk perceptions and self efficacy beliefs: concerns, control, beliefs/attitudes, and prevention. CONCLUSIONS: High levels of knowledge and risk perception do not necessarily promote increased self-efficacy to prevent cardiometabolic disease among American Indian women with previous gestational diabetes. Findings indicate the need to further explore women's self-efficacy beliefs in the context of American Indian culture prior to developing interventions aimed at increasing self-efficacy to prevent or delay type 2 diabetes and cardiovascular disease. Women with previous gestational diabetes are at increased risk for developing cardiovascular disease, independent of a diagnosis of type 2 diabetes. PMID- 22834851 TI - Exploring the patterns, practices, and experiences of military women who managed genitourinary symptoms in deployed settings. AB - OBJECTIVE: To gain a better understanding of genitourinary (GU) health during deployment in the context of a military culture. DESIGN: An ethnographic study design was selected to understand how military women managed GU symptoms during deployment. SETTING: The deployed experiences were recalled from various locations around the world. PARTICIPANTS: The final sample consisted of 43 military women from the U.S. Army, Air Force, and Navy who were either deployed or had been deployed within the past year. METHODS: Audio recorded interviews ranged from 30 to 75 min in length. Semistructured interviews were used to gather women's stories about their illness behaviors in the deployed setting. Formal interviews, informal interviews, and field notes were included in the data analysis. RESULTS: Three themes were identified: (a) life in the deployed setting described the location women were referring when they experienced GU symptoms; (b) the dynamics of trust described individuals or entities that were trusted sources of information, supplies, or support; and (c) the sphere of control described the activities utilized to maintain health or manage GU symptoms. CONCLUSION: This study is significant to nursing research because it exposes the influence of culture on GU symptom management. Recommendations from this investigation include the following: provide better incremental, predeployment, and in-theater education for women and medics; inform leaders about the need to ensure the supply of self-care treatments and women's feminine hygiene products are available; and promote the role of family support stateside as a resource for information, supplies, and emotional support. PMID- 22834852 TI - Mentors offering maternal support: a support intervention for military mothers. AB - OBJECTIVE: To evaluate the effectiveness of the Mentors Offering Maternal Support (MOMS) program to promote maternal fetal attachment, maternal adaptation to pregnancy, self-esteem, and perceived community support in women within a military environment. DESIGN: A randomized, controlled, repeated measured pilot study compared two groups of pregnant military wives, a control group receiving standard prenatal care and an intervention group receiving a structured eight session MOMS program. SETTING: The study was conducted at two Air Force installations in Florida having joint (Air Force, Army, and Navy) operations and high deployment requirements. PARTICIPANTS: Sixty-five military wives in their first trimester of pregnancy (control group, n = 36 and intervention group, n = 29) completed all aspects of the study. METHODS: Women randomized to the MOMS program received eight structured classes starting in the first trimester of pregnancy and occurring every other week until the third trimester. Outcome measures were obtained in each trimester. The women in the control group received usual prenatal care. RESULTS: No statistically significant differences were found between the two groups for any of the outcome variables. The interaction of the amount of contact the women had with their deployed husbands and group assignment was statistically different for two variables, the Relationship with Husband Scale and the Rosenberg Self-Esteem Inventory. PMID- 22834853 TI - A Tri-service perspective on the implementation of a centering pregnancy model in the military. AB - With the rising cost of health care, group prenatal care has come into the forefront as a viable, evidence-based option for care delivery. In this article, the authors from three different branches of service (Army, Navy, Air Force) review the strategies and challenges of implementing a centering pregnancy model at military treatment facilities. PMID- 22834854 TI - Cardiac arrest survival is rare without prehospital return of spontaneous circulation. AB - BACKGROUND: Emergency medical services (EMS) are crucial in the management of out of-hospital cardiac arrest (OHCA). Despite accepted termination-of-resuscitation criteria, many patients are transported to the hospital without achieving field return of spontaneous circulation (ROSC). OBJECTIVE: We examine field ROSC influence on OHCA survival to hospital discharge in two large urban EMS systems. METHODS: A retrospective analysis of prospectively collected data was conducted. Data collection is a component of San Antonio Fire Department's comprehensive quality assurance/quality improvement program and Cincinnati Fire Department's participation in the Cardiac Arrest Registry to Enhance Survival (CARES) project. Attempted resuscitations of medical OHCA and cardiac OHCA for San Antonio and Cincinnati, respectively, from 2008 to 2010 were analyzed by city and in aggregate. RESULTS: A total of 2,483 resuscitation attempts were evaluated. Age and gender distributions were similar between cities, but ethnic profiles differed. Cincinnati had 17% (p = 0.002) more patients with an initial shockable rhythm and was more likely to initiate transport before field ROSC. Overall survival to hospital discharge was 165 of 2,483 (6.6%). More than one-third (894 of 2,483, 36%) achieved field ROSC. Survival with field ROSC was 17.2% (154 of 894) and without field ROSC was 0.69% (11 of 1,589). Of the 11 survivors transported prior to field ROSC, nine received defibrillation by EMS. No asystolic patient survived to hospital discharge without field ROSC. CONCLUSION: Survival to hospital discharge after OHCA is rare without field ROSC. Resuscitation efforts should focus on achieving field ROSC. Transport should be reserved for patients with field ROSC or a shockable rhythm. PMID- 22834855 TI - Refining developmental coordination disorder subtyping with multivariate statistical methods. AB - BACKGROUND: With a large number of potentially relevant clinical indicators penalization and ensemble learning methods are thought to provide better predictive performance than usual linear predictors. However, little is known about how they perform in clinical studies where few cases are available. We used Random Forests and Partial Least Squares Discriminant Analysis to select the most salient impairments in Developmental Coordination Disorder (DCD) and assess patients similarity. METHODS: We considered a wide-range testing battery for various neuropsychological and visuo-motor impairments which aimed at characterizing subtypes of DCD in a sample of 63 children. Classifiers were optimized on a training sample, and they were used subsequently to rank the 49 items according to a permuted measure of variable importance. In addition, subtyping consistency was assessed with cluster analysis on the training sample. Clustering fitness and predictive accuracy were evaluated on the validation sample. RESULTS: Both classifiers yielded a relevant subset of items impairments that altogether accounted for a sharp discrimination between three DCD subtypes: ideomotor, visual-spatial and constructional, and mixt dyspraxia. The main impairments that were found to characterize the three subtypes were: digital perception, imitations of gestures, digital praxia, lego blocks, visual spatial structuration, visual motor integration, coordination between upper and lower limbs. Classification accuracy was above 90% for all classifiers, and clustering fitness was found to be satisfactory. CONCLUSIONS: Random Forests and Partial Least Squares Discriminant Analysis are useful tools to extract salient features from a large pool of correlated binary predictors, but also provide a way to assess individuals proximities in a reduced factor space. Less than 15 neuro visual, neuro-psychomotor and neuro-psychological tests might be required to provide a sensitive and specific diagnostic of DCD on this particular sample, and isolated markers might be used to refine our understanding of DCD in future studies. PMID- 22834856 TI - Moxidectin has a lower neurotoxic potential but comparable brain penetration in P glycoprotein-deficient CF-1 mice compared to ivermectin. AB - The anti-parasitic drugs ivermectin (IVM) and moxidectin (MOX) normally show limited brain penetration in vertebrates because of effective drug efflux at the blood-brain barrier by P-glycoprotein, encoded by the multi-drug resistance (MDR1) gene. However, dogs with homozygous nt230(del4) mutation in the MDR1 gene do not express a functionally active P-glycoprotein and show increased brain penetration of these drugs, resulting in neurological toxicity to different degrees. Thus, whereas IVM provokes neurological toxicity at 0.1 mg/kg, MOX is tolerated at this dosage. To investigate whether this difference is attributable to lower brain penetration of MOX in the absence of P-glycoprotein or to their neurotoxic potential, we applied IVM and MOX to P-glycoprotein-deficient CF-1 mice and comparatively analysed the absolute drug concentrations in the brain. Furthermore, we quantified drug-induced neurotoxicity by measuring the walking performance of the mice on a rotarod setup. We found that at a dosage of 0.2 mg/kg, representing 0.23 MUmol/kg IVM and 0.31 MUmol/kg MOX, the absolute drug concentrations in the brain were comparable with 100.8 pmol/g and 140.2 pmol/g, respectively. However, MOX induced the same degree of neurotoxicosis at the higher dosage of 1.09 MUmol/kg (0.7 mg/kg) compared with IVM at 0.40 MUmol/kg (0.35 mg/kg), demonstrating the 2.7-fold lower neurotoxic potential of MOX compared to IVM. This could be explained by a lower binding affinity or lower intrinsic activity of MOX at the relevant central nervous system receptors compared with IVM. PMID- 22834857 TI - Solubility enhancement effect of cyclodexin on groundwater pollutants. AB - Cyclodextrin (CD) molecules are polycyclic glucose oligomers that have a hydrophilic exterior and a hydrophobic cavity. This structure provides CD the characteristic of enhancing the solubility of groundwater pollutants. The degree to which CD increases the apparent aqueous solubility of certain chemicals has been defined as the solubility enhancement factor (SEF). In this study, a novel and experimentally simple method has been developed to determine the SEF, which can be mathematically obtained by ratio of apparent and traditional Henry's law constants. The effects of temperature and CD concentration on the SEFs and CD cavity occupation have been investigated. Our results show that SEF values are inversely related to temperature for most examined chemicals, which is consistent with the assertion that the CD-chemical complexes are less stable at higher temperatures. The exception is toluene that shows the least SEF fluctuation within the temperature range studied (5 to 65 degrees C). This may indicate that the toluene-CD complex is particularly stable. As the definition of SEF predicted, linear relationships were found between the SEFs and CD concentrations for all the subject chemicals. The CD cavity occupation fraction at 5 degrees C were 3.14, 2.55, 2.04, 1.60, and 1.67 times greater than the values at 65 degrees C for of trichloroethylene, perchloroethylene, bezene, ethylbenze, and o xylene, respectively. The fraction of CD cavities occupied was found to be inversely related to the CD concentration for all tested chemicals when pollutant mass are held constant. This study provides important information to accurately evaluate the performance of CD when used for aquifer remediation. PMID- 22834858 TI - Synthetic routes to fluorescent dyes exhibiting large Stokes shifts. AB - Derivatives of isomeric 2-(hydroxytolyl)-4,6-dimethylamino-1,3,5-triazines have been synthesized in high yields in a controlled manner using a multistep reaction sequence. Iodination of either 2-(1'-hydroxy-6'-methylphen-2'-yl)- or 2-(1' hydroxy-4'-methylphen-2'-yl)-4,6-dimethylamino-1,3,5-triazine with ICl provides species differing in the positioning of the iodo group relative to the hydroxyl which readily undergo Suzuki, Sonogashira, and Heck reactions under Pd(0) catalysis. Thus, thienyl, bisthienyl, and 3,4-ethylenedioxythienyl groups have been directly grafted, while unsubstituted polycyclic aromatics such as pyrene and perylene have been linked via alkyne bridges, as have ethynyldifluoroborondipyrromethane (BODIPY) dyes prepared in situ. The presence of a hydrogen bond in the ground state involving the hydroxyl substituent has been established by proton NMR and several X-ray structure determinations. All of the new dyes with a simple substituent (phenyl, thienyl) exhibited a pronounced green fluorescence resulting from an intramolecular proton transfer in the excited state (ESIPT) which produces a large Stokes shift (>10,000 cm(-1)). With other dyes, the fluorescence of the keto form responsible for the ESIPT process could be used as the input energy in efficient intramolecular energy transfer processes. Replacing perylene with pyrene allowed reversal of the direction of energy transfer from the polyaromatic module to the keto form. PMID- 22834860 TI - Energy migration in dendritic oligothiophene-perylene bisimides. AB - A series of novel oligothiophene-perylene bisimide hybrid (DOTPBI) dendrimers up to the second generation (G0, G1, and G2) were investigated. Optical measurements such as nonlinear optical and time-resolved spectroscopy, including two-photon absorption, fluorescence upconversion, and excited state transient absorption were carried out. Results of these measurements revealed the ability of these molecules to undergo intramolecular fluorescence resonance energy transfer (FRET) from the dendritic oligothiophenes (DOT) to the perylene bismide (PBI) moiety. The delocalization length and the photoinduced electron transfer (PET) rate were investigated as a function of dendrimer generation. A fast energy transfer process from the DOT dendron to the PBI core was observed. For the case of the G2 dendrimer, with relatively large thiophene dendrons attached to the bay area of the perylene bisimide, the PBI core is highly twisted and its ability to self assemble into pi-pi stacked aggregates is destroyed. As a result, among the three generations studied, G1, which has the best two-photon cross section and the most efficient energy transfer, is the best light harvesting material. PMID- 22834859 TI - Class 3 semaphorins as a therapeutic target. AB - INTRODUCTION: The semaphorins were initially described as axon guidance molecules that play important roles in the development of nervous system. Recent studies suggest that semaphorins and their receptors also exert such diverse functions as immune response, control of vascular endothelial cell motility and invasion of many types of cancer cells. AREAS COVERED: The available results concerning application of class 3 semaphorins and their inhibitors for the treatment in animal disease models. EXPERT OPINION: Because semaphorins are now recognized as key players in immune, cardiovascular, bone metabolism and neurological system, semaphorins and their receptors are most promising therapeutic targets for various disease states. As semaphorins exert their diverse or even opposing activities in vivo, more elaborate studies on pathophysiology and signal transduction mechanisms of semaphorins are required. PMID- 22834861 TI - Comparison between CHADS2 and CHA2 DS2 -VASc score in a stroke cohort with atrial fibrillation. AB - BACKGROUND AND PURPOSE: In patients with atrial fibrillation (AF), stroke risk stratification schemes have been developed to optimize antithrombotic treatment. The CHADS(2) score is frequently used but has limitations. The CHA(2) DS(2) -VASc score improves risk prediction. Our objectives are to describe CHADS(2) and CHA(2) DS(2) -VASc score distribution in a cohort of patients with AF and first ever ischaemic stroke (FIS) and to identify differences in embolic risk stratification. METHODS: Our cohort included 589 patients with FIS, previous modified Rankin score <= 3, and non-valvular AF. We recorded demographic data, vascular risk factors, and antithrombotic pre-treatment. The CHADS(2) and CHA(2) DS(2) -VASc scores were calculated according to clinical status before stroke onset. RESULTS: In 186 (31.6%) patients, AF was previously unknown. Of patients with known AF and CHADS(2) >= 2 (n=320), only 103 (32.2%) were taking anticoagulants; more than half of these patients had an INR <2. The CHADS(2) score placed 142 (24.1%) patients in the low-intermediate risk (score <= 1) category compared with 21 (3.6%) with CHA(2) DS(2) -VASc, P < 0.001. Applying CHA(2) DS(2) -VASc reclassified 121 (85.2%) subjects in the CHADS(2) low intermediate risk category as high risk (>= 2), an indication for anticoagulants. Of the 21 patients who suffered a stroke despite their low CHA(2) DS(2) -VASc score (<= 1), seven (33.3%) reported alcohol overuse, and six (28.5%) had a concomitant stroke etiology. CONCLUSIONS: About 25% of FIS patients with AF had a CHADS(2) score <= 1. Despite the high CHADS(2) score of our population, few patients received the recommended antithrombotic treatment according to their thromboembolic risk. Using the CHA(2) DS(2) -VASc schema significantly increased the percentage of patients indicated for anticoagulation. PMID- 22834862 TI - First clinical experience in urologic surgery with a novel robotic lightweight laparoscope holder. AB - PURPOSE: To report the feasibility and the safety of a surgeon-controlled robotic endoscope holder in laparoscopic surgery. PATIENTS AND METHODS: From March 2010 to September 2010, 20 patients were enrolled prospectively to undergo a laparoscopic procedure using an innovative robotic endoscope holder. Two surgeons performed six adrenalectomies, four sacrocolpopexies, five pyeloplasties, four radical prostatectomies, and one radical nephrectomy. Demographic data, overall setup time, operative time, number of assistants needed were reviewed. Surgeon satisfaction regarding the ergonomics was assessed using a 10-point scale. Postoperative clinical outcomes were reviewed at day 1 and 1 month postoperatively. RESULTS: The per-protocol analysis was performed on 17 patients for whom the robot was effectively used for surgery. Median age was 63 years; 10 (59%) patients were female. Median body mass index was 26.8. Surgical procedures were completed with the robot in 12 (71%) cases. Median number of surgical assistant was 0. Overall setup time with the robot was 19 minutes; operative time was 130 minutes during which the robot was used 71% of the time. Mean hospital stay was 6.94 +/- 2.3 days. Median score regarding the easiness of use was 7. Median pain level was 1.5/10 at day 1 and 0 at 1 month postoperatively. Open conversion was needed in one (6%) case, and four minor complications occurred in two (12%) patients. CONCLUSION: This use of this novel robotic laparoscope holder is safe, feasible, and provides good comfort to the surgeon. PMID- 22834863 TI - Ion exchange model for reversible sorption of divalent metals on calcite: implications for natural environments. AB - Most of the thermodynamic models available in the literature describing the speciation of the calcite surface do not predict a significant concentration of sorbed Ca(II), whereas previous electrokinetics studies clearly show that Ca(2+) is the main cation determining the potential of the calcite surface. This study proposes a new thermodynamic model based on ion-exchange theory that is able to describe the reversible sorption of Ca(2+) on calcite. To constrain the model, concentrations of Ca(II) sorbed reversibly on the mineral surface were obtained as a function of pH. Such experimental data were obtained using solutions in equilibrium with both calcite and fixed p(CO2(g)) values (from 10(-5) to 10(-2) atm). The concentration of (de)sorbed Ca(II) is almost constant in the [7-9.5] pH range, having a value of approximately 1.2 * 10(-6) +/- 0.4 * 10(-7) eq.g(-1). Such a value agrees with total sorption site densities that were previously calculated by crystallography and is used to obtain a selectivity coefficient between H(+) and Ca(2+) species by fitting the experimental data. Then, selectivity coefficients between H(+) and different metallic cations (Zn(2+), Cd(2+), Pb(2+)) that are able to accurately describe previously published data are proposed. Finally, the model is used to predict the contribution of calcite in the overall sorption of Cd(II) on a natural and complex solid (calcareous aquifer sand). PMID- 22834864 TI - Xeno-free production of human embryonic stem cells in stirred microcarrier systems using a novel animal/human-component-free medium. AB - Currently, stem cell research faces a major bottleneck related to the low efficiency of methods to produce large quantities of human embryonic stem cells (ESC) for use in clinical trials. Most culture media currently employed for human ESC cultivation contain animal compounds, and cells are grown in static flasks. Besides the immediate contamination with nonhuman compounds, cell expansion in flasks tends to be laborious and nonefficient. Here we cultured human ESC in stirred microcarrier (MC) systems using an animal/human-component-free medium, to overcome both issues. The method developed to culture cells on suspended beads combined the use of polymeric MCs in stirred vessels with an optimized culture medium free of supplements of animal and human origin. This approach generated approximately 160 million cells within 6 days, which were shown to remain pluripotent. The process developed herein provides a step forward toward therapy due to the economic advantages in the production of human ESC and to their consequent low immunogenic potential. PMID- 22834865 TI - Autologous split-thickness skin graft for penile coverage in the treatment of buried (trapped) penis after radical circumcision. PMID- 22834866 TI - Mobile elogbook application for urology trainees. PMID- 22834867 TI - En bloc transurethral resection of bladder lesions: a trick to retrieve specimens up to 4.5 cm. PMID- 22834869 TI - The Heroic Side of Urology: Christchurch earthquake brings out the best in four urologists. PMID- 22834870 TI - Is commercially available point finder accurate and reliable in detecting active auricular acupuncture points? AB - OBJECTIVES: This study was done to determine the specificity and sensitivity of a commercial Pointer Plus (Point finder) in detecting a region of low skin resistance on the ear. DESIGN: This was a prospective blinded study. SETTING/LOCATION: The study was done at the Yale New Haven Hospital, New Haven, CT. SUBJECTS: The subjects were men and women who work at Yale New Haven Hospital. INTERVENTIONS: There were no interventions. OUTCOME MEASURES: Correlations were made between self-reported musculoskeletal pain and the detection of low skin resistance on the ear. RESULTS: The positive predictive value for Pointer Plus detecting low skin resistance correlating to the neck region of French auricular map is 0.76 (76%). The positive predictive value for Pointer Plus to detect low skin resistance area correlating to the low back region of French auricular map is 0.25. The positive predictive value for Pointer Plus in detecting any low in skin resistance on the external auricles in patients who complained of more than two musculoskeletal pains is 0.29. CONCLUSIONS: The specificity and sensitivity of a commercial Pointer Plus (point finder) in detecting a region of low skin resistance on the ear being unreliable, depending on the correlating area based on a published auricular map. Additional assessments are needed to support the clinical practice. PMID- 22834871 TI - Impact of elevated intact parathyroid hormone on mortality and renal disease progression in patients with chronic kidney disease stages 3 and 4. AB - OBJECTIVE: To estimate the impact of elevated intact parathyroid hormone levels on time to death and renal replacement therapy in patients with chronic kidney disease stages 3 and 4. METHODS: A retrospective cohort analysis from 01/1996 to 09/2007 was conducted in 11,092 patients with chronic kidney disease stages 3 and 4 patients using Cockroft-Gault and Modification of Diet in Renal Disease equations to estimate their glomerular filtration rates. Patients' highest parathyroid hormone levels were used to define the index date and cohort (followed for 1 year). Mortality and renal replacement therapy events were evaluated among cohorts at pre-defined parathyroid hormone levels. RESULTS: As the intact parathyroid hormone levels increased, the mean age, number of females and estimated glomerular filtration rates decreased. Patients with an intact parathyroid hormone level<50 pg/mL were defined as the reference group. Similar results were found using the Modification of Diet in Renal Disease equation for calculating estimated glomerular filtration rate, which was possible in 48% of the patients where race could be identified. Combined mortality and renal replacement therapy adjusted hazard ratio using Cox regression for intact parathyroid hormone level 51-110 pg/mL was 1.12 (0.82-1.54), intact parathyroid hormone level 111-199 pg/mL was 2.42 (1.78-3.29), intact parathyroid hormone level 200-299 pg/mL was 3.01 (2.14-4.27), intact parathyroid hormone level 300 399 pg/mL was 3.12 (2.09-4.60), intact parathyroid hormone level 400-499 pg/mL was 3.91 (2.61-5.85) and intact parathyroid hormone level>500 pg/mL was 2.67 (1.84-3.84). CONCLUSION: Intact parathyroid hormone levels>50 pg/mL in patients with chronic kidney disease stages 3 and 4 are associated with an escalating combined risk of death or RRT. PMID- 22834872 TI - Endogenous MCM7 microRNA cluster as a novel platform to multiplex small interfering and nucleolar RNAs for combinational HIV-1 gene therapy. AB - Combinational therapy with small RNA inhibitory agents against multiple viral targets allows efficient inhibition of viral production by controlling gene expression at critical time points. Here we explore combinations of different classes of therapeutic anti-HIV-1 RNAs expressed from within the context of an intronic MCM7 (minichromosome maintenance complex component-7) platform that naturally harbors 3 microRNAs (miRNAs). We replaced the endogenous miRNAs with anti-HIV small RNAs, including small interfering RNAs (siRNAs) targeting HIV-1 tat and rev messages that function to induce post-transcriptional gene silencing by the RNA interference pathway, a nucleolar-localizing RNA ribozyme that targets the conserved U5 region of HIV-1 transcripts for degradation, and finally nucleolar trans-activation response (TAR) and Rev-binding element (RBE) RNA decoys designed to sequester HIV-1 Tat and Rev proteins inside the nucleolus. We demonstrate the versatility of the MCM7 platform in expressing and efficiently processing the siRNAs as miRNA mimics along with nucleolar small RNAs. Furthermore, three of the combinatorial constructs tested potently suppressed viral replication during a 1-month HIV challenge, with greater than 5-log inhibition compared with untransduced, HIV-1-infected CEM T lymphocytes. One of the most effective constructs contains an anti-HIV siRNA combined with a nucleolar-localizing U5 ribozyme and TAR decoy. This represents the first efficacious example of combining Drosha-processed siRNAs with small nucleolar ribonucleoprotein (snoRNP)-processed nucleolar RNA chimeras from a single intron platform for effective inhibition of viral replication. Moreover, we demonstrated enrichment/selection for cells expressing levels of the antiviral RNAs that provide optimal inhibition under the selective pressure of HIV. The combinations of si/snoRNAs represent a new paradigm for combinatorial RNA-based gene therapy applications. PMID- 22834873 TI - Relationship between regional lung compliance and ventilation homogeneity in the supine and prone position. AB - BACKGROUND: The prone position (PP) improves ventilation homogeneity in acute respiratory distress syndrome. The aim of this study was to investigate whether the alleviation of ventilation inhomogeneity in PP was due to changes in regional lung compliance. METHODS: Ten lung-lavaged piglets were mechanically ventilated in supine position (SP) and in PP. In each position, positive end-expiratory pressure (PEEP) was reduced from 20 to 6 cmH(2)O in steps of 2 cmH(2)O every 10 min after full lung recruitment. Respiratory mechanics, blood gas, haemodynamic data and whole-lung computed tomography scans were recorded at each PEEP. The compliances of normally aerated (C(normal)) and newly recruited (C(recruited)) lung regions were calculated. Open lung PEEP (OL-PEEP) was defined as the lowest PEEP to maintain full lung recruitment. RESULTS: At OL-PEEP, PP significantly increased normally aerated lung regions, decreased poorly aerated and hyperinflated lung regions and decreased tidal recruitment and hyperinflation. C(normal) was significantly reduced in PP compared with SP (12.8 +/- 4.2 ml/cmH(2)O vs. 20.1 +/- 6.2 ml/cmH(2)O, P < 0.001), whereas C(recruited) was increased in PP (13.9 +/- 3.9 ml/cmH(2)O vs. 9.4 +/- 2.4 ml/cmH(2)O, P < 0.001). C(normal) was correlated with hyperinflated lung regions at end-expiration (rho = 0.67) and end-inspiration (rho = 0.56) at OL-PEEP. C(recruited) was correlated with normally (r(2) = 0.36) and poorly aerated lung regions (rho = -0.58) at OL PEEP. CONCLUSION: This surfactant-depleted model shows that the improvement of ventilation homogeneity in PP is related to an increase in C(recruited) and a decrease in C(normal). PMID- 22834874 TI - "Voices of fear and safety" women's ambivalence towards breast cancer and breast health: a qualitative study from Jordan. AB - BACKGROUND: Breast cancer is the leading cause of cancer mortality among Jordanian women. Breast malignancies are detected at late stages as a result of deferred breast health-seeking behaviour. The aim of this study was to explore Jordanian women's views and perceptions about breast cancer and breast health. METHODS: We performed an explorative qualitative study with purposive sampling. Ten focus groups were conducted consisting of 64 women (aged 20 to 65 years) with no previous history and no symptoms of breast cancer from four governorates in Jordan. The transcribed data was analysed using latent content analysis. RESULTS: Three themes were constructed from the group discussions: a) Ambivalence in prioritizing own health; b) Feeling fear of breast cancer; and c) Feeling safe from breast cancer. The first theme was seen in women's prioritizing children and family needs and in their experiencing family and social support towards seeking breast health care. The second theme was building on women's perception of breast cancer as an incurable disease associated with suffering and death, their fear of the risk of diminished femininity, husband's rejection and social stigmatization, adding to their apprehensions about breast health examinations. The third theme emerged from the women's perceiving themselves as not being in the risk zone for breast cancer and in their accepting breast cancer as a test from God. In contrast, women also experienced comfort in acquiring breast health knowledge that soothed their fears and motivated them to seek early detection examinations. CONCLUSIONS: Women's ambivalence in prioritizing their own health and feelings of fear and safety could be better addressed by designing breast health interventions that emphasize the good prognosis for breast cancer when detected early, involve breast cancer survivors in breast health awareness campaigns and catalyse family support to encourage women to seek breast health care. PMID- 22834875 TI - Protection against L-NAME-induced reduction in cardiac output persists even after cessation of angiotensin-converting enzyme inhibitor treatment. AB - AIM: We have demonstrated that short-term angiotensin-converting enzyme (ACE) inhibition in adult spontaneously hypertensive rats produces cardiac changes that persist following cessation of treatment that result in a reduced inflammatory, proliferative and fibrotic response to the nitric oxide synthase inhibitor N(omega) -Nitro-l-arginine methyl ester (L-NAME). The present study examines whether prior ACE inhibition with enalapril also protects against L-NAME-induced cardiac dysfunction. METHODS: Rats were treated with enalapril (Enal + L) or tap water (Con, Con + L) for 2 weeks followed by a 2-week washout period. At this point, Con + L and Enal + L rats were treated with L-NAME for 10 days. Hearts were perfused in the working mode, mean arterial pressure (MAP) was assessed via radiotelemetry, and myocardial injury was evaluated in hematoxylin and eosin stained sections. RESULTS: L-NAME increased MAP by a similar magnitude in Con + L and Enal + L. L-NAME-induced statistically significant decreases in flow-mediated functional parameters in Con + L rats including cardiac output, stroke volume and coronary flow. This was prevented by prior enalapril treatment. Prior enalapril did not prevent L-NAME-induced myocardial injury, but may have lessened the degree of it. Regardless of treatment, changes in cardiac function did not correlate with myocardial injury. CONCLUSION: Despite equivalent impact on MAP and incidence of myocardial infarction, prior enalapril treatment resulted in the preservation of cardiac function following L-NAME. Understanding the mechanisms by which transient ACE inhibition protects against reductions in cardiac function in the absence of ongoing treatment may reveal novel targets for heart failure treatment. PMID- 22834876 TI - Long-term treatment with alendronate increases the surgical difficulty during simple exodontias - an in vivo observation in Holtzman rats. AB - BACKGROUND: Atraumatic teeth extractions protocols are highly encouraged in patients taking bisphosphonates (Bps) to reduce surgical trauma and, consequently, the risk of jaws osteonecrosis development. In this way, this paper aims to report the findings of increased surgical difficulty during simple exodontias in animals treated with bisphosphonates. METHODS: Sixty male Holtzman rats were randomly distributed into three groups of 20 animals and received daily subcutaneous administration of 1 mg/kg (AL1) or 3 mg/kg (AL3) of alendronate or saline solution (CTL). After 60 days of drug therapy all animals were submitted to first lower molars extractions under general anesthesia. Operatory surgical time and the frequency of teeth fractures were measured as principal outcomes and indicators of surgical difficulty degree. RESULTS: Animals treated with alendronate (AL1 and AL3) were associated to higher operatory times and increased frequency of teeth fractures compared to match controls. CONCLUSIONS: The bisphosphonate therapy may be associated with an increased surgical difficulty and trauma following simple exodontias protocols, which is considered a critical issue when it comes to osteonecrosis development. PMID- 22834877 TI - Current landscape of phosphodiesterase 10A (PDE10A) inhibition. PMID- 22834878 TI - A Rasch analysis of nurses' ethical sensitivity to the norms of the code of conduct. AB - AIMS AND OBJECTIVES: To develop an instrument to measure nurses' ethical sensitivity and, secondarily, to use this instrument to compare nurses' ethical sensitivity between groups. BACKGROUND: Professional codes of conduct are widely accepted guidelines. However, their efficacy in daily nursing practice and influence on ethical sensitivity is controversial. DESIGN: A descriptive cross sectional study was conducted. PARTICIPANTS: One hundred and forty-three registered nurses from Barcelona (Spain) participated in the study, of whom 45.83% were working in primary health care and 53.84% in hospital wards. METHODS: A specifically designed confidential, self-administered questionnaire assessing ethical sensitivity was developed. Knowledge of the nursing code and data on ethical sensitivity were summarised, with the quality of the questionnaire assessed using Rasch analysis. RESULTS: Item on knowledge of the code showed that one-third of nurses knew the contents of the code and two-thirds had limited knowledge. To fit the Rasch model, it was necessary to rescore the rating scale from five to three categories. Residual principal components analysis confirmed the unidimensionality of the scale. Three items of the questionnaire presented fit problems with the Rasch model. Although nurses generally have high ethical sensitivity to their code of conduct, differences were found according to years of professional practice, place of work and knowledge of the code (p<0.05). CONCLUSIONS: The questionnaire showed acceptable psychometric properties to achieve the proposed objective. Nurses' ethical sensitivity to the norms of the code was high. However, many factors might influence the degree of ethical sensitivity. Further research to measure ethical sensitivity using invariant measures such as Rasch units would be valuable. RELEVANCE TO CLINICAL PRACTICE: Other factors, such as assertiveness or courage, should be considered to improve ethical sensitivity to the code of conduct. Rigorous measurement studies and analysis in applied ethics are needed to assess ethical performance in practice. PMID- 22834879 TI - Reflections on the importance of the nurse. PMID- 22834880 TI - Maternal vitamin D status as a critical determinant in gestational diabetes. AB - OBJECTIVE: To synthesize published research to determine the evidence for the association between maternal vitamin D status during pregnancy and the development of gestational diabetes mellitus (GDM). DATA SOURCES: Literature searches were conducted for data based articles that examined maternal vitamin D during pregnancy, GDM, glucose tolerance, and insulin resistance using the PubMed, CINAHL, and SCOPUS data bases and reference lists from reviewed papers. STUDY SELECTION: Primary research studies published in the English language between 1999 and 2011 reporting findings regarding the association of vitamin D with glucose homeostasis during pregnancy and GDM. DATA EXTRACTION: Study characteristics and findings related to vitamin D status determinants, gestational timing, and measures of glucose homeostasis and insulin resistance. DATA SYNTHESIS: Six data based articles met the criteria for study inclusion. Study findings comprised solely Level-2 evidence for the association of maternal vitamin D deficiency and risk of GDM. The majority of studies (66%) were conducted between 24 and 30 weeks gestation. Five (83%) studies reported an inverse relationship between circulating vitamin D levels and markers of glucose homeostasis associated with gestational diabetes or an increased risk for GDM associated with reduced maternal levels of vitamin D. In one study, researchers did not identify an association between vitamin D and GDM but did identify an association between higher vitamin D levels and lower fasting glucose and insulin levels. CONCLUSION: Maternal vitamin D deficiency and insufficiency is prevalent among gravid women and is associated with markers of altered glucose homeostasis. These findings underscore the need for mechanistic and clinical studies to determine optimal vitamin D status in pregnancy for reduction in the risk for GDM with implications for vitamin D supplementation as a potential target for GDM prevention. PMID- 22834881 TI - A cross-sectional analysis of the effect of patient-controlled epidural analgesia versus patient controlled analgesia on postcesarean pain and breastfeeding. AB - OBJECTIVE: To assess patient controlled epidural analgesia (PCEA) versus patient controlled analgesia (PCA) for postcesarean analgesia and to determine the impact of analgesic modality on breastfeeding in the first 24 hours postpartum. DESIGN: A retrospective, descriptive, comparative, correlational design. SETTING: A metropolitan, community, teaching hospital in the northeast United States. PARTICIPANTS: Medical records for all women with cesarean births in 2007 of at least 34 weeks gestational age (N = 621). METHODS: Following Institutional Review Board approval, electronic medical records and clinical charts were reviewed by the study team. Data were analyzed with PASW version 18.0. RESULTS: Women with PCEA reported significantly less average pain (p = .000) and required significantly less analgesic adjuvant medication doses (p = .038) than women with PCA. Statistically significant negative correlations were found for average total pain score with number of breastfeeding sessions (p = .023). Controlling for confounders, women with PCEA had 2.2 times the odds of mild pain compared to PCA (p = .03). Women with mild pain (adjusted odds ratio [aOR] = 2.4, p = .03), term neonate (aOR = 3.2, p = .006), breastfeeding within 2 hours (aOR = 3.2, p = .000), and no supplemental feedings (aOR = 6.9, p = .002) had significantly greater odds of breastfeeding 6+ times in the first 24 hours. CONCLUSION: Patient controlled epidural anesthesia confers greater pain control postcesarean than PCA. Women with greater pain are less likely to breastfeed six or more times within the first 24 hours. This could potentially affect duration of breastfeeding. Intraprofessional measures to improve pain management are warranted. PMID- 22834882 TI - Biophysiologic and social stress relationships with breast milk feeding pre- and post-discharge from the neonatal intensive care unit. AB - OBJECTIVE: To determine influences on incidence of breast milk feeding (BMF) at time of discharge and 6 months later among infants cared for in the neonatal intensive care unit (NICU). DESIGN: A 2-year prospective descriptive NICU hospital-based cohort design. SETTING: Academic Center Level III-IV NICU. PARTICIPANTS: Five hundred and thirty-five infants cared for in NICU and a subgroup of one hundred twenty-nine participant mothers who answered questionnaires. METHODS: Predischarge data were collected using maternal and infant medical records. Post-discharge data were collected from maternal questionnaires. RESULTS: At NICU discharge, biophysiologic stressors predictive of not receiving BMF included birth weight <1500 grams (p < .035), heart surgery (p = .014), and inhaled nitric oxide treatment (p = .002). Teenage mothers were less likely to BMF (p = .022). After discharge, BMF duration correlated with BMF duration of a prior infant (p < .009). Most mothers reported BMF >4 months, 91% continued pumping, and 89% indicated an interest in a hospital support group. Logistic regression analysis (R(2) 0.45) identified factors that significantly increased the likelihood of BMF > 4 months: BMF plan (p < .001), convenience (p = .018), and family as resource (p = .025). Negative associations were: awareness of immune benefits (p = .025), return to work (p = .002), and infants requiring surgical ligation of the patent ductus arterious (p = .019). CONCLUSIONS: Social and medical stressors contribute to BMF duration pre- and post-NICU discharge. We speculate that active NICU BMF support targeting vulnerable infants and their families and assisting with plans for BMF pre- and post-discharge will help overcome barriers. PMID- 22834883 TI - Hospital-based perinatal nurses identify the need to improve nursing care of adolescent mothers. AB - OBJECTIVE: To determine whether hospital-based perinatal nurses with expertise in adolescent mother-friendly care identify a need to improve inpatient nursing care of adolescent mothers and how well perinatal units support nurses' capacity to provide adolescent mother-friendly care. DESIGN/SETTING/PARTICIPANTS: A key informant survey of nurses from eight perinatal units at three hospitals (four separate sites) in a Canadian city. METHODS: Perinatal nurses expert in the care of adolescent mothers were identified by their managers and colleagues. These nurses and all perinatal clinical educators were invited to participate. Twenty seven of 34 potential key informants completed the survey. RESULTS: Key informants rated their own skill in caring for adolescent mothers higher (median 8.0) than they rated the skill of other nurses (median 6.0) on their units. They attributed their expertise working with adolescent mothers to their clinical and life experiences and their ability to develop rapport with adolescents. A common reason for the assigned lower peer-group ratings was the judgmental manner in which some nurses care for adolescent mothers. Key informants also identified that hospital-based perinatal nurses lack adequate knowledge of community-based resources for adolescent mothers, educational programs related to adolescent mother-friendly care were insufficient, and policies to inform the nursing care of adolescent mothers were not available or known to them. CONCLUSION: A minority of perinatal nurses have expertise in adolescent mother-friendly care. There is a need for perinatal unit-level interventions to support the development of nurses' skills in caring for adolescent mothers and their knowledge of community-based resources. Peer mentoring and self-reflective practice are promising strategies. PMID- 22834884 TI - Comparison of temporal artery and axillary temperatures in healthy newborns. AB - OBJECTIVE: To compare temperature readings of temporal artery and axillary thermometers in healthy late preterm and term infants in an effort to standardize practice. DESIGN: Descriptive comparative. SETTING: Thirty-bed, healthy mother/baby unit in an inner-city Level-1 trauma center, averaging 2,500 births per year. PARTICIPANTS: Healthy newborns (N = 125) admitted to mother/baby unit after birth, at least 35 weeks gestation, and weighing greater than 1,900 grams. METHODS: Temperatures were taken at regular intervals per unit protocol. At each interval temporal and axillary temperatures were recorded. RESULTS: Temporal temperatures were significantly higher (M = 36.9 degrees C, SD = .59) than axillary temperatures (M = 36.7 degrees C, SD = .68), t(124) = 6.74, p < .0001. Although statistical significance was shown between the two groups, no meaningful clinical difference was detected. CONCLUSION: Our study findings supported a new nursing practice standard for measuring infant temperatures in our mother/baby unit. Using temporal artery thermometers is now our unit's standard of care for healthy newborns. PMID- 22834885 TI - Pregnancy intention and contraceptive use at six months postpartum among women with recent preterm delivery. AB - OBJECTIVE: To describe pregnancy intention and contraceptive use among women with a recent delivery that occurred at 35 weeks gestation or fewer and who were enrolled in a large-scale randomized control trial. DESIGN: In this descriptive study we used data from assessments conducted at 6 months postpartum as part of a randomized controlled clinical trial, the Philadelphia Collaborative Preterm Prevention Project (PCPPP). PARTICIPANTS AND SETTING: Participants were recruited following a preterm birth (PTB) in one of the 12 urban birth hospitals. All women enrolled in PCPPP, who completed their 6-month postpartum assessment, and who were sexually active at the time of that assessment (n = 566), were included in the analysis. METHODS: Data were collected during face-to-face interviews. Study questionnaires included questions about participants' plans for the timing of subsequent pregnancies, contraceptive behaviors, and other health variables. RESULTS: Nearly all of the participants (90.1%, n = 509) reported they did not want to get pregnant within one year of the index PTB. However, more than one half of these women (54.6%) reported contraceptive practices of low or moderate effectiveness. Most predictive of intending another pregnancy within the year was the death of the index PTB infant (odds ratio [OR]= 18.2,95% confidence interval [CI] [8.9, 37.0]). CONCLUSIONS: Discordant pregnancy intention and contraceptive use were reported among this group of mothers of PTB infants who are at particularly high risk for a poor outcome of any subsequent pregnancy. The findings highlight the need for further investigation of the causes, correlates, and consequences of discordant pregnancy intentions and contraceptive practices. PMID- 22834886 TI - Loss of CBL E3-ligase activity in B-lineage childhood acute lymphoblastic leukaemia. PMID- 22834887 TI - Optical pH detection within a protein crystal. AB - The pH is one of the key parameters governing protein conformation and activity. In protein crystals, however, the pH is so far not accessible by experiment. Here, we report on the optical detection of the pH in a lysozyme crystal employing the pH-sensitive fluorescent dyes SNARF-1 and SNARF-4F. The molecular probes were loaded into the crystal by diffusion. Two-dimensional fluorescence spectra of the labeled protein crystal were recorded, and the average pH of the crystal at different bath pH's was determined by calibrating fluorescence peak ratios. In addition, we used two-photon microscopy to spatially resolve the pH inside a lysozyme crystal three-dimensionally and to follow pH changes in response to a pH change of the bath over time. At equilibrium at bath pH between 5.5 and 8.0, we found a pH in the water-filled crystal channels that was DeltapH = -0.3 to -1.0 lower than that of the bath. This corresponds to a 2- to 10-fold higher proton concentration in the crystal channels than in the bath. The lower pH at equilibrium in the crystal channels can be explained by slower proton diffusion in the channels than in the bath and a resulting proton accumulation in the crystal for conservation of mass and so an equilibrium of proton flux. PMID- 22834888 TI - Termination of resuscitation for adult traumatic cardiopulmonary arrest. AB - The National Association of EMS Physicians (NAEMSP) and the American College of Surgeons Committee on Trauma (ACS-COT) believe that emergency medical services (EMS) systems should have protocols that allow EMS providers to terminate resuscitative efforts for certain adult patients in traumatic cardiopulmonary arrest. This document is the official position of the NAEMSP and ACS-COT. PMID- 22834889 TI - Reliability of self-reported health risk factors and chronic conditions questions collected using the telephone in South Australia, Australia. AB - BACKGROUND: Accurate monitoring of health conditions and behaviours, and health service usage in the population, using an effective and economical method is important for planning and evaluation. This study examines the reliability of questions asked in a telephone survey by conducting a test/retest analysis of a range of questions covering demographic variables, health risk factors and self reported chronic conditions among people aged 16 years and over. METHODS: A Computer Assisted Telephone Interviewing (CATI) survey on health issues of South Australians was re-administered to a random sub-sample of 154 respondents between 13-35 days (mean 17) after the original survey. Reliability between questions was assessed using Cohen's kappa and intraclass correlation coefficients. RESULTS: Demographic questions (age, gender, number of adults and children in the household, country of birth) showed extremely high reliability (0.97 to 1.00). Health service use (ICC = 0.90 95% CI 0.86-0.93) and overall health status (Kappa = 0.60 95% CI 0.46-0.75) displayed moderate agreement. Questions relating to self reported risk factors such as smoking (Kappa = 0.81 95% CI 0.72-0.89) and alcohol drinking (ICC 0.75 = 95% CI 0.63-0.83) behaviour showed good to excellent agreement, while questions relating to self-reported risk factors such as time spent walking for physical activity (ICC 0.47 = 95% CI 0.27-0.61), fruit (Kappa(w) = 0.60 95% CI 0.45-0.76) and vegetable consumption (Kappa(w) = 0.50 95% CI 0.32-0.69) showed only moderate agreement. Self-reported chronic conditions displayed substantial to almost perfect agreement (0.72 to 1.00) with the exception of moderate agreement for heart disease (Kappa = 0.82 95% CI 0.57 0.99). CONCLUSION: These results show the questions assessed to be reliable in South Australia for estimating health conditions and monitoring health related behaviours using a CATI survey. PMID- 22834890 TI - Catalytic mechanisms and biocatalytic applications of aspartate and methylaspartate ammonia lyases. AB - Ammonia lyases catalyze the formation of alpha,beta-unsaturated bonds by the elimination of ammonia from their substrates. This conceptually straightforward reaction has been the emphasis of many studies, with the main focus on the catalytic mechanism of these enzymes and/or the use of these enzymes as catalysts for the synthesis of enantiomerically pure alpha-amino acids. In this Review aspartate ammonia lyase and 3-methylaspartate ammonia lyase, which represent two different enzyme superfamilies, are discussed in detail. In the past few years, the three-dimensional structures of these lyases in complex with their natural substrates have revealed the details of two elegant catalytic strategies. These strategies exploit similar deamination mechanisms that involve general-base catalyzed formation of an enzyme-stabilized enolate anion (aci-carboxylate) intermediate. Recent progress in the engineering and application of these enzymes to prepare enantiopure l-aspartic acid derivatives, which are highly valuable as tools for biological research and as chiral building blocks for pharmaceuticals and food additives, is also discussed. PMID- 22834892 TI - Predicting water table response to rainfall events, central Florida. AB - A rise in water table in response to a rainfall event is a complex function of permeability, specific yield, antecedent soil-water conditions, water table level, evapotranspiration, vegetation, lateral groundwater flow, and rainfall volume and intensity. Predictions of water table response, however, commonly assume a linear relationship between response and rainfall based on cumulative analysis of water level and rainfall logs. By identifying individual rainfall events and responses, we examine how the response/rainfall ratio varies as a function of antecedent water table level (stage) and rainfall event size. For wells in wetlands and uplands in central Florida, incorporating stage and event size improves forecasting of water table rise by more than 30%, based on 10 years of data. At the 11 sites studied, the water table is generally least responsive to rainfall at smallest and largest rainfall event sizes and at lower stages. At most sites the minimum amount of rainfall required to induce a rise in water table is fairly uniform when the water table is within 50 to 100 cm of land surface. Below this depth, the minimum typically gradually increases with depth. These observations can be qualitatively explained by unsaturated zone flow processes. Overall, response/rainfall ratios are higher in wetlands and lower in uplands, presumably reflecting lower specific yields and greater lateral influx in wetland sites. Pronounced depth variations in rainfall/response ratios appear to correlate with soil layer boundaries, where corroborating data are available. PMID- 22834891 TI - Children with heavy prenatal alcohol exposure experience reduced control of isotonic force. AB - BACKGROUND: Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of this study was to determine whether these children exhibit similar deficits when producing isotonic (i.e., graded) force. METHODS: Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5 or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. RESULTS: Compared with control children, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. CONCLUSIONS: These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children. PMID- 22834893 TI - Birnessite-induced binding of phenolic monomers to soil humic substances and nature of the bound residues. AB - The nature of the abiotic birnessite (delta-MnO(2))-catalyzed transformation products of phenolic compounds in the presence of soil organic matter is crucial for understanding the fate and stability of ubiquitous phenolic carbon in the environment. (14)C-radioactive and (13)C-stable-isotope tracers were used to study the mineralization and transformation by delta-MnO(2) of two typical humus and lignin phenolic monomers--catechol and p-coumaric acid--in the presence and absence of agricultural and forest soil humic acids (HAs) at pH 5-8. Mineralization decreased with increasing solution pH, and catechol was markedly more mineralized than p-coumaric acid. In the presence of HAs, the mineralization was strongly reduced, and considerable amounts of phenolic residues were bound to the HAs, independent of the solution pH. The HA-bound residues were homogeneously distributed within the humic molecules, and most still contained the unchanged aromatic ring as revealed by (13)C NMR analysis, indicating that the residues were probably bound via ester or ether bonds. The study provides important information on delta-MnO(2) stimulation of phenolic carbon binding to humic substances and the molecular distribution and chemical structure of the bound residues, which is essential for understanding the environmental fates of both naturally occurring and anthropogenic phenolic compounds. PMID- 22834894 TI - Insular stroke is associated with acute sympathetic hyperactivation and immunodepression. AB - BACKGROUND AND PURPOSE: Post-stroke immunodepression has been related to brain lesion size but not a specific lesion location. Here, we studied the influence of lesion location within middle cerebral artery (MCA) territory on parameters related to activation of sympathetic adrenomedullar pathway, immunodepression, and associated infection. METHODS: We analyzed clinical, brain imaging, and laboratory data of 384 patients (174 women; mean age 70.8 +/- 12.9 years) consecutively admitted to the stroke unit no later than 24 h after onset of acute ischaemic stroke involving the MCA territory. RESULTS: Patients with lesion affecting >33% of MCA territory had increased serum metanephrine and normetanephrine levels, elevated neutrophil counts but decreased eosinophil, helper T lymphocyte, and cytotoxic T lymphocyte counts compared to patients with lesion in <33% of MCA territory. Patients with large infarctions had increased frequency of infections within 14 days after stroke, especially chest infections (P < 0.001). Considering only patients with non-lacunar infarction in <33% of MCA territory, those with insular lesion had significantly higher normetanephrine levels, higher neutrophil but lower eosinophil and helper T lymphocyte counts than those with non-insular lesion, despite similar lesion diameters. This coincided with an increased frequency of chest infections (P < 0.01) in patients with insular lesion. Whilst patients with right insular lesion showed decreased heart rate variability, lesion laterality had no impact on laboratory findings or infection frequency. CONCLUSION: These findings suggest a specific role of insular lesion in the pathogenesis of stroke-induced sympathetic hyperactivation and immunodepression. Neuroimaging studies applying lesion volume calculation techniques are warranted to confirm these findings. PMID- 22834895 TI - Recapitulating aspects of the oxygen and substrate environment of the damaged joint milieu for stem cell-based cartilage tissue engineering. AB - Human infrapatellar fat pad contains a source of mesenchymal stem cells (FPSCs) that potentially offer a novel population for the treatment of damaged or diseased articular cartilage. Existing cartilage repair strategies such as microfracture harness the presence of a low-oxygen microenvironment, fibrin clot formation at sites of microfracture, and elevations in growth factors in the damaged joint milieu. Bearing this in mind, the objective of this study was to determine the chondrogenic potential of diseased human FPSCs in a model system that recapitulates some of these features. In the first phase of the study, the role of transforming growth factor beta-3 (TGF-beta3) and fibroblast growth factor-2 (FGF-2), in addition to an altered oxygen-tension environment, on the colony-forming unit-fibroblast (CFU-F) capacity and growth kinetics of human FPSCs during monolayer expansion was evaluated. The subsequent chondrogenic capacity of these cells was quantified in both normoxic (20%) and low- (5%) oxygen conditions. Expansion in FGF-2 was shown to reduce CFU-F numbers, but simultaneously increase both the colony size and the cell yield compared to standard expansion conditions. Supplementation with both FGF-2 and TGF-beta3 significantly reduced cell-doubling time. Expansion in FGF-2, followed by differentiation at 5% oxygen tension, was observed to synergistically enhance subsequent sulfated glycosaminoglycan (sGAG) accumulation after chondrogenic induction. FPSCs expanded in FGF-2 were then encapsulated in either agarose or fibrin hydrogels in an attempt to engineer cartilaginous grafts. sGAG synthesis was higher in fibrin constructs, and was further enhanced by differentiation at 5% oxygen tension, accumulating 2.7% (ww) sGAG after 42 days in culture. These results indicate that FPSCs, a readily accessible cell population, form cartilage in an in vitro environment that recapitulates several key biological features of cartilage repair during microfracture and also point toward the potential utility of such cells when combined with fibrin hydrogel scaffolds. PMID- 22834896 TI - Spontaneous intracranial hypotension syndrome treated with a double epidural blood patch. AB - Spontaneous intracranial hypotension (SIH) is considered to be a very rare disease. It is characterised by an orthostatic headache in the absence of a past history of a trauma or a dural puncture. SIH is caused by a spontaneous spinal cerebrospinal fluid (CSF) leakage demonstrated by neuroradiological studies in most of the patients. Conservative treatment usually includes bed rest, hydration and administration of caffeine or steroids. However, when the patient is refractory to the conservative treatment, an epidural blood patch (EBP) is performed. We report a 34-year-old woman with SIH and no neuroradiologically demonstrable clear point of CSF leakage, who was treated with a double EBP at two different levels (lumbar and thoracic) in the same procedure. The patient was successfully managed, and she was still asymptomatic at the 18 months follow-up. After review of literature, we observed that execution of a double EBP at the same time is not a common procedure for treatment of SIH. We consider that simultaneous use of two EBP could be useful as a novel treatment in those cases of SIH without demonstration of CSF leakage. PMID- 22834897 TI - Human biology at the interface of paediatrics: measuring bone mineral accretion during childhood. AB - BACKGROUND: Professor Tanner established a paradigm for the study of growth and development that demands precise growth measurements, description of normal variability through development to adulthood, consideration of the effects of tempo and the study of factors that influence growth outcomes. The relatively new field of paediatric bone health assessment fits this paradigm and reflects the collaboration of human biologists and paediatricians in understanding the growth of the human skeleton. REVIEW: This review describes the reasons for clinical assessment of bone density in children, the technological developments in bone health assessment in children, the development of reference curves and the effects of growth, body composition, pubertal timing, genetics and lifestyle on bone health outcomes. PMID- 22834898 TI - Re: which is more important in predicting the outcome of extracorporeal shockwave lithotripsy of solitary renal stones: stone location or stone burden? (From: Khalil MM. J Endourol 2012;26:535-539.). PMID- 22834900 TI - High physician adherence to phenotype-specific asthma guidelines, but large variability in phenotype assessment in children. AB - BACKGROUND: The implementation of international pediatric asthma guidelines hinges on the distinction between intermittent and persistent phenotypes and the prescription of recommended phenotype-specific pharmacotherapy. OBJECTIVES: To ascertain key factors associated with specialist-confirmed phenotype and document physicians' adherence to practice recommendations in an academic pediatric asthma center. DESIGN/METHODS: Using electronic health records, we identified a cohort of children aged 1-17 years who presented to a tertiary-care asthma center between 2002 and 2007 and received a diagnosis of asthma from a pediatric specialist. Outcomes included: determinants of phenotypes and conformity with phenotype-specific treatment recommendations. RESULTS: Of the 3490 eligible children (11,119 visits), most (47%) were preschoolers, 35% were 6-11 years and 18%, 13-17 years. Of children with confirmed asthma, 59% were classified on presentation as having intermittent, 41% as persistent, asthma. The within patient phenotype varied over time with a consistency index of 0.76 (best=1); the latter was significantly lower in preschoolers than older children (p<0.0001). The persistent phenotype was highly physician-dependent; it was also positively associated with child's age, asthma severity, multiple triggers, calendar year, and duration of follow-up. Compared to 33% of children with intermittent asthma, 82% of those with persistent asthma were prescribed a maintenance controller, most as monotherapy; combination therapy was usually prescribed after a trial of monotherapy. CONCLUSION: Pediatric asthma specialists were highly adherent to phenotype-specific pharmacotherapy. However, even in an academic center, the notable degree of intra-patient and between-physician variation in phenotype, particularly in preschoolers, was an important impediment to prescribing a maintenance controller. The findings underline the importance of developing validated and standardized means of assessing phenotypes, applicable to the whole pediatric age spectrum. PMID- 22834901 TI - Management of heavy menstrual bleeding in general practice. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is a common symptom that leads women to seek medical treatment. Sources of HMB are variable; patients may present with obvious uterine pathology, systemic disease, or even localized hemostatic dysregulation that defies clinical measurement. Whereas surgical intervention even in the absence of overt pathology had historically been the most common route of treatment for HMB, an expanding therapeutic armamentarium provides greater options and the possibility of maintaining fertility in affected women. SCOPE: A descriptive literature review was performed to identify relevant articles discussing the management of HMB. The PubMed database was searched using the terms 'heavy menstrual bleeding', 'menorrhagia', 'abnormal uterine bleeding', or 'dysfunctional uterine bleeding' in combination with 'diagnosis', 'treatment', 'management', or 'guidelines'. Results were limited to articles published in English within the past 10 years. Additional statements, consensus documents, and clinical guidelines were located through review of professional society websites. FINDINGS: For practical purposes, a subjective definition of HMB (i.e., excessive menstrual blood loss that is not tolerated by the patient and adversely affects quality of life) rather than objective measures can be used by the clinician as the basis for further investigation. Standard diagnostic examinations and initiation of therapy are well within the purview of the general practitioner. A wide variety of medical therapy options are available, although few treatments are specifically indicated for the management of HMB. The approval of tranexamic acid in the United States specifically for the treatment of HMB is a recent development that provides practitioners with an effective, noncontraceptive alternative medical therapy. For women without evidence of uterine pathology, invasive/surgical procedures are generally considered as a second-line treatment option. CONCLUSIONS: Given the breadth of available medical and surgical treatment choices, identifying a suitable therapeutic strategy should be feasible for all patients, even in this highly heterogeneous population. PMID- 22834902 TI - Discovery of a novel noniminosugar acid alpha glucosidase chaperone series. AB - Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Many disease causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models. PMID- 22834903 TI - A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2 hydroxyglutaric aciduria. AB - BACKGROUND: L-2-hydroxyglutaric aciduria is a metabolic repair deficiency characterized by elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid. Neurological signs associated with the disease in humans and dogs include seizures, ataxia and dementia. CASE PRESENTATION: Here we describe an 8 month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog's behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2 hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional. CONCLUSIONS: We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a non-functional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies. PMID- 22834904 TI - Application of concentrated deep sea water inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice. AB - BACKGROUND: Mineral water from deep-sea bedrock, formed over thousands of years, is rich in minerals such as Ca, Mg, Na, K, Fe and others. Our present study was to investigate the preventive effects of natural deep-sea water on developing atopic dermatitis (AD). METHODS: We elicited AD by application of DNCB (2,4 dinitro-chlorobezene) in Nc/Nga mouse dorsal skin. Deep Sea water (DSW) was filtered and concentrated by a nanofiltration process and reverse osmosis. We applied concentrated DSW (CDSW) to lesions five times per week for six weeks, followed by evaluation. 1% pimecrolimus ointment was used as positive control. The severity of skin lesions was assessed macroscopically and histologically. Levels of inflammatory mediators and cytokines in the serum were detected by Enzyme-linked immunosorbent assay (ELISA) and the levels of CD4+ and CD8+ spleen lymphocytes were determined by flow cytometry analysis. RESULTS: DNCB-treated mice showed atopic dermatitis-like skin lesions. Treatment of mice with CDSW reduced the severity of symptoms in the skin lesions, including edema, erythema, dryness, itching, and transepidermal water loss (TEWL). Histological analyses demonstrated that epidermal thickness and infiltration of inflammatory cells were decreased after CDSW treatment. Given these interesting observations, we further evaluated the effect of CDSW on immune responses in this AD model. Treatment AD mice with CDSW inhibited up-regulation of IgE, histamine, and pro-inflammatory cytokines in the serum. Also, the CD4+/CD8+ ratio in spleen lymphocyte was down regulated after treatment with CDSW. Finally, cytokines, especially IL-4 and IL 10 which are important for Th2 cell development, were reduced. CONCLUSIONS: Our data suggests that topical application of CDSW could be useful in preventing the development of atopic dermatitis. PMID- 22834905 TI - All-cause mortality and periodontitis in 60-70-year-old men: a prospective cohort study. AB - OBJECTIVE: To investigate the association between periodontitis and mortality from all causes in a prospective study in a homogenous group of 60- to 70-year old West European men. METHODOLOGY: A representative sample of 1400 dentate men, (mean age 63.8, SD 3.0 years), drawn from the population of Northern Ireland, had a comprehensive periodontal examination between 2001 and 2003. Men were divided into thirds on the basis of their mean periodontal attachment loss (PAL). The primary endpoint, death from any cause, was analysed using Kaplan-Meier survival plots and Cox's proportional hazards model. RESULTS: In total, 152 (10.9%) of the men died during a mean follow-up of 8.9 (SD 0.7) years; 37 (7.9%) men in the third with the lowest PAL (<1.8 mm) died compared with 73 (15.7%) in the third with the highest PAL (>2.6 mm). The unadjusted hazard ratio (HR) for death in the men with the highest level of PAL compared with those with the lowest PAL was 2.11 (95% CI 1.42-3.14), p < 0.0001. After adjustment for confounding variables (age, smoking, hypertension, BMI, diabetes, cholesterol, education, marital status and previous history of a cardiovascular event) the HR was 1.57 (1.04 2.36), p = 0.03. CONCLUSION: The European men in this prospective cohort study with the most severe loss of periodontal attachment were at an increased risk of death compared with those with the lowest loss of periodontal attachment. PMID- 22834906 TI - Selective and hyperactive uptake of foreign DNA by adaptive immune systems of an archaeon via two distinct mechanisms. AB - Central to the disparate adaptive immune systems of archaea and bacteria are clustered regularly interspaced short palindromic repeats (CRISPR). The spacer regions derive from invading genetic elements and, via RNA intermediates and associated proteins, target and cleave nucleic acids of the invader. Here we demonstrate the hyperactive uptake of hundreds of unique spacers within CRISPR loci associated with type I and IIIB immune systems of a hyperthermophilic archaeon. Infection with an environmental virus mixture resulted in the exclusive uptake of protospacers from a co-infecting putative conjugative plasmid. Spacer uptake occurred by two distinct mechanisms in only one of two CRISPR loci subfamilies present. In two loci, insertions, often multiple, occurred adjacent to the leader while in a third locus single spacers were incorporated throughout the array. Protospacer DNAs were excised from the invading genetic element immediately after CCN motifs, on either strand, with the secondary cut apparently produced by a ruler mechanism. Over a 10-week period, there was a gradual decrease in the number of wild-type cells present in the culture but the virus and putative conjugative plasmid were still propagating. The results underline the complex dynamics of CRISPR-based immune systems within a population infected with genetic elements. PMID- 22834907 TI - 'Uninterested in anything except food': the work of nurses feeding the liberated inmates of Bergen-Belsen. AB - AIMS AND OBJECTIVES: The aim of this article is to explore the work of nurses feeding and helping liberate the inmates of Bergen-Belsen concentration camp in the spring of 1945. BACKGROUND: A considerable amount has been published on the relief of Belsen, but the majority of the research has focused on the medical staff and the army in general. The exception to this is an article published by Ellen Ben-Sefer, but its analysis of the actual work of the nurses is limited. DESIGN: The data are explored through the medium of nurses' work, especially feeding work and its place in the historiography. METHODS: This article will offer an analysis of archival material, including official reports and personal testimony and published primary sources. RESULTS: Nurses were very much hidden from the liberation picture, partly through government policy, partly because of gendered ideologies and partly because of the desire of many to hide their memories. However, the data identify the pivotal role of nurses in the saving of lives and rehabilitation of inmates. This article demonstrates this role through the work of feeding. CONCLUSION: The nurses had to continually negotiate and renegotiate their place in the liberation. As women, their place at Belsen was problematic and often thwarted by the ideologies of the day. Nevertheless, the services of registered nurses during the war had proved indispensible. The Allied governments and Royal Army Medical Corps were ultimately to rely on their professional expertise. The nurses' work in the feeding of starving inmates demonstrates their value. RELEVANCE TO CLINICAL PRACTICE: This article demonstrates the importance of nurses' feeding work and their role in the caring of people's humanity. PMID- 22834908 TI - Modeling variably saturated subsurface solute transport with MODFLOW-UZF and MT3DMS. AB - The MT3DMS groundwater solute transport model was modified to simulate solute transport in the unsaturated zone by incorporating the unsaturated-zone flow (UZF1) package developed for MODFLOW. The modified MT3DMS code uses a volume averaged approach in which Lagrangian-based UZF1 fluid fluxes and storage changes are mapped onto a fixed grid. Referred to as UZF-MT3DMS, the linked model was tested against published benchmarks solved analytically as well as against other published codes, most frequently the U.S. Geological Survey's Variably-Saturated Two-Dimensional Flow and Transport Model. Results from a suite of test cases demonstrate that the modified code accurately simulates solute advection, dispersion, and reaction in the unsaturated zone. Two- and three-dimensional simulations also were investigated to ensure unsaturated-saturated zone interaction was simulated correctly. Because the UZF1 solution is analytical, large-scale flow and transport investigations can be performed free from the computational and data burdens required by numerical solutions to Richards' equation. Results demonstrate that significant simulation runtime savings can be achieved with UZF-MT3DMS, an important development when hundreds or thousands of model runs are required during parameter estimation and uncertainty analysis. Three-dimensional variably saturated flow and transport simulations revealed UZF MT3DMS to have runtimes that are less than one tenth of the time required by models that rely on Richards' equation. Given its accuracy and efficiency, and the wide-spread use of both MODFLOW and MT3DMS, the added capability of unsaturated-zone transport in this familiar modeling framework stands to benefit a broad user-ship. PMID- 22834910 TI - Three insulation methods to minimize intravenous fluid administration set heat loss. AB - OBJECTIVE: To assess the effect of three methods for insulating an intravenous (IV) fluid administration set on the temperature of warmed fluid delivered rapidly in a cold environment. METHODS: The three chosen techniques for insulation of the IV fluid administration set involved enclosing the tubing of the set in 1) a cotton conforming bandage, 2) a reflective emergency blanket, and 3) a combination of technique 2 followed by technique 1. Intravenous fluid warmed to 44 degrees C was infused through a 20-drop/mL 180-cm-long fluid administration set in a controlled environmental temperature of 5 degrees C. Temperatures in the IV fluid bag, the distal end of the fluid administration set, and the environment were continuously measured with resistance thermosensors. Twenty repetitions were performed in four conditions, namely, a control condition (with no insulation) and the three different insulation methods described above. One-way analysis of variance was used to assess the mean difference in temperature between the IV fluid bag and the distal fluid administration set under the four conditions. RESULTS: In the control condition, a mean of 5.28 degrees C was lost between the IV fluid bag and the distal end of the fluid administration set. There was a significant difference found between the four conditions (p < 0.001). A mean of 3.53 degrees C was lost between the IV fluid bag and the distal end of the fluid administration set for both the bandage and reflective emergency blanket, and a mean of 3.06 degrees C was lost when the two methods were combined. CONCLUSION: Using inexpensive and readily available materials to insulate a fluid administration set can result in a reduction of heat loss in rapidly infused, warmed IV fluid in a cold environment. PMID- 22834909 TI - An updated prostate cancer staging nomogram (Partin tables) based on cases from 2006 to 2011. AB - OBJECTIVE: To update the 2007 Partin tables in a contemporary patient population. PATIENTS AND METHODS: The study population consisted of 5,629 consecutive men who underwent RP and staging lymphadenectomy at the Johns Hopkins Hospital between January 1, 2006 and July 30, 2011 and met inclusion criteria. Polychotomous logistic regression analysis was used to predict the probability of each pathologic stage category: organ-confined disease (OC), extraprostatic extension (EPE), seminal vesicle involvement (SV+), or lymph node involvement (LN+) based on preoperative criteria. Preoperative variables included biopsy Gleason score (6, 3+4, 4+3, 8, and 9-10), serum PSA (0-2.5, 2.6-4.0, 4.1-6.0, 6.1-10.0, greater than 10.0 ng/mL), and clinical stage (T1c, T2c, and T2b/T2c). Bootstrap re sampling with 1000 replications was performed to estimate 95% confidence intervals for predicted probabilities of each pathologic state. RESULTS: The median PSA was 4.9 ng/mL, 63% had Gleason 6 disease, and 78% of men had T1c disease. 73% of patients had OC disease, 23% had EPE, 3% had SV+ but not LN+, and 1% had LN+ disease. Compared to the previous Partin nomogram, there was no change in the distribution of pathologic state. The risk of LN+ disease was significantly higher for tumours with biopsy Gleason 9-10 than Gleason 8 (O.R. 3.2, 95% CI 1.3-7.6). The c-indexes for EPE vs. OC, SV+ vs. OC, and LN+ vs. OC were 0.702, 0.853, and 0.917, respectively. Men with biopsy Gleason 4+3 and Gleason 8 had similar predicted probabilities for all pathologic stages. Most men presenting with Gleason 6 disease or Gleason 3+4 disease have <2% risk of harboring LN+ disease and may have lymphadenectomy omitted at RP. CONCLUSIONS: The distribution of pathologic stages did not change at our institution between 2000-2005 and 2006-2011. The updated Partin nomogram takes into account the updated Gleason scoring system and may be more accurate for contemporary patients diagnosed with prostate cancer. PMID- 22834912 TI - Nonreplicating protocells. AB - Prebiotic soup experiments have shown that the molecular building blocks of life can be built under prebiotically plausible conditions. From this starting point, researchers have launched continued studies of polymerization and explorations of the breadth of RNA function. Recently, effort has intensified to examine experimentally another stage of the origins of life: the assembly of the molecular parts into model protocells intended to represent the first primitive, cell-like systems to emerge on Earth. Although it may not be possible to recreate the precise sequence of events that led to cellular life, laboratory experiments have begun to show what was and was not possible. Prebiotically plausible lipid vesicles form easily and have many properties that are conducive to cellular function. In addition to protecting nascent replicating genetic systems from parasitic sequences, vesicles facilitate evolution. The data thus far suggest that prebiotically plausible vesicles could have grown, divided, and promoted competition between distinct chemical systems. Most protocellular studies to date have probed the role of self-replication, one feature of extant life in the emergence of the first cellular system. Undoubtedly replicating systems were crucial for protocellular evolution, but other features of life must have been important as well. For example, life does not exist in isolation. A living system must cope with and adapt to environmental fluctuations to survive. The protocell must have generated some of these fluctuations because cellular activity necessarily modifies its surroundings by selectively absorbing nutrients and releasing unwanted molecules. It seems likely that life would have faced this challenge early and either emerged in dynamic locales that continuously regenerated conditions conducive to life or exploited mechanisms to physically move to new areas not depleted in resources. Further studies that explore non replication-based aspects of the origins of life could reveal a more complete picture of the transition from prebiotic chemistry to early life. PMID- 22834911 TI - Manganese superoxide dismutase is dispensable for post-natal development and lactation in the murine mammary gland. AB - Mammary gland development is a multistage process requiring tightly regulated spatial and temporal signalling pathways. Many of these pathways have been shown to be sensitive to oxidative stress. Understanding that the loss of manganese superoxide dismutase (Sod2) leads to increased cellular oxidative stress, and that the loss or silencing of this enzyme has been implicated in numerous pathologies including those of the mammary gland, we sought to examine the role of Sod2 in mammary gland development and function in situ in the mouse mammary gland. Using Cre-recombination driven by the mouse mammary tumor virus (MMTV) promoter, we created a mammary-specific post-natal conditional Sod2 knock-out mouse model. Surprisingly, while substantial decreases in Sod2 were noted throughout both virgin and lactating adult mammary glands, no significant changes in developmental structures either pre- or post-pregnancy were observed histologically. Moreover, mothers lacking mammary gland expression of Sod2 were able to sustain equal numbers of litters, equal pups per litter, and equal pup weights as were control animals. Overall, our results demonstrate that loss of Sod2 expression is not universally toxic to all cell types and that excess mitochondrial superoxide can apparently be tolerated during the development and function of post-natal mammary glands. PMID- 22834913 TI - Etanercept treatment in Fanconi anaemia; combined US and Italian experience. PMID- 22834914 TI - Restless legs syndrome and functional limitations among American elders in the Health and Retirement Study. AB - BACKGROUND: Restless legs syndrome (RLS) is a common condition associated with decreased quality of life in older adults. This study estimates the prevalence, risk factors, and functional correlates of among U.S. elders. METHODS: Subjects (n = 1,008) were sub-sampled from the 2002 cross-sectional interview survey of the Health and Retirement Study (HRS), a nationally representative study of U.S. elders. Symptoms and sleep disturbances consistent with RLS were identified. Activities of daily living (ADL), instrumental activities of daily living (IADL), and limitations for mobility, large muscle groups, gross and fine motor function were measured using standardized questions. Incident functional limitations were detected over six years of observation. RESULTS: The prevalence of RLS among U.S. elders born before 1947 was 10.6%. Factors associated with increased prevalence RLS at baseline included: overweight body mass index (multivariate adjusted prevalence ratio = 1.77; 95% confidence interval (CI) 1.05-2.99); mild-to moderate pain (2.67, 1.47-4.84) or pain inferring with activity (3.44, 2.00 5.93); three or more chronic medications (2.54, 1.26-5.12), highest quartile of out-of-pocket medical expenses (2.12, 1.17-3.86), frequent falls (2.63, 1.49 4.66), health limiting ability to work (2.91, 1.75-4.85), or problems with early waking or frequent wakening (1.69, 1.09-2.62 and 1.55, 1.00-2.41, respectively). Current alcohol consumption (0.59, 0.37-0.92) and frequent healthcare provider visits (0.49, 0.27-0.90) were associated with decreased RLS prevalence. RLS did not predict incident disability for aggregate measures but was associated with increased risk for specific limitations, including: difficulty climbing several stair flights (multivariate-adjusted hazard ratio = 2.38, 95% CI 1.39-4.06), prolonged sitting (2.17, 1.25-3.75), rising from a chair (2.54, 1.62-3.99), stooping (2.66, 1.71-4.15), moving heavy objects (1.79, 1.08-2.99), carrying ten pounds (1.61, 1.05-2.97), raising arms (1.76, 1.05-2.97), or picking up a dime (1.97, 1.12-3.46). CONCLUSIONS: RLS sufferers are more likely to have functional disability, even after adjusting for health status and pain syndrome correlates. PMID- 22834915 TI - In vitro exposures in diesel exhaust atmospheres: resuspension of PM from filters versus direct deposition of PM from air. AB - One of the most widely used in vitro particulate matter (PM) exposures methods is the collection of PM on filters, followed by resuspension in a liquid medium, with subsequent addition onto a cell culture. To avoid disruption of equilibria between gases and PM, we have developed a direct in vitro sampling and exposure method (DSEM) capable of PM-only exposures. We hypothesize that the separation of phases and post-treatment of filter-collected PM significantly modifies the toxicity of the PM compared to direct deposition, resulting in a distorted view of the potential PM health effects. Controlled test environments were created in a chamber that combined diesel exhaust with an urban-like mixture. The complex mixture was analyzed using both the DSEM and concurrently collected filter samples. The DSEM showed that PM from test atmospheres produced significant inflammatory response, while the resuspension exposures at the same exposure concentration did not. Increasing the concentration of resuspended PM sixteen times was required to yield measurable IL-8 expression. Chemical analysis of the resuspended PM indicated a total absence of carbonyl compounds compared to the test atmosphere during the direct-exposures. Therefore, collection and resuspension of PM into liquid modifies its toxicity and likely leads to underestimating toxicity. PMID- 22834916 TI - Use of AUDIT-based measures to identify unhealthy alcohol use and alcohol dependence in primary care: a validation study. AB - BACKGROUND: As programs for screening, brief intervention, and referral to treatment (SBIRT) for unhealthy alcohol use disseminate, evidence-based approaches for identifying patients with unhealthy alcohol use and alcohol dependence (AD) are needed. While the National Institute on Alcohol Abuse and Alcoholism Clinician Guide suggests use of a single alcohol screening question (SASQ) for screening and Diagnostic and Statistical Manual checklists for assessment, many SBIRT programs use alcohol use disorders identification test (AUDIT) "zones" for screening and assessment. Validation data for these zones are limited. This study used primary care data from a bi-ethnic southern U.S. population to examine the ability of the AUDIT zones and other AUDIT-based approaches to identify unhealthy alcohol use and dependence. METHODS: Existing data were analyzed from interviews with 625 female and male adult drinkers presenting to 5 southeastern primary care practices. Timeline follow-back was used to identify at-risk drinking, and diagnostic interview schedule was used to identify alcohol abuse and dependence. Validity measures compared performance of AUDIT, AUDIT-C, and AUDIT dependence domains scores, with and without a 30-day binge drinking measure, for detecting unhealthy alcohol use and dependence. RESULTS: Optimal AUDIT scores for detecting unhealthy alcohol use were lower than current commonly used cutoffs (5 for men, 3 for women). Improved performance was obtained by combining AUDIT cutoffs of 6 for men and 4 for women with a 30-day binge drinking measure. AUDIT scores of 15 for men and 13 for women detected AD with 100% specificity but low sensitivity (20 and 18%, respectively). AUDIT dependence subscale scores of 2 or more showed similar specificity (99%) and slightly higher sensitivity (31% for men, 24% for women). CONCLUSIONS: Combining lower AUDIT cutoff scores and binge drinking measures may increase the detection of unhealthy alcohol use in primary care. Use of lower cutoff scores and dependence subscale scores may increase diagnosis of AD; however, better measures for detecting dependence are needed. PMID- 22834917 TI - Optimization of fiber coating structure enables direct immersion solid phase microextraction and high-throughput determination of complex samples. AB - This study presents a new approach for improving the structure, and hence the robustness, of the SPME fiber coating applied for gas chromatography (GC) analysis. It involves application of an external layer of poly(dimethyl siloxane) (PDMS) over the commercial PDMS/divinyl benzene (DVB) extraction phase. The fiber provided extraction capabilities similar to that exhibited by the original PDMS/DVB fiber toward triazole pesticides from water samples. Furthermore, the fiber could be utilized for over 100 extractions in direct contact with a complex food matrix such as whole grape pulp, with no sample pretreatment required. The amount of extracted pesticides from whole grape pulp had RSD values below 20% throughout 130 extraction/desorption/conditioning cycles, which is a dramatic improvement when compared to commercial PDMS/DVB fiber coating applied in food analysis facilitating high-throughput automation. PMID- 22834918 TI - A biocompatible tissue scaffold produced by supercritical fluid processing for cartilage tissue engineering. AB - Supercritical fluids are used in various industrial fields, such as the food and medical industries, because they have beneficial physical and chemical properties and are also nonflammable and inexpensive. In particular, supercritical carbon dioxide (ScCO(2)) is attractive due to its mild critical temperature, pressure values, and nontoxicity. Poly(L-lactide-co-E-caprolactone) (PLCL), which is a biocompatible, biodegradable, and very elastic polymer, has been used in cartilage tissue engineering. However, organic solvents, such as chloroform or dichloromethane, are usually used for the fabrication of a PLCL scaffold through conventional methods. This leads to a cytotoxic effect and long processing time for removing solvents. To alleviate these problems, supercritical fluid processing is introduced here. In this study, we fabricated a mechano-active PLCL scaffold by supercritical fluid processing for cartilage tissue engineering, and we compared it with a scaffold made by a conventional solvent-casting method in terms of physical and biological performance. Also, to examine the optimum condition for preparing scaffolds with ScCO(2), we investigated the effects of pressure, temperature, and the depressurization rate on PLCL foaming. The PLCL scaffolds produced by supercritical fluid processing had a homogeneously interconnected porous structure, and they exhibited a narrow pore size distribution. Also, there was no cytotoxicity of the scaffolds made with ScCO(2) compared to the scaffolds made by the solvent-pressing method. The scaffolds were seeded with chondrocytes, and they were subcutaneously implanted into nude mice for up to 4 weeks. In vivo accumulation of extracellular matrix of cell-scaffold constructs demonstrated that the PLCL scaffold made with ScCO(2) formed a mature and well-developed cartilaginous tissue compared to the PLCL scaffold formed by solvent pressing. Consequently, these results indicated that the PLCL scaffolds made by supercritical fluid processing offer well-interconnected and nontoxic substrates for cell growth, avoiding problems associated with a solvent residue. This suggests that these elastic PLCL scaffolds formed by supercritical fluid processing could be used for cartilage tissue engineering. PMID- 22834919 TI - The potential prognostic role of cardiovascular autonomic failure in alpha synucleinopathies. AB - Cardiovascular autonomic failure is the second most common dysautonomic feature of alpha-synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in alpha-synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword-based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all alpha-synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood-brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in alpha-synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course. PMID- 22834920 TI - Editorial comment for Sandhu et al. PMID- 22834921 TI - The perioperative combination of methadone and ketamine reduces post-operative opioid usage compared with methadone alone. AB - BACKGROUND: A synergy between ketamine and methadone (ME) to produce antinociception has been demonstrated in experimental neuropathy. We wanted to compare post-operative opioid requirements in patients undergoing multilevel lumbar arthrodesis after the administration combined ME-ketamine (MK) or ME alone. METHODS: This was a randomised double-blind study. During sevoflurane remifentanil anaesthesia, 11 patients in each group received the following: ketamine bolus (0.5 mg/kg) after tracheal intubation, followed by an infusion of 2.5 MUg/kg/min in the MK or saline bolus plus infusion in the ME group. Post operative analgesia - during 48 h - was provided by patient-controlled analgesia (PCA), delivering bolus containing the following: ME 0.25 mg plus ketamine 0.5 mg in the MK group or ME 0.5 mg in the ME group. Lockout was 10 min, maximum of 3 boluses/h in both groups. Before closing the wound, all the patients received intravenous (i.v.) ME 0.1 mg/kg, dexketoprophen and paracetamol. Pain intensity was evaluated by a numerical rating scale (NRS), on arrival at recovery room (RR) and 24 and 48 h after surgery. In the RR, i.v. ME was administered until NRS was 3 when PCA was started. Dexketoprophen and paracetamol were administered 48 h. RESULTS: Remifentanil requirements were higher in the MK group (P = 0.004). Patients in the MK group received 70% less ME by PCA at 24 h (MK vs. ME group, median and interquartile range) - 3.43 mg (1.9-6.5) vs. 15 mg (9.65-17.38) (P < 0.001) - and at 48 h - 2 mg (0.5-3.63) vs. 9.5 mg (3.5-13.75) (P = 0.001). Patients in the MK group also attempted less doses, at 24 h: 19.5 (12.75-79.5) vs. 98 (41.5-137) (P = 0.043). Both groups had similar NRS values and comparable side effects. CONCLUSIONS: Perioperative ketamine-ME combination significantly decreased opioid consumption by PCA. PMID- 22834922 TI - siRNA knockdown of GPR18 receptors in BV-2 microglia attenuates N-arachidonoyl glycine-induced cell migration. AB - BACKGROUND: Neurons are known to employ the endogenous cannabinoid system to communicate with other cells of the CNS. Endocannabioid signaling recruits microglia toward neurons by engaging cannabinoid CB2 and abnormal cannabidiol (Abn-CBD) receptors. The Abn-CBD receptor is a prominent atypical cannabinoid receptor that had been discriminated by means of various pharmacological and genetic tools but remained to be identified at the molecular level. We recently introduced N-arachidonoyl glycine (NAGly) signaling via GPR18 receptors as an important novel signaling mechanism in microglial-neuronal communication. NAGly is an endogenous, enzymatically oxygenated metabolite of the endocannabinoid N arachidonoyl ethanolamide (AEA). Our recent studies support strongly two hypotheses; first that NAGly initiates directed microglial migration in the CNS through activation of GPR18, and second that GPR18 is the Abn-CBD receptor. Here we present siRNA knockdown data in further support of these hypotheses. FINDINGS: A GPR18-targetting siRNA pSUPER G418 GFP cDNA plasmid was created and transfected into BV-2 microglia. Successfully transfected GFP+ GPR18 siRNA BV-2 microglia displayed reduced GPR18 mRNA levels and immunocytochemical staining. Cell migration induced by 1 MUM concentrations of NAGly, O-1602 and Abn-CBD were significantly attenuated in GFP+ cells. CONCLUSIONS: Our data provide definitive evidence that these compounds, characteristic of Abn-CBD receptor pharmacology, are acting via GPR18 in BV-2 microglia. A fuller understanding of the hitherto unidentified cannabinoid receptors such as GPR18; their molecular interactions with endogenous ligands; and how phytocannabinoids influence their signaling is vital if we are to comprehensively assess the function of the endogenous cannabinoid signaling system in human health and disease. PMID- 22834923 TI - Melanogenesis inhibitory and fibroblast proliferation accelerating effects of noroleanane- and oleanane-type triterpene oligoglycosides from the flower buds of Camellia japonica. AB - A 28-noroleanane-type triterpene oligoglycoside, camellioside E (4), an oleanane type triterpene oligoglycoside, camellioside F (5), and the known compounds camelliosides A (1) and D (3) were isolated from a 50% EtOH extract of Camellia japonica flower buds from Korea. The principal constituents (1 and 5) significantly inhibited melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells. Camellioside B (2), a major constituent of C. japonica grown in Japan, showed potent inhibition of melanogenesis [95.0 +/- 1.0% (p < 0.01) at 20 MUM]. The inhibitory effects of 1, 2, and 5 were stronger than that of the reference compound, arbutin. We believe the melanogenesis inhibitory effects of 2 and 5 are partly related to the proliferation inhibitory effects in B16 melanoma 4A5 cells. Conversely, camelliosides tended to enhance proliferation in normal human neonatal skin fibroblasts. Interestingly, camellioside B (2) significantly accelerated fibroblast proliferation. This biological selectivity could make camellioside B useful for treating skin disorders. Herein, we report the first scientific investigation of a triterpene that displays an inhibitory effect on melanogenesis, but that also has an enhancing effect on fibroblast proliferation. PMID- 22834924 TI - Insulin resistance and polycystic ovary syndrome through life. AB - The heterogeneity of Polycystic Ovary Syndrome (PCOS) emphasizes the need for a consensual review of the data concerning its diagnosis and treatment and for determination of the relationship between the development of PCOS and the ethnic origin, the social status and the lifespan. Insulin resistance is an important characteristic in women with PCOS that aggravates features of PCOS. This review is focused in the diagnosis and treatment of insulin resistance and the risk factors for PCOS during childhood, adolescence and postmenopause. The role of endocrine disruptors and/or their interaction with PCOS have also been analyzed. PMID- 22834925 TI - Morphometric analysis of anatomical implant forms for minimally invasive acetabular fracture osteosynthesis. AB - INTRODUCTION: Anatomical implants enable minimally invasive osteosynthesis (MIO) and represent ideal complements of computer-assisted surgical workflows. This 3D morphometric study analyzes anatomical implant forms (AIF) for acetabular fracture osteosynthesis (AFO). MATERIALS AND METHODS: Three-dimensional pelvis models were created from clinical CT data of 99 European-Caucasian patients (50 females, 49 males). The mean age of the patients was 60.1 years (range: 20-89; SD 10.8). Definition of a referential region of interest (ROI) corresponding to an AIF for AFO was followed by automated ROI computation for each of the 198 hemipelvises. Three-dimensional statistical modeling and analysis of the resulting 198 homologous ROIs consisted of thin-plate spline transformation, generalized Procrustes fit, and principal component analysis. RESULTS: The mean ROI length was 18.2 cm (range: 16.1-20.1 cm; SD 0.76). The first principal component (PC1) mainly modeled the ROI length, which correlated well with body height (r = 0.325; p < 0.001). PC1 comprised 47.4% of the overall ROI form variation. PC2 primarily influenced the ROI curvature in the anterior-posterior (inlet) view. Curvatures were more pronounced in female patients compared to males (p < 0.001). There was no gender-specific ROI size variation. PC1-4 contained 80.2% of the total ROI form variation. Left and right ROI forms displayed symmetry. CONCLUSION: This 3D morphometric study demonstrates the feasibility of anatomical implants for minimally invasive acetabular fracture osteosynthesis. Implant size/length is by far the most important variable of form variation. The necessity of gender-specific implant forms requires further investigation. The non-fractured, contralateral hemipelvis can be used for preoperative surgical planning. Ultimately, the plate design will depend on prospective implant fit tests based on the required fit as defined by the clinician. PMID- 22834926 TI - Time course analysis of Candida albicans metabolites during biofilm development. AB - Biofilm-associated infections are difficult to treat because of their decreased susceptibility to antimicrobial therapy. Candida albicans is the most common fungal pathogen associated with colonization and biofilm formation on the surfaces of indwelling medical devices which show intrinsic resistance to many commonly used antifungal agents. In this study, a metabonomic method using gas chromatography-mass spectrometry (GC/MS) was developed to characterize metabolic profiles during the whole biofilm developmental phases compared to the planktonic mode in C. albicans. Thirty-one differentially produced metabolites between the biofilm and planktonic specimens at each time point were identified, and they were mainly involved in the tricarboxylic acid (TCA) cycle, lipid synthesis, amino acid metabolism, glycolysis, and oxidative stress. Further experiments showed that lack of trehalose, one of the metabolites differentially produced between biofilm and planktonic cells, resulted in abnormal biofilm formation and increased sensitivity to amphotericin B and miconazole. This study provides a systemic view of the metabolic pattern during the development of C. albicans biofilms, indicating that multicomponent, phase-specific mechanisms are operative in the process of biofilm formation. PMID- 22834927 TI - Identification of synthetic cannabinoids in herbal incense blends in the United States. AB - Synthetic cannabinoid agonists are chemically diverse with multiple analogs gaining popularity as drugs of abuse. We report on the use of thin layer chromatography, gas chromatography mass spectrometry, high-performance liquid chromatography, and liquid chromatography time of flight mass spectrometry for the identification and quantitation of these pharmacologically active chemicals in street drug dosage forms. Using these approaches, we have identified the synthetic cannabinoids JWH-018, JWH-019, JWH-073, JWH-081, JWH-200, JWH-210, JWH 250, CP47,497 (C=8) (cannabicyclohexanol), RCS-4, RCS-8, AM-2201, and AM-694 in various commercially available products. Other noncannabinoid drugs including mitragynine have also been detected. Typical concentrations of drug in the materials are in the range 5-20 mg/g, or 0.5-2% by weight for each compound, although many products contained more than one drug. PMID- 22834928 TI - Perspectives on modelling human growth: mathematical models and growth biology. AB - CONTEXT: James Tanner had a foundational role in promoting the modelling of growth data as an important step in further understanding the science of human growth. OBJECTIVE: A perspective on how growth models have determined the questions researchers ask and the methods used to analyse data is historically informative. Alternatively, it is useful to review that mathematical models are representations of growth as a function of time and carry assumptions that require consideration in terms of the goals of a research inquiry. METHODS: An overview of the history of the study of human growth models and modelling is summarized with reference to the important roles that these have played in the perceptions of the human growth process. RESULTS: Growth models are important descriptive summaries, embody empirical evidence and provide the opportunity for hypotheses-testing that aides the understanding, explanation and prediction of growth processes and systems. These models are modified as novel data emerge. More frequent sampling protocols and the development of mathematical models has advanced mechanistic investigations of the human growth process. CONCLUSIONS: Technical advances in science are important to investigate potential underlying mechanisms of growth and develop interventions based on a more accurate model of growth biology. PMID- 22834929 TI - The highly dynamic CRISPR1 system of Streptococcus agalactiae controls the diversity of its mobilome. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) confer immunity against mobile genetic elements (MGEs) in prokaryotes. Streptococcus agalactiae, a leading cause of neonatal infections contains in its genome two CRISPR/Cas systems. We show that type 1-C CRISPR2 is present in few strains but type 2-A CRISPR1 is ubiquitous. Comparative sequence analysis of the CRISPR1 spacer content of 351 S. agalactiae strains revealed that it is extremely diverse due to the acquisition of new spacers, spacer duplications and spacer deletions that witness the dynamics of this system. The spacer content profile mirrors the S. agalactiae population structure. Transfer of a conjugative transposon targeted by CRISPR1 selected for spacer rearrangements, suggesting that deletions and duplications pre-exist in the population. The comparison of protospacers located within MGE or the core genome and protospacer-associated motif-shuffling demonstrated that the GG motif is sufficient to discriminate self and non-self and for spacer selection and integration. Strikingly more than 40% of the 949 different CRISPR1 spacers identified target MGEs found in S. agalactiae genomes. We thus propose that the S. agalactiae type II-A CRISPR1/Cas system modulates the cohabitation of the species with its mobilome, as such contributing to the diversity of MGEs in the population. PMID- 22834930 TI - Estimation of body-size traits by photogrammetry in large mammals to inform conservation. AB - Photography, including remote imagery and camera traps, has contributed substantially to conservation. However, the potential to use photography to understand demography and inform policy is limited. To have practical value, remote assessments must be reasonably accurate and widely deployable. Prior efforts to develop noninvasive methods of estimating trait size have been motivated by a desire to answer evolutionary questions, measure physiological growth, or, in the case of illegal trade, assess economics of horn sizes; but rarely have such methods been directed at conservation. Here I demonstrate a simple, noninvasive photographic technique and address how knowledge of values of individual-specific metrics bears on conservation policy. I used 10 years of data on juvenile moose (Alces alces) to examine whether body size and probability of survival are positively correlated in cold climates. I investigated whether the presence of mothers improved juvenile survival. The posited latter relation is relevant to policy because harvest of adult females has been permitted in some Canadian and American jurisdictions under the assumption that probability of survival of young is independent of maternal presence. The accuracy of estimates of head sizes made from photographs exceeded 98%. The estimates revealed that overwinter juvenile survival had no relation to the juvenile's estimated mass (p < 0.64) and was more strongly associated with maternal presence (p < 0.02) than winter snow depth (p < 0.18). These findings highlight the effects on survival of a social dynamic (the mother-young association) rather than body size and suggest a change in harvest policy will increase survival. Furthermore, photographic imaging of growth of individual juvenile muskoxen (Ovibos moschatus) over 3 Arctic winters revealed annual variability in size, which supports the idea that noninvasive monitoring may allow one to detect how some environmental conditions ultimately affect body growth. PMID- 22834931 TI - Antioxidant potential of zinc-flavonol complex studied in streptozotocin-diabetic rats. AB - BACKGROUND: Diabetic oxidative stress coexists with a reduction in the antioxidant status, which can further increase the deleterious effects of free radicals. Zinc is an essential trace element with significant antidiabetic activity. However, the acceptance of zinc compounds as promising therapeutic antidiabetic agents has been slowed due to concerns regarding chronic toxicity. Recently, we have designed, synthesized and characterized a novel zinc-flavonol complex and evaluated its antidiabetic efficacy in streptozotocin (STZ)-diabetic rats. The aim of the present study was to evaluate the role of the zinc-flavonol complex in the antioxidant status of diabetic rats. METHODS: Diabetes was induced in rats by i.p. injection of STZ. Diabetic rats were then treated with the zinc flavonol complex (5 mg/kg, p.o.) for 30 days. The extent of oxidative stress was assessed by determining lipid peroxide levels, pancreatic tissue antioxidant enzyme activities and plasma concentrations of non-enzymatic antioxidants. In addition, nuclear levels of nuclear factor (NF)-kappaB p65, pancreatic nitric oxide (NO), and plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were determined. Pancreatic tissues were examined histologically. RESULTS: Oral treatment with the zinc-flavonol complex significantly improved antioxidant levels and alleviated levels of oxidative stress markers. Furthermore, significant increases were seen in NF-kappaB p65, NO, TNF-alpha, IL-1beta and IL-6 levels. Histological observations revealed that the zinc-flavonol complex effectively protects pancreatic beta-cells against oxidative damage. CONCLUSION: The results of the present study indicate that the zinc-flavonol complex has an antioxidative and anti-inflammatory role in the diabetic milieu. PMID- 22834932 TI - Combined photoablative and photodynamic diode laser therapy as an adjunct to non surgical periodontal treatment: a randomized split-mouth clinical trial. AB - AIM: Comparing the efficacy of photoablative and photodynamic diode laser in adjunct to scaling -root planing (SRP) and SRP alone for the treatment of chronic periodontitis. MATERIALS AND METHODS: Twenty-six patients were studied. Maxillary left or right quadrants were randomly assigned to sham-laser treatment + SRP or laser + SRP. This consisted of photoablative intra/extra-pocket de-epithelization with diode laser (lambda = 810 nm), followed by single SRP and multiple photodynamic treatments (once weekly, 4-10 applications, mean +/- SD: 3.7 +/- 2.4) using diode laser (lambda = 635 nm) and 0.3% methylene blue as photosensitizer. The patients were monitored at days 0 and 365 by clinical assessment (probing depth, PD; clinical attachment level, CAL; bleeding on probing, BOP) and at days 0, 15, 30, 45, 60, 75, 90, 365 by cytofluorescence analysis of gingival exfoliative samples taken in proximity of the teeth to be treated (polymorphonuclear leukocytes, PMN; red blood cells, RBC; damaged epithelial cells, DEC; bacteria). RESULTS: At day 365, compared with the control quadrants, the laser + SRP therapy yielded a significant (p < 0.001) reduction in PD (-1.9 mm), CAL (-1.7 mm) and BOP (-33.2% bleeding sites), as well as in bacterial contamination - especially spirochetes - and PMN and RBC shedding in the gingival samples (p < 0.001). CONCLUSIONS: Diode laser treatment (photoablation followed by multiple photodynamic cycles) adjunctive to conventional SRP improves healing in chronic periodontitis patients. PMID- 22834933 TI - Anti-glomerular basement membrane glomerulonephritis and thrombotic microangiopathy in first degree relatives: a case report. AB - BACKGROUND: Anti-glomerular basement membrane glomerulonephritis and thrombotic microangiopathy are rare diseases with no known coherence. CASE PRESENTATION: A daughter and her biological mother were diagnosed with pregnancy-induced thrombotic microangiopathy and anti-glomerular basement membrane glomerulonephritis, respectively. Both developed end-stage renal disease. Exploration of a common aetiology included analyses of HLA genotypes, functional and genetic aspects of the complement system, ADAMTS13 activity and screening for autoantibodies.The daughter was heterozygous carrier of the complement factor I G261D mutation, previously described in patients with membranoproliferative glomerulonephritis and atypical haemolytic uremic syndrome. The mother was non carrier of this mutation. They shared the disease associated complement factor H silent polymorphism Q672Q (79602A>G). CONCLUSION: An unequivocal functional or molecular association between these two family cases was not found suggesting that the patients probably share another, so far undiagnosed and unknown, predisposing factor. It seems highly unlikely that two infrequent immunologic diseases would occur by unrelated pathophysiological mechanisms within first degree relatives. PMID- 22834934 TI - SOX2 anophthalmia syndrome in adulthood - a neurodegenerative picture? PMID- 22834935 TI - Antisocial symptoms decrease to normal levels in long-term abstinence. AB - BACKGROUND: We have previously shown highly elevated antisocial symptoms and measures of social deviance proneness and antisocial disposition in long-term abstinent alcohol dependence versus non-substance-abusing controls (NSAC). Current antisocial symptoms were reduced to subdiagnostic levels in long-term abstinence; however, the number of current symptoms was not measured beyond its being subdiagnostic. METHODS: Here we measured social deviance proneness, antisocial disposition, and both lifetime and current antisocial symptoms in short-term and long-term abstinent substance-dependent and NSAC samples. RESULTS: Lifetime antisocial symptoms (and diagnoses) and social deviance proneness and antisocial disposition were highly elevated in both short- and long-term abstinence, replicating earlier findings. Current antisocial symptoms were dramatically reduced in long-term versus short-term abstinent samples, close to levels in controls. In contrast, social deviance proneness and antisocial disposition remain highly elevated in long-term abstinence. CONCLUSIONS: These findings suggest that antisocial behavior is reduced in extended abstinence, despite continued elevated social deviance proneness an antisocial disposition. This suggests a top-down model in extended abstinence, whereby executive control inhibits deviance-prone tendencies. PMID- 22834936 TI - The locus of pain control in patients with lower limb ulcerations. AB - AIMS AND OBJECTIVES: (1) To analyse the distribution of pain control profiles of individuals suffering from the lower limb ulcerations. (2) To identify sociodemographic and clinical factors determine the locus of pain control in this group of patients. BACKGROUND: The locus of pain control can play a critical role in determining the quality of life in patients with lower limb ulcerations, and identification of individuals with an unfavourable pain control profile would enable the opportunity of offering them dedicated psychological counselling. DESIGN: Quantitative survey. METHODS: This study included 298 patients with lower limb ulcerations resulting from chronic venous insufficiency (n = 101), lower limb atherosclerosis (n = 98), or having mixed arteriovenous aetiology (n = 99). The study included the completion of the Polish version of the Beliefs about Pain Control Questionnaire. RESULTS: The most important role in the control of pain was assigned to the powerful others locus. This locus correlated directly with poorer educational level and higher professional activity. Additionally, the intensity of usual pain correlated inversely with the powerful others locus. Respondents' age was the only sociodemographic variable decreasing the level of the internal locus. Moreover, the severity of usual and maximal pain and the area of ulceration correlated inversely with the internal locus of pain control. In contrast, the aetiology of lower limb ulceration did not affect significantly any of the dimensions of pain control. CONCLUSION: The control of pain in ulceration patients is mostly determined by the support of medical personnel, which generally should be considered a negative finding. Relevance to clinical practice. Determination of the locus of pain control should be included in the complex medical evaluation of individuals suffering from ulcerations. PMID- 22834937 TI - Intestinal microbiota contribute to the endogenous formation of thiouracil in livestock. AB - In recent years, the frequent detection of the banned substance thiouracil (TU) in livestock urine has been related to its endogenous formation following consumption of glucosinolate-rich Brassicaceae crops. Besides, TU residues have been recovered in these crops upon plant-derived myrosinase hydrolysis. Through in vitro bovine and porcine static digestive simulations, the influence of gastrointestinal digestion of Brassicaceae-derived matrixes on TU formation was assessed. Following derivatization and LC-MS(2) analysis, TU was detected in colonic suspensions with traditional rapeseed, coarse colza "00" meal, cauliflower, and broccoli ranging from 3.47 to 30.96 MUg kg(-1) (bovine) and from 3.55 to 26.34 MUg kg(-1) (porcine). In stomach and small intestinal fluids, TU remained unfound, whereas upon rumen simulation TU was detected for coarse colza "00" meal (4.43 MUg kg(-1)) and grounded traditional rapeseed (0.35 MUg kg(-1)). The origin of this detection was investigated through filter-sterilizing and autoclaving the fecal inoculum causing a significant decrease in TU concentration, thereby reinforcing the possibility of an active bacterial involvement, which however was characterized with a high interanimal variation. In conclusion, these results support the previously proven endogenous origin of TU and acknowledge the active role of the gastrointestinal bacteria in TU formation, through production of an extracellular component. PMID- 22834938 TI - Prehospital care of left ventricular assist device patients by emergency medical services. AB - Left ventricular assist devices (LVADs) are frequently implanted as permanent (bridge to destination [BTD]) or temporary (bridge to transplantation [BTT]) cardiac support. When LVAD patients are discharged to home, they are very likely to require emergency medical services (EMS), but there is very little literature on out-of-hospital emergency care for patients with LVADs. We present two typical cases of LVAD patients for whom EMS was called. In the first case, the patient was in an ambulance two hours distant from our university hospital when a pulsatile system malfunctioned. In the second case, EMS was called to an unconscious LVAD patient. Emergency reference cards, training programs for emergency medical staff, and a 24-hour emergency hotline for the local VAD team are advisable. PMID- 22834939 TI - Outcomes of intrarenal Bacillus Calmette-Guerin/interferon-alpha2B for biopsy proven upper-tract carcinoma in situ. AB - BACKGROUND AND PURPOSE: While nephroureterectomy (NU) remains the gold-standard treatment for upper-tract carcinoma in situ (UT-CIS), it may be unnecessarily aggressive in comparison with the treatment of bladder CIS. Upper-tract administration of bacillus Calmette-Guerin (BCG) has shown promise for UT-CIS, but with limited reports and varied results. Furthermore, all previous reports included patients with positive cytology results without biopsy-proven CIS, or combined BCG with other topical therapies that are used for bladder CIS. We report our experience using a novel technique to directly instill BCG with interferon-alpha2B (BCG/IFN) into the upper-tract in patients with biopsy-proven UT-CIS. PATIENTS AND METHODS: Patients who received a diagnosis of isolated, biopsy-proven UT-CIS from September 2003 to January 2012 were included. After biopsy, all patients received a 6-week induction course of BCG/IFN, administered via an open-ended ureteral catheter. Initial follow-up was scheduled 1 month after the completion of the intrarenal therapy and consisted of flexible ureteroscopy, selective urinary cytology, retrograde pyelography, and rebiopsy of the upper tract. Complete response (CR) was defined as the absence of visualized lesions on ureteroscopy, negative selective cytology results, and absence of clinical progression. Absence of visualized lesions with persistently positive cytology results or persistence of lesions after induction was considered no response (NR). New upper-tract lesions after an initial CR were considered recurrences. Patients with a CR were placed on maintenance therapy for 2 years. Surveillance was performed every 3 months with ureteroscopy, selective cytology, and imaging. RESULTS: Eleven patients (mean age=73 years) were followed for a median of 13.5 months (3.7-103.3 mos). Eight patients had an initial CR, while three initially had NR. Two of the NR patients had negative biopsy results but persistently positive cytology results; both of these patients underwent a second induction course and achieved a CR. The third NR patient had persistence of lesions after induction and was offered a nephroureterctomy. Total kidney preservation rate was 91% (10/11). There were no treatment-related adverse events. CONCLUSION: This study demonstrates the safety and efficacy of intrarenal BCG/IFN maintenance therapy for patients with UT-CIS. Unlike other mechanisms of delivery, including percutaneous administration or reflux via double pigtail stents, this office-based technique spares the morbidity of a chronically indwelling nephrostomy tube or ureteral stent. PMID- 22834940 TI - O-atom exchange between H2O and CO2 mediated by a bis(dithiolene)tungsten complex. AB - Inspired by the CO(2)-reductatse activity of tungsten-dependent formate dehydrogenases (W-FDHs), a reduced W-FDH model, [W(IV)(OH)(S(2)C(2)Ph(2))(2)](-), was prepared in situ through hydrolysis of [W(IV)(OPh)(S(2)C(2)Ph(2))(2)](-) (1) and its reactivity with CO(2) was investigated. The reaction between [W(IV)(OH)(S(2)C(2)Ph(2))(2)](-) and CO(2) at room temperature leads to the formation of [W(IV)(O)(S(2)C(2)Ph(2))(2)](2-) (2), which slowly oxidizes to [W(V)(O)(S(2)C(2)Ph(2))(2)](-) (3). Isotopic labeling experiments reveal that the O atom in CO(2) incorporates into 3. This implies that there is carbonic anhydrase like activity, in which carbonation and decarboxylation are mediated by a bis(dithiolene)tungsten complex. PMID- 22834941 TI - Flabelliferins A and B, sesterterpenoids from the South Pacific sponge Carteriospongia flabellifera. AB - Two new sesterterpenoids named flabelliferins A (1) and B (2) were isolated from the lipophilic extract of the sponge Cateriospongia flabellifera, collected in the South Pacific near Vanuatu. The structure and absolute configuration of these two compounds were assigned by a combination of one- and two-dimensional NMR spectroscopy and by Mosher's ester analysis. Flabelliferin A (1) has a rare 25 homocheilanthane carbon skeleton, while flabelliferin B (2) is a 24-nor-25 homoscalarane sesterterpenoid. PMID- 22834942 TI - Immunotoxicity in mice induced by short-term exposure to methoxychlor, parathion, or piperonyl butoxide. AB - Exposure to environmental agents can compromise numerous immunological functions. Immunotoxicology focuses on the evaluation of the potential adverse effects of xenobiotics on immune mechanisms that can lead to harmful changes in host responses such as: increased susceptibility to infectious diseases and tumorigenesis; the induction of hypersensitivity reactions; or an increased incidence of autoimmune disease. In order to assess the immunosuppressive response to short-term exposure to some commonly used pesticides, the studies here focused on the response of mice after exposures to the organochlorine pesticide methoxychlor, the organophosphorus pesticide parathion, or the agricultural insecticide synergist piperonyl butoxide. In these studies, 7-week old mice were orally administered (by gavage) methoxychlor, parathion, or piperonyl butoxide daily for five consecutive days. On Day 2, all mice in each group were immunized with sheep red blood cells (SRBC), and their SRBC-specific IgM responses were subsequently assessed. In addition, levels of B-cells in the spleen of each mouse were also analyzed via surface antigen expression. The results of these studies indicated that treatments with these various pesticides induced marked decreases in the production of SRBC-specific IgM antibodies as well as in the expression of surface antigens in IgM- and germinal center positive B-cells. Based on these outcomes, it is concluded that the short-term exposure protocol was able to detect potential immunosuppressive responses to methoxychlor, parathion, and piperonyl butoxide in situ, and, as a result, may be useful for detecting other environmental chemical-related immunotoxicities. PMID- 22834943 TI - Salivary high-sensitivity cardiac troponin T levels in patients with acute myocardial infarction. AB - OBJECTIVE: Accurate and rapid diagnosis of acute myocardial infarction (MI) is of major medical and economic importance. The objective of this study was to identify whole saliva high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute MI. SUBJECTS AND METHODS: A case-control study was carried out in 30 normal healthy individuals, and 30 patients with acute MI were hospitalized in CCU of Imam Hossein hospital, Tehran, Iran. The hs-cTnT levels were assayed in serum and whole saliva in the first and second morning following the MI by ELISA method. Statistical analysis of the Student's t-test and Pearson correlation coefficient was performed. RESULTS: The mean stimulated and unstimulated saliva and serum levels of hs-cTnT at both the first and the second morning following the acute MI were significantly higher in patients with acute MI compared with healthy individuals. Furthermore, stimulated and unstimulated saliva hs-TnT levels correlated significantly with serum hs-TnT level (r = 0.415, P < 0.023; r = 0.466, P < 0.021, respectively). CONCLUSION: Results suggest that salivary hs cTnT can be used as an alternative to serum hs-cTnT for diagnosis and monitoring of myocardial infarction. PMID- 22834945 TI - Condor-COPASI: high-throughput computing for biochemical networks. AB - BACKGROUND: Mathematical modelling has become a standard technique to improve our understanding of complex biological systems. As models become larger and more complex, simulations and analyses require increasing amounts of computational power. Clusters of computers in a high-throughput computing environment can help to provide the resources required for computationally expensive model analysis. However, exploiting such a system can be difficult for users without the necessary expertise. RESULTS: We present Condor-COPASI, a server-based software tool that integrates COPASI, a biological pathway simulation tool, with Condor, a high-throughput computing environment. Condor-COPASI provides a web-based interface, which makes it extremely easy for a user to run a number of model simulation and analysis tasks in parallel. Tasks are transparently split into smaller parts, and submitted for execution on a Condor pool. Result output is presented to the user in a number of formats, including tables and interactive graphical displays. CONCLUSIONS: Condor-COPASI can effectively use a Condor high throughput computing environment to provide significant gains in performance for a number of model simulation and analysis tasks. Condor-COPASI is free, open source software, released under the Artistic License 2.0, and is suitable for use by any institution with access to a Condor pool. Source code is freely available for download at http://code.google.com/p/condor-copasi/, along with full instructions on deployment and usage. PMID- 22834944 TI - PTX3 genetic variation and dizygotic twinning in the Gambia: could pleiotropy with innate immunity explain common dizygotic twinning in Africa? AB - Dizygotic (DZ) twinning has a genetic component and is common among sub-Saharan Africans; in The Gambia its frequency is up to 3% of live births. Variation in PTX3, encoding Pentraxin 3, a soluble pattern recognition receptor that plays an important role both in innate immunity and in female fertility, has been associated with resistance to Mycobacterium tuberculosis pulmonary disease and to Pseudomonas aeruginosa infection in cystic fibrosis patients. We tested whether PTX3 variants in Gambian women associate with DZ twinning, by genotyping five PTX3 single nucleotide polymorphisms (SNPs) in 130 sister pairs (96 full sibs and 34 half sibs) who had DZ twins. Two, three and five SNP haplotypes differed in frequency between twinning mothers and those without a history of twinning (from P = 0.006 to 3.03e-06 for two SNP and three SNP haplotypes, respectively). Twinning mothers and West African tuberculosis-controls from a previous study shared several frequent haplotypes. Most importantly, our data are consistent with an independently reported association of PTX3 and female fertility in a sample from Ghana. Taken together, these results indicate that selective pressure on PTX3 variants that affect the innate immune response to infectious agents, could also produce the observed high incidence of DZ twinning in Gambians. PMID- 22834946 TI - Reactions and surface interactions of saccharides in cement slurries. AB - Glucose, maltodextrin, and sucrose exhibit significant differences in their alkaline reaction properties and interactions in aluminate/silicate cement slurries that result in diverse hydration behaviors of cements. Using 1D solution and solid-state (13)C nuclear magnetic resonance (NMR), the structures of these closely related saccharides are identified in aqueous cement slurry solutions and as adsorbed on inorganic oxide cement surfaces during the early stages of hydration. Solid-state 1D (29)Si and 2D (27)Al{(1)H} and (13)C{(1)H} NMR techniques, including the use of very high magnetic fields (18.8 T), allow the characterization of the hydrating silicate and aluminate surfaces, where interactions with adsorbed organic species influence hydration. These measurements establish the molecular features of the different saccharides that account for their different adsorption behaviors in hydrating cements. Specifically, sucrose is stable in alkaline cement slurries and exhibits selective adsorption at hydrating silicate surfaces but not at aluminate surfaces in cements. In contrast, glucose degrades into linear saccharinic or other carboxylic acids that adsorb relatively weakly and nonselectively on nonhydrated and hydrated cement particle surfaces. Maltodextrin exhibits intermediate reaction and sorption properties because of its oligomeric glucosidic structure that yields linear carboxylic acids and stable ring-containing degradation products that are similar to those of the glucose degradation products and sucrose, respectively. Such different reaction and adsorption behaviors provide insight into the factors responsible for the large differences in the rates at which aluminate and silicate cement species hydrate in the presence of otherwise closely related saccharides. PMID- 22834947 TI - Creep mechanisms of a new Ni-Co-base disc superalloy at an intermediate temperature. AB - The microstructures of a new Ni-Co-base disc superalloy, TMW-4M3, before and after the creep test at 725 degrees C/630 MPa have been systematically investigated by transmission electron microscopy (TEM). The crept microstructures were marked as three different deformation stages (I, II and III) corresponding to the gradually increased strain. At stage I, stacking fault (SF) shearing was the main deformation mechanism. The SF was extrinsic and lay on {111} plane. However, deformation microtwinning became the dominant mode at stage II and III. The average spacing of deformation twins decreased from 109 +/- 15 nm at stage II to 76 +/- 12 nm at stage III, whereas the twin thickness did not change significantly. The influence of stacking fault energy (SFE) of gamma matrix on the deformation mechanism is discussed. It is suggested that lower SFE in TMW-4M3 is partly responsible for the enhanced creep resistance. PMID- 22834948 TI - Two intercellular signals required for fruiting body formation in Myxococcus xanthus act sequentially but non-hierarchically. AB - Starvation-induced fruiting body formation in Myxococcus xanthus depends on intercellular signalling. A-signal functions after 2 h of starvation and its synthesis depends on the asg genes. C-signal functions after 6 h of starvation and is generated by proteolytic cleavage of a precursor by the protease PopC. Previous gene expression studies suggested that the A- and C-signal lie on a hierarchical pathway. Here we explored the causal relationship between the A- and C-signal. The asgA and asgB mutants have reduced popC expression, PopC accumulation and C-signal accumulation. popC expression was shown not to depend on A-signal but on the AsgA and AsgB proteins. Restored popC expression in the two mutants rescued PopC and C-signal accumulation as well as C-signalling and the developmental defects of the two mutants without restoring A-signalling. Based on these results we suggest that A- and C-signal do not lie on a hierarchical, dependent pathway. Instead the A- and C-signal act sequentially and without a causal relationship suggesting that they are linked by a shared timing mechanism, which ensures the early and late onset of A-signalling and C signalling, respectively, during starvation. This pathway topology represents a novel architecture for bacterial intercellular signalling systems involving more than one signal. PMID- 22834949 TI - Metabolic inflammation: connecting obesity and insulin resistance. AB - Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing beta-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID- 22834950 TI - Giant benign lymphangioendothelioma. AB - Benign lymphangioendothelioma is a rare locally infiltrative vascular neoplasm, presenting as a slow-growing, asymptomatic, reddish-violaceous plaque. Histopathologically, it is characterized by irregular and thin-walled vascular spaces, lined by a single and discontinuous layer of flat endothelial cells, dissecting dermal collagen bundles. We present the case of a 75-year-old man with a giant benign lymphangioendothelioma, to our knowledge, the largest example described in the literature. The immunohistochemical expression of Wilms tumor 1 gene is useful in vascular lesions to differentiate malformations from proliferative endothelial lesions. In our case, the positivity for WT1 supports the neoplastic nature of this lesion. PMID- 22834951 TI - Immunity to melanin and to tyrosinase in melanoma patients, and in people with vitiligo. AB - BACKGROUND: The aim of this study was to determine the presence and the intensity of humoral immunity to melanoma-associated antigens: tyrosinase and melanin, in patients with melanoma, in persons with vitiligo and in control healthy people. METHODS: The study involved 63 patients with melanoma and 19 persons with vitiligo. Control group consisted up to 41 healthy volunteers. Mushroom tyrosinase and synthetic melanin were used as the antigens. RESULTS: ELISA test showed significantly (p < 0.0000004 and p < 0.04) lower levels of IgM anti tyrosinase autoantibodies, in melanoma and vitiligo patients respectively, compared to controls.Although there was no significant difference between the levels of IgA anti-melanin autoantibodies in melanoma or vitiligo patients in comparison with controls, the enhanced concentrations of anti-melanin IgA autoantibodies were preferentially found in melanoma patients with metastatic disease. Significantly high percentage in the Fc alphaRI (CD89) positive cells was determined in melanoma patients (p < 0.002 and p < 0.008) in comparison to that found in healthy people or in patients with vitiligo, in the already mentioned order, pointing that IgA dependent cellular cytotoxicity is not important for the immune action against melanoma, even more that it is included in some immune suppression.Levels of IgG autoantibodies to mentioned antigens in melanoma patients although low were not significantly lower from controls. These findings analyzed together with the statistically significant low percentage of FcgammaRIII, (CD16) positive immunocompetent cells (p < 0.0007 and p < 0.003), which was found in patients with melanoma compared with healthy or vitiligo people respectively, and statistically significant low percentage of (CD16 + CD56+) natural killer (NK) cells (p < 0.005) found in melanoma patients in comparison to healthy controls pointed to the low probability for anti-melanoma IgG mediated, antibody mediated cellular cytotoxicity, (ADCC) and NK cytotoxicity. Moreover the ratio of the percentages of granulocytes and percentage of lymphocytes was statistically higher in patients with melanoma in relation to healthy people as well as to people with vitiligo (p < 0.0007 and p < 0.05 respectively). CONCLUSION: Autoantibodies to tyrosinase and to melanin which are found even in healthy people, point that consummation of edible mushrooms that carry the antigen tyrosinase and melanin, could influence the humoral anti melanoma immune response.Levels of different immunoglobulin classes of anti melanin and anti-tyrosinase antibodies varied depending on the presence and the stage of studied diseases. Besides, the statistically enhanced ratio of the percentages of granulocytes and percentage of lymphocytes, together with statistically decreased percentage of NK cells is found in analyzed melanoma patients. PMID- 22834952 TI - Sensitive detection of microRNAs with hairpin probe-based circular exponential amplification assay. AB - MicroRNAs (miRNAs) play important regulatory roles in a wide range of biological processes, and their aberrant expression is associated with cancer development and a variety of diseases. Here, we develop a simple, sensitive, and specific miRNA assay on the basis of circular exponential amplification in combination with the hairpin probes. The binding of target miRNA with a linear DNA template initiates the first strand displacement amplification (SDA) and generates the universal triggers which are complementary to the 3' protruding end of a hairpin probe. These universal triggers function not only as the primers to unfold the hairpin probes through an extension reaction, generating distinct fluorescence signals, but also as the amplification templates to initiate the second SDA reaction. Moreover, the second SDA reaction can release new triggers to initiate the above two consecutive SDA reactions, thus constituting a circular exponential amplification which enables the conversion of a small amount of miRNAs to a large number of universal triggers to unfold abundant hairpin probes. This hairpin probe-based circular exponential amplification assay exhibits high sensitivity with a detection limit of 3.80 * 10(-13) M and a detection range of 4 orders of magnitude. It can even discriminate single-nucleotide difference between miRNA family members and perform well in real sample analysis. Notably, in this assay, the long-stem hairpin probes are unfolded through an extension reaction rather than through a conventional hybridization reaction controlled by the thermodynamic equilibrium in the case of molecular beacons, making the design of hairpin probes very simple. This hairpin probe-based circular exponential amplification assay holds a great promise for further application in biomedical research and early clinical diagnosis. PMID- 22834953 TI - Cancer risk among elderly persons with end-stage renal disease: a population based case-control study. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) have elevated cancer risk. Cancer risk increases with age, but associations of ESRD with specific malignancies are incompletely studied for older individuals. METHODS: We conducted a population-based case-control study (1,029,695 cancer and 99,610 controls) among the U.S. elderly using SEER-Medicare linked data. We defined ESRD as presence of dialysis claims in the 3 months prior to selection. RESULTS: Although ESRD was not associated with excess cancer risk overall (odds ratio 1.02; 95%CI 0.91-1.14), risk was specifically increased for cancers of the stomach (1.45; 1.16-1.81), small intestine (1.92; 1.27-2.92), colon (1.17; 1.00 1.36), liver (1.53; 1.16-2.01), biliary tract (1.78; 1.20-2.65), lung (1.17; 1.02 1.34), cervix (2.12; 1.39-3.23), kidney (2.42; 2.01-2.92), and for multiple myeloma (1.77; 1.40-2.24) and chronic myeloid leukemia (1.74; 1.08-2.80). The association between liver cancer and ESRD was attenuated upon adjustment for hepatitis B and C infection or diabetes mellitus. Multiple myeloma risk was highest with short ESRD duration (p < 0.0001), possibly reflecting reverse causality, while kidney cancer risk showed a borderline rise over time (p = 0.08). CONCLUSIONS: Among elderly individuals with ESRD, the excess risks for some cancers may reflect immune dysfunction or a high prevalence of other risk factors, such as viral infections or diabetes mellitus. Our results underscore the need for studying biological pathways of carcinogenesis in ESRD. PMID- 22834955 TI - Relations between conspecific density and effects of ultraviolet-b radiation on tadpole size in the striped marsh frog. AB - Global increases in ultraviolet-B radiation (UVBR) associated with stratospheric ozone depletion are potentially contributing to the decline of numerous amphibian species around the world. Exposure to UVBR alone reduces survival and induces a range of sublethal effects in embryonic and larval amphibians. When additional environmental stressors are present, UVBR can have compounding negative effects. Thus, examination of the effects of UVBR in the absence of other stressors may substantially underestimate its potential to affect amphibians in natural habitats. We examined the independent and interactive effects of increased UVBR and high conspecific density would have embryonic and larval striped marsh frogs (Limnodynastes peronii). We exposed individuals to a factorial combination of low and high UVBR levels and low, medium, and high densities of striped marsh frog tadpoles. The response variables were time to hatching, hatching success, posthatch survival, burst-swimming performance of tadpoles (maximum instantaneous swim speed following an escape response), and size and morphology of tadpoles. Consistent with results of previous studies, we found that exposure to UVBR alone increased the time to hatching of embryos and reduced the burst-swimming performance and size of tadpoles. Similarly, increasing conspecific density increased the time to hatching of embryos and reduced the size of tadpoles, but had no effect on burst-swimming performance. The negative effect of UVBR on tadpole size was not apparent at high densities of tadpoles. This result suggests that tadpoles living at higher densities may invest relatively less energy in growth and thus have more energy to repair UVBR-induced damage. Lower densities of conspecifics increased the negative effects of UVBR on developing amphibians. Thus, low-density populations, which may include declining populations, may be particularly susceptible to the detrimental effects of increased UVBR and thus may be driven toward extinction faster than might be expected on the basis of results from single-factor studies. PMID- 22834954 TI - Ethanol-induced Htr3a promoter methylation changes in mouse blood and brain. AB - BACKGROUND: Abnormal DNA methylation has been observed in promoter regions of a number of genes in human alcoholics. It is unclear whether DNA methylation changes in alcoholics result directly from alcohol consumption or predated the occurrence of alcohol abuse or dependence and whether altered DNA methylation influences gene expression. METHODS: We investigated ethanol (EtOH)-induced DNA methylation changes in mouse serotonin receptor 3a gene (Htr3a). A 5-day drinking in-the-dark paradigm was applied to 28 male outbred CD-1 mice (15 EtOH-drinking and 13 water-drinking). The Sequenom MassARRAY approach was used to quantify methylation levels of 8 CpGs around Htr3a transcription start site in trunk blood and 9 brain regions (dorsomedial prefrontal cortex [DMPFC], ventromedial prefrontal cortex, ventral tegmental area, dorsolateral striatum, dorsomedial striatum [DMSTR], ventral striatum, amygdala, hippocampus [HIPPO], and cerebellum). DNA methylation differences between the 2 groups of mice (EtOH- and water-drinking) were analyzed using multivariate analysis of covariance with consideration of EtOH consumption amount. Expression levels of Htr3a in the DMSTR were measured by real-time PCR in 14 EtOH-drinking and 14 water-drinking male CD 1 mice. RESULTS: EtOH drinking increased methylation levels of specific Htr3a promoter CpGs in mouse blood (CpG-27: p = 0.028; CpG+54: p = 0.044) and HIPPO (CpG+151: p = 0.012) but reduced methylation levels of specific Htr3a promoter CpGs in mouse DMSTR (CpG-96: p = 0.020; CpG-27: p = 0.035) and DMPFC (CpG+138: p = 0.011; CpG+151: p = 0.040). Nevertheless, methylation levels of Htr3a promoter CpGs in 6 other brain regions were not significantly altered by EtOH consumption. Additionally, the expression level of Htr3a in the DMSTR was 1.43-fold higher in alcohol-drinking mice than in water-drinking mice (p = 0.044). CONCLUSIONS: Our findings indicate that alcohol consumption may induce tissue-specific DNA methylation changes and further suggest that Htr3a promoter methylation levels may be reversely correlated with Htr3a expression levels in specific brain regions such as DMSTR. PMID- 22834956 TI - Adam10 haploinsufficiency causes freckle-like macules in Hairless mice. AB - The Hairless nuclear receptor co-repressor is required for hair follicle regeneration during the hair cycle. The classical Hairless(Hr) /Hairless(Hr) mouse mutant loses all hair between 2 and 3 weeks of age. As the mice age, their trunk skin develops epidermal pigmentation, a feature of human skin which is not found in normal haired mice. In this report, we present a new, dominant mouse mutation, Pied, which arose within a colony of Hairless(Hr) /Hairless(Hr) mice and causes freckle-like macules on the skin. The Pied macules require Hairless(Hr) homozygosity to form and are composed of localized clusters of epidermal melanocytes. Through linkage analysis, we find that the Pied mutation is a 1914 base pair loss-of-function deletion in the Adam10 zinc metalloprotease gene. The pathways that specifically maintain long-term pigmentation patterns in adults are not well understood. We have identified Adam10 as an inhibitor of melanocyte expansion in adult skin. PMID- 22834957 TI - Microcarrier suspension cultures for high-density expansion and differentiation of human pluripotent stem cells to neural progenitor cells. AB - Neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) can be differentiated to neural cells that model neurodegenerative diseases and be used in the screening of potential drugs to ameliorate the disease phenotype. Traditionally, NPCs are produced in 2D cultures, in low yields, using a laborious process that includes generation of embryonic bodies, plating, and colony selections. To simplify the process and generate large numbers of hiPSC-derived NPCs, we introduce a microcarrier (MC) system for the expansion of a hiPSC line and its subsequent differentiation to NPC, using iPS (IMR90) as a model cell line. In the expansion stage, a process of cell propagation in serum-free MC culture was developed first in static culture, which is then scaled up in stirred spinner flasks. A 7.7-fold expansion of iPS (IMR90) and cell yield of 1.3*106 cells/mL in 7 days of static MC culture were achieved. These cells maintained expression of OCT 3/4 and TRA-1-60 and possessed a normal karyotype over 10 passages. A higher cell yield of 6.1*106 cells/mL and 20-fold hiPSC expansion were attained using stirred spinner flasks (seeded from MC static cultures) and changing the medium-exchange regimen from once to twice a day. In the differentiation stage, NPCs were generated with 78%-85% efficiency from hiPSCs using a simple serum-free differentiation protocol. Finally, the integrated process of cell expansion and differentiation of hiPSCs into NPCs using an MC in spinner flasks yielded 333 NPCs per seeded hiPSC as compared to 53 in the classical 2D tissue culture protocol. Similar results were obtained with the HES-3 human embryonic stem cell line. These NPCs were further differentiated into betaIII-tubulin+ neurons, GFAP+ astrocytes, and O4+ oligodendrocytes, showing that cells maintained their multilineage differentiation potential. PMID- 22834958 TI - Kinematics and laxity of a linked total elbow arthroplasty following computer navigated implant positioning. AB - Aseptic loosening in total elbow arthroplasty (TEA) remains the most common cause of long-term failure. While several different mechanisms of implant loosening have been suggested, it is likely that one important underlying cause is implant malpositioning, resulting in changes in joint kinematics and loading. Although use of computer navigation has been shown to improve component positioning in other joints, no such system currently exists for the elbow. This study used real time computer feedback for humeral, ulnar, and radial component positioning in 11 cadaveric extremities. An elbow motion simulator evaluated joint kinematics. Endosteal abutment of the stems of the humeral and ulnar components precluded optimal positioning in 5 and 6 specimens, respectively. Loss of the normal valgus angulation following elbow arthroplasty (p < 0.05) suggests that errors in humeral component positioning translate directly into changes in joint kinematics during active motion. These findings suggest that although computer navigation can reproduce normal joint kinematics, optimal implant positioning may require a TEA system which allows for some modularity to accommodate the normal variations in osseous morphology of the elbow. PMID- 22834959 TI - Global rating scale for the assessment of paramedic clinical competence. AB - OBJECTIVE: The aim of this study was to develop and critically appraise a global rating scale (GRS) for the assessment of individual paramedic clinical competence at the entry-to-practice level. METHODS: The development phase of this study involved task analysis by experts, contributions from a focus group, and a modified Delphi process using a national expert panel to establish evidence of content validity. The critical appraisal phase had two raters apply the GRS, developed in the first phase, to a series of sample performances from three groups: novice paramedic students (group 1), paramedic students at the entry-to practice level (group 2), and experienced paramedics (group 3). Using data from this process, we examined the tool's reliability within each group and tested the discriminative validity hypothesis that higher scores would be associated with higher levels of training and experience. RESULTS: The development phase resulted in a seven-dimension, seven-point adjectival GRS. The two independent blinded raters scored 81 recorded sample performances (n = 25 in group 1, n = 33 in group 2, n = 23 in group 3) using the GRS. For groups 1, 2, and 3, respectively, interrater reliability reached 0.75, 0.88, and 0.94. Intrarater reliability reached 0.94 and the internal consistency ranged from 0.53 to 0.89. Rater differences contributed 0-5.7% of the total variance. The GRS scores assigned to each group increased with level of experience, both using the overall rating (means = 2.3, 4.1, 5.0; p < 0.001) and considering each dimension separately. Applying a modified borderline group method, 54.9% of group 1, 13.4% of group 2, and 2.9% of group 3 were below the cut score. CONCLUSION: The results of this study provide evidence that the scores generated using this scale can be valid for the purpose of making decisions regarding paramedic clinical competence. PMID- 22834960 TI - Antioxidant metabolism during fruit development of different acerola (Malpighia emarginata D.C) clones. AB - The present research work describes the major changes in the antioxidant properties during development of acerola from five different clones. Ripening improved fruit physicochemical quality parameters; however, total vitamin C and total soluble phenols (TSP) contents declined during development, which resulted in a lower total antioxidant activity (TAA). Despite the decline in TSP, at ripening, the anthocyanin and yellow flavonoid content increased and was mainly constituted of cyanidin 3-rhamnoside and quercetin 3-rhamnoside, respectively. The activities of oxygen-scavenging enzymes also decreased with ripening; furthermore, the reduction in vitamin C was inversely correlated to membrane lipid peroxidation, indicating that acerola ripening is characterized by a progressive oxidative stress. Among the studied clones, II47/1, BRS 237, and BRS 236 presented outstanding results for vitamin C, phenols, and antioxidant enzyme activity. If antioxidants were to be used in the food supplement industry, immature green would be the most suitable harvest stage; for the consumer's market, fruit should be eaten ripe. PMID- 22834961 TI - Testing the concept of hypervalency: charge density analysis of K2SO4. AB - One of the most basic concepts in chemical bonding theory is the octet rule, which was introduced by Lewis in 1916, but later challenged by Pauling to explain the bonding of third-row elements. In the third row, the central atom was assumed to exceed the octet by employing d orbitals in double bonding leading to hypervalency. Ever since, polyoxoanions such as SO(4)(2-), PO(4)(3-), and ClO(4)( ) have been paradigmatic examples for the concept of hypervalency in which the double bonds resonate among the oxygen atoms. Here, we examine S-O bonding by investigating the charge density of the sulfate group, SO(4)(2-), within a crystalline environment based both on experimental and theoretical methods. K(2)SO(4) is a high symmetry inorganic solid, where the crystals are strongly affected by extinction effects. Therefore, high quality, very low temperature single crystal X-ray diffraction data were collected using a small crystal (~30 MUm) and a high-energy (30 keV) synchrotron beam. The experimental charge density was determined by multipole modeling, whereas a theoretical density was obtained from periodic ab initio DFT calculations. The chemical bonding was jointly analyzed within the framework of the Quantum Theory of Atoms In Molecules only using quantities derived from an experimental observable (the charge density). The combined evidence suggests a bonding situation where the S-O interactions can be characterized as highly polarized, covalent bonds, with the "single bond" description significantly prevailing over the "double bond" picture. Thus, the study rules out the hypervalent description of the sulfur atom in the sulfate group. PMID- 22834962 TI - An exploration of undergraduate nursing and physiotherapy students' views regarding education for patient handling. AB - AIMS AND OBJECTIVES: To ascertain the views of undergraduate student nurses and physiotherapists regarding their education in patient handling. BACKGROUND: Musculo-skeletal injuries are an important cause of staff sickness absence and attrition from the nursing profession and are a recognised problem within the physiotherapy profession. Nurses and physiotherapists are at risk of musculo skeletal injuries as a result of their role in assisting patients with movement. METHODS: A questionnaire survey was undertaken of undergraduate nursing and physiotherapy students (n = 371) at one university. RESULTS: Most students agreed that university teaching about moving and handling prepared them for clinical practice (64%). Over a third reported that they had never undertaken a written moving and handling risk assessment in clinical practice (38%). Almost half of the sample (40%) admitted undertaking unsafe moving and handling activities. Half (50%) also stated that they would rather 'fit' into the team than challenge unsafe practice. Almost a third (29%) stated that they had begun to experience pain since becoming a student. There were significant differences between nursing and physiotherapy students. Physiotherapy students were more likely to report being supervised when moving and handling and reported being more assertive about adhering to safe practice. CONCLUSIONS: The well-being of both nursing and physiotherapy undergraduate students is threatened when students undertake work placements in clinical settings. University-based education in safe patient handling, though important, can be undermined by workplace settings where unsafe practices occur. Collaboration is needed between university educators, managers and practice-based mentors to support students to maintain safe approaches to moving and handling patients. RELEVANCE TO CLINICAL PRACTICE: A third of students reported developing pain since becoming a healthcare student. Students entering their professions already injured may leave the workforce owing to poor physical well-being. It is vital that the clinical workplace supports safe systems of working. PMID- 22834963 TI - Evaluating the learning curve of experienced laparoscopic surgeons in robot assisted radical prostatectomy. AB - BACKGROUND AND PURPOSE: Radical prostatectomy is the gold standard surgical treatment for organ-confined prostate cancer. There is no consensus on the impact of previous laparoscopic experience on the learning curve of robot-assisted laparoscopic prostatectomy (RALP). We compared the perioperative complications and early patient outcomes from our initial 100 cases of RALP with laparoscopic prostatectomy (LRP) cases performed well beyond the learning curve. PATIENTS AND METHODS: Between July 2011 and January 2012, 110 RALP were performed by one of two surgeons, each with previous experience of more than 1000 LRP. The cases were pair matched from among the last 208 patients who had undergone LRP by the same surgeons at the same time. The clinical parameters, operative details, postoperative complications, and short-term outcomes from these patients, collected prospectively, were compared between the two groups. RESULTS: The prostate-specific antigen (PSA) level and age of the two groups was similar. The operative time (128.4 vs 153.9 min; P=0.01) and blood loss (200 vs 254 mL; P=0.01) was significantly less for the LRP group, but the duration of catheterization was similar (5.89 vs 6.2 days). The complication rate was low. No procedures needed conversions, and no patient had a visceral injury or blood transfusion. Twenty-three patients in the LRP group and 33 patients in the RALP group had extraprostatic disease, and the positive margin rate was 14% and 19% for these respective groups. At 3 months, PSA level was undetectable in 94% of LRP and 92% RALP patients, while 56% and 65% (P=0.062) patients in these groups were using 0 to 2 pads per day. CONCLUSIONS: The initial results of the outcome of RALP are at least at par with those of LRP and with those of previously published RALP series. This suggests the lack of a steep learning curve for experienced laparoscopic surgeons in performing RALP. PMID- 22834965 TI - The role of nitric oxide in the induction of caudal-type homeobox 2 through epidermal growth factor receptor in the development of Barrett's esophagus. AB - OBJECTIVE: The high concentration of nitric oxide (NO) around the gastro esophageal junction (GEJ) might play an important role in the development of Barrett's esophagus (BE), a precursor of Barrett's adenocarcimona. Although previous studies revealed that the expression of caudal-type homeobox 2 (CDX2), an important marker of BE, might be induced through Epidermal Growth Factor Receptor (EGFR), the roles of NO in this signal transduction remain unclear. MATERIAL AND METHODS: First, we investigated the expressions of EGFR, CDX2 and nitrotyrosine by immunohistochemical study for BE and squamous epithelium of human specimens. Second, we studied the effect of peroxynitrite, peroxynitrite stimulator, SIN-1, or NO donor, NOC7, on the expression of phosphorylated EGFR and CDX2 in KYSE30, an EGFR-rich human esophageal squamous cell carcinoma cell line. Specific inhibitors for EGFR, AG1478 and small interfering RNA for EGFR (EGFR-siRNA) were employed to elucidate the role of EGFR in the induction of CDX2. RESULTS: The immunohistochemical study revealed that the expressions of EGFR, CDX2 and nitrotyrosine in BE were stronger than those in squamous epithelium with positive correlations. Exposure to peroxynitrite, SIN-1 or NOC7 induced EGFR phosphorylation and CDX2 expression in dose- and time-dependent manners. Both EGFR phosphorylation and CDX2 induction were significantly diminished by AG 1478 and EGFR-siRNA. CONCLUSIONS: We revealed for the first time that extrinsic NO might directly induce CDX2 expression through EGFR phosphorylation. We suggested that NO had an important role in the development of BE from squamous epithelium around GEJ. PMID- 22834964 TI - Factors influencing doctors' selection of dabigatran in non-valvular atrial fibrillation. AB - RATIONALE, AIMS AND OBJECTIVES: This study was designed to examine the factors that influence doctors' decision in initiating or switching from warfarin to dabigratran. METHOD: A survey questionnaire was sent to 181 doctors who were most likely to prescribe dabigatran (e.g. cardiologists and general internists) at the University of California, San Francisco Medical Center between November 2011 and February 2012. Survey participants were asked to complete an electronic or a paper version of the questionnaire, which consisted of 17 multiple-choice questions. Fisher's exact test and Cochran-Mantel-Haenszel test were used to compare survey responses between cardiologists and general internists. RESULTS: A total of 65 survey responses were received (35.9% response rate). There were 13 cardiologists and 51 general internists who participated in the study. Cost (25%), renal function (21%) and CHADS2 score (18%) were the three factors doctors considered most often to determine a patient's eligibility for dabigatran in warfarin-naive patients. On the other hand, histories of unstable international normalized ratio (37%) and missed appointments (17%) along with cost (19%) were most often considered in patients on warfarin. Cardiologists had prescribed dabigatran more often and had a significantly higher level of comfort with prescribing the drug than general internists (P = 0.003; 77% vs. 27%). CONCLUSIONS: Cost was the most important factor influencing doctors' decision to prescribe dabigatran. Safety and effectiveness of dabigatran as well as patient preference were additional factors influencing their decision. General internists were less comfortable with prescribing dabigatran than cardiologists. PMID- 22834966 TI - Analyzing multiple-probe microarray: estimation and application of gene expression indexes. AB - Gene expression index estimation is an essential step in analyzing multiple probe microarray data. Various modeling methods have been proposed in this area. Amidst all, a popular method proposed in Li and Wong (2001) is based on a multiplicative model, which is similar to the additive model discussed in Irizarry et al. (2003a) at the logarithm scale. Along this line, Hu et al. (2006) proposed data transformation to improve expression index estimation based on an ad hoc entropy criteria and naive grid search approach. In this work, we re-examined this problem using a new profile likelihood-based transformation estimation approach that is more statistically elegant and computationally efficient. We demonstrate the applicability of the proposed method using a benchmark Affymetrix U95A spiked in experiment. Moreover, We introduced a new multivariate expression index and used the empirical study to shows its promise in terms of improving model fitting and power of detecting differential expression over the commonly used univariate expression index. As the other important content of the work, we discussed two generally encountered practical issues in application of gene expression index: normalization and summary statistic used for detecting differential expression. Our empirical study shows somewhat different findings from the MAQC project (MAQC, 2006). PMID- 22834967 TI - Butyrate induces reactive oxygen species production and affects cell cycle progression in human gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Short-chain fatty acids, such as butyric acid and propionic acid, are metabolic by-products generated by periodontal microflora such as Porphyromonas gingivalis, and contribute to the pathogenesis of periodontitis. However, the effects of butyrate on the biological activities of gingival fibroblasts (GFs) are not well elucidated. MATERIAL AND METHODS: Human GFs were exposed to various concentrations of butyrate (0.5-16 mm) for 24 h. Viable cells that excluded trypan blue were counted. Cell cycle distribution of GFs was analyzed by propidium iodide-staining flow cytometry. Cellular reactive oxygen species (ROS) production was measured by flow cytometry using 2',7' dichlorofluorescein (DCF). Total RNA and protein lysates were isolated and subjected to RT-PCR using specific primers or to western blotting using specific antibodies, respectively. RESULTS: Butyrate inhibited the growth of GFs, as indicated by a decrease in the number of viable cells. This event was associated with an induction of G0/G1 and G2/M cell cycle arrest by butyrate (4-16 mm) in GFs. However, no marked apoptosis of GFs was noted in this experimental condition. Butyrate (> 2 mm) inhibited the expression of cdc2, cdc25C and cyclinB1 mRNAs and reduced the levels of Cdc2, Cdc25C and cyclinB1 proteins in GFs, as determined using RT-PCR and western blotting, respectively. This toxic effect of butyrate was associated with the production of ROS. CONCLUSION: These results suggest that butyrate generated by periodontal pathogens may be involved in the pathogenesis of periodontal diseases via the induction of ROS production and the impairment of cell growth, cell cycle progression and expression of cell cycle-related genes in GFs. These events are important in the initiation and prolongation of inflammatory processes in periodontal diseases. PMID- 22834968 TI - Effect of adalimumab on sleep parameters in patients with psoriasis and obstructive sleep apnea: a randomized controlled trial. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is frequently seen in patients with psoriasis vulgaris. The effect of adalimumab, a TNF-alpha antagonist, on OSA is unknown. METHODS: Patients with at least 5% of their body surface area covered with psoriasis and a sleep apnea defined as an apnea/hypopnea index (AHI) of at least 15 were recruited. They were randomized to either adalimumab 80 mg followed by adalimumab 40 mg every other week for 7 weeks or placebo. Patients were evaluated by polysomnography at baseline and day 56. The objective of this trial was to study the efficacy of adalimumab on sleep parameters in patients with psoriasis and OSA. The primary end point of this double-blind study was the change in AHI between baseline and day 56. RESULTS: A total of 20 patients who were randomized completed the trial. There was no significant difference (p = 0.485) (95% CI = -21.07-42.73) at day 56 in the change from baseline in AHI between groups. CONCLUSIONS: Adalimumab used for 8 weeks at 40 mg every other week for the treatment of psoriasis did not improve OSA in this 20-patient study. PMID- 22834970 TI - Laser-polarization effects on coherent vibronic excitation of molecules with quasi-degenerate electronic states. AB - The laser-polarization effects on nonadiabatically coupled pi-electron rotation (ring current) and molecular vibration have been theoretically analyzed for aromatic molecules with quasi-degenerate excited states irradiated by an ultrashort laser pulse of arbitrary polarization. We first derived general formulations of the coherent electronic wave packet and expectation value of electronic angular momentum within a frozen-nuclei model. The relative quantum phase of the superposed quasi-degenerate states, which determines the oscillating behavior of angular momentum, can be manipulated by the ellipticity and orientation of the incident laser. Nuclear wave packet simulations with a model molecule confirmed the controllability of pi-electron rotation, although the angular momentum is gradually reduced by nonadiabatic couplings. The amplitude of molecular vibration depends prominently on the orientation of linear polarization vectors rather than the helicity of circular polarization. The characteristic feature in vibrational amplitudes is attributed to the interference in nonadiabatic transition governed by the relative quantum phase between nuclear wave packets. This offers a new strategy for laser control of molecular vibrations through the wave packet interference in nonadiabatic transition. PMID- 22834969 TI - Human serum metabolic profiles are age dependent. AB - Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32-81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 * 10(-04) to 7.8 * 10(-42) , alpha(corr) = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging. PMID- 22834971 TI - Comparison of endoscopic and microscopic trans-sphenoidal pituitary surgery: early results in a single centre. AB - INTRODUCTION: Pituitary surgery has seen a recent shift from a microscopic to an endoscopic trans-sphenoidal approach. We present our early experience with endoscopic surgery and compare the outcome with our recent microscopic experience. METHODS: From January 2008 until present time, 80 consecutive patients underwent trans-sphenoidal pituitary surgery in our institution. Until September 2009, all patients had a microscopic trans-septal approach. After this time, the patients underwent endoscopic trans-sphenoidal surgery. All patients underwent pre- and post-operative MRI and full endocrinological evaluation. Data was collected prospectively including tumour volume, endocrine function, visual function, length of stay and complications. RESULTS: There were 40 patients in each group. In the microscopic group, there were 26 non-functioning tumours and 14 functioning tumours. In the endoscopic group, there were 24 non-functioning and 16 functioning tumours. There were significantly better results in terms of tumour resection (p = 0.002) and remission (p = 0.018) in the endoscopic group. In this group there was also a lower incidence of CSF leaks and a shorter length of stay for secreting tumours (p = 0.005). 1 patient in the endoscopic group died at day 43 post-operatively, having initially presented in a poor clinical state with pituitary apoplexy. CONCLUSION: Microscopic trans-sphenoidal surgery remains the benchmark for future surgical techniques. Our early results suggest that endoscopic trans-sphenoidal surgery provides favourable results in both tumour resection and control of secreting tumours in comparison with microscopic surgery. Further longer-term evaluation is required to ensure the outcome of endoscopic surgery. PMID- 22834972 TI - Unusual complications of a benign tumour - our experience with midline posterior fossa epidermoids. AB - Epidermoids of the brain are uncommon benign tumours. Their midline posterior fossa location is exceedingly rare. Fifteen patients with this condition were operated during a 14-year period. Majority of the patients presented in their middle age with mean duration of symptoms of 10 months. Gait imbalance was the commonest symptom observed. Seven patients had features suggestive of raised intracranial tension. Computed tomography scanning showed typical hypodense lesions. On MRI, tumours were hypo-intense on T1 weighted images and hyper intense on T2 weighted images. All patients underwent microsurgical excision. We encountered certain complications in the post-operative period. This prompted us for a review of our case material and literature and is the basis of the present article. Implications of these findings are discussed. PMID- 22834973 TI - Medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome. AB - BACKGROUND: Medullary nephrocalcinosis and distal renal tubular acidosis are closely associated and each can lead to the other. These clinical entities are rare in patients with nephrotic syndrome and polycythaemia is an unusual finding in such patients. We describe the presence of medullary nephrocalcinosis, distal renal tubular acidosis and polycythaemia in a patient with nephrotic syndrome due to minimal change disease. Proposed mechanisms of polycythaemia in patients with nephrotic syndrome and distal renal tubular acidosis include, increased erythropoietin production and secretion of interleukin 8 which in turn stimulate erythropoiesis. CASE PRESENTATION: A 22 year old Sri Lankan Sinhala male with nephrotic syndrome due to minimal change disease was investigated for incidentally detected polycythaemia. Investigations revealed the presence of renal tubular acidosis type I and medullary nephrocalcinosis. Despite extensive investigation, a definite cause for polycythaemia was not found in this patient. Treatment with potassium and bicarbonate supplementation with potassium citrate led to correction of acidosis thereby avoiding the progression of nephrocalcinosis and harmful effects of chronic acidosis. CONCLUSION: The constellation of clinical and biochemical findings in this patient is unique but the pathogenesis of erythrocytosis is not clearly explained. The proposed mechanisms for erythrocytosis in other patients with proteinuria include increased erythropoietin secretion due to renal hypoxia and increased secretion of interleukin 8 from the kidney. This case illustrates that there may exist hitherto unknown connections between tubular and glomerular dysfunction in patients with nephrotic syndrome. PMID- 22834975 TI - Halide and hydroxide linearly bridged bimetallic copper(II) complexes: trends in strong antiferromagnetic superexchange interactions. AB - Centrosymmetric [Cu(2)(MU-X)(MU-L(m)*)(2)](ClO(4))(3) (X = F(-), Cl(-), Br(-), OH(-), L(m)* = m-bis[bis(3,5-dimethyl-1-pyrazolyl)methyl]benzene)], the first example of a series of bimetallic copper(II) complexes linked by a linearly bridging mononuclear anion, have been prepared and structurally characterized. Very strong antiferromagnetic exchange coupling between the copper(II) ions increases along the series F(-) < Cl(-) < OH(-) < Br(-), where -J = 340, 720, 808, and 945 cm(-1). DFT calculations explain this trend by an increase in the energy along this series of the antibonding antisymmetric combination of the p orbital of the bridging anion interacting with the copper(II) d(z(2)) orbital. PMID- 22834974 TI - Individual differences in voluntary ethanol consumption lead to differential activation of the central amygdala in rats: relationship to the anxiolytic and stimulant effects of low dose ethanol. AB - BACKGROUND: Although alcohol use disorders and anxiety disorders are highly comorbid, the relationship between these 2 disorders is not fully understood. Previous work from our laboratory shows that anxiety-like behavior is highly variable in outbred Long-Evans rats and is related to the level of voluntary ethanol (EtOH) consumption, suggesting that basal anxiety state influences EtOH intake. To further examine the relationship between the acquisition of EtOH consumption and anxiety phenotype, Long-Evans rats were assessed for anxiety-like behavior and neuronal activation following voluntary EtOH consumption in a limited access drinking paradigm. METHODS: Rats were allowed to self-administer EtOH (6% v/v) for 4 days using a limited access drinking in the dark paradigm and divided into high- and low-drinking groups based on a median split of average daily EtOH intake. Immediately following the fourth drinking session, animals were tested on the elevated plus maze and evaluated for anxiety-like behaviors. Fos immunoreactivity was assessed in the central and basolateral amygdala, as well as the bed nucleus of the stria terminalis. RESULTS: High EtOH drinkers spent significantly more time on the open arms of the plus maze than low EtOH drinkers. High EtOH drinkers also had increased locomotor activity as compared to both low EtOH drinkers and water drinkers. Fos immunoreactivity was positively correlated with EtOH consumption in all brain regions examined, although Fos positive cell counts were only significantly different between high and low EtOH drinkers in the central amygdala (CeA). CONCLUSIONS: Our findings demonstrate that outbred rats will voluntarily consume behaviorally effective doses of EtOH in a short-term access model and EtOH consumption is positively correlated with increased neuronal activation in the CeA. PMID- 22834976 TI - Intravenous hypertonic saline to reduce intraocular pressure. AB - PURPOSE: To quantitate the effect of intravenous hypertonic saline (IVHTS) injection on elevated intraocular pressure (IOP). METHODS: Nineteen patients (median age, 65 years; range, 41-84 years) with glaucoma and an IOP 30 mmHg or higher were recruited. A bolus of IVHTS (sodium chloride concentration 23.4%) was injected in an antecubital vein over 10-20 seconds. The IOP and systolic and diastolic blood pressure (BP) were measured frequently for 2 hr. The dosage was 0.5 mmol/kg sodium in 11 patients (Group 1) and 1.0 mmol/kg in eight patients (Group 2). RESULTS: In both groups, a median absolute IOP reduction of 7 mmHg was achieved in 5 min. The maximum median reduction was 7 mmHg (range, 4-16) and 9 mmHg (range, 3-14) at 5 and 16 min after IVHTS in Group 1 and 2, respectively, at which point the median IOP had reduced from 38 and 35 mmHg to 31 and 27 mmHg (p < 0.001), respectively. In both groups, the IOP remained 7 mmHg reduced 2 hr after IVHTS. Systolic BP increased a median of 14.5 mmHg at 3 min and was comparable with baseline after 6 min. CONCLUSION: Intravenous hypertonic saline solution reduces IOP moderately within minutes for up to 2 hr. PMID- 22834977 TI - Chemistry and biology of the genus Voacanga. AB - CONTEXT: Herbal remedies have been employed for the treatment and management of various ailments since the beginning of human civilization. Voacanga is an extensive genus of the family Apocynaceae and consists of small trees inhabiting the tropical and subtropical regions of Africa. Voacanga plants have been used in the treatment of leprosy, diarrhea, and generalized edema, convulsions in children as well as to treat cases of orchitis, ectopic testes and gonorrhea. OBJECTIVES: The aim of this review is to present as much information as was established from the available scientific literature. The present review comprises the ethnopharmacological, phytochemical and therapeutic potential of the plant genus Voacanga. METHODS: The present review reports on 111 natural products as found in 44 references compiled from the major databases, viz., Chemical Abstracts, Science Direct, SciFinder, PubMed, Dr. Dukes Phytochemical and Ethnobotany, CIMER, and InteliHealth. RESULTS: An exhaustive survey of the literature revealed that indole alkaoids and steroids constitute the major classes of phytoconstituents of this genus. Pharmacological reports revealed that products derived from this genus have been used for the treatment of cancer, and for CNS, cardiotonic, antituberculosis, acetylcholinesterase (AChE), butyrylcholinesterase, antagonistic, anti-diarrheal activities. PMID- 22834978 TI - Exploring barriers to participation and adoption of telehealth and telecare within the Whole System Demonstrator trial: a qualitative study. AB - BACKGROUND: Telehealth (TH) and telecare (TC) interventions are increasingly valued for supporting self-care in ageing populations; however, evaluation studies often report high rates of non-participation that are not well understood. This paper reports from a qualitative study nested within a large randomised controlled trial in the UK: the Whole System Demonstrator (WSD) project. It explores barriers to participation and adoption of TH and TC from the perspective of people who declined to participate or withdrew from the trial. METHODS: Qualitative semi-structured interviews were conducted with 22 people who declined to participate in the trial following explanations of the intervention (n = 19), or who withdrew from the intervention arm (n = 3). Participants were recruited from the four trial groups (with diabetes, chronic obstructive pulmonary disease, heart failure, or social care needs); and all came from the three trial areas (Cornwall, Kent, east London). Observations of home visits where the trial and interventions were first explained were also conducted by shadowing 8 members of health and social care staff visiting 23 people at home. Field notes were made of observational visits and explored alongside interview transcripts to elicit key themes. RESULTS: Barriers to adoption of TH and TC associated with non-participation and withdrawal from the trial were identified within the following themes: requirements for technical competence and operation of equipment; threats to identity, independence and self-care; expectations and experiences of disruption to services. Respondents held concerns that special skills were needed to operate equipment but these were often based on misunderstandings. Respondents' views were often explained in terms of potential threats to identity associated with positive ageing and self-reliance, and views that interventions could undermine self-care and coping. Finally, participants were reluctant to risk potentially disruptive changes to existing services that were often highly valued. CONCLUSIONS: These findings regarding perceptions of potential disruption of interventions to identity and services go beyond more common expectations that concerns about privacy and dislike of technology deter uptake. These insights have implications for health and social care staff indicating that more detailed information and time for discussion could be valuable especially on introduction. It seems especially important for potential recipients to have the opportunity to discuss their expectations and such views might usefully feed back into design and implementation. PMID- 22834979 TI - Storage temperatures for cold-chain delivery in cell therapy: a study of alginate encapsulated liver cell spheroids stored at -80 degrees c or -170 degrees c for up to 1 year. AB - INTRODUCTION: A bioartificial liver comprising alginate-encapsulated liver cell spheroids (ELS) could bridge the gap to transplant or spontaneous recovery in acute liver failure, but will be required for emergency use, necessitating cryopreservation. A cryopreservation protocol has been developed, but beyond this, the feasibility of cold-chain storage is considered here. Cryopreservation will be increasingly required for timely delivery of tissue and bioengineered products, and significant, but often, over-looked factors that impact on cost and ease of clinical application are the storage temperature and useful preservation time. Storage in the vapor phase of liquid nitrogen (~-170 degrees C) is the gold standard, but for safety and economic purposes, storing ELS in electric freezers at -80 degrees C may be preferable. METHODS: ELS were cryopreserved using an optimized protocol and stored at either -80 degrees C or at -170 degrees C for up to 1 year. ELS were removed from storage after 1, 2, 3, 6, 9, or 12 months, and recovery was assessed 24 h postwarming. Cell recovery was assessed using viability (fluorescent staining with image analysis), cell number (nuclei count), and functional (hepatospecific protein enzyme-linked immunosorbent assay) assays. RESULTS: Viability, the viable cell number, and function of ELS stored at -170 degrees C were maintained at similar values throughout the year. In contrast, ELS stored at -80 degrees C exhibited decreased viability, viable cell numbers, and function by as early as 1 month. Progressive deterioration was subsequently observed. After 12 months of storage at -80 degrees C, viable cell recovery of ELS was ~15% that of ELS stored at -170 degrees C. CONCLUSIONS: While convenience and cost might support the use of -80 degrees C for storage of multicellular bioengineered products such as ELS, results indicate rapid deterioration in functional recoveries after only a few weeks. This study demonstrates that storage temperature is an important consideration in regenerative medicine and caution should be applied by limiting storage at -80 degrees C to only a few weeks. PMID- 22834980 TI - Haloperidol augmentation of fluvoxamine in skin picking disorder: a case report. AB - INTRODUCTION: Compulsive skin picking, being part of the broader category of impulse control disorders, is considered a residual diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. It is characterized by excessive scratching or picking of normal skin, or skin with minor surface irregularities, and occurs in 2% of patients attending dermatology clinics. Despite the clinical relevance of this disorder, no clear guidelines are available yet; clinical management is, therefore, compromised and the day-to-day clinical practice is burdened by difficulties. Studies on selective serotonin reuptake inhibitors and anti-epileptic drugs have provided limited results. The association between anti-depressants and anti-epileptics has been found to be beneficial in some impulse control disorders, but in skin picking no previous studies have been conducted on this pharmacological approach. There are very few reports on the efficacy of anti-psychotics in skin picking. CASE PRESENTATION: The therapeutic path described in this case report produced good results for a 59 year-old Caucasian woman. The first therapeutic approach, with fluvoxamine and oxcarbazepine was partially effective; then, the suspension of oxcarbazepine and haloperidol augmentation of fluvoxamine were adopted. After 10 weeks, a significant improvement of the disease was observed: the clinical picture and the associated symptoms were nearly solved. CONCLUSIONS: To the best of our knowledge, this is the first article reporting the association of fluvoxamine and haloperidol in skin picking disorder. It might be useful to perform further research regarding the treatment of skin picking disorder: in clinical practice, several variables might limit the choice of certain drugs. Therefore, it would be useful for the clinician to be aware of other therapeutic options. PMID- 22834981 TI - Impact of increasing prevalence of minimally invasive prostatectomy on open prostatectomy observed in the national inpatient sample and national surgical quality improvement program. AB - BACKGROUND AND PURPOSE: Laparoscopic and especially robot-assisted minimally invasive prostatectomy (MIP) has increased in popularity over the past decade. We analyzed how the increasing prevalence of MIP has affected the outcomes of MIP and open radical prostatectomy (RRP). METHODS: In the Nationwide Inpatient Sample, 23,473 patients undergoing MIP and 118,266 undergoing RRP between 2002 and 2008 are reported. We analyzed length of stay (LOS), hospital charges (THC), complication rates (CR), and socioeconomic characteristics. We used the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) to identify complication rates (RRP n=666, and MIP n=2205). RESULTS: The proportion of MIP increased from 1.4% in 2002 to 29.5% in 2008. Mean LOS decreased for MIP (2.4 days in 2002, 1.6 days in 2008) and RRP (3.1 days in 2002, 2.1 days in 2008). Mean THC for MIP decreased ($46k in 2002, $34k in 2008) and increased for RRP ($18k in 2002, $32k in 2008). After 2005, overall CRs of MIP were lower than for RRP. High-volume centers reported lower CRs for both procedures. MIP was associated with fewer transfusions and wound complications. Men living in ZIP codes with the top quartile of yearly mean household income were more likely to undergo MIP than RRP (P<0.001). Although there were more white patients receiving MIP and black or Hispanic patients more frequently underwent RRP, there was no statistically significant difference. CONCLUSIONS: Increasing use of MIP led to decreased hospital stay for all patients, increase charges for RRP, and decreased CRs for both MIP and RRP. In recent years, MIP was associated with fewer complications. Charges for RRP have increased over time to approach those for MIP, and patients with increased socio-economic status were more likely to undergo MIP. PMID- 22834982 TI - Multifrequency interrogation of nanostructured gas sensor arrays: a tool for analyzing response kinetics. AB - This paper presents a unique perspective on enhancing the physicochemical mechanisms of two distinct highly sensitive nanostructured metal oxide micro hot plate gas sensors by utilizing an innovative multifrequency interrogation method. The two types of sensors evaluated here employ an identical silicon transducer geometry but with a different morphological structure of the sensitive film. While the first sensing film consists of self-ordered tungsten oxide nanodots, limiting the response kinetics of the sensor-chemical species pair only to the reaction phenomena occurring at the sensitive film surface, the second modality is a three-dimensional array of tungsten oxide nanotubes, which in turn involves both the diffusion and adsorption of the gas during its reaction kinetics with the sensitive film itself. By utilizing the proposed multifrequency interrogation methodology, we demonstrate that the optimal temperature modulation frequencies employed for the nanotubes-based sensors to selectively detect hydrogen, carbon monoxide, ethanol, and dimethyl methyl phosphonate (DMMP) are significantly higher than those utilized for the nanodot-based sensors. This finding helps understand better the amelioration in selectivity that temperature modulation of metal oxides brings about, and, most importantly, it sets the grounds for the nanoengineering of gas-sensitive films to better exploit their practical usage. PMID- 22834984 TI - Effects of insulin-like growth factor I on alveolar bone remodeling in diabetic rats. AB - BACKGROUND AND OBJECTIVE: Diabetes is a chronic hyperglycemic disorder and results in a tendency to develop osteoporosis. Furthermore, the delayed healing of tooth-extraction wounds, the activation of alveolar resorption and the suppressed formation of bone around implants are difficult for dentists to resolve. In diabetes, insulin-like growth factor I (IGF-I) appears to enhance the differentiation of osteoblasts and to activate the mineralization of bone. Hence, the aim of this study was to investigate the effects of insulin-like growth factor I on the remodeling of alveolar bone in diabetic rats. MATERIAL AND METHODS: Diabetes was induced in 40 male Sprague-Dawley rats by intravenous administration of alloxan. The teeth of the rats were extracted to investigate remodeling of alveolar bone. Insulin-like growth factor I was administered, via intraperitoneal injection, to diabetic rats following tooth extraction. The remodeling of alveolar bone was determined using radiographic data, histological analyses and tetracycline fluorescence labeling. RESULTS: Compared with the control group, diabetes decreased alveolar bone formation. The height of alveolar bone and the bone-formation rate was significantly lower in the untreated diabetic group than in the control group or in the treated rats. Treatment with insulin-like growth factor I not only regulated abnormal blood glucose levels but also increased the height of the alveolar bone and increased the bone-formation rate relative to the results in diabetic animals. Furthermore, the expression of glucose transporter-1, the main transporter of glucose, was changed by hyperglycemia. CONCLUSION: The results suggest that insulin-like growth factor I treatment increases the volume of newly formed bone following tooth extraction and normalizes the expression of glucose transporter-1 in diabetic rats, which may play an important role in bone formation and mineralization. PMID- 22834986 TI - Long-term clinical and economic outcomes associated with liraglutide versus sitagliptin therapy when added to metformin in the treatment of type 2 diabetes: a CORE Diabetes Model analysis. AB - BACKGROUND: A recent open-label, parallel group trial showed that liraglutide is superior to sitagliptin for reduction of HbA1c, and is well tolerated with minimum risk of hypoglycemia. Although these findings support the use of liraglutide as an effective GLP-1 agent to add to metformin, the value of liraglutide needs to be quantified in the framework of a cost-effectiveness (CE) analysis in a US setting. OBJECTIVE: This current study sets out to assess the long-term cost-effectiveness outcomes of liraglutide vs sitagliptin based on treatment effects data from the 1860-LIRA-DPP-4 52-week trial. METHODS: The IMS CORE Diabetes Model (CDM), a non-product-specific, validated computer simulation model that projects the long-term outcomes related to interventions for type 2 diabetes, is used for simulation of these interventions. In the model, patients were treated initially on one of the three treatment options: liraglutide 1.2 mg daily, 1.8 mg daily, or sitagliptin 100 mg daily, each used as add-on therapy to metformin for 5 years. After 5 years all patients switched to basal insulin treatment for the remainder of the simulation (35-year time horizon overall). Incremental cost-effectiveness ratios (ICERs) were generated for liraglutide 1.2 mg compared with sitagliptin and liraglutide 1.8 mg compared with sitagliptin. Transition probabilities, health state utility values, and complication costs were obtained from published sources. All outcomes were discounted at 3% per annum, and the analysis was conducted from the perspective of a third-party payer in the US. Sensitivity analyses were performed to test robustness of the base case scenario. RESULTS: For liraglutide 1.8 mg vs sitagliptin, the ICER was $37,234 per QALY gained, while for liraglutide 1.2 mg vs sitagliptin, the ICER was $25,742 per QALY gained. In all sensitivity analyses, including setting the change in HbA1c to the lower limits of the 95% confidence intervals, the ICERs remained below US$ 50,000/QALY, a commonly accepted threshold in the US, except for the shortest time horizon of 10 years. CONCLUSIONS: The availability of liraglutide 1.2 mg and 1.8 mg with improved efficacy profiles over sitagliptin could improve patient care, with the incremental cost effectiveness ratio below $50,000 per QALY gained as add-on to metformin. PMID- 22834985 TI - Decreased body fat, elevated plasma transforming growth factor-beta levels, and impaired BMP4-like signaling in biglycan-deficient mice. AB - Biglycan (BGN), a small leucine-rich proteoglycan, binds the pro-fibrotic cytokine transforming growth factor beta (TGFbeta) and inhibits its bioactivity in vitro. Nevertheless, it is controversial whether BGN plays an inhibitory role in vivo. Therefore, the purpose of this study was to evaluate the effect of BGN deficiency on TGFbeta activity in vivo by studying 1-year-old Bgn null and wild type (WT) mice on an Ldlr-null background. Phenotypic and metabolic characterization showed that the Bgn null mice had lower body weight, shorter body length, and shorter femur length (all p < 0.05). Surprisingly, the Bgn null mice also exhibited a striking reduction in percent body fat compared to WT mice (p == 0.006), but no changes were observed in plasma triglycerides, total cholesterol, or glycohemoglobin. Both total and bioactive TGFbeta1 concentrations in plasma were markedly elevated in Bgn null mice compared to WT mice (4-fold and 11-fold increase, respectively, both p < 0.001), but no changes were found in hepatic levels of mRNA for Tgfbeta1 or its receptors. Bgn null mice exhibited elevated expression of hepatic fibronectin protein (p = 0.034) without changes in hepatic or renal histology, and Bgn null mice had decreased urinary albumin/creatinine ratio (p = 0.01). Two key downstream targets of bone morphogenetic protein 4-like signaling, SMAD1/3/5 phosphorylation and Id2 gene expression, were found dramatically reduced in Bgn null livers (p = 0.034). Thus, BGN deficiency decreases body fat in this hyperlipidemic mouse model without changing liver or kidney histology. Overall, we propose that this unexpected phenotype arises from the effects of BGN deficiency in vivo to elevate TGFbeta levels while decreasing bone morphogenetic protein 4-like signaling. PMID- 22834987 TI - Listeria monocytogenes peritonitis: presentation, clinical features, treatment, and outcome. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a serious complication in cirrhotic patients. Gram (-) (E. coli, Klebsiella pneumoniae), and Gram (+) (Streptococci, Staphylococci) bacteria are most frequently cultured from patients'ascites. Listeria monocytogenes (Lm) is scarcely reported as a causative agent. OBJECTIVE: Our objective is to describe Lm peritonitis as a clinical entity, including its presentation, clinical features, treatment, and the potential factors that might affect survival outcome. MATERIAL AND METHODS: DATA SOURCES: MEDLINE, Scholar.Google, Scopus databases, including English, Spanish, French, and German language papers published between 1966 and June 2011, and reference lists. DATA EXTRACTION: investigators abstracted details about medical history, disease presentation, laboratory data, treatment and outcome. DATA SYNTHESIS: One-hundred and twenty-eight cases with known survival outcome--eighty six cirrhotics, seventeen individuals undergoing continuous ambulatory peritoneal dialysis and another twenty-five with other or no underline condition were reviewed. An additional number of twenty-five cases with unknown outcome were searched in Listeria studies published from 1990 to 2009 and were only used for calculating worldwide distribution. CONCLUSION: Cirrhotics, mostly alcoholics, presented with fever and abdominal pain. Those who succumbed had significantly higher peripheral WBC count (15622 vs. 8155 cells/mm(3), p = 0.01) and (%) polymorphonuclear cells in differential count (83.3 vs. 71%, p = 0.001). Higher mortality was experienced in those with comorbidities, and those who presented with encephalopathy. Lower mortality was experienced in patients on continuous ambulatory peritoneal dialysis. Ascites was neutrocytic in 86% of the samples. In the sum of the cases mortality was 27.3%, with significantly highest rates in the elderly, in patients with bacteremia, immunosuppression, hematological malignancies, and lowest rates in those who presented with abdominal pain and in diabetics (type I or II). The latter observation was surprising and could be considered a single fortuitous fact. Initial appropriate treatment was associated with significantly better outcome (p = 0.002) than inappropriate; combination therapy with an aminoglycoside was superior to monotherapy (p = 0.038). PMID- 22834988 TI - An initial evaluation of a family-based approach to weight management in adolescents attending a community weight management group. AB - BACKGROUND: Family-based approaches are recommended for the prevention and management of childhood obesity. Given the large numbers of obese children, scalable practical solutions are required. The present study evaluated a family based national programme that aimed to empower adolescents to adopt healthier lifestyles. METHODS: Group facilitators supporting more than six young members (11-15 years) participated in the study. A questionnaire was designed to determine the characteristics of the adult attending with the adolescent, any health professional recommendations given and the young member's integration within traditional adult weight management groups. Data on measured height and weight [and calculated body mass index (BMI)], sex and attendance were collated from member's records. RESULTS: Questionnaires were completed by 22 facilitators (15% response rate), representing data for 128 young members with complete weight data available for 106. All members had a joining BMI > 91st centile, with 68% >98th centile. The mean (SD) number of weeks attended was 12.5 (8.1), with 19% (20) having attended for more than 20 weeks with 62% still attending. A mean (SD) BMI Z-score change of 2.49 (0.72) to 2.27 (0.74) was achieved (P < 0.001). The relationship of the adult supporter to the young member was varied, with 62% either already members or joining alongside their daughter/son. Limited guidance was provided by health professionals before or during attendance. Facilitators were comfortable about the age mix within groups. CONCLUSIONS: The community weight management organisation studied takes a family-based approach and successfully supports young members to manage their weight. PMID- 22834990 TI - Chronic pain and the family: the experience of the partners of people living with chronic pain. AB - AIMS AND OBJECTIVES: The purpose of this study was to explore the impact of chronic pain on the partner and family of a person with chronic pain. BACKGROUND: Chronic pain impacts not only on the individual but also their partner and/or other family members. Families of people with chronic pain have reported feeling powerless, alienated, emotionally distressed, and isolated. These impacts have affected their relationship with the person with chronic pain. DESIGN: An interpretive qualitative design using in-depth interviews and thematic analysis was undertaken. METHODS: Purposive sampling and in-depth interviewing were undertaken to develop a rich description of the experience. RESULTS: Findings indicate the impact of chronic pain on the family is extensive, resulting in physical, social, and emotional changes. Four themes were revealed: (1) Family loss, (2) Life changes, (3) Emotional impact of pain, and (4) Future plans. CONCLUSION: This study reinforces and expands current knowledge regarding the impact of chronic pain on partners and families. Understanding this phenomenon opens opportunities for nurses and other health workers to develop and implement strategies to better support partners/families in the future. RELEVANCE TO CLINICAL PRACTICE: Nurses can help reduce the negative impact of pain by including families in assessment, education, referral and treatment processes, and by offering support and education to partners/families. PMID- 22834989 TI - Electrochemical sensing of total antioxidant capacity and polyphenol content in wine samples using amperometry online-coupled with microdialysis. AB - This work describes the method for total antioxidant capacity (TAC) and/or total content of phenolics (TCP) analysis in wines using microdialysis online-coupled with amperometric detection using a carbon microfiber working electrode. The system was tested on 10 selected wine samples, and the results were compared with total reactive antioxidant potential (TRAP), oxygen radical absorbance capacity (ORAC), and chemiluminescent determination of total antioxidant capacity (CL TAC) methods using Trolox and catechin as standards. Microdialysis online-coupled with amperometric detection gives similar results to the widely used cyclic voltammetry methodology and closely correlates with ORAC and TRAP. The problem of electrode fouling is overcome by the introduction of an electrochemical cleaning step (1-2 min at the potential of 0 V vs Ag/AgCl). Such a procedure is sufficient to fully regenerate the electrode response for both red and white wine samples as well as catechin/Trolox standards. The appropriate size of microdialysis probes enables easy automation of the electrochemical TAC/TCP measurement using 96-well microtitration plates. PMID- 22834991 TI - Altered expression and function of hepatic natural killer T cells in obese and diabetic KK-A(y) mice. AB - AIM: To evaluate the role of natural killer (NK)T cells in the pathogenesis of non-alcoholic steatohepatitis (NASH), here we investigated the expression and function of hepatic NKT cells in KK-A(y) mice, an animal model of metabolic syndrome. METHODS: Male, 8-week-old KK-A(y) and C57Bl/6 mice were fed a high fat (HF) diet for 4 weeks. Some mice were given daily intragastric injections of pioglitazone for 5 days prior to or after dietary treatment. RESULTS: In untreated KK-A(y) mice, the percentages of NKT cells in liver mononucleolar cells were nearly one-third of those in C57Bl/6 controls. Elevations in interleukin (IL)-4 and interferon (IFN)-gamma mRNA in the liver after a single injection of alpha-galactosylceramide (GalCer) were blunted in KK-A(y) mice largely. Percentages of NKT cells, as well as GalCer-induced increases in IL-4 mRNA, were blunted significantly in both strains after HF diet feeding for 4 weeks. Interestingly, KK-A(y) mice pretreated with pioglitazone showed significant increases in NKT cell proportion, and GalCer-induced increases in IL 4 and IFN-gamma mRNA were also enhanced by pioglitazone. In KK-A(y) mice, the percentages of annexin V positive NKT cells were nearly 2.5-fold higher than those in C57Bl/6 controls; however, pioglitazone decreased annexin V positive cells significantly. Moreover, pioglitazone increased NKT cell fraction in KK A(y) mice even after HF diet feeding. CONCLUSION: KK-A(y) mice exhibit proportional and functional alterations in hepatic NKT cells in close relation with the development of steatohepatitis, and it is postulated that pioglitazone improves steatohepatitis in part through restoration of hepatic NKT cells. PMID- 22834992 TI - The impact of nocturnal hemodialysis on sexual function. AB - BACKGROUND: Sexual dysfunction is common in patients with end stage renal disease (ESRD) and treatment options are limited. Observational studies suggest that nocturnal hemodialysis may improve sexual function. We compared sexual activity and responses to sexual related questions in the Kidney Disease Quality of Life Short Form questionnaire among patients randomized to frequent nocturnal or thrice weekly conventional hemodialysis. METHODS: We performed a secondary analysis of data from an RCT which enrolled 51 patients comparing frequent nocturnal and conventional thrice weekly hemodialysis. Sexual activity and responses to sexual related questions were assessed at baseline and six months using relevant questions from the Kidney Disease Quality of Life Short Form questionnaire. RESULTS: Overall, there was no difference in sexual activity, or the extent to which people were bothered by the impact of kidney disease on their sex life between the two groups between randomization and 6 months. However, women and patients age < 60 who were randomized to frequent nocturnal hemodialysis were less bothered by the impact of kidney disease on their sex life at 6 months, compared with patients allocated to conventional hemodialysis (p = 0.005 and p = 0.024 respectively). CONCLUSIONS: Our results suggest that frequent nocturnal hemodialysis is not associated with an improvement in sexual activity in all patients but might have an effect on the burden of kidney disease on sex life in women and patients less than 60 years of age. The validity of these subgroup findings require confirmation in future RCTs. PMID- 22834993 TI - Estimating propensity scores and causal survival functions using prevalent survival data. AB - This article develops semiparametric approaches for estimation of propensity scores and causal survival functions from prevalent survival data. The analytical problem arises when the prevalent sampling is adopted for collecting failure times and, as a result, the covariates are incompletely observed due to their association with failure time. The proposed procedure for estimating propensity scores shares interesting features similar to the likelihood formulation in case control study, but in our case it requires additional consideration in the intercept term. The result shows that the corrected propensity scores in logistic regression setting can be obtained through standard estimation procedure with specific adjustments on the intercept term. For causal estimation, two different types of missing sources are encountered in our model: one can be explained by potential outcome framework; the other is caused by the prevalent sampling scheme. Statistical analysis without adjusting bias from both sources of missingness will lead to biased results in causal inference. The proposed methods were partly motivated by and applied to the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data for women diagnosed with breast cancer. PMID- 22834994 TI - Controversies about the chromosomal stability of cultivated mesenchymal stem cells: their clinical use is it safe? AB - The usefulness of adult stem cells in research and therapeutic applications highly relies on their genomic integrity and stability. Many laboratories including ours have addressed this concern using methods such as karyotyping, Qbanding, fluorescent in situ hybridization, array CGH, flow cytometry and Pap test to evaluate number and structure of chromosomes and cellular phenotype. This review attempts to summarize the findings reported so far for the studies on chromosomal aberrations in adult stem cells and warrant to perform certain basic tests before transplantation to avoid any adverse reactions, which will thus aid in better therapeutic output after cellular transplantation in the treatment of various diseases. PMID- 22834995 TI - Continuous renal replacement therapy in children post-hematopoietic stem cell transplantation: the present and the future. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) use has expanded markedly to treat different disorders like hematologic malignancies, immunodeficiency, and inborn errors of metabolism. However, it is commonly associated with complications that limit the benefit of this therapy. Acute renal failure occurs commonly after HSCT and results in increased risk of mortality. In many instances, children post-HSCT develop acute renal insufficiency in the context of other organ failure, necessitating intensive care unit admission for management. Recently, continuous renal replacement therapy (CRRT) has emerged as the favored modality of renal replacement therapy in the care of critically ill children who are hemodynamically unstable. Currently, CRRT is being utilized more often in the care of critically ill post- HSCT children to treat renal failure or to prevent fluid overload (FO). FO > 20% has been shown in many studies to be an independent risk of mortality in critically ill children and therefore, many clinicians will initiate this therapy due to FO even without overt renal failure. CRRT may be beneficial in disease processes as acute lung injury due to removal of fluid. CRRT results in improved oxygenation in post-HSCT children with acute lung injury and this improvement is sustained for at least 48 hours after initiation of this therapy. Survival in post-HSCT children requiring this therapy ranges from 17% to 45%, however, long term survival is still poor. This review will discuss current practice of CRRT in children post-HSCT, as well as future directions. PMID- 22834996 TI - A meta-analysis on the impact of alcohol dependence on short-term resting-state heart rate variability: implications for cardiovascular risk. AB - BACKGROUND: Alcohol dependence is associated with an increased likelihood of cardiac events. Reductions in heart rate variability (HRV) may be one mechanism linking dependence with these events. HRV may also be related to poor social functioning and the lack of impulse control commonly observed in alcohol dependent individuals. However, prior studies on the impact of alcohol dependence on HRV have reported contradictory findings highlighting the need for a meta analysis. METHODS: Studies comparing short-term HRV in alcohol-dependent populations and healthy controls who were nondependent were considered for meta analysis. Only studies reporting findings from participants without cardiovascular disease were included in the analysis. RESULTS: Meta-analyses were based on 6 articles that fulfilled inclusion criteria, comprising a total of 177 alcohol-dependent participants and 216 nondependent participants. Alcohol dependent participants displayed reduced HRV (Hedges' g = -0.6, p > 0.001) in comparison with nondependent participants. No differences were observed between the summary effect sizes obtained from different HRV domains (Q = 1.19, p = 0.55). CONCLUSIONS: Alcohol dependence is associated with reduced HRV, an effect associated with a medium effect size. Findings highlight the importance of monitoring alcohol-dependent patients for cardiac disease and emphasize the need for cardiovascular risk reduction strategies in these patients. PMID- 22834997 TI - Outcome of T cell and other high risk subtypes of acute lymphoblastic leukemia in India: an under-reported entity. PMID- 22834998 TI - Anticoagulant treatment of pulmonary embolism: impact and implications of the EINSTEIN PE study. AB - Pulmonary embolism (PE), which can develop as a consequence of deep vein thrombosis (DVT), is a serious and potentially fatal venous thromboembolic event. Patients with PE are at increased risk of venous thromboembolism (VTE) recurrence and serious complications such as chronic thromboembolic pulmonary hypertension. Anticoagulants, namely heparins and vitamin K antagonists (VKAs), have been the main treatments for PE in patients who are haemodynamically stable. However, use of these agents can be complex and is associated with an increased risk of bleeding (a characteristic that is common to all anticoagulants). Simplified, effective treatment regimens for PE would be very beneficial for patients, physicians and payers. Compared with DVT, PE is a different clinical manifestation of VTE; phase III trials have now started to focus specifically on patients with PE. Trials in patients with PE can provide further information on the optimal management of these patients. Results of the phase III EINSTEIN PE study demonstrated non-inferiority in the efficacy and safety of oral rivaroxaban compared with standard of care (enoxaparin/VKA) for the treatment of patients with acute symptomatic PE (with or without symptomatic DVT). Rates of major bleeding were significantly lower in patients receiving rivaroxaban. This review will discuss the findings of recent trials, particularly the potential impact of single, oral agents for both the initial and long-term treatment of a range of patients with PE, and how these results may influence the clinical management of PE. PMID- 22834999 TI - Does imaging modality used for percutaneous renal access make a difference? A matched case analysis. AB - OBJECTIVE: To assess perioperative outcomes of percutaneous nephrolithotomy (PCNL) using ultrasound or fluoroscopic guidance for percutaneous access. METHODS: A prospectively collected international Clinical Research Office of the Endourological Society (CROES) database containing 5806 patients treated with PCNL was used for the study. Patients were divided into two groups based on the methods of percutaneous access: ultrasound versus fluoroscopy. Patient characteristics, operative data, and postoperative outcomes were compared. RESULTS: Percutaneous access was obtained using ultrasound guidance only in 453 patients (13.7%) and fluoroscopic guidance only in 2853 patients (86.3%). Comparisons were performed on a matched sample with 453 patients in each group. Frequency and pattern of Clavien complications did not differ between groups (p=0.333). However, postoperative hemorrhage and transfusions were significantly higher in the fluoroscopy group: 6.0 v 13.1% (p=0.001) and 3.8 v 11.1% (p=0.001), respectively. The mean access sheath size was significantly greater in the fluoroscopy group (22.6 v 29.5F; p<0.001). Multivariate analysis showed that when compared with an access sheath <= 18F, larger access sheaths of 24-26F were associated with 3.04 times increased odds of bleeding and access sheaths of 27 30F were associated with 4.91 times increased odds of bleeding (p<0.05). Multiple renal punctures were associated with a 2.6 odds of bleeding. There were no significant differences in stone-free rates classified by the imaging method used to check treatment success. However, mean hospitalization was significantly longer in the ultrasound group (5.3 v 3.5 days; p<0.001). CONCLUSIONS: On univariate analysis, fluoroscopic-guided percutaneous access was found to be associated with a higher incidence of hemorrhage. However, on multivariate analysis, this was found to be related to a greater access sheath size (>= 27F) and multiple punctures. Prospective randomized trials are needed to clarify this issue. PMID- 22835000 TI - Crystallographic and magnetic phase transitions in the layered ruthenium oxyarsenides TbRuAsO and DyRuAsO. AB - The crystallographic and physical properties of TbRuAsO and DyRuAsO at and below room temperature are reported, including full structure refinements from powder X ray diffraction data and measured electrical and thermal transport properties, magnetic susceptibility, and heat capacity. Both compounds are isostructural to LaFeAsO (ZrCuSiAs-type, P4/nmm) at room temperature. However, DyRuAsO undergoes a symmetry-lowering crystallographic phase transition near 25 K, and adopts an orthorhombic structure (Pmmn) below this temperature. This structural distortion is unlike those observed in the analogous Fe compounds. Magnetic phase transitions are observed in both compounds which suggest antiferromagnetic ordering of lanthanide moments occurs near 7.0 K in TbRuAsO and 10.5 K in DyRuAsO. The nature of the structural distortion as well as thermal conductivity and heat capacity behaviors indicate strong coupling between the magnetism and the lattice. The behaviors of both materials show magnetic ordering of small moments on Ru may occur at low temperatures. PMID- 22835001 TI - Dissociation energy and electronic and vibrational spectroscopy of Co(+)(H2O) and its isotopomers. AB - The electronic spectra of Co(+)(H(2)O), Co(+)(HOD), and Co(+)(D(2)O) have been measured from 13,500 to 18,400 cm(-1) using photodissociation spectroscopy. Transitions to four excited electronic states with vibrational and partially resolved rotational structure are observed. Each electronic transition has an extended progression in the metal-ligand stretch, v(3), and the absolute vibrational quantum numbering is assigned by comparing isotopic shifts between Co(+)(H(2)(16)O) and Co(+)(H(2)(18)O). For the low-lying excited electronic states, the first observed transition is to v(3)' = 1. This allows the Co(+) (H(2)O) binding energy to be determined as D(0)(0 K)(Co(+)-H(2)O) = 13730 +/- 90 cm(-1) (164.2 +/- 1.1 kJ/mol). The photodissociation spectrum shows a well resolved K(a) band structure due to rotation about the Co-O axis. This permits determination of the spin rotation constants epsilon(aa)" = -6 cm(-1) and epsilon(aa)' = 4 cm(-1). However, the K(a) rotational structure depends on v(3)'. These perturbations in the spectrum make the rotational constants unreliable. From the nuclear spin statistics of the rotational structure, the ground state is assigned as (3)B(1). The electronic transitions observed are from the Co(+)(H(2)O) ground state, which correlates to the cobalt ion's (3)F, 3d(8) ground state, to excited states which correlate to the (3)F, 3d(7)4s and (3)P, 3d(8) excited states of Co(+). These excited states of Co(+) interact less strongly with water than the ground state. As a result, the excited states are less tightly bound and have longer metal-ligand bonds. Calculations at the CCSD(T)/aug-cc-pVTZ level also predict that binding to Co(+) increases the H-O-H angle in water from 104.1 degrees to 106.8 degrees , as the metal removes electron density from the oxygen lone pairs. The O-H stretching frequencies of the ground electronic state of Co(+)(H(2)O) and Co(+)(HOD) have been measured by combining IR excitation with visible photodissociation in a double resonance experiment. In Co(+)(H(2)O) the O-H symmetric stretch is nu(1)" = 3609.7 +/- 1 cm(-1). The antisymmetric stretch is nu(5)" = 3679.5 +/- 2 cm(-1). These values are 47 and 76 cm(-1), respectively, lower than those in bare H(2)O. In Co(+)(HOD) the O-H stretch is observed at 3650 cm(-1), a red shift of 57 cm(-1) relative to bare HOD. PMID- 22835002 TI - Life-threatening coma and full-thickness sunburn in a patient treated with transdermal fentanyl patches: a case report. AB - INTRODUCTION: Fentanyl transdermal patches have been widely used in the treatment of chronic pain and in palliative care settings since 1991 in cases where prolonged opioid use is often necessary. Transdermal drug delivery is deemed safe and effective with the advantages of delivering a steady dose of the drug and improving patient compliance due to its ease of use. However, intentional and unintentional misuse and overdose using transdermal opioid patches has been widely reported in the literature. CASE PRESENTATION: We describe the case of a 77-year-old Caucasian woman who developed severe opioid toxicity while sun tanning, likely due to altered fentanyl transdermal patch function in a heated environment. As a result of prolonged sun exposure due to an opioid-induced coma she then sustained hyperthermia and severe burns to her abdomen and lower limbs. This inadvertent fentanyl overdose necessitated initial treatment in intensive care and follow on care in a specialist burn unit. CONCLUSION: Patients who are using fentanyl patches and their relatives should be educated about how to use the patch safely. Healthcare practitioners should warn patients about the possibility of overdosing on transdermally delivered drugs if used incorrectly. They should avoid strenuous activities and external heat sources such as warming blankets, hot water bottles, saunas, hot tubs or sunbathing and should seek medical attention if they develop a fever. Additionally, any burns sustained in the context of altered consciousness levels such as in this case with opioid overdose should raise suspicion about a potential deeper burn injury than is usually observed. PMID- 22835004 TI - Specific ion-protein interactions dictate solubility behavior of a monoclonal antibody at low salt concentrations. AB - The perturbation of salt ions on the solubility of a monoclonal antibody was systematically studied at various pHs in Na(2)SO(4), NaNO(3), NaCl, NaF, MgSO(4), Mg(NO(3))(2) and MgCl(2) solutions below 350 mM. At pH 7.1, close to the pI, all of the salts increased the solubility of the antibody, following the order of SO(4)(2-) > NO(3)(-) > Cl(-) > F(-) for anions and Mg(2+) > Na(+) for cations. At pH 5.3 where the antibody had a net positive charge, the anions initially followed the order of SO(4)(2-) > NO(3)(-) > Cl(-) > F(-) for effectiveness in reducing the solubility and then switched to increasing the solubility retaining the same order. Furthermore, the antibody was more soluble in the Mg(2+) salt solutions than in the corresponding Na(+) salt solutions with the same anion. At pH 9.0 where the antibody had a net negative charge, an initial decrease in the protein solubility was observed in the solutions of the Mg(2+) salts and NaF, but not in the rest of the Na(+) salt solutions. Then, the solubility of the antibody was increased by the anions in the order of SO(4)(2-) > NO(3)(-) > Cl(-) > F(-). The above complex behavior is explained based on the ability of both cation and anion from a salt to modulate protein-protein interactions through their specific binding to the protein surface. PMID- 22835003 TI - Effect of oxygen concentration on viability and metabolism in a fluidized-bed bioartificial liver using 31P and 13C NMR spectroscopy. AB - Many oxygen mass-transfer modeling studies have been performed for various bioartificial liver (BAL) encapsulation types; yet, to our knowledge, there is no experimental study that directly and noninvasively measures viability and metabolism as a function of time and oxygen concentration. We report the effect of oxygen concentration on viability and metabolism in a fluidized-bed NMR compatible BAL using in vivo 31P and 13C NMR spectroscopy, respectively, by monitoring nucleotide triphosphate (NTP) and 13C-labeled nutrient metabolites, respectively. Fluidized-bed bioreactors eliminate the potential channeling that occurs with packed-bed bioreactors and serve as an ideal experimental model for homogeneous oxygen distribution. Hepatocytes were electrostatically encapsulated in alginate (avg. diameter, 500 MUm; 3.5*107 cells/mL) and perfused at 3 mL/min in a 9-cm (inner diameter) cylindrical glass NMR tube. Four oxygen treatments were tested and validated by an in-line oxygen electrode: (1) 95:5 oxygen:carbon dioxide (carbogen), (2) 75:20:5 nitrogen:oxygen:carbon dioxide, (3) 60:35:5 nitrogen:oxygen:carbon dioxide, and (4) 45:50:5 nitrogen:oxygen:carbon dioxide. With 20% oxygen, beta-NTP steadily decreased until it was no longer detected at 11 h. The 35%, 50%, and 95% oxygen treatments resulted in steady beta-NTP levels throughout the 28-h experimental period. For the 50% and 95% oxygen treatment, a 13C NMR time course (~5 h) revealed 2-13C-glycine and 2-13C-glucose to be incorporated into [2-13C-glycyl]glutathione (GSH) and 2-13C-lactate, respectively, with 95% having a lower rate of lactate formation. 31P and 13C NMR spectroscopy is a noninvasive method for determining viability and metabolic rates. Modifying tissue-engineered devices to be NMR compatible is a relatively easy and inexpensive process depending on the bioreactor shape. PMID- 22835006 TI - Phase transformation and lithiation effect on electronic structure of Li(x)FePO4: an in-depth study by soft X-ray and simulations. AB - Through soft X-ray absorption spectroscopy, hard X-ray Raman scattering, and theoretical simulations, we provide the most in-depth and systematic study of the phase transformation and (de)lithiation effect on electronic structure in Li(x)FePO(4) nanoparticles and single crystals. Soft X-ray reveals directly the valence states of Fe 3d electrons in the vicinity of Fermi level, which is sensitive to the local lattice distortion, but more importantly offers detailed information on the evolution of electronic states at different electrochemical stages. The soft X-ray spectra of Li(x)FePO(4) nanoparticles evolve vividly with the (de)lithiation level. The spectra fingerprint the (de)lithiation process with rich information on Li distribution, valency, spin states, and crystal field. The high-resolution spectra reveal a subtle but critical deviation from two-phase transformation in our electrochemically prepared samples. In addition, we performed both first-principles calculations and multiplet simulations of the spectra and quantitatively determined the 3d valence states that are completely redistributed through (de)lithiation. This electronic reconfiguration was further verified by the polarization-dependent spectra collected on LiFePO(4) single crystals, especially along the lithium diffusion direction. The evolution of the 3d states is overall consistent with the local lattice distortion and provides a fundamental picture of the (de)lithiation effects on electronic structure in the Li(x)FePO(4) system. PMID- 22835007 TI - The societal burden of pain in Germany: health-related quality-of-life, health status and direct medical costs. AB - OBJECTIVES: The purpose of this paper is to estimate the impact of the severity and frequency of pain on health-related quality-of-life (HRQoL), self-reported health status, and direct medical costs in Germany. METHODS: Data are from the internet-based 2010 National Health and Wellness Survey (NHWS). Estimates of the impact of pain experience are generated by a series of regression models. In the case of HRQoL the physical and mental summary scores from the SF-12, together with SF-6D utilities, are evaluated within an ordinary least squares framework. Health status is assessed through an ordered logit model. Direct medical costs are estimated through a semi-logarithmic healthcare cost function. Socioeconomic characteristics, health risk behaviors, and the Charlson Comorbidity Index (CCI) are introduced as control variables in all regressions. RESULTS: An estimated 23.96% of the adult German population (16.39 million) reported experiencing pain in the last 30 days. Of these 13.16% reported severe pain. The experience of frequent severe and moderate pain has a significant deficit impact on HRQoL. For those experiencing severe daily pain, the deficit in the SF-12 physical component score (PCS) is -17.930 (95% CI: -18.720 to -17.140), the SF-12 mental component score (MCS) is -8.787 (05% CI: -9.857 to -7.716), and SF-6D absolute utilities 0.201 (95% CI: -0.214 to -0.188); with self-reported health status the deficit impact of severe daily pain is also substantial (OR=29.000; 95% CI: 23.000 36.580). In the case of direct medical costs severe daily pain increases healthcare provider costs by 101.6% and total direct costs by 123.9%. LIMITATIONS: The NHWS is an internet survey. The principal limitation is that as a self-report there is no separate validation of pain severity or chronicity. CONCLUSIONS: The experience of pain has a substantial negative impact on HRQoL, health status, and resource utilization in Germany. If pain is considered as a disease in its own right, the experience of chronic pain presents policy-makers with a major challenge. PMID- 22835005 TI - Effect of nonsurgical periodontal therapy on serum and gingival crevicular fluid cytokine levels during pregnancy and postpartum. AB - BACKGROUND AND OBJECTIVE: A low-grade systemic inflammatory status originating from periodontal infection has been proposed to explain the association between periodontal disease and systemic conditions, including adverse obstetric outcomes. The aim of this study was to evaluate the effect of periodontal therapy during pregnancy on the gingival crevicular fluid and serum levels of six cytokines associated with periodontal disease and preterm birth. MATERIAL AND METHODS: A subsample of 60 women (18-35 years of age) up to 20 gestational weeks, previously enrolled in a larger randomized clinical trial, was recruited for the present study. Participants were randomly allocated to receive either comprehensive nonsurgical periodontal therapy before 24 gestational weeks (n = 30, test group) or only one appointment for supragingival calculus removal (n = 30, control group). Clinical data, and samples of blood and gingival crevicular fluid, were collected at baseline, at 26-28 gestational weeks and 30 d after delivery. The levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12p70 and tumor necrosis factor-alpha were analyzed by flow cytometry. RESULTS: After treatment, a major reduction in periodontal inflammation was observed in the test group, with bleeding on probing decreasing from 49.62% of sites to 11.66% of sites (p < 0.001). Periodontal therapy significantly reduced the levels of IL 1beta and IL-8 in gingival crevicular fluid (p < 0.001). However, no significant effect of therapy was observed on serum cytokine levels. After delivery, the levels of IL-1beta in the gingival crevicular fluid of the test group were significantly lower than were those in the control group (p < 0.001), but there were no significant differences between test and control groups regarding serum cytokine levels. CONCLUSION: Although periodontal therapy during pregnancy successfully reduced periodontal inflammation and gingival crevicular fluid cytokine levels, it did not have a significant impact on serum biomarkers. PMID- 22835009 TI - Red cell distribution width and inflammation in patients with non-dipper hypertension. AB - Red cell distribution width (RDW) is independently associated with morbidity and mortality in cardiovascular diseases. RDW is elevated in hypertensive patients compared with normotensives. Based on the nocturnal course, hypertension classified as dipper and non-dipper. Non-dipper hypertension is associated with higher inflammation and worse prognosis. We aimed to investigate whether RDW and high-sensitive C-reactive protein (hsCRP) are elevated in non-dipper hypertensive patients compared with dippers. The study included total 247 essential hypertensive patients. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed for each patient. Thereafter patients were divided into the two groups on the basis of the results of 24-h ABPM: 127 dipper hypertensives and 120 non-dipper hypertensives. Complete blood count and biochemistry were measured by standard methods and hsCRP was assessed by using BN2 model nephelometer. Non dippers had significantly higher RDW levels than dippers [14.6 (13.8-17.0) vs 13.0 (12.5-13.4), p < 0.001, respectively]. After adjustment for hemoglobin, low density lipoprotein-cholesterol, sex, age and hs-CRP, mean RDW values were for dipper and non-dippers 13.4 (12.4-13.2) and 14.5 (13.7-16.8), respectively (p < 0.001). RDW was negatively correlated with the percentage decline of systolic and diastolic BP from day to night (r = - 0.392, p < 0.001 and r = - 0.294, p < 0.001, respectively). Serum hsCRP levels were also significantly higher in the non-dippers (p < 0.001) and it was significantly positively correlated with RDW (r = 0.403, p < 0.001). In receiver-operating characteristic curve analysis, the optimal cut-off value of RDW to predict non-dipping pattern was > 13.8%, with 80% sensitivity and 75% specificity. RDW is significantly increased in patients with non-dipper hypertension compared with the dipper hypertension. Inflammatory activity was closely related to RDW in non-dipper hypertensives. RDW, as easy and quick measurable tool, can predict non-dipping pattern in essential hypertension. PMID- 22835008 TI - Role of nociceptin/orphanin FQ and NOP receptors in the response to acute and repeated restraint stress in rats. AB - Central nociceptin/orphanin FQ (N/OFQ)-expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of the hypothalamic-pituitary-adrenal axis (HPA) and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the nonpeptidic NOP antagonist, JTC-801 [N-(4-amino-2-methylquinolin 6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride], during the HPA axis response to acute physical/psychological stress (60 min of restraint). Although i.v. JTC-801 (0.05 mg/kg in 100 MUl) had no significant effect on restraint induced plasma corticosterone release at 30 or 60 min post-injection, i.v. JTC 801 (0.05 mg/kg in 100 MUl) in quiescent rats significantly increased basal plasma corticosterone at the 30-min time-point compared to i.v. vehicle (1% dimethysulphoxide in sterile saline). Central injection of JTC-801 i.c.v. was associated with increased Fos expression in the parvocellular paraventricular nucleus 90 min after infusion compared to vehicle control. These findings contrast to the effects of i.c.v. UFP-101, a NOP antagonist that we have previously shown to have no effect on HPA activity in quiescent rats. To determine whether restraint stress was associated with compensatory changes in N/OFQ precursor (ppN/OFQ) or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase-polymerase chain reaction and in situ hybridisation analysis of ppN/OFQ and NOP transcripts in the brains of male Sprague-Dawley rats. In support of an endogenous role for central N/OFQ in psychological stress, we found that acute restraint significantly decreased preproN/OFQ transcript expression in the hippocampus 2 h after stress compared to unstressed controls. PpN/OFQ mRNA was also reduced in the mediodorsal forebrain 4 h after stress. NOP mRNA was reduced in the hypothalamus 2 h after restraint and at 4 h in mediodorsal forebrain and hippocampus. In situ hybridisation analysis showed that acute restraint significantly decreased ppNN/OFQ in the central amygdala, with significantly increased expression in bed nucleus and reticular thalamus associated with repeated restraint. There was a strong trend for reduced NOP mRNA in the bed nucleus of acute and repeated restraint groups, although there were no other significant changes seen. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous N/OFQ system is involved in both acute and chronic restraint stress responses. In summary, our findings confirm the significant role of endogenous NOP receptors and tonic N/OFQ function in the response to the psychological stress of restraint. PMID- 22835010 TI - Depletion of enteric gonadotropin-releasing hormone is found in a few patients suffering from severe gastrointestinal dysmotility. AB - OBJECTIVE: Many patients, especially women, suffer from severe gastrointestinal pain and dysmotility for several years without being diagnosed. Depletion of gonadotropin-releasing hormone (GnRH) in the enteric nervous system (ENS) has been described in some patients. The aim of this study was to examine the expression of GnRH in ENS and antibodies against GnRH in serum, in a dysmotility patient cohort of southern Sweden. MATERIALS AND METHODS: All consecutive patients (n = 35) referred for laparoscopic full-thickness biopsy because of symptoms or signs of severe dysmotility between 1998 and 2009, or patients with a severe dysmotility disorder having had a bowel resection within the time frame, were considered for inclusion. In 22 cases, representative biopsy material containing ganglia was available, and these patients were included. Medical records were scrutinized. The expression of GnRH was determined by immunohistochemistry in bowel biopsies from these patients and in patients with carcinoma or diverticulosis without ENS histopathology. Antibodies against GnRH in serum were determined by ELISA in patients and controls. RESULTS: 14 patients were diagnosed with enteric dysmotility (ED) and 8 with chronic intestinal pseudo obstruction due to varying etiology. Immunostained biopsies showed expression of GnRH in the ENS. A reduced expression of GnRH-containing neurons was found in 5 patients, as well as antibodies against GnRH in serum. 3 of these patients had a history of in vitro fertilization (IVF) using GnRH analogs. CONCLUSIONS: A subgroup of patients with severe dysmotility had a reduced expression of GnRH containing neurons in the ENS and expressed antibodies against GnRH in serum. PMID- 22835011 TI - A multicenter, randomized, double-blind study comparing different FK778 doses (manitimus) with tacrolimus and steroids vs. MMF with tacrolimus and steroids in renal transplantation. AB - BACKGROUND: This multicenter phase II study in renal transplantation compared 3 concentration-controlled ranges of FK778 (manitimus) with mycophenolate mofetil (MMF) both given in combination with tacrolimus and corticosteroids. METHODS: 364 patients were randomized to 12-month treatment: high-level FK778 group (H, N=87) received 4 x 600 mg/day (4 days) followed by 120 mg/day; mid-level FK778 group (M, N=92) received 3 x 600 mg/day (3 days) followed by 110 mg/day, low-level FK778 group (L, N=92) received 2 x 600 mg/day (2 days) followed by 100 mg/day, and control group received MMF 1 g/day (MMF, N=93). After week 6, FK778 doses were adjusted to trough ranges of 75-125 MUg/mL (H), 50-100 MUg/mL (M) and 25-75 MUg/mL (L). Tacrolimus and steroids were administered at the same dose in each of the 4 groups. RESULTS: Biopsy proven acute rejection (BPAR) at 24 weeks, the primary study endpoint, was comparable in the L (22.8%) and MMF (17.2%) groups but higher in the H (34.5%) and M (29.3%) groups. BPAR at 12 months was comparable in the L (23.9%) and MMF (19.4%) groups but higher in the H (34.5%) and M (31.5%) groups. Graft and patient survival were lowest in the H group and renal function was poorest in the H and M groups. Premature study withdrawal was highest in the H group. CONCLUSIONS: Efficacy was similar between the low-level FK778 and MMF groups. Increased FK778 exposure was poorly tolerated and did not improve efficacy. PMID- 22835012 TI - Increased macroautophagy in the pathological process of intervertebral disc degeneration in rats. AB - OBJECTIVE: Macroautophagy increases with age in rat intervertebral discs; however, the effect of macroautophagy on the process of intervertebral disc degeneration (IVDD) is still unclear. The aim of this study was to examine the presence of autophagosome, as well as the levels of Beclin-1 and LC3 proteins, in vivo. Additionally, in vitro evidence of macroautophagy and GRP78 and GADD153 protein levels were investigated to explore the mechanism of macroautophagy in the process of IVDD. METHODS: Male Sprague-Dawley rats, aged 2 months, were randomly divided into six groups (three control and three model groups, n = 8 per group). At the 6-, 12-, and 18-week time points, autophagosomes in nucleus pulposus cells were detected with transmission electron microscope (TEM). Expression of Beclin-1 and LC3 protein levels within intervertebral disc was detected using Western blotting analysis. Then, the rat annulus fibrosus cells were isolated and cultured with Earle's balanced salt solution. At 1, 2, and 3 hr of culture, autophagosomes were detected using monodansylcadaverine assay, and LC3, Beclin-1, GRP78, and GADD153 protein levels were detected using Western blotting analysis. RESULTS: Transmission electron microscopy revealed autophagosomes within nucleus pulposus cells in both the control and model groups. At 6-, 12-, and 18-week posttreatments, the levels of Beclin-1 and the LC3-II/LC3-I protein ratio in the model groups were higher than those in the control groups (p < 0.05). Compared with the control rats, amino acid starvation increased the number of monodansylcadaverine-positive cells and the LC3-II/LC3-I protein ratio in the model rats. Moreover, the in vitro levels of Beclin-1, GRP78, and GADD153 proteins were increased with the prolongation of amino acid starvation (p < 0.05). CONCLUSIONS: Macroautophagy was present and was associated with increased pathological process of IVDD in rats. Macroautophagy of intervertebral disc cells is possibly secondary to endoplasmic reticulum stress. PMID- 22835013 TI - Evidence for a minor gene-for-minor gene interaction explaining nonhypersensitive polygenic partial disease resistance. AB - ABSTRACT Partial resistance is a quantitative type of resistance that, by definition of Parlevliet, is not based on hypersensitivity. It is largely pathotype nonspecific, although some minor isolate-specific responses have been reported. In order to elucidate the isolate specificity of individual genes for partial resistance, three barley recombinant inbred line mapping populations were analyzed for resistance to the leaf rust fungus Puccinia hordei. The mapping populations were inoculated with one isolate avirulent and two isolates virulent to resistance gene Rph7g. Six significant quantitative trait loci (QTLs) were detected. Of these, two (Rphq3 and Rphq11) were detected with only the avirulent isolate (1.2.1.) and one (Rphq18) only with both virulent isolates (CO-04 and 28.1). The effectiveness of these QTLs was tested with 14 isolates, using a tester set of genotypes containing alleles for resistance or susceptibility for these QTLs. QTL Rphq18 was effective to only two isolates, CO-04 and 28.1, whereas Rphq3 and Rphq11 were ineffective to CO-04 and 28.1 but effective to all other isolates, except one. This resulted in a significant Person's differential interaction, which is a hallmark of a gene-for-gene interaction. The minor gene for-minor gene interaction is not based on hypersensitivity and there is no evidence that the resistance is based on genes belonging to the nucleotide binding leucine-rich repeat class. PMID- 22835014 TI - Rank regression for analyzing ordinal qualitative data for treatment comparison. AB - ABSTRACT Ordinal qualitative data are often collected for phenotypical measurements in plant pathology and other biological sciences. Statistical methods, such as t tests or analysis of variance, are usually used to analyze ordinal data when comparing two groups or multiple groups. However, the underlying assumptions such as normality and homogeneous variances are often violated for qualitative data. To this end, we investigated an alternative methodology, rank regression, for analyzing the ordinal data. The rank-based methods are essentially based on pairwise comparisons and, therefore, can deal with qualitative data naturally. They require neither normality assumption nor data transformation. Apart from robustness against outliers and high efficiency, the rank regression can also incorporate covariate effects in the same way as the ordinary regression. By reanalyzing a data set from a wheat Fusarium crown rot study, we illustrated the use of the rank regression methodology and demonstrated that the rank regression models appear to be more appropriate and sensible for analyzing nonnormal data and data with outliers. PMID- 22835015 TI - Association of on-treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e-antigen positive chronic hepatitis B. AB - AIM: This study evaluated the on-treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off-treatment sustained virological response (SVR). METHODS: Fifty-one consecutive patients with hepatitis B e-antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off-treatment without reappearance of HBeAg. RESULTS: Twenty-two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off-treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log(10) IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off-treatment. A decline of HBsAg of 0.5 log(10) IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86 142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18-185.73 [P = 0.036]; respectively). CONCLUSION: On-treatment serum HBsAg level predicted early off treatment SVR to NUC therapy in patients infected with genotype C. PMID- 22835016 TI - A study of risk factors for infection with HPAI H5N1 in small poultry farms in Thailand using a questionnaire survey. AB - A questionnaire was used to collect data on small poultry farm management and wild bird observed in poultry keeping areas to identify putative risk factors for infection with HPAI H5N1. The study was conducted in 2008 in four subdistricts of central Thailand that had experienced outbreaks of HPAI H5N1 in poultry. Descriptive and inferential analyses including univariable analyses and multivariable logistic regression were used to identify putative risk factors. Risk factors included purchasing native chickens/fighting cocks from commercial hatcheries, replacing or restocking birds individually, and observing lesser whistling ducks (Dendrocygna javanica) on the farm daily. Selecting healthy animals when purchasing animals to ensure that they were disease free was a protective factor. To fully understand the epidemiology of infection of small poultry farms with HPAI H5N1, control of movement of domestic poultry and serological and virological testing of the poultry population should be applied. PMID- 22835017 TI - Foot health and self-care activities of older people in home care. AB - AIMS AND OBJECTIVES: To assess the foot health of older people and their self care activities in home care. The ultimate goal is to prevent foot problems in older people and to develop the assessment skills of nurses working in home care. BACKGROUND: Foot health problems are one reason why older people seek home care services. These problems are prevalent in older people, and they can impair performance of daily activities and threaten functional ability. However, studies in this field have concentrated on foot problems related to specific diseases. Non-disease-related research on foot health from the preventative perspective is lacking. DESIGN: A descriptive explorative design was used. METHODS: The foot health of older people was assessed by visiting home nurses with the Foot Health Assessment Instrument, and older people's foot self-care activities were evaluated with the Foot Self-Care Activities Structured Interview in 2010. The data were analysed statistically. RESULTS: Older people in home care have multiple foot health problems. The most prevalent problems were oedema, dry skin, thickened and discoloured toenails and hallux valgus. Caring for one's feet was a problem for many older people. CONCLUSIONS: Older people's foot health needs to be assessed regularly to recognise foot health and self-care problems. Health care professionals have a vital role in preventing, recognising and caring for foot health in older people. RELEVANCE TO CLINICAL PRACTICE: The foot health of older people needs to be improved by supporting older people in foot self-care and developing preventive nursing interventions. Regular foot health assessments and their documentation are crucial in preventing serious foot problems in older people. Moreover, multiprofessional collaboration is important to promote foot health in older people. PMID- 22835018 TI - Prevalence and clinical features of HIV and malaria co-infection in hospitalized adults in Beira, Mozambique. AB - BACKGROUND: Mozambique presents a very high prevalence of both malaria and HIV infection, but the impact of co-cancel infection on morbidity in this population has been rarely investigated. The aim of this study was to describe the prevalence and clinical characteristics of malaria in hospitalized adult HIV positive patients, treated and untreated with combination anti-retroviral therapy (ART) and cotrimoxazole (CTX)-based chemoprophylaxis, compared to HIV negatives. METHODS: From November to December 2010, all adult patients consecutively admitted to the Department of Internal Medicine of Beira Central Hospital, Sofala Province, Mozambique, were submitted to HIV testing, malaria blood smear (MBS) and, in a subgroup of patients, also to the rapid malaria test (RDT). Socio demographical and clinical data were collected for all patients. The association of both a positive MBS and/or RDT and diagnosis of clinical malaria with concomitant HIV infection (and use of CTX and/or ART) was assessed statistically. Frequency of symptoms and hematological alterations in HIV patients with clinical malaria compared to HIV negatives was also analysed. Sensitivity and specificity for RDT versus MBS were calculated for both HIV-positive and negative patients. RESULTS: A total of 330 patients with available HIV test and MBS were included in the analysis, 220 of whom (66.7%) were HIV-positive. In 93 patients, malaria infection was documented by MBS and/or RDT. RDT sensitivity and specificity were 94% and 96%, respectively. According to laboratory results, the initial malaria suspicion was discarded in about 10% of cases, with no differences between HIV positive and negative patients. A lower malaria risk was significantly associated with CTX prophylaxis (p=0.02), but not with ART based on non nucleoside reverse transcriptase inhibitors (NNRTIs). Overall, severe malaria seemed to be more common in HIV-positive patients (61.7%) compared to HIV-negatives (47.2%), while a significantly lower haemoglobin level was observed in the group of HIV-positive patients (9.9 +/- 2.8 mg/dl) compared to those HIV-negative (12.1 +/- 2.8 mg/dl) (p=0.003). CONCLUSIONS: Malaria infection was rare in HIV-positive individuals treated with CTX for opportunistic infections, while no independent anti-malarial effect for NNRTIs was noted. When HIV and malaria co-infection occurred, a high risk of complications, particularly anaemia, should be expected. PMID- 22835019 TI - Consider drugs as a cause or an exacerbating factor in patients diagnosed with subacute cutaneous lupus erythematosus! PMID- 22835020 TI - Topical sunscreens and vitamin D. PMID- 22835021 TI - What amount of hair do women want? PMID- 22835022 TI - IVIg in TEN: time to re-evaluate the efficacy of intravenous immunoglobulin in the management of toxic epidermal necrolysis. PMID- 22835023 TI - Updates from the British Association of Dermatologists 91st annual meeting, 5-7 July 2011, London, U.K. AB - This is a synopsis of the significant research and clinical papers presented at the British Association of Dermatologists (BAD) meeting held on the 5-7 July 2011 in London, U.K. The conference and satellite symposia highlighted the recent biological, epidemiological and therapeutic advances in dermatology. This report is not meant as a substitute for reading the conference proceedings and related references quoted in this article. PMID- 22835024 TI - Recurrent heterozygous missense mutation, p.Gly573Ser, in the TRPV3 gene in an Indian boy with sporadic Olmsted syndrome. AB - Olmsted syndrome (OS) is a rare genodermatosis that is often difficult to diagnose because of clinical overlap with other disorders and its uncertain mode of inheritance. The molecular basis of OS was investigated in an Indian boy using comparative exome sequencing and Sanger sequencing data. Sequencing identified a G-to-A transition at position c.573 in the TRPV3 gene, producing the missense mutation p.Gly573Ser in the proband. This mutation was not identified in the mother. This study supports the recent finding of TRPV3 as the gene implicated in OS and suggests that the mutation p.Gly573Ser may be a recurrent abnormality in this genodermatosis. PMID- 22835025 TI - The inflammatory markers in psoriasis. PMID- 22835027 TI - Dopamine-secreting corticomedullary mixed tumor of the adrenal gland. PMID- 22835028 TI - A time course analysis of the extracellular proteome of Aspergillus nidulans growing on sorghum stover. AB - BACKGROUND: Fungi are important players in the turnover of plant biomass because they produce a broad range of degradative enzymes. Aspergillus nidulans, a well studied saprophyte and close homologue to industrially important species such as A. niger and A. oryzae, was selected for this study. RESULTS: A. nidulans was grown on sorghum stover under solid-state culture conditions for 1, 2, 3, 5, 7 and 14 days. Based on analysis of chitin content, A. nidulans grew to be 4-5% of the total biomass in the culture after 2 days and then maintained a steady state of 4% of the total biomass for the next 12 days. A hyphal mat developed on the surface of the sorghum by day one and as seen by scanning electron microscopy the hyphae enmeshed the sorghum particles by day 5. After 14 days hyphae had penetrated the entire sorghum slurry. Analysis (1-D PAGE LC-MS/MS) of the secretome of A. nidulans, and analysis of the breakdown products from the sorghum stover showed a wide range of enzymes secreted. A total of 294 extracellular proteins were identified with hemicellulases, cellulases, polygalacturonases, chitinases, esterases and lipases predominating the secretome. Time course analysis revealed a total of 196, 166, 172 and 182 proteins on day 1, 3, 7 and 14 respectively. The fungus used 20% of the xylan and cellulose by day 7 and 30% by day 14. Cellobiose dehydrogenase, feruloyl esterases, and CAZy family 61 endoglucanases, all of which are thought to reduce the recalcitrance of biomass to hydrolysis, were found in high abundance. CONCLUSIONS: Our results show that A. nidulans secretes a wide array of enzymes to degrade the major polysaccharides and lipids (but probably not lignin) by 1 day of growth on sorghum. The data suggests simultaneous breakdown of hemicellulose, cellulose and pectin. Despite secretion of most of the enzymes on day 1, changes in the relative abundances of enzymes over the time course indicates that the set of enzymes secreted is tailored to the specific substrates available. Our findings reveal that A. nidulans is capable of degrading the major polysaccharides in sorghum without any chemical pre-treatment. PMID- 22835029 TI - Analysis of low temperature-induced genes (LTIG) in wine yeast during alcoholic fermentation. AB - Fermentations carried out at low temperatures, that is, 10-15 degrees C, not only enhance the production and retention of flavor volatiles, but also increase the chances of slowing or arresting the process. In this study, we determined the transcriptional activity of 10 genes that were previously reported as induced by low temperatures and involved in cold adaptation, during fermentation with the commercial wine yeast strain QA23. Mutant and overexpressing strains of these genes were constructed in a haploid derivative of this strain to determine the importance of these genes in growth and fermentation at low temperature. In general, the deletion and overexpression of these genes did affect fermentation performance at low temperature. Most of the mutants were unable to complete fermentation, while overexpression of CSF1, HSP104, and TIR2 decreased the lag phase, increased the fermentation rate, and reached higher populations than that of the control strain. Another set of overexpressing strains were constructed by integrating copies of these genes in the delta regions of the commercial wine strain QA23. These new stable overexpressing strains again showed improved fermentation performance at low temperature, especially during the lag and exponential phases. Our results demonstrate the convenience of carrying out functional analysis in commercial strains and in an experimental set-up close to industrial conditions. PMID- 22835030 TI - Bonding trends traversing the tetravalent actinide series: synthesis, structural, and computational analysis of An(IV)((Ar)acnac)4 complexes (An = Th, U, Np, Pu; (Ar)acnac = ArNC(Ph)CHC(Ph)O; Ar = 3,5-(t)Bu2C6H3). AB - A series of tetravalent An(IV) complexes with a bis-phenyl beta-ketoiminate N,O donor ligand has been synthesized with the aim of identifying bonding trends and changes across the actinide series. The neutral molecules are homoleptic with the formula An((Ar)acnac)(4) (An = Th (1), U (2), Np (3), Pu (4); (Ar)acnac = ArNC(Ph)CHC(Ph)O; Ar = 3,5-(t)Bu(2)C(6)H(3)) and were synthesized through salt metathesis reactions with actinide chloride precursors. NMR and electronic absorption spectroscopy confirm the purity of all four new compounds and demonstrate stability in both solution and the solid state. The Th, U, and Pu complexes were structurally elucidated by single-crystal X-ray diffraction and shown to be isostructural in space group C2/c. Analysis of the bond lengths reveals shortening of the An-O and An-N distances arising from the actinide contraction upon moving from 1 to 2. The shortening is more pronounced upon moving from 2 to 4, and the steric constraints of the tetrakis complexes appear to prevent the enhanced U-O versus Pu-O orbital interactions previously observed in the comparison of UI(2)((Ar)acnac)(2) and PuI(2)((Ar)acnac)(2) bis-complexes. Computational analysis of models for 1, 2, and 4 (1a, 2a, and 4a, respectively) concludes that both the An-O and the An-N bonds are predominantly ionic for all three molecules, with the An-O bonds being slightly more covalent. Molecular orbital energy level diagrams indicate the largest 5f-ligand orbital mixing for 4a (Pu), but spatial overlap considerations do not lead to the conclusion that this implies significantly greater covalency in the Pu-ligand bonding. QTAIM bond critical point data suggest that both U-O/U-N and Pu-O/Pu-N are marginally more covalent than the Th analogues. PMID- 22835031 TI - Protective effect of deferricoprogen isolated from Monascus purpureus NTU 568 on citrinin-induced apoptosis in HEK-293 cells. AB - Monascus species have traditionally been used in Asian food, with rice as their fermentation substrate. Red mold rice (RMR) contains citrinin, a nephrotoxic agent capable of exerting oxidative stress and cellular apoptosis. We investigated the components in RMR that could minimize the adverse effects of citrinin. Combining chemical separations and bioactivity assays, we identified an antioxidative component called deferricoprogen (DFC) in the fermented rice of Monascus purpureus NTU 568. The DFC structure was confirmed by nuclear magnetic resonance (NMR) and mass spectra analysis. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging activity of DFC was similar to that of vitamin E. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometric analysis showed the effect of DFC and citrinin on cell viability and cell cycle. DFC was found to be protective against the cytotoxicity and cell death induced by citrinin on human embryonic kidney (HEK-293) cells. DFC also demonstrated anti-apoptotic property in preventing citrinin-induced apoptosis. PMID- 22835032 TI - Re: Phantom study of a novel stereotactic prostate biopsy system integrating preinterventional magnetic resonance imaging and live ultrasonography fusion (from: Kuru TH, Roethke M, Popeneclu V, et al. J Endourol 2012;26:807-813.). PMID- 22835033 TI - Commentary on Fitzpatrick and colleagues (2012): Forecasting the effect of the amethyst initiative on college drinking. AB - BACKGROUND: There is considerable evidence that heavy episodic drinking (HED) is a serious problem among college students. Concern with this problem has led 135 college presidents to endorse the Amethyst Initiative, which promotes the lowering of the minimum legal drinking age (MLDA) from 21 to 18. The Amethyst Initiative claims that the current MLDA of 21 encourages underage college students to drink in unsupervised locations where they adopt misconceptions regarding the normative level of student drinking that leads to excessive consumption or HED. The study by Fitzpatrick and colleagues (2012) in this issue challenges this hypothesis by contrasting the potential reduction in misapprehension of the drinking norm against the increase in consumption that would be expected if the MLDA was lowered to 18. METHODS: This commentary places the Fitzpatrick study within the larger context of the MLDA, noting that full consideration of the lowering the MLDA requires the inclusion of 18- to 20-year old noncollege youths in the work force and 15- to 17-year-old high school students who will have increased access to alcohol through their 18-year-old peers. RESULTS: Research suggests that alcohol consumption and its associated problems will increase for 15- to 20-year-olds if the MLDA was lowered. This commentary also identifies alternative strategies for reducing college student HED that do not require lowering the MLDA. CONCLUSIONS: Although college binge drinking is a significant problem, reducing the drinking age is unlikely to be effective. Instead, it will increase the risk of alcohol problems faced by even younger high school students. PMID- 22835034 TI - Smart multilayered assembly for biocompatible siRNA delivery featuring dissolvable silica, endosome-disrupting polycation, and detachable PEG. AB - Multifunctional delivery systems of small interfering RNA (siRNA) are needed to overcome the intrinsic biological barriers toward efficient gene silencing in the cell cytoplasm. In this report, a smart multilayered assembly (SMA) was fabricated by a layer-by-layer method with polyionic materials. The SMA was designed to feature a siRNA-loaded core, a transiently core-stabilizing silica interlayer, an endosome-disrupting polycation interlayer, and a biocompatible poly(ethylene glycol) (PEG) shell with reductive environment-responsive detachability. The SMA was confirmed to be approximately 160 nm in size with narrow distribution and spherical morphology by DLS and TEM analyses. The PEG detachability of the SMA based on disulfide cleavage was also confirmed by the increase in both zeta-potential and size due to the exposure of the polycation interlayer and the compromised colloidal stability. The silica interlayer rendered the SMA highly tolerant to dissociation induced by anionic lipids, while after 24 h dialysis siRNA release from the SMA was clearly observed, presumably due to gradual dissolution of the silica interlayer based on the equilibrium shift to silicate ions. The entrapment ratio of siRNA delivered by the SMA within the endosome was significantly lower than that by nondisulfide control (NDC) without PEG detachability, suggesting the improved endosomal escape of SMA with the exposed, endosome-disrupting interlayer after PEG detachment. SMAs induced significantly higher gene silencing efficiency in various cultured cells, compared to NDC, without associated cytotoxicity. The systemic administration of SMAs for subcutaneous tumor-bearing mice achieved significant endogenous gene silencing in tumor tissue without hematological toxicity. PMID- 22835035 TI - Comparison of oncological and functional outcomes of pure versus robotic-assisted laparoscopic radical prostatectomy performed by a single surgeon. AB - OBJECTIVE: The aim of this study was to compare oncological and functional outcomes of pure laparoscopic radical prostatectomy (LRP) and robotic-assisted laparoscopic radical prostatectomy (RALRP) performed by a single surgeon. MATERIAL AND METHODS: In total, 327 consecutive patients with prostate cancer who underwent radical prostatectomy (144 with LRP and 183 with RALRP) were enrolled. No significant differences were found in prostate-specific antigen level, biopsy Gleason score, clinical T stage or D'Amico risk stratification between the two groups. The operating time was longer in the LRP group (p < 0.001). The RALRP group patients had significantly lower postoperative pain numerical rating scale (NRS) (p = 0.016) and catheter duration (p < 0.001). There were no differences in pathological Gleason score, pathological T stage or positive surgical margin rate. No differences were found in biochemical recurrence-free survival. Postoperative pad-free continence rates revealed a more rapid recovery in the RALRP group, but rates at 12 months were not significantly different. Multivariate analysis showed that the type of surgery was a strong independent factor to predict early postoperative pad use. Postoperative potency rates were not significantly different at 3, 6 and 12 months in patients who underwent nerve sparing procedures. CONCLUSIONS: LRP and RALRP performed by a single surgeon yielded similar results in terms of safety and oncological outcomes. More favorable outcomes were noted in operating time, pain NRS and catheter duration, as well as urinary continence recovery time. Therefore, RALRP showed more favorable components in terms of postoperative quality of life than LRP. PMID- 22835036 TI - Theoretical study of the importance of the spectator groups on the hydrolysis of phosphate triesters. AB - The spontaneous hydrolysis of a series of five triaryl and two dialkyl aryl phosphate triesters, previously studied experimentally, is examined theoretically using two different hybrid density functional methods, B3LYP and M06; two basic sets, 6-31+G(d) and 6-311++G(d,p); and the Gaussian 09 program. The B3LYP/6 31+G(d) methodology combined excellent accuracy with minor computational cost. The calculations show excellent quantitative agreement with experiment, which is best in the presence of three discrete water molecules. The results support a two step mechanism involving a pentacovalent addition intermediate, with a lifetime of tenths of a millisecond. The rate-determining formation of this intermediate involves general base catalysis, defined by concerted proton transfers in a six membered cyclic activated complex (TS1), which involves two hydrogen-bonded water molecules supporting a well-developed H(2)O...P bond (mean % evolution 77.83 +/- 0.97). The third water molecule is hydrogen-bonded to P?O and subsequently involved in product formation via TS2. The effects on reactivity of all the groups attached to phosphorus in TS1 are examined in detail: the two non-leaving groups in particular are found to play an important role, accounting for the substantial difference in reactivity between triaryl and dialkyl aryl phosphate triesters. PMID- 22835037 TI - Mitigating conflicts of interest in chemical safety testing. PMID- 22835038 TI - Geriatric screening in first opinion practice - results from 45 dogs. AB - OBJECTIVES: To evaluate and report the results of screening geriatric dogs in a first opinion practice. METHODS: A prospective health screen of dogs over nine years-old involving history taking, physical examination and urinalysis. RESULTS: At least one previously unrecognised problem was identified in 80% of 45 dogs and 353 findings (mean 7.8 per dog) were recorded. Owners often failed to recognise and report serious signs of age-related disease. However, they most often reported increased sleeping (31%), loss of hearing (29%) or sight (20%), stiffness or lameness (22%) and "slowing down" (20%). Increased lens opacity (64%), increased thirst (58%), pain (24%), increased frequency of urination (24%), signs of osteoarthritis (24%) and dental disease (22%) were most frequently identified at the time of consultation. Potentially, life-threatening findings included respiratory distress, palpable abdominal masses and metastatic lung disease. Screening resulted in 29 further diagnostic procedures, including 10 dental procedures, seven medical treatments, two surgical procedures and euthanasia of two dogs. CLINICAL SIGNIFICANCE: Screening elderly dogs identified unrecognised and unreported health risk factors resulting in lifestyle modification and ongoing monitoring, as well as signs of age-related diseases resulting in diagnostic investigations, early diagnoses and surgical and medical interventions to improve quality of life. PMID- 22835039 TI - Luminescence and energy transfer in Lu3Al5O12 scintillators co-doped with Ce3+ and Tb3+. AB - Lu(3)Al(5)O(12) (LuAG) doped with Ce(3+) is a promising scintillator material with a high density and a fast response time. The light output under X-ray or gamma-ray excitation is, however, well below the theoretical limit. In this paper the influence of codoping with Tb(3+) is investigated with the aim to increase the light output. High resolution spectra of singly doped LuAG (with Ce(3+) or Tb(3+)) are reported and provide insight into the energy level structure of the two ions in LuAG. For Ce(3+) zero-phonon lines and vibronic structure are observed for the two lowest energy 5d bands and the Stokes' shift (2 350 cm(-1)) and Huang-Rhys coupling parameter (S = 9) have been determined. Tb(3+) 4f-5d transitions to the high spin (HS) and low spin (LS) states are observed (including a zero-phonon line and vibrational structure for the high spin state). The HS-LS splitting of 5400 cm(-1) is smaller than usually observed and is explained by a reduction of the 5d-4f exchange coupling parameter J by covalency. Upon replacing the smaller Lu(3+) ion with the larger Tb(3+) ion, the crystal field splitting for the lowest 5d states increases, causing the lowest 5d state to shift below the (5)D(4) state of Tb(3+) and allowing for efficient energy transfer from Tb(3+) to Ce(3+) down to the lowest temperatures. Luminescence decay measurements confirm efficient energy transfer from Tb(3+) to Ce(3+) and provide a qualitative understanding of the energy transfer process. Co-doping with Tb(3+) does not result in the desired increase in light output, and an explanation based on electron trapping in defects is discussed. PMID- 22835040 TI - Genetic privacy in sports: clearing the hurdles. AB - As genomic medicine continues to advance and inform clinical care, knowledge gained is likely to influence sports medicine and training practices. Susceptibility to injury, sudden cardiac failure, and other serious conditions may one day be tackled on a subclinical level through genetic testing programs. In addition, athletes may increasingly consider using genetic testing services to maximize their performance potential. This paper assesses the role of privacy and genetic discrimination laws that would apply to athletes who engage in genetic testing and the limits of these protections. PMID- 22835041 TI - A label-free, electrochemical SERS-based assay for detection of DNA hybridization and discrimination of mutations. AB - A label-free, surface-enhanced Raman spectroscopy-based assay for detecting DNA hybridization at an electrode surface and for distinguishing between mutations in DNA is demonstrated. Surface-immobilized DNA is exposed to a binding agent that is selective for dsDNA and acts as a reporter molecule. Upon application of a negative potential, the dsDNA denatures into its constituent strands, and the changes in the spectra of the reporter molecule are monitored. This method has been used to distinguish between a wild-type, 1653C/T single-point mutation and DeltaF508 triplet deletion in the CFTR gene. The use of dsDNA-selective binding agents as reporter molecules in a discrimination assay removes the burden of synthetically modifying the target to be detected, while retaining flexibility in the choice of the reporter molecule. PMID- 22835042 TI - Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM). AB - INTRODUCTION: Laparoscopic myomectomy has recently gained wide acceptance but this procedure remains technically highly demanding and concerns have been raised about the increased blood loss and an higher risk of postoperative uterine rupture of the pregnant uterus. OBJECTIVE: The aim of the present study is to evaluate the fertility and endocrine outcome in women underwent robot-assisted laparoscopic myomectomy (RALM). METHODS: Data from 48 RALM performed in our department between the years 2007 and 2011 have been collected. Conception rate, abortion rate, incidence of feto-maternal morbidity or severe pregnancy and labor related complications were reported; FSH and AMH levels and ultrasound valuation of AFC has been made before and 6 months after operation. Number of cesarean sections and vaginal deliveries were described. RESULTS: The average age of the patients was 35 years and median Body Mass Index was 23 kg/m(2) (range 18-35 kg/m(2)). Seven women (13%) became pregnant after RALM with eight pregnancies. One pregnancy is actually on going; there were six deliveries with caesarian section and one spontaneous delivery. No spontaneous abortions. No uterine ruptures occurred. No significant modification of ovarian function was found after myomectomy. CONCLUSION: RALM seems to have a favorable impact on the reproductive outcome of young patients with no impact on the ovarian function. PMID- 22835043 TI - Mean platelet volume/platelet count ratio in hepatocellular carcinoma. AB - Mean platelet volume (MPV) has been actively investigated in liver disease such as steatosis, cirrhosis and hepatitis. Recently, MPV/platelet count (PC) ratio has been proposed as a predictor of long-term mortality after myocardial infarction. As PC is known to be decreased in various liver diseases such as cirrhosis, hepatosplenomegaly and malignancy, we planned to evaluate MPV/PC ratio in patients with hepatocellular carcinoma (HCC) in this study. Mean of MPV levels showed significant difference, which were 8.69 fl (range 6.7-12.2 fl) in patients group and 8.02 fl in control group (range 6.7-11.0 fl). In receiver operating characteristic (ROC) curve analysis, the MPV/PC ratio (fl/(10(9)/l)) presented 74.5% of sensitivity and 96.5% of specificity at the criterion > 0.0491 (area under the curve (AUC) = 0.884), while MPV alone showed 57.4% of sensitivity and 81.4% of specificity at the criterion > 8.4 fl. Further studies should evaluate underlying pathogenic mechanisms of MPV/PC ratio difference and various possibilities of this ratio as an indicator of presence of a tumor in HCC. PMID- 22835044 TI - Editorial comment to similar functional outcomes after partial nephrectomy for clinical T1b and T1a renal cell carcinoma. PMID- 22835046 TI - Asexual evolution: do intragenomic parasites maintain sex? AB - Resolving the paradox of sex, with its twofold cost to genic transmission, remains one of the major unresolved questions in evolutionary biology. Counting this genetic cost has now gone genomic. In this issue of Molecular Ecology, Kraaijeveld et al. (2012) describe the first genome-scale comparative study of related sexual and asexual animal lineages, to test the hypothesis that asexuals bear heavier loads of deleterious transposable elements. A much higher density of such parasites might be expected, due to the inability of asexual lineages to purge transposons via mechanisms exclusive to sexual reproduction. They find that the answer is yes--and no--depending upon the family of transposons considered. Like many such advances in testing theory, more questions are raised by this study than answered, but a door has been opened to molecular evolutionary analyses of how responses to selection from intragenomic parasites might mediate the costs of sex. PMID- 22835045 TI - Brief intensive therapy for older adults with newly diagnosed Burkitt or atypical Burkitt lymphoma/leukemia. AB - Older patients with Burkitt lymphoma/leukemia (BL) have inferior outcomes. Because cyclophosphamide is highly active in BL and can be dose-escalated without stem-cell rescue, we designed a short, cyclophosphamide-intensive regimen without anthracyclines for patients aged >= 30 with untreated, non-HIV-associated BL/atypical BL. Two cycles involving cyclophosphamide 1500 mg/m(2), vincristine, rituximab, prednisone, methotrexate 3 g/m(2), and intrathecal cytarabine were delivered 2 weeks apart, followed by intensification with high-dose cyclophosphamide (50 mg/kg/day for 4 days) and rituximab. Of 21 patients, median age 53 (range, 34-75), 71% had stage IV, 95% were high-risk and 29% had performance status 3-4. Response occurred in all evaluable patients post-cycle 2 and in 76% post-intensification. Five non-relapse deaths occurred (four before intensification). The estimated 1-year and 3-year event-free survival was 52%; 1 year and 3-year overall survival was 57%. Seventeen (81%) received intensification (median 30 days to intensification). Brief, anthracycline sparing, intensive cyclophosphamide (BASIC) therapy yields durable remissions in poorer-risk BL/atypical BL. PMID- 22835047 TI - Novel insights into the emergence of pathogens: the case of chestnut blight. AB - Exotic, invasive pathogens have emerged repeatedly and continue to emerge to threaten the world's forests. Ecosystem structure and function can be permanently changed when keystone tree species such as the American chestnut (Castanea dentata) are eliminated from a whole range by disease. The fungal ascomycete pathogen Cryphonectria parasitica is responsible for causing chestnut blight. Once the pathogen was introduced into the Eastern US, where chestnuts were predominant, chestnuts were all but eliminated. This pathogen is currently causing extensive damage in Europe. A study in this issue of Molecular Ecology sheds new light on the pattern and process of emergence of this devastating plant pathogen (Dutech et al. 2012). The authors used microsatellite markers to investigate the evolutionary history of C. parasitica populations introduced into North America and Europe. To infer sources of migrants and the migration events, the authors included putative source populations endemic to China and Japan, inferred potentially unsampled populations and conducted a multivariate population genetic and complex ABC analysis. Cryphonectria parasitica emerges as an example of an introduced pathogen with limited genotypic diversity and some admixture in the invaded ranges, yet repeated invasions into different areas of Europe and the United States. This work sheds new light on the emergence of C. parasitica providing compelling evidence that this pathogen emerged by repeated migration and occasional admixture. PMID- 22835048 TI - Langerhans cell histiocytosis first presenting in the skin in adults: frequent association with a second haematological malignancy. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) in adults first presenting in the skin is rare. Guidelines for staging, treatment and follow-up are lacking. OBJECTIVES: To better define staging procedures, treatment results and clinical course in adult patients with LCH first presenting in the skin. METHODS: Eighteen adult patients with LCH first presenting in the skin were collected from five centres collaborating in the Dutch Cutaneous Lymphoma Group. Clinical records and (skin) biopsy specimens were reviewed and follow-up data were obtained. A literature search on adult patients with LCH presenting in the skin was performed. RESULTS: Staging procedures showed extracutaneous disease in three of 16 patients who were adequately staged. One patient had a histologically confirmed lytic LCH bone lesion, while two patients had a myelodysplastic syndrome. During follow-up two of 18 patients developed extracutaneous localizations of LCH. Five patients developed a second haematological malignancy, including (myelo)monocytic leukaemia (two cases), histiocytic sarcoma (one case), diffuse large B-cell lymphoma (one case) and peripheral T-cell lymphoma (one case). Review of the literature revealed six other adult patients with a second haematological malignancy preceding or following a diagnosis of LCH. CONCLUSIONS: The results of the present study suggest an increased risk of a second haematological malignancy in adult patients with LCH presenting in the skin. Extensive staging at presentation and long-term follow-up are therefore warranted in such patients. PMID- 22835049 TI - Increased risks of malaria due to limited residual life of insecticide and outdoor biting versus protection by combined use of nets and indoor residual spraying on Bioko Island, Equatorial Guinea. AB - BACKGROUND: Malaria is endemic on Bioko Island, Equatorial Guinea, with year round transmission. In 2004 an intensive malaria control strategy primarily based on indoor residual spraying (IRS) was launched. The limited residual life of IRS poses particular challenges in a setting with year-round transmission, such as Bioko. Recent reports of outdoor biting by Anopheles gambiae are an additional cause for concern. In this study, the effect of the short residual life of bendiocarb insecticide and of children spending time outdoors at night, on malaria infection prevalence was examined. METHODS: Data from the 2011 annual malaria indicator survey and from standard WHO cone bioassays were used to examine the relationship between time since IRS, mosquito mortality and prevalence of infection in children. How often children spend time outside at night and the association of this behaviour with malaria infection were also examined. RESULTS: Prevalence of malaria infection in two to 14 year-olds in 2011 was 18.4%, 21.0% and 28.1% in communities with median time since IRS of three, four and five months respectively. After adjusting for confounders, each extra month since IRS corresponded to an odds ratio (OR) of 1.44 (95% CI 1.15-1.81) for infection prevalence in two to 14 year-olds. Mosquito mortality was 100%, 96%, 81% and 78%, at month 2, 3, 4 and 5 respectively after spraying. Only 4.1% of children spent time outside the night before the survey between the hours of 22.00 and 06.00 and those who did were not at a higher risk of infection (OR 0.87, 95% CI 0.50-1.54). Sleeping under a mosquito net provided additive protection (OR 0.68, 95% CI 0.54-0.86). CONCLUSIONS: The results demonstrate the epidemiological impact of reduced mosquito mortality with time since IRS. The study underscores that in settings of year-round transmission there is a compelling need for longer-lasting IRS insecticides, but that in the interim, high coverage of long-lasting insecticidal nets (LLINs) may ameliorate the loss of effect of current shorter-lasting IRS insecticides. Moreover, continued use of IRS and LLINs for indoor-oriented vector control is warranted given that there is no evidence that spending time outdoors at night increases infection prevalence in children. PMID- 22835050 TI - Percutaneous nephrolithotomy in spinal cord neuropathy patients: a single institution experience. AB - BACKGROUND AND PURPOSE: Patients with spinal neuropathy are at an increased risk for urolithiasis. Data on percutaneous nephrolithotomy (PCNL) in this population are limited. Our objective is to review our experience in managing stones with PCNL in patients with spinal neuropathy. PATIENTS AND METHODS: Twenty-one patients with spinal neuropathy underwent PCNL at our institution between January 2005 and August 2011. Their medical records were reviewed retrospectively to collect data relating to stone characteristics, treatment outcomes, and complications. RESULTS: Forty-two PCNL were performed on 26 kidneys. Five patients had bilateral stones. They were 14 (66.7%) patients with spinal cord injury, 5 (23.8%) with spina bifida, and 2 (9.5%) with other neurologic abnormalities. There were 90.5% of patients with preoperative bacteriuria and 47.6% with severe scoliosis, making positioning for PCNL challenging. Complete staghorn stones occurred in 46.2% of kidneys, and 50% of stones were struvite. Only 53.8% of kidneys were stone free after the first PCNL. The success rate increased to 80.8% after the second and 88.5% after the third PCNL. Urosepsis developed in three (14.3%) patients, necessitating admission to the intensive care unit postoperatively. Six (28.6%) patients needed blood transfusion. One patient had a pneumothorax and another had a perforation of the collecting system. CONCLUSIONS: Based on our experience, PCNL in patients with spinal neuropathy had a stone clearance rate comparable with that of the general population. These patients, however, needed multiple PCNLs to be stone free and had a higher incidence of complications (especially infectious). PMID- 22835051 TI - Salmonella prevalence among reptiles in a zoo education setting. AB - Clinically healthy reptiles may shed Salmonella and therefore act as a potential zoonotic threat. Most people in Northern European countries are rarely exposed to reptiles, but many zoos have education departments where children have direct contact with this group of animals. The objectives of this study were to determine the prevalence and serotype distribution of Salmonella among reptiles in the Education Department (n = 55) at Copenhagen Zoo and compare it to the Zoo's main reptile collection (n = 145) to evaluate the zoonotic risk. Salmonella was isolated from cloacal swabs by selective enrichment, and a single isolate from each positive sample was further identified by biochemical tests and serotyped. The overall prevalence was 35% (69/200) with significant difference between the Education Department (64%, 35/55) and the main reptile collection (23%, 34/145). A total of 28 serotypes were detected. Ten serotypes were isolated from more than one specimen and four from more than one species. Salmonella enterica subsp. enterica serovar Eastbourne was the predominant serotype (32%, 22/69) and was also the serotype isolated from most reptile species (n = 7). Transmission of serotypes from one department to another was very limited indicated by the serotype distribution. Despite the relative high prevalence observed among the reptiles in the Zoo's Education Department compared to the reptiles in the Zoo's main reptile collection, no Salmonella cases have been linked to the Zoo, and Salmonella ser. Eastbourne is very rarely isolated from humans in Denmark. Simple hygienic procedures such as hand washing which is consistently carried out following handling of reptiles at the Education Department may reduce the risk and therefore contribute to this low prevalence. PMID- 22835052 TI - Exposure to liquid detergent capsules: a study undertaken by the UK National Poisons Information Service. AB - OBJECTIVE: To ascertain the reported toxicity of liquid detergent capsules. METHODS: Between 1 March 2008 and 30 April 2009 the UK National Poisons Information Service collected prospectively 647 telephone enquiries relating to liquid detergent capsules. RESULTS: The majority of enquiries (96.1%) concerned children of 5 years of age or less. Exposure to these products occurred mainly as a result of ingestion alone (n = 518; 80.1%), with eye contact alone (n = 61; 9.4%), and skin contact alone (n = 7; 1.1%) being less common; multiple routes of exposure were involved in 61 (9.4%) enquiries. Following ocular exposure, conjunctivitis with or without eye pain (n = 61), eye pain alone (n = 11) and keratitis (n = 4) developed; in one case the keratitis persisted for nine days, though recovery occurred in all cases as far as is known. The most common features reported following ingestion alone were nausea and vomiting (n = 143), followed by coughing (n = 21). Eleven children less than 2 years of age also developed drowsiness. A rash occurred in nine patients where ingestion was considered to be the route of exposure, probably due to topical contact with the capsule. Seven children aged 3 or less were exposed via the dermal route alone and developed rash (n = 4), irritation (n = 2), chemical burn (n = 2), and paresthesia (n = 1). CONCLUSIONS: Ocular exposure may lead to conjunctivitis and keratitis; recovery is to be expected in all cases within 7-10 days. Ingestion may also result in drowsiness. Greater consumer awareness is required to reduce injury from liquid detergent capsules, particularly that involving the eye. Parents have a vital role to play in ensuring that these products are stored safely at all times. PMID- 22835053 TI - Paracetamol (acetaminophen) overdose and acetylcysteine administration: should the United Kingdom adopt a single '150-line'? PMID- 22835054 TI - Quality of life of elderly ischaemic stroke patients one year after thrombolytic therapy. A comparison between patients with and without thrombolytic therapy. AB - BACKGROUND: An observational study to examine whether thrombolytic therapy in stroke patients realizes better quality of life outcomes compared to patients without thrombolytic therapy one year after stroke. We also examined whether daily functioning, mental functioning and activities improved after thrombolytic treatment. METHODS: A total of 88 stroke patients were interviewed at home one year post-stroke. Health-related quality of life (HRQOL) was assessed using the RAND-36, disability with the Barthel Index, depression and anxiety with the Hospital Anxiety and Depression Scale, and a questionnaire about patient way of life was completed. People aged under 60, moving to a nursing home or with a haemorrhage were excluded. RESULTS: The thrombolysis group (TG) had more severe stroke (higher NIHSS) scores and were younger than the group without thrombolytic therapy (WTG). The primary outcome was HRQOL, which was high and nearly identical in both groups, however the TG had significantly better HRQOL for the 'mental health' and 'vitality' scales. Patients who stopped or reduced their hobbies because of stroke had a significantly worse HRQOL. One year after stroke, more patients in the TG were totally or severely ADL dependent (12% TG and 0% WTG, p = 0.022). The level of dependence decreased in the TG (p = 0.042) and worsened in the WTG (p < 0.001) after one year. Being more dependent is related to diminishing daily occupations in both groups. In the TG the level of dependence had less impact on visiting family and friends and going on holiday. The prevalence of anxiety disorder and depression was low compared to other studies and there is no significant difference between the two groups. CONCLUSION: No major differences in the primary outcome (HRQOL) could be found between the two groups. In addition, no essential difference could be found in mental functioning and participation. We expected that patients undergoing thrombolytic therapy would have worse quality of life because of the greater initial severity of their stroke. Therefore, thrombolytic therapy seems to be of great importance in achieving better quality of life in ischemic stroke patients who respond to this therapy. PMID- 22835055 TI - Prevalence and bother of postmicturition dribble in Finnish men aged 30-80 years: Tampere Ageing Male Urologic Study (TAMUS). AB - OBJECTIVE: The aim of this study was to determine the prevalence and bother of postmicturition dribble in relation to age in the male population. MATERIAL AND METHODS: Information for a population-based study was collected by means of a mailed self-administered questionnaire, which was returned by 4384 men out of 7470 (58.7%). The participants were men aged 30-80 years from the Pirkanmaa Region in Finland. The Danish Prostatic Symptom Score (DAN-PSS-1) questionnaire was used to evaluate their urinary symptoms. SPSS was used in the data analysis. Two-sided chi-squared test and Kendall tau-b test were used for analysis. RESULTS: The overall prevalence of postmicturition dribble was 58.1% (95% confidence interval 56.6-59.6). Prevalence of postmicturition dribble increased with age (p < 0.001). In men aged 60-80 years, two-thirds reported postmicturition dribble and approximately one out of four had dribbling into their trousers after voiding. In the 30-year-old group, over 40% reported postmicturition dribble and almost one out of five had also dribbling into their trousers. One out of five men in the 30-year-old group reported minor bother; the proportion of men reporting bother increased with age to one-third of the men in the oldest cohort (p < 0.001). CONCLUSIONS: The prevalence of the postmicturition dribble was found to be high in this survey. Half of the 30-year-old men and two thirds of the men aged 60-80 years had postmicturition dribble. Dribbling into trousers increased with age but as a severe symptom, it was rare (0.5%). Minor problems from postmicturition dribble were common, but major bother occurred seldom (1.1%). PMID- 22835056 TI - How the FDA food safety modernization act responds to terrorism threats: a primer. PMID- 22835057 TI - Theoretical investigation of paramagnetic NMR shifts in transition metal acetylacetonato complexes: analysis of signs, magnitudes, and the role of the covalency of ligand-metal bonding. AB - Ligand chemical shifts are calculated and analyzed for three paramagnetic transition metal tris-acetylacetonato (acac) complexes, namely high-spin Fe(III) and Cr(III), and low-spin Ru(III), using scalar relativistic density functional theory (DFT). The signs and magnitudes of the paramagnetic NMR ligand chemical shifts are directly related to the extent of covalent acac oxygen-to-metal sigma donation involving unoccupied metal valence d(sigma) acceptor orbitals. The role of delocalization of metal-centered spin density over the ligand atoms plays a minor secondary role. Of particular interest is the origin of the sign and magnitude of the methyl carbon chemical shift in the acac ligands, and the role played by the DFT delocalization error when calculating such shifts. It is found that the alpha versus beta spin balance of oxygen sigma donation to metal valence d acceptor orbitals is responsible for the sign and the magnitude of the ligand methyl carbon chemical shift. A problematic case is the methyl carbon shift of Fe(acac)(3). Most functionals produce shifts in excess of 1400 ppm, whereas the experimental shift is approximately 279 ppm. Range-separated hybrid functionals that are optimally tuned for Fe(acac)(3) based on DFT energetic criteria predict a lower limit of about 2000 ppm for the methyl carbon shift of the high-spin electronic configuration. Since the experimental value is based on a very strongly broadened signal it is possibly unreliable. PMID- 22835058 TI - Limits of the creation of electronic wave packets using time-dependent density functional theory. AB - Explicitly time-dependent density functional theory (TDDFT) has often been suggested as the method of choice for controlling the correlated dynamics of many electron systems. However, it is not yet clear which control tasks can be achieved reliably and how this depends on the functionals used. In this article, we show that the control task of creating a simple wave packet, having a population of 50% in the excited state, can indeed be achieved if a certain condition is fulfilled. This result is in contrast to the observation that a full population inversion is extremely difficult to achieve. In addition, we identify a rule to predict when TDDFT produces the correct wave packet. To illustrate our findings, we study the molecules Li(2)C(2), Li(7)OH, and B(2)N(2)CO using two different functionals as well as time-dependent Hartree-Fock (TDHF). To assess the performance of TDDFT and TDHF, we compare with time-dependent configuration interaction calculations. PMID- 22835059 TI - Comparison of the effects of three cell saver devices on erythrocyte function during cardiopulmonary bypass procedure--a pilot study. AB - Cell salvage devices are routinely used to process red blood cells (RBCs) shed during cardiac surgery. The purpose of this study was to evaluate three commercially available cell saver (CS) devices in terms of erythrocyte function and the quality of washed RBCs during cardiopulmonary bypass (CPB). Thirty patients undergoing CPB were randomly allocated to three CS devices: Group C (Cell Saver 5+; Haemonetics, n = 10), Group M (autolog; Medtronic, n = 10), and Group F (CATS; Fresenius HemoCare, n = 10). Blood samples were collected from reservoirs and transfusion bags. Reservoirs and washed RBCs were analyzed for erythrocyte aggregation index, deformation index (DI) and hematocrit viscosity, 2,3-diphosphoglycerate (2,3-DPG), hematocrit (Hct), hemoglobin (Hb), free Hb removal (DeltafHb), glucose (Glu), lactate (Lac), and blood urea nitrogen. After processing, Groups C (P = 0.026) and M (P = 0.032) had relatively higher erythrocyte DI compared with Group F. Group C had lower Delta2,3-DPG compared with Groups M (P = 0.001) and F (P = 0.001). Group F provided the maximum concentration of Hct (P = 0.021; 0.046) and Hb (P = 0.008; 0.013). In addition, Groups C (P = 0.035) and M (P = 0.038) had a higher removal of fHb (DeltafHb), differing significantly with Group F. In conclusion, CS devices use the same theory of centrifugation; however, based on different designs, the function of the washed erythrocyte and undesirable content removal efficiency differs widely from one device to another. PMID- 22835060 TI - Microchimerism in vitiligo. PMID- 22835061 TI - Predicting adult fish acute lethality with the zebrafish embryo: relevance of test duration, endpoints, compound properties, and exposure concentration analysis. AB - The zebrafish embryo toxicity test has been proposed as an alternative for the acute fish toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported fish acute toxicity was explored. Our results confirm a very strong correlation of zebrafish embryo to fish acute toxicity. When toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal effects led to a reduced number of outliers. Yet, two types of compounds were less lethal to embryos than to adult fish: a neurotoxic compound acting via sodium channels (permethrin) and a compound requiring metabolic activation (allyl alcohol). PMID- 22835062 TI - Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction: Health check-up study of Japanese men. AB - AIM: Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects. METHODS: A total of 5588 Japanese male subjects who underwent a health check-up were classified into three groups according to alcohol consumption: non- or light drinkers (15 g/day >= ethanol); mild drinkers (15 g/day < ethanol <= 30 g/day); and moderate- or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment - Insulin Resistance (HOMA IR), respectively. RESULTS: WC was significantly increased, while HOMA-IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non-significant determinant of liver dysfunction as alcohol consumption increased. CONCLUSION: Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver-induced liver dysfunction. PMID- 22835063 TI - Omentin as a novel biomarker of metabolic risk factors. AB - BACKGROUND: Omentin is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of omentin with the number of metabolic risk factors. FINDING: The study population comprised 201 Japanese men who underwent annual health checkups. Plasma omentin levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to omentin levels. A reduction of plasma omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, dyslipidemia, high blood pressure and glucose intolerance. CONCLUSIONS: Circulating omentin levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that omentin acts as a biomarker of metabolic disorders. PMID- 22835064 TI - The antidiabetic drug metformin inhibits uterine leiomyoma cell proliferation via an AMP-activated protein kinase signaling pathway. AB - Uterine leiomyomas are the most common gynecological benign tumors and greatly affect reproductive health and wellbeing. Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. In order to understand metformin's anti-tumorigenic potential better, in this study, we investigated the inhibitory effect of metformin and expression of key targets of metformin cell signaling in leiomyoma cells. Cell proliferation was assessed after exposure to metformin. Apoptosis was assessed by western blotting for cleaved-PARP and TUNEL staining. The expressions of phosphorylated AMPK and phosphorylated S6 were determined by western blotting. Metformin potently inhibited ELT-3 cell proliferation in a dose dependent manner. Western blotting analysis demonstrated that metformin induced phosphorylation of AMPK and the inhibitory effect was attenuated with AMPK inhibitor, compound C. In parallel, treatment with metformin decreased phosphorylation of S6 protein. These experimental findings show that metformin is a potent inhibitor of cell proliferation in leiomyoma cells. This effect is mediated by AMPK activation and subsequent inhibition of the mTOR pathway. Thus, this study provides a possible mechanism of the action of metformin in the inhibition of leiomyoma cell growth. PMID- 22835065 TI - "Sexual pleasure on equal terms": young women's ideal sexual situations. AB - OBJECTIVE: The aim of this study was to identify young women's ideal images of sexual situations and expectations on themselves in sexual situations. STUDY DESIGN: We conducted audio-taped qualitative individual interviews with 14 women aged 14 to 20 years, visiting two youth centers in Sweden. Data were analysed with constant comparative analysis, the basis of grounded theory methodology. RESULTS: The women's ideal sexual situations in heterosexual practice were characterized by sexual pleasure on equal terms, implying that no one dominates and both partners get pleasure. There were obstacles to reaching this ideal, such as influences from social norms and demands, and experiences of the partner's "own run". An incentive to reach the ideal sexual situation was the wish to experience the well of pleasure. CONCLUSIONS: Our research further accentuates the importance of finding ways to focus on the complexity of unequal gender norms in youth heterosexuality. A better understanding of these cognitions is essential and useful among professionals working with youths' sexual health. PMID- 22835066 TI - Synthesis of 2-Aryl benzothiazoles via K2S2O8-mediated oxidative condensation of benzothiazoles with aryl aldehydes. AB - Nontransition metal-catalyzed synthesis of 2-aryl benzothiazoles was achieved through K(2)S(2)O(8)-mediated oxidative condensation of benzothiazoles with aryl aldehydes. The same transformation can also be effected when the aryl aldehydes were replaced with phenylglyoxylic acids. PMID- 22835067 TI - Increasing the isolated quantities and purities of volatile compounds by using a triple Deans-switch multidimensional preparative gas chromatographic system with an apolar-wax-ionic liquid stationary-phase combination. AB - A novel preparative-scale triple gas chromatographic system, equipped with three Deans-switch devices, is herein described. The isolation of volatile compounds was achieved by using a lab-made collection system. Considerations are made on the possibility to inject high volumes of neat sample, maintaining, at the same time, high resolution levels. The degree of recovery of a series of compounds, characterized by a differing volatility, is also reported. In this respect, different collection conditions were evaluated, namely, the presence (or not) of packing material as well as CO(2) cooling, in various combinations. Finally, the interconnected features, that is time requirements and the isolation of "acceptable" analyte quantities (e.g., milligram level for NMR characterization), are related to parameters such as analyte concentration, injected volume, collection conditions, and number of GC runs. The results herein reported will demonstrate the need for a high-resolution GC step, prior to analyte collection, in the prep-GC analysis of complex samples. PMID- 22835069 TI - Canine idiopathic epilepsy: prevalence, risk factors and outcome associated with cluster seizures and status epilepticus. AB - OBJECTIVES: To evaluate the prevalence of cluster seizures and status epilepticus in dogs with idiopathic epilepsy and determine risk factors for cluster seizure frequency, severity and patient outcome. METHODS: Retrospective review of medical records of 407 dogs with idiopathic epilepsy was made. Follow-up questionnaires were evaluated in cases with cluster seizures. RESULTS: Mean age at diagnosis of idiopathic epilepsy was 4 years. Cluster seizures were documented in 169 (41%) dogs. German shepherds and boxers were significantly (P=0.04 and 0.01, respectively) more likely to suffer from cluster seizures compared to Labrador retrievers. There was no association between the occurrence of status epilepticus and cluster seizures and frequency and severity of cluster seizures and status epilepticus episodes with age or breed. Intact males were twice as likely (P=0.003) than neutered dogs to suffer from cluster seizures. Intact females had significantly (P=0.007) more frequent cluster seizures than neutered dogs. The median survival time for all dogs with cluster seizures was 95 months. Significantly (P=0.03) more dogs with frequent cluster seizures were euthanased because of the cluster seizures. CLINICAL SIGNIFICANCE: There was a high prevalence of cluster seizures in dogs with idiopathic epilepsy. Neutering status appears to influence cluster seizure occurrence with intact females more likely to experience more frequent episodes. Euthanasia is associated with frequency of cluster seizure episodes. PMID- 22835070 TI - Treatment satisfaction and health status in patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is a rare connective tissue disease. Few data are available on treatment satisfaction, determinants of quality of life, and the health status of dermatology patients with SSc. PATIENTS AND METHODS: Cross-sectional study based on 72 consecutive dermatological patients with SSc. Objective clinical data were collected with a physician's questionnaire and subjective data were collected with a patients' questionnaire on disease characteristics, treatment satisfaction, quality of life, depressive symptoms, and Antonovsky's sense of coherence (SOC). We also tested the significance of possible determinants of treatment satisfaction. RESULTS: Treatment satisfaction was 72.0 (+/- 22.2; VAS 1-100). The assessment of professional competence of the treating physician was the most important determinant of treatment satisfaction and was independent of the patient's age and sex. The assessment of physician empathy, information about the disease, and the patient's own evaluation of the severity of disease were also associated with treatment satisfaction. The mean health-related quality of life (QoL; EQ-5D) was 0.74 (+/- 0.28) and the mean SOC was 72.6 (+/- 10.6). 58 % of patients reported moderate to severe pain and 13 % were treated for pain symptoms. In 69 % there was evidence of probable depression (CES-D $ 22); 8 % were on antidepressants. CONCLUSIONS: Treatment satisfaction was average and correlated especially with the sense of professional competence of the treating physician. In SSc patients, a diminished health-related quality of life as well as pain and evidence of depression are common and seem to be inadequately treated. However, the SOC indicates a lower general vulnerability. In the future, screening for pain and symptoms of depression should part of routine practice in SSc patients and, if necessary, interdisciplinary care should be initiated. PMID- 22835068 TI - Electrochemical immunosensors for detection of cancer protein biomarkers. AB - Bioanalytical methods have experienced unprecedented growth in recent years, driven in large part by the need for faster, more sensitive, more portable ("point of care") systems to detect protein biomarkers for clinical diagnosis. Electrochemical detection strategies, used in conjunction with immunosensors, offer advantages because they are fast, simple, and low cost. Recent developments in electrochemical immunosensors have significantly improved the sensitivity needed to detect low concentrations of biomarkers present in early stages of cancer. Moreover, the coupling of electrochemical devices with nanomaterials, such as gold nanoparticles, carbon nanotubes, magnetic particles, and quantum dots, offers multiplexing capability for simultaneous measurements of multiple cancer biomarkers. This review will discuss recent advances in the development of electrochemical immunosensors for the next generation of cancer diagnostics, with an emphasis on opportunities for further improvement in cancer diagnostics and treatment monitoring. Details will be given for strategies to increase sensitivity through multilabel amplification, coupled with high densities of capture molecules on sensor surfaces. Such sensors are capable of detecting a wide range of protein quantities, from nanogram to femtogram (depending on the protein biomarkers of interest), in a single sample. PMID- 22835071 TI - Polymer/Ordered mesoporous carbon nanocomposite platelets as superior sensing materials for gas detection with surface acoustic wave devices. AB - We have prepared nanocomposites of polymers and platelet CMK-5-like carbon and have demonstrated their superior performance for gravimetric gas detection. The zirconium-containing platelet SBA-15 was used as hard template to prepare CMK-5 like carbon, which was then applied as a lightweight and high-surface-area scaffold for the growth of polymers by radical polymerization. Mesoporous nanocomposites composed of four different polymers were used as sensing materials for surface acoustic wave devices to detect ppm-level ammonia gas. The sensors showed much better sensitivity and reversibility than those coated with dense polymer films, and the sensor array could still generate a characteristic pattern for the analyte with a concentration of 16 ppm. The results show that the nanocomposite sensing materials are promising for highly sensitive gravimetric type electronic nose applications. PMID- 22835072 TI - Quantitation of mycotoxins in food and feed from Burkina Faso and Mozambique using a modern LC-MS/MS multitoxin method. AB - In this study an LC-MS/MS multitoxin method covering a total of 247 fungal and bacterial metabolites was applied to the analysis of different foods and feedstuffs from Burkina Faso and Mozambique. Overall, 63 metabolites were determined in 122 samples of mainly maize and groundnuts and a few samples of sorghum, millet, rice, wheat, soy, dried fruits, other processed foods and animal feeds. Aflatoxin B(1) was observed more frequently in maize (Burkina Faso, 50% incidence, median = 23.6 MUg/kg; Mozambique, 46% incidence, median = 69.9 MUg/kg) than in groundnuts (Burkina Faso, 22% incidence, median = 10.5 MUg/kg; Mozambique, 14% incidence, median = 3.4 MUg/kg). Fumonisin B(1) concentrations in maize were higher in Mozambique (92% incidence, median = 869 MUg/kg) than in Burkina Faso (81% incidence, median = 269 MUg/kg). In addition, ochratoxin A, zearalenone, deoxynivalenol, nivalenol, and other less reported mycotoxins such as citrinin, alternariol, cyclopiazonic acid, sterigmatocystin, moniliformin, beauvericin, and enniatins were detected. Up to 28 toxic fungal metabolites were quantitated in a single sample, emphasizing the great variety of mycotoxin coexposure. Most mycotoxins have not been reported before in either country. PMID- 22835073 TI - Vitiligo: an update on current pharmacotherapy and future directions. AB - INTRODUCTION: Vitiligo is a common pigmentary skin disorder, characterized by the appearance of white macules on the skin, mucosal or hair. Treatment is often a tough challenge and involves a wide range of therapies. AREAS COVERED: This review focuses on available first- and second-line pharmacological treatments for vitiligo. In particular, the mechanisms of action, the main indications, the efficacy and the most important side effects are reviewed. Moreover, a brief discussion is provided, regarding other nonpharmacological treatments, such as phototherapy and surgical options, due to their importance and successful outcomes in vitiligo treatment. Finally, a concise overview regarding the future directions in vitiligo therapy is presented. EXPERT OPINION: The promising outcomes reported here demonstrate that it is possible to achieve a satisfactory and often stable repigmentation of vitiligo lesions. Topical corticosteroids, calcineurin inhibitors, phototherapy and photochemotherapy represent the first line therapeutic options, due to their safety and efficacy, whereas vitamin D analogues, targeted phototherapy, oral corticosteroids and surgery should be used as second-line therapies. Other therapies, such as antioxidants, can be used in association with other therapeutic options, whereas depigmenting agents should be used only in cases of extensive vitiligo, recalcitrant to other treatments. PMID- 22835074 TI - Stress vulnerability and the effects of moderate daily stress on sleep polysomnography and subjective sleepiness. AB - The purpose of this study was to investigate if and how sleep physiology is affected by naturally occurring high work stress and identify individual differences in the response of sleep to stress. Probable upcoming stress levels were estimated through weekly web questionnaire ratings. Based on the modified FIRST-scale (Ford insomnia response to stress) participants were grouped into high (n = 9) or low (n = 19) sensitivity to stress related sleep disturbances (Drake et al., 2004). Sleep was recorded in 28 teachers with polysomnography, sleep diaries and actigraphs during one high stress and one low stress condition in the participants home. EEG showed a decrease in sleep efficiency during the high stress condition. Significant interactions between group and condition were seen for REM sleep, arousals and stage transitions. The sensitive group had an increase in arousals and stage transitions during the high stress condition and a decrease in REM, whereas the opposite was seen in the resilient group. Diary ratings during the high stress condition showed higher bedtime stress and lower ratings on the awakening index (insufficient sleep and difficulties awakening). Ratings also showed lower cognitive function and preoccupation with work thoughts in the evening. KSS ratings of sleepiness increased during stress for the sensitive group. Saliva samples of cortisol showed no effect of stress. It was concluded that moderate daily stress is associated with a moderate negative effect on sleep sleep efficiency and fragmentation. A slightly stronger effect was seen in the sensitive group. PMID- 22835075 TI - Analyte-driven switching of DNA charge transport: de novo creation of electronic sensors for an early lung cancer biomarker. AB - A general approach is described for the de novo design and construction of aptamer-based electrochemical biosensors, for potentially any analyte of interest (ranging from small ligands to biological macromolecules). As a demonstration of the approach, we report the rapid development of a made-to-order electronic sensor for a newly reported early biomarker for lung cancer (CTAP III/NAP2). The steps include the in vitro selection and characterization of DNA aptamer sequences, design and biochemical testing of wholly DNA sensor constructs, and translation to a functional electrode-bound sensor format. The working principle of this distinct class of electronic biosensors is the enhancement of DNA mediated charge transport in response to analyte binding. We first verify such analyte-responsive charge transport switching in solution, using biochemical methods; successful sensor variants were then immobilized on gold electrodes. We show that using these sensor-modified electrodes, CTAP III/NAP2 can be detected with both high specificity and sensitivity (K(d) ~1 nM) through a direct electrochemical reading. To investigate the underlying basis of analyte binding induced conductivity switching, we carried out Forster Resonance Energy Transfer (FRET) experiments. The FRET data establish that analyte binding-induced conductivity switching in these sensors results from very subtle structural/conformational changes, rather than large scale, global folding events. The implications of this finding are discussed with respect to possible charge transport switching mechanisms in electrode-bound sensors. Overall, the approach we describe here represents a unique design principle for aptamer-based electrochemical sensors; its application should enable rapid, on-demand access to a class of portable biosensors that offer robust, inexpensive, and operationally simplified alternatives to conventional antibody-based immunoassays. PMID- 22835076 TI - Paraoxonase 1 (PON1) 55 polymorphism, lipid profiles and psoriasis. AB - BACKGROUND: Paraoxonase 1 (PON1) is a serum high-density lipoprotein-bound enzyme with antioxidant function. It hydrolyses lipid peroxides, protecting low-density lipoproteins from oxidative modifications. Patients with psoriasis are at greater risk of oxidative stress, which is associated with abnormal plasma lipid metabolism. OBJECTIVES: In this study, association of the PON1 55 M allele with serum arylesterase (ARE) activity, malondialdehyde (MDA), lipid profiles and psoriasis was investigated. METHODS: The present case-control study consisted of 100 patients with psoriasis with and without cardiovascular diseases (mean age 35.3 years) and 100 sex- and age-matched unrelated healthy controls (mean age 35.7 years) from the population of western Iran. The PON1 55 Met>Leu polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism. Serum ARE activity, MDA, and lipid and apolipoprotein levels were determined spectrophotometrically, by high-performance liquid chromatography and by enzyme assay, respectively. RESULTS: The presence of the PON1 55 M allele was found to be associated with psoriasis (odds ratio = 1.96, P = 0.017). The patients with psoriasis with the PON1 M (M/L + M/M) allele had higher MDA levels (4.12 +/- 0.88 vs. 2.24 +/- 0.55 MUmol L(-1) , P < 0.001), apolipoprotein B (APOB)/APOA1 ratio (0.91 +/- 0.66 vs. 0.66 +/- 0.35, P = 0.004), APOB (111 +/- 38.7 vs. 88.3 +/- 22.5 mg mL(-1) , P = 0.001) and lipoprotein(a) [LP(a)] (21.9 +/ 18.4 vs. 15.8 +/- 16.6 mg mL(-1) , P = 0.034), but lower ARE activity (39.6 +/- 11 vs. 45.9 +/- 11.8 U mL(-1) , P = 0.031) than the control subjects. ARE activity showed a significant positive correlation with APOA1 and a negative correlation with MDA concentration in patients with psoriasis. CONCLUSIONS: The PON1 55 M allele is a risk factor for psoriasis. Carriers of this allele have high levels of MDA, APOB and LP(a), a high APOB/APOA1 ratio and low ARE activity. These results indicate that oxidative stress, impairment of the antioxidant system and abnormal lipid metabolism may play a role in the pathogenesis and progression of psoriasis and its related complications. These data suggest that patients with psoriasis are more susceptible to vascular diseases. PMID- 22835077 TI - GOLD or lower limit of normal definition? A letter and authors' response. PMID- 22835080 TI - Horseshoe kidney for transplantation: technical considerations. AB - Owing to the ongoing shortage of cadaver organs, kidneys with an atypical anatomy such as horseshoe kidneys must be considered for transplantation. Owing to its low prevalence, experience with the transplantation of a horseshoe kidney is very limited. This article reports on the transplantation of a horseshoe kidney to a 58-year-old man with renal failure from chronic glomerulonephritis. Because of a relatively thick isthmus, which indicated a complex urinary collecting and intrarenal vessel system, the kidney was transplanted en bloc. Together with optimal placement of the kidney, only adequate length and positioning of the vessels, especially the venous drainage, could prevent postoperative complications such as kinking of the vessels and thrombosis. These problems could be solved by cutting the renal veins without using a vena cava patch. Careful positioning of the kidney within the intraperitoneal cavity is also necessary. The decision to transplant the kidney en bloc or after separation depends on many factors and should be made individually. PMID- 22835079 TI - The efficacy of parecoxib on systemic inflammatory response associated with cardiopulmonary bypass during cardiac surgery. AB - AIMS: Cardiopulmonary bypass (CPB) during cardiac surgery is well known to be associated with the development of a systemic inflammatory response. The efficacy of parecoxib in attenuating this systemic inflammatory response is still unknown. METHODS: Patients undergoing elective mitral valve replacement with CPB were assessed, enrolled and randomly allocated to receive parecoxib (80 mg) or placebo. Blood samples were collected in EDTA vials for measuring serum cytokine concentrations, troponin T, creatinekinase myocardial-brain isoenzyme CK-MB concentrations and white cell counts. RESULTS: Compared with the control group, IL-6 and IL-8-values in the parecoxib group increased to a lesser extent, peaking at 2 h after the end of CPB (IL-6 31.8 pg ml-1 +/- 4.7 vs. 77.0 pg ml-1 +/- 14.1, 95% CI -47.6, -42.8, P < 0.001; IL-8 53.6 pg ml-1 +/- 12.6 vs. 105.7 pg ml-1 +/- 10.8, 95% CI -54.8, -49.4, P < 0.001). Peak concentrations of anti-inflammatory cytokine IL-10 occurred immediately after termination of CPB and were higher in the parecoxib group (115.7 pg ml-1 +/- 10.5 vs. 88.4 pg ml-1 +/- 12.3, 95% CI 24.7, 29.9, P < 0.001). Furthermore, the increase in neutrophil counts caused by CPB during cardiac surgery was inhibited by parecoxib. The increases in serum troponin T and CK-MB concentrations were also significantly attenuated by parecoxib in the early post-operative days. Peak serum concentrations of CK-MB in both groups occurred at 24 h post-CPB (17.4 MUg l-1 +/- 5.2 vs. 26.9 MUg l-1 +/- 6.9, 95% CI -10.9, -8.1, P < 0.001). Peak troponin T concentrations occurred at 6 h post-bypass (2 MUg l-1 +/- 0.62 vs. 3.5 MUg l-1 +/- 0.78, 95% CI -1.7, -1.3, P < 0.001). CONCLUSION: Intra-operative parecoxib attenuated the systemic inflammatory response associated with CPB during cardiac surgery and lowered the biochemical markers of myocardial injury. PMID- 22835078 TI - Do children with central venous line (CVL) dysfunction have increased risk of symptomatic thromboembolism compared to those without CVL-dysfunction, while on cancer therapy? AB - BACKGROUND: Thromboembolism (TE) and infection are two common complications of central venous line (CVL). Thrombotic CVL-dysfunction is a common, yet less studied, complication of CVL. Two retrospective studies have reported significant association of CVL-dysfunction and TE. Recent studies indicate association of CVL related small clot with infection. Infection is the most common cause of non cancer related mortality in children with cancer. We and others have shown reduced overall survival (OS) in children with cancer and CVL-dysfunction compared to those without CVL-dysfunction. Despite these observations, to date there are no prospective studies to evaluate the clinical significance of CVL dysfunction and it's impact on the development of TE, infection, or outcome of children with cancer. STUDY DESIGN: This is a prospective, analytical cohort study conducted at five tertiary care pediatric oncology centers in Ontario. Children (<= 18 years of age) with non-central nervous system cancers and CVL will be eligible for the study. Primary outcome measure is symptomatic TE and secondary outcomes are infection, recurrence of cancer and death due to any cause. Data will be analyzed using regression analyses. DISCUSSION: The overall objective is to delineate the relationship between CVL-dysfunction, infection and TE. The primary aim is to evaluate the role of CVL-dysfunction as a predictor of symptomatic TE in children with cancer. We hypothesize that children with CVL dysfunction have activation of the coagulation system resulting in an increased risk of symptomatic TE. The secondary aims are to study the impact of CVL dysfunction on the rate of infection and the survival [OS and event free survival (EFS)] of children with cancer. We postulate that patients with CVL-dysfunction have an occult CVL-related clot which acts as a microbial focus with resultant increased risk of infection. Further, CVL-dysfunction by itself or in combination with associated complications may cause therapy delays resulting in adverse outcome.This study will help to identify children at high risk for TE and infection. Based on the study results, we will design randomized controlled trials of prophylactic anticoagulant therapy to reduce the incidence of TE and infection. This in turn will help to improve the outcome in children with cancer. PMID- 22835081 TI - Planning influenza vaccination programs: a cost benefit model. AB - BACKGROUND: Although annual influenza vaccination could decrease the significant economic and humanistic burden of influenza in the United States, immunization rates are below recommended levels, and concerns remain whether immunization programs can be cost beneficial. The research objective was to compare cost benefit of various immunization strategies from employer, employee, and societal perspectives. METHODS: An actuarial model was developed based on the published literature to estimate the costs and benefits of influenza immunization programs. Useful features of the model included customization by population age and risk level, potential pandemic risk, and projection year. Various immunization strategies were modelled for an average U.S. population of 15,000 persons vaccinated in pharmacies or doctor's office during the 2011/12 season. The primary outcome measure reported net cost savings per vaccinated (PV) from the perspective of various stakeholders. RESULTS: Given a typical U.S. population, an influenza immunization program will be cost beneficial for employers when more than 37% of individuals receive vaccine in non-traditional settings such as pharmacies. The baseline scenario, where 50% of persons would be vaccinated in non-traditional settings, estimated net savings of $6 PV. Programs that limited to pharmacy setting ($31 PV) or targeted persons with high-risk comorbidities ($83 PV) or seniors ($107 PV) were found to increase cost benefit. Sensitivity analysis confirmed the scenario-based findings. CONCLUSIONS: Both universal and targeted vaccination programs can be cost beneficial. Proper planning with cost models can help employers and policy makers develop strategies to improve the impact of immunization programs. PMID- 22835082 TI - Correlates of HAART adherence among immigrant Latinos in the Southeastern United States. AB - We explored the relationships between sociocultural and psychological constructs and adherence to antiretroviral therapy among predominantly Spanish-speaking immigrant Latinos in the southeastern United States. A cross-sectional clinic based sample of immigrant Latino men and women participated in an interviewer administered assessment. Self-reported prevalence of adherence was assessed along with demographic characteristics, acculturation, physician trust, social support, and theory of planned behavior (TPB) constructs: attitude, subjective norm (SN), and perceived behavioral control (PBC). A total of 66 respondents met inclusion criteria. Average age was 38 years old, 74% of respondents were male, 71% heterosexual, and 86% reported being from Mexico or Central America. Prevalence of "complete" adherence (i.e., not missing a single dose) in the past 30 days was 71%. Social support was significantly and inversely associated with adherence, PBC, and attitude. Positive correlates of adherence included attitude, PBC, and employment status. In multivariable analysis, SN and PBC were significantly associated with social support, controlling for acculturation, physician trust, and number of behavioral referents. TPB constructs have utility in explaining ART adherence among immigrant Latinos in the "Deep South." Further research is necessary to understand the complex relationships between social support, attribution processes, and ART adherence outcomes. PMID- 22835083 TI - Chemical mechanism identification from frequency response to small temperature modulation. AB - The description of interactions between biochemical species and the elucidation of the corresponding chemical mechanisms encounter an increasing interest both for the comprehension of biological pathways at the molecular scale and for the rationalization of drug design. Relying on powerful experimental tools such as thermal microfluidics and fluorescence detection, we propose a methodology to determine the chemical mechanism of a reaction without fitting parameters. A mechanism consistent with the accessible knowledge is assumed, and the assumption is checked through an iterative protocol. The test is based on the frequency analysis of the response of a targeted reactive species to temperature modulation. We build specific functions of the frequency that are constant for the assumed mechanism and show that the graph of these functions can be drawn from appropriate data analysis. The method is general and can be applied to any complex mechanism. It is here illustrated in detail in the case of single relaxation time mechanisms. PMID- 22835084 TI - Verruciform Xanthoma results from epidermal apoptosis with galectin-7 overexpression. PMID- 22835085 TI - The progressive wave pump: numerical multiphysics investigation of a novel pump concept with potential to ventricular assist device application. AB - This article describes the numerical fluid-structure interaction (FSI) validation of a new pumping concept and the possibility for application of a further developed type, as an implantable ventricular assist device (VAD). The novel principle of the so-called progressive wave pump is based on the interaction of an elastic membrane actuated by forced excitation with a surrounding fluid and the pump housing. By applying forced vibrations to one end of the membrane, a transversal wave builds up and progresses to the far end generating both a positive pressure gradient and flow rate. Among others, two axisymmetric geometrical configurations are possible, namely the discoidal and the tubular design. The first one has been built as a physical prototype and is experimentally investigated. In addition, a corresponding numerical FSI model is set up and validated against the experimental findings. Based on this validated numerical method, further numerical investigations are conducted focusing on the development of a tubular progressive wave pump concept with regard to its potential for application as a VAD in the future. To address VAD-relevant issues such as size, hydraulic performance, and blood trauma, corresponding numerical simulations involving macroscopic blood trauma models have been performed. Although being still in an early phase of development, the results are promising and indicate that the wave pump concept in its present state is feasible and can be further developed and investigated as a new type of blood pump. PMID- 22835086 TI - Post-transplant critical care outcomes for pediatric multivisceral and intestinal transplant patients. AB - This study reviews the post-operative management of pediatric intestinal transplant patients at a single center with reporting of standard PICU benchmarks for quality of care. It is a retrospective, descriptive, chart review describing our institution's experience between 2006 and 2010. Twenty patients were included. Median age at transplant was 1.6 yr. Median length of PICU stay was 12 days. Median ventilation time was two days. Median time for continuous sedation infusion was two days, with median continuous pain medication infusion of three days. All patients were placed on parental nutrition and started on enteral feedings between days 3 and 4. Forty percent of patients required hemodynamic support. Only 35% of patients required insulin therapy. Diuretics were frequently used in this patient population. There were no episodes of early rejection. The survival rate to PICU discharge was 95%. Our institution's experience over the past four yr has been very successful with a short duration of mechanical ventilation, limited use of pain and sedation drips, early initiation of enteral feedings, minimal hemodynamic support, and a low mortality rate to PICU discharge despite a preponderance of complex MVTx recipients. PMID- 22835087 TI - Kinetics of the water/air phase transition of radon and its implication on detection of radon-in-water concentrations: practical assessment of different on site radon extraction methods. AB - The on-site measurement of radon-in-water concentrations relies on extraction of radon from the water followed by its detection by means of a mobile radon-in-air monitor. Many applications of radon as a naturally occurring aquatic tracer require the collection of continuous radon concentration time series, thus necessitating the continuous extraction of radon either from a permanent water stream supplied by a water pump or directly from a water body or a groundwater monitoring well. Essentially, three different types of extraction units are available for this purpose: (i) a flow-through spray chamber, (ii) a flow-through membrane extraction module, and (iii) a submersible (usually coiled) membrane tube. In this paper we discuss the advantages and disadvantages of these three methodical approaches with particular focus on their individual response to instantaneously changing radon-in-water concentrations. After a concise introduction into theoretical aspects of water/air phase transition kinetics of radon, experimental results for the three types of extraction units are presented. Quantitative suggestions for optimizing the detection setup by increasing the water/air interface and by reducing the air volume circulating through the degassing unit and radon detector are made. It was shown that the flow-through spray chamber and flow-through membrane perform nearly similarly, whereas the submersible membrane tubing has a significantly larger delay in response to concentration changes. The flow-through spray chamber is most suitable in turbid waters and to applications where high flow rates of the water pump stream can be achieved (e.g., where the power supply is not constrained by field conditions). The flow-through membrane is most suited to radon extraction from clear water and in field conditions where the power supply to a water pump is limited, e.g., from batteries. Finally, the submersible membrane tube is most suitable if radon is to be extracted in situ without any water pumping, e.g., in groundwater wells with a low yield, or in long-term time series, in which short term variations in the radon concentration are of no relevance. PMID- 22835088 TI - Photochemical production of NADH using cobaloxime catalysts and visible-light energy. AB - In this study, a visible-light-driven photocatalytic system for the generation of dihydronicotinamide adenine dinucleotide (NADH) from aqueous protons was examined using cobaloxime as a catalyst, eosin as a photosensitizer, and triethanolamine as a sacrificial electron donor. Irradiation of a reaction solution containing cobaloxime, eosin, and triethanolamine (TEOA) converted NAD(+) to NADH with a yield of 36% in a phosphate buffer. The reaction rates for the production of NADH were dependent on the concentrations of the catalyst, NAD(+), and TEOA. Introduction of an electron-donating or -withdrawing substituent in the para position of the pyridine changed the rate constant and affected the conversion efficiency. The rates obtained by the different substituents were linearly correlated with the Hammett coefficients of the introduced substituents. Last, reduction of CO(2) was carried out in the presence of formate dehydrogenase using NADH photochemically generated using the cobaloxime/eosin/TEOA system. PMID- 22835089 TI - The first imported cutaneous myiasis due to Cordylobia anthropophaga in China. PMID- 22835090 TI - Is there a relationship between wound infections and laceration closure times? AB - BACKGROUND: Lacerations account for a large number of ED visits. Is there a "golden period" beyond which lacerations should not be repaired primarily? What type of relationship exists between time of repair and wound infection rates? Is it linear or exponential? Currently, the influence of laceration age on the risk of infection in simple lacerations repaired is not clearly defined. We conducted this study to determine the influence of time of primary wound closure on the infection rate. METHODS: This is a prospective observational study of patients who presented to the Emergency Department (ED) with a laceration requiring closure from April 2009 to November 2010. The wound closure time was defined as the time interval from when the patient reported laceration occurred until the time of the start of the wound repair procedure. Univariate analysis was performed to determine the factors predictive of infection. A non-parametric Wilcoxon rank-sum test was performed to compare the median differences of time of laceration repair. Chi-square (Fisher's exact) tests were performed to test for infection differences with regard to gender, race, location of laceration, mechanism of injury, co-morbidities, type of anesthesia and type of suture material used. RESULTS: Over the study period, 297 participants met the inclusion criteria and were followed. Of the included participants, 224 (75.4%) were male and 73 (24.6%) were female. Ten patients (3.4%) developed a wound infection. Of these infections, five occurred on hands, four on extremities (not hands) and one on the face. One of these patients was African American, seven were Hispanic and two were Caucasian (p = 0.0005). Median wound closure time in the infection group was 867 min and in the non-infection group 330 min (p = 0.03). CONCLUSIONS: Without controlling various confounding factors, the median wound closure time for the lacerations in the wound infection group was statistically significantly longer than in the non-infection group. PMID- 22835091 TI - One-pot synthesis of 2,4-disubstituted thiazoline from beta-azido disulfide and carboxylic acid. AB - A concise and efficient one-pot four-step synthesis of 2,4-disubstituted thiazoline via a cascade disulfide bond cleavage/thiocarbonylation/Staudinger reduction/aza-Wittig reaction is established. Treatment of various carboxylic acids with beta-azido disulfides under this one-pot procedure obtained the desired thiazolines in good to excellent isolated yields. PMID- 22835092 TI - Increased risk of placenta previa is associated with endometriosis and tubal factor infertility in assisted reproductive technology pregnancy. AB - Although assisted reproductive technology (ART) is suspected to increase the risk of placenta previa, a life-threatening complication of pregnancy, the reason is poorly understood. We recruited consecutive 318 pregnancies conceived by ART in our clinic and examined relation of ten variables, i.e. maternal age, gravidity, parity, male or female fetus, previous abortion, previous cesarean delivery, endometriosis, ovulatory disorder, tubal disease, and male infertility, to placenta previa, by logistic regression analysis. As a result, we found that endometriosis (odds ratio = 15.1; 95% CI = 7.6-500.0) and tubal disease (odds ratio = 4.4; 95% CI = 1.1-26.3) were significantly associated with placenta previa. It would be preferable to take the increased risk of placenta previa into account in treating ART pregnancy with endometriosis and tubal disease. PMID- 22835133 TI - The dynamic nature of bacterial surfaces: implications for metal-membrane interaction. AB - Bacterial envelopes are chemically complex, diverse structures. Chemical and physical influences from cellular microenvironments force lipids, proteins, and sugars to organize dynamically. This constant reorganization serves to maintain compartmentalization and function, but also affects the influence of charged functional groups that drive electrochemical interactions with metal ions. The interactions of metal species with cell walls are of particular interest because (i) metals must be taken up or excluded to maintain cell function, and (ii) electrochemical interactions between charged metals and anionic ligands are inevitable. In this review we explore the associations of metals with metal reactive ligands found within bacterial envelopes, and outward to include those within biofilm matrics. The mechanisms that underpin metal binding to these ligands have not been well considered with respect to the dynamic organization of the biological structures themselves. Bacteria respond sensitively and rapidly to growth environment with de novo syntheses of chemical constituents, which can impact metal interactions. We discuss causes of membrane chemical variability as observed in laboratory experiments, and offer consequences for this adaptability in natural settings. The structural impacts of metal ion associations with bacterial envelopes are often overlooked. This review explores how dynamic bacterial surface chemistry influences metal binding and, in turn, how metal ions impact membrane organization in laboratory and natural conditions. PMID- 22835134 TI - Evaluation of clinical and financial outcomes of a new no-sting barrier film and barrier cream in a large UK primary care organisation. AB - The study involves 95 subjects within a UK Primary Care Organisation and was undertaken in two arms. The objective was to determine the clinical outcomes and clinical acceptability of a newly available range of no-sting barrier film and no sting barrier cream products offering significant financial benefits. The importance of undertaking this study is underpinned by evidence in the literature relating to the use of no-sting barrier preparations within clinical practice. The first part of the study (arm 1) involved extensive evaluation of either the film or cream barrier in 36 patients and was compared to existing standardised barrier protection care within the organisation. The results indicated that the new product range met all the criteria for formulary inclusion and following this the barrier range was further evaluated in arm 2, 33 patients with barrier cream and 26 patients with barrier film. The entire study was conducted over a 3-month period with patient treatment lasting a minimum of 2 days to a maximum 4-week period adhering to the agreed evaluation protocol as approved by clinical governance. In arm 1 (n = 36), the clinical expectation of the product was met in 32 cases relating to ease of use, conformability, no-sting, quick drying, ease of absorption, compatibility with devices, frequency of application, prevention and management including visual skin improvement resulting in a recommendation for formulary listing in 31 of 36 cases. In arm 2 (n = 59), barrier film and barrier cream performance was consistently rated same as, better than or much better than the existing barrier used. A formulary listing recommendation was made in 51 of 59 cases. PMID- 22835135 TI - Mulberrofuran G and isomulberrofuran G from Morus alba L.: anti-hepatitis B virus activity and mass spectrometric fragmentation. AB - Mulberrofuran G (1) and isomulberrofuran G (2), a pair of isomeric Diels-Alder type adducts, were isolated from the root bark of Morus alba L. Isomulberrofuran G (2) as a new IIB-type Diels-Alder-type adduct, was elucidated by extensive (1)H, (13)C, and two-dimensional (2D) nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectroscopic analyses. A fragmentation study on compounds 1 and 2 was performed by high-resolution electrospray ionization (ESI) multistage tandem mass spectrometry linked with ion-trap (IT) and time-of-flight (TOF) mass analyzers (ESI-MS(n)/IT-TOF) in negative mode, which resulted in obviously different fragmentations. In the MS(2) experiments, the characteristic ions at m/z 451 and 439 could be revealed as their respective diagnostic ions. Mulberrofuran G (1) showed moderate activity, inhibiting hepatitis B virus (HBV) DNA replication with the IC(50) value of 3.99 MUM, according to the anti-HBV assay on the HepG 2.2.15 cell line in vitro. PMID- 22835136 TI - Stroke, food groups, and dietary patterns: a systematic review. AB - Stroke is the fourth leading cause of mortality in the United States, yet it is 80% preventable by addressing lifestyle factors including nutrition. Evaluating the impact of nutrition at the food group and dietary pattern level will provide greater insight into the role of nutrition in stroke. For this purpose, a review of the literature was conducted using the PubMed, Web of Science, and CINAHL Plus online databases. While fruits, vegetables, and soy demonstrated a protective effect, variable findings were observed for fish, animal products, and whole grains. Adherence to DASH, Mediterranean, and prudent dietary patterns reduced the risk of stroke, whereas the Western dietary pattern was associated with increased stroke risk. Low-fat diet was not found to have a protective effect. Additional epidemiological evidence is needed to elucidate the impact of specific dietary patterns and food groups on stroke. Future research should consider developing dietary recommendations for stroke prevention, which are based on clinical trials and have an emphasis on food groups and dietary patterns that are palatable to the general public. PMID- 22835137 TI - Effect of prebiotics on biomarkers of colorectal cancer in humans: a systematic review. AB - Prebiotics may prevent colorectal cancer (CRC) development in humans by modifying the composition or activity of the colorectal microflora. Epidemiologic and animal studies have shown a reduction in CRC or CRC biomarkers after the administration of prebiotics. Studies using indirect chemical biomarkers of CRC in humans, however, gave mixed results. Recently, human studies measuring direct physical indices of CRC risk after prebiotic consumption have been published. The purpose of this review is to summarize those studies to provide recommendations for the use of prebiotics in CRC risk reduction. A PubMed search was conducted, revealing nine studies. One tested lactulose, two evaluated a blend of oligofructose and inulin, and six measured resistant starch. Lactulose reduced adenoma recurrence, while resistant starch had no effect on adenoma or CRC development. Crypt mitotic location, gene expression, and DNA methylation were somewhat improved after resistant starch consumption. No changes in cell proliferation and apoptosis, crypt morphology, or aberrant crypt foci were found. More human studies measuring physical changes to the gut are needed. PMID- 22835138 TI - Role of dietary beta-glucans in the prevention of the metabolic syndrome. AB - The present review examines the evidence regarding the effect of beta-glucan on variables linked to the metabolic syndrome (MetS), including appetite control, glucose control, hypertension, and gut microbiota composition. Appetite control can indirectly influence MetS by inducing a decreased energy intake, and promising results for a beta-glucan intake to decrease appetite have been found using gut hormone responses and subjective appetite indicators. Beta-glucan also improves the glycemic index of meals and beneficially influences glucose metabolism in patients with type 2 diabetes or MetS, as well as in healthy subjects. Furthermore, a blood-pressure-lowering effect of beta-glucan in hypertensive subjects seems fairly well substantiated. The gut microbiota composition might be an interesting target to prevent MetS, and preliminary results indicate the prebiotic potential of beta-glucan. The evidence that beta glucan influences appetite control and gut microbiota in a positive way is still insufficient or difficult to interpret, and additional studies are needed in this field. Still, much evidence indicates that increased beta-glucan intake could prevent MetS. Such evidence should encourage increased efforts toward the development of beta-glucan-containing functional foods and promote the intake of beta-glucan-rich foods, with the aim of reducing healthcare costs and disease prevalence. PMID- 22835139 TI - From clock genes to telomeres in the regulation of the healthspan. AB - Biological clocks are classified into oscillatory (clock genes) and unidirectional hourglass clocks (telomeres). Clock genes align behavioral and biochemical processes with the day/night cycle. Telomeres, the repeated series of DNA sequences that cap the ends of chromosomes, become shorter during cell division. Shortened telomeres have been documented in various pathological states associated with aging. Human activity is driven by NADH and ATP produced from nutrients, and the resulting NAD and AMP play a predominant role in energy regulation. Caloric restriction increases both AMP and NAD and is known to extend the healthspan (healthy lifespan) of animals. Silent information regulator T1 (SIRT1), the NAD-dependent deacetylase, attenuates telomere shortening, while peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a master modulator of gene expression, is phosphorylated by AMP kinase and deacetylated by SIRT1. Thus, PGC-1alpha is a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism. Reactive oxygen species produced in clock mutants result in telomere shortening. The circadian rhythms produced by clock genes and lifestyle factors are ultimately controlled by the human brain and drive homeostatic and hedonic feeding and daily activity. PMID- 22835140 TI - Worldwide consumption of functional foods: a systematic review. AB - The present systematic review was performed to assess differences in the worldwide consumption of functional foods. The Medline and Scopus databases were used to search the existing literature. A total of 23 studies that examined functional food consumption and included information on the country, gender, and age of participants were identified for inclusion. The studies investigated a variety of functional foods, and analysis of the findings indicates it is not possible to reach generalized conclusions about consumer choices regarding functional food consumption. Gender, age, level of education, and personal health status may each predict consumption of one or more functional foods. Further studies aimed at gaining a better understanding of the factors that influence consumption of functional foods are needed. PMID- 22835141 TI - Retraction. Alpha-lipoic acid supplementation and diabetes. PMID- 22835143 TI - Advances in modulating thermosensory TRP channels. AB - INTRODUCTION: Thermosensory channels are a subfamily of the transient receptor potential (TRP) channel family that are activated by changes in the environmental temperature. These channels, known as thermoTRPs, cover the entire spectrum of temperatures, from noxious cold (< 15 degrees C) to injurious heat (> 42 degrees C). In addition, dysfunction of these channels contributes to the thermal hypersensitivity that accompanies painful conditions. Moreover, because of their wide tissue and cellular distribution, thermoTRPs are also involved in the pathophysiology of several diseases, from inflammation to cancer. AREAS COVERED: Although the number of thermoTRPs is increasing with the identification of novel members such as TRPM3, we will cover the recent advances in the pharmacology of the classical thermosensory channels, namely TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. This review will focus on the therapeutic progress carried out for all these channels and will highlight the tenet that TRPV1, TRPM8 and TRPA1 are the most exploited channels, and that the interest on TRPV3 and TRPV4 is growing with the first TRPV3 antagonist that moves into Phase-II clinical trials. In contrast, the pharmacology of TRPV2 is yet in its infancy. EXPERT OPINION: Despite the tremendous academic and industrial investment to develop therapeutic modulators of thermoTRPs, it apparently seems that we are still far from the first successful product, although hope is maintained high for all compounds currently in clinical trials. A major concern has been the appearance of side effects. A better knowledge of the thermosensory protein networks (signal-plexes), along with the application of system biology approaches may provide novel strategies to modulate thermoTRPs activity with improved therapeutic index. A case in point is TRPV1, where acting on interacting proteins is providing new therapeutic opportunities. PMID- 22835144 TI - Enantioselective synthesis of chiral sulfones by Ir-catalyzed asymmetric hydrogenation: a facile approach to the preparation of chiral allylic and homoallylic compounds. AB - A highly efficient and enantioselective Ir-catalyzed hydrogenation of unsaturated sulfones was developed. Chiral cyclic and acyclic sulfones were produced in excellent enantioselectivities (up to 98% ee). Coupled with the Ramberg-Backlund rearrangement, this reaction offers a novel route to chiral allylic and homoallylic compounds in excellent enantioselectivities (up to 97% ee) and high yields (up to 94%). PMID- 22835145 TI - Added value of a mandible movement automated analysis in the screening of obstructive sleep apnea. AB - In-laboratory polysomnography is the 'gold standard' for diagnosing obstructive sleep apnea syndrome, but is time consuming and costly, with long waiting lists in many sleep laboratories. Therefore, the search for alternative methods to detect respiratory events is growing. In this prospective study, we compared attended polysomnography with two other methods, with or without mandible movement automated analysis provided by a distance-meter and added to airflow and oxygen saturation analysis for the detection of respiratory events. The mandible movement automated analysis allows for the detection of salient mandible movement, which is a surrogate for arousal. All parameters were recorded simultaneously in 570 consecutive patients (M/F: 381/189; age: 50+/-14 years; body mass index: 29+/-7 kg m(-2) ) visiting a sleep laboratory. The most frequent main diagnoses were: obstructive sleep apnea (344; 60%); insomnia/anxiety/depression (75; 13%); and upper airway resistance syndrome (25; 4%). The correlation between polysomnography and the method with mandible movement automated analysis was excellent (r: 0.95; P<0.001). Accuracy characteristics of the methods showed a statistical improvement in sensitivity and negative predictive value with the addition of mandible movement automated analysis. This was true for different diagnostic thresholds of obstructive sleep severity, with an excellent efficiency for moderate to severe index (apnea hypopnea index >=15h(-1) ). A Bland & Altman plot corroborated the analysis. The addition of mandible movement automated analysis significantly improves the respiratory index calculation accuracy compared with an airflow and oxygen saturation analysis. This is an attractive method for the screening of obstructive sleep apnea syndrome, increasing the ability to detect hypopnea thanks to the salient mandible movement as a marker of arousals. PMID- 22835146 TI - Different points of a continuum? Cross sectional comparison of the current and pre-contact psychosocial problems among the different categories of adolescents in institutional care in Nigeria. AB - BACKGROUND: The combination of adverse social indicators and a predominantly youthful population puts Nigeria, and indeed many countries of sub-Sahara Africa, at the risk of explosion in the number of youth coming in contact with the juvenile justice system. Despite this risk, custodial childcare systems in the region are still poorly developed with both juvenile offenders and neglected adolescents coming in contact with the systems being kept in the same incarcerating facility. The needs of these different groups of adolescents may be different. Knowing their common and unique needs can inform common prevention strategies and ensure that specific service-needs of different categories of adolescents in institutional custody are met. METHODS: Data on the family background, pre-contact social circumstance, neurological and anthropometric profiles, and certain aspects of mental health of adolescents drawn from two juvenile justice institutions in Nigeria were obtained. The results for the adolescents on 'criminal code' and those admitted as a case of child neglect were compared using chi-square and odd ratios. RESULTS: Participants were 211 adolescents comprising of 158 on 'criminal code' and 53 declared as 'neglected'. A lot of similarities were found. For instance, the prevalence of parental separation, family transition, experience of street-life and lifetime exposure to traumatic events and posttraumatic stress was equally high among the two groups of adolescents. The adolescents on 'criminal code' however had significantly higher prevalence of conduct and alcohol/substance use disorders while the child neglect group had poorer anthropometric profiles and higher prevalence of neurological disorders. CONCLUSIONS: Child neglect and juvenile delinquency in Nigeria may truly be different points of a continuum. There are however fundamental differences that can warrant specific prevention strategies and tailor-made service provision while in custodial care. PMID- 22835147 TI - Chronic idiopathic urticaria (CIU) is no longer idiopathic: time for an update. PMID- 22835148 TI - The identification of clinical and professional leadership activities of advanced practitioners: findings from the Specialist Clinical and Advanced Practitioner Evaluation study in Ireland. AB - AIM: To report a case study that identifies how leadership is enacted by advanced practitioners in nursing and midwifery and differentiates between clinical and professional leadership in advanced practice. BACKGROUND: A national evaluation of advanced practitioners in nursing and midwifery was commissioned to inform policy makers' decision-making about future developments in Ireland. Leadership is a key aspect of the advanced practitioner role. However, leadership in the advanced practice context is under researched and lacks empirical evidence on how advanced practitioners enact their clinical and professional leadership function in practice. DESIGN: A multiple case study methodology was used to identify the leadership activities of advanced practitioners. METHODS: Purposive sampling of advanced practitioners in nursing and midwifery across various specialities and health regions in Ireland was employed. Data sources included non-participant observation of advanced practitioners, interviews with key stakeholders, and documentary evidence including audits, policies, and guidelines. Collectively these data were used to identify the leadership activities of advanced practitioners in practice. The study was conducted between December 2008-December 2010. RESULTS: Seven key activities that indicated clinical leadership and three key activities for professional leadership at advanced practice level were identified. CONCLUSIONS: The leadership activities identified provide greater clarity in distinguishing between professional and clinical leadership and in specifying the nature and scope of leadership activities. PMID- 22835149 TI - Insertion of a myc-tag within alpha-dystroglycan domains improves its biochemical and microscopic detection. AB - BACKGROUND: Epitope tags and fluorescent fusion proteins have become indispensable molecular tools for studies in the fields of biochemistry and cell biology. The knowledge collected on the subdomain organization of the two subunits of the adhesion complex dystroglycan (DG) enabled us to insert the 10 amino acids myc-tag at different locations along the alpha-subunit, in order to better visualize and investigate the DG complex in eukaryotic cells. RESULTS: We have generated two forms of DG polypeptides via the insertion of the myc-tag 1) within a flexible loop (between a.a. 170 and 171) that separates two autonomous subdomains, and 2) within the C-terminal domain in position 500. Their analysis showed that double-tagging (the beta-subunit is linked to GFP) does not significantly interfere with the correct processing of the DG precursor (pre-DG) and confirmed that the alpha-DG N-terminal domain is processed in the cell before alpha-DG reaches its plasma membrane localization. In addition, myc insertion in position 500, right before the second Ig-like domain of alpha-DG, proved to be an efficient tool for the detection and pulling-down of glycosylated alpha-DG molecules targeted at the membrane. CONCLUSIONS: Further characterization of these and other myc-permissive site(s) will represent a valid support for the study of the maturation process of pre-DG and could result in the creation of a new class of intrinsic doubly-fluorescent DG molecules that would allow the monitoring of the two DG subunits, or of pre-DG, in cells without the need of antibodies. PMID- 22835150 TI - Nitric oxide inhibits the ATPase activity of the chaperone-like AAA+ ATPase CDC48, a target for S-nitrosylation in cryptogein signalling in tobacco cells. AB - NO has important physiological functions in plants, including the adaptative response to pathogen attack. We previously demonstrated that cryptogein, an elicitor of defence reaction produced by the oomycete Phytophthora cryptogea, triggers NO synthesis in tobacco. To decipher the role of NO in tobacco cells elicited by cryptogein, in the present study we performed a proteomic approach in order to identify proteins undergoing S-nitrosylation. We provided evidence that cryptogein induced the S-nitrosylation of several proteins and identified 11 candidates, including CDC48 (cell division cycle 48), a member of the AAA+ ATPase (ATPase associated with various cellular activities) family. In vitro, NtCDC48 (Nicotiana tabacum CDC48) was shown to be poly-S-nitrosylated by NO donors and we could identify Cys(110), Cys(526) and Cys(664) as a targets for S-nitrosylation. Cys(526) is located in the Walker A motif of the D2 domain, that is involved in ATP binding and was previously reported to be regulated by oxidative modification in Drosophila. We investigated the consequence of NtCDC48 S-nitrosylation and found that NO abolished NtCDC48 ATPase activity and induced slight conformation changes in the vicinity of Cys(526). Similarly, substitution of Cys(526) by an alanine residue had an impact on NtCDC48 activity. More generally, the present study identified CDC48 as a new candidate for S-nitrosylation in plants facing biotic stress and further supports the importance of Cys(526) in the regulation of CDC48 by oxidative/nitrosative agents. PMID- 22835151 TI - Development of a multi-target TaqMan assay to detect eastern equine encephalitis virus variants in mosquitoes. AB - Disease outbreaks caused by eastern equine encephalitis virus (EEEV; Togaviridae, Alphavirus) may be prevented by implementing effective surveillance and intervention strategies directed against the mosquito vector. Methods for EEEV detection in mosquitoes include a real-time reverse transcriptase PCR technique (TaqMan assay), but we report its failure to detect variants isolated in Connecticut in 2011, due to a single base-pair mismatch in the probe-binding site. To improve the molecular detection of EEEV, we developed a multi-target TaqMan assay by adding a second primer/probe set to provide redundant targets for EEEV detection. The multi-target TaqMan assay had similar performance characteristics to the conventional assay, but also detected newly-evolving strains of EEEV. The approach described here increases the reliability of the TaqMan assay by creating back-up targets for virus detection without sacrificing sensitivity or specificity. PMID- 22835152 TI - Flight performance and teneral energy reserves of two genetically-modified and one wild-type strain of the yellow fever mosquito Aedes aegypti. AB - The ability of sterile males to survive, disperse, find, and mate with wild females is key to the success of sterile insect technique (SIT). The Release of Insects carrying a Dominant Lethal (RIDL) system is a genetics-based SIT strategy for Aedes aegypti. We examine two aspects of insect performance, flight potential (dispersal ability) and teneral energy reserves, by comparing wild-type (WT) males with genetically-modified lines carrying the tetracycline-repressible constructs OX513A and OX3604C. Our results show significant differences in the flight capacity of the modified lines. OX513A males bred with tetracycline covered 38% less distance, while OX3604C males reared without tetracycline spent 21% less time in flight than their WT counterparts. Such differences in flight performance should be considered when designing release programs (e.g., by placing release sites sufficiently close together to achieve adequate coverage). All mosquito lines had similar teneral carbohydrate contents, though males of the OX3604C line contained more lipids. The addition of tetracycline to the larval diet did not influence the flight potential of the males; however, it did change the teneral sugar reserves of the WT and the lipid reserves of both the WT and the OX3604C lines. PMID- 22835154 TI - Expanding the genetics of amyotrophic lateral sclerosis and frontotemporal dementia. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. It is now recognized that ALS and frontotemporal lobar degeneration (FTLD) form a clinical spectrum of disease with overlapping clinical, pathological and genetic features. This past year, the genetic causes of ALS have expanded to include mutations in the genes OPTN, VCP, and UBQLN2, and the hexanucleotide repeat expansion in C9ORF72. The C9ORF72 repeat expansion solidifies the notion that ALS and FTLD are phenotypic variations of a disease spectrum with a common molecular etiology. Furthermore, the C9ORF72 expansion is the genetic cause of a substantial portion of apparently sporadic ALS and FTLD cases, showing that genetics plays a clear role in sporadic disease. Here we describe the progress made in the genetics of ALS and FTLD, including a detailed look at how new insights brought about by C9ORF72 have both broadened and unified current concepts in neurodegeneration. PMID- 22835153 TI - Zoonotic infections among employees from Great Smoky Mountains and Rocky Mountain National Parks, 2008-2009. AB - U.S. National Park Service employees may have prolonged exposure to wildlife and arthropods, placing them at increased risk of infection with endemic zoonoses. To evaluate possible zoonotic risks present at both Great Smoky Mountains (GRSM) and Rocky Mountain (ROMO) National Parks, we assessed park employees for baseline seroprevalence to specific zoonotic pathogens, followed by evaluation of incident infections over a 1-year study period. Park personnel showed evidence of prior infection with a variety of zoonotic agents, including California serogroup bunyaviruses (31.9%), Bartonella henselae (26.7%), spotted fever group rickettsiae (22.2%), Toxoplasma gondii (11.1%), Anaplasma phagocytophilum (8.1%), Brucella spp. (8.9%), flaviviruses (2.2%), and Bacillus anthracis (1.5%). Over a 1-year study period, we detected incident infections with leptospirosis (5.7%), B. henselae (5.7%), spotted fever group rickettsiae (1.5%), T. gondii (1.5%), B. anthracis (1.5%), and La Crosse virus (1.5%) in staff members at GRSM, and with spotted fever group rickettsiae (8.5%) and B. henselae (4.3%) in staff at ROMO. The risk of any incident infection was greater for employees who worked as resource managers (OR 7.4; 95% CI 1.4,37.5; p=0.02), and as law enforcement rangers/rescue crew (OR 6.5; 95% CI 1.1,36.5; p=0.03), relative to those who worked primarily in administration or management. The results of this study increase our understanding of the pathogens circulating within both parks, and can be used to inform the development of effective guidelines and interventions to increase visitor and staff awareness and help prevent exposure to zoonotic agents. PMID- 22835155 TI - Home environment relationships with children's physical activity, sedentary time, and screen time by socioeconomic status. AB - BACKGROUND: Children in households of lower socioeconomic status (SES) are more likely to be overweight/obese. We aimed to determine if home physical activity (PA) environments differed by SES and to explore home environment mediators of the relation of family SES to children's PA and sedentary behavior. METHODS: Participants were 715 children aged 6 to 11 from the Neighborhood Impact on Kids (NIK) Study. Household SES was examined using highest educational attainment and income. Home environment was measured by parent report on a survey. Outcomes were child's accelerometer-measured PA and parent-reported screen time. Mediation analyses were conducted for home environment factors that varied by SES. RESULTS: Children from lower income households had greater media access in their bedrooms (TV 52% vs. 14%, DVD player 39% vs. 14%, video games 21% vs. 9%) but lower access to portable play equipment (bikes 85% vs. 98%, jump ropes 69% vs. 83%) compared to higher income children. Lower SES families had more restrictive rules about PA (2.5 vs. 2.0). Across SES, children watched TV/DVDs with parents/siblings more often than they engaged in PA with them. Parents of lower SES watched TV/DVDs with their children more often (3.1 vs. 2.5 days/week). Neither total daily and home-based MVPA nor sedentary time differed by SES. Children's daily screen time varied from 1.7 hours/day in high SES to 2.4 in low SES families. Media in the bedroom was related to screen time, and screen time with parents was a mediator of the SES--screen time relationship. CONCLUSIONS: Lower SES home environments provided more opportunities for sedentary behavior and fewer for PA. Removing electronic media from children's bedrooms has the potential to reduce disparities in chronic disease risk. PMID- 22835156 TI - A social epidemiological study on HIV/AIDS in a village of Henan Province, China. AB - The HIV/AIDS epidemic caused by commercial blood donation in rural Henan Province of China in the early- to mid-1990s is the largest known cohort in the world related to blood donation but is not fully described. The objectives of this study were to describe the epidemic, epidemiology, and social epidemiology of commercial blood donation and HIV/AIDS. Both qualitative and quantitative mixed methods were used. A village was randomly selected from the 38 key HIV/AIDS pandemic villages in Henan Province. "Demographic Data Form" was applied to collect demographic information of each resident. Focus groups were held for the managers, some residents, members of "HIV/AIDS Work-Team" (organized by the Henan Provincial Government) in the village. Every village physician, people living with HIV/AIDS (PLWHA), school header, and other stakeholders were interviewed individually. The social epidemiology of HIV/AIDS was analyzed under three perspectives of the framework: individual, social, and structural perspectives. In this village, there were 2335 residents, 484 (20.3%) were former donors, 107 (4.6%) were PLWHA, and 96.3% of PLWHA were infected through commercial blood donation. Individually, low education and plasma donation were the risky factors of HIV/AIDS infection. Socially, the epidemic was geography-, kinship-, and conformity-related. Structurally, the related macrostructure factor was policy endorsement of national blood products. The microstructure factors were poverty and value belief on male child in passing down generations. It is concluded that commercial blood donation and HIV/AIDS epidemic in the village are symbiotically related. The epidemic is temporary and socially determined. PMID- 22835157 TI - Hyalinosis cutis et mucosae manifests in different features in two sisters. PMID- 22835158 TI - Physical rehabilitation should be required for all pediatric heart transplant recipients. PMID- 22835159 TI - Effects of a low-dose oral estrogen only treatment on bone mineral density and quantitative ultrasonometry in postmenopausal women. AB - INTRODUCTION: The aim of this study was to evaluate an oral low-dose estrogen therapy on bone mineral density (BMD) and quantitative ultrasonometry (QUS) in osteopenic postmenopausal women. MATERIAL AND METHODS: This prospective, open label cohort study investigated 120 postmenopausal hysterectomized women. Forty seven women had been treated with 0.3 mg conjugated equine estrogen daily (ET). Primary end point was the change in BMD at the spine after 24 months. Secondary end points were among other changes in QUS at the os calcis and phalanges. RESULTS: After matching 42 participants in the ET group, 42 controls were analyzed. The change in BMD differed significantly after 24 months (p = 0.019). Women on ET showed significant increase of spine and hip Z-score, whereas controls showed significant decreases in spine and total hip BMD. In QUS of the os calcis and the phalanges, a number of variables showed a significant improvements with ET. CONCLUSION: Our results comprised a positive effect of an oral low-dose estrogen therapy on BMD. Limitations of the study are the small sample size and the open-label, non-randomized cohort study design. The findings are in accordance to the common literature and support the use of ET in the primary prevention of postmenopausal bone loss. PMID- 22835160 TI - Parabola-like shaped pH-rate profile for phenols oxidation by aqueous permanganate. AB - Oxidation of phenols by permanganate in the pH range of 5.0-9.0 generally exhibits a parabola-like shape with the maximum reaction rate obtained at pH close to phenols' pK(a). However, a monotonic increase or decrease is observed if phenols' pK(a) is beyond the pH range of 5.0-9.0. A proton transfer mechanism is proposed in which the undissociated phenol is directly oxidized by permanganate to generate products while a phenolate-permanganate adduct, intermediate, is formed between dissociated phenol and permanganate ion and this is the rate limiting step for phenolates oxidation by permanganate. The intermediate combines with H(+) and then decomposes to products. Rate equations derived based on the steady-state approximation can well simulate the experimentally derived pH-rate profiles. Linear free energy relationships (LFERs) were established among the parameters obtained from the modeling, Hammett constants, and oxygen natural charges in phenols and phenolates. LFERs reveal that chlorine substituents have opposite influence on the susceptibility of phenols and phenolates to permanganate oxidation and phenolates are not necessarily more easily oxidized than their neutral counterparts. The chlorine substituents regulate the reaction rate of chlorophenolates with permanganate mainly by influencing the natural charges of the oxygen atoms of dissociated phenols while they influence the oxidation of undissociated chlorophenols by permanganate primarily by forming intramolecular hydrogen bonding with the phenolic group. PMID- 22835161 TI - Theoretical study of hyperfine interactions in small arsenic-containing radicals. AB - Various density functional theory (DFT) and ab initio MP2 and CCSD methods were employed in calculations of arsenic isotropic and anisotropic hyperfine parameters in three small radicals, AsH(2), AsO(2), and H(2)AsO. Convergent basis sets for these calculations were specially derived starting from Dunning's correlation-consistent sets. DFT methods proved to be particularly appropriate choice, because the results obtained with the suitable functionals are in accordance with the available experimental values. Additionally, mechanisms of hyperfine couplings were investigated by examining individual orbital contributions to spin density. The spin polarization mechanism in AsH(2) was studied by evaluating one- and two-electron integrals in spin-restricted and unrestricted case. Apart from nonrelativistic, scalar-relativistic Douglas-Kroll Hess DFT calculations were performed to examine relativistic impacts on spin density distribution. PMID- 22835162 TI - Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a potentially fatal disease with high mortality. Our aim was to summarize the current evidence for use of neuromuscular blocking agents (NMBA) in the early phase of ARDS. METHODS: Systematic review and meta-analysis of publications between 1966 and 2012. The Medline and CENTRAL databases were searched for studies on NMBA in patients with ARDS. The meta-analysis was limited to: 1) randomized controlled trials; 02) adult human patients with ARDS or acute lung injury; and 03) use of any NMBA in one arm of the study compared with another arm without NMBA. The outcomes assessed were: overall mortality, ventilator-free days, time of mechanical ventilation, adverse events, changes in gas exchange, in ventilator settings, and in respiratory mechanics. RESULTS: Three randomized controlled trials covering 431 participants were included. Patients treated with NMBA showed less mortality (Risk ratio, 0.71 [95 % CI, 0.55 - 0.90]; number needed to treat, 1 - 7), more ventilator free days at day 28 (p = 0.020), higher PaO2 to FiO2 ratios (p = 0.004), and less barotraumas (p = 0.030). The incidence of critical illness neuromyopathy was similar (p = 0.540). CONCLUSIONS: The use of NMBA in the early phase of ARDS improves outcome. PMID- 22835206 TI - Wound healing isn't everything. PMID- 22835207 TI - Botanical origin causes changes in nutritional profile and antioxidant activity of fermented products obtained from honey. AB - Honey as rich source of enzymatic and nonenzymatic antioxidants serves as health promoting nutrient in the human body. Here, we present the first time a comparative study of nutritional profiles (e.g., acidities, sugar, organic acid profile, total polyphenolic, flavonoid content) for different unifloral, multifloral honeys and their fermented products, in correlation with their antioxidant activity. Additionally, an optimized method for HPLC separation of organic acids from honey was established. The total phenolic content of honey samples varied widely among the honey types compared to fermented products. High amounts of total flavonoids were quantified in heather honey, followed by raspberry, multifloral, black locust, and linden honey. A positive correlation between the content of polyphenols, flavonoids, and antioxidant activity was observed in honey samples. After fermentation, the flavonoid content of dark honey fermented products decreased significantly. Black locust and linden honeys are more suitable for fermentation because the decrease in antioxidant substances is less pronounced. PMID- 22835208 TI - Cross-trienamines in asymmetric organocatalysis. AB - Cross-conjugated trienamines are introduced as a new concept in asymmetric organocatalysis. These intermediates are applied in highly enantioselective Diels Alder and addition reactions, providing functionalized bicyclo[2.2.2]octane compounds and gamma'-addition products, respectively. The nature of the transformations and the intermediates involved are investigated by computational calculations and NMR analysis. PMID- 22835209 TI - The association between cognitive impairment and neuropsychiatric symptoms in patients with Parkinson's disease dementia. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) are common in patients with dementia associated with Parkinson's disease (PDD). The relationship between cognition and NPS in PDD has not been well studied. METHODS: Patients diagnosed with PDD were assessed for cognitive function and NPS. The instruments used were the Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and semantic verbal fluency according to the recommendation of the Movement Disorder Society Task Force. RESULTS: We evaluated 127 PDD patients (76 males/51 females; mean age 77 +/- 6.3 years). Their mean MMSE score was 17 +/- 6.5 and the mean NPI score was 19 +/- 20.4. The most prevalent NPI items were anxiety (57.5%), sleep problems (53.5%), and apathy (52.0%). Principal component factor analysis revealed that 12 items formed three factors, namely "mood and psychosis" (delusion, hallucination, agitation, depression, anxiety, apathy, and irritability), "vegetative" (sleep and appetite problems), and "frontal" (euphoria, disinhibition, and aberrant motor behavior). Symptoms of hallucination were significantly associated with MMSE score, even after controlling for the confounding variables. CONCLUSION: NPS are common and diverse among patients with PDD. Three specific subgroups of NPS were identified. Hallucination was significantly correlated with cognitive impairment, and could be a predictor of cognition in PDD patients. PMID- 22835210 TI - Recent advances in polymeric microspheres for parenteral drug delivery--part 1. AB - INTRODUCTION: Polymeric microspheres have been established as a valuable parenteral drug delivery system for sustained release of therapeutic agents via subcutaneous or intramuscular injection. AREAS COVERED: Biodegradable polymers which are either synthetic or from natural sources are reviewed with respect to recent advances in exploring their applications for microsphere fabrications. New information on the impact of formulation variables on the properties of microspheres formed by an emulsion method was also presented. The characterization of microspheres using advanced physical analytical techniques was also reviewed and the utilization of the information in assessing in vivo performance of the product was also highlighted. EXPERT OPINION: The broad clinical use of microspheres for delivery of therapeutic agents in particular biologics such as proteins has not been realized commercially. The limited availability of biodegradable polymers with a long history of regulatory approval and the challenges in gaining regulatory approval of a new polymer have hindered the development of microspheres for parenteral drug delivery. PMID- 22835212 TI - Incidence of nonmelanoma skin cancer in Ireland. PMID- 22835211 TI - Ketogenic diet does not affect strength performance in elite artistic gymnasts. AB - BACKGROUND: Despite the increasing use of very low carbohydrate ketogenic diets (VLCKD) in weight control and management of the metabolic syndrome there is a paucity of research about effects of VLCKD on sport performance. Ketogenic diets may be useful in sports that include weight class divisions and the aim of our study was to investigate the influence of VLCKD on explosive strength performance. METHODS: 8 athletes, elite artistic gymnasts (age 20.9 +/- 5.5 yrs) were recruited. We analyzed body composition and various performance aspects (hanging straight leg raise, ground push up, parallel bar dips, pull up, squat jump, countermovement jump, 30 sec continuous jumps) before and after 30 days of a modified ketogenic diet. The diet was based on green vegetables, olive oil, fish and meat plus dishes composed of high quality protein and virtually zero carbohydrates, but which mimicked their taste, with the addition of some herbal extracts. During the VLCKD the athletes performed the normal training program. After three months the same protocol, tests were performed before and after 30 days of the athletes' usual diet (a typically western diet, WD). A one-way Anova for repeated measurements was used. RESULTS: No significant differences were detected between VLCKD and WD in all strength tests. Significant differences were found in body weight and body composition: after VLCKD there was a decrease in body weight (from 69.6 +/- 7.3 Kg to 68.0 +/- 7.5 Kg) and fat mass (from 5.3 +/- 1.3 Kg to 3.4 +/- 0.8 Kg p < 0.001) with a non-significant increase in muscle mass. CONCLUSIONS: Despite concerns of coaches and doctors about the possible detrimental effects of low carbohydrate diets on athletic performance and the well known importance of carbohydrates there are no data about VLCKD and strength performance. The undeniable and sudden effect of VLCKD on fat loss may be useful for those athletes who compete in sports based on weight class. We have demonstrated that using VLCKD for a relatively short time period (i.e. 30 days) can decrease body weight and body fat without negative effects on strength performance in high level athletes. PMID- 22835213 TI - Evaluation of obturator foramen suggests no differences between sexes in young bovines. AB - Among the numerous bovine pelvic traits displaying sex differences, no detailed studies of bovine obturator foramen are available in the veterinary literature. The purpose of this work was to study quantitatively this structure using lineal biometrics, shape indexes and Fourier analysis. The material consisted of 60 hemicoxae belonging to young bovines of approximately 1 year of age. Although significant differences were found in area, perimeter and length of obturator foramen, none of the analyses used were able to differentiate between sexes and thus cannot be used as a natural trait for determining sex, at least in young bovines. PMID- 22835214 TI - A novel mutation in the ED1 gene in a patient with X-linked hypohidrotic ectodermal dysplasia. PMID- 22835215 TI - Fulfilling the metabolic requirements for cell proliferation. AB - The activity of key metabolic enzymes is regulated by the ubiquitin ligases that control the function of the cyclins; therefore the activity of these ubiquitin ligases explains the coordination of cell-cycle progression with the supply of substrates necessary for cell duplication. APC/C (anaphase-promoting complex/cyclosome)-Cdh1, the ubiquitin ligase that controls G(1)- to S-phase transition by targeting specific degradation motifs in cell-cycle proteins, also regulates the glycolysis-promoting enzyme PFKFB3 (6-phosphofructo-2 kinase/fructose-2,6-bisphosphatase isoform 3) and GLS1 (glutaminase 1), a critical enzyme in glutaminolysis. A decrease in the activity of APC/C-Cdh1 in mid-to-late G(1) releases both proteins, thus explaining the simultaneous increase in the utilization of glucose and glutamine during cell proliferation. This occurs at a time consistent with the point in G(1) that has been described as the nutrient-sensitive restriction point and is responsible for the transition from G(1) to S. PFKFB3 is also a substrate at the onset of S-phase for the ubiquitin ligase SCF (Skp1/cullin/F-box)-beta-TrCP (beta-transducin repeat containing protein), so that the activity of PFKFB3 is short-lasting, coinciding with a peak in glycolysis in mid-to-late G(1), whereas the activity of GLS1 remains high throughout S-phase. The differential regulation of the activity of these proteins indicates that a finely-tuned set of mechanisms is activated to fulfil specific metabolic demands at different stages of the cell cycle. These findings have implications for the understanding of cell proliferation in general and, in particular, of cancer, its prevention and treatment. PMID- 22835216 TI - What lies beneath: natural products from marine organisms as nuclear receptor modulators. AB - The marine environment has long been known to be species-rich and to be a source of molecules with interesting and beneficial biochemical and clinical properties. However, despite some notable successes the potential of the 'marine pipeline' has yet to be fully realized. Recent studies involving members of the nuclear receptor superfamily illustrate the chemical richness of molecules from marine species and helps to re-emphasize the translational possibilities of natural products in drug discovery. In this issue of the Biochemical Journal Wang et al. describe the identification and characterization of such a compound, an agonist for the retinoic acid receptor isolated from the sponges Luffariella sp. and Fascaplysinopsis. PMID- 22835217 TI - Omega3 fatty acids may reduce hyperlipidemia in pediatric renal transplant recipients. AB - Life expectancy after pediatric renal transplantation remains lower than that of the normal population largely due to cardiovascular morbidity and mortality. Hyperlipidemia is a potentially modifiable risk factor for cardiovascular morbidity. Retrospective chart review of all available pediatric renal transplant patients (26) in a single center with assessment of anthropometry, renal function, steroid, calcineurin or mTOR inhibitor exposure and Omega3 FA supplementation. Eighteen transplant recipients without Omega3 FA supplementation served as control. Nutrition and supplement surveys were conducted with standardized questionnaires. Fasting cholesterol values were compared using the latest value prior to start of Omega3 FA and at last follow-up. Eight patients (five receiving mTOR inhibitor) started Omega3 FA supplementation at a mean dose of 29.2 +/- 12 mg of EPA/kg and 16.1 +/- 7.4 mg DHA/kg body weight. Median duration of treatment was 2.5 yr (range 0.8-5.9 yr) and their total fasting cholesterol at last follow-up dropped significantly from 5.08 +/- 0.97 (control group 3.77 +/- 0.81, p = 0.0084) to 4.17 +/- 0.54 mm (p = 0.0158). High-density lipoprotein cholesterol increased not significantly from 1.74 +/- 0.49 to 2.02 +/ 0.93 mm. No patient had increased bleeding. Supplementation of omega-3 FAs may reduce hyperlipidaemia after pediatric renal transplantation. PMID- 22835218 TI - Trophic diversity in the evolution and community assembly of loricariid catfishes. AB - BACKGROUND: The Neotropical catfish family Loricariidae contains over 830 species that display extraordinary variation in jaw morphologies but nonetheless reveal little interspecific variation from a generalized diet of detritus and algae. To investigate this paradox, we collected delta13C and delta15N stable isotope signatures from 649 specimens representing 32 loricariid genera and 82 species from 19 local assemblages distributed across South America. We calculated vectors representing the distance and direction of each specimen relative to the delta15N/delta13C centroid for its local assemblage, and then examined the evolutionary diversification of loricariids across assemblage isotope niche space by regressing the mean vector for each genus in each assemblage onto a phylogeny reconstructed from osteological characters. RESULTS: Loricariids displayed a total range of delta15N assemblage centroid deviation spanning 4.90/00, which is within the tissue-diet discrimination range known for Loricariidae, indicating that they feed at a similar trophic level and that delta15N largely reflects differences in their dietary protein content. Total range of delta13C deviation spanned 7.40/00, which is less than the minimum range reported for neotropical river fish communities, suggesting that loricariids selectively assimilate a restricted subset of the full basal resource spectrum available to fishes. Phylogenetic regression of assemblage centroid-standardized vectors for delta15N and delta13C revealed that loricariid genera with allopatric distributions in disjunct river basins partition basal resources in an evolutionarily conserved manner concordant with patterns of jaw morphological specialization and with evolutionary diversification via ecological radiation. CONCLUSIONS: Trophic partitioning along elemental/nutritional gradients may provide an important mechanism of dietary segregation and evolutionary diversification among loricariids and perhaps other taxonomic groups of apparently generalist detritivores and herbivores. Evolutionary patterns among the Loricariidae show a high degree of trophic niche conservatism, indicating that evolutionary lineage affiliation can be a strong predictor of how basal consumers segregate trophic niche space. PMID- 22835219 TI - DHEA supplementation improves follicular microenviroment in poor responder patients. AB - OBJECTIVE: To analyze the effect of dehydroepiandrosterone (DHEA) supplementation on follicular microenvironment and on in vitro fertilization (IVF) outcomes among poor responder patients. STUDY DESIGN: We enrolled 24 patients diagnosed as poor responders based on ESHRE consensus criteria. One group received 25 mg/die three times daily of DHEA supplementation for 3 months previous to IVF cycle, while the other did not receive any treatment. COH was performed with rFSH and hMG, and a GnRH antagonist was administered according to a flexible protocol. We evaluated perifollicular vascularization of recruited follicles through power Doppler blood flow analysis and follicles were graded as described by Chui et al. Follicular fluids (FF) from F3-F4 follicles were collected, and FF levels of vascular endothelial growth factor (VEGF) and hypoxic inducible factor1 (HIF1) were measured. RESULTS: FF levels of HIF1 were statistically significant lower in women treated with DHEA (14.76 +/- 51.13 vs. 270.03 +/- 262.18 pg/ml; p = 0.002). On the contrary, VEGF levels did not differ between the two groups. Concerning COH, in the DHEA-group the mean duration of treatment was significantly shorter (9.83 +/- 1.85 vs. 12.09 +/- 2.81; p = 0.023). Total numbers of oocytes retrieved, fertilized oocytes, good quality embryos, number of transferred embryos and clinical pregnancies tended to be higher in study group, but the results were not significant. On the other hand, considering the oocytes retrieved in selected F3-F4 follicles, there was a relation between HIF1 levels and oocytes quality. In fact, mature oocytes retrieved in selected follicles were significantly more numerous in DHEA-group (0.50 +/- 0.52 vs. 0.08 +/- 0.29; p = 0.018). CONCLUSIONS: The improvement of reproductive parameters after DHEA supplementation in poor responders may be explained through the effect that this pro-hormone exerts on follicular microenvironment. PMID- 22835221 TI - Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. AB - INTRODUCTION: In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information. METHODS: Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added. RESULTS: For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table. CONCLUSIONS: In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions. PMID- 22835220 TI - Obstetrical outcome of anti-inflammatory and anticoagulation therapy in women with recurrent pregnancy loss or unexplained infertility. AB - PROBLEM: Women with a history of recurrent pregnancy losses (RPL) and unexplained infertility (UI) have a high incidence of preeclampsia (PE) and other obstetrical complications. We aimed to investigate the incidence of PE and other obstetrical complications in women with RPL or UI who were treated with anti-inflammatory and anticoagulant treatment. METHODS: The medical records of 72 women who delivered a live born infant from January 2008 to December 2009 with anti-inflammatory (prednisone and/or intravenous immunoglobulin G) and anticoagulant (low-molecular weight heparin and low-dose aspirin) treatment were reviewed retrospectively. A total of 41 women with a history of RPL and 31 with UI were enrolled as a study group. RESULTS: All patients had at least one or more positive test results for autoantibodies, thrombophilic gene mutations, elevated proportion of peripheral blood CD56(+) NK cells or NK cell cytotoxicities, or high T helper 1 to T helper 2 cytokine-producing CD3(+) /CD4(+) cell ratios. The incidence of PE was 5.6% (n = 4), which was comparable to that of general population (2009 CDC data) (P > 0.05); one of them developed HELLP syndrome and none exacerbated to eclampsia. Preterm birth was more frequent in study group than general population (21.7 versus 10.4%, P < 0.028); however, early preterm birth (<34 weeks of gestation, 1.72%), small or large for gestation (SGA or LGA) (10.6 and 4.3%, each), gestational diabetes (GDM) (4.2%), and abruptio placentae (0 of 72) were not increased in study group as compared to general population data. CONCLUSION: The incidences of PE, GDM, SGA, LGA, early preterm birth, and abruptio placentae are not increased in women with RPL or UI who were administered anti-inflammatory and anticoagulation treatment compared to general population. The potential role of anti-inflammatory and anticoagulation treatment in prevention of obstetrical complications in women with immune abnormalities and thrombophilia is suggested. PMID- 22835222 TI - X-ray diffraction, calorimetric, and dielectric relaxation study of the amorphous and smectic states of a main chain liquid crystalline polymer. AB - Liquid crystalline polymers (LCPs) are complex systems that include features of both orientationally ordered mesophases and amorphous polymers. Frequently, the isotropic amorphous state cannot be studied due to the rapid mesophase formation. Here, a new main chain LCP, poly(triethyleneglycol methyl p,p'-bibenzoate), PTEMeB, has been synthesized. It shows a rather slow mesophase formation making possible to study independently both the amorphous and the liquid crystalline states. The structure and phase transitions of PTEMeB have been investigated by calorimetry, variable-temperature MAXS/WAXS employing synchrotron radiation, and X-ray diffraction in oriented fibers. These experiments have pointed out the presence of two glass transitions, related to the amorphous or to the liquid crystal phases. Additionally, the mesophase seems to be a coexistence of orthogonal and tilted smectic phases. A dielectric relaxation study of PTEMeB over broad ranges of temperature and pressure has been performed. The dynamic glass transition turns out to be slower for the amorphous state than for the liquid crystal. Monitoring of the alpha relaxation has allowed us to follow the isothermal mesophase formation at atmospheric pressure. Additionally, the dynamical behavior at high pressures has pointed out the fast formation of the mesophase induced by sudden pressure changes. PMID- 22835223 TI - Lab-on-chip measurement of nitrate and nitrite for in situ analysis of natural waters. AB - Microfluidic technology permits the miniaturization of chemical analytical methods that are traditionally undertaken using benchtop equipment in the laboratory environment. When applied to environmental monitoring, these "lab-on chip" systems could allow high-performance chemical analysis methods to be performed in situ over distributed sensor networks with large numbers of measurement nodes. Here we present the first of a new generation of microfluidic chemical analysis systems with sufficient analytical performance and robustness for deployment in natural waters. The system detects nitrate and nitrite (up to 350 MUM, 21.7 mg/L as NO(3)(-)) with a limit of detection (LOD) of 0.025 MUM for nitrate (0.0016 mg/L as NO(3)(-)) and 0.02 MUM for nitrite (0.00092 mg/L as NO(2)(-)). This performance is suitable for almost all natural waters (apart from the oligotrophic open ocean), and the device was deployed in an estuarine environment (Southampton Water) to monitor nitrate+nitrite concentrations in waters of varying salinity. The system was able to track changes in the nitrate salinity relationship of estuarine waters due to increased river flow after a period of high rainfall. Laboratory characterization and deployment data are presented, demonstrating the ability of the system to acquire data with high temporal resolution. PMID- 22835224 TI - Socio-cultural and economic antecedents of adolescent sexual decision-making and HIV-risk in rural Uganda. AB - With more than half of new infections occurring among youth, HIV/AIDS remains a major contributor to morbidity and mortality in Uganda. Semi-structured interviews were performed with 48 adolescents and 15 adult key informants in a rural Ugandan community to identify influences on adolescent sexual decision making. Inductive data analytic methods revealed five thematic influences: (1) social pressure, (2) decline of the Senga (a familial figure who traditionally taught female adolescents about how to run a household), (3) cultural barriers to condom use, (4) knowledge of HIV transmission and modes of prevention, and (5) a moral injunction against sex before marriage. Influences were classified as HIV/AIDS risk and protective factors and organized to form an explanatory framework of adolescent sexual risk-taking. Risk factors pull youth toward risky behavior, while protective factors push them away. Predominance of risk over protective influences explains persistent sexual risk-taking by Ugandan youth. HIV prevention programs designed for Ugandan adolescents should take competing factors and sociocultural and economic influences into account. PMID- 22835225 TI - An empirically based tool for analyzing morbidity associated with operations for congenital heart disease. AB - OBJECTIVE: Congenital heart surgery outcomes analysis requires reliable methods of estimating the risk of adverse outcomes. Contemporary methods focus primarily on mortality or rely on expert opinion to estimate morbidity associated with different procedures. We created an objective, empirically based index that reflects statistically estimated risk of morbidity by procedure. METHODS: Morbidity risk was estimated using data from 62,851 operations in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2002-2008). Model-based estimates with 95% Bayesian credible intervals were calculated for each procedure's average risk of major complications and average postoperative length of stay. These 2 measures were combined into a composite morbidity score. A total of 140 procedures were assigned scores ranging from 0.1 to 5.0 and sorted into 5 relatively homogeneous categories. RESULTS: Model-estimated risk of major complications ranged from 1.0% for simple procedures to 38.2% for truncus arteriosus with interrupted aortic arch repair. Procedure-specific estimates of average postoperative length of stay ranged from 2.9 days for simple procedures to 42.6 days for a combined atrial switch and Rastelli operation. Spearman rank correlation between raw rates of major complication and average postoperative length of stay was 0.82 in procedures with n greater than 200. Rate of major complications ranged from 3.2% in category 1 to 30.0% in category 5. Aggregate average postoperative length of stay ranged from 6.3 days in category 1 to 34.0 days in category 5. CONCLUSIONS: Complication rates and postoperative length of stay provide related but not redundant information about morbidity. The Morbidity Scores and Categories provide an objective assessment of risk associated with operations for congenital heart disease, which should facilitate comparison of outcomes across cohorts with differing case mixes. PMID- 22835226 TI - Right aortic arch and an aberrant left subclavian artery arising from a Kommerell diverticulum complicated by acute aortic dissection. PMID- 22835227 TI - Evaluation of surgical margins in Basal cell carcinoma by surgical specialty. AB - BACKGROUND: Complete surgical excision is the most common treatment for basal cell carcinoma (BCC), and this intervention is often performed by surgeons who are not dermatologists (e.g., plastic surgeons, general surgeons, oral and maxillofacial surgeons, ophthalmologists, and otorhinolaryngologists). OBJECTIVES: To determine positive margin rates in BCCs removed by surgeons from different specialties and to identify clinical and pathologic factors that might explain potential differences between specialties. METHODS: We retrospectively reviewed the pathology reports of all BCCs diagnosed at Hospital Universitari Vall d'Hebron between January 2009 and March 2001. The statistical methods included a descriptive analysis of clinical and pathologic variables, standard statistical analyses, and multivariate logistic regression. RESULTS: We included 921 BCCs from 750 patients; 549 of the tumors had been excised by a dermatologist. The overall positive margin rate was 12.6%, but the rate for tumors removed by dermatologists was significantly lower than that for those removed by other specialists (6.7% vs 21.5%). There was a 3.8-fold increased relative risk of positive margins following excision by a surgeon who was not a dermatologist, independently of patient age, tumor site, maximum diameter of the resected specimen, and histologic subtype. CONCLUSIONS: Accurate macroscopic identification of tumor margins, which are often difficult to see, and familiarity with the natural history of BCC are key factors in the successful surgical treatment of BCCs. The higher rate of tumor-free margins achieved by dermatologists in this study is probably mainly due to their greater experience in these 2 areas. PMID- 22835228 TI - On the different growth conditions affecting silver antimicrobial efficacy on Listeria monocytogenes and Salmonella enterica. AB - Silver is known to inhibit microorganisms and therefore it is an ideal candidate for its incorporation in a wide variety of materials for food applications. However, there is still a need for understanding how silver prolonged exposure to bacterial contamination affects the bioavailability of the active silver species. In the present study, growth curves of Listeria monocytogenes and Salmonella enterica were performed for 3-5 days in Tryptic Soy Broth (TSB) and M9 minimal medium (M9) in the presence of silver ions and silver solutions previously in contact with the growth media. The cultivability of the bacteria under these conditions was correlated with the viability of the bacterial populations as measured by flow cytometry analysis (FC) using a LIVE/DEAD BacLight kit. It was found that, after a period where viable counts were not detected, bacterial populations recovered and were able to proliferate in most cases. The resuscitation of the cultures was explained by both the existence of a resilient fraction of bacteria in a compromised state and the parallel inactivation of the silver species. This inactivation was found to be highly influenced by time dependant chemical reactions taking place in the environment of exposure, producing differences of at least 3 fold between results for nutrient rich environments and results for limiting environments. This study points out the need for understanding these chemical interactions and bacterial mechanisms of adaptation and may have relevance in the design of silver-based antimicrobial systems for food-related applications. PMID- 22835229 TI - Study of the antifungal potential of novel cellulose/copper composites as absorbent materials for fruit juices. AB - Cellulose/copper composites with antifungal properties have been synthesized by physical/chemical methods. Physical treatments by heat or by a combination of heat and UV radiation provided composites with metallic copper and excellent interfacial adhesion; in contrast, chemical reduction with borohydride generated small although partially aggregated copper oxide nanoparticles. Copper micro/nano particles and copper ions (Cu(2+)) were released from the cellulose matrix at an adequate rate to achieve a strong antimicrobial activity against Saccharomyces cerevisiae in in vitro experiments. Moreover, the copper oxide composites showed an excellent antifungal activity in pineapple and melon juice, reducing about 4 log cycles the loads of spoilage-related yeasts and moulds. The metallic copper composites reduced in 4 log cycles the load of yeasts and moulds in pineapple juice, although their antifungal activity was weaker in contact with melon juice. Copper loaded absorbent materials could be selectively implemented during the shelf-life of minimally processed fruits to reduce the number of spoilage-related microorganisms in the drip. PMID- 22835260 TI - In silico analysis of trypanosomatids' helicases. AB - Trypanosomatids are unicellular protozoan parasites that cause many diseases in animals, including humans, and plants. These early divergent eukaryotes have many singular structures and processes, including the hyper-modified 'base J', a mitochondrial DNA network, RNA editing, and trans-splicing; all of these unique features involve a wide variety of specific DNA/RNA helicases. In this work, the genomes of trypanosomatids were analyzed by data mining, searching for genes coding for DNA/RNA helicases. Specific motifs and full-length sequences from all families present in the helicase's superfamilies (SFs) 1 and 2 were used as baits for genome analyses. A total of 328 putative helicases were identified; 204 genes were assigned to the SF2, 42 genes to the SF1, and 76 genes remain unclassified. Eight species-specific SF2 helicases were also found; Trypanosoma cruzi has three DEAD-box and one DEAH/RHA-specific helicases, while Leishmania major has three Swi2/Snf2 and Trypanosoma brucei has only one RigI helicase. Finally, to identify helicases that could be used as future therapeutic targets, all obtained genes were compared with those present in the human genome. Forty-two helicases underrepresented in the human genome were identified; constituting 16 orthologs groups from L. major, T. brucei, and T. cruzi. PMID- 22835261 TI - Potentiation of hypolipidemic and weight-reducing influence of dietary tender cluster bean (Cyamopsis tetragonoloba) when combined with capsaicin in high-fat fed rats. AB - Soluble fiber-rich tender cluster bean pod (Cyamopsis tetragonoloba) (CB) and a combination of CB and capsaicin, a thermogenic spice compound, were evaluated for weight-reducing effect in high-fat-fed Wistar rats. Freeze-dried CB and capsaicin were included at 15 and 0.015%, respectively, in the high-fat (30%) diet for 8 weeks. Excretion of dietary fat, fat deposition in adipose, and activities of enzymes involved in lipolysis and lipogenesis were examined. CB and capsaicin additively decreased weight gain in high-fat-fed rats, without affecting feed intake. The antiobesity potential of CB was through impeding fat accumulation in adipose and enhancing fat excretion. Decrease in adipose triglyceride by the combination was higher than their individual effects and was accompanied by enhanced activity of hormone-sensitive lipase-facilitating mobilization of depot fat. Increased fecal excretion of triglycerides by the combination of CB and capsaicin was additive. Whereas the hypolipidemic effect of the combination was higher than their individual effects, the decrease in hepatic cholesterol and triglycerides produced by the combination was additve. Thus, dietary CB significantly checked weight gain and adverse changes in lipid profile in high fat-fed condition amounting to a cardioprotective effect. These beneficial effects were potentiated by coadministration of capsaicin. PMID- 22835262 TI - Ultrastructure of acantholysis in pemphigus foliaceus re-examined from the current perspective. AB - BACKGROUND: Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein (Dsg) 1. OBJECTIVES: To examine early acantholysis in the skin of patients with PF at an ultrastructural level. METHODS: Two Nikolsky-negative (N ), five Nikolsky-positive (N+) and two lesional skin biopsies from immunoserologically defined patients with PF were studied by light and electron microscopy. RESULTS: We found no abnormalities in N- PF skin, whereas all the N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell. CONCLUSION: We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of nonjunctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of nonjunctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic desmosomes and a decreased number of desmosomes. In addition, antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis. PMID- 22835264 TI - Stable alkanes containing very long carbon-carbon bonds. AB - The metal-induced coupling of tertiary diamondoid bromides gave highly sterically congested hydrocarbon (hetero)dimers with exceptionally long central C-C bonds of up to 1.71 A in 2-(1-diamantyl)[121]tetramantane. Yet, these dimers are thermally very stable even at temperatures above 200 degrees C, which is not in line with common C-C bond length versus bond strengths correlations. We suggest that the extraordinary stabilization arises from numerous intramolecular van der Waals attractions between the neighboring H-terminated diamond-like surfaces. The C-C bond rotational dynamics of 1-(1-adamantyl)diamantane, 1-(1-diamantyl)diamantane, 2-(1-adamantyl)triamantane, 2-(1-diamantyl)triamantane, and 2-(1 diamantyl)[121]tetramantane were studied through variable-temperature (1)H- and (13)C NMR spectroscopies. The shapes of the inward (endo) CH surfaces determine the dynamic behavior, changing the central C-C bond rotation barriers from 7 to 33 kcal mol(-1). We probe the ability of popular density functional theory (DFT) approaches (including BLYP, B3LYP, B98, B3LYP-Dn, B97D, B3PW91, BHandHLYP, B3P86, PBE1PBE, wB97XD, and M06-2X) with 6-31G(d,p) and cc-pVDZ basis sets to describe such an unusual bonding situation. Only functionals accounting for dispersion are able to reproduce the experimental geometries, while most DFT functionals are able to reproduce the experimental rotational barriers due to error cancellations. Computations on larger diamondoids reveal that the interplay between the shapes and the sizes of the CH surfaces may even allow the preparation of open-shell alkyl radical dimers (and possibly polymers) that are strongly held together exclusively by dispersion forces. PMID- 22835263 TI - A comparative study of clinical characteristics, work-up, treatment, and association to malignancy in dermatomyositis between two tertiary skin centers in the USA and Singapore. AB - BACKGROUND: To date, no study has compared the clinical characteristics, malignancy associations, and treatment of dermatomyositis in predominantly Caucasian vs. Asian populations. MATERIALS AND METHODS: This prospective study was conducted to compare clinical characteristics of dermatomyositis, its relationship to malignancy, and treatment between two tertiary medical centers in the USA and Singapore. A total of 19 newly-diagnosed patients in the USA and 15 patients in Singapore were enrolled. Dermatomyositis or amyopathic dermatomyositis were diagnosed based on clinical assessment, skin and muscle biopsies, and muscle testing. RESULTS: Ninety-five percent of patients in the USA group were of Caucasian descent, while 93% of patients in the Singapore group were of Chinese descent. Both groups were predominantly female. Pruritus was the most common initial symptom reported in both groups, while periungual erythema and Gottron's papules were the most common skin presentations. Heliotrope eruption was more common in the Singapore group, occurring in 80% of patients vs. 32% of patients in the USA group (P = 0.007). Three patients in the Singapore group developed a malignancy, with two of these patients having nasopharyngeal carcinoma. None of the USA patients developed malignancies in a follow- up period of 2-5 years. Immunosuppressive steroid sparing therapy with hydroxychloroquine was more frequently used in Singapore, while topical tacrolimus was more frequently used in the USA. CONCLUSION: The clinical presentations of dermatomyositis vary among different ethnic populations. Chinese patients with dermatomyositis have a significant risk for nasopharyngeal carcinoma. PMID- 22835265 TI - Predictors of health anxiety among older and young adults. AB - BACKGROUND: Many older adults have at least one chronic disease and experience greater health problems than young adults. However, little is known about factors other than health that account for health anxiety (HA) among older adults. The overall objective of the present study was to develop a better understanding of HA among older and young adults. METHODS: We examined how anxiety-related constructs (anxiety sensitivity, intolerance of uncertainty, anxiety control, and emotion regulation) predict two core components of HA described in the cognitive behavioral model of HA (illness likelihood and negative consequences) in older and young adults. We also examined the extent to which the predictor variables differentially account for HA in both age groups. Older and young adult participants completed several self-report surveys. RESULTS: Young adults reported higher levels of HA than older adults. Anxiety sensitivity and reappraisal predicted illness likelihood for older and young adults. Intolerance of uncertainty predicted negative consequences in both age groups. Anxiety sensitivity predicted negative consequences for older adults only. Anxiety control did not predict illness likelihood or negative consequences for either age group. CONCLUSIONS: Results suggest that anxiety sensitivity and intolerance of uncertainty may predispose older and young adults to HA, which is influenced by reappraisal. Implications for the cognitive-behavioral model of HA in both age groups are discussed. PMID- 22835266 TI - Standards for quality care in respiratory rehabilitation in patients with chronic pulmonary disease. Quality Healthcare Committee. Spanish Society of Pneumology and Thoracic Surgery (SEPAR). AB - Respiratory rehabilitation (RR) has been shown to be effective with a high level of evidence in terms of improving symptoms, exertion capacity and health-related quality of life (HRQL) in patients with COPD and in some patients with diseases other than COPD. According to international guidelines, RR is basically indicated in all patients with chronic respiratory symptoms, and the type of program offered depends on the symptoms themselves. As requested by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), we have created this document with the aim to unify the criteria for quality care in RR. The document is organized into sections: indications for RR, evaluation of candidates, program components, characteristics of RR programs and the role of the administration in the implementation of RR. In each section, we have distinguished 5 large disease groups: COPD, chronic respiratory diseases other than COPD with limiting dyspnea, hypersecretory diseases, neuromuscular diseases with respiratory symptoms and patients who are candidates for thoracic surgery for lung resection. PMID- 22835267 TI - Supplementation of Acqua Lete(r) (Bicarbonate Calcic Mineral Water) improves hydration status in athletes after short term anaerobic exercise. AB - BACKGROUND: Experimental studies suggest that mineral waters with high concentrations of calcium and bicarbonate can impact acid-base balance. The purpose of this study was to test the effect on acid-base balance and specific urine gravity, of a bicarbonate calcic mineral water (Acqua Lete(r)) compared to a minimally mineralized water. METHODS: 88 amateur male athletes underwent two experimental trials with a modified Wingate test: the first was carried out without hydration (Control Test, Test C, n = 88); the second was carried out after one week of controlled hydration (Test with hydration, Test H, n = 88), with 1.5 L/day of a very low mineral content water (Group A, n = 44) or 1.5 L/day of Acqua Lete(r) (Group B, n = 44). Measure of body temperature, bioimpedance analysis, muscular ultrasound, and urinalysis were taken before (t0), immediately after (t1), 5' (t2), and 30' (t3) after exercise. RESULTS: Hydration results in a decreased core temperature; muscular ultrasound showed increased muscle thickness after exercise related to content of body water. Regarding urinalysis, in test H, we found in both groups after exercise a significant decrease of specific urine gravity with significantly lower levels in Group B. We also found a significant increase of pH in the same Group B. CONCLUSIONS: In conclusion all the athletes hydrated with Acqua Lete(r) showed a positive impact on hydration status after anaerobic exercise with significant decrease of specific urine gravity and a positive effect on pH. PMID- 22835268 TI - Profiles of Malawian adolescents at risk for HIV infections: implications for targeted prevention, policy, and practices. AB - Young people are at the center of the HIV epidemic. In fact, HIV has been referred to as a "youth-driven disease" worldwide. This cross-sectional study identified a typology of risk for HIV among Malawian adolescents, examined the distribution of HIV status within each group in the typology, and tested the association between class membership and changes in sexual behaviors to avoid HIV. The sample was restricted to males and females between the ages of 15 and 18 from three regions in Malawi who reported never having been married. Latent Class Analysis was conducted to examine youth population clusters based on shared characteristics. A chi-squared test was used to test whether class membership was associated with changes in sexual behaviors to avoid HIV. The study results indicate that two classes of risk exist among Malawian youths in this sample: At High Risk class and At Risk class. Individuals in the At High Risk class were significantly more likely than the At Risk class to perceive themselves as currently infected with HIV. The At High Risk class was not significantly less likely than the At Risk class to report changes in their sexual behaviors to avoid HIV. Findings are discussed and recommendations are suggested for clinicians to consider the heterogeneity among Malawi adolescents and tailor services accordingly. We provide suggestions on potential interventions that target the specific needs for the two groups to mitigate the spread of HIV among adolescents in Malawi. PMID- 22835269 TI - Pericardial hematoma after blunt chest trauma. PMID- 22835270 TI - [Amniocentesis trainer: development of a cheap and reproducible new training model]. AB - Amniocentesis is the most common invasive procedure for prenatal diagnosis. It is essential to master this sampling technique prior to performing more complex ultrasound-guided interventions (cordocentesis, drain insertion). Training is a challenge because of the risks associated with the procedure, as well as the impact on the patient's anxiety. An amniocentesis simulator allows for safe training and repeats interventions, thus accelerating the learning curve, and also allows for periodic evaluation of proficiency. We present here a new, simple, and cost-effective amniotrainer model that reproduces real life conditions, using chicken breast and condoms filled with water. PMID- 22835271 TI - Fusarium graminearum Tri12p influences virulence to wheat and trichothecene accumulation. AB - The gene Tri12 encodes a predicted major facilitator superfamily protein suggested to play a role in export of trichothecene mycotoxins produced by Fusarium spp. It is unclear, however, how the Tri12 protein (Tri12p) may influence trichothecene sensitivity and virulence of the wheat pathogen Fusarium graminearum. In this study, we establish a role for Tri12 in toxin accumulation and sensitivity as well as in pathogenicity toward wheat. Tri12 deletion mutants (tri12) are reduced in virulence and result in decreased trichothecene accumulation when inoculated on wheat compared with the wild-type strain or an ectopic mutant. Reduced radial growth of tri12 mutants on trichothecene biosynthesis induction medium was observed relative to the wild type and the ectopic strains. Diminished trichothecene accumulation was observed in liquid medium cultures inoculated with tri12 mutants. Wild-type fungal cells grown under conditions that induce trichothecene biosynthesis develop distinct subapical swelling and form large vacuoles. A strain expressing Tri12p linked to green fluorescent protein shows localization of the protein consistent with the plasma membrane. Our results indicate Tri12 plays a role in self-protection and influences toxin production and virulence of the fungus in planta. PMID- 22835272 TI - A polyketide synthase gene, ACRTS2, is responsible for biosynthesis of host selective ACR-toxin in the rough lemon pathotype of Alternaria alternata. AB - The rough lemon pathotype of Alternaria alternata produces host-selective ACR toxin and causes Alternaria leaf spot disease of rough lemon (Citrus jambhiri). The structure of ACR-toxin I (MW = 496) consists of a polyketide with an alpha dihydropyrone ring in a 19-carbon polyalcohol. Genes responsible for toxin production were localized to a 1.5-Mb chromosome in the genome of the rough lemon pathotype. Sequence analysis of this chromosome revealed an 8,338-bp open reading frame, ACRTS2, that was present only in the genomes of ACR-toxin-producing isolates. ACRTS2 is predicted to encode a putative polyketide synthase of 2,513 amino acids and belongs to the fungal reducing type I polyketide synthases. Typical polyketide functional domains were identified in the predicted amino acid sequence, including beta-ketoacyl synthase, acyl transferase, methyl transferase, dehydratase, beta-ketoreductase, and phosphopantetheine attachment site domains. Combined use of homologous recombination-mediated gene disruption and RNA silencing allowed examination of the functional role of multiple paralogs in ACR toxin production. ACRTS2 was found to be essential for ACR-toxin production and pathogenicity of the rough lemon pathotype of A. alternata. PMID- 22835273 TI - Synergistic interaction of CLAVATA1, CLAVATA2, and RECEPTOR-LIKE PROTEIN KINASE 2 in cyst nematode parasitism of Arabidopsis. AB - Plant-parasitic cyst nematodes secrete CLAVATA3 (CLV3)/ENDOSPERM SURROUNDING REGION (CLE)-like effector proteins. These proteins act as ligand mimics of plant CLE peptides and are required for successful nematode infection. Previously, we showed that the CLV2/CORYNE (CRN) heterodimer receptor complex is required for nematode CLE signaling. However, there was only a partial reduction in nematode infection when this signaling was disrupted, indicating that there might be additional nematode CLE receptors. In this study, we demonstrate that CLV1 and RECEPTOR-LIKE PROTEIN KINASE 2/TOADSTOOL2 (RPK2), two additional receptors that can transmit the CLV3 signal independent of CLV2/CRN for shoot apical meristem maintenance, also play a role in nematode CLE perception. Localization studies showed that both receptors are expressed in nematode-induced syncytia. Infection assays with clv1 and rpk2 single mutants revealed a decrease in both nematode infection and syncytium size. Significantly, further reduction in nematode infection was observed when rpk2 was combined with clv1 and clv2 mutants. Taken together, our results indicate that parallel signaling pathways involving CLV1, CLV2, and RPK2 are important for nematode parasitism. PMID- 22835274 TI - Nitric oxide-mediated stress imprint in potato as an effect of exposure to a priming agent. AB - We investigated how potato exposed to a chemical agent could activate nitric oxide (NO)-dependent events facilitating more potent defense responses to a subsequent pathogen attack. Obtained data revealed that all applied inducers, i.e., beta-aminobutyric acid (BABA), gamma-aminobutyric acid (GABA), laminarin, or 2,6-dichloroisonicotinic acid (INA), were active stimuli in potentiating NO synthesis in the primed potato. It is assumed, for the mechanism proposed in this paper, that priming involves reversible S-nitrosylated protein (S-nitrosothiols [SNO]) storage as one of the short-term stress imprint components, apart from epigenetic changes sensitized by NO. Based on BABA- and GABA-induced events, it should be stated that a rise in NO generation and coding the NO message in SNO storage at a relatively low threshold together with histone H2B upregulation might create short-term imprint activation, facilitating acquisition of a competence to react faster after challenge inoculation. Laminarin elicited strong NO upregulation with an enhanced SNO pool-altered biochemical imprint in the form of less effective local recall, nevertheless being fully protective in distal responses against P. infestans. In turn, INA showed the most intensified NO generation and abundant formation of SNO, both after the inducer treatment and challenge inoculation abolishing potato resistance against the pathogen. Our results indicate, for the first time, that a precise control of synthesized NO in cooperation with reversible SNO storage and epigenetic modifications might play an important role in integrating and coordinating defense potato responses in the priming phenomenon. PMID- 22835275 TI - The Nicotiana benthamiana mitogen-activated protein kinase cascade and WRKY transcription factor participate in Nep1(Mo)-triggered plant responses. AB - Many bacterial, fungal, and oomycete species secrete necrosis and ethylene inducing peptide 1 (Nep1)-like proteins (NLP) that trigger programmed cell death (PCD) and innate immune responses in dicotyledonous plants. However, how NLP induce such immune responses is not understood. Here, we show that silencing of the MAPKKKalpha-MEK2-WIPK mitogen-activated protein kinase (MAPK) cascade through virus-induced gene silencing compromises hydrogen peroxide accumulation and PCD induced by Nep1(Mo) from Magnaporthe oryzae. WIPK interacts with NbWRKY2, a transcription factor in Nicotiana benthamiana, in vitro and in vivo, suggesting an effector pathway that mediates Nep1(Mo)-induced cell death. Unexpectedly, salicylic acid-induced protein kinase (SIPK)- and NbWRKY2-silenced plants showed impaired Nep1(Mo)-induced stomatal closure, decreased Nep1(Mo)-promoted nitric oxide (NO) production in guard cells, and a reduction in Nep1(Mo)-induced resistance against Phytophthora nicotianae. Expression studies by real-time polymerase chain reaction suggested that the MEK2-WIPK-NbWRKY2 pathway regulated Nep1(Mo)triggered NO accumulation could be partly dependent on nitrate reductase, which was implicated in NO synthesis. Taken together, these studies demonstrate that the MAPK cascade is involved in Nep1(Mo)-triggered plant responses and MAPK signaling associated with PCD exhibits shared and distinct components with that for stomatal closure. PMID- 22835276 TI - Oligogalacturonides: novel signaling molecules in Rhizobium-legume communications. AB - Oligogalacturonides are pectic fragments of the plant cell wall, whose signaling role has been described thus far during plant development and plant-pathogen interactions. In the present work, we evaluated the potential involvement of oligogalacturonides in the molecular communications between legumes and rhizobia during the establishment of nitrogen-fixing symbiosis. Oligogalacturonides with a degree of polymerization of 10 to 15 were found to trigger a rapid intracellular production of reactive oxygen species in Rhizobium leguminosarum bv. viciae 3841. Accumulation of H(2)O(2), detected by both 2',7'-dichlorodihydrofluorescein diacetate-based fluorescence and electron-dense deposits of cerium perhydroxides, was transient and did not affect bacterial cell viability, due to the prompt activation of the katG gene encoding a catalase. Calcium measurements carried out in R. leguminosarum transformed with the bioluminescent Ca(2+) reporter aequorin demonstrated the induction of a rapid and remarkable intracellular Ca(2+) increase in response to oligogalacturonides. When applied jointly with naringenin, oligogalacturonides effectively inhibited flavonoid-induced nod gene expression, indicating an antagonistic interplay between oligogalacturonides and inducing flavonoids in the early stages of plant root colonization. The above data suggest a novel role for oligogalacturonides as signaling molecules released in the rhizosphere in the initial rhizobium-legume interaction. PMID- 22835278 TI - Leydig cell hyperplasia and Leydig cell tumour in postmenopausal women: report of two cases. AB - Leydig cell hyperplasia and Leydig cell tumours of the ovary are rare. We present two cases in which patients had increased blood levels of testosterone and frank hirsutism. Imaging showed minimal abnormalities. After adrenal disease had been ruled out, they underwent a bilateral oophorectomy. One case showed a Leydig cell hyperplasia, the other a Leydig cell tumour. An androgen producing tumour should be excluded in every woman with evidence of hirsutism or frank virilization and markedly elevated testosterone levels. Adrenal disease with androgen hypersecretion can be suspected by detailed clinical, laboratory and radiologic imaging. Although DHEAS has a good sensitivity in the detection of adrenal origin of hyperandrogenism (and hence a good negative predictive value) it is not specific (specificity ranging from 85 to 98%). Imaging of the ovaries can be helpful but does not rule out ovarian disease if normal. Indeed, diffuse stromal Leydig cell hyperplasia and Leydig cell tumours (usually small) may escape imaging and in some cases diagnosis can only be made on pathology. As these clinical entities represent a diagnostic and therapeutic challenge, oophorectomy should be considered in postmenopausal women with hirsutism and elevated testosterone levels, after the exclusion of adrenal causes. The procedure is relatively safe and effective. Follow-up remains indicated. PMID- 22835277 TI - Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. AB - INTRODUCTION: Although the formation of neutrophil (PMN) extracellular traps (NETs) has been detected during infection and sepsis, their role in vivo is still unclear. This study was performed in order to evaluate the influence of NETs depletion by administration of recombinant human (rh)DNase on bacterial spreading, PMN tissue infiltration and inflammatory response in a mouse model of polymicrobial sepsis. METHODS: In a prospective controlled double-armed animal trial, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). After CLP, mice were treated with rhDNase or phosphate buffered saline, respectively. Survival, colony forming unit (CFU) counts in the peritoneal cavity, lung, liver and blood were determined. PMN and platelet counts, IL-6 and circulating free (cf)-DNA/NETs levels were monitored. PMN infiltration, as well as organ damage, was analyzed histologically in the lungs and liver. Capability and capacity of PMN to form NETs were determined over time. RESULTS: cf-DNA/NETs were found to be significantly increased 6, 24, and 48 hours after CLP when compared to the levels determined in sham and naive mice. Peak levels after 24 hours were correlated to enhanced capacity of bone marrow-derived PMN to form NETs after ex vivo stimulation with phorbol-12-myristate-13-acetate at the same time. rhDNase treatment of mice resulted in a significant reduction of cf DNA/NETs levels 24 hours after CLP (P < 0.001). Although overall survival was not affected by rhDNase treatment, median survival after 24 hours was significantly lower when compared with the CLP group (P < 0.01). In mice receiving rhDNase treatment, CFU counts in the lung (P < 0.001) and peritoneal cavity (P < 0.05), as well as serum IL-6 levels (P < 0.001), were found to be already increased six hours after CLP. Additionally, enhanced PMN infiltration and tissue damage in the lungs and liver were found after 24 hours. In contrast, CFU counts in mice without rhDNase treatment increased later but more strongly 24 hours after CLP (P < 0.001). Similarly, serum IL-6 levels peaked after 24 hours (P < 0.01). CONCLUSIONS: This study shows, for the first time, that depletion of NETs by rhDNase administration impedes the early immune response and aggravates the pathology that follows polymicrobial sepsis in vivo. PMID- 22835279 TI - Sample size: how many is enough? AB - Sample size is an element of research design that significantly affects the validity and clinical relevance of the findings identified in research studies. Factors that influence sample size include the effect size, or difference expected between groups or time points, the homogeneity of the study participants, the risk of error that investigators consider acceptable and the rate of participant attrition expected during the study. Appropriate planning in regard to each of these elements optimises the likelihood of finding an important result that is both clinically and statistically meaningful. PMID- 22835280 TI - Trauma care in Scotland: the importance of functional outcomes and quality of life. PMID- 22835281 TI - New insights into the genetics of immune responses in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a common autoimmune disease with a strong genetic component. Numerous aberrant immune responses have been described during the evolution of the disease. In later years, the appearance of anti-citrullinated protein antibodies (ACPAs) has become a hallmark for the diagnosis and prognosis of RA. The post-translational transformation of arginine residues of proteins and peptides into citrulline (citrullination) is a natural process in the body, but for unknown reasons autoreactivity towards citrullinated residues may develop in disposed individuals. ACPAs are often found years before clinical manifestations. ACPAs are present in about 70% of RA patients and constitute an important disease marker, distinguishing patient groups with different prognoses and different responses to various treatments. Inside the human leukocyte antigen (HLA) region, some HLA-DRB1 alleles are strongly associated with their production. Genome-wide association studies in large patient cohorts have defined a great number of single nucleotide polymorphisms (SNPs) outside of the HLA region that are associated with ACPA positive (ACPA+) RA. The SNPs are generally located close to or within genes involved in the immune response or signal transduction in immune cells. Some environmental factors such as tobacco smoking are also positively correlated with ACPA production. In this review, we will describe the genes and loci associated with ACPA+ RA or ACPA- RA and attempt to clarify their potential role in the development of the disease. PMID- 22835282 TI - Nomenclature for factors of the HLA system, update March 2012. PMID- 22835283 TI - Silica chloride catalyzed efficient route to novel 1-amidoalkyl-2-naphthylamines under sonic condition in water. AB - A one-pot three-component condensation of an aldehyde, 2-naphthylamine, and acetamide has been achieved by sonication at 35 kHz. The reaction is catalysed by silica chloride in aqueous medium. This protocol afforded corresponding 1 amidoalkyl-2-naphthylamines in shorter reaction durations, and in high yields. The method involves simple work-up procedure, and avoids use of hazardous reagents. PMID- 22835329 TI - High-throughput analysis using AmpFlSTR(r) Identifiler(r) with the Applied Biosystems 3500xl Genetic Analyser. AB - High throughput analysis of buccal scrape reference samples using the Identifiler system on the Applied Biosystems 3500xl Genetic Analyser is described. This platform is much more sensitive than previous platforms, e.g. 3130xl. The range of signal detection is also much greater and this means that the system is more tolerant to a wide range of input template concentrations. DNA quantity is not a limiting factor in the analysis of buccal scrapes, hence the entire analytical procedure (process) was designed around a target input of 1.5ng, to minimise low level DNA profiles and associated events of allele dropout. A universal stochastic threshold/limit of detection (LOD) of 300relative fluorescent units (rfu) was applied across all loci. This level is twice that of comparable systems such as SGM Plus analysed on 3130xl instruments. After analysis of dropout probabilities, heterozygous balance, drop-in and stutter characteristics, rule sets were programmed into the FSS i-cubed software. The process has a success rate >95%. No discordances or mis-designations occurred when applied to a validation set of more than 1000 samples. PMID- 22835331 TI - Perceived discrimination, social support, and perceived stress among people living with HIV/AIDS in China. AB - Perceived stress among people living with HIV/AIDS (PLWH) was associated with severe mental health problems and risk behaviors. Discrimination toward PLWH in China is prevalent. Both perceived discrimination and social supports are determinants of the stress level among PLWH. Psychological support services for PLWH in China are scarce. It is unknown whether social support is a buffer between the perceived discrimination and perceived stress. With written consent, this study surveyed 258 PLWH recruited from multiple sources in two cities in China. Instruments were validated in previous or the present study, including the perceived stress scale for PLWH (PSSHIV), the perceived social support scale (PSSS), and the perceived discrimination scale for PLWH (PDSHIV). Pearson correlations and multiple regression models were fit. PDSHIV was associated with the Overall Scale and all subscales of PSSHIV, whilst lower socioeconomic status in general and lower scores of PSSS were associated with various subscales of PSSHIV. The interaction item (PSSS*PSDHIV) was nonsignificant in modeling PSSHIV, hence no significant moderating effect was detected. Whilst perceived discrimination is a major source of stress and social support can reduce stress among PLWH in China, improved social support cannot buffer the stressful consequences due to perceived discrimination. The results highlight the importance to reduce discrimination toward PLWH and the difficulty to alleviate its negative consequences. It is warranted to improve mental health among PLWH in China and it is still important to foster social support among PLWH as it has direct effects on perceived stress. PMID- 22835332 TI - CSACI Position statement on the testing of food-specific IgG. PMID- 22835330 TI - The frontal-anatomic specificity of design fluency repetitions and their diagnostic relevance for behavioral variant frontotemporal dementia. AB - On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer's disease, semantic dementia, progressive supranuclear palsy, or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD. (JINS, 2012, 18, 1-11). PMID- 22835333 TI - Infertility and pregnancy loss in euthyroid women with thyroid autoimmunity. AB - Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 5 20% of women during the age of fertility. Prevalence of thyroid autoimmunity is significantly higher among infertile women, especially when the cause of infertility is endometriosis or polycystic ovary syndrome. Presence of thyroid autoimmunity does not interfere with normal embryo implantation and have been observed comparable pregnancy rates after assisted reproduction techniques in patients with or without thyroid autoimmunity. Instead, the risk of early miscarriage is substantially raised with the presence of thyroid autoimmunity, even if there was a condition of euthyroidism before pregnancy. Furthermore the controlled ovarian hyperstimulation, used as preparation for assisted reproduction techniques, can severely impair thyroid function increasing circulating estrogen levels. Systematic screening for thyroid disorders in women with a female cause of infertility is controversial but might be important to detect thyroid autoimmunity before to use assisted reproduction techniques and to follow-up these parameters in these patients after controlled ovarian hyperstimulation and during pregnancy. PMID- 22835334 TI - Replacement of charged and polar residues in the coiled-coiled interface of huntingtin-interacting protein 1 (HIP1) causes aggregation and cell death. AB - HIP1 crystal structures solved in our laboratory revealed abnormalities in the coiled-coil region, suggesting intrinsic plasticity. To test this, specific amino acids in the coiled-coil were mutated. The apparent thermal stability of HIP1 was altered when Thr528 and Glu531 were replaced by leucine, and was enhanced when Lys510 was also mutated. In cells, HIP1 mutant expression produced aggregation. MTS and flow cytometry indicate a correlation between aggregated HIP1 and enhanced cell death. These data support the idea that flexibility of the HIP1 coiled-coil domain is important for normal function and may lead to new insights into Huntington's disease. PMID- 22835335 TI - Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. AB - INTRODUCTION: Critically ill chronic obstructive pulmonary disease (COPD) patients are at particular risk of invasive pulmonary aspergillosis (IPA). Our aims were to determine whether bronchoalveolar lavage fluid (BALF) galactomannan (GM) has a higher sensitivity and specificity than serum GM or lower respiratory tract (LRT) sample culture. Furthermore, we aimed to investigate what the optimal cut-off value would be for BALF GM. METHODS: In this prospective single-center study, BALF and serum samples were collected from critically ill COPD patients on the first day of their intensive care unit admission. RESULTS: Of 50 critically ill COPD patients admitted, BALF and serum samples were collected in 34 patients. According to the receiver operating characteristics (ROC) curve, an optical density (OD) ratio of 0.8 was chosen as the cut-off value for GM in BALF. Compared to serum GM and LRT Aspergillus isolation, BALF GM yield a better sensitivity, specificity, positive and negative predictive values of 88.9%, 100%, 100% and 94.4%, respectively. Areas under the ROC curve were 0.912 (95%CI, 0.733 to 0.985) for BALF GM, and 0.879 (95%CI, 0.691 to 0.972) for serum GM results from the first day of ICU admission. Pairwise comparison of ROC curves showed P = 0.738. The OD ratio of BALF GM in IPA patients were significantly higher than those of non-IPA patients (2.88 +/- 2.09 versus 0.49 +/- 0.19, P = 0.009), and the OD ratio of BALF GM was significantly higher than serum GM in IPA patients (2.88 +/- 2.09 versus 0.87 +/- 0.47, P = 0.023). Positive BALF GM was seen earlier than LRT secretion culture (1 day versus 3.8 days). CONCLUSIONS: Compared to serum GM and LRT Aspergillus isolation, BALF GM seems to have a better sensitivity in the diagnosis of IPA in critically ill COPD patients. The ROC curve suggests a possible cut-off value of 0.8 for GM from BALF specimens in critically ill COPD patients. PMID- 22835336 TI - Major histocompatibility complex class I chain related gene-A microsatellite polymorphism shows secondary association with type 1 diabetes and celiac disease in North Indians. AB - Microsatellite polymorphism in exon 5 of major histocompatibility complex class I chain related gene-A (MIC-A) has been implicated in the etiology of autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD). In this study on North Indian population, the MIC-A5.1 allele, carrying a premature termination codon in transmembrane region, was observed with increased frequency in T1D (29.6%, odds ratio OR = 2.1, P = 0.00017) and CD patients (40.3%, OR = 3.37, P = 1.67E-05) than in controls (16.7%). When the MIC-A5.1 association was adjusted for linkage with human leukocyte antigen (HLA)-DR3, the statistical significance of the association was abolished. This implies that the observed association of MIC-A5.1 is due to its linkage disequilibrium (D' = 0.94) with HLA-B8-DR3-DQ2 haplotype and is secondary to the overall association with DR3 positive MHC haplotypes. PMID- 22835378 TI - Cyanamide-mediated Inhibition of N-acetyltransferase 1. AB - Cyanamide has been used for decades for medical intentions in the treatment of alcoholism and for agricultural purposes as a plant growth regulator and bud breaking agent. Its therapeutic effect is mediated by reversible inhibition of aldehyde dehydrogenase and it was reported to be metabolized in vivo mainly via coenzyme A dependent N-acetylation by N-acetyltransferases. Although described to be a substrate for N-acetyltransferases (NATs), cyanamide has a different molecular structure to arylamines and hydrazines, the preferred substrates for N acetyltransferases. Therefore, a more detailed investigation of its interrelations with N-acetyltransferases was performed. We analyzed the impact of cyanamide on NAT1 activities of human monocytes (monocytic THP-1 cells) using the classical substrate p-aminobenzoic acid. We found that a 24h treatment with physiologically relevant concentrations of cyanamide decreased the NAT1 activity significantly. Based on this observation we performed additional experiments using recombinant human NAT1 and NAT2 to achieve further insights. In detail a significant dose- and time-dependent inhibition of NAT1 activity was observed for 100 and 1000MUM cyanamide using recombinant human NAT1*4. However, cyanamide did not inhibit recombinant NAT2*4. Experiments testing cyanamide as substrate did not provide evidence that cyanamide is metabolized via coenzyme A dependent N acetylation in vitro by human NAT1 or NAT2, THP-1 or human liver cytosol. Therefore we can conclude that the observed enzyme inhibition (around 50% and 25% after treatment with 0.5 and 0.25mM CA, respectively) is not based on substrate dependent down-regulation of NAT1. Further mechanistic and kinetic studies indicated that cyanamide reacts with the active site cysteine residue of NAT1, leading to its rapid inhibition (significant inhibition after 30min and 2h for 1000 and 100MUM CA, respectively). Addition of the reduction agent dithiothreitol (DTT) did not modify the effect, indicating that oxidative processes that can be reversed by 5mM DTT are not likely involved in the inhibition. Taken together our results show that cyanamide is able to inhibit NAT1 most likely via interaction with the active site cysteine residue. Thereby cyanamide might modulate NAT1 dependent detoxification and activation of arylamines. PMID- 22835379 TI - Novel MEMS-based gas-cell/heating specimen holder provides advanced imaging capabilities for in situ reaction studies. AB - In prior research, specimen holders that employ a novel MEMS-based heating technology (AduroTM) provided by Protochips Inc. (Raleigh, NC, USA) have been shown to permit sub-Angstrom imaging at elevated temperatures up to 1,000 degrees C during in situ heating experiments in modern aberration-corrected electron microscopes. The Aduro heating devices permit precise control of temperature and have the unique feature of providing both heating and cooling rates of 106 degrees C/s. In the present work, we describe the recent development of a new specimen holder that incorporates the Aduro heating device into a "closed-cell" configuration, designed to function within the narrow (2 mm) objective lens pole piece gap of an aberration-corrected JEOL 2200FS STEM/TEM, and capable of exposing specimens to gases at pressures up to 1 atm. We show the early results of tests of this specimen holder demonstrating imaging at elevated temperatures and at pressures up to a full atmosphere, while retaining the atomic resolution performance of the microscope in high-angle annular dark-field and bright-field imaging modes. PMID- 22835380 TI - Full modeling versus summarizing gene-tree uncertainty: method choice and species tree accuracy. AB - With the proliferation of species-tree methods, empiricists now have to confront the daunting task of method choice. Such decisions might be made based on theoretical considerations alone. However, the messiness of real data means that theoretical ideals may not hold in practice (e.g., with convergence of complicated MCMC algorithms and computational times that limit analyses to small data sets). On the other hand, simplifying assumptions made by some approaches may compromise the accuracy of species-tree estimates. Here we examine the purported tradeoff between accuracy and computational simplicity for species-tree analysis, focusing on the different ways the approaches treat gene-tree uncertainty. By considering a diversity of species trees, as well as different sampling designs and total sampling efforts, we not only compare the accuracy of species-tree estimates across methods, but we also partition the variation in accuracy across factors to identify their relative importance. This analysis shows that although the method of analysis affects accuracy, other factors - namely, the history of species divergence and aspects of the sampling design - have a larger impact. Despite a full modeling of gene tree uncertainty (e.g., using a Bayesian framework), species-tree estimates may not be accurate, particularly for recent diversification histories. Nevertheless, we demonstrate how factors within the control of the empirical investigator (e.g., decisions about sampling) improve the accuracy of species tree estimates, and more so than the method of analysis. Lastly, with much of the attention on species-tree analyses focused on the discord among loci arising from the coalescent, this work also highlights a previously overlooked key determinant of species-tree accuracy for recent divergences - the level of genetic variation at a locus, which has important implications for improving species-tree estimates in practice. PMID- 22835381 TI - Genome and low-iron response of an oceanic diatom adapted to chronic iron limitation. AB - BACKGROUND: Biogeochemical elemental cycling is driven by primary production of biomass via phototrophic phytoplankton growth, with 40% of marine productivity being assigned to diatoms. Phytoplankton growth is widely limited by the availability of iron, an essential component of the photosynthetic apparatus. The oceanic diatom Thalassiosira oceanica shows a remarkable tolerance to low-iron conditions and was chosen as a model for deciphering the cellular response upon shortage of this essential micronutrient. RESULTS: The combined efforts in genomics, transcriptomics and proteomics reveal an unexpected metabolic flexibility in response to iron availability for T. oceanica CCMP1005. The complex response comprises cellular retrenchment as well as remodeling of bioenergetic pathways, where the abundance of iron-rich photosynthetic proteins is lowered, whereas iron-rich mitochondrial proteins are preserved. As a consequence of iron deprivation, the photosynthetic machinery undergoes a remodeling to adjust the light energy utilization with the overall decrease in photosynthetic electron transfer complexes. CONCLUSIONS: Beneficial adaptations to low-iron environments include strategies to lower the cellular iron requirements and to enhance iron uptake. A novel contribution enhancing iron economy of phototrophic growth is observed with the iron-regulated substitution of three metal-containing fructose-bisphosphate aldolases involved in metabolic conversion of carbohydrates for enzymes that do not contain metals. Further, our data identify candidate components of a high-affinity iron-uptake system, with several of the involved genes and domains originating from duplication events. A high genomic plasticity, as seen from the fraction of genes acquired through horizontal gene transfer, provides the platform for these complex adaptations to a low-iron world. PMID- 22835382 TI - Ludwig: the bioengineer. AB - On the basis of the strict exclusion of the vis vitalis, the demand was raised by Carl Ludwig, Helmholtz, Du Bois-Reymond, and Brucke for a physiology which was causal-analytical and physically and chemically experimental. If, out of these four investigators, we pick Ludwig as the actual founder of modern physiology, the grounds for this must be justified specifically. That modern physiology is not to be contemplated without the works of the three great students of Johannes Muller is explicitly emphasized. However, Carl Ludwig occupies a special position for physiology. PMID- 22835385 TI - Stereotactic radiosurgery: a "targeted" therapy for cancer. AB - The developments of medicine always follow innovations in science and technology. In the past decade, such innovations have made cancer-related targeted therapies possible. In general, the term "targeted therapy" has been used in reference to cellular and molecular level oriented therapies. However, improvements in the delivery and planning of traditional radiation therapy have also provided cancer patients more options for "targeted" treatment, notably stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). In this review, the progress and controversies of SRS and SBRT are discussed to show the role of stereotactic radiation therapy in the ever evolving multidisciplinary care of cancer patients. PMID- 22835384 TI - Id2 regulates the proliferation of squamous cell carcinoma in vitro via the NF kappaB/Cyclin D1 pathway. AB - Squamous cell carcinoma(SCC) is a significant cause of cancer morbidity and mortality worldwide, with an incidence of up to 166 cases per 100 000 population. It arises in the skin, upper aerodigestive tract, lung, and cervix and affects more than 200 000 Americans each year. We report here that a microarray experiment comparing 41 SCC and 13 normal tissue specimens showed that Id2, a gene that controls the cell cycle, was significantly up-regulated in SCC. Enforced expression of Id2 in vitro stimulated the proliferation of SCC cells and up-regulated the transcription of nuclear factor kappa B (NF-kappaB) and cyclin D1. Enhancement of the NF-kappaB activity with p65 significantly increased the cell proliferation and the transcription of cyclin D1, whereas inhibition of the NF-kappaB activity with I kappa B alpha mutant (IkappaBalphaM) and pyrroline dithiocarbamate (PDTC) abrogated cell proliferation and transcription of cyclin D1. Furthermore, a mutated NF-kappaB binding site in the cyclin D1 promoter fully abrogated the Id2-induced transcription of cyclin D1. Taken together, these data indicate that Id2 induces SCC tumor growth and proliferation through the NF kappaB/cyclin D1 pathway. PMID- 22835386 TI - Targeting autophagic pathways for cancer drug discovery. AB - Autophagy, an evolutionarily conserved lysosomal degradation process, has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy. PMID- 22835387 TI - Radiation-related risk of basal cell carcinoma: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in the United States. Ionizing radiation is an established risk factor in certain populations, including cancer survivors. We quantified the association between ionizing radiation dose and the risk of BCC in childhood cancer survivors. METHODS: Participants in the Childhood Cancer Survivor Study who reported a BCC (case subjects, n = 199) were matched on age and length of follow-up to three study participants who had not developed a BCC (control subjects, n = 597). The radiation-absorbed dose (in Gy) to the BCC location was calculated based on individual radiotherapy records using a custom-designed dosimetry program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and treatment factors, therapeutic radiation dose, and surrogate markers of sun sensitivity (skin and hair color) and the risk of BCC. A linear dose-response model was fitted to evaluate the excess odds ratio per Gy of radiation dose. RESULTS: Among case subjects, 83% developed BCC between the ages of 20 and 39 years. Radiation therapy, either alone or in combination with chemotherapy, was associated with an increased risk of BCC compared with no chemotherapy or radiation. The odds ratio for subjects who received 35 Gy or more to the skin site vs no radiation therapy was 39.8 (95% CI = 8.6 to 185). Results were consistent with a linear dose response relationship, with an excess odds ratio per Gy of 1.09 (95% CI = 0.49 to 2.64). No other treatment variables were statistically significantly associated with an increased risk of BCC. CONCLUSIONS: Radiation doses to the skin of more than 1 Gy are associated with an increased risk of BCC. PMID- 22835389 TI - J. Leonard Goldner Award 2011: changes in pain, function, and gait mechanics two years following total ankle arthroplasty performed with two modern fixed-bearing prostheses. AB - BACKGROUND: Total ankle replacement (TAR) continues to grow as an alternative to arthrodesis for patients who suffer from end-stage ankle arthritis. The purpose of this study was to examine changes in gait mechanics from before surgery to 1 and 2 years after surgery in patients who received a fixed-bearing TAR. METHODS: Fifty-one patients with a primary fixed-bearing TAR and no complications requiring further surgery were identified from a database and enrolled in this non-randomized study. Subjects were examined preoperatively, and at 1 and 2 years postoperatively. Three-dimensional joint mechanics and ground reaction forces (GRF) were collected during level walking. The Four Square Step Test, Timed Up and Go (TUG), VAS, and the AOFAS-Hindfoot score were assessed for each subject at each time point. RESULTS: TUG, VAS and AOFAS-Hindfoot score along with all measured kinetic parameters demonstrated significant improvements across all of the time points (p < 0.05). Four Square Step Test time was significantly improved between the preoperative and 2-year postoperative time point (p < 0.05). Measured ankle dorsiflexion angles did not demonstrate significant change between any time points. CONCLUSIONS: All of the observed changes suggest improved or maintained functioning in patients who received a TAR with the greatest improvement occurring within the first year. Sagittal plane ankle range of motion and dorsiflexion angle at heel strike were unchanged across all of the time points. The results of this study indicate that patients with end-stage osteoarthritis demonstrate improvements in pain and gait up to 2 years following surgery while maintaining ankle range of motion. PMID- 22835388 TI - Temporal trends in cause of death among Swedish and US men with prostate cancer. AB - BACKGROUND: A growing proportion of men diagnosed with localized prostate cancer detected through prostate-specific antigen testing are dying from causes other than prostate cancer. Temporal trends in specific causes of death among prostate cancer patients have not been well described. METHODS: We analyzed causes of death among all incident prostate cancer cases recorded in the nationwide Swedish Cancer Registry (1961-2008; n = 210 112) and in the US Surveillance, Epidemiology, and End Results Program (1973-2008; n = 490 341). We calculated the cumulative incidence of death due to seven selected causes that accounted for more than 80% of the reported deaths (including ischemic heart disease and non prostate cancer) and analyzed mortality trends by calendar year and age at diagnosis and length of follow-up. RESULTS: During follow-up through 2008, prostate cancer accounted for 52% of all reported deaths in Sweden and 30% of reported deaths in the United States among men with prostate cancer; however, only 35% of Swedish men and 16% of US men diagnosed with prostate cancer died from this disease. In both populations, the cumulative incidence of prostate cancer-specific death declined during follow-up, while the cumulative incidences of death from ischemic heart disease and non-prostate cancer remained constant. The 5-year cumulative incidence of death from prostate cancer among all men was 29% in Sweden and 11% in the United States. CONCLUSIONS: In Sweden and the United States, men diagnosed with prostate cancer are less likely to die from prostate cancer than from another cause. Because many of these other causes of death are preventable through changes in lifestyle, interventions that target lifestyle factors should be integrated into prostate cancer management. PMID- 22835390 TI - Prevalence of interdigital nerve enlargements in an asymptomatic population. AB - BACKGROUND: Morton's neuroma is a common primary diagnosis for referral to foot and ankle surgeons. On presentation, many patients have had an ultrasound reporting the presence of Morton's neuroma, which may not correlate with the clinical examination findings. The prevalence of such sonographic findings in the general population remains unknown. METHODS: In this observational prospective study, patients with asymptomatic forefeet who were seen by two foot and ankle surgeons for unrelated mid- or hind foot pathology were examined clinically and sonographically for the presence of interdigital nerve thickening. Forty-eight volunteers participated in the study (96 feet). For the purpose of this study, asymptomatic thickenings greater than 5 mm in diameter were termed sonographic neuromas. Ultrasound examination was performed by two specialist musculoskeletal radiologists. RESULTS: Fifty-four percent of the volunteers (26 of 48) had sonographic nerve thickening and in 17 cases (35.4%) enlarged nerves were found bilaterally. Differences for gender, original diagnosis or side of original pathology were not significant. Older subjects were more likely to have a sonographic neuroma (p = 0.018). Feet with a positive Mulder's click were more likely to have a sonographic neuroma (p = 0.015). CONCLUSION: Ultrasound, even in highly skilled hands, has a high rate of incidental finding of an asymptomatic interdigital nerve enlargement, which can lead to a false diagnosis of a Morton's neuroma. Sonographic evidence of Morton's neuroma per se is unreliable unless it is correlated with an equivocal clinical examination. Clinical examination is still the gold standard for the diagnosis of a Morton's neuroma. PMID- 22835392 TI - Early results after tibialis anterior tendon transfer for severe varus in total ankle replacement. AB - BACKGROUND: Treatment of severe ankle arthritis with varus malalignment remains controversial. METHODS: In 14 consecutive total ankle replacements (TAR) with tibiotalar varus malalignment of above 15 (range, 16 to 41) degrees, a complete transfer of the tibialis anterior tendon together with other soft-tissue and bony realignment measures was added to the primary procedure. RESULTS: After mean followup time of 33.4 (range, 21 to 49) months, only one case showed minor tibiotalar tilt in the frontal plane. The overall clinical results were good to excellent in all but two cases with an average AOFAS-score of 86.4 (range, 70 to 98) points. However, three cases of tibial nerve neuropathy due to entrapment or overtensioning were observed; one of these cases developed clinical problems with incomplete recovery. CONCLUSION: Tibialis anterior tendon transfer can be recommended in conjunction with TAR in cases of varus malalignment with severe muscular or ligamentous imbalance with neuropathy of the tibial nerve being the main complication. PMID- 22835391 TI - Axial load weightbearing radiography in determining lateral malleolus fracture stability: a cadaveric study. AB - BACKGROUND: Ankle fractures are the most common fracture treated by orthopaedic surgeons in the United States. Isolated lateral malleolus fractures are treated nonoperatively, while associated deltoid disruption injuries are unstable and usually treated by fixation of the fracture. Various stress radiographs and MRI have been used to determine deltoid competency and the subsequent need for operative stabilization of lateral malleolus fractures. To date, no standardization of stress radiography has been performed. The aim of this study was to evaluate the ability of weightbearing ankle X-rays to determine stability and their reliability. METHODS: This study sought to utilize simulated weightbearing radiography as a potential method to determine the need for lateral malleolus fixation. Twelve cadaveric ankle specimens were tested by obtaining ankle mortise radiographs for interpretation of medial clear space. Each ankle was tested with 0, 25, 36, and 50 kg of axially applied weight. The groups of measurements obtained were: intact ankles (Group A), ankles with an isolated oblique fibular osteotomy (Group B), and osteotomized ankles after complete deltoid ligament transaction (Group C). Three authors measured the medial clear space for every ankle using PACSR software. Instability of the ankle mortise was defined as medial clear space widening of greater than 2 mm from the intact ankle. RESULTS: An isolated lateral malleolus fracture (Group B) and a lateral malleolus fracture with an incompetent deltoid ligament (Group C) showed no statistical medial clear space widening with simulated axial weightbearing radiography when compared to intact ankles (Group A). ANOVA's between Group A and B had p < 0.001, and between Group A and C of p < 0.001. CONCLUSION: Our model did not find instability with an osteotomized fibula and a disrupted deltoid. CLINICAL RELEVANCE: This study suggests a weightbearing radiograph of an isolated lateral malleolus fracture cannot determine deltoid ligament integrity and thus need for fibular operative fixation. PMID- 22835393 TI - MOJE ceramic metatarsophalangeal arthroplasty: disappointing clinical results at two to eight years. AB - BACKGROUND: Among the surgical treatment options for osteoarthritis of the first metatarsophalangeal joint (MTPJ) are a number of different designs of total arthroplasty, including the MOJE, a ceramic press fit arthroplasty. We present a 2- to 8-year followup of 31 procedures. METHODS: Thirty-two MOJE arthroplasties were undertaken for painful hallux rigidus in 30 patients (nine male, 21 female) over 6 years (mean age 61.9; range, 37 to 76). At followup patients' symptoms, levels of function and radiographs were scored using SF-36, modified Kitaoka and AOFAS systems. Followup rate was 97%, with mean followup time 58 months (range, 28 to 97). RESULTS: Mean scores were: Kitaoka 53.8 (15 to 75), AOFAS 61.3/100 (range, 18 to 100), SF-36 physical combined 48.6 (27.6 to 58.7) SF-36 mental score 52.2 (19.5 to 62.2). Sixteen showed radiological evidence of component loosening (either lucency, subsidence or both) and one radiograph revealed component fracture. Eight implants have been revised. In patients who had not undergone subsequent fusion, 15 had less than 36 degrees of movement, nine had 36 to 45 degrees, four were in the 46 to 60 range, and only one had more than 60 degrees. There were no infections. CONCLUSION: Although previous studies have suggested favorable initial outcomes with the MOJE prosthesis, all have focused only on the early results. In our series, the reoperation rate of 26% at up to 8 years is worryingly high, especially given that 16 (52%) showed loosening. Although there appears to be a cohort of patients who have satisfactory outcomes with the MOJE, we would suggest the continued use of this implant. PMID- 22835394 TI - Lesser metatarsophalangeal instability: presentation, management, and outcomes. AB - BACKGROUND: Lesser metatarsophalangeal (MTP) instability is a common cause of forefoot pain. In this prospective study, we looked at its presentation, management and outcome. METHODS: We studied characteristics of patients presenting to a specialist foot and ankle clinic with lesser MTP instability. We used the drawer test to diagnose and stage instability. Patients were followed up in clinic or by telephone interview. RESULTS: We identified 154 patients with lesser MTP instability; 127 (82%) were female, median age was 56 years. One foot was affected in 107 patients (69%). The second toe only was affected in 99 patients (64%) and multiple toes in 52 (34%) but always involving the second toe if multiple toes involved. 150 toes (52%) had Grade 1 instability, 108 (37%) Grade 2 and 21 (7%) Grade 3 instability. Twelve toes (4%) presented dislocated. Ninety nine patients (64%) were treated nonoperatively, using functional taping, shoe modifications, and injections. Fifty five patients (36%) were treated operatively, including lesser toe straightening, flexor-extensor transfer, Weil and Stainsby procedures. At followup, the mean AOFAS score and standard deviation was 69 +/- 16.3 for the nonoperative group compared to 67 +/- 17.8 in the operative group. The mean pain score and standard deviation was 31 mm +/- 23.7 mm for the nonoperative group and 23 mm +/- 24.1 mm in the operative group. Thirty nine patients (52%) were either satisfied or very satisfied with treatment in the nonoperative group compared to 31 patients (66%) in the operative group. None of these differences were statistically significant. CONCLUSION: Painful MTP instability is a common cause of forefoot pain. Most patients can be treated nonoperatively. Operatively treated patients had no significant improvement in outcomes with regards to pain or function. PMID- 22835396 TI - Ultrasound-guided minimally invasive surgery for achilles tendon rupture: preliminary results. AB - BACKGROUND: Many surgeons prefer surgical repair for Achilles tendon ruptures in an attempt to reduce the risk of rerupture. To minimize wound complications, the use of minimally invasive surgery has become more popular recently. In line with this, the use of ultrasound to guide Achilles tendon repair is reported in this study. METHODS: From March 2005 to January 2008, 23 patients with Achilles tendon rupture were repaired by the same surgeon. The ages of the patients ranged from 19 to 67 years old, with an average of 43 years old. The repair of the Achilles tendon was achieved through a stab wound under the guidance of ultrasonography. A control group consisted of 25 patients who received traditional open Achilles tendon repair. RESULTS: The average operation time was 52 minutes, and the average wound size was 1.1 cm. The short leg cast was removed 4 weeks after the surgery, and serial casting was used for another 3 to 4 weeks. The postoperative AOFAS ankle-hindfoot scores were 98.7 in the experimental group, 96.5 in the control group with no significant difference. The rates of local infection, stiffness of the ankle, pain of the scar and sural nerve injury were better in the experimental group than in the control group with significant difference. CONCLUSIONS: Ultrasound-guided surgery was a good choice due to its availability and real-time soft tissue visualization. It can further minimize the size of the surgical wound. Our method has the potential to achieve reliable results. PMID- 22835395 TI - Nonoperative management of retrocalcaneal pain with AFO and stretching regimen. AB - BACKGROUND: Retrocalcaneal heel pain is caused by a spectrum of etiologies all resulting in the same symptom of pain at the tendon-Achilles insertion. Several studies have reported the outcomes of operative treatment, but none have reported the outcomes or success rates of nonoperative treatment. We describe a detailed treatment algorithm and report the clinical outcomes. METHODS: One hundred thirty five patients were prescribed a treatment regimen consisting of an AFO and stretching program and were enrolled in our prospective study. One hundred three patients completed pre- and post-treatment Foot Function Indices and were included in the analysis. The effect on FFI from clinical and radiographic factors was examined. RESULTS: Of the study population, 76% had a BMI greater than 25, 80% were older than 50 years, and 75% had an exostosis on radiographs. The mean pre-treatment FFI was 48.4 and the mean post-treatment FFI was 18.6 indicating a statistically significant improvement in function of 29.8. Neither BMI nor age had a significant effect on the magnitude of improvement; though, smokers had significantly less improvement. FFI improvement in patients with an exostosis were less than those without an exostosis. Patients with an exostosis less than 1 cm had less improvement than those with an exostosis of 1 cm or more. Patients with Types I and III exostoses had significantly less improvement in FFI compared to Types II and IV. Twelve of the 103 (11.6%) were not pleased with the results of nonoperative treatment and elected to have a procedure performed. CONCLUSION: Our study is the first to report the outcome of non operatively treated retrocalcaneal heel pain and to classify retrocalcaneal exostoses. Using our treatment algorithm, we had an 88% success rate in alleviating symptoms and avoiding surgery. Our data suggests that the use of an AFO and stretching regimen may benefit patients suffering from retrocalcaneal heel pain. PMID- 22835397 TI - Magnetic resonance imaging features of osteochondral lesions of the talus. AB - BACKGROUND: Osteochondral lesions of the talus (OLT) traditionally have been thought to occur anterolaterally or posteromedially. Recent studies utilizing magnetic resonance imaging (MRI) have questioned this teaching. The purpose of this study was to use MRI to describe the location, frequency, and morphology of OLT and determine if any correlations exist between lesion location and other data points. METHODS: The location, frequency, and size of OLT based on a nine zone grid were recorded on 77 MRI examinations. Lateral ligaments were inspected for evidence of injury. Stability of the lesions was assessed based on four MRI criteria: presence or absence of cartilage defects, edema-like signal abnormality, T2 bright rim, and/or subchondral cysts. Demographic data including patient age, injury mechanism, and chronicity were recorded. An ANOVA model was used to determine if statistical differences existed between lesion size and location. Pearson correlation coefficients were used to examine any association between lesion location and demographic data. RESULTS: Most of the lesions were located medially and centrally on the talar dome (54.5%), with the second highest frequency found laterally and centrally (31.2%). With the numbers available there was no statistical difference between the size of the lesions based on location. No strong correlations were found between lesion location and demographic data. CONCLUSION: This study refutes traditional teachings regarding the location of OLT and supports recent studies showing that most lesions are located medially and centrally on the talar dome. PMID- 22835398 TI - Fifth toe plantar plate repair in a professional soccer player: case report. PMID- 22835399 TI - Functional results of posterior tibial tendon reconstruction, calcaneal osteotomy, and gastrocnemius recession. AB - BACKGROUND: This study aimed to assess and provide prospective outcome data following reconstruction of Stage II posterior tibial tendon insufficiency, as well as evaluate the effect of reconstruction with gastrocnemius recession on plantarflexion strength. METHODS: A prospective evaluation of 24 patients undergoing reconstruction for Stage II posterior tibial tendon insufficiency was granted IRB approval. The reconstructive procedures consisted of a flexor digitorum longus transfer, medial displacement calcaneal osteotomy, lateral column lengthening, and gastrocnemius recession. Patients were asked to complete multiple outcome measures preoperatively, 6 months, 1 year, and 2 years postoperatively. A dynamometer was utilized to evaluate peak torque plantarflexion preoperatively, 6 months, and 1 year postoperatively. RESULTS: In the study, 14 patients completed preoperative surveys, and 23 patients had 2-year followup. Patients were highly satisfied with the results of their surgery. All outcome measures showed statistically significant improvement. Improvement was seen at 6 months, but results continued to improve at the 1-year mark. By the second year, improvement largely reached a plateau. Biodex testing showed no loss of plantarflexion strength after reconstruction and gastrocnemius recession. CONCLUSION: Reconstruction of the flexible adult acquired flatfoot with FDL transfer, double calcaneal osteotomy, and gastrocnemius recession yielded excellent functional results for the treatment of Stage II posterior tibial tendon insufficiency. Plantarflexion weakness was not found to be a concern. A good functional outcome can be anticipated after the early postoperative period. However, it should be expected to take at least 1 year for maximal benefit. PMID- 22835400 TI - Topical review: skin infections in the foot and ankle patient. AB - There are numerous cutaneous disorders that affect the foot, but of these conditions skin infections have the most significant impact on overall patient morbidity and clinical outcome. Skin infections in foot and ankle patients are common, with often devastating consequences if left unrecognized and untreated in both surgical and nonsurgical cases. There is a diverse array of infectious dermatoses that afflict the foot and ankle patient including tinea pedis, onychomycosis, paronychia, pitted keratolysis, verruca, folliculitis, and erysipelas. Prompt diagnosis, treatment, and surveillance of these common infectious conditions are critical in managing these dermatoses that can potentially progress to form deep abscesses and osteomyelitis. Infections can be managed with a combination of ventilated shoewear and synthetic substances to keep the feet dry, topical and oral antimicrobial agents, and patient education regarding preventative hygiene measures. The purpose of this review is to aid foot and ankle surgeons and other physicians in the diagnosis and treatment of infectious dermatoses affecting the foot. PMID- 22835401 TI - FootForum: roadblocks to medical advances. PMID- 22835402 TI - The brown marmorated stinkbug as a new aeroallergen. PMID- 22835403 TI - Food allergy-related quality of life after double-blind, placebo-controlled food challenges in adults, adolescents, and children. AB - BACKGROUND: Currently, the longitudinal validity (validity over time) and responsiveness (ability to measure change over time) of the Food Allergy Quality of Life Questionnaire-Adult Form (FAQLQ-AF), the Food Allergy Quality of Life Questionnaire-Teenager Form (FAQLQ-TF), and the Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF) are unknown. Additionally, the self-reported impact of a double-blind, placebo-controlled food challenge (DBPCFC) on health related quality of life (HRQL) in adults (>=18 years of age), adolescents (13-17 years of age), and children (8-12 years of age) is unknown. OBJECTIVE: The aims of this study were to assess the longitudinal validity and responsiveness of the FAQLQ-AF, FAQLQ-TF, and FAQLQ-CF and to assess the impact of a DBPCFC on HRQL. METHODS: Two hundred twenty-one participants suspected of food allergy were included from Dutch allergy centers. Participants undergoing a DBPCFC (experimental group) completed the FAQLQ and Food Allergy Independent Measure (FAIM) 1 month before (baseline) and 6 months after (follow-up) a DBPCFC. Participants not undergoing a DBPCFC (control group) completed the questionnaire package twice with a 7-month interval. RESULTS: HRQL scores improved after a DBPCFC, with greater improvements in HRQL scores after a negative outcome (food allergy ruled out) than a positive outcome (food allergy confirmed), demonstrating responsiveness of the FAQLQs. Significant correlations were shown between the change (follow-up minus baseline) in FAQLQ and FAIM scores supporting longitudinal validity of these questionnaires: FAQLQ-AF (Pearson correlation coefficient = 0.71, P < .001), FAQLQ-TF (Pearson correlation coefficient = 0.35, P = .018), and FAQLQ-CF (Pearson correlation coefficient = 0.51, P < .001). CONCLUSIONS: Our findings demonstrate the longitudinal validity and responsiveness of the FAQLQs. Greater improvements in HRQL scores were shown after a negative outcome than after a positive outcome. PMID- 22835404 TI - Food protein-induced enterocolitis syndrome can occur in adults. PMID- 22835405 TI - Re: Focused ultrasound to expel calculi from the kidney: A. Shah, J. D. Harper, B. W. Cunitz, Y. N. Wang, M. Paun, J. C. Simon, W. Lu, P. J. Kaczkowski and M. R. Bailey. J Urol 2012; 187: 739-743. PMID- 22835407 TI - Intravascular ultrasound analysis of plaque characteristics and postpercutaneous coronary intervention catheterization outcomes according to the remodeling pattern in narrowed saphenous vein grafts. AB - We assessed the plaque characteristics and postpercutaneous coronary intervention (PCI) outcome according to the remodeling pattern (positive remodeling [PR], n = 113; and intermediate/negative remodeling [IR/NR], n = 198) in 311 saphenous vein graft lesions using intravascular ultrasound. The remodeling index was the ratio of the lesion site saphenous vein graft area to the mean of the proximal and distal references (PR/remodeling index >1.05, IR 0.95 to 1.05, and NR <0.95). Tissue prolapse was defined as tissue extrusion through the stent strut after PCI, and the tissue prolapse volume was calculated by subtracting the lumen volume from the stent volume. The presence of hypoechoic plaque (59% vs 36%, p = 0.001), plaque rupture (26% vs 16%, p = 0.042), multiple plaque rupture (12% vs 5%, p = 0.020), and an intraluminal mass (59% vs 41%, p = 0.002) were more common in the PR lesions than in the IR/NR lesions. The plaque cavity area was significantly greater in the PR lesions than in the IR/NR lesions (0.83 +/- 1.43 mm(2) vs 0.42 +/- 1.07 mm(2), p = 0.009). Post-PCI no-reflow (19% vs 9%, p = 0.019) and post-PCI tissue prolapse (53% vs 27%, p <0.001) were observed more frequently, and the tissue prolapse volume was significantly greater after PCI for PR lesions than for IR/NR lesions (0.86 +/- 1.30 mm(3) vs 0.34 +/- 0.74 mm(3), p <0.001). PR was the independent predictor of post-PCI no-reflow (odds ratio 2.58, 95% confidence interval 1.25 to 5.64, p = 0.040) and post-PCI tissue prolapse (odds ratio 2.45, 95% confidence interval 1.46 to 5.41, p = 0.045). In conclusion, saphenous vein graft lesions with PR have vulnerable plaque and are associated with no-reflow and tissue prolapse after PCI. PMID- 22835408 TI - Determinants of prognostically relevant intracoronary electrocardiogram ST segment shift during coronary balloon occlusion. AB - The prognostic relevance of quantitative an intracoronary occlusive electrocardiographic (ECG) ST-segment shift and its determinants have not been investigated in humans. In 765 patients with chronic stable coronary artery disease, the following simultaneous quantitative measurements were obtained during a 1-minute coronary balloon occlusion: intracoronary ECG ST-segment shift (recorded by angioplasty guidewire), mean aortic pressure, mean distal coronary pressure, and mean central venous pressure (CVP). Collateral flow index (CFI) was calculated as follows: (mean distal coronary pressure minus CVP)/(mean aortic pressure minus CVP). During an average follow-up duration of 50 +/- 34 months, the cumulative mortality rate from all causes was significantly lower in the group with an ST-segment shift <0.1 mV (n = 89) than in the group with an ST segment shift >=0.1 mV (n = 676, p = 0.0211). Factors independently related to intracoronary occlusive ECG ST-segment shift <0.1 mV (r(2) = 0.189, p <0.0001) were high CFI (p <0.0001), intracoronary occlusive RR interval (p = 0.0467), right coronary artery as the ischemic region (p <0.0001), and absence of arterial hypertension (p = 0.0132). "High" CFI according to receiver operating characteristics analysis was >=0.217 (area under receiver operating characteristics curve 0.647, p <0.0001). In conclusion, absence of ECG ST-segment shift during brief coronary occlusion in patients with chronic coronary artery disease conveys a decreased mortality and is directly influenced by a well developed collateral supply to the right versus left coronary ischemic region and by the absence of systemic hypertension in a patient's history. PMID- 22835410 TI - Persistent angina pectoris, cardiac mortality and myocardial infarction during a 12 year follow-up in 273 variant angina patients without significant fixed coronary stenosis. AB - The incidence of cardiac events in patients with variant angina pectoris without significant coronary stenosis and ST-segment elevation was analyzed during a 12 year follow-up period in 273 consecutive patients (82% men) admitted from 1986 through 2010. Among the 252 patients who underwent electrocardiography during pain, 205 had ST-segment elevation (82%) and 45 had ST-segment depression (18%). During index hospitalization, angina occurred in 179 patients (66%), ventricular tachycardia or fibrillation in 28 (10%), and complete atrioventricular block in 3 (1%), but there were no deaths or myocardial infarctions (MIs). At 140 months, angina was still present in 129 patients (47%), but frequent angina (>10 episodes/year) occurred in only 6%. Total mortality, cardiac mortality, and MI rates were 24%, 7.0%, and 6%, respectively. Cardiac death or MI occurred in 28 patients (10%), associated with tobacco smoking (p = 0.004), antecedent "first wind" angina (p = 0.020), and angina during hospitalization (p = 0.044) and with continued smoking (p = 0.056) and recurrent angina during follow-up (p <0.001). Multivariate analysis identified age (p = 0.001), antecedent infarction (p = 0.005), first-wind angina (p = 0.009), and smoking at index hospitalization (p = 0.027) as predictors of total mortality and treatment with calcium antagonists (p = 0.047) and smoking during follow-up (p = 0.110) for cardiac mortality and MI. In conclusion, during 12-year follow-up, patients with variant angina pectoris, mostly with ST-segment elevation during pain, had a reduced incidence of cardiac mortality and MI, associated with first-wind angina, persistent angina, and continued smoking. PMID- 22835409 TI - Prevalence and characteristics of anergia (lack of energy) in patients with acute coronary syndrome. AB - Anergia, a commonly occurring syndrome in older adults and patients with cardiovascular diseases, is associated with functional and clinical limitations. To date, the prevalence and clinical-demographic characteristics of anergia in patients with acute coronary syndrome (ACS) have not been elucidated. We examined the prevalence and clinical-demographic characteristics of anergia in a multiethnic sample of patients with ACS. Hospitalized patients with ACS (n = 472), enrolled in the Prescription Usage, Lifestyle, and Stress Evaluation (PULSE) prospective cohort study, completed assessments of demographic, behavioral, and clinical characteristics within 7 days of hospitalization for an ACS event. Current depressive disorder was ascertained using a structured psychiatric interview 3 to 7 days after discharge. Anergia was assessed at baseline and defined using patients' binary responses (yes/no) to 7 items related to energy level. At least 1 complaint of anergia was reported by 79.9% of patients (n = 377) and 32% of patients (n = 153) met criteria for anergia. In a multivariable logistic regression model, anergia was independently associated with being a woman, being white (compared to black), having bodily pain, participating in exercise, having current depressive disorder, and having higher values on the Charlson Co-morbidity Index. In conclusion, anergia is a highly prevalent syndrome in patients with ACS. It is distinct from depression and is associated with modifiable clinical factors such as participation in exercise and bodily pain that may be appropriate targets for intervention. PMID- 22835411 TI - Meta-analysis of the effect of cardiac rehabilitation interventions on depression outcomes in adults 64 years of age and older. AB - Heart disease is a major cause of hospitalization and is associated with greater impairment than arthritis, diabetes mellitus, or lung disease. Depression is prevalent and a serious co-morbidity in heart disease with negative consequences including higher levels of chronic physical illness, decreased psychological well being, and increased health care costs. The objective of the study was to examine with meta-analysis the impact of community-based cardiac rehabilitation (CR) treatment on depression outcomes in older adults. Randomized controlled trials comparing patients (>=64 years old) receiving CR to cardiac controls were considered. Meta-analyses were based on 18 studies that met inclusion criteria, comprising 1,926 treatment participants and 1,901 controls. Effect sizes (ESs) ranged from -0.39 (in favor of control group) to 1.09 (in favor of treatment group). Mean weighted ES was 0.28, and 11 studies showed positive ESs. Meta analysis suggests that most CR programs delivered in the home can significantly mitigate depression symptoms. Tailored interventions combined with psychosocial interventions are likely to be more effective in decreasing depression in older adults with heart disease than usual care. PMID- 22835412 TI - Comparison of need for operative therapy in patients with mitral valve prolapse involving both leaflets versus posterior leaflet only. AB - Mitral valve prolapse may involve 1 leaflet or 2 leaflets, yet management guidelines do not differentiate posterior leaflet (PML) from bileaflet (BML) prolapse. We hypothesized that patients with BML have a prolonged natural history with more severe atrial and ventricular enlargement but less severe mitral regurgitation (MR) compared to patients with PML. Patients with mitral valve prolapse undergoing mitral repair were identified and preoperative characteristics were recorded. Patients with predominant PML prolapse (n = 304) versus BML prolapse (n = 131) were identified based on preoperative echocardiographic and intraoperative findings. Timing of operation was based on standard guidelines. Despite being equally symptomatic, patients with BML differed significantly from those with PML in being younger (54 vs 60 years, p <0.0001), more likely to be women (51% vs 24%, p <0.0001), and having a larger valve (37 vs 32 mm, p <0.0001). Despite similar cardiac function and dimensions, patients with BML had less severe MR (24% vs 13% with <4+ MR, p = 0.01) and less severe pulmonary hypertension (14% vs 31%, p <0.0001) at time of operation. In conclusion, patients with BML often meet indications for mitral valve repair with similar cardiac enlargement but less MR than patients with PML prolapse. Patients with BML prolapse may benefit from timing mitral repair based more on symptomatic 3+ MR or cardiac enlargement and less on presence of severe MR. PMID- 22835413 TI - Comparison of five-year outcome of sirolimus-eluting stent implantation for chronic total occlusions versus for non-chronic total occlusion (from the j Cypher registry). AB - The aim of this study was to evaluate the 5-year clinical outcomes of patients who underwent sirolimus-eluting stent implantation for chronic total occlusion (CTO). Among 10,759 patients treated exclusively with sirolimus-eluting stent in the j-Cypher registry, clinical outcomes were compared between 1,210 patients with revascularization for CTO and 9,549 patients with revascularization for non CTO only. The cumulative 5-year incidence of all-cause death (13.2% vs 14.3%, p = 0.56) and definite stent thrombosis (1.9% vs 1.6%, p = 0.76) was similar between the 2 groups. The adjusted risk for CTO relative to non-CTO for all-cause death and definite stent thrombosis was insignificant (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.81 to 1.16, and HR 0.99, 95% CI 0.6 to 1.65, respectively). The cumulative incidence of target lesion revascularization was significantly higher in the CTO group (20.7% vs 14.8%, p <0.001). The adjusted risk for target lesion revascularization was significant (HR 1.31, 95% CI 1.13 to 1.52, p <0.001). In the subgroup analysis, the risk for CTO for all-cause death tended to be lower in the subgroup of patients with left ventricular ejection fractions <=40% (HR 0.68, 95% CI 0.45 to 1.01, p = 0.053), while the risk was significantly higher in the subgroup of patients with end-stage renal disease without hemodialysis (HR 1.66, 95% CI 1.02 to 2.70, p = 0.04). In conclusion, sirolimus-eluting stent implantation for CTO appears to be as safe as that for non-CTO for up to 5 years, except for the modestly elevated risk for target lesion revascularization and the higher risk for all-cause death in patients with end-stage renal disease without hemodialysis. PMID- 22835414 TI - Relation of systemic and urinary neutrophil gelatinase-associated lipocalin levels to different aspects of impaired renal function in patients with acute decompensated heart failure. AB - Both urine and serum neutrophil gelatinase-associated lipocalin (NGAL) reflect active chronic kidney disease and predict acute kidney injury. However, a direct comparison of these markers in acute decompensated heart failure has not been performed. We prospectively evaluated 93 patients admitted with acute decompensated heart failure and treated with intravenous furosemide and measured both systemic (serum) and urine NGAL levels and their corresponding markers of estimated glomerular filtration rate, natriuresis (urine sodium), and diuretic response (net output, urine sodium/furosemide ratio). In our study cohort, the median urine and serum NGAL level was 34 ng/ml (interquartile range 24 to 86) and 252 ng/ml (interquartile range 175 to 350), respectively. The urine and serum NGAL levels correlated modestly (r = 0.37, p <0.001). Higher urine (but not systemic) NGAL correlated with the markers of impaired natriuresis and reduced diuresis (p <0.005 for all). In contrast, higher serum NGAL demonstrated a stronger relation with reduced glomerular filtration function (p <0.0001). Both markers predicted acute kidney injury (urine NGAL, odds ratio 1.7, p = 0.035; serum NGAL, odds ratio 1.9, p = 0.009). In conclusion, in patients with acute decompensated heart failure, urine NGAL levels reflect renal distal tubular injury with impaired natriuresis and diuresis, and systemic NGAL levels demonstrate a stronger association with glomerular filtration function. Both systemic and urine NGAL predict worsening renal function. PMID- 22835416 TI - Hypovitaminosis D and peripheral arterial disease: emerging link beyond cardiovascular risk factors. AB - Vitamin D has received increasing interest for its beneficial effect on health. Beyond its conventional role in bone metabolism, emerging evidence suggests a possible link between low vitamin D levels and cardiovascular disease (CVD), including peripheral arterial disease (PAD), and cardiovascular risk factors. Vitamin D interacts either directly with the vascular tree or indirectly through its association with cardiovascular risk factors, but the exact mechanism remains controversial. This review outlines the association between hypovitaminosis D and PAD. Both entities are quite prevalent in the general population and, therefore, their potential association might have important clinical implications. Whether vitamin D deficiency represents a novel risk factor for PAD/CVD, and whether vitamin D supplementation would reduce the burden of CVD still remains to be answered. Until then, vitamin D intake is not recommended for PAD/CVD prevention. Outdoor physical activity, coupled with adequate but safe sun exposure, is a healthy lifestyle practice suggested for the prevention of both PAD and hypovitaminosis D. PMID- 22835415 TI - Depressed mood and cause-specific mortality: a 40-year general community assessment. AB - PURPOSE: The current study describes how the excess mortality risk associated with depression translates into specific causes of death occurring during a 40 year follow-up period, with focus on deaths related to injuries, cardiovascular diseases, and cancer. METHODS: Data come from a cross-sectional survey (Community Mental Health Epidemiology Study) conducted in the early 1970s in Washington County, Maryland. Random sampling for the survey resulted in 2762 interviews. For the current analyses, baseline depressed mood was linked to current participant vital status through the use of death certificates. RESULTS: The relative subdistribution hazards for cardiovascular deaths (3.08 [1.74-5.45]) and fatal injuries (4.63 [1.76-12.18]) were significant during the entire 40-year period for young adults (18-39 years old at baseline). The relative subdistribution hazard for cardiovascular deaths during the first 15 years of follow-up was pronounced in elderly (>= 65 years) males (2.99 [1.67-5.37]) subjects. There were no significant associations between depressed mood and cancer deaths. CONCLUSIONS: Individuals in the general community with depressed mood may be at increased risk of deaths as the result of cardiovascular disease and injury, even several decades after exposure assessment. Young adults with depressed mood appear to be particularly vulnerable to these associations. PMID- 22835417 TI - In vitro failure and fracture resistance of veneered and full-contour zirconia restorations. AB - OBJECTIVES: This study evaluated the failure and fracture resistance of zirconia based fixed partial dentures (FPDs) under the influence of different surface treatments and adjustment procedures. METHODS: Seven groups (n=8/group) of three unit zirconia-based FPDs were fabricated in anatomic design (AD) or anatomically reduced design (ARD) and surfaces were prepared according to clinical relevance: #1: AD - sintered; #2: AD - sintered - glazed; #3: AD - sintered - sandblasted - glazed; #4: AD - sintered - polished - grinded (contact points adjusted); #5: AD sintered - polished - grinded - repolished; #6: ARD - sintered - veneered; #7: control: analogous to #3 but without thermal cycling (TC) and mechanical loading (ML). FPDs were adhesively bonded to polymethylmethacrylate abutment teeth. TCML (TC: 6000 * 5 degrees /55 degrees ; ML: 1.2 * 10(6)* 50 N, 1.6 Hz) was conducted in a chewing simulator with steatite spheres as antagonists. Failures were monitored and fracture resistance was determined after ageing. Data were analysed statistically with Mann-Whitney U-test (Kolmogorov-Smirnov-test; alpha=0.05). FPDs were subjected to scanning electron microscopy for fractographic failure analysis. RESULTS: None of the FPDs failed during TCML, but showed wear at contact points. Median fracture force ranged between 1173.5 N (#4) and 1316.0 N (#3) without significant (p=0.910) differences between the groups or in comparison to the control (p>0.462). CONCLUSIONS: Zirconia restorations showed high resistance to failures and fracture under different surface treatment variations. Full-contour polished or glazed zirconia FPDs might be an alternative to common veneered restorations. PMID- 22835418 TI - Simplistic approach to prognosis after cardiopulmonary resuscitation-value of pH and lactate. AB - PURPOSE: The purpose was to determine the prognostic value of broadly available clinical parameters such as pH and lactate for early stratification of outcome after cardiopulmonary resuscitation. METHODS: We analyzed patients with status postresuscitation who were admitted to the Frankfurt University hospital. Arterial pH and serum lactate levels were dichotomized as "high" or "low." Primary end point was a combination of death or severe hypoxic brain damage within 30 days. RESULTS: In total, 67% of 206 patients (66 +/- 12 years) reached the primary end point. Univariate analysis showed that age more than 65 years (hazard ratio [HR] 1.7; 95% confidence interval (CI), 1.2-2.4), high lactate (>6.94 mmol/L [62.5 mg/dL)]; HR 2.8; 95% CI 2.0-3.9), and low pH (<7.21; HR 2.7; 95% CI 1.9-3.8) on admission were associated with the end point. Upon multivariate analysis, age more than 65 years, high lactate, and low pH on admission remained as independent predictors. Specificity and sensitivity to detect patients with an end point were 0.51 and 1.0 for the combination of low pH, high lactate, and age more than 65 years (negative predictive value, 1.0). CONCLUSION: A combination of clinical data and broadly available parameters can help to stratify prognosis of patients after cardiopulmonary resuscitation with sufficiently high predictive value. Interestingly, a combination of the 3 parameters-age more than 65 years, high lactate, and low pH upon admission-had a sensitivity of 1.0 for a poor outcome after return of spontaneous circulation. PMID- 22835419 TI - Improved aneurysmal subarachnoid hemorrhage outcomes: a comparison of 2 decades at an academic center. AB - OBJECTIVE: Management of aneurysmal subarachnoid hemorrhage (aSAH) has evolved over the past 2 decades, including refinement of neurosurgical techniques, availability of endovascular options, and evolution of neurocritical care; their impact on SAH outcomes is unclear. DESIGN/METHODS: Prospectively collected data of patients with aSAH admitted to Johns Hopkins Medical Institutions between 1991 and 2009 were analyzed. We compared survival to discharge and functional outcomes at initial clinic appointment postdischarge (30-120 days) in patients admitted between 1991 and 2000 (phase 1 [P1]) and 2000 and 2009 (phase 2 [P2]), respectively, using dichotomized Glasgow Outcome Scale (good outcome: Glasgow Outcome Scale 4-5). RESULTS: A total of 1134 consecutive patients with aSAH were included in the analysis (P1 46.4%, P2 53.6%). There were higher rates of poor grade Hunt and Hess (P1 23%, P2 28%; P < .05), admission Glasgow Coma Scale score lower than 8 (P1 14%, P2 21%; P < .005), known medical comorbidites (P1 54%, P2 64%; P = .005), associated intraventricular hemorrhage (P1 47%, P2 55%; P < .05), and older population (P1 51.5%, P2 53.5%; P < .05) in P2. Good outcomes were more common in P2 (71.5%) compared with P1 (65.2%), with 2-fold adjusted odds of good outcomes after correction for various confounding factors (P < .001). CONCLUSIONS: Our institutional experience over 2 decades confirms that patients with aSAH have shown significant outcome improvements over time. PMID- 22835420 TI - Medication issues experienced by patients and carers after discharge from the intensive care unit. AB - PURPOSE: Medication-related problems (MRPs) frequently occur at the interfaces of care settings. We examined this further because little has been published about MRPs experienced by patients/carers after discharge from the intensive care unit (ICU). METHODS AND MATERIALS: Medication history data were collected before, during, and after ICU admission and by face-to-face semistructured interviews with 21 patients and 13 carers attending the ICU Follow-up Clinic (FC) of our 35 bed adult ICU. RESULTS: A total of 122 drugs were prescribed regularly before ICU admission, 168 on ICU discharge, 132 at hospital discharge, and 128 at the FC. Medication-related problems were identified with hypnotics/anxiolytics, antidepressants, proton pump inhibitors, and analgesics. Good follow-up was observed in all 4 cases where the antidysrhythmic agent amiodarone was initiated on ICU. Patients/carers described 20 cases of difficulty in obtaining appropriate and timely supplies and 19 of insufficient information. CONCLUSIONS: These results show that our incidence of MRPs after ICU discharge was encouragingly infrequent, in which we attribute it to targeted medicine reconciliation and the availability of our FC. However, MRPs were perceived to stem from inadequate communication at the interfaces of care and the lack of opportunity for patients/carers to obtain relevant information. We recommend that FC should focus on MRPs during their consultation and that further research in this area should be performed to examine our observations further. PMID- 22835421 TI - Parental satisfaction, involvement, and presence after pediatric intensive care unit admission. AB - PURPOSE: To describe satisfaction, involvement, presence, and preferences of parents following their child's admission to an intensive care unit (ICU). METHODS: A survey, administered 1 month after their child's ICU admission, described perceptions of parental satisfaction with their interaction with healthcare providers, their presence during resuscitation, involvement in treatment decision-making, and preferences if events were to be re-enacted. RESULTS: One hundred three parents of 91 patients were enrolled; 64 primary parents (70%) completed the survey at 1 month. The mean (SD) satisfaction rating was 87.6 (+/-14.8) and involvement rating was 70.2 (+/-34.4) on a scale from 0 (not satisfied/involved) to 100 (completely satisfied/involved). There were no differences in satisfaction (P = .46), involvement (P = .69) and change in preferences (P = .97) between parents who were present and not present. After adjusting for child's baseline illness, receipt of more ICU therapies was associated with worse parental satisfaction (P = .03). Twenty-four (38%) parents reported that if events were repeated, they would have changed their preferences. CONCLUSIONS: Overall, parental satisfaction ratings were high, lower in parents of children receiving more ICU therapies, and not associated with presence during resuscitation. These data contrast the American Heart Association's recommendation and suggestion of benefit from parental presence during periods of intensive therapies. PMID- 22835422 TI - Expression of acute-phase cytokines, surfactant proteins, and epithelial apoptosis in small airways of human acute respiratory distress syndrome. AB - PURPOSE: Recent studies suggest a role for distal airway injury in acute respiratory distress syndrome (ARDS). The epithelium lining the small airways secretes a large number of molecules such as surfactant components and inflammatory mediators. There is little information on how these small airway secretory functions are altered in ARDS. MATERIALS AND METHODS: We studied the lungs of 31 patients with ARDS (Pao(2)/fraction of inspired oxygen <=200, 45 +/- 14 years, 16 men) and 11 controls (52 +/- 16 years, 7 men) submitted to autopsy and quantified the expression of interleukin (IL) 6, IL-8, surfactant proteins (SP) A and SP-B in the epithelium of small airways using immunohistochemistry and image analysis. In addition, an index of airway epithelial apoptosis was determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase nick-end labeling assay, caspase 3, and Fas/Fas ligand expression. The density of inflammatory cells expressing IL-6 and IL-8 within the small airway walls was also quantified. RESULTS: Acute respiratory distress syndrome airways showed an increase in the epithelial expression of IL-8 (P = .006) and an increased density of inflammatory cells expressing IL-6 (P = .004) and IL-8 (P < .001) compared with controls. There were no differences in SP-A and SP-B epithelium expression or in epithelial apoptosis index between ARDS and controls. CONCLUSION: Distal airways are involved in ARDS lung inflammation and show a high expression of proinflammatory interleukins in both airway epithelial and inflammatory cells. Apoptosis may not be a major mechanism of airway epithelial cell death in ARDS. PMID- 22835423 TI - Energy expenditure in patients with severe head injury: controlled normothermia with sedation and neuromuscular blockade. AB - OBJECTIVES: Providing optimal caloric intake is important for patients with severe traumatic brain injury. Insufficient nutrition worsens prognosis, and excessive nutrition may lead to complications such as weaning delay from mechanical ventilation. However, using controlled normothermia with sedation and neuromuscular blockade for patients with anticipated severe brain edema, the optimal caloric intake is still unclear. METHODS: Ten patients with severe traumatic brain injury were studied. All patients received midazolam and vecuronium or pancuronium to control body temperature to 36.0 degrees C. Energy expenditure was measured using indirect calorimetry. Age, body height, body weight, heart rate, blood pressure, body temperature, and minute ventilation volume were evaluated at the time of the study. Differences between the mean measured energy expenditures (MEEs) and predicted basal energy expenditures (PEEs from the Harris-Benedict equation) were analyzed using paired t test. Furthermore, the relationships between these variables and MEEs were analyzed with multiple regression analysis. RESULTS: The result of MEE was 1279+/-244 kcal/d. When compared with PEE, MEE/PEE was 87.2% +/- 10%. Multiple regression analysis showed that age, body height, body weight, heart rate, and minute ventilation volume were related with MEE. CONCLUSIONS: Energy expenditure in patients with severe traumatic brain injury who need mechanical ventilation and have received controlled normothermia with sedation and neuromuscular blockade was 13% less than predicted basal levels. Energy expenditure might be obtained from age, body height, body weight, heart rate, and minute ventilation. PMID- 22835424 TI - Classification of dermatological disorders in critical care patients: a prospective observational study. AB - PURPOSE: The objective of this study was to identify dermatological disorders detected in the intensive care unit (ICU), to analyze their specific characteristics, and to define a useful classification for intensive care physicians. MATERIALS AND METHODS: This was a prospective, observational study over a 3-year period (2006-2009) in a mixed ICU. This included all patients presenting with dermatological disorders that were detected at the time of ICU admission or developed along the ICU stay. We recorded the specific characteristics of the disorders and its evolution and treatment, which enabled us to classify the different observed conditions. As general variables, we analyzed demographic factors, the principal diagnosis, ICU procedures, the severity score (Acute Physiology and Chronic Health Evaluation II), length of stay, and mortality. RESULTS: One hundred thirty-three patients showed at least one dermatological disorder (9.3%) and were classified into (1) preexisting dermatological disorders, (2) life-threatening dermatologic disorders, (3) systemic dermatological disorders, (4) infectious dermatological disorders, (5) reactive dermatological disorders, and (6) others. CONCLUSIONS: Dermatological disorders are a frequent problem in the ICU, and their recognition is key to set up an appropriate care plan. We propose a classification and description of the different types of dermatological disorders that are most commonly found in ICUs. PMID- 22835425 TI - Allogeneic peripheral blood stem cell transplantation significantly increases risk of chronic graft-versus-host disease of lung compared with bone marrow transplantation. AB - The risk factors for lung chronic graft-versus-host disease (cGVHD) are not fully elucidated. We attempted to identify clinical risk factors for lung cGVHD after allogeneic hematopoietic cell transplantation (HCT). A total of 401 patients who underwent allogeneic HCT between 2000 and 2007 at Princess Margaret Hospital, Toronto, Canada, were evaluated for lung cGVHD serially starting on day 120 and then annually therafter. The stem cell source for HCT was peripheral blood stem cells (PBSCs) in 280 patients (69.8%) and bone marrow (BM) in 121 patients (30.2%). With a median follow-up of 36.8 months, 68 patients (17%) had a diagnosis of lung cGVHD, with a median time of onset of 11.4 months after HCT. Stem cell source was the sole risk factor identified in univariate analyses. The incidence of lung cGVHD was significantly higher in the patients receiving PBSCs (14.2% at 1 year and 22.7% at 2 years) compared with those receiving BM (6.8 at 1 year and 14.9% at 2 years; hazard ratio, 1.937; P = .02). Multivariate analyses also confirmed the use of PBSCs as an independent risk factor for lung cGVHD (hazard ratio, 2.408; 95% confidence interval, 1.289-4.496; P = .0058). The use of PBSCs is associated with an increased risk of lung cGVHD compared with the use of BM for allogeneic HCT. PMID- 22835426 TI - Kaempferol regulates MAPKs and NF-kappaB signaling pathways to attenuate LPS induced acute lung injury in mice. AB - Recent studies show that mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) signaling pathways are two pivotal roles contributing to the development of lipopolysaccharide (LPS)-induced acute lung injury (ALI). The present study aimed to investigate the protective effect of kaempferol (Kae), a naturally occurring flavonoid compound, on ALI and explore its possible mechanisms. Male BALB/c mice with ALI, induced by intranasal instillation of LPS, were treated or not with Kae (100 mg/kg, intragastrically) 1h prior to LPS exposure. Kae treatment attenuated pulmonary edema of mice with ALI after LPS challenge, as it markedly decreased the lung W/D ratio of lung samples, protein concentration and the amounts of inflammatory cells in BALF. Similarly, LPS mediated overproduction of proinflammatory cytokines in BALF, including TNF alpha, IL-1beta and IL-6, was strongly reduced by Kae. Histological studies demonstrated that Kae substantially inhibited LPS-induced alveolar wall thickness, alveolar hemorrhage and leukocytes infiltration in lung tissue with evidence of reduced myeloperoxidase (MPO) activity. Kae also efficiently increased superoxide dismutase (SOD) activity of lung sample when compared with LPS group, which was obviously reduced by LPS administration. In addition, Western blot analysis indicated that the activation of MAPKs and NF-kappaB signaling pathways stimulated by LPS was significantly blocked by Kae. Taken together, our results suggest that Kae exhibits a protective effect on LPS induced ALI via suppression of MAPKs and NF-kappaB signaling pathways, which may involve the inhibition of tissue oxidative injury and pulmonary inflammatory process. PMID- 22835427 TI - Humoral and cell-mediated immunity following vaccination with synthetic Candida cell wall mannan derived heptamannoside-protein conjugate: immunomodulatory properties of heptamannoside-BSA conjugate. AB - Chemically defined glycoprotein conjugate composed of synthetically prepared mannan-derived heptamannoside with terminal beta-1,2-linked mannose residue attached to the alpha-1,3-linked mannose residues and BSA as carrier protein (M7 BSA conjugate) was analysed for the capacity to induce protective humoral immunity and appropriate alteration cellular immunity. To identify protective antigenic structure of Candida cell wall mannan M7-BSA conjugate was used for BALB/c mice immunization. The obtained results were compared with placebo group and with heat-inactivated C. albicans whole cells immunization. The administration route of M7-BSA conjugate secondary booster injection significantly affected the intensity of humoral immune response and the specificity of produced antibodies. All prepared sera were able to elevate candidacidal activity of polymorphonuclear leukocytes (PMN) in cooperation with complement. Moreover, polyclonal sera obtained after secondary subcutaneous (s.c.) booster injection of M7-BSA conjugate were able to induce candidacidal activity of PMN also in complement independent manner. M7-BSA conjugate immunization induced increases of phagocytic activity and respiratory burst of granulocytes, caused a raise of the proportion of CD3(+) T lymphocytes and increased the CD4(+)/CD8(+) T lymphocyte ratio. We observed also an increasing proportion of CD4(+)CD25(+) T cells compared to immunization with heat inactivated whole C. albicans cells, which in turn promoted an increase of the CD8(+)CD25(+) cell proportion. Immunization with M7-BSA conjugate induced Th1, Th2 and Th17 immune responses as indicated by the elevation of relevant cytokines levels. These data provide some insights on the immunomodulatory properties of oligomannosides and contribute to the development of synthetic oligosaccharide vaccines against fungal diseases. PMID- 22835428 TI - Paeoniflorin inhibits function and down-regulates HLA-DR and CD80 expression of human peripheral blood monocytes stimulated by rhIL-1beta. AB - Paeoniflorin has been demonstrated to exert anti-inflammatory and immunomodulatory effects in the animal study. The purpose of the present study was to investigate the effect of paeoniflorin on the recombinant human interleukin-1beta (rhIL-1beta)-stimulated monocytes from the peripheral blood of healthy adults in vitro. Monocytes, collected from the peripheral blood of healthy adults by the Ficoll density gradient centrifugation, were co-cultured with rhIL-1beta to imitate inflammatory circumstance in vitro. After exposure of rhIL-1beta (0.01, 0.1, 1, 10 MUg.l(-1)) for 24h or rhIL-1beta (1 MUg.l(-1)) for different time periods (3, 6, 12, 24h), we observed that the phagocytic function and the production of TNF-alpha and PGE(2) with monocytes were promoted significantly by rhIL-1beta. MTT assay demonstrated that paeoniflorin (concentrations ranged from 10(-4)mol.l(-1) to 10(-9)mol.l(-1)) showed low cytotoxicity with rhIL-1beta-stimulated monocytes. Paeoniflorin (10(-9), 10(-8), 10(-7), 10(-6), 10(-5)mol.l(-1)) significantly suppressed phagocytic function of rhIL-1beta-induced monocytes (P<0.05), and decreased the levels of TNF-alpha and PGE(2) production in a concentration-dependent manner (r=-0.820 and r=-0.836, respectively). The flow cytometry analysis showed that the stimulation of rhIL 1beta significantly increased the mean fluorescence rates of HLA-DR in a time dependent manner (r=0.977). Administration of paeoniflorin (10(-9), 10(-8), 10( 7), 10(-6), 10(-5)mol.l(-1)) significantly inhibited the mean fluorescence rates of HLA-DR and CD80 with rhIL-1beta-stimulated monocytes (P<0.05). These results indicated that paeoniflorin might inhibit activation of human peripheral blood monocytes stimulated by rhIL-1beta, suppress function of monocytes, and down regulate expression of HLA-DR and CD80, suggesting that paeoniflorin might alleviate the chronic inflammation by inhibiting human monocytes. PMID- 22835429 TI - Altered let-7 expression in Myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells. AB - Myasthenia gravis (MG) is a T cell-dependent and B cell-mediated autoimmune disease of neuromuscular junctions and cytokines may play a crucial role in the pathogenesis and perpetuation of MG. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states. In this study, miRNA microarrays identified let-7 family to be decreased in peripheral blood mononuclear cells (PBMCs) from MG patients compared to the healthy controls. We next demonstrated the differential expression of let-7 family in larger samples by quantitative real-time PCR. Using a combination of bioinformatics and molecular approaches, we confirmed IL-10 as a target for let-7c. IL-10 expression also showed a negative correlation with let 7c expression in PBMCs from MG patients. Further experiments revealed that induced levels of IL-10 were inversely related to let-7c levels. We also showed that let-7c could regulate IL-10 expression in Jurkat cells. In summary, our results suggest that abnormal expression/regulation of microRNAs may contribute to or be indicative of the initiation and progression of MG. PMID- 22835431 TI - Do the basal ganglia inhibit seizure activity in temporal lobe epilepsy? AB - There is substantial evidence in the literature that the basal ganglia (BG), namely the striatum and pallidum, are involved in temporal lobe epilepsy (TLE). The BG are probably not involved in elaborating clinical seizures, as they do not produce specific epileptiform activity and there is no evident change in the electrical activity in the BG immediately after seizure onset. The data we obtained by direct ictal recording in the BG [1,2], as well as a large body of experimental and clinical evidence reported by other groups, suggest an inhibitory role of the BG during temporal lobe seizures. The BG may have a remote influence on cortical oscillatory processes related to control of epileptic seizures via their feedback pathways to the cortex. PMID- 22835430 TI - Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis. AB - Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of epileptogenesis. However, the mechanisms underlying the protective effects of P against epileptogenesis remain unclear. In this study, we investigated the role of P derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5alpha-reductase converts P to allopregnanolone and related neurosteroids that retard epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of epileptogenesis and investigated the effect of finasteride, a 5alpha-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic epileptogenesis and temporal lobe epilepsy. PMID- 22835432 TI - Development and evaluation of a multiplex screening assay for Plasmodium falciparum exposure. AB - Transfusion transmitted malaria (TTM) in non-endemic countries is reduced by questioning blood donors and screening of donated blood. Conventional screening is performed by Indirect Fluorescence Antibody Test (IFAT). This method is manual and difficult to standardize. Here we study the diagnostic performance of a multiplex assay for detection of antibodies against Plasmodium falciparum in donor blood using IFAT as a comparator. A multiplex assay (MPA) containing the antigens GLURP-R0, GLURP-R2, MSP3, MSP1 hybrid and AMA1 was constructed using xMAP(r) technology. A discrimination index for exposure to P. falciparum malaria was calculated by comparing travelers with clinical malaria (n=52) and non exposed blood donors (n=119). The index was evaluated on blood donors with suspected malaria exposure (n=249) and compared to the diagnostic performance of IFAT. At a specificity of 95.8 %, the MPA discrimination index exhibited a diagnostic sensitivity of 90.4 % in travelers hospitalized with malaria. Percent agreement with IFAT was 92.3 %. Screening plasma from blood donors with suspected malaria exposure, we found 4.8 % to be positive by IFAT and 5.2 % by MPA with an agreement of 93.2 %. The calculated index from the MPA exhibits similar diagnostic performance as IFAT for detection of P. falciparum malaria. Combining the antibody response against multiple antigens in a discrimination index increased the sensitivity of the MPA and reduced the readout to a single value. PMID- 22835433 TI - Evaluation of chemically modified carrier proteins for developing monoclonal antibodies against a clinically relevant mutation of cKIT. AB - In this report we show that combining double-chemically modified carrier proteins and hetero-functional cross-linkers allows preparing tailor-made hapten-protein carrier conjugates. Accordingly, a new carrier protein has been designed where carboxylic groups were transformed into highly reactive primary amino groups by reaction with ethylendiamine after activation with EDCI. The aminated protein carrier is then modified by different cross-linkers (hyper-activated proteins) at different conditions in order to control the conjugation ratio from 1 to >12 molecules of hapten per carrier protein. Finally, this novel strategy has been successfully used to develop antibodies against a short specific peptide corresponding to a point mutation (D816V) of cKIT, which is a clinically relevant mutation related to mastocytosis and gastrointestinal stroma tumor. PMID- 22835435 TI - A model for educational simulation of the effect of oxytocin on uterine contractions. AB - Fetal oxygenation is sometimes compromised due to hyperstimulation of uterine contractions (UC) following labor augmentation with oxytocin. We present a model for educational simulation that incorporates the pharmacokinetic-pharmacodynamic properties of oxytocin, reproducing the effect of this drug on UC features. Six UC tracings were generated, reflecting different relevant situations. Three independent experts identified correctly the simulated situations in all tracings and attributed an average realism score of 9.4 (0-10). The model presented for simulation of the effect of oxytocin on UC provides sufficiently realistic results to be used in healthcare education and can easily be adapted to different patients and educational scenarios. PMID- 22835434 TI - Flow cytometry of v-Abl transformed pre-B cells heterogeneous in ectopic expression levels reveals Ras dose-response. AB - Flow cytometry is a powerful tool for quantitative biology because it can perform single-cell analysis of large cell populations using multiple parameters. Results are often visualized as a two-dimensional scatter or contour plot. Because these plots can be relatively diffuse, it is not always straightforward to discern a relationship between measured parameters. We have demonstrated that quantitative trends can be fit to the single-cell data generated from a heterogeneous population. We engineered Abelson virus-transformed pre-B cells to express a broad range of oncogenic Ras levels. Instead of individual cultures with individual expression levels, a continuous range of levels was expressed by different cells in one heterogeneous culture. We then stained cells for downstream Erk phosphorylation to monitor MAPK signaling or employed an E2F responsive genetic reporter to monitor cell-cycle activity. Subsequent analysis by flow cytometry and locally weighted scatterplot smoothing (LOWESS) revealed that increasing Ras oncogene expression led to increasing MAPK signaling. In contrast, E2F activity peaked at an optimal, intermediate level of Ras. To make this analytical method widely available to others, we have provided a software application that performs LOWESS on any two-parameter population data collected by flow cytometry. PMID- 22835436 TI - Lung function measurement with multiple-breath-helium washout system. AB - Multiple-breath-washout (MBW) measurements are regarded as a sensitive technique which can reflect the ventilation inhomogeneity of respiratory airways. Typically nitrogen is used as the tracer gas and is washed out by pure oxygen in multiple breath-nitrogen washout (MBNW) tests. In this study, instead of using nitrogen, (4)He is used as the tracer gas with smaller gas density which may be able to reach deeper into our lungs in a given time and the helium washout results may be more sensitive to the ventilation inhomogeneity in small airways. A multiple breath-helium-washout (MBHW) system developed for the lung function study is also presented. Quartz tuning forks with a resonance frequency of 32,768Hz have been used for detecting the change of the respiratory gas density. The resonance frequency of the quartz tuning fork decreases linearly with increasing density of the surrounding gas. Knowing the CO2 concentration from the infrared carbon dioxide detector, the helium concentration can be determined. Results from 14 volunteers (3 mild asthmatics, 4 tobacco smokers, 1 with asthma history, 1 with COPD history, 5 normal) have shown that mild asthmatics have higher ventilation inhomogeneity in either conducting or acinar airways (or both). A feature has been found in washout curve of single breaths from 4 tobacco smokers with different length of smoking history which may indicate the early stage of respiratory ventilation inhomogeneity in acinar airways. PMID- 22835437 TI - Fractal dimension and mechanical properties of human cortical bone. AB - Fractal dimension (FD) can be used to characterize microstructure of porous media, particularly bone tissue. The porous microstructure of cortical bone is observable in micro-CT (MUCT) images. Estimations of fractal dimensions of MUCT images of coupons of human cortical bone are obtained. The same samples were tested on a tensile test machine and Young's modulus (YM) and Failure stress were obtained. When both types of measures were compared, a clear correlation was found (R=-81%, P<0.01). Young's modulus of each sample and the FD of its MUCT images are correlated. From the assumption that cortical bone is approximately a fractal set, a non-linear constitutive relation involving FD is obtained for YM. Experimental results show good agreement with this constitutive relation. Additional parameters in the non-linear relation between YM and FD have been estimated from experimental results and related to physical parameters. PMID- 22835438 TI - Japanese encephalitis virus RNA detected in Culex pipiens mosquitoes in Italy. AB - Mosquitoes collected in northern Italy were screened for flavivirus RNA. Positive amplicons were sequenced and found most similar to insect flavivirus (ISF), Usutu virus (USUV) and surprisingly also to Japanese encephalitis virus (JEV). The sequence (167 bp), obtained from one pool of Culex pipiens, was found identical to JEV strains from bats in China. Unfortunately additional sequence data or virus isolations were not obtained in this study. Confirmation of potential introduction of JEV to Italy and other European countries is urgently needed. PMID- 22835439 TI - Public health response to an outbreak of Legionnaires' disease in Edinburgh, United Kingdom, June 2012. AB - We report an outbreak comprising 50 confirmed cases of Legionnaires' disease in Edinburgh, Scotland, June 2012. In addition, there were 49 suspected cases. Epidemiological evidence suggests that a common outdoor airborne exposure occurred over south-west Edinburgh. This probably emanated from cooling towers in the north-east of the affected area, although not yet clearly linked by scientific evidence. The co-ordinated public health, environmental and clinical response helped prevent ongoing exposure and mitigated associated mortality and morbidity. PMID- 22835440 TI - Investigations and actions taken during 2011 due to the first finding of Echinococcus multilocularis in Sweden. AB - Echinococcus multilocularis is a parasite that can cause alveolar echinococcosis disease. After the first positive finding of E. multilocularis in Sweden in 2011, a consulting group with representatives from relevant authorities was summoned. In this group, all relevant information was shared, strategies for information dissemination and any actions to be taken due to the finding of E. multilocularis were discussed and decided. The present paper describes the actions taken during 2011 and the results thereof, including surveillance in animals, risk assessment for humans to become infected and recommendations given to the public. Further discussion about whether the parasite was introduced, and if so, how, as well as possible future development of the infection in animals and humans in Sweden and future actions are included. PMID- 22835441 TI - Surveillance of tularaemia in Kosovo, 2001 to 2010. AB - Tularaemia, caused by Francisella tularensis, had not been registered in Kosovo before an outbreak in 1999 and 2000. A national surveillance system has been implemented in Kosovo since 2000 to monitor a number of diseases, including tularaemia. Antibody detection in human sera was used for laboratory diagnosis of tularaemia and F. tularensis lipopolysaccharide antigen was used as a marker of infection. The purpose of this study is to describe the incidence of tularaemia in Kosovo after the 1999-00 outbreak. In 2001 and 2002, a second outbreak occurred, with 327 serologically confirmed cases. From 2001 to 2010, 25-327 cases were registered per year, giving a mean annual incidence of 5.2 per 100,000 population. The most likely sources of infection were contaminated drinking water and food. The dominant clinical manifestations were the glandular (79%) and ulcero-glandular (21%) forms. By 2010, the disease had spread throughout Kosovo. Presumably as a result of war and subsequent environmental disruption, mass population displacement and breakdown of sanitation and hygiene, the two major outbreaks of tularaemia resulted in the establishment of an active endemic area of tularaemia in Kosovo. PMID- 22835445 TI - Improved implantation and ongoing pregnancy rates after single-embryo transfer with an optimized protocol for in vitro oocyte maturation in women with polycystic ovaries and polycystic ovary syndrome. AB - OBJECTIVE: To describe an optimized protocol for oocyte in vitro maturation (IVM) that achieves improved implantation and ongoing pregnancy rates in women with polycystic ovaries (PCO) and polycystic ovary syndrome (PCOS). DESIGN: Prospective cohort study. SETTING: Hospital fertility unit. PATIENT(S): Women with PCO and PCOS undergoing treatment for infertility. INTERVENTION(S): Follicle stimulating hormone (FSH) priming, IVM, blastocyst culture, hormone replacement therapy. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): Our optimized IVM protocol achieves implantation and ongoing pregnancy rates comparable to in vitro fertilization. From 66 oocyte collections, 844 oocytes were collected (12.8 oocytes/cycle), 588 oocytes matured after IVM (69.7% maturation rate), 420 oocytes fertilized after ICSI (71.4% fertilization rate), and 175 blastocyst-stage embryos resulted (41.7% blastocyst-development rate). Of these, 62 blastocyst-stage embryos were transferred as single embryos, resulting in 29 clinical pregnancies (43.9%/oocyte collection, 46.7%/embryo transfer) and 28 live births (42.4%/oocyte collection, 45.2%/embryo transfer). CONCLUSION(S): In women with PCO or PCOS, improved implantation, clinical pregnancy, and live birth rates can be achieved after single-embryo transfer by the use of an optimized IVM protocol. PMID- 22835446 TI - Time-dependent O2 consumption patterns determined optimal time ranges for selecting viable human embryos. AB - OBJECTIVE: To evaluate correlations between metabolic activity and implantation potential of transferred embryos in a study based on oxygen (O(2)) consumption (OC) measurements, because O(2) uptake is directly related to the capacity of an embryo to produce energy via adenosine triphosphate. DESIGN: Retrospective cohort study. SETTING: Infertility institute. PATIENT(S): Five hundred seventy-five injected oocytes in 56 first oocyte donation cycles with embryo transfer on day 3. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We analyzed embryo destination viability and implantation depending on the embryo OC rate obtained from 47,741 measurements (up to 85 measurements per embryo, 2-3 measurements per hour). OC patterns were analyzed in relation to the time elapsed from sperm microinjection, to the final destination of the embryos (transferred, frozen, or discarded), to ongoing pregnancy, and by successful implantation. RESULT(S): OC was found to decrease during embryonic development. OC patterns from 52 hours onward showed the strongest correlation with implantation success. Regarding embryo destination, the same patterns were observed. CONCLUSION(S): OC from individual embryos revealed significant differences, mainly close to the time of transfer, when OC pattern was associated with successful implantation. Therefore, measuring the OC pattern of human embryos culture up to 72 hours could be used to select the embryo with best developmental potential. PMID- 22835447 TI - Oxidative DNA damage in human sperm can be detected by Raman microspectroscopy. AB - OBJECTIVE: To determine whether Raman microspectroscopy can identify different levels of oxidative sperm nDNA damage and to corroborate the findings using an established method and an alternative but complementary spectroscopic technique. DESIGN: Three-way comparison of Raman profiles, Fourier transform infrared spectroscopy (FTIR) spectra, and flow-cytometric assessments of sperm nDNA damage. SETTING: University-based research laboratory. PATIENT(S): Thirty-eight men attending the infertility clinic at the Centre of Reproductive Medicine and Andrology. INTERVENTION(S): Induction of oxidative damage by Fenton's reaction on semen samples. MAIN OUTCOME MEASURE(S): Raman profiles, FTIR spectra, and flow cytometric analysis of DNA fragmentation. RESULT(S): Raman and FTIR spectra contained distinctive differences between untreated and fragmented nDNA sperm that were indicative of oxidative attack. The changes in Raman profiles were similar to those previously seen and corresponded to the DNA backbone. The peak attributions were corroborated by the FTIR spectra. Principal component analysis of the entire Raman spectra distinguished samples with varying degrees of damage. After determination of a cutoff value (0.63), estimation of the percentage of sperm with nDNA damage using the intensity ratio of Raman peaks (1,050/1,095 cm( 1)) correlated linearly to the flow-cytometric assessment. CONCLUSION(S): Raman microspectroscopy still requires further validation but may potentially provide a means of assessing the nDNA status of a living sperm. PMID- 22835448 TI - Evaluation and treatment of recurrent pregnancy loss: a committee opinion. AB - The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology. PMID- 22835449 TI - Using family members as gamete donors or surrogates. AB - The use of intrafamilial gamete donors and surrogates is generally ethically acceptable when all participants are fully informed and counseled, but arrangements that replicate the results of true consanguineous or incestuous unions should be prohibited, child to parent arrangements are generally unacceptable, and parent to child arrangements are acceptable in limited situations. Programs that choose to participate in intrafamilial arrangements should be prepared to spend additional time counseling participants and ensuring that they have made free, informed decisions. PMID- 22835450 TI - Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome. AB - OBJECTIVE: To study the association of adrenal and ovarian androgen levels with metabolic parameters in a large cohort of women with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Outpatient clinic of an academic hospital. PATIENT(S): Six hundred twenty-two women with PCOS. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Analysis of the association of endocrine dehydroepiandrosterone sulfate (DHEAS) and free testosterone (FT) parameters with metabolic measurements. RESULT(S): In multivariate adjusted logistic regression analyses, the odds ratio (OR) for insulin resistance was statistically significantly higher (4.42, range: 2.26-8.67) for women with PCOS who had elevated FT levels compared with the women with normal DHEAS and FT levels (reference group). We found no statistically significant differences when women with PCOS with elevated DHEAS or a combined elevation of DHEAS and FT levels were compared with the reference group. Women with PCOS and a high DHEAS/FT ratio had a more beneficial metabolic profile compared with the women with a low DHEAS/FT ratio. In multivariate adjusted binary logistic regression analyses, we found a statistically significantly lower risk for insulin resistance in the women with PCOS in the highest DHEAS/FT-ratio quartile compared with women with PCOS in the lowest quartile (OR 0.35, range: 0.14-0.89). CONCLUSION(S): Our results suggest that the distinction between adrenal and ovarian hyperandrogenism is important when evaluating metabolic risk in PCOS. PMID- 22835451 TI - The impact of recurrent dislocation on shoulder rotator muscle balance (a prospective study of 102 male patients). AB - PURPOSE OF THE STUDY: We performed an isokinetic analysis of both shoulders in 102 male patients suffering from shoulder instability after several trauma related anterior or anterior-inferior dislocations. The analysis was part of a comprehensive medical and radiological assessment (with standard X-rays and cross sectional imaging) prior to surgery. The study's objective was to measure the strength of the patients' internal and external rotators after recurrent dislocations (by comparing injured and healthy sides) and to evaluate the dislocations' impact on the muscles on the injured side. MATERIALS AND METHODS: The mean patient age was 24.8 (range: 16-47). We analysed the impact of instability on rotator muscle performance according to the side (dominant or non dominant), the number of dislocations and the severity of any associated bone damage. The isokinetic analysis was performed at least one month after the last shoulder dislocation. The same operator performed all procedures. The modified Davies position was adopted, in order to record the peak torque of the internal and external rotators during concentric contractions at 60 degrees and 180 degrees per second. Means and standard deviations for peak torque to body weight ratios and external/internal rotator peak torque ratios were reported. RESULTS: After several anterior or anterior-inferior shoulder dislocations, there was a non-significant difference in the external rotator/internal rotator ratio when comparing injured and healthy sides - regardless of whether the injured side was dominant or not, the number of dislocations and the severity of bone damage. CONCLUSION: Systematic, presurgical, isokinetic testing of the shoulder does not appear to be of value in post-traumatic instability in male patients. PMID- 22835452 TI - Transforming growth factor-beta and the kidney revisited: introduction. PMID- 22835454 TI - TGF-beta/Smad signaling in kidney disease. AB - Chronic progressive kidney diseases typically are characterized by active renal fibrosis and inflammation. Transforming growth factor-beta1 (TGF-beta1) is a key mediator in the development of renal fibrosis and inflammation. TGF-beta1 exerts its biological effects by activating Smad2 and Smad3, which is regulated negatively by an inhibitory Smad7. In the context of fibrosis, although Smad3 is pathogenic, Smad2 and Smad7 are protective. Under disease conditions, Smads also interact with other signaling pathways, such as the mitogen-activated protein kinase and nuclear factor-kappaB pathways. In contrast to the pathogenic role of active TGF-beta1, latent TGF-beta1 plays a protective role in renal fibrosis and inflammation. Furthermore, recent studies have shown that TGF-beta/Smad signaling plays a regulating role in microRNA-mediated renal injury. Thus, targeting TGF beta signaling by gene transfer of either Smad7 or microRNAs into diseased kidneys has been shown to retard progressive renal injury in a number of experimental models. In conclusion, TGF-beta/Smad signaling plays a critical role in renal fibrosis and inflammation. Advances in understanding of the mechanisms of TGF-beta/Smad signaling in renal fibrosis and inflammation during chronic kidney diseases should provide a better therapeutic strategy to combat kidney diseases. PMID- 22835453 TI - How does TGF-beta mediate tubulointerstitial fibrosis? AB - Tubulointerstitial fibrosis mediates the development of end-stage renal disease from renal injuries of all etiologies and is considered an important predictor of renal survival. Transforming growth factor-beta (TGF-beta) is one of the most important growth factors that promotes tubulointerstitial fibrosis, but the mechanisms whereby this occurs are not well defined. This is because TGF-beta has pleiotropic effects that depend on the target cell type. This review discusses how TGF-beta signaling in each of the relevant cell types (eg, tubular epithelium, fibroblasts) may contribute to tubulointerstitial fibrosis progression and suggests ways in which future research can improve our understanding of TGF-beta-mediated tubulointerstitial fibrosis. PMID- 22835455 TI - TGF-beta signaling via TAK1 pathway: role in kidney fibrosis. AB - In progressive kidney diseases, fibrosis represents the common pathway to end stage kidney failure. Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. Emerging evidence shows a complex scheme of signaling networks that enable multifunctionality of TGF-beta1 actions. Specific targeting of the TGF beta signaling pathway is seemingly critical and an attractive molecular therapeutic strategy. TGF-beta1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways involving the Smad and the non-Smad. The Smad signaling axis is known as the canonical pathway induced by TGF-beta1. Importantly, recent investigations have shown that TGF beta1 also induces various non-Smad signaling pathways. In this review, we focus on current insights into the mechanism and function of the Smad-independent signaling pathway via TGF-beta-activated kinase 1 and its role in mediating the profibrotic effects of TGF-beta1. PMID- 22835456 TI - MicroRNA circuits in transforming growth factor-beta actions and diabetic nephropathy. AB - Diabetes is associated with significantly increased rates of kidney disease or diabetic nephropathy (DN), a severe microvascular complication that can lead to end-stage renal disease. End-stage renal disease needs to be treated by dialysis or kidney transplantation and also is associated with cardiovascular disease and macrovascular complications. Therefore, effective renal protection is critical to reduce the rates of mortality associated with diabetes. Although key signal transduction and gene regulation mechanisms have been identified and several drugs are currently in clinical use, the rates of DN are still escalating, suggesting the imperative need to identify new biomarkers and drug targets. The recent discovery of microRNAs (miRNAs) and their cellular functions provide an opportunity to fill these critical gaps. Because miRNAs can modulate the actions of key factors involved in DN such as transforming growth factor-beta, they could be novel targets for the treatment of DN. This review covers the recent studies on the roles of miRNAs and miRNA circuits in transforming growth factor-beta actions and in DN. PMID- 22835457 TI - Sugar, sex, and TGF-beta in diabetic nephropathy. AB - TGF-beta is well known to play a critical role in diabetic kidney disease, and ongoing clinical studies are testing the potential therapeutic promise of inhibiting TGF-beta production and action. An aspect of TGF-beta action that has not received much attention is its potential role in explaining sex-related proclivity for kidney disease. In this review, we discuss recent studies linking TGF-beta signaling to sex-related effects in diabetic kidney disease and suggest targets for future studies. PMID- 22835458 TI - Effect of dietary salt on regulation of TGF-beta in the kidney. AB - Dietary sodium chloride (salt) has long been considered injurious to the kidney by promoting the development of glomerular and tubulointerstitial fibrosis. Endothelial cells throughout the vasculature and glomeruli respond to increased dietary salt intake with increased production of transforming growth factor-beta (TGF-beta) and nitric oxide. High-salt intake activates large-conductance, voltage- and calcium-activated potassium (BK(Ca)) channels in endothelial cells. Activation of BK(Ca) channels promotes signaling through proline-rich tyrosine kinase-2, cellular-sarcoma (c-Src), Akt (also known as protein kinase B), and mitogen-activated protein kinase pathways that lead to endothelial production of TGF-beta and nitric oxide. TGF-beta signaling is broadly accepted as a strong stimulator of renal fibrosis. The classic description of TGF-beta signaling pathology in renal disease involves signaling through Smad proteins resulting in extracellular matrix deposition and fibrosis. Active TGF-beta1 also causes fibrosis by inducing epithelial-mesenchymal transition and apoptosis. By enhancing TGF-beta signaling, increased dietary salt intake leads to progressive renal failure from nephron loss and glomerular and tubulointerstitial fibrosis. PMID- 22835459 TI - Heme oxygenase-1 as a target for TGF-beta in kidney disease. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory cytokine that is implicated in a variety of kidney diseases, including diabetic nephropathy and chronic transplant rejection, where it promotes stimulation of the extracellular matrix deposition, cell proliferation, and migration. TGF-beta exerts its biological functions largely via its downstream complex signaling molecules, Smad proteins. Paradoxically, TGF-beta also is essential for normal homeostasis and suppression of inflammation through mechanisms that are yet to be fully elucidated. One feasible mechanism by which TGF-beta may exert its beneficial properties is through induction of heme oxygenase-1 (HO-1). Induction of this redox-sensitive enzyme is known to be cytoprotective through its potent antioxidant, anti-inflammatory, and anti-apoptotic properties in different conditions including several kidney diseases. In this overview, recent advances in our understanding of the role of TGF-beta in kidney disease, its molecular regulation of HO-1 expression, and the potential role of HO-1 induction as a therapeutic modality in TGF-beta-mediated kidney diseases are highlighted. PMID- 22835460 TI - Retinoid and TGF-beta families: crosstalk in development, neoplasia, immunity, and tissue repair. AB - Transforming growth factor-beta (TGF-beta) isoforms are profibrotic cytokines, par excellence, and have complex multifunctional effects on many systems, depending on the biologic setting. Retinoids are vitamin A derivatives that also have diverse effects in development, physiology, and disease. The interactions between these classes of molecules are, not surprisingly, highly complex and are dependent on the tissue, cellular, and molecular settings. PMID- 22835462 TI - Contact inhibition (of proliferation) redux. AB - It has long been appreciated that proliferation of many cells is inhibited by density, a phenomenon that is often attributed to cell-cell contact. The basic properties of this phenomenon were established in the 1960s, along with the observation that such density-dependence was also lost in transformed cells. The mechanistic basis of contact inhibition of proliferation (CIP) has been slower to reveal itself. Here we discuss recent progress in elucidating the roles that cell cell adhesion molecules play as receptors for CIP and in characterising the intracellular signaling pathways that mediate adhesion-dependent proliferative inhibition. PMID- 22835461 TI - Transforming growth factor-beta, bioenergetics, and mitochondria in renal disease. AB - The transforming growth factor-beta (TGF-beta) family comprises more than 30 family members that are structurally related secreted dimeric cytokines, including TGF-beta, activins, and bone morphogenetic proteins/growth and differentiation factors. TGF-beta are pluripotent regulators of cell proliferation, differentiation, apoptosis, migration, and adhesion of many different cell types. TGF-beta pathways are highly evolutionarily conserved and control embryogenesis, tissue repair, and tissue homeostasis in invertebrates and vertebrates. Aberrations in TGF-beta activity and signaling underlie a broad spectrum of developmental disorders and major pathologies in human beings, including cancer, fibrosis, and autoimmune diseases. Recent observations have indicated an emerging role for TGF-beta in the regulation of mitochondrial bioenergetics and oxidative stress responses characteristic of chronic degenerative diseases and aging. Conversely, energy and metabolic sensory pathways cross-regulate mediators of TGF-beta signaling. Here, we review TGF-beta and regulation of bioenergetic and mitochondrial functions, including energy and oxidant metabolism and apoptotic cell death, as well as their emerging relevance in renal biology and disease. PMID- 22835463 TI - Is statin use associated with reduced mortality after pneumonia? A systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis of the effects of statins on mortality following pneumonia. METHODS: We searched MEDLINE, EMBASE, BIOSIS, Cochrane CENTRAL Register of Controlled Trials, Cambridge Scientific Abstracts, BIOSIS, and Scopus. Studies were included if they involved: participants >=18 years of age; patients with community-acquired pneumonia; current statin users; and reported overall or adjusted mortality after pneumonia. RESULTS: Of 491 citations identified, 13 studies involving 254,950 patients met eligibility criteria. Pooled unadjusted data showed that statin use was associated with lower mortality after pneumonia (odds ratio [OR] 0.62, 95% confidence interval [CI], 0.54-0.71). Pooling of adjusted data also showed reduced mortality after pneumonia (OR 0.66, 95% CI, 0.55-0.79). However, this effect was attenuated in subgroup analysis by confounders and in prospective studies. CONCLUSIONS: Although statin use is associated with decreased mortality after pneumonia, this effect weakens in important subgroups. Only a randomized controlled study can fully explore the link between statins and pneumonia mortality. PMID- 22835464 TI - Burton's line. PMID- 22835466 TI - Increasing trends of gonorrhoea and syphilis and the threat of drug-resistant gonorrhoea in Europe. PMID- 22835465 TI - Prevalence and morbidity associated with muscle cramps in patients with cirrhosis. AB - PURPOSE: Patients with cirrhosis often experience muscle cramps with varying severity. We investigated the factors associated with the prevalence and morbidity associated with muscle cramps. METHODS: A total of 150 adult patients with cirrhosis were enrolled consecutively. Cramp questionnaire with visual analogue scale for pain, Chronic Liver Disease Questionnaire (CLDQ), and blood for measurement of 25-(OH) vitamin D levels were obtained after informed consent. RESULTS: A total of 101 patients (67%) reported muscle cramps in the preceding 3 months. Patients with cramps had significantly lower serum albumin (3.1+/-0.6 g/dL vs 3.3+/-0.7 g/dL, P=.04) and CLDQ scores (107+/-37 vs 137+/-34, P<.0001) compared with those without cramps. The median composite symptom score, defined as product of frequency and severity of cramps, in the study cohort was 12 with a range of 0.3 to 200. There were no clinical or biochemical predictors for occurrence of any cramps or severe cramps (composite symptom score>12). Muscle cramps (P<.001) and hepatic encephalopathy (P=.009) were associated independently with decreased CLDQ scores. Vitamin D deficiency was seen in 66% of the study cohort, but the serum 25-(OH) vitamin D levels were not significantly different between patients with and without cramps (18.0+/-8.9 ng/mL vs 19.6+/-9.5 ng/mL, P=.49). CONCLUSIONS: Muscle cramps are associated with significantly diminished quality of life in patients with cirrhosis. More research is needed to better understand their mechanism to develop effective treatment. PMID- 22835467 TI - Syphilis on the rise again in Germany--results from surveillance data for 2011. AB - In Germany, syphilis is notified anonymously. In 2011, 3,698 cases (incidence 4.5/100,000 inhabitants) were notified, an increase of 22% over 2010. The increase was higher in men (23%) than women (13%) and 94% of the cases were male. Information on the possible way of transmission was available for 72% of cases. Of these, 84% were men who have sex with men, who seem to play a major role in the renewed increase in syphilis cases. PMID- 22835468 TI - Recent trends in gonorrhoea and syphilis epidemiology in Sweden: 2007 to 2011. AB - Gonorrhoea incidence in Sweden continued to increase during 2007-2011, while for syphilis, there was a very minor decrease, but no clear trend. Gonorrhoea incidence increased most among heterosexually infected men and women while for syphilis, the major burden was among men who have sex with men. Neisseria gonorrhoeae resistance to first-line antimicrobials increased annually. Surveillance of infection and antimicrobial resistance along with continuous analysis are needed, to develop prevention activities to reduce risk behaviours. PMID- 22835469 TI - Rapid increase in gonorrhoea and syphilis diagnoses in England in 2011. AB - There has been a rapid rise in the number of gonorrhoea and syphilis diagnoses in England during 2011, an increase of 25% and 10% respectively. Large increases of both gonorrhoea (61%) and syphilis (28%) were observed among men who have sex with men. Although these rises can partly be attributed to increased testing, ongoing high-levels of unsafe sexual behaviour probably contributed to the rise. The rise in gonorrhoea rates is worrying in an era of decreased susceptibility to treatments. PMID- 22835470 TI - An ongoing large outbreak of measles in Merseyside, England, January to June 2012. AB - From 1 January to 30 June 2012, 359 confirmed and 157 probable cases of measles were reported in Merseyside, England. The most affected age groups were children under five years and young adults from 15 years of age. Most cases have been sporadic. There have been few outbreaks in nurseries; however, no outbreaks have been reported in schools. Of the cases eligible for vaccination, only 3% of the confirmed cases were fully immunised. PMID- 22835471 TI - The regulation of health care providers' payments when horizontal and vertical differentiation matter. AB - This paper analyzes the regulation of payment schemes for health care providers competing in both quality and product differentiation of their services. The regulator uses two instruments: a prospective payment per patient and a cost reimbursement rate. When the regulator can only use a prospective payment, the optimal price involves a trade-off between the level of quality provision and the level of horizontal differentiation. If this pure prospective payment leads to underprovision of quality and overdifferentiation, a mixed reimbursement scheme allows the regulator to improve the allocation efficiency. This is true for a relatively low level of patients' transportation costs. We also show that if the regulator cannot commit to the level of the cost reimbursement rate, the resulting allocation can dominate the one with full commitment. This occurs when the transportation cost is low or high enough, and the full commitment solution either implies full or zero cost reimbursement. PMID- 22835472 TI - The impact of direct-to-consumer television and magazine advertising on antidepressant use. AB - We examine whether exposure to direct-to-consumer advertising (DTCA) for antidepressant drugs affects individual use of these medications among those suffering from depression. Prior studies have almost exclusively relied on making connections between national or market-level advertising volume/expenditures and national or individual-level usage of medications. This is the first study to: estimate the impact of individual-level exposure to DTCA on individual-level use of antidepressants; estimate the impact of individual-level exposure to television DTCA on individual-level use in any drug class; consider the relative and interactive impact of DTCA in two different media in any drug class; and, consider the heterogeneity of impact among different populations in an econometric framework in the antidepressant market. There are also important limitations to note. Unlike prior market level studies that use monthly data, we are limited to aggregated annual data. Our measures of potential advertising exposure are constructed assuming that media consumption patterns are stable during the year. We are also not able to study the impact of advertising on use of antidepressants for conditions other than depression, such as anxiety disorders. We find that: DTCA impacts antidepressant use in a statistically and economically significant manner; that these effects are present in both television and magazine advertising exposure but do not appear to have interactive effects; are stronger for women than for men in the magazine medium, but are about equally strong for men and women in the TV medium; and, are somewhat stronger for groups suffering from more severe forms of depression. The overall size of the effect is a 6-10 percentage point increase in antidepressant use from being exposed to television advertising; the corresponding magazine effects are between 3 and 4 percentage points. PMID- 22835473 TI - Pilot study on effects of nanoparticle exposure on Crassostrea virginica hemocyte phagocytosis. AB - Little is known about engineered nanoparticles (NPs) exposures on oysters. As sessile filter feeders, oysters are likely to be exposed to NPs suspended in the water column with unknown effects of NP exposure on oyster functioning. Our study indicates that waterborne NPs alter oyster hemocyte phagocytosis dynamics, an indication of sub-lethal effects of NP exposures. Silver NPs, titanium dioxide (TiO(2)) NPs, and silver nitrate exposures reduced phagocytosis compared to the control. Increasing TiO(2) NPs and silver nitrate concentrations reduced phagocytosis. Silver NPs, up to 120ppb, increased phagocytosis, but higher concentrations reduced phagocytosis. PMID- 22835474 TI - Gss1 protein of the methylotrophic yeast Pichia pastoris is involved in glucose sensing, pexophagy and catabolite repression. AB - In the yeast Saccharomyces cerevisiae, the one-at-a-time deletions of either the high-affinity glucose sensor gene SNF3 or the low-affinity glucose sensor gene RGT2 only slightly reduced pexophagy; however, deleting both genes greatly reduced pexophagy, evincing interaction beyond the sum of the additive effects, as recently shown. The present study identifies the only ScSNF3/RGT2 ortholog in the methylotrophic yeast Pichia pastoris (designated as PpGSS1, from GlucoSe Sensor) and describes its roles in autophagic pathways (non-selective and selective). GSS1 knock-out strain has been constructed. The experiments support the hypothesis that Gss1 plays an important role in autophagic degradation of peroxisomes and glucose catabolite repression in P. pastoris. PMID- 22835475 TI - Ovarian cancer G-protein-coupled receptor 1 induces the expression of the pain mediator prostaglandin E2 in response to an acidic extracellular environment in human osteoblast-like cells. AB - Although bone pain in osteoporosis and skeletal metastasis is an expected consequence of fracture, there are other underlying causes responsible. Our study demonstrated that ovarian cancer G-protein-coupled receptor 1 detected extracellular protons in MG63 cells, and regulated osteoblast functions, such as prostaglandin E2 production, in response to acidic circumstances. In this work, we measured inositol phosphate production, intracellular Ca(2+) concentration, prostaglandin E2 production, and cyclic adenosine monophosphate accumulation in MG63 cells exposed to extracellular acidification. Extracellular acidity induced a transient increase in Ca(2+) concentration and inositol phosphate production. Acidification also induced prostaglandin E2 production, resulting in cyclic adenosine monophosphate accumulation. A small interfering RNA specific for the ovarian cancer G-protein-coupled receptor 1 markedly inhibited these proton induced actions in MG63 cells. These results indicated that the involvement of ovarian cancer G-protein-coupled receptor 1 in acidic extracellular environment may be an underlying mechanism responsible for bone pain in osteoporosis or bone metastasis without clinically proved fractures. PMID- 22835477 TI - Twelve-year trend in treatment seeking for buprenorphine abuse in Finland. AB - BACKGROUND: Buprenorphine abuse is becoming increasingly common worldwide. However, large-scale long-term studies of buprenorphine abuse are lacking. The objective of this study was to examine the trend in characteristics of clients seeking treatment for buprenorphine abuse and compare them to those seeking treatment for heroin and amphetamine abuse. METHODS: A 12-year descriptive study was conducted at the Helsinki Deaconess Institute (HDI), a public utility foundation responsible for providing treatment for substance abuse in the greater Helsinki area. All clients seeking treatment between 31 January 1997 and 31 August 2008 received a structured clinical interview concerning demographic characteristics and abuse patterns. Characteristics of clients who reported that their primary drug of abuse was buprenorphine (n=780) were compared to those whose primary drug of abuse was either heroin (n=598) or amphetamine (n=1249). RESULTS: The annual proportion of buprenorphine clients increased from 3.0% in 1998 to 38.4% in 2008. Daily abuse (73.8%) and intravenous administration (80.6%) were common among buprenorphine clients. Concurrent abuse of prescription medications (p<0.001), stimulants (p=0.001) and alcohol (p<0.001) increased from 1997 to 2008. Treatment seeking for heroin abuse declined to approximately 1% of clients annually after 2002. Buprenorphine clients were more likely to be daily users of their primary drug (p<0.001), abuse prescription medications (p<0.001) and administer drugs intravenously (p=0.001 from 1997 to 2001) compared to heroin and amphetamine clients. CONCLUSIONS: Our results highlight the increasing abuse of buprenorphine in Finland. Buprenorphine clients had risky abuse patterns in terms of daily use and intravenous administration. Concurrent substance abuse increased during the study period. PMID- 22835478 TI - A nonradioisotope chemiluminescent assay for evaluation of 2-deoxyglucose uptake in 3T3-L1 adipocytes. Effect of various carbonyls species on insulin action. AB - We have developed a rapid nonradioisotope chemiluminescent assay adapted to high throughput screening experiments, to evaluate glucose uptake activity in cultured cells. For chemiluminescence quantification of 2-deoxyglucose, we used a luminol oxidation reaction after an enzymatic dephosphorylation of 2-deoxyglucose-6 phosphate. All reactions were performed at 37 degrees C by consecutive addition of reagents, and the assay is able to quantify 2DG in picomole per well. To confirm the reliability of this method, we have evaluated the dose-effect of insulin, GLUT4 inhibitors and insulin-sensitizing agent on 2DG uptake into 3T3-L1 cells. The results obtained with the assay for 2DG uptake in vitro in the absence or presence of insulin stimulation, were similar to those obtained by the previous radioisotopic and enzymatic methods. We have also used this assay to evaluate the effect of various reactive carbonyl and oxygen species on insulin stimulated 2DG-uptake into adipocytes. All reactive carbonyl species tested decreased insulin-stimulated glucose uptake in a time- and dose-dependent manner without affecting basal glucose uptake in 3T3-L1 cells. 4-hydroxynonenal was found to be the most potent in the impairment of glucose uptake. This new enzymatic chemiluminescent assay is rapid and useful for measurement of 2DG uptake in insulin-responsive in cultured cells. PMID- 22835476 TI - Tsetse-Wolbachia symbiosis: comes of age and has great potential for pest and disease control. AB - Tsetse flies (Diptera: Glossinidae) are the sole vectors of African trypanosomes, the causative agent of sleeping sickness in human and nagana in animals. Like most eukaryotic organisms, Glossina species have established symbiotic associations with bacteria. Three main symbiotic bacteria have been found in tsetse flies: Wigglesworthia glossinidia, an obligate symbiotic bacterium, the secondary endosymbiont Sodalis glossinidius and the reproductive symbiont Wolbachia pipientis. In the present review, we discuss recent studies on the detection and characterization of Wolbachia infections in Glossina species, the horizontal transfer of Wolbachia genes to tsetse chromosomes, the ability of this symbiont to induce cytoplasmic incompatibility in Glossina morsitans morsitans and also how new environment-friendly tools for disease control could be developed by harnessing Wolbachia symbiosis. PMID- 22835479 TI - Palliative care among second-generation Holocaust survivors: communication barriers. PMID- 22835480 TI - Lack of muscle contractile property changes at the time of perceived physical exhaustion suggests central mechanisms contributing to early motor task failure in patients with cancer-related fatigue. AB - CONTEXT: Fatigue is one of the most common symptoms reported by cancer survivors, and fatigue worsens when patients are engaged in muscle exertion, which results in early motor task failure. Central fatigue plays a significant role, more than muscle (peripheral) fatigue, in contributing to early task failure in cancer related fatigue (CRF). OBJECTIVES: The purpose of this study was to determine if muscle contractile property alterations (reflecting muscle fatigue) occurred at the end of a low-intensity muscle contraction to exhaustion and if these properties differed between those with CRF and healthy controls. METHODS: Ten patients (aged 59.9+/-10.6 years, seven women) with advanced solid cancer and CRF and 12 age- and gender-matched healthy controls (aged 46.6+/-12.8 years, nine women) performed a sustained contraction of the right arm elbow flexion at 30% maximal level until exhaustion. Peak twitch force, time to peak twitch force, rate of peak twitch force development, and half relaxation time derived from electrical stimulation-evoked twitches were analyzed pre- and post-sustained contraction. RESULTS: CRF patients reported significantly greater fatigue as measured by the Brief Fatigue Inventory and failed the motor task earlier, 340+/ 140 vs. 503+/-155 seconds in controls. All contractile property parameters did not change significantly in CRF but did change significantly in controls. CONCLUSION: CRF patients perceive physical exhaustion sooner during a motor fatigue task with minimal muscular fatigue. The observation supports that central fatigue is a more significant factor than peripheral fatigue in causing fatigue feelings and limits motor function in cancer survivors with fatigue symptoms. PMID- 22835481 TI - Enhancing cancer patient well-being with a nonpharmacological, heritage-focused intervention. AB - CONTEXT: Nonpharmacological, arts-focused interventions in health care have demonstrated considerable improvements in cancer patient well-being, although there is a little clinically robust, empirical evidence to demonstrate the value of heritage-focused practices. OBJECTIVES: This study examined the effectiveness of a novel, nonpharmacological, heritage-focused intervention with adult female inpatients receiving cancer treatment in oncology wards of a large, central London hospital. METHODS: In the tactile experimental condition, participants handled and discussed a selection of museum objects with a facilitator, whereas in the visual control condition, participants discussed photographs of the same objects. Sessions were conducted on a one-to-one basis at patients' bedsides and lasted about half an hour. Quantitative measures of psychological well-being with proven reliability and validity were used in a pretest/post-test control group, quasi-experimental design. RESULTS: Levels of positive emotion, well-being, and happiness were significantly enhanced in the experimental condition compared with the control condition for both oncology and nononcology patients. CONCLUSION: Findings indicate a future role for heritage-focused practices in enhancing health care environments. PMID- 22835482 TI - Self-reported constipation in patients with advanced cancer: a preliminary report. AB - CONTEXT: Constipation is often inadequately assessed and underdiagnosed in patients with advanced cancer. Many studies use patient-reported constipation (PRC) as an outcome. OBJECTIVES: The aim was to compare the accuracy of PRC as compared with the modified Rome III (ROME) criteria and to determine the agreement between PRC, physician assessment of constipation, and objective assessment of constipation by modified ROME criteria among outpatients with advanced cancer. METHODS: Patients with advanced cancer attending a supportive care clinic were screened. Constipation was assessed using the modified ROME criteria, patient report (yes or no and rated 0-10; 10=worst possible symptom), and physician assessments (yes or no and rated 0-10). RESULTS: One hundred patients were enrolled, and 50 of 100 patients (50%) met the modified ROME criteria for constipation. Disagreement between ROME criteria and the patient report (yes/no) was found in 33 patients (33%) and between ROME criteria and the physician assessment (yes/no) in 39 patients (39%). The best combination of sensitivity (0.84) and specificity (0.62) was found with scores >=3/10 for PRC. CONCLUSION: We found a high frequency of constipation. The limited agreement with modified ROME criteria suggests that a patient's self-report as yes or no is not useful for clinical practice. Patient self-rating on a 0 to 10 scale (score of three or greater) seems to be the best tool for constipation screening among this population. More research is needed to identify the best way to assess constipation in patients with advanced cancer. PMID- 22835483 TI - Exploring racial disparities in CHD mortality between blacks and whites across the United States: a geographically weighted regression approach. AB - Coronary heart disease (CHD) mortality is one of the major contributors to racial disparities in health in the United States (US). We examined spatial heterogeneity in black-white differences in CHD mortality across the US and assessed the contributions of poverty and segregation. We used county-level, age adjusted CHD mortality rates for blacks and whites in the continental US between 1996 and 2006. Geographically weighted regression was employed to assess spatial heterogeneity. There was significant spatial heterogeneity in black-white differences in CHD mortality (median black-white difference 17.7 per 100,000, 25th-75th percentile (IQR): 4.0, 34.0, P value for spatial non-stationarity <0.0001) before controlling for poverty and segregation. This heterogeneity was no longer present after accounting for county differences in race-specific poverty and segregation and interactions of these variables with race (median black-white difference -13.5 per 100,000, IQR: -41.3, 15.7,P value for spatial non-stationarity=0.4346). The results demonstrate the importance of spatial heterogeneity in understanding and eliminating racial disparities in CHD mortality. Additional research to identify the individual and contextual factors that explain the local variations in racial disparities is warranted. PMID- 22835484 TI - Reducing potentially preventable hospital transfers: results from a thirty nursing home collaborative. AB - BACKGROUND: Nursing home (NH) residents experience frequent hospital transfers, some potentially avoidable. The objective of this report is to describe a replication of the Interventions to Reduce Acute Care Transfers program among member facilities of a New York City area NH provider association (INTERACT NY) and estimate its effect on hospital transfers. METHODS: INTERACT is a program that provides tools and strategies to assist NH staff in early identification, communication, and documentation of changes in resident status. Funding was obtained from a New York State health workforce training grant to conduct 13 INTERACT education and training sessions in 2010-2011. INTERACT NY session topics included the implementation process; use of its simple standardized communication tools, advance care planning tools, care paths, and change in condition support tools; quality review of hospital transfers; exercises for refining clinical skills; teamwork; and lessons learned. Sessions engaged NH executives, department heads, front-line nursing staff and their labor union, and staff from NHs' partner hospitals. Pre-/post- INTERACT NY hospitalization rates per 1000-resident days were compared using paired t-tests, stratified by level of facility engagement with the program and by baseline hospitalization rates. RESULTS: All 100% of participating NHs were non-profit or public. Those with complete evaluation data had 377 beds on average. There were a total of 333 attendees of the program (mean 25.6 per session; mean 11.1 per facility over the course of the program; range 1-44 per facility). The most common attendees in order of frequency were (1) nurse administrators, (2) unit-based nurses, (3) medical directors and attending physicians, (4) nursing home administrators, (5) certified nursing assistants, and (6) case managers and social workers. Sixteen nursing homes implemented at least one INTERACT tool. Overall, there was a nonsignificant 10.6% reduction in hospital admissions from 4.07 to 3.64 per 1000 resident-days from pre- to post-INTERACT NY (P = .332). Among nursing homes with high engagement there was a nonsignificant 14.3% reduction in hospital admissions from 4.19 to 3.59 per 1000 resident-days (P = 0.213). Finally, among nursing homes in the highest tertile of baseline (pre-INTERACT NY) hospital admission rate, there was a nonsignificant 27.2% reduction in hospital admissions from 7.32 to 5.33 per 1000 resident-days (P = .102). Planning and implementation lessons from INTERACT NY leaders and participants are reported. CONCLUSIONS: INTERACT NY, a novel collaborative training program, resulted in good uptake of the INTERACT tools and processes among its member nursing homes. Changes in hospitalization rates associated with INTERACT NY were similar to those observed in previous implementations of INTERACT. The program addresses a growing interest in reducing potentially preventable hospital admissions among nursing home residents and providing alternatives to hospital care through standardized approaches to communication, early identification of clinical issues, decision-support, and support for partnerships between acute and post-acute care providers. PMID- 22835486 TI - Pulsed or continuous flow in long-term assist devices: a debated topic. AB - The end-stage cardiomyopathy is an increasing worldwide problem. Cardiac transplantation lacks sufficient donors to treat all patients, and there is thus debate about alternative strategies. The use of left ventricular assist devices for long-term support is increasing with a positive impact on patient survival. Although there is an ongoing debate regarding the risks and benefits of maintaining pulsatile flow during long-term ventricular assist device support, there has been a significant move towards implantation of continuous flow devices due to the lower surgical morbidity and better long-term reliability of these pumps. The following is a review of the literature on continuous and pulsatile flow for long-term support. Starting from the definition of flow, we analyze the current evidence and consider gastrointestinal complications. PMID- 22835485 TI - A cross-species view on viruses. AB - We describe the creative ways that virologists are leveraging experimental cross species infections to study the interactions between viruses and hosts. While viruses are usually well adapted to their hosts, cross-species approaches involve pairing viruses with species that they do not naturally infect. These cross species infections pit viruses against animals, cell lines, or even single genes from foreign species. We highlight examples where cross-species infections have yielded insights into mechanisms of host innate immunity, viral countermeasures, and the evolutionary interplay between viruses and hosts. PMID- 22835487 TI - The influence of footwear on the electromyographic activity of selected lower limb muscles during walking. AB - The purpose of this study was to compare the effects of a standard flexible shoe and a stability running shoe on lower limb muscle activity during walking. Twenty eight young asymptomatic adults with flat-arched feet were recruited. While walking, electromyographic (EMG) activity was recorded from tibialis posterior and peroneus longus via intramuscular electrodes; and from tibialis anterior and medial gastrocnemius via surface electrodes. Three experimental conditions were assessed: (i) barefoot, (ii) a standard flexible shoe, (iii) a stability running shoe. Results showed significant differences for the peak amplitude and the time of peak amplitude for tibialis anterior, peroneus longus and medial gastrocnemius when comparing the three experimental conditions (p < 0.05). Significant differences were detected primarily between the barefoot and shoe conditions and with relatively small effect sizes for peroneus longus, tibialis anterior and medial gastrocnemius. Few significant differences were found between the two shoe styles. We discuss how these changes are most likely associated with the shoe upper bracing the foot, the shape of the shoe outer-sole and weight of the shoes. Further research is needed to investigate differences between these shoe styles when participants walk for longer distances (i.e. over 1000 m) and following fatigue. PMID- 22835488 TI - Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection. AB - Regulatory T cells (Tregs) suppress the innate inflammation associated with kidney ischemia-reperfusion injury (IRI), but the mechanism is not well understood. Tregs express CD73, the final enzyme involved in the production of extracellular adenosine, and activation of the adenosine 2A receptor (A(2A)R) on immune cells suppresses inflammation and preserves kidney function after IRI. We hypothesized that Treg-generated adenosine is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A(2A)Rs on inflammatory cells and, in an autocrine manner, on Tregs themselves. We found that adoptively transferred wild-type Tregs protected wild type mice from kidney IRI, but the absence of adenosine generation (CD73 deficient Tregs) or adenosine responsiveness (A(2A)R-deficient Tregs) led to inhibition of Treg function. Pharmacologic stimulation of A(2A)R before adoptive transfer augmented the ability of wild-type and CD73-deficient Tregs to suppress kidney IRI. Microarray analysis and flow cytometry revealed that A(2A)R activation enhanced surface PD-1 expression on Tregs in the absence of any other activation signal. Treatment of Tregs with a PD-1 blocking antibody before adoptive transfer reversed their protective effects, even if pretreated with an A(2A)R agonist. Taken together, these results demonstrate that the simultaneous ability to generate and respond to adenosine is required for Tregs to suppress innate immune responses in IRI through a PD-1-dependent mechanism. PMID- 22835489 TI - Homotopic language reorganization in the right hemisphere after early left hemisphere injury. AB - To determine the areas involved in reorganization of language to the right hemisphere after early left hemisphere injury, we compared fMRI activation patterns during four production and comprehension tasks in post-surgical epilepsy patients with either left (LH) or right hemisphere (RH) speech dominance (determined by Wada testing) and healthy controls. Patient groups were carefully matched for IQ, lesion location and size. RH patients' activation across all tasks was greatest in right hemisphere areas homotopic to areas activated by LH and control participants. Differences in right vs. left dominant hemisphere activation were limited to homologous areas typically activated by language tasks, supporting the hypothesis that language localization following transfer to the RH is the mirror-image of localization in the absence of transfer. The similarity of these findings to those in patients with larger, peri-sylvian lesions suggests that these areas in both hemispheres may be uniquely predisposed to subserve various language functions. PMID- 22835490 TI - Changes in bowel symptoms 1 year after rectocele repair. AB - OBJECTIVE: We sought to evaluate changes in bowel symptoms after rectocele repair and identify risk factors for persistent symptoms. STUDY DESIGN: We conducted ancillary analysis of a randomized surgical trial for rectocele repair. Subjects underwent examinations and completed questionnaires for bowel symptoms at baseline and 12 months postoperatively. Outcomes included resolution, persistence, or de novo bowel symptoms. We used multiple logistic regression to identify risk factors for bowel symptom persistence. RESULTS: A total of 160 women enrolled: 139 had baseline bowel symptoms and 85% had 12-month data. The prevalence of bowel symptoms decreased after rectocele repair (56% vs 23% splinting, 74% vs 37% straining, 85% vs 19% incomplete evacuation, 66% vs 14% obstructive defecation; P < .001 for all). On multiple logistic regression, a longer history of splinting was a risk factor for persistent postoperative splinting (adjusted odds ratio, 2.25; 95% confidence interval, 1.02-4.93). CONCLUSION: Bowel symptoms may improve after rectocele repair, but almost half of women will have persistent symptoms. PMID- 22835491 TI - Placental pathology, birthweight discordance, and growth restriction in twin pregnancy: results of the ESPRiT Study. AB - OBJECTIVE: We sought to evaluate the association between placental histological abnormalities and birthweight discordance and growth restriction in twin pregnancies. STUDY DESIGN: We performed a multicenter, prospective study of twin pregnancies. Placentas were examined for evidence of infarction, retroplacental hemorrhage, chorangioma, subchorial fibrin, or abnormal villus maturation. Association of placental lesions with chorionicity, birthweight discordance, and growth restriction were assessed. RESULTS: In all, 668 twin pairs were studied, 21.1% monochorionic and 78.9% dichorionic. Histological abnormalities were more frequent in placentas of smaller twins of birthweight discordant pairs (P = .02) and in placentas of small for gestational age infants (P = .0001) when compared to controls. The association of placental abnormalities with both birthweight discordance and small for gestational age was significant for dichorionic twins (P = .01 and .0001, respectively). No such association was seen in monochorionic twins. CONCLUSION: In a large, prospective, multicenter study, we observed a strong relationship between abnormalities of placental histology and birthweight discordance and growth restriction in dichorionic, but not monochorionic, twin pregnancies. PMID- 22835492 TI - Customized estimated fetal weight: a novel antenatal tool to diagnose abnormal fetal growth. AB - OBJECTIVE: We sought to apply customized standards to ultrasound-derived estimated fetal weight (EFW), and assess the frequency of abnormal growth when compared to population-based standards. We also evaluated association with adverse perinatal outcomes. STUDY DESIGN: This was a historical cohort using prenatal ultrasound examination data at >=24 weeks over a 1-year period. Ultrasound-derived EFW and growth percentile (population-based EFW [popEFW]) were reported and compared to a customized EFW (custEFW). RESULTS: In all, 782 women met inclusion criteria. More fetuses were identified as small for gestational age (SGA) (15.1% vs 3.8%; P < .0001) and large for gestational age (LGA) (6.8% vs 1.7%; P < .0001) using custEFW, and adverse perinatal outcomes were more frequent among those identified by the custEFW compared to the popEFW. Both SGA and LGA diagnosed by custEFW were predictive of a neonatal SGA (positive likelihood ratio, 8.64) and LGA (positive likelihood ratio, 15.4). CONCLUSION: CustEFW was a better predictor of abnormal birthweight and adverse outcomes compared to traditional popEFW standards. PMID- 22835493 TI - The commercialization of robotic surgery: unsubstantiated marketing of gynecologic surgery by hospitals. AB - OBJECTIVE: We analyzed the content, quality, and accuracy of information provided on hospital web sites about robotic gynecologic surgery. STUDY DESIGN: An analysis of hospitals with more than 200 beds from a selection of states was performed. Hospital web sites were analyzed for the content and quality of data regarding robotic-assisted surgery. RESULTS: Among 432 hospitals, the web sites of 192 (44.4%) contained marketing for robotic gynecologic surgery. Stock images (64.1%) and text (24.0%) derived from the robot manufacturer were frequent. Although most sites reported improved perioperative outcomes, limitations of robotics including cost, complications, and operative time were discussed only 3.7%, 1.6%, and 3.7% of the time, respectively. Only 47.9% of the web sites described a comparison group. CONCLUSION: Marketing of robotic gynecologic surgery is widespread. Much of the content is not based on high-quality data, fails to present alternative procedures, and relies on stock text and images. PMID- 22835494 TI - Prepregnancy maternal body mass index and preterm delivery. AB - OBJECTIVE: The purpose of this study was to determine the influence of maternal prepregnancy body mass index on preterm delivery (PTD), controlling for health and lifestyle variables. STUDY DESIGN: Prospective data were from 83,544 pregnancies in the Norwegian Mother and Child Cohort Study. PTD was divided into early PTD (22 + 0 to 31 + 6 weeks' gestation) and late PTD (32 + 0 to 36 + 6 weeks' gestation). RESULTS: The overall prevalence of PTD was 5.1%. Increased body mass index was associated with an increased risk of PTD; adjusted odds ratio (aOR) ranged from 1.11 (95% confidence interval [CI], 1.03-1.20) for preobesity to 2.00 (95% CI, 1.48-2.71) for grade-III obesity in the group that included all PTD subgroups. Grade-III obese women had an increased risk of both early and late PTD: aOR, 3.24 (95% CI, 1.71-6.14) and 1.81 (95% CI, 1.29-2.54), respectively. CONCLUSION: Prepregnancy maternal overweight increases the risk of both early and late PTD. PMID- 22835495 TI - High-density lipoproteins after acute coronary syndromes: evaluation of residual risk. PMID- 22835496 TI - Facts and figures about patient associations in the Netherlands between 2007 and 2009: review of their activities and aims. AB - INTRODUCTION: To facilitate empowerment, the government encourages patient associations to participate in policy making discussions. To play a crucial role as one of the partners for the government in formulating policy on healthcare, information was needed about the activities and aims of Dutch patient associations. This article describes the development of the monitor in 2005 and 2006 and the most important outcomes and trends for 2007, 2008 and 2009. METHODS: Seven years ago, a yearly monitor of patient associations was started to quantify the activities of the patient and consumer movement in the Netherlands. We analyze individual Dutch patient associations focusing on empowerment and advocacy for their own members. RESULTS: Different types of associations pursue different goals to provide a 'voice' for their members. There was a very slight decline in individual members when comparing 2007 and 2009. More than a third of all associations have professional, paid employees. Organizations for disabled or mental disorders have the most volunteers. Peer support meetings for their own members remain the most popular activities. There are many small organizations and a few big ones. Advocacy remains important although the motives differ between patient associations. CONCLUSION: Dutch patient organizations reported activities they are expected to perform. They try to reduce information asymmetry by informing patients better through several media. They also provide peer support groups to their members. They reach the general public through their social media activities. Their primary focus is providing services to their members. PMID- 22835497 TI - The effect of colonoscopic tattooing on lymph node retrieval and sentinel lymph node mapping. AB - BACKGROUND: In colorectal cancer (CRC), colonoscopic tattooing is performed to mark the tumor site before laparoscopic surgery. OBJECTIVE: To determine whether colonoscopic tattooing can be used to refine staging accuracy by increasing the lymph node (LN) yield per specimen and to determine its accuracy as a sentinel LN procedure. DESIGN: Retrospective, case-control study. All LNs were microscopically examined for the presence of carbon particles. SETTING: A university hospital and a teaching hospital. PATIENTS: A consecutive series of 95 tattooed patients who had surgery for CRC between 2005 and 2009. A series of 210 non-tattooed patients who had surgery in the same time period served as controls. MAIN OUTCOME MEASUREMENTS: Total number of LNs retrieved, detection rate, and sensitivity of tattooing as a sentinel node procedure. RESULTS: A higher LN yield was observed in patients with preoperative tattooing, median (interquartile range) 15 (10-20) versus 12 (9-16), (P = .014). In multivariable analysis, the presence of carbon-containing LNs was an independent predictive factor for a higher LN yield (P = .002). The detection rate was 71%, with a median of 5 carbon containing LNs per specimen. If preoperative tattooing was used for sentinel node mapping, the overall accuracy of predicting LN status was 94%. In the 24 N1 cases, there were 4 false-negative procedures (sensitivity 83%). LIMITATIONS: Retrospective series. CONCLUSION: After tattooing of CRC, the LN yield was higher than in a control group, and it could be used as a sentinel node procedure with acceptable accuracy rates. Because LN yield and sentinel node mapping are associated with improved diagnostic accuracy of LN involvement, preoperative tattooing can refine staging. PMID- 22835498 TI - A critical reappraisal of the ATLS classification of hypovolaemic shock: does it really reflect clinical reality? AB - AIM: The aim of this study was to validate the classification of hypovolaemic shock given by the Advanced Trauma Life Support (ATLS). METHODS: Patients derived from the TraumaRegister DGU((r)) database between 2002 and 2010 were analyzed. First, patients were allocated into the four classes of hypovolaemic shock by matching the combination of heart rate (HR), systolic blood pressure (SBP) and Glasgow Coma Scale (GCS) according to ATLS. Second, patients were classified by only one parameter (HR, SBP or GCS) according to the ATLS classification and the corresponding changes of the remaining two parameters were assessed within these four groups. Analyses of demographic, injury and therapy characteristics were performed as well. RESULTS: 36,504 patients were identified for further analysis. Only 3411 patients (9.3%) could be adequately classified according to ATLS, whereas 33,093 did not match the combination of all three criteria given by ATLS. When patients were grouped by HR, there was only a slight reduction of SBP associated with tachycardia. The median GCS declined from 12 to 3. When grouped by SBP, GCS dropped from 13 to 3 while there was no relevant tachycardia observed in any group. Patients with a GCS=15 presented normotensive and with a HR of 88/min, whereas patients with a GCS<12 showed a slight reduced SBP of 117mmHg and HR was unaltered. CONCLUSION: This study indicates that the ATLS classification of hypovolaemic shock does not seem to reflect clinical reality accurately. PMID- 22835499 TI - Fate and occurrence of steroids in swine and dairy cattle farms with different farming scales and wastes disposal systems. AB - Fate and occurrence of fourteen androgens, four estrogens, five glucocorticoids and five progestagens were investigated in three swine farms and three dairy cattle farms with different farming scales and wastes disposal systems in China. Twenty-one, 22, and 12 of total 28 steroids were detected in feces samples with concentrations ranging from below method limit of quantitation (=20/40, and 81.8% of eyes were +/-0.5 D of the intended refraction. In 74.5% postoperative UCVA was equal to or better than preoperative BSCVA; 2 eyes lost 2 or more lines of BSCVA postoperatively because of the development of synechiae. In 75.5% of eyes the remaining cylinder was +/-0.5 D. There was a significant decrease in ECD after 3 months (4.8% +/- 11.9%), with no additional decline between 3 and 6 months. There were few complications, except for the incidence of pigment and nonpigment precipitates (14.8% and 12.2%, respectively at 6 months). Mean misalignment was 0.6 +/- 1.5 degrees (range 0-8). CONCLUSIONS: The Artiflex Toric pIOL effectively and safely corrects myopia and astigmatism in the short term, with stable and predictable visual results after 6 months, when strict inclusion criteria are applied. Deposition of pigment and nonpigment precipitates on the pIOL warrants further investigation. PMID- 22835513 TI - Patterns and costs associated with progression of age-related macular degeneration. AB - PURPOSE: To evaluate patterns of disease progression among individuals with age related macular degeneration (AMD) and to compare costs over time. DESIGN: Retrospective data analysis using 5% Medicare claims data from 1997 through 2009. METHODS: Beneficiaries were included if they had no diagnosis of AMD in 1997, were 65 years of age or older, had data through 2009, and had no major ophthalmic conditions. Two cohorts were identified: those who had dry AMD in 1998 (cases) and matched controls who never had AMD. RESULTS: There were 52,607 beneficiaries who never had AMD and 1184 who were diagnosed with dry AMD in 1998. Among beneficiaries with dry AMD, the disease progressed in 20.4% to the wet form by 2009. From 1999 to 2009, average annual Medicare expenditures increased from $11,265 to $24,494 (cases whose disease did not progress) and from $11,712 to $34,308 (cases whose disease progressed). Among beneficiaries without AMD, expenditures also increased over time (from $4736 in 1999 to $17,473 in 2009), but consistently were lower than cases' expenditures. Considering ophthalmic expenditures, the pattern was more pronounced: beneficiaries without AMD had annual expenditures less than $100, those with dry AMD had expenditures at least 3 times more, and wet AMD beneficiaries' costs were at least 5-fold more than that of those with dry disease. A subgroup analysis of beneficiaries without hypertension revealed similar patterns, although expenditures were lower than in the general population. CONCLUSIONS: AMD progression seems to be associated with increased annual Medicare expenditures. Findings suggest that halting or slowing disease progression using proven treatment such as Age-Related Eye Disease Study endorsed vitamins or novel technologies could have a substantial positive impact by lowering public health expenditures. PMID- 22835512 TI - Risk factors for visual field progression in the low-pressure glaucoma treatment study. AB - PURPOSE: To investigate risk factors associated with visual field progression in the Low-pressure Glaucoma Treatment Study, a prospective trial designed to compare the effects of the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% on visual function in low pressure glaucoma. DESIGN: Prospective cohort study. METHODS: Low-pressure Glaucoma Treatment Study patients with >=5 visual field tests during follow-up were included. Progression was determined using pointwise linear regression analysis, defined as the same 3 or more visual field locations with a slope more negative than -1.0 dB/year at P < 5%, on 3 consecutive tests. Ocular and systemic risk factors were analyzed using Cox proportional hazards model and further tested for independence in a multivariate model. RESULTS: A total of 253 eyes of 127 subjects (mean age, 64.7 +/- 10.9 years; mean follow-up, 40.6 +/- 12 months) were analyzed. Eyes randomized to timolol progressed faster than those randomized to brimonidine (mean rates of progression, -0.38 +/- 0.9 vs 0.02 +/- 0.7 dB/y, P < .01). In the final multivariate model adjusting for all tested covariates, older age (hazard ratio [HR] = 1.41/decade older, 95% confidence interval [CI] = 1.05 to 1.90, P = .022), use of systemic antihypertensives (HR = 2.53, 95% CI = 1.32 to 4.87, P = .005), and mean ocular perfusion pressure (HR = 1.21/mm Hg lower, 95% CI = 1.12 to 1.31, P < .001) were associated with progression whereas randomization to brimonidine revealed a protective effect (HR = 0.26, 95% CI = 0.12 to 0.55, P < .001). CONCLUSIONS: While randomization to brimonidine 0.2% was protective compared to timolol 0.5%, lower mean ocular perfusion pressure increased the risk for reaching a progression outcome in the Low-pressure Glaucoma Treatment Study. This suggests that the beneficial effect of randomization to the brimonidine arm was independent of possible differences in ocular perfusion pressures between the 2 treatment arms. The current results and large number of drop-outs in the brimonidine 0.2% arm suggest that more research is necessary before altering clinical practice paradigms. PMID- 22835514 TI - Spectral-domain optical coherence tomography of the choroid during valsalva maneuver. AB - PURPOSE: To evaluate the influence of Valsalva maneuver on the morphology and thickness of the choroid at the macular area. DESIGN: Prospective interventional case series. METHODS: Institutional setting. Nine healthy volunteers performed macular spectral-domain optical coherence tomography using enhanced-depth imaging at rest and during a Valsalva maneuver. Horizontal and vertical B-scans centered on the fovea were acquired. Subfoveal and average choroidal thickness in the central 3 mm were compared in the resting position and during the Valsalva maneuver using manual and semiautomatic measuring tools. Changes in choroidal thickness were evaluated. RESULTS: There was no statistically significant difference in choroidal thickness at rest or during Valsalva maneuver in any of the compared groups. The subfoveal thickness difference was -4.1 MUm on horizontal scans (P = .28) and 1.4 MUm on vertical scans (P = .75). The mean choroidal thickness difference in the central 3000 MUm was 8.5 MUm on horizontal scans (P = .73) and -5.3 MUm on vertical scans (P = .41). CONCLUSIONS: Valsalva maneuver does not change choroidal thickness at the posterior pole. The increase in ocular pressure caused by this maneuver cannot be explained by an increase in choroidal thickness in this portion of the uveal tract. PMID- 22835515 TI - Fovea-sparing internal limiting membrane peeling for myopic traction maculopathy. AB - PURPOSE: To investigate the effectiveness and safety of a new surgical technique of fovea-sparing internal limiting membrane (ILM) peeling for the treatment of foveal retinal detachments (RDs) in eyes with myopic traction maculopathy. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Forty five eyes of 45 consecutive patients who underwent vitrectomy and ILM peeling for the treatment of a foveal RD attributable to myopic traction maculopathy were studied. The patients were divided into 2 groups by the area of ILM peeled: complete macular ILM peeled group (30 eyes) and fovea-sparing ILM peeled group (15 eyes). A gas tamponade was used in all of the eyes. The main outcome measures were the rate of development of a full-thickness macular hole (MH) and the best corrected visual acuity (BCVA). All of the patients were followed for more than 6 months. RESULTS: A full-thickness MH developed in 5 of 30 eyes (16.7%) in the complete ILM peeled group and in none of the 15 eyes in the fovea-sparing ILM peeled group. Postoperative OCT examination showed a contraction of the residual ILM on the fovea and reduction of the outer lamellar holes in the fovea-sparing ILM peeled group. The postoperative BCVA was significantly better than the preoperative BCVA in the fovea-sparing ILM peeled group (P = .04), but not in the complete ILM peeled group. CONCLUSIONS: Fovea-sparing ILM peeling results in better visual and anatomic outcomes for the treatment of foveal RD attributable to myopic traction maculopathy. These were accomplished by reducing the development of a full-thickness MH. PMID- 22835516 TI - Disappearance of an activated EGFR mutation after treatment with EGFR tyrosine kinase inhibitors. AB - A 34-year-old Japanese woman presented with left supraclavicular lymph node swelling. Computed tomography scans revealed a mass on the left lower lobe, pulmonary nodules, and pleural effusion. A lymph node biopsy revealed large-cell carcinoma with an epidermal growth factor receptor (EGFR) deletion mutation, L747 T751 in exon 19. Although malignant pleural effusions carried the same EGFR mutation, progressive pleural effusions after treatment with chemotherapy, gefitinib, and erlotinib did not show any EGFR mutation. A cell line established from the pleural effusion 3 days before the patient expired also did not harbor the EGFR mutation. Histological sections of the lymph node of the patient were similar to those of the xenograft tumor of the cell line. There may be genetic heterogeneity in EGFR mutant tumors. PMID- 22835518 TI - Is reaction time variability consistent across sensory modalities? Insights from latent variable analysis of single-trial P3b latencies. AB - Recent years have witnessed a steep increase in cognitive, differential and clinical neuroscience research on the neural basis of intra-subject variability of reaction times. Most theoretical accounts make the implicit assumption that individual differences in intra-subject variability are consistent across sensory modalities, but this remains largely untested. The present EEG study aims to fill this gap by analyzing, for the first time, stimulus- and response-locked single trial P3bs across visual and auditory sensory modalities, and employing an innovative supra-task latent variables approach. We found unidimensionality of intra-subject variability variables across modalities as well as high correlations between the latency jitter of stimulus- and response-locked P3bs. These findings support the hypothesis that intra-subject variability represents a unitary construct, and that the processes underlying that generalises not only across different cognitive tasks, but also across different sensory modalities. PMID- 22835519 TI - LIF maintains progenitor phenotype of endothelial progenitor cells via Kruppel like factor 4. AB - BACKGROUND: Endothelial progenitor cells (EPCs) participate in post-natal vasculogenesis. Maintaining the preliminary progenitor phenotype and good proliferation capacity of EPCs is key to their use in treating cardiovascular ischemic diseases. However, transcriptional regulation in EPCs remains largely unknown. We investigated the effect of leukemia inhibitory factor (LIF) combined with vascular endothelial growth factor (VEGF) on EPCs and the potential roles of Kruppel-like transcription factors (KLFs). METHODS AND RESULTS: Co-treatment with LIF and VEGF (100 ng/ml each) (V+L) could increase EPC colony-forming units and CD34 expression, which reflects the EPC progenitor phenotype and alleviated differentiation of EPCs. The effect was associated with Akt activation and increased expression of KLF4. Upregulation of KLF4 induced by V+L could be inhibited by transfection with dominant-negative Akt adenovirus. Furthermore, overexpression of KLF4 in EPCs enhanced the expression of CD34 and alleviated cell differentiation but did not increase the phosphorylation of Akt. CONCLUSIONS: LIF combined with VEGF can maintain the preliminary, progenitor phenotype of EPCs and alleviate cell differentiation by upregulating KLF4, which may provide new insights into transcriptional regulation in EPCs. PMID- 22835520 TI - Elevated serum levels of AGEs, sRAGE, and pentosidine in Tunisian patients with severity of diabetic retinopathy. AB - OBJECTIVES: The advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis activity are implicated in diabetic vascular complications. We measured serum AGE, sRAGE and pentosidine levels in Tunisian patients with diabetic retinopathy (DR) and examined whether these biomarkers are related to the severity of DR. DESIGN AND METHODS: We included 30 healthy control subjects and 100 diabetic patients were divided into 2 subgroups: 40 patients with nonproliferative diabetic retinopathy (NPDR), and 60 patients with proliferative diabetic retinopathy (PRD). AGEs, sRAGE and pentosidine were measured in serum by ELISA. RESULTS: Serum levels of AGEs, sRAGE and pentosidine were significantly increased in patients with diabetes mellitus compared to nondiabetic controls (P<.01, P<.001, P<.001 respectively). In diabetic patients, serum AGEs, sRAGE and pentosidine levels were significantly higher in patients who had PDR than in those with NPDR (P=.001, P=.01, P=.005 respectively). Furthermore, in stepwise multivariate regression analysis, the levels of pentosidine and duration of diabetes were independently associated with severity of DR. CONCLUSION: Serum AGEs, sRAGE, and pentosidine levels are related with the presence of DR. Duration of diabetes and pentosidine were independently correlated with the severity of DR. PMID- 22835521 TI - The effect of vasoactive agents on post-pressure hyperemia. AB - The cutaneous hyperemic response following the release of direct pressure occlusion lasts much longer than the short-term hyperemia that occurs after proximal arterial occlusion. Post-pressure hyperemia may be an important mechanism to prevent pressure induced injury to the skin. The role of vasoactive mediators in modulating post-pressure hyperemia is unknown. In an effort to better understand this phenomenon, we performed an initial study using microdialysis infusion to measure the effect of several known mediators of vascular response on post-pressure hyperemia. A vise clamp was used to apply direct occlusive pressure to a laser Doppler sensor on the skin surface overlying the microdialysis fiber. Skin blood flow was measured continuously pre, during and post-occlusion while infusing the vasoactive substance or control phosphate buffer. Angiotensin II, Calcitonin gene related peptide and histamine had minimal effect on post pressure blood flow. Conversely, prostaglandin E1, prostaglandin E2, and L-NAME diminished the early phase of the post-occlusion hyperemic response. Perhaps the most profound effect we observed was the decrease in post occlusive blood flow due to administration of epinephrine, dopamine and prostaglandin F2alpha. In contrast, adenosine and caffeine augmented blood flow post occlusion. In this initial survey study, we have demonstrated differential effects of various vascular mediators on the post-pressure hyperemic phenomenon. Our findings may lead to the development of agents to prevent pressure sores by augmenting the skin blood flow response to locally applied pressure. PMID- 22835523 TI - Inhibition of phospholipase A1, lipase and galactolipase activities of pancreatic lipase-related protein 2 by methyl arachidonyl fluorophosphonate (MAFP). AB - Methyl arachidonyl fluorophosphonate (MAFP) is a known inhibitor of cytosolic phospholipase A2 and some other serine enzymes. MAFP was found here to be an irreversible inhibitor of human pancreatic lipase-related protein 2 (HPLRP2), an enzyme displaying lipase, phospholipase A1 and galactolipase activities. In the presence of MAFP, mass spectrometry analysis of HPLRP2 revealed a mass increase of 351Da, suggesting a covalent binding of MAFP to the active site serine residue. When HPLRP2 was pre-incubated with MAFP before measuring residual activity, a direct inhibition of HPLRP2 occurred, confirming that HPLRP2 has an active site freely accessible to solvent and differs from most lipases in solution. HPLRP2 activities on tributyrin (TC4), phosphatidylcholine (PC) and monogalactosyl dioctanoylglycerol (C8-MGDG) were equally inhibited under these conditions. Bile salts were not required to trigger the inhibition, but they significantly increased the rate of HPLRP2 inhibition, probably because of MAFP micellar solubilization. Since HPLRP2 is active on various substrates that self organize differently in the presence of water, HPLRP2 inhibition by MAFP was tested in the presence of these substrates after adding MAFP in the course of the lipolysis reaction. In this case, the rates of inhibition of lipase, phospholipase A1 and galactolipase activities were not equivalent (triglycerides>PC>MGDG), suggesting different enzyme/inhibitor partitioning between the aqueous phase and lipid aggregates. The inhibition by MAFP of a well identified phospholipase A1 (HPLRP2), present in pancreatic juice and also in human monocytes, indicates that MAFP cannot be used for discriminating phospholipase A2 from A1 activities at the cellular level. PMID- 22835524 TI - Fabrication of titanium based MALDI bacterial chips for rapid, sensitive and direct analysis of pathogenic bacteria. AB - For the first time, we report the fabrication of a titanium bacterial chip for MALDI-MS produced from a simple, cost effective and rapid heat treatment process. This bacterial chip can be reused many times and is highly versatile. These bacterial chips serve dual roles: (1) They can be applied as MALDI-MS target plates for direct and highly sensitive bacterial analysis. (2) They can be used as bacterial sensors for direct analysis of the captured bacteria using MALDI-MS. The sensitivity of these chips when used as bacterial sensors is <10(3)cfu/mL. The lowest detectable concentration for direct MALDI-MS analysis was found to be 10(4)cfu/mL. The results were further justified by using standard plate counting method combined with Tukey-Kramer statistical analysis and fluorescence imaging followed by image processing for fluorescence quantification using ImageJ software to substantiate the MALDI-MS results. PMID- 22835522 TI - Lipid phosphate phosphatase (LPP3) and vascular development. AB - Lipid phosphate phosphatases (LPP) are integral membrane proteins with broad substrate specificity that dephosphorylate lipid substrates including phosphatidic acid, lysophosphatidic acid, ceramide 1-phosphate, sphingosine 1 phosphate, and diacylglycerol pyrophosphate. Although the three mammalian enzymes (LPP1-3) demonstrate overlapping catalytic activities and substrate preferences in vitro, the phenotypes of mice with targeted inactivation of the Ppap2 genes encoding the LPP enzymes reveal nonredundant functions. A specific role for LPP3 in vascular development has emerged from studies of mice lacking Ppap2b. A meta analysis of multiple, large genome-wide association studies identified a single nucleotide polymorphism in PPAP2B as a novel predictor of coronary artery disease. In this review, we will discuss the evidence that links LPP3 to vascular development and disease and evaluate potential molecular mechanisms. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 22835525 TI - SPR detection of human hepcidin-25: a critical approach by immuno- and biomimetic based biosensing. AB - The human hepcidin-25 hormone has a key role in iron regulation in blood. The clinical relevance of this hepatic ~2.8 kDa cysteine-rich peptide is rapidly increasing, since altered levels can be associated with inflammatory events and iron dysfunctions, such as hereditary hemochromatosis and iron overload. Moreover, hepcidin has also attracted the anti-doping field for its possible role as indirect marker of erythropoietin blood doping. Methods currently reported are based on immunoassays (ELISA and RIA), or various types of mass spectroscopy (MS) based protocols, semi-quantitative or quantitative. Despite the great effort in optimizing robust and simple assays measuring hepcidin in real matrices, at present this challenge remains still an open issue. To explore the possibility to face hepcidin detection through the development of affinity-based biosensors, we set up a comparative study by surface plasmon resonance (SPR) technology. An immuno-based, on anti-hepcidin-25 IgG, and a biomimetic-based, on a synthetic peptide corresponding to the hepcidin-binding site on ferroportin (HBD), biosensors were developed. Here we report behaviors and analytical performances of the two systems, discussing limits and potentialities. PMID- 22835526 TI - Global gene expression analysis in skin biopsies of European red deer experimentally infected with bluetongue virus serotypes 1 and 8. AB - Bluetongue virus (BTV) is a double-stranded RNA virus transmitted by blood feeding biting midges of the genus Culicoides to wild and domestic ruminants, causing high morbidity and variable mortality. The aim of this study was to characterize differential gene expression in skin biopsies of red deer (Cervus elaphus) hinds experimentally infected with BTV serotypes 1 and 8. Skin biopsies were collected from BTV-1 and BTV-8 experimentally infected and control hinds at 14 and 98 days post-infection (dpi). Global gene expression profile in response to BTV infection was characterized at 14 dpi using a bovine microarray together with real-time RT-PCR analysis of differentially expressed genes at 14 and 98 dpi. Eighteen genes were upregulated and three were downregulated in response to virus infection, with no significant differences between BTV-1 and BTV-8 infected hinds. Seven unique genes, six upregulated (ISG15, PSMB8, PSMB9, BOLA, C1qA, C4) and one downregulated (FOS) were over-represented after conditional test for biological process gene ontology, which affected five molecular pathways (RIG-1, proteasome, MHC-1, complement, TLR) implicated in host immune response. BTV infection had a minor and transient effect on gene expression in hinds, as shown by the very few genes that were differentially expressed in response to infection at 14 dpi, most of which had similar expression levels between infected and uninfected animals at 98 dpi. These results suggested that red deer could control BTV infection with little effect on host molecular pathways. PMID- 22835527 TI - Bluetongue virus genetic and phenotypic diversity: towards identifying the molecular determinants that influence virulence and transmission potential. AB - Bluetongue virus (BTV) is the prototype member of the Orbivirus genus in the family Reoviridae and is the aetiological agent of the arthropod transmitted disease bluetongue (BT) that affects both ruminant and camelid species. The disease is of significant global importance due to its economic impact and effect on animal welfare. Bluetongue virus, a dsRNA virus, evolves through a process of quasispecies evolution that is driven by genetic drift and shift as well as intragenic recombination. Quasispecies evolution coupled with founder effect and evolutionary selective pressures has over time led to the establishment of genetically distinct strains of the virus in different epidemiological systems throughout the world. Bluetongue virus field strains may differ substantially from each other with regards to their phenotypic properties (i.e. virulence and/or transmission potential). The intrinsic molecular determinants that influence the phenotype of BTV have not clearly been characterized. It is currently unclear what contribution each of the viral genome segments have in determining the phenotypic properties of the virus and it is also unknown how genetic variability in the individual viral genes and their functional domains relate to differences in phenotype. In order to understand how genetic variation in particular viral genes could potentially influence the phenotypic properties of the virus; a closer understanding of the BTV virion, its encoded proteins and the evolutionary mechanisms that shape the diversity of the virus is required. This review provides a synopsis of these issues and highlights some of the studies that have been conducted on BTV and the closely related African horse sickness virus (AHSV) that have contributed to ongoing attempts to identify the molecular determinants that influence the virus' phenotype. Different strategies that can be used to generate BTV mutants in vitro and methods through which the causality between particular genetic modifications and changes in phenotype may be determined are also described. Finally examples are highlighted where a clear understanding of the molecular determinants that influence the phenotype of the virus may have contributed to risk assessment and mitigation strategies during recent outbreaks of BT in Europe. PMID- 22835528 TI - Neuroplastic modulation of inhibitory motor cortical networks by spaced theta burst stimulation protocols. AB - BACKGROUND: Continuous theta burst stimulation (cTBS) suppresses the excitability of motor networks responsible for generating motor evoked potentials (MEPs), and may also modulates the excitability of inhibitory motor networks. However, its effects on intracortical inhibition are modest in comparison to the effects on MEPs. The repeated, spaced, application of cTBS protocols results in more MEP suppression than seen with a single cTBS protocol, but whether this approach is also effective at modulating intracortical inhibition has not been tested. OBJECTIVE: To determine whether the paired application of cTBS effectively modulates the excitability of intracortical inhibitory motor networks. METHODS: Single and paired-pulse transcranial magnetic stimulation (TMS) were used to assess resting motor threshold (RMT), MEP amplitude, short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI) before and during two time periods (0-10 and 30-40 min) following application of either a single or paired cTBS protocols. RESULTS: Both the single and paired cTBS conditions induced a significant reduction in both MEP amplitudes and the level of SICI. While paired cTBS produced a significantly greater MEP suppression than single cTBS, the effects on SICI were similar. Neither single nor paired cTBS had an effect on RMT or LICI. CONCLUSIONS: Although the repeated application of cTBS protocols may be effective for enhancing modulation of the MEP-generating excitatory motor networks, these findings suggest that this approach offers little advantage when targeting intracortical inhibitory networks. PMID- 22835529 TI - Simulated unobtrusive falls detection with multiple persons. AB - One serious issue related to falls among the elderly living at home or in a residential care facility is the "long lie" scenario, which involves being unable to get up from the floor after a fall for 60 min or more. This research uses a simulated environment to investigate the potential effectiveness of using wireless ambient sensors (dual-technology (microwave/infrared) motion detectors and pressure mats) to track the movement of multiple persons and to unobtrusively detect falls when they occur, therefore reducing the rate of occurrence of "long lie" scenarios. A path-finding algorithm (A*) is used to simulate the movement of one or more persons through the residential area. For analysis, the sensor network is represented as an undirected graph, where nodes in the graph represent sensors, and edges between nodes in the graph imply that these sensors share an overlapping physical region in their area of sensitivity. A second undirected graph is used to represent the physical adjacency of the sensors (even where they do not overlap in their monitored regions). These graphical representations enable the tracking of multiple subjects/groups within the environment, by analyzing the sensor activation and adjacency profiles, hence allowing individuals/groups to be isolated when multiple persons are present, and subsequently monitoring falls events. A falls algorithm, based on a heuristic decision tree classifier model, was tested on 15 scenarios, each including one or more persons; three scenarios of activity of daily living, and 12 different types of falls (four types of fall, each with three postfall scenarios). The sensitivity, specificity, and accuracy of the falls algorithm are 100.00%, 77.14%, and 89.33%, respectively. PMID- 22835530 TI - A dynamic risk score to identify increased risk for heart failure decompensation. AB - A method for combining heart failure (HF) diagnostic information in a Bayesian belief network (BBN) framework to improve the ability to identify when patients are at risk for HF hospitalization (HFH) is investigated in this paper. Implantable devices collect HF related diagnostics, such as intrathoracic impedance, atrial fibrillation (AF) burden, ventricular rate during AF, night heart rate, heart rate variability, and patient activity, on a daily basis. Features were extracted that encoded information regarding out of normal range values as well as temporal changes at weekly and monthly time scales. A BBN is used to combine the features to generate a risk score defined as the probability of a HFH given the diagnostic evidence. Patients with a very high risk score at follow-up are 15 times more likely to have a HFH in the next 30 days compared to patients with a low-risk score. The combined score has improved ability to identify patients at risk for HFH compared to the individual diagnostic parameters. A score of this nature allows clinicians to manage patients by exception; a patient with higher risk score needs more attention than a patient with lower risk score. PMID- 22835531 TI - Transillumination imaging for blood oxygen saturation estimation of skin lesions. AB - Detecting the early stages of melanoma can be greatly assisted by an accurate estimate of subsurface blood volume and blood oxygen saturation, indicative of angiogenesis. Visualization of this blood volume present beneath a skin lesion can be achieved through the transillumination of the skin. As the absorption of major chromophores in the skin is wavelength dependent, multispectral imaging can provide the needed information to separate out relative amounts of each chromophore. However, a critical challenge to this strategy is relating the pixel intensities observed in a given image to the wavelength-dependent total absorption existing at each spatial location. Consequently, in this paper, we develop an extension to Beer's law, estimated through a novel voxel-based, parallel processing Monte Carlo simulation of light propagation in skin which takes into account the specific geometry of our transillumination imaging apparatus. We then use this relation in a linear mixing model, solved using a multispectral image set, for chromophore separation and oxygen saturation estimation of an absorbing object located at a given depth within the medium. Validation is performed through the Monte Carlo simulation, as well as by imaging on a skin phantom. Results show that subsurface oxygen saturation can be reasonably estimated with good implications for the reconstruction of 3-D skin lesion volumes using transillumination toward early detection of malignancy. PMID- 22835532 TI - A novel technology for motion capture using passive UHF RFID tags. AB - Although there are several existing methods for human motion capture, they all have important limitations and hence there is the need to explore fundamentally new approaches. Here, we present a method based on a radio frequency identification (RFID) system with passive ultra high frequency (UHF) tags placed on the body segments whose kinematics is to be captured. Dual polarized antennas are used to estimate the inclination of each tag based on the polarization of the tag responses. The method has been validated experimentally for the shank and thigh in the sagittal plane during treadmill walking. The reference segment angles for the validation were obtained by an optoelectronic system. Although the method is in its initial phase of development, the results of the validation are promising and show that the movement information can be extracted from the RFID response signals. PMID- 22835533 TI - ZmMKK3, a novel maize group B mitogen-activated protein kinase kinase gene, mediates osmotic stress and ABA signal responses. AB - Mitogen-activated protein kinase (MAPK) cascades are important intracellular signaling modules and function as a convergent point for crosstalk during abiotic stress signaling. In this article, we isolated a novel group B MAPKK gene, ZmMKK3, from Zea mays. ZmMKK3 protein might be localized in both the cytoplasm and the nucleus. RNA blot analysis indicated that the ZmMKK3 transcription was up regulated by abscisic acid (ABA), hydrogen peroxide (H(2)O(2)) and PEG, and that H(2)O(2) mediated PEG-induced expression of ZmMKK3. Constitutive expression of ZmMKK3 in Nicotiana tabacum reduced H(2)O(2) accumulation under osmotic stress by affecting antioxidant defense systems and alleviated reactive oxygen species mediated injury under oxidative stress. Transgenic tobacco exhibited attenuated ABA sensitivity by means of an increased germination rate and main root growth. Taken together, these results indicate that ZmMKK3 is a positive regulator of osmotic tolerance and ABA signaling in plants. PMID- 22835535 TI - Pulpal and periradicular response to caries: current management and regenerative options. AB - The pulp-dentin complex is a strategic and dynamic barrier to various insults that plague the dentition. Researchers have yet to understand the complete potential of this shifting junction and its components. The most common cause of injury to the pulp-dentin complex is carious breakdown of enamel and dentin. In recent years, there has been a change in restorative management of caries. The emphasis is on strategies to preserve dentin and protect the pulp. This article provides a brief review of the effect of caries on the pulp, of subsequent events on the periradicular tissues, and of current understanding of treatment modalities. PMID- 22835536 TI - Regenerative therapy: a periodontal-endodontic perspective. AB - Periodontal and endodontic diseases are inflammatory responses leading to periodontal and pulpal tissue loss. Regenerative therapies aim to restore the lost structures to vitality and function. Various materials and treatments methods have been used such as bone grafts, guided tissue regeneration, enamel matrix derivatives, growth and differentiation factors, and stem cells. Although the current materials and methods demonstrated adequate clinical results, true and complete biological tissue regeneration is not yet attainable. The current article reviews chronologically the materials and methods used in periodontal and endodontic regeneration highlighting their clinical success and shortcomings, and discussing future directions in regenerative therapy. PMID- 22835537 TI - Dental stem cells and their sources. AB - The search for more accessible mesenchymal stem cells than those found in bone marrow has propelled interest in dental tissues. Human dental stem/progenitor cells (collectively termed dental stem cells [DSCs]) that have been isolated and characterized include dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. Common characteristics of these cell populations are the capacity for self-renewal and the ability to differentiate into multiple lineages. In vitro and animal studies have shown that DSCs can differentiate into osseous, odontogenic, adipose, endothelial, and neural-like tissues. PMID- 22835539 TI - Constructs and scaffolds employed to regenerate dental tissue. AB - Dental tissue injury and regeneration affects the daily lives of almost everyone. Tissue engineering is emerging as a promising therapy to regenerate missing teeth and dental tissues. The aim of regenerative dental therapies is to restore patients to full oral health. This means restoring normal function to missing or damaged tissue. Regeneration approaches use a combination of scaffolds, stem cells, growth factors, tissue engineering, organ tissue culture, transplantation, and tissue grafting. There are 8 key elements to create and use tissue constructs for tissue regeneration. These will be described in detail in this article. PMID- 22835534 TI - Stem cell and biomaterials research in dental tissue engineering and regeneration. AB - This review summarizes approaches used in tissue engineering and regenerative medicine, with a focus on dental applications. Dental caries and periodontal disease are the most common diseases resulting in tissue loss. To replace or regenerate new tissues, various sources of stem cells have been identified such as somatic stem cells from teeth and peridontium. Advances in biomaterial sciences including microfabrication, self-assembled biomimetic peptides, and 3 dimensional printing hold great promise for whole-organ or partial tissue regeneration to replace teeth and periodontium. PMID- 22835538 TI - Effects of growth factors on dental stem/progenitor cells. AB - The primary goal of regenerative endodontics is to restore the vitality and functions of the dentin-pulp complex, as opposed to filing of the root canal with bioinert materials. A myriad of growth factors regulates multiple cellular functions including migration, proliferation, differentiation, and apoptosis of several cell types intimately involved in dentin-pulp regeneration. Recent work showing that growth factor delivery, without cell transplantation, can yield pulp dentin-like tissues in vivo provides one of the tangible pathways for regenerative endodontics. This review synthesizes knowledge on many growth factors that are known or anticipated to be efficacious in dental pulp-dentin regeneration. PMID- 22835540 TI - Harnessing the natural regenerative potential of the dental pulp. AB - Biological solutions for the repair and regeneration of the dental tissues offer significant potential for improved clinical treatment outcomes. Translation of dental tissue-engineering approaches to the clinic will make considerable contributions to these outcomes in the future, but exploiting the natural regenerative potential of dentin-pulp to enhance wound-healing responses offers solutions for maintaining pulp vitality now. Strategies to harness the natural regenerative potential of the pulp must be based on a sound biological understanding of the cellular and molecular events taking place, and require careful consideration of the interplay of infection, inflammation, and regeneration. PMID- 22835541 TI - Clinical considerations for regenerative endodontic procedures. AB - The management of a tooth with incomplete root maturation and a necrotic pulp is an endodontic and a restorative challenge. Apexification procedures alone leave the tooth in a weakened state and at risk for reinfection. Regenerative endodontic procedures potentially offer advantages, including the possibility of hard tissue deposition and continued root development. Case studies have reported regeneration of human pulplike tissues in vivo, but there is no protocol that reliably regenerates pulplike tissue. This article summarizes historical, current, and future regenerative treatment approaches. PMID- 22835542 TI - Outcomes of regenerative endodontic procedures. AB - The use of regenerative endodontic techniques holds great promise for the treatment of immature teeth with necrotic pulp tissue. Several published case reports and case series have demonstrated radiographic evidence of apical bone healing, increases in root length, and root wall thickness. Although histologic changes have been demonstrated in animal models, histology in human teeth is lacking. A summary of these outcomes is discussed in this article. PMID- 22835543 TI - Regenerative endodontics: barriers and strategies for clinical translation. AB - Regenerative endodontics has encountered substantial challenges toward clinical translation. The adoption by the American Dental Association of evoked pulp bleeding in immature permanent teeth is an important step for regenerative endodontics. However, there is no regenerative therapy for most endodontic diseases. Simple recapitulation of cell therapy and tissue engineering strategies that are under development for other organ systems has not led to clinical translation in regeneration endodontics. Recent work using novel biomaterial scaffolds and growth factors that orchestrate the homing of host endogenous cells represents a departure from traditional cell transplantation approaches and may accelerate clinical translation. PMID- 22835545 TI - Regenerative endodontics and tissue engineering: what the future holds? AB - The work performed by researchers in regenerative endodontics and tissue engineering over the last decades has been superb; however, many questions remain to be answered. The basic biologic mechanisms must be elucidated that will allow the development of dental pulp and dentin in situ. Stress must be placed on the many questions that will lead to the design of effective, safe treatment options and therapies. This article discusses those questions, the answers to which may become the future of regenerative endodontics. The future remains bright, but proper support and patience are required. PMID- 22835546 TI - Dental clinics of North America. PMID- 22835544 TI - Therapeutic potential of mesenchymal stem cells for oral and systemic diseases. AB - Mesenchymal stem cells (MSCs) are adult stem cells whose self-renewal, multipotency, and immunosuppressive functions have been investigated for therapeutic applications. MSCs have used for various systemic organ regenerative therapies, allowing rescue of tissue function in damaged or failing organs. This article reviews the regenerative and immunomodulatory functions of MSCs and their applications in dental, orofacial, and systemic tissue regeneration and treatment of inflammatory disorders. It also addresses challenges to MSC-mediated therapeutics arising from tissue and MSC aging and host immune response against allogenic MSC transplantation, and discusses alternative sources of MSCs aimed at overcoming these limitations. PMID- 22835547 TI - Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-zeta pathways. AB - We determined the precise role of relaxin family peptide (RXFP) receptors-1 and 2 in the regulation of MMP-9 and -13 by relaxin, and delineated the signaling cascade that contributes to relaxin's modulation of MMP-9 in fibrocartilaginous cells. Relaxin treatment of cells in which RXFP1 was silenced resulted in diminished induction of MMP-9 and -13 by relaxin, whereas overexpression of RXFP1 potentiated the relaxin-induced expression of these proteinases. Suppression or overexpression of RXFP2 resulted in no changes in the relaxin-induced MMP-9 and 13. Studies using chemical inhibitors and siRNAs to signaling molecules showed that PI3K, Akt, ERK and PKC-zeta and the transcription factors Elk-1, c-fos and, to a lesser extent, NF-kappaB are involved in relaxin's induction of MMP-9. Our findings provide the first characterization of signaling cascade involved in the regulation of any MMP by relaxin and offer mechanistic insights on how relaxin likely mediates extracellular matrix turnover. PMID- 22835548 TI - Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. AB - We previously established that Indole-3-Carbinol (I3C), a natural hydrolysis product of glucobrassicin in cruciferous vegetables, arrests the proliferation of estrogen-dependent human breast cancer cells and induces protein degradation of Estrogen Receptor-alpha (ERalpha). We demonstrate in human MCF-7 breast cancer cells that I3C ablates expression of Insulin-like Growth Factor Receptor-1 (IGF1R) and Insulin Receptor Substrate-1 (IRS1), downstream effectors of the IGF1 signaling pathway. Exogenous ERalpha reversed the I3C mediated loss of IGF1R and IRS1 gene expression demonstrating that down-regulation of ERalpha is functionally linked to I3C control of IGF1R and IRS1 expression. I3C disrupted binding of endogenous ERalpha, but not Sp1, to ERE-Sp1 composite elements within the IGF1R/IRS1 promoters. Exogenous ERalpha abrogated, and combined expression of IGF1R and IRS1 attenuated, the I3C mediated cell cycle arrest. Therefore, I3C inhibits proliferation of estrogen-sensitive breast cancer cells through disruption of ERalpha-mediated transcription of cell signaling components within the IGF1 cascade. PMID- 22835549 TI - Shear bond strength of three dual-cured resin cements to dentin analyzed by finite element analysis. AB - OBJECTIVES: To determine the shear bond strength to bovine dentin of dual-cured resin cements cured in different circumstances, the contraction stress and volumetric shrinkage in both polymerization modes, and to review the failure stress distribution at the cement-tooth interface with finite element analysis. METHODS: The volumetric shrinkage of RelyX Unicem, Panavia F 2.0 and DC Core Automix was determined by mercury dilatometry. Polymerization contraction stress was determined using a constraint tensilometer set-up. For the shear bond strength test, cement discs on bovine root dentin (self-cured and dual-cured), composite discs cemented to dentin (self-cured and dual-cured), and dentin cemented to dentin (self-cured) specimens were fabricated. Specimens were stored in water for 24h (37 degrees C, 100% humidity) and tested (crosshead speed 1mmmin(-1)). FE modeling of the specimens was carried out in order to calculate the maximum shear stresses in the cement-dentin interface. Differences between groups were determined using two-way ANOVA with Tukey post hoc tests, and paired samples t-tests (alpha<0.05). RESULTS: Panavia F2.0 showed significantly lower volumetric shrinkage than the other cements. Dual-curing lead to higher contraction stresses for all tested cements compared to self-curing. RelyX Unicem showed higher volumetric shrinkage when dual-cured. Shear bond strength and maximum shear stress was positively influenced by dual-curing. DC Core Automix performed best and Panavia F2.0 worst in terms of shear bond strength and maximum shear stress. SIGNIFICANCE: Curing mode may play an important role in the final bond strength to dentin of indirect restorations, depending on the material used. PMID- 22835550 TI - Mitral valve surgical procedures in the elderly. AB - BACKGROUND: Mitral valve (MV) surgical procedures in the elderly are associated with profound operative and long-term mortality. We report our experience and results for MV surgical procedures in the elderly, especially with regard to the influence of comorbidities. METHODS: Our hospital database was assessed to identify all patients who underwent MV surgical procedures at the age of 70 years and older between 1999 and 2009. The data were retrospectively analyzed. RESULTS: A total of 2,503 patients operated on during this 10-year period were identified. In 97% of patients, mitral regurgitation (MR) was the primary indication for operation, followed by coronary artery disease in 41.6% and aortic valve stenosis in 21.3%. The 30-day mortality rate was 3.1%, and the long-term survival at 5 years was 55.2% (95% confidence interval, 52.3% to 57.5%). Coronary artery bypass grafting was identified to be associated with inferior short-term and long-term survival. Numerous comorbidities significantly influenced long-term survival. The observed mortality was significantly lower than predicted by EuroSCORE (17.2%). CONCLUSIONS: MV operations in the elderly can be performed with a low early mortality and promising long-term survival. However, our large series demonstrates that comorbidities are to be attributed as the real burden for successful treatment of elderly patients undergoing MV procedures. PMID- 22835551 TI - Improved functional mitral regurgitation after off-pump revascularization in acute coronary syndrome. AB - BACKGROUND: We evaluated the effect of isolated off-pump coronary artery bypass grafting on functional ischemic mitral regurgitation (IMR) associated with acute coronary syndrome. METHODS: Of 1,419 acute coronary syndrome patients who underwent coronary revascularization between 2000 and 2010 (1,324 off-pump and 95 on-pump), 59 OPCAB patients had greater than mild degree functional IMR preoperatively (31 mild to moderate, 23 moderate, 5 severe). Clinical outcomes and results from echocardiography, angiography, and myocardial single-photon emission computed tomography performed early and 1 year postoperatively were analyzed. RESULTS: Operative mortality was 5.1% (3 of 59). All survivors underwent early postoperative echocardiograms, which showed 0 patients with worsened IMR; 41 with less than or equal to mild degree residual IMR (NMR group); and 15 with greater than mild degree IMR (RMR group). Myocardial single-photon emission computed tomography revealed that RMR patients had more reversible ischemic myocardial segments preoperatively than NMR patients (p=0.009). Successful right coronary revascularization with proven graft patency was a predictor of early improvement of IMR (p=0.024). There were no differences in postoperative morbidities between the 2 groups. One-year follow-up echocardiograms demonstrated further improvement in 10 of 13 RMR patients. No patients experienced mitral valve-related events during follow-up. Overall survival and major adverse cardiac event-free survival rates at 5 years were 84.6% and 78.1%, respectively, with no intergroup differences. CONCLUSIONS: Most functional IMR associated with acute coronary syndrome, including severe degree IMR, improved during the first postoperative year after off-pump coronary artery bypass grafting. PMID- 22835552 TI - Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: microcirculatory and systemic effects. AB - BACKGROUND: Controversy exists regarding the optimal perfusion modality during cardiopulmonary bypass (CPB). Here we compare the effects of pulsatile versus nonpulsatile perfusion on microvascular blood flow during and after CPB. METHODS: High-risk cardiac surgical patients were randomly assigned to have pulsatile (n=10) or nonpulsatile (n=10) flow during CPB. The sublingual microcirculation was assessed using orthogonal polarization spectral imaging. Hemodynamic and microvascular variables were obtained after anesthesia (baseline), during CPB, and post-CPB. RESULTS: Compared with baseline, a normal microcirculatory blood flow pattern was accomplished at all time points under pulsatile flow conditions. Peaking 24 hours postoperatively, a higher proportion of normally perfused microvessels occurred under pulsatile versus nonpulsatile flow (56.0%+/-3.9% vs 33.3%+/-4.1%; p<0.05). Concurrently, pulsatility resulted in a reduction in the prevalence of pathologic hyper-dynamically perfused vessels (6.0%+/-3.4% vs 19.6%+/-8.8%; p<0.05). Leukocyte adherence decreased relative to the nonpulsatile group both during and after CPB. Furthermore, peak lactate levels were reduced under pulsatile flow conditions postoperatively. CONCLUSIONS: Pulsatile perfusion is superior to nonpulsatile perfusion at preserving the microcirculation, which may reflect attenuation of the systemic inflammatory response during CPB. We suggest the implementation of pulsatile flow can better optimize microvascular perfusion, and may lead to improved patient outcomes in high-risk cardiac surgical procedures requiring prolonged CPB time. PMID- 22835553 TI - Contrast-induced nephropathy and risk of acute kidney injury and mortality after cardiac operations. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is a predictor of long-term morbidity and mortality. We assessed whether patients in whom CIN developed at diagnostic coronary angiography also had an increased risk of acute kidney injury (AKI) and higher mortality after cardiac operations. METHODS: We evaluated 949 patients who underwent cardiac procedures at the Minneapolis Veterans Administration (VA) Medical Center from 2004 to 2010. CIN was defined as a rise in the serum creatinine (SCr) level to >=0.5 mg/dL from baseline within 5 days after angiography. Outcomes were operative mortality and postoperative AKI using the Acute Injury Network and Risk, Injury, Failure, Loss, End-Stage (RIFLE) definitions. Multivariable logistic regression analysis adjusting for the VA mortality risk score was performed to assess the effect of CIN on postoperative mortality. RESULTS: Of the 949 patients, 62 (6.5%) experienced CIN after coronary angiography. Short (30-day) and long-term postoperative mortality was higher in patients who experienced CIN versus those who did not (6.5% versus 1.2% and 23% versus 10%, respectively; both p<0.01). In multivariable analysis, the development of CIN was associated with a 4.2-fold increase in postoperative mortality after cardiac procedures (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.3-13.7; p=0.02). CIN was also associated with increased risk of postoperative AKI according to the Acute Kidney Network and RIFLE definitions (p<0.0001 for all). CONCLUSIONS: The development of CIN at diagnostic angiography is an independent predictor of postoperative AKI and mortality after cardiac procedures. PMID- 22835554 TI - Coronary ostioplasty for congenital atresia of the left main coronary artery ostium. AB - BACKGROUND: Coronary ostial atresia is a rare anomaly, most frequently managed with coronary artery bypass grafting. This condition is often misdiagnosed as anomalous left coronary artery from the pulmonary artery until the time of surgical intervention, leaving the surgeon little time to contemplate the best operative technique. METHODS: In this single-center experience, three cases of congenital atresia of the left main coronary artery presenting during childhood were surgically managed with homograft patch ostioplasty. RESULTS: Antegrade left coronary artery blood flow was successfully established in all three cases without the use of a bypass graft. Two children survived and are clinically well; the third had visibly necrotic myocardium at the time of surgical ostioplasty and did not survive to hospital discharge. CONCLUSIONS: Surgical ostioplasty with a homograft patch should be considered as an alternative to bypass grafting for coronary ostial atresia in children. PMID- 22835555 TI - Outcomes for lung transplantation for lung cancer in the United Network for Organ Sharing Registry. AB - BACKGROUND: Advanced bronchoalveolar carcinoma (BAC) carries a poor prognosis, with median survival of approximately 1 year. More extended survivals have been reported after lung transplantation for BAC; however, fewer than 50 patients have been reported. To compare outcomes of lung transplantation for advanced BAC, we studied this population in a compulsory, prospectively maintained database. METHODS: The United Network for Organ Sharing (UNOS) database was queried for patients undergoing lung transplant from 1987 to 2010 for the diagnosis of BAC or cancer. Pathology reports of explanted specimens were reviewed. RESULTS: Twenty nine patients underwent lung transplantation for BAC, representing 0.13% of the 21,553 lung transplants during the study period. BAC patients had better forced expiratory volume in 1 second percent predicted (60% vs 35%, p<0.0001) and received more double-lung transplants (79% vs 54%, p=0.006). Pure BAC was present in only 52% of the explants, whereas 41% had some degree of invasive tumor, and 7% had pure adenocarcinoma. The BAC and general lung transplantation cohorts had similar 30-day mortality (10% vs 7%, p=0.44) and 5-year survival (57% vs 50%, p=0.66). CONCLUSIONS: Survival after lung transplantation for BAC appears to be consistent with that of lung transplantation for other diagnoses and is better than that reported with chemotherapy. Further study is warranted to identify the subgroup of patients with lung cancer who will have a maximum survival advantage after lung transplantation. PMID- 22835556 TI - Patient disposition and long-term outcomes after valve surgery in octogenarians. AB - BACKGROUND: Valve surgery is performed routinely in octogenarians. This study explored variables affecting patient discharge disposition (home versus other facility) and whether patient disposition was related to long-term survival. METHODS: Patients 80 years or older who presented for aortic valve or mitral valve surgery from 2002 to 2010 were included. Baseline demographic, perioperative, and long-term outcomes were captured. Disposition was categorized into 2 groups; home (n=184) or other facility (n=123). The National Death Index and Social Security Death Index verified deaths. RESULTS: Mean age was 82.9+/ 2.5; 46% (140 of 307) were female. Discharge location logistic regression, adjusted for gender (odds ratio [OR]=1.45, p=0.17) and European System for Cardiac Operative Risk Evaluation score (OR=1.09, p=0.10), predicted that older (OR=1.18, p<0.001), unmarried (OR=2.07, p=0.006) patients with at least 1 major complication (OR=3.86, p<0.001) were more likely to be not discharged home. Kaplan-Meier analysis found significantly lower 1- and 2-year (85.8% vs 94.6%, p=0.009; 80.1% vs 90.3%, respectively, p=0.01) cumulative survival in patients not discharged home. A multivariate Cox proportional hazards model demonstrated poorer 1- and 2-year survival (hazard ratio [HR]=2.56, p=0.04; HR=2.06, p=0.05, respectively). Predictors of follow-up mortality for patients not discharged home were length of stay (OR=1.06, p=0.03) and any major complication (OR=6.90, p=0.002); lower body mass index was marginally significant (OR=1.12, p=0.06). The significant predictor for patients discharged home was length of stay (OR=1.17, p=0.002). CONCLUSIONS: Octogenarians can expect excellent survival after valve surgery. Those not discharged home had poorer long-term survival. Therefore, adequate resources should be secured so sicker patients receive the appropriate level of care. PMID- 22835557 TI - Long-term outcomes after transmyocardial revascularization. AB - BACKGROUND: Two independent reports documented substantially higher operative mortality associated with transmyocardial revascularization (TMR) when used in isolation than that reported in the premarket clinical trials. To clarify the state of the art, this article assesses temporal trends in the use of TMR, short term and long-term outcomes, and outcomes stratified by procedure type (TMR only and TMR + coronary artery bypass graft [CABG]) and by the 2 specific TMR devices. METHODS: The study population included all patients undergoing TMR in isolation or in combination with CABG at 435 cardiothoracic hospitals in the United States participating in the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) from January 2000 through November 2006 (n = 15,386). Analysis of long-term outcomes was accomplished through linkage to Medicare claims data. Short-term and long-term (7 years) adverse outcomes were assessed and compared between the 2 TMR device types. RESULTS: The use of TMR in conjunction with CABG surgery is increasing. This study showed modest differences in short-term morbidity and mortality between the 2 devices. In combination with CABG, after risk adjustment, patients treated with the holmium:YAG laser (experienced a higher rate of operative mortality (3.5% vs 2.5%; adjusted hazard ratio 1.39, 95% confidence level 1.03 to 1.87) but no difference in the composite short-term rate of major morbidity or mortality, compared with the Heart Laser CO2 transmyocardial revascularization system (PLC Medical Systems, Inc, Milford, MA). However, there were no clinically meaningful differences in long-term results. CONCLUSIONS: Modest differences in short-term morbidity and mortality between the 2 devices suggest the usefulness of further research. PMID- 22835559 TI - Turbulent-PSO-Based Fuzzy Image Filter With No-Reference Measures for High Density Impulse Noise. AB - Digital images are often corrupted by impulsive noise during data acquisition, transmission, and processing. This paper presents a turbulent particle swarm optimization (PSO) (TPSO)-based fuzzy filtering (or TPFF for short) approach to remove impulse noise from highly corrupted images. The proposed fuzzy filter contains a parallel fuzzy inference mechanism, a fuzzy mean process, and a fuzzy composition process. To a certain extent, the TPFF is an improved and online version of those genetic-based algorithms which had attracted a number of works during the past years. As the PSO is renowned for its ability of achieving success rate and solution quality, the superiority of the TPFF is almost for sure. In particular, by using a no-reference Q metric, the TPSO learning is sufficient to optimize the parameters necessitated by the TPFF. Therefore, the proposed fuzzy filter can cope with practical situations where the assumption of the existence of the "ground-truth" reference does not hold. The experimental results confirm that the TPFF attains an excellent quality of restored images in terms of peak signal-to-noise ratio, mean square error, and mean absolute error even when the noise rate is above 0.5 and without the aid of noise-free images. PMID- 22835558 TI - Characteristics associated with the use of nonanatomic resections among Medicare patients undergoing resections of early-stage lung cancer. AB - BACKGROUND: Racial disparities in access to surgical resection for treatment of early-stage non-small-cell lung cancer (NSCLC) are well documented. However it is unclear how race, clinical, and hospital characteristics affect the surgical approach among patients undergoing resection. METHODS: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)/Medicare linked database, we identified patients 67 years of age or older diagnosed with stage I NSCLC who underwent surgical resection from 2000 to 2007. Surgical approach was categorized as lobectomy or segmentectomy (anatomic) versus wedge resection (nonanatomic). We used logistic regression to identify the association between demographic, clinical, and hospital factors and the use of nonanatomic resections. RESULTS: There were 8,986 patients in the sample (mean age, 75 years; 53% women); 12.8% underwent nonanatomic resection. The use of nonanatomic resection increased significantly, from 11.0% in 2000 to 15.9% in 2007 (p=0.008). In multivariable analysis, race was not associated with the receipt of nonanatomic resection. Factors associated with the use of nonanatomic resections included age greater than 80 years (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.15-1.98), T1a primary tumor status, chronic obstructive pulmonary disease (COPD) (OR, 1.81; 95% CI, 1.55-2.12), and volume of hospital lung resections performed (highest versus lowest hospital volume, OR, 1.58; 95% CI, 1.23-2.04). More nonanatomic resections were performed in 2007 than in 2000 (OR, 1.73; 95% CI, 1.27-2.37). After stratifying by tumor size, the temporal trend in the use of nonanatomic resection remained significant only among patients with tumors greater than 3 cm. CONCLUSIONS: Since 2000, the use of nonanatomic resections in stage I NSCLC has increased, most significantly among patients with larger tumors. After adjusting for clinical factors, there was no relation between race and type of surgical resection. PMID- 22835560 TI - A Cluster Validity Framework Based on Induced Partition Dissimilarity. AB - We describe a new cluster validity framework (CVF) that compares structure in the data (in dissimilarity form) to the structure of dissimilarity matrices induced by a matrix transformation of the partition being tested. As part of this framework, we show two possible cluster validation measures: one, visual cluster validity, that that uses visual comparison and another one, correlation cluster validity, based on correlation. Unlike many existing measures, the measures we propose can be applied to crisp or soft partitions obtained by any relational or object data clustering algorithm. We illustrate the new measures and compare them to several well-known existing measures using real and artificial data sets. PMID- 22835561 TI - Ant Colony Optimization With Combining Gaussian Eliminations for Matrix Multiplication. AB - One of the main unsolved problems in computer algebra is to determine the minimal number of multiplications which is necessary to compute the product of two matrices. For practical value, the small format is of special interest. This leads to a combinatorial optimization problem which is unlikely solved in polynomial time. In this paper, we present a method called combining Gaussian eliminations to reduce the number of variables in this optimization problem and use heuristic ant colony algorithm to solve the problem. The results of experiments on 2 * 2 case show that our algorithm achieves significant performance gains. Extending this algorithm from 2 * 2 case to 3 * 3 case is also discussed. Index Terms-Ant colony optimization (ACO), evolutionary algorithms, Gaussian eliminations, matrix multiplication, multiplicative complexity, Strassen's algorithm. PMID- 22835562 TI - Open surgical and endovascular conduits for difficult access during endovascular aortic aneurysm repair. AB - Endovascular aortic aneurysm repair has gained widespread acceptance as the primary method of treatment of abdominal and thoracic aortic aneurysms. Difficult access because of small, narrowed, tortuous, or severely calcified iliac and femoral arteries poses a significant challenge and remains a common cause of inadvertent arterial disruption and conversion to open repair. Vascular complications associated with difficult access are associated with major morbidity and mortality. This article summarizes open surgical and endovascular alternatives to dealing with difficult iliofemoral access during endovascular aortic interventions. PMID- 22835563 TI - The ongoing battle between infrapopliteal angioplasty and bypass surgery for critical limb ischemia. AB - BACKGROUND: Critical limb ischemia (CLI) represents the extreme of the peripheral arterial occlusive disease spectrum and is associated with high mortality. Limb salvage often requires infrapopliteal revascularization by either angioplasty or bypass surgery. The past decade has witnessed a paradigm shift in CLI management toward endovascular treatment. This narrative review describes the clinical outcome, treatment strategy, and limitations of both modalities. METHOD: A literature search was performed of the PubMed and Cochrane databases. All articles, published until September 2011, describing treatment by infrapopliteal arterial revascularization were included. RESULTS: Angioplasty and bypass surgery are both related to a limb salvage rate of approximately 80% at 3-year follow-up. Patency rates appear to be higher after surgery. A reliable comparison of the two modalities, however, is complicated by various confounders, including patient selection, lesion characteristics, and complication rates. Additionally, most studies did not describe the standard use of best medical treatment or outcome for relief of ischemic pain, wound healing, or functional improvement. CONCLUSION: Infrapopliteal angioplasty and bypass surgery both provide an acceptable limb salvage rate, but patency appears to be better after bypass surgery. Both modalities are likely to be complementary. Additional randomized trials are indicated to provide a treatment algorithm for patients with CLI and infrapopliteal arterial occlusive disease. PMID- 22835564 TI - Maximal venous outflow velocity: an index for iliac vein obstruction. AB - Leg swelling is a common cause for vascular surgical evaluation, and iliocaval obstruction due to May-Thurner syndrome (MTS) can be difficult to diagnose. Physical examination and planar radiographic imaging give anatomic information but may miss the fundamental pathophysiology of MTS. Similarly, duplex ultrasonographic examination of the legs gives little information about central impedance of venous return above the inguinal ligament. We have modified the technique of duplex ultrasonography to evaluate the flow characteristics of the leg after tourniquet-induced venous engorgement, with the objective of revealing iliocaval obstruction characteristic of MTS. Twelve patients with signs and symptoms of MTS were compared with healthy control subjects for duplex-derived maximal venous outflow velocity (MVOV) after tourniquet-induced venous engorgement of the leg. The data for healthy control subjects were obtained from a previous study of asymptomatic volunteers using the same MVOV maneuvers. The tourniquet-induced venous engorgement mimics that caused during vigorous exercise. A right-to-left ratio of MVOV was generated for patient comparisons. Patients with clinical evidence of MTS had a mean right-to-left MVOV ratio of 2.0, asymptomatic control subjects had a mean ratio of 1.3, and MTS patients who had undergone endovascular treatment had a poststent mean ratio of 1.2 (P = 0.011). Interestingly, computed tomography and magnetic resonance imaging results, when available, were interpreted as positive in only 53% of the patients with MTS according to both our MVOV criteria and confirmatory venography. After intervention, the right-to-left MVOV ratio in the MTS patients was found to be reduced similar to asymptomatic control subjects, indicating a relief of central venous obstruction by stenting the compressive MTS anatomy. Duplex-derived MVOV measurements are helpful for detection of iliocaval venous obstruction, such as MTS. Right-to-left MVOV ratios and postengorgement spectral analysis are helpful adjuncts to duplex imaging for leg swelling. The MVOV maneuvers are well tolerated by patients and yields physiological data regarding central venous obstruction that computed tomography and magnetic resonance imaging fail to detect. PMID- 22835565 TI - Nonsuture anastomosis of arteries and veins using the magnetic pinned-ring device: a histologic and scanning electron microscopic study. AB - BACKGROUND: The goal of this study was to evaluate the performance of the magnetic pinned-ring device for nonsuture vascular anastomosis. METHODS: The magnetic pinned-ring device consists of paired magnetic rings that are coated with titanium nitride and embedded in a polypropylene shell; the rings are equipped with alternately spaced holes and titanium pins. The vascular anastomosis procedure using the novel magnetic pinned-ring device was performed on 14 mongrel dogs, and the traditional hand-sewing technique was used on 14 additional dogs. In situ end-to-end anastomoses were performed in the femoral artery and the inferior vena cava. Patency was confirmed through ultrasonographic scans at different time points as late as 24 weeks after surgery. Gross observation, histological staining, and scanning electron microscopy were used to evaluate the results at 24 weeks postoperatively. RESULTS: The time required to perform the vascular anastomosis was significantly shorter for the magnetic device than for hand sewing. A continuity of re-endothelialization was confirmed in all anastomotic stomas after 24 weeks, and neither formation of aneurysms nor thickening of the vascular wall was noted. The re-endothelialization was smooth at the anastomotic site of the magnetic device, whereas hand sewing resulted in rough and uneven re-endothelialization and the presence of visible sutures. Moreover, the endothelial cells were regularly arranged at the anastomotic site of the magnetic device, whereas different-sized and irregularly aligned endothelial cells were present at the hand-sewn anastomotic site. Use of the magnetic device was associated with significantly decreased deposition of fibrotic collagen and depressed infiltration of inflammatory cells compared with use of the hand-sewing technique. CONCLUSIONS: The magnetic pinned-ring device offers a simple, fast, reliable, and efficacious technique for nonsuture vascular anastomosis. Use of this device shortens operation time, maintains a high patency rate, and improves the healing of vascular tissue. PMID- 22835566 TI - Pasteurella multocida-infected expanded polytetrafluoroethylene hemodialysis access graft. AB - Infections are among the risks related to prosthetic hemodialysis access grafts. However, dialysis access graft infections caused by Pasteurella multocida have not been reported previously. We report a case of a P. multocida-infected nonfunctioning expanded polytetrafluoroethylene graft in the forearm after a cat bite. At surgery, the graft was completely unincorporated and was completely excised. Operative culture results were positive for P. multocida, a common oral flora found in cats and dogs. The patient was treated with intravenous ceftriaxone, and the wounds healed with local care. PMID- 22835567 TI - Role of ultrasound arterial mapping in planning therapeutic options for critical ischemia of lower limbs in diabetic patients. AB - BACKGROUND: To assess the role of ultrasound arterial mapping in planning therapeutic options for critical limb ischemia (CLI) in diabetic patients. METHODS: This observational and comparative study included 244 patients with CLI. All participants (64% were diabetic) underwent ultrasound arterial mapping before planning surgical treatment. We established two groups: diabetic (n = 156) and nondiabetic (n = 88). Arterial mapping was divided into segments. We studied 2,021 individual segments and used arteriography when ultrasound arterial mapping was not conclusive. We compared the degree of pathology between the groups, agreement between the treatment decision made after ultrasound mapping and the final surgical decision in both groups, and agreement between ultrasound mapping and arteriography in patients who underwent both procedures. RESULTS: Diabetic patients had a significantly higher degree of pathology in all segments, except the common iliac artery. Decisions made after ultrasound mapping matched the final surgical decision 90% and 94% of the time in diabetic patients and nondiabetic patients, respectively. Decisions made on the basis of ultrasound arterial mapping matched decisions made on the basis of arteriography in 86.3%. CONCLUSIONS: Ultrasound arterial mapping allowed for good therapeutic planning for CLI in diabetic patients, even though these patients had more severe arterial pathology. PMID- 22835568 TI - Development of a novel, physiologically relevant cytotoxicity model: application to the study of chemotherapeutic damage to mesenchymal stromal cells. AB - There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated. In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy. Minimal modifications would enable this novel co culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in vitro study. PMID- 22835569 TI - Segmentation and tracing of single neurons from 3D confocal microscope images. AB - In order to understand the brain, we need to first understand the morphology of neurons. In the neurobiology community, there have been recent pushes to analyze both neuron connectivity and the influence of structure on function. Currently, a technical road block that stands in the way of these studies is the inability to automatically trace neuronal structure from microscopy. On the image processing side, proposed tracing algorithms face difficulties in low contrast, indistinct boundaries, clutter, and complex branching structure. To tackle these difficulties, we develop Tree2Tree, a robust automatic neuron segmentation and morphology generation algorithm. Tree2Tree uses a local medial tree generation strategy in combination with a global tree linking to build a maximum likelihood global tree. Recasting the neuron tracing problem in a graph-theoretic context enables Tree2Tree to estimate bifurcations naturally, which is currently a challenge for current neuron tracing algorithms. Tests on cluttered confocal microscopy images of Drosophila neurons give results that correspond to ground truth within a margin of +/-2.75% normalized mean absolute error. PMID- 22835570 TI - Using platelet-rich plasma for the treatment of symptomatic cervical ectopy. AB - OBJECTIVE: To evaluate the effectiveness of autologous platelet-rich plasma (PRP) applications in the treatment of benign cervical ectopy. METHODS: Symptomatic women with benign cervical ectopy (n=120) were randomized to a PRP or a laser group. In the PRP group, PRP was applied twice on the cervical erosion with a 1 week interval. In the laser group, an Nd-YAG laser was used once for tissue vaporization. RESULTS: The complete cure rates were 93.7% for the PRP and 92.4% for the laser group (P>0.05). The mean time to re-epithelialization was significantly shorter in the PRP (6.41 +/- 2.05 weeks) than in the laser group (8.28 +/- 1.72 weeks) (P<0.01). The rate of adverse treatment effects (i.e. vaginal discharge or vaginal bleeding) was much lower in the PRP than that in the laser group (P<0.01) and the effects were milder. Eleven patients in the PRP group had mild or moderate vaginal bleeding after treatment but none had heavy bleeding. Of 25 patients with vaginal bleeding in the laser group, 2 had heavy bleeding necessitating tamponade. CONCLUSION: Autologous PRP applications appear promising for the treatment of cervical ectopy in symptomatic women, as they generate a shorter tissue healing time and milder adverse effects than laser treatment. PMID- 22835571 TI - Charcot arthropathy presenting with primary bone resorption. AB - BACKGROUND: The clinical presentation of acute Charcot arthropathy in the diabetic population usually follows the Eichenholtz classification. We present three usual cases of Charcot arthropathy presenting with rapid primary bone resorption in the absence of subluxation, dislocation and/or fracture. METHODS: A review of the literature was performed. To our knowledge Charcot arthropathy has not been previously described as primary bone resorption. CASE REPORTS: Three cases encountered at our specialist multidisciplinary High Risk Foot Clinic (HRFC) presented with primary bony resorption without features of subluxation, dislocation and/or fracture. DISCUSSION: Aggressive primary bone resorption was initially thought due to infection; a diagnostic dilemma that delayed optimal treatment. Late bone resorption in typical Charcot is linked to unregulated proinflammatory cytokines (IL-1beta, IL-6 and TNFalpha) that lead to increased osteoclastic activity. The pathophysiology of osteolysis in aggressive primary bony resorption may relate to a disturbance in the balance between RANK-L and OPG. CONCLUSION: Primary resorption of bone without subluxation, dislocation and/or fracture can represent an active Charcot process. Prudent use of serial radiography and early MRI to look for the widespread bone and soft tissue oedema is recommended. PMID- 22835572 TI - Early post-operative results of neglected tendo-Achilles rupture reconstruction using short flexor hallucis longus tendon transfer: a prospective review. AB - BACKGROUND: Various repair techniques have been reported for neglected tendo Achilles rupture. OBJECTIVE: This study aimed to prospectively investigate the impact of short flexor hallucis longus (FHL) transfer to the calcaneus for patients with neglected rupture secondary to trauma. METHODS: One surgeon operated on a series of patients with neglected tendo-Achilles rupture. Ankle function and patient health were assessed pre and post-operatively using the American Orthopaedic Foot and Ankle Score (AOFAS) and the SF-36 score. RESULTS: 11 patients (6 male; mean age 52.6) were included. Median time from injury to surgery was 13.3 weeks (range 6-104 weeks). The mean pre-operative AOFAS was 51.4 (range 26-87), 79.8 (range 64-94) at 3 months and 91.9 (range 77-100) at 6 months post-operatively. The mean pre-operative SF-36 score was 87.4 (range 75.4-109.5), 103.2 (range 74.1-115.4) at 3 months and 111.8 (range 103.9-116.2) at 6 months. All patients had improved SF-36 at 6 months. At 6 months 10 out 11 patients had resumed pre-injury daily activities. CONCLUSION: Direct transfer of FHL to the calcaneum with an interference screw allows correct tensioning and secure fixation. The procedure has low morbidity and reliable outcomes. The majority of patients were able to return to daily working activities with no restrictions. PMID- 22835573 TI - Posterior reversible encephalopathy syndrome (PRES): features on CT and MR imaging. AB - Posterior reversible encephalopathy syndrome (PRES) is a rare but severe condition of the central nervous system. It develops in a variety of clinical settings and it has diverse patterns of expression, which can sometimes make diagnosis difficult. Characteristic features are often demonstrated on computed tomography imaging and/or magnetic resonance imaging, meaning that when there is a suspicious clinical picture, this diagnosis should suggest itself. However, clinicians should be aware of some of the less typical features in order to more fully understand this condition, in which early treatment is key to good clinical progress. PMID- 22835575 TI - Endotherapy for organized pancreatic necrosis: perspectives after 20 years. AB - It has been nearly 20 years since the first peroral endoscopic necrosectomy was performed for patients with pancreatitis. We have since increased our understanding of pancreatitis, and the nomenclature has changed to define disease in which necrosis becomes organized (called "walled-off"). Endoscopic approaches to evaluate and treat pancreatitis have progressed from making small transmural tracts for irrigation to making large tracts, which allow the endoscope to move directly into necrotic cavities and perform endoscopic necrosectomy. The purpose of endoscopic debridement is to irrigate and/or remove areas of necrosis. Collaboration between therapeutic endoscopists and interventional radiologists has led to a combined approach to organized pancreatic necrosis. We discuss the history of peroral endoscopic treatment of organized (walled-off) pancreatic necrosis and current endoscopic approaches to therapy. PMID- 22835574 TI - Polyps with advanced neoplasia are smaller in the right than in the left colon: implications for colorectal cancer screening. AB - BACKGROUND & AIMS: Colonoscopy is consistently associated with reduced left sided, but not right-sided, colorectal cancer (CRC) incidence and mortality. This might be because polyps with advanced pathology are smaller and more easily missed in the right vs left colon. We explored this postulate by evaluating the relationship among size, location, and histology of polyps from a large nationwide sample. METHODS: We conducted a cross-sectional study of 233,414 polyps from 142,686 patients (47% women; mean age, 60 years), which were reviewed by Miraca Life Sciences in 2009. We assessed polyp histology, location, and size of largest fragment submitted. We compared size distribution of right vs left polyps with high-grade dysplasia (HGD) or adenocarcinoma as well as any advanced neoplasia. RESULTS: The average size of right-sided polyps was smaller than that of left-sided polyps with HGD or adenocarcinoma (8.2 vs 12.4 mm, respectively); the same was true for polyps with advanced neoplasia (7.6 vs 11.1 mm, respectively) (P < .001). Most right-sided polyps with HGD, adenocarcinoma, or any advanced neoplasia were <=9 mm, whereas most left-sided polyps with these findings were >9 mm. Polyps with advanced pathology were 5-fold more likely to be <6 mm in the right vs left colon: odds ratio, 5.27; 95% confidence interval, 4.06 6.82 for HGD or adenocarcinoma; odds ratio, 4.89; 95% confidence interval, 4.34 5.51 for advanced neoplasia. CONCLUSIONS: Polyps with features of HGD, adenocarcinoma, or advanced neoplasia were significantly smaller in the right vs left colon. Strategies to prevent right-sided CRC require more accurate detection of small, advanced polyps. PMID- 22835576 TI - Spontaneous clearance of pancreatic stones. PMID- 22835578 TI - Primary sclerosing cholangitis and distribution of inflammatory bowel disease. PMID- 22835579 TI - Fecalith presenting as a submucosal cecal mass. PMID- 22835580 TI - Novel colonoscopic imaging. PMID- 22835577 TI - Strategies for the care of adults hospitalized for active ulcerative colitis. AB - Ulcerative colitis is a chronic inflammatory disease of the colon; as many as 25% of patients with this disease require hospitalization. The goals of hospitalization are to assess disease severity, exclude infection, administer rapidly acting and highly effective medication regimens, and determine response. During hospitalization, patients should be given venous thromboembolism prophylaxis and monitored for the development of toxic megacolon. Patients who do not respond to intravenous corticosteroids should be considered for rescue therapy with infliximab or cyclosporine. Patients who are refractory to medical therapies or who develop toxic megacolon should be evaluated promptly for colectomy. Patients who do respond to medical therapies should be discharged on an appropriate maintenance regimen when they meet discharge criteria. We review practical evidence-based management principles and propose a day-by-day algorithm for managing patients hospitalized for ulcerative colitis. PMID- 22835582 TI - Hemoperitoneum caused by spontaneous rupture of the umbilical vein in cirrhosis. PMID- 22835581 TI - Liver test results do not identify liver disease in adults with alpha(1) antitrypsin deficiency. AB - BACKGROUND & AIMS: Liver disease is a significant cause of death among adults with alpha(1)-antitrypsin (A-AT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test A-AT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with A-AT deficiency to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease. METHODS: We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross section of A AT-deficient adults (n = 647) with and without liver disease; individuals without A-AT deficiency were used as controls (n = 152). Results from ALT tests were compared between groups. RESULTS: The prevalence of liver disease among individuals with A-AT deficiency was 7.9%; an increased level of ALT was observed in 7.8% of A-AT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only gamma-glutamyl transpeptidase was significantly higher in the A-AT-deficient group than in controls (43 vs 30 IU/mL; P < .003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis. CONCLUSIONS: An increased level of ALT does not identify adults with A-AT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk. PMID- 22835583 TI - Tissue-engineered collateral ligament composite allografts for scapholunate ligament reconstruction: an experimental study. AB - PURPOSE: In patients with chronic scapholunate (SL) dissociation or dynamic instability, ligament repair is often not possible, and surgical reconstruction is indicated. The ideal graft ligament would recreate both anatomical and biomechanical properties of the dorsal scapholunate ligament (dorsal SLIL). The finger proximal interphalangeal joint (PIP joint) collateral ligament could possibly be a substitute ligament. METHODS: We harvested human PIP joint collateral ligaments and SL ligaments from 15 cadaveric limbs. We recorded ligament length, width, and thickness, and measured the biomechanical properties (ultimate load, stiffness, and displacement to failure) of native dorsal SLIL, untreated collateral ligaments, decellularized collateral ligaments, and SL repairs with bone-collateral ligament-bone composite collateral ligament grafts. As proof of concept, we then reseeded decellularized bone-collateral ligament bone composite grafts with green fluorescent protein-labeled adipo-derived mesenchymal stem cells and evaluated them histologically. RESULTS: There was no difference in ultimate load, stiffness, and displacement to failure among native dorsal SLIL, untreated and decellularized collateral ligaments, and SL repairs with tissue-engineered collateral ligament grafts. With pair-matched untreated and decellularized scaffolds, there was no difference in ultimate load or stiffness. However, decellularized ligaments revealed lower displacement to failure compared with untreated ligaments. There was no difference in displacement between decellularized ligaments and native dorsal SLIL. We successfully decellularized grafts with recently described techniques, and they could be similarly reseeded. CONCLUSIONS: Proximal interphalangeal joint collateral ligament-based bone-collateral ligament-bone composite allografts had biomechanical properties similar to those of native dorsal SLIL. Decellularization did not adversely affect material properties. CLINICAL RELEVANCE: These tissue-engineered grafts may offer surgeons another option for reconstruction of chronic SL instability. PMID- 22835584 TI - An anatomical study of the watershed line on the volar, distal aspect of the radius: implications for plate placement and avoidance of tendon ruptures. AB - PURPOSE: The watershed line is a useful surgical landmark for positioning a volar locking plate. Implants placed on or distal to it can impinge on flexor tendons and cause injury. However, the details of the anatomy of this line are unclear. We studied macroscopically and histologically the structures of the volar aspect of the distal radius. METHODS: We studied 20 distal forearm regions of 10 cadavers (5 males and 5 females; mean age, 79 y [range, 56-88 y]) to clarify the details of the watershed line. In 16 specimens, we investigated the macroscopic appearance of the volar aspect of the radius and the relationships among the bone, the volarradiocarpal ligaments, and the pronator quadratus. Histological analyses were performed in 4 specimens of 2 cadavers to examine the morphology of the margin of the bony structures. RESULTS: In the medial half of the distal volar radius, 2 lines were identified by direct macroscopic visualization; one was the proximal line that corresponded to the distal ridge of the pronator fossa, and the other was the distal line, which was more prominent. A medial bony prominence was situated on the distal line. In the lateral half, the distal and proximal lines of the medial half merged to form a single line. A lateral prominence was situated on this line. CONCLUSIONS: The watershed line might not be a distinct line, and it corresponds to the distal margin of the pronator fossa in the lateral half of the volar radius and to a hypothetical line between the distal and proximal lines in the medial half. The medial and lateral bony prominences on the volar radius should be key structures for accurate plate placement to avoid flexor tendon injury. CLINICAL RELEVANCE: The present study suggests bony landmarks for positioning a volar locking plate. PMID- 22835585 TI - The natural course of traumatic triangular fibrocartilage complex tears in distal radial fractures: a 13-15 year follow-up of arthroscopically diagnosed but untreated injuries. AB - PURPOSE: To evaluate the long-term results of a prospective, longitudinal case series of untreated, traumatic triangular fibrocartilage complex (TFCC) tears found in displaced distal radial fractures. METHODS: Between 1995 and 1997, 51 patients (24 men, 27 women; age, 20-57 y) with a displaced distal radius fracture had wrist arthroscopy to identify associated injuries. Forty-three patients had complete or partial tears of the TFCC, which were not treated. All patients were contacted in 2010, 13-15 years after the injury. One patient had had a TFCC reattachment due to painful distal radioulnar joint instability and was excluded. Thirty-eight patients returned for a radiographic and clinical follow-up that recorded strength, distal radioulnar joint laxity, range of motion, pain scale score, and subjective and objective outcome scores. RESULTS: After 13-15 years, 17/38 patients were lax in the distal radioulnar joint. The mean grip strength was worse in the patients with a lax distal radioulnar joint (83%, SD 15 of the contralateral side vs 103%, SD 33). The median Gartland and Werley score was 5 (good; range, 0-15) in the lax group compared to 1 (excellent; range, 0-9) in the non-lax group, and the median Disabilities of the Arm, Shoulder, and Hand scores were 14 (range, 0-59) and 5 (range, 0-70) respectively. CONCLUSIONS: In this 13 15 year, prospective, longitudinal outcome study of the natural course of TFCC tears associated with distal radius fracture, only 1 patient had been operated on for painful instability since the injury. The subjective and objective results did not provide evidence that a TFCC injury would influence the long-term outcome. However, trends were found and, by speculation, the low number of patients in the series and the risk for a type II error could be the cause of absent statistically significance. Larger, preferably prospective, randomized studies are needed to find out whether a more aggressive treatment is beneficial. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic I. PMID- 22835586 TI - Treatment of ulnar neuropathy at the elbow: cost-utility analysis. AB - PURPOSE: The choice of surgical treatment for ulnar neuropathy at the elbow (UNE) remains controversial. A cost-utility analysis was performed for 4 surgical UNE treatment options. We hypothesized that simple decompression would emerge as the most cost-effective strategy. METHODS: A cost-utility analysis was performed from the societal perspective. A decision analytic model was designed comparing 4 strategies: (1) simple decompression followed by a salvage surgery (anterior submuscular transposition) for a poor outcome, (2) anterior subcutaneous transposition followed by a salvage surgery for a poor outcome, (3) medial epicondylectomy followed by a salvage surgery for a poor outcome, and (4) anterior submuscular transposition. A poor outcome when anterior submuscular transposition was the initial surgery was considered an end point in the model. Preference values for temporary health states for UNE, the surgical procedures, and the complications were obtained through a time trade-off survey administered to family members and friends who accompanied patients to physician visits. Probabilities of clinical outcomes were derived from a Cochrane Collaboration meta-analysis and a systematic MEDLINE and EMBASE search of the literature. Medical care costs (in 2009 U.S. dollars) were derived from Medicare reimbursement rates. The model estimated quality-adjusted life-years and costs for a 3-year time horizon. A 3% annual discount rate was applied to costs and quality-adjusted life-years. Incremental cost-effectiveness ratios were calculated, and sensitivity analyses performed. RESULTS: Simple decompression as an initial procedure was the most cost-effective treatment strategy. A multi-way sensitivity analysis varying the preference values for the surgeries and a model structure sensitivity analysis varying the model assumptions did not change the conclusion. Under all evaluated scenarios, simple decompression yielded incremental cost-effectiveness ratios less than US$2,027 per quality-adjusted life-year. CONCLUSIONS: Simple decompression as an initial treatment option is cost-effective for UNE according to commonly used cost-effectiveness thresholds. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and Decision Analysis III. PMID- 22835587 TI - Posterior interosseous and ulnar nerve motor palsies after a minimally displaced radial neck fracture. AB - Peripheral nerve injury is a serious potential complication following an upper extremity fracture. A rare case of acute posterior interosseous nerve and ulnar nerve palsy following a minimally displaced radial neck fracture is reported. With nonsurgical management, both nerves demonstrated excellent functional recovery. Although rare, nerve palsies can occur during a variety of upper extremity clinical situations, including minimally displaced fractures, and the importance of a detailed neurologic examination cannot be overstated. PMID- 22835588 TI - Early results of surgical intervention for elbow deformity in cerebral palsy based on degree of contracture. AB - PURPOSE: Elbow flexion posture, caused by spasticity of the muscles on the anterior surface of the elbow, is the most common elbow deformity seen in patients with cerebral palsy. This study retrospectively evaluated early results of 2 surgical interventions for elbow flexion deformities based on degree of contracture. We hypothesized that by guiding surgical treatment to degree of preoperative contracture, elbow extension and flexion posture angle at ambulation could be improved while preserving maximum flexion. METHODS: Eighty-six patients (90 elbows) were treated for elbow spasticity due to cerebral palsy. Seventy-one patients (74 elbows) were available for follow-up. Fifty-seven patients with fixed elbow contractures less than 45 degrees were surgically treated with a partial elbow muscle lengthening, which included partial lengthening of the biceps and brachialis and proximal release of the brachioradialis. Fourteen patients (17 elbows) with fixed elbow contractures >= 45 degrees had a more extensive full elbow release, with biceps z-lengthening, partial brachialis myotomy, and brachioradialis proximal release. RESULTS: Age at surgery averaged 10 years (range, 3-20 y) for partial lengthening and 14 years (range, 5-20 y) for full elbow release. Follow-up averaged 22 months (range, 7-144 mo) for partial lengthening and 18 months (range, 6-51 mo) for full elbow release. Both groups achieved meaningful improvement in flexion posture angle at ambulation, active and passive extension, and total range of motion. Elbow flexion posture angle at ambulation improved by 57 degrees and active extension increased 17 degrees in the partial lengthening group, with a 4 degrees loss of active flexion. In the full elbow release group, elbow flexion posture angle at ambulation improved 51 degrees and active extension improved 38 degrees , with a loss of 19 degrees of active flexion. CONCLUSIONS: Surgical treatment of spastic elbow flexion in cerebral palsy can improve deformity. We obtained excellent results by guiding the surgical intervention by the amount of preoperative elbow contracture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22835589 TI - Tapered fingertips. PMID- 22835590 TI - New mini-invasive decompression for pronator teres syndrome. AB - The pronator teres syndrome is a set of signs and symptoms that result from compression of the median nerve in the upper forearm. It is a dynamic syndrome that is frequently associated with compression of the same nerve at the carpal tunnel. The literature describes different anatomic structures that can cause this syndrome. Experience showed us that the deep fascia of the superficial head of the pronator teres is the only anatomic structure that causes compression of the median nerve in the upper forearm. If the flexor digitorum test is negative, selective release of the deep fascia of the superficial head of the pronator teres ends the symptoms. Our surgical technique uses a mini-invasive approach that takes into account the anatomic knowledge of this region. A 3.5-cm oblique skin incision is done 6 cm distal to the medial epicondyle, over the flexor/pronator muscle mass. The medial cutaneous nerve is atraumatically retracted. The superficial fascia of the flexor/pronator muscles is opened transversely. With the section of the septum between the pronator teres and the flexor carpi radialis, access to the deep fascia of the superficial head of the pronator teres is obtained. This structure is released. The median nerve is now easily visualized, and other types of possible compression causes are excluded. The same surgeon treated 44 cases with this technique. Two assistants were always needed for this mini-invasive approach. Pronator teres symptoms disappeared in 93% of cases. PMID- 22835591 TI - Radial styloid fractures. AB - Radial styloid fractures can occur in isolation or in association with other injuries, including complex intra-articular distal radius fractures, carpal fractures, carpal dislocations, and radiocarpal dislocations. The anatomy surrounding the radial styloid is complex, and complications related to surgical approach, treatments, and symptomatic hardware can occur. Operative treatments vary according to the injury pattern present, and pattern recognition is the key to optimizing treatment of these injuries. Outcomes are related to the precision of the reconstruction as well as the magnitude of the injury; better results are associated with lower-energy patterns. PMID- 22835593 TI - Basal joint surgical alternatives. PMID- 22835595 TI - Extravasation of chemotherapy: an alternative clinical application of integra in hand and upper extremity surgery. PMID- 22835597 TI - A randomized trial of DHA intake during infancy: school readiness and receptive vocabulary at 2-3.5 years of age. AB - BACKGROUND: Studies investigating the effects of docosahexaenoic acid (DHA) in infant formula on language development yield conflicting results. No study to date has investigated the effects of DHA in infant formula on school readiness. AIM: To determine the effects of different dietary concentrations of DHA provided during the first 12 months of life on language development and school readiness. DESIGN: This was a double-masked, randomized, controlled, prospective trial. A total of 182 infants were enrolled at 1-9 days of age and assigned randomly to receive infant formula with one of four levels of DHA: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA. All formulas with DHA also contained 0.64% arachidonic acid. One hundred forty-one children completed the 12-month feeding trial and were eligible for this study. Consent was obtained from 131 participants. School readiness was assessed at 2.5 years using the Bracken Basic Concept Scale-Revised (BBCS-R) and receptive vocabulary was assessed at 2 and 3.5 years using the Peabody Picture Vocabulary Test-Third Edition (PPVT-III). RESULTS: There were no diet group differences on any of the BBCS-R subscales. On the PPVT-III, the control group had higher raw scores and standard scores than both the 0.32% and 0.96% groups at 2 years of age. These differences were not evident at 3.5 years. CONCLUSIONS: Dietary DHA during the first year of life did not enhance school readiness or language development. Children who consumed infant formula with 0.32% and 0.96% DHA showed lower receptive vocabulary scores than controls at 2 but not 3.5 years of age. PMID- 22835598 TI - Assessment of gestational age using cerebellar measurements at cranial ultrasound: what is the best approach? AB - BACKGROUND AND AIMS: Clinical assessment of gestational age (GA) in preterm infants can be challenging. Several ultrasound approaches for estimating GA using cerebellar measurements are reported, claiming to be simpler and more accurate than clinical assessment, but they are not widely used. We aimed to compare the accuracy of four previously described measurements and compare their use in preterm infants. METHODS: We studied infants <32weeks of GA defined by in-vitro fertilization date or early fetal ultrasound, excluding infants with neurological problems. Vermis anterior-posterior diameter (VAPD), vermis height (VH), and transverse cerebellar diameter via anterior (TCDa) and mastoid fontanelles (TCDm) were measured.Estimated PMA was calculated using published equations, and compared to known PMA using intraclass correlation coefficient (ICC). Intra and inter-observer reliability were determined. RESULTS: We studied 80 infants (mean GA 28.5weeks [range 24-32], mean post-natal age 5.7days). ICC was 0.761 (VAPD), 0.632 (VH), 0.115 (TCDa) and 0.825 (TCDm). The TCDm equation gave the best estimate of GA (mean estimate -2days; 95% CI+/-13.8days). TCDa and TCDm absolute measurements were similar for each infant. Accuracy for estimating GA was similar for appropriately grown and small-for-gestation infants. Inter and intra-observer reliability was very good for all measurements. CONCLUSIONS: Three previously described equations for estimating GA from cerebellar measurements gave good estimates of GA in preterms. The equation described for TCDm gave the narrowest 95% CI. We recommend the TCDm equation for the estimation of GA in VLBW infants but the TCD measurement can be made via either the anterior or mastoid fontanelle. PMID- 22835599 TI - Association between IGF2BP2 rs4402960 polymorphism and risk of type 2 diabetes mellitus: need for clarification of data in a recent meta-analysis. PMID- 22835600 TI - Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis. AB - BACKGROUND AND AIMS: We undertook this study to assess the effects of omega-3 polyunsaturated fatty acids (PUFAs) (administered at >=2.7 g/day) for a minimum duration of 3 months on clinical outcomes in patients with rheumatoid arthritis (RA). METHODS: The authors surveyed randomized controlled trials (RCTs) that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients using Medline and the Cochrane Controlled Trials Register and by performing manual searches. Meta-analysis of RCTs was performed using fixed and random effects models. Outcomes are presented as standardized mean differences (SMD). RESULTS: Ten RCTs involving 183 RA patients and 187 placebo-treated RA controls were included in this meta-analysis. The analysis showed that omega-3 PUFAs clearly reduced nonsteroidal anti-inflammatory drug (NSAID) consumption (SMD -0.518, 95% CI -0.915 to -0.121, p = 0.011) without between-study heterogeneity (I(2) = 0%). Tender joint count (SMD -0.214, 95% CI-0.489-0.062, p = 0.128), swollen joint count (SMD -0.170, 95% CI-0.454-0.114, p = 0.241), morning stiffness (SMD -0.224, 95% CI-0.955-0.212, p = 0.221), and physical function (SMD 0.264, 95% CI-0.232 0.724, p = 0.314) showed a trend to improve more in patients treated with omega-3 PUFAs than in placebo-treated controls, but they did not reach statistical significance. CONCLUSIONS: This meta-analysis suggests that the use of omega-3 PUFAs at dosages >2.7 g/day for >3 months reduces NSAID consumption by RA patients. Further studies are needed to explore the clinical and NSAID-sparing effects of omega-3 PUFAs in RA. PMID- 22835601 TI - Effect on the expression of MMP-2, MT-MMP in laryngeal carcinoma Hep-2 cell line by antisense glucose transporter-1. AB - BACKGROUND AND AIMS: Glucose transporter protein-1 (Glut-1) is correlated with biological behaviors of malignant tumors. However, there was no evidence that overexpression of Glut-1 mechanistically lead to invasion or metastasis of cancer cells. We hypothesized that Glut-1 regulates the expression of membrane type 1 MMP (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). METHODS: Analysis of the expression of Glut-1, MMP-2, beta-actin, and MT1-MMP was performed using RT-PCR. Expression of Glut-1 protein, MMP-2, and MT1-MMP was detected by Western blotting. RESULTS: At mRNA and protein levels, Glut-1 and MMP-2 were co-expressed in the Hep-2 laryngeal carcinoma cell line. After transfection, Glut-1 antisense oligodeoxynucleotide (AS-ODN) decreased the expression of MMP-2 mRNA and protein as well as Glut-1 mRNA and protein. Glut-1 AS-ODN also decreased the expression of MT1-MMP mRNA. CONCLUSIONS: Co-expression of Glut-1 and MMP-2 in Hep-2 laryngeal carcinoma cells and Glut-1 may regulate MMP-2 and MT1-MMP expression. PMID- 22835602 TI - Hodgkin's lymphoma in adults. AB - Management of Hodgkin's lymphoma continues to develop. Outcomes for patients with favourable-risk, early-stage disease are excellent, and serial reductions in intensity of treatment have been made to retain the excellent prognosis while reducing the late effects of treatment. Prognosis is also very good in advanced stage disease but the rate of relapse is higher than in early-stage disease, and the optimum first-line treatment is unclear. Workers are investigating the role of functional imaging to assess whether treatment can be tailored according to response, with the most intensive therapies reserved for patients predicted to have poor outcomes. In this Seminar we critically appraise the management of Hodgkin's lymphoma in early-stage disease, advanced-stage disease, and at relapse, with a focus on late effects of treatment. PMID- 22835603 TI - Non-Hodgkin lymphoma. AB - Lymphomas are solid tumours of the immune system. Hodgkin's lymphoma accounts for about 10% of all lymphomas, and the remaining 90% are referred to as non-Hodgkin lymphoma. Non-Hodgkin lymphomas have a wide range of histological appearances and clinical features at presentation, which can make diagnosis difficult. Lymphomas are not rare, and most physicians, irrespective of their specialty, will probably have come across a patient with lymphoma. Timely diagnosis is important because effective, and often curative, therapies are available for many subtypes. In this Seminar we discuss advances in the understanding of the biology of these malignancies and new, available treatments. PMID- 22835605 TI - Recognition of dementia in ancient China. AB - A search of previous records in the literatures was done to summarize the opinions for dementia in ancient China. The earliest description of dementia was traced in the Yellow emperor's internal classic, a book written 2000 years ago. Hua Tuo (AD 140-208) in Han Dynasty first denominated "dementia" in the book, Hua Tuo Shen Yi Mi Zhuan. The pathogenesis of dementia could be generalized as the insufficiency of Qi, a flowing energy; the stagnation of phlegm, a harmful liquid substance in the body; and the blood stasis, which were also regarded as therapeutic targets. Therefore, we can conclude that dementia has been recognized and investigated in traditional Chinese medicine, which is definitely before the industrial civilization era. PMID- 22835604 TI - Rho guanine nucleotide exchange factor is an NFL mRNA destabilizing factor that forms cytoplasmic inclusions in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive disorder of unknown etiology characterized by the selective degeneration of motor neurons. Recent evidence supports the hypothesis that alterations in RNA metabolism in motor neurons can explain the development of protein inclusions, including neurofilamentous aggregates, observed in this pathology. In mice, p190RhoGEF, a guanine nucleotide exchange factor, is involved in neurofilament protein aggregation in an RNA-triggered transgenic model of motor neuron disease. Here, we observed that rho guanine nucleotide exchange factor (RGNEF), the human homologue of p190RhoGEF, binds low molecular weight neurofilament mRNA and affects its stability via 3' untranslated region destabilization. We observed that the overexpression of RGNEF in a stable cell line significantly decreased the level of low molecular weight neurofilament protein. Furthermore, we observed RGNEF cytoplasmic inclusions in ALS spinal motor neurons that colocalized with ubiquitin, p62/sequestosome-1, and TAR (trans-active regulatory) DNA-binding protein 43 (TDP-43). Our results provide further evidence that RNA metabolism pathways are integral to ALS pathology. This is also the first described link between ALS and an RNA binding protein with aggregate formation that is also a central cell signaling pathway molecule. PMID- 22835606 TI - Specific oral tolerance induction in paediatric patients with persistent egg allergy. AB - INTRODUCTION: Desensitisation or specific oral tolerance induction (SOTI) to food is a new topical-therapeutic approach of food allergy for those children who have not achieved tolerance spontaneously. The objective of this study is to induce clinical tolerance in children with persistent allergy using an oral desensitisation protocol with powdered pasteurised egg. METHODS: Seventy-two patients with egg allergy confirmed by open oral challenge test were randomly assigned to SOTI or elimination diet as a control group. Forty children (5-15 years) underwent a SOTI beginning with 1mg and increasing the dosage weekly until a dose of 10g, equivalent to an egg. The control group included 32 patients (4-15 years). RESULTS: The procedure's average duration was 10 weeks (range 4-28 weeks). Three patients were withdrawn from the protocol for persistent gastrointestinal symptoms. During SOTI, 21 children (52.5%) presented symptoms. In eight the symptoms were mild and required no treatment. In the other 13 (61.90%), the reactions were more severe. Seventeen children finished the treatment over a year ago and 20 in the past 6-12 months. Thirty-seven patients (92.5%) in the active group achieved tolerance to egg, versus 21.8% in the control group. We only found statistically significant differences (p<0.05) for skin prick tests with powdered egg at various dilutions and IgG levels with egg white after SOTI. Specific IgE concentration did not change significantly. CONCLUSIONS: Our SOTI protocol is a safe, effective treatment for food allergy and of reasonable duration, confirming that tolerance can be induced in children who have not achieved it spontaneously. PMID- 22835607 TI - Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats. AB - Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of alpha(v)beta(3) integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined. PMID- 22835608 TI - Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer. AB - The transcription factors SRY-related HMG box (SOX)2 and octamer-binding transcription factor (OCT)4 regulate the expression of the miR-302-367 cluster. miR-145 regulates SOX2 and OCT4 translation and p53 regulates miR-145 expression. We analysed the expression of the miR-302-367 cluster and miR-145 and the mutational status of p53 in resected nonsmall cell lung cancer (NSCLC) patients and correlated results with time to relapse (TTR). Tumour and paired normal tissue samples were obtained from 70 NSCLC patients. MicroRNA expression was assessed with TaqMan MicroRNA Assays. p53 exons 5 to 8 were sequenced. miR-145 was downregulated (p<0.0001) and miR-367 was upregulated (p<0.0001) in tumour compared with normal tissue. Mean TTR was 18.4 months for patients with low miR 145 levels and 28.2 months for those with high levels (p=0.015). Mean TTR was 29.1 months for patients with low miR-367 levels and 23.4 months for those with high levels (p=0.048). TTR was shorter for patients with both unfavourable variables (p=0.009). Low miR-145 expression (p=0.049), the combination of unfavourable microRNA levels (p=0.02) and the combination of low miR-145 with p53 mutations (p=0.011) were independent markers of shorter TTR. In conclusion, miR 145 and miR-367 expression could be novel markers for relapse in surgically treated NSCLC. p53 may play a role in modulating miR-145 expression in NSCLC. PMID- 22835609 TI - Radial probe EBUS versus CT-guided needle biopsy for evaluation of peripheral pulmonary lesions: an economic analysis. AB - Selection of the optimal procedure for minimally invasive diagnosis of peripheral pulmonary lesions (PPLs) may be based on clinical factors; however, selection of diagnostic strategy may also be influenced by cost. Economic analysis of minimally invasive diagnosis of PPL has not been performed previously. Decision tree analysis was applied to compare downstream costs of endobronchial ultrasound guided transbronchial lung biopsy (EBUS-TBLB) with computed tomography-guided percutaneous needle biopsy (CT-PNB). Calculations were based on real costs derived from patient data. Sensitivity analyses and probabilistic sensitivity analysis were undertaken to identify the more cost-beneficial approach for varying input parameter values. Cost-effectiveness calculations were based on estimated disutility, according to the wait-trade-off technique. For base-case analysis, initial evaluation with CT-PNB was cost-beneficial (AU$2,724 versus EBUS-TBLB AU$2,748). The variable which exerted the most influence on cost benefit outcomes was the cost of managing complications. CT-PNB remained the more cost-effective procedure at base-case parameters, although thresholds were identified during sensitivity analysis where EBUS-TBLB became more cost effective. The costs of EBUS-TBLB and CT-PNB to evaluate PPL appear to be equivalent, but specific clinical-radiologic factors known to influence procedural outcomes will influence cost-benefit outcomes. Further evaluation of patient preferences and their influence on cost-effectiveness are required. PMID- 22835610 TI - Correlation of radio- and histomorphological pattern of pulmonary adenocarcinoma. AB - Recently, a novel classification system based on tumour architecture and with high prognostic impact has been proposed for pulmonary adenocarcinomas (ADCs). For imaging-based prediction of histological ADC subtypes and, thus, prognosis, it is of paramount importance to investigate the correlations of radio- and histomorphological parameters. Associations between histomorphological ADC growth patterns (lepidic, acinar, papillary, micropapillary and solid) and data from pre operative assessment by computed tomography (CT) imaging of 174 resected pulmonary ADCs were analysed. Margin configuration as well as solidity/ground glass opacity of an ADC was associated with distinct histomorphological ADC growth patterns. Solid-predominant ADCs usually had smooth margins and were also solid in CT scans, while lepidic-predominant ADCs had no predominant margin pattern, were located in the periphery, showed a positive bronchogram and were frequently associated with solidity/ground glass opacity. In addition, nonspherical tumour growth was a negative predictor of overall and disease specific patient survival. We defined CT morphological parameters that were associated with histomorphological growth patterns of pulmonary ADCs. These data may form the basis for the development of future prognostic algorithms in the palliative setting, which include an integrated evaluation of biopsy histomorphology and CT scan morphology of nonresectable pulmonary ADC. PMID- 22835611 TI - Insomnia related to sleep apnoea: effect of long-term auto-adjusting positive airway pressure treatment. AB - Insomnia related to sleep apnoea (IA) is highly prevalent, and its proper treatment is still debated. The aim of this study was to test the hypothesis that long-term auto-adjusting positive airway pressure (APAP) treatment improves IA symptoms. 80 patients (mean+/-sd age 54.9+/-10.6 yrs, respiratory disturbance index (RDI) 45.0+/-24.6 events.h(-1)) receiving APAP treatment were followed prospectively for 24 months. Somnolence and depression were assessed at baseline (T0) with the Epworth and the QD2A scales, respectively. Nightly APAP use was measured after 24 months of treatment (T24). The assessment of insomnia at T0 and T24 used the insomnia severity index (ISI). The combination of ISIT0 >=15 and ISIT0-ISIT24 >=9 defined the APAP-responding insomnia (APAP-RI) group. A logistic regression analysis identified the factors independently associated with the APAP RI group. The ISI (13.7+/-5.7 versus 8.2+/-6.3) decreased significantly from T0 to T24 (p = 0.0001) for the patients as a whole, with a mean decrease of 13.5+/ 2.9. Among the 39 insomniac subjects (T0), 20 belonged to the APAP-RI group (51%). The Epworth score (OR 1.536, 95% CI 1.093-2.159; p = 0.01) and the RDI (OR 1.080, 95% CI 1.010-1.154; p = 0.02) increased the risk of belonging to the APAP RI group. IA symptoms improved with APAP treatment, and improvement was associated with the initial severity of the disease and somnolence in our population. PMID- 22835612 TI - Prognostic factors in resected pathological N1-stage II nonsmall cell lung cancer. AB - Stage II nonsmall cell lung cancer (NSCLC) has been redefined in the seventh edition of tumour, node, metastasis (TNM) classification for lung cancer. Stages IIa and IIb both contain node-negative (N0) and node-positive (N1) subgroups. The aim of this study was to evaluate the prognostic factors for overall survival in patients with resected N1-stage II NSCLC. Between January 1992 and December 2010, we retrospectively reviewed the clinicopathological characteristics of 163 N1 stage II (T1a-T2bN1M0) NSCLC in patients undergoing curative resection as primary treatment. Median follow-up time was 37.2 months. The 1-, 3- and 5-yr overall survival rates were 85.3%, 62.1% and 43.5%, respectively. Tumour involvement of the hilar/interlobar nodal zone and poorly differentiated histological grade were significant predictors for worse overall survival using multivariate analysis (p = 0.001 and p = 0.015, respectively). There were trends toward worse overall survival in older patients and those with larger tumour size (p = 0.063 and p = 0.075, respectively). In resected N1-stage II NSCLC, hilar/interlobar nodal involvement and poorly differentiated histological grade were significant predictors of worse overall survival. The differences in survival between these subgroups of patients may lead to the use of different adjuvant therapies or post surgical follow-up strategies. PMID- 22835614 TI - Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma. AB - Malignant mesothelioma (MM) is an aggressive tumour with poor prognosis whose early diagnosis is difficult. Mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin have attracted attention as biomarkers. The aim of the present review is to provide an overview regarding these candidate biomarkers for MM, and discuss their potential role in today's clinical practice. Mesothelin and MPF have good specificity but sub-optimal sensitivity for detection of MM, being negative both in the sarcomatoid histological sub-type and in almost half of epithelioid mesothelioma, especially in the early stages. Osteopontin is a marker of the duration of asbestos exposure, but lacks specificity for mesothelioma. Several patient characteristics influence the diagnostic accuracy of biomarkers and make the establishment of the "optimal" diagnostic threshold difficult. Mesothelin and MPF have proved useful in assessing response to treatment. Combining different markers together may lead to an improvement in diagnostic accuracy, but there is still need for research in this area. Extensive validation and further research is required to improve the use of serum markers in mesothelioma management. In the near future, their application in clinical practice is probably in monitoring response to therapy, rather than in guiding diagnostic decisions and risk assessment of asbestos-exposed populations. PMID- 22835613 TI - The role of bronchodilator treatment in the prevention of exacerbations of COPD. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea. These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD. Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (>= 2 per year) independently of disease severity. Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis. The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting beta(2)-agonists (LABAs) and long-acting anti muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS). While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance. Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation. Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations. Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations. PMID- 22835615 TI - Use of continuous positive airway pressure reduces airway reactivity in adults with asthma. AB - Asthma is characterised by airway hyperreactivity, which is primarily treated with beta-adrenergic bronchodilators and anti-inflammatory agents. However, mechanical strain during breathing is an important modulator of airway responsiveness and we have previously demonstrated in animal models that continuous positive airway pressure (CPAP) resulted in lower in vivo airway reactivity. We now evaluated whether using nocturnal CPAP decreased airway reactivity in clinically-stable adults with asthma. Adults with stable asthma and normal spirometry used nocturnal CPAP (8-10 cmH(2)O) or sham treatment (0-2 cmH(2)O) for 7 days. Spirometry and bronchial challenges were obtained before and after treatment. The primary outcome was the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC(20)). The CPAP group (n=16) had a significant decrease in airway reactivity (change in (Delta)logPC(20) 0.406, p<0.0017) while the sham group (n=9) had no significant change in airway reactivity (DeltalogPC(20) 0.003, p=0.9850). There was a significant difference in the change in airway reactivity for the CPAP versus the sham group (DeltalogPC(20) 0.41, p<0.043). Our findings indicate that chronic mechanical strain of the lungs produced using nocturnal CPAP for 7 days reduced airway reactivity in clinically stable asthmatics. Future studies of longer duration are required to determine whether CPAP can also decrease asthma symptoms and/or medication usage. PMID- 22835616 TI - Simvastatin suppresses RANTES-mediated neutrophilia in polyinosinic-polycytidylic acid-induced pneumonia. AB - Recently, statins have been shown to have anti-inflammatory effects on lung inflammatory diseases. However, the mechanisms of action of simvastatin in viral pneumonia have yet to be elucidated, although viral infection remains a considerable health threat. In this study, we hypothesised that simvastatin inhibits polyinosinic-polycytidylic acid (poly I:C)-induced airway inflammation, such as RANTES (regulated on activation, normal T-cell expressed and secreted) expression and inflammatory cell recruitment. In bronchial cells, the effect of simvastatin on poly I:C-induced RANTES expression and signal transducer and activator of transcription (STAT)3-mediated signal transduction was determined using an ELISA and short hairpin (sh)RNA system. In a poly I:C-induced pneumonia mouse model, immunological changes in the lungs after simvastatin inhalation, such as inflammatory cell recruitment and cytokine/chemokine release, were examined. In poly I:C-stimulated bronchial cells, RANTES secretion was increased by STAT3 activation, and simvastatin suppressed poly I:C-induced STAT3 activation, resulting in inhibition of RANTES expression. In BALB/c mice stimulated with inhaled poly I:C, RANTES expression and neutrophil infiltration into the airway were elevated. However, simvastatin treatment attenuated STAT3 activation, RANTES release and subsequent neutrophilia in the lungs. These findings suggest that simvastatin inhibits airway inflammation, but there are other mechanisms that need to be fully elucidated. PMID- 22835617 TI - Quality of life and healthcare utilisation in cystic fibrosis: a multicentre study. AB - The aim of our study was to discover the health status and healthcare utilisation associated with pulmonary exacerbations in cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection. Patients with CF from five UK CF centres attended two visits, 8-12 weeks apart. They were classified at visit 1 as being in one of the three health states: no current pulmonary exacerbation; "mild" (no hospitalisation) pulmonary exacerbation; and "severe" (hospitalisation) pulmonary exacerbation. All patients completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and EuroQol (EQ-5D) and a clinical form, and forced expiratory volume in 1 s (FEV1) was measured at visits 1 and 2. Annual healthcare utilisation data were collected. 94 patients of mean+/-sd age 28.5+/-8.2 yrs and FEV1 58.7+/-26.8% were recruited. 60 patients had no pulmonary exacerbation, 15 had a mild and 19 had a severe pulmonary exacerbation at visit 1. EQ-5D and CFQ-R data showed that the worse the exacerbation, the poorer the health-related quality of life (HRQoL). There were strong relationships between the CFQ-R and EQ-5D domain scores. The mean rate of pulmonary exacerbations per patient per year was 3.6 (1.5 in hospital and 2.2 at home). The mean length of stay per hospital pulmonary exacerbation was 9 days. As exacerbation status worsens, patients experience worse HRQoL. There is a significant healthcare burden associated with treatment of pulmonary exacerbation and long-term prophylaxis. PMID- 22835620 TI - Oropharyngeal dysphagia is a risk factor for community-acquired pneumonia in the elderly. AB - The aim of this study was to explore whether oropharyngeal dysphagia is a risk factor for community-acquired pneumonia (CAP) in the elderly and to assess the physiology of deglutition of patients with pneumonia. In the case-control study, 36 elderly patients (aged >= 70 years) hospitalised with pneumonia were matched by age and sex with two independently living controls. All subjects were given the volume-viscosity swallow test to identify signs of oropharyngeal dysphagia. In the pathophysiological study, all cases and 10 healthy elderly subjects were examined using videofluoroscopy. Prevalence of oropharyngeal dysphagia in the case-control study was 91.7% in cases and 40.3% in controls (p<0.001). Adjusting for functionality and comorbidities, dysphagia showed an independent effect on pneumonia (OR 11.9, 95% CI 3.03-46.9). Among cases in the pathophysiological study, 16.7% showed safe swallow, 30.6% high penetrations, 36.1% severe penetrations and 16.7% silent aspirations during videofluoroscopy, while in the healthy elderly subjects these percentages were 80%, 20%, 0% and 0%, respectively (p<0.001). A delay in closure of the laryngeal vestibule (0.414 +/- 0.029 s versus 0.200 +/- 0.059 s, p<0.01) was the main mechanism of impaired airway protection. In elderly subjects, oropharyngeal dysphagia is strongly associated with CAP, independently of functionality and comorbidities. Elderly patients with pneumonia presented a severe impairment of swallow and airway protection mechanisms. We recommend universal screening of dysphagia in older persons with pneumonia. PMID- 22835619 TI - Effect of urbanisation on the relationship between total serum IgE and asthma. AB - It is unclear if the relationship of total serum IgE with asthma varies with degree of urbanisation. We hypothesised that the relationship of total serum IgE to asthma is more pronounced in an urban versus a rural environment. We enrolled 1441 children aged 13-15 years in a peri-urban shanty town in Lima, Peru (n=725) and 23 villages in rural Tumbes, Peru (n=716). We asked participants about asthma and allergy symptoms, environmental exposures and sociodemographics; and performed spirometry, and exhaled nitric oxide and allergy skin testing. We obtained blood for total serum IgE in 1143 (79%) participants. Geometric means for total serum IgE were higher in Lima versus Tumbes (262 versus 192 kU.L(-1); p<0.001). The odds of asthma increased by factors of 1.6 (95% CI 1.3-2.0) versus 1.4 (95% CI 0.9-2.1) per log unit increase in total serum IgE in Lima versus Tumbes, respectively. Atopy was an effect modifier of the relationship of total serum IgE on asthma. Among atopics and non-atopics, the odds of asthma increased by a factor of 2.0 (95% CI 1.5-2.7) and 1.0 (95% CI 0.7-1.4) per log unit increase in total serum IgE, respectively. Total serum IgE was associated with atopic asthma but not with non-atopic asthma. Urbanisation did not appear to be an effect modifier of this relationship. PMID- 22835618 TI - Outcomes in females hospitalised with community-acquired pneumonia are worse than in males. AB - There is little recent information on sex-specific outcomes of patients with community-acquired pneumonia (CAP). The objective of this study was to determine whether female sex is associated with better clinical outcomes in hospitalised patients with CAP. A secondary analysis was conducted by the Community Acquired Pneumonia Organization regarding male and female patients with CAP from 80 hospitals in 17 countries from June 1, 2001 to August 2, 2011. Outcomes were time to clinical stability, length of stay and in-hospital and 28-day mortality. Propensity-adjusted, multivariate regression models were used to predict the probability of occurrence of each of the study outcomes. There were 6718 patients in this study, of whom 40% were female. The adjusted hazard ratio (HR) for time to clinical stability was 0.91 (95% CI 0.85-0.97; p=0.005). The adjusted HR for length of stay was 0.94 (95% CI 0.88-1.01; p=0.089). The adjusted risk ratio for in-hospital mortality was 1.04 (95% CI 0.86-1.24; p=0.717), and for 28-day mortality was 1.15 (95% CI 1.02-1.30; p=0.018). This study demonstrates that the epidemiology of CAP may be changing, and that females have worse outcomes for CAP than males. They are more likely to take longer to reach clinical stability, have longer hospital stays and are 15% more likely to have died after 28 days. Current pneumonia scoring systems may need to be revised regarding female mortality risk. PMID- 22835621 TI - Isolation rearing significantly perturbs brain metabolism in the thalamus and hippocampus. AB - Psychosocial neglect during childhood severely impairs both behavioral and physical health. The isolation rearing model in rodents has been employed by our group and others to study this clinical problem at a basic level. We previously showed that immediate early gene (IEG) expression in the hippocampus and medial prefrontal cortex (mPFC) is decreased in isolation-reared (IR) compared to group reared (GR) rats. In the current study, we sought to evaluate: (1) whether these changes in IEG expression would be detected by the measurement of brain glucose metabolism using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and (2) whether PET FDG could illuminate other brain regions with different glucose metabolism in IR compared to GR rats. We found that there were significant differences in FDG uptake in the hippocampus that were consistent with our findings for IEG expression (decreased mean FDG uptake in IR rats). In contrast, in the mPFC, the FDG uptake between IR and GR rats did not differ. Finally, we found decreased mean FDG uptake in the thalamus of the IR rats, a region we had not previously examined. The results suggest that PET FDG has the potential to be utilized as a biomarker of molecular changes in the hippocampus. Further, the differences found in thalamic brain FDG uptake suggest that further investigation of this region at the molecular and cellular levels may provide an important insight into the neurobiological basis of the adverse clinical outcomes found in children exposed to psychosocial deprivation. PMID- 22835622 TI - Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo. AB - FK-506 accelerates nerve regeneration and improves functional recovery in vivo; its immunosuppressive properties, however, limit its clinical utility. Geldanamycin (GA), a non-immunosuppressive agent, shares a common binding target (heat shock protein 90) with FK-506 and may accelerate nerve regeneration through a similar mechanism. GA has been shown to augment neurite outgrowth in vitro but has not been tested in vivo. The current study investigated the effect of GA on the rate of axonal regeneration and functional recovery following peripheral nerve injury. In the first experiment, Thy1-GFP transgenic rats underwent serial transmuscular imaging to quantify the rate of axonal regeneration following saphenous nerve crush injury. In subsequent experiments, Lewis rats underwent tibial nerve crush or transection-and-repair injuries and were assessed for functional recovery by walking track analysis. All animals were randomized to receive daily administration of FK-506 (2mg/kg), GA (0.2mg/kg), or a control vehicle (dimethyl sulfoxide, 1 mL/kg) starting 3 days prior to injury. Both GA and FK-506 significantly increased the rate of axonal regeneration following crush injury in Thy1-GFP rats. In Lewis rats undergoing tibial nerve crush injury, earlier functional recovery occurred at day 5 and day 6 in animals treated with FK-506 and GA respectively, vs. day 13 for controls. Over a truncated 21-day timeframe, Lewis rats undergoing tibial nerve transection-and repair injury and treated with FK-506 regained function at day 16, whereas those treated with GA or the control vehicle did not regain normal function. GA-treated animals, however, did exhibit significant functional improvement vs. controls. The current study demonstrated that GA accelerates axonal regeneration and enhances functional recovery in vivo. Its ability to increase the rate at which peripheral axons regenerate is comparable to that of FK-506. GA, however, did not match the performance of FK-506 in injury models where Wallerian degeneration (WD) is ongoing in the distal stump. This provides evidence that FK-506 accelerates axonal regeneration through two parallel mechanisms: the first being its well-established effect on neurons; the second is likely a newly described, as-yet poorly defined mechanism that affects WD. Finally, given the decrease in observed toxicity with GA administration, it might be a suitable non immunosuppressive alternative to FK-506 for accelerating peripheral nerve regeneration in cases of clinical nerve injury. PMID- 22835623 TI - A model for the perception of surface pressure on human foot. AB - The psychophysical relationship between the magnitude of pressure on thirteen test locations of twenty healthy subjects' feet with four probe areas at three indentation speeds and the corresponding perceived sensations were analyzed. The dependency of pressure pain thresholds (PPT) on area, A, and speed, v, can be mathematically modeled in the form, PPT(i) = [a(i) + bLn(v)]A(beta)i = 1,2...13 where beta and b are constants and are dependent on location and gender, and a(i) is a constant highly correlated with foot tissue stiffness. The relationship between the sensory intensity to pressure magnitude appears to follow a modified Stevens' power law with power exponents less than 1.0 and consistent across the 13 test locations with a mean of 0.82 and a range from 0.67 to 0.98. This particular model helps to understand the sensation of pressure threshold and its impact in the design of consumer products. PMID- 22835624 TI - A survey to identify physically demanding tasks performed during storm damage operations by Australian State Emergency Services personnel. AB - PURPOSE: To identify and characterize the physically demanding tasks performed by SES personnel during storm damage work. METHODS: Thirty-six tasks identified as the most operationally important to storm damage work were included in a survey which was available to all SES volunteers. The survey aimed to identify the physical demand, operational importance, frequency, duration, principal actions and fitness components of each task. RESULTS: Twelve tasks were identified as the most physically demanding. Of these, carrying sandbags, lifting sandbags and shoveling sand (with hands) rated highest. Covering roof damages with tarpaulin and erecting external weather proofing were ranked highest for operational importance. Box lifting (single-person) and erecting external weather proofing returned the highest mode values for frequency, whereas tasks involving handling sandbags returned the highest mean and median frequency values. Covering roof damages with tarpaulin was identified as the longest task. Bending, lifting, twisting and carrying were the most common actions identified for the physically demanding tasks. Muscular strength and muscular endurance were the primary fitness components identified for the twelve tasks. CONCLUSION: SES personnel perform a variety of storm response tasks, many of which are physically demanding. All or most of the physically demanding tasks contain elements of bending, lifting, twisting and carrying, and call upon personnel's muscular strength and muscular endurance capabilities. PMID- 22835625 TI - Effect of control order on steering a simulated underground coal shuttle car. AB - Most terrestrial vehicles are steered via a first-order control for vehicle heading, such as a conventional steering wheel. A joystick which provides second order control of vehicle heading is used to steer some underground coal shuttle cars. A desktop virtual simulation of the situation was employed to compare the steering accuracy of 24 novice participants randomly assigned to either first order or second-order joystick steering conditions. The average steering accuracy of participants assigned to the first-order joystick condition was superior, however there was considerable individual variability and some participants assigned to the second-order steering condition were able to perform the task equally and successfully. Desktop virtual simulation may be a useful component of training and competency assessment for operators of these vehicles. PMID- 22835626 TI - Evaluation of atrioventricular septal defects by three-dimensional echocardiography: benefits of navigating the third dimension. AB - Atrioventricular septal defects comprise a disease spectrum characterized by deficient atrioventricular septation, with several common features seen in all affected hearts and variability in atrioventricular valve morphology and interatrial and interventricular communications. Atrioventricular septal defects are among the more common defects encountered by pediatric cardiologists and echocardiographers. Despite advances in understanding, standard two-dimensional echocardiography may not be the optimal method for the morphologic and functional evaluation of this lesion, particularly malformations of the atrioventricular valve(s). In this review, the authors summarize the role of three-dimensional echocardiography in the diagnostic evaluation of atrioventricular septal defects. PMID- 22835627 TI - Molecular mechanism of the interactions between inhibitory tripeptides and angiotensin-converting enzyme. AB - Angiotensin I-converting enzyme (ACE) is a key therapeutic target for combating hypertension and related cardiovascular diseases. ACE inhibitory peptides offer the prospect of enhanced potency, high specificity, and no or low side effect. The ACE inhibitory tripeptides LKP and IKP differ from each other by one amino acid but their inhibitory potencies for ACE differ significantly. To uncover the molecular mechanism underlying this phenomenon, we have investigated the tripeptide/ACE complexes through molecular dynamics simulations coupled with quantum mechanical simulations. Comparative structural analysis has identified a hydrophobic subsite in the active site of cACE comprising hydrophobic residues Val379, Val380, Phe457, Phe527, and Ala418. The interactions of the side chains of Leu and Ile with the hydrophobic residues determine the binding positions of N terminal residues of the tripeptides, that influence the interaction of the residues of tripeptides with the active site of cACE. This work presents the molecular mechanism of the interactions between the inhibitory tripeptides and ACE, and deciphers the structural basis for the high affinity LKP inhibition of ACE. PMID- 22835628 TI - Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk. AB - OBJECTIVE: Leukotrienes (LT) play a role in inflammation, cardiovascular diseases, and cancer. Although some studies suggest that there are genes that determine variability of some LT-related phenotypes, the genetic influence on these phenotypes has not been evaluated. METHODS: The relative contributions of genetic and environmental influences to the 5-lipoxygenase pathway-related phenotypes (5-Lipoxygenase, five lipoxygenase activating protein (FLAP), LTA(4) hydrolase and LTC(4)-synthase expression, and LTB(4)-plasma concentration and LTB(4) production by stimulated whole blood) were assessed in a sample of 934 individuals in 35 extended families. Our design is based on extended families recruited through a probands with idiopathic thrombophilia. This strategy allows us the analysis of the effects of measured covariates (such as sex, age and smoking), genes, and environmental variables shared by members of a household. RESULTS: All of these phenotypes showed significant genetic contributions, with heritabilities ranging from 0.33 to 0.51 for enzyme expression and from 0.25 to 0.50 for LTB(4) production of the residual phenotypic variance. Significant phenotypic and genetic correlation among the LT-related traits was found. More importantly, FLAP and LTA(4)-hydrolase expression exhibit significant genetic correlations with arterial thrombosis, indicating that some of the genes that influence quantitative variation in these phenotypes also influence the risk of thrombosis. CONCLUSION: This is the first study that quantifies the genetic component of 5-Lipoxygenase pathway phenotypes. The high heritability of these traits and the significant genetic correlations between arterial thrombosis and some of these phenotypes suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes. PMID- 22835629 TI - Low ankle-brachial index is an independent predictor of poor functional outcome in acute cerebral infarction. AB - OBJECTIVE: The ankle-brachial blood pressure index (ABI) is an established clinical test for assessment of peripheral arterial disease and an indicator of generalized atherosclerosis. We investigated whether low ABI is associated with long-term functional outcome in patients with acute cerebral infarction. METHODS: We included 775 patients with acute cerebral infarction who were admitted within 7 days from stroke onset and had completed an ABI measurement during admission. Poor functional outcome was defined as a modified Rankin Scale of more than 2 at three months from stroke onset. The association between low ABI and poor functional outcome was analyzed using logistic regression analysis. RESULTS: A low ABI (<0.9) was present in 10.1% of patients. At three months from stroke onset, 16.9% of patients showed poor functional outcome (mRS > 2). After adjusting for conventional cardiovascular risk factors and the presence of cerebral atherosclerosis, a low ABI was independently associated with poor functional outcome (odds ratio 2.523, 95% CI 1.330-4.785, p = 0.005). CONCLUSIONS: The presence of a low ABI was associated with an increased risk of poor functional outcome in patients with acute cerebral infarction. Screening for low ABI among stroke patients may be necessary to identify individuals at increased risk of poor functional outcome. Proper and individualized treatment for patients with a low ABI may improve long-term functional outcome following acute cerebral infarction. PMID- 22835630 TI - Changes in passive range of motion and development of glenohumeral internal rotation deficit (GIRD) in the professional pitching shoulder between spring training in two consecutive years. AB - BACKGROUND: Pitching causes increased mechanical stress to the arm and is thought to result in alterations in range of motion (ROM) as a result of osseous and soft tissue adaptations. Understanding the factors that contribute to alterations in ROM will allow for improved understanding of the pitching shoulder. This study examined humeral torsion (HT) and shoulder mobility over 2 consecutive years. METHODS: Bilateral shoulder mobility and HT were assessed in 33 asymptomatic professional pitchers over 2 spring trainings. A repeated-measures analysis of covariance was used to assess the change in motion of the dominant side/nondominant side across seasons while quantifying pre-existing HT. Prevalence of glenohumeral internal rotation deficit (GIRD) between seasons was compared with chi(2) analysis, and GIRD and non-GIRD pitchers were compared with the independent t test. RESULTS: The dominant shoulder displayed increased external rotation (11.5 degrees +/- 0.1 degrees , P = .02) and decreased internal rotation (-8.4 degrees +/- 11.0 degrees , P = .03) and horizontal adduction (-17.6 degrees +/- 13.8 degrees , P = .01). The nondominant shoulder remained the same. Mean HT was significantly different (P = .001) in the dominant (10 degrees +/- 11 degrees ) arm than in the nondominant arm (23 degrees +/- 11 degrees ). A significant number of pitchers had with GIRD (P < .01) at each assessment. CONCLUSIONS: ROM was significantly altered between seasons of pitching. These changes likely resulted from soft tissue adaptations because we accounted for humeral retrotorsion. Pitchers who developed GIRD displayed a 7 degrees increase in retrotorsion on the dominant shoulder. Changes in the pitching shoulder over time accounting for humeral retrotorsion may suggest pitching ROM is transient and should be monitored. PMID- 22835631 TI - Estimation of internal noise using double passes: does it matter how the second pass is delivered? AB - Human sensory processing is inherently noisy: if a participant is presented with the same set of stimuli multiple times and is asked to perform a task related to some property of the stimulus by pressing one of two buttons, the set of responses generated by the participant will differ on different presentations even though the set of stimuli remained the same. This response variability can be used to estimate the amount of internal noise (i.e. noise that is not present in the stimulus but in the participant's decision making process). The procedure by which the same set of stimuli is presented twice is referred to as double-pass (DP) methodology. This procedure is well-established, but there is no accepted recipe for how the repeated trials may be delivered (e.g. in the same order as they were originally presented, or in a different order); more importantly, it is not known whether the choice of delivery matters to the resulting estimates. Our results show that this factor (as well as feedback) has no measurable impact. We conclude that, for the purpose of estimating internal noise using the DP method, the system can be assumed to have no inter-trial memory. PMID- 22835632 TI - Does a single endometrial biopsy regimen (S-EBR) improve ICSI outcome in patients with repeated implantation failure? A randomised controlled trial. AB - OBJECTIVE: To evaluate the effect of a single endometrial biopsy regimen (S-EBR) in the cycle preceding the ICSI cycle in patients with repeated implantation failure. STUDY DESIGN: This was a prospective randomized controlled trial which included two-hundred infertile women with a history of repeated implantation failure. The subjects were randomly divided into two groups. Group A subjects underwent hysteroscopy and endometrial scraping by Novak curette in the cycle preceding the ICSI cycle, while group B subjects underwent hysteroscopy without endometrial scraping. Implantation rate, clinical pregnancy rate, abortion rate and live birth rate were compared between both groups. RESULTS: The number of retrieved oocytes in group A was 11.6 +/- 3 and in group B was 11.6 +/- 2.8 with no statistically significant difference (p=0.787). There were statistically significant differences regarding the implantation rate, the clinical pregnancy rate and live birth rate. The implantation rate in group A was 12% while in group B it was 7% (p=0.015), the clinical pregnancy rate was 32% in group A while it was only 18% in group B (p=0.034) and the live birth rate was 28% in group A while it was 14% in group B (p=0.024). CONCLUSIONS: The single endometrial biopsy regimen (S-EBR) performed during hysteroscopy has statistically significant higher implantation rate, clinical pregnancy rate and live birth rate than hysteroscopy without endometrial scraping. PMID- 22835633 TI - [The pathophysiology of preeclampsia in view of the two-stage model]. AB - Preeclampsia is a common and severe disease in pregnancy, a major cause of maternal and fetal morbidity and mortality. The main features of the disease are de novo hypertension after the 20th gestational week and proteinuria, and it is frequently accompanied by edema and other subjective symptoms. The origin of the disease is the placenta, but its sequelae affect multiple organ systems. According to the two-stage model of preeclampsia, the abnormal and hypoperfused placenta (stage 1) releases factors to the bloodstream, which are responsible for the maternal symptoms (stage 2). Oxidative stress, impaired function of nitric oxide synthase, cellular and humoral immunological factors play an important role in the pathophysiology of the placenta. Endothelial dysfunction is the common denominator of the clinical symptoms. The theory explains the origins of hypertension, proteinuria, edema and other symptoms as well. PMID- 22835634 TI - [Hungarian Diet and Nutritional Status Survey -- the OTAP2009 study. V. Intake of microelements in the Hungarian population]. AB - For a healthy status the adequate intake of microelements is vital. AIM AND METHOD: The Hungarian Diet and Nutritional Status Survey - joining to the European Health Interview Survey - studied the dietary habits of the Hungarian population. The present paper demonstrates the microelement intake. RESULTS: While the intake of iron, copper and zinc was sufficient in males, it was deficient in females according to the Hungarian recommendations. Especially women in their reproductive age ingested iron below the recommendation, thus representing a health risk. In comparison to earlier Hungarian data, zinc and chromium intake decreased unfavorable. CONCLUSIONS: Since in Hungary the consumption of the whole grain products with high trace element content is traditionally low, as also reflected in the present study, it would be desirable to increase the contribution of these foods in the diet in order to enhance the intake of microelements. PMID- 22835635 TI - [Diagnostic delay of rare diseases in Europe and in Hungary]. AB - The long diagnostic delay is a characteristic problem of rare disease patients. AIMS: Diagnostic delay was studied in 14 countries by EurordisCare2 involving patient organizations. METHODS: 252 Hungarian patients (cystic fibrosis; Duchenne muscular dystrophy; tuberous sclerosis, retinitis pigmentosa, and Williams' syndrome) completed the questionnaires. RESULTS: The median delay was longer in Hungary than in Europe (cystic fibrosis: 227 vs. 45 days; Duchenne muscular dystrophy: 467 vs. 360 days; tuberous sclerosis: 155 vs. 120 days). Patients' experience was similar in Hungary and in Europe. The proportion of misdiagnosis was 30.8% in Hungary (Europe: 41%), 34.8% of patients got diagnosis outside of living place region (EU: 26%) and 19.9% of them found the personal expenses too high (EU: 10%). Delivery of the diagnosis was unnecessary according to 27.4% of Hungarian patients (EU: 35%). CONCLUSIONS: The qualitative survey demonstrated that the problems with the diagnosis of rare diseases are widespread, the identified areas require interventions, and it confirmed the importance of centralized care. PMID- 22835636 TI - [Diffusion-weighted MR imaging; the significance of ADC and perfusion values in the differential diagnosis of pancreatic adenocarcinoma and mass forming pancreatitis]. AB - Despite the increasing diagnostic accuracy of cross sectional imaging modalities, the correct differentiation between pancreatic adenocarcinoma and mass forming pancreatitis has remained a challenge. AIM: Based on their 2 and 1/2 -year experience, the aim of the authors was to assess the clinical utility of diffusion-weighted magnetic resonance imaging in the diagnosis and discernment of pancreatic adenocarcinoma and mass forming pancreatitis. METHODS: 3 b-values diffusion-weighted magnetic resonance examinations were performed in 19 patients suffering from adenocarcinoma and in 8 patients with pancreatitis. 12 healthy patients were examined as reference. Apparent diffusion coefficient and perfusion values were calculated. Malignancy was verified by pathology in all cases. An inflammatory disease was diagnosed on the basis of previous medical history, changes in laboratory values, follow-up computer tomographic examinations and improvement in the patients' condition. RESULTS: Comparison of the apparent diffusion coefficient and perfusion values revealed significant differences between healthy pancreatic tissues and those affected by inflammation or tumor. The highest apparent diffusion coefficient and perfusion values were detected in the normal pancreas. Mass forming pancreatitis had diminished the apparent diffusion coefficient and perfusion values, whereas these values were the lowest in tumorous tissues. CONCLUSION: In agreement with literature data, the authors conclude that diffusion-weighted magnetic resonance imaging is a promising differential-diagnostic imaging tool in the distinction of circumscribed pancreatic lesions. PMID- 22835638 TI - Expression pattern of Sox2 during mouse tooth development. AB - The transcription factor Sox2 plays important roles in maintaining the pluripotency of embryonic stem cells and adult progenitors. However, whether Sox2 is involved in odontogenesis has not been reported. In this study, we examined the expression pattern of Sox2 during mouse incisor and molar development using real-time PCR, in situ hybridization and immunohistochemistry. Sox2 mRNA was expressed in the dental epithelium and mesenchyme while Sox2 protein was mainly detected in the epithelium from embryonic day (E) 11.5 to postnatal (PN) day 20. In the case of incisor, Sox2 mRNA and protein were expressed in most of dental epithelial cells from E11.5 to E14.5, and they were both highly expressed in the labial cervical loop area from E16.5 to PN20. During molar development, we observed an asymmetrical distribution of Sox2 protein in the epithelium from E13.5 to E16.5, with stronger signals in the lingual side. From E18.5 to PN2, Sox2 was expressed within the cervical loop area, and the stellate intermediate layer. From PN6 to PN14, Sox2 expression was confined mainly to the apical end of hertwig's epithelium root sheath (HERS) cells. Sox2 was also detected within the perivascular region of the dental pulp at PN14 and PN20. Our results suggested that: (1) Sox2 was involved in mouse odontogenesis, and (2) it might participate in maintaining the pluripotency of the epithelial stem cells of labial cervical loop in mouse incisor development and the epithelium progenitors during molar development, (3) Sox2 might be regulated at post-transcription level during mouse odontogenesis. PMID- 22835639 TI - Executive function and developmental disorders: the flip side of the coin. AB - Several common developmental disorders emerge during early to middle childhood (e.g. autism, attention deficit and hyperactivity disorder) and are associated with impairments in executive function (EF). Contrary to the prevailing view, I suggest that, within populations at-risk, the association with EF is found because individuals with strong EF skills are better able to compensate for atypicalities in other brain systems early in life, and are therefore less likely to receive a diagnosis later in life. I discuss evidence consistent with this view from considerations of individual variability, neuroimaging, and genetics. To the extent that this view is correct, it offers hope for remediation of some later emerging symptoms, as evidence from typical groups indicates that training programs for EF in preschoolers may be effective in improving skills. PMID- 22835640 TI - [Multidetector computed tomography assessment of cardiac comorbidity in patients with chronic obstructive pulmonary disease]. AB - Cardiac comorbidity is one of the most important prognostic factors in lung disease, especially in chronic obstructive pulmonary disease (COPD). The imaging techniques available for the study of this systemic manifestation concomitant with COPD include heart catheterization, transthoracic echocardiography, and magnetic resonance imaging. Multidetector computed tomography (MDCT) represents a significant advance in this field because it enables the acquisition of simultaneous studies of the cardiopulmonary anatomy that go beyond anatomic and morphologic analysis to include a functional approach to this condition. In this article, we review the practical aspects necessary to evaluate cardiac comorbidity in patients with COPD, both from the point of view of pulmonary hypertension and of the analysis of ventricular dysfunction and coronary heart disease. PMID- 22835641 TI - [Dual-energy computed tomography: what is it useful for?]. AB - Dual-energy CT is one of the newest and most attractive fields in radiology today. New generation scanners can acquire datasets with different X-ray spectra, which facilitates the characterization of certain chemical elements, making it possible to detect functional alterations in the absence of morphologic or densitometric anomalies. The capability of characterizing these elements is enabling new applications to be developed for clinical practice and changing the way we work. The aim of this article is to explain what dual-energy CT studies are, the techniques available for performing them, the advantages and disadvantages of these studies, and what we might expect from this field in the future. PMID- 22835642 TI - The responses to surface wettability gradients induced by chitosan nanofilms on microtextured titanium mediated by specific integrin receptors. AB - Microtexture and chemistry of implant surfaces are important variables for modulating cellular responses. Surface chemistry and wettability are connected directly. While each of these surface properties can influence cell response, it is difficult to decouple their specific contributions. To address this problem, the aims of this study were to develop a surface wettability gradient with a specific chemistry without altering micron scale roughness and to investigate the role of surface wettability on osteoblast response. Microtextured sandblasted/acid-etched (SLA, Sa = 3.1 MUm) titanium disks were treated with oxygen plasma to increase reactive oxygen density on the surface. At 0, 2, 6, 10, and 24 h after removing them from the plasma, the surfaces were coated with chitosan for 30 min, rinsed and dried. Modified SLA surfaces are denoted as SLA/h in air prior to coating. Surface characterization demonstrated that this process yielded differing wettability (SLA0 < SLA2 < SLA10 < SLA24) without modifying the micron scale features of the surface. Cell number was reduced in a wettability dependent manner, except for the most water-wettable surface, SLA24. There was no difference in alkaline phosphatase activity with differing wettability. Increased wettability yielded increased osteocalcin and osteoprotegerin production, except on the SLA24 surfaces. mRNA for integrins alpha1, alpha2, alpha5, beta1, and beta3 was sensitive to surface wettability. However, surface wettability did not affect mRNA levels for integrin alpha3. Silencing beta1 increased cell number with reduced osteocalcin and osteoprotegerin in a wettability-dependent manner. Surface wettability as a primary regulator enhanced osteoblast differentiation, but integrin expression and silencing beta1 results indicate that surface wettability regulates osteoblast through differential integrin expression profiles than microtexture does. The results may indicate that both microtexture and wettability with a specific chemistry have important regulatory effects on osseointegration. Each property had different effects, which were mediated by different integrin receptors. PMID- 22835644 TI - Response of bone marrow stromal cells to graded co-electrospun scaffolds and its implications for engineering the ligament-bone interface. AB - Biomaterial scaffolds with gradients in architecture, mechanical and chemical properties have the potential to improve the osseointegration of ligament grafts by recapitulating phenotypic gradients that exist at the natural ligament-bone (L B) interface. Towards the larger goal of regenerating the L-B interface, this in vitro study was performed to investigate the potential of two scaffolds with mineral gradients in promoting a spatial gradient of osteoblastic differentiation. Specifically, the first graded scaffold was fabricated by co electrospinning two polymer solutions (one doped with nano-hydroxyapatite particles) from offset spinnerets, while the second was created by immersing the first scaffold in a 5 * simulated body fluid. Rat bone marrow stromal cells, cultured in the presence of osteogenic supplements, were found to be metabolically active on all regions of both scaffolds after 1 and 7 days of culture. Gene expression of bone morphogenic protein-2 and osteopontin was elevated on mineral-containing regions as compared to regions without mineral, while the expression of alkaline phosphatase mRNA revealed the opposite trend. Finally, the presence of osteopontin and bone sialoprotein confirmed osteoblastic phenotypic maturation by day 28. This study indicates that co-electrospun scaffolds with gradients in mineral content can guide the formation of phenotypic gradients and may thus promote the regeneration of the L-B interface. PMID- 22835643 TI - Synergistic effects of SDF-1alpha chemokine and hyaluronic acid release from degradable hydrogels on directing bone marrow derived cell homing to the myocardium. AB - Poor cell engraftment in the myocardium is a limiting factor towards the use of bone marrow derived cells (BMCs) to treat myocardial infarction (MI). In order to enhance the engraftment of circulating BMCs in the myocardium following MI, we have developed in situ forming hyaluronic acid (HA) hydrogels with degradable crosslinks to sustain the release of recombinant stromal cell-derived factor-1 alpha (rSDF-1alpha) and HA to the injured myocardium. Both rSDF-1alpha and the crosslinkable HA macromer stimulate BMC chemotaxis up to 4-fold in vitro through CXCR4 and CD44 receptor signaling, respectively. Moreover, the HA macromer binds rSDF-1alpha with a dissociation constant of 36 +/- 5 MUM through electrostatic interaction. When formed into hydrogels via photoinitiated crosslinking, release of encapsulated rSDF-1alpha and crosslinked HA was sustained for over 7 days, and these molecules significantly increased BMC chemotaxis in vitro. When applied to the heart following experimental MI in mice, the HA gel containing rSDF-1alpha significantly increased the number of systemically infused BMCs in the heart by ~8.5 fold after 7 days, likely through both systemic and local effects of released molecules. We conclude that sustained release of rSDF-1alpha and HA from our engineered HA hydrogels enhances BMC homing to the remodeling myocardium better than delivery of rSDF-1alpha alone. PMID- 22835645 TI - PEI protected aptamer molecular probes for contrast-enhanced in vivo cancer imaging. AB - Aptamers have emerged as promising molecular probes for cancer diagnosis. However, their application for in vivo cancer imaging remains limitation due to the poor stability in blood and the degradation by nucleases. In the present study, we generated PEI/aptamer molecular complexes for cancer imaging in vivo by using deoxyribonuclease (DNase)-activatable fluorescence probes (DFProbes) to monitor DNA degradation. The results showed that the complexes with PEI at the N/P ratio from 3.8 to 15 effectively prevented the degradation of DFProbes both in vitro and in vivo. Moreover, PEI successfully protected TD05 aptamers from DNase degradation without affecting its specific recognition of Ramos cells. In tumor bearing mice, PEI/aptamer molecular complexes further demonstrated superior passive tumor targeting and extended circulation time as compared with free aptamer. Hence, the well-defined PEI/aptamer probe is a novel strategy to deliver targeted aptamer for tumor diagnosis and imaging in vivo. PMID- 22835647 TI - Influence of surface model extraction parameter on computational fluid dynamics modeling of cerebral aneurysms. AB - Threshold image intensity for reconstructing patient-specific vascular models is generally determined subjectively. We assessed the effects of threshold image intensity differences on computational fluid dynamics (CFD) using a simple method of threshold determination. This study included 11 consecutive patients with internal carotid artery aneurysms collected retrospectively between April 2009 and March 2010. In 3-dimensional rotational angiography image data, we set a line probe across the coronal cross-section of the parent internal carotid artery, and calculated a profile curve of the image intensity along this line. We employed the threshold coefficient (C(thre)) value in this profile curve, in order to determine the threshold image intensity objectively. We assessed the effects of C(thre) value differences on vascular model configuration and the wall shear stress (WSS) distribution of the aneurysm. The threshold image intensity increased as the C(thre) value increased. The frequency of manual editing increased as the C(thre) value decreased, while disconnection of the posterior communicating artery occurred more frequently as the C(thre) value increased. The volume of the vascular model decreased and WSS increased according to the C(thre) value increase. The pattern of WSS distribution changed remarkably in one case. Threshold image intensity differences can produce profound effects on CFD. Our results suggest the uniform setting of C(thre) value is important for objective CFD. PMID- 22835646 TI - Improving the correction of eddy current-induced distortion in diffusion-weighted images by excluding signals from the cerebral spinal fluid. AB - Iterative cross-correlation (ICC) is the most popularly used schema for correcting eddy current (EC)-induced distortion in diffusion-weighted imaging data, however, it cannot process data acquired at high b-values. We analyzed the error sources and affecting factors in parameter estimation, and propose an efficient algorithm by expanding the ICC framework with a number of techniques: (1) pattern recognition for excluding brain ventricles; (2) ICC with the extracted ventricle for parameter initialization; (3) gradient-based entropy correlation coefficient (GECC) for optimal and finer registration. Experiments demonstrated that our method is robust with high accuracy and error tolerance, and outperforms other ICC-family algorithms and popular approaches currently in use. PMID- 22835648 TI - The effect of running speed on knee mechanical loading in females during side cutting. AB - BACKGROUND: Side cutting involves mechanical loading of the knee which has been associated with anterior cruciate ligament injury risk. Despite a fast growing body of research, the relationship between loading mechanisms and running speed is still unclear. The aim of this study was to investigate how running speed determines a likely trade-off between task achievement and actual mechanical loading. METHODS: Fourteen female participants (mean age=20.6+/-0.7yr, height=1.66+/-0.05m, mass=57.5+/-6.9kg) performed 45 degrees side cutting manoeuvres at 2, 3, 4 and 5ms(-1) approach speeds. Three dimensional motion and ground reaction forces were recorded to calculate whole body centre of mass (CoM) velocity and lower limb kinematics and kinetics, focusing on knee flexion angle at touch-down and peak knee valgus loading during weight acceptance. One-way repeated measures ANOVA and one-dimensional statistical parametric mapping were used to identify significant speed effects on task achievement and mechanical loading. RESULTS: Analysis of CoM velocities revealed that side cutting manoeuvres at higher running speeds matched the task requirements to a lesser extent. Despite a gradual increase of anterior-posterior deceleration and medio lateral acceleration with running speed, knee loading mechanisms only reached meaningful levels from a 4ms(-1) running speed. CONCLUSION: Our results confirmed a trade-off between task achievement and actual mechanical loading. This identified a need for standardisation of reporting running speeds. Taking into account also safety considerations, standardisation of a 4ms(-1) running speed is proposed for female athletes. PMID- 22835649 TI - Optimal field-splitting algorithm in intensity-modulated radiotherapy: evaluations using head-and-neck and female pelvic IMRT cases. AB - To develop an optimal field-splitting algorithm of minimal complexity and verify the algorithm using head-and-neck (H&N) and female pelvic intensity-modulated radiotherapy (IMRT) cases. An optimal field-splitting algorithm was developed in which a large intensity map (IM) was split into multiple sub-IMs (>=2). The algorithm reduced the total complexity by minimizing the monitor units (MU) delivered and segment number of each sub-IM. The algorithm was verified through comparison studies with the algorithm as used in a commercial treatment planning system. Seven IMRT, H&N, and female pelvic cancer cases (54 IMs) were analyzed by MU, segment numbers, and dose distributions. The optimal field-splitting algorithm was found to reduce both total MU and the total number of segments. We found on average a 7.9 +/- 11.8% and 9.6 +/- 18.2% reduction in MU and segment numbers for H&N IMRT cases with an 11.9 +/- 17.4% and 11.1 +/- 13.7% reduction for female pelvic cases. The overall percent (absolute) reduction in the numbers of MU and segments were found to be on average -9.7 +/- 14.6% (-15 +/- 25 MU) and -10.3 +/- 16.3% (-3 +/- 5), respectively. In addition, all dose distributions from the optimal field-splitting method showed improved dose distributions. The optimal field-splitting algorithm shows considerable improvements in both total MU and total segment number. The algorithm is expected to be beneficial for the radiotherapy treatment of large-field IMRT. PMID- 22835650 TI - Influence of compensator thickness, field size, and off-axis distance on the effective attenuation coefficient of a cerrobend compensator for intensity modulated radiation therapy. AB - Intensity-modulated radiation therapy (IMRT) can be performed by using compensators. To make a compensator for an IMRT practice, it is required to calculate the effective attenuation coefficient (MU(eff)) of its material, which is affected by various factors. We studied the effect of the variation of the most important factors on the calculation of the MU(eff) of the cerrobend compensator for 6-MV photon beams, including the field size, compensator thickness, and off-axis distance. Experimental measurements were carried out at 100 cm source-to-surface distance and 10 cm depth for the 6-MV photon beams of an Elekta linac using various field size, compensator thickness, and off-axis settings. The field sizes investigated ranged from 4 * 4 to 25 * 25 cm2 and the cerrobend compensator thicknesses from 0.5-6 cm. For a fixed compensator thickness, variation of the MU(eff) with the field size ranged from 3.7-6.8%, with the highest value attributed to the largest compensator thickness. At the reference field size of 10 * 10 cm2, the MU(eff) varied by 16.5% when the compensator thickness was increased from 0.5-6 cm. However, the variation of the MU(eff) with the off-axis distance was only 0.99% at this field size, whereas for the largest field size, it was more significant. Our results indicated that the compensator thickness and field size have the most significant effect on the calculation of the compensator MU(eff) for the 6-MV photon beam. Therefore, it is recommended to consider these parameters when calculating the compensator thickness for an IMRT practice designed for these beams. The off-axis distance had a significant effect on the calculation of the MU(eff) only for the largest field size. Hence, it is recommended to consider the effect of this parameter only for field sizes larger than 25 * 25 cm2. PMID- 22835651 TI - Fluid consumption in lithium-treated rats: roles of stimulus novelty and context novelty. AB - In 5 experiments thirsty rats received an injection of lithium chloride or of saline, and their consumption of fluid was monitored at 5-min intervals for 30 min. The novelty of the fluid and the novelty of the test context was varied. In Experiment 1 a novel fluid (a sucrose solution) was offered in a novel context; in Experiment 2 the fluid was novel and the context was familiar (the home cage); in Experiment 3 the fluid was familiar and the context was novel; and in Experiment 4 both fluid and context were familiar. Lithium influenced fluid consumption in those designs that included at least one novel feature (Experiments 1, 2, and 3, but not in Experiment 4). Consumption was initially enhanced (with respect to the controls) when the context was novel, but was suppressed when the fluid was novel. In Experiment 5, the flavor was over ingested after lithium treatment when it was presented in a short (5 min) test conducted in a novel place, but was rejected in a subsequent consumption in the home cages. It is argued that the effect of lithium depends on two factors: enhanced attention to salient cues that modifies the exploratory responses evoked by a novel context; rapid conditioning of an aversion when the fluid consumed is novel. Implications for the use of fluid consumption as an index of lithium induced nausea are considered. PMID- 22835652 TI - Chronic pre-exposure to methamphetamine following 31 days of withdrawal impairs sexual performance but not sexual conditioning in male Japanese quail. AB - In the current study, male quail were administered methamphetamine (3.0 or 5.6 mg/kg IP) or saline once daily for 10 days and locomotor activity was assessed. Following a 31-day withdrawal period, sexual conditioning trials were conducted such that a conditioned stimulus (CS) was presented prior to a copulatory opportunity with a female quail. Male quail treated with methamphetamine (5.6 mg/kg) showed a decrease in locomotor activity from Trial 1 to Trial 10 suggesting a potential tolerance effect. Following the 31-day withdrawal period, all male quail that received the CS paired with a copulatory opportunity showed enhanced approach to the CS, regardless of treatment history. Thus, chronic pre exposure to methamphetamine did not alter sexual conditioning. In contrast, chronic pre-exposure to methamphetamine (3.0 mg/kg) decreased the frequency of successful copulations suggesting that it impaired sexual performance. The findings suggest that methamphetamine may differentially affect the neural circuitry involved in motivational systems compared with those involved in consummatory aspects of sexual behavior. These effects may last long after drug cessation. PMID- 22835653 TI - Farmers' contribution to landscape services in the Netherlands under different rural development scenarios. AB - Landscape services represent the benefits human populations derive, directly or indirectly, from (agro-)ecosystem functions at the landscape scale. Many of these services are the result of farmers' decision making to allocate resources to other activities than food production and therefore are the result of farm the adoption of on-farm rural activities. With changing agricultural and rural policies, the future provision of landscape services to fulfill societal demands is not guaranteed. This study aims at mapping the spatial distribution of the adoption of on-farm rural activities under different explorative scenarios. For a Dutch landscape, storylines at the landscape scale were developed by combining global storylines, resulting from the Global Environmental Outlook, with local storylines resulting from key informant interviews. Subsequently these storylines were translated into quantitative scenarios that were implemented into a simulation procedure based on spatially explicit econometric models of farmer's decision making. Results show that further market liberalization leads to a decrease of landscape services in the study area. In our study, only increased cooperation between government, farmers and citizens appears to result in a general increase of all landscape services across the entire landscape. PMID- 22835654 TI - Bioaccumulation and biosorption of copper and lead by a unicellular algae Chlamydomonas reinhardtii in single and binary metal systems: a comparative study. AB - A comparative evaluation of bioaccumulation and biosorption of Cu (II) and Pb (II) ions by algal cells of Chlamydomonas reinhardtii was conducted in single and binary metal systems. Experiments were performed in solutions containing 5 * 10( 7) M of free metal at 30 degrees C and pH 6. Algal cells were used in the concentration of 0.2 g/L. Both processes tend to be more important as contact time between heavy metals and algal cells increases. Under studied conditions, dead cells showed higher removal efficiency than living cells for both metal ions. Removal efficiency of Pb increases from 8% to 40% when comparing the results obtained by living cells and dead cells. For Cu (II) ions, the removal efficiency of dead cells was about 2 times higher than living cells (55% vs. 28%). Living cells showed similar bioaccumulation capacity for both ions. Synergistic and antagonistic effects between copper and lead were observed in binary metal systems which imply that bioaccumulation process is much more dynamic than assumed in the equilibrium models. In contrast, dead algal cells showed a higher affinity for Pb (II) ions compared to Cu (II) ions and no competitive effect was observed in the biosorption of copper and lead by the inert cells in binary metal mixtures. Biosorption of Cu (II) and Pb (II) seems to occur at different binding sites on the surface of algal biomass. The obtained results showed that the mostly advantageous process of metal ions binding is biosorption and the biomass of C. reinhardtii is suitable for the development of an efficient and economic biosorbent for the removal of heavy metals from aqueous environments. PMID- 22835655 TI - Identification of metabolites from benzo[a]pyrene oxidation by ligninolytic enzymes of Polyporus sp. S133. AB - The biodegradation of benzo[a]pyrene (BaP) by using Polyporus sp. S133, a white rot fungus isolated from oil-contaminated soil was investigated. Approximately 73% of the initial concentration of BaP was degraded within 30 d of incubation. The isolation and characterization of 3 metabolites by thin layer chromatography, column chromatography, and UV-vis spectrophotometry in combination with gas chromatography-mass spectrometry, indicated that Polyporus sp. S133 transformed BaP to BaP-1,6-quinone. This quinone was further degraded in 2 ways. First, BaP 1,6-quinone was decarboxylated and oxidized to form coumarin, which was then hydroxylated to hydroxycoumarin, and finally to hydroxyphenyl acetic acid by addition of an epoxide group. Second, Polyporus sp. S133 converted BaP-1,6 quinone into a major product, 1-hydroxy-2-naphthoic acid. During degradation, free extracellular laccase was detected with reduced activity of lignin peroxidase, manganese-dependent peroxidase and 2,3-dioxygenase, suggesting that laccase and 1,2-dioxygenase might play an important role in the transformation of PAHs compounds. PMID- 22835656 TI - Effects of phytoestrogen supplementation in the feed on the shell gland of laying hens at the end of the laying period. AB - Shell quality decreases as laying hens age and the aim of present study was to investigate how a supplement of daidzein, a natural phytoestrogen in soya, affects key factors in the shell gland and eggshell quality in late-stage laying hens. Hybrids of Lohmann Selected Leghorn (LSL) and Lohmann Brown (LB), received either a daidzein diet (50 mg/kg feed) or a control diet from 60 to 72 weeks of age. Both the total number of capillaries and capillaries with carbonic anhydrase (CA) activity were higher in the LSL hybrid than in the LB. After daidzein supplementation the number of CA positive capillaries was unaffected in the LSL but increased in the LB hybrid indicating a higher sensitivity to daidzein in this hybrid. Estrogen receptor alpha and beta (ERalpha, ERbeta) were localized and the complete picture of the two ERs can now be described in shell gland of domestic hens. Nuclear and cytoplasmic staining was generally stronger for ERbeta, while membrane associated staining was present only for ERalpha. Interestingly, capillary endothelium contained only ERbeta and since estrogen regulation of CA is well documented, the presence of an endothelial ER provides one possible route for the increase in CA positive capillaries found in LB hybrids. Eggshell quality or egg production was not affected by daidzein supplementation. The hybrids used in this study showed anatomical differences and reacted differently to daidzein supplementation, but if this can be explained by the divergences in ERbeta localization noted between the hybrids remains to be clarified. PMID- 22835657 TI - Three-dimensional mandibular change after sagittal split ramus osteotomy with a semirigid sliding plate system for fixation of a mandibular setback surgery. AB - OBJECTIVE: This study proposes a new plate system, a sliding plate, after sagittal split ramus osteotomy (SSRO). The sliding plate was designed to adjust the spatial relationship between the proximal and distal segments during the postoperative period. This plate was used for mandibular setback surgery to minimize forward early relapse. STUDY DESIGN: Twenty-six Korean subjects who had undergone mandibular setback surgery by SSRO were included in this study. Skeletal stability was evaluated with lateral cephalograms and 3-dimensional cone beam computerized tomography. RESULTS: Forward mandibular movement during the postoperative period was ~2 mm. The condyles rotated inward on the axial view after surgery. Postoperatively, the condyle rotated outward on the axial view, inward on the coronal view, and forward on the sagittal view by a statistically significant amount. CONCLUSIONS: The fixation method with sliding plates after SSRO was stable and convenient for the operators during surgery and postoperative care. PMID- 22835658 TI - An acoustical analysis of the effects of maxillary sinus augmentation on voice quality. AB - OBJECTIVE: Increased experience in sinus lifting procedures has led to a number of literature reports, but the potential effects of sinus lifting on voice quality is not clearly addressed in clinical studies. The aim of this study was to objectively investigate the effects of sinus lifting on alterations in voice quality and, in particular, on vocal resonance. STUDY DESIGN: A total of 17 patients who were in need of bilateral sinus augmentation were recruited. Acoustic analyses were performed before and after surgery. Volume changes in the sinuses were recorded before and after surgery using dental volumetric tomography. The Friedman test with Bonferroni correction was used to analyze the data. RESULTS: Changes in the perturbation parameters of acoustic sound analysis were found to be statistically significant. CONCLUSIONS: We recommend that all patients (especially voice professionals) be informed about the possible effects of sinus lifts on speech and voice alterations. PMID- 22835659 TI - An indolent swelling of the parasymphyseal area. PMID- 22835660 TI - Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjogren's syndrome. AB - BACKGROUND/PURPOSE: Primary Sjogren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. METHODS: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. RESULTS: Mean vitamin-D levels were comparable between SS patients and control 21.2 +/- 9.4 ng/ml and 22.4 +/- 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 +/- 5.5 ng/ml vs. 22.6+/-8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 +/- 6.25 ng/ml), compared to SS patients without lymphoma (22 +/- 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. CONCLUSIONS: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested. PMID- 22835661 TI - [Metabolic and osteogenic pattern of prostate cancer bone metastases]. AB - The current protocols include the bone scintigraphy and choline PET/CT to localize recurrence in patients having elevated serum PSA after treatment for prostate cancer. Both methods show good agreement in the diagnosis of bone metastases, however conflicting results can be found. We present three cases in which a PET/CT was performed with (18)F-Fluoride due to disagreement between the bone scintigraphy and (11)C-Choline PET/CT. The (18)F-Fluoride PET/CT was capable of confirming the existence of bone metastasis in all of them, so it may be an alternative to the MRI as a tracer of second bone imaging modality, although its use is limited by cost and availability. PMID- 22835663 TI - Mechano-electrical feedback explains T-wave morphology and optimizes cardiac pump function: insight from a multi-scale model. AB - In the ECG, T- and R-wave are concordant during normal sinus rhythm (SR), but discordant after a period of ventricular pacing (VP). Experiments showed that the latter phenomenon, called T-wave memory, is mediated by a mechanical stimulus. By means of a mathematical model, we investigated the hypothesis that slow acting mechano-electrical feedback (MEF) explains T-wave memory. In our model, electromechanical behavior of the left ventricle (LV) was simulated using a series of mechanically and electrically coupled segments. Each segment comprised ionic membrane currents, calcium handling, and excitation-contraction coupling. MEF was incorporated by locally adjusting conductivity of L-type calcium current (g(CaL)) to local external work. In our set-up, g(CaL) could vary up to 25%, 50%, 100% or unlimited amount around its default value. Four consecutive simulations were performed: normal SR (with MEF), acute VP, sustained VP (with MEF), and acutely restored SR. MEF led to T-wave concordance in normal SR and to discordant T-waves acutely after restoring SR. Simulated ECGs with a maximum of 25-50% adaptation closely resembled those during T-wave memory experiments in vivo and also provided the best compromise between optimal systolic and diastolic function. In conclusion, these simulation results indicate that slow acting MEF in the LV can explain a) the relatively small differences in systolic shortening and mechanical work during SR, b) the small dispersion in repolarization time, c) the concordant T-wave during SR, and d) T-wave memory. The physiological distribution in electrophysiological properties, reflected by the concordant T wave, may serve to optimize cardiac pump function. PMID- 22835664 TI - [Comment: "laparoendoscopic radical cystectomy with orthotopic ileal neobladder through umbilical single port"]. PMID- 22835662 TI - The zebrafish as a novel animal model to study the molecular mechanisms of mechano-electrical feedback in the heart. AB - Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by "T wave memory", it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only 90 min of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart. PMID- 22835665 TI - Invasive explorations in children younger than 3 years. AB - PURPOSE: In children with drug-resistant focal epilepsy who are candidates for surgery, invasive exploration is sometimes required. However, this is being controversially discussed for children younger than 3 years. The question of its necessity, feasibility and its risks is often raised, since it concerns primarily lesional epilepsy and a lesionectomy might be proposed right away. However, this attitude does not take into account the specificities of epilepsy at this age, including poor specificity of electroclinical semiology and the ongoing myelination challenging the interpretation of magnetic resonance imaging (MRI). METHODS: We retrospectively studied the records of children with drug-resistant epilepsy who were younger than 3 years of age at the time of their invasive exploration at our institution from 2000 to 2009. We reviewed the clinical, imaging and electrophysiological data, and included post-operative outcome for those who underwent surgery. KEY FINDINGS: 26 Children met the inclusion criteria. All had drug-resistant epilepsy that started at an average of 5.2 months (range 0-20 months) with multiple daily seizures in all and developmental delay in 16. The average age at the time of exploration was 21.8 months (range 5 35). In 20 children, subdural electrodes in combination with two or three depth electrodes were implanted, and in six children aged over 2 years a stereo-electro encephalography (SEEG) was performed. SEEG was considered technically difficult to achieve before the age of 2 years. The tolerance of invasive exploration was good with a 3% morbidity consisting of one subdural hematoma during exploration by subdural electrodes, evacuated without any particular sequelae. In 25 patients, the exploration permitted to propose a focal resection. The surgical intervention was in the frontal lobe in 12 cases, the parietal lobe in six, the occipital lobe in two patients, and the temporal lobe in one child who underwent an additional resection. Four children had a resection of two or three lobes. Five underwent a second surgery, following a second invasive exploration. Histologically, the resected tissue revealed focal cortical dysplasia in 21 cases (including three patients with tuberous sclerosis), two post-ischemic lesions, one dysembryoplastic neuroepithelial tumor, and one gangliglioma associated with dysplasia. The mean postoperative follow-up period was 51 months (range 4-110). For the children operated on twice, follow-up was counted from the second surgery on. Seventeen children (68%) had an outcome of Engel class 1. In five (20%), seizure frequency was significantly improved (Engel class 3). In two of three patients without improvement in seizure frequency (Engel class 4), a new SEEG is planned and the third is presently a candidate for hemispherotomy. SIGNIFICANCE: Invasive exploration is feasible, well tolerated and carries a low morbidity in children under 3 years of age. At this age, it is indicated for drug-resistant lesional epilepsy associated with developmental delay. It permits delineating the lesion, which is not possible with MRI. The choice of the technique is in part age-dependent. The discussion of its indication arises in the same way as in the older child. PMID- 22835666 TI - Epilepsy surgery after treatment of pediatric malignant brain tumors. AB - Epilepsy surgery is common in the face of benign brain tumors, but rarely for patients with a history of malignant brain tumors. Seizures are a common sequelae in survivors of malignant pediatric brain tumors. Medical management alone may not adequately treat epilepsy, including in this group. We report four cases of patients who previously underwent gross total resection, radiation therapy, and chemotherapy for successful treatment of malignant brain neoplasia, yet suffered from medically intractable seizures. All underwent surgery for treatment of epilepsy with extension of the original resection. Despite the aggressive primary treatment of the neoplasm, and the potential for diffuse cerebral insults, all benefited from focal surgical resection. Aggressive surgical management of intractable epilepsy can be considered in survivors of malignant brain tumors. PMID- 22835667 TI - The year in heart failure. PMID- 22835668 TI - Second-generation everolimus-eluting stents versus first-generation sirolimus eluting stents in acute myocardial infarction. 1-year results of the randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. AB - OBJECTIVES: The goal of this study was to compare the efficacy and safety of second-generation everolimus-eluting stents (EES) with first-generation sirolimus eluting stents (SES) in primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: Drug-eluting stents (DES) in AMI are still feared for possible late and very late stent thrombosis (ST). Newer generation DES, with more hemocompatible polymers and improved healing, may show promise regarding increased efficacy of DES with improved safety. However, no randomized trials in AMI are available. METHODS: A total of 625 patients with AMI were randomized (2:1) to receive EES or SES in the XAMI (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. Primary endpoint was major adverse cardiac events (MACE) at 1 year consisting of cardiac death, nonfatal AMI, or any target vessel revascularization. The study was powered for noninferiority of EES. Secondary endpoints comprised ST rates and MACE rate up to 3 years. RESULTS: The MACE rate was 4.0% for EES and 7.7% for SES; the absolute difference was -3.7% (95% confidence interval: -8.28 to -0.03; p = 0.048) and relative risk was 0.52 (95% confidence interval: 0.27 to 1.00). One-year cardiac mortality was low at 1.5% for EES versus 2.7% for SES (p = 0.36), and 1-year incidence of definite and/or probable ST was 1.2% for EES versus 2.7% for SES (p = 0.21). CONCLUSIONS: In this all-comer, randomized, multicenter AMI trial, second-generation EES was noninferior to SES, and superiority for MACE was suggested. ST rate in EES at 1-year was low, but long-term follow-up and larger studies will have to show whether very late ST rates will also be improved in newer DES. (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction [XAMI]; NTR1123). PMID- 22835670 TI - Scaring myocardial scars: new targets for the electrical fairy? PMID- 22835669 TI - Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. AB - OBJECTIVES: We tested whether an assessment of myocardial scarring by cardiac magnetic resonance imaging (MRI) would improve risk stratification in patients evaluated for implantable cardioverter-defibrillator (ICD) implantation. BACKGROUND: Current sudden cardiac death risk stratification emphasizes left ventricular ejection fraction (LVEF); however, most patients suffering sudden cardiac death have a preserved LVEF, and many with poor LVEF do not benefit from ICD prophylaxis. METHODS: One hundred thirty-seven patients undergoing evaluation for possible ICD placement were prospectively enrolled and underwent cardiac MRI assessment of LVEF and scar. The pre-specified primary endpoint was death or appropriate ICD discharge for sustained ventricular tachyarrhythmia. RESULTS: During a median follow-up of 24 months the primary endpoint occurred in 39 patients. Whereas the rate of adverse events steadily increased with decreasing LVEF, a sharp step-up was observed for scar size >5% of left ventricular mass (hazard ratio [HR]: 5.2; 95% confidence interval [CI]: 2.0 to 13.3). On multivariable Cox proportional hazards analysis, including LVEF and electrophysiological-study results, scar size (as a continuous variable or dichotomized at 5%) was an independent predictor of adverse outcome. Among patients with LVEF >30%, those with significant scarring (>5%) had higher risk than those with minimal or no (<=5%) scarring (HR: 6.3; 95% CI: 1.4 to 28.0). Those with LVEF >30% and significant scarring had risk similar to patients with LVEF <=30% (p = 0.56). Among patients with LVEF <=30%, those with significant scarring again had higher risk than those with minimal or no scarring (HR: 3.9; 95% CI: 1.2 to 13.1). Those with LVEF <=30% and minimal scarring had risk similar to patients with LVEF >30% (p = 0.71). CONCLUSIONS: Myocardial scarring detected by cardiac MRI is an independent predictor of adverse outcome in patients being considered for ICD placement. In patients with LVEF >30%, significant scarring (>5% LV) identifies a high-risk cohort similar in risk to those with LVEF <=30%. Conversely, in patients with LVEF <=30%, minimal or no scarring identifies a low risk cohort similar to those with LVEF >30%. PMID- 22835671 TI - Identifying the etiology of a "finger-like" structure inside the left ventricle using cardiac magnetic resonance. PMID- 22835672 TI - Rhinotillexis: a possible heuristic to reduce inappropriate noninvasive cardiac imaging? PMID- 22835673 TI - CTCA versus MPI = anatomical versus functional. PMID- 22835675 TI - Angiographic evidence of reperfusion injury after carotid artery stenting. PMID- 22835676 TI - Titanium phosphate glass microspheres for bone tissue engineering. AB - We have demonstrated the successful production of titanium phosphate glass microspheres in the size range of ~10-200 MUm using an inexpensive, efficient, easily scalable process and assessed their use in bone tissue engineering applications. Glasses of the following compositions were prepared by melt-quench techniques: 0.5P2O5-0.4CaO-(0.1-x)Na2O-xTiO2, where x=0.03, 0.05 and 0.07 mol fraction (denoted as Ti3, Ti5 and Ti7 respectively). Several characterization studies such as differential thermal analysis, degradation (performed using a novel time lapse imaging technique) and pH and ion release measurements revealed significant densification of the glass structure with increased incorporation of TiO2 in the glass from 3 to 5 mol.%, although further TiO2 incorporation up to 7 mol.% did not affect the glass structure to the same extent. Cell culture studies performed using MG63 cells over a 7-day period clearly showed the ability of the microspheres to provide a stable surface for cell attachment, growth and proliferation. Taken together, the results confirm that 5 mol.% TiO2 glass microspheres, on account of their relative ease of preparation and favourable biocompatibility, are worthy candidates for use as substrate materials in bone tissue engineering applications. PMID- 22835677 TI - Adjustable degradation and drug release of a thermosensitive hydrogel based on a pendant cyclic ether modified poly(epsilon-caprolactone) and poly(ethylene glycol)co-polymer. AB - The convenient and precise fabrication of drug-hydrogel formulations with satisfactory degradability and a well-controlled drug release profile are crucial factors for injectable hydrogel formulations in clinical applications. Here a new injectable thermosensitive hydrogel formed from poly(epsilon-caprolactone) (PCL) poly(ethylene glycol)-poly(epsilon-caprolactone) amphiphilicco-polymers with 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) moieties incorporated in the poly(epsilon-caprolactone) (PCL)block (PECT) was constructed to provide a route to tailor the degradation and drug release behavior. The effect of hydrophilic cyclic ether moieties on the degradation of and drug release by PECT hydrogels were evaluated in vitro and in vivo. The results indicated that a freeze-dried powder of paclitaxel-loaded PECT nanoparticles rapidly dissolved in water at ambient temperature with slightly shaking and formed a stable injectable in situ drug-hydrogel formulation at body temperature, which is convenient for clinical operations because it avoids the need for pre-quenching or long-term incubation. The paclitaxel distribution was also more quantitative and homogeneous on entrapping paclitaxel in PECT nanoparticles. Further, the small number of pendant cyclic ether groups in PCL could decrease the cystallinity and hydrophobicity and, as a result, the in vitro and in vivo retention time of PECT hydrogels and the release of entrapped paclitaxel could be tuned from a few weeks to months by varying the amount of PTOSUO in the hydrophobic block. Significantly, paclitaxel loaded PECT nanoparticles and free paclitaxel could be simultaneously released during the in vitro paclitaxel release from PECT hydrogels. A histopathological evaluation indicated that in vivo injected PECT hydrogels produced only a modest inflammatory response. Thus pendant cyclic ether modification of PCL could be an effective way to achieve the desired degradation and drug release profiles of amphiphilicco-polymer thermosensitive hydrogels and PECT hydrogels may be suitable for local drug delivery. PMID- 22835678 TI - Carbohydrate composition of amphiphilic macromolecules influences physicochemical properties and binding to atherogenic scavenger receptor A. AB - Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) mediated by scavenger receptor A (SR-A) and counteract foam cell formation, the characteristic "atherosclerotic" phenotype. A series of AMs was prepared by altering the carbohydrate chemistry to evaluate the influence of backbone architecture on the physicochemical and biological properties. Upon evaluating the degree of polymer-based inhibition of oxLDL uptake in human embryonic kidney cells expressing SR-A, two AMs (2a and 2c) were found to have the most efficacy. Molecular modeling and docking studies show that these same AMs have the most favorable binding energies and most close interactions with the molecular model of the SR-A collagen-like domain. Thus, minor changes in the AMs' architecture can significantly affect the physicochemical properties and inhibition of oxLDL uptake. These insights can be critical for designing optimal AM-based therapeutics for the management of cardiovascular disease. PMID- 22835679 TI - Developmental changes in spiral artery blood flow in the human placenta observed with colour Doppler ultrasonography. AB - OBJECTIVES: Our current knowledge of the physiological dilatation of spiral arteries in pregnancy, is based on histology. Real-time ultrasound visualisation of these changes may aid understanding of abnormal placentation. This study aimed to investigate if changes in the spiral artery blood flow can be followed 'in vivo' and explore the novel phenomenon of the larger 'mega-jets'. METHODS: Colour Doppler ultrasonography was used to identify the most prominent jets at blood from the spiral artery into the intervillous space. Their velocity, width and length were recorded seven set time points during pregnancy. RESULTS: Fifty two uncomplicated, term normotensive pregnancies were studied. Width and length of the jets' Doppler signals increased with gestation, the velocity decreased. The length of the jets shows a bi-modal frequency distribution. The width of the signals of longer ('mega') jets was significantly greater (p = 0.001) than that of the jets (mean 4.3 mm (3.1-5.9) versus 3.8 mm (1.8-5.8) respectively) at 34 weeks. However, there was no significant difference in the peak systolic velocity (p = 0.2). CONCLUSION: This study confirms that ultrasound can be used to study the gestation dependent changes in the haemodynamics of the placental basal plate predicted, but not proven, by histologic data. The bi-modal distribution of jet lengths suggests that mega-jets are a separate entity to 'normal' jets. That they are significantly wider than 'normal' jets and yet maintain the same velocity of blood flow suggests that they have a greater volume of blood flow. The mechanism for this is hypothesised and their apparent relationship with simple placental lakes discussed. PMID- 22835680 TI - Placental expression of D-chiro-inositol phosphoglycans in preeclampsia. AB - Abnormalities in glucose metabolism linked to D-chiro-inostol phosphoglycans (IPGs) have been described in human placentas of preeclamptic women. In this study, a semi-quantitative approach to assess the histological assessment of IPGs revealed no significant differences between early and late onset preeclampsia and gestational age matched controls. However, there was a tendency towards higher values in early onset preeclampsia for villous stroma and placental vessels. Moreover, in control cases staining of plasma in placental vessels was present only in one part of vessels of mature intermediate villi while in preeclamptic specimens all placental vessels showed a similar staining. The tendencies of more staining in villous stroma associated with a differential staining of placental vessels only in preeclamptic specimens support a vectoral movement of D-chiro inositol phosphoglycans from the fetus to the placenta. PMID- 22835681 TI - Patterns of placental pathology in preterm infants with a periventricular haemorrhagic infarction: association with time of onset and clinical presentation. AB - BACKGROUND: A periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth with serious consequences. While various risk factors are recognized, little is known about the role of the placenta in the pathogenetic pathway of this type of white matter injury. AIM: To evaluate prenatal, maternal and neonatal risk factors and describe placental pathology in infants with typical and atypical timing and presentation of PVHI. METHODS: PVHI was defined as typical when the onset was within 6-96 h after birth in the context of established risk factors. PVHI was determined to be atypical when presumed antenatal (<6 h after birth) OR late in the postpartum course (>96 h). Maternal, prenatal and neonatal risk factors were collected retrospectively from patient charts. Microscopic placental pathology was described in 38/45 (84%) preterm infants (GA <34 wks) with a typical PVHI and 14/19 (74%) with an atypical presentation of PVHI. RESULTS: Using univariate analysis clinical factors significantly associated with a typical PVHI were mechanical ventilation (p = 0.00), while fetal heart rate abnormalities (p = 0.00), a planned caesarean section (p = 0.00) and hypertensive disorders (p = 0.01) were associated with an atypical PVHI. Placental pathology was different between the typical vs atypical group with respect to chorioamnionitis (p = 0.04), funisitis (p = 0.05), fetal thrombosis (p = 0.01) and placental infarction (p = 0.00). CONCLUSION: Chorioamnionitis and funisitis were significantly more common in infants with a typical PVHI. Fetal thrombosis and placental infarction were significantly more often associated with an atypical PVHI. Placental pathology in infants with PVHI reflects underlying disease processes and clinical conditions which may interact with the pathogenic mechanism of PVHI. PMID- 22835682 TI - Darkening of third molar roots on panoramic radiographs: is it really predominantly thinning of the lingual cortex? AB - This study investigated the exact intra-alveolar aetiology of a panoramic high risk sign, darkening of the third molar roots. 83 mandibular third molar surgical removals demonstrating dark bands on the third molar roots in preoperative radiographs were included in this prospective study. Exposure of the inferior alveolar nerve (IAN), the root morphology of the third molar (e.g. groove or hook) and the integrity of the mandibular canal or lingual cortical wall were observed. Differences between single (increased radiolucency alone) and multiple darkening cases (increased radiolucency with accompanying 'high risk' signs) and between IAN exposure and groove formation were analysed. In 38 cases (45.8%), the IAN was visible during the operation. Groove was present in 37.4% of cases. 26.5% of the cases showed lingual cortical thinning, while specious root conformation explained the formation of darkening on the radiographic images of an additional 9.6% of the cases. IAN exposure (P<0.001) and groove formation (P<0.001) were significantly more frequent in multiple darkening cases than in single darkening cases. According to these findings, darkening of the third molar roots is more often the result of fenestration of the inferior alveolar canal wall or groove formation of the root than lingual cortical thinning. PMID- 22835683 TI - Ultrasound-guided intralesional laser treatment of venous malformation in the oral cavity. AB - An ultrasound-guided intralesional photocoagulation (ILP) technique using a laser is described for treatment of deep venous malformations in the oral cavity. ILP is basically a blind operation and has a risk of unintended destruction of surrounding normal tissue, therefore the authors now routinely use guidance by ultrasonography using a mini-probe to improve the safety and reliability of ILP. This approach enables safe fibre insertion, appropriate laser irradiation, and intraoperative assessment of coagulation. The use of this technique is described in 8 patients. The authors conclude that ultrasound-guided ILP with a laser is a promising technique for less-invasive treatment of a vascular malformation in the oral cavity. PMID- 22835684 TI - Comparing participation in activities among children with disabilities. AB - INTRODUCTION: Compared to typically developing peers, children with disabilities due to neurodevelopmental disorders and disabilities (NDD/D) and to chronic medical conditions (CMC) have reduced participation in activities. The extent to which these two groups of children have different levels of participation is unknown and was examined in this study. METHODS: The 2006 Participation and Activity Limitation Survey children dataset collected by Statistics Canada was analyzed. Children with disabilities due to NDD/D and CMC were identified following review and classification of all ICD-10 codes in the dataset by two pediatricians. Dependent variables were parent-reported child participation in supervised and unsupervised physical activities within and outside of school, educational activities, and social/recreational activities. Logistic regression analyses, with relevant covariates (child and familial characteristics), were used to analyze the data. RESULTS: Children with NDD/D were significantly more likely to take part in supervised and unsupervised physical activity at school than children with CMC (p<0.001). A similar trend was observed for participation in school outings, although the effect was not significant at p<0.01. Finally, a trend in the opposite direction was observed for educational activities, as children with NDD/D were less likely to take part in these activities than children with CMC. DISCUSSION: Finding decreased participation among children with CMC compared with NDD/D was not predicted a priori but has potential implications for their mental and physical health. CONCLUSIONS: Gaining a better understanding of the barriers to participation in physical activity may contribute to improving the overall health status of children with CMC. PMID- 22835686 TI - Hydrodynamic radius determination with asymmetrical flow field-flow fractionation using decaying cross-flows. Part I. A theoretical approach. AB - Direct determination of hydrodynamic radius from retention time is an advantage of the field-flow fractionation techniques. However, this is not always completely straight forward since non-idealities exist and assumptions have been made in deriving the retention equations. In this study we investigate the effect on accuracy from two factors: (1) level of sophistication of the equations used to determine channel height from a calibration experiment and (2) the influence of secondary relaxation on the accuracy of hydrodynamic radius determination. A new improved technique for estimating the channel height from calibration experiments is suggested. It is concluded that severe systematic error can arise if the most common channel height equations are used and an alternative more rigorous approach is described. For secondary relaxation it is concluded that this effect increases with the cross-flow decay rate. The secondary relaxation effect is quantified for different conditions. This is part one of two. In the second part the determination of hydrodynamic radius are evaluated experimentally under similar conditions. PMID- 22835685 TI - Differential brain responses to cries of infants with autistic disorder and typical development: an fMRI study. AB - This study used fMRI to measure brain activity during adult processing of cries of infants with autistic disorder (AD) compared to cries of typically developing (TD) infants. Using whole brain analysis, we found that cries of infants with AD compared to those of TD infants elicited enhanced activity in brain regions associated with verbal and prosodic processing, perhaps because altered acoustic patterns of AD cries render them especially difficult to interpret, and increased activity in brain regions associated with emotional processing, indicating that AD cries also elicit more negative feelings and may be perceived as more aversive and/or arousing. Perceived distress engendered by AD cries related to increased activation in brain regions associated with emotional processing. This study supports the hypothesis that cry is an early and meaningful anomaly displayed by children with AD. It could be that cries associated with AD alter parent-child interactions much earlier than the time that reliable AD diagnosis normally occurs. PMID- 22835687 TI - Allergic asthma exhaled breath metabolome: a challenge for comprehensive two dimensional gas chromatography. AB - Allergic asthma represents an important public health issue, most common in the paediatric population, characterized by airway inflammation that may lead to changes in volatiles secreted via the lungs. Thus, exhaled breath has potential to be a matrix with relevant metabolomic information to characterize this disease. Progress in biochemistry, health sciences and related areas depends on instrumental advances, and a high throughput and sensitive equipment such as comprehensive two-dimensional gas chromatography-time of flight mass spectrometry (GC*GC-ToFMS) was considered. GC*GC-ToFMS application in the analysis of the exhaled breath of 32 children with allergic asthma, from which 10 had also allergic rhinitis, and 27 control children allowed the identification of several hundreds of compounds belonging to different chemical families. Multivariate analysis, using Partial Least Squares-Discriminant Analysis in tandem with Monte Carlo Cross Validation was performed to assess the predictive power and to help the interpretation of recovered compounds possibly linked to oxidative stress, inflammation processes or other cellular processes that may characterize asthma. The results suggest that the model is robust, considering the high classification rate, sensitivity, and specificity. A pattern of six compounds belonging to the alkanes characterized the asthmatic population: nonane, 2,2,4,6,6 pentamethylheptane, decane, 3,6-dimethyldecane, dodecane, and tetradecane. To explore future clinical applications, and considering the future role of molecular-based methodologies, a compound set was established to rapid access of information from exhaled breath, reducing the time of data processing, and thus, becoming more expedite method for the clinical purposes. PMID- 22835688 TI - Component correlation between related samples by using comprehensive two dimensional gas chromatography-time-of-flight mass spectrometry with chemometric tools. AB - A chemometric strategy has been developed to discover component difference and similarity between two chromatograms (correlation) by using comprehensive two dimensional (2D) gas chromatography with time-of-flight mass spectrometry (GC*GC TOFMS). It allows for rapid determination of the presence or absence of analytes of interest in both pure and overlapping peak clusters, and then locates elution windows of target components. First, representative elution windows of analytes are extracted from the 2D GC*GC map to characterize the spectral space and further construct an orthogonal projection matrix for analysis. Next, multi component spectral correlative chromatography (MSCC) is employed to scan the whole or pre-selected GC*GC-TOFMS data range to obtain component features. An auto-correlative projection curve is proposed to assess the projection residual from MSCC by defining a new evaluation index as reference, based on fixed-size moving window evolving factor analysis. In principle, the method can also be utilized to locate specific compounds whose known spectra are available. It is not restricted by data with high homoscedastic and heteroscedastic noise. Simulated GC-MS data and an extremely complicated herbal product mixture comprising 9 herbs demonstrates that the two-dimensional correlative distribution graph is effective for chemical interpretation between GC*GC-TOFMS data. It allows discovery of information buried in this type of highly complex dataset, especially for rapid and effective data comparison, where specific molecular identity might otherwise be hidden. PMID- 22835689 TI - Counterion effects on protein adsorption equilibrium and kinetics in polymer grafted cation exchangers. AB - Protein binding equilibrium and mass transfer kinetics are studied for cation exchangers containing charged polymer grafts as well as for a macroporous matrix in pH 5 acetate buffers using sodium, tetra-n-butylammonium (TBAH), arginine, and calcium as counterions and a monoclonal antibody (mAb) as a model protein. Dynamic light scattering shows that there is no significant effect of the counterion type on the mAb aqueous diffusivity. The counterion type also does not affect substantially the structure of the polymer grafts, nor does it affect the stoichiometry of the protein ion exchange process. While no counterion effects are also observed on the protein mass transfer kinetics for the macroporous matrix, very large effects are seen for the polymer grafted matrices with protein adsorption rates increasing dramatically in the order Ca++> Arg+> Na+> TBAH+. This order is the same order in which the relative protein binding strength decreases. Accordingly, the counterions leading to weaker protein binding also lead to faster protein diffusion. Although the quantitative aspects are different, the same trends hold for different proteins (lysozyme and lactoferrin) and for an agarose-based matrix also containing grafted polymers (CaptoTM S). The underlying mechanism is qualitatively consistent with protein transport occurring through a hopping process driven by the adsorbed protein concentration within the apparently flexible network structure formed by the grafted polymers. From a practical viewpoint, the results show that improved protein adsorption kinetics in polymer-grafted cation exchanger and, hence, improved performance, can be obtained by selecting particular counterions. PMID- 22835690 TI - Enantiomeric separation of nonproteinogenic amino acids by high-performance liquid chromatography. AB - Amino acids are essential for life, and have many functions in metabolism. One particularly important function is to serve as the building blocks of peptides and proteins, giving rise complex three dimensional structures through disulfide bonds or crosslinked amino acids. Peptides are frequently cyclic and contain proteinogenic as well as nonproteinogenic amino acids in many instances. Since most of the amino acids contain a chiral carbon atom, the stereoisomers of all these amino acids and the peptides in which they are to be found may possess differences in biological activity in living systems. The development of methods for the separation of enantiomers has attracted great interest, since it became evident that the potential biological or pharmacological applications are mostly restricted to one of the enantiomers. The important analytical task of the separation of isomers is achieved mainly by chromatographic and electrophoretic methods. This special review surveys indirect and direct high-performance liquid chromatographic (HPLC) methods of biologically and pharmaceutically important enantiomers of nonproteinogenic amino acids and related compounds, with emphasis on the literature published from the beginning. PMID- 22835691 TI - Overload behavior and apparent efficiencies in chromatography. AB - Over the last 50 years, many analysts have attempted to analyze column overloading by measuring the drop of the column HETP with increasing sample size and to predict elution band profiles from overloaded columns by combining the influences of the thermodynamic overloading and of axial dispersion, using a simplistic perturbation model. This approach violates the principle of mass conservation. The results of the predictions do not agree with those of exact calculations made with the equilibrium-dispersive (ED) model of chromatography for constant axial dispersion. The plots of the reduced apparent column efficiency N/N(kin), versus the injected concentration, logC0, or the injected mass, logm0, may provide useful information only regarding the onset of overloading of any particular column but they are meaningless to compare the overloading behavior of columns packed with different packing materials, unless the columns used satisfy impractical requirements (same efficiency, same retention factors, and sample sizes used proportional to the volume of stationary phase in the column). PMID- 22835692 TI - Preparation of porous polymer monolithic column incorporated with graphene nanosheets for solid phase microextraction and enrichment of glucocorticoids. AB - Novel monolithic capillary columns with embedded graphene were developed and used for polymer monolith microextraction (PMME) coupled to LC-MS analysis. The column was prepared inside fused silica capillaries (320 MUm, i.d.) using thermally initiated free-radical polymerization with butyl methacrylate (BMA) as monomer, ethylene dimethacrylate (EDMA) as cross-linker, and 1,4-butanediol and 1-propanol as porogens. Graphene (GN) was incorporated into the poly(BMA-EDMA) monolith to enhance the loading capacity. The obtained GN and the poly(BMA-EDMA-GN) monolith were characterized by transmission electron microscope (TEM), atomic force microscopic (AFM) and scanning electron microscopy (SEM). The extraction performance of the monolithic column was evaluated by glucocorticoids (GCs) as the analytes. The operation parameters of PMME including desorption solvent, sample flow rate, sample volume, sample pH, and eluent flow rate were studied and optimized. When compared to the parent poly(BMA-EDMA) column and direct sample analysis, high enrichment capacity was observed in the case of GN-entrapped monolith. The GN incorporated monolithic capillary showed satisfactory reusability and stability during extraction. The limits of detection (S/N=3) for nine GCs were in the range of 0.13-1.93 ng/mL. Relative standard deviations for the determination of the target GCs were less than 14.5%. Finally, the PMME method, based on the developed monolithic capillary as the extraction media, was successfully applied to the determination of nine GCs in cosmetics. The recoveries of GCs spiked in different matrices ranged from 83.7% to 103.8%. PMID- 22835693 TI - Chemical differentiation of Boswellia sacra and Boswellia carterii essential oils by gas chromatography and chiral gas chromatography-mass spectrometry. AB - Major botanical and scientific references currently identify two species of frankincense, Boswellia carterii and Boswellia sacra, as being synonymous. We evaluated the Somalian (B. carterii) and Omani/Yemeni (B. sacra) species by chemical analyses to determine if there were any minor or major differences between the two species of frankincense. Components identified with their average percent for B. sacra are alpha-thujene (0.6%), alpha-pinene (68.2%), camphene (2.1%), sabinene (2.9%), beta-pinene (2.0%), myrcene (0.7%), limonene+beta phellandrene (6.2%). Components identified with their average percent for B. carterii are alpha-thujene (7.9%), alpha-pinene (37.3%), camphene (0.8%), sabinene (4.9%), beta-pinene (1.8%), myrcene (7.3%), limonene+beta-phellandrene (14.4%). Initially, GC-MS analysis did not reveal major statistical differences. However, optical rotation values, B. Sacra (+30.1 degrees ) and B. carterii ( 13.3 degrees ), demonstrated a greater significant difference. Enantiomeric ratio (+)/(-) values of alpha-pinene for B. sacra and B. carterii are 8.24 and 0.68, respectively, were also calculated aiding our conclusion that B. sacra and B. carterii are not synonymous but rather two distinct and individual frankincense species. PMID- 22835694 TI - Capillary electrophoresis with capacitively coupled contactless conductivity detection: a universal tool for the determination of supported liquid membrane selectivity in electromembrane extraction of complex samples. AB - Monitoring the selectivity of supported liquid membranes (SLMs) is of paramount importance since the amount and type of compounds that are transferred across a SLM directly influence the transfer efficiency, reproducibility and accuracy. To apply a correct SLM in particular sample pretreatment, rapid determination of the transfer of analytes and matrix compounds across the SLM is necessary, which requires the use of an analytical method with universal detection technique. Capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C(4)D) has proven to be a useful tool for the determination of SLM selectivity. Background electrolyte solution consisting of 1M acetic acid (pH 2.4) was used for simultaneous separation and detection of three basic drugs (nortriptyline, haloperidol and loperamide) and major matrix components (inorganic cations, proteins, amino acids, etc.) after electromembrane extraction (EME) of standard solutions and complex samples. The CE-C(4)D method has evidenced for the first time that large proteins, such as human serum albumin, are efficiently retained on all examined SLMs and that transfer of other matrix components and the analytes is strongly SLM dependent. Excellent transfer of the analytes was achieved across SLMs impregnated with 2-nitrophenyl octyl ether (NPOE) or 1-ethyl-2-nitrobenzene, however, an increased co-extraction of interfering matrix components, which disabled quantitative determination of haloperidol with the current CE-C(4)D setup, was observed for the latter. After addition of a commonly used ion carrier (bis(2-ethylhexyl)phosphate) to NPOE, a wide range of matrix components were transferred across the SLM with no measurable transfer of the analytes. Best selectivity regarding transfer of the basic drugs and elimination of matrix components was obtained using SLM impregnated with NPOE. An optimized EME-CE-C(4)D method was used to determine the basic drugs in various samples and satisfactory analytical parameters were obtained. PMID- 22835695 TI - Versatility of cinchona-based zwitterionic chiral stationary phases: enantiomer and diastereomer separations of non-protected oligopeptides utilizing a multi modal chiral recognition mechanism. AB - Cinchona alkaloid-based zwitterionic chiral stationary phases with diverse sulfonic acid cation exchanger groups were applied for enantiomer separations of small homochiral oligopeptides (all-l/all-d Ala-n, Val-n, Phe-n) using slightly acidic polar-organic mobile phase conditions which facilitated the ionization of ion exchanger sites of the chiral selectors as well as promoting zwitterion formation of the chiral selectands. Our studies focused on retention factors and selectivity as the main chromatographic parameters illustrating selector selectand interactions. The results confirmed that bulky, aromatic side chains such as the benzyl group of Phe are analyte-inherent structural features promoting enantiorecognition. Regarding the zwitterionic selectors, a flexible spacer between the anion exchanger-carbamoyl and the cation exchanger sites was found to enhance stereoselectivity toward bulky and aromatic peptides while a rigid cation exchanger moiety contributed favorably to enantiomer distinction of peptides with small, aliphatic side chains. The investigations included all 28 stereoisomers of Phe-2 through Phe-4 to demonstrate the applicability of zwitterionic chiral stationary phases for the separation of sequential stereoisomers. Selectivity was shown to be governed by the Cinchona alkaloid motif but heavily dependent on effective hydrogen bonding between the carbamoyl motif and the amide groups of the peptide backbone. Contrary to previous studies on enantioselectivity which found pseudo-enantiomeric behavior of quinine and quinidine-based CSPs, in peptide stereoisomer separations CSPs based on quinidine undeniably performed better. PMID- 22835696 TI - More accurate matrix-matched quantification using standard superposition method for herbal medicines. AB - Various analytical technologies have been developed for quantitative determination of marker compounds in herbal medicines (HMs). One important issue is matrix effects that must be addressed in method validation for different detections. Unlike biological fluids, blank matrix samples for calibration are usually unavailable for HMs. In this work, practical approaches for minimizing matrix effects in HMs analysis were proposed. The matrix effects in quantitative analysis of five saponins from Panax notoginseng were assessed using high performance liquid chromatography (HPLC). Matrix components were found to interfere with the ionization of target analytes when mass spectrometry (MS) detection were employed. To compensate the matrix signal suppression/enhancement, two matrix-matched methods, standard addition method with the target-knockout extract and standard superposition method with a HM extract were developed and tested in this work. The results showed that the standard superposition method is simple and practical for overcoming matrix effects for quantitative analysis of HMs. Moreover, the interference components were observed to interfere with light scattering of target analytes when evaporative light scattering detection (ELSD) was utilized for quantitative analysis of HMs but was not indicated when Ultraviolet detection (UV) were employed. Thus, the issue of interference effects should be addressed and minimized for quantitative HPLC-ELSD and HPLC-MS methodologies for quality control of HMs. PMID- 22835697 TI - 20beta-hydroxysteroid dehydrogenase gene promoter: potential role for cyclic AMP and xenobiotic responsive elements. AB - Teleostean 20beta-hydroxysteroid dehydrogenase (20beta-HSD) is involved in final oocyte maturation and steroid hormone metabolism. It has structural and functional similarities to mammalian carbonyl reductases that are involved in the metabolism of endogenous carbonyl and xenobiotic compounds. To understand the transcriptional regulation of 20beta-HSD, here we report the cloning of 20beta HSD promoter from two fish species, rainbow trout and air-breathing catfish. Analysis of the promoter motifs, in silico identified the presence of several sites for transcription factor binding including cAMP, xenobiotic and steroid hormone responsive elements. Luciferase reporter assays with progressive deletion constructs demonstrated that 20beta-HSD type B of trout has no promoter activity while 20beta-HSD type A of trout and catfish 20beta-HSD promoters showed basal promoter activity. A TATA box flanked by a CAAT box is important for basal transcription. Deletion of cAMP responsive element in the promoter decreased basal promoter activity significantly. Reporter assays with forskolin and IBMX, drugs that increase intracellular cAMP induced the promoter activity over the basal level. Intriguingly, beta-nafthoflavone, an arylhydrocarbon receptor ligand, induced the 20beta-HSD promoter activity and is further evidenced by the induction of 20beta-HSD expression in the livers of catfish, in vivo. These results demonstrate for the first time that 20beta-HSD expression is not only modulated by cAMP but also by xenobiotics and further studies may provide significance to the ubiquitous distribution and broad substrate specificity of this enzyme. PMID- 22835698 TI - Transcriptional regulation by post-transcriptional modification--role of phosphorylation in Sp1 transcriptional activity. AB - Sp1 is a ubiquitously expressed transcription factor involved in the regulation of a large number of genes including housekeeping genes as well as actively regulated genes. Although Sp1 was discovered nearly three decades ago, its functional diversity is still not completely understood. One of the ways that make Sp1 versatile in transcriptional regulation is its post-transcriptional modification, which alters Sp1 structure in different cells and at different times. Compared to other types of modifications of the Sp1 protein, phosphorylation has been studied far more extensively. This review focuses on the inducers, pathways, enzymes, and biological effects of Sp1 phosphorylation. Recent data are beginning to reveal the biological significance and universal presence of Sp1 phosphorylation-related cell/molecular responses. Studies in this field provide a quick glance at how a simple chemical modification of a transcription factor could produce significant functional diversity of the protein. PMID- 22835699 TI - Epigenetic regulation of stem cells differentiating along the neural lineage. AB - Many lineage-specific genes are poised and silenced in stem cells. Upon differentiation, genes that are related to self-renewal and alternative lineages are stably silenced. CpG methylation at proximal promoters and PRC2-mediated H3K27me3 play a role in silencing genes temporarily or permanently, with or without coexistence of active epigenetic marks, respectively. Interestingly, DNA methylation on neuronal genes that is distal to transcription start site enable transcription activation owing to its ability to repel PRC2-mediated inhibition. In addition, DNA demethylase Tet proteins play a role in regulation of changes in DNA methylation and related H3K27me3 during differentiation. Collectively, a complex epigenetic network formed by H3K4me3, histone acetylation/deacetylation, H3K27me3 and DNA methylation/demethylation act together to regulate stem cell self-renewal and differentiation. PMID- 22835700 TI - A modified glucomannan mycotoxin-adsorbing agent counteracts the reduced weight gain and diminishes cecal colonization of Salmonella Typhimurium in T-2 toxin exposed pigs. AB - The aim of the study was to investigate the effect of a modified glucomannan binder on the course of a Salmonella Typhimurium infection in pigs. Therefore, four pig diets were provided during 23 days: (1) free of mycotoxins, (2) containing 1g binder per kg feed, (3) containing 83 MUg T-2 toxin per kg feed and (4) containing 83 MUg T-2 toxin and 1g binder per kg feed. After 18 days, all pigs were inoculated with Salmonella Typhimurium and euthanized five days later. The addition of the binder to T-2 toxin contaminated feed counteracted the reduced weight gain of pigs caused by T-2 toxin and reduced the amount of Salmonella Typhimurium in the cecum and cecal contents. In vitro findings might indicate that the binder captures Salmonella. We thus conclude that the binder counteracts T-2 toxin induced weight loss and possibly binds Salmonella, resulting in a reduced cecal colonization. PMID- 22835702 TI - Cost/benefit of synbiotics in acute infectious gastroenteritis: spend to save. AB - The cost/benefit ratio of probiotics in the ambulatory treatment of acute infectious gastro-enteritis with or without a synbiotic food supplement (containing fructo-oligosaccharides and probiotic strains of Streptoccoccus thermophilus, Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium infantis) has been studied. 111 children (median age 37 and 43 months for the synbiotic and placebo group, respectively) with acute infectious gastroenteritis were included in a randomised, prospective placebo controlled trial performed in primary health care. All children were treated with an oral rehydration solution and with the synbiotic food supplement (n=57) or placebo (n=54). Physicians were allowed to prescribe additional medication according to what they considered as 'necessary'. Cost of add-on medication and total healthcare cost were calculated. Median duration of diarrhoea was 1 day shorter (95% confidence interval -0.6 to -1.9 days) in the symbiotic than in the placebo group (P<0.005). Significantly more concomitant medication (antibiotics, antipyretics, antiemetics) was prescribed in the placebo group (39 prescriptions in 28 patients) compared to the synbiotic group (12 prescriptions in 7 patients) (P<0.001). The difference was most striking for antiemetics: 28 vs. 5 prescriptions. The cost of add-on medication in the placebo group was evaluated at ? 4.04/patient (median 4.97 (interquartile (IQ) 25-75: 0-4.97)) vs. ? 1.13 /patient in the synbiotic arm (P<0.001). If the cost of the synbiotic is considered, median cost raised to ? 7.15/patient (IQ 25-75: 7.15-7.15) (P<0.001). The extra consultations needed to prescribe the concomitant medication resulted in a higher health care cost in the placebo group (? 14.41 vs. ? 10.74/patient, P<0.001). Synbiotic food supplementation resulted in a 24 h earlier normalisation of stool consistency. Although use of the synbiotic supplementation increased cost, add-on medication and extra consultations were reduced, resulting in a reduction of health care cost of 25%. PMID- 22835703 TI - Lactobacilli differently regulate expression and secretion of CXCL8 in urothelial cells. AB - Modulation of the immune response is an established feature of certain lactobacilli. CXCL8 is an inflammatory chemokine released by the urinary tract mucosa after contact with uropathogenic Escherichia coli during urinary tract infection and is crucial for proper infiltration of immune cells. Nevertheless, persistently high levels of CXCL8 are associated with pathogenicity and malignancy. In this study, we tested twelve Lactobacillus strains for their ability to influence CXCL8 release from urothelial cells. We evaluated how strains from different Lactobacillus species could regulate CXCL8 in human 5637 urothelial cells, either resting cells or cells concomitantly challenged with heat-killed E. coli. A majority of the tested species altered CXCL8 release from the urothelial cells after 24 hours of stimulation. Most species increased CXCL8 release, whereas a few lactobacilli efficiently suppressed CXCL8 secretion from E. coli-challenged cells. While strong CXCL8 modulators such as Lactobacillus reuteri and Lactobacillus delbrueckii were unable to degrade CXCL8 in the extracellular environment, effects on IL8 transcription were evident for selected lactobacilli. Although IL8 transcription was affected by lactobacilli, the influence on mRNA transcript did not correlate to the impact on CXCL8 release. Phylogenetic analysis based on a 16S rRNA dendrogram of the tested lactobacilli and their effect on CXCL8 revealed some linkage to specific Lactobacillus groups. Testing the immunomodulatory nature of lactobacilli can prove important when selecting new probiotic microbes. Moreover, we believe that phylogenetic and phenotypic similarities could be used to analyse the traits governing such modulation. PMID- 22835704 TI - Economic, clinical, and humanistic outcomes (ECHOs) of pharmaceutical care services for minority patients: a literature review. AB - BACKGROUND: The U.S. population of racial/ethnic minorities continues to increase; however, health disparities and poor health outcomes among many of them continue to be a major public health problem confronting the U.S. health care system. OBJECTIVES: The objective of this review was to summarize published pharmaceutical care services literature reporting economic, clinical, and/or humanistic outcomes (ECHOs) among racial/ethnic minorities. Studies that reported differences by race/ethnicity and studies where most participants were from multiracial/ethnic minorities were included. METHODS: PubMed and International Pharmaceutical Abstracts databases were searched for articles that reported the effects of pharmaceutical care on ECHOs among racial/ethnic minorities published between January 1980 and November 2010. The literature review was focused on racial groups that included black/African-American, Native American, Indian American Asian, Alaska Native, Native Hawaiian, and Pacific Islander patients, and ethnic group that was non-white Hispanic/Latino patients. RESULTS: There were 24 articles that studied the impact of pharmaceutical care on ECHOs by race/ethnicity or where most participants were from multiracial/ethnic minorities. Twenty-three studies reported that pharmaceutical care has a positive impact on health outcomes of the studied populations. About half of the studies meeting inclusion criteria evaluated only 1 type of patient outcome, primarily clinical outcomes. Education/consultation and medication/therapy management were the most commonly evaluated types of pharmaceutical care services throughout the studied groups. Comprehensive disease management was evaluated mainly in multiracial/ethnic populations and blacks/African-Americans. Few studies adopted randomized controlled designs, which make it difficult to attribute changes in patient outcomes to the provision of pharmaceutical care. Nine studies that involved cooperation between pharmacists and other medical professionals reflect an increased tendency for interprofessional collaboration in the current health care system. CONCLUSION: This review shows that there is a positive relationship between pharmaceutical care and ECHOs in patients from racial/ethnic minority groups. However, more studies are needed to document the effects of pharmaceutical care on reducing racial/ethnic health disparities and to determine which interventions are most effective among certain groups with health disparities. PMID- 22835706 TI - Assessing readability formula differences with written health information materials: application, results, and recommendations. AB - BACKGROUND: Readability formulas are often used to guide the development and evaluation of literacy-sensitive written health information. However, readability formula results may vary considerably as a result of differences in software processing algorithms and how each formula is applied. These variations complicate interpretations of reading grade level estimates, particularly without a uniform guideline for applying and interpreting readability formulas. OBJECTIVES: This research sought to (1) identify commonly used readability formulas reported in the health care literature, (2) demonstrate the use of the most commonly used readability formulas on written health information, (3) compare and contrast the differences when applying common readability formulas to identical selections of written health information, and (4) provide recommendations for choosing an appropriate readability formula for written health-related materials to optimize their use. METHODS: A literature search was conducted to identify the most commonly used readability formulas in health care literature. Each of the identified formulas was subsequently applied to word samples from 15 unique examples of written health information about the topic of depression and its treatment. Readability estimates from common readability formulas were compared based on text sample size, selection, formatting, software type, and/or hand calculations. Recommendations for their use were provided. RESULTS: The Flesch-Kincaid formula was most commonly used (57.42%). Readability formulas demonstrated variability up to 5 reading grade levels on the same text. The Simple Measure of Gobbledygook (SMOG) readability formula performed most consistently. Depending on the text sample size, selection, formatting, software, and/or hand calculations, the individual readability formula estimated up to 6 reading grade levels of variability. CONCLUSIONS: The SMOG formula appears best suited for health care applications because of its consistency of results, higher level of expected comprehension, use of more recent validation criteria for determining reading grade level estimates, and simplicity of use. To improve interpretation of readability results, reporting reading grade level estimates from any formula should be accompanied with information about word sample size, location of word sampling in the text, formatting, and method of calculation. PMID- 22835705 TI - A qualitative analysis of perceptions and barriers to therapeutic lifestyle changes among homeless hypertensive patients. AB - BACKGROUND: Homeless individuals have higher rates of hypertension when compared to the general population. Therapeutic lifestyle changes (TLCs) have the potential to decrease the morbidity and mortality associated with hypertension, yet TLCs can be difficult for homeless persons to implement because of competing priorities. OBJECTIVES: To identify: (1) Patients' knowledge and perceptions of hypertension and TLCs and (2) Barriers to implementation of TLCs. METHODS: This qualitative study was conducted with patients from an urban health care for the homeless center. Patients >=18 years old with a diagnosis of hypertension were eligible. Three focus groups were conducted at which time saturation was deemed to have been reached. Focus group sessions were audio recorded and transcribed for data analysis. A systematic, inductive analysis was conducted to identify emerging themes. RESULTS: A total of 14 individuals participated in one of the 3 focus groups. Most were female (n=8) and African-American (n=13). Most participants were housed in a shelter (n=8). Others were staying with family or friends (n=3), living on the street (n=2), or had transitioned to housing (n=1). Participants had a mixed understanding of hypertension and how TLCs impacted hypertension. They were most familiar with dietary and smoking recommendations and less familiar with exercise, alcohol, and caffeine TLCs. Participants viewed TLCs as being restrictive, particularly with regard to diet. Family and friends were viewed as helpful in encouraging some lifestyle changes such as healthy eating, but less helpful in having a positive influence on quitting smoking. Participants indicated that they often have difficulty implementing lifestyle changes because of limited meal choices, poor access to exercise equipment, and being uninformed about recommendations. CONCLUSIONS: Despite the benefits of TLCs, homeless individuals experience unique challenges to implementing TLCs. Future research should focus on developing and testing interventions that facilitate TLCs among homeless persons. The findings from this study should assist health care practitioners, including pharmacists, with providing appropriate and effective education. PMID- 22835707 TI - The pharmacist as prescriber: a discourse analysis of newspaper media in Canada. AB - BACKGROUND: Legislation to expand the scope of practice for pharmacists to include authority to independently prescribe medications in Alberta, Canada was announced in 2006 and enacted in April 2007. To date, very little research has explored public views of pharmacist prescribing. OBJECTIVE: This study analyzes newspaper media coverage of pharmacist prescribing 1 year before and 2 years after prescribing was implemented. METHODS: News items related to pharmacist prescribing were retrieved from 2 national, Canadian newspapers and 5 local newspapers in Alberta over a 3-year period after the announcement of pharmacist prescribing. A purposive sample of 66 texts including news items, editorials, and letters were retrieved electronically from 2 databases, Newscan and Canadian Newsstand. This study uses social positioning theory as a lens for analyzing the discourse of pharmacist prescribing. RESULTS: The results demonstrate a binary positioning of the debate on pharmacist prescribing rights. Using social positioning theory as a lens for analysis, the results illustrate self- and other positioning of pharmacists' expected roles as prescribers. Themes related to the discourse on pharmacist prescribing include qualifications, diagnosis, patient safety, physician support, and conflict of interest. Media representations of pharmacist prescribing point to polarized views that may serve to shape public, pharmacist, physician, and others' opinions of the issue. CONCLUSIONS: Multiple and contradictory views of pharmacist prescribing coexist. Pharmacists and pharmacy organizations are challenged to bring clarity and consistency about pharmacist prescribing to better serve the public interest in understanding options for health care services. PMID- 22835708 TI - Counterfeit drug demand: perceptions of policy makers and community pharmacists in Sudan. AB - BACKGROUND: The counterfeit drug trade has become widespread and has developed into a substantial threat to both the public's health and the pharmaceutical industry. OBJECTIVES: The aim of this study was to seek insights into the determining factors of counterfeit drug purchases among health policy makers and community pharmacists in a developing country. METHODS: In-depth qualitative interviews with Sudanese policy makers and community pharmacists were undertaken in 2 Sudanese states, namely Khartoum and Gadaref. A semistructured interview guide was developed by incorporating information from existing literature. A purposive sample of knowledgeable policy makers and community pharmacists was interviewed. RESULTS: Thematic content analysis of the interviews identified 8 major themes: understanding the term "counterfeit drug," presence of counterfeit drugs in the Sudanese market, vulnerability to counterfeit drugs, price-quality inference, awareness of societal consequences of counterfeit drugs, subjective social norms, difference in vulnerability according to demographic characteristics, and education pertaining to counterfeit drugs. Unaffordability of medicines and desperate need were emphasized by both policy makers and community pharmacists as major influencing factors that increased consumers' vulnerability to counterfeit drugs. CONCLUSIONS: This study concluded that high prices and the unaffordability of medicines have a major role in increasing vulnerability to counterfeit drugs, in addition to lack of knowledge about counterfeiting and the implications of use of these products. Because very limited studies have been conducted in developing countries to explore perceptions about counterfeit drugs, the present study provides information from which policy makers and key stakeholders in the supply chain can benefit. PMID- 22835709 TI - Working in interprofessional primary health care teams: what do pharmacists do? AB - BACKGROUND: Interprofessional teams are forming in primary health care. Little is known about how health care professional roles and routines develop in this environment. OBJECTIVES: This article describes the evolving routines of pharmacists working in new interprofessional teams, their perceptions of their roles, and perceptions of other providers toward the pharmacist role. METHODS: Ethnographic methods were used. Qualitative data derived from practice documents, field notes from practice activity and provider-patient interaction observations, and transcripts from interviews with patients and practice staff were analyzed in an exploratory manner using a constant comparative approach and immersion/crystallization. For this article, data pertaining to the role of pharmacists comprised a case study subanalysis. RESULTS: Two typologies emerged with some pharmacists found to be (1) physician oriented: responding to physician requests for drug information and other projects, and others found to be (2) working at multiple levels of interaction: providing patient-centered care, provider education/information, and initiating system-level interventions to improve drug therapy. CONCLUSIONS: Pharmacist routines and their own perception of their roles differed across interprofessional teams. Differences could be attributed to different educational background, philosophy of practice or characteristics of individual pharmacists, and also affected by leadership and communication within family health teams (FHTs). FHT leaders wanting to include a pharmacist to improve medication therapy should demonstrate leadership and vision by articulating needs and hiring a pharmacist with matching knowledge, skills, and qualities. A similar, generic approach may be useful to determine the need for and roles of any health care professional joining the team. PMID- 22835710 TI - Over-the-counter prescribing and pharmacists' adoption of new medicines: diffusion of innovations. AB - BACKGROUND: More than 90 medicines in the United Kingdom alone have been reclassified from "prescription only" to "pharmacy" availability, and many of these have further been deregulated to "general sales" status. Pharmacist perspectives of reclassified medicines adoption into practice are important to inform future reclassifications. OBJECTIVES: The aim of this research was to explore the factors associated with adoption into practice of newly reclassified medicines by community pharmacists based on the theoretical framework of diffusion of innovations. METHODS: Focus groups and qualitative interviews with 20 community pharmacists selected randomly from 4 Health Boards in Scotland were conducted. Results were analyzed using a framework method for thematic analysis. RESULTS: Factors associated with pharmacists' decision making regarding adoption into practice of newly reclassified medicines related to pharmacists' perceived attributes of newly reclassified medicines such as evidence of benefits and risks to patients (ie, efficacy and safety); organizational contextual factors such as sources of information and training; external factors, such as support from wider stakeholders; and adopter characteristics such as pharmacists' perception toward adopting new behaviors. Many newly reclassified medicines were highlighted by participants to have been highly adopted into practice or were less/not adopted based on these diverse factors. Decisions at organizational level to stock new medicines did not necessarily translate into adoption at practitioner level. CONCLUSIONS: Pharmacists' decision making regarding adoption of newly reclassified medicines is a complex and multidimensional process. This is the first study of this sort, and results of this qualitative study will aid development of a research instrument aimed at quantifying the importance of the factors identified. PMID- 22835711 TI - A qualitative exploration of the reasons for the discontinuation of smoking cessation treatment among Quit Smoking Clinics' defaulters and health care providers in Malaysia. AB - BACKGROUND: Treatment default among the smokers hinders the effectiveness of the delivery of cessation services. While many studies have predicted the defaulters' characteristics, the reasons why these smokers dropped out and continued smoking are seldom explored. OBJECTIVES: This study examined the barriers encountered by such smokers and their respective health care providers (HCPs) in relation to the discontinuation of cessation treatment. METHODS: From May 2010 to March 2011, 15 current adult smokers and 9 HCPs from 2 Quit Smoking Clinics (QSCs) in the Melaka Tengah District, Malacca, Malaysia were interviewed on smoking, cessation, and the QSC. Interviews were audio recorded and transcribed verbatim. The transcripts were subsequently translated into English and analyzed using thematic analysis. RESULTS: The barriers encountered were categorized as Individual- and Clinic level. Both smokers and HCPs acknowledged that the smokers' low intrinsic motivation was the individual-level barrier. The clinic-level barriers were the mismatched perceptions of smokers and HCPs regarding the HCPs' roles, skills, and attitudes, as well as the availability and efficacy of smoking cessation aids (SCAs). While the smokers viewed the program as not helpful, the HCPs cited the lack of organizational support as their main barrier. CONCLUSIONS: The reasons for treatment default centered on the overall dissatisfaction with the treatment (due to the program, HCP, and SCA factors) combined with the smokers' low intrinsic motivation. Optimizing the interplay of the extrinsic motivational cues, such as the HCP and SCA factors, would complement the smoker's low intrinsic motivation and thus encourage treatment retention. However, it is necessary to strike a balance between the individual smoker's needs and the availability of organizational support. PMID- 22835712 TI - Pharmacists' perceptions of a live continuing education program comparing distance learning versus local learning. AB - BACKGROUND: Constraints in geography and time require cost efficiencies in professional development for pharmacists. Distance learning, with its growing availability and lower intrinsic costs, will likely become more prevalent. OBJECTIVE: The objective of this nonexperimental, postintervention study was to examine the perceptions of pharmacists attending a continuing education program. One group participated in the live presentation, whereas the second group joined via a simultaneous webcast. METHODS: After the presentation, both groups were surveyed with identical questions concerning their perceptions of their learning environment, course content, and utility to their work. Comparisons across group responses to the summated scales were conducted through the use of Kruskal-Wallis tests. RESULTS: Analysis of the data showed that both the distance and local groups were demographically similar and that both groups were satisfied with the presentation method, audio and visual quality, and both felt that they would be able to apply what they learned in their practice. However, the local group was significantly more satisfied with the learning experience. CONCLUSIONS: Distance learning does provide a viable and more flexible method for pharmacy professional development, but does not yet replace the traditional learning environment in all facets of learner preference. PMID- 22835713 TI - Exploring patient expectations for pharmacist-provided literacy-sensitive communication. AB - BACKGROUND: Limited health literacy is common and associated with adverse health care outcomes. Although pharmacies and pharmacists are accessible to most patients, research has indicated that they do not routinely report efforts to target interventions for patients with suboptimal health literacy. Moreover, little is known about the use and expectation of literacy-based communication techniques in pharmacies from the patient perspective. OBJECTIVE: The intent of this pilot study was to describe the use of health literacy-based communication techniques, expectations for their use, and satisfaction with communication as reported by patients at high risk for medication misadventures who receive care at a clinic-based community pharmacy. METHODS: A cross-sectional telephonic interview of a purposive sample of patients aged 65 years or older who were prescribed at least 8 unique medications was conducted. Patients were recruited from 1 clinic-based pharmacy that serves a predominantly urban low-income population. A telephonic interview guide was derived from previous literature and included 52 questions related to respondent characteristics, perceptions of experiences regarding verbal communications with the pharmacist, expectations for communication with the pharmacist, and satisfaction with current pharmacy communication techniques. Responses were summarized and described. RESULTS: Nineteen patients completed the telephonic interviews. Patients commonly reported that the pharmacist provided the following counseling for new prescriptions: how to take their medication (88.9%), side effects (84.2%), and indication (47.4%). In contrast, only 44.4%, 55.6%, and 33.3% of patients expected the pharmacist to engage in these same counseling behaviors. A minority of patients reported the use of various recommended clear health communication techniques by the pharmacist, and an even smaller percentage expressed expectations for their use. Despite the limited use of literacy-based communication techniques, 73.7% of patients reported being very satisfied with pharmacy counseling, and 94.7% reported good to excellent understanding of their medications. CONCLUSION: Patient-pharmacist interactions consistently met or exceeded patient expectations. However, pharmacists use of literacy-based communication techniques was low as were patient expectations. Future research and training efforts should focus on not only increasing pharmacists' use of literacy-based communication techniques but also raising patients' expectations for performing these activities. PMID- 22835714 TI - Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery. AB - OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare idiopathic disease that is characterized by clonal proliferation of Langerhans histiocytes in various parts of the body. These atypical cells have been found to infiltrate single or multiple organs, including bone, lungs, liver, spleen, lymph nodes, and skin. Central nervous system invasion in LCH patients has rarely been reported, especially in the adult population. METHODS AND RESULTS: We describe three histopathologically confirmed cases of adult LCH that involves both the pituitary stalk and hypothalamus, and report our limited experience of such cases in this location that has been treated with CyberKnife radio surgery. CONCLUSION: The treatment goal of controlling lesion growth is achieved by CyberKnife radiosurgery in this case series. All patients tolerated the treatment well without obvious complications. PMID- 22835716 TI - Eight-and-a-half syndrome combined with an ipsilateral vertical gaze palsy: a pathophysiological explanation. PMID- 22835715 TI - Prothrombin complex concentrates to reverse warfarin-induced coagulopathy in patients with intracranial bleeding. AB - Prothrombin complex concentrates (PCCs) offer a means for the rapid reversal of warfarin, particularly in the setting of life-threatening bleeding. We evaluated the effectiveness and safety of a PCC-based protocol in patients with warfarin associated intracerebral hemorrhage (ICH), subdural hematoma (SDH), or subarachnoid hemorrhage (SAH). This was a retrospective case-series review of patients treated with an institution-approved warfarin reversal protocol. Patients with intracranial hemorrhage and known warfarin use with an international normalized ratio (INR)>1.4 received fresh frozen plasma (FFP), vitamin K (phytonadione), and weight-based, 3-factor PCC (Profilnine((r)) SD) dose based on the initial INR. Demographic and clinical information, the degree of and time to INR normalization, and adverse events were recorded. The thirty study patients included 19 with primary ICH, 7 with SDH, and 4 with SAH. The mean age was 72.8 (+/-11) years, including 11 (37%) patients >=80years old. The median presenting INR was 2.3 (IQR 2-3.3) and post-treatment INR was 1.4 (IQR 1.3-1.5, Z score 6.4, p<0.001). Median time from PCC administration to the first follow up INR was 95 (IQR 50-140) min. No patient's INR increased by more than 0.3 over 72h. Nine patients (30%) underwent neurosurgical procedures after PCC administration and no procedure-related bleeding complication was noted. Adverse events included 3 instances of early hematoma expansion, one ischemic stroke in a patient with endocarditis on post-PCC day 1, one pulmonary embolism 5weeks after PCC treatment, and one coronary in-stent thrombosis 60days after PCC treatment. 6 patients died prior to hospital discharge of anticipated complications of their initial event, and none from identifiable thrombotic complications of PCC. A 3 factor PCC preparation (Profilnine((r)) SD), administered with FFP and vitamin K to patients with acute warfarin-associated intracranial bleeding is a reasonable approach to urgent warfarin reversal. However, randomized, prospective trials are needed to verify the safety and clinical effectiveness of PCC administration in this population. PMID- 22835718 TI - Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. AB - OBJECTIVE: Diagnostic factors are needed to improve the currently used serum CA125 and risk of malignancy index (RMI) in differentiating ovarian cancer (OC) from other pelvic masses, thereby achieving precise and fast referral to a tertiary center and correct selection for further diagnostics. The aim was to evaluate serum Human Epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) for these purposes. METHODS: Serum from 1218 patients in the prospective ongoing pelvic mass study was collected prior to diagnosis. The HE4 and CA125 data were registered and evaluated separately and combined in ROMA and compared to RMI. RESULTS: 809 benign tumors, 79 borderline ovarian tumors, 252 OC (64 early and 188 late stage), 9 non-epithelial ovarian tumors and 69 non-ovarian cancers were evaluated. Differentiating between OC and benign disease the specificity was 62.2 (CA125), 63.2 (HE4), 76.5 (ROMA) and 81.5 (RMI) at a set sensitivity of 94.4 which corresponds to RMI=200. The areas under the curve (AUC) were 0.854 (CA125), 0.864 (HE4), 0,897 (ROMA) and 0.905 (RMI) for benign vs. early stage OC. For premenopausal benign vs. OC AUC were 0.925 (CA125), 0.905 (HE4), 0.909 (ROMA) and 0.945 (RMI). CONCLUSION: HE4 and ROMA helps differentiating OC from other pelvic masses, even in early stage OC. ROMA performs equally well as the ultrasound depending RMI and might be valuable as a first line biomarker for selecting high risk patients for referral to a tertiary center and further diagnostics. Further improvements of HE4 and ROMA in differentiating pelvic masses are still needed, especially regarding premenopausal women. PMID- 22835717 TI - Clinico-pathologic comparison of type II endometrial cancers based on tamoxifen exposure. AB - OBJECTIVE: To compare clinico-pathologic variables and protein expression of potential regulatory components in patients who develop type II endometrial cancer with and without antecedent tamoxifen. METHODS: Clinico-pathologic variables were compared for all surgically staged patients (2000-2008) with grade 3 endometrioid, papillary serous, clear cell, and carcinosarcoma of the uterus based on tamoxifen exposure [Tam (+) vs. Tam (-)]. Overall survival was analyzed using a multivariable Cox regression model and Kaplan-Meier estimates. Protein expression of ERalpha, PR, mTOR, p-mTOR, IGF-1R, EGFR, VEGF and HER-2/neu was compared by immunohistochemistry using a semiquantitative scoring system. RESULTS: Of 115 patients with high grade endometrial cancers, 15 received tamoxifen. These patients were older at diagnosis than Tam (-) patients. A higher percentage of Tam (+) patients had carcinosarcoma compared to Tam (-) patients (60% vs. 30%, P=0.038). Overall survival for Tam (+) patients was shorter than Tam (-) patients (16.6 vs. 32.2 months, P=0.004). The hazard ratio for death for Tam (+) patients was 2.53 (P=0.014), controlling for age and stage. Intensity and extent of staining were similar for ERalpha, PR, VEGF, EGFR, p-mTOR and HER 2/neu. The average expression score for IGF-1R and mTOR in the Tam (+) group was significantly higher than the Tam (-) group: 10.3 vs 7.0, P=0.001 and 6.0 vs 3.1, P=0.029, respectively. CONCLUSION: There are differences in the biology of type II endometrial cancers that develop in women with prior tamoxifen exposure. Tamoxifen associated cancers show higher expression of IGF-1R and mTOR, which should be further investigated. PMID- 22835719 TI - Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2. AB - As part of an effort to identify novel selective modulators of sirtuins, we synthesized and tested several isosteres and constrained analogues of nicotinamide. Biological data suggest that compound 2 is selective for Sirt3 over Sirt1 and Sirt2. PMID- 22835721 TI - Atypical fluoroquinolone gold(III) chelates as potential anticancer agents: relevance of DNA and protein interactions for their mechanism of action. AB - Quinolones are known for their antimicrobial and antitumor activities. Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. In this work three gold(III) complexes of the fluoroquinolones antimicrobial agents norfloxacin (NOR), levofloxacin (LEVO) and sparfloxacin (SPAR) were prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, NOR, LEVO and SPAR act as bidentate neutral ligands bound to gold(III) through the nitrogen atoms of the piperazine ring, which is an unusual mode of coordination for this class of compounds. Two chloride ions occupy the remaining coordination sites. The cytotoxic activity of the fluoroquinolones and their gold(III) complexes was tested against the A20 (murine lymphoma), B16-F10 (murine melanoma) and K562 (human myeloid leukemia) tumor cell lines as well as the L919 (murine lung fibroblasts) and MCR-5 (human lung fibroblasts) normal cells lines. All complexes were more active than their corresponding free ligands. Complex [AuCl(2)(LEVO)]Cl was selected for DNA fragmentation and cell cycle analysis. Spectroscopic titration with calf-thymus DNA (CT DNA) showed that the complexes can bind weakly to CT DNA, probably by an external contact (electrostatic or groove binding). The complexes exhibit good binding propensity to bovine serum albumin (BSA) having relatively high binding constant values. PMID- 22835720 TI - Design, synthesis and biological evaluation of some novel thienopyrimidines and fused thienopyrimidines as anti-inflammatory agents. AB - Some new substituted thienopyrimidine derivatives comprising thioxo, thioalkyl and pyrazolyl derivatives as well as fused thienotriazolopyrimidine and thienopyrimidinotriazine ring systems were prepared from 3-benzyl-2-hydrazino-5 methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide 4. The designed compounds were evaluated for their anti-inflammatory activity. Compounds 4, 9, 10 and 13 showed the highest anti-inflammatory effect compared with the reference drug diclofenac sodium. PMID- 22835722 TI - Synthesis and classical pathway Complement inhibitory activity of C7 functionalized filifolinol derivatives, inspired in K-76 COOH. AB - A series of carboxylic acids carrying various functionalization on C-7 of their common 3H-spiro[benzofuran-2,1'-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural Complement inhibitor K-76 COOH. In order to probe the relevance of the C-7 functionalization on their bioactivity, the ability of the analogs to inhibit Complement activation through the classical pathway was determined. The observed results suggest that functionalization of C 7 can modulate the inhibitory activity of the tested compounds. The 7 trifluoromethyl derivative was the compound with the lowest IC(50) value among the tested analogs (IC(50) = 100 MUM), being more potent than K-76 COOH (IC(50) = 570 MUM). PMID- 22835723 TI - Near total calcanectomy with rotational flap closure of large decubitus heel ulcerations complicated by calcaneal osteomyelitis. AB - Osteomyelitis is a common late-stage sequela of deep heel ulceration and frequently results in leg amputation, because few options exist to effectively treat this challenging problem. A technique that has been successful at our institution is near total calcanectomy with rotational flap closure of large decubitus heel ulcers complicated by calcaneal osteomyelitis. A case series is presented of 3 patients with differing locations or "zones" of heel decubitus ulceration with acute osteomyelitis. A description of our preferred flap choice, given the zone of the ulceration, is demonstrated, as are the surgical principles for the treatment approach. This procedure is an effective option, provided specific principles are followed to achieve complete wound coverage and minimize pressure points both when in bed and when walking. PMID- 22835724 TI - Chronic Achilles rupture reconstructed with Achilles tendon allograft: a case report. AB - Chronic ruptures of the Achilles tendon are more difficult to treat than acute tendon rupture. It has been shown that surgical treatment of chronic Achilles tendon rupture provides better functional results than nonoperative treatment. We present a case of neglected Achilles tendon rupture with a 12-cm defect that was repaired using an Achilles tendon allograft with interferential screws to fix the graft in the calcaneus. The patient recovered his ankle function to normal activities after rehabilitation. PMID- 22835725 TI - Allelopathic and bioherbicidal potential of Cladonia verticillaris on the germination and growth of Lactuca sativa. AB - Responses to germination and initial growth of Lactuca sativa (lettuce) submitted to organic extracts and purified compounds of Cladonia verticillaris ("salambaia") were analyzed in this work. The experiments were conducted in laboratory conditions using extracts and pure compounds at different concentrations. None of the assays showed any influence on the germination of L. sativa seeds using C. verticillaris extracts; however, modifications in leaf area and seedling hypocotyl and root development occurred. In the growth experiments, seedlings exposed to ether or acetone extract showed diminished hypocotyl growth in detriment to the root stimulus, compared to controls. Increases in extract concentrations led to the formation of abnormal seedlings. To determine the allelochemicals of C. verticillaris, its principal components, fumarprotocetraric and protocetraric acids, were isolated and then analyzed by high performance liquid chromatography (HPLC). When the seedlings were exposed to the two acids separately, presented increased leaf area at all concentrations. In contrast, hypocotyl and root stimulus was observed only in the presence of protocetraric acid at different concentrations. Fumarprotocetraric as well as protocetraric acids, isolated and purified from C. verticillaris and Parmotrema dilatatum respectively, influenced the development of L. sativa seedlings at high concentrations, indicating a possible bioherbicide potential of these acids. PMID- 22835726 TI - Inflammatory and degranulation effect of yellow sand on RBL-2H3 cells in relation to chemical and biological constituents. AB - Recent studie pointed out that allergic diseases have increased during the Asian dust storm event (ADSE) in Japan. Daily observations and the atmospheric concentrations of yellow sand (YS) aerosol have been increasing. In this study, YS samples collected from three sites of Japan during ADSE in 2009-2010 were used. The particles were analyzed by X-ray photoelectron spectroscopy (XPS) and X ray fluorescence-energy dispersive spectrometer (XRF-EDS). We investigate ability of YS extract on enhancing the chemical mediator release and cytokine production from rat basophilic leukemia (RBL-2H3) cells. The dust particles at Fukuoka and Tsukuba were abundant in aluminum (Al), iron (Fe), potassium (K) and titan (Ti) than those at Naha. Concentration of the trace endotoxin and Cryptomeria japonica pollen allergen (Cry j 1) were measured in YS extract. After exposure of RBL-2H3 cells to YS extract, the beta-hexosaminidase (beta-hex) release, tumor necrosis factor-alpha (TNF-alpha) production were enhanced in RBL-2H3 cells. This process depends on endotoxin, Cry j 1 and other allergen present in the YS extract. YS water extract also show a strong cytotoxic effect on the cells. This data suggest that low levels of endotoxin and Cry j 1 in YS may cause allergy during the ADSE. PMID- 22835727 TI - Implications of cytochrome 450 isoenzymes, aryl-esterase and oxonase activity in the inhibition of the acetylcholinesterase of Chirostoma jordani treated with phosphorothionate pesticides. AB - Organophosphate pesticides must be metabolized by cytochrome-P450 isoenzymes such CYP 2C19 as CYP 3A4 to induce neurotoxicity, but damage apparently depends on the activity of aryl esterases of the oxonase type that are involved in detoxication of these compounds. However, information on this subject is not available in fish. Chirostoma jordani has sustained significant population reductions, probably due to changes in land-use as well as pesticide impact; nevertheless, no specific studies demonstrating this are available. This study shows for the first time that the activity of cytochrome-P450 isoenzymes (CYP 2B6, CYP 2C19, CYP 3A4) in C. jordani is involved in diazinon and chlorpyrifos bioactivation. However, higher toxicity of chlorpyrifos cannot be explained solely because its bioactivation. Differences in toxicity between both pesticides are due to the activity of aryl esterases and oxonases that are responsible for oxon detoxication. Both hepatic enzymes metabolize diazoxon more efficiently than chlorpyrifos oxon. At lethal concentrations, detoxication is particularly important since mortality was lower with diazinon (LC50=1.5 MUg/L) than with chlorpyrifos (LC50=0.17 MUg/L). At sublethal levels, maximum acetylcholinesterase inhibition took place at 4h in both brain and muscle and was of lower magnitude in diazinon-treated fish. This is due to the higher affinity of both aryl esterases for diazoxon, which allows higher detoxication rates and therefore greater recovery of acetylcholinesterase activity. PMID- 22835728 TI - Assessment of spatial distribution and potential ecological risk of the heavy metals in relation to granulometric contents of Veeranam lake sediments, India. AB - The contents and spatial distributions of heavy metals (Cd, Cr, Cu, Ni, Pb and Zn) have been studied in surface sediments of Veeranam lake, Tamilnadu, India. Heavy metal contents are higher in open water area (limnetic zone) (OWA) than other two regions such as inflow river mouth (littoral zone) (IFR) and outflow river mouth region (OFR). Present metal contents are compared with both background and toxicological reference values. The comparative results suggest that the present metals except Cd and Pb create an adverse effect on the aquatic ecosystems associated with this lake. The Pollution Load Index (PLI) and Potential Ecological Risk (PER) are calculated and calculated PLI values (range: 1.18-4.09 with an average of 2.03) show that the present sediments are polluted significantly and these values are higher in OWA region. From the PER values, each single element has low potential ecological risk. However, Cd shows higher ecological risk. The comprehensive PER index of the sediments shows moderate degree. The magnetic susceptibility is higher in OWA region. Granulometric analysis confirms that the silt is major content. Multivariate Statistical analyses (Pearson Correlation, Cluster and Factor analysis) were carried out and obtained results suggested that the heavy metals in present lake have complicated contamination sources or controlling factors and the heavy metals such as Cr, Cu, Ni and Zn may be incorporated in magnetic minerals which are presented in silt grains. Also it shows that the role of silt is incorporating the cations on their surface and raising the level of magnetic susceptibility and heavy metal contents. The present study recommends that the heavy metal levels are unlikely to cause additional adverse health risks to the aquatic ecosystem associated with this lake. PMID- 22835729 TI - Endoscopic investigation and evaluation of anxiety for the management of globus sensation. AB - OBJECTIVE: To verify whether the severity of globus sensation would be affected by the results of investigations on possible underlying serious pathology in the head, neck and esophagus. METHODS: Thirty-six patients with globus sensation were enrolled in this study. All the patients suffered relatively persistent globus sensation which remained after conventional laryngoscopy at their family doctors. These patients were investigated for possible underlying oropharyngeal and esophageal lesions using fiberoptic endoscopy. The severity of globus was evaluated by the visual analog scales (VAS), and the degree of anxiety was evaluated by the state section of State Trait Anxiety Inventory (STAI-s). The questionnaires were administered at their first visits, and 9.6+/-3.2 months after endoscopy. The follow-up data obtained from 22 patients were incorporated in the further evaluations. Multiple regression analysis was used to evaluate the relationship between the improvement of VAS scores and that of STAI-s scores. Afterwards, Pearson product-moment correlation coefficient was measured. The recorded images of fiberoptic endoscopy were retrospectively verified by an expert of upper gastrointestinal endoscopy. RESULTS: No malignancies were observed in the endoscopic examination. Despite no treatment administered during the follow-up period, significant improvement of VAS scores was observed from the initial scores (40+/-21) to follow-up scores (27+/-27, p=0.014) in the patients examined in this study. The multiple linear regression analysis proved that the improvement of STAI-s scores was the only factor significantly affected the improvement of VAS scores (p=0.029) among the dependent valuables. The retrospective evaluation of the recorded images revealed comorbid esophagitis in 10 out of the 22 patients. When patients were stratified with the presence of comorbid esophagitis, significant improvement of VAS scores was observed only in the group without comorbid esophagitis at their follow up (17+/-20, p=0.026) compared with their initial scores (36+/-17). The multiple linear regression analysis proved that the improvement of VAS scores was significantly affected by the improvement of STAI-s scores (p=0.047) in this group. Moreover, significant positive relationship between the improvement of VAS scores and that of STAI-s scores was observed only in the group without comorbid esophagitis (r=0.61, p=0.047). CONCLUSION: Proper investigation to prove no underlying serious pathology may lead to the improvement of globus sensation in the patients without comorbid esophagitis through the reduction of their anxiety even when their symptoms are relatively persistent. Our results also indicated that some treatments against esophagitis may be helpful for the improvement of globus sensation in the patients with this comorbid disease. PMID- 22835730 TI - Distribution of circulating natural killer cells and T lymphocytes in head and neck squamous cell carcinoma. AB - OBJECTIVE: Natural killer (NK) cells are capable of eliminating malignantly transformed cells without prior sensitization. In contrast to NK-cells, T lymphocytes possess antitumourous activity that is restricted to major histocompatibility complex (MHC) recognition. The aim of this study was to determine the causes of the different distributions of these cell types in the peripheral blood of patients with head and neck squamous cell carcinomas (HNSCC). METHODS: A cohort of 105 subjects was divided into three clinical groups: non treated HNSCC patients, treated relapse-free HNSCC patients and healthy control subjects. Peripheral blood mononuclear cells (PBMC) were isolated from venous blood, subsets were depleted, flow cytometric counts were made and subsequently correlation analyses with clinical parameters were performed. RESULTS: Treated relapse-free HNSCC patients have a significantly increased mean proportion of NK cells in PBMC of 26.39% (p<0.001), whereas T lymphocytes and natural killer-T (NKT) cells of treated patients have a significantly decreased mean proportion in PBMC of 55.15% (p<0.05) at least 12 months after treatment. This inverse redistribution of these two subsets is reflected in a significantly increased mean NK/T-ratio of 0.54 (p<0.05) in treated patients. The NK/T-ratio correlates with the systemic invasiveness of the type of therapy patients undergo and is highest after surgery with adjuvant radiochemotherapy (0.64, rs=0.334, p<0.01). This appears to be a post-therapeutic long-term effect in treated patients, as they had a mean relapse-free period until venous puncture of 47.9 months in our study. We also demonstrated age-dependent changes in the peripheral distribution of T- and NK-cells. CONCLUSION: These findings reveal new aspects in understanding tumour biology and interactions with the cellular immune system which provide novel starting points for further research. PMID- 22835731 TI - Spontaneous nystagmus in horizontal canal benign paroxysmal positional vertigo. AB - OBJECTIVE: Benign paroxysmal positional vertigo of horizontal semicircular canal (HSC-BPPV) is characterized by either geotropic or apogeotropic nystagmus induced by head roll test. Some patients also present with spontaneous nystagmus. The aim of this study is to examine the clinical manifestation of spontaneous nystagmus in HSC-BPPV and evaluate the effect on the treatment outcome. PATIENTS AND METHODS: Electronystagmography and video eye movement recordings of 125 patients diagnosed as HSC-BPPV were reviewed retrospectively. Presence of spontaneous nystagmus was analyzed and treatment outcome after repositioning therapy was compared. RESULTS: Overall, spontaneous nystagmus was observed in 19 patients (15.2%) with HSC-BPPV at initial presentation. In canalolithiasis group (n=64), the treatment outcome did not differ between patients with or without spontaneous nystagmus. However, in cupulolithiasis group (n=61), patients presenting with spontaneous nystagmus (n=10) required more repositioning therapy sessions. CONCLUSION: The presence of spontaneous nystagmus at initial presentation may implicate poorer treatment outcome in cupulolithiasis HSC-BPPV patients. PMID- 22835732 TI - Field distribution and activity of chlorinated solvents degrading bacteria by combining CARD-FISH and real time PCR. AB - Nowadays several advanced molecular techniques are applied for quantifying bacteria involved in contaminant degradation processes. However, despite the fact that significant efforts have been taken to make these tools more reliable and specific, their application for the analysis of field samples is hardly ever applied. In this study, a combination of three methods (CARD-FISH, qPCR and RT qPCR) was successfully applied to evaluate the distribution and the activity of known chlorinated solvent dechlorinating bacteria in a contaminated site where no remedial actions have been undertaken. CAtalysed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) specifically provided the cell densities of known dechlorinating bacteria and was found to be more sensitive than quantitative PCR (qPCR) for the quantification of 'Dehalococcoides' cell numbers in the aquifer. Among the screened dechlorinators, 'Dehalococcoides' spp. were mainly found and nearly homogenously distributed in the aquifers at concentrations ranging from 8.1*10(5)+/-1.2*10(5) to 2.5*10(7)+/-5.6*10(6)cells per liter of groundwater (with a relative abundance out of the total Bacteria of 0.7-15%). Further, the dechlorination potentialities of 'Dehalococcoides' species living in the aquifer were evaluated by analyzing the abundance and the expression of 16S rRNA genes and reductive dehalogenase (RDase) encoding functional genes by qPCR and Reverse Transcription qPCR (RT-qPCR). 'Dehalococcoides'tceA gene, known to be associated to strains capable of reducing chlorinated solvents beyond cis-DCE, was found and expressed in the field. Overall, this study proved the existence of a well-established dechlorinating microbial community able to use contaminants as substrates for their metabolic activity and indicated the occurrence of reductive dechlorination at the site. PMID- 22835733 TI - Acute hemodynamic effects of landiolol, an ultra-short-acting beta-blocker, in patients with acute coronary syndrome: preliminary study. AB - OBJECTIVES: We aimed to evaluate acute hemodynamic effects and safety of landiolol in patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). BACKGROUND: Beta-blockers have been proven to be effective for the treatment of ischemic heart disease in both the acute and chronic phases. Landiolol, an ultra-short-acting and highly cardioselective beta-1 blocker, has become available in Japan. In the clinical setting, the hemodynamic response to landiolol administration remains unclear in patients presenting with ACS. METHODS: From August 2007 to April 2008, landiolol was administered intravenously immediately before reperfusion procedure in 22 consecutive ACS patients (mean age, 63+/-9 years; 15 men) with a heart rate (HR) of >=70 beats/min. The initial intravenous administration dose of landiolol was 20 MUg/kg/min in all patients. The maintenance dose was titrated with the aim of reducing HR by 15%. Acute hemodynamic data including HR and systolic and diastolic blood pressure were serially evaluated. RESULTS: HR dropped significantly (from 87+/-11 to 72+/-8beats/min, p<0.001) 20 min after landiolol initiation. However, systolic and diastolic pressure remained unchanged during administration of landiolol. Although landiolol was discontinued in 2 patients because of sinus bradycardia, no serious complications such as advanced degree atrioventricular block, requiring temporary cardiac pacing, severe hypotension, cardiogenic shock, or deterioration of heart failure were observed in the patients receiving landiolol. CONCLUSIONS: Landiolol was safe and effective in reducing oxygen demand of the ischemic heart by reducing only HR without lowering blood pressure in patients with ACS undergoing PCI. PMID- 22835734 TI - Biomimetic monolayer films of monogalactosyldiacylglycerol incorporating ubiquinone. AB - Ubiquinone and plastoquinone are two of the main electron and proton shuttle molecules in biological systems, and monogalactosyldiacylglycerol (MGDG) is the most abundant lipid in the thylakoid membrane of chloroplasts. Saturated MGDG, ubiquinone-10 (UQ) and MGDG:UQ mixed monolayers at the air/water interface have been studied using surface pressure-area isotherms and Brewster Angle Microscopy. Moreover, the transferred Langmuir-Blodgett films have been observed by Atomic Force Microscopy. The results show that MGDG:UQ mixtures present more fluid phase than pure MGDG, indicating a higher order degree for the later. It is also observed an important influence of UQ on the MGDG matrix before UQ collapse pressure and a low influence after this event, due to UQ expulsion from the MGDG matrix. This expulsion leads to a similar remaining UQ content for all the tested mixtures, indicating a limiting content of this molecule in the MGDG matrix at high surface pressures. The thermodynamic studies confirm the stability of the MGDG:UQ mixtures at low surface pressures, although presenting a non-ideal behaviour. Results point to consider UQ as a good candidate for studies of artificial photosynthesis. PMID- 22835735 TI - Biologically plausible and evidence-based risk intervals in immunization safety research. AB - In immunization safety research, individuals are considered at risk for the development of certain adverse events following immunization (AEFI) within a specific period of time referred to as the risk interval. These intervals should ideally be determined based on biologic plausibility considering features of the AEFI, presumed or known pathologic mechanism, and the vaccine. Misspecification of the length and timing of these intervals may result in introducing bias in epidemiologic and clinical studies of immunization safety. To date, little work has been done to formally assess and determine biologically plausible and evidence-based risk intervals in immunization safety research. In this report, we present a systematic process to define biologically plausible and evidence-based risk interval estimates for two specific AEFIs, febrile seizures and acute disseminated encephalomyelitis. In addition, we review methodologic issues related to the determination of risk intervals for consideration in future studies of immunization safety. PMID- 22835736 TI - Evaluation of a toolkit to introduce standing orders for influenza and pneumococcal vaccination in adults: a multimodal pilot project. AB - BACKGROUND: Immunization of adults with influenza vaccine and pneumococcal polysaccharide vaccine remains lower than recommended levels. Standing order programs (SOPs) in which non-physician medical personnel are permitted to assess an adult patient's immunization status and administer vaccines without an individual physician order are a proven method of increasing adult vaccinations, yet they are used by less than one half of primary care physicians caring for adults. METHODS: Following a national survey of primary care physicians about barriers to SOPs for adult immunizations, a SOP toolkit was developed. After review by a panel of experts, the toolkit was pilot tested in three primary care practices in a health care network with the same electronic medical record (EMR) system and low adult vaccination rates. Practice staffs were trained in the use of SOPs and the toolkit at a group meeting. This study was designed to pilot-test and evaluate the toolkit with the express intention of improving it. Three methods were used to evaluate the toolkit: (1) direct observation and interviews of each practice's staff; (2) surveys of each practice's staff; and (3) influenza and pneumococcal polysaccharide vaccine (PPV) vaccination rates. RESULTS: The staffs at all sites were equally likely to find the presentations and toolkit useful and did not differ in their knowledge of using SOPs for vaccination. They expressed a common set of barriers to implementing SOPs despite using the toolkit, and provided ideas for improving implementation. One site viewed SOPs in general in a more negative light and expressed that SOPs unfairly increased their workload. Vaccination rates in this site did not differ from those of the control site. CONCLUSION: The evaluation suggested that the SOP toolkit should be expanded to include additional strategies to improve its applicability and effectiveness. PMID- 22835737 TI - Report of the ad-hoc consultation on aging and immunization for a future WHO research agenda on life-course immunization. AB - WHO convened a meeting of around 30 experts to address the topic of aging and immunization in March 2011 in Geneva. The purpose of the meeting was to develop a global research agenda to eventually inform WHO policy recommendations regarding immunization beyond childhood and into old age. This issue is becoming more critical, since the population aged 60 and above will reach two billion people - three-quarters of whom will be in developing countries - in the next 40 years. The meeting reviewed current knowledge and gaps in information about: (1) the epidemiology of infectious diseases in the elderly in developed and developing countries and their contribution to disability in old age; (2) the deterioration of the immune system with age ("immune senescence") and possible ways to measure and counteract it; and (3) immunization approaches to maintain or improve health in older persons. These approaches include the concept of a "life-course vaccination" schedule to help sustain immunity to vaccine-preventable diseases beyond childhood and into old age; strategies to strengthen older persons' responses to vaccines (e.g., by adding adjuvants to vaccines, increasing vaccine dosage, and intradermal vaccine administration); and the possible development of new vaccines targeted specifically for older adults. Participants proposed priority research topics as well as strategies to facilitate and coordinate the research, including the establishment of networks of collaborators, with WHO playing a key coordinating role. PMID- 22835738 TI - Mucosal IgA responses in influenza virus infections; thoughts for vaccine design. AB - The current challenge in influenza vaccine design is to induce long-lasting protection not only against the vaccine strain, but also against drifted (point mutations in the surface antigens HA or NA) and even shifted (exchange of genome segments) strains. Several immune mediators that can induce cross-protection have been described, such as CD4 T-cells, CD8 T-cells and antibodies, including IgA. However, most vaccines are now administered intramuscularly or subcutaneously and subsequently relatively little is known on the role of local, mucosal responses. Since local IgA responses have been shown to play an important role in responses to natural infection, and IgA responses in mice were shown to also be involved in cross-protection, the research on mucosal influenza vaccines is currently expanding. However, the functioning of the mucosal immune system, especially in the respiratory tract, is just beginning to be revealed. Here, the current knowledge on the induction of IgA, the role of influenza specific IgA producing B cells in anti-influenza immunity as well as the role of humoral memory responses induced upon vaccination will be reviewed. PMID- 22835739 TI - The changing epidemiology of hepatitis A in Arizona following intensive immunization programs (1988-2007). AB - INTRODUCTION: Arizona had the highest hepatitis A incidence of any U.S. state during 1987-1997. In 1995, the first hepatitis A vaccines became available in the U.S. A series of hepatitis A vaccination policies and recommendations were implemented in 1996-2006. Our objective was to examine the shifting epidemiologic patterns in hepatitis A in Arizona from 1988 to 2007. METHODS: Passive surveillance reports to the Arizona Department of Health Services were used to compare hepatitis A rates by age, race/ethnicity and geographic area, before and after widespread vaccination. Reported risk factors and possible sources of infection were compared for two time periods. Age-adjusted incidence during three periods was mapped. RESULTS: Overall hepatitis A incidence in Arizona fell from 58 cases per 100,000 in 1988 to 2 per 100,000 in 2007. The proportion of reported cases among children dropped from 62% in 1994-1995 to 32% in 2006-2007. Racial/ethnic disparities between American Indians and non-Hispanic White populations have been eliminated. The geographic distribution of cases within the state has shifted. Earlier cases were likely to report contact with another hepatitis A case or childcare facilities, while later cases indicated recent international travel. CONCLUSION: A major shift in the overall burden of hepatitis A and hepatitis A transmission has occurred in Arizona since the widespread implementation of immunization policies and the concomitant rise in vaccination rates in the state. Current transmission has shifted to older age groups and disparities by race/ethnicity are now highest in Hispanic populations. Future strategies to further reduce hepatitis A transmission may require broadening recommendations to include general adult populations without previous vaccination history. PMID- 22835740 TI - Characterization of size, structure and purity of serogroup X Neisseria meningitidis polysaccharide, and development of an assay for quantification of human antibodies. AB - Serogroup X Neisseria meningitidis (MenX) has recently emerged as a cause of localized disease outbreaks in sub-Saharan Africa. In order to prepare for vaccine development, MenX polysaccharide (MenX PS) was purified by standard methods and analyzed for identity and structure by NMR spectroscopy. This study presents the first full assignment of the structure of the MenX PS using (13)C, (1)H and (31)P NMR spectroscopy and total correlation spectroscopy (TOCSY) and (1)H-(13)C heteronuclear single quantum coherence (HSQC). Molecular size distribution analysis using HPLC-SEC with multi-angle laser light scattering (MALLS) found the single peak of MenX PS to have a weight-average molar mass of 247,000g/mol, slightly higher than a reference preparation of purified serogroup C meningococcal polysaccharide. MenX PS tended to be more thermostable than serogroup A PS. A method for the quantification of MenX PS was developed by use of high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). A novel and specific ELISA assay for quantification of human anti-MenX PS IgG based on covalent linkage of the MenX PS to functionally modified microtitre plates was developed and found valid for the assessment of the specific antibody concentrations produced in response to MenX vaccination or natural infection. The current work thus provides the necessary background for the development of a MenX PS-based vaccine to prevent meningococcal infection caused by bacteria bearing this capsule. PMID- 22835741 TI - Vaccine trials in the developing world: operational lessons learnt from a phase IV poliomyelitis vaccine trial in South Africa. AB - BACKGROUND: Conducting vaccine trials in developing nations is necessary but operationally complex. We describe operational lessons learnt from a phase IV poliomyelitis vaccine trial in a semi-rural region of South Africa. METHODS: We reviewed operational data collected over the duration of the trial with respect to staff recruitment and training, participant recruitment and retention, and cold chain maintenance. RESULTS-LESSONS LEARNT: The recruitment model we used that relied on the 24h physical presence of a team member in the birthing unit was expensive and challenging to manage. Forecasting of enrolment rates was complicated by incomplete baseline data and by the linear nature of forecasts that do not take into account changing variables. We found that analyzing key operational data to monitor progress of the trial enabled us to identify problem areas timeously, and to facilitate a collegial problem-solving process by the extended trial team. Pro-actively nurturing a working relationship with the public sector health care system and the community was critical to our success. Despite the wide geographical area and lack of fixed addresses, we maintained an excellent retention rate through community assistance and the use of descriptive residential information. Training needs of team members were ongoing and dynamic and we discovered that these needs that were best met by an in-house, targeted and systemized training programme. The use of vaccine refrigerators instead of standard frost-free refrigerators is cost-effective and necessary to maintain the cold-chain. CONCLUSION: Operational challenges of a vaccine trial in developing world populations include inexperienced staff, the close liaison required between researchers and public health care services, impoverished participants that require complex recruitment and retention strategies, and challenges of distance and access. These challenges can be overcome by innovative strategies that allow for the unique characteristics of the setting, trial population, and trial team. PMID- 22835743 TI - Neoplasms of dendritic cells: related cell origins and diagnostic markers. Fibroblastic reticulum cells and fibroblastic reticulum cell tumors show several immunophenotypic profiles. PMID- 22835742 TI - Heightened adaptive immune responses following vaccination with a temperature sensitive, live-attenuated influenza virus compared to adjuvanted, whole inactivated virus in pigs. AB - In the United States there are currently two influenza vaccine platforms approved for use in humans-conventional inactivated virus and live-attenuated influenza virus (LAIV). One of the major challenges for influenza A virus (IAV) vaccination is designing a platform that provides protection across strains. Pandemic H1N1 (pH1N1) IAV swept the globe in 2009 and crossed the species barrier, infecting swine in several countries. Pigs are a natural host for IAV and serve as a model for evaluating immune responses following vaccination and challenge. Recently, a temperature-sensitive (ts) LAIV was developed by introducing modifications in the polymerase genes of a swine-like triple reassortant (tr) virus and when paired with pandemic HA and NA, provided sterilizing immunity upon intratracheal challenge with virulent pH1N1 virus. The utility of a ts LAIV is expanded in this report to show vaccination of pigs induced a cell-mediated immune response characterized by an increased number of antigen-specific IFN-secreting cells and expanded T cell populations when compared to pigs vaccinated with a whole inactivated virus (WIV) vaccine. Following challenge, there was a significant increase in the percentage of proliferating lymphocytes in the LAIV group compared to the WIV group following restimulation with pH1N1 in vitro. Also, there was an increase in the percentage of CD4/CD8 double-positive memory T cells in LAIV vaccinated pigs compared to WIV vaccinated pigs. Hemagglutination inhibition and serum neutralization titers were significantly higher in the LAIV vaccinated pigs compared to the WIV vaccinated pigs following the initial dose of vaccine. Taken together, these results indicate the ts LAIV vaccine, generated from a triple reassortant IAV, elicits greater cell-mediated and humoral immune responses in pigs. PMID- 22835744 TI - Go hybrid: EM, crystallography, and beyond. AB - A mechanistic understanding of the molecular transactions that govern cellular function requires knowledge of the dynamic organization of the macromolecular machines involved in these processes. Structural biologists employ a variety of biophysical methods to study large macromolecular complexes, but no single technique is likely to provide a complete description of the structure-function relationship of all the constituent components. Since structural studies generally only provide snapshots of these dynamic machines as they accomplish their molecular functions, combining data from many methodologies is crucial to our understanding of molecular function. PMID- 22835745 TI - Crisis emergencies for individuals with severe, persistent mental illnesses: a situation-specific theory. AB - This article presents an extension of Ball's midrange theory of crisis for individuals with severe, persistent mental illnesses (SPMI) by placing Balls' model in the specific situation of the individual seeking help in an emergency setting, creating the situation-specific theory of crisis emergencies for individuals with SPMI. There is a large and growing presence of clients with SPMI in crisis engaging nurses in emergency departments. Through application of an integrative approach, a situation-specific theory for nurses in emergency departments to distinguish between a need for mental health crisis intervention and mental health emergency intervention has been developed, with implications for nursing practice, policy, and research. PMID- 22835746 TI - Needs of persons with serious mental illness following discharge from inpatient treatment: patient and family views. AB - Patients with serious mental illnesses often struggle with persistent symptoms that interfere with daily functioning in the community. The first days and weeks following inpatient treatment for an acute episode may be a critical time for patients to connect with the recommended community follow-up. Residual symptoms may interfere with their ability to access and benefit from these services to meet their needs. A descriptive study was conducted to explore perceptions of patients and families of patients' needs, functioning, coping and social support in the first 4 weeks after inpatient treatment. Results suggested that these patients had residual symptoms after discharge that interfered with functioning despite the availability of follow-up services. Patients identified unmet needs related to their illness. Family members identified concerns related to the lack of improvement in their ill relatives over time. Patients expressed satisfaction with care and felt supported by their families. Both patients and families seemed to lack a thorough understanding of goals for follow-up care. PMID- 22835747 TI - Engagement in primary care treatment by persons with severe and persistent mental illness. AB - Even when primary care provider relationships exist, persons with severe and persistent mental illness (SPMI) are more likely to be undertreated and seek care from emergency room settings. The purpose of this study was to describe the social process of engagement in primary care treatment from the perspective of persons with SPMI. Using grounded theory and semistructured interviews, 32 adults were interviewed. The process of engagement includes mattering, being perceived as credible and capable, and working together. Clinical, education, and research implications are discussed. Future studies should explore engagement in primary care with this population from the perspective of providers. PMID- 22835748 TI - Psychosocial rehabilitation activities, empowerment, and quality of community based life for people with schizophrenia. AB - Many variables influencing quality of life (QOL) for outpatients with schizophrenia have been identified from prior studies. Symptom severity, psychosocial rehabilitation activities, and empowerment have all been clearly identified as key variables. However, which variables are the most influential and important factors remains unknown; factors influencing QOL, either directly or indirectly and to what degree, need to be examined. The aim of this study was to test the hypothesis that empowerment is a possible mediator of how (a) psychiatric symptoms and (b) psychosocial rehabilitation activities affect QOL for outpatients with schizophrenia in the community. We used the probability proportional to size random sampling for 190 outpatients with schizophrenia at 10 community rehabilitation centers in Taipei, such that samples consisted of adults who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. The instruments included the questionnaire to gather demographic and disease information, the Empowerment Scale, the Psychiatric Symptoms Scale, the psychosocial rehabilitation activity (PRA), and the Quality of Life Scale for Psychiatric Patients. Beyond descriptive statistics, correlation and structural equation models were computed. Findings showed that empowerment in outpatients with schizophrenia mediates QOL, whereas psychosocial rehabilitation activities seem to increase empowerment, which may in turn increase QOL. Psychotic symptoms seem to have a direct effect of decreasing QOL that could not be mediated by empowerment. Empowerment had a significant effect on QOL for outpatients with schizophrenia. The findings of this study support the importance of empowerment and rehabilitation activities for promoting QOL among community outpatients. We suggest that various rehabilitation programs and empowerment health education are needed to enhance QOL for schizophrenia outpatients in the community. PMID- 22835749 TI - Sense of coherence and quality of life in family caregivers of persons with schizophrenia living in the community. AB - The purpose of this study was to clarify the sense of coherence (SOC) and quality of life (QOL) of caregivers of persons with schizoprenia. Thirty-four families were investigated using the SOC-13, the 26-item World Health Organization Quality of Life, and an interview guide. Family caregivers in their 50s, 60s, and 70s with higher SOC scores showed higher QOL scores; older groups showed higher mean SOC and QOL scores; and a significant difference in the scores for the environment domain was observed among the 3 groups. SOC was considered to be influenced by the family caregivers' age, educational level, duration of ilness, and whether they live with the patients. PMID- 22835750 TI - Determinants of seclusion after aggression in psychiatric inpatients. AB - Some aggressive incidents in psychiatric wards result in seclusion, whereas others do not. We used the Staff Observation Aggression Scale-Revised and the mental health trust's database to identify determinants that predicted seclusion after aggression. These consisted of demographic, diagnostic, contextual, and aggression characteristics and were analyzed in a multilevel logistic regression. This showed associations between seclusion and aggression for the following: younger age, involuntary status, history of previous aggression, physical or dangerous violence, aggression being directed against objects, and a more severe incident. Thus, seclusion after aggression appears to be mainly predicted by aggression itself. PMID- 22835751 TI - A comparison of suboxone and clonidine treatment outcomes in opiate detoxification. AB - PURPOSE: This retrospective quality improvement study was to evaluate if Suboxone therapy reduced the risk of terminating treatment against medical advice compared with the use clonidine in men aged 18--55 years. METHODS: Data were collected through chart review for all opioid-addicted male clients admitted voluntarily to a community-based treatment center between July 1, 2009, and December 30, 2009. FINDINGS: The chi-square test of independence between treatment completion and treatment noncompletion was found to be significant at the 5% critical level (P = .027) for Suboxone therapy. CONCLUSIONS: Suboxone treatment decreased premature termination of opioid detoxification completion when compared with clonidine. PMID- 22835752 TI - The experiences of nurses with mental health problems: colleagues' perspectives. AB - A 3-stage qualitative study conducted in 2008 aimed to explore the issues to inform a mental health education program to deliver to nurses. This article presents the findings of Stage 1. Data were collected from semistructured interviews conducted with 14 Australian nurses. The interviews explored nurses' knowledge and understanding of mental health problems and their workplace experiences of working with nurses with mental health problems. The interviews were audiotaped, transcribed, and analyzed for the main themes: textbook knowledge, day-to-day support, and workplace considerations. These nurses' narratives guided the implementation of a mental health education workshop targeting nurses (Stage 2). PMID- 22835753 TI - Psychiatric mental health nurses: stigma issues we fail to see. PMID- 22835754 TI - Remembrance of Mary Jo Regan Kubinski. PMID- 22835755 TI - Family stress and posttraumatic stress: the impact of military operations on military health care providers. AB - This study uses data from the 2005 Department of Defense Survey of Health-Related Behaviors Among Military Personnel to examine relationships between family stress and posttraumatic stress symptoms across 4 subgroups of Operation Iraqi Freedom deployed (i.e., war in Iraq) or Operation Enduring Freedom-deployed (i.e., war in Afghanistan) active-duty military service members. Results suggest the following: (a) the greatest positive correlation of family stressors with posttraumatic stress symptoms was found within the military health care officer group, and (b) these military health care officers differed in family stressors mediating posttraumatic stress with divorce and financial problems accounting for significant and unique portions of the variance. Implications for care of service members and their families are discussed. PMID- 22835756 TI - Families' and decision makers' experiences with mental health care reform: the challenge of collaboration. AB - Family-driven collaboration is fundamental to developing a new model of health care and eliminating fragmented services in mental health. The province of Quebec (Canada) recently undertook major transformations of its mental health care system. These transformations represent an opportunity to improve collaboration between families and health care practitioners and to understand which factors facilitate this collaboration. This article describes how families and decision makers perceive collaboration in the context of a major transformation of mental health services and identifies the factors that facilitate and hinder family collaboration. PMID- 22835757 TI - Seroepidemiology of hepatitis A and E virus infections in Tehran, Iran: a population based study. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) are enteric hepatotropic viruses and their prevalence is related to the sanitary conditions of the region under investigation. There are only a few studies on the seroepidemiology of these two viruses in the general Iranian population. The purpose of this investigation was to measure the prevalence of hepatitis A and E infections in the general population. Between 2006 and 2007, a cross sectional study was performed in Tehran, Iran. Blood specimens were collected and questionnaires were filled in for 551 persons. Patient sera were tested by ELISA for anti-HEV and anti-HAV IgGs. The chi(2) test and independent t-test were used for statistical analysis and p<0.05 was considered significant. The overall seroprevalence rates of anti-HEV IgG and anti-HAV IgG were 9.3% and 90%, respectively. The prevalence of antibodies to HAV and HEV was greater among men than women and increased with age. However, there was no significant relationship between age and gender with the existence of anti- HAV and HEV IgG antibodies. Our results show the seroprevalence of HAV and HEV antibodies are high and both viruses are endemic in this region. These findings are in accordance with results obtained from previous studies. We recommend that foreign travelers to Iran are vaccinated against HAV. PMID- 22835758 TI - Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification. AB - The relationship between parasite burden and vertical transmission of Trypanosoma cruzi was studied in pairs of chronically infected women and their children in a non-endemic area. Parasitemia was quantified by quantitative polymerase chain reaction (qPCR) in the peripheral blood amplifying a nuclear T. cruzi DNA and expressed as equivalent amounts of CL Brener parasites DNA per ml (eP/ml). Similar levels of parasitemia were found in non-transmitting pregnant women and in non-pregnant women: 1.8 +/- 0.5 and 1.5 +/- 0.7 eP/ml, respectively. In women pregnant with infected children parasitemia was 11.0 +/- 2.7 eP/ml (n=20). In 12 of their neonates the infection was detected by microscopic observation of the parasites in peripheral blood in the 1(st) month of age. These children had variable levels of parasitemia (13,000 +/- 7000 eP/ml), that were about 600-fold higher than that found in their mothers. To our knowledge, this is the first quantitative evaluation of parasitemia in these three groups of women and in their congenitally infected children. These parasite quantifications could be a basis to plan the control of mother-to-child transmission of T. cruzi. PMID- 22835759 TI - Perturbation of myelin basic protein (Mbp) splice variant expression in developing rat cerebellum following perinatal exposure to methylmercury. AB - Myelin sheaths surrounding axons are essential for saltatory conduction of nerve impulse in the central nervous system. A major protein constituent of myelin sheaths is produced by the myelin basic protein (Mbp) gene, whose expression in oligodendrocytes is conserved across vertebrates. In rat, five Mbp splice variants resulting from alternative splicing of exons 2, 5 and/or 6 are characterized. We developed a PCR-based strategy to quantify individual Mbp splice variants and characterized a sixth Mbp splice variant lacking only exon 5. This newly identified splice variant is predominantly expressed in developing rat brain and has orthologs in mouse and human. Many neurotoxic chemicals can perturb myelination and Mbp gene expression. Regulation of Mbp gene expression at the post-transcriptional level was assessed following perinatal exposure to neurotoxic methylmercury (2 mg/kg b.w./day). Similar reductions in total and individual Mbp splice variant mRNA levels suggest that methylmercury-induced perturbation in Mbp gene expression occurred as a consequence of decreased oligodendrocyte cell population in absence of a significant impact on its post transcriptional regulation. PMID- 22835760 TI - Length of polyglutamine tract affects secondary and tertiary structures of huntingtin protein. AB - The role of polyglutamine (polyQ) tract on protein stability and disease pathology remains ambiguous. We monitored the unfolding/refolding patterns of huntingtin proteins with varying polyQ lengths. In the presence of urea, minor differences in unfolding and refolding efficiencies were observed. However, in the presence of guanidinium hydrochloride, the protein with a longer polyQ stretch was able to regain its secondary but not tertiary structure on step-wise removal of denaturant. Thus, in case of Huntington's disease, the higher aggregation propensity of the mutant protein is likely to be due to the lower stability of the protein due to elongated polyQ tract. PMID- 22835761 TI - The impact of enzyme-inducing antiepileptic drugs on antiretroviral drug levels: a case-control study. AB - PURPOSE: To evaluate the impact of enzyme-inducing antiepileptic drugs (EI-AEDs) on serum antiretroviral (ARV) levels in patients with HIV. METHODS: Data from the U.S. Military HIV Natural History Study were screened to identify participants taking ARVs with EI-AEDs and controls taking ARVs with non enzyme-inducing AEDs (NEI-AEDs). The proportion of serum ARV levels below the recommended minimum concentrations (C(min)) was compared between these groups. RESULTS: ARV levels were available for 10 individuals exposed to 16 intervals on combined ARVs/EI AEDs (phenytoin and carbamazepine) and for 25 controls exposed to 30 overlap intervals on combined ARVs/NEI-AEDs. The percentage of overlap intervals with >=1 ARV levels below C(min) was higher in the EI-AED group than in controls (37.5% vs. 23.3%; p=0.124). After excluding intervals associated with serum levels of EI AEDs below the reference range (n=6), the proportion of intervals with >=1 ARV level below C(min) was significantly greater among EI-AED recipients (60%) compared to controls (23.3%; p=0.008). CONCLUSIONS: ARV levels below C(min) were more common in participants receiving EI-AEDs, the difference being statistically significant for intervals associated with EI-AED levels within the reference range. These data suggest that, in agreement with current guidelines, EI-AEDs should be avoided in patients receiving ARV therapy. PMID- 22835762 TI - Early results from the ENGAGE registry: real-world performance of the Endurant Stent Graft for endovascular AAA repair in 1262 patients. AB - OBJECTIVE: The ENGAGE registry was undertaken to examine the real-world outcome after endovascular abdominal aortic aneurysm (AAA) repair (EVAR) with the Endurant Stent Graft in a large, contemporary, global series of patients. METHODS: From March 2009 to April 2011, 1262 AAA patients (89.6% men; mean age 73.1 years, range 43-93 years) were enrolled from 79 sites in 30 countries and treated with Endurant. Results are described following the reporting standards for EVAR. Follow-up data were tabulated for all 1262 patients at a 30-day follow up and for the first 500 patients at a 1-year follow-up. RESULTS: Intra-operative technical success was achieved in 99.0% of cases. Within 30 days, adverse events were reported in 3.9% of patients, including a 1.3% mortality rate. Type-I or III endoleaks were identified in 1.5% of cases. Estimated overall survival, aneurysm-related survival and freedom from secondary interventions at 1 year were 91.6%, 98.6% and 95.1%, respectively. At 1 year, aneurysm size increased >= 5 mm in 2.8% and decreased >= 5 mm in 41.3% of cases. CONCLUSION: Early results from this real world, global experience are promising and indicate that endovascular AAA repair with the Endurant Stent Graft is safe and effective across different geographies and standards of practice. Longer-term follow-up is necessary to assess durability of these results. PMID- 22835763 TI - The impact of female gender on outcome following carotid revascularisation. PMID- 22835764 TI - Commentary on 'Outcome after VAC therapy for infected bypass grafts in the lower limb'. PMID- 22835765 TI - Commentary on 'Factors related to postoperative delirium in patients with lower limb ischaemia: a prospective cohort study, Sasajima et al.'. PMID- 22835766 TI - Commentary on: 'In vitro identification of distinctive metabolic signatures of intact varicose vein tissue via magic angle spinning nuclear magnetic resonance spectroscopy'. PMID- 22835767 TI - Ex-vivo haemodynamic models for the study of Stanford type B aortic dissection in isolated porcine aorta. AB - OBJECTIVES: The aim of this study is to present novel ex-vivo models in the study of complex haemodynamical changes in Stanford type B aortic dissection (TBAD). MATERIALS AND METHODS: Fifteen fresh porcine aortas were harvested and preserved with 4 degrees C saline. Ex-vivo models were developed to simulate TBAD in three different situations: model A with patent false lumen, model B with distal re entry only and model C with proximal primary entry only. These models were connected to standardised pulsatile pumps and the pressure waveforms were monitored and compared. The aortas were scanned with ultrasonography and subjected to post-experiment autopsy. RESULTS: The three different models were successfully created (n = 13). Pulsatile flow testing was successful and the shapes of the pressure waveforms were similar to those taken from human aorta. Post-testing gross examination confirmed the success of modelling. CONCLUSION: Porcine aortas may prove to be useful ex-vivo models in the study of aortic dissection haemodynamics. These models are reproducible and may be used in the study of complex haemodynamic forces during the development and propagation of TBAD. Our three porcine models give a potential possibility in helping clinicians isolate and analyse complex haemodynamical factors in the development, propagation and prognosis of TBAD. PMID- 22835768 TI - Highly stable and regenerable Mn-based/SBA-15 sorbents for desulfurization of hot coal gas. AB - A series of mesoporous xCuyMn/SBA-15 sorbents with different Cu/Mn atomic ratios were prepared by wet impregnation method and their desulfurization performance in hot coal gas was investigated in a fixed-bed quartz reactor in the range of 700 850 degrees C. The successive nine desulfurization-regeneration cycles at 800 degrees C revealed that 1Cu9Mn/SBA-15 presented high performance with durable regeneration ability due to the high dispersion of Mn(2)O(3) particles incorporated with a certain amount of copper oxides. The breakthrough sulfur capacity of 1Cu9Mn/SBA-15 observed 800 degrees C is 13.8 g S/100g sorbents, which is remarkably higher than these of 40 wt%LaFeO(3)/SBA-15 (4.8 g S/100g sorbents) and 50 wt%LaFe(2)O(x)/MCM-41 (5.58 g S/100g sorbents) used only at 500-550 degrees C. This suggested that the loading of Mn(2)O(3) active species with high thermal stability to SBA-15 support significantly increased sulfur capacity at relatively higher sulfidation temperature. The fresh and used xCuyMn/SBA-15 sorbents were characterized by means of BET, XRD, XPS, XAES, TG/DSC and HRTEM techniques, confirmed that the structure of the sorbents remained intact before and after hot coal gas desulfurization. PMID- 22835769 TI - Iron-complexed adsorptive membrane for As(V) species in water. AB - Selective preconcentration of a target analyte in the solid phase is an effective route not only to enhance detection limit of the conventional analytical method but also for elimination of interfering matrix. An adsorptive membrane was developed for selective preconcentration and quantification of ultra-trace (ppb) amounts of As(V) present in a variety of aqueous samples. The precursor membrane was prepared by UV-initiator induced graft polymerization of sulphate and phosphate bearing monomers (1:1 mol proportion) in pores of the host microporous poly(propylene) membrane. Fe(3+) ions were loaded in the precursor membrane to make it selective for As(V) ions. The presence of phosphate functional groups prevent leaching of Fe(3+) ions from the membrane when it comes in contact with solution like seawater having high ionic strength. The optimized membrane was characterized in terms of its physical structure, chemical structure and experimental conditions affecting As(V) uptake in the membrane. The possibility of quantifying total preconcentration of As content was also explored by converting As(III) to As(V). To quantify As(V), the membrane samples were subjected to instrumental neutron activation analysis (INAA). The studies carried in the present work showed that quantification of inorganic arsenic species in natural water samples is easily possible in 2-3 ppb concentration range. PMID- 22835770 TI - Influence of impregnation method on metal retention of CCB-treated wood in slow pyrolysis process. AB - In the present work, the effects of copper, chromium and boron on the pyrolysis of wood and their distribution in the pyrolysis products were investigated. For this, the wood has been impregnated with chromium-copper-boron (CCB). In addition, to describe the effects of impregnation method, vacuum-pressure and dipping methods were also conducted. Thermogravimetric analysis (TGA) results show that an increase in the final residue and decrease in degradation temperature on both methods of treated wood compared to untreated wood. Then, slow pyrolysis experiments were carried out in a laboratory reactor. The mass balance of pyrolysis products is confirmed by TGA. Furthermore, the concentration of metals in the final residue is measured by inductively coupled plasma mass spectroscopy (ICP-MS). The results show that the final residue contains more than 45% of the initial amount of metal present in the treated wood. The phenomenon is more pronounced with vacuum-pressure treated wood. The heating values of pyrolysis products were analyzed. The heating value of charcoal obtained from treated and untreated wood is approximately same. But the heating value of tar from untreated wood is higher than the heating value of the tar from treated wood. PMID- 22835771 TI - Zinc(II) phthalocyanines immobilized in mesoporous silica Al-MCM-41 and their applications in photocatalytic degradation of pesticides. AB - In the present study the authors investigated a set of three new zinc(II) phthalocyanines (zinc(II) tetranitrophthalocyanine (ZnTNPc), zinc(II) tetra(phenyloxy)phthalocyanine (ZnTPhOPc) and the tetraiodide salt of zinc(II)tetra(N,N,N-trimethylaminoethyloxy) phthalocyaninate (ZnTTMAEOPcI)) immobilized into Al-MCM-41 prepared via ship-in-a-bottle methodology. The samples were fully characterized by diffuse reflectance-UV-vis spectroscopy (DRS-UV-vis), luminescence, thermogravimetric analysis (TG/DSC), N(2) adsorption techniques and elemental analysis. A comparative study was made on the photocatalytic performance upon irradiation within the wavelength range 320-460nm of these three systems in the degradation of pesticides fenamiphos and pentachlorophenol. ZnTNPc@Al-MCM-41 and ZnTTMAEOPcI@Al-MCM-41 were found to be the most active systems, with the best performance observed with the immobilized cationic phthalocyanine, ZnTTMAEOPcI@Al-MCM-41. This system showed high activity even after three photocatalytic cycles. LC-MS product characterization and mechanistic studies indicate that singlet oxygen ((1)O(2)), produced by excitation of these immobilized photosensitizers, is a key intermediate in the photocatalytic degradation of both pesticides. PMID- 22835772 TI - Effects of heavy metal concentrations (Cd, Zn and Pb) in agricultural soils near different emission sources on quality, accumulation and food safety in soybean [Glycine max (L.) Merrill]. AB - Argentina is one of the major producers of soybean in the world, this generates a high global demand for this crop leading to find it everywhere, even close to human activities involving pollutant emissions. This study evaluated heavy metal content, the transfer of metals and its relation to crop quality, and the toxicological risk of seed consumption, through soil and soybean sampling. The results show that concentrations of Pb and Cd in soils and soybeans at several sites were above the maximum permissible levels. The heavy metal bioaccumulation depending on the rhizosphere soil compartment showed significant and high regression coefficients. In addition, the similar behavior of Cd and Zn accumulation by plants reinforces the theory of other studies indicating that these metals are incorporated into the plant for a common system of transport. On the other hand, the seed quality parameters did not show a clear pattern of response to metal bioacumulation. Taken together, our results show that soybeans grown nearby to anthropic emission sources might represent a toxicological hazard for human consumption in a potential Chinese consumer. Hence, further studies should be carried out taking into account the potential negative health effects from the consumption of soybeans (direct or indirect through consumption of meat from cattle) in these conditions. PMID- 22835773 TI - Size-controlled preparation of Cu2O nanoparticles from waste printed circuit boards by supercritical water combined with electrokinetic process. AB - In this work, an effective and size-controlled process for preparing Cu(2)O nanomaterials from waste PCBs by supercritical water (SCW) combined with electrokinetic (EK) technique was developed. SCW was used for the pretreatment of waste PCBs, and highly uniform and monodisperse Cu(2)O nanoparticles with different sizes were prepared successfully from waste PCBs in EK process. Cu(2)O nanoparticles with average sizes of 5, 11, 25 and 40 nm could be prepared in the presence of nanoparticles stabilizer (PVP) with the concentrations of 40, 30, 20 and 10 g/L, respectively. The average size of Cu(2)O nanoparticles decreased from 49.5 to 18.2 nm when current density increased from 10 to 20 mA/cm(2), and the size uniformity of nanoparticles was improved distinctly at a higher current density. The size of Cu(2)O nanoparticles increased with the increase of EK time, and agglomeration of particles was observed after 8h EK reaction. Up to 90 wt% of the Cu in waste PCBs could be recovered as Cu(2)O nanoparticles under optimized condition. It is believed that the process developed in this study is simple and practical for size-controlled preparation of nanomaterials from waste PCBs or other Cu-rich solid wastes. PMID- 22835774 TI - Prevalence of breastfeeding in industrialized countries. AB - BACKGROUND: Given the benefits of breastfeeding (BF), healthcare institutions recommend that a child should be breastfed for the first 6 months of its life. This study provides a review of BF as a function of socioeconomic criteria in various industrialized countries. METHODS: A review was carried out between 1st January 1998 and 1st March 2009, using Medline and the Public Health Database. The papers were selected independently by two persons, using a methodological grid designed to evaluate the quality of the studies. From 1126 initially selected papers, 26 from 16 different countries were retained for further analysis. RESULTS: The prevalence of exclusive BF initiation was the highest in Norway, Denmark, and Japan with, respectively, 99, 98.7, and 98.3%. This prevalence was the lowest in the United Kingdom, the United States, and France with, respectively, 70, 69.5, and 62.6%. Women who breastfeed less were most commonly found to be young, single, from a low socioeconomic group, or with a low level of education. Women from immigrant population groups breastfed more than the native-born population during their pregnancy. CONCLUSION: Knowledge of the sociodemographic distribution of women who breastfeed is essential for the definition of preventive policies, which are needed to reduce health-related social inequalities. An in-depth analysis of existing primary healthcare programs would allow new strategies to be defined. PMID- 22835776 TI - A proteomic study of Xanthomonas oryzae pv. oryzae in rice xylem sap. AB - Xanthomonas oryzae pv. oryzae (Xoo) is the second most important rice pathogen, causing a disease called bacterial leaf blight. Xoo colonizes and infects the vascular tissue resulting in tissue necrosis and wilting causing significant yield losses worldwide. In this study Xoo infected vascular fluid (xylem sap) was recovered and analyzed for secreted Xoo proteins. Three independent experiments resulted in the identification of 324 different proteins, 64 proteins were found in all three samples which included many of the known virulence-associated factors. In addition, 10 genes encoding for the identified proteins were inactivated and one mutant displayed statistically a significant loss in virulence when compared to the wild type Xoo, suggesting that a new virulence associated factor has been revealed. The usefulness of this approach in understanding the lifestyle and unraveling the virulence-associated factors of phytopathogenic vascular bacteria is discussed. PMID- 22835775 TI - Murine macrophages response to iron. AB - Macrophages play a critical role at the crossroad between iron metabolism and immunity, being able to store and recycle iron derived from the phagocytosis of senescent erythrocytes. The way by which macrophages manage non-heme iron at physiological concentration is still not fully understood. We investigated protein changes in mouse bone marrow macrophages incubated with ferric ammonium citrate (FAC 10 MUM iron). Differentially expressed spots were identified by nano RP-HPLC-ESI-MS/MS. Transcriptomic, metabolomics and western immunoblotting analyses complemented the proteomic approach. Pattern analysis was also used for identifying networks of proteins involved in iron homeostasis. FAC treatment resulted in higher abundance of several proteins including ferritins, cytoskeleton related proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) at the membrane level, vimentin, arginase, galectin-3 and macrophage migration inhibitory factor (MIF). Interestingly, GAPDH has been recently proposed to act as an alternative transferrin receptor for iron acquisition through internalization of the GAPDH-transferrin complex into the early endosomes. FAC treatment also induced the up-regulation of oxidative stress-related proteins (PRDX), which was further confirmed at the metabolic level (increase in GSSG, 8 isoprostane and pentose phosphate pathway intermediates) through mass spectrometry-based targeted metabolomics approaches. This study represents an example of the potential usefulness of "integarated omics" in the field of iron biology, especially for the elucidation of the molecular mechanisms controlling iron homeostasis in normal and disease conditions. This article is part of a Special Issue entitled: Integrated omics. PMID- 22835777 TI - Circulation of almost genetically identical hepatitis E virus of genotype 4 in France. PMID- 22835778 TI - Development of a population-based cost-effectiveness model of chronic graft versus-host disease in Spain. AB - BACKGROUND: Chronic graft-versus-host disease (cGvHD) is the leading cause of late nonrelapse mortality (transplant-related mortality) after hematopoietic stem cell transplant. Given that there are a wide range of treatment options for cGvHD, assessment of the associated costs and efficacy can help clinicians and health care providers allocate health care resources more efficiently. OBJECTIVE: The purpose of this study was to assess the cost-effectiveness of extracorporeal photopheresis (ECP) compared with rituximab (Rmb) and with imatinib (Imt) in patients with cGvHD at 5 years from the perspective of the Spanish National Health System. METHODS: The model assessed the incremental cost effectiveness/utility ratio of ECP versus Rmb or Imt for 1000 hypothetical patients by using microsimulation cost-effectiveness techniques. Model probabilities were obtained from the literature. Treatment pathways and adverse events were evaluated taking clinical opinion and published reports into consideration. Local data on costs (2010 Euros) and health care resources utilization were validated by the clinical authors. Probabilistic sensitivity analyses were used to assess the robustness of the model. RESULTS: The greater efficacy of ECP resulted in a gain of 0.011 to 0.024 quality-adjusted life-year in the first year and 0.062 to 0.094 at year 5 compared with Rmb or Imt. The results showed that the higher acquisition cost of ECP versus Imt was compensated for at 9 months by greater efficacy; this higher cost was partially compensated for (?517) by year 5 versus Rmb. After 9 months, ECP was dominant (cheaper and more effective) compared with Imt. The incremental cost-effectiveness ratio of ECP versus Rmb was ?29,646 per life-year gained and ?24,442 per quality-adjusted life-year gained at year 2.5. Probabilistic sensitivity analysis confirmed the results. The main study limitation was that to assess relative treatment effects, only small studies were available for indirect comparison. CONCLUSION: ECP as a third-line therapy for cGvHD is a more cost-effective strategy than Rmb or Imt. PMID- 22835779 TI - [Direct total body CT scan in multi-trauma patients]. AB - BACKGROUND: Immediate total body computed tomography (CT) scanning has become important in the early diagnostic phase of trauma care because of its high diagnostic accuracy. However, literature provides limited evidence whether immediate total body CT leads to better clinical outcome then conventional radiographic imaging supplemented with selective CT scanning in trauma patients. The aim of the REACT-2 trial is to determine the value of immediate total body CT scanning in trauma patients. DESIGN: The REACT-2 trial is an international, multicenter randomized clinical trial. METHODS: All participating trauma centers have a multi-slice CT scanner located in the trauma room or at the Emergency Department (ED). All adult, non-pregnant, severely injured trauma patients according to predefined criteria will be included. The intervention group will receive a contrast-enhanced total body CT scan (head to pelvis) during the primary survey. The control group will be evaluated according to local conventional trauma imaging protocols (based on ATLS guidelines) supplemented with selective CT scanning. Primary outcome will be in-hospital mortality. Secondary outcomes are differences in mortality and morbidity during the first year post trauma, several trauma work-up time intervals, radiation exposure, general health and quality of life at 6 and 12 months post trauma and cost effectiveness. CONCLUSION: The REACT-2 trial is the first multicenter randomized clinical trial that will provide evidence on the value of immediate total body CT scanning during the primary survey of severely injured trauma patients. PMID- 22835780 TI - Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL). AB - PURPOSE: To assess the clinical activity of irinotecan as single drug in children with refractory or recurrent hepatoblastoma. PATIENTS AND METHODS: Four cycles of irinotecan were administered (20mg/m(2)/day intravenous (i.v.) infusion on days 1 5 and 8-12, every 21days) unless tumour progression occurred or resectability was achieved earlier. Tumour response was assessed according to modified SIOPEL and Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Main end-points were best overall response rate (RR), early progression rate (EPR) and progression free survival (PFS). RESULTS: Twenty-four eligible patients (median age 58.0months; 19 boys) were enrolled in the study (11 relapses, 13 refractory diseases). Of the 23 evaluable patients six had an overall partial response, 11 stable disease and six progressive disease, of which four were early progression (RR: 26%, EPR: 17%). In eight patients the residual tumour could be completely resected; seven patients became tumour free. At last follow-up 12 patients were alive (six with no evidence of disease, six with disease). PFS at 1year was 24%. Patients with relapse had a higher RR than patients with refractory disease (46% versus 8%) and patients with isolated lung lesions showed a better response than patients with other tumour localisations (50% versus 13%). The main grade 3-4 toxicities, diarrhoea and neutropenia, occurred in half of the patients. CONCLUSION: Irinotecan has a significant anti-tumour activity and acceptable toxicity in patients with relapsed hepatoblastoma and therefore should be considered for the treatment of these patients. Exploration of the role of irinotecan in the initial treatment of hepatoblastoma is warranted. PMID- 22835781 TI - The value of 3.0Tesla diffusion-weighted MRI for pelvic nodal staging in patients with early stage cervical cancer. AB - OBJECTIVE: The purpose of this study is to investigate the diagnostic accuracy of 3.0Tesla (3T) diffusion-weighted magnetic resonance imaging (MRI) in addition to conventional MRI for the detection of lymphadenopathy in patients with early stage cervical cancer compared to histopathological evaluation of the systematically removed pelvic lymph nodes as reference standard. METHODS: 68 federation internationale de gynecologie obstetrique (FIGO) stage Ia2 to IIb cervical cancer patients were included. Sensitivity and specificity rates for two experienced observers were computed for the detection of lymphatic metastasis. Reproducibility of conventional MRI was tested by kappa statistics. The variables included in the analysis were: size of the long axis, short axis, ratio short to long axis and apparent diffusion coefficient (ADC). RESULTS: Nine patients had 15 positive pelvic nodes at histopathological examination. The sensitivity and specificity of lymphatic metastasis detection by predefined conventional MRI characteristics was 33% (95% Confidence Interval (CI) 3-64) and 83% (95% CI 74 93) on patient level, and 33% (95% CI 7-60) and 97% (95% CI 95-99) on regional level respectively for observer 1. For observer 2 the sensitivity was 33% (95% CI 3-64) and the specificity 93% (95% CI 87-100) on patient level, and 25% (95% CI 1 50) and 98% (95% CI 97-100) on regional level, respectively. The kappa-value for reproducibility of metastasis detection on regional level was 0.50. The short axis diameter showed the highest diagnostic accuracy (area under the curve (AUC)=0.81 95% CI 0.70-0.91); ADC did not improve diagnostic accuracy (AUC=0.83 95% CI 0.73-0.93). CONCLUSIONS: Diffusion-weighted MRI did not result in additional diagnostic value compared to conventional MRI. PMID- 22835782 TI - Long-term treatment outcome of recurrent nasopharyngeal carcinoma treated with salvage intensity modulated radiotherapy. AB - PURPOSE: To evaluate the long-term treatment outcome in patients with recurrent nasopharyngeal carcinoma (NPC) treated with salvage intensity modulated radiotherapy (IMRT). MATERIALS AND METHODS: One hundred and fifty one previously irradiation NPC patients with recurrent disease and re-irradiated by IMRT between 2001 and 2006 had been reviewed. The disease was re-stage I in 7, re-stage II in 21, re-stage III in 50 and re-stage IV in 73. Thirty-seven patients received concurrent chemotherapy, 39 had induction chemotherapy and 75 had radiotherapy alone. RESULTS: All patients completed the planned IMRT. The median volume of the recurrent gross target volume of nasopharynx (rGTVnx) was 42.2 cm(3) (range 1.5 146.3 cm(3)). The median mean re-irradiation dose to the rGTVnx was 70.4Gy (range 62.1-77.6Gy). The median follow-up time after re-irradiation was 40.0 months (range 1.9-116.9 month). The 5-year local control rate (LCR) and overall survival rate (OS) for re-stage I, II, III, IV were 80.0%, 85.0%, 80.0%, 78.7% and 71.4%, 62.9%, 35.5%, 30.2%, respectively. Multivariate analysis indicated that rT classification (hazard ratio (HR), 2.02; 95%confidence interval (CI), 1.03-3.97; P=0.04) and the volume of rGTVnx (HR, 2.05; 95%CI, 1.31-3.22; P<0.01) were independent predictors for OS. Patients (39.0%) with re-stage III or IV disease experienced Grade 3 or 4 late toxicities. CONCLUSION: Re-irradiation by IMRT for recurrent NPC resulted in encouraging local control. The clinical outcome for patients with early re-stage diseases was satisfactory. Further investigations, focus on optimising radiation dose and establishing effective treatment strategies, are warranted for advanced recurrent disease in order to improve overall survival and minimise late toxicity. PMID- 22835783 TI - Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. AB - BACKGROUND: Previous studies have reported a poor outcome for synovial sarcoma patients whose tumours relapse. METHODS: This study analysed 44 relapsing cases in a series of 118 consecutive patients <21 yr of age with non-metastatic synovial sarcoma prospectively enrolled in Italian paediatric protocols between 1979 and 2006. In an effort to identify a possible risk-adapted stratification enabling a better planning of second-line treatment, the relapsing patients' outcome was analysed vis-a-vis their clinical picture at onset, first-line treatments, clinical findings at the time of first relapse and second-line treatment modalities. RESULTS: The first event was a local recurrence in only 15 cases, and metastatic in 29 (associated with local relapse too in 7 cases). The time to relapse ranged from 4 to 108 months (median 20 months). Overall survival was 29.7% and 21.0% five and ten years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (combined) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. CONCLUSIONS: Our study confirmed a largely unsatisfactory prognosis after recurrences in children and adolescents with synovial sarcoma: the chances of survival can be estimated on the basis of several variables for the purposes of planning risk-adapted salvage protocols. An aggressive surgical approach should be recommended. New effective systemic agents are warranted, and experimental therapies can be offered to patients with little chance of salvage. PMID- 22835784 TI - Sphingolipids: critical players in Alzheimer's disease. AB - Alzheimer's disease is characterized by the progressive accumulation of extracellular deposits of the amyloid beta-peptide (Abeta) and intraneuronal aggregates of the microtubule associated protein tau. Strong genetic, biochemical and cell biological evidence indicates critical roles of Abeta in the initiation of the pathogenic process, while tau might mediate its toxicity and neurodegeneration. Abeta is generated by proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases. Alternatively, APP can also be cleaved by alpha-secretase within the Abeta domain, thereby precluding subsequent production of Abeta. APP and the three secretases are integral membrane proteins and follow secretory and endocytic trafficking pathways. Thus, the membrane lipid composition could play important roles in trafficking and metabolism of Alzheimer's disease related proteins. Sphingolipids and especially complex gangliosides are abundant and characteristic components of neuronal membranes. Together with cholesterol, they confer unique characteristics to membrane domains, thereby regulating subcellular trafficking and signaling pathways. Thus, sphingolipids emerged to important modulators of biological processes including cell growth, differentiation, and senescence. Defects in sphingolipid catabolism are long known to cause severe lysosomal storage disorders, often characterized by neurological phenotypes. In recent studies it became evident that impaired sphingolipid metabolism could also be involved in Alzheimer's disease. PMID- 22835785 TI - Cryptococcus. PMID- 22835786 TI - Endosymbiosis. AB - The phenomenon of endosymbiosis, or one organism living within another, has deeply impacted the evolution of life and continues to shape the ecology of countless species. Traditionally, biologists have viewed evolution as a largely bifurcating pattern, reflecting mutations and other changes in existing genetic information and the occasional speciation and divergence of lineages. While lineage bifurcation has clearly been important in evolution, the merging of two lineages through endosymbiosis has also made profound contributions to evolutionary novelty. Mitochondria and chloroplasts are relicts of ancient bacterial endosymbionts that ultimately extended the range of acceptable habitats for life by allowing hosts to thrive in the presence of oxygen and to convert light into energy. Today, the sheer abundance of endosymbiotic relationships across diverse host lineages and habitats testifies to their continued significance. PMID- 22835787 TI - Selfish-herd behaviour of sheep under threat. AB - Flocking is a striking example of collective behaviour that is found in insect swarms, fish schools and mammal herds. A major factor in the evolution of flocking behaviour is thought to be predation, whereby larger and/or more cohesive groups are better at detecting predators (as, for example, in the 'many eyes theory'), and diluting the effects of predators (as in the 'selfish-herd theory') than are individuals in smaller and/or dispersed groups. The former theory assumes that information (passively or actively transferred) can be disseminated more effectively in larger/cohesive groups, while the latter assumes that there are spatial benefits to individuals in a large group, since individuals can alter their spatial position relative to their group-mates and any potential predator, thus reducing their predation risk. We used global positioning system (GPS) data to characterise the response of a group of 'prey' animals (a flock of sheep) to an approaching 'predator' (a herding dog). Analyses of relative sheep movement trajectories showed that sheep exhibit a strong attraction towards the centre of the flock under threat, a pattern that we could re-create using a simple model. These results support the long-standing assertion that individuals can respond to potential danger by moving towards the centre of a fleeing group. PMID- 22835788 TI - Bats eavesdrop on the sound of copulating flies. AB - The idea that copulation might increase predation risk is a classic suggestion, but empirical evidence to support it is surprisingly scarce. While some early work found decreased vulnerability to predation during mating, two lab and one very recent field study documented increased predation during mating in freshwater amphipods, water striders and locusts. Decreased vigilance, less efficient escape responses, and increased conspicuousness of mating pairs have been suggested as mechanisms that might underpin elevated predation risk during copulation. However, these putative mechanisms have never been investigated empirically. Here we describe a bat-insect system within which copulation greatly increases predation risk. We experimentally demonstrate that wild Natterer's bats (Myotis nattereri) 'eavesdrop' on acoustic cues emanating from copulating flies (Musca domestica) in a cowshed (). With this evidence, we pinpoint increased conspicuousness as a relevant mechanism for elevated predation risk during mating. PMID- 22835789 TI - Visual neuroscience: how flies segregate moving objects from the optic flow field. AB - Moving animals often have difficulty detecting moving objects because self generated optic flow patterns confound image motion. The new hypothesis of 'regressive motion salience' reveals simple rules used by fruit flies. PMID- 22835790 TI - Cell polarity: overdosing on PCPs. AB - Several spatial cues combine to influence cell polarity within the plane of the Drosophila wing epithelium, orienting two separable mechanisms of short-range intercellular communication, one utilizing the 'core' polarity proteins, and another utilizing the protocadherins Dachsous and Fat, and the atypical myosin Dachs. PMID- 22835791 TI - Circadian biology: a 2.5 billion year old clock. AB - A recent study suggests that circadian clocks may have evolved at the time of the Great Oxidation Event 2.5 billion years ago in order to drive detoxification of reactive oxygen species. PMID- 22835792 TI - Visual system: prostriata--a visual area off the beaten path. AB - Recent work establishes that Prostriata, a little-studied area of the visual cortex neighboring V1, has distinct but hybrid visual properties which are suggestive of an unsuspected role in the rapid analysis and integration of peripheral visual stimuli. PMID- 22835793 TI - Neural tube closure: the curious case of shrinking junctions. AB - Your brain and spinal cord began as a flat sheet, which narrowed, elongated, and rolled up to form a tube. A new study identifies a key molecular link underlying vertebrate neural tube formation, connecting planar cell polarity patterning to contraction of specific cell-cell junctions. PMID- 22835794 TI - Vesicle trafficking: ROP-RIC roundabout. AB - Mechanisms governing dynamic protein recycling include small GTPases that activate/inactivate their partner proteins to affect cytoskeletal dynamics, and thereby polar growth, asymmetric cell shape and physiological responses to external stimuli. Three recent studies illustrate the control of PIN endocytosis by ROP-RIC activity in leaf pavement cells and root cells. PMID- 22835795 TI - Stem cell niches: famished Paneth cells, gluttonous stem cells. AB - Adult tissue stem cells adjust to environmental changes. A new study in the mouse intestine reveals that caloric restriction causes Paneth cells to repress mTORC1 signaling; this in turn stimulates proliferation of neighboring stem cells. PMID- 22835796 TI - Epinephrine autoinjector warning. PMID- 22835797 TI - Using the 6-minute walk test for screening summit success on Mount Aconcagua. PMID- 22835798 TI - In tribute to James A. Wilkerson III, MD. PMID- 22835801 TI - Morbidity pattern of the 27th Indian Indian Scientific Expedition to Antarctica. AB - OBJECTIVE: To evaluate morbidity prototype of 27th Indian Scientific Expedition to Antarctica (ISEA). METHODS: Twenty-six team members of 27th ISEA wintered over at the Indian Antarctic Station, Maitri, from February 2008 to January 2009. The morbidity pattern was sourced from the medical records. Preexisting illnesses were also considered in this analysis. RESULTS: The team consisted of men between 27 and 59 years of age (mean age, 43 years). Nine team members had preexisting illnesses. A total of 93 illness incidents were recorded during the stay in Antarctica. Most of these (27) were musculoskeletal injuries, bruises, and lacerations. Thirty-two (34%) incidents of illness were noted under the purview of medicine; 26 (28%), surgery; 15 (16%), orthopedics; 9 (10%), otorhinolaryngology; 8 (9%), ophthalmology; 2 (2%), dentistry; and 3 (3%), psychiatry. Oral ulcers were noted in 8 (8%) participants primarily during early wintering. CONCLUSIONS: Injuries continue to be the most common cause of morbidity in Antarctica. Nutritional deficiencies and cold-related injuries are relatively less common. PMID- 22835802 TI - Frostbite and other cold injuries in the heroic age of Antarctic exploration. AB - Frostbite and other cold injuries on the early polar expeditions were common. This paper explains how frostbite was described, prevented, and treated on the Antarctic expeditions of the heroic age, comparing them with modern recommendations. Nonfreezing cold injury probably also occurred but was not differentiated from frostbite, and chilblains were also described. PMID- 22835803 TI - Soft tissue foreign body removal technique using portable ultrasonography. AB - Retained foreign objects account for as much as 2% of soft tissue injuries sustained in the wilderness. Subcutaneously embedded fragments are often missed during the initial medical evaluation and may result in morbidity secondary to delayed removal. Although the utility of ultrasonography in the emergency department for the detection of retained objects is established, the potential use of point-of-care ultrasound to aid with foreign body removal in the field has not been well described. We present 2 case reports that demonstrate the value of ultrasonography in detecting and successfully removing foreign bodies sustained in the wilderness, and outline a procedural technique that minimizes morbidity and uses equipment available in wilderness medical field kits. We propose that with the advent of portable and handheld ultrasound units, foreign body removal in the field has become feasible and may decrease the morbidity of soft tissue injuries, particularly in austere and wilderness environments with limited access to immediate medical care. PMID- 22835805 TI - Compassionate allowance for people with schizophrenia? PMID- 22835804 TI - The effects of combining Web-based eHealth with telephone nurse case management for pediatric asthma control: a randomized controlled trial. AB - BACKGROUND: Asthma is the most common pediatric illness in the United States, burdening low-income and minority families disproportionately and contributing to high health care costs. Clinic-based asthma education and telephone case management have had mixed results on asthma control, as have eHealth programs and online games. OBJECTIVES: To test the effects of (1) CHESS+CM, a system for parents and children ages 4-12 years with poorly controlled asthma, on asthma control and medication adherence, and (2) competence, self-efficacy, and social support as mediators. CHESS+CM included a fully automated eHealth component (Comprehensive Health Enhancement Support System [CHESS]) plus monthly nurse case management (CM) via phone. CHESS, based on self-determination theory, was designed to improve competence, social support, and intrinsic motivation of parents and children. METHODS: We identified eligible parent-child dyads from files of managed care organizations in Madison and Milwaukee, Wisconsin, USA, sent them recruitment letters, and randomly assigned them (unblinded) to a control group of treatment as usual plus asthma information or to CHESS+CM. Asthma control was measured by the Asthma Control Questionnaire (ACQ) and self reported symptom-free days. Medication adherence was a composite of pharmacy refill data and medication taking. Social support, information competence, and self-efficacy were self-assessed in questionnaires. All data were collected at 0, 3, 6, 9, and 12 months. Asthma diaries kept during a 3-week run-in period before randomization provided baseline data. RESULTS: Of 305 parent-child dyads enrolled, 301 were randomly assigned, 153 to the control group and 148 to CHESS+CM. Most parents were female (283/301, 94%), African American (150/301, 49.8%), and had a low income as indicated by child's Medicaid status (154/301, 51.2%); 146 (48.5%) were single and 96 of 301 (31.9%) had a high school education or less. Completion rates were 127 of 153 control group dyads (83.0%) and 132 of 148 CHESS+CM group dyads (89.2%). CHESS+CM group children had significantly better asthma control on the ACQ (d = -0.31, 95% confidence limits [CL] -0.56, 0.06, P = .011), but not as measured by symptom-free days (d = 0.18, 95% CL 0.88, 1.60, P = 1.00). The composite adherence scores did not differ significantly between groups (d = 1.48%, 95% CL -8.15, 11.11, P = .76). Social support was a significant mediator for CHESS+CM's effect on asthma control (alpha = .200, P = .01; beta = .210, P = .03). Self-efficacy was not significant (alpha = .080, P = .14; beta = .476, P = .01); neither was information competence (alpha = .079, P = .09; beta = .063, P = .64). CONCLUSIONS: Integrating telephone case management with eHealth benefited pediatric asthma control, though not medication adherence. Improved methods of measuring medication adherence are needed. Social support appears to be more effective than information in improving pediatric asthma control. TRIAL REGISTRATION: Clinicaltrials.gov NCT00214383; http://clinicaltrials.gov/ct2/show/NCT00214383 (Archived by WebCite at http://www.webcitation.org/68OVwqMPz). PMID- 22835807 TI - Mirror neuron dysfunction-a neuro-marker for social cognition deficits in drug naive schizophrenia. PMID- 22835806 TI - Psychotic symptoms and gray matter deficits in clinical pediatric populations. AB - BACKGROUND: Neuroanatomic studies have not yet addressed how subtle phenotypic distinctions in psychosis alter the underlying brain changes, and whether there is evidence for psychosis as a dimensional construct. We explored the relationship of cortical GM thickness to psychotic phenotypes in children. METHODS: Cross-sectional comparison of anatomic brain imaging between patients referred as childhood-onset schizophrenia (COS) but ruled out after a drug free inpatient observation. Groups included: patients with no evidence of psychosis (n=22) after drug free observation, patients with psychosis not otherwise specified (PNOS; total n=29) further divided into those without other axis I diagnoses (n=13) and those with other axis I comorbidities (n=16), age/sex matched COS patients (n=48), and 51 matched healthy controls. GM cortical thickness was compared between the groups, and regressed on patients' SAPS, SANS and GAS scores. RESULTS: Patients with no evidence of psychosis showed no cortical GM deficits. Presence of psychosis (PNOS with or without co-morbidities) showed some areas of temporal and prefrontal deficits, more subtle compared to the extensive bilateral cortical deficits seen for COS. GAS SAPS and SANS scores showed a relationship with cortical GM thickness although it did not survive adjustment for multiple comparisons. CONCLUSIONS: These results highlight the need for careful phenotypic characterization, as subtle diagnostic distinctions appear to reflect distinct underlying patterns of brain deficits. The incremental nature of cortical deficits from no psychosis to PNOS to COS may further support dimensional model for psychosis. PMID- 22835808 TI - Visual perception during mirror gazing at one's own face in schizophrenia. AB - BACKGROUND: In normal observers gazing at one's own face in the mirror for some minutes, at a low illumination level, triggers the perception of strange faces, a new perceptual illusion that has been named 'strange-face in the mirror'. Subjects see distortions of their own faces, but often they see monsters, archetypical faces, faces of dead relatives, and of animals. METHODS: We designed this study to primarily compare strange-face apparitions in response to mirror gazing in patients with schizophrenia and healthy controls. The study included 16 patients with schizophrenia and 21 healthy controls. In this paper we administered a 7 minute mirror gazing test (MGT). Before the mirror gazing session, all subjects underwent assessment with the Cardiff Anomalous Perception Scale (CAPS). When the 7minute MGT ended, the experimenter assessed patients and controls with a specifically designed questionnaire and interviewed them, asking them to describe strange-face perceptions. RESULTS: Apparitions of strange-faces in the mirror were significantly more intense in schizophrenic patients than in controls. All the following variables were higher in patients than in healthy controls: frequency (p<.005) and cumulative duration of apparitions (p<.009), number and types of strange-faces (p<.002), self-evaluation scores on Likert-type scales of apparition strength (p<.03) and of reality of apparitions (p<.001). In schizophrenic patients, these Likert-type scales showed correlations (p<.05) with CAPS total scores. CONCLUSIONS: These results suggest that the increase of strange-face apparitions in schizophrenia can be produced by ego dysfunction, by body dysmorphic disorder and by misattribution of self-agency. MGT may help in completing the standard assessment of patients with schizophrenia, independently of hallucinatory psychopathology. PMID- 22835809 TI - Misdiagnosis of cystic fibrosis: experience from Germany. AB - BACKGROUND: Misdiagnosis of cystic fibrosis (CF) is rare. We investigated patients with misdiagnoses of CF in Germany, and compared patients diagnosed before and after 1990. METHODS: We analysed data from the German CF quality assurance project and rechecked the data with CF-centre directors. RESULTS: Between 1989 and 2004, CF diagnoses were withdrawn in 51 patients after 5.79 years (median), whose diagnosis was based on nonspecific symptoms between 1979 and 2001 at the median age of 4.33 years. CF transmembrane conductance regulator (CFTR) dysfunction was indicated by unreliable sweat tests (45.1%), pathologic sweat chloride (37.3%), genetic tests (3.9%), and nasal potential difference measurements (13.1%). Patients diagnosed after 1990 were older (6.13 vs 1.21 years), more frequently fulfilled the diagnostic criteria (77.4% vs 20%) and experienced respiratory symptoms (83.9% vs 50%). CONCLUSIONS: To detect misdiagnoses of CF, CF-centres should re-evaluate patients with atypical courses and new or transferred patients. PMID- 22835810 TI - Garlic extract attenuating rat liver fibrosis by inhibiting TGF-beta1. AB - BACKGROUND & AIMS: We previously demonstrated the efficacy of garlic extract (GE) in the prevention of rat liver fibrosis by inhibiting tissue transglutaminase (tTG) activity. In the present study we aimed to evaluate the potential of GE in the regression of liver fibrosis and the underlining mechanism. METHODS: Male Wistar rats were i.p. injected, twice a week, for 7 weeks, with CCl(4) to develop liver fibrosis. Successively, a group was immediately sacrificed, while the remaining two groups received the GE or the vehicle, respectively, over the following 2 wks. A group of normal rats was also included in the study. Liver function, histology, and collagen deposition in parallel with gene and protein expression of alpha-SMA, tTG, TGF-beta1, SEMA-7A, and metalloproteinase inhibitor 1 (TIMP1) as well as measure of active by total TGF-beta1 were assessed. RESULTS: CCl(4) administration increased alanine-aminotransferase (ALT) activity, hepatic collagen deposition and gene and protein expression of all monitored markers. GE, but not the sole vehicle, restored liver histology and function by decreasing fibrogenesis markers (alpha-SMA, tTG, TGF-beta1, SEMA-7A and TIMP1). Active by total TGF-beta1 was significantly reduced (p < 0.05) in GE treated rats compared to the CCl(4) at 7 weeks, and vehicle rats. CONCLUSIONS: These findings concurrently suggested that GE elicited therapeutic effect against liver fibrosis. Regression of liver fibrosis occurred by reducing myofibroblasts (through modulation of HSCs activation mechanisms), remodelling extracellular matrix (through increase of its degradation) and regenerating liver tissue and functions: three processes regulated by fine mechanisms where active TGF-beta1 and tTG play a central role. PMID- 22835811 TI - On the role of the type III phosphate transporters in vascular calcification. PMID- 22835812 TI - Pre- and postsynaptic serotonergic differences in males with extreme levels of impulsive aggression without callous unemotional traits: a positron emission tomography study using (11)C-DASB and (11)C-MDL100907. AB - BACKGROUND: Impulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders. METHODS: Healthy male subjects (mean age 34 +/- 9 years) without high CU traits were recruited with IA ratings in the high (n = 14) and low (n = 13) population extremes. Serotonin transporter (SERT) and 5 HT(2A) receptor availability was measured in multiple brain regions using positron emission tomography with (11)C-DASB and (11)C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT(2A) receptor availability, impulsivity and aggression, and childhood adversity. RESULTS: Compared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% +/- 11.4%) and modestly lower across cortical regions (by 11.1% +/- 6.0%), whereas 5 HT(2A) receptors were also modestly lower (by 8.6% +/- 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma (r = .76 in midbrain). CONCLUSIONS: Pre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional behavioral control. PMID- 22835813 TI - Cytotoxicity and acetylcholinesterase inhibitory activity of an isolated crinine alkaloid from Boophane disticha (Amaryllidaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Boophane disticha of the family Amaryllidaceae is used traditionally in southern Africa in the treatment of several neurological disorders. AIM OF THE STUDY: Although acetylcholinesterase (AChE) inhibitory activity has been reported for this plant, the aim of the study was to identify and characterise the compound responsible for this activity using bioassay guided fractionation. Toxicity of the isolated compound was also assessed. MATERIALS AND METHODS: Bioassay guided isolation of the active compound from the methanol extract was carried out using column chromatography, TLC and preparative thin layer chromatography. Structural elucidation was carried out using high field 1D and 2D NMR and mass spectroscopy. AChE inhibitory activity was determined using the Ellman's colorimetric method. Cytotoxicity assessment was determined in human neuroblastoma (SH-SY5Y) cells using the MTT and neutral red uptake assays. RESULTS: The data obtained from the integration of the (1)H spectra confirmed the compound to be a 3:1 mixture of two epimers, with epimer A, 6alpha hydroxycrinamine as the major epimer. The IC(50) value for AChE inhibitory activity of the compound was 445 MUM. The compound was observed to be cytotoxic in both the MTT and neutral red assays with IC(50) values of 54.5 and 61.7 MUM, respectively. CONCLUSION: The present study describes for the first time, the isolation of 6-hydroxycrinamine, a crinine alkaloid, from the methanol extract of the bulbs of B. disticha. Although this compound possessed AChE inhibitory activity, it was found to be toxic to the neuroblastoma cells. Quantitative structure-activity relationship studies could be carried out to modify the structure in order to make it less toxic and improve its activity. PMID- 22835814 TI - Apocynum venetum leaf extract, an antihypertensive herb, inhibits rat aortic contraction induced by angiotensin II: a nitric oxide and superoxide connection. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves extract of Apocynum venetum (AVLE), also known as "luobuma", have long been used in traditional Chinese medicine to treat hypertension and depression in parts of China and it has been shown to possess anti-oxidant and anti-lipid peroxidation effects. AVLE (10 MUg/ml) has been reported to have a long-lasting endothelium-dependent relaxant effect and this effect has been proposed to be due to its nitric oxide(NO)-releasing and superoxide anion(SOA)-scavenging properties. AIM OF THE STUDY: The present study seeks to evaluate the differential actions of AVLE extract between Ang II- and PE induced vasoconstriction and the involvement of superoxide anions. MATERIALS AND METHODS: Single dose of Ang II (100 nM and 1 nM)- or PE (0.1 MUM)-induced contraction were assessed in both endothelium-intact and -denuded aortic rings after pre-incubation of AVLE (10 MUg/ml) for 15 min. The experiment was repeated in either the presence of NO synthase inhibitor, L-NAME (300 MUM) or selective AT(1) receptor inhibitor, losartan (0.1 nM), or superoxide scavenger, tiron (1 mM) or a combination of L-NAME and AVLE. Superoxide production was measured by using enhanced-chemiluminescence assay. RESULTS: We have demonstrated that AVLE (10 MUg/ml) effectively suppressed the Ang II-induced contraction (100 nM and 1 nM) of both endothelium-intact and -denuded rat aortic rings. In endothelium intact rings, L-NAME, reversed AVLE-induced inhibition of Ang II-contraction. PE induced contraction was significantly inhibited by AVLE in endothelium-intact rings, but not in endothelium-denuded rings. The inhibition by AVLE of PE-induced contraction was totally abolished in the presence of L-NAME. Ang II-induced SOA production concentration dependently with the optimal effect seen at 100 nM of Ang II, and AVLE (0.3, 1, 10 MUg/ml) reduced this effect. SOA production in Ang II-stimulated rings was significantly higher than unstimulated control rings, while PE did not stimulate SOA production at all. SOA formation in the presence of Ang II was also inhibited in the presence of SOD (superoxide scavenger), DPI (NADPH inhibitor) and losartan (specific AT(1) receptor antagonist). CONCLUSION: These results collectively suggest that the ability of AVLE in inhibiting Ang II induced contraction via its SOA scavenging properties and nitric oxide releasing effect may account for its usage as an antihypertensive treatment in traditional folk medicine. PMID- 22835815 TI - Quantitative ethnobotany of traditional Siddha medical practitioners from Radhapuram taluk of Tirunelveli District, Tamil Nadu, India. AB - ETHNOBOTANICAL RELEVANCE: The aim of the present study was to document the knowledge of traditional Siddha medical practitioners from Radhapuram taluk of Tirunelveli district in Tamil Nadu, India, and to quantitatively analyze the data to identify some useful leads for further studies. MATERIALS AND METHODS: Successive free listing was the method adopted for the interview. In this study, 84 traditional Siddha medical practitioners were included and their knowledge on medicinal plants was gathered. The data were assessed with the help of two indices viz., Informant Consensus Factor (F(ic)) and Informant Agreement on Remedies (IAR). RESULTS: The present survey is in accordance with some of the aspects of our previous surveys. Regarding the demography of the informants, it exhibited unevenness in male-female ratio and majority of the informants were poorly educated. Practicing this system of medicine as part time job by majority of the informants might indicate the reduced social status of this medicinal system. The present study had recorded the usage of 217 species which were used to prepare 448 formulations, which in turn yielded 812 use reports. Conversion of use reports had yielded a total of 625 claims and 84.16% of the claims were 'singletons'. The illness category 'adjuvants' holds a high F(ic) value. Among the other illness categories, kapha ailments and dermatological ailments have a high percentage of use-reports. Ailments of blood, jaundice and fever were the other illness categories with high F(ic) values. Some of the claims viz., Mukia madarasepatana (kapha ailments), Mollugo nudicaulis (febrifuge), Indigofera asphalathoides (dermatological ailments), Aerva lanata (urinary ailments), Abutilon indicum (hemorrhoids) and Hybanthus enneaspermus (aphrodisiac), which have relatively high consensus can be taken up for further biomedical studies, since no substantial studies have been conducted on them. CONCLUSION: One of the major aims of National Rural Health Mission is to implement traditional Indian system of medicines into the main stream. In such scenario, scientific validation of community-based local health traditions becomes necessary for their rational implementation. Through this study we have highlighted some claims which are at high use in the study area but having little scientific support. Studies on such claims will provide scientific base which in turn will be useful to improve the health of indigenous people. PMID- 22835816 TI - A new method of medial epicanthoplasty for patients with blepharophimosis-ptosis epicanthus inversus syndrome. AB - PURPOSE: To describe a medial epicanthoplasty technique using the skin redraping method and review the surgical outcome in patients with blepharophimosis-ptosis epicanthus inversus syndrome (BPES). DESIGN: Retrospective, noncomparative, interventional case series with the description of a new surgical technique. PARTICIPANTS: Sixteen consecutive Asian patients with BPES. METHODS: The charts of patients with BPES who underwent medial epicanthoplasty using the skin redraping method were reviewed retrospectively. Preoperative and postoperative inner intercanthal distance (IICD), interpupillary distance (IPD), horizontal palpebral fissure length (HPFL), and visibility of the scar were measured. The ratio of the IICD to IPD (IICD ratio) was calculated. MAIN OUTCOME MEASURES: Postoperative improvement in IICD ratio and the visibility of the surgical scar. RESULTS: The preoperative median IICD ratio was 1.65 (range, 1.49-1.83) and decreased to 1.27 (range, 1.02-1.48) postoperatively. The median reduction in IICD ratio was 21.7% (range, 16.7%-38.2%) (P<0.001, Wilcoxon signed-rank test). Fourteen patients (87.5%) had no visible scarring or scarring only visible under close inspection. Two patients (12.5%) had a more apparent scar, but no patient had severe scarring that required revision. CONCLUSIONS: Medial epicanthoplasty using the skin redraping method is an effective technique in the treatment of epicanthus inversus and telecanthus in patients with BPES, with excellent cosmetic outcomes. PMID- 22835817 TI - Co-phylogeography and morphological evolution of sika deer lice (Damalinia sika) with their hosts (Cervus nippon). AB - Lice are obligate parasites of mammals and birds and have become an important model for studies of host-parasite co-evolution and co-phylogenetics. Population genetic and phylogeographic studies represent an important bridge between microevolution and co-phylogenetic patterns. We examine co-phylogeographic patterns in sika deer and their parasitic lice. Co-phylogeographic patterns in deer and lice were evaluated using homologous regions of mitochondrial COI sequences. The phylogeographic breaks recovered for deer populations matched those of previous studies. Comparisons of the phylogeographic tree topology for deer lice with that of their hosts revealed a significant level of congruence. However, comparisons of genetic distances between deer and lice suggested that one of the estimated co-divergence events is more likely a recent host switch. Taking into account genetic divergence, there is not strong evidence for complete phylogeographic co-divergence between deer and their parasitic lice. However, mitochondrial phylogenies only track genetic structure of female lineages, and the incongruence between deer and louse phylogeography may be explained by louse migration mediated by male deer. Morphological analysis of head shape variation based on an elliptic Fourier descriptor showed that overall morphological variation contained phylogenetic signal, suggesting that in general morphology of these lice evolves congruent to population history. PMID- 22835818 TI - Second site mutation in the virus envelope expands the host range of a cytopathic variant of Moloney murine leukemia virus. AB - Spl574 MLV (murine leukemia virus) is a variant of Moloney ecotropic MLV (MoMLV) that is cytopathic in Mus dunni cells and restricted by other mouse cells. Its host range and cytopathicity are due to a mutation, S82F, at a site critical for binding to the CAT-1 receptor. To identify residues that affect affinity for receptor variants, virus with S82F was passed in restrictive cells. The env genes of the adapted viruses contained 18 novel mutations, including one, E114G, present in 6 of 30 sequenced envs. MoMLV-E114G efficiently infected all mouse cells as well as ecotropic MLV resistant Chinese hamster cells. Virus with E114G and S82F induced large multinucleated syncytia in NIH 3T3 and SC-1 cells as well as M. dunni cells. Inoculation of Mo-S82F,E114G into mice produced lymphomas typical of MoMLV. Residues at env position 114 are thus important determinants of host range, and E114G suppresses host range restriction due to S82F, but does not affect S82F-governed cytopathicity. PMID- 22835819 TI - Publication criteria for evoked magnetic fields of the human brain: a proposal. AB - Magnetoencephalography (MEG) is a record of the magnetic fields produced by the electrical activities of the brain using MEG systems. There are three types of sensors for MEG systems: magnetometer and two types of gradiometer. Among them, two types of gradiometer, axial and planar, have been used worldwide. Unfortunately, the waveforms recorded by the two types of gradiometer are often different from each other. This poses a serious problem in comparing and evaluating the data from the two gradiometers. We consider that the MEG study should be published in a way that allows other workers using different types of gradiometer to evaluate and replicate the results of MEG studies. There have been, however, no publication criteria for reports of studies on stimulus-evoked or event-related magnetic fields in human subjects. In this article, we propose publication criteria for evoked or event-related magnetic fields of the human brain: original waveforms of selected channels covering a region of interest, a root mean-squared (RMS) waveform and a contour map at an appropriate time. PMID- 22835820 TI - Sex differences in attentional processes in adult rats as measured by performance on the 5-choice serial reaction time task. AB - The goal of the current study was to explore sex differences in attentional processes in adult rats using a test of attention shown to be dependent upon the prefrontal cortex. Male and female adult Long-Evans rats were trained on the 5 choice serial reaction time task. This task requires rats to identify the location of a brief light stimulus among five possible locations. Performance was assessed under baseline conditions and under behavioral challenge conditions during which task difficulty was increased. Behavioral challenge conditions included shortening the stimulus duration, shortening the time before the onset of the stimulus, lengthening the time before the onset of the stimulus, and presenting a distracting noise. Analyses across baseline and all challenge conditions revealed that vigilance or sustained attention was more disrupted in female rats than it was in male rats, as measured by percent correct and number of omissions. Analyses also revealed that inhibitory control was more disrupted in male rats than it was in female rats, as measured by number of premature responses. These differences were most prominent when the onset of the stimulus was unpredictably lengthened. There were no differences in reward collection latency or correct response latency indicating no differences in motivation or sensory processes between the sexes. These results indicate that under challenging conditions adult female rats are more prone to make errors of vigilance than are adult male rats, and adult male rats are more prone to make errors of inhibitory control than are adult female rats. PMID- 22835821 TI - Factors influencing fluoxetine-induced sexual dysfunction in female rats. AB - Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined. Ovariectomized, Fischer rats were primed with 10 MUg estradiol benzoate and 500 MUg progesterone. Partner preference, active investigation of the male, and measures of sexual behavior were examined after injection with 15 mg/kg fluoxetine. Factors (pretesting for sexual behavior, size of the test arena, non-contact time with a male) that differ among experiments designed to study antidepressant-induced female rat sexual dysfunction were studied. The male preference ratio was not affected by fluoxetine treatment but active investigation of the male was reduced; lordosis behavior was inhibited and pretesting for sexual receptivity amplified fluoxetine's inhibition; size of the testing arena or non-contact experience with the male had no effect. Regardless of test condition, when given the opportunity to escape from the male, fluoxetine treated females displayed escape behavior. Measures of male preference and active investigation, but not lordosis behavior, appeared to be affected by fluoxetine's impact on activity. The collective data provided a behavioral profile of fluoxetine-induced sexual dysfunction. These findings reinforce the value of multiple measures when attempting to model antidepressant-induced female sexual dysfunction. PMID- 22835822 TI - Evaluation of neurobehavioral deficits following different severities of cerebral ischemia in rats: a comparison between the modified hole board test and the Morris water maze test. AB - OBJECTIVE: While histological injury following cerebral ischemia has been extensively characterized in rodents, evidence on the effects on executive functioning is still missing. This study was designed to evaluate neuropsychological outcome following different severities of cerebral ischemia in rats with the modified hole board test or the Morris water maze. SETTING: With institutional review board approval, anesthetized rats were exposed to bilateral carotid artery occlusion (BCAO) for escalating time intervals (0-12.5 min). Postoperatively cognitive performance was assessed using either the modified hole board test (mHB) or the Morris water maze (MWM). On postoperative day 14 rats were euthanized and intact neurons in five cerebral regions were counted. RESULTS: Rats of the 0 and 5 min groups showed normal functional outcome with mild histological damage after 5 min of BCAO. Following 7.5 min of BCAO the mHB test showed cognitive deficits reflecting histological damage of the hippocampus while the MWM revealed normal functional outcome. Rats of the 10 and 12.5 min groups showed cognitive deficits in both tests, motor dysfunction and behavioral alterations in the mHB test and profound histological damage. CONCLUSIONS: The results indicate that the mHB is not inferior to the MWM for the evaluation of cognitive impairment following incomplete forebrain ischemia in rats. As the mHB additionally investigates a variety of behavioral dimensions and motor parameters in the same test environment, it is advantageous for the evaluation of interacting and potentially confounding behavioral changes following cerebral ischemia in rats. PMID- 22835823 TI - Cryptoccocal meningitis and HIV in the era of HAART in Cote d'Ivoire. AB - OBJECTIVE: The authors had for aim to describe the management of cryptococcal meningitis in HIV infected adults, in Ivory Coast. PATIENTS AND METHODS: A retrospective study was made from January 1, 2005 to December 31, 2008 on the files of consecutive hospitalized patients presenting with cryptococcal meningitis, at the Treichville University Hospital, Infectious and tropical diseases department (Abidjan). The socio-demographic, clinical, and biological aspects as well as the outcome were analyzed. RESULTS: Eighty patients presenting with cryptococcal meningitis, (2.6% of hospitalized patients) were included: 41 men (51.25%) and 39 women (48.75%); mean age: 40 years (range 26 to 58 years). The delay before consultation was 5.4 days, range 2-12 days). The mains symptoms were headache (83.7%), fever (63.7%), and consciousness disorders (60%). Meningo encephalitis accounted for 75% of the clinical presentations; 54 patients (67.5%) were naive of antiretroviral treatment (mean CD4: 45/mm(3) (range 5-103/mm(3)), while 26 (32.5%) had received antiretrovirals before presenting with cryptococcal meningitis (Nadir CD4=81/mm(3)). Amphotericin B relayed by fluconazole was prescribed to 86.2% of the patients, associated with a therapeutic lumbar puncture for 30 patients. The death rate was 41.2%. CONCLUSION: In spite of antiretroviral treatment availability in Ivory Coast, cryptococcal meningitis remains frequent with a high death rate. This study stresses the importance of early management to improve the prognosis. PMID- 22835824 TI - The relationship between Cyclin G1 and survival in patients treated surgically for HCC. AB - BACKGROUND/AIM: Cyclin G1 is a cell-cycle-regulatory protein that is frequently seen in elevated amounts in malignant tissue, including astrocytomas; melanoma; carcinoma of the esophagus, lung, and breast; as well as cancer of the cervix, uterus, and ovary. By contrast, it has demonstrated inhibitory activity in human hepatocellular carcinoma (HCC). METHODOLOGY: We investigated the role of cyclin G1 in HCC tissue obtained from 76 donors using immunohistochemistry and Western blot analysis to explore its relationship with HCC pathology and univariate and multivariate analyses to explore its relationship with surgical prognosis and patient survival. RESULTS: We found that cyclin G1 levels were increased in normal tissue compared with HCC tissue and vary over the course of the cell cycle, with equal distribution between the nucleus and cytoplasm observed during normal serum support and accelerated release from the nucleus into the cytoplasm observed during serum starvation. CONCLUSION: Our findings suggest a role for cyclin G1 in anti-HCC gene therapy. PMID- 22835825 TI - Functional neuro-vascularized muscle transfer for oncological reconstruction of extremity sarcoma. AB - The strategy of limb salvage following surgical resection of skeletal tumor has led to an increased demand for more complex reconstructive options in order to achieve better functional outcomes. Functional neuro-vascularized muscle transfer (FMT) is a beneficial tool for restoring joint movement involving the reconstruction of "movement" in the affected extremity. Until now, however, the clinical application of FMT was mainly limited to trauma cases and to date, very few studies have focused on musculoskeletal oncology. In this study, we reviewed patients who underwent wide resection for extremity sarcoma and functional reconstruction using FMT and discussed the advantages, indications and complications of the procedure. PMID- 22835826 TI - Determination of 22 synthetic cannabinoids in human hair by liquid chromatography tandem mass spectrometry. AB - Herbal mixtures of the "Spice"-type contain a variety of synthetic cannabinoids. To prove the contact of a person with synthetic cannabinoids in a previous period of up to several months, hair testing is ideally suited. A rapid, simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to determine 22 synthetic cannabinoids in human hair. The synthetic cannabinoids JWH-007, JWH-015, JWH-018, JWH-019, JWH-020, JWH-073, JWH-081, JWH 122, JWH-200, JWH-203, JWH-210, JWH-250, JWH-251, JWH-398, AM-694, AM-2201, methanandamide, RCS-4, RCS-4 ortho isomer, RCS-8, WIN 48,098 and WIN 55,212-2 were extracted from 50 mg hair by 3-h ultrasonification in ethanol. The extracts were analysed on a triple-quadrupole linear ion trap mass-spectrometer in scheduled multiple reaction monitoring mode (sMRM). The method was fully validated and proved to be accurate, precise, selective and specific with satisfactory linearity within the calibrated range and a lower limit of quantification of 0.5 pg/mg for 20 compounds. Authentic hair samples from chronic consumers showed the presence of two to six synthetic cannabinoids in the same segment. In the first segment, concentrations of up to 78 pg/mg JWH-081 were present. In segmented hair, the concentrations of most substances increased from the first (proximal) to the third segment. The highest concentration was ca. 1100 pg/mg JWH-081. The results of segmental hair analysis in chronic users suggest incorporation of the drugs in head hair via side-stream smoke condensation as a major route. In summary, the method can be used to prove the contact with herbal mixtures containing synthetic cannabinoids and thus contributes to an efficient abstinence control. PMID- 22835827 TI - Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. AB - Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts a proangiogenic function in exercised skeletal muscle. Mdm2 hypomorphic (Mdm2(Puro/Delta7-9)) mice have a 60% reduction in Mdm2 expression compared with that in wild-type animals. Capillary staining on muscle sections from Mdm2(Puro/Delta7-9) sedentary mice with a wild-type or knockout background for p53 revealed that deficiency in Mdm2 resulted in 20% capillary regression independently of p53 status. In response to one bout of exercise, protein expression of the proangiogenic vascular endothelial growth factor-A (VEGF-A) was increased by 64% in muscle from wild-type animals, and endothelial cell outgrowth from exercised muscle biopsy samples cultured in a 3-dimensional collagen gel was enhanced by 37%. These proangiogenic responses to exercise were impaired in exercised Mdm2(Puro/Delta7-9) mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wild-type muscles. However, exercise training-induced angiogenesis was abolished in Mdm2(Puro/Delta7-9) mice. Finally, exercise training restored Mdm2, VEGF-A, and capillarization levels in skeletal muscles from obese Zucker diabetic fatty rats compared with those in healthy animals. Our results define Mdm2 as a crucial regulator of capillary maintenance and exercise-induced angiogenesis in skeletal muscle. PMID- 22835829 TI - Translation of Pur-alpha is targeted by cellular miRNAs to modulate the differentiation-dependent susceptibility of monocytes to HIV-1 infection. AB - The postentry restriction of HIV-1 replication in monocytes can be relieved when they differentiate to dendritic cells (DCs) or macrophages. Multiple mechanisms have been proposed to interpret the differentiation-dependent susceptibility of monocytes to HIV-1 infection, and the absence of host-cell-encoded essential factors for HIV-1 completing the life cycle may provide an explanation. We have analyzed the gene expression profile in monocytes by mRNA microarray and compared it with that of differentiated DCs. We demonstrated that purine-rich element binding protein alpha (Pur-alpha), a host-cell-encoded ubiquitous, sequence specific DNA- and RNA-binding protein, showed inadequate expression in monocytes, and the translation of Pur-alpha mRNA was repressed by cell-expressed microRNA (miRNA). These Pur-alpha-targeted miRNAs modulated the differentiation-dependent susceptibility of monocytes/DCs to HIV-1 infection, because rescue of Pur-alpha expression by transfection of miRNA inhibitors relieved the restriction of HIV-1 infection in monocytes, and ectopic input of miRNA mimics significantly reduced HIV-1 infection of monocyte-derived DCs (MDDCs). Collectively, our data emphasized that inadequate host factors contribute to HIV-1 restriction in monocytes, and cellular miRNAs modulate differentiation-dependent susceptibility of host cells to HIV-1 infection. Elaboration of HIV-1 restriction in host cells facilitates our understanding of viral pathogenesis and the search for a new antiviral strategy. PMID- 22835828 TI - T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy. AB - Autophagy, the cytoprotection mechanism that takes place under metabolic impairment, has been implicated in the pathogenesis of autoimmunity. Here, we investigated the spontaneous and induced autophagic behavior of T lymphocytes from patients with systemic lupus erythematosus (SLE) compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule associated protein 1 light chain 3 (LC3)-II. No significant differences in spontaneous autophagy were found between T lymphocytes from patients with SLE and from healthy donors, apart from CD4(+) naive T cells from patients with SLE in which constitutively higher levels of autophagy (P<0.001) were detected. At variance, whereas treatment of T lymphocytes from healthy donors with serum IgG from patients with SLE resulted in a 2-fold increase in LC3-II levels (P<0.001), T lymphocytes from SLE patients were resistant to autophagic induction and also displayed an up-regulation of genes negatively regulating autophagy, e.g., alpha synuclein. These findings could open new perspectives in the search for pathogenetic determinants of SLE progression and in the development of therapeutic strategies aimed to recover T-cell compartment homeostasis by restoring autophagic susceptibility. PMID- 22835830 TI - Accelerated aging of the GABAergic septohippocampal pathway and decreased hippocampal rhythms in a mouse model of Alzheimer's disease. AB - Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPP(Sw,Ind); J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal theta and gamma rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities. PMID- 22835831 TI - A structural and functional analysis of Nna1 in Purkinje cell degeneration (pcd) mice. AB - The axotomy-inducible enzyme Nna1 defines a subfamily of M14 metallocarboxypeptidases, and its mutation underlies the Purkinje cell degeneration (pcd) mouse. However, the relationship among its catalytic activity, substrate specificities, and the critical processes of neurodegeneration/axon regeneration is incompletely understood. Here we used a transgenic rescue strategy targeting expression of modified forms of Nna1 to Purkinje cells in pcd mice to determine structure-activity relationships for neuronal survival and in parallel characterized the enzymatic properties of purified recombinant Nna1. The Nna1 subfamily uniquely shares conserved substrate-determining residues with aspartoacylase that, when mutated, cause Canavan disease. Homologous mutations (D1007E and R1078E) inactivate Nna1 in vivo, as does mutation of its catalytic glutamate (E1094A), which implies that metabolism of acidic substrates is essential for neuronal survival. Consistent with reports that Nna1 is a tubulin glutamylase, recombinant Nna1-but not the catalytic mutants-removes glutamate from tubulin. Recombinant Nna1 metabolizes synthetic substrates with 2 or more C terminal glutamate (but not aspartate) residues (V(max) for 3 glutamates is ~7 fold higher than 2 glutamates although K(M) is similar). Catalysis is not ATP/GTP dependent, and mutating the ATP/GTP binding site of Nna1 has no effect in vivo. Nna1 is a monomeric enzyme essential for neuronal survival through hydrolysis of polyglutamate-containing substrates. PMID- 22835834 TI - Afferent units and somatic sensation. PMID- 22835833 TI - Development and application of a method for identification of isothiocyanate targeted molecules in colon cancer cells. AB - In this study, we have developed a novel method to identify isothiocyanate (ITC) targeted molecules using two well-studied ITCs: benzyl ITC (BITC) and phenethyl ITC (PEITC). The principle of this method is based on identifying a pattern of differences between BITC and PEITC given that they show similar chemical and biological behaviors. For method validation, dithiothreitol-reduced bovine insulin as a model molecule was incubated with either BITC or PEITC, and digested peptides were analyzed by ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) and liquid chromatography quadrupole TOF-MS (LC-Q TOF-MS). Three peptides-NYCN, FVNQHLCGSHLVE, and ALYLVCGE-were identified as being adducted with BITC or PEITC on their cysteine residues. Each set of peptides adducted with either BITC or PEITC showed retention times (RT(BITC)0.05). CONCLUSIONS: TNF alpha -308 polymorphic variants might be a predisposing factor for acne susceptibility, with no apparent relation to its severity whereas IL-10 -1082 variants showed no association with both acne susceptibility and severity. PMID- 22835836 TI - Impact of galvanic corrosion on lead release from aged lead service lines. AB - Partial lead service line replacement (PLSLR) may be performed when tap water lead concentrations exceed the action level and in association with water main replacement or other maintenance. Partially replacing lead pipes with copper tubing can create a galvanic couple if the lead and copper are connected by a metal coupling, which can potentially enhance lead release by galvanic corrosion. The effect of two types of couplings, brass and plastic, on lead release after a simulated PLSLR was investigated in a set of laboratory-scale experiments. Experiments were conducted in a recirculation flow mode with intermittent stagnation periods using aged lead pipes harvested from Providence, RI. Release of both dissolved and particulate lead was higher for the brass-coupled systems than for the plastic-coupled systems, and galvanic corrosion was the primary cause of significant particulate lead release from the brass-coupled systems. For brass-coupled systems, longer stagnation times resulted in dramatically more release of particulate lead. Sampling of different volumes following stagnation showed that lead release for the brass-coupled systems was locally much higher in the region closest to the coupling. The impact of galvanic corrosion persisted for the six weeks of the experiment. PMID- 22835837 TI - Nitrous oxide emission and nutrient removal in aerobic granular sludge sequencing batch reactors. AB - Application of aerobic granular sludge into wastewater treatment is promising due to its excellent settling ability and high microbial concentrations. However, its spatial structure could induce incomplete denitrification, leading to generation of nitrous oxide (N(2)O) - a potent greenhouse gas. Under the temperature of 14 +/- 4 degrees C, three identical laboratory-scale aerobic granular sludge sequencing batch reactors (SBRs) were established to treat synthetic wastewater simulating a mixture of liquid pig manure digestate and municipal wastewater at three aeration rates (0.2, 0.6 and 1.0 L air/min) and three COD:N ratios (1:0.22, 1:0.15 and 1:0.11). The studies show the proportions of N(2)O emission to the influent nitrogen loading rate at the aeration rates of 0.2, 0.6 and 1.0 L air/min were 8.2%, 6.1% and 3.8% at a COD:N ratio of 1:0.22; 7.0%, 5.1% and 3.5% at a COD:N ratio of 1:0.15; and 4.4%, 2.9% and 2.2% at a COD:N ratio of 1:0.11, respectively. With NO(2)(-) as the only nitrogen source in the liquid phase, the specific N(2)O generation rates via denitrification were 1.7, 1.6 and 1.3 MUg N(2)O/(g SS. min) at the aeration rates of 0.2, 0.6 and 1.0 L air/min, respectively, which were 40.9%, 44.8%, 39.9% higher than those with NO(3)(-) as the only nitrogen source, respectively. N(2)O generation by aerobic granular sludge due to NH(4)(+)-N nitrification was not sensitive to the aeration rate, and the average specific N(2)O generation rate was 0.8 +/- 0.02 MUg N(2)O/(g SS. min). PMID- 22835838 TI - Fate of dissolved organic nitrogen in two stage trickling filter process. AB - Dissolved organic nitrogen (DON) represents a significant portion of nitrogen in the final effluent of wastewater treatment plants (WWTPs). Biodegradable portion of DON (BDON) can support algal growth and/or consume dissolved oxygen in the receiving waters. The fate of DON and BDON has not been studied for trickling filter WWTPs. DON and BDON data were collected along the treatment train of a WWTP with a two-stage trickling filter process. DON concentrations in the influent and effluent were 27% and 14% of total dissolved nitrogen (TDN). The plant removed about 62% and 72% of the influent DON and BDON mainly by the trickling filters. The final effluent BDON values averaged 1.8 mg/L. BDON was found to be between 51% and 69% of the DON in raw wastewater and after various treatment units. The fate of DON and BDON through the two-stage trickling filter treatment plant was modeled. The BioWin v3.1 model was successfully applied to simulate ammonia, nitrite, nitrate, TDN, DON and BDON concentrations along the treatment train. The maximum growth rates for ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria, and AOB half saturation constant influenced ammonia and nitrate output results. Hydrolysis and ammonification rates influenced all of the nitrogen species in the model output, including BDON. PMID- 22835839 TI - An empirical investigation of the effectiveness of the broad-minded affective coping procedure (BMAC) to boost mood among individuals with posttraumatic stress disorder (PTSD). AB - The broaden-and-build theory postulates that positive emotions broaden people's cognitions and actions, and facilitate the building of personal and social resources which enhance resilience in a range of clinical populations. The Broad Minded Affective Coping procedure (BMAC) is a recently developed clinical technique which utilizes the recall of positive autobiographical memories and mental imagery to elicit positive affect. This study aims to investigate the ability of the BMAC to boost mood among 50 individuals diagnosed currently (n = 31) or previously (n = 19) with Posttraumatic Stress Disorder (PTSD). To assess mood, a series of Visual Analog Scales (VASs) and Likert scales measuring feelings of sadness, calmness, happiness, hopelessness, defeat and frustration were administrated at baseline, immediately following the completion of the BMAC and two hours and two days afterwards. Participants in the BMAC condition demonstrated greater increases in self-reported levels of positive emotions and greater reductions in self-reported levels of negative emotions following the BMAC technique compared to those in the control condition. The results suggest that the BMAC is a useful clinical technique which can be incorporated into other clinical interventions such as cognitive behavioral therapy to elicit positive affect and promote resilience. PMID- 22835840 TI - Moving beyond the trait conceptualization of self-esteem: the prospective effect of impulsiveness, coping, and risky behavior engagement. AB - Past research has largely focused on examining self-esteem as an independent as opposed to a dependent variable. At the same time, research suggests that during adolescence, self-esteem is subject to yearly, monthly, as well as daily change, and consequently, it is important to identify underlying vulnerability factors and behaviors, which shape self-esteem lability. In the current multi-wave, longitudinal study, 142 adolescents between the ages of 12-18 completed monthly assessments across 4 months. At the initial assessment, adolescents provided self report data pertaining to impulsiveness, maladaptive coping, risky behavior engagement, and self-esteem. At each of the follow-up assessments, adolescents provided information about risky behavior engagement and self-esteem. Results of time-lagged, idiographic multilevel mediation analyzes indicated that risky behavior engagement mediated the relationship between impulsiveness/maladaptive coping and subsequent low self-esteem. Critically, when included in the same model, impulsiveness was significant above and beyond maladaptive coping. Additionally, the reverse model with self-esteem as the predictor and risky behavior included as the dependent variable was not significant suggesting that our effect was unidirectional. As a whole, these findings suggest that impulsive youth may engage in behaviors, which ultimately precipitate negative self evaluations and transient declines in self-esteem. PMID- 22835841 TI - Extinction treatment in multiple contexts attenuates ABC renewal in humans. AB - Renewal has been implicated as one of the underlying mechanisms in return of fear following exposure therapy. ABC renewal is clinically more relevant than ABA renewal and yet it is a weaker form of renewal, suggesting that conducting extinction treatment in multiple contexts may be sufficient to attenuate ABC renewal. Using self-reported expectancy of shock and startle blink responses the current study examined the effects of conducting extinction treatment in multiple contexts on ABC fear renewal. Participants (N = 68) received conditional stimulus (CS) and unconditional stimulus (US) pairings in one context (A) followed by extinction treatment (CS presentations alone) in either one other context (B) or three other contexts (BCD). Non-reinforced test trials in a novel context (E) resulted in renewal of extinguished conditioned behaviour for those who received extinction in only one context. However, renewal was attenuated for those who received extinction treatment in three contexts. No renewal was found for the control group that received the test trial in the same context as during extinction. Suggestions are provided for clinicians seeking to prevent or attenuate return of fear following exposure therapy. PMID- 22835842 TI - A longitudinal test of the bi-directional relations between avoidance coping and PTSD severity during and after PTSD treatment. AB - Avoidance coping and symptoms of posttraumatic stress disorder (PTSD) covary. However, relatively little research has examined the bi-directional relation between these constructs among individuals in treatment for PTSD. The current longitudinal study examined the reciprocal associations between avoidance coping and PTSD symptom severity during and after residential PTSD treatment among a sample of 1073 military veterans (88.9% male; M(age) = 52.39 years) with chronic, treatment-resistant PTSD. Greater avoidance coping at intake predicted more severe PTSD symptoms at discharge, and severity of PTSD symptoms at discharge predicted increased avoidance at follow-up. Conversely, PTSD symptom severity at intake was not related to avoidance coping at discharge, and in turn avoidance coping at discharge was not related to PTSD symptom severity at follow-up. These findings offer a number of important clinical implications including evidence suggesting avoidance may predict poorer treatment response among individuals seeking treatment for chronic PTSD, and that greater end-of-treatment PTSD symptom severity may predict increased avoidance following treatment. PMID- 22835844 TI - Coping behaviors in relation to depressive symptoms and suicidal ideation among middle-aged workers in Japan. AB - BACKGROUND: In Japan, the annual number of deaths by suicide markedly increased in 1998 and leveled off at approximately 30,000 per year thereafter. The coping behaviors used to deal with stress may have implications for the prevention of depression and suicidal ideation. This study examined coping behaviors in relation to depression and suicidal ideation. METHODS: In this cross-sectional study, a total of 6762 workers (40-60 years of age; 4119 males and 2643 females) completed both the Center for Epidemiologic Studies Depression scale (CES-D) and a questionnaire measuring suicidal ideation. A cut-off score of 19 was used to define probable depression for the CES-D. Stress-coping behaviors were surveyed via an inventory of 14 items that reflected of actual behaviors covering problem focused, emotion-focused, and avoidant strategies. RESULTS: In relation to depression, logistic regression analyses revealed that in both genders, the highest odds ratios (OR) for avoidant coping strategy and the lowest OR was associated with a problem-focused strategy after adjusting for covariates. After making the same adjustments, logistic regression analyses revealed that in both genders, the highest OR were for emotional distraction coping strategies in relation to suicidal ideation. LIMITATIONS: The cross-sectional nature of this study does not allow for causal assumptions regarding the sequential nature of the relationship between coping behaviors and the onset of depressive symptoms or suicidal ideation. CONCLUSIONS: These findings indicate that coping behaviors may affect both depressive symptoms and suicidal ideation. Furthermore, gender differences in coping behaviors among middle-aged workers were identified. Additional studies are needed to examine the relationships among coping behaviors, depression and suicidal ideation using a longitudinal design. PMID- 22835843 TI - Novel surveillance of psychological distress during the great recession. AB - BACKGROUND: Economic stressors have been retrospectively associated with net population increases in nonspecific psychological distress (PD). However, no sentinels exist to evaluate contemporaneous associations. Aggregate Internet search query surveillance was used to monitor population changes in PD around the United States' Great Recession. METHODS: Monthly PD query trends were compared with unemployment, underemployment, homes in delinquency and foreclosure, median home value or sale prices, and S&P 500 trends for 2004-2010. Time series analyses, where economic indicators predicted PD one to seven months into the future, were performed in 2011. RESULT: PD queries surpassed 1,000,000 per month, of which 300,000 may be attributable to the Great Recession. A one percentage point increase in mortgage delinquencies and foreclosures was associated with a 16% (95%CI, 9-24) increase in PD queries one-month, and 11% (95%CI, 3-18) four months later, in reference to a pre-Great Recession mean. Unemployment and underemployment had similar associations half and one-quarter the intensity. "Anxiety disorder", "what is depression", "signs of depression", "depression symptoms", and "symptoms of depression" were the queries exhibiting the strongest associations with mortgage delinquencies and foreclosures, unemployment or underemployment. Housing prices and S&P 500 trends were not associated with PD queries. LIMITATIONS: A non-traditional measure of PD was used. It is unclear if actual clinically significant depression or anxiety increased during the Great Recession. Alternative explanations for strong associations between the Great Recession and PD queries, such as media, were explored and rejected. CONCLUSIONS: Because the economy is constantly changing, this work not only provides a snapshot of recent associations between the economy and PD queries but also a framework and toolkit for real-time surveillance going forward. Health resources, clinician screening patterns, and policy debate may be informed by changes in PD query trends. PMID- 22835845 TI - Antidepressant combination for major depression in incomplete responders--a systematic review. AB - BACKGROUND: Antidepressant combination has been suggested as a strategy to increase treatment efficacy. The objective of this study was to perform a systematic review and meta-analysis of studies that assessed the effect of antidepressant combination for major depression in patients with incomplete response to an initial antidepressant. METHODS: Studies were retrieved from PubMed (1966-February, 2012), Cochrane Library (-February, 2012), Embase (1980 February, 2012), PsycINFO (1980-February, 2012), Lilacs (1982-February, 2012), clinical trials registry, thesis database (www.capes.gov.br), and secondary references. Included studies had an open label phase in which an initial antidepressant was used for the treatment of major depression and a double blind phase for the incomplete responders that compared monotherapy with the first antidepressant versus the association of a second antidepressant to the first one. RESULTS: Out of the 4,884 studies retrieved, only five satisfied the inclusion criteria. The total number of patients included was 483. Only two small trials reported benefits of adding a second antidepressant to the initial antidepressant. Dropouts due to side effects were not reported in three studies. Meta-analysis was not performed due to the small number of studies, the inconsistency in the direction of effect and the possible instability of effect size. Only limited kinds of combination, involving mianserin, mirtazapine and desipramine were studied. Some properties of the first two drugs such as the anxiolytic, sedative, and orexigenic effects, can mimic depression improvement. LIMITATIONS: Publication bias cannot be ruled out. Only one study included a monotherapy arm with the antidepressant used for augmentation of the first antidepressant. CONCLUSIONS: The practice of using a combination of antidepressants for major depression in incomplete responders is not warranted by the literature. PMID- 22835846 TI - Total sleep deprivation followed by sleep phase advance and bright light therapy in drug-resistant mood disorders. AB - BACKGROUND: Drug-resistant depression is a major therapeutic issue in psychiatry and the development of non-drug therapies that treat drug-resistant depression is required. Sleep deprivation (SD) is a non-drug treatment classified as a form of chronotherapy in addition to bright light therapy (BLT) and sleep phase advance (SPA). Combined chronotherapy is hypothesized to improve drug-resistant depression. In this study, we investigated the benefits of total sleep deprivation (TSD) followed by SPA and BLT in drug-resistant depression alongside ongoing antidepressant medication and observed the added effectiveness of the combined chronotherapy. METHODS: Thirteen drug-resistant inpatients affected by a major depressive episode were studied. They were treated by TSD followed by SPA (three days) and BLT (five days) with ongoing drug treatment. Effectiveness was rated using the Hamilton Rating Scale for Depression (HAM-D), the Zung Self Rating Depression Scale (SDS), and the Visual Analogue Scale (VAS) over 3 weeks. RESULTS: Significant improvements of depressive symptoms were observed in both objective mood ratings (HAM-D) and subjective mood ratings (SDS and VAS). Eight out of 13 patients maintained this responsiveness (50% or greater changes in HAM D) across the study period. Moreover, no patients dropped out of the combined chronotherapy procedure. LIMITATIONS: The study did not have a placebo group, and more subjects may be needed. CONCLUSION: The trial of combined chronotherapy successfully induced rapid improvement in depressive symptoms in drug-resistant patients without early relapse or obvious side effects. PMID- 22835847 TI - Frequency and clinical features of patients who attempted suicide by charcoal burning in Japan. AB - BACKGROUND: To date, the clinical features between patients in Japan who have attempted suicide by charcoal burning and those who have attempted suicide by other methods in the context of a mental disorder diagnosis as assessed by structured interviews have not been reported. METHODS: We enrolled 647 consecutive patients who attempted suicide and were hospitalized for inpatient treatment. Psychiatric diagnoses, frequency of suicide attempts, and clinical features were compared between charcoal burning and other suicide methods. RESULTS: Twenty of the 647 patients (3.1%) had attempted suicide by charcoal burning. The ratio of men to women was significantly higher by this method compared with that of other methods. The proportion of patients with mood disorders was significantly higher in the charcoal burning group than that in the other methods group. The occurrence of a psychiatric history in patients in the charcoal burning group was significantly lower than that in the other methods group. LIMITATIONS: The study sample was limited to a single hospital. CONCLUSIONS: The results demonstrate the clinical characteristics of patients who attempted suicide by charcoal burning. Therefore, it is necessary to identify the clinical features of patients who have attempted suicide by charcoal burning in Japan. PMID- 22835848 TI - Tryptophan hydroxylase 2 gene polymorphisms and poststroke anxiety disorders. AB - BACKGROUND: Anxiety is common in stroke survivors and may adversely affect recovery. Polymorphisms of tryptophan hydroxylase2 (THP2) gene have been shown to be associated with anxiety disorders and other affective disorders. This study was aimed to investigate the association of two polymorphisms of THP2 gene, rs4570625 and rs4565946, with poststroke anxiety disorders in a Han Chinese population. METHODS: This case control study included 112poststroke anxiety patients and 246 non-anxious controls. All participants completed Hamilton Anxiety Rating Scale and DNA was extracted from blood and genotyped for the two polymorphisms of THP2 gene. RESULTS: Results revealed that the G allele of rs4570625 was associated with the increased risk of poststroke anxiety. In the female subgroup, both the GG genotype and G allele were observed to be significantly higher in case than in control. No significant difference in genotype and allele frequencies of the rs4565946 was found between case and control. Haplotype analysis identified that patients with the G-C haplotype had significantly increased the risk of poststroke anxiety. LIMITATIONS: More than 20 TPH2 polymorphisms have been detected, some of which are tightly-linked and may function together, only two SNPs of TPH2 were investigated in this study. CONCLUSIONS: The findings suggest that these polymorphisms in TPH2 gene are involved in development of poststroke anxiety in the Han Chinese population. PMID- 22835850 TI - The categorisation of dysthymic disorder: can its constituents be meaningfully apportioned? AB - BACKGROUND: Since its introduction in DSM-III, the validity of dysthymia has been debated. Our objective is to further examine the concept of dysthymia in an outpatient sample, and explore whether its constituents can be meaningfully apportioned. METHODS: 318 patients attending the Black Dog Institute Depression Clinic were assessed by the Mini-International Neuropsychiatric Interview, and completed several self-report measures, in addition to a clinical assessment by an Institute psychiatrist. The characteristics of patients with major depressive disorder (MDD), dysthymic disorder and double depression were examined. Latent Class Analysis (LCA) and Latent Profile Analysis (LPA) were then conducted with the aim of detecting distinct classes based on depressive symptomatology and personality domains, respectively. Finally, clinicians' formulations of the study patients were examined. RESULTS: Depression groups mainly differed on parameters of severity. Although LCA and LPA analyses indicated the presence of distinct classes, these only moderately correlated with the MINI-diagnosed groups. Finally, there was evidence for considerable heterogeneity within clinicians' formulations of dysthymia. LIMITATIONS: Inadequate sample numbers for various measures limited the power of the LPA and our sample was weighted to patients with a more severe depressive condition which may affect the detection of a distinct 'dysthymic' personality profile. CONCLUSIONS: Despite employing a variety of techniques, we were unable to obtain a clear homogeneous picture of dysthymia. Rather, there was evidence for a distinct heterogeneity in clinician derived diagnoses. These findings allude to the questionable discriminant validity of dysthymia and may encourage future research and discussion on this important topic. PMID- 22835849 TI - Antisocial personality disorder and borderline symptoms are differentially related to impulsivity and course of illness in bipolar disorder. AB - BACKGROUND: Interactions between characteristics of bipolar and Axis II cluster B disorders are clinically and diagnostically challenging. Characteristics associated with personality disorders may be dimensional aspects of bipolar disorder. We investigated relationships among antisocial personality disorder (ASPD) or borderline personality disorder symptoms, impulsivity, and course of illness in bipolar disorder. METHODS: Subjects with bipolar disorder were recruited from the community. Diagnosis was by structured clinical interview for DSM-IV (SCID-I and -II), psychiatric symptom assessment by the change version of the schedule for affective disorders and schizophrenia (SADS-C), severity of Axis II symptoms by ASPD and borderline personality disorder SCID-II symptoms, and impulsivity by the Barratt impulsiveness scale (BIS-11). RESULTS: ASPD and borderline symptoms were not related to clinical state or affective symptoms. Borderline symptoms correlated with BIS-11 impulsivity scores, and predicted history of suicide attempts independently of the relationship to impulsivity. ASPD symptoms were more strongly related to course of illness, including early onset, frequent episodes, and substance-related disorders. These effects persisted after allowance for gender and substance-use disorder history. CONCLUSIONS: Personality disorder symptoms appear to be dimensional, trait-like characteristics of bipolar disorder. ASPD and Borderline symptoms are differentially related to impulsivity and course of illness. PMID- 22835851 TI - Chlamydophila (Chlamydia) pneumoniae infection promotes vascular smooth muscle cell adhesion and migration through IQ domain GTPase-activating protein 1. AB - The mechanisms for Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) infection induced atherosclerosis are still unclear. Cell adhesion has important roles in vascular smooth muscle cell (VSMC) migration required in the development of atherosclerosis. However, it is still unknown whether IQ domain GTPase-activating protein 1 (IQGAP1) plays pivotal roles in C. pneumoniae infection-induced the adhesion and migration of rat primary VSMCs. Accordingly, in this study, we demonstrated that rat primary VSMC adhesion (P < 0.001) and migration (P < 0.01) measured by cell adhesion assay and Transwell assay, respectively, were significantly enhanced after C. pneumoniae infection. Reverse transcription polymerase chain reaction analysis revealed that the mRNA expression levels of IQGAP1 in the infected rat primary VSMCs were found to increase gradually to reach a peak and then decrease gradually to a level similar to the control. We further showed that the increases in rat primary VSMC adhesion to Matrigel (P < 0.001) and migration (P < 0.01) caused by C. pneumoniae infection were markedly inhibited after IQGAP1 knockdown by a pool of four short hairpin RNAs. Taken together, our results suggest that C. pneumoniae infection may promote the adhesion and migration of VSMCs possibly by upregulating the IQGAP1 expression. PMID- 22835852 TI - Increased disulphide dimer formation of latent associated peptide fusions of TGF beta by addition of L-cystine. AB - The development of novel protein therapeutics relies on the ability to express appreciable amounts of correctly folded recombinant proteins. Latent IFN-beta is engineered using the latency-associated peptide (LAP) of transforming growth factor beta1 (TGF-beta1) to maintain IFN-beta in a biologically inactive form until such time as it is released at sites of inflammation by matrix metalloproteinase activity (see Adams et al., 2003). CHO cells cultured in suspension were used for expression of latent IFN-beta to allow medium scale transient transfection. However, the recombinant protein expressed in this system consisted of a mixture of properly linked disulphide dimers and monomers. The ratio of dimer:monomer produced could be significantly altered towards increased dimer production by the addition of L-cystine to the CHO culture medium. The total yield of latent IFN-beta was increased by co-transfection of plasmid coding for the simian virus (SV) 40 large T antigen to the plasmid with the SV40 origin of replication expressing latent IFN-beta DNA. These results provide valuable new insights for developing protocols to produce substantial quantities of latent cytokine dimers in CHO cells in suspension. PMID- 22835853 TI - A novel impeller configuration to improve fungal physiology performance and energy conservation for cephalosporin C production. AB - Effects of impeller configuration on fungal physiology and cephalosporin C production were investigated by an industrial strain Acremonium chrysogenum in a 12 m(3) bioreactor equipped with conventional and novel impeller configuration, respectively. The cell growth and oxygen uptake rate (OUR) profiles were little affected by the impeller configurations. However, differing impeller combinations significantly affected the morphology, which in turn influenced cephalosporin C production. Under the novel impeller configuration, the production of cephalosporin C was 10% higher and an excessive amount of dispersed arthrospores was also observed. Computational fluid dynamics (CFD) simulation further revealed that poor mass and energy exchange as well as inhomogeneous environment existed in the bioreactor equipped with conventional impeller configuration. For equivalent power dissipation, the volume oxygen transfer coefficient (K(L)a) could be enhanced by 15% compared with that of conventional impeller configuration. Power consumption was dramatically decreased by 25% by using novel impeller configuration. PMID- 22835854 TI - Diabetes is associated with cognitive impairment no dementia in the Aging, Demographics, and Memory Study (ADAMS). PMID- 22835855 TI - High-throughput screening method for promoter activity using bead display and a ligase ribozyme. AB - In this report, we describe the development of a novel in vitro high-throughput system for detecting and screening promoter activity; the method employs emulsified reactions and a ligase ribozyme. In our study, a promoter DNA fragment containing the ribozyme gene was immobilized on a bead by using emulsion PCR, followed by in vitro transcription of the immobilized DNA in water-in-oil emulsions. Owing to the self-ligation activity of the ribozyme, it was co transcriptionally linked to the active promoter immobilized on the beads. The bead complex containing the active promoter sequence was then labeled by reverse transcription with a fluorescently labeled primer. Employing flow cytometry, the fluorescence intensity corresponding to the strength of each promoter was observed, indicating the applicability of the system for promoter evaluation. Moreover, two rounds of screening with T7 RNA polymerase using a cell sorter enriched the T7 promoter fragment by 70 folds from a 1:100 mixture of T7 promoter and SP6 promoter fragments, suggesting that this system can be used to screen promoters. PMID- 22835856 TI - Trajectories and predictors of the course of mental health after spinal cord injury. AB - OBJECTIVE: To study the course and predictors of mental health in the period between the start of active spinal cord injury (SCI) rehabilitation and 5 years after discharge. The hypothesis was that different mental health trajectories would be identified. DESIGN: Multicenter prospective cohort study with measurements at the start of active rehabilitation, after 3 months, at discharge, 1, 2, and 5 years after discharge. SETTING: Eight Dutch rehabilitation centers with specialized SCI units. PARTICIPANTS: Persons (N=206) with recently acquired SCI aged between 18 and 65 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The 5-item Mental Health Index with a total score between 0 (lowest mental health) and 100 (highest mental health). RESULTS: Levels of mental health increased between the start of active rehabilitation and 3 months later, remained stable thereafter, and increased again between 2 and 5 years after discharge. Latent class growth mixture modeling revealed 5 trajectories: (1) high scores (above 80) at all time-points (52%), (2) low scores (<=60) at all time-points (4%), (3) early recovery from 40 to scores above 70 (13%), (4) intermediate scores from 60 to scores above 70 (29%), and (5) severe deterioration of scores above 70 to scores below 30 (2%). Pain, sex, and education level were predictors to distinguish between the 5 trajectories. CONCLUSIONS: Five different mental health trajectories were identified between the start of active rehabilitation and 5 years after discharge. About one third of the persons with SCI still perceived moderate to severe mental health problems 5 years after discharge. Pain, sex, and education level only predicted a small part of the variance in mental health trajectories. PMID- 22835857 TI - Clinical outcomes of secondary stent-in-stent self-expanding metal stent placement for primary stent malfunction in malignant gastric outlet obstruction. AB - BACKGROUND: Although a substantial number of patients require secondary stents insertion due to primary stent malfunction in malignant gastric outlet obstruction, data on the outcomes of secondary self-expanding metal stents are sparse. AIM: To investigate clinical outcomes and factors related with secondary stent malfunction in patients with malignant gastric outlet obstruction given secondary stent-in-stent self-expanding metal stent insertion. METHODS: For this retrospective study, a total 77 patients who underwent secondary stent-in-stent self-expanding metal stent placement for primary stent malfunction in malignant gastric outlet obstruction were enrolled. We compared the effectiveness and complications of secondary covered and uncovered stents and explored the predictive factors for stent malfunction. RESULTS: Stent-in-stent self-expanding metal stent placements were technically successful in all patients. Both groups also had comparable clinical success rates (covered stent, 87.2% and uncovered stent, 90.0%, P = 1.000). Stent malfunction rates (31.9% and 36.7% respectively, P = 0.805) and median patency time of stent (165 [95% confidence interval: 112 218] and 165 [95% confidence interval: 126-204] days, respectively, P = 0.358) were similar between secondary covered and uncovered stents. Longer patients' survival time (>= 100 days) was associated with increased risk of stent malfunction (odds ratio: 4.598; 95% confidence interval: 1.473-14.355; P = 0.009). CONCLUSIONS: Secondary stent-in-stent self-expanding metal stent placement is feasible and effective treatment for primary stent malfunctions in malignant gastric outlet obstruction. Covered and uncovered stent are equally acceptable in terms of stent-related complications and stent patency, regardless of primary stent type. PMID- 22835858 TI - Protective effects of erythropoietin on cirrhotic cardiomyopathy in rats. AB - INTRODUCTION: Erythropoietin exerts cardioprotective effects. The present study aimed to investigate the therapeutic effects of erythropoietin on cirrhotic cardiomyopathy. MATERIALS AND METHODS: Rats were divided into 5 groups: sham control; sham+ erythropoietin; bile duct ligation; bile duct ligation+erythropoietin; bile duct ligation+erythropoietin+anti-tumour necrosis factor alpha (TNFalpha) antibody and were studied 4 wk after surgery. Erythropoietin was administrated for 10 days before the study date. TNFalpha, erythropoietin receptor-1 expression and oxidative stress-related parameters were measured. In separate groups, isolated cardiomyocytes were subjected to contractile and relaxation studies. Cardiomyocyte cell line was used to test the direct effect of erythropoietin on nuclear factor (erythroid-derived 2)-like 2(Nrf2). RESULTS: Erythropoietin receptor-1, TNFalpha and oxidative modified proteins were significantly increased (p<0.01), and the antioxidant regulator Nrf2 transcription decreased in cirrhotic hearts (p<0.01). Erythropoietin reversed these parameters. Maximal cardiac contractile and relaxation velocity was significantly decreased in cirrhotic cardiomyocytes. Erythropoietin significantly reversed these inhibitions. Anti-TNFalpha antibody significantly decreased cardiac TNFalpha content but did not further increase contractility. CONCLUSIONS: TNFalpha and oxidative stress are involved in cardiac dysfunction in the cirrhotic heart. Erythropoietin significantly decreased TNFalpha and oxidative stress and reversed the impaired cardiac function. PMID- 22835859 TI - Matched comparison of kinematics in knees with mild and severe varus deformity using fixed- and mobile-bearing total knee arthroplasty. AB - BACKGROUND: We examined knee kinematics in three 16-knee cohorts with the same implant design to clarify the influence of bearing mobility and preoperative deformity on the kinematics of posterior-stabilized knee arthroplasty. Compared to knees with mild deformity and a fixed-bearing implant, we hypothesized that a matched group of knees with mobile-bearing prostheses would show greater tibial axial rotation. We hypothesized that knees with the same fixed-bearing implant, but severe preoperative deformity, would have less axial rotation. METHODS: A total of 58 knees in 48 patients were involved in this study from a consecutive single-surgeon total knee arthroplasty series. Sixteen knees received mobile bearing prostheses, and a best-matched cohort of knees with fixed-bearing implants was selected. The 16 fixed-bearing knees with most severe preoperative deformity were selected as a third group. All knees were examined at least 1.5 years after surgery. Flexion, femoral external rotation, anteroposterior translation of both femoral condyles during squatting and deep knee flexion activities were evaluated using model-image registration techniques. FINDINGS: We found some statistically significant, but small differences among the three groups in dynamic and static knee kinematics. In squatting, total femoral rotation for knees with fixed- and mobile-bearing implants, and knees with fixed bearing implants after severe preoperative varus deformity, was not significantly different. [7 degrees (SD3 degrees ), 9 degrees (SD3 degrees ), 8 degrees (SD3 degrees ), respectively, P=0.08]. INTERPRETATION: Similar kinematic results for knees with different tibial bearing surfaces and preoperative deformities indicate a robust treatment with this posterior stabilized implant. However, knees did not exhibit normal femoral rotations or functional flexion ranges. PMID- 22835860 TI - The influence of wheelchair propulsion technique on upper extremity muscle demand: a simulation study. AB - BACKGROUND: The majority of manual wheelchair users will experience upper extremity injuries or pain, in part due to the high force requirements, repetitive motion and extreme joint postures associated with wheelchair propulsion. Recent studies have identified cadence, contact angle and peak force as important factors for reducing upper extremity demand during propulsion. However, studies often make comparisons between populations (e.g., able-bodied vs. paraplegic) or do not investigate specific measures of upper extremity demand. The purpose of this study was to use a musculoskeletal model and forward dynamics simulations of wheelchair propulsion to investigate how altering cadence, peak force and contact angle influence individual muscle demand. METHODS: Forward dynamics simulations of wheelchair propulsion were generated to emulate group-averaged experimental data during four conditions: 1) self-selected propulsion technique, and while 2) minimizing cadence, 3) maximizing contact angle, and 4) minimizing peak force using biofeedback. Simulations were used to determine individual muscle mechanical power and stress as measures of muscle demand. RESULTS: Minimizing peak force and cadence had the lowest muscle power requirements. However, minimizing peak force increased cadence and recovery power, while minimizing cadence increased average muscle stress. Maximizing contact angle increased muscle stress and had the highest muscle power requirements. INTERPRETATION: Minimizing cadence appears to have the most potential for reducing muscle demand and fatigue, which could decrease upper extremity injuries and pain. However, altering any of these variables to extreme values appears to be less effective; instead small to moderate changes may better reduce overall muscle demand. PMID- 22835861 TI - Relationship between plasma progesterone and pregnancy-associated glycoprotein concentrations during early pregnancy in dairy cows. AB - The relationship between the concentration of plasma progesterone (P4) during embryo attachment or at recognition of pregnancy, and that of pregnancy associated glycoprotein (PAG) was assessed in dairy cows. The outcome of artificial insemination (AI) was classified as positive (AI+), negative (AI-), or late embryonic mortality (EM) by measuring circulating PAG concentrations and by ultrasonography. Based on P4 concentrations at either day 21 or day 15, AI+ and EM cows were classified into 'low' (P4 concentrationsmean) P4 groups. In both experiments, the threshold of P4 concentration between the 'low' and 'high' groups was approximately 6ng/mL. PAG concentrations were lower in the 'low' group only when P4 concentrations were below the threshold. The study findings suggest that a possible P4 threshold exists below which PAG secretion may be impaired. PMID- 22835862 TI - Pharmacokinetics of dexamethasone after intravenous and intramuscular administration in broiler chickens. AB - The aim of this study was to determine the pharmacokinetics of dexamethasone in broiler chickens. Dexamethasone sodium phosphate (0.3mg/kg bodyweight) was injected IV or IM and blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 and 24h after administration. Dexamethasone in the plasma samples was measured using a liquid chromatography-tandem mass spectrometry method and the pharmacokinetics analysed according to a one-compartmental model. The maximum plasma concentration after IM administration occurred at 0.37h. The elimination half-life for dexamethasone was 0.46h and 0.70h following IV and IM administration, respectively, which was shorter than other species, while the clearance (1.26L/hkg) was higher than has been reported for other species (<0.5L/hkg). The volume of distribution (~1L/kg) was similar to values reported for other species and the bioavailability of dexamethasone after IM administration was 100%. The results from this study will be useful in investigating whether inflammatory disease may affect the pharmacokinetic parameters of dexamethasone in chickens. PMID- 22835863 TI - Chronic pancreatitis in dogs: a retrospective study of clinical, clinicopathological, and histopathological findings in 61 cases. AB - The objective of this study was to characterize the clinical, clinicopathological, and histopathological findings of dogs with chronic pancreatitis. The necropsy database at Texas A&M University was searched for reports of dogs with histological evidence of chronic pancreatitis defined as irreversible histologic changes of the pancreas (i.e. fibrosis or atrophy). A reference necropsy population of 100 randomly selected dogs was used for signalment and concurrent disease comparisons. Cases were categorized as clinical or incidental chronic pancreatitis based on the presence of vomiting, decreased appetite, or both vs. neither of these signs. All archived pancreas samples were scored histologically using a published scoring system. Sixty-one dogs with chronic pancreatitis were included. The most frequent clinical signs were lethargy, decreased appetite, vomiting, and diarrhea. Compared to the reference necropsy population, chronic pancreatitis cases were more likely to be older, neutered, of the non-sporting/toy breed group, and to have concurrent endocrine, hepatobiliary, or neurological disease. Clinical cases had significantly higher histological scores for pancreatic necrosis and peripancreatic fat necrosis, and were significantly more likely to have hepatobiliary or endocrine disease as well as increased liver enzyme activities, or elevated cholesterol and bilirubin concentrations. In conclusion, clinical disease resulting from chronic pancreatitis might be related to the presence of pancreatic necrosis and pancreatic fat necrosis. The signalment, presentation, and concurrent diseases of dogs with chronic pancreatitis are similar to those previously reported for dogs with acute pancreatitis. PMID- 22835864 TI - In vitro activity of Lantana camara, Alpinia zerumbet, Mentha villosa and Tagetes minuta decoctions on Haemonchus contortus eggs and larvae. AB - The resistance of gastrointestinal nematodes to anthelmintics has increased the need to evaluate natural products that can replace or assist current strategies to control gastrointestinal nematodes. The objective of this study was to evaluate the effect of decoctions of Lantana camara (DLc), Alpinia zerumbet (DAz), Mentha villosa (DMv) and Tagetes minuta (DTm) on Haemonchus contortus by two in vitro tests. The effects of increasing concentrations of lyophilized decoctions (0.31 to 10mg/ml) were assessed using the egg hatch test (EHT). The decoctions were then tested in the larval artificial exsheathment assay. H. contortus third stage larvae (L3) were exposed to 0.31 mg/ml A. zerumbet and M. villosa decoctions and 0.62 mg/ml T. minuta and L. camara decoctions for 3h and then exsheathment procedure at 10 min intervals. An inhibitor of tannins, polyvinyl polypyrrolidone (PVPP), was used to study if tannins were responsible for the inhibitory effect on hatching and exsheathment of larvae. A. zerumbet, M. villosa and T. minuta showed a dose-dependent effect in the EHT, which did not disappear after the addition of PVPP. No effect was observed for L. camara in the EHT. However, the decoctions inhibited the process of larval exsheathment, which may be related to tannin action because the addition of PVPP reversed the inhibitory effect. A. zerumbet, M. villosa and T. minuta decoctions showed inhibitory activity on H. contortus larvae hatching and exsheathing. The decoctions of these plants could be used to control gastrointestinal nematodes following confirmation of their anthelmintic activity in vivo. PMID- 22835866 TI - Comparison of the characteristics of extracellular polymeric substances for two different extraction methods and sludge formation conditions. AB - The characteristics of extracellular polymeric substances (EPSs) were compared for two different extraction methods and dissimilar sludge formation conditions (aerobic versus anaerobic). The measured characteristics included specific ultraviolet absorbance (SUVA) values, fluorescence excitation-emission matrices, molecular weight distributions, Fourier transform infrared (FT-IR) spectra, and the binding affinities for pyrene and Hg(II). The analyses demonstrated that the EPS extracted using cation exchange resin (CER) were composed of more aromatic and more condensed structures with higher molecular weight than those using formaldehyde/NaOH. The FT-IR results further revealed that the EPS using CER contained relatively lower content of protein to carbohydrate and less acidic functional groups (i.e., COOH or OH groups). The observed differences between the two extraction methods were more pronounced for the EPS of anaerobic sludge compared to those of aerobic sludge. The extent of pyrene binding and the apparent stability constants for Hg(II) were very consistent with the implications from the previous EPS physicochemical characteristics. The highest extent of pyrene binding was observed for the EPS of anaerobic sludge using CER while no measurable Hg(II) stability constant was found for the same EPS sample. Our results demonstrated that the EPS characteristics including their binding affinities are likely strongly affected by the sludge formation conditions as well as the extraction methods although the latter produced more differences. PMID- 22835867 TI - Assessment of chemical and mineralogical characteristics of airborne dust in the Sistan region, Iran. AB - Windblown transport and deposition of dust is widely recognized as an important physical and chemical concern to climate, human health and ecosystems. Sistan is a region located in southeast Iran with extensive wind erosion, severe desertification and intense dust storms, which cause adverse effects in regional air quality and human health. To mitigate the impact of these phenomena, it is vital to ascertain the physical and chemical characteristics of airborne and soil dust. This paper examines for the first time, the mineralogical and chemical properties of dust over Sistan by collecting aerosol samples at two stations established close to a dry-bed lake dust source region, from August 2009 to August 2010. Furthermore, soil samples were collected from topsoil (0-5 cm depth) at several locations in the dry-bed Hamoun lakes and downwind areas. These data were analyzed to investigate the chemical and mineralogical characteristics of dust, relevance of inferred sources and contributions to air pollution. X-ray Diffraction (XRD) analysis of airborne and soil dust samples shows that the dust mineralogy is dominated mainly by quartz (30-40%), calcite (18-23%), muscovite (10-17%), plagioclase (9-12%), chlorite (~6%) and enstatite (~3%), with minor components of dolomite, microcline, halite and gypsum. X-ray Fluorescence (XRF) analyses of all the samples indicate that the most important oxide compositions of the airborne and soil dust are SiO(2), CaO, Al(2)O(3), Na(2)O, MgO and Fe(2)O(3), exhibiting similar percentages for both stations and soil samples. Estimates of Enrichment Factors (EFs) for all studied elements show that all of them have very low EF values, suggesting natural origin from local materials. The results suggest that a common dust source region can be inferred, which is the eroded sedimentary environment in the extensive Hamoun dry lakes lying to the north of Sistan. PMID- 22835865 TI - Cortico-cerebellar abnormalities in adolescents with heavy marijuana use. AB - There are currently no studies that have evaluated the motor network, including the cerebellum, in adolescent marijuana (MJ) smokers. The current study aimed to evaluate whether there were activation differences in Brodmann's area 4 (BA4), Brodmann's area 6 (BA6), cingulate (CG) and cerebellum between MJ-using adolescents and healthy controls (HC) on a functional magnetic resonance imaging (fMRI) bilateral finger-tapping task. Twenty-four adolescents (aged 18.2 +/- 0.7 years) with heavy MJ use and 24 HC (18.0 +/- 1.9) had MRI scans on a 3T Siemens scanner, including a standard bilateral fMRI finger-tapping sequence. Imaging data were analyzed using SPM5 in Matlab. As regions of interest, BA4, BA6, cingulate (CG) and cerebellum were selected, and significant clusters of activity were thresholded at p<0.05, corrected. Healthy controls had significantly greater activation than MJ users for the CG and cerebellum. In addition, activation of the cerebellum and CG correlated with lifetime MJ smokes. This is one of the first studies to evaluate cortico-cerebellar circuits in adolescents with heavy MJ use. The study, which used a bilateral finger-tapping fMRI task, provides evidence for both CG and cerebellar dysfunction in MJ abuse and indicates that lifetime MJ use may impact the developing brain. PMID- 22835868 TI - The oxidation mechanism of polychlorinated dibenzo-p-dioxins under the atmospheric conditions - a theoretical study. AB - The atmospheric polychlorinated dibenzo-p-dioxins (PCDDs) partition appreciably in the gas phase, where they undergo rapid oxidation. The atmospheric oxidation mechanisms of a few PCDDs, initiated by OH radical, are studied using density functional theory calculations. The oxidations start with OH-addition to the aromatic rings, dominantly at gamma-sites, followed by the non-chlorinated beta sites; while additions to the alpha-sites or chlorinated sites are negligible. For PCDDs with all beta-sites being chlorinated, formation of PCDD-gamma-OH adducts become virtually the only reaction path. Under the atmospheric conditions, the PCDD-beta/gamma-OH adducts combine with O(2) slowly at rates <1s( 1). Instead, the PCDD-beta-OH adducts will react with O(2) through hydrogen abstraction at rates <50s(-1), forming PCDD-beta-ol, and the PCDD-gamma-OH adducts will decompose to the substituted phenoxy radicals by fused-ring C-O bond cleavage at rates of 10(3) ~10(5) s(-1). The reaction mechanisms of PCDDs are drastically different from the peroxy mechanism for the atmospheric oxidations of benzene and dibenzofuran. PMID- 22835869 TI - Persistent organochlorine contaminants in hair samples of Northern Poland population, 1968-2009. AB - The concentrations of persistent chlorinated organic pollutants were determined in hair samples (n=40) collected from inhabitants of Northern Poland in 1968, 1989 and 2009 using gas chromatography ion-trap tandem mass spectrometry (GC MS/MS). Among the analytes were beta- and gamma-isomers of hexachlorocyclohexane (beta- and gamma-HCH), dichlorodiphenyltrichloroethane (p,p'-DDT) and its metabolites (p,p'-DDE, o,p'-DDD, o,p'-DDT and p,p'-DDD) and 6 polychlorinated biphenyl (PCB) congeners (IUPAC Nos. 28, 52, 101, 138, 153 and 180). The following: p,p'-DDE, o,p'-DDT, p,p'-DDT and PCB congeners: 28, 52 and 101 could be quantified in all samples. Overall total organochlorines level was found to decrease in that order: 1968>1989>2009. The most significant time-dependent decrease was noticed for sum of mean values, ?DDTs (1658, 143.9 and 36.5 ng g( 1)) and ?PCBs (42.2, 29.4 and 14.9 ng g(-1)) while ?HCHs (beta-HCH and gamma-HCH) were present at comparable levels (22.2, 9.8 and 12.6 ng g(-1)) in 1968, 1989 and 2009 respectively. The highest concentrations of DDTs were found in samples from 1968. Despite the long storage time of samples, metabolites either parent compound p,p'-DDT are still present in those samples at very high concentrations. p,p'-DDE as the predominant and stable metabolite of DDT was detected in every sample in the highest concentration. A significant, continuous decrease of total concentration of all studied PCB congeners was observed over the studied period of time. Current results confirm previous reports of other authors upon the utility of hair as an alternative matrix for evaluation of human exposure to persistent organic pollutants. PMID- 22835870 TI - Modulation of DNA repair by pharmacological inhibitors of the PIKK protein kinase family. AB - Modulation of DNA repair pathways in oncology has been an area of intense interest in the last decade, not least as a consequence of the promising clinical activity of poly(ADP-ribose) polymerase (PARP) inhibitors. In this review article, we highlight inhibitors of the phosphatidylinositol 3-kinase related kinase (PIKK) family as of potential interest in the treatment of cancer, both in combination with DNA-damaging therapies and as stand-alone agents. PMID- 22835871 TI - Small molecule modulators of aggregation in synthetic melanin polymerizations. AB - There are numerous potential applications for melanin-binding compounds, and new methods are of interest to identify melanin-binding agents. A portion of the polymerization to eumelanin, the black to brown pigment in humans, is thought to be supramolecular aggregation of nanoparticles derived from dihydroxyindoles. Starting with chloroquine, a known eumelanin-binding compound, the ability of small molecules to influence aggregation in synthetic eumelanin polymerizations was investigated. Twenty-eight compounds were tested, including pharmaceuticals, dyes, aromatics, and amines. Compounds that either accelerate or delay the appearance of macroscopic particles in synthetic eumelanin polymerizations were uncovered. PMID- 22835872 TI - Design, synthesis and molecular simulation studies of dihydrostilbene derivatives as potent tyrosinase inhibitors. AB - The synthesis, molecular modeling and biological evaluation of substituted deoxybenzoins and optimized dihydrostilbenes are reported. Preliminary structure activity relationship data were elucidated and lead compounds suitable for further optimization were discovered. Dihydrostilbene 7 is a particularly potent inhibitor (IC(50)=8.44 MUM, more potent than kojic acid). PMID- 22835873 TI - Anion inhibition studies of an alpha-carbonic anhydrase from the thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1. AB - The newly discovered thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 encodes an alpha-carbonic anhydrases (CAs, EC 4.2.1.1) which is highly catalytically active and thermostable. Here we report the inhibition of this enzyme, denominated SspCA, with inorganic and complex anions and other molecules interacting with zinc proteins. SspCA was inhibited in the micromolar range by diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic and phenylarsonic acid, trithiocarbonate and selenocyanide (K(I)s of 4-70 MUM) and in the submillimolar one by iodide, cyanide, (thio)cyanate, hydrogen sulfide, azide, nitrate, nitrite, many complex anions incorporating heavy metal ions and iminodisulfonate (K(I)s of 0.48-0.86 mM). SspCA was not substantially inhibited by bicarbonate and carbonate, hydrogensulfite and peroxidisulfate (K(I)s in the range of 21.1-84.6mM). The exceptional thermostability and lack of strong affinity for hydrogensulfide, bicarbonate, and carbonate make this enzyme an interesting candidate for biotechnological applications of enzymatic CO(2) fixation. PMID- 22835874 TI - Gender differences in the relation between depression and social support in later life. AB - BACKGROUND: Prevalence of depression is twice as high in women as in men, also in older adults. Lack of social support is a risk factor for late-life depression. The relation between depression and social support may be different for men and women. METHODS: Data from the Longitudinal Aging Study Amsterdam were used to investigate gender differences in the relation between social support and depression in a population-based sample aged 55-85 years, with n = 2,823 at baseline and using the 13-year follow-up data on onset of depression. RESULTS: Respondents without a partner in the household, with a small network, and with low emotional support were more often depressed, with men showing higher rates of depression than women. A high need for affiliation was associated with depression in women but not in men. Lack of a partner in the household and having a small network predicted onset of depression in men but not in women. In respondents with high affiliation need and low social support, depression rates were higher, with men being more often depressed than women. CONCLUSIONS: Low social support and a high need for affiliation were related to depression in later life, with men being more vulnerable for depression than women. Considering the serious consequences of depression, especially in older people, it is important to identify the persons with low social support and a high need for affiliation, and to help them to increase their social support or to adjust their needs. PMID- 22835875 TI - Intra-biliary contrast-enhanced ultrasound for evaluating biliary obstruction during percutaneous transhepatic biliary drainage: a preliminary study. AB - OBJECTIVES: The aimed of this study was to investigate the value of intra-biliary contrast-enhanced ultrasound (IB-CEUS) for evaluating biliary obstruction during percutaneous transhepatic biliary drainage (PTBD). MATERIALS AND METHODS: 80 patients with obstructive jaundice who underwent IB-CEUS during PTBD were enrolled. The diluted ultrasound contrast agent was injected via the drainage catheter to perform IB-CEUS. Both conventional ultrasound and IB-CEUS were used to detect the tips of the drainage catheters and to compare the detection rates of the tips. The obstructive level and degree of biliary tract were evaluated by IB-CEUS. Fluoroscopic cholangiography (FC) and computer tomography cholangiography (CTC) were taken as standard reference for comparison. RESULTS: Conventional ultrasound displayed only 43 tips (43/80, 53.8%) of the drainage catheters within the bile ducts while IB-CEUS identified all 80 tips (80/80, 100%) of the drainage catheters including 4 of them out of the bile duct (P<0.001). IB-CEUS made correct diagnosis in 44 patients with intrahepatic and 36 patients with extrahepatic biliary obstructions. IB-CEUS accurately demonstrated complete obstruction in 56 patients and incomplete obstruction in 21 patients. There were 3 patients with incomplete obstruction misdiagnosed to be complete obstruction by IB-CEUS. The diagnostic accuracy of biliary obstruction degree was 96.3% (77/80). CONCLUSION: IB-CEUS could improve the visualization of the drainage catheters and evaluate the biliary obstructive level and degree during PTBD. IB-CEUS may be the potential substitute to FC in the PTBD procedure. PMID- 22835876 TI - Charlson Comorbidity Index predicts patient outcome, in cases of inoperable non small cell lung cancer treated with radiofrequency ablation. AB - PURPOSE: The Charlson Comorbidity Index (CCI) has been shown to be a significant prognostic indicator in the treatment of many types of cancer. The aim of this study is to evaluate the degree to which the CCI predicts survival in patients with inoperable non-small cell lung cancer (NSCLC) treated with radiofrequency ablation (RFA). MATERIALS AND METHODS: Eighty-two (34 men, 48 women) consecutive RFA treatments for medically inoperable NSCLC were performed at our institution from 1/1/2000 to 1/30/2009. With institutional IRB approval and in full HIPAA compliance, the medical records of these patients were examined for data relating to pre-treatment comorbid conditions, and a retrospective analysis was conducted. Survival curves were estimated by the Kaplan-Meier method. Risk factors for mortality were determined by single-factor comparisons of curves using Wilcoxon weighted chi-square and multiple Cox regressions. RESULTS: The patients ranged in age from 59 to 91 years (mean: 75.5). Eighty-eight percent (72 patients) were tumor stage IA or IB. Patients were followed for a total of five years; three year overall survival was 50.6%. Hospital mortality was 0%. Gender, stage, histology and CCI score were each associated with significantly impaired survival (p<0.001 in all cases). After covarying for age, tumor stage>IB, squamous histology and gender, multiple Cox regressions showed that an increasing CCI score was significantly associated with an increased risk of death (HR 1.3, 95% CI 25.5, 58.2). CONCLUSIONS: The CCI is validated as an important, independent predictor of patient survival, in cases of inoperable NSCLC treated with RFA. PMID- 22835877 TI - Radiation protection of patients in diagnostic and interventional radiology in Asian countries: impact of an IAEA project. AB - Recognizing the lack of information on image quality and patient doses in most countries in Asia, the International Atomic Energy Agency (IAEA) initiated a project to assess the status of imaging technology, practice in conventional radiography, mammography, computed tomography (CT) and interventional procedures, and to implement optimisation actions. A total of 20 countries participated. Obsolete practices of use of fluoroscopy for positioning, photofluorography, chest fluoroscopy and conventional tomography were reported by 4 out of 7 countries that provided this information. Low-kV technique for chest radiography is in use in participating countries for 20-85% of cases, and manual processing is in 5-85% of facilities in 5 countries. Instances of the use of adult CT protocol for children in three participating countries were observed in 10-40% of hospitals surveyed. After implementation of a Quality Control programme, the image quality in conventional radiography improved by zero to 13 percentage points in certain countries and dose reduction was from 10% to 85%. In mammography, poor quality, ranging from 10 to 29% of images in different countries was observed. The project increased attention to dose quantities and dose levels in computed tomography, although doses in most cases were not higher than reference levels. In this study 16-19% of patients in interventional cardiology received doses that have potential for either stochastic risk or tissue reaction. This multi-national study is the first of its kind in the Asia, and it provided insight into the situation and opportunities for improvement. PMID- 22835878 TI - Coronary computed tomography and triple rule out CT in patients with acute chest pain and an intermediate cardiac risk for acute coronary syndrome: part 2: economic aspects. AB - OBJECTIVE: To evaluate the economic impact of integrating coronary CT angiography (cCTA) or whole chest "triple-rule-out" CTA (TRO-CTA) in the work-up of patients with acute chest pain. MATERIALS AND METHODS: 100 consecutive emergency department patients with acute chest pain and an intermediate cardiac risk for ACS underwent cCTA or TRO-CTA (cCTA group). Diagnostic performance, rate and length of hospitalization, hospital costs, hospital reimbursement and hospital profit were analyzed. All findings were compared to those of 100 different patients with acute chest pain that were evaluated with a standard of care (SOC) diagnostic algorithm (SOC group) that did not include cCTA. Diagnostic performance ("safety") of both algorithms was defined as the absence of major adverse cardiac events (MACE) over a 90-day follow-up period. RESULTS: In the cCTA group 60/100 patients were safely discharged at the same day. 19/100 patients were hospitalized due to significant coronary stenosis on cCTA, which was confirmed by invasive coronary catheterization (ICC) in 17/19 patients. Relevant non-coronary disease that led to hospitalization were found in 21 patients of the cCTA group. In the SOC group all patients were hospitalized. 87 of these hospitalized patients underwent ICC for exclusion of coronary artery stenosis. A significant coronary artery stenosis was found in only 25 of these patients. Within the cCTA group no patient suffered from MACE over the 90-day follow-up period. In the SOC group 2 patients were rehospitalized during the 90 day follow-up period due to recurrent chest pain and 1 patient because of a pseudoaneurym of the left femoral artery after ICC. The median hospital costs per patient were significantly lower in the cCTA group than in the SOC group (428.9? vs. 1575.0?, p<0.001). The median reimbursement of the cCTA group was less compared to the SOC group (589.8? vs. 2412.1?, p<0.001) and patients in the cCTA group gained less profit than patients in the SOC group (57.0? vs. 448.4?, p<0.001). CONCLUSION: Integrating cCTA or TRO-CTA in a SOC algorithm can safely reduce the number of hospitalized patients and reduce total health care costs. PMID- 22835879 TI - Recent decrease in the prevalence of congenital heart defects in Europe. AB - OBJECTIVES: To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. STUDY DESIGN: We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. RESULTS: We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. CONCLUSIONS: The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere. PMID- 22835881 TI - A child with edema, lower limb deformity, and recurrent diarrhea. PMID- 22835880 TI - Unexplained death due to possible infectious diseases in infants-United States, 2006. AB - OBJECTIVES: To quantify and examine factors related to unexplained death due to possible infectious causes (UDPIC) in infants and to analyze the associations between these factors in unexplained deaths and infants with fatal and nonfatal outcomes. STUDY DESIGN: Infant deaths meeting the International Classification of Diseases, Tenth Revision code inclusion and exclusion criteria for UDPIC were selected from the 2006 US Linked Birth and Infant Death data set. Two control groups of surviving and nonsurviving infants were selected and compared with the infants with UDPIC using a case-control study design with multivariate logistic regression models stratified by birth weight category. Comparisons with infants with identified infectious causes of death were also made. RESULTS: During 2006, 3570 infant deaths (12.5% of all US infant deaths) were categorized as a UDPIC. The highest rates for these unexplained infants deaths were found in blacks and American Indians/Alaska Natives. Infants of black mothers were more likely to experience UDPIC. Birth weight was a significant effect modifier in these models. CONCLUSIONS: Many factors may contribute to an infant's death being classified as a UDPIC, including race and marital status. Other factors, such as Hispanic ethnicity and maternal age, also may play a role. Infant characteristics, such as birth weight, may be related to factors that influence the decision not to conduct a postmortem examination in infant death cases. Additional research is needed to determine the true extent of infectious disease and its relationship to UDPIC in infants. PMID- 22835882 TI - Does the relationship between prenatal care and birth weight vary by oral clefts? evidence using South American and United States samples. AB - OBJECTIVE: To evaluate if the association between prenatal care use and birth weight (BW) varies for infants with cleft lip and/or cleft palate (CL/P), classified into isolated and non-isolated forms, compared with unaffected infants. STUDY DESIGN: The study employed 2 datasets. The first included a multi country sample of 2405 infants with CL/P and 24046 infants without CL/P born in 1996-2007 in South America. The second was a sample of 2122 infants with CL/P and 297415 without CL/P from the United States 2004 natality dataset. Separate analyses were performed for the South American and United States samples. The association between prenatal care and BW was evaluated separately for isolated CL/P, non-isolated CL/P, and unaffected infants using regression models adjusting for several background characteristics. RESULTS: Prenatal care was associated with improved BW for all infant groups, with greater BW increases for infants with CL/P particularly non-isolated forms. In the South American sample, BW increased by 108, 69, and 40 g on average per prenatal visit for infants with non isolated CL/P, infants with isolated CL/P, and unaffected infants, respectively. In the United States sample, BW increased by 51, 21, and 16 g on average per prenatal visit for these infant groups, respectively. CONCLUSIONS: Prenatal care was associated with larger BW increases for pregnancies complicated with CL/P, particularly non-isolated forms, compared with unaffected pregnancies. Given that reduced BW is a well-recognized comorbidity of CL/P, the findings highlight the importance of prenatal care for at-risk pregnancies as a tertiary-prevention intervention to reduce the health burden of CL/P. PMID- 22835883 TI - School attendance in childhood cancer survivors and their siblings. AB - OBJECTIVE: To investigate school absenteeism among childhood cancer survivors and their siblings and examine factors related to absenteeism in survivors. STUDY DESIGN: A cross-sectional study was conducted among consecutive cancer survivors attending a large pediatric cancer survivor clinic. Absenteeism rates were obtained for survivors and their closest in age sibling from school report cards. Absenteeism was compared with a population control group of 167752 students using 1-sample t tests. The Child Vulnerability Scale, Pediatric Quality of Life Inventory, and Behavior Assessment System for Children were administered to survivors. Univariate and multiple regression analyses assessed variables associated with days absent. RESULTS: One hundred thirty-one survivors (median age at assessment: 13.4 years, range 8.0-19.2; median age at diagnosis: 9.4 years, range 4.3-17.3) and 77 siblings (median age at assessment: 13 years, age range 7-18) participated. Survivors and siblings missed significantly more school days than the population control group (mean +/- SD: 9.6 +/- 9.2 and 9.9 +/- 9.8 vs 5.0 +/- 5.6 days, respectively, P < .0001). Among matched survivor-sibling pairs (N = 77), there was no difference in absenteeism (9.6 +/- 9.2 vs 9.9 +/- 9.8 days, P = .85). Absenteeism in survivors was significantly associated with a low Pediatric Quality of Life Inventory Physical Health Summary Score (P = .01). Parents' perception of their child's vulnerability and emotional and social functioning were not associated with absenteeism. CONCLUSIONS: Childhood cancer survivors and siblings miss more school than the general population. The only predictor of absenteeism in survivors is poor physical quality of health. More research should be devoted to school attendance and other outcomes in siblings of childhood cancer survivors. PMID- 22835884 TI - Yield of skeletal surveys in children <= 18 months of age presenting with isolated skull fractures. AB - OBJECTIVE: To measure the yield of a skeletal survey in children <= 18 months old presenting with isolated skull fractures without significant intracranial injury. STUDY DESIGN: A retrospective chart review was conducted on all children <= 18 months old presenting with an isolated skull fracture not associated with a motor vehicle crash or shopping cart fall between January 1, 2004 and December 31, 2010. An institutional protocol requires a skeletal survey and social work consult on all such children. We analyzed the association of mechanism of injury, type of skull fracture, and presence of "red flags" with a positive skeletal survey using chi(2) and Fisher exact tests. RESULTS: Of 175 eligible patients, 150 (86%) underwent a skeletal survey. Of the 9 patients (6%) who had another fracture in addition to the presenting one, only 1 child was older than 6 months. Eight patients with additional fractures had a simple skull fracture (not complex) and 7 patients with other fractures had at least 1 red flag. Regarding skull fractures, the majority of long falls (81%) resulted in a simple skull fracture. CONCLUSION: The skeletal survey in patients with isolated skull fractures revealed additional fractures in 6% of patients. Thus, a skeletal survey may yield clinically and forensically relevant data in such patients. However, it may be possible to restrict the window for obtaining a skeletal survey to younger infants, particularly those who are premobile. PMID- 22835885 TI - JAKing up AML1-ETO. PMID- 22835886 TI - PLADO and kids: earlier/increased bleeding after HSCT. PMID- 22835887 TI - Factor VIIa: on its own and loving it. PMID- 22835889 TI - Common perceptions of parents requesting personal exemption from vaccination. AB - School nurses, as vaccination advocates, need to be aware of parents' common concerns regarding vaccines, so the nurse can develop strategies to communicate with parents. The purpose of this cross-sectional, descriptive study was to identify common reasons parents in Utah seek exempting rather than vaccinating their children. Data were collected from a convenience sample of 801 parents responding to a 16-item questionnaire about why they exempted their children from receiving vaccinations. The most commonly reported reason for seeking a personal exemption included vaccines conflicting with philosophical beliefs. Parents exempting from one vaccine most commonly exempted the hepatitis series. Most parents communicated their vaccine concerns with their health care provider prior to seeking exemption. The majority of exempting parents did not use the Internet when researching vaccines even though they had Internet access. Considering the common vaccine-related perceptions of parents may be helpful when developing strategies to overcome these barriers to vaccination. PMID- 22835890 TI - Male vaccination against human papillomavirus. PMID- 22835891 TI - New research and development strategy for tuberculosis diagnostics urgently needed. PMID- 22835892 TI - Interferon-gamma release assays for prediction of tuberculosis. PMID- 22835893 TI - HIV-1 drug resistance in antiretroviral-naive patients in sub-Saharan Africa. PMID- 22835894 TI - Streptococcus vaccination and MRSA. PMID- 22835895 TI - Training in infectious diseases in India. PMID- 22835896 TI - A multidrug-resistance surveillance network: 1 year on. PMID- 22835897 TI - Changes to the life cycle of liver flukes: dams, roads, and ponds. PMID- 22835898 TI - Toxic cytological alteration and mitochondrial dysfunction in PC12 cells induced by 1-octyl-3-methylimidazolium chloride. AB - Ionic liquids have recently received considerable attention due to their negligible vapor pressure and substitute for conventional organic solvents. However, their solubility in water and a great deal of literature regarding their toxicity on aquatic organisms have caused much concern in recent years. This study aims to evaluate the cytotoxicity of 1-octyl-3-methylimidazolium chloride ([C(8)mim][Cl]) on the rat pheochromocytoma (PC12) cell line by cell viability assay and to determine the cytological alterations and damages in PC12 cells after 24h of exposure at the concentrations of 0.07, 0.14, and 0.28 mM of [C(8)mim][Cl]. The results show that [C(8)mim][Cl] inhibits PC12 cell growth and decreases their viabilities in a remarkable dose-dependent manner, and the 24h EC(50) of [C(8)mim][Cl] for PC12 cells is calculated to be around 0.56 mM. Our results also reveal that [C(8)mim][Cl]-exposure induces DNA damage, sustained increase of intracellular Ca(2+), overproduction of reactive oxygen species, gradually exhausted cellular ATP, mitochondrial permeability transition, and apoptosis in PC12 cells. We suppose that mitochondrial permeability transition and mitochondrial dysfunction maybe the major cytotoxicity mechanism of [C(8)mim]Cl for PC12 cells. PMID- 22835899 TI - Infectious bronchitis virus nucleoprotein specific CTL response is generated prior to serum IgG. AB - Infectious bronchitis (IB) is an acute and highly contagious viral respiratory disease of chickens. To understand the kinetics and relationships between the humoral (Ab) and antigen specific T cell immunity as well as pathological changes during infectious bronchitis virus (IBV) infection and immunization, one-week-old SPF chickens were vaccinated with live IBV H52 strain and challenged with IBV M41 15 days post primary infection. Chickens were sacrificed every 3 days to monitor antigen specific serum IgG and IBV nucleoprotein-specific immune responses using a chicken MHC I tetramer developed in our laboratory. The results demonstrated that T cell responses developed more rapidly than the humoral (Ab) immune response after vaccination with H52. However, serum IgG dramatically increased after M41 challenge. Chickens from the control, non-vaccinated group developed severe respiratory symptoms and demonstrated significant pathological changes in lung, kidney and bursa of Fabricius post challenge with M41. However, chickens vaccinated with H52 did not demonstrate clinical signs or histological changes post challenge with M41. These results indicated that the live IBV H52 inoculation effectively protected chickens from morbidity and pathological changes associated with IBV infection. These data facilitates the design of a new generation of IBV vaccine. PMID- 22835900 TI - A combination of biocompatible peritoneal dialysis solutions and residual renal function, peritoneal transport, and inflammation markers: a randomized clinical trial. AB - BACKGROUND: The benefits of biocompatible peritoneal dialysis (PD) fluids, particularly for residual renal function (RRF), are controversial. Moreover, the clinical effects of a PD regimen consisting of different biocompatible PD fluids have not been fully established. STUDY DESIGN: Prospective, randomized, controlled, open-label study. SETTING & PARTICIPANTS: Patients with end-stage kidney disease newly started on continuous ambulatory PD therapy (N = 150). INTERVENTION: A 12-month intervention with 3 biocompatible PD fluids (a neutral pH, low glucose degradation product, 1.5% glucose solution; a solution with 1.1% amino acid; and a fluid with 7.5% icodextrin) or conventional PD fluid. OUTCOMES: The primary outcome was change in RRF and daily urine volume. Secondary outcomes were peritoneal transport and inflammation markers. MEASUREMENTS: RRF, daily urine volume, serum and dialysate cytokine levels. RESULTS: RRF(3.24 +/- 1.98 vs 2.88 +/- 2.43 mL/min/1.73 m(2); P = 0.9) and rate of decline in RRF (-0.76 +/- 1.77 vs -0.91 +/- 1.92 mL/min/1.73 m(2) per year; P = 0.6) did not differ between the biocompatible- and conventional-PD-fluid groups. However, patients using the biocompatible PD fluids had better preservation of daily urine volume (959 +/- 515 vs 798 +/- 615 mL/d in the conventional group, P = 0.02 by comparison of difference in overall change by repeated-measures analysis of variance). Their dialysate-plasma creatinine ratio at 4 hours was higher at 12 months (0.78 +/- 0.13 vs 0.68 +/- 0.12; P = 0.01 for comparison of the difference in overall change by repeated-measures analysis of variance). They also had significantly higher serum levels of adiponectin and overnight spent dialysate levels of cancer antigen 125, adiponectin, and interleukin 6 (IL-6). No differences between the 2 groups were observed for serum C-reactive protein and IL-6 levels. LIMITATIONS: Unblinded, relatively short follow-up; no formal sample-size calculations. CONCLUSIONS: Use of a combination of 3 biocompatible PD fluids for 12 months compared with conventional PD fluid did not affect RRF, but was associated with better preservation of daily urine volume. The biocompatible PD fluids also lead to changes in small-solute transport and an increase in dialysate cancer antigen 125, IL-6, adiponectin, and systemic adiponectin levels, but have no effect on systemic inflammatory response. The clinical significance of these changes, while of great interest, remains to be determined by further studies. PMID- 22835901 TI - Albuminuria, estimated GFR, traditional risk factors, and incident cardiovascular disease: the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. AB - BACKGROUND: Abnormal levels of both albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers. STUDY DESIGN: Prospective community based cohort study. SETTING & PARTICIPANTS: 8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality. PREDICTOR OR FACTOR: The contribution of albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed. OUTCOMES: The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality. MEASUREMENTS: At the baseline visit, albuminuria was measured in 2 consecutive 24 hour urine samples. eGFR was calculated using the serum creatinine-based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. RESULTS: In multivariable Cox regression models, albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of albuminuria). When added to the risk model consisting of Framingham risk factors, albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P<0.001) and increase in relative incremental discrimination improvement of 3.0% (95% CI, 0.9%-5.1%; P=0.006). LIMITATIONS: The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities. CONCLUSION: In a general population cohort, albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all cause mortality. PMID- 22835902 TI - Acute kidney injury and bilateral symmetrical enlargement of the kidneys as first presentation of B-cell lymphoblastic lymphoma. AB - Lymphoblastic lymphoma is an uncommon subtype of lymphoid neoplasm in adults. Acute kidney injury at initial presentation due to lymphoblastic lymphoma infiltration of the kidneys has rarely been described. We report a 19-year-old woman who presented with acute kidney injury due to massive lymphomatous infiltration of the kidneys. The diagnosis of B-cell lymphoblastic lymphoma was established by immunohistochemical study of the biopsied kidney. The patient had an excellent response to the VDCLP protocol (vincristine, daunomycin, cyclophosphamide, asparaginase, and dexamethasone) with sustained remission. We recommend that lymphomatous infiltration be considered in patients presenting with unexplained acute kidney injury and enlarged kidneys. PMID- 22835903 TI - Dialysis patient safety: safeguards to prevent iatrogenic hypoglycemia in patients receiving icodextrin. PMID- 22835904 TI - Positionally biased gene loss after whole genome duplication: evidence from human, yeast, and plant. AB - Whole genome duplication (WGD) has made a significant contribution to many eukaryotic genomes including yeast, plants, and vertebrates. Following WGD, some ohnologs (WGD paralogs) remain in the genome arranged in blocks of conserved gene order and content (paralogons). However, the most common outcome is loss of one of the ohnolog pair. It is unclear what factors, if any, govern gene loss from paralogons. Recent studies have reported physical clustering (genetic linkage) of functionally linked (interacting) genes in the human genome and propose a biological significance for the clustering of interacting genes such as coexpression or preservation of epistatic interactions. Here we conduct a novel test of a hypothesis that functionally linked genes in the same paralogon are preferentially retained in cis after WGD. We compare the number of protein protein interactions (PPIs) between linked singletons within a paralogon (defined as cis-PPIs) with that of PPIs between singletons across paralogon pairs (defined as trans-PPIs). We find that paralogons in which the number of cis-PPIs is greater than that of trans-PPIs are significantly enriched in human and yeast. The trend is similar in plants, but it is difficult to assess statistical significance due to multiple, overlapping WGD events. Interestingly, human singletons participating in cis-PPIs tend to be classified into "response to stimulus." We uncover strong evidence of biased gene loss after WGD, which further supports the hypothesis of biologically significant gene clusters in eukaryotic genomes. These observations give us new insight for understanding the evolution of genome structure and of protein interaction networks. PMID- 22835906 TI - Effect of 2-(4-fluorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole on the molecular organisation and structural properties of the DPPC lipid multibilayers. AB - Interactions and complex formation between lipids and biologically active compounds are crucial for better understanding of molecular mechanisms occurring in living cells. In this paper a molecular organisation and complex formation of 2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT) in DPPC multibilayers are reported. The simplified pseudo binary phase diagram of this system was created based on the X-ray diffraction study and fourier transform infrared spectroscopic data. The detailed analysis of the refraction effect indicates a much higher concentration of FABT in the polar zones during phase transition. Both the lipid and the complex ripple after cooling. It was found that FABT occupied not only the hydrophilic zones of the lipid membranes but also partly occupied the central part of the non polar zone. The infrared spectroscopy study reveals that FABT strongly interact with hydrophilic (especially PO(2)(-)) and hydrophobic (especially "kink" vibrations of CH(2) group). The interactions of FABT molecules with these groups are responsible for changes of lipid multibilayers observed in X-ray diffraction study. PMID- 22835907 TI - Perforated mitral valve annular phlegmon with ventriculo-atrial fistula. AB - Herein we describe a case of perforated mitral valve annular abscess/phlegmon that presented as a new pan-systolic murmur in the setting of hallux osteomyelitis requiring amputation. We discuss the investigations, imaging and complex management challenges arising from this rare condition and the importance of considering a diagnosis of infective endocarditis in patients with a new cardiac murmur. PMID- 22835905 TI - Novel roles for KLF1 in erythropoiesis revealed by mRNA-seq. AB - KLF1 (formerly known as EKLF) regulates the development of erythroid cells from bi-potent progenitor cells via the transcriptional activation of a diverse set of genes. Mice lacking Klf1 die in utero prior to E15 from severe anemia due to the inadequate expression of genes controlling hemoglobin production, cell membrane and cytoskeletal integrity, and the cell cycle. We have recently described the full repertoire of KLF1 binding sites in vivo by performing KLF1 ChIP-seq in primary erythroid tissue (E14.5 fetal liver). Here we describe the KLF1-dependent erythroid transcriptome by comparing mRNA-seq from Klf1(+/+) and Klf1(-/-) erythroid tissue. This has revealed novel target genes not previously obtainable by traditional microarray technology, and provided novel insights into the function of KLF1 as a transcriptional activator. We define a cis-regulatory module bound by KLF1, GATA1, TAL1, and EP300 that coordinates a core set of erythroid genes. We also describe a novel set of erythroid-specific promoters that drive high-level expression of otherwise ubiquitously expressed genes in erythroid cells. Our study has identified two novel lncRNAs that are dynamically expressed during erythroid differentiation, and discovered a role for KLF1 in directing apoptotic gene expression to drive the terminal stages of erythroid maturation. PMID- 22835908 TI - [Esophageal atresia]. AB - Most of the children operated for esophageal atresia will survive the neonatal period. However, medium-term and late complications are frequent in this population. Gastroesophageal reflux disease is observed in 26 to 75% of the cases and can be responsible for peptic esophagitis, anastomotic stenosis, and Barrett esophagus, which is a risk factor for adenocarcinoma of the esophagus. Dysphagia is frequently observed, sometimes several years after the surgery, affecting up to 45% of children at the age of 5 years. Growth retardation is present in nearly one-third of children at the age of 5 years. Ear, nose, and throat and respiratory complications are also very frequent but tend to improve with time. Tracheomalacia is found in 75% of these children at birth, sometimes responsible for severe complications (malaise, bradycardia). Respiratory symptoms are dominated by chronic cough, wheezing, and infections reported in 29% of the children by the age of 5 years. Restrictive, obstructive syndromes and bronchial hyperactivity can be observed, but usually remain moderate. All these complications can influence the patient's quality of life, which is moderately impaired compared to healthy controls. The high frequency of late sequelae in esophageal atresia justifies regular and multidisciplinary follow-up through adulthood. PMID- 22835909 TI - [Neonatal medicine: which lessons are to be learned from past and present?]. PMID- 22835910 TI - Self-assembly of montmorillonite platelets during drying. AB - This work is prompted by the quest for nanocomposites in which ordered, layered reinforcement preforms similar in structure to the arrangements seen in nacre are achieved without complex automated layer-by-layer assembly. Lamellar structures were obtained in montmorillonite films simply by slow drying without the use of additives. Clay alignment was found in films derived from suspensions of less than 0.9 vol%, ranging over a pH range of 2-11, at low drying rates and with both the natural ionic strength of the clay suspension and adjusted ionic strength. The greatest degree of order was found at the unadjusted pH and ionic strength. This method offers a potentially simple way of preparing clay preforms for polymer-clay nanocomposites at a drying rate at or below 23 nm s(-1). PMID- 22835911 TI - The high frequency of periodic limb movements in patients with Lewy body dementia. AB - BACKGROUND: Although dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimer's disease (AD), the clinical diagnosis is frequently difficult. Because both REM sleep behavior disorders and Parkinson's disease also have alpha-synucleinopathy similar to DLB, and show an increase in periodic limb movements (PLM), we evaluated the association between DLB and PLM, which may serve as an additional information to differentiate AD and DLB. METHODS: Overnight polysomnographic recordings were performed for the inpatients in our hospital who were suspected to have dementia. The quality of sleep, oxygen-desaturation index and periodic limb movements were compared among the patients clinically diagnosed with DLB, AD or as having no dementia. RESULTS: Nine DLB patients, twelve AD patients and ten non-demented patients were enrolled in the study. The number of PLM during sleep per hour of total sleep time (PLMS index) was significantly higher in the DLB patients than the AD patients or the non-demented patients. No significant differences were found between the AD patients and the non-demented patients. To differentiate DLB from AD, a PLMS index of more than 15.0 had a sensitivity of 88.9% and a specificity of 83.3%. CONCLUSIONS: The DLB patients exhibited a higher PLMS index than the AD patients, and this index could be clinically useful for the diagnostic differentiation of DLB from AD. PMID- 22835913 TI - Dementia: toward contextual understanding. PMID- 22835912 TI - Abnormal neural activity of brain regions in treatment-resistant and treatment sensitive major depressive disorder: a resting-state fMRI study. AB - BACKGROUND: Patients with treatment-resistant depression (TRD) and those with treatment-sensitive depression (TSD) responded to antidepressants differently. Previous studies have commonly shown that patients with TRD or TSD had abnormal neural activity in different brain regions. In the present study, we used a coherence-based ReHo (Cohe-ReHo) approach to test the hypothesis that patients with TRD or TSD had abnormal neural activity in different brain regions. METHODS: Twenty-three patients with TRD, 22 with TSD, and 19 healthy subjects (HS) matched with gender, age, and education level participated in the study. RESULTS: ANOVA analysis revealed widespread differences in Cohe-ReHo values among the three groups in different brain regions which included bilateral superior frontal gyrus, bilateral cerebellum, left inferior temporal gyrus, left occipital cortex, and both sides of fusiform gyrus. Compared to HS, lower Cohe-ReHo values were observed in TRD group in bilateral superior frontal gyrus and left cerebellum; in contrast, in TSD group, lower Cohe-ReHo values were mainly found in bilateral superior frontal gyrus. Compared to TSD group, TRD group had lower Cohe-ReHo in bilateral cerebellum and higher Cohe-ReHo in left fusiform gyrus. There was a negative correlation between Cohe-ReHo values of the left fusiform gyrus and illness duration in the pooled patients (r = 0.480, p = 0.001). The sensitivity and specificity of cerebellar Cohe-ReHo values differentiating TRD from TSD were 83% and 86%, respectively. CONCLUSIONS: Compared to healthy controls, both TRD and TSD patients shared the majority of brain regions with abnormal neural activity. However, the lower Cohe-ReHo values in the cerebellum might be as a marker to differentiate TRD from TSD with high sensitivity and specificity. PMID- 22835914 TI - Function of transected or avulsed rectus muscles following recovery using an anterior orbitotomy approach. AB - PURPOSE: To assess the function of muscles retrieved from a retrobulbar location using an anterior orbitotomy approach and to identify the prognostic factors favoring a good outcome. METHODS: The records of all patients undergoing anterior orbitotomy for the retrieval of a transected or avulsed muscle in a retrobulbar location were reviewed. Ocular motility, before and after retrieval (with ductions scaled from -4 to +4), was evaluated. RESULTS: Record review identified 11 patients who had suffered trauma to 12 muscles (5 inferior, 6 medial, and 1 lateral rectus muscle). Ductions improved from -4 +/- 0.4 preoperatively to -2.7 +/- 0.9 postoperatively (P = 0.002); mean primary position deviation improved from 34(Delta) +/- 14(Delta)-15(Delta) +/- 9(Delta) (P < 0.001), and mean deviation in the field of action improved from 47(Delta) +/- 20(Delta)-20(Delta) +/- 22(Delta) (P = 0.02). Ductions improved by at least two units in three patients, all of whom had medial rectus trauma. Single binocular vision in primary gaze was achieved in 6 patients. Patients with medial rectus muscle injury and patients injured by sinus surgery had the lowest likelihood of recovering single binocular vision. CONCLUSIONS: Our results are similar to historical series in which muscles were not retrieved and transpositions performed; however, muscle retrieval avoids risks associated with transposition surgeries such as anterior segment ischemia. Muscle recovery via the anterior orbitotomy approach may be reasonable to consider in those cases with a reasonable possibility of having active force generation postoperatively. PMID- 22835915 TI - Spectral domain optical coherence tomography findings in retinal folds associated with posterior microphthalmos. AB - Posterior microphthalmos is a rare congenital malformation characterized by normal anterior segment dimensions with an abnormally small posterior segment resulting in high hyperopia. Reduced visual acuity in these cases is sometimes caused by the presence of papillomacular retinal folds. We report two cases of posterior microphthalmos in which the papillomacular folds could be visualized on spectral domain optical coherence tomography with sufficient detail to illustrate that only the layers of neural retina within the external limiting membrane were involved. PMID- 22835916 TI - Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European Institute of Oncology of Milan (SOUND: Sentinel node vs Observation after axillary UltraSouND). AB - Sentinel lymph node biopsy (SLNB) is the standard approach for axillary staging in patients with early breast cancer. Recent data showed no outcome difference in patients with positive sentinel node between axillary dissection vs no further axillary surgery, raising doubts on the role of SLNB itself. Therefore, a new trial was designed comparing SLNB vs observation when axillary ultra-sound is negative in patients with small breast cancer candidates to breast conserving surgery. PMID- 22835917 TI - Does breast cancer tumor size really matter that much? AB - Tumor size should be taken into consideration when planning treatments, but final decisions should also be made on the basis of the biological characteristics of the tumor in order to achieve a personalized approach to each individual cancer and to offer the best possible treatment to each patient. PMID- 22835918 TI - Predictive value of breast cancer molecular subtypes in Chinese patients with four or more positive nodes after postmastectomy radiotherapy. AB - The molecular subtypes of breast cancer based on status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) expression are associated with markedly different clinical outcomes. We retrospectively analyzed 774 breast cancer patients with four or more positive nodes, who underwent mastectomy between March 1999 and December 2007. Treatment with postmastectomy radiotherapy (PMRT) reduced the rates of locoregional recurrence-free survival (LRFS; 6.7% vs. 26.6%), distant metastasis-free survival (DMFS; 26.9% vs. 50.0%), and mortality (24.4% vs. 45.3%) for luminal-A subtypes (ER+ or PR+, Her2-) and reduced LRFS (12.1% vs. 27.5%) for the luminal-B subtype (ER+ or PR+, Her2+) compared with patients not receiving PMRT. However, PMRT did not affect the endpoints for the Her2-enriched or basal subtypes. Thus, understanding the differences in patterns of relapse between the different subtypes of breast cancer may enable targeted adjuvant therapy and improved surveillance decisions. PMID- 22835919 TI - The effect of demographic and lifestyle changes on the burden of breast cancer in Iranian women: a projection to 2030. AB - Iran is rapidly becoming an "ageing society" with a related increase in cancer incidence including breast cancer. This paper evaluates the trend in breast cancer incidence from the past to the present, in order to predict the future burden in Iran and to quantify the effect of changes in known risk factors on incidence over time. Currently, breast cancer incidence in Iran is low with approximately 5000 new cases annually. Under conservative assumptions, the number of new cases of breast cancer in 2030 will be more than 15000. In addition to demographic factors, changes in the prevalence of established risk factors such as reproductive factors and obesity are likely to result in changes in breast cancer patients over time. Extrapolating the increasing prevalence of obesity to the future, we expect that this specific factor will strongly contribute to the increased breast cancer incidence in the future unless preventive measures counteract this effect. PMID- 22835920 TI - Post-disaster psychosocial services across Europe: the TENTS project. AB - At present post-disaster activities and plans seem to vary widely. An adequate estimation of the availability of post-disaster psychosocial services across Europe is needed in order to compare them with recently developed evidence informed psychosocial care guidelines. Here we report on the results of a cross sectional web-based survey completed in 2008 by two hundred and eighty-six representatives of organizations involved in psychosocial responses to trauma and disaster from thirty-three different countries across Europe. The survey addressed planning and delivery of psychosocial care after disaster, methods of screening and diagnosis, types of interventions used, and other aspects of psychosocial care after trauma. The findings showed that planning and delivery of psychosocial care was inconsistent across Europe. Countries in East Europe seemed to have less central coordination of the post-disaster psychosocial response and fewer post-disaster guidelines that were integrated into specific disaster or contingency plans. Several forms of psychological debriefing, for which there is no evidence of efficacy to date, were still used in several areas particularly in North Europe. East European countries delivered evidence-based interventions for PTSD less frequently, whilst in South- and South-Eastern European countries anxiety suppressing medication such as benzodiazepines were prescribed more frequently to disaster victims than in other areas. Countries across Europe are currently providing sub-optimal psychosocial care for disaster victims. This short report shows that there is an urgent need for some countries to abandon non effective interventions and others to develop more evidence based and effective services to facilitate the care of those involved in future disasters. PMID- 22835921 TI - Behavioral adjustment to avian flu in Europe during spring 2006: the roles of knowledge and proximity to risk. AB - The threat of a widespread avian flu influenza outbreak represented a significant public health challenge for the European region during late 2005 and early 2006. Little is known, however, about how individuals learn about new global-level health risks, especially influenza outbreaks. We empirically test the hypothesis that knowledge about and geographic proximity to avian flu play a role in individuals' consumption behavior regarding this health risk. This article employs Eurobarometer survey data collected in spring 2006 to examine how Europeans (from 27 European Union countries plus Croatia and Turkey) altered their consumption of poultry, eggs and egg-based products during the virus' emergence in Europe. Our findings are consistent with the hypothesis that behavioral change indeed depends on proximity to those risks. Significant differences emerged between individuals' likelihood of behavioral change in countries where avian flu had been found in humans either in individuals' countries of residence or in bordering countries. Furthermore, we find that those who were more knowledgeable about avian flu risks were less likely to have reduced their consumption of poultry, eggs or egg-related products in the spring of 2006 compared to six months prior. Yet, the influence knowledge has on consumption behavior is found to change depending on proximity to avian flu risks. These findings have implications for our larger understanding of how individuals alter their behavior in the face of new health risks. PMID- 22835922 TI - The logical underpinnings and benefits of pooled pharmaceutical procurement: a pragmatic role for our public institutions? AB - Multi-national pharmaceutical companies have long operated across national boundaries, and exercised significant leverage because of the breadth and depth of their market control. The goals of public health can be better served by redressing the imbalance in market leverage between supply and demand. Consolidation of purchasing power across borders, as well as within countries across organizational entities, is one means to addressing this imbalance. In those existing pooled procurement models that consolidate purchasing across national boundaries, benefits have included: 1) reductions in unit purchase prices; 2) improved quality assurance; 3) reduction or elimination of procurement corruption; 4) rationalized choice through better-informed selection and standardization; 5) reduction of operating costs and administrative burden; 6) increased equity between members; 7) augmented practical utility in the role of the host institutions (regional or international) administering the system; and finally, 8) increased access to essential medical products within each participating country. Many barriers to implementation of a multi-country pooled procurement system are eliminated when the mechanism is established within a regional or international institution, especially where participating countries are viewed (and view themselves) as clients/members of the institution, so that they have some sense of ownership over the procurement mechanism. This review article is based on two literature reviews, conducted between 2007 and 2009 (including publications from 1996 through 2009), and interviews with key informants. PMID- 22835923 TI - The mental health gender-gap in urban India: patterns and narratives. AB - Women report significantly higher levels of mental distress than men in community studies around the world. We provide further evidence on the origins of this mental health gender-gap using data from 789 adults, primarily spousal pairs, from 300 families in Delhi, India. These data were collected between 2001 and 2003. We first confirm that, like in other studies, women report higher levels of mental distress and that gender differences in education, household expenditures and age do not explain the mental health gender-gap. In contrast, women report significantly higher levels of distress than men in families with adverse reproductive outcomes, particularly the death of a child. Controlling for adverse reproductive outcomes sharply reduces the mental health gender-gap. Finally, mental health is strongly correlated with physical health for both men and women, but there is little evidence of a differential response by sex. We complement this empirical description with anthropological analysis based on ethnographic interviews with 100 men and 100 women. With the help of these ethnographic interviews we show how adverse life events for women are experienced as the inability to maintain the domestic, which seems to be at stake within their life worlds. We raise issues for further research on the apparent finding that the mental health of women and men are differentially affected by adverse reproductive events in the family in this sample. PMID- 22835924 TI - Raynaud, digital ulcers and calcinosis in scleroderma. AB - Raynaud, digital ulcers and calcinosis are frequent manifestations of patients with systemic sclerosis. Digital ulcers are seen in more than half of the patients with scleroderma. Hospitalizations, ischemic complications and impairment of hand function are frequently observed in patients with digital ulcers, especially if treatment is delayed. Rapid and intensive treatment escalation in patients with scleroderma and refractory Raynaud's phenomenon is one of the most effective preventive action available in order to avoid the development of digital ulcers and tissue loss. PMID- 22835925 TI - Shift work and vascular events: systematic review and meta-analysis. AB - OBJECTIVE: To synthesise the association of shift work with major vascular events as reported in the literature. DATA SOURCES: Systematic searches of major bibliographic databases, contact with experts in the field, and review of reference lists of primary articles, review papers, and guidelines. STUDY SELECTION: Observational studies that reported risk ratios for vascular morbidity, vascular mortality, or all cause mortality in relation to shift work were included; control groups could be non-shift ("day") workers or the general population. DATA EXTRACTION: Study quality was assessed with the Downs and Black scale for observational studies. The three primary outcomes were myocardial infarction, ischaemic stroke, and any coronary event. Heterogeneity was measured with the I(2) statistic and computed random effects models. RESULTS: 34 studies in 2,011,935 people were identified. Shift work was associated with myocardial infarction (risk ratio 1.23, 95% confidence interval 1.15 to 1.31; I(2)=0) and ischaemic stroke (1.05, 1.01 to 1.09; I(2)=0). Coronary events were also increased (risk ratio 1.24, 1.10 to 1.39), albeit with significant heterogeneity across studies (I(2)=85%). Pooled risk ratios were significant for both unadjusted analyses and analyses adjusted for risk factors. All shift work schedules with the exception of evening shifts were associated with a statistically higher risk of coronary events. Shift work was not associated with increased rates of mortality (whether vascular cause specific or overall). Presence or absence of adjustment for smoking and socioeconomic status was not a source of heterogeneity in the primary studies. 6598 myocardial infarctions, 17,359 coronary events, and 1854 ischaemic strokes occurred. On the basis of the Canadian prevalence of shift work of 32.8%, the population attributable risks related to shift work were 7.0% for myocardial infarction, 7.3% for all coronary events, and 1.6% for ischaemic stroke. CONCLUSIONS: Shift work is associated with vascular events, which may have implications for public policy and occupational medicine. PMID- 22835926 TI - Cochleopathy in Egyptian adolescents with Type 1 diabetes mellitus. AB - BACKGROUND: Diabetic neuropathy is recognized as the most common clinical picture of nervous system disorders caused by diabetes mellitus (DM). Although peripheral and autonomic nervous system involvements are frequently encountered, data about the incidence of central diabetic neuropathies is limited. OBJECTIVE: Our study aimed to detect early asymptomatic auditory impairment whether at the level of outer hair cells (OHCs), inner hair cells (IHCs) and or olivo-cochlear bundle and the relationship between these abnormalities and other variables such as diabetes duration, degree of the metabolic control, or presence of microvascular complications. SUBJECTS AND METHODS: Seventy five adolescents with Type 1 DM and thirty three healthy controls participated in the study. Duration of DM, glycated hemoglobin (HbA1c) levels, microvascular complications were analyzed. All underwent basic audiological assessment to ensure normal hearing and normal middle ear function. Other tests comprised: transiently evoked otoacoustic emissions (TEOAEs) testing OHCs, TEOAEs with contralateral suppression (testing the integrity of olivo-cochlear bundle) and threshold equalizing noise (TEN) testing IHCs as evidenced by dead regions within the cochlea. RESULTS: Early asymptomatic OHCs involvement as reflected by partial pass in 33.3% of cases with diminished suppression as compared to 9.1% control group. Eleven patients (7.33%) showed positive TEN Test reflecting resistance of IHCs to hyperglycemic injury. Diabetic patients had significantly higher amplitude on TEOAEs with noise suppression when compared to controls (P=0.002). The mean difference in amplitude of TEOAEs before and after suppression was significantly higher in diabetics with microvascular complications when compared to diabetic children without complications at all frequencies (P<0.001 for all). Duration of diabetes and microvascular complications (nephropathy, peripheral and autonomic neuropathy) were not correlated with the lack of suppression except for retinopathy (P=0.02). In contrast, poor metabolic control was associated with poor suppression (r= 0.443, P=0.001). CONCLUSIONS: Cochleopathy can be detected in a relatively high proportion of subjects with Type 1 diabetes in spite of a normal audiometric hearing threshold. It should be considered as early manifestation of diabetic neuropathy which is related to the degree of metabolic control and retinopathy independent of other microvascular complications. PMID- 22835927 TI - Adenoidectomy in young children and serum IgG antibodies to pneumococcal surface protein A and choline binding protein A. AB - OBJECTIVE: We have previously reported that surgical removal of the nasopharyngeal adenoid in young children resulted in increased risk of nasopharyngeal colonization by pneumococci. We now investigated whether adenoidectomy influences the development of serum IgG antibodies to pneumococcal choline-binding protein A (CbpA) and pneumococcal surface protein A (PspA). METHODS: Altogether 217 children aged 12-48 months who had recurrent or persistent otitis media were randomized to undergo or not to undergo adenoidectomy. All the children underwent insertion of tympanostomy tubes. 166 children were followed-up for 3 years. The main outcome measures were concentrations of serum IgG antibodies to CbpA and PspA three years after randomization. Nasopharyngeal colonization by pneumococci was assessed 1, 2, and 3 years after randomization. RESULTS: Adenoidectomy decreased concentrations of CbpA antibodies by ca. 25% independently of the observed increase in pneumococcal carriage (OR of log(10) transformed concentrations 0.74, 95% CI 0.58-0.94, P=0.016). Concentrations of PspA antibodies were lower and they seemed not to be influenced by adenoidectomy. CONCLUSIONS: Adenoidectomy in young children causes a small but detectable impairment in the development of serum IgG antibodies to pneumococcal CbpA. The adenoid seems to have a role in augmenting systemic immunity against pneumococci. PMID- 22835928 TI - Investigation on the music perception skills of Italian children with cochlear implants. AB - OBJECTIVE: To compare the music perception skills of a group of Italian-speaking children with cochlear implants to those of a group of normal hearing children; to analyze possible correlations between implanted children's musical skills and their demographics, clinical characteristics, phonological perception, and speech recognition and production abilities. METHODS: 18 implanted children aged 5-12 years and a reference group of 23 normal-hearing subjects with typical language development were enrolled. Both groups received a melody identification test and a song (i.e. original version) identification test. The implanted children also received a test battery aimed at assessing speech recognition, speech production and phoneme discrimination. RESULTS: The implanted children scored significantly worse than the normal hearing subjects in both musical tests. In the cochlear implant group, phoneme discrimination abilities were significantly correlated with both melody and song identification skills, and length of device use was significantly correlated with song identification skills. CONCLUSIONS: Experience with device use and phonological perception had a moderate-to-strong correlation to implanted children's music perception abilities. In the light of these findings, it is reasonable to assume that a rehabilitation program specifically aimed at improving phonological perception could help pediatric cochlear implant recipients better understand the basic elements of music; moreover, a training aimed at improving the comprehension of the spectral elements of music could enhance implanted children's phonological skills. PMID- 22835929 TI - Implant double tissue expanders superposingly in mastoid region for total ear reconstruction without skin grafts. AB - OBJECTIVE: To present our clinical experience in using two skin soft-tissue expanders implanted superposingly in the mastoid region and Medpor ear framework for congenital microtia reconstruction. METHODS AND MATERIALS: The process of our technique is divided into three stages. In the first surgical stage, a 50 cm(3) and 80 cm(3) kidney-shaped expander is implanted under the fatty layer in mastoid region. Overlay the big expander on the small one. After the first surgery stage they are inflated alternately. In the second surgical stage, we remove two skin soft-tissue expanders and fix the Medpor ear framework to the fascial tissue which is covered by the expanded skin flap wholly without application of fascial flap. In the third stage, we perform the transposition of the auricular lobule to the designated position, construction of the tragus and refinement the new reconstructed ear. From January 2009 to December 2010, 27 patients were treated by this method of total ear reconstruction. RESULTS: 27 patients acquired symmetrical, subtle contour, prominent reconstructed auricles. The new reconstructed ear had a good contour and its skin color and texture were nearly the same as the normal surrounding skin. The postauricular sulcus was stable and satisfactory. The postoperative follow-up time ranged from 1 to 3 years. The expanded skin flap took well without necrosis. Exposure of the skin expander occurred in 2 patients (7.4%). The Medpor ear framework was extrused in one patient (3.7%). In addition, the hematoma was observed in 3 patients (11.1%). No other severe complications happened. CONCLUSION: Overlying implantation of two skin-soft skin expanders solves the problem of insufficient amount of the skin flap, avoids postauricular skin grafting, simplifies the surgical procedure and shortens the operation time significantly. PMID- 22835930 TI - The music perception abilities of prelingually deaf children with cochlear implants. AB - OBJECTIVE: To investigate the music perception abilities of prelingually deaf children with cochlear implants, in comparison to a group of normal-hearing children, and to consider the factors that contribute to music perception. METHODS: The music perception abilities of 39 prelingually deaf children with unilateral cochlear implants were compared to the abilities of 39 normal hearing children. To assess the music listening abilities, the MuSIC perception test was adopted. The influence of the child's age, age at implantation, device experience and type of sound-processing strategy on the music perception were evaluated. The effects of auditory performance, nonverbal intellectual abilities, as well as the child's additional musical education on music perception were also considered. RESULTS: Children with cochlear implants and normal hearing children performed significantly differently with respect to rhythm discrimination (55% vs. 82%, p<0.001), instrument identification (57% vs. 88%, p<0.001) and emotion rating (p=0.022). However we found no significant difference in terms of melody discrimination and dissonance rating between the two groups. There was a positive correlation between auditory performance and melody discrimination (r=0.27; p=0.031), between auditory performance and instrument identification (r=0.20; p=0.059) and between the child's grade (mark) in school music classes and melody discrimination (r=0.34; p=0.030). In children with cochlear implant only, the music perception ability assessed by the emotion rating test was negatively correlated to the child's age (r(S)=-0.38; p=0.001), age at implantation (r(S)= 0.34; p=0.032), and device experience (r(S)=-0.38; p=0.019). The child's grade in school music classes showed a positive correlation to music perception abilities assessed by rhythm discrimination test (r(S)=0.46; p<0.001), melody discrimination test (r(S)=0.28; p=0.018), and instrument identification test (r(S)=0.23; p=0.05). CONCLUSIONS: As expected, there was a marked difference in the music perception abilities of prelingually deaf children with cochlear implants in comparison to the group of normal hearing children, but not for all the tests of music perception. Additional multi-centre studies, including a larger number of participants and a broader spectrum of music subtests, considering as many as possible of the factors that may contribute to music perception, seem reasonable. PMID- 22835931 TI - Adjuvant strategies for potentiation of antibiotics to overcome antimicrobial resistance. AB - Alarming facts about the occurrence and spreading of multiple antibiotic resistant bacteria have caught the attention of global surveillance authorities and public media. The demand for novel effective antimicrobial drugs is high and on the rise while, at the same time, the supply of fresh 'magic bullets' is drying up. This review summarizes examples of recent strategies for development of adjunctive antibiotic therapies that overcome microbial resistance and thus rejuvenate the existing arsenal of drugs. Recent studies have demonstrated the potential of compounds that inhibit the action of the repressor protein implicated in ethionamide resistance, thus stimulating activation of the drug and thereby restoring the activity of the antibiotic for treatment of Mycobacterium tuberculosis. Such specific interference with regulators or signal transduction mechanisms involved in antibiotic resistance or virulence provides a new toolbox for novel combinations of antimicrobial drugs with adjuvant molecules lacking intrinsic antibiotic activity. In addition to the development of new antibiotics and vaccination initiatives this strategy of restoring or potentiating the activity of existing antibiotics may help to postpone the day when antibiotics are no longer generally efficacious. PMID- 22835932 TI - A molecular model and Monte Carlo simulation of flavivirus envelope building block. AB - A molecular model of mature dengue virus envelope building block consisting of two E and two M protein subunits is constructed. Monte Carlo optimisation is performed for the model in the implicit membrane system. Interactions between the ectodomains and membrane parts of E and M proteins are studied, and possible role of conserved residues is suggested. The opening of E protein detergent binding site and its fixation in the open state by the M non-structured loop is observed. PMID- 22835933 TI - The N-terminus of TDP-43 promotes its oligomerization and enhances DNA binding affinity. AB - TDP-43 is a DNA/RNA-binding protein associated with different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). Here, the structural and physical properties of the N terminus on TDP-43 have been carefully characterized through a combination of nuclear magnetic resonance (NMR), circular dichroism (CD) and fluorescence anisotropy studies. We demonstrate for the first time the importance of the N terminus in promoting TDP-43 oligomerization and enhancing its DNA-binding affinity. An unidentified structural domain in the N-terminus is also disclosed. Our findings provide insights into the N-terminal domain function of TDP-43. PMID- 22835935 TI - Transition between nuclear and quark-gluon descriptions of hadrons and light nuclei. AB - We provide a perspective on studies aimed at observing the transition between hadronic and quark-gluonic descriptions of reactions involving light nuclei. We begin by summarizing the results for relatively simple reactions such as the pion form factor and the neutral pion transition form factor as well as that for the nucleon and end with exclusive photoreactions in our simplest nuclei. A particular focus will be on reactions involving the deuteron. It is noted that a firm understanding of these issues is essential for unravelling important structure information from processes such as deeply virtual Compton scattering as well as deeply virtual meson production. The connection to exotic phenomena such as color transparency will be discussed. A number of outstanding challenges will require new experiments at modern facilities on the horizon as well as further theoretical developments. PMID- 22835934 TI - Progesterone induced mesenchymal differentiation and rescued cystic dilation of renal tubules of Pkd1(-/-) mice. AB - Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary disease affecting the kidneys, is caused in 85% of cases by mutations in the PKD1 gene. The protein encoded by this gene, polycystin-1, is a renal epithelial cell membrane mechanoreceptor, sensing morphogenetic cues in the extracellular environment, which regulate the tissue architecture and differentiation. However, how such mutations result in the formation of cysts is still unclear. We performed a precise characterization of mesenchymal differentiation using PAX2, WNT4 and WT1 as a marker, which revealed that impairment of the differentiation process preceded the development of cysts in Pkd1(-/-) mice. We performed an in vitro organ culture and found that progesterone and a derivative thereof facilitated mesenchymal differentiation, and partially prevented the formation of cysts in Pkd1(-/-) kidneys. An injection of progesterone or this derivative into the intraperitoneal space of pregnant females also improved the survival of Pkd1( /-) embryos. Our findings suggest that compounds which enhance mesenchymal differentiation in the nephrogenesis might be useful for the therapeutic approach to prevent the formation of cysts in ADPKD patients. PMID- 22835936 TI - Characterization of cell membrane parameters of clinical isolates of Staphylococcus aureus with varied susceptibility to alpha-melanocyte stimulating hormone. AB - Staphylococcus aureus (S. aureus), a major human pathogen of hospital and community acquired infections, is becoming resistant to almost all commercially available antibiotics. This has prompted development of antimicrobial peptides as therapeutic options. Alpha melanocyte stimulating hormone (alpha-MSH) is one such peptide known to possess antimicrobial properties. In the present study, we analyzed the antimicrobial activity of alpha-MSH against 75 clinical strains of S. aureus including both methicillin susceptible S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) strains. Results of our previous study showed that membrane damage is the major mechanism of staphylocidal activity of alpha-MSH. In this context, we compared the various bacterial membrane parameters, viz., membrane fluidity, lipid composition, and surface charge of a few selected MSSA and MRSA strains that showed variable susceptibility to the melanocortin peptide. Our results showed that alpha-MSH killed both type of strains efficiently (>= 70% killing in 84% clinical strains after exposure with 6 MUM of alpha-MSH for 1h). It was observed that compared to the alpha-MSH-susceptible strains, the alpha-MSH non-susceptible strains had a different membrane order and phospholipid pattern. There was no consistent pattern of cell surface charge to distinguish alpha-MSH susceptible strain from a non-susceptible strain. In conclusion, alpha-MSH possessed potential staphylocidal activity for both against MSSA and MRSA strains. S. aureus strains not susceptible to the peptide exhibited a rigid membrane and a higher amount of the cationic phospholipid as compared to the alpha-MSH-susceptible strains. PMID- 22835937 TI - Potential hazards of precipitation associated with calcium chloride in parenteral nutrition admixtures: response to Migaki et al. PMID- 22835939 TI - Efficient synthesis of silver nanoparticles from Prosopis juliflora leaf extract and its antimicrobial activity using sewage. AB - In this paper, aqueous extract of fresh leaves of Prosopis juliflora was used for the synthesis of silver (Ag) nanoparticles. UV-Vis spectroscopy studies were carried out to asses silver nanoparticles formation within 5 min, scanning electron microscopic was used to characterize shape of the Ag nanoparticles, X ray diffraction analysis confirms the nanoparticles as crystalline silver and facecentered cubic type and Fourier transform infra-red assed that shows biomolecule compounds which are responsible for reduction and capping material of silver nanoparticles. The anti microbial activity of silver nanoparticle was performed using sewage. The approach of plant-mediated synthesis appears to be cost efficient, eco-friendly and easy methods. PMID- 22835940 TI - Carotid plaque high-resolution MRI at 3 T: evaluation of a new imaging score for symptomatic plaque assessment. AB - PURPOSE: To assess the sensitivity and specificity of intra-plaque hemorrhage (IPH), large lipid-rich necrotic core (LR-NC) and ulceration or cap rupture (UCR) for symptomatic carotid plaque characterization and to evaluate a new imaging score [Hemorrhage, Ulceration or cap rupture, Lipid-rich necrotic Core (HULC) score based on the sum of presence/absence of IPH, UCR and LR-NC; range 0-3] for assessment of recently symptomatic carotid plaques. MATERIAL AND METHODS: Twenty seven recently symptomatic (<8 weeks) and 36 asymptomatic patients with a carotid plaque thicker than 2 mm were prospectively imaged on a 3-T magnetic resonance (MR) system using high-resolution, multi-contrast MR sequences. Prior to analysis, all images were reviewed to assess image quality of each sequence. Sensitivity and specificity of IPH, LR-NC, UCR and HULC scores were calculated. RESULTS: Fifty-one patients were analyzed (26 symptomatic carotids and 67 asymptomatic carotids) after exclusion of studies with poor image quality. Sensitivity and specificity for symptomatic carotid plaque was, respectively, 46.1% and 97% for IPH, 84.6% and 73.1% for UCR and 80.7% and 76.1% for LR-NC. A HULC score of 2 or more showed a sensitivity of 73% and a specificity of 92.5%. CONCLUSION: At 3 T, intra-plaque hemorrhage is the most specific criterion to characterize symptomatic carotid plaque. The HULC score offers the best compromise between sensitivity and specificity. PMID- 22835941 TI - Monitoring the brain metabolites of children with acute encephalopathy caused by the H1N1 virus responsible for the 2009 influenza pandemic: a quantitative in vivo 1H MR spectroscopy study. AB - BACKGROUND AND PURPOSE: Influenza viral infection, which results in central nervous system dysfunction, is a major cause of acute encephalopathy (AE). The purpose of this study was to investigate the changes in the concentrations of brain metabolites in children with AE using single-voxel magnetic resonance spectroscopy (MRS) and to provide diagnostic information about the relationship between the symptoms of AE and metabolite concentrations. MATERIALS AND METHODS: The subjects were 10 children (mean age: 6.2 years; range: 1-13) with AE caused by the novel influenza A virus responsible for the 2009 influenza pandemic. The serial MRS data (TE/TR=30/5000 ms, 3 T) acquired from the basal ganglia (BG) and centrum semiovale (CS) of each patient were categorized into three periods: (1) initial neurological symptom presentation and the start of treatment (n=10), (2) short-term follow-up (n=9) and (3) long-term follow-up (n=3). As controls, the magnetic resonance (MR) spectra of eight age-matched children were also investigated. RESULTS: In both regions, the concentrations of the major metabolites (N-acetylaspartate, creatine, choline, myo-inositol, glutamate/glutamine complex and glutamate) only showed minor fluctuations between the three periods. On the other hand, higher levels of taurine (Tau) were observed in the BG during the second period (P=.005), and increased levels of glucose were observed in the CS during the first (P=.005) and second (P=.036) periods. CONCLUSIONS: Serial monitoring of brain metabolite changes was carried out with a clinical MR system. The concentrations of major metabolites only displayed very minor fluctuations in response to mild H1N1-related AE. However, a higher Tau concentration was found to be associated with neurological symptoms. Further studies are required to improve our understanding of the detailed activity of Tau in AE. PMID- 22835942 TI - Quantification of low fat contents: a comparison of MR imaging and spectroscopy methods at 1.5 and 3 T. AB - Magnetic resonance spectroscopy (MRS) has long been considered the golden standard for non-invasive measurement of tissue fat content. With improved techniques for fat/water separation, imaging has become an alternative to MRS for fat quantification. Several imaging models have been proposed, but their performance relative to MRS at very low fat contents is yet not fully established. In this work, imaging and spectroscopy were compared at 1.5 T and 3 T in phantoms with 0-3% fat fraction (FF). We propose a multispectral model with individual a priori R(2) relaxation rates for water and fat, and a common unknown R(2)' relaxation. Magnitude and complex image reconstructions were also compared. Best accuracy was obtained with the imaging method at 1.5 T. At 3 T, the FFs were underestimated due to larger fat-water phase shifts. Agreement between measured and true FF was excellent for the imaging method at 1.5 T (imaging: FF(meas)=0.98 FF(true)-0.01%, spectroscopy: FF(meas)=0.77 FF(true)+0.08%), and fair at 3 T (imaging: FF(meas)=0.91 FF(true)-0.19%, spectroscopy: FF(meas)=0.79 FF(true)+0.02%). The imaging method was able to quantify FFs down to approx. 0.5%. We conclude that the suggested imaging model is capable of fat quantification with accuracy and precision similar to or better than spectroscopy and offers an improvement vs. a model with a common R(2)* relaxation only. PMID- 22835943 TI - Beyond laparoscopy: 3-T magnetic resonance imaging in the evaluation of posterior cul-de-sac obliteration. AB - OBJECTIVES: Endometriosis is the ectopic localization of endometrial glands. Symptoms include a wide variety of chronic pelvic pain. Ovarian endometriosis represents the most frequent site of implantation followed by the Douglas pouch which is undepicted unless peritoneal fluid is present. Pelvic exams may be reported as normal in 40% of evaluations, although multiple nodularities are located in this region. Nowadays, laparoscopy represents the standard technique for endometriosis evaluation. However, magnetic resonance imaging (MRI) remains the best noninvasive technique for the evaluation of pelvic lesions. According to the importance of a precise preoperative diagnosis of deep infiltrative endometriosis involving the Douglas pouch, we evaluated feasibility of a 3-T system in the evaluation of this particular region. METHODS: We enrolled 19 women coming with either ultrasound or anamnestic suspicion of endometriosis. Pelvic MRI examination was performed on the 3-T system. We applied a standard exam protocol including pulse sequences [single-shot fast spin echo (FSE)] and high resolution T2W and T1W FSE sequences with and without FS. RESULTS: MRI diagnosed posterior cul-de-sac obliteration in 15/19 patients. MRI findings were compared with laparoscopy, thus obtaining the following statistical values: mean sensitivity, specificity, positive predictive value and negative predictive value, respectively, of 93%, 75%, 93% and 75%. Moreover, we calculated an interobserver agreement k value of 0.72 with a substantial degree of agreement between two radiologists of a sensitivity value of 93% and specificity value of 75%. CONCLUSIONS: Precise preoperative mapping of posterior cul-de-sac region is essential for a preoperative planning. In our work, the 3-T MRI was shown to be excellent in the evaluation of posterior cul-de-sac obliteration associated to an optimal evaluation of the uterosacral ligaments due to the higher contrast spatial resolution. PMID- 22835944 TI - Type II-dependent secretion of a Pseudomonas aeruginosa DING protein. AB - Pseudomonas aeruginosa is an opportunistic bacterial pathogen that uses a wide range of protein secretion systems to interact with its host. Genes encoding the PAO1 Hxc type II secretion system are linked to genes encoding phosphatases (LapA/LapB). Microarray genotyping suggested that Pseudomonas aeruginosa clinical isolates, including urinary tract (JJ692) and blood (X13273) isolates, lacked the lapA/lapB genes. Instead, we show that they carry a gene encoding a protein of the PstS family. This protein, which we call LapC, also has significant similarities with LapA/LapB. LapC belongs to the family of DING proteins and displays the canonical DINGGG motif within its N terminus. DING proteins are members of a prokaryotic phosphate binding protein superfamily. We show that LapC is secreted in an Hxc-dependent manner and is under the control of the PhoB response regulator. The genetic organization hxc-lapC found in JJ692 and X13273 is similar to PA14, which is the most frequent P. aeruginosa genotype. While the role of LapA, LapB and LapC proteins remains unclear in P. aeruginosa pathogenesis, they are likely to be part of a phosphate scavenging or sensing system needed to survive and thrive when low phosphate environments are encountered within the host. PMID- 22835945 TI - Real-time monitoring of the adherence of Streptococcus anginosus group bacteria to extracellular matrix decorin and biglycan proteoglycans in biofilm formation. AB - Members of the Streptococcus anginosus group (SAGs) are significant pathogens. However, their pathogenic mechanisms are incompletely understood. This study investigates the adherence of SAGs to the matrix proteoglycans decorin and biglycan of soft gingival and alveolar bone. Recombinant chondroitin 4 sulphate(C4S)-conjugated decorin and biglycan were synthesised using mammalian expression systems. C4S-conjugated decorin/biglycan and dermatan sulphate (DS) decorin/biglycan were isolated from ovine alveolar bone and gingival connective tissue, respectively. Using surface plasmon resonance, adherence of the SAGs S. anginosus, Streptococcus constellatus and Streptococcus intermedius to immobilised proteoglycan was assessed as a function of real-time biofilm formation. All isolates adhered to gingival proteoglycan, 59% percent of isolates adhered to alveolar proteoglycans, 70% to recombinant decorin and 76% to recombinant biglycan. Higher adherence was generally noted for S. constellatus and S. intermedius isolates. No differences in adherence were noted between commensal and pathogenic strains to decorin or biglycan. DS demonstrated greater adherence compared to C4S. Removal of the glycosaminoglycan chains with chondroitinase ABC resulted in no or minimal adherence for all isolates. These results suggest that SAGs bind to the extracellular matrix proteoglycans decorin and biglycan, with interaction mediated by the conjugated glycosaminoglycan chain. PMID- 22835946 TI - Attenuated Listeria monocytogenes, a Mycobacterium tuberculosis ESAT-6 antigen expression and delivery vector for inducing an immune response. AB - We selectively expressed protective Mycobacterium tuberculosis antigen ESAT-6 in recombinant strains Lm(esat-6) and LmDeltaactA/plcB(esat-6) to evaluate the capacity of Listeria monocytogenes to deliver antigens from M. tuberculosis, and we studied the pathogenicity and immunogenicity of these strains compared with virulent parental strain yzuLm4 and attenuated strain LmDeltaactA/plcB. The two recombinant strains retained listeriolysin O hemolytic activity, escaped into the cytosol niche and established replication in the macrophage-like RAW264.7 cell line; however, these strains showed decreased virulence in C57BL/6 mice. Histopathology revealed no obvious pathological changes following administration of the recombinant strains to mice, indicating that they were significantly safer than parental strains. Moreover, intravenous vaccination of mice with the recombinant strains elicited specific Th1-type cellular immunity, splenocyte proliferation and effective CTL activity in vivo. Thus, attenuated L. monocytogenes strains can be used as effective vectors for delivering M. tuberculosis ESAT-6 and inducing a cellular immune response, suggesting that such vectors may be effective as novel vaccines for preventing tuberculosis. PMID- 22835947 TI - Real-time infrared thermography for ureter detection during hysterectomy. AB - BACKGROUND: Recognition of different anatomic structures might be difficult in the presence of diseases such as neoplasm or endometriosis that can subvert the anatomy. This can be a challenge for young surgeons approaching gynecologic surgery. The aim of the present study was to evaluate the effectiveness of infrared thermocamera to identify the anatomic structures in gynecologic surgery. MATERIALS AND METHODS: From February 2010 to May 2011, consecutive patients who required abdominal hysterectomy were considered for eligibility. During a procedure for benign disease, we evaluated the temperature difference between the ureter and infundibulopelvic vessel (experiment A). In patients with gynecologic cancer, the thermal gradient was determined between the iliac vessels and the ureter (experiment B). RESULTS: The data from 21 patients were recorded, 12 for experiment A and 9 for experiment B. We found a statistically significant difference between the ureter and vessels in both experiments (31.675 degrees C +/- 0.673 degrees C for the ureter and 33.332 degrees C +/- 0.828 degrees C for the infundibulopelvic vessel, P < 0.0001; 31.706 degrees C +/- 0.751 degrees C for the ureter, 33.787 degrees C +/- 0.63 degrees C for the iliac vein, and 33.784 degrees C +/- 0.639 degrees C for the iliac artery, P < 0.0001). CONCLUSIONS: Infrared imaging allowed us to identify the anatomic structures in laparotomy, providing preliminary data for its application in laparoscopy. PMID- 22835948 TI - Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation. AB - BACKGROUND: In renal tubular cells, cytochrome P4503A enzyme and adenosine triphosphate-binding cassette transporter activities result in intracellular drug or metabolite exposure variability, depending on genetic polymorphisms. Our aim was to establish whether long-term renal function is affected by genetic polymorphisms in biotransformation enzymes and drug transporters of the donor after kidney transplantation. MATERIALS AND METHODS: The study was conducted in a selected cohort of 97 kidney recipients. Genotyping of donors was performed on renal biopsy samples obtained before transplantation. Serum creatinine levels and Cockcroft-Gault estimated glomerular filtration rate were considered 1 y after transplantation and at the last follow-up. RESULTS: Long-term function was significantly better in recipients of an organ from donors carrying the ABCB1 1199A mutated allele (median and range creatinine values were 1.1 mg/dL [0.8 1.5mg/dL] in case of at least one ABCB1 1199A allele versus 1.5 mg/dL [0.7-3.7 mg/dL] for homozygous carriers of wild-type allele, P < 0.01). ABCB1 1199G>A polymorphism and donor age had an independent impact on both serum creatinine and estimated glomerular filtration rate. Unlike donor age, the mutated ABCB1 1199A allele was found to have a protective effect on renal function. CONCLUSIONS: Donor age and ABCB1 1199G>A polymorphism affect long-term renal function after transplantation. Analysis of genetic factors offers a promising approach to calcineurin inhibitor toxicity risk assessment. PMID- 22835949 TI - 17beta-Estradiol protects the liver against cold ischemia/reperfusion injury through the Akt kinase pathway. AB - BACKGROUND: Hepatic ischemia-reperfusion (IR) injury occurs during liver resection and transplantation. Recent studies have shown that 17beta-estradiol (E2) can protect the heart and liver against warm IR. The present study focused on the cytoprotective effects of E2 on cold IR injury to the liver. MATERIALS AND METHODS: Sprague-Dawley male rats were randomly divided into three groups: sham, IR, and IR plus E2. The model of rat orthotopic liver transplantation was used. The rats in the IR plus E2 group were intraperitoneally injected with E2 (100 MUg/kg/d) for 7 d before surgery. The sham and IR group received the same quantity of saline. The donor livers were then orthotopically transplanted into rats after cold ischemia preservation for 4 h at 4 degrees C lactated Ringer's solution. After 6 h reperfusion, liver function, bile flow volume, hepatocyte apoptosis, and activation of Akt, glycogen synthase kinase-3beta, and Bcl-2 associated death promoter were assessed. The survival rate of the rats was also investigated. RESULTS: The administration of E2 significantly prolonged the survival of liver grafts by improving liver function and decreasing hepatocyte apoptosis. Rats undergoing E2 demonstrated a greater level activation of Akt in the liver compared with the IR group. In addition, E2 also inhibited the activities of glycogen synthase kinase-3beta, Bcl-2-associated death promoter, and caspase-3-induced by IR injury. CONCLUSIONS: E2 pretreatment attenuated the hepatocellular damage caused by hepatic cold IR injury through the Akt pathway. Estrogen therapy might be important in clinical settings associated with cold IR injury during liver transplantation. PMID- 22835950 TI - Changes in group II phospholipase A2 gene expression in rat heart during sepsis. AB - BACKGROUND: This study was undertaken to investigate alterations of group II phospholipase A2 (PLA2) gene expression and its underlying mechanism in rat heart during different phases of sepsis. MATERIALS AND METHODS: Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups, control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. PLA2 enzyme activity, group II PLA2 protein level, messenger RNA (mRNA) abundance, transcription rate, and half-life were measured. RESULTS: PLA2 activity was decreased by 29% during early sepsis but it was increased by 49% during late sepsis. Group II PLA2 protein level was decreased by 27% during early sepsis but it was increased by 35.3% during late sepsis. Group II PLA2 mRNA was decreased by 21% during early sepsis but it was increased by 141% during late sepsis. The transcription rate of group II PLA2 mRNA was reduced by 25% during early sepsis but it was elevated by 67% during late sepsis. The half-life of group II PLA2 mRNA remained unaltered during early and late phases of sepsis. CONCLUSIONS: These results demonstrate that PLA2 activity, group II PLA2 protein level, the mRNA abundance, and transcription rate were concurrently underexpressed during early sepsis, while they were overexpressed during late sepsis, with no change in the degradation of gene transcript. These data indicate that the biphasic changes in group II PLA2 gene expression are regulated transcriptionally during sepsis. PMID- 22835951 TI - Safety of living donor liver transplantation using older donors. AB - BACKGROUND: There is limited information concerning older donors in living donor liver transplantation (LDLT). In the present study, we attempted to clarify whether it is safe to use older donors in LDLT. METHODS: A total of 129 cases were reviewed in the present study. Donors and recipients were divided into group A (donors aged >= 50 y, n=21) and group B (donors aged <50 y, n=108). The pre-, intra-, and postoperative variables of the two groups were statistically compared. RESULTS: Donors' complication rates were 38.10% and 28.70% for groups A and B, respectively (P=0.719). The overall 1-, 3-, and 5-y survival rates were 90%, 80%, and 66% for group A and 86%, 83%, and 75% for group B, respectively (P=0.573). Similar Clavien III or more complication rates for recipients were observed. CONCLUSIONS: The present study suggested that LDLT using older donors had no negative influence on the outcomes of both donors and recipients. PMID- 22835952 TI - Commentary on: Lipid peroxidation in machine perfusion of older donor kidneys. PMID- 22835953 TI - In vivo modeling of biofilm-infected wounds: a review. AB - Chronic wounds continue to represent a difficult and complex problem for both patients and healthcare providers. Bacterial biofilms represent a critical component of nonhealing wounds, utilizing several different mechanisms to inhibit innate inflammatory pathways and resist traditional therapeutics. Although in vitro biofilm systems have been well described and studied, understanding the intricacies of wound biofilm pathology requires appropriate in vivo models to understand the interactions between bacteria and host. In an effort to clarify the available literature, this review describes and critically evaluates all of the in vivo wound biofilm models currently published to-date, including model advantages and clinical applicability. We will also address the need for continued therapeutic development and testing using these currently available in vivo models. PMID- 22835954 TI - Synergic effect of photodynamic therapy using talaporfin sodium with conventional anticancer chemotherapy for the treatment of bile duct carcinoma. AB - BACKGROUND: Photodynamic therapy (PDT) is an effective laser treatment for locally treating advanced bile duct carcinoma (BDC). The study objective was to evaluate the synergic effect of PDT using a new photosensitizer, talaporfin sodium (Laserphyrin), in combination with conventional anticancer drug treatments. METHODS: The range of the necrotic area, the percentage of apoptosis positive cells, the vascular endothelial growth factor expression quantification, and the proliferating cell nuclear antigen-labeling index, as treatment effects, were examined in the BDC cell line (NOZ) in vitro and in vivo (4-wk-old male BALB/c mice). RESULTS: Tumor viability was determined by an in vitro MTS assay. PDT with a single treatment of 5-fluorouracil, gemcitabine, oxaliplatin, and cis diamminedichloroplatinum showed a significantly lower viability compared with the control or the PDT-alone group (P<0.05). Furthermore, administering PDT combined with two anticancer drugs showed a further decline in the tumor viability. A treatment of PDT combined with oxaliplatin and gemcitabine showed the least viability (P<0.05). Thus, this regimen was administered in the in vivo study. The tumor necrotic area, apoptosis positivity, and the vascular endothelial growth factor expression rate were higher in the PDT with anticancer drugs group compared with those of the other groups (P<0.05). The proliferating cell nuclear antigen-labeling index results in the PDT with the anticancer drugs group were significantly lower than those of the other groups (P<0.05). CONCLUSIONS: A treatment of PDT combined with gemcitabine and oxaliplatin showed the best synergic effect for necrosis, apoptosis, and cytostatic alterations for the treatment of BDC. PMID- 22835955 TI - Ambient air pollution exposure and blood pressure changes during pregnancy. AB - BACKGROUND: Maternal exposure to ambient air pollution has been associated with adverse birth outcomes such as preterm delivery. However, only one study to date has linked air pollution to blood pressure changes during pregnancy, a period of dramatic cardiovascular function changes. OBJECTIVES: We examined whether maternal exposures to criteria air pollutants, including particles of less than 10 MUm (PM(10)) or 2.5 MUm diameter (PM(2.5)), carbon monoxide (CO), nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), and ozone (O(3)), in each trimester of pregnancy are associated with magnitude of rise of blood pressure between the first 20 weeks of gestation and late pregnancy in a prospectively followed cohort of 1684 pregnant women in Allegheny County, PA. METHODS: Air pollution measures for maternal ZIP code areas were derived using Kriging interpolation. Using logistic regression analysis, we evaluated the associations between air pollution exposures and blood pressure changes between the first 20 weeks of gestation and late pregnancy. RESULTS: First trimester PM(10) and ozone exposures were associated with blood pressure changes between the first 20 weeks of gestation and late pregnancy, most strongly in non-smokers. Per interquartile increases in first trimester PM(10) and O(3) concentrations were associated with mean increases in systolic blood pressure of 1.88 mm Hg (95% CI=0.84 to 2.93) and 1.84 (95% CI=1.05 to 4.63), respectively, and in diastolic blood pressure of 0.63 mm Hg (95% CI=-0.50 to 1.76) and 1.13 (95% CI=-0.46 to 2.71) in non-smokers. CONCLUSIONS: Our novel finding suggests that first trimester PM(10) and O(3) air pollution exposures increase blood pressure in the later stages of pregnancy. These changes may play a role in mediating the relationships between air pollution and adverse birth outcomes. PMID- 22835956 TI - Characterizing the development of visual search expertise in pathology residents viewing whole slide images. AB - The goal of this study was to examine and characterize changes in the ways that pathology residents examine digital whole slide images as they progress through the residency training. A series of 20 digitized breast biopsy whole slide images (half benign and half malignant biopsies) were individually shown to 4 pathology residents at four points in time--at the beginning of their first, second, third, and fourth years of residency. Their task was to examine each image and select three areas that they would most want to zoom in on in order to view the diagnostic detail at higher resolution. Eye position was recorded as they scanned each whole slide image at low magnification. The data indicate that with each successive year of experience, the residents' search patterns do change. Overall, with time, it takes significantly less time to view an individual slide and decide where to zoom, significantly fewer fixations are generated overall, and there is less examination of nondiagnostic areas. Essentially, the residents' search becomes much more efficient. These findings are similar to those in radiology, and support the theory that an important aspect of the development of expertise is improved pattern recognition (taking in more information during the initial Gestalt or gist view) as well as improved allocation of attention and visual processing resources. Progression in improvements in visual search strategies was similar, but not identical, for the 4 residents. PMID- 22835957 TI - Microsatellite instability and retrieval of lymph nodes in stage III colon cancer: harbinger or hermit? PMID- 22835958 TI - Pathological and toxicological findings in glyphosate-surfactant herbicide fatality: a case report. AB - Glyphosate herbicide is promoted by the manufacturer as having no risks to human health, with acute toxicity being very low in normal use. In Thailand, however, poisoning from glyphosate agricultural herbicides has been increasing. A case of rapid lethal intoxication from glyphosate-surfactant herbicide involved a 37-year old woman, who deliberately ingested approximately 500 mL of concentrated Roundup formulation (41% glyphosate as the isopropylamine salt and 15% polyoxyethylene amine; Mosanto Company). The postmortem examination revealed that the stomach contained 550 mL of yellow fluid. The gastric mucosa of anterior fundus revealed hemorrhage and the small intestines had marked dilatation and thin walls. We used the high-performance liquid chromatography method for determination of serum and gastric content levels of glyphosate. The glyphosate levels of serum and gastric content were 3.05 and 59.72 mg/mL, respectively. Toxic effects of polyoxyethylene amine and Roundup were caused by their ability to erode tissues including mucous membranes and linings of the gastrointestinal and respiratory tracts. A mild degree of pulmonary congestion and edema was observed in both lungs. We proposed that the characteristic picture of microvesicular steatosis of the hepatocytes, seen predominantly in centrilobular zones of the liver, resembled drug-induced hepatic toxicity or secondary hypoxic stress. PMID- 22835959 TI - Spontaneous external rupture of femoral pseudoaneurysm: fatal hemorrhage related to drug abuse. AB - Drug abuse can lead to many life-threatening complications, the most frequent of which are overdoses and infections.We report here the case of a 38-year-old long term drug abuser found dead in a near-sitting position on his bed at home, by his roommate. A pillow imbued with blood was recovered on his right groin region. At autopsy, we observed a ruptured pseudoaneurysm (false aneurysm) of the right common femoral artery. No obvious signs of infection were present. This article focuses the attention of the reader on an unusual complication of parenteral drug abuse with a rare but potentially lethal outcome; to the best of our knowledge, this is the first report of a fatal hemorrhage from a ruptured arterial femoral pseudoaneurysm as a complication of drug injection in the forensic literature. PMID- 22835960 TI - Organ weight changes associated with body mass index determined from a medical autopsy population. AB - CONTEXT: Existing organ weight charts used by pathologists for patients undergoing medical autopsy do not illustrate the effect of obesity and age on organ weights among a general population of older individuals with multiple comorbidities. METHODS: We retrospectively reviewed 300 medical autopsy reports to extract data to analyze the effect of obesity and age on organ weights. RESULTS: In both men and women, there were statistically significant increases in organ weights with body mass index (BMI) but decreases with age for liver, spleen, and kidneys. In men, increased age was associated with increased left ventricular wall thickness, whereas increased BMI was associated with increased heart weight. In women, only BMI was associated with changes in all 3 anatomic cardiac parameters (heart weight and thickness of the right and left ventricular walls). Age effects were not observed for heart parameters in women. Thyroid weight increased with BMI in men but not in women. CONCLUSIONS: The findings demonstrate changes in organ weights/sizes with obesity and age in a population of patients with multiple comorbidities. The differential effects of age and BMI on the heart between men and women raise the possibility that increased BMI in women may have a greater impact on cardiovascular causes of death than that in men. PMID- 22835961 TI - Diabetic ketoacidosis: a silent death. AB - Diabetic ketoacidosis (DKA) results from severe insulin deficiency and can be diagnosed at autopsy despite no known history of the disease. Diabetic ketoacidosis may be the initial manifestation of type 1 diabetes or may result from increased insulin requirement in type 1 diabetic patients. The purpose of this study was to determine the percentage of DKA death investigated by the Office of Chief Medical Examiner that was not associated with a known history of diabetes.Cases investigated by the Office of Chief Medical Examiner during a 6 year period whose cause of death was DKA were identified using a centralized database. To determine the percentage with known history of diabetes, investigation reports were reviewed for any documentation of this history. The toxicology reports of all DKA deaths were reviewed together with histologic slides, if available, for possible microscopic changes. Concentrations of vitreous glucose, vitreous acetone, and blood acetone were used to diagnose DKA in these autopsied cases.Nearly a third of all death from DKA (32 of 92 during a 6-year period) occurred in individuals who had no known history of diabetes, emphasizing the importance of regular physicals that include a check of glucose concentration, and especially if any warning signs are present. In a case of sudden death, it is recommended that the volatile toxicology analysis at a medical examiner's office should include tests for acetone concentration, which when elevated, together with an elevated vitreous glucose, indicates DKA. PMID- 22835962 TI - Extraction of DNA from bones in cases where expectations for success are low. AB - To resolve cases involving unidentified cadavers, the study of polymorphic DNA markers of old bones is an invaluable but often challenging tool used in forensic genetics. Some of the difficulties encountered involve the limited quantity of endogenous DNA, its subsequent degradation (a result of elapsed time, environmental conditions, and the microorganisms that develop during the postmortem phase), and the coextraction of substances that inhibit amplification reactions. For these reasons, it is necessary to direct research toward the development of new extraction techniques with the goal of obtaining adequate quantities of high-quality DNA.The aim of this study was to improve the collection of extracted DNA compared with the amount of DNA obtained with the NucleoSpin DNA Trace Kit (Macherey Nagel) protocol for the extraction of genomic DNA from human bones. A modified version of the standard protocol is presented.The modified method for the extraction of genomic DNA, followed by amplification reaction, allowed for identification of 4 cadavers and typification of 1 cadaver. The study carried out involved unidentified cadavers, or their remains, discovered after a long period from time of death. PMID- 22835963 TI - Unusual foreign body aspiration as a cause of asphyxia in adults: an autopsy case report. AB - Most asphyxia deaths caused by foreign body aspiration occur in children and the elderly. It can also occur in specific high-risk groups of adults, such as those with underlying esophageal diseases, prisoners, those with mental retardation, and those with psychiatric illnesses. We report the case of a 49-year-old man, without previous medical history, who died rapidly after aspirating a sole fish while he was unraveling the fishing net using his teeth. At autopsy, the foreign body was found in the trachea, wedged in the carina and obstructing the right bronchus origin. The finding from the usual toxicological screening was negative. PMID- 22835964 TI - Drug- and alcohol-related deaths at a pediatric institution in the United kingdom. AB - AIM: The study aimed to identify the incidence, clinical presentation, and demographic features of drug- and alcohol-related deaths diagnosed at a pediatric pathology department between 2004 and 2010. MATERIAL AND METHODS: Databases of the histopathology and toxicology departments were searched. Three groups were defined as follows: (1) cause of death is toxicologically related; (2) drugs present are consistent with therapeutic range use; and (3) a drug was detected, but the contribution of this drug to the mechanism of death was not clear. RESULTS: Fifty-five cases (36 males, 19 females; mean, 4.8 years; range, 2 hours to 17 years) were identified. This corresponded to 3.3% (55/1669) of all postmortems. Ten cases were group 1, 42 cases were group 2, and 3 cases were group 3. The results in group 1 were methadone (n = 2); methadone, alcohol, and dothiepin (n = 1); diazepam (n = 1); dothiepin (n = 1); carbon monoxide (n = 2); tramadol (n = 1); codeine and paracetamol (n = 1); and dihydrocodeine, citalopram, amitriptyline, and paracetamol (n = 1). The types of death were considered accidental (n = 2), suicide (n = 2), and undetermined (n = 6). CONCLUSIONS: The presence of a toxin in lethal concentration was found in 10 (0.6%) of 1669 of any kind of postmortem examinations. This increased to 2.2% when the analysis was restricted to "sudden deaths." These results demonstrate the need to conduct toxicological screening in all postmortems of this sort. PMID- 22835965 TI - Intrapleural rupture of a pulmonary arteriovenous fistula. AB - A 72-year-old white woman was admitted to the hospital for mitral valve replacement with a metallic valve. A few days after surgery, the patient experienced a sudden cardiac arrest and died because of the intrapleural rupture of a pulmonary arteriovenous fistula. PMID- 22835966 TI - The utility of routine histological examination of gunshot wounds. AB - Determining the range of fire is a crucial part of a forensic examination of gunshot wound victims. Traditionally, this has been accomplished by noting the gross appearance of soot or powder around the wound. This study was undertaken to determine the utility of routine histological examination of gunshot wounds as related to range-of-fire determination. A prospective study was performed, and a total of 69 gunshot wounds were examined both macroscopically and microscopically. Of the 45 entrance wounds examined, there was 100% concordance between macroscopic and microscopic analysis for the close-range wounds and 67% concordance for the distant wounds, with 33% of these wounds showing no evidence of soot or powder grossly but where residue was seen microscopically. In addition, 21% of the exit wounds examined showed microscopic evidence of soot/powder residues when none were visible macroscopically. As described in previous studies, it can be assumed that the bullet itself can deposit small residues along the wound track (bullet wipe) that can be seen microscopically and is unrelated to the range of fire. Therefore, the authors conclude there is no utility in the routine histological examination of gunshot wounds for the determination of range of fire. PMID- 22835967 TI - Acute Ibuprofen intoxication: report on a case and review of the literature. AB - A fatality following the ingestion of ibuprofen is reported. Ibuprofen is a prototypical nonsteroidal anti-inflammatory drug widely prescribed as an analgesic, anti-inflammatory, and antipyretic agent. To date, there are few case reports of fatal overdose with ibuprofen, following ibuprofen self-poisoning or accidental overdose. We report the case of a 51-year-old man with medical history of psychiatric disease, who was brought to the emergency department by ambulance with a chief complaint of having taken large amounts of drugs in a suicide attempt.Multiple empty containers of medications (ibuprofen, meloxicam, celecoxib, risperidone, citalopram, ketorolac, bromazepam) were found at the scene. He died 4 hours after admission to the emergency department, despite vigorous supportive care. Toxicological analyses were performed using a gas chromatography/mass spectrometry technique. The estimated ibuprofen concentration in the plasma was 600 MUg/mL; gastric content was 200 MUg/mL for this compound. Our report describes results of the forensic investigation and discuss the review of the literature. PMID- 22835968 TI - Importance of seat belt wear in preventing traffic fatalities in Japan. PMID- 22835969 TI - QuikClot masquerading as Glaser shot: a new forensic pathology artifact? AB - Although in the forensic sphere, Glaser ammunition or handgun shot cartridges represent one of the most significant advances in firearms ballistics in the past 100 years, the mineral-based zeolite hemostatic agent QuikClot represents a no less significant development in the surgical and clinical context of the trauma induced management of battlefield wounding and hemorrhage. Because of the essential structural configuration of both Glaser ammunition and QuikClot, consisting as they do of metallic beads on the one hand and mineral-based spherules on the other, the possibility exists that a medicolegal autopsy on a victim of gunshot wounding and on whom surgery has been performed with introduction of QuikClot in an effort to stem bleeding, the spherules of QuikClot might be misinterpreted as the pellets of handgun shot cartridges.We present a case of fatal wounding by a 9-mm handgun in which the discovery of QuikClot in the peritoneal cavity at autopsy initially raised the possibility of wounding by Glaser ammunition. PMID- 22835970 TI - Pituitary abscess presenting a very rapid progression: report of a fatal case. AB - Pituitary abscess is a rare disease presenting with nonspecific clinical symptoms, and diagnosis is often difficult. This disease is potentially life threatening, but most cases have a chronic and indolent course. We report a case of a 60-year-old man with a pituitary abscess associated with pituitary adenoma who died 5 days after the onset of clinical symptoms without a definitive diagnosis. Postmortem computed tomography and autopsy findings revealed a sellar mass with cystic change and extension toward the optic chiasm. Histopathology of the lesion demonstrated an abscess with suppurative meningitis and encephalitis. The disturbance of the cardiac autonomic nervous system because of hypothalamus involvement was suggested as the cause of rapid progression and death. This case provides useful information for clinicians to avoid a lethal outcome. PMID- 22835971 TI - Lung injury similar to blast lung in a case of shotgun wound of the head. AB - Primary blast lung injury after explosions has been well described in the literature. A case of injury to the lung, after a shotgun wound to the head, similar to primary blast lung, is presented. Histological appearances of the lung revealed alveolar over distension, rupture and intra-alveolar hemorrhage. Primary blast lung injury is considered the reserve of high-order explosives; however, this case reveals similar injuries from a shotgun (low-order explosive), which has not been reported before to the best of our knowledge. PMID- 22835972 TI - Postmortem ethanol in the setting of ethanol-containing automotive fuel. AB - The pilot of a light aircraft that crashed after a loss of power was found to have ethanol in the vitreous and the blood, but almost none in the urine. The globes of the eyes were intact, and the body was refrigerated after recovery until the autopsy was performed the following morning. The pilot was described as a "nondrinker," and additional specialized toxicology testing results were inconsistent with ethanol ingestion. The pilot's body was extensively exposed to fuel during the prolonged extraction. Investigation determined that the aircraft had been fueled with gasoline that contained 10% ethanol. Although exposure to automotive fuel has not been previously described as a source of ethanol in postmortem specimens, it may represent a source for the ethanol detected during postmortem toxicology testing in this case, and this finding may be relevant to other cases with similar exposure. PMID- 22835973 TI - Amniotic fluid embolism: a cause of sudden maternal death and police inquest. AB - Amniotic fluid embolism (AFE) is a rare, unforeseeable, unpreventable, and dreadful complication of pregnancy. Histological diagnosis is still the criterion standard for its detection because of the lack of any reliable clinical laboratory tests. The diagnosis of AFE has a close association with medicolegal aspects of obstetric death. Amniotic fluid embolism occurs when massive amount of amniotic fluid abnormally enters the maternal venous system. We report a case of a 33-year-old healthy woman (G2, P2, L1) admitted to a private nursing care hospital with 37 weeks gestation for delivery. She normally delivered a healthy 2.8-kg infant boy. After 15 minutes of delivery, she developed tonic-clonic seizures, breathlessness, and loss of consciousness and died within 4 hours after onset of symptoms. The sudden death of a healthy mother led to medical negligence claim by the relatives, and a police case was filed against the private nursing care obstetrician. Despite a brief clinical history, meticulous microscopic examination of lungs revealed pulmonary microvasculature filled with fetal squamous cells, hair, and mucin. The final cause of sudden maternal death was given as AFE and pulmonary edema. This report highlights the importance of detailed microscopic examination of lungs and the need to study as many histopathologic sections as possible to rule out this entity. PMID- 22835974 TI - Suicide by pedestrian versus motor vehicle: a case report. AB - Suicide is the deliberate act of ending one's own life. Historically, men commit suicide more frequently than do women; however, rates have increased for women worldwide in recent years. Transportation injuries have been widely reported as means of suicide such as operators of motor vehicles or jumpers into the pathway of trains. Few definitive reports exist of pedestrians deliberately jumping into the pathway of a motor vehicle. A security camera demonstrates a pedestrian deliberately entering the pathway of a moving vehicle resulting in death from multiple blunt force trauma. PMID- 22835975 TI - One case, 3 rare simultaneous findings: intramyocardial bronchogenic cyst, P.H558R variant of SCN5A gene, and granular cell tumor of the esophagus. AB - We describe the sudden death of a 42-year-old white man. The decedent was a healthy young man with a short clinical history of chest pain, fatigue, dizziness, and pyrosis. Two weeks before his death, he underwent medical evaluation for the aforementioned symptoms. Electrocardiogram, chest x-ray, and serum troponin were all within normal limits. Gastroesophageal reflux disease was suspected, and the decedent was treated with omeprazole. Medicolegal autopsy disclosed an incidental intramyocardial bronchogenic cyst and p.H558R variant of the SCN5A gene. The cyst was located between the epicardium and myocardium of the posterior face of the left superior ventricular wall, adjacent to the base of the heart. An incidental granular cell tumor of the esophagus was also identified, which was likely unrelated to death. PMID- 22835976 TI - New and emerging genomics-based approaches in crop breeding. PMID- 22835977 TI - Epigenomic modification and epigenetic regulation in rice. AB - Epigenomes including genome-wide histone modification and DNA methylation profiles are important for genome activity and for defining gene expression patterns of plant development and responses to various environmental conditions. Rice is the most important crop plant and serves as a model for cereal genomics. Rice epigenomic landscape is emerging and the function of chromatin modification regulators in gene expression, transposon repression and plant development is being characterized. Epigenomic variation that gives rise to stable or transgenerational heritable epialleles related to variation of important agronomical traits or stress responses is being characterized in rice. Implication of epigenomic variation in rice heterosis is being exploited. PMID- 22835978 TI - Recent developments of genomic research in soybean. AB - Soybean is an important cash crop with unique and important traits such as the high seed protein and oil contents, and the ability to perform symbiotic nitrogen fixation. A reference genome of cultivated soybeans was established in 2010, followed by whole-genome re-sequencing of wild and cultivated soybean accessions. These efforts revealed unique features of the soybean genome and helped to understand its evolution. Mapping of variations between wild and cultivated soybean genomes were performed. These genomic variations may be related to the process of domestication and human selection. Wild soybean germplasms exhibited high genomic diversity and hence may be an important source of novel genes/alleles. Accumulation of genomic data will help to refine genetic maps and expedite the identification of functional genes. In this review, we summarize the major findings from the whole-genome sequencing projects and discuss the possible impacts on soybean researches and breeding programs. Some emerging areas such as transcriptomic and epigenomic studies will be introduced. In addition, we also tabulated some useful bioinformatics tools that will help the mining of the soybean genomic data. PMID- 22835979 TI - Dissecting the genetic basis of extremely large grain shape in rice cultivar 'JZ1560'. AB - Rice grain shape, grain length (GL), width (GW), thickness (GT) and length-to width ratio (LWR), are usually controlled by multiple quantitative trait locus (QTL). To elucidate the genetic basis of extremely large grain shape, QTL analysis was performed using an F(2) population derived from a cross between a japonica cultivar 'JZ1560' (extremely large grain) and a contrasting indica cultivar 'FAZ1' (small grain). A total number of 24 QTLs were detected on seven different chromosomes. QTLs for GL, GW, GT and LWR explained 11.6%, 95.62%, 91.5% and 89.9% of total phenotypic variation, respectively. Many QTLs pleiotropically controlled different grain traits, contributing complex traits correlation. GW2 and qSW5/GW5, which have been cloned previously to control GW, showed similar chromosomal locations with qGW2-1/qGT2-1/qLWR2-2 and qGW5-2/qLWR5-1 and should be the right candidate genes. Plants pyramiding GW2 and qSW5/GW5 showed a significant increase in GW compared with those carrying one of the two major QTLs. Furthermore, no significant QTL interaction was observed between GW2 and qSW5/GW5. These results suggested that GW2 and qSW5/GW5 might work in independent pathways to regulate grain traits. 'JZ1560' alleles underlying all QTLs contributed an increase in GW and GT and the accumulation of additive effects generates the extremely large grain shape in 'JZ1560'. PMID- 22835980 TI - A pyramid breeding of eight grain-yield related quantitative trait loci based on marker-assistant and phenotype selection in rice (Oryza sativa L.). AB - 1000-Grain weight and spikelet number per panicle are two important components for rice grain yield. In our previous study, eight quantitative trait loci (QTLs) conferring spikelet number per panicle and 1000-grain weight were mapped through sequencing-based genotyping of 150 rice recombinant inbred lines (RILs). In this study, we validated the effects of four QTLs from Nipponbare using chromosome segment substitution lines (CSSLs), and pyramided eight grain yield related QTLs. The new lines containing the eight QTLs with positive effects showed increased panicle and spikelet size as compared with the parent variety 93-11. We further proposed a novel pyramid breeding scheme based on marker-assistant and phenotype selection (MAPS). This scheme allowed pyramiding of as many as 24 QTLs at a single hybridization without massive cross work. This study provided insights into the molecular basis of rice grain yield for direct wealth for high-yielding rice breeding. PMID- 22835981 TI - Identification and analyses of miRNA genes in allotetraploid Gossypium hirsutum fiber cells based on the sequenced diploid G. raimondii genome. AB - The plant genome possesses a large number of microRNAs (miRNAs) mainly 21-24 nucleotides in length. They play a vital role in regulation of target gene expression at various stages throughout the whole plant life cycle. Here we sequenced and analyzed ~ 10 million non-coding RNAs (ncRNAs) derived from fiber tissue of the allotetraploid cotton (Gossypium hirsutum) 7 days post-anthesis using ncRNA-seq technology. In terms of distinct reads, 24 nt ncRNA is by far the dominant species, followed by 21 nt and 23 nt ncRNAs. Using ab initio prediction, we identified and characterized a total of 562 candidate miRNA gene loci on the recently assembled D(5) genome of the diploid cotton G. raimondii. Of all the 562 predicted miRNAs, 22 were previously discovered in cotton species and 187 had sequence conservation and homology to homologous miRNAs of other plant species. Nucleotide bias analysis showed that the 9th and 1st positions were significantly conserved among different types of miRNA genes. Among the 463 putative miRNA target genes, most significant up/down-regulation occurred in 10-20 days post anthesis, indicating that miRNAs played an important role during the elongation and secondary cell wall synthesis stages of cotton fiber development. The discovery of new miRNA genes will help understand the mechanisms of miRNA generation and regulation in cotton. PMID- 22835982 TI - Whole genome duplication of intra- and inter-chromosomes in the tomato genome. AB - Whole genome duplication (WGD) events have been proven to occur in the evolutionary history of most angiosperms. Tomato is considered a model species of the Solanaceae family. In this study, we describe the details of the evolutionary process of the tomato genome by detecting collinearity blocks and dating the WGD events on the tree of life by combining two different methods: synonymous substitution rates (Ks) and phylogenetic trees. In total, 593 collinearity blocks were discovered out of 12 pseudo-chromosomes constructed. It was evident that chromosome 2 had experienced an intra-chromosomal duplication event. Major inter chromosomal duplication occurred among all the pseudo-chromosome. We calculated the Ks value of these collinearity blocks. Two peaks of Ks distribution were found, corresponding to two WGD events occurring approximately 36-82 million years ago (MYA) and 148-205 MYA. Additionally, the results of phylogenetic trees suggested that the more recent WGD event may have occurred after the divergence of the rosid-asterid clade, but before the major diversification in Solanaceae. The older WGD event was shown to have occurred before the divergence of the rosid asterid clade and after the divergence of rice-Arabidopsis (monocot-dicot). PMID- 22835983 TI - Excess dietary sodium and inadequate potassium intake in Italy: results of the MINISAL study. AB - OBJECTIVE: As excess sodium and inadequate potassium intake are causally related to hypertension and cardiovascular disease, the MINISAL-GIRCSI Program aimed to provide reliable estimates of dietary sodium and potassium intake in representative samples of the Italian population. DESIGN AND METHODS: Random samples of adult population were collected from 12 Italian regions, including 1168 men and 1112 women aged 35-79 yrs. Electrolyte intake was estimated from 24 hour urine collections and creatinine was measured to estimate the accuracy of the collection. Anthropometric indices were measured with standardised procedures. RESULTS: The average sodium excretion was 189 mmol (or 10.9 g of salt/day) among men and 147 mmol (or 8.5 g) among women (range 27-472 and 36-471 mmol, respectively). Ninety-seven % of men and 87% of women had a consumption higher than the WHO recommended target of 5g/day. The 24 h average potassium excretion was 63 and 55 mmol, respectively (range 17-171 and 20-126 mmol), 96% of men and 99% of women having an intake lower than 100 mmol/day (European and American guideline recommendation). The mean sodium/potassium ratio was 3.1 and 2.8 respectively, i.e. over threefold greater than the desirable level of 0.85. The highest sodium intake was observed in Southern regions. Sodium and potassium excretion were both progressively higher the higher the BMI (p < 0.0001). CONCLUSIONS: These MINISAL preliminary results indicate that in all the Italian regions thus far surveyed dietary sodium intake was largely higher and potassium intake lower than the recommended intakes. They also highlight the critical association between overweight and excess salt intake. PMID- 22835985 TI - Choline-containing compounds quantification by 1H NMR spectroscopy using external reference and noise measurements. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) is largely exploited in clinical settings to non-invasively investigate chemical compounds in human tissues. Applications of (1)H-MRS in oncology field are connected to the detection of abnormal levels of choline compounds in more active tumours, providing useful information for cancer diagnosis and treatment monitoring. Since benign lesions may also show presence of a choline peak, implementing absolute evaluation will help differentiating benign from malignant tumours. An external reference procedure was described to provide choline quantification in standard unit of measurements. Spectra were acquired on a 1.5 T scanner using both phantoms and healthy volunteers with a PRESS sequence. The implemented quantification procedure used metabolite and noise measurements on the spectrum to remove large part of scanner settings contributing to metabolites of interest. A standard quantification was also used to compare performances of the noise based method. In vitro quantification had accuracy and precision in the range (95 99)% and (5-13)%, respectively. When applied to in vivo studies on healthy volunteers, the method provided very close values of choline concentration, more exactly (1.73 +/- 0.24) mmol/l. The method proposed can quantify the proper choline content in phantoms as well as in human structures, as brain. The method is ease of use, computational costless and it can be rapidly calibrated and implemented in any centre. PMID- 22835984 TI - Fish consumption, insulin sensitivity and beta-cell function in the Insulin Resistance Atherosclerosis Study (IRAS). AB - BACKGROUND AND AIMS: Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population. METHODS AND RESULTS: We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as <2 vs. >=2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (S(I)) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Higher fish consumption was independently associated with lower S(I)-adjusted AIR (beta = -0.13 [-0.25, 0.016], p = 0.03, comparing >=2 vs. <2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted beta = 0.073 [-0.014, 0.16] for intact proinsulin/C-peptide ratio, beta = 0.031 [-0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted beta = 2.27 [0.68, 3.86], p = 0.005). We found no association between fish consumption and S(I) (multivariable-adjusted beta = 0.015 [-0.083, 0.053]) or fasting insulin (multivariable-adjusted beta = 0.016 [ 0.066, 0.10]). CONCLUSIONS: Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction. PMID- 22835986 TI - Lemierre syndrome: two cases requiring surgical intervention. PMID- 22835987 TI - Role of free flaps in the management of craniofacial neurofibromatosis: soft tissue coverage and attempted facial reanimation. PMID- 22835988 TI - Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers? AB - BACKGROUND: Soluble ST2 is a marker of cellular stress and injury whose natural ligand is interleukin-33. We investigate, for the first time, the relationship of IL-33 and ST2 with death at 30-days, 1-year and beyond in unselected STEMI patients. We assess the incremental value they offer over GRACE score and NT proBNP. Secondary endpoints were heart failure readmission and re-infarction. METHODS: ST2 and IL-33 were measured in 677 patients 3-5 days after admission. Median follow-up was 587 (134-2818) days during which 101 (15%) patients died. RESULTS: ST2 was higher in those who died when compared to event-free survivors (median [range] 1125 [123-15781] vs. 630 [59-11729] pg/ml, p<0.001) as was IL-33 (75 [5.4-17893] vs. 5.4 [5.4-16466] pg/mL, p=0.006). Multivariate Cox regression analysis reveals that elevated ST2 is associated with increased risk of mortality at 30-days (HR 9.34, p<0.001) and 1-year (HR 3.15, p=0.001). These relationships continued after further adjustment for GRACE-RS and NT-proBNP. Combining ST2 (c statistic 0.82, p<0.001), GRACE-RS (0.82, p<0.001) and NT-proBNP (0.84, p<0.001) leads to a significant improvement in the c-statistic for 30-day mortality to 0.90 (p=0.01). IL-33 above 5.4 pg/ml was independently associated with increased mortality at 30-days (HR 4.16, p=0.007) and 1-year (HR 2.29, p=0.008) but, did not add incremental prognostic value over using GRACE-RS and NT-proBNP. The ratio IL-33/ST2 was not associated with events. CONCLUSIONS: Elevated ST2 and IL-33 were both associated with increased mortality. ST2 demonstrated incremental value over contemporary risk markers but, IL-33 did not. ST2 has a potential role in risk stratification using a multi-marker approach. PMID- 22835989 TI - Triple-orifice valve repair in severe Barlow disease with multiple-jet mitral regurgitation: report of mid-term experience. AB - OBJECTIVES: Barlow disease represents a surgical challenge for mitral valve repair (MR) in the presence of mitral insufficiency (MI) with multiple regurgitant jets. We hereby present our mid-term experience using a modified edge to-edge technique to address this peculiar MI. METHODS: From March 2003 till December 2010, 25 consecutive patients (mean age 54 +/- 7 years, 14 males) affected by severe Barlow disease with multiple regurgitant jets were submitted to MR. Preoperative transesophageal echo (TEE) in all the cases showed at least 2 regurgitant jets, involving one or both leaflets in more than one segment. In all the patients, a triple orifice valve (TOV) repair with annuloplasty was performed. Intra-operative TEE and postoperative transthoracic echocardiography (TTE) were carried out to evaluate results of the TOV repair. RESULTS: There was no in-hospital death and one late death (non-cardiac related). At intra-operative TEE, the three orifices showed a mean total valve area of 2.9 +/- 0.1cm(2) (range 2.5-3.3 cm(2)) with no residual regurgitation (2 cases of trivial MI) and no sign of valve stenosis (mean transvalvular gradient 4.6 +/- 1.5 mmHg). At follow up (mean 38 +/- 22 months), TTE showed favourable MR and no recurrence of significant MI (6 cases of trivial and 1 of mild MI). Stress TTE was performed in 5 cases showing persistent effective valve function (2 cases of trivial MI at peak exercise). All the patients showed significant NYHA functional class improvement. CONCLUSIONS: This report indicates that the TOV technique is effective in correcting complex Barlow mitral valves with multiple jets. Further studies are required to confirm long-term applicability and durability in more numerous clinical cases. PMID- 22835990 TI - Self-reported depressive symptoms, diagnosed clinical depression and cardiac morbidity and mortality after myocardial infarction. AB - BACKGROUND: Self-reported depressive symptoms and clinical depression after myocardial infarction (MI) are both associated with poor cardiac prognosis. It is important to distinguish between the two when assessing cardiac prognosis, but few studies have done so. The present article evaluates the independent prognostic impact of self-reported depressive symptoms and clinical depression on cardiac outcomes after MI. METHODS: 2704 MI-patients were administered the Beck Depression Inventory (BDI) and underwent the Composite International Diagnostic Interview at 3 months post-MI. All-cause mortality, cardiac mortality and cardiovascular readmissions were evaluated up till 10 years post-MI (mean: 6 years), representing 16,783 persons-years of follow-up. Event-free survival was evaluated using Cox regression analysis. RESULTS: Analyses on mortality and cardiovascular readmissions included 2493 and 2434 patients respectively. Compared to patients scoring <5 on the BDI, those scoring >= 19 had age- and sex adjusted HR's (95% CI) of 3.20 (2.16-4.74, p<0.001) for all-cause mortality, 3.97 (2.06-7.65, p<0.001) for cardiac mortality, and 1.45 (1.08-1.95, p<0.05) for cardiovascular readmissions. Cardiac disease severity and cardiac risk factors explained one third to half of the relationship. The presence of clinical depression was associated with all-cause (HR: 1.72 (1.29-2.30, p<0.001)) and cardiac mortality (HR: 1.67 (1.01-2.77, p<0.05)). However, adjusting for BDI scores decreased these HR's with 53% and 72% respectively, rendering them non significant. Dichotomized BDI-scores remained to predict cardiac prognosis independently from the presence of clinical depression. CONCLUSIONS: After MI, self-reported depressive symptoms are a more accurate predictor of cardiac morbidity and mortality than clinical depression. This association is confounded largely by cardiac disease severity. PMID- 22835992 TI - Psychometric evaluation of 3-set 4P questionnaire. AB - This is a further development of a specific questionnaire, the 3-set 4P, to be used for measuring former ICU patients' physical and psychosocial problems after intensive care and the need for follow-up. The aim was to psychometrically test and evaluate the 3-set 4P questionnaire in a larger population. The questionnaire consists of three sets: "physical", "psychosocial" and "follow-up". The questionnaires were sent by mail to all patients with more than 24-hour length of stay on four ICUs in Sweden. Construct validity was measured with exploratory factor analysis with Varimax rotation. This resulted in three factors for the "physical set", five factors for the "psychosocial set" and four factors for the "follow-up set" with strong factor loadings and a total explained variance of 62 77.5%. Thirteen questions in the SF-36 were used for concurrent validity showing Spearman's r(s) 0.3-0.6 in eight questions and less than 0.2 in five. Test-retest was used for stability reliability. In set follow-up the correlation was strong to moderate and in physical and psychosocial sets the correlations were moderate to fair. This may have been because the physical and psychosocial status changed rapidly during the test period. All three sets had good homogeneity. In conclusion, the 3-set 4P showed overall acceptable results, but it has to be further modified in different cultures before being considered a fully operational instrument for use in clinical practice. PMID- 22835993 TI - Does phage P22 contribute to resistance of Salmonella to oxidative stress? AB - Resistance to oxidative stress belongs to key virulence factors of bacterial pathogens including Salmonella. Typing of prophages in the genome is used to identify individual Salmonella strains. Some of the prophages and prophage remnants contain genes coding for important and metabolically active enzymes. We hypothesize that antioxidative status of the host Salmonella is affected by the bactoprenol glucosyltransferase (gtrB) from the P22 phage and that this effect is mediated by enhanced production of antioxidative selenoproteins. Our hypothesis is testable using targeted bacterial mutants exposed to oxidative stress in vivo and in vitro. PMID- 22835994 TI - Can a pediatric trauma center improve the response to a mass casualty incident? AB - Recent events including the 2001 terrorist attacks on New York; Hurricane Katrina; the 2010 Haitian and Chilean earthquakes; and the 2011 earthquake, tsunami, and nuclear disaster in Japan have reminded disaster planners and responders of the tremendous scale of mass casualty disasters and their resulting human devastation. Although adult disaster medicine is a well-developed field with roots in wartime medicine, we are increasingly recognizing that children may comprise up to 50% of disaster victims, and response mechanisms are often designed without adequate preparation for the number of pediatric victims that can result. In this short educational review, we explore the differences between the pediatric and adult disaster and trauma populations, the requirements for designation of a site as a pediatric trauma center (PTC), and the magnitude of the problem of pediatric disaster patients as described in the literature, specifically as it pertains to the availability and use of designated PTCs as opposed to trauma centers in general. We also review our own experience in planning and simulating pediatric mass casualty events and suggest strategies for preparedness when there is no PTC available. We aim to demonstrate from this brief survey that the availability of a designated PTC in the setting of a mass casualty disaster event is likely to significantly improve the outcome for the pediatric demographic of the affected population. We conclude that the relative scarcity of disaster data specific to children limits epidemiologic study of the pediatric disaster population and offer suggestions for strategies for future study of our hypothesis. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 22835995 TI - Utility of cervical spinal and abdominal computed tomography in diagnosing occult pneumothorax in patients with blunt trauma: Computed tomographic imaging protocol matters. AB - BACKGROUND: Small pneumothoraces (PXs), which are not initially recognized with a chest x-ray film and diagnosed by a thoracic computed tomography (CT), are described as occult PX (OCPX). The objective of this study was to evaluate cervival spine (C-spine) and abdominal CT (ACT) for diagnosing OCPX and overt PX (OVPX). METHODS: All patients with blunt trauma who presented consecutively to the emergency department during a 26-months period were included. Among all the chest CTs (CCTs) (6,155 patients) conducted during that period, 254 scans were confirmed to have a true PX. The findings in their C-spine CT and ACT were compared with the findings in CCTs. RESULTS: Among these patients, 254 had a diagnosis of PX confirmed with CCT. OCPXs were identified on the chest computed tomographic scan of 128 patients (70.3%), whereas OVPXs were evident in 54 patients (29.7%). Computed tomographic imaging of the C-spine was performed in 74% of patients with OCPX and 66.7% of patients with OVPX trauma. Only 45 (35.2%) cases of OCPX and 42 (77.8%) cases of OVPX were detected by C-spine CT. ACT was performed in almost all patients, and 121 (95.3%) of 127 of these correctly identified an existing OCPX. Sensitivity of C-spine CT and ACT was 35.1% and 96.5%, respectively; specificity was 100% and 100%, respectively. CONCLUSION: Almost all OCPXs, regardless of intrathoracic location, could be detected by ACT or by combining C-spine and abdominal computed tomographic screening for patients. If the junction of the first and second vertebra is used as the caudad extent, C-spine CT does not have sufficient power to diagnose more than a third of the cases. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 22835996 TI - Nail-gun head trauma: A comprehensive review of the literature. PMID- 22835997 TI - Screening ultrasonography of 2,204 patients with blunt abdominal trauma in the Wenchuan earthquake. AB - BACKGROUND: Abdominal injuries constitute a small proportion of all earthquake related traumas; however, it often resulted in fatal hemorrhage. Ultrasonography has been described as an effective triage tool in the evaluation of blunt abdominal trauma. We aimed to present an overview of the diagnostic accuracy of screening ultrasonography for patients with blunt abdominal trauma admitted to various hospitals during the Wenchuan earthquake in China. METHODS: We retrospectively analyzed the patients with blunt abdominal trauma who underwent ultrasonography after admission to various hospitals. Ultrasonography findings were considered positive if evidence of free fluid or a parenchymal injury was identified. Ultrasonography findings were compared with the findings of computed tomography, diagnostic peritoneal lavage, repeated ultrasonography, cystography, operation, and/or the clinical course. RESULTS: Findings from 2,204 ultrasonographic examinations were evaluated. Findings of 199 ultrasonographic examinations (9.0%) were considered positive. Of the patients, 12 (0.5%) had a false-negative ultrasonographic findings; of this group, 3 (25%) required exploratory laparotomy. Ultrasonography had a sensitivity of 91.9%, specificity of 96.9%, and an accuracy of 96.6% for detection of abdominal injuries. Positive predictive value was 68.3%, and negative predictive value was 99.4%. CONCLUSION: Screening ultrasonography is highly reliable in the setting of blunt abdominal trauma after earthquake. It should be used as an initial diagnostic modality in the evaluation of most blunt abdominal trauma. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 22835998 TI - Management of secondary hemorrhage from early graft failure in military extremity wounds. AB - BACKGROUND: Secondary hemorrhage after a dehisced vascular reconstruction is a dreaded complication, yet few reports describe the initial management and outcome of casualties with ruptured grafts from military wounds. We aimed to report a single-center experience of graft ruptures after evacuation of casualties to a tertiary hospital in the continental United States. METHODS: Trauma records of US combat casualties were retrospectively reviewed from April 2005 to August 2007. Casualties who underwent an extremity vascular reconstruction in Iraq or Afghanistan and experienced a ruptured graft were included. RESULTS: Ten graft ruptures (mean time, 14 days) occurred during the study period. All casualties were males with penetrating injuries by secondary blast effects (5, 50%) or gunshot wounds (5, 50%). Mean age and Injury Severity Score were 28.2 years (range, 20-41 years) and 21.1 (range 10-32), respectively. Repairs were performed on the superficial femoral (4, 40%), popliteal (2, 20%), brachial (1, 10%), axillary (1, 10%), iliac (1, 10%), and common femoral (1, 10%) arteries using reversed saphenous vein grafts (10, 100%). Initial management included control of hemorrhage and extra-anatomic reconstruction with a vein graft (4), prosthetic graft (4), end-to-end anatomosis (1), or primary amputation (1). Secondary complications in those 10 limbs requiring reintervention included 4 thrombotic graft failures (40%), and 1 transfemoral amputation from a graft infection. Ruptures were frequently associated with long-bone fractures (6, 60%), large soft tissue open wounds (5, 50%) and infection (7, 70%). At a mean follow-up of 37 months, the amputation rate in this series was 30%, with an amputation-free survival of 70%. CONCLUSION: Contaminated military wounds with bony fractures may predispose a graft of any type (vein or prosthetic) to anastomotic dehiscence. Wounds must be carefully debrided, and when grafts cannot be covered with viable muscle, they should be routed around the zone of injury. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 22835999 TI - Who should we feed? Western Trauma Association multi-institutional study of enteral nutrition in the open abdomen after injury. AB - BACKGROUND: The open abdomen is a requisite component of a damage control operation and treatment of abdominal compartment syndrome.Enteral nutrition (EN) has proven beneficial for patients with critical injury, but its application in those with an open abdomen has not been defined. The purpose of this study was to analyze the use of EN for patients with an open abdomen after trauma and the effect of EN on fascial closure rates and nosocomial infections. METHODS: We reviewed patients with an open abdomen after injury from January 2002 to January 2009 from 11 trauma centers. RESULTS: During the 7-year study period, 597 patients required an open abdomen after trauma. Most were men (77%) sustaining blunt trauma (72%), with a mean (SD) age of 38 (0.7) years, an Injury Severity Score of 31 (0.6), an abdominal injury score of 3.8(0.1), and an Abdominal Trauma Index score of 26.8 (0.6). Of the patients, 548 (92%) had an open abdomen after a damage control operation, whereas the remainder experienced an abdominal compartment syndrome. Of the 597 patients, 230 (39%)received EN initiated before the closure of the abdomen at mean (SD) day 3.6 (1.2) after injury. EN was started with an open abdomen in one quarter of the 290 patients with bowel injuries. For the 307 patients without a bowel injury, logistic regression indicated that EN is associated with higher fascial closure rates (odds ratio [OR], 5.3; p G 0.01), decreased complication rates(OR, 0.46; p = 0.02), and decreased mortality (OR, 0.30; p = 0.01). For the 290 patients who experienced a bowel injury,regression analysis showed no significant association between EN and fascial closure rate (OR, 0.6; p = 0.2), complication rate (OR, 1.7; p = 0.19), or mortality (OR, 0.79; p = 0.69). CONCLUSION: EN in the open abdomen after injury is feasible. For patients without a bowel injury, EN in the open abdomen is associated with increased fascial closure rates, decreased complication rates, and decreased mortality. EN should be initiated in these patients once resuscitation is completed. Although EN for patients with bowel injuries did not seem to affect the outcome in this study,prospective randomized controlled trials would further clarify the role of EN in this subgroup. PMID- 22836000 TI - Management of pediatric blunt splenic injury at a rural trauma center. AB - BACKGROUND: Patterns for nonoperative management of pediatric blunt splenic injuries (BSIs) vary significantly within and between institutions. The indications for repeated imaging, duration of activity restrictions, as well as the impact of volume and type of trauma center (pediatric vs. adult) on outcomes remain unclear. METHODS: A retrospective review of all patients younger than 16 years with BSI managed at a rural American College of Surgeons-verified adult Level II trauma center from January 1995 to December 2008 was completed. Patients were identified from the trauma registry by DRG International Classification of Diseases-9th Rev. (865.00-865.09) and management codes (41.5, 41.43, and 41.95). Variables reviewed included demographics, mechanism of injury, Injury Severity Score, grade of splenic injury, degree of hemoperitoneum, presence of arterial phase contrast blush on computed tomography at admission, admission and nadir hemoglobin level, blood transfused, length of stay, disposition, outpatient clinical and radiographic follow-up, interval of return to unrestricted activity, and clinical outcomes. RESULTS: During the 13-year study period, 38 children with BSI were identified. Thirty-seven (97%) were successfully managed nonoperatively. Median grade of splenic injury was 3 (range, 1-5); 73% had moderate-to-large hemoperitoneum. Median Injury Severity Score was 10 (range, 4-34). Three patients with isolated contrast blush on initial computed tomography were successfully managed nonoperatively with no angiographic intervention. One patient failed nonoperative management and underwent successful splenorrhaphy. All patients were discharged home. Thirty-day mortality was zero. Median follow-up duration was 5.5 years, with no late complications identified. Of the patients successfully managed nonoperatively, 92% had their follow-up at our institution; 74% underwent subsequent imaging, and none resulted in intervention or alteration of management plan. CONCLUSION: Pediatric BSI can be managed in adult trauma centers with success rates of nonoperative management comparable to dedicated children's hospitals. Routine follow-up imaging is not necessary. Overall splenic injury salvage rate in our experience was 100%. LEVEL OF EVIDENCE: Therapeutic/epidemiologic study, level IV. PMID- 22836001 TI - Brain injury risk from primary blast. AB - BACKGROUND: Military service members are often exposed to at least one explosive event, and many blast-exposed veterans present with symptoms of traumatic brain injury. However, there is little information on the intensity and duration of blast necessary to cause brain injury. METHODS: Varying intensity shock tube blasts were focused on the head of anesthetized ferrets, whose thorax and abdomen were protected. Injury evaluations included physiologic consequences, gross necropsy, and histologic diagnosis. The resulting apnea, meningeal bleeding, and fatality were analyzed using logistic regressions to determine injury risk functions. RESULTS: Increasing severity of blast exposure demonstrated increasing apnea immediately after the blast. Gross necropsy revealed hemorrhages, frequently near the brain stem, at the highest blast intensities. Apnea, bleeding, and fatality risk functions from blast exposure to the head were determined for peak overpressure and positive-phase duration. The 50% risk of apnea and moderate hemorrhage were similar, whereas the 50% risk of mild hemorrhage was independent of duration and required lower overpressures (144 kPa). Another fatality risk function was determined with existing data for scaled positive-phase durations from 1 millisecond to 20 milliseconds. CONCLUSION: The first primary blast brain injury risk assessments for mild and moderate/severe injuries in a gyrencephalic animal model were determined. The blast level needed to cause a mild/moderate brain injury may be similar to or less than that needed for pulmonary injury. The risk functions can be used in future research for blast brain injury by providing realistic injury risks to guide the design of protection or evaluate injury. PMID- 22836002 TI - Percutaneous cardiopulmonary support for catastrophic pulmonary fat embolism in pigs. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of percutaneous cardiopulmonary support (PCPS) for fatal fat embolism. METHODS: Twelve piglets were randomly assigned into either a conventional treatment group (CT group, n = 6) or a PCPS group (n = 6) after receiving 0.3 mL/kg of fat intravenously. The piglets in the CT group received conventional treatments including mechanical ventilation with 100% oxygen, steroid, fluids, anticoagulant, and positive inotropic agents. In addition to conventional treatments, the piglets in the PCPS group received PCPS after fat injection. Mean arterial pressure, central venous pressure, pressure of end tidal carbon dioxide, oxygen saturation, partial pressure of oxygen in arterial blood, arterial carbon dioxide pressure or tension, plasmic lactic acid, and free fatty acid were monitored. The survival rate and the consumption of positive inotropic agents were also recorded. RESULTS: The survival rate of piglets 10 hours after fat injection was much higher in the PCPS group than that in the CT group (100% vs. 0%, p < 0.01). The dosages of positive inotropic agents in the PCPS group were much lower than that in the CT group (p < 0.01). Oxygen saturation, partial pressure of oxygen in arterial blood, and arterial carbon dioxide pressure or tension were significantly improved in the PCPS group in the first 3 hours after fat injection when compared with those in the CT group (p < 0.05 or 0.01), but there were no statistical differences between the two groups in mean arterial pressure, central venous pressure, free fatty acid, and lactic acid at the period. CONCLUSION: PCPS can increase the survival rate of piglets with fatal fat embolism by providing effective cardiopulmonary support. This study suggests that PCPS might be an effective treatment for a patient with severe fat embolism if conventional treatments have not worked. PMID- 22836003 TI - The impact of injury severity and transfer status on reimbursement for care of femur fractures. AB - BACKGROUND: This study investigates the impact of injury severity, patient origin, and payer on charges and payments associated with treatment of femoral fractures at a Level I trauma center. We hypothesized that transfer patients and patients with minor injury would be underinsured, whereas reimbursement rate would be higher for patients with severe injury. METHODS: Medical and financial records of 420 adult patients treated for femoral fractures at a public, urban Level I trauma center were reviewed. Facility and professional charges and payments were determined. Reimbursement rate was defined as the ratio of payment to charge. Payer groups included Medicare, Medicaid, commercial, managed care, workers' compensation, and self-pay. Severe injury was defined by Injury Severity Score of 18 or higher. RESULTS: Patients with Injury Severity Score of less than 18 were more often uninsured compared with the severe injury group (25% vs. 14%, p = 0.005). Patients with severe injury had higher facility (0.47 vs. 0.39, p = 0.005) and total reimbursement rates (0.41 vs. 0.34, p = 0.002) compared with patients with minor injury. Likewise, transfer patients trended toward higher overall reimbursement rate compared with nontransfer patients (0.42 vs. 0.37, p = 0.056). Patients with severe injury were more likely to have commercial insurance (28 vs. 20%, p = 0.06), and transferred patients were more likely to have insurance (88% vs. 79%, p = 0.034). CONCLUSION: The higher proportion of self-pay in the nontransfer group may be caused by the large population of uninsured patients in the area surrounding our trauma center. Favorable payer mix and higher facility reimbursement rate for patients with severe injury may be an incentive for trauma centers to continue providing care for patients with multiple injuries. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. Economic analysis, level IV. PMID- 22836005 TI - Assessing gait adaptability in people with a unilateral amputation on an instrumented treadmill with a projected visual context. AB - BACKGROUND: Gait adaptability, including the ability to avoid obstacles and to take visually guided steps, is essential for safe movement through a cluttered world. This aspect of walking ability is important for regaining independent mobility but is difficult to assess in clinical practice. OBJECTIVE: The objective of this study was to investigate the validity of an instrumented treadmill with obstacles and stepping targets projected on the belt's surface for assessing prosthetic gait adaptability. DESIGN: This was an observational study. METHODS: A control group of people who were able bodied (n=12) and groups of people with transtibial (n=12) and transfemoral (n=12) amputations participated. Participants walked at a self-selected speed on an instrumented treadmill with projected visual obstacles and stepping targets. Gait adaptability was evaluated in terms of anticipatory and reactive obstacle avoidance performance (for obstacles presented 4 steps and 1 step ahead, respectively) and accuracy of stepping on regular and irregular patterns of stepping targets. In addition, several clinical tests were administered, including timed walking tests and reports of incidence of falls and fear of falling. RESULTS: Obstacle avoidance performance and stepping accuracy were significantly lower in the groups with amputations than in the control group. Anticipatory obstacle avoidance performance was moderately correlated with timed walking test scores. Reactive obstacle avoidance performance and stepping accuracy performance were not related to timed walking tests. Gait adaptability scores did not differ in groups stratified by incidence of falls or fear of falling. LIMITATIONS: Because gait adaptability was affected by walking speed, differences in self-selected walking speed may have diminished differences in gait adaptability between groups. CONCLUSIONS: Gait adaptability can be validly assessed by use of an instrumented treadmill with a projected visual context. When walking speed is taken into account, this assessment provides unique, quantitative information about walking ability in people with a lower-limb amputation. PMID- 22836004 TI - Diagnostic accuracy of fall risk assessment tools in people with diabetic peripheral neuropathy. AB - BACKGROUND: Diabetic peripheral neuropathy affects nearly half of individuals with diabetes and leads to increased fall risk. Evidence addressing fall risk assessment for these individuals is lacking. OBJECTIVE: The purpose of this study was to identify which of 4 functional mobility fall risk assessment tools best discriminates, in people with diabetic peripheral neuropathy, between recurrent "fallers" and those who are not recurrent fallers. DESIGN: A cross-sectional study was conducted. SETTING: The study was conducted in a medical research university setting. PARTICIPANTS: The participants were a convenience sample of 36 individuals between 40 and 65 years of age with diabetic peripheral neuropathy. MEASUREMENTS: Fall history was assessed retrospectively and was the criterion standard. Fall risk was assessed using the Functional Reach Test, the Timed "Up & Go" Test, the Berg Balance Scale, and the Dynamic Gait Index. Sensitivity, specificity, positive and negative likelihood ratios, and overall diagnostic accuracy were calculated for each fall risk assessment tool. Receiver operating characteristic curves were used to estimate modified cutoff scores for each fall risk assessment tool; indexes then were recalculated. RESULTS: Ten of the 36 participants were classified as recurrent fallers. When traditional cutoff scores were used, the Dynamic Gait Index and Functional Reach Test demonstrated the highest sensitivity at only 30%; the Dynamic Gait Index also demonstrated the highest overall diagnostic accuracy. When modified cutoff scores were used, all tools demonstrated improved sensitivity (80% or 90%). Overall diagnostic accuracy improved for all tests except the Functional Reach Test; the Timed "Up & Go" Test demonstrated the highest diagnostic accuracy at 88.9%. LIMITATIONS: The small sample size and retrospective fall history assessment were limitations of the study. CONCLUSIONS: Modified cutoff scores improved diagnostic accuracy for 3 of 4 fall risk assessment tools when testing people with diabetic peripheral neuropathy. PMID- 22836006 TI - How the National Heart, Lung, and Blood Institute (NHLBI) develops research priorities and supports critical care research. AB - This report provides a brief overview of some relevant ongoing research on critical care and how research priorities are determined by the National Heart, Lung, and Blood Institute. Long-term and patient-centered outcomes have become more prominent research questions for clinical studies in patients who are critically ill. Rehabilitation research would be appropriate in this context, and funding is most likely received through investigator-initiated R01 applications. National Institutes of Health program staff are available for discussion and advice and encourage contact from extramural investigators. PMID- 22836007 TI - What follows survival of critical illness? Physical therapists' management of patients with post-intensive care syndrome. AB - Historically, the management of patients in the intensive care unit (ICU) has involved immobilization and sedation, with care focused on physiological impairments and survival. Because more ICU patients are now surviving their hospital stay, it is imperative that their ICU care be managed with the goal of long-term health, wellness, and functioning. The evidence confirms that mobilization and exercise are feasible in the ICU and demonstrates that the benefits of early mobilization include reduced length of stay in the ICU and hospital. In 2010, the Society of Critical Care Medicine (SCCM) invited key stakeholder groups, including the American Physical Therapy Association (APTA), to identify strategies to improve long-term consequences following ICU discharge, including early mobilization in the ICU and integration of the physical therapist as a member of the ICU team. This model appears to be successful in some institutions, but there is variation among institutions. The SCCM Task Force developed major areas of focus that require multidisciplinary action to improve long-term outcomes after discharge from an ICU. This article describes physical therapist practice in the management of ICU survivors, the importance of long term follow-up after ICU discharge, and how APTA is taking steps to address the major areas of focus identified by the SCCM Task Force to improve long-term outcomes after ICU discharge. PMID- 22836008 TI - Attention and memory biases toward body-related images among restrained eaters. AB - This study examined biases in attention and memory toward body-related images among restrained (n=31) and unrestrained (n=29) eaters. Attentional allocation to images of thin and overweight bodies during a visual search task was measured by tracking participants' eyegaze. This task was followed by a recognition test assessing participants' memory for those images. Restrained and unrestrained eaters allocated more attention to body-related images than to control images, but there was no difference in attentional allocation between the two groups. Restrained eaters showed better recognition of body-related images that they had previously seen during the visual search task. Finally, increased attention was associated with better recognition of body-related images for both restrained and unrestrained eaters, but restrained eaters had better overall recognition regardless of the level of attention. These findings suggest that restrained eaters may have more organized strategies for processing body-related information than do unrestrained eaters. PMID- 22836009 TI - SORL1 and SIRT1 mRNA expression and promoter methylation levels in aging and Alzheimer's Disease. AB - Alzheimer's Disease (AD) is a neurodegenerative disorder and the most common cause of dementia among the elderly. Efforts have been made to understand the genetic and epigenetic mechanisms involved in the development of this disease. As SORL1 (sortilin-related receptor) and SIRT1 (sirtuin 1) genes have been linked to AD pathogenesis, we aimed to investigate their mRNA expression and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly subjects and AD patients. We also evaluated these levels in peripheral blood leukocytes from young, healthy elderly and AD patients, investigating whether there was an effect of age on these profiles. The comparative CT method by Real Time PCR and MALDI-TOF mass spectrometry were used to analyze gene expression and DNA methylation, respectively. SORL1 gene was differently expressed in the peripheral blood leukocytes and might act as a marker of aging in this tissue. Furthermore, we found that SORL1 promoter DNA methylation might act as one of the mechanisms responsible for the differences in expression observed between blood and brain for both healthy elderly and AD patients groups. The impact of these studied genes on AD pathogenesis remains to be better clarified. PMID- 22836010 TI - Optical spatial solitons: historical overview and recent advances. AB - Solitons, nonlinear self-trapped wavepackets, have been extensively studied in many and diverse branches of physics such as optics, plasmas, condensed matter physics, fluid mechanics, particle physics and even astrophysics. Interestingly, over the past two decades, the field of solitons and related nonlinear phenomena has been substantially advanced and enriched by research and discoveries in nonlinear optics. While optical solitons have been vigorously investigated in both spatial and temporal domains, it is now fair to say that much soliton research has been mainly driven by the work on optical spatial solitons. This is partly due to the fact that although temporal solitons as realized in fiber optic systems are fundamentally one-dimensional entities, the high dimensionality associated with their spatial counterparts has opened up altogether new scientific possibilities in soliton research. Another reason is related to the response time of the nonlinearity. Unlike temporal optical solitons, spatial solitons have been realized by employing a variety of noninstantaneous nonlinearities, ranging from the nonlinearities in photorefractive materials and liquid crystals to the nonlinearities mediated by the thermal effect, thermophoresis and the gradient force in colloidal suspensions. Such a diversity of nonlinear effects has given rise to numerous soliton phenomena that could otherwise not be envisioned, because for decades scientists were of the mindset that solitons must strictly be the exact solutions of the cubic nonlinear Schrodinger equation as established for ideal Kerr nonlinear media. As such, the discoveries of optical spatial solitons in different systems and associated new phenomena have stimulated broad interest in soliton research. In particular, the study of incoherent solitons and discrete spatial solitons in optical periodic media not only led to advances in our understanding of fundamental processes in nonlinear optics and photonics, but also had a very important impact on a variety of other disciplines in nonlinear science. In this paper, we provide a brief overview of optical spatial solitons. This review will cover a variety of issues pertaining to self-trapped waves supported by different types of nonlinearities, as well as various families of spatial solitons such as optical lattice solitons and surface solitons. Recent developments in the area of optical spatial solitons, such as 3D light bullets, subwavelength solitons, self-trapping in soft condensed matter and spatial solitons in systems with parity-time symmetry will also be discussed briefly. PMID- 22836011 TI - Inflammatory activation enhances NMDA-triggered Ca2+ signalling and IL-1beta secretion in primary cultures of rat astrocytes. AB - The aim of the present study was to measure the effects of NMDA receptor antagonists on rat astroglial-enriched primary cultures after incubation with lipopolysaccharide (LPS), with a view to explaining the role of NMDA receptors in the inflammatory activation of astrocytes. First, the presence of NMDA receptor subunits was confirmed at the protein level by immunocytochemical methods. The presence of functional NMDA receptors containing GluN2B subunits was then established by ratiometric fluorescent Ca(2+) imaging which revealed transient NMDA-triggered Ca(2+) responses. These responses could be blocked by the competitive antagonist 2-amino-5-phosphonopentoate (APV) and the non-competitive GluN2B subunit-selective antagonist ifenprodil. The NMDA-evoked Ca(2+) transients were dependent on Ca(2+) release from intracellular stores via interaction with InsP3-sensitive receptors as they were blocked by thapsigargin or xestospongin C. Following 24h incubation with LPS, astroglial inflammatory activation increased IL-1beta secretion and NMDA-triggered Ca(2+) transients. The addition of APV or ifenprodil inhibited these enhanced responses, suggesting that LPS exposure stimulates IL-1beta release from astrocytes through a mechanism that requires NMDA receptor stimulation. PMID- 22836012 TI - Neuronal expression of bitter taste receptors and downstream signaling molecules in the rat brainstem. AB - Previous studies have shown that molecules of the taste transduction pathway may serve as biochemical markers for chemoreceptive cells in respiratory and gastrointestinal tracts. In this study, we tested the hypothesis that brainstem neurons contain signaling molecules similar to those in taste buds which may sense the chemical composition of brain extracellular fluids. We used the reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunohistochemical techniques to evaluate presence of different bitter responsive type 2 taste receptors (T2Rs), their associated G-protein alpha gustducin, the downstream signaling molecules phospholipase C isoform beta2 (PLC beta2) and transient receptor potential melastatin 5 (TRPM5) in the brainstem of rats. RT-PCR confirmed the mRNA coding for alpha-gustducin, PLC-beta2, TRPM5 and rT2R1 but not that of rT2R16, rT2R26 and rT2R38 in the medulla oblongata. Western blotting confirmed the presence of alpha-gustducin at the protein level in rat brainstem. Immunohistochemistry identified cells expressing alpha-gustducin and PLC-beta2 at multiple cardiorespiratory and CO(2)/H(+) chemosensory sites, including rostral ventral medulla, facial, parapyramidal, solitary tract, hypoglossal and raphe nuclei. In the medullary raphe, alpha-gustducin and PLC beta2 were colocalized with a subpopulation of tryptophan hydroxylase (TPH) immunoreactive serotonergic neurons, a subset of which has respiratory CO(2)/H(+) chemosensitivity. Presence of the T2R1 gene and other genes and proteins of the bitter taste transduction pathway in the brainstem implies additional functions for taste receptors and their effector molecules apart from their gustatory function. PMID- 22836013 TI - Effects of halothane on GABAergic and glutamatergic transmission in isolated hippocampal nerve-synapse preparations. AB - We evaluated the effects of halothane on synaptic and extrasynaptic GABA(A) and glutamate receptor responses using mechanically dissociated rat hippocampal CA3 neurons in which the well isolated neurons retain functional native nerve endings (the 'synaptic bouton' preparation). The preparation allows the simultaneous comparison of extrasynaptic GABA(A) and glutamate receptors, activated by bath applied GABA and glutamate, respectively, to the synaptic receptors measured as spontaneous and evoked postsynaptic currents. Paired-pulse synaptic responses evoked by focal electrical stimulation were also measured to evaluate any presynaptic effects. Halothane enhanced the extrasynaptic GABA(A)-receptor mediated postsynaptic responses in a concentration dependent fashion. At clinically relevant concentrations, halothane significantly increased both the amplitude and frequency of spontaneous postsynaptic inhibitory currents (sIPSCs) mediated by synaptic GABA(A) receptors. The relative amplitude of evoked IPSCs (eIPSCs) was also increased, concurrent with a decrease in failure rate and a significantly decreased eIPSC paired-pulse ratio. Halothane concentration dependently decreased the extrasynaptic glutamate-receptor induced postsynaptic responses but had no effects on spontaneous or evoked excitatory postsynaptic currents. These results suggest that halothane acts predominantly at presynaptic sites at GABAergic synapses to enhance inhibitory transmission at CA3 synapses, although it also increases extra-synaptic GABA responses. At excitatory synapses on to CA3 neurons, halothane has no presynaptic action-effecting only extrasynaptic receptors. Our results have clarified the locus of effects of the volatile anesthetic halothane at excitatory and inhibitory synapses, drawing somewhat different conclusions from those deduced from slices and culture systems. PMID- 22836014 TI - Modulation of immune signalling by inhibitors of apoptosis. AB - The inhibitor of apoptosis (IAP) genes are critical regulators of multiple pathways that control cell death, proliferation, and differentiation. Several members of the IAP family regulate innate and adaptive immunity through modulation of signal transduction pathways, cytokine production, and cell survival. The regulation of immunity by the IAPs is primarily mediated through the ubiquitin ligase function of cellular IAP (cIAP)1, cIAP2, and X-linked IAP (XIAP), the targets of which impact nuclear factor (NF)-kappaB and mitogen activated protein kinase (MAPK) signalling pathways. In addition, neuronal apoptosis inhibitory protein (NAIP), cIAP1, and cIAP2 modulate innate immune responses through control of the inflammasome complex. This review examines the role of mammalian IAPs in regulating immunity and describes the implications of a new class of pan-IAP antagonists for the treatment of immune disorders. PMID- 22836015 TI - Clinical aspects of microbleeds in Alzheimer's disease. AB - Microbleeds are small lesions, appearing as black dots on T2-weighted magnetic resonance imaging. They occur frequently in Alzheimer's disease (AD), but the clinical relevance of these radiological observations remains unclear. In this paper an overview is given on currently available evidence on the clinical relevance of microbleeds in AD. The evidence linking microbleeds to severity of cognitive impairment in AD is not unambiguous. From the existing literature, it seems reasonable to conclude that multiple microbleeds negatively impact cognitive performance, but there is less consensus on the importance of location of microbleeds in this respect. Regarding progression of disease, there is hardly any evidence that microbleeds affect disease course in terms of progression to AD in patients with MCI or with respect to rate of cognitive decline in AD patients. This may imply that microbleeds simply do not affect disease course, but an alternative explanation for the negative findings would be that these studies are hampered by selective drop-out, as individuals with many microbleeds have an increased risk of (stroke-related) mortality. PMID- 22836016 TI - Altered serum content of brain-derived neurotrophic factor isoforms in multiple sclerosis. AB - In multiple sclerosis (MS), brain-derived neurotrophic factor (BDNF) provides neuroprotection, but can also promote disease through the maintenance of autoreactive T cells. One aspect that has not been explored yet in MS is related to the opposite functions of BDNF protein isoforms consisting of the pro-BDNF precursor, which has pro-apoptotic effects, and two proteolytic isoforms, the mature BDNF with pro-survival effects and truncated BDNF, with unknown functions. Using ELISA and semi-quantitative Western-blot we determined the relative serum levels of BDNF isoforms in 20 relapsing-remitting MS patients without any disease modifying therapy and 20 age and gender-matched healthy controls and searched for clinical correlates. Total serum BDNF was lower in MS than in HC. We demonstrate that the capture and detection antibodies of the ELISA kit from Promega are able to recognize all three isoforms but with different efficiency. Using Western-blot analysis, we show that the percentage of serum mature BDNF and pro-BDNF with respect to total serum BDNF was significantly decreased, while truncated BDNF was increased. No correlation between BDNF isoform percentage and clinical or demographic features was found. Serum Fas (sFas) was increased. These results support and expand the current hypothesis on the role of BDNF in multiple sclerosis, in that low pro-BDNF and high sFas might result in a failure to limit autoreactive T cells by apoptotic deletion and decreased mature BDNF may not provide enough neuroprotection, while truncated BDNF percent increase could be a compensatory mechanism. Hence, future studies on MS should take into account BDNF proteolytic processing. PMID- 22836018 TI - Cognitive assessment protocol design in the ISSYS (Investigating Silent Strokes in hYpertensives: a magnetic resonance imaging Study). AB - Hypertension and silent cerebrovascular lesions (SCL) detected by brain magnetic resonance imaging (MRI) are associated with an increased risk of cognitive decline. In a prospective observational study in 1000 hypertensive patients, aged 50-70 years, with no prior history of stroke or dementia, we will study the presence of mild cognitive impairment (MCI) and the relationship between SCL and cognition. All participants will be assessed by means of the Dementia Rating Scale-2 (DRS-2) and will undergo a brain MRI. In order to better characterize MCI and future dementia risk in our cohort, those patients that are suspected to be cognitively impaired according to the DRS-2 results will have a further neurological evaluation and complete neuropsychological testing. Follow-up for the entire cohort is planned to last for at least 3 years. PMID- 22836019 TI - Cysticerci-related parenchymal brain enhancing lesion. PMID- 22836020 TI - Analysis of stem-cell-like properties of human CD161++IL-18Ralpha+ memory CD8+ T cells. AB - CD161(++)IL-18Ralpha(+)CD8(+) human T cells have recently been identified as a new subset of memory cells but their exact role remains unclear. CD161(++)IL 18Ralpha(+)CD8(+), mucosal-associated invariant T cells express a semi-invariant TCR Valpha7.2-Jalpha33, which recognizes the MHC-related protein 1. On the basis of properties including the expression of the ABC-B1 transporter, cKit expression and survival after chemotherapy, CD161(++)IL-18Ralpha(+)CD8(+) T cells have been designated as 'stem' cells. Here we analyse location and functional properties of CD161(++)IL-18Ralpha(+) CD8(+) T cells and question whether they have other traits that would mark them as genuine 'stem' cells. CD161(++)IL 18Ralpha(+)CD8(+) T cells were found in peripheral blood, spleen and bone marrow but interestingly hardly at all in lymph nodes (LNs), which may possibly be explained by the finding that these cells express a specific set of chemokine receptors that allows migration to inflamed tissue rather than to LNs. In addition to TCR ligation and co-stimulation, CD161(++)IL-18Ralpha(+) CD8(+) T cells require cytokines for proliferation. The CD161(++)IL-18Ralpha(+) CD8(+) pool contains cells reactive towards peptides, derived from both persisting and cleared viruses. Although CD161(++)IL-18Ralpha(+) CD8(+) T cells express the ABC B1 transporter, they have shorter telomeres and less telomerase activity and do not express aldehyde dehydrogenase. Finally, CD161(++)IL-18Ralpha(+) CD8(+) T cells show similarities to terminally differentiated T cells, expressing IFNgamma, KLRG1 and the transcription factor Blimp-1. In conclusion, CD161(++)IL 18Ralpha(+) CD8(+) T cells lack many features of typical 'stem' cells, but appear rather to be a subset of effector-type cells. PMID- 22836021 TI - Double expression of CD34 and CD117 on bone marrow progenitors is a hallmark of the development of functional mast cell of Callithrix jacchus (common marmoset). AB - Mast cells (MCs) are developed from hematopoietic progenitor cells and play an important role in inflammation. Study of the kinetics of development and accumulation of primate MC in vivo is crucial for the control of human inflammatory diseases, as evolution of the immune system is quite rapid and inflammation including MC response is considered to be different between mouse and human. In the present study, we examined the development of MC from hematopoietic progenitors of Callithrix jacchus (common marmoset), an experimental animal of nonhuman primates. Bone marrow cells were fractionated for the expression of CD34 and CD117 by cell sorting. MCs were developed in vitro or by transplanting the cells to NOD/SCID/IL-2gammac knockout (NOG) mice. In vitro culture of CD34(+)CD117(+) (double positive, DP) cells with stem cell factor could generate high-affinity Fc epsilon receptor (FcepsilonR)-expressing CD117(+) cells with typical granules. The developed MC released beta-hexosaminidase and produced leukotriene C(4) after the stimulation of FcepsilonRI. Transplantation of DP cells gave rise to a marked expansion of CD34( )CD45(+)CD117(+)FcepsilonR(+) cells in NOG mice. They expressed transcripts encoding chymase 1 and tryptase beta. Differentiation of CD34(-)CD117(+) cells to MCs was relatively limited compared with the DP cells, similarly to human MCs. These results suggest that this marmoset system provides a good model for human MC development. PMID- 22836022 TI - PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells. AB - AbstractToll-like receptor 5 (TLR5), a sensor for bacterial flagellin, mounts innate and adaptive immune responses, and has been implicated in infectious diseases, colitis and metabolic syndromes. Although TLR5 is believed to belong to cell surface TLRs, cell surface expression has never been verified. Moreover, it has remained unclear which types of immune cells express TLR5 and contribute to flagellin-dependent responses. In this study we established an anti-mouse TLR5 monoclonal antibody and studied the cell surface expression of TLR5 on immune cells. The macrophage cell line J774 expressed endogenous TLR5 on the cell surface and produced IL-6 and G-CSF in response to flagellin. Cell surface expression of TLR5 and flagellin-induced responses were completely abolished by silencing a TLR-specific chaperone protein associated with TLR4 A (PRAT4A), demonstrating that TLR5 is another client of PRAT4A. In the in vivo immune cells, cell surface TLR5 was mainly found on neutrophils and CD11b (hi) Ly6C (hi) classical monocytes in the bone marrow, circulation, spleen and inflammatory lesions. Ly6C (hi) classical monocytes, but not neutrophils, produced cytokines in response to flagellin. Splenic CD8 (-) CD4 (+) conventional dendritic cells and CD11c (hi) CD11b (hi) lamina propria DCs, also clearly expressed cell surface TLR5. Collectively, cell surface expression of TLR5 is dependent on PRAT4A and restricted to neutrophils, classical monocytes and specific DC subsets. PMID- 22836023 TI - Conducting go-along interviews to understand context and promote health. AB - Go-along interviewing is an innovative approach to obtaining contextualized perspectives by conducting mobile interviews in which the participant acts as a navigational guide of the real or virtual space within which he or she lives. In this study, we used go-along interviews to obtain college students' contextualized perceptions of sexual health resources. Seventy-eight undergraduate students showed and described the resources on and near five campuses in a Midwestern state. In this article, we focus on the methodology of go-along interviews. The go-along, a relatively new methodology in health research, is a format in which participants take an active role in shaping the interview, and it facilitates identification of resources that might be overlooked using traditional interview formats. The go-along methodology is promising for researchers wanting to ground health-promotion efforts in the context of environmental or community-based strengths and needs. PMID- 22836024 TI - [Invasive procedures in patients hospitalized in Spanish internal medicine departments]. AB - AIMS: Invasive procedures (IP) have become routine techniques that benefit an important number of patients on improving their quality of life or avoiding more aggressive treatments. We have conducted a study on the IPs performed in Spanish Internal Medicine (IM) Departments between 2005 and 2009. PATIENTS AND METHODS: IP performed to patients admitted to Spanish Internal Medicine departments were analyzed based on the information obtained from the Minimum Basis Data Set (CMBD). IP was defined as the following: filter placement in the inferior vena cava, chest tube placement, biliary, esophageal and colon prosthesis placement, pleurodesis, nephrostomy, external biliary drain placement, gastrostomy tube placement, thoracocentesis and peritoneal catheter placement. RESULTS: During the study period, a total of 75,853 invasive procedures on 70,239 admittances were performed in 2,766,673 patients (2.5%). IP subjects were younger (68.1 vs 71.4; P<.001), predominantly male (61.9 vs 53.2%; P<.001), with higher mortality (14.6 vs 9.9%; P<.001) and longer stay (18.4 vs 9.6 days; P<0.001). Cost of admittance was clearly higher than the rest of the patients (5,600? vs 3,835?; P<.001). CONCLUSIONS: IPs are performed on a low percentage of IM Department hospitalized patients. They are costly, entail high mortality and a longer stay period compared to the mean population admitted to IM. A considerable proportion of the patients receiving IP suffer from neoplastic diseases, frequently in advances stages, which justifies the high inhospital mortality of this population. PMID- 22836026 TI - A multilayer braided scaffold for Anterior Cruciate Ligament: mechanical modeling at the fiber scale. AB - An adapted scaffold for Anterior Cruciate Ligament (ACL) tissue engineering must match biological, morphological and biomechanical requirements. Computer-aided tissue engineering consists of finding the most appropriate scaffold regarding a specific application by using numerical tools. In the present study, the biomechanical behavior of a new multilayer braided scaffold adapted to computer aided tissue engineering is computed by using a dedicated Finite Element (FE) code. Among different copoly(lactic acid-co-(epsilon-caprolactone)) (PLCL) fibers tested in the present study, PLCL fibers with a lactic acid/epsilon-caprolactone ratio of 85/15 were selected as a constitutive material for the scaffold considering its strength and deformability. The mechanical behavior of these fibers was utilized as material input in a Finite Element (FE) code which considers contact/friction interactions between fibers within a large deformation framework. An initial geometry issued from the braiding process was then computed and was found to be representative of the actual scaffold geometry. Comparisons between simulated tensile tests and experimental data show that the method enables to predict the tensile response of the multilayer braided scaffold as a function of different process parameters. As a result, the present approach constitutes a valuable tool in order to determine the configuration which best fits the biomechanical requirements needed to restore the knee function during the rehabilitation period. The developed approach also allows the mechanical stimuli due to external loading to be quantified, and will be used to perform further mechanobiological analyses of the scaffold under dynamic culture. PMID- 22836025 TI - Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium. AB - There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multidose therapy with a non- or minimally invasive delivery approach. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly(methylvinylether-co-maleic anhydride) were used for the first time in active transdermal delivery of the LMWH nadroparin calcium (NC). Importantly, an array loading of 630IU of NC was achieved without compromising the array mechanical strength or drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single-step 'poke and release' approach allowed permeation of approximately 10.6% of the total NC load over a 48-h study period. The cumulative amount of NC that permeated DHS at 24h and 48h attained 12.28+/-4.23IU/cm(2) and 164.84+/-8.47IU/cm(2), respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offers great potential as a relatively low-cost functional delivery system for enhanced transdermal delivery of LMWH and other macromolecules. PMID- 22836027 TI - Thermoelectric transport in the three terminal quantum dot. AB - The thermoelectric transport in the system composed of a quantum dot in contact with superconducting, ferromagnetic and normal metal electrodes has been studied. Such a system can support pure spin current in the normal electrode. In the limit of a large superconducting gap and weak coupling between the dot and the electrodes we investigate the sub-gap charge and spin transport via Andreev mechanism using the standard master equation technique, which is known to be valid in the sequential tunnelling regime. The Zeeman splitting of the dot level induces pure spin current in the ferromagnetic electrode under an appropriate bias. This opens a novel possibility to switch the spin current between two electrodes by electric means. The calculated spin and charge thermopower coefficients attain very large values, of the order of a few hundreds MUV K(-1), and show similar dependences on the position of the on-dot energy level and temperature. PMID- 22836028 TI - Food-package assignments and breastfeeding initiation before and after a change in the Special Supplemental Nutrition Program for Women, Infants, and Children. AB - BACKGROUND: In 2009, the USDA implemented an interim rule that changed the prescribed foods in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Options for mother and infant dyads include a full breastfeeding package with no infant formula, a partial breastfeeding package with some infant formula, and a full formula package with a smaller postpartum food package for the mother. The changes were designed to encourage WIC mothers to choose breastfeeding for their infants. OBJECTIVE: The purpose of this study was to measure changes in the following 3 outcomes: WIC food-package assignments, WIC infant formula amounts, and breastfeeding initiation. DESIGN: We compared outcomes before and after implementation of the interim rule in a national random sample of 17 local WIC agencies (LWAs). The data source was administrative records for 206,092 dyads with an infant aged 0-5 mo in the sampled LWAs. RESULTS: There were changes in WIC food-package assignments and infant formula amounts but no change in breastfeeding initiation. For dyads in whom the infant was in his or her birth month, the percentage of mothers who received the partial breastfeeding package fell from 24.7% (preimplementation) to 13.8% (postimplementation), the percentage of mothers who received the full breastfeeding package rose from 9.8% (preimplementation) to 17.1% (postimplementation), and the percentage of mothers who received the full formula package rose from 20.5% (preimplementation) to 28.5% (postimplementation). CONCLUSIONS: After the change, fewer WIC mothers of new infants received the partial breastfeeding package. More WIC mothers received the full breastfeeding package, but more mothers also received the full formula package. PMID- 22836029 TI - Lifestyle determinants of the drive to eat: a meta-analysis. AB - BACKGROUND: Obesity is emerging as the most significant health concern of the 21st century. Although this is attributable in part to changes in our environment including the increased prevalence of energy-dense food-it also appears that several lifestyle factors may increase our vulnerability to this calorie-rich landscape. Epidemiologic studies have begun to show links between adiposity and behaviors such as television watching, alcohol intake, and sleep deprivation. However, these studies leave unclear the direction of this association. In addition, studies that investigated the acute impact of these factors on food intake have reported a wide variety of effect sizes, from highly positive to slightly negative. OBJECTIVE: The purpose of this article was to provide a meta analysis of the relation between lifestyle choices and increases in acute food intake. DESIGN: An initial search was performed on PubMed to collect articles relating television watching, sleep deprivation, and alcohol consumption to food intake. Only articles published before February 2012 were considered. Studies that took place in a controlled, laboratory setting with healthy individuals were included. Studies were analyzed by using 3 meta-analyses with random-effects models. In addition, a 1-factor ANOVA was run to discover any main effect of lifestyle. RESULTS: The 3 most prominent lifestyle factors-television watching, alcohol intake, and sleep deprivation-had significant short-term effects on food intake, with alcohol being more significant (Cohen's d = 1.03) than sleep deprivation (Cohen's d = 0.49) and television watching (Cohen's d = 0.2). CONCLUSIONS: Our results suggest that television watching, alcohol intake, and sleep deprivation are not merely correlated with obesity but likely contribute to it by encouraging excessive eating. Because these behaviors are all known to affect cognitive functions involved in reward saliency and inhibitory control, it may be that they represent common mechanisms through which this eating is facilitated. PMID- 22836032 TI - Endogenous proteins in terminal ileal digesta of adult subjects fed a casein based diet. AB - BACKGROUND: Although there are several published estimates of the endogenous amino acid composition of ileal digesta in humans, to our knowledge, there are no systematic studies of ileal digesta endogenous proteins. OBJECTIVES: We determined the nature and composition of endogenous nitrogen-containing substances lost from the upper digestive tract of humans. DESIGN: Digesta were collected from the terminal ileum for a period of 8 h by using a nasoileal tube in 6 adult subjects fed a single meal that contained 22% of casein as the only source of nitrogen. RESULTS: The total nitrogen that passed the terminal ileum was 39.3 mg/g native digesta dry matter. Of this amount, 86% was proteinaceous, ~60% was bacterial protein, ~7% was soluble-free protein, ~15% was mucin protein, and ~5% was protein from intact mucosal cells. For nonprotein nitrogen, ~5% of the total nitrogen was ammonia, and ~4% of the total nitrogen was urea. Bacterial and human mucosal cellular DNA nitrogen were collectively ~0.5% of the total nitrogen. Approximately 30% of the nonprotein nitrogen (4% of the total nitrogen) remained unidentified. This amount was assumed to include free amino acids, RNAs, amines, and the tetrapyrroles bilirubin and biliverdin. Bacterial nitrogen, combined with ammonia and urea nitrogen, represented >68% of total ileal nitrogenous losses. CONCLUSIONS: Findings are presented on the endogenous nitrogen-containing compounds that left the terminal ileum. Of particular significance is the observation that mucin was the most abundant truly endogenous component within the terminal ileal digesta. Bacterial protein, which was strictly nondietary rather than endogenous, contributed the highest proportion, by far, of nondietary protein, the result of which makes a significant contribution to published estimates of ileal endogenous amino acids and protein. The high concentration of bacterial protein and the presence of ammonia and urea nitrogen indicate potentially substantial microbial activity within the human distal small intestine. PMID- 22836031 TI - The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. AB - BACKGROUND: Breast milk is recognized as the most important postpartum element in metabolic and immunologic programming of health of neonates. The factors influencing the milk microbiome and the potential impact of microbes on infant health have not yet been uncovered. OBJECTIVE: Our objective was to identify pre- and postnatal factors that can potentially influence the bacterial communities inhabiting human milk. DESIGN: We characterized the milk microbial community at 3 different time points by pyrosequencing and quantitative polymerase chain reaction in mothers (n = 18) who varied in BMI, weight gain, and mode of delivery. RESULTS: We found that the human milk microbiome changes over lactation. Weisella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcus were predominant in colostrum samples, whereas in 1- and 6-mo milk samples the typical inhabitants of the oral cavity (eg, Veillonella, Leptotrichia, and Prevotella) increased significantly. Milk from obese mothers tended to contain a different and less diverse bacterial community compared with milk from normal weight mothers. Milk samples from elective but not from nonelective mothers who underwent cesarean delivery contained a different bacterial community than did milk samples from individuals giving birth by vaginal delivery, suggesting that it is not the operation per se but rather the absence of physiological stress or hormonal signals that could influence the microbial transmission process to milk. CONCLUSIONS: Our results indicate that milk bacteria are not contaminants and suggest that the milk microbiome is influenced by several factors that significantly skew its composition. Because bacteria present in breast milk are among the very first microbes entering the human body, our data emphasize the necessity to understand the biological role that the milk microbiome could potentially play for human health. PMID- 22836030 TI - Race-ethnic, family income, and education differentials in nutritional and lipid biomarkers in US children and adolescents: NHANES 2003-2006. AB - BACKGROUND: Children from ethnic minority and low-income families in the United States have higher rates of poor health and higher mortality rates. Diet, an acknowledged correlate of health, may mediate the known race-ethnic and socioeconomic differentials in the health of US children. OBJECTIVE: The objective was to examine the independent association of race-ethnicity, family income, and education with nutritional and lipid biomarkers in US children. DESIGN: We used data from the NHANES 2003-2006 to examine serum concentrations of vitamins A, D, E, C, B-6, and B-12; serum concentrations of folate, carotenoids, and lipids; and dietary intakes of corresponding nutrients for 2-19-y-old children (n = ~2700-7500). Multiple covariate-adjusted regression methods were used to examine the independent and joint associations of race-ethnicity, family income, and education with biomarker status. RESULTS: Non-Hispanic blacks had lower mean serum concentrations of vitamins A, B-6, and E and alpha-carotene than did non-Hispanic whites. Both non-Hispanic blacks and Mexican Americans had higher mean serum vitamin C, beta-cryptoxanthin, and lutein + zeaxanthin but lower folate and vitamin D concentrations compared with non-Hispanic whites. In comparison with non-Hispanic whites, non-Hispanic blacks were less likely to have low serum HDL cholesterol or high triglycerides. Family income and education predicted few biomarker or dietary outcomes, and the observed associations were weak. Moreover, modification of race-ethnic differentials by income or education (or vice versa) was noted for very few biomarkers. CONCLUSION: Race-ethnicity, but not family income or education, was a strong independent predictor of serum nutrient concentrations and dietary micronutrient intakes in US children and adolescents. PMID- 22836033 TI - Body-composition development during early childhood and energy expenditure in response to physical activity in 1.5-y-old children. AB - BACKGROUND: The prevalence of childhood overweight and obesity has increased recently, but the mechanisms involved are incompletely known. Previous research has shown a correlation between the percentage of total body fat (TBF) and physical activity level (PAL). However, the PAL values used may involve a risk of spurious correlations because they are often based on predicted rather than measured estimates of resting energy metabolism. OBJECTIVES: We studied the development of body composition during early childhood and the relation between the percentage of TBF and PAL on the basis of the measured resting energy metabolism. DESIGN: Body composition was previously measured in 108 children when they were 1 and 12 wk old. When 44 of these children (21 girls and 23 boys) were 1.5 y old, their total energy expenditure and TBF were assessed by using the doubly labeled water method. Resting energy metabolism, which was assessed by using indirect calorimetry, was used to calculate PAL. RESULTS: Significant correlations were shown for TBF (r = 0.32, P = 0.035) and fat-free mass (r = 0.34, P = 0.025) between values (kg) assessed at 12 wk and 1.5 y of age. For TBF (kg) a significant interaction (P = 0.035) indicated a possible sex difference. PAL at 1.5 y was negatively correlated with the percentage of TBF (r = -0.40, P = 0.0076) and the increase in the percentage of TBF between 12 wk and 1.5 y (r = 0.38, P = 0.0105). CONCLUSIONS: The results indicate that body fatness and physical activity interact during early childhood and thereby influence obesity risk. Our results are based on a small sample, but nevertheless, they motivate additional studies in boys compared with girls regarding the development of body composition during early life. PMID- 22836034 TI - Gastric bypass surgery for obesity decreases the reward value of a sweet-fat stimulus as assessed in a progressive ratio task. AB - BACKGROUND: Obesity is among the leading causes of disease and death. Bariatric surgery is the most effective treatment of obesity. There is increasing evidence that after gastric bypass surgery, patients and animal models show a decreased preference for sweet and fatty foods. The underlying mechanism may include alterations in taste function. OBJECTIVE: We hypothesize that a gastric bypass reduces the reward value of sweet and fat tastes. DESIGN: In this prospective case-control study, 11 obese patients who were scheduled to undergo a gastric bypass and 11 normal-weight control subjects in the fed state clicked a computer mouse to receive a sweet and fatty candy on a progressive ratio schedule 10 wk apart (in patients, testing took place 2 wk before and 8 wk after gastric bypass surgery). Subjects worked progressively harder to obtain a food reward (reinforcer) until they stopped clicking (ie, the breakpoint), which was a measure of the reinforcer value. Breakpoints were assessed by the number of mouse clicks in the last completed ratio. The experiment was repeated in a different cohort by using vegetable pieces as the reinforcer. RESULTS: Breakpoints in the test sessions of control subjects correlated highly for both reinforcers. The median breakpoint for candies, but not vegetables, was reduced by 50% in the obese group after gastric bypass. Patients with the largest reduction in the breakpoint had the largest decrease in BMI. CONCLUSIONS: Gastric bypass surgery resulted in the selective reduction of the reward value of a sweet and fat tastant. This application of the progressive ratio task provided an objective and reliable evaluation of taste-driven motivated behavior for food stimuli after obesity surgery. PMID- 22836035 TI - Management practices associated with the bulk tank milk prevalence of Mycoplasma spp. in dairy herds in Northwestern Portugal. AB - The objective of this study was to evaluate the effect of some management practices on the prevalence of Mycoplasma spp. in Northwestern Portuguese dairy farms from bulk tank milk (BTM) samples. Additionally, the within-herd prevalence of Mycoplasma spp. was also determined, but only in BTM positive herds. From May 2007 to November 2008, 492 BTM samples from 164 dairies randomly chosen in a population of 1234 dairy farms were analyzed. Five herds (3.0%) had positive mycoplasmal culture results, from which 4 out of 164 (2.4%) were Mycoplasma bovis, with simultaneous presence of Mycoplasma bovigenitalium or Mycoplasma canadense in two of those samples. In one out of 164 (0.6%) herds Mycoplasma capricolum subsp. capricolum was also found. In BTM positive Mycoplasma spp. herds, the apparent intra-herd prevalence was low and varied between 2.5% and 4.5%. Multiple locus variable-number of tandem-repeat analysis was conducted in order to compare the genetic relationship between the isolates. Mycoplasma spp. was found to be present in cows with subclinical mastitis with or without California Mastitis Test positive results, hence all cows should be tested when the agent is isolated from bulk tank rather than selecting suspected cows. A multivariable logistic regression using the Firth's penalized maximum likelihood estimation was performed showing that increasing number of lactating cows (OR=1.05; P<0.01) was associated with a higher probability of isolating Mycoplasma spp. On the other hand, identifying problem cows was associated with a lower probability (OR=0.06; P<0.05). Particular importance was given to the prevalence of M. bovis, and the results obtained highlight the need to include this agent in mastitis control protocols in national dairies and in sanitary controls of transitioned animals between European countries. PMID- 22836036 TI - Expanded endonasal endoscopic approach for resection of a growth hormone secreting pituitary macroadenoma coexistent with a cavernous carotid artery aneurysm. AB - The co-existence of pituitary adenomas (PA) and carotid artery aneurysms has been described and may be particularly frequent in acromegaly. The co-occurrence of an intracranial aneurysm in the setting of a PA presents significant risk to the patient, particularly when the aneurysm is within or near the operative field. We describe a 48-year-old, right-handed female patient with a large skull base lesion who had a left cavernous carotid artery aneurysm detected on her preoperative imaging studies. This patient was managed using a staged approach. She first underwent endovascular stent-assisted coiling of the aneurysm followed, six months later, by resection of the tumor via an expanded endonasal endoscopic approach. Histopathological analysis revealed a pituitary macroadenoma with neuronal metaplasia. Angiographic embolization followed by an expanded endonasal endoscopic approach is a safe and effective treatment for such lesions. Vascular imaging studies and a low index for suspicion are required for preoperative identification of such complex situations. PMID- 22836037 TI - Radiation-induced meningiomas after high-dose cranial irradiation. AB - Radiation-induced meningiomas (RIM) are known to occur after high and low dose cranial radiation therapy. Currently, RIM are the most common form of radiation induced neoplasm reported. We present the largest series of RIM induced by high dose radiation reported thus far and review the literature. Radiation therapy was most commonly given for childhood malignancy. We compared our group of 26 patients with RIM with previously published reports of RIM, and also with 364 patients with spontaneous meningioma (SM) treated at The Royal Melbourne Hospital between 2007 and 2011 with regard to age, gender, and histopathology. In our group of patients with RIM, the mean age at presentation was 38.5 years, in comparison to 60.1 years for patients with SM. The female-to-male ratio was 1.88:1 in RIM compared to 2.37:1 for SM. Of the RIM, 86.5% were World Health Organization (WHO) grade I and 11.5% were grade II (atypical) meningiomas. There were no anaplastic or malignant RIM. Of the SM, 91.5% were WHO grade I, 7.1% WHO grade II, and 1.4% WHO grade III meningiomas. The characteristics of RIM induced by low dose radiation therapy have been well described. It is timely to consider RIM due to high dose radiation, which is now frequently employed in the management of various childhood and other malignancies. PMID- 22836038 TI - The distribution of genetic diversity of KIR genes in the Chinese Mongolian population. AB - Killer cell immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and as such regulate their response against infection and malignancy. KIR genes are variable in gene content and type, which results in different KIR haplotypes, and can be used to discriminate individuals and populations from different regions or ethnic groups. In the present study, we represent the first report on the KIR gene frequency and content diversities of 14 KIR genes (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and 2 pseudogenes (KIR3DP1 and 2DP1) in the Chinese Mongolian population. The 16 detected KIR genes were all observed. All the individuals were typed positive for the four framework genes KIR3DL3, 3DL2, 2DL4 and the pseudogene KIR3DP1, as well as for the pseudogene KIR2DP1. The observed carrier gene frequencies (OF) of the other KIR genes ranged from 16% at the KIR2DL2 locus to 93% at the KIR3DL1 locus. Over all, 48 different gene profiles were found in the study population and the most commonly observed KIR gene profile with a frequency of 14% consisted of KIR2DL4, 3DL2, 3DL3, 2DP1, 3DP1, 2DL1, 2DL3 and 3DL1 which belongs to the AA genotype. Principal component analysis (PCA) and the dendrogram illustrated the genetic distances between our study population and previously published populations from other ethnic groups or regions. The results of the present study show that the KIR gene family is highly polymorphic and can be a valuable tool for enriching the Chinese ethnical gene information resources, for anthropological studies, as well as for KIR gene related disease research. PMID- 22836039 TI - Immunological effects of transglutaminase-treated gluten in coeliac disease. AB - Coeliac disease pathogenesis is characterized by an immune response triggered, in genetically predisposed subjects, by ingested gluten and its withdrawal from the diet is the only available therapy. However, enzymatic modification of gluten through the insertion of lysine to avoid antigen presentation could represent a new therapeutical approach for patients. Sixty-six duodenal biopsies from 17 coeliac patients were cultured for 48 h with gluten or enzymatically-modified gluten (treated with human recombinant transglutaminase type 2 or bacterial transglutaminase, with or without lysine). Interferongamma, anti endomisium and anti transglutaminase IgA antibodies, lactate dehydrogenase and transglutaminase activity were measured in the culture medium. Transglutaminase type 2 expression was evaluated on biopsies by immunohistochemistry. Gluten and transglutaminase treated gluten increased by 13-15 fold interferon gamma release, as well as antibodies, transglutaminase activity, and the immunohistochemical expression of transglutaminase type 2. Addition of lysine to the enzymatic modification of gluten normalized interferon gamma, antibodies, transglutaminase activity and immunohistochemical expression of transglutaminase type 2. Lactate dehydrogenase did not differ among the studied groups. Enzymatic modification of gluten by transglutaminase plus lysine prevents the immunologic effects on cultured duodenal biopsies from coeliac patients and could be tested as an alternative therapy in coeliac disease. PMID- 22836040 TI - Activating KIR2DS5 receptor is a risk for thyroid cancer. AB - Natural killer (NK) cells are key members of innate immunity against tumor and infection. Killer cell immunoglobulin-like receptor (KIR) genes regulates NK cell function, which varies substantially between individuals in the number and type. Specific KIRs are associated with certain diseases. Herein we investigated if KIR genes are associated with thyroid cancer risk. Eighty-five patients with thyroid cancer were characterized for the presence and absence of 11 variable KIR genes using a gene-specific PCR typing system, and compared with our recently published healthy control data. Overall, a trend toward more activating KIR receptors was observed in thyroid cancer patients compared to the healthy controls. Particularly, the activating KIR2DS5 gene was significantly increased in patients compared to the controls. Additionally, three other genes (3DS1-2DL5-2DS1) that are strongly linked to KIR2DS5 at the telomeric region of the KIR gene complex [called Telomeric 4 (T4) gene cluster] were also more predominant in the thyroid cancer patient group than in healthy controls. A similar trend of having more of the T4 gene cluster was also reported in a previous study with cervical neoplasia. Together, these data suggest that specific activating KIR genes in cancer patients could generate a chronic inflammatory condition resulting in a tumor microenvironment that may favor tumor growth. PMID- 22836041 TI - Single-nucleotide polymorphism in the promoter region of the osteopontin gene at nucleotide -443 as a marker predicting the efficacy of pegylated interferon/ribavirin-therapy in Egyptians patients with chronic hepatitis C. AB - Osteopontin (OPN) is an extracellular matrix glycophosphoprotein produced by several types of cells including the immune system. The present study examined the possibility that single-nucleotide polymorphisms (SNP) in the promoter region of the OPN at nt -443 is a marker predicting the therapeutic efficacy of pegylated interferon (peg-IFN-alpha2b)-ribavirin combination therapy in Egyptian patients with chronic hepatitis C. Blood was collected from 95 patients with chronic hepatitis C who had received peg-IFN-alpha2b-ribavirin combination therapy and 100 age and sex matched controls. SNP in OPN at nucleotide (nt) -443 and its serum protein level were analyzed. Sustained virological response (SVR) was higher in patients with T/T at nt -443 than in those with C/C or C/T. A univariate logistic regression analysis showed that fibrosis grade, serum OPN protein level and T/T homozygotes of SNP at -443 were significant predictors for response. Receiver operating characteristics (ROC) analysis revealed the diagnostic and prognostic efficacy of serum OPN. It can be concluded that SNP in the promoter region of OPN at nt -443 and serum OPN protein level are predictors of response to the efficacy of peg-IFN-alpha2b-ribavirin therapy in Egyptian patients with chronic hepatitis C. PMID- 22836042 TI - KIR2DL2/S2 and HLA-C C1C1 genotype is associated with better response to treatment and prolonged survival of patients with non-small cell lung cancer in a Polish Caucasian population. AB - Non-small cell lung carcinoma (NSCLC) is a multifactorial disease influenced by both environmental and genetic factors. Here, we examined whether the repertoire of genes encoding killer immunoglobulin-like receptors (KIR) and genes for their ligands, C1/C2 and Bw4, may affect a susceptibility to NSCLC and response to treatment. We typed 269 NSCLC patients and 690 healthy control individuals for KIR genes and for their ligands. KIR genes were not associated with NSCLC. C1C2 genotype was less frequent whereas both C1C1 and C2C2 homozygotes were more frequent in patients than in controls (chi(2)=7.73; df=2; p=0.021). Patients positive for KIR2DL2 and KIR2DS2 gene and homozygous for the C1 ligand were 6 times more likely to respond to treatment than those with other genotypes (p=0.034). In accordance with this, patients with the KIR2DL2+/KIR2DS2+, C1C1 genotype survived longer than others (p=0.0094). Median survival was 23months for KIR2DL2/2DS2/C1C1-positive patients, but only 10 months for those with other genotypes. PMID- 22836043 TI - Killer cell immunoglobulin-like receptor (KIR) genes in 4 distinct populations and 51 families in mainland China. AB - In this study, we investigated the killer cell immunoglobulin-like receptor (KIR) genes and HLA-C1/C2 dimorphism in 819 healthy, unrelated individuals composed of two southern Chinese Han populations (Hunan Han and Guangdong Han) and two northern Chinese populations (Inner Mongolia Han and Inner Mongolia Mongol), using polymerase chain reaction-sequence-specific priming (PCR-SSP) method. Fifty one Chinese families were used to determine KIR haplotypic configuration. Our data showed that KIR2DL4, KIR3DL2, KIR3DL3, and KIR3DP1 genes were present in all of the 819 individuals. However, KIR2DL4 and KIR3DP1 genes were not detected in two members of a northern Chinese family. None of the KIR genes showed significant difference between the four populations. Thirty-five different KIR gene profiles were identified, one of which has not been previously reported in the Allele Frequencies KIR database. Eleven distinct KIR haplotypic configurations were determined through family analysis. Individuals with KIR2DLl and KIR2DL3 genes but lacking KIR2DSl and KIR2DS2 genes, coupled with HLA-C1 (Asn(80)) homozygosity, predominated in each population. At least one known inhibitory KIR-HLA pair was detected in each individual. The findings shown here are valuable for future studies of the potential role of KIR genes as well as KIR HLA interaction in disease susceptibility in related ethnic groups. PMID- 22836044 TI - Association between polymorphisms in FOXP3 and EBI3 genes and the risk for development of allergic rhinitis in Chinese subjects. AB - OBJECTIVE: To investigate whether polymorphisms in forkhead box protein 3 (FOXP3) and EBV-induced gene 3 (EBI3) genes are associated with allergic rhinitis (AR) in Chinese patients. METHODS: A population-based case-control association study design was used to assess the risk of AR conferred by single nucleotide polymorphisms (SNPs) in FOXP3 and EBI3 gene regions. DNA was extracted from 378 patients with AR and 330 healthy controls and analyzed for selected and tagged SNPs. Overall, 9 SNPs were selected and genotyped. RESULTS: In the single-locus analyses of AR risk, the allele frequencies of rs428253 in EBI3 gene were significantly different between the AR patients and control subjects (P=1.00E 04); even after 10,000 permutations (P<0.05). Logistic regression analyses, adjusted for age and gender, further showed a significant association between EBI3 rs428253 and protective effects against AR (P=0.015, OR=0.624 for CG/CC). The diplotype rs3761548-rs4824747 in FOXP3 gene with "AG" was associated with risk of AR (P=0.031, OR=1.755). CONCLUSIONS: The findings of this study support the potential role of regulatory T cells and genetic variations in the regions around FOXP3 and EBI3 genes in modifying the risk for AR development in Chinese patients. PMID- 22836045 TI - Bullae secondary to prolonged cupping. PMID- 22836046 TI - Meta-analysis: amantadine may lower the efficacy of pegylated interferon plus ribavirin in treatment-naive hepatitis C genotype 1 patients. AB - OBJECTIVE: The current standard therapy for hepatitis C virus genotype 1 (HCV-1) infection is still suboptimal. Whether adding amantadine (AMA) to pegylated interferon (PEG-IFN) plus ribavirin (RBV) improves the virological response in treatment-naive HCV-1 patients remains unclear. METHODS: Searches of the electronic databases including Embase, Medline, Cochrane Controlled Trials Register, and PubMed (updated to September 2011) and manual searches of the bibliographies were carried out. A meta-analysis of randomized clinical trials (RCT) comparing triple therapy (PEG-IFN+RBV+AMA) and double therapy (PEG-IFN+RBV) was performed. RESULTS: Five RCTs including 1425 patients were assessed. The meta analysis based on the intention-to-treat analysis indicated that the sustained virological response (SVR) rate was significantly lower in the triple therapy group than in the double therapy group (44.2% vs. 49.2%, risk ratio (RR) 0.90, 95% confidence interval (CI) 0.80-1.00, p=0.05). The frequency of discontinuing therapy because of adverse events was similar in the two groups (RR 1.26, 95% CI 0.90-1.78, p=0.18). The sensitivity analysis including the four studies involving Caucasian populations revealed significantly lower SVR rates in the triple therapy group. The other sensitivity analyses also showed similar trends, but did not reach statistical significance. CONCLUSIONS: This meta-analysis suggests no beneficial effect of adding AMA to PEG-IFN+RBV in treatment-naive HCV-1 patients and even a trend towards a lower virological response rate in the triple therapy group. This study shows that the administration of AMA should be avoided in the management of treatment-naive HCV-1 patients. PMID- 22836047 TI - A prospective study of the utility of magnetic resonance imaging in determining candidacy for partial breast irradiation. AB - PURPOSE: Retrospective data have demonstrated that breast magnetic resonance imaging (MRI) may change a patient's eligibility for partial breast irradiation (PBI) by identifying multicentric, multifocal, or contralateral disease. The objective of the current study was to prospectively determine the frequency with which MRI identifies occult disease and to establish clinical factors associated with a higher likelihood of MRI prompting changes in PBI eligibility. METHODS AND MATERIALS: At The University of Chicago, women with breast cancer uniformly undergo MRI in addition to mammography and ultrasonography. From June 2009 through May 2011, all patients were screened prospectively in a multidisciplinary conference for PBI eligibility based on standard imaging, and the impact of MRI on PBI eligibility according to National Surgical Adjuvant Breast and Bowel Project protocol B-39/Radiation Therapy Oncology Group protocol 0413 entry criteria was recorded. Univariable analysis was performed using clinical characteristics in both the prospective cohort and in a separate cohort of retrospectively identified patients. Pooled analysis was used to derive a scoring index predictive of the risk that MRI would identify additional disease. RESULTS: A total of 521 patients were screened for PBI eligibility, and 124 (23.8%) patients were deemed eligible for PBI based on standard imaging. MRI findings changed PBI eligibility in 12.9% of patients. In the pooled univariable analysis, tumor size >= 2 cm on mammography or ultrasonography (P=.02), age <50 years (P=.01), invasive lobular histology (P=.01), and HER-2/neu amplification (P=.01) were associated with a higher likelihood of MRI changing PBI eligibility. A predictive score was generated by summing the number of significant risk factors. Patients with a score of 0, 1, 2, and 3 had changes to eligibility based on MRI findings in 2.8%, 13.2%, 38.1%, and 100%, respectively (P<.0001). CONCLUSIONS: MRI identified additional disease in a significant number of patients eligible for PBI, based on standard imaging. Clinical characteristics may be useful in directing implementation of MRI in the staging of PBI candidates. PMID- 22836048 TI - Poor baseline pulmonary function may not increase the risk of radiation-induced lung toxicity. AB - PURPOSE: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). METHODS AND MATERIALS: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade >=2 radiation pneumonitis and fibrosis. RESULTS: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). CONCLUSIONS: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability. PMID- 22836049 TI - Rhabdomyosarcoma arising in a previously irradiated field: an analysis of 43 patients. AB - Patients with soft tissue sarcomas that arise from previously irradiated fields have traditionally been reported to have a poor prognosis. In this report, we examined the characteristics and outcomes of patients who developed a rhabdomyosarcoma in a previously irradiated field (RMS-RIF); we hypothesize that these patients should have a better outcome compared to other postradiation soft tissue sarcomas as these tumors are chemosensitive and radiosensitive. A PubMed search of the literature from 1961-2010 yielded 33 studies with data for patients with RMS-RIF. The study included 43 patients with a median age of 6.5 years at the time of radiation therapy (RT) for the initial tumor. The median RT dose was 48 Gy. The median latency period, the time from RT to development of RMS-RIF, was 8 years. The 3-year overall survival for RMS-RIF was 42%. The 3-year overall survival was 66% for patients receiving chemotherapy and local treatment (surgery and/or RT) compared to 29% for those who had systemic treatment only or local treatment only (P=.049). Other factors associated with increased 3-year overall survival included retinoblastoma initial diagnosis (P<.001), age <= 18 years at diagnosis of RMS-RIF (P=.003), favorable site (P=.008), and stage 1 disease (P=.002). Age at time of RMS-RIF, retinoblastoma initial tumor, favorable site, stage 1 disease, and use of both systemic and local treatment were found to be favorable prognostic factors for 3-year overall survival. PMID- 22836050 TI - Pathophysiology and natural history of anorectal sequelae following radiation therapy for carcinoma of the prostate. AB - PURPOSE: To characterize the prevalence, pathophysiology, and natural history of chronic radiation proctitis 5 years following radiation therapy (RT) for localized carcinoma of the prostate. METHODS AND MATERIALS: Studies were performed in 34 patients (median age 68 years; range 54-79) previously randomly assigned to either 64 Gy in 32 fractions over 6.4 weeks or 55 Gy in 20 fractions over 4 weeks RT schedule using 2- and later 3-dimensional treatment technique for localized prostate carcinoma. Each patient underwent evaluations of (1) gastrointestinal (GI) symptoms (Modified Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales including effect on activities of daily living [ADLs]); (2) anorectal motor and sensory function (manometry and graded balloon distension); and (3) anal sphincteric morphology (endoanal ultrasound) before RT, at 1 month, and annually for 5 years after its completion. RESULTS: Total GI symptom scores increased after RT and remained above baseline levels at 5 years and were associated with reductions in (1) basal anal pressures, (2) responses to squeeze and increased intra-abdominal pressure, (3) rectal compliance and (4) rectal volumes of sensory perception. Anal sphincter morphology was unchanged. At 5 years, 44% and 21% of patients reported urgency of defecation and rectal bleeding, respectively, and 48% impairment of ADLs. GI symptom scores and parameters of anorectal function and anal sphincter morphology did not differ between the 2 RT schedules or treatment techniques. CONCLUSIONS: Five years after RT for prostate carcinoma, anorectal symptoms continue to have a significant impact on ADLs of almost 50% of patients. These symptoms are associated with anorectal dysfunction independent of the RT schedules or treatment techniques reported here. PMID- 22836051 TI - Higher levels of c-Met expression and phosphorylation identify cell lines with increased sensitivity to AMG-458, a novel selective c-Met inhibitor with radiosensitizing effects. AB - PURPOSE: c-Met is overexpressed in some non-small cell lung cancer (NSCLC) cell lines and tissues. Cell lines with higher levels of c-Met expression and phosphorylation depend on this receptor for survival. We studied the effects of AMG-458 on 2 NSCLC cell lines. METHODS AND MATERIALS: 3-(4,5-Dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays assessed the sensitivities of the cells to AMG-458. Clonogenic survival assays illustrated the radiosensitizing effects of AMG-458. Western blot for cleaved caspase 3 measured apoptosis. Immunoblotting for c-Met, phospho-Met (p-Met), Akt/p-Akt, and Erk/p-Erk was performed to observe downstream signaling. RESULTS: AMG-458 enhanced radiosensitivity in H441 but not in A549. H441 showed constitutive phosphorylation of c-Met. A549 expressed low levels of c-Met, which were phosphorylated only in the presence of exogenous hepatocyte growth factor. The combination of radiation therapy and AMG-458 treatment was found to synergistically increase apoptosis in the H441 cell line but not in A549. Radiation therapy, AMG-458, and combination treatment were found to reduce p-Akt and p-Erk levels in H441 but not in A549. H441 became less sensitive to AMG-458 after small interfering RNA knockdown of c-Met; there was no change in A549. After overexpression of c-Met, A549 became more sensitive, while H441 became less sensitive to AMG-458. CONCLUSIONS: AMG-458 was more effective in cells that expressed higher levels of c-Met/p-Met, suggesting that higher levels of c-Met and p-Met in NSCLC tissue may classify a subset of tumors that are more sensitive to molecular therapies against this receptor. PMID- 22836052 TI - Is androgen deprivation therapy necessary in all intermediate-risk prostate cancer patients treated in the dose escalation era? AB - PURPOSE: The benefit of adding androgen deprivation therapy (ADT) to dose escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). METHODS: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and <=6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. RESULTS: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, <=T2b or GS 3+4, <=T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). CONCLUSIONS: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low risk disease. In patients with GS 4+3 or T2c disease, the addition of ADT to dose escalated RT did improve FFF. PMID- 22836053 TI - DNA double-strand break analysis by gamma-H2AX foci: a useful method for determining the overreactors to radiation-induced acute reactions among head-and neck cancer patients. AB - PURPOSE: Interindividual variability in normal tissue toxicity during radiation therapy is a limiting factor for successful treatment. Predicting the risk of developing acute reactions before initiation of radiation therapy may have the benefit of opting for altered radiation therapy regimens to achieve minimal adverse effects with improved tumor cure. METHODS AND MATERIALS: DNA double strand break (DSB) induction and its repair kinetics in lymphocytes of head-and neck cancer patients undergoing chemoradiation therapy was analyzed by counting gamma-H2AX foci, neutral comet assay, and a modified version of neutral filter elution assay. Acute normal tissue reactions were assessed by Radiation Therapy Oncology Group criteria. RESULTS: The correlation between residual DSBs and the severity of acute reactions demonstrated that residual gamma-H2AX foci in head and-neck cancer patients increased with the severity of oral mucositis and skin reaction. CONCLUSIONS: Our results suggest that gamma-H2AX analysis may have predictive implications for identifying the overreactors to mucositis and skin reactions among head-and-neck cancer patients prior to initiation of radiation therapy. PMID- 22836054 TI - Scrotal irradiation in primary testicular lymphoma: review of the literature and in silico planning comparative study. AB - We examined adjuvant irradiation of the scrotum in primary testicular lymphoma (PTL) by means of a literature review in MEDLINE, a telephone survey among Dutch institutes, and an in silico planning comparative study on scrotal irradiation in PTL. We did not find any uniform adjuvant irradiation technique assuring a safe planning target volume (PTV) coverage in published reports, and the definition of the clinical target volume is unclear. Histopathologic studies of PTL show a high invasion rate of the tunica albuginea, the epididymis, and the spermatic cord. In retrospective studies, a prescribed dose of at least 30 Gy involving the scrotum is associated with best survival. The majority of Dutch institutes irradiate the whole scrotum without using a planning computed tomography scan, with a single electron beam and a total dose of 30 Gy. The in silico planning comparative study showed that all evaluated approaches met a D(95%) scrotal dose of at least 85% of the prescription dose, without exceeding the dose limits of critical organs. Photon irradiation with 2 oblique beams using wedges resulted in the best PTV coverage, with a mean value of 95% of the prescribed dose, with lowest maximum dose. Adjuvant photon or electron irradiation of the whole scrotum including the contralateral testicle with a minimum dose of 30 Gy is recommended in PTL. Computed tomography-based radiation therapy treatment planning with proper patient positioning and position verification guarantees optimal dose coverage. PMID- 22836055 TI - Association of clinical response and long-term outcome among patients with biopsied orbital pseudotumor receiving modern radiation therapy. AB - PURPOSE: To retrospectively evaluate institutional outcomes for patients treated with modern radiation therapy (RT) for biopsied orbital pseudotumor (OP). METHODS AND MATERIALS: Twenty patients (26 affected orbits) with OP were treated with RT between January 2002 and December 2011. All patients underwent biopsy with histopathologic exclusion of other disease processes. Sixteen patients (80%) were treated with intensity modulated RT, 3 (15%) with opposed lateral beams, and 1 (5%) with electrons. Median RT dose was 27 Gy (range 25.2-30.6 Gy). Response to RT was evaluated at 4 months post-RT. Partial response (PR) was defined as improvement in orbital symptoms without an increase in steroid dose. Complete response (CR) 1 and CR 2 were defined as complete resolution of orbital symptoms with reduction in steroid dose (CR 1) or complete tapering of steroids (CR 2). The median follow-up period was 18.6 months (range 4-81.6 months). RESULTS: Seventeen patients (85%) demonstrated response to RT, with 7 (35%), 1 (5%), and 9 (45%) achieving a PR, CR 1, and CR 2, respectively. Of the 17 patients who had >= PR at 4 months post-RT, 6 (35%) experienced recurrence of symptoms. Age (>46 years vs <= 46 years, P=.04) and clinical response to RT (CR 2 vs CR 1/PR, P=.05) were significantly associated with pseudotumor recurrence. Long-term complications were seen in 7 patients (35%), including 4 with cataract formation, 1 with chronic dry eye, 1 with enophthalmos, and 1 with keratopathy. CONCLUSIONS: RT is an effective treatment for improving symptoms and tapering steroids in patients with a biopsy supported diagnosis of OP. Older age and complete response to RT were associated with a significantly reduced probability of symptom recurrence. The observed late complications may be related to RT, chronic use of steroids/immunosuppressants, medical comorbidities, or combination of factors. PMID- 22836056 TI - Parotid gland sparing with helical tomotherapy in head-and-neck cancer. AB - PURPOSE: This study evaluated the ability of helical tomotherapy to spare the function of the parotid glands in patients with head-and-neck cancer by analyzing dose-volume histograms, salivary gland scintigraphy, and quality of life assessment. METHODS AND MATERIALS: Data from 76 consecutive patients treated with helical tomotherapy (Hi-Art Tomotherapy) at the University Hospital Brussel were analyzed. During planning, priority was given to planning target volume (PTV) coverage: >= 95% of the dose must be delivered to >= 95% of the PTV. Elective nodal regions received 54 Gy (1.8 Gy/fraction). A dose of 70.5 Gy (2.35 Gy/fraction) was prescribed to the primary tumor and pathologic lymph nodes (simultaneous integrated boost scheme). Objective scoring of salivary excretion was performed by salivary gland scintigraphy. Subjective scoring of salivary gland function was evaluated by the European Organization for Research and Treatment of Cancer quality of life questionnaires Quality of Life Questionnaire C30 (QLQ-C30) and Quality of Life Questionnaire-Head and Neck 35 (H&N35). RESULTS: Analysis of dose-volume histograms (DVHs) showed excellent coverage of the PTV. The volume of PTV receiving 95% of the prescribed dose (V95%) was 99.4 (range, 96.3-99.9). DVH analysis of parotid gland showed a median value of the mean parotid dose of 32.1 Gy (range, 17.5-70.3 Gy). The median parotid volume receiving a dose <26 Gy was 51.2%. Quality of life evaluation demonstrated an initial deterioration of almost all scales and items in QLQ-C30 and QLQ-H&N35. Most items improved in time, and some reached baseline values 18 months after treatment. CONCLUSION: DVH analysis, scintigraphic evaluation of parotid function, and quality of life assessment of our patient group showed that helical tomotherapy makes it possible to preserve parotid gland function without compromising disease control. We recommend mean parotid doses of <34 Gy and doses <26 Gy to a maximum 47% of the parotid volume as planning goals. Intensity modulated radiotherapy should be considered as standard treatment in patients with head-and-neck cancer. PMID- 22836057 TI - Randomized, multicenter trial on the effect of radiation therapy on plantar fasciitis (painful heel spur) comparing a standard dose with a very low dose: mature results after 12 months' follow-up. AB - PURPOSE: To conduct a randomized trial of radiation therapy for painful heel spur, comparing a standard dose with a very low dose. METHODS AND MATERIALS: Sixty-six patients were randomized to receive radiation therapy either with a total dose of 6.0 Gy applied in 6 fractions of 1.0 Gy twice weekly (standard dose) or with a total dose of 0.6 Gy applied in 6 fractions of 0.1 Gy twice weekly (low dose). In all patients lateral opposing 4- to 6-MV photon beams were used. The results were measured using a visual analogue scale, the Calcaneodynia score, and the SF12 health survey. The fundamental phase of the study ended after 3 months, and the follow-up was continued up to 1 year. Patients with insufficient pain relief after 3 months were offered reirradiation with the standard dosage at any time afterward. RESULTS: Of 66 patients, 4 were excluded because of withdrawal of consent or screening failures. After 3 months the results in the standard arm were highly significantly superior compared with those in the low-dose arm (visual analogue scale, P=.001; Calcaneodynia score, P=.027; SF12, P=.045). The accrual of patients was stopped at this point. Further evaluation after 12 months' follow-up showed the following results: (1) highly significant fewer patients were reirradiated in the standard arm compared with the low-dose arm (P<.001); (2) the results of patients in the low-dose arm who were reirradiated were identical to those in the standard arm not reirradiated (reirradiation as a salvage therapy if the lower dose was ineffective); (3) patients experiencing a favorable result after 3 months showed this even after 12 months, and some results even improved further between 3 and 12 months. CONCLUSIONS: This study confirms the superior analgesic effect of radiation therapy with 6-Gy doses on painful heel spur even for a longer time period of at least 1 year. PMID- 22836058 TI - The significance of tumoral ERCC1 status in patients with locally advanced cervical cancer treated with chemoradiation therapy: a multicenter clinicopathologic analysis. AB - PURPOSE: ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters. METHODS AND MATERIALS: A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years. RESULTS: The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067). CONCLUSIONS: In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on multivariate analysis. PMID- 22836059 TI - Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. AB - PURPOSE: To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). METHODS AND MATERIALS: Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. RESULTS: During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. CONCLUSION: Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies. PMID- 22836060 TI - Distance-to-agreement investigation of Tomotherapy's bony anatomy-based autoregistration and planning target volume contour-based optimization. AB - PURPOSE: To compare Tomotherapy's megavoltage computed tomography bony anatomy autoregistration with the best achievable registration, assuming no deformation and perfect knowledge of planning target volume (PTV) location. METHODS AND MATERIALS: Distance-to-agreement (DTA) of the PTV was determined by applying a rigid-body shift to the PTV region of interest of the prostate from its reference position, assuming no deformations. Planning target volume region of interest of the prostate was extracted from the patient archives. The reference position was set by the 6 degrees of freedom (dof)-x, y, z, roll, pitch, and yaw-optimization results from the previous study at this institution. The DTA and the compensating parameters were calculated by the shift of the PTV from the reference 6-dof to the 4-dof-x, y, z, and roll-optimization. In this study, the effectiveness of Tomotherapy's 4-dof bony anatomy-based autoregistration was compared with the idealized 4-dof PTV contour-based optimization. RESULTS: The maximum DTA (maxDTA) of the bony anatomy-based autoregistration was 3.2 +/- 1.9 mm, with the maximum value of 8.0 mm. The maxDTA of the contour-based optimization was 1.8 +/- 1.3 mm, with the maximum value of 5.7 mm. Comparison of Pearson correlation of the compensating parameters between the 2 4-dof optimization algorithms shows that there is a small but statistically significant correlation in y and z (0.236 and 0.300, respectively), whereas there is very weak correlation in x and roll (0.062 and 0.025, respectively). CONCLUSIONS: We find that there is an average improvement of approximately 1 mm in terms of maxDTA on the PTV going from 4-dof bony anatomy-based autoregistration to the 4-dof contour-based optimization. Pearson correlation analysis of the 2 4-dof optimizations suggests that uncertainties due to deformation and inadequate resolution account for much of the compensating parameters, but pitch variation also makes a statistically significant contribution. PMID- 22836061 TI - Serum amyloid a as a predictive marker for radiation pneumonitis in lung cancer patients. AB - PURPOSE: To investigate serum markers associated with radiation pneumonitis (RP) grade >=3 in patients with lung cancer who were treated with radiation therapy. METHODS AND MATERIALS: Pretreatment serum samples from patients with stage Ib-IV lung cancer who developed RP within 1 year after radiation therapy were analyzed to identify a proteome marker able to stratify patients prone to develop severe RP by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Dosimetric parameters and 3 biological factors were compared. RESULTS: Serum samples from 16 patients (28%) with severe RP (grade 3 4) and 42 patients (72%) with no or mild RP (grade 0-2) were collected for analysis. All patients received a median of 54 Gy (range, 42-70 Gy) of three dimensional conformal radiation therapy with a mean lung dose (MLD) of 1502 cGy (range, 700-2794 cGy). An m/z peak of 11,480 Da was identified by SELDI-TOF-MS, and serum amyloid A (SAA) was the primary splitter serum marker. The receiver operating characteristic area under the curve of SAA (0.94; 95% confidence interval [CI], 0.87-1.00) was higher than those of C-reactive protein (0.83; 95% CI, 0.72-0.94), interleukin-6 (0.79; 95% CI, 0.65-0.94), and MLD (0.57; 95% CI, 0.37-0.77). The best sensitivity and specificity of combined SAA and MLD for predicting RP were 88.9% and 96.0%, respectively. CONCLUSIONS: Baseline SAA could be used as an auxiliary marker for predicting severe RP. Extreme care should be taken to limit the lung irradiation dose in patients with high SAA. PMID- 22836062 TI - Expression of hPNAS-4 radiosensitizes Lewis lung cancer. AB - PURPOSE: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. METHODS AND MATERIALS: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. RESULTS: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). CONCLUSIONS: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer. PMID- 22836063 TI - Radiation-free weekend rescued! Continuous accelerated irradiation of 7-days per week is equal to accelerated fractionation with concomitant boost of 7 fractions in 5-days per week: report on phase 3 clinical trial in head-and-neck cancer patients. AB - PURPOSE: To report long-term results of randomized trial comparing 2 accelerated fractionations of definitive radiation therapy assessing the need to irradiate during weekend in patients with head and neck squamous cell carcinoma. METHODS AND MATERIALS: A total of 345 patients with SCC of the oral cavity, larynx, and oro- or hypo-pharynx, stage T2-4N0-1M0, were randomized to receive continuous accelerated irradiation (CAIR: once per day, 7 days per week) or concomitant accelerated boost (CB: once per day, 3 days per week, and twice per day, 2 days per week). Total dose ranged from 66.6-72 Gy, dose per fraction was 1.8 Gy, number of fractions ranged from 37-40 fractions, and overall treatment time ranged from 37-40 days. RESULTS: No differences for all trial end-points were noted. At 5 and 10 years, the actuarial rates of local-regional control were 63% and 60% for CAIR vs 65% and 60% for CB, and the corresponding overall survival were 40% and 25% vs 44% and 25%, respectively. Confluent mucositis was the main acute toxicity, with an incidence of 89% in CAIR and 86% in CB patients. The 5 year rate of grade 3-4 late radiation morbidity was 6% for both regimens. CONCLUSIONS: Results of this trial indicate that the effects of accelerated fractionation can be achieve by delivering twice-per-day irradiation on weekday(s). This trial has also confirmed that an accelerated, 6-weeks schedule is a reasonable option for patients with intermediate-stage head-and-neck squamous cell carcinoma because of the associated high cure rate and minimal severe late toxicity. PMID- 22836064 TI - From the editor: what are the important questions for clinical trials? PMID- 22836065 TI - Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists' Collaboration meta-analysis for low-density lipoprotein lowering. AB - Researchers from the Cholesterol Treatment Trialists' (CTT) Collaboration have argued for maximal lowering of low-density lipoprotein cholesterol (LDL-C) by the use of pharmacologic agents, with the strongest evidence coming from the five comparison statin studies in their second meta-analysis. The CTT meta-analysis has many strengths but also a number of limitations, which have not been discussed and which, given the clinical implications, require consideration. Among these are: (1) the impact and validity of including revascularizations within a composite primary end point; (2) the inclusion of the A-Z study, whose design does not allow for valid comparisons of two statin regimens; (3) the fact that baseline LDL-C levels in the comparison studies were not low enough to test whether statin therapy reduces risk significantly in groups with an initial low LDL-C; and, most important, (4) authors of the five studies compared doses at the extremes of statin regimens. However, the clinical choice is not between the lowest and the greatest dose of a statin statin regimens, for example, between 10 and 80 mg atorvastatin, but, more realistically, between intermediate and high dose, that is, between 40 and 80 mg atorvastatin. On the basis of the CTT meta analysis, we calculate that any potential gain from increasing the dose from 40 to 80 mg atorvastatin would be very small, at best a further 2% further reduction in clinical events. The increase in dose, unfortunately, would likely be associated with increased side effects and decreased compliance. Accordingly, whether net benefit would be demonstrable cannot be assumed. It follows that definitive evidence supporting maximal lowering of LDL-C or maximal dose of statins is still lacking and guidelines, if they are to be evidence-based, should acknowledge this uncertainty. PMID- 22836066 TI - Statin treatment in patients with elevated liver enzymes: pitch to proceed. PMID- 22836067 TI - Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake: still problematic after the primary publication. PMID- 22836068 TI - Initial combination therapy with metformin plus colesevelam improves lipoprotein particles in patients with early type 2 diabetes mellitus. AB - BACKGROUND: The bile acid sequestrant colesevelam has been shown to significantly reduce low-density lipoprotein particle concentration (LDL-P) in adults with primary hyperlipidemia or type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess the effect of initial combination therapy with metformin plus colesevelam on lipoprotein particles in patients with T2DM (secondary efficacy variables). METHODS: This 16-week, randomized, double-blind, placebo-controlled study enrolled drug-naive adults with T2DM, glycated hemoglobin 6.5%-10.0%, low-density lipoprotein cholesterol (LDL-C) >=100 mg/dL, and triglycerides <500 mg/dL. Patients were randomized 1:1 to either open-label metformin (titrated to 1700 mg/day) plus double-blind colesevelam 3.75 g/day or open-label metformin plus double-blind placebo. RESULTS: In total, 286 patients were randomized (metformin plus colesevelam [n = 145]; metformin plus placebo [n = 141]). Compared with metformin plus placebo, the combination of metformin plus colesevelam significantly reduced LDL-C (mean treatment difference: -16.3%), total cholesterol (-6.1%), non-high-density lipoprotein cholesterol (-8.3%), and apolipoprotein (apo) B (-8.0%) and significantly increased triglycerides (median treatment difference: 18.6%) and apoA-I (mean treatment difference: 4.4%; all P < .001). Metformin plus colesevelam significantly reduced total LDL-P (mean treatment difference: absolute change -186 nmol/L [percent change -11.7%]; both P < .0001), largely attributable to a reduction in small LDL-P, and increased total very-low-density lipoprotein particle concentration (mean treatment difference: absolute change 6 nmol/L; P = .03 [percent change 8.3%; P = .06]) and total high density lipoprotein particle concentration (1.0 MUmol/L; P = .03 [4.5%; P = .01]) versus metformin plus placebo. CONCLUSION: Initial combination therapy with metformin plus colesevelam improved the atherogenic lipoprotein profile of patients with early T2DM by significantly reducing LDL-P. ClinicalTrials.gov identifier: NCT00570739. PMID- 22836069 TI - Prevalence of lipid abnormalities in the United States: the National Health and Nutrition Examination Survey 2003-2006. AB - BACKGROUND: The association between increased low-density lipoprotein cholesterol (LDL-C) and increased risk for cardiovascular events is well established, with treatment focusing on LDL-C lowering. Other lipid abnormalities are also associated with increased cardiovascular risk (eg, low high-density lipoprotein cholesterol [HDL-C], high triglycerides [TG], and high non-HDL-C). Despite national lipid guidelines, the prevalence of these abnormal lipid parameters alone or in combination (mixed dyslipidemia) is not well recognized. OBJECTIVE: We assessed the prevalence of high LDL-C, low HDL-C, high TG, high non-HDL-C, and mixed dyslipidemia by using National Health and Nutrition Examination Survey (NHANES) data to estimate the proportions of U.S. adults not at guideline recommended lipid goals. METHODS: NHANES 2003-2006 fasting blood serum data were used to categorize adults aged >=20 years by LDL-C (risk stratum-specific), HDL-C (men, <40 mg/dL; women, <50 mg/dL), non-HDL-C (in subjects with TG >=200 mg/dL), and TG (>=150 mg/dL) target levels with use of the NCEP ATP III definitions based on coronary heart disease (CHD) risk. RESULTS: An estimated 53% (105.3M) of U.S. adults have lipid abnormalities: 27% (53.5M) have high LDL-C, 23% (46.4M) have low HDL-C, and 30% (58.9M) have high TG. Among patients with serum TG levels >=200 mg/dL, approximately 13% (25.7M) of adults have non-HDL-C levels >=130 mg/dL. Also, 21% (42.0M) of U.S. adults have mixed dyslipidemia (high LDL-C with either low HDL-C and/or high TG), with nearly 6% (11.6M) having all three lipid abnormalities. For LDL-C, an estimated 23M adults with CHD or a CHD risk equivalent and 17M with >=2 risk factors but a Framingham risk <=20% are not at goals of <100 and <130 mg/dL, respectively. CONCLUSION: Prevalence of dyslipidemia in the United States continues to be high, with the majority of U.S. adults now affected by some form of lipid abnormality. Efforts to promote screening, risk stratification, and initiating appropriate treatment should be intensified. PMID- 22836070 TI - Apheresis in homozygous familial hypercholesterolemia: the results of a follow-up of all Norwegian patients with homozygous familial hypercholesterolemia. AB - BACKGROUND: Homozygous familial hypercholesterolemia (HoFH), which affects 1 in a million individuals, leads to extremely elevated levels of cholesterol and early onset cardiovascular disease. OBJECTIVE: The aim of this study was to assess all 7 HoFH patients treated with low-density lipoprotein (LDL) apheresis in Norway with respect to quality of life, clinical and laboratory assessments, and cardiovascular status. METHODS: Apheresis treatment and assessment of cardiovascular status was performed at local hospitals but coordinated by the Lipid Clinic that has followed all patients since diagnosis. Quality of life was evaluated by a validated questionnaire. RESULTS: Results are shown as median (min max). LDL cholesterol at diagnosis (untreated) was 704 (592-1268) mg/dL (18.2 [15.3-32.8] mmol/L). Medication was initiated at age 9 (2-35) years, and apheresis treatment at age 10 (6-44) years. Regular once-weekly apheresis combined with the maximum-tolerable doses of a statin and ezetimibe reduced LDL cholesterol to 197 (170-282) mg/dL (5.1 [4.5-7.3] mmol/L) pre-apheresis and 85 (50-108) mg/dL (2.2 [1.3-2.8] mmol/L) post-apheresis. Calculated interval mean LDL cholesterol was 162 (135-220) mg/dL (4.2 [3.5-5.7] mmol/L). Duration of apheresis treatment was 11 (1-24) years. Cardiovascular manifestations progressed in most patients despite the apheresis treatment. The subjects' quality of life was comparable with that of a healthy population, with the exception of two patients, who were significantly affected by coronary disease. CONCLUSIONS: Well tolerated, once-weekly LDL apheresis achieves lower interval mean LDL cholesterol levels between apheresis treatments than previously reported for apheresis every second week. However, progressions of cardiovascular manifestations still occurred, which highlights the importance of earlier and even more aggressive treatment and follow-up in HoFH. PMID- 22836071 TI - Evaluation of short-term safety and efficacy of HMG-CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). AB - BACKGROUND: We evaluated the safety and efficacy of the 3-hydroxyl-3 methylglutaryl coenzyme A reductase inhibitors atorvastatin and pitavastatin in patients with mild-to-moderate increased levels of hepatic enzymes. METHODS AND RESULTS: In this 12-week, prospective, randomized, open-label, active drug controlled, and dose-titration study, 189 subjects with elevated low-density lipoprotein cholesterol (>=3.36 mmol/L) and alanine transaminase (ALT; *1.25>= and <=*2.5 ULN; 50-100 IU/L) concentrations, but nonalcoholic and serologically negative for viral hepatitis markers at screening, were randomized to 12 weeks of treatment with pitavastatin 2-4 mg/day (PITA, n = 97) or atorvastatin 10-20 mg/day (ATOR, n = 92). Pitavastatin and atorvastatin equally reduced low-density lipoprotein cholesterol concentrations (-34.6 +/- 16.0% and -38.1 +/- 16.2%, respectively, P < .0001 each by analysis of variance). Seven (n = 4 PITA, n = 3 ATOR) and 10 (n = 5 PITA, n = 5 ATOR) patients experienced episodes of ALT >100 IU/L at weeks 4 and 12, respectively, with one patient in each group excluded because of severe ALT elevation >3* ULN (>120 IU/L) at week 4. The 135 patients with persistently increased ALT concentrations at screening and randomization showed significant reductions in ALT after 12 weeks of treatment with PITA (n = 68, -8.4%) or ATOR (n = 67, -8.9%; P < .05, analysis of variance). Serial nonenhanced computed tomography in 38 subjects (n = 18 PITA, n = 20 ATOR) showed that both statins reduced the severity of hepatic steatosis, especially in subjects with clear hepatic steatosis at baseline (n = 9 PITA, n = 10 ATOR). Statin treatment of another 38 subjects with spontaneous normalization of ALT at randomization had little effect on ALT levels but did not induce severe ALT elevation (>100 IU/L). CONCLUSIONS: Conventional doses of pitavastatin and atorvastatin effectively and safely reduce elevated hepatic enzyme concentrations. PMID- 22836072 TI - A meta-analysis of randomized controlled trials that compare the lipid effects of beef versus poultry and/or fish consumption. AB - BACKGROUND: Limited consumption of red meat, including beef, is one of many often suggested strategies to reduce the risk of coronary heart disease (CHD). However, the role that beef consumption specifically plays in promoting adverse changes in the cardiovascular risk factor profile is unclear. OBJECTIVE: A meta-analysis of randomized, controlled, clinical trials (RCTs) was conducted to evaluate the effects of beef, independent of other red and processed meats, compared with poultry and/or fish consumption, on lipoprotein lipids. METHODS: RCTs published from 1950 to 2010 were considered for inclusion. Studies were included if they reported fasting lipoprotein lipid changes after beef and poultry/fish consumption by subjects free of chronic disease. A total of 124 RCTs were identified, and 8 studies involving 406 subjects met the prespecified entry criteria and were included in the analysis. RESULTS: Relative to the baseline diet, mean +/- standard error changes (in mg/dL) after beef versus poultry/fish consumption, respectively, were -8.1 +/- 2.8 vs. -6.2 +/- 3.1 for total cholesterol (P = .630), -8.2 +/- 4.2 vs. -8.9 +/- 4.4 for low-density lipoprotein cholesterol (P = .905), -2.3 +/- 1.0 vs. -1.9 +/- 0.8 for high-density lipoprotein cholesterol (P = .762), and -8.1 +/- 3.6 vs. -12.9 +/- 4.0 mg/dL for triacylglycerols (P = .367). CONCLUSION: Changes in the fasting lipid profile were not significantly different with beef consumption compared with those with poultry and/or fish consumption. Inclusion of lean beef in the diet increases the variety of available food choices, which may improve long-term adherence with dietary recommendations for lipid management. PMID- 22836073 TI - The high-dose rosuvastatin once weekly study (the HD-ROWS). AB - BACKGROUND: Alternative dosing is often used clinically to address common barriers with statin therapy, such as intolerance and cost. Previous findings have demonstrated significant and clinically similar reductions in low-density lipoprotein (LDL) cholesterol to daily dosing, when comparing similar total weekly doses. OBJECTIVE: To determine whether rosuvastatin 80 mg once weekly produced comparable lipid and high-sensitivity C-reactive protein (hsCRP) changes to atorvastatin 10 mg daily, when measured at key points after last dose. METHODS: This was a randomized, double-blind, parallel group, 8-week pilot study. Eligible subjects, 18 to 65 years of age, had documented dyslipidemia with LDL cholesterol >100 mg/dL and triglycerides <200 mg/dL. Participants were randomized to receive either rosuvastatin 80 mg once weekly (n = 10) or atorvastatin 10 mg daily (n = 10), for 8 weeks. Lipid panels and hsCRP were measured at baseline and 1-4 and 5-8 days after the last dose. RESULTS: Participants in each arm experienced significant and comparable reductions from baseline in total cholesterol, total cholesterol/high-density lipoprotein cholesterol ratio, non high-density lipoprotein cholesterol, and overall LDL cholesterol (-29%). Changes in high-density lipoprotein cholesterol, triglycerides, and hsCRP were nonsignificant and similar between groups. Each regimen was well tolerated, with no major adverse events reported. CONCLUSION: Rosuvastatin 80 mg once weekly produced comparable lipid changes to atorvastatin 10 mg daily when measured at specific points after the last dose. Our findings support previous data demonstrating a significant reduction in LDL-C with once weekly statin dosing. PMID- 22836074 TI - Lipoprotein(a) particle concentration and lipoprotein(a) cholesterol assays yield discordant classification of patients into four physiologically discrete groups. AB - There is little known about the relative predictive value of different lipoprotein(a) [Lp(a)] assays in clinical use, although each has been shown to predict similar incremental risk over conventional clinical and lipid risk factors. Thus, we examined the classification behavior of two commonly used Lp(a) assays and their associations with other lipid parameters. Serum lipid and Lp(a) concentrations were measured in 144 primary and secondary prevention patients. Lp(a) cholesterol [Lp(a)-C] was measured with the Vertical Auto Profile (upper limit of normal, 10 mg/dL). Lp(a) particle concentrations [Lp(a)-P] were measured with an isoform-independent molar assay (upper limit of normal, 70 nmol/L). The subjects were divided into the following four groups on the basis of their Lp(a) C and Lp(a)-P levels: normal Lp(a)-P and Lp(a)-C; high Lp(a)-P and normal Lp(a) C; normal Lp(a)-P and high Lp(a)-C; and high Lp(a)-P and Lp(a)-C. The proportion of subjects with values above the upper limit of normal was similar with both assays (P = .15). However, the Lp(a)-C and Lp(a)-P assays discordantly classified 23% of the study's subjects. In addition, the four Lp(a)-defined groups displayed differences in their relationships with other lipoproteins. The two groups with elevated Lp(a)-C showed significant associations with higher high-density lipoprotein cholesterol, apolipoprotein AI, and high-density lipoprotein cholesterol/apolipoprotein AI ratios. Triglycerides were also noted to be above normal in discordant and normal within concordant Lp(a) groups. Finally, the amount of cholesterol per Lp(a) particle [Lp(a)-C/Lp(a)-P] varied widely across the four groups. These findings suggest that the four Lp(a)-defined groups are physiologically discrete. Further investigation is warranted to assess which parameters among Lp(a)-P, Lp(a)-C, and Lp(a)-C/Lp(a)-P can be used to more accurately characterize Lp(a)-associated cardiovascular risk. PMID- 22836075 TI - Risk of coronary heart disease is associated with triglycerides and high-density lipoprotein cholesterol in women and non-high-density lipoprotein cholesterol in men. AB - BACKGROUND: Although the physiologic interrelationships between triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) are not fully understood, studies typically are adjusted for one when one is examining the role of the other. If the mechanism of coronary heart disease (CHD) risk is mediated through the other, then controlling for the second factor may mask the true effect of the first. We investigated the relationship between the combined effect of increased (?) TG and decreased (?) HDL-C compared with isolated ?TG or isolated ?HDL-C on CHD risk in men and women and compared these TG/HDL-C categories to non-HDL cholesterol (non-HDL-C). METHODS: Subjects (936 women and 746 men) from the San Luis Valley Study were grouped on the basis of 4 sex-specific NCEP-ATP III cutpoints (?TG >=150 mg/dL, and ?HDL-C, <40 and <50 mg/dL for men and women, respectively). Descriptive statistics and survival analyses were used. The reference group was ?TG/?HDL-C (TG <150, and HDL-C >50 and >40 mg/dL for women and men, respectively). Non-HDL-C was analyzed as a continuous variable. RESULTS: Among women, all groups had greater risk of CHD compared with the ?TG/?HDL-C reference in univariate analysis: ?TG/?HDL-C HR = 2.82 [95% confidence interval 1.12-7.1], ?TG/?HDL-C HR = 3.82 [1.50-9.74], ?TG/?HDL-C HR= 4.32 [1.91-9.80]. The risk remained significant in the ?TG/?HDL-C group (HR= 3.27 [1.26-8.50] and marginally significant in other groups in multivariable analysis. Neither ?TG nor ?HDL-C was related to CHD risk in men. Non-HDL cholesterol was significantly related to CHD in men but not in women. CONCLUSIONS: The CHD risk associated with ?HDL-C in women was >2- to 4-fold elevated depending on TG levels. Non-HDL cholesterol was a significant predictor of CHD in men. Examining the combined effects of risk factors that share physiologic pathways may reveal important associations that can be otherwise obscured. Further dissection of gender specific pathways that affect HDL-C and TG and non-HDL cholesterol are important in understanding CHD risk. PMID- 22836076 TI - Non-high-density lipoprotein cholesterol is associated more closely with albuminuria in Chinese type 2 diabetic patients with normal renal function, compared with traditional lipid parameters. AB - BACKGROUND: Urinary albumin excretion rate (UAER) is a remarkable index reflecting the progression of kidney disease in diabetic subjects. The link between UAER and lipid metabolism is still unclear. The correlation of Apolipoprotein B (ApoB) to albuminuria has been investigated. The National Cholesterol Education Program-Adult Treatment Panel III recommends that clinicians consider non-high-density lipoprotein cholesterol (non-HDL-c) as a surrogate marker for ApoB. OBJECTIVE: We sought to evaluate the relationship of UAER with lipid profile, especially with non-HDL-c in type 2 diabetic patients without renal dysfunction. METHODS: A total of 507 type 2 diabetic patients with normal renal function participated in this study. Demographic and anthropometric data were collected; 24-hour urine samples were collected for UAER measurement. Blood samples were collected for lipid parameters and HbA1c measurement. RESULTS: The patients with albuminuria had greater levels of non-HDL-c and ApoB. The frequencies of albuminuria among the four quartiles of lipid parameters, ie, triglycerides, total cholesterol, non-HDL-c, and ApoB, demonstrated significantly linearly increasing (P for trend <.01). After adjustment, UAER was significantly correlated with total cholesterol, triglycerides, ApoB, and non-HDL-c but not with low-density lipoprotein cholesterol (LDL-c) or lipoprotein(a) [Lp(a)]. Stepwise regression analysis showed that age (beta = .255, P = .000), systolic blood pressure (beta = .261, P = .000), non-HDL-c (beta = .164, P = .000), and duration of diabetes (beta = .105, P = .024) were independently correlated with UAER in diabetic patients without renal dysfunction. CONCLUSION: Compared with the lipid parameters of total cholesterol, triglycerides, HDL-c, LDL-c, ApoB, Apolipoprotein A-I (ApoA-I), and Lp(a), non-HDL-c was more closely associated with albuminuria in Chinese type 2 diabetic patients without impaired renal function. PMID- 22836077 TI - Significant reduction of elevated serum lipoprotein(a) concentrations during levo thyroxine-replacement therapy in a hypothyroid patient. AB - In a number of previous studies investigators have reported the effect of the thyroid status on the changes of the serum lipoprotein concentrations, whereas reports on serum Lp(a) concentrations have been limited and the results are controversial. Recently, we encountered a hypothyroid patient with elevated serum Lp(a) concentrations in whom serial measurements of serum Lp(a) concentration were performed during the hormone replacement therapy. Our observation on this patient is of particular interest: the serum Lp(a) concentrations tended to continue to decrease even after 1 year 5 months, suggesting that the effects of thyroid hormone on the serum Lp(a) levels may continue for much longer than those on the serum LDL-C. Our findings may suggest a possible role of this hormone in the regulation of Lp(a) metabolism. Together with the recent reports indicating that a thyroid hormone analogue lowered serum Lp(a) levels, our observation may also pave the way for the development of Lp(a)-lowering agents. PMID- 22836078 TI - Predicting the stress distribution within scaffolds with ordered architecture. AB - Current tissue engineering technologies involve the seeding of cells on porous scaffolds, within which the cells can proliferate and differentiate, when cultured in bioreactors. The flow of culture media through the scaffolds generates stresses that are important for both cell differentiation and cell growth. A recent study [Appl. Phys. Lett. 97 (2010), 024101] showed that flow induced stresses inside highly porous and randomly structured scaffolds follow a three-point gamma probability density function (p.d.f.). The goal of the present study is to further investigate whether the same p.d.f. can also describe the distribution of stresses in structured porous scaffolds, what is the range of scaffold porosity for which the distribution is valid, and what is the physical reason for such behavior. To do that, the p.d.f. of flow-induced stresses in different scaffold geometries were calculated via flow dynamics simulations. It was found that the direction of flow relative to the internal architecture of the scaffolds is important for stress distributions. The stress distributions follow a common distribution within statistically acceptable accuracy, when the flow direction does not coincide with the direction of internal structural elements of the scaffold. PMID- 22836079 TI - Comparative study of Newtonian and non-Newtonian simulations of drug transport in a model drug-eluting stent. AB - To elucidate the difference between Newtonian and shear thinning non-Newtonian assumptions of blood in the analysis of DES drug delivery, we numerically simulated the local flow pattern and the concentration distribution of the drug at the lumen-tissue interface for a structurally simplified DES deployed in a curved segment of an artery under pulsatile blood flow conditions. The numerical results showed that when compared with the Newtonian model, the Carreau (shear thinning) model could lead to some differences in the luminal surface drug concentration in certain areas along the outer wall of the curved vessel. In most areas of the vessel, however, there were no significant differences between the 2 models. Particularly, no significant difference between the two models was found in terms of the area-averaged luminal surface drug concentration. Therefore, we believe that the shear thinning property of blood may play little roles in DES drug delivery. Nevertheless, before we draw the conclusion that Newtonian assumption of blood can be used to replace its non-Newtonian one for the numerical simulation of drug transport in the DES implanted coronary artery, other more complex mechanical properties of blood such as its thixotropic behavior should be tested. PMID- 22836080 TI - Cell-free layer and wall shear stress variation in microvessels. AB - In this study, we simulated multiple red blood cells flowing through straight microvessels with the immersed-boundary lattice-Boltzmann model to examine the shear stress variation on the microvessel surface and its relation to the properties of cell-free layer. Significant variation in shear stress has been observed due to the irregular configuration of blood cells flowing near the microvessel wall. A low shear stress is typically found at locations where there is a cell flowing close to the wall, and a large shear stress at locations with a relatively wide gap between cell and wall. This relationship between the shear stress magnitude and the distance between cell and wall has been attributed to the reverse pressure difference developed between the front and rear sides of a cell flowing near the vessel wall. We further studied the effects of several hemodynamic factors on the variation of shear stress, including the cell deformability, the flow rate, and the aggregation among red blood cells. These simulations show that the shear stress variation is less profound in situations with wider cell-free layers, since the reverse pressure difference around the edge cells is less evident, and the influence of this pressure difference on wall shear stress becomes weaker. This study also demonstrates the complexity of the flow field in the gap between cell and wall. More precise experimental techniques are required accurately measure such shear stress variation in microcirculation. PMID- 22836081 TI - Viscoelastic properties of the passive mechanical behavior of the porcine carotid artery: influence of proximal and distal positions. AB - The viscoelastic properties of porcine carotid tissue are investigated in this work. Experimental uniaxial stress relaxation tests along the longitudinal and circumferential directions of the vessel were performed for carotid strips extracted from 10 vessels. Directional and local differences--distal versus proximal position--in the tissue behavior were investigated. The experimental tests reveal a highly anisotropic, non-linear viscoelastic response and local dependence of the samples. The carotid artery shows anisotropic relaxation behavior for both proximal and distal samples. The highest stress relaxation was found in the circumferential tensile test for the highest applied strain at the distal position. For the circumferential direction, the relaxation stress was higher than in the longitudinal being at its highest in the distal position. These facts show that the stress relaxation is higher in the distal than in the proximal position. However, there are no differences between both positions in the longitudinal direction. In addition, a constitutive law that takes into account the fundamental features, including non-linear viscoelasticity, of the arterial tissue is proposed. The present results are correlated with the purely elastic response and the microstructural analysis of the tissue by means of histological quantification presented in a previous study. PMID- 22836082 TI - Changes in carrot (Daucus carota) parenchyma at higher temperatures detected in vivo by dynamic mechanical (thermal) analysis. AB - The outer parenchyma of carrot was tested using dynamic mechanical analysis (DMA), in air with 90% humidity between 30 and 90 degrees C. Temperature plots of storage (SM i.e. elastic) and loss (LM i.e. inelastic) moduli were obtained. The SM and LM values were the basis for the calculation of the loss tangent (LT), the parameter expressing the ratio of inelastic to elastic parenchyma toughness. As expected, the tissue toughness decreased with increasing temperature. For both moduli, two characteristic temperature areas with temperature slope minima were observed--they were termed low (I) and high (II) temperature negative peaks on the temperature slope plots. It was shown that the negative peaks were related to an increase in the inelastic part of the tissue toughness. All plots were dependent on the temperature rate: increasing the temperature rate (from 0.5 to 2 degrees C/min) resulted in a shift of both the negative peaks I and II to higher temperatures, thereby reducing I and increasing II. It was shown that the observed behaviour cannot be described by simple kinetic equations due to the time dependent and complicated character of the thermally induced changes. These changes were interpreted as a consequence of pore protein denaturation followed by changes of the stress inside the parenchyma cells. PMID- 22836084 TI - Delivery of IL-12p40 ameliorates DSS-induced colitis by suppressing IL-17A expression and inflammation in the intestinal mucosa. AB - IL-12p40 homodimer is a natural antagonist of IL-12 and IL-23, which are potent pro-inflammatory cytokines required for Th1 and Th17 immune responses, respectively. It has been reported that Th17 response is involved in inflammatory bowel disease (IBD), a chronic disorder of the digestive system with steadily increasing incidence. Here, we investigated the effects of IL-12p40 delivered via recombinant adenovirus (rAd/IL-12p40) or mesenchymal stem cells (MSC/IL-12p40) in a dextran sulfate sodium salt (DSS)-induced colitis model. Injection of rAd/IL 12p40 or MSC/IL-12p40 efficiently attenuated colitis symptoms and tissue damage, leading to an increased survival rate. Moreover, IL-12p40 delivery suppressed IL 17A, but enhanced IFN-gamma production from mesenteric lymph node cells, supporting the preferential suppression of IL-23 by IL-12p40 homodimer in vitro and the suppression of Th17 responses in vivo. Our results demonstrate that IL 12p40 delivery ameliorates DSS-induced colitis by suppressing IL-17A production and inflammation in the intestinal mucosa, providing an effective new therapeutic strategy for IBDs. PMID- 22836086 TI - Can we all just get along? PMID- 22836088 TI - AXL and acquired resistance to EGFR inhibitors. PMID- 22836089 TI - Genome stability, progressive kidney failure and aging. PMID- 22836085 TI - Metabolic regulation of organelle homeostasis in lupus T cells. AB - Abnormal T-cell signaling and activation are characteristic features in systemic lupus erythematosus (SLE). Lupus T cells are shifted toward an over-activated state, important signaling pathways are rewired, and signaling molecules are replaced. Disturbances in metabolic and organelle homeostasis, importantly within the mitochondrial, endosomal, and autophagosomal compartments, underlie the changes in signal transduction. Mitochondrial hyperpolarization, enhanced endosomal recycling, and dysregulated autophagy are hallmarks of pathologic organelle homeostasis in SLE. This review is focused on the metabolic checkpoints of endosomal traffic that control immunological synapse formation and mitophagy and may thus serve as targets for treatment in SLE. PMID- 22836090 TI - The paradoxical TGF-beta vasculopathies. PMID- 22836096 TI - Leveraging models of cell regulation and GWAS data in integrative network-based association studies. PMID- 22836097 TI - Clinical reasoning during simulation: comparison of student and faculty ratings. AB - A recently developed tool, the Lasater Clinical Judgment Rubric (LCJR), was used to evaluate nursing students' clinical reasoning during simulated patient care scenarios. For two semesters, students and nursing faculty completed the clinical reasoning tool after participating in and observing students' reactions to simulated emergent patient simulations. Scores were compared between nursing students and faculty and between programs, associate (AS) and baccalaureate of science (BS). Students' scores differed statistically based on program, BS means greater than AS, but student and faculty ratings were rarely significantly different. Additional research across multiple programs for a larger sample size and additional testing of the clinical reasoning tool are needed. To promote more realistic self-appraisals, students may need more opportunities to self-assess clinical reasoning behaviors in conjunction with feedback on performance from faculty throughout the nursing program. PMID- 22836098 TI - Comparing illicit drug use in 19 European cities through sewage analysis. AB - The analysis of sewage for urinary biomarkers of illicit drugs is a promising and complementary approach for estimating the use of these substances in the general population. For the first time, this approach was simultaneously applied in 19 European cities, making it possible to directly compare illicit drug loads in Europe over a 1-week period. An inter-laboratory comparison study was performed to evaluate the analytical performance of the participating laboratories. Raw 24 hour composite sewage samples were collected from 19 European cities during a single week in March 2011 and analyzed for the urinary biomarkers of cocaine, amphetamine, ecstasy, methamphetamine and cannabis using in-house optimized and validated analytical methods. The load of each substance used in each city was back-calculated from the measured concentrations. The data show distinct temporal and spatial patterns in drug use across Europe. Cocaine use was higher in Western and Central Europe and lower in Northern and Eastern Europe. The extrapolated total daily use of cocaine in Europe during the study period was equivalent to 356 kg/day. High per capita ecstasy loads were observed in Dutch cities, as well as in Antwerp and London. In general, cocaine and ecstasy loads were significantly elevated during the weekend compared to weekdays. Per-capita loads of methamphetamine were highest in Helsinki and Turku, Oslo and Budweis, while the per capita loads of cannabis were similar throughout Europe. This study shows that a standardized analysis for illicit drug urinary biomarkers in sewage can be applied to estimate and compare the use of these substances at local and international scales. This approach has the potential to deliver important information on drug markets (supply indicator). PMID- 22836099 TI - Association between side-impact airbag deployment and risk of injury: A matched cohort study using the CIREN and the NASS-CDS. AB - BACKGROUND: Side-impact airbags (SABs) are designed to protect the head and thorax during a side-impact motor vehicle collision (MVC). Research on the effectiveness of SAB deployment has been limited. The objective of this study was to assess the effectiveness of deployed SABs in reducing head and thoracic injuries during side-impact MVCs. METHODS: The 2000-2009 National Automotive Sampling System-Crashworthiness Data System and the Crash Injury Research Engineering Network databases were used to evaluate front seat occupants involved in side-impact MVCs using a matched cohort study design. The risk of serious head and thoracic injuries for occupants with and without deployed SABs were compared. RESULTS: Occupants in vehicles with a deployed SAB designed to protect the head had a 30% lower risk of head injuries with an Abbreviated Injury Scale score of 2+ (relative risk [RR], 0.70; 95% confidence interval [CI], 0.51-0.97). Regarding thoracic injury, occupants in vehicles with a deployed SAB designed to protect the torso had a risk of injury similar to that of occupants without a deployed SAB (RR, 0.99; 95% CI, 0.79-1.24), although the risk increased for occupants 50 years and older (RR, 1.27; 95% 0.84-1.93). CONCLUSION: The results of the current suggest that although SABs protect occupants from head injury, the protective effect for thoracic injury is limited. Future research should focus on whether the association with thoracic injury is modified by occupant seating posture. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 22836100 TI - Soluble serum Klotho in diabetic nephropathy: relationship to VEGF-A. AB - OBJECTIVES: Both kidney expression and soluble serum Klotho are influenced by chronic kidney disease (CKD) and diabetes. Serum Klotho is a yet poorly explored biomarker. We describe, for the first time to our knowledge, serum Klotho in diabetic patients with CKD and its relationship to vascular endothelial growth factor A (VEGF-A). DESIGN AND METHODS: We included 43 controls and 146 diabetic patients with different stages of CKD. Laboratory evaluation, urinary albumin/creatinine ratio (UACR), Klotho (ELISA), VEGF-A (ELISA) were performed. RESULTS: Klotho was 0.40(0.10-1.30)ng/mL in diabetic patients without CKD and 0.80(0.30-1.30)ng/mL in controls, p=0.20; VEGF-A was higher in diabetic patients 73.85(57.32-119.00)pg/mL than in controls 43.20(30.1-65.9)pg/mL, p<0.0001. Klotho increased with CKD stage: 0.2(0.10-0.40)ng/mL in CKD 1/2, 0.60(0.20-1.1)ng/mL in CKD 3/4 and 1.45(0.425-2.90)ng/mL in dialysis patients, p<0.0001; it also increased with decreasing glomerular filtration rate (GFR). Klotho was lower in albuminuric (UACR>30 mg/g) patients 0.20(0.10-0.70)ng/mL than in normoalbuminuric (UACR<30 mg/g) ones 0.50(0.20-1.30)ng/mL, p=0.03; lowest Klotho was found in microalbuminuric (UACR 30-300 mg/g) patients, p=0.07. VEGF was lower in microalbuminuric patients but was not influenced by GFR. In diabetic patients but not in controls, Klotho correlated to VEGF-A (r=0.29, p=0.0003); in multiple regression VEGF-A was the only significant predictor of Klotho: b=0.27, 95%CI (0.01-0.04), p=0.001. CONCLUSIONS: In diabetic patients, Klotho is decreased in early CKD and increases thereafter, paralleling reduced GFR. VEGF-A is higher in diabetic patients than in controls. Both Klotho and VEGF-A are decreased in the presence of microalbuminuria. In diabetes, Klotho strongly correlates to VEGF-A. PMID- 22836101 TI - BCL2L1 (BCL-X) promotes survival of adult and developing retinal ganglion cells. AB - The Bcl-2 family is responsible for regulating cell death pathways in neurons during development, after injury and in disease. The activation of the pro-death family member BAX is often the final step before cell death in neurons. Pro survival family members such as BCL-X (BCL2L1) act to inhibit BAX activation. Overexpression studies have suggested that BCL-X could play an important physiological role in mediating neuronal viability. Loss-of-function studies performed in vivo have implicated BCL-X as a mediator of neuronal survival during the early stages of neurodevelopment. To assess whether BCL-X is needed to promote the survival of neurons in the central nervous system throughout life, Bcl-x was conditionally removed from the optic cup or throughout the adult mouse. During development BCL-X was required for the survival of differentiating retinal ganglion cells (RGCs) leading up to their normal window of developmental death. Despite its expression in adult RGCs, BCL-X was not required for maintaining RGC viability in adult retinas. However, the loss of BCL-X in adult RGCs did significantly increase the rate of death of RGCs after axonal injury. Thus, in developing and injured RGCs there appears to be an active cell survival program preventing neuronal death. PMID- 22836102 TI - Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis. AB - INTRODUCTION: Several clinical trials are currently evaluating stem cell therapy for patients with critical limb ischemia that have no other surgical or endovascular options for revascularization. However, these trials are conducted with different protocols, including use of different stem cell populations and different injection protocols, providing little means to compare trials and guide therapy. Accordingly, we developed a murine model of severe ischemia to allow methodic testing of relevant clinical parameters. METHODS: High femoral artery ligation and total excision of the superficial femoral artery was performed on C57BL/6 mice. Mononuclear cells (MNCs) were isolated from the bone marrow of donor mice, characterized using fluorescence-activated cell sorting, and injected (5*10(5) to 2*10(6)) into the semimembranosus (proximal) or gastrocnemius (distal) muscle. Vascular and functional outcomes were measured using invasive Doppler imaging, laser Doppler perfusion imaging, and the Tarlov and ischemia scores. Histologic analysis included quantification of muscle fiber area and number as well as capillary density. RESULTS: Blood flow and functional outcomes were improved in MNC-treated mice compared with controls over 28 days (flow: P<.0001; Tarlov: P=.0004; ischemia score: P=.0002). MNC-treated mice also showed greater gastrocnemius fiber area (P=.0053) and increased capillary density (P=.0004). Dose-response analysis showed increased angiogenesis and gastrocnemius fiber area but no changes in macroscopic vascular flow or functional scores. Overall functional outcomes in mice injected proximally to the ischemic area were similar to mice injected more distally, but muscle flow, capillary density, and gastrocnemius fiber area were increased (P<.05). CONCLUSIONS: High femoral ligation with complete excision of the superficial femoral artery is a reliable model of severe hind limb ischemia in C57BL/6 mice that shows a response to MNC treatment for functional and vascular outcomes. A dose response to the injection of MNCs appears to be present, at least microscopically, suggesting that an optimal cell number for stem cell therapy exists and that preclinical testing needs to be performed to optimally guide human trials. Injection of MNCs proximal to the site of ischemia may provide different outcomes compared with distal injection and warrants additional study. PMID- 22836103 TI - Treatment of infrainguinal thromboembolic complications during peripheral endovascular procedures with AngioJet rheolytic thrombectomy, intraoperative thrombolysis, and selective stenting. AB - OBJECTIVE: This study investigated the safety and effectiveness of the infrainguinal use of the AngioJet rheolytic mechanical thrombectomy system (Possis Medical, Minneapolis, Minn) for the treatment of acute infrainguinal thromboembolism occurring during lower limb revascularization procedures. METHODS: For the interval between January 2000 and January 2011, our hospital's database was meticulously searched for all patients with acute thromboembolism that occurred during lower limb angioplasty, with or without stenting procedures, who were treated with infrainguinal AngioJet thrombectomy. Baseline patient demographics and procedural details were analyzed. Primary end points included technical success, defined as the complete revascularization of the acutely occluded vessel; clinical success, defined as the absence of death or amputation <= 60 days; and procedure-related complication. Secondary end points included embolized vessel primary patency and overall patient survival. RESULTS: During this 12-year period, 3147 peripheral percutaneous procedures of angioplasty, with or without stenting, were performed in our department. Intraoperative, clinically, and angiographically evident thromboembolism occurred in 18 of 3147 procedures (0.57%), and 14 (77.7%) were managed using the AngioJet thrombectomy system. In total, 22 arteries were treated (13 infrapopliteal, 3 femoropopliteal, and 6 popliteal arteries). All patients had a completion angiogram for the assessment of the runoff vessels' status. Technical and clinical success occurred in 13 of 14 (92.8%). Adjunctive local thrombolysis or clot trapping, or both, with stenting was used in 64.3% and 42.8% of the procedures, respectively. Mean time follow-up was 38.1 +/- 49.0 months. The 1-year embolized vessel primary patency rate was 50.9%, and the survival rate was 53.5% up to 11.5 years of follow-up, as estimated by Kaplan-Meier analysis. The 1-year limb salvage rate was 92.3%. There were no procedure-related minor amputations and one (7.1%) procedure-related major above-knee amputation. CONCLUSIONS: The use of AngioJet rheolytic thrombectomy and adjunctive local thrombolysis or stenting, or both, under filter protection, is safe and effective for the management of severe thromboembolic complications occurring in the femoropopliteal and infrapopliteal arteries during peripheral endovascular procedures. PMID- 22836105 TI - Expanding the use of simulation in open vascular surgical training. AB - Simulation technology has a well-defined role in nonmedical professions such as aviation and over the last two decades has permeated medical training. The most successful surgical simulation is in the fields of laparoscopic and endovascular surgery. These two-dimensional scenarios, as in the aviation industry, lend themselves to simulation. Open simulators have been met with more resistance than their laparoscopic counterparts because of the difficulties in simulating the three-dimensional field. Engaging in persistent practice is what makes the expert and all trainees should aspire to this. Without knowing, all surgical trainees have engaged in deliberate practice when first learning to tie surgical knots. This deliberate practice should be used in all aspects of vascular surgical practice, and it is no longer acceptable to perform procedures such as arterial anastomoses for the first time on patients. Simulators exist for all aspects of vascular surgical training and vary in complexity and price. Some of these simulators are suitable for use at home or in a skills laboratory whereas others are more suitable for use in a specialized skills center. Training on these simulators can be offered at a local level or at a regional level in the skills center. Where surgical procedures are not commonly performed or expertise is required for a new innovation, it is more appropriate to have national or internationally based workshops under the auspices of surgical boards or societies. Simulation of crisis management, well known in aviation, has also been applied to vascular surgical practice and can offer benefit to senior trainees even when their performance on a noncrisis simulator has reached a plateau. This article identifies the areas where simulation in open vascular surgery can benefit the trainee. PMID- 22836106 TI - Remodeling of proximal neck angulation after endovascular aneurysm repair. AB - OBJECTIVE: This study investigated the remodeling of proximal neck (PN) angulations of abdominal aortic aneurysms (AAAs) after endovascular aneurysm repair (EVAR). METHODS: A 64-row multidetector computed tomography scan of AAAs treated with EVAR was reviewed, and the PN angulation was measured on a volume rendered three-dimensional image. The computed tomography scan was examined preoperatively, after EVAR at 1 week, 1 month, 6 months, 1 year, 1.5 years, 2 years, and then yearly. The study enrolled 78 patients, comprising 54 Zenith devices (Cook Medical, Bloomington, Ind) and 24 Excluder devices (W. L. Gore and Associates, Flagstaff, Ariz). RESULTS: PN angulation was 50 degrees +/- 20 degrees preoperatively, and after EVAR was 36 degrees +/- 14 degrees at 1 week, 32 degrees +/- 14 degrees at 1 year, and 28 degrees +/- 13 degrees at 3 years. PN angulations <= 60 degrees (n = 70, 77%) were 41 degrees +/- 13 degrees preoperatively, 31 degrees +/- 12 degrees 1 week after EVAR, 28 degrees +/- 12 degrees at 1 year, and 26 degrees +/- 13 degrees after 3 years. An angulation >60 degrees (n = 18, 23%) was 78 degrees +/- 14 degrees preoperatively, 51 degrees +/- 11 degrees 1 week after EVAR, 44 degrees +/- 11 degrees at 1 year, and 40 degrees +/- 12 degrees after 3 years. The greater the preoperative PN angulation, the greater its reduction immediately after EVAR (r = .72, P < .001). The diameter shrinkage of AAAs with a PN angulation >60 degrees was 3 +/- 6 mm after 1 year; a significantly smaller shrinkage than with a PN angulation <= 60 degrees (7 +/- 7 mm, P < .05). AAAs with a PN angulation >60 degrees had a larger angulation reduction and a smaller diameter shrinkage after the EVAR procedure. The PN angulation of the 54 AAAs treated by Zenith was 49 degrees +/- 22 degrees preoperatively, 34 degrees +/- 14 degrees 1 week after EVAR, and 25 degrees +/- 13 degrees after 3 years. The corresponding angulation of the 24 AAAs treated by Excluder devices was 52 degrees +/- 17 degrees , 41 degrees +/- 14 degrees , and 38 degrees +/- 9 degrees , respectively. The PN angulation reduction of Zenith and Excluder was similar 1 week after the EVAR procedure. Unlike Excluder, however, the PN angulation in Zenith continued to reduce for a long period at a slow pace. There were no significant correlations between PN angulation reduction and diameter change and between PN length and diameter change (P = .86 and .18, respectively). CONCLUSIONS: Although the instructions for use of most commercially available stent grafts provide for a PN angulation of <= 60 degrees , PN angulation was not a major issue in a midterm follow-up of AAAs with adequate PN length for patients in this series who received a Zenith or Excluder graft. PMID- 22836107 TI - Computation of the infrared active modes in single-walled boron nitride nanotube bundles. AB - In this work, the infrared active modes are computed for homogeneous bundles of single-walled boron nitride nanotubes (BBNNTs), using the so-called spectral moments method. The dependence of the wavenumber on these modes in terms of diameters, lengths, and numbers of tubes, is investigated. To this end, use is made of a Lennard-Jones potential for describing the van der Waals interactions between tubes in a bundle. We find that, for a finite homogeneous bundle, additional modes appear as a specific signature. Finally, these results are useful for the interpretation of the experimental infrared spectra of BBNNTs. PMID- 22836108 TI - Spasticity in children and young people with non-progressive brain disorders: summary of NICE guidance. PMID- 22836109 TI - Royal college recommends national system to recognise deteriorating patients. PMID- 22836110 TI - Medically diagnosed infections and risk of childhood leukaemia: a population based case-control study. AB - BACKGROUND: Previous studies on the association between childhood infections and childhood leukaemia have produced inconsistent results, likely due to the recall error/bias of infection data reported by the parents. The current study used a population-based and record-based case-control design to evaluate the association between childhood leukaemia and infections using the National Health Insurance Research Database of Taiwan. METHODS: In all, 846 childhood acute lymphoblastic leukaemia (ALL) and 193 acute myeloid leukaemia (AML) patients newly diagnosed between 2000 and 2008, aged >1 and <10 years, were included. Up to four controls (3374 for ALL and 766 for AML) individually matched to each case on sex, birth date and time of diagnosis (reference date for the controls) were identified. Conditional logistic regression was performed to assess the association between childhood leukaemia and infections. RESULTS: Having any infection before 1 year of age was associated with an increased risk for both childhood ALL (odds ratio = 3.2, 95% confidence interval 2.2-4.7) and AML (odds ratio = 6.0, 95% confidence interval 2.0-17.8), with a stronger risk associated with more episodes of infections. Similar results were observed for infections occurring >1 year before the cases' diagnosis of childhood leukaemia. CONCLUSIONS: Children with leukaemia may have a dysregulated immune function present at an early age, resulting in more episodes of symptomatic infections compared with healthy controls. However, confounding by other infectious measures such as birth order and day care attendance could not be ruled out. Finally, the results are only relevant to the medically diagnosed infections. PMID- 22836111 TI - A cysteine probe with high selectivity and sensitivity promoted by response assisted electrostatic attraction. AB - A new turn-on fluorescent probe for fast detection of cysteine in physiological conditions, based on a new response-assisted electrostatic attraction strategy, is reported. The practical utility of the probe in fluorescent protein labeling and subcellular imaging is also demonstrated. PMID- 22836112 TI - Bilateral supraclavicular swelling: an unusual presentation of ruptured Poly Implant Prosthese (PIP) breast implants. AB - Breast implants manufactured by the French company Poly Implant Prosthese (PIP) have gained notoriety in the International media since the realisation that industrial grade silicone was used in their manufacture with consequent increased risk of implant rupture. At present, it is estimated that there are estimated to be over 40,000 women in the UK with PIP implants. We report an unusual presentation of PIP breast implant rupture as swelling in the supraclavicular fossae. This has not previously been reported in the literature. PMID- 22836113 TI - Development of low-calorie guava preserves with prebiotics and evaluation of their effects on carcinogenesis biomarkers in rats. AB - Faced with the search for healthy products that provide additional benefits to consumers' health, the main objectives of this work were to develop a low-calorie preserve containing prebiotics (lactulose and polydextrose) and to evaluate the effects of these prebiotics on oxidative stress and colon carcinogenesis in male rats treated with 1,2-dimethylhydrazine (DMH). A total of 62.5% w/w of the sucrose in conventional preserves was replaced by polydextrose, and lactulose was added at 0%, 16%, 19.5% or 23% w/w concentrations. The acceptance of these four low-calorie guava preserve samples and the conventional sample was equal (P>0.05), with a score of 6.49. The level of degradation of lactulose was low (18.45 g100 g(-1)lactulose), ensuring that even at a lower concentration of this prebiotic (16% w/w), the concentration remained above the minimum level considered functional. We found that consumption of the low-calorie preserves with prebiotics does not have an effect on the development of mucin-negative ACF and classical ACF in the initiation phase of the mutagenic process. However, the consumption of 1.5 g of the preserve/rat/day potentiated lipid peroxidation and proteic oxidation in the liver. PMID- 22836114 TI - Driver's lane keeping ability with eyes off road: Insights from a naturalistic study. AB - Many studies have shown that driver inattention can influence lane-keeping ability. The majority of studies on lane keeping have been conducted in controlled on-road networks or in simulated environments. However, few studies have examined lane-keeping ability in naturalistic settings for the same purpose. In this current study, the relationship between driver inattention and lane keeping ability was examined using naturalistic data for 24 drivers. Driver inattention was placed into two categories based on whether drivers were looking forward toward the roadway (inattention with eyes-on-road) or not looking forward (inattention with eyes-off-road) while engaged in a secondary task. Repeated measures regression models were used to account for within-subject correlations. The results showed that, after accounting for driving speed and lane width, the eyes-off-road significantly increased the standard deviation of lane position (SDLP). The findings from this study are consistent with other studies that show that the amount of time drivers spend looking away from the road can impact drivers' ability to maintain their lane position. Additionally, this paper demonstrates how driver inattention can be examined with real world data while accounting for the roadway, environment, and driver behavior. PMID- 22836115 TI - Developing a self-reporting method to measure pedestrian behaviors at all ages. AB - The objective of this study was to develop and validate a self-reporting scale to measure injury risk behaviors among pedestrians of all ages. The Pedestrian Behavior Scale (PBS) was developed that included 47 items enabling respondents to evaluate the frequency with which they had different types of pedestrian behaviors. The validation study was carried out on 343 participants (126 men and 217 women) between the ages of 15 and 78. Factor analyses were used to differentiate between 4 axes. Factor 1, "transgression", included items concerning offence of legal rules and errors. Factor 2 included "lapses" items. Factor 3 comprised "aggressive behavior" items and factor 4 included "positive behavior" items. A revised version of the PBS with 20 items was produced by selecting those items that loaded most strongly on the four factors. The 20-item version had good internal reliability. The effects of demographic and mobility variables on the PBS scores were investigated. This instrument will be useful in measuring the frequency of these different types of behaviors among the pedestrians who are most at risk, analyzing the psychological factors used to predict PBS scores and thus better adapt preventive actions to the different populations of vulnerable road users of all ages. PMID- 22836116 TI - Driving anger, emotional and instrumental aggressiveness, and impulsiveness in the prediction of aggressive and transgressive driving. AB - The present study investigates the potential contribution of three predictors of aggressive and transgressive behaviors on the road: driving anger, impulsiveness and aggressiveness. A total of 455 participants (laypersons), of all age and gender, filled self-reported measures evaluating driving anger, impulsiveness, two forms of aggressiveness (instrumental and emotional forms), driving behaviors and aggressive and transgressive behaviors. Main results indicate: (1) a significant gender effect for almost all variables; (2) gender was involved in the prediction of Lapses and Errors; (3) driving anger, impulsiveness and aggressiveness were involved in a complementary manner in the prediction of aggressive and transgressive driving; (4) Aggressiveness and Impeded Progress were the best predictors of violations and aggressive violations. Results support that transgressive driving behaviors are relevant indicators of aggressive driving. PMID- 22836117 TI - Pedestrians' intention to jaywalk: Automatic or planned? A study based on a dual process model in China. AB - The present study investigates the determining factors of Chinese pedestrians' intention to violate traffic laws using a dual-process model. This model divides the cognitive processes of intention formation into controlled analytical processes and automatic associative processes. Specifically, the process explained by the augmented theory of planned behavior (TPB) is controlled, whereas the process based on past behavior is automatic. The results of a survey conducted on 323 adult pedestrian respondents showed that the two added TPB variables had different effects on the intention to violate, i.e., personal norms were significantly related to traffic violation intention, whereas descriptive norms were non-significant predictors. Past behavior significantly but uniquely predicted the intention to violate: the results of the relative weight analysis indicated that the largest percentage of variance in pedestrians' intention to violate was explained by past behavior (42%). According to the dual-process model, therefore, pedestrians' intention formation relies more on habit than on cognitive TPB components and social norms. The implications of these findings for the development of intervention programs are discussed. PMID- 22836118 TI - Calcinosis and antisynthetase syndrome. PMID- 22836119 TI - CD14brightLAP+ mononuclear cells in peripheral blood positively correlate with BASRI scores in patients with ankylosing spondylitis: a pilot study. PMID- 22836120 TI - Disseminated cryptococcosis revealed by vertebral osteomyelitis in an immunocompetent patient. PMID- 22836121 TI - Synthesis, structure, photophysics and electrochemiluminescence of Re(I) tricarbonyl complexes with cationic 2,2-bipyridyl ligands. AB - Two water soluble Re(I) tricarbonyl diimine complexes containing cationic 2,2' bipyridyl ligands [Re(L1)(CO)(3)(AN)](2+) (1) and [Re(L2)(CO)(3)(AN)](3+) (2) (L1 and L2: a cationic 2,2'-bipyridyl ligand, AN: acetonitrile) were synthesized and characterized. Their photophysical, electrochemical and electrochemiluminescent properties were investigated. The crystal structures of the two complexes have also been determined. Electrochemiluminescence (ECL) of the two complexes 1 and 2 have been studied in aqueous buffer solution in the presence of co-reactant tri-n propylamine (TPrA) or 2-(dibutylamino)ethanol (DBAE) at a Au working electrode. The ECL behavior of the complexes was also studied in the presence of several surfactants such as Triton X-100 and Zonyl FSN. The ECL signals of the rhenium(I) complex were enhanced about 190-fold and 70-fold at a Au electrode in the presence of Triton X-100 for the [Re(L1)(CO)(3)(AN)](2+)/TPrA and [Re(L1)(CO)(3)(AN)](2+)/DBAE systems, respectively. PMID- 22836123 TI - Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report. AB - Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc. In this article, we report a patient with SRC induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc. PMID- 22836122 TI - Links between genome integrity and BRCA1 tumor suppression. AB - BRCA1 and BRCA2 are two major breast and ovarian cancer susceptibility genes. BRCA1 was the first discovered and has been a focus of research for these cancers. BRCA1 mediates tumor suppression in part through pleiotropic interactions with a network of DNA repair proteins on chromatin. BRCA1 mutations cause homologous recombination (HR)-mediated DNA repair deficiency, genomic instability, and DNA-damaging agent hypersensitivity. Although BRCA1 and BRCA2 have some shared functions in cancer predisposition and therapy response, there are also key differences indicating divergent roles for each protein. This review summarizes and highlights recent insights into the molecular events responsible for BRCA1 tumor suppression, emphasizing the DNA repair function of BRCA1 as a nexus between its roles in cancer development and therapy. PMID- 22836124 TI - Passenger lymphocyte syndrome with hemophagocytic syndrome after peripheral blood stem-cell transplantation from an HLA-matched full biological sibling: case report. AB - Massive hemolysis due to passenger lymphocyte syndrome (PLS) is rare after peripheral blood stem-cell (PBSC) transplantation with a minor ABO mismatch. We present, in a 16-year-old boy (group A Rh+), PLS with hemophagocytic syndrome (HPS) after PBSC transplantation from his HLA (human leukocyte antigens)-matched biological sister (group O Rh+). Mild-to-moderate hemolysis was evident from day +11 to day +15 after transplantation. HPS was diagnosed by bone marrow examination on day +16, while antibodies against the recipient's red blood cell antigens were detected on days +15 and +27. This hemolysis may have been due to PLS with HPS. Therefore, measurement of antibodies may provide a useful hallmark of immune hemolysis. PMID- 22836125 TI - Water-soluble adsorbent beta-cyclodextrin-grafted polyethyleneimine for removing bilirubin from plasma. AB - A water-soluble adsorbent was developed for removing bilirubin from the plasma of hyperbilirubinemia patient. The adsorbent was synthesized by grafting beta cyclodextrin (beta-CD) to branched polyethyleneimine (PEI) matrix. The resulting beta-CD-PEI polymer had an average molecular weight of 163.7 kD, and it contained 56.3 beta-CD functional groups. In beta-CD-PEI-spiked dialysis, 35.8% of plasma bilirubin was removed, which was higher than that removed by the same concentration of bovine serum albumin. beta-CD-PEI also removed aromatic amino acids and bile acids. The results indicated that beta-CD-PEI could be an effective adsorbent for blood purification application aiming at the removal of toxins. PMID- 22836127 TI - Generation of miRNA sponge constructs. AB - MicroRNA (miRNA) sponges are RNA molecules with repeated miRNA antisense sequences that can sequester miRNAs from their endogenous targets and thus serve as a decoy. Stably expressed miRNA sponges are especially valuable for long-term loss-of-function studies and can be used in vitro and in vivo. We describe here a straightforward method to generate retroviral miRNA sponge constructs using a single directional ligation reaction. This approach allows generation of sponges containing more than 20 miRNA binding sites. We provide a basis for the design of the sponge constructs with respect to the sequence of the miRNA binding site and the sequences flanking the miRNA binding sites. In-silico validation approaches are presented to test the predicted efficiencies of the sponges in comparison to known target genes. In addition, we describe in vitro validation experiments to confirm the effectiveness of the miRNA sponges. Finally, we describe how the here described procedure can be adapted to easily generate sponges that target multiple miRNAs simultaneously. In summary, our approach allows rapid generation of single or combination miRNA sponges that can be used for long-term miRNA loss of-function studies. PMID- 22836126 TI - Bioinformatic analysis of barcoded cDNA libraries for small RNA profiling by next generation sequencing. AB - The characterization of post-transcriptional gene regulation by small regulatory RNAs of 20-30 nt length, particularly miRNAs and piRNAs, has become a major focus of research in recent years. A prerequisite for the characterization of small RNAs is their identification and quantification across different developmental stages, normal and diseased tissues, as well as model cell lines. Here we present a step-by-step protocol for the bioinformatic analysis of barcoded cDNA libraries for small RNA profiling generated by Illumina sequencing, thereby facilitating miRNA and other small RNA profiling of large sample collections. PMID- 22836129 TI - The Cross-and-Capture system: a versatile tool in yeast proteomics. AB - High-throughput technologies such as affinity purification and yeast two-hybrid (Y2H) screening have been applied to explore protein-protein interactions (PPIs) in the model organism Saccharomyces cerevisiae. The "Cross-and-Capture" system is an alternative approach for an assessment of PPIs using two arrayed collections of differentially tagged yeast strains. In its current implementation, Cross-and Capture encompasses ~500 endogenously tagged yeast proteins, predominantly with roles in DNA metabolism and maintenance. The tagged arrays can also serve other purposes in yeast proteomics, such as monitoring of protein expression and the detection of posttranslational protein modifications. In this article, I summarize the development of this tool and describe its application to detect protein complexes and to screen for novel PPIs. PMID- 22836128 TI - ORF phage display to identify cellular proteins with different functions. AB - Open reading frame (ORF) phage display is a new branch of phage display aimed at improving its efficiency to identify cellular proteins with specific binding or functional activities. Despite the success of phage display with antibody libraries and random peptide libraries, phage display with cDNA libraries of cellular proteins identifies a high percentage of non-ORF clones encoding unnatural short peptides with minimal biological implications. This is mainly because of the uncontrollable reading frames of cellular proteins in conventional cDNA libraries. ORF phage display solves this problem by eliminating non-ORF clones to generate ORF cDNA libraries. Here I summarize the procedures of ORF phage display, discuss the factors influencing its efficiency, present examples of its versatile applications, and highlight evidence of its capability of identifying biologically relevant cellular proteins. ORF phage display coupled with different selection strategies is capable of delineating diverse functions of cellular proteins with unique advantages. PMID- 22836130 TI - The intron 7 -33T>C polymorphism in TFPI gene and cerebral venous thrombosis: evidence for a protective role. PMID- 22836131 TI - Fibrinolysis alterations in infertile women during controlled ovarian stimulation: influence of BMI and genetic components. AB - INTRODUCTION: Ovarian stimulation protocols have been described to induce prothrombotic phenotype through alterations of both coagulation and fibrinolysis pathways. We investigated fibrinolytic changes during ovarian stimulation through a global test (CLT) and PAI-1 and TAFI concentrations at different times of ovarian stimulation procedure, and the influence of polymorphisms in genes encoding for fibrinogen chains (FGA, FGB, FGG), t-PA (PLAT), TAFI (CBP2), FXIII (FXIIA1, FXIIIB), plasminogen (PLG) and PAI-1 (PAI1) on their intermediate phenotype. MATERIALS AND METHODS: We evaluated fibrinolytic and genetic parameters in 110 infertile women undergoing ovarian stimulation procedure (in vitro fertilization, IVF or intracytoplasmic sperm injection, ICSI). All women were observed during the mid-luteal phase of cycle (T(0)) and on day 5 (T(1)), 7 (T(2)) and 9 (T(3)) of the ovarian stimulation. RESULTS: Significant changes in fibrinolytic parameters from T(0) to T(3) of ovarian stimulation were found (CLT p=0.003; TAFI p=0.009 and PAI-1 p=0.003). CLT values, TAFI and PAI-1 concentrations significantly increased from baseline to T(1) (p<0.0001, p=0.01, p=0.005, respectively)(,) and decreased at T(2,) but remained higher than those at T(0). Moreover, at baseline overweight women showed longer CLT, higher TAFI and PAI-1 concentrations than normal weight women, as well as at T(1) two-fold longer CLT and higher PAI-1 concentrations were observed (p=0.001 and p=0.05, respectively). Significant differences of TAFI and PAI-1 concentrations during ovarian stimulation according to TAFI and PAI1 polymorphisms were observed. CONCLUSIONS: This study shows alterations of fibrinolysis and suggests the contribution of TAFI and PAI1 genes in modulating fibrinolysis changes during the ovarian stimulation cycle. PMID- 22836132 TI - Prospective evaluation of the toxicity profile of proteasome inhibitor-based therapy in renal transplant candidates and recipients. AB - BACKGROUND: A prospective intermediate-term evaluation of toxicities associated with bortezomib therapy for antibody-mediated rejection (AMR) and desensitization was conducted. METHODS: Patients were graded for bortezomib-related toxicities: hematologic and gastrointestinal toxicities by Common Terminology Criteria for Adverse Events and peripheral neuropathy by modified Functional Assessment of Cancer Therapy questionnaire and Common Terminology Criteria for Adverse Events. RESULTS: Fifty-one patients treated for AMR and 19 patients treated for desensitization received 96 bortezomib cycles (1.3 mg/m(2) *4 doses); mean (SD) follow-up was 16.3 (9.0) months. Patients treated for AMR and patients treated for desensitization were similar in age, gender, ethnicity, and baseline peripheral neuropathy. Patients treated for AMR received a mean (SD) of 4.9 (2.0) bortezomib doses in 1.3 (0.5) cycles; and patients treated for desensitization, a mean of 7.3 (1.6) doses in 1.8 (0.4) cycles. Prevalence of diabetes and anemia were higher at baseline in patients treated for AMR. In the AMR cohort, two cases of cytomegalovirus infection, two cases of BK virus infection, and one case of Epstein-Barr virus infection were observed. No cases of viral infection were observed in the desensitization cohort. Malignancies were not observed. Significant bortezomib toxicities included anemia and peripheral neuropathy, which were manageable. Anemia was more common in patients treated for AMR; and peripheral neuropathy, more common in patients treated for desensitization. CONCLUSIONS: Bortezomib-related toxicities in kidney transplant candidates and recipients are low in incidence and severity and vary based on treatment population. PMID- 22836133 TI - The implications of acute rejection for allograft survival in contemporary U.S. kidney transplantation. AB - BACKGROUND: We examined the frequency and clinical impact of acute rejection (AR) in contemporary U.S. kidney transplantation. METHODS: Data for Medicare-insured kidney transplant recipients in 2000 to 2007 (n=48,179) were drawn from the United States Renal Data System. AR events were ascertained from Organ Procurement and Transplantation Network reports. AR was subclassified as antibody (Ab)-treated AR or other management (non-Ab-treated AR). Associations of AR with subsequent all-cause graft loss were estimated with time-varying Cox regression. Covariates included recipient, donor, and transplant factors in the United Network for Organ Sharing Kidney Allocation Review Committee survival model. RESULTS: The frequencies of non-Ab-treated AR per 100 graft-years at risk among standard criteria donor recipients over the first 6, 12, 24, and 36 months after transplantation were 9.93, 8.43, 5.71, and 4.70, respectively. Non-Ab-treated AR was consistently more than twice as common as Ab-treated AR by risk period and donor type. Development of Ab-treated AR predicted a greater risk of graft loss than non-Ab-treated AR. The relative risk for graft loss from Ab-treated AR continuously increased with later timing of AR after transplantation, whereas risk associated with non-Ab-treated AR peaked for events reported in months 13 to 24 after kidney transplantation. Regardless of the diagnosis time, the relative risk of graft loss was higher in the first 89 days after a given AR report compared with 90 days and beyond. CONCLUSIONS: AR events recognized later after transplantation have more serious graft loss implications, especially within the first 89 days after AR reporting. This observation may reflect reduced intensity of monitoring, delays in diagnosis, or clinicopathologic features of late AR. PMID- 22836134 TI - Factors influencing viral clearing and renal function during polyomavirus BK associated nephropathy after renal transplantation. AB - BACKGROUND: The course of BK virus nephropathy (BKVN) is difficult to predict. METHODS: Between 2008 and 2010, we diagnosed BKVN in 46 (5.5%) of 859 patients with transplant biopsies by simian virus 40 (SV40) staining and routine serum polymerase chain reaction. We measured the influence of different variables on glomerular filtration rate (DeltaGFR increasing or decreasing) and the time for viral polymerase chain reaction reduction by 1 log (<=13 or >13 weeks). At diagnosis, we either reduced calcineurin inhibitor (CNI) and mycophenolate mofetil by 30% to 50% (n=23), or we switched from CNI to mammalian target of rapamycin (mTOR) inhibitor (n=7) or from CNI to mTOR inhibitor as a second step in patients with protracted viral reduction (n=16). Results are the following: GFR stabilized or increased in 61% of patients and decreased in 39% (graft failure, 15%). Viral reduction by 1 log was rapid in 54% (<=13 weeks) and slow in 46% (>13 weeks). Rapid viral reduction was associated with stable or increasing GFR (84%), compared with slow viral reduction (33%; P=0.0004). High peak viral load, tacrolimus treatment, and late diagnosis (biopsy for cause vs. protocol biopsy) had a negative influence on GFR and viral reduction time. Defining 1-log viral load reduction as an event, tacrolimus compared with cyclosporine was associated with slow viral reduction (P=0.0043). In 88% of patients with slow viral reduction, the secondary switch from CNI to mTOR inhibitor favored viral load decrease. CONCLUSIONS: We conclude that peak viral load, tacrolimus treatment, delayed diagnosis, and viral reduction time influence outcomes in patients with BKVN. PMID- 22836135 TI - The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. AB - Recent studies highlight the importance of translational control in determining protein abundance, underscoring the value of measuring gene expression at the level of translation. We present a protocol for genome-wide, quantitative analysis of in vivo translation by deep sequencing. This ribosome profiling approach maps the exact positions of ribosomes on transcripts by nuclease footprinting. The nuclease-protected mRNA fragments are converted into a DNA library suitable for deep sequencing using a strategy that minimizes bias. The abundance of different footprint fragments in deep sequencing data reports on the amount of translation of a gene. In addition, footprints reveal the exact regions of the transcriptome that are translated. To better define translated reading frames, we describe an adaptation that reveals the sites of translation initiation by pretreating cells with harringtonine to immobilize initiating ribosomes. The protocol we describe requires 5-7 days to generate a completed ribosome profiling sequencing library. Sequencing and data analysis require a further 4-5 days. PMID- 22836137 TI - Local structure of LiCoO2 nanoparticles studied by Co K-edge x-ray absorption spectroscopy. AB - We have studied the local structure of LiCoO(2) nanoparticles by Co K-edge x-ray absorption spectroscopy as a function of particle size. Extended x-ray absorption fine structure data reveal substantial changes in the near neighbor distances and the associated mean square relative displacements with decreasing particle size. X-ray absorption near edge structure spectra show clear local geometrical changes with decreasing particle size, similar to those that appear in the charging (delithiation) process. The results suggest that the LiCoO(2) nanoparticles are characterized by a large atomic disorder confined to the Co-O octahedra, similar to the distortions generated during the delithiation, and this disorder should be the primary limiting factor for a reversible diffusion of Li ions when nanoparticles of LiCoO(2) are used as cathode material in rechargeable Li ion batteries. PMID- 22836136 TI - A complete workflow for the analysis of full-size ChIP-seq (and similar) data sets using peak-motifs. AB - This protocol explains how to use the online integrated pipeline 'peak-motifs' (http://rsat.ulb.ac.be/rsat/) to predict motifs and binding sites in full-size peak sets obtained by chromatin immunoprecipitation-sequencing (ChIP-seq) or related technologies. The workflow combines four time- and memory-efficient motif discovery algorithms to extract significant motifs from the sequences. Discovered motifs are compared with databases of known motifs to identify potentially bound transcription factors. Sequences are scanned to predict transcription factor binding sites and analyze their enrichment and positional distribution relative to peak centers. Peaks and binding sites are exported as BED tracks that can be uploaded into the University of California Santa Cruz (UCSC) genome browser for visualization in the genomic context. This protocol is illustrated with the analysis of a set of 6,000 peaks (8 Mb in total) bound by the Drosophila transcription factor Kruppel. The complete workflow is achieved in about 25 min of computational time on the Regulatory Sequence Analysis Tools (RSAT) Web server. This protocol can be followed in about 1 h. PMID- 22836138 TI - Outcome and complications after dual mobility total hip replacement: fifty cases with a minimum of six months clinical and radiographic follow-up. AB - OBJECTIVES: To report the clinical and radiographic outcome of a canine total hip prosthesis with a dual mobility acetabular component, with a minimum of six months follow-up. METHODS: The outcome of dogs that underwent primary cemented unilateral dual mobility hip prosthesis surgery by one of the authors for hip dysplasia or trauma, and which had a minimum of six months clinical and radiologic follow-up, was evaluated. RESULTS: Fifty dogs were included in the study. Follow-up ranged from six to 38 months (mean 14.4 months). Perioperative complications were acetabular collapse (n = 1) and greater trochanter fracture (n = 1), both of which were successfully managed perioperatively. Postoperative complications were aseptic loosening of the acetabular component (n = 2; both surgically revised), implant sepsis (n = 3; all explanted), acetabular fracture (n = 1; conservatively managed), greater trochanter fracture (n = 1; conservatively managed) and sciatic neurapraxia (n = 1). No cases of postoperative luxation or femoral implant aseptic loosening were encountered. Outcome was poor for three cases (3 implant sepsis), fair for three cases (including 1 acetabular component loosening and 1 acetabular fracture), and good or excellent for 44 cases (88%). CLINICAL SIGNIFICANCE: There were not any cases of postoperative coxofemoral luxation observed in this series of 50 dogs with dual mobility hip prosthesis. Studies with more patients and longer follow-up are needed to confirm the satisfactory results observed to date with this implant. PMID- 22836140 TI - [Ultrasound-guided perineural catheters]. PMID- 22836139 TI - Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation. AB - PURPOSE: To evaluate whether extracorporeal carbon dioxide removal by means of a pumpless extracorporeal lung-assist (PECLA) device could be an effective and safe alternative to invasive mechanical ventilation in patients with chronic pulmonary disease and acute hypercapnic ventilatory failure not responding to noninvasive ventilation (NIV). METHODS: In this multicentre, retrospective study, 21 PECLA patients were compared with respect to survival and procedural outcomes to 21 matched controls with conventional invasive mechanical ventilation. Matching criteria were underlying diagnosis, age, Simplified Acute Physiology Score II and pH at ICU admission. RESULTS: Of the 21 patients treated with PECLA, 19 (90 %) did not require intubation. Median PaCO(2) levels and pH in arterial blood prior to PECLA were 84.0 mmHg (54.2-131.0) and 7.28 (7.10-7.41), respectively. Within 24 h, median PaCO(2) levels and pH had significantly improved to 52.1 (33.0-70.1; p < 0.001) and 7.44 (7.27-7.56; p < 0.001), respectively. Two major and seven minor bleeding complications related to the device occurred. Further complications were one pseudoaneurysm and one heparin-induced thrombocytopenia type 2. Compared to the matched control group, there was a trend toward a shorter hospital length of stay in the PECLA group (adjusted p = 0.056). There was no group difference in the 28-day (24 % vs. 19 %, adjusted p = 0.845) or 6-month mortality (33 % vs. 33 %). CONCLUSIONS: In this study the use of extracorporeal carbon dioxide removal allowed avoiding intubation and invasive mechanical ventilation in the majority of patients with acute on chronic respiratory failure not responding to NIV. Compared to conventional invasive ventilation, short- and long-term survivals were similar. PMID- 22836141 TI - [Ultrasound-guided infraclavicular block]. PMID- 22836142 TI - [Keeping a blog: a new tool during the initial training for anaesthesia residents!]. PMID- 22836143 TI - Antenatal insults modify newborn olfactory function by nitric oxide produced from neuronal nitric oxide synthase. AB - Newborn feeding, maternal, bonding, growth and wellbeing depend upon intact odor recognition in the early postnatal period. Antenatal stress may affect postnatal odor recognition. We investigated the exact role of a neurotransmitter, nitric oxide (NO), in newborn olfactory function. We hypothesized that olfactory neuron activity depended on NO generated by neuronal NO synthase (NOS). Utilizing in vivo functional manganese enhanced MRI (MEMRI) in a rabbit model of cerebral palsy we had shown previously that in utero hypoxia-ischemia (H-I) at E22 (70% gestation) resulted in impaired postnatal response to odorants and poor feeding. With the same antenatal insult, we manipulated NO levels in the olfactory neuron in postnatal day 1 (P1) kits by administration of intranasal NO donors or a highly selective nNOS inhibitor. Olfactory function was quantitatively measured by the response to amyl acetate stimulation by MEMRI. The relevance of nNOS to normal olfactory development was confirmed by the increase of nNOS gene expression from fetal ages to P1 in olfactory epithelium and bulbs. In control kits, nNOS inhibition decreased NO production in the olfactory system and increased MEMRI slope enhancement. In H-I kits the MEMRI slope did not increase, implicating modification of endogenous NO-mediated olfactory function by the antenatal insult. NO donors as a source of exogenous NO did not significantly change function in either group. In conclusion, olfactory epithelium nNOS in newborn rabbits probably modulates olfactory signal transduction. Antenatal H-I injury remote from delivery may affect early functional development of the olfactory system by decreasing NO-dependent signal transduction. PMID- 22836144 TI - Rolipram promotes remyelination possibly via MEK-ERK signal pathway in cuprizone induced demyelination mouse. AB - OBJECTIVE: Rolipram, a 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase 4 (PDE4) inhibitor, has long been studied for its immune modulating effects in the treatment of experimental autoimmune encephalomyelitis (EAE). In the current study, we investigated the effects of rolipram on remyelination after cuprizone- or lysolecithin-induced demyelination and the signal transduction pathways potentially modulating this response. MATERIALS AND METHODS: Cuprizone-induced demyelination in mice and lysolecithin (LPC)-induced demyelination in rat cerebellum slice culture were treated with rolipram. Demyelination was evaluated by Luxol fast blue (LFB) or myelin basic protein (MBP) staining and western blot. Oligodendroglial cells were cultured with different concentrations of rolipram, and 2', 3'-cyclic nucleotide phosphodiesterase (CNPase) activity, MBP expression, and extracellular signal regulated kinase (ERK) phosphorylation were measured. RESULTS: Rolipram antagonized lysolecithin (LPC)-induced demyelination in rat cerebellar slice cultures and cuprizone-fed mice. In vitro, rolipram treatment promoted oligodendrocyte precursor cell (OPC) maturation, an effect that was partially blocked by the inhibitors of the mitogen activated protein kinase kinase (MEK). CONCLUSION: Rolipram promotes the maturation of OPCs, facilitates remyelination, and increases ERK phosphorylation. All of these actions are involved in an action against cuprizone-induced demyelination that may occur partly via the MEK-ERK pathway. Importantly, this may have therapeutic implications for MS. PMID- 22836145 TI - In vivo imaging: a dynamic imaging approach to study spinal cord regeneration. AB - Upon spinal cord injury, severed axons and the surrounding tissue undergo a series of pathological changes, including retraction of proximal axon ends, degeneration of distal axon ends and formation of a dense fibrotic scar that inhibits regenerative axonal growth. Until recently it was technically challenging to study these dynamic events in the mammalian central nervous system. Here, we describe and discuss the recently established genetic tract tracing approach of in vivo imaging. This technique allows studying acute pathological events following a spinal cord lesion. In addition, the novel development of chronic spinal cord preparations such as the implanted spinal chamber now also enables long-term imaging studies. Hence, in vivo imaging allows the direct observation of acute and chronic dynamic degenerative and regenerative events of individual neurons after traumatic injury in the living animal. PMID- 22836146 TI - Low nigrostriatal reserve for motor parkinsonism in nonhuman primates. AB - OBJECTIVE: Nigrostriatal reserve refers to the threshold of neuronal injury to dopaminergic cell bodies and their terminal fields required to produce parkinsonian motor deficits. Inferential studies have estimated striatal dopamine reserve to be at least 70%. Knowledge of this threshold is critical for planning interventions to prevent symptom onset or reverse nigrostriatal injury sufficient to restore function in people with Parkinson disease. In this study, we determine the nigrostriatal reserve in a non-human primate model that mimics the motor manifestations of Parkinson disease. METHODS: Fifteen macaque monkeys received unilateral randomized doses of the selective dopaminergic neuronal toxin 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine. We compared blinded validated ratings of parkinsonism to in vitro measures of striatal dopamine and unbiased stereologic counts of nigral neurons after tyrosine hydroxylase immunostaining. RESULTS: The percent of residual cell counts in lesioned nigra correlated linearly with the parkinsonism score at 2 months (r=-0.87, p<0.0001). The parkinsonism score at 2 months correlated linearly with the percent residual striatal dopamine (r=-0.77, p=0.016) followed by a flooring effect once nigral cell loss exceeded 50%. A reduction of about 14 to 23% of nigral neuron counts or 14% to 37% of striatal dopamine was sufficient to induce mild parkinsonism. CONCLUSIONS: The nigral cell body and terminal field injury needed to produce parkinsonian motor manifestations may be much less than previously thought. PMID- 22836148 TI - TNF-alpha-mediated anxiety in a mouse model of multiple sclerosis. AB - Multiple sclerosis (MS) causes a variety of motor and sensory deficits and it is also associated with mood disturbances. It is unclear if anxiety and depression in MS entirely reflect a subjective reaction to a chronic disease causing motor disability or rather depend on specific effects of neuroinflammation in neuronal circuits. To answer this question, behavioral, electrophysiological, and immunofluorescence experiments were performed in mice with experimental autoimmune encephalomyelitis (EAE), which models MS in mice. First, we observed high anxiety indexes in EAE mice, preceding the appearance of motor defects. Then, we demonstrated that tumor necrosis factor alpha (TNF-alpha) has a crucial role in anxiety associated with neuroinflammation. In fact, intracerebroventricular (icv) administration of etanercept, an inhibitor of TNF alpha signaling, resulted in anxiolytic-like effects in EAE-mice. Accordingly, icv injection of TNF-alpha induced per se overt anxious behavior in control mice. Moreover, we propose the striatum as one of the brain regions potentially involved in EAE anxious behavior. We observed that before disease onset EAE striatum presents elevated TNF-alpha levels and strong activated microglia, early signs of inflammation associated with alterations of striatal excitatory postsynaptic currents (EPSCs). Interestingly, etanercept corrected the synaptic defects of pre-symptomatic EAE mice while icv injection of TNF-alpha in non-EAE mice altered EPSCs, thus mimicking the synaptic effects of EAE. In conclusion, anxiety characterizes EAE course since the very early phases of the disease. TNF alpha released from activated microglia mediates this effect likely through the modulation of striatal excitatory synaptic transmission. PMID- 22836149 TI - Prevention of infective endocarditis in developing countries. PMID- 22836150 TI - First annual congress of the Faculty of Consulting Physicians of South Africa, 18 20 May 2012. PMID- 22836147 TI - Scar-mediated inhibition and CSPG receptors in the CNS. AB - Severed axons in adult mammals do not regenerate appreciably after central nervous system (CNS) injury due to developmentally determined reductions in neuron-intrinsic growth capacity and extracellular environment for axon elongation. Chondroitin sulfate proteoglycans (CSPGs), which are generated by reactive scar tissues, are particularly potent contributors to the growth limiting environment in mature CNS. Thus, surmounting the strong inhibition by CSPG-rich scar is an important therapeutic goal for achieving functional recovery after CNS injuries. As of now, the main in vivo approach to overcoming inhibition by CSPGs is enzymatic digestion with locally applied chondroitinase ABC (ChABC), but several disadvantages may prevent using this bacterial enzyme as a therapeutic option for patients. A better understanding of the molecular mechanisms underlying CSPG action is needed in order to develop more effective therapies to overcome CSPG-mediated inhibition of axon regeneration and/or sprouting. Because of their large size and dense negative charges, CSPGs were thought to act by non-specifically hindering the binding of matrix molecules to their cell surface receptors through steric interactions. Although this may be true, recent studies indicate that two members of the leukocyte common antigen related (LAR) phosphatase subfamily, protein tyrosine phosphatase sigma (PTPsigma) and LAR, are functional receptors that bind CSPGs with high affinity and mediate CSPG inhibitory effects. CSPGs also may act by binding to two receptors for myelin-associated growth inhibitors, Nogo receptors 1 and 3 (NgR1 and NgR3). If confirmed, it would suggest that CSPGs have multiple mechanisms by which they inhibit axon growth, making them especially potent and difficult therapeutic targets. Identification of CSPG receptors is not only important for understanding the scar-mediated growth suppression, but also for developing novel and selective therapies to promote axon sprouting and/or regeneration after CNS injuries, including spinal cord injury (SCI). PMID- 22836152 TI - Hermansky-Pudlak/Chediak-Higashi syndromes. PMID- 22836151 TI - Prevalence of cardiovascular risk factors in an urban area of Togo: a WHO STEPS wise approach in Lome, Togo. AB - OBJECTIVE: To determine the prevalence of hypertension and other cardiovascular risk factors in the general adult population of Lome. METHODS: A cross-sectional household survey was conducted in Lome from October 2009 to January 2010, which focused on hypertension and other cardiovascular risk factors in 2 000 subjects 18 years and older. The World Health Organisation's STEPS-wise approach on non communicable diseases was used. During the first session, blood pressure (BP) was measured on three successive occasions, one minute apart, and the mean was recorded. A second measurement session was done three weeks later in patients with BP >= 140/90 mmHg during the first session. Hypertension was defined as BP > 140/90 mmHg after the second session, or on antihypertensive treatment. The other risk factors were studied by clinical and blood analysis. RESULTS: We found 532 hypertensive patients out of a total of 2 000 subjects. The prevalence of hypertension was 26.6%. The mean age of hypertensive patients was 45 +/- 10 years, ranging from 18 to 98 years. The prevalence of other cardiovascular risk factors was: stress (43%), sedentary lifestyle (41%), hypercholesterolaemia (26%), obesity (25.2%), hypertriglyceridaemia (21%), smoking (9.3%), alcohol use (11%) and diabetes (7.3%). CONCLUSIONS: The prevalence of hypertension and other cardiovascular risk factors in the population of Lome is high. These findings should draw the attention of authorities to define a national policy to combat hypertension and other cardiovascular risk factors. PMID- 22836153 TI - Association between plasma homocysteine and myocardial SPECT abnormalities in patients referred for suspected myocardial ischaemia. AB - BACKGROUND: Elevated plasma homocysteine level has emerged as a relatively newly recognised risk factor for coronary artery disease (CAD). However, reduction of plasma homocysteine levels in large prospective studies did not appear to reduce the risk for subsequent cardiac events. In this study, we investigated the association between plasma homocysteine levels and quantitative indices of myocardial perfusion SPECT imaging in patients referred for myocardial ischaemia. METHODS: Quantitative myocardial perfusion SPECT indices were obtained for 120 patients who were recruited for the study. All patients underwent a two-day rest stress myocardial perfusion imaging. Plasma venous sampling was done on all patients after an overnight fast. Of the 120 participants (mean age 56 years, 53% males), 33% had elevated plasma homocysteine levels. The plasma homocysteine level was then compared to the results of imaging and other known risk factors. RESULTS: After adjustment for traditional risk factors of coronary artery disease, patients with elevated homocysteine levels had a significantly higher mean summed stress score (SSS) (11.3 vs 6.9, p = 0.02) than patients with a normal homocysteine level. This was true for both single- and multivessel disease. Also, patients with elevated homocysteine levels had a higher stress end systolic volume (SESV) (137 vs 105 ml, p = 0.03) and lower post-stress left ventricular ejection fraction (SEF) (54 vs 64%, p = 0.02). The patients with elevated plasma homocysteine levels also had a significantly lower mean body mass index (BMI) (26.6 vs 30.6 kg/m(2), p = 0.002). There was a significant relationship between the total number of known risk factors in a patient with CAD and the proportion of patients presenting with elevated plasma homocysteine levels (p = 0.03). Also, the extent of infarct, as measured by the summed rest score (SRS), was more closely correlated with an elevated homocysteine level than with the degree of ischaemia. CONCLUSION: There was a correlation between plasma homocysteine level and the presence and extent of myocardial perfusion abnormalities in patients with established coronary artery disease, in particular those with multiple risk factors and multi-vessel infarction. PMID- 22836154 TI - A prospective review of acute coronary syndromes in an urban hospital in sub Saharan Africa. AB - OBJECTIVES: To determine the epidemiology of acute coronary syndromes (ACS) in sub-Saharan Africa. METHODS: A prospective survey was carried out of all patients with a diagnosis of ACS who were admitted to the critical care unit of a tertiary teaching hospital over a 25-month period. Demographics, presentation, management and outcomes were subsequently recorded. RESULTS: A total of 111 (5.1% of all hospitalisations) patients were recruited, with 56% presenting with ST-elevation myocardial infarction (STEMI) and the rest non-ST-elevation myocardial infarction (NSTEMI) or unstable angina (UA). Chest pain was the most common presenting symptom, and up to one-third of all STEMI patients did not receive any form of reperfusion therapy, primarily due to late presentation. As in the developed world, diabetes, hypertension and cigarette smoking still account for the most common predisposing risk-factor profile, and the mortality associated with ACS is about six to 10% in our unit. CONCLUSIONS: ACS, contrary to common belief, is increasingly more prevalent in sub-Saharan Africa, with similar risk profiles to that in the developed world. Late presentation to hospital is common and accounts for the increased mortality associated with this condition. PMID- 22836155 TI - Assessment of serum leptin, pregnancy-associated plasma protein A and CRP levels as indicators of plaque vulnerability in patients with acute coronary syndrome. AB - INTRODUCTION: A multifactorial aetiology of coronary artery disease (CAD) has been established in the recent past. Extensive research is now underway to understand the mechanisms responsible for plaque vulnerability. The identification of a novel biomarker that will help in the assessment of plaque status is urgently needed for the purpose of patient stratification and prognostication. The aim of the present study was to evaluate leptin, pregnancy associated plasma protein A (PAPP-A) and C-reactive protein (CRP) levels in patients with acute coronary syndrome and to assess their diagnostic efficacy in the identification of vulnerable plaques. METHODS: The study group comprised 105 patients who had chest pain along with ECG changes (ST elevation, ST depression, T inversion) and raised cardiac enzyme levels. Sixty-two patients with chest pain and ECG changes but with normal cardiac enzyme profiles were included in the control group. Lipid profiles, and leptin, PAPP-A and CRP levels were assessed in these two groups. Receiver operating characteristics (ROC) curves were plotted to determine the utility of the parameters under study as markers of plaque vulnerability. RESULTS: Significantly higher levels of serum lipoprotein (a), leptin, PAPP-A and high-sensitivity CRP (hs-CRP) were observed in the cases than in the controls. A positive correlation was observed between CRP and PAPP-A levels as well as CRP and leptin concentrations. ROC curve analysis revealed similar efficacies of CRP and PAPP-A levels in their ability to detect unstable plaques with areas under the curve of 0.762 and 0.732, respectively. Multivariate analysis established the superiority of hs-CRP as a predictor of plaque instability. CONCLUSIONS: Our study highlights the utility of both CRP and PAPP-A levels as determinants of plaque instability. Our findings necessitate population based follow-up studies to establish the superiority of either of the two biomarkers in the field of preventive cardiology. PMID- 22836156 TI - Oral health of patients with severe rheumatic heart disease. AB - In order to determine whether adequate attention is paid to the maintenance of good oral health in patients at risk of developing infective endocarditis, we studied 44 black patients with severe rheumatic heart disease before they had cardiac surgery. Plaque and gingival index scores were calculated and panoramic radiographs were done in all patients. There were 17 males and 27 females (mean age: 30.6 years). The plaque and gingival index scores were classified as poor in 31.8 and 54.6% of patients, respectively. Panoramic radiographic findings included caries in 56.8% of patients, peri-apical pathology in 18.1% and retained roots in 22.7% of patients. This study demonstrates that inadequate attention is paid to the maintenance of good oral health in patients with severe rheumatic heart disease. The oral and dental care of patients at risk of developing infective endocarditis needs to be improved. PMID- 22836157 TI - An investigation of the frequency of bacteraemia following dental extraction, tooth brushing and chewing. AB - We conducted a study to determine the frequency of bacteraemias following dental extraction and common oral procedures, namely tooth brushing and chewing, and the relationship between bacteraemia and oral health in black patients. Positive blood cultures were detected in 29.6% of patients after dental extraction, in 10.8% of patients after tooth brushing and in no patients after chewing. No relationship between the state of oral health, which was assessed using the plaque and gingival indices, and the incidence of bacteraemia was found. The duration of bacteraemia was less than 15 minutes. One patient had a positive blood culture prior to dental extraction; his oral health status was poor. Our study confirmed that bacteraemia occurs after tooth brushing. PMID- 22836158 TI - Focus on omega-3 PUFAs in heart failure. PMID- 22836159 TI - Thrombotic complications associated with atrial fibrillation in three dogs. AB - Atrial fibrillation (AF) is the most common chronic pathologic arrhythmia in dogs, and whereas thromboembolism is a common complication of AF in humans, this complication has not been previously reported in dogs. This report describes thrombotic complications associated with AF in three dogs. A spherical left atrial mass consistent with a thrombus was identified in two dogs during echocardiographic examination. A third dog experienced arterial thromboembolism confirmed with ultrasound and postmortem examination. These cases provide a unique antemortem description of intra-atrial thrombus formation and cardioembolic disease associated with AF in dogs, and raise awareness of the importance of thorough echocardiographic evaluation of the atria for thrombus prior to pharmacologic cardioversion or direct current cardioversion. PMID- 22836160 TI - Radioembolisation with (90)Y-labelled resin microspheres in the treatment of liver metastasis from breast cancer. AB - OBJECTIVES: Metastatic breast cancer is a heterogeneous disease, commonly affecting the liver. We report our experience with (90)Y radioembolisation (RE) and its effects on the survival of patients with treatment-refractory breast cancer liver metastases. METHODS: A total of 77 female patients affected by breast cancer were accepted into our department for RE. Inclusion criteria were inoperable and chemotherapy-refractory hepatic metastases, acceptable performance status, sufficient residual liver, no significant hepato-pulmonary shunts. Patients were divided in two groups: group 1 (29 patients) included those with Eastern Cooperative Oncology Group (ECOG) score 0, liver involvement (0-25 %) and no extrahepatic disease (EHD); group 2 (23 patient) included patients with ECOG score 1-2, liver involvement (26-50 %) and evidence of EHD. RESULTS: A total of 25 patients were considered ineligible. The median age of the remaining 52 patients was 57.5 years. The median overall survival was 11.5 months and better in those whose performance status and liver function were preserved (14.3 versus 8.2 months). According to Response Evaluation Criteria in Solid Tumor (RECIST), partial response (PR) was achieved in 29 patients (56 %), stable disease (SD) was achieved in a further 18 patients (35 %) and 5 patients showed progressive disease (PD) (10 %). DISCUSSION: (90)Y RE is effective in the treatment of liver metastases from breast cancer. We demonstrated a relevant survival and encouragingly high response rate in patients with treatment-refractory disease. PMID- 22836161 TI - Separation of advanced from mild hepatic fibrosis by quantification of the hepatobiliary uptake of Gd-EOB-DTPA. AB - OBJECTIVES: To apply dynamic contrast-enhanced (DCE) MRI on patients presenting with elevated liver enzymes without clinical signs of hepatic decompensation in order to quantitatively compare the hepatocyte-specific uptake of Gd-EOB-DTPA with histopathological fibrosis stage. METHODS: A total of 38 patients were prospectively examined using 1.5-T MRI. Data were acquired from regions of interest in the liver and spleen by using time series of single-breath-hold symmetrically sampled two-point Dixon 3D images (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB DTPA (0.025 mmol/kg). The signal intensity (SI) values were reconstructed using a phase-sensitive technique and normalised using multiscale adaptive normalising averaging (MANA). Liver-to-spleen contrast ratios (LSC_N) and the contrast uptake rate (K (Hep)) were calculated. Liver biopsy was performed and classified according to the Batts and Ludwig system. RESULTS: Area under the receiver operating characteristic curve (AUROC) values of 0.71, 0.80 and 0.78, respectively, were found for K (Hep), LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for K (Hep) (borderline), LSC_N10 and LSC_N20. CONCLUSIONS: Liver fibrosis stage strongly influences the hepatocyte-specific uptake of Gd-EOB-DTPA. Potentially the normalisation technique and K (Hep) will reduce patient and system bias, yielding a robust approach to non-invasive liver function determination. PMID- 22836162 TI - Quantification of intracranial internal carotid artery calcification on brain unenhanced CT: evaluation of its feasibility and assessment of the reliability of visual grading scales. AB - OBJECTIVES: Previous studies have evaluated intracranial internal carotid artery calcifications (ICACs) qualitatively using different visual grading scales, which could lead to inconsistent results. The purpose of this study was to evaluate the feasibility of ICAC volume measurement and to correlate the volume with visual grading scales. METHODS: We included 49 patients (>50 years) who underwent unenhanced cranial CT. Two observers evaluated four visual grading scales and measured ICAC volumes semi-automatically, and interobserver agreements were assessed. Differences in ICAC volume between visual grades of each scale were tested. The relationship between the visual grading and volume was assessed. RESULTS: Interobserver agreements ranged from 0.841 to 0.901 for visual grading and 0.997 for volume measurement. Mean volumes were not significantly different between the visual grades (P > 0.05) except when comparing grade 4 with the other grades. The grades of each visual grading correlated well with ICAC volumes (Spearman's rho = 0.849-0.881, P < 0.001). The relationship between the visual grades and volume was described by a quadratic model (R (2), 0.31-0.50, P < 0.01). CONCLUSIONS: ICAC volume measurement is feasible and reproducible, whereas visual grades poorly reflect the actual volume; therefore, volume measurement may be warranted for future research. PMID- 22836163 TI - Comprehensive phenotyping of salt-induced hypertensive heart disease in living mice using cardiac magnetic resonance. AB - OBJECTIVES: To characterise the effects of high-salt diet (HSD) on left ventricular (LV) mass, systolic function and coronary reserve in living mice using cardiac magnetic resonance imaging (MRI). METHODS: Thirty C57BL/6 1-month old female mice were fed either a control (n = 15) or an HSD (n = 15). After 3 months, LV volumes, ejection fraction and mass were assessed using time-resolved three-dimensional (3D) black-blood manganese-enhanced MRI, and coronary flow velocity reserve (CFVR) was assessed using dynamic MR angiography at rest and during adenosine-induced hyperaemia. Hearts were excised to assess LV wet mass and micro-vascular remodelling at histology. RESULTS: Micro-vascular remodelling was found at histology in all investigated hearts from the HSD group and none from the control group. No difference between the HSD and control groups was found in terms of heart weight, LV volumes and ejection fraction. Heart to body weight ratio was higher in the HSD group (4.39 +/- 0.24 vs 4.02 +/- 0.16 mg/g, P < 0.001), because of lower body weight (22.3 +/- 0.9 vs 24.0 +/- 1.4 g, P < 0.001). CFVR was lower in the HSD group (1.73 +/- 0.11 vs 1.94 +/- 0.12, P < 0.001). CONCLUSIONS: Phenotyping of hypertensive heart disease is feasible in living mice using dynamic MR angiography and time-resolved 3D black-blood manganese-enhanced MRI. HSD is associated with early impairment of coronary reserve, before the onset of significant hypertrophy. PMID- 22836164 TI - Normal and premature rupture of fetal membranes at term delivery differ in regional chemotactic activity and related chemokine/cytokine production. AB - A gradient of immunological mediators exists in the fetal membranes from the periplacental zone (PZ) to the rupture zone (RZ) at term delivery (rupture of fetal membranes [ROM]). However, it is unknown if this gradient is different in premature rupture of these tissues (premature rupture of fetal membranes [PROM]). We therefore analyzed leukocyte chemotactic activity and chemokine/cytokine production in fetal membrane zones in ROM and PROM. In ROM, leukocyte chemotactic activity increased from the PZ to the RZ; however, this did not occur in PROM. This was due to consistently elevated leukocyte chemotactic activity in PROM compared to ROM tissues. In the RZ, ROM was characterized by increased T-cell attraction and high levels of chemokine (C-X-C motif) ligand 8 (CXCL 8)/interleukin 8, and PROM by increased granulocyte attraction and high levels of granulocyte-macrophage colony-stimulating factor and CXCL-10/interferon gamma induced protein 10. We conclude that normal and premature rupture of fetal membranes differ in regional chemotactic activity and related chemokine/cytokine production, which may represent evidence for differential mechanisms of rupture at term delivery. PMID- 22836165 TI - High efficiency co-sensitized solar cell based on luminescent lanthanide complexes with pyridine-2,6-dicarboxylic acid ligands. AB - Two lanthanide complexes, Ln(HPDA)(3).4EtOH (Ln = Tb, Dy) (H(2)PDA = pyridine-2,6 dicarboxylic acid, EtOH = ethanol), have been successfully synthesized using hydrothermal or solvothermal methods, and their crystal structures were analyzed by single crystal XRD. Both crystals have orthorhombic symmetry with space group Pbcn, exhibiting three-dimensional (3D) supramolecular architecture through hydrogen bonding interactions. The metal center was coordinated to nine atoms by three pyridine-2,6-dicarboxylic acid ligands. The nine-coordinated lanthanide metal complexes were assembled onto a nanocrystalline TiO(2) film to form co sensitized photoelectrodes with N719 for dye-sensitized solar cells, and their photoelectrochemical performance was studied. In the tandem structure of composite electrodes, the energy levels of lanthanide metal complexes are reorganized in their single-crystal form, as verified by ab initio calculations. The co-sensitized systems are far superior for electron-injection and hole recovery compared with single N719-sensitized systems. Luminescence properties were measured and electrochemical analysis was also performed on these complexes. PMID- 22836168 TI - Correlation between coordinated water content and proton conductivity in Ca-BTC based metal-organic frameworks. AB - Proton conductivity of five Ca-based MOFs which depends on the amount of water molecules coordinated to the Ca-centres has been reported. These MOFs show high temperature proton conductivity due to the strong hydrogen bonding between the lattice and coordinated water molecules. PMID- 22836166 TI - Mass spectrometric identification of proteins that interact through specific domains of the poly(A) binding protein. AB - Poly(A) binding protein (PAB1) is involved in a number of RNA metabolic functions in eukaryotic cells and correspondingly is suggested to associate with a number of proteins. We have used mass spectrometric analysis to identify 55 non ribosomal proteins that specifically interact with PAB1 from Saccharomyces cerevisiae. Because many of these factors may associate only indirectly with PAB1 by being components of the PAB1-mRNP structure, we additionally conducted mass spectrometric analyses on seven metabolically defined PAB1 deletion derivatives to delimit the interactions between these proteins and PAB1. These latter analyses identified 13 proteins whose associations with PAB1 were reduced by deleting one or another of PAB1's defined domains. Included in this list of 13 proteins were the translation initiation factors eIF4G1 and eIF4G2, translation termination factor eRF3, and PBP2, all of whose previously known direct interactions with specific PAB1 domains were either confirmed, delimited, or extended. The remaining nine proteins that interacted through a specific PAB1 domain were CBF5, SLF1, UPF1, CBC1, SSD1, NOP77, yGR250c, NAB6, and GBP2. In further study, UPF1, involved in nonsense-mediated decay, was confirmed to interact with PAB1 through the RRM1 domain. We additionally established that while the RRM1 domain of PAB1 was required for UPF1-induced acceleration of deadenylation during nonsense-mediated decay, it was not required for the more critical step of acceleration of mRNA decapping. These results begin to identify the proteins most likely to interact with PAB1 and the domains of PAB1 through which these contacts are made. PMID- 22836167 TI - Transcriptional network analysis of the tryptophan-accumulating rice mutant during grain filling. AB - In a previous study, we selected a high tryptophan (Trp)-accumulating rice (Oryza sativa L.) mutant line by in vitro mutagenesis using gamma rays. To obtain detailed information about the Trp biosynthetic pathway during the grain-filling in rice, we investigated the gene expression profiles in the wild-type (cv. Dongan) and the high-level Trp-accumulating mutant line (MRVII-33) at five different grain-filling stages using microarray analysis. The mutant line showed approximately 6.3-fold higher Trp content and 2.3-fold higher amino acids compared with the original cultivar at the final stage (stage V). The intensity of gene expression was analyzed and compared between the wild-type and mutant line at each of the five grain-filling stages using the Rice 4 * 44K oligo DNA microarray. Among the five stages, stage III showed the highest gene expression changes for both up- and down-regulated genes. Among the Trp biosynthesis-related genes, trpG showed high expression in the mutant line during stages I to IV and trpE showed higher at stage III. Gene clustering was performed based on the genes of KEGG's amino acid metabolism, and a total of 276 genes related to amino acid metabolism were placed into three clusters. The functional annotation enrichment analysis of the genes classified into the three clusters was also conducted using ClueGO. It was found that cluster 3 uniquely included biological processes related to aromatic amino acid metabolism. These results suggest that gene analysis based on microarray data is useful for elucidating the biological mechanisms of Trp accumulation in high Trp-accumulating mutants at each of the grain-filling stages. PMID- 22836169 TI - Pregnancy exposure to atmospheric pollutants and placental weight: an approach relying on a dispersion model. AB - BACKGROUND: Epidemiologic studies suggest an association between air pollution exposure and foetal growth. The possible underlying biological mechanisms have little been studied in humans, but animal studies suggest an impact of atmospheric pollutants on placental function. OBJECTIVES: Our aim was to investigate the association between exposure to atmospheric pollutants' levels during pregnancy and placental weight, birth weight and the placental to foetal weights ratio (PFR). For comparison purposes, the effects of active smoking on the same measures at birth have also been estimated. METHODS: The study relies on women from Eden mother-child cohort recruited in the middle-sized cities of Poitiers and Nancy (France). Nitrogen dioxide (NO(2)) and particulate matter with diameter <10 MUm (PM10) home address levels during pregnancy were assessed using ADMS-Urban dispersion model. We characterized associations of NO(2), PM10 levels and active smoking with placental, birth weights and PFR by distinct linear regression models. RESULTS: Air pollution levels were higher and had greater variability in Nancy (5th-95th centiles, 19.9-27.9 MUg/m(3) for PM10) than in Poitiers (5th-95th centiles, 14.3-17.8 MUg/m(3)). Associations differed by study area: in Nancy (355 births), air pollution levels were associated with decreased placental weight and PFR, while in Poitiers (446 births), opposite or null associations were observed. Cigarette smoking was not associated with placental weight while it was associated with a decrease in birth weight and an increase in PFR. CONCLUSION: Results regarding air pollution estimated effects were not similar in both study areas and should therefore be taken with caution. The placental weight decrease observed with air pollutants in the more polluted area of Nancy is consistent with a recent epidemiological study. In this area, maternal active smoking and PM10 levels tended to have opposite effects on the PFR, suggesting different mechanisms of action of both pollutants on foetal growth. PMID- 22836170 TI - Cooling off health security hot spots: getting on top of it down under. AB - Australia is free of many diseases, pests and weeds found elsewhere in the world due to its geographical isolation and relatively good health security practices. However, its health security is under increasing pressure due to a number of ecological, climatic, demographic and behavioural changes occurring globally. North Queensland is a high risk area (a health security hot spot) for Australia, due in part to its connection to neighbouring countries via the Torres Strait and the Indo-Papuan conduit, its high diversity of wildlife reservoirs and its environmental characteristics. Major outbreaks of exotic diseases, pests and weeds in Australia can cost in excess of $1 billion; however, most expenditure on health security is reactive apart from preventive measures undertaken for a few high profile diseases, pests and weeds. Large gains in health security could therefore be made by spending more on pre-emptive approaches to reduce the risk of outbreaks, invasion/spread and establishment, despite these gains being difficult to quantify. Although biosecurity threats may initially have regional impacts (e.g. Hendra virus), a break down in security in health security hot spots can have national and international consequences, as has been seen recently in other regions with the emergence of SARS and pandemic avian influenza. Novel approaches should be driven by building research and management capacity, particularly in the regions where threats arise, a model that is applicable both in Australia and in other regions of the world that value and therefore aim to improve their strategies for maintaining health security. PMID- 22836172 TI - EEG-assisted retrospective motion correction for fMRI: E-REMCOR. AB - We propose a method for retrospective motion correction of fMRI data in simultaneous EEG-fMRI that employs the EEG array as a sensitive motion detector. EEG motion artifacts are used to generate motion regressors describing rotational head movements with millisecond temporal resolution. These regressors are utilized for slice-specific motion correction of unprocessed fMRI data. Performance of the method is demonstrated by correction of fMRI data from five patients with major depressive disorder, who exhibited head movements by 1-3mm during a resting EEG-fMRI run. The fMRI datasets, corrected using eight to ten EEG-based motion regressors, show significant improvements in temporal SNR (TSNR) of fMRI time series, particularly in the frontal brain regions and near the surface of the brain. The TSNR improvements are as high as 50% for large brain areas in single-subject analysis and as high as 25% when the results are averaged across the subjects. Simultaneous application of the EEG-based motion correction and physiological noise correction by means of RETROICOR leads to average TSNR enhancements as high as 35% for extended brain regions. These TSNR improvements are largely preserved after the subsequent fMRI volume registration and regression of fMRI motion parameters. The proposed EEG-assisted method of retrospective fMRI motion correction (referred to as E-REMCOR) can be applied to improve quality of fMRI data with severe motion artifacts and to reduce spurious correlations between the EEG and fMRI data caused by head movements. It does not require any specialized equipment beyond the standard EEG-fMRI instrumentation and can be applied retrospectively to any existing EEG-fMRI data set. PMID- 22836173 TI - Enhanced functional networks in absolute pitch. AB - Functional networks in the human brain give rise to complex cognitive and perceptual abilities. While the decrease of functional connectivity is linked to neurological and psychiatric disorders, less is known about the consequences of increased functional connectivity. One population that has exceptionally enhanced perceptual abilities is people with absolute pitch (AP) - an ability to categorize tones into pitch classes without reference. AP has been linked to exceptional talent as well as to psychiatric and neurological conditions. Here we show that AP possessors have increased functional activation during music listening, as well as increased degrees, clustering, and local efficiency of functional correlations, with the difference being highest around the left superior temporal gyrus. Our results provide the first evidence that increased functional connectivity in a small-world brain network is related to exceptional perceptual abilities in a healthy population. PMID- 22836175 TI - Investigation of the spatial correlation in human white matter and the influence of age using 3-dimensional variography applied to MP-RAGE data. AB - A novel method for the quantification of heterogeneity and spatial correlation in 3D MP-RAGE images of white matter is presented. The technique is based on the variogram, a tool commonly used in geosciences for the analysis of spatial data, and was tailored to the special requirements of MR image analysis. Influences from intensity non-uniformities, noise and arbitrary greyscale were quantified and considered in the calculations. The obtained variograms were fitted with spherical model functions to infer parameters that quantify heterogeneity and size of the correlation structures of the tissue. Numerically generated samples with well-defined correlation properties were employed to validate the estimation process and to provide an interpretation of the parameters obtained. It is shown that the method gives reliable results in an interval of correlation structures sized between 2mm and 20mm. The method was applied to 24 MP-RAGE datasets of healthy female volunteers ranging in age from 19 to 73 years. White matter was found to have two prominent correlation structures with sizes of approximately 3mm and 23 mm. The heterogeneity of the smaller structure increases significantly with age (r=0.83, p<10(-6)). PMID- 22836174 TI - Quantitative mouse brain phenotyping based on single and multispectral MR protocols. AB - Sophisticated image analysis methods have been developed for the human brain, but such tools still need to be adapted and optimized for quantitative small animal imaging. We propose a framework for quantitative anatomical phenotyping in mouse models of neurological and psychiatric conditions. The framework encompasses an atlas space, image acquisition protocols, and software tools to register images into this space. We show that a suite of segmentation tools (Avants, Epstein et al., 2008) designed for human neuroimaging can be incorporated into a pipeline for segmenting mouse brain images acquired with multispectral magnetic resonance imaging (MR) protocols. We present a flexible approach for segmenting such hyperimages, optimizing registration, and identifying optimal combinations of image channels for particular structures. Brain imaging with T1, T2* and T2 contrasts yielded accuracy in the range of 83% for hippocampus and caudate putamen (Hc and CPu), but only 54% in white matter tracts, and 44% for the ventricles. The addition of diffusion tensor parameter images improved accuracy for large gray matter structures (by >5%), white matter (10%), and ventricles (15%). The use of Markov random field segmentation further improved overall accuracy in the C57BL/6 strain by 6%; so Dice coefficients for Hc and CPu reached 93%, for white matter 79%, for ventricles 68%, and for substantia nigra 80%. We demonstrate the segmentation pipeline for the widely used C57BL/6 strain, and two test strains (BXD29, APP/TTA). This approach appears promising for characterizing temporal changes in mouse models of human neurological and psychiatric conditions, and may provide anatomical constraints for other preclinical imaging, e.g. fMRI and molecular imaging. This is the first demonstration that multiple MR imaging modalities combined with multivariate segmentation methods lead to significant improvements in anatomical segmentation in the mouse brain. PMID- 22836176 TI - Serotonin-1A receptor binding is positively associated with gray matter volume -- a multimodal neuroimaging study combining PET and structural MRI. AB - Animal models revealed that the serotonin-1A (5-HT(1A)) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT(1A) receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT(1A) receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R(2) values ranged from 0.308 to 0.503, p<0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R(2)=0.656, p=0.001). We also observed a broad range between 5-HT(1A) receptor binding and GMV. Given the congruence of altered 5-HT(1A) receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders. PMID- 22836177 TI - Good vibrations: oscillatory phase shapes perception. AB - In the current study, we provide compelling evidence to answer the long-standing question whether perception is continuous or periodic. Spontaneous brain oscillations are assumed to be the underlying mechanism of periodic perception. Depending on the phase angle of the oscillations, an identical stimulus results in different perceptual outcomes. Past results, however, can only account for a correlation of perception with the phase of the ongoing brain oscillations. Therefore, it is desirable to demonstrate a causal relation between phase and perception. One way to address this question is to entrain spontaneous brain oscillations by applying an external oscillation and then demonstrate behavioral consequences of this oscillation. We conducted an auditory detection experiment with humans, recorded the electroencephalogram (EEG) concurrently and simultaneously applied oscillating transcranial direct current stimulation at 10Hz (alpha-tDCS). Our approach revealed that detection thresholds were dependent on the phase of the oscillation that was entrained by alpha-tDCS. This behavioral effect was accompanied by an electrophysiological effect: alpha-power was enhanced after alpha-tDCS as compared to a pre-stimulation period. By showing a causal relation between phase and perception, our results extend findings of previous studies that were only able to demonstrate a correlation. We found that manipulation of the phase resulted in different detection thresholds, which supports the notion that perception can be periodically modulated by oscillatory processes. This demonstrates that tDCS can serve as a tool in neuroscience to extend the knowledge of the functional significance of brain oscillations. PMID- 22836179 TI - Neural correlates of combinatorial semantic processing of literal and figurative noun noun compound words. AB - The right hemisphere's role in language comprehension is supported by results from several neuropsychology and neuroimaging studies. Special interest surrounds right temporoparietal structures, which are thought to be involved in processing novel metaphorical expressions, primarily due to the coarse semantic coding of concepts. In this event related fMRI experiment we aimed at assessing the extent of semantic distance processing in the comprehension of figurative meaning to clarify the role of the right hemisphere. Four categories of German noun noun compound words were presented in a semantic decision task: a) conventional metaphors; b) novel metaphors; c) conventional literal, and; d) novel literal expressions, controlled for length, frequency, imageability, arousal, and emotional valence. Conventional literal and metaphorical compounds increased BOLD signal change in right temporoparietal regions, suggesting combinatorial semantic processing, in line with the coarse semantic coding theory, but at odds with the graded salience hypothesis. Both novel literal and novel metaphorical expressions increased activity in left inferior frontal areas, presumably as a result of phonetic, morphosyntactic, and semantic unification processes, challenging predictions regarding right hemispheric involvement in processing unusual meanings. Meanwhile, both conventional and novel metaphorical expressions induced BOLD signal change in left hemispherical regions, suggesting that even novel metaphor processing involves more than linking semantically distant concepts. PMID- 22836178 TI - Behavioral and electrophysiological correlates of training-induced cognitive control improvements. AB - Cognitive control--the ability to exert control over thoughts, attention and behavior in order to achieve a goal--is essential to adaptive functioning and its disruption characterizes various neuropsychiatric and neurodegenerative disorders. In recent years, increased attention has been devoted to investigating the effects of training on performance and brain function, but little is known about whether cognitive control can be improved through training. To fill this gap, we designed a brief training targeting various components of cognitive control, including conflict monitoring and interference resolution. Twenty participants performed a 3-day training protocol, preceded and followed by identical pre- and post-training sessions, respectively, which included event related potential (ERP) recordings. To detect transfer effects, the training and pre-/post-training sessions employed different tasks hypothesized to rely on similar interference resolution mechanisms. We hypothesized that training would selectively improve performance for high-interference (i.e., incongruent) trials and be associated with reduced amplitudes in the N2 component, a waveform known to index interference. Trial-to-trial behavioral adjustments were also analyzed to assess potential mechanisms of training-induced improvements. Relative to pre training, participants showed reduced reaction time (RT) and N2 amplitude for incongruent, but not congruent, trials, suggesting improved interference resolution. Critically, participants showing the greatest reductions in interference effects during the course of the training displayed the largest pre- to post-training reductions in N2 amplitudes in a separate task, highlighting transfer effects. Overall, results suggest that a brief training can improve cognitive control, specifically the ability to inhibit task-irrelevant information. PMID- 22836180 TI - Brain responses to handwritten and printed letters differentially depend on the activation state of the primary motor cortex. AB - Previous studies demonstrated that visual perception of handwritten letters activates the left primary motor cortex more strongly than printed letters. Here, we used EEG to record cortical responses evoked by single letters to directly test if their visual processing is actually influenced by their motor content. We manipulated the "motor familiarity" of letters that we considered high for letters written by the observers themselves, medium for letters written by other individuals, and low for printed, machine designed letters. In order to relate the effects of motor familiarity to the activation of the primary motor cortex, we also directly manipulated its availability during the visual task: we computed Event-Related Potentials (ERPs) over the posterior cortex during a dual task where participants had to observe the letters while performing unrelated self paced brief movements of the right hand approximately every 5s (allowing the primary motor cortex to successively activate and "idle"). At 300-350 ms and 500 600 ms after stimulus onset, the amplitude of the ERP components markedly reflected the level of motor familiarity of the observed letter. Nonetheless, this was true only when the primary motor cortex was in an "idling" state: when the motor cortex was in an activation state, this motor familiarity effect was dropped. This clearly indicates that, at these latencies, the motor information embedded in letters is processed in the brain and that this processing depends on the activation state of the left primary motor cortex. PMID- 22836181 TI - Design choices in imaging speech comprehension: an Activation Likelihood Estimation (ALE) meta-analysis. AB - The localisation of spoken language comprehension is debated extensively: is processing located anterior or posterior on the left temporal lobe, and is it left- or bilaterally organised? An Activation Likelihood Estimation (ALE) analysis was conducted on functional MRI and PET studies investigating speech comprehension to identify the neural network involved in comprehension processing. Furthermore, the analysis aimed to establish the effect of four design choices (scanning paradigm, non-speech baseline, the presence of a task, and the type of stimulus material) on this comprehension network. The analysis included 57 experiments contrasting intelligible with less intelligible or unintelligible stimuli. A large comprehension network was found across bilateral Superior Temporal Sulcus (STS), Middle Temporal Gyrus (MTG) and Superior Temporal (STS) bilaterally, in left Inferior Frontal Gyrus (IFG), left Precentral Gyrus, and Supplementary Motor Area (SMA) and pre-SMA. The core network for post-lexical processing was restricted to the temporal lobes bilaterally with the highest ALE values located anterior to Heschl's Gyrus. Activations in the ALE comprehension network outside the temporal lobes (left IFG, SMA/pre-SMA, and Precentral Gyrus) were driven by the use of sentences instead of words, the scanning paradigm, or the type of non-speech baseline. PMID- 22836182 TI - Long-term phonological learning begins at the level of word form. AB - Incidental learning of phonological structures through repeated exposure is an important component of native and foreign-language vocabulary acquisition that is not well understood at the neurophysiological level. It is also not settled when this type of learning occurs at the level of word forms as opposed to phoneme sequences. Here, participants listened to and repeated back foreign phonological forms (Korean words) and new native-language word forms (Finnish pseudowords) on two days. Recognition performance was improved, repetition latency became shorter and repetition accuracy increased when phonological forms were encountered multiple times. Cortical magnetoencephalography responses occurred bilaterally but the experimental effects only in the left hemisphere. Superior temporal activity at 300-600 ms, probably reflecting acoustic-phonetic processing, lasted longer for foreign phonology than for native phonology. Formation of longer-term auditory-motor representations was evidenced by a decrease of a spatiotemporally separate left temporal response and correlated increase of left frontal activity at 600-1200 ms on both days. The results point to item-level learning of novel whole-word representations. PMID- 22836183 TI - A large deformation diffeomorphic metric mapping solution for diffusion spectrum imaging datasets. AB - Spatial transformation for diffusion spectrum imaging (DSI) is an important step for group analyses of DSI datasets. In this study, we developed a transformation method for DSI datasets under the framework of large deformation diffeomorphic metric mapping (LDDMM), which is termed LDDMM-DSI. The proposed method made use of the fact that a DSI dataset is 6D, and generalized the original 2D/3D LDDMM algorithm to the 6D case with some modifications made for the DSI datasets. In this manner, the conventional reorientation problem that arises from transforming diffusion-weighted datasets was avoided by making the DSI datasets capable of being freely deformed in the q-space. The algorithm treated the data-matching task as a variational problem under the LDDMM framework and sought optimal velocity fields from which the generated transformations were diffeomorphic and the transformation curve was a geodesic. The mathematical materials and numerical implementation are detailed in the paper, and experiments were performed to analyze the proposed method on real brain DSI datasets. The results showed that the method was capable of registering different DSI datasets in both global structural shapes and local diffusion profiles. In conclusion, the proposed method can facilitate group analyses of DSI datasets and the generation of a DSI template. PMID- 22836184 TI - Preclinical studies of YK-4-272, an inhibitor of class II histone deacetylases by disruption of nucleocytoplasmic shuttling. AB - PURPOSE: The HDAC shuttling inhibitor, YK-4-272 functions by restricting nuclear shuttling of Class II HDACs. Pre-clinical investigations of YK-4-272 bioavailability, pharmacokinetics, in vivo toxicity and tumor growth inhibition were performed to determine its potential as an HDAC shuttling disruptor for use in clinical applications. METHODS: The solubility, lipophilicity, in vitro metabolic stability, in vitro intestinal permeability, and in vivo pharmacokinetics of YK-4-272 were determined by HPLC methods. The anti-tumor activity of YK-4-272 was determined by monitoring athymic Balb/c nude mice bearing PC-3 xenografts. RESULTS: Oral bioavailability of YK-4-272 is supported by its solubility (0.537 mg/mL) and apparent partition coefficient of 2.0. The compound was chemically and metabolically stable and not a substrate for CYP450. In Caco-2 cell transport studies, YK-4-272 was highly permeable. The time concentration profile of YK-4-272 in plasma resulted in a C ( max ) of 2.47 MUg/mL at 0.25 h with a AUC of 3.304 MUg * h/mL. Treatment of PC-3 tumor xenografts with YK-4-272 showed significant growth delay. CONCLUSIONS: YK-4-272 is stable and bio-available following oral administration. Growth inhibition of cancer cells and tumors was observed. These studies support advancing YK-4-272 for further evaluation as a novel HDAC shuttling inhibitor for use in cancer treatment. PMID- 22836185 TI - Clinicopathologic characteristics and mucin expression in Brunner's gland proliferating lesions. AB - BACKGROUND: Brunner's gland proliferating lesions, termed Brunner's gland hamartoma, hyperplasia, or adenoma, is regarded as a benign condition. However, cancerous changes have been reported in Brunner's gland proliferating lesions. AIMS: The purpose of this study was to define the characteristic features of Brunner's gland proliferating lesions and evaluate any observed cancerous changes. METHODS: We analysed clinicopathologic features and mucin expression in 25 Brunner's gland proliferating lesions. RESULTS: Brunner's gland proliferating lesions were categorized as Brunner's gland hamartoma or hyperplasia according to their tissue components. Brunner's gland hamartoma commonly occurred in the duodenal bulb and exhibited a polypoid appearance, while Brunner's gland hyperplasia was primarily observed in the second portion of duodenum as a submucosal mass and was accompanied by symptoms more frequently than Brunner's gland hamartoma. The Brunner's glands in Brunner's gland proliferating lesions exhibited various morphologic characteristics, from normal-appearing glands to sclerotic glandular foci with atypia. Changes in MUC5 expression observed in both sclerotic glandular foci and dilated Brunner's glands suggest that they might share a common mechanism and are associated with gastric foveolar metaplasia. CONCLUSIONS: These findings indicate that most Brunner's gland proliferating lesions are either hamartoma or hyperplasia, and that true neoplastic Brunner's gland proliferating lesions are very rare. Thus, Brunner's gland adenomas or carcinomas arising in Brunner's gland proliferating lesions should be confirmed by ancillary tests, including immunostaining or molecular analysis, in addition to morphological criteria. PMID- 22836186 TI - Combination of apolipoprotein E4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice. AB - The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment. PMID- 22836187 TI - Lessons from epidemiologic research about risk factors, modifiers, and progression of late onset Alzheimer's Disease in New York City at Columbia University Medical Center. AB - This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer's disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer's disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer's disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer's disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer's disease PMID- 22836188 TI - A review of the major vascular risk factors related to Alzheimer's disease. AB - The present review is dedicated to the epidemiology of vascular risk factors proven to play a role in facilitating onset and progression of cognitive impairment. These include hypertension, hypercholesterolemia, diabetes, obesity, atherosclerosis, and cardiac diseases. The targeted, chance-free identification and management of traditional vascular risk factors in midlife is a general public health strategy against the onset of mild to severe cognitive impairment in advanced age. This preventive action must be routinely carried out with outmost awareness by physicians in order to be effective. In advanced age, the individually shaped assessment and management of vascular risk factors assumes particular importance as some of them show a strong age-dependent pattern. The relative strategies with this purpose cannot be separated from a thorough lifestyle anamnesis including nutrition, physical exercise, and cognitive and social activities. PMID- 22836189 TI - Numerical simulation of endovenous laser treatment of the incompetent great saphenous vein with external air cooling. AB - Endovenous laser treatment (ELT) has been proposed as an alternative in the treatment of reflux of the great saphenous vein. Before the procedure, peri saphenous subcutaneous tumescent saline solution infiltration is usually performed. However, diffusion of this tumescent fluid is rapidly observed and can potentially reduce the efficacy as a heat sink. External skin cooling with cold air was proposed as an alternative solution. The objective of this study is to compare endovenous laser treatment without and with air cooling by realistic numerical simulations. An optical-thermal damage model was formulated and implemented using finite element modeling. The general model simulated light distribution using the diffusion approximation of the transport theory, temperature rise using the bioheat equation, and laser-induced injury using the Arrhenius damage model. Parameters, used in clinical procedures, were considered: power, 15 W; pulse duration, 1 s; fiber pull back, 3-mm increments every second; cold air applied in continuous mode during ELT; and no tumescent anesthesia. Simulations were performed for vein locations at 5, 10, and 15 mm in depth, with and without air cooling. For a vein located at 15 mm in depth, no significant difference was observed with and without cooling. For a vein located at 10 mm in depth, surface temperature increase up to 45 degrees C is observed without cooling. For a vein located at 5 mm, without cooling, temperature increase leads to irreversible damage of dermis and epidermis. Conversely, with air cooling, surface temperature reaches a maximum of 38 degrees C in accordance with recordings performed on patients. ELT of the incompetent great saphenous vein with external air cooling system is a promising therapy technique. Use of cold air on the skin continuously flowing in the area of laser shot decreased significantly the heat extent and the thermal damage in the perivenous tissues and the skin. PMID- 22836190 TI - Discovery and biological evaluation of novel 4-amino-2-phenylpyrimidine derivatives as potent and orally active GPR119 agonists. AB - Novel 4-amino-2-phenylpyrimidine derivatives were synthesized and evaluated as GPR119 agonists. Optimization of the substituents on the phenyl ring at the 2 position and the amino group at the 4-position led to the identification of 3,4 dihalogenated and 2,4,5-trihalogenated phenyl derivatives showing potent GPR119 agonistic activity. The advanced analog (2R)-3-{[2-(4-chloro-2,5-difluorophenyl) 6-ethylpyrimidin-4-yl]amino}propane-1,2-diol (24g) was found to improve glucose tolerance at 1mg/kg po in mice and to show excellent pharmacokinetic profiles in mice and monkeys. Compound 24g also showed an excellent antidiabetic effect in diabetic kk/Ay mice after one week of single daily treatment. These results demonstrate that novel GPR119 agonist 24g improves glucose tolerance not only by enhancing glucose-dependent insulin secretion but also by preserving pancreatic beta-cell function. PMID- 22836191 TI - Right atrium tumor thrombus. PMID- 22836192 TI - Lung toxicity and Nitrofurantoin: the tip of the iceberg? PMID- 22836193 TI - Unilateral leg swelling and hydronephrosis. PMID- 22836194 TI - Another 20th century epidemic. PMID- 22836195 TI - Biologic treatments in Sjogren's syndrome. AB - Primary Sjogren's Syndrome (pSS) is characterized by focal lymphocytic infiltration of secretory exocrine glands associated with severe dryness of eyes and mouth in particular. Systemic features such as disabling fatigue, cutaneous vasculitis, lung, neurological, haematological or other systemic involvement also occur. Conventional immunosuppressive therapies such as corticosteroids or disease-modifying drugs, have been used in some patients with these systemic features with variable benefit. Current therapy for dryness is principally symptomatic although medications to stimulate residual glandular secretion can be helpful for appropriate individuals. As the pathogenesis of the condition becomes better understood, particularly, in recent years, the role of systemic B-cell activation, biologic therapies specifically targeted against molecules involved in disease pathogenesis represent a more targeted approach to therapeutic intervention. The greatest experience in pSS is with rituximab, an anti-CD20 (expressed on a subset of B-cells) monoclonal antibody already in use for the treatment of some B-cell lymphomas and rheumatoid arthritis. Randomised placebo controlled studies in pSS are currently underway. This review discusses the rationale for using biologic therapies in pSS, the current data on rituximab and the potential use of other biologic therapies in pSS in the future. PMID- 22836196 TI - [The management of errors and scientific fraud by biomedical journals: They cannot replace Institutions]. AB - Research integrity is not negotiable, but we regularly observe research misconduct, and journals are victims or guilty. Journals do not have the objective to assess research integrity: that's the Institutions' roles. Journals discover research misconduct when articles are reviewed (an editor or a reviewer detect signals), or after the article's publication when a reader or a whistleblower call the journal. The editors and reviewers' research misconduct are less described and not publicized in the medias. The peer-review system is criticised. If authors were fair-play, and reviews well done, the journals should not publish articles containing false data. The opponents to the peer-review system propose no alternatives to replace it. The anonymous peer reviews are questioned: it has never been proved that quality of anonymous reading was better than quality of open reading. The Open Access facilitated the creation of many journals. Some journals are excellent and got an impact factor; most journals have a poor quality and don't follow the publications ethics standards. When errors and fraud are identified, journals can publish 3 statements: erratum for errors, expression of concern for errors or fraud when evidence is not established, and retraction when evidence is obvious. PMID- 22836197 TI - Pathophysiological cytokine network in primary Sjogren's syndrome. AB - The continuing progress in discovering lymphocyte subsets and the lengthening list of cytokines involved, together with how they are affected in primary Sjogren's syndrome (pSS), has further fuelled the debate on pSS pathogenesis. In this review the "interferon signature" observed in the salivary glands and the role of T-cell derived cytokines (Th1/Th2 polarization, Th17 and regulatory T cells) will be discussed. A particular emphasis has been placed on the B-cell derived cytokines and especially on FLT3-Ligand, a cytokine associated with lymphoma in pSS, and B-cell activating factor (BAFF) that prevents apoptosis of autoreactive B cells. It has indeed become a challenge to understand how the interaction between several interconnected networks of cytokines impact so different cell population in the immunopathogenesis of pSS. PMID- 22836198 TI - An embedded-atom-method model for alkali-metal vibrations. AB - We present an embedded-atom-method (EAM) model that accurately describes the vibrational dynamics in the alkali metals Li, Na, K, Rb and Cs. The bulk dispersion curves, frequency-moment Debye temperatures and temperature-dependent entropy Debye temperatures are all in excellent agreement with experimental results. The model is also well suited for studying surface vibrational dynamics in these materials, as illustrated by calculations for the Na(110) surface. PMID- 22836199 TI - Too few school nurses to administer proposed flu vaccination programme, experts say. PMID- 22836200 TI - GP in Baby P case has conditions on his practice revoked. PMID- 22836201 TI - Five-year follow-up of participants in a randomised controlled trial showing benefits from exercise for breast cancer survivors during adjuvant treatment. Are there lasting effects? AB - PURPOSE: In an earlier randomised controlled trial, we showed that early stage breast cancer patients who received a supervised exercise programme, with discussion of behaviour change techniques, had psychological and functional benefits 6 months after the intervention. The purpose of this study was to determine if benefits observed at 6 months persisted 18 and 60 months later. METHODS: Women who were in the original trial were contacted at 18 and 60 months after intervention. Original measures were repeated. RESULTS: Of the 148 women from the original study who agreed to be contacted again, 114 attended for follow up at 18 months and 87 at 60 months. Women in the original intervention group reported more leisure time physical activity and more positive moods at 60 months than women in the original control group. Irrespective of original group allocation, women who were more active consistently reported lower levels of depression and increased quality of life compared to those who were less active. CONCLUSIONS: We have shown that there are lasting benefits to an exercise intervention delivered during treatment to breast cancer survivors. Regular activity should be encouraged for women with early stage breast cancer as this can have lasting implications for physical and psychological functioning. PMID- 22836202 TI - An unusual case of urinary incontinence in a female child. AB - We report a case of a 3-year-old female child presenting with continuous urinary incontinence since birth. After relevant investigations, a diagnosis of bilateral single-system ectopic ureters into a vaginalized urogenital sinus was made. We discuss the extreme rarity of the case, importance of an accurate history, along with various treatment options. PMID- 22836203 TI - Rare association in a female DSD case of phallus, accessory phallic urethra, perineal lipoma and anterior ectopic anus. AB - Disorders of sex differentiation (DSD) are a heterogeneous and broad spectrum group of diseases with a varied appearance. Presence of an accessory phallus with a phallic urethra in association with a normal vagina in a female is an extremely uncommon anomaly. We present a rare case of a genotypically female child with a normal urethra and vagina in association with a phallus, accessory phallic urethra, perineal lipoma and anterior ectopic anus. PMID- 22836204 TI - Biological variation in tPA-induced plasma clot lysis time. AB - Hypofibrinolysis is a risk factor for venous and arterial thrombosis, and can be assessed by using a turbidimetric tPA-induced clot lysis time (CLT) assay. Biological variation in clot lysis time may affect the interpretation and usefulness of CLT as a risk factor for thrombosis. Sufficient information about assay variation and biological variation in CLT is not yet available. Thus, this study aimed to determine the analytical, within-subject and between-subject variation in CLT. We collected blood samples from 40 healthy individuals throughout a period of one year (average 11.8 visits) and determined the CLT of each plasma sample in duplicate. The mean (+/- SD) CLT was 83.8 (+/- 11.1) minutes. The coefficients of variation for total variation, analytical variation, within-subject variation and between-subject variation were 13.4%, 2.6%, 8.2% and 10.2%, respectively. One measurement can estimate the CLT that does not deviate more than 20% from its true value. The contribution of analytical variation to the within-subject variation was 5.0%, the index of individuality was 0.84 and the reference change value was 23.8%. The CLT was longer in the morning compared to the afternoon and was slightly longer in older individuals (> 40 years) compared to younger (<=40 years) individuals. There was no seasonal variation in CLT and no association with air pollution. CLT correlated weakly with fibrinogen, C-reactive protein, prothrombin time and thrombin generation. This study provides insight into the biological variation of CLT, which can be used in future studies testing CLT as a potential risk factor for thrombosis. PMID- 22836205 TI - Blocking bimolecular activation pathways leads to different regioselectivity in metal-organic framework catalysis. AB - Chiral metal-organic frameworks built from a Co-salen derived dicarboxylate bridging ligand exhibited different regioselectivities from the corresponding homogeneous catalyst by shutting down bimolecular activation pathways. PMID- 22836206 TI - Amperometric biosensor for oxalate determination in urine using sequential injection analysis. AB - An amperometric flow biosensor for oxalate determination in urine samples after enzymatic reaction with oxalate oxidase immobilized on a modified magnetic solid is described. The solid was magnetically retained on the electrode surface of an electrode modified with Fe (III)-tris-(2-thiopyridone) borate placed into a sequential injection system preceding the amperometric detector. The variables involved in the system such as flow rate, aspired volumes (modified magnetic suspension and sample) and reaction coil length were evaluated using a Taguchi parameter design. Under optimal conditions, the calibration curve of oxalate was linear between 3.0-50.0 mg.L-1, with a limit of detection of 1.0 mg.L-1. The repeatability for a 30.0 mg.L-1 oxalate solution was 0.7%. The method was validated by comparing the obtained results to those provided by the spectrophotometric method; no significant differences were observed. PMID- 22836207 TI - Screening and analysis of the potential bioactive components in rabbit plasma after oral administration of hot-water extracts from leaves of Bambusa textilis McClure. AB - Bambusa textilis McClure is a traditional Chinese medicinal plant belonging to the Bambusoideae subfamily and used to treat chronic fever and infectious diseases. To investigate the bioactive compounds absorbed in the rabbit blood after oral administration of hot-water extracts from the leaves of B. textilis McClure, a validated chromatographic fingerprint method was established using LC Q-TOF-MS. Twenty compounds in bamboo leaves and three potential bioactive compounds in rabbit plasma were detected. Of the twenty detected compounds in vitro, fifteen of which were tentatively identified either by comparing the retention time and mass spectrometry data with that of reference compounds or by reviewing the literature. Three potential bioactive compounds, including (E) pcoumaric acid, (Z)-p-coumaric acid, and apigenin-8-C-beta-D-(2"-O-alpha-L rhamnosyl)-glucopyranoside, were detected in both the leaves of B. textilis McClure and rabbit plasma. Of the three compounds, apigenin-8-C-beta-D-(2"-O alpha-L-rhamnosyl)glucopyranoside was identified based on its UV, MS, and NMR spectra. This study provides helpful chemical information for further pharmacology and active mechanism research on B. textilis McClure. PMID- 22836208 TI - Protective effect of polyphenols extract of adlay (Coix lachryma-jobi L. var. ma yuen Stapf) on hypercholesterolemia-induced oxidative stress in rats. AB - The present study examines the effect of polyphenols extract of adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) (APE) on high cholesterol diet fed rats (HCD). APE was orally administrated by gavage at doses of 10, 40 and 200 mg total phenolics/kg body weight of rats once a day for 28 days. At the end of four weeks, serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C), and markers of oxidative stress viz., malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the serum and liver of HCD and normal rats were assessed and compared. The results showed that administration of APE was significantly effective in decreasing the serum levels of TC, LDL-C and MDA, increasing the serum level of HDL-C and antioxidant capacity. In addition, oral gavage of APE could also increase the antioxidant capacity, CAT and GSH-Px activities in liver. These results suggested that APE exerted a high hypocholesterolemic and antioxidant activities, which might be characterized by a protective effect on cardiovascular health in vivo. PMID- 22836209 TI - The photodegradation of quercetin: relation to oxidation. AB - The photostability of quercetin in alcoholic solutions was studied. Both UVA and UVB light induced degradation of quercetin, yielding a single product 1 deriving from oxidation and addition of an alcohol molecule to the 2,3 double bond. The same mechanism operated when quercetin was dissolved in alkaline solutions, and again a product 2 due to oxidation and addition of water was characterized. Comparison with quercetin analogs confirmed that, despite the presence of five hydroxy groups in quercetin, those in positions 3, 3', and 4' are mainly involved in the antioxidant activity of the compound , as well as in its photolability. PMID- 22836210 TI - Synthesis and sensory evaluation of ent-kaurane diterpene glycosides. AB - Catalytic hydrogenation of the three ent-kaurane diterpene glycosides isolated from Stevia rebaudiana, namely rubusoside, stevioside, and rebaudioside-A has been carried out using Pd(OH)2 and their corresponding dihydro derivatives have been isolated as the products. Synthesis of reduced steviol glycosides was performed using straightforward chemistry and their structures were characterized on the basis of 1D and 2D NMR spectral data and chemical studies. Also, we report herewith the sensory evaluation of all the reduced compounds against their corresponding original steviol glycosides and sucrose for the sweetness property of these molecules. PMID- 22836211 TI - Gastroprotection of suaveolol, isolated from Hyptis suaveolens, against ethanol induced gastric lesions in Wistar rats: role of prostaglandins, nitric oxide and sulfhydryls. AB - Hyptis suaveolens is a medicinal plant that is, according to traditional medicine, considered useful in the treatment of gastric ulcers. Although its gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim of the present study was to identify at least one active compound potentially responsible for the gastroprotective activity of H. suaveolens by using a bioassay guided study with an ethanol-induced gastric ulcer experimental model in rats. The results show that the hexane extract had protective activity (close to 70% when using doses between 10 and 100 mg/kg), and that the compound suaveolol, isolated from this extract, was one of the active gastroprotective agents. This is the first report about the gastroprotective activity of suaveolol. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 12.6, 21.3, 39.6 and 70.2% gastroprotection respectively. The effect elicited by suaveolol (at 100 mg/kg) was attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of this compound involves NO, prostaglandins and sulfhydryl groups. PMID- 22836212 TI - Anti-platelet aggregation and vasorelaxing effects of the constituents of the rhizomes of Zingiber officinale. AB - In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty nine compounds including one new compound, O-methyldehydrogingerol. Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol and [6] shogaol exhibited potent anti-platelet aggregation bioactivity. In addition, [10] gingerol inhibited the Ca2+-dependent contractions in high K+ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism. PMID- 22836213 TI - Detection of sulfur-fumigated Paeoniae Alba Radix in complex preparations by high performance liquid chromatography tandem mass spectrometry. AB - Detection of sulfur-fumigated Paeoniae Alba Radix (PAR) in different complex preparations is challenging due to the relatively lower content of PAR and interference from more complicated components in complex preparations with different multiple constituent herbs. In this study, a high performance liquid chromatography- triple-quadrupole tandem mass spectrometry method was developed for detecting sulfur-fumigated PAR in different complex preparations. Paeoniflorin, the major component of PAR, and paeoniflorin sulfonate, the characteristic artifact transformed from paeoniflorin during sulfur-fumigation of PAR, were used as chemical markers. Multiple reaction monitoring (MRM) scan was employed to maximize sensitivity and selectivity. Through optimizing full mass scan and daughter ion scan conditions, two mass transitions were selected and employed respectively for unequivocal identification of paeoniflorin and paeoniflorin sulfonate. The detection limits for paeoniflorin and paeoniflorin sulfonate using MRM were much lower than those detected with UV 270 nm. Paeoniflorin and paeoniflorin sulfonate could be simultaneously detected in different commercial PAR-containing complex preparations without interference of other components using the established method, indicating that the newly established method was selective and sensitive enough for screening sulfur fumigated PAR in commercial complex preparations. PMID- 22836214 TI - Syntheses of enantiopure aliphatic secondary alcohols and acetates by bioresolution with lipase B from Candida antarctica. AB - The lipase B from Candida antarctica (Novozym 435(r), CALB) efficiently catalyzed the kinetic resolution of some aliphatic secondary alcohols: (+/-)-4-methylpentan 2-ol, (+/-)-5-methylhexan-2-ol, (+/-)-octan-2-ol, (+/-)-heptan-3-ol and (+/-)-oct 1-en-3-ol. The lipase showed excellent enantioselectivities in the transesterifications of racemic aliphatic secondary alcohols producing the enantiopure alcohols (>99% ee) and acetates (>99% ee) with good yields. Kinetic resolution of rac-alcohols was successfully achieved with CALB lipase using simple conditions, vinyl acetate as acylating agent, and hexane as non-polar solvent. PMID- 22836215 TI - Ratiometric fluorescence off-on-off sensor for Cu2+ in aqueous buffer by a lower rim triazole linked benzimidazole conjugate of calix[4]arene. AB - A benzimidazole appended triazole linked 1,3-diconjugate of calix[4]arene (L) has been synthesized and characterized. The conjugate L has been found to recognize Cu(2+) among the thirteen different metal ions studied by exhibiting ratiometric fluorescence changes through newly generated excimer band at ~380 nm. Fluorescence off-on-off behavior has been clearly demonstrated on the basis of the binding variability of Cu(2+) to L. The binding has been elicited through the changes observed in the fluorescence, ESI MS and (1)H NMR titrations. All the other metal ions studied do not show any new band and further do not interfere with the recognition of Cu(2+) by L, even when these are present in the same medium. The structural features of both the mono- and di-nuclear complexes were established by DFT computational calculations and found to display highly distorted geometry about the copper centers that deviate from both the tetrahedral and the square planar. PMID- 22836216 TI - Physiological and biochemical basis of clinical liver function tests: a review. AB - OBJECTIVE: To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. BACKGROUND: Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. METHODS: A MEDLINE search was performed using the key words "liver function tests," "functional studies in the liver," "compromised liver," "physiological basis," and "mechanistic background," with and without Boolean operators. RESULTS: Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques ((99m)Tc galactosyl serum albumin scintigraphy and (99m)Tc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. CONCLUSIONS: Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, (99m)Tc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver. PMID- 22836217 TI - Fibrinogen Tokushima II: a new case of congenital dysfibrinogenemia with a gamma methionine-310 to threonine substitution. PMID- 22836218 TI - Morphology of distal border synovial invaginations of the equine distal sesamoid bone: comparison between computed tomography and a hoof-specific radiographic projection. AB - OBJECTIVES: To compare the difference and agreement of the morphology of distal border synovial invaginations on a dorsoproximal-palmarodistal oblique (DPr PaDiO) projection with hoof-specific angle versus computed tomography. METHODS: Computed tomography (CT) images and a DPr-PaDiO radiographic projection with hoof specific angle were obtained on 50 cadaveric forefeet from 25 Warmblood horses. Computed tomography was assumed to be the gold standard. The number, shape and depth of penetration of distal border synovial invaginations into the distal sesamoid bone were evaluated with both methods, and the comparison of their measurements was statistically described. RESULTS: Significantly more invaginations were seen on CT compared to radiography, with an observed average difference of 1.2. In none of the cases did radiography have a higher number than that observed with CT. No statistically significant difference for depth between CT and the DPr-PaDiO projection was seen, however, there was quite a large variation of the actual difference of measurements against their mean found. Radiography was underestimated when high mean values applied. The agreement between both modalities for shape was moderate to good. A very high specificity of the specific DPr-PaDiO projection for shape was found (97%). CLINICAL SIGNIFICANCE: The radiographic projection with hoof-specific angle differs significantly from CT concerning the number and depth of the distal border synovial invaginations. Therefore, this specific view may not be considered useful in the evaluation of these invaginations. PMID- 22836219 TI - The effect of training the deep cervical flexors on neck pain, neck mobility, and dizziness in a patient with chronic nonspecific neck pain after prolonged bed rest: a case report. AB - STUDY DESIGN: Case report. BACKGROUND: Immobilization and chronic neck pain may cause a transformation of muscle tissue fibers. These changes affect the ability to effectively control 3-D movement of the cervical spine. This case report describes the effect of specific deep cervical flexor (DCF) musculature training in a patient with chronic neck pain and dizziness. CASE DESCRIPTION: A 19-year old woman presented with a 24-month history of neck pain and dizziness. Symptoms started during a 2-month immobilization period while in the intensive care unit for the treatment of brainstem encephalitis. Outcome measures included pain level, limitations in activities, fear avoidance, range of motion, dizziness, and function of the DCFs. Treatment was aimed at restoring altered motor control of the neck muscles using DCF training integrated with functional activities for 10 treatment sessions over 12 weeks. OUTCOMES: At the time of discharge, the patient reported full recovery and no restriction in her daily activities. Her score on the Neck Disability Index had improved by 28 points, active range of motion had increased, and her symptoms of dizziness were resolved. These results were maintained at 6-month follow-up. DISCUSSION: This patient responded positively to DCF training, resulting in an increase in cervical spine range of motion and a reduction of dizziness, pain, and limitations in activities. PMID- 22836220 TI - Formation of spin-polarons in the ferromagnetic Kondo lattice model away from half-filling. AB - Even though realistic one-dimensional experiments in the field of half-metallic semiconductors are not at hand yet, we are interested in the underlying fundamental physics. In this regard we study a one-dimensional ferromagnetic Kondo lattice model, a model in which a conduction band is coupled ferromagnetically to a background of localized d moments with coupling constant J(H), and investigate the T = 0 phase diagram as a function of the antiferromagnetic interaction J between the localized moments and the band filling n, since it has been observed that doping of the compounds has led to formation of magnetic domains. We explore the spin-polaron formation by looking at the nearest-neighbour correlation functions in the spin and charge regimes for which we use the density matrix renormalization group method, which is a highly efficient method to investigate quasi-one-dimensional strongly correlated systems. PMID- 22836221 TI - Management of delivery with FVIII/VWF concentrates in a pregnant woman with type 3 von Willebrand disease and alloantibodies. PMID- 22836223 TI - Re-examining the mechanisms of competing pericyclic reactions of 1,3,7 octatriene. AB - DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5 hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels-Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions. PMID- 22836222 TI - Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention. AB - Fragility fractures are common, affecting almost one in two older women and one in three older men. Every fragility fracture signals increased risk of future fractures as well as risk of premature mortality. Despite the major health care impact worldwide, currently there are few systems in place to identify and "capture" individuals after a fragility fracture to ensure appropriate assessment and treatment (according to national guidelines) to reduce future fracture risk and adverse health outcomes. The Task Force reviewed the current evidence about different systematic interventional approaches, their logical background, as well as the medical and ethical rationale. This included reviewing the evidence supporting cost-effective interventions and developing a toolkit for reducing secondary fracture incidence. This report presents this evidence for cost effective interventions versus the human and health care costs associated with the failure to address further fractures. In particular, it summarizes the evidence for various forms of Fracture Liaison Service as the most effective intervention for secondary fracture prevention. It also summarizes the evidence that certain interventions, particularly those based on patient and/or community focused educational approaches, are consistently, if unexpectedly, ineffective. As an international group, representing 36 countries throughout Asia-Pacific, South America, Europe, and North America, the Task Force reviewed and summarized the international data on barriers encountered in implementing risk-reduction strategies. It presents the ethical imperatives for providing quality of care in osteoporosis management. As part of an implementation strategy, it describes both the quality improvement methods best suited to transforming care and the research questions that remain outstanding. The overarching outcome of the Task Force's work has been the provision of a rational background and the scientific evidence underpinning secondary fracture prevention and stresses the utility of one form or another of a Fracture Liaison Service in achieving those quality outcomes worldwide. (c) 2012 American Society for Bone and Mineral Research. PMID- 22836224 TI - Septic venous thromboembolism. PMID- 22836225 TI - Spontaneous perirenal hematoma due to multiple renal artery aneurysms in a patient with presumed polyarteritis nodosa. PMID- 22836226 TI - Dietary acculturation and body composition predict American Hmong children's blood pressure. AB - OBJECTIVES: Determine how dietary acculturation, anthropometric measures (height, weight, circumferences, and skinfolds), body mass index (BMI), and waist hip ratios (WHRs) are associated with blood pressure (BP) measures in Hmong children living in Minnesota. METHODS: Acculturation was measured using responses to questions regarding language usage, social connections, and diet. Dietary assessment was completed using the multiple-pass 24-h dietary recall method on two different days. Anthropometric and BP measurement were taken using standard procedures, and BMI and WHR were calculated. Data analyses included descriptive statistics, ANOVA, and stepwise regression analyses. RESULTS: Using stepwise regression analysis, hip circumference (HC) predicted boys' systolic (S)BP (R(2) = 0.55). For girls' SBP, mid-upper arm circumference, WHR, low calcium consumption, and height percentile jointly explained 41% of the total variation. Mid upper arm circumference (MAC) and carbohydrate consumption predicted 35% of the variance for boys' diastolic (D)BP, and HC, dairy consumption, and calcium intake predicted 31% of the total variance for girls' DBP. Responses to dietary acculturation questions revealed between group differences for breakfast with half of the younger Born-Thailand/Laos (Born-T/L) consuming mostly Hmong food, while at dinner Born-US consumed a mixed diet and Born-T/L were more likely to consume Hmong food. CONCLUSION: Dietary acculturation and body composition predict Hmong children's BP. PMID- 22836227 TI - Serotonin modulation of cerebral glucose metabolism: sex and age effects. AB - The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20-79 years) underwent two resting positron emission tomography studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. PMID- 22836228 TI - Risk factors for recurrence after Bankart repair a systematic review. AB - PURPOSE: Arthroscopic Bankart repair of anterior shoulder instability is a common practice in orthopedics. The aim of this study was to evaluate pre-operative risks factors associated with recurrent instability and to delineate possible indications for revision surgery. METHODS: A systematic review was performed including the following keywords: arthroscopy, Bankart repair, anterior shoulder instability, recurrence of instability, suture anchors and treatment outcome. Studies eligible for inclusion in the review were clinical trials published in the last 10 years investigating patients with anterior shoulder instability managed by an arthroscopic repair technique with suture anchors. The studies had to report data about recurrence of instability and investigational parameters (risk factors) that influenced the results referred to the rate of recurrence. Twenty-four articles were identified that met the inclusion criteria and underwent further review. Data from these studies were collected, and the risk of treatment failure was statistically recalculated. An estimate of the overall recurrence rate was obtained by pooling data about failure from the trials. RESULTS: The rate of recurrent instability at 10 years of follow-up ranged from 3.4 to 35 %. Epidemiological parameters significantly associated with the recurrence of instability were age below 22 years old, male gender, the number of preoperative dislocations and participation in competitive sports. Surgical parameters significantly associated with recurrence of instability were repair with fewer than three anchors and the use of knotless anchors. The patho anatomical factors significantly associated with recurrences were substantial associated glenoid or humeral head bone loss and the presence of anterior labroligamentous periosteal sleeve avulsion. CONCLUSIONS: Knowledge of risk factors for post-operative outcomes allows surgeons to provide appropriate preoperative counselling to patients and support more realistic expectations. An accurate analysis of causes of failure should enable the correct revision strategy to be adopted. LEVEL OF EVIDENCE: II. PMID- 22836229 TI - Clinical outcome and structural integrity of all-arthroscopic repair of degenerative subscapularis tendon tears. AB - PURPOSE: The purpose of this study was to evaluate the clinical outcome of all arthroscopic repair of degenerative subscapularis tendon tears and post-operative structural integrity using magnetic resonance imaging with a short-term follow up. METHODS: Twenty-one patients were treated all-arthroscopically for a full thickness degenerative subscapularis tendon tear. Median patient age was 55 years (range, 41-69). Median follow-up was 25 months (range, 15-44). Patients were evaluated prior to surgery and at follow-up: active range of motion, VAS pain, Simple Shoulder Test (SST), and the Disabilities of the Arm, Shoulder, and Hand score (DASH). At final follow-up, the Constant-Murley score was evaluated. RESULTS: Mean active range of motion showed significant post-operative improvement (p < 0.001). VAS pain improved from 8.3 (SD +/- 1.3) pre-operatively to 2.7 (SD +/- 1.8) post-operatively (<0.001); SST increased from 20 % (SD +/- 26) pre-operatively to 83 % (SD +/- 27) post-operatively (<0.001); DASH scores improved 67 (SD +/- 19) to 18 (SD +/- 21) post-operatively (<0.001). Post operative Constant-Murley score was 79 (SD +/- 12). Two patients had failure of the repair on post-operative MRI. Twelve cases (57 %) showed post-operative progression of fatty muscle infiltration. CONCLUSION: All-arthroscopic repair is an effective treatment modality for degenerative subscapularis tendon tears with an anterosuperior tear pattern with good clinical results and high patient satisfaction. Although there was a high tendon-to-bone healing rate, fatty muscle infiltration was progressive in more than half of the patients. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 22836230 TI - Dhat syndrome, an emergent condition within urology in Spain. AB - BACKGROUND: Dhat syndrome (DS) consists of vague somatic symptoms and at times sexual dysfunction which the patient falsely attributes to involuntary emissions of semen outside of sexual relations. OBJECTIVE: Describe and analyse the occurrences of DS in patients attending the clinic and clarify the existence of this condition within the Spanish Urological service. MATERIALS AND METHODS: Patients reporting semen loss in urine or involuntarily outside of sexual relations were studied during a period from May 2006 to December 2007. Variables of age, nationality, marital status, family situation, medical history, reasons for the consultation, physical condition and additional tests were studied. All treatments and its effectiveness were also recorded. RESULTS: DS affected predominantly southern Asian continent citizens (n = 32). The average age was 35.44. Seventeen patients reported semen loss during urination; 20 at the end of urination; 11 spontaneously; 5 while sleeping; 4 during defecation; 1 while showering; 1 while eating meat; and 3 produced by noticing stained clothing. In 28 cases, the supposed loss of semen was linked to sex-related symptoms. All examinations and tests ruled out the existence of actual loss of semen. CONCLUSIONS: In urology consultations, we have been witnessing the unusual appearance of DS, a condition known by psychologists and psychiatrists and practically unheard of by urologists. A previously unknown condition in Spain, immigration from Asia, is causing the appearance of this syndrome. Its rapid identification will prevent patients from paying costly and unnecessary tests and provide alternative therapies, within a multidisciplinary approach involving psychologists and psychiatrists. PMID- 22836231 TI - Photophysical properties of new cyclometalated ruthenium complexes and their use in dye sensitized solar cells. AB - A new class of cyclometalated ruthenium complexes, Ru(C^N^N')(N^N'^N'').Cl where N^N'^N'' = 4,4',4''-tricarboxy-2,2':6',2''-terpyridine and C^N^N' = substituted 6 phenyl-2,2'-bipyridine, for Dye Sensitized Solar Cells (DSSCs) is proposed. We have investigated the effect of different substituents (R = COOH, thiophen-2-yl, F and OCH(3)) on the ancillary C^N^N' ligand on the photophysical properties and performance of the six different cyclometalated ruthenium complexes in DSSCs. Using an ionic liquid based electrolyte, efficiencies up to eta = 3.06% have been attained under 1 sun irradiation. Moreover, the T66 based DSSC exhibited a good stability under 1000 W m(2) light soaking at 60 degrees C for 24 days, retaining 92.8% of its initial efficiency. PMID- 22836232 TI - Adipose triglyceride lipase (ATGL) clone, expression pattern, and regulation by different lipid sources and lipid levels in large yellow croaker (Pseudosciaena crocea R.). AB - Adipose triglyceride lipase (ATGL) was recently identified as a triglyceride (TG) specific lipase. In this study, we first obtained from large yellow croaker fish a 1,820-bp (GenBank ID: HQ916211) ATGL cDNA fragment with a 141-bp 5'UTR, a 1,485 bp open reading frame, and a 194-bp 3'UTR. The predicted fish ATGL had 494 amino acids (GenBank ID: ADY89608) and a calculated molecular weight of 55.1 kDa. ATGL was highly expressed in liver and, to a lesser degree, in heart, muscle, and abdominal fat. ATGL gene expression was high at 4.5 g and then decreased at 157.9 g and increased again at 474.2 g. The effects of lipid levels and lipid sources on ATGL expression in vivo were also investigated. A high-lipid diet decreased ATGL expression in fish significantly (P < 0.01). Fish in soybean oil group exhibited significantly lower ATGL expression than fish in the fish oil and beef tallow groups (P < 0.01). These data enhance our understanding of ATGL in fish lipid metabolism. PMID- 22836234 TI - Generation of mesenchymal stem cell lines from murine bone marrow. AB - Mesenchymal stem cells (MSC), because of their multipotency and ease of purification and amplification, are an ideal stem cell source for cell therapies. Bone-marrow-derived stem cells (BMSC) can be used to develop MSC-like immortalized cell lines with large proliferation and differentiation potentialities. Their immortalized status prevents the maintenance of MSC function and characters; this can be negated by modifying the isolation and maintenance protocol. Adult murine BMSC were isolated and maintained in media without additional growth factors together with passage-dependent reseeding following trypsinization. Cells maintained over 25 passages were considered as putative cell lines and characterized. The phenotypic and genotypic characteristics and multilineage differentiation potential of the cells were assessed by morphological, phenotypic, and molecular assays at various passages. The putative BMSC cell lines showed the characteristics of MSC and were able to maintain these characteristics, even after immortalization. The phenotypic data demonstrated difference among two cell lines; this was further validated by the difference in their multilineage differentiation potential following specific induction. More importantly, no changes were observed in the genotypic level in comparison with control cells, even after more than 50 passages. Our protocol thus advances the isolation and maintenance of BMSC and the development of putative BMSC cell lines that maintain characteristics of MSC, including multilineage differentiation potential, after more than 40 passages. PMID- 22836233 TI - The short-term effect of 24-h average and peak air pollution on mortality in Oslo, Norway. AB - Numerous epidemiological studies have shown associations between increases in outdoor air pollution and all-cause mortality as well as cardiovascular and respiratory related mortality. The majority of studies has used the routine monitoring network and thus has not been able to characterize the small-scale variation in daily averages and peak concentrations within urban settings. To address possible short term impact on mortally by air pollution we used a time stratified case-crossover design to estimate associations of traffic-related air pollution and wood burning and daily mortality during a period of 10 years among residents above 50 years of age in Oslo, Norway. A dispersion model was used to assess short-term air pollution for daily (24-h) averages and peak concentrations of nitrogen dioxide (NO(2)) from exhaust and particulate matter with a diameter of 2.5 MUm or less (PM(2.5)) from exhaust and wood-burning at residential neighbourhood level for each individual. We found an overall increased risk from exposure at the lag of 0-5 days before the day of death for both pollutants. The excess risk was highest for PM(2.5) with a 2.8 % (95 % confidence interval: 1.2 4.4) increase per 10 MUg per cubic meter change in daily exposure. Short-term traffic-related air pollution was associated with increased risk for mortality among individuals above 50 years of age, especially for circulatory outcomes. PMID- 22836235 TI - Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice. AB - Numerous epidemiological studies have established acute brain injury as one of the major risk factors for the Alzheimer's disease (AD). However, the lack of animal models of AD-like degeneration triggered by a defined injury hampered the development of adequate therapies. Here we report that the surgical damage of the olfactory bulbs triggers the development of several pathologies, including amyloid-beta accumulation and strong decrease of neuron density in the cortex and hippocampus as well as significant disturbance of spatial memory. Characteristically, these harmful consequences of the olfactory bulbectomy (OBX) have a peculiar dynamics in time with maximal manifestation in periods of 1-1.5 months and 8 months after the surgery and, hence, exhibit biphasic pattern with almost complete recovery period taking place at 5-6 months after the operation. The quantitative determination of endogenous inducible form of Hsp70 in different brain areas of OBX mice demonstrated characteristic fluctuations of Hsp70 levels depending on the time after the operation and age of mice. Interestingly, maximal induction of Hsp70 synthesis in the hippocampus exhibits clear-cut coincidence with the recovery period in OBX animals. The observed correlation enables to suggest curing effect of Hsp70 synthesis at an earlier period of pathology development and establishes it as a possible therapeutic agent for secondary grave consequences of brain injury, such as AD-like degeneration, for which neuroprotective therapy is urgently needed. PMID- 22836236 TI - Cu(I)-catalyzed atom transfer radical cyclization of trichloroacetamides tethered to electron-deficient, -neutral, and -rich alkenes: synthesis of polyfunctionalized 2-azabicyclo[3.3.1]nonanes. AB - A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(I) catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported. PMID- 22836237 TI - Surgery for craniopharyngioma. AB - Craniopharyngiomas are rare benign sellar region tumors, which are diagnosed either in childhood or adolescence due to local mass effects on visual pathways, pituitary and hypothalamus, or because of an increased intracranial pressure resulting from obstructive hydrocephalus. The neurosurgeons challenge is to achieve tumor control without aggravating the symptoms. There are essentially two different surgical philosophies. Although only gross tumor resection has been proven to provide cure, the accompanying surgical hazard is substantial. Thus, less aggressive operations with partial or subtotal tumor resection or drainage of cystic portions followed by irradiation may relieve the patient's symptoms and benefit the patient more than a heroic tumor resection-since to date several variants of radiation therapy are available which also serve to control tumor progression. In the present brief review, the surgical techniques and outcomes of operations in craniopharyngiomas with special focus on the resulting morbidity and mortality are summarized. PMID- 22836238 TI - Augmented ocular vestibular evoked myogenic potentials to air-conducted sound in large vestibular aqueduct syndrome. AB - OBJECTIVE: To demonstrate the value of recording air-conducted ocular Vestibular Evoked Myogenic Potentials (oVEMP) in a patient with bilaterally enlarged vestibular aqueducts. DESIGN: Cervical VEMP and oVEMP were recorded from a patient presenting with bilateral hearing loss and imbalance, attributable to large vestibular aqueduct syndrome. The stimuli were air-conducted tone bursts at octave frequencies from 250 to 2000 Hz. Amplitudes and thresholds were measured and compared with the normal response range of 32 healthy control subjects. RESULTS: oVEMP reflexes demonstrated pathologically increased amplitudes and reduced thresholds for low-frequency tone bursts. Cervical VEMP amplitudes and thresholds were within normal limits for both ears across all frequencies of stimulation. CONCLUSIONS: This study is the first to describe the augmentation of AC oVEMPs in an adult with large vestibular aqueduct syndrome. PMID- 22836240 TI - Doctors urge hospitals to adopt national system for scoring acutely ill patients. PMID- 22836239 TI - Release from perceptual masking for children and adults: benefit of a carrier phrase. AB - OBJECTIVES: The purpose of this study was to test the hypothesis that a carrier phrase can improve word recognition performance for both children and adults by providing an auditory grouping cue. It was hypothesized that the carrier phrase would benefit listeners under conditions in which they have difficulty in perceptually separating the target word from the competing background. To test this hypothesis, word recognition was examined for maskers that were believed to vary in their ability to create perceptual masking. In addition to determining the conditions under which a carrier-phrase benefit is obtained, age-related differences in both susceptibility to masking and carrier-phrase benefit were examined. DESIGN: Two experiments were conducted to characterize developmental effects in the ability to benefit from a carrier phrase (i.e., "say the word") before the target word. Using an open-set task, word recognition performance was measured for three listener age groups: 5- to 7-year-old children, 8- to 10-year old children, and adults (18-30 years). For all experiments, target words were presented in each of two carrier-phrase conditions: (1) carrier-present and (2) carrier-absent. Across experiments, word recognition performance was assessed in the presence of multi-talker babble (Experiment 1), two-talker speech (Experiment 2), or speech-shaped noise (Experiment 2). RESULTS: Children's word recognition performance was generally poorer than that of adults for all three masker conditions. Differences between the two age groups of children were seen for both speech-shaped noise and multi-talker babble, with 5- to 7-year-olds performing more poorly than 8- to 10-year-olds. However, 5- to 7-year-olds and 8- to 10-year olds performed similarly for the two-talker masker. Despite developmental effects in susceptibility to masking, both groups of children and adults showed a carrier phrase benefit in multi-talker babble (Experiment 1) and in the two-talker masker (Experiment 2). The magnitude of the carrier-phrase benefit was similar for a given masker type across age groups, but the carrier-phrase benefit was greater in the presence of the two-talker masker than in multi-talker babble. Specifically, the children's average carrier-phrase benefit was 7.1% for multi talker and 16.8% for the two-talker masker condition. No carrier-phrase benefit was observed for any age group in the presence of speech-shaped noise. CONCLUSIONS: Effects of auditory masking on word recognition performance were greater for children than for adults. The time course of development for susceptibility to masking seems to be more prolonged for a two-talker speech masker than for multi-talker babble or speech-shaped noise. Unique to the present study, this work suggests that a carrier phrase can provide an effective auditory grouping cue for both children and adults under conditions expected to produce substantial perceptual masking. PMID- 22836241 TI - Brownian motion-magnetophoresis of nano/micro-particles. AB - A new magnetophoresis method to determine the magnetic susceptibility of single nano/microparticles was developed by applying Brownian motion analysis to determine the size of the particle. This method could measure simultaneously both the magnetophoretic velocity and the radius of the identical single nano/microparticles, which are necessary for the determination of the magnetic susceptibility of the particle. The advantage of this method was demonstrated by the measurement of the diamagnetic susceptibilities of polystyrene particles 500 nm-3 MUm in diameter in a paramagnetic 0.5 M manganese(II) chloride solution under a high magnetic field gradient of 5180 T(2) m(-1) generated by a small magnetic circuit. PMID- 22836242 TI - Minimally displaced tibial tuberosity avulsion fracture in nine skeletally immature large breed dogs. AB - OBJECTIVE: The objective of this study was to describe the clinical and radiographic features, as well as the treatment and outcome of minimally displaced tibial-tuberosity-avulsion-fractures (MDTTAF). MATERIALS AND METHODS: Signalment, history, diagnostics, therapy, and outcome were recorded. Follow-up was documented as re-examination, radiographic assessment or telephone conversation. RESULTS: Nine large breed dogs that were presented with lameness originating from the proximal tibia were included. All showed signs of pain when pressure was applied to the tibial tuberosity. There was no stifle instability or intra-articular disease. The main feature on mediolateral radiographs was a widened tibial-tuberosity-physis with reactive new bone and loss of edge definition of the epiphyseal and metaphyseal margins. Non-surgical treatment was chosen in eight dogs, and surgery in one dog. Radiographic follow-up showed progressive closure of the tibial-tuberosity-physis and healing. Clinical signs resolved at a median of 28 days (range: 14-120). DISCUSSION: Minimally displaced tibial-tuberosity-avulsion-fractures should be a differential diagnosis in skeletally immature large breed dogs older than nine months of age with signs of subtle pelvic-limb lameness, and signs of proximal tibial pain, but no evidence of stifle joint disease. Thorough clinical examination and critical review of bilateral radiographs are important to diagnose MDTTAF. The outcome in these cases suggests that the prognosis for MDTTAF is excellent. Age and size of the affected dogs in this study differ from an earlier publication that illustrated more severely displaced tibial tuberosity avulsion fractures, occurring mainly in terriers around five months of age. PMID- 22836243 TI - On Coulomb drag in double layer systems. AB - We argue, for a wide class of systems including graphene, that in the low temperature, high density, large separation and strong screening limits the drag resistivity behaves as d(-4), where d is the separation between the two layers. The results are independent of the energy dispersion relation, the dependence on momentum of the transport time, and the electronic wave function structure. We discuss how a correct treatment of the electron-electron interactions in an inhomogeneous dielectric background changes the theoretical analysis of the experimental drag results of Kim et al (2011 Phys. Rev. B 83 161401). We find that a quantitative understanding of the available experimental data (Kim et al 2011 Phys. Rev. B 83 161401) for drag in graphene is lacking. PMID- 22836244 TI - Differential diagnosis and management of ankylosing spondylitis masked as adhesive capsulitis: a resident's case problem. AB - STUDY DESIGN: Resident's case problem. BACKGROUND: Ankylosing spondylitis is a potentially debilitating seronegative spondyloarthropathy, with inflammatory low back pain as the most commonly reported symptom. In the absence of low back pain, identification of other diagnostic criteria or associated impairments and joint involvement, such as involvement of the hip or shoulder, may be beneficial. DIAGNOSIS: A 32-year-old man with right shoulder pain and decreased range of motion was referred with a diagnosis of adhesive capsulitis. He had been managed by multiple healthcare providers for 3 years before being referred to a physical therapist. Glenoid labral pathology was evident on prior magnetic resonance imaging, which had led to a persistent focus on the shoulder. The evaluation by the physical therapist revealed significant mobility deficits in the cervical, thoracic, and lumbar spine. Radiographs and laboratory tests were ordered and a referral was made to rheumatology after the initial physical therapy assessment. The diagnostic work-up confirmed the diagnosis of ankylosing spondylitis and led to multidisciplinary management of the disease. DISCUSSION: Low back pain is often the primary symptom of ankylosing spondylitis later in the disease process. Earlier indicators of ankylosing spondylitis, such as severely impaired mobility and spine stiffness, may help guide detection in the absence of spinal pain. In this case, an appropriate diagnosis led to improvement in the management strategy of what might have appeared to be unrelated shoulder pain. Early differential diagnosis is important, as emerging interventions show promise when used earlier in the disease process. PMID- 22836245 TI - Cortical selectivity through random connectivity. PMID- 22836246 TI - Optogenetic activation of basal forebrain cholinergic neurons modulates neuronal excitability and sensory responses in the main olfactory bulb. AB - The main olfactory bulb (MOB) in mammals receives massive centrifugal input from cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, the activity of which is thought to be correlated with animal behaving states, such as attention. Cholinergic signals in the bulb facilitate olfactory discrimination and learning, but it has remained controversial how the activity of HDB cholinergic neurons modulates neuronal excitability and olfactory responses in the MOB. In this study, we used an optogenetic approach to selectively activate HDB cholinergic neurons and recorded the effect of this activation on the spontaneous firing activity and odor-evoked responses of mouse MOB neurons. Cells were juxtacellularly labeled and their specific types were morphologically determined. We find that light stimulation of HDB cholinergic neurons inhibits the spontaneous firing activity of all major cell types, including mitral/tufted (M/T) cells, periglomerular (PG) cells, and GABAergic granule cells. Inhibitions are significantly produced by stimulation at 10 Hz and further enhanced at higher frequencies. In addition, cholinergic activation sharpens the olfactory tuning curves of a majority of M/T cells but broadly potentiates odor-evoked responses of PG cells and granule cells. These results demonstrate strong effects of the basal forebrain cholinergic system on modulating neuronal excitability in the MOB and support the hypothesis that cholinergic activity increases olfactory discrimination capability. PMID- 22836248 TI - alpha-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling pool homeostasis. AB - Although the presynaptic protein alpha-synuclein is a recognized player in neurodegeneration, its precise physiologic function(s) and/or role in human disease remains unclear. An emerging consensus from previous studies in lower order systems is that alpha-synuclein interferes with vesicle-trafficking pathways; however putative neuronal correlates are unknown. Here we explore consequences of alpha-synuclein modulation in cultured mouse hippocampal neurons; coupling alpha-synuclein overexpression and knock-out model-systems with contemporary imaging paradigms. Our studies reveal an unexpected role of alpha synuclein in attenuating the mobility of recycling pool (RP) vesicles between presynaptic boutons--called "superpool" trafficking--and also in maintaining the overall size of RPs at synapses. While an excess of alpha-synuclein led to smaller RPs and inhibited intersynaptic trafficking, an absence of alpha synuclein triggered converse changes with larger RPs and enhanced intersynaptic trafficking. The data collectively suggest a model where alpha-synuclein maintains RP homeostasis by modulating intersynaptic vesicular dynamics, and provide a putative neuronal correlate of alpha-synuclein-induced impairments in vesicle-trafficking previously reported in lower-order systems. PMID- 22836250 TI - Simultaneous glucocorticoid and noradrenergic activity disrupts the neural basis of goal-directed action in the human brain. AB - Stress promotes a shift from goal-directed action-outcome learning toward habitual stimulus-response learning. This shift is mediated by an interaction of noradrenergic activity and glucocorticoid stress hormones. In the present experiment, we examined the neural correlates of the stress (hormone)-induced shift from goal-directed to habit learning in the human brain. Healthy participants were administered hydrocortisone, the alpha2-adrenoceptor antagonist yohimbine, or both before they were trained in two instrumental actions leading to two distinct food rewards. After training, one of the rewards was devalued by feeding participants to satiety on that food. Finally, participants were presented the two instrumental actions in extinction. We collected functional magnetic resonance images both during instrumental training and during extinction testing. Our behavioral data confirmed that the simultaneous administration of hydrocortisone and yohimbine renders instrumental behavior insensitive to the outcome devaluation (and thus habitual), whereas hydrocortisone or yohimbine alone have no such effect. At the neural level, the combined administration of hydrocortisone and yohimbine reduced the sensitivity of the orbitofrontal and medial prefrontal cortex to changes in outcome value. Brain areas that have been previously implicated in habit learning were not modulated by hydrocortisone and yohimbine. These findings suggest that concurrent glucocorticoid and noradrenergic activity disrupts the neural bases of goal-directed action and thus renders behavior habitual. PMID- 22836249 TI - NADPH oxidase-4 maintains neuropathic pain after peripheral nerve injury. AB - Reactive oxygen species (ROS) contribute to sensitization of pain pathways during neuropathic pain, but little is known about the primary sources of ROS production and how ROS mediate pain sensitization. Here, we show that the NADPH oxidase isoform Nox4, a major ROS source in somatic cells, is expressed in a subset of nonpeptidergic nociceptors and myelinated dorsal root ganglia neurons. Mice lacking Nox4 demonstrated a substantially reduced late-phase neuropathic pain behavior after peripheral nerve injury. The loss of Nox4 markedly attenuated injury-induced ROS production and dysmyelination processes of peripheral nerves. Moreover, persisting neuropathic pain behavior was inhibited after tamoxifen induced deletion of Nox4 in adult transgenic mice. Our results suggest that Nox4 essentially contributes to nociceptive processing in neuropathic pain states. Accordingly, inhibition of Nox4 may provide a novel therapeutic modality for the treatment of neuropathic pain. PMID- 22836247 TI - Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. AB - Alzheimer's disease is associated with a disruption of amyloid beta (Abeta) homeostasis, resulting in the accumulation and subsequent deposition of Abeta peptides within the brain. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor that acts in a coupled metabolic cycle with Liver X Receptors (LXRs) to increase brain apolipoprotein E (apoE) levels. apoE functions to promote the proteolytic clearance of soluble forms of Abeta, and we found that the synthetic PPARgamma agonist, pioglitazone, stimulated Abeta degradation by both microglia and astrocytes in an LXR and apoE dependent manner. Remarkably, a brief 9 d oral treatment of APPswe/PS1Deltae9 mice with pioglitazone resulted in dramatic reductions in brain levels of soluble and insoluble Abeta levels which correlated with the loss of both diffuse and dense-core plaques within the cortex. The removal of preexisting amyloid deposits was associated with the appearance of abundant Abeta-laden microglia and astrocytes. Pioglitazone treatment resulted in the phenotypic polarization of microglial cells from a proinflammatory M1 state, into an anti-inflammatory M2 state that was associated with enhanced phagocytosis of deposited forms of amyloid. The reduction in amyloid levels was associated with a reversal of contextual memory deficits in the drug-treated mice. These data provide a mechanistic explanation for how PPARgamma activation facilitates amyloid clearance and supports the therapeutic utility of PPARgamma agonists for the treatment of Alzheimer's disease. PMID- 22836251 TI - Pan-neuronal expression of APL-1, an APP-related protein, disrupts olfactory, gustatory, and touch plasticity in Caenorhabditis elegans. AB - Patients with Alzheimer's disease show age-related cognitive decline. Postmortem autopsy of their brains shows the presence of large numbers of senile plaques, whose major component is the beta-amyloid peptide. The beta-amyloid peptide is a cleavage product of the amyloid precursor protein (APP). In addition to the neurodegeneration associated with beta-amyloid aggregation in Alzheimer's disease patients, mutations in APP in mammalian model organisms have also been shown to disrupt several behaviors independent of visible amyloid plaque formation. However, the pathways in which APP function are unknown and difficult to unravel in mammals. Here we show that pan-neuronal expression of APL-1, the Caenorhabditis elegans ortholog of APP, disrupts several behaviors, such as olfactory and gustatory learning behavior and touch habituation. These behaviors are mediated by distinct neural circuits, suggesting a broad impact of APL-1 on sensory plasticity in C. elegans. Furthermore, we found that disruption of these three behaviors requires activity of the TGFbeta pathway and reduced activity of the insulin pathway. These results suggest pathways and molecular components that may underlie behavioral plasticity in mammals and in patients with Alzheimer's disease. PMID- 22836253 TI - Intrinsic organization of the anesthetized brain. AB - The neural mechanism of unconsciousness has been a major unsolved question in neuroscience despite its vital role in brain states like coma and anesthesia. The existing literature suggests that neural connections, information integration, and conscious states are closely related. Indeed, alterations in several important neural circuitries and networks during unconscious conditions have been reported. However, how the whole-brain network is topologically reorganized to support different patterns of information transfer during unconscious states remains unknown. Here we directly compared whole-brain neural networks in awake and anesthetized states in rodents. Consistent with our previous report, the awake rat brain was organized in a nontrivial manner and conserved fundamental topological properties in a way similar to the human brain. Strikingly, these topological features were well maintained in the anesthetized brain. Local neural networks in the anesthetized brain were reorganized with altered local network properties. The connectional strength between brain regions was also considerably different between the awake and anesthetized conditions. Interestingly, we found that long-distance connections were not preferentially reduced in the anesthetized condition, arguing against the hypothesis that loss of long-distance connections is characteristic to unconsciousness. These findings collectively show that the integrity of the whole-brain network can be conserved between widely dissimilar physiologic states while local neural networks can flexibly adapt to new conditions. They also illustrate that the governing principles of intrinsic brain organization might represent fundamental characteristics of the healthy brain. With the unique spatial and temporal scales of resting-state fMRI, this study has opened a new avenue for understanding the neural mechanism of (un)consciousness. PMID- 22836252 TI - Balanced increases in selectivity and tolerance produce constant sparseness along the ventral visual stream. AB - Although popular accounts suggest that neurons along the ventral visual processing stream become increasingly selective for particular objects, this appears at odds with the fact that inferior temporal cortical (IT) neurons are broadly tuned. To explore this apparent contradiction, we compared processing in two ventral stream stages (visual cortical areas V4 and IT) in the rhesus macaque monkey. We confirmed that IT neurons are indeed more selective for conjunctions of visual features than V4 neurons and that this increase in feature conjunction selectivity is accompanied by an increase in tolerance ("invariance") to identity preserving transformations (e.g., shifting, scaling) of those features. We report here that V4 and IT neurons are, on average, tightly matched in their tuning breadth for natural images ("sparseness") and that the average V4 or IT neuron will produce a robust firing rate response (>50% of its peak observed firing rate) to ~10% of all natural images. We also observed that sparseness was positively correlated with conjunction selectivity and negatively correlated with tolerance within both V4 and IT, consistent with selectivity-building and invariance-building computations that offset one another to produce sparseness. Our results imply that the conjunction-selectivity-building and invariance building computations necessary to support object recognition are implemented in a balanced manner to maintain sparseness at each stage of processing. PMID- 22836254 TI - Multiple inhibitory G-protein-coupled receptors resist acute desensitization in the presynaptic but not postsynaptic compartments of neurons. AB - Acute desensitization is a common property of G(i/o)-coupled receptors. Recent data, however, suggest that, unlike MU-opioid receptors (MORs) located somatodendritically in neurons or expressed in heterologous systems, MORs in the presynaptic compartment of neurons are resistant to acute desensitization. It is not yet clear whether this differential desensitization is a shared property of many G(i/o)-coupled receptors nor whether receptors located presynaptically and postsynaptically in a single cell type display differential desensitization. Here, whole-cell recordings were made from proopiomelanocortin (POMC) neurons in mouse brain slices. Agonists for MU-opioid, nociceptin, and GABA(B) receptors induced postsynaptic currents that desensitized within minutes, whereas inhibition of presynaptic transmitter release mediated by these receptors was maintained throughout agonist exposure. Expression of channelrhodopsin2 in POMC neurons allowed for light-evoked transmitter release from POMC neuron terminals, which was detected by recording postsynaptic currents in downstream neurons. Light-evoked currents were inhibited throughout the application of all agonists tested. Thus, the same receptors that desensitize when expressed in the postsynaptic compartment of POMC neurons resist desensitization when located in the presynaptic compartment. Pharmacologic knockdown of MORs revealed that depletion of receptor reserve does not account for presynaptic resistance to desensitization. In ~25% of recordings with GABA(B) agonist application, presynaptic GABA(B) receptors desensitized, suggesting that resistance to desensitization is not due to an intrinsic property of the terminals themselves. Together, the results indicate that a variety of presynaptic receptors can continue to function after their postsynaptic counterparts desensitize and suggest that a compartment-specific modification may confer resistance to desensitization. PMID- 22836255 TI - Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology. AB - Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that the therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD. PMID- 22836256 TI - Directional responding of C57BL/6J mice in the Morris water maze is influenced by visual and vestibular cues and is dependent on the anterior thalamic nuclei. AB - Recent findings indicate that rats navigate in spatial tasks such as the Morris water maze (MWM) using a local cue-based reference frame rather than a distal cue based reference frame. Specifically, rats swim in a particular direction to a location relative to pool-based cues, rather than to an absolute location defined by room-based cues. Neural mechanisms supporting this bias in rodents for relative responding in spatial tasks are not yet understood. Anterior thalamic neurons discharge according to the current directional heading of the animal. The contribution of head direction (HD) cell activity to navigation has been difficult to elucidate. We found that male C57BL/6J mice trained for 4 or 7 d in the MWM exhibited an overwhelming preference for swimming in a direction relative to pool-based cues over absolute responding during a platform-less probe test. Rotation of extramaze cues caused a corresponding rotation of the direction mice swam during the probe test, suggesting that both pool- and room-based reference frames guide platform search. However, disorienting the mice before the probe test disturbed relative responding. Therefore, relative responding is guided by both internal and external cue sources. Selective inactivation of anterior thalamic nuclei (ATN) by microinfusion of muscimol or fluorophore-conjugated muscimol caused a near complete shift in preference from relative to absolute responding. Interestingly, inactivation of the dorsal CA1 region of the hippocampus did not affect relative responding. These data suggest that ATN, and HD cells therein, may guide relative responding in the MWM, a task considered by most to reflect hippocampal processing. PMID- 22836257 TI - alpha6* nicotinic acetylcholine receptor expression and function in a visual salience circuit. AB - Nicotinic acetylcholine receptors (nAChRs) containing alpha6 subunits are expressed in only a few brain areas, including midbrain dopamine (DA) neurons, noradrenergic neurons of the locus ceruleus, and retinal ganglion cells. To better understand the regional and subcellular expression pattern of alpha6 containing nAChRs, we created and studied transgenic mice expressing a variant alpha6 subunit with green fluorescent protein (GFP) fused in-frame in the M3-M4 intracellular loop. In alpha6-GFP transgenic mice, alpha6-dependent synaptosomal DA release and radioligand binding experiments confirmed correct expression and function in vivo. In addition to strong alpha6* nAChR expression in glutamatergic retinal axons, which terminate in superficial superior colliculus (sSC), we also found alpha6 subunit expression in a subset of GABAergic cell bodies in this brain area. In patch-clamp recordings from sSC neurons in brain slices from mice expressing hypersensitive alpha6* nAChRs, we confirmed functional, postsynaptic alpha6* nAChR expression. Further, sSC GABAergic neurons expressing alpha6* nAChRs exhibit a tonic conductance mediated by standing activation of hypersensitive alpha6* nAChRs by ACh. alpha6* nAChRs also appear in a subpopulation of SC neurons in output layers. Finally, selective activation of alpha6* nAChRs in vivo induced sSC neuronal activation as measured with c-Fos expression. Together, these results demonstrate that alpha6* nAChRs are uniquely situated to mediate cholinergic modulation of glutamate and GABA release in SC. The SC has emerged as a potential key brain area responsible for transmitting short-latency salience signals to thalamus and midbrain DA neurons, and these results suggest that alpha6* nAChRs may be important for nicotinic cholinergic sensitization of this pathway. PMID- 22836258 TI - Unravelling the intrinsic functional organization of the human lateral frontal cortex: a parcellation scheme based on resting state fMRI. AB - Human and nonhuman primates exhibit flexible behavior. Functional, anatomical, and lesion studies indicate that the lateral frontal cortex (LFC) plays a pivotal role in such behavior. LFC consists of distinct subregions exhibiting distinct connectivity patterns that possibly relate to functional specializations. Inference about the border of each subregion in the human brain is performed with the aid of macroscopic landmarks and/or cytoarchitectonic parcellations extrapolated in a stereotaxic system. However, the high interindividual variability, the limited availability of cytoarchitectonic probabilistic maps, and the absence of robust functional localizers render the in vivo delineation and examination of the LFC subregions challenging. In this study, we use resting state fMRI for the in vivo parcellation of the human LFC on a subjectwise and data-driven manner. This approach succeeds in uncovering neuroanatomically realistic subregions, with potential anatomical substrates including BA 46, 44, 45, 9 and related (sub)divisions. Ventral LFC subregions exhibit different functional connectivity (FC), which can account for different contributions in the language domain, while more dorsal adjacent subregions mark a transition to visuospatial/sensorimotor networks. Dorsal LFC subregions participate in known large-scale networks obeying an external/internal information processing dichotomy. Furthermore, we traced "families" of LFC subregions organized along the dorsal-ventral and anterior-posterior axis with distinct functional networks also encompassing specialized cingulate divisions. Similarities with the connectivity of macaque candidate homologs were observed, such as the premotor affiliation of presumed BA 46. The current findings partially support dominant LFC models. PMID- 22836259 TI - Soluble alpha-synuclein is a novel modulator of Alzheimer's disease pathophysiology. AB - Recent evidence has emphasized soluble species of amyloid-beta (Abeta) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Abeta, tau, and alpha-synuclein (alphaSyn) can promote each other's aggregation, the potential contribution of soluble alphaSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble alphaSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble alphaSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Abeta and tau levels. To examine a putative role for alphaSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type alphaSyn. The results revealed that an approximate threefold elevation of alphaSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble alphaSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Abeta/APP and human tau seems to be responsible for the abnormal elevation of soluble alphaSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal alphaSyn in AD pathophysiology. PMID- 22836260 TI - Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens. AB - DeltaFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of DeltaFosB mRNA and faster accumulation of DeltaFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of DeltaFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. A cocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine. PMID- 22836261 TI - Supplementary eye field during visual search: salience, cognitive control, and performance monitoring. AB - How supplementary eye field (SEF) contributes to visual search is unknown. Inputs from cortical and subcortical structures known to represent visual salience suggest that SEF may serve as an additional node in this network. This hypothesis was tested by recording action potentials and local field potentials (LFPs) in two monkeys performing an efficient pop-out visual search task. Target selection modulation, tuning width, and response magnitude of spikes and LFP in SEF were compared with those in frontal eye field. Surprisingly, only ~2% of SEF neurons and ~8% of SEF LFP sites selected the location of the search target. The absence of salience in SEF may be due to an absence of appropriate visual afferents, which suggests that these inputs are a necessary anatomical feature of areas representing salience. We also tested whether SEF contributes to overcoming the automatic tendency to respond to a primed color when the target identity switches during priming of pop-out. Very few SEF neurons or LFP sites modulated in association with performance deficits following target switches. However, a subset of SEF neurons and LFPs exhibited strong modulation following erroneous saccades to a distractor. Altogether, these results suggest that SEF plays a limited role in controlling ongoing visual search behavior, but may play a larger role in monitoring search performance. PMID- 22836262 TI - Perception via the deviated eye in strabismus. AB - Misalignment of the eyes can lead to double vision and visual confusion. However, these sensations are rare when strabismus is acquired early in life, because the extra image is suppressed. To explore the mechanism of perceptual suppression in strabismus, the visual fields were mapped binocularly in 14 human subjects with exotropia. Subjects wore red/blue filter glasses to permit dichoptic stimulation while fixating a central target on a tangent screen. A purple stimulus was flashed at a peripheral location; its reported color ("red" or "blue") revealed which eye's image was perceived at that locus. The maps showed a vertical border between the center of gaze for each eye, splitting the visual field into two separate regions. In each region, perception was mediated by only one eye, with suppression of the other eye. Unexpectedly, stimuli falling on the fovea of the deviated eye were seen in all subjects. However, they were perceived in a location shifted by the angle of ocular deviation. This plasticity in the coding of visual direction allows accurate localization of objects everywhere in the visual scene, despite the presence of strabismus. PMID- 22836263 TI - Reward prediction error signaling in posterior dorsomedial striatum is action specific. AB - Neural correlates of reward prediction errors (RPEs) have been found in dorsal striatum. Such signals may be important for updating associative action representations within striatum. In order that the appropriate representations can be updated, it might be important for the RPE signal to be specific for the action that led to that error. However, RPEs signaled by midbrain dopamine neurons, which project heavily to striatum, are not action-specific. Here we tested whether RPE-like activity in dorsal striatum is action-specific; we recorded single-unit activity in posterior dorsomedial and dorsolateral striatum as rats performed a task in which the reward predictions associated with two different actions were repeatedly violated, thereby eliciting RPEs. We separately analyzed fast firing neurons (FFNs) and phasically firing neurons (total n = 1076). Only among FFNs recorded in posterior dorsomedial striatum did we find a population with RPE-like characteristics (19 of all 196 FFNs, 10%). This population showed a phasic increase in activity during unexpected rewards, a phasic decrease in activity during unexpected omission of rewards, and a phasic increase in activity during cues when they predicted high-value reward. However, unlike a classical RPE signal, this signal was linked to the action that elicited the prediction error, in that neurons tended to signal RPEs only after their anti preferred action. This action-specific RPE-like signal could provide a mechanism for updating specific associative action representations in posterior dorsomedial striatum. PMID- 22836264 TI - Diverse strategies engaged in establishing stereotypic wiring patterns among neurons sharing a common input at the visual system's first synapse. AB - Sensory circuits use common strategies, such as convergence and divergence, typically at different synapses, to pool or distribute inputs. Inputs from different presynaptic cell types converge onto a common postsynaptic cell, acting together to shape neuronal output (Klausberger and Somogyi, 2008). Also, individual presynaptic cells contact several postsynaptic cell types, generating divergence of signals. Attaining such complex wiring patterns relies on the orchestration of many events across development, including axonal and dendritic growth and synapse formation and elimination (reviewed by Waites et al., 2005; Sanes and Yamagata, 2009). Recent work has focused on how distinct presynaptic cell types form stereotypic connections with an individual postsynaptic cell (Morgan et al., 2011; Williams et al., 2011), but how a single presynaptic cell type diverges to form distinct wiring patterns with multiple postsynaptic cell types during development remains unexplored. Here we take advantage of the compactness of the visual system's first synapse to observe development of such a circuit in mouse retina. By imaging three types of postsynaptic bipolar cells and their common photoreceptor targets across development, we found that distinct bipolar cell types engage in disparate dendritic growth behaviors, exhibit targeted or exploratory approaches to contact photoreceptors, and adhere differently to the synaptotropic model of establishing synaptic territories. Furthermore each type establishes its final connectivity patterns with the same afferents on separate time scales. We propose that such differences in strategy and timeline could facilitate the division of common inputs among multiple postsynaptic cell types to create parallel circuits with diverse function. PMID- 22836265 TI - Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex. AB - The ventromedial prefrontal cortex (vmPFC) is thought to be related to emotional experience and to the processing of stimulus and action values. However, little is known about how single vmPFC neurons process the prediction and reception of rewards and punishments. We recorded from monkey vmPFC neurons in an experimental situation with alternating blocks, one in which rewards were delivered and one in which punishments were delivered. Many vmPFC neurons changed their activity between blocks. Importantly, neurons in ventral vmPFC were persistently more active in the appetitive "reward" block, whereas neurons in dorsal vmPFC were persistently more active in the aversive "punishment" block. Furthermore, within ventral vmPFC, posterior neurons phasically encoded probability of reward, whereas anterior neurons tonically encoded possibility of reward. We found multiple distinct nonlinear valuation mechanisms within the primate prefrontal cortex. Our findings suggest that different subregions of vmPFC contribute differentially to the processing of valence. By conveying such multidimensional and nonlinear signals, the vmPFC may enable flexible control of decisions and emotions to adapt to complex environments. PMID- 22836266 TI - Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility. AB - The cannabinoid receptor 1 (CB(1)R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB(1)R that regulate these physiological functions are unknown. CB(1)R is widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB(1)R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB(1)R in afferent and efferent branches of the vagus nerve (Cnr1(flox/flox); Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1(flox/flox); Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1(flox/flox) control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4 chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB(1)R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1(flox/flox); Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB(1)R in the vagus nerve as a key component underlying normal gastrointestinal motility. PMID- 22836267 TI - Compromise of auditory cortical tuning and topography after cross-modal invasion by visual inputs. AB - Brain damage resulting in loss of sensory stimulation can induce reorganization of sensory maps in cerebral cortex. Previous research on recovery from brain damage has focused primarily on adaptive plasticity within the affected modality. Less attention has been paid to maladaptive plasticity that may arise as a result of ectopic innervation from other modalities. Using ferrets in which neonatal midbrain damage results in diversion of retinal projections to the auditory thalamus, we investigated how auditory cortical function is impacted by the resulting ectopic visual activation. We found that, although auditory neurons in cross-modal auditory cortex (XMAC) retained sound frequency tuning, their thresholds were increased, their tuning was broader, and tonotopic order in their frequency maps was disturbed. Multisensory neurons in XMAC also exhibited frequency tuning, but they had longer latencies than normal auditory neurons, suggesting they arise from multisynaptic, non-geniculocortical sources. In a control group of animals with neonatal deafferentation of auditory thalamus but without redirection of retinal axons, tonotopic order and sharp tuning curves were seen, indicating that this aspect of auditory function had developed normally. This result shows that the compromised auditory function in XMAC results from invasion by ectopic visual inputs and not from deafferentation. These findings suggest that the cross-modal plasticity that commonly occurs after loss of sensory input can significantly interfere with recovery from brain damage and that mitigation of maladaptive effects is critical to maximizing the potential for recovery. PMID- 22836268 TI - ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons. AB - Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of alpha9 integrin promotes axon regeneration, so we have investigated alpha9beta1 trafficking and transport in axons and at the growth cone. We have previously found that alpha9 and beta1 integrins traffic via Rab11 positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied alpha9 and beta1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of beta1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury. PMID- 22836269 TI - Differential ubiquitination and proteasome regulation of Ca(V)2.2 N-type channel splice isoforms. AB - Ca(V)2.2 (N-type) calcium channels control the entry of calcium into neurons to regulate essential functions but most notably presynaptic transmitter release. Ca(V)2.2 channel expression levels are precisely controlled, but we know little of the cellular mechanisms involved. The ubiquitin proteasome system (UPS) is known to regulate expression of many synaptic proteins, including presynaptic elements, to optimize synaptic efficiency. However, we have limited information about ubiquitination of Ca(V)2 channels. Here we show that Ca(V)2.2 proteins are ubiquitinated, and that elements in the proximal C terminus of Ca(V)2.2 encoded by exon 37b of the mouse Cacna1b gene predispose cloned and native channels to downregulation by the UPS. Ca(V)2.2 channels containing e37b are expressed throughout the mammalian nervous system, but in some cells, notably nociceptors, sometimes e37a--not e37b--is selected during alternative splicing of Ca(V)2.2 pre mRNA. By a combination of biochemical and functional analyses we show e37b promotes a form of ubiquitination that is coupled to reduced Ca(V)2.2 current density and increased sensitivity to the UPS. Cell-specific alternative splicing of e37a in nociceptors reduces Ca(V)2.2 channel ubiquitination and sensitivity to the UPS, suggesting a role in pain processing. PMID- 22836271 TI - Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. AB - Growing evidence suggests that galectin-3 is involved in fine tuning of the inflammatory responses at the periphery, however, its role in injured brain is far less clear. Our previous work demonstrated upregulation and coexpression of galectin-3 and IGF-1 in a subset of activated/proliferating microglial cells after stroke. Here, we tested the hypothesis that galectin-3 plays a pivotal role in mediating injury-induced microglial activation and proliferation. By using a galectin-3 knock-out mouse (Gal-3KO), we demonstrated that targeted disruption of the galectin-3 gene significantly alters microglia activation and induces ~4-fold decrease in microglia proliferation. Defective microglia activation/proliferation was further associated with significant increase in the size of ischemic lesion, ~2-fold increase in the number of apoptotic neurons, and a marked deregulation of the IGF-1 levels. Next, our results revealed that contrary to WT cells, the Gal3 KO microglia failed to proliferate in response to IGF-1. Moreover, the IGF-1 mediated mitogenic microglia response was reduced by N-glycosylation inhibitor tunicamycine while coimmunoprecipitation experiments revealed galectin-3 binding to IGF-receptor 1 (R1), thus suggesting that interaction of galectin-3 with the N linked glycans of receptors for growth factors is involved in IGF-R1 signaling. While the canonical IGF-1 signaling pathways were not affected, we observed an overexpression of IL-6 and SOCS3, suggesting an overactivation of JAK/STAT3, a shared signaling pathway for IGF-1/IL-6. Together, our findings suggest that galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. PMID- 22836270 TI - TAG1 regulates the endocytic trafficking and signaling of the semaphorin3A receptor complex. AB - Endocytic trafficking of membrane proteins is essential for neuronal structure and function. We show that Transient Axonal Glycoprotein 1 (TAG1 or CNTN2), a contactin-related adhesion molecule, plays a central role in the differential trafficking of components of the semaphorin3A (Sema3A) receptor complex into distinct endosomal compartments in murine spinal sensory neuron growth cones. The semaphorin3A receptor is composed of Neuropilin1 (NRP1), PlexinA4, and L1, with NRP1 being the ligand-binding component. TAG1 interacts with NRP1, causing a change in its association with L1 in the Sema3A response such that L1 is lost from the complex following Sema3A binding. Initially, however, L1 and NRP1 endocytose together and only become separated intracellularly, with NRP1 becoming associated with endosomes enriched in lipid rafts and colocalizing with TAG1 and PlexinA4. When TAG1 is missing, NRP1 and L1 fail to separate and NRP1 does not become raft associated; colocalization with PlexinA4 is reduced and Plexin signaling is not initiated. These observations identify a novel role for TAG1 in modulating the intracellular sorting of signaling receptor complexes. PMID- 22836273 TI - Attentional cues affect accuracy and reaction time via different cognitive and neural processes. AB - We investigated whether symbolic endogenous attentional cues affect perceptual accuracy and reaction time (RT) via different cognitive and neural processes. We recorded magnetoencephalography in 19 humans while they performed a cued somatosensory discrimination task in which the cue-target interval was varied between 0 and 1000 ms. Comparing behavioral and neural measures, we show that (1) attentional cueing affects accuracy and RT with different time courses and (2) the time course of our neural measure (anticipatory suppression of neuronal oscillations in stimulus-receiving sensory cortex) only accounts for the accuracy time course. A model is proposed in which the effect on accuracy is explained by a single process (preparatory excitability increase in sensory cortex), whereas the effect on RT is explained by an additional process that is sensitive to cue target compatibility (post-target comparison between expected and actual stimulus location). These data provide new insights into the mechanisms underlying behavioral consequences of attentional cueing. PMID- 22836272 TI - Left-right locomotor circuitry depends on RhoA-driven organization of the neuroepithelium in the developing spinal cord. AB - RhoA is a key regulator of cytoskeletal dynamics with a variety of effects on cellular processes. Loss of RhoA in neural progenitor cells disrupts adherens junctions and causes disorganization of the neuroepithelium in the developing nervous system. However, it remains essentially unknown how the loss of RhoA physiologically affects neural circuit formation. Here we show that proper neuroepithelial organization maintained by RhoA GTPase in both the ventral and dorsal spinal cord is critical for left-right locomotor behavior. We examined the roles of RhoA in the ventral and dorsal spinal cord by deleting the gene in neural progenitors using Olig2-Cre and Wnt1-Cre mice, respectively. RhoA-deleted neural progenitors in both mutants exhibit defects in the formation of apical adherens junctions and disorganization of the neuroepithelium. Consequently, the ventricular zone and lumen of the dysplastic region are lost, causing the left and right sides of the gray matter to be directly connected. Furthermore, the dysplastic region lacks ephrinB3 expression at the midline that is required for preventing EphA4-expressing corticospinal neurons and spinal interneurons from crossing the midline. As a result, aberrant neuronal projections are observed in that region. Finally, both RhoA mutants develop a rabbit-like hopping gait. These results demonstrate that RhoA functions to maintain neuroepithelial structures in the developing spinal cord and that proper organization of the neuroepithelium is required for appropriate left-right motor behavior. PMID- 22836274 TI - Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. AB - Many studies have reported the roles played by regulated proteolysis in synaptic plasticity and memory, but the role of autophagy in neurons remains unclear. In mammalian cells, autophagy functions in the clearance of long-lived proteins and organelles and in adaptation to starvation. In neurons, although autophagy related proteins (ATGs) are highly expressed, autophagic activity markers, autophagosome (AP) number, and light chain protein 3-II (LC3-II) are low compared with other cell types. In contrast, conditional knock-out of ATG5 or ATG7 in mouse brain causes neurodegeneration and behavioral deficits. Therefore, this study aimed to test whether autophagy is especially regulated in neurons to adapt to brain functions. In cultured rat hippocampal neurons, we found that KCl depolarization transiently increased LC3-II and AP number, which was partially inhibited with APV, an NMDA receptor (NMDAR) inhibitor. Brief low-dose NMDA, a model of chemical long-term depression (chem-LTD), increased LC3-II with a time course coincident with Akt and mammalian target of rapamycin (mTOR) dephosphorylation and degradation of GluR1, an AMPA receptor (AMPAR) subunit. Downstream of NMDAR, the protein phosphatase 1 inhibitor okadaic acid, PTEN inhibitor bpV(HOpic), autophagy inhibitor wortmannin, and short hairpin RNA mediated knockdown of ATG7 blocked chem-LTD-induced autophagy and partially recovered GluR1 levels. After chem-LTD, GFP-LC3 puncta increased in spines and in dendrites when AP-lysosome fusion was blocked. These results indicate that neuronal stimulation induces NMDAR-dependent autophagy through PI3K-Akt-mTOR pathway inhibition, which may function in AMPAR degradation, thus suggesting autophagy as a contributor to NMDAR-dependent synaptic plasticity and brain functions. PMID- 22836275 TI - Depletion of GGA1 and GGA3 mediates postinjury elevation of BACE1. AB - Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Abeta. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro, indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Abeta levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury. PMID- 22836276 TI - Activity-dependent fusion pore expansion regulated by a calcineurin-dependent dynamin-syndapin pathway in mouse adrenal chromaffin cells. AB - Neuroendocrine chromaffin cells selectively secrete a variety of transmitter molecules into the circulation as a function of sympathetic activation. Activity dependent release of transmitter species is controlled through regulation of the secretory fusion pore. Under sympathetic tone, basal synaptic excitation drives chromaffin cells to selectively secrete modest levels of catecholamine through a restricted secretory fusion pore. In contrast, elevated sympathetic activity, experienced under stress, results in fusion pore expansion to evoke maximal catecholamine release and to facilitate release of copackaged peptide transmitters. Therefore, fusion pore expansion is a key control point for the activation of the sympatho-adrenal stress response. Despite the physiological importance of this process, the molecular mechanism by which it is regulated remains unclear. Here we employ fluorescence imaging with electrophysiological and electrochemical-based approaches to investigate the role of dynamin I in the regulation of activity-mediated fusion pore expansion in mouse adrenal chromaffin cells. We show that under elevated stimulation, dynamin I is dephosphorylated at Ser-774 by calcineurin. We also demonstrate that disruption of dynamin I-syndapin binding, an association regulated by calcineurin-dependent dynamin dephosphorylation, limits fusion pore expansion. Last, we show that perturbation of N-WASP function (a syndapin substrate) limits activity-mediated fusion pore expansion. Our results suggest that fusion pore expansion is regulated by a calcineurin-dependent dephosphorylation of dynamin I. Dephosphorylated dynamin I acts via a syndapin/N-WASP signaling cascade to mediate pore expansion. PMID- 22836277 TI - Associations of vertebral deformities and osteoarthritis with back pain among Japanese women: the Hizen-Oshima study. AB - We examined the spinal distribution of the types of vertebral deformities and the associations of vertebral deformities and osteoarthritis with back pain in Japanese women. Midthoracic and upper lumbar vertebrae were more susceptible to deformity. Vertebral deformity and osteoarthritis were frequent and were associated with back pain. INTRODUCTION: Vertebral fractures due to osteoporosis and osteoarthritis are both common and significant health problems in aged people. However, little is known about the descriptive epidemiology of the individual deformity types and the relative clinical impact in women in Japan. METHODS: Lateral radiographs were obtained from 584 Japanese women ages 40 to 89 years old. Deformities were defined as vertebral heights of more than 3 standard deviations (SDs) below the normal mean. Osteoarthritis was defined as Kellgren Lawrence (KL) grade 2 or higher. Information on upper or low back pain during the previous month was collected by questionnaire. We compared the spinal distribution of the three types of vertebral deformities (wedge, endplate, and crush) typical of fractures and examined the associations of number and type of vertebral deformities and osteoarthritis with back pain. RESULTS: Fifteen percent of women had at least one vertebral deformity and 74% had vertebral osteoarthritis. The prevalence of upper or low back pain was 30.1%. Deformities were most common in the midthoracic and upper lumbar regions and wedge was the frequent type, followed by endplate and crush. Multiple logistic regression analysis showed that the odds of back pain was 3.0 (95% CI 1.5-6.3) times higher for women with a single wedge deformity and 3.2 (95% CI 1.0--0.6) times higher for women with two or more wedge deformities, compared to women with no wedge deformity. Vertebral osteoarthritis was associated with back pain (OR 1.8, 95% CI 1.1-2.9), independent of other covariates including age and deformities. CONCLUSION: Our results in this group of Japanese women are similar to and consistent with results reported previously in other populations of Japanese and Caucasians. PMID- 22836278 TI - Treatment failure in osteoporosis. AB - Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided. INTRODUCTION: This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. METHODS: A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. RESULTS: In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. CONCLUSION: The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue. PMID- 22836281 TI - Conformational analysis of triphenylphosphine in square planar organometallic complexes: [(PPh3)(ML1L2L3)] and [M(acac)(L')(PPh3)]. AB - The conformation analysis of free PPh(3) and PPh(3) coordinated to tetrahedral, trigonal-bipyramidal, octahedral or square planar achiral metal centres is discussed. Results from ADF calculations, in agreement with experimental structures, show that favoured degenerate conformations of complex-bound PPh(3) in square planar [(PPh(3))(ML(1)L(2)L(3))] and [M(acac)(L')(PPh(3))] complexes can be obtained by applying the following principles (P helicity, view along P-M axis), (i) superimpose C(ortho) of the vertical ring A onto the nadir plane perpendicular to the square plane and allow ring A to tilt towards the smallest ligand, (ii) allow ring B to tilt in the space below the smallest ligand in the quadrant between the nadir plane below the complex and a horizontal plane through the SQP of the complex, (iii) tilt ring C over the largest ligand and (iv) allow correlated tilting of rings A, B and C to minimize inter ring-ring and inter ring ligand interactions. PMID- 22836280 TI - Alteration of the platelet transcriptome in chronic kidney disease. AB - Bleeding and thrombotic disorders are major complications affecting patients with chronic kidney disease (CKD). Exposure of circulating platelets to uraemic toxins and contact with artificial surfaces during dialysis induce platelet abnormalities and alter the platelet proteome. We hypothesised that these changes may be subsequent to changes in the composition and/or regulation of the platelet transcriptome. In this study, we investigated the circulating platelets of 10 CKD patients (i.e. five chronic haemodialysis patients and five stage 4 CKD uraemic patients) and five age- and sex-matched healthy subjects. We observed an alteration of the platelet messenger RNA (mRNA) and microRNA transcriptome in CKD patients. Impaired in uraemic platelets, the levels of some mRNAs and of most microRNAs appeared to be corrected by dialysis, which is consistent with a beneficial effect of dialysis and a mRNA regulatory role of platelet microRNAs. Reduced in platelets of uraemic patients, phosphatidylcholine transfer protein (PCTP) and WD repeat-containing protein 1 (WDR1) were found to be regulated by microRNAs, the latter of which involving hsa-miR-19b, a microRNA increased in platelets of uraemic patients and involved in platelet reactivity. These results suggest that an alteration of microRNA-based mRNA regulatory mechanisms may underlie the platelet response to uremia and entail the development of platelet related complications in CKD. PMID- 22836282 TI - Effect of nitrate on anaerobic azo dye reduction. AB - The aim of the study was to investigate the effect of nitrate on anaerobic color removal efficiencies. For this aim, anaerobic-aerobic sequencing batch reactor (SBR) fed with a simulated textile effluent including Remazol Brilliant Violet 5R azo dye was operated with a total cycle time of 12 h, including anaerobic (6 h) and aerobic cycles (6 h). Microorganism grown under anaerobic phase of the reactor was exposed to different amounts of competitive electron acceptor (nitrate) and performance of the system was determined by monitoring color removal efficiency, nitrate removal, nitrite formation and removal, oxidation reduction potential, color removal rate, chemical oxygen demand (COD), specific anaerobic enzyme (azo reductase) and aerobic enzyme (catechol 1,2 dioxygenase), and formation and removal of aromatic amines. Variations of population dynamics of microorganisms exposed to various amount of nitrate were identified by denaturing gradient gel electrophoresis (DGGE). It was found that nitrate has adverse effect on anaerobic color removal efficiency and color removal was achieved after denitrification process was completed. It was found that nitrate stimulates the COD removal efficiency and accelerates the COD removal in the first hour of anaerobic phase. About 90 % total COD removal efficiencies were achieved in which microorganism exposed to increasing amount of nitrate. Population dynamics of microorganisms exposed to various amount of nitrate were changed and diversity was increased. PMID- 22836283 TI - Clinical trials of interventional oncology. AB - Interventional oncology has great potential to be a good treatment modality in the field of oncology, because its procedures are minimally invasive and fairly quick. However, except for a few procedures such as percutaneous radiofrequency ablation and trans-catheter arterial chemo-embolization that have been recognized as standard treatments for hepatocellular carcinoma, most procedures have not been established as the standard treatment modality due to the limited number of clinical trials with compelling evidence. There are several common problems when performing clinical trials of interventional oncology. The first is that the outcomes of clinical trials are greatly influenced by the level of technical skill of the physicians. The second is that equipment and devices vary widely in countries and regions, and they also influence the outcomes. The third is that the methodology of clinical trials for techniques such as interventional oncology has not yet been established. The fourth is the difficulty of setting appropriate endpoints; quality of life is suitable for evaluating interventional oncology in palliative care, but it is not easy to set as the endpoint. The fifth is the difficulty of employing a blinded design, because the procedure cannot be performed without the physician's awareness. Despite such difficult situations, many multi-institutional clinical trials of interventional oncology have been carried out in Japan, with some challenging results. Establishing evidence is critical to making interventional oncology the standard treatment. Interventional radiologists should know the importance of clinical trials, and should move ahead in this direction in a step-by-step manner. PMID- 22836284 TI - Resource use and cost of hepatitis C-related care. AB - BACKGROUND: Chronic hepatitis because of the hepatitis C virus (CHC) is a major health problem that can lead to decompensated cirrhosis, hepatocellular carcinoma, and eventually death, all of which are associated with significant healthcare costs. AIM: To update the cost of care of CHC according to the different severity stages of the disease in a west European country (Belgium). METHODS: Medical records of 157 patients, who were referred to the medical specialist at different stages of disease, were reviewed to identify the medical costs over a follow-up period of 3 years or 2 years in the case of liver transplantation (LT). Six disease stages were defined on the basis of histology (Metavir classification) and/or clinical data. RESULTS: In comparison with mild disease, the cost increased 1.6 times in the case of decompensated cirrhosis, 1.9 times in the case of hepatocellular carcinoma, and 3.4 in the case of LT. The costs for medication, hospitalization, and ambulatory care were, respectively, on the one hand, 81, 8, and 11% for mild disease and, on the other, 18, 79, and 3% for LT. In the case of a sustained viral response, the cost of follow-up within 3 years decreased by 45% for patients with mild and moderate disease. CONCLUSION: Antiviral treatment is the most important factor governing cost in mild and moderate disease, but once complications of CHC occur, hospitalization costs far exceed the cost of antiviral therapy. Already during the first 3 years of follow up, sustained viral response decreased the cost significantly. Treatment of patients with CHC in an early stage has the potential to be cost-effective. PMID- 22836285 TI - Treatment of leptomeningeal spread of NSCLC: a continuing challenge. AB - OPINION STATEMENT: Leptomeningeal metastasis is a serious and frequently fatal complication of non-small cell lung cancer. Curative treatment remains elusive, but careful use of radiation, systemic chemotherapy, intrathecal chemotherapy, and symptoms management can greatly improve quality of life and survival. For most patients, we recommend a combination of skull-based radiation with focal radiation to any symptomatic spinal segments followed by systemic chemotherapy. For patients with EGFR mutations, erlotinib may be used as first-line therapy in a daily or high-dose regimen. Pemetrexed has promise for use in patients with brain and leptomeningeal metastases. Patients with multiple comorbidities or low performance status may tolerate intrathecal therapy better than systemic chemotherapy. The most commonly used intrathecal chemotherapies are methotrexate and liposomal cytarabine, although newer agents, such as topotecan and mafosfamide, may be more effective. Elevated intracranial pressure, which causes headaches, vertigo, nausea, and vomiting, should be treated with dexamethasone and acetazolamide. In select patients, cerebrospinal fluid shunting may be considered. The use of antidepressants, central nervous system stimulants, benzodiazepines, antiemetics, and pain medications can increase quality of life in patients with leptomeningeal metastases. PMID- 22836286 TI - Effects of radial shock waves therapy on osteoblasts activities. AB - Radial shock waves therapy (RSWT) differs from extracorporeal shock waves therapy (ESWT) in that it produces a non-focused wave that is dissipated radially at the skin. Few studies have yet explored the effects of RSWT on bone tissue. Osteoblasts in culture flasks were studied by polymerase chain reaction after treatment with RSW (500 impulses, 0.05 mJ/mm(2)). An inhibited osteoblastogenesis was observed, with a statistically significant reduction in type 1 collagen, osterix, bone sialoprotein and receptor activator NF kappa ligand expression at 24 and 48 h, of osteocalcin at 24, 48 and 72 h, and osteopontin at 48 and 72 h. These findings show that RSWT is not indicated for treatment of delayed fracture union, pseudoarthrosis, and complex regional pain syndrome. The observed reduction in the receptor activator of nuclear factor-kB ligand/osteoprotegerin ratio suggests that it has an inhibiting effect on osteoclastogenesis, which could make it a useful tool for applications in proliferative diseases. PMID- 22836287 TI - The course of childhood anxiety symptoms: developmental trajectories and child related factors in normal children. AB - This three-wave longitudinal study explored developmental trajectories for various types of childhood anxiety symptoms (i.e., specific fears, social anxiety, generalized anxiety, and separation anxiety) and examined how these trajectories were associated with several factors thought to be involved in the pathogenesis of anxiety. Parents of a community sample of 224 children aged 4 to 11 years repeatedly completed a standardized questionnaire of anxiety symptoms during a 2-year period. At Time 1, parents also filled out scales for measuring children's level of behavioral inhibition (BI), internalizing and externalizing symptoms, and prosocial behaviors, while an interview was conducted with children to assess Theory-of-Mind (TOM) ability. Growth Mixture Modeling identified multiple developmental trajectories in childhood anxiety symptoms of which the 'stable-low' or 'stable-medium' reflected the normative trajectories. Further, multinomial regression analyses indicated that the higher developmental trajectories of anxiety were associated with higher levels of BI and internalizing symptoms at Time 1. In sum, results show heterogeneity in the development of anxiety symptoms and underline the importance of early prevention programs for children at high risk for developing an anxiety disorder. PMID- 22836289 TI - The role of mutation status of the epidermal growth factor receptor gene in advanced non-small cell lung cancer. AB - OBJECTIVE: The aim of this study was to examine the prevalence of epidermal growth factor receptor (EGFR) gene mutations among patients with advanced nonsquamous non-small cell lung cancer (NSCLC) treated in our institution and to evaluate the associations between EGFR mutations and clinicopathological characteristics. MATERIALS AND METHODS: A total of 103 patients with NSCLC were examined from April 2010 to September 2011. The patients were screened for EGFR mutations in exons 19 and 21 using sequence analysis. RESULTS: EGFR mutations were detected in 10 patients (9.71%): 23.1% of women and 5.2% of men (P<0.05), 31.8% of never-smokers and 4.7% of smokers (P<0.05), and 12.3% of patients with adenocarcinomas and 6.25% of patients with large cell carcinomas (P>0.05). Eight mutations (80.0%) were found in exon 21: 7 patients had the L858R mutation and 1 patient had the L861G mutation. Two mutations (20.0%) were found in exon 19: 1 patient had the L747-A748 deletion and 1 patient had the L747-A750insE deletion. The overall response rate was significantly greater in the EGFR mutation-positive group than in the EGFR mutation-negative or control groups (P<0.05). The median progression-free survival in the EGFR mutation-negative group and the control group that received systemic standard chemotherapy was 5.6 months (95% CI, 4.3 to 7.0) and 5.3 months (95% CI, 4.9 to 5.7), respectively, but it was not achieved in the EGFR mutation-positive group that received EGFR tyrosine kinase inhibitors (P<0.05). CONCLUSIONS: The frequency of EGFR mutations in our patients with nonsquamous NSCLC was found to be similar to that reported in Europe. EGFR mutations were more frequent in women and never-smokers. PMID- 22836290 TI - Uterine rupture in the second trimester of pregnancy as an iatrogenic complication of laparoscopic myomectomy. AB - Uterine rupture is one of the most dangerous obstetric emergencies carrying a high risk for the mother and the fetus. Reports about uterine rupture in pregnancy following previous laparoscopic surgery have not been frequent; however, an increasing rate of the occurrence of this complication has been observed and reviewed in contemporary literature. We report a case of a spontaneous uterine rupture at 22 weeks of gestation in a 25-year old primigravida, who had had a laparoscopic removal of a small, peduncular, asymptomatic myoma located in the right uterine horn 20 months earlier. Ultrasound examination and subsequent urgent laparotomy confirmed a spontaneous uterine rupture with a nonviable fetus in the peritoneal cavity. Women planning to become pregnant should be qualified for laparoscopic myomectomy with special carefulness. Special attention must be paid to the potential solutions that limit the risk of postoperative uterine rupture, if the absolute necessity for the enucleation of myomas during the reproductive age occurs and a decision about laparoscopic intervention is made. PMID- 22836288 TI - 5-HTTLPR X stress in adolescent depression: moderation by MAOA and gender. AB - Depression surges in adolescence, especially among girls. Most evidence indicates that the short allele of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) interacts with stress to influence the onset of depression. This effect appears to be less robust in adolescents, particularly among boys, and may be moderated by other genetic polymorphisms. Seeking to explain the adolescent gender difference in depression, this study examined the effects of 5-HTTLPR (rs25531), the monoamine oxidase A-upstream variable number tandem repeat (MAOA-uVNTR), and negative life events (NLE). A community-based longitudinal sample of 309 adolescents reported depressive symptoms and NLE at ages 11, 13, and 15. 5-HTTLPR and MAOA-uVNTR genotypes were ascertained via buccal swabs. A significant four-way interaction of 5-HTTLPR, MAOA-uVNTR, NLE at age 13, and gender predicted depressive symptoms at age 15. Girls were most likely to exhibit elevated depressive symptoms when experiencing NLE if they possessed low-expression MAOA-uVNTR alleles and short 5-HTTLPR alleles, whereas low-expression MAOA-uVNTR alleles but long 5-HTTLPR alleles were implicated in boys. The results indicate that the commonly reported 5-HTTLPR by stress interaction for depression may be limited to individuals with low-expression MAOA uVNTR alleles. These data also provide new evidence that the short allele of 5 HTTLPR confers susceptibility to stress differently for females compared with males. PMID- 22836291 TI - Effect of (1->3),(1->6)-beta-glucan on in vitro production of cytokines by leukocytes of patients with periodontitis. AB - BACKGROUND. The aim of the study was to investigate the effect of (1->3), (1->6) beta-glucan on the production of interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-alpha) in vitro by peripheral blood leukocytes of patients with periodontitis. MATERIAL AND METHODS. In total, 20 patients suffering from untreated severe chronic generalized periodontitis were enrolled in this study. Periodontitis was confirmed by clinical and radiologic examination. Besides, 20 periodontally healthy patients served as a control group. Peripheral venous blood was sampled from the patients, and isolated leukocytes were treated with (1 >3),(1->6)-beta-glucan from yeast at different concentrations. The levels of IL 10 and TNF-alpha secreted by the leukocytes unstimulated and stimulated with unopsonized E. coli in vitro were determined by the enzyme amplified sensitivity immunoassay method. RESULTS. Our data showed that (1->3),(1->6)-beta-glucan induced a significant decrease (P<0.05) in the TNF-alpha level and a significant increase (P<0.001) in the IL-10 level in the media of unstimulated and stimulated leukocytes of the patients with periodontitis in comparison with those of the healthy subjects. CONCLUSIONS. The present in vitro study showed that (1->3),(1 >6)-beta-glucan modulated the response of leukocytes of the patients with periodontitis differently in comparison with those of the healthy subjects. It increased the release of IL-10, which is protective of the tooth-supporting tissues in patients with periodontal disease, but decreased the release of TNF alpha, which is mainly responsible for the destruction of the tooth-supporting tissues during periodontal disease. PMID- 22836292 TI - The development of Eudragit(r) NM-based controlled-release matrix tablets. AB - Eudragit(r) NM was investigated as a matrix former in combination with microcrystalline cellulose as an insoluble filler for preparing controlled release tablets containing model drugs with different solubility. MATERIAL AND METHODS: Three sets of matrix tablets differing in the drug-to-filler ratio (1:1, 2:1, and 4:1) and polymer amount with diltiazem hydrochloride (freely soluble) or caffeine (sparingly soluble) were prepared. Samples were evaluated by the dissolution test at pH 6.8 corresponding to the upper part of the small intestine; the selected samples were tested at a changing pH level to better simulate in vivo conditions. RESULTS: The prepared matrix tablets fulfilled all the requirements of the European Pharmacopoeia. Tablets with Eudragit(r) NM showed excellent mechanical characteristics. In vitro studies showed that the set 1:1 was the most suitable for the sustained release of a freely soluble drug concerning the burst effect and the total drug amount released within 12 hours. The significant effect of the drug-to-filler ratio and polymer amount on the dissolution profile was confirmed by similarity factor analysis. A faster drug release was observed during the dissolution test within changing pH levels because of the pH-dependent solubility of diltiazem. A prolonged release of the sparingly soluble drug was not achieved, and a trend for fast disintegration was observed. CONCLUSIONS: The combination of Eudragit(r)NM with microcrystalline cellulose as an insoluble filler seems to be suitable only for freely soluble drugs, when the amount of the drug and the filler is similar. PMID- 22836293 TI - Application of multifrequency bioelectrical impedance analysis method for the detection of dehydration status in professional divers. AB - BACKGROUND AND OBJECTIVE: The level of dehydration has been known to be a predisposing factor for the development of decompression sickness in divers. The aim of this study was to determine the level of dehydration in divers who dove with heliox and to determine whether the source of this dehydration was intracellular and/or extracellular by means of multifrequency bioelectrical impedance analysis (MF-BIA). MATERIAL AND METHODS: Eleven male professional divers were enrolled in the study. In order to determine the level of dehydration, MF-BIA was carried out (at 5, 50, and 100 kHz) and capillary hematocrit (Hct) was measured two times: one before diving and the other after leaving the pressure room. RESULTS: When prediving and postdiving parameters were compared, significant increases in the resistance at 5 kHz (P<0.001), 50 kHz, (P<0.001), and 100 kHz (P<0.01) and Hct (P<0.01) were observed after the diving. Similarly, a statistically significant fluid shift was found: total body water, 1.30 L (P<0.001), extracellular water, -0.85 L (P<0.001); and intracellular water, -0.45 L (P=0.011). CONCLUSIONS: Our results showed that mild dehydration occurred both in the intracellular and extracellular compartments in divers after deep diving. This study also indicates that MF-BIA could be a reliable new method for determining the dehydration status in divers. PMID- 22836294 TI - Diet and dyslipidemias in a Lithuanian rural population aged 25-64: the CINDI survey. AB - The aim of the study was to evaluate the dietary intake of a Lithuanian rural population and to assess the relationship between diet and dyslipidemias. MATERIAL AND METHODS: A cross-sectional health survey was carried out in 5 municipalities of Lithuania in 2007. The random sample was obtained from lists of 25- to 64-year-old inhabitants registered at primary health care centers (n=1739). The food frequency questionnaire and 24-hour recall was used for the evaluation of nutrition habits. The levels of serum lipids were determined using enzymatic methods. Factor analysis was employed in order to reduce the number of food items. The scores of food factors were used in linear regression analysis of associations between nutrition and serum lipid levels. RESULTS: The diet of the study population was very high in fat, especially in saturated fatty acids. The content of cholesterol in the diet of men was higher than recommended. The main sources of fat and protein were meat, milk, and their products. Cereals were the main source of carbohydrates. The major proportion of monosaccharide and disaccharides was derived from confectionary and fruits. The mean serum total cholesterol level was 5.60 mmol/L in men and 5.51 mmol/L in women. CONCLUSIONS: Healthier food patterns were associated with the lower levels of total, low density lipoprotein cholesterol, and triglyceride. PMID- 22836295 TI - Effect of single physical load of different duration and intensity on cognitive function. AB - The aim of this study was to determine the effect of a single physical load of different duration and intensity on cognitive function. MATERIAL AND METHODS: The study population comprised 90 male soldiers. The subjects were randomly divided into two groups: experimental (n=60) and control group (n=30). The soldiers in the experimental group undertook 3 specific loads of different types, durations, and intensities. Attention concentration and tapping tests were carried out, and the reaction time was measured. RESULTS: After the physical load, the soldiers in the experimental group performed the attention concentration test faster, the number of committed mistakes decreased, and the rate of processing information increased as compared to the corresponding values before physical load (all P<0.05). However, the indices of fatigue, such as the tapping test score and reaction time, in the experimental group were found to be worse than before physical loads (P<0.05). No significant changes were observed in the control group of soldiers. CONCLUSION: Despite fatigue, a single physical load of different duration and intensity improved the cognitive function. PMID- 22836296 TI - Coats' retinitis or retinoblastoma in a 3-year-old girl: a case report. AB - Coats' disease is an idiopathic disorder defined by an abnormal development of retinal vessels with a progressive deposition of intraretinal or subretinal exudates, leading to exudative retinal detachment. The most difficult task is to differentiate Coats' disease from retinoblastoma. We present a rare case of Coats' disease diagnosed in a 3-year-old girl. From the age of 6 months, the girl was followed up 2 times a year at the Department of Ophthalmology, Hospital of Lithuanian University of Health Sciences, due to congenital convergent strabismus and refractive errors. At the age of 3.6 years, a routine examination of the fundus of the right eye revealed hard exudates, telangiectasia and tortuosity, gray color lesion below the optic nerve disc, submacular exudation in the inferior nasal part of the retina, and exudative retinal detachment, which extended from the 7-o'clock position to the 4-o'clock position. Before this examination, no abnormalities were found in the fundus of her both eyes. The girl was not treated with laser photocoagulation, cryocoagulation, or intravitreal injections, as the diagnosis of retinoblastoma could not be excluded; therefore, only eye drops were prescribed. In order to exclude the diagnosis of retinoblastoma, ultrasonography, magnetic resonance imaging, and computed tomography were carried out, and an appointment to see an ophthalmic oncologist was scheduled. Due to early and appropriate treatment, the progression of Coats' disease in patients could be arrested. However, in some cases, when the diagnosis is ambiguous, it is better to follow up the patient and to treat only with eye drops. PMID- 22836297 TI - Discontinuous ammonia excretion and glutamine storage in littoral Oniscidea (Crustacea: Isopoda): testing tidal and circadian models. AB - A key evolutionary development facilitating land colonization in terrestrial isopods (Isopoda: Oniscidea) is the intermittent liberation of waste nitrogen as volatile ammonia. Intermittent ammonia release exploits glutamine (Gln) as an intermediary nitrogen store. Here, we explore the relationship between temporal patterns of ammonia release and Gln accumulation in three littoral oniscideans from Southern California. Results are interpreted in terms of water availability, habitat, activity patterns, and ancestry. A two-way experimental design was used to test whether ammonia excretion and Gln accumulation follow a tidal or diel periodicity. Ammonia excretion was studied in the laboratory using chambers with or without available seawater and using an acid trap to collect volatile ammonia. Ligia occidentalis releases ammonia directly into seawater and accumulates Gln during low tide (48.9 +/- 6.5 MUmol g-1 at low tide, 24.1 +/- 3.0 MUmol g-1 at high tide), indicating that excretion is tidally constrained. Alloniscus perconvexus and Tylos punctatus can excrete ammonia directly into seawater or utilize volatilization. Both species burrow in sand by day and show a diel excretory pattern, accumulating Gln nocturnally (31.8 +/- 2.7 MUmol g-1 at dawn and 21.8 +/- 2.3 MUmol g-1 at dusk for A. perconvexus; 85.7 +/- 15.1 MUmol g-1 at dawn and 25.4 +/- 2.9 MUmol g-1 at dusk for T. punctatus) and liberating ammonia diurnally. Glutaminase shows higher activity in terrestrial (0.54-0.86 U g-1) compared to intertidal (0.25-0.31 U g-1) species, consistent with the need to generate high PNH3 for volatilization. The predominant isoform in Armadillidium vulgare is phosphate dependent and maleate independent; phosphate is a plausible regulator in vivo. PMID- 22836298 TI - The ability of the Antarctic nematode Panagrolaimus davidi to survive intracellular freezing is dependent upon nutritional status. AB - The Antarctic nematode Panagrolaimus davidi is the best documented example of an animal surviving intracellular freezing and the only animal so far shown to survive such freezing throughout its tissues. However, a recent study found that after exposure to a freezing stress that produced intracellular freezing in a proportion of nematodes, the resulting survival levels could be explained if those nematodes that froze intracellularly had died. We have thus re-examined the survival of intracellular freezing in this nematode. The ability to survive a freezing exposure that is likely to produce intracellular freezing (freezing at 10 degrees C) declines with culture age. In cultures that are fed regularly, the ability to survive freezing at -10 degrees C increases, but in starved cultures freezing survival declines. Survival of intracellular freezing in fed cultures was confirmed using cryomicroscopy, staining of cells with vital dyes and by freeze substitution and transmission electron microscopy. We have thus confirmed that P. davidi can survive intracellular freezing and shown that this ability is dependent upon them being well fed. The effect of culture conditions on the nutrient status of the nematodes should thus be an important factor in the design of experiments. PMID- 22836299 TI - Strain relief and growth optimization of GaSb on GaP by molecular beam epitaxy. AB - In this paper, the impact of growth parameters on the strain relaxation of highly lattice mismatched (11.8%) GaSb grown on GaP substrate by molecular beam epitaxy has been investigated. The surface morphology, misfit dislocation and strain relaxation of the GaSb islands are shown to be highly related to the initial surface treatment, growth rate and temperature. More specifically, Sb-rich surface treatment is shown to promote the formation of Lomer misfit dislocations. Analysis of the misfit dislocation and strain relaxation as functions of the growth temperature and rate led to an optimal growth window for a high quality GaSb epitaxial layer on (001) GaP. With this demonstrated optimized growth, a high mobility (25,500 cm(2) V (-1) s(-1) at room temperature) AlSb/InAs heterostructure on a semi-insulating (001) GaP substrate has been achieved. PMID- 22836300 TI - Reducing susceptibility artefacts in magnetic resonance images of the canine stifle following surgery for cranial cruciate ligament deficiency. AB - BACKGROUND: Magnetic resonance (MR) images of the postoperative canine stifle are adversely affected by susceptibility artefacts associated with metallic implants. OBJECTIVES: To determine empirically to what extent susceptibility artefacts could be reduced by modifications to MR technique. METHODS: Three cadaveric limbs with a tibial plateau levelling osteotomy (TPLO), tibial tuberosity advancement (TTA), or extra-capsular stabilization (ECS) implant, respectively, were imaged at 1.5T. Series of proton density and T2-weighted images were acquired with different combinations of frequency-encoding gradient (FEG) direction and polarity, stifle flexion or extension, echo spacing (ES), and readout bandwidth (ROBW), and ranked. The highest rank (a rank of 1) corresponded to the smallest artefact. RESULTS: Image ranking was affected by FEG polarity (p = 0.005), stifle flexion (p = 0.01), and ROBW (p = 0.0001). For TPLO and TTA implants, the highest ranked images were obtained with the stifle flexed, lateromedial FEG, and medial polarity for dorsal images, and craniocaudal FEG and caudal polarity for sagittal images. For the ECS implant, the highest ranked images were obtained with the stifle extended, a proximodistal FEG and proximal polarity for dorsal images, and craniocaudal FEG and cranial polarity for sagittal images. CLINICAL SIGNIFICANCE: Susceptibility artefacts in MR images of postoperative canine stifles do not preclude clinical evaluation of joints with ECS or TTA implants. PMID- 22836302 TI - An 1,3,4-oxadiazole-based OFF-ON fluorescent chemosensor for Zn2+ in aqueous solution and imaging application in living cells. AB - A new 1,3,4-oxadiazole-based fluorescence chemosensor 1, N-(2-ethoxy-2-oxoethyl) N-(5-(2-hydroxy-3,5-di-tert-butylphenyl)-[1,3,4]oxadiazol-2-yl)glycine ethyl ester, has been designed and synthesized. Its fluorescence properties and selectivity for various metal ions were investigated in detail. A prominent fluorescence enhancement only for Zn(2+) was found in aqueous acetonitrile solution and the response mechanism of 1 was analyzed by time-resolved fluorescence decay and DFT calculations. Furthermore, the fluorescence imaging of Zn(2+) in living cells was successfully applied. PMID- 22836301 TI - Spirolactonized Si-rhodamine: a novel NIR fluorophore utilized as a platform to construct Si-rhodamine-based probes. AB - Spirolactonized Si-rhodamine was prepared as a platform to construct Si-rhodamine based probes by following the design strategy widely used in rhodamine systems. Among them, the reaction-based probe SiR-Hg was operated for NIR sensing and bioimaging of Hg(2+) in living cells based on the similar irreversible spirolactam ring-opening process to traditional rhodamine derivatives. PMID- 22836303 TI - Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. AB - We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient's genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management. PMID- 22836304 TI - Current management of antenatal hydronephrosis. AB - The strategy for the management of children with urinary tract anomalies has changed considerably as a result of the development of ultrasound equipment and techniques that allow for detailed fetal evaluation. Hydronephrosis is the most common urogenital anomaly detected, suggesting that an obstructive process may be potentially present. The goal of postnatal management is to identify and treat those patients whose renal function is at risk, while leaving alone the high percentage of patients who are at no risk of renal damage. This management involves a spectrum of radiological, medical, and surgical interventions for diagnosis, surveillance, and treatment. In this article, we review our current understanding of the natural history of antenatal hydronephrosis and its management. PMID- 22836306 TI - Numerical simulation of exciton dynamics in Cu2O at ultra-low temperatures within a potential trap. AB - We have studied theoretically the relaxation behaviour of excitons in cuprous oxide (Cu(2)O) at ultra-low temperatures when excitons are confined within a potential trap by solving numerically the Boltzmann equation. As relaxation processes, we have included in this paper deformation potential phonon scattering, radiative and non-radiative decay and Auger decay. The relaxation kinetics has been analysed for temperatures in the range between 0.3 and 5 K. Under the action of deformation potential phonon scattering only, we find for temperatures above 0.5 K that the excitons reach local equilibrium with the lattice, i.e. that the effective local temperature is coming down to the bath temperature, while below 0.5 K a non-thermal energy distribution remains. Interestingly, for all temperatures the global spatial distribution of excitons does not reach the equilibrium distribution, but stays at a much higher effective temperature. If we include further a finite lifetime of the excitons and the two particle Auger decay, we find that both the local and the global effective temperature do not come down to the bath temperature. In the first case we find that a Bose-Einstein condensation (BEC) occurs for all temperatures in the investigated range. Comparing our results with the thermal equilibrium case, we find that BEC occurs for a significantly higher number of excitons in the trap. This effect could be related to the higher global temperature, which requires an increased number of excitons within the trap to observe the BEC. In the case of Auger decay, we do not find a BEC at any temperature due to the local heating of the exciton gas. PMID- 22836307 TI - Hepatic blood perfusion estimated by dynamic contrast-enhanced computed tomography in pigs: limitations of the slope method. AB - OBJECTIVE: The aim of this study was to determine whether dynamic contrast enhanced computed tomography (DCE-CT) and the slope method can provide absolute measures of hepatic blood perfusion from the hepatic artery (HA) and portal vein (PV) at experimentally varied blood flow rates. MATERIALS AND METHODS: Ten anesthetized 40-kg pigs underwent DCE-CT of the liver during periods of normocapnia (normal flow), hypocapnia (decreased flow), and hypercapnia (increased flow), which were induced by adjusting the ventilation. Reference blood flows in the HA and PV were measured continuously by surgically placed ultrasound transit-time flowmeters. For each capnic condition, the DCE-CT estimated absolute hepatic blood perfusion from the HA and PV were calculated using the slope method and compared with flowmeter-based absolute measurements of hepatic perfusions and relative errors were analyzed. RESULTS: The relative errors (mean +/- SEM) of the DCE-CT based perfusion estimates were -21% +/- 23% for HA and 81% +/- 31% for PV during normocapnia, 9% +/- 23% for HA and 92% +/- 42% for PV during hypocapnia, and 64% +/- 28% for HA and -2% +/- 20% for PV during hypercapnia. The mean relative errors for HA were not significantly different from 0 during hypocapnia and normocapnia, and the DCE-CT slope method could detect relative changes in HA perfusion between scans. Infusion of contrast agent led to significantly increased hepatic blood perfusion, which biased the PV perfusion estimates. CONCLUSIONS: Using the DCE-CT slope method, HA perfusion estimates were accurate at low and normal flow rates, whereas PV perfusion estimates were inaccurate and imprecise. At high flow rate, both HA perfusion estimates were significantly biased. PMID- 22836305 TI - Association between common iron store markers and hemoglobin in children with chronic kidney disease. AB - BACKGROUND: Serum ferritin and transferrin saturation (TSAT) are used to assess iron status in children with chronic kidney disease (CKD), but their sensitivity in identifying those at risk of lower hemoglobin (HGB) values is unclear. METHODS: We assessed the association of iron status markers (ferritin, TSAT, and serum iron) with age- and gender-related HGB percentile in mild-to-moderate CKD in 304 children in the Chronic Kidney Disease in Children (CKiD) Study. Standardized HGB percentile values were examined by KDOQI-recommended ferritin (>= 100 ng/ml) and TSAT (>= 20 %) thresholds. Regression tree methods were used to identify iron status markers and clinical characteristics most associated with lower HGB percentiles. RESULTS: The cohort was 62 % male, 23 % African American, and 12 % Hispanic, median age 12 years, and median HGB 12.9 g/dl. 34 % had low TSAT and 93 % low ferritin as defined by KDOQI. Distribution of HGB percentile values was lower in those with ferritin >= 100 ng/ml, while TSAT >= 20 % was associated with only modest increase in HGB percentile. In regression tree analysis, lower glomerular filtration rate (GFR), serum iron <50 MUg/dl and ferritin >= 100 ng/ml were most strongly associated with lower HGB percentile. CONCLUSIONS: The level of GFR was significantly associated with HGB. Higher serum ferritin was associated with lower HGB in this cohort. Low serum iron in the context of normal/increased ferritin and low HGB may be a useful indicator of iron-restricted erythropoiesis. PMID- 22836308 TI - Attenuation-based automatic kilovolt selection in abdominal computed tomography: effects on radiation exposure and image quality. AB - OBJECTIVES: Dose reduction has become a major issue in computed tomography (CT). The benefit of kilovolt (kV) reduction has been demonstrated in CT angiography. We sought to evaluate an attenuation-based fully automated kV-selection and milliampere second-adaption algorithm for CT and to assess radiation dose and image quality in comparison with a standard 120 kV protocol in contrast-enhanced (CE) portal-venous thoracoabdominal imaging. MATERIALS AND METHODS: One hundred patients (mean age, 58.4 +/- 5.7 years; mean body mass index [BMI], 26.1 +/- 5.1 kg/m(2)) underwent CE CT using automated selection of the tube potential (80-140 kV) with milliampere second adaption based on the attenuation profile of the scout scan. The estimated CT dose index was recorded for the proposed scan setting and standard 120-kV protocol. Regions of interest measurements were performed at different locations for objective assessment of image quality. Signal-to-noise ratio and contrast-to-noise ratio (CNR) were calculated. The subjective image quality was assessed by 2 observers with a 4-point scale using previous CT examinations with the 120-kV standard protocol as the reference for comparison. RESULTS: The kV-selection algorithm could be applied in all examinations without problems. Image quality was high, and there were no significant differences compared with previous examinations of the patients performed at 120 kV. Eighty kilovolts was used in 9% of examinations (mean BMI, 22.8 +/- 2.8 kg/m(2)); 100 kV, in 75% (mean BMI, 23.7 +/- 4.7 kg/m(2)); 120 kV, in 16% (mean BMI, 30 +/- 3.3 kg/m(2)); and 140 kV, in a single case (BMI, 49.4 kg/m(2)). The average estimated CT dose index reduction was 25.3% in the 80-kV group, 14.5% in the 100-kV group, and 11.4% overall. The CNR did not differ significantly, whereas the signal-to-noise ratio was significantly higher in the 80- and 100-kV examinations. CONCLUSION: The attenuation-based kV-selection algorithm was demonstrated to be applicable in clinical routine of CE thoracoabdominal CT, to keep CNR constant, and to result in a significant dose reduction while preserving image quality. PMID- 22836309 TI - Quantification of hepatic steatosis with dual-energy computed tomography: comparison with tissue reference standards and quantitative magnetic resonance imaging in the ob/ob mouse. AB - OBJECTIVE: The aim of this study was to compare dual-energy computed tomography (DECT) and magnetic resonance imaging (MRI) for fat quantification using tissue triglyceride concentration and histology as references in an animal model of hepatic steatosis. MATERIALS AND METHODS: This animal study was approved by our institution's Research Animal Resource Center. After validation of DECT and MRI using a phantom consisting of different triglyceride concentrations, a leptin deficient obese mouse model (ob/ob) was used for this study. Twenty mice were divided into 3 groups based on expected levels of hepatic steatosis: low (n = 6), medium (n = 7), and high (n = 7) fat. After MRI at 3 T, a DECT scan was immediately performed. The caudate lobe of the liver was harvested and analyzed for triglyceride concentration using a colorimetric assay. The left lateral lobe was also extracted for histology. Magnetic resonance imaging fat-fraction (FF) and DECT measurements (attenuation, fat density, and effective atomic number) were compared with triglycerides and histology. RESULTS: Phantom results demonstrated excellent correlation between triglyceride content and each of the MRI and DECT measurements (r(2) >= 0.96, P <= 0.003). In vivo, however, excellent triglyceride correlation was observed only with attenuation (r(2) = 0.89, P < 0.001) and MRI-FF (r(2) = 0.92, P < 0.001). Strong correlation existed between attenuation and MRI-FF (r(2) = 0.86, P < 0.001). Nonlinear correlation with histology was also excellent for attenuation and MRI-FF. CONCLUSIONS: Dual-energy computed tomography (CT) data generated by the current Gemstone Spectral Imaging analysis tool do not improve the accuracy of fat quantification in the liver beyond what CT attenuation can already provide. Furthermore, MRI may provide an excellent reference standard for liver fat quantification when validating new CT or DECT methods in human subjects. PMID- 22836311 TI - Extracellular volume fractions in chronic myocardial infarction. AB - OBJECTIVES: The aim of this study was to assess and delineate chronic myocardial infarction (CMI) using precontrast and postcontrast T1 mapping techniques including quantification of extracellular volume fractions (ECVs). MATERIALS AND METHODS: A total of 26 patients with CMI were examined at 1.5 T applying a modified Look-Locker Inversion Recovery sequence before and 10 minutes after contrast at 3 short-axis slice positions. An inversion recovery gradient recalled echo sequence (standard of reference) was used for imaging late gadolinium enhancement. Precontrast and postcontrast T1 maps were calculated, and CMI was defined as areas with T1 values more than 3 SDs different compared with normal myocardium (MYO). T1 values of CMI, MYO, and blood pool were measured, and ECVs of CMI and MYO were calculated. Two-tailed Student t test was used for statistical analysis of T1 values and ECVs. Sensitivities and specificities for detection of CMI on precontrast and postcontrast T1 maps were calculated. Receiver operating characteristic (ROC) analysis was performed for postcontrast T1 values and ECV for discrimination of CMI. RESULTS: The comparison of T1 values of CMI and MYO revealed significant differences in precontrast and postcontrast scans (1159 +/- 64 vs 1001 +/- 47 milliseconds, P < 0.001, and 238 +/- 74 vs 379 +/- 59 milliseconds, P < 0.001). Sensitivities and specificities for detection of CMI on T1 mapping were 41.7% and 100% in precontrast Look-Locker Inversion Recovery scans and 95.8% and 99.3% in postcontrast images, respectively. Average ECV for MYO and CMI were 28% +/- 5% and 53% +/- 10% (P < 0.001). ROC analysis revealed nonsignificantly different areas under the curve of 0.937 and 0.997 for T1 values and ECV, respectively (P = 0.137). Sensitivities and specificities were 92.3% and 92.3% for detecting CMI by postcontrast T1 values and 95.5% and 100% for ECV, with cutoff values being 305 milliseconds or less and greater than 42%. Combined criteria did not result in any further improvement of sensitivity for CMI detection. CONCLUSIONS: Postcontrast T1 values and ECV of chronically infarcted MYO are significantly different compared with respective values of normal MYO. Both parameters allow for accurate detection of CMI with ECV showing marginally higher sensitivity and specificity. Precontrast T1 values lack accuracy in delineation of CMI. PMID- 22836312 TI - Biological performance of a size-fractionated core-shell tantalum oxide nanoparticle x-ray contrast agent. AB - OBJECTIVES: Metal-containing nanoparticles show great promise as x-ray contrast media and could enable reduced radiation dose, increased contrast, and the visualization of smaller anatomic features. In this study, we report progress toward these goals using a size-fractionated core-shell tantalum oxide nanoparticle contrast agent. MATERIALS AND METHODS: A core-shell tantalum oxide nanoparticle contrast agent was synthesized and size fractionated for preclinical investigation of biodistribution, blood half-life, organ retention, and histopathology. Fractionated agent was injected at anticipated clinical dose and at 3 times the anticipated clinical dose to evaluate biological performance. Computed tomography (CT) imaging studies were also performed to evaluate short term clearance kinetics and new imaging applications. RESULTS: Improved control of 2-diethylphosphatoethylsilane-TaO nanoparticle size resulted in significantly reduced retention of injected tantalum. In vivo and in vitro CT imaging studies demonstrated short-term biodistribution differences in the kidney between small molecule iodinated contrast media and fractionated 2-diethylphosphatoethylsilane TaO, as well as preliminary data about new "Ta-only" imaging applications using multienergy CT image acquisition. CONCLUSIONS: Size-fractionated core-shell tantalum oxide nanoparticles with a well-defined particle size distribution have several key features required of clinically viable vascular imaging compounds and may be used in developing multienergy CT imaging applications. PMID- 22836310 TI - Quantitative computed tomography of the lungs and airways in healthy nonsmoking adults. AB - OBJECTIVES: The purposes of this study were to evaluate the reference range of quantitative computed tomography (QCT) measures of lung attenuation and airway parameter measurements in healthy nonsmoking adults and to identify sources of variation in those measures and possible means to adjust for them. MATERIALS AND METHODS: Within the COPDGene study, 92 healthy non-Hispanic white nonsmokers (29 men, 63 women; mean [SD] age, 62.7 [9.0] years; mean [SD] body mass index [BMI], 28.1 [5.1] kg/m(2)) underwent volumetric computed tomography (CT) at full inspiration and at the end of a normal expiration. On QCT analysis (Pulmonary Workstation 2, VIDA Diagnostics), inspiratory low-attenuation areas were defined as lung tissue with attenuation values -950 Hounsfield units or less on inspiratory CT (LAA(I-950)). Expiratory low-attenuation areas were defined as lung tissue -856 Hounsfield units or less on expiratory CT (LAA(E-856)). We used simple linear regression to determine the impact of age and sex on QCT parameters and multiple regression to assess the additional impact of total lung capacity and functional residual capacity measured by CT (TLC(CT) and FRC(CT)), scanner type, and mean tracheal air attenuation. Airways were evaluated using measures of airway wall thickness, inner luminal area, wall area percentage (WA%), and standardized thickness of an airway with inner perimeter of 10 mm (Pi10). RESULTS: Mean (SD) %LAA(I-950) was 2.0% (2.7%), and mean (SD) %LAA(E-856) was 9.2% (6.8%). Mean (SD) %LAA(I-950) was 3.6% (3.2%) in men, compared with 1.3% (2.0%) in women (P < 0.001). The %LAA(I-950) did not change significantly with age (P = 0.08) or BMI (P = 0.52). %LAA(E-856) did not show any independent relationship with age (P = 0.33), sex (P = 0.70), or BMI (P = 0.32). On multivariate analysis, %LAA(I-950) showed a direct relationship to TLC(CT) (P = 0.002) and an inverse relationship to mean tracheal air attenuation (P = 0.003), and %LAA(E-856) was related to age (P = 0.001), FRC(CT) (P = 0.007), and scanner type (P < 0.001). Multivariate analysis of segmental airways showed that inner luminal area and WA% were significantly related to TLC(CT) (P < 0.001) and age (0.006). Moreover, WA% was associated with sex (P = 0.05), axial pixel size (P = 0.03), and slice interval (P = 0.04). Lastly, airway wall thickness was strongly influenced by axial pixel size (P < 0.001). CONCLUSIONS: Although the attenuation characteristics of normal lung differ by age and sex, these differences do not persist on multivariate analysis. Potential sources of variation in measurement of attenuation-based QCT parameters include depth of inspiration/expiration and scanner type. Tracheal air attenuation may partially correct variation because of scanner type. Sources of variation in QCT airway measurements may include age, sex, BMI, depth of inspiration, and spatial resolution. PMID- 22836313 TI - Gamma-secretase inhibitor DAPT suppresses glioblastoma growth via uncoupling of tumor vessel density from vessel function. AB - The objective of the current study was to investigate the regulation of VEGF signaling and tumor angiogenesis by gamma-secretase inhibitor DAPT in glioblastoma. Effects of DAPT on VEGFR1, VEGFR2, endothelial cell proliferation and vessel function were evaluated using mouse microvascular endothelial H5V cell line and U87MG xenograft mouse models. We found that DAPT efficiently inhibited Notch signaling, increased VEGFR2 expression, but decreased VEGFR1 expression. DAPT treatment enhanced endothelial cell proliferation when used combined with VEGF, but exerted no effect if used alone. In U87MG xenograft mouse models, DAPT treatment increased tumor vessel density but compromised vessel function, as evidenced by poor perfusion and aggravated hypoxia. Therefore, DAPT treatment results in an uncoupling of tumor vessel density from vessel function and suppresses glioblastoma growth; disturbance of angiogenesis with DAPT presents a novel therapeutic approach for glioblastoma. PMID- 22836322 TI - Prevalence and incidence of autism spectrum disorder in an Israeli population. AB - The prevalence of autism spectrum disorders has been steadily rising. In most parts of the world, rates as high as 1 % are reported, including in the United States. In Israel, previously reported prevalence rates have been in the 0.2 % range, and were based on parental reporting of diagnosis. In this study, records from one of the largest Israeli Health Maintenance organizations were used to calculate both incidence and prevalence of autism spectrum disorder (ASD) in Israel. Israeli prevalence of ASD was calculated at 0.48 % for 1-12 years olds and 0.65 % for 8 year old children in 2010, higher than previous Israeli reports, but still lower than prevalence estimates for the US. Incidence calculations ranged from 0.65 to 0.84 per 1,000 children for children 1-12 year olds. Reasons for these differences are suggested and discussed. PMID- 22836323 TI - [Management of coronary artery disease in diabetic patients with lower limb critical ischaemia: assessment of operational risk, drug therapy and indications for interventions]. AB - Despite obvious progress in management of diabetes mellitus, the DM-related complications rate remains inadmissibly high. Macroangiopathy is known to rank first amongst complications of diabetes mellitus, and coronary artery disease remains to be the major cause of death. Analysed herein are peculiarities of the clinical course in diabetic patients presenting with coronary artery disease and lower limb critical ischaemia, followed by discussing the issues concerning drug therapy, preoperative examination, and methods of diagnosis in this cohort of patients prior to vascular operations, assessment of the preoperative risk, indications for coronarography and myocardial revascularization. Also presented are the results of the main clinical trials dedicated to preoperative myocardial revascularization, including those in diabetic patients with limb critical ischaemia, and finally highlighting current importance of optimizing approaches to managing and working out algorithms of treatment policy for diabetic patients with a combination of coronary artery disease, diabetes mellitus, and critical limb ischaemia. PMID- 22836324 TI - [Safety and efficacy of various regimens of heparin-mediated prevention of venous thromboses in patients with intracranial haemorrhage]. AB - Analysed in the article is the incidence rate of the development of venous thromboembolic complications in a total of 79 patients presenting with various aetiology intracranial haemorrhage in different regimens of heparin-mediated prevention. The authors have revealed that early (on day 2-4 after the onset of the disease) administration of preventive doses of heparin in patients with intracerebral and intracranial haematomas is a safe and efficient regimen, since it decreases the rate of venous thromboses in the system of the vena cava inferior and fatal thromboembolic complications as compared with a later term (on day 5 and more) of initiating heparin-mediated prevention. PMID- 22836325 TI - [Inflammation of the vascular wall and hyperhomocysteinemia in patients with atherosclerosis obliterans of lower limb arteries]. AB - Presented herein are the findings of examination of 176 people. Of these, 128 were found to suffer lower limb atherosclerosis (LLA) and 48 were apparently healthy people constituting a control group. Amongst the 128 patients, 74 (58%) had atherosclerotic lesions of the iliac arteries, 54 (42%) subjects had lesions of the femoral and popliteal arteries. The average age of the patients amounted to 62.4+/-4.3 years. There were ten (8%) women and 118 (92%) men. The control group consisted of 42 (89%) men and six (11%) women. The mean age of the control group patients was 58.9+/-3.2 years. All underwent functional and laboratory examinations including angiography, duplex scanning and dopplerography of lower limb arteries, as well as determining blood serum markers of inflammation (hs-CRP and IL-6), as well as endothelial lesion markers (ET-1 and VWF). The comparative analysis revealed that patients with LLA had signs of chronic vascular inflammation accompanied in the majority of cases by hyperhomocysteinemia with endothelial dysfunction, as well as direct association between the degree of the vascular inflammatory reaction and severity of clinical manifestations of lower limb ischaemia. PMID- 22836326 TI - [Radial diagnosis MRT and MSCT in assessing the outcomes of surgical correction for complicated congenital heart defects: discordant atrioventricular connections with double outlet right ventricle]. AB - Discordant atrioventricular connection with double outlet right ventricle is a rare complicated congenital heart defect (CHD) requiring accurate diagnosis and appropriate correction. Magnetic resonance imaging (MRI) and multiple spiral computed tomography (MSCT) were used to assess long-term outcomes of the "classical" repair of the double outlet right ventricle in a patient presenting with discordant atrioventricular connection. Using a modified segmental approach provided all necessary anatomical evidence concerning the condition of the heart, major vessels, and an extracardiac pulmonary valve-containing conduit. MSCT made it possible to evaluate the degree of calcinosis and stenosis of the conduit and to visualize the coronary arteries. MRI was employed to assess the pressure gradient at the level of stenosis of the conduit, the relationship between the pulmonary and systemic circulation, transvalvular regurgitation, and ventricular contractility. Comprehensive use of present-day tomographic methods of imaging made it possible to obtain complete anatomical and functional information about the condition of the heart, vessels, extracardiac vascular transplant, as well as to reveal complications and determine the indications for a repeat operative intervention. PMID- 22836327 TI - [Informative value of various methods of radiodiagnosis of anastomotic pseudoaneurysms after reconstructive operations on lower-limb major arteries]. AB - The work was aimed at determining and comparing sensitivity and specificity of various methods of radiodiagnosis of anastomotic pseudoaneurysms after reconstructive operations on the aortic-iliac-femoral segment. The authors identified and analysed the findings of examination of 87 patients presenting with anastomotic false aneurysms following the above-mentioned interventions (with the incidence rate amounting to 5.9%), having diagnosed a total of 105 cases of the formation of false aneurysms of proximal and distal anastomoses. The diagnosis was made using of the following methods: ultrasonographic duplex scanning (USDS), selective contrast- enhanced angiography (CEA), spiral and multispiral CT angiography (SCTA and MSCTA), and magnetic resonance angiography (MRA). Sensitivity and specificity of the methods employed were determined in relation not only to their ability to detect anastomotic pseudoaneurysms but also to identify different characteristics thereof with due regard for the number of the true positive (TPR), true negative (TNR), false positive (FPR), and false negative (FNR) results. Comparing the findings of the comprehensive examination of the patients demonstrated that all methods of the study, except for selective angiography (sensitivity of 85.7%) yielded high sensitivities and specificities in diagnosis of false aneurysms. PMID- 22836328 TI - [Endovascular radiofrequency denervation of renal arteries as an innovation method of treatment of refractory arterial hypertension. First experience in Russia]. AB - Excessive activation of the sympathetic nervous system forms the basis of pathogenesis of essential arterial hypertension (AH). The present work was aimed at evaluating efficacy and safety of endovascular radiofrequency denervation of renal arteries in patients with AH refractory AH based on the initial first experience in with using this methodology in the Russian Federation. The interventions were carried out on December 14-15th, 2011 in the first five patients presenting with AH refractory to antihypertensive therapy consisting of three and more drugs in therapeutic doses, one of which was a diuretic. The selection criteria were systolic arterial pressure (SAP) >=160 mm Hg or >=150 mm Hg in the presence of type 2 diabetes mellitus. The obligatory conditions for selection were the preserved renal function [glomerular filtration rate (GFR) >=45 ml/min] and the absence of the secondary form of AH. The procedure of denervation was performed in the conditions of roentgen-operating room using special Medtronic Ardian Simplicity Catheter SystemTM. In all cases we managed to perform bilateral denervation of renal arteries with the radiofrequency effect in not less than 4 zones of each of vessels. Efficacy of each of the effect was registered with due regard for reaching certain temperature and values of impedance. The interventions were not accompanied by the development of any complications either in the area of manipulations or the site of puncture. Neither were there any complications from the side of the cardiovascular or excretory systems of the body. Diurnal monitoring of AP (DMAP) registered a significant decrease in SAP averagely from 174+/-12 to 145+/-10 mm Hg three days after the intervention. A persistent antihypertensive effect was confirmed by the DMAP findings one month after denervation - the SAP level averagely amounted to 131+/-6 mm Hg. Endovascular radiofrequency denervation of renal arteries is a safe and efficient method of treatment of AH resistant to multicomponent antihypertensive therapy. PMID- 22836329 TI - [Angiographic assessment of the incidence rate of atypical variants of the development of crural and plantar arteries]. AB - OBJECTIVE: assessing the incidence rate of atypical anatomical variants of the development of the popliteal artery and plantar arteries according to the findings of digital subtraction angiography. MATERIAL: Retrospective analysis of angiograms of 2,456 lower limbs in 1,305 patients. The character of the arterial lesion and the quality of the angiograms allowed of evaluating the anatomy of the popliteal artery and plantar arteries on a total of 1,609 extremities (65%). RESULTS: The incidence of atypical ramification of the popliteal artery amounted to 9%. Altered blood supply of the foot was observed in 7.6% of cases. The total incidence rate of atypical anatomical variants in men and women did not differ significantly. In the presence of a typical anatomical variant on one extremity, the prevalence of atypical blood supply of the other limb amounted to 16.3%. In the presence of an atypical anatomical variant on one limb, the incidence of atypical blood supply of the other amounted to 42%. In case of atypical blood supply of the foot on one limb, the incidence rate of the same-type abnormality on the other equalled 48%. CONCLUSION: In a typical variant of blood supply of one extremity, the probability of typical blood supply of the other amounted to 83 .7%, in an atypical variant decreasing to 58%. In case of atypical blood supply of one foot, one should suppose an analogous anatomical variant on the other foot in half of the cases. PMID- 22836330 TI - [Diagnosis and treatment of varicose disease of small pelvic veins]. AB - The study was based on the findings of examination and treatment of fifty-four 19 to-55- year-old female patients (mean age 35.3 +/- 7.3 years) presenting with varicosity of small pelvis veins. Of these, seventeen women with stenosis of the left renal vein were subjected to the following reconstructive operations on small pelvis veins: creating proximal ovarian-iliac anastomoses - 10 procedures, establishment of sapheno-ovarian anastomoses - 5 operations, one procedure of prosthetic repair of the left renal vein and one operation of transposition of the left renal vein. All interventions were completed with resection of the distal segments of the ovarian vein. A further 19 women with idiopathic reflux along the ovarian veins underwent uni- or bilateral embolization thereof, with multi-stage embolization of the branches of the internal iliac vein performed in one patient. The remaining eighteen endured the following interventions: unilateral resection of the left ovarian vein performed in twelve cases (3 endoscopic operations), bilateral resection in four cases (3 endoscopic resections). In seven cases the operations were supplemented with microphlebectomy of the varicosely altered perineal veins. Two patients underwent operations of crossectomy and resection of the pathologically altered internal pudendal vein. Five-year follow up showed that good-to-satisfactory results were obtained in 45 (83.3%) cases, with a disease relapse revealed in seven cases. PMID- 22836331 TI - [Micronized purified flavonoid fraction in treatment of pelvic varicose veins]. AB - Presented herein are the results of studying efficacy of micronized purified flavonoid fraction (MPFF) in treatment of pelvic varicose veins (PVV) using reference ray-tracing methods of study. We examined a total of 85 patients with PVV. Of these, 65 subjects were found to have isolated dilatation of pelvic venous plexuses (study group), and 20 were diagnosed as having combined dilation of gonadal veins and venous plexuses of the pelvis (control group). Besides clinical examination, the patients were subjected to ultrasonographic angioscanning (USAS) and emission computed tomography (ECT) of pelvic veins before treatment and 2, 6, 12, 24, 36 and 60 months after the beginning of phlebotrophic therapy. Based on the findings of the clinical and instrumental studies, it was determined that MPFF was most efficient in patients with isolated dilatation of uterine and parametrial veins. In this group of patients, pelvic pain and other symptoms of the disease disappeared completely and the clinical effect persisted for a long time (up to 6-9 months). In the control group, venotonic therapy had a positive effect which was less pronounced as compared to the control group, and pelvic pain reappeared in the nearest time (up to 3 weeks) after withdrawal of MPFF. PMID- 22836332 TI - [Aortic-bicarotid-subclavian trifurcation bypass grafting with a synthetic prosthesis]. AB - The authors describe herein a case of successful surgical management of a 55-year old male patient presenting with a multifocal atherosclerotic lesion of brachiocephalic arteries. The diagnosis was confirmed by DS with CDM, MSCT angiography. Intraoperatively revealed were up to 80% stenosis of the ostium of the left common carotid artery and up to 80% stenosis of the brachiocephalic trunk. The patient underwent aortic-bicarotid-subclavian trifurcation bypass grafting with a synthetic prosthesis. Analysing the early postoperative period and the findings obtained by MSCT angiography showed satisfactory therapeutic outcomes. PMID- 22836333 TI - [Own experience endovascular prosthetic repair of abdominal aortic aneurysms]. AB - Endovascular prosthetic repair has increasingly been used over the last several decades. This type of intervention is indicated for patients running a high surgical and anaesthesiological risk of an open surgical procedure. The experience gained in endovascular prosthetic repair of abdominal aortic aneurysms makes it possible to extend the indications for its practical application. The authors describe herein their experience gained in a total of 20 procedures of endovascular prosthetic repair of abdominal aortic aneurysms using the Gore Excluder endograft device in patients running a high risk of an open surgical intervention. There were neither short -nor long-term lethal outcomes. Three patients after endovascular prosthetic repair were found to have type 1 endoleak and two appeared to have type 2 endoleak. Type 1 endoleaks were coped with intraoperationally. Dynamic follow-up (at 1, 6, 12 months after surgery) of patients including computed tomography showed no complications whatsoever (i. e., no endoleaks, endograft migration, nor increase in the aneurysm's diameter). After endografting of abdominal aortic aneurysms there were neither cardiac nor respiratory complications in the immediate postoperative period. Hence, endografting of an abdominal aortic aneurysm is a method of choice for high-risk patients. PMID- 22836334 TI - [Hybrid operations in high-operative risk patients with limb critical ischaemia and lesion of the aortoiliac segment]. AB - The article deals with outcomes of managing a total of twenty-nine patients of high operational risk with TASK II type S and D lesions of the aortoiliac segment. All patients were subjected to single-stage hybrid operations: open reconstructive interventions on the infrainguinal zone and stenting of iliac arteries. High risk of coronary complications these patients were running was confirmed in accordance with the European guidelines on perioperative assessment of the patients being elected for extracardiac operative treatment. Critical ischaemia was in all cases reliably relieved. Two patients during predilatation developed haemorrhage due to iliac artery rupture which was the cause of changing over to open operation. No lethal outcomes were observed. PMID- 22836335 TI - Remote results of reconstructive operations in pathological deformity of the internal carotid artery. AB - OBJECTIVE: to study remote results of surgical treatment of patients presenting with a pathological deformity of the internal carotid artery. METHODS: the study was based on retrospectively analysing the findings of examination and the outcomes of surgical treatment of 142 patients presenting with an isolated pathological deformity of the internal carotid artery (ICA), who underwent a total of 166 reconstructive operations. RESULTS: 7% of patients were operated on at the asymptomatic stage, more than half (56%) of the patients were found to have transient (21%) or persistent neurological deficit (35%), 37% of patients had stage III cerebrovascular insufficiency. Twenty-five (15%) operations were performed for C- and S-shape tortuosity, ninety-seven (58%) procedures for kinking of the internal carotid artery, and forty-four (27%) interventions for coiling. The operation of choice was resection with redressation of the internal carotid artery and reimplantation into the old ostium (74%). Analysing the results of surgical treatment showed its high neurological efficiency in prevention of cerebral circulation impairments (93% of patients at terms up to 25 years had no such complications), as well as clinical efficacy (relief of cerebrovascular insufficiency symptoms in 91.1% of patients). The effect obtained appeared to preserve during 2 and 5 years in 96% and 92% of patients, respectively, and at terms up to 25 years in 83%. The 3-, 5- and up- to-25-year survival amounted to 95%, 92% and 75%, respectively. Restenosis of the internal carotid artery was significantly more often observed after prosthetic repair of the artery (p <0.05) as compared with other methods of reconstruction employed. Thromboses of the internal carotid artery were encountered with similar frequency (8%) only after prosthetic repair and resection of the internal carotid artery with an "end-to-end" anastomosis, which was significantly more often than in resection with redressation (p <0.05). Stroke incidence in the remote postoperative period amounted to 0.8% and the "stroke + stroke-related mortality" parameter equalled 1.6%. CONCLUSION: the remote results of surgical treatment for pathological deformity of the internal carotid artery are strongly suggestive of high efficacy of this method of prevention of impairments of cerebral circulation and treatment of cerebrovascular insufficiency in patients with the pathology concerned. The operation of choice in pathological deformity of the internal carotid artery is resection with redressation of the internal carotid artery and reimplantation into the original ostium. PMID- 22836336 TI - [Outcomes of carotid endarterectomy and stenting in patients with carotid artery stenosis]. AB - Analysed in the article are the outcomes of treating a total of 156 patients diagnosed with carotid artery stenosis. Of these, carotid endarterectomy was performed in 82 patients and stenting of carotid arteries was carried out in the remaining 74 patients. The incidence rate of perioperative stroke in the carotid endarterectomy group amounted to 3.6%, being in the stenting group 4.8%, P = 0.57. Multifactorial analysis was used to reveal risk factors for each method. Thus, in the carotid endarterectomy group, the risk factors for cerebrovascular complications appeared to be contralateral occlusion in patients with a history of stroke endured within less than six previous months (P<0.05), as well as the age over 75 years amongst the patients requiring placement of a temporary intraluminal bypass graft (P<0.05). For carotid stenting, risk factors of cerebrovascular complications included a hypoechogenic heterogeneous type of an atherosclerotic plaque (P<0.05) and ulceration of its surface (P<0.05). The presence of the patient's baseline functional class III angina of effort appeared to be a risk factor for the development of cardiovascular complications for carotid endarterectomy (P<0.05). No cardiovascular risk factors for carotid stenting were revealed. Based on the assessment of the risk factors thus detected, the authors worked out an algorithm of choosing an optimal treatment policy for patients presenting with carotid artery stenosis. PMID- 22836337 TI - [Role of ocular ischaemic syndrome in establishing indications for revasculization of the carotid basin in stenotic lesions of extracranial portions of carotid arteries]. AB - The article is dedicated to the problem concerning indications for revascularization of the carotid basin. The aim was to determine significance of ocular ischaemic syndrome in establishing indications for revascularization of the carotid basin in stenotic lesions of extracranial portions of carotid arteries. PMID- 22836338 TI - [Substantiation of surgical decision making in congenital lesions involving the inguinal major vessels n injection drug abusers]. AB - The article is dedicated to surgical policy pursued in lesions involving femoral major vessels in the inguinal region, having developed due to long-term abuse of injection narcotic drugs. Analysed herein are the outcomes of surgical management of thirty-one patients presenting with a pulsating haematoma and inguinal pseudoaneurysms of post-injection aetiology. According to the authors' opinion, choosing the appropriate scope of the would-be operation is too complicated largely due to peculiarities of the pyo-necrotic process in this zone. Revealed and systematized characteristic of this category of risk factors that pose a real threat of severe consequences when any type of surgery. The authors recommend using only 2 categories of operations: ligation of damaged vessels in the groin area as an independent operation and ligation of vessels with the restoration of blood flow through lateral bypass autovein. Indications for their use, particularity of performing the ligated operations in the inguinal region was given. PMID- 22836339 TI - [Single-step surgical management of lesions of the ascending aorta and aortic arch, coronary and carotid arteries in a male patient with multifocal atherosclerosis]. AB - Described in the article is a clinical case report concerning single-step surgical management of a male patient presenting with multifocal atherosclerosis accompanied by an aneurysm of the ascending aorta and proximal segment of the aortic arch combined with lesions of the coronary and brachiocephalic vessels, thus showing a possibility of surgical treatment in this cohort of patients, if completely and timely diagnosed. Performing a one-stage operation without aggravating the surgical intervention makes it possible to decrease the risk of complications of both the heart and brain in the intra- and postoperative periods. PMID- 22836340 TI - [A clinical example of operative intervention on previously stented peripheral artery in a patient with critical ischaemia of lower limbs]. AB - The problem of open surgery of peripheral arteries after previously performed interventions is currently of considerable interest. This is associated with the development of roentgenoendovascular technologies, on the one hand, and with the fact that it is not always possible to use them properly, on the other. Nowadays, one may single out a small group of patients having endured balloon angioplasty and stenting of the arterial segment followed by open operation. Of special interest are patients with critical ischaemia of lower extremities. No results of randomized studies dedicated to this problem have yet been published. The present article deals with a clinical case concerning a patient having endured multiple interventional therapeutic procedures including stenting of the iliac-femoral segment. The consequent development of critical ischaemia of lower limbs required emergency revascularization by an open method on the previously stented vessels. The duration of postoperative follow up is more than 12 months. PMID- 22836341 TI - [Comparative characteristics of laser-mediated and radiofrequency-powered thermal obliteration in varicose disease]. AB - The article deals with a comparative analysis of the two most commonly used methods techniques of thermal ablation used for elimination of truncal varicosis in varicose disease, i. e., endovasal laser-mediated and radiofrequency-powered obliteration, underlining differences in the mechanisms of physical impact of the two competitive methods, clinical peculiarities of their application, as well as economic aspects of these interventions under the conditions of the present-day Russia. PMID- 22836342 TI - Letter to the editor: a meta-analysis of MMP-2 expression on the survival of patients with colorectal cancer. PMID- 22836344 TI - SNMMI/ABNM joint position statement on optimizing training in nuclear medicine in the era of hybrid imaging. PMID- 22836343 TI - In situ click chemistry: from small molecule discovery to synthetic antibodies. AB - Advances in the fields of proteomics, molecular imaging, and therapeutics are closely linked to the availability of affinity reagents that selectively recognize their biological targets. Here we present a review of Iterative Peptide In Situ Click Chemistry (IPISC), a novel screening technology for designing peptide multiligands with high affinity and specificity. This technology builds upon in situ click chemistry, a kinetic target-guided synthesis approach where the protein target catalyzes the conjugation of two small molecules, typically through the azide-alkyne Huisgen cycloaddition. Integrating this methodology with solid phase peptide libraries enables the assembly of linear and branched peptide multiligands we refer to as Protein Catalyzed Capture Agents (PCC Agents). The resulting structures can be thought of as analogous to the antigen recognition site of antibodies and serve as antibody replacements in biochemical and cell based applications. In this review, we discuss the recent progress in ligand design through IPISC and related approaches, focusing on the improvements in affinity and specificity as multiligands are assembled by target-catalyzed peptide conjugation. We compare the IPISC process to small molecule in situ click chemistry with particular emphasis on the advantages and technical challenges of constructing antibody-like PCC Agents. PMID- 22836345 TI - Correlation of the genotype of paragangliomas and pheochromocytomas with their metabolic phenotype on 3,4-dihydroxy-6-18F-fluoro-L-phenylalanin PET. AB - Paragangliomas and pheochromocytomas are genetically heterogeneous diseases. The purpose of this study was to determine the sensitivity and specificity of PET with 3,4-dihydroxy-6-(18)F-fluoro-L-phenylalanin ((18)F-DOPA) for the detection and staging of pheochromocytomas/paragangliomas. Furthermore, we assessed whether the genotypes of pheochromocytomas and paragangliomas correlate with the uptake of (18)F-DOPA. METHODS: We retrospectively analyzed 101 consecutive patients who underwent (18)F-DOPA PET or (18)F-DOPA PET/CT for known or suspected pheochromocytomas or paragangliomas. Maximum (18)F-DOPA tumor uptake was quantified relative to uptake in the liver. RESULTS: Histopathology, cross sectional imaging, and follow-up indicated the presence of paragangliomas and pheochromocytomas in 68 patients and the absence of a tumor in 33 patients. The average (18)F-DOPA uptake by paragangliomas and pheochromocytomas, expressed as a tumor-to-liver ratio, was 5.9 +/- 5.2. There was no significant difference in uptake among patients with von Hippel Lindau syndrome (VHL; n = 19), succinate dehydrogenase B-D mutation (n = 21), neurofibromatosis type 1 (n = 1), RET (n = 1), no germline mutation (n = 20), or unknown mutation status (n = 6) (P = 0.84). All 8 patients with an SDHD mutation were true-positive on (18)F-DOPA PET. There were 2 cases of false-negative results each in the group with SDHB (2/12) and VHL mutations (2/19) and 1 false-negative result in the subgroup of patients with unknown mutation status (1/6). Overall, (18)F-DOPA PET yielded a sensitivity of 93% and a specificity of 88% for the detection of paragangliomas and pheochromocytomas on a patient basis (positive and negative predictive value, 94% and 85%, respectively). CONCLUSION: (18)F-DOPA PET is a sensitive and specific imaging modality for the detection and staging of pheochromocytomas and paragangliomas in different genotypes, including VHL-, SDHB-, and SDHD-mutation carriers, and in patients with no germline mutation. PMID- 22836347 TI - Highly pi electron-rich macro-aromatics: bis(p-aminophenyl)-carbo-benzenes and their DBA acyclic references. AB - A series of stable quadrupolar bis(p-aminophenyl)-carbo-benzenes, featuring both donor-donor-donor pi-frustration and central macro-aromaticity, is described and compared to the acyclic dibutatrienylacetylene (DBA) reference series. PMID- 22836346 TI - A broad-range method to detect genomic DNA of multiple pathogenic bacteria based on the aggregation strategy of gold nanorods. AB - It remains challenging to detect unknown pathogenic bacteria in diagnostic, clinical and environmental fields. This work describes the approach to the development of a sensitive, broad-range genosensing assay targeting the conserved 16S rDNA region existing in most bacteria, by monitoring the aggregation level of gold nanorods (GNRs)-based nanoprobes through their localized surface plasmon resonance (LSPR) property. In the quantitative detection of artificial sequence, the limit of detection (LOD) of such a bioassay is demonstrated to reach the 5 pM level. This pair of universal GNRs-based nanoprobes can further identify at least 6 species of bacteria that were most prevalent in platelet concentrates (PCs) and have no cross-reaction with other pathogens. Moreover, it also exhibits higher sensitivity than other broad-range methods in analysing Serratia marcescens spiked PCs. Therefore, the presented strategy not only provides a novel and effective DNA analysis method to detect multiple bacterial contaminations in PCs, but also opens up possibilities for its future use of detecting unknown bacteria in other systems, such as food and water, even at ultralow levels. PMID- 22836348 TI - Influence of peer context on the relationship between body dissatisfaction and eating pathology in women and men. AB - OBJECTIVE: This study examined the influence of peer context on the relationship between body dissatisfaction and eating pathology in women and men. METHOD: Secondary analyses were conducted using survey data from a large community sample of women and men (N = 2,060). RESULTS: The frequency of friend comments on weight and diet moderated the relationship between body dissatisfaction and eating pathology such that more frequent comments strengthened the relationship between body dissatisfaction and eating pathology in women. This effect was not significant in analyses of men. Instead, friend comments were directly related to eating pathology in men. DISCUSSION: Both women and men may benefit from peer-led interventions, with the greatest potential benefits for women with high body dissatisfaction, consistent with results from selective peer-led prevention programs in sororities. PMID- 22836349 TI - Essential and toxic elements in infant foods from Spain, UK, China and USA. AB - Spanish gluten-free rice, cereals with gluten, and pureed baby foods were analysed for essential macro-elements (Ca and Na), essential trace elements (Fe, Cu, Zn, Mn, Se, Cr, Co and Ni) and non-essential trace elements (As, Pb, Cd and Hg) using ICP-MS and AAS. Baby cereals were an excellent source of most of the essential elements (Ca, Fe, Cu, Mn and Zn). Sodium content was high in pureed foods to improve their flavour; fish products were also rich in Se. USA pure baby rice samples had the highest contents of all studied essential elements, showing a different nutrient pattern compared to those of other countries. Mineral fortification was not always properly stated in the labelling of infant foods. Complementary infant foods may also contain significant amounts of contaminants. The contents of Hg and Cd were low enough to guarantee the safety of these infant foods. However, it will be necessary to identify the source and reduce the levels of Pb, Cr and As in Spanish foods. Pure baby rice samples contained too much: Pb in Spain; As in UK; As, Cr and Ni in USA; and Cr and Cd in China. PMID- 22836350 TI - European stroke science workshop. AB - The European Stroke Organisation held its first European Stroke Science Workshop in Garmisch-Partenkirchen, Germany (December 15-17, 2011). Stroke experts based in Europe were invited to present and discuss their current research. The scope of the workshop was to review the most recent findings of selected topics in stroke, to exchange ideas, to stimulate new research, and to enhance collaboration between European stroke research groups. Seven scientific sessions were held, each starting with a keynote lecture to review the state of the art of the given topic, followed by 4 or 5 short presentations by experts. They were asked to limit their presentations to 10 slides containing only recent information. The meeting was organized by the executive committee of the European Stroke Organisation (Heinrich Mattle, chairman, Michael Brainin, Angel Chamorro, Werner Hacke, Didier Leys) and supported by the European Stroke Conference (Michael Hennerici). The following sections summarize the content of the workshop. PMID- 22836351 TI - Poststroke balance improves with yoga: a pilot study. AB - BACKGROUND AND PURPOSE: Balance impairment is common after stroke; modified yoga may be able to improve balance and other important poststroke variables. Scientific-evidence is needed to support such treatment interventions. The purpose of this study was to assess the impact of a yoga-based rehabilitation intervention on balance, balance self-efficacy, fear of falling (FoF), and quality of life after stroke. METHODS: This was a prospective, randomized, pilot study of yoga-based rehabilitation for people with chronic stroke. All yoga sessions were taught by a registered yoga therapist, occurred twice per week for 8 weeks and included seated, standing, and floor postures with relaxation and meditation. Balance was assessed with the Berg Balance Scale, balance self efficacy with the Activities-specific Balance Confidence Scale, FoF with a dichotomous yes/no question, and quality of life with the Stroke Specific Quality of Life scale. RESULTS: There were no significant differences between wait-list control (n=10) and yoga (n=37) groups in baseline or follow-up scores. However, using within-group comparisons, yoga group data demonstrated significant improvement in balance (Berg Balance Scale, 41.3+/-11.7 vs 46.3+/-9.1; P<0.001) and FoF (51% vs 46% with FoF; P<0.001). CONCLUSIONS: A group yoga-based rehabilitation intervention for people with chronic stroke has potential in improving multiple poststroke variables. Group yoga may be complementary to rehabilitation, may be possible in medical-based and community-based settings, and may be cost-effective. Further testing of group yoga-based rehabilitation interventions is warranted. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT01109602. PMID- 22836352 TI - Cerecyte coil trial: angiographic outcomes of a prospective randomized trial comparing endovascular coiling of cerebral aneurysms with either cerecyte or bare platinum coils. AB - BACKGROUND AND PURPOSE: We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups. METHODS: Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat. RESULTS: Four hundred ninety four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram (P=0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum (P=0.064; range, 4-34 months). The clinical outcomes did not differ between the groups. CONCLUSIONS: There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory. Clinical Trial Registration Information- URL: www.controlled-trials.com. Unique Identifier: ISRCTN82461286. PMID- 22836353 TI - A fungal anticodon nuclease ribotoxin exploits a secondary cleavage site to evade tRNA repair. AB - PaOrf2 and gamma-toxin subunits of Pichia acaciae toxin (PaT) and Kluyveromyces lactis zymocin are tRNA anticodon nucleases. These secreted ribotoxins are assimilated by Saccharomyces cerevisiae, wherein they arrest growth by depleting specific tRNAs. Toxicity can be recapitulated by induced intracellular expression of PaOrf2 or gamma-toxin in S. cerevisiae. Mutational analysis of gamma-toxin has identified amino acids required for ribotoxicity in vivo and RNA transesterification in vitro. Here, we report that PaOrf2 residues Glu9 and His287 (putative counterparts of gamma-toxin Glu9 and His209) are essential for toxicity. Our results suggest a similar basis for RNA transesterification by PaOrf2 and gamma-toxin, despite their dissimilar primary structures and distinctive tRNA target specificities. PaOrf2 makes two sequential incisions in tRNA, the first of which occurs 3' from the mcm(5)s(2)U wobble nucleoside and depends on mcm(5). A second incision two nucleotides upstream results in the net excision of a di-nucleotide. Expression of phage and plant tRNA repair systems can relieve PaOrf2 toxicity when tRNA cleavage is restricted to the secondary site in elp3 cells that lack the mcm(5) wobble U modification. Whereas the endogenous yeast tRNA ligase Trl1 can heal tRNA halves produced by PaOrf2 cleavage in elp3 cells, its RNA sealing activity is inadequate to complete the repair. Compatible sealing activity can be provided in trans by plant tRNA ligase. The damage-rescuing ability of tRNA repair systems is lost when PaOrf2 can break tRNA at both sites. These results highlight the logic of a two-incision mechanism of tRNA anticodon damage that evades productive repair by tRNA ligases. PMID- 22836354 TI - Multiple binding of repressed mRNAs by the P-body protein Rck/p54. AB - Translational repression is achieved by protein complexes that typically bind 3' UTR mRNA motifs and interfere with the formation of the cap-dependent initiation complex, resulting in mRNPs with a closed-loop conformation. We demonstrate here that the human DEAD-box protein Rck/p54, which is a component of such complexes and central to P-body assembly, is in considerable molecular excess with respect to cellular mRNAs and enriched to a concentration of 0.5 mM in P-bodies, where it is organized in clusters. Accordingly, multiple binding of p54 proteins along mRNA molecules was detected in vivo. Consistently, the purified protein bound RNA with no sequence specificity and high nanomolar affinity. Moreover, bound RNA molecules had a relaxed conformation. While RNA binding was ATP independent, relaxing of bound RNA was dependent on ATP, though not on its hydrolysis. We propose that Rck/p54 recruitment by sequence-specific translational repressors leads to further binding of Rck/p54 along mRNA molecules, resulting in their masking, unwinding, and ultimately recruitment to P-bodies. Rck/p54 proteins located at the 5' extremity of mRNA can then recruit the decapping complex, thus coupling translational repression and mRNA degradation. PMID- 22836355 TI - Differential association of microRNAs with polysomes reflects distinct strengths of interactions with their mRNA targets. AB - While microRNAs have been shown to copurify with polysomes, their relative fraction in the translation pool (polysome occupancy) has not yet been measured. Here, we introduce a high-throughput method for quantifying polysome occupancies of hundreds of microRNAs and use it to investigate factors affecting these occupancies. Analysis in human embryonic stem cells (hESCs) and foreskin fibroblasts (hFFs) revealed microRNA-specific preferences for low, medium, or high polysome occupancy. Bioinformatics and functional analysis based on overexpression of endogenous and chimeric microRNAs showed that the polysome occupancy of microRNAs is specified by its mature sequence and depends on the choice of seed. Nuclease treatment further suggested that the differential occupancy of the microRNAs reflects interactions with their mRNA targets. Indeed, analysis of microNRA*mRNA duplexes showed that pairs involving high occupancy microRNAs exhibit significantly higher binding energy compared to pairs with low occupancy microRNAs. Since mRNAs reside primarily in polysomes, strong interactions lead to high association of microRNAs with polysomes and vice versa for weak interactions. Comparison between hESCs and hFFs data revealed that hESCs tend to express lower occupancy microRNAs, suggesting that cell type-dependent translational features may be affected by expression of a particular set of microRNAs. PMID- 22836356 TI - Association of Argonaute proteins and microRNAs can occur after cell lysis. AB - MicroRNA (miRNA) target identification is a challenging but important endeavor. Global analyses of the direct mRNA targets of miRNAs have relied heavily upon immunopurification techniques, wherein a core protein component of the miRNA protein complex, Argonaute (Ago), is immunoprecipitated to isolate associated RNAs. This approach involves the assumption that the selected RNAs were bound to the Ago protein in vivo and that the methodology did not significantly perturb endogenous interactions or produce novel interaction artifacts. To test whether RNAs that coimmunoprecipitate with human Ago were bound in vivo or could associate post-cell lysis, we used an experimental approach that distinguishes between these two origins of interaction. We show that a transfected miRNA mimic, but not a plasmid-expressed miRNA, can interact with human Ago proteins post lysis. Our results have important implications for the design of miRNP immunoprecipitation experiments. PMID- 22836357 TI - Continuous noninvasive hemodynamic monitoring in decompensated heart failure. AB - BACKGROUND: The clinical and hemodynamic assessment at the bedside and the use of pulmonary artery catheter for the estimation of hemodynamic data have been used in decompensated heart failure. However, there are no data on the use of continuous noninvasive hemodynamic monitoring. OBJECTIVE: To compare the data obtained through noninvasive hemodynamic monitoring with invasive ones in patients with decompensated heart failure and refractory to treatment. METHODS: The non-invasive hemodynamic measurements were obtained through continuous monitoring of systemic blood pressure by the pulse wave model (Modelflow) and compared with measurements obtained by the passage of a pulmonary artery catheter, simultaneously. RESULTS: A total of 56 measurements were performed in 14 patients studied on different days and time periods. The correlation index between systolic blood pressure measurements was r = 0.26 (95% CI = 0.00 to 0.49, p = 0.0492) and diastolic ones, r = 0.50 (95% CI = 0.27 to 0.67, p <0.0001). The correlation was r = 0.55 (95% CI = 0.34 to 0.71, p <0.0001) for cardiac index and r = 0.32 (95% CI = 0.06 to 0 53, p = 0.0178) for systemic vascular resistance. CONCLUSION: There was a correlation between the hemodynamic measurements when compared to noninvasive pulmonary artery catheter measurements. The continuous noninvasive hemodynamic monitoring may be useful for hospitalized patients with decompensated heart failure. PMID- 22836358 TI - Hemodynamic profile of severity at pulmonary vasoreactivity test in schistosomiasis patients. AB - BACKGROUND: The pulmonary vasoreactivity rate of Schistosomal Pulmonary Artery Hypertension (SPAH) is not known. Hemodynamic data obtained by cardiac catheterization are associated with the most commonly used clinical criteria of severity. OBJECTIVE: To estimate the percentage of positive vasoreactivity to nitric oxide in schistosomal pulmonary arterial hypertension and verify the association of hemodynamic parameters with WHO functional classification and the six-minute walk test in these patients. METHODS: A total of 84 patients with schistosomal pulmonary hypertension were selected from a database, who had been submitted to the right and left cardiac catheterization and pulmonary vasoreactivity test with nitric oxide. Data on WHO functional classification and six-minute walk test were collected for comparison with invasive data. RESULTS: Of the 84 patients with SPAH, 3 (3.5%) had positive criteria for pulmonary vasoreactivity. The increase in pulmonary vascular resistance was significantly associated with lower exercise capacity measured by the six-minute walk test (p = 0.045) and greater symptom severity by higher functional classifications (WHO class III/IV) (p = 0.013). The decrease in oxygen saturation in the pulmonary artery was significantly associated with higher functional classifications (p = 0.041). CONCLUSION: The pulmonary response rate to the vasodilation test of schistosomiasis patients is below the values found for idiopathic pulmonary hypertension. Pulmonary vascular resistance and oxygen saturation in the pulmonary artery are hemodynamic data that can be used as markers of severity in schistosomal pulmonary hypertension. PMID- 22836359 TI - Effects of age and aerobic fitness on heart rate recovery in adult men. AB - BACKGROUND: Physiological aging leads to cardiac autonomic dysfunction, which is associated with the onset and worsening of cardiovascular disease and an increased risk of death. Currently, physical exercise is considered a cardioprotective strategy and more research is needed on its benefit on cardiac autonomic function. OBJECTIVE: To evaluate the autonomic control of heart rate in healthy young and middle-aged volunteers with different levels of aerobic fitness. METHODS: The study included 68 volunteers, stratified for age and level of aerobic fitness. Based on aerobic fitness assessed by the submaximal exercise test, subjects were separated into two groups, good fitness and poor fitness. Assessment of cardiac autonomic control was performed based on measurements of heart rate variability at rest and heart rate recovery post-exercise. Analysis of variance with two factors was used to compare the variables investigated. RESULTS: The heart rate variability is significantly lower in middle-aged volunteers than in young individuals, regardless of the aerobic fitness level (p <0.01). Higher levels of aerobic fitness in middle-aged volunteers are associated with earlier post-effort vagal reentry - rate of HR decline after 1min30s: 39.6% good aerobic fitness vs. poor 28.4% (p < 0.01). CONCLUSION: Better levels of aerobic fitness act beneficially on the autonomic control of post-exercise heart rate, preserving the vagal reentry velocity in healthy middle-aged volunteers. However, it does not attenuate the decrease in heart rate variability due to the natural aging process. PMID- 22836360 TI - Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines. AB - Extracellular RNA (eRNA), released from cells under conditions of injury or vascular disease, acts as potent prothrombotic factor and promotes vascular hyperpermeability related to oedema formation in vivo. In this study, we aimed to investigate the mechanism by which eRNA triggers inflammatory processes, particularly associated with different steps of leukocyte recruitment. Using intravital microscopy of murine cremaster muscle venules, eRNA (but not DNA) significantly induced leukocyte adhesion and transmigration in vivo, which was comparable in its effects to the function of tumour-necrosis-factor-alpha (TNF alpha). In vitro, eRNA promoted adhesion and transmigration of monocytic cells on and across endothelial cell monolayers. eRNA-induced monocyte adhesion in vitro was mediated by activation of the vascular endothelial growth factor (VEGF)/VEGF-receptor-2 system and was abolished by neutralising antibodies against intercellular adhesion molecule-1 or the beta2-integrin Mac-1. Additionally, eRNA induced the release of TNF-alpha from monocytic cells in a time- and concentration-dependent manner, which involved activation of TNF-alpha converting enzyme (TACE) as well as the nuclear factor kappaB signalling machinery. In vivo, inhibiton of TACE significantly reduced eRNA-induced leukocyte adhesion. Our findings present evidence that eRNA in connection with tissue/vascular damage provokes a potent inflammatory response by inducing leukocyte recruitment and by mobilising proinflammatory cytokines from monocytes. PMID- 22836361 TI - Organocatalytic, asymmetric synthesis of 3-sulfenylated N-Boc-protected oxindoles. AB - Sulfenylated oxindoles: The first asymmetric sulfenylation of N-Boc-protected oxindoles has been developed to provide products containing a tetrasubstituted stereogenic center in high to excellent yields (86-98 %) and, in most cases, excellent enantioselectivities (up to 96 % ee; see scheme). PMID- 22836362 TI - Osteopetrosis rescue upon RANKL administration to Rankl(-/-) mice: a new therapy for human RANKL-dependent ARO. AB - In the last decades the molecular basis of monogenic diseases has been largely unraveled, although their treatment has often remained unsatisfactory. Autosomal recessive osteopetrosis (ARO) belongs to the small group of genetic diseases that are usually treated with hematopoietic stem cell transplantation (HSCT). However, this approach is not effective in the recently identified form carrying mutations in the receptor activator of NF-kappaB ligand (RANKL) gene. In this subset, therapy replacement approach based on RANKL delivery has a strong rationale. Here we demonstrate that the systematic administration of RANKL for 1 month to Rankl( /-) mice, which closely resemble the human disease, significantly improves the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, we provide evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial. PMID- 22836363 TI - Far lateral approaches (XLIF) in adult scoliosis. AB - PURPOSE: To review the literature on the use of extreme lateral interbody fusion (XLIF) in adult spinal deformity, to discuss on its limits and advantages and to propose a guide to surgical strategy. METHODS: Surgical technique XLIF is a minimally invasive surgery (MIS) technique to anteriorly access the spine from midthoracic to L5. Important aspects of the technique are a muscle splitting approach through the psoas, use of advanced neuromonitoring to detect the lumbar plexus within the psoas, bilateral annulus release and large footprint interbody cages, supported by the stronger bone of ring apophyses. Large, laterally inserted cages provide strong correction of coronally asymmetrical disc spaces. Literature review MEDLINE database, the Web using Google Scholar and proceedings of the Society for Lateral Access Surgery meetings were searched for relevant articles on technique, results and complications. RESULTS: XLIF with posterior percutaneous pedicle screw instrumentation provides 40-75 % correction of coronal curves, with modest increase of lordosis. Only anterior XLIF can provide less correction. Self-limited thigh symptoms are frequent after transpsoas access. Permanent neural deficit and visceral complications have also been reported. Combined XLIF-MIS could have a lower complication compared to open circumferential surgery in historical series. CONCLUSIONS: XLIF is a promising MIS option for adult deformity. Specific surgical strategies are needed to avoid imbalance and define ideal fusion levels and methods. An XLIF-based MIS strategy with a reduced number of levels of lumbar scoliosis can lead to significant advantages. Evaluation of the incidence, complications, their avoidance and real impact on patients' outcomes is necessary to better understand the advantages of this approach. Studies comparing effectiveness and safety of traditional versus XLIF approaches are needed to assist evidence-based decision making. PMID- 22836364 TI - Validation of a novel spinal posture monitor: comparison with digital videofluoroscopy. AB - PURPOSE: A novel, minimally invasive posture monitor which can monitor lumbar postures outside the laboratory has demonstrated excellent reliability, as well as concurrent validity compared to a surface marker-based motion analysis system. However, it is unclear if this device reflects underlying vertebral motion. METHODS: Twelve participants performed full range sagittal plane lumbo-pelvic movements during sitting and standing. Their posture was measured simultaneously using both this device (BodyGuardTM) and digital videofluoroscopy. RESULTS: Strong correlations were observed between the two methods (all r (s) > 0.88). Similarly, the coefficients of determination were high (all r (2) > 0.78). The maximum mean difference between the measures was located in the mid-range of motion and was approximately 3.4 degrees in sitting and 3.9 degrees in standing. CONCLUSION: The BodyGuardTM appears to be a valid method for analysing vertebral motion in the sagittal plane and is a promising tool for long-term monitoring of spinal postures in laboratory and clinical settings in people with low back pain. PMID- 22836366 TI - Neurological improvement and prognosis after occipito-thoracic fusion in patients with mutilating-type rheumatoid arthritis. AB - INTRODUCTION: Mutilating-type rheumatoid arthritis, the most aggressive type of rheumatoid arthritis, is frequently associated with destructive cervical involvement, both at the high-cervical and subaxial levels, causing significant neurological deficit, and their natural course of the disease and the survival are discouraging. For such cases, we have been actively performing occipito thoracic fusion since 1991. Although medical treatment for rheumatoid patients has represented a marked improvement, it could not treat all of these patients because of several reasons. Therefore, it is still important to evaluate the past treatment results. METHODS: We investigated the neurological improvement and prognosis in 51 mutilating-type rheumatoid arthritis patients who underwent occipito-thoracic fusion between 1991 and 2010. The neurological status was evaluated using modified Ranawat classification; class IIIB was subdivided into IIIBa (able to sit upright) and IIIBb (bedridden). RESULTS: The preoperative neurologic status was IIIBa in 19 patients and IIIBb in 17 patients. 15 of the 19 patients with class IIIBa improved to being able to walk (79 %), whereas only 3 of the 17 patients with class IIIBb improved to being able to walk (18 %) after surgery. Of the 51 patients, 28 died during follow-up; the mean age at death was 67.2 years. The postoperative 5- and 10-year survival rates were 60.3 and 26.4 %, respectively. CONCLUSION: The neurological improvement and prognosis after surgery was poorer in class IIIBb patients than in the other patient groups. Occipito-thoracic fusion can improve the neurological symptoms and prognosis. However, early surgical intervention is recommended, before a patient becomes bedridden (class IIIBb). PMID- 22836365 TI - Effectiveness of preventive back educational interventions for low back pain: a critical review of randomized controlled clinical trials. AB - PURPOSE: A systematic search was conducted to study the efficiency of preventive educational interventions mainly focused on a biomechanical/biomedical model. METHODS: The PubMed electronic database and the Cochrane Library were searched based on a combination of keywords related to low back pain (LBP) and posture education. Only randomized controlled trial (RCT) studying the efficiency on outcomes directly related to LBP of a preventive intervention programme mainly based on education of proper care of the back for subjects not seeking treatment were included. References of the articles meeting these inclusion criteria were also checked to identify other potential citations. Besides, a methodological study assessment of the included RCTs was performed. RESULTS: Nine studies, all conducted at the workplace were included in this review. Their mean quality level was low (5.1/12) and among the four studies with a huge sample size (n > 400 subjects), only one had an acceptable methodological quality score (6/12). The education interventions differed widely from one study to another. No significant differences between the control and education groups were found at the follow-up in eight out of the nine studies on the incidence of back pain, disability and sick leave. CONCLUSIONS: The results of the RCTs included in this review suggest that educational interventions mainly focused on a biomechanical/biomedical model are not effective in preventing LBP. However, taking into account the methodological quality level of the RCTs as well as the very short and heterogeneous interventions often proposed, additional high-quality studies with a longer education period are needed to conclude that such interventions are inefficient. PMID- 22836367 TI - Pure hyperextension injury of the lower lumbar spine with an ureteral impingement. AB - INTRODUCTION: Pure hyperextension thoracolumbar spinal fractures are unusual and occur primarily in patients with ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis due to the rigidity of the spine. MATERIAL AND METHODS: A 62-year-old female with osteoporosis presented with a significantly displaced fourth vertebral body fracture after being hit by a motorcycle. An imaging study showed widening of the vertebral height of L4 anteriorly with a horizontal fracture extending across the vertebral body. An in situ instrumented lumbar fusion from the second to fifth lumbar vertebrae was performed. Postoperatively, the patient complained of abdominal pain and difficulty in voiding. Computed tomography and intravenous pyelography showed that the right ureter was impinged between the fractured gaps of the vertebral body of L4. RESULTS: Solid bony union was obtained with surgical intervention. CONCLUSIONS: This case reports a rare distractive extension injury in the lower lumbar spine with ureteral impingement. One should be aware of possible complications such as ureteral impingement following a pure hyperextension injury in the lower lumbar spine. PMID- 22836368 TI - Insulin-like growth factor I regulates G2/M progression through mammalian target of rapamycin signaling in oligodendrocyte progenitors. AB - Extrinsic factors including growth factors influence decisions of oligodendrocyte progenitor cells (OPCs) to continue cell cycle progression or exit the cell cycle and terminally differentiate into oligodendrocytes capable of producing myelin. Multiple studies have elucidated how the G1/S transition is regulated in OPCs; however, little is known about how S phase progression and the G2/M transition are regulated in these cells. Herein, we report that insulin-like growth factor (IGF)-I coordinates with FGF-2 to promote S phase progression but regulates G2/M progression independently. During S phase, IGF-I/FGF-2 enhances protein expression of cyclin A and cdk2, and further increases effective complex formation resulting in enhanced cdk2 activity. Surprisingly, however, OPCs exposed to FGF-2 in the absence of IGF-I fail to traverse through G2/M. Consistent with this observation, OPCs exposed to IGF-I, but not FGF-2, increase cell number over 48 h. IGF-I enhances cdk1 kinase activity during G2/M by promoting nuclear localization of cyclin B/cdk1 as well as of Cdc25C, an activator of cdk1. IGF-I also induces phosphorylation of histone 3 indicating traverse of cells through mitosis. Finally, we demonstrate that IGF-I-mediated G2/M regulation requires mammalian target of rapamycin activity. These data support an important function for IGF-I in G2/M progression in OPCs. PMID- 22836369 TI - Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen. AB - RATIONALE: Acute and/or chronic exposure to cocaine can affect cognitive performance, which may influence rate of recovery during treatment. OBJECTIVE: Effects of the GABA-B receptor agonist baclofen were assessed for potency to reverse the negative influence of acute, pre-session, intravenous (IV) injection of cocaine on cognitive performance in Macaca mulatta nonhuman primates. METHODS: Animals were trained to perform a modified delayed match to sample (DMS) task incorporating two types of trials with varying degrees of cognitive load that had different decision requirements in order to correctly utilize information retained over the delay interval. The effects of cocaine (0.2, 0.4, and 0.6 mg/kg, IV) alone and in combination with baclofen (0.29 and 0.40 mg/kg, IV) were examined with respect to sustained performance levels. Brain metabolic activity during performance of the task was assessed using PET imaged uptake of [(18) F] fluorodeoxyglucose. RESULTS: Acute cocaine injections produced a dose-dependent decline in DMS performance selective for trials of high cognitive load. The GABA receptor agonist baclofen, co-administered with cocaine, reversed task performance back to nondrug (saline IV) control levels. Simultaneous assessment of PET-imaged brain metabolic activity in prefrontal cortex (PFC) showed alterations by cocaine compared to PFC metabolic activation in nondrug (saline, IV) control DMS sessions, but like performance, PFC activation was returned to control levels by baclofen (0.40 mg/kg, IV) injected with cocaine. CONCLUSIONS: The results show that baclofen, administered at a relatively high dose, reversed the cognitive deficits produced by acute cocaine intoxication that may have implications for use in chronic drug exposure. PMID- 22836370 TI - Effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and quipazine on heroin self-administration in rhesus monkeys. AB - RATIONALE: The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids. OBJECTIVE: This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys. RESULTS: Heroin (0.0001-0.1 mg/kg/infusion) generated an inverted U-shaped dose-response function. Non contingent administration of DOM (0.1-0.32 mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032 mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non contingent (0.32-3.2 mg/kg) and contingent (0.0032-0.56 mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys. CONCLUSION: This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability. PMID- 22836371 TI - Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. AB - RATIONALE: The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal deficits in learning, then strains of mice exhibiting withdrawal deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs. OBJECTIVES: Here, we examined the effects of nicotine withdrawal on fear conditioning and [(3)H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids. METHODS: Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/day) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 h after cessation of nicotine treatment. RESULTS: Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [(3)H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine. CONCLUSIONS: Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal deficits in contextual conditioning and genetic background modulates these effects. PMID- 22836372 TI - The NMDA antagonist ketamine and the 5-HT agonist psilocybin produce dissociable effects on structural encoding of emotional face expressions. AB - RATIONALE: Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases. OBJECTIVES: This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases. METHODS: S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP. RESULTS: Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces. CONCLUSION: This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases. PMID- 22836373 TI - Comparison of the classically conditioned withdrawal reflex in cerebellar patients and healthy control subjects during stance: I. electrophysiological characteristics. AB - The aim of this study was to demonstrate the involvement of the human cerebellum in the classically conditioned lower limb withdrawal reflex in standing subjects. Electromyographic activity was recorded from the main muscle groups of both legs of eight patients with cerebellar disease (CBL) and eight control subjects (CTRL). The unconditioned stimulus (US) consisted of electrical stimulation of the tibial nerve at the medial malleolus. The conditioning stimulus (CS) was an auditory signal given via headphones. Experiments started with 70 paired conditioning stimulus-unconditioned stimulus(CSUS) trials followed by 50 US-alone trials. The general reaction consisted of lifting and flexing the stimulated (stepping) leg with accompanying activation of the contralateral (supporting) leg. In CTRL, the ipsilateral (side of stimulation) flexor and contralateral extensor muscles were activated characteristically. In CBL, the magnitudes of ipsilateral flexor and contralateral extensor muscle activation were reduced comparably. In CTRL, the conditioning process increased the incidence of conditioned responses (CR), following a typical learning curve, while CBL showed a clearly lower CR incidence with a marginal increase, albeit, at a shorter latency. Conditioning processes also modified temporal parameters by shortening unconditioned response (UR) onset latencies and UR times to peak and, more importantly in CBL, also the sequence of activation of muscles, which became similar to that of CTRL. The expression of this reflex in standing subjects showed characteristic differences in the groups tested with the underlying associative processes not being restricted exclusively to the CR but also modifying parameters of the innate UR. PMID- 22836375 TI - Introducing the WHOQOL-SRPB BREF: developing a short-form instrument for assessing spiritual, religious and personal beliefs within quality of life. AB - PURPOSE: The aim was to develop and conduct preliminary testing of a short-form measure to assess spiritual, religious and personal beliefs (SRPB) within quality of life (QoL). METHODS: Existing data from the 132 items of the WHOQOL-SRPB (n = 5087) obtained in 18 cultures were first analysed to select the 'best' performing item from each of the eight SRPB facets. These were integrated with the 26 WHOQOL BREF items to give 34 items in the WHOQOL-SRPB BREF. A focus group of hospital chaplains reviewed this new short-form. The WHOQOL-SRPB BREF was administered to a UK community sample (n = 230) either with an adapted WHOQOL-SRPB Importance measure or the SWBQ. A subset received both WHOQOL measures twice. RESULTS: Completed in 8 mins, the WHOQOL-SRPB BREF was acceptable and feasible; Importance 5.5 mins. Good internal consistency reliability was found overall (alpha = 0.85), for the SRPB domain (alpha = 0.83), and Importance (alpha = 0.90). Domains were moderately correlated. Domain test-retest reliability was acceptable in both WHOQOL measures, except for SRPB Importance. Sleep was linked with religious beliefs. Hope and wholeness were widely associated with non-spiritual facets. Factor analysis (maximum likelihood) of items largely confirmed the WHOQOL domain structure, adding SRPB as a significant fifth domain. Internally, SRPB distinguished religious from existential beliefs, and was validated by association with personal and transcendental well-being from the SWBQ. CONCLUSION: Preliminary evidence shows that the WHOQOL-SRPB BREF is sound for use in, and beyond health care. Extracted from a measure already available in 18 languages, this short-form can be immediately used where such translations exist. PMID- 22836374 TI - Perceived social support and preventive health behavioral outcomes among older women. AB - Although research has documented that social support is a positive pathway to healthpromoting behavioral practices, very few longitudinal studies have assessed the relationship between social support and health-promoting behaviors among older, diverse women. Three waves of data from the Americans' Changing Lives (ACL) survey assessed whether or not changes in perceived social support influenced behavioral outcomes among 671 African American women and non-Hispanic white women aged 60 years and older. Positive social support from friends was the most successful in predicting physical activity across the life span while positive spousal support, positive support from children, and health behavior specific support were insignificant determinants of physical activity. The results suggest that social support from friends may be an important predictive factor in engaging older women in physical activity during the aging process. PMID- 22836376 TI - Adaptation into Spanish of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) and preliminary validation in a student sample. AB - PURPOSE: There is growing interest in the assessment of positive mental health as a global indicator of societal wealth. We aimed to adapt the Warwick-Edinburgh Mental Well-being scale (WEMWBS) into Spanish and to perform a preliminary evaluation of its metric properties. METHODS: Forward and back-translations and cognitive debriefing were carried out. University students (n = 148) were recruited to evaluate the final Spanish version, following the UK original study. Distribution of WEMWBS responses, internal consistency, test-retest reliability, construct validity, and factor structure were assessed. RESULTS: Only 4 (out of 14) items of the initial Spanish version were not rated as conceptually and linguistically equivalent to the original and were modified. The final version was clear and comprehensible. Global score's Cronbach's alpha (0.90), item-total score correlations (0.44-0.76), and test-retest ICC (0.84) were all satisfactory. Moderate to high correlations (r = 0.45-0.70) were observed between the WEMWBS and validity scales. Preliminary confirmatory factor analyses did not support the hypothesis of a single factor. CONCLUSIONS: A conceptually equivalent Spanish version of the WEMWBS was obtained with high internal consistency, good test retest reliability, and similar construct validity as the original instrument. Further validity and factorial studies are necessary in larger and more heterogeneous samples. PMID- 22836377 TI - Performance of the parent emotional functioning (PREMO) screener in parents of children undergoing hematopoietic stem cell transplantation. AB - PURPOSE: Parents of children undergoing hematopoietic stem cell transplantation (HSCT) may face emotional distress while managing intense treatments with uncertain outcomes. We evaluated a brief parental emotional functioning (PREMO) screener from a health-related quality of life instrument to identify parental emotional distress, as measured by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). METHODS: As part of a longitudinal pediatric HSCT study, parents (N = 165) completed the Child Health Ratings Inventories, which contain the 7-item PREMO screener. Some parents (n = 117) also completed SCID modules for Anxiety, Mood, and Adjustment disorders at baseline and/or 12 months. A composite outcome was created for threshold or subthreshold levels of any of these disorders. Receiver operating characteristic (ROC) analysis assessed how the PREMO screener predicted emotional distress as measured by the SCID. A prediction model was then built. RESULTS: Fifty-two percent of parents completing the SCID had an Axis I disorder at baseline, while 41 % had an Axis I disorder at 12 months. The area under the ROC curve was 0.75 for the PREMO screener and 0.81 for the prediction model. CONCLUSIONS: The PREMO screener may identify parents with, or at risk for, emotional distress and facilitate further evaluation and intervention. PMID- 22836379 TI - Enantioselective analysis of melagatran via an LSPR biosensor integrated with a microfluidic chip. AB - The impact of chiral compounds on pharmacological and biological processes is well known. With the increasing need for enantiomerically pure compounds, effective strategies for enantioseparation and chiral discrimination are in great demand. Herein we report a simple but efficient approach for the enantioselective determination of chiral compounds based on a localized surface plasmon resonance (LSPR) biosensor integrated with a microfluidic chip. A glass microfluidic chip with an effective volume of ~0.75 MUL was fabricated for this application. Gold nanorods (AuNRs) with an aspect ratio of ~2.6 were self-assembled onto the surface of the inner wall of the chip to serve as LSPR transducers, which would translate the analyte binding events into quantitative concentration information. Human alpha-thrombin was immobilized onto the AuNR surface for enantioselective sensing of the enantiomers of melagatran. The proposed sensor was found to be highly selective for RS-melagatran, while the binding of its enantiomer, SR melagatran, to the sensor was inactive. Under optimal conditions, the limit of detection of this sensor for RS-melagatran was found to be 0.9 nM, whereas the presence of 10,000-fold amounts of SR-melagatran did not interfere with the detection. To the best of our knowledge, this is the first demonstration of an LSPR-based enantioselective biosensor. PMID- 22836380 TI - Low frequency excitations in multiferroic MnWO4. AB - Dynamic anomalies have been found in the magnetically ordered phases of multiferroic MnWO(4) using polarized Raman scattering. Strong phonon damping is observed for several B(g) modes within the ferroelectric phase and has been attributed to spin-phonon interactions. Moreover, a new low frequency excitation was detected near 33 cm(-1) that grows in intensity on cooling into the antiferromagnetic phases. It is argued that this signal is most probably due to a two-magnon process. PMID- 22836381 TI - Growth status among low-income Mexican and Mexican-American elementary school children. AB - OBJECTIVES: Childhood obesity remains a problem among Latino children in the United States. Acculturation to an American diet and sedentary lifestyle may be causative factors. The research purpose was to assess child growth status, including sitting height, in relation to acculturation among Mexican and Mexican American children. METHODS: Anthropometric measures of weight, height, and sitting height were taken in a cross-sectional survey of Mexican and Mexican American elementary school children (N = 484) in Phoenix, Arizona. Height-for-age (HAZ), weight-for-age (WAZ), and body mass index (BMI) Z-scores were calculated based on the Centers for Disease Control 2000 growth reference. Sitting height Z scores (SHZ) were determined from the NHANES III reference values. Questions about language usage were asked of the children as a proxy for acculturation. Differences in growth measures and acculturation between those born in the United States or Mexico were evaluated by chi-square or t-tests. RESULTS: The mean HAZ value (-0.23) was close to the reference median. There were no significant differences in HAZ or SHZ by birth country or gender. WAZ values for boys were significantly higher than for girls. More girls (64%) than boys (54%) had normal BMIs. More Mexican-born boys (28%) were obese than Mexican-born girls (17%; P = 0.026) in comparison to the US-born boys (31%) and girls (24%; P = n.s.). Acculturation scale score and male gender predicted a small percentage of the variation in BMIZ. CONCLUSIONS: Environmental and cultural factors that promote obesity among low-income Mexican and Mexican-American children are similar regardless of birth country but boys may be at greater risk of obesity than girls. PMID- 22836382 TI - Cavity-enhanced Raman spectroscopy with optical feedback cw diode lasers for gas phase analysis and spectroscopy. AB - A variant of cavity-enhanced Raman spectroscopy (CERS) is introduced, in which diode laser radiation at 635 nm is coupled into an external linear optical cavity composed of two highly reflective mirrors. Using optical feedback stabilisation, build-up of circulating laser power by 3 orders of magnitude occurs. Strong Raman signals are collected in forward scattering geometry. Gas phase CERS spectra of H(2), air, CH(4) and benzene are recorded to demonstrate the potential for analytical applications and fundamental molecular studies. Noise equivalent limits of detection in the ppm by volume range (1 bar sample) can be achieved with excellent linearity with a 10 mW excitation laser, with sensitivity increasing with laser power and integration time. The apparatus can be operated with battery powered components and can thus be very compact and portable. Possible applications include safety monitoring of hydrogen gas levels, isotope tracer studies (e.g., (14)N/(15)N ratios), observing isotopomers of hydrogen (e.g., radioactive tritium), and simultaneous multi-component gas analysis. CERS has the potential to become a standard method for sensitive gas phase Raman spectroscopy. PMID- 22836384 TI - [Anemia in patients with rheumatoid arthritis]. AB - One of the most frequent extra-articular organ manifestations in rheumatoid arthritis (RA) is anemia. As anemia in RA patients may result in severe symptoms and aggravation of other disease manifestations (e.g. arteriosclerosis), the influence on the course of RA is profound. However, the importance of anemia in RA patients is frequently underestimated. The etiology of anemia in RA is complex. Anemia of inflammation (AI) and iron deficiency anemia, alone or in combination are the most frequent forms of anemia in RA. Changes in iron metabolism are the leading causes of anemia in RA patients and mainly induced by the altered synthesis and function of hepcidin and ferroportin. Hepcidin, a peptide produced in the liver and immunocompetent cells, impairs the expression of ferroportin on iron-secreting cells, thus reducing iron bioavailability. The typical changes of iron metabolism and hepcidin synthesis in RA are induced by proinflammatory cytokines, primarily interleukin-6. Hence, the treatment of RA with cytokine antagonists has significant therapeutic implications on anemia in the context of inflammation and impaired iron metabolism. PMID- 22836383 TI - Regulation of reproductive development by non-coding RNA in Arabidopsis: to flower or not to flower. AB - Plants monitor environmental factors, such as temperature and day length, and also endogenous factors, such as their age and phytohormones, to decide when to flower. These cues are utilized to control expression levels of genes required for flowering. Thus, flowering time control is a unique model for understanding how gene activity is precisely regulated at the transcriptional level. In Arabidopsis, a remarkable number of non-coding RNA molecules have been identified by advanced sequencing technology. Recent progress in the flowering field has revealed several non-coding RNAs that play a major role in determining flowering time. Here, we introduce how two types of non-coding RNA species, microRNA (miRNA) and long noncoding RNA (lncRNA), contribute to flowering via regulation of target gene activity involved in this vital developmental transition. PMID- 22836385 TI - [Macrophage activation syndrome]. AB - Macrophage activation syndrome (MAS) is an infrequent but potentially life threatening complication of various autoimmune diseases. It is characterized by excessive activation of macrophages induced by a dysfunction of the immune system, although the underlying abnormalities remain to be delineated. Sepsis like symptoms accompanied by cytopenia, hepatosplenomegaly, coagulopathy and multiple organ dysfunctions are typical disease manifestations. Due to the lack of validated classification criteria and distinct laboratory markers, the diagnosis of MAS is often difficult to establish. However, early diagnosis and therapy is of utmost importance to ensure best possible outcome. Treatment regimens include high doses of glucocorticoids, classical immunosuppressive agents as well as novel biologics. PMID- 22836386 TI - Impact of the AT(2) receptor agonist C21 on blood pressure and beyond. AB - It is now widely accepted that the angiotensin AT(2) receptor (AT(2)R) plays an important protective role during pathophysiologic conditions, acting as a repair system. The development of the first selective nonpeptide AT(2)R agonist C21 accelerated our understanding of AT(2)R-mediated protective signaling and actions. This article reviews the impact of C21 on blood pressure in normotensive and hypertensive animal models. Although C21 does not act as a classical antihypertensive drug, it could be useful in preventing hypertension-induced vascular and other end organ damages via anti-apoptotic, anti-fibrotic and anti inflammatory actions. In particular, a strong body of evidence started to emerge around its anti-inflammatory feature. This property should be further investigated for potential clinical indications in cardiovascular diseases and beyond. PMID- 22836387 TI - Nocturnal medications dosing: does it really make a difference in blood pressure control among patients with chronic kidney disease? AB - Ambulatory blood pressure (BP) monitoring is superior to clinic BP monitoring in predicting long-term consequences of hypertension. This has raised interest in diurnal variation in BP and elevation in nighttime BP as a prognostic and therapeutic target. Several studies have identified prevalence of nocturnal hypertension in patients with accelerated progression of chronic kidney disease and target organ damage. Some studies suggest that nocturnal BP can be lowered by changing administration of antihypertensive medication to bed time; whether that results in retarding kidney disease progression is not very clear. Further research is needed to determine if certain classes of medications or interventions are superior in controlling nocturnal hypertension, and protocols need to be developed to screen patients for monitoring nocturnal BP. Further studies are needed to evaluate long-term renal outcomes of evening dosing in patients with nocturnal hypertension and chronic kidney disease. PMID- 22836388 TI - Comparative performance of four equations estimating glomerular filtration rate in adult Chinese diabetics. AB - BACKGROUND: The Cockcroft-Gault equation, abbreviated Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and improved abbreviated MDRD equation were used to evaluate renal function in diabetic patients. However, little is known regarding their applicability and precision in Chinese diabetic patients. AIM: To compare the accuracy of four methods evaluating Chinese diabetic patients' renal function. MATERIALS AND METHODS: This study included 329 Chinese diabetic patients. Standard GFR (sGFR) was measured via 99mTc-DTPA dynamic renal imaging. Estimated GFR (eGFR) was calculated by four equations separately. Applicability of these four equations in Chinese diabetic patients was determined by correlation studies, agreement test, and receiver operating characteristic (ROC) curves. RESULTS: For Chinese diabetic patients, four methods assessing eGFR correlated well with sGFR. Overall, eGFR calculated via improved abbreviated MDRD had less bias and greater accuracy than the other algorithms estimating GFR (p <= 0.01). For patients with sGFR >= 60 ml/min/1.73 m2, all four equations significantly underestimated actual GFR, with the improved abbreviated MDRD equation best approximating actual GFR (p <= 0.01). Conversely, in patients with sGFR<60 ml/min/1.73 m2, all four equations overestimated actual GFR; GFR(improved MDRD) was relatively the most accurate (p <= 0.01). CONCLUSIONS: While all four equations were inaccurate, the improved abbreviated MDRD equation best diagnosed and stratified renal failure in Chinese diabetic patients. PMID- 22836389 TI - Platelets directly enhance neutrophil transmigration in response to oxidised low density lipoprotein. AB - Beyond their primary role in haemostasis and tissue repair, platelets are causally involved in the onset of inflammatory reactions, cell proliferation and immune response. Platelet activation and platelet binding to the endothelium result in release of chemokines and increased expression of adhesion molecules, which promote the recruitment of leukocytes that will eventually migrate across the endothelium into the tissue. Here, we provide the first evidence that platelets stimulated with oxidised low-density lipoprotein (oxLDL) directly enhance recruitment and transmigration of neutrophils, via cell-cell interaction. OxLDL immediately activates platelets, which then rapidly bind to neutrophils, foster their activation and facilitate transmigration through an endothelial monolayer. The observed effects of oxLDL on platelet-neutrophil aggregate (PNA) formation depend on incubation time, lipoprotein concentration and the degree of oxidative modification of LDL. PNA form within minutes following stimulation by oxLDL and remain for up to 1 h post stimulation, while native LDL is unable to induce platelet-neutrophil interactions. In the presence of acetylsalicylic acid the formation of PNA in response to oxLDL is virtually absent, and platelets fail to further enhance oxLDL-induced neutrophil transmigration. P2Y1 and P2Y12 inhibitors have less pronounced effects on PNA formation in response to oxLDL. Furthermore, we demonstrate that the PI3K pathway is essential for efficient neutrophil transmigration induced by oxLDL. Consequently, platelets enhance neutrophil transmigration in response to oxLDL and might thereby contribute essentially to the amplification of inflammatory processes within the vessel wall, which fosters the development of atherosclerosis. PMID- 22836390 TI - Soil organic carbon sequestration as affected by afforestation: the Darab Kola forest (north of Iran) case study. AB - Following the ratification of the Kyoto Protocol, afforestation of formerly arable lands and/or degraded areas has been acknowledged as a land-use change contributing to the mitigation of increasing atmospheric CO(2) concentration in the atmosphere. In the present work, we study the soil organic carbon sequestration (SOCS) in 21 year old stands of maple (Acer velutinum Bioss.), oak (Quercus castaneifolia C.A. Mey.), and red pine (Pinus brutia Ten.) in the Darab Kola region, north of Iran. Soil samples were collected at four different depths (0-10, 10-20, 20-30, and 30-40 cm), and characterized with respect to bulk density, water content, electrical conductivity, pH, texture, lime content, total organic C, total N, and earthworm density and biomass. Data showed that afforested stands significantly affected soil characteristics, also raising SOCS phenomena, with values of 163.3, 120.6, and 102.1 Mg C ha(-1) for red pine, oak and maple stands, respectively, vs. 83.0 Mg C ha(-1) for the control region. Even if the dynamics of organic matter (OM) in soil is very complex and affected by several pedo-climatic factors, a stepwise regression method indicates that SOCS values in the studied area could be predicted using the following parameters, i.e., sand, clay, lime, and total N contents, and C/N ratio. In particular, although the chemical and physical stabilization capacity of organic C by soil is believed to be mainly governed by clay content, regression analysis showed a positive correlation between SOCS and sand (R = 0.86(**)), whereas a negative correlation with clay (R = -0.77(**)) was observed, thus suggesting that most of this organic C occurs as particulate OM instead of mineral-associated OM. Although the proposed models do not take into account possible changes due to natural and anthropogenic processes, they represent a simple way that could be used to evaluate and/or monitor the potential of each forest plantation in immobilizing organic C in soil (thus reducing atmospheric C concentration), as well as to select more appropriate species during forestation plan management at least in the north of Iran. PMID- 22836391 TI - Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes. AB - Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L(5) vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes. PMID- 22836392 TI - Soft X-ray imaging and spectromicroscopy: new insights in chemical state and morphology of the key components in operating fuel-cells. AB - Fuel cells are one of the most appealing environmentally friendly devices for the effective conversion of chemical energy into electricity and heat, but still there are key barriers to their broad commercialization. In addition to efficiency, a major challenge of fuel-cell technology is the durability of the key components (interconnects, electrodes, and electrolytes) that can be subject to corrosion or undesired morphology and chemical changes occurring under operating conditions. The complementary capabilities of synchrotron-based soft X ray microscopes in terms of imaging, spectroscopy, spatial and time resolution, and variable probing depths are opening unique opportunities to shed light on the multiple processes occurring in these complex systems at microscopic length scales. This type of information is prerequisite for understanding and controlling the performance and durability of such devices. This paper reviews the most recent efforts in the implementation of these methods for exploring the evolving structure and chemical composition of some key fuel cell components. Recent achievements are illustrated by selected results obtained with simplified versions of proton-exchange fuel-cells (PEFC) and solid-oxide fuel-cells (SOFC), which allow in situ monitoring of the redox reactions resulting in: 1) undesired deposits at interconnects and electrodes (PEFC); 2) material interactions at the electrode-electrolyte interface (PEFC); 3) release of corrosion products to the electrolyte phase (PEFC, and 4) mass-transport processes and structural changes occurring at the high operation temperatures of SOFC and promoted by the polarization. PMID- 22836393 TI - Response and responsibility. PMID- 22836394 TI - Methadone and oral care. PMID- 22836395 TI - Better prepared. PMID- 22836396 TI - Long-term appearance. PMID- 22836397 TI - Digital natives. PMID- 22836398 TI - Failed smile design. PMID- 22836399 TI - Should be credited. PMID- 22836400 TI - Developed and refined. PMID- 22836401 TI - A logical service. PMID- 22836413 TI - Dental erosion in the 21st century: what is happening to nutritional habits and lifestyle in our society? AB - Several developments in Western Europe may have contributed to the increased prevalence of dental erosion during the last decades. Exposing children to sour taste at an early age increases the preference for acidic food and drinks later in life. Acidic fruits and beverages became widely available due to economic prosperity. New types of acidic candies were developed, some of which are kept in the mouth for very long times. Children are exposed to intense marketing of these acidic products, which are widely available in supermarkets and school canteens. In the meantime, much less attention has been paid to the development and marketing of less erosive food products. PMID- 22836414 TI - Oral diagnosis and treatment planning: part 2. Dental caries and assessment of risk. AB - Dental caries or tooth decay may be defined as a dynamic process causing progressive destruction of hard tooth substance (enamel, dentine and cementum) involving demineralisation of the inorganic portion of the tooth, and dissolution of the organic portion. The onset and progression of carious lesions involves multiple host, micro-organism and substrate factors interacting in a continuous flux. The diagnosis of initial lesions remains a challenge for practitioners and, despite numerous studies, the assessment of future caries risk is still based largely on a patient's past caries experience. If caries is allowed to progress then pulpitis will occur, which may result in subsequent pulpal necrosis and lead to a local periapical and perhaps a systemic infection. PMID- 22836419 TI - Summary of: Career choice, pathways and continuing professional development of dental nurses at one institution. PMID- 22836420 TI - Summary of: the impact of General Dental Council registration and continuing professional development on UK dental care professionals: (1) dental nurses. PMID- 22836421 TI - Induction training for senior house officers in oral and maxillofacial surgery: literature review and local evaluation. AB - Induction for junior doctors is an important part of training where they can gain knowledge, confidence and integration into the hospital team. Dentally trained oral and maxillofacial surgery (OMFS) senior house officers (SHOs) enter into this unfamiliar environment often with limited experience. The OMFS SHO induction process is an expected and essential part of hospital training. There are, however, no standards set by the governing bodies regarding content or delivery methods. The current literature and local departmental evaluation suggests changes are required. There appear to be discrepancies in the perceived role of induction and the inductions provided. The literature review and study examines the attitudes towards induction training and recommendations for improvement. PMID- 22836422 TI - The ethics of dental practice in London in the sixteenth century. 2. Sir Thomas More's 'Ordinances' for the Barber-Surgeons, 1530. AB - Sir Thomas More's Ordinances can tell us much about London dental practice in the sixteenth century, providing an overview of training, development and practice within a healthcare service much like our own. PMID- 22836423 TI - Buccolam((r)) (buccal midazolam): a review of its use for the treatment of prolonged acute convulsive seizures in the dental practice. AB - This article is published in response to a query from reader Sarah Clements, based at Golding House Dental Practice Ltd in Kent, regarding the BDJ paper entitled 'Updated guidance on medical emergencies and resuscitation in the dental practice' (BDJ 2012; 212: 41-43). Sarah wished to be provided with further clarification on the ordering, prescribing and administration of midazolam. PMID- 22836443 TI - Career choice, pathways and continuing professional development of dental nurses at one institution. AB - OBJECTIVE: To explore the career pathways and continuing professional development of dental nurses employed at one institution relative to the scope of practice. METHOD: A questionnaire exploring career pathways and continuing professional development of dental nurses was compiled and delivered to clinical departments. Responses were entered onto SPSS v17 for analysis. RESULTS: Ninety-eight percent (n = 64) of available nurses responded to the questionnaire survey. Eighty percent (n = 51) of the dental nurses were aged between 25 and 44 years, and 95% (n = 61) were female. The ethnicity of the workforce varied; 58% (n = 37) were White and this consequently constituted the largest ethnic group in the workforce. The dental nurses reported that they chose their profession for a wide variety of reasons, the most common one being the opportunity to progress in the dental sector. Before commencing training 38% (n = 24) were aware of their options for progression; this increased subsequent to training with between 55% (n = 35) and 66% (n = 42), depending on the option, stating that they were aware of their options for progression. Eighty-three percent (n = 53) were trained in an additional skill and all of those who were not (n = 11) stated that they would like this training. Conscious sedation was the most frequently possessed additional skill and radiography was the additional skill in which the highest proportion would like to be trained. Personal satisfaction was the most significant factor affecting the willingness of the workforce to pursue career progression. CONCLUSION: The findings suggest that amongst dental nurses employed in one institution there is evidence that the majority benefit from continuing professional development opportunities, possess additional skills and are motivated to further their skills and progress in their careers. PMID- 22836444 TI - The impact of General Dental Council registration and continuing professional development on UK dental care professionals: (1) dental nurses. AB - OBJECTIVE: To investigate the impact of GDC registration and mandatory CPD on dental nurses' views, job satisfaction and intention to leave. DESIGN: Postal/online survey, conducted in parallel with a survey of dental technicians. SETTING: UK private and NHS practices, community services, dental hospitals. SUBJECTS AND METHODS: Representative sample of General Dental Council registrants. MAIN OUTCOME MEASURES: Job satisfaction; intention to leave profession (dependent variable in regression analysis). RESULTS: Eleven were ineligible (left profession, moved abroad); 267 (44% of those eligible) responded, all female. Respondents' mean age was 38.2 years (sd 10.74). The general principle of registration was endorsed by 67%, and compulsory registration by 51%, but the fee level by only 6%. Most nurses did not feel that registration had affected their view of dental nursing as a career (56%), their role (74%) or status (86%) within the dental team, or that CPD helped them to do their job better (76%). Fifty-six percent were not satisfied with their job, and 22% intended to leave the profession. Intention to leave was predicted by younger age and greater dissatisfaction with physical working conditions and opportunities to progress. CONCLUSIONS: Widely held criticisms regarding the costs and relevance of registration and CPD coupled with a potentially high level of attrition from the profession suggest a review of the fee and salary structure and greater financial support for CPD is warranted. PMID- 22836445 TI - Dicer1 and MiR-9 are required for proper Notch1 signaling and the Bergmann glial phenotype in the developing mouse cerebellum. AB - MicroRNAs (miRNAs) have important roles in the development of the central nervous system (CNS). Several reports indicate that tissue development and cellular differentiation in the developing forebrain are disrupted in the absence of miRNAs. However, the functions of miRNAs during cerebellar development have not been systematically characterized. Here, we conditionally knocked out the Dicer1 gene under the control of the human glial fibrillary acidic protein (hGFAP) promoter to examine the effect of miRNAs in the developing cerebellum. We particularly focused on the phenotype of Bergmann glia (BG). The hGFAP-Cre activity was detected as early as embryonic day 13.5 (E13.5) at the rhombic lip (RL) in the cerebellar plate, and later in several postnatal cerebellar cell types, including BG. Dicer1 ablation induces a smaller and less developed cerebellum, accompanied by aberrant BG morphology. Notch1 signaling appears to be blocked in Dicer1-ablated BG, with reduced expression of the Notch1 target gene, brain lipid binding protein (BLBP). Using neuronal co-culture assays, we showed an intrinsic effect of Dicer1 on BG morphology and Notch1 target gene expression. We further identified miR-9 as being differentially expressed in BG and showed that miR-9 is a critical, but not the only, miRNA component of the Notch1 signaling pathway in cultured BG cells. PMID- 22836446 TI - Facile fabrication and adsorption property of a nano/microporous coordination polymer with controllable size and morphology. AB - A porous coordination polymer [Cu(3)(btc)(2)] with controllable size and morphology from nanocube to microoctahedron was readily synthesized in an ethanol water mixture at room temperature by adjusting the concentration of the surfactant and the polymer shows size- and morphology-dependent sorption properties. PMID- 22836448 TI - FDA approval summary: sunitinib for the treatment of progressive well differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. AB - On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (Sutent(r); Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies. PMID- 22836447 TI - Altered insula activation during pain anticipation in individuals recovered from anorexia nervosa: evidence of interoceptive dysregulation. AB - OBJECTIVE: Recent evidence raises the possibility that symptoms of anorexia nervosa (AN) could be related to impaired interoception. Pain is an interoceptive process with well-characterized neuroanatomical pathways that may overlap to a large degree with neural systems that may be dysregulated in individuals with AN, such as the insula. METHOD: Functional magnetic resonance imaging (fMRI) was used to assess neural substrates of pain anticipation and processing in 10 healthy control women (CW) and 12 individuals recovered from AN (REC AN) in order to avoid the confounding effects of malnutrition. Painful heat stimuli were applied while different colors signaled the intensity of the upcoming stimuli. RESULTS: REC AN compared with CW showed greater activation within right anterior insula (rAI), dorsolateral prefrontal cortex (dlPFC) and cingulate during pain anticipation, and greater activation within dlPFC and decreased activation within posterior insula during painful stimulation. Greater anticipatory rAI activation correlated positively with alexithymic feelings in REC AN participants. DISCUSSION: REC AN showed a mismatch between anticipation and objective responses, suggesting altered integration and, possibly, disconnection between reported and actual interoceptive state. Alexithymia assessment provided additional evidence of an altered ability to accurately perceive bodily signals in women recovered from AN. PMID- 22836450 TI - Do we need a new look in the definition of X-linked recessive disorders? PMID- 22836451 TI - A critical view of magnetic resonance imaging in the evaluation of motor neuron diseases. PMID- 22836449 TI - Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: a critical review. AB - BACKGROUND: Loss of bone mineral density is an unintended consequence of androgen deprivation therapy in men with prostate cancer. Supplementation with calcium and/or vitamin D in these men seems logical and is advocated by many lay and professional groups. METHODS: We reviewed guidelines for calcium and vitamin D supplementation and the results of clinical trials of calcium and vitamin D supplementation on bone mineral density in men with prostate cancer undergoing androgen deprivation therapy. RESULTS: Whether supplementation of men undergoing androgen deprivation therapy with calcium and/or vitamin D results in higher bone mineral density than no supplementation has not been tested. The results of 12 clinical trials show that, at the doses commonly recommended, 500-1,000 mg calcium and 200-500 IU vitamin D per day, men undergoing androgen deprivation lose bone mineral density. CONCLUSION: The doses of calcium and vitamin D that have been tested are inadequate to prevent loss of bone mineral density in men undergoing androgen deprivation therapy. In light of evidence that high levels of dietary calcium and calcium supplement use are associated with higher risks for cardiovascular disease and advanced prostate cancer, intervention studies should evaluate the safety as well as the efficacy of calcium and vitamin D supplementation in these men. PMID- 22836452 TI - X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers. AB - X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. OBJECTIVES: To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. METHODS: We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. RESULTS: The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. CONCLUSIONS: Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes. PMID- 22836453 TI - Objective and subjective analysis of women's voice with idiopathic Parkinson's disease. AB - OBJECTIVE: To compare the voice quality of women with idiopathic Parkinson's disease and those without it. METHODS: An evaluation was performed including 19 female patients diagnosed with idiopathic Parkinson's disease, with an average age of 66 years, and 27 women with an average of 67 years-old in the Control Group. The assessment was performed by computed acoustic analysis and perceptual evaluation. RESULTS: Parkinson's disease patients presented moderate rough and unstable voice quality. The parameters of grade, roughness, and instability had higher scores in Parkinson's disease patients with statistically significant differences. Acoustic measures of Jitter and period perturbation quotient (PPQ) significantly differ between groups. CONCLUSIONS: Parkinson's disease female individuals showed more vocal alterations compared to the Control Group, when both perceptual and acoustic evaluations were analyzed. PMID- 22836454 TI - Reliability and validity study of a Brazilian-Portuguese version of the fatigue severity scale in Parkinson's disease patients. AB - The Fatigue Severity Scale (FSS) is one of the most frequently used self-rating scales for fatigue in Parkinson's disease (PD) and it lacks a validated Brazilian Portuguese version. OBJECTIVE: To determine the construct validity and reproducibility of a Brazilian-Portuguese version of the FSS in patients with PD. METHODS: In a cross-sectional study, a Portuguese-language version of the FSS was applied to 30 patients with PD (62+/-11 years-old). The Parkinson's disease questionnaire (PDQ-39) was used as the validation criterion, while the Hoehn and Yahr scale, the Unified Parkinson's Disease Rating Scale (UPDRS), and the Beck Depression Inventory were employed to analyze the correlations with the FSS score. RESULTS: The test-retest intraclass correlation coefficient was 0.91 (p<0.01) for the Brazilian-Portuguese version of the FSS score, which was highly correlated with the PDQ-39 overall score (r=0.93; p<0.01) and the Beck Depression Inventory (r=0.75; p<0.01). It showed a correlation with the Hoehn and Yahr scale (r=0.40; p=0.02), and with the UPDRS as well (r=0.45, p=0.01). CONCLUSIONS: The Brazilian-Portuguese version of the FSS is valid and reproducible for using in Brazilian patients with PD. PMID- 22836455 TI - Refractory nonconvulsive status epilepticus in coma: analysis of the evolution of ictal patterns. AB - OBJECTIVE: Nonconvulsive status epilepticus (NCSE) is currently considered as one of the most frequent types of status epilepticus (SE). The objective of the present study was to identify the natural history of the electrographical evolution of refractory NCSE and to establish the relationship between ictal patterns and prognosis. METHODS: We analyzed, retrospectively, 14 patients with loss of consciousness and NCSE. The ictal patterns were classified as discrete seizures (DS), merging seizures (MS), continuous ictal discharges (CID), continuous ictal discharges with flat periods (CID-F), and periodic lateralized epileptiform discharges (PLEDs). RESULTS: The ictal patterns were DS (n=7; 50.0%), PLEDs (n=3; 1.4%), CID (n=2; 14.3%), MS (n=1; 7.1%), and CID-F (n=1; 7.1%). CONCLUSIONS: NCSE electrographic findings are heterogeneous and do not follow a stereotyped sequence. PLEDs were related to a higher probability of neurological morbidity and mortality. PMID- 22836456 TI - Cognitive mechanisms and motor control during a saccadic eye movement task: evidence from quantitative electroencephalography. AB - The saccadic movement is an important behavioral measure used to investigate several cognitive processes, including attention and sensorimotor integration. The present study aimed at investigating changes in beta coherence over frontal, motor, occipital, and parietal cortices during the performance of two different conditions of a prosacadic paradigm. The conditions involved a different pattern of stimulus presentation: a fixed and random stimulus presentation. Twelve healthy volunteers (three male, mean age of 26.25 (SD=4.13) performed the task, while their brain activity pattern was recorded using quantitative electroencephalography. The results showed an interaction between factors condition and moment for the pair of electrode C3/C4. We observed a main effect for moment to CZ/C4, FZ/F3, and P3/PZ. We also found a main effect for condition to FZ/F4, P3/P4, and O1/O2. Our results demonstrated an important role of the inter-connection of the two hemispheres in visual search and movement preparation. The study demonstrates an automation of action and reduction of the focus of attention during the task. We also found that the inter-hemispheric beta coherence plays an important role in the differentiation of the two conditions, and that beta in the right frontal cortex is able to differentiate the conditions, demonstrating a greater involvement of procedural memory in fixed condition. Our results suggest a neuronal specialization in the execution of prosacadic paradigm involving motor task sequence. PMID- 22836457 TI - Management of desmoid-type fibromatosis involving peripheral nerves. AB - Desmoid-type fibromatosis is an uncommon and aggressive neoplasia, associated with a high rate of recurrence. It is characterized by an infiltrative but benign fibroblastic proliferation occurring within the deep soft tissues. There is no consensus about the treatment of those tumors. We present a surgical series of four cases, involving the brachial plexus (two cases), the median nerve and the medial brachial cutaneous nerve. Except for the last case, they were submitted to multiple surgical procedures and showed repeated recurrences. The diagnosis, the different ways of treatment and the prognosis of these tumoral lesions are discussed. Our results support the indication of radical surgery followed by radiotherapy as probably one of the best ways to treat those controversial lesions. PMID- 22836458 TI - Number of coils necessary to treat cerebral aneurysms according to each size group: a study based on a series of 952 embolized aneurysms. AB - OBJECTIVE: The Brazilian public health system determines a quantity of coils allowed to treat a cerebral aneurysm. The goal of this paper was to determine the number of coils necessary to treat an aneurysm based on size. METHODS: All patients harboring an aneurysm treated by endovascular approach between 1999 and 2003 were reviewed. RESULTS: There were 952 aneurysms included. Mean diameter sac was 8.2 mm with 7.9 coils per aneurysm. Out of 462 small aneurysms, mean size was 4.8 mm, with 4.6 coils/aneurysm used. A total of 315 medium aneurysms were treated, mean size was 8.6 mm, with 8.2 coils. Out of 135 large, mean size was 17 mm, with 16.1 coils. Forty giant aneurysms were treated with a mean size of 32 mm and 28.7 coils. CONCLUSIONS: We propose size as a reference to predict the number of coils necessary to treat each aneurysm: one coil for each millimeter of diameter. PMID- 22836459 TI - Clinical complications in patients with severe cervical spinal trauma: a ten-year prospective study. AB - OBJECTIVE: To determine the complications due to severe acrescentar sigla apos o nome (CST). METHODS: Between 1997 and 2006, 217 patients (191 men and 26 women) were prospectively evaluated. The mean age was 36.75+/-1.06 years. RESULTS: Forty five percent of the patients had medical complications. The most important risk factor was alcoholic beverage use. The most important associated injury was head trauma (HT). Patients with American Spine Injury Association (ASIA) A or B had a 2.3-fold greater relative risk of developing complications. Thirty-three patients (15.2%) died. Patients with neurological deficit had a 16.9-fold higher risk of death. There was no influence of age and time between trauma and surgery on the presence of complications. CONCLUSIONS: Of the patients, 45% had clinical complications and 7.5% had associated injuries; pneumonia was the most important complication; patient age and time between trauma and surgery did not influence the development of medical complications; neurological status was the most important factor in determining morbidity and mortality. PMID- 22836460 TI - Clinical correlates of the restless legs syndrome. AB - OBJECTIVE: To determine the clinical correlates of the restless legs syndrome (RLS) in a Brazilian sleep disorders center. METHODS: We retrospectively studied 118 patients with RLS from January, 2004, to December, 2010. The analyzed variables were: age at disease onset, gender, race, years of school instruction, primary and secondary RLS, and treatment options. RESULTS: Among the studied patients, 83.9% were women with a female/male sex ratio of 5:1. Mean age of the patients at symptom onset +/- standard deviation was 41.7+/-17.9 years-old. The primary RLS was found in 85% of patients. The other 15% remainders consisted of secondary forms, and they were associated with neuropathy, iron deficiency anemia, end-stage renal disease, or Parkinson's disease. Drug therapy for RLS was introduced in 67% of patients. CONCLUSIONS: Most patients presented primary RLS with an early disease onset. Further epidemiological studies are welcomed to provide better information on secondary RLS in Brazil. PMID- 22836461 TI - Is magnetic resonance imaging a plausible biomarker for upper motor neuron degeneration in amyotrophic lateral sclerosis/primary lateral sclerosis or merely a useful paraclinical tool to exclude mimic syndromes? A critical review of imaging applicability in clinical routine. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the cerebral cortex, brainstem, and spinal cord, brain regions in which conventional magnetic resonance imaging is often uninformative. Although the mean time from symptom onset to diagnosis is estimated to be about one year, the current criteria only prescribe magnetic resonance imaging to exclude "ALS mimic syndromes". Extensive application of non-conventional magnetic resonance imaging (MRI) to the study of ALS has improved our understanding of the in vivo pathological mechanisms involved in the disease. These modern imaging techniques have recently been added to the list of potential ALS biomarkers to aid in both diagnosis and monitoring of disease progression. This article provides a comprehensive review of the clinical applicability of the neuroimaging progress that has been made over the past two decades towards establishing suitable diagnostic tools for upper motor neuron (UMN) degeneration in ALS. PMID- 22836462 TI - What do we know about the neurogenic potential of different stem cell types? AB - Cell therapies, based on transplantation of immature cells, are being considered as a promising tool in the treatment of neurological disorders. Many efforts are being concentrated on the development of safe and effective stem cell lines. Nevertheless, the neurogenic potential of some cell lines, i.e., the ability to generate mature neurons either in vitro or in vivo, is largely unknown. Recent evidence indicate that this potential might be distinct among different cell lines, therefore limiting their broad use as replacement cells in the central nervous system. Here, we have reviewed the latest advancements regarding the electrophysiological maturation of stem cells, focusing our attention on fetal derived-, embryonic-, and induced pluripotent stem cells. In summary, a large body of evidence supports the biological safety, high neurogenic potential, and in some diseases probable clinical efficiency related to fetal-derived cells. By contrast, reliable data regarding embryonic and induced pluripotent stem cells are still missing. PMID- 22836463 TI - Tourette's syndrome: from demonic possession and psychoanalysis to the discovery of gene. AB - In this paper we make a brief historical review of the hypothesis concerning the etiology of Tourette's syndrome (TS), focusing on varying trends over time: at first, its presumed relation to witchcraft and demonic possessions, followed by the psychoanalytical theory, which attributed TS to a masturbatory equivalent. Then, progressing to modern time, to the immunological theory and finally the advent of genetics and their role in the etiology of TS. PMID- 22836464 TI - Nontraumatic clival cerebrospinal fluid rhinorrhea. PMID- 22836465 TI - A patient with primary progressive aphasia developing dementia due to Alzheimer's disease. PMID- 22836466 TI - Complex visual hallucinations and delusional infestation comorbidity. PMID- 22836467 TI - Transverse myelitis with Brown-Sequard syndrome after H1N1 immunization. PMID- 22836471 TI - Good obstetric outcome in a patient with Segawa disease. PMID- 22836472 TI - Dengue and psychiatry disorder. PMID- 22836474 TI - The prevalence of multiple sclerosis in the city of Santos has remained unaltered for five years. PMID- 22836475 TI - Pharmacotherapy treatment of depression in patients with neurodegenerative diseases: where are we? PMID- 22836477 TI - Ref.Article:Romero FR, Bertolini F, Velozo VN, Venturini I, Figueiredo EG. Outcomes from intracerebral hemorrhage among patients pre-treated with statins. Arq Neuropsiquiatr 2011;69:452-454. PMID- 22836478 TI - Atrial tachycardia originating from the hepatic segment of inferior vena cava in interruption of inferior vena cava with azygos continuation. AB - Interruption of inferior vena cava (IVC) with azygos continuation is a rare venous anomaly, and arrhythmogenic IVC is also rarely reported. Arrhythmogenicity of the hepatic segment of IVC in interruption of IVC has never been reported. We describe the case of a 37-year-old female with interrupted left IVC with azygos continuation to right superior vena cava and atrial tachycardia originating from the hepatic segment of IVC. PMID- 22836479 TI - Non-physiological increase of AV conduction time in sinus disease patients programmed in AAIR-based pacing mode. AB - PURPOSE: The EVOCAV(DS) trial aimed to quantify the paradoxal atrioventricular (AV) conduction time lengthening in sinus node (SD) patients (pts) paced in AAIR based pacing mode. METHODS: SD pts, implanted with dual-chamber pacemaker programmed in AAIR-based pacing mode, were randomized in two arms for a 1-month period: the low atrial pacing (LAP; basic rate at 60 bpm, dual sensor with minimal slope) and the high atrial pacing (HAP; basic rate at 70 bpm, dual sensor with optimized slope, overdrive pacing) arm. At 1 month, crossover was performed for an additional 1-month period. AV conduction time, AV block occurrence and AV conduction time adaptation during exercise were ascertained from device memories at each follow-up. RESULTS: Seventy-nine pts participated to the analysis (75 +/- 8 years; 32 male; PR = 184 +/- 38 ms; bundle branch block n = 12; AF history n = 36; antiarrhythmic treatment n = 53; beta-blockers n = 27; class III/Ic n = 18; both n = 8). The mean AV conduction time was significantly greater during the HAP (275 +/- 51 ms) vs. LAP (263 +/- 49 ms) period (p < 0.0001). Class III/Ic drugs were the only predictors of this abnormal behaviour. Degree II/III AV blocks occurred in 49 % of pts in the HAP vs. 19 % in the LAP period (p < 0.0001). Fifty two patients (66 %) presented a lengthening of AV conduction time during exercise. CONCLUSION: AAIR-based pacing in SD pts may induce a significant lengthening of pts' AV conduction time, including frequent abnormal adaptation of AV conduction time during exercise. PMID- 22836480 TI - Surgical technique and the mechanism of atrial tachycardia late after open heart surgery. AB - INTRODUCTION: Diverse atrial tachycardias (ATs) can develop after open heart surgery. The aim of our study was to examine the determinants of the mechanism of postoperative AT. METHODS AND RESULTS: One hundred patients with AT occurring at least 3 months after open heart surgery were studied. Patients were grouped according to the atrial incision applied at the time of surgery. During 127 electrophysiology procedures, 151 ATs were studied. Eighty-eight patients had cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL), 49 patients had at least one non-CTI-dependent AFL and 11 patients had focal AT. While CTI-dependent AFL was equally prevalent across groups, the finding of a non-CTI-dependent AFL was progressively more common as more extensive atriotomy was applied (p < 0.001). Among patients who had right atrial (RA) operations, RA incisional tachycardia was the most common non-CTI-dependent circuit, while the finding of perimitral or left atrial (LA) roof-dependent AFL was associated with LA atriotomy (p = 0.002 and p = 0.041, respectively). After adjustment for possible confounders, surgical group remained independent predictor of non-CTI-dependent AFLs (p < 0.001). No predictor was identified for focal AT, which originated from typical predilection sites and in 36% from the vicinity of surgical scar. Radiofrequency ablation was highly effective for all ATs, but the recurrence rate of AFL and atrial fibrillation was high at 22% and 27%, respectively, during 19 +/- 15 months of follow-up. CONCLUSION: While CTI-dependent AFL is the most common AT late after open heart surgery, atypical AFL becomes progressively more common with more extensive atriotomy. Right atrial incisional tachycardia is the dominant non-CTI-dependent AFL after opening of the RA, while a perimitral or roof-dependent LA circuit can be expected after LA operations. PMID- 22836481 TI - UPLC-Q-TOF-MS analysis of non-volatile migrants from new active packaging materials. AB - Ultra-performance liquid chromatography (UPLC) coupled to mass spectrometry (MS) is a useful tool in the analysis of non-volatile compounds, and the use of a quadrupole-time-of-flight (Q-TOF) mass analyzer allows a high sensitivity and accuracy when acquiring full fragment mode, providing a high assurance of correct identification of unknown compounds. In this work, UPLC-Q-TOF-MS technology has been applied to the analysis of non-volatile migrants from new active packaging materials. The materials tested were based on polypropylene (PP), ethylene-vinyl alcohol copolymer (EVOH), and poly(ethylene terephthalate) (PET). The active packaging materials studied were one PP film containing a natural antioxidant, and two PP/EVOH films, two PET/EVOH films and one coextruded PP/EVOH/PP film containing natural antimicrobials. The chemical structure of several compounds was unequivocally identified. The analysis revealed the migration of some of the active substances used in the manufacture of active packaging, such as caffeine (0.07 +/- 0.01 MUg/g), carvacrol (0.31 +/- 0.03 MUg/g) and citral (0.20 +/- 0.01 MUg/g). Unintentionally added substances were also found, such as citral reaction compounds, or citral impurities present in the raw materials. PMID- 22836482 TI - Screening test of silver nanoparticles in biological samples by graphite furnace atomic absorption spectrometry. AB - A simple, rapid and inexpensive screening test is presented to determine the presence of silver (Ag) nanoparticles in biological samples. The method is based on graphite furnace-atomic absorption spectrometry (Zeeman background correction) where an increase in the atomization temperature is observed with an increase in the particle size of Ag. The method is able to determine the presence of Ag ions from the presence of nano-Ag of 20, 60 and 80 nm, but the methodology was less apt to resolve nanoparticles between 20 and 60 nm. The proposed methodology was capable of determining the presence of dissolved Ag(+) from 20 nm in prepared mixtures, and in the liver of rainbow trout exposed to either dissolved or 20-nm nano-Ag. PMID- 22836483 TI - Predictors of a functional somatic syndrome diagnosis in patients with persistent functional somatic symptoms. AB - BACKGROUND: Functional somatic syndromes (FSS) are characterized by the existence of multiple persistent functional somatic symptoms. Not many patients fulfilling the criteria for an FSS, receive a formal diagnosis, and it is unknown which factors explain this discrepancy. Patients that tend to worry and patients that gather more health information may have an increased chance of an FSS diagnosis. We hypothesized that high intelligence and high neuroticism increase the probability of an FSS diagnosis in patients with persistent functional somatic symptoms. PURPOSE: This study aims to investigate patient factors that might be important in the process of syndrome labeling. METHODS: Our study was performed in a large, representative population cohort (n = 976) in Groningen, The Netherlands, and included two assessment waves. Intelligence was measured using the General Aptitude Test Battery version B 1002-B. Neuroticism was measured using the 12-item neuroticism scale of the Eysenck Personality Questionnaire Revised. Functional somatic symptoms were measured with the somatization section of the Composite International Diagnostic Interview. Current FSS diagnosis was assessed with a questionnaire. We performed multivariable logistic regression analyses including sum scores of neuroticism, intelligence scores, sex, number of functional somatic symptoms, and age as potential predictors of having an FSS diagnosis. RESULTS: From the 976 participants that completed measurements at follow-up, 289 (26.4 %) participants reported at least one persistent functional somatic symptom, and these subjects were included in the main analyses (38.4 % males, mean age of 55.2 years (SD = 10.7), 36-82 years). High numbers of functional somatic symptoms ((OR) = 1.320; 95 % (CI) = 1.097-1.588), female sex (OR = 9.068; 95 % CI = 4.061-20.251), and high intelligence (OR = 1.402; 95 % CI = 1.001-1.963) were associated with an FSS diagnosis, while age (OR = 0.989; 95 % CI = 960-1.019) and neuroticism (OR = 0.956; 95 % CI = 0.872-1.048) were not. CONCLUSION: This study suggests that high intelligence, but not high neuroticism, increases the chance of syndrome labeling in patients with persistent functional somatic symptoms. PMID- 22836484 TI - Investigation of atomic anti-site disorder and ferrimagnetic order in the half metallic Heusler alloy Mn2VGa. AB - The band structure calculation for the compound Mn(2)VGa carried out using the plane wave self-consistent field package with generalized gradient approximation shows that the compound is nearly half-metallic at the equilibrium lattice parameter. However, theoretical investigations have shown that a certain percentage of atomic anti-site disorder can destroy the half-metallic nature of the sample. Hence it is important to quantify the site disorder in these systems. We have deduced the percentage of atomic anti-site disorder from the refinement of the higher angle room temperature (300 K) neutron diffraction (ND) pattern and it was observed to be roughly 8% in our sample. The field variation of resistance recorded at different temperatures shows a positive slope at low temperatures and a negative slope at higher temperatures, indicating the half-metallic character at low temperatures. The ab initio calculations predict a ferrimagnetic ground state for this system. The analysis of the magnetic structure from ND data measured at 6 K yields magnetic moment values of 1.28 MU(B) and -0.7 MU(B) for Mn and V, respectively, confirming the ferrimagnetic ordering. PMID- 22836485 TI - Hyperlipidaemia in trypanosomiasis of naturally infected horses: possible cachexia-anorexia syndrome? AB - Trypanosomiasis caused by Trypanosoma evansi commonly produces wasting disease with signs of emaciation and cachexia mainly at the end stage. The present study was conducted to explore the possible hyperlipaemia or hyperlipidaemia and its association with cachexia-anorexia in equine trypanosomiasis. Out of the fifteen confirmed animals, none of the plasma sample was opaque. There was a significant increase in plasma triglyceride, total cholesterol and blood urea nitrogen and a highly significant increase in low-density lipoprotein (LDL) levels. A mild increase in high-density lipoprotein (HDL) and very low-density lipoprotein levels were observed, while the relative percentage of HDL and LDL was altered with high significance. A moderate increase in triglyceride and highly significant increase in LDL might be the reasons for retention of appetite and lipolysis. Possible protein breakdown and presence of lipolysis might be the reasons for cachexia in equine trypanosomiasis. PMID- 22836486 TI - Performance of growing pigs fed diets based on by-products of maize and wheat processing. AB - Forty-eight crossbred Landrace * Large white pigs with an average body weight of 8.5 +/- 0.4 kg and aged 2 months were used to evaluate performance and carcass characteristics of pigs fed two diets in which bran from maize or wheat was used as the energy source. A third diet based on whole maize grain was used as a control. Animals in groups of four, balanced for litter, sex and weight were allotted to dietary treatments in a completely randomised design with four replications. Data were collected on feed intake and weight gain for a period of 4 months. A digestibility trial was carried at the end of the feeding trial using two male pigs per treatment while six pigs per treatment were randomly selected for slaughter to determine carcass characteristics. Daily gain averaged 0.23, 0.31 and 0.13 kg/day, for pigs fed maize bran, wheat bran and whole maize diets, respectively. Average feed intake and final body weight were significantly (P < 0.05) affected by diets. Digestibility of dry matter, crude fibre and calcium were higher (P < 0.05) for pigs fed maize bran while crude protein digestibility was highest (P < 0.05) for the pigs fed wheat bran. There were significant differences (P < 0.05) between the diets in carcass yield, ham, head, trotters and heart weights and also for rib weight, rib eye muscle and other tissues. This study indicates that comparable performance of growing pigs fed cereal bran and full-grain diets are real. PMID- 22836487 TI - Use of the obturator-outlet oblique view to guide percutaneous retrograde posterior column screw placement. AB - In contrast to open reduction internal fixation, percutaneous fixation is a relatively new option for operative fixation of acetabular fractures. The techniques for percutaneous insertion of anterior and posterior column screws have been previously described. For technical aspects of retrograde percutaneous posterior column screws, much attention has been paid to the proper start point. However, descriptions of proper trajectory and end point have not been as clearly delineated. Understanding of posterior column anatomy and its radiographic correlates are fundamental in the safe placement of this screw. Herein, we present technical advice for acquisition and interpretation of fluoroscopic images needed to ensure a safe trajectory and end point in retrograde percutaneous posterior column screw placement. We highlight our steps to ensure correct placement in a small series. PMID- 22836488 TI - Protein-templated gold nanoclusters as fluorescence probes for the detection of methotrexate. AB - In this contribution, bovine serum albumin stabilized gold nanoclusters as novel fluorescent probes were successfully utilized for the detection of methotrexate for the first time. Our prepared gold nanoclusters exhibited strong emission with peak maximum at 633.5 nm. However, the addition of methotrexate induced the strong fluorescence intensity of the gold nanoclusters to decrease. The decrease in fluorescence intensity of the gold nanoclusters caused by methotrexate allowed the sensitive detection of methotrexate in the range of 0.0016 MUg mL(-1) to 24 MUg mL(-1). The detection limit for methotrexate is 0.9 ng mL(-1) at a signal-to noise ratio of 3. The present sensor for methotrexate detection possessed a low detection limit and wide linear range. In addition, the real samples were analyzed with satisfactory results. PMID- 22836489 TI - Alterations of LXRalpha and LXRbeta expression in the hypothalamus of glucose intolerant rats. AB - Liver X receptor (LXR) alpha and beta are nuclear receptors that are crucial for the regulation of carbohydrate and lipid metabolism. Activation of LXRs in the brain facilitates cholesterol clearance and improves cognitive deficits, thus they are considered as promising drug targets to treat diseases such as atherosclerosis and Alzheimer's disease. Nevertheless, little is known about the function and localization of LXRs in the brain. Here, we studied the expression of LXR in the brains of rats that received free access to 10% (w/v) fructose group (FG) in their beverages or water control drinks (control group (CG)). After 6 weeks rats in the FG presented with hypertriglyceridemia, hyperinsulinemia, and became glucose intolerant, suggesting a progression toward type 2 diabetes. We found that hypothalamic LXR expression was altered in fructose-fed rats. Rats in the FG presented with a decrease in LXRbeta levels while showing an increase in LXRalpha expression in the hypothalamus but not in the hippocampus, cerebellum, or neocortex. Moreover, both LXRalpha and beta expression correlated negatively with insulin and triglyceride levels. Interestingly, LXRbeta showed a negative correlation with the area under the curve during the glucose tolerance test in the CG and a positive correlation in the FG. Immunocytochemistry revealed that the paraventricular and ventromedial nuclei express mainly LXRalpha whereas the arcuate nucleus expresses LXRbeta. Both LXR immunosignals were found in the median preoptic area. This is the first study showing a relationship between glucose and lipid homeostasis and the expression of LXRs in the hypothalamus, suggesting that LXRs may trigger neurochemical and neurophysiological responses for the control of food intake and energy expenditure through these receptors. PMID- 22836490 TI - Index of glucose effectiveness derived from oral glucose tolerance test. AB - Aim of this study was to formulate an index for glucose effectiveness (Sg), SgIo, based on 3-point (0, 30 and 120 min) 75 g oral glucose tolerance test (OGTT). The equation for SgI(O) was developed in the Chikuma cohort (n = 502). Firstly, post loading plasma glucose without insulin action and Sg (PPG-without insulin and Sg) was calculated as follows: fasting plasma glucose (mg/dl) + [0.75 * 75,000]/[0.19 * BW(kg) * 10]. Secondly, 'PPG-without insulin/with Sg' was obtained from inverse correlation between log(10)DI(O) and 2-h post-glucose plasma glucose at OGTT (2hPG) in each glucose tolerance category: DI(O) denotes oral disposition index, a product of the Matsuda Index and deltaIRI(0-30)/deltaPG(0-30). Thirdly, expected 2hPG (2hPG(E)) of a given subject was obtained from the regression, and the ratio of 2hPG to 2hPG(E) (2hPG/2hPG(E)) was determined as an adjustment factor. Lastly, SgI(O) ([mg/dl]/min) was calculated as [PPG-without insulin and Sg]-[PPG-without insulin / with Sg] x [(2hPG) / 2hPG(E)]. SgI(O) was validated against Sg obtained by frequently sampled intravenous glucose tolerance test in the Jichi cohort (n = 205). Also, the accuracy of prediction of Sg by SgIo was tested by the Bland-Altman plot. SgI(O) was 3.61 +/- 0.73, 3.17 +/- 0.74 and 2.15 +/- 0.60 in subjects with normal glucose tolerance (NGT), non-diabetic hyperglycemia and diabetes, respectively, in the Chikuma cohort. In the Jichi cohort, SgI(O) was significantly correlated with Sg in the entire group (r = 0.322, P < 0.001) and in subjects with NGT (r = 0.286, P < 0.001), and SgIo accurately predicted Sg. In conclusion, SgI(O) could be a simple, quantitative index for Sg. PMID- 22836491 TI - Venous thromboembolism in cancer patients - risk scores and recent randomised controlled trials. AB - Cancer patients are at increased risk of developing venous thromboembolism (VTE). Guidelines recommend routine thromboprophylaxis in hospitalised acutely ill cancer patients and in myeloma patients receiving combination treatments including thalidomide or lenalidomide. Currently, thromboprophylaxis is not recommended in cancer outpatients. It is the aim of this review to give an overview of studies that applied scores for the risk assessment of cancer-related VTE. We will also discuss randomised controlled trials (RCTs) that investigated primary thromboprophylaxis in cancer patients. Recently, Khorana et al. published a practical and reproducible risk assessment score that includes clinical and laboratory parameters for the stratification of cancer patients according to their propensity to develop VTE. Patients assigned to the high-risk group are likely to benefit most from primary thromboprophylaxis. This score was validated in prospective and retrospective observational studies. In the Vienna Cancer and Thrombosis Study (CATS) the score was expanded by adding two biomarkers, and the prediction of VTE was considerably improved. In recent RCTs including cancer patients with different malignancies it was shown that thromboprophylaxis is safe and effective. However, VTE incidence rates were low. To date, no data is available from interventional studies applying thromboprophylaxis in cancer patients categorised into high-risk groups on the basis of risk assessment with scores. From the available literature we conclude that risk assessment for VTE is feasible in cancer patients; however, interventional studies to investigate the safety and efficacy of thromboprophylaxis in a high risk cancer population have yet to be performed. PMID- 22836492 TI - Smart role of plant 14-3-3 proteins in response to phosphate deficiency. AB - Higher plants adapt to phosphorus deficiency through a complex of biological processes. Among of them, two adaptive processes are very important for the response of higher plants to phosphorus deficiency. One is the enhancement of root growth by regulating carbohydrate metabolism and allocation, and the other is rhizosphere acidification to acquire phosphorus efficiently from soil. TFT6 and TFT7, two different members of tomato 14-3-3 gene family, play the distinct roles in the adaption of plants to phosphorus deficiency by taking part in the two processes respectively. TFT6 which acts mainly in leaves is involved in the systemic response to phosphorus deficiency by regulating leaf carbon allocation and increasing phloem sucrose transport to promote root growth, while TFT7 directly functions in root by activating root plasma membrane H (+) -ATPase to release more protons under phosphorus deficiency. Based on these results, we propose that 14-3-3 proteins play the smart role in response to phosphorus deficiency in higher plants. PMID- 22836493 TI - Roles of constitutive photomorphogenic 10 in Arabidopsis stomata development. AB - Stomata are epidermal bi-celled structures that differentiate within special cell lineages initiated by a subset of protodermal cells. Recently, we showed that the Arabidopsis photomorphogenic repressor COP10 controls specific cell-lineage and cell-signaling developmental mechanisms in stomatal lineages. Loss-of-function cop10-1 mutant cotyledons and leaves produced (in the light and in the dark) abundant stomatal clusters, but nonlineage epidermal cells were not affected. Here we examine COP10 role in hypocotyls, cylindrical organs displaying a distinct epidermal organization with alternate files of protruding and non protruding cells, with the latter producing a limited number of stomata. COP10 prevents stomatal clusters and restricts stomata production in hypocotyls; these roles are specific to lineage cells as in cotyledons, since COP10 loss of function does not elicit stomatal fate in nonlineage cells; COP10 also sustains the directional cell expansion of all hypocotyl epidermal cell types, and seems necessary for the differentiation between protruding and non-protruding cell files. PMID- 22836494 TI - 14-3-3 proteins act as scaffolds for GmMYB62 and GmMYB176 and regulate their intracellular localization in soybean. AB - Isoflavonoids are plant natural compounds predominantly found in leguminous plant. They play important functions in both nitrogen fixation and stress resistance. Many clinical studies have linked dietary intake of isoflavonoids to human health benefits. Binding of 14-3-3 proteins to GmMYB176, an isoflavonoid regulator, modulates expression of key isoflavonoids gene expression and its biosynthesis. We have recently demonstrated that the interaction of 14-3-3 proteins with GmMYB176 regulates nuclear-cytoplasmic localization of GmMYB176 thereby affecting target gene expression. Here, we report GmMYB62 as a new R1 MYB client protein of soybean 14-3-3s that may function together with GmMYB176 for gene regulation in soybean. PMID- 22836495 TI - Evolutionary appearance of the plasma membrane H (+) -ATPase containing a penultimate threonine in the bryophyte. AB - The plasma membrane H (+) -ATPase provides the driving force for solute transport via an electrochemical gradient of H (+) across the plasma membrane, and regulates pH homeostasis and membrane potential in plant cells. However, the plasma membrane H (+) -ATPase in non-vascular plant bryophyte is largely unknown. Here, we show that the moss Physcomitrella patens, which is known as a model bryophyte, expresses both the penultimate Thr-containing H (+) -ATPase (pT H (+) ATPase) and non-pT H (+) -ATPase as in the green algae, and that pT H (+) -ATPase is regulated by phosphorylation of its penultimate Thr. A search in the P. patens genome database revealed seven H (+) -ATPase genes, designated PpHA (Physcomitrella patens H (+) -ATPase). Six isoforms are the pT H (+) -ATPase; a remaining isoform is non-pT H (+) -ATPase. An apparent 95-kD protein was recognized by anti-H (+) -ATPase antibodies against an isoform of Arabidopsis thaliana and was phosphorylated on the penultimate Thr in response to a fungal toxin fusicoccin and light in protonemata, indicating that the 95-kD protein contains pT H (+) -ATPase. Furthermore, we could not detect the pT H (+) -ATPase in the charophyte alga Chara braunii, which is the closest relative of the land plants, by immunological methods. These results strongly suggest the pT H (+) ATPase most likely appeared for the first time in bryophyte. PMID- 22836496 TI - Genetic analyses of the Arabidopsis 26S proteasome regulatory particle reveal its importance during light stress and a specific role for the N-terminus of RPT2 in development. AB - The 26S proteasome subunit RPT2 is a component of the hexameric ring of AAA ATPases that forms the base of the 19S regulatory particle (RP). This subunit has specific roles in the yeast and mammalian proteasomes by helping promote assembly of the RP with the 20S core protease (CP) and gate the CP to prevent indiscriminate degradation of cytosolic and nuclear proteins. In plants, this subunit plays an important role in diverse processes that include shoot and root apical meristem maintenance, cell size regulation, trichome branching, and stress responses. Recently, we reported that mutants in RPT2 and several other RP subunits have reduced histone levels, suggesting that at least some of the pleiotropic phenotypes observed in these plants result from aberrant nucleosome assembly. Here, we expand our genetic analysis of RPT2 in Arabidopsis to shed additional light on the roles of the N- and C-terminal ends. We also present data showing that plants bearing mutations in RP subunit genes have their seedling phenotypes exacerbated by prolonged light exposure. PMID- 22836497 TI - Cladodes, leaf-like organs in Asparagus, show the significance of co-option of pre-existing genetic regulatory circuit for morphological diversity of plants. AB - Plants in the genus Asparagus have determinate leaf-like organs called cladodes in the position of leaf axils. Because of their leaf-like morphology, axillary position, and morphological variation, it has been unclear how this unusual organ has evolved and diversified. In the previous study, we have shown that cladodes in the genus Asparagus are modified axillary shoots and proposed a model that cladodes have arisen by co-option and deployment of genetic regulatory circuit (GRC) involved in leaf development. Moreover, we proposed that the alteration of the expression pattern of genes involved in establishment of adaxial/abaxial polarity has led to the morphological diversification from leaf-like to rod-like form of cladodes in the genus. Thus, these results indicated that the co-option and alteration of pre-existing GRC play an important role in acquisition and subsequent morphological diversification. Here, we present data of further expression analysis of A. asparagoides. The results suggested that only a part of the GRC involved in leaf development appears to have been co-opted into cladode development. Based on our study and several examples of the morphological diversification, we briefly discuss the importance of co-option of pre-existing GRC and its genetic modularity in the morphological diversity of plants during evolution. PMID- 22836498 TI - The use of light in prey capture by the tropical pitcher plant Nepenthes aristolochioides. AB - Nepenthes pitcher plants deploy tube-shaped pitchers to catch invertebrate prey; those of Nepenthes aristolochioides possess an unusual translucent dome. The hypothesis was tested that N. aristolochioides pitchers operate as light traps, by quantifying prey capture under three shade treatments. Flies are red-blind, with visual sensitivity maxima in the UV, blue, and green wavebands. Red celluloid filters were used to reduce the transmission of these wavebands into the interior of the pitchers. Those that were shaded at the rear showed a 3-fold reduction in Drosophila caught, relative to either unshaded control pitchers, or pitchers that were shaded at the front. Thus, light transmitted through the translucent dome is a fundamental component of N. aristolochioides' trapping mechanism. PMID- 22836499 TI - Relationship between chloroplastic H 2O 2 and the salicylic acid response. AB - Reactive oxygen species (ROS) act as signaling molecules for regulating plant responses to abiotic and biotic stress and there exist source- and kind-specific pathways for ROS signaling. Recently, we created a novel system for producing H 2O 2 in Arabidopsis chloroplasts by chemical-dependent thylakoid membrane-bound ascorbate peroxidase (tAPX) silencing using an estrogen-inducible RNAi method. Microarray analysis revealed that the expression of a large set of genes was altered in response to tAPX silencing, some of which are known to be involved in pathogen response/resistance. Furthermore, we found that tAPX silencing enhances the levels of salicylic acid (SA) and the response to SA, a central regulator for biotic stress response. In this addendum, we describe the relationship between chloroplastic H 2O 2 and SA in stress response, and discuss the function of the kind- and source-specific ROS signaling in SA-mediated stress response. PMID- 22836500 TI - Snakin/GASA proteins: involvement in hormone crosstalk and redox homeostasis. AB - Snakin/GASA proteins are widely distributed among plant species. They are expressed in different plant organs with high tissue and temporal specificity, and their subcellular localization varies among the different members. Interestingly, all of them maintain 12 cysteines of the C-terminus in highly conserved positions of the aminoacid sequences that are essential for their biochemical activity and probably responsible for their protein structure. Despite their common features, their functions are not completely elucidated and little is known about their mode of action. This review focuses on the current knowledge about this intriguing family of peptides and advances comprising gene regulation analyses, expression pattern studies and phenotypic characterization of mutants and transgenic plants. Furthermore, we discuss the roles of Snakin/GASA proteins in several aspects of plant development, plant responses to biotic or abiotic stress and their participation in hormone crosstalk and redox homeostasis. PMID- 22836501 TI - Probing the mechanical contributions of the pectin matrix: insights for cell growth. AB - The plant cell wall has a somewhat paradoxical mechanical role in the plant: it must be strong enough to resist the high turgor of the cell contents, but at the right moment it must yield to that pressure to allow cell growth. The control of the cell wall's mechanical properties underlies its ability to regulate growth correctly. Recently, we have reported on changes in cell wall elasticity associated with organ formation at the shoot apical meristem in Arabidopsis thaliana. These changes in cell wall elasticity were strongly correlated with changes in pectin matrix chemistry, and we have previously shown that changes in pectin chemistry can dramatically effect organ formation. These findings point to a important role of the cell wall pectin matrix in cell growth control of higher plants. In this addendum we will discuss the biological significance of these new observations, and will place the scientific advances made possible through Atomic Force Microscopy-based nano-indentations in a relatable context with past experiments on cell wall mechanics. PMID- 22836502 TI - A specific variant of the PHR1 binding site is highly enriched in the Arabidopsis phosphate-responsive phospholipase DZ2 coexpression network. AB - PLDZ2 is a member of the Arabidopsis phospholipase D gene family that is induced in both shoot and root in response to phosphate (Pi) starvation. Recently, through deletion and gain-of-function analyses of the PLDZ2 promoter, we identified a 65 bp region (denominated enhancer EZ2) capable of conferring tissue specific and low-Pi responses to a minimal inactive promoter. The EZ2 element contains two P1BS motifs, each of which is the binding site for PHR1 and related transcription factors. This structural organization is evolutionarily conserved in orthologous promoters within the rosid clade. To determine whether EZ2 is significantly over-represented in Arabidopsis genes coexpressed with PLDZ2, we constructed a PLDZ2 coexpression network containing 26 genes, almost half of them encoding enzymes or regulatory proteins involved in Pi recycling. A variant of the P1BS motif was found to be highly enriched in the promoter regions of these coexpressed genes, showing an EZ2-like arrangement in seven of them. No other motifs were significantly enriched. The over-representation of the EZ2 arrangement of P1BS motifs in the promoters of genes coexpressed with PLDZ2, suggests this unit has a particularly important role as a regulatory element in a coexpression network involved in the release of Pi from phospholipids and other molecules under Pi-limiting conditions. PMID- 22836503 TI - Down-regulation of SlIAA15 in tomato altered stem xylem development and production of volatile compounds in leaf exudates. AB - The Aux/IAA family genes encode short-lived nuclear proteins that function as transcriptional regulators in auxin signal transduction. Aux/IAA genes have been reported to control many processes of plant development. Our recent study showed that down-regulation of SlIAA15 in tomato reduced apical dominance, altered pattern of axillary shoot development, increased lateral root formation and leaves thickness. The SlIAA15 suppressed lines display strong reduction of trichome density, suggesting that SlIAA15 is involved in trichome formation. Here, we reported that SlIAA15-suppressed transgenic lines display increased number of xylem cells compared to wild-type plants. Moreover, the monoterpene content in trichome exudates are significantly reduced in SlIAA15 down-regulated leaves. The results provide the roles of SlIAA15 in production of volatile compounds in leaf exudates and xylem development, clearly indicating that members of the Aux/IAA gene family can play distinct and specific functions. PMID- 22836504 TI - Intramolecular uncoupling of chromophore photoconversion from structural signaling determinants drive mutant phytochrome B photoreceptor to far-red light perception. AB - The phytochrome (phy) photoreceptor family regulates almost all aspects of plant development in a broad range of light environments including seed germination, onset of the photomorphogenic program in seedling stage, the shade avoidance syndrome in competing plant communities, flowering induction and senescence of adult plants. During evolution two clearly distinct classes of phy-s emerged covering these very different physiological tasks. ( 1) PhyA is rapidly degraded in its activated state. PhyA functions in controlling seed germination at very low light intensities (very low fluence response, VLFR) and seedling establishment under photosynthetic shade conditions (high irradiance response, HIR) where the far-red portion of the transmitted light to understorey habitats is substantially enhanced. Arabidopsis phyB together with phyC, D and E belongs to the relatively stable sensor class in comparison to the light labile phyA. PhyB functions at all stages of development including seed germination and seedling establishment, mediates classical red/far-red reversible low fluence responses (LFR) as well as red light high irradiance responses, and it is considered to be the dominating phytochrome sensor of its class. PMID- 22836505 TI - Hip fracture and risk of acute myocardial infarction: a nationwide study. AB - Osteoporotic fractures are associated with increased mortality risk. However, little data are available on the risk of acute myocardial infarction (AMI) after hip fracture. Therefore, we investigated whether hip fracture increased the risk of AMI in a large, nationwide cohort study. We obtained data from 8758 patients diagnosed with hip fracture from 2000 to 2009 and from 4 matched controls for each patient from the Longitudinal Health Insurance Database (LHID 2000), Taiwan. Controls were matched for age, sex, comorbid disorders, and enrollment date. All subjects were followed up from the date of enrollment until AMI, death, or the end of data collection (2009). Cox's regression model adjusted for age, sex, comorbid disorders, and medication was used to assess independent factors determining the risk of development of AMI. As expected, despite the matching, the hip fracture patients had more risk factors for AMI at baseline. A total of 8758 subjects with hip fractures and 35,032 controls were identified. Among these patients, 1183 (257 hip fracture patients and 926 controls) developed AMI during the median 3.2-year (interquartile range 1.4 to 5.8 years) follow-up period. Patients with hip fractures had a higher incidence of AMI occurrence when compared with controls (8.7/1000 person-years versus 6.82/1000 person-years). Multivariate analysis adjusted for baseline covariates indicated that hip fracture was associated with a greater risk for AMI development (hazard ratio [HR] = 1.29; 95% confidence interval [CI] 1.12-1.48; p < 0.001). We conclude that hip fracture is independently associated with a higher risk of subsequent AMI. PMID- 22836506 TI - Therapeutic alliance in two treatments for adolescent anorexia nervosa. AB - OBJECTIVE: The aim of this study was to examine the relationship between therapeutic alliance and treatment outcome (remission status) in family-based treatment (FBT) and adolescent-focused therapy (AFT) for adolescents with anorexia nervosa (AN). METHOD: Independent observers rated audiotapes of early therapy sessions using the Working Alliance Inventory-Observer Version (WAI-o). Outcome was defined using established cut-points for full and partial remission. To control for effects of early symptom improvement, changes in weight- and eating-related psychopathology prior to the alliance session were calculated and entered as a covariate in each analysis. RESULTS: Participants in AFT had significantly higher alliance scores; however, overall scores were high in both therapies. The alliance was not a predictor of full remission for either treatment, though it was a non-specific predictor for partial remission. DISCUSSION: Therapeutic alliance is achievable in adolescents with AN in both AFT and FBT, but demonstrated no relationship to full remission of the disorder. PMID- 22836507 TI - Vertebral levels of key landmarks in the neck. AB - Vertebral levels of key landmarks in the neck are well documented in anatomy texts but are they accurate? This study aimed to investigate the vertebral levels of the hard palate, hyoid bone, thyroid cartilage, cricoid cartilage, and bifurcation of the common carotid artery (CCA) using computed tomography (CT). After excluding patients with distorting pathology, 52 CT scans of the neck from supine adults with a standardized head position (mean age 63 +/- 17 years, range 30-94 years; 21 female) were available for analysis by dual consensus reporting. Only the vertebral level of the hard palate (C1) was consistent with contemporary descriptions. Other landmarks were located most frequently at the following vertebral levels: the center of the body of the hyoid bone at C4 (54% of cases); the superior limit of the laminae of the thyroid cartilage at C4 in women (60%) and C5 in men (52%) (P = 0.02); the inferior border of the cricoid cartilage in the midline anteriorly at C6 in women (37%) and C7 in men (47%) (P = 0.008); and the bifurcation of the left and right common carotid arteries at C3 (left 56%, right 62%). The bifurcation of the CCA was a mean of 1.6 +/- 1.2 cm above the superior border of the thyroid laminae. Vertebral levels of key bony/cartilaginous structures in the neck differ from standard descriptions but in the absence of a standardized cervical axial plane have limited value and clinical utility. PMID- 22836508 TI - Cardiorespiratory fitness and physical activity in Luo, Kamba, and Maasai of rural Kenya. AB - BACKGROUND: Although habitual physical activity energy expenditure (PAEE) and cardio-respiratory fitness (CRF) are now well-established determinants of metabolic disease, there is scarcity of such data from Africa. The aim of this study was to describe objectively measured PAEE and CRF in different ethnic populations of rural Kenya. METHODS: A cross-sectional study was done among 1,099 rural Luo, Kamba, and Maasai of Kenya. Participants were 17-68 years old and 60.9% were women. Individual heart rate (HR) response to a submaximal steptest was used to assess CRF (estimated VO(2) max). Habitual PAEE was measured with combined accelerometry and HR monitoring, with individual calibration of HR using information from the step test. RESULTS: Men had higher PAEE than women (~78 vs. ~67 kJ day(-1) kg(-1) , respectively). CRF was similar in all three populations (~38 and ~43 mlO(2) .kg(-1) min(-1) in women and men, respectively), while habitual PAEE measures were generally highest in the Maasai and Kamba. About 59% of time was spent sedentary (<1.5 METs), with Maasai women spending significantly less (55%). Both CRF and PAEE were lower in older compared to younger rural Kenyans, a difference which was most pronounced for PAEE in Maasai (-6.0 and 11.9 kJ day(-1) kg(-1) per 10-year age difference in women and men, respectively) and for CRF in Maasai men (-4.4 mlO(2) .min(-1) kg(-1) per 10 years). Adjustment for hemoglobin did not materially change these associations. CONCLUSION: Physical activity levels among rural Kenyan adults are high, with highest levels observed in the Maasai and Kamba. The Kamba may be most resilient to age-related declines in physical activity. PMID- 22836509 TI - Coffee and black tea consumption and breast cancer mortality in a cohort of Swedish women. AB - BACKGROUND: Coffee and black tea contain a mixture of compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee and black tea consumption and breast cancer survival are sparse. METHODS: We investigated the association between coffee and black tea consumption and survival among 3243 women with invasive breast cancer in the Swedish Mammography Cohort. Intake was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: From 1987 to 2010 there were 394 breast cancer-specific deaths and 973 total deaths. Coffee and black tea were not associated with breast cancer-specific or overall mortality. Women consuming 4+ cups of coffee per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.14 (0.71 1.83; p(trend)=0.81) compared with those consuming <1 cup per day. Women consuming 2+ cups of black tea per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.02 (0.67 1.55; p(trend)=0.94) compared with non-tea drinkers. Caffeine was also not associated with breast cancer-specific (HR for top to bottom quartile=1.06; 95% CI=0.79-1.44; p(trend)=0.71) or overall mortality. CONCLUSION: Our findings suggest that coffee, black tea, and caffeine consumption before breast cancer diagnosis do not influence breast cancer-specific and overall survival. PMID- 22836510 TI - Downregulation of miR-126 induces angiogenesis and lymphangiogenesis by activation of VEGF-A in oral cancer. AB - BACKGROUND: MicroRNA (miRNA)-126 (miR-126) is an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7). However, the role of miR-126 in cancer is controversial. METHODS: We examined the function of miR-126 in oral squamous cell carcinoma (OSCC) cells. Furthermore, a series of 118 cases with OSCC were evaluated for the expression levels of miR 126. RESULTS: MicroRNA-126 (miR-126) was associated with cell growth and regulation of vascular endothelial growth factor-A activity, and demethylation treatment increased expression levels of miR-126 and EGFL7 in OSCC cells. A significant association was found between miR-126 expression and tumour progression, nodal metastasis, vessel density, or poor prognosis in OSCC cases. In the multivariate analysis, decreased miR-126 expression was strongly correlated with disease-free survival. CONCLUSION: The present results suggest that miR-126 might be a useful diagnostic and therapeutic target in OSCC. PMID- 22836511 TI - Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum sensitive ovarian cancer patients. AB - BACKGROUND: The CALYPSO phase III trial compared CD (carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatin-paclitaxel) in patients with platinum-sensitive recurrent ovarian cancer (ROC). Overall survival (OS) data are now mature. METHODS: Women with ROC relapsing > 6 months after first- or second line therapy were randomised to CD or CP for six cycles in this international, open-label, non-inferiority trial. The primary endpoint was progression-free survival. The OS analysis is presented here. RESULTS: A total of 976 patients were randomised (467 to CD and 509 to CP). With a median follow-up of 49 months, no statistically significant difference was observed between arms in OS (hazard ratio = 0.99 (95% confidence interval 0.85, 1.16); log-rank P = 0.94). Median survival times were 30.7 months (CD) and 33.0 months (CP). No statistically significant difference in OS was observed between arms in predetermined subgroups according to age, body mass index, treatment-free interval, measurable disease, number of lines of prior chemotherapy, or performance status. Post-study cross over was imbalanced between arms, with a greater proportion of patients randomised to CP receiving post-study PLD (68%) than patients randomised to CD receiving post-study paclitaxel (43%; P < 0.001). CONCLUSION: Carboplatin-PLD led to delayed progression and similar OS compared with carboplatin-paclitaxel in platinum-sensitive ROC. PMID- 22836512 TI - betaV-tubulin expression is associated with outcome following taxane-based chemotherapy in non-small cell lung cancer. AB - BACKGROUND: Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both betaIII- and betaV-tubulins are expressed by cancer cells and may lead to resistance against TBAs. METHODS: Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of betaIII- and betaV-tubulin was morphometrically quantified. RESULTS: Median pre-treatment H-score for betaIII tubulin was 110 (range: 0-290), and 160 for betaV-tubulin (range: 0-290). Low betaIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high betaV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high betaV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy. CONCLUSION: Expression of betaV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of betaIII-tubulin. Prospective evaluation of betaIII/betaV tubulin expression in NSCLC is warranted. PMID- 22836513 TI - Chronic cranberry juice consumption restores cholesterol profiles and improves endothelial function in ovariectomized rats. AB - PURPOSE: Postmenopausal women experience higher risks for cardiovascular diseases than age-matched men and pre-menopausal women. There is a need for better treatment strategy for estrogen-deficient-related cardiovascular complications. We and others have recently reported that activated renin-angiotensin system and the associated oxidative stress impaired endothelium-dependent relaxation in ovariectomized rat, while angiotensin receptor blocker rescues endothelial dysfunction. Dietary supplements and lifestyle modifications provide an alternative way to improve cardiovascular health. The present study tests the hypothesis that chronic cranberry juice consumption improves cholesterol profiles and vascular functions in estrogen-deficient animal model. The effect of cranberry consumption on expression and activity of renin-angiotensin system in the vasculature will be determined. METHODS: Ovariectomized rats were treated daily with commercial cranberry juice at 7 mg/kg for 8 weeks, a dosage comparable to recent clinical studies. Serum was collected for measuring cholesterol levels while aorta was isolated for isometric force assay and expression studies. RESULTS: Cranberry juice consumption reduced circulating levels of total cholesterol, triacylglycerols, HDL, nHDL, and nHDL/HDL ratio. Meanwhile, cranberry juice consumption improved endothelium-dependent relaxation in aorta of ovariectomized rats by restoring p-eNOS level (endothelial nitric oxide synthase phosphorylated at ser-1177), reversing the up-regulated levels of renin angiotensin system markers (angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor), and normalizing the elevated NAD(P)H oxidase expression and oxidative stress. CONCLUSIONS: Our data demonstrate the novel cardiovascular benefits of cranberry juice consumption in improving both vascular functions and cholesterol profiles, providing insight into developing cranberry products into useful dietary supplements for postmenopausal women. PMID- 22836515 TI - Tetrahedral versus planar four-coordinate carbon: a sulfonyl-substituted methandiide. PMID- 22836514 TI - Milk phospholipid and plant sterol-dependent modulation of plasma lipids in healthy volunteers. AB - PURPOSE: Hypolipidemic and/or hypocholesterolemic effects are presumed for dietary milk phospholipid (PL) as well as plant sterol (PSt) supplementation. The aim was to induce changes in plasma lipid profile by giving different doses of milk PL and a combination of milk PL with PSt to healthy volunteers. METHODS: In an open-label intervention study, 14 women received dairy products enriched with moderate (3 g PL/day) or high (6 g PL/day) dose of milk PL or a high dose of milk PL combined with PSt (6 g PL/day + 2 g PSt/day) during 3 periods each lasting 10 days. RESULTS: Total cholesterol concentration and HDL cholesterol concentration were reduced following supplementation with 3 g PL/day. No significant change in LDL cholesterol concentration was found compared with baseline. High PL dose resulted in an increase of LDL cholesterol and unchanged HDL cholesterol compared with moderate PL dose. The LDL/HDL ratio and triglyceride concentration remained constant within the study. Except for increased phosphatidyl ethanolamine concentrations, plasma PL concentrations were not altered during exclusive PL supplementations. A combined high-dose PL and PSt supplementation led to decreased plasma LDL cholesterol concentration, decreased PL excretion, increased plasma sphingomyelin/phosphatidyl choline ratio, and significant changes in plasma fatty acid distribution compared with exclusive high-dose PL supplementation. CONCLUSION: Milk PL supplementations influence plasma cholesterol concentrations, but without changes of LDL/HDL ratio. A combined high dose milk PL and PSt supplementation decreases plasma LDL cholesterol concentration, but it probably enforces absorption of fatty acids or fatty acid containing hydrolysis products that originated during lipid digestion. PMID- 22836516 TI - The prenylated dioxopiperazine alkaloid Cristatin A has selective telomeric DNA G quadruplex stabilising properties. AB - Cristatin A (1a/b), a prenylated dioxopiperazine alkaloid, has been shown to bind selectively to telomeric quadruplex DNA using a FRET-based DNA melting assay. Crucially, the molecule is more drug-like than most previously identified quadruplex-binding agents, and provides a unique chemical scaffold for future chemical biology and drug discovery studies. PMID- 22836517 TI - Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy. AB - It has been recognized that macroautophagy constitutes an important survival mechanism that allows both the maintenance of cellular homeostasis and the regulation of programmed cell death pathways (e.g., apoptosis). Although several pathogens have been described to induce autophagy, the prosurvival function of this process in infectious models remains poorly characterized. Our recent studies on chikungunya virus (CHIKV), the causative agent of major epidemics in India, Southeast Asia and southern Europe, reveal a novel mechanism by which autophagy limits the cytopathic effects of CHIKV by impinging upon virus-induced cell death pathways. PMID- 22836518 TI - Hydroxamate represents a versatile zinc binding group for the development of new carbonic anhydrase inhibitors. AB - Hydroxamates (R-CONHOH) have been scarcely investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs). An inhibition/structural study of PhCONHOH is reported against all human isoforms. Comparing aliphatic (R = Me and CF(3)) and aromatic (R = Ph) hydroxamates as CAIs, we prove that CONHOH is a versatile zinc binding group. Depending on the nature of the R moiety, it can adopt different coordination modes to the catalytic ion within the CA active site. PMID- 22836519 TI - The optimal interstimulus interval and repeatability of paired associative stimulation when the soleus muscle is targeted. AB - Changes in the excitability of the cortical projections to muscles in the upper and lower limbs can be induced in the intact human by paired associative stimulation (PAS). An interstimulus interval (ISI) of 25 ms between peripheral nerve and transcranial magnetic stimuli has been found to be effective when targeting hand muscles. The optimal ISI to induce plasticity changes in the cortical projections to lower limbs is still not well established. The purpose of this study was twofold: first, to investigate the effect of PAS with four different ISIs based on the individual latency of the sensory evoked potential (SEP plus 6, 12, 18 and 24 ms) and second, to evaluate the repeatability of the established optimal ISI. Transcranial magnetic stimulation was used to measure changes in the motor evoked potentials (MEPs) of the soleus (SOL) muscle before and after the PAS interventions. Significant increases in the amplitude of SOL MEPs (88 %) were attained with an ISI of SEP latency plus 18 ms (P32 + 18 ms). The PAS effect was long-lasting, input-specific and supraspinal in origin. The intraclass correlation coefficient to test the repeatability of the PAS intervention with the optimal ISI was 0.85. The results show that the excitability of cortical projections to the soleus muscle can be repeatedly increased after PAS with an optimal ISI of SEP plus 18 ms. PMID- 22836520 TI - Differential working memory correlates for implicit sequence performance in young and older adults. AB - Our recent work has revealed that visuospatial working memory (VSWM) relates to the rate of explicit motor sequence learning (Bo and Seidler in J Neurophysiol 101:3116-3125, 2009) and implicit sequence performance (Bo et al. in Exp Brain Res 214:73-81, 2011a) in young adults (YA). Although aging has a detrimental impact on many cognitive functions, including working memory, older adults (OA) still rely on their declining working memory resources in an effort to optimize explicit motor sequence learning. Here, we evaluated whether age-related differences in VSWM and/or verbal working memory (VWM) performance relates to implicit performance change in the serial reaction time (SRT) sequence task in OA. Participants performed two computerized working memory tasks adapted from change detection working memory assessments (Luck and Vogel in Nature 390:279 281, 1997), an implicit SRT task and several neuropsychological tests. We found that, although OA exhibited an overall reduction in both VSWM and VWM, both OA and YA showed similar performance in the implicit SRT task. Interestingly, while VSWM and VWM were significantly correlated with each other in YA, there was no correlation between these two working memory scores in OA. In YA, the rate of SRT performance change (exponential fit to the performance curve) was significantly correlated with both VSWM and VWM, while in contrast, OA's performance was only correlated with VWM, and not VSWM. These results demonstrate differential reliance on VSWM and VWM for SRT performance between YA and OA. OA may utilize VWM to maintain optimized performance of second-order conditional sequences. PMID- 22836521 TI - Robotic guidance benefits the learning of dynamic, but not of spatial movement characteristics. AB - Robotic guidance is an engineered form of haptic-guidance training and intended to enhance motor learning in rehabilitation, surgery, and sports. However, its benefits (and pitfalls) are still debated. Here, we investigate the effects of different presentation modes on the reproduction of a spatiotemporal movement pattern. In three different groups of participants, the movement was demonstrated in three different modalities, namely visual, haptic, and visuo-haptic. After demonstration, participants had to reproduce the movement in two alternating recall conditions: haptic and visuo-haptic. Performance of the three groups during recall was compared with regard to spatial and dynamic movement characteristics. After haptic presentation, participants showed superior dynamic accuracy, whereas after visual presentation, participants performed better with regard to spatial accuracy. Added visual feedback during recall always led to enhanced performance, independent of the movement characteristic and the presentation modality. These findings substantiate the different benefits of different presentation modes for different movement characteristics. In particular, robotic guidance is beneficial for the learning of dynamic, but not of spatial movement characteristics. PMID- 22836522 TI - Saccadic eye movements in children: a developmental study. AB - To our knowledge, there are no studies exploring the development of voluntary and reflexive saccades in children using different types of paradigms to investigate horizontal saccades. In the present study, we examined the development of horizontal saccades in children aged 6-15 years. Binocular eye movements were recorded using an infrared video-oculography system (mobileEBT((r)), e(ye)BRAIN) in seventy-two children (aged 6-15). Several paradigms were used to stimulate reflexive and voluntary horizontal saccades: gap, step and overlap paradigms. Horizontal anti-saccades were also examined. In all paradigms, the latency of saccades decreased with the age of children and it did not depend on the direction of the saccades (left/right); the error rate in the anti-saccade task decreased with age; the gain of horizontal saccades improved with age; the peak velocity of horizontal saccades was stable throughout childhood. We conclude that saccadic performances are influenced by age and cortical circuits responsible for the preparation of reflexive or voluntary saccades are completed at 12 years old. These data could be used as reference values for further studies dealing with pathologic development. PMID- 22836523 TI - Neuropathology of explosive blast traumatic brain injury. AB - During the conflicts of the Global War on Terror, which are Operation Enduring Freedom (OEF) in Afghanistan and Operation Iraqi Freedom (OIF), there have been over a quarter of a million diagnosed cases of traumatic brain injury (TBI). The vast majority are due to explosive blast. Although explosive blast TBI (bTBI) shares many clinical features with closed head TBI (cTBI) and penetrating TBI (pTBI), it has unique features, such as early cerebral edema and prolonged cerebral vasospasm. Evolving work suggests that diffuse axonal injury (DAI) seen following explosive blast exposure is different than DAI from focal impact injury. These unique features support the notion that bTBI is a separate and distinct form of TBI. This review summarizes the current state of knowledge pertaining to bTBI. Areas of discussion are: the physics of explosive blast generation, blast wave interaction with the bony calvarium and brain tissue, gross tissue pathophysiology, regional brain injury, and cellular and molecular mechanisms of explosive blast neurotrauma. PMID- 22836525 TI - Lymphoid follicles: FDCs--ubiquitous and ready for action. PMID- 22836524 TI - Therapeutic hypothermia for traumatic brain injury. AB - Experimental evidence demonstrates that therapeutic temperature modulation with the use of mild induced hypothermia (MIH, defined as the maintenance of body temperature at 32-35 degrees C) exerts significant neuroprotection and attenuates secondary cerebral insults after traumatic brain injury (TBI). In adult TBI patients, MIH has been used during the acute "early" phase as prophylactic neuroprotectant and in the sub-acute "late" phase to control brain edema. When used to control brain edema, MIH is effective in reducing elevated intracranial pressure (ICP), and is a valid therapy of refractory intracranial hypertension in TBI patients. Based on the available evidence, we recommend: applying standardized algorithms for the management of induced cooling; paying attention to limit potential side effects (shivering, infections, electrolyte disorders, arrhythmias, reduced cardiac output); and using controlled, slow (0.1 0.2 degrees C/h) rewarming, to avoid rebound ICP. The optimal temperature target should be titrated to maintain ICP <20 mmHg and to avoid temperatures <35 degrees C. The duration of cooling should be individualized until the resolution of brain edema, and may be longer than 48 h. Patients with refractory elevated ICP following focal TBI (e.g. hemorrhagic contusions) may respond better to MIH than those with diffuse injury. Randomized controlled trials are underway to evaluate the impact of MIH on neurological outcome in adult TBI patients with elevated ICP. The use of MIH as prophylactic neuroprotectant in the early phase of adult TBI is not supported by clinical evidence and is not recommended. PMID- 22836526 TI - Rotator cuff muscles perform different functional roles during shoulder external rotation exercises. AB - The aim of this study was to compare activity in shoulder muscles during an external rotation task under conditions of increasing arm support to investigate whether changing support requirements would influence muscle recruitment levels, particularly in the rotator cuff (RC) muscles. Electromyographic recordings were collected from seven shoulder muscles using surface and indwelling electrodes. The dominant shoulder of 14 healthy participants were examined during dynamic shoulder external rotation performed at 90 degrees abduction with the arm fully supported, partially supported, and unsupported. Linear regressions between arm support load and the averaged muscle activity across participants for each muscle showed infraspinatus predominantly contributing to rotating the shoulder whilst supraspinatus, deltoid, upper trapezius, and serratus anterior were predominantly functioning in support/stabilization roles. During dynamic shoulder external rotation in mid-range abduction, the RC muscles perform different functional roles. Infraspinatus is responsible for producing external rotation torque, supraspinatus is playing a larger joint stabilizer role, and subscapularis is contributing minimally to joint stability. The results also indicate that increasing support load requirements during an external rotation task may be a functionally specific way to retrain the stabilization function of axioscapular muscles. Manipulating joint stabilization requirements while maintaining constant rotational load is a novel method of investigating the differential contribution of muscles to joint movement and stabilization during a given task. PMID- 22836528 TI - The role of the public health practitioner in creating active living communities. PMID- 22836529 TI - A proportional public health response to physical inactivity. PMID- 22836527 TI - Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. AB - The aim of this study was to analyze quantitatively cellular respiration in intraoperational tissue samples taken from human breast cancer (BC) patients. We used oxygraphy and the permeabilized cell techniques in combination with Metabolic Control Analysis (MCA) to measure a corresponding flux control coefficient (FCC). The activity of all components of ATP synthasome, and respiratory chain complexes was found to be significantly increased in human BC cells in situ as compared to the adjacent control tissue. FCC(s) were determined upon direct activation of respiration with exogenously-added ADP and by titrating the complexes with their specific inhibitors to stepwise decrease their activity. MCA showed very high sensitivity of all complexes and carriers studied in human BC cells to inhibition as compared to mitochondria in normal oxidative tissues. The sum of FCC(s) for all ATP synthasome and respiratory chain components was found to be around 4, and the value exceeded significantly that for normal tissue (close to 1). In BC cells, the key sites of the regulation of respiration are Complex IV (FCC = 0.74), ATP synthase (FCC = 0.61), and phosphate carrier (FCC = 0.60); these FCC(s) exceed considerably (~10-fold) those for normal oxidative tissues. In human BC cells, the outer mitochondrial membrane is characterized by an increased permeability towards adenine nucleotides, the mean value of the apparent K(m) for ADP being equal to 114.8 +/- 13.6 MUM. Our data support the two compartment hypothesis of tumor metabolism, the high sum of FCC(s) showing structural and functional organization of mitochondrial respiratory chain and ATP synthasome as supercomplexes in human BC. PMID- 22836531 TI - Using stand/sit workstations in classrooms: lessons learned from a pilot study in Texas. AB - Childhood obesity has grown into a national epidemic since the 1980s. Many school based intervention efforts that target childhood obesity involve curriculum and programming that demands instructional time, which disincentivizes school participation. Stand-biased classrooms are an environmental intervention that promotes standing rather than sitting by utilizing standing height desks that allow students to stand during normal classroom activities. The quasi experimental pilot study was conducted in 5 first-grade classrooms in a Texas elementary school, with 2 control classrooms, 2 treatment classrooms, and 1 classroom that was a control in the fall and treatment in the spring (to allow for within-group comparisons). This intervention has been shown effective in significantly increasing caloric expenditure. In addition, the present study reveals potential behavioral effects from standing. This article presents lessons learned from the pilot study that may prove useful for others implementing similar interventions and calls for additional research on the academic benefits of standing for students. PMID- 22836530 TI - Where is obesity prevention on the map?: distribution and predictors of local health department prevention activities in relation to county-level obesity prevalence in the United States. AB - CONTEXT: The system of local health departments (LHDs) in the United States has the potential to advance a locally oriented public health response in obesity control and reduce geographic disparities. However, the extent to which obesity prevention programs correspond to local obesity levels is unknown. OBJECTIVE: This study examines the extent to which LHDs across the United States have responded to local levels of obesity by examining the association between jurisdiction-level obesity prevalence and the existence of obesity prevention programs. DESIGN: Data on LHD organizational characteristics from the Profile Study of Local Health Departments and county-level estimates of obesity from the Behavioral Risk Factor Surveillance System were analyzed (n = 2300). Since local public health systems are nested within state infrastructure, multilevel models were used to examine the relationship between county-level obesity prevalence and LHD obesity prevention programming and to assess the impact of state-level clustering. SETTING: Two thousand three hundred local health department jurisdictions defined with respect to county boundaries. PARTICIPANTS: Practitioners in local health departments who responded to the 2005 Profile Study of Local Health Departments. MAIN OUTCOME MEASURES: Likelihood of having obesity prevention activities and association with area-level obesity prevalence. RESULTS: The existence of obesity prevention activities was not associated with the prevalence of obesity in the jurisdiction. A substantial portion of the variance in LHD activities was explained by state-level clustering. CONCLUSIONS: This article identified a gap in the local public health response to the obesity epidemic and underscores the importance of multilevel modeling in examining predictors of LHD performance. PMID- 22836532 TI - Does the effect of a school recess intervention on physical activity vary by gender or race? Results from the Ready for Recess pilot study. AB - BACKGROUND AND OBJECTIVES: The recess environment in schools has been identified as an integral part of school-based programs to enhance physical activity (PA). The purpose of this study was to report pilot findings on the extent to which the Ready for Recess intervention was associated with a different amount of increase in moderate to vigorous PA (MPVA) during recess and the rest of the school day between girls and boys, and between nonwhites and whites. METHODS: The Ready for Recess intervention modified the recess environment of schools by providing staff training and recreational equipment. The MPVA levels of 3rd, 4th, and 5th grade students (n = 93) at 2 schools were measured pre- and post-intervention using ActiGraph accelerometers. Multiple regression models with robust variance were utilized to test for the interaction of intervention with gender and race/ethnicity. RESULTS: The intervention was associated with an adjusted increase of 4.7 minutes (P <.001) in moderate/vigorous PA during recess. There was no evidence that this effect varied by gender (P = .944) or race (P = .731). The intervention was also associated with an adjusted increase of 29.6 minutes (P < .001) in moderate/vigorous PA during rest of the school day. While this effect did not vary by gender, there was some evidence (P = .034) that nonwhites benefited more from the intervention than whites. CONCLUSION: Simple strategies such as staff training and recreational equipment may be an effective way to increase PA in children (despite gender or ethnicity) during recess time as well as during the rest of the school day. PMID- 22836533 TI - Association of available parkland, physical activity, and overweight in America's largest cities. AB - OBJECTIVE: To examine associations between the densities of available parkland, parkland provided per capita, and levels of physical activity (PA) and overweight in urban United States. DESIGN: Cross-sectional correlation research using data drawn from the Trust for Public Land's 2010 City Park Facts and The Behavioral Risk Factor Surveillance System (BRFSS). City Park Facts is a report containing "basic information on urban park systems--from acreage, to facilities, to staffing, to budgets, to usership, and more" for America's 85 largest cities. The Behavioral Risk Factor Surveillance System is a state-based surveillance system that collects information on health risk behaviors, preventive health practices, and health care access primarily related to chronic disease and injury. SETTING: Sixty-seven metropolitan statistical areas in the United States that provided data for both reports. PARTICIPANTS: Randomly selected adults aged 18 years and older who participated in the 2009 Behavioral Risk Factor Surveillance Survey in the 67 metropolitan statistical areas. MAIN OUTCOME MEASURE(S): Total parkland per acre of metropolitan area was correlated to inactivity, engaging in recommended levels of moderate or vigorous PA, engaging in recommended levels of vigorous PA, and body weight. Parkland acreage per 1000 residents was correlated to these same variables. Multilevel models considered these relationships while controlling for race, family income, and age of respondents and accounting for clustering by metropolitan statistical area. RESULTS: There were significant, positive correlations between park density and PA (r(s) = 0.37, n = 67, P < .01) and between park density and exercise (r(s) = 0.35, n = 67, P < .01), and a negative correlation between park density and being above normal weight (r(s) = 0.32, n = 67, P < .01). Adjusted multilevel models showed that parkland density in the highest versus lowest quartile was associated with significantly higher odds of meeting PA guidelines (aOR = 1.19, 95% CI: 1.08-1.30) and reduced odds of being overweight/obese (aOR = 0.85, 95% CI: 0.76-0.95). CONCLUSIONS: Each of these findings substantiates the need for providing parkland in a community. As such, this research helps to support the notion that the development of a strong park system may lead to positive PA and health outcomes for that community. PMID- 22836534 TI - Research to reality: a process evaluation of a mini-grants program to disseminate evidence-based nutrition programs to rural churches and worksites. AB - OBJECTIVES: To describe a project that used mini-grants plus technical assistance to disseminate evidence-based programs, to understand how the project worked in different settings, and to generate recommendations for future programming and evaluation. DESIGN: Process evaluation using program records, activity forms completed by grantees, interviews, and focus groups. SETTING: Churches and worksites in rural, southwest Georgia. PARTICIPANTS: Site coordinators (n = 10), organizational leaders (n = 7), and project committee members (n = 25) involved in program implementation at 7 funded organizations. INTERVENTION: The Emory Cancer Prevention and Control Research Network solicited applications from churches and worksites to implement one of 2 evidence-based nutrition programs: Body & Soul for churches and Treatwell 5-a-Day for worksites. Successful applicants (n = 7) received funding and technical assistance from Emory and agreed to conduct all required elements of the evidence-based program. MAIN OUTCOME MEASURES: We assessed adoption, reach, implementation, and maintenance of specific programs and their core elements, as well as contextual influences and the resources required to implement the mini-grants program. RESULTS: Four of the 7 funded organizations conducted all programmatic core elements; all 7 sites conducted at least 6 of 8 core elements, including at least 1 food-related policy or environmental change as a result of the program. Program reach varied widely across sites and core elements. All site coordinators stated that they intend to continue at least some of the activities conducted under the project. Sites reported that contextual factors such as the program's fit with the organization's mission, leadership support, and leadership or staffing transitions influenced program implementation. Over 18 months, Emory staff spent 47.7 hours providing technical assistance to grantees. CONCLUSIONS: A mini-grants and technical assistance model has the potential to be an effective mechanism for disseminating evidence-based programs to community organizations, and further study of this method is warranted. PMID- 22836535 TI - Energy expenditure associated with the use of neighborhood parks in 2 cities. AB - CONTEXT: Availability of public neighborhood parks is associated with physical activity. Little is known about how parks contribute to population energy balance. PURPOSE: This study estimated energy expenditure associated with the use of neighborhood parks and compared energy expenditure by activity areas within parks and by neighborhood race/ethnicity and income. DESIGN: The System for Observing Play and Leisure Activity among Youth (SOPLAY), a direct observation approach, was used to estimate energy expenditure in 10 Tampa (Florida) parks and 19 Chicago (Illinois) parks. SETTING: Parks were selected from census tracts with a moderate to high representation of white, Latino, and African American populations. PARTICIPANTS: A total of 9454 park users were observed. OUTCOME: Sedentary, moderate, and vigorous activities were assigned metabolic equivalence intensity (MET) values of 1.5, 3, and 6, respectively. RESULTS: Park use in Tampa generated 15 336 total METs over the study period. Chicago parks generated 7305.6 METs. Mean METs varied by activity areas in parks. For Chicago parks, mean METs were higher for parks in African American and higher-income neighborhoods. CONCLUSIONS: Public parks can contribute to population energy balance. Policies to make parks available, promotions to encourage park use, and programs to encourage active use of parks are necessary to achieve this potential. PMID- 22836536 TI - Micro- and macro-level correlates of adiposity in children. AB - CONTEXT: Recently, studies using a social ecological perspective have identified important micro- and macro-level risk factors for excessive adiposity in youth. Although considerable research exists examining these relationships, few studies have applied a socioecological approach to simultaneously examine both micro- and macro-level factors in young children while objectively assessing adiposity via dual-energy x-ray absorptiometry (DXA). OBJECTIVE: To examine race and sex differences in adiposity measured by DXA in a large sample of young children and to identify both micro- and macro-level correlates of adiposity. DESIGN: Cross sectional. SETTING AND PARTICIPANTS: Elementary school children (N = 495) from the southeastern United States participated. Anthropometrics, percentage body fat via DXA, and psychosocial variables via questionnaire were assessed in the Fall of 2003. Community-level sociodemographic data and built-environment variables via geographic information system were collected in Spring 2009. Data analyses were completed in the Spring of 2010. RESULTS: Percentage body fat in white children was higher than in nonwhite children. Higher percentage body fat and poorer cardiovascular fitness were found in females compared with males. Percentage body fat was higher in children who had lower athletic competence and lived in neighborhoods with higher percentages of minority residents. CONCLUSION: This study provides preliminary support for the social-ecological model to explain variance in adiposity in children. Developers of health promotion programs for children living in minority neighborhoods should consider factors at multiple levels of the ecological model when designing and implementing programs. PMID- 22836537 TI - Functions of environmental epidemiology and surveillance in state health departments. AB - Public health surveillance and epidemiology are the foundations for disease prevention because they provide the factual basis from which agencies can set priorities, plan programs, and take actions to protect the public's health. Surveillance for noninfectious diseases associated with exposure to agents in the environment like lead and pesticides has been a function of state health departments for more than 3 decades, but many state programs do not have adequate funding or staff for this function. Following the efforts to identify core public health epidemiology functions in chronic diseases, injury, and occupational health and safety, a workgroup of public health environmental epidemiologists operating within the organizational structure of the Council of State and Territorial Epidemiologists has defined the essential core functions of noninfectious disease environmental epidemiology that should be present in every state health department and additional functions of a comprehensive program. These functions are described in terms of the "10 Essential Environmental Public Health Services" and their associated performance standards. Application of these consensus core and expanded functions should help state and large metropolitan health departments allocate resources and prioritize activities of their environmental epidemiologists, thus improving the delivery of environmental health services to the public. PMID- 22836538 TI - The importance of substate surveillance in detection of geographic oral health inequalities in a small state. AB - CONTEXT: Considering that 42% of children and adolescents and 91% of dentate adults experience dental caries, oral disease is a public health problem. Although the population's oral health is improving, certain subgroups remain at increased risk for dental disease. OBJECTIVE: To assess the oral health status at the substate level and explore the possibility of geographic oral health inequalities in New Hampshire while building upon existing surveillance data sets. DESIGN: We used the Third Grade Oral Health and NH Behavioral Risk Factor Surveillance System surveys. We ensured the availability of substate level data and compared county/region specific estimates. SETTING: New Hampshire. PARTICIPANT: Adults and third-grade students in public schools. MAIN OUTCOME MEASURES: The prevalence of dental caries, untreated caries, and dental sealants among children; and the insurance status, utilization of dental services, and edentulism among adults. RESULTS: Of the 10 counties, the northernmost Coos County had consistently worse outcomes when compared with other counties. Only 64% of adult Coos County residents reported a dental visit in the past year; of these, 66% reported dental cleaning. Among adults 65 years and older, 29% were edentulous. In comparison with the state overall, these estimates were 76%, 77%, and 19%, respectively. Coos County third-grade students had the highest prevalence of dental caries experience (64% compared with 44% in New Hampshire) and untreated caries (31% compared with 12%), and only 24% had dental sealants (state prevalence is 60%). CONCLUSIONS: Overall oral health status in our state is favorable and comparable with the nation, yet significant geographic inequalities exist among children and adults. The oral health status of disparate groups can be improved using tailored interventions such as community water fluoridation or expansion of school-based dental sealant programs. Surveillance at the substate level is an essential part of the planning, targeting, and progress monitoring. PMID- 22836539 TI - Educating refugees to improve their home environmental health. AB - Rochester's Healthy Home was a hands-on home environmental health museum that educated more than 3500 visitors between June 2006 and December 2009. The Healthy Home provided visitors with the tools, resources, and motivation to make their homes healthier by reducing environmental hazards. The Healthy Home focused on empowering low-income renters to protect their families from home health risks, but served a broad audience. On the basis of the Healthy Home's initial successes with diverse visitors, in 2009 the county health department provided funding for a 6-month project to educate 200 recently arrived refugees. This report summarizes the project's innovative approach to home health education, presents evaluation data on impacts on refugees and other visitors, suggests implications for resettlement agencies, and provides guidelines for those interested in replicating this approach in their own community. PMID- 22836540 TI - Walking the walk. PMID- 22836541 TI - Medical Reserve Corps program commemorates 10 years of improving community resiliency. PMID- 22836542 TI - Collaborative capacity building in complex community-based health partnerships: a model for translating knowledge into action. AB - Partnerships among multiple organizations across a range of sectors that bring together multiple perspectives are a common way of addressing community health and building capacity. To function successfully, partnerships depend on the careful orchestration of a collaborative culture and the facilitation of collective action. Using a systematic method, we developed a synthesis of evidence about collaborative capacity building, integrating this diverse knowledge base into a usable framework. Seventeen published models of collaborative capacity building met the inclusion criteria and were combined to derive a matrix that could guide the actions of those responsible for partnership management. This matrix may make the process of developing partnerships less complicated in future. PMID- 22836543 TI - A multistate examination of partnership activity among local public health systems using the National Public Health Performance Standards. AB - This study examines whether partnership-related measures in the second version of the National Public Health Performance Standards (NPHPS) are useful in evaluating level of activity as well as identifying latent constructs that exist among local public health systems (LPHSs). In a sample of 110 LPHSs, descriptive analysis was conducted to determine frequency and percentage of 18 partnership-related NPHPS measures. Principal components factor analysis was conducted to identify unobserved characteristics that promote effective partnerships among LPHSs. Results revealed that 13 of the 18 measures were most frequently reported at the minimal-moderate level (conducted 1%-49% of the time). Coordination of personal health and social services to optimize access (74.6%) was the most frequently reported measure at minimal-moderate levels. Optimal levels (conducted >75% of the time) were reported most frequently in 2 activities: participation in emergency preparedness coalitions and local health departments ensuring service provision by working with state health departments (67% and 61% of respondents, respectively) and the least optimally reported activity was review partnership effectiveness (4% of respondents). Factor analysis revealed categories of partnership-related measures in 4 domains: resources and activities contributing to relationship building, evaluating community leadership activities, research, and state and local linkages to support public health activities. System-oriented public health assessments may have questions that serve as proxy measures to examine levels of interorganizational partnerships. Several measures from the NPHPS were useful in establishing a national baseline of minimal and optimal activity levels as well as identifying factors to enhance the delivery of the 10 essential public health services among organizations and individuals in public health systems. PMID- 22836544 TI - Outdoor smoking ban at a cancer center: attitudes and smoking behavior among employees and patients. AB - Policies restricting indoor worksite tobacco use began being implemented more than a decade ago. More recently, the scope of these policies has been expanding to outdoors, with hospitals leading the trend in restricting smoking throughout their grounds. However, research on the effects such bans have on employees is scarce. The purpose of the current study was to examine the impact of a campus wide smoking ban on employees and patients at a cancer center. Employees completed anonymous questionnaires during the months before (n = 607; 12% smokers) and 3 months after the ban implementation (n = 511; 10% smokers). Patients (n = 278; 23% smokers) completed an anonymous questionnaire preban. Results showed that 86% of nonsmokers, 20% of employees who smoke, and 57% of patients who smoke supported the ban. More than 70% of smokers were planning or thinking about quitting at both time points and nearly one-third were interested in cessation services following the ban. Before the ban, 32% expected the ban to have a negative effect on job performance and 41% thought their smoking before and after work would increase. Postban, 22% reported a negative impact on job performance, 35% increased smoking before and after work, and 7% quit. Overall, these data revealed an overwhelming support for an outdoor smoking ban by nonsmoker employees and patients. Although a majority of employee smokers opposed the ban, a significant proportion was interested in cessation. Compared with preban expectations, a lower proportion experienced negative effects postban. Findings suggest a need for worksite cessation programs to capitalize on the window of opportunity created by tobacco bans, while also addressing concerns about effects on work performance. PMID- 22836545 TI - The "tele" factor in surgery today and tomorrow: implications for surgical training and education. AB - New technological developments in the field of telecommunications have allowed a wide range of potentially novel surgical applications. The introduction of the World Wide Web in 1991 has been followed by a steep rise of the relevance of telemedicine, as it is witnessed in the latest scientific literature. There has been a consistent, positive trend in publications dealing, respectively, with telemedicine and the Internet. This article reviews telemedicine and other surgery-related innovations that benefit from telecommunication advances, and presents data from a quantitative bibliographic analysis. A number of applications, such as telementoring, teleproctoring and robotic telesurgery are described and their huge potentials are discussed. The integration between surgery and telecommunications could constitute one of the major achievements of modern medicine, and its safe integration into clinical practice should be a priority for modern surgeons. PMID- 22836546 TI - Hydatid cyst of the thyroid gland: report of three cases. AB - Cystic Echinococcosis is a parasitic infestation that is distributed world-wide. It may be found in nearly any part of the body, most often in the liver and the lungs, but occasionally in other structures such as the thyroid gland. The present study reports three cases of hydatid cysts of the thyroid gland, in patient ranging from 18 to 25 years of age. Two patients had concomitant hydatid disease involving organs other than the thyroid gland (secondary disease), and one had, sole, involvement of the thyroid gland itself (primary disease). Moreover, an occult papillary thyroid carcinoma was detected incidentally in one case, involving the unilateral thyroid lobe as the hydatid cyst. While several surgical procedures including left lobectomy and isthmectomy were undertaken in one patient, two patients underwent total thyroidectomy. No disease recurrence was observed in any of the three patients during the postoperative follow-up period. No study reporting the concomitance of hydatid cyst and neoplasia of the thyroid gland has been previously published. This concomitance indicates the importance of the differential diagnosis of lesions characterized by calcifications in the thyroid gland, especially in endemic regions. PMID- 22836547 TI - [How free is free will? Neuro-scientific and philosophical aspects of motivation and decision-making]. AB - The question concerning the postulated freedom of will continues to occupy the neuro-sciences, psychiatry, law and neuro-philosophy. Do current research results really show that freedom and responsibility were only illusions, since previously supposed free decisions were only accompanying features of long held neuronal activations? Did Julien de La Mettrie have a great vision, when, already in the Eighteenth Century, he expected a "monsieur Machine"?This article attempts to summarize and evaluate findings that are currently available. The autonomy of human action is not only founded in a subjectively perceived act of will but far more in the ability of the human being to act according to an inner drive which is steered consciously and rationally. The autonomy of human action is not only restricted to the perceived ego, but comprises body and soul, brain and spirit and consequently the whole human being with all their characteristics, values and aims. Modern science thereby supports the old philosophical theory of a conditional freedom of will. PMID- 22836548 TI - [Not Available]. AB - Previous investigations concerning the influence of the therapist's sex on treatments showed various and inconsistent results. Recently conducted studies on gender differences in psychiatric and psychotherapeutic treatments, medical consultation techniques, also concerning the different dyadic constellations, are presented and compared with formerly conducted investigations. Persistent for decades, results display a communication style influenced by cut and dried opinions and gender-role stereotypes. In conclusion, socialization processes, as well as subjectively important (unconscious) meanings and attributions play a specific role in communication processes that have to be considered in clinical situations as well as in research strategies. Therefore the differentiation between science and social science is important. PMID- 22836549 TI - [The effects of depressive symptoms on quality of life, sexual satisfaction and cognitive performance after orthotopic liver transplantation]. AB - BACKGROUND: Our cross-sectional study aimed to explore the existence of depressive symptoms among orthotopic liver transplantation recipients and to investigate how depressive symptoms are linked to health-related quality of life, sexual satisfaction and cognitive performance. METHODS: We recruited 76 liver transplantation recipients. All patients were treated at the Department of Surgery, Division of Transplantation Surgery, University of Medicine of Graz, Graz, Austria. The psychometric observer-rating scale Hamilton Depression Scale was administered to evaluate depressive symptoms. Cognitive performance was based on the SKT. The data on health-related quality of life were obtained from the SF 36 and the data on sexual satisfaction were obtained from the FLZ. RESULTS: After the orthotopic liver transplantation (OLT) 53,9% (n = 41) of the sample suffered from depressive symptoms. Impaired sexual functioning and impaired cognitive performance are a common feature in liver transplantation recipients with depressive symptoms. In the sample of patients suffering from depressive symptoms significant impairments in health-related quality of life were found in all SF-36 domains. CONCLUSIONS: Liver transplantation recipients may face a major risk of liver transplantation-related depressive symptoms. Depressive symptoms are highly associated with impairments in quality of life, sexual satisfaction and cognitive performance. PMID- 22836550 TI - [Impaired resonance in offenders with psychopathic traits]. AB - BACKGROUND: Resonance is the phenomenon of unconsciously mirroring the motor actions of another person. Beside autism and schizophrenia psychopathic personality traits are associated with empathy dysfunction. METHODS: We explore empathic resonance in terms of contagion by laughing and yawning in a group of offenders with psychopathic traits. Offenders with psychopathic traits (n = 12) and matched controls (n = 10) were video-taped while watching short video sequences of yawning, laughing or neutral faces. They were rated regarding contagion. Further, we assessed a self-report on psychopathy and on empathic tendencies. RESULTS: Compared to the control group, the offenders showed significantly less contagion and less self-reported empathic tendencies. Individuals who rated themselves as more empathic showed more contagion. CONCLUSIONS: The observed reduced resonance in terms of contagion may illuminate the cold-heartedness, with which some psychopathic offenders treat their victims: When embodied experiencing of other's physical and emotional situation is missing, a natural inhibition of violence may be overcome. The small sample size limits the generalisability of these findings. PMID- 22836552 TI - [In Process Citation]. PMID- 22836553 TI - [In Process Citation]. PMID- 22836551 TI - [Quality of life in mild cognitive impairment, patients with different stages of Alzheimer disease and healthy control subjects]. AB - OBJECTIVE: The aim of the current study is to evaluate quality of life in patients with different stages of dementia, MCI patients and healthy control subjects. METHODS: The study comprises a number of 92 elderly patients (23 healthy control subjects, 24 subjects diagnosed with mild cognitive impairment, 28 patients with early AD and 17 patients with moderate AD). Quality of life was measured with the SF36. RESULTS: We found significant differences between the diagnostic groups in the scales: perception of general health, vitality, limits in role performance due to emotional problems and mental health Generally, healthy control subjects and patients diagnosed with moderate AD showed better quality of life scores than patients with MCI and early stages of dementia. Additionally, we found a significant negative correlation between depression and all scales of the SF36. CONCLUSIONS: Our results confirm that mood seems to be the strongest predictor of quality of life in elderly persons and patients in different stages of cognitive decline. PMID- 22836555 TI - [In Process Citation]. PMID- 22836556 TI - Tumor bed control with balloon-based accelerated partial breast irradiation: incidence of true recurrences versus elsewhere failures in the American Society of Breast Surgery MammoSite((r)) Registry Trial. AB - BACKGROUND: Randomized trials demonstrate that lumpectomy plus whole-breast irradiation (WBI) yields survival equivalent to mastectomy. Studies that use WBI, however, typically report higher tumor bed recurrence rates than elsewhere failures (EF) (historically considered new primary lesions). The rate of true recurrence (TR) versus EF was queried for a large patient cohort treated with accelerated partial breast irradiation (APBI). METHODS: A total of 1,449 cases of early-stage breast cancer were treated on the American Society of Breast Surgeons MammoSite((r)) Registry Trial with lumpectomy plus balloon-based APBI (34 Gy, 10 BID fractions). A total of 1,255 cases (87 %) had invasive breast cancer, and 194 patients (13 %) had ductal carcinoma in situ. Rates of TR versus EF were calculated and compared to historical WBI controls. RESULTS: Median follow-up was 60 (range 0-109) months. Fifty patients (3.5 %) developed an ipsilateral breast tumor recurrence (IBTR). The 5-year actuarial rate of IBTR was 3.6 % (invasive breast cancer 3.6 %, ductal carcinoma in situ 3.4 %). Fourteen IBTR (1.1 %) were TR, while 36 (2.6 %) were EF. Estrogen receptor-negative status was associated with IBTR for invasive malignancies as well as for EF only (p < 0.001). Trends for increased rates of EF were noted for increased tumor size (p = 0.067) and extensive intraductal component (p = 0.087). No pathologic factors were explicitly associated with TR. CONCLUSIONS: IBTR after balloon-based APBI is low and similar to rates reported for WBI. In this data set, APBI had fewer tumor bed recurrences (presumably initial cancer recurrences) than EF (presumably new primary lesions). This suggests that balloon-based APBI has a tumor bed control rate that is at least equal to (and potentially higher than) WBI. PMID- 22836557 TI - Is neck dissection necessary after induction plus concurrent chemoradiotherapy in complete responder head and neck cancer patients with pretherapy advanced nodal disease? AB - BACKGROUND: The aim of the present study was to assess, in the setting of a single-institution prospective clinical trial, the necessity of planned neck dissection (PND) in physically and radiologically complete responders with pretherapy advanced nodal disease. METHODS: Between January 2000 and July 2007 a total of 139 patients were enrolled to receive a regimen of platinum-based multidrug induction-concurrent chemoradiotherapy (IC/CCRT). A total of 75 of the enrolled patients with advanced nodal disease were included in this retrospective study. Between 8 and 12 weeks from the end of treatment, the response to IC/CCRT was evaluated by fiber-optic endoscopy and head and neck contrast-enhanced computed tomography or magnetic resonance imaging. RESULTS: The complete clinical response (cCR) rate was 68%. Among the 51 patients who achieved locoregional cCR at the end of CCRT, 8 underwent PND according to the study recommendation. Of the 43 patients with cCR who did not undergo PND, 2 patients (4.7%) experienced isolated regional recurrences with the 5-year regional control being 82%. Patients with cCR did not have a significantly lower regional control compared with patients with cCR who underwent ND (P=.962). Pathological evidence of residual disease was found in 81% of the patients with less than cCR who underwent ND. CONCLUSIONS: In physically and radiologically complete responders to IC/CCRT, a PND appears not justified. Conversely, PND should be performed in patients clinically suspected of having residual disease in the neck, as a significant proportion have viable tumor cell in post CCRT ND. PMID- 22836558 TI - Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: detoxifying mechanisms and potential therapeutic options. AB - Oxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro oxidant milieu, several antioxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk. PMID- 22836561 TI - Continuum theory of edge states of topological insulators: variational principle and boundary conditions. AB - We develop a continuum theory to model low energy excitations of a generic four band time reversal invariant electronic system with boundaries. We propose a variational energy functional for the wavefunctions which allows us to derive natural boundary conditions valid for such systems. Our formulation is particularly suited for developing a continuum theory of the protected edge/surface excitations of topological insulators both in two and three dimensions. By a detailed comparison of our analytical formulation with tight binding calculations of ribbons of topological insulators modelled by the Bernevig-Hughes-Zhang (BHZ) Hamiltonian, we show that the continuum theory with a natural boundary condition provides an appropriate description of the low energy physics. PMID- 22836560 TI - First detection and complete genome sequence of Deformed wing virus in Chilean honeybees. AB - Deformed wing virus (DWV) is one of the most common viruses affecting honey bee specimens. Although the presence of DWV has been reported in many countries, there is no data of the current situation in Chile. In this report, we detected the presence of DWV in apiaries from two different locations in central Chile. Furthermore, the genome of a Chilean DWV isolate was completely sequenced. This is the first report of the presence of a honey bee virus in Chile. PMID- 22836559 TI - Molecular characterization of the complete genome of a street rabies virus WH11 isolated from donkey in China. AB - The complete genomic sequence of a rabies virus isolate WH11, isolated from brain tissue of a rabid donkey in China, was determined and compared with other rabies viruses. This is the first Chinese street strain which was isolated from donkey and the entire length and organization of the virus was similar to that of other rabies viruses. Multiple alignments of amino acid sequences of the nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and large protein of WH11 with those of other rabies viruses were undertaken to examine the conservative degree of functional regions. Phylogenetic analysis using the complete genomic sequence of WH11 determined that this isolate is most closely related with rabies viruses previously isolated in China and the attenuated Chinese vaccine strain CTN181. PMID- 22836562 TI - [Medical malpractice: the surgeon's view]. PMID- 22836563 TI - Limb amputation for squamous cell carcinoma of the skin: factors involved in this poor evolution. AB - OBJECTIVE: To analyze retrospectively a series of cases culminating in amputation for advanced squamous cell carcinoma. METHODS: We studied eight patients with histologically confirmed squamous cell carcinoma of the skin that had limbs amputated by tumor invasion at our institution between 2005 and 2008. We evaluated the histological factors and the institutional and psychosocial factors that contributed to this unfavorable outcome. RESULTS: The mean age at diagnosis was 63 years, 37.5% of patients (three patients) had a history of abusive and continuous exposure to sunlight and six (75%) patients had other risk factors for SCC of the skin. Seven patients were diagnosed when the tumor was already larger than 2cm, and it required a large period of time (6.7 years on average) between the onset of the initial lesion and the correct histopathological diagnosis of locally advanced tumor. CONCLUSION: The unfavorable outcome (amputation) in patients with squamous cell carcinoma may be associated with aggressiveness of cancer and related comorbidities, and may also be influenced by factors such as access to public health, quality of care and patient's relationship with the disease. PMID- 22836564 TI - Changes in clinical and laboratory parameters in obese patients with type 2 diabetes mellitus submitted to Roux-en-y gastrojejunal bypass without ring. AB - OBJECTIVES: 1) To assess the changes in body weight and body mass index in grade 2 and 3 obese patients with type 2 diabetes mellitus, pre and postoperatively; 2) to assess the changes in pre and postoperative fasting blood glucose, postprandial glucose, glycated hemoglobin and insulin. METHODS: A prospective study was undertaken with 40 selected patients with grade 2 and 3 obesity and type 2 diabetes mellitus, all with indication for surgical treatment of obesity. All patients underwent Roux-en-Y gastric bypass without ring. The clinical parameters weight and body mass index were analyzed, as well as the laboratory parameters fasting blood glucose, postprandial glucose, glycated hemoglobin, and insulin. The analyses were carried out in the preoperative period and at 60 days postoperatively. Statistical analysis was conducted with Student's t and the Kolmogorov-Smirnov tests. RESULTS: Mean preoperative weight was 107.3 kg, declining to 89.5 kg postoperatively. Mean initial body mass index was 39.5 kg/m2, and 32.9 kg/m2 at 60 postoperative days. Preoperative fasting blood glucose was 132 mg/dL, which was reduced to 40.4 mg/dL, on average, postoperatively. Postprandial blood glucose was 172 mg/dL in the preoperative period and 111.6 mg/dL in the postoperative measurement. Initial glycated hemoglobin was 7%, declining to 5.7% postoperatively. Preoperative and postoperative insulin levels were 29.6 uIU/mL and 13.9 uIU/mL, respectively. The level of significance was p<0.001 for all variables. CONCLUSION: There was a statistically significant reduction in body weight and body mass index between the pre and postoperative periods, as well as in fasting blood glucose, postprandial glucose, glycated hemoglobin. PMID- 22836565 TI - Minor gastric resections with modified lymphadenectomy in early gastric cancer with negative sentinel node. AB - OBJECTIVE: To study the sentinel lymph node in early gastric cancer as a diagnostic method of unsuspected lymph node metastasis, which may allow the performance, in those with negative lymph nodes, of smaller gastric resections with limited lymphadenectomy. METHODS: We studied seven patients with early gastric cancer treated at the Hospital Universitario Clementino Fraga Filho, Federal University of Rio de Janeiro, from September 2008 to May 2011, who underwent sentinel lymph node exams, performed by intraoperative peritumoral endoscopic injection of patent blue dye. RESULTS: We found an average of three sentinel nodes per patient. The frozen biopsy of lymph nodes was negative for metastases, which allowed the realization of atypical gastric resection in three cases and antrectomy with BI reconstruction in four. The performed lymphadenectomy was modified D1. There was no operative mortality. The duration of postoperative follow-up ranged from five to 37 months, without evidence of recurrence. One patient developed a second early tumor 13 months after the initial surgery and underwent total gastrectomy. CONCLUSION: The sentinel lymph node in early gastric cancer proved to be an effective method for the evaluation of nodal metastases in seven patients and allowed for smaller gastric resections and limited lymphadenectomies. These minor procedures reduce the risk of postoperative complications, maintaining, on the other hand, the oncological radicality that is required in the treatment of gastric cancer. PMID- 22836566 TI - Postoperative abdominal CT findings in patients submitted to Roux-en-y gastric bypass without ring. AB - OBJECTIVE: To evaluate by CT scan in patients undergoing laparoscopic Roux-en-Y gastric bypass without a ring for treatment of morbid obesity that looked for medical assistance after the operation. METHODS: We studied 40 CT exams from patients attended at the radiology service with the intention to clarify abdominal complains. The patients were in post-bariatric surgical follow-up and were operated in the same hospital. We excluded patients who had undergone bariatric surgery by other surgical techniques, operated by another surgical team and the ones who did not agree with the administration of oral or intravenous iodinated contrast media and exceeding the weight limit of the examination table. RESULTS: The patients were aged from 23 to 70 years, 11 male and 29 female. There were no extra-abdominal changes, and 30 of the 40 patients had CT findings within normal limits. The presence of stenosis at the gastrojejunal anastomosis was found in one patient, internal hernias occurred in five, anastomotic leak in one and the presence of abscess occurred in three of patients. CONCLUSION: Total abdominal CT failed to inform the cause of the symptoms in 87.5% of patients seeking medical re-evaluation for symptoms of post-operative bariatric surgery. PMID- 22836567 TI - Abdominal hernia repair with mesh surrounded by fibrous tissue: experimental study in Wistar rats. AB - OBJECTIVE: To assess the efficacy and complications of surgical repair of incisional hernias by grafting of polypropylene mesh surrounded by fibrous tissue, compared to polypropylene mesh. METHODS: twenty-five male and female Wistar rats were divided into two groups: control and experimental. The 15 animals of the experimental group underwent implantation of the mesh in the subcutaneous tissue. After 21 days, the screen was removed and served to correct an induced abdominal hernia. The animals were euthanized after 21 days and submitted to macroscopic, microscopic and tension analises. The control group had undergone usual abdominal hernia repair with polypropylene mesh. RESULTS: There was a significant difference in macroscopic adhesions. The control group had a higher degree of adhesions when compared to the experiment ones (p = 0.003). We could not determine whether there were significant differences in tensile strength and microscopy. CONCLUSION: The polypropylene mesh surrounded by fibrous tissue was effective in the correction of induced abdominal hernias, with a lower degree of macroscopic adhesions when compared to polypropylene mesh. PMID- 22836568 TI - Comparative study of intraperitoneal adhesions associated with the use of meshes of polypropylene and polypropylene coated with omega-3 fatty acid. AB - OBJECTIVE: To compare intraperitoneal adhesion formation with placement of polypropylene mesh and use of lightweight polypropylene mesh coated with omega-3 fatty in rats. METHODS: Twenty-seven Wistar rats were randomized into three groups. In group 0 no mesh was placed; in group 1 we implanted a polypropylene mesh; and in group 2 there was implantation of a polypropylene mesh coated with omega-3 fatty acid. We evaluated adhesions presence and degree, breaking strength, percentage of area covered and retraction of the implanted meshes. RESULTS: Group 0 had no adhesion. Groups 1 and 2 showed adhesions on the surface of the mesh, omentum, liver and intestinal loops. There were grades 1 and 2 adhesions in 100% of the polypropylene coated group and in 60% of the polypropylene group. The remaining were grade 3 adhesions, and differed significantly between groups (p <0.001). The breaking strength of adhesions on the polypropylene coated group was significantly higher than with the polypropylene alone (p = 0.016). There was no difference in mesh retraction or area covered by the mesh. The analysis of the mesh coated with omega-3 fatty acid distribution showed adhesions preferentially located at the edges when compared to polypropylene, predominantly in the center. CONCLUSION: The type of adhesions, percentage of surface affected and retraction were not significantly different between meshes. The fatty acids coated mesh had a lower degree of adhesions and these required a greater force to rupture, possibly by their occurrence at the edges of the mesh. PMID- 22836569 TI - Experimental model of mesenteric ischemia: reperfusion by abdominal aorta clamping in Wistar rats. AB - OBJECTIVE: To develop an experimental model of global normothermic ischemia able to demonstrate the transient ischemia and reperfusion periods required for development of ischemia/reperfusion injury in the small intestines of Wistar rats by clamping the abdominal aorta. METHODS: Twenty adult male Wistar rats weighing 250-350g were randomly divided into five groups with four rats each and submitted to increasing times of ischemia (0 - 30 - 45 - 60 - 90 minutes). Within each group, except the control one, two rats underwent 60 minutes of reperfusion and two 90 minutes. After the procedures, histological analysis was conducted by measurement of areas of necrosis. RESULTS: The degree of intestinal necrosis ranged from 15% to 54% (p = 0.0004). There was progressive increase in the degree of injury related to increase in ischemic time. However, greater degrees of injury were observed in the lowest times of reperfusion. The analysis of the coefficient of variation of necrosis among the ten groups of ischemia/reperfusion showed a statistically significant difference in 15 areas, 13 related to the control group. CONCLUSION: The model was able to show the periods required for the occurrence of ischemia/reperfusion injury by aortic clamping and can serve as a basis to facilitate the development of studies that aim at understanding this kind of injury. PMID- 22836570 TI - Evaluation of liver regeneration by modulation with ischemic preconditioning after ischemia and reperfusion and partial hepatectomy. AB - OBJECTIVE: To evaluate liver regeneration modulated by ischemic preconditioning after ischemia, reperfusion and partial hepatectomy. METHODS: We used 24 Wistar rats of 12 weeks of age, which were randomly assigned into four groups: control (SHAM), hepatectomy (HEP), ischemia and reperfusion (IRG) and Ischemic Preconditioning (SRG). Analyses were made on liver enzymes ALT and AST, assessment of regeneration through the initial and final weight of the liver and the proliferation of hepatocytes by immunohistochemical analysis with Proliferating Cell Nuclear Antigen (PCNA). RESULTS: In all groups there was liver regeneration, with no statistically significant difference between them. There were significant differences in ALT and AST between groups HEP and SHAM, PRE and GIR, GIR and SHAM and PRE and SHAM (p <0.05). There were also significant differences in the PCNA labeling of the SHAM group as compared to other groups (p <0.05). CONCLUSION: The ischemic preconditioning decreased liver injury, but did not influence the regeneration up to 48 hours. PMID- 22836571 TI - Pulmonary effects after partial liver ischemia and reperfusion: experimental model. AB - OBJECTIVE: To describe an experimental model of hepatic ischemia/reperfusion injury with systemic manifestations, represented by pulmonary involvement, which may be used by those who intend to comprehend this phenomenon. METHODS: Fourteen Male Wistar rats (200-250g) were allocated to two groups, G1 with eight rats submitted only to laparotomy and G2, six rats submitted to hepatic ischemia and reperfusion. Hepatic (serum aminotransferases, mitochondrial respiration, histology) and pulmonary (Evans blue test) functions were analyzed. RESULTS: There was a statistically significant difference (p< 0.05) between G1 and G2 comparing values of AST (24,3 +/- 108 and 5406 +/- 2263), ALT (88,5 +/- 28,5 and 5169 +/- 2690), respiratory control ratio (3,41 +/- 0,17 and 1,91 +/- 0,55) and ADP/O relation (1,93 +/- 0,03 and 1,45 +/- 0,27), histological lesions (necrosis, inflammatory cells, hemorrhage, microsteatosis) and Evans blue test (194,31 +/- 53 and 491,8 +/- 141). CONCLUSION: The model has proven useful to study hepatic I/R injury. PMID- 22836572 TI - [Must all diaphragmatic penetrating wounds be sutured?]. AB - Wounds to the abdominal-thoracic region are associated with diaphragm wounds in up to 48% of cases. Lesions secondary to diaphragm trauma are present in the majority of cases, facilitating the diagnosis of diaphragm lesion and subsequent surgical management. However, diaphragm lesions are isolated in 8 to 10% of cases and because they present few or no symptoms may be overlooked. In such situations, can the diaphragm be treated conservatively without suturing? Based on experiments in animals and a review of the literature, we concluded there is currently insufficient evidence to affirm that diaphragm injuries require no suturing. PMID- 22836573 TI - [The first dual left lobe adult-to-adult liver transplantation in Brazil]. AB - Living donor liver transplantation expanded the therapeutic possibilities for liver failure patients. The necessary correct match between the liver mass donated and received sometimes limits its use. A case that was used two left liver grafts from adult living donors is reported. PMID- 22836574 TI - [Prehospital care to multiple victims with simulated trauma]. AB - OBJECTIVE: To assess the quality of prehospital care agencies conducted in Vitoria, capital of Espirito Santo State, Brazil. METHODS: We conducted a retrospective study in the archives of the League of Academic Surgery and Trauma Care of Espirito Santo (Lacates) regarding 40 victims of a simulated crash between a bus and two cars. The patients were treated by four teams: Military Fire Department of Espirito Santo, Samu 192, County Guard and Civil Defense. The performance of these teams was evaluated by Lacates, through analysis of a check list with pre-established guidelines for each victim. RESULT: The Fire Department of Espirito Santo (CBMES), which extricated victims, outlined the danger zones and carried out the screening by the method START, acted correctly in 92.5% of cases. The Samu 192 victims, which attended victims by the mnemonic method (ABCDE) in medical outposts, acted correctly in 92.5% of cases in the category Airway; 97.5% in breathing, 92.5% in circulation, 90% in Neurological Assessment, and 50% in the Exhibition and Environmental Control. The analysis showed that the ABCDE care was correct in 42.5% of cases. The transport of patients was performed correctly in 95% of cases. The County Guard secured the patency of the avenues for transportation of patients and Civil Defense successfully coordinated the work of teams involved in the command post. CONCLUSION: The triage and transport of victims have been performed satisfactorily. However, more attention should be given to exposure and hypothermia protection of victims, since this item compromised treatment. PMID- 22836575 TI - Management of hemorrhage in patients with pelvic fracture and hemodynamically unstable. PMID- 22836576 TI - [Primary esophageal lymphoma]. AB - We describe the case of a 54 year old woman seen with an esophageal mass diagnosed as a primary esophageal lymphoma. The main symptom was dysphagia of seven months duration. The treatment consisted in resection of the tumor, and reconstruction of the defect with a reversed pleural flap, followed by a chemotherapy regimen that consisted of five drugs, cyclophosphamid, prednisone, doxorubicin, rituximab and vincristine (R-CHOP). The patient developed an esophageal pleural fistula treated with pleural drainage and irrigation that closed in 45 days. Two and one half years later she is doing well and disease free. PMID- 22836577 TI - Evaluation of Canadian family practice anesthesia training programs: can the Resident Logbook help? AB - PURPOSE: Without a core curriculum for the training and evaluation of Canada's family practice anesthetists, little is known regarding the training process of these physicians. This article offers a description of the variety of cases and procedures experienced by family practice anesthesiology (FPA) residents during their training year based on records in the Resident Logbook. METHODS: Data were extracted from the Resident Logbook, an online program wherein FPA residents across Canada record their daily activities. Data were extracted for four residents from 2009/2010 and four from 2010/2011 who had recorded the largest number of patient encounters for the academic year. Medians were calculated for cases and procedures relevant to the practice of a family practice anesthetist. RESULTS: Residents in FPA use the Resident Logbook inconsistently. The trainees we selected entered a median of 1,418 encounters for 2009/2010 and 1,074 for 2010/2011. Residents appear to have most of their clinical encounters with cases and procedures relevant to FPA. There is still a need, though, to improve areas previously cited as requiring augmentation, such as trauma management and peripheral nerve blocks. CONCLUSIONS: Although FPA residents use the Resident Logbook inconsistently, the data obtained offer an initial description of the composition of the FPA training year. We believe that the Resident Logbook offers an excellent tool for furthering the goal of a standardized curriculum and assessment program for FPA training. PMID- 22836578 TI - Long-range genomic interactions epigenetically regulate the expression of a cytokine receptor. AB - Current research on the cytokine-mediated signalling towards the polarization and differentiation of a T-helper cell lineage lacks mechanistic insights on the transcriptional regulation of cytokine receptor genes. Here, we propose a new mechanism for the transcriptional regulation of the interferon gamma receptor 1 gene via long-range intrachromosomal interactions with the Ifngamma locus mediated by the protein CTCF. These interactions sustain the monoallelic expression of the differentially methylated IfngammaR1 gene and are persistent on blockade of active transcription. Our findings suggest that regulatory elements for a cytokine gene locus can also positively regulate the transcription of its receptor. PMID- 22836579 TI - NEDDylation regulates E2F-1-dependent transcription. AB - The ubiquitin-like molecule NEDD8 modifies cullin-RING ubiquitin E3 ligases. NEDD8 has been shown to have a few additional substrates, but the extent to which this modification targets non-cullins and the functional significance of such modifications remain unclear. Here, we demonstrate that the cell-cycle-regulating transcription factor E2F-1 is a substrate for NEDD8 post-translational modification. NEDDylation results in decreased E2F-1 stability, lower transcriptional activity and slower cell growth. The lysine residues in E2F-1 targeted for NEDDylation can also be methylated, pointing to a possible interplay between these modifications. These results identify a new mode of E2F-1 regulation and highlight the emerging role of NEDD8 in regulating transcription factor stability and function. PMID- 22836581 TI - The (bi)sexual brain. Science & Society Series on Sex and Science. PMID- 22836580 TI - Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue. AB - LeuT serves as the model protein for understanding the relationships between structure, mechanism and pharmacology in neurotransmitter sodium symporters (NSSs). At the present time, however, there is a vigorous debate over whether there is a single high-affinity substrate site (S1) located at the original, crystallographically determined substrate site or whether there are two high affinity substrates sites, one at the primary or S1 site and the other at a second site (S2) located at the base of the extracellular vestibule. In an effort to address the controversy over the number of high-affinity substrate sites in LeuT, one group studied the F253A mutant of LeuT and asserted that in this mutant substrate binds exclusively to the S2 site and that 1 mM clomipramine entirely ablates substrate binding to the S2 site. Here we study the binding of substrate to the F253A mutant of LeuT using ligand binding and X-ray crystallographic methods. Both experimental methods unambiguously show that substrate binds to the S1 site of the F253A mutant and that binding is retained in the presence of 1 mM clomipramine. These studies, in combination with previous work, are consistent with a mechanism for LeuT that involves a single high-affinity substrate binding site. PMID- 22836582 TI - Highly sensitive and quantitative detection of rare pathogens through agarose droplet microfluidic emulsion PCR at the single-cell level. AB - Genetic alternations can serve as highly specific biomarkers to distinguish fatal bacteria or cancer cells from their normal counterparts. However, these mutations normally exist in very rare amount in the presence of a large excess of non mutated analogs. Taking the notorious pathogen E. coli O157:H7 as the target analyte, we have developed an agarose droplet-based microfluidic ePCR method for highly sensitive, specific and quantitative detection of rare pathogens in the high background of normal bacteria. Massively parallel singleplex and multiplex PCR at the single-cell level in agarose droplets have been successfully established. Moreover, we challenged the system with rare pathogen detection and realized the sensitive and quantitative analysis of a single E. coli O157:H7 cell in the high background of 100,000 excess normal K12 cells. For the first time, we demonstrated rare pathogen detection through agarose droplet microfluidic ePCR. Such a multiplex single-cell agarose droplet amplification method enables ultra high throughput and multi-parameter genetic analysis of large population of cells at the single-cell level to uncover the stochastic variations in biological systems. PMID- 22836583 TI - Targeting autophagy: the Achilles' heel of cancer. AB - In recent years, tremendous progress has been made toward unveiling the mechanism of autophagy and its exploitation by many different cancer types. This year the American Association for the Advancement of Science held a one day Symposium on Autophagy: An Emerging Therapeutic Target in Human Disease in Vancouver, British Columbia and brought together experts in cell biology, drug discovery, and clinical translation to share their research findings and prospects. Currently, autophagy is being investigated on several fronts, from modulation of gene expression to in vivo studies, and more recently clinical trials in cancer. Key topics of discussion were determining which stage of autophagy would be the ideal target for inhibition to produce the highest impact, and which cancers or cancer subtypes would be the most sensitive to autophagy inhibitors; the answers to these questions may be a turning point in cancer therapy research. PMID- 22836584 TI - 3-Nitro-2H-chromenes as a new class of inhibitors against thioredoxin reductase and proliferation of cancer cells. AB - A series of 3-nitrochromenes were designed and synthesized. These compounds showed good inhibitory activity against thioredoxin reductase (TrxR) and the proliferation of A549 cancer cells. The structure-activity relationship analysis indicates that the 3-nitrochromene scaffold is the crucial pharmacophore for achieving good inhibitory activity. The bromo-substitutions at the 6- and 8 position of 3-nitrochromene significantly increase the inhibitory activity. PMID- 22836585 TI - Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density. AB - During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open-label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% +/- 371%, p < 0.0001) and decreased in the ALN (360% +/- 153%, p < 0.0001) and RAL (482% +/- 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% +/- 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% +/- 72%, p = 0.39), and remained elevated in the RAL combination group (179% +/- 341%, p < 0.0001). The increase in lumbar spine BMD was 5% +/- 6.3% in the ALN and 6% +/- 5.2% in the RAL combination groups compared with 2.8% +/- 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% +/- 5.3% for the ALN combination group and 1.4% +/- 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% +/- 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown. PMID- 22836586 TI - Reactivity control of C-H bond activation over vanadium-silver bimetallic oxide cluster cations. AB - Vanadium-silver bimetallic oxide cluster ions (V(x)Ag(y)O(z)(+); x=1-4, y=1-4, z=3-11) are produced by laser ablation and reacted with ethane in a fast-flow reactor. A reflectron time of flight (Re-TOF) mass spectrometer is used to detect the cluster distribution before and after the reactions. Hydrogen atom abstraction (HAA) reactions are identified over VAgO(3)(+), V(2)Ag(2)O(6)(+), V(2)Ag(4)O(7)(+), V(3)AgO(8)(+), V(3)Ag(3)O(9)(+), and V(4)Ag(2)O(11)(+) ions, in which the oxygen-centered radicals terminally bonded on V atoms are active sites for the facile HAA reactions. DFT calculations are performed to study the structures, bonding, and reactivity. The reaction mechanisms of V(2)Ag(2)O(6)(+) +C(2)H(6) are also given. The doped Ag atoms with a valence state of +1 are highly dispersed at the periphery of the V(x)Ag(y)O(z)(+) cluster ions. The reactivity can be well-tuned gradually by controlling the number of Ag atoms. The steric protection due to the peripherally bonded Ag atoms greatly enhances the selectivity of the V-Ag bimetallic oxide clusters with respect to the corresponding pure vanadium oxide systems. PMID- 22836587 TI - The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signaling and increase of iNOS expression. AB - Enteroviruses, such as coxsackieviruses of group B (CVB), are able to induce a chronic inflammation of the myocardium, which may finally lead to the loss of functional tissue, remodeling processes and the development of fibrosis, thus affecting the proper contractile function of the heart. In other fibrotic diseases like scleroderma, the prostacyclin agonist iloprost was found to inhibit the extracellular signal-regulated kinase (ERK, p44/42 MAPK), a mitogen-activated protein kinase, and consecutively, the expression of the profibrotic cytokine connective tissue growth factor (CTGF), thereby preventing the development of fibrosis. As CTGF was found to mediate fibrosis in chronic CVB3 myocarditis as well, we evaluated whether the in vivo application of iloprost is capable to reduce the development of ERK/CTGF-mediated fibrosis in enteroviral myocarditis. Unexpectedly, the application of iloprost resulted in a prolonged myocardial inflammation and an aggravated fibrosis and failed to reduce activation of ERK and expression of CTGF at later stages of the disease. In addition, viral replication was found to be increased in iloprost-treated mice. Notably, the expression of cardiac inducible nitric oxide synthase (iNOS), which is known to aggravate myocardial damage in CVB3-infected mice, was strongly enhanced by iloprost. Using cultivated bone marrow macrophages (BMM), we confirmed these results, proving that iloprost potentiates the expression of iNOS mRNA and protein in CVB3-infected and IFN-gamma stimulated BMM. In conclusion, these results suggest a critical reflection of the clinical use of iloprost, especially in patients possibly suffering from an enteroviral myocarditis. PMID- 22836588 TI - Gly143Glu polymorphism of the human carboxylesterase1 gene in an Asian population. PMID- 22836589 TI - Ru complexes of thienyl-functionalized dipyrrins as NCS-free sensitizers for the dye-sensitized solar cell. AB - We report the first case of Ru(II) dipyrrinates employed as dyes in dye sensitized solar cells. These complexes exhibit panchromatic light harvesting that results in significant DSSC current densities, rendering them promising for photovoltaic applications. Adjustment of the lowest excited state energy is required to boost the power conversion efficiency. PMID- 22836590 TI - A brief observational instrument for the assessment of infant home environment: development and psychometric testing. AB - The present paper reports on the development and the psychometric properties of a brief observational assessment of home environments for use in large-scale investigations with young infants. We generated observational items conceptually relevant for child development by two methods. First, we adapted the Infant Toddler Home Observation for Measurement of the Environment (IT-HOME) inventory for use in an exclusively observational context. Second, we added new observational items following a review of relevant literature and consulting professionals. The quality of the instrument was first evaluated in a pilot study (n = 926). In our study sample of 3406 families and their children (median age = 3.1 months, range = 1.6-6.0), exploratory factor analysis was used to identify latent constructs, Cronbach's alpha was used as a measure of internal consistency, and convergent validity was evaluated against family socio demographic characteristics. Inter-observer agreement was investigated in a sub sample of the respondents (n = 124). The results supported good psychometric properties of the instrument based on: (a) exploratory factor analysis yielding three meaningful latent constructs, (b) Cronbach's alphas ranging from alpha = 0.66 to alpha = 0.90, (c) inter-observer agreement ranging from r = 0.75 to r = 0.91, and (d) associations between the instrument and socio-demographic characteristics in the expected direction [e.g. Odds Ratio for low income = 15.24, 95% confidence interval (11.60, 20.01)]. PMID- 22836591 TI - Etiology of myofascial trigger points. AB - Myofascial pain syndrome (MPS) is described as the sensory, motor, and autonomic symptoms caused by myofascial trigger points (TrPs). Knowing the potential causes of TrPs is important to prevent their development and recurrence, but also to inactivate and eliminate existing TrPs. There is general agreement that muscle overuse or direct trauma to the muscle can lead to the development of TrPs. Muscle overload is hypothesized to be the result of sustained or repetitive low level muscle contractions, eccentric muscle contractions, and maximal or submaximal concentric muscle contractions. TrPs may develop during occupational, recreational, or sports activities when muscle use exceeds muscle capacity and normal recovery is disturbed. PMID- 22836592 TI - Alcohol consumption trajectory patterns in adult women with HIV infection. AB - HIV-infected women with excessive alcohol consumption are at risk for adverse health outcomes, but little is known about their long-term drinking trajectories. This analysis included longitudinal data, obtained from 1996 to 2006, from 2,791 women with HIV from the Women's Interagency HIV Study. Among these women, the proportion in each of five distinct drinking trajectories was: continued heavy drinking (3 %), reduction from heavy to non-heavy drinking (4 %), increase from non-heavy to heavy drinking (8 %), continued non-heavy drinking (36 %), and continued non-drinking (49 %). Depressive symptoms, other substance use (crack/cocaine, marijuana, and tobacco), co-infection with hepatitis C virus (HCV), and heavy drinking prior to enrollment were associated with trajectories involving future heavy drinking. In conclusion, many women with HIV change their drinking patterns over time. Clinicians and those providing alcohol-related interventions might target those with depression, current use of tobacco or illicit drugs, HCV infection, or a previous history of drinking problems. PMID- 22836593 TI - Membrane protein distribution in composite polymer-lipid thin films. AB - We present a model system to demonstrate that the positioning of biomolecules (membrane proteins) in a nonnative, complex thin film environment can be regulated by the phase behavior of film components. Partial separation between an amphiphilic polymer and a lipid drives the protein to a fluid phase, mechanically more similar to a cellular bilayer. PMID- 22836594 TI - Effects of LPS on P2X3 receptors of trigeminal sensory neurons and macrophages from mice expressing the R192Q Cacna1a gene mutation of familial hemiplegic migraine-1. AB - A knockin (KI) mouse model with the R192Q missense mutation in the Cacna1a gene commonly detected in familial hemiplegic migraine was used to study whether trigeminal ganglia showed a basal inflammatory profile that could be further enhanced by the lipopolysaccharide (LPS) toxin. Adenosine-5'-triphosphate (ATP) gated purinergic ionotropic receptor 3 (P2X3) currents expressed by the large majority of trigeminal sensory neurons were taken as functional readout. Cultured R192Q KI trigeminal ganglia showed higher number of active macrophages, basal release of tumor necrosis factor alpha (TNFalpha), and larger P2X3 receptor currents with respect to wild type (WT) cells. After 5 h application of LPS in vitro, both WT and R192Q KI cultures demonstrated significant increase in macrophage activation, very large rise in TNFalpha mRNA content, and ambient protein levels together with fall in TNFalpha precursor, suggesting potent release of this inflammatory mediator. Notwithstanding the unchanged expression of P2X3 receptor protein in WT or R192Q KI cultures, LPS evoked a large rise in WT neuronal currents that recovered faster from desensitization. Basal R192Q KI currents were larger than WT ones and could not be further augmented by LPS. These data suggest that KI cultures had a basal neuroinflammatory profile that might facilitate the release of endogenous mediators (including ATP) to activate constitutively hyperfunctional P2X3 receptors and amplify nociceptive signaling by trigeminal sensory neurons. PMID- 22836595 TI - Cytotoxicity of quantum dots assay on a microfluidic 3D-culture device based on modeling diffusion process between blood vessels and tissues. AB - In this work, a novel quantum dot (QD) cytotoxicity assay platform on a microfluidic three-dimensional (3D) culture device via imitating the diffusion process between blood vessels and tissues was developed. The device is composed of a main channel and two sets of cell culture chambers. The cell culture chambers were located at different distances from the main channel and were divided into "close chambers" and "far chambers". HepG2 cells were cultured in an agarose matrix under 3D conditions and kept at high viability for at least three days. Fluorescein sodium and fluorescein isothiocyanate conjugated to bovine serum albumin (FITC-BSA) were used as models to demonstrate the diffusion process between main channel and cell culture chambers. QD cytotoxicity was evaluated by determining cell apoptosis, intracellular reactive oxygen species (ROS) and glutathione (GSH) with specific fluorescence probes. Cell autophagy inhibitor 3 methyladenine (3-MA) could reduce cell apoptosis at low concentrations of QDs, which proves that cell autophagy plays a key role in QD cytotoxicity. The effect of a series of 3-MA solutions on cell apoptosis at QD concentration of 40 MUg mL( 1) was investigated, which showed that the percentage of cell apoptosis decreased ~15% from 0 to 12 mM 3-MA. The device shows potential as a high-throughput, low cost and time-saving platform and constructs a more vivid biomimetic microenvironment for the QD cytotoxicity study. PMID- 22836596 TI - Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials--common patterns in TRITON, RECORD, and PLATO? AB - Central adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (MI) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated MI's (CAMI's) from the official trial publication with the site-reported MI (SRMI's) count from the Food and Drug Administration's secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI's by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast, in the RECORD trial, the CAMI count was less than the SRMI count (from 24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this case diminishing cardiovascular hazards in favour of rosiglitazone. In conclusion, central adjudication in the TRITON, the RECORD, and the PLATO trial turned out to have a critical impact on study outcomes. Trial publications should in the future include site-reported major efficacy and safety endpoints to preserve data integrity. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site reported events influencing the results of a major clinical trial. PMID- 22836597 TI - The neglected cranial nerve: nervus terminalis (cranial nerve N). AB - The nervus terminalis (NT; terminal nerve) was clearly identified as an additional cranial nerve in humans more than a century ago yet remains mostly undescribed in modern anatomy textbooks. The nerve is referred to as the nervus terminalis because in species initially examined its fibers were seen entering the brain in the region of the lamina terminalis. It has also been referred to as cranial nerve 0, but because there is no Roman symbol for zero, an N for the Latin word nulla is a better numerical designation. This nerve is very distinct in human fetuses and infants but also has been repeatedly identified in adult human brains. The NT fibers are unmyelinated and emanate from ganglia. The fibers pass through the cribriform plate medial to those of the olfactory nerve fila. The fibers end in the nasal mucosa and probably arise from autonomic/neuromodulatory as well as sensory neurons. The NT has been demonstrated to release luteinizing-releasing luteinizing hormone and is therefore thought to play a role in reproductive behavior. Based on the available evidence, the NT appears to be functional in adult humans and should be taught in medical schools and incorporated into anatomy/neuroanatomy textbooks. PMID- 22836598 TI - Out-of-field dose measurements in a water phantom using different radiotherapy modalities. AB - This investigation focused on the characterization of the lateral dose fall-off following the irradiation of the target with photons, protons and carbon ions. A water phantom was irradiated with a rectangular field using photons, passively delivered protons as well as scanned protons and carbon ions. The lateral dose profile in the depth of the maximum dose was measured using an ion chamber, a diamond detector and thermoluminescence detectors TLD-600 and TLD-700. The yield of thermal neutrons was estimated for all radiation types while their complete spectrum was measured with bubble detectors during the irradiation with photons. The peripheral dose delivered by photons is significantly higher compared to both protons and carbon ions and exceeds the latter by up to two orders of magnitude at distances greater than 50 mm from the field. The comparison of passive and active delivery techniques for protons shows that, for the chosen rectangular target shape, the former has a sharper penumbra whereas the latter has a lower dose in the far-out-of-field region. When comparing scanning treatments, carbon ions present a sharper dose fall-off than protons close to the target but increasing peripheral dose with increasing incident energy. For photon irradiation, the contribution to the out-of-field dose of photoneutrons appears to be of the same order of magnitude as the scattered primary beam. Charged particles show a clear supremacy over x-rays in achieving a higher dose conformality around the target and in sparing the healthy tissue from unnecessary radiation exposure. The out-of-field dose for x-rays increases with increasing beam energy because of the production of biologically harmful neutrons. PMID- 22836599 TI - Genome dynamics in three different geographical isolates of white spot syndrome virus (WSSV). AB - White spot syndrome virus (WSSV), the sole member of the monotypic family Nimaviridae, is considered an extremely lethal shrimp pathogen. Despite its impact, some essential biological characteristics related to WSSV genome dynamics, such as the synonymous codon usage pattern and selection pressure in genes, remain to be elucidated. The results show that compositional limitations and mutational pressure determine the codon usage bias and base composition in WSSV. Furthermore, different forces of selective pressure are acting across various regions of the WSSV genome. Finally, this study points out the possible occurrence of two major recombination events. PMID- 22836600 TI - Effect of different training workload on overhead throwing performance with different weighted balls. AB - The purpose of this study was to investigate the effect of a single and a double training workload with 3-kg medicine ball on the throwing speed in 2-handed overhead throwing movement. Second, what the effect of training with 3-kg medicine balls had on throwing speed with other ball weights. Forty high school students (age 15.9 +/- 1.0 year, mass 60.9 +/- 9 kg, height 1.68 +/- 0.08 m), divided into 3 speed-matched groups, participated in the study. The first group was a control group and did not train any throwing program regimen, whereas the other 2 groups trained overhead throwing with a single (3 series of 6 throws with a 3-kg medicine ball) or double training workload (6 series of 6 throws with a 3 kg medicine ball) for 6 weeks. Throwing speed with 0.35-, 0.45-, 1-, and 3-kg medicine balls was tested before and after a training period of 6 weeks with 2 sessions per week. A significant (p <= 0.05) increase in throwing speed was found after the 6-week training period with the 0.35- (5.1%), 1- (3.5%), and 3-kg medicine balls (5.2%) for both training groups, but not with the 0.45-kg ball (0.6%). This increase was mainly caused by the increase of the double workload group. This indicates that training workload is of importance in these subjects for enhancement of ball throwing performance and in designing training programs. Furthermore, that throwing with high enough training volume of throws with a 3-kg medicine ball also can increase ball speed with lighter balls. PMID- 22836601 TI - Influence of game format and number of players on heart rate responses and physical demands in small-sided soccer games. AB - The aim of the study was to examine the extent to which changing the game format (possession play vs. regulation goals and goalkeepers vs. small goals only) and the number of players (3 vs. 3, 5 vs. 5 and 7 vs. 7) influenced the physiological and physical demands of small-sided games (SSGs) in soccer in semiprofessional players. Fourteen semiprofessional male soccer players were monitored with global positioning system and heart rate devices. Heart rate, player load, distance covered, running speed, and the number of accelerations were recorded for 9 different SSGs. The results show that changes both in game format and the number of players affect the players' physiological and physical demands. Possession play places greater physiological and physical demands on players, although reducing the number of players only increases the physiological load. In the 7 vs. 7 games, changing the game format did not alter the heart rate responses. Finally, in the possession play format, changing the number of players did not produce significant differences in heart rate responses, although physical demands did decrease in line with a reduction in the number of players. These results should help coaches to understand how modifying different aspects of SSGs has a differential effect on the players' physiological and physical demands. Moreover, coaches in semiprofessional and amateur teams have now consistent information to design and optimize their training time in mixing the technical, tactical, and physical aspects. PMID- 22836602 TI - The effect of post-match alcohol ingestion on recovery from competitive rugby league matches. AB - This study investigated the effects of alcohol ingestion on lower-body strength and power and physiological and cognitive recovery after competitive Rugby League matches. Nine male Rugby players participated in 2 matches, followed by 1 of 2 randomized interventions, a control or alcohol ingestion session. Four hours post match, participants consumed either beverages containing a total of 1 g of ethanol per kilogram bodyweight (vodka and orange juice; ALC) or a caloric and taste-matched nonalcoholic beverage (orange juice; CONT). Before the match, immediately post-match, 2 hours post-, and 16 hours post-match measures of countermovement jump (CMJ); maximal voluntary contraction (MVC); voluntary activation (VA); and damage and stress markers of creatine kinase (CK), C reactive protein (CRP), cortisol, and testosterone analyzed from venous blood collection; and cognitive function (modified Stroop test) were determined. Alcohol resulted in large effects for decreased CMJ height (-2.35 +/- 8.14% and 10.53 +/- 8.36% decrement for CONT and ALC, respectively; p = 0.15, d = 1.40), without changes in MVC (p = 0.52, d = 0.70) or VA (p = 0.15, d = 0.69). Furthermore, alcohol resulted in a significant slowing of total time in a cognitive test (p = 0.04, d = 1.59) while exhibiting large effects for detriments in congruent reaction time (p = 0.19, d = 1.73). Despite large effects for increased cortisol after alcohol ingestion during recovery (p = 0.28, d = 1.44), post-match alcohol consumption did not unduly affect testosterone (p = 0.96, d = 0.10), CK (p = 0.66, d = 0.70), or CRP (p = 0.75, d = 0.60). It seems that alcohol consumption during the evening after competitive rugby matches may have some detrimental effects on peak power and cognitive recovery the morning after a Rugby League match. Accordingly, practitioners should be aware of the potential associated detrimental effects of alcohol consumption on recovery and provide alcohol awareness to athletes at post-match functions. PMID- 22836603 TI - Similar electromyographic activities of lower limbs between squatting on a reebok core board and ground. AB - Reebok Core Boards (RCB) used as a platform in training provide an unstable environment for resistance training. The objective of this study was to examine the effect of unstable surface on muscle electromyographic (EMG) activities during a deep squat task. Thirteen male subjects participated in the study. Electromyographic activities of soleus (SO), vastus lateralis (VL), vastus medialis (VM), rectus femoris (RF), biceps femoris (BF), gluteus maximus (GMa), gluteus medius (GMe), and upper lumbar erector spinae (ULES) muscles were collected when subjects were performing a deep squat task on a RCB and ground with different weight loads (body weight, 30%RM (repetition maximum) and 60%RM). No significant difference was observed for all muscle EMG between unstable and stable surface during all weight load conditions (p > 0.05). Muscle EMG significantly increased when the weight load increased (p < 0.05). Similar muscle activities were observed when subjects performed a deep squat task on a stable and unstable surface. Simply applying unstable surface might not provide extra stimulation to the superficial muscles during squatting in resistance-trained students. PMID- 22836604 TI - The relationship between the cortisol awakening response, mood states, and performance. AB - This study examined the variation in the diurnal profile of cortisol, with an emphasis on the cortisol awakening response (CAR), in relation to mood states and performance during a professional swimming contest. Eleven athletes were examined during 2 consecutive days of competition and during a recreated event 2 weeks later that was matched to the time of the day and day of the week of the competition. On each day, salivary cortisol was determined upon awakening (07:00 hours); 30 and 60 minutes post-awakening; immediately before warming up for competition (16:00 hours); and 5 minutes (18:20 hours), 20 minutes (18:40 hours), and 40 minutes (19:00 hours) after competition. Psychometric instruments included the Profile of Mood States and self-reports of performance. Cortisol awakening responses did not differ between days of competition and control and were not related to performance on any day. However, a difference was observed in the concentration of cortisol before and after the contest between the competition and control days. Higher levels of cortisol before competition were associated with feelings of tension, anxiety, and hostility. The perceived demands of the day ahead might not produce the same magnitude of variation in the CAR in well trained men. Explanations for this probably include better coping mechanisms and responses to the phase and time of competition. PMID- 22836605 TI - Visual gaze behavior of near-expert and expert fast pitch softball umpires calling a pitch. AB - The purpose of this study was to examine the difference in visual gaze behavior between near expert (NE) and expert (E) umpires in a simulated pitch-hit situation in fast pitch softball. An Applied Science Laboratory mobile eye tracker was worn by 4 NE and 4 E fast pitch umpires and recorded their visual gaze behavior while following pitches (internal view). A digital camera located behind the pitcher recorded the external view of the pitcher, hitter, catcher, and umpire actions for each pitch. The internal and external video clips of 10 representative pitches--5 balls and 5 strikes--were synchronized and displayed in a split screen and were then coded for statistical analyses using Quiet eye solution software. Analysis of variance and multivariate analysis of variance statistical analyses of the umpires' gaze behavior during onset, duration, offset, and frequency (fixation/pursuit tracking, saccades, and blinks) were conducted between and within the 5 stages (pitcher's preparation, delivery and release, ball in flight, and umpire call) by umpire's skill level. Significant differences (p < 0.05) observed for combined gaze behavior frequency, type of gaze by phase, quiet eye duration and onset, and ball duration tracking indicated that E umpires' visual control was more stable and economical than NE umpires. Quiet eye significant results indicated that E umpires had an earlier onset (mean = 50.0 +/- 13.9% vs. 56 +/- 9.5%) and longer duration (mean = 15.1 +/- 11.3% vs. 9.3 +/- 6.5%) of the pitcher's release area than NE umpires. These findings suggest that gaze behavior of expert fast pitch umpires was more economical, fixated earlier and for a longer period of time on the area where the ball would be released, and was able to track the ball earlier and for a longer period of time. PMID- 22836606 TI - Effects of respiratory muscle training on performance in athletes: a systematic review with meta-analyses. AB - The purpose of this study was to perform a systematic review to determine if respiratory muscle training (RMT) improves sport performance and respiratory muscle strength and endurance. Methodology followed the Cochrane Collaboration protocol. MEDLINE, CINAHL, SPORTDiscus, PEDro, EMBASE, EBM reviews, and COCHRANE electronic databases were searched until July 2011. Articles were included if: (a) participants were athletes; (b) RMT was compared with sham or control in a randomized controlled design and included outcomes of respiratory muscle and sport performance; and (d) published in English. Quality assessment using PEDro and data abstraction was performed by 2 authors. Outcomes evaluated were measures of sport performance, exercise capacity, spirometry, and respiratory muscle strength and endurance. Meta-analyses were performed on outcomes reported in 2 or more papers. Results of this systematic review revealed that of the 6,923 citations retrieved from the search strategy, 21 met the inclusion criteria. Meta analyses demonstrated a significant positive effect of RMT on sport performance outcomes of time trials, exercise endurance time, and repetitions on Yo-Yo tests. Inspiratory muscle strength and endurance improved in most studies, which in part, was dependent on the type of RMT employed. Determination of the type of athlete that may benefit most from RMT was limited by small sample sizes, differing RMT protocols, and differences in outcome measures across studies. In conclusion, RMT can improve sport performance. Closer attention to matching the ventilatory demands of RMT to those required during athletic competition and more aggressive progression of training intensity may show greater improvements in future studies. PMID- 22836607 TI - Validation of a new method to measure contact and flight times during treadmill running. AB - The purpose of this study was to validate a new method to measure contact and flight times during treadmill running and to test its reliability and sensitivity. Fifteen well-trained runners performed 7 sets of running at different speeds (from 10 to 22 km.h). Contact and flight times were simultaneously recorded by a high-speed video system (gold standard method) and a new method based on laser technology (SportJump System Pro). Athletes were classified according to their foot strike pattern (rearfoot vs. midfoot and forefoot). The new method overestimated the contact time and underestimated the flight time with respect to the gold standard method (p < 0.001). However, relationships and intraclass correlation coefficients (ICCs) between both systems were very strong (r and ICC > 0.99, p < 0.001). Contact time differences between the 2 systems depended on running speed (p < 0.001) but not on foot strike pattern or runners' body mass. This allowed to correct the differences in contact time and flight time. The new method was sensitive for detecting small differences in contact time (<20 ms) when the running speed increased and when the type of foot strike patterns changed. Additionally, a low intraindividual step variability (coefficient of variation = 2.0 +/- 0.5%) and high intra- (ICC = 0.998) and interobserver (ICC = 0.977) reliability were shown. In conclusion, the new method was validated, being reliable and sensitive for detecting small differences in contact and flight times during treadmill running. Therefore, it could be used to compare biomechanical variables between groups in cross sectional studies and to verify the influence of some independent variables (i.e., training, running economy, or performance) on running biomechanics. PMID- 22836608 TI - Characteristics of anterior shoulder instability and hyperlaxity in the weight training population. AB - Despite case reports implicating anterior instability (AI) as an etiological source of shoulder pain among weight-training (WT) participants, a paucity of case-controlled evidence exists to support this premise. The purpose of this study was to determine if WT participants have clinical characteristics of AI and hyperlaxity. Additionally, we investigated the role of exercise selection. One hundred fifty-nine healthy male participants (mean age 28 years) were recruited and included 123 individuals who engaged in WT a minimum of 2 days per week and 36 controls with no history of WT participation. Before testing, participants completed a questionnaire summarizing their training patterns. Upon completing the questionnaire, 3 reliable and valid tests used to identify clinical characteristics of AI were performed on both groups and included the load and shift, apprehension, and relocation maneuvers. Load and shift test results identified significantly greater anterior glenohumeral joint hyperlaxity in the WT group compared with controls (p = 0.004). The presence of positive apprehension (p < 0.001) and relocation (p < 0.001) tests were also significantly greater in the WT group. A significant association existed between performance of exercises that require the "high-five" position (behind-the-neck latissimus pull downs and military press) and clinical characteristics of AI. Conversely, an inverse association between performance of external rotator strengthening and clinical characteristics of AI existed. Findings from this study suggest that individuals participating in WT may be predisposed to AI and hyperlaxity. Modification of exercises requiring the high-five position, as well as efforts to strengthen the external rotators, may serve as a useful means to mitigate characteristics associated with AI and hyperlaxity. Future intervention-based trials are needed to investigate a causative effect of exercises. PMID- 22836609 TI - Subtarsal eyelid examination using an oblique slit lamp mirror in cases of eyelid shortening. PMID- 22836611 TI - Synthesis and pharmacological investigation of 2-(4-dimethylaminophenyl)-3,5 disubstituted thiazolidin-4-ones as anticonvulsants. AB - A new series of 2-(4-dimethylaminophenyl)-3-substituted thiazolidin-4-one-5-yl acetyl acetamides/benzamides were synthesized by the nucleophilic substitution of 3-substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetylchloride with acetamide and benzamide. The starting material 3-substituted-2-(4 dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetylchloride was synthesized from 3 substituted-2-(4-dimethylaminophenyl)-thiazolidin-4-one-5-yl-acetic acid, which in turn was prepared by one-pot reaction of amino component, p-dimethylamino benzaldehyde and mercapto succinic acid. The title compounds were investigated for their anticonvulsant activities; among the test compounds, compound 2-(4 dimethylaminophenyl)-3-phenylamino-thiazolidine-4-one-5-yl-acetylbenzamide (14) emerged as the most active compound of the series and as moderately more potent than the reference standard diazepam. PMID- 22836612 TI - Neutrophil extracellular trap in human diseases. AB - NETosis is a unique death pathway that differs from apoptosis and necrosis and depends on the generation of reactive oxygen species (ROS) by NADPH oxidase. During this process, neutrophil extracellular traps (NETs) are created. NETs are extracellular structures composed of chromatin and variety of proteins from cells granules that bind and kill microorganisms. Recently, novel functions of NET have been proposed. It seems that neutrophil traps play an essential role during autoimmunity. They can induce and exacerbate diseases based on immune system malfunction. PMID- 22836613 TI - Tiotropium increases PPARgamma and decreases CREB in cells isolated from induced sputum of COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and chronic inflammation of airways and lung parenchyma. Our aim was to assess two important elements of intracellular signaling involved in regulation of inflammation in COPD in patients subjected to long-acting beta2 agonist or long-acting beta2-agonist plus long-acting antimuscarinic: peroxisome proliferator-activated receptor gamma (PPARgamma) protein, which has antiinflammatory and immunomodulatory properties and cAMP response element binding protein (CREB) and activated (CREB-P) protein which has histone acetyltransferase activity and increases histone acetylation and transcriptional activation of chromatin. Twenty one stable COPD patients (18 males and 3 females, mean age 65 years) receiving 12 MUg B.I.D formoterol were assayed before and after 3 month add-on therapy, consisting of 18 MUg Q.D. tiotropium. In all patients, sputum induction, spirometry, lung volumes, and DLCO were performed before and after therapy. Sputum cells were isolated and processed to isolate cytosolic and nuclear fractions. PPARgamma, CREB, or CREB-P proteins were quantified in subcellular fractions using Western blot. Tiotropium add-on therapy improved respiratory parameters: FEV1 and lung volumes. After therapy mean expression of PPARgamma in cell nuclei was significantly increased by about 180%, while CREB and phosphorylated CREB levels in cytosol and nuclei were decreased by about 30%. Our data show that the mechanism whereby tiotropium reduces exacerbations may be associated not only with persistent increase in airway functions and reduced hyperinflation mediated by muscarinic receptors, but also with possible anti-inflammatory effects of the drug, involving increased PPARgamma and decreased CREB signaling. PMID- 22836614 TI - Expression of Ki-67, Bcl-2, Survivin and p53 Proteins in Patients with Pulmonary Carcinoma. AB - Apoptosis is the fundamental process necessary for eliminating damaged or mutated cells. Alterations in the apoptotic pathway appear to be key events in cancer development and progression. Bcl-2 is the key member of the Bcl-2 family of apoptosis regulator proteins with anti-apoptotic effects. Survivin acts as an inhibitor of apoptosis as well and has been implicated in both inhibition of apoptosis and mitosis regulation. p53 is one of the tumor suppressor proteins, prevents tumor formation through cell cycle blocking and eliminates damaged cells via the activation of apoptosis. The Ki-67 protein is a cellular marker for proliferation. To investigate the possible interactions of the aforementioned proteins, we examined their expression in 76 patients with diagnosed lung cancer using immunohistochemical visualisation. Ki-67 protein was expressed in the cancer cells of all patients with small cell lung cancer (SCLC). We found a negative correlation between survivin and p53 expression. A decreased intensity of survivin expression and fewer cells positive for survivin (66.7%) in SCLC in comparison with other lung cancer types (98.0%) was detected. Reversely, expression of Bcl-2 was found in more than 90% of cases with SCLC. We hypothesize that high expression and intensity of Bcl-2 protein could be a factor behind a bad prognosis in SCLC. PMID- 22836615 TI - Indacaterol add-on therapy improves lung function, exercise capacity and life quality of COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is a progressive, inflammatory condition, involving airways and lung parenchyma. The disease leads to airflow limitation, and pulmonary hyperinflation, resulting in dyspnea, decreased exercise tolerance, and impaired quality of life. COPD pharmacotherapy guidelines are based on a combination of long-acting beta2-agonists (LABA), long-acting antimuscarinic agents (LAMA) and methyloxantins. Recently, indacaterol, ultralong acting beta2-agonist, has been introduced. The aim of our study was to assess the impact of indacaterol add-on therapy on lung function, exercise tolerance and quality of life of COPD patients. Thirty four COPD patients, receiving stable bronchodilator therapy were randomly allocated into two arms of add-on treatment (1:1 - indacaterol:placebo) for 3 months. Indacaterol replaced LABA in all patients receiving LABA. Spirometry, lung volumes, DLCO, St George's Respiratory Questionnaire (SGRQ) and 6 min Walk Distance (6MWD) were performed before and after therapy. We found that in the indacaterol group FEV1 did not changed significantly. However, there were significant improvements in ERV, 6MWD, and 6MWD-related dyspnea score. We also found that the degree of desaturation before and after 6MWD, and fatigue levels significantly improved in the indacaterol group. The patients' quality of life also changed favorably in the indacaterol treatment arm. We conclude that the add-on therapy with indacaterol exerts positive effects in COPD patients. PMID- 22836616 TI - Rapid DNA extraction protocol for detection of alpha-1 antitrypsin deficiency from dried blood spots by real-time PCR. AB - The dried blood spot (DBS) specimens have been successfully employed for the large-scale diagnostics of alpha1-antitrypsin (AAT) deficiency as an easy to collect and transport alternative to plasma/serum. In the present study we propose a fast, efficient, and cost effective protocol of DNA extraction from dried blood spot (DBS) samples that provides sufficient quantity and quality of DNA and effectively eliminates any natural PCR inhibitors, allowing for successful AAT genotyping by real-time PCR and direct sequencing. DNA extracted from 84 DBS samples from chronic obstructive pulmonary disease patients was genotyped for AAT deficiency variants by real-time PCR. The results of DBS AAT genotyping were validated by serum IEF phenotyping and AAT concentration measurement. The proposed protocol allowed successful DNA extraction from all analyzed DBS samples. Both quantity and quality of DNA were sufficient for further real-time PCR and, if necessary, for genetic sequence analysis. A 100% concordance between AAT DBS genotypes and serum phenotypes in positive detection of two major deficiency S- and Z- alleles was achieved. Both assays, DBS AAT genotyping by real-time PCR and serum AAT phenotyping by IEF, positively identified PI*S and PI*Z allele in 8 out of the 84 (9.5%) and 16 out of 84 (19.0%) patients, respectively. In conclusion, the proposed protocol noticeably reduces the costs and the hand-on-time of DBS samples preparation providing genomic DNA of sufficient quantity and quality for further real-time PCR or genetic sequence analysis. Consequently, it is ideally suited for large-scale AAT deficiency screening programs and should be method of choice. PMID- 22836617 TI - CRAC ion channels and airway defense reflexes in experimental allergic inflammation. AB - Calcium release-activated calcium channels (CRAC) play unambiguous role in secretory functions of mast cells, T cells, and eosinophils. Less knowledge exists about the role of CRAC, widely distributed in airway smooth muscle (ASM) cells, in airway contractility. The presented study seeks to determine the possible participation of CRAC in ASM-based inflammatory airway disorders in guinea pigs. The acute and long-term administration (14 days) of the CRAC antagonist 3-fluoropyridine-4-carboxylic acid was used to examine the ASM contractility and associated reflexes in the guinea pig model of allergic airway inflammation by the following methods: (i) evaluation of specific airway resistance in vivo; (ii) evaluation of the contractile response of isolated ASM strips in vitro; and (iii) citric acid-induced cough reflex; (iv) measurement of exhaled NO levels (E(NO)). Allergic airway inflammation was induced by repetitive exposure of guinea pigs to ovalbumin (10(-6) M). The CRAC antagonist administered in a single dose to guinea pigs with confirmed allergic inflammation significantly reduced the cough response and the airway resistance, which corresponded with the findings in vitro. Long-term application of the CRAC antagonist had more strongly expressed effects. The results confirm the role of CRAC in the pathophysiology of experimental animal asthma and have a potential meaning for anti-asthma therapy. PMID- 22836618 TI - Experimental model of allergic asthma. AB - The aim of the study was to prepare and evaluate the experimental model of allergic asthma. Changes in chough reflex, bronchoconstriction and the degree of inflammation were studied in ovalbumin (OVA) sensitized guinea pigs after 0, 7, 14, 21 days of exposure. The cough reflex was induced by citric acid inhalation in conscious animals in a double chamber body plethysmograph. Tracheal smooth muscle reactivity was assessed by examining the in vitro response to histamine (H) (10(-8)-10(-3) mol/l) and in vivo to H nebulization (10(-6) mol/l). BALF levels of IL-4, IL-5 and the eosinophil count were used as parameters of airway inflammation. After 7 days of OVA sensitization, there was an increase in tracheal smooth muscle contractility in vitro to cumulative concentration of H and an increase in cough parameters. After 14 days of OVA sensitization, there was a further increase in tracheal smooth muscle contractility to H, an increase in airway resistance, and a small increase in cough parameters. After 21 day of OVA sensitization, cough parameters were significantly reduced, airway resistance after H inhalation was increased, and there were significant increases in IL-4, IL-5, and eosinophils in BALF. In conclusion, progress in asthmatic inflammation during 21-day OVA sensitization caused a gradual increase in inflammatory mediators, a decline in cough reflex, and enhanced bronchoconstriction. This experimental model of allergic asthma can be used for pharmacological modulations of defense reflexes and inflammation. PMID- 22836619 TI - Effects of selective inhibition of PDE4 and PDE7 on airway reactivity and cough in healthy and ovalbumin-sensitized guinea pigs. AB - Phosphodiesterases (PDEs) are enzymes responsible for degradation of cAMP and cGMP in cells. Thus, PDE inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim of the present study was to evaluate the effects of selective PDE4 (rolipram, ROL) and PDE7 inhibitors (BRL50481, BRL) on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs. The drugs tested were administered intraperitoneally to male guinea pigs once daily for 7 days - ROL 1 mg/kg, BRL 1 mg/kg, and ROL+BRL 0.5 mg/kg. Double chamber whole body plethysmography was used for the evaluation of citric acid (0.6 M)-induced cough and specific airway resistance. An organ bath method was used for the measurement of tracheal and lung tissue strip contractions evoked by cumulative doses (10(-8) 10(-3) mol/L) of acetylcholine (ACH) and histamine (HIS). In healthy guinea pigs, the only significant relaxation was observed after ROL in ACH-induced contractions in vitro and the effect on cough was negligible. In ovalbumin sensitized animals, more pronounced in vitro relaxing effects of BRL in HIS induced contractions and of combination (ROL+BRL) in ACH-induced contractions were observed, with similar results in vivo, and no significant change in the number of cough efforts was observed in any of the groups tested. The results suggest that PDE4 and PDE7 inhibitors have stronger anti-inflammatory effects compared with direct effects on smooth muscle and cough, with a potential benefit of their concomitant administration. PMID- 22836620 TI - Naloxone blocks suppression of cough by codeine in anesthetized rabbits. AB - Opioid receptors which are involved in cough generation are abundantly expressed in the brainstem. Codeine is a potent MU-opioid receptor agonist. In the present study we examined the effects of naloxone, a MU-opioid receptor antagonist, on mechanically-induced tracheobronchial cough and on the cough suppressing effect of codeine in six pentobarbitone anesthetized spontaneously breathing rabbits. A single dose of naloxone (0.4 mg/kg) followed by a single dose of codeine (7 mg/kg) were administered intravenously. The number and amplitude of cough and sneeze reflexes were examined sequentially; before and after naloxone, and then after codeine. We found that neither did naloxone alone nor codeine given after prior naloxone pretreatment appreciably affect coughing or sneezing. Likewise, there were no significant differences in the diaphragm and abdominal muscles electromyographic moving averages, or the inspiratory and expiratory esophageal pressure amplitudes. However, we detected a tendency for the rise in expiratory motor drive during coughing and sneezing after injection of naloxone. The respiratory rate was significantly higher after naloxone in comparison with control (P < 0.001). No significant differences in arterial blood pressure were observed. We conclude that the failure of codeine to suppress the cough reflex on the background of naloxone pretreatment confirms the involvement of MU-opioid mechanism in the central antitussive effect of codeine. PMID- 22836621 TI - Influence of sublingual immunotherapy on the expression of Mac-1 integrin in neutrophils from asthmatic children. AB - Asthma can be effectively treated with sublingual immunotherapy. The influence of -sublingual immunotherapy on the function of granulocytes in asthmatic patients is largely unknown. Mac-1 integrin is a transmembrane protein containing alpha (CD11b) and beta (CD18) chains. High expression of the complex is found on the surface of neutrophils, NK cells, and macrophages. CD11b/CD18 may bind to CD23, ICAM-1, ICAM-2, and ICAM-4. It plays a crucial role in diapedesis of neutrophils. The aim of the present study was to assess Mac-1 expression on neutrophils from asthmatic children before and after sublingual immunotherapy. Twenty five children aged of 8.1 +/- 3.1 suffering from atopic asthma and allergic rhinitis, shortlisted for specific immunotherapy, served as the study group. Fifteen healthy individuals, aged 9.8 +/- 3.4, served as a control group. The assessment of CD11b and CD18 expression on cells from peripheral blood was performed with a flow cytometer. The tests were performed before and after 12 months of sublingual immunotherapy. In the asthmatic children, 98.08 (90.79-99.12)% of Mac-1 positive neutrophils were detected. The group was divided into two subgroups: of more than 98% and less than 95% of neutrophils with CD11b/CD18 expression in the sample. After immunotherapy, the percentage of Mac-1 positive granulocytes increased to 99.60 (99.29-99.68)%, p = 0.01. In the control group, 90.56 (87.08-88.86)% granulocytes were Mac-1 positive, p = 0.002. We conclude that sublingual immunotherapy strongly influences the function of the immunological system, including Mac-1 expression on neutrophils. PMID- 22836622 TI - L-arginine supplementation and experimental airway hyperreactivity. AB - The interest in L-arginine metabolism was triggered primarily by the discovery of nitric oxide (NO) synthesis in mammals and its remarkable biological roles. The real role of L-arginine in the airway hyperreactivity (AHR) has not been established yet. Therefore, we studied whether supplementation of L-arginine can influence the experimental AHR evoked by two different triggers - allergen and exogenous irritant (toluene vapours). Male TRIK strain guinea pigs were used in the study. We used two patterns of pretreatment with L-arginine in vivo, short- and long-term, in a dose of 300 mg/kg administered i.p., after which we studied reactivity of airway smooth muscles in vitro. Pretreatment with L-arginine for 3 days decreased the airway smooth muscle reactivity induced by toluene vapour, whereas pretreatment for 17 days was without any additional effect on smooth muscle reactivity. The short-term pretreatment in ovalbumin-induced hyperreactivity caused an increase in airway smooth muscle reactivity to lower concentrations of both bronchoconstrictors. On the other side, this pretreatment significantly decreased smooth muscle reactivity to high concentrations of both bronchoconstrictors. Supplementation of L-arginine resulted in a modification of the airway smooth muscle response. The effect of supplementation was different depending on the AHR trigger, airway region and pretreatment duration. The results also underscore the importance of an optimal L-arginine level for the control of bronchial tone. PMID- 22836623 TI - Polyphenols and their components in experimental allergic asthma. AB - The aim of the study was to investigate the potential anti-inflammatory effects in -experimental allergic asthma of natural polyphenolic compounds or their single major components. The experiment was performed after 21-days sensitization of guinea pigs with ovalbumin suspension. Changes in airway reactivity after the long-term treatment with the polyphenolic compounds Provinol and Flavin-7 and their single major components quercetin and resveratrol during were assessed using a whole body plethysmography. Reactivity of tracheal smooth muscle was studied in vitro in response to cumulative doses of the bronchoconstrictive mediators histamine and acetylcholine. Furthermore, concentrations of the inflammatory cytokines IL-4 and IL-5 were measured in bronchoalveolar lavage fluid. The results demonstrate significant anti-inflammatory effects of Provinol and Flavin-7 exerted in the airways. In contrast, chronic treatment with quercetin and resveratrol, single components of the two polyphenols, did not show such activity. We conclude that polyphenolic compounds are more effective in the anti-inflammatory effects in the airways than their separate components. PMID- 22836624 TI - Green tea and its major polyphenol EGCG increase the activity of oral peroxidases. AB - Oral peroxidases (OPO) consist mainly of salivary peroxidase and myeloperoxidase and are involved in oral defense mechanisms. Salivary peroxidase is synthesized and secreted by salivary glands, whereas myeloperoxidase is found in polymorphonuclear leukocytes, which migrate into the oral cavity at gingival crevices. Green tea is the world's second most popular drink after water. Polyphenols are the most biologically active group of tea components. The purpose of our study was to elucidate the interaction between green tea & EGCG (Epigallocatechin 3-gallate), its main polyphenol and OPO. In previous studies we have shown that elderly trained people who drink green tea for 3 months, have a higher level of OPO activity compared to non-drinkers. Thus, we decided to extend our project in order to understand the above observations by studying the interaction of green tea and OPO both in vitro and in vivo. Addition of green tea and black tea infusions (50 MUl/ml) and EGCG (50 MUM) to saliva, resulted in a sharp rise of OPO activity +280% (p = 0.009), 54% (p = 0.04) and 42% (p = 0.009), respectively. The elevation of OPO activity due to addition of green tea and EGCG was in a dose dependent manner: r = 0.91 (p = 0.001) and r = 0.637 (p = 0.019), respectively. Also, following green tea infusion mouth rinsing, a rise of OPO activity was observed: +268% (p = 0.159). These results may be of great clinical importance, as tea consumer's oral epithelium may have better protection against the deleterious effects of hydroxyl radicals, produced by not removed hydrogen peroxides in the presence of metal ions. Higher OPO activity upon green tea drinking may provide an extra protection against oxidative stress in the oral cavity. PMID- 22836625 TI - Mangiferin and its traversal into the brain. AB - Mangiferin, the main active substance of the mango tree bark (Mangifera indica L.), is known for its use in natural medicine, not only as a health enhancing panacea or adjunct therapeutic, but also for brain functions improvement. In this context, we deemed it worthwhile to establish whether mangiferin could traverse into the brain after systemic administration; an essential piece of information for the rational use of a compound as a neurotherapeutic, remaining so far inconclusive regarding mangiferin. We addressed this issue by studying recoverability of mangiferin in membrane and cytosolic fractions of rat brain homogenates after its intraperitoneal administration in a dose of 300 mg/kg. We used three preparations of mangiferin of decreasing purity to find out whether its penetration to the brain could have to do with the possible presence of contaminants. The qualitative methods of thin-layered-chromatography and UV/VIS spectrophotometry were employed in this study. The results were clearly negative, as we failed to trace mangiferin in the brain fractions with either method, which makes it unlikely that the compound traverse the blood-brain barrier after being systemically administered. We conclude that it is improbable that mangiferin could act via direct interaction with central neural components, but rather has peripheral, target specific functions which could be secondarily reflected in brain metabolism. PMID- 22836626 TI - Plasma selectins in patients with obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is an independent risk factor in the pathogenesis of -cardiovascular diseases. The aim of the study was to analyze three specific adhesion molecules involved in the development of an atherosclerotic plaque: E selectin (endothelium), L-selectin (leukocyte surface), and P-selectin (from platelet), circulating in plasma in patients at different OSA severity. Eighty non-smoking male Caucasians aged 30-64 were enrolled into the study after clinical, biochemical, and polysomnographic examinations. The patients were divided into four groups based on the results of apnea/hypopnea index (AHI): OSA 0 with AHI 0-4.9 (n = 20), OSA-1 with AHI 5-15 (n = 21), OSA-2 with AHI 16-30 (n = 18), OSA-3 with AHI >= 31 (n = 21). Complete blood count, oral glucose tolerance test, fasting lipid profile, C-reactive protein and insulin, and plasma concentrations of soluble E-selectin, P-selectin and L-selectin were measured. We found a progressive increase in the concentrations of all three selectins with the severity of OSA. In conclusion, the level of plasma adhesion molecules may be indicative of OSA severity and may contribute to cardiovascular sequelae. PMID- 22836627 TI - Blood antioxidant status, dysglycemia and obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) patients present increased cardiovascular morbidity and mortality. Oxidative stress is involved in OSA and cardiovascular pathology. The aim of the study was to assess oxidative stress markers in the blood of OSA males during oral glucose tolerance test (OGTT). The study involved OSA-suspected obese males (BMI >= 25 kg/m(2)) aged 35-64, with no acute or chronic disorders, appointed for polysomnography to diagnose OSA (AHI >= 5). The results of OGTT allowed to select prediabetic (Pre) subjects and normal glucose tolerance (N), excluding newly diagnosed diabetes. Blood was collected at 0 min (fasting) and 120 min of the test. Plasma glucose, total antioxidant status (TAS), thiobarbituric acid-reacting substances (TBARS), and activity of superoxide dismutase-1 (SOD) in erythrocytes, were determined at the two time points and the difference (D) between the 120 and 0 min time points was calculated for either oxidative stress variable (D-TAS, D-SOD and D-TBARS). Fasting serum insulin and lipids also were measured fasting. There were four groups of subjects, each consisting of 22 individuals N-OSA-neg(ative), N-OSA-pos(itive), Pre-OSA-neg and Pre-OSA-pos. The N-OSA-pos and Pre-OSA-pos subjects demonstrated decreased SOD-0 compared with OSA-negative groups. In N-OSA-neg and N-OSA-pos groups, the positive differences D-SOD and D-TAS were observed, while Pre-OSA subjects presented negative differences. In conclusion, prediabetic OSA patients may consume blood antioxidant factors to counter the effects of oxidative stress, more than individuals with normal glucose tolerance. PMID- 22836628 TI - Anti-natrium/iodide symporter antibodies and other anti-thyroid antibodies in children with Turner's syndrome. AB - Antibodies against the Na/I symporter (anti-NIS ab) have been found in adult patients with autoimmune thyroid diseases. As easily available for the immune system, NIS can play a role in the initial stage of autoimmune thyroid diseases. Children with Turner's syndrome (TS) being at high risk of autoimmune thyroid disease development seem a valuable group for the investigation of the early autoimmune process. The aim of the study was to investigate the presence of anti NIS ab and its potential clinical significance in TS children. Fifty four girls with TS were examined (age 11.9 +/- 2.46 years), and 23 healthy girls with normal thyroid function, free of autoimmune diseases. Anti-NIS antibodies were measured by the in-house ELISA method and the Western blotting. Sera considered positive for anti-NIS ab were used for the iodide uptake bioassay using COS7 cells stably transfected with hNIS. In all patients the thyroid function, antithyroid antibodies presence and thyroid ultrasonography were evaluated. In 20% of the patients a subclinical hypothyroidism was diagnosed and 70.4% had antithyroid antibodies (anti-TPO - 64.8% and Anti-Tg - 24%). Anti-NISab were present in 14.8% girls with TS and in none of the control group. Their presence was unrelated to other antithyroid antibodies titre or patients' age. A positive correlation between the anti-NIS ab presence and the hypothyroidism was found (p < 0.04). Anti-NIS ab-positive sera did not suppress iodine uptake. In conclusion, anti-NIS antibodies were present in 14.8% of children with TS and they were related to the presence of hypothyroidism. PMID- 22836629 TI - Influence of sera from interstitial lung disease patients on angiogenic activity of mononuclear cells. AB - Chronic inflammation stimulates of neovascularization. The aim of this study was to evaluate the effect of sera from interstitial lung diseases (ILD) patients on angiogenic capabilities of different subsets of mononuclear cells. Serum samples were obtained from 22 patients with sarcoidosis, 20 with hypersensitivity pneumonitis, 20 with idiopathic pulmonary fibrosis, 9 with systemic sclerosis, 6 with pulmonary Langerhans cells histiocytosis, and from 20 healthy volunteers. Animal model of leukocyte induced angiogenesis assay was used as an angiogenic test. The pattern of angiogenic reaction was different in different diseases. Sera from systemic sclerosis and pulmonary Langerhans cells histiocytosis patients exerted inhibitory effects on angiogenesis, but sera from sarcoidosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis patients stimulated angiogenesis. Sera from sarcoidosis and pulmonary Langerhans cells histiocytosis primed monocytes for the production of angiogenic factors. The number of microvessels created after incubation of mononuclear cells depleted of monocytes with sera from systemic sclerosis patients significantly decreased. We conclude that the role of monocytes in the modulation of angiogenesis varies depending on the type of ILD. Sera from sarcoidosis stimulate and from pulmonary Langerhans cells histiocytosis patients inhibit neovascularization induced by monocyte mediators. Sera from systemic sclerosis inhibit angiogenesis induced by lymphocyte products. PMID- 22836630 TI - Antiendothelial cells antibodies in patients with systemic sclerosis in relation to pulmonary hypertension and lung fibrosis. AB - Although scleroderma is generally considered a fibrosing disease, it is now recognized that the underlying vascular pathology is playing a fundamental role in its pathogenesis. The present study was aimed at testing the prevalence of anti-endothelial cell antibodies (AECA) in systemic scleroderma (SSc) patients with and without pulmonary hypertension (PH) and in relation to the presence of pulmonary fibrosis. Fifty four SSc patients (50 females and 4 male, mean age 55.7 +/- 16.3 years) were prospectively screened. All patients underwent transthoracic echocardiography with the estimation of pulmonary artery pressure (PAP) and tricuspid regurgitant peak gradient (TRPG). All patients suspected to have pulmonary hypertension were referred for right heart catheterization. Restrictive lung disease was confirmed by HRCT. A healthy control group included (n = 27; 7 men and 20 women, mean age 49.8 +/- 12.1 years). The study of AECA was performed using the indirect immunofluorescence method on commercially available human umbilical vein endothelial cells. The HRCT scans in patients with suspected interstitial lung disease revealed signs of lung fibrosis in 15 (out of the 36 examined patients). TRPG at rest of 31 mmHg was demonstrated in 14 (21%) patients. During cardiac catheterization, arterial PH was found in two patients. Resting venous PH was found in one patient and an excessive post capillary PAP elevation at rest was demonstrated in 11 patients. At the baseline, 14/54 patients (26%) were positive for AECA. In the control group, the frequency of the antibodies was 3/27 (11%). No statistical correlation between antibody titter and the presentation of the disease existed. AECA were highly prevalent in a subgroup of patients suffering from interstitial pulmonary fibrosis. Out of the 15 patients suffering from lung fibrosis, 7 were AECA positive. The presence of AECA correlated very well with antinuclear antibodies (ANA), but was not related to the profile of ANA. Our findings support evidence that endothelial cell damage is involved in SSc, as there was increased prevalence of circulating AECA of the IgG isotype in SSc patients. AECA may also be related to the complications of SSc, like pulmonary fibrosis. PMID- 22836631 TI - Leptin receptor in childhood acute leukemias. AB - Ob-R receptor is encoded by db gene and belongs to class I cytokine receptors family. Its expression was observed in hematopoietic CD34+ stem cells, erythropoietic, myeloid and lymphoblastic lineages cell lines and in human leukemic blast cells in lymphomas, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). The studies on human bone marrow cells show that JAK/STAT pathway plays a substantial role in signal transduction in young bone marrow cells. The aim of the study was to examine the relationship between leptin receptor expression and the proliferation of neoplastic hematopoietic cells in bone marrow. The study was performed in a total of 57 children of both sexes aged 3 months to 16 years. A group of 46 patients with acute leukemia involved 25 children with ALLB, 11 children with ALLT and 10 children with ANNL. The control group consisted of 11 non-obese children with non-malignant hematological disturbances. The tests were performed on bone marrow samples. The assessments of membrane expression of Ob-R and the antigens determining the phenotype of bone marrow cells were performed using a flow cytometry method. In acute lymphoblastic leukemia, a significant decrease of Ob-R expression on leukemic blasts was observed in comparison with respective populations of normal bone marrow cells. Also in progenitor cells populations a significant decrease of CD34+Ob-R+w ALLT and ALLB was observed in comparison with the cells from normal bone marrow. No statistically significant differences in the percentage of Ob-R+ cells in ANNL bone marrow and in control bone marrow were observed. PMID- 22836632 TI - Expression of cytotoxic T lymphocyte antigen-4 in T cells from children with Hashimoto's thyroiditis. AB - The cytotoxic T lymphocyte antigen-4 (CTLA-4) (CD152) is a basic negative regulatory molecule of T cell activation and its hypo-function is associated with severe lymphoproliferative syndrome. The aim of the present study was to evaluate the intracellular and surface expression of CTLA-4 on peripheral T cells before and after T cell activation in children with Hashimoto's thyroiditis (HT). Blood samples were obtained from 46 children: 25 with Hashimoto's thyroiditis and 21 controls free of autoimmune disease or thyroid disorders. T cell phenotype was evaluated by flow cytometry with the use of monoclonal antibodies combination: CD4- FITC/ CD28 -PC5/ CD152 -PE and CD8 -FITC/ CD28 -PC5/ CD152 -PE on T cell surface and intracellularly at baseline and after 48 h of T cell culture with the mitogen 48-PHA. We found that the number of T cells with intracellular CD152 expression was comparable in HT patients and controls at baseline and increased after 48-PHA, in CD4 subset only, in both patients and controls. However, the increase was more evident in the HT patients. The number of T cells with the surface expression of CD152 at baseline was significantly lower in the HT patients than in controls (p < 0.0002) in non-stimulated CD4+ and CD8+ T cells. After 48-PHA, surface CD152 expression in CD4+T cells increased in both groups; the increase was greater in controls. In conclusion, impaired function of CTLA-4 in HT patients may depend on the imbalance of intracellular/surface expression of CD152 in T cells. PMID- 22836633 TI - Exercise in cold air and hydrogen peroxide release in exhaled breath condensate. AB - Athletes have changes in the lung epithelial cells caused by inhalation of cold and dry air. The exhaled breath condensate contains a number of mediators from the respiratory system and H(2)O(2) is described as a marker of airways inflammation. The aim of this study was to determine the influence of exercise combined with cold air on the H(2)O(2) release in the exhaled breath. Twelve males (23.1 +/- 1.5 years) were randomly assigned at 2 different days (1 day rest) to perform a 50 min run (75-80% of their max. heart rate) under normal (N) laboratory (18.1 +/- 1.1 degrees C) or cold (C) field condition (-15.2 +/- 3.1 degrees C). Before and immediately after each run, the EBC was collected under laboratory conditions and was analyzed amperometrically. Prior to the two runs, H(2)O(2) concentrations were 145.0 +/- 31.0 (N) and 160.0 +/- 49.1 nmol/L (C) and theoretical release was 70.3 +/- 37.1 (N) and 82.6 +/- 27.1 pmol/min (C) (p > 0.05). After each run, H(2)O(2) concentration increased significantly to 388.0 +/ 22.8 nmol/L (N) and 622.1 +/- 44.2 nmol/L (C) (p < 0.05), along with an increase in the theoretical release: 249.2 +/- 35.7 pmol/min (N) and 400.9 +/- 35.7 pmol/min (C) (p < 0.05). We conclude that release of H(2)O(2) into the EBC takes place under both resting conditions and after exercise. The concentration and release of H(2)O(2) increased after exercise in cold air compared to resting and laboratory conditions, which points to an increase in inflammatory and oxidative stress. PMID- 22836634 TI - Non-invasive assessment of exhaled breath pattern in patients with multiple chemical sensibility disorder. AB - Multiple chemical sensitivity (MCS) is a complex disorder initiated by chemical exposure, particularly through the airways. MCS patients report sensitivity or intolerance to low levels of a wide spectrum of chemicals. Symptoms could include asthma-like signs, rhinitis, fatigue, cognitive dysfunction, psycho-physiological alteration, and other specific tissue reactions resembling hypoxic and oxidative stress effects. To recognize physiological signs that would allow the diagnosis of MCS in a non-invasive way we investigated the potential application of a new sensor system. In healthy volunteers, we measured exhaled breath content in the control condition and under exposure to olfactory stressors that mimic hypoxic or pollutant stressors playing a potential role in the generation of the MCS disorder. The recording system used is based on metal oxide semiconductor (MOS) sensor having a sensing range of 450-2,000 ppm CO(2) equivalents, which is able to detect a broad range of compounds playing a potential role in the generation of the MCS disorder, while correlating directly with the CO(2) levels. The results indicate that the recording system employed was suitable for the analysis of exhaled breath content in humans. Interestingly, the system was able to detect and discriminate between the exhaled breath content taken from the control condition and those from conditions under stress that mimicked exposures to pollutant or hypoxia. The results suggest that chronic hypoxia could be involved in the MCS disorder. PMID- 22836635 TI - Anti-inflammatory treatment in dysfunction of pulmonary surfactant in meconium induced acute lung injury. AB - Inflammation, oxidation, lung edema, and other factors participate in surfactant dysfunction in meconium aspiration syndrome (MAS). Therefore, we hypothesized that anti-inflammatory treatment may reverse surfactant dysfunction in the MAS model. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg; Mec) or saline (Sal). Thirty minutes later, meconium-instilled animals were treated by glucocorticoids budesonide (0.25 mg/kg, i.t.) and dexamethasone (0.5 mg/kg, i.v.), or phosphodiesterase inhibitors aminophylline (2 mg/kg, i.v.) and olprinone (0.2 mg/kg, i.v.), or the antioxidant N-acetylcysteine (10 mg/kg, i.v.). Healthy, non-ventilated animals served as controls (Con). At the end of experiments, left lung was lavaged and a differential leukocyte count in sediment was estimated. The supernatant of lavage fluid was adjusted to a concentration of 0.5 mg phospholipids/ml. Surfactant quality was evaluated by capillary surfactometer and expressed by initial pressure and the time of capillary patency. The right lung was used to determine lung edema by wet/dry (W/D) weight ratio. Total antioxidant status (TAS) in blood plasma was evaluated. W/D ratio increased and capillary patency time shortened significantly, whereas the initial pressure increased and TAS decreased insignificantly in Sal vs. Con groups. Meconium instillation potentiated edema formation and neutrophil influx into the lungs, reduced capillary patency and TAS, and decreased the surfactant quality compared with both Sal and Con groups (p > 0.05). Each of the anti-inflammatory agents reduced lung edema and neutrophil influx into the lung and partly reversed surfactant dysfunction in the MAS model, with a superior effect observed after glucocorticoids and the antioxidant N-acetylcysteine. PMID- 22836636 TI - Microcirculation in the lungs: special features of construction and dynamics. AB - In this study we investigated microcirculation in the lungs in their in situ physiological location inside the thorax. The study was performed with the use of a system of contact optics. A 'window', 4 * 4 mm in size, was made in thorax tissues and pleura of an anaesthetized rat. The lung collapsed and then was filled with oxygen or hypoxic gas mixture under the pressure of 10-15 cm H(2)O through a tracheostomic canula. This almost excluded the respiratory movements of the lung. Then, the lung was brought in contact with a lens (1.7 mm aperture). We showed that there is a whole system of wide microvessels (20-30 MUm in diameter) which run between the alveoli; the finding contradicting the hitherto notion that each alveolus is supplied with blood via the thinnest (5-10 MUm in diameter) lung arterioles. The microvessels we visualized surround each alveolus almost from all sides. In this way, each alveolus receives a maximum amount of blood. Such a structure of lung circulation accounts for a substantial blood flow through the lungs (up to 6 l per min in humans) and for a rapid saturation of the blood with oxygen (about 100 ml per second). The alveoli saturate the blood with oxygen and subsequently the microvessels form the lung veins entering the left auricle. The photographs and video films of the alveoli at a high magnification were presented, demonstrate the special features of the structure and circulation in the alveoli. The plausible mechanisms of rapid saturation of the blood with oxygen are discussed. PMID- 22836637 TI - Immunotargeting of the pulmonary endothelium via angiotensin-converting-enzyme in isolated ventilated and perfused human lung. AB - Vascular immunotargeting of catalase via angiotensin-converting-enzyme (ACE) attenuated lung ischemia reperfusion injury in the rat. As this might be a promising modality for extension of the viability of human lung grafts for transplantation we tested the hypothesis whether anti-ACE antibodies are suitable for human lung protection within the model of isolated perfused and ventilated human lung resections. Right after surgery for lung cancer, human lung specimens were isolated, ventilated and perfused under physiological conditions with 500 MUg of either mouse monoclonal antibodies (mAb) to human ACE (9B9, I2H5, 3G8) or non-immune mouse IgG (as a negative control) followed by wash-out perfusion. Perfusion pressure, pH and lung weight gain were measured before and during perfusion. After mAb perfusion and wash-out perfusion period lung tissue was tested for the uptake of mAbs by immunohistochemistry and by enzyme-capture technique. Furthermore, antibody concentration and ACE shedding were measured within the perfusate. We found that ACE activity in tumor and normal lung tissue did not differ between the groups perfused with different mAbs. However, ACE activity in normal lung tissue (17.0 +/- 6.0 U/g) was significantly higher compared to tumor tissue (6.0 +/- 3.0; p < 0.01). Absolute retaining of mAbs was with 1.3 +/- 1.1% of injected dose per gram of tissue in normal lung tissue, 0.7 +/- 0.7% of injected dose per gram of tumor tissue and was significantly higher compared to non-immune mouse IgG (0.1 +/- 0.1%/g; p < 0.01). Anti-ACE mAbs concentration in the perfusate dropped significantly to 47 +/- 11% (p < 0.001) at 40 min of perfusion. No significant difference between different anti-ACE mAbs in the depletion from perfusate has been observed. mAb 9B9 showed the most intense immunostaining (i.e., most significant lung uptake) after each experiment in normal and tumor lung tissue compared to mAbs i2H5 and 3G8 (p < 0.01). These results validate the possibility of immunotargeting of pulmonary endothelium in the human lung tissue by anti-ACE mAbs under in vivo conditions. Furthermore, the model might be useful to investigate targeted therapies in lung cancer without side effects for the patient. PMID- 22836638 TI - Angiogenic activity of sera from interstitial lung disease patients in relation to angiotensin-converting enzyme activity. AB - The role of angiogenesis in the pathogenesis of interstitial lung diseases (ILD) is unknown. Angiotensin-converting enzyme (ACE) is a marker of sarcoidosis activity and may modulate angiogenesis. The aim of this study was to examine the relationship between ACE activity in ILD patients' sera and their effect on microvessels formation in an in vivo model of leukocyte-induced angiogenesis. The study population consisted of 77 sarcoidosis patients, 22 idiopathic pulmonary fibrosis patients, 16 bird fanciers lung patients, eight silicosis patients and 14 healthy donors. Serum ACE activity was assayed by spectrophotometric method. As an angiogenic test, a leukocyte-induced angiogenesis assay in an animal model was used. Sera from interstitial lung disease patients significantly stimulated angiogenic activity of mononuclear cells compared with healthy donors (p < 0.001). The highest ACE serum activity was measured in sera from the silicosis patients, and lowest in sera from the sarcoidosis and IPF patients. A significantly lower serum ACE activity was detected in the bird fanciers lung patients. Serum angiogenic activity of ILD patients measured by angiogenesis index negatively correlated with ACE serum activity (r = ;-0.52; p < 0.01). This correlation was highest in the sarcoidosis group (r = -0.6; p < ). Sera from ILD patient constitute the source of factors modulating angiogenesis. PMID- 22836639 TI - Development and aging are oxygen-dependent and correlate with VEGF and NOS along life span. AB - During development and aging, vascular remodeling represents a critical adaptive response to modifications in oxygen supply to tissues. Hypoxia inducible factor (HIF) has a crucial role and is modulated by oxygen levels, with an age-dependent response in neonates, adult, and aged people. ROS are generated under hypoxic conditions and the accumulation of free radicals during life reduces the ability of tissues to their removal. In this immunohistochemical study we investigated the presence and localization of VEGF and iNOS in human carotid bodies (CB) sampled at autopsy from three children (mean age - 2 years), four adult young subjects (mean age - 44.3 years), and four old subjects (mean age - 67.3 years). VEGF immunoreactivity was significantly enhanced in CB tissues from the children (7.2 +/- 1.2%) and aged subjects (4.7 +/- 1.7%) compared with the young adults (1.4 +/- 0.7%). On the other hand, iNOS immunoreactivity was enhanced in CB tissues from the children (0.4 +/- 0.04%) and young adult subjects (0.3 +/- 0.02%) compared with the old subjects (0.2 +/- 0.02%). Prevention of oxygen desaturation, reducing all causes of hypoxemia from neonatal life to aging would decrease the incidence of diseases in the elderly population with lifespan extension. PMID- 22836640 TI - Sarcoidosis and tuberculosis: a connection to the human leukocyte antigen system. AB - Infectious, genetic factors, and autoimmunity have been considered as potential causes of sarcoidosis (SA). Pathological similarities between SA and tuberculosis (TB) suggest M. tuberculosis antigen(s) as causative agent(s). Our published comparative analysis of the human leukocyte antigens (HLA) system in patients with SA or TB in the same ethnic group revealed that some antigens were connected with high risk of developing of SA or TB, but other were comparable in both patient populations. Is it possible that the predominating occurrence of HLA antigens characteristic for TB may cause tuberculosis in patients with SA? To answer this question we evaluated the HLA class I and II alleles frequency by PCR amplification with sequence-specific primers in three women with histopathologically proven pulmonary SA, who developed bacteriologically confirmed TB on a corticosteroids (CS) therapy. Analysis of HLA in every case separately revealed a trend for higher occurrence of both alleles predisposing and protecting from TB than SA, in comparison with healthy individuals in our previously mentioned HLA genotyping study. Overall, the number of alleles predisposing to TB was statistically greater than the number of alleles connected with a high risk of developing SA. Also, the frequency of protecting alleles was statistically higher for TB than for SA. Therefore, SA in these patients developed at first, and the presence of additional environmental factors, e.g., age, CS might decrease an immune response and provoked TB. There is a possibility that the occurrence of HLA antigen more associated with high risk of developing TB than SA causes the development of tuberculosis in our patients with sarcoidosis. PMID- 22836641 TI - Toll-like receptor-9 polymorphisms in sarcoidosis and chronic obstructive pulmonary disease. AB - The etiology of inflammatory diseases of the lung like sarcoidosis and chronic obstructive pulmonary disease (COPD) is multifactorial. The main trigger for developing a COPD is tobacco smoking while exogenous factors causing sarcoidosis are unclear. In both diseases there is an underlying genetic susceptibility determining both the onset and the course of the diseases. Toll-like receptor (TLR)-9 plays an important role in innate immunity by recognizing bacterial CpG DNA motifs. It is unclear whether single nucleotide polymorphisms (SNPs) in TLR-9 are able to alter the course of sarcoidosis or COPD, or raise the susceptibility for developing one of the disorders. We examined two SNPs in the promoter region of the TLR-9 gene (T1486C and T1237C) in 175 COPD patients (59% with a stable course of the disease, 41% with an instable course with more than 3 exacerbations over the last 3 years) and 166 sarcoidosis patients (19% with an acute and 81% with a chronic course of the disease lasting >2 years) comparing each group to 233 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was used for genotyping. The C-allele frequency of T1486C was significantly elevated in COPD patients (p = 0.008). For T1237C there were no significant associations comparing the COPD cohort with the controls. In the sarcoidosis cohort, we could observe a significantly higher prevalence of the C-allele for T1237C in the chronic sarcoidosis cohort in comparison to the control group (p = 0.026). For T1486 there no statistical association was observed. This is the first study showing an association between a SNP (T1486C) in the TLR-9 gene and the onset of COPD. Moreover, we could demonstrate that T1237C is able to alter the course of sarcoidosis as a disease modifying gene. This study underlines that SNPs in TLR-9 might be involved in acquiring and maintaining lung diseases such as sarcoidosis and COPD. PMID- 22836642 TI - Association of adiponectin gene G276T polymorphism with atherogenic indicators in obese children. AB - Adiponectin plays a protective role against atherosclerosis. Genetic investigation has revealed that G276T adiponectin gene polymorphism is related to adiponectin concentration and metabolic disturbances. The aim of the present study was to investigate the association of adiponectin gene G276T polymorphism with indices of atherosclerosis in obese children. We examined 159 children (125 obese and 34 non-obese). G276T of adiponectin gene polymorphism was identified using a PCR-RFLP method. The intima media thickness (IMT) was evaluated in 82 patients. In all children, the anthropometric indices, fasting plasma total cholesterol (TC), HDL and LDL cholesterol, triglycerydes (TG), C-reactive protein (CRP), and adiponectin were measured. Oral glucose tolerance test (OGTT) also was performed. We found that the obese patients presented with higher values of atherogenic indicators than the non-obese patients. The indicators positively correlated with CRP and lipid concentrations. Ninety one percent of obese children presented with elevated IMT which correlated with CRP. The children with GG genotype (GG + GT allele) had lower values of BMI, TC, and TG but higher adiponectin concentrations. The mean level of adiponectin was statistically decreased in the compared with the homozygous TT children. The other anthropometric and atherogenic indicators did not differ between these two sets of obese children. We conclude that adiponectin concentrations were decreased in children with polymorphism G276T in adiponectin gene. The study, however, failed to show significant associations between carotid IMT, lipid markers, blood pressure, or HOMA-IR in obese children. PMID- 22836643 TI - Relation of fat-mass and obesity-associated gene polymorphism to fat mass content and body mass index in obese children. AB - Fat mass content, fat distribution, and fat-mass and obesity associated (FTO) gene have been reported among a broad spectrum of genetic variation connected with body weight. The aim of our study was to investigate whether the T/A rs9939609 polymorphism of the FTO gene may influence obesity and metabolic indices in children. A 160 children were examined (136 obese and 24 non-obese). The anthropometric measurements and calculations included: height, weight, waist and hip circumference, sum of the thickness of 3 and 10 skin folds, % of fat content, % FAT- BIA , % LBM-BIA. BMI, SDS of BMI, WHR, and WHtR. Fasting plasma total cholesterol (TC), HDL and LDL-cholesterol, triglycerides (TG), oral glucose tolerance test (OGTT), and HOMA-IR were analyzed and the blood pressure were measured. The rs9939609 polymorphism of FTO gene was genotyped by allele-specific real-time polymerase chain- reaction (RT-PCR). We found that the mean concentrations of TC, TG, LDLC, and HOMA-IR were significantly higher, and HDL was lower in the obese than in non-obese children. The presence of TT, but not AA alleles, related to the percentage of fat content, BMI, and z-score of BMI. None of the other anthropometric indices did differ between the children with gene polymorphism and wild homozygous. In conclusion, rs9939609 polymorphism in the fat-mass and obesity-associated gene is associated with BMI and the percent of fat content in children. PMID- 22836644 TI - Rapid test for influenza in diagnostics. AB - In Poland no vaccines against influenza type A/H1N1 were available in the epidemic season 2009/2010. In our Department within 45 days (November-December 2009) 17 influenza suspected children (24%) were positive for influenza type A (QiuckVue Influenza A + B rapid tests). Of these 17 children, seven were hospitalized at the pediatric department. In six of them the presence of the A/H1N1v virus RNA was confirmed with real-time reverse transcription polymerase chain reaction (RT-PCR, Polymerase Chain Reaction). The initial presentation of influenza was unspecific. The possibility of performing the rapid test for influenza in the epidemic season proved to be very useful in the clinical diagnostics and management. PMID- 22836645 TI - Infections with A(H1N1)2009 influenza virus in Poland during the last pandemic: experience of the National Influenza Center. AB - This study presents epidemiological and clinical data on non-sentinel patients considered by physicians as suspected to be infected with pandemic A(H1N1)2009 virus, from whom clinical specimens were sent for testing to the National Influenza Center, NIPH-NIH in Warsaw, Poland. Between April 28, 2009 and August 10, 2010, 988 (15.7%) out of the 6,311 specimens were tested by the National Influenza Center, including 798 from non-sentinel sources and 190 from sentinel influenza surveillance network. The non-sentinel specimens were tested by conventional RT-PCR to detect influenza A and in the case of positive specimens - one-step real-time RT-PCR to detect the pandemic virus A(H1N1)2009. In 145 (18.2%) cases, infections with the pandemic virus were confirmed, with the highest number in patients aged 15-25. In 45% of the confirmed cases, a history of travel to other countries was registered. The most common symptoms were fever >=38 degrees C (72.7%), cough (50%), sore throat, and myalgia (26.1%). In 40.7% of the swabbed patients, clinical and epidemiological criteria for the novel influenza A(H1N1)2009, set by the European Commission, were met. There were, however, specimens from persons without any reasonable indication for testing for the pandemic virus, specimens collected incorrectly, and documentation without basic information. These weaknesses resulted in unnecessary costs and overload of health care units. An improvement should be achieved in the area of communication between different pandemic players in the future. More attention is also needed to ensure that requirements and recommendations are known and used. PMID- 22836646 TI - Immune response to influenza vaccine in hemodialysis patients with chronic renal failure. AB - Chronic renal failure and dialysis belong to contraindications to vaccination with live vaccines. The objective of this study was to evaluate the humoral response to influenza vaccination consisting of the formation of antibodies against hemagglutinin and neuraminidase in patients undergoing chronic hemodialysis due to chronic renal failure. The study included 173 patients treated at a dialysis station in the Silesian region in Poland. The patients were assigned to the following groups: Group A-71 hemodialysis patients, mean age 65.4 +/- 14.5 years; mean time of dialysis therapy 38.9 +/- 31.7 months, vaccinated against influenza; Group B-39 hemodialysis patients, mean age 64 +/- 13.5 years; mean time of dialysis therapy 45.0 +/- 45.2 months, not vaccinated against influenza; and Group C-63 healthy patients, mean age 44.1 +/- 21.2 years, vaccinated against influenza - control group. The vaccinated patients (Groups A & C) received a single dose of Agrippal influenza vaccine (Novartis) containing hemagglutinin from three strains of the influenza virus: A/Brisbane/59/2007 (H1N1), A/Brisbane/10/2007 (H3N2), and B/Brisbane/60/2008. The serological response to vaccination was assessed from antihemagglutinin (anti-HA) and antineuraminidase antibody assays (anti-NA). We found that the protection level of antibodies (protection rate) against H1 was only 40% among the vaccinated hemodialysis patients, as opposed to 65% in controls. The level of anti-H3 antibodies was similar in both groups of vaccines; 68% in dialysis patients and 75% in controls. The level of anti-HB antibodies was higher in the dialysis patient than in controls; 70% vs. 38%, respectively. The response rate to H1 antigen a month after vaccination was almost twice lower in the hemodialysis patients than in healthy controls vaccinated against influenza; 37% vs. 65%, respectively. We conclude that there is a rather insufficient serological response in the group of hemodialysis patients vaccinated with a single dose of influenza vaccine. PMID- 22836647 TI - Co-infections with influenza and other respiratory viruses. AB - Clinicians often do not consider the presence of more than one viral etiologic agent in respiratory infection, and in many cases they order diagnostics for influenza viruses or recently even only for A(H1N1)2009 virus. However, in a substantial number of patients with a respiratory tract disease, co-infection with various viral pathogens has been confirmed. Although the association between the occurrence of co-infection and substantially higher severity of disease is still unclear, a rapid and proper diagnostics of wide spectrum of viral respiratory pathogens reveals an accurate picture of the disease and is essential for appropriate therapeutic management and control of infection. In the present study we reported five cases of multiple respiratory infection in hospitalized immunosuppressed patients: two double infections with influenza virus (IV) type A/respiratory syncytial virus (RSV) type A and IV type A/coronavirus (CoV) OC43, one infection with four viruses - IV type A/RSV type A and B/CoV OC43, and two cases of mixed infections caused by five viral agents - IV type A and B/RSV type A and B/ parainfluenza type 3 or CoV OC43. Each patient had an underlying chronic disease and received immunosuppressive treatment. Despite a low number of tested specimens, our study shows that the inclusions of multiplex PCR methods for diagnostics of respiratory tract infections and the extension of diagnostic strategies by clinicians to detect viruses other than influenza are very important and make a contribution to identifying the true rate of co-infections and their correlation with the clinical symptoms and severity of disease. PMID- 22836648 TI - Flow cytometry in detection of abnormalities of natural killer cell. AB - The population of natural killer (NK) cells is very heterogeneous and plays a role in the immune system. Several NK cells subpopulations are recognized, differing in phenotype, cytokine release and cytotoxic ability. Different expression of biologically relevant molecules on the surface of NK cells may indicate their multiple functions. The activity of NK cells has mainly to do with their cytotoxic nature. A complete analysis of NK cells function requires application of many tests because a defect may be present at different stages of the cytotoxic process, from signal transduction through lysosome degranulation to target cells destruction. Flow cytometry is actually one of the best methods for the identification of NK cells and tracking their defects. PMID- 22836649 TI - sVEGF R1 and Tie-2 levels during chemotherapy of lung cancer patients. AB - Angiogenesis plays important role in tumor growth and development. Protein ligands and their receptor tyrosine kinases are crucial in tumor related angiogenesis. Ligand/receptor systems such as vascular endothelial growth factor (VEGF), and tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (Tie) family play important role in this phenomenon. The aim of this study was to evaluate the concentration of soluble receptor of VEGF (sVEGF R1) and Tie-2 domain in plasma of lung cancer patients before and after chemotherapy. Forty four lung cancer patients, 11 with small lung cancer (SCLC), 5 females and 6 males (mean age 60.2, range 39-72 years), and 33 patients with non-small cell lung cancer (N-SCLC), 6 females and 27 males (mean age 61.9, range 42-78 years) received four courses of chemotherapy. Control group consisted of 44 patients with COPD, 4 females and 40 males (mean age 37.1, 18-60 years). In all cases clinical partial response was achieved. Both sVEGF R1 and Tie-2 concentrations were elevated in cancer group before treatment compared with control: sVEGF (pg/ml): 60.7 and 66.2 vs. 48.8 and Tie-2 (ng/ml): 37.3 and 37.5 vs. 30.7 in SCLC and N-SCLC vs. C, respectively. Treatment decreased sVEGF R1 (pg/ml): 66.7 vs. 11.6 (p < 0.05) and 66.2 vs. 14.39 (p < 0.001), and Tie-2 (ng/ml): 37.3 vs. 26.3 (p < 0.05) and 37.5 vs. 25.7 (p < 0.001) in SCLC and N SCLC, respectively. We conclude that VEGF R1and Tie-2 receptors may play important role in lung cancer development and their receptor concentrations may reflect the patients' response to treatment. PMID- 22836650 TI - Reliable detection of rare mutations in EGFR gene codon L858 by PNA-LNA PCR clamp in non-small cell lung cancer. AB - PNA-LNA PCR clamp real-time PCR method represents allele-specific approach to mutation analysis of EGFR gene in NSCLC. Due to its unique design, it is characterized by exceptionally high specificity and sensitivity but also allows detection of rare or not specifically-targeted EGFR mutations within examined exons, otherwise undetectable by other mutation-specific fluorescent probes. We herein present two cases of rare mutations revealed by PNA-LNA PCR clamping of NSCLC samples referred for routine EGFR gene molecular diagnostics. In one, the EGFR gene L858 codon mutation was detected by standard PNA-LNA PCR clamping, subsequently reconfirmed and characterized by direct sequencing of allele specific amplification products as the missense mutation c.2572C>A (p.L858M) paired with L861Q mutation on the same allele (in cis). In the second sample, low quality FFPE material from pleural biopsy, c.2573C>T missense mutation (p.L858P) was revealed. Still, repeated DNA analysis by PNA-LNA PCR clamp and direct sequencing demonstrated low level of mutant allele existing in a total allele pool suggesting rather artifactual c.2572C>T transition, a phenomenon quite frequent in low-volume FFPE samples upon fixation procedures. In conclusion, superior sensitivity and unique design of PNA-LNA PCR clamping are crucial for its excellent diagnostic effectiveness. As we demonstrated, the method allows detecting rare EGFR mutations, although it increases the risk of detection of a very low signal, e.g., generated by a small pool of mutated allele. Therefore, applicability of PNA-LNA PCR clamp product for the direct sequencing reevaluation is of key importance enabling reliable validation of results. PMID- 22836651 TI - Neurological paraneoplastic syndromes in lung cancer patients. AB - Lung cancer is recognized among the most frequent causes of paraneoplastic neurological syndromes (PNS). Neurological syndromes in subjects with systemic malignancy remain a clinical and diagnostic challenge. The aim of the study was to evaluate the frequency of NPS, their clinical manifestation and association with onconeural antibodies in patients with lung cancer. Fifty patients hospitalized with the diagnosis of PNS participated in the study. Neurological evaluation consisted of the Rankin scale (mRS), the Barthel index (BI), and testing for the presence of onconeural antibodies by means of indirect immunofluorescence, as screening, and Western blotting as confirmation. The majority of lung cancer patients (64%) aged 62 +/- 10 had NPS symptoms. Their neurological condition and daily living activities were reasonable: mRS (1.0; 0.0 4.0) and BI (100; 7.4-100) scores. Classical PNS were found in 30% of cases and included sensory neuropathy (16%), paraneoplastic cerebellar degeneration (12%) as the most frequent symptoms. Autoimmune reaction was observed in 42% of lung cancer patients and in 20% was represented by well-characterized onconeural antibodies. Anti-Hu antibody was identified as the most frequent. In conclusion, PNS signs in lung cancer patients have both classical and non-classical features. In the course of SCLC only well-characterized onconeural antibodies were identified. The presence of well-characterized onconeural antibodies is strongly associated with classical features of PNS. PMID- 22836652 TI - Cardiovascular side effects of aminophylline in meconium-induced acute lung injury. AB - As inflammation plays an important role in the pathogenesis of neonatal meconium aspiration syndrome (MAS), anti-inflammatory agents including inhibitors of phosphodiesterases (PDE) are increasingly used in the treatment. To evaluate side effects of PDE inhibitors, this study analyzed changes in blood pressure, heart rate (HR) and heart rate variability (HRV) during and after intravenous aminophylline in the animal model of MAS. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg) or saline. Thirty minutes later, the animals were treated by intravenous aminophylline (Syntophyllin, 2 mg/kg) or saline (sham-treated controls). A second dose of the treatment was given 2 h later. During (5 min) and immediately after (5 min) the treatment, and during 5 h after the treatment, mean blood pressure in the femoral artery (MAP), HR and HRV were evaluated. In meconium-instilled animals, increases in MABP, HR, and HRV were observed already 5 min after aminophylline administration, while in saline instilled animals aminophylline increased HR and caused inconsistant changes in HRV parameters compared to sham-treated animals. Within 5 h after the treatment administration, MAP, HR, and HRV parameters gradually returned to the initial values. Concluding, intravenous aminophylline may lead to acute cardiovascular changes. Thus, if aminophylline is used for treatment of MAS, its possible cardiovascular effects should be considered, particularly in patients with cardiovascular instability. PMID- 22836653 TI - Proteomic analysis of the carotid body: a preliminary study. AB - We present a proteomic analysis of the rat carotid body (CB) preparation by comparison between normoxia and hypoxia. Proteomic investigation would be helpful to identify the stress-induced protein during hypoxia and to know what O(2) species are being sensed by CB cells. Adult Wistar rats were used, one group was kept in room air (21% O(2)) as control, and the other was kept in a Plexiglas chamber for 12 days in chronic hypoxia (10-11% inspired oxygen). A total protein extract for each lysated tissue was separated using a broad pH range no-linear IPG strip (3-10) and the second dimension was performed on a 9-16% polyacrylamide gel. Exposure to hypoxia for 12 days produced significant changes in protein expression, providing an initial insight into the mechanism underlying differences in susceptibility to hypoxia. Further investigation is needed to have an overview of the specific set of proteins present in the CB and the functions of such proteins in signal transduction and adaptation during hypoxia. PMID- 22836654 TI - Effects of body positions on respiratory muscle activation during maximal inspiratory maneuvers. AB - We evaluated the maximal mouth inspiratory pressure and the EMG patterns of major respiratory and accessory muscles used in the generation of voluntary inspiratory maneuvers during different body positions. Ten healthy subjects (F/M-4/6), the mean age 22.000B10.6 years, participated in the study. The maximal inspiratory mouth pressure (MIP) during Muller's maneuver was measured from residual volume in the standing, sitting, right-sided (RSL) and left-sided lying (LSL), supine, and head-down-tilt (HDT) (3000B0; relatively horizon) positions. EMG of the diaphragmatic (D), parasternal (PS), sternocleidomastoid (SM), and genioglossus (GG) muscles were assessed in each body position. The baseline MIP was 105.3 00B1; 12.0 in men and 59.9 00B110.1 cmH(2)O in women in the standing position and did not appreciable differ in the other positions, except the HDT where it was lower by 23 and 27% in men and women, respectively (P003C0.05). During Mullers maneuver, diaphragmatic EMG activity also was similar in all the body positions, but it was significantly enhanced in the HDT. In contrast, PS EMG showed the highest level of activation in the standing position, taken as the control, reference level, and was lower in the HDT. Activation of SM during the maneuver was near the control in the sitting position, lower in the supine (79%), RSL (85%), LSL (80%), and HDT (72%) positions (P 003C0.05). GG EMG was significantly greater during maximal inspiratory effort in the supine and HDT positions (125and 130%, respectively), while it was lower in the sitting, LRS, and LLS positions (76, 57, and 43%) compared with standing (P 003C; 0.05). We conclude that the inspiratory pressure generated during Muller maneuver is a reflection of complex interactions between several muscle groups during changes in body positions. PMID- 22836656 TI - Object representations in visual memory: evidence from visual illusions. AB - Human visual memory is considered to contain different levels of object representations. Representations in visual working memory (VWM) are thought to contain relatively elaborated information about object structure. Conversely, representations in iconic memory are thought to be more perceptual in nature. In four experiments, we tested the effects of two different categories of visual illusions on representations in VWM and in iconic memory. Unlike VWM that was affected by both types of illusions, iconic memory was immune to the effects of within-object contextual illusions and was affected only by illusions driven by between-objects contextual properties. These results show that iconic and visual working memory contain dissociable representations of object shape. These findings suggest that the global properties of the visual scene are processed prior to the processing of specific elements. PMID- 22836655 TI - The effects of circadian phase, time awake, and imposed sleep restriction on performing complex visual tasks: evidence from comparative visual search. AB - Cognitive performance not only differs between individuals, but also varies within them, influenced by factors that include sleep-wakefulness and biological time of day (circadian phase). Previous studies have shown that both factors influence accuracy rather than the speed of performing a visual search task, which can be hazardous in safety-critical tasks such as air-traffic control or baggage screening. However, prior investigations used simple, brief search tasks requiring little use of working memory. In order to study the effects of circadian phase, time awake, and chronic sleep restriction on the more realistic scenario of longer tasks requiring the sustained interaction of visual working memory and attentional control, the present study employed two comparative visual search tasks. In these tasks, participants had to detect a mismatch between two otherwise identical object distributions, with one of the tasks (mirror task) requiring an additional mental image transformation. Time awake and circadian phase both had significant influences on the speed, but not the accuracy of task performance. Over the course of three weeks of chronic sleep restriction, speed but not accuracy of task performance was impacted. The results suggest measures for safer performance of important tasks and point out the importance of minimizing the impact of circadian phase and sleep-wake history in laboratory vision experiments. PMID- 22836657 TI - Antibodies against neutralization epitopes of human cytomegalovirus gH/gL/pUL128 130-131 complex and virus spreading may correlate with virus control in vivo. AB - PURPOSE: Recently, human cytomegalovirus (HCMV) UL128-131 locus gene products have been found to be associated with glycoprotein H (gH) and glycoprotein L (gL) to form a pentameric glycoprotein complex gH/gL/pUL128-130-131, which is present in the virus envelope and elicits production of neutralizing antibodies. Purpose of this study was to verify whether in vitro activities of these antibodies may correlate with protection in vivo. METHODS: By using potently neutralizing human monoclonal antibodies (mAbs) targeting 10 different epitopes of the pentameric complex, a competitive ELISA assay was developed, in which the pentamer bound to the solid-phase was reacted competitively with human sera and murinized human mAbs. In addition, inhibition of virus spreading (plaque formation and leukocyte transfer) by neutralizing human mAbs and sera was investigated. RESULTS: In the absence of any reactivity of sera from HCMV-seronegative subjects, antibodies to all 10 epitopes were detected in HCMV-seropositive individuals. During primary HCMV infection in pregnancy antibodies to some epitopes showed a trend towards an earlier appearance in mothers not transmitting the virus to the fetus as compared to transmitting mothers. In addition, the activity of neutralizing human mAbs and sera in blocking virus cell-to-cell spreading and virus transfer to leukocytes from infected endothelial cells was shown to develop during the convalescent phase of primary infection. CONCLUSIONS: Dissection of the neutralizing/inhibiting activities of human sera may be helpful in the study of their protective role in vivo. In particular, neutralizing antibodies to the pentamer may be a surrogate marker of protection in vivo. PMID- 22836658 TI - Grape seed proanthocyanidin extract attenuates allergic inflammation in murine models of asthma. AB - BACKGROUND: Antioxidants have been suggested to alleviate the pathophysiological features of asthma, and grape seed proanthocyanidin extract (GSPE) has been reported to have powerful antioxidant activity. PURPOSE: This study was performed to determine whether GSPE has a therapeutic effect on allergic airway inflammation in both acute and chronic murine model of asthma. METHODS: Acute asthma model was generated by intraperitoneal sensitization of ovalbumin (OVA) with alum followed by aerosolized OVA challenges, whereas chronic asthma model was induced by repeated intranasal challenges of OVA with fungal protease twice a week for 8 weeks. GSPE was administered by either intraperitoneal injection or oral gavage before OVA challenges. Airway hyperresponsiveness (AHR) was measured, and airway inflammation was evaluated by bronchoalveolar lavage (BAL) fluid analysis and histopathological examination of lung tissue. Lung tissue levels of various cytokines, chemokines, and growth factors were analyzed by quantitative polymerase chain reaction and ELISA. Glutathione assay was done to measure oxidative burden in lung tissue. RESULTS: Compared to untreated asthmatic mice, mice treated with GSPE showed significantly reduced AHR, decreased inflammatory cells in the BAL fluid, reduced lung inflammation, and decreased IL-4, IL-5, IL 13, and eotaxin-1 expression in both acute and chronic asthma models. Moreover, airway subepithelial fibrosis was reduced in the lung tissue of GSPE-treated chronic asthmatic mice compared to untreated asthmatic mice. Reduced to oxidized glutathione (GSH/GSSG) ratio was increased after GSPE treatment in acute asthmatic lung tissue. CONCLUSION: GSPE effectively suppressed inflammation in both acute and chronic mouse models of asthma, suggesting a potential role of GSPE as a therapeutic agent for asthma. PMID- 22836659 TI - Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although antiresorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials show improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI causing Gly->Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI. PMID- 22836660 TI - Descriptive study of HTLV infection in a population of pregnant women from the state of Para, Northern Brazil. AB - INTRODUCTION: In Brazil, studies have shown that HTLV seroprevalence among pregnant women varies from 0 to 1.8%. However, this seroprevalence was unknown in the State of Para, Brazil. The present study describes, for the first time, the HTLV seroprevalence among pregnant women from the State of Para, Northern Brazil. METHODS: 13,382 pregnant women were submitted to HTLV screening during prenatal care, and those with non-seronegative results to anti-HTLV were submitted to Western blot (WB) test to confirm and separate HTLV-1 and HTLV-2 carriers. RESULTS: HTLV seroprevalence in the population of pregnant women was 0.3%, and HTLV-1 was identified in 95.3% of patients. The demographic profile of HTLV carriers was as follows: women with age between 20 and 40 years old (78.4%); residing in the metropolitan region of Belem, Para (67.6%); and with educational level of high school (56.8%). Other variables related to infection were as follows: beginning of sexual intercourse between the age of 12 and 18 years old (64.9%) and have being breastfed for more than 6 months (51.4%). Most of the women studied had at least two previous pregnancies (35.1%) and no abortion (70.3%). Coinfections (syphilis and HIV) were found in 10.8% (4/37) of these pregnant women. CONCLUSIONS: Seroprevalence of HTLV infection in pregnant women assisted in basic health units from the State of Para, Northern Brazil, was 0.3% similar to those described in other Brazilian studies. The variables related to infection were important indicators in identifying pregnant women with a higher tendency to HTLV seropositivity, being a strategy for disease control and prevention, avoiding vertical transmission. PMID- 22836661 TI - Phlebotomine sandflies fauna (Diptera: Psychodidae) at rural settlements in the municipality of Caceres, State of Mato Grosso, Brazil. AB - INTRODUCTION: Leishmaniasis is expanding across Brazil, including the State of Mato Grosso (MT). The aim of this study was to characterize the phlebotomine sandfly fauna at threerural settlements located in the municipality of Caceres, MT, from August 2010 to July 2011. METHODS: Sandfly captures were conducted at the forest border and in intra and peridomicile areas with automatic light traps, biweekly, from 5pm to 6am. RESULTS: Of the 630 sandflies collected, 348 were female, and 282 were male. Captured specimens were distributed across 11 genera - Brumptomyia, Evandromyia, Expapillata, Lutzomyia, Martinsmyia, Micropygomyia, Nyssomyia, Pintomyia, Psathyromyia, Psychodopygus, and Sciopemyia - and 28 species. Among these, six species had not been marked yet in MT (Brumptomyia avellari, Br. mangabeirai, Evandromyia aldafalcaoae, Micropygomyia echinatopharynx, Micropygomyia peresi, and Pa. campograndensis). Nyssomyia whitmani was the most abundant species across ecotopes at all settlements. Interestingly, Lutzomyia longipalpis and Lutzomyia cruzi were found in sympatry. CONCLUSIONS: The disorganized occupation of the environment that is happening at the rural settlements of Mata Comprida, Laranjeira I and II could provide opportunities for the domiciliation of wild populations of phlebotomine, including vectors of leishmaniasis. Therefore, more studies are needed to understand the epidemiology of the disease in these areas and its impact on the human population. PMID- 22836662 TI - Cutaneous leishmaniasis in northeastern Brazil: a critical appraisal of studies conducted in State of Pernambuco. AB - American cutaneous leishmaniasis (ACL) is a complex disease with clinical and epidemiological features that may vary from region to region. In fact, at least seven different Leishmania species, including Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis, Leishmania (Viannia) lainsoni, Leishmania (Viannia) naiffi, Leishmania (Viannia) shawi, Leishmania (Viannia) lindenbergi, and Leishmania (Leishmania) amazonensis, have been implicated in the etiology of ACL in Brazil, and numerous phlebotomine sandfly species of the genus Lutzomyia have been regarded as putative or proven vectors. Because ACL is a focal disease, understanding the disease dynamics at the local level is essential for the implementation of more effective control measures. The present paper is a narrative review about the ACL epidemiology in Pernambuco, northeastern Brazil. Furthermore, the need for more effective diagnosis, treatment, control and prevention strategies for the affected populations is highlighted. This paper will provide researchers with a critical appraisal of ACL in Pernambuco. Hopefully, it will also be helpful for public health authorities to improve current control strategies against ACL at the state and country levels. PMID- 22836663 TI - Ultrasound and magnetic resonance imaging findings in Schistosomiasis mansoni: expanded gallbladder fossa and fatty hilum signs. AB - INTRODUCTION: There is no study relating magnetic resonance imaging (MRI) to ultrasound (US) findings in patients with Schistosomiasis mansoni. Our aim was to describe MRI findings inpatients with schistosomal liver disease identified by US. METHODS: Fifty-four patients (mean age 41.6+/-13.5years) from an area endemic for Schistosomiasis mansoni were selected for this study.All had US indicating liver schistosomal fibrosis and were evaluated with MRI performed witha 1.5-T superconducting magnet unit (Sigma). RESULTS: Forty-seven (87%) of the 54 patientsshowing signs of periportal fibrosis identified through US investigation had confirmed diagnosesby MRI. In the seven discordant cases (13%), MRI revealed fat tissue filling in the hilar periportalspace where US indicated isolated thickening around the main portal vein at its point of entryto the liver. We named this the fatty hilum sign. One of the 47 patients with MRI evidence ofperiportal fibrosis had had his gallbladder removed previously. Thirty-five (76.1%) of the other46 patients had an expanded gallbladder fossa filled with fat tissue, whereas MRI of the remainingeleven showed pericholecystic signs of fibrosis. CONCLUSIONS: Echogenic thickening of thegallbladder wall and of the main portal vein wall heretofore attributed to fibrosis were frequentlyidentified as fat tissue in MRI. However, the gallbladder wall thickening shown in US (expandedgallbladder fossa in MRI) is probably secondary to combined hepatic morphologic changes inschistosomiasis, representing severe liver involvement. PMID- 22836664 TI - Factors associated with Leishmania chagasi infection in domestic dogs from Teresina, State of Piaui, Brazil. AB - INTRODUCTION: Many studies have evaluated risk factors for human visceral leishmaniasis, but few have focused on the infection among dogs. The objective of this study was to assess the association between peridomestic socioeconomic and environmental factors and the presence of dogs seropositive for Leishmania chagasi in the City of Teresina, Brazil. METHODS: This case-control study was based on the results of a routine seroepidemiological survey among domestic dogs carried out in 2007. Serological tests were performed by means of indirect immunofluorescence antibody test. All dwellings in which at least one seropositive dog was detected were considered cases, and controls were a random sample of dwellings in which only seronegative dogs were identified. Associations between variables were expressed as odds ratios (OR) and their respective 95% confidence intervals (95%CI) estimated using multivariate logistic regression. RESULTS: Dwellings with a history of dogs removed by the visceral leishmaniasis control program in the last 12 months had five-fold higher odds of having at least one seropositive dog as compared with dwellings having no history of dog removal (OR = 5.19; 95%CI = 3.20-8.42). Dwellings with cats had 58% increased odds of dog infection as compared with those having no cats (OR = 1.58; 95%CI = 1.01-2.47). CONCLUSIONS: Identification of factors associated with canine visceral leishmaniasis might be used for the delimitation of areas of higher risk for human visceral leishmaniasis, since infection in dogs generally precedes the appearance of human cases. PMID- 22836665 TI - Nanoparticle self-assembled hollow TiO2 spheres with well matching visible light scattering for high performance dye-sensitized solar cells. AB - Submicrometer-sized hollow TiO(2) spheres are directly self-assembled from TiO(2) nanoparticles without using any template or surfactant as a scattering layer for dye-sensitized solar cells, showing good visible light scattering match to significantly improve the photoconversion efficiency. PMID- 22836666 TI - In the beginning there was babble... PMID- 22836668 TI - Electric field orientation for gene delivery using high-voltage and low-voltage pulses. AB - Electropermeabilization is a biological physical process in response to the presence of an applied electric field that is used for the transfer of hydrophilic molecules such as anticancer drugs or DNA across the plasma membranes of living cells. The molecular processes that support the transfer are poorly known. The aim of our study was to investigate the effect of high-voltage and low voltage (HVLV) pulses in vitro with different orientations on cell permeabilization, viability and gene transfection. We monitored the permeabilization with unipolar and bipolar HVLV pulses with different train repetition pulses, showing that HVLV pulses increase cell permeabilization and cell viability. Gene transfer was also observed by measuring green fluorescent protein (GFP) expression. The expression was the same for HVLV pulses and electrogenotherapy pulses for in vitro experimentation. As the viability was better preserved for HVLV-pulsed cells, we managed to increase the number of GFP expressing cells by up to 65% under this condition. The use of bipolar HVLV train pulses increased gene expression to a higher extent, probably by affecting a larger part of the cell surface. PMID- 22836667 TI - Ser/Thr motifs in transmembrane proteins: conservation patterns and effects on local protein structure and dynamics. AB - We combined systematic bioinformatics analyses and molecular dynamics simulations to assess the conservation patterns of Ser and Thr motifs in membrane proteins, and the effect of such motifs on the structure and dynamics of alpha-helical transmembrane (TM) segments. We find that Ser/Thr motifs are often present in beta-barrel TM proteins. At least one Ser/Thr motif is present in almost half of the sequences of alpha-helical proteins analyzed here. The extensive bioinformatics analyses and inspection of protein structures led to the identification of molecular transporters with noticeable numbers of Ser/Thr motifs within the TM region. Given the energetic penalty for burying multiple Ser/Thr groups in the membrane hydrophobic core, the observation of transporters with multiple membrane-embedded Ser/Thr is intriguing and raises the question of how the presence of multiple Ser/Thr affects protein local structure and dynamics. Molecular dynamics simulations of four different Ser-containing model TM peptides indicate that backbone hydrogen bonding of membrane-buried Ser/Thr hydroxyl groups can significantly change the local structure and dynamics of the helix. Ser groups located close to the membrane interface can hydrogen bond to solvent water instead of protein backbone, leading to an enhanced local solvation of the peptide. PMID- 22836669 TI - Optimization of electrotransfection conditions of mammalian cells with different biological features. AB - We introduced eukaryotic expression plasmid pEGFP-N1 encoding green fluorescent protein (GFP) genes into cells with different biological features through electroporation. The effects of conditions, including voltage, capacitor flow, pulse cycle, DNA dosage and buffer, on transfection efficiency were investigated based on fluorescent microscopy and posttransfection survival rate of cells by staining with trypan blue. Better electrotransfection outcomes were achieved in the following epithelial cells: Vero cells at 300 V/850 MUF, PK15 cells at 300 V/500 MUF, MDCK cells at 200 V/600 MUF, F81 cells at 200 V/500 MUF, cancer cells MB49 at 300 V/400 MUF, Hela cells at 200 V/450 MUF, HF-29 cells at 300 V/800 MUF and B16F1 cells at 200 V/650 MUF. Among fibroblast cells, better electrotransfection was achieved in BHK21 cells at 300 V/600 MUF and ST cells at 200 V/750 MUF. RPMI-1640 medium without antibiotics and serum demonstrated higher electrotransfection efficiency and cell survival rate than other cell culture media as electroporation buffer. Our findings further prove that electroporation transfection is an effective method for genetic transfection. Cells with different biological features require varying transfection conditions to obtain higher transfection efficiency of target genes. PMID- 22836670 TI - Decreased redox-sensitive erythrocyte cation channel activity in aquaporin 9 deficient mice. AB - Survival of the malaria pathogen Plasmodium falciparum in host erythrocytes requires the opening of new permeability pathways (NPPs) in the host cell membrane, accomplishing entry of nutrients, exit of metabolic waste products such as lactate and movement of inorganic ions such as Cl-, Na+ and Ca2+. The molecular identity of NPPs has remained largely elusive but presumably involves several channels, which partially can be activated by oxidative stress in uninfected erythrocytes. One NPP candidate is aquaporin 9 (AQP9), a glycerol permeable water channel expressed in erythrocytes. Gene-targeted mice lacking functional AQP9 (aqp-/-) survive infection with the malaria pathogen Plasmodium berghei better than their wild-type littermates (aqp9+/+). In the present study whole-cell patch-clamp recordings were performed to explore whether ion channel activity is different in erythrocytes from aqp-/- and aqp9+/+ mice. As a result, the cation conductance (K+ > Na+ > Ca2+ ? NMDG+) was significantly lower in erythrocytes from aqp-/- than in erythrocytes from aqp9+/+ mice. Oxidative stress by exposure for 15-30 min to 1 mM H2O2 or 1 mM tert-butyl-hydroperoxide enhanced the cation conductance and increased cytosolic Ca2+ concentration, effects significantly less pronounced in erythrocytes from aqp-/- than in erythrocytes from aqp9+/+ mice. In conclusion, lack of AQP9 decreases the cation conductance of erythrocytes, an effect that possibly participates in the altered susceptibility of AQP9-deficient mice to infection with P. berghei. PMID- 22836672 TI - Macrocyclic architecture: tuning cavity size and shape through maleimide photochemistry. PMID- 22836671 TI - A molecular dynamics study of DMPC lipid bilayers interacting with dimethylsulfoxide-water mixtures. AB - The diffusion process of dimethylsulfoxide (DMSO) through zwitterionic dimyristoylphosphatidylcholine (DMPC) lipid bilayer was studied by means of molecular dynamics (MD) simulations. To account for the cryoprotectant concentration difference between the inside and the outside of the cell, dual DMPC lipid bilayers which separate two aqueous reservoirs with and without DMSO were modeled. The initial configuration of the simulation model had DMSO molecules present in one of the aqueous phases (outside the cell) at two different concentrations of ~3 and ~6 mol%. MD simulations were performed on the systems for 50 ns at 323 K and 1 bar. Although the simulation time considered in the study was insufficient for the DMSO molecules to reach the other aqueous phase and equilibrium, early stages of the diffusion process indicated that DMSO molecules had a tendency to diffuse towards the other aqueous phase. The effects of DMSO on bilayer structural characteristics during the diffusion process were investigated. Simulations were analyzed to correlate the following properties of lipid bilayers in the presence of two different aqueous phases: area per lipid, lipid thickness, mass density profiles, lipid tail order parameter and water dipole orientation. Area per lipid calculated for the leaflet facing the aqueous DMSO-water mixture did not show any significant difference compared to area per lipid for the DMSO-free pure DMPC bilayer. Mass density profiles revealed that DMSO molecules had a strong tendency to diffuse toward the aqueous phase with pure water. The lipid tail order parameter calculated for the sn-1 tail of the leaflet facing the aqueous DMSO-water mixture showed that the ordering of lipid tails decreased compared to the leaflet exposed to pure water. However, the ordering of lipid tails in a system where a single bilayer is hydrated by an aqueous DMSO-water mixture is far lower. PMID- 22836673 TI - Syncope in the athlete. AB - Syncope in the athlete requires a complete evaluation, as this may be the only warning prior to an episode of sudden cardiac death. This should include a detailed history which includes specific details of the event as well as bystander descriptions when possible. Following the history should be a careful physical examination and subsequent diagnostic testing based on the individual's needs. The purpose of the evaluation is to determine if structural or electrical heart disease is present that may lead to sudden death. If absent, the patient, family and staff can be reassured that it is safe to resume athletic activity. Careful attention to the athlete with syncope may both prevent potential disasters in some, while at the same time enjoyment of intense physical activity in others. PMID- 22836674 TI - Wish list for viral vaccinologists. PMID- 22836675 TI - Cysteine as a green corrosion inhibitor for Cu37Zn brass in neutral and weakly alkaline sulphate solutions. AB - The aim of this study was to investigate electrochemical properties of brass in neutral and weakly alkaline solutions in the presence of cysteine as a nontoxic and ecological corrosion inhibitor. Potentiodynamic measurements, open circuit potential measurements, as well as chronoamperometric measurements were the methods used during investigation of the inhibitory effect of cysteine on the corrosion behaviour of brass. Potentiodynamic measurements showed that cysteine behaves as a mixed-type inhibitor in the investigated media. Based on polarization curves for brass in a weakly alkaline solution of sodium sulphate at varying cysteine concentrations, an interaction occurs between Cu(+) ions and the inhibitor, resulting in the formation of a protective complex on the electrode surface. The results of chronoamperometric measurements confirm the results obtained by potentiodynamic measurements. Optical microphotography of the brass surface also confirms the formation of a protective film in the presence of a 1 * 10(-4) mol/dm(3) cysteine. Adsorption of cysteine on the brass surface proceeds according to the Langmuir adsorption isotherm. PMID- 22836676 TI - Plant growth enhancing effects by a siderophore-producing endophytic streptomycete isolated from a Thai jasmine rice plant (Oryza sativa L. cv. KDML105). AB - An endophytic Streptomyces sp. GMKU 3100 isolated from roots of a Thai jasmine rice plant (Oryza sativa L. cv. KDML105) showed the highest siderophore production on CAS agar while phosphate solubilization and IAA production were not detected. A mutant of Streptomyces sp. GMKU 3100 deficient in just one of the plant growth promoting traits, siderophore production, was generated by inactivation of a desD-like gene encoding a key enzyme controlling the final step of siderophore biosynthesis. Pot culture experiments revealed that rice and mungbean plants inoculated with the wild type gave the best enhancement of plant growth and significantly increased root and shoot biomass and lengths compared with untreated controls and siderophore-deficient mutant treatments. Application of the wild type in the presence or absence of ferric citrate significantly promoted plant growth of both plants. The siderophore-deficient mutant clearly showed the effect of this important trait involved in plant-microbe interaction in enhancement of growth in rice and mungbean plants supplied with sequestered iron. Our results highlight the value of a substantial understanding of the relationship of the plant growth promoting properties of endophytic actinomycetes to the plants. Endophytic actinomycetes, therefore, can be applied as potentially safe and environmentally friendly biofertilizers in agriculture. PMID- 22836677 TI - A genome sequence-based approach to taxonomy of the genus Nocardia. AB - The genus Nocardia includes both pathogens and producers of useful secondary metabolites. Although 16S rRNA analysis is required to accurately discriminate among phylogenetic relationships of the Nocardia species, most branches of 16S rRNA-based phylogenetic trees are not reliable. In this study, we performed in silico analyses of the genome sequences of Nocardia species in order to understand their diversity and classification for their identification and applications. Draft genome sequences of 26 Nocardia strains were determined. Phylogenetic trees were prepared on the basis of multilocus sequence analysis of the concatenated sequences of 12 genes (atpD-dnaJ-groL1-groL2-gyrB-recA-rpoA-secA secY-sodA-trpB-ychF) and a bidirectional best hit. To elucidate the evolutionary relationships of these genes, the genome-to-genome distance was investigated on the basis of the average nucleotide identity, DNA maximal unique matches index, and genome-to-genome distance calculator. The topologies of all phylogenetic trees were found to be essentially similar to each other. Furthermore, whole genome-derived and multiple gene-derived relationships were found to be suitable for extensive intra-genus assessment of the genus Nocardia. PMID- 22836678 TI - Preparation of 3-bromo-L-tyrosine and 3,5-dibromo-L-tyrosine. AB - L-Tyrosine is converted to 3-bromo-L-tyrosine in good yield by reaction with 1.2 equiv. of DMSO in HBr/AcOH, while reaction with 2.2 equiv. of DMSO under comparable conditions results in formation of 3,5-dibromo-L-tyrosine in good yield. This is the simplest, safest and most efficient method for the preparation of gram quantities of either 3-bromo-L-tyrosine or 3,5-dibromo-L-tyrosine. PMID- 22836679 TI - The incidence and etiology of overactive bladder in patients after cerebrovascular accident. AB - Cerebrovascular accident or stroke is a devastating neurologic event that can have both short and long term urologic complications. The purpose of this article is to provide an up-to-date review of the incidence and causes of voiding dysfunction after stroke, the evaluation of voiding dysfunction in patients after stroke, and the recommendations on the management of voiding dysfunction following stroke. The reported incidence of urinary incontinence varies from 28 79 % and the causes of urinary incontinence following stroke are multifactorial. Detrusor overactivity is predominant and detrusor underactivity is somewhat less prevalent. Urodynamic findings in patients with stroke vary depending upon timing of the study and associated comorbidities. Currently there are no large longitudinal studies linking urodynamic findings with location or degree of infarct. Based on current studies, we conclude that patients with detrusor underactivity should be managed with clean intermittent catheterization or indwelling Foley catheter, while timed voiding with or without anticholinergic therapy may be an effective treatment for patients with detrusor overactivity after stroke. PMID- 22836680 TI - The calcaneus channel: a propos of a new anatomical variant. PMID- 22836681 TI - Client predictors of short-term psychotherapy outcomes among Asian and white American outpatients. AB - PURPOSE: To examine predictors of psychotherapy outcomes, focusing on client characteristics that are especially salient for culturally diverse clients. METHOD: Sixty clients (31 women; 27 White Americans, 33 Asian Americans) participated in this treatment study. Client characteristics were measured at pretreatment, and outcomes were measured postfourth session via therapist ratings of functioning and symptomatology. Regression analyses were utilized to test for predictors of outcomes, and bootstrap analyses were utilized to test for mediators. RESULTS: Higher levels of somatic symptoms predicted lower psychosocial functioning at posttreatment. Avoidant coping style predicted more negative symptoms and more psychological discomfort. Non-English language preference predicted worse outcomes; this effect was mediated by an avoidant coping style. CONCLUSIONS: Language preference, avoidant coping style, and somatic symptoms predicted treatment outcome in a culturally diverse sample. Findings suggest that race/ethnicity-related variables may function through mediating proximal variables to affect outcomes. PMID- 22836682 TI - Synthesis and discovery of novel pyrazole carboxamide derivatives as potential osteogenesis inducers. AB - A series of novel N-aryl-3-aryl-1-arylmethyl-1H-pyrazole-5-carboxamide derivatives 4a-l was synthesized by the reaction of 3-aryl-1-arylmethyl-1H pyrazole-5-carbonyl chloride with substituted aniline in good to excellent yields. Structures of the compounds were determined by IR, (1) H NMR, and HR-MS spectroscopy. The molecular structure was confirmed by the X-ray crystal analysis of one compound (4j) that was prone to crystallization. These compounds were used to induce mouse osteoblast precursors MC3T3-E1 into osteoblasts and the induction was assessed by alkaline phosphatase (ALP) activity and the gene expression of bone sialoprotein (BSP). The results showed that the compounds 4a-d, 4g, 4h, and 4k could increase the ALP activity in comparison with the negative control group and compound 4h was the most effective one which could induce osteogenesis. Furthermore, mRNA expression of BSP which is a marker of osteogenesis was up regulated by the compound 4h. PMID- 22836683 TI - Fibrinogen gene regulation. AB - The Aalpha, Bbeta and gamma polypeptide chains of fibrinogen are encoded by a three gene cluster on human chromosome four. The fibrinogen genes (FGB-FGA-FGG) are expressed almost exclusively in hepatocytes where their output is coordinated to ensure a sufficient mRNA pool for each chain and maintain an abundant plasma fibrinogen protein level. Fibrinogen gene expression is controlled by the activity of proximal promoters which contain binding sites for hepatocyte transcription factors, including proteins which influence fibrinogen transcription in response to acute-phase inflammatory stimuli. The fibrinogen gene cluster also contains cis regulatory elements; enhancer sequences with liver activities identified by sequence conservation and functional genomics. While the transcriptional control of this gene cluster is fascinating biology, the medical impetus to understand fibrinogen gene regulation stems from the association of cardiovascular disease risk with high level circulating fibrinogen. In the general population this level varies from about 1.5 to 3.5 g/l. This variation between individuals is influenced by genotype, suggesting there are genetic variants contributing to fibrinogen levels which reside in fibrinogen regulatory loci. A complete picture of how fibrinogen genes are regulated will therefore point towards novel sources of regulatory variants. In this review we discuss regulation of the fibrinogen genes from proximal promoters and enhancers, the influence of acute-phase stimulation, post-transcriptional regulation by miRNAs and functional regulatory variants identified in genetic studies. Finally, we discuss the fibrinogen locus in light of recent advances in understanding chromosomal architecture and suggest future directions for researching the mechanisms that control fibrinogen expression. PMID- 22836685 TI - Copy number variations associated with obesity-related traits in African Americans: a joint analysis between GENOA and HyperGEN. AB - Obesity is a highly heritable trait and a growing public health problem. African Americans (AAs) are a genetically diverse, yet understudied population with a high prevalence of obesity (BMI >30 kg/m(2)). Recent studies based upon single nucleotide polymorphisms (SNPs) have identified genetic markers associated with obesity. However, a large proportion of the heritability of obesity remains unexplained. Copy number variation (CNV) has been cited as a possible source of missing heritability in common diseases such as obesity. We conducted a CNV genome-wide association study of BMI in two African-American cohorts from Genetic Epidemiology Network of Arteriopathy (GENOA) and Hypertension Genetic Epidemiology Network (HyperGEN). We performed independent and identical association analyses in each study, then combined the results in a meta-analysis. We identified three CNVs associated with BMI, obesity, and other obesity-related traits after adjusting for multiple testing. These CNVs overlap the PARK2, GYPA, and SGCZ genes. Our results suggest that CNV may play a role in the etiology of obesity in AAs. PMID- 22836686 TI - Racial differences in urinary F2-isoprostane levels and the cross-sectional association with BMI. AB - Levels of four urinary F(2)-isoprostanes (F(2)-IsoPs) were examined in a large sample of the Insulin Resistance Atherosclerosis Study (IRAS) multiethnic cohort: 237 African Americans (AAs), 342 non-Hispanic whites (NHWs), and 275 Hispanic whites (HWs). F(2)-IsoP isomers - iPF2a-III, 2,3-dinor-iPF2a-III, iPF2a-VI, and 8,12-iso-iPF2a-VI - were measured in 854 urine samples using liquid chromatography with tandem mass spectrometry detection. In AAs, levels of all four F(2)-IsoPs were lower compared with NHWs and HWs (P values <0.05). When stratified by BMI, this gap was not observed among participants with normal BMI but appeared among overweight participants and increased among obese participants. Examining the slopes of the associations between BMI and F(2)-IsoPs showed no association between these variables among AAs (P values >0.2), and positive associations among whites (P values <0.05). Taking into account that positive cross-sectional associations between systemic F(2)-IsoP levels and BMI have been consistently demonstrated in many study populations, the lack of such an association among AAs reveals a new facet of racial/ethnic differences in obesity-related risk profiles. PMID- 22836687 TI - Increased death of adipose cells, a path to release cell-free DNA into systemic circulation of obese women. AB - Remodeling of adipose tissue is required to support the expansion of adipose mass. In obesity, an increased death of adipocytes contributes to the accelerated cellular turnover. We have shown that obesity in pregnancy is associated with metabolic and immune alterations in the adipose tissue. In this study, we characterized the mechanisms responsible for increased death of adipose cells of pregnant obese women and its functional consequences. We postulated that a higher turnover of dead cells in white adipose tissue of obese women would translate into release of cell-free DNA (cfDNA) into their systemic circulation. Increase in adipose mass of obese compared to lean women results from a lesser number of hypertrophic adipocytes and an accumulation of macrophages in the stromal vascular fraction (SVF). The adipocytes of obese displayed enhanced necrosis with a loss of perilipin staining at the plasma membrane. Apoptosis was prominent in SVF cells with an increased expression of caspase 9 and caspase 3 and a higher rate of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) positive CD68 macrophages in obese vs. lean. Whereas circulating fetal cfDNA concentrations were not changed, there was a twofold increase in circulating glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cfDNA and adipose tissue GAPDH mRNA in obese women. The maternal systemic GAPDH cfDNA was positively correlated with BMI and gestational weight gain. These data suggest that the active remodeling of adipose tissue of obese pregnant women results in an increased release of cfDNA of maternal origin into the circulation. PMID- 22836694 TI - A multichannel dampened flow system for studies on shear stress-mediated mechanotransduction. AB - Shear stresses are powerful regulators of cellular function and potent mediators of the development of vascular disease. We have designed and optimized a system allowing the application of flow to cultured cells in a multichannel format. By using a multichannel peristaltic pump, flow can be driven continuously in the system for long-term studies in multiple isolated flow loops. A key component of the system is a dual-chamber pulse dampener that removes the pulsatility of the flow without the need for having an open system or elevated reservoir. We optimized the design parameters of the pulse dampening chambers for the maximum reduction in flow pulsation while minimizing the fluid needed for each isolated flow channel. Human umbilical vein endothelial cells (HUVECs) were exposed to steady and pulsatile shear stress using the system. We found that cells under steady flow had a marked increased production of eNOS and formation of actin stress fibers in comparison to those under pulsatile flow conditions. Overall, the results confirm the utility of the device as a practical means to apply shear stress to cultured cells in the multichannel format and provide steady, long term flow to microfluidic devices. PMID- 22836695 TI - The effect of spinal shortening after total en bloc spondylectomy: a biomechanical study in the thoracic spine. AB - STUDY DESIGN: A biomechanical study using human cadaveric thoracic spine specimens. OBJECTIVE: To evaluate and compare the biomechanical effects of spinal shortening and cross-links in reconstruction after total en bloc spondylectomy (TES). SUMMARY OF BACKGROUND DATA: There have been no studies that have examined the biomechanical effects of spinal reconstruction after multilevel TES or the biomechanical effects of spinal shortening in reconstruction after TES. METHODS: Eight human cadaveric spines (T2-T9) were used. After the intact specimen had been biomechanically tested to determine the stiffness in compression, flexion, extension, left and right lateral bending, and left and right axial rotation, a TES at T5-6 was carried out. Three reconstruction methods were tested biomechanically (same as for the intact specimen) for their ability to restore stiffness to the specimen: (1) anterior short cage and multilevel posterior instrumentation at T3-8 with 2 cross-links (S2C), (2) anterior short cage and multilevel posterior instrumentation at T3-8 with 1 cross-link (S1C), and (3) anterior long cage and multilevel posterior instrumentation at T3-8 with 2 cross links (L2C). A cage that was 6-10 mm shorter in height than the space created by the TES at T5-6 was selected as the "short cage" and a cage 10 mm taller in height than the short cage was selected as the "long cage" in each specimen. RESULTS: All 3 reconstruction methods using an anterior cage and multilevel posterior instrumentation provides a stiffer construct than that shown by the intact specimen. The reconstruction method using the 10-mm shorter cage (S2C vs. L2C) provided more stiffness than the one using the longer cage. The reconstruction using 2 cross-links (S2C vs. S1C) did not provide a stiffer construct than the one using 1 cross-link. CONCLUSIONS: The reconstructions using an anterior cage and multilevel posterior instrumentation provided a stiffer construct than that shown by the intact specimen. The reconstruction using a 10 mm shorter cage provided a stiffer construct than the reconstruction using the longer cage. PMID- 22836696 TI - Smart hydrogels from laterally-grafted peptide assembly. AB - Small peptides carrying laterally-grafted azobenzene units self-assemble into photo-responsive hydrogels which are applied as a smart matrix for controlling the dye molecules release. We demonstrate that a delicate balance among peptides interactions plays a pivotal role in the photo-responsive gel-sol transition. PMID- 22836697 TI - Targeted synthesis of a porous borazine-linked covalent organic framework. AB - The first microcrystalline borazine-linked polymer, BLP-2(H), has been synthesized. BLP-2(H) crystallizes into 2D sheets that stack in an eclipsed AA fashion, has high thermal stability (~420 degrees C) and high porosity (SA(BET) = 1178 m(2) g(-1)) and it can store up to 2.4 wt% of hydrogen at 77 K and 15 bar with isosteric heat of adsorption of 6.8 kJ mol(-1). PMID- 22836698 TI - Stakeholder perspectives on decision-analytic modeling frameworks to assess genetic services policy. AB - PURPOSE: Genetic services policymakers and insurers often make coverage decisions in the absence of complete evidence of clinical utility and under budget constraints. We evaluated genetic services stakeholder opinions on the potential usefulness of decision-analytic modeling to inform coverage decisions, and asked them to identify genetic tests for decision-analytic modeling studies. METHODS: We presented an overview of decision-analytic modeling to members of the Western States Genetic Services Collaborative Reimbursement Work Group and state Medicaid representatives and conducted directed content analysis and an anonymous survey to gauge their attitudes toward decision-analytic modeling. Participants also identified and prioritized genetic services for prospective decision-analytic evaluation. RESULTS: Participants expressed dissatisfaction with current processes for evaluating insurance coverage of genetic services. Some participants expressed uncertainty about their comprehension of decision-analytic modeling techniques. All stakeholders reported openness to using decision analytic modeling for genetic services assessments. Participants were most interested in application of decision-analytic concepts to multiple-disorder testing platforms, such as next-generation sequencing and chromosomal microarray. CONCLUSION: Decision-analytic modeling approaches may provide a useful decision tool to genetic services stakeholders and Medicaid decision-makers. PMID- 22836699 TI - Implementing frailty into clinical practice: we cannot wait. PMID- 22836700 TI - A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. AB - OBJECTIVE: To validate the FRAIL scale. DESIGN: Longitudinal study. SETTING: Community. PARTICIPANTS: Representative sample of African Americans age 49 to 65 years at onset of study. MEASUREMENTS: The 5-item FRAIL scale (fatigue, resistance, ambulation, illnesses, and loss of weight), at baseline and activities of daily living (ADLs), instrumental activities of daily living (IADLs), mortality, short physical performance battery (SPPB), gait speed, one leg stand, grip strength and injurious falls at baseline and 9 years. Blood tests for CRP, SIL6R, STNFR1, STNFR2 and 25 (OH) vitamin D at baseline. RESULTS: Cross sectionally the FRAIL scale correlated significantly with IADL difficulties, SPPB, grip strength and one-leg stand among participants with no baseline ADL difficulties (N=703) and those outcomes plus gait speed in those with no baseline ADL dependencies (N=883). TNFR1 was increased in pre-frail and frail subjects and CRP in some subgroups. Longitudinally (N=423 with no baseline ADL difficulties or N=528 with no baseline ADL dependencies), and adjusted for the baseline value for each outcome, being pre-frail at baseline significantly predicted future ADL difficulties, worse one-leg stand scores, and mortality in both groups, plus IADL difficulties in the dependence-excluded group. Being frail at baseline significantly predicted future ADL difficulties, IADL difficulties, and mortality in both groups, plus worse SPPB in the dependence-excluded group. CONCLUSION: This study has validated the FRAIL scale in a late middle-aged African American population. This simple 5-question scale is an excellent screening test for clinicians to identify frail persons at risk of developing disability as well as decline in health functioning and mortality. PMID- 22836701 TI - Birth weight and muscle strength: a systematic review and meta-analysis. AB - OBJECTIVE: Lower muscle strength is associated with a range of adverse health outcomes in later life. The variation in muscle strength between individuals is only partly accounted for by factors in adult life such as body size and physical activity. The aim of this review was to assess the strength of the association between intrauterine development (indicated by birth weight) and subsequent muscle strength. DESIGN: Systematic review and meta-analysis of studies that assessed the association between birth weight and subsequent muscle strength. RESULTS: Nineteen studies met inclusion criteria with 17 studies showing that higher birth weight was associated with greater muscle strength. Grip strength was used as a single measure of muscle strength in 15 studies. Meta-analysis (13 studies, 20 481 participants, mean ages 9.3 to 67.5) showed a 0.86 kg (95% CI 0.58, 1.15) increase in muscle strength per additional kilogram of birth weight, after adjustment for age, gender and height at the time of strength measurement. CONCLUSION: This review has found consistent evidence of a positive association between birth weight and muscle strength which is maintained across the lifecourse. Future work will be needed to elucidate the biological mechanisms underlying this association, but it suggests the potential benefit of an early intervention to help people maintain muscle strength in later life. PMID- 22836702 TI - Relationship between protein intake and dynapenia in postmenopausal women. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between protein intake and dynapenia. DESIGN: A cross-sectional/observational study. SETTING: Department of Kinanthropology at the University of Quebec at Montreal. PARTICIPANTS: Seventy-two non-frail postmenopausal women aged between 50 to 75 years were recruited. MEASUREMENTS: Body weight (BW), lean body mass (LBM; %) and skeletal muscle mass (bio-electrical impedancemetry analysis), maximum voluntary handgrip strength (using hand dynamometer), aerobic capacity (VO2peak) and dietary intake were measured. Women were divided according to dynapenia criteria. RESULTS: The strongest correlation between muscle strength and protein intake was observed when we express the amount of protein in g/d/BW. No differences for age, BMI, status of menopause, fat mass and VO2peak were observed between non dynapenic, type I dynapenic and type II dynapenic women, independently of the criteria used. We observed significant differences in protein intake (g/d/BW) between non-dynapenic and type II dynapenic (p<0.01) as well as between type I dynapenic and type II dynapenic (p<0.01) when dynapenia was expressed in kg/BW and in kg/LBM, respectively. It should be noted that no differences in LBM between the three groups were observed when dynapenia was expressed in kg/BW and kg/LBM. Protein intake for all groups respected the RDA of 0.8 to 1.2 g/d/BW (non dynapenic: 1.44/1.38; type I dynapenic: 1.30/1.33; type II dynapenic: 1.05/1.08 g/d/BW). CONCLUSIONS: Protein intake seems to play a role in the development of dynapenia particularly at the level of type II dynapenia. Therefore, an increase in the recommended daily allowance for protein intake may be warranted. PMID- 22836703 TI - Self-reported reading and writing skills in elderly who never attended school influence cognitive performances: results from the Coyoacan cohort study. AB - OBJECTIVES: Beyond the well-known effect of educational level on cognitive performances, the present study investigates the specific effect of literacy acquisition independently of education. DESIGN: A sample of 175 unschooled elderly participants was selected from a larger Mexican population-based cohort study. PARTICIPANTS: The sample of 175 subjects who never went to school was divided in two groups: 109 who never acquired literacy skills and 66 who declared having acquired reading and writing abilities. MEASUREMENTS: Cognitive performances on commonly used tests (mini mental state examination, Isaacs set test, free and cued selective reminding test and clock-drawing test) were compared between the two groups taking into account several potentially confounding factors. RESULTS: The participants with reading and writing skills performed better than their counterparts in most tests, even though no difference was observed for the Isaacs Set Test and the delayed recall of the free and cued selective reminding test. CONCLUSION: Writing and reading skills in elderly people with no formal education influence performances in very commonly used test. Not only educational level but also literacy acquisition should be taken into account when conducting cognitive assessment in very low educated elderly people. PMID- 22836704 TI - Fruit, vegetables and prevention of cognitive decline or dementia: a systematic review of cohort studies. AB - BACKGROUND: Regular consumption of fruit and vegetables has been considered to be associated with a reduced risk of dementia and age-associated cognitive decline, although the association is currently unsupported by a systematic review of the literature. METHODS: We searched Medline, Embase, Biosis, ALOIS, the Cochrane library, different publisher databases as well as bibliographies of retrieved articles. All cohort studies with a follow-up of 6 months or longer were included if they reported an association of Alzheimer's disease or cognitive decline in regard to the frequency of fruit and vegetables consumption. FINDINGS: Nine studies with a total of 44,004 participants met the inclusion criteria. Six studies analyzed fruit and vegetables separately and five of them found that higher consumption of vegetables, but not fruit is associated with a decreased risk of dementia or cognitive decline. The same association was found by three further studies for fruit and vegetable consumption analytically combined. CONCLUSION: Increased intake of vegetables is associated with a lower risk of dementia and slower rates of cognitive decline in older age. Yet, evidence that this association is also valid for high fruit consumption is lacking. PMID- 22836705 TI - Mild cognitive impairment associates with concurrent decreases in serum cholesterol and cholesterol-related lipoprotein subclasses. AB - BACKGROUND AND OBJECTIVE: Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years. DESIGN: Longitudinal. SETTING: City of Kuopio, Finland. PARTICIPANTS: 45 elderly individuals of which 20 developed mild cognitive impairment (MCI) during the follow-up. MEASUREMENTS: On each visit participants underwent an extensive neuropsychological and clinical assessment. Lipoprotein levels were measured via 1H NMR from native serum samples. RESULTS: Serum cholesterol and many primarily cholesterol-associated lipoprotein measures clearly decreased in MCI while the trends were increasing for those elderly people who maintained normal cognition. CONCLUSION: These findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline. PMID- 22836706 TI - The Veterans Affairs Saint Louis University mental status exam (SLUMS exam) and the Mini-mental status exam as predictors of mortality and institutionalization. AB - OBJECTIVE: To evaluate predictive validity of cognitive dysfunction of the Saint Louis University mental status (SLUMS) exam or mini-mental state exam (MMSE) for institutionalization and mortality after 7.5-years. DESIGN: Longitudinal study. SETTING: Geriatric Research, Education and Clinical Center Veterans Affairs Hospital St. Louis, MO. PARTICIPANTS: Patients (N=705) were screened for cognitive dysfunction in 2003 using the SLUMS exam and MMSE, and mortality and institutionalization up to 7.5-years later were evaluated as outcome measures. MEASUREMENT: The associations between outcome measures and MMSE and SLUMS exam total scores, and cognitive status were examined using Kaplan-Meier curves and Cox proportional-hazards regression. RESULTS: Five hundred thirty-three charts were reviewed, 176/533(33%) patients had died and 31/526 (6%) were institutionalized during 7.5-year follow-up period. All subjects were male with a mean age of 75 years and most had high school education or greater (71%). MMSE dementia, SLUMS dementia (ps<.001) and MCI (p<.05) groups had significantly lower survival rates than normal cognition group in the Kaplan-Meier curves. Scores classified as dementia on SLUMS (HR=2.4, 95% CI 1.6-3.7; p <.001) or MMSE (HR=2.3, 95% CI 1.5-3.6; p <.001) both predicted mortality and, also, institutionalization (SLUMS: HR=3.5, 95% CI 1.3-9.1; p <.01; MMSE: HR=3.8, 95% CI 1.6-9.0; p <.001) after adjustment for covariates. Unadjusted SLUMS exam MCI predicted morality (HR=1.5, 95% CI 1.1-2.2; p <.019) but not institutionalization. CONCLUSION: The SLUMS exam and MMSE both predict mortality and institutionalization for male patients screened as positive for dementia. PMID- 22836707 TI - Tai chi diminishes oxidative stress in Mexican older adults. AB - OBJECTIVE: To determine the effect of Tai Chi on oxidative stress in a population of elderly Mexican subjects. DESIGN: It was carried out a quasi-experimental study with a sample of 55 healthy subjects randomly divided into two age-matched groups: (i) a control group with 23 subjects and (ii) an experimental group with 32 subjects. The experimental group received daily training in Tai Chi for 50 min. MEASUREMENTS: It was measured before and after 6-month of exercise period: thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS), superoxide dismutase (SOD), and glutathione peroxidase (GPx). RESULTS: It was found that the experimental group exhibited a statistically significant decrease in glucose levels, total cholesterol, low-density lipoprotein cholesterol (LDLC), and systolic blood pressure, as well as an increase in SOD and GPx activity and TAS compared with the control group (p < 0.05). CONCLUSIONS: Our findings suggest that the daily practice of Tai Chi is useful for reducing OxS in healthy older adults. PMID- 22836708 TI - Glomerular filtration rate estimated by Cockcroft-Gault formula better predicts anti-Xa levels than modification of the diet in renal disease equation in older patients with prophylactic enoxaparin. AB - OBJECTIVES: Older people have an increased risk of low molecular weight heparin accumulation leading to an increased bleeding risk. The objective of this study was to assess whether reduced glomerular filtration rate (GFR), estimated by the Cockcroft-Gault or modification of the diet in renal disease (MDRD) equations, indicates drug accumulation by increased anti-Xa levels in older subjects receiving prophylactic enoxaparin treatment. DESIGN: Cohort study. SETTING: Acute geriatric units in Nancy Hospital. PARTICIPANTS: Ninety-two consenting consecutive patients, 65 and older, confined to bed for an acute medical condition requiring enoxaparin for prevention of venous thromboembolism, and hospitalized for at least six days were enrolled. MEASUREMENTS: Serum creatinine and peak plasma anti-Xa levels 3 to 4 hours after the daily injection of enoxaparin were measured at days 3, 6, 9 and 12 (first dose of enoxaparin at day one). Analyses of variance for repeated measures were used to evaluate significant predictors of peak anti-Xa activity in univariate and multivariate analyses. RESULTS: A significant correlation was observed between anti-Xa activity and GFR estimated with the Cockcroft formula r=0.43. Following univariate analysis, the three factors associated with higher anti-Xa levels were a lower Cockcroft-Gault GFR (p=0.0002), female gender (p=0.0003) and a lower bodyweight (p<.0001). No significant association between anti-Xa levels and MDRD GFR (p=0.33) was observed. Following multivariate analysis, female gender (p=0.02), bodyweight (p=0.04) and Cockcroft GFR (p=0.05) remained independent determinants of anti-Xa levels. CONCLUSION: In hospitalized patients older than 65 years old, the Cockcroft-Gault equation, in contrast to the MDRD equation, is able to predict the risk of higher anti-Xa levels. PMID- 22836709 TI - Predicting falls in elderly receiving home care: the role of malnutrition and impaired mobility. AB - To investigate the role of malnutrition, impaired mobility and care dependency in predicting fallers in older Dutch home care clients. DESIGN: This study is a secondary analysis of data of the annual independent national prevalence measurement of care problems of Maastricht University. The design involves a cross-sectional, multicentre point prevalence measurement (malnutrition, mobility), and a 30 days incidence measurement (falls). SETTING: Dutch home care organisations. PARTICIPANTS: 2971 clients (older than 65 years) from 22 home care organizations participated. MEASUREMENTS: A standardized questionnaire was used to register amongst others data of weight, height, number and type of diseases (like for example neurologic diseases, dementia, CVA, COPD, eye/ear disorders, musculoskeletal disorders), nutritional intake, use of psychopharmaca, undesired weight loss, fall history, mobility, and care dependency. RESULTS: The study was able to show that fallers are more often malnourished than non-fallers in the univariate analysis. Most importantly the study indicated by multivariate analysis that fallers could be predicted by the risk factors immobility ((OR 2.516 95% CI 1.144-5.532), high care dependency (OR 1.684 95% CI 1.121-2.532) and malnutrition (OR 1.978 95% CI 1.340-2.920). CONCLUSION: The findings of this study stress that malnutrition, impaired mobility and care dependency are potential reversible factors related to falls. Therefore early identification and management of nutritional status, impaired mobility and care dependency are important aspects for a possible fall prevention strategy. PMID- 22836710 TI - Validation of screening tools to assess appetite among geriatric patients. AB - Poor appetite is one of the main contributing factors of poor nutritional status among elderly individuals. Recognizing the importance of assessment of appetite, a cross sectional study was conducted to determine the validity of appetite screening tools namely, the Council on Nutrition Appetite questionnaire (CNAQ) and the simplified nutritional appetite questionnaire (SNAQ) against the appetite, hunger and sensory perception questionnaire (AHSPQ), measures of nutritional status and food intake among geriatric patients at the main general hospital in Malaysia. Nutritional status was assessed using the subjective global assessment (SGA) while food intake was measured using the dietary history questionnaire (DHQ). Anthropometric parameters included weight, height, body mass index (BMI), calf circumference (CC) and mid upper arm circumference (MUAC). A total of 145 subjects aged 60 to 86 years (68.3 +/- 5.8 years) with 31.7% men and 68.3% women were recruited from outpatients (35 subjects) and inpatients (110 subjects) of Kuala Lumpur Hospital of Malaysia. As assessed by SGA, most subjects were classified as mild to moderately malnourished (50.4%), followed by normal (38.6%) and severely malnourished (11.0%). A total of 79.3% and 57.2% subjects were classified as having poor appetite according to CNAQ and SNAQ, respectively. CNAQ (80.9%) had a higher sensitivity than SNAQ (69.7%) when validated against nutritional status as assessed using SGA. However, the specificity of SNAQ (62.5%) was higher than CNAQ (23.2%). Positive predictive value for CNAQ and SNAQ were 62.6% and 74.7%, respectively. Cronbach's alpha for CNAQ and SNAQ were 0.546 and 0.578, respectively. History of weight loss over the past one year (Adjusted odds ratio 2.49) (p < 0.01) and thiamine intake less than the recommended nutrient intake (RNI) (Adjusted odds ratio 3.04) (p < 0.05) were risk factors for poor appetite among subjects. In conclusion, malnutrition and poor appetite were prevalent among the geriatric outpatients and inpatients. SNAQ was more reliable and valid as an appetite screening tool among this special group of population. There is a need to regularly include nutritional and appetite assessment for early intervention measures in order to prevent consequences of malnutrition. PMID- 22836711 TI - Relative validity of the Geisinger Rural Aging Study food frequency questionnaire. AB - OBJECTIVE: To determine the relative validity of a population specific food frequency questionnaire (FFQ) and evaluate the effectiveness of the instrument for assessing nutritional risk in older adults. DESIGN: A cross-over design with participants completing two different dietary assessment instruments in random order. SETTING: The Geisinger Rural Aging Study (GRAS), a longitudinal study of over 20,000 adults living in the central, northern and eastern counties of Pennsylvania. PARTICIPANTS: A subset of GRAS consisting of 245 older adults (60% women) ranging in age from 70 to 95 years. MEASUREMENTS: Energy and nutrient intakes were assessed from two instruments: a population specific food frequency questionnaire (FFQ) and four 24-hour dietary recalls conducted over a two week period. RESULTS: Pearson correlation coefficients between the FFQ and dietary recalls for most nutrients were 0.5 or higher which suggests that the FFQ provided relatively valid estimates of macro and micronutrient intakes examined. Bland-Altman plots were generated to examine the agreement between instruments. Data are shown for energy, folate and zinc with close agreement at lower intakes indicative of risk for folate and zinc. Sensitivity results also showed that the FFQ was able to correctly classify individuals adequately at risk for most nutrients examined. CONCLUSION: This population specific FFQ appears to be a valid instrument for use in in evaluating risk for many nutrients that are of particular concern in older adults residing throughout many predominately rural counties in Pennsylvania. PMID- 22836712 TI - A comparative cellular and molecular biology of longevity database. AB - Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity. Here, we introduce a Comparative Cellular and Molecular Biology of Longevity Database, available at ( http://genomics.brocku.ca/ccmbl/ ), as a compendium of comparative cell and molecular data presented in the context of longevity. This open access database will facilitate the meta-analysis of amalgamated datasets using standardized maximum lifespan (MLSP) data (from AnAge). The first edition contains over 800 data records describing experimental measurements of cellular stress resistance, reactive oxygen species metabolism, membrane composition, protein homeostasis, and genome homeostasis as they relate to vertebrate species MLSP. The purpose of this review is to introduce the database and briefly demonstrate its use in the meta-analysis of combined datasets. PMID- 22836713 TI - The subcutaneous defibrillator. AB - OPINION STATEMENT: Prevention of sudden cardiac death (SCD) remains an important clinical problem. Currently, therapeutic goals for SCD prevention include identification of high risk patients and aggressively treating comorbidities underlying. However, many patients remain at increased risk despite optimal medical management (eg, coronary artery disease and cardiomyopathy) whereas others have nonmodifiable risk for sudden death (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy, Brugada syndrome, long QT syndrome, and hypertrophic cardiomyopathy). In such patients, device therapy with an implantable defibrillator remains the most effective therapy for SCD prevention. However, implantable cardioverter defibrillators (ICDs), which are typically implanted with at least 1 lead placed within the heart, are associated with risks related to device implantation, as well as the presence of chronic endovascular leads. The durability of chronic leads is variable and can require either new leads to be placed or require lead extraction, which is associated with significant morbidity and mortality. The recently developed subcutaneous ICD (S ICD) does not rely on any component to be placed within the heart or vasculature and therefore may mitigate the risks associated with endovascular leads. Therefore, it may be preferred for patients who are young, have inherited channelopathies, are immunocompromised, have indwelling catheters, or in whom venous access is obstructed or unfavorable due to congenital heart disease. Though long-term data regarding S-ICD performance are not yet available it may prove to be an effective therapeutic option for prevention of SCD. PMID- 22836714 TI - Manual aspiration thrombectomy through balloon tipped guide catheter for rapid clot burden reduction in endovascular therapy for ICA L/T occlusion. PMID- 22836715 TI - Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden. AB - A first episode of depression after 65 years of age has long been associated with both severe macrovascular and small microvascular pathology. Among the three more frequent forms of depression in old age, post-stroke depression has been associated with an abrupt damage of cortical circuits involved in monoamine production and mood regulation. Late-onset depression (LOD) in the absence of stroke has been related to lacunes and white matter lesions that invade both the neocortex and subcortical nuclei. Recurrent late-life depression is thought to induce neuronal loss in the hippocampal formation and white matter lesions that affect limbic pathways. Despite an impressive number of magnetic resonance imaging (MRI) studies in this field, the presence of a causal relationship between structural changes in the human brain and LOD is still controversial. The present article provides a critical overview of the contribution of neuropathology in post-stroke, late-onset, and late-life recurrent depression. Recent autopsy findings challenge the role of stroke location in the occurrence of post-stroke depression by pointing to the deleterious effect of subcortical lacunes. Despite the lines of evidences supporting the association between MRI assessed white matter changes and mood dysregulation, lacunes, periventricular and deep white matter demyelination are all unrelated to the occurrence of LOD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of aging-related neurodegenerative changes in the human brain. However, they also provide data in favor of the neurotoxic theory of depression by showing that neuronal loss occurs in the hippocampus of chronically depressed patients. These three paradigms are discussed in the light of the complex relationships between psychosocial determinants and biological vulnerability in affective disorders. PMID- 22836716 TI - Stereochemistry of molecular figures-of-eight. AB - A trans isomer of a figure-of-eight (Fo8) compound was prepared from an electron withdrawing cyclobis(paraquat-p-phenylene) derivative carrying trans-disposed azide functions between its two phenylene rings. Copper(I)-catalyzed azide-alkyne cycloadditions with a bispropargyl derivative of a polyether chain, interrupted in its midriff by an electron-donating 1,5-dioxynaphthalene unit acting as the template to organize the reactants prior to the onset of two click reactions, afforded the Fo8 compound with C(i) symmetry. Exactly the same chemistry is performed on the cis-bisazide of the tetracationic cyclophane to give a Fo8 compound with C(2) symmetry. Both of these Fo8 compounds exist as major and very minor conformational isomers in solution. The major conformation in the trans series, which has been characterized by X-ray crystallography, adopts a geometry which maximizes its C-H...O interactions, while maintaining its pi...pi stacking and C-H...pi interactions. Ab initio calculations at the M06L level support the conformational assignments to the major and minor isomers in the trans series. Dynamic (1)H NMR spectroscopy, supported by 2D (1)H NMR experiments, indicates that the major and minor isomers in both the cis and trans series equilibrate in solution on the (1)H NMR timescale rapidly above and slowly below room temperature. PMID- 22836717 TI - High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study. AB - Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low circulating sclerostin levels cause high bone mass. We hypothesized that postmenopausal women with increased sclerostin levels have a greater risk for osteoporosis-related fractures. We examined the association between circulating sclerostin together with bone turnover markers and osteoporosis-related fracture risk in 707 postmenopausal women, in a population-based study with a mean follow up period of 5.2 +/- 1.3 years. Multivariate Cox proportional hazards regression models were used to analyze fracture risk, adjusted for age, body mass index, and other confounding risk factors. High sclerostin levels were strongly associated with increased fracture risk. After adjustment for age and other confounders, the relative fracture risk was more than sevenfold among postmenopausal women for each 1-SD increment increase in sclerostin level. Women in the highest quartile of sclerostin levels had about a 15-fold increase in fracture risk. Results were similar when we compared sclerostin at the 1-year visit to an average of two to three annual measurements. Fracture risk attributable to sclerostin levels was 56.6% in the highest quartile. Only high levels of bone resorption markers (plasma cross-linked C-terminal telopeptide of type 1 collagen [p-CTx], urinary CTx [u-CTx], and urinary N-telopeptide of type 1 collagen [u-NTx]) were predictive of osteoporosis-related fractures but at much lower hazard ratio (HR) values than that of serum sclerostin. Associations between sclerostin levels and fracture risk were independent of bone mineral density and other confounding risk factors. High sclerostin levels are a strong and independent risk factor for osteoporosis-related fractures among postmenopausal women. (c) 2012 American Society for Bone and Mineral Research. PMID- 22836720 TI - Utilisation of transdermal fentanyl in Germany from 2004-2006 by Edeltraut Garbe and colleagues. PMID- 22836718 TI - Reactive carbonyl compounds (RCCs) cause aggregation and dysfunction of fibrinogen. AB - Fibrinogen is a key protein involved in coagulation and its deposition on blood vessel walls plays an important role in the pathology of atherosclerosis. Although the causes of fibrinogen (fibrin) deposition have been studied in depth, little is known about the relationship between fibrinogen deposition and reactive carbonyl compounds (RCCs), compounds which are produced and released into the blood and react with plasma protein especially under conditions of oxidative stress and inflammation. Here, we investigated the effect of glycolaldehyde on the activity and deposition of fibrinogen compared with the common RCCs acrolein, methylglyoxal, glyoxal and malondialdehyde. At the same concentration (1 mmol/L), glycolaldehyde and acrolein had a stronger suppressive effect on fibrinogen activation than the other three RCCs. Fibrinogen aggregated when it was respectively incubated with glycolaldehyde and the other RCCs, as demonstrated by SDS-PAGE, electron microscopy and intrinsic fluorescence intensity measurements. Staining with Congo Red showed that glycolaldehyde- and acrolein-fibrinogen distinctly formed amyloid-like aggregations. Furthermore, the five RCCs, particularly glycolaldehyde and acrolein, delayed human plasma coagulation. Only glycolaldehyde showed a markedly suppressive effect on fibrinogenesis, none did the other four RCCs when their physiological blood concentrations were employyed, respectively. Taken together, it is glycolaldehyde that suppresses fibrinogenesis and induces protein aggregation most effectively, suggesting a putative pathological process for fibrinogen (fibrin) deposition in the blood. PMID- 22836719 TI - Effects of potential food sources on biological and demographic parameters of the predatory mites Kampimodromus aberrans, Typhlodromus pyri and Amblyseius andersoni. AB - Kampimodromus aberrans, Typhlodromus pyri and Amblyseius andersoni are generalist predatory mites important in controlling tetranychid and eriophyoid mites in European vineyards. They can persist by exploiting various non-prey foods when their main prey is absent or scarce. A comparative analysis of the effects of various prey and non-prey foods on the life history of these predators is lacking. In the laboratory, predatory mites were reared on herbivorous mites (Panonychus ulmi, Eotetranychus carpini and Colomerus vitis), a potential alternative prey (Tydeus caudatus) and two non-prey foods, i.e. the pollen of Typha latifolia and the mycelium of Grape downy mildew (GDM) Plasmopara viticola. Developmental times, survival, sex ratio and fecundity as well as life table parameters were estimated. Kampimodromus aberrans developed faster on E. carpini, C. vitis or pollen than on P. ulmi and laid more eggs on pollen than on prey. Low numbers of this predator developed on GDM infected leaves. Tydeus caudatus was not suitable as prey for any of the three predatory mites. Kampimodromus aberrans showed the highest intrinsic rate of population increase when fed on pollen. Developmental times of T. pyri on prey or pollen were similar but fecundity was higher on pollen than on P. ulmi. Typhlodromus pyri had higher intrinsic rates of population increase on C. vitis and pollen than on P. ulmi; E. carpini showed intermediate values whereas GDM resulted in the lowest r ( m ) values. Development of A. andersoni females was faster on pollen and C. vitis than on P. ulmi and GDM. Fecundity was higher on pollen and mites compared to GDM. Life table parameters of A. andersoni did not differ when predators were fed with prey or pollen while GDM led to a lower r ( m ) value. On a specific diet A. andersoni exhibited faster development and higher fecundity than T. pyri and K. aberrans. These findings improve knowledge on factors affecting the potential of predatory mites in controlling phytophagous mites in European vineyards. PMID- 22836723 TI - Retraction. Direct to consumer Internet advertising of statins: an assessment of safety. PMID- 22836721 TI - Mortality and the self-controlled case series method: letter to the editor. PMID- 22836725 TI - Evidence-based surface anatomy. PMID- 22836724 TI - Bedside echocardiography in critically ill patients: a true hemodynamic monitoring tool. AB - Echocardiography is a versatile, accurate and noninvasive tool suited to examination of shocked patients. Since the 1980s, intensive care practitioners have used ultrasound widely for hemodynamic evaluation and for cardiac anatomy visualization. This article will describe transthoracic and transesophageal echocardiography, their scope, and the classic windows needed to interpret the examination properly. We will also report the main indications of echocardiography and the corresponding parameters. Finally, we will indicate educational programs and define minimum training that enable self-sufficiency. PMID- 22836726 TI - Probing thermal behaviour of microbial transglutaminase with fluorescence and in silico methods. AB - BACKGROUND: Knowledge of transglutaminase behaviour at thermal treatment allows efficient applications in food processing. The heat-induced conformational changes of microbial transglutaminase were studied by fluorescence spectroscopy and a molecular modelling approach. RESULTS: The experimental results indicate the unfolding of transglutaminase in a single-phase reaction, at temperatures over 60 degrees C. The incidence of conformational changes is also supported by the increase of both intrinsic and 1-anilino-8-naphthalene sulfonate fluorescence intensity with temperature. Changes in the secondary and tertiary structure of transglutaminase were outlined after running molecular dynamics simulations at temperatures ranging from 25 degrees C to 80 degrees C. CONCLUSION: The motif's particularities varied with the temperature, suggesting structural rearrangements of the protein, mainly in helices. The largest deviation from the structure equilibrated at 25 degrees C was observed at 80 degrees C. PMID- 22836727 TI - Ultrasound elastic tensor imaging: comparison with MR diffusion tensor imaging in the myocardium. AB - We have previously proven the feasibility of ultrasound-based shear wave imaging (SWI) to non-invasively characterize myocardial fiber orientation in both in vitro porcine and in vivo ovine hearts. The SWI-estimated results were in good correlation with histology. In this study, we proposed a new and robust fiber angle estimation method through a tensor-based approach for SWI, coined together as elastic tensor imaging (ETI), and compared it with magnetic resonance diffusion tensor imaging (DTI), a current gold standard and extensively reported non-invasive imaging technique for mapping fiber architecture. Fresh porcine (n = 5) and ovine (n = 5) myocardial samples (20 * 20 * 30 mm3) were studied. ETI was firstly performed to generate shear waves and to acquire the wave events at ultrafast frame rate (8000 fps). A 2.8 MHz phased array probe (pitch = 0.28 mm), connected to a prototype ultrasound scanner, was mounted on a customized MRI compatible rotation device, which allowed both the rotation of the probe from -90 degrees to 90 degrees at 5 degrees increments and co-registration between two imaging modalities. Transmural shear wave speed at all propagation directions realized was firstly estimated. The fiber angles were determined from the shear wave speed map using the least-squares method and eigen decomposition. The test myocardial sample together with the rotation device was then placed inside a 7T MRI scanner. Diffusion was encoded in six directions. A total of 270 diffusion weighted images (b = 1000 s mm-2, FOV = 30 mm, matrix size = 60 * 64, TR = 6 s, TE = 19 ms, 24 averages) and 45 B0 images were acquired in 14 h 30 min. The fiber structure was analyzed by the fiber-tracking module in software, MedINRIA. The fiber orientation in the overlapped myocardial region which both ETI and DTI accessed was therefore compared, thanks to the co-registered imaging system. Results from all ten samples showed good correlation (r2 = 0.81, p < 0.0001) and good agreement (3.05 degrees bias) between ETI and DTI fiber angle estimates. The average ETI-estimated fractional anisotropy (FA) values decreased from subendocardium to subepicardium (p < 0.05, unpaired, one-tailed t-test, N = 10) by 33%, whereas the corresponding DTI-estimated FA values presented a change of 10% (p > 0.05, unpaired, one-tailed t-test, N = 10). In conclusion, we have demonstrated that the fiber orientation estimated by ETI, which assesses the shear wave speed (and thus the stiffness), was comparable to that measured by DTI, which evaluates the preferred direction of water diffusion, and have validated this concept within the myocardium. Moreover, ETI was shown capable of mapping the transmural fiber angles with as few as seven shear wave propagation directions. PMID- 22836728 TI - Histone H2A monoubiquitination and Polycomb repression: the missing pieces of the puzzle. AB - Polycomb group (PcG) proteins were originally identified as negative regulators of HOX genes in Drosophila but have since emerged as a widely used transcriptional repression system that controls a variety of developmental processes in animals and plants. PcG proteins exist in multi-protein complexes that comprise specific chromatin-modifying enzymatic activities. Genome-wide binding studies in Drosophila and in mammalian cells revealed that these complexes co-localize at a large set of genes encoding developmental regulators. Recent analyses in Drosophila have begun to explore how the different chromatin modifying activities of PcG protein complexes contribute to the repression of individual target genes. These studies suggest that monoubiquitination of histone H2A (H2Aub) by the PcG protein Sce is only essential for repression of a subset of PcG target genes but is not required for the Polycomb-mediated repression of other targets. Calypso/dBap1, a major deubiquitinase for H2Aub is also critically needed for repression of a subset of PcG target genes. Here, we review our current understanding of the role of H2A monoubiquitination and deubiquitination in Polycomb repression in Drosophila. We discuss unresolved issues concerning the immunological detection of H2Aub and critically evaluate experiments that used Sce and Ring1B point mutants with impaired H2A ubiquitinase activity to study H2Aub-dependent and -independent functions of these proteins in transcriptional repression. PMID- 22836729 TI - Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes. AB - The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading. PMID- 22836730 TI - Hierarchically plasmonic photocatalysts of Ag/AgCl nanocrystals coupled with single-crystalline WO3 nanoplates. AB - The hierarchical photocatalysts of Ag/AgCl@plate-WO3 have been synthesized by anchoring Ag/AgCl nanocrystals on the surfaces of single-crystalline WO3 nanoplates that were obtained via an intercalation and topochemical approach. The heterogeneous precipitation process of the PVP-Ag+-WO3 suspensions with a Cl- solution added drop-wise was developed to synthesize AgCl@WO3 composites, which were then photoreduced to form Ag/AgCl@WO3 nanostructures in situ. WO3 nanocrystals with various shapes (i.e., nanoplates, nanorods, and nanoparticles) were used as the substrates to synthesize Ag/AgCl@WO3 photocatalysts, and the effects of the WO3 contents and photoreduction times on their visible-light driven photocatalytic performance were investigated. The techniques of TEM, SEM, XPS, EDS, XRD, N2 adsorption-desorption and UV-vis DR spectra were used to characterize the compositions, phases and microstructures of the samples. The RhB aqueous solutions were used as the model system to estimate the photocatalytic performance of the as-obtained Ag/AgCl@WO3 nanostructures under visible light (lambda >= 420 nm) and sunlight. The results indicated that the hierarchical Ag/AgCl@plate-WO3 photocatalyst has a higher photodegradation rate than Ag/AgCl, AgCl, AgCl@WO3 and TiO2 (P25). The contents and morphologies of the WO3 substrates in the Ag/AgCl@plate-WO3 photocatalysts have important effects on their photocatalytic performance. The related mechanisms for the enhancement in visible-light-driven photodegradation of RhB molecules were analyzed. PMID- 22836731 TI - Fracture clinic redesign: improving standards in patient care and interprofessional education. AB - INTRODUCTION: Current fracture clinic models, especially with the advent of reductions in junior doctors' hours, may limit outpatient trainee education and patient care. We have designed a new fracture clinic model, involving an initial consultant-led case review focused on patient management and trainee education. METHODS: Prospective outcomes for all new patients attending the redesigned fracture clinic over a 3-week period in 2010 (n = 240) were compared with a historical cohort from the same period in 2009 (n = 296). The primary outcome measure was the proportion of patients with direct consultant input. Secondary outcome measures included patient discharge rates, return rates, use of the nurse led fracture clinic and the incidence of adverse event reporting. Trainees attending each clinic completed a five-point Likert questionnaire assessing the adequacy of education, support, staff morale and standards of patient care, before and after introduction of the clinic redesign. Using a separate Likert questionnaire, emergency room (ER) staff were evaluated to determine the impact of the new style clinic on their education, daily practice and interprofessional relations. Adverse events were gathered from the 'incident record 1' (IR1) reporting system. RESULTS: The percentage of cases given consultant input increased significantly from 33% in 2009 to 84% in 2010 (p <0.0001), while the proportion of patients requiring physical review by a consultant fell by 21% (p <0.0001). Return rates were reduced by 14% (p = 0.013) and use of the nurse-led fracture clinic improved by 10% (p = 0.0028). There was a median improvement in trainee perception of education from 2 (interquartile range 1.25-2.75) to 5 (4.25 5, p = 0.011), senior support from 2 (2-3) to 5 (4-5, p = 0.017) and patient care from 3 (3-4) to 5 (4-5, p = 0.015). ER staff found the new style clinic was educational, practice changing and improved interprofessional relations, but that it did not interfere with ER duties. The incidence of adverse incidents reported fell from 8 per year to 0 per year after the introduction of the new style clinic. CONCLUSIONS: Our model of fracture-clinic redesign has significantly enhanced consultant input into patient care without additional funding. In addition, we have demonstrated increased service efficiency and significant improvements in staff support, morale and education. In the face of current economic and training challenges, we recommend this new model as a tool that will enhance patient and trainee experience. PMID- 22836732 TI - Associations between adolescent depression and parental mental health, before and after treatment of adolescent depression. AB - The negative impacts of parental mental health problems on children and adolescents are well known, but the relationship between a child's depression and their parents' health is not so well understood. Being a carer/parent of someone with mental illness can be associated with negative outcomes for the caregiver. This paper reports the associations between the mental health of adolescents with major depression and their parents, before and after treatment of the adolescent's depression. Data were collected as part of the Adolescent Depression Antidepressants and Psychotherapy Trial, a randomised controlled trial of selective serotonin reuptake inhibitors with and without cognitive behaviour therapy in 208 clinic-recruited adolescents with major depression. The baseline severity of depression in the adolescent was significantly associated with both maternal and paternal mental health (as rated by the General Health Questionnaire). This effect was not confounded by other psychiatric symptoms. The degree of improvement in parental and child mental health was positively correlated across time. Our results support the hypothesis that there is a significant association between parental mental health and adolescent depressive symptoms. This study was not able to establish the direction of this association. In clinical practice, the findings demonstrate the importance of considering the mental health of the parents when treating depressed adolescents. PMID- 22836733 TI - Medical conditions affect the outcome of early intervention in preschool children with autism spectrum disorders. AB - The aim was to explore the frequency of genetic and other medical conditions, including epilepsy, in a population-based group of 208 preschool children with early diagnosis of Autism spectrum disorders (ASD) and to relate outcome at a 2 year follow-up to the co-existing medical findings. They had all received early intervention. The Vineland Adaptive Behaviour Scales (VABS-II) composite score served as the primary outcome measure. In the total group, 38/208 children (18 %) had a significant medical or genetic condition. Epilepsy was present in 6.3 % at the first assessment and in 8.6 % at follow-up and was associated with more severe intellectual impairment. A history of regression was reported in 22 %. Children with any medical/genetic condition, including epilepsy, as well as children with a history of regression had significantly lower VABS-II scores at the 2-year follow-up. Children with a medical/genetic condition, including epilepsy, had been diagnosed with ASD at an earlier age than those without such conditions, and early age at diagnosis also correlated negatively with adaptive functioning outcome. The results underscore the importance of considering medical/genetic aspects in all young children with ASD and the requirement to individualize and tailor interventions according to their specific needs. PMID- 22836734 TI - A novel regulatory element between the human FGA and FGG genes. AB - High circulating fibrinogen levels correlate with cardiovascular disease (CVD) risk. Fibrinogen levels vary between people and also change in response to physiological and environmental stimuli. A modest proportion of the variation in fibrinogen levels can be explained by genotype, inferring that variation in genomic sequences that regulate the fibrinogen genes ( FGA , FGB and FGG ) may affect hepatic fibrinogen production and perhaps CVD risk. We previously identified a conserved liver enhancer in the fibrinogen gene cluster (CNC12), between FGB and FGA . Genome-wide Chromatin immunoprecipitation-sequencing (ChIP seq) demonstrated that transcription factors which bind fibrinogen gene promoters also interact with CNC12, as well as two potential fibrinogen enhancers (PFE), between FGA and FGG . Here we show that one of the PFE sequences has potent hepatocyte enhancer activity. Using a luciferase reporter gene system, we found that PFE2 enhances minimal promoter- and FGA promoter-driven gene expression in hepatoma cells, regardless of its orientation with respect to the promoters. A region within PFE2 bears a short series of conserved nucleotides which maintain enhancer activity without flanking sequence. We also demonstrate that PFE2 is a liver enhancer in vivo, driving enhanced green fluorescent protein expression in transgenic zebrafish larval livers. Our study shows that combining public domain ChIP-seq data with in vitro and in vivo functional tests can identify novel fibrinogen gene cluster regulatory sequences. Variation in such elements could affect fibrinogen production and influence CVD risk. PMID- 22836735 TI - Radiosynthesis of 68Ga-labelled DOTA-biocytin (68Ga-r-BHD) and assessment of its pharmaceutical quality for clinical use. AB - OBJECTIVES: Biocytin analogues labelled with indium-111, yttrium-90 and lutetium 177 have shown their effectiveness in the imaging of infections/inflammation in patients with osteomyelitis and function as efficient tools in pretargeted antibody-guided radioimmunotherapy. In this study, the labelling of a biocytin analogue coupled with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), namely, r-BHD, with gallium-68 (68Ga) was optimized, and the quality and stability of the preparations were assessed for clinical use. MATERIALS AND METHODS: Synthesis of 68Ga-r-BHD was carried out by heating a fraction of the 68Ge/68Ga eluate in a reactor containing the biocytin analogue with the appropriate buffer. The influence of the precursor amount (from 2.5 to 140 nmol), the pH of the reaction (from 2 to 5.5) and the buffer species (1.5 mol/l sodium acetate, 1.5 mol/l sodium formate, 4.5 mol/l HEPES) on radiochemical yield and radiochemical purity was assessed. Studies on stability and binding to avidin (Av) were also conducted in different media. RESULTS: Under the best labelling condition (56 nmol of precursor, 3.8 pH, sodium formate buffer) synthesis of 68Ga r-BHD resulted in a yield of 64 +/- 3% (not decay corrected). Radiochemical purity was around 95% because a 68Ga-coordinated sulfoxide form of the ligand was detected as a by-product of the reaction (68Ga-r-SBHD). The by-product was identified and characterized by liquid chromatography-electrospray ionization tandem mass spectrometry. At the natural 1 : 4 Av/68Ga-r-BHD molar ratio, affinity results were 62 +/- 2 and 80 +/- 2% in saline and human serum, respectively. Stability of 68Ga-r-BHD and of the radiotracer/Av complex remains almost constant over 180 min. 68Ga-r-BHD appears to be a good candidate for clinical applications. PMID- 22836736 TI - 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with 18F-FMISO. AB - OBJECTIVE: Hypoxia is an important negative prognostic factor for radiation treatment of head and neck (H&N) cancer. The focus of this study was to evaluate the feasibility of 18F-HX4 (3-[18F]fluoro-2-(4-((2-nitro-1Himidazol- 1-yl)methyl) 1H-1,2,3,-triazol-1-yl)-propan-1-ol) on hypoxia imaging compared with 18F fluoromisonidazole (18F-FMISO) mainly in human H&N cancer. METHODS: 18F-HX4 precursor, standards, and methods were provided by Siemens Molecular Imaging Inc. 18F-HX4 was prepared in an automated module. Twelve patients with H&N cancer were recruited into this study. Each patient underwent 18F-HX4 PET/CT imaging, followed by 18F-FMISO and 18F-fluorodeoxyglucose (18F-FDG) PET/CT on separate days. 18F-HX4 and 18F-FMISO images of the H&N areas were acquired 1.5 and 2 h after injection, respectively. Standard uptake values and tumor-to-muscle (T/M) ratios were calculated. Immunohistochemical analysis of the hypoxia-associated marker CA-IX was carried out to investigate the relationship with PET uptake. RESULTS: 18F-HX4 and 18F-FMISO in the patients gave similar hot spots well within the 18F-FDG uptake region. At 1.5 h postinjection 18F-HX4 yielded a T/M similar to that of 18F-FMISO at 2 h postinjection (1.94+/-1.03 vs. 1.85+/-1.01; P> 0.05). A total of 12 lesions were identified. Among them, eight lesions were positive and two lesions were negative on both 18F-HX4 and 18F-FMISO images; one of the other two lesions was positive only on 18F-HX4, whereas the other one was positive only on 18F-FMISO. The CA-IX expression result correlated with the hypoxia imaging but not with 18F-FDG imaging. CONCLUSION: 18F-HX4 is a safe and feasible agent in hypoxia imaging of H&N cancer patients. We could assume that 18F-HX4 may have higher sensitivity and specificity, faster clearance, and shorter injection-acquisition time compared with traditional 18F-FMISO. Additional evaluations need to be carried out to validate the assumption. Further development of 18F-HX4 for eventual targeting of antihypoxia therapies is warranted. PMID- 22836737 TI - Nucleic acid-mediated gold oxidation: novel biolithography for surface microfabrication and new insight into gold-based biomaterials. AB - In Nature, certain organisms can perform microbial corrosion on base metals by oxidation of neutral metallic atoms (H. L. Ehrlich, Appl. Microbiol. Biotechnol., 1997). Herein we describe the first discovery of biological nucleic acids able to catalyze and mediate gold oxidation from neutral Au(0) to trivalent Au(III) under certain oxidative environments provided by mild oxidizing reagent N bromosuccinimide or amino acids. A new biolithography technique for gold patterning is further developed. PMID- 22836738 TI - Standards for diagnostic spirometry within-session repeatability in primary care. PMID- 22836739 TI - Using COPD multidimensional indices in routine clinical practice: DOSE meets all criteria. PMID- 22836740 TI - Anticipating the outcomes and care choices for people living with COPD. PMID- 22836741 TI - Notification about seasonal influenza vaccination: what is the best way to increase uptake? PMID- 22836742 TI - Frequency of non-asthma GP visits predicts asthma exacerbations: an observational study in general practice. AB - BACKGROUND: Being able to identify patients at risk of exacerbations is useful as it enables resources to be targeted at these patients. AIMS: To test the theoretically-derived prediction that the frequency of non-asthma related visits to the general practitioner (GP) predicts exacerbations. METHODS: Clinical and demographic data and both self-report and prescription-based adherence data were obtained from 166 patients diagnosed with asthma attending a GP clinic, all of whom were prescribed inhaled corticosteroids (ICS). Asthma exacerbations (treated by the GP or in hospital) and non-asthma visits and symptoms were assessed from notes for the subsequent 5 years. RESULTS: Exacerbations correlated with non asthma visits (0.35), severity as measured by BTS step (0.28), and with prescription-based adherence (0.28). Asthma severity correlated with non-asthma visits (0.35). Receiver operating curves showed that >=2 non-asthma visits per year provided 79% sensitivity and 58% specificity for detecting >=3 exacerbations over 5 years. Poor adherence predicted outcomes only for patients with high levels of non-asthma visits (>=3) and only for those reporting regular-but-less ICS use but not symptom-directed ICS use. CONCLUSIONS: Non-asthma visits are a good predictor of asthma exacerbations, particular in non-adherent patients. These results are consistent with a mechanism where exacerbations result from a combination of random oscillating specific and non-specific inflammatory processes. It is important to consider the total patient rather than just the lung when managing patients with asthma. PMID- 22836743 TI - 2012 and never been KISSed: we need to improve the care of children with asthma. PMID- 22836744 TI - Case finding for COPD in primary care: a systematic review. PMID- 22836745 TI - Nitrofurantoin-induced lung disease and prophylaxis of urinary tract infections. AB - Nitrofurantoin is commonly used for the treatment and prophylaxis of recurrent urinary tract infections (UTIs). Although relatively rare, nitrofurantoin is one of the commonest causes of drug-induced pulmonary disease, which can be potentially serious and even fatal. Knowledge of such potential adverse effects is essential to enable early recognition and withdrawal of the drug. Patients on long-term nitrofurantoin should be reviewed and monitored regularly. Management involves early consideration of the condition, and prompt withdrawal of the drug. We report three cases of nitrofurantoin-induced lung disease in patients who were on long-term nitrofurantoin for UTI prophylaxis and present a brief review of the literature on this subject. PMID- 22836746 TI - Examination of risk and resiliency in a pediatric sickle cell disease population using the psychosocial assessment tool 2.0. AB - OBJECTIVE: To evaluate the Psychosocial Assessment Tool 2.0 (PAT) as an appropriate screening measure of risk for patient and family psychological distress in pediatric sickle cell disease (SCD). METHODS: 219 caregivers completed the PAT during regular hematology clinic visits. Confirmatory factor analysis and tests of reliability were conducted. Multilevel modeling examined change and predictors of risk scores across four assessments. RESULTS: Confirmatory factor analysis factor loadings ranged from .03 to .81, and reliability coefficients ranged from .43 to .83. Risk for patient and sibling emotional problems, family problems, and parent stress reaction decreased over time. Increased patient age, chronic blood transfusion, lower caregiver education, caregivers being divorced, fewer adults and more children in the home, and greater financial difficulties were independent predictors of psychosocial risk. CONCLUSIONS: Results suggest that the PAT has utility in a pediatric sickle cell disease sample. Most caregivers reported low distress and high resiliency factors in this population. PMID- 22836747 TI - Acute stress reactions in couples after a burn event to their young child. AB - OBJECTIVE: This multicenter study examines acute stress reactions in couples following a burn event to their preschool child. METHODS: Participants were 182 mothers and 154 fathers, including 143 couples, of 193 children (0-4 years) with acute burns. Parents' self-reported acute stress reactions and emotions regarding the burn event were measured within the first month postburn. RESULTS: More mothers than fathers reported clinically significant acute stress reactions. Multilevel analysis revealed that individual parent reactions were associated with parent gender and negative emotions about the burn event. Interestingly, avoidance symptoms overlapped to an important extent within couples, whereas intrusion symptoms were mainly intra-individual. Burn characteristics, such as burn size, contributed to acute stress within couples. CONCLUSIONS: Mothers and fathers are seriously affected by their child's burn trauma and share a part of their acute stress reactions. These results emphasize the importance of a family based approach to support adjustment after pediatric medical trauma. PMID- 22836748 TI - A target-activated autocatalytic DNAzyme amplification strategy for the assay of base excision repair enzyme activity. AB - Based on a target-activated autocatalytic DNAzyme amplification strategy, novel fluorescence sensing platforms were constructed for highly sensitive and selective assay of base excision repair enzyme activity. By using a rolling circle amplification (RCA)-coupled amplification cascade, an extremely low detection limit (0.002 U mL(-1)) was achieved. PMID- 22836749 TI - Effects of inoculum physiological stage on the growth characteristics of Chlorella sorokiniana cultivated under different CO(2) concentrations. AB - In order to maximize microalgae biomass production and reduce its overall costs, it is important to optimize inoculum conditions based on its physical and physiological characteristics. Chlorella sorokiniana cultures inoculated with inoculum at three different physiological stages (lag, exponential, and stationary) diluted to the same optical density were cultivated for 12 days under three different CO(2) concentrations (0.038, 5, or 10 % CO(2) v/v) and growth pattern and biomass production was observed. Samples inoculated with lag phase inoculum supplied with 5 % CO(2) achieved the maximum biomass production, whereas samples supplied with 0.038 % CO(2) never reached exponential growth. The better growth of samples inoculated with lag phase inoculum was attributed to its increased number of cells compared to the other two inocula. PMID- 22836750 TI - Hydrogen and methane production, energy recovery, and organic matter removal from effluents in a two-stage fermentative process. AB - This study evaluates the potential for using different effluents for simultaneous H(2) and CH(4) production in a two-stage batch fermentation process with mixed microflora. An appreciable amount of H(2) was produced from parboiled rice wastewater (23.9 mL g(-1) chemical oxygen demand [COD]) and vinasse (20.8 mL g( 1) COD), while other effluents supported CH(4) generation. The amount of CH(4) produced was minimum for sewage (46.3 mL g(-1) COD), followed by parboiled rice wastewater (115.5 mL g(-1) COD) and glycerol (180.1 mL g(-1) COD). The maximum amount of CH(4) was observed for vinasse (255.4 mL g(-1) COD). The total energy recovery from vinasse (10.4 kJ g(-1) COD) corresponded to the maximum COD reduction (74.7 %), followed by glycerol (70.38 %, 7.20 kJ g(-1) COD), parboiled rice wastewater (63.91 %, 4.92 kJ g(-1) COD), and sewage (51.11 %, 1.85 kJ g(-1) COD). The relatively high performance of vinasse in such comparisons could be attributed to the elevated concentrations of macronutrients contained in raw vinasse. The observations are based on kinetic parameters of H(2) and CH(4) production and global energy recovery of the process. These observations collectively suggest that organic-rich effluents can be deployed for energy recovery with sequential generation of H(2) and CH(4). PMID- 22836751 TI - Platelets and P-selectin control tumor cell metastasis in an organ-specific manner and independently of NK cells. AB - The prometastatic role of platelets has long been recognized with proposed mechanisms of action including shielding tumor cells from natural killer (NK) cell destruction and aiding endothelial attachment and extravasation of tumor cells with platelet P-selectin being implicated in these processes. However, many aspects of the prometastatic function of platelets remain unclear. In this study, we used mouse models of metastatic breast cancer and melanoma to investigate the platelet effect, focusing on organ specificity, the relationship with NK cells and the relative importance of platelet-derived versus endothelial-derived P selectin. We found that platelets promote lung metastasis in the absence of NK cells in both acute and spontaneous metastasis models. In addition, the prometastatic action of platelets was found to be organ specific, clearly enhancing lung metastasis but not affecting B16F1 liver metastasis, in fact, liver metastasis was enhanced in the absence of platelets. Furthermore, the profound antimetastatic activity of NK cells was equally effective in the presence or absence of platelets and chronologically distinct from the prometastatic role of platelets. Finally, it was shown that endothelial-derived P selectin is just as important as platelet-derived P-selectin in promoting lung metastasis and also plays an important role in liver metastasis. Taken together, our findings help clarify the roles of platelets, NK cells and P-selectin in metastasis, and they identify P-selectin as an attractive therapeutic target for preventing metastasis in multiple organs. PMID- 22836752 TI - INK4a/ARF [corrected] inactivation with activation of the NF-kappaB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma. AB - Although human angiosarcoma has been associated frequently with mutational inactivation of the tumor suppressor gene Ink4a/Arf, the underlying mechanisms have not been delineated. Here we report that malignant angiosarcoma is associated with high levels of RelA/NF-kappaB and IL-6 in contrast to normal vessels or benign hemagiomas. Studies of Ink4a/Arf deficient mice not only recapitulate genetic traits observed in human angiosarcoma, but also unveil a possible therapeutic link comprised of the NF-kB/IL-6/Stat3 signaling axis. In Ink4a/Arf(-/-) cells, NF-kappaB controlled Stat3 signaling by transcriptionally controlling the expression of IL-6, gp130, and Jak2. Further, IL-6 mediated Stat3 signaling through the sIL-6R. Inhibition of Ikkbeta solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkbeta, IL-6, or Stat3 markedly inhibited angiosarcoma growth. Our findings offer clinical implications for targeting the NF-kB/IL-6/STAT3 pathway as a rational strategy to treat angiosarcoma. PMID- 22836753 TI - Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer. AB - Oncolytic virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic. PMID- 22836754 TI - B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. AB - Both the PI3K -> Akt -> mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K -> Akt -> mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K -> Akt -> mTOR and ERK1/2 MAPK signaling pathways. PMID- 22836755 TI - Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T cell expansion that may contribute to breast cancer progression. AB - Infiltration and dysfunction of immune cells have been documented in many types of cancers. We previously reported that plasmacytoid dendritic cells (pDC) within primary breast tumors correlate with an unfavorable prognosis for patients. The role of pDC in cancer remains unclear but they have been shown to mediate immune tolerance in other pathophysiologic contexts. We postulated that pDC may interfere with antitumor immune response and favor tolerance in breast cancer. The present study was designed to decipher the mechanistic basis for the deleterious impact of pDC on the clinical outcome. Using fresh human breast tumor biopsies (N = 60 patients), we observed through multiparametric flow cytometry increased tumor-associated (TA) pDC (TApDC) rates in aggressive breast tumors, i.e., those with high mitotic index and the so-called triple-negative breast tumors (TNBT). Furthermore, TApDC expressed a partially activated phenotype and produced very low amounts of IFN-alpha following toll-like receptor activation in vitro compared with patients' blood pDC. Within breast tumors, TApDC colocalized and strongly correlated with TA regulatory T cells (TATreg), especially in TNBT. Of most importance, the selective suppression of IFN-alpha production endowed TApDC with the unique capacity to sustain FoxP3(+) Treg expansion, a capacity that was reverted by the addition of exogenous IFN-alpha. These findings indicate that IFN-alpha-deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo, contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-alpha production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer. PMID- 22836756 TI - MicroRNA-21 modulates the levels of reactive oxygen species by targeting SOD3 and TNFalpha. AB - MicroRNA-21 (miR-21) is an oncomir overexpressed in most human tumors in that it promotes malignant growth and progression by acting on multiple targets. Here, we broaden the impact of miR-21 in cancer by showing that it regulates the formation of reactive oxygen species (ROS) that promote tumorigenesis. Key targets of miR 21 in mediating this function were SOD3 and TNFalpha. We found that miR-21 inhibited the metabolism of superoxide to hydrogen peroxide, produced either by endogenous basal activities or exposure to ionizing radiation (IR), by directing attenuating SOD3 or by an indirect mechanism that limited TNFa production, thereby reducing SOD2 levels. Importantly, both effects contributed to an elevation of IR-induced cell transformation. Our findings, therefore, establish that miR-21 promotes tumorigenesis to a large extent through its regulation of cellular ROS levels. PMID- 22836757 TI - MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells. AB - Bone marrow-derived endothelial progenitor cells (EPC) contribute to the angiogenesis-dependent growth of tumors in mice and humans. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. miRNAs have emerged as key regulators of several cellular processes including angiogenesis; however, whether miRNAs contribute to bone marrow-mediated angiogenesis has remained unknown. Here, we show that genetic ablation of miRNA-processing enzyme Dicer, specifically in the bone marrow, decreased the number of circulating EPCs, resulting in angiogenesis suppression and impaired tumor growth. Furthermore, genome-wide deep sequencing of small RNAs revealed tumor EPC-intrinsic miRNAs including miR-10b and miR-196b, which have been previously identified as key regulators of HOX signaling and adult stem cell differentiation. Notably, we found that both miR-10b and miR-196b are responsive to vascular endothelial growth factor stimulation and show elevated expression in human high-grade breast tumor vasculature. Strikingly, targeting miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth in mice. Targeting these miRNAs may constitute a novel strategy for inhibiting tumor angiogenesis. PMID- 22836758 TI - Examining the association between implementation and outcomes : state-wide scale up of school-wide positive behavior intervention and supports. AB - Although there is an established literature supporting the efficacy of a variety of prevention programs, there has been less empirical work on the translation of such research to everyday practice or when scaled-up state-wide. There is a considerable need for more research on factors that enhance implementation of programs and optimize outcomes, particularly in school settings. The current paper examines how the implementation fidelity of an increasingly popular and widely disseminated prevention model called, School-wide Positive Behavioral Interventions and Supports (SW-PBIS), relates to student outcomes within the context of a state-wide scale-up effort. Data come from a scale-up effort of SW PBIS in Maryland; the sample included 421 elementary and middle schools trained in SW-PBIS. SW-PBIS fidelity, as measured by one of three fidelity measures, was found to be associated with higher math achievement, higher reading achievement, and lower truancy. School contextual factors were related to implementation levels and outcomes. Implications for scale-up efforts of behavioral and mental health interventions and measurement considerations are discussed. PMID- 22836759 TI - Incidence of C-shaped root canal systems in mandibular second molars in the native Chinese population by analysis of clinical methods. AB - The aims of the study were to investigate the incidence of C-shaped root canal systems in mandibular second molars in a native Chinese population using radiography and clinical examination under microscope and to compare the relative efficacies of these methods. For the recognition of C-shaped root canal system, 1 146 mandibular second molars were selected and examined. Teeth with C-shaped canal systems were categorized by using the radiographic classification criteria and the modified Melton's method. C-shaped canals were identified in 397 (34.64%) mandibular second molars by radiography (type I, 31.23%; type II, 38.29%; type III, 30.48%). Clinical examination showed that 449 (39.18%) cases exhibited C shaped canal systems (C1, 22.94%; C2, 48.11%; C3a, 15.59%; C3b, 13.36%). As for the result of the radiographic and clinical combined examination, C-shaped root canals were found in 473 (41.27%) mandibular second molars (C1, 21.78%; C2, 45.67%; C3a, 16.70%; C3b, 15.86%). The incidence of C-shaped root canal diagnosed by radiographic method was statistically different from that by clinical examination and the combined examination (P<0.05). The study indicated a high incidence of C-shaped canal system in a Chinese population. The combination of microscopic and radiographic examination is an effective method in identifying the C-shaped root canal system. PMID- 22836760 TI - Behavior of SD-OCT-detected hyperreflective foci in the retina of anti-VEGF treated patients with diabetic macular edema. AB - PURPOSE: Hyperreflective foci (HFs) are observable within the neurosensory retina in diabetic macular edema (DME) using spectral domain optical coherence tomography (SD-OCT). HFs have also been seen in wet age-related macular degeneration (AMD), although the origin is still unknown; however, they reduced significantly during anti-VEGF (vascular endothelial growth factor) therapy, and their baseline amount seemed to correlate with treatment success. In this study the behavior of HFs was evaluated during anti-VEGF therapy for DME. METHODS: Fifty-one patients (mean age: 67 years) underwent SD-OCT before and one month after one anti-VEGF injection (ranibizumab: n = 30; bevacizumab: n = 21). The HFs were semiquantitatively counted, assigned to three groups (group A: HFs n = 1-10; group B: n = 11-20; group C: n > 20), and correlated to the course of visual acuity and foveal thickness (paired t-test). Additionally the baseline HbA1c was categorized and correlated to baseline HFs (Spearman Rho). RESULTS: In all eyes, HFs of various amounts were detected in the foveal and parafoveal area. The mean number of HFs reduced significantly from 16.02 to 14.32 in all patients (P = 0.000), whereas foveal thickness reduced from 445.5 to 373.9 MUm (P = 0.000) and visual acuity increased from 62.0 to 66.0 ETDRS letters (P = 0.003). Regarding the three HF groups, a reduction of the level stages was observed in 43.1% (stable: 54.9%; more: 2.0%). This reflects a HF distribution change from 31.4% to 62.7% (group A), from 45.1% to 31.4% (group B), and from 23.5% to 5.9% (group C). The HbA1c correlated significantly to the overall HF amount at baseline (0.880; P = 0.000); however, no distinct overall correlation was found between the HF reduction and the course of visual acuity or retinal thickness. Only in cases of complete edema resolution (25%) did HFs reduce significantly (P = 0.008). CONCLUSIONS: As in wet AMD, HFs are frequently found in DME and behave similarly under anti-VEGF therapy. Thus, a HF reduction was observable mainly in cases of complete edema resolution; however, no distinct correlation with visual acuity was noticed, presumably mainly due to the enhanced inhomogeneity in the disease progress of DME. Interestingly, the baseline HF amount seems to correlate positively with HbA1c values indicating the severity of disease. PMID- 22836761 TI - Comparative ocular microbial communities in humans with and without blepharitis. AB - PURPOSE: The aims of our study were to compare the ocular microbial communities of humans with and without blepharitis in an attempt to elucidate which microorganisms may cause blepharitis. METHODS: Bacterial 16S rRNA genes of eyelash and tear samples from seven blepharitis patients and four healthy controls were sequenced using a pyrosequencing method, and their bacterial community structures were compared bioinformatically. RESULTS: Phylotypic analysis demonstrated that eyelash and tear samples had highly diverse bacterial communities with many previously undescribed bacteria. Bacterial communities in eyelash samples from subjects with blepharitis were less diverse than those from healthy controls, while the bacterial communities of tear subjects with blepharitis were more diverse than those of healthy subjects. Statistical analyses using UniFrac and a principle coordinate analysis showed that the bacterial communities of tear samples from subjects with blepharitis were well clustered, regardless of individual, while the bacterial communities of all eyelash samples and healthy tear samples were not well clustered due to high interpersonal variability. Bioinformatic analysis revealed that Propionibacterium, Staphylococcus, Streptophyta, Corynebacterium, and Enhydrobacter were the common ocular bacteria. An increase of Staphylococcus, Streptophyta, Corynebacterium, and Enhydrobacter, and a decrease of Propionibacterium were observed from blepharitis subjects, in terms of the relative abundances. CONCLUSIONS: Higher abundances of Streptophyta, Corynebacterium, and Enhydrobacter in blepharitis subjects suggested that human blepharitis might be induced by the infestations of pollens, dusts, and soil particles. These results will provide valuable information for the prevention and treatment of human blepharitis based on ocular microbial flora. PMID- 22836762 TI - Muscarinic antagonist control of myopia: evidence for M4 and M1 receptor-based pathways in the inhibition of experimentally-induced axial myopia in the tree shrew. AB - PURPOSE: The broadband muscarinic antagonist atropine is effective in stopping the progression of myopia in animals and humans. The partially selective M(1)/M(4) antagonist pirenzepine also slows progression of myopia, although not as effectively as atropine. Due to the supra maximal doses utilized in these studies, it is unclear if this antimyopia effect occurs through a receptoral based mechanism, and if so, which receptors are involved. Studies in chicks indicate the involvement of the M(4) muscarinic receptor. The current study investigated the effect of the highly selective muscarinic antagonists Muscarinic Toxin 3 (MT3) (M(4) selective) and Muscarinic Toxin 7 (MT7) (M(1) selective) on experimental myopia in a mammalian model. METHODS: Tree shrews (n = 23) underwent daily intravitreal injections of MT3, MT7, or vehicle (phosphate buffered saline) for five days in the treated eye, combined with deprivation of vision with a translucent occluder (MD). The contralateral eye was unocccluded and underwent intravitreal injections of vehicle for the same period. Two additional groups (n = 10) underwent daily intravitreal injections of MT7 or vehicle for 10 days in the treated eye combined with negative lens (-9.5 diopter [D]) defocus (LIM). The control eye was injected with saline and wore a plano lens. RESULTS: Both MT3 and MT7 treatment reduced the development of deprivation-induced myopia (treated control eye [T-C]; vehicle-MD; -4.3 +/- 0.6 D versus MT3-MD; -0.7 +/- 0.2 D and MT7-MD; -0.7 +/- 0.4 D; P < 0.001). MT7 treatment was effective at inhibiting lens-induced myopia (T-C; vehicle-LIM; -4.6 +/- 0.5 D versus MT7-LIM; 0.2 +/- 0.2 D; P < 0.05). CONCLUSIONS: The findings demonstrate that inhibition of form deprivation myopia by muscarinic antagonists involves both M(4) and M(1) muscarinic receptor signaling pathways in mammals. PMID- 22836763 TI - A perioculomotor nitridergic population in the macaque and cat. AB - PURPOSE: We determined the distribution of cells containing synthetic enzymes for the unconventional neurotransmitter, nitric oxide, with respect to the known populations within the oculomotor complex. METHODS: The oculomotor complex was investigated in monkeys and cats by use of histochemistry to demonstrate nicotinamide adenine dinucleotide phosphate diaphorase positive (NADPHd(+)) cells and antibodies to localize neuronal nitric oxide synthase positive (NOS(+)) cells. In some cases, wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) was injected into extraocular muscles to allow comparison of retrogradely labeled and NADPHd(+) cell distributions. RESULTS: The distribution of the NADPHd(+) and NOS(+) neurons did not coincide with that of preganglionic and extraocular motoneurons in the oculomotor complex. However, labeled perioculomotor neurons were observed. Specifically, in monkeys, they lay in an arc that extended from between the oculomotor nuclei into the supraoculomotor area (SOA). Comparison of WGA-HRP-labeled medial and superior rectus motoneurons with NADPHd staining confirmed that the distributions overlapped, but showed that the C- and S-group cells were not NADPHd(+). This suggested that NADPHd(+) cells are part of the centrally projecting Edinger-Westphal population (EWcp). Examination of the NADPHd(+) cell distribution in the cat showed that these cells were indeed found primarily within its well-defined EWcp. CONCLUSIONS: Based on their similar distributions, it appears that the peptidergic EWcp neurons, which project widely in the brain, also may be nitridergic. While the preganglionic and C- and S-group motoneuron populations do not use this nonsynaptic neurotransmitter, nitric oxide produced by surrounding NADPHd(+) cells may modulate the activity of these motoneurons. PMID- 22836764 TI - Aldose reductase deficiency reduced vascular changes in neonatal mouse retina in oxygen-induced retinopathy. AB - PURPOSE: Retinal neovascularization is the major pathologic process in many ocular diseases and is associated with oxidative stress. Deficiency of aldose reductase (AR), the first enzyme in the polyol pathway for glucose metabolism, has been shown to reduce oxidative stress and blood vessel leakage. The present study aimed to investigate the effect of AR deficiency on retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model. METHODS: Seven-day-old wild-type (WT) and AR-deficient (AR(-/-)) mice were exposed to 75% oxygen for 5 days and then returned to room air. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. Immunohistochemistry for AR, nitrotyrosine (NT), poly(ADP-ribose) (PAR), glial fibrillary acidic protein (GFAP), and Iba-1, as well as Western blots for vascular endothelial growth factor (VEGF), phospho-Erk (p-Erk), phospho-Akt (p Akt), and phospho-IkappaB (p-IkappaB) were performed. RESULTS: Compared with WT OIR retinae, AR(-/-) OIR retinae displayed significantly smaller central retinal vaso-obliterated area, less neovascularization, and reduced blood vessel leakage. Significantly reduced oxidative stress and glial responses were also observed in AR(-/-) OIR retinae. Moreover, reduced microglial response in the avascular area but increased microglial responses in the neovascular area were found with AR deficiency. Furthermore, expression levels of VEGF, p-Erk, p-Akt, and p-IkappaB were significantly reduced in AR(-/-) OIR retinae. CONCLUSIONS: Our observations indicated that AR deficiency reduced retinal vascular changes in the mouse model of OIR, indicating that AR can be a potential therapeutic target in ischemia induced retinopathy. PMID- 22836765 TI - Prevalence of myopia and its association with body stature and educational level in 19-year-old male conscripts in seoul, South Korea. AB - PURPOSE: To examine prevalence of refractive errors and its associated factors, such as body stature and educational level, among 19-year-old males in Seoul, Korea. METHODS: A population-based cross-sectional study was performed in male subjects (n = 23,616; age = 19 years) who were normally resident in Seoul for male compulsory conscripts during the study period (2010). Refractive examination was performed with cycloplegia. Height, weight, and educational level were examined. Myopia was defined as a spherical equivalent less than -0.5 diopters (D) and high myopia less than -6.0 D. The association of myopia with body stature and educational level was analyzed using logistic regression analysis. RESULTS: The prevalence of myopia in 19-year-old males in Seoul was 96.5%. The prevalence of high myopia was 21.61%. Body stature was not significantly associated with myopia. Four- to 6-year university students (odds ratio [OR] 1.69; P < 0.001) and 2 to 3-year college students (OR 1.68; P < 0.001) showed significantly higher risk for myopia than those with lower academic achievement (< high school graduation). CONCLUSIONS: The 19-year-old male population in Seoul, Korea, demonstrated a very high myopic prevalence. Myopic refractive error was associated with academic achievement, not with body stature. PMID- 22836766 TI - Peripheral vision of youths with low vision: motion perception, crowding, and visual search. AB - PURPOSE: Effects of low vision on peripheral visual function are poorly understood, especially in children whose visual skills are still developing. The aim of this study was to measure both central and peripheral visual functions in youths with typical and low vision. Of specific interest was the extent to which measures of foveal function predict performance of peripheral tasks. METHODS: We assessed central and peripheral visual functions in youths with typical vision (n = 7, ages 10-17) and low vision (n = 24, ages 9-18). Experimental measures used both static and moving stimuli and included visual crowding, visual search, motion acuity, motion direction discrimination, and multitarget motion comparison. RESULTS: In most tasks, visual function was impaired in youths with low vision. Substantial differences, however, were found both between participant groups and, importantly, across different tasks within participant groups. Foveal visual acuity was a modest predictor of peripheral form vision and motion sensitivity in either the central or peripheral field. Despite exhibiting normal motion discriminations in fovea, motion sensitivity of youths with low vision deteriorated in the periphery. This contrasted with typically sighted participants, who showed improved motion sensitivity with increasing eccentricity. Visual search was greatly impaired in youths with low vision. CONCLUSIONS: Our results reveal a complex pattern of visual deficits in peripheral vision and indicate a significant role of attentional mechanisms in observed impairments. These deficits were not adequately captured by measures of foveal function, arguing for the importance of independently assessing peripheral visual function. PMID- 22836767 TI - Assessment of vision-related quality of life in dry eye patients. AB - PURPOSE: To determine vision-related quality of life (QoL) measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) and the Ocular Surface Disease Index (OSDI) in dry eye patients, and establish potential correlations with the Zung Self Rating Anxiety Scales (SAS), the Zung Self Rating Depression Scales (SDS), ocular surface parameters, and sociodemographic measures. METHODS: The comparative study included 87 dry eye patients and 71 healthy volunteers who visited the department of ophthalmology, Eye and Ear Nose and Throat (EENT) Hospital of Fudan University, Shanghai, China, between June 2009 and December 2009. Surveys were administered to participants to evaluate their sociodemographic characteristics and disease-related factors. Data collected from the NEI-VFQ and OSDI survey instruments were analyzed to identify potential differences between the dry eye group and the control group. Correlations with sociodemographic characteristics, clinical parameters, and psychological status were evaluated. RESULTS: Compared with the control group, our patient group had lower (worse) NEI-VFQ scores for the subscales of general health, general vision, ocular pain, short distance vision activities, long distance vision activities, vision related social function, vision related mental health, vision related role difficulties, vision related dependency, and driving (all P < 0.05), and higher (worse) OSDI composite and subscale scores of ocular symptoms, vision-related function, and environmental triggers (all P < 0.001). Significant correlations were found between QoL scores and patient anxiety and depression levels. CONCLUSIONS: Vision-related QoL in dry eye patients was impaired and was correlated with anxiety and depression, further implicating this condition as an important public health problem deserving increased attention and resources. PMID- 22836768 TI - Decline in DJ-1 and decreased nuclear translocation of Nrf2 in Fuchs endothelial corneal dystrophy. AB - PURPOSE: This study sought to determine factors involved in nuclear factor erythroid 2-related factor 2 (Nrf2) regulation and their response to oxidative stress in Fuchs endothelial corneal dystrophy (FECD) and normal corneal endothelial cells (CECs). METHODS: FECD corneal buttons were obtained from transplantations and normal human corneas from tissue banks. Oxidative stress was induced by tert-butyl hydroperoxide (tBHP). Protein and mRNA levels of Nrf2, DJ 1, p53, and Kelch-like ECH-associated protein1 (Keap1) were investigated using Western blotting and real-time PCR. Immunoprecipitation was used to detect levels of oxidized DJ-1 protein and Cullin 3- (Cul3)-regulated degradation of DJ-1 in immortalized FECD (FECDi) and normal CEC (HCECi) cell lines. Nrf2 subcellular localization was assessed by immunocytochemistry. RESULTS: Nrf2 protein stabilizer, DJ-1, decreased significantly in FECD CECs compared with normal, whereas Nrf2 protein repressor, Keap1, was unchanged at baseline but increased under oxidative stress. Under oxidative stress, normal CECs upregulated DJ-1 protein synthesis, whereas FECD CECs did not. DJ-1 decline correlated with increased DJ-1 oxidative modification and carbonylation in FECDi as compared with HCECi. Increased labeling of immunoprecipitated DJ-1 protein with anti-Cul3 antibody indicated enhanced DJ-1 degradation in FECDi as compared with HCECi. Following tBHP treatment, Nrf2 translocated from cytoplasm to nuclei in normal CECs, whereas Nrf2 nuclear localization was not observed in FECD. CONCLUSIONS: Decreased levels of DJ-1 in FECD at baseline and under oxidative stress correlate with impaired Nrf2 nuclear translocation and heightened cell susceptibility to apoptosis. Targeting the DJ-1/Nrf2 axis could yield a mechanism to slow CEC degeneration in FECD. PMID- 22836769 TI - Influence of anterior segment power on the scan path and RNFL thickness using SD OCT. AB - PURPOSE: Retinal nerve fiber layer (RNFL) thickness measures with spectral domain optical coherence tomography (SD-OCT) provide important information on the health of the optic nerve. As with most retinal imaging technologies, ocular magnification characteristics of the eye must be considered for accurate analysis. While effects of axial length have been reported, the effects of anterior segment optical power on RNFL thickness measures have not been described fully to our knowledge. The purpose of our study was to determine the influence of the optical power change at the anterior corneal surface, using contact lenses, on the location of the scan path and measurements of RNFL thickness in normal healthy eyes. METHODS: We recruited 15 normal subjects with less than 6 diopters (D) of ametropia and no ocular pathology. One eye of each subject was selected randomly for scanning. Baseline SD-OCT scans included raster cubes centered on the optic nerve and macula, and a standard 12-degree diameter RNFL scan. Standard 12-degree RNFL scans were repeated with 10 separate contact lenses, (Proclear daily, Omafilcon A/60%) ranging from +8 to -12 D in 2-D steps. The extent of the retinal scan, and RNFL thickness and area measures were quantified using custom MATLAB programs that included ocular biometry measures (IOL Master). RESULTS: RNFL thickness decreased (0.52 MUm/D, r = -0.33, P < 0.01) and the retinal region scanned increased (0.52%/D, r = 0.97, P < 0.01) with increase in contact lens power (-12 to +8). The normalized/percentage rates of change of RNFL thickness (-0.11/mm, r = -0.67, P < 0.01) and image size (0.11/mm, r = 0.96, P < 0.01) were related to axial length. Changes in the retinal region scanned were in agreement with transverse scaling, computed with a three surface schematic eye (R(2) = 0.97, P < 0.01). RNFL area measures, that incorporated the computed transverse scaling, were not related significantly to contact lens power (863 MUm(2)/D, r = 0.06, P = 0.47). CONCLUSIONS: Measurements of RNFL thickness by SD-OCT are dependent on the optics of the eye, including anterior segment power and axial length. The relationships between RNFL thickness measures and optical power are a direct reflection of scan path location with respect to the optic nerve head rim, caused by relative magnification. An incorporation of transverse scaling to RNFL area measures, based on individualized ocular biometry, eliminated the magnification effect. PMID- 22836770 TI - Comparison of different methods of glycerol preservation for deep anterior lamellar keratoplasty eligible corneas. AB - PURPOSE: To compare different methods of glycerol-preserved corneas intended for deep anterior lamellar keratoplasty (DALK). METHODS: We analyzed transparency, transmittance, thickness, biomechanics, morphology, and antigenicity of donor corneas preserved by four different glycerol-based methods (n = 6 per group) for 3 months, as follows: tissues in anhydrous glycerol without aluminosilicate molecular sieves at room temperature (GRT); tissues in anhydrous glycerol with aluminosilicate molecular sieves at room temperature (SRT); tissues in anhydrous glycerol without aluminosilicate molecular sieves at -78 degrees C (G78); and tissues in anhydrous glycerol without aluminosilicate molecular sieves at -20 degrees C (G20). RESULTS: Slit lamp images and transmittance curves obtained by spectrophotometer show that the G78 cornea was the most transparent tissue. Stress-strain behavior indicated that corneas in the G78 group were the most pliable, and SRT corneas were the stiffest. Electron microscopy analysis indicated that corneal cytoarchitecture and keratocyte integrity was destroyed in all glycerol-preserved corneas. Disorganized stromal collagen fibers were evident in groups stored at RT. Especially in SRT corneas, parallelism was lost, fibrils were extremely tortuous and discontinuous, and widespread fibril degeneration could be found. Antigenicity of tissue, assessed via immunohistochemistry for CD45-positive cells, HLA-ABC and HLA-DR, was lowered after glycerol preservation relative to fresh cornea tissues, and immunoreactivity was located mainly on corneal epithelium and limbus rather than stroma. CONCLUSIONS: Anhydrous glycerol preservation without molecular sieves in a -78 degrees C freezer was the best method to obtain DALK-eligible tissues that were both transparent and pliable. PMID- 22836772 TI - Determinants of ganglion cell-inner plexiform layer thickness measured by high definition optical coherence tomography. AB - PURPOSE: To determine the distribution, variation, and determinants of ganglion cell-inner plexiform layer (GC-IPL) thickness in nonglaucomatous eyes measured by high-definition optical coherence tomography (HD-OCT). METHODS: Six hundred twenty-three Chinese adults aged 40 to 80 years were consecutively recruited from a population-based study. All subjects underwent a standardized interview, ophthalmic examination, and automated perimetry. HD-OCT with macular cube protocol was used to measure the GC-IPL thickness. Univariate and multiple linear regression analyses were performed to examine the relationship between GC-IPL thickness with ocular and systemic factors. RESULTS: The mean (+/-SD) age of study subjects was 52.84 +/- 6.14 years, 50.1% were male, and all subjects had normal visual fields with no signs of glaucoma or glaucoma suspect. The mean overall, minimum, superior, and inferior GC-IPL thicknesses were 82.78 +/- 7.01 MUm, 79.67 +/- 9.17 MUm, 83.30 +/- 7.89 MUm, and 80.16 +/- 8.31 MUm, respectively. In multiple linear regression analysis, GC-IPL thickness was significantly associated with age (beta = -0.202, P < 0.001), female sex (beta = 2.367, P < 0.001), axial length (beta = -1.279, P = 0.002), and mean peripapillary retinal nerve fiber layer (RNFL) thickness (beta = 0.337, P < 0.001). IOP, central corneal thickness, disc area, serum glucose level, and history of diabetes mellitus had no significant influence on GC-IPL thickness. CONCLUSIONS: Thinner GC-IPL was independently associated with older age, female sex, longer axial length, and thinner RNFL thickness. These factors should be taken into account when interpreting GC-IPL thickness measurements with HD-OCT for glaucoma assessment. PMID- 22836771 TI - Mesenchymal stem cells derived from human limbal niche cells. AB - PURPOSE: We investigated whether human limbal niche cells generate mesenchymal stem cells. METHODS: Limbal niche cells were isolated from the limbal stroma by collagenase alone or following dispase removal of the limbal epithelium (D/C), and cultured on plastic in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS), or coated or three-dimensional Matrigel in embryonic stem cell medium with leukemia inhibitory factor and basic fibroblast growth factor. Expression of cell markers, colony-forming units-fibroblast, tri-lineage differentiation, and ability of supporting limbal epithelial stem/progenitor cells were compared to limbal residual stromal cells. RESULTS: Stromal cells expressing angiogenesis markers were found perivascularly, subjacent to limbal basal epithelial cells, and in D/C and limbal residual stromal cells. When seeded in three-dimensional Matrigel, D/C but not limbal residual stromal cells yielded spheres of angiogenesis progenitors that stabilized vascular networks. Similar to collagenase-isolated cells, D/C cells could be expanded on coated Matrigel for more than 12 passages, yielding spindle cells expressing angiogenesis and mesenchymal stem cells markers, and possessing significantly higher colony forming units-fibroblast and more efficient tri-lineage differentiation than D/C and limbal residual stromal cells expanded on plastic in DMEM with 10% FBS, of which both lost the pericyte phenotype while limbal residual stromal cells turned into myofibroblasts. Upon reunion with limbal epithelial stem/progenitor cells to form spheres, D/C cells expanded on coated Matrigel maintained higher expression of p63alpha and lower expression of cytokeratin 12 than those expanded on plastic in DMEM with 10% FBS, while spheres formed with human corneal fibroblasts expressed cytokeratin 12 without p63alpha. CONCLUSIONS: In the limbal stroma, cells subjacent to limbal basal epithelial cells serve as niche cells, and generate progenitors with angiogenesis and mesenchymal stem cells potentials. They might partake in angiogenesis and regeneration during corneal wound healing. PMID- 22836773 TI - Does retinal vascular geometry vary with cardiac cycle? AB - PURPOSE: Changes in retinal vascular parameters have been shown to be associated with systemic vascular diseases. In this study, we assessed the physiologic variations in retinal vascular measurements during the cardiac cycle. METHODS: Fundus images were taken using electrocardiogram-synchronized retinal camera at nine distinct cardiac points from 15 healthy volunteers (135 images). Analyses of retinal vessel geometric measures, including retinal vessel caliber (individual and summary), tortuosity, branching angle, length-diameter ratio (LDR), and optimality deviation, were performed using semiautomated computer software. Repeated-measures ANOVAs were used to obtain the means and to estimate the variation of each cardiac point compared with cardiac point 1. RESULTS: There was a significant variation of the caliber of the individual arteriolar and venular vessels. However, there was no significant variation found for vessel caliber summary, represented by the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). There was also no significant variation found for tortuosity and branching angle, and LDR showed none or very little variations at different cardiac points: variations in caliber ranges between 0 and 4.1%, tortuosity 0 and 1.5%, branching angle 0 and 3.5%, and LDR 0 and 2%; all values for variations, P > 0.1; linear trend, P > 0.5; and nonlinear trend, P > 0.8. CONCLUSIONS: This study showed that there were minimal variations in the CRAE, CRVE, tortuosity, and branching angle that are clinically used for two-dimensional measures of retinal vascular geometry during cardiac cycles. However, there was significant variation in the caliber of the individual vessels over the cardiac cycle. PMID- 22836774 TI - The association between retinal vessel diameter and retinal nerve fiber layer thickness in asymmetric normal tension glaucoma patients. AB - PURPOSE: The aim of this study was to evaluate the associations between retinal vessel diameter and retinal nerve fiber layer (RNFL) thickness in patients with normal tension glaucoma (NTG). METHODS: This study included 67 untreated patients with asymmetric NTG, with no evidence of glaucoma in the contralateral eyes, and 48 age- and sex-matched normal control subjects. We included patients from 20 to 70 years of age who had no history of hypertension, diabetes, or other vascular diseases. All subjects underwent detailed eye examinations that included red-free photography, stereoscopic optic disc photography, automated perimetry, and measurement of RNFL thickness with optical coherence tomography. We compared RNFL thicknesses, temporal retinal arteriolar diameters (TRAD), and temporal retinal venular diameters (between quadrants with and without RNFL defects) with computer assisted imaging software. RESULTS: The mean diameter of the temporal retinal vessels in the quadrants with RNFL defects were significantly smaller in patients with NTG than in those with quadrants without RNFL defects (P < 0.001) and in control subjects (P < 0.001). TRADs were correlated with RNFL defects and RNFL thicknesses (P < 0.05) in binary logistic regression analysis and in multiple linear regression analysis (P < 0.001). There were no statistically significant differences between vessel diameters in control subjects and those in nondefective quadrants of the affected NTG eyes or the unaffected eyes of patients with NTG. CONCLUSIONS: Our results show that narrower retinal vessels are found in areas of RNFL defects. Considering previous reports and our analysis, this is likely due to the decreased demand for retinal blood flow in damaged areas of the retina. PMID- 22836776 TI - Effect of vitrectomy on aqueous VEGF concentration and pharmacokinetics of bevacizumab in macaque monkeys. AB - PURPOSE: To evaluate the effect of vitrectomy on the concentration of vascular endothelial growth factor (VEGF) and the pharmacokinetics of intravitreally injected bevacizumab in the aqueous humor in cynomolgus macaques. METHODS: Pars plana lensectomy and a standard three-port vitrectomy were performed in one eye each of six macaques. After a minimal 12-week healing period, the vitrectomized eyes received an intravitreal injection of bevacizumab (1.25 mg/50 MUL). Aqueous humor and venous blood samples were obtained from the macaques just before vitrectomy, just before injection of bevacizumab, on days 1, 3, and 7, and during weeks 2, 4, 6, and 8 after the injection. The bevacizumab and VEGF concentrations were measured by using enzyme-linked immunosorbent assay. RESULTS: The VEGF concentrations in the aqueous humor ranged from 52.6 to 113.9 pg/mL (mean +/- standard deviation [SD], 81.7 +/- 27.0 pg/mL) before vitrectomy and 20.7 to 72.7 pg/mL (mean +/- SD, 51.4 +/- 20.5 pg/mL) 3 months after vitrectomy, a difference that reached significance (P = 0.03). The aqueous VEGF concentrations decreased to less than 9.0 pg/mL, the lower limit of detection, in all eyes between 1 and 7 days after injection of bevacizumab. The mean half-life of 1.25 mg intravitreally injected bevacizumab was 1.5 +/- 0.6 days (range, 1.0-2.4 days) in the aqueous humor. CONCLUSIONS: The VEGF concentration in the aqueous humor decreased and the half-life of the intravitreally injected bevacizumab was shorter in vitrectomized eyes. PMID- 22836775 TI - Wavelength-dependent change of retinal nerve fiber layer reflectance in glaucomatous retinas. AB - PURPOSE: Retinal nerve fiber layer (RNFL) reflectance is often used in optical methods for RNFL assessment in clinical diagnosis of glaucoma, yet little is known about the reflectance property of the RNFL under the development of glaucoma. This study measured the changes in RNFL reflectance spectra that occurred in retinal nerve fiber bundles with different degrees of glaucomatous damage. METHODS: A rat model of glaucoma with laser photocoagulation of trabecular meshwork was used. Reflectance of the RNFL in an isolated retina was measured at wavelengths of 400-830 nm. Cytostructural distribution of the bundles measured optically was evaluated by confocal imaging of immunohistochemistry staining of cytoskeletal components, F-actin, microtubules, and neurofilaments. RNFL reflectance spectra were studied in bundles with normal-looking appearance, early F-actin distortion, and apparent damage of all cytoskeletal components. Changes of RNFL reflectance spectra were studied at different radii (0.22, 0.33, and 0.44 mm) from the optic nerve head (ONH). RESULTS: Bundles in 30 control retinas and 41 glaucomatous retinas were examined. In normal retinas, reflectance spectra were similar along the same bundles. In glaucomatous retinas, reflectance spectra changed along bundles with the spectra becoming flatter as bundle areas approached the ONH. CONCLUSIONS: Elevation of intraocular pressure (IOP) causes nonuniform changes in RNFL reflectance across wavelengths. Changes of reflectance spectra occur early in bundles near the ONH and prior to apparent cytoskeletal distortion. Using the ratio of RNFL reflectance measured at different wavelengths can provide early and sensitive detection of glaucomatous damage. PMID- 22836777 TI - Quantitative confocal imaging of the retinal microvasculature in the human retina. AB - PURPOSE: We investigated quantitatively the distribution of blood vessels in different neural layers of the human retina. METHODS: A total of 16 human donor eyes was perfusion-fixed and labeled for endothelial f-actin. Retinal eccentricity located 3 mm superior to the optic disk was studied using confocal scanning laser microscopy. Immunohistochemical methods applied to whole-mount and transverse sections were used to colocalize capillary networks with neuronal elements. Capillary morphometry, diameter, and density measurements were compared among networks. RESULTS: Four different capillary networks were identified and quantified in the following regions: Nerve fiber layer (NFL), retinal ganglion cell (RGC) layer, border of the inner plexiform layer (IPL) and superficial boundary of the inner nuclear layer (INL), and boundary of the deep INL and outer plexiform layer. The innermost and outermost capillary networks demonstrated a laminar configuration, while IPL and deep INL networks displayed a complex three dimensional configuration. Capillary diameter in RGC and IPL networks were significantly less than in other networks. Capillary density was greatest in the RGC network (26.74%), and was significantly greater than in the NFL (13.69%), IPL (11.28%), and deep INL (16.12%) networks. CONCLUSIONS: The unique metabolic demands of neuronal sub-compartments may influence the morphometric features of regional capillary networks. Differences in capillary diameter and density between networks may have important correlations with neuronal function in the human retina. These findings may be important for understanding pathogenic mechanisms in retinal vascular disease. PMID- 22836778 TI - In vivo oxygen uptake into the human cornea. AB - PURPOSE: We provide a new procedure to quantify in situ corneal oxygen uptake using the micropolarographic Clark electrode. METHODS: Traditionally, upon placing a membrane-covered Clark microelectrode onto a human cornea, the resulting polarographic signal is interpreted as the oxygen partial pressure at the anterior corneal surface. However, the Clark electrode operates at a limiting current. Hence, oxygen flux is directly detected rather than partial pressure. We corrected this misunderstanding and devised a new analysis to quantify oxygen uptake into the cornea. The proposed analysis is applied to new polarographic data for 10 human subjects during open-eye oxygen uptake. RESULTS: Average open eye corneal oxygen uptake over 10 subjects is approximately 11 MUL/(cm(2) h), approximately five times larger than the average reported by researchers who invoke the original mathematical analysis. Application of the classical interpretation scheme to our experimental data also garners uptake values that are approximately a factor of three to five times smaller than those obtained with our new procedure. CONCLUSIONS: The classical procedure originally developed by Fatt and colleagues misinterprets the behavior of the Clark microelectrode. We corrected the analysis of the in situ polarographic technique to provide a simple yet rigorous procedure for analyzing both previous data in the literature and those newly obtained. Our proposed interpretation scheme thus provides a reliable tool for in vivo assessment of corneal oxygen uptake. PMID- 22836779 TI - Elevated serum interleukin-33 levels in patients with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis and is known as an immunoglobulin (Ig) A related immune complex-mediated disease. However, the molecular mechanisms in the development of HSP are not yet fully understood. Herein, we investigated the serum levels of Interleukin (IL)-33 and soluble ST2 (sST2) in HSP patients and their association with disease severity and IgA autoantibodies production. The serum levels of IL-33 and sST2 were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA) in the serum of 33 patients with HSP and 22 controls. Serum levels of IgA anti endothelial cell antibodies (AECA) and IgA anticardiolipin antibodies (ACA) in HSP patients were detected by double antigen sandwich ELISA. Our results indicated that serum levels of IL-33 but not sST2 were significantly elevated in patients with HSP in acute stage and restored to normal levels in convalescent stage. Moreover, serum IL-33 levels were correlated with the severity of HSP and serum concentrations of AECA-IgA and ACA-IgA. Taken together, we show firstly that serum IL-33 is abnormally elevated in HSP patients. IL-33 might be associated with the IgA autoantibodies production in the pathogenesis of HSP. PMID- 22836780 TI - Whole-body MRI and MRA for evaluation of the prevalence of atherosclerosis in a cohort of subjectively healthy individuals. AB - OBJECTIVES: To assess the prevalence of cardiovascular findings in asymptomatic individuals by means of 1.5-T whole-body magnetic resonance imaging and angiography. METHODS: A cohort of 138 individuals (118 men, 20 women) with a mean age of 54 years (SD +/- 7.55) was referred to whole-body MRI at 1.5-T, including contrast-enhanced whole-body MR angiography (MRA) and cardiac MRI. A total of 2,065/2,070 vessel segments (99.8%) and cardiac function were evaluated. RESULTS: Approximately one-fourth of the participating individuals had vascular abnormalities. In 17 subjects (12.3% of all subjects) significant luminal narrowing was observed in at least one vascular segment. Luminal narrowing (mild to severe) was observed in 1 (0.7% of all subjects respectively) of the renal arteries, 7 (5.0%) of the carotid arteries, and 3 (2.2%) of the pelvic and upper leg arteries, and in 17 segments (12.3%) of arteries in the lower leg. In cardiac function and perfusion imaging, wall motion disorders were observed in six patients (4.3%), with additional delayed enhancement and isolated delayed enhancement present in two cases. Functional parameters differed from reference values in 55 cases. CONCLUSIONS: Even in an asymptomatic cohort of middle-aged predominantly male individuals, atherosclerotic disease is not uncommon and is detectable by whole-body MRI. MAIN MESSAGES: * In middle-aged predominantly male individuals, atherosclerotic disease is not uncommon. * Even in an asymptomatic collective, approximately one fourth had vascular abnormalities. * Using whole body MR angiography (MRA), 99.8% of 2,070 vessel segments could be evaluated. PMID- 22836781 TI - Connecting membrane fluidity and surface charge to pore-forming antimicrobial peptides resistance by an ANN-based predictive model. AB - Efficiency of antibacterial chemotherapy is gradually more challenged by the emergence of pathogenic strains exhibiting high levels of antibiotic resistance. Pore-forming antimicrobial peptides (PF-AMPs) such as alamethicin (Alm) are therefore in the focus of extensive research efforts. In the present study, an artificial neural network (ANN)-based quantitative structure-activity relationship (SAR) modeling of membrane phospholipids vs. PF-AMPs, in context to membrane fluidity and surface charge, was carried out. We observed that the potency of PF-AMPs depends on the fatty acyl chain and polar head group of phospholipids. Alm showed surface interactions with zwitterionic phospholipids however could penetrate deeper inside the hydrophobic core of anionic membranes. Here, the resistance developed in bacterial cells was coupled to membrane fluidity and surface charge, and simultaneously, these principles could be applied for combating resistance against PF-AMPs. The correlation coefficient between observed CR and predicted CR using ANN was found to be 0.757. Thus, ANN could be used as a reliable modeling method for predicting CR, given the structure of the biomimetic membrane in terms of membrane fluidity and surface charge. Fully explored mechanisms of resistance, a forward modeling step in the design cycle of AMPs, can be cross-linked to the inward modeling using ANN to complete the peptide design cycle. The SAR between membrane phospholipids and PF AMPs could furnish valuable information regarding their design to provide us efficacious peptides against premier pathogens. So far, this is the only report available to predict and quantify interactions of PF-AMPs with membrane phospholipids. PMID- 22836782 TI - Patients' motives for participating in active post-marketing surveillance. AB - PURPOSE: Web-based intensive monitoring is a method to actively collect information about adverse drug reactions (ADRs) using patients as a source of information. To date, little is known about patients' motivation to participate in this kind of active post-marketing surveillance (PMS). Increased insight in this matter can help us to better understand and interpret patient reported information, and it can be used for developing and improving patient-based pharmacovigilance tools. The aim of this study is to gain insight into patients' motives for participating in active PMS and investigate their experiences with such a system. METHOD: A mixed model approach combining qualitative and quantitative research methods was used. For both parts, patients participating in a web-based intensive monitoring study about the safety of anti-diabetic drugs (excluding insulins) were used. A questionnaire was developed based on the results from qualitative interviews. The data collected through the questionnaires was analysed with descriptive statistics. Relations between patient characteristics and motives were analysed using a t-test or a Chi-squared test. RESULTS: 1332 (54.6%) patients responded to the questionnaire. The main motive for participation was altruism. Often experiencing ADRs or negative experiences with drugs were not important motives. The patient's gender played a role in the different motives for participation. For men, potential future personal benefit from the results was more important than for women. The overall opinion about the system was positive. CONCLUSION: The knowledge that patients participate in this kind of research from an altruistic point of view may strengthen patient involvement in pharmacovigilance. PMID- 22836783 TI - Incidence of atypical nontraumatic diaphyseal fractures of the femur. AB - Bisphosphonates reduce the rate of osteoporotic fractures in clinical trials and community practice. "Atypical" nontraumatic fractures of the diaphyseal (subtrochanteric or shaft) part of the femur have been observed in patients taking bisphosphonates. We calculated the incidence of these fractures within a defined population and examined the incidence rates according to duration of bisphosphonate use. We identified all femur fractures from January 1, 2007 until December 31, 2011 in 1,835,116 patients older than 45 years who were enrolled in the Healthy Bones Program at Kaiser Southern California, an integrated health care provider. Potential atypical fractures were identified by diagnostic or procedure codes and adjudicated by examination of radiographs. Bisphosphonate exposure was derived from internal pharmacy records. The results showed that 142 patients had atypical fractures; of these, 128 had bisphosphonate exposure. There was no significant correlation between duration of use (5.5 +/- 3.4 years) and age (69.3 +/- 8.6 years) or bone density (T-score -2.1 +/- 1.0). There were 188,814 patients who had used bisphosphonates. The age-adjusted incidence rates for an atypical fracture were 1.78/100,000/year (95% confidence interval [CI], 1.5-2.0) with exposure from 0.1 to 1.9 years, and increased to 113.1/100,000/year (95% CI, 69.3-156.8) with exposure from 8 to 9.9 years. We conclude that the incidence of atypical fractures of the femur increases with longer duration of bisphosphonate use. The rate is much lower than the expected rate of devastating hip fractures in elderly osteoporotic patients. Patients at risk for osteoporotic fractures should not be discouraged from initiating bisphosphonates, because clinical trials have documented that these medicines can substantially reduce the incidence of typical hip fractures. The increased risk of atypical fractures should be taken into consideration when continuing bisphosphonates beyond 5 years. PMID- 22836784 TI - Emerging technologies in bioremediation: constraints and opportunities. AB - Intensive industrialisation, inadequate disposal, large-scale manufacturing activities and leaks of organic compounds have resulted in long-term persistent sources of contamination of soil and groundwater. This is a major environmental, policy and health issue because of adverse effects of contaminants on humans and ecosystems. Current technologies for remediation of contaminated sites include chemical and physical remediation, incineration and bioremediation. With recent advancements, bioremediation offers an environmentally friendly, economically viable and socially acceptable option to remove contaminants from the environment. Three main approaches of bioremediation include use of microbes, plants and enzymatic remediation. All three approaches have been used with some success but are limited by various confounding factors. In this paper, we provide a brief overview on the approaches, their limitations and highlights emerging technologies that have potential to revolutionise the enzymatic and plant-based bioremediation approaches. PMID- 22836785 TI - Rabbit supraspinatus motor endplates are unaffected by a rotator cuff tear. AB - Rotator cuff tears are a major cause of morbidity. Following rotator cuff tears, muscle atrophy and fatty infiltration begin in the tissue, limiting repair potential and leading to a higher re-tear rate and a worse functional outcome. We evaluated whether fatty degeneration resulting from a complete supraspinatus tear with retraction is associated with an injury to the suprascapular nerve. Four skeletally mature New Zealand white rabbits were randomized to receive an index procedure on either their right or left shoulder with the opposite shoulder serving as a control. At the index procedure, the supraspinatus tendon was transected at its insertion and allowed to retract. At 3 months, the rabbits were euthanized, and both supraspinatus muscles were harvested. The specimens were then examined with confocal microscopy and histology. Atrophy was grossly visible in all four test muscles, and fatty infiltration was confirmed with osmium tetroxide staining. In all four rabbits, the degree of denervation (p = 0.71) and partial denervation (p = 0.91) was not significantly different between control and experimental muscle. Rotator cuff tear does not affect the motor endplate or innervation status of the supraspinatus. Fatty infiltration occurs independent of denervation of the supraspinatus. PMID- 22836786 TI - Exploratory factor analysis of the pain outcomes profile. AB - The Pain Outcomes Profile (POP) is a brief, multidimensional measure intended to assess pain intensity, functioning, and affect. It is presented as a practical measure with clinical utility. Results of studies support its concurrent, construct and predictive validity at the scale level. However, there have been no published studies of the measure at the item level. The present study was intended to assess the construct validity of the POP by way of factor analysis. A sample of 447 assessments of patients at a chronic non-cancer pain outpatient treatment center was employed. The 20 substantive items comprising the POP were entered into a factor analysis with oblique rotation. Five salient factors were obtained. Item-inclusion was generally consistent with factor loadings although noteworthy exceptions were observed in the Fear, Mobility and Vitality scales. Recommendations for further study and limitations of the current project are delineated. PMID- 22836787 TI - Mercury in fruiting bodies of dark honey fungus (Armillaria solidipes) and beneath substratum soils collected from spatially distant areas. AB - BACKGROUND: This paper reports data on bioconcentration potential and baseline mercury concentrations of fruiting bodies of dark honey fungus (Armillaria solidipes) Peck and soil substrate layer (0-10 cm) from 12 spatially distant sites across Poland. Mercury content of caps, stipes and soil samples were determined using validated analytical procedure including cold-vapor atomic absorption spectroscopy after thermal decomposition of the sample matrix and further amalgamation and desorption of mercury from gold wool. RESULTS: Mean mercury concentrations ranged from 20 +/- 8 to 300 +/- 70 ng g(-1) dry weight (dw) in caps, from 20 +/- 6 to 160 +/- 40 ng g(-1) dw in stipes, and in underlying soil were from 20 +/- 2 to 100 +/- 130 ng g(-1) dw. The results showed that stipes mercury concentrations were 1.1- to 1.7-fold lower than those of caps. All caps and the majority of stipes were characterized by bioconcentration factor values > 1, indicating that dark honey fungus can be characterized as a moderate mercury accumulator. CONCLUSION: Occasional or relatively frequent eating of meals including caps of dark honey fungus is considered safe in view of the low total mercury content, and the mercury intake rates are below the current reference dose and provisionally tolerable weekly intake limits for this hazardous metal. PMID- 22836788 TI - Enhanced capacitive deionization of graphene/mesoporous carbon composites. AB - Capacitive deionization (CDI) with low-energy consumption and no secondary waste is emerging as a novel desalination technology. Graphene/mesoporous carbon (GE/MC) composites have been prepared via a direct triblock-copolymer-templating method and used as CDI electrodes for the first time. The influences of GE content on the textural properties and electrochemical performance were studied. The transmission electron microscopy and nitrogen adsorption-desorption analysis indicate that mesoporous structures are well retained and the composites display improved specific surface area and pore size distribution, as well as pore volume. Well dispersed GE nanosheets are deduced to be beneficial for enhanced electrical conductivity. The electrochemical performance of electrodes in an NaCl aqueous solution was characterized by cyclic voltammetry, galvanostatic charge discharge and electrochemical impedance spectroscopy measurements. The composite electrodes perform better on the capacitance values, conductive behaviour, rate performance and cyclic stability. The desalination capacity of the electrodes was evaluated by a batch mode electrosorptive experiment and the amount of adsorbed ions can reach 731 MUg g-1 for the GE/MC composite electrode with a GE content of 5 wt%, which is much higher than that of MC alone (590 MUg g-1). The enhanced CDI performance of the composite electrodes can be attributed to the better conductive behaviour and higher specific surface area. PMID- 22836789 TI - The obliquus capitis inferior myodural bridge. AB - This study was designed to examine the obliquus capitis inferior (OCI) muscle from a gross anatomical perspective. The objective was to isolate and identify the OCI myodural bridge, while examining its course and contributing elements. An earlier study of the posterior cervical spine briefly reported a connection between the OCI and the cervical dura mater. To the best of our knowledge, a study has not yet been conducted specifically on this muscle and its relation to the dura mater. In this study, the suboccipital regions of nine embalmed cadavers were dissected. A total of 14 OCI muscles were isolated for examination. All findings were documented via photograph. Of the 14 OCI muscles isolated, all emitted fibrous tissue bands from the anterolateral portion of the muscular belly. These fibers attached to the posterolateral cervical dura mater by route of the atlantoaxial interspace. The OCI myodural bridge appeared to coalesce with the rectus capitis posterior major myodural bridge, giving the appearance of a single atlantoaxial structure that links these two muscles to the dura mater. In conclusion, the OCI was attached to the dura mater in all of the 14 muscle specimens. We hypothesize that the OCI myodural bridge may play a physiological role in monitoring dural tension and preventing dural infolding. It may also contribute to certain clinical symptoms manifesting from alterations in dural tone. PMID- 22836790 TI - Information about medication in HIV-infected patients and its relation to adherence. AB - QUESTIONS UNDER STUDY: In HIV-infected patients, comprehension of medication instructions is an essential condition for adherence to Highly Active Antiretroviral Therapy (HAART). In this study, we used a self-reported questionnaire to know which sources of medication information HIV-infected patients used and their impact on adherence. In secondary objectives, we determined profiles of non-adherent patients and specified the role of the pharmacist. METHODS: A cross-sectional, observational study was conducted in one community pharmacy and one French university hospital pharmacy, in HAART-naive or not patients, from April to June 2009. RESULTS: During the 3-month study period, 233 HIV-infected patients were included. The majority of patients sought information about their HAART treatments from the hospital physician (79.8%), the community physician (74.2%), and patient information leaflets (73.8%). The community and hospital pharmacists were consulted by respectively 16.3% and 3.4% of patients. According to multivariate regression analysis, adherence seemed to be associated with the sources of information "community physician", "hospital physician", "internet", and the potential support of patient associations. A total of 65.7% of patients were considered to be adherent. CONCLUSIONS: In our study, among sources used by HIV-infected outpatients, their physicians are the most helpful sources of information about HAART. Regarding practice implications, the key role of the pharmacist is underutilised, indicating the need for improved communication between the pharmacist and outpatients. PMID- 22836791 TI - Fly culture collapse disorder: detection, prophylaxis and eradication of the microsporidian parasite Tubulinosema ratisbonensis infecting Drosophila melanogaster. AB - Drosophila melanogaster is a robust model to investigate many biological problems. It is however prone to some infections, which may endanger fly stocks if left unchecked for. One such infection is caused by an obligate fungal intracellular parasite, Tubulinosema ratisbonensis, which can be found in laboratory stocks. Here, we identify and briefly characterize a T. ratisbonensis strain that was infesting our Drosophila cultures and that required intensive measures to contain and eradicate the infection. We describe the phenotypes of infested stocks. We also report PCR-based techniques that allow the detection of infested stocks with a high sensitivity. We have developed a high-throughput qPCR assay that allows the efficient parallel screening of a large number of potentially-infested stocks. We also have investigated several prophylactic measures to prevent the further contamination of stocks, namely UV-exposure, ethanol treatment, bleaching, and desiccation. Bleaching was found to kill all spores. Other treatments were less effective but were found to be sufficient to prevent further contamination of noninfested stocks. Two treatments were efficacious in curing infested stocks (1) bleaching of eggs and subsequent raising of the larvae in clean vials; (2) fumagillin treatment. These cures only work on stocks that have not become too weak to withstand the procedures. PMID- 22836792 TI - Orbital fibrous histiocytoma mimicking cavernous hemangioma on dynamic contrast enhanced MRA imaging. AB - Orbital lesions include a broad spectrum of tumors, vascular abnormalities, and inflammatory conditions. High-resolution imaging has become an invaluable tool toward formulating an accurate diagnosis, and facilitates proper counseling regarding appropriate interventions. Imaging may guide whether partial excision to minimize damage to orbital structures, or en bloc removal to prevent potential recurrence, as seen in mesenchymal tumors, is indicated., Recently, dynamic contrast-enhanced magnetic resonance angiography (MRA) has demonstrated use in helping differentiate orbital vascular lesions. This imaging modality uses rapid MRI acquisition to provide noninvasive, dynamic flow information with high spatial resolution. However, even with modern imaging, reaching a diagnosis prior to histopathological analysis can be challenging. We present a case of orbital fibrous histiocytoma that appeared nearly identical to cavernous hemangioma on dynamic contrast-enhanced MRA. PMID- 22836793 TI - Collateral damage: heat transfer as a possible mechanism of optic nerve injury during neurosurgical intervention. AB - PURPOSE: To determine factors associated with increased heat transfer during neurosurgical drilling as a mechanism for optic nerve injury. METHODS: On a nonembalmed cadaver, the optic canal was exposed through a standard craniotomy and optic nerve sparing exenteration. The temperature was measured with a thermocoupler during each 30-second continuous drill session using 2 types of neurosurgical drills. The location of the probe, drill site, drill power, and irrigation rate were varied. RESULTS: A <1 degrees C change was measured in the optic canal at all test distances with the Cavitron Ultrasonic Surgical Aspirator and diamond drill. The use of manual irrigation decreased the mean change in temperature (DeltaT) in the sphenoid bone from 4.7 degrees C without irrigation to 1.3 degrees C with irrigation. Increasing Cavitron Ultrasonic Surgical Aspirator power from 50% to 80% at an irrigation rate of 4 ml/minute more than doubled DeltaT in sphenoid bone from 3.2 degrees C at 50% to 8.1 degrees C at 80%. Increasing irrigation from 2 to 4 ml/minute decreased mean DeltaT by -1.1 degrees C (3.2 degrees C at 2 ml/minute versus 2.1 degrees C at 4 ml/minute) at Cavitron Ultrasonic Surgical Aspirator power of 50%, but at Cavitron Ultrasonic Surgical Aspirator power of 80%, increasing irrigation increased mean DeltaT by 3.0 degrees C (3.7 degrees C at 2 ml/minute versus 6.8 degrees C at 4 ml/minute). CONCLUSIONS: Care must be taken during neurosurgical procedures to decrease heat transfer during drilling to nearby structures. With increase in drill power, there is a noticeable increase in temperature change from baseline. These temperature changes can be mediated by irrigation, although the effect of increasing irrigation rate to suppress the raise in temperature decreases with increasing drill power. PMID- 22836794 TI - Investigating the role of metal fatigue in a case of ritleng probe fracture: its causes and prevention. AB - Complications with the Ritleng probe have not been reported previously. Herein, we report a case in which the Ritleng probe tip fractured during use on a patient undergoing nasolacrimal duct intubation requiring subsequent retrieval. A root cause analysis was conducted which help to elicit possible ways to prevent such a complication in the future. Most notably the use of the stylet, documented as a cleaning device, seems to offer additional support to prevent metal fatigue and tip fracture. PMID- 22836795 TI - Hyperplastic intradiploic meningothelial tissue in the orbital roof mimicking metastatic disease. AB - Osteolytic lesions are highly suggestive of metastatic disease or in rare instances may result from primary extradural meningiomas. Herein, we describe a rare case of a patient who presented with a large area of osteolysis on the right orbital roof. An excisional biopsy revealed that the lesion was associated with the presence of hyperplastic intra-osseous meningothelial tissue. To our best knowledge, this is the first evidence that ectopic nonneoplastic meningothelial cells may induce osteolysis on the orbital walls. PMID- 22836796 TI - Hydrogel explant extrusion masquerading as a malignant eyelid lesion. AB - Hydrogel was a commonly used material for scleral buckling in the early 1980s to the mid-1990s. Use of hydrogel ceased due to a high complication rate, including frequent migration. Various symptoms and clinical findings have been reported with hydrogel migration. There have been no published reports of hydrogel migration to the eyelid anterior to the orbital septum with erosion of the orbicularis and bleeding as a presenting symptom. The authors describe a patient with hydrogel migration to the upper eyelid, with symptomology and clinical findings consistent with a malignant eyelid lesion. Excisional biopsy of extraorbital hydrogel is recommended in these cases. PMID- 22836797 TI - The ophthalmology surgical competency assessment rubric for lateral tarsal strip surgery. AB - PURPOSE: To produce an internationally valid tool to assess skill in performing lateral tarsal strip surgery. METHODS: A panel of 7 content experts adapted a previously published tool for assessing lateral tarsal strip surgery by using a modified Dreyfus scale of skill acquisition and providing behavioral descriptors for each level of skill in each category. The tools were then reviewed by 11 international content experts for their constructive comments. RESULTS: Experts' comments were incorporated, establishing face and content validity. CONCLUSIONS: The tool International Council of Ophthalmology-Ophthalmology Surgical Competency Assessment Rubric for Lateral Tarsal Strip Surgery has face and content validity. It can be used globally to assess lateral tarsal strip surgical skill. Reliability and predictive validity still need to be determined. PMID- 22836798 TI - Primary canaliculitis: clinical features, microbiological profile, and management outcome. AB - PURPOSE: To describe the demographic profile, clinical presentation, microbiological profile, and management outcome of primary canaliculitis. METHODS: Single-center, retrospective, interventional case series. Clinical records of all patients diagnosed with primary canaliculitis and treated at the Department of Ophthalmic Plastic Surgery, LV Prasad Eye Institute, Hyderabad, India, between 1987 and 2010 were reviewed. Retrospective data analysis included demographic profile, clinical presentation, microbiological profile, and management outcomes. The management outcome was further analyzed regarding conservative medical treatment alone, versus punctoplasty with canalicular curettage. RESULTS: Of the 74 patients, 40 (54%) were women. Mean age at presentation was 48 years. Right eye was involved in 38 (51%) patients, left eye in 34 (46%) patients, and both eyes in 2 (3%) patients. The mean delay in diagnosis was 10 months. Lower canaliculus was involved in 48 (65%) patients, upper canaliculus in 17 (23%) patients, and both canaliculi in 9 (12%) patients. The most common presenting symptom was epiphora, noted in 63 (85%) patients, and the most common clinical sign was thickening of canalicular portion of eyelid seen in 53 (72%) patients. Microbiological workup was available in 54 patients, of whom 49 (91%) yielded positive results. The most common isolate was staphylococcus species in 19 (39%) patients. Conservative medical therapy (punctal dilatation, canalicular expression, and topical antibiotics) resulted in resolution in 35 of 51 (69%) patients, whereas punctoplasty with canalicular curettage resulted in resolution in all 39 (100%) patients. Of the 74 patients, 57 (70%) resolved completely with single intervention, 14 (19%) with 2 interventions, 6 (8%) with 3 interventions, and 2 (3%) with 4 interventions. Recurrence was noted in 2 (3%) patients that subsequently resolved with treatment. CONCLUSION: Primary canaliculitis is predominantly a unilateral disease with a significant delay in diagnosis. The microbiological profile of canaliculitis is evolving, with staphylococcus species emerging as the most common pathogen. Although conservative medical therapy is beneficial, punctoplasty with canalicular curettage combined with topical antibiotic therapy is the gold standard treatment for canaliculitis. PMID- 22836799 TI - Clinical usefulness of orbital and facial Time-Resolved Imaging of Contrast KineticS (TRICKS) magnetic resonance angiography. AB - PURPOSE: The clinical usefulness of orbital and facial Time-Resolved Imaging of Contrast KineticS (TRICKS) MRI was assessed quantitatively and qualitatively. METHODS: A retrospective chart review of the years 2001 to 2011 was conducted at the University of Wisconsin, Madison. Patients were selected based on tumor location (extracranial head and neck) and evaluation with TRICKS imaging at any stage of the clinical course. The TRICKS protocol presented in this article allows measurement of specific tumor characteristics including lesion morphology, vascular anatomy, flow dynamics within the lesion, rapidity and sequential nature of contrast enhancement, and lesion distensibility. Cases involving changes in diagnoses and/or management as a result of TRICKS interpretation are presented in detail. RESULTS: The imaging records of 49 patients were reviewed. Most lesions were located in or around the orbit (32 lesions, 65%). Benign vascular tumors comprised the largest subcategory (32 lesions, 65%) in the cohort. Of the 20 cases with histopathological data, interpretation of MRI with TRICKS magnetic resonance angiography successfully predicted 17 (85%). Characteristic enhancement patterns for the most commonly encountered lesions are presented, in addition to a qualitative analysis of how TRICKS contributed to select cases. TRICKS helped clarify diagnosis and/or redirect management in 19 of the 49 cases in this series. CONCLUSION: To the best of the authors' knowledge, this is the largest study to date of patients evaluated with TRICKS MRI/magnetic resonance angiography for orbital and facial tumors. MRI with TRICKS magnetic resonance angiography imaging protocol offers a minimally invasive, safe, and effective diagnostic instrument in selected patients with clinical diagnostic uncertainty and in those patients requiring high-resolution vascular mapping for management planning. PMID- 22836800 TI - In vivo examination of meibomian gland morphology in patients with facial nerve palsy using infrared meibography. AB - PURPOSE: The aim of this study was to investigate the effect of orbicularis oculi weakness on meibomian gland morphology using infrared meibography. METHODS: This was a cross-sectional study. Patients were recruited from the University of Iowa Hospitals and Clinics. Inclusion criteria required the patient to be at least 18 years of age and have a unilateral facial nerve palsy. A total of 32 affected eyelids from 20 patients were studied. The aforementioned participant group was examined using infrared video meibography. The contralateral unaffected eyelids served as control. Eyelids with previous surgery were excluded. Data collected included age and gender in addition to laterality, duration, and cause of the palsy. Each eyelid was assigned a "meibograde" based on morphological changes of the meibomian glands. RESULTS: The main outcome measure was the "meibograde" based on infrared morphology of the meibomian glands. Fourteen upper and 18 lower eyelids affected by facial nerve palsies of various durations were examined. Mean patient age was 57.6 years (range 20-86). The affected lower eyelid meibograde (n = 12) was significantly different than the control (p = 0.001) in patients with weakness for more than 3 months. No difference was found in the upper eyelids at less than (n = 6) or more than (n = 8) 3 months duration. Similarly, the lower eyelids affected for less than 3 months (n = 6) showed no statistically significant difference. CONCLUSIONS: Over time, weakness of the orbicularis oculi is associated with morphological changes in the lower lid representing increased meibomian gland dysfunction. This may represent an overlooked cause of ocular surface disease in patients with facial nerve weakness. PMID- 22836801 TI - Plexiform neurofibroma of the eye region occurring in patients without neurofibromatosis type 1. AB - PURPOSE: The purpose of the present study was to investigate the correlation between Plexiform Neurofibroma (PN) of the eye region and Neurofibromatosis type 1 (NF1). According to the textbooks of ophthalmology, PN and NF1 are very closely linked. Our clinical experience raised doubts about this, however. METHODS: All biopsy reports from the Eye Pathology Institute, Copenhagen, for the 10-year period from 1999 to 2008 with PN as the histological diagnosis were identified. From the pathology referral forms, we determined whether the patients had had a history of NF1, and the medical records were reviewed for symptoms and signs of NF1. Patients with no known NF1 were invited for a clinical examination and a blood test for mutation analysis. RESULTS: 13 patients had been given the histological diagnosis of PN of the eye region during the 10-year period. Of these, 10 patients fulfilled the National Institute of Health (NIH) diagnostic criteria for NF1, but 3 patients had PN of the eye region as the only sign, and thus did not have NF1. In 2 of these patients, mutation analysis was performed on blood, and was negative. CONCLUSION: PN of the eye region is suggestive of NF1 but not pathognomonic of this disease. PMID- 22836802 TI - Intraductal meibomian gland probing in the management of ocular rosacea. AB - PURPOSE: Rosacea is a significant cause of ocular surface disease, and our current therapeutic armamentarium is often ineffective. Intraductal meibomian gland probing is a novel technique to address dry eye syndrome, although its use has not been described in the management of ocular surface disease from rosacea. METHODS: Patients with ocular rosacea, meibomian gland dysfunction, and surface disease, which was refractory to conventional management, underwent intraductal meibomian gland probing. Each patient completed the Ocular Surface Disease Index (OSDI) questionnaire before the procedure and at the 1- and 6-month postoperative visits. RESULTS: Forty eyelids of 10 patients (5 men, 5 women; mean age = 42.1 years) underwent intraductal meibomian gland probing. All patients reported subjective improvement in their symptoms of discomfort, tearing, and blurred vision. The mean preoperative, 1-month, and 6-month OSDI scores were 78.11 (standard deviation [SD] = 5.33), 37.54 (SD = 7.25), and 43.00 (SD = 5.49), respectively. The differences between the preoperative and one- and six-month scores were statistically significant (p < 0.05). Nine of the ten patients in this study were able to discontinue their doxycycline use after surgery, and 10 out of 10 patients reported decreased frequency of artificial tear use. No complications were identified in the 6-month follow-up period. CONCLUSIONS: Intraductal meibomian gland probing is a safe, effective technique to address the ocular surface disease, tearing, and discomfort associated with ocular rosacea, and this intervention results in a dramatic improvement in these symptoms. This study provides the first documentation of these findings and represents the first quantitative demonstration of the use of intraductal meibomian gland probing in the peer-reviewed literature. PMID- 22836803 TI - Impact of ERbeta and CD44 expression on the prognosis of patients with stage II colon cancer. AB - The correlation of ERbeta/CD44 expression and progression of patients with stage II of colon cancer were explored in this work. A total of 220 paraffin-embedded specimens with stage II colon cancer from 1995 to 2003 were included for assessing ERbeta and CD44 by immunohistochemistry in normal mucosa and tumor tissues. Kaplen-Meier method, log-rank test, and the Cox proportional hazards regression model were used to analyze the overall survival data. ROC curve was used to describe the capacity of variables in prognosis prediction. Jackknife method was used to perform cross validation of predictions. The survival rates were significantly different between the patients with high expression and low expression of CD44-tumor tissues (61 % vs. 90 %, p < 0.0001) and between the patients with high expression and low expression of ERbeta-tumor tissue (99 % vs. 36 %, p < 0.0001), respectively. In addition, the interaction between expression of ERbeta and CD44 was found that the impact of CD44 to the overall survive appeared only when expression of ERbeta was low; and the high expression of ERbeta-tumor could be regarded as a protective factor for overall survival. This study suggest that low expression of ERbeta-tumor and high expression of CD44 tumor are risk factors for overall survival in patients with stage II colon cancer. PMID- 22836804 TI - Tumor-derived mesenchymal stem cells and orthotopic site increase the tumor initiation potential of putative mouse mammary cancer stem cells derived from MMTV-PyMT mice. AB - The ability to transplant mammary cancer stem cells, identified by the phenotype CD24(+)CD29(+)CD49f(+)Sca-1(low), is dependent on the microenvironment in which the cells are placed. Using the MMTV-PyMT mouse model of mammary cancer, we now report two methods of tumor growth enhancement: contributions of tumor stroma in the form of tumor-derived mesenchymal stem cells and orthotopic vs. heterotopic transplantation sites. To support evidence of stem cell function, tumor-derived mesenchymal stem cells differentiated into adipocyte- and osteocyte-like cells after culture in specific medium. Co-injection of tumor-initiating cells with tumor-derived mesenchymal stem cells significantly increased tumor initiation compared to subcutaneous injection of TICs alone; co-injection also allowed tumor initiation with a single TIC. Interestingly, we observed the formation of sarcomas after co-injections of tumor-derived mesenchymal stem cells or mouse embryonic fibroblasts with TICs; sarcomas are not observed in spontaneous MMTV PyMT tumors and rarely observed in injections of TICs alone. Tumor initiation was also significantly increased in the orthotopic injection site compared to heterotopic injections. We conclude that tumor stroma and orthotopic sites both enhance tumor initiation by mammary cancer stem cells. PMID- 22836806 TI - Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis. AB - Although factor V Leiden (FVL) is a major determinant of thrombotic risk, the reason why less than 10% of carriers eventually develop venous thromboembolic (VTE) events is unknown. Recent observations suggest that circulating levels of microparticles (MP) may contribute to the thrombogenic profile of FVL carriers. We measured the plasma level of annexin V-MP (AMP) platelet-MP (PMP), endothelial MP (EMP), leukocyte-MP (LMP) and tissue factor-bearing MP (TF(+)MP), and the MP procoagulant activity (PPL) in 142 carriers of FVL (of these 30 homozygous and 49 with prior VTE), and in 142 age and gender-matched healthy individuals. The mean (+/- SD) level of AMP was 2,802 +/- 853 MP/MUl in carriers and 1,682 +/- 897 in controls (p<0.0001). A statistically significant difference between homozygous and heterozygous carriers of FVL was seen in the level of PMP, EMP and LMP, but not in that of the remaining parameters. When the analysis was confined to carriers with and without a VTE history, the mean level of AMP was 3,110 +/- 791 MP/MUl in the former, and 2,615 +/- 839 MP/MUl in the latter (p<0.005). The mean level of all subtypes of circulating MP showed a similar pattern. The PPL clotting time was 39 +/- 9 seconds (sec) in carriers, and 52 +/- 15 sec in controls (p=0.003); and was 35 +/- 8 sec in carriers with prior thrombosis, and 41 +/- 10 sec in thrombosis-free carriers (p<0.005). Our study results suggest that circulating MP may contribute to the development of thrombosis in carriers of FVL mutation. PMID- 22836807 TI - Efficient synthesis of 2'-C-alpha-aminomethyl-2'-deoxynucleosides. AB - Starting from methyl 3,5-di-O-benzyl-2-keto-alpha-D-ribofuranoside, a convergent, six-step synthesis is developed to give efficiently all four 2'-C-alpha aminomethyl-2'-deoxynucleosides (U, C, A, G) in 38%, 42%, 12%, 12% yield, respectively. Convergence is achieved by the glycosylation of persilylated nucleobases with methyl 2-alpha-phthalimidomethyl ribofuranoside. PMID- 22836805 TI - Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma. AB - Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus, its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (Kazal-type serine peptidase inhibitor domain 1 (KAZALD1), transmembrane protein 30B (TMEM30B), and mitogen activated protein kinase 13 (MAPK13)). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Laser capture microdissection was used to separate diseased sections of formalin-fixed paraffin embedded samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulphite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B, and MAPK13). TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid type peritoneal mesothelioma. We first report that the KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma. PMID- 22836808 TI - Withdrawal from biobank research: considerations and the way forward. AB - The right to withdraw one's consent after having agreed to participate in research is a fundamental principle in contemporary research ethics. However, it has been questioned whether this right should apply to research conducted on donated biological samples, including stem cells and tissues from which stem cells can be derived. In this article we present some of the concerns that have been expressed related to this question. We then identify five areas that one needs to pay greater attention to before any conclusions can be drawn as to whether donors should be given the right to withdraw, or under what circumstances withdrawal should be allowed. PMID- 22836810 TI - Hirtionosides A-C, gallates of megastigmane glucosides, 3-hydroxyoctanoic acid glucosides and a phenylpropanoid glucoside from the whole plants of Euphorbia hirta. AB - From the 1-BuOH-soluble fraction of a MeOH extract of Euphorbia hirta, collected in the Okinawa islands, three new megastigmane glucoside gallates, named hirtionosides A-C, 3-hydroxyoctanoic acid glucosides and a phenylpropanoid glucoside were isolated along with 15 known compounds. The structures of the new compounds were elucidated by detailed analysis of physical data, including one- and two-dimensional NMR spectra, and those of known compounds were determined by comparison of physico-chemical data with those reported in the literature. The absolute structures of the megastigmanes were determined by comparison of NMR data and Cotton effects in the CD spectra. The modified Mosher's method was applied to determine the absolute structure of the chiral center in 3 hydroxyoctanoic acid. The DPPH radical-scavenging properties of megastigmane glucoside gallates were assayed and, as expected, they showed moderate activity. PMID- 22836811 TI - Perspective on radiation risk in CT imaging. AB - Awareness of and communication about issues related to radiation dose are beneficial for patients, clinicians, and radiology departments. Initiating and facilitating discussions of the net benefit of CT by enlisting comparisons to more familiar activities, or by conveying that the anticipated radiation dose to an exam is similar to or much less than annual background levels help resolve the concerns of many patients and providers. While radiation risk estimates at the low doses associated with CT contain considerable uncertainty, we choose to err on the side of safety by assuming a small risk exists, even though the risk at these dose levels may be zero. Thus, radiologists should individualize CT scans according to patient size and diagnostic task to ensure that maximum benefit and minimum risk is achieved. However, because the magnitude of net benefit is driven by the potential benefit of a positive exam, radiation dose should not be reduced if doing so may compromise making an accurate diagnosis. The benefits and risks of CT are also highly individualized, and require consideration of many factors by patients, clinicians, and radiologists. Radiologists can assist clinicians and patients with understanding many of these factors, including test performance, potential patient benefit, and estimates of potential risk. PMID- 22836809 TI - Promising role of reduced-toxicity hematopoietic stem cell transplantation (PART I). AB - Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potential curative option for many patients with hematological malignancies (HM). However, the high rate of transplantation-related mortality (TRM) restricted the use of standard myeloablative HSCT to a minority of young and fit patients. Over the past few years, it has become evident that the alloreactivity of the immunocompetent donor cells mediated anti-malignancy effects independent of the action of high dose chemoradiotherapy. The use of reduced intensity conditioning (RIC) regimens has allowed a graft-versus-malignancy (GvM) effect to be exploited in patients who were previously ineligible for HSCT on the grounds of age and comorbidity. Retrospective analysis showed that RIC has been associated with lower TRM but a higher relapse rate leading to similar intermediate term overall and progression-free survivals when compared to standard myeloablative HSCT. However, the long term antitumor effect of this approach is less well established. Prospective studies are ongoing to define which patients might most benefit from reduced toxicity stem cell transplant (RT-SCT) and which transplant protocols are suitable for the different types of HM. The advent of RT-SCT permits the delivery of a potentially curative GvM effect to the majority of patients with HM whose outcome with conventional chemotherapy would be dismal. Remaining challenges include development of effective strategies to reduce relapse rates by augmenting GvM effects without increasing toxicity. PMID- 22836813 TI - Retraction note: Impact of different treatment of whole-body cryotherapy on circulatory parameters. PMID- 22836812 TI - A randomized trial of a mailed intervention and self-scheduling to improve osteoporosis screening in postmenopausal women. AB - Guidelines recommend bone density screening with dual-energy X-ray absorptiometry (DXA) in women 65 years or older, but <30% of eligible women undergo DXA testing. There is a need to identify a systematic, effective, and generalizable way to improve osteoporosis screening. A group randomized, controlled trial of women >=65 years old with no DXA in the past 4 years, randomized to receive intervention materials (patient osteoporosis brochure and a letter explaining how to self-schedule a DXA scan) versus usual care (control) was undertaken. Outcome of interest was DXA completion. Of 2997 women meeting inclusion criteria, 977 were randomized to the intervention group. A total of 17.3% of women in the intervention group completed a DXA, compared to 5.2% in the control group (12.1% difference, p < 0.0001). When including only those medically appropriate, we found a difference of 19% between the two groups (p < 0.0001). DXA receipt was greater in main clinic patients compared to satellite clinic patients (20.9% main clinic versus 10.1% satellite clinic). The cost to print and mail the intervention was $0.79 per patient, per mailing. The number of women to whom intervention needed to be mailed to yield one extra DXA performed was 9, at a cost of $7.11. DXA scan completion was significantly improved through use of a mailed osteoporosis brochure and the availability for patients to self-schedule. This simple approach may be an effective component of a multifaceted quality improvement program to increase rates of osteoporosis screening. PMID- 22836814 TI - Remembering Marvin Weinstein (1916-2011). PMID- 22836815 TI - Chromosomal anomalies and additional sonographic findings in fetuses with open neural tube defects. AB - OBJECTIVE: To evaluate the results and the necessity of chromosome analysis in fetuses prenatally detected with a neural tube defect and to determine the significance of ultrasonographic evaluation for the identification of underlying or accompanying chromosomal anomalies. METHODS: Ninety fetuses that underwent prenatal and/or postnatal chromosome analysis after being diagnosed with open neural tube defects (NTD) between the years 2006 and 2010 in the Department of Obstetrics and Gynecology at Ondokuz Mayis University School of Medicine were included in this study. Detailed fetal ultrasonography was performed in all cases in order to investigate any additional anomalies. Karyotype was determined in the prenatal period by amniocentesis in 72 (80%) of the 90 fetuses, and by cordocentesis in 5 (5.5%). In 13 (13.3%) fetuses, karyotype was determined in the postnatal period by blood sampling. RESULTS: Fourteen (15.5%) of the 90 fetuses were diagnosed with acrania/anencephaly, 14 (15.5%) with encephalocele, 2 (2.2%) with iniencephaly, 60 (66.6%) with open spina bifida. None of the 90 fetuses with open NTD who had undergone chromosome analysis was diagnosed with chromosomal anomalies. None of the 19 (21.1%) fetuses diagnosed with additional ultrasound findings had a chromosomal abnormality, either. Seventy-one (78.9%) fetuses having sonograhically isolated NTD were also isolated in postmortem examination. CONCLUSION: In fetuses with open NTD, we could not find the chromosomal anomaly rate as high as reported in previous literature. The necessity of fetal karyotyping should be questioned especially in isolated cases. PMID- 22836816 TI - An audit about labour induction, using prostaglandin, in women with a scarred uterus. AB - OBJECTIVES: Induction of labour after a previous caesarean section is still controversial. We aim to analyse, in a population of women who have a uterine scar, the maternal, foetal and neonatal complications in relation to the mode of labour and delivery. STUDY DESIGN: Retrospective analysis of collected data from all the singleton deliveries of patients with a scarred uterus (N=798), admitted to the hospital between August 2006 and March 2009. OUTCOMES: maternal and perinatal complications. RESULTS: Among 798 singleton deliveries, 36.1% had a spontaneous labour, 12.6% a prostaglandin-induced labour and 2.9% an ocytocin induced labour, and 48.4% had an elective caesarean section. The chance of delivering vaginally was respectively 84.4% for those who had a spontaneous labour, 75.2% for those who were induced using prostaglandin, 82.6% after induction using ocytocin. There were eight uterine ruptures, four after spontaneous labour (1.4%), two after prostaglandin induction (2%) and two at the time of an iterative caesarean section (0.5%). There were no differences between groups, except the risk of haemorrhage (17.4% after spontaneously induced labour, 34.8% after ocytocin, 17.8% after prostaglandin and 44.6% after iterative caesarean section; p<0.005) and the neonatal admissions when analysed by intention to treat only (8.3% after spontaneously induced labour, 9.1% after ocytocin, 12% after prostaglandin and 16.8% after iterative caesarean section; p<0.009). CONCLUSION: Although no increase in maternal or perinatal outcome was observed in relation to prostaglandin-induced labour after caesarean section, this study is too underpowered to exclude an increased risk. PMID- 22836817 TI - Self-regenerated solar-driven photocatalytic water-splitting by urea derived graphitic carbon nitride with platinum nanoparticles. AB - A natural self-regeneration step for urea derived graphitic carbon nitride with platinum nanoparticles is found by simply opening the system to air in the dark under ambient conditions, following its solar-driven hydrogen production. The produced peroxides deactivate the graphitic carbon nitride. Release of weakly bound peroxides on the polymeric semiconductor surface is a crucial process for regeneration. PMID- 22836818 TI - Course and predictors of depressive symptoms among family caregivers of terminally ill cancer patients until their death. AB - OBJECTIVE: Few studies have investigated the impact of providing end-of-life care on family caregivers' depressive symptoms over time, especially until the patient's death. The purpose of this study was to identify the course and predictors of depressive symptoms in caregivers of terminally ill cancer patients until they died. METHODS: For this prospective, longitudinal study of 193 caregivers, data were collected using the Center for Epidemiological Studies Depression Scale, Symptom Distress Scale, Medical Outcomes Study Social Support Survey, and Caregiver Reaction Assessment scale. The course and predictors of depressive symptoms were analyzed using the generalized estimating equation model. RESULTS: Caregivers' depressive symptoms increased as the patient's death approached. Spousal or adult child family caregivers suffered more depressive symptoms if they self-identified as lacking social support and confidence in offering substantial assistance for younger terminally ill cancer patients with higher levels of symptom distress. Caregivers were susceptible to higher levels of depressive symptoms if they were heavily burdened by caregiving, that is, experienced more disruptions in schedules, greater health deterioration, stronger sense of family abandonment, and lower caregiver esteem. CONCLUSIONS: Psychological well-being of caregivers of terminally ill cancer patients deteriorated in response to progression of the patient's disease and impending death. Effective interventions should be developed and provided to high-risk caregivers as identified in our study. Increasing caregivers' strength of perceived social support, facilitating their confidence in caregiving, and alleviating their subjective burden may lessen the development of depressive symptoms in caregivers of terminally ill cancer patients throughout the dying process. PMID- 22836819 TI - Interaction between maternal obesity and Bishop score in predicting successful induction of labor in term, nulliparous patients. AB - OBJECTIVE: Determine the Bishop score most predictive of induction of labor (IOL) success for different maternal weight groups. STUDY DESIGN: Retrospective cohort study. Prospectively collected database utilized to determine the optimum Bishop score within each prepregnancy body mass index (BMI) category of term, nulliparous patients undergoing IOL. RESULTS: For the total group (n = 696), Bishop score >= 5 was most predictive of success (75% versus 56%, p < 0.0001). Within each BMI category, Bishop score >= 5 remained most predictive: normal weight (79% versus 64%, p < 0.01); overweight (72% versus 58%, p = 0.03); and obese (73% versus 45%, p < 0.0001). Overall, nonobese patients had more success than obese patients (70% versus 59%, p < 0.01). The nonobese group had more success than the obese group when the Bishop score was < 3 (57% versus 39%, p < 0.05) but not when it was >= 3 (72% versus 65%, p = 0.1). Also, there was a higher fraction of patients with Bishop score < 3 in the obese group compared with the nonobese group (25% versus 14%, p < 0.001). CONCLUSION: The optimum Bishop score for predicting successful IOL in nulliparous patients was 5 regardless of BMI class. The higher IOL failure rate observed in obese women was associated with lower starting Bishop scores and was compounded by higher failure rates in obese women with Bishop scores < 3. PMID- 22836821 TI - Adverse obstetric outcomes in women with previous cesarean for dystocia in second stage of labor. AB - OBJECTIVE: To evaluate obstetric outcomes in women undergoing a trial of labor (TOL) after a previous cesarean for dystocia in second stage of labor. METHODS: A retrospective cohort study of women with one previous low transverse cesarean undergoing a first TOL was performed. Women with previous cesarean for dystocia in first stage and those with previous dystocia in second stage were compared with those with previous cesarean for nonrecurrent reasons (controls). Multivariable regressions analyses were performed. RESULTS: Of 1655 women, those with previous dystocia in second stage of labor (n = 204) had greater risks than controls (n = 880) to have an operative delivery [odds ratio (OR): 1.5; 95% confidence intervals (CI) 1.1 to 2.2], shoulder dystocia (OR: 2.9; 95% CI 1.1 to 8.0), and uterine rupture in the second stage of labor (OR: 4.9; 95% CI 1.1 to 23), and especially in case of fetal macrosomia (OR: 29.6; 95% CI 4.4 to 202). The median second stage of labor duration before uterine rupture was 2.5 hours (interquartile range: 1.5 to 3.2 hours) in these women. CONCLUSION: Previous cesarean for dystocia in the second stage of labor is associated with second stage uterine rupture at next delivery, especially in cases of suspected fetal macrosomia and prolonged second stage of labor. PMID- 22836820 TI - Inadequate prenatal care utilization and risks of infant mortality and poor birth outcome: a retrospective analysis of 28,729,765 U.S. deliveries over 8 years. AB - OBJECTIVE: To evaluate the association between adequacy of prenatal care utilization and risk of fetal and neonatal mortality and adverse outcomes. METHODS: We conducted a population-based cohort study using the Center for Disease Control and Prevention's Linked Birth-Infant Death and Fetal Death data on all deliveries in the United States between 1995 and 2002. Inclusion criteria were singleton births >=22 weeks of gestation with no known congenital malformation. Inadequate prenatal care was defined according to the Adequacy of Prenatal Care Utilization Index, and its effect on fetal and neonatal death was estimated using unconditional logistic regression analysis adjusting for maternal age, race, education, and other confounding variables. RESULTS: During our 8-year study period, 32,206,417 births occurred, 28,729,765 (89.2%) of which met inclusion criteria. Inadequate prenatal care utilization occurred in 11.2% of expectant mothers, more commonly among women <=20 years, black non-Hispanic and Hispanic women, and those without high school education. Relative to adequate care, inadequate care was associated with increased risk of prematurity 3.75 (3.73 to 3.77), stillbirth 1.94 (1.89 to 1.99), early neonatal dearth 2.03 (1.97 to 2.09), late neonatal death 1.67 (1.59 to 1.76), and infant death 1.79 (1.76 to 1.82). CONCLUSION: Risk of prematurity, stillbirth, early and late neonatal death, and infant death increased linearly with decreasing care. Given the population effect of this association, public health initiatives should target program expansion to ensure timely and adequate access, particularly for women <=20 years, Black non-Hispanic and Hispanic women, and those without high school education. PMID- 22836822 TI - Survival outcomes of twin-twin transfusion syndrome stage I: a systematic review of literature. AB - OBJECTIVE: To review literature about treatment of twin-twin transfusion syndrome (TTTS) stage I. MATERIALS: A search in PubMed, EMBASE, Medline, and reference lists was performed. Inclusion criteria were TTTS diagnosed with standard criteria and classified with Quintero staging and survival rates (SR) stratified for stage and first-choice treatment. Outcomes were SR and progression to advanced stages. Preferred Reporting Items for Systematic reviews and Meta Analyses guidelines were followed. RESULTS: Seven articles pooled 262 twin sets treated with amnioreduction (16%), conservative management (22%), and laser therapy (62%). The overall SR was 77% after amnioreduction, 86% in the conservative management group, and 85% in the laser therapy group. Progression rate occurred in 30%, 15%, and 0%, respectively. Outcomes were similar between laser therapy as first- versus second-choice treatment. Because most studies were observational and not comparative, a meta-analysis was not performed. CONCLUSION: Conservative management of TTTS stage I is a reasonable option until randomized clinical trials are presented. PMID- 22836824 TI - The role of massive transfusion protocols in obstetrics. AB - Obstetric hemorrhage is a leading cause of maternal mortality worldwide. New concepts involving the pathophysiology of hemorrhage have been described and include early activation of both the protein C and fibrinolytic pathways. New tendencies in hemorrhage treatment include the use of hemostatic resuscitation. Massive transfusion protocols involve the early utilization of blood products and limit the traditional approach of early massive crystalloid based resuscitation. The evidence behind hemostatic resuscitation is still limited. PMID- 22836825 TI - Reinvestigation of the sex pheromone of the wild silkmoth Bombyx mandarina: the effects of bombykal and bombykyl acetate. AB - Sex pheromone investigations of the domesticated silkmoth, Bombyx mori (Lepidoptera: Bombycidae), helped elucidate the molecular and physiological fundamentals of chemical communication in moths, yet little is known about pheromone evolution in bombycid species. Therefore, we reexamined the sex pheromone communication in the wild silkmoth, Bombyx mandarina, which is considered ancestral to B. mori. Our investigations revealed that (a) B. mandarina females produce (E,Z)-10,12-hexadecadienol (bombykol), but not (E,Z) 10,12-hexadecadienal (bombykal) or (E,Z)-10,12-hexadecadienyl acetate (bombykyl acetate), which are pheromone components in other bombycid moths; (b) antennae of male B. mandarina respond strongly to bombykol as well as to bombykal and bombykyl acetate; and (c) bombykal and bombykyl acetate strongly inhibit attraction of B. mandarina males to bombykol in the field. The present study clarifies the evolution of pheromone communication in bombycid moths. PMID- 22836823 TI - The investment case for preventing NICU-associated infections. AB - BACKGROUND: Nosocomial [hospital-associated or neonatal intensive care unit (NICU)-associated] infections occur in as many as 10 to 36% of very low-birth weight infants cared for in NICUs. OBJECTIVE: To determine the potentially avoidable, incremental costs of care associated with NICU-associated bloodstream infections. STUDY DESIGN: This retrospective study included all NICU admissions of infants weighing 401 to 1500 g at birth in the greater Cincinnati region from January 1, 2005, through December 31, 2007. Nonphysician costs of care were compared between infants who developed at least one bacterial bloodstream infection prior to NICU discharge or death and infants who did not. Costs were adjusted for clinical and demographic characteristics that are present in the first 3 days of life and are known associates of infection. RESULTS: Among 900 study infants with no congenital anomaly and no major surgery, 82 (9.1%) developed at least one bacterial bloodstream infection. On average, the cost of NICU care was $16,800 greater per infant who experienced NICU-associated bloodstream infection. CONCLUSION: Potentially avoidable costs of care associated with bloodstream infection can be used to justify investments in the reliable implementation of evidence-based interventions designed to prevent these infections. PMID- 22836826 TI - Characterization of epoxytrienes derived from (3Z,6Z,9Z)-1,3,6,9-tetraenes, sex pheromone components of arctiid moths and related compounds. AB - Cis-9,10-epoxy-(3Z,6Z)-1,3,6-henicosatriene has been identified from a pheromone gland of arctiid species, such as Hyphantria cunea. Since the diversity of lepidopteran species suggests that structurally related compounds of the 9,10 epoxide are also utilized as a sex pheromone components, epoxytrienes derived from (3Z,6Z,9Z)-1,3,6,9-tetraenes with a C(19)-C(21) chain were systematically synthesized and characterized. While 1,2-epoxy-3,6,9-triene was not obtained, peracid oxidation of each tetraene produced a mixture of three cis-epoxides (3,4 epoxy-1,6,9-triene, 6,7-epoxy-1,3,9-triene, and 9,10-epoxy-1,3,6-triene), which were separable by LC as well as GC. Detailed inspection of the mass spectra of the C(19)-C(21) epoxides indicated the following diagnostic ions for determining the chemical structures: m/z 79, M-70, and M-41 for the 3,4-epoxytrienes; m/z 79, 95, 109, and 149 for the 6,7-epoxytrienes; and m/z 79, 106, 120, M-121, and M-107 for the 9,10-epoxytrienes. Resolution of two enantiomers of each C(21) epoxytriene was accomplished by HPLC equipped with a chiral column, and analysis of the pheromone extracted from virgin females of H. cunea revealed the 9S,10R configuration of the natural epoxytriene as the same configuration of C(21) 9,10 epoxydiene, a main pheromone component of this species. GC-EAD analysis of the optically pure epoxides showed that the antennae of male H. cunea were stimulated more strongly (>100 times) by the (9S,10R)-isomers than the antipodes. PMID- 22836827 TI - Regeneration of complex oil-gland secretions and its importance for chemical defense in an oribatid mite. AB - Most oribatid mites possess a pair of opisthonotal exocrine glands that produce mostly complex, species-specific secretions. Such blends may contain more than 10 different compounds, but hardly anything is known about their primary biosynthesis or regeneration. I analyzed recovery of the 6 main components from the 11-compound secretion of the oribatid mite Archegozetes longisetosus Aoki, including the main chemical classes hydrocarbons, aromatics, and terpenes, during a 20-day time course after complete gland depletion. About 10 % of the original total secretion amount was restored after 24 hr, and after 2-6 days, the amount had reached the range of total amount observed in the control group. Most compounds were recovered at similar rates within the first 48 hr. An important exception was pentadecane, which was predominantly produced in the first few hours, suggesting that this compound is the main solvent of the secretion. Although relative amounts of the main compounds differed significantly over time, the complex profile of the whole secretion was stable and not confidently distinguishable among the sampling dates. The general recovery rate was high during the first 48 hr, about 25 times higher than in the remaining 18 days. The biological importance of this high initial investment was supported by predation experiments: the predacious rove beetle Stenus juno was first repelled after 48 hr when at least 25 % of secretions was restored. PMID- 22836828 TI - The role of fluoride on the process of titanium corrosion in oral cavity. AB - Titanium is known to possess excellent biocompatibility as a result of corrosion resistance, lack of allergenicity when compared with many other metals. Fluoride is well known as a specific and effective caries prophylactic agent and its systemic application has been recommended widely over recent decades. Nevertheless, high fluoride concentrations impair the corrosion resistance of titanium. The purpose of this article is to summarize the current data regarding the influence of fluoride on titanium corrosion process in the last 5 years. These data demonstrate noxious effects induced by high fluoride concentration as well as low pH in the oral cavity. Therefore, such conditions should be considered when prophylactic actions are administrated in patients containing titanium implants or other dental devices. PMID- 22836829 TI - Biological and cytoselective anticancer properties of copper(II)-polypyridyl complexes modulated by auxiliary methylated glycine ligand. AB - A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3).xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3).11/2H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24 h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2 MUM while the corresponding values for normal cell line NP69 are greater than 13.0 MUM. All complexes, at 5 MUM, induced 41-60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells. PMID- 22836830 TI - Optically active alpha-phenylethylamine as efficient organocatalyst in the solvent-free reactions between 2,3-butanedione and conjugated nitroolefins. AB - (R)-(+) and (S)-(-)-1-phenylethylamine have been shown to promote highly diastereoselective and complementary enantioselective formal [3 + 2]carbocyclization reactions between 2,3-butanedione and conjugated nitroalkenes with formation of enantiomerically rich 2-hydroxy-3-nitrocyclopentanone derivatives. The reactions were carried out both in solvent and under solvent free conditions. The absolute configurations of the products were assigned by X ray and circular dichroism spectra analyses. PMID- 22836832 TI - Identification of the western tarnished plant bug (Lygus hesperus) olfactory co receptor Orco: expression profile and confirmation of atypical membrane topology. AB - Lygus hesperus (western tarnished plant bug) is an agronomically important pest species of numerous cropping systems. Similar to other insects, a critical component underlying behaviors is the perception and discrimination of olfactory cues. Consequently, the molecular basis of olfaction in this species is of interest. To begin to address this issue, we utilized homology-based PCR as a commonly accepted abbreviation but if necessary it is polymerase chain reaction methods to identify the L. hesperus olfactory receptor co-receptor (Orco) ortholog, a receptor that has been shown to be essential for olfaction. The L. hesperus Orco (LhOrco) shares significant sequence homology with known Orco proteins in other insects. Parallel experiments using the sympatric sister species, Lygus lineolaris (tarnished plant bug), revealed that the Lygus Orco gene was completely conserved. Surprisingly, a majority of the membrane topology prediction algorithms used in the study predicted LhOrco to have both the N and C terminus intracellular. In vitro immunofluorescent microscopy experiments designed to probe the membrane topology of transiently expressed LhOrco, however, refuted those predictions and confirmed that the protein adopts the inverted topology (intracellular N terminus and an extracellular C terminus) characteristic of Orco proteins. RT-PCR analyses indicated that LhOrco transcripts are predominantly expressed in adult antennae and to a lesser degree in traditionally nonolfactory chemosensory tissues of the proboscis and legs. Expression is not developmentally regulated because transcripts were detected in all nymphal stages as well as eggs. Taken together, the results suggest that LhOrco likely plays a critical role in mediating L. hesperus odorant perception and discrimination. PMID- 22836831 TI - Molecular modeling to investigate the binding of Congo red toward GNNQQNY protofibril and in silico virtual screening for the identification of new aggregation inhibitors. AB - Understanding the nature of the recognition between amyloid protofibrils and dye molecules at the molecular level is essential to improving instructive guides for designing novel molecular probes or new inhibitors. However, the atomic details of the binding between dyes and amyloid fibrils are still not fully understood. In this study, molecular docking, consensus scoring, molecular dynamics (MD), and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analyses were integrated to investigate the binding between Congo red (CR) and the GNNQQNY protofibril from yeast prion protein Sup35 and to further evaluate their binding stabilities and affinities. Our results reveal that there are four CR binding sites located on GNNQQNY protofibril surface. These four CR binding sites adopt dual binding modes by which CR binding with its long axis parallel and perpendicular to the long axis of the protofibril. In addition, CR was also found to bind to the edge of the protofibril via hydrophobic/aromatic and hydrogen bonding interactions, which is inferred as the possible inhibition mechanism to prevent the elongation of the protofibril from the addition of incoming peptides. Virtual screening from National Cancer Institute (NCI) database obtained three hit compounds with higher binding affinity than CR to the edge of the protofibril due to the fact that the central parts of these compounds are able to form additional hydrogen bonds with the protofibril. The results of the study could be useful for the development of new molecular probes or inhibitors for clinical applications. PMID- 22836833 TI - Enzyme deactivation treatments did not decrease the beneficial role of oat food in intestinal microbiota and short-chain fatty acids: an in vivo study. AB - BACKGROUND: Steaming and roasting treatments are widely used enzyme deactivation methods in the oat food industry in China. Whether or not the enzyme deactivation treatments affect the nutritional function of oat foods is unknown. In the current study, we examined the effects of 4-week ingestion of steamed or roasted oat foods on the intestinal bacteria and short-chain fatty acids of rats. RESULTS: Compared with rats taking no oat foods, rats taking normal oat foods or enzyme-deactivated oat foods showed significantly higher (P < 0.05) counts of Lactobacillus spp. and Bifidobacterium spp. in colon, significantly lower (P < 0.05) counts of Enterococcus spp. and coliforms in colon, and significantly higher (P < 0.05) levels of butyrate and acetate in colonic digesta. In addition, rats taking infrared roasting (IR)-treated oat foods also demonstrated significantly higher (P < 0.05) fecal Lactobacillus spp. counts and significantly lower (P < 0.05) cecal and fecal counts of E. coli, Enterococcus spp. and coliforms than rats taking no oat foods. As for the comparison between the enzyme undeactivated oat group and the three enzyme-deactivated oat groups, there were no significant differences in most of the parameters (P > 0.05), though a few exceptions did exist. CONCLUSION: Enzyme deactivation treatments did not decrease the beneficial role of oat food in the intestinal microbes and short-chain fatty acids of rats. PMID- 22836834 TI - Competency is not enough: integrating identity formation into the medical education discourse. AB - Despite the widespread implementation of competency-based medical education, there are growing concerns that generally focus on the translation of physician roles into "measurable competencies." By breaking medical training into small, discrete, measurable tasks, it is argued, the medical education community may have emphasized too heavily questions of assessment, thereby missing the underlying meaning and interconnectedness of how physician roles shape future physicians. To address these concerns, the authors argue that an expanded approach be taken that includes a focus on professional identity development. The authors provide a conceptual analysis of the issues and language related to a broader focus on understanding the relationship between the development of competency and the formation of identities during medical training. Including identity alongside competency allows a reframing of approaches to medical education away from an exclusive focus on "doing the work of a physician" toward a broader focus that also includes "being a physician." The authors consider the salient literature on identity that can inform this expanded perspective about medical education and training. PMID- 22836835 TI - Do U.S. research institutions meet or exceed federal mandates for instruction in responsible conduct of research? A national survey. AB - PURPOSE: To explore the extent to which U.S. research institutions are meeting or exceeding National Institutes of Health and National Science Foundation mandates to provide instruction in responsible conduct of research (RCR). METHOD: In summer 2011, the authors sent an e-mail survey to officials responsible for overseeing RCR instructional programs at the 200 top-funded research institutions in the United States and Puerto Rico. They cross-classified the proportions exceeding federal mandates by the types of additional individuals required to receive training and by medical school presence/absence. RESULTS: Responses were received from 144 institutions (72%); all had an RCR program. Of these 144 institutions, 69 (47.9%) required only federally mandated individuals to take RCR training, whereas 75 (52.1%) required additional individuals to be trained as well. A greater proportion of institutions with medical schools (62.3%; 53/85) went beyond the federal mandates than did those without (37.3%; 22/59). Types of additional individuals required to receive training included all students in selected programs (23.6%; 34/144), all students participating in externally funded research (12.5%; 18/144), all graduate students (11.1%; 16/144), all faculty/staff participating in externally funded research (9.7%; 14/144), all postdoctoral students or fellows (8.3%; 12/144), all doctoral-level students (4.9%; 7/144), all faculty/staff involved in human subjects research (4.9%; 7/144), and all faculty/staff involved in animal research (2.1%; 3/144). CONCLUSIONS: More institutions with medical schools exceeded federal RCR training mandates than did those without. The authors encourage other institutions to expand their RCR requirements to promote research integrity. PMID- 22836836 TI - Does applicant personality influence multiple mini-interview performance and medical school acceptance offers? AB - PURPOSE: To examine relationships among applicant personality, Multiple Mini Interview (MMI) performance, and medical school acceptance offers. METHOD: The authors conducted an observational study of applicants who participated in the MMI at the University of California, Davis, School of Medicine during the 2010 2011 admissions cycle and responded to the Big Five Inventory measuring their personality factors (agreeableness, conscientiousness, extraversion, neuroticism, openness). Individuals' MMI performance at 10 stations was summarized as a total score. Regression analyses examined associations of personality factors with MMI score, and associations of personality factors and MMI score with acceptance offers. Covariates included sociodemographic and academic performance measures. RESULTS: Among the 444 respondents, those with extraversion scores in the top (versus bottom) quartile had significantly higher MMI scores (adjusted parameter estimate = 5.93 higher, 95% CI: 4.27-7.59; P < .01). In a model excluding MMI score, top (versus bottom) quartile agreeableness (AOR = 3.22; 95% CI 1.57-6.58; P < .01) and extraversion (AOR = 3.61; 95% CI 1.91-6.82; P < .01) were associated with acceptance offers. After adding MMI score to the model, high agreeableness (AOR = 4.77; 95% CI 1.95-11.65; P < .01) and MMI score (AOR 1.33; 95% CI 1.26 1.42; P < .01) were associated with acceptance offers. CONCLUSIONS: Extraversion was associated with MMI performance, whereas both extraversion and agreeableness were associated with acceptance offers. Adoption of the MMI may affect diversity in medical student personalities, with potential implications for students' professional growth, specialty distribution, and patient care. PMID- 22836837 TI - An intervention with third-year medical students to encourage the reporting and management of occupational exposures. AB - PURPOSE: Medical students are particularly vulnerable to occupational exposures to blood-borne pathogens because of their inexperience. Although exposure rates for medical students remain high, they often do not report such incidents or seek the proper medical care. The authors describe and evaluate an intervention at the Yale University School of Medicine to prevent and manage occupational exposures among medical students. METHOD: Since 2001, students have met with key faculty during orientation and again before clinical clerkships to discuss the circumstances under which most exposures occur, examine the equipment used to draw blood and start IVs, and review instructions about postexposure management. They are also given a laminated card summarizing this information. In 2010 and 2011, the authors surveyed graduating students about their experiences. RESULTS: Two hundred twenty-five of 245 (92%) students responded to the survey, and 82 (36%) had experienced 103 exposures. Forty-seven of those 82 (57%) students reported their exposure, 52 (56%) had the laminated card on them at the time of the incident, and 15 (18%) started postexposure prophylaxis. The most common reasons students cited for not reporting an incident were a low-risk exposure, a sense of embarrassment, or perceived difficulties in getting care. CONCLUSIONS: The authors recommend continuing to educate medical students about the importance of reporting exposures and seeking the proper care. They also recommend educating physicians and residents in an attempt to change the environment around exposures so that medical students no longer feel discouraged from reporting incidents. PMID- 22836838 TI - The current state and future possibilities of recruiting leaders of academic health centers. AB - For more than 30 years, commentators have been questioning the processes that medical schools and teaching hospitals use to search and recruit their leaders. Recent studies suggest that these problems persist, not only within academic medicine but across industries and countries.The authors' thesis in this article is that the search process, although always important, will be of even greater consequence than before, given the current environment for academic medicine. They (1) demonstrate why the academic medicine sector faces an impending talent crisis, (2) review the evidence on how a systematic approach to talent development has important organizational outcomes, (3) review the current state of the search and recruitment process for leaders in academic medicine centers, and (4) underscore the use of a continuous improvement approach as a way to improve the search process.The authors describe one such approach, which included retaining a core set of search committee members from one search to the next, appointing an associate dean for leadership development who instilled consistency in search and recruitment processes, and evaluating and making improvements to the search process via participant and stakeholder feedback. PMID- 22836839 TI - Implementing the leadership development plans of faculty education fellows: a structured approach. AB - The literature about medical education faculty fellowship programs, which have grown in popularity, quantifies program characteristics, provides exemplars, and reports on delivery strategies. Evaluation is generally limited to satisfaction measures, with a few longitudinal studies of postprogram achievements, but none on the process of making these changes.The authors describe the development of faculty members' postfellowship leadership plans and a structured process to support plan implementation. They also compare the implementation of initiatives specified in individual leadership development plans of two cohorts of faculty. The participants were graduates of a fellowship program at the George Washington University School of Medicine and Health Sciences. One cohort participated in a structured process of monthly reciprocal peer coaching, followed by journaling and quarterly interviews with the program director; a second cohort functioned as a comparison with no structured process supporting them. (Study years are not provided because they could inadvertently lead to the identification of the participants.) Despite similar implementation challenges expressed by both cohorts, the cohort participating in the structured process implemented 23% more of their planned initiatives, including 2 times as many educational leadership initiatives and 3.5 times as many initiatives related to developing new curriculum. The combination of plan development, reciprocal peer coaching, journaling, and interview discussions provided faculty with focus, structure, and personal support. This structured process supporting leadership plan development and implementation can be easily transferred to other fellowship programs in medical education, adapted for use with residents and fellows, and used in similar development programs. PMID- 22836840 TI - Implementing a nurse-shadowing program for first-year medical students to improve interprofessional collaborations on health care teams. AB - Although physicians and nurses play critical roles in providing team-based collaborative care, the literature on current relationships between physicians and nurses in typical health care settings reveals troublesome characteristics that affect the quality of the patient care that they provide. Studies report communication failures, poor coordination, and fragmented care within and across organizations, which then have been associated with medication errors, patient safety issues, and patient deaths. Because the physician-nurse relationship is a critical component of a high-functioning patient care team, curricular interventions are needed to improve communication between physicians and nurses and to avoid professional conflict that can potentially compromise the quality of the patient care they offer.Currently, medical schools provide students with limited education and training on the roles of other health care professionals. In 2009, to begin addressing this need in the curriculum, the authors implemented a nurse-shadowing program at the University of Michigan Medical School. They set out to help first-year medical students learn more about the role of nurses in health care to positively influence their attitudes toward nurses and improve their understanding of nurses' roles in health care teams. Pre- and postprogram survey results revealed that medical students' attitudes toward nurses improved and their knowledge of the profession increased as a result of this intervention. In this article, the authors provide a description of the half-day program, evidence of its effectiveness, the implications of those findings, and future directions for teaching medical students about effectively working on interprofessional teams. PMID- 22836841 TI - The successful, rapid transition to a new model of graduate medical education in Singapore. AB - Graduate medical education (GME) in Singapore recently underwent major reform (2009-2012), leading to accreditation of residency programs by the Accreditation Council for Graduate Medical Education-International (ACGME-I) within two years of the initial commitment to change. The main aims of the reforms were to implement best practices in GME, to provide better support structures for program administration, and to bring all specialty training under one administrative umbrella. The authors outline the historic development of GME in Singapore, the complexities of the model in place immediately prior to ACGME-I accreditation, and the difficulties addressed by the proposed changes, leading to a description of implementation efforts at the National University Hospital of Singapore, a university-affiliated academic medical center. The authors describe the institutional factors uniting hospital leaders in support of reform, the recruitment of a team to manage change within the institution, the inauguration of a new office for GME, and the faculty development initiatives needed to educate faculty leading the change process. The preparation and execution of specific initiatives designed to improve GME and the communication strategies needed to coordinate and publicize change efforts are outlined, as well as strategies for sustaining improvements and building them into the culture of the institution. The authors demonstrate that external accreditation can be a powerful driver of educational reform and summarize key lessons derived from Kotter principles, a current model of change management. PMID- 22836842 TI - Perspective: agency and activism: rethinking health advocacy in the medical profession. AB - Health advocacy is being formalized as a professional activity for physicians across North America, but the accommodation of this activity into conceptions of daily practice has been controversial and confusing. There appears to be a lack of clarity around what a physician should do as a health advocate and how this should manifest in daily practice. In this article, the authors explore how the medical community has characterized the health advocate role and the roots of the debates regarding its place within training and practice, using the example of the CanMEDS Health Advocate Role. They argue that the confusion might be a result of subsuming two distinct activities, agency and activism, under the rubric of health advocacy. They propose that these activities and their associated skills are sufficiently distinct as to merit separate discussions. Agency involves advancing the health of individual patients ("working the system"), and activism involves advancing the health of communities and populations ("changing the system"). The authors suggest that distinguishing between agency and activism within health advocacy provides opportunities to explore their distinct goals and skill sets in a manner that will advance the debate about health advocacy, a conversation that remains critically important to the medical profession. PMID- 22836843 TI - Content and conceptual frameworks of preceptor feedback related to residents' educational needs. AB - PURPOSE: The development of clinical expertise depends not only on frequent practice opportunities but also on receiving quality feedback, especially regarding difficult aspects of learning. The purpose of this study was to investigate the content and conceptual frameworks of preceptor feedback to residents during case presentations. METHOD: The authors conducted a qualitative and correlational study in which 25 clinical preceptors from one Canadian medical school's internal medicine and family medicine residency programs responded to six written, case-based vignettes depicting residents seeking help regarding a variety of educational issues. Preceptors were asked probing follow-up questions about their responses. The authors analyzed response content, conceptual frameworks used in formulating responses, and the correlation between the two. RESULTS: Overall, the preceptors generated 806 responses, representing 96 distinct topics. The five topics mentioned most frequently related to reading suggestions, leading diagnosis, contrasting clinical findings, patient follow-up, and resident's concerns/feelings about the case. Seventy-three percent of the topics were specific to one or two vignettes. The preceptors used 18 distinct conceptual frameworks in formulating responses (e.g., analytical versus nonanalytical reasoning, problem representation, therapeutic alliance, patient centered approach). Use of conceptual frameworks was positively associated with greater diversity of responses (r = 0.43, P = .03). CONCLUSIONS: The vignettes stimulated rich and extensive lists of topics and conceptual frameworks. These findings represent but one step in the exploration of the content and conceptual frameworks of preceptor feedback and of the interrelatedness of feedback content and process, which have important implications for teaching and faculty development. PMID- 22836844 TI - Preparing students for clerkship: a resident shadowing program. AB - The preparation of medical students for clerkship has been criticized, in terms of both students understanding of their new role as clinical trainees and their ability to carry out that role. To begin to address this gap, the authors report the development, implementation, and assessment of a novel program in which first year medical students shadow first-year residents during their clinical duties. The program matches each student to a single resident, whom they shadow for several hours, once per month, for eight months. In the programs inaugural year (2009-10), 83 student-resident pairs participated; over 70% responded to pre- and post-intervention questionnaires, which included an 18-item preparedness scale. The authors used those responses to evaluate the program. Compared to students in a control group, the students in the program assessed themselves as better prepared to learn in a clinical setting. The low-cost student-resident shadowing program described in this article provided an early and structured introduction to the clinical environment, which may help prepare students for the transition into clerkship. PMID- 22836845 TI - Perspective: is it time for advocacy training in medical education? AB - As the modern medical system becomes increasingly complex, a debate has arisen over the place of advocacy efforts within the medical profession. The authors argue that advocacy can help physicians fulfill their social contract. For physicians to become competent in patient-centered, clinical, administrative, or legislative advocacy, they require professional training. Many professional organizations have called for curricular reform to meet society's health needs during the past 30 years, and the inclusion of advocacy training in undergraduate, graduate, and continuing medical education is supported on both pragmatic and ethical grounds. Undergraduate medical education, especially, is an ideal time for this training because a standard competency can be instilled across all specialties. Although the Accreditation Council for Graduate Medical Education includes advocacy training in curricula for residency programs, few medical schools or residency programs have advocacy electives. By understanding the challenges of the health care system and how to change it for the better, physicians can experience increased professional satisfaction and effectiveness in improving patient care, systems-based practice, and public health. PMID- 22836846 TI - Residents as role models: impact on undergraduate trainees. AB - PURPOSE: Although researchers have investigated the value of physician role models, residents as role models have received less attention. The objectives of this study were to (1) investigate the importance of resident role models in the education and career choices of medical students, (2) examine the types of factors students judge to be most important in selecting resident role models, and (3) evaluate the specific attributes (within each factor type) that students perceive to be most important, comparing these attributes with those previously published on physician role models. METHOD: This was a cross-sectional, survey based study, conducted in 2011, in which graduating medical students at McGill University completed a questionnaire on their perceptions of resident role models. The authors analyzed data using descriptive statistics and, for items with scalar responses, repeated measures analysis of variance. RESULTS: Of 165 possible student respondents, 151 (92%) completed the questionnaire. The findings suggest that (1) resident role models play an important role in both the education and career choice of medical students, (2) resident and attending staff role models are equally important to the education of medical students, although attending staff role models appear to be more important for students' career choices, and (3) the factors and specific attributes important in selecting resident role models align with those in previously published literature on physician role models. CONCLUSIONS: This study, suggesting that resident and attending physician role models are equally important to undergraduate education, highlights the importance of supporting residents in their status as role models. PMID- 22836847 TI - Eradicating medical student mistreatment: a longitudinal study of one institution's efforts. AB - PURPOSE: Since 1995, the David Geffen School of Medicine at UCLA (DGSOM) has created policies to prevent medical student mistreatment, instituted safe mechanisms for reporting mistreatment, provided resources for discussion and resolution, and educated faculty and residents. In this study, the authors examined the incidence, severity, and sources of perceived mistreatment over the 13-year period during which these measures were implemented. METHOD: From 1996 to 2008, medical students at DGSOM completed an anonymous survey after their third year clerkships and reported how often they experienced physical, verbal, sexual harassment, ethnic, and power mistreatment, and who committed it. The authors analyzed these data using descriptive statistics and the students' descriptions of these incidents qualitatively, categorizing them as "mild," "moderate," or "severe." They compared the data across four periods, delineated by milestone institutional measures to eradicate mistreatment. RESULTS: Of 2,151 eligible students, 1,946 (90%) completed the survey. More than half (1,166/1,946) experienced some form of mistreatment. Verbal and power mistreatment were most common, but 5% of students (104/1,930) reported physical mistreatment. The pattern of incidents categorized as "mild," "moderate," or "severe" remained across the four study periods. Students most frequently identified residents and clinical faculty as the sources of mistreatment. CONCLUSIONS: Despite a multipronged approach at DGSOM across a 13-year period to eradicate medical student mistreatment, it persists. Aspects of the hidden curriculum may be undermining these efforts. Thus, eliminating mistreatment requires an aggressive approach both locally at the institution level and nationally across institutions. PMID- 22836848 TI - The clinical conscientiousness index: a valid tool for exploring professionalism in the clinical undergraduate setting. AB - PURPOSE: The need to develop effective tools to measure professionalism continues to challenge medical educators; thus, as a follow-up to a recent examination of the "Conscientiousness Index" (CI, a novel measure of one facet of professionalism) in one setting with preclinical medical students, the authors aimed to investigate the validity of the CI as a proxy measure of professionalism in a different context and in the clinical phase of undergraduate medical education. METHOD: In academic year 2009-2010, the authors collected data similar to those collected for the original preclinical study. In an effort to create a Clinical Conscientiousness Index (CCI) score, they collected the following information on 124 third-year medical students completing their clinical rotations: attendance, timeliness of assessment submissions, and completion of rotation evaluations. Then, they compared the resultant CCI scores with faculty views on professionalism and with formal assessments of students' professionalism (i.e., their portfolios and objective structured clinical examinations [OSCEs]). RESULTS: The authors demonstrate significant correlations between CCI scores and faculty views on professionalism (rS = 0.3; P = .001), and between CCI scores and OSCE score (rS = 0.237; P = .008), but not between CCI scores and portfolio assessment (rS = 0.084; P = .354). The authors also present relationships between CCI scores and demographics. CONCLUSION: The CCI is a practical, valid proxy measure of professionalism, achieving good correlation with faculty views on professionalism and clinical competency examinations, but not portfolio assessment, in one clinical undergraduate setting. PMID- 22836849 TI - Research subject advocacy: program implementation and evaluation at clinical and translational science award centers. AB - PURPOSE: In 2000, the National Center for Research Resources mandated that general research centers create a research subject advocate (RSA) position. In 2008, the Clinical and Translational Science Award (CTSA) consortium endorsed a new advocacy model based on four RSA Best Practice Functions. The authors surveyed CTSA centers to learn about their implementation of programs to fulfill the RSA functions. METHOD: In 2010, the RSA taskforce developed a two-part online survey to examine leadership, organizational structure, governance, scope, collaboration and integration, and funding and evaluation of RSA activities implemented at CTSA centers. RESULTS: Respondents from 45 RSA programs at 43 CTSA centers completed the survey. Senior university or CTSA officials led all programs. Ninety-six percent (43/45) of programs were funded by a CTSA core. Eighty percent (36/45) designated an individual "RSA." Ninety-eight percent (44/45) provided diverse services either in collaboration with or complementary to other departments, including development of data and safety monitoring plans (16/45; 36%), informed consent observation (10/45; 22%), training responsive to audit findings (12/45; 27%), and direct advocacy services to participants (11/45; 24%). Eighty-six percent (24/28) reported qualitative evaluation methods for these activities. CONCLUSIONS: RSA programs conduct both collaborative and unique research protection activities. This survey, an initial step in developing a more robust mechanism for evaluating RSA programs, collected valuable feedback. The authors recommend defining and developing outcome-based evaluation measures that take the heterogeneity of the individual RSA programs into account while advancing their value and effectiveness in protecting human research subject participants. PMID- 22836850 TI - Perspective: the negativity bias, medical education, and the culture of academic medicine: why culture change is hard. AB - Despite ongoing efforts to improve working conditions, address well-being of faculty and students, and promote professionalism, many still feel the culture of academic medicine is problematic. Depression and burnout persist among physicians and trainees. The authors propose that culture change is so challenging in part because of an evolutionary construct known as the negativity bias that is reinforced serially in medical education. The negativity bias drives people to attend to and be more greatly affected by the negative aspects of experience. Some common teaching methods such as simulations, pimping, and instruction in clinical reasoning inadvertently reinforce the negativity bias and thereby enhance physicians' focus on the negative. Here, the authors examine the concept of negativity bias in the context of academic medicine, arguing that culture is affected by serially emphasizing the inherent bias to recognize and remember the negative. They explore the potential role of practices rooted in positive psychology as powerful tools to counteract the negativity bias and aid in achieving desired culture change. PMID- 22836851 TI - Student uncertainties drive teaching during case presentations: more so with SNAPPS. AB - PURPOSE: To compare the nature of uncertainties expressed by medical students using the six-step SNAPPS technique for case presentations (Summarize history and findings; N>arrow the differential; Analyze the differential; Probe preceptors about uncertainties; Plan management; Select case-related issues for self-study) versus those expressed by students doing customary presentations and to elucidate how preceptors respond. METHOD: The authors performed a secondary analysis in 2009 of data from a 2004-2005 randomized study, comparing SNAPPS users' case presentations with other students' presentations. Authors coded transcriptions of audiotaped presentations to family medicine preceptors for type of student uncertainties, nature of preceptor responses, alignment of preceptor responses with uncertainty types, and expansion of preceptors' responses beyond addressing uncertainties. RESULTS: The analysis included 19 SNAPPS and 41 comparison presentations. SNAPPS students expressed uncertainties in all case presentations, nearly twice as many as the comparison group (chi1df = 12.89, P = .0001). Most SNAPPS users' uncertainties (24/44 [55%]) focused on diagnostic reasoning compared with 9/38 (24%) for comparison students' (chi1df = 8.08, P = .004). Uncertainties about clinical findings and medications/management did not differ significantly between groups. Preceptors responded with teaching aligned with the uncertainties and expanded 24/66 (36%) of their comments. CONCLUSION: Students can drive the content of the teaching they receive based on uncertainties they express to preceptors during case presentations. Preceptors are ready to teach at "the drop of a question" and align their teaching with the content of students' questions; these learning moments-in context and just-in-time-can be created by students. PMID- 22836852 TI - The relationship between physician empathy and disease complications: an empirical study of primary care physicians and their diabetic patients in Parma, Italy. AB - PURPOSE: To test the hypothesis that scores of a validated measure of physician empathy are associated with clinical outcomes for patients with diabetes mellitus. METHOD: This retrospective correlational study included 20,961 patients with type 1 or type 2 diabetes mellitus from a population of 284,298 adult patients in the Local Health Authority, Parma, Italy, enrolled with one of 242 primary care physicians for the entire year of 2009. Participating physicians' Jefferson Scale of Empathy scores were compared with occurrence of acute metabolic complications (hyperosmolar state, diabetic ketoacidosis, coma) in diabetes patients hospitalized in 2009. RESULTS: Patients of physicians with high empathy scores, compared with patients of physicians with moderate and low empathy scores, had a significantly lower rate of acute metabolic complications (4.0, 7.1, and 6.5 per 1,000 patients, respectively, P < .05). Logistic regression analysis showed physicians' empathy scores were associated with acute metabolic complications: odds ratio (OR) = 0.59 (95% confidence interval [CI], 0.37-0.95, contrasting physicians with high and low empathy scores). Patients' age (>=69 years) also contributed to the prediction of acute metabolic complications: OR = 1.7 (95% CI, 1.2-1.4). Physicians' gender and age, patients' gender, type of practice (solo, association), geographical location of practice (mountain, hills, plain), and length of time the patient had been enrolled with the physician were not associated with acute metabolic complications. CONCLUSIONS: These results suggest that physician empathy is significantly associated with clinical outcome for patients with diabetes mellitus and should be considered an important component of clinical competence. PMID- 22836853 TI - Stability of medical student career interest: a prospective study. AB - PURPOSE: To examine the stability and switching patterns of student career interests over the course of medical school. METHOD: From 2001 through 2004, during the first two weeks of classes, a survey on career interest was distributed to first-year students in 15 classes at eight Canadian medical schools. Students indicated interest in eight broad career paths (emergency medicine, family medicine, internal medicine, obstetrics-gynecology, pediatrics, psychiatry, surgery, and "other") and ranked their top three. Following these students' residency match three to four years later, student residency career choice was linked to their career interest at medical school entry. For students whose career interests switched be-tween medical school entry and exit, switching patterns were examined in terms of careers' matching difficulty scores (MDSs). RESULTS: Of 1,941 eligible students, 1,542 contributed to the final analysis. Family medicine, internal medicine, and surgery had the greatest student interest at both the beginning and end of medical school. Family medicine, surgery, obstetrics-gynecology, psychiatry, and "other" careers showed a net gain of student interest during medical school with the remaining careers showing a loss of interest. The most stable careers were family medicine, surgery, and internal medicine. The least stable were pediatrics and obstetrics-gynecology. Students tended to switch between careers with similar MDSs. CONCLUSIONS: Student career choice is relatively stable with a number of careers showing approximately 50% of stability from the entrance to the exit of medical school. Students tend to switch to careers with similar MDS, but some specific switching patterns exist. PMID- 22836854 TI - Comparative study on experimental autoimmune pancreatitis and its extrapancreatic involvement in mice. AB - OBJECTIVE: The objective of the study was to study the relationship between autoimmune pancreatitis (AIP) and colitis in C57BL/6 interleukin 10-deficient (IL 10KO) mice and to compare the extrapancreatic involvement of AIP between IL-10KO and MRL/Mp mice that developed pancreatitis. METHODS: Six-week-old female IL-10KO and MRL/Mp mice were injected intraperitoneally with polyinosinic polycytidylic acid (poly I:C) twice weekly for 8 or 12 weeks, respectively. The mice were killed, and the severity of inflammation in the pancreas, colon, liver, bile duct, and salivary gland was assessed using histological scoring systems. T-cell subsets derived from IL-10KO mice with pancreatitis were adoptively transferred into recombination activating gene 2-deficient mice. RESULTS: Administration of poly I:C induced pancreatitis and accelerated the development of colitis in IL 10KO mice. Pancreatitis was characterized by specific destruction of exocrine glands and the production of various autoantibodies. Involvement of the liver and bile duct was observed in both IL-10KO and MRL/Mp mice, but sialadenitis was present only in MRL/Mp mice. Adoptive transfer of CD4(+) T cells from AIP mice induced pancreatitis in recipient mice. CONCLUSIONS: Pancreatitis in IL-10KO mice resembles human type 1 AIP and is not associated with colitis. Genetic background may affect susceptibility to extrapancreatic involvement in type 1 AIP. PMID- 22836855 TI - Patients with chronic pancreatitis are at increased risk for osteoporosis. AB - OBJECTIVES: Patients with chronic pancreatitis may be at an increased risk of low bone density because of malabsorption of vitamin D and calcium, poor diet, pain, alcoholism, and smoking. We investigated the rates of osteoporosis in patients with chronic pancreatitis compared to matched controls. METHODS: The study was cross sectional in design. Sixty-two patients (mean age, 47.9 years; 72.6% male) and 66 matched controls were recruited. Dual-energy x-ray absorptiometry, smoking, and socioeconomic data were recorded. RESULTS: Thirty-four percent of patients had osteoporosis compared to 10.2% of controls. T-scores at the right femoral neck were lower in patients than controls (P = 0.005). Patients in the highest smoking tertile had the poorest T-scores at the lumbar vertebrae and total hip. Patients in the youngest age tertile had the highest T-scores (P = 0.003), but there was no sex difference. CONCLUSIONS: Patient osteoporosis rates were triple that of controls, and almost 7 times what has been previously reported. Given the resource burden of osteoporosis, we suggest that routine bone density assessment is performed in patients with chronic pancreatitis. PMID- 22836856 TI - Changes in miR-143 and miR-21 expression and clinicopathological correlations in pancreatic cancers. AB - OBJECTIVES: Despite advances in clinical management of pancreatic cancer (PC), there is still room for improvement in early detection, diagnosis, and treatment strategies. The role of microRNAs (miRNAs) in tumor biology might pinpoint an alteration in expression of miRNAs as new diagnostic/prognostic biomarkers. METHODS: Expression levels of miR-143 and miR-21 and correlations with clinicopathological features were analyzed in 26 matched pairs of tumor and adjacent noncancerous tissue samples collected from patients with PCs, including 18 pancreatic ductal adenocarcinomas (PDACs) and 8 adenocarcinomas of Vater's papilla (PVACs). RESULTS: Compared to normal tissues, miR-143 was up-regulated in both PDAC and PVAC tumor samples (P = 0.0028 and P = 0.039, respectively). Conversely, alterations in miR-21 expression were significantly different in PDAC versus PVAC samples (P = 0.0049). Tumor levels of miR-21 were associated with preoperative serum levels of CA 19-9 (r = 0.63, P = 0.0022), whereas miR-143 expression was negatively correlated to lymph node spreading (r = -0.64; P = 0.0004). Correlation between miR-143 and miR-21 expression levels in patients with PDAC was observed (r = 0.53, P = 0.023). CONCLUSIONS: Deregulation of miR 143 and miR-21 may reflect histological features and biological behavior of different PCs. Association data with clinical parameters might indicate a prognostic significance for miR-143 and miR-21 in PCs. PMID- 22836858 TI - Systematic review and meta-analysis of case-matched studies comparing open and laparoscopic distal pancreatectomy: is it a safe procedure? AB - OBJECTIVES: Distal pancreatectomies and enucleations have become the most popular laparoscopic pancreatic resections and in some centers outnumber the traditional open approach. The aim of this study was to systematically review the literature on the safety of laparoscopic distal pancreatectomies (LDP) in relation to open distal pancreatectomies in the management of adult patients and, where possible, perform a meta-analysis of reported outcomes. METHODS: We searched MEDLINE, EMBASE, Web of knowledge, and the Cochrane Database of Systematic Reviews using the following keywords: pancreas, pancreatectomy, pancreatic, laparoscopic, laparoscopy. Publication dates and language restrictions were applied. The Newcastle Ottawa scale was used for study quality assessment. RESULTS: Four eligible studies were identified with a total of 665 patients. On average, LDPs had a longer operation time by 17.7 minutes (9.5%) and a reduced hospital stay by 2.7 days. Morbidity and mortality were low using both approaches. CONCLUSIONS: This study represents the strongest evidence (level 3a) to date that LDPs are a safe operation. However, there is still a need for randomized controlled trials to confirm this. PMID- 22836857 TI - Exenatide-induced chronic damage of pancreatic tissue in rats. AB - OBJECTIVE: The study aimed to explore exenatide-induced damage of pancreatic tissue in rats. METHODS: At first stage, 30 male rats were randomly divided into exenatide and control groups. At second stage, 10 male and 10 female rats were treated according to sex, exenatide dose and time, and with or without inhibitor. Exenatide was injected subcutaneously twice a day, and body weights were measured once a week. At approximately 10 weeks, blood and pancreatic tissue samples were harvested. Amylase, lipase, interleukin 1, interleukin 6, and tumor necrosis factor alpha in serums were determined. Pancreatic tissues were divided for dry wet ratio, myeloperoxidase, hematoxylin-eosin staining, and electric microscope imaging. RESULTS: Compared with the control group, myeloperoxidase in pancreatic tissue of rats administered with exenatide exhibited a significantly high level; dry-wet ratio of pancreatic tissue in rats administered with exenatide exhibited a significantly low level. Chronic pancreatic damage was observed in 30% of rats from exenatide group for both sexes and showed pycnosis of acinar cells, increased cytoplasmic vacuoles, widened cellular gap, and inflammatory cell infiltration in pancreatic tissue. No pancreatic damage was observed in the control and the inhibitor groups. Histopathological evaluation scores in exenatide group were significantly higher than those of the control group. CONCLUSION: Long-term administration of exenatide in rats can result in chronic pancreatic damage. PMID- 22836859 TI - Efficacy of low-fat diet against dyspepsia associated with nonalcoholic mild pancreatic disease diagnosed using the Rosemont criteria. AB - OBJECTIVES: The objective of this study was to examine the efficacy of low-fat diet against dyspepsia in patients who had endosonographic evidence of nonalcoholic mild pancreatic disease. METHODS: Patients with unknown cause of upper abdominal pain suggesting pancreatic disease without a history of alcohol consumption were prescribed a low-fat diet (<20 g of fat/d) for 4 weeks. Based on endoscopic ultrasonographic findings and the Rosemont criteria, the patients were distributed into those with 5 or more minor features of chronic pancreatitis (suggestive group), those with 3 or 4 (indeterminate group), and those with 2 or less (control group). Patients with major features were excluded. Symptom severity was recorded before and after the diet therapy using a 10-cm visual analog scale. Improvement of symptoms was compared among the 3 groups. RESULTS: Of 45 patients, 14 were in the suggestive group, 18 were in the indeterminate group, and 13 served as controls. Improvement of visual analog scale score was significantly greater in the suggestive group than in the indeterminate group (P < 0.001) and the control group (P < 0.001). CONCLUSIONS: A low-fat diet may be effective in patients with dyspepsia associated with endosonographic evidence of mild pancreatic disease, who do not habitually drink alcohol. PMID- 22836860 TI - Does prophylactic administration of somatostatin decrease the rates of complications after pancreatic resection?: A clinical and electron microscopy study. AB - OBJECTIVES: The postoperative morbidity after pancreatectomy remains high. The role of somatostatin and its analogs in reducing complications after pancreatic resection is controversial. The aim of the study was to evaluate the ability of somatostatin to influence pancreatic cell's function with consequence the decrease of postoperative complications. METHODS: Between January 2006 and December 2009, 67 patients for which pancreatectomy was indicated were randomized into 2 groups. At surgery, biopsies of the pancreas were taken to be studied by electron microscopy and analyzed for ultrastructural morphometry. RESULTS: The total mortality was 4.4% (n = 3/67; 2 patients from the control group and 1 patient from the treatment group). The overall morbidity was 35.8% (n = 24/67). Eighteen patients in the control group (n = 18/32; 56.25%) and 6 patients in the treatment group (n = 6/35; 17.14%) developed postoperative complications (2 tailed Fisher exact test; P = 0.001). The most common complication was the presence of fistula (n = 6/67; 8.95%). CONCLUSIONS: Perioperative administration of intravenous somatostatin at rates applied in this study was able to inhibit the exocrine pancreatic function. This finding supports the prophylactic effect of somatostatin on the early postoperative complications of pancreatic surgery shown in this study. PMID- 22836861 TI - Early oral refeeding wisdom in patients with mild acute pancreatitis. AB - OBJECTIVES: To evaluate the safety and efficacy of early oral refeeding (EORF) in patients with mild acute pancreatitis (AP) and to investigate the optimal duration to commence EORF. METHODS: A prospective, randomized, controlled trial was conducted in patients with mild AP. Patients with EORF (started oral feeding once they subjectively felt hungry) were compared with patients receiving routine oral refeeding (RORF) for time interval between disease onset and initiation of oral refeeding, total length of hospitalization (LOH), postrefeeding LOH, and adverse gastrointestinal events. RESULTS: There were 75 and 74 patients in the EORF group and the RORF group, respectively, with comparable baseline characteristics. Patients in the EORF group started refeeding significantly earlier than those in the RORF group (4.56 +/- 1.53 vs 6.75 +/- 2.29 days; P < 0.05). Moreover, patients in the EORF group had significantly shorter total (6.8 +/- 2.1 vs 10.4 +/- 4.1 days; P < 0.01) and post refeeding LOH (2.24 +/- 0.52 vs 3.27 +/- 0.61 days; P < 0.01). There was no significant difference in adverse gastrointestinal events between the 2 groups. CONCLUSION: In patients with mild AP, EORF, with the subjective feeling of hunger, is safe, feasible, and reduces LOH. PMID- 22836862 TI - Evidence for treatment and survival disparities by age in pancreatic adenocarcinoma: a population-based analysis. AB - OBJECTIVES: Studies demonstrate safety and survival benefits of surgical resection in older individuals with pancreatic adenocarcinoma. We investigated treatment disparities by age. METHODS: The Surveillance, Epidemiology, and End Results database for survival and treatment of pancreatic adenocarcinoma between 1983 and 2007 stratified by age: younger than 50 years, between 50 and 70 years, or older than 70 years. Kaplan-Meier curves and Cox proportional hazards models were used for survival differences, and logistic regression models were used for treatment disparities and the decision to refuse surgery. RESULTS: A total of 45,509 patients had microscopically confirmed pancreatic adenocarcinoma. Of these, 7374 (16%) received surgery and 9842 (22%) received radiation. Younger patients were more likely to receive both surgery and radiation. The prevalence of surgery decreased from 21% for those younger than 50 years to 19% for those between 50 and 70 years to 13% for those older than 70 years (P < 0.001). Radiation decreased from 28% to 25% to 17% (P < 0.001). Overall survival decreased with increasing age at diagnosis, 10.4 months (age <50 years) to 9.1 months (age 50-70 years) to 6.4 months (age >70 years) controlling for stage, sex, race, radiation, and surgery (P < 0.001). Increasing age negatively predicted the odds of receiving both surgery and radiation and increased the likelihood of refusing surgery. CONCLUSIONS: Treatment disparities exist by age despite advances in radiation and surgical treatment. Increased treatment in the elderly will increase overall survival from pancreatic adenocarcinoma. PMID- 22836863 TI - Atrial fibrillation in pigs induces left atrial endocardial transcriptional remodelling. AB - The leading cause of cardioembolic stroke is atrial fibrillation (AF), which predisposes to atrial thrombus formation. Although rheological alterations promote a hypercoagulable environment, as yet undefined factors contribute to thrombogenesis. The role of the endocardium has barely been explored. To approach this topic, rapid atrial pacing (RAP) was applied in four pigs to mimic AF. Left and right endocardial cells were isolated separately and their gene expression pattern was compared with that of four control pigs. The AF-characteristic rhythm disorders and endothelial nitric oxide synthase down-regulation were successfully reproduced, and validated RAP to mimic AF. A change was observed in the transcriptomic endocardial profile after RAP: the expression of 364 genes was significantly altered (p<0.01), 29 of them having passed the B>0 criteria. The left atrial endocardium [325 genes (7 genes, B>0)] was largely responsible for such alterations. Blood coagulation, blood vessel morphogenesis and inflammatory response are among the most significant altered functions, and help to explain the activation of coagulation observed after RAP: D-dimer, 0.49 (1.63) vs. 0.23 (0.24) mg/l [median (interquartile range)] in controls, p=0.02. Furthermore, three genes directly related to thrombotic processes were differentially expressed after RAP: FGL2 [fold change (FC)=0.85; p=0.007], APLP2 (FC=-0.47; p=0.005) and ADAMTS-18 (FC=-0.69; p=0.004). We demonstrate for the first time that AF induces a global expression change in the left atrial endocardium associated with an activation of blood coagulation. The nature of some of the altered functions and genes provides clues to identify new therapeutic targets. PMID- 22836864 TI - Biological tissue imaging with a position and time sensitive pixelated detector. AB - We demonstrate the capabilities of a highly parallel, active pixel detector for large-area, mass spectrometric imaging of biological tissue sections. A bare Timepix assembly (512 * 512 pixels) is combined with chevron microchannel plates on an ion microscope matrix-assisted laser desorption time-of-flight mass spectrometer (MALDI TOF-MS). The detector assembly registers position- and time resolved images of multiple m/z species in every measurement frame. We prove the applicability of the detection system to biomolecular mass spectrometry imaging on biologically relevant samples by mass-resolved images from Timepix measurements of a peptide-grid benchmark sample and mouse testis tissue slices. Mass-spectral and localization information of analytes at physiologic concentrations are measured in MALDI-TOF-MS imaging experiments. We show a high spatial resolution (pixel size down to 740 * 740 nm(2) on the sample surface) and a spatial resolving power of 6 MUm with a microscope mode laser field of view of 100-335 MUm. Automated, large-area imaging is demonstrated and the Timepix' potential for fast, large-area image acquisition is highlighted. PMID- 22836865 TI - Is [Co4(H2O)2(alpha-PW9O34)2](10-) a genuine molecular catalyst in photochemical water oxidation? Answers from time-resolved hole scavenging experiments. AB - Water oxidation catalysts: evolution of [Co(4)(H(2)O)(2)(alpha-PW(9)O(34))(2)](10 ) to catalytically active species is assessed by laser flash photolysis in sacrificial photocatalytic cycles with Ru(bpy)(3)(2+) as a photosensitizer. PMID- 22836866 TI - Fabricating pH-stable and swellable very thin hyperbranched poly(ethylene imine) oligosaccharide films fabricated without precoating: first view on protein adsorption. AB - For using successful (ultra)thin dendritic macromolecule films in (bio)sensing and microfluidic devices and for obtaining reproducible film properties, alteration effects arising from precoatings have to be avoided. Here, oligosaccharide-modified hyperbranched poly(ethylene imine)s (PEI-OS) were used to fabricate very thin PEI-OS films (15-20 nm in dry state), cross-linked with citric acid under condensation, and vacuum condition. However, no reactive precoating is necessary to obtain stable films, which allows very simple film preparation and avoids alteration of the PEIS-OS film properties arising from precoating. Several methods [(in situ) ellipsometry, AFM, XPS, (in situ) ATR-IR, streaming potential measurements] were applied to characterize homogeneity, surface morphology, and stability of these PEI-OS films between pH 2 and pH 10, but also the low protein adsorption behavior. PMID- 22836868 TI - Sliding mode control of outbreaks of emerging infectious diseases. AB - This paper proposes and analyzes a mathematical model of an infectious disease system with a piecewise control function concerning threshold policy for disease management strategy. The proposed models extend the classic models by including a piecewise incidence rate to represent control or precautionary measures being triggered once the number of infected individuals exceeds a threshold level. The long-term behaviour of the proposed non-smooth system under this strategy consists of the so-called sliding motion-a very rapid switching between application and interruption of the control action. Model solutions ultimately approach either one of two endemic states for two structures or the sliding equilibrium on the switching surface, depending on the threshold level. Our findings suggest that proper combinations of threshold densities and control intensities based on threshold policy can either preclude outbreaks or lead the number of infected to a previously chosen level. PMID- 22836867 TI - Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro. AB - Fibroblast growth factor 23 (FGF23) is responsible for phosphate wasting and the phenotypic changes observed in human diseases such as X-linked hypophosphatemia (XLH). Targeted overexpression of nuclear high-molecular weight fibroblast growth factor 2 isoforms (HMW isoforms) in osteoblasts resulted in a transgenic mouse with phenotypic changes similar to XLH, including increased FGF23, hypophosphatemia, and rickets/osteomalacia. The goal of this study was to assess whether HMW isoforms also reduced mineralized bone formation via phosphate independent effects in bone marrow stromal cells (BMSCs) by modulating FGF23/FGF receptor (FGFR)/extracellular signal-regulated kinase (ERK) signaling. To determine if decreased bone formation in BMSC cultures from HMW transgenic mice could be rescued by blocking this pathway, an FGF23 neutralizing antibody, the FGFR tyrosine kinase inhibitor SU5402 and the mitogen-activated protein kinase (MAPK) inhibitor PD98059 were used. FGF23 levels in the conditioned medium of HMW BMSC cultures were dramatically increased compared to BMSC from control (Vector) mice. Mineralized nodule formation was significantly decreased in HMW BMSC cultures compared with control cultures. The decreased nodule formation in HMW cultures was partially rescued by the FGF23 neutralizing antibody, SU5402 and PD98059. mRNA levels for the osteoblast-related genes, osteocalcin, Runt-related transcription factor 2 (Runx2), and osterix, and the osteocyte-related gene dentin matrix acidic phosphoprotein 1 (Dmp1) were significantly decreased in HMW cultures compared with control cultures, and the decreases were partially rescued by SU5402 or PD98059 treatment. Matrix-gla-protein (Mgp) mRNA was significantly higher in HMW cultures compared with control cultures, reduced by SU5402, but further increased by PD98059. Our results suggest that phosphate-independent effects of HMW isoforms in vitro may be directly mediated in part via FGF23 and that HMW isoforms signal via FGF23/FGFR/MAPK to inhibit bone formation in vitro. PMID- 22836871 TI - Vagal nerve stimulation for refractory epilepsy: the surgical procedure and complications in 100 implantations by a single medical center. AB - In 1997, the US Food and Drug Administration approved the use of intermittent stimulation of the left vagal nerve as adjunctive therapy for seizure control. Vagal nerve stimulation (VNS) has since been considered a safe and effective treatment for medically intractable seizures. The objective of this study is to present our experience with the surgical procedure and outcomes after VNS insertion in the first 100 consecutive patients treated at the Tel-Aviv "Sourasky" Medical Center (TASMC). All patients who underwent VNS device implantation by the authors at TASMC between 2005 and 2011 were studied. The collected data included age at onset of epilepsy, seizure type, duration of epilepsy, age at VNS device implantation, seizure reduction, surgical complications, and adverse effects of VNS over time. Fifty-three males and 47 females, age 21.2 +/- 11.1 years, underwent VNS implantation. Indications for surgery were medically refractory epilepsy. The most common seizure type was focal (55 patients, 55 %). Seizure duration until implantation was 14.4 +/- 9 years. Mean follow-up time after device insertion was 24.5 +/- 22 months. Complications were encountered in 12 patients. The most common complication was local infection (6 patients, 6 %). Six devices were removed-four due to infection and two due to loss of clinical effect. Currently, 63 patients remain in active long-term follow-up; of these, 35 patients have >50 % reduction in frequency of attacks.VNS is a well-tolerated and effective therapeutic alternative in the management of medically refractory epilepsy. The surgical procedure is safe and has a low complication rate. PMID- 22836872 TI - Prophylactic theophylline for the prevention of severe renal dysfunction in term and post-term neonates with perinatal asphyxia: a systematic review and meta analysis of randomized controlled trials. AB - OBJECTIVE: To examine the effect of prophylactic theophylline for the prevention of severe renal dysfunction in post-asphyxiated term and post-term infants. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing prophylactic theophylline vs placebo in term infants following perinatal asphyxia. RESULT: Four RCTs involving 197 infants were included in the meta-analysis. Compared with placebo, prophylactic theophylline was associated with a significant reduction in the incidence of severe renal dysfunction (pooled relative risk) using fixed-effects model was 0.38 (95% confidence interval, 0.25 to 0.57; P<0.001). CONCLUSION: The meta-analysis provides evidence that prophylactic theophylline significantly reduce the incidence of severe renal dysfunction. However, because of the lack of information on the long-term renal and neurodevelopmental outcome and measured theophylline levels with relation to adverse effects observed, prudence with the clinical use of prophylactic theophylline is required. Additionally, the included trials were prior to the era of therapeutic hypothermia and thus inference of renal benefit in an infant undergoing hypothermia therapy cannot be made. PMID- 22836869 TI - Role of mineralocorticoid receptors on the hypothalamus-pituitary-adrenal axis in humans. AB - This clinical review will summarize the available data regarding the role of mineralocorticoid receptors (MRs) on the hypothalamus-pituitary-adrenal (HPA) axis control in physiological and pathological conditions and in the memory processes involved in the control and appraisal of a stress event. MRs are predominantly expressed in the limbic structures, with the hippocampus being the main localization, although MRs are also found at the hypothalamic level. It is known that hyppocampal MRs control the proactive feedback involved in the maintenance of the basal HPA activity, mainly at the nadir of the circadian rhythm. In physiological conditions, the administration of pharmacological doses of both MR antagonists and agonists is able to interact with the HPA activity, modifying the quiescent phase-nadir of the circadian rhythm, although some data in the literature do not support these observations. Also, in a physiological condition such as aging, an enhanced HPA axis activity is found in the time window, when MRs are predominantly occupied by cortisol circulating levels, possibly reflecting an MR impairment in this period of life. In pathology, major depression has been correlated to MR qualitative-quantitative alterations which could reflect differences on psychological and physiological responses, possibly predicting psychopathologies. Most of the remarks reported in this review seem to indicate, in agreement with animal data, a role played by MRs in the delicate control of the HPA axis in humans and the possible predisposition to the development of pathologies in case of their alterations. PMID- 22836873 TI - Effect of magnesium sulfate exposure on term neonates. AB - OBJECTIVE: To compare neonatal intensive care unit and special care unit (NICU) admission rates between term neonates exposed to antenatal magnesium sulfate (MS) and those unexposed. STUDY DESIGN: We performed a retrospective cohort study of all singleton neonates >=37 weeks born to women with pre-eclampsia from August 2006 to July 2008. Cases were defined by antenatal exposure to MS and controls by absence of MS exposure. The primary outcome was NICU admission. Data were analyzed via univariable and multivariable regression analyses. RESULT: In all, 28 (14.7%) out of 190 MS-exposed neonates >=37 weeks were admitted to the NICU, compared with 4 (5.4%) of 74 non-exposed neonates (P=0.04). This association persisted after controlling for potential confounding variables including severe pre-eclampsia and cesarean delivery (AOR 3.69, 1.13 to 11.99). NICU admission was associated in a dose-dependent relationship with total hours and mean dose of MS exposure. Number needed to harm with MS was 11 per NICU admission. Among neonates admitted to the NICU, MS-exposed were more likely to require fluid and nutritional support than unexposed neonates (60.7 vs 0%, P=0.04), and trended toward more frequent requirement for respiratory support and greater length of stay. CONCLUSION: In term neonates, MS exposure may be associated independently with NICU admission in a dose-dependent relationship. Requirements for fluid and nutritional support are common in this group, likely due to feeding difficulties in exposed neonates. Assessment of acute care needs among all neonates exposed to MS for maternal eclampsia prophylaxis should be considered. PMID- 22836874 TI - [(CF3)4Au2(C5H5N)2]--a new alkyl gold(II) derivative with a very short Au-Au bond. AB - A new gold(II) species [(CF(3))(4)Au(2)(C(5)H(5)N)(2)] with a very short unsupported Au-Au bond (250.62(9) pm) was generated by photo irradiation of a silver aurate, [Ag(Py)(2)][Au(CF(3))(2)], unambiguously characterized by (19)F and (109)Ag NMR studies. PMID- 22836875 TI - Contralateral nasolabial flap for reconstruction of midface defects. AB - Reconstruction of defects in the midface near the nasolabial fold or the inner canthus of the eye can be a challenge for plastic surgeons. Many methods such as skin grafting and skin flaps have been proposed for reconstruction of these defects. This report presents the results of using a contralateral nasolabial flap with a pedicle containing the lateral nasal branch of the angular artery. A flap with a pedicle approximately 10 mm wide was transferred to the opposite side through a tunnel at the nasion near the inner canthus for reconstruction of defects with surface areas ranging from 5.3 to 31.0 cm(2) and depths ranging 2.2 6.5 mm. Since 2008, with careful design, eight patients with skin tumor excisions have obtained effective functional and aesthetic results. This method is a suitable surgical procedure for reconstruction of moderate to wide side defects in the special midface area of the nasal sidewall toward the medial canthus. Level of Evidence V This journal requires that authors assign a level of evidence to each article. PMID- 22836876 TI - Predicting two-year quality of life after breast cancer surgery using artificial neural network and linear regression models. AB - The purpose of this study was to validate the use of artificial neural network (ANN) models for predicting quality of life (QOL) after breast cancer surgery and to compare the predictive capability of ANNs with that of linear regression (LR) models. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and its supplementary breast cancer measure were completed by 402 breast cancer patients at baseline and at 2 years postoperatively. The accuracy of the system models were evaluated in terms of mean square error (MSE) and mean absolute percentage error (MAPE). A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and to rank the variables in order of importance. Compared to the LR model, the ANN model generally had smaller MSE and MAPE values in both the training and testing datasets. Most ANN models had MAPE values ranging from 4.70 to 19.96 %, and most had high prediction accuracy. The ANN model also outperformed the LR model in terms of prediction accuracy. According to global sensitivity analysis, pre-operative functional status was the best predictor of QOL after surgery. Compared with the conventional LR model, the ANN model in the study was more accurate for predicting patient-reported QOL and had higher overall performance indices. Further refinements are expected to obtain sufficient performance improvements for its routine use in clinical practice as an adjunctive decision making tool. PMID- 22836877 TI - Changes in close relationships between cancer patients and their partners. AB - PURPOSE: Distress caused by cancer may have an important impact on the quality of a couple's relationship. This investigation examined perceived relationship changes in a sample of cancer patients and their partners, accounting for gender and role (i.e., patient or partner). PATIENTS AND METHODS: A total of 209 patients with different cancer types and stages and their partners completed questionnaires with items on psychological distress (anxiety and depression), quality of life, and perceptions regarding positive and negative relationship changes. RESULTS: A total of 149 patients (71.3%) and 156 partners (74.6%) reported that the diagnosis of cancer had changed their relationship. Of these, 121 (57.9%) patients and 116 (55.5%) partners reported positive changes only, whereas eight patients (3.8%) and 18 partners (8.6%) indicated negative changes only. Twenty patients (9.6%) and 22 partners (10.5%) had experienced both positive and negative changes. In male patients and partners, negative dyadic changes were associated with lower quality of life and higher levels of anxiety and depression. This finding was similar in female partners, but not in female patients. The association between perceived negative relationship changes and both increased psychological distress and reduced quality of life remained significant even when controlled for gender and congruency of perception. CONCLUSIONS: Although most couples in our sample reported growing closer while dealing with cancer, a small but sizeable percentage observed negative changes in their relationships, and these negative changes resulted in increased psychological distress and worse quality of life. Female partners were at greatest risk for these negative perceptions. PMID- 22836880 TI - High prevalence of antimicrobial-resistant Escherichia coli from animals at slaughter: a food safety risk. AB - BACKGROUND: There has been concern about the increase of antimicrobial resistant bacteria and protection of animal and public health, along with food safety. In the present study, we evaluate the incidence of antimicrobial resistance among 192 strains of Escherichia coli isolated from faecal samples of healthy food producing animals at slaughter in Portugal. RESULTS: Ninety-seven % of the pig isolates, 74% from sheep and 55% from cattle were resistant to one or more antimicrobial agents, with the resistances to ampicillin, streptomycin, tetracycline and trimethoprim-sulfamethoxazole the most common phenotype detected. Genes encoding resistance to antimicrobial agents were detected in most of the resistant isolates. Ninety-three % of the resistant isolates were included in the A or B1 phylogenetic groups, and the virulence gene fimA (alone or in association with papC or aer genes) was detected in 137 of the resistant isolates. Five isolates from pigs belonging to phylogroup B2 and D were resistant to five different antimicrobial agents. CONCLUSION: Our data shows a high percentage of antibiotic resistance in E. coli isolates from food animals, and raises important questions in the potential impact of antibiotic use in animals and the possible transmission of resistant bacteria to humans through the food chain. PMID- 22836879 TI - DNA hypermethylation biomarkers to predict response to cisplatin treatment, radiotherapy or chemoradiation: the present state of art. AB - BACKGROUND: Concurrent platinum-based chemoradiation significantly improved survival of advanced stage cervical patients over radiotherapy alone. However, the 5-year overall survival is still only 66%. Presently, no biomarkers are available to select those cervical cancer patients that might benefit from concurrent platinum-based chemoradiation therapy. DNA methylation is a well established contributor to the regulation of gene transcription, predominantly causing transcriptional silencing. Differences in promoter hypermethylation patterns and subsequent silencing, could contribute to the variety of responses observed in clinical practice. Several clinical trials on various malignancies reported a better response when Decitabine was administered prior to or in combination with standard therapy. This sensitization is thought to be due to re expression of tumor suppressor genes. However, not all patients might benefit from demethylating agents, since re-expression of oncogenes could render patients more resistant. AIM: In this review, we summarized the present state of art regarding hypermethylated genes and their affected signaling pathways that are associated with outcome after cisplatin treatment, radiotherapy or chemoradiation. Since only few studies were reported in cervical cancer, other malignancies were reviewed as well. CONCLUSIONS: From the data presented in this review, we conclude that, in order to select patients that benefit most optimally from demethylating strategies, a comprehensive screening of a large panel of methylation markers, associated with both good as well as poor clinical outcome have to be investigated. Since such panels are not available at this moment, global methylation screening approaches are required to profile such methylated genes. Such methylated gene profiles might be very useful to optimize personalized treatment planning not only in cervical cancer but also in other malignancies. PMID- 22836881 TI - Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study. AB - The association between osteoporosis and cardiovascular diseases has been demonstrated. Higher cardiovascular risk has also been correlated with vertebral fractures. However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain. This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture. Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age- and sex-matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005. Both groups were followed-up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan-Meier and Cox regression analyses. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% confidence interval [CI], 27.5-51.2) was significantly higher than in the comparison group (14.0 per 1000 person-years; 95% CI, 12.0-16.4, p < 0.001). Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89-3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p < 0.001). In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies. PMID- 22836884 TI - Laser mass spectrometry with circularly polarized light: two-photon circular dichroism. AB - Extensive studies of two-photon circular dichroism (TPCD) on 3 methylcyclopentanone are presented following the first TPCD experiment of gas phase molecules by Compton et al. [J. Chem. Phys.125 (2006) 144304]. (2 + 1) Multiphoton ionization in a specially designed time-of-flight mass analyzer has been used to perform these studies. CD of two-photon transitions from the molecular ground state to low lying Rydberg states is strongly enhanced with respect to corresponding one-photon transitions in good agreement with Compton. Differences between CD values determined via the molecular ion and via fragment ions indicate strong molecular ion CD effects. This would be the first time that circular dichroism of isolated molecular ions has been measured. PMID- 22836885 TI - [Adolescence, health, lifestyle. Development and philosophy of the HBSC Project]. PMID- 22836882 TI - Effects of chronic stress on prefrontal cortex transcriptome in mice displaying different genetic backgrounds. AB - There is increasing evidence that depression derives from the impact of environmental pressure on genetically susceptible individuals. We analyzed the effects of chronic mild stress (CMS) on prefrontal cortex transcriptome of two strains of mice bred for high (HA)and low (LA) swim stress-induced analgesia that differ in basal transcriptomic profiles and depression-like behaviors. We found that CMS affected 96 and 92 genes in HA and LA mice, respectively. Among genes with the same expression pattern in both strains after CMS, we observed robust upregulation of Ttr gene coding transthyretin involved in amyloidosis, seizures, stroke-like episodes, or dementia. Strain-specific HA transcriptome affected by CMS was associated with deregulation of genes involved in insulin secretion (Acvr1c, Nnat, and Pfkm), neuropeptide hormone activity (Nts and Trh), and dopamine receptor mediated signaling pathway (Clic6, Drd1a, and Ppp1r1b). LA transcriptome affected by CMS was associated with genes involved in behavioral response to stimulus (Fcer1g, Rasd2, S100a8, S100a9, Crhr1, Grm5, and Prkcc), immune effector processes (Fcer1g, Mpo, and Igh-VJ558), diacylglycerol binding (Rasgrp1, Dgke, Dgkg, and Prkcc), and long-term depression (Crhr1, Grm5, and Prkcc) and/or coding elements of dendrites (Crmp1, Cntnap4, and Prkcc) and myelin proteins (Gpm6a, Mal, and Mog). The results indicate significant contribution of genetic background to differences in stress response gene expression in the mouse prefrontal cortex. PMID- 22836883 TI - Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: implications for identifying coagulopathic mechanisms in humans. AB - Identifying coagulation abnormalities in patients with combined bleeding and thrombosis history is clinically challenging. Our goal was to probe the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. The patient is a 56-year-old female with a history of haematomas, poor wound healing, and thrombosis (retinal artery occlusion and transient cerebral ischaemia). She had a normal activated partial thromboplastin time, prolonged thrombin and reptilase times, and decreased functional and antigenic fibrinogen levels, and was initially diagnosed with hypodysfibrinogenaemia. This diagnosis was supported by DNA analysis revealing a novel FGB mutation (c.656A>G) predicting a Q189R mutation in the mature chain that was present in the heterozygote state. However, turbidity analysis showed that purified fibrinogen polymerisation and degradation were indistinguishable from normal, and Bbeta chain subpopulations appeared normal by two-dimensional difference in-gel electrophoresis, indicating the mutated chain was not secreted. Interestingly, plasma thrombin generation testing revealed the patient's thrombin generation was higher than normal and could be attributed to elevated levels of factor VIII (FVIII, 163-225%). Accordingly, in an arterial injury model, hypofibrinogenaemic mice (Fgn(+/-)) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline infused Fgn(+/-) mice. Together, these data associate the complex bleeding and thrombotic presentation with combined hypofibrinogenaemia plus plasma hypercoagulability. These findings suggest previous cases in which fibrinogen abnormalities have been associated with thrombosis may also be complicated by co existing plasma hypercoagulability and illustrate the importance of "global" coagulation testing in patients with compound presentations. PMID- 22836886 TI - [Trends in subjective health and well-being of children and adolescents in Germany: results of the Health Behaviour in School-aged Children (HBSC) Study 2002 to 2010]. AB - The monitoring of health through the analysis of trends provides important information on the long-term development of key outcome parameters for health. Currently, Germany does not have any reliable data on trends in the health situation of young people.The presented results are based on the German trend data from the Health Behaviour in School-aged Children (HBSC) Study. Data were analysed for a representative sample of 11-, 13- and 15-year-old school children from 2002 (N=5 650), 2006 (N=7 274) and 2010 (N=5 005). First, a comparison between German and international HBSC trend data was conducted for subjective health, life satisfaction and health complaints in 2002, 2006 and 2010. Next, a logistic regression was calculated to further describe the trends for these outcomes in the German data set.Overall, children and adolescents in Germany report good health. The comparison with the international data further supports this finding. Detailed analyses of trends showed that the health level generally improved between 2002 and 2010 for German children. In particular, better subjective health and lower rates of multiple recurrent health complaints were reported. Irrespective of the survey year, girls and older adolescents reported the highest level of health impairment.Trend analyses contribute towards health politics not only by providing information on the health situation across time, but also by pointing out the long-term effects of measures at the macro level (such as national health programmes, interventions) on children's health. PMID- 22836887 TI - [Changes in body weight and body image in children and adolescents--developmental trends from 2002-2006-2010 in Germany]. AB - The aim of this study is to examine the development of body weight as well as the development of the subjective body image among German youth focusing on trends (2002-2006-2010). The analysis focuses on those children and adolescents who consider themselves as "a bit too fat" or "much too fat" in spite of the fact that they are "about the right size" (risk group). Based on the findings, recommendations for prevention and intervention measures will be derived, which can be applied in youth work.The trend analysis is based on german data from the international WHO study Health Behaviour in School-aged Children (HBSC) from the survey years 2002, 2006 and 2010. In addition to the socio-demographic variables (sex, age, family affluence status), the analysis also included variables on weight status (BMI), body image, dieting and breakfast consumption (independent variables). Using binary logistic regression analyses, the relationship between the independent and dependent variable (distorted body image) was examined.For the 13- and as well as for the 15-year-old adolescents in the overall trend the fraction of those that are underweight decreases in contrast to the increasing fraction of the overweight subjects. The results show that in the year 2010, the risk for adolescents for being overweight is 1.3-times higher than in the reference year 2002. Furthermore it can be proven in the timeline that the risk to perceive the own body as "too fat" is slightly higher. A distorted perception regarding the body image (normal weight but perceiving themselves as "too fat") is primarily a problem of the girls: they have in the year 2006 and 2010 a 2 times higher chance to belong to the group of the distorted perceivers than in 2002. Dieting as a strategy in dealing with an alleged fat body has in a comparison still a major role, however in 2010 far fewer young people made use of it.The observed trends will be discussed against the background of gender specific health promotion. PMID- 22836888 TI - [HBSC-Trend Supplement]. PMID- 22836889 TI - [Health-related quality of life and mental health of children and adolescents in Germany: results from the German HBSC Study 2006-2010]. AB - With medical advances, acute -disease in childhood and adolescence could be substantially reduced, thus shifting the focus towards chronic and mental health problems. Currently there is a lack of studies on trends in health-related quality of life (HRQoL) and mental well-being and their determinants in the context of children's and adolescents' environment (e. g., family, school). The aim of this paper is to describe the trend in HRQoL in children and adolescents from 2006 to 2010 and to analyse factors associated with HRQoL and mental well being of children and adolescents.Results are based on the German sample (11-, 13 and 15-year-old school children) of the international WHO Study from the 2006 (n=6 896) and 2010 (n=4 723) surveys. HRQoL was assessed by means of KIDSCREEN 10. The Strengths and Difficulties Questionnaire (SDQ), a screening instrument for mental health problems, was used as an indicator of mental health. Logistic regressions were performed to analyse the effects of covariates on HRQoL as well as on mental health problems.HRQoL remained fairly stable between 2006 and 2010 for both boys and girls. Approximately 85% of the school children report a high or normal HRQoL, whereby girls indicate a lower HRQoL than boys. Overall, 14,3% of the pupils show signs of mental health problems. The model results show that poor communication with parents, spending little time with friends, lack of perceived support from classmates and a negative attitude towards school are negatively associated with mental health.The majority of children and adolescents report a high HRQoL over time. The fact that every 7th 11- to 15-year-old shows signs of mental health problems raises concern and suggests that addressing mental health problems needs to gain more priority in public health measures. PMID- 22836890 TI - [Child and adolescent health in Germany: findings from the Health Behaviour in School-aged Children (HBSC)-WHO-Youth Health Survey 2002-2010]. AB - For many years, the HBSC-Study has provided important insight and information on the health situation and health behaviours of young people 11- through 15 years of age living in Germany. The papers in this supplement take a first look at the trends in selected indicators of health and health behaviour of this group and draw important conclusions about the association between prevention and health promotion measures and individual health across time. This short report gives an overview on the key results and findings of the 10 papers in the supplement. PMID- 22836891 TI - [Changes in tobacco, alcohol and cannabis use by adolescents from 2002 to 2010 in Germany]. AB - So far, little is known about long-term trends in the use of psychoactive substances by adolescents in Germany. However, these results are urgently required for a target-orientated prevention. The aim of the present study is to analyse age- and gender-specific prevalences and trends in tobacco, alcohol und cannabis use among young people in Germany from 2002 to 2010.Data were obtained from the German part of the WHO collaborative study "Health Behaviour in School aged Children (HBSC)" conducted in 2002, 2006, and 2010. The analysis is based on 11 917 students aged 13 and 15 years. Age- and gender-specific trend analyses were done using log binomial regression models.The prevalences of regular tobacco and alcohol use among 13- and 15-year-olds decreased from 2002 to 2010, independent of gender. A similar effect was found for repeated drunkenness and for the 12-month prevalence of cannabis use. In 2010 about 15% of the 15-year olds consumed tobacco and alcohol at least once a week, 30% reported 2 or more episodes of drunkenness and 11% used cannabis in the last 12 months. The corresponding values for 13-year-olds with a prevalence of 3-5% on average are considerably lower.Following an increase over the 1990s the HBSC data shows a strong decrease in the use of psychoactive substances over the last 8 years which can be interpreted as a success of recent preventive efforts. However, noticeable is a clear flattening of the decrease from 2006 to 2010. This underlines that preventive actions must continue play a central role in health policy and practice. PMID- 22836893 TI - [Time trends in sex differences in adolescents' health behaviour from 2001 to 2010]. AB - Health behaviours are influenced by gender-specific conceptions and norms of the society. These conceptions and norms are changing over time. The aim of this analysis is to describe gender differences in health behaviour of adolescents and to interpret these gender differences in terms of theories of social construction.We used the national German data of the Health-Behaviour in School aged Children (HBSC) studies conducted in the years 2001/02, 2005/06 und 2009/10 with respect to the following health behaviours: tobacco use, binge drinking, diet, fruit and vegetable consumption, daily breakfast and physical activity. We describe the difference in frequencies between girls and boys and used a series of logistic regressions to test the significance of the gender difference in health behaviours with survey year as the predictor.There is only a small difference -between girls and boys with respect to tobacco use and binge drinking. For binge drinking girls nearly converge with the figures of boys. Relatively stable gender differences over time are existing for diet, nutrition and physical activity.From a theoretical gender perspective it might be possible that with respect to risky behaviours like tobacco use and alcohol consumption a clear gender specific connotation has changed over time. In other words risk behaviours become less important in presenting oneself as masculine. A gender sensible development of preventive interventions should consider the changes over time of gender-related -social constructions. PMID- 22836892 TI - [Socioeconomic inequalities in subjective health among 11- to 15-year-olds in Germany. A trend analysis from 2002-2010]. AB - Health is strongly linked to social position. Several studies showed consistent or increasing health inequalities in the last decades. So far, few studies focused on trends in social inequalities in health among children and adolescents. The objective of this study was to determine changes in socioeconomic differences in subjective health between 2002 and 2010 of 11- to 15 year-old students in Germany.Data were obtained from the German part of the cross sectional WHO "Health Behaviour in School-aged Children" survey in 2002 (n=5.221), 2006 (n=6.896) and 2010 (n=4.723). Log binomial regression models were used to assess the extent of inequalities in self-rated health across the survey years. Socioeconomic position was measured using the family affluence scale (FAS) and perceived family wealth.A relatively small improvement in good/excellent self rated health was observed in both boys and girls from 2002 (85.2%) to 2010 (87%). Despite this improvement, inequalities in self-rated health could be identified for all survey years, regardless of which socioeconomic indicator was used (RR 1.4 up to 1.8). The level of these differences remained virtually unchanged in girls and boys in that time period.The same relationship of family affluence, family wealth and self-rated health has persisted for almost a decade in Germany. Recent strategies could not tackle existing inequalities in self-rated health which indicates an increasing need to develop and implement innovative measures and to intensify efforts of social and health policy. PMID- 22836894 TI - [How healthy are German schools? Trends from the years 2002 to 2010]. AB - This study aims to analyse the time trends of several conditions of the school environment (satisfaction with school, school demands, quality of instruction, classmate support) in Germany that are known to affect the health of pupils.We used the national German data of the Health-Behaviour in School-aged Children (HBSC) studies conducted in the years 2002, 2006 und 2010. The time trends of these four var-iables are described by using linear and logistic regression analyses considering survey year, age group (11, 13, 15 years), gender, and school track as independent variables.We found an increase of the perceived quality of instruction and of the student's satisfaction with school from the year 2002 to the year 2010. Furthermore, pupils report slightly less support from their classmates in the present survey compared to 2002. There are no changes in the reported demands.These trend results are discussed in the light of the impact of the PISA study and the efforts to implement settings-based health promoting schools in Germany. PMID- 22836895 TI - [Young people's health in single-parent families]. AB - This paper aims to investigate the effects of sin-gle-parent families on the health of young peo-ple. Database is the 2010 HBSC survey as well as the 2002 and 2006 data for trend analysis. Findings show that there is a weak but significant effect of single-parent families on the health and health-behaviour of young people. There has been little change in the findings between 2002 and 2010. PMID- 22836896 TI - [Mobbing and violence at school. Trends from 2002 to 2010]. AB - The purpose of this study was to undertake an assessment and differentiated examination of the development of bullying and violence in schools between 2002 and 2010 in Germany.We examined the national German data of Health Behaviour in School-aged Children (HBSC) study in 2002, 2006 and 2010. A paper-pencil questionnaire was distributed to a representative sample (N=17 929) of 11-, 13- and 15-year-old school children. The evaluation of the data was done by descriptive statistics and logistic regression analyses, controlled by age, gender, family affluence, school type and survey year.A clear positive trend could be identified: from 2002 to 2010 the number of bullies and bully victims decreased whereas the group of the uninvolved pupils increased. There was a delay in this trend for children with low family affluence.The obvious success in the prevention of violence is shown by the decreasing rate of bullies. The paper discusses whether future prevention should focus more on victims and children with educationally deprived background. PMID- 22836897 TI - [The HBSC Study in Germany--study design and methodology]. AB - The aim of the HBSC-Study is to collect data on the physical and mental health and health behaviour of children and adolescents and to gain a deeper insight into their situation and the specific environment they grow up in. The HBSC-study is an international school-based cross-sectional survey conducted in collaboration with the World Health Organization (WHO). The survey takes place every 4 years since 1982 and is based on a standardised protocol. In Germany the survey was first conducted in 1994 as a pilot study in North Rhine-Westphalia. The German sample is based on a random sample of classes in all public schools in Germany. 11-, 13-, and 15-year-old pupils are surveyed by means of a paper and pencil questionnaire. The questionnaire comprises a broad selection of -topics, including sociodemographics, health and risk behaviours, family, school and peers. The reported trends in the supplement are based on the data from surveys in 2002 (N=5.650), 2006 (N=7.274) and 2010 (N=5.005). The representative samples for each of the survey years are defined as follows: in 2002 the data is based on information collected in 4 Federal States (Berlin, Hesse, North Rhine-Westphalia, Saxony); in 2006 5 states define the German data file (Berlin, Hamburg, Hesse, North Rhine-Westphalia, Saxony). The data from the 2010 survey comprises data from 15 Federal States. The HBSC-data contributes towards a better understanding of the relationship between health and living conditions of young people. The papers in this supplement deliver important insights into the living context of young people and in doing this they provide important information about their health and the long-term effectiveness of public-health-measures. PMID- 22836899 TI - Cancer prevention by different forms of tocopherols. AB - Many epidemiological studies have suggested that a low vitamin E nutritional status is associated with increased cancer risk. However, several recent large scale human trials with high doses of alpha-tocopherol (alpha-T) have produced disappointing results. This points out the need for a better understanding of the biological activities of the different forms of tocopherols. Using a naturally occurring tocopherol mixture (gamma-TmT) that is rich in gamma-T, we demonstrated the inhibition of chemically induced lung, colon, and mammary cancer formation as well as the growth of xenograft tumors derived from human lung and prostate cancer cells. This broad anticancer activity of gamma-TmT has been attributed mainly to the trapping of reactive oxygen and nitrogen species and inhibition of arachidonic acid metabolism. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and the inhibition of estrogen signaling have also been observed in the inhibition of mammary cancer development. delta-T has been shown to be more active than gamma-T in inhibiting the growth of human lung cancer cells in a xenograft tumor model and the development of aberrant crypt foci in azoxymethane-treated rats, whereas alpha-T is not effective in these models. The higher inhibitory activities of delta-T and gamma-T (than alpha-T) are proposed to be due to their trapping of reactive nitrogen species and their capacity to generate side-chain degradation products, which retain the intact chromanol ring structure and could have cancer preventive activities. PMID- 22836900 TI - Peripheral polypoidal choroidal vasculopathy as a cause of peripheral exudative hemorrhagic chorioretinopathy: a report of 10 eyes. AB - PURPOSE: Polypoidal choroidal vasculopathy (PCV) is characterized by polyp-like sub-retinal pigment epithelium vascular abnormalities predominantly found in the macula and peripapillary region. Less commonly, PCV can be found peripherally and be a cause of peripheral exudative hemorrhagic chorioretinopathy (PEHCR). We sought to further describe the clinical spectrum of this ill-defined subgroup of PEHCR. METHODS: A retrospective observational case series, of 10 eyes of 8 patients diagnosed with PEHCR caused by peripheral PCV, was conducted. In all cases, the presence of PCV was confirmed with indocyanine green angiography and/or fluorescein angiography and optical coherence tomography. The clinical presentation, natural history, and clinical outcomes with or without intervention were studied. RESULTS: Patients with PEHCR caused by peripheral PCV were most commonly men, white, asymptomatic, and had a concomitant diagnosis of age-related macular degeneration. The mean age was 70 years (range, 59-82 years) with a mean follow-up of 32.5 months (range, 4-91 months). Four patients had unilateral involvement with minimal subretinal hemorrhage that resolved spontaneously, one patient had unilateral involvement outside the macula that responded to anti vascular endothelial growth factor therapy, one patient had unilateral involvement with subretinal hemorrhage threatening the macula that responded to anti-vascular endothelial growth factor therapy, and two patients had extensive bilateral subretinal hemorrhage requiring surgical intervention. Both patients with multiple lesions in one eye had bilateral lesions (two of eight patients). Lesions were most commonly located in the temporal periphery (8 of 10 eyes). CONCLUSION: A new subclassification is proposed that includes both eyes with polyps and those without polyps within the spectrum of disease described previously as PEHCR. Within the spectrum of disease described previously as PEHCR exists a subgroup of lesions caused by peripheral PCV, which has not been well defined before this report. The largest case series to date of eyes with PEHCR due to peripheral PCV, a unique form of type 1 neovascularization, is further classified and described. These eyes have a spectrum of disease, including small, medium-sized, and large lesions. Although most eyes with PEHCR from peripheral PCV experience a benign course with spontaneous resolution, a subset of eyes may experience macula-threatening hemorrhage, requiring treatment with laser-based therapies, anti-vascular endothelial growth factor injections, or surgical intervention. PMID- 22836901 TI - Dialysis nanoprecipitation of polystyrene nanoparticles. AB - Using a facile dialysis nanoprecipitation method, nanoparticles of several hundred nanometers have been successfully generated from a "traditional," non biodegradable polymer, that is, polystyrene. The effect of initial polymer concentration inside the dialysis membrane, as well as the polymer/solvent system and the ionic strength (electrolyte concentration) of the dialysis solution, on nanoparticle size is examined. A nucleation-aggregation mechanism has been provided to explain the observed trends. Furthermore, we determine the zeta potential as a function of ionic strength for the generated nanoparticles and show that anionic charging may be present in the system. PMID- 22836902 TI - [Echocardiography in emergency diagnostics]. AB - Echocardiography plays an important role in emergency medicine because this non invasive method is universally available and provides crucial diagnostic findings for acute decision making. The cardiac etiology in the presence of acute chest pain, acute dyspnea, hemodynamic instability or shock, new heart murmurs, chest trauma, peripheral embolism and cardiac arrest can be determined by echocardiography in the emergency scenario. The analysis of left ventricular function documents myocardial ischemia and myocardial infarction. Analysis of right ventricular function documents right heart infarction, pulmonary embolism, tension pneumothorax and sequelae of chest trauma. Echocardiography differentiates between different entities of shock. The analysis of heart valves is a domain of echocardiography. Affections of the pericardium and the hemodynamic sequelae can also be determined. It is obvious that echocardiography with its multiple diagnostic applications can only be well performed, especially in emergency medicine after in-depth education and training in this method. PMID- 22836903 TI - Appendiceal mucocele due to mucinous cystadenocarcinoma arising from the appendiceal stump: preoperative diagnosis based on the "onion skin sign". PMID- 22836898 TI - A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. AB - Oxidative stress is caused by an imbalance of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidative stress defense systems in cells. ROS/RNS or carcinogen metabolites can attack intracellular proteins, lipids, and nucleic acids, which can result in genetic mutations, carcinogenesis, and other diseases. Nrf2 plays a critical role in the regulation of many antioxidative stress/antioxidant and detoxification enzyme genes, such as glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1), UDP glucuronyl transferases (UGTs), and heme oxygenase-1 (HO-1), directly via the antioxidant response element (ARE). Recently, many studies have shown that dietary phytochemicals possess cancer chemopreventive potential through the induction of Nrf2-mediated antioxidant/detoxification enzymes and anti inflammatory signaling pathways to protect organisms against cellular damage caused by oxidative stress. In addition, carcinogenesis can be caused by epigenetic alterations such as DNA methylation and histone modifications in tumor suppressor genes and oncogenes. Interestingly, recent studies have shown that several naturally occurring dietary phytochemicals can epigenetically modify the chromatin, including reactivating Nrf2 via demethylation of CpG islands and the inhibition of histone deacetylases (HDACs) and/or histone acetyltransferases (HATs). The advancement and development of dietary phytochemicals in cancer chemoprevention research requires the integration of the known, and as-yet unknown, compounds with the Nrf2-mediated antioxidant, detoxification, and anti inflammatory systems and their in vitro and in vivo epigenetic mechanisms; human clinical efficacy studies must also be performed. PMID- 22836904 TI - Detection of liver metastasis: is diffusion-weighted imaging needed in Gd-EOB DTPA-enhanced MR imaging for evaluation of colorectal liver metastases? AB - PURPOSE: We compared diagnostic ability for detecting hepatic metastases between gadolinium ethoxy benzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) on a 1.5-T system, and determined whether DWI is necessary in Gd-EOB-DTPA-enhanced MRI for diagnosing colorectal liver metastases. MATERIALS AND METHODS: We assessed 29 consecutive prospectively enrolled patients with suspected metachronous colorectal liver metastases; all patients underwent surgery and had preoperative Gd-EOB-DTPA-enhanced MRI. Overall detection rate, sensitivity for detecting metastases and benign lesions, positive predictive value, and diagnostic accuracy (Az value) were compared among three image sets [unenhanced MRI (DWI set), Gd-EOB-DTPA-enhanced MRI excluding DWI (EOB set), and combined set]. RESULTS: Gd-EOB-DTPA-enhanced MRI yielded better overall detection rate (77.8-79.0 %) and sensitivity (87.1-89.4 %) for detecting metastases than the DWI set (55.9 % and 64.7 %, respectively) for one observer (P < 0.001). No statistically significant difference was seen between the EOB and combined sets, although several metastases were newly detected on additional DWI. CONCLUSIONS: Gd-EOB-DTPA-enhanced MRI yielded a better overall detection rate and higher sensitivity for detecting metastases compared with unenhanced MRI. Additional DWI may be able to reduce oversight of lesions in Gd-EOB-DTPA-enhanced 1.5-T MRI for detecting colorectal liver metastases. PMID- 22836905 TI - Combination of elastography and tissue quantification using the acoustic radiation force impulse (ARFI) technology for differential diagnosis of breast masses. AB - PURPOSE: We evaluated the diagnostic performance of elastography and tissue quantification using acoustic radiation force impulse (ARFI) technology for differential diagnosis of breast masses. MATERIALS AND METHODS: There were 161 mass lesions. First, lesion correspondence on ARFI elastographic images to those on the B-mode images was evaluated: no findings on ARFI images (pattern 1), lesions that were bright inside (pattern 2), lesions that were dark inside (pattern 4), lesions that contained both bright and dark areas (pattern 3). In addition, pattern 4 was subdivided into 4a (dark area same as B-mode lesion) and 4b (dark area larger than lesion). Next, shear wave velocity (SWV) was measured using virtual touch tissue quantification. RESULTS: There were 13 pattern 1 lesions and five pattern 2 lesions; all of these lesions were benign, whereas all pattern 4b lesions (n = 43) were malignant. When the value of 3.59 m/s was chosen as the cutoff value, the combination of elastography and tissue quantification showed 91 % (83-91) sensitivity, 93 % (65-70) specificity, and 92 % (148-161) accuracy. CONCLUSION: The combination of elastography and tissue quantification is thought to be a promising ultrasound technique for differential diagnosis of breast-mass lesions. PMID- 22836906 TI - Lung-cancer related chest events detected by periodical follow-up CT after stereotactic body radiotherapy for stage I primary lung cancer: retrospective analysis of incidence of lung-cancer related chest events and outcomes of salvage treatment. AB - PURPOSE: Follow-up by chest CT is often performed routinely after stereotactic body radiotherapy (SBRT) for primary lung cancer. We investigated how often periodical chest CT detected lung-cancer related chest events (failure in the chest, new primary lung cancer), and how often chest CT follow-ups led to curative intent salvage treatment. MATERIALS AND METHODS: Between 2006 and 2009, 90 stage I primary lung cancers in 86 patients received SBRT. In principle, chest CT was scheduled every 2-3 months in the first two years, and every 3-4 months thereafter. RESULTS: Median time to follow-up by chest CT was 26 months (1-61 months). Twenty-seven lung-cancer related chest events were detected by periodical chest CT after SBRT. The three-year lung-cancer related chest event free rate was 62 %. It was possible to apply curative-intent salvage treatment to 56 % of the lung-cancer related chest events. The two-year overall survival rate was 66 % among the 13 patients who received curative-intent salvage treatment (radiotherapy, 11; surgery, 2). CONCLUSION: Post-SBRT lung-cancer related chest events (as detected by periodical chest CT) were not uncommon (approximately 40 % at 3 years from SBRT), and it was possible to treat more than half of these lesions with curative-intent salvage treatment. PMID- 22836907 TI - Identification of a calmodulin-binding site within the domain I of Bacillus thuringiensis Cry3Aa toxin. AB - Bacillus thuringiensis Cry3Aa toxin is a coleopteran specific toxin highly active against Colorado Potato Beetle (CPB).We have recently shown that Cry3Aa toxin is proteolytically cleaved by CPB midgut membrane associated metalloproteases and that this cleavage is inhibited by ADAM metalloprotease inhibitors. In the present study, we investigated whether the Cry3Aa toxin is a calmodulin (CaM) binding protein, as it is the case of several different ADAM shedding substrates. In pull-down assays using agarose beads conjugated with CaM, we demonstrated that Cry3Aa toxin specifically binds to CaM in a calcium-independent manner. Furthermore, we used gel shift assays and (1)H NMR spectra to demonstrate that CaM binds to a 16-amino acid synthetic peptide corresponding to residues N256 V271 within the domain I of Cry3Aa toxin. Finally, to investigate whether CaM has any effect on Cry3Aa toxin CPB midgut membrane associated proteolysis, cleavage assays were performed in the presence of the CaM-specific inhibitor trifluoperazine. We showed that trifluoperazine significantly increased Cry3Aa toxin proteolysis and also decreased Cry3Aa larval toxicity. PMID- 22836908 TI - The Melkersson-Rosenthal syndrome: a retrospective study of biopsied cases. AB - Melkersson-Rosenthal syndrome (MRS) is a rare neuromucocutaneous syndrome marked by the triad of recurrent nonpitting orofacial edema, fissured dorsal tongue (lingua plicata), and lower motoneuron facial paralysis. Large case series including treatment are limited. A retrospective records review was performed for the diagnoses Melkersson-Rosenthal syndrome, granulomatous cheilitis, and orofacial granulomatosis, confirmed by noncaseating granulomas on biopsy, at the Mayo Clinic in Rochester, Minnesota (1979-2009). There were 72 patients [51 women (71 %), mean age at presentation 39 years (range 8-79)] identified with facial edema with noncaseating granulomas on skin biopsy. Lingua plicata occurred in 34 cases (47 %, 95 % confidence interval 35.3-59.3 %). Unilateral or partial facial nerve palsy occurred in 14 cases (19.4, 95 % confidence interval 11.4-30.8 %). Comorbidities among those with facial edema included periodontal disease (n = 10, 14 %), history of allergic disease (n = 10, 14 %), Crohn's Disease (n = 6, 8 %), migraine headaches (n = 5, 7 %), and systemic lupus erythematosus (n = 2, 3 %). There were no patients who had low C1q or C4 levels among those who were tested. Overall, the full triad canonical of Melkersson-Rosenthal syndrome was observed in nine patients (seven female, median age at symptomatic presentation 35 years (range 10-74 years), 13 %, (95 % confidence interval 6.2-22.9 %) with a median time from first symptoms to diagnosis of 4 years (range 1-35). The medication treatments attempted in the nine patients with the full triad of symptoms included non-steroidal anti-inflammatory drugs, oral and intra-lesional steroids, metronidazole, dapsone, acyclovir, methotrexate, and thalidomide with no consistent treatment responses. The Melkersson-Rosenthal syndrome may present over the course of most of the lifespan and may require several years of observation to be diagnosed. Neurologists who observe a combination of facial edema and facial palsy in a patient should consider the diagnosis of MRS and proceed to a diagnostic skin biopsy and a trial of steroid treatment for their patient. PMID- 22836910 TI - Simple one-step synthesis of highly luminescent carbon dots from orange juice: application as excellent bio-imaging agents. AB - Highly photoluminescent carbon dots with a PL quantum yield of 26% have been prepared in one step by hydrothermal treatment of orange juice. Due to high photostability and low toxicity these carbon dots are demonstrated as excellent probes in cellular imaging. PMID- 22836909 TI - Patent foramen ovale and atrial septal aneurysm can cause ischemic stroke in patients with antiphospholipid syndrome. AB - The purpose of the present study was to evaluate the contributions of embolic etiologies, patent foramen ovale (PFO) and atrial septal aneurysm (ASA) to the pathogenesis of ischemic stroke in patients with antiphospholipid syndrome (APS). We performed transesophageal echocardiography (TEE) examination for consecutive stroke patients who had been diagnosed with APS (APS group) to detect potential embolic sources. APS was diagnosed based on the modified Sapporo criteria. The control stroke group comprised age- and sex-matched cryptogenic stroke patients undergoing TEE. We assessed and compared the clinical characteristics and TEE findings between stroke patients with APS and control stroke groups. Among 582 patients, nine patients (nine women; mean age, 50 +/- 18 years) were classified into the APS group. In 137 patients undergoing TEE, 41 age-matched female stroke patients were recruited to the control stroke group. Prevalences of PFO and ASA were significantly higher in the APS group than in the control stroke group (89 vs. 41 %, p = 0.027; 67 vs. 20 %, p = 0.015, respectively). Multiple logistic regression analysis showed that PFO (odds ratio (OR), 13.71; 95 % confidence interval (CI), 1.01-185.62; p = 0.049) and ASA (OR, 8.06; 95 % CI, 1.17-55.59; p = 0.034) were independently associated with the APS group. PFO and ASA were strongly associated with the APS group, and could thus represent potential embolic sources in ischemic stroke patients with APS. PMID- 22836911 TI - The hunting of targets: challenge in miRNA research. AB - MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of around 60% of the human protein-coding genes. In the past decade, deregulation of miRNAs (by expression and/or function) has been associated with the pathogenesis, progression and prognosis of different diseases, including leukemia. The number of discovered genes encoding miRNAs has risen exponentially in this period, but the numbers of miRNA-target genes discovered and validated lag far behind. Scientists have gained more in-depth knowledge of the basic mechanism of action of miRNAs, but the main challenge still remaining is the identification of direct targets of these important 'micro-players', to understand how they fine-tune so many biological processes in both healthy and diseased tissue. Many technologies have been developed in the past few years, some with more potential than others, but all with their own pros and cons. Here, we review the most common and most potent computational and experimental approaches for miRNA-target gene discovery and discuss how the hunting of targets is challenging but possible by taking the experimental limitations in consideration and choosing the correct cellular context for identifying relevant target genes. PMID- 22836912 TI - Expression and retinoic acid regulation of the zebrafish nr2f orphan nuclear receptor genes. AB - BACKGROUND: The vertebrate nuclear receptor subfamily 2, group f (nr2f) genes encode orphan receptors that have the capacity to act as negative regulators of retinoic acid (RA) signaling. RESULTS: We describe embryonic and larval expression of four of the six zebrafish nr2f genes, nr2f1a, nr2f1b, nr2f2, and nr2f5. These genes show highly regulated patterns of expression within the central nervous system, including in the developing hindbrain, as well as in the mesoderm and endoderm. We also investigated the role of RA and fibroblast growth factor (Fgf) signaling in regulating early nr2f gene expression. RA is not required for nr2f expression in the hindbrain; however, exogenous RA can repress this expression. Conversely, we find that RA positively regulates nr2f1a expression in trunk endoderm and mesoderm. Fgf signaling is not required for nr2f expression onset in the hindbrain; however, it may play a role in maintaining rhombomere-specific expression. CONCLUSIONS: We report detailed expression analysis of four nr2f genes in all three germ layers. The onset of nr2f expression in the hindbrain does not require RA or Fgf signals. Our finding that RA positively regulates nr2f1a expression in the trunk supports the possibility that Nr2fs function in a negative feedback loop to modulate RA signaling in this region. PMID- 22836914 TI - Changes in the choice of colorectal cancer screening tests in primary care settings from 7,845 prospectively collected surveys. AB - PURPOSE: Colorectal cancer (CRC) is one of the leading causes of cancer mortality worldwide. This study examined factors influencing the choice of participants between colonoscopy and fecal immunochemical test (FIT) in a screening program and the impact of an unbiased educational session on influencing this decision. METHODS: Data from 7,845 participants who underwent screening between May 2008 and April 2011 was analyzed. Binary logistic regression and multinomial regression were performed to calculate the odds of selection of colonoscopy instead of FIT and the impact of the educational session on final participant choice, respectively. RESULTS: Of the 7,845 participants, 4,796 (61 %) underwent FIT and 3,049 (39 %) underwent colonoscopy. A significant number of participants changed their initial choice after the educational session, with 27.1 % changing to FIT from colonoscopy and 8 % changing from FIT to colonoscopy. Age, educational level, occupation, income, family history of CRC, perception of risk of CRC, and perceptions regarding CRC screening were significantly different among the groups choosing FIT and colonoscopy. Family history of CRC and high self-perception of CRC risk resulted in higher odds of choosing colonoscopy, whereas older age, single marital status, and negative perception of CRC screening resulted in lower odds. Perceptions of overall health status, occupation, low income, younger age, and negative perceptions of CRC screening were associated with higher odds of change in screening choice. CONCLUSIONS: Those at higher odds of changing CRC screening options should be supported with more detailed explanations by primary care physicians to secure a more informed and considered choice. PMID- 22836913 TI - Epigenetics as a therapeutic target in breast cancer. AB - Epigenetics refers to alterations in gene expression due to modifications in histone acetylation and DNA methylation at the promoter regions of genes. Unlike genetic mutations, epigenetic alterations are not due to modifications in the gene primary nucleotide sequence. The importance of epigenetics in the initiation and progression of breast cancer has led many investigators to incorporate this novel and exciting field in breast cancer drug development. Several drugs that target epigenetic alterations, including inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT), are currently approved for treatment of hematological malignancies and are available for clinical investigation in solid tumors. In this manuscript, we review the critical role of epigenetics in breast cancer including the potential for epigenetic alterations to serve as biomarkers determining breast cancer prognosis and response to therapy. We highlight initial promising results to date with use of epigenetic modifiers in patients with breast cancer and the ongoing challenges involved in the successful establishment of these agents for the treatment of breast cancer. PMID- 22836915 TI - Detection of ochratoxin A in tropical wine and grape juice from Brazil. AB - BACKGROUND: Ochratoxin A (OTA) is the main mycotoxin found in grapes, wines and grape juices and is considered one of the most harmful contaminants to human health. In this study, samples of tropical wines and grape juices from different grape varieties grown in Brazil were analysed for their OTA content by high performance liquid chromatography. RESULTS: The detection and quantification limits for OTA were 0.01 and 0.03 ug L(-1) respectively. OTA was detected in 13 (38.24%) of the samples analysed, with concentrations ranging from < 0.03 to 0.62 ug L(-1). OTA was not detected in any of the grape juice samples. Most of the red wine samples proved to be contaminated with OTA (75%), while only one white wine sample was contaminated. However, the OTA levels detected in all samples were well below the maximum tolerable limit (2 ug L(-1)) in wine and grape juice established by the European Community and Brazilian legislature. CONCLUSION: The results of this study indicate a low risk of exposure to OTA by consumption of tropical wines and grape juices from Brazil. PMID- 22836916 TI - Regulation of APC/C-Cdh1 and its function in neuronal survival. AB - Neurons are post-mitotic cells that undergo an active downregulation of cell cycle-related proteins to survive. The activity of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that regulates cell cycle progression in proliferating cells, plays a relevant role in post-mitotic neurons. Recent advances in the study of the regulation of APC/C have documented that the APC/C-activating cofactor, Cdh1, is essential for the function(s) of APC/C in neuronal survival. Here, we review the normal regulation of APC/C activity in proliferating cells and neurons. We conclude that in neurons the APC/C-Cdh1 complex actively downregulates the stability of the cell cycle protein cyclin B1 and the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase-3. Keeping these proteins destabilized is critical both for preventing the aberrant reentry of post-mitotic neurons into the cell cycle and for maintaining their reduced antioxidant status. Further understanding of the pathophysiological regulation of these proteins by APC/C-Cdh1 in neurons will be important for the search for novel therapeutic targets against neurodegeneration. PMID- 22836917 TI - [Myocardial revascularization]. AB - Coronary artery disease (CAD) is a leading cause of morbidity and mortality in western countries and is of significant socio-economic importance due to its increasing prevalence. Until percutaneous coronary interventions (PCI) were established, CAD could only be treated by surgical revascularization or pharmacological therapy. In-stent restenosis remains a major problem after stent implantation. However, the use of new materials and stent coatings have led to a significant reduction in in-stent restenosis. Thus, surgical revascularization and PCI are currently of equal value for the treatment of CAD. The decision making for PCI or surgical revascularization depends on various factors such as number of diseased vessels, complexity of the coronary stenoses, concomitant diseases, and the patient's general condition. The therapeutic regime of every patient should be adjusted to the recommendations of the European and German Society for Cardiology, while controversial and complex cases should be discussed in an interdisciplinary case conference ("heart team"). PMID- 22836918 TI - Infected large pore meshes may be salvaged by topical negative pressure therapy. AB - PURPOSE: To evaluate the efficacy of negative pressure therapy for superficial and deep mesh infections after ventral and incisional hernia repair by a prospective monocentric observational study. METHODS: During a 6-year period, 724 consecutive open ventral and incisional hernia repairs were performed. Pre- and intraoperative data as well as postoperative complications were prospectively recorded. In case of wound infection, negative pressure therapy (NPT) was our primary treatment. RESULTS: Sixty-three patients (8.7 %) were treated using negative pressure therapy after primary ventral and incisional hernia repair. Infectious complications needing NPT occurred in 54 patients in the retromuscular group (54/523; 10.3 %), none when laparoscopically treated and in 9 patients (9/143; 6.3 %) treated by an open intraperitoneal mesh technique. Considering outcome, all meshes were completely salvaged in the retromuscular mesh group after a median of 5 dressing changes (range, 2-9), while in the intraperitoneal mesh, group 3 meshes needed complete (n = 2) or partial (n = 1) excision. Mean duration to complete wound closure was 44 days (range, 26-63 days). CONCLUSION: NPT is a useful adjunct for salvage of deep infected meshes, particularly when large pore monofilament mesh is used. PMID- 22836919 TI - Obturator nerve injury in laparoscopic inguinal hernia mesh repair. AB - Injury to pelvic nerves during laparoscopy mostly occurs in gynecological and urological procedures. In abdominal surgery, these complications are infrequent. We present a case report of a patient who suffered a rare obturator nerve injury during a laparoscopic hernioplasty caused by clipping the nerve to the edge of the mesh. After revision and release of nerve from the clip and scars tissue, the associated pain rapidly disappeared and thigh adduction strength improved. Now, 4 years later, MRI and EMG show no sign of nerve compression. PMID- 22836920 TI - Psychometric properties of the 8-item Morisky Medication Adherence Scale in patients taking warfarin. AB - There is no patient-reported medication adherence measure that has been validated in Singapore. This study aimed to validate the 8-item Morisky Medication Adherence Scale (MMAS) in patients taking warfarin in Singapore. A cross sectional survey was conducted in a convenience sample of 151 patients taking warfarin at an anticoagulation clinic in 2011. Respondents completed the MMAS in English or Chinese depending on their preference. The MMAS had a Cronbach's alpha of 0.56 and good criterion-related validity as the scale scores were associated with warfarin refill rates (p = 0.04). Respondents with higher MMAS scores were found to have a higher percentage of International Normalised Ratios (INRs) within the therapeutic range (p = 0.01), higher adherence to diet recommendations (p = 0.02), and less perceived difficulty in taking all medications (p < 0.001); they were also more likely to take warfarin at the same time every day (p < 0.001). Confirmatory factor analysis showed that the eight items loaded onto one factor (RMSEA = 0.03). The sensitivity, specificity, positive predictive value and negative predictive value of the MMAS for identifying patients with poor INR control were 73.0%, 35.6%, 49.5% and 60.5%, respectively, using the time in the therapeutic INR range as the gold standard. This study shows that the 8-item MMAS has good validity and moderate reliability in patients taking warfarin. Future research is needed to investigate the scale's psychometric properties in other patient populations and clinical settings. PMID- 22836921 TI - Climate change adaptation among Tibetan pastoralists: challenges in enhancing local adaptation through policy support. AB - While researchers are aware that a mix of Local Ecological Knowledge (LEK), community-based resource management institutions, and higher-level institutions and policies can facilitate pastoralists' adaptation to climate change, policy makers have been slow to understand these linkages. Two critical issues are to what extent these factors play a role, and how to enhance local adaptation through government support. We investigated these issues through a case study of two pastoral communities on the Tibetan Plateau in China employing an analytical framework to understand local climate adaptation processes. We concluded that LEK and community-based institutions improve adaptation outcomes for Tibetan pastoralists through shaping and mobilizing resource availability to reduce risks. Higher-level institutions and policies contribute by providing resources from outside communities. There are dynamic interrelationships among these factors that can lead to support, conflict, and fragmentation. Government policy could enhance local adaptation through improvement of supportive relationships among these factors. While central government policies allow only limited room for overt integration of local knowledge/institutions, local governments often have some flexibility to buffer conflicts. In addition, government policies to support market-based economic development have greatly benefited adaptation outcomes for pastoralists. Overall, in China, there are still questions over how to create innovative institutions that blend LEK and community-based institutions with government policy making. PMID- 22836923 TI - "Pattern of venous collateral development after splenic vein occlusion in an extended whipple procedure". PMID- 22836922 TI - Is resection equivalent to transplantation for early cirrhotic patients with hepatocellular carcinoma? A meta-analysis. AB - BACKGROUND: Whether liver resection or liver transplantation is optimal therapy for patients with hepatocellular carcinoma (HCC) remains undefined. A meta analysis was conducted to answer this question. STUDY DESIGN: This study performed a systematic review of the published literature between January 2000 and April 2012. RESULTS: Nine retrospective studies, totaling 2,279 patients (989 resected and 1,290 transplanted), met the selection criteria. Older patients with larger tumors and less severe cirrhosis were identified in the resection group. At 1 year, resection demonstrated significantly higher overall [odds ratio (OR) = 1.54; 95 % confidence interval (CI), 1.19-1.98; p = 0.001], but equivalent disease-free survival (OR = 0.93; 95 % CI, 0.53-1.63; p = 0.80). At 5 years, there was no difference in overall survival (OR = 0.86; 95 % CI, 0.61-1.21; p = 0.38), but a higher disease-free survival in transplanted patients was observed (OR = 0.39; 95 % CI, 0.24-0.63; p < 0.001). When limiting our analysis to studies conducted in an intent-to-treat fashion, there was no difference in 5 year overall survival (OR = 1.18; 95 % CI, 0.92-1.51; p = 0.19), but a significantly higher disease-free survival (OR = 0.76; 95 % CI, 0.57-1.00; p = 0.05) in transplanted patients. At 10 years, transplantation had higher overall and disease-free survival rates. CONCLUSION: Liver transplantation in patients with HCC results in increased late disease-free and overall survival when compared with liver resection. Nonetheless, the benefit of liver transplantation is offset by higher short-term mortality, donor organ availability, and long transplant wait times associated with more patient deaths. Understanding these differences in survival is helpful in guiding treatment. However, a properly controlled prospective trial is needed to define how best to treat HCC patients who are candidates for either therapy. PMID- 22836924 TI - Utilizing 3D SERS active volumes in aligned carbon nanotube scaffold substrates. PMID- 22836926 TI - Polysiloxane-backbone block copolymers in a one-pot synthesis: a silicone platform for facile functionalization. AB - Block copolymers consisting exclusively of a silicon-oxygen backbone are synthesized by sequential anionic ring-opening polymerization of different cyclic siloxane monomers. After formation of a poly(dimethylsiloxane) (PDMS) block by butyllithium-initiated polymerization of D3, a functional second block is generated by subsequent addition of tetramethyl tetravinyl cyclotetrasiloxane (D4(V) ), resulting in diblock copolymers comprised a simple PDMS block and a functional poly(methylvinylsiloxane) (PMVS) block. Polymers of varying block length ratios were obtained and characterized. The vinyl groups of the second block can be easily modified with a variety of side chains using hydrosilylation chemistry to attach compounds with Si-H bond. Conversion of the hydrosilylation used for polymer modification was investigated. PMID- 22836927 TI - Mass transport controlled oxygen reduction at anthraquinone modified 3D-CNT electrodes with immobilized Trametes hirsuta laccase. AB - Carbon nanotubes covalently modified with anthraquinone were used as an electrode for the immobilization of Trametes hirsuta laccase. The adsorbed laccase is capable of oxygen reduction at a mass transport controlled rate (up to 3.5 mA cm( 2)) in the absence of a soluble mediator. The storage and operational stability of the electrode are excellent. PMID- 22836925 TI - Grapheme-color synesthesia can enhance immediate memory without disrupting the encoding of relational cues. AB - Previous evidence has suggested that grapheme-color synesthesia can enhance memory for words, but little is known about how these photisms cue retrieval. Often, the encoding of specific features of individual words can disrupt the encoding of ordered relations between words, resulting in an overall decrease in recall accuracy. Here we show that the photisms arising from grapheme-color synesthesia do not function like these item-specific cues. The influences of high and low word frequency on the encoding of ordered relations and the accuracy of immediate free recall were compared across a group of 10 synesthetes and 48 nonsynesthetes. The main findings of Experiment 1 showed that the experience of synesthesia had no adverse effect on the encoding of ordered relations (as measured by input-output correspondence); furthermore, it enhanced recall accuracy in a strictly additive fashion across the two word frequency conditions. Experiment 2 corroborated these findings by showing that the synesthetes only outperformed the nonsynesthetes when the materials involved words and letters, not when they involved digits and spatial locations. Altogether, the present findings suggest that synesthesia can boost immediate memory performance without disrupting the encoding of ordered relations. PMID- 22836928 TI - Health outcomes can be improved by implementing an occupational physiotherapy provider programme. AB - PURPOSE: To evaluate the return to work and health outcomes of a physiotherapy network provider programme. METHOD: A prospective case-control study was conducted with 21 clients of network occupational physiotherapy (OP) providers and 21 matched clients of non-network providers. OUTCOME MEASURES: Health outcomes and return to work were recorded 3 and 6 months following the commencement of physiotherapy. Health outcomes included the Short Form (SF)-12, return to usual activities and the global perceived effect of treatment. Within group changes and between-group differences were analysed. RESULTS: Within-group changes showed the OP group improved significantly in physical functioning (p = 0.006), and the control group deteriorated in mental health status (p = 0.016) as measured by the SF-12. Mean change over time between groups from the 3-month to 6 month follow-ups showed a significant difference favouring the OP group for return to usual activities (p = 0.027) and the physical component of the SF-12 (p = 0.009). All job-attached participants returned to work following their accident, so there was no difference between the groups. CONCLUSION: The OP clients demonstrated a greater change in physical functioning health outcomes over time. This study provides preliminary support for the implementation of the OP scheme. PMID- 22836929 TI - Development of a framework for recovery in older people with mental disorder. AB - OBJECTIVE: To evaluate whether a conceptual framework of recovery developed for working age adults holds value for users of older people's mental health services, including those with dementia. METHOD: Thirty-eight qualitative interviews were undertaken with service users and carers from an older people's mental health service in South London and were analysed using grounded theory methods. RESULTS: Components of recovery, which appear to be meaningful to older people with mental disorder include the following: (i) the impact of illness, (ii) the significance of personal responsibility, and (iii) specific coping strategies. Unlike their younger peers, older people did not aspire to a new and revised sense of identity, nor did they seek peer support from others with lived experience of mental illness. Three components of recovery were identified as being distinct to older people: the significance of an established and enduring sense of identity; coping strategies, which provide continuity and reinforce identity; and the associated impact of physical illness. Finally, two additional components of recovery were identified for people with dementia: (i) the changing experience over time and (ii) support from others. CONCLUSION: Mental health policy is increasingly framed in terms of 'recovery'. This paper provides empirical evidence of how it applies to users of older people's mental health services. Practice implications include the need to focus on the maintenance of identity, and embed the values of empowerment, agency and self-management within service delivery. PMID- 22836930 TI - gem-Dialkylthio vinylallenes: alkylthio-regulated reactivity and application in the divergent synthesis of pyrroles and thiophenes. AB - gem-Dialkylthio vinylallenes were obtained for the first time and applied to the divergent synthesis of fully-substituted pyrroles and thiophenes by domino cyclizations. These two cyclization pathways were regulated by alkylthio groups. Plausible reaction mechanisms were presented and supported by DFT calculations. An unprecedented metal-free carbothiolation was discovered in the formation of thiophenes. PMID- 22836931 TI - [Remuneration distribution - should morbidity-dependent overall remuneration also be distributed after adjustments for morbidity?]. AB - INTRODUCTION: In the 2009 reform of the German collective remuneration system for outpatient medical care, on the level of overall remuneration, the morbidity risk was transferred to the health funds fulfilling a long-term demand of physicians. Nevertheless not transferring morbidity adjustment to the levels of physician groups and singular practices can lead to budgets not related to patient needs and to incentives for risk selection for individual doctors. METHODS: The systematics of the distribution of overall remuneration in the German remuneration system for outpatient care are analysed focusing on the aspect of morbidity adjustment. Using diagnostic and pharmaceutical information of about half a million insured subjects, a risk adjustment model able to predict individual expenditures for outpatient care for different provider groups is presented. This model enables to additively split the individual care burden into several parts attributed to different physician groups. Conditions for the use of the model in the distribution of overall remuneration between physician groups are developed. A simulation of the use of diagnoses-based risk adjustment in standard service volumes then highlights the conditions for a successfull installation of standard service volumes representing a higher degree of risk adjustment. RESULTS: The presented estimation model is generally applicable for the distribution of overall remuneration to different physician groups. The simulation of standard service volumes using diagnosis-based risk adjustment does not provide a more accurate prediction of the expenditures on the level of physician practices than the age-related calculation currently used in the German remuneration system for outpatient medical care. CONCLUSION: Using elements of morbidity-based risk adjustment the current German collective system for outpatient medical care could be transformed towards a higher degree of distributional justice concerning medical care for patients and more appropriate incentives avoiding risk selection. Limitations of the applicability of risk adjustment can be especially pointed out when a high share of lump-sum-payments is used for the remuneration of some physician groups. PMID- 22836932 TI - [Modeling the requirements on routine data of general practitioners from the health-care researcher's point of view with the help of unified modeling langauge (UML)]. AB - BACKGROUND AND AIMS: Health-care research is, besides primary acquired study data, based on data from widely differing secondary sources. In order to link, compare and analyze data sources uniform models and methods are needed. This could be facilitated by a more structured description of requirements, models and methods of health-care research than those currently used. Suitable methods of presentation were sought in an approach to this target and the unified modeling language (UML) identified as a possible alternative. METHODS: Using different tools 3 UML diagrams were created to represent some individual aspects of a scientific use file (SUF): A use case diagram as well as an activity and a class diagram. In the use case diagram we attempted to represent the general use cases of an SUF based on general practitioners routine data. Secondly a class diagram was constructed to visualize the contents and structure of a SUF. Thirdly an activity diagram was developed to graphically represent the concept of a general practitioner's episode of care. RESULTS: The creation of the UML diagrams was possible without any technical difficulties. Regarding the content the 3 diagrams must still be considered as prototypes. The use case diagram shows possible uses and users of an SUF, e. g. a research worker, industry but also the general practitioner who supplies the data. The class diagram reveals a general data structure that can serve information processes in practice and research. Besides aggregation, possibilities for specialization and generalization are essential elements of the class diagram that can be used meaningfully. The activity diagram for the schematic representation of a general practitioner's episode of care reveals the existence of multiple endpoints of an episode and the possibility to form relationships by means of episodes (diagnosis>therapy). CONCLUSION: The constructed diagrams are preliminary results and should be refined in future steps. Use case diagrams enable a rapid overview of the meaning and purpose of a system, in this case an SUF. Class diagrams can help at a professional level to describe relationships between entities (classes/objects) more clearly than with the existing methods of representation. Activity diagrams are successors to classic flow charts. They are complemented appropriately by status diagrams. UML is suitable to uniformly and graphically describe a system (here an SUF) from various points of view. In future, validated UML models will help us to present scientific concepts and results in a more structured form than before and to promote the technological use of these concepts in practice. PMID- 22836933 TI - [An innovative system for analysis and further development of long-term care for older people - results of the European PROject INTERLINKS]. AB - In the light of recent demographic changes, the continued development of structures of long-term care (LTC) for older people is needed across Europe. In Germany, as in many other European countries, existing provisions of LTC are neither adequately coordinated nor user-oriented. The integration of relevant institutions and actors constitutes a central challenge for a high quality of care. The European research project INTERLINKS asked how the interfaces within fragmented structures of LTC are currently managed. Thematic foci included quality assessment and assurance, embedding preventive and rehabilitative aspects into LTC, the involvement and support of informal care-givers, and questions regarding the governance and financing of LTC. Using a framework developed by INTERLINKS, the project included the construction of an instrument for a detailed and comprehensive analysis of LTC systems. As an online platform with more than 100 examples of innovative approaches to coordination and integration in practice, this framework facilitates an exchange among experts - both within countries and at a European level - that will help stimulate the further development of LTC. The website also offers a German translation of the database in order to facilitate its use by German speakers. PMID- 22836934 TI - [10 years of assessing prevention and early diagnosis programmes by the Federal Joint Committee of Germany - a methodological analysis]. AB - Medical benefit is the crucial factor in the evidence-based decision-making process of the Federal Joint Committee (G-BA) of Germany. To review the decisions on population-based screening methods from January 2000 to December 2009, we analysed the coverage decisions. During this period of time, the G-BA decided on 14 screening methods, predominantly dealing with the early diagnoses of serious diseases. In 8 cases a positive assessment led to reimbursement by the statutory health insurance funds, in 5 cases the assessment was negative and in one case the conditions were changed. For 7 assessments, a fully reported review was available, 4 of this were positively evaluated. In 2 of these cases, controlled screening studies documented the benefit of the screening method. In another case there was only a case series without a control group. For the fourth method, the question for the benefit of the screening method was divided into 3 sub questions, investigated separately in different studies. The methods of benefit assessments have changed very much over time. A revision of the rules of procedure for the assessment of medical screening methods is advisable. PMID- 22836935 TI - [Linkage of secondary data with cancer registry data on the basis of encrypted personal identifiers - results from a pilot study in North Rhine-Westphalia]. AB - BACKGROUND: The Cancer Registry of North-Rhine-Westphalia stores exclusively encrypted personal identifiers of registered cancer patients. Therefore, comparisons with secondary data sets can only be performed by record linkage procedures that are based on encrypted personal identifiers. We report on a pilot study which linked encrypted personal data from the disease management program for patients with diabetes mellitus type 2 (DMP-DM2) with the database of the EKR NRW in order to test the feasibility and efficiency of these record linkage procedures. METHODS: Personal identifying variables of the DMP records were encrypted in a 2-stage process before being sent electronically to the EKR NRW where they were subsequently submitted to a probabilistic record linkage with the registry data. The study included 27 450 participants who were insured at the AOK NordWest, residents of the district Munster and who were aged 40-79 years at the time of first enrolment to the DMP-DM2 between June 2003-July 2008. RESULTS: The electronic processing time of the semi-automatic record linkage procedure took about 24 h. Approximately 2% of the records had to be reviewed manually. After exclusion of prevalent cancer cases, multiple primaries and inadequate data, 26 742 participants (47.3% men; 52.7% women) remained in the data set. About 1 364 cohort members (759 men, 605 women) were diagnosed with cancer after submission to the disease management program. DISCUSSION: The DMP-DM2 records were encrypted and linked to cancer registry data with a moderate personnel and financial input and high efficiency. Linked records were instantly usable for epidemiological analyses. Experiences of the pilot study suggest that future linkage studies can further advance the level of data protection, without losses in efficiency, by moderately complex software modifications and amendments of the data flow. PMID- 22836936 TI - [Early detection of prostate cancer by PSA testing: the results of a qualitative study on barriers caused by physicians in Austria implementing informed decision making]. AB - OBJECTIVES: In the context of the Austrian Periodic Health Examination and on the basis of current evidence based medicine a systematic screening for prostate specific antigen (PSA) is inadvisable. General practitioners (GPs) are expected to inform their patients about risks and benefits of screening before undergoing a PSA test. Ideally, this information corresponds to the model of informed decision making (IDM).The aim of this qualitative pilot-study is to explore factors, which gain insight into GPs' practice of counselling about the PSA test. METHODS: This qualitative pilot study involves 5 focus groups with 30 GPs and 4 internists and in-depth interviews with 8 GPs. Both the discussions and the interviews were audio-taped, transcribed verbatim, and qualitatively analysed. Data were analysed by using typological analysis and qualitative content analysis as methodological approaches and by means of the software MAXqda. RESULTS: The results of the in-depth interviews show 2 groups of GPs which can be classified by frequency of performing a PSA test: (i) routine screeners, who recommend PSA testing to all patients of 50 years and older, and (ii) non-routine screeners, who inform the patients only if they formally wish it. In-depth interviews as well as focus groups reveal that risks and adverse effects are rarely reported in GP counselling. More often they discuss the potential benefit of the testing. They regard balanced information as unacceptable for both the GP and the patient. Influencing factors concerning the patient (cognitive and emotional demand, preference of the authoritarian doctor, discouraging), factors concerning the GP (own belief in the efficacy of PSA screening, lack of knowledge) and structural factors (lack of time, lack of remuneration) were detected. CONCLUSION: The results indicate a selective presentation of aspects of screening for prostate cancer within the GP practice of counselling, which seem to overvalue the benefits of the screening and undervalue the associated risks of the PSA test. It should be made clear that the aim - the implementation of informed decision making (IDM) within the context of counselling about PSA test - within the Austrian Periodic Health Examination has not yet been put into practice. Results show that it is necessary to improve GPs' practice of communication, for example, by integrating IDM into the context of GPs' continuous training. PMID- 22836937 TI - The psychosocial work environment and mental health of teachers: a comparative study between the United Kingdom and Hong Kong. AB - PURPOSE: There is limited research on teachers' psychosocial work environment and mental health, and most has been conducted in predominantly Western countries that share a number of important common characteristics that distinguish them from countries in many other regions of the world. Within the framework of the effort-reward imbalance (ERI) theoretical model, the relationship between the psychosocial work environment and mental health of teachers in the United Kingdom (UK) and Hong Kong (HK) was investigated. METHODS: Full-time qualified teachers from both the UK and HK (N = 259) participated in the research. They were asked to fill in a set of questionnaires that measured their perceived stress, mental health, psychosocial work environment and demographic information. RESULTS: Perceived stress was found to predict teachers' mental health. Overcommitment, the intrinsic component of the ERI model, predicted mental health among HK teachers. There were significant differences in the psychosocial variables between UK and HK teachers. CONCLUSION: The results showed support for the ERI model and in particular for the relationship between stress and mental health and demonstrated the role of overcommitment in the teaching profession. Some implications are discussed for combating cultural differences in managing the psychosocial work environment of teachers. PMID- 22836938 TI - Parent-adolescent relationship quality as a moderator for the influences of parents' religiousness on adolescents' religiousness and adjustment. AB - Prior investigations have demonstrated that parents' religiousness is related inversely to adolescent maladjustment. However, research remains unclear about whether the link between parents' religiousness and adolescent adjustment outcomes--either directly or indirectly via adolescents' own religiousness- varies depending on relationship context (e.g., parent-adolescent attachment). This study examined the moderating roles of parent-adolescent attachment on the apparent effects of the intergenerational transmission of religiousness on adolescent internalizing and externalizing symptoms using data from 322 adolescents (mean age = 12.63 years, 45 % girls, and 84 % White) and their parents. Structural equation models indicated significant indirect effects suggesting that parents' organizational religiousness was positively to boys' organizational religiousness--the latter of which appeared to mediate the negative association of parents' organizational religiousness with boys' internalizing symptoms. Significant interaction effects suggested also that, for both boys and girls, parents' personal religiousness was associated positively with adolescent internalizing symptoms for parent-adolescent dyads with low attachment, whereas parents' personal religiousness was not associated with adolescent internalizing symptoms for parent-adolescent dyads with high attachment. The findings help to identify the family dynamics by which the interaction of parents' religiousness and adolescents' religiousness might differentially influence adolescent adjustment. PMID- 22836939 TI - Goal setting and self-efficacy among delinquent, at-risk and not at-risk adolescents. AB - Setting clear achievable goals that enhance self-efficacy and reputational status directs the energies of adolescents into socially conforming or non-conforming activities. This present study investigates the characteristics and relationships between goal setting and self-efficacy among a matched sample of 88 delinquent (18 % female), 97 at-risk (20 % female), and 95 not at-risk adolescents (20 % female). Four hypotheses related to this were tested. Findings revealed that delinquent adolescents reported fewest goals, set fewer challenging goals, had a lower commitment to their goals, and reported lower levels of academic and self regulatory efficacy than those in the at-risk and not at-risk groups. Discriminant function analysis indicated that adolescents who reported high delinquency goals and low educational and interpersonal goals were likely to belong to the delinquent group, while adolescents who reported high educational and interpersonal goals and low delinquency goals were likely to belong to the not at-risk group. The at-risk and not at-risk groups could not be differentiated. A multinomial logistic regression also revealed that adolescents were more likely to belong to the delinquent group if they reported lower self regulatory efficacy and lower goal commitment. These findings have important implications for the development of prevention and intervention programs, particularly for those on a trajectory to delinquency. Specifically, programs should focus on assisting adolescents to develop clear self-set achievable goals and support them through the process of attaining them, particularly if the trajectory towards delinquency is to be addressed. PMID- 22836940 TI - Spatiotemporal regulation of keratin 5 and 17 in the axolotl limb. AB - BACKGROUND: Amphibians have greater regeneration capability than higher vertebrates. They can regenerate their limbs after an amputation. As a limb is regenerated, a regeneration-specific epithelium called the apical epithelial cap (AEC) is induced. The AEC is an essential structure for limb regeneration. Despite the importance of the AEC, molecular marker genes have not been well studied at the molecular level. RESULTS: In the present study, keratin5 (KRT5) and KRT17 were investigated in an axolotl-regenerating limb. KRT5 and KRT17 were expressed in a regenerating limb but down-regulated in a differentiating limb. KRT5 showed characteristic regulation in a regenerating blastema. KRT5 was suppressed in the basal layer of the AEC. This KRT5 suppression was correlated to the blastema differentiation and nerve presence. Simple skin wounding could also upregulate both KRT5 and KRT17 gene expression. But these genes were suppressed within a shorter time than in limb regeneration. CONCLUSIONS: The KRT5 and KRT17 gene profile can be a useful marker gene to investigate AEC in limb regeneration. PMID- 22836941 TI - [Renal aspergilloma: first manifestation of an occult sarcomatoid carcinoma]. AB - A patient with b-symtoms and a sonographically detected kidney tumor entered hospital for a nephrectomy. An aspergillosis had been histologically accounted for. Up to that point, there was no indication of an immunodeficiency or invasive aspergillosis. Three months later, the patient was readmitted to hospital due to an indefinite retroperitoneal and hepatic mass on the right side. A punch biopsy ascertained a remanifestation of an aspergillosis at both localizations. The mass increased during systemic and antimycotic therapy, indicating the surgical resection of hepatic and retroperitoneal findings. The histological report yielded the diagnosis of a poorly differentiated sarcomatous carcinoma. Thus, an aspergillosis was the initial manifestation of what had up to that point been an occult sarcomatous carcinoma. PMID- 22836942 TI - [Treatment of stress urinary incontinence after radical prostatectomy: adjustable transobturator male system - results of a multicenter prospective observational study]. AB - BACKGROUND: The adjustable transobturator male system (ATOMS(r)) is a new method for the treatment of male stress urinary incontinence. This article presents the results of a prospective multicenter observational study with this system. PATIENTS AND METHODS: Between March 2009 and March 2011 a total of 124 patients with persistent stress urinary incontinence after radical prostatectomy received the ATOMS system. Postoperative adjustments via the implanted port chamber were performed after 6 weeks and thereafter when necessary. Postoperative evaluation consisted of medical history, mictionary protocol, 24-h pad tests, 24-h pad counts and sonography. RESULTS: The mean age of the patients was 71.2 +/- 5.5 years (range 58-85 years). Previous incontinence surgery had been carried out in 36.3% of patients while 34.5% of patients had a previous history of radiation treatment. The mean operation time was 48.3 +/- 11.2 min (range 36-116 min) and the mean hospital stay was 3.8 +/- 1.2 days (range 2-6 days). No intraoperative urethral or bladder injuries occurred. After removal of the transurethral catheter on the first postoperative day, temporary urinary retention occurred in 3 patients who were conservatively treated. Transient perineal/scrotal pain or dysesthesia was observed in 75 patients (60.5%) and resolved after 3-4 weeks of non-opioid analgesics. There were no perineal infections; however, infections at the port site occurred in 3 patients (2.4%) leading to explantation of the system in all cases. The average number of adjustments to achieve the desired result was 4.3 +/- 1.8 (range 2-7). After a mean follow-up of 19.1 +/- 2.2 months (range 12 36 months), there was a significant reduction in the mean number of pads/24 h from 8.8 to 1.8 (p<0.001). The overall success rate was 93.8% with 61.6% of the patients being dry and 32.2% of the patients showing improvement. CONCLUSIONS: The results of the study demonstrate the safety and efficacy to date of the ATOMS system for treatment of stress urinary incontinence after radical prostatectomy. PMID- 22836943 TI - Two thioredoxin reductases, trxr-1 and trxr-2, have differential physiological roles in Caenorhabditis elegans. AB - Thioredoxin reductase (TrxR) is a member of the pyridine nucleotide-disulfide reductase family, which mainly functions in the thioredoxin system. TrxR is found in all living organisms and exists in two major ubiquitous isoenzymes in higher eukaryotic cells; One is cytosolic and the other mitochondrial. Mitochondrial TrxR functions to protect mitochondria from oxidative stress, where reactive oxidative species are mainly generated, while cytosolic TrxR plays a role to maintain optimal oxido-reductive status in cytosol. In this study, we report differential physiological functions of these two TrxRs in C. elegans. trxr-1, the cytosolic TrxR, is highly expressed in pharynx, vulva and intestine, whereas trxr-2, the mitochondrial TrxR, is mainly expressed in pharyngeal and body wall muscles. Deficiency of the non-selenoprotein trxr-2 caused defects in longevity and delayed development under stress conditions, while deletion mutation of the selenoprotein trxr-1 resulted in interference in acidification of lysosomal compartment in intestine. Interestingly, the acidification defect of trxr 1(jh143) deletion mutant was rescued, not only by selenocystein-containing wild type TRXR-1, but also cysteine-substituted mutant TRXR-1. Both trxr-1 and trxr-2 were up-regulated when worms were challenged by environmental stress such as heat shock. These results suggest that trxr-1 and trxr-2 function differently at organismal level presumably by their differential sub-cellular localization in C. elegans. PMID- 22836944 TI - Liver cell line derived conditioned medium enhances myofibril organization of primary rat cardiomyocytes. AB - Cardiomyocytes are the fundamental cells of the heart and play an important role in engineering of tissue constructs for regenerative medicine and drug discovery. Therefore, the development of culture conditions that can be used to generate functional cardiomyocytes to form cardiac tissue may be of great interest. In this study, isolated neonatal rat cardiomyocytes were cultured with several culture conditions in vitro and characterized for cell proliferation, myofibril organization, and cardiac functionality by assessing cell morphology, immunocytochemical staining, and time-lapse confocal scanning microscopy. When cardiomyocytes were cultured in liver cell line derived conditioned medium without exogenous growth factors and cytokines, the cell proliferation increased, cell morphology was highly elongated, and subsequent myofibril organization was highly developed. These developed myofibril organization also showed high level of contractibility and synchronization, representing high functionality of cardiomyocytes. Interestingly, many of the known factors in hepatic conditioned medium, such as insulin-like growth factor II (IGFII), macrophage colony stimulating factor (MCSF), leukemia inhibitory factor (LIF), did not show similar effects as the hepatic conditioned medium, suggesting the possibility of synergistic activity of the several soluble factors or the presence of unknown factors in hepatic conditioned medium. Finally, we demonstrated that our culture system could provide a potentially powerful tool for in vitro cardiac tissue organization and cardiac function study. PMID- 22836945 TI - The pharmacokinetic analysis of cyclosporine is essential for the management of refractory pure red cell aplasia. PMID- 22836946 TI - The use of adjusted ideal body weight for overweight patients undergoing HPC mobilisation for autologous transplantation. AB - Generally, patients' actual body weight (ABW) is used to calculate the number of CD34+ cells to be harvested for autologous haematopoietic progenitor cell (HPC) transplantation. In our institution, 'overweight' patients weighing at least 25% more than their ideal body weight (IBW) have their adjusted ideal body weight (AdjIBW) used for determination of blood volume to be processed to achieve a minimum target of CD34+ cells per kilogram, as well as CD34+ cell dosage calculation at transplant. AdjIBW is calculated as follows: AdjIBW = IBW + 0.25 * (actual weight - IBW). We have used AdjIBW for 65/153 patients who have had autologous HPC harvests, with a median AdjIBW of 69 kg (range, 50-110 kg). Median actual weight was 90 kg (range, 62-175 kg). Median volume of peripheral blood processed to achieve a minimum 2 * 106 CD34+ cells/kg for these patients was 13.2 L (range, 5-35 L), and the median CD34+ cells * 106/kg collected for AdjIBW was 6.3 (range, 1.7-33). For normal-weight patients (n = 88; median ABW, 75 kg; range, 49-98 kg), the corresponding median apheresis volume was 16 L (range, 7-24 L), and median CD34+ cells * 106/kg harvested was 4.5 (range, 1.4-15.9). In total, 35 in a total transplant cohort of 82 patients had AdjIBW used to determine CD34+ cell dose at time of transplant, with a median of 4.5 * 106/kg, (if their ABW was used in the calculation; 3.1 * 106/kg), compared to median dose of 3.2 * 106/kg ABW for the normal-weight patient cohort. All patients engrafted with no significant difference between median times to neutrophil and platelet engraftment for the overweight (13 and 15 days, respectively) compared with normal-weight (12 and 14 days, respectively) patient cohorts. We conclude that the use of AdjIBW is a useful tool for successful harvest and subsequent transplant for overweight patients, with no adverse effect on engraftment times. PMID- 22836947 TI - 1H, 13C and 13N resonance assignments of TbTFIIS2-2 PWWP domain from Trypanosoma brucei. AB - PWWP domains are found in eukaryotic proteins from yeast to mammals and are involved in DNA methylation, DNA repair and regulation of transcription. Here we report the resonance assignments of TbTFIIS2-2 PWWP domain from Trypanosoma brucei for further understanding of the relationship between its structure and function. PMID- 22836948 TI - Backbone 1H, 13C and 15N resonance assignments of an intrinsically unstructured betagamma-crystallin from Hahella chejuensis. AB - The sequence specific backbone (1)H, (13)C and (15)N resonance assignments of an intrinsically unstructured betagamma-crystallin from Hahella chejuensis are reported. The secondary structure chracterization of the unstructured protein reveals that large fraction of residues exhibits beta-strand propensity, as in the case of the Ca(2+)-bound structured protein. PMID- 22836949 TI - A comparison of sniff bottle staircase and olfactometer-based threshold tests. AB - Olfactometers have been gaining popularity as research tools, but they have yet to replace established testing procedures in a variety of laboratory and clinical settings, including absolute threshold tests. In this research, we designed and operated a simple olfactometer with which to assess threshold. To do this, we used a method-of-adjustment test that was compared to the three-alternative forced choice ascending sniff bottle staircase method, which is currently a standard threshold test procedure. We found that the olfactometer threshold test correlated highly with the staircase method, and that it possessed suitable test retest reliability. The advantages of the olfactometer threshold test include faster test time and reduced cleaning and reassembly demands. Future use of the olfactometer in olfactory identification and/or detection thresholds amongst odors is also outlined. PMID- 22836950 TI - Outcomes of positive randomised controlled clinical trials: double-blind or double vision? Editorial on Serebruany, Atar: 'Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials--common patterns in TRITON, RECORD, and PLATO?' (Thromb Haemost 2012; 108.3). PMID- 22836951 TI - Facile decrease in the electron-transfer rate and surface roughness of gold by ultrasonic treatment. AB - This communication reports that the electron-transfer rate and surface roughness of Au electrodes can be decreased simply by ultrasonic treatment. It seems that the hydroxyl radical generated during ultrasonic treatment plays an important role, as in the case of treatment with Fenton's reagent. PMID- 22836952 TI - Erratum to: effect of patient- and medication-related factors on inpatient medication reconciliation errors. PMID- 22836953 TI - Succeeding as a Clinician Educator: useful tips and resources. AB - Clinician Educators (CEs) play an essential role in the education and patient care missions of academic medical centers. Despite their crucial role, academic advancement is slower for CEs than for other faculty. Increased clinical productivity demands and financial stressors at academic medical centers add to the existing challenges faced by CEs. This perspective seeks to provide a framework for junior CEs to consider with the goal of maximizing their chance of academic success. We discuss six action areas that we consider central to flourishing at academic medical centers: 1. Clarify what success means and define goals; 2. Seek mentorship and be a responsible mentee; 3. Develop a niche and engage in relevant professional development; 4. Network; 5. Transform educational activities into scholarship; and 6. Seek funding and other resources. PMID- 22836954 TI - Facile synthesis of linear and hyperbranched ladder poly(p-phenylene)s without structural defects. AB - Linear and hyperbranched ladder polymers are facilely synthesized by a Pd(0) catalyzed Suzuki polycondensation and Friedel-Crafts alkylation. The polymers show blue light emission with typical features of ladder polymers, such as well resolved absorption and emission spectra, and small Stokes shifts. The polymers contain fewer structural defects and they exhibit good optical and thermal stability. No spectral change is observed after the films of ladder polymers are heated at 110 degrees C in air for 24 h. PMID- 22836955 TI - Piezoelectric fibers for conformal acoustics. AB - Ultrasound transducers have many important applications in medical, industrial, and environmental settings. Large-active-area piezoelectric fibers are presented here, which can be woven into extended and flexible ultrasound transducing fabrics. This work opens significant opportunities for large-area, flexible and adjustable acoustic emission and sensing for a variety of emerging applications. PMID- 22836956 TI - [A guide to the peer review of scientific papers]. AB - The "peer-review" of scientific manuscripts is an honorable and important task to optimize the quality of a medical journal. The reviewer has the following 2 tasks: first, to provide to the editor an overall assessment of the manuscript and make a recommendation regarding the acceptance, revision or rejection of a scientific manuscript. Second, to supply the authors with objective and constructive criticism and also with detailed suggestions for improvement of a manuscript -aiming to improve its scientific quality.The aim of this paper is to provide recommendations for a systematic assessment in order to further improve the quality of the peer review process. Both general principles specific criteria are addressed. Our target is to further enhance the academic value of the journal Handchirurgie, Mikrochirurgie, Plastische Chirurgie by optimizing the peer review process. PMID- 22836957 TI - Extremely slow Li ion dynamics in monoclinic Li2TiO3--probing macroscopic jump diffusion via 7Li NMR stimulated echoes. AB - A thorough understanding of ion dynamics in solids, which is a vital topic in modern materials and energy research, requires the investigation of diffusion properties on a preferably large dynamic range by complementary techniques. Here, a polycrystalline sample of Li(2)TiO(3) was used as a model substance to study Li motion by both (7)Li spin-alignment echo (SAE) nuclear magnetic resonance (NMR) and ac-conductivity measurements. Although the two methods do probe Li dynamics in quite different ways, good agreement was found so that the Li diffusion parameters, such as jump rates and the activation energy, could be precisely determined over a dynamic range of approximately eleven decades. For example, Li solid-state diffusion coefficients D(sigma) deduced from impedance spectroscopy range from 10(-23) m(2) s(-1) to 10(-12) m(2) s(-1) (240-835 K). These values are in perfect agreement with the coefficients D(SAE) deduced from SAE NMR spectroscopy. As an example, D(SAE) = 2 * 10(-17) m(2) s(-1) at 433 K and the corresponding activation energy determined by NMR amounts to 0.77(2) eV (400-600 K). At room temperature D(sigma) takes a value of 3 * 10(-21) m(2) s(-1). PMID- 22836958 TI - Establishing a procedure for dimethyl sulfoxide removal from cardiovascular allografts: a quantitative study. AB - The success of allotransplants is critically dependent on both tissue viability and efficient removal of potentially toxic cryopreservants. In this study we analysed the dimethyl sulphoxide (Me2SO) content of cardiovascular tissue samples stored in tissue banks and optimized a washing protocol to be used before surgical implant. We compared the Me2SO content of heart valves, arteries and veins and quantitatively determined by HPLC the washing kinetics of each group of tissue samples under strictly controlled conditions using an industrial washing medium (BASE). Our results showed that heart valves and arteries have significantly slower Me2SO release kinetics than veins. Approximately 20 % of the initial content of cryopreservant could still be detected in the valves and arterial tissue after 15 min of continuous washing. Conversely, veins were almost completely cleared of the cryoprotectant under the same conditions. We propose a washing protocol consisting of two sequential washing with BASE for a total of 25 min for valves and arteries and 15 min for veins. In our hands, this protocol reliably ensures the removal of more than 95 % of the initial Me2SO content. PMID- 22836960 TI - Protect and serve. PMID- 22836961 TI - Secret disservice. PMID- 22836959 TI - Human anterior lens capsule serving as a substrate for human trabecular meshwork cells cultivation. AB - To investigate if human anterior lens capsule is a suitable substrate for the culture of primary human trabecular meshwork (HTM) cells. Trabecular meshwork cells derived from four human donors were seeded on anterior lens capsules that were prepared from the lenses of donor eyes. Cell morphology and viability were examined at 1, 3, 5 and 7 days. Cell viability was measured based on a two-colour fluorescence assay (membrane-impermeable propidium iodide and membrane permeable Hoechst 33342). Immunocytochemistry studied Zonula occludens-1 (ZO-1), vimentin, tissue transglutaminase (tTgase) and Na(+)/K(+)-adenosine triphosphatase (Na(+)/K(+)-ATPase). Morphology of the cultivated cells followed a typical model while their viability was > 95% in all cases. ZO-1 was found at the cell boundaries of the HTM-AC complex. Vimentin was located at the lateral membranes of the HTM cells. Na(+)/K(+)-ATPase was found at the basolateral membrane of the HTM cells. tTgase was also identified. Anterior lens capsule can be considered as a suitable alternative substrate for cultivation of HTM cells and assist the expansion of existing knowledge about glaucoma pathophysiology and therapy. PMID- 22836962 TI - Error prone. PMID- 22836963 TI - Writers should not fear jargon. PMID- 22836975 TI - TB drugs chalk up rare win. PMID- 22836976 TI - Cuts loom for US science. PMID- 22836977 TI - End of an age for Aquarius. PMID- 22836978 TI - Contest to sequence centenarians kicks off. PMID- 22836979 TI - US drug agency spied on scientists. PMID- 22836980 TI - A giant bid to etch tiny circuits. PMID- 22836982 TI - Planetary science: The time machine. PMID- 22836981 TI - US fusion in budget vice. PMID- 22836983 TI - Methods: Face up to false positives. PMID- 22836986 TI - Astronomy: More medieval clues to cosmic-ray event. PMID- 22836987 TI - Research accountability: Mandate ethics methods in papers. PMID- 22836988 TI - Open access: Hard on lone authors. PMID- 22836989 TI - Schizophrenia: Patients' research priorities get funded. PMID- 22836990 TI - Eutrophication: Political backing to save the Baltic Sea. PMID- 22836991 TI - Astronomy: Planets on the spot. PMID- 22836992 TI - Neuroscience: The wrap that feeds neurons. PMID- 22836993 TI - Device physics: Put the pedal to the metal. PMID- 22836994 TI - Immunology: Malnutrition promotes rogue bacteria. PMID- 22836995 TI - HIV: Shock and kill. PMID- 22836996 TI - Materials science: The abilities of instabilities. PMID- 22836997 TI - Vision: Looking to develop sight. PMID- 22836999 TI - Alignment of the stellar spin with the orbits of a three-planet system. AB - The Sun's equator and the planets' orbital planes are nearly aligned, which is presumably a consequence of their formation from a single spinning gaseous disk. For exoplanetary systems this well-aligned configuration is not guaranteed: dynamical interactions may tilt planetary orbits, or stars may be misaligned with the protoplanetary disk through chaotic accretion , magnetic interactions or torques from neighbouring stars. Indeed, isolated 'hot Jupiters' are often misaligned and even orbiting retrograde. Here we report an analysis of transits of planets over starspots on the Sun-like star Kepler-30 (ref. 8), and show that the orbits of its three planets are aligned with the stellar equator. Furthermore, the orbits are aligned with one another to within a few degrees. This configuration is similar to that of our Solar System, and contrasts with the isolated hot Jupiters. The orderly alignment seen in the Kepler-30 system suggests that high obliquities are confined to systems that experienced disruptive dynamical interactions. Should this be corroborated by observations of other coplanar multi-planet systems, then star-disk misalignments would be ruled out as the explanation for the high obliquities of hot Jupiters, and dynamical interactions would be implicated as the origin of hot Jupiters. PMID- 22837000 TI - The 'Higgs' amplitude mode at the two-dimensional superfluid/Mott insulator transition. AB - Spontaneous symmetry breaking plays a key role in our understanding of nature. In relativistic quantum field theory, a broken continuous symmetry leads to the emergence of two types of fundamental excitation: massless Nambu-Goldstone modes and a massive 'Higgs' amplitude mode. An excitation of Higgs type is of crucial importance in the standard model of elementary particle physics, and also appears as a fundamental collective mode in quantum many-body systems. Whether such a mode exists in low-dimensional systems as a resonance-like feature, or whether it becomes overdamped through coupling to Nambu-Goldstone modes, has been a subject of debate. Here we experimentally find and study a Higgs mode in a two dimensional neutral superfluid close to a quantum phase transition to a Mott insulating phase. We unambiguously identify the mode by observing the expected reduction in frequency of the onset of spectral response when approaching the transition point. In this regime, our system is described by an effective relativistic field theory with a two-component quantum field, which constitutes a minimal model for spontaneous breaking of a continuous symmetry. Additionally, all microscopic parameters of our system are known from first principles and the resolution of our measurement allows us to detect excited states of the many-body system at the level of individual quasiparticles. This allows for an in-depth study of Higgs excitations that also addresses the consequences of the reduced dimensionality and confinement of the system. Our work constitutes a step towards exploring emergent relativistic models with ultracold atomic gases. PMID- 22837001 TI - Collective bulk carrier delocalization driven by electrostatic surface charge accumulation. AB - In the classic transistor, the number of electric charge carriers--and thus the electrical conductivity--is precisely controlled by external voltage, providing electrical switching capability. This simple but powerful feature is essential for information processing technology, and also provides a platform for fundamental physics research. As the number of charges essentially determines the electronic phase of a condensed-matter system, transistor operation enables reversible and isothermal changes in the system's state, as successfully demonstrated in electric-field-induced ferromagnetism and superconductivity. However, this effect of the electric field is limited to a channel thickness of nanometres or less, owing to the presence of Thomas-Fermi screening. Here we show that this conventional picture does not apply to a class of materials characterized by inherent collective interactions between electrons and the crystal lattice. We prepared metal-insulator-semiconductor field-effect transistors based on vanadium dioxide--a strongly correlated material with a thermally driven, first-order metal-insulator transition well above room temperature--and found that electrostatic charging at a surface drives all the previously localized charge carriers in the bulk material into motion, leading to the emergence of a three-dimensional metallic ground state. This non-local switching of the electronic state is achieved by applying a voltage of only about one volt. In a voltage-sweep measurement, the first-order nature of the metal insulator transition provides a non-volatile memory effect, which is operable at room temperature. Our results demonstrate a conceptually new field-effect device, extending the concept of electric-field control to macroscopic phase control. PMID- 22837002 TI - Inland thinning of West Antarctic Ice Sheet steered along subglacial rifts. AB - Current ice loss from the West Antarctic Ice Sheet (WAIS) accounts for about ten per cent of observed global sea-level rise. Losses are dominated by dynamic thinning, in which forcings by oceanic or atmospheric perturbations to the ice margin lead to an accelerated thinning of ice along the coastline. Although central to improving projections of future ice-sheet contributions to global sea level rise, the incorporation of dynamic thinning into models has been restricted by lack of knowledge of basal topography and subglacial geology so that the rate and ultimate extent of potential WAIS retreat remains difficult to quantify. Here we report the discovery of a subglacial basin under Ferrigno Ice Stream up to 1.5 kilometres deep that connects the ice-sheet interior to the Bellingshausen Sea margin, and whose existence profoundly affects ice loss. We use a suite of ice penetrating radar, magnetic and gravity measurements to propose a rift origin for the basin in association with the wider development of the West Antarctic rift system. The Ferrigno rift, overdeepened by glacial erosion, is a conduit which fed a major palaeo-ice stream on the adjacent continental shelf during glacial maxima. The palaeo-ice stream, in turn, eroded the 'Belgica' trough, which today routes warm open-ocean water back to the ice front to reinforce dynamic thinning. We show that dynamic thinning from both the Bellingshausen and Amundsen Sea region is being steered back to the ice-sheet interior along rift basins. We conclude that rift basins that cut across the WAIS margin can rapidly transmit coastally perturbed change inland, thereby promoting ice-sheet instability. PMID- 22837003 TI - ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. AB - Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea. PMID- 22837006 TI - Atmospheric oxygenation and volcanism. PMID- 22837004 TI - Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. AB - Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly. PMID- 22837008 TI - The vascular disrupting agent STA-9584 exhibits potent antitumor activity by selectively targeting microvasculature at both the center and periphery of tumors. AB - Vascular disrupting agents (VDAs) are an emerging class of therapeutics targeting the existing vascular network of solid tumors. However, their clinical progression has been hampered because of limited single-agent efficacy, primarily caused by the persistence of surviving cells at the well perfused "viable rim" of tumors, which allows rapid tumor regrowth to occur. In addition, off-target adverse events, including cardiovascular toxicities, underscore a need for compounds with improved safety profiles. Here, we characterize the mechanism of action, antitumor efficacy, and cardiovascular safety profile of (S)-2-amino-N-(2 methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamide hydrochloride (STA-9584), a novel tubulin-binding VDA. In vitro, 2-methoxy-5-(5 (3,4,5-trimethoxyphenyl)isoxazol-4-yl)aniline (STA-9122) (active metabolite of STA-9584) displayed increased potency relative to other tubulin-binding agents and was highly cytotoxic to tumor cells. STA-9584 induced significant tumor regressions in prostate and breast xenograft models in vivo and, in an aggressive syngeneic model, demonstrated superior tumor growth inhibition and a positive therapeutic index relative to combretastatin A-4 phosphate (CA4P). It is noteworthy that histological analysis revealed that STA-9584 disrupted microvasculature at both the center and periphery of tumors. Compared with CA4P, STA-9584 induced a 73% increase in central necrotic area, 77% decrease in microvasculature, and 7-fold increase in tumor cell apoptosis in the remaining viable rim 24 h post-treatment. Ultrasound imaging confirmed that STA-9584 rapidly and efficiently blocked blood flow in highly perfused tumor regions. Moreover, cardiovascular effects were evaluated in the Langendorff assay and telemetered dogs, and cardiovascular toxicity was not predicted to be dose limiting. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new therapeutic VDA candidate. PMID- 22837009 TI - Identification of the plant steroid alpha-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties. AB - The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic extract produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compounds isolated from the dichloromethane fraction, only alpha-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, alpha-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. alpha-Spinasterol was able to displace [3H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and alpha-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mechanical threshold of naive mice. The treatment with alpha-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addition, alpha-spinasterol and the dichloromethane fraction reduced the edema, mechanical, and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and alpha spinasterol did not affect body temperature or locomotor activity. In conclusion, alpha-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect. PMID- 22837011 TI - The effects of direct thrombin inhibition with dabigatran on plaque formation and endothelial function in apolipoprotein E-deficient mice. AB - The recently developed oral anticoagulant dabigatran (Dabi) etexilate directly inhibits thrombin after activation by plasma esterases to dabigatran. Thrombin is involved in the pathogenesis of atherosclerosis. We investigated the effects of direct thrombin inhibition on atherosclerosis and endothelial function in a hypercholesterolemic mouse model with accelerated atherosclerosis {[apolipoprotein E-deficient (ApoE(-/-)] mice}. ApoE(-/-) mice were treated with a cholesterol-rich diet for 12 weeks and either dabigatran etexilate (900 mg/kg body weight) or vehicle. Wild-type (C57/B6) mice served as control. Endothelial function was assessed with carbachol (endothelium dependent) by using glyceroltrinitrate (endothelium independent) as control in aortic rings. Atherosclerotic lesion formation was evaluated with Oil Red staining, and vascular collagen content was determined by Sirius Red staining. Reactive oxygen species (ROS) production was determined by semiquantitative immunohistochemical staining. Measurement of dabigatran plasma levels (622.3+/-169 ng/ml) and a performed coagulation test (diluted thrombin time) revealed a relevant anticoagulatory concentration. Dabigatran etexilate attenuated increased atherosclerotic plaque formation [ApoE(-/-) Dabi: 16.1+/-3.8% of ApoE(-/-) control; p<0.001], decreased collagen content [ApoE(-/-) Dabi: 49.1+/-10% of ApoE(-/-) control; p=0.01], and ROS production in dihydroethidium staining [ApoE( /-) Dabi: 46.3+/-5.4% of ApoE(-/-) control; p=0.005] in parallel to an improvement of endothelial function [ApoE(-/-) control 42.6+/-2.7 versus ApoE(-/ ) Dabi 62.9+/-3.3% of phenylephrine-induced contraction; p=0.001] at 100 MUmol carbachol. These data suggest that direct thrombin inhibition in a relevant dosage improved endothelial function and reduced atherosclerotic lesion size, collagen content, and oxidative stress in hypercholesterolemic atherosclerosis. Interference with the coagulation system might provide a therapeutic target to modify atherosclerotic disease progression. PMID- 22837013 TI - Dielectric spectroscopy for non-invasive monitoring of epithelial cell differentiation within three-dimensional scaffolds. AB - In this study, we introduce a cellular differentiation cellular model based on dielectric spectroscopy that characterizes epithelial differentiation processes. Non-invasive cellular monitoring was achieved within a three-dimensional microenvironment consisting of a cell-containing collagen I gel seeded onto microfabricated scaffolds. In this proof-of-concept investigation, Madin-Darby canine kidney cells were cultured within microfabricated, geometrically controlled scaffolds and allowed us to differentiate to hollow cyst-like structures. This transformation within the three-dimensional environment is monitored and characterized through dielectric spectroscopy while maintaining cell culture in vitro. PMID- 22837010 TI - Identification of granulocyte colony-stimulating factor and interleukin-6 as candidate biomarkers of CBLB502 efficacy as a medical radiation countermeasure. AB - Given an ever-increasing risk of nuclear and radiological emergencies, there is a critical need for development of medical radiation countermeasures (MRCs) that are safe, easily administered, and effective in preventing and/or mitigating the potentially lethal tissue damage caused by acute high-dose radiation exposure. Because the efficacy of MRCs for this indication cannot be ethically tested in humans, development of such drugs is guided by the Food and Drug Administration's Animal Efficacy Rule. According to this rule, human efficacious doses can be projected from experimentally established animal efficacious doses based on the equivalence of the drug's effects on efficacy biomarkers in the respective species. Therefore, identification of efficacy biomarkers is critically important for drug development under the Animal Efficacy Rule. CBLB502 is a truncated derivative of the Salmonella flagellin protein that acts by triggering Toll-like receptor 5 (TLR5) signaling and is currently under development as a MRC. Here, we report identification of two cytokines, granulocyte colony-stimulating factor (G CSF) and interleukin-6 (IL-6), as candidate biomarkers of CBLB502's radioprotective/mitigative efficacy. Induction of both G-CSF and IL-6 by CBLB502 1) is strictly TLR5-dependent, 2) occurs in a CBLB502 dose-dependent manner within its efficacious dose range in both nonirradiated and irradiated mammals, including nonhuman primates, and 3) is critically important for the ability of CBLB502 to rescue irradiated animals from death. After evaluation of CBLB502 effects on G-CSF and IL-6 levels in humans, these biomarkers will be useful for accurate prediction of human efficacious CBLB502 doses, a key step in the development of this prospective radiation countermeasure. PMID- 22837012 TI - Melatonin down-regulates volume-sensitive chloride channels in fibroblasts. AB - Melatonin has been reported to present with vasorelaxant and anti-fibrotic properties. We hypothesized that melatonin may down-regulate volume-regulated anion channels (VRAC) in fibroblasts to limit their migration and proliferation. While acute exposure of L929 fibroblasts to melatonin did not result in a significant decrease in VRAC current, pretreatment with 100 MUM melatonin for 1 h decreased swelling-dependent activation of anion currents by 83% as measured by whole-cell perforated patch-clamp technique. This down-regulation of VRAC currents was dose-dependent with a half-maximal inhibition of 3.02 +/- 0.48 MUM. Overnight treatment of cells with 100 nM melatonin had the same inhibitory potency as a 1-h treatment with 100 MUM. A similar down-regulatory effect of melatonin on VRAC was observed in primary rat lung fibroblasts. The effect of melatonin was prevented by luzindole and K185 that suggests implication of MT2 receptor. GF109203X, a protein kinase C inhibitor, blocked melatonin's action on VRAC, indicating that MT2 receptor activation results in stimulation of PKC. Consequently, melatonin inhibited regulatory volume decrease following hypotonic swelling of cells. Melatonin also decreased the migration of L929 fibroblasts through the same pathways that blocked VRAC. There was no significant inhibition of cell proliferation. Our study suggests that the attenuation of fibrosis and vascular remodeling by melatonin seen in animal models of hypertension and pulmonary fibrosis might be, in part, related to blunted fibroblast migration possibly through protein kinase C-mediated decrease in chloride channel activity. PMID- 22837014 TI - Editorial on special issue "lifestyle and ageing in muscle disease". PMID- 22837015 TI - Mapping differentiation kinetics in the mouse retina reveals an extensive period of cell cycle protein expression in post-mitotic newborn neurons. AB - BACKGROUND: Knowledge of gene expression kinetics around neuronal cell birth is required to dissect mechanisms underlying progenitor fate. Here, we timed cell cycle and neuronal protein silencing/induction during cell birth in the developing murine retina. RESULTS: The pan-cell cycle markers Pcna and Mcm6 were present in the post-mitotic ganglion cell layer. Although confined to the neuroblastic layer (NBL), 6-7% of Ki67(+) cells lacked six progenitor/cell cycle markers, and expressed neuronal markers. To define protein extinction/induction timing, we defined G2/M length throughout retinogenesis, which was typically 1-2 h, but <10% cells took double this time. BrdU-chase analyses revealed that at E12.5, Tubb3 (Tuj1) appeared at M-phase, followed by Calb2 and Dcx at ~2 h, Elavl2/3/4 at ~4 h, and Map2 at ~6 h after cell birth, and these times extended with embryonic age. Strikingly, Ki67 was not extinguished until up to a day after cell cycle exit, coinciding with exit from the NBL and induction of late markers such as Map1b/Uchl1/Rbfox3. CONCLUSIONS: A minor population of progenitors transits slowly through G2/M and, most importantly, some cell cycle proteins are retained for an unexpectedly long period in post-mitotic neurons. The high resolution map of cell birth kinetics reported here provides a framework to better define mechanisms that regulate neurogenesis. PMID- 22837016 TI - Molecular mapping of soybean rust resistance in soybean accession PI 561356 and SNP haplotype analysis of the Rpp1 region in diverse germplasm. AB - Soybean rust (SBR), caused by Phakopsora pachyrhizi Sydow, is one of the most economically important and destructive diseases of soybean [Glycine max (L.) Merr.] and the discovery of novel SBR resistance genes is needed because of virulence diversity in the pathogen. The objectives of this research were to map SBR resistance in plant introduction (PI) 561356 and to identify single nucleotide polymorphism (SNP) haplotypes within the region on soybean chromosome 18 where the SBR resistance gene Rpp1 maps. One-hundred F(2:3) lines derived from a cross between PI 561356 and the susceptible experimental line LD02-4485 were genotyped with genetic markers and phenotyped for resistance to P. pachyrhizi isolate ZM01-1. The segregation ratio of reddish brown versus tan lesion type in the population supported that resistance was controlled by a single dominant gene. The gene was mapped to a 1-cM region on soybean chromosome 18 corresponding to the same interval as Rpp1. A haplotype analysis of diverse germplasm across a 213-kb interval that included Rpp1 revealed 21 distinct haplotypes of which 4 were present among 5 SBR resistance sources that have a resistance gene in the Rpp1 region. Four major North American soybean ancestors belong to the same SNP haplotype as PI 561356 and seven belong to the same haplotype as PI 594538A, the Rpp1-b source. There were no North American soybean ancestors belonging to the SNP haplotypes found in PI 200492, the source of Rpp1, or PI 587886 and PI 587880A, additional sources with SBR resistance mapping to the Rpp1 region. PMID- 22837017 TI - Improvement in insulin resistance after short-term treatment with abatacept: case report and short review. AB - Insulin resistance, a key feature of type 2 diabetes, is an independent risk factor for developing cardiovascular diseases (CVD), and represents the core of metabolic syndrome (MetS). Actually, an intriguing correlation between MetS and inflammation associated with rheumatoid arthritis (RA) is largely accepted but not yet completely clarified in detail. Recently, the therapeutic arsenal against RA has been enriched of abatacept, a fusion protein (CTLA4 immunoglobulin) designed to modulate the T cell co-stimulatory signal mediated through the CD28 CD80/86 pathway. Here, we report a case of dramatic improvement in insulin resistance, estimated with the surrogate measure HOMA-IR, after treatment with abatacept. Lastly, we shortly review the preclinical evidences supporting a possible role of T lymphocytes in rheumatoid arthritis-associated insulin resistance and how abatacept could improve glucose metabolism by suppressing adipose tissue infiltrating cells. PMID- 22837018 TI - Periodic fever as the manifestation of primary Sjogren's syndrome: a case report and literature review. AB - A 56-year-old male had periodic fever for 5 years and suffered from auditory hallucination and hearing impairment for 3 years. Xerostomia, xerophthalmia, elevated anti-SSA/Ro tilter, positive Schirmer's test, and lymphocyte infiltrate of mucoserous gland in lip biopsy of this case confirmed the diagnosis of primary Sjogren's syndrome (pSS). We review literature for fever and neuropsychiatric involvement in pSS case series. Though fever is present in 6-41 % pSS cases, periodic fever has not been reported. Auditory hallucination was rare in cases with pSS. The literature review alerts clinicians that fever and neurological manifestations were not uncommon in pSS cases. PMID- 22837019 TI - Noninvasive mapping of water diffusional exchange in the human brain using filter exchange imaging. AB - We present the first in vivo application of the filter-exchange imaging protocol for diffusion MRI. The protocol allows noninvasive mapping of the rate of water exchange between microenvironments with different self-diffusivities, such as the intracellular and extracellular spaces in tissue. Since diffusional water exchange across the cell membrane is a fundamental process in human physiology and pathophysiology, clinically feasible and noninvasive imaging of the water exchange rate would offer new means to diagnose disease and monitor treatment response in conditions such as cancer and edema. The in vivo use of filter exchange imaging was demonstrated by studying the brain of five healthy volunteers and one intracranial tumor (meningioma). Apparent exchange rates in white matter range from 0.8+/-0.08 s(-1) in the internal capsule, to 1.6+/-0.11 s(-1) for frontal white matter, indicating that low values are associated with high myelination. Solid tumor displayed values of up to 2.9+/-0.8 s(-1). In white matter, the apparent exchange rate values suggest intra-axonal exchange times in the order of seconds, confirming the slow exchange assumption in the analysis of diffusion MRI data. We propose that filter-exchange imaging could be used clinically to map the water exchange rate in pathologies. Filter-exchange imaging may also be valuable for evaluating novel therapies targeting the function of aquaporins. PMID- 22837020 TI - Natural Bond Critical Point analysis: quantitative relationships between natural bond orbital-based and QTAIM-based topological descriptors of chemical bonding. AB - We have developed a "Natural Bond Critical Point" (NBCP) module for the natural bond orbital (NBO) program that allows mutual analysis of NBO-based versus Bader type quantum theory of atoms in molecules (QTAIM) topological descriptors of chemical bonding interactions. Conventional QTAIM bond path and bond critical point (BCP) descriptors deduced from total electron density rho(r) can thereby be compared with analogous "natural" (NBCP) descriptors for idealized densities rho(NAIM)(r) composed solely from NBO-based "natural atoms in molecules" (NAIM) at the terminal nuclei. Standard rho(r(BCP)) and [nabla](2)rho(r(BCP)) descriptors can also be decomposed into unique contributions from individual NBOs or other localized, semilocalized, or delocalized orbital components. These results allow one to recognize many relationships between QTAIM and NBO analyses, showing why close correlations are often found between NBO-based versus rho(r(BCP))-based characterizations of chemical bonding interactions, despite strongly divergent conceptions of "the atom in the molecule." PMID- 22837021 TI - Anodic electrogenerated chemiluminescence of quantum dots: size and stabilizer matter. AB - The electrogenerated chemiluminescence (ECL) of semiconductor quantum dots (QDs) is generally believed to be independent of particle sizes or the capping agents used. Herein, we demonstrate that CdTe QDs with different sizes and stabilizers evidently exhibit different ECL behavior in aqueous solution. The ECL of CdTe QDs stabilized by 3-mercaptopropionic acid (MPA) displays two waves at potentials of about +1.17 V and +1.74 V vs. Ag/AgCl, respectively. ECL spectra confirm that the ECL of QDs is attributed to their band gap luminescence, in which the peak positions are changed with QD sizes. The ECL mechanism of CdTe QDs involves superoxide radical generation by reduction of dissolved oxygen at lower potential or water splitting at higher potential. Direct evidence for superoxide radicals in this medium was obtained via electron spin resonance (ESR) experiments. In comparison, the 2-mercaptoethylamine (MEA)-capped CdTe QDs did not exhibit any ECL in air-saturated pH 7.4 PBS. Both ESR and X-ray photon spectroscopy (XPS) experiments revealed that amine groups in MEA-capped QDs were responsible for the absence of ECL. The reaction of an amine group with a superoxide radical leads to the quenching of ECL. The ECL quenching of MPA-capped CdTe QDs was further used to detect melamine. Under the optimum conditions, the inhibited ECL was linear with the logarithm of concentration of melamine within the concentration range of 10-9 to 10-5 M and the detection limit was found to be 6.74 * 10-10 M, which was 100-100,000 times lower than that of the most previous methods. PMID- 22837023 TI - The influence of surgery on quality of life in patients with intracranial meningiomas: a prospective study. AB - Meningiomas may influence both survival and neurological functions. Studies assessing the impact of surgery on health-related quality of life (HRQL) remain absent. In this prospective study we aimed to describe HRQL dynamics before and after surgery in patients with meningiomas. HRQL assessments were performed using EuroQol-5D (EQ-5D), a generic HRQL instrument. All adult patients with suspected intracranial meningioma from 2007 through 2011 were eligible for inclusion, and 54 patients were included after informed consent. All patients received a histopathological diagnosis of meningioma. The average preoperative EQ-5D index value (+/-SD) was 0.69 +/- 0.26. The mean improvement 6 weeks after surgery was 0.06 (95 % CI, -0.03 to 0.16; p = 0.161) and the mean long term improvement was 0.09 (95 % CI, 0.00-0.17; p = 0.040). Surgery reduced pain/discomfort and anxiety/depression and improved the capability of performing usual activities. Clinically significant improvement at long-term assessment was noted in 25 patients (49 %) while a significant deterioration was reported in 10 patients (20 %). Patients who reported postoperative worsening of HRQL were also reporting better preoperative scores, suggesting a possible ceiling effect of EQ-5D in some of these patients. In our patients a modest average improvement in HRQL was seen after surgery for meningioma. About half of the patients reported a clinical important improvement at the late follow-up assessment. This improvement was mainly observed in the domains usual activities, pain/discomfort and anxiety/depression. However, one in five patients fared worse on late follow-up assessment, a figure of particular importance when treating asymptomatic meningiomas. PMID- 22837024 TI - Yield of training exchanges between Europe and Sub-Saharan Africa. AB - Opportunities that allow neurologists-in-training from Western Europe and Sub Saharan Africa to benefit from exchanges between their respective neurological departments are rare. In a pilot exchange program, we compare the patterns of neurological diseases encountered in neurological wards of public hospitals in Brussels and Yaounde to underline educational benefits. For 5 months the age, sex, mortality, HIV cases and clinical characteristics of admitted patients were prospectively analyzed. Eighty Cameroonian and 105 Belgian patients were classified into the following neurological entities: infectious, vascular, immune related, epileptic, degenerative, neoplastic, psychogenic and movement disorders. Means and proportions were compared using Student's test and Fisher's exact test, respectively. Patients were younger in Yaounde (mean age 45.3 vs. 54.0 years, p = 0.002), but died four times more (23.75 vs. 4.75 % of admissions, p < 0.001). HIV proportion was 43.75 % in Yaounde and nil in Brussels. Infectious complications were responsible for 100 % of deaths in HIV-positive patients against 44 % in HIV negative patients (p = 0.0108). The proportions of vascular, neoplastic and movement disorders were comparable. Neurological complications of infections occurred ten times more in Yaounde (69 vs. 6.7 %, p < 0.0001). Multiple sclerosis accounted for 11.4 % of admissions in Brussels but other immune-related diseases were more frequent in Yaounde (8.75 vs. 2 %, p = 0.04). Epileptic, degenerative and psychogenic diseases were more frequent in Brussels: 38.1 versus 12.5 % (p < 0.001), 16.2 versus 5 % (p < 0.0194) and 3.75 versus 14.3 % (p < 0.0224), respectively. Exchanges between Western Europe and Sub-Saharan neurological wards could offer neurologists-in-training firsthand experience with diseases seldom met; otherwise, an understanding of different healthcare systems and a better understanding of the concept of neurology as a public health challenge. PMID- 22837025 TI - Lacunar thalamic infarction with isolated dysesthesia in contralateral fingers. PMID- 22837026 TI - Chronic low back pain caused by osteopetrosis type 2. AB - Causes for low back pain usually involve damages in bone, muscle or nerve tissues of spine. Hereditary sclerosing bone disorders are rarely presented with low back pain. This report is intended to remind that osteopetrosis type 2, which is a rare disorder in differential diagnosis of low back pain, should be taken into consideration. PMID- 22837027 TI - Head-to-head or indirect comparisons of the novel oral anticoagulants in atrial fibrillation: what's next? PMID- 22837028 TI - In vivo MRI visualization of different cell populations labeled with PARACEST agents. AB - Conventional T1- or T2-MRI contrast agents do not allow to track the distribution of different cell populations simultaneously because the effects of relaxation enhancers are additive. Herein, it is shown that paramagnetic chemical exchange saturation transfer agents offer the opportunity to visualize different cell populations in vitro and in vivo by 1H-MRI. Yb- and Eu-HPDO3A complexes have been used to label murine macrophages (J774.A1) and melanoma cells (B16-F10), respectively. By selective irradiation of the highly-shifted OH resonances of the two chemical exchange saturation transfer agents, it has been shown that tracking of the two cell types is possible. These PARAmagnetic Chemical Exchange Saturation Transfer agents have a tremendous potential for clinical translation as they share the same stability and in vivo pharmacokinetic properties of Gd HPDO3A (ProHance(r)), which is a widely used clinically approved MRI agent. PMID- 22837029 TI - Natural bond orbital analysis: a critical overview of relationships to alternative bonding perspectives. AB - We sketch the basic principles of natural bond orbital (NBO) theory, including critical discussion of its relationship to alternative bonding concepts and selected illustrations of its application to a broad spectrum of chemical bonding motifs. Particular emphasis is placed on the close NBO connections to prequantal bonding, and electromerism concepts, as well as the deep roots in quantal eigenvalue, superposition, and Pauli exclusion concepts that are manifested in many aspects of NBO donor-acceptor analysis. With respect to leading alternative perspectives, we identify similarities and differences that distinguish NBO theory from the corresponding precepts of valence bond theory, molecular orbital theory, and Bader's quantum theory of atoms in molecules, with critical discussion of the assumptions underlying characteristic differences in each case. PMID- 22837030 TI - Focus on neuro-immune interactions. PMID- 22837031 TI - Navigating uncertain waters. AB - Mice lacking NMDA receptors in the dentate gyrus and CA1 subfields of the hippocampus form spatial memories just as well as wild-type mice, but they disregard them when confounded by ambiguous local cues. Hippocampal NMDA receptors may influence spatial memory more subtly than previously thought. PMID- 22837032 TI - When the electricity (and the lights) go out: transient changes in excitability. AB - Natural or artificially induced electrical activity changes can alter ion balance so as to briefly influence firing. An optogenetics study delineates one mechanism: Cl- shifts causing seconds-long excitability changes after silencing. PMID- 22837033 TI - New game for hunger neurons. AB - Hypothalamic neurons that express agouti-related protein have been thought to regulate appetite by counteracting the melanocortin signaling pathway. Evidence now indicates that these neurons can also modulate dopamine signaling. PMID- 22837034 TI - DNA methylation in cognition comes of age. AB - A study reveals that aged mice have decreased hippocampal expression of the DNA methyltransferase Dnmt3a2; re-expression in aged mice reverses memory deficits, and knockdown in young mice impairs memory formation. PMID- 22837035 TI - Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. AB - The peripheral nervous and immune systems are traditionally thought of as serving separate functions. The line between them is, however, becoming increasingly blurred by new insights into neurogenic inflammation. Nociceptor neurons possess many of the same molecular recognition pathways for danger as immune cells, and, in response to danger, the peripheral nervous system directly communicates with the immune system, forming an integrated protective mechanism. The dense innervation network of sensory and autonomic fibers in peripheral tissues and high speed of neural transduction allows rapid local and systemic neurogenic modulation of immunity. Peripheral neurons also seem to contribute to immune dysfunction in autoimmune and allergic diseases. Therefore, understanding the coordinated interaction of peripheral neurons with immune cells may advance therapeutic approaches to increase host defense and suppress immunopathology. PMID- 22837036 TI - P2X4R+ microglia drive neuropathic pain. AB - Neuropathic pain, the most debilitating of all clinical pain syndromes, may be a consequence of trauma, infection or pathology from diseases that affect peripheral nerves. Here we provide a framework for understanding the spinal mechanisms of neuropathic pain as distinct from those of acute pain or inflammatory pain. Recent work suggests that a specific microglia response phenotype characterized by de novo expression of the purinergic receptor P2X4 is critical for the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Stimulating P2X4 receptors initiates a core pain signaling pathway mediated by release of brain-derived neurotrophic factor, which produces a disinhibitory increase in intracellular chloride in nociceptive (pain transmitting) neurons in the spinal dorsal horn. The changes caused by signaling from P2X4R(+) microglia to nociceptive transmission neurons may account for the main symptoms of neuropathic pain in humans, and they point to specific interventions to alleviate this debilitating condition. PMID- 22837037 TI - Animal models of multiple sclerosis: the good, the bad and the bottom line. AB - Multiple sclerosis (MS) is a spontaneous, acquired, inflammatory demyelinating disease of the human CNS. Because it involves a complex interaction between two of the most intricate biological systems, immune system and CNS, animal modeling has been critical for addressing MS pathogenesis. MS models were originally developed serendipitously more than 75 years ago. Immune-mediated, toxic, viral and genetic models of demyelination are now used to understand the manifold aspects of MS. MS treatments evolved in part from animal model research, and further progress is envisaged in large part because these systems have been continually refined and their use focused on questions whose relevance was established by studying the human disease. PMID- 22837038 TI - Cross-talk between neural stem cells and immune cells: the key to better brain repair? AB - Systemic or intracerebral delivery of neural stem and progenitor cells (NSPCs) and activation of endogenous NSPCs hold much promise as potential treatments for diseases in the human CNS. Recent studies have shed new light on the interaction between the NSPCs and cells belonging to the innate and adaptive arms of the immune system. According to these studies, the immune cells can be both beneficial and detrimental for cell genesis from grafted and endogenous NSPCs in the CNS, and the NSPCs exert their beneficial effects not only by cell replacement but also by immunomodulation and trophic support. The cross-talk between immune cells and NSPCs and their progeny seems to determine both the efficacy of endogenous regenerative responses and the mechanism of action as well as the fate and functional integration of grafted NSPCs. Better understanding of the dialog between NSPCs and innate and adaptive immune cells is crucial for further development of effective strategies for CNS repair. PMID- 22837039 TI - Neural circuitry engaged by prostaglandins during the sickness syndrome. AB - During illnesses caused by infectious disease or other sources of inflammation, a suite of brain-mediated responses called the sickness syndrome occurs, which includes fever, anorexia, sleepiness, hyperalgesia and elevated corticosteroid secretion. Much of the sickness syndrome is mediated by prostaglandins acting on the brain and can be prevented by nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen, that block prostaglandin synthesis. By examining which prostaglandins are produced at which sites and how they interact with the nervous system, researchers have identified specific neural circuits that underlie the sickness syndrome. PMID- 22837041 TI - Snowballing radical generation leads to ultrahigh molecular weight polymers. AB - Styrene is the classical monomer obeying zero-one kinetics in radical emulsion polymerization. Accordingly, particles that are less than 100 nm in diameter contain either one or no growing radical(s). We describe a unique photoinitiated polymerization reaction accelerated by snowballing radical generation in a continuous flow reactor. Even in comparison to classical emulsion polymerization, these unprecedented snowballing reactions are rapid and high-yielding, with each particle simultaneously containing more than one growing radical. This is a consequence of photoinitiator incorporation into the nascent polymer backbone and repeated radical generation upon photo-irradiation. PMID- 22837040 TI - Immune surveillance in the central nervous system. AB - The CNS, which consists of the brain and spinal cord, is continuously monitored by resident microglia and blood-borne immune cells such as macrophages, dendritic cells and T cells to detect for damaging agents that would disrupt homeostasis and optimal functioning of these vital organs. Further, the CNS must balance between vigilantly detecting for potentially harmful factors and resolving any immunological responses that in themselves can create damage if left unabated. We discuss the physiological roles of the immune sentinels that patrol the CNS, the molecular markers that underlie their surveillance duties, and the consequences of interrupting their functions following injury and infection by viruses such as JC virus, human immunodeficiency virus, herpes simplex virus and West Nile virus. PMID- 22837043 TI - Early stages of oxide growth in H-terminated silicon nanowires: determination of kinetic behavior and activation energy. AB - Silicon nanowires (Si NWs) terminated with hydrogen atoms exhibit higher activation energy under ambient conditions than equivalent planar Si(100). The kinetics of sub-oxide formation in hydrogen-terminated Si NWs derived from the complementary XPS surface analysis attribute this difference to the Si-Si backbond and Si-H bond propagation which controls the process at lower temperatures (T < 200 degrees C). At high temperatures (T>= 200 degrees C), the activation energy was similar due to self-retarded oxidation. This finding offers the understanding of early-stage oxide growth that affects the conductance of the near-gap channels leading towards more efficient Si NW electronic devices. PMID- 22837042 TI - Odontogenic myxoma with diffuse calcifications: a case report and review of the literature. AB - This is a case report of an unusual odontogenic myxoma with calcifications, one of three reported in the literature. It had a typical radiographic appearance although it presented in an older patient. The presence of osteo-cementum-like calcification raises other differential diagnoses but does not in and of itself mitigate the diagnosis. The patient has not shown recurrence 14 months after resection and 11 months after reconstruction and continues to be closely monitored. PMID- 22837044 TI - Flexible pyroelectric nanogenerators using a composite structure of lead-free KNbO(3) nanowires. AB - Pyroelectric nanogenerators fabricated using a lead-free KNbO(3) nanowire-PDMS polymer composite are reported for the first time. The voltage/current output of the nanogenerators can be controlled by electric fields and enhanced by increasing the rate of change in temperature. The fabricated nanogenerators can be used to harvest energy from sunlight illumination and have potential applications in self-powered nanodevices and nanosystems. PMID- 22837045 TI - Decision-making and associative color learning in harnessed bumblebees (Bombus impatiens). AB - In honeybees, the conditioning of the proboscis extension response (PER) has provided a powerful tool to explore the mechanisms underlying olfactory learning and memory. Unfortunately, PER conditioning does not work well for visual stimuli in intact honeybees, and performance is improved only after antennal amputation, thus limiting the analysis of visual learning and multimodal integration. Here, we study visual learning using the PER protocol in harnessed bumblebees, which exhibit high levels of odor learning under restrained conditions. We trained bumblebees in a differential task in which two colors differed in their rewarding values. We recorded learning performance as well as response latency and accuracy. Bumblebees rapidly learned the task and discriminated the colors within the first two trials. However, performance varied between combinations of colors and was higher when blue or violet was associated with a high reward. Overall, accuracy and speed were negatively associated, but both components increased during acquisition. We conclude that PER conditioning is a good tool to study visual learning, using Bombus impatiens as a model, opening new possibilities to analyze the proximate mechanisms of visual learning and memory, as well as the process of multimodal integration and decision-making. PMID- 22837046 TI - Magnetic resonance electrical impedance tomography (MREIT) based on the solution of the convection equation using FEM with stabilization. AB - Most algorithms for magnetic resonance electrical impedance tomography (MREIT) concentrate on reconstructing the internal conductivity distribution of a conductive object from the Laplacian of only one component of the magnetic flux density (?2B(z)) generated by the internal current distribution. In this study, a new algorithm is proposed to solve this ?2B(z)-based MREIT problem which is mathematically formulated as the steady-state scalar pure convection equation. Numerical methods developed for the solution of the more general convection diffusion equation are utilized. It is known that the solution of the pure convection equation is numerically unstable if sharp variations of the field variable (in this case conductivity) exist or if there are inconsistent boundary conditions. Various stabilization techniques, based on introducing artificial diffusion, are developed to handle such cases and in this study the streamline upwind Petrov-Galerkin (SUPG) stabilization method is incorporated into the Galerkin weighted residual finite element method (FEM) to numerically solve the MREIT problem. The proposed algorithm is tested with simulated and also experimental data from phantoms. Successful conductivity reconstructions are obtained by solving the related convection equation using the Galerkin weighted residual FEM when there are no sharp variations in the actual conductivity distribution. However, when there is noise in the magnetic flux density data or when there are sharp variations in conductivity, it is found that SUPG stabilization is beneficial. PMID- 22837047 TI - Crosstalk between JNK and NF-kappaB in the KDO2-mediated production of TNFalpha in HAPI cells. AB - Both nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases mediate production of proinflammatory cytokines in many types of cells. c-Jun N terminal kinases (JNK) is a key regulator of many cellular events including cell inflammation and/or programmed cell death (apoptosis). In addition to mediating immune and inflammatory responses, NF-kappaB transcription factors control cell survival. It is reported that activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers. It has been reported that NF-kappaB activation results in rapid inactivation of JNK in tumor necrosis factor alpha (TNFalpha)-treated murine embryonic fibroblasts. It is not clear about the relationship of JNK and NF-kappaB in the microglial cells induced by TLR4 activity. In the present study, we investigated the relationship of JNK and NF kappaB in the highly aggressively proliferating immortalized microglial cell line treated with KDO2 (a TLR4 agonist). KDO2 treatment significantly induced the phosphorylation of JNK and NF-kappaB, and released TNFalpha. Knockdown of TLR4 with TLR4 siRNA significantly reduced phosphorylation of JNK (pJNK), phosphorylation of NF-kappaB, and release of TNFalpha. Inhibition of JNK reduced the release of TNFalpha, but not phosphorylation of NF-kappaB. Unexpectedly, inhibition of NF-kappaB enhanced pJNK and the release of TNFalpha. These results showed that TNFalpha induced by KDO2 was JNK-dependent, and that NF-kappaB negatively modulated both pJNK and TNFalpha in the cultured microglial cell line. The current study may provide a new insight in the modulation of TNFalpha in the microglial cell line. PMID- 22837049 TI - Facile synthesis of red-emitting lysozyme-stabilized Ag nanoclusters. AB - A facile approach was developed to prepare positively charged and red-emitting lysozyme-stabilized Ag nanoclusters (Lys-AgNCs) using NaBH4 as a reducing agent at room temperature. The Lys-AgNCs can be applied in the highly selective detection of Hg2+. PMID- 22837048 TI - Participation of microRNA 124-CREB pathway: a parallel memory enhancing mechanism of standardised extract of Bacopa monniera (BESEB CDRI-08). AB - Bacosides, the effective component of standardised leaf extract of Bacopa monniera (BESEB CDRI-08) has been reported to have memory enhancing effect. Our previous reports suggested that BESEB CDRI-08 (BME) improves memory in postnatal rats by enhancing serotonin [5-hydroxytryptamine (5-HT)] metabolism, its transportation and subsequently activates 5-HT(3A) receptor during hippocampus dependent learning. In this study, we examine whether the up-regulated 5-HT(3A) receptor activity by BME modulate microRNA 124-CREB pathway to enhance synaptic plasticity. Wistar rat pups received single dose of vehicle solution (0.5 % gum acacia + 0.9 % saline)/BME (80 mg/kg)/mCPBG (10 mg/kg)/BME + mCPBG during the postnatal days (PND) 15-29. On PND 30, individuals were trained at brightness discrimination task and 24 h later, they were tested on the task. The BME treated group exhibited significantly lower percentage of errors during retention than acquisition. In addition, pre-miR-124 expression in hippocampus was significantly down-regulated in the BME and mCPBG + BME treated groups combined with a significant increase in the plasticity related genes, cAMP response element binding protein, its phosphorylation and postsynaptic density protein 95. Our results suggest that this may be one of the mechanisms of bacosides present in BME for the memory enhancement. PMID- 22837050 TI - Characterization and functional study of a cluster of four highly conserved orphan adhesion-GPCR in mouse. AB - BACKGROUND: Adhesion G protein-coupled receptors (aGPCR) constitute a structurally and functionally diverse class of seven-transmembrane receptor proteins. Although for some of the members important roles in immunology, neurology, as well as developmental biology have been suggested, most receptors have been poorly characterized. RESULTS: We have studied evolution, expression, and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115, and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using transcriptional profiling on wild-type and knockout/LacZ reporter knockin mice strains, we have obtained detailed expression maps that show ubiquitous expression of Gpr116, co expression of Gpr111 and Gpr115 in developing skin, and expression of Gpr110 in adult kidney. Loss of Gpr110, Gpr111, or Gpr115 function did not result in detectable defects, indicating that genes of this aGPCR group might function redundantly. CONCLUSIONS: The aGPCR cluster Gpr110, Gpr111, Gpr115, and Gpr116 developed from one common ancestor in vertebrates. Expression suggests a role in epithelia, and one can speculate about a possible redundant function of GPR111 and GPR115. PMID- 22837051 TI - Molecular characterization of the pentacyclic triterpenoid biosynthetic pathway in Catharanthus roseus. AB - Catharanthus roseus is an important medicinal plant and the sole commercial source of monoterpenoid indole alkaloids (MIA), anticancer compounds. Recently, triterpenoids like ursolic acid and oleanolic acid have also been found in considerable amounts in C. roseus leaf cuticular wax layer. These simple pentacyclic triterpenoids exhibit various pharmacological activities such as anti inflammatory, anti-tumor and anti-microbial properties. Using the EST collection from C. roseus leaf epidermome ( http://www.ncbi.nlm.nih.gov/dbEST ), we have successfully isolated a cDNA (CrAS) encoding 2,3-oxidosqualene cyclase (OSC) and a cDNA (CrAO) encoding amyrin C-28 oxidase from the leaves of C. roseus. The functions of CrAS and CrAO were analyzed in yeast (Saccharomyces cerevisiae) systems. CrAS was characterized as a novel multifunctional OSC producing alpha- and beta-amyrin in a ratio of 2.5:1, whereas CrAO was a multifunctional C-28 oxidase converting alpha-amyrin, beta-amyrin and lupeol to ursolic-, oleanolic- and betulinic acids, respectively, via a successive oxidation at the C-28 position of the substrates. In yeast co-expressing CrAO and CrAS, ursolic- and oleanolic acids were detected in the yeast cell extracts, while the yeast cells co-expressing CrAO and AtLUP1 from Arabidopsis thaliana produced betulinic acid. Both CrAS and CrAO genes show a high expression level in the leaf, which was consistent with the accumulation patterns of ursolic- and oleanolic acids in C. roseus. These results suggest that CrAS and CrAO are involved in the pentacyclic triterpene biosynthesis in C. roseus. PMID- 22837052 TI - Detoxification potential and expression analysis of eutypine reducing aldehyde reductase (VrALR) during progressive drought and recovery in Vigna radiata (L.) Wilczek roots. AB - Generation of reactive oxygen species (ROS) in plants is an inevitable consequence of adverse environmental cues and the ability to detoxify deleterious by-products of ROS-mediated oxidation reactions reflect an important defence strategy to combat abiotic stress. Here, we have cloned the eutypine reducing aldehyde reductase gene (VrALR) from Vigna radiata (L.) Wilczek roots. We have expressed and purified the VrALR protein and analyzed its enzyme kinetic parameters and catalytic efficiency with three different substrates to confirm its identity. The functional characterization of this enzyme was unravelled through heterologous expression of the gene in Escherichia coli BL21 and an oxidative stress-sensitive Saccharomyces cerevisiae mutant strain, W3O3-1-A. Finally, the endogenous VrALR enzyme activity and the mRNA expression patterns of the VrALR gene in the roots of V. radiata in response to progressive drought stress in vivo was studied to correlate the ROS-detoxifying role of this important enzyme under the influence of progressive drought stress. Our results, for the first time, demonstrate that eutypine reducing VrALR provides varying degree of stress tolerance in bacteria, yeast systems and also plays a promising protective role against oxidative stress in V. radiata roots during gradual water deprivation. The present study provides an unequivocal evidence to understand the crucial role of aldehyde reductase ROS-detoxifying system which is highly essential for developing stress tolerance in economically important crop plants. PMID- 22837053 TI - A novel class of sticky peel and light green mutations causes cuticle deficiency in leaves and fruits of tomato (Solanum lycopersicum). AB - The plant cuticle consists of aliphatic wax and cutin, and covers all the aerial tissues, conferring resistance to both biotic and abiotic stresses. In this study, we performed phenotypic characterizations of tomato mutants having both sticky peel (pe) and light green (lg) mutations. Our genetic analysis showed that these two mutations are tightly linked and behave like a monogenic recessive mutation. The double mutant (pe lg) produced glossy soft fruits with light green leaves, most likely due to defects in cuticle formation. Cytological analysis revealed that the thickness of the fruit cuticle layer was dramatically reduced in the pe lg mutant. The epidermal cells of the leaves were also deformed in the pe lg mutant, suggesting that leaf cuticle formation was also disrupted in the mutant. Consistent with this, transmission electron microscopic analysis showed that the electron density of the cuticle layer of the adaxial surface of the leaf was reduced in the pe lg mutant compared to WT, suggesting that there are changes in cuticle structure and/or composition in the pe lg mutant. Both physiological analysis to measure the rate of transpiration, and staining of the fruits and leaves with toluidine blue, revealed that water permeability was enhanced in the pe lg mutant, consistent with the reduced thickness of its cuticle layer. Taken together the preliminary analyses of the cuticle components, the PE LG is most likely involved in proper cuticle formation. PMID- 22837055 TI - A new approach to improve cycle performance of rechargeable lithium-sulfur batteries by inserting a free-standing MWCNT interlayer. AB - A conductive multiwalled carbon nanotube (MWCNT) interlayer acting as a pseudo upper current collector not only reduces the charge transfer resistance of sulfur cathodes significantly, but also localizes and retains the dissolved active material during cycling. PMID- 22837054 TI - Accelerated fluorine-19 MRI cell tracking using compressed sensing. AB - Cell tracking using perfluorocarbon labels and fluorine-19 (19F) MRI is a noninvasive approach to visualize and quantify cell populations in vivo. In this study, we investigated three-dimensional compressed sensing methods to accelerate 19F MRI data acquisition for cell tracking and evaluate the impact of acceleration on 19F signal quantification. We show that a greater than 8-fold reduction in imaging time was feasible without pronounced image degradation and with minimal impact on the image signal-to-noise ratio and 19F quantification accuracy. In 19F phantom studies, we show that apparent feature topology is maintained with compressed sensing reconstruction, and false positive signals do not appear in areas devoid of fluorine. We apply the three-dimensional compressed sensing 19F MRI methods to quantify the macrophage burden in a localized wounding inflammation mouse model in vivo; at 8-fold image acceleration, the 19F signal distribution was accurately reproduced, with no loss in signal-to-noise ratio. Our results demonstrate that three-dimensional compressed sensing methods have potential for advancing in vivo 19F cell tracking for a wide range of preclinical and translational applications. PMID- 22837056 TI - [Role and limitations of vertebroplasty and kyphoplasty in the management of spinal metastases]. AB - The spine is the most common site for skeletal metastases. Tumor-induced osteolysis may lead to pain, dysfunction and ultimately vertebral fracture. In some patients conventional surgery is not suitable because of the palliative therapy approach. Just for this patient population it was shown that cement augmentation of the vertebra is an effective therapy option and plays an important role. Nevertheless, cement augmentation of the vertebra has its limitations and should only be applied by appropriate indications. PMID- 22837057 TI - Severe EBV hepatitis treated with valganciclovir. AB - We describe the case of an 18-year-old immunocompetent male patient with severe hepatitis during primary Epstein-Barr virus infection, treated with oral valganciclovir. During the initial therapy with corticosteroids, the patient's clinical condition and liver function worsened, so we decided to add oral valganciclovir for its good bio-availability and previous encouraging experiences in different clinical settings, with rapid resolution of the symptoms. PMID- 22837058 TI - Intraindividual comparison of 1,470 nm diode laser versus carbon dioxide laser for tonsillotomy: a prospective, randomized, double blind, controlled feasibility trial. AB - INTRODUCTION: The need for reduction of post-tonsillectomy hemorrhage has led to promotion of tonsillotomy techniques for tonsil tissue reduction in obstructive tonsillar hypertrophy. This trial compares ablative tissue effects using 1,470 nm diode laser and carbon dioxide laser for tonsillotomy in an intraindividual design. METHODS: 21 children aged 3-13 years (mean age 6.3 years) underwent laser tonsillotomy for obstructive tonsillar hypertrophy in this double blind, prospective, randomized, clinical feasibility trial. In each of the blinded patients, tonsillotomy was performed using fiber guided 1,470 nm diode laser (contact mode, 15 W power) on the one side and carbon dioxide laser (12 W power) on the other side. An independent, blinded physician documented clinical presentation and patients' symptoms preoperatively and on Days 1, 3, 7, 14, and 21 post-operatively using standardized questionnaire including VAS for each side separately. RESULTS: The mean duration of operative treatment was 2.7 min using 1,470 nm laser and 4.9 min using carbon dioxide laser respectively. Intraoperative bleeding and the frequency of bipolar forceps use for intraoperative bleeding control was significantly less using 1,470 nm diode laser system. There was no difference in post-operative pain scores between the carbon dioxide laser treated and the 1,470 nm fiber guided diode laser treated side. No infections, hemorrhages or other complications occurred in the course of the 3 weeks post-operative period. CONCLUSIONS: A fiber-guided 1,470 nm diode laser system offers an efficient and safe method for tonsillotomy as treatment of obstructive tonsillar hypertrophy. Compared to our standard practice (carbon dioxide laser), 1,470 nm laser application provides comparable tissue ablation effects with less intraoperative bleeding and shorter operation time. PMID- 22837059 TI - Development and cross-species/genera transferability of microsatellite markers discovered using 454 genome sequencing in chokecherry (Prunus virginiana L.). AB - Chokecherry (Prunus virginiana L.) (2n = 4x = 32) is a unique Prunus species for both genetics and disease-resistance research due to its tetraploid nature and X disease resistance. However, no genetic and genomic information on chokecherry is available. A partial chokecherry genome was sequenced using Roche 454 sequencing technology. A total of 145,094 reads covering 4.8 Mbp of the chokecherry genome were generated and 15,113 contigs were assembled, of which 11,675 contigs were larger than 100 bp in size. A total of 481 SSR loci were identified from 234 (out of 11,675) contigs and 246 polymerase chain reaction (PCR) primer pairs were designed. Of 246 primers, 212 (86.2 %) effectively produced amplification from the genomic DNA of chokecherry. All 212 amplifiable chokecherry primers were used to amplify genomic DNA from 11 other rosaceous species (sour cherry, sweet cherry, black cherry, peach, apricot, plum, apple, crabapple, pear, juneberry, and raspberry). Thus, chokecherry SSR primers can be transferable across Prunus species and other rosaceous species. An average of 63.2 and 58.7 % of amplifiable chokecherry primers amplified DNA from cherry and other Prunus species, respectively, while 47.2 % of amplifiable chokecherry primers amplified DNA from other rosaceous species. Using random genome sequence data generated from next generation sequencing technology to identify microsatellite loci appears to be rapid and cost-efficient, particularly for species with no sequence information available. Sequence information and confirmed transferability of the identified chokecherry SSRs among species will be valuable for genetic research in Prunus and other rosaceous species. Key message A total of 246 SSR primers were identified from chokecherry genome sequences. Of which, 212 were confirmed amplifiable both in chokecherry and other 11 other rosaceous species. PMID- 22837060 TI - Subsistence and the evolution of religion. AB - We present a cross-cultural analysis showing that the presence of an active or moral High God in societies varies generally along a continuum from lesser to greater technological complexity and subsistence productivity. Foragers are least likely to have High Gods. Horticulturalists and agriculturalists are more likely. Pastoralists are most likely, though they are less easily positioned along the productivity continuum. We suggest that belief in moral High Gods was fostered by emerging leaders in societies dependent on resources that were difficult to manage and defend without group cooperation. These leaders used the concept of a supernatural moral enforcer to manipulate others into cooperating, which resulted in greater productivity. Reproductive success would accrue most to such leaders, but the average reproductive success of all individuals in the society would also increase with greater productivity. Supernatural enforcement of moral codes maintained social cohesion and allowed for further population growth, giving one society an advantage in competition with others. PMID- 22837061 TI - Isolation and differentiation properties of neural crest stem cells. AB - A wide array of neural and non-neural cell types arises from the neural crest during vertebrate embryogenesis. The neural crest forms transiently in the dorsal neural primordium to yield migratory cells that will invade nearly all tissues and later, differentiate into bones and cartilages, vascular smooth muscle cells, connective tissues, neurons and glial cells of the peripheral nervous system, endocrine cells, and melanocytes. Due to the amazingly diversified array of cell types they generate, the neural crest cells represent an attractive model in the stem cell field. We review here in vivo and in vitro studies of individual cells, which led to the discovery and characterization of neural crest progenitors endowed with multipotency and stem cell properties. We also present an overview of the diverse types, marker expression, and locations of the neural crest derived stem cells identified in the vertebrate body, with emphasis on those evidenced recently in mammalian adult tissues. PMID- 22837062 TI - Cooperative effects of two optical dipole antennas coupled to plasmonic Fabry Perot cavity. AB - We investigate the cooperative effects of two optical dipole antennas that are coupled to a finite Au nanowire acting as plasmonic Fabry-Perot (F-P) cavity. The coherent coupling between one single antenna and the F-P cavity can result in Fano resonance, and the coupling strength is antenna position dependent. For two antennas coupled to the F-P cavity, constructive or destructive interference between antennas could be achieved by adjusting their positions along the F-P cavity. Consequently, the Fano resonance will become stronger or weaker correspondingly. PMID- 22837064 TI - Emergent limited perioperative transesophageal echocardiography: should new guidelines exist for limited echocardiography training for anesthesiologists? AB - Bedside limited echocardiography, or focused cardiac ultrasound, continues to gain popularity in many emergency rooms, intensive care units, and operating rooms as a rapid method of assessing unstable patients. Effective monitoring of cardiovascular function in conditions like cardiac arrest or near-arrest is the crucial step to guide successful resuscitative efforts. Transesophageal echocardiography (TEE) has emerged as one of the preferred cardiac diagnostic and monitoring modalities in the intraoperative setting due to the fact that it is less invasive than many other monitors, is immediately accessible, and allows for continuous real-time monitoring of cardiac function. However, the minimum training requirements needed for the anesthesia provider to obtain the competency, knowledge, and skills for basic certification in perioperative TEE far exceed those developed for other medical specialties. We believe there is an urgent need to develop (1) practical guidelines for emergent perioperative TEE use for anesthesiologists and (2) a requisite educational curriculum to teach the basic skills necessary to aid in the diagnosis and treatment of cardiac arrest or near-arrest scenarios. The measures elucidated in this report summarize the efforts of the Department of Anesthesiology at the University of Florida in establishing the necessary steps to make this process not only practical, but accessible to all trainees.We hope that these collective efforts will provide more trainees the confidence in utilizing TEE to aid in establishing a diagnosis in critical situations. PMID- 22837063 TI - Intramolecular gas-phase reactions of synthetic nonheme oxoiron(IV) ions: proximity and spin-state reactivity rules. AB - The intramolecular gas-phase reactivity of four oxoiron(IV) complexes supported by tetradentate N(4) ligands (L) has been studied by means of tandem mass spectrometry measurements in which the gas-phase ions [Fe(IV)(O)(L)(OTf)](+) (OTf = trifluoromethanesulfonate) and [Fe(IV) (O)(L)](2+) were isolated and then allowed to fragment by collision-induced decay (CID). CID fragmentation of cations derived from oxoiron(IV) complexes of 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane (tmc) and N,N'-bis(2-pyridylmethyl)-1,5-diazacyclooctane (L(8)Py(2)) afforded the same predominant products irrespective of whether they were hexacoordinate or pentacoordinate. These products resulted from the loss of water by dehydrogenation of ethylene or propylene linkers on the tetradentate ligand. In contrast, CID fragmentation of ions derived from oxoiron(IV) complexes of linear tetradentate ligands N,N'-bis(2-pyridylmethyl)-1,2-diaminoethane (bpmen) and N,N'-bis(2-pyridylmethyl)-1,3-diaminopropane (bpmpn) showed predominant oxidative N-dealkylation for the hexacoordinate [Fe(IV)(O)(L)(OTf)](+) cations and predominant dehydrogenation of the diaminoethane/propane backbone for the pentacoordinate [Fe(IV)(O)(L)](2+) cations. DFT calculations on [Fe(IV)(O)(bpmen)] ions showed that the experimentally observed preference for oxidative N-dealkylation versus dehydrogenation of the diaminoethane linker for the hexa- and pentacoordinate ions, respectively, is dictated by the proximity of the target C-H bond to the oxoiron(IV) moiety and the reactive spin state. Therefore, there must be a difference in ligand topology between the two ions. More importantly, despite the constraints on the geometries of the TS that prohibit the usual upright sigma trajectory and prevent optimal sigma(CH)-sigma*(z2) overlap, all the reactions still proceed preferentially on the quintet (S = 2) state surface, which increases the number of exchange interactions in the d block of iron and leads thereby to exchange enhanced reactivity (EER). As such, EER is responsible for the dominance of the S = 2 reactions for both hexa- and pentacoordinate complexes. PMID- 22837065 TI - Multiple functional effects of RET kinase domain sequence variants in Hirschsprung disease. AB - The REarranged during Transfection (RET) gene encodes a receptor tyrosine kinase required for maturation of the enteric nervous system. RET sequence variants occur in the congenital abnormality Hirschsprung disease (HSCR), characterized by absence of ganglia in the intestinal tract. Although HSCR-RET variants are predicted to inactivate RET, the molecular mechanisms of these events are not well characterized. Using structure-based models of RET, we predicted the molecular consequences of 23 HSCR-associated missense variants and how they lead to receptor dysfunction. We validated our predictions in biochemical and cell based assays to explore mutational effects on RET protein functions. We found a minority of HSCR-RET variants abrogated RET kinase function, while the remaining mutants were phosphorylated and transduced intracellular signals. HSCR-RET sequence variants also impacted on maturation, stability, and degradation of RET proteins. We showed that each variant conferred a unique combination of effects that together impaired RET protein activity. However, all tested variants impaired RET-mediated cellular functions, including cell transformation and migration. Our data indicate that the molecular mechanisms of impaired RET function in HSCR are highly variable. Although a subset of variants cause loss of RET kinase activity and downstream signaling, enzymatic inactivation is not the sole mechanism at play in HSCR. PMID- 22837066 TI - Detection of rapidly exchanging compounds using on-resonance frequency-labeled exchange (FLEX) transfer. AB - Frequency-labeled exchange transfer is a promising MRI technique for labeling and detecting exchanging protons of low-concentration solutes through the water signal. Early frequency-labeled exchange studies have used off-resonance excitation-based labeling schemes that are well suited to study rapidly exchanging protons or molecules far from the water resonance (e.g., water in paramagnetic contrast agents) or slowly exchanging protons close to the water resonance (e.g., some amide protons). However, off-resonance labeling is not efficient for rapidly exchanging protons close to water. Here, we show that a new frequency-labeled exchange labeling scheme with excitation pulses applied on the water resonance gives much higher exchange contrast for rapidly exchanging protons resonating close to the water resonance frequency. This labeling scheme is particularly suited for studying rapidly exchanging hydroxyl, amine, and imino protons in diamagnetic chemical exchange saturation transfer agents. PMID- 22837067 TI - Serum apoptosis markers in HIV-infected patients with human herpesvirus type 8 and herpes simplex virus type 2 co-infection. AB - This study aimed to examine the influence of human herpesvirus type 8 (HHV-8) and herpes simplex virus type 2 (HSV-2) co-infections on apoptosis serum markers in human immunodeficiency virus (HIV)-infected patients. Sera from 110 HIV-infected and 59 HIV-uninfected individuals were analyzed for soluble Fas (sFas), sFas ligand (sFasL), caspase-8, and Bcl-2. The findings of HIV-infected patients with no co-infection (n = 37), HIV-infected patients with HHV-8 co-infection (n = 22), HIV-infected patients with HSV-2 co-infection (n = 51), and patients with HSV-2 co-infection and no HIV infection (n = 20) were compared to controls (reference group) with no HIV, HSV-2, and HHV-8 co-infections (n = 39). Soluble Fas and sFasL concentrations were the highest in HIV and HHV-8 co-infected patients (medians, 912.7 pg/ml and 74.3 pg/mL, respectively). No difference in caspase-8 concentrations was found, whereas Bcl-2 concentrations were the highest in HIV and HHV-8 co-infected individuals. Older age was associated with higher sFas (p < 0.001) and lower sFasL (p = 0.04) concentrations. In a robust regression model adjusted for age, the log-transformed sFas concentrations were significantly lower in HIV-infected patients with no co-infections (beta = -0.244; p < 0.001) and higher in HIV and HHV-8 co-infected patients (beta = 0.216; p = 0.012) compared to the reference group. Soluble FasL was significantly lower in HIV infected patients with no co-infections (beta = -0.284; p = 0.005) and in HIV infected patients with HSV-2 co-infection (beta = -0.381; p < 0.001) compared to the reference group. Soluble FasL was also higher in HIV and HHV-8 co-infected patients compared to controls (beta = 0.248; p = 0.036). Our results suggest that HHV-8 and HSV-2 may have a significant effect on Fas-FasL-mediated apoptosis in HIV-1 patients. HHV-8 upregulates while HSV-2 downregulates sFas and sFasL. PMID- 22837068 TI - [Significant improvement in compliance with the face-down position after vitrectomy and gas tamponade]. AB - BACKGROUND: The positioning of a patient in a "prone position" ("face down position", fdp) after pars plana vitrectomy with gas tamponade has been discussed controversially since the beginning of macular surgery. The "prone positioning" is almost standard although the duration varies. In most of the study designs for macular surgery "face-down positioning" is advised. However it is not clearly described how the "prone position" was achieved. In most of the studies it is not shown if the patients had suitable aids and how long and how efficiently they used them. Experience while practising this shows that the patient's compliance is a great challenge. Patients are mostly unable to comply, which could result in refusal. METHODS: In our prospective, controlled and randomised pilot study we observed postoperatively 40 patients who all underwent a pars-plana vitrectomy and sulfur hexafluoride-gastamponade (SF6 25%). All patients of the supported group (SG) and the control group (CG) were requested to keep their face downwards until the gas bubble was resorbed completely. In the postoperative time in hospital the participants of the SG used a simple prone-positioning support. In the time at home after hospital, the patients were supplied with an inflatable device. In this trial we wanted to show whether or not it is possible to improve the patient's compliance by using a prone-positioning support, designed to be particularly comfortable, so that real time in "face-down position" in hours per day could be increased significantly. Additionally, the contentment of the patient in reference to the available supports and the appearance of complications has been reported. RESULTS: In particular the real time of "fdp" in hours per day (24 h) varied greatly (SG: 19.5/24; CG: 5.5/24; P < 0.0001). Equivalent results were reflected in the contentment in reference to the available supports (SG: 99%; CG: 25%; P < 0.0001). Postoperative complications such as moderate or severe back-, neck- or headache only were observed in the CG. Development of a postoperative cataract was observed mainly in the non-supported group. CONCLUSIONS: By placing supports at the disposal of the patients, it is possible to improve significantly the compliance after surgery. To succeed in using the prone position also at home it is necessary to supply the patient with a support which is comfortable, cheap and easy to handle. PMID- 22837069 TI - Determination of docetaxel in rat plasma and its application in the comparative pharmacokinetics of Taxotere and SID530, a novel docetaxel formulation with hydroxypropyl-beta-cyclodextrin. AB - In this study, a sensitive, simple and reliable method for the quantification of docetaxel in rat plasma was developed and validated using liquid chromatography tandem mass spectrometry (LC-MS/MS). The plasma samples were prepared by protein precipitation, and paclitaxel was used as an internal standard (IS). Chromatographic separation was achieved using a Gemini C(18) column (2.0 * 150 mm, 5 um) with a mobile phase consisting of 0.1% formic acid-acetonitrile (30:70, v/v). The precursor-product ion pairs used for multiple reaction monitoring were m/z 808.5 -> 527.5 (docetaxel) and m/z 854.2 -> 286.5 (IS, paclitaxel). A calibration curve for docetaxel was constructed over the range 1-1000 ng/mL. The developed method was specific, precise and accurate, and no matrix effect was observed. The validated method was applied in a comparative pharmacokinetic study in which two docetaxel formulations, SID530, a new parenteral formulation of docetaxel with hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and Taxotere, were administered to rats at a dose of 5 mg/kg. For SID530 and Taxotere, the mean C(0) values were 1494 and 1818 ng/mL, respectively, and the AUC(last) values were 837 and 755 h ng/mL, respectively. These two formulations did not show any statistical differences with regard to the pharmacokinetic parameters, thus establishing that the SID530 and Taxotere products are pharmacokinetically comparable in male rats. PMID- 22837071 TI - Congenital unilateral facial nerve palsy as an unusual presentation of BOR syndrome. AB - Congenital facial nerve palsy (CFNP) is a rare condition that can be generally categorized as developmental or traumatic. Though trauma during birth is the most common cause, sometimes CFNP is observed in association with genetic syndromes and congenital hearing loss and structural anomalies of the middle and inner ear. CFNP is infrequently reported in association with branchio-oto-renal (BOR) syndrome. We present a case of a 4-day-old infant girl with a familial history of renal disease, who was hospitalized because of congenital unilateral facial palsy, which subsequently appeared to be a part of BOR syndrome and led to the diagnosis of congenital bilateral renal hypoplasia, renal failure, and secondary arterial hypertension. This case proves that sometimes rare manifestations of BOR syndrome may be one of the first signs of an underlying syndrome. Issues regarding patterns of BOR syndrome inheritability and expressivity that we encountered are also discussed. Patients with a familial history of BOR syndrome should be carefully inspected after birth, especially in suspected cases such as newborns with preauricular pits and/or facial nerve palsy. PMID- 22837070 TI - Assessment of motor functioning in the preschool period. AB - The assessment of motor functioning in young children has become increasingly important in recent years with the acknowledgement that motor impairment is linked with cognitive, language, social and emotional difficulties. However, there is no one gold standard assessment tool to investigate motor ability in children. The aim of the current paper was to discuss the issues related to the assessment of motor ability in young pre-school children and to provide guidelines on the best approach for motor assessment. The paper discusses the maturational changes in brain development at the preschool level in relation to motor ability. Other issues include sex differences in motor ability at this young age, and evidence for this in relation to sociological versus biological influences. From the previous literature it is unclear what needs to be assessed in relation to motor functioning. Should the focus be underlying motor processes or movement skill assessment? Several key assessment tools are discussed that produce a general measure of motor performance followed by a description of tools that assess specific skills, such as fine and gross motor, ball and graphomotor skills. The paper concludes with recommendations on the best approach in assessing motor function in pre-school children. PMID- 22837072 TI - Parental bonds in children at high and low familial risk for panic disorder. AB - A rejecting and overprotective parenting style is considered to be an important risk factor for the development of anxiety disorders. This study examined the role of perceived parental bonding as a potential environmental risk factor for panic disorder (PD) in unaffected offspring with parental PD. Children with a biological parent with PD (n = 71) and children of parents with no psychiatric history (n = 80) participated in the study. Results indicate that high risk children do not perceive their parents as being more protective and less caring than low risk controls. The optimal bonding type (high care, low protection) was the most frequently reported parenting style across groups. The constraining type of maternal bonding (high care, high protection) was less frequently reported by high risk children (p < 0.05). Overall, these data suggest that parental PD does not compromise the parent-child bonds in never-ill offspring. PMID- 22837073 TI - Contemplative practice, chronic fatigue, and telomerase activity: a comment on Ho et al. PMID- 22837074 TI - Image cytometry-based detection of aneuploidy by fluorescence in situ hybridization in suspension. AB - Cytogenetic abnormalities are important diagnostic and prognostic criteria for hematologic malignancies. Karyotyping and fluorescence in situ hybridization (FISH) are the conventional methods by which these abnormalities are detected. The sensitivity of these microscopy-based methods is limited by the abundance of the abnormal cells in the samples and therefore these analyses are commonly not applicable to minimal residual disease (MRD) stages. A flow cytometry-based imaging approach was developed to detect chromosomal abnormalities following FISH in suspension (FISH-IS), which enables the automated analysis of several log magnitude higher number of cells compared with the microscopy-based approaches. This study demonstrates the applicability of FISH-IS for detecting numerical chromosome aberrations, establishes accuracy, and sensitivity of detection compared with conventional FISH, and feasibility to study procured clinical samples of acute myeloid leukemia (AML). Male and female healthy donor peripheral blood mononuclear cells hybridized with combinations of chromosome enumeration probes (CEP) 8, X, and Y served as models for disomy, monosomy, and trisomy. The sensitivity of detection of monosomies and trisomies amongst 20,000 analyzed cells was determined to be 1% with a high level of precision. A high correlation (R(2) = 0.99) with conventional FISH analysis was found based on the parallel analysis of diagnostic samples procured from 10 AML patients with trisomy 8 (+8). Additionally, FISH-IS analysis of samples procured at the time of clinical remission demonstrated the presence of residual +8 cells indicating that this approach may be used to detect MRD and associated chromosomal defects. PMID- 22837077 TI - Selected-control synthesis of monodisperse Fe3O4@C core-shell spheres, chains, and rings as high-performance anode materials for lithium-ion batteries. AB - A method is reported for the first time for the selected-control, large-scale synthesis of monodispersed Fe(3)O(4)@C core-shell spheres, chains, and rings with tunable magnetic properties based on structural evolution from eccentric Fe(2)O(3)@poly(acrylic acid) core-shell nanoparticles. The Fe(3)O(4)@C core-shell spheres, chains, and rings were investigated as anode materials for lithium-ion batteries. Furthermore, a possible formation mechanism of Fe(3)O(4)@C core-shell chains and rings has also been proposed. PMID- 22837076 TI - The association between glaucoma prevalence and supplementation with the oxidants calcium and iron. PMID- 22837078 TI - Facile control of intra-fiber porosity and inter-fiber voids in electrospun fibers for selective adsorption. AB - We report a facile method to control intra-fiber porosity via varying the relative humidity and inter-fiber voids through the blending of two different polymeric fibers via multi-nozzles spinning of electrospun fibers for selective adsorption of oil from water. PMID- 22837079 TI - Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder. AB - Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene. PMID- 22837080 TI - Management of sexual disorders in spinal cord injured patients. AB - Spinal cord injured (SCI) patients have sexual disorders including erectile dysfunction (ED), impotence, priapism, ejaculatory dysfunction and infertility. Treatments for erectile dysfunction include four steps. Step 1 involves smoking cessation, weight loss, and increasing physical activity. Step 2 is phosphodiesterase type 5 inhibitors (PDE5I) such as Sildenafil (Viagra), intracavernous injections of Papaverine or prostaglandins, and vacuum constriction devices. Step 3 is a penile prosthesis, and Step 4 is sacral neuromodulation (SNM). Priapism can be resolved spontaneously if there is no ischemia found on blood gas measurement or by Phenylephrine. For anejaculatory dysfunction, massage, vibrator, electrical stimulation and direct surgical biopsy can be used to obtain sperm which can then be used for intra-uterine or in-vitro fertilization. Infertility treatment in male SCI patients involves a combination of the above treatments for erectile and anejaculatory dysfunctions. The basic approach to and management of sexual dysfunction in female SCI patients are similar as for men but do not require treatment for erectile or ejaculatory problems. PMID- 22837081 TI - Timing of surgery for aneurysmal subarachnoid hemorrhage. AB - Despite the many studies about timing for surgery in subarachnoid hemorrhage (SAH), the optimum time is still unclear. The aim of this study was to determine the results of early and late surgery for aneurysmal subarachnoid hemorrhage. In this cross-sectional study we evaluated the results of 70 consecutive surgery for aneurysmal subarachnoid hemorrhage in in Firuzgar hospital from 2005 to 2008. Surgery was performed in 50 cases (71.4%) in early period after SAH (first 4 days) and in 20 cases (28.6%) in at least 7 days after SAH. Statitical analysis was done by SPSS software, using Chi-square and t-test. Mean age of patients was 48.54+/-13.4 years. 41.4% of patients were male and 58.6% were female. Most (77.2%) of patients had clinical grade I or II. 92.9% of aneurysms were single. Hypertension was the most common associated disease (34.3%). The most common site of aneurysms was anterior communicating artery (41.4%), followed by middle cerebral artery (35.7%). The outcome of surgery was favorable in 70% and unfavorable in 30%. Mortality rate was 24.3%. Outcome was favorable in 66% of early surgeries and 80% of late surgeries. There was no statistically significant difference between early and late surgery in terms of complications and outcome. Mean hospital stay of patients in the early surgery group was significantly lower than late group (16.46+/-9.36 vs. 22.5+/-7.97 days; P=0.01). The results of early and late surgery for aneurysmal subarachnoid hemorrhage is similar and decision making for timing of surgery should be based on each patient individual clinical conditions, age, size and site of aneurysm. PMID- 22837082 TI - Diagnosis of latent tuberculosis infection in candidates for kidney transplantation (comparison of two tests). AB - It is assumed that about 10% of individuals infected with Mycobacterium tuberculosis develop tuberculosis. The rate of tuberculosis in solid organ transplant recipients has been estimated to be 50-fold higher than in the general population. Candidates for solid organ transplantation are routinely screened for latent tuberculosis infection (LTBI). In this study we aimed to compare Tuberculin Skin Test (TST) with QuantiFERON-TB Gold In-Tube (QFT) for the detection of LTBI in candidate for kidney transplantation. Between October 2009 and November 2010, 64 candidates for kidney transplant who referred to the transplant clinic in Imam Khomeini Hospital, were enrolled in the study. Patients were screened for LTBI with both QFT and TST. Concordance between two test results and variables associated with test discordance were assessed. The mean age of patients was 38.5 years (range 16-65); female/male ratio was 26/38. Positive results were found in 21.9% and 21.9%, by TST and QFT, respectively. Four patients (6.3%) had indeterminate QFT. Overall agreement between QFT and TST was 75% (k=0.28 and P=0.028). BCG vaccination and past positive TST were not associated with positive QFT result (P=0.13 and P=0.09 respectively). Overall agreement between test results was fair. Comparison among test results showed that TST andQFT can be used interchangeably for latent TB screening in kidney transplant candidates. The decision to select QFT or TST will depend on the purpose of testing and resource availability. PMID- 22837083 TI - Frontal lobe function in chess players. AB - Chess is considered as a cognitive game because of severe engagement of the mental resources during playing. The purpose of this study is evaluation of frontal lobe function of chess players with matched non-players. Wisconsin Card Sorting Test (WCST) data showed no difference between the player and non-player groups in preservation error and completed categories but surprisingly showed significantly lower grade of the player group in correct response. Our data reveal that chess players don't have any preference in any stage of Stroop test. Chess players don't have any preference in selective attention, inhibition and executive cognitive function. Chess players' have lower shifting abilities than non-players. PMID- 22837084 TI - Helicobacter pylori in diabetic and non-diabetic patients with dyspepsia. AB - Helicobacter pylori (H. pylori) is one of the most common chronic infections in patients with gastrointestinal disorders. Recent reports suggested that H. pylori might have high prevalence among patients with diabetes. The aim of this cross sectional study was to assess the prevalence of H. pylori infection in diabetes mellitus and to study the relationship between histological findings and H. pylori infection in diabetic patients. Eighty patients with dyspepsia that were referred to our gastrointestinal department between May 2007 and May 2008 were included in our study. We checked fasting blood sugar for all of the study samples. All of patients underwent upper endoscopy and biopsy specimens were obtained from the antrum and the corpus. The specimens for the presence of H. pylori were colored by Giemsa stains. A single pathologist evaluated the histology slides. We found that prevalence of H. pylori infection was significantly higher in diabetics than in non-diabetics (P=0.001). Indeed, the prevalence of gastritis did differ significantly between the two groups (P=0.001). According to our results diabetes mellitus is one of the risk factor that must be considered in evaluation of H. pylori infection in diabetic patients with dyspepsia. PMID- 22837085 TI - Substance abuse disorders in the parents of ADHD children, and parents of normal children. AB - The objective of the study was to compare the attention-deficit/ hyperactivity, and substance abuse disorders background in the parents of children with attention-deficit/ hyperactivity disorder (ADHD), and the parents of normal children. The available sampling method was used to choose 400 parents of children (200 parents of children with ADHD and 200 parents of normal children), the ages of children were 6-18 years old. The data were collected through the Schedule for Affective Disorders and Schizophrenia (SADS) for parents and the Kiddy Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL), Connors Adult ADHD Rating Scale (CAARS) and the Wender Utah Rating Scale (WURS) for adult ADHD. The results were analyzed by using SPSS-17 software, based on two-variable Chi-Square and t-tests.and P value in all disorders were equals to P<0.05. The results indicated that substance abuse in parents of children with ADHD is 21% more prevalent, and parents of children with ADHD compared to parents of normal children have 2% ADHD, 9% attention deficit disorder, and 1% hyperactivity disorder more in their background. Therefore, we conclude that there exists a significant difference between the above mentioned disorders in the parents of children with ADHD, and parents of normal children. The high prevalence rate of disorders and background of ADHD in families of individuals with ADHD shows the probability of effect of inheritance in the disorder. Also, it shows that parents of children with ADHD have more substance abuse and history of ADHD in their background. PMID- 22837086 TI - A survey of characteristics of self-immolation in the east of Iran. AB - The aim of this study was investigating the characteristic and outcome of self immolation cases admitted to the Burn Centre of Birjand, Iran over an eight year period. This study is a retrospective review of case notes for patients with self Immolation and admitted to our referral burn centre in the last 8 years (January 2003-January 2011). A performa was designed to collect the data such as: demographic information, length of hospital stay, extent of the burn injuries as %TBSA (Total Body Surface Area) and final outcome. Data was analyzed by SPSS software. Between 2003 and 2011, 188 self-immolation cases admitted. The mean age was 26.97 +/-12.6 years. Female to male ratio was 1.7:1. Housewives represented the largest group (43.1%) and kerosene was the most frequent agent used (74.6%). There was significant different between mortality and TBSA and low educational level (P=0.0001). There was a significant fluctuation time trend in the incidence (per 100,000 population) of self-immolation from 2003 (4.64, CI 95%: 4.62-4.65) to 2008 (5.2, CI 95%: 5.19-5.21). Mortality rate was 64%. The survival rates at three weeks survival for patients who self-immolated was 24 percent (CI 95%: 17 31). The mean and median survival times were 6 days (CI 95%: 4.8-7.2) and 17.5 days (CI 95%: 13.3-21.6), respectively. Our study has shown a lower incidence of self-immolation (5.3%) in the South Khorasan region, when compared with other parts of Iran, as well as a relatively low mortality rate. We have also reported self-immolation in pregnant women which has rarely been reported in medical literature. PMID- 22837087 TI - Bullous pemphigoid in Iranian patients: a descriptive study on 122 cases. AB - Bullous pemphigoid is an immunobullous disease with high mortality and morbidity. Different aspects and characteristics in the patients vary in different areas in the world. Our objective was to study clinical and demographic characteristics of bullous pemphigoid in Iranian patients. In a retrospective descriptive study, we reviewed 122 patients with bullous pemphigoid within 1987-2007. Demographic characteristics, clinical manifestations, treatment, relapses and outcome were evaluated. The mean age of 122 patients was 65 +/- 18.11 years including 35.2% male and 64.8% female. The most common manifestations were cutaneous bullae (97.5%). 27% had oral lesions. 30.3% had eosinophillia. 90 patients(73.8%) received oral prednisolone, 29 patients (23.8%) topical steroid, 2 patients tetracycline and 1 patient dapsone. 89 patients were followed after admission. Out of them 44 patients experienced first relapse and 22 patients second relapse. 41 cases (46%) were completely controlled. 11 cases (12%) were not controlled. Clinical and general characteristics of bullous pemphigoid patients differ in various regions in the world. PMID- 22837088 TI - Clinical characteristics and remedies in 45 Iranians with carotid body tumors. AB - Carotid body tumors (CBTs) are rare, slow-growing tumors that should be considered in evaluating every lateral neck mass. This single center study was performed to define demographic features, clinical characteristics and remedies of Iranian patients with CBT. A retrospective review of prospectively collected data was done on 45 patients with 50 CBTs who have been referred to Sina Hospital, Tehran, Iran, during a 10-year period, were investigated in this study. The demographic characteristics, clinical and pathologic features, imagings, preoperative treatments, surgical approach and complications were analyzed. The study group predominantly consisted of females (82%). Age of diagnosis was 18 to 75 years old. Five patients had bilateral CBT. Family history of CBT was positive in seven patients. Most of CBTs were <= 3cm in size. All of the patients presented with a neck mass, mostly without pain (84%). Other symptoms included vertigo 4%, dysphasia 4% and tinnitus 2%. There was no patient with cranial nerve involvement at presentation. The most common imaging helping the diagnosis was color Doppler sonography. Three patients had preoperative embolization. All patients underwent surgery and seven patients had post-operative cranial nerve injury. Nine cases underwent external carotid artery ligation and four ones had external carotid repair. Post operative mortality rate was one patient. This study provides epidemiological data on patients with CBT in Iran, which could be useful for health care workers in prompt diagnosis and appropriate work ups for patient's families in bilateral CBTs. PMID- 22837089 TI - Cryptococcal antigenemia in anti-retroviral naive AIDS patients: prevalence and its association with CD4 cell count. AB - Cryptococcus neoformans is the most incriminated fungal pathogen causing meningitis in acquired immune deficiency syndrome (AIDS) patients, and is known to constitute a major cause of deaths in AIDS patients. This study aimed to determine the sero-prevalence and effect of CD4 count on seropositivity for Cryptococcus neoformans antigen (crag) in antiretroviral- naive (ART-naive) AIDS patients. This study included 150 (61 males and 89 females) ART-naive AIDS patients attending the Human Immunodeficiency Virus (HIV) clinic of the University of Benin teaching hospital, Benin City, Nigeria within the period February 2011- July 2011. 40 (18 males and 22 females) HIV positive outpatients with CD4 counts >200 cells/ul who are ART-naive were recruited and used as controls. The prevalence of crag in the patients and control group was determined using the cryptococcal antigen latex agglutination system (CALAS) (Meridian Bioscience, Europe) and CD4 counts were measured using flow cytometry (Partec flow cytometer, Germany). Of 150 ART-naive AIDS patients with CD4 counts <= 200 cells/uL, 19 (12.7%) were positive for serum Cryptococcal antigen. ART-naive AIDS patients with CD4 count <=50 cells/ul had the highest prevalence of serum crag. Lower CD4 counts were significantly associated with positivity for serum crag (P<0.001). Age and Sex had no significant effect on the sero-positivity for serum crag. 1 (2.5%) of the control was sero-positive for crag. Serum crag was significantly associated with AIDS but not with HIV (P<0.001). This study uncovers a high prevalence of crag in ART-naive AIDS patients in Benin City. There is an urgent need to introduce early and routine screening for crag in ART naive AIDS patients for prompt intervention. PMID- 22837090 TI - Neonatal urinary tract infection: clinical response to empirical therapy versus in vitro susceptibility at Bahrami Children's Hospital- Neonatal Ward: 2001-2010. AB - Urinary tract infection (UTI) is a neonatal life threatening infection which is usually treated with ampicillin plus an aminoglycoside or a third-generation cephalosporin. Recently, growing number of Escherchia coli species resistant to ampicillin and aminoglycosides have raised concerns regarding the necessity to change the empirical therapy. This motivates us to determine neonatal UTI clinical response to the used empirical antibiotics. This study was designed as a Case Series. All neonates admitted to Bahrami Children Hospital, Tehran, Iran, during 2001- 2010 with a diagnosis of UTI surveyed by simple non-random sampling. Totally, 97 cases (including 83 (85.6%) term, 8 (8.2%) post-term and 6 (6.2%) preterm neonates) with a mean age of 15.85 +/- 7.05 days at admission ,average weight of 3195.57 +/- 553g at birth and 3276.29 +/- 599.182 g at admission were studied. Ampicillin resistance in 93 cases (95.9%), gentamicin resistance in 51 cases (52.6%) and trimethoprim- sulfamethoxazole resistance in 44 cases (45.4%) were the leading resistances in this study. Escherichia coli was the dominant organism in 76.3% (74 patients) of study population which was resistant to ampicillin in 95.9% (71 cases). Despite the observed resistant to initial empirical regimen antibiotics (especially ampicillin), 81.4% of patients responded to empirical therapy. However, we believe till conductance of more detailed studies regarding the relationship between empirical therapy and antibiogram concordance, physicians take ampicillin-resistant E coli infection issue into accounts from the first steps of management of critically ill neonates. PMID- 22837091 TI - Papillary thyroid carcinoma associated with parathyroid adenoma. AB - Concomitant papillary thyroid cancer and parathyroid adenoma is rare. We report a 55 years old female with papillary cancer admitted for surgery. Preoperative laboratory findings revealed hypercalcemia and then primary hyperparathyroidism. Thyroidectomy, neck dissection and excision of parathyroid adenoma were performed. Histological examination revealed parathyroid adenoma. Serum calcium returned to normal range after surgery. We recommend preoperative check of calcium in patients with thyroid cancer. PMID- 22837092 TI - Pneumothorax following feeding tube placement: precaution and treatment. AB - Nasojejunal feeding tubes are being used at an increased frequency, but it is not without complications that could be life-threatening. We report two cases of pneumothorax following small-bore feeding tube insertion into the pleural cavity, resulting in pneumothorax. We further discuss the potential measures that can be taken to prevent and treat this serious complication. PMID- 22837093 TI - Carotid body tumors: radiotherapy as an alternative approach. PMID- 22837094 TI - Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis. AB - Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 MUg V710 (with or without adjuvant), 90 MUg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a >=2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a >=2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis. PMID- 22837095 TI - Characterization of a therapeutic model of inhalational anthrax using an increase in body temperature in New Zealand white rabbits as a trigger for treatment. AB - The development of an appropriate animal therapeutic model is essential to assess the potential efficacy of therapeutics for use in the event of a Bacillus anthracis exposure. We conducted a natural history study that showed New Zealand White rabbits exhibited a significant increase in body temperature (SIBT), changes in hematologic parameters, and increases in C-reactive protein and succumbed to disease with an average time to death of approximately 73 h following aerosol challenge with B. anthracis Ames spores. The SIBT was used as a trigger to treat with a fully human monoclonal antibody directed at protective antigen (PA). Ninety percent (9/10) of the treated rabbits survived the lethal inhalational challenge of B. anthracis. Further characterization investigated the protective window of opportunity for anti-PA antibody administration up to 12 h post-onset of SIBT. Eighty-three percent (5/6) of the rabbits treated at SIBT and 100% (6/6) of those treated at 6 h after SIBT survived challenge. Only 67% (4/6) of the rabbits treated at 12 h after SIBT survived. The increase in body temperature corresponded with both bacteremia and antigenemia (PA in the blood), indicating that SIBT is a suitable trigger to initiate treatment in a therapeutic model of inhalational anthrax. PMID- 22837096 TI - Protective immunity conferred by the C-terminal fragment of recombinant Pasteurella multocida toxin. AB - Pasteurella multocida serogroup D, producing P. multocida toxin (PMT), is a causative pathogen of progressive atrophic rhinitis (PAR) in swine. To evaluate the protective immunity and vaccination efficacy of the truncated form of PMT, a C-terminal form of recombinant PMT (designated PMT2.3; amino acid residues 505 to 1285 of PMT) was expressed in an Escherichia coli expression system, and the humoral and cellular immune responses to PMT2.3 were investigated. PMT2.3 vaccination in mice led to high levels of the anti-PMT antibody with a high neutralizing antibody titer. PMT2.3 also induced a cellular immune response to PMT, as demonstrated by the lymphocyte proliferation assay. Furthermore, strong protection against a homologous challenge with P. multocida was also observed in mice vaccinated with PMT2.3. In PMT2.3 vaccination in swine, high levels of serum antibody titers were observed in offspring from sows vaccinated with PMT2.3. Offspring from sows vaccinated with PMT2.3 or toxoid showed a good growth performance as depicted by mean body weight at the time of sacrifice, as well as in average daily gain in the postweaning period. Low levels of pathological lesions in turbinate atrophy and pneumonia were also observed in these offspring. Therefore, we consider PMT2.3--in the truncated and nontoxic recombinant PMT form -to be an attractive candidate for a subunit vaccine against PAR induced by P. multocida infection. PMID- 22837097 TI - A DNA-based candidate HIV vaccine delivered via in vivo electroporation induces CD4 responses toward the alpha4beta7-binding V2 loop of HIV gp120 in healthy volunteers. AB - Administration of a clade C/B' candidate HIV-1 DNA vaccine, ADVAX, by in vivo electroporation (EP) was safe and more immunogenic than intramuscular administration without EP. The breadth and specificity of T-cell responses to full-length Env were mapped. Responses to multiple Env regions were induced, with most focusing on V3/C4 and V2 regions, including the alpha4beta7 integrin-binding domain. The breadth of responses induced by this DNA vaccine regimen was comparable to that of viral-vectored vaccine regimens. PMID- 22837098 TI - Prospective calculation of identification power for individual genes in analyses controlling the false discovery rate. AB - Recent work on prospective power and sample size calculations for analyses of high-dimension gene expression data that control the false discovery rate (FDR) focuses on the average power over all the truly nonnull hypotheses, or equivalently, the expected proportion of nonnull hypotheses rejected. Using another characterization of power, we adapt Efron's ([2007] Ann Stat 35:1351 1377) empirical Bayes approach to post hoc power calculation to develop a method for prospective calculation of the "identification power" for individual genes. This is the probability that a gene with a given true degree of association with clinical outcome or state will be included in a set within which the FDR is controlled at a specified level. An example calculation using proportional hazards regression highlights the effects of large numbers of genes with little or no association on the identification power for individual genes with substantial association. PMID- 22837099 TI - Enteric coccidiosis in the brown kiwi (Apteryx mantelli). AB - Enteric coccidiosis may cause significant morbidity and mortality in juvenile brown kiwi (Apteryx mantelli). Morphology of sporulated oocysts indicates that at least two Eimeria species are able to infect the brown kiwi. A histological study of the endogenous stages of coccidia was undertaken in the intestinal tracts of ten naturally infected young kiwi. Sequential sectioning of the entire intestinal tract allowed identification and recording of the distribution of the various coccidial life stages. Macromeronts measuring 268 * 162 MUm when mature were found mainly within the lamina propria of the proximal one third of the small intestine. A smaller form of lamina propria meront was also identified (8.7 * 6.4 MUm) with a similar distribution to the macromeronts. Small meronts (4.4 * 3.8 MUm) were also identified in mucosal epithelial cells, with the overall peak in distribution within the intestinal tract being distal to the lamina propria meronts. Three morphologically distinctive gametocytes were identified. Type A gametocytes contained within epithelial cells shared the same distribution as the epithelial meronts. Polyps containing large numbers of type B gametocytes within the distal intestinal tract were found in two cases, and type C gametocytes were identified throughout the entire intestinal tract in one case only. The observational nature of this study precludes complete knowledge of the parasite life cycles using histology alone. However, it is likely that each of the three morphologically distinct gametocytes represents a separate species of enteric coccidia. PMID- 22837100 TI - Multicomponent DNA vaccine-encoding Toxoplasma gondii GRA1 and SAG1 primes: anti Toxoplasma immune response in mice. AB - A multicomponent DNA vaccine, encoding Toxoplasma gondii GRA1 and SAG1, was constructed and tested for its ability to confer protection. BALB/c mice were challenged with tachyzoites of the virulent T. gondii RH strain at 4 weeks following the last immunization, and immune responses and survival times were observed. The results show that vaccination by the multicomponent vaccine prolonged survival of mice challenged with the T. gondii RH strain (from average 4.50 +/- 0.22 to 7.60 +/- 0.74 days); induced high levels of IgG antibody (from 0.252 +/- 0.080 to 0.790 +/- 0.083), IFN-gamma (from 598.74 +/- 67.50 to 853.77 +/- 66.74 pg/ml), and IL-2 (from 89.44 +/- 10.66 to 192.24 +/- 19.90 pg/ml); changed the CD4(+)/CD8(+) lymphocyte ratio (from 1.81 +/- 0.14 to 1.09 +/- 0.19); and stimulated NK cell-killing activity (from 46.81 +/- 3.96 to 64.15 +/- 7.71 %). These findings demonstrate that a multicomponent DNA vaccine, encoding GRA1 and SAG1, primes a strong humoral and cellular immune response and enhances protection against T. gondii challenge. The new, combined DNA vaccine provides another means to combat T. gondii infection. PMID- 22837101 TI - In vivo infection by Trypanosoma cruzi: a morphometric study of tissue changes in mice. AB - Nifurtimox and benznidazole, medications currently used for the treatment of the Chagas disease, are not always successful. We determine whether (-)-cubebin and ( )-hinokinin could be used as alternative drugs for the treatment of parasitic infections by Trypanosoma cruzi. To this end, male BALB/c mice were treated with both drugs, and the nuclear parameters (largest diameter, smallest diameter, and perimeter) were determined from slides prepared from the spleen, liver, and heart. The cytotoxicity of the substances was determined after 24-h treatment. Results revealed increased cell nuclei in untreated infected animals as compared to uninfected mice. The values obtained for infected animals treated with (-) cubebin and (-)-hinokinin were close to those observed for uninfected mice. For the spleen, perimeter values of 10.85 MUm (p < 0.01) and 10.90 MUm (p < 0.05) were obtained for mice treated with (-)-cubebin 50 mg/kg and (-)-hinokinin 20 mg/kg, respectively, whereas untreated infected animals furnished a perimeter of 11.76 MUm. As for the liver, perimeter values of 19.06 MUm (p < 0.01) and 18.61 MUm (p < 0.001) were achieved for mice treated with (-)-cubebin 50 mg/kg and (-) hinokinin 20 mg/kg, respectively, whereas a perimeter of 18.54 MUm was obtained for untreated infected animals. The cytotoxicity assays demonstrated that (-) cubebin and (-)-hinokinin does not display toxicity. Therefore, (-)-cubebin and ( )-hinokinin are promising therapeutic agents and could be used in future clinical studies concerning treatment of the Chagas disease. Even if the karyometry is not used frequently, it can complement other methods, such as PCR, and furthermore, it is a simple method which is easily possible to analyze the activity of substances in the tissues of treated infected animals compared to uninfected animals. PMID- 22837103 TI - State regulations for nursing home residents with serious mental illness. AB - To identify state regulations for nursing home residents with Serious Mental Illness (SMI). We reviewed state regulations for policies relating to nursing home residents with SMI, and conducted interviews with expert stakeholders. A framework for analyzing state regulations was generated by identifying four discrete categories: States with specific mental illness regulations, Alzheimer's or dementia regulations, minor mention of mental illness, and no mention of mental illness. A large majority of the states have little or no mention of mental illness in their nursing home regulations, suggesting limited attention to all forms of mental illness by most state regulatory bodies. PMID- 22837102 TI - Toxicology and carcinogenesis study of styrene-acrylonitrile trimer in F344/N rats (perinatal and postnatal feed studies). AB - Styrene-acrylonitrile trimer (SAN Trimer) is a mixture of isomers formed by the condensation of two moles of acrylonitrile and one mole of styrene and has a molecular weight of 210. The mixture is composed of two structural forms: 4-cyano 1,2,3,4-tetrahydro-a-methyl-1-naphthaleneacetonitrile (THNA, CAS No. 57964-39-3) and 4-cyano-1,2,3,4-tetrahydro-1-naphthalenepropionitrile (THNP, CAS No. 57964-40 6). The THNA form consists of four stereoisomers. [Structure:see text]. The THNP form consists of two stereoisomers. [Structure:see text]. SAN Trimer is a by product of the production of acrylonitrile styrene plastics and is created in specific manufacturing processes for polymers of acrylonitrile and styrene. In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress. Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats. 7-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm SAN Trimer (equivalent to average daily doses of approximately 50, 90, 175, 270, or 410 mg SAN Trimer/kg body weight to males and 45, 90, 185, 295, or 430 mg/kg to females) for 2 weeks postweaning; the dams of these rats were fed the same concentrations of SAN Trimer from gestation day 7 until the pups were weaned. One 4,000 ppm male rat died 3 days after weaning; all other rats that started the postweaning phase survived to the end of the study. Mean body weights of 1,000, 2,000, and 4,000 ppm males and 2,000 and 4,000 ppm females were significantly less than those of the controls; weaning mean body weights were reduced in 4,000 ppm males and females and in 2,000 ppm females. Feed consumption by 2,000 and 4,000 ppm males and females was less than that by the control groups. Thinness in 4,000 ppm male rats was the only clinical finding related to SAN Trimer exposure. Nonneoplastic lesions were observed in the brain, thymus, spleen, liver, kidney, and reproductive organs of males and females and were considered due to overt toxicity. 18-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets of 0, 100, 200, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of 10, 20, 40, 80, or 150 mg/kg to males and females) for 3 months postweaning; the dams of these rats were fed the same concentrations from gestation day 7 until the pups were weaned. All rats survived to the end of the study. Mean body weights of 1,600 ppm males and females exposed to 200 ppm or greater were significantly less than those of the controls. At termination, brown staining of the urogenital fur was observed in females exposed to 200 ppm or greater. The liver weights of all exposed groups of males and the spleen weights of 800 and 1,600 ppm males and 1,600 ppm females were significantly greater than those of the controls. There were no significant differences in sperm parameters of male rats or the estrous cyclicity of female rats administered 400, 800, or 1,600 ppm in the diet when compared to the control groups. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female core study rats were fed diets of 0, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of approximately 20, 40, or 75 mg/kg to males and 20, 40, or 85 mg/kg to females) for 2 years. Special study groups of 20 males and 20 females were fed the same exposure concentrations and were evaluated at 27, 52, and 78 weeks for hematology and clinical chemistry or at 26, 51, and 77 weeks for urinalysis. The dams of core and special study rats were fed the same concentrations from gestation day 7 until the pups were weaned. Mean body weights of 1,600 ppm males were less than 90% of the controls after week 1; mean body weights of 800 and 1,600 ppm females were less than 90% of the controls after weeks 41 and 13, respectively. Feed consumption by exposed groups of males and females was generally similar to that by the control groups. Brown staining of the urogenital fur was observed in all exposed groups, and the number of animals affected increased with increasing exposure concentration. Rare neoplasms were present in the central nervous system of male and female rats. In the original evaluation, the 800 and 1,600 ppm groups of male rats each had one astrocytoma and one granular cell tumor in the brain. Also in the brain, one 400 ppm female had a granular cell tumor and one control, one 400 ppm, and one 800 ppm female had a mixed cell glioma. In the spinal cord, one astrocytoma was noted in a 1,600 ppm male in the original evaluation. In the expanded review of the spinal cord, one granular cell tumor was found in a 400 ppm male and one meningioma was found in an 800 ppm female. There were statistically significant increases in the incidence of spinal nerve root degeneration in 1,600 ppm males and the incidences of sciatic nerve degeneration in 800 and 1,600 ppm females. More importantly, there were increases in the severities of both nerve lesions in males and in the severity of spinal nerve root degeneration in females. The incidences of bone marrow hyperplasia were significantly increased in 1,600 ppm males and females and 800 ppm females. Incidences of bone marrow granulomatous inflammation were increased in 1,600 ppm males and 800 and 1,600 ppm females, and the increase in the 800 ppm females was significant. Because this lesion is very rare and did not occur in control animals, it should be considered biologically significant. In the liver, the incidence of eosinophilic focus was significantly increased in 1,600 ppm males and the incidences of mixed cell focus were significantly increased in 400 and 1,600 ppm males. Incidences of mixed cell focus were increased in the liver of all exposed groups of females, and the increase was significant in the 1,600 ppm group. The incidence of transitional epithelial hyperplasia of the urinary bladder in 1,600 ppm females was significantly greater than that in the controls. There were significant decreases in the incidences of pituitary gland pars distalis adenoma in 1,600 ppm males and females, and the incidences in both sexes occurred with negative trends. The incidences of mammary gland fibroadenoma occurred in females with a negative trend, and the incidences in 800 and 1,600 ppm females were significantly less than that in the control group. The incidences of mononuclear cell leukemia in all exposed groups of males and females were significantly less than those in the controls. GENETIC TOXICOLOGY: SAN Trimer (Batch 3) was not mutagenic in Salmonella typhimurium strains TA98 or TA100 or in Escherichia coli strain WP2 uvrA/pKM101 in tests conducted with and without exogenous metabolic activation. In vivo, however, results of a comet assay indicated significantly increased levels of DNA damage in brain cells of male and female juvenile rats following administration of SAN Trimer (Batch 3) by oral gavage. Dose-related increases in DNA damage in liver cells of these rats were also observed, but the increases were smaller than those observed in brain cells and were judged to be equivocal in both males and females. Indications of DNA damage following exposure to SAN Trimer were also seen in leukocytes of male and female rats. Increases in male rats were significant, but in females, observed levels of DNA damage did not correlate with dose. Therefore, the results were judged to be positive in males and equivocal in females. In addition to the positive comet assay results, significant increases in the frequencies of micronucleated reticulocytes were observed in peripheral blood of male and female juvenile rats dosed with SAN Trimer. CONCLUSIONS: Under the conditions of this 2 year feed study preceded by perinatal exposure, there was no evidence of carcinogenic activity of SAN Trimer in male and female F344/N rats given feed containing 400, 800, or 1,600 ppm SAN Trimer. Exposure to SAN Trimer resulted in increased incidences and/or severities of peripheral nerve degeneration in male and female F344/N rats, increased incidences of nonneoplastic lesions of the bone marrow and liver in male and female F344/N rats, and of nonneoplastic urinary bladder lesions in female F344/N rats. The incidences of pituitary gland adenoma and mononuclear cell leukemia in male and female F344/N rats and mammary gland fibroadenoma in female F344/N rats were decreased. PMID- 22837104 TI - Use of a computerized medication shared decision making tool in community mental health settings: impact on psychotropic medication adherence. AB - Healthcare reform emphasizes patient-centered care and shared decision-making. This study examined the impact on psychotropic adherence of a decision support center and computerized tool designed to empower and activate consumers prior to an outpatient medication management visit. Administrative data were used to identify 1,122 Medicaid-enrolled adults receiving psychotropic medication from community mental health centers over a two-year period from community mental health centers. Multivariate linear regression models were used to examine if tool users had higher rates of 180-day medication adherence than non-users. Older clients, Caucasian clients, those without recent hospitalizations, and those who were Medicaid-eligible due to disability had higher rates of 180-day medication adherence. After controlling for sociodemographics, clinical characteristics, baseline adherence, and secular changes over time, using the computerized tool did not affect adherence to psychotropic medications. The computerized decision tool did not affect medication adherence among clients in outpatient mental health clinics. Additional research should clarify the impact of decision-making tools on other important outcomes such as engagement, patient-prescriber communication, quality of care, self-management, and long-term clinical and functional outcomes. PMID- 22837105 TI - Housing and home-leaving experiences of young adults with psychotic disorders: a comparative qualitative study. AB - Housing stability is a key component of rehabilitation for individuals with severe mental illnesses but remains a challenge for mental health service providers, particularly with young adults experiencing early mental health difficulties. The aim of this study is to explore perceptions of housing and home leaving processes among young adults with emerging psychotic disorders and to compare it to the perceptions of young adults without psychotic disorders. A qualitative, grounded theory based, multiple case study was conducted among 52 adults aged 18-30 years old. Two core categories emerged in relation with perception of housing: choice/control over the residential environment, and housing opportunities over time. Difference between the groups include more coerced home-leaving for young adults with first-episode psychosis and low levels of choice, control and opportunities for a sub-group of participants living in group homes. The housing situation of young adults is analyzed and discussed from a systemic perspective. PMID- 22837106 TI - 'Individualism-collectivism' as an explanatory device for mental illness stigma. AB - The aim of this study is investigate whether the cross-cultural value paradigm 'individualism-collectivism' is a useful explanatory model for mental illness stigma on a cultural level. Using snowball sampling, a quantitative questionnaire survey of 305 individuals from four UK-based cultural groups (white-English, American, Greek/Greek Cypriot, and Chinese) was carried out. The questionnaire included the 'Community Attitudes to Mental Illness scale' and the 'vertical horizontal individualism-collectivism scale'. The results revealed that the more stigmatizing a culture's mental illness attitudes are, the more likely collectivism effectively explains these attitudes. In contrast, the more positive a culture's mental illness attitudes, the more likely individualism effectively explains attitudes. We conclude that a consideration of the individualism collectivism paradigm should be included in any future research aiming to provide a holistic understanding of the causes of mental illness stigma, particularly when the cultures stigmatization levels are particularly high or low. PMID- 22837107 TI - Polyploidy and chromatin remodeling in hepatocytes from insulin-dependent diabetic and normoglycemic aged mice. AB - Changes in polyploidization, chromatin supraorganization, and chromatin accessibility were investigated in hepatocytes collected from adult, nonobese diabetic (NOD) mice with increasing hyperglycemia and compared with adult normoglycemic controls and 56-week-old normoglycemic BALB/c mice. Our goal was to determine the changes in ploidy degrees and chromatin characteristics in mouse hepatocytes that are associated with insulin-dependent diabetes and to detect similarities in these aspects with those verified with aging, with greater accuracy than previous studies. Image analysis of Feulgen-stained nuclei revealed changes in ploidy degrees and chromatin supraorganization. Chromatin accessibility was assessed with micrococcal nuclease (MNase) digestion. Increased polyploidy was associated with increasing levels of glycemia, and this trend toward polyploidy was found even under normoglycemic conditions in NOD mice. Although high degrees of ploidy were also detected in aged BALB/c mice, the magnitude of polyploidy was not the same magnitude as that in the diabetic mice. While there was increased homogeneity of chromatin packaging with increasing polyploidy under conditions of severe hyperglycemia (and even under conditions of normoglycemia) in NOD mice, an inverse relationship was observed in aged BALB/c mice. Chromatin accessibility to MNase increased under severe hyperglycemia and advanced age, but it was much higher in the diabetic mice. In conclusion, although similarities in polyploidy were observed between the hepatocytes from increasingly hyperglycemic adult mice and those from normoglycemic aged mice, the relationship between chromatin remodeling and increases in ploidy degrees was not the same between the hepatocytes of these two groups. These findings demonstrate that strict similarities between diabetes and aging are not always true at the cellular level. This discordance is likely due to differences in the metabolic state of mouse hepatocytes during aging and diabetic conditions consequent to specificities in their gene regulatory programs. PMID- 22837108 TI - [Ru2Bi14Br4](AlCl4)4 by mobilization and reorganization of complex clusters in ionic liquids. AB - Two polymorphs of the new cluster compound [Ru(2)Bi(14)Br(4)](AlCl(4))(4) have been synthesized from Bi(24)Ru(3)Br(20) in the Lewis acidic ionic liquid [BMIM]Cl/AlCl(3) ([BMIM](+) : 1-n-butyl-3-methylimidazolium) at 140 degrees C. A large fragment of the precursor's structure, namely the [(Bi(8))Ru(Bi(4)Br(4))Ru(Bi(5))](5+) cluster, dissolved as a whole and transformed into a closely related symmetrical [(Bi(5))Ru(Bi(4)Br(4))Ru(Bi(5))](4+) cluster through structural conversion of a coordinating Bi(8)(2+) to a Bi(5)(+) polycation, while the remainder was left intact. Both modifications have monoclinic unit cells that comprise two formula units (alpha form: P2(1)/n, a=982.8(2), b=1793.2(4), c=1472.0(3) pm, beta=109.05(3) degrees ; beta form: P2(1)/n, a=1163.8(2), b=1442.7(3), c=1500.7(3), beta=97.73(3) degrees ). The [Ru(2)Bi(14)Br(4)](4+) cluster can be regarded as a binuclear inorganic complex of two ruthenium(I) cations that are coordinated by terminal Bi(5)(+) square pyramids and a central Bi(4)Br(4) ring. The presence of a covalent Ru-Ru bond was established by molecular quantum chemical calculations utilizing real-space bonding indicator ELI-D. Structural similarity of the new and parent cluster suggests a structural reorganization or an exchange of the bismuth polycations as mechanisms of cluster formation. In this top-down approach a complex-structured unit formed at high temperature was made available for low-temperature use. PMID- 22837110 TI - Enantioselective, protecting group-free synthesis of 1S-ethyl-4-substituted quinolizidines. AB - A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The Grignard addition reaction to 6 takes place stereoselectively to give 1-ethyl-4 substituted quinolizidines 4-epi-207I and 7-9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents to 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. The theoretical study is in agreement with the experimental results. PMID- 22837109 TI - Correlating multiallelic copy number polymorphisms with disease susceptibility. AB - The human genome contains a significant amount of sequence variation, from single nucleotide polymorphisms to large stretches of DNA that may be present in a range of different copies between individuals. Several such regions are variable in >1% of the population (referred to as copy number polymorphisms or CNPs), and many studies have looked for associations between the copy number of genes within multiallelic CNPs and disease susceptibility. Associations have indeed been described for several genes, including the beta-defensins (DEFB4, DEFB103, DEFB104), chemokine ligand 3 like 1 (CCL3L1), Fc gamma receptor 3B (FCGR3B), and complement component C4 (C4). However, follow-up replication in independent cohorts has failed to reproduce a number of these associations. It is clear that replicated associations such as those between C4 and systemic lupus erythematosus, and beta-defensin and psoriasis, have used robust genotyping methodologies. Technical issues associated with genotyping sequences of high identity may therefore account for failure to replicate other associations. Here, we compare and contrast the most popular approaches that have been used to genotype CNPs, describe how they have been applied in different situations, and discuss potential reasons for the difficulty in reproducibly linking multiallelic CNPs to complex diseases. PMID- 22837111 TI - Cryopreservation of platelets using trehalose: the role of membrane phase behavior during freezing. AB - In blood banks, platelets are stored at 20-24 degrees C, which limits the maximum time they can be stored. Platelets are chilling sensitive, and they activate when stored at temperatures below 20 degrees C. Cryopreservation could serve as an alternative method for long term storage of platelet concentrates. Recovery rates using dimethyl sulfoxide (DMSO) as cryoprotective agent, however, are low, and removal of DMSO is required before transfusion. In this study, we have explored the use of trehalose for cryopreservation of human platelets while using different cooling rates. Recovery of membrane intact cells and the percentage of nonactivated platelets were used as a measure for survival. In all cases, survival was optimal at intermediate cooling rates of 20 degrees C min( 1). Cryopreservation using DMSO resulted in high percentages of activated platelets; namely 54% of the recovered 94%. When using trehalose, 98% of the platelets had intact membranes after freezing and thawing, whereas 76% were not activated. Using Fourier transform infrared spectroscopy, subzero membrane phase behavior of platelets has been studied in the presence of trehalose and DMSO. Furthermore, membrane hydraulic permeability parameters were derived from these data to predict the cell volume response during cooling. Both trehalose and DMSO decrease the activation energy for subzero water transport across cellular membranes. Platelets display a distinct lyotropic membrane phase transition during freezing, irrespective of the presence of cryoprotective agents. We suggest that concomitant uptake of trehalose during freezing could explain the increased survival of platelets cryopreserved with trehalose. PMID- 22837113 TI - What is the optimal test for diagnosis of latent tuberculosis? PMID- 22837112 TI - The semen quality of 1158 men with testicular cancer at the time of cryopreservation: results of the French National CECOS Network. AB - Testicular cancer is the most common cancer in young men. Several studies have reported an alteration in semen quality in nonseminoma tumors, but this result has not been confirmed in all of the published data. We performed a retrospective study in a population of 1158 men with testicular cancer who banked sperm between 1999 and 2003 in 11 French Centre d'Etude et de Conservation des Oeufs et du Sperme humain laboratories. Our study evaluated prefreeze and postthaw sperm parameters according to patient medical history, tumor histological type, and disease stage. Pure seminomas were found in 48% of our population. Testicular cancer was generally diagnosed at stage I. In cases of a history of unilateral cryptorchidism, testicular cancer occurred preferentially in the maldescended testis. Semen samples were preferentially collected after orchiectomy. The sperm concentration and total sperm number were significantly lower before orchiectomy in seminomas compared with nonseminoma tumors (P < .001). After orchiectomy, these parameters decreased for nonseminoma tumors and did not vary for seminomas. Semen parameters were more severely impaired for stage III tumors, and when patients had a history of cryptorchidism or when they were less than 20 years of age. Azoospermia was more frequently observed before than after orchiectomy. In this study, we determined that sperm cryobanking should preferentially be performed before orchiectomy and that testicular sperm extraction concurrent with orchiectomy should be used in severe spermatogenesis impairment. Our study highlights that seminomas alter sperm production more significantly than nonseminoma tumors and seem to preferentially impair spermatogenesis in tumor-bearing testes. PMID- 22837114 TI - Update on the management of ulcerative colitis. AB - The present treatment goals for inflammatory bowel diseases (IBD) especially ulcerative colitis (UC) include rapid induction of clinical remission, steroid free maintenance of clinical remission, mucosal healing and improvement of quality of life in UC patients. Immunomodulators have been reserved for steroid- dependent or steroid- refractory UC patients. Among these agents, azathioprine/6 mercaptopurine should be used for maintenance of remission in quiescent UC. Calcineurin inhibitors can be prescribed as a short-term rescue therapy in steroid- refractory UC patients, but the long term efficacy of these agents remains unclear. According to retrospective studies, methotraxate is not recommended for inducing and maintaining remission in UC. Novel biological therapies targeting different specific immunological pathways continue to be developed and introduced for a variety of clinical scenarios in IBD. Infliximab is currently used for induction and maintenance therapy in patients who have moderately to severely active UC with an inadequate response to conventional agents such as aminosalicylates, corticosteroids, or immunomodulators. Other anti TNF agents and biologic therapies are undergoing evaluation in clinical trials for their efficacy in IBD. Most patients who start biologics should continue treatment for the foreseeable future and potential consequences of discontinuation should be discussed with individual patients. Currently, data do not exist to administer biologics as first-line therapy in UC. Emerging data suggest that biologics may have the potential to prevent complications and limit disease progression. If such benefits are proven, biologics may be used in the future to modulate subclinical inflammation and to prevent the development of clinical disease. PMID- 22837115 TI - Effects of lithium on peripheral neuropathy induced by vincristine in rats. AB - Vincristine (VCR) as a frequently used antimitotic agent which is commonly prescribed for wide spectrum of neoplasm, causes mixed sensorimotor neuropathy. Several evidences show lithium could be a neuroprotective agent, therefore to assess whether a pretreatment and at subtherapeutic dose it could prevent the peripheral neuropathy produced by VCR, rats were treated with VCR 0.1mg/kg i.p. for 3 alternative doses and / or lithium chloride (20mg/kg or 40 mg/kg i.p. daily from the first day to the day of sacrifice). Erythrocyte lithium concentration (ELC) and plasma lithium concentration (PLC) were measured at the seventh day of study and the day of scarification. After seventh day of lithium administration, PLC and ELC reached to a steady state at subtheraputic dose and they did not significantly change at normal housing situation. Hot plate, open field test and nerve conduction velocity were used to evaluate the sensory and motor neuropathy. Only VCR treated rats showed behavioral, electrophysiological and histological evidences of a mixed sensorimotor neuropathy by significant increase in hot plate latencies and a marked decrease in total distance moved and conduction velocities in both sensory and motor nerves. Lithium at the dose of 20mg/kg and specially 40mg/kg robustly reduced the rate of mortality, general toxicity and was able to ameliorate mixed sensorimotor neuropathy induced by VCR. These results suggest that lithium at dose of 20mg/kg and 40 mg/kg, potentially by its effects on cell survival pathways such as inhibition of glycogen synthase kinase-3 (GSK3beta), can prevent both motor and sensory components of VCR neuropathy. PMID- 22837116 TI - Impact of morphine dependency on secondary intention wound healing in rat. AB - Wound healing has always been among important and crucial subjects in medicine. Morphine dependency has also been a social and health problem in the Middle East. This study was aimed to investigate the effects of morphine dependency on pro inflammatory and fibroblast cell recruitment, as well as re-epithelialization and the revascularization processes involved in secondary intention wound healing in rats. A full-thickness wound (2*2 cm in diameters) was created on the dorsum of two groups of rats, a control group and a second group consisted of morphine dependent rats. During the first 14 days of post wounding the wound was excised consecutively at priorly planned days with peripheral margins of normal skin. The specimens were evaluated by two pathologists, who were blind to the study design, and the cellular population, re-epithelialization and revascularization were reported by them. Histological examination of the wound tissue showed evidence of increased population of fibroblasts and a plateau or decreased recruitment of macrophage and neutrophile cells. In the dependent group re-epithelialization was observed to be enhanced significantly in comparison to the control group while having an inhibitory effect on revascularization. The present study demonstrates that morphine dependency enhances re-epithelialization as well as tissue recruitment of fibroblasts; thereby probably enhancing secondary intention wound healing. PMID- 22837117 TI - Staged repair of giant recurrent omphalocele and gastroschesis "camel-litter method"-a new technique. AB - The aim of this article is to present a new Technique of giant omphaloceles repair in neonatal period and also later in life in patients that the primary repair has been failed. From 1999 to 2006, seven consecutive children (male/female ratio 0.4) with giant omphalocele (n=6) and Gastroschesis (n=2) were underwent this new operation in our center. In this technique, there were two operations. The mean of hospital stay was 38 days (range, 23-42 days), and full enteral feeding was achieved on the 8 to 25 postoperative day (Mean, 14 day). The final closure, in all patients was achieved between the 14 to 32 days after the first operation (Mean, 21 day). Mechanical ventilation was necessary for the mean of 5 days (range, 2-8 days). All patients are alive and have no complication due to the operation (1 month-7 years). Giant omphalocele and Gastroschesis can be safely repaired. The placement of an intraperitoneal tissue expander and traction of abdominal muscles can create the needed space for closure in several weeks in patients with giant omphalocele/ Gastroschesis. PMID- 22837118 TI - The effect of ondansetron and meperedin on preventing shivering after off-pump coronary artery bypass graft. AB - One of the most common complications of operation and anesthesia is shivering. The purpose of this study was to compare the effectiveness of Ondanseton and Meperedine in preventing shivering after off-pump coronary artery bypass graft (OPCAB). In this double-blind randomized clinical trial, the sample consisted of 90 patients, who were candidates of CABG under general anesthesia. These patients were assigned to three groups, each containing 30 subjects: meperedine group (A), ondansetron group (B) and control group (C). Group (A) received 0.4 mg/Kg/IV of meperedine, group (B) received 8mg/IV of ondansetron and group (C) received Normal Saline. All these drugs were injected 15 minutes before the end of surgery. After the end of surgery, the intubated patients were transferred to the ICU and their body temperature was assessed through eardrum by a specialist who was blind to the research. The incidence of shivering in groups A, B, and C was 46.48%, 31.18%, and 60.83%, respectively (P=<0.01). The incidence of shivering was 64.4% in males and 35.6% in females (P=0.222). Also, the amount of incidence of shivering up to 3 hours after surgery was 75.87 % (P=0.064). Bradycardia was 3.3% in group (A) and 0.0 % in group (B). Other variables (myoclonus, seizure and rash) showed no statistically significant difference (P=0.353). According to the findings, it was demonstrated that ondansetron is more effective in preventing shivering after Off-pump CABG than meperedine. PMID- 22837119 TI - Evaluation of fibronectin and C-reactive protein levels in patients with sepsis: a case-control study. AB - Sepsis is a significant health problem with an estimated 750,000 new cases in the USA annually. It is also the third leading cause of death in developed countries, equaling the number of fatalities from acute myocardial infarction. The high sepsis-related mortalities mean there is an urgent need to improve the diagnosis and management of sepsis patients. The aim of this study was the evaluation of fibronectin and C-reactive protein (CRP) plasma levels in patients with sepsis and other infectious diseases without sepsis. In a case-control study, 90 patients with sepsis and 90 patients with other infectious diseases without sepsis were studied. Serum levels of fibronectin and CRP were measured. The data were analyzed by SPSS version 15. The mean levels of fibronectin in the cases and controls were 288.97+/-89.10 mg/l and 341.24+/-110.53 mg/l respectively (P=0.001). The mean levels of CRP in the cases and controls were 89.42+/-54.05 ug/ml and 27.42+/-25.89 ug/ml respectively (P<0.001). Concerning the source of infection, the mean CRP levels were significantly higher in septic patients with urinary tract infection, pneumonia, and soft tissue infection (P<0.001). Decreased levels of fibronectin and increased levels of CRP may be considered as reliable diagnostic markers for sepsis. Also, CRP could be a better predictive factor for sepsis than fibronectin. PMID- 22837120 TI - Maternal and neonatal complications of substance abuse in Iranian pregnant women. AB - There is an increased prevalence of maternal substance abuse during pregnancy in younger women in all socioeconomic classes and races. Our aim was to determine the prevalence and correlates of self-reported substance abuse among pregnant women and obstetric complications or neonatal outcomes in Iran. This retrospective cohort study is covering a five year period on medical records of pregnant women attending the maternity unit of four major hospitals (Mahdieh, Taleghani, Imam Hossein and Akbarabadi Hospitals). Women who reported using opium, heroin, crack, cannabis or methamphetamine were compared with women with no reported history of drug abuse for obstetric complications and prenatal morbidity and neonatal mortality. From 100,620 deliveries substance abuse was recorded for 519 women giving a prevalence of 0.5%. Opium was the most prevalent substance abused followed by crack (a mix of heroin and amphetamines). The exposed group had significantly more obstetric complications including preterm low birth weight and postpartum hemorrhage than the non-exposed group. The exposed group had significantly worse prenatal outcomes including more admissions to intensive care unit and higher infant mortality than the non-exposed group. None of the women in the exposed group was on methadone treatment at time of delivery. Risks of maternal and neonatal complications were increased in substance using pregnant women, especially preterm birth and low birth weight. We recommend a multidisciplinary team to provide methadone maintenance therapy for substance using pregnant women and urinary screen of all pregnant women presenting to hospital. PMID- 22837121 TI - Study motives and career choices of Iranian medical and dental students. AB - To compare the study motives and career choices of senior undergraduate medical and dental students in Iran. A cross-sectional questionnaire-based survey study involving final year medical and dental students from 4 dental and medical schools was conducted in 2010. The questionnaire was designed in three sections (Demographic details, motivational items and career choice items) and after confirming the validity and reliability of the questions, it was distributed among the students. Data were entered into SPSS; statistical analysis included logistic regression and multiple linear regression. The response rate was 62% (n=219) for medical and 64% (n=300) for dental students. The factor analysis identified six motivational items: "Social and professional status", "Health care and people", "Others' recommendation", "personal interest and nature of occupation", "Occupational experience" and "Personal life". Medical students were more influenced by "Playing a role in community health" and "Personal interest". "Work independence" and "Social factors" however were two major influential factors among dental students. There were significant differences in important influences by age (Social and professional status, Others' recommendation), Parents' education (Social and professional status, Health care and people, Personal life) and marital status (single >married: Occupational experience, married > single: Personal life). Engaging in postgraduate studies was the first career preference among 90.9% and 89.8% of dental and medical students respectively. Medical and dental students report a wide range of motivational factors in studying medicine/dentistry and future career plans which is affected by age, parents' education and marital status. PMID- 22837122 TI - Medication errors in an internal intensive care unit of a large teaching hospital: a direct observation study. AB - Medication errors account for about 78% of serious medical errors in intensive care unit (ICU). So far no study has been performed in Iran to evaluate all type of possible medication errors in ICU. Therefore the objective of this study was to reveal the frequency, type and consequences of all type of errors in an ICU of a large teaching hospital. The prospective observational study was conducted in an 11 bed internal ICU of a university hospital in Shiraz. In each shift all processes that were performed on one selected patient was observed and recorded by a trained pharmacist. Observer would intervene only if medication error would cause substantial harm. The data was evaluated and then were entered in a form that was designed for this purpose. The study continued for 38 shifts. During this period, a total of 442 errors per 5785 opportunities for errors (7.6%) occurred. Of those, there were 9.8% administration errors, 6.8% prescribing errors, 3.3% transcription errors and, 2.3% dispensing errors. Totally 45 interventions were made, 40% of interventions result in the correction of errors. The most common causes of errors were observed to be: rule violations, slip and memory lapses and lack of drug knowledge. According to our results, the rate of errors is alarming and requires implementation of a serious solution. Since our system lacks a well-organize detection and reporting mechanism, there is no means for preventing errors in the first place. Hence, as the first step we must implement a system where errors are routinely detected and reported. PMID- 22837123 TI - Antimicrobial resistance and molecular typing of pseudomonas aeruginosa isolated from surgical wounds in Lagos, Nigeria. AB - The aim of the study was to determine the resistance patterns of Pseudomonas aeruginosa isolates recovered from patients with surgical wounds in hospitals and also to investigate their epidemiological relatedness using molecular typing techniques. Twenty Pseudomonas sp. isolated from surgical wounds were subjected to antibiotic susceptibility testing by disk diffusion, plasmid profile, SDS-PAGE and PCR using the parC, gyr A gene and RAPD using the 1254 primer. The isolates showed resistance to 12 different antibiotics with six being 100% resistant. Plasmids were detected in 16 (80%) of the isolates. The RAPD-PCR using the primer 1254, SDS-PAGE classified the 20 Pseudomonas spp. into 5 and 6 types respectively. Pseudomona aeruginosa strains isolated from surgical wounds were generally resistant to a broad range of antibiotics and this is rather worrisome. The typing techniques classified the 20 isolates into 5 and 6 groups. PMID- 22837124 TI - Simultaneous shoulder and hip dislocation in a 12-year-old girl with Hutchinson Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder that is characterized by accelerated degenerative changes of the cutaneous, musculoskeletal and cardiovascular systems. Mean age at diagnosis is 2.9 years and generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. Orthopedic manifestations of HGPS are multiple and shoulder dislocation is a rare skeletal trauma in progeria syndrome. Our patient had simultaneous shoulder and hip dislocation associated with a low energy trauma. This subject has not been reported. Treatment accomplished as close reduction under general anesthesia and immobilization. PMID- 22837125 TI - Cerebral sinovenous thrombosis (CSVT) in a neonate with different manifestations. AB - Cerebral sinovenous thrombosis (CSVT) is increasingly diagnosed in neonates. Despite many studies which have addressed diagnosis and management of pediatric CSVT, diagnosis of CVSD in neonates is difficult. A female neonate born by natural vaginal delivery was diagnosed with CSVT after initiation of seizure. The seizure was stabilized and after performing diagnostic tests, the diagnosis of CSVT was made. This report describes diagnosis of this rare condition in a newborn baby in order to make awareness about this serious condition in neonates. PMID- 22837126 TI - Hemodynamic changes after static and dynamic exercises and treadmill stress test; different patterns in patients with primary benign exertional headache? AB - The pathophysiology of primary benign exertional headache (EH) is not still clearly defined. Some researchers have suggested an impaired vascular response as the etiology of this disorder. In this study we investigated whether there are any differences in blood pressure (BP) and heart rate (HR) of the subjects in course of the static and dynamic exercises and the treadmill stress test between those with and without EH. From university students, 22 patients with EH (mean age: 19.8 +/- 2.10, Female to Male: 7:15) and 20 normal subjects (mean age: 19.3 +/- 1.97, Female: Male: 8:12) were recruited. All the subjects performed the static and dynamic exercises at 30 and 20 percent of the maximal voluntary contraction (MVC) and Bruce treadmill stress test according to the standard protocols. HR and BP of all the cases at the baseline and during and immediately after each test were measured. No significant difference was found between the mean rise of HR, systolic and diastolic BP of the subjects with and without EH in static and dynamic exercises and also treadmill stress test. It seems that between those with and without EH, there is no significant difference in rise of HR and BP response to static and dynamic exercises and treadmill stress test. Further studies are required to find the pathophysiology and risk factors of EH. PMID- 22837127 TI - CD14, CD16 and HLA-DR reliably identifies human monocytes and their subsets in the context of pathologically reduced HLA-DR expression by CD14(hi) /CD16(neg) monocytes: Expansion of CD14(hi) /CD16(pos) and contraction of CD14(lo) /CD16(pos) monocytes in acute liver failure. AB - Changes in monocytes and their subsets (CD14(hi)/CD16(neg), CD14(hi)/CD16(pos) and CD14(lo)/CD16(pos)) have been described in several diseases. The combination of CD14, CD16 and HLA-DR has been suggested to discriminate monocytes from the CD16(pos) /HLA-DR(neg) NK-cells and neutrophils but no data exist whether this strategy can be used in situations when monocyte HLA-DR expression is pathologically reduced. Monocytes and their subsets were concurrently identified through negative (exclusion of CD66b(pos) neutrophils, CD56(pos) NKcells, CD19(pos) B-cells, and CD3(pos) T-cells) and positive gating (inclusion of monocytes by expression of CD14, CD16, and HLA-DR) strategies on 30 occasions [9 healthy controls (HC) and 21 patients with conditions associated with low monocyte HLA-DR expression]. Bland-Altman and Passing and Bablok regression statistics did not demonstrate any significant measurement bias between the two strategies of monocyte identification. Monocyte subset phenotype was then compared in 18 HC and 41 patients with acute liver failure (ALF). Compared with HC, in ALF, the percentage of CD14(hi)/CD16(pos) monocytes was higher (7% vs 4%) whilst the percentage of CD14(lo)/CD16(pos) was lower (1.9% vs. 7%) (P <= 0.001); HLA-DR and CD86 MFIs on all monocyte subsets were lower, whilst CCR5, CD64, and CD11b MFIs were higher (P < 0.05). The relative expression by monocyte subsets of HLA-DR, CCR2, CCR5, CX3CR1, and CD11a was similar in ALF patients and HCs. Repeat analysis of an identical antibody-fluorochrome "backbone" targeting HLA-DR, CD14, and CD16 was assessed in 189 samples across 5 different experiments. There was excellent agreement in the results obtained using the positive gating strategy (interclass correlation coefficients > 0.8). Monocytes and their subsets can be reliably identified using an antibody-fluorochrome "backbone" of HLA-DR, CD14, and CD16. CD16(pos) monocytes continue to constitutively express HLA-DR even in conditions where HLA-DR is pathologically reduced on CD14(hi)/CD16(neg) monocytes. Understanding the changes in monocyte pheontype in ALF and similar clinico-pathological diseases may allow the development of novel biomarkers or therapeutic strategies. PMID- 22837128 TI - Hepatic arterial infusion in colorectal carcinoma: is anatomical targeting still relevant in an era of molecularly targeted therapy? AB - BACKGROUND: Historically, metastatic colorectal carcinoma was regarded as a tumor that is relatively resistant to cytotoxic-agents. Due to the limited number of treatment options, methods have been investigated to enhance selectivity. One method for enhancing selectivity is anatomical targeting, including hepatic arterial infusion (HAI). METHODS: A comprehensive review of the literature. RESULTS: Early studies with HAI used fluoropyrimidines, 5-fluorouracil or floxuridine. Several randomized trials comparing the HAI of fluoropyrimidines with systemic administration of fluoropyrimidines or best supportive care that were conducted in the 1980s and early 1990s demonstrated a superior objective response rate, but usually not a prolongation of survival in patients treated with HAI. The current standard of first line systemic chemotherapy of metastatic colorectal carcinoma is combination chemotherapy (fluoropyrimidines, oxaliplatin and/or irinotecan) administered with targeted agents. A number of trials have reported promising activity of the HAI of oxaliplatin and/or irinotecan with fluoropyrimidines, but only pilot studies are available for the combination of HAI of cytotoxic agents with targeted drugs. Factors that limit the effectiveness and utilization of HAI include catheter or port system related complications, the presence of extrahepatic metastases, or increased risk of hepatic toxicity. CONCLUSIONS: HAI could be considered in clinical practice in different settings, including patients after liver resection, as second line therapy in patients failing standard front line regimens and as neodjuvant therapy to convert to resectability. Future studies should specifically concentrate on identifying regimens that would result in increased cure rates in patients with isolated hepatic metastases. For this reason, exploiting anatomical selectivity may still be a useful approach, even in the era of targeted therapy. PMID- 22837129 TI - Photodynamic therapy for enhancing antitumour immunity. AB - BACKGROUND: Photodynamic therapy (PDT) is a new modality in cancer treatment. It is based on the tumour-selective accumulation of a photosensitizer followed by irradiation with light of a specific wavelength. PDT is becoming widely accepted owing to its relative specificity and selectivity along with absence of the harmful side-effects of chemo and radiotherapy. There are three known distinct mechanisms of tumour destruction following PDT, generation of reactive oxygen species which can directly kill tumour cells, tumour vascular shutdown which can independently lead to tumour destruction via lack of oxygen and nutrients and thirdly enhanced antitumour immunity. METHODS: A review based on the literature acquired from the PubMed database from 1983 with a focus on the enhanced antitumour immunity effects of PTD. RESULTS AND CONCLUSION: Tumour cell death is accompanied by the release of a large number of inflammatory mediators. These induce a non-specific inflammatory response followed by gradual adaptive antitumour immunity. Further, a combination of PDT with the immunological approach has the potential to improve PDT efficiency and increase the cure rate. This short review covers specific methods for achieving these goals. PMID- 22837130 TI - Prostate cancer - the role of magnetic resonance imaging. AB - BACKGROUND: This article reviews the potential of magnetic resonance imaging (MRI) in prostate cancer diagnosis. METHODS: Systematic scan of Pubmed, Ovid, Medline, Elsevier search engines was used, additional information was found through bibliographic review of relevant articles. Results. Substantial progress has been made in the imaging of prostate cancer in MR imaging, as well as in advanced MR spectroscopy. CONCLUSIONS: MRI is a non-invasive and direct imaging modality useful for cancer staging, therapy response, detection of recurrence and guided biopsy in previous negative biopsies. MRI with 3.0T system, whole-body MRI, dynamic contrast enhanced MRI, diffusion-weighted imaging (DWI) and MR spectroscopy (MRS) have improved tumor staging, assessment of tumor volume, aggressiveness or recurrence. Implementation of endorectal/phased array superficial MRI findings on 1.5 or 3.0T systems into nomograms for prostate pretreatment prediction is warranted. Surface phasedarray coil MRI accurately defines prostate cancer with elevated risk of extraprostatic disease. PMID- 22837131 TI - Epidemiological of and risk factors for Alzheimer's disease: a review. AB - BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. It is a degenerative, incurable and terminal disease. The increasing prevalence of AD is, among other reasons, due to population aging, which is, to a certain extent, seen worldwide. Continuous advances in health care keep increasing life expectancy. Official statistics are likely to significantly underestimate the actual prevalence of AD. Alzheimer's disease represents an important public health problem. Its aetiology is still unknown and for this reason, it is necessary to study all potential risk factors which may contribute to the development of this disease. METHODS: We searched original and review articles addressing Alzheimer's disease using key words Alzheimer's disease, epidemiology, risk factors and prevention. We found and used one hundred and four references. CONCLUSIONS: Based on epidemiological studies, genetic studies, neuroimaging methods and neuropathology research, three basic etiological hypotheses of the development of AD have been formulated: genetic, vascular and psychosocial. At present, the level of evidence is insufficient for the etiological role of other factors, such as nutrition, occupational exposure to various substances and inflammation. From the point of view of early diagnosis and application of primary or secondary prevention principles, genetic factors are the most important. PMID- 22837132 TI - Analysis of covalent ellipticine- and doxorubicin-derived adducts in DNA of neuroblastoma cells by the 32P-postlabeling technique. AB - BACKGROUND: Ellipticine and doxorubicin are antineoplastic agents, whose action is based mainly on DNA damage such as intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts. The key target to resolve which of these mechanisms are responsible for ellipticine and doxorubicin anticancer effects is the development of suitable methods for identifying their individual DNA-damaging effects. Here, the (32)P-postlabeling method was tested to detect covalent DNA adducts formed by ellipticine and doxorubicin. METHODS: The standard procedure of (32)P-postlabeling assay, this procedure under ATP-deficient conditions, the version using extraction of adducts with n-butanol and the nuclease P1 enrichment version were used to analyze ellipticineand/ or doxorubicin-derived DNA adducts. RESULTS: Two covalent ellipticine-derived DNA adducts, which are associated with cytotoxicity of ellipticine to human UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines, were detected by the (32)P-postlabeling method. These adducts are identical to those formed by the ellipticine metabolites, 13-hydroxy- and 12-hydroxyellipticine. In contrast, no covalent adducts formed by doxorubicin in DNA of these neuroblastoma cells and in DNA incubated with this drug and formaldehyde in vitro were detectable by the (32)P postlabeling assay. CONCLUSIONS: The results presented in this paper are the first to demonstrate that in contrast to covalent DNA adducts formed by ellipticine, the adducts generated by formaldehyde-mediated covalent binding of doxorubicin to DNA are not detectable by the (32)P-postlabeling assay. No DNA adducts were, detectable either in vitro, in incubations of DNA with doxorubicin or in DNA of neuroblastoma cells treated with this drug. The results also suggest that covalent binding of ellipticine to DNA of UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines is the predominant mechanism responsible for the cytotoxicity of this drug. To understand the mechanisms of doxorubicin anticancer effects on neuroblastoma cells, development of novel methods for identifying covalent doxorubicin-derived DNA adducts is the major challenge for further research. PMID- 22837133 TI - Nanotechnology and mesenchymal stem cells with chondrocytes in prevention of partial growth plate arrest in pigs. AB - INTRODUCTION: This study describes the results achieved using a combination of allogeneic mesenchymal stem cells (MSCs) with chondrocytes (CHC) and a new scaffold consisting of type-I collagen and chitosan nanofibers in the prevention of partial growth plate arrest after iatrogenic injury in pigs. MATERIAL AND METHODS: The miniature pig was selected as an experimental model to compare the results in the left femoral bones (MSCs and CHC in scaffold transplantation into the iatrogenic partial distal growth plate defect) and right femoral bones (scaffold alone transplantation). The experimental group consisted of 10 animals. Bone marrow from os ilium as the source of MSCs was used. A porous cylinder consisting of 0.5% by weight type-I collagen and 30% by weight chitosan, was the optimal choice. The length of the bone and angular deformity of distal femur after the healing period was measured and the quality and structure of the newly formed cartilage was histologically examined. RESULTS: Transplantation of the composite scaffold in combination with MSCs and chondrocytes led to the prevention of growth disorder and angular deformity in the distal epiphysis of the left femur. Compared to the right (control) femur, tissue similar to hyaline cartilage with signs of columnar organization typical of the growth plate occurred in most cases. CONCLUSIONS: The promising results of this study reveal the new and effective means for the prevention of bone bridge formation after growth plate injury. PMID- 22837134 TI - Analysis of the prognostic impact of nestin expression in non-small cell lung cancer. AB - BACKGROUND: Nestin is an intermediary filament protein, expressed in progenitor cells of neural and muscle origin and in activated endothelium. The expression of this protein in tumours can be associated with degree of differentiation, biological potential and/or neoangiogenesis. AIMS: The aim of this study was to examine the immunohistochemical expression of nestin in primary non-small cell lung carcinomas (NSCLC) and to determine its prognostic significance. METHODS: Immunohistochemical detection of nestin was carried out on tissue microarrays constructed from 114 formalin-fixed and paraffin-embedded NSCLC samples. These included 78 squamous cell carcinomas and 37 adenocarcinomas. Expression of nestin was also analysed in 35 primary tumour independent NSCLC brain metastasis. The H score and degree of nestin positive microvascularisation were determined. Both parameters correlated with the clinicopathological characteristics including disease-free and overall survival. Results. We demonstrated that expression of nestin is not significantly higher in tumour cells of adenocarcinomas than in sqamous cell carcinomas despite the fact that adenocarcinomas were more frequently positive (P<=0.30). On the other hand, nestin positivity and nestin positive neovascularisation were significantly more often found in stage IIIa tumours than tumours in stages I and II (P<=0.04, P<=0.02). Nestin expression was also significantly higher in brain metastases of squamous cell carcinomas than brain metastases of adenocarcinomas (P<=0.003). The expression of nestin, in general, did not significantly correspond to disease-free or overall survival. CONCLUSION: Nestin expression in NSCLCs is associated with poorer prognosis and with greater nestin-positive microvessel density. PMID- 22837135 TI - Improvements in colorectal cancer screening programmes - quantitative immunochemical faecal occult blood testing - how to set the cut-off for a particular population. AB - OBJECTIVE: The aim of the study was to determine the optimum cut-off value of the quantitative immunochemical test (q-FIT) OC-Sensor for colorectal cancer and advanced adenomatous polyps in a particular population. METHODS: 815 patients were referred for colonoscopy and were offered two q-FIT examinations at two different colonoscopy centers. The patients were classified according to the colonoscopic findings. Test sensitivity, specificity, and accuracy were statistically evaluated using one test and two tests at the levels of 50, 75, 100, 125, and 150 ng/mL of faecal hemoglobin in those patients with advanced polyps and colorectal cancer. The optimum cut-off test level for clinically significant neoplasia was determined using one test. RESULTS: The optimum cut-off value of q-FIT OC-Sensor for the detection of clinically significant neoplasia in our particular population was determined as 75 ng/mL using one test. This value provides an optimum proportion of 73% sensitivity (+/-95% CI 60.3% - 83.4%) and 90% specificity (+/-95% CI 86.8% - 92.8%), PPV and NPV were determined as 54.76% and 95.43% respectively. CONCLUSIONS: The first step in the implementation of q FIT test in the screening program in our country is to determine the optimum cut off level for a population, and to estimate the number of tests performed with respect to the optimum cost effectiveness and economical climate. Using one test, the optimum level of q-FIT OC-Sensor(r) in the Czech Republic was determined as 75 ng/mL. This study could serve as a model for further studies in other countries, where screening does not yet exist. PMID- 22837136 TI - Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD. AB - AIMS: The impact of ApoE polymorphism on angiographic parameters was assessed in patients referred for coronary angiography. METHODS: Elective coronary angiography was performed in 671 subjects (525 men, 146 women, mean age 60 +/- 10 years) with symptoms of ischemic heart disease. The patients were divided into: no CAD group (smooth coronary vessels, n=83), one-vessel (n=155), two-vessel (n=170) and three-vessel disease (n=196). Patients with stenoses 0-50% were excluded. Within patients with CAD, we evaluated overall extent of CAD measured by the number of stenotic segments according to AHA (1 segment vs. 2-3 vs. >=4), and the severity of the most serious stenosis (in percent). ApoE genotype was determined using real-time PCR. RESULTS: The frequency of epsilon2/epsilon3 genotype (n=56) was lower in the three-vessel disease group compared to one vessel disease (OR=0.25, P=0.0019), two-vessel disease (OR=0.31, P=0.0114) or no CAD group (OR=0.24, P=0.0057). Frequency of epsilon2/epsilon3 decreased with the number of affected segments (1 vs. >=4: OR=0.35, P=0.0143). The epsilon3/epsilon4+epsilon4/epsilon4 genotypes (n=123) were more frequent in CAD patients altogether compared with no CAD group (OR=2.30, P=0.019), while no impact of the epsilon4 allele on angiographic parameters within the CAD patients was detected. In epsilon2/epsilon3 carriers with CAD, lower LDL-cholesterol, total cholesterol and lower use of lipid-lowering drugs were observed. CONCLUSIONS: The results show predominantly focal form of CAD in patients with epsilon2/epsilon3 genotype. Lower LDL-cholesterol and total cholesterol may play the key role, although other contributing factors are discussed. PMID- 22837137 TI - The efficacy of conversion from IUI to IVF-ET in infertility patients with hyper response to ovulation induction: a retrospective study. AB - BACKGROUND: The aim of the study was to determine the efficacy of in vitro fertilization and embryo transfer (IVF-ET) in patients with hyper-response to ovulation induction for intrauterine insemination (IUI). METHODS: Patients with polycystic ovary syndrome (PCOS) who were initially treated with IUI in our centre between Jan 2007 and Oct 2010 were retrospectively analyzed. The ovarian hyper-stimulation syndrome (OHSS) found in 50 patients was then treated with IVF ET following informed consent. RESULTS: The fresh transfer had 42 cycles and a total of 87 embryos were transferred. Urine pregnancy tests were positive in 15 patients and fetal heart beat was detected in 12 patients by transvaginal ultrasound, from which 3 patients had two fetuses, 2 patients had three fetuses, and 7 patients had a single fetus. The overall clinical pregnancy rate was 28.5% (12/42) for the fresh embryo transfer. A total of 21 cycles of frozen embryo transfer with up to 55 embryos were conducted for patients who were not pregnant at the end of fresh embryo transfer cycles or who did not receive fresh embryo transfer in the first place. Urine pregnancy tests were positive in 10 patients and fetal heart beat was detected in 8 patients. The clinical pregnancy rate was 38.1% (8/21) for frozen embryo transfer. CONCLUSION: We conclude that IVF-ET is an effective method for patients with hyper-response to ovulation induction in IUI. PMID- 22837138 TI - Inter- and intrastrand DNA crosslinks by 2-fluoro-substituted pyrrolobenzodiazepine dimers: stability, stereochemistry and drug orientation. AB - A 2-fluoro-substituted pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer with a 1,4 di-n-propyl piperazine linker was studied with respect to its binding and crosslinking capability towards double-helical DNA targets. Duplex thermal stabilizations upon drug binding as measured by UV melting experiments suggest that two guanine bases separated by four AT base pairs constitute the favorable binding site for the PBD dimer. Large stabilizations were observed for the self complementary duplex d(AACAATTGTT)(2) as well as for the non-self-complementary duplex d(AAGAATTGTT).d(AACAATTCTT) with both guanines located on the same strand. Formation of interstrand and intrastrand crosslinks by the covalent binding of both PBD moieties of the dimer to the exocyclic 2-amino group of the two guanine bases within the duplex minor groove was confirmed by NMR structural studies. In both the symmetric and non-symmetric DNA-PBD adducts the newly created stereogenic center at C11 of the tricyclic PBD subunits favors an S configuration. Different orientations of the PBD aromatic A-ring with respect to the covalently modified guanine as observed in the non-symmetric complex are shown to result in characteristic changes of PBD H11 and H11a proton chemical shifts. Based on a compilation of available NMR data on various PBD complexes, these differences may be used as valuable probes for the identification of PBD orientational preferences in DNA-PBD adducts. PMID- 22837139 TI - Application of a structure/oxidation-state correlation to complexes of bridging azo ligands. AB - Based on data from more than 40 crystal structures of metal complexes with azo based bridging ligands (2,2'-azobispyridine, 2,2'-azobis(5-chloropyrimidine), azodicarbonyl derivatives), a correlation between the N-N bond lengths (d(NN)) and the oxidation state of the ligand (neutral, neutral/back-donating, radical anionic, dianionic) was derived. This correlation was applied to the analysis of four ruthenium compounds of 2,2'-azobispyridine (abpy), that is, the new asymmetrical rac-[(acac)(2)Ru1(MU-abpy)Ru2(bpy)(2)](ClO(4))(2) ([1](ClO(4))(2)), [Ru(acac)(2)(abpy)] (2), [Ru(bpy)(2)(abpy)](ClO(4))(2) ([3](ClO(4))(2)), and meso [(bpy)(2)Ru(MU-abpy)Ru(bpy)(2)(ClO(4))(3) ([4](ClO(4))(3); acac(-) =2,4 pentanedionato, bpy=2,2'-bipyridine). In agreement with DFT calculations, both mononuclear species 2 and 3(2+) can be described as ruthenium(II) complexes of unreduced abpy(0), with 1.295(5)C and rs1290349:C>A) showed a protective effect against spastic CP, and interestingly both were associated to a decreased epidemiological expression of IL-18 protein. By joining protein data to genetic information, we have provided new data suggesting IL18's involvement in the pathogenesis of spastic CP. PMID- 22837142 TI - Biotransformation of 2,6-diaminopurine nucleosides by immobilized Geobacillus stearothermophilus. AB - An efficient and green bioprocess to obtain 2,6-diaminopurine nucleosides using thermophilic bacteria is herein reported. Geobacillus stearothermophilus CECT 43 showed a conversion rate of 90 and 83% at 2 h to obtain 2,6-diaminopurine-2' deoxyriboside and 2,6-diaminopurine riboside, respectively. The selected biocatalyst was successfully stabilized in an agarose matrix and used to produce up to 23.4 g of 2,6-diaminopurine-2'-deoxyriboside in 240 h of process. These nucleoside analogues can be used as prodrug precursors or in antisense oligonucleotide synthesis. PMID- 22837143 TI - Flow cytometry increases the sensitivity of detection of leukemia and lymphoma cells in bronchoalveolar lavage specimens. AB - BACKGROUND: Recent studies have definitively determined that flow cytometry (FC) is significantly more sensitive than cytomorphology (CM) in detection of hematolymphoid neoplasms (HLNs). However, its utility in paucicellular bronchoalveolar lavage (BAL) specimens has not been established. METHODS: FC was performed on BAL specimens submitted from 44 patients with a prior diagnosis of HLN. Panels chosen were based upon cellularity of specimen and patient history. FC results were compared with concurrent CM evaluations. RESULTS: All 44 BALs were deemed satisfactory for FC and yielded informative results that assisted in diagnosis. Diagnoses included 22/44 B-cell neoplasms, 16/44 T-cell neoplasms, four/44 myeloid neoplasms, and two/44 plasma cell neoplasms. Overall concordance was demonstrated between FC and CM in 77% (34/44) of cases. In nine/44 cases (20%), one technique (FC or CM) clearly detected malignant cells when the other did not. FC was more sensitive than CM in detecting a HLN in eight/nine discordant cases. In only one case (one/44, 2%) were malignant HLN cells suspected by CM, but not identified by FC (one/44, 2%). CONCLUSION: We demonstrate, in the largest series published to date, that FC can be performed on BAL specimens. FC is indicated in evaluation of BAL for HLN and improves sensitivity of detection of HLN over CM alone. An integrated FC and CM approach is superior to either technique alone in diagnostic evaluation of BAL. PMID- 22837144 TI - Perceived and objective breast cancer risk assessment in Chilean women living in an underserved area. AB - BACKGROUND: Breast cancer is the most frequently diagnosed malignancy among Chilean women and an increasingly significant public health threat. This study assessed the accuracy of breast cancer risk perception among underserved, Chilean women. METHODS: Women aged 50 to 70 years, with no mammogram during the last 2 years, were randomly selected from a community clinic registry in Santiago, Chile (n = 500). Perceived risk was measured using three methods: absolute risk, comparative risk, and numerical risk. Risk comprehension was measured by comparing women's perceived and objective risk estimates. Multivariate logistic regression was used to assess overestimation of perceived risk. RESULTS: Women at high risk of breast cancer were more likely than average risk women to perceive themselves at high or higher risk, using absolute and comparative risk approaches (P < 0.001). The majority of participants (67%) overestimated their breast cancer risk, on the basis of risk comprehension; although, participants achieved higher accuracy with comparative risk (40%) and absolute risk (31.6%) methods. [Age, breast cancer knowledge and Breast Cancer Risk Assessment Tool (BCRAT) 5-year risk were significantly associated (P < 0.01) with accuracy of perceived risk]. CONCLUSION: Chilean women residing in an underserved community may not accurately assess their breast cancer risk, although risk perception and level of accuracy differed between perceived risk measures. Comparative and absolute risk methods may better reflect women's interpretation and accuracy of risk perception. IMPACT: Improving our understanding of Chilean women's perceptions of developing breast cancer may lead to the development of culturally relevant efforts to reduce the breast cancer burden in this population. PMID- 22837145 TI - Serum vitamin D and risk of bladder cancer in PLCO--letter. PMID- 22837147 TI - Screening Brazilian Macrophomina phaseolina isolates for alkaline lipases and other extracellular hydrolases. AB - Macrophomina phaseolina, phylum Ascomycota, is a phytopathogenic fungus distributed worldwide in hot dry areas. There are few studies on its secreted lipases and none on its colony radial growth rate, an indicator of fungal ability to use nutrients for growth, on media other than potato-dextrose agar. In this study, 13 M. phaseolina isolates collected in different Brazilian regions were screened for fast-growth and the production of hydrolases of industrial interest, especially alkaline lipases. Hydrolase detection and growth rate determination were done on citric pectin, gelatin, casein, soluble starch, and olive oil as substrates. Ten isolates were found to be active on all substrates tested. The most commonly detected enzymes were pectinases, amylases, and lipases. The growth rate on pectin was significantly higher (P < 0.05), while the growth rates on the different media identified CMM 2105, CMM 1091, and PEL as the fastest-growing isolates. The lipase activity of four isolates grown on olive oil was followed for 4 days by measuring the activity in the cultivation broth. The specific lipolytic activity of isolate PEL was significantly higher at 96 h (130 mU mg protein(-1)). The broth was active at 37 degrees C, pH 8, indicating the potential utility of the lipases of this isolate in mild alkaline detergents. There was a strong and positive correlation (0.86) between radial growth rate and specific lipolytic activity. PMID- 22837148 TI - Surface alteration of realgar (As(4)S(4)) by Acidithiobacillus ferrooxidans. AB - The chemical and physical characteristics of realgar (an arsenic sulfide mineral that occurs in several crystalline forms) in the presence of Acidithiobacillus ferrooxidans BY-3 were investigated in this work. Grains of the mineral were incubated for 10, 20, and 30 days with A. ferrooxidans cultured in 9K medium at 30 degrees C and at 150 rpm agitation. Abiotic control experiments were conducted in identical solutions. The effect of bioleaching on the surface properties of realgar was characterized by scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), inductively coupled plasma atomic emission spectroscope (ICP-AES), X-ray diffraction (XRD), and Raman spectroscopy. SEM and EDS analyses confirmed the ability of A. ferrooxidans to modify surfaces of realgar and to efficiently enhance its dissolution. ICP-AES showed the dissolution and precipitation of realgar during bioleaching. Based on the XRD pattern and the Raman spectra, the decrease in arsenic in the liquid phase was due to co-precipitation of the mineral with Fe(III) or Fe(III) compounds (e.g., jarosite or goethite). Thus, not only did Fe(III) alter the surface of realgar, but it also promoted its dissolution during bioleaching. PMID- 22837149 TI - Bacterial isolates from the bryozoan Membranipora membranacea: influence of culture media on isolation and antimicrobial activity. AB - From specimens of the bryozoan Membranipora membranacea collected in the Baltic Sea, bacteria were isolated on four different media, which significantly increased the diversity of the isolated groups. All isolates were classified according to 16S rRNA gene sequence analysis and tested for antimicrobial properties using a panel of five indicator strains and six different media. Each medium featured a unique set of isolated phylotypes, and a phylogenetically diverse collection of isolates was obtained. A total of 96 isolates were assigned to 49 phylotypes and 29 genera. Only one-third of the members of these genera had been isolated previously from comparable sources. The isolates were affiliated with Alpha- and Gammaproteobacteria, Bacilli, and Actinobacteria. A comparable large portion of up to 22 isolates, i.e., 15 phylotypes, probably represent new species. Likewise, 47 isolates (approximately 50%) displayed antibiotic activities, mostly against grampositive indicator strains. Of the active strains, 63.8 % had antibiotic traits only on one or two of the growth media, whereas only 12.7 % inhibited growth on five or all six media. The application of six different media for antimicrobial testing resulted in twice the number of positive hits as obtained with only a single medium. The use of different media for the isolation of bacteria as well as the variation of media considered suitable for the production of antibiotic substances significantly enhanced both the number of isolates obtained and the proportion of antibiotic active cultures. Thus the approach described herein offers an improved strategy in the search for new antibiotic compounds. PMID- 22837150 TI - Phylogenetic diversity of methyl-coenzyme M reductase (mcrA) gene and methanogenesis from trimethylamine in hypersaline environments. AB - Methanogens have been reported in complex microbial communities from hypersaline environments, but little is known about their phylogenetic diversity. In this work, methane concentrations in environmental gas samples were determined while methane production rates were measured in microcosm experiments with competitive and non-competitive substrates. In addition, the phylogenetic diversity of methanogens in microbial mats from two geographical locations was analyzed: the well studied Guerrero Negro hypersaline ecosystem, and a site not previously investigated, namely Laguna San Ignacio, Baja California Sur, Mexico. Methanogenesis in these microbial mats was suspected based on the detection of methane (in the range of 0.00086 to 3.204 %) in environmental gas samples. Microcosm experiments confirmed methane production by the mats and demonstrated that it was promoted only by non-competitive substrates (trimethylamine and methanol), suggesting that methylotrophy is the main characteristic process by which these hypersaline microbial mats produce methane. Phylogenetic analysis of amino acid sequences of the methyl coenzyme-M reductase (mcrA) gene from natural and manipulated samples revealed various methylotrophic methanogens belonging exclusively to the family Methanosarcinaceae. Moderately halophilic microorganisms of the genus Methanohalophilus were predominant (>60 % of mcrA sequences retrieved). Slightly halophilic and marine microorganisms of the genera Methanococcoides and Methanolobus, respectively, were also identified, but in lower abundances. PMID- 22837151 TI - Contribution of sortase A to the regulation of Listeria monocytogenes LPXTG surface proteins. AB - Gram-positive bacteria of the genus Listeria contain many surface proteins covalently bound to the peptidoglycan. In the pathogenic species Listeria monocytogenes, some of these surface proteins mediate adhesion and entry into host cells. Specialized enzymes called sortases anchor these proteins to the cell wall by a mechanism involving processing and covalent linkage to the peptidoglycan. How bacteria coordinate the production of sortases and their respective protein substrates is currently unknown. The present work investigated whether the functional status of the sortase influences the level at which its cognate substrates are produced. The relative amounts of surface proteins containing an LPXTG sorting motif recognized by sortase A (StrA) were determined in isogenic wild-type and DeltasrtA strains of L. monocytogenes. The possibility of regulation at the transcriptional level was also examined. The results showed that the absence of SrtA did not affect the expression of any of the genes encoding LPXTG proteins. However, marked differences were found at the protein level for some substrates depending on the presence/absence of SrtA. In addition to the known "mis-sorting" of some LPXTG proteins caused by the absence of SrtA, the total amount of certain LPXTG protein species was lower in the DeltasrtA mutant. These data suggested that the rate of synthesis and/or the stability of a subset of LPXTG proteins could be regulated post-transcriptionally depending on the functionality of SrtA. For some LPXTG proteins, the absence of SrtA resulted in only a partial loss of the protein that remained bound to the peptidoglycan, thus providing support for additional modes of cell-wall association in some members of the LPXTG surface protein family. PMID- 22837152 TI - Genomic analysis of a hybridoma batch cell culture metabolic status in a standard laboratory 5 L bioreactor. AB - Currently, there is a gap in the knowledge of the culture responses to controlled bioreactor environment during the course of batch cell culture from early exponential phase to stationary-phase. If available, such information could be used to designate gene transcripts for predicting cell status and as a quality predictor for a controlled bioreactor. In this study, we used oligonucleotide microarrays to obtain baseline gene expression profiles during the time-course of a hybridoma batch cell culture in a 5 L bench-scale bioreactor. Gene expression changes that were up or down modulated from early-to-late in batch culture, as well as invariant gene profiles with significant expression were identified using microarray. Typical cellular functions that seemed to be correlated with transcriptomics were oxidative stress response, DNA damage response, apoptosis, and cellular metabolism. As confirmatory evidence, microarray findings were verified with a more rigorous semiquantitative gene-specific Reverse transcriptase-polymerase chain reaction (RT-PCR). The results of this study suggest that under predefined bioreactor culture conditions, significant gene changes from lag to log to stationary phase could be identified, which could then be used to track the culture state. PMID- 22837153 TI - Effect of carbon coating on the physico-chemical properties and toxicity of copper and nickel nanoparticles. AB - The primary aim of these interdisciplinary studies is to investigate the effect of surface carbon coating on the physico-chemical properties and toxicity of carbon-coated and noncoated copper and nickel nanoparticles (C-Cu, Cu, C-Ni, Ni NPs) in A549 alveolar epithelial cells. Compared to Cu NPs, C-Cu NPs exhibit protection against surface oxidation, tenfold higher cellular uptake, and fourfold lower release of soluble Cu. The toxicity of C-Cu NPs and Cu NPs is associated with pronounced damage to mitochondrial function and plasma membrane integrity, respectively. Compared to Cu and C-Cu NPs, Ni and C-Ni NPs are less toxic. These studies demonstrate that correlations can be drawn between physico chemical properties and resultant toxicity of NPs as a function of surface carbon coating. PMID- 22837154 TI - Preparation of sandwich-structured graphene/mesoporous silica composites with C8 modified pore wall for highly efficient selective enrichment of endogenous peptides for mass spectrometry analysis. AB - In this study, sandwich-structured graphene/mesoporous silica composites (C8 modified graphene@mSiO(2)) were synthesized by coating mesoporous silica onto hydrophilic graphene nanosheets through a surfactant-mediated cocondensation sol gel process. The newly prepared C8-modified graphene@mSiO(2) nanocomposites possess unique properties of extended plate-like morphology, good water dispersibility, highly open pore structure, uniform pore size (2.8 nm), high surface area (632 m(2)/g), and C8-modified-interior pore walls. The unique structure of the C8-modified graphene@mSiO(2) composite nanosheets not only provide extended planes with hydrophilic surface that prevents aggregation in solution, but also offer a huge number of C8-modified mesopores with high surface area that can ensure an efficient adsorption of peptides through hydrophobic hydrophobic interaction between C8-moified pore walls and target molecules. The obtained C8-modified graphene@mSiO(2) materials were utilized for size selectively and specifically enriching peptides in standard peptide mixtures and endogenous peptides in real biological samples (mouse brain tissue). PMID- 22837155 TI - Cardiac dysfunction and prolonged hemodynamic deterioration after implantable cardioverter-defibrillator shock in patients with systolic heart failure. AB - BACKGROUND: We investigated the acute effects of implantable cardioverter defibrillator shock on myocardium, cardiac function, and hemodynamics in relation to left ventricular systolic function. METHODS AND RESULTS: We studied 50 patients who underwent implantable cardioverter-defibrillator implantation and defibrillation threshold (DFT) testing: 25 patients with left ventricular ejection fraction (LVEF) >= 45% and 25 patients with LVEF <45%. We measured cardiac biomarkers (creatine kinase, creatine kinase-MB, myoglobin, cardiac troponin T and I, and N-terminal probrain natriuretic peptide). Left ventricular relaxation was assessed by global longitudinal strain rate during the isovolumetric relaxation period using speckle-tracking echocardiography. Blood sampling and echocardiography were performed before, immediately after, and 5 minutes and 4 hours after DFT testing. Mean arterial pressure was measured directly during DFT testing. Cardiac biomarkers showed no significant changes in either group. LVEF was decreased until 5 minutes after DFT testing and had recovered to the baseline at 4 hours in the group with reduced LVEF (P<0.001), whereas LVEF reduction was not observed in the group with preserved LVEF (P=0.637). Global isovolumetric relaxation period was decreased until 5 minutes after DFT testing and had recovered to the baseline at 4 hours in both groups (preserved LVEF: 0.39 +/- 0.14 versus 0.23 +/- 0.13* versus 0.23 +/- 0.13* versus 0.40 +/- 0.13 s(-1), *P<0.001 versus baseline; reduced LVEF: 0.15 +/- 0.05 versus 0.08 +/- 0.04? versus 0.09 +/- 0.04? versus 0.15 +/- 0.05 s(-1), ?P<0.001 versus baseline, repeated-measures ANOVA). Time to recovery of mean arterial pressure to the baseline was prolonged in the group with reduced LVEF (P<0.001). CONCLUSIONS: Implantable cardioverter-defibrillator shock transiently impairs cardiac function and hemodynamics especially in patients with systolic dysfunction, although significant tissue injury is not observed. PMID- 22837156 TI - Profiling of the human monocytic cell secretome by quantitative label-free mass spectrometry identifies stimulus-specific cytokines and proinflammatory proteins. AB - The immune response to pathogens or injury relies on the concerted release of cytokines and proteins with biological activity important for host protection, host defense, and wound healing. Consequently, the secretome of immune cells provides a promising resource for discovery of specific molecular markers and targets for pharmacological intervention. Here, we employ label-free MS for unbiased, quantitative profiling of the human monocytic cell secretome under different proinflammatory stimuli. The quantitative secretome profiles reveal the highly stimulus-dependent cellular response and differential, specific secretion of more than 200 proteins, including important proinflammatory proteins and cytokines. PMID- 22837157 TI - A Bovine PeptideAtlas of milk and mammary gland proteomes. AB - Proteome information resources of farm animals are lagging behind those of the classical model organisms despite their important biological and economic relevance. Here, we present a Bovine PeptideAtlas, representing a first collection of Bos taurus proteome data sets within the PeptideAtlas framework. This database was built primarily as a source of information for designing selected reaction monitoring assays for studying milk production and mammary gland health, but it has an intrinsic general value for the farm animal research community. The Bovine PeptideAtlas comprises 1921 proteins at 1.2% false discovery rate (FDR) and 8559 distinct peptides at 0.29% FDR identified in 107 samples from six tissues. The PeptideAtlas web interface has a rich set of visualization and data exploration tools, enabling users to interactively mine information about individual proteins and peptides, their prototypic features, genome mappings, and supporting spectral evidence. PMID- 22837158 TI - Unexpected T-cell recognition of an altered peptide ligand is driven by reversed thermodynamics. AB - The molecular basis underlying T-cell recognition of MHC molecules presenting altered peptide ligands is still not well-established. A hierarchy of T-cell activation by MHC class I-restricted altered peptide ligands has been defined using the T-cell receptor P14 specific for H-2D(b) in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM). While substitution of tyrosine to phenylalanine (Y4F) or serine (Y4S) abolished recognition by P14, the TCR unexpectedly recognized H-2D(b) in complex with the alanine-substituted semiagonist Y4A, which displayed the most significant structural modification. The observed functional hierarchy gp33 > Y4A > Y4S = Y4F was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H-2D(b) /gp33 was strictly enthalpy driven, recognition of the weak agonist H-2D(b) /Y4A was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P14 with H-2D(b) /gp33 compared with H-2D(b) /Y4A can possibly be explained by higher water entrapment at the TCR/MHC interface, which is also consistent with the measured opposite entropy contributions for the interactions of P14 with both MHCs. In conclusion, this study demonstrates that P14 makes use of different strategies to adapt to structural modifications in the MHC/peptide complex. PMID- 22837159 TI - "Click & seed" approach to the biomimetic modification of material surfaces. AB - A simple, versatile, protein-repulsive, substrate-independent biomimetic surface modification is presented that is based on the creation of a PEO brush on a polydopamine anchoring layer and its capacity for selective follow-up modifications with various ligands using a copper-catalyzed alkyne-azide cycloaddition reaction. The desired surface concentration of peptide biomimetic ligands can be controlled by adjusting the peptide concentration in the reaction mixture, then measuring the activity of (125)I-radiolabeled peptides that are immobilized on the substrates. The performance of the prepared substrates is tested in cell cultures with MEF cells and a human ECC line. PMID- 22837160 TI - Plasmid DNA microgels for a therapeutical strategy combining the delivery of genes and anticancer drugs. AB - Plasmid DNA (pDNA) is encapsulated into biocompatible microgels by an inverse microemulsion polymerization method. Plasmid DNA and doxorubicin are successfully released from pDNA microgels and their release profiles are characterized by appropriate release models. The co-delivery of genes and drugs from the microgels is evaluated as an enhancer of clinical treatment. Moreover, the release of the encapsulated pDNA is capable of transfection in vitro resulting in the expression of p53 protein. As a whole, a novel pDNA-based system is described that may find biomedical uses, especially in the cancer treatment through the combined action of chemotherapy and gene delivery approach. PMID- 22837161 TI - Reprogramming the beat: kicking it up a notch. PMID- 22837162 TI - Community care in England: reducing socioeconomic inequalities in heart failure. AB - BACKGROUND: Socioeconomic deprivation is associated with increased heart failure (HF) incidence, hospitalization rates, and mortality. However, whether the delivery of survival-enhancing medical therapy is equitable remains uncertain. We examined secular trends in the uptake of key medical therapies (angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, spironolactone) stratified by socioeconomic circumstances in patients with HF. Secondary analyses examined trends in HF incidence, prevalence, and survival. METHODS AND RESULTS: This study was a cross-sectional observational analysis of nationally representative primary care data from England. Treatments for patients with HF in 1999 and 2007 (n=13 330) were extracted from the General Practice Research Database. Socioeconomic circumstances were defined with the Index of Multiple Deprivation 2007, a weighted composite of 7 area-level deprivation domains. Treatment uptake estimates were age standardized. The incidence and prevalence of HF decreased year to year. Although clear socioeconomic gradients in both the incidence and prevalence of HF were apparent, the absolute difference between most and least deprived reduced over time. Uptake of therapies improved over time in both men and women. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker uptake increased from 46% to 64%, beta blocker uptake from 12% to 41%, and spironolactone uptake from 3% to 20%. Modest age and sex inequalities were apparent. However, no consistent socioeconomic gradients were observed in either treatment or case fatality. CONCLUSIONS: Socioeconomic gradients in the incidence and prevalence of HF are reducing. Treatment is generally equitable and independent of socioeconomic circumstances. Most important, no significant inequality in outcomes was apparent. Future strategies should continue to address inequalities in the underlying causes of HF and to increase overall treatment levels further. PMID- 22837163 TI - Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. AB - BACKGROUND: Notch signaling has previously been shown to play an essential role in regulating cell fate decisions and differentiation during cardiogenesis in many systems including Drosophila, Xenopus, and mammals. We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells. METHODS AND RESULTS: In hearts where Notch signaling is activated within the myocardium from early development onward, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system-specific genes and cell autonomous changes in electrophysiology. With the use of an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome, and in action potential characteristics, consistent with reprogramming to a conduction-like phenotype. CONCLUSIONS: Notch can instruct the differentiation of chamber cardiac progenitors into specialized conduction-like cells. Plasticity remains in late stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues. PMID- 22837164 TI - Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules. AB - Vascular remodeling has been implicated in many inflammation-involved diseases. This study aims to investigate the microvascular remodeling-associated alterations in cell-cell adhesion and cytoskeleton reactions to inflammatory stimuli and their impact on microvessel permeability. Experiments were conducted in individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp), and endothelial intracellular calcium concentration, [Ca(2+)](i), was measured in fura-2-perfused vessels. Alterations in VE-cadherin and F-actin arrangement were examined by confocal imaging. Vascular wall cellular composition and structural changes were evaluated by electron microscopy. Vessels exposed to platelet activating factor (PAF) on day 1 were reevaluated 3 days later in rats that had undergone survival surgery. Initial PAF exposure and surgical disturbance increased microvascular wall thickness along with perivascular cell proliferation and altered F-actin arrangement. Although basal permeability was not changed, upon reexposure to PAF, peak endothelial [Ca(2+)](i) was augmented and the peak Lp was 9.3 +/- 1.7 times higher than that of day 1. In contrast to patterns of PAF-induced stress fiber formation and VE-cadherin redistribution observed in day 1 vessels, the day 4 vessels at the potentiated Lp peak exhibited wide separations of VE-cadherin between endothelial cells and striking stress fibers throughout the vascular walls. Confocal images and ultrastructural micrographs also revealed that the largely separated VE-cadherin and endothelial gaps were completely covered by F actin bundles in extended pericyte processes at the PAF-induced Lp peak. These results indicate that inflammation-induced vascular remodeling increased endothelial susceptibility to inflammatory stimuli with augmented Ca(2+) response resulting in upregulated contractility and potentiated permeability increase. Weakened adhesions between the endothelial cells and contractile mechanisms are both involved in increasing permeability in the intact microvessels and are aggravated during remodeling. The perivascular cells play important roles in stabilizing the microvessel wall, while lessening an otherwise much greater magnitude of leakage during cytoskeletal contraction. PMID- 22837165 TI - Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans. AB - We sought to determine the influence of sympathoexcitation on dynamic cerebral autoregulation (CA), cerebrovascular reactivity, and ventilatory control in humans at high altitude (HA). At sea level (SL) and following 3-10 days at HA (5,050 m), we measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined alpha- and beta adrenergic blockade. Dynamic CA was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Ventilatory control was assessed from the hypercapnia and during isocapnic hypoxia. Arterial Pco(2) and ventilation and its control were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated (P < 0.01 vs. SL), but MCAv remained unchanged. Blockade reduced MAP more at HA than at SL (26 vs. 15%, P = 0.048). At HA, gain and coherence in the very-low-frequency (VLF) range (0.02-0.07 Hz) increased, and phase lead was reduced (all P < 0.05 vs. SL). Following blockade at SL, coherence was unchanged, whereas VLF phase lead was reduced (-40 +/- 23%; P < 0.01). In contrast, blockade at HA reduced low-frequency coherence (-26 +/- 20%; P = 0.01 vs. baseline) and elevated VLF phase lead (by 177 +/- 238%; P < 0.01 vs. baseline), fully restoring these parameters back to SL values. Irrespective of this elevation in VLF gain at HA (P < 0.01), blockade increased it comparably at SL and HA (~43-68%; P < 0.01). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced (P < 0.05) it comparably at SL and HA, effects we attributed to the hypotension and/or abolition of the hypercapnic-induced increase in MAP. With the exception of dynamic CA, we provide evidence of a redundant role of sympathetic nerve activity as a direct mechanism underlying changes in cerebrovascular reactivity and ventilatory control following partial acclimatization to HA. These findings have implications for our understanding of CBF function in the context of pathologies associated with sympathoexcitation and hypoxemia. PMID- 22837166 TI - Reduced short-interval intracortical inhibition after eccentric muscle damage in human elbow flexor muscles. AB - The purpose of this study was to use paired-pulse transcranial magnetic stimulation (TMS) to examine the effect of eccentric exercise on short-interval intracortical inhibition (SICI) after damage to elbow flexor muscles. Nine young (22.5 +/- 0.6 yr; mean +/- SD) male subjects performed maximal eccentric exercise of the elbow flexor muscles until maximal voluntary contraction (MVC) force was reduced by ~40%. TMS was performed before, 2 h after, and 2 days after exercise under Rest and Active (5% MVC) conditions with motor-evoked potentials (MEPs) recorded from the biceps brachii (BB) muscle. Peripheral electrical stimulation of the brachial plexus was used to assess maximal M-waves, and paired-pulse TMS with a 3-ms interstimulus interval was used to assess changes in SICI at each time point. The eccentric exercise resulted in a 34% decline in strength (P < 0.001), a 41% decline in resting M-wave (P = 0.01), changes in resting elbow joint angle (10 degrees , P < 0.001), and a shift in the optimal elbow joint angle for force production (18 degrees , P < 0.05) 2 h after exercise. This was accompanied by impaired muscle strength (27%, P < 0.001) and increased muscle soreness (P < 0.001) 2 days after exercise, which is indicative of muscle damage. When the test MEP amplitudes were matched between sessions, we found that SICI was reduced by 27% in resting and 23% in active BB muscle 2 h after exercise. SICI recovered 2 days after exercise when muscle pain and soreness were present, suggesting that delayed onset muscle soreness from eccentric exercise does not influence SICI. The change in SICI observed 2 h after exercise suggests that eccentric muscle damage has widespread effects throughout the motor system that likely includes changes in motor cortex. PMID- 22837167 TI - Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum. AB - Although exercise usually improves motor performance, the underlying cellular changes in the cerebellum remain to be elucidated. This study aimed to investigate whether and how chronic treadmill exercise in young rats induced Purkinje cell changes to improve motor performance and rendered the cerebellum less vulnerable to toxin insults. After 1-wk familiarization of treadmill running, 6-wk-old male Wistar rats were divided into exercise and sedentary groups. The exercise group was then subjected to 8 wk of exercise training at moderate intensity. The rotarod test was carried out to evaluate motor performance. Purkinje cells in cerebellar slices were visualized by lucifer yellow labeling in single neurons and by calbindin immunostaining in groups of neurons. Compared with sedentary control rats, exercised rats not only performed better in the rotarod task, but also showed finer Purkinje cell structure (higher dendritic volume and spine density with the same dendritic field). The exercise improved cerebellar functions were further evaluated by monitoring the long lasting effects of intraventricular application of OX7-saporin. In the sedentary group, OX7-saporin treatment retarded the rotarod performance and induced ~60% Purkinje cell loss in 3 wk. As a comparison, the exercise group showed much milder injuries in the cerebellum by the same toxin treatment. In conclusion, exercise training in young rats increased the dendritic density of Purkinje cells, which might play an important role in improving the motor performance. Furthermore, as Purkinje cells in the exercise group were relatively toxin resistant, the exercised rats showed good motor performance, even under toxin treated conditions. PMID- 22837168 TI - Airway closure on imaging relates to airway hyperresponsiveness and peripheral airway disease in asthma. AB - The regional pattern and extent of airway closure measured by three-dimensional ventilation imaging may relate to airway hyperresponsiveness (AHR) and peripheral airways disease in asthmatic subjects. We hypothesized that asthmatic airways are predisposed to closure during bronchoconstriction in the presence of ventilation heterogeneity and AHR. Fourteen asthmatic subjects (6 women) underwent combined ventilation single photon emission computed tomography/computed tomography scans before and after methacholine challenge. Regional airway closure was determined by complete loss of ventilation following methacholine challenge. Peripheral airway disease was measured by multiple-breath nitrogen washout from which S(cond) (index of peripheral conductive airway abnormality) was derived. Relationships between airway closure and lung function were examined by multiple linear regression. Forced expiratory volume in 1 s was 87.5 +/- 15.8% predicted, and seven subjects had AHR. Methacholine challenge decreased forced expiratory volume in 1 s by 23 +/- 5% and increased nonventilated volume from 16 +/- 4 to 29 +/- 13% of computed tomography lung volume. The increase in airway closure measured by nonventilated volume correlated independently with both S(cond) (partial R(2) = 0.22) and with AHR (partial R(2) = 0.38). The extent of airway closure induced by methacholine inhalation in asthmatic subjects is greater with increasing peripheral airways disease, as measured by ventilation heterogeneity, and with worse AHR. PMID- 22837169 TI - Bimodal collagen fibril diameter distributions direct age-related variations in tendon resilience and resistance to rupture. AB - Scaling relationships have been formulated to investigate the influence of collagen fibril diameter (D) on age-related variations in the strain energy density of tendon. Transmission electron microscopy was used to quantify D in tail tendon from 1.7- to 35.3-mo-old (C57BL/6) male mice. Frequency histograms of D for all age groups were modeled as two normally distributed subpopulations with smaller (D(D1)) and larger (D(D2)) mean Ds, respectively. Both D(D1) and D(D2) increase from 1.6 to 4.0 mo but decrease thereafter. From tensile tests to rupture, two strain energy densities were calculated: 1) u(E) [from initial loading until the yield stress (sigma(Y))], which contributes primarily to tendon resilience, and 2) u(F) [from sigma(Y) through the maximum stress (sigma(U)) until rupture], which relates primarily to resistance of the tendons to rupture. As measured by the normalized strain energy densities u(E)/sigma(Y) and u(F)/sigma(U), both the resilience and resistance to rupture increase with increasing age and peak at 23.0 and 4.0 mo, respectively, before decreasing thereafter. Multiple regression analysis reveals that increases in u(E)/sigma(Y) (resilience energy) are associated with decreases in D(D1) and increases in D(D2), whereas u(F)/sigma(U) (rupture energy) is associated with increases in D(D1) alone. These findings support a model where age-related variations in tendon resilience and resistance to rupture can be directed by subtle changes in the bimodal distribution of Ds. PMID- 22837170 TI - Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome. AB - Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 +/- 5 and 105 +/- 9 MUm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 +/- 3 and 31 +/- 3 MUm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 +/- 2 and 30 +/- 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 * 10(6) +/- 0.7 * 10(6) and 1.1 * 10(6) +/- 0.2 * 10(6) dyn/cm(2) in Lean and MetS, respectively, P < 0.001; BSI: 10.3 +/- 0.4 and 7.3 +/ 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS. PMID- 22837172 TI - Brain stem oxidative stress and its associated signaling in the regulation of sympathetic vasomotor tone. AB - There is now compelling evidence from studies in humans and animals that overexcitation of the sympathetic nervous system plays an important role in the pathogenesis of cardiovascular diseases. An excellent example is neurogenic hypertension, in which central sympathetic overactivation is involved in the development, staging, and progression of the disease, and one of the underlying mechanisms involves oxidative stress in key brain stem sites that are engaged in the regulation of sympathetic vasomotor tone. Using the rostral ventrolateral medulla (RVLM) and nucleus tractus solitarii (NTS) as two illustrative brain stem neural substrates, this article provides an overview of the impact of reactive oxygen species and antioxidants on RVLM and NTS in the pathogenesis of neurogenic hypertension. This is followed by a discussion of the redox-sensitive signaling pathways, including several kinases, ion channels, and transcription factors that underpin the augmentation in sympathetic vasomotor tone. In addition, the emerging view that brain stem oxidative stress is also causally related to a reduction in sympathetic vasomotor tone and hypotension during brain stem death, methamphetamine intoxication, and temporal lobe status epilepticus will be presented, along with the causal contribution of the oxidant peroxynitrite formed by a reaction between nitric oxide synthase II (NOS II)-derived nitric oxide and superoxide. Also discussed as a reasonable future research direction is dissection of the cellular mechanisms and signaling cascades that may underlie the contributory role of nitric oxide generated by different NOS isoforms in the differential effects of oxidative stress in the RVLM or NTS on sympathetic vasomotor tone. PMID- 22837171 TI - Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717. AB - Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ~50% reduction in respiratory frequency in vitro (50 MUM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA(A) receptors, which was exacerbated by hypoxic (8% O(2)) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 MUM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression. PMID- 22837173 TI - Relating components of pressure-volume area in Suga's formulation of cardiac energetics to components of the stress-time integral. AB - The concept of pressure-volume area (PVA) in whole heart studies is central to the phenomenological description of cardiac energetics proposed by Suga and colleagues (Physiol Rev 70: 247-277, 1990). PVA consists of two components: an approximately rectangular work loop (W) and an approximately triangular region of potential energy (U). In the case of isovolumic contractions, PVA consists entirely of U. The utility of Suga's description of cardiac energetics is the observation that the oxygen consumption of the heart (Vo(2)) is linearly dependent on PVA. By using isolated ventricular trabeculae, we found a basis on which to correlate the components of stress-length area (SLA; i.e., the 1-D equivalent of PVA) with specific regions of the stress-time integral (STI; i.e., the area under the force-time profile of a single twitch). In each case, proportionality obtains and is robust, independent of the type of twitch contraction (isometric or isotonic), and insensitive to changes of preload or afterload. We apply our results by examining retrospectively the interpretations reached in three independent studies published in the literature. PMID- 22837176 TI - UNDERSTANDING HETEROGENEITY IN NORMAL OLDER ADULT POPULATIONS VIA CLUSTERING OF LONGITUDINAL DATA. AB - Populations of healthy older individuals are often highly heterogeneous, as prevalence of various underlying pathologies increases with age. Finding coherent groups of normal older adults may allow to identify subpopulations that are at risk of developing Alzheimer's disease (AD). In this paper, we propose an approach that utilizes longitudinal magnetic resonance imaging (MRI) data to obtain natural groupings of older adult subjects via an unsupervised (i.e., clustering) technique. We develop a k-medoids-like clustering algorithm that simultaneously finds clusters of longitudinal images, as well as weights brain regions in such a way that the obtained clusters are maximally coherent. We propose a cluster-based measure that reflects the individual subject's cognitive decline. The proposed method is unsupervised and is suitable for analyzing AD at its very early stages. PMID- 22837174 TI - Fc-fusion proteins: new developments and future perspectives. AB - Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas. PMID- 22837175 TI - Explant culture: a simple, reproducible, efficient and economic technique for isolation of mesenchymal stromal cells from human adipose tissue and lipoaspirate. AB - Adipose tissue has emerged as a preferred source of mesenchymal stem/stromal cells (MSC), due to its easy accessibility and high MSC content. The conventional method of isolation of adipose tissue-derived stromal cells (ASC) involves enzymatic digestion and centrifugation, which is a costly and time-consuming process. Mechanical stress during isolation, use of bacterial-derived products and potential contamination with endotoxins and xenoantigens are other disadvantages of this method. In this study, we propose explant culture as a simple and efficient process to isolate ASC from human adipose tissue. This technique can be used to reproducibly isolate ASC from fat tissue obtained by liposuction as well as surgical resection, and yields an enriched ASC population free from contaminating haematopoietic cells. We show that explanting adipose tissue results in a substantially higher yield of ASC at P0 per gram of initial fat tissue processed, as compared to that obtained by enzymatic digestion. We demonstrate that ASC isolated by explant culture are phenotypically and functionally equivalent to those obtained by enzymatic digestion. Further, the explant-derived ASC share the immune privileged status and immunosuppressive properties implicit to MSC, suggesting that they are competent to be tested and applied in allogeneic clinical settings. As explant culture is a simple, inexpensive and gentle method, it may be preferred over the enzymatic technique for obtaining adipose tissue-derived stem/stromal cells for tissue engineering and regenerative medicine, especially in cases of limited starting material. PMID- 22837177 TI - Strontium- and magnesium-enriched biomimetic beta-TCP macrospheres with potential for bone tissue morphogenesis. AB - During the last two decades, biogenic mineral ions have become important additives in treatments for bone regeneration and repair. Prominent among these is strontium, which is a potent suppressor of osteoclast bone resorption. Another is magnesium, which has a key influence in mineralization processes. The shells of benthic foraminiferans, hydrothermally converted into beta-TCP, have been shown to effectively release a number of bone-promoting drugs at clinically relevant levels. In this study we characterized the effects of converted foraminiferan calcium dissolution and the concomitant release profile of intrinsic strontium and magnesium. We tested the effects of strontium- and magnesium-enriched macrospheres on human osteoblast (SaOS-2) and monocytoid (U937) cell lines, which can be induced to express equivalent phagocytic activities to osteoclasts. On dissolution in a biomimetic physiological solution, the macrospheres released biologically significant quantities of calcium and phosphate ions in the first 18 days. At 3 days, during which biogenic mineral ions are released, the number of U937 osteoclast-like monocyte cells decreased, while 4 days later the osteoblast cell number increased. These results show that strontium and magnesium naturally enriched macrospheres are capable of altering the metabolic activities of the cells regulating bone homeostasis. These unique macrospheres are natural origin bone void filler particles that resorb, and release physiologically significant levels of incorporated strontium, magnesium and calcium, which together make a uniquely multifunctional in situ remedy for bone regeneration and repair and the treatment of bone-wasting diseases. PMID- 22837178 TI - Tracheal cartilage - evaluating the potential of a novel biomaterial for reconstructive cardiovascular procedures. AB - Modern cardiovascular medicine aims for procedures that preferably involve biological materials and, ideally, living implants. Thereby, the regenerative capacity of the target organ may be preserved or even supported, with a potential implant growth capacity during the following time. In the current study we sought to evaluate the integrative capacity of vital and non-vital tracheal cartilage rings (TCRs) of allogenic or xenogenic origin (allo-/xeno-vTCR; allo-/xeno-nvTCR) as biomaterials under the in vivo functional load of the circulatory system. Ovine and porcine vTCRs and nvTCRs were implanted in the mitral valve (MV) position for 3 and 9 months (n = 3 each), respectively, in lambs. MV function and TCR position were analysed by echocardiography. Tissue morphology (planimetry), vitality (live/dead-assay) and implant endothelialization (scanning electron microscopy) were analysed. No functional impairment or significant MV insufficiency or stenosis was observed in any group. TCR shrinkage was observed in all xeno-TCRs and allo-nvTCRs at 3 months. Only TCRs of allogenic groups at 9 months and allo-vTCRs at 3 months showed a ring area comparable to its size at implantation. Moreover, allogenic vital cartilage showed superior tissue integration, greater endothelialization, less inflammation and calcification. Interestingly, in this group viable cartilage cells were found up to 9 months after implantation. Allogenic viable cartilage may represent a well-suited living material for reconstructive cardiovascular procedures, and further studies are warranted to elucidate the benefits of this novel material, particularly as a structurally supportive component in growing recipients. PMID- 22837179 TI - Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma. AB - PURPOSE: Myeloid-derived suppressor cells (MDSC) have emerged as an immune regulatory cell type that is expanded in tumor-bearing mice, but less is known about their immune-suppressive role in patients with cancer. EXPERIMENTAL DESIGN: To study the importance of MDSC in patients with melanoma, we characterized the frequency, phenotype, and suppressive function of blood myeloid-derived cells and tumor-infiltrating myeloid cells in 26 freshly resected melanomas. RESULTS: Blood and tumor-infiltrating myeloid cells (Lin(-) CD11b(+)) could be phenotypically and morphologically classified into monocytes/macrophages, neutrophils, eosinophils, and immature myeloid cells according to marker expression (CD14(+), CD14(-) CD15(hi), CD14(-) CD15(int), and CD14(-) CD15(-), respectively). In contrast to the expansion of MDSC reported in tumor-bearing mice, we found no differences in the frequency and phenotype of myeloid subsets in the blood of patients with melanoma compared with healthy donors. Myeloid cells represented 12% of the live cells in the melanoma cell suspensions, and were phenotypically diverse with high tumor-to-tumor variability. Interestingly, a positive association was found between the percentage of Tregs and granulocytic cells (Lin(-) CD11b(+) CD14(-)CD15(+)) infiltrating melanoma tumors. However, melanoma infiltrating myeloid cells displayed impaired suppression of nonspecific T-cell proliferation compared with peripheral blood myeloid cells, in which monocytes and eosinophils were suppressive. CONCLUSIONS: Our findings provide a first characterization of the nature and suppressive function of the melanoma myeloid infiltrate and indicate that the suppressive function of MDSC in patients with melanoma seems far less than that based on murine tumor models. PMID- 22837180 TI - Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. AB - PURPOSE: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. EXPERIMENTAL DESIGN: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. RESULTS: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. CONCLUSIONS: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-kappaB signaling pathway, which may be promising targets for future therapeutic strategies. PMID- 22837182 TI - The enamel microstructures of bovine mandibular incisors. AB - Bovine teeth have been considered as an excellent substitute for human teeth for dental research, however, the enamel microstructures of bovine incisors that include arrangements of prisms and interprisms, and their spatial relationships have not been well described. The aim of this study was to investigate the detail enamel microstructures of bovine incisors. Eight bovine mandibular incisors were cut into 77 pieces at eight equal intervals either in the longitudinal direction or in the horizontal direction before each piece had been tangentially cut (parallel to enamel-dentin junction) through the middle of the enamel thickness. All the sectioned surfaces were treated 1 M HCl for 10 sec to expose the prisms and interprisms before observation by scanning electron microscopy. The parallel enamel prisms were located in all the outer enamel, the cervical region and the incisal ridge of the bovine incisors. Most labial inner enamel and the cingulum of lingual inner enamel were composed of the Hunter-Schreger bands with the characteristics of decussating groups of prisms and decussating planes between interprisms and prisms. The interprisms were thicker in the inner enamel than in the outer enamel. PMID- 22837181 TI - A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. AB - PURPOSE: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer. EXPERIMENTAL DESIGN: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a "3+3" design, cohorts of three to six patients received paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort. RESULTS: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42-82) with a median of 2 prior regimens (range: 0-6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS(6-month) actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. CONCLUSIONS: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity. PMID- 22837184 TI - Online monitoring of heterogeneous polymerizations in supercritical carbon dioxide by Raman spectroscopy. AB - A novel setup is described to monitor the kinetics of homogeneous and heterogeneous reactions online using Raman spectroscopy under high pressure. The arrangement is based on a high-pressure reactor equipped with a sapphire window in combination with a mobile probe that allows the collection of the back scattered Raman signal at 360 degrees . PMID- 22837186 TI - Successful treatment of tumor-induced osteomalacia with CT-guided percutaneous ethanol and cryoablation. AB - CONTEXT: Tumor-induced osteomalacia is a rare condition usually caused by benign mesenchymal tumors. When the tumor can be found, patients are usually managed by wide excision of the tumor. OBJECTIVE: We report a 51-yr-old male with clinical and biochemical evidence of tumor-induced osteomalacia caused by a mesenchymal tumor in the right iliac bone. He declined surgery and appears to have been successfully managed by computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation. RESULTS: Our patient appears to have had an excellent clinical and biochemical response to computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation. We found one prior case of image-guided ablation using radiofrequency ablation for tumor-induced osteomalacia. CONCLUSIONS: Although the standard treatment for tumor-induced osteomalacia is wide excision of the tumor, image-guided ablation may be an option in patients who cannot have appropriate surgery or who decline surgery. PMID- 22837187 TI - Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open label trial. AB - CONTEXT: Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib. OBJECTIVE: The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC. DESIGN: This was a phase II, open-label trial using a two-stage accrual design. SETTING: The study was conducted at two tertiary referral centers. PATIENTS: Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study. INTERVENTION: The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off). MAIN OUTCOME MEASURE: Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation). RESULTS: Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naive estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction. CONCLUSION: Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naive ACC patients. PMID- 22837188 TI - The utility of menstrual cycle length as an indicator of cumulative hormonal exposure. AB - CONTEXT: Associations between menstrual cycle length and chronic diseases are hypothesized to be due to differences in underlying hormonal patterns. OBJECTIVE: The aim of the study was to evaluate the association between menstrual cycle length and the hormonal profile and anovulation. DESIGN AND SETTING: We conducted a prospective cohort study at the University at Buffalo from 2005 to 2007. PARTICIPANTS: We recruited 259 healthy, regularly menstruating women aged 18-44 yr. MAIN OUTCOME MEASURES: Cycle length was observed for up to two cycles. Serum estradiol, progesterone, LH, and FSH were measured up to eight times per cycle for up to two cycles. RESULTS: Women with short cycles (<26 d) had higher FSH concentrations during menses and in the late luteal phase, higher follicular estradiol concentrations, and lower LH concentrations across the cycle. Among women with longer cycles (>35 d), estradiol and LH peaks occurred on average about 3 d later, and FSH peaks about 1 d later compared to women with normal length cycles. Both short and long cycles, compared with normal-length cycles, had an increased probability of anovulation. In general, per-cycle exposure to hormones was less in short cycles based on the area under the curve, although over time the cumulative exposure to estradiol would be greater for women with short cycles. CONCLUSIONS: Short ovulatory cycles were associated with higher follicular phase estradiol, an earlier rise in FSH, and an increased risk of anovulation. These results suggest that menstrual cycle length may be a relevant indicator of estradiol exposure and risk of anovulation among regularly cycling women. PMID- 22837189 TI - Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. AB - CONTEXT: Nonalcoholic fatty liver disease may be evident in women with polycystic ovary syndrome (PCOS), both conditions being associated with obesity and insulin resistance. However, few studies have accounted for the high prevalence of obesity in PCOS. OBJECTIVE: The aim of this study was to determine whether PCOS is independently associated with hepatic steatosis, compared with healthy controls of similar age and body mass index (BMI), and whether steatosis is associated with hyperandrogenemia. DESIGN AND SETTING: We conducted a cross sectional, case-control study at two tertiary referral centers. PATIENTS: Twenty nine women with PCOS diagnosed by the Rotterdam criteria [aged 28 yr; 95% confidence interval (CI), 26-31; BMI, 33 kg/m2; 95% CI, 31-36] and 22 healthy controls (aged 29 yr; 95% CI, 28-31; BMI, 30 kg/m2; 95% CI, 28-33) were studied. METHODS: Proton-magnetic resonance spectroscopy quantified hepatic and skeletal muscle fat; whole body magnetic resonance imaging quantified internal, visceral, and sc adipose tissue volumes. Differences were assessed between PCOS and controls using t tests, and between hyperandrogenic (HA) PCOS, PCOS with normal androgens (NA), and controls using analysis of covariance. RESULTS: After statistical adjustment for BMI, HA-PCOS had significantly higher liver fat vs. NA PCOS (3.7%; 95% CI, 0.6-13.1) and vs. controls (2.1%; 95% CI, 0.3-6.6). Similarly, after adjustment for homeostasis model assessment for insulin resistance, internal and visceral adipose tissue volumes, liver fat remained significantly greater in HA-PCOS compared to NA-PCOS and controls. CONCLUSION: These data suggest that HA-PCOS is associated with hepatic steatosis, independent of obesity and insulin resistance. PMID- 22837190 TI - Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial. AB - CONTEXT: Low levels of soluble receptor for advanced glycation end-products (sRAGE) have been linked to systemic inflammation and vascular complications in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: We examined the effects of exercise on sRAGE and its association with diverse cardiometabolic risk factors and indicators of atherosclerosis in patients with T2DM. DESIGN, SETTING, AND PARTICIPANTS: Seventy-five patients with T2DM were randomized into a control group and an aerobic exercise group (60 min at moderate intensity, five times/wk for 12 wk). MAIN OUTCOME MEASURES: We evaluated sRAGE, energy expenditure, dietary energy intake, cardiorespiratory fitness, inflammatory markers, visceral fat area, pulse-wave velocity, and flow-mediated dilatation. RESULTS: Baseline sRAGE concentrations were independently associated with age, glycated hemoglobin, glucose, triglyceride, and high-density lipoprotein cholesterol levels (R2=0.244). After 12 wk of exercise training, the exercise group showed significantly decreased body weight, waist circumference, blood pressure, glycated hemoglobin, apolipoprotein B, and free fatty acid levels. Concurrently, cardiorespiratory fitness assessed by oxygen uptake at anaerobic threshold was improved, and body fat percentage and visceral fat area were significantly decreased in the exercise group, although pulse-wave velocity and flow-mediated dilatation were not changed. Furthermore, sRAGE levels were increased and high sensitivity C-reactive protein levels were decreased in the exercise group but not in the control group. Percent change of sRAGE level was negatively correlated with that of high-sensitivity C-reactive protein during the study period (r= 0.27; P=0.019). CONCLUSIONS: Aerobic exercise increases sRAGE levels along with improvement of various cardiometabolic risk factors in patients with T2DM. PMID- 22837191 TI - Computer-assisted learning in anatomy at the international medical school in Debrecen, Hungary: a preliminary report. AB - The University of Debrecen's Faculty of Medicine has an international, multilingual student population with anatomy courses taught in English to all but Hungarian students. An elective computer-assisted gross anatomy course, the Computer Human Anatomy (CHA), has been taught in English at the Anatomy Department since 2008. This course focuses on an introduction to anatomical digital images along with clinical cases. This low-budget course has a large visual component using images from magnetic resonance imaging and computer axial tomogram scans, ultrasound clinical studies, and readily available anatomy software that presents topics which run in parallel to the university's core anatomy curriculum. From the combined computer images and CHA lecture information, students are asked to solve computer-based clinical anatomy problems in the CHA computer laboratory. A statistical comparison was undertaken of core anatomy oral examination performances of English program first-year medical students who took the elective CHA course and those who did not in the three academic years 2007-2008, 2008-2009, and 2009-2010. The results of this study indicate that the CHA-enrolled students improved their performance on required anatomy core curriculum oral examinations (P < 0.001), suggesting that computer assisted learning may play an active role in anatomy curriculum improvement. These preliminary results have prompted ongoing evaluation of what specific aspects of CHA are valuable and which students benefit from computer-assisted learning in a multilingual and diverse cultural environment. PMID- 22837192 TI - Motion planning and synchronized control of the dental arch generator of the tooth-arrangement robot. AB - BACKGROUND: The traditional, manual method of reproducing the dental arch form is prone to numerous random errors caused by human factors. The purpose of this study was to investigate the automatic acquisition of the dental arch and implement the motion planning and synchronized control of the dental arch generator of the multi-manipulator tooth-arrangement robot for use in full denture manufacture. METHODS: First, the mathematical model of the dental arch generator was derived. Then the kinematics and control point position of the dental arch generator of the tooth arrangement robot were calculated and motion planning of each control point was analysed. A hardware control scheme is presented, based on the industrial personal computer and control card PC6401. In order to gain single-axis, precise control of the dental arch generator, we studied the control pulse realization of high-resolution timing. Real-time, closed-loop, synchronous control was applied to the dental arch generator. Experimental control of the dental arch generator and preliminary tooth arrangement were gained by using the multi-manipulator tooth-arrangement robotic system. RESULTS: The dental arch generator can automatically generate a dental arch to fit a patient according to the patient's arch parameters. Repeated positioning accuracy is 0.12 mm for the slipways that drive the dental arch generator. The maximum value of single-point error is 1.83 mm, while the arc width direction (x axis) is -33.29 mm. CONCLUSION: A novel system that generates the dental arch has been developed. The traditional method of manually determining the dental arch may soon be replaced by a robot to assist in generating a more individual dental arch. The system can be used to fabricate full dentures and bend orthodontic wires. PMID- 22837193 TI - Increased genetic and phenotypic stability of a promising live-attenuated respiratory syncytial virus vaccine candidate by reverse genetics. AB - Human respiratory syncytial virus (RSV) is the most important viral cause of serious pediatric respiratory illness worldwide. Currently, the most promising live-attenuated vaccine candidate is a temperature-sensitive (ts) cDNA-derived virus named rA2cp248/404/1030DeltaSH, in reference to its set of attenuating mutations. In a previous clinical study, more than one-third of postvaccination nasal wash isolates exhibited partial loss of the ts phenotype. Most of this instability appeared to be due to reversion at a missense point mutation called 1030. This 1030 mutation is a single-nucleotide tyrosine-to-asparagine substitution at position 1321 (Y1321N) of the polymerase L protein that contributes to the ts and attenuation phenotypes of the vaccine candidate. The goals of the present study were to identify a reversion-resistant codon at position 1321 conferring a comparable level of attenuation and to use this to develop a genetically stable version of the vaccine virus. We modified wild-type (wt) RSV to insert each of the 20 possible amino acids at position 1321; 19 viruses were recoverable. We also investigated small deletions at or near this position, but these viruses were not recoverable. Phenotypic analysis identified alternative attenuating amino acids for position 1321. Several of these amino acids were predicted, based on the genetic code, to be refractory to deattenuation. Classical genetics, using temperature stress tests in vitro combined with nucleotide sequencing, confirmed this stability but identified a second site with a compensatory mutation at position 1313. It was possible to stabilize the 1313 site as well, providing a stable 1030 mutation. Further stress tests identified additional incidental mutations, but these did not reverse the ts/attenuation phenotype. An improved version of the vaccine candidate virus was constructed and validated in vitro by temperature stress tests and in vivo by evaluation of attenuation in seronegative chimpanzees. In addition to developing an improved version of this promising live-attenuated RSV vaccine candidate, this study demonstrated the propensity of an RNA virus to escape from attenuation but also showed that, through systematic analysis, genetics can be used to cut off the routes of escape. PMID- 22837194 TI - HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term. AB - HIV controllers are rare individuals who spontaneously control HIV replication in the absence of antiretroviral therapy. To identify parameters of the CD4 response that may contribute to viral control rather than merely reflect a persistently low viremia, we compared the T helper profiles in two groups of patients with more than 10 years of viral suppression: HIV controllers from the Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) CO18 cohort (n = 26) and efficiently treated patients (n = 16). Cells specific for immunodominant Gag and cytomegalovirus (CMV) peptides were evaluated for the production of 10 cytokines and cytotoxicity markers and were also directly quantified ex vivo by major histocompatibility complex (MHC) class II tetramer staining. HIV controller CD4(+) T cells were characterized by a higher frequency of gamma interferon (IFN-gamma) production, perforin(+)/CD107a(+) expression, and polyfunctionality in response to Gag peptides. While interleukin 4 (IL-4), IL-17, and IL-21 production did not differ between groups, the cells of treated patients produced more IL-10 in response to Gag and CMV peptides, pointing to persistent negative immunoregulation after long-term antiretroviral therapy. Gag293 tetramer positive cells were detected at a high frequency (0.12%) and correlated positively with IFN-gamma-producing CD4(+) T cells in the controller group (R = 0.73; P = 0.003). Tetramer-positive cells were fewer in the highly active antiretroviral therapy (HAART) group (0.04%) and did not correlate with IFN-gamma production, supporting the notion of a persistent immune dysfunction in HIV specific CD4(+) T cells of treated patients. In conclusion, HIV controllers maintained a population of highly efficient Th1 effectors directed against Gag in spite of a persistently low antigenemia, while patients treated in the long term showed a loss of CD4 effector functions. PMID- 22837195 TI - Human parvovirus B19 DNA replication induces a DNA damage response that is dispensable for cell cycle arrest at phase G2/M. AB - Human parvovirus B19 (B19V) infection is highly restricted to human erythroid progenitor cells, in which it induces a DNA damage response (DDR). The DDR signaling is mainly mediated by the ATR (ataxia telangiectasia-mutated and Rad3 related) pathway, which promotes replication of the viral genome; however, the exact mechanisms employed by B19V to take advantage of the DDR for virus replication remain unclear. In this study, we focused on the initiators of the DDR and the role of the DDR in cell cycle arrest during B19V infection. We examined the role of individual viral proteins, which were delivered by lentiviruses, in triggering a DDR in ex vivo-expanded primary human erythroid progenitor cells and the role of DNA replication of the B19V double-stranded DNA (dsDNA) genome in a human megakaryoblastoid cell line, UT7/Epo-S1 (S1). All the cells were cultured under hypoxic conditions. The results showed that none of the viral proteins induced phosphorylation of H2AX or replication protein A32 (RPA32), both hallmarks of a DDR. However, replication of the B19V dsDNA genome was capable of inducing the DDR. Moreover, the DDR per se did not arrest the cell cycle at the G(2)/M phase in cells with replicating B19V dsDNA genomes. Instead, the B19V nonstructural 1 (NS1) protein was the key factor in disrupting the cell cycle via a putative transactivation domain operating through a p53-independent pathway. Taken together, the results suggest that the replication of the B19V genome is largely responsible for triggering a DDR, which does not perturb cell cycle progression at G(2)/M significantly, during B19V infection. PMID- 22837196 TI - Evidence for multiple cell death pathways during development of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression: apoptosis, necroptosis, and pyroptosis. AB - AIDS-related human cytomegalovirus (HCMV) retinitis remains a major ophthalmologic problem worldwide. Although this sight-threatening disease is well characterized clinically, many pathogenic issues remain unresolved, among them a basic understanding of the relative roles of cell death pathways during development of retinal tissue destruction. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus induced immunosuppression (MAIDS), we initially investigated MCMV-infected eyes for evidence of apoptosis-associated molecules in mice with MAIDS of 4 weeks' (MAIDS-4) and 10 weeks' (MAIDS-10) duration, which were resistant and susceptible to retinal disease, respectively, but which harbored equivalent amounts of infectious MCMV. Whereas MCMV-infected eyes of MAIDS-4 mice showed little evidence of apoptosis-associated molecules, MCMV-infected eyes of MAIDS-10 mice showed significant amounts of tumor necrosis factor alpha (TNF-alpha), TNF receptors 1 and 2, active caspase 8, active caspase 3, TNF-related apoptosis inducing ligand (TRAIL), TRAIL-R(DR5), Fas, and Fas ligand mRNAs and/or proteins, all detected at peak amounts prior to development of most severe retinal disease. Immunohistochemical staining showed macrophages, granulocytes (neutrophils), Muller cells, and microglial cells as TNF-alpha sources. Remarkably, quantification of apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP biotin nick end labeling (TUNEL) assay suggested that apoptosis contributed minimally to retinal disease in MCMV-infected eyes of MAIDS-10 mice. Subsequent studies demonstrated that MCMV-infected eyes of MAIDS-10 mice, but not MAIDS-4 mice, showed evidence of significant increases in molecules associated with two additional cell death pathways, necroptosis (receptor-interacting protein 1 [RIP1] and RIP3 mRNAs) and pyroptosis (caspase 1, interleukin 1beta [IL-1beta], and IL-18 mRNAs). We conclude that apoptosis, necroptosis, and pyroptosis participate simultaneously during MAIDS-related MCMV retinitis, and all may play a role during AIDS-related HCMV retinitis. PMID- 22837197 TI - TLR7 recognition is dispensable for influenza virus A infection but important for the induction of hemagglutinin-specific antibodies in response to the 2009 pandemic split vaccine in mice. AB - Recognition of pathogen-associated molecular patterns by pattern recognition receptors of the innate immune system is crucial for the initiation of innate and adaptive responses and for immunological memory. We investigated the role of TLR7 in the induction of adaptive immunity and long-term memory following influenza virus infection and vaccination in C57BL/6 mice. During infection with influenza A/PR8/34 virus, the absence of either TLR7 or MyD88 leads to reduced virus specific antibodies in the serum and antibody-secreting cells in their secondary lymphoid organs, particularly in bone marrow. In spite of this, the absence of TLR7/MyD88 signaling did not impair the production of protective antibodies. Following immunization with the 2009 pandemic inactivated split vaccine, TLR7(-/ ) mice had significantly lower levels of germinal center formation, antibody secreting cells, and circulating influenza virus-specific antibodies than control animals. Consequently, TLR7(-/-) mice failed to develop protective immunological memory upon challenge. Furthermore, the immunogenicity of the split vaccine was likely due to TLR7 recognition of virion RNA, as its removal from the split vaccine significantly reduced the levels of influenza virus-specific antibodies and compromised the vaccine protective efficacy in mice. Taken together, our data demonstrate that TLR7 plays an important role in vaccine-induced humoral immune responses to influenza virus through the interaction with viral RNA present in the split vaccine. PMID- 22837198 TI - Control of early Theiler's murine encephalomyelitis virus replication in macrophages by interleukin-6 occurs in conjunction with STAT1 activation and nitric oxide production. AB - During Theiler's murine encephalomyelitis virus (TMEV) infection of macrophages, it is thought that high interleukin-6 (IL-6) levels contribute to the demyelinating disease found in chronically infected SJL/J mice but absent in B10.S mice capable of clearing the infection. Therefore, IL-6 expression was measured in TMEV-susceptible SJL/J and TMEV-resistant B10.S macrophages during their infection with TMEV DA strain or responses to lipopolysaccharide (LPS) or poly(I . C). Unexpectedly, IL-6 production was greater in B10.S macrophages than SJL/J macrophages during the first 24 h after stimulation with TMEV, LPS, or poly(I . C). Further experiments showed that in B10.S, SJL/J, and RAW264.7 macrophage cells, IL-6 expression was dependent on extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and enhanced by exogenous IL 12. In SJL/J and RAW264.7 macrophages, exogenous IL-6 resulted in decreased TMEV replication, earlier activation of STAT1 and STAT3, production of nitric oxide, and earlier upregulation of several antiviral genes downstream of STAT1. However, neither inhibition of IL-6-induced nitric oxide nor knockdown of STAT1 diminished the early antiviral effect of exogenous IL-6. In addition, neutralization of endogenous IL-6 from SJL/J macrophages with Fab antibodies did not exacerbate early TMEV infection. Therefore, endogenous IL-6 expression after TMEV infection is dependent on ERK MAPK, enhanced by IL-12, but too slow to decrease viral replication during early infection. In contrast, exogenous IL-6 enhances macrophage control of TMEV infection through preemptive antiviral nitric oxide production and antiviral STAT1 activation. These results indicate that immediate early production of IL-6 could protect macrophages from TMEV infection. PMID- 22837199 TI - The H275Y neuraminidase mutation of the pandemic A/H1N1 influenza virus lengthens the eclipse phase and reduces viral output of infected cells, potentially compromising fitness in ferrets. AB - The H275Y amino acid substitution of the neuraminidase gene is the most common mutation conferring oseltamivir resistance in the N1 subtype of the influenza virus. Using a mathematical model to analyze a set of in vitro experiments that allow for the full characterization of the viral replication cycle, we show that the primary effects of the H275Y substitution on the pandemic H1N1 (H1N1pdm09) strain are to lengthen the mean eclipse phase of infected cells (from 6.6 to 9.1 h) and decrease (by 7-fold) the viral burst size, i.e., the total number of virions produced per cell. We also find, however, that the infectious-unit-to particle ratio of the H275Y mutant strain is 12-fold higher than that of the oseltamivir-susceptible strain (0.19 versus 0.016 per RNA copy). A parallel analysis of the H275Y mutation in the prior seasonal A/Brisbane/59/2007 background shows similar changes in the infection kinetic parameters, but in this background, the H275Y mutation also allows the mutant to infect cells five times more rapidly. Competitive mixed-strain infections in vitro, where the susceptible and resistant H1N1pdm09 strains must compete for cells, are characterized by higher viral production by the susceptible strain but suggest equivalent fractions of infected cells in the culture. In ferrets, however, the mutant strain appears to suffer a delay in its infection of the respiratory tract that allows the susceptible strain to dominate mixed-strain infections. PMID- 22837200 TI - Site-specific cleavage of the host poly(A) binding protein by the encephalomyocarditis virus 3C proteinase stimulates viral replication. AB - Although picornavirus RNA genomes contain a 3'-terminal poly(A) tract that is critical for their replication, the impact of encephalomyocarditis virus (EMCV) infection on the host poly(A)-binding protein (PABP) remains unknown. Here, we establish that EMCV infection stimulates site-specific PABP proteolysis, resulting in accumulation of a 45-kDa N-terminal PABP fragment in virus-infected cells. Expression of a functional EMCV 3C proteinase was necessary and sufficient to stimulate PABP cleavage in uninfected cells, and bacterially expressed 3C cleaved recombinant PABP in vitro in the absence of any virus-encoded or eukaryotic cellular cofactors. N-terminal sequencing of the resulting C-terminal PABP fragment identified a 3C(pro) cleavage site on PABP between amino acids Q437 and G438, severing the C-terminal protein-interacting domain from the N-terminal RNA binding fragment. Single amino acid substitution mutants with changes at Q437 were resistant to 3C(pro) cleavage in vitro and in vivo, validating that this is the sole detectable PABP cleavage site. Finally, while ongoing protein synthesis was not detectably altered in EMCV-infected cells expressing a cleavage-resistant PABP variant, viral RNA synthesis and infectious virus production were both reduced. Together, these results establish that the EMCV 3C proteinase mediates site-specific PABP cleavage and demonstrate that PABP cleavage by 3C regulates EMCV replication. PMID- 22837201 TI - Human cytomegalovirus stimulates monocyte-to-macrophage differentiation via the temporal regulation of caspase 3. AB - Monocytes are primary targets for human cytomegalovirus (HCMV) infection and are proposed to be responsible for hematogenous dissemination of the virus. Biologically, monocytes have a short life span of 48 h in the circulation, a period of time during which monocytes must make a cell fate decision on whether to undergo apoptosis or differentiate into a macrophage. We have previously shown that HCMV infection stimulates monocyte-to-macrophage differentiation; however, the mechanism(s) by which HCMV-infected monocytes simultaneously navigate the 48 h "viability gate" and undergo macrophagic differentiation has remained elusive. Studies have demonstrated that the level of caspase 3 and 8 activities in monocytes may mediate the delicate balance between apoptosis and macrophage colony-stimulating factor (M-CSF)-induced myeloid differentiation. Here, we show that HCMV infection, unlike M-CSF treatment, does not induce caspase 8 activity to promote myeloid differentiation. However, HCMV infection does induce a temporal activation of caspase 3, with only a low level of active caspase 3 being observed after the 48-h viability checkpoint. Consistent with the role of a time dependent activation of caspase 3 in promoting myeloid differentiation, the inhibition of caspase 3 blocked HCMV-induced monocyte-to-macrophage differentiation. Temporal transcriptome and functional analyses identified heat shock protein 27 (HSP27) and Mcl-1, two known regulators of caspase 3 activation, as being upregulated prior to the 48-h viability gate following HCMV infection. Using small interfering RNAs (siRNAs), we demonstrate that HCMV targets the rapid induction of HSP27 and Mcl-1, which cooperatively function to precisely control caspase 3 activity in order to allow for HCMV-infected monocytes to successfully traverse the 48-h cell fate decision checkpoint and commence macrophage maturation. Overall, this study highlights a unique regulatory mechanism employed by HCMV to tightly modulate the caspase 3 activity needed to promote myeloid differentiation, a key process in the viral dissemination and persistence strategy. PMID- 22837202 TI - Entry of influenza A Virus with a alpha2,6-linked sialic acid binding preference requires host fibronectin. AB - The receptor binding specificity of influenza A virus is one of the major determinants of viral tropism and host specificity. In general, avian viral hemagglutinin prefers to bind to alpha2,3-linked sialic acid, whereas the human viral hemagglutinin prefers to bind to alpha2,6-linked sialic acid. Here, we demonstrate that host fibronectin protein plays an important role in the life cycle of some influenza A viruses. Treating cells with anti-fibronectin antibodies or fibronectin-specific small interfering RNA can inhibit the virus replication of human H1N1 influenza A viruses. Strikingly, these inhibitory effects cannot be observed in cells infected with H5N1 viruses. By using reverse genetics techniques, we observed that the receptor binding specificity, but not the origin of the hemagglutinin subtype, is responsible for this differential inhibitory effect. Changing the binding preference of hemagglutinin from alpha2,6 linked sialic acid to alpha2,3-linked sialic acid can make the virus resistant to the anti-fibronectin antibody treatment and vice versa. Our further characterizations indicate that anti-fibronectin antibody acts on the early phase of viral replication cycle, but it has no effect on the initial binding of influenza A virus to cell surface. Our subsequent investigations further show that anti-fibronectin antibody can block the postattachment entry of influenza virus. Overall, these results indicate that the sialic acid binding preference of influenza viral hemagglutinin can modulate the preferences of viral entry pathways, suggesting that there are subtle differences between the virus entries of human and avian influenza viruses. PMID- 22837204 TI - A combination of broadly neutralizing HIV-1 monoclonal antibodies targeting distinct epitopes effectively neutralizes variants found in early infection. AB - Neutralizing antibody protection against HIV-1 may require broad and potent antibodies targeting multiple epitopes. We tested 7 monoclonal antibodies (MAbs) against 45 viruses of diverse subtypes from early infection. The CD4 binding site MAb NIH45-46W was most broad and potent (91% coverage; geometric mean 50% inhibitory concentration [IC(50)], 0.09 MUg/ml). Combining NIH45-46W and a V3 specific MAb, PGT128, neutralized 96% of viruses, while PGT121, another V3 specific MAb, neutralized the remainder. Thus, 2 or 3 antibody specificities may prevent infection by most HIV-1 variants. PMID- 22837203 TI - Myd88-dependent toll-like receptor 7 signaling mediates protection from severe Ross River virus-induced disease in mice. AB - Arthralgia-associated alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), pose significant public health threats because of their ability to cause explosive outbreaks of debilitating arthralgia and myalgia in human populations. Although the host inflammatory response is known to contribute to the pathogenesis of alphavirus-induced arthritis and myositis, the role that Toll-like receptors (TLRs), which are major regulators of host antiviral and inflammatory responses, play in the pathogenesis of alphavirus-induced arthritis and myositis has not been extensively studied. Using a mouse model of RRV-induced myositis/arthritis, we found that myeloid differentiation primary response gene 88 (Myd88)-dependent TLR7 signaling is involved in protection from severe RRV associated disease. Infections of Myd88- and TLR7-deficient mouse strains with RRV revealed that both Myd88 and TLR7 significantly contributed to protection from RRV-induced mortality, and both mouse strains exhibited more severe tissue damage than wild-type (WT) mice following RRV infection. While viral loads were unchanged in either Myd88 or TLR7 knockout mice compared to WT mice at early times postinfection, both Myd88 and TLR7 knockout mice exhibited higher viral loads than WT mice at late times postinfection. Furthermore, while high levels of RRV-specific antibody were produced in TLR7-deficient mice, this antibody had very little neutralizing activity and had lower affinity than WT antibody. Additionally, TLR7- and Myd88-deficient mice showed defects in germinal center activity, suggesting that TLR7-dependent signaling is critical for the development of protective antibody responses against RRV. PMID- 22837205 TI - Hepatitis C virus-induced autophagy is independent of the unfolded protein response. AB - Hepatitis C virus (HCV) has been shown to induce autophagy and the unfolded protein response (UPR), but the mechanistic link between the induction of these two cellular processes remains unclear. We demonstrate here that HCV infection induces autophagy, as judged by accumulation of lipidated LC3-II, and that this induction occurs rapidly after infection, preceding the stimulation of the UPR, which occurs only at later stages, after the viral envelope glycoproteins have been expressed to high levels. Furthermore, both genotype 1b and 2a subgenomic replicons expressing nonstructural (NS3-5B) proteins and JFH-1 virus lacking the envelope glycoproteins potently induced autophagy in the absence of detectable UPR. This ability was also shared by a subgenomic replicon derived from the related GB virus B (GBV-B). We also show that small interfering RNA (siRNA) mediated silencing of the key UPR inducer, Ire1, has no effect on HCV genome replication or the induction of autophagy, further demonstrating that the UPR is not required for these processes. Lastly, we demonstrate that the HCV replicase does not colocalize with autophagosomes, suggesting that the induction of autophagy is not required to generate the membrane platform for HCV RNA replication. PMID- 22837206 TI - The attenuated genotype of varicella-zoster virus includes an ORF0 transitional stop codon mutation. AB - Varicella-zoster virus (VZV) is the first of the human herpesviruses to be attenuated and subsequently approved as a live vaccine to prevent varicella and herpes zoster. Both the attenuated VZV vaccine, called vaccine Oka or vOka, and the parental strain pOka have been completely sequenced. Yet the specific determinants of attenuation are uncertain. The open reading frame (ORF) with the most single nucleotide polymorphisms (SNPs), ORF62, encodes the regulatory protein IE62, but IE62 studies have failed to define a specific SNP associated with attenuation. We have completed next-generation sequencing of the VZV Ellen genome, a strain known to be highly attenuated by its very limited replication in human skin xenografts in the SCID mouse model of VZV pathogenesis. A comparative analysis of the Ellen sequence with all other complete VZV sequences was extremely informative. In particular, an unexpected finding was a stop codon mutation in Ellen ORF0 (herpes simplex virus UL56 homolog) identical to one found in vOka, combined with the absence of polymorphisms in most Ellen ORFs that were known to be mutated in vOka. The mutated ORF0 protein was also imaged in both two dimensions and three dimensions by confocal microscopy. The probability of two VZV strains not connected by a recent common ancestor having an identical ORF0 SNP by chance would be 1 * 10(-8), in other words, extremely unlikely. Taken together, these bioinformatics analyses strongly suggest that the stop codon ORF0 SNP is one of the determinants of the attenuation genotype of live VZV vaccines. PMID- 22837207 TI - Nonstructural Nipah virus C protein regulates both the early host proinflammatory response and viral virulence. AB - Nipah virus (NiV) is a highly pathogenic, negative-strand RNA paramyxovirus that has recently emerged from flying foxes to cause serious human disease. We have analyzed the role of the nonstructural NiV C protein in viral immunopathogenesis using recombinant virus lacking the expression of NiV C (NiVDeltaC). While wild type NiV was highly pathogenic in the hamster animal model, NiVDeltaC was strongly attenuated. Replication of NiVDeltaC was followed by the production of NiV-specific antibodies and associated with higher recruitment of inflammatory cells and less intensive histopathological lesions in different organs than in wild-type-NiV-infected animals. To analyze the molecular basis of NiVDeltaC attenuation, we studied early changes in gene expression in infected primary human endothelial cells, a major cellular target of NiV infection. The transcriptomic approach revealed the striking difference between wild-type and mutant NiV in the expression of genes involved in immunity, with the particularly interesting differential patterns of proinflammatory cytokines. Compared to wild type virus, NiVDeltaC induced increased expression of interleukin 1 beta (IL 1beta), IL-8, CXCL2, CXCL3, CXCL6, CCL20, and beta interferon. Furthermore, the expression of NiV C in stably transfected cells decreased the production of the same panel of cytokines, revealing a role of the C protein in the regulation of cytokine balance. Together, these results suggest that NiV C regulates expression of proinflammatory cytokines, therefore providing a signal responsible for the coordination of leukocyte recruitment and the chemokine-induced immune response and controlling the lethal outcome of the infection. PMID- 22837208 TI - LGP2 downregulates interferon production during infection with seasonal human influenza A viruses that activate interferon regulatory factor 3. AB - LGP2, a member of the RIG-I-like receptor family, lacks the amino-terminal caspase activation recruitment domains (CARDs) required for initiating the activation of interferon regulatory factor 3 (IRF3) and interferon (IFN) transcription. The role of LGP2 in virus infection is controversial, and the only LGP2 experiments previously carried out with mammalian influenza A viruses employed an attenuated, mouse-adapted H1N1 A/PR/8/34 (PR8) virus that does not encode the NS1 protein. Here we determine whether LGP2 has a role during infection with wild-type, nonattenuated influenza A viruses that have circulated in the human population, specifically two types of seasonal influenza A viruses: (i) H3N2 and H1N1 viruses that activate IRF3 and IFN transcription and (ii) recent H1N1 viruses that block these two activations. In human cells infected with an H3N2 virus that activates IRF3, overexpression of LGP2 or its repressor domain decreased STAT1 activation and IFN-beta transcription approximately 10 fold. Overexpression of LGP2 also caused a 10-fold decrease of STAT1 activation during infection with other seasonal influenza A viruses that activate IRF3. Using LGP2(+/+) and LGP2(-/-) mouse cells, we show that endogenous LGP2 decreased IFN production during H3N2 virus infection 3- to 4-fold. In contrast, in both mouse and human cells infected with H1N1 viruses that do not activate IRF3, LGP2 had no detectable role. These results demonstrate that LGP2 downregulates IFN production during infection by seasonal influenza A viruses that activate IRF3 and IFN transcription. It is intriguing that LGP2, a host protein induced during influenza A virus infection, downregulates the host antiviral IFN response. PMID- 22837209 TI - Tick-borne Nyamanini virus replicates in the nucleus and exhibits unusual genome and matrix protein properties. AB - Tick-borne Nyamanini virus (NYMV) is the prototypic member of a recently discovered genus in the order Mononegavirales, designated Nyavirus. The NYMV genome codes for six distinct genes. Sequence similarity and structural properties suggest that genes 1, 5, and 6 encode the nucleoprotein (N), the glycoprotein (G), and the viral polymerase (L), respectively. The function of the other viral genes has been unknown to date. We found that the third NYMV gene codes for a protein which, when coexpressed with N and L, can reconstitute viral polymerase activity, suggesting that it represents a polymerase cofactor. The second viral gene codes for a small protein that inhibits viral polymerase activity and further strongly enhances the formation of virus-like particles when coexpressed with gene 4 and the viral glycoprotein G. This suggests that two distinct proteins serve a matrix protein function in NYMV as previously described for members of the family Filoviridae. We further found that NYMV replicates in the nucleus of infected cells like members of the family Bornaviridae. NYMV is a poor inducer of beta interferon, presumably because the viral genome is 5' monophosphorylated and has a protruding 3' terminus as observed for bornaviruses. Taken together, our results demonstrate that NYMV possesses biological properties previously regarded as typical for filoviruses and bornaviruses, respectively. PMID- 22837210 TI - Reverse genetics recovery of Lujo virus and role of virus RNA secondary structures in efficient virus growth. AB - Arenaviruses are rodent-borne viruses with a bisegmented RNA genome. A genetically unique arenavirus, Lujo virus, was recently discovered as the causal agent of a nosocomial outbreak of acute febrile illness with hemorrhagic manifestations in Zambia and South Africa. The outbreak had a case fatality rate of 80%. A reverse genetics system to rescue infectious Lujo virus from cDNA was established to investigate the biological properties of this virus. Sequencing the genomic termini showed unique nucleotides at the 3' terminus of the S segment promoter element. While developing this system, we discovered that reconstructing infectious Lujo virus using the previously reported L segment intergenic region (IGR), comprising the arenaviral transcription termination signal, yielded an attenuated Lujo virus. Resequencing revealed that the correct L segment IGR was 36 nucleotides longer, and incorporating it into the reconstructed Lujo virus restored the growth rate to that of the authentic clinical virus isolate. These additional nucleotides were predicted to more than double the free energy of the IGR main stem-loop structure. In addition, incorporating the newly determined L IGR into a replicon reporter system enhanced the expression of a luciferase reporter L segment. Overall, these results imply that an extremely stable secondary structure within the L-IGR is critical for Lujo virus propagation and viral protein production. The technology for producing recombinant Lujo virus now provides a method to precisely investigate the molecular determinants of virulence of this newly identified pathogen. PMID- 22837211 TI - The secreted G protein of human respiratory syncytial virus antagonizes antibody mediated restriction of replication involving macrophages and complement. AB - The respiratory syncytial virus (RSV) G and F glycoproteins are the neutralization antigens, and G also is expressed in a soluble form (sG). Previously, sG was demonstrated to reduce the efficiency of RSV antibody-mediated neutralization by serving as an antigen decoy and to inhibit the antibody mediated antiviral effects of Fc receptor-bearing leukocytes. The present study demonstrated that effective antibody-mediated restriction in vivo, and the evasion of this restriction by sG, involves pulmonary macrophages and complement, but not neutrophils. PMID- 22837212 TI - Epstein-Barr virus latent membrane protein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through alphav-integrin membrane translocation. AB - Epstein-Barr virus (EBV) is a highly prevalent herpesvirus associated with epithelial cancers, including nasopharyngeal carcinoma (NPC). The EBV protein latent membrane protein 2 (LMP2) is expressed in NPC tumor tissue and has been shown to induce transformation, inhibit differentiation, and promote migration of epithelial cells. In this study, the effect of LMP2A on migration of human epithelial cells was further analyzed. LMP2A expression induced migration in human foreskin keratinocytes (HFK) and HaCaT keratinocytes measured by wound healing scratch assay and chemoattractant-induced Transwell migration assay. The induction of migration by LMP2A required the ITAM signaling domain of LMP2A and activation of the Syk tyrosine kinase. LMP2A-induced Transwell migration required the Akt signaling pathway, and activation of Akt by LMP2A required the ITAM signaling domain of LMP2A. LMP2A also induced phosphorylation of the Akt target GSK3beta, a Wnt signaling mediator that has been shown to regulate the activity of focal adhesion kinase (FAK), a tyrosine kinase activated by clustering and ligand interaction of integrins. Inhibition of either FAK or its signaling mediator Src kinase inhibited LMP2A-induced migration. Interestingly, alphaV integrin was greatly increased in membrane-enriched fractions by LMP2A, and a neutralizing antibody to alphaV-integrin blocked migration, suggesting that the effects of LMP2A on membrane-localized alphaV-integrin promoted migration. The results of this study indicate that LMP2A expression in human epithelial cells induces alphaV-integrin-dependent migration through a mechanism requiring ITAM mediated Syk and Akt activation and inducing membrane translocation or stabilization of alphaV-integrin and FAK activation. The specific effects of LMP2A on an integrin with a diverse repertoire of ligand specificities could promote migration of different cell types and be initiated by multiple chemoattractants. PMID- 22837213 TI - Chikungunya virus nsP3 blocks stress granule assembly by recruitment of G3BP into cytoplasmic foci. AB - Chikungunya virus nonstructural protein nsP3 has an essential but unknown role in alphavirus replication and interacts with Ras-GAP SH3 domain-binding protein (G3BP). Here we describe the first known function of nsP3, to inhibit stress granule assembly by recruiting G3BP into cytoplasmic foci. A conserved SH3 domain binding motif in nsP3 is essential for both nsP3-G3BP interactions and viral RNA replication. This study reveals a novel role for nsP3 as a regulator of the cellular stress response. PMID- 22837214 TI - Reovirus replication protein MU2 influences cell tropism by promoting particle assembly within viral inclusions. AB - The double-stranded RNA virus mammalian reovirus displays broad cell, tissue, and host tropism. A critical checkpoint in the reovirus replication cycle resides within viral cytoplasmic inclusions, which are biosynthetic centers of genome multiplication and new-particle assembly. Replication of strain type 3 Dearing (T3) is arrested in Madin-Darby canine kidney (MDCK) cells at a step subsequent to inclusion development and prior to formation of genomic double-stranded RNA. This phenotype is primarily regulated by viral replication protein MU2. To understand how reovirus inclusions differ in productively and abortively infected MDCK cells, we used confocal immunofluorescence and thin-section transmission electron microscopy (TEM) to probe inclusion organization and particle morphogenesis. Although no abnormalities in inclusion morphology or viral protein localization were observed in T3-infected MDCK cells using confocal microscopy, TEM revealed markedly diminished production of mature progeny virions. T3 inclusions were less frequent and smaller than those formed by T3-T1M1, a productively replicating reovirus strain, and contained decreased numbers of complete particles. T3 replication was enhanced when cells were cultivated at 31 degrees C, and inclusion ultrastructure at low-temperature infection more closely resembled that of a productive infection. These results indicate that particle assembly in T3-infected MDCK cells is defective, possibly due to a temperature sensitive structural or functional property of MU2. Thus, reovirus cell tropism can be governed by interactions between viral replication proteins and the unique cell environment that modulate efficiency of particle assembly. PMID- 22837216 TI - Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction. AB - Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time- and dose-dependent manner. The alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl-2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP-ribose) polymerase. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N acetyl-L-cysteine, whereas other antioxidant (polyethylene glycol (PEG)-catalase and PEG-superoxide-dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF-kappaB into nucleus; however, NF-kappaB inhibitor, SN50 failed to potentiate alantolactone-induced apoptosis indicating that alantolactone induces NF-kappaB-independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, alantolactone may become a potential lead compound for future development of antiglioma therapy. PMID- 22837217 TI - Microstructural organization of corpus callosum projections to prefrontal cortex predicts bimanual motor learning. AB - The corpus callosum (CC) is the largest white matter tract in the brain. It enables interhemispheric communication, particularly with respect to bimanual coordination. Here, we use diffusion tensor imaging (DTI) in healthy humans to determine the extent to which structural organization of subregions within the CC would predict how well subjects learn a novel bimanual task. A single DTI scan was taken prior to training. Participants then practiced a bimanual visuomotor task over the course of 2 wk, consisting of multiple coordination patterns. Findings revealed that the predictive power of fractional anisotropy (FA) was a function of CC subregion and practice. That is, FA of the anterior CC, which projects to the prefrontal cortex, predicted bimanual learning rather than the middle CC regions, which connect primary motor cortex. This correlation was specific in that FA correlated significantly with performance of the most difficult frequency ratios tested and not the innately preferred, isochronous frequency ratio. Moreover, the effect was only evident after training and not at initiation of practice. This is the first DTI study in healthy adults which demonstrates that white matter organization of the interhemispheric connections between the prefrontal structures is strongly correlated with motor learning capability. PMID- 22837215 TI - Eastern chimpanzees, but not bonobos, represent a simian immunodeficiency virus reservoir. AB - Chimpanzees in west central Africa (Pan troglodytes troglodytes) are endemically infected with simian immunodeficiency viruses (SIVcpzPtt) that have crossed the species barrier to humans and gorillas on at least five occasions, generating pandemic and nonpandemic forms of human immunodeficiency virus type 1 (HIV-1) as well as gorilla SIV (SIVgor). Chimpanzees in east Africa (Pan troglodytes schweinfurthii) are also infected with SIVcpz; however, their viruses (SIVcpzPts) have never been found in humans. To examine whether this is due to a paucity of natural infections, we used noninvasive methods to screen wild-living eastern chimpanzees in the Democratic Republic of the Congo (DRC), Uganda, and Rwanda. We also screened bonobos (Pan paniscus) in the DRC, a species not previously tested for SIV in the wild. Fecal samples (n = 3,108) were collected at 50 field sites, tested for species and subspecies origin, and screened for SIVcpz antibodies and nucleic acids. Of 2,565 samples from eastern chimpanzees, 323 were antibody positive and 92 contained viral RNA. The antibody-positive samples represented 76 individuals from 19 field sites, all sampled north of the Congo River in an area spanning 250,000 km(2). In this region, SIVcpzPts was common and widespread, with seven field sites exhibiting infection rates of 30% or greater. The overall prevalence of SIVcpzPts infection was 13.4% (95% confidence interval, 10.7% to 16.5%). In contrast, none of the 543 bonobo samples from six sites was antibody positive. All newly identified SIVcpzPts strains clustered in strict accordance to their subspecies origin; however, they exhibited considerable genetic diversity, especially in protein domains known to be under strong host selection pressure. Thus, the absence of SIVcpzPts zoonoses cannot be explained by an insufficient primate reservoir. Instead, greater adaptive hurdles may have prevented the successful colonization of humans by P. t. schweinfurthii viruses. PMID- 22837218 TI - Direct identification of bacteria from BacT/ALERT anaerobic positive blood cultures by MALDI-TOF MS: MALDI Sepsityper kit versus an in-house saponin method for bacterial extraction. AB - In cases of bacteraemia, a rapid species identification of the causal agent directly from positive blood culture broths could assist clinicians in the timely targeting of empirical antimicrobial therapy. For this purpose, we evaluated the direct identification of micro-organisms from BacT/ALERT (bioMerieux) anaerobic positive blood cultures without charcoal using the Microflex matrix-assisted laser desorption/ionization (MALDI) time of flight MS (Bruker), after bacterial extraction by using two different methods: the MALDI Sepsityper kit (Bruker) and an in-house saponin lysis method. Bruker's recommended criteria for identification were expanded in this study, with acceptance of the species identification when the first three results with the best matches with the MALDI Biotyper database were identical, whatever the scores were. In total, 107 monobacterial cultures and six polymicrobial cultures from 77 different patients were included in this study. Among monomicrobial cultures, we identified up to the species level 67 and 66 % of bacteria with the MALDI Sepsityper kit and the saponin method, respectively. There was no significant difference between the two extraction methods. The direct species identification was particularly inconclusive for Gram-positive bacteria, as only 58 and 52 % of them were identified to the species level with the MALDI Sepsityper kit and the saponin method, respectively. Results for Gram-negative bacilli were better, with 82.5 and 90 % of correct identification to the species level with the MALDI Sepsityper kit and the saponin method, respectively. No misidentifications were given by the direct procedures when compared with identifications provided by the conventional method. Concerning the six polymicrobial blood cultures, whatever the extraction method used, a correct direct identification was only provided for one of the isolated bacteria on solid medium in all cases. The analysis of the time-to result demonstrated a reduction in the turnaround time for identification ranging from 1 h 06 min to 24 h 44 min, when performing the blood culture direct identification in comparison with the conventional method, whatever the extraction method. PMID- 22837219 TI - Premenstrual vaginal colonization of Candida and symptoms of vaginitis. AB - Although premenstrual exacerbation of vulvovaginal symptoms attributed to Candida spp. is well documented, the causation of these symptoms is not well understood. This study describes the daily vaginal colonization of Candida in three women. A single pilot study was designed to test the methodology of the proposed randomized controlled trial, Garlic and Candida. This study reports the colonization of Candida spp. in three women. Ten women aged 18-50 who reported at least one episode of vulvovaginal candidiasis were recruited by the University of Melbourne. Each participant took daily vaginal swabs for 2 weeks during the luteal phase of their menstrual cycle, which were analysed for quantitative colony counts of Candida spp. Of these, three women were colonized with Candida spp. For the first time, to our knowledge, daily colonization of Candida during the luteal phase of the menstrual cycle is described in three women, demonstrating an increase in the colony count preceding symptom development. This small study demonstrated the colonization of Candida spp. during the luteal phase of the menstrual cycle in three women. Candida colonization is poorly understood, yet investigating the relevance of the link between symptom exacerbation and the menstrual cycle in those women who experience recurrent episodes of vulvovaginal candidiasis may influence the management of this condition. PMID- 22837220 TI - Combined genomarkers approach to Salmonella characterization reveals that nucleotide sequence differences in the phase 1 flagellin gene fliC are markers for variation within serotypes. AB - The characterization and tracking of pathogenic micro-organisms in the clinical laboratory and public health environment demand schemes that are easy to standardize and use, are automated and high-throughput, and provide portable data. A combined genomarkers approach for Salmonella enterica based on comparative sequence analysis by mass spectrometry has been developed. The scheme targets genes encoding synthesis and assembly of antigens, metabolic pathway enzymes, virulence factors and fluoroquinolone resistance, covering the essential sequences that distinguish between and identify variation within serotypes. This study demonstrated how this single method could replace the combination of methods currently required to determine serotypes, subtypes, antibiotic resistance profiles and the genomic relatedness of Salmonella isolates. The results revealed genomic variation within seven serotypes previously unreported. This variation can be detected by using nucleotide sequence differences in the Salmonella flagellin gene fliC as markers that are not detected by traditional serotyping methods. PMID- 22837269 TI - Safety and complications of percutaneous kidney biopsies in 715 children and 8573 adults in Norway 1988-2010. AB - BACKGROUND AND OBJECTIVES: Skepticism about performing renal biopsies is often because of uncertainty regarding risk of complications. The aim of this study was to evaluate safety and relevant complications of renal biopsies in pediatric and adult patients in a large national registry study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney biopsies reported in the Norwegian Kidney Biopsy Registry from 1988 to 2010 were included. Risk factors for major complications (blood transfusion and/or surgical or catheter intervention) were analyzed using logistic regression statistics. RESULTS: Of the 9288 biopsies included, 715 were from children, and 8573 were from adults (>=18 years). Median age was 49 years (range=2 weeks to 94 years). Gross hematuria appeared after biopsy in 1.9% of the patients; 0.9% of patients needed blood transfusion, and 0.2% of patients needed surgical intervention/catheterization. The frequencies were 1.9%, 0.9%, and 0.2% in adults and 1.7%, 0.1% and 0.1% in children, respectively; 97.9% of the biopsies were without complications. In unadjusted analyses, risk factors for major complications were age>60 years, estimated GFR<60 ml/min per 1.73 m(2), systolic hypertension, acute renal failure, and smaller clinical center size (<30 biopsies/yr). Adjusted analyses (adjusted for age and/or estimated GFR) showed higher odds ratios (OR) only for smaller clinical center (OR=1.60 [1.02-2.50]) and low estimated GFR (estimated GFR=30-59 ml/min per 1.73 m(2) [OR=4.90 (1.60 14.00)] and estimated GFR<30 ml/min per 1.73 m(2) [OR 15.50 (5.60-43.00)]). CONCLUSIONS: Percutaneous renal biopsy is a low-risk procedure in all ages. Reduced estimated GFR and smaller center size are associated with an increased risk of major complications. PMID- 22837270 TI - Extracorporeal treatment for thallium poisoning: recommendations from the EXTRIP Workgroup. AB - BACKGROUND: The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatment (ECTR) in poisoning. To test and validate its methods, the workgroup reviewed data for thallium (Tl). METHODS: After an extensive search, the co-chairs reviewed the articles, extracted the data, summarized findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Blinded votes were compiled, returned, and discussed during a conference call. A second vote determined the final recommendations. RESULTS: Forty-five articles met inclusion criteria. Only case reports and case series were identified, yielding a very low quality of evidence for all recommendations. Data on 74 patients, including 11 who died, were abstracted. The workgroup concluded that Tl is slightly dialyzable and made the following recommendations: ECTR is recommended in severe Tl poisoning (1D). ECTR is indicated if Tl exposure is highly suspected on the basis of history or clinical features (2D) or if the serum Tl concentration is >1.0 mg/L (2D). ECTR should be initiated as soon as possible, ideally within 24-48 hours of Tl exposure (1D), and be continued until the serum Tl concentration is <0.1 mg/L for a minimal duration of 72 hours (2D). CONCLUSION: Despite Tl's low dialyzability and the limited evidence, the workgroup strongly recommended extracorporeal removal in the case of severe Tl poisoning. PMID- 22837271 TI - Pulmonary embolism in patients with CKD and ESRD. AB - BACKGROUND AND OBJECTIVES: CKD and ESRD are growing burdens. It is unclear whether these conditions affect pulmonary embolism (PE) risk, given that they affect both procoagulant and anticoagulant factors. This study examined the frequency and associated outcomes of PE in CKD and ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Healthcare Cost and Utilization Project's Nationwide Inpatient Sample was used to estimate the frequency and outcomes of PE in adults with CKD and ESRD. Hospitalizations for the principal diagnosis of PE and presence of CKD or ESRD were identified using International Classification of Diseases, Ninth Revision codes. Data from the annual US Census and US Renal Data System reports were used to calculate the number of adults with CKD, ESRD, and normal kidney function (NKF) as well as the annual incidence of PE in each group. Logistic regression modeling was used to compare in-hospital mortality among persons admitted for PE who had ESRD or CKD to those without these conditions. RESULTS: The annual frequency of PE was 527 per 100,000, 204 per 100,000, and 66 per 100,000 persons with ESRD, CKD, and NKF, respectively. In-hospital mortality was higher for persons with ESRD and CKD (P<0.001) compared with persons with NKF. Median length of stay was longer by 1 day in CKD and 2 days in ESRD than among those with NKF. CONCLUSIONS: Persons with CKD and ESRD are more likely to have PE than persons with NKF. Once they have PE, they are more likely to die in the hospital. PMID- 22837272 TI - Calcium builds strong bones, and more is better--correct? Well, maybe not. AB - Calcium supplementation has been considered the gold standard therapy for osteoporosis in the general population. It is given in both the placebo and treatment groups of trials evaluating antifracture efficacy of new therapies. Similarly, calcium-based phosphate binders have been considered the gold standard comparator for all new phosphate binders. However, large randomized trials demonstrate conflicting data on the antifracture efficacy of calcium supplementation, particularly in high doses, in patients with osteoporosis without CKD. In addition, recent data suggest an increased risk for cardiovascular events. These new studies raise safety concerns for the general approach with calcium supplementation and binders. This review describes recent data on the adverse effects of calcium supplementation for osteoporosis and how these new data should affect the strategy for phosphate binder use in CKD. PMID- 22837274 TI - Subgroup analyses in nephrology clinical trials. PMID- 22837273 TI - Association of race and insurance type with delayed assessment for kidney transplantation among patients initiating dialysis in the United States. AB - BACKGROUND AND OBJECTIVES: The extent to which racial and socioeconomic disparities in access to kidney transplantation are related to not being assessed for transplant suitability before or shortly after the time of initiation of dialysis is not known. The aims of this study were to determine whether there were disparities based on race, ethnicity, or type of insurance in delayed assessment for transplantation and whether delayed assessment was associated with lower likelihood of waitlisting and kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study used data from the US Renal Data System and included 426,489 adult patients beginning dialysis in the United States between January 1, 2005 and September 30, 2009 without prior kidney transplant. RESULTS: Overall, 12.5% of patients had reportedly not been assessed for transplantation. Patients without private insurance were more likely to be reported as not assessed (multivariable adjusted odds ratio=1.33, 95% confidence interval=1.28-1.40 for Medicaid), with a pronounced racial disparity but no ethnic disparity among patients aged 18 to <35 years (odds ratio=1.27, 95% confidence interval=1.13-1.43; P<0.001 for interaction with age). Not being assessed for transplant around the time of dialysis initiation was associated with lower likelihood of waitlisting in multivariable analysis (hazard ratio=0.59, 95% confidence interval=0.57-0.62 in the first year) and transplantation (hazard ratio=0.46, 95% confidence interval=0.41-0.51 in the first year), especially within the first 2 years. CONCLUSIONS: Racial and insurance-related disparities in transplant assessment potentially delay transplantation, particularly among younger patients. PMID- 22837275 TI - Exploring the association between macroeconomic indicators and dialysis mortality. AB - BACKGROUND AND OBJECTIVES: Mortality on dialysis varies greatly worldwide, with patient-level factors explaining only a small part of this variation. The aim of this study was to examine the association of national-level macroeconomic indicators with the mortality of incident dialysis populations and explore potential explanations through renal service indicators, incidence of dialysis, and characteristics of the dialysis population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Aggregated unadjusted survival probabilities were obtained from 22 renal registries worldwide for patients starting dialysis in 2003-2005. General population age and health, macroeconomic indices, and renal service organization data were collected from secondary sources and questionnaires. Linear modeling with log-log transformation of the outcome variable was applied to establish factors associated with survival on dialysis. RESULTS: Two-year survival on dialysis ranged from 62.3% in Iceland to 89.8% in Romania. A higher gross domestic product per capita (hazard ratio=1.02 per 1000 US dollar increase), a higher percentage of gross domestic product spent on healthcare (1.10 per percent increase), and a higher intrinsic mortality of the dialysis population (i.e., general population-derived mortality risk of the dialysis population in that country standardized for age and sex; hazard ratio=1.04 per death per 10,000 person years) were associated with a higher mortality of the dialysis population. The incidence of dialysis and renal service indicators were not associated with mortality on dialysis. CONCLUSIONS: Macroeconomic factors and the intrinsic mortality of the dialysis population are associated with international differences in the mortality on dialysis. Renal service organizational factors and incidence of dialysis seem less important. PMID- 22837277 TI - Sonography for surveillance of patients with Crohn disease. PMID- 22837276 TI - Two-year follow-up of a prospective clinical trial of cyclosporine for frequently relapsing nephrotic syndrome in children. AB - BACKGROUND AND OBJECTIVES: Although the safety and efficacy of cyclosporine in children with frequently relapsing nephrotic syndrome (FRNS) have been confirmed, no prospective follow-up data on relapse after cyclosporine have appeared. This study is a prospective follow-up trial after 2-year treatment with cyclosporine to investigate cyclosporine dependency after its discontinuation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants who had undergone 2-year protocol treatment with microemulsified cyclosporine for FRNS between January 2000 and December 2005 were followed for an additional 2 years. The primary end point was relapse-free survival after the complete discontinuation of cyclosporine, and the secondary end point was regression-free survival (time to regression to FRNS). RESULTS: After exclusion of 7 patients who showed regression to FRNS during the 2-year treatment period, 49 children (median age, 6.5 years) were followed, and classified as children without (n=32; group A) and with (n=17; group B) relapse during the initial cyclosporine treatment. Overall, relapse-free survival probability at 24 months after cyclosporine discontinuation was 15.3% and regression to FRNS-free survival probability was 40.8%. By group, the probability of relapse-free survival was significantly higher in group A (17.9%) than in group B (8.3%) (P<0.001). CONCLUSIONS: Children with FRNS who receive cyclosporine are at high risk of relapse after discontinuation, particularly those who experience relapse during cyclosporine treatment. PMID- 22837278 TI - Sonography as the first line of evaluation in children with suspected acute appendicitis. PMID- 22837279 TI - Effects of intermittent theta burst stimulation on cerebral blood flow and cerebral vasomotor reactivity. AB - OBJECTIVES: To determine whether intermittent theta burst stimulation influences cerebral hemodynamics, we investigated changes induced by intermittent theta burst stimulation on the middle cerebral artery cerebral blood flow velocity and vasomotor reactivity to carbon dioxide (CO(2)) in healthy participants. The middle cerebral artery flow velocity and vasomotor reactivity were monitored by continuous transcranial Doppler sonography. Changes in cortical excitability were tested by transcranial magnetic stimulation. METHODS: In 11 healthy participants, before and immediately after delivering intermittent theta burst stimulation, we tested cortical excitability measured by the resting motor threshold and motor evoked potential amplitude over the stimulated hemisphere and vasomotor reactivity to CO(2) bilaterally. The blood flow velocity was monitored in both middle cerebral arteries throughout the experimental session. In a separate session, we tested the effects of sham stimulation under the same experimental conditions. RESULTS: Whereas the resting motor threshold remained unchanged before and after stimulation, motor evoked potential amplitudes increased significantly (P = .04). During and after stimulation, middle cerebral artery blood flow velocities also remained bilaterally unchanged, whereas vasomotor reactivity to CO(2) increased bilaterally (P = .04). The sham stimulation left all variables unchanged. CONCLUSIONS: The expected intermittent theta burst stimulation-induced changes in cortical excitability were not accompanied by changes in cerebral blood flow velocities; however, the bilateral increased vasomotor reactivity suggests that intermittent theta burst stimulation influences the cerebral microcirculation, possibly involving subcortical structures. These findings provide useful information on hemodynamic phenomena accompanying intermittent theta burst stimulation, which should be considered in research aimed at developing this noninvasive, low-intensity stimulation technique for safe therapeutic applications. PMID- 22837280 TI - Characteristics of duplex sonographic parameters over time after successful carotid artery stenting. AB - OBJECTIVES: Carotid duplex sonography is the primary tool for surveillance after carotid artery stenting, but the course of sonographic velocities over time after successful stenting is unclear. The purpose of this study was to describe carotid duplex sonographic velocity parameters after successful carotid artery stenting and to determine the predictors of poststent sonographic velocities. METHODS: We queried institutional carotid stent and noninvasive vascular laboratory databases for internal carotid artery stents placed between January 2004 and June 2007. We included patients with stenosis of 20% or less on completion angiograms who had carotid duplex sonography within 30 days before and 7 days after stenting. The prestent peak systolic velocity (PSV), end-diastolic velocity (EDV), internal-to common carotid artery PSV ratio, contralateral internal carotid artery velocities, stent type, open- versus closed-cell stent design, and days of follow up were tested as potential predictors of poststent velocities. RESULTS: Eighty two of 498 patients met inclusion criteria. The mean PSV and PSV ratio decreased from 423.6 cm/s and 7.1 before stenting to 98.5 cm/s and 1.3 after stenting (both P < .001). During a median follow-up of 370 days, poststent velocities remained stable. All poststent velocities (PSV, EDV, and PSV ratio) were dependent on prestent ipsilateral and contralateral velocities. The poststent EDV was dependent on the type of stent. The upper range for 0% to 20% stenosis in the stented internal carotid artery was a PSV of 141 cm/s, an EDV of 42 cm/s, and a PSV ratio of 2.1 or lower. CONCLUSIONS: With a median follow-up of 1 year, the PSV and PSV ratio remained stable over time in successfully stented carotid arteries. Deviations in sonographic parameters after initial poststent carotid duplex sonography should prompt an investigation for possible in-stent restenosis. PMID- 22837281 TI - Left ventricular radial systolic dysfunction in diabetic patients assessed by myocardial acceleration derived from velocity vector imaging. AB - OBJECTIVES: The purpose of this study was to determine whether left ventricular (LV) radial systolic dysfunction occurred in diabetic patients with a normal left ventricular ejection fraction (LVEF) and impaired longitudinal contraction. METHODS: Velocity vector imaging was performed in 22 patients with type 2 diabetes without microangiopathy (12 men and 10 women; mean age +/- SD, 49 +/- 7 years), 21 patients with microangiopathy (12 men and 9 women; mean age, 50 +/- 6 years), and 21 healthy control participants (11 men and 10 women; mean age, 49 +/ 8 years). The groups were matched for age and sex. All had no clinical symptoms of heart disease, coronary artery disease, or hypertension. RESULTS: The LVEF, fractional shortening, and end-diastolic diameter were statistically comparable in all groups. The left ventricular wall thickness was significantly greater in diabetic patients than controls (P < .05). Average peak early diastolic accelerations at all LV levels were significantly lower in diabetic patients than controls in the long-and short-axis directions (all P < .05). In the long-axis direction, a significantly lower average peak isovolumic contraction acceleration was found at the mid and apical levels in patients without microangiopathy and at all LV levels in patients with microangiopathy than controls (all P < .05). In the short-axis direction, a significantly lower average isovolumic contraction acceleration was found at the apical level in patients without microangiopathy and at the basal and apical levels in patients with microangiopathy (all P < .05). CONCLUSIONS: In diabetic patients with a normal LVEF, myocardial systolic dysfunction occurs not only in the long-axis direction but also in the short-axis direction. PMID- 22837282 TI - Reevaluating the transcranial Doppler criteria for estimation of anterior circulation artery stenosis: transcranial Doppler sonography versus digital subtraction angiography. AB - OBJECTIVES: The criteria for evaluating cerebral artery stenosis by transcranial Doppler sonography are inconsistent. We aimed to identify the accuracy of transcranial Doppler criteria compared with digital subtraction angiography for diagnosis of anterior circulation artery stenosis. METHODS: A total of 170 patients who underwent transcranial Doppler sonography and digital subtraction angiography were recruited. The anterior circulation arteries were evaluated by transcranial Doppler sonography and digital subtraction angiography. We defined the best cutoff value for substantial anterior circulation artery stenosis by receiver operating characteristic curve analyses and calculated the sensitivity, specificity, and positive and negative predictive values. RESULTS: An anterior circulation artery peak systolic velocity (PSV) of 120 cm/s had the largest area under the receiver operating characteristic curve compared with PSVs of 110, 130, and 140 cm/s and mean flow velocities of 60, 70, and 80 cm/s. The sensitivity, specificity, false-positive rate, false-negative rate, accuracy, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and Youden index for transcranial Doppler sonography were 90.6%, 85.0%, 15.0%, 9.4%, 87.9%, 87.2%, 88.9%, 6.04, 0.11, and 0.756, respectively. The reliability index included the agreement rate and kappa value, which were 87.9% and 0.757. CONCLUSIONS: A PSV of 120 cm/s combined with additional parameters was an accurate criterion for diagnosing anterior circulation artery stenosis. Transcranial Doppler sonography could be considered a valuable method for screening diagnosis of cerebral artery stenosis. PMID- 22837283 TI - Selective 360 degrees percutaneous extensor carpi radialis brevis tendon release for tennis elbow: an experimental study. AB - OBJECTIVES: The purpose of this study was to define in volunteers and cadavers the positions of structures at risk and the extensor carpi radialis brevis (ECRB) origin limits for sonographically guided percutaneous tendon release in tennis elbow. METHODS: First, in volunteers, we used Doppler sonography to determine the position (danger zone) of the structures at risk (neurovascular bundle and radial collateral ligament) from the most lateral point of the epicondyle (point of entry). Second, in cadavers, we studied the footprint of the ECRB's origin for finally performing sonographically guided tendon release (1- to 2-mm incision) away from the danger zone. Efficacy was measured in terms of detachment ratios for the ECRB and safety as the absence of neurovascular bundle or radial collateral ligament injuries. RESULTS: In 10 volunteers (20 elbows), the neurovascular bundle was located 18.1 mm or greater anteromedially from the point of entry. The neurovascular bundle was not in direct contact with the bone. In 13 formaldehyde-embalmed cadaver elbows, the distance between the origin of the ECRB and the radial collateral ligament was 0 mm or greater. The anterior origin of the ECRB did not contact the neurovascular bundle. The maximum attachment limits of the ECRB were at 15, 5, 15, and 16 mm from the point of entry (anterior, posterior, proximal, and distal margins, respectively). Average detachment ratios were excellent for anterior and distal margins and good for posterior and proximal margins, without neurovascular bundle or radial collateral ligament injuries. CONCLUSIONS: This study determined a danger zone to avoid and an area of probability in which to enclose most of the ECRB's origin for sonographically guided percutaneous tendon release. A 360 degrees ECRB detachment can be performed safely and effectively. Clinically, sonographically guided percutaneous tendon release should selectively target pathologic regions. PMID- 22837284 TI - Sonography of supraspinatus tendon abnormalities in the neutral versus Crass and modified Crass positions: a prospective study. AB - OBJECTIVES: The purpose of this study was to investigate how well the neutral arm position correlates with the Crass and modified Crass positions in sonographic evaluation of supraspinatus tendon abnormalities. METHODS: A prospective study was performed on 32 shoulders in 31 patients with shoulder pain. Images were acquired in the long axis of the supraspinatus tendon in the neutral, Crass, and modified Crass positions and were reviewed independently of each other by 2 radiologists in consensus. The images were evaluated for visualized tendon length, tendinosis, partial- or full-thickness tears, calcific tendinosis, subdeltoid bursitis, and enthesopathic changes. Kappa values of agreement between neutral and Crass and neutral and modified Crass positions were determined. RESULTS: The mean visualized tendon lengths were 1.78, 2.83, and 2.77 cm in the neutral, Crass, and modified Crass positions, respectively. Kappa agreements between neutral and Crass and neutral and modified Crass positions were as follows: perfect agreement for calcific tendinosis (neutral versus Crass, kappa =1.00; neutral versus modified Crass, kappa = 1.00), almost perfect agreement for full-thickness tears (neutral versus Crass, kappa = 0.85; neutral versus modified Crass: kappa= 0.92) and tendinosis (neutral versus Crass, kappa = 0.93; neutral versus modified Crass, kappa = 0.86), substantial agreement for enthesopathic changes (neutral versus Crass, kappa= 0.80; neutral versus modified Crass, kappa= 0.61) and subdeltoid bursitis (neutral versus Crass, kappa = 0.63; neutral versus modified Crass, kappa = 0.75), and moderate agreement for partial tears (neutral versus Crass, kappa = 0.44; neutral versus modified Crass, kappa = 0.47). CONCLUSIONS: For patients who cannot tolerate the Crass or modified Crass position, the neutral position can show full-thickness tears, tendinosis, calcific tendinosis, enthesopathic changes, and bursitis. PMID- 22837285 TI - Office-based elastographic technique for quantifying mechanical properties of skeletal muscle. AB - OBJECTIVES: Our objectives were to develop a new, efficient, and easy-to administer approach to ultrasound elastography and assess its ability to provide quantitative characterization of viscoelastic properties of skeletal muscle in an outpatient clinical environment. We sought to show its validity and clinical utility in assessing myofascial trigger points, which are associated with myofascial pain syndrome. METHODS: Ultrasound imaging was performed while the muscle was externally vibrated at frequencies in the range of 60 to 200 Hz using a handheld vibrator. The spatial gradient of the vibration phase yielded the shear wave speed, which is related to the viscoelastic properties of tissue. The method was validated using a calibrated experimental phantom, the biceps brachii muscle in healthy volunteers (n = 6), and the upper trapezius muscle in symptomatic patients with axial neck pain (n = 13) and asymptomatic (pain-free) control participants (n = 9). RESULTS: Using the experimental phantom, our method was able to quantitatively measure the shear moduli with error rates of less than 20%. The mean shear modulus +/- SD in the normal biceps brachii measured 12.5 +/- 3.4 kPa, within the range of published values using more sophisticated methods. Shear wave speeds in active myofascial trigger points and the surrounding muscle tissue were significantly higher than those in normal tissue at high frequency excitations (>100 Hz; P < .05). CONCLUSIONS: Off-the-shelf office-based equipment can be used to quantitatively characterize skeletal muscle viscoelastic properties with estimates comparable to those using more sophisticated methods. Our preliminary results using this method indicate that patients with spontaneous neck pain and symptomatic myofascial trigger points have increased tissue heterogeneity at the trigger point site and the surrounding muscle tissue. PMID- 22837286 TI - Evaluation of tumor angiogenesis in a mouse PC-3 prostate cancer model using dynamic contrast-enhanced sonography. AB - OBJECTIVES: The purpose of this study was to evaluate tumor angiogenesis in a mouse xenograft model injected with human PC-3 prostate cancer cells using contrast-enhanced sonography. METHODS: Sixteen nude mice were injected with human prostate cancer cells on the back or the flank. Contrast-enhanced sonography was performed with a 5- to 12-MHz broadband linear transducer after a 500-MUL bolus injection of a sonographic contrast agent composed of lipid shells and sulfur hexafluoride. Contrast-enhanced sonograms were obtained by the pulse inversion coded harmonic technique with a low mechanical index of 0.07. A region of interest was drawn to encompass the tumor, and time-intensity curves were acquired. After fitting the curve by a gamma variate function, the maximum intensity, area under the curve for up to 50 seconds, time to peak, shape parameter, and scale parameter were derived. The tumor volume, percentage of vascular endothelial growth factor expression, and CD31-positive vessel count (microvessel density) were correlated with the parameters derived from the time intensity curve. RESULTS: The maximum intensity was positively correlated with the microvessel density with statistical significance (r = 0.552; P = .03). The percentage of vascular endothelial growth factor expression did not have any correlation with the parameters from the curve. CONCLUSIONS: Contrast-enhanced sonography can reflect tumor vascularity in a prostate cancer animal model. Sonography of tumor angiogenesis may permit functional assessment of the tumor vasculature and provide an imaging biomarker for tumor responses to antiangiogenic therapies. PMID- 22837287 TI - New approach to intracardiac hemodynamic measurements in small animals: echo guided percutaneous apical puncture. AB - OBJECTIVES: Invasive measurements of intracardiac hemodynamics in animal models have allowed important advances in the understanding of cardiac disease. Currently they are performed either through a carotid arteriotomy or via a thoracotomy and apical insertion. Both of these techniques have disadvantages and are not conducive to repeated measurements. Therefore, the purpose of this study was to develop a new technique for measuring intracardiac hemodynamics. METHODS: In 13 male rats, hemodynamic measurements were performed using a new echocardiographically guided percutaneous apical technique. An intravenous catheter was percutaneously inserted into the left ventricle (LV) in the direction of the LV long axis. Through this catheter, a micromanometer-tipped pressure catheter was inserted, and invasive hemodynamic traces were recorded. After LV recordings, the pressure catheter was advanced into the aorta where pressures were obtained. In 11 rats, measurements were repeated after 1 week (n = 2), 2 weeks (n = 4), 3 weeks (n = 4), or 4 weeks (n = 1). In 3 rats, invasive measurements were performed using a carotid arteriotomy before the percutaneous technique. RESULTS: Among the 13 rats subjected to the procedure, the survival rate was 85%. Of the 11 rats that had the procedure repeated, 3 died (27%). The mean differences +/- SD when comparing the two techniques were 10 +/- 4 mm Hg for the LV end-systolic pressure and 1 +/- 1 mm Hg for the LV end-diastolic pressure. The mean procedure times were 21 +/- 3 and 6 +/- 1 minutes for the carotid and percutaneous techniques, respectively. CONCLUSIONS: We have successfully developed a percutaneous technique for insertion of LV microtip catheters in rats. PMID- 22837288 TI - Reliable measurement by virtual touch tissue quantification with acoustic radiation force impulse imaging: phantom study. AB - OBJECTIVES: The purpose of this study was to evaluate the factors that may affect shear wave velocity (SWV) measurements by using a phantom. METHODS: The SWVs (meters per second) of 4 phantom targets and background, each of different hardness (Young modulus, 8-80 kPa), were measured in the virtual touch tissue quantification mode. Ten SWV measurements were performed on each target, and the mean SWV and its standard deviation were calculated. To assess the effect of the distance between the probe and region of interest (ROI) settings, mean SWV measurements of the background at 5 to 80 mm in depth were performed with a convex probe and at 5 to 40 mm with a high-frequency linear probe. RESULTS: The linear correlation between the nominal Young modulus of the phantom and those calculated from the mean SWV was highly significant for the linear probe (y = 0.98x - 0.70; r(2) = 0.99; P = .0007). For the convex probe, the linear correlation between the nominal Young modulus of the phantom and those calculated from the mean SWV was highly significant between 8 and 40 kPa (y =1.26x + 1.01; r(2) = 0.98; P = .011). Measurement variations for the linear probe were little influenced by the distance between the probe and ROI, but those for the convex probe were dependent on the distance. CONCLUSIONS: The accuracy of the mean SWV measurement was dependent on the probe used and the distance between the probe and ROI settings. The linear probe provides accurate measurements throughout its range for all but its deepest limit. Measurements of 40 mm or deeper are better performed with a convex probe. Probe selection should be based on individual lesion depth. PMID- 22837289 TI - Liver and spleen stiffness measured by acoustic radiation force impulse elastography for noninvasive assessment of liver fibrosis and esophageal varices in patients with chronic hepatitis B. AB - OBJECTIVES: To evaluate the performance of liver and spleen stiffness measured by acoustic radiation force impulse (ARFI) elastography for noninvasive assessment of liver fibrosis and esophageal varices in patients with chronic hepatitis B virus. METHODS: Two hundred sixty-four participants, of whom 60 were healthy volunteers (classified as stage 0), 66 were patients with chronic hepatitis B who had undergone liver biopsy, and 138 were patients with hepatitis B-related cirrhosis, were enrolled in this study. Median liver and spleen stiffness values (meters per second) from 10 successful measurements per participant were obtained. Patients with cirrhosis were examined by upper endoscopy. RESULTS: Significant linear correlations were found between liver (Spearman rho = 0.87; P < .001) and spleen (Spearman rho = 0.76; P < .001) stiffness and the fibrosis stage. Liver and spleen stiffness values increased as fibrosis progressed; however, overlaps in liver stiffness were detected in stages 0 and 1 and 1 and 2, and overlaps in spleen stiffness were observed in stages 0 and 1, 1 and 2, and 2 and 3. Liver stiffness cutoff values were 1.69 m/s for predicting stage 3 or greater (area under the receiver operating characteristic curve [AUROC] = 0.99) and 1.88 m/s for stage 4 (AUROC = 0.97). The spleen stiffness cutoff value was 2.72 m/s for stage 4 (AUROC = 0.96). Liver stiffness was not correlated with the varix grade, whereas a significant linear correlation (Spearman rho = 0.65; P < .001) between spleen stiffness and the varix grade was found. The optimal spleen stiffness cutoff value for predicting varices was 3.16 m/s (AUROC = 0.83). CONCLUSIONS: Liver and spleen stiffness values measured by ARFI elastography are reliable predictors of liver fibrosis. Spleen stiffness measured by ARFI can be used as a non-invasive method for determining the presence and severity of esophageal varices; however, evidence to support a similar role for liver stiffness is lacking. PMID- 22837290 TI - Compact ultrasound donations to medical facilities in low-resource countries: a survey-based assessment of the current status and trends. AB - OBJECTIVES: Many ultrasound (US) specialists, independently or as part of institutionally directed teams, have donated compact US equipment and training to rural and urban clinics in low-resource regions. The objective of our study was to assess the scope, impact, and characteristics of these donation and training activities. METHODS: We designed a 1-page, 10-question survey soliciting responses on donors, equipment, donation sites, training, and follow-up. Physicians and sonographers with qualifying donation experience were located by means of personal references, professional networking, and referral from US manufacturers. Respondents were also solicited at several online sites for medical imagers. The survey was active from May 2010 to March 2011 and was available via an interactive website (www.surveymonkey.com) or as an electronic download directly from the authors. RESULTS: Fifteen respondents provided data on deployments spanning a 7-year period from 2004 to early 2011. Forty-eight compact US units were donated to sites in 15 different nations on 4 continents; 69% of the units went to sites in Africa. All but 4 sites received initial training. Donated systems were reported as "operational and functional" for all units for which the current status was available. CONCLUSIONS: Results suggest involvement by a broad variety of participants. The number of successful deployments and excellent equipment durability support the premise that small-scale, individual donation and training activities have the potential for a substantial public health impact. The authors recommend better coordination of effort and the need for additional data. PMID- 22837291 TI - Ultrasound and autism: association, link, or coincidence? AB - Autism spectrum disorders (ASDs) affect an estimated 1% of children in the United States. The etiology is probably multifactorial, including genetic components and exposure to infections, toxins, and other environmental factors, particularly unfavorable perinatal and neonatal conditions. There has been an increase in the frequency of diagnosis of ASDs over the last 20 years with a parallel increase in the use of obstetric diagnostic ultrasound, with prenatal ultrasound exposure mentioned as the possible main etiology for autism "epidemics." Central nervous system alterations have been described in ASDs, and certain similar changes have been described in animals after exposure to ultrasound. However, analysis of in utero exposure in humans has failed to show harmful effects in neonates or children, particularly in school performance, attention disorders, and behavioral changes. There is no independently confirmed peer-reviewed published evidence that a cause-effect relationship exists between in utero exposure to clinical ultrasound and development of ASDs in childhood. Ultrasound is a form of energy with effects in the tissues it traverses, and its use should be restricted to medical indications, by trained professionals, for as short a period and as low an intensity as compatible with accurate diagnosis. PMID- 22837292 TI - The birds and the beans: a low-fidelity simulator for chorionic villus sampling skill acquisition. AB - Because no simulation models are described for chorionic villus sampling (CVS), we sought to design and construct a CVS training simulator. Using materials available from our labor floor and local supermarket, we built and demonstrated a practical model for learning transabdominal and transcervical CVS. The simulator can be used to teach single- or dual-operator transabdominal CVS and traditional transcervical CVS. Aspirated "villi" immediately inform the teacher and learner of successful procedures. No image degradation or sonographically visible tracks resulted from use, permitting more than one trainee to benefit from a model. This model for transabdominal and transcervical CVS provides realistic imaging, tactile sensations, and immediate feedback. PMID- 22837293 TI - Preliminary study of ergonomic behavior during simulated ultrasound-guided regional anesthesia using a head-mounted display. AB - A head-mounted display provides continuous real-time imaging within the practitioner's visual field. We evaluated the feasibility of using head-mounted display technology to improve ergonomics in ultrasound-guided regional anesthesia in a simulated environment. Two anesthesiologists performed an equal number of ultrasound-guided popliteal-sciatic nerve blocks using the head-mounted display on a porcine hindquarter, and an independent observer assessed each practitioner's ergonomics (eg, head turning, arching, eye movements, and needle manipulation) and the overall block quality based on the injectate spread around the target nerve for each procedure. Both practitioners performed their procedures without directly viewing the ultrasound monitor, and neither practitioner showed poor ergonomic behavior. Head-mounted display technology may offer potential advantages during ultrasound-guided regional anesthesia. PMID- 22837294 TI - Solid ectopic cervical thymus in neonates with thyroid agenesis. AB - We report a series of ectopic thymus glands as detected by sonography in infants with thyroid agenesis. The patients were children who underwent nuclear medicine and sonography for congenital hypothyroidism. Of the 12 patients with a diagnosis of thyroid agenesis over a 5-year period, 4 (33%) were shown to have ectopic thymic tissue. Although a cervical ectopic thymus has been previously reported, there is very little discussion of it occurring in conjunction with thyroid agenesis. This case series highlights the importance of recognition of ectopic thymic tissue when examining for thyroid tissue in the setting of congenital hypothyroidism. PMID- 22837295 TI - Idiopathic constriction of the fetal ductus arteriosus: three cases and review of the literature. AB - Premature constriction or closure of the ductus arteriosus can occur during fetal life. It is a rare phenomenon and has been described secondary to medication or structural lesions or as idiopathic constriction. Premature closure of the ductus arteriosus can lead to progressive right heart dysfunction with tricuspid regurgitation, congestive heart failure, fetal hydrops, and intrauterine death. This series describes diagnosis of fetal ductus arteriosus constriction of unknown etiology in 3 cases, prenatal management, and outcomes. Constriction of the ductus arteriosus can be diagnosed prenatally with careful interrogation of the ductal arch using pulsed Doppler sonography and complete fetal echocardiography. Close monitoring is mandatory to rule out development of right heart failure and to determine the intervention time. PMID- 22837296 TI - Fetal megacystis in an asymptomatic patient with an intact tubal pregnancy at 11 weeks' gestation. PMID- 22837297 TI - Spontaneous antepartum vesicouterine fistula causing severe oligohydramnios in a patient with a previous cesarean delivery. PMID- 22837298 TI - Three-dimensional sonography of fetal iniencephaly. PMID- 22837299 TI - Appearance of the epiglottis during upper airway sonography. PMID- 22837300 TI - AIUM practice guideline for the performance of an ultrasound examination of the abdomen and/or retroperitoneum. PMID- 22837301 TI - AIUM practice guideline for the performance of physiologic evaluation of extremity arteries. PMID- 22837302 TI - Lipid diversity among botulinum neurotoxin-producing clostridia. AB - Clostridium botulinum has been classified into four groupings (groups I to IV) based on physiological characteristics and 16S rRNA sequencing. We have examined the lipid compositions of 11 representative strains of C. botulinum and a strain of Clostridium sporogenes by 2D-TLC and by MS. All strains contained phosphatidylglycerol (PG), cardiolipin (CL) and phosphatidylethanolamine (PE) in both the all-acyl and the alk-1'-enyl (plasmalogen) forms. Five strains in proteolytic group I, which are related to C. sporogenes, contained varying amounts of an ethanolamine-phosphate derivative of N-acetylglucosaminyl diradylglycerol, which is also present in C. sporogenes. Three strains in group II, which are related to Clostridium butyricum, Clostridium beijerinckii and Clostridium acetobutylicum, contained lipids characteristic of these saccharolytic species: a glycerol acetal and a PG acetal of the plasmalogen form of PE. Two group III strains, which are related to Clostridium novyi, contained amino-acyl derivatives of PG, which are also found in C. novyi. A strain in group IV had PE, PG and CL, but none of the distinguishing lipids. This work shows that the lipidome of C. botulinum is consistent with its classification by other methods. PMID- 22837304 TI - The all0458/lti46.2 gene encodes a low temperature-induced Dps protein homologue in the cyanobacteria Anabaena sp. PCC 7120 and Anabaena variabilis M3. AB - DNA-binding proteins from starved cells (Dps), which are encoded by many bacterial genomes, protect genomic DNA via non-specific DNA binding, as well as inhibition of free radical formation by chelating Fe(II). In the filamentous cyanobacterium Anabaena, the second gene (lti46.2) in the low temperature-induced gene operon lti46 in strain M3 was found to encode a homologue of Dps, but for a long time this gene remained poorly characterized. A gene cluster, all0459 all0458-all0457, was found later to be 100% identical to the lti46 gene cluster in a closely related strain, PCC 7120. In the present study, we detected ferroxidase activity of the Lti46.2/All0458 protein, which formed a dodecamer, as found in other Dps proteins. In addition, three homologues of all0458 were found in strain PCC 7120, namely, all1173, alr3808 and all4145. We analysed expression of the lti46 or all0459-8-7 gene cluster in both strains, M3 and PCC 7120, and confirmed its induction by low temperature. We found that the All0458-GFP fusion protein and the All1173-GFP fusion protein were localized to the nucleoids. In the all0458 null mutant, the transcript of the alr3808 gene accumulated. These results suggest that there might be complex cooperation of various members of the dps family in protecting the genome from environmental stresses such as changing temperature. PMID- 22837303 TI - BfpL is essential for type IV bundle-forming pilus biogenesis and interacts with the periplasmic face of BfpC. AB - Enteropathogenic Escherichia coli (EPEC) causes diarrhoea among infants in developing countries. The bundle-forming pilus (BFP), a type IV pilus found on the surface of EPEC, is essential for full virulence of typical EPEC strains. The machinery for BFP assembly and function is encoded by an operon of 14 genes. Here we investigate the role in pilus biogenesis of BfpL, a small protein with a single N-terminal predicted transmembrane domain reminiscent of pilin-like proteins. We confirmed that a bfpL mutant lacks BFP, and associated auto aggregation and localized adherence phenotypes. Furthermore, we found that a double mutant unable to express both the putative retraction ATPase BfpF and BfpL also lacks BFP and associated phenotypes, distinguishing BfpL from pilin-like proteins. Western blots of sheared pilus preparations did not suggest that BfpL is a component of BFP. Topology studies using C-terminal truncations and a dual reporter revealed that most of the BfpL protein resides in the periplasm. Further, we demonstrated through yeast two-hybrid assays and confirmed by fluorescence anisotropy that BfpL interacts with the periplasmic face of BfpC. Thus, BfpL has a function distinct from those of pilin-like proteins and is instead part of an inner-membrane subassembly complex that is believed to extract bundlin, the main pilus subunit, from the inner membrane to be incorporated into BFP. PMID- 22837305 TI - Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell surface GRP78/MTJ-1 complex. AB - It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. PMID- 22837306 TI - C1q/TNF-related protein-3 (CTRP-3) and pigment epithelium-derived factor (PEDF) concentrations in patients with type 2 diabetes and metabolic syndrome. AB - Recent studies have suggested that a novel adipokine, C1q/tumor necrosis factor related protein-3 (CTRP-3), a paralog of adiponectin, may play an important role in the regulation of glucose metabolism and innate immunity. Pigment epithelium derived factor (PEDF), a multifunctional protein with antioxidant and anti inflammatory properties, is associated with insulin resistance and metabolic syndrome. We examined circulating CTRP-3 and PEDF concentrations in 345 subjects with diverse glucose tolerance statuses. Furthermore, we evaluated the involvement of CTRP-3 and PEDF with cardiometabolic risk factors including insulin resistance, high-sensitivity C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), and brachial-ankle pulse wave velocity (baPWV). CTRP-3 concentrations were significantly higher in patients with type 2 diabetes or prediabetes than the normal glucose tolerance group, whereas PEDF levels were not different. Subjects with metabolic syndrome showed significantly higher levels of both CTRP-3 and PEDF compared with subjects without metabolic syndrome. Both CTRP-3 and PEDF were significantly associated with cardiometabolic parameters, including waist-to-hip ratio, triglycerides, HDL-cholesterol, alanine aminotransferase, eGFR, hsCRP, and baPWV. In conclusion, circulating CTRP-3 concentrations were elevated in patients with glucose metabolism dysregulation. Both CTRP-3 and PEDF concentrations were increased in subjects with metabolic syndrome and associated with various cardiometabolic risk factors. PMID- 22837308 TI - Experimental evaluation of immediate recanalization effect and recanalization efficacy of a new thrombus retriever for acute stroke treatment in vivo. AB - BACKGROUND AND PURPOSE: Currently, several new stent retriever devices for acute stroke treatment are under development and early clinical evaluation. Preclinical testing under standardized conditions is an important first step to evaluate the technical performance and potential of these devices. The aim of this study was to evaluate the immediate recanalization effect, recanalization efficacy, thrombus-device interaction, and safety of a new stent retriever intended for thrombectomy in patients with acute stroke. MATERIAL AND METHODS: The pREset thrombectomy device (4 * 20 mm) was evaluated in 16 vessel occlusions in an established swine model. Radiopaque thrombi (10-mm length) were used for visualization of thrombus-device interaction during application and retrieval. Flow-restoration effect immediately after deployment and after 5-minute embedding time before retrieval, recanalization rate after retrieval, thromboembolic events, and complications were assessed. High-resolution FPCT was performed to illustrate thrombus-device interaction during the embedding time. RESULTS: Immediate flow restoration was achieved in 75% of occlusions. An increase or stable percentage of recanalizations during embedding time before retrieval was seen in 56.3%; a decrease, in 12.5%; reocclusion of a previously recanalized vessel, in 18.8%; and no recanalization effect at all, in 12.5%. Complete recanalization (TICI 3) after retrieval was achieved in 93.8%; partial recanalization (TICI 2b), in 6.2%. No distal thromboembolic events were observed. High-resolution FPCT illustrated entrapment of the thrombus between the stent struts and compression against the contralateral vessel wall, leading to partial flow restoration. During retrieval, the thrombus was retained in a straight position within the stent struts. CONCLUSIONS: In this experimental study, the pREset thrombus retriever showed a high recanalization rate in vivo. High resolution FPCT allows detailed illustration of the thrombus-device interaction during embedding time and is advocated as an add-on tool to the animal model used in this study. PMID- 22837307 TI - High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin induced inhibition of thromboxane synthesis in human platelets. AB - Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5-25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1-300 MUmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA-induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA-induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action. PMID- 22837309 TI - Prediction of carotid plaque characteristics using non-gated MR imaging: correlation with endarterectomy specimens. AB - BACKGROUND AND PURPOSE: Electrocardiographic gating, commonly used in MR carotid plaque imaging, can negatively affect intraplaque contrast if the TR is inappropriate. The present study aimed to determine whether a non-gated technique with appropriate TRs can accurately evaluate intraplaque characteristics in specimens excised by CEA. MATERIALS AND METHODS: We prospectively examined 40 consecutive patients who underwent CEA (59-82 years of age) by using a 1.5T scanner. Axial T1WI with a TR of 500 ms and PDWI and T2WI with a TR of 3000 ms with a self-navigated rotating-blade scan instead of cardiac gating were obtained. Signal intensities of the plaque and adjacent muscle were measured, and the CR on T1WI, PDWI, and T2WI as well as the gray-scale median on US were correlated with the pathologic findings of the CEA specimens. RESULTS: On T1WI, the CRs of the carotid plaques differed significantly among groups in which the main components were histologically confirmed as fibrous tissue, lipid/necrosis, and hemorrhage (0.54-1.17, 1.16-1.53, and 1.40-2.29, respectively). The sensitivity and specificity for discriminating lipid/necrosis/hemorrhage from fibrous tissue were 96% and 100%, respectively. On T2WI, the CRs of plaques with lipid/necrosis were significantly higher than those of other groups, but the CRs on PDWI and the gray-scale median on US were not significantly different among the groups. CONCLUSIONS: Non-gated MR plaque imaging, particularly T1WI, can readily predict the intraplaque main components of the carotid artery with high sensitivity and specificity. PMID- 22837310 TI - Imaging features of midface injectable fillers and associated complications. AB - Injectable fillers are increasingly used for midface augmentation, which can be performed for facial rejuvenation and treatment of HIV facial lipoatrophy. A variety of temporary and permanent filler agents has been developed, including calcium hydroxylapatite, collagen, liquid silicone, polytetrafluoroethylene, hyaluronic acid, poly-l-lactic acid, and polyacrylamide gel. Facial fillers are sometimes encountered on radiologic imaging incidentally and should not be mistaken for pathology. Alternatively, patients with facial fillers may undergo imaging specifically to evaluate associated complications, such as infection, overfilling, migration, foreign-body reaction, and scarring. Therefore, it is important to be familiar with the imaging appearances of the various filler materials and their complications. PMID- 22837311 TI - A meta-analysis of observational intra-arterial stroke therapy studies using the Merci device, Penumbra system, and retrievable stents. AB - BACKGROUND AND PURPOSE: The time from arterial puncture to successful recanalization is an important milestone toward timely recanalization. With the significant improvement in recanalization rates by using thrombectomy devices, procedural time to recanalization is becoming a determinant factor in choosing among available devices. We aimed to assess the impact of time to recanalization on the outcome of intra-arterial stroke therapies. MATERIALS AND METHODS: We conducted a meta-analysis of studies reporting procedural times in patients with stroke treated with the MD, PS, and RS. RESULTS: We identified 16 eligible studies: 4 on the MD (n = 357), 8 on the PS (n = 455), and 4 on RS (n = 113). Merci device studies described total procedural duration, while PS and RS studies described puncture-to-recanalization times. With a random-effects model, mean procedural duration for the MD was 120 minutes (95% CI, 105.7-134.2 minutes). Mean puncture to recanalization time for the PS was 64.6 minutes (95% CI, 44.4 84.8 minutes) and 54.7 minutes for RS (95% CI, 47.3-62.2 minutes). Successful recanalization was achieved in 211 of 357 patients (59.1%) in the MD studies (95% CI, 49.3-77.7), 394 of 455 (86.6%) in the PS studies (95% CI, 84.1-93.8), and 105 of 113 (92.9%) in the RS studies (95% CI, 90.9-99.9). Functional independence (mRS <=2) was achieved in 31.5% of patients in the MD studies, 36.6% in the PS studies, and 46.9% in the RS studies. CONCLUSIONS: The use of the PS and RS was associated with comparable procedural time to recanalization. Available data did not allow this parameter to be determined for trials using the MD. Retrievable stents achieved the highest rate of successful recanalization and functional outcome and the lowest mortality. PMID- 22837312 TI - T2* mapping with background gradient correction using different excitation pulse shapes. AB - SUMMARY: Background gradients induced by magnetic susceptibility variations near air-filled cavities in the brain cause signal-intensity loss in gradient-echo images and shorten T2* considerably. With a correction method in which the exponential decay is restored with section-profile-dependent correction factors, parts of the signal intensity can be recovered. While uncorrected T2* values drop by 20% at a gradient strength of 75 MUT/m, with correction and exponential excitation pulses, this boundary is pushed to 220 MUT/m. PMID- 22837313 TI - The clinical and radiographic importance of distinguishing partial from near complete reperfusion following intra-arterial stroke therapy. AB - BACKGROUND AND PURPOSE: Reperfusion following intra-arterial stroke therapy is associated with improved clinical outcomes. However, the degree of reperfusion needed to achieve successful outcomes is unknown. The purpose of this analysis was to determine whether the degree of reperfusion has an impact on final infarct volumes and clinical outcomes. MATERIALS AND METHODS: A retrospective analysis identified 88 consecutive patients who underwent intra-arterial therapy for acute anterior circulation stroke. Reperfusion was graded by using the TICI scale into none (TICI 0 or 1), partial (TICI 2a), or near-complete (TICI 2b/3). Baseline characteristics were compared. For each of these groups, we compared discharge disposition and final infarct volumes. RESULTS: Near-complete, partial, and no reperfusion occurred in 44.3%, 26.1%, and 29.6% of patients, respectively. Baseline characteristics were similar across all 3 groups. The median NIHSS score was 15. Significant differences in discharge disposition were seen, with 41.0% of the TICI 2b/3 group discharged home versus 17.4% of TICI 2a and 7.7% of TICI 0/1. In-hospital mortality was 12.8% for TICI 2b/3 compared with 39.1% for TICI 2a and 34.6% for TICI 0/1. Patients with near-complete reperfusion were significantly more likely to have infarct volumes <=70 mL (OR = 12.1; 95% CI, 2.7-54.2), compared with patients with partial reperfusion (OR = 2.2; 95% CI, 0.5-9.6). CONCLUSIONS: Significant differences exist in outcomes and infarct volumes between partial (TICI 2a) and near-complete (TICI 2b/3) reperfusion following intra-arterial stroke therapy. Further trials should separately report these groups to facilitate comparison among treatment paradigms. PMID- 22837314 TI - Cysteine residues in the transmembrane (TM) 9 to TM11 region of the human equilibrative nucleoside transporter subtype 1 play an important role in inhibitor binding and translocation function. AB - Inhibitor and substrate interactions with equilibrative nucleoside transporter 1 (ENT1; SLC29A1) are known to be affected by cysteine-modifying reagents. A previous study from our laboratory established Cys222 in transmembrane (TM) 6 as the residue responsible for methyl methanethiosulfonate (a membrane-permeable sulfhydryl modifier)-mediated enhancement of the binding of the ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR) in intact cells. However, the capacity of charged sulfhydryl reagents to inhibit the binding of NBMPR in broken cell preparations (allowing cytoplasmic access) was not affected by mutation of any of the cysteines (Cys87, 193, 213, or 222) in the N-terminal half of the protein. We thus hypothesized that the inhibitory effects of the modifiers were due to the one or more of the six cysteine residues in the C-terminal half of ENT1, particularly one or both of those in the fifth intracellular loop (Cys414 and Cys416). Each of the cysteines were mutated to serine or alanine and expressed in nucleoside transport-deficient PK15 cells and probed with a series of methanethiosulfonate sulfhydryl-modifying reagents. Transporter function was assessed by the site-specific binding of [(3)H]NBMPR and the cellular uptake of [(3)H]2-chloroadenosine. These studies established that Cys378 is an extracellular-located residue modified by [2-(trimethylammonium)ethyl] methane thiosulfonate (MTSET) to inhibit the binding of NBMPR to intact cells. Mutation of Cys414 led to an enhancement of the ability of MTSET to inhibit NBMPR binding, and this enhancement was eliminated by the comutation of Cys378, indicating that disruption of the fifth intracellular loop modifies the conformation of TM10 and its extracellular extension. Mutation of Cys416 led to the loss of the ability of the charged sulfhydryl reagents to inhibit NBMPR binding in isolated membranes and also led to the loss of transport function. This finding further supports an allosteric interaction between the fifth intracellular loop and the extracellular NBMPR binding domain and implicates this region in the translocation function of human ENT1. PMID- 22837315 TI - Serratia marcescens necrotizing fasciitis presenting as bilateral breast necrosis. AB - Serratia marcescens is an extremely rare cause of necrotizing fasciitis. We report the first case of necrotizing fasciitis of the chest wall due to infection with S. marcescens that initially manifested as bilateral breast necrosis. The patient had a fulminant course leading to death within 72 h of presentation. Literature pertinent to S. marcescens-mediated necrotizing fasciitis is also reviewed. PMID- 22837316 TI - Prevalence of Streptococcus pneumoniae in respiratory samples from patients with tracheostomy in a long-term-care facility. AB - We aimed to study the prevalence of Streptococcus pneumoniae in respiratory samples from institutionalized patients with chronic tracheostomy. A total of 264 pairs of nasopharyngeal and endotracheal cultures were collected. There was no difference in the proportion of positive cultures between children (21%) and adults (18%). However, the proportion of positive endotracheal cultures was higher than that of nasopharyngeal cultures in adults (18% versus 3%, respectively; P < 0.001) but not in children (17% in both sites). PMID- 22837317 TI - Galactomannan enzymatic immunoassay cross-reactivity caused by Prototheca species. AB - We report a reactive Aspergillus galactomannan enzymatic immunoassay against the serum of a patient with invasive Prototheca zopfii infection. Analysis of the supernatants of suspensions of P. zopfii and other Prototheca isolates revealed positive results as well. These data suggest cross-reactivity with the serum Aspergillus galactomannan assay in invasive protothecosis. PMID- 22837318 TI - Microbial dysbiosis in pediatric patients with Crohn's disease. AB - Microbial dysbiosis has been suggested to be involved in the pathogenesis of Crohn's disease (CD); however, many studies of gut microbial communities have been confounded by environmental and patient-related factors. In this study, the microbial flora of fecal samples from 19 children newly diagnosed with CD and 21 age-matched controls were analyzed using high-throughput sequencing to determine differences in the microbial composition between CD patients and controls. Analysis of the microbial composition of specific bacterial groups revealed that Firmicutes percentages were significantly lower in CD patients than in controls and that this was due largely to changes in the class Clostridia. Bacteroidetes and Proteobacteria percentages were higher and significantly higher in CD patients than in controls, respectively. Both the detection frequencies of Bacteroidetes and Firmicutes correlated (positively and negatively, respectively) with the calculated pediatric Crohn's disease activity index scores of patients. Upon further analysis, differences in the microbial compositions of patients with mild disease and moderate to severe disease were identified. Our findings indicate that a combination of different bacterial species or a dynamic interplay between individual species is important for disease and is consistent with the dysbiosis hypothesis of CD. PMID- 22837319 TI - Utilizing rapid multiple-locus variable-number tandem-repeat analysis typing to aid control of hospital-acquired Clostridium difficile Infection: a multicenter study. AB - The early identification of outbreaks is crucial for the control of Clostridium difficile infection. This study aimed to determine if the number of hospital acquired C. difficile infections could be reduced by rapidly typing C. difficile strains using multiple-locus variable-number tandem-repeat analysis (MLVA) compared to typing using PCR ribotyping. A total of 16 hospitals were recruited to the study, and all periods of increased incidence (PIIs) of C. difficile infection were identified. The hospitals were randomized into two study arms, the test and the control, with all isolates typed in the test using MLVA and in the control using PCR ribotyping. Following a PII, each hospital received a structured questionnaire regarding control measures implemented or stopped prior to or following the typing results. During the study period, there were a total of 1,682 hospital-apportioned C. difficile toxin-positive cases, with 868 in the control and 814 in the test, with modeling demonstrating no differences between the two arms. A total of 245 PIIs occurred, involving 785 patients. There was a significant difference in the mean turnaround time between the ribotyping and MLVA typing (13.6 and 5.3 days, respectively [P < 0.001]). The discriminatory ability of MLVA was greater than ribotyping, with 85 outbreaks being confirmed by ribotyping and 62 by MLVA. In the test arm, 40.6% of respondents strongly agreed that the typing result had aided their management of clusters, as opposed to 9.9% in the control. The study demonstrated the utility of rapidly typing C. difficile strains, demonstrating that it aided the management of clusters, enabling effective targeting of infection control resources. PMID- 22837321 TI - Evaluation of double-disk potentiation and disk potentiation tests using dipicolinic acid for detection of metallo-beta-lactamase-producing pseudomonas spp. and Acinetobacter spp. AB - Accurate detection of metallo-beta-lactamase (MBL)-producing Pseudomonas spp. and Acinetobacter spp. became very important with the increasing prevalence of carbapenem-nonsusceptible clinical isolates. The performance of phenotypic MBL detection methods may depend on the types of MBL and the characteristics of the isolates. A high false-positive rate is a problem with EDTA-based MBL detection methods. We evaluated the performance of double-disk potentiation tests (DDPTs) and disk potentiation tests (DPTs) with dipicolinic acid (DPA) using 44 isolates of Pseudomonas spp. and Acinetobacter spp. producing IMP-1-like, VIM-2-like, and SIM-1 type MBLs. Also, we characterized P. aeruginosa isolates with positive imipenem (IPM)-DPA DDPT, but negative meropenem (MEM)-DPA DDPT, and determined possibility of improving a DDPT by using MacConkey agar. Among five different DDPT methods, the IPM-DPA 250-MUg method showed the highest sensitivity (97.7%) and specificity (100%). Among four DPT tests, the highest sensitivity (100%) was shown by the IPM-EDTA 1,900-MUg disk method, but the specificity was very low (11.4%). Five of six P. aeruginosa isolates with false-negative DDPTs with MEM DPA 250-MUg disks carried bla(IMP-6,) and the high level resistance to MEM (MIC >= 512 MUg/ml) was reduced by the presence of phenylalanine arginine beta naphtylamide. Improvement of DDPTs was observed when MacConkey agar was used instead of Mueller-Hinton agar. In conclusion, DPA is a better MBL inhibitor than EDTA for detection of Pseudomonas spp. and Acinetobacter spp. with IMP-1-like, VIM-2-like, and SIM-1-type MBLs. In DPA DDPTs, IPM disks perform better than MEM disks when the isolates are highly resistant to MEM due to the overexpression of efflux pumps. PMID- 22837322 TI - Detection of new methicillin-resistant Staphylococcus aureus strains that carry a novel genetic homologue and important virulence determinants. AB - In this study, 18 methicillin-resistant Staphylococcus aureus (MRSA) isolates harboring staphylococcal cassette chromosome mec (SCCmec) type XI, recovered in the Dutch-German Euregio, were characterized by DNA microarrays. In contrast to previous data, we found two MRSA strains of different clonal lineages possessing SCCmec XI that carried important virulence determinants. The worrisome emergence of such toxigenic MRSA strains raises concerns that MRSA strains with enhanced virulence potential and impaired detectability by standard molecular assays may spread in Europe. PMID- 22837320 TI - Rapid detection and identification of Aspergillus from lower respiratory tract specimens by use of a combined probe-high-resolution melting analysis. AB - Diagnosis of invasive aspergillosis (IA) requires increasingly rapid molecular methods that enable sensitive detection and discrimination between species. We designed and evaluated a real-time PCR-based method that combined melting temperature (T(m)) calling analysis of a specific probe with high-resolution melting analysis of the full amplicon. The test correctly identified 78 isolates of Aspergillus section Fumigati and non-Fumigati sections of Aspergillus with a limit of detection of 10(2) conidia/ml (10(2) fg/ml). No cross-reactivity with other fungi was found. The assay was further validated on lower respiratory tract specimens containing Aspergillus or not. It successfully identified Aspergillus to section level in 56 of 59 specimens. With culture as the gold standard, our assay shows 100% sensitivity and specificity and constitutes an efficient alternative for identification of Aspergillus in lower respiratory tract samples. PMID- 22837323 TI - Quantitative genomic and antigenomic enterovirus RNA detection in explanted heart tissue samples from patients with end-stage idiopathic dilated cardiomyopathy. AB - Standardized one-step real-time RT-PCR assay detected enterovirus RNA in cardiac biopsy samples from 4 of 20 patients suffering from idiopathic dilated cardiomyopathy (IDCM). The median viral load was 287 copies per microgram of total extracted nucleic acids, with positive- to negative-strand RNA ratios ranging from 2 to 20. These results demonstrate enterovirus persistence in the heart of IDCM patients, characterized by low viral loads and low positive- to negative-RNA ratios. PMID- 22837324 TI - Modeling uncertainty in single-copy assays for HIV. AB - We present a simple computational model of measurement accuracy for single-copy sensitivity assays (SCA) of HIV RNA that was developed from first principles. The model shows that the SCA is significantly right-skewed. Measured virus concentrations of 1 and 10 virions/ml had overlapping 95% confidence intervals and were statistically indistinguishable. PMID- 22837325 TI - Real-time PCR for diagnosing Helicobacter pylori infection in patients with upper gastrointestinal bleeding: comparison with other classical diagnostic methods. AB - The aim of this study was to determine the diagnostic usefulness of quantification of the H. pylori genome in detection of infection in patients with upper gastrointestinal bleeding (UGB). A total of 158 consecutive patients with digestive disorders, 80 of whom had clinical presentation of UGB, were studied. The number of microorganisms was quantified using a real-time PCR system which amplifies the urease gene with an internal control for eliminating the false negatives. A biopsy sample from the antrum and corpus of each patient was processed. The rapid urease test, culture, histological study, stool antigen test, and breath test were done. The gold standard was a positive culture or positive results in at least two of the other techniques. When a positive result was defined as any number of microorganisms/human cell, the sensitivity of real time PCR was greater in bleeding patients, especially in the gastric corpus: 68.4% (95% confidence interval [CI], 52.3 to 84.5%) in non-UGB patients versus 91.5% (95% CI, 79.6 to 97.6%) in UGB patients. When a positive result was defined as a number of microorganisms/human cell above the optimal value that maximizes the Youden index (>3.56 microorganisms/human cell in the antrum and >2.69 in the corpus), the sensitivity and specificity in UGB patients were over 80% in both antrum and corpus. Our findings suggest that some bleeding patients with infection caused by H. pylori may not be correctly diagnosed by classical methods, and such patients could benefit from the improved diagnosis provided by real-time PCR. However, the clinical significance of a small number of microorganisms in patients with negative results in classical tests should be evaluated. PMID- 22837326 TI - Probability of negative mycobacterium tuberculosis complex cultures based on time to detection of positive cultures: a multicenter evaluation of commercial-broth based culture systems. AB - We conducted a multicenter study to determine whether Mycobacterium tuberculosis complex (MTBC) cultures in automated broth-based systems could reliably be considered negative sooner than 6 weeks. Laboratory sites used Bactec MGIT or BacT/Alert and tracked results of time to detection of all mycobacteria (TTD-all, n = 1547) and of MTBC (TTD-MTBC, n = 466) over 6-month periods from primarily (93%) respiratory specimens. Cumulative percentages by day detected and median TTD of initial and follow-up specimens were analyzed. The median TTD-MTBC for MGIT (n = 6 sites) was 14 days. For laboratories using standard processing procedures, 100% of MTBC were detected from initial and follow-up specimens in 28 and 35 days, respectively, and no yield of MTBC on solid or MGIT liquid media was observed after 5 weeks. The median TTD-MTBC for BacT/Alert (n = 3 sites) was 18 days, with 95% and 100% detected within 37 and 42 days, respectively. Analysis of TTD of positive MTBC cultures in broth can predict the probability of culture negativity at defined time points. Receipt of interim negative reports earlier than 6 weeks could assist clinicians in considering alternative diagnoses and could alter the timing and prioritization of public health interventions. Laboratories should analyze their own TTD data to inform protocol decisions. Laboratories using MGIT could issue reports of no growth of MTBC on initial specimens as early as 4 weeks and for patients undergoing treatment as early as 5 weeks postinoculation. PMID- 22837327 TI - The genus corynebacterium and other medically relevant coryneform-like bacteria. AB - Catalase-positive Gram-positive bacilli, commonly called "diphtheroids" or "coryneform" bacteria were historically nearly always dismissed as contaminants when recovered from patients, but increasingly have been implicated as the cause of significant infections. These taxa have been underreported, and the taxa were taxonomically confusing. The mechanisms of pathogenesis, especially for newly described taxa, were rarely studied. Antibiotic susceptibility data were relatively scant. In this minireview, clinical relevance, phenotypic and genetic identification methods, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) evaluations, and antimicrobial susceptibility testing involving species in the genus Corynebacterium and other medically relevant Gram positive rods, collectively called coryneforms, are described. PMID- 22837328 TI - Abundant drug-resistant NS3 mutants detected by deep sequencing in hepatitis C virus-infected patients undergoing NS3 protease inhibitor monotherapy. AB - The high genetic variation of hepatitis C virus (HCV) results in rapid selection of drug resistance mutations (DRMs) during monotherapy with direct-acting antivirals (DAAs). It has been proposed that each possible single mutant preexists in infected individuals; however, the levels of preexisting DRMs are too low to be directly quantified in most patients using current techniques. In this study, we evaluated the presence of DRMs in HCV-infected patients treated with the HCV protease inhibitors GS-9256 or GS-9451 as monotherapy using deep sequencing in 137 longitudinal samples from 45 patients. Software was developed to analyze deep-sequencing results with an assay cutoff of 0.25%. No NS3 DRMs that confer resistance to GS-9256 and GS-9451 (R155K, A156T, and D168V/E) were observed in 33 baseline samples at >0.25%. In contrast, these and other substitutions at NS3 positions 155, 156, and 168 were detected in 19/27 patients at day 2 (24 h) and 21/21 at day 4 (84 h) of monotherapy but not in placebo treated patients. Based on the DRM growth kinetics during drug treatment, pretreated NS3 mutations at amino acids 155, 156, and 168 were estimated on average at 0.025% and 0.015% per genotype 1a and 1b HCV-infected patients, respectively. Relative fitness of the DRM viruses was shown to be significantly lower than the wild type. Deep-sequencing analyses of NS3 protease inhibitor treated HCV-infected patients suggest a limit of HCV viral load suppression of 3.6 to 3.8 log(10) with NS3 protease inhibitor monotherapy that does not suppress the identified preexisting NS3 DRMs and thus a need for a combination therapy. PMID- 22837329 TI - Molecular epidemiology of methicillin-resistant Staphylococcus aureus isolates from patients newly identified as nasal carriers. AB - We aimed to determine whether additional molecular and microbiological evaluations of methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients newly identified as nasal carriers were useful for control strategies and whether longitudinal testing during the same or repeat hospitalization changed MRSA status. Nasal swabs from patients positive by Xpert MRSA PCR and not known to be colonized in the previous year were cultured for S. aureus. Isolates were tested for resistance to a variety of antibiotics, including high-level mupirocin resistance (HLMR) and low-level mupirocin resistance (LLMR) and the presence of genes mecA and mupA and those for Panton-Valentine leukocidin (PVL), USA300, and USA400. Repeat nasal screens during the 6-month study were tested for continued presence of MRSA. Among 130 patients, cultures revealed MRSA in 85 (65.4%), methicillin-susceptible S. aureus in 19 (14.6%), and no growth in 26 (20%). MRSA isolates were USA300 positive in 13/85 (15.3%) and LLMR in 8/85 (9.4%) patients. No isolates were HLMR or mupA positive. mecA dropout was detected in 9/130 (6.9%) patients. The rate of subsequent MRSA infections in USA300-positive versus -negative patients was not different. MRSA nasal status remained concordant in 69/70 (98.6%) patients who had follow-up testing. The findings do not support expanding MRSA surveillance to include routine detection of genes for USA300, PVL, or mupA, all of which were either of low frequency or not significantly associated with MRSA infection risk in our population of newly identified nasal carriers. Repeat nasal screening for MRSA during the same or subsequent hospitalizations over 6 months could also be deferred, reducing costs associated with screening. PMID- 22837331 TI - Workers with occupational contact dermatitis: workplace characteristics and prevention practices. AB - BACKGROUND: There are many gaps in knowledge related to prevention practices in place for workers who subsequently develop occupational contact dermatitis (OCD). AIMS: To describe the workplace characteristics and the prevention practices in workplaces where workers developed hand dermatitis. METHODS: Consecutive cases of probable OCD were enrolled from a specialist occupational health clinic. At the time of the initial assessment, questionnaires were administered to collect information about clinical presentation, workplace characteristics and prevention practices at work. RESULTS: 100 workers with hand dermatitis were enrolled in the study and 78 were considered to have OCD. Two-thirds of these had had some occupational health and safety or Workplace Hazardous Materials Information System (WHMIS) training in their workplace, however, training related to glove use and skin care was less common. Unionized workers were more likely to have received training. Workers involved in wet work were less likely to report training. CONCLUSIONS: These findings suggest that there are gaps in prevention programs for work-related skin disease. Research is needed on effective strategies that are sustainable in the workplace. PMID- 22837330 TI - Subtractive hybridization yields a silver resistance determinant unique to nosocomial pathogens in the Enterobacter cloacae complex. AB - The heterogeneity and the increasing clinical importance of the Enterobacter cloacae complex have often been discussed. However, little is known about molecular factors causing pathogenicity within this nomenspecies. Here, we analyzed the genetic differences between an avirulent plant isolate and a pathogenic strain causing an outbreak with septicemia in three patients. We identified an IncHI-2 plasmid as a major difference between these two strains. Besides resistance to several antibiotics, this plasmid encoded a silver resistance determinant. We further showed that this sil determinant was present not only in the analyzed outbreak strain but also in the vast majority of clinical isolates of the E. cloacae complex, predominantly in (sub)species that frequently cause nosocomial infections. The identified sil determinant was highly conserved within the E. cloacae complex and mediated resistance to up to 600 MUM silver nitrate. As silver is often used as a disinfectant and treatment for burn wounds, we present here an important fitness factor within the clinically most prevalent subspecies of the E. cloacae complex. This provides a possible explanation for their unequal involvement in nosocomial and especially burn wound infections. PMID- 22837332 TI - Audit of the recording of occupational asthma in primary care. AB - BACKGROUND: Occupational asthma (OA) remains common; 1 in 10 cases of adult-onset asthma is due to work. Health outcomes are better with early diagnosis, but there is considerable delay, largely due to lack of enquiry about work effect in primary care. National guidelines (2008) recommend asking two screening questions, which together have a high sensitivity in identifying OA. AIMS: To audit how working-age asthmatics are currently screened for OA in a local primary care population. METHODS: An audit of the electronic patient records of working age asthmatics, from four Birmingham primary care practices was undertaken. Practice-level data (list size, gender, prevalence of asthma and OA and socio economic status) and patient-level data (gender, age, onset, occupation and work effect enquiry and lung function) were collected. RESULTS: The total practice population was 27,295 of which 17,564 (64%) were of working age. The audit sample was 396 of whom 49% were male. The prevalence of asthma in working-age adults was 12% (8-15%) and the prevalence of OA in working-age asthmatics was 0.3% (0-0.8%). Occupation was recorded in only 55/396 (14%) cases with very few (2) documented within the asthma-review template. Occupation was only recorded in 13/55 adult onset asthmatics in high-risk occupations. Of 396, 9 (2%) had any work-effect enquiry and 4 patients had work-effect enquiry at diagnosis in those with traceable notes (n = 117). CONCLUSIONS: The prevalence of OA was low, suggesting under-diagnosis plus under-reporting in primary care. Occupation and work-effect enquiry is lacking despite guidelines for identifying OA. Existing electronic templates for recording asthma review could be modified to include these elements. PMID- 22837333 TI - Commission seeks views on food from cloned animals. PMID- 22837334 TI - Response to antimicrobial prescribing survey exceeds expectations. PMID- 22837335 TI - 'Clear decrease' in cases of SBV in sheep across Europe. PMID- 22837336 TI - New drugs to be assessed for treating animal African trypanosomosis. PMID- 22837337 TI - Industry-led group to help tackle sheep scab in Wales. PMID- 22837338 TI - Breathing problems 'considered normal' by owners of short-nosed dogs. PMID- 22837339 TI - Ensuring the welfare of assistance animals. PMID- 22837340 TI - More kittens required for health and welfare study. PMID- 22837341 TI - Flea control: owners seek advice from vets, but buy products elsewhere. PMID- 22837342 TI - Findings in cases of SBV infection in sheep in the south-east. PMID- 22837343 TI - Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses. AB - Clinical studies indicate that cigarette smoking increases the risk for developing acute pancreatitis. The nicotine metabolite 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) is a major cigarette smoke toxin. We hypothesized that NNK could sensitize to pancreatitis and examined its effects in isolated rat pancreatic acini and in vivo. In acini, 100 nM NNK caused three- and fivefold activation of trypsinogen and chymotrypsinogen, respectively, above control. Furthermore, NNK pretreatment in acini enhanced zymogen activation in a cerulein pancreatitis model. The long-term effects of NNK were examined in vivo after intraperitoneal injection of NNK (100 mg/kg body wt) three times weekly for 2 wk. NNK alone caused zymogen activation (6-fold for trypsinogen and 2-fold for chymotrypsinogen vs. control), vacuolization, pyknotic nuclei, and edema. This NNK pretreatment followed by treatment with cerulein (40 MUg/kg) for 1 h to induce early pancreatitis responses enhanced trypsinogen and chymotrypsinogen activation, as well as other parameters of pancreatitis, compared with cerulein alone. Potential targets of NNK include nicotinic acetylcholine receptors and beta-adrenergic receptors; mRNA for both receptor types was detected in acinar cell preparations. Studies with pharmacological inhibitors of these receptors indicate that NNK can mediate acinar cell responses through an nonneuronal alpha(7)-nicotinic acetylcholine receptor (alpha(7)-nAChR). These studies suggest that prolonged exposure to this tobacco toxin can cause pancreatitis and sensitize to disease. Therapies targeting NNK-mediated pathways may prove useful in treatment of smoking-related pancreatitis. PMID- 22837345 TI - Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is one of the most common gastrointestinal ailments among those seeking health care for gastrointestinal disorders. Despite its prevalence, IBS pathophysiology is still not completely understood. Continued elucidation of IBS etiological mechanisms will lead to a greater appreciation of possible therapeutic targets. In the past decade, there has been increasing focus on the possible connection between increased intestinal mucosal permeability, inflammation, and visceral hypersensitivity. Increased permeability in subsets of IBS patients has been observed and the possible mechanisms underlying this defect are just beginning to be understood. The objectives of this review are to summarize the role of the healthy intestinal epithelium as a barrier between the lumen and the rest of the body with a focus on tight junctions; to examine the lines of evidence that suggest that different triggers lead to increased intestinal mucosal permeability and disruption of tight junctions in IBS patients; and to explore how this increased permeability may elicit immune responses that affect afferent nerves, resulting in the pain associated with IBS. PMID- 22837344 TI - Importance of apical membrane delivery of 1,25-dihydroxyvitamin D3 to vitamin D responsive gene expression in the colon. AB - Synthetic conjugation of a glucuronide to 1,25-dihydroxyvitamin D3 (1,25D3) to produce beta-25-monoglucuronide-1,25D3 (betaGluc-1,25D3) renders the hormone biologically inactive and resistant to mammalian digestive enzymes. However, beta glucuronidase produced by bacteria in the lower intestinal tract can cleave off the glucuronide, releasing the active hormone. In mice given a single oral dose of 1,25D3, 24-hydroxylase (Cyp24a1) gene expression was strongly enhanced in the duodenum, but not in the colon, despite circulating concentrations of 1,25D3 that peaked at ~3.0 nmol/l. In contrast, in mice treated with an equimolar dose of betaGluc-1,25D3, Cyp24a1 gene expression increased 700-fold in the colon but was significantly weaker in the duodenum compared with mice treated with 1,25D3. Similar results were observed with another vitamin D-dependent gene. When administered subcutaneously, 1,25D3 weakly stimulated colon Cyp24a1 gene expression while betaGluc-1,25D3 again resulted in strong enhancement. Surgical ligation to block passage of ingesta beyond the upper intestinal tract abolished upregulation of colon Cyp24a1 gene expression by orally and subcutaneously administered betaGluc-1,25D3. Feeding betaGluc-1,25D3 for 5 days revealed a linear, dose-dependent increase in colon Cyp24a1 gene expression but did not significantly increase plasma 1,25D3 or calcium concentrations. This study indicates that the colon is relatively insensitive to circulating concentrations of 1,25D3 and that the strongest gene enhancement occurs when the hormone reaches the colon via the lumen of the intestinal tract. These findings have broad implications for the use of vitamin D compounds in colon disorders and set the stage for future therapeutic studies utilizing betaGluc-1,25D3 in their treatment. PMID- 22837346 TI - Effect of aging on norepinephrine-related proliferative response in primary cultured periportal and perivenous hepatocytes. AB - Norepinephrine (NE) amplifies the mitogenic effect of EGF in a rat liver through the adrenergic receptor coupled with G protein, Ghalpha. Ghalpha is also known as a transglutaminase 2 (TG2), whose cross-linking activity is implicated in hepatocyte growth. Recently, we found that NE-induced amplification of EGF induced DNA synthesis in hepatocytes obtained from perivenous regions of liver is caused by inhibiting the downregulation of EGF receptor (EGFR) by TG2. In the present study, we investigated the effect of aging on NE-related proliferative response. Hepatocytes were obtained from the liver of 7- and 90-wk-old rats. To examine this in detail, periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) were isolated using the digitonin/collagenase perfusion technique. EGF or NE receptor binding was analyzed by Scatchard analysis. Changes in NE-induced DNA synthesis, G protein activity, and TG2 activity were measured. NE slightly potentiated [125I]EGF binding to EGFR, and EGF-induced DNA synthesis in PVH but not in PPH. [3H]NE binding studies indicated that PVH have a greater number of receptors than PPH, and that the number of receptors in both subpopulations increased with aging. NE-induced changes in G protein activity and TG2 activity in 90-wk-old rats were slight compared with 7-wk-old rats. These results suggest that NE results in a slight recovery effect on the age-related decline in EGF induced DNA synthesis because of incomplete switching of the function from TG2 to Ghalpha. PMID- 22837347 TI - Denosumab, a RANK ligand inhibitor, for postmenopausal women with osteoporosis. AB - OBJECTIVE: To review the evidence for use of denosumab for the treatment of postmenopausal osteoporosis. DATA SOURCES: A search of MEDLINE and EMBASE databases was conducted during January 2012, using the terms denosumab and osteoporosis, with index dates of 2000 to 2011. Additional information was gathered from Amgen and references cited in articles retrieved. STUDY SELECTION AND DATA EXTRACTION: English-language articles including clinical trials involving denosumab for treatment of osteoporosis and review articles were reviewed. Articles using denosumab in males or as treatment for conditions other than osteoporosis or osteopenia were excluded. DATA SYNTHESIS: Many clinical trials have supported the safety and efficacy of denosumab in postmenopausal women with bone loss. It has been shown to improve bone mineral density, decrease markers of bone turnover, and prevent new vertebral fractures. It shows improvement over placebo in studies and has at least similar efficacy to alendronate in measurements of bone mineral density, with less risk for osteonecrosis of the jaw and atypical fracture, but with an increased risk of infections and neoplasms. European cost-effectiveness studies have also demonstrated that denosumab is a cost-effective choice compared to risedronate and no treatment for fracture prevention for postmenopausal women with osteoporosis. CONCLUSIONS: Denosumab has demonstrated efficacy and safety as a first-line treatment for postmenopausal osteoporosis in multiple clinical trials over at least 6 years. It may be most cost-effective for women who are unable or refuse to take bisphosphonate drugs. PMID- 22837348 TI - Psychiatry, the pharmaceutical industry, and the road to better therapeutics. PMID- 22837349 TI - Still searching for lost truths about the bitter sorrows of childhood. PMID- 22837350 TI - Crisis intervention for people with severe mental illnesses. PMID- 22837351 TI - Multidisciplinary approaches to understanding auditory hallucinations in schizophrenia and nonschizophrenia populations: the International Consortium on Hallucination Research. AB - This special theme issue of Schizophrenia Bulletin presents a series of related articles focusing on auditory hallucinations, prepared by members of the International Consortium on Hallucination Research [InCoHR] working groups. The InCoHR is a large collaborative framework that serves as a platform for researchers to meet and collaborate on multidisciplinary projects relating to auditory hallucinations [AH] and discuss methodological issues facing transdiagnostic research. Laroi et al. observe the similarities in characteristic features of AHs in different clinical and nonclinical groups, but they also note that differences exist, reflecting the contribution of disease-related process. Waters et al. use findings of shared cognitive impairments across different diagnostic groups with AHs to propose a novel theoretical cognitive framework. Allen et al. describe that the neurobiological substrates of AHs include neural systems involved in language processing, as well as sensory and nonsensory brain regions and that studies are increasingly using fine-grain analysis of patients' characteristics in analyzing neuroimaging data. Ford et al. discuss different neurophysiological approaches and describes hallucination-related alterations in activity in temporal and frontal regions of the brain and particularly in auditory cortical areas. Finally, Sommer et al. review different treatment options for AHs in schizophrenia and other disorders, including pharmacological treatment, cognitive-behavioral therapy [CBT] and acceptance and commitment therapy [ACT], transcranial magnetic stimulation [TMS], and electroconvulsive therapy [ECT]. These related publications describe the current substance and direction of research on AHs across different diagnostic groups. PMID- 22837356 TI - Dissecting functions of KATANIN and WRINKLED1 in cotton fiber development by virus-induced gene silencing. AB - Most of the world's natural fiber comes from cotton (Gossypium spp.), which is an important crop worldwide. Characterizing genes that regulate cotton yield and fiber quality is expected to benefit the sustainable production of natural fiber. Although a huge number of expressed sequence tag sequences are now available in the public database, large-scale gene function analysis has been hampered by the low-efficiency process of generating transgenic cotton plants. Tobacco rattle virus (TRV) has recently been reported to trigger virus-induced gene silencing (VIGS) in cotton leaves. Here, we extended the utility of this method by showing that TRV-VIGS can operate in reproductive organs as well. We used this method to investigate the function of KATANIN and WRINKLED1 in cotton plant development. Cotton plants with suppressed KATANIN expression produced shorter fibers and elevated weight ratio of seed oil to endosperm. By contrast, silencing of WRINKLED1 expression resulted in increased fiber length but reduced oil seed content, suggesting the possibility to increase fiber length by repartitioning carbon flow. Our results provide evidence that the TRV-VIGS system can be used for rapid functional analysis of genes involved in cotton fiber development. PMID- 22837357 TI - Fast isogenic mapping-by-sequencing of ethyl methanesulfonate-induced mutant bulks. AB - Mapping-by-sequencing (or SHOREmapping) has revitalized the powerful concept of forward genetic screens in plants. However, as in conventional genetic mapping approaches, mapping-by-sequencing requires phenotyping of mapping populations established from crosses between two diverged accessions. In addition to the segregation of the focal phenotype, this introduces natural phenotypic variation, which can interfere with the recognition of quantitative phenotypes. Here, we demonstrate how mapping-by-sequencing and candidate gene identification can be performed within the same genetic background using only mutagen-induced changes as segregating markers. Using a previously unknown suppressor of mutants of like heterochromatin protein1 (lhp1), which in its functional form is involved in chromatin-mediated gene repression, we identified three closely linked ethyl methanesulfonate-induced changes as putative candidates. In order to assess allele frequency differences between such closely linked mutations, we introduced deep candidate resequencing using the new Ion Torrent Personal Genome Machine sequencing platform to our mutant identification pipeline and thereby reduced the number of causal candidate mutations to only one. Genetic analysis of two independent additional alleles confirmed that this mutation was causal for the suppression of lhp1. PMID- 22837359 TI - Analysis of xylem sap from functional (nonembolized) and nonfunctional (embolized) vessels of Populus nigra: chemistry of refilling. AB - It is assumed that the refilling of drought-induced embolism requires the creation of an osmotic gradient between xylem parenchyma cells and vessel lumens to generate the water efflux needed to fill the void. To assess the mechanism of embolism repair, it is crucial to determine if plants can up-regulate the efflux of osmotically active substances into embolized vessels and identify the major components of the released osmoticum. Here, we introduce a new approach of sap collection designed to separate water from nonembolized (functional) and embolized (nonfunctional) vessels. This new approach made possible the chemical analysis of liquid collected from both types of vessels in plants subjected to different levels of water stress. The technique also allowed us to determine the water volumes in nonfunctional vessels as a function of stress level. Overall, with the increase of water stress in plants, the osmotic potential of liquid collected from nonfunctional vessels increased while its volume decreased. These results revealed the presence of both sugars and ions in nonfunctional vessels at elevated levels in comparison with liquid collected from functional vessels, in which only traces of sugars were found. The increased sugar concentration was accompanied by decreased xylem sap pH. These results provide new insight into the biology of refilling, underlining the role of sugar and sugar transporters, and imply that a large degree of hydraulic compartmentalization must exist in the xylem during the refilling process. PMID- 22837358 TI - Auxin and epigenetic regulation of SKP2B, an F-box that represses lateral root formation. AB - In plants, lateral roots originate from pericycle founder cells that are specified at regular intervals along the main root. Here, we show that Arabidopsis (Arabidopsis thaliana) SKP2B (for S-Phase Kinase-Associated Protein2B), an F-box protein, negatively regulates cell cycle and lateral root formation as it represses meristematic and founder cell divisions. According to its function, SKP2B is expressed in founder cells, lateral root primordia and the root apical meristem. We identified a novel motif in the SKP2B promoter that is required for its specific root expression and auxin-dependent induction in the pericycle cells. Next to a transcriptional control by auxin, SKP2B expression is regulated by histone H3.1/H3.3 deposition in a CAF-dependent manner. The SKP2B promoter and the 5' end of the transcribed region are enriched in H3.3, which is associated with active chromatin states, over H3.1. Furthermore, the SKP2B promoter is also regulated by H3 acetylation in an auxin- and IAA14-dependent manner, reinforcing the idea that epigenetics represents an important regulatory mechanism during lateral root formation. PMID- 22837361 TI - Sociodemographic disparities in the composition of metabolic syndrome components among adults in South Korea. AB - OBJECTIVE Metabolic syndrome (MetS) is becoming a serious public health concern in many countries, including South Korea, which has faced remarkable changes in lifestyles and disease patterns in recent decades. We examined sex and socioeconomic status (SES) disparities in MetS and its components among South Koreans using recent, nationally representative data. RESEARCH DESIGN AND METHODS Data from the 2007-2008 Korea National Health and Nutrition Examination Surveys for 7,289 adults 19-65 years of age were used to examine the patterns of MetS components (defined using International Diabetes Federation criteria), and regression models were used to study the association of MetS with SES, indicated by education and family income levels. RESULTS MetS prevalence increased with age, from 4.6% at age 19-29 years to 25.0% at age 50-65 years. More men had MetS than women (15.8 vs. 11.6%); men had worse levels of all MetS components. In women, the low-income and low-education group was more likely to have MetS (odds ratio 2.75 [95% CI 1.75-4.31]); the high-income and high-education group was 52% less likely to have MetS (0.48 [0.25-0.89]) compared with the middle-income and middle-education group. The most common combination of MetS components was central obesity + low HDL cholesterol (HDL-C) + hypertriglyceridemia, which occurred in 15.5% of all MetS patients and in 3.4% of all South Korean adults (4.1% in men and 2.9% in women). CONCLUSIONS Those who were older and male as well as low-SES female had higher rates of MetS and its components in South Korea. The SES-MetS association was not found in men. Central obesity + low HDL-C + hypertriglyceridemia was the most common MetS pattern regardless of the SES. PMID- 22837360 TI - Effects of drought on gene expression in maize reproductive and leaf meristem tissue revealed by RNA-Seq. AB - Drought stress affects cereals especially during the reproductive stage. The maize (Zea mays) drought transcriptome was studied using RNA-Seq analysis to compare drought-treated and well-watered fertilized ovary and basal leaf meristem tissue. More drought-responsive genes responded in the ovary compared with the leaf meristem. Gene Ontology enrichment analysis revealed a massive decrease in transcript abundance of cell division and cell cycle genes in the drought stressed ovary only. Among Gene Ontology categories related to carbohydrate metabolism, changes in starch and Suc metabolism-related genes occurred in the ovary, consistent with a decrease in starch levels, and in Suc transporter function, with no comparable changes occurring in the leaf meristem. Abscisic acid (ABA)-related processes responded positively, but only in the ovaries. Related responses suggested the operation of low glucose sensing in drought stressed ovaries. The data are discussed in the context of the susceptibility of maize kernel to drought stress leading to embryo abortion and the relative robustness of dividing vegetative tissue taken at the same time from the same plant subjected to the same conditions. Our working hypothesis involves signaling events associated with increased ABA levels, decreased glucose levels, disruption of ABA/sugar signaling, activation of programmed cell death/senescence through repression of a phospholipase C-mediated signaling pathway, and arrest of the cell cycle in the stressed ovary at 1 d after pollination. Increased invertase levels in the stressed leaf meristem, on the other hand, resulted in that tissue maintaining hexose levels at an "unstressed" level, and at lower ABA levels, which was correlated with successful resistance to drought stress. PMID- 22837362 TI - The effect of direct renin inhibition alone and in combination with ACE inhibition on endothelial function, arterial stiffness, and renal function in type 1 diabetes. AB - OBJECTIVE: Diabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes. RESEARCH DESIGN AND METHODS: Arterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril. RESULTS: Blood pressure-lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (-3.4 +/- 11.2 to -8.0 +/- 11.5 to -14.3 +/- 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 +/- 3.3 to 7.5 +/- 3.0 to 10.8 +/- 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia. CONCLUSIONS: In patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation. PMID- 22837363 TI - Superficial wound swabbing: a novel method of sampling and processing wound fluid for subsequent immunoassay analysis in diabetic foot ulcerations. AB - OBJECTIVE: In diabetic foot ulcers, wound fluid inflammatory mediators have previously been proposed as surrogate markers for nonhealing. However, currently available wound fluid sampling techniques are not suitable for clinical practice due to low levels of exudate and a high logistical effort. The aim of this investigation was to assess 1) the technique of superficial wound swabbing for harvesting wound fluid; and 2) the quality of the collected fluid for immunoassay analysis of inflammatory mediators. RESEARCH DESIGN AND METHODS: Both nylon flocked swabs and film dressings were used to collect wound fluid from foot ulcers of diabetic patients. In randomly selected patients, levels of wound fluid inflammatory mediators and matrix metalloproteases were determined using multiplexed bead-based sandwich immunoassays with respect to both sampling methods. Wound fluid spike-in experiments were performed to evaluate the impact of different sample processing protocols on subsequent immunoassay analysis. RESULTS: Using the swabbing technique, a median amount of 40 uL (2-120 uL) wound exudate was collected, which allowed the measurement of several multiplex panels. Comparing both sampling methods, a similar qualitative protein recovery was observed with a trend to analyte enrichment by swabbing. Sample processing using swabs did not affect analyte recovery, with the exception of interleukin (IL)-8, thymus and activation-regulated chemokine, IL-17A, interferon-gamma-induced protein 10, and IL-4. CONCLUSIONS: The quality of wound fluid collected by superficial swabbing is not inferior to the current standard technique. Combined with subsequent bead-based sandwich immunoassay analysis, this new method offers a noninvasive technique, suitable for daily clinical routines, for assessment of inflammatory activity in diabetic foot ulcers. PMID- 22837364 TI - Monitoring of Individual Needs in Diabetes (MIND)-2: follow-up data from the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) MIND study. AB - OBJECTIVE: To test the effects of implementing computer-assisted Monitoring of Individual Needs in Diabetes (MIND) in routine diabetes care on psychological status and glycemic control, identify predictors of poor psychological outcomes, and evaluate care providers' experiences. RESEARCH DESIGN AND METHODS: The MIND procedure was implemented as part of the annual review in diabetes clinics across eight countries in a prospective observational study with a 1-year follow-up. MIND encompasses well-being (World Health Organization Five Well-Being Index [WHO 5]), diabetes-related distress (Problem Areas in Diabetes [PAID]), a Life Event Inventory, and the patient's agenda for their consultation. Medical data and agreed case-management actions were retrieved from the charts. RESULTS: Of the total 1,567 patients, 891 patients (57%) were monitored at a 1-year follow-up. Twenty-eight percent of the patients screened positive for depression and/or diabetes distress at baseline and considered cases, 17% of whom were receiving psychological care. Cases were significantly more often female and had type 2 diabetes and worse glycemic control compared with noncases. Clinically relevant improvements in WHO-5 and PAID were observed over time in cases, irrespective of referral (effects sizes 0.59 and 0.48, respectively; P < 0.0001). Glycemic control did not change. Female sex, life events, and concomitant chronic diseases were predictors of poor psychological outcomes. MIND was well received by patients and staff. CONCLUSIONS: MIND appears suitable for screening and discussion of emotional distress as part of the annual review. Broader dissemination in diabetes care is recommendable, but sustainability will depend on reimbursement and availability of support services. PMID- 22837365 TI - Psychometric evaluation of the adherence in diabetes questionnaire. AB - OBJECTIVE: To assess the psychometric properties of a short, new, self administered questionnaire (17-19 items) for evaluating the adherence behavior of children and adolescents with type 1 diabetes and their caregivers. This instrument has separate versions depending on the means of insulin administration, i.e., continuous subcutaneous insulin infusion (Adherence in Diabetes Questionnaire [ADQ]-I), or conventional insulin injection (ADQ-C). RESEARCH DESIGN AND METHODS: A total of 1,028 caregivers and 766 children and adolescents 2-17 years of age were recruited through the Danish Registry of Childhood Diabetes and completed the national web survey, including the ADQ and psychosocial measures of self-efficacy, parental support, family conflict, and aspects of diabetes-related quality of life. Blood samples were obtained for central HbA(1c) analysis. The psychometric properties of the ADQ were evaluated, and the association with glycemic control was assessed. RESULTS: There was good internal consistency for both the youth and caregiver reports and strong agreement between the caregiver and youth reports. Higher ADQ scores, indicating better adherence, were associated with better self-efficacy, more parental support, less diabetes-related conflict, and less experience with treatment barriers. Factor analysis supported maintaining the one-factor structure of the ADQ. Higher ADQ scores were associated with lower HbA(1c) levels. CONCLUSIONS: The ADQ showed good psychometric properties. Although the test-retest reliability and sensitivity to change of the instrument still need to be established, the ADQ appears to be a valuable tool for assessing adherence in families with children and adolescents with type 1 diabetes in both clinical and research settings. PMID- 22837366 TI - Increased pulse pressure independently predicts incident atrial fibrillation in patients with type 2 diabetes. AB - OBJECTIVE: To examine whether baseline pulse pressure (PP), a marker of arterial stiffness, is associated with subsequent development of atrial fibrillation (AF) in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 350 type 2 diabetic patients, who were free from AF at baseline, were followed for 10 years. A standard electrocardiogram was performed annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. RESULTS: During the follow-up, 32 patients (9.1% of total) developed incident AF. After adjustments for age, sex, BMI, diabetes duration, presence of left ventricular hypertrophy, hypertension treatment, kidney dysfunction, and pre-existing history of coronary heart disease, heart failure, and mild valvular disease, baseline PP was associated with an increased incidence of AF (adjusted odds ratio 1.76 for each SD increment [95% CI 1.1-2.8]; P < 0.01). CONCLUSIONS: Our findings suggest that increased PP independently predicts incident AF in patients with type 2 diabetes. PMID- 22837367 TI - Comparison of two creatinine-based estimating equations in predicting all-cause and cardiovascular mortality in patients with type 2 diabetes. AB - OBJECTIVE: To compare the performance of two glomerular filtration rate (GFR) estimating equations in predicting the risk of all-cause and cardiovascular mortality in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We followed 2,823 type 2 diabetic outpatients for a period of 6 years for the occurrence of all-cause and cardiovascular mortality. GFR was estimated using the four-variable Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: At baseline, an estimated GFR (eGFR) <60 mL/min/1.73 m(2) was present in 22.0 and 20.2% of patients using the MDRD study equation and the CKD-EPI equation, respectively. A total of 309 patients died during the follow-up (152 patients from cardiovascular causes). Both creatinine-based equations were associated with an increased risk of all-cause and cardiovascular mortality. However, the CKD-EPI equation provided a more accurate risk prediction of mortality than the MDRD study equation. Receiving operating characteristic curves showed that the areas under the curve (AUCs) for all-cause mortality (AUC 0.712 [95% CI 0.682-0.741]) and cardiovascular mortality (0.771 [0.734-0.808]) using eGFR(CKD-EPI) were significantly greater (P < 0.0001 by the z statistic) than those obtained by using eGFR(MDRD) (0.679 [0.647-0.711] for all-cause mortality and 0.739 [0.698 0.783] for cardiovascular mortality). CONCLUSIONS: Our findings suggest that the estimation of GFR using the CKD-EPI equation more appropriately stratifies patients with type 2 diabetes according to the risk of all-cause and cardiovascular mortality compared with the MDRD study equation. PMID- 22837368 TI - Subjective sleep complaints are associated with insulin resistance in individuals without diabetes: the PPP-Botnia Study. AB - OBJECTIVE: Sleep disorders and subjective sleep complaints have been associated with increased risk of type 2 diabetes. The evidence with respect to insulin resistance (IR) and insulin secretion in individuals without type 2 diabetes has been scarce and elusive. We examined if subjective sleep complaints and their co occurrence were associated with IR and insulin secretion in adult women and men without diabetes. RESEARCH DESIGN AND METHODS: Women (n = 442) and men (n = 354) 18-75 years of age without type 2 diabetes underwent an oral glucose tolerance test (OGTT), with insulin and glucose measured at fasting and at 30 and 120 min. Complaints related to sleep apnea, insomnia, and daytime sleepiness were self rated with the Basic Nordic Sleep Questionnaire. RESULTS: In comparison with individuals with no or minor sleep complaints, those with more frequent complaints of sleep apnea, insomnia, and daytime sleepiness were more insulin resistant, as evidenced by higher fasting insulin concentrations and insulin and glucose responses to OGTT, and more frequently had high homeostasis model assessment of IR and low insulin sensitivity index values. The likelihood of being insulin resistant increased significantly and linearly according to the accumulation of co-occurring sleep complaints. These associations changed only a little when adjusted for mediating and confounding factors and for depressive symptoms. Sleep complaints were not associated with indices of deficiency in insulin secretion. CONCLUSIONS: Subjective sleep complaints were associated with IR. The likelihood of being insulin resistant increased according to accumulation of co-occurring sleep complaints. Sleep complaints were not associated with deficiency in insulin secretion. PMID- 22837369 TI - Health utility scores for people with type 2 diabetes in U.S. managed care health plans: results from Translating Research Into Action for Diabetes (TRIAD). AB - OBJECTIVE: To estimate the health utility scores associated with type 2 diabetes, its treatments, complications, and comorbidities. RESEARCH DESIGN AND METHODS: We analyzed health-related quality-of-life data, collected at baseline during Translating Research Into Action for Diabetes, a multicenter, prospective, observational study of diabetes care in managed care, for 7,327 individuals with type 2 diabetes. We measured quality-of-life using the EuroQol (EQ)-5D, a standardized instrument for which 1.00 indicates perfect health. We used multivariable regression to estimate the independent impact of demographic characteristics, diabetes treatments, complications, and comorbidities on health related quality-of-life. RESULTS: The mean EQ-5D-derived health utility score for those individuals with diabetes was 0.80. The modeled utility score for a nonobese, non-insulin-treated, non-Asian, non-Hispanic man with type 2 diabetes, with an annual household income of more than $40,000, and with no diabetes complications, risk factors for cardiovascular disease, or comorbidities, was 0.92. Being a woman, being obese, smoking, and having a lower household income were associated with lower utility scores. Arranging complications from least to most severe according to the reduction in health utility scores resulted in the following order: peripheral vascular disease, other heart diseases, transient ischemic attack, cerebral vascular accident, nonpainful diabetic neuropathy, congestive heart failure, dialysis, hemiplegia, painful neuropathy, and amputation. CONCLUSIONS: Major diabetes complications and comorbidities are associated with decreased health-related quality-of-life. Utility estimates from our study can be used to assess the impact of diabetes on quality-of-life and conduct cost-utility analyses. PMID- 22837370 TI - Periodontal infection, systemic inflammation, and insulin resistance: results from the continuous National Health and Nutrition Examination Survey (NHANES) 1999-2004. AB - OBJECTIVE: Adverse microbial exposures might contribute to diabetogenesis. We hypothesized that clinical periodontal disease (a manifestation of microbial exposures in dysbiotic biofilms) would be related to insulin resistance among diabetes-free participants. The roles of inflammatory mediation and effect modification were also studied. RESEARCH DESIGN AND METHODS: The continuous National Health and Nutrition Examination Survey 1999-2004 enrolled 3,616 participants (51% women) who received a periodontal examination and fasting blood draw. Participants were mean age (+/- SD) 43 +/- 17 years and 28% Hispanic, 52% Caucasian, 17% African American, and 3% other. Log-transformed values of the homeostasis model assessment of insulin resistance (HOMA-IR) or HOMA-IR >=3.30 (75th percentile) were regressed across full-mouth periodontal probing depth (PD) levels using linear and logistic models. White blood cell (WBC) count and C reactive protein (CRP) were considered as either mediators or effect modifiers in separate analyses. Risk ratios (RRs) stem from marginal predictions derived from the logistic model. Results were adjusted for multiple periodontal disease and insulin resistance risk factors. RESULTS: In linear regression, geometric mean HOMA-IR levels increased by 1.04 for every 1-mm PD increase (P = 0.007). WBC mediated 6% of the association (P < 0.05). Among participants with WBC <=6.4 * 10(9), PD was unrelated to HOMA-IR >=3.30. Fourth-quartile PD was associated with HOMA-IR >=3.30 among participants with WBC >7.9 * 10(9); RR 2.60 (1.36-4.97) (P for interaction = 0.05). Findings were similar among participants with CRP >3.0 mg/L (P for interaction = 0.04). CONCLUSIONS: Periodontal infection was associated with insulin resistance in a nationally representative U.S. sample of diabetes-free adults. These data support the role of inflammation as both mediator and effect modifier of the association. PMID- 22837371 TI - Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies. AB - OBJECTIVE: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. RESEARCH DESIGN AND METHODS: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. RESULTS: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81 1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little. CONCLUSIONS: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies. PMID- 22837372 TI - Plasma COOH-terminal proendothelin-1: a marker of fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in type 2 diabetes? (ZODIAC-29). AB - OBJECTIVE: The aim of this study was to investigate the association between plasma COOH-terminal proendothelin-1 (CT-proET-1) and fatal cardiovascular events, all-cause mortality, and new-onset albuminuria in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,225 patients with type 2 diabetes participated in this prospective observational study of two combined cohorts. Three clinical end points were studied: fatal cardiovascular events, all cause mortality, and new-onset albuminuria. After a median follow-up of 3 or 10 years, Cox proportional hazard modeling was used to investigate the association between CT-proET-1 and the end points. Harrell C statistic, the Groennesby and Borgan test, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI) were used to evaluate whether CT-proET-1 is of additional value compared with classic cardiovascular and renal risk factors. RESULTS: During follow-up, 364 (30%) patients died, 150 (42%) of whom died of cardiovascular disease; 182 (26.7%) of 688 patients with normoalbuminuria at baseline developed albuminuria. CT-proET-1 was associated with fatal cardiovascular events, all-cause mortality, and new-onset albuminuria with hazard ratios of 1.59 (95% CI 1.15-2.20), 1.41 (95% CI 1.14-1.74), and 1.48 (95% CI 1.10 2.01), respectively. Addition of CT-proET-1 to a model containing traditional risk factors leads only to improved prediction of fatal cardiovascular events. The IDI appeared significant for fatal cardiovascular events (0.82 [0.1-1.54]) and all-cause mortality (0.4 [0.05-0.92]), but not for new-onset albuminuria. CONCLUSIONS: CT-proET-1 has additional value for the prediction of fatal cardiovascular events and new-onset albuminuria in patients with type 2 diabetes, compared with conventional risk factors, but not for all-cause mortality. PMID- 22837373 TI - Pharmacodynamic effect of cilostazol plus standard clopidogrel versus double-dose clopidogrel in patients with type 2 diabetes undergoing percutaneous coronary intervention. AB - OBJECTIVE: To determine the effect of adding cilostazol (100 mg b.i.d.) to standard-dose clopidogrel (75 mg/d) (TRIPLE) compared with double-dose clopidogrel (150 mg/d) (DOUBLE) and the influence of the cytochrome P450 (CYP2C19*2/*3, CYP3A5*3)and ATP-binding cassette subfamily B1(ABCB1 C3435T) genetic polymorphisms in type 2 diabetes (T2DM) patients. RESEARCH DESIGN AND METHODS: T2DM patients were treated with TRIPLE (n = 41) or DOUBLE (n = 39) after percutaneous coronary intervention. Conventional aggregometry and VerifyNow were performed at baseline and at 30 days. The primary end point was absolute change in 20-MUM ADP-induced maximal platelet aggregation (DeltaMPA(20)) between baseline and switching values. RESULTS: TRIPLE versus DOUBLE showed greater DeltaMPA(20) (22.9 +/- 11.6 vs.12.7 +/- 15.5%; difference, 10.2% [95% CI 4.2 16.3]; P < 0.001). Carriage of one (beta coefficient, -5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (-8.3%; P = 0.007) were associated with lower DeltaMPA(20) in DOUBLE-treated patients, but not in TRIPLE-treated patients. CONCLUSIONS: Among T2DM patients, adding cilostazol achieves greater platelet inhibition compared with clopidogrel (150 mg/d), which is not influenced by genetic polymorphisms. PMID- 22837374 TI - Cyclical variation in the incidence of childhood type 1 diabetes in Western Australia (1985-2010). AB - OBJECTIVE: To examine the incidence of childhood type 1 diabetes in Western Australia from 1985-2010. RESEARCH DESIGN AND METHODS: Incidence rates were calculated for children aged 0-14 years and were analyzed by calendar year, sex, and age at diagnosis. RESULTS: There were 1,873 cases, and the mean incidence was 18.1/100,000 person-years (95% CI: 17.5-19.2). The incidence increased by 2.3% a year (1.6-2.9%) with a sinusoidal 5-year cyclical variation of 14% (7-22%). The lowest rate of increase in incidence was observed in 0-4-year-olds. CONCLUSIONS: The cyclical pattern in incidence observed supports the role of environmental factors in childhood type 1 diabetes. PMID- 22837375 TI - Assessment of pulmonary neutrophilic inflammation in emphysema by quantitative positron emission tomography. AB - RATIONALE: Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. OBJECTIVES: To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and alpha(1) antitrypsin deficiency (AATD). METHODS: (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. MEASUREMENTS AND MAIN RESULTS: (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. CONCLUSIONS: Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18). PMID- 22837376 TI - Endobronchial ultrasound skills and tasks assessment tool: assessing the validity evidence for a test of endobronchial ultrasound-guided transbronchial needle aspiration operator skill. AB - RATIONALE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is becoming standard of care for the sampling of mediastinal adenopathy. The need for a safe, effective, accurate procedure makes EBUS-TBNA ideal for mastery training and testing. OBJECTIVES: The Endobronchial Ultrasound Skills and Tasks Assessment Tool (EBUS-STAT) was created as an objective competency-oriented assessment tool of EBUS-TBNA skills and knowledge. This study demonstrates the reliability and validity evidence of this tool. METHODS: The EBUS-STAT objectively scores the EBUS-TBNA operator's skills, including atraumatic airway introduction and navigation, ultrasound image acquisition and optimization, identification of mediastinal nodal and vascular structures, EBUS-TBNA sampling, and recognition of EBUS/computed tomography images of mediastinal structures. It can be administered at the bedside or using combination of low- and high-fidelity simulation platforms. Two independent testers administered the EBUS-STAT to 24 operators at three levels of EBUS-TBNA experience (8 beginners, 8 intermediates, and 8 experienced) at three institutions; operators were also asked to self assess their skills. Scores were analyzed for intertester reliability, correlation with prior EBUS-TBNA experience, and association with self assessments. MEASUREMENTS AND MAIN RESULTS: Intertester reliability between testers was very high (r = 0.9991, P < 0.00005). Mean EBUS-STAT scores for beginner, intermediate, and experienced groups, respectively, were 31.1, 74.9, and 93.6 out of 100 (F(2,21) = 118.6, P < 0.0001). Groups were nonoverlapping: post hoc tests showed each group differed significantly from the others (P < 0.001). Self-assessments corresponded closely to actual EBUS-STAT scores (r(2) = 0.81, P < 0.001). CONCLUSIONS: The EBUS-STAT can be used to reliably and objectively score and classify EBUS-TBNA operators from novice to expert. Its use to assess and document the acquisition of knowledge and skill is a step toward the goal of mastery training in EBUS-TBNA. PMID- 22837377 TI - Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial. AB - RATIONALE: Twenty-eight percent of people with mild to moderate obstructive sleep apnea experience daytime sleepiness, which interferes with daily functioning. It remains unclear whether treatment with continuous positive airway pressure improves daytime function in these patients. OBJECTIVES: To evaluate the efficacy of continuous positive airway pressure treatment to improve functional status in sleepy patients with mild and moderate obstructive sleep apnea. METHODS: Patients with self-reported daytime sleepiness (Epworth Sleepiness Scale score >10) and an apnea-hypopnea index with 3% desaturation and from 5 to 30 events per hour were randomized to 8 weeks of active or sham continuous positive airway pressure treatment. After the 8-week intervention, participants in the sham arm received 8 weeks of active continuous positive airway pressure treatment. MEASUREMENTS AND MAIN RESULTS: The Total score on the Functional Outcomes of Sleep Questionnaire was the primary outcome measure. The adjusted mean change in the Total score after the first 8-week intervention was 0.89 for the active group (n = 113) and 0.06 for the placebo group (n = 110) (P = 0.006). The group difference in mean change corresponded to an effect size of 0.41 (95% confidence interval, 0.14 0.67). The mean (SD) improvement in Functional Outcomes of Sleep Questionnaire Total score from the beginning to the end of the crossover phase (n = 91) was 1.73 +/- 2.50 (t[90] = 6.59; P < 0.00001) with an effect size of 0.69. CONCLUSIONS: Continuous positive airway pressure treatment improves the functional outcome of sleepy patients with mild and moderate obstructive sleep apnea. PMID- 22837379 TI - Obesity and asthma: an inflammatory disease of adipose tissue not the airway. AB - RATIONALE: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese. OBJECTIVES: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity. METHODS: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time. MEASUREMENTS AND MAIN RESULTS: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = -0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery. CONCLUSIONS: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation. PMID- 22837380 TI - A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1. AB - RATIONALE: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. OBJECTIVES: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes. METHODS: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. MEASUREMENTS AND MAIN RESULTS: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 * 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. CONCLUSIONS: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis. PMID- 22837381 TI - Impact of intensive care unit organ failures on mortality during the five years after a critical illness. AB - RATIONALE: The relationship between organ failure during critical illness and long-term survival is uncertain, especially among intensive care unit (ICU) survivors. OBJECTIVES: To describe the relationship between individual organ failures, total organ failure burden, and mortality during the 5 years after an episode of critical illness. METHODS: We studied a cohort of sequential admissions to 10 Scottish ICUs (n = 872). Logistic regression was used to explore independent associations between organ failures and mortality over a 5-year time horizon, adjusting for potential confounders. MEASUREMENTS AND MAIN RESULTS: Daily Sequential Organ Failure Assessment scores described organ dysfunction during ICU stay. The sum of the worst scores at any time point during the ICU stay for each organ system except neurological dysfunction was used to calculate total organ failure burden. Mortality was obtained from the national death register. Five-year mortality was 58.2%; 34.4% of deaths occurred within 28 days. In adjusted analyses, cardiovascular (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.8-3.7), liver (OR, 2.3; 95% CI, 1.1-5.0), and respiratory failure (OR, 2.1; 95% CI, 1.3-3.5) were independently associated with 5-year mortality. Organ failure burden was strongly associated with mortality; 81% of patients in the highest tertile died during follow-up (OR, 6.3 relative to lowest tertile; P < 0.001). Patients surviving more than 12 months post-ICU were still more likely to subsequently die if they experienced greater organ failure burden in the ICU (OR, 2.4; P = 0.02, highest vs. lowest tertile). CONCLUSIONS: Cardiovascular, respiratory, and liver failures during critical illness strongly predict subsequent 5-year survival. Acute organ failure burden is associated with long-term mortality even among patients who survive up to 1 year after ICU admission. PMID- 22837378 TI - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. AB - RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta analysis. CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction. PMID- 22837382 TI - Recommendations to limit life support: a national survey of critical care physicians. AB - RATIONALE: There is debate about whether physicians should routinely provide patient surrogates with recommendations about limiting life support. OBJECTIVES: To explore physicians' self-reported practices and attitudes. METHODS: A cross sectional, stratified survey of 1,000 randomly selected US critical care physicians was mailed. We included a vignette to experimentally examine how surrogate desire for a recommendation and physician agreement with the surrogate modified whether physicians would provide a recommendation. MEASUREMENTS AND MAIN RESULTS: Proportion of respondents reporting they routinely provide surrogates with a recommendation and how responses varied based on vignette characteristics. A total of 608 (66%) of 922 eligible physicians participated. Approximately one (22%) in five reported always providing surrogates with a recommendation, whereas 1 (11%) in 10 reported rarely or never doing so. Almost all respondents reported comfort making recommendations (92%) and viewed them as appropriate (93%). Most also viewed recommendations as a critical care physician's duty (87%) and did not view them as unduly influential (80%). Approximately two-fifths (41%) believed recommendations were only appropriate if sought by surrogates. In response to the vignettes, nearly all respondents (91%) provided a recommendation when the surrogate requested a recommendation and the physician agreed with the surrogate's likely decision. Physicians were less likely to provide an unwanted recommendation, both when physicians agreed (29%) and disagreed with the surrogate's likely decision (44%). CONCLUSIONS: There is substantial variation among physicians' self-reported use of recommendations to surrogates of critically ill adults. Surrogates' desires for recommendations and physicians' agreement with surrogates' likely decisions may have important influence on whether recommendations are provided. PMID- 22837383 TI - Compartmentalized control of skin immunity by resident commensals. AB - Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease. PMID- 22837384 TI - UV dosage levels in summer: increased risk of ozone loss from convectively injected water vapor. AB - The observed presence of water vapor convectively injected deep into the stratosphere over the United States can fundamentally change the catalytic chlorine/bromine free-radical chemistry of the lower stratosphere by shifting total available inorganic chlorine into the catalytically active free-radical form, ClO. This chemical shift markedly affects total ozone loss rates and makes the catalytic system extraordinarily sensitive to convective injection into the mid-latitude lower stratosphere in summer. Were the intensity and frequency of convective injection to increase as a result of climate forcing by the continued addition of CO(2) and CH(4) to the atmosphere, increased risk of ozone loss and associated increases in ultraviolet dosage would follow. PMID- 22837385 TI - Identification of the Cdc48*20S proteasome as an ancient AAA+ proteolytic machine. AB - Proteasomes are the major energy-dependent proteolytic machines in the eukaryotic and archaeal domains of life. To execute protein degradation, the 20S core peptidase combines with the AAA+ ring of the 19S regulatory particle in eukarya or with the AAA+ proteasome-activating nucleotidase ring in some archaea. Here, we find that Cdc48 and 20S from the archaeon Thermoplasma acidophilum interact to form a functional proteasome. Cdc48 is an abundant and essential double-ring AAA+ molecular machine ubiquitously present in archaea, where its function has been uncertain, and in eukarya where Cdc48 participates by largely unknown mechanisms in diverse cellular processes, including multiple proteolytic pathways. Thus, proteolysis in collaboration with the 20S peptidase may represent an ancestral function of the Cdc48 family. PMID- 22837386 TI - A mechanism of extreme growth and reliable signaling in sexually selected ornaments and weapons. AB - Many male animals wield ornaments or weapons of exaggerated proportions. We propose that increased cellular sensitivity to signaling through the insulin/insulin-like growth factor (IGF) pathway may be responsible for the extreme growth of these structures. We document how rhinoceros beetle horns, a sexually selected weapon, are more sensitive to nutrition and more responsive to perturbation of the insulin/IGF pathway than other body structures. We then illustrate how enhanced sensitivity to insulin/IGF signaling in a growing ornament or weapon would cause heightened condition sensitivity and increased variability in expression among individuals--critical properties of reliable signals of male quality. The possibility that reliable signaling arises as a by product of the growth mechanism may explain why trait exaggeration has evolved so many different times in the context of sexual selection. PMID- 22837387 TI - Transforming fusions of FGFR and TACC genes in human glioblastoma. AB - The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition. PMID- 22837388 TI - Pharmacokinetics of oral D-serine in D-amino acid oxidase knockout mice. AB - D-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-amino acids including D-serine, a full agonist at the glycine modulatory site of the N-methyl d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral D-serine, plasma D-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although D serine levels were rapidly diminished in wild-type mice (t(1/2) = 1.2 h), sustained drug levels over the course of 4 h (t(1/2) > 10 h) were observed in mice lacking DAAO. Coadministration of D-serine with 6-chlorobenzo[d]isoxazol-3 ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma D-serine levels, although CBIO seems to have only temporary effects on the plasma D-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of D-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma D-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia. PMID- 22837389 TI - Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. AB - Results from clinical studies suggest that pregnancy alters hepatic drug metabolism in a cytochrome P450 (P450) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study was to comprehensively characterize the effects of estrogen and progesterone on the expression and activity of major drug metabolizing P450s. To this end, primary human hepatocytes were treated with estradiol and progesterone, and mRNA expression and activity levels of 10 different P450 isoforms were determined. The results showed that estradiol enhances CYP2A6, CYP2B6, and CYP3A4 expression, whereas progesterone induces CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. The induction was mainly observed when the average hormone concentrations were at the levels reached during pregnancy, suggesting that these effects are likely pregnancy-specific. Estradiol also increased enzyme activities of CYP2C9 and CYP2E1 without affecting the mRNA expression levels by unknown mechanisms. Taken together, our results show differential effects of estrogen and progesterone on P450 expression, suggesting involvement of different regulatory mechanisms in female hormone mediated P450 regulation. Our findings potentially provide a basis in mechanistic understanding for altered drug metabolism during pregnancy. PMID- 22837390 TI - Vitamin D receptor activation enhances benzo[a]pyrene metabolism via CYP1A1 expression in macrophages. AB - Benzo[a]pyrene (BaP) activates the aryl hydrocarbon (AHR) and induces the expression of genes involved in xenobiotic metabolism, including CYP1A1. CYP1A1 is involved not only in BaP detoxification but also in metabolic activation, which results in DNA adduct formation. Vitamin D receptor (VDR) belongs to the NR1I subfamily of the nuclear receptor superfamily, which also regulates expression of xenobiotic metabolism genes. We investigated the cross-talk between AHR and VDR signaling pathways and found that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a potent physiological VDR agonist, enhanced BaP-induced transcription of CYP1A1 in human monocytic U937 cells and THP-1 cells, breast cancer cells, and kidney epithelium-derived cells. 1,25(OH)(2)D(3) alone did not induce CYP1A1, and 1,25(OH)(2)D(3) plus BaP did not increase CYP1A2 or CYP1B1 mRNA expression in U937 cells. The combination of 1,25(OH)(2)D(3) and BaP increased CYP1A1 protein levels, BaP hydroxylation activity, and BaP-DNA adduct formation in U937 cells and THP-1 cells more effectively than BaP alone. The combined effect of 1,25(OH)(2)D(3) and BaP on CYP1A1 mRNA expression in U937 cells and/or THP-1 cells was inhibited by VDR knockdown, VDR antagonists, and alpha-naphthoflavone, an AHR antagonist. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that VDR directly bound to an everted repeat (ER) 8 motif in the human CYP1A1 promoter. Thus, CYP1A1 is a novel VDR target gene involved in xenobiotic metabolism. Induction of CYP1A1 by the activation of VDR and AHR may contribute to BaP-mediated toxicity and the physiological function of this enzyme. PMID- 22837391 TI - A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. AB - OBJECTIVE: To evaluate the effects and safety of 300-600 mg alpha-lipoic acid (ALA) given i.v. for diabetic peripheral neuropathy (DPN). METHODS: We searched the databases of Medline, Embase, and Cochrane central register of Controlled Trials and Chinese biological medicine for clinical trials of ALA in the treatment of DPN. Data were extracted to examine methodological quality and describe characteristics of studies. The primary outcomes were efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, and peroneal SNCV. Secondary outcomes were adverse events. RESULTS: Fifteen randomized controlled trials met the inclusion criteria. The treatment group involved the administration of ALA 300-600 mg i.v. per day. And the control group used the same interventions except for ALA. Compared with the control group, nerve conduction velocities increased significantly in the treatment group. The weighted mean differences in nerve conduction velocities were 4.63 (95% confidence interval 3.58-5.67) for median MNCV, 3.17 (1.75-4.59) for median SNCV, 4.25 (2.78-5.72) for peroneal MNCV, and 3.65 (1.50-5.80) for peroneal SNCV in favor of the treatment group. The odds ratio in terms of efficacy was 4.03 (2.73-5.94) for ALA. Furthermore, no serious adverse events were observed during the treatment period. CONCLUSIONS: The results of this meta analysis provide evidence that treatment with ALA (300-600 mg/day i.v. for 2-4 weeks) is safe and that the treatment can significantly improve both nerve conduction velocity and positive neuropathic symptoms. However, the evidence may not be strong because most of the studies included in this meta-analysis have poor methodological quality. PMID- 22837392 TI - Neurons expressing trace amine-associated receptors project to discrete glomeruli and constitute an olfactory subsystem. AB - Some chemoreceptors of the trace amine-associated receptor (TAAR) family detect innately aversive odors and are proposed to activate hardwired olfactory circuits. However, the wiring of TAAR neurons, the regulatory mechanisms of Taar gene choice, and the subcellular localization of TAAR proteins remain unknown. Here, we reveal similarities between neurons expressing TAARs and odorant receptors (ORs), but also unexpected differences. Like ORs, TAARs seem to be monoallelically expressed and localized both in cilia, the site of odor detection, and in axons, where they may participate in guidance. TAAR neurons project to discrete glomeruli predominantly localized to a confined bulb region. Taar expression involves different regulatory logic than OR expression, as neurons choosing a Taar5 knockout allele frequently express a second Taar without silencing the deleted allele. Moreover, the epigenetic signature of OR gene choice is absent from Taar genes. The unique molecular and anatomical features of the TAAR neurons suggest that they constitute a distinct olfactory subsystem. PMID- 22837394 TI - Improving risk assessment for biodiversity conservation. PMID- 22837393 TI - Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis. AB - Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost. PMID- 22837395 TI - Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. AB - Multiple covalent modifications on a histone tail are often recognized by linked histone reader modules. UHRF1 [ubiquitin-like, containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1], an essential factor for maintenance of DNA methylation, contains linked two-histone reader modules, a tandem Tudor domain and a PHD finger, tethered by a 17-aa linker, and has been implicated to link histone modifications and DNA methylation. Here, we present the crystal structure of the linked histone reader modules of UHRF1 in complex with the amino-terminal tail of histone H3. Our structural and biochemical data provide the basis for combinatorial readout of unmodified Arg-2 (H3-R2) and methylated Lys-9 (H3-K9) by the tandem tudor domain and the PHD finger. The structure reveals that the intermodule linker plays an essential role in the formation of a histone H3-binding hole between the reader modules by making extended contacts with the tandem tudor domain. The histone H3 tail fits into the hole by adopting a compact fold harboring a central helix, which allows both of the reader modules to simultaneously recognize the modification states at H3-R2 and H3-K9. Our data also suggest that phosphorylation of a linker residue can modulate the relative position of the reader modules, thereby altering the histone H3-binding mode. This finding implies that the linker region plays a role as a functional switch of UHRF1 involved in multiple regulatory pathways such as maintenance of DNA methylation and transcriptional repression. PMID- 22837396 TI - Soluble guanylyl cyclase requires heat shock protein 90 for heme insertion during maturation of the NO-active enzyme. AB - Heme insertion is key during maturation of soluble guanylyl cyclase (sGC) because it enables sGC to recognize NO and transduce its multiple biological effects. Although sGC is often associated with the 90-kDa heat shock protein (hsp90) in cells, the implications are unclear. The present study reveals that hsp90 is required to drive heme insertion into sGC and complete its maturation. We used a mammalian cell culture approach and followed heme insertion into transiently and endogenously expressed heme-free sGC. We used pharmacological hsp90 inhibitors, an ATP-ase inactive hsp90 mutant, and heme-dependent or heme-independent sGC activators as tools to decipher the role of hsp90. Our findings suggest that hsp90 complexes with apo-sGC, drives heme insertion through its inherent ATPase activity, and then dissociates from the mature, heme-replete sGC. Together, this improves our understanding of sGC maturation and reveals a unique means to control sGC activity in cells, and it has important implications for hsp90 inhibitor-based cancer therapy. PMID- 22837398 TI - Fungal endophyte communities reflect environmental structuring across a Hawaiian landscape. AB - We surveyed endophytic fungal communities in leaves of a single tree species (Metrosideros polymorpha) across wide environmental gradients (500-5,500 mm of rain/y; 10-22 degrees C mean annual temperature) spanning short geographic distances on Mauna Loa Volcano, Hawai'i. Using barcoded amplicon pyrosequencing at 13 sites (10 trees/site; 10 leaves/tree), we found very high levels of diversity within sites (a mean of 551 +/- 134 taxonomic units per site). However, among-site diversity contributed even more than did within-site diversity to the overall richness of more than 4,200 taxonomic units observed in M. polymorpha, and this among-site variation in endophyte community composition correlated strongly with temperature and rainfall. These results are consistent with suggestions that foliar endophytic fungi are hyperdiverse. They further suggest that microbial diversity may be even greater than has been assumed and that broad scale environmental controls such as temperature and rainfall can structure eukaryotic microbial diversity. Appropriately constrained study systems across strong environmental gradients present a useful means to understand the environmental factors that structure the diversity of microbial communities. PMID- 22837399 TI - Dynamic differential methylation facilitates pathogen stress response in Arabidopsis. PMID- 22837397 TI - Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death. AB - Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine deficient media and quantitation of the methionine salvage substrate, 5' methylthioadenosine. Reducing expression of APIP or exogenous addition of 5' methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology. PMID- 22837400 TI - Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/beta-catenin complex. AB - The evolution of cadherins, which are essential for metazoan multicellularity and restricted to metazoans and their closest relatives, has special relevance for understanding metazoan origins. To reconstruct the ancestry and evolution of cadherin gene families, we analyzed the genomes of the choanoflagellate Salpingoeca rosetta, the unicellular outgroup of choanoflagellates and metazoans Capsaspora owczarzaki, and a draft genome assembly from the homoscleromorph sponge Oscarella carmela. Our finding of a cadherin gene in C. owczarzaki reveals that cadherins predate the divergence of the C. owczarzaki, choanoflagellate, and metazoan lineages. Data from these analyses also suggest that the last common ancestor of metazoans and choanoflagellates contained representatives of at least three cadherin families, lefftyrin, coherin, and hedgling. Additionally, we find that an O. carmela classical cadherin has predicted structural features that, in bilaterian classical cadherins, facilitate binding to the cytoplasmic protein beta-catenin and, thereby, promote cadherin-mediated cell adhesion. In contrast with premetazoan cadherin families (i.e., those conserved between choanoflagellates and metazoans), the later appearance of classical cadherins coincides with metazoan origins. PMID- 22837401 TI - A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. AB - Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult. PMID- 22837402 TI - Quantum rotation of ortho and para-water encapsulated in a fullerene cage. AB - Inelastic neutron scattering, far-infrared spectroscopy, and cryogenic nuclear magnetic resonance are used to investigate the quantized rotation and ortho-para conversion of single water molecules trapped inside closed fullerene cages. The existence of metastable ortho-water molecules is demonstrated, and the interconversion of ortho-and para-water spin isomers is tracked in real time. Our investigation reveals that the ground state of encapsulated ortho water has a lifted degeneracy, associated with symmetry-breaking of the water environment. PMID- 22837403 TI - Role of proton ordering in adsorption preference of polar molecule on ice surface. AB - Adsorption of polar monomers on ice surface, relevant to the physical/chemical reaction in ice clouds as well as growth of ice, remains an open issue partially due to the unusual surface characteristics with protons at the top layer of ice. Using first-principle calculations, we explore the adsorption properties of ice surface in terms of a surface proton order parameter, which characterizes the inhomogeneity of the dangling atoms on ice surface. We show that, due to an effective electric field created by dangling OH bonds and lone pairs of water molecules not only directly neighboring but also further away from the adsorbed polar molecule on the ice surface, the adsorption energy of polar monomer on ice surface exhibits large variance and a strong correlation with the proton order parameter of ice surface. Our results about the positive correlation between the inhomogeneity of ice surface and adsorption energies suggest that the physical/chemical reactions as well as the growth of ice may prefer to occur firstly on surfaces with larger proton order parameter. PMID- 22837404 TI - Nucleic acid scavengers inhibit thrombosis without increasing bleeding. AB - Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have been shown to activate blood coagulation. In this report, we evaluate the anticoagulant and antithrombotic activity of nucleic acid-binding polymers in vitro and in vivo. Such polymers bind to DNA, RNA, and inorganic polyphosphate molecules with high affinity and inhibit RNA- and polyphosphate induced clotting and the activation of the intrinsic pathway of coagulation in vitro. Moreover, [NH(2)(CH(2))(2)NH(2)](G = 3);dendri PAMAM(NH(2))(32) (PAMAM G 3) prevents thrombosis following carotid artery injury and pulmonary thromboembolism in mice without significantly increasing blood loss from surgically challenged animals. These studies indicate that nucleic acid-binding polymers are able to scavenge effectively prothrombotic nucleic acids and other polyphosphates in vivo and represent a new and potentially safer class of antithrombotic agents. PMID- 22837405 TI - Development of microsatellite markers from Cercis chinensis (Fabaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed to characterize the level of genetic diversity and population genetic structure of Cercis chinensis, a widely cultivated garden plant in China with congeneric species disjunctly distributed in East Asia, North America, and the Mediterranean. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) protocol, eight microsatellite markers were developed in C. chinensis. Seven of the markers displayed polymorphism, with the number of alleles ranging from one to four in four populations of C. chinensis. Four to six microsatellite loci exhibited interspecific transferability in C. glabra, C. chuniana, and C. chingii. CONCLUSIONS: These are the first microsatellite markers developed for C. chinensis, which will be further used in investigation of population genetic structure and phylogeographic pattern of C. chinensis and its congeneric species. PMID- 22837406 TI - Isolation and characterization of 10 microsatellite loci in Cneorum tricoccon (Cneoraceae), a Mediterranean relict plant. AB - PREMISE OF THE STUDY: The main aim of this study was to isolate and characterize microsatellite loci in Cneorum tricoccon (Cneoraceae), a Mediterranean shrub relict of the early Tertiary, which inhabits western Mediterranean islands and coasts. Microsatellites will be useful for investigating biogeography and landscape genetics across the species distribution range, including current or past gene flow. METHODS AND RESULTS: Seventeen microsatellite loci were characterized, of which 10 were polymorphic and amplified for a total of 56 alleles in three populations of C. tricoccon. The markers revealed average coefficients of expected heterozygosity (H(e) = 0.425), observed heterozygosity (H(o) = 0.282), and inbreeding coefficient value per population (F(IS) = 0.408). CONCLUSIONS: These microsatellite primers will potentially be useful in the study of population and landscape genetics, conservation status of isolated populations, island-continental distribution, current or historical movements between populations, and in the investigation of the consequences of dispersal mechanisms of these plants. PMID- 22837408 TI - Development of 12 microsatellite markers for Platycrater arguta (Hydrangeaceae) endemic to East Asia. AB - PREMISE OF THE STUDY: Microsatellite markers were characterized in Platycrater arguta, a rare endemic shrub from eastern China and southern Japan, to investigate its population genetic structure, phylogeographic patterns, and breeding system. METHODS AND RESULTS: Using both the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) protocol and the compound microsatellite marker technique, we developed 12 microsatellite markers. All primers showed polymorphism when assessed in 43 individuals from two populations in eastern China and southern Japan. Overall, the number of alleles ranged from five to 21, with an average of 14.91 alleles per locus. CONCLUSIONS: These markers can be used in further studies on population genetics, phylogeography, and breeding system of P. arguta. PMID- 22837409 TI - Microsatellite markers for Duperrea pavettifolia (Rubiaceae). AB - PREMISE OF THE STUDY: The development of microsatellite primers for Duperrea pavettifolia will be the foundation for mating system analysis and conservation research. METHODS AND RESULTS: Nineteen microsatellite markers were developed and characterized in two wild populations by using the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) protocol. Polymorphisms were evaluated in 24 individuals from two natural populations. Eleven of these primers generated polymorphic loci. CONCLUSIONS: These microsatellite markers will be useful in future investigations into the population genetics and mating system of D. pavettifolia. PMID- 22837410 TI - Characterization and systematic implications of the diversity in timing of programmed cell death of the suspensors in Leguminosae. AB - PREMISE OF THE STUDY: In angiosperm seeds, the developing embryo acquires nutrients via a suspensor that typically undergoes programmed cell death (PCD) at the early cotyledon stage. However, in Leguminosae (the third largest angiosperm family), the suspensors can disappear at the heart-shaped stage (i.e., prior to the cotyledon stage) or still persist at the cotyledon stage. Here, in a comprehensive survey of legume suspensors and embryos, the variation and the evolutionary direction of timing of suspensor PCD in Leguminosae were characterized, and systematic implications were evaluated. METHODS: Suspensor development and morphology for 66 leguminous species from 49 genera, 21 tribes, and 3 subfamilies were comparatively studied using standard paraffin sectioning and light microscopy. KEY RESULTS: Three patterns of suspensor PCD were observed at the early cotyledon stage. (A) The suspensor persisted. (B) The suspensor separated from the wall of the embryo sac and persisted as a vestige at the radicle apex. (C) The suspensor disappeared completely, and the absorption of nutrients by embryo was carried out via a "contact zone" between the embryo and the endosperm. Pattern C of early suspensor PCD was found only in the tribe Fabeae. An ancestral character reconstruction revealed that the long-lived suspensors of pattern A represented a plesiomorphic condition in Leguminosae and that the suspensors of pattern C evolved only once in the common ancestor of Fabeae. CONCLUSIONS: In Leguminosae, short-lived suspensors have thus evolved multiple times from long-lived suspensors. It remains largely unknown, however, how the embryo acquires nutrients after the early suspensor PCD. PMID- 22837411 TI - Microsatellite markers for the endangered root holoparasite Dactylanthus taylorii (Balanophoraceae) from 454 pyrosequencing. AB - PREMISE OF THE STUDY: Microsatellite loci were isolated and developed as polymorphic markers for the New Zealand endemic root holoparasite Dactylanthus taylorii for use in population and conservation genetics studies. METHODS AND RESULTS: Shotgun 454 pyrosequencing was performed on genomic DNA pooled from three individuals of D. taylorii. From 61709 individual sequence reads, primers for 753 microsatellite loci were developed in silico and 72 of these were tested for consistent amplification and variability. Ten microsatellite loci were found to be polymorphic and consistently scorable when screened in 44 individuals from five geographically distant populations. The number of alleles per locus ranged from four to 16 with an average of 9.7, and average observed heterozygosity per locus was between 0.182 and 0.634. CONCLUSIONS: These polymorphic microsatellite markers establish an important resource for ongoing conservation initiatives and planned population genetic studies of D. taylorii. PMID- 22837412 TI - Microsatellites for Tetracentron sinense (Trochodendraceae), a Tertiary relict endemic to East Asia. AB - PREMISE OF THE STUDY: Tetracentron sinense (Trochodendraceae) is a Tertiary relict endemic to East Asia. Microsatellite markers were developed and characterized to investigate the population genetics of the species. METHODS AND RESULTS: Microsatellite markers were isolated from the genome of T. sinense using the protocol of Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO). Eight polymorphic microsatellite markers were assessed in 44 samples collected from three wild populations. The number of alleles observed for each locus ranged from two to five. The observed and expected heterozygosities ranged from 0.0000 to 0.9375 and 0.0000 to 0.7681, respectively. CONCLUSIONS: The microsatellite markers will be helpful in further studies of the population genetics and phylogeography of T. sinense. PMID- 22837413 TI - Isolation and characteristics of eight novel polymorphic microsatellite loci in Lippia alba (Verbenaceae). AB - PREMISE OF THE STUDY: A set of eight microsatellite (simple sequence repeat [SSR]) markers for Lippia alba, an important medicinal and cosmetic plant, was developed to aid studies of genetic diversity and to define efficient strategies for breeding programs. METHODS AND RESULTS: Using a (CT)(8)- and (GT)(8)-enriched library, a total of 11 SSR loci were developed and optimized in L. alba. Of the 11 loci, eight were found to be polymorphic after screening 61 accessions from two populations. The parameters used to characterize loci were expected heterozygosity (H(e)) and number of alleles. A total of 44 alleles were identified, with an average of 5.5 alleles per loci, which were moderately to highly informative according to H(e). CONCLUSIONS: These new SSR markers have potential for informing genetic diversity, allele mining, and mapping studies and will be used to generate information for breeding programs of L. alba. PMID- 22837415 TI - Assembly of the viroplasm by viral non-structural protein Pns10 is essential for persistent infection of rice ragged stunt virus in its insect vector. AB - Rice ragged stunt virus (RRSV), an oryzavirus, is transmitted by brown planthopper in a persistent propagative manner. In this study, sequential infection of RRSV in the internal organs of its insect vector after ingestion of virus was investigated by immunofluorescence microscopy. RRSV was first detected in the epithelial cells of the midgut, from where it proceeded to the visceral muscles surrounding the midgut, then throughout the visceral muscles of the midgut and hindgut, and finally into the salivary glands. Viroplasms, the sites of virus replication and assembly of progeny virions, were formed in the midgut epithelium, visceral muscles and salivary glands of infected insects and contained the non-structural protein Pns10 of RRSV, which appeared to be the major constituent of the viroplasms. Viroplasm-like structures formed in non-host insect cells following expression of Pns10 in a baculovirus system, suggesting that the viroplasms observed in RRSV-infected cells were composed basically of Pns10. RNA interference induced by ingestion of dsRNA from the Pns10 gene of RRSV strongly inhibited such viroplasm formation, preventing efficient virus infection and spread in its insect vectors. These results show that Pns10 of RRSV is essential for viroplasm formation and virus replication in the vector insect. PMID- 22837414 TI - Microsatellite markers for Saussurea gnaphalodes (Asteraceae), a native Himalayan mountain species. AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Saussurea gnaphalodes to investigate its genetic variation and population structure. METHODS AND RESULTS: Using the combined biotin capture method, 46 microsatellite primer sets were isolated and characterized across 48 S. gnaphalodes individuals from three Tibetan populations. Seventeen of these markers showed polymorphism, and the number of alleles ranged from two to 17. The observed and expected heterozygosities per population ranged from 0 to 0.938 and from 0 to 0.905, respectively. CONCLUSIONS: These markers provide a useful tool to investigate the genetic diversity and population structure of S. gnaphalodes, and to facilitate further studies on conservation and utilization. PMID- 22837407 TI - Spatially variable natural selection and the divergence between parapatric subspecies of lodgepole pine (Pinus contorta, Pinaceae). AB - PREMISE OF THE STUDY: Plant populations arrayed across sharp environmental gradients are ideal systems for identifying the genetic basis of ecologically relevant phenotypes. A series of five uplifted marine terraces along the northern coast of California represents one such system where morphologically distinct populations of lodgepole pine (Pinus contorta) are distributed across sharp soil gradients ranging from fertile soils near the coast to podzolic soils ca. 5 km inland. METHODS: A total of 92 trees was sampled across four coastal marine terraces (N = 10-46 trees/terrace) located in Mendocino County, California and sequenced for a set of 24 candidate genes for growth and responses to various soil chemistry variables. Statistical analyses relying on patterns of nucleotide diversity were employed to identify genes whose diversity patterns were inconsistent with three null models. KEY RESULTS: Most genes displayed patterns of nucleotide diversity that were consistent with null models (N = 19) or with the presence of paralogs (N = 3). Two genes, however, were exceptional: an aluminum responsive ABC-transporter with F(ST) = 0.664 and an inorganic phosphate transporter characterized by divergent haplotypes segregating at intermediate frequencies in most populations. CONCLUSIONS: Spatially variable natural selection along gradients of aluminum and phosphate ion concentrations likely accounted for both outliers. These results shed light on some of the genetic components comprising the extended phenotype of this ecosystem, as well as highlight ecotones as fruitful study systems for the detection of adaptive genetic variants. PMID- 22837417 TI - In planta localization and interactions of impatiens necrotic spot tospovirus proteins. AB - Impatiens necrotic spot tospovirus (INSV) is a significant pathogen of ornamentals. The tripartite negative- and ambi-sense RNA genome encodes six proteins that are involved in cytoplasmic replication, movement, assembly, insect transmission and defence. To gain insight into the associations of these viral proteins, we determined their intracellular localization and interactions in living plant cells. Nucleotide sequences encoding the nucleoprotein N, non structural proteins NSs and NSm, and glycoproteins Gn and Gc of a Kentucky isolate of INSV were amplified by RT-PCR, cloned, sequenced and transiently expressed as fusions with autofluorescent proteins in leaf epidermal cells of Nicotiana benthamiana. All proteins accumulated at the cell periphery and co localized with an endoplasmic reticulum marker. The Gc protein fusion also localized to the nucleus. N and NSm protein self-interactions and an NSm-N interaction were observed by using bimolecular fluorescence complementation. A tospovirus NSm homotypic interaction had not been reported previously. PMID- 22837416 TI - Rescue of a genotype 4 human hepatitis E virus from cloned cDNA and characterization of intergenotypic chimeric viruses in cultured human liver cells and in pigs. AB - Hepatitis E virus (HEV) is an important but extremely understudied human pathogen. Genotypes 1 and 2 are restricted to humans, whereas genotypes 3 and 4 are zoonotic, infecting both humans and pigs. This report describes, for the first time, the successful rescue of infectious HEV in vitro and in vivo from cloned cDNA of a genotype 4 human HEV (strain TW6196E). The complete genomic sequence of the TW6196E virus was determined and a full-length cDNA clone (pHEV 4TW) was assembled. Capped RNA transcripts from the pHEV-4TW clone were replication competent in Huh7 cells and infectious in HepG2/C3A cells. Pigs inoculated intrahepatically with capped RNA transcripts from pHEV-4TW developed an active infection, as evidenced by faecal virus shedding and seroconversion, indicating the successful rescue of infectious genotype 4 HEV and cross-species infection of pigs by a genotype 4 human HEV. To demonstrate the utility of the genotype 4 HEV infectious clone and to evaluate the potential viral determinant(s) for species tropism, four intergenotypic chimeric clones were constructed by swapping various genomic regions between genotypes 1 and 4, and genotypes 1 and 3. All four chimeric clones were replication competent in Huh7 cells, but only the two chimeras with sequences swapped between genotypes 1 and 4 human HEVs produced viruses capable of infecting HepG2/C3A cells. None of the four chimeras was able to establish a robust infection in pigs. The availability of a genotype 4 HEV infectious clone affords an opportunity to delineate the molecular mechanisms of HEV cross-species infection in the future. PMID- 22837418 TI - Evolution of the hepatitis E virus hypervariable region. AB - The presence of a hypervariable (HVR) region within the genome of hepatitis E virus (HEV) remains unexplained. Previous studies have described the HVR as a proline-rich spacer between flanking functional domains of the ORF1 polyprotein. Others have proposed that the region has no function, that it reflects a hypermutable region of the virus genome, that it is derived from the insertion and evolution of host sequences or that it is subject to positive selection. This study attempts to differentiate between these explanations by documenting the evolutionary processes occurring within the HVR. We have measured the diversity of HVR sequences within acutely infected individuals or amongst sequences derived from epidemiologically linked samples and, surprisingly, find relative homogeneity amongst these datasets. We found no evidence of positive selection for amino acid substitution in the HVR. Through an analysis of published sequences, we conclude that the range of HVR diversity observed within virus genotypes can be explained by the accumulation of substitutions and, to a much lesser extent, through deletions or duplications of this region. All published HVR amino acid sequences display a relative overabundance of proline and serine residues that cannot be explained by a local bias towards cytosine in this part of the genome. Although all published HVRs contain one or more SH3-binding PxxP motifs, this motif does not occur more frequently than would be expected from the proportion of proline residues in these sequences. Taken together, these observations are consistent with the hypothesis that the HVR has a structural role that is dependent upon length and amino acid composition, rather than a specific sequence. PMID- 22837420 TI - Specific cell tropism and neutralization of human parechovirus types 1 and 3: implications for pathogenesis and therapy development. AB - Human parechoviruses (HPeVs) are picornaviruses frequently infecting humans. While HPeV1 is associated with mild disease, HPeV3 is the cause of neonatal sepsis and meningitis. To test whether in vitro replication kinetics of HPeV1 and HPeV3 could be related to pathogenicity, HPeV1 and HPeV3 strains isolated from patients were cultured on cell lines of gastrointestinal, respiratory and neural origin, and replication kinetics were measured by real-time PCR. No relationship was found between clinical symptoms and in vitro replication of the HPeV1 strains. In contrast, the HPeV3 strains showed faster replication in neural cells and there was a relationship between higher in vitro replication kinetics and neuropathogenicity in the patient. Furthermore, HPeV1 could be neutralized efficiently by its specific antibody and by intravenous immunoglobulins (IVIG), while most HPeV3 strains could not be neutralized. In IVIG, very low neutralizing antibody (nAb) titres against HPeV3 were found. Additionally, very low nAb titres were observed in sera of two HPeV3-infected donors, while high nAb titres against HPeV1 could be detected. Our data suggest that the mild clinical course of HPeV1 infection is primarily influenced by strong nAb responses, while HPeV3 might be difficult to neutralize in vivo and therefore the course of infection will mainly be determined by in vivo cell tropism. PMID- 22837419 TI - Genomic analysis of 16 Colorado human NL63 coronaviruses identifies a new genotype, high sequence diversity in the N-terminal domain of the spike gene and evidence of recombination. AB - This study compared the complete genome sequences of 16 NL63 strain human coronaviruses (hCoVs) from respiratory specimens of paediatric patients with respiratory disease in Colorado, USA, and characterized the epidemiology and clinical characteristics associated with circulating NL63 viruses over a 3-year period. From 1 January 2009 to 31 December 2011, 92 of 9380 respiratory specimens were found to be positive for NL63 RNA by PCR, an overall prevalence of 1 %. NL63 viruses were circulating during all 3 years, but there was considerable yearly variation in prevalence and the month of peak incidence. Phylogenetic analysis comparing the genome sequences of the 16 Colorado NL63 viruses with those of the prototypical hCoV-NL63 and three other NL63 viruses from the Netherlands demonstrated that there were three genotypes (A, B and C) circulating in Colorado from 2005 to 2010, and evidence of recombination between virus strains was found. Genotypes B and C co-circulated in Colorado in 2005, 2009 and 2010, but genotype A circulated only in 2005 when it was the predominant NL63 strain. Genotype C represents a new lineage that has not been described previously. The greatest variability in the NL63 virus genomes was found in the N-terminal domain (NTD) of the spike gene (nt 1-600, aa 1-200). Ten different amino acid sequences were found in the NTD of the spike protein among these NL63 strains and the 75 partial published sequences of NTDs from strains found at different times throughout the world. PMID- 22837421 TI - Molecular evolution and phylogeography of potato virus Y based on the CP gene. AB - Potato virus Y (PVY) is an important plant pathogen with a wide host range that includes, among others, potato, tobacco, tomato and pepper. The coat protein (CP) of PVY has been commonly used in phylogenetic studies for strain classification. In this study, we used a pool of 292 CP sequences from isolates collected worldwide. After detecting and removing recombinant sequences, we applied Bayesian techniques to study the influence of geography and host species in CP population structure and dynamics. Finally, we performed selection and covariation analyses to identify specific amino acids involved in adaptation. Our results show that PVY CP diversification is significantly accounted for by both geographical and host-driven adaptations. Amino acid positions detected as positively selected concentrate in the N-terminal region of the protein. Some of these selected positions may discriminate among strains, and to a much lesser extent, between potato and non-potato isolates. PMID- 22837422 TI - Hantaviruses in rodents and humans, Xi'an, PR China. AB - Xi'an, the capital of Shaanxi province, located in north-west China, is one of the major endemic areas for haemorrhagic fever with renal syndrome (HFRS). In this study, the epidemiological data of HFRS in Xi'an from 1959 to 2010, especially in the past ten years (2001-2010), were surveyed. The features of hantavirus (HV) host carriers, the molecular characteristics of the HV S gene from hosts and patients, and the genome of the viral isolate were also investigated. Data showed that there might be a ten-year cycle of HFRS in Xi'an. Although the main population group infected over the past ten years was still the 16-59-year-old male farmers, the composition of the population and geographical distribution of HFRS cases have changed slowly, accompanied by the development of environmental and socio-economic situations. Apodemus agrarius remains the dominant host of HV. The HV strains from host rodents and patients in Xi'an belonged to the Hantaan virus (HTNV); no Seoul virus strains were found. Phylogenetic analysis of the small segments of strains taken from hosts and patients, and the whole genome of a viral isolate showed that the virus circulating in Xi'an had high similarity to Guizhou strains. The study also indicated that the vaccine candidate strain A16 isolated during the past century in Xi'an might be a recombinant strain of HTNV and the Amur virus, thus it may not be an optimal vaccine strain. PMID- 22837423 TI - Multilevel computational modeling and quantitative analysis of bone remodeling. AB - Our work focuses on bone remodeling with a multiscale breadth that ranges from modeling intracellular and intercellular RANK/RANKL signaling to tissue dynamics, by developing a multilevel modeling framework. Several important findings provide clear evidences of the multiscale properties of bone formation and of the links between RANK/RANKL and bone density in healthy and disease conditions. Recent studies indicate that the circulating levels of OPG and RANKL are inversely related to bone turnover and Bone Mineral Density (BMD) and contribute to the development of osteoporosis in postmenopausal women, and thalassemic patients. We make use of a spatial process algebra, the Shape Calculus, to control stochastic cell agents that are continuously remodeling the bone. We found that our description is effective for such a multiscale, multilevel process and that RANKL signaling small dynamic concentration defects are greatly amplified by the continuous alternation of absorption and formation resulting in large structural bone defects. This work contributes to the computational modeling of complex systems with a multilevel approach connecting formal languages and agent-based simulation tools. PMID- 22837424 TI - MORE: mixed optimization for reverse engineering--an application to modeling biological networks response via sparse systems of nonlinear differential equations. AB - Reverse engineering is the problem of inferring the structure of a network of interactions between biological variables from a set of observations. In this paper, we propose an optimization algorithm, called MORE, for the reverse engineering of biological networks from time series data. The model inferred by MORE is a sparse system of nonlinear differential equations, complex enough to realistically describe the dynamics of a biological system. MORE tackles separately the discrete component of the problem, the determination of the biological network topology, and the continuous component of the problem, the strength of the interactions. This approach allows us both to enforce system sparsity, by globally constraining the number of edges, and to integrate a priori information about the structure of the underlying interaction network. Experimental results on simulated and real-world networks show that the mixed discrete/continuous optimization approach of MORE significantly outperforms standard continuous optimization and that MORE is competitive with the state of the art in terms of accuracy of the inferred networks. PMID- 22837426 TI - Effect of fatigue on tibial rotation after single- and double-bundle anterior cruciate ligament reconstruction: a 3-dimensional kinematic and kinetic matched group analysis. AB - BACKGROUND: Fatigue is an extrinsic factor adversely affecting joint proprioception and neuromuscular response, thereby increasing anterior cruciate ligament (ACL) strain and injury risk. The effectiveness of the single- and double-bundle techniques for ACL reconstruction to control residual rotational knee laxity under fatigue has not been examined. HYPOTHESIS: Fatigue results in a significant increase in tibial rotation angles and moments in both ACL-intact and single- and double-bundle ACL-reconstructed knees. The 2 groups with ACL reconstructed knees will show no significant differences in tibial rotation angles and moments either pre- or postfatigue. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-four male patients who underwent successful single-bundle (n = 12) or double-bundle (n = 12) ACL reconstructions and 10 matched healthy controls were subjected to a standard lower limb muscle fatigue protocol using an isokinetic dynamometer. Three-dimensional motion analysis was used to measure tibial rotation and rotational knee moments in the pre- and postfatigue states, during a swinging maneuver on the weightbearing leg from a standing position with the knee in extension. RESULTS: Tibial rotation of the single-bundle group significantly increased postfatigue (prefatigue 22 degrees +/- 10 degrees vs 29 degrees +/- 15 degrees postfatigue, P = .015). In contrast, the double-bundle group showed similar tibial rotation values pre- and postfatigue (16 degrees +/- 6 degrees vs 18 degrees +/- 4 degrees , P = .22). The double-bundle group showed a trend toward decreased tibial rotation values pre- and post-fatigue compared with controls (22 +/- 4 and 23 +/- 4) (P = .065 and .08, respectively). In the prefatigue state, rotational moments (N.mm/Kg) of the single-bundle (339 +/- 148) and double-bundle (317 +/- 97) groups were significantly lower than that of controls (465 +/- 134) (P = .05 and .03, respectively). In the postfatigue state, an increase was observed in rotational moments of the single-bundle (388 +/- 131) and double-bundle (408 +/- 187) groups compared with prefatigue values, whereas a decrease was noted in the control group (411 +/- 117). CONCLUSION: Single-bundle ACL-reconstructed knees demonstrate a reduced ability to resist rotational loads under fatigue. Double bundle reconstructed knees had significantly better control of tibial rotation when fatigued. However, they demonstrate an excessive, yet not significant, reduction in tibial rotation compared with the intact knee, suggesting a possible overcorrection in rotational laxity. PMID- 22837427 TI - Arthroscopic treatment of rotator cuff tears with shoulder stiffness: a comparison of functional outcomes with and without capsular release. AB - BACKGROUND: In a single arthroscopic surgery for rotator cuff tears with a stiff shoulder, closed manipulation with or without arthroscopic capsular release has been combined with the repair. Few studies have reported functional results after this surgery, and a clinical comparison has not been reported. PURPOSE: To compare functional outcomes with and without capsular release in arthroscopic treatment of rotator cuff tears with a stiff shoulder. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Among patients who underwent arthroscopic rotator cuff repairs with a concomitant stiff shoulder, 34 patients were treated with either manipulation and arthroscopic capsular release (group A; n = 18) or manipulation without capsular release (group B; n = 16). Preoperative mean passive forward flexion was 118 degrees in group A and 117 degrees in group B, whereas external rotation at the side was 28 degrees and 29 degrees , respectively. All patients were evaluated at a minimum 2-year follow-up in terms of visual analog scale for pain, muscle power, range of motion, Constant score, modified American Shoulder and Elbow Surgeons (ASES) shoulder evaluation form, and modified University of California at Los Angeles (UCLA) scores. RESULTS: The mean modified ASES score was 90.3 for group A and 87.7 for group B (P = .086). The mean UCLA scores were 34.3 and 33.0, respectively (P = .247). The 2 groups showed a significant difference in forward flexion and external rotation post operatively, as group B recovered more slowly. There was no difference in the mean visual analog scale for pain at the last follow-up, but a 13 degrees difference in forward flexion (P < .001) and a 10 degrees difference in external rotation (P =.001) were seen. CONCLUSION: Overall satisfactory results could be achieved by either method, whereas rapid recovery and improvement of range of motion could be achieved by using a single arthroscopic repair and concomitant release for patients with rotator cuff tears with stiff shoulder. PMID- 22837428 TI - Tibial plateau geometry influences lower extremity biomechanics during landing. AB - BACKGROUND: Intersubject differences in lateral and medial posterior tibial plateau slope, coronal tibial slope (CTS), and medial tibial plateau depth (MTD) may influence one's susceptibility for anterior cruciate ligament (ACL) injury. Understanding how these structural characteristics influence hip and knee joint biomechanics during weightbearing activity may advance our understanding of how tibial plateau geometry influences one's injury risk potential. Purpose/ HYPOTHESES: To determine the extent to which tibial plateau geometry is associated with frontal and transverse plane hip and knee joint biomechanics during the initial landing phase of a double-legged drop landing. Greater lateral tibial slope combined with lower medial/lateral tibial slope ratio would predict greater tibial internal rotation motion and moments. Lower CTS would predict greater hip adduction and knee valgus motion and reduced internal peak varus moments. These associations would be stronger when combined with a shallower MTD. STUDY DESIGN: Descriptive laboratory study. METHODS: Magnetic resonance scans of the knee were obtained on 23 female participants who were also assessed for hip and knee joint biomechanics during the initial landing phase of double-legged drop jumps. RESULTS: Once controlling for the respective initial hip flexion or initial knee flexion angle at ground contact, lower CTS consistently predicted greater initial and peak hip adduction and knee valgus angles (R (2) range, .212 .427, P < .027). Greater coronal and lateral tibial slope predicted greater hip internal rotation (femur relative to pelvis) at initial contact (R (2) = .504) and greater CTS and lower medial/lateral tibial slope ratio predicted greater knee internal rotation (tibia relative to femur) excursions (R (2) = .594, P = .001). Joint geometry was not associated with hip or knee peak joint moments. CONCLUSION: These data confirm substantial intersubject differences in tibial condylar geometry that are associated with intersubject differences in hip and knee motion patterns when landing from a jump. CLINICAL RELEVANCE: The current findings may partially explain a female's greater likelihood of demonstrating combined motion patterns of knee valgus and external rotation during landing. Although tibial geometry cannot be modified through training, these associations suggest that tibial geometry may have a substantial influence on tibiofemoral joint biomechanics when the knee is subjected to external loads and deserves further study in our understanding of ACL injury. PMID- 22837425 TI - Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. AB - Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate related one-carbon metabolic pathways. PMID- 22837429 TI - Epidemiology of United States high school sports-related fractures, 2008-09 to 2010-11. AB - BACKGROUND: High school athletes sustain millions of injuries annually, many of which are fractures. Fractures can severely affect athletes physically, emotionally, and financially and should be targeted with focused prevention methods. HYPOTHESIS: Patterns and primary mechanisms of fractures differ by sport and gender. STUDY DESIGN: Descriptive epidemiology study. METHODS: High school sports-related injury data were collected from academic years 2008-09 to 2010-11 for 18 sports and from 2009-10 to 2010-11 for 2 additional sports. We used linear regression to describe annual fracture rate trends and calculated fractures rates, rate ratios (RRs), and injury proportion ratios (IPRs). RESULTS: From 2008 09 to 2010-11, certified athletic trainers reported a total of 21,251 injuries during 11,544,455 athlete exposures (AEs), of which 2103 (9.9%) were fractures, with an overall rate of 1.82 fractures per 10,000 AEs. Fracture rates were highest in football (4.37 per 10,000 AE), boys' ice hockey (3.08), and boys' lacrosse (2.59). Boys sustained 79.1% of all fractures, and the overall rates of fractures were greater in boys' sports than in girls' sports for competition (RR, 2.82; 95% CI, 2.45-3.24) and practice (RR, 2.43; 95% CI, 2.07-2.86). The most commonly fractured body sites were the hand/finger (32.1%), lower leg (10.1%), and wrist (9.5%). Overall, 17.2% of fractures required surgery, which was higher than for all other injuries combined (IPR, 3.14; 95% CI, 2.81-3.52). The most common mechanism of fracture involved contact with another player (45.5%). Using linear regression, we found the proportion of all injuries that were fractures was inversely correlated with the athlete's age (P = .02) but was not correlated with the athletes' age- and gender-adjusted body mass index. CONCLUSION: Fractures are a significant problem for high school athletes. Targeted preventive interventions should be implemented to reduce the burdens these injuries cause the athletes. PMID- 22837430 TI - Changes in the length of the medial patellofemoral ligament: an in vivo analysis using 3-dimensional computed tomography. AB - BACKGROUND: The ideal points for medial patellofemoral ligament (MPFL) reconstruction have not been precisely defined. PURPOSE: To determine at which flexion angles the grafts should be fixed to best restore patellar stability as well as to compare the length change of various femoral and patellar fixation sites for current MPFL reconstruction during knee flexion in vivo. STUDY DESIGN: Descriptive laboratory study. METHODS: The right knees of 10 living patients were scanned with a high-resolution computed tomography scanner at 0 degrees , 30 degrees , 60 degrees , 90 degrees , and 120 degrees of knee flexion, and 3 dimensional knee models were constructed using customized software. Based on recent anatomic studies and current surgical techniques, 4 femoral points (A: adductor tubercle; B: midpoint between the medial epicondyle and the adductor tubercle; C: medial epicondyle; and D: 10 mm inferior to the adductor tubercle) and 2 patellar points (30% [point 1] and 45% [point 2] from the proximal pole of the patella) were marked. The lengths of the 8 ligaments were digitally measured, and the length changes of these ligaments at the 5 different knee flexion angles were calculated. RESULTS: Two ligaments including the adductor tubercle (A1, A2) showed an increase while the knee was flexed over 60 degrees . Four ligaments (B1, B2, D1, D2) showed a slight increase as the knee flexed from 0 degrees to 30 degrees and a decrease as the flexion angle exceeded 30 degrees . Length changes in these 6 ligaments were not significantly different. There was no significant difference between 2 patellar points in the length changes of these 6 ligaments. Two ligaments including the medial epicondyle (C1, C2) showed an excessive decrease during knee flexion and showed greatest length changes. CONCLUSION: The femoral fixation sites should be located at point B or point D. Point A and point C are not ideal femoral fixation sites. The best angle for graft fixation would be near 30 degrees of knee flexion. CLINICAL RELEVANCE: The data obtained for length and length change pattern in each virtual ligament will serve as a useful basis for improved MPFL reconstruction. PMID- 22837431 TI - Histological assessment of mechanoreceptors in Achilles allografts after anterior cruciate ligament reconstruction. AB - BACKGROUND: There is a lack of histological studies investigating the presence of mechanoreceptors in anterior cruciate ligament (ACL) allografts. HYPOTHESIS: Mechanoreceptors would not grow in Achilles allografts after ACL reconstruction. STUDY DESIGN: Case series study; Level of evidence, 4. METHODS: Tissue samples were obtained from 11 patients who underwent ACL reconstruction using Achilles tendon allografts. They underwent biopsies during second-look arthroscopies. The mean period from ACL reconstruction to harvesting tissue was 26.63 months (range, 12-120 months). The control group consisted of 2 normal ACLs procured from 42- and 45-year-old men who underwent amputation above the knee due to trauma. RESULTS: Ruffini corpuscles and free nerve endings were shown to be present in the specimens of the control group by processing hematoxylin-eosin stains and immunohistochemical stains with monoclonal antibodies against S-100. In the Achilles allografts, mechanoreceptors were not observed. However, fibroblasts, collagen fibers, and vessels that were not present in fresh-frozen Achilles allografts before surgery were observed. CONCLUSION: The results demonstrate that Achilles tendon allografts appeared similar to normal ligaments except for the lack of histological evidence of mechanoreceptors. In other words, there are no newly ingrown mechanoreceptors in ACL allografts. PMID- 22837432 TI - Engineering enzymatically activated "molecular grenades" for cancer. AB - Animal toxicology and clinical phase I trial data have documented that the PSMA activated thapsigargin drug, G202 is non-myelosuppressive. This lack of myelosuppression facilitates G202 combination with a variety of additional clinically approved drugs. For example, thapsigargin's ability to induce ER stress raises its potential for synergy when combined with radiation and cytotoxic chemotherapies. Finally, G202-based delivery of the thapsigargin analog causes marked reduction of expression of the androgen receptor (AR) in prostate cancer cells and the estrogen receptor (ER) protein in breast cancer. These results suggest that combination therapy with anti-androgen/estrogens and G202 could be synergistic against prostate and/or breast cancer. These combinatorial approaches are currently under pre-clinical evaluation in our laboratories. PMID- 22837433 TI - Mutations in circulating mitochondrial DNA: Cassandra of oral cancer? AB - Cell-free circulating nucleic acids in human blood are increasing being researched as a source of diagnostic and prognostic biomarkers for clinical oncology. High copy number per cell and frequent mutations in various malignancies make mitochondrial genome an attractive target for such an investigation, but practical development and validation of biomarkers based on cell-free mitochondrial DNA has been lagging. Uzawa and colleagues report in the July issue of Oncotarget that in a retrospective study of patients with oral cancer the load of mutant mitochondrial DNA in patient's serum was a strong indicator of postoperative recurrence. Based on these observations, the predictive value of circulating mutant mitochondrial DNA merits further evaluation in patients with oral and other malignancies. PMID- 22837434 TI - Ionic liquids as matrices in microfluidic sample deposition for high-mass matrix- assisted laser desorption/ionization mass spectrometry. AB - Sample preparation for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) via a microfluidic deposition device using ionic liquid matrices addresses several problems of standard protocols with crystalline matrices, such as the heterogeneity of sample spots due to the co-crystallization of sample and matrix and the limited capability for high-throughput analysis. Since ionic liquid matrices do not solidify during the measurement, the resulting sample spots are homogeneous. The use of these matrices is also beneficial for automated sample preparation, since crystallization of the matrix is avoided and, thus, no clogging of the spotting device can occur. The applicability of ionic liquids to the analysis of biomolecules with high molecular weights, up to ~ 1 MDa is shown, as well as a good sensitivity (5 fmol) for recombinant human fibronectin, a protein with a molecular weight of 226 kDa. Microfluidic sample deposition of proteins with high molecular weights will, in the future, allow parallel sample preparation for MALDI-MS and for electron microscopy. PMID- 22837435 TI - Artifacts in amine analysis from anodic oxidation of organic solvents upon electrospray ionization for mass spectrometry. AB - Different phenylenediamines were used to explore anodic oxidation in solution during electrospray ionization (ESI) mass spectrometry analysis. In our experiments, a series of unknown ionic species was detected in the phenylenediamine solutions. Our results propose that reactions of phenylenediamines with species formed by anodic oxidation of typical ESI solvents during the electrospray ionization process such as formaldehyde are producing these peaks. Identification of these compounds inter alia suggests formal alkylation, a reaction not reported so far as a result of electrolytic oxidation in the prospective organic solvents. PMID- 22837436 TI - Application of proteomics to hordein screening in the malting process. AB - This study was undertaken to investigate the effect of the malting process on hordein composition. For this purpose, combination of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and the method of isotopic peptides labeling iTRAQ was used. Barley proteins are essential components determining the quality of both malt and beer. Since hordeins represent the most abundant proteins accounting for about 40-50% of total protein fraction of mature barley grain, our research was focused on them. In this respect, the proteins of interest were extracted from milled samples of barley grain, germinated barley grain (samples collected at different time intervals), green malt and malt, respectively. Particular hordein extracts were firstly fractionated via SDS- PAGE, which was used as a relatively rapid and reliable technique providing information about hordein profile of analyzed samples. Then, separated proteins were in-gel digested and resulting peptides were measured by mass spectrometry. In addition, the chosen proteins, after in-gel digestion, were subjected to the iTRAQ method and the screening of proteins during malting process was evaluated. Our results have revealed that most of the hordein components present in the barley grain can be found in all stages of the malting process as well as in the final malt. The amount of hordeins decreases during the malting process; in the case of C hordein, the protein decrease is approximately 65%. On the other hand, significant degradation of D hordein was detected. The suggested procedure can be used to follow the development of the hordein profile during germination, which is of great technological importance in beer production. PMID- 22837437 TI - Identifying the related compounds using electrospray ionization tandem mass spectrometry: bromotyrosine alkaloids from marine sponge Psammaplysilla purpurea. AB - We have investigated extracts of marine sponge Psammaplysilla purpurea during three collections from Mandapam (Tamil Nadu, India) and Okha (Gujarat, India) and indentified two new bromotyrosine alkaloids, purpurealidin I (7) and J (8) using electrospray ionization tandem mass spectrometry (ESI-MS/MS). This sponge has tremendous chemical diversity of bromotyrosine alkaloids. Here we have used the proteomics approach in identifying related bromotyrosine alkaloids based on the predicated mass fragmentation pattern. The focus is on the examination of detailed product ion spectra of six known compounds that allowed identification of new compounds based on its mass fragmentation pattern. The isotopic pattern of the peaks for protonated molecules indicated the number of bromine atoms present in the molecule. During MS/MS studies, the most prominent product ion peak is for the presence of side chain propane with either free NH(2) or NHMe or Nme(2). The cleavage at C-C bond between oxime-amide carbonyl and amide-phenoxy moiety also gave characteristic product ions. The ESI-MS spectra for all three collections show that the bromotyrosine metabolites vary during different season and also geographical location. Although, some common metabolites were observed during the three collections. Thus, ESI-MS/MS is a method of choice in identifying the related compounds. PMID- 22837438 TI - An improved calibration method for the matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resononance analysis of 15N metabolically- labeled proteome digests using a mass difference approach. AB - High mass measurement accuracy of peptides in enzymatic digests is critical for confident protein identification and characterization in proteomics research. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) can provide low or sub-ppm mass accuracy and ultrahigh resolving power. While for ESI FT-ICR-MS, the mass accuracy is generally 1 ppm or better, with matrix-assisted laser desorption/ionization (MALDI)-FT-ICR-MS, the mass errors can vary from sub ppm with internal calibration to over 100 ppm with conventional external calibration. A novel calibration method for (15)N-metabolically labeled peptides from a batch digest of a proteome is described which corrects for space charge induced frequency shifts in FT-ICR spectra without using an internal calibrant. This strategy utilizes the information from the mass difference between the (14)N/(15)N peptide peak pairs to correct for space charge induced mass shifts after data collection. A procedure for performing the mass correction has been written into a computer program and has been successfully applied to high performance liquid chromatography-MALDI-FT- ICR-MS measurement of (15)N-metabolic labeled proteomes. We have achieved an average measured mass error of 1.0 ppm and a standard deviation of 3.5 ppm for 900 peptides from 68 MALDI-FT-ICR mass spectra of the proteolytic digest of a proteome from Methanococcus maripaludis. PMID- 22837439 TI - Studies on the formation of N-methylperfluoroalkylnitrile cations from perfluoroacylphenethylamines in electron ionisation mass spectrometry: unique marker ion fragments in methamphetamine analysis. AB - The mass spectra of the perfluoroacyl derivatives of methamphetamine show a unique and characteristic fragment ion identified as the N methylperfluoroalkylnitrile cation (C(n)F(2n+1)CNCH(3))(+). This ion appears at various m/z values depending on the nature of the perfluoroacyl species and is generated via rearrangement of the perfluoroacyl immonium fragment formed by loss of the benzyl-radical from the molecular ion. Analogous ions have been described in the mass spectra of other methamphetamine-like side chain substances regardless of the aromatic ring substitution pattern. The scope and limitation of this rearrangement pathway were evaluated in this study by preparing a set of substituted phenethylamines and related compounds of varying structure. The perfluoroacyl moiety leads to the formation of the highest abundance of the N methyl nitrile cation fragment while hydrocarbon acyl groups do not show the N methylnitrile cation as a significant peak. The N-methyl group is required for the formation of the N-methyl nitrile cation and higher N-alkyl homologues eliminate the corresponding alkene species from the acyl immonium fragment. The loss of benzaldehyde and acetone from the perfluoroacylimmonium species produces the highest relative abundance of the unique N- methylperfluoroalkylnitrile cation. PMID- 22837440 TI - Mass spectrometic study of speciation in aluminium-fluoroquinolone solutions. AB - Fluoroquinolones (FQLs) are synthetic antibacterial agents containing a 4-oxo-1,4 dihydroquinoline skeleton. When concomintantly administered with other drugs which may contain metal ions, particularly Al(3+) (antacids, phosphate binders, vaccines etc) they may form metal-drug complexes. Pharmacokinetic studies showed that aluminium-quinolone interactions lead to reduced bio- availability and altered activity of the drug with possible development of the toxic effects of aluminum ion. Reliable speciation in Al(3+) - quinolone systems at micromolar concentration level is needed to better understand pharmaco- and toxicokinetics of the FQLs in the presence of Al. In this work, the speciation in solutions containing Al(3+) and FQL family members (fleroxacin, moxifloxacin and ciprofloxacin) was studied by electrospray mass spectrometry (ESI-MS), ESI-MS/MS, and laser desorption ionization (LDI) MS. The dominating species identified in all the three Al(3+)-FQL solutions, at ca 30-50 umol L(-1) total Al concentration and 2:1 to 1:3 metal-to-ligand ratio in the pH range 3.0- 6.0, were the ions related to the complexes AlL(2+), AlL(2)(+) and AlL(3)(0) (L = ligand in the monodeprotonated form). Mixed protonated and hydroxo complexes were also formed at lower and higher pH values respectively and, as expected, dimeric and polymeric species were not observed in ESI spectra. LDI measurements confirmed the existence of the mononuclear complexes found by ESI, and indicated the formation of polymeric species. The ion [2Al(3+) +5(-)](+) was identified with all three FQLs. This ionic species most probably arises from Al(2)L(2) by clustering with free ligand anions. Comparison of literature potentiometric data with mass spectral data indicated good agreement between speciation schemes. The obtained results suggest the presence of strong interaction between FQLs and Al(3+) which may be important in affecting absorption of these drugs in the gastrointestinal tract. PMID- 22837441 TI - Identification of novel HCV deletion mutants in chronic hepatitis C patients. AB - BACKGROUND: The HCV genome consists of a positive 9.6 kb single-strand of RNA. Nucleotide substitutions in the HCV genome are common and a 2 kb deletion has been reported. METHODS: A total of 117 chronic hepatitis C (CHC) patients who were treated with pegylated interferon plus ribavirin combination therapy were enrolled in this study. Total RNA was extracted from the patients' sera and reverse transcription and PCR were performed. Statistical analysis was performed to evaluate the effects of HCV deletion mutants on treatment with combination therapy. RESULTS: By amplifying entire HCV genomes using long-distance PCR, novel large deletion mutants were identified. Sequence analysis revealed that these deletions extended approximately 6 kb from the core/E2 region to the NS5A region and that there are three kinds of deletions that are identical at their 3' and 5' extremities. The subgenome virus particles appeared to coexist with full-genome virus particles in the sera of CHC patients despite lacking essential components for HCV viral replication. These short fragments were detected in 26 of 117 patients and were associated with significantly higher HCV RNA levels (P=0.018) and poor response to combination therapy (P=0.043). Moreover, the existence of HCV deletion mutants was significantly associated with virological relapse following combination therapy (P=0.046, OR=3.4). CONCLUSIONS: HCV deletion mutants may affect the HCV life cycle and reduce the antiviral effects of interferon therapy for CHC. PMID- 22837442 TI - Trends in HIV-1 reverse transcriptase resistance-associated mutations and antiretroviral prescription data from 2003-2010. AB - BACKGROUND: The selection of antiretroviral (ARV) drugs for treatment of HIV-1 infection is based on several factors including potency, toxicity, resistance and ease of administration. Emtricitabine (FTC) or lamivudine (3TC), components of recommended initial ARV regimens, are structurally related and share the same resistance mutation (M184V/I). However they differ with respect to potency and incidence of M184V/I. METHODS: Resistance-associated mutation (RAM) prevalence data were obtained from genotype test results performed in a large reference laboratory from 2003-2010; subsets of data were defined by mutation pattern to resemble those following failure of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination therapy. Mutational trend data were compared to contemporaneous ARV prescription information. RESULTS: In the unfiltered data set (n=107,231), the prevalence in 2010 decreased compared to 2003 for all nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs, such as M184V/I (44.0% to 17.9%), T215Y (22.7% to 4.1%), and K65R (4.3% to 2.1%). Among samples resembling those typical of first-line NNRTI-based failures, prevalence of K103N increased slightly, but prevalence of M184V/I decreased (49.8% to 36.8%), as did other NRTI RAMs. These decreases were coincident with a shift in ARV prescriptions away from zidovudine and 3TC towards tenofovir and FTC, and an increase in use of fixed-dose combinations. CONCLUSIONS: RAM prevalence decreased substantially since 2003 among samples submitted for resistance testing in the US. The causes of this decrease are multifactorial, but our results suggest a possible role of increased use of potent ARVs that are available as fixed-dose combinations or as single-tablet regimens. PMID- 22837443 TI - Influenza nucleoprotein: promising target for antiviral chemotherapy. AB - In the search for new anti-influenza agents, the viral polymerase has often been targeted due to the involvement of multiple conserved proteins and their distinct activities. Polymerase associates with each of the eight singled-stranded negative-sense viral RNA segments. These transcriptionally competent segments are coated with multiple copies of nucleoprotein (NP) to form the ribonucleoprotein. NP is an abundant essential protein, possessing operative and structural functions, and participating in genome organization, nuclear trafficking and RNA transcription and replication. This review examines the NP structure and function, and explores NP as an emerging target for anti-influenza drug development, focusing on recently discovered aryl piperazine amide inhibitor chemotypes. PMID- 22837444 TI - Electronic individual identification of zebrafish using radio frequency identification (RFID) microtags. AB - Although individual electronic tagging using passive integrated acoustic (PIT) tags is established, it is mainly for fish >60 mm in length and is unsuitable for fish of <30 mm, like zebrafish. We used radio frequency identification (RFID) microtags (1 mm in diameter and 6 mm in length, with a mass of ~10 mg) to individually identify juvenile zebrafish (length 16-42 mm, mass 138-776 mg) for the first time, and studied the effects of intracoelomic implantation on fish survival and microtag loss, growth, spawning and exploratory behaviour. After 5.5 months, both high survival (82%) and low microtag loss (11%) were achieved. The smallest surviving fish weighed 178 mg, and success in microtag reading was 73% for the size class 350-450 mg (26 mm). Greater success was achieved when fish were larger at the time of tagging but no negative effects on growth were observed for any size class and some tagged fish spawned. No significant differences in behavioural responses could be detected between tagged fish and untagged controls after 2 months. Overall, the results suggest that the tagging method is highly suitable for fish as small as zebrafish juveniles. We think this method will provide significant advances for researchers of the ever-growing fish model community and more generally for all small-fish users. Tagging is essential when one needs to identify fish (e.g. particular genotypes with no external cue), to run longitudinal monitoring of individual biological traits (e.g. growth) or to repeat assays with the same individual at discrete points in time (e.g. behaviour studies). Such a method will find applications in physiology, genetics, behaviour and (eco)toxicology fields. PMID- 22837445 TI - The dive response redefined: underwater behavior influences cardiac variability in freely diving dolphins. AB - A hallmark of the dive response, bradycardia, promotes the conservation of onboard oxygen stores and enables marine mammals to submerge for prolonged periods. A paradox exists when marine mammals are foraging underwater because activity should promote an elevation in heart rate (f(H)) to support increased metabolic demands. To assess the effect of the interaction between the diving response and underwater activity on f(H), we integrated interbeat f(H) with behavioral observations of adult bottlenose dolphins diving and swimming along the coast of the Bahamas. As expected for the dive response, f(H) while resting during submergence (40+/-6 beats min(-1)) was significantly lower than f(H) while resting at the water surface (105+/-8 beats min(-1)). The maximum recorded f(H) (f(H,max)) was 128+/-7 beats min(-1), and occurred during post-dive surface intervals. During submergence, the level of bradycardia was modified by activity. Behaviors such as simple head bobbing at depth increased f(H) by 40% from submerged resting levels. Higher heart rates were observed for horizontal swimming at depth. Indeed, the dolphins operated at 37-58% of their f(H,max) while active at depth and approached 57-79% of their f(H,max) during anticipatory tachycardia as the animals glided to the surface. f(H) was significantly correlated with stroke frequency (range=0-2.5 strokes s(-1), r=0.88, N=25 dives) and calculated swim speed (range=0-5.4 m s(-1), r=0.88, N=25 dives). We find that rather than a static reflex, the dive response is modulated by behavior and exercise in a predictable manner. PMID- 22837446 TI - Dietary protein level affects iridescent coloration in Anna's hummingbirds, Calypte anna. AB - Many animal displays involve colorful ornamental traits that signal an individual's quality as a mate or rival. Brilliant iridescent ornaments are common, but little is currently known about their production cost and signaling value. One potential cost of colorful ornaments is the acquisition of limited dietary resources that may be involved, directly or indirectly, in their production. Protein, the primary component of bird feathers and of many nanostructural components of iridescent traits, is naturally restricted in hummingbird diets (comprised mostly of sugars), suggesting that iridescent coloration may be especially challenging to produce in these animals. In this study, we experimentally investigated the effect of dietary protein availability during molt on iridescent color expression in male Anna's hummingbirds (Calypte anna). We fed captive birds either a 6% (high) or a 3% (low) protein diet and stimulated molt by plucking half the gorget and crown ornaments on each bird as well as the non-ornamental iridescent green tail feathers. We found that birds receiving more protein grew significantly more colorful crown feathers (higher red chroma and redder hue) than those fed the low-protein diet. Diet did not affect gorget coloration, but regrowth of feathers in captivity affected both gorget and crown coloration. Additionally, birds on the high-protein diet grew yellower (higher hue) green tail feathers than birds on the low-protein diet. These results indicate that iridescent ornamental feathers are sensitive to diet quality and may serve as honest signals of nutrition to mates or rivals. Further, because both ornamental and non-ornamental iridescent coloration were affected by conditions during their growth, iridescent color in these birds appears to be generally condition dependent. PMID- 22837447 TI - Short-range homing in a site-specific fish: search and directed movements. AB - Sedentary and territorial rockfish of the genus Sebastes exhibit distinctive homing ability and can travel back to an original location after displacements of metres or even kilometres. However, little is known about the behavioural and sensory mechanisms involved in homing. Although our previous study demonstrated that nocturnal black rockfish Sebastes cheni predominantly use their olfactory sense for homing from an unfamiliar area, the possibility of using landmarks in a familiar area cannot be discounted; i.e. site-specific fish are likely to use three-dimensional spatial memory for navigation and orientation. Using high resolution acoustic telemetry, we investigated whether S. cheni exhibit distinctive homing paths. Results show that all of the eight rockfish increased their effort within a small area of an unfamiliar region around the release site just after displacement, suggesting that the rockfish probably searched for the homeward direction. The rockfish showed the search movement in the upstream and/or downstream direction, which did not lead home. Finally, after returning to their familiar area, the rockfish exhibited more directed movements with faster speeds at a shallower depth, which was similar to the depth utilised in daily life as well as that of the fish capture. PMID- 22837448 TI - Spectral tuning by selective chromophore uptake in rods and cones of eight populations of nine-spined stickleback (Pungitius pungitius). AB - The visual pigments of rods and cones were studied in eight Fennoscandian populations of nine-spined stickleback (Pungitius pungitius). The wavelength of maximum absorbance of the rod pigment (lambda(max)) varied between populations from 504 to 530 nm. Gene sequencing showed that the rod opsins of all populations were identical in amino acid composition, implying that the differences were due to varying proportions of chromophores A1 and A2. Four spectral classes of cones were found (two S-cones, M-cones and L-cones), correlating with the four classes of vertebrate cone pigments. For quantitative estimation of chromophore proportions, we considered mainly rods and M-cones. In four populations, spectra of both photoreceptor types indicated A2 dominance (population mean lambda(max)=525-530 nm for rods and 535-544 nm for M-cones). In the four remaining populations, however, rod spectra (mean lambda(max)=504-511 nm) indicated strong A1 dominance, whereas M-cone spectra (mean lambda(max)=519-534 nm) suggested substantial fractions of A2. Quantitative analysis of spectra by three methods confirmed that rods and cones in these populations use significantly different chromophore proportions. The outcome is a shift of M-cone spectra towards longer wavelengths and a better match to the photic environment (light spectra peaking >560 nm in all the habitats) than would result from the chromophore proportions of the rods. Chromophore content was also observed to vary partly independently in M- and L-cones with potential consequences for colour discrimination. This is the first demonstration that selective processing of chromophore in rods and cones, and in different cone types, may be ecologically relevant. PMID- 22837449 TI - Intracellular Na+, K+ and Cl- activities in Acheta domesticus Malpighian tubules and the response to a diuretic kinin neuropeptide. AB - The mechanism of primary urine production and the activity of a diuretic kinin, Achdo-KII, were investigated in malpighian tubules of Acheta domesticus by measuring intracellular Na(+), K(+) and Cl(-) activities, basolateral membrane voltage (V(b)), fluid secretion and transepithelial ion transport. Calculated electrochemical gradients for K(+) and Cl(-) across the basolateral membrane show they are actively transported into principal cells, and basolateral Ba(2+) sensitive K(+) channels do not contribute to net transepithelial K(+) transport and fluid secretion. A basolateral Cl(-) conductance was revealed after the blockade of K(+) channels with Ba(2+), and a current carried by the passive outward movement of Cl(-) accounts for the hyperpolarization of V(b) in response to Ba(2+). Ion uptake via Na(+)/K(+)/2Cl(-) cotransport, driven by the inwardly directed Na(+) electrochemical gradient, is thermodynamically feasible, and is consistent with the actions of bumetanide, which reduces fluid secretion and both Na(+) and K(+) transport. The Na(+) gradient is maintained by its extrusion across the apical membrane and by a basolateral ouabain-sensitive Na(+)/K(+) ATPase. Achdo-KII has no significant effect on the intracellular ion activities or V(b). Electrochemical gradients across the apical membrane were estimated from previously published values for the levels of Na(+), K(+) and Cl(-) in the secreted fluid. The electrochemical gradient for Cl(-) favours passive movement into the lumen, but falls towards zero after stimulation by Achdo-KII. This coincides with a twofold increase in Cl(-) transport, which is attributed to the opening of an apical Cl(-) conductance, which depolarises the apical membrane voltage. PMID- 22837450 TI - Trafficking of bdelloid rotifer late embryogenesis abundant proteins. AB - The bdelloid rotifer Adineta ricciae is an asexual microinvertebrate that can survive desiccation by entering an ametabolic state known as anhydrobiosis. Two late embryogenesis abundant (LEA) proteins, ArLEA1A and ArLEA1B, have been hypothesized to contribute to desiccation tolerance in these organisms, since in vitro assays suggest that ArLEA1A and ArLEA1B stabilize desiccation-sensitive proteins and membranes, respectively. To examine their functions in vivo, it is important to analyse the cellular distribution of the bdelloid LEA proteins. Bioinformatics predicted their translocation into the endoplasmic reticulum (ER) via an N-terminal ER translocation signal and persistence in the same compartment via a variant C-terminal retention signal sequence ATEL. We assessed the localization of LEA proteins in bdelloids and in a mammalian cell model. The function of the N-terminal sequence of ArLEA1A and ArLEA1B in mediating ER translocation was verified, but our data showed that, unlike classical ER retention signals, ATEL allows progression from the ER to the Golgi and limited secretion of the proteins into the extracellular medium. These results suggest that the N-terminal ER translocation signal and C-terminal ATEL sequence act together to regulate the distribution of rotifer LEA proteins within intracellular vesicular compartments, as well as the extracellular space. We speculate that this mechanism allows a small number of LEA proteins to offer protection to a large number of desiccation-sensitive molecules and structures both inside and outside cells in the bdelloid rotifer. PMID- 22837451 TI - Transgenerational effects of microcystin-LR on Daphnia magna. AB - Anthropogenic and climate factors increase the frequency of problematic cyanobacterial blooms in freshwater. Among other toxins, some cyanobacteria produce microcystins (MCs), which inhibit phosphatases type 1 and type 2A and provokes oxidative stress. Toxic cyanobacteria affect the growth, survival and reproduction of zooplankton, particularly those from the genus Daphnia, which have a central position in pelagic food webs. However, one possibility to ameliorate effects is to biotransform MC via glutathione S transferase (GST) to a less toxic glutathione conjugate. This process was hypothesised to underlie the ability of Daphnia to withstand MC and to explain the enhanced tolerance of the offspring from mothers exposed to toxic cyanobacteria. Thus we conducted multigenerational experiments with D. magna, exposing the parental generation to MC for 1 or 7 days and determining the enzyme-mediated tolerance to MC in their offspring by assessing the acute effect of MC on biotransformation and antioxidant and metabolism enzymes, and through 21 day chronic tests on toxicity and growth. Seven days of exposure of the parental generation to MC induced higher activity of GST and malate dehydrogenase in the offspring and enabled them to increment the catalase activity when challenged with MC, whereas 1 day of exposure of the parental generation did not. Offspring from non-exposed and 1-day exposed mothers suffered decreased survival when exposed to MC compared with offspring from 7-day-exposed mothers; survival was correlated with the elevated activity of GST, malate dehydrogenase and catalase, suggesting maternal transfer of activation factors. However, increased survival occurred at the expense of individual growth. These results suggest that transgenerational effects are provoked by MC in D. magna, which may explain the observed acquirement of enhanced tolerance over generations. PMID- 22837452 TI - Evaporative water loss, relative water economy and evaporative partitioning of a heterothermic marsupial, the monito del monte (Dromiciops gliroides). AB - We examine here evaporative water loss, economy and partitioning at ambient temperatures from 14 to 33 degrees C for the monito del monte (Dromiciops gliroides), a microbiotheriid marsupial found only in temperate rainforests of Chile. The monito's standard evaporative water loss (2.58 mg g(-1) h(-1) at 30 degrees C) was typical for a marsupial of its body mass and phylogenetic position. Evaporative water loss was independent of air temperature below thermoneutrality, but enhanced evaporative water loss and hyperthermia were the primary thermal responses above the thermoneutral zone. Non-invasive partitioning of total evaporative water loss indicated that respiratory loss accounted for 59 77% of the total, with no change in respiratory loss with ambient temperature, but a small change in cutaneous loss below thermoneutrality and an increase in cutaneous loss in and above thermoneutrality. Relative water economy (metabolic water production/evaporative water loss) increased at low ambient temperatures, with a point of relative water economy of 15.4 degrees C. Thermolability had little effect on relative water economy, but conferred substantial energy savings at low ambient temperatures. Torpor reduced total evaporative water loss to as little as 21% of normothermic values, but relative water economy during torpor was poor even at low ambient temperatures because of the relatively greater reduction in metabolic water production than in evaporative water loss. The poor water economy of the monito during torpor suggests that negative water balance may explain why hibernators periodically arouse to normothermia, to obtain water by drinking or via an improved water economy. PMID- 22837453 TI - The skylight gradient of luminance helps sandhoppers in sun and moon identification. AB - To return to the ecologically optimal zone of the beach, the sandhopper Talitrus saltator (Montagu) maintains a constant sea-land direction based on the sun and moon compasses. In this study, we investigated the role of the skylight gradient of luminance in sun and moon identification under natural and artificial conditions of illumination. Clock-shifted (inverted) sandhoppers tested under the sun (during their subjective night) and under the full moon (during their subjective day) exhibit orientation in accordance with correct identification of the sun and the moon at night. Tested in artificial conditions of illumination at night without the artificial gradient of luminance, the artificial astronomical cue is identified as the moon even when the conditions of illumination allow sun compass orientation during the day. When the artificial gradient of luminance is added, the artificial astronomical cue is identified as the sun. The role of the sky gradient of luminance in sun and moon identification is discussed on the basis of present and past findings. PMID- 22837454 TI - Early life experience primes resistance to oxidative stress. AB - The extent to which early stress exposure is detrimental to darwinian fitness may depend on its severity, with mild stress exposure actually having a stimulatory and, possibly, beneficial effect through a hormetic response to the stressful stimulus. We need to understand such hormetic processes to determine how the early environment can help shape a phenotype adapted to the conditions the organism is most likely to experience in its adult environment. Using the zebra finch (Taeniopygia guttata), we tested the hypothesis that individuals exposed to mild heat stress earlier in life will suffer less oxidative stress when faced with high heat stress in adulthood than will individuals either not pre-exposed to heat stress or exposed to high heat stress earlier in life. Our findings demonstrate that early life exposure to mild heat stress primes the system to better withstand oxidative stress when encountering heat stress as an adult. These findings point to a potential mechanism linking early life experiences to future darwinian fitness. PMID- 22837455 TI - Taste preference for amino acids is dependent on internal nutritional state in Drosophila melanogaster. AB - Like mammals, insects need to ingest proteins from foods because they cannot synthesise several amino acids. Amino acids are also essential nutrients for Drosophila melanogaster, especially for female egg production, but how flies detect amino acids and how the feeding response to amino acids is regulated are unknown. In this study, the two-choice preference test, the proboscis extension reflex test and a CAFE assay were performed to explore the ability of D. melanogaster to detect and discriminate amino acids. To determine whether D. melanogaster change their feeding preference to amino acids after being deprived of them, as previously reported in the locust, two groups of flies raised on the usual medium or on glucose medium were compared. Amino-acid-deprived flies demonstrated enhanced preference to an amino acid mixture and to several amino acids. These flies ingested amino acids even when they were replete with glucose. The proboscis extension reflex to particular amino acids was induced only in amino-acid-deprived flies. Our findings indicate that the sensitivity of labellar taste cells to amino acids may change when flies are deficient in amino acid supply, and also reveal that the detection pathways for individual amino acids may differ. We suggest the existence of an amino acid receptor and a monitoring system regulating the feeding responses to amino acids. PMID- 22837456 TI - Flies dynamically anti-track, rather than ballistically escape, aversive odor during flight. AB - Tracking distant odor sources is crucial to foraging, courtship and reproductive success for many animals including fish, flies and birds. Upon encountering a chemical plume in flight, Drosophila melanogaster integrates the spatial intensity gradient and temporal fluctuations over the two antennae, while simultaneously reducing the amplitude and frequency of rapid steering maneuvers, stabilizing the flight vector. There are infinite escape vectors away from a noxious source, in contrast to a single best tracking vector towards an attractive source. Attractive and aversive odors are segregated into parallel neuronal pathways in flies; therefore, the behavioral algorithms for avoidance may be categorically different from tracking. Do flies plot random ballistic or otherwise variable escape vectors? Or do they instead make use of temporally dynamic mechanisms for continuously and directly avoiding noxious odors in a manner similar to tracking appetitive ones? We examine this question using a magnetic tether flight simulator that permits free yaw movements, such that flies can actively orient within spatially defined odor plumes. We show that in-flight aversive flight behavior shares all of the key features of attraction such that flies continuously 'anti-track' the noxious source. PMID- 22837457 TI - Interlocking of chelae is a key factor for dominance hierarchy formation in crayfish. AB - We characterized the role of chelae during agonistic encounters of the crayfish Procambarus clarkii. Physical asymmetries in body length, body mass and chelae size were directly related to dominance hierarchy formation. More than 80% of winning crayfish had longer body and chelae lengths, and winners were usually heavier in body mass, even if their differences were less than 3% compared with losing opponents. In mismatched pairings, large crayfish with short chelae were beaten by small crayfish with large chelae. Three physical elements of body length, body mass and chelae length equally affected the outcome of agonistic bouts. Chelae restriction, in which chelae were tightly closed using rubber bands, affected the outcome of agonistic bouts between large and small crayfish. Before chelae restriction, large crayfish won in all pairings. Following chelae restriction for at least 30 days from the first encounters, the winning rate of large crayfish that were previous winners decreased significantly in the second encounters against the same opponents that were previous losers. The handicap of chelae restriction significantly prolonged the time to formation of the winner loser relationship. Individual fights escalated during agonistic bouts between large crayfish with one chela restricted and small crayfish with intact chelae, whereas the number of fights increased but the duration of individual fights did not increase in large crayfish with both chelae restricted. Furthermore, when the chelae of both large and small crayfish were disabled, the dominance order was frequently not formed during 30 min of agonistic bouts. Preventing chelae from interlocking prevented escalation of agonistic bouts. We show that interlocking of chelae acted as a key factor for the formation of dominance hierarchy. PMID- 22837458 TI - Measuring airborne components of seismic body vibrations in a Middle-Asian sand dwelling Insectivora species, the piebald shrew (Diplomesodon pulchellum). AB - Self-produced seismic vibrations have been found for some subterranean rodents but have not been reported for any Insectivora species, although seismic sensitivity has been confirmed for blind sand-dwelling chrysochlorid golden moles. Studying the vocal behaviour of captive piebald shrews, Diplomesodon pulchellum, we documented vibrations, apparently generated by the whole-body wall muscles, from 11 (5 male, 6 female) of 19 animals, placed singly on a drum membrane. The airborne waves of the vibratory drumming were digitally recorded and then analysed spectrographically. The mean frequency of vibration was 160.5 Hz. This frequency matched the periodicity of the deep sinusoidal frequency modulation (159.4 Hz) found in loud screech calls of the same subjects. The body vibration was not related to thermoregulation, hunger-related depletion of energy resources or fear, as it was produced by well-fed, calm animals, at warm ambient temperatures. We hypothesize that in the solitary, nocturnal, digging desert piebald shrew, body vibrations may be used for seismic exploration of substrate density, to avoid energy-costly digging of packed sand for burrowing and foraging. At the same time, the piercing quality of screech calls due to the deep sinusoidal frequency modulation, matching the periodicity of body vibration, may be important for agonistic communication in this species. PMID- 22837459 TI - Spectral transmission of the principal-eye corneas of jumping spiders: implications for ultraviolet vision. AB - Ultraviolet (UV) vision plays an important role in interspecific and intraspecific communication in many animals. However, UV vision and its adaptive significance have been investigated in only approximately 1% of more than 5000 species of jumping spiders (Araneae: Salticidae), renowned for their unique, complex eyes that support exceptional spatial acuity and visually based behaviour. To appreciate the adaptive significance of UV vision, it is important to establish whether salticids can perceive UV and whether the perception of UV varies with ecological factors such as light environment. In this study, we measured the UV-transmission properties of the principal-eye corneas of 128 salticid species. We found that the corneas of all measured species were able to transmit UV light, making the perception of UV possible. Three classes of corneal spectral transmission curves were identified; the majority of species had a Class II curve with a less-steep slope and a gradual onset of the transmission cut-off; all the remaining species had a Class I curve with a very steep slope and a sharp cut-off except for one species that had a Class III curve with an intermediate step, which appeared as a shoulder on the descending part of the transmission curve. The T(50) cut-off transmission values (the wavelength at which 50% of the maximum transmission is reached) in salticid corneas vary with species and light habitat. The corneas of species inhabiting open bush had a higher relative transmission at short wavelengths in the UV than forest species. This is the first investigation of corneal transmission in spiders and suggests that UV perception is widespread in salticids. PMID- 22837460 TI - The relative cost of using luminescence for sex and defense: light budgets in cypridinid ostracods. AB - Luminescent signals can be used by animals for a number of purposes, including courtship and defense, sometimes by the same individual. However, the relative costs of producing these different behaviors are largely unknown. In the marine ostracod Photeros annecohenae, males utilize extracellular luminescence for complex courtship displays, and both males and females luminesce as a predation defense. We compared the relative luminescent output of courtship with that of defensive displays and also with respect to their total luminescent stores. Courtship displays are relatively inexpensive compared with defensive displays, with an average defensive display releasing 50 times more luminescence than the average courtship display. Furthermore, in order to completely exhaust its stores, a male would have to produce 450 typical courtship displays or approximately 10 average defensive displays. Both courtship pulses and defensive displays show first-order decay kinetics, yet courtship pulses decay three times faster than defensive displays, suggesting that there is differential release of the luciferin, luciferase and mucus in order to control the reaction kinetics. PMID- 22837461 TI - Median fin function during the escape response of bluegill sunfish (Lepomis macrochirus). I: Fin-ray orientation and movement. AB - The fast-start escape response is critically important to avoid predation, and axial movements driving it have been studied intensively. Large median dorsal and anal fins located near the tail have been hypothesized to increase acceleration away from the threat, yet the contribution of flexible median fins remains undescribed. To investigate the role of median fins, C-start escape responses of bluegill sunfish (Lepomis macrochirus) were recorded by three high-speed, high resolution cameras at 500 frames s(-1) and the 3-D kinematics of individual dorsal and anal fin rays were analyzed. Movement and orientation of the fin rays relative to the body axis were calculated throughout the duration of the C-start. We found that: (1) timing and magnitude of angular displacement varied among fin rays based on position within the fin and (2) kinematic patterns support the prediction that fin rays are actively resisting hydrodynamic forces and transmitting momentum into the water. We suggest that regions within the fins have different roles. Anterior regions of the fins are rapidly elevated to increase the volume of water that the fish may interact with and transmit force into, thus generating greater total momentum. The movement pattern of all the fin rays creates traveling waves that move posteriorly along the length of the fin, moving water as they do so. Flexible posterior regions ultimately act to accelerate this water towards the tail, potentially interacting with vortices generated by the caudal fin during the C-start. Despite their simple appearance, median fins are highly complex and versatile control surfaces that modulate locomotor performance. PMID- 22837462 TI - Median fin function during the escape response of bluegill sunfish (Lepomis macrochirus). II: Fin-ray curvature. AB - Although kinematic analysis of individual fin rays provides valuable insight into the contribution of median fins to C-start performance, it paints an incomplete picture of the complex movements and deformation of the flexible fin surface. To expand our analysis of median fin function during the escape response of bluegill sunfish (Lepomis macrochirus), patterns of spanwise and chordwise curvature of the soft dorsal and anal fin surfaces were examined from the same video sequences previously used in analysis of fin-ray movement and orientation. We found that both the span and chord undergo undulation, starting in the anterior region of either fin. Initiated early in Stage 1 of the C-start, the undulation travels in a postero-distal direction, reaching the trailing edge of the fins during early Stage 2. Maximum spanwise curvature typically occurred among the more flexible posterior fin rays, though there was no consistent correlation between maximum curvature and fin-ray position. Undulatory patterns suggest different mechanisms of action for the fin regions. In the anterior fin region, where the fin rays are oriented dorsoventrally, undulation is directed primarily chordwise, initiating a transfer of momentum into the water to overcome the inertia of the flow and direct the water posteriorly. Within the posterior region, where the fin rays are oriented caudally, undulation is predominantly directed spanwise; thus, the posterior fin region acts to ultimately accelerate this water towards the tail to increase thrust forces. Treatment of median fins as appendages with uniform properties does not do justice to their complexity and effectiveness as control surfaces. PMID- 22837463 TI - Myo-inositol as a main metabolite in overwintering flies: seasonal metabolomic profiles and cold stress tolerance in a northern drosophilid fly. AB - Coping with seasonal changes in temperature is an important factor underlying the ability of insects to survive over the harsh winter conditions in the northern temperate zone, and only a few drosophilids have been able to colonize sub-polar habitats. Information on their winter physiology is needed as it may shed light on the adaptive mechanisms of overwintering when compared with abundant data on the thermal physiology of more southern species, such as Drosophila melanogaster. Here we report the first seasonal metabolite analysis in a Drosophila species. We traced changes in the cold tolerance and metabolomic profiles in adult Drosophila montana flies that were exposed to thermoperiods and photoperiods similar to changes in environmental conditions of their natural habitat in northern Finland. The cold tolerance of diapausing flies increased noticeably towards the onset of winter; their chill coma recovery times showed a seasonal minimum between late autumn and early spring, whereas their survival after cold exposure remained high until late spring. The flies had already moderately accumulated glucose, trehalose and proline in autumn, but the single largest change occurred in myo inositol concentrations. This increased up to 400-fold during the winter and peaked at 147 nmol mg(-1) fresh mass, which is among the largest reported accumulations of this compound in insects. PMID- 22837464 TI - Encephalic photoreception and phototactic response in the troglobiont Somalian blind cavefish Phreatichthys andruzzii. AB - Many physiological and behavioural responses to changes in environmental lighting conditions are mediated by extraocular photoreceptors. Here we investigate encephalic photoreception in Phreatichthys andruzzii, a typical cave-dwelling fish showing an extreme phenotype with complete anophthalmy and a reduction in size of associated brain structures. We firstly identified two P. andruzzii photopigments, orthologues of rod opsin and exo-rod opsin. In vitro, both opsins serve as light-absorbing photopigments with lambda(max) around 500 nm when reconstituted with an A(1) chromophore. When corrected for the summed absorption from the skin and skull, the spectral sensitivity profiles shifted to longer wavelengths (rod opsin: 521 nm; exo-rod opsin: 520 nm). We next explored the involvement of both opsins in the negative phototaxis reported for this species. A comparison of the spectral sensitivity of the photophobic response with the putative A(2) absorbance spectra corrected for skin/skull absorbance indicates that the A(2) versions of either or both of these pigments could explain the observed behavioural spectral sensitivity. PMID- 22837465 TI - Primiparous and multiparous females differ in mammary gland alveolar development: implications for milk production. AB - Mammary gland capacity is influenced by the number of secretory cells in the gland, the activity of those cells and the size and arrangement of the alveoli that they form. Although reproductive experience has been shown to affect the total number of secretory cells in the gland, its potential effect on the structural development of lobulo-alveolar tissues has not been directly investigated. To examine whether reproductive experience affects lobulo-alveolar development, we took mammary gland biopsies at early and peak lactation from primiparous and multiparous grey seal (Halichoerus grypus) females and used histological techniques to compare cell density, alveolar density and alveolar size within secretory lobules. Primiparous females had a significantly higher cell density compared with multiparous females throughout lactation, suggesting that primiparous females have smaller, less-developed secretory cells. Primiparous females had a significantly smaller average alveolar size compared with multiparous females throughout lactation. Although alveolar density was higher in primiparous females compared with multiparous females at early lactation, there was no significant difference between the groups at peak lactation. These results suggest that the mammary gland of primiparous females may have both a lower secretory capacity and a lower storage capacity on a relative basis than those of multiparous females and demonstrate, for the first time, that reproductive experience has a significant effect on both the rate and pattern of mammary gland alveolar development and, potentially, on a female's capacity for milk production. PMID- 22837466 TI - The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster. AB - During hibernation, small mammals alternate between periods of metabolic suppression and low body temperature ('torpor') and periods of full metabolic recovery with euthermic temperatures ('arousal'). Previously, we demonstrated marked structural remodeling of the lung during torpor, which is rapidly reversed during arousal. We also found that cooling of hamster cells increased endogenous production of H(2)S through the enzyme cystathionine-beta-synthase (CBS). H(2)S suppresses the immune response and increases deposition of collagen. Therefore, we examined inflammatory markers and matrix metalloproteinase (MMP) activity in relation to CBS expression and H(2)S levels in lungs of euthermic and hibernating Syrian hamsters. Lung remodeling during torpor was confirmed by a strong increase in both collagenous and non-collagenous hydroxyproline content. The number of leukocytes in lung was unchanged in any phase of hibernation, while adhesion molecules VCAM-1 and ICAM-1, and the inflammatory marker NF-kappaB (P65) were modestly upregulated in torpor. Gelatinase activity was decreased in lungs from torpid animals, indicating inhibition of the Zn(2+)-dependent MMP-2 and MMP-9. Moreover, expression of CBS and tissue levels of H(2)S were increased in torpor. All changes normalized during arousal. Inhibition of gelatinase activity in torpor is likely caused by quenching of Zn(2+) by the sulphide ion of H(2)S. In accord, inhibition of CBS normalized gelatinase activity in torpid animals. Conversely, NaHS decreased the gelatinase activity of euthermic animals, which was attenuated by excess Zn(2+). Similar results were obtained on the activity of the Zn(2+)-dependent angiotensin converting enzyme. Our data indicate that increased production of H(2)S through CBS in hamster lungs during torpor contributes to remodeling by inhibition of gelatinase activity and possibly by suppression of the inflammatory response. Although administration of H(2)S is known to induce metabolic suppression in non-hibernating mammals ('suspended animation'), this is the first report implying endogenous H(2)S production in natural hibernation. PMID- 22837467 TI - Unpredictable food availability induces metabolic and hormonal changes independent of food intake in a sedentary songbird. AB - Environments often vary with regard to their temporal resource availability, but little is understood concerning how resource predictability impacts animals. The adaptive regulation hypothesis suggests that organisms act to conserve their current energetic state during periods of diminished food access and recuperate their energetic reserves (fat and muscle) during periods of greater food availability. In contrast, the chronic stress hypothesis suggests that variation in access to food can induce a prolonged stress response, resulting in maladaptive usage of energy reserves and increased behavioral activity. To distinguish between these hypotheses we compared the behavioral, hormonal and metabolic responses of captive curve-billed thrashers, Toxostoma curvirostre, fed varying amounts each day (variable group) with those of birds fed a constant amount every day (constant feeding group). Birds of both groups consumed, on average, a similar total amount of food during the course of the study, but birds in the variable feeding group lost mass and increased their circulating initial levels of the stress hormone corticosterone, showed evidence for increased secretion of a hypothalamic stress peptide, vasotocin, used greater amounts of fat and protein energy reserves, and were more behaviorally active than birds in the constant feeding group. Overall, these findings support the chronic stress hypothesis and suggest that birds such as thrashers may be particularly susceptible to the perception of unpredictable variation in food supplies independent of actual energetic constraints. PMID- 22837468 TI - Platelets derived from the bone marrow of diabetic animals show dysregulated endoplasmic reticulum stress proteins that contribute to increased thrombosis. AB - OBJECTIVE: Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering. METHODS AND RESULTS: Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls-BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD. CONCLUSIONS: Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels. PMID- 22837469 TI - Immunization with a combination of 2 peptides derived from the C5a receptor significantly reduces early atherosclerotic lesion in Ldlr(tm1Her) Apob(tm2Sgy) J mice. AB - OBJECTIVE: The goal of this study was to assess whether immunization of Ldlr(tm1Her) Apob(tm2Sgy) J mice with 2 peptides located at the N-terminus of the C5a receptor (C5aR), either alone or in combination, is effective in reducing atherosclerotic lesions. METHODS AND RESULTS: Five- to 6-week-old female Ldlr(tm1Her)Apob(tm2Sgy) J mice were immunized using a repetitive immunization multiple sites strategy with keyhole limpet hemocyanin-conjugated peptides derived from the C5aR, either alone (designated as C5aR-P1 [aa 1-21] and C5aR-P2 [aa 19-31]) or in combination (designated as C5aR-P1+C5aR-P2). Mice were fed a high-fat diet for 10 weeks. Lesions were evaluated histologically; local and systemic immune responses were analyzed by immunohistochemistry of aorta samples and cytokine measurements in plasma samples and splenocyte supernatants. Immunization of Ldlr(tm1Her)Apob(tm2Sgy) J mice with these peptides elicited high concentrations of antibodies against each peptide. Immunization with the single peptide inhibited plaque development. Combined inoculation with C5aR-P1+C5aR-P2 had an additive effect on reducing the lesion in the aorta sinus and descending aortas when compared with controls. This effect correlated with cellular infiltration and cytokine/chemokine secretion in the serum or in stimulated spleen cells as well as specific cellular immune responses when compared with controls. CONCLUSIONS: Immunization of mice with C5aR-P1 and C5aR-P2, either alone or in combination, was effective in reducing early atherosclerotic lesion development. The combined peptide is more potential than either epitope alone to reduce atherosclerotic lesion formation through the induction of a specific Treg cell response as well as blockage of monocyte differentiation into macrophages. PMID- 22837470 TI - Sphingosine-1-phosphate receptor-1 controls venous endothelial barrier integrity in zebrafish. AB - OBJECTIVE: Endothelial sphingosine-1-phosphate (S1P) receptor-1 (S1P(1)) affects different vascular functions, including blood vessel maturation and permeability. Here, we characterized the role of the zS1P(1) ortholog in vascular development in zebrafish. METHODS AND RESULTS: zS1P(1) is expressed in dorsal aorta and posterior cardinal vein of zebrafish embryos at 24 to 30 hours postfertilization. zS1P(1) downregulation by antisense morpholino oligonucleotide injection causes early pericardial edema, lack of blood circulation, alterations of posterior cardinal vein structure, and late generalized edema. Also, zS1P(1) morphants are characterized by downregulation of vascular endothelial cadherin (VE-cadherin) and Eph receptor EphB4a expression and by disorganization of zonula occludens 1 junctions in posterior cardinal vein endothelium, with no alterations of dorsal aorta endothelium. VE-cadherin knockdown results in similar vascular alterations, whereas VE-cadherin overexpression is sufficient to rescue venous vascular integrity defects and EphB4a downregulation in zS1P(1) morphants. Finally, S1P(1) small interfering RNA transfection and the S1P(1) antagonist (R)-3-amino-(3 hexylphenylamino)-4-oxobutylphosphonic acid (W146) cause EPHB4 receptor down modulation in human umbilical vein endothelial cells and the assembly of zonula occludens 1 intercellular contacts is prevented by the EPHB4 antagonist TNYL-RAW peptide in these cells. CONCLUSIONS: The data demonstrate a nonredundant role of zS1P(1) in the regulation of venous endothelial barrier in zebrafish and identify a S1P(1)/VE-cadherin/EphB4a genetic pathway that controls venous vascular integrity. PMID- 22837471 TI - Evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes. AB - OBJECTIVE: To develop a normative data set and to study the relationship among arterial structure, different anthropometric measures, blood pressure, and arterial function during healthy childhood using very-high-resolution ultrasound (25-55 MHz). METHODS AND RESULTS: In 135 healthy children between 0 and 18 years of age, we assessed the structure of the carotid arteries, larger peripheral arteries, aorta, and left ventricle with ultrasound. Arterial stiffness was assessed by pulse wave velocity and endothelial function by brachial flow mediated dilation. Reference curves adjusted for age and body surface area of arterial lumen diameters, intima-media thickness, and adventitia thickness were developed. Arterial walls thicken during childhood predominantly as a result of a progressive increase in intima-media thickness. There were significant associations among lumen diameter (R(2) range, 0.20-0.88 for different arteries; P<0.001), intima-media thickness (R(2) range, 0.47-0.85; P<0.001), left ventricular mass (R(2)=0.90; P<0.001), and adventitia thickness (R(2) range, 0.15 0.22; P<0.001) with sex, age, body surface, and systolic blood pressure. Arterial wall stress was associated with lumen diameter (R(2) range, 0.52-0.83; P<0.001) and intima-media thickness (R(2) range, 0.53-0.88; P<0.001). Limited relationships were found among arterial wall layer thickness, stiffness, and endothelial function. CONCLUSIONS: In healthy children, the evolution of the arterial structure is mainly related to anthropometrics and blood pressure. PMID- 22837472 TI - Two types of procoagulant platelets are formed upon physiological activation and are controlled by integrin alpha(IIb)beta(3). AB - OBJECTIVE: Phosphatidylserine (PS) externalization by platelets upon activation is a key event in hemostasis and thrombosis. It is currently believed that strong stimulation of platelets forms 2 subpopulations, only 1 of which expresses PS. METHODS AND RESULTS: Here, we demonstrate that physiological stimulation leads to the formation of not 1 but 2 types of PS-expressing activated platelets, with dramatically different properties. One subpopulation sustained increased calcium level after activation, whereas another returned to the basal low-calcium state. High-calcium PS-positive platelets had smaller size, high surface density of fibrin(ogen), no active integrin alpha(IIb)beta(3), depolarized mitochondrial membranes, gradually lost cytoplasmic membrane integrity, and were poorly aggregated. In contrast, the low-calcium PS-positive platelets had normal size, retained mitochondrial membrane potential and cytoplasmic membrane integrity, and combined retention of fibrin(ogen) with active alpha(IIb)beta(3) and high proaggregatory function. Formation of low-calcium PS-positive platelets was promoted by platelet concentration increase or shaking and was decreased by integrin alpha(IIb)beta(3) antagonists, platelet dilution, or in platelets from kindlin-3-deficient and Glanzmann thrombasthenia patients. CONCLUSIONS: Identification of a novel PS-expressing platelet subpopulation with low calcium regulated by integrin alpha(IIb)beta(3) can be important for understanding the mechanisms of PS exposure and thrombus formation. PMID- 22837473 TI - Ferritin is independently associated with the presence of coronary artery calcium in 12,033 men. AB - OBJECTIVE: Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors. METHODS AND RESULTS: Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3-291.9) compared with 182.2 (128.1-253.6) in people with a CACS=0; P<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (P<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (P<0.0001), hypertension (P<0.0001), coronary heart disease (P=0.003), and a Framingham Risk Score >10% (P<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3-1.98]; P=0.0001). CONCLUSIONS: Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation. PMID- 22837474 TI - Differences in health status affect susceptibility and mapping of genetic loci for atherosclerosis (fatty streak) in inbred mice. AB - OBJECTIVE: We observed differences in atherosclerosis susceptibility in mouse inbred strains over the years as the health status of our animal rooms increased. Therefore, we investigated the effect of animal room health status on atherosclerosis susceptibility in different strains. As these data can also be used for genome-wide association mapping, we performed a mapping study and compared our results with previously found quantitative trait loci for atherosclerosis in mouse and humans. METHODS AND RESULTS: Males and females from 48 inbred strains were housed in 2 animal rooms with different health status and given an atherogenic diet. We compared atherosclerosis susceptibility between animal rooms and between sexes and found that susceptibility is dependent on both health status and sex. Subsequently, the data were used for associations with loci on the mouse genome using 63 222 single nucleotide polymorphism. Three loci in males and 4 loci in females were identified using the data from the low-health status room. No significant associations were identified using the data from the high-health status room. CONCLUSIONS: Health status influences susceptibility to atherosclerosis and suggests that microbiological pressure plays an important role in the development of atherosclerosis in many strains. As we were only able to map susceptibility loci using the data from the lower health status room, we argue that susceptibility under these conditions is determined by a few key loci, whereas in the higher health status room different mechanisms might play a role in the differences in atherosclerosis susceptibility between strains and we did not have enough power to map the loci that are involved. PMID- 22837475 TI - Selkirk Rex: morphological and genetic characterization of a new cat breed. AB - Rexoid, curly hair mutations have been selected to develop new domestic cat breeds. The Selkirk Rex is the most recently established curly-coated cat breed originating from a spontaneous mutation that was discovered in the United States in 1987. Unlike the earlier and well-established Cornish and Devon Rex breeds with curly-coat mutations, the Selkirk Rex mutation is suggested as autosomal dominant and has a different curl phenotype. This study provides a genetic analysis of the Selkirk Rex breed. An informal segregation analysis of genetically proven matings supported an autosomal, incomplete dominant expression of the curly trait in the Selkirk Rex. Homozygous curl cats can be distinguished from heterozygous cats by head and body type, as well as the presentation of the hair curl. Bayesian clustering of short tandem repeat (STR) genotypes from 31 cats that represent the future breeding stock supported the close relationship of the Selkirk Rex to the British Shorthair, Scottish Fold, Persian, and Exotic Shorthair, suggesting the Selkirk as part of the Persian breed family. The high heterozygosity of 0.630 and the low mean inbreeding coefficient of 0.057 suggest that Selkirk Rex has a diverse genetic foundation. A new locus for Selkirk autosomal dominant Rex, SADRE, is suggested for the curly trait. PMID- 22837476 TI - Mefloquine gap junction blockade and risk of pregnancy loss. AB - Obstetric use of the antimalarial drug mefloquine has historically been discouraged during the first trimester and immediately before conception owing to concerns of potential fetal harm. With the rise of resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP), mefloquine is now being considered as a replacement for SP for universal antenatal administration to women from malaria endemic regions. Recent recommendations have also suggested that mefloquine may be used cautiously among pregnant travelers who cannot otherwise avoid visiting these areas. Mefloquine has been demonstrated to cause blockade of gap junction protein alpha 1 (GJA1) gap junction intercellular communication (GJIC), and recent evidence suggests that GJA1 GJIC is critical to successful embryonic implantation and early placental development. During routine use, mefloquine accumulates in organ and peripheral tissue, crosses the blood-placental barrier, and may plausibly accumulate in developing decidua and trophoblast at concentrations sufficient to interfere with GJA1 GJIC and, thus, cause deleterious effects on fetal outcomes. This conclusion is supported by epidemiological evidence that demonstrates use of the drug during early development is associated with an increased risk of miscarriage and stillbirth. Confirmatory studies are pending, but the available experimental and epidemiological evidence support renewed adherence, where feasible, to existing mefloquine package insert guidance that women avoid the drug during the periconceptional period. PMID- 22837477 TI - Gestational protein restriction reduces expression of Hsd17b2 in rat placental labyrinth. AB - Accumulating evidence strongly supports the premise that testosterone may be a key player in fetal programming on hypertension. Studies have shown that gestational protein restriction doubles the plasma testosterone levels in pregnant rats. In this study, we hypothesized that elevated testosterone levels in response to gestational protein restriction were caused by enhanced expression of steroidogenic enzymes or impaired expression of Hsd17b2, a known testosterone inactivator that converts testosterone to androstenedione in placenta. Pregnant Sprague-Dawley rats were fed normal (20% protein, control; n = 10) or a low protein diet (6% protein, PR; n = 10) from Day 1 of pregnancy until killed at Days 14, 18, or 21. Junctional (JZ) and labyrinth (LZ) zones of placenta were collected for expression assay on steroidogenic genes (Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b2, and Srd5a1) by real-time PCR. The main findings include the following: 1) expressions of Cyp11a1, Hsd3b1, and Cyp17a1 in JZ were not affected by diet but were affected by day of pregnancy; 2) expression of Hsd17b2 in both female and male JZs was remarkably increased by PR at Days 18 and 21 of pregnancy; 3) expressions of Hsd17b2 were reduced by PR in both female and male LZ at Day 18 of pregnancy and in female LZ at Day 21 of pregnancy; and 4) expression of Srd5a1in LZ was not affected by day of pregnancy, gender, or diet. These results indicate that in response to gestational protein restriction, Hsd17b2 may be a key regulator of testosterone levels and associated activities in placental zones, apparently in a paradoxical manner. PMID- 22837478 TI - Molecular filtration properties of the mouse expanded cumulus matrix: controlled supply of metabolites and extracellular signals to cumulus cells and the oocyte. AB - While formation of the expanded cumulus matrix and its importance for oocyte maturation and ovulation are well described, its function in these processes remains unknown. The degree of expansion and expression of cumulus matrix genes are positively correlated with oocyte quality, suggesting that this matrix plays a key role in oocyte maturation. Based on recognized filtration properties of analogous matrices, we investigated whether the cumulus matrix acts as a molecular filter by assessing diffusion of fluorescently labeled dextrans (neutral and negatively charged) and hydrophilic (glucose) and hydrophobic (cholesterol) metabolites in cumulus oocyte complexes (COCs). Expanded in vivo matured COCs resisted absorption of glucose and cholesterol compared to unexpanded COCs. In vitro-matured (IVM) COCs have a pronounced deficiency in cumulus matrix proteins and have poor oocyte quality. Here we demonstrate that IVM cumulus matrix has deficient filtration properties, with dextran and glucose and cholesterol molecules diffusing more readily into IVM than in vivo-matured COCs. Taking the inverse approach, we found that prostaglandin E2 (PGE2), synthesized by cumulus cells, is retained within the matrix of in vivo-matured COCs but IVM COCs have reduced capacity to retain PGE2, secreting significantly more into the medium. This is the first demonstration of a biophysical property of the cumulus matrix. The ability to regulate metabolite supply from the surrounding environment while sequestering vital signaling factors, such as PGE2, is likely to impact oocyte maturation. Thus, IVM may reduce oocyte quality due to dysregulated control of metabolites and signaling molecules. PMID- 22837479 TI - Aurora kinase A drives MTOC biogenesis but does not trigger resumption of meiosis in mouse oocytes matured in vivo. AB - Aurora kinase A (AURKA) is an important mitotic kinase involved in the G2/M transition, centrosome maturation and separation, and spindle formation in somatic cells. We used transgenic models that specifically overexpress in mouse oocytes either wild-type (WT-AURKA) or a catalytically inactive (kinase-dead) (KD AURKA) AURKA to gain new insights regarding the role of AURKA during oocyte maturation. AURKA activation occurs shortly after hCG administration that initiates maturation in vivo. Although AURKA activity is increased in WT-AURKA oocytes, resumption of meiosis is not observed in the absence of hCG administration. Control oocytes contain one to three microtubule organizing centers (MTOCs; centrosome equivalent) at prophase I. At the time of germinal vesicle breakdown (GVBD), the first visible marker of resumption of meiosis, the MTOC number increases. In WT-AURKA oocytes, the increase in MTOC number occurs prematurely but transiently without GVBD, whereas the increase in MTOC number does not occur in control and KD-AURKA oocytes. AURKA activation is biphasic with the initial activation not requiring CDC25B-CDK1 activity, whereas full activation, which is essential for the increase in MTOCs number, depends on CDK1 activity. AURKA activity also influences spindle length and regulates, independent of its protein kinase activity, the amount of MTOC associated with gamma-tubulin. Both WT-AURKA and KD-AURKA transgenic mice have normal fertility during first 6 mo of life. These results suggest that although AURKA is not a trigger kinase for G2/M transition in mouse oocytes, it regulates MTOC number and spindle length, and, independent of its protein kinase activity, gamma-tubulin recruitment to MTOCs. PMID- 22837481 TI - Alterations to the bull sperm surface proteins that bind sperm to oviductal epithelium. AB - Three Binder of SPerm proteins (BSP1, BSP3, BSP5) are secreted by bovine seminal vesicles into seminal plasma and adsorbed onto sperm. When sperm inseminated into the female reach the oviduct, the BSP proteins bind them to its epithelial lining, forming a sperm storage reservoir. Previously, we reported that binding of capacitated sperm to oviductal epithelium in vitro is lower than that of uncapacitated sperm and we proposed that reduced binding was due to loss of BSP proteins during capacitation. Because of differences in amino acid sequences, we predicted that each BSP would respond differently to capacitating conditions. To test whether all three BSP proteins were lost from sperm during capacitation and whether the kinetics of loss differed among the three BSP proteins, ejaculated bull sperm were incubated under various capacitating conditions, and then the amounts of BSP proteins remaining on the sperm were assayed by Western blotting. Capacitation was assayed by analysis of protein tyrosine phosphorylation. While loss of BSP1 was not detected, most of the BSP5 was lost from sperm during incubation in TALP medium, even without addition of the capacitation enhancers heparin and dbcAMP-IBMX. Surprisingly, a smaller molecular mass was detected by anti-BSP3 antibodies in extracts of incubated sperm. Its identity was confirmed as BSP3 by mass spectrometry, indicating that BSP3 undergoes modification on the sperm surface. These changes in the composition of BSP proteins on sperm could play a role in releasing sperm from the storage reservoir by modifying sperm interactions with the oviductal epithelium. PMID- 22837482 TI - Sox9 and Sox8 are required for basal lamina integrity of testis cords and for suppression of FOXL2 during embryonic testis development in mice. AB - The sex-determining gene Sry and its target gene Sox9 initiate the early steps of testis development in mammals. Of the related Sox genes Sox8, Sox9, and Sox10, all expressed during Sertoli cell differentiation, only inactivation of Sox9 before the sex determination stage at Embryonic Day 11.5 (E11.5) causes XY sex reversal, while Sox9 inactivation after this stage has no effect on testis cord differentiation. We have previously shown that both Sox9 and Sox8 are essential for maintaining testicular function in post-E14.0 Sertoli cells. To gain insight into the molecular and cellular processes underlying the abnormal development of Sox9 and Sox8 mutant testes, we performed a detailed developmental study of embryonic and neonatal stages. We observe a progressive disruption of the basal lamina surrounding the testis cords that starts at E17.5 and already at E15.5 reduced expression levels of collagen IV, collagen IXa3 and testatin, structural components of the basal lamina, and the extracellular matrix transcriptional regulator Scleraxis. Lineage tracing reveals that mutant Sertoli cells delaminate from testis cords and are present as isolated cells between remaining cords. Also, Sox10 expression is strongly reduced in the absence of Sox9 and/or Sox8. Finally, we document increasing expression of the ovarian marker FOXL2 in mutant cords starting at E15.5, indicating progressive transdifferentiation of mutant Sertoli cells. This study shows that Sox9 and Sox8 maintain integrity of the basal lamina to prevent testis cord disintegration and that both factors actively suppress the ovarian program during early testis development. PMID- 22837480 TI - Metabolic substrates exhibit differential effects on functional parameters of mouse sperm capacitation. AB - Although substantial evidence exists that sperm ATP production via glycolysis is required for mammalian sperm function and male fertility, conflicting reports involving multiple species have appeared regarding the ability of individual glycolytic or mitochondrial substrates to support the physiological changes that occur during capacitation. Several mouse models with defects in the signaling pathways required for capacitation exhibit reductions in sperm ATP levels, suggesting regulatory interactions between sperm metabolism and signal transduction cascades. To better understand these interactions, we conducted quantitative studies of mouse sperm throughout a 2-h in vitro capacitation period and compared the effects of single substrates assayed under identical conditions. Multiple glycolytic and nonglycolytic substrates maintained sperm ATP levels and comparable percentages of motility, but only glucose and mannose supported hyperactivation. These monosaccharides and fructose supported the full pattern of tyrosine phosphorylation, whereas nonglycolytic substrates supported at least partial tyrosine phosphorylation. Inhibition of glycolysis impaired motility in the presence of glucose, fructose, or pyruvate but not in the presence of hydroxybutyrate. Addition of an uncoupler of oxidative phosphorylation reduced motility with pyruvate or hydroxybutyrate as substrates but unexpectedly stimulated hyperactivation with fructose. Investigating differences between glucose and fructose in more detail, we demonstrated that hyperactivation results from the active metabolism of glucose. Differences between glucose and fructose appeared to be downstream of changes in intracellular pH, which rose to comparable levels during incubation with either substrate. Sperm redox pathways were differentially affected, with higher levels of associated metabolites and reactive oxygen species generated during incubations with fructose than during incubations with glucose. PMID- 22837483 TI - B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets. AB - Programmed death receptor 1 (PD-1) is an important signaling molecule often involved in tumor-mediated suppression of activated immune cells. Binding of this receptor to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), attenuates T cell activation, reduces IL-2 and IFN-gamma secretion, decreases proliferation and cytotoxicity, and induces apoptosis. B7-DC-Ig is a recombinant protein that binds and targets PD-1. It is composed of an extracellular domain of murine B7-DC fused to the Fc portion of murine IgG2a. In this study, we demonstrate that B7-DC-Ig can enhance the therapeutic efficacy of vaccine when combined with cyclophosphamide. We show that this combination significantly enhances Ag specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. We identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect that is distinctly different from direct blocking of the PD-L1-PD-1 interaction. In this study, we demonstrate that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play critical roles in anti-tumor immune effect exhibited by B7-DC-Ig through inhibiting proliferation of PD-1(high) CD4 T cells, leading to a significant decrease in the level of these cells, which are enriched for regulatory T cells, within the tumor. In addition, it also leads to a decrease in PD-1(high) CD8 T cells, tipping the balance toward nonexhausted functional PD 1(low) CD8 T cells. We believe that the PD-1 expression level on T cells is a crucial factor that needs to be considered when designing PD-1-targeting immune therapies. PMID- 22837484 TI - Phospholipase Cgamma2 plays a role in TCR signal transduction and T cell selection. AB - One of the important signaling events following TCR engagement is activation of phospholipase Cgamma (PLCgamma). PLCgamma has two isoforms, PLCgamma1 and PLCgamma2. It is known that PLCgamma1 is important for TCR signaling and TCR mediated T cell selection and functions, whereas PLCgamma2 is critical for BCR signal transduction and BCR-mediated B cell maturation and functions. In this study, we report that PLCgamma2 was expressed in primary T cells, and became associated with linker for activated T cells and Src homology 2-domain containing leukocyte protein of 76 kDa and activated upon TCR stimulation. PLCgamma1/PLCgamma2 double-deficient T cells displayed further block from CD4 and CD8 double-positive to single-positive transition compared with PLCgamma1 single deficient T cells. TCR-mediated proliferation was further impaired in PLCgamma1/PLCgamma2 double-deficient T cells compared with PLCgamma1 single deficient T cells. TCR-mediated signal transduction, including Ca2+ mobilization and Erk activation, was further impaired in PLCgamma1/PLCgamma2 double-deficient relative to PLCgamma1 single-deficient T cells. In addition, in HY TCR transgenic mouse model, thymic positive and negative selections were reduced in PLCgamma1 heterozygous- and PLCgamma2 homozygous-deficient (PLCgamma1+/-PLCgamma2-/-) relative to wild-type, PLCgamma2 single-deficient (PLCgamma2-/-), or PLCgamma1 heterozygous-deficient (PLCgamma1+/-) mice. Taken together, these data demonstrate that PLCgamma2 participates in TCR signal transduction and plays a role in T cell selection. PMID- 22837485 TI - Dynamics of the splenic innate-like CD19+CD45Rlo cell population from adult mice in homeostatic and activated conditions. AB - In the adult spleen, CD19+CD45R(-/lo) (19+45R(lo)) lymphocytes of embryonic origin exist as a distinct population to that of the conventional B cell lineage. These cells display a plasmablast phenotype, and they spontaneously secrete IgG1 and IgA, whereas the bone marrow population of 19+45R(lo) cells contains B1 progenitors. In this study, we show that 19+45R(lo) cells are also present in Peyer's patches and in the spleen throughout the life span of wild-type mice, beginning at postnatal day 7. Although this population is heterogeneous, the surface phenotype of most of these cells distinguishes them from follicular, transitional, marginal zone, and B1 cells. In CBA/CaHN mice, few 19+45R(lo) cells were detected at postnatal day 7, and none was observed in the adult spleen. Splenic 19+45R(lo) cells exhibited homeostatic BrdU uptake in vivo and actively transcribed cell cycle genes. When transferred to immunodeficient RAG2-/ gammachain-/- recipient mice, 19+45R(lo) cells survived and differentiated into IgG1- and IgA-plasma cells. Moreover, in vitro stimulation of splenic 19+45R(lo) cells with LPS, CpG, BAFF/IL4, and CD40/IL4 induced cell proliferation, IgG1/IgA secretion and the release of IL-10, suggesting a potential immunoregulatory role for this subset of innate-like B cells. PMID- 22837486 TI - CD4+ T cell-dependent IFN-gamma production by CD8+ effector T cells in Mycobacterium tuberculosis infection. AB - Both CD4+ and CD8+ T cells contribute to immunity to tuberculosis, and both can produce the essential effector cytokine IFN-gamma. However, the precise role and relative contribution of each cell type to in vivo IFN-gamma production are incompletely understood. To identify and quantitate the cells that produce IFN gamma at the site of Mycobacterium tuberculosis infection in mice, we used direct intracellular cytokine staining ex vivo without restimulation. We found that CD4+ and CD8+ cells were predominantly responsible for production of this cytokine in vivo, and we observed a remarkable linear correlation between the fraction of CD4+ cells and the fraction of CD8+ cells producing IFN-gamma in the lungs. In the absence of CD4+ cells, a reduced fraction of CD8+ cells was actively producing IFN-gamma in vivo, suggesting that CD4+ effector cells are continually required for optimal IFN-gamma production by CD8+ effector cells. Accordingly, when infected mice were treated i.v. with an MHC-II-restricted M. tuberculosis epitope peptide to stimulate CD4+ cells in vivo, we observed rapid activation of both CD4+ and CD8+ cells in the lungs. Indirect activation of CD8+ cells was dependent on the presence of CD4+ cells but independent of IFN-g responsiveness of the CD8+ cells. These data provide evidence that CD4+ cell deficiency impairs IFN-gamma production by CD8+ effector cells and that ongoing cross-talk between distinct effector T cell types in the lungs may contribute to a protective immune response against M. tuberculosis. Conversely, defects in these interactions may contribute to susceptibility to tuberculosis and other infections. PMID- 22837488 TI - Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL 27. AB - GM-CSF is a potent proinflammatory cytokine that plays a pathogenic role in the CNS inflammatory disease experimental autoimmune encephalomyelitis. As IL-27 alleviates experimental autoimmune encephalomyelitis, we hypothesized that IL-27 suppresses GM-CSF expression by T cells. We found that IL-27 suppressed GM-CSF expression in CD4+ and CD8+ T cells in splenocyte and purified T cell cultures. IL-27 suppressed GM-CSF in Th1, but not Th17, cells. IL-27 also suppressed GM-CSF expression by human T cells in nonpolarized and Th1- but not Th17-polarized PBMC cultures. In vivo, IL-27p28 deficiency resulted in increased GM-CSF expression by CNS-infiltrating T cells during Toxoplasma gondii infection. Although in vitro suppression of GM-CSF by IL-27 was independent of IL-2 suppression, IL-10 upregulation, or SOCS3 signaling, we observed that IL-27-driven suppression of GM CSF was STAT1 dependent. Our findings demonstrate that IL-27 is a robust negative regulator of GM-CSF expression in T cells, which likely inhibits T cell pathogenicity in CNS inflammation. PMID- 22837487 TI - Antibodies generated against conserved antigens expressed by bacteria and allergen-bearing fungi suppress airway disease. AB - There has been a sharp rise in allergic asthma and asthma-related deaths in the developed world, in contrast to many childhood illnesses that have been reduced or eliminated. The hygiene hypothesis proposes that excessively sanitary conditions early in life result in autoimmune and allergic phenomena because of a failure of the immune system to receive proper microbial stimulation during development. We demonstrate that Abs generated against conserved bacterial polysaccharides are reactive with and dampen the immune response against chitin and Aspergillus fumigatus. A reduction in Ag uptake, cell influx, cell activation, and cytokine production occurred in the presence of anti polysaccharide Abs, resulting in a striking decrease in the severity of allergic airway disease in mice. Overall, our results suggest that Ag exposure--derived from environmental sources, self-antigens, or vaccination--during the neonatal period has dramatic effects on the adult Ab response and modifies the development of allergic airway disease. PMID- 22837489 TI - A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing. AB - Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure. We report in this article that the common ERAP2 single nucleotide polymorphism rs2549782 that codes for amino acid variation N392K leads to alterations in both the activity and the specificity of the enzyme. Specifically, the 392N allele excises hydrophobic N-terminal residues from epitope precursors up to 165-fold faster compared with the 392K allele, although both alleles are very similar in excising positively charged N-terminal amino acids. These effects are primarily due to changes in the catalytic turnover rate (k(cat)) and not in the affinity for the substrate. X-ray crystallographic analysis of the ERAP2 392K allele suggests that the polymorphism interferes with the stabilization of the N terminus of the peptide both directly and indirectly through interactions with key residues participating in catalysis. This specificity switch allows the 392N allele of ERAP2 to supplement ERAP1 activity for the removal of hydrophobic N-terminal residues. Our results provide mechanistic insight to the association of this ERAP2 polymorphism with disease and support the idea that polymorphic variation in Ag processing enzymes constitutes a component of immune response variability in humans. PMID- 22837490 TI - Combined action of influenza virus and Staphylococcus aureus panton-valentine leukocidin provokes severe lung epithelium damage. AB - Staphylococcus aureus necrotizing pneumonia is a life-threatening disease that is frequently preceded by influenza infection. The S. aureus toxin Panton-Valentine leukocidin (PVL) is most likely causative for necrotizing diseases, but the precise pathogenic mechanisms of PVL and a possible contribution of influenza virus remain to be elucidated. In this study, we present a model that explains how influenza virus and PVL act together to cause necrotizing pneumonia: an influenza infection activates the lung epithelium to produce chemoattractants for neutrophils. Upon superinfection with PVL-expressing S. aureus, the recruited neutrophils are rapidly killed by PVL, resulting in uncontrolled release of neutrophil proteases that damage the airway epithelium. The host counteracts this pathogen strategy by generating PVL-neutralizing antibodies and by neutralizing the released proteases via protease inhibitors present in the serum. These findings explain why necrotizing infections mainly develop in serum-free spaces (eg, pulmonary alveoli) and open options for new therapeutic approaches. PMID- 22837491 TI - beta-defensin genomic copy number is associated with HIV load and immune reconstitution in sub-saharan Africans. AB - AIDS, caused by the retrovirus human immunodeficiency virus (HIV), is the leading cause of death of economically active people (age, 15-59 years) in sub-Saharan Africa. The host genetic variability of immune response to HIV and immune reconstitution following initiation of highly active antiretroviral therapy (HAART) is poorly understood. Here we focused on copy number variation of the beta-defensin genes, which have been shown to have anti-HIV activity, and are important chemoattractants for Th17 lymphocytes via the chemokine receptor CCR6. We determined beta-defensin gene copy number for 1002 Ethiopian and Tanzanian patients. We show that higher beta-defensin copy number variation is associated with increased HIV load prior to HAART (P=.005) and poor immune reconstitution following initiation of HAART (P=.003). We suggest a model where variable amounts of beta-defensin expression by mucosal cells, due to gene copy number variation, alters the efficacy of recruitment of Th17 lymphocytes to the site of infection, altering the dynamics of infection. PMID- 22837498 TI - Polar science. Needed Antarctic upgrades would trim science budget. PMID- 22837492 TI - Extended evaluation of the virologic, immunologic, and clinical course of volunteers who acquired HIV-1 infection in a phase III vaccine trial of ALVAC-HIV and AIDSVAX B/E. AB - BACKGROUND: The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection. METHODS: CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VEP) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models. RESULTS: There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VEP (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04). CONCLUSIONS: Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study. PMID- 22837493 TI - Longitudinal study of influenza molecular viral shedding in Hutterite communities. AB - BACKGROUND: The nature of influenza viral shedding during naturally acquired infection is not well understood. METHODS: A cohort study was conducted in Hutterite colonies in Alberta, Canada. Flocked nasal swabs were collected during 3 influenza seasons (2007-2008 to 2009-2010) from both symptomatic and asymptomatic individuals infected with influenza. Samples were tested by real time reverse-transcription polymerase chain reaction for influenza A and influenza B, and the viral load (VL) was determined for influenza A positive samples. RESULTS: Eight hundred thirty-nine participants were included in the cohort; 25% (208) tested positive for influenza viruses. They experienced 238 episodes of viral shedding, of which 23 (10%) were not accompanied by symptoms. For seasonal and pandemic H1N1, VL peaked at or before onset of acute respiratory infection. For H3N2, VL peaked 2 days after the onset of acute respiratory infection, which corresponded to peaks in systemic and respiratory symptom scores. Although the duration of shedding was shorter for asymptomatic participants, the peak level of VL shedding was similar to that of symptomatic participants. Viral loads for children and adults revealed similar patterns. CONCLUSIONS: Molecular viral shedding values follow symptom scores, but timing of peak VL varies by subtype. Asymptomatic infections are infrequent. PMID- 22837499 TI - Astronomy. Data dispute revives exoplanet claim. PMID- 22837501 TI - Climate change. Using radiocarbon to go beyond good faith in measuring CO2 emissions. PMID- 22837500 TI - Biomedical research. Panel votes to end prevention fund, cut economics studies, freeze NIH. PMID- 22837502 TI - Science education. U.S.'s best science and math teachers to get bonuses. PMID- 22837503 TI - Solar system exploration. Planetary science is busting budgets. PMID- 22837504 TI - Transboundary rivers. For China and Kazakhstan, no meeting of the minds on water. PMID- 22837505 TI - Joint Congress on Evolutionary Biology. Insulin may guarantee the honesty of beetle's massive horn. PMID- 22837506 TI - Joint Congress on Evolutionary Biology. Texas wildflower's red keeps it a species. PMID- 22837507 TI - Joint Congress on Evolutionary Biology. By the skin of their teeth. PMID- 22837508 TI - Pollution in the Yangtze. PMID- 22837509 TI - Reducing red tape for research in Europe. PMID- 22837510 TI - Stemming the U.S. HIV epidemic: act local. PMID- 22837511 TI - Neuroscience. The mind of a male? PMID- 22837512 TI - Materials science. A roadmap for the assembly of polyhedral particles. PMID- 22837513 TI - Neuroscience. dSarm-ing axon degeneration. PMID- 22837514 TI - Immunology. HD6 defensin nanonets. PMID- 22837515 TI - Molecular biology. Use and abuse of RNAi to study mammalian gene function. PMID- 22837516 TI - Retrospective. Phillip V. Tobias (1925-2012). PMID- 22837517 TI - IBI series winner. Aipotu: simulation from nucleotides to populations and back again. PMID- 22837518 TI - IBI series winner. Engaging students in molecular biology via case-based learning. PMID- 22837520 TI - Explosive backpacks in old termite workers. AB - By nature, defensive behavior is risky. In social insects, such behavior is more likely to occur in individuals whose potential for other tasks is diminished. We show that workers of the termite Neocapritermes taracua develop an exceptional two-component suicidal apparatus consisting of copper-containing protein crystals, stored in external pouches, and internal salivary glands. During aggressive encounters, their bodies rupture, and the crystals react with the salivary gland secretion to produce a toxic droplet. Both the amount of defensive substances and the readiness to explode increase with workers' age, as their food collecting ability declines. PMID- 22837519 TI - New paradigms in type 2 immunity. AB - Nearly half of the world's population harbors helminth infections or suffers from allergic disorders. A common feature of this population is the so-called "type 2 immune response," which confers protection against helminths, but also promotes pathologic responses associated with allergic inflammation. However, the mechanisms that initiate and control type 2 responses remain enigmatic. Recent advances have revealed a role for the innate immune system in orchestrating type 2 responses against a bewildering array of stimuli, from nanometer-sized allergens to 20-meter-long helminth parasites. Here, we review these advances and suggest that the human immune system has evolved multiple mechanisms of sensing such stimuli, from recognition of molecular patterns via innate immune receptors to detecting metabolic changes and tissue damage caused by these stimuli. PMID- 22837521 TI - The connectome of a decision-making neural network. AB - In order to understand the nervous system, it is necessary to know the synaptic connections between the neurons, yet to date, only the wiring diagram of the adult hermaphrodite of the nematode Caenorhabditis elegans has been determined. Here, we present the wiring diagram of the posterior nervous system of the C. elegans adult male, reconstructed from serial electron micrograph sections. This region of the male nervous system contains the sexually dimorphic circuits for mating. The synaptic connections, both chemical and gap junctional, form a neural network with four striking features: multiple, parallel, short synaptic pathways directly connecting sensory neurons to end organs; recurrent and reciprocal connectivity among sensory neurons; modular substructure; and interneurons acting in feedforward loops. These features help to explain how the network robustly and rapidly selects and executes the steps of a behavioral program on the basis of the inputs from multiple sensory neurons. PMID- 22837522 TI - Binary interaction dominates the evolution of massive stars. AB - The presence of a nearby companion alters the evolution of massive stars in binary systems, leading to phenomena such as stellar mergers, x-ray binaries, and gamma-ray bursts. Unambiguous constraints on the fraction of massive stars affected by binary interaction were lacking. We simultaneously measured all relevant binary characteristics in a sample of Galactic massive O stars and quantified the frequency and nature of binary interactions. More than 70% of all massive stars will exchange mass with a companion, leading to a binary merger in one-third of the cases. These numbers greatly exceed previous estimates and imply that binary interaction dominates the evolution of massive stars, with implications for populations of massive stars and their supernovae. PMID- 22837523 TI - Excitation of orbital angular momentum resonances in helically twisted photonic crystal fiber. AB - Spiral twisting offers additional opportunities for controlling the loss, dispersion, and polarization state of light in optical fibers with noncircular guiding cores. Here, we report an effect that appears in continuously twisted photonic crystal fiber. Guided by the helical lattice of hollow channels, cladding light is forced to follow a spiral path. This diverts a fraction of the axial momentum flow into the azimuthal direction, leading to the formation of discrete orbital angular momentum states at wavelengths that scale linearly with the twist rate. Core-guided light phase-matches topologically to these leaky states, causing a series of dips in the transmitted spectrum. Twisted photonic crystal fiber has potential applications in, for example, band-rejection filters and dispersion control. PMID- 22837524 TI - Plasmonic nanolaser using epitaxially grown silver film. AB - A nanolaser is a key component for on-chip optical communications and computing systems. Here, we report on the low-threshold, continuous-wave operation of a subdiffraction nanolaser based on surface plasmon amplification by stimulated emission of radiation. The plasmonic nanocavity is formed between an atomically smooth epitaxial silver film and a single optically pumped nanorod consisting of an epitaxial gallium nitride shell and an indium gallium nitride core acting as gain medium. The atomic smoothness of the metallic film is crucial for reducing the modal volume and plasmonic losses. Bimodal lasing with similar pumping thresholds was experimentally observed, and polarization properties of the two modes were used to unambiguously identify them with theoretically predicted modes. The all-epitaxial approach opens a scalable platform for low-loss, active nanoplasmonics. PMID- 22837525 TI - Predictive self-assembly of polyhedra into complex structures. AB - Predicting structure from the attributes of a material's building blocks remains a challenge and central goal for materials science. Isolating the role of building block shape for self-assembly provides insight into the ordering of molecules and the crystallization of colloids, nanoparticles, proteins, and viruses. We investigated 145 convex polyhedra whose assembly arises solely from their anisotropic shape. Our results demonstrate a remarkably high propensity for thermodynamic self-assembly and structural diversity. We show that from simple measures of particle shape and local order in the fluid, the assembly of a given shape into a liquid crystal, plastic crystal, or crystal can be predicted. PMID- 22837526 TI - Isotropic events observed with a borehole array in the Chelungpu fault zone, Taiwan. AB - Shear failure is the dominant mode of earthquake-causing rock failure along faults. High fluid pressure can also potentially induce rock failure by opening cavities and cracks, but an active example of this process has not been directly observed in a fault zone. Using borehole array data collected along the low stress Chelungpu fault zone, Taiwan, we observed several small seismic events (I type events) in a fluid-rich permeable zone directly below the impermeable slip zone of the 1999 moment magnitude 7.6 Chi-Chi earthquake. Modeling of the events suggests an isotropic, nonshear source mechanism likely associated with natural hydraulic fractures. These seismic events may be associated with the formation of veins and other fluid features often observed in rocks surrounding fault zones and may be similar to artificially induced hydraulic fracturing. PMID- 22837527 TI - The structure and catalytic cycle of a sodium-pumping pyrophosphatase. AB - Membrane-integral pyrophosphatases (M-PPases) are crucial for the survival of plants, bacteria, and protozoan parasites. They couple pyrophosphate hydrolysis or synthesis to Na(+) or H(+) pumping. The 2.6-angstrom structure of Thermotoga maritima M-PPase in the resting state reveals a previously unknown solution for ion pumping. The hydrolytic center, 20 angstroms above the membrane, is coupled to the gate formed by the conserved Asp(243), Glu(246), and Lys(707) by an unusual "coupling funnel" of six alpha helices. Comparison with our 4.0-angstrom resolution structure of the product complex suggests that helix 12 slides down upon substrate binding to open the gate by a simple binding-change mechanism. Below the gate, four helices form the exit channel. Superimposing helices 3 to 6, 9 to 12, and 13 to 16 suggests that M-PPases arose through gene triplication. PMID- 22837528 TI - Memory's penumbra: episodic memory decisions induce lingering mnemonic biases. AB - How do we decide if the people we meet and the things we see are familiar or new? If something is new, we need to encode it as a memory distinct from already stored episodes, using a process known as pattern separation. If familiar, it can be used to reactivate a previously stored memory, by a process known as pattern completion. To orchestrate these conflicting processes, current models propose that the episodic memory system uses environmental cues to establish processing biases that favor either pattern separation during encoding or pattern completion during retrieval. To assess this theory, we measured how people's memory formation and decisions are influenced by their recent engagement in episodic encoding and retrieval. We found that the recent encoding of novel objects improved subsequent identification of subtle changes, a task thought to rely on pattern separation. Conversely, recent retrieval of old objects increased the subsequent integration of stored information into new memories, a process thought to rely on pattern completion. These experiments provide behavioral evidence that episodic encoding and retrieval evoke lingering biases that influence subsequent mnemonic processing. PMID- 22837529 TI - Membrane damage and repair in primary monocytes exposed to human beta-defensin-3. AB - Interactions of AMPs with plasma membranes of primary human immune cells are poorly characterized. Analysis of PI exclusion as a measure of membrane integrity indicated that hBD-3 caused membrane perturbations in monocytes but not T or B cells at concentrations typically used to kill bacteria or to induce activation of APCs. Bleb-like structures were observed in monocytes exposed to hBD-3. These cells also increased surface expression of LAMP1, a membrane repair marker after exposure to hBD-3. Furthermore, cell death was enhanced by adding an inhibitor of membrane repair. Removal of cholesterol from membranes resulted in greater susceptibility of cells to hBD-3, but cholesterol content was not different between the cell types, as assessed by filipin staining. Freshly isolated monocytes expressed higher levels of the negatively charged phospholipid, PS, on their outer leaflet compared with B or T cells. Preincubation of monocytes with molecules that bind PS protected these cells from hBD-3-induced membrane damage, suggesting that outer-membrane PS expression can at least partially explain monocyte susceptibility to hBD-3. The potential for membrane disruption caused by AMPs should be evaluated in various cell types when considering these molecules for therapeutic applications in humans. PMID- 22837530 TI - Mast cells play a protumorigenic role in primary cutaneous lymphoma. AB - Primary cutaneous lymphomas (PCLs) are clonal T- or B-cell neoplasms, which originate in the skin. In recent years, mast cells were described as regulators of the tumor microenvironment in different human malignancies. Here, we investigated the role of mast cells in the tumor microenvironment of PCL. We found significantly increased numbers of mast cells in skin biopsies from patients with cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL). Mast cell infiltration was particularly prominent in the periphery, at lymphoma rims. Interestingly, CTCL and CBCL patients with a progressive course showed higher mast cell counts than stable patients, and mast cell numbers in different stages of CTCL correlated positively with disease progression. In addition, mast cell numbers positively correlated with microvessel density. Incubating primary CTCL cells with mast cell supernatant, we observed enhanced proliferation and production of cytokines. In line with our in vitro experiments, in a mouse model of cutaneous lymphoma, tumor growth in mast cell-deficient transgenic mice was significantly decreased. Taken together, these experiments show that mast cells play a protumorigenic role in CTCL and CBCL. Our data provide a rationale for exploiting tumor-associated mast cells as a prognostic marker and therapeutic target in PCL. PMID- 22837531 TI - Tyrosine 201 is required for constitutive activation of JAK2V617F and efficient induction of myeloproliferative disease in mice. AB - The JAK2V617F mutation has been detected in most cases of Ph-negative myeloproliferative neoplasms (MPNs). The JAK2V617F protein is a constitutively activated tyrosine kinase that leads to transformation of hematopoietic progenitors. Previous studies have shown that several tyrosine residues within JAK2 are phosphorylated on growth factor or cytokine stimulation. However, the role of these tyrosine residues in signaling and transformation mediated by JAK2V617F remains unclear. In this study, we sought to determine the role of tyrosine 201, which is a potential binding site for Src homology 2 domain containing proteins, in JAK2V617F-induced hematopoietic transformation by introducing a tyrosine-to-phenylalanine point mutation (Y201F) at this site. We observed that the Y201F mutation significantly inhibited cytokine-independent cell growth and induced apoptosis in Ba/F3-EpoR cells expressing JAK2V617F. The Y201F mutation also resulted in significant inhibition of JAK2V617F-mediated transformation of hematopoietic cells. Biochemical analyzes revealed that the Y201F mutation almost completely inhibited constitutive phosphorylation/activation of JAK2V617F. We also show that the Y201 site of JAK2V617F promotes interaction with Stat5 and Shp2, and constitutive activation of downstream signaling pathways. Furthermore, using a BM transduction/transplantation approach, we found that tyrosine 201 plays an important role in the induction of MPNs mediated by JAK2V617F. PMID- 22837532 TI - Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. AB - For a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1-ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis. PMID- 22837535 TI - In the public interest? AB - Restrictive patenting and licensing for cell-free fetal DNA testing has serious consequences for technology advances and benefits to public health. PMID- 22837533 TI - How I treat plasma cell leukemia. AB - Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell proliferative disorder with a very poor prognosis and with distinct biologic, clinical, and laboratory features. Compared with multiple myeloma, pPCL presents more often with extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, elevated serum beta(2)-microglobulin and lactate dehydrogenase levels, as well as impaired renal function. Many of the genetic aberrations observed in newly diagnosed pPCL are typically found in advanced multiple myeloma. These cytogenetic abnormalities and mutations lead to increased proliferation, enhanced inhibition of apoptosis, escape from immune surveillance, and independence from the BM microenvironment, with changes in expression of adhesion molecules or chemokine receptors. The outcome of pPCL has improved with the introduction of autologous stem cell transplantation and combination approaches with novel agents, including bortezomib and immunomodulatory drugs, such as lenalidomide. In this review, we provide an overview of currently available therapeutic options with recommendations of how these treatment modalities can best be used to improve outcome for plasma cell leukemia patients. PMID- 22837534 TI - Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression. AB - The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on 2 other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points before therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL. PMID- 22837536 TI - MHC-resident variation affects risks after unrelated donor hematopoietic cell transplantation. AB - Blood malignancies can be cured with hematopoietic cell transplantation from human leukocyte antigen (HLA)-matched unrelated donors; however, acute graft versus-host disease (GVHD) affects up to 80% of patients and contributes to increased mortality. To test the hypothesis that undetected patient-donor differences for non-HLA genetic variation within the major histocompatibility complex (MHC) could confer risks after HLA-matched transplantation, we conducted a discovery-validation study of 4205 transplants for 1120 MHC region single nucleotide polymorphisms (SNPs). Two SNPs were identified as markers for disease free survival and acute GVHD. Among patients with two or more HLA-matched unrelated donors identified on their search, SNP genotyping of patients and their potential donors demonstrated that most patients have a choice of SNP-matched donors. In conclusion, the success of HLA-matched unrelated donor hematopoietic cell transplantation depends on non-HLA MHC region genetic variation. Prospective SNP screening and matching provides an approach for lowering risks to patients. PMID- 22837537 TI - Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation. AB - Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation. PMID- 22837539 TI - The NEO Personality Inventory-Revised: factor structure and gender invariance from exploratory structural equation modeling analyses in a high-stakes setting. AB - This study presents new analyses of NEO Personality Inventory-Revised (NEO-PI-R) responses collected from a large British sample in a high-stakes setting. The authors show the appropriateness of the five-factor model underpinning these responses in a variety of new ways. Using the recently developed exploratory structural equation modeling (ESEM) technique, the authors show that model fits improve markedly over conventional confirmatory factor analyses (CFA) of the same data set, but that (a) factor interpretations do not change under ESEM analyses, (b) ESEM factor scores, just like CFA factors scores, correlate at near unity with sums of observed scores, (c) NEO-PI-R facets under ESEM analyses are invariant across gender, and (d) ESEM highlights the inappropriateness of alpha and beta as a higher order representation of NEO-PI-R facets, whereas a CFA approach might lead researchers to believe in the appropriateness of these higher order factors. These results, coupled with the existing validity evidence for the NEO-PI-R, suggest that the five-factor structure is the most parsimonious structure for summarizing NEO-PI-R responses from high-stakes settings in the United Kingdom. PMID- 22837538 TI - Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. AB - Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. PMID- 22837540 TI - Stable cystatin C serum levels confirm normal renal function in patients with dronedarone-associated increase in serum creatinine. AB - Dronedarone is a new antiarrhythmic drug for patients with nonpermanent atrial fibrillation (AF). A relatively consistent finding in all trials studying dronedarone was a moderate but significant elevation of serum creatinine. Since dronedarone competes for the same organic cation transporter in the distal renal tubule with creatinine, serum creatinine and its derived estimated glomerular filtration rate might not reflect true renal function in patients on dronedarone. We therefore investigated alternative markers for renal function in these patients. We prospectively included 20 patients with nonpermanent AF in whom dronedarone 400 mg twice daily was started. Patients had normal renal function and serum creatinine; serum cystatin C and creatinine clearance were measured before treatment and 10 and 90 days after treatment started. Mean serum creatinine level for all 20 patients at baseline (day 0) was 84.55 +/- 12.14 and 87.8 +/- 17.59 umol/L on day 10. This slight increase in all patients was not significant. Patients were now divided into the predefined groups of "increased creatinine" (increase in serum creatinine level > 1 standard deviation) and "not increased creatinine." Patients with increased creatinine levels (n = 5) showed a significant elevation of serum creatinine levels from day 0 to day 10 (82.4 +/- 9.18 to 104.4 +/- 12.74 umol/L; P = .003), whereas change in serum creatinine levels in the not increased creatinine group (n = 15) was not significant. Serum cystatin C levels remained stable in both of these groups (increased creatinine group: 0.76 +/- 0.08 to 0.78 +/- 0.08 mg/L; P = .65; not increased creatinine group: 0.77 +/- 0.108 to 0.77 +/- 0.107 mg/L; P = .906). In conclusion, cystatin C represents an easily available and reliable biomarker for estimation of true renal function in patients on dronedarone treatment. PMID- 22837541 TI - Improving balance control and self-reported lower extremity function in community dwelling older adults: a randomized control trial. AB - OBJECTIVES: To evaluate the effect of a group-based functional and specific balance training programme that included dual-task exercises on balance function in healthy older adults. DESIGN: A single-blind randomized controlled trial. SETTING: General community. PARTICIPANTS: Sixty-six community-dwelling older adults (age 77.0 +/- 6.5 years), without functional balance impairment were recruited and allocated at random to an intervention group (n = 33) or a reference group (n = 33). INTERVENTION: The intervention group received 24 training sessions over three months that included perturbation as well as dual task exercises. The reference group received no intervention. OUTCOME MEASURES: The voluntary step execution times during single- and dual-task conditions, stabilogram-diffusion analysis in upright standing, and self-reported physical function; all were measured assessed at baseline and at the end of intervention. The intervention group was retested after six months. RESULTS: Compared with the reference group, participation in group-based functional and specific balance training led to faster voluntary step execution times under single-task (P = 0.02; effect size (ES) = 0.34) and dual-task (P = 0.036; ES = 0.55) conditions; lower transition displacement and shorter transition time of the stabilogram diffusion analysis under eyes-closed conditions (P = 0.007, ES = 0.30 and P = 0.08, ES = 0.44, respectively); and improved self-reported lower extremity function (P = 0.006, ES = 0.37). Effects were lost at six-month follow-up. CONCLUSIONS: Functional and specific balance training can improve voluntary stepping and balance control in healthy older non-fallers, parameters previously found to be related to increased risk of falls and injury in older adults. PMID- 22837542 TI - Trial participants' experiences of early enhanced speech and language therapy after stroke compared with employed visitor support: a qualitative study nested within a randomized controlled trial. AB - OBJECTIVES: To explore trial participants' experiences of the process and outcomes of early, enhanced speech and language therapy after stroke with support from an employed visitor. DESIGN: Qualitative study nested within a randomized controlled trial. PARTICIPANTS: Twney-two people who, after stroke, had a diagnosis of aphasia (12), dysarthria (5) or both (5) and who participated in the ACT NoW study. SETTING: Eight English NHS usual care settings. METHOD: Individual interviews. Thematic content analysis assisted by a bespoke data transformation protocol for incorporating non-verbal and semantically ambiguous data. RESULTS: Participants highly regarded regular and sustained contact with someone outside of immediate family/friends who engaged them in deliberate activities/communication in the early months after stroke. Participants identified differences in the process of intervention between speech and language therapists and employed visitors. But no major discriminations were made between the impact or value of this contact according to whether provided by a speech and language therapist or employed visitor. Participant-defined criteria for effectiveness of contact included: impact on mood and confidence, self recognition of progress and the meeting of individual needs. CONCLUSIONS: As in the randomized controlled trial, participants reported no evidence of added benefit of early communication therapy beyond that from attention control. The findings do not imply that regular contact with any non-professional can have beneficial effects for someone with aphasia or dysarthria in the early weeks following a stroke. The study points to specific conditions that would have to be met for contact to have a positive effect. PMID- 22837543 TI - Comparison of the effects of Buteyko and pranayama breathing techniques on quality of life in patients with asthma - a randomized controlled trial. AB - OBJECTIVE: To compare two breathing exercises (Buteyko and pranayama) with a control group in patients with asthma. DESIGN: Randomized controlled trial. SUBJECTS: One hundred and twenty subjects were randomized to three groups through block randomization. Subjects with an Asthma Quality of Life Questionnaire score <5.5 participated in the study. SETTING: Outpatient pulmonary medicine department. INTERVENTIONS: Subjects in the Buteyko and pranayama groups were trained for 3-5 days and instructed to practise the exercises for 15 minutes twice daily, and for three months duration. The control group underwent routine pharmacological management during the study period. OUTCOME MEASURES: Asthma Quality of Life Questionnaire, Asthma Control Questionnaire and pulmonary function test. RESULTS: The baseline characteristics were similar in all three groups. Post intervention, the Buteyko group showed better trends of improvement (mean (95% confidence interval), P-value) in total Asthma Quality of Life Questionnaire score than the pranayama (0.47 (-0.008-0.95), P = 0.056) and control groups (0.97 (0.48-1.46), P = 0.0001). In comparison between the pranayama and control groups, pranayama showed significant improvement (0.50 (0.01-0.98), P = 0.042) in total Asthma Quality of Life Questionnaire score. CONCLUSION: The Buteyko group showed better trends of improvement in quality of life and asthma control than the group performing the pranayama breathing exercise. PMID- 22837544 TI - Validity of the Sitting Balance Scale in older adults who are non-ambulatory or have limited functional mobility. AB - OBJECTIVE: To determine whether the Sitting Balance Scale is an acceptable alternative to the Trunk Impairment Scale for measuring the construct of sitting balance, to examine relationships with other clinical outcomes and to establish discriminative validity. DESIGN: Prospective descriptive methodological study. SETTING: Acute care, inpatient rehabilitation, skilled nursing facility and home health. PARTICIPANTS: Patients receiving physical therapy (N = 98; n = 20 acute care, n = 18 inpatient rehabilitation, n = 30 skilled nursing facility, n = 30 home setting) mean (SD) age, 80.5 (7.9) years. Nineteen were non-ambulatory and 79 had limited functional mobility with Timed Up and Go scores >=20 seconds. MAIN MEASURES: Sitting Balance Scale, Trunk Impairment Scale, Timed Up and Go, length of stay and setting specific clinical measures of sitting balance (OASIS-C M1850; MDS G-3b). RESULTS: Moderate association between ambulatory status and sitting balance measures (Sitting Balance Scale r = 0.67, Trunk Impairment Scale r = 0.61; P = 0.0001). Moderate to strong relationships between Sitting Balance Scale, Trunk Impairment Scale and clinical outcomes varying by setting. MANOVA results revealed differences between ambulators and non-ambulators and among diagnostic categories for both instruments (P < 0.001). CONCLUSIONS: The Sitting Balance Scale is comparable to the Trunk Impairment Scale for measuring sitting balance in older adults who are non-ambulatory or have limited mobility. PMID- 22837545 TI - Effectiveness of aerobic physical training for treatment of chronic asymptomatic bacteriuria in subjects with spinal cord injury: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness and safety of aerobic physical training for treatment of chronic asymptomatic bacteriuria in subjects with spinal cord injury. DESIGN: Randomized controlled trial. SETTING: University hospital. SUBJECTS: Forty-two participants with spinal cord injury between C8 and T12 segments were randomly assigned to intervention or control groups. INTERVENTION: In the intervention group, subjects received a risk evaluation, stress test and urinary culture before the start of the study and after 16 weeks. The study consisted of aerobic physical conditioning with moderate intensity for the intervention group while the control group was asked to maintain their daily life activities. MAIN MEASURES: Increase of estimated peak oxygen consumption and also if there was a decrease in the proportions of positive urinary culture. RESULTS: The intervention group showed an increase of estimated peak oxygen consumption of between 939 (714-1215) and 1154 (1005-1351) mL/min (P = 0.009) and a reduction of chronic asymptomatic bacteria of between 52.3% (29.8-74.3%) and 14.2% (3-36.3%) (P < 0.001). No adverse effects related to physical activity were recorded during the period of training. CONCLUSION: The regular practice of physical activity of moderate intensity applied to patients with spinal cord injury may be an effective and safe method for the treatment of chronic asymptomatic bacteriuria. PMID- 22837546 TI - Low-level environmental exposure to lead and renal adverse effects: a cross sectional study in the population of children bordering the Mbeubeuss landfill near Dakar, Senegal. AB - This study deals with the health effects within a child population, neighbouring a landfill. After detecting metals in soil and air samples collected in the surroundings of the landfill and in a control site, we have studied: (i) levels of lead (Pb) and exposure biomarkers in blood and urine, (ii) oxidative stress biomarkers and (iii) renal injury by applying a set of early effect biomarkers. Levels of Pb were higher in the exposed site (i.e. 1129 mg/kg and 640 ng/m(3) in soil and air samples, respectively) versus those in the control site (i.e. 14.3 mg/kg and 9.3 ng/m(3) in soil and air samples, respectively). Pb impregnation and levels of delta-aminolevulinic acid in urine were influenced by the living site that shows the prevailingly alarming situation in the Mbeubeuss landfill. Malondialdehyde changes indicated Pb-induced excessive production of reactive oxygen species. Lactate dehydrogenase activities and proteinuria were found to be higher in the children living in the exposed site. These evidences may reveal the usefulness of these two effect biomarkers to monitor the kidney injury entailed by relatively low-environmental exposure to Pb. Overall, these results show that the Mbeubeuss landfill constitutes a real source of environmental and health risk, be it living or working on site, of the surrounding population, predominantly for children. PMID- 22837548 TI - Association between story recall and other language abilities in schoolchildren with ADHD. AB - OBJECTIVE: The present study aimed to investigate the effect of working memory, vocabulary, and grammar on narrative comprehension in children with ADHD. METHOD: Participants were 25 schoolchildren with ADHD and 25 typically developing (TD) children matched for chronological age and performance IQ. Children were assessed with the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), a verbal IQ test, and a story recall task. RESULTS: It was shown that children with ADHD recall less information from the stories than did TD children, while they are less sensitive to the importance of the information they recall. Moreover, it was found that children with ADHD experience problems in answering factual questions. Further analysis revealed that deficiencies in narrative comprehension may be accounted for by problems in working memory. CONCLUSION: The discussion focuses on the role of working memory in narrative comprehension and the implications of these findings for intervention approaches. PMID- 22837547 TI - A brief motivational intervention for heavy alcohol use in dental practice settings: rationale and development. AB - Although brief alcohol interventions have proven effective in a variety of health care settings, the present article describes the development of the first brief intervention for heavy drinkers in dental practice. Elements of motivational interviewing and personalized normative feedback were incorporated in a 3- to 5 minute intervention delivered by dental hygienists. The intervention is guided by a one-page feedback report providing personalized normative feedback regarding the patient's current oral health practices, their drinking in comparison to others, and oral cancer risk associated with current smoking and drinking. Future publications will present data regarding intervention effectiveness from an ongoing randomized trial. PMID- 22837549 TI - Do ADHD children with and without child behavior checklist-dysregulation profile have different clinical characteristics, cognitive features, and treatment outcomes? AB - OBJECTIVE: The Child Behavior Checklist-Dysregulation Profile (CBCL-DP), characterized by elevated scores on the "Attention Problems," "Aggressive Behavior," and "Anxious/Depressed" scales in the CBCL, has been associated with later severe psychopathology. In a sample of children with ADHD, this study sought to further explore the clinical characteristics, the response to methylphenidate medication, and the cognitive features of ADHD children with CBCL DP. METHOD: The sample consisted of 173 ADHD outpatients (age = 10.9 +/- 2.81) assessed using symptom severity scales, personality questionnaires (Emotionality Activity Sociability [EAS] and Junior Temperament and Character Inventory [JTCI]), and neuropsychological tests. A subsample of 136 participants was reassessed after optimal adjustment of methylphenidate dosage. RESULTS AND CONCLUSION: Variables that were independently associated with CBCL-DP were clinical severity (ADHD Rating Scale [ADHD-RS]), internalized disorders, high emotionality (EAS), and low self-directedness (JTCI). CBCL-DP was associated neither with poorer response to methylphenidate nor with more side effects. There were no differences in cognitive performances between participants with and without CBCL-DP. PMID- 22837550 TI - Do symptoms of ADHD at ages 7 and 10 predict academic outcome at age 16 in the general population? AB - OBJECTIVE: To examine the value of the Conners 10-item scale to predict academic outcomes at age 16 years in schoolchildren aged 7 and 10 years. METHOD: A cohort study of N = 544 children in a municipality of Stockholm County was conducted. Using the parent and teacher version of the Conners 10-item scale, 7- and 10-year olds were screened for ADHD symptoms and followed-up for school outcome at age 16 years. RESULTS: The best predictors for school outcome at age 16 years were the Conners items, "child failing to finish tasks" and "being inattentive, easily distracted," with a high specificity (90%-97%) but low sensitivity (18%-39%). CONCLUSION: This study indicates a considerable association between certain symptoms of inattentiveness in young schoolchildren and academic underachievement at age 16 years. Screening for one to two symptoms of inattention in schoolchildren identifies 30% to 40% of participants at risk for later poor school attainment. PMID- 22837551 TI - Socio-economic inequalities and oral health in Canada and the United States. AB - This paper describes and compares the magnitude of socio-economic inequalities in oral health among adults in Canada and the US over the past 35 years. We analyzed data from nationally representative examination surveys in Canada and the US: Nutrition Canada National Survey (1970-1972, N = 11,546), Canadian Health Measures Survey (2007-2009, N = 3,508), The First National Health and Nutrition Examination Survey (1971-1974, N = 13,131), and National Health and Nutrition Examination Survey (2007-2008, N = 5,707). Oral health outcomes examined were prevalence of edentulism, proportion of individuals having at least 1 untreated decayed tooth, and proportion of individuals having at least 1 filled tooth. Sociodemographic indicators included in our analysis were place of birth, education, and income. Data were age-adjusted, and survey weights were used to account for the complex survey design in making population inferences. Our findings demonstrate that oral health outcomes have improved for adults in both countries. In the 1970s, Canada had a higher prevalence of edentulism and dental decay and lower prevalence of filled teeth. This was also combined with a more pronounced social inequality gradient among place of birth, education, and income groups. Over time, both countries demonstrated a decline in absolute socio economic inequalities in oral health. PMID- 22837554 TI - Nerve tumour as a rare cause of anterior interosseous nerve palsy. PMID- 22837552 TI - White-spot lesions and gingivitis microbiotas in orthodontic patients. AB - White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL. PMID- 22837555 TI - Intergroup conflict: Ecological predictors of winning and consequences of defeat in a wild primate population. AB - In many social species, competition between groups is a major factor proximately affecting group-level movement patterns and space use and ultimately shaping the evolution of group living and complex sociality. Here we evaluated the factors influencing group-level dominance among 5 social groups of wild baboons (Papio cynocephalus), in particular focusing on the spatial determinants of dominance and the consequences of defeat. When direct conflict occurred between conspecific baboon groups, the winning group was predicted by differences in the number of adult males in each group and/or groups that had used the areas surrounding the encounter location more intensively than their opponent in the preceding 9 or 12 months. Relative intensity of space use over shorter timescales examined (3 and 6 months) was a poor predictor of the interaction's outcome. Losing groups but not winning groups experienced clear short-term costs. Losing groups used the area surrounding the interaction less following an agonistic encounter (relative to their intensity of use of the area prior to the interaction). These findings offer insight into the influences and consequences of intergroup competition on group-level patterns of space use. PMID- 22837557 TI - Cutaneous manifestations of internal malignancy. AB - BACKGROUND: Many malignancies affecting the internal organs display cutaneous manifestations which may be either specific (tumor metastases) or nonspecific lesions. AIMS: The study is aimed at determining the frequency and significance of cutaneous manifestations among patients with internal malignancy. MATERIALS AND METHODS: 750 cases of proven internal malignancy, who attended a cancer chemotherapy center in South India, were studied. Specific infiltrates were confirmed by histopathology, fine needle aspiration cytology (FNAC) and marker studies. RESULTS: Out of the 750 patients with internal malignancy, skin changes were seen in a total of 52 (6.93%) patients. CONCLUSION: Cutaneous metastases (specific lesions) were seen in 20 patients (2.66%): contiguous in 6 (0.8%), and non-contiguous in 14 (1.86%). Nonspecific skin changes were seen in 32 patients (4.26%). None of our patients presented with more than one type of skin lesions. Herpes zoster was the most common nonspecific lesion noticed in our patients, followed by generalized pruritus, multiple eruptive seborrheic keratoses, bullous disorder, erythroderma, flushing, purpura, pyoderma gangrenosum, insect bite allergy and lichenoid dermatitis. PMID- 22837556 TI - Rational and ethical use of topical corticosteroids based on safety and efficacy. AB - Topical corticosteroids (TC) have greatly contributed to the dermatologist's ability to effectively treat several difficult dermatoses. The available range of formulations and potency gives flexibility to treat all groups of patients, different phases of disease, and different anatomic sites. However, the rapid rise in incidence of improper use of these drugs by dermatologists, general physicians, and patients threatens to bring disrepute to the entire group of these amazing drugs. Responsibility to disseminate proper knowledge regarding when, where, and how to use TC both to internists and patients rests primarily with the dermatologist. Benefits of rational and ethical use and the harm of overuse and misuse for nonmedical, specially for cosmetic purposes, should be clearly conveyed before penning a prescription involving TC. Simultaneous efforts to use political, legal, and other institutions to prevent misuse of these drugs by rationing their availability only through proper prescriptions will greatly help the cause. This will hopefully bring down both the extremes of ever increasing cases of steroid-induced dermatoses on one hand and the irrational fears of using TC in well justified indications on the other. PMID- 22837558 TI - Netherton syndrome in one Chinese adult with a novel mutation in the SPINK5 gene and immunohistochemical studies of LEKTI. AB - BACKGROUND: Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis, and frequent bacterial infections. The disease is caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, a new type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. We report one Chinese adult with NS. The patient had typical manifestation of NS except for trichorrhexis invaginata with an atopic diathesis and recurrent staphylococcal infections since birth. AIMS: To evaluate the gene mutation and of its product activity of SPINK5 gene in confirmation of the diagnosis of one Chinese adult with NS. MATERIALS AND METHODS: To screen mutations in the SPINK5 gene, 33 exons and flanking intron boundaries of SPINK5 were amplified with polymerase chain reaction (PCR) and used for direct sequencing. In addition, immunohistochemical staining of LEKTI (lymphoepithelial Kazal-type-related inhibitor) with specific antibody was used to confirm the diagnosis of NS. The results were compared with that of healthy individuals (twenty-five blood samples). RESULTS: A G318A mutation was found at exon 5 of patient's SPINK5 gene which is a novel missense mutation. The PCR amplification products with mutation-specific primer were obtained only from the DNA of the patients and their mother, but not from their father and 25 healthy individuals. Immunohistochemical studies indicated there was no LEKTI expression in NS patient's skin and there was a strong LEKTI expression in the normal human skin. CONCLUSION: In this report, we describe heterozygous mutation in the SPINK5 gene and expression of LEKTI in one Chinese with NS. The results indicate that defective expression of LEKTI in the epidermis and mutations of SPINK5 gene are reliable for diagnostic feature of NS with atypical clinical symptoms. PMID- 22837559 TI - A clinico-epidemiological study of macular amyloidosis from north India. AB - BACKGROUND: Macular amyloidosis (MA) is the most subtle form of cutaneous amyloidosis, characterized by brownish macules in a rippled pattern, distributed predominantly over the trunk and extremities. MA has a high incidence in Asia, Middle East, and South America. Its etiology has yet to be fully elucidated though various risk factors such as sex, race, genetic predisposition, exposure to sunlight, atopy and friction and even auto-immunity have been implicated. AIM: This study attempts to evaluate the epidemiology and risk factors in the etiology of MA. MATERIALS AND METHODS: Clinical history and risk factors of 50 patients with a clinical diagnosis of MA were evaluated. Skin biopsies of 26 randomly selected patients were studied for the deposition of amyloid. RESULTS: We observed a characteristic female preponderance (88%) with a female to male ratio of 7.3:1, with a mean age of onset of MA being earlier in females. Upper back was involved in 80% of patients and sun-exposed sites were involved in 64% cases. Incidence of MA was high in patients with skin phototype III. Role of friction was inconclusive CONCLUSION: Lack of clear-cut etiological factors makes it difficult to suggest a reasonable therapeutic modality. Histopathology is not specific and amyloid deposits can be demonstrated only in a small number of patients. For want of the requisite information on the natural course and definitive etiology, the disease MA remains an enigma and a source of concern for the suffering patients. PMID- 22837560 TI - Pattern of pediatric dermatoses in a tertiary care centre of South West Rajasthan. AB - BACKGROUND: The evaluation for skin disorders forms an important component of primary health care practice for all including children. The prevalence of certain skin diseases in children can reflect status of health, hygiene, and personal cleanliness of a community. AIMS: This study was planned to evaluate the magnitude of skin diseases, pattern of various dermatoses, factors contributing to these dermatoses and concurrent systemic disease among children up to five years of age. MATERIALS AND METHODS: Consecutive 1000 children, aged up to five years, attending the Dermatology OPD of RNT Medical College and MB Government Hospital, Udaipur were the subjects of this study. A detailed general, systemic and cutaneous examination followed by relevant investigations were carried out. The findings were recorded in a proforma for analysis and interpretation of data. RESULTS: One thousand twenty seven (1027) diagnoses were made in 1000 children. Etiological analysis revealed that majority (417; 40.60%) of dermatoses belonged to infection and infestation group followed by eczematous (358; 34.86%) and hypersensitivity (105; 10.22%) groups. Of the infection and infestation group, bacterial infection (141; 13.72%) was the most common entity followed by scabies (107; 10.42%), fungal (67; 6.52%), and viral infection (35; 3.40%). CONCLUSION: This study provides a preliminary baseline data for future clinical research. It might also help to assess the changing trends of pediatric dermatoses. PMID- 22837561 TI - Efficacy of 2% metronidazole gel in moderate acne vulgaris. AB - BACKGROUND: Acne vulgaris is an inflammatory disease of the pilosebaceous units. Various systemic and topical options are available for its treatment. AIMS: This study aimed to evaluate the efficacy of 2% metronidazole gel in acne vulgaris. MATERIALS AND METHODS: Double-blind, randomized, placebo-controlled, split-face clinical trial. Seventy young adults with moderate acne vulgaris received 2% metronidazole gel on the right side of their face and placebo on the left side of their face twice daily for 8 weeks. The number of inflamed and noninflamed facial lesions and side effects of treatment were documented on weeks 1, 2, 4, and 8. The patients' overall satisfaction was recorded at the end of the study. For statistical analysis we used the repeated-measures analysis, the chi-square test, Fisher's exact test, and the independent-samples t-test as appropriate. RESULTS: Counts of inflamed and noninflamed facial lesions were comparable between the two sides at baseline. The number of the lesions was significantly lower on the metronidazole-treated side at all follow-up visits. Erythema and oily face decreased by 85.7% and 87.1%, respectively, on the metronidazole-treated side. Mild burning sensation and dryness on the metronidazole-treated side was reported by 3.4% and 22.9% of the patients, respectively. Eighty-eight percent of the patients were satisfied with the results of treatment on the metronidazole treated side. CONCLUSIONS: Metronidazole gel (2%) is an effective, safe, and well tolerated topical medication for moderate acne vulgaris. PMID- 22837562 TI - Efficacy of suction blister epidermal graft without phototherapy for locally stable and resistant vitiligo. AB - INTRODUCTION: Surgical methods for treatment of vitiligo include punch grafts, blister grafts, follicular grafts and cultured melanocyte grafts. The aim of this study was to determine the efficacy of suction blister grafts for treatment of vitiligo, without the use of phototherapy. MATERIALS AND METHODS: This clinical trial study was conducted on 10 patients with vitiligo that was resistant to usual treatments and with limited involvement in the affected sites. We used cryotherapy and a manual suction device for blistering at the recipient and donor sites, respectively. The blister was separated and fixed with sutures and a dressing to the recipient site. Repigmentation of lesions was evaluated monthly for 6 months after treatment. Repigmentation rates higher than 90%, between 71% 90%, from 51%-70%, and less than 50% were graded as complete, good, moderate, and poor, respectively. RESULTS: Ten patients (five females with a mean age of 23.2+/ 3.96 years and five males with a mean age of 30.60+/-4.15 years) were enrolled in the study. Reponses to treatment after a 6-month follow-up were 'complete,' 'good,' and 'moderate' in 7 (70%), 1 (10%), and 2 (20%) patients, respectively. CONCLUSION: With this technique, patients with restricted sites of involvement, that did not respond to the usual treatments showed very good repigmentation without any additional phototherapy over a 6-month follow-up; moreover, there were no side effects such as scarring. PMID- 22837563 TI - Chronic bullous disease of childhood with IgG predominance: what is the locus standi? AB - Linear IgA disease (LAD) is an acquired, autoimmune, subepidermal, blistering disease, characterized by linear deposition of IgA along the dermoepidermal junction on immunofluorescence. Some cases known as 'mixed immunobullous disease' show weak staining with other immune reactants like IgG, IgM or C3. We report a rare case of a child having typical manifestations of LAD (chronic bullous disease of childhood), but with IgG predominance rather than IgA. Obviously it is improper to term this as linear IgA disease. Such cases are reported in literature as variants of LAD, with a multitude of terms like mixed immune bullous disease, linear IgG / IgA disease, linear IgA / IgG disease, and so on. In view of the tremendous confusion that these multiple terms cause in the absence of any practical benefit, we propose that the broad term 'chronic bullous disease of childhood' be applied to all childhood cases, irrespective of the nature of the immune deposits. PMID- 22837564 TI - Tinea capitis in the form of concentric rings in an HIV positive adult on antiretroviral treatment. AB - Dermatophyte infection may present in the form of concentric rings caused by Trichophyton concentricum, known as Tinea Imbricata. In immunosuppressed patients, there are reports of lesions in the form of concentric rings caused by dermatophytes other than Trichophyton concentricum too, mostly by Trichophyton tonsurans, known as Tinea indesiciva or Tinea pseudoimbricata. We report a case of tinea capitis in a HIV-positive adult woman on antiretroviral therapy, who presented with concentric rings of papules and pustules with slight scaling on the scalp along with diffuse thinning of hair. Both Potassium hydroxide mount and culture showed the presence of Dermatophytes. Tinea capitis is considered rare in adults, but new cases are being reported in immunocompromised as well as in immunocompetent patients. The pertinent features of this case are: HIV-positive adult female on antiretroviral therapy, presenting with tinea capitis in the form of concentric rings; culture from the lesion grew Microsporum audouinii; responding to oral Terbinafine. PMID- 22837565 TI - In-transit metastases from squamous cell carcinoma penis. AB - An in-transit metastasis is one that is located between the primary tumor and the closest lymph node region and results from tumor emboli getting trapped in the lymphatic channels. A 65-year-old male patient who had undergone partial amputation of the penis and bilateral inguinal lymph node resection for squamous cell carcinoma of the penis 4 months earlier developed multiple cutaneous metastatic lesions in the pubic region and scrotum. The case is reported for the uncommon presentation of in-transit metastases. PMID- 22837566 TI - Retraction notice. PMID- 22837567 TI - Congenital calcinosis cutis of the foot. AB - Calcinosis cutis is a rare disease characterized by deposition of insoluble calcium salts in the skin. Subepidermal calcified nodule is a form of idiopathic calcinosis cutis that commonly affects children but rarely presents at birth. Herein we describe a healthy 10-month-old boy who had a solitary hard nodule on the left foot since birth. Surgical excision of the nodule was done and histopathology confirmed the diagnosis of subepidermal calcified nodule. PMID- 22837568 TI - Syphilis d' emblee. AB - A 28-year-old male patient presented to Skin, V.D. and Leprosy outpatient with a single gray white plaque on the left side of the lower lip for last 8 months and multiple papulosquamous lesions all over the body for last 6 months. There was history of blood transfusion for anemia 1 year back. Histopathology of lip lesion and reactive VDRL and TPHA tests confirmed the diagnosis as syphilis. We report this rare case of Syphilis d' emblee. PMID- 22837569 TI - Cardiofaciocutaneous syndrome: a rare entity. AB - The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation and characteristic dysmorphic features. We, thus, report a rare case of this syndrome in a 1-year-old child who presented with typical features of CFC syndrome. PMID- 22837570 TI - Multicentric reticulohistiocytosis: a rare case report. AB - A 58-year-old lady presented with polyarthritis followed by multiple shiny erythematous dome-shaped papulonodules mainly over the face, around joints and coral bead sign on fingers without any mucosal involvement. Characteristic histopathology with well-defined dermal infiltrate consisting of multinucleated giant cells and large macrophages having abundant eosinophilic cytoplasm clinched the diagnosis of multicentric reticulohistiocytosis. PMID- 22837571 TI - Not just skin deep: a case report of multiple endocrine neoplasia type 1. AB - Multiple endrocrine neoplasia (MEN) type 1 is characterized by mainly a triad of pancreatic, pituitary and parathyroid involvement. This is a case report of a 41 year-old male in whom recognition of collagenoma and gingival papule led to the identification of MEN type 1. Often the recognition of such dermatological manifestations help in the presymptomatic diagnosis of complex syndromes. PMID- 22837572 TI - Fusarium Solani: a causative agent of skin and nail infections. AB - Fusarium spp are non-dermatophytic hyaline moulds found as saprophytes and plant pathogens. Human infections are probably a result of various precipitating predisposing factors of impaired immune status. Immunocompetent individuals of late are also vulnerable to various unassuming saprophytic and plant pathogens. To stress the need to identify correctly and institute appropriate antifungal therapy in newly emerging human fungal infectious agents. Repeated mycological sampling of the skin and nails of the suspected fungal infection were processed as per the standard format including direct microscopy and fungal culture on Sabouraud's dextrose agar. The fungus was isolated as Fusarium solani. Fusarium is an important plant pathogen and soil saprophyte. Infection is acquired by direct inoculation or inhalation of spores. It is associated with a variety of diseases like keratitis, onychomycosis, eumycetoma, skin lesions and disseminated diseases. PMID- 22837573 TI - Giant seborrheic keratosis of the genitalia. AB - Genital seborrheic keratosis (SK) is a rare entity, which can be easily misdiagnosed as genital warts. Dermoscopy is a useful tool to make diagnosis of SK in such cases. We report a 50-year-old woman with a large polypoidal growth on the external genitalia. Dermoscopic examination showed fissures and ridges, cerebriform appearance, and comedo-like openings consistent with SK. The histopathology confirmed the diagnosis of SK. PMID- 22837574 TI - Eccrine angiomatous naevus revisited. AB - Hamartomatous, circumscribed swellings of the extremities make an interesting study. Presentations are manifold and the naevi are not always present from birth. Excessive growth of hairs leads to remarkable appearance of such swellings. A young woman presented to the dermatology department, complaining of tenderness over 4(th) finger of her left hand. The defect was present for the last couple of years and was typified by visible hyperhidrosis on gentle tapping. Counseling of the affected lady made her agree for a skin biopsy. The histopathology revealed it to be of the nature of eccrine angiomatous hamartoma. Blood vessels were scarce. Eccrine ducts were plentiful without other associated anomalies. The deformity was removed by simple excision with good result. PMID- 22837575 TI - High risk factors for severe hand, foot and mouth disease: a multicenter retrospective survey in Anhui Province China, 2008-2009. AB - OBJECTIVES: This study sought to determine the high risk factors for severe hand, foot, and mouth disease (HFMD). MATERIALS AND METHODS: Retrospective 229 severe HFMD cases from four hospitals in FuYang, HeFei, and BoZhou (Anhui Provincial Hospital, Fuyang City People's Hospital, No. 2 People's Hospital of Fuyang and Bozhou city People's Hospital) in 2008-2009 were studied, with 140 mild HFMD cases in the same area. Using univariate and multivariate logistic regression analyses, the high risk factors of HFMD were identified by comparing clinical and laboratory findings between severe cases and mild cases. RESULTS: There was a significant difference in age, total duration of fever, rate of respiratory and heart, shake of limbs, white blood cell count, blood sugar, and CK-MB between the two groups. Univariate logistic regression analysis showed that severe cases were associated with age (<3 years), withdrawnness and lethargy, shake of limbs, tachycardia, total leukocyte count (>=17*109/l), blood sugar (>=7 mmol/l), and CK MB (>=16 mmol/l). Furthermore, age (<3 years), withdrawnness, and lethargy, shake of limbs, WBC (>=17*109/l), and CK-MB (>=16 mmol/l) were found to be high risk factors for severe cases after multivariate logistic regression analysis. CONCLUSIONS: Clinicians should give importance to these risk factors. Early recognition of children at risk and timely intervention is the key to reduce acute mortality and morbidity. PMID- 22837576 TI - Clinicomycological study of 150 cases of dermatophytosis in a tertiary care hospital in South India. PMID- 22837577 TI - Dramatic response to oral zinc in a case of subacute form of generalized pustular psoriasis. PMID- 22837578 TI - Mometasone menace in melasma. PMID- 22837579 TI - Extensive discoid lupus erythematosus in a HIV patient responding to hydroxychloroquine monotherapy. PMID- 22837580 TI - Zosteriform fixed drug eruption to levofloxacin. PMID- 22837581 TI - Twenty nail dystrophy in association with zosteriform lichen planus. PMID- 22837582 TI - Granular cell tumor of skin diagnosed on fine needle aspiration cytology. PMID- 22837583 TI - Clinicopathological evaluation of non-melanoma skin cancer. PMID- 22837584 TI - Modulation of Ligand Fluorescence by the Pt(II)/Pt(IV) Redox Couple. AB - The dangling carboxylic acid moiety of the known platinum(II) complex, [Pt(edma)Cl(2)] (edma = ethylenediaminemonoacetic acid), was functionalized via amide coupling chemistry with benzyl amine and dansyl ethylenediamine to afford the derivatives [Pt(edBz)Cl(2)] (1) and [Pt(edDs)Cl(2)] (2). Subsequent oxidation of these platinum(II) complexes with iodobenzene dichloride in DMF yielded the respective platinum(IV) analogues, [Pt(edBz)Cl(4)] (3) and [Pt(edDs)Cl(4)] (4). All four platinum complexes were characterized by multinuclear NMR spectroscopy, IR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis. In addition, compounds 1 and 3 were structurally characterized by X-ray crystallography. The photophysical properties of the compounds bearing the fluorescent dansyl moiety, 2 and 4, were evaluated. The emission quantum yields of 2 and 4 in DMF are 27% and 1.6%, respectively. This large difference in emission efficiency indicates that the platinum(IV) center in 4 is more effective at quenching the dansyl-based fluorescence than the platinum(II) center in 2. Time-dependent density functional theory calculations indicate that 4 has several low-lying singlet excited states that energetically lie below the primary radiation-accessible excited state of the dansyl fluorophore. These low-energy excited states may offer non-radiative decay pathways that lower the overall emission quantum yield. Treatment of 4 with biologically relevant reducing agents in pH 7.4 phosphate-buffered saline induces a 6.3-fold increase in emission intensity. These results demonstrate that 4 and future derivatives thereof may be useful for imaging the reduction of platinum(IV) complexes in living systems, chemistry of importance for future platinum-based anticancer drug strategies. PMID- 22837585 TI - [Sexual Behavior and Self-Efficacy for the Negotiation of Safer Sex in Heterosexual Persons.] AB - Self-efficacy has been defined as one of the factors that may facilitate or impede safer sex. Studies reveal that peoples in steady relationships practice safer sex less often that those in casual relationships. We conducted a study with 447 sexually active heterosexual adults. A self-administered questionnaire was designed to study the sexual behavior, the male condom use and the practice of mutual masturbation, and the self-efficacy toward these practices. Results show that most men are sexually active and that there is a low frequency of male condom use and the practice of mutual masturbation as safer sex. The majority of those who use the male condom are engage in casual relationships. However, participants have high levels of self-efficacy toward these practices. Although self-efficacy is one of the factors that influence in deciding to practice safer sex, it is not sufficient to reach this goal. PMID- 22837586 TI - Synthesis of Hemigossypol and its Derivatives. AB - Hemigossypol (3), a sesquiterpene natural product, was previously isolated from Gossypium barbadense and was shown to display improved anti-fungal activity compared to gossypol (1), the disesquiterpene dimer of hemigossypol (3). Gossypol exhibits multiple biological activities. In order to study whether hemigossypol and it derivatives retain the various bioactivities of gossypol, we developed a short and convenient synthetic scheme to synthesize hemigossypol. This is the first de novo synthesis of this natural product. In addition derivatives of hemigossypol with various 2,5-alkyl substituents were synthesized. Modification of the synthetic scheme also afforded the natural product hemigossylic lactone (4) and its 2,5-substituted derivatives. PMID- 22837587 TI - The Painful Face - Pain Expression Recognition Using Active Appearance Models. AB - Pain is typically assessed by patient self-report. Self-reported pain, however, is difficult to interpret and may be impaired or in some circumstances (i.e., young children and the severely ill) not even possible. To circumvent these problems behavioral scientists have identified reliable and valid facial indicators of pain. Hitherto, these methods have required manual measurement by highly skilled human observers. In this paper we explore an approach for automatically recognizing acute pain without the need for human observers. Specifically, our study was restricted to automatically detecting pain in adult patients with rotator cuff injuries. The system employed video input of the patients as they moved their affected and unaffected shoulder. Two types of ground truth were considered. Sequence-level ground truth consisted of Likert type ratings by skilled observers. Frame-level ground truth was calculated from presence/absence and intensity of facial actions previously associated with pain. Active appearance models (AAM) were used to decouple shape and appearance in the digitized face images. Support vector machines (SVM) were compared for several representations from the AAM and of ground truth of varying granularity. We explored two questions pertinent to the construction, design and development of automatic pain detection systems. First, at what level (i.e., sequence- or frame level) should datasets be labeled in order to obtain satisfactory automatic pain detection performance? Second, how important is it, at both levels of labeling, that we non-rigidly register the face? PMID- 22837588 TI - Treating Metaphor Interpretation Deficits Subsequent to Right Hemisphere Brain Damage: Preliminary Results. AB - PURPOSE: This investigation sought to determine whether a structured intervention focused on improving use of semantic associations could improve patients' ability to provide oral interpretations of metaphors following Right Hemisphere Damage (RHD). METHODS: Principles of single subject experimental design provided the basis for the study. Five patients received either 10 or 20 baseline assessments of oral metaphor interpretation and, as a control, assessments of line orientation skill. They then received approximately 10 one-hour sessions of structured intervention to improve oral metaphor interpretation followed by post training assessments and a 3 month follow up. RESULTS: Patients' performances revealed evidence of good response to training as shown by patients' ability to reach criterion on all intervention tasks and by their significant improvement on oral metaphor interpretation. There was relatively little improvement on the line orientation task. DISCUSSION: The results of this study support the clinical usefulness of this new approach to treating communication deficits associated with RHD due to stroke, even years post-onset. There are, however, questions that remain unanswered. For example, additional data will be needed to gauge how a patient's severity of impairment relates to the potential for improvement, to chart the durability and scope of improvement associated with the training, and to determine the type of visuospatial ability needed for using this type of pictorial material. PMID- 22837589 TI - Generalization of a Novel, Implicit Treatment for Coarse Coding Deficit in Right Hemisphere Brain Damage: A Single Subject Experiment. AB - BACKGROUND: This manuscript reports generalization effects of Contextual Constraint Treatment for an adult with right hemisphere brain damage (RHD). Contextual Constraint Treatment is designed to stimulate inefficient language comprehension processes implicitly, by providing linguistic context to prime, or constrain, the intended interpretations of treatment stimuli. The study participant had a coarse coding deficit, defined as delayed mental activation of particularly distant semantic features of words (e.g., rotten as a feature of "apple"). Treatment effects were expected to generalize to auditory comprehension of narrative discourse, and perhaps to figurative language interpretation, because coarse coding has been hypothesized and/or demonstrated to support these abilities. AIMS: This treatment study aimed to induce generalization of Contextual Constraint Treatment in an adult with RHD with inefficient coarse coding. METHODS #ENTITYSTARTX00026; PROCEDURES: The participant in this study was a 75 year old man with RHD and a coarse coding deficit. A single subject experimental design across behaviors (stimulus lists) was used to document performance in baseline, treatment, and follow-up phases. Treatment consisted of providing brief, spoken context sentences to prestimulate, or constrain, intended interpretations of stimulus items. The participant made no explicit associations or metalinguistic judgments about the constraint sentences or stimulus words; rather, these contexts served only as implicit primes. Probe tasks were adapted from prior work on coarse coding in RHD. The dependent measure was the percentage of responses that met predetermined response time criteria. There were two levels of contextual constraint, Strong and Moderate. Treatment for each item began with the provision of the Strong constraint context, to minimize the production or reinforcement of erroneous or exceedingly slow responses. Generalization was assessed to a well-standardized measure of narrative discourse comprehension and to several metalinguistic tasks of figurative language interpretation. OUTCOMES #ENTITYSTARTX00026; RESULTS: Treatment-contingent gains, associated with respectable effect sizes, were evident after a brief period of treatment on one stimulus list. Generalization occurred to untrained items, suggesting that the treatment was facilitating the underlying coarse coding process. Most importantly, generalization was evident to narrative comprehension performance, for both overall accuracy and accuracy answering questions about implied information, and all of these gains maintained through three follow-up sessions. CONCLUSIONS: Though the results are still preliminary, this single-subject experimental design documents the potential for meaningful gains from a novel treatment that implicitly targets an underlying language comprehension process in an adult with RHD. PMID- 22837590 TI - Theory Testing Using Quantitative Predictions of Effect Size. AB - Traditional Null Hypothesis Testing procedures are poorly adapted to theory testing. The methodology can mislead researchers in several ways, including: (a) a lack of power can result in an erroneous rejection of the theory; (b) the focus on directionality (ordinal tests) rather than more precise quantitative predictions limits the information gained; and (c) the misuse of probability values to indicate effect size. An alternative approach is proposed which involves employing the theory to generate explicit effect size predictions that are compared to the effect size estimates and related confidence intervals to test the theoretical predictions. This procedure is illustrated employing the Transtheoretical Model. Data from a sample (N = 3,967) of smokers from a large New England HMO system were used to test the model. There were a total of 15 predictions evaluated, each involving the relation between Stage of Change and one of the other 15 Transtheoretical Model variables. For each variable, omega squared and the related confidence interval were calculated and compared to the predicted effect sizes. Eleven of the 15 predictions were confirmed, providing support for the theoretical model. Quantitative predictions represent a much more direct, informative, and strong test of a theory than the traditional test of significance. PMID- 22837591 TI - Career Development From Adolescence Through Emerging Adulthood Insights From Information Technology Occupations. AB - Career development theories suggest that social-contextual experiences are influential in individuals' career interests, aspirations, and skill development and may be a source of gender and ethnic differences in certain career fields. In this mixed methods study, we examine the supportive and obstructive career related experiences of 13 men and 13 women (modal age 25). Interviews focused primarily on the pathway toward or away from an information technology (IT) career. Thematic coding indicated that parents were mostly supportive, while experiences in school and work occasionally made individuals reconsider their career plans. Social influences often changed developmentally as participants entered full-time jobs. Gendered participation in IT was often attributed to women's perception that it is a male-oriented field. PMID- 22837592 TI - Laparoscopic, robotic and open method of radical hysterectomy for cervical cancer: A systematic review. AB - BACKGROUND: Over the last two decades, numerous studies have indicated the feasibility of minimally invasive surgery for early cervical cancer without compromising the oncological outcome. OBJECTIVE: Systematic literature review and meta analysis aimed at evaluating the outcome of laparoscopic and robotic radical hysterectomy (LRH and RRH) and comparing the results with abdominal radical hysterectomy (ARH). SEARCH STRATEGY: Medline, PubMed, Embase, Cochrane library and Reference lists were searched for articles published until January 31(st) 2011, using the terms radical hysterectomy, laparoscopic radical hysterectomy, robotic radical hysterectomy, surgical treatment of cervical cancer and complications of radical hysterectomy. SELECTION CRITERIA: Studies that reported outcome measures of radical hysterectomy by open method, laparoscopic and robotic methods were selected. DATA COLLECTION AND ANALYSIS: Two independent reviewers selected studies, abstracted and tabulated the data and pooled estimates were obtained on the surgical and oncological outcomes. RESULTS: Mean sample size, age and body mass index across the three types of RH studies were similar. Mean operation time across the three types of RH studies was comparable. Mean blood loss and transfusion rate are significantly higher in ARH compared to both LRH and RRH. Duration of stay in hospital for RRH was significantly less than the other two methods. The mean number of lymph nodes obtained, nodal metastasis and positive margins across the three types of RH studies were similar. Post operative infectious morbidity was significantly higher among patients who underwent ARH compared to the other two methods and a higher rate of cystotomy in LRH. CONCLUSIONS: Minimally invasive surgery especially robotic radical hysterectomy may be a better and safe option for surgical treatment of cervical cancer. The laparoscopic method is not free from complications. However, experience of surgeon may reduce the complications rate. PMID- 22837593 TI - Single-port transumbilical laparoscopic cholecystectomy: A prospective randomised comparison of clinical results of 140 cases. AB - INTRODUCTION: A novel single port access (SPA) cholecystectomy approach is described in this study. We have designed a randomised comparative study in order to elucidate any possible differences between the standard treatment and this novel technique. MATERIALS AND METHODS: Between July 2009 and March 2010, 140 adult patients with gallbladder pathologies were enrolled in this multicentre study. Two surgeons (RV and UB) randomised patients to either a standard laparoscopic (SL) approach group or to an SPA cholecystectomy group. Two types of trocars were used for this study: the TriPortTM and the SILSTM Port. Outcomes including blood loss, operative time, complications, length of stay and pain were recorded. RESULTS: There were 69 patients in the SPA group and 71 patients in the SL group. The mean age of the patients was 43.2 (17-77) for the SPA group and 42.6 (19-70) for the SL group. The mean operative time was 63.9 min in the SPA group and 58.4 min in the SL group. For one patient, the SPA procedure was converted to a standard laparoscopic technique and to open approach in the SL group. Complications occurred in eight patients: Five seromas (two in the SPA group) and three hernias (one in the SPA group).The mean hospital stay was 38.5 h in the SPA group and 24.1 h in the SL group. Pain was evaluated and was 2 in the SPA and 2.9 in the SL group, according to the visual analogue scale (VAS) after 24 h (P<0.001). The degree of satisfaction was higher in the SPA group (8.3 versus 6.7). Similar results were found for the aesthetic result (8.8 versus 7.5). (P<0.001). CONCLUSION: Single-port transumbilical laparoscopic cholecystectomy can be feasible and safe. When technical difficulties arise, early conversion to a standard laparoscopic technique is advised to avoid serious complications. The SPA approach can be undertaken without the expense of additional operative time and provides patients with minimal scarring. The cosmetic results and the degree of satisfaction appear to be significant for the SPA approach. PMID- 22837594 TI - Laparoendoscopic single site surgery in urology: A single centre experience. AB - OBJECTIVE: To analyze our experience of 87 cases with single port surgery, which is also known as laparoendoscopic single site surgery (LESS). MATERIALS AND METHODS: Case records of all LESS procedures performed between December 2007 and June 2010 were analysed. The procedures performed were donor nephrectomy (n=45), simple nephrectomy (n=27), radical nephrectomy (n=5), pyeloplasty (n=9), and ureteroneocystostomy (n=1). Parameters analysed were operating room (OR) time, estimated blood loss (EBL), visual analogue score (VAS), and complications in all patients undergoing LESS procedure and additionally, warm ischaemia time (WIT) and graft outcome in patients undergoing LESS donor nephrectomy. In reconstructive procedures, the functional assessment was performed with a diuretic renogram at 6 months. RESULTS: In LESS donor nephrectomy, the mean WIT was 6.9 +/- 1.9 min. Mean serum creatinine in recipients at 1 month was 0.96 +/- 0.21 mg%. We encountered one instance each of renal artery injury, renal vein injury, large bowel injury, minor cortical laceration at the upper pole and two instances of diaphragmatic injury. In LESS simple nephrectomy, the average OR time was 148.7 +/- 52.2 min and hospital stay was 3.7 +/- 1.2 days. There was one instance of large bowel injury during specimen retrieval. In LESS radical nephrectomy, the average OR time was 202.5 +/- 35.7 min and average hospital stay was 4.2 +/- 1.3 days. 6 patients of LESS pyeloplasty completed follow up with a diuretic renogram showing a good drainage. LESS ureteroneocystostomy could also be performed successfully without any complications. CONCLUSION: LESS surgery can be accomplished safely in nephrectomy and reconstructive procedures such as pyeloplasty and ureteroneocystostomy with equivalent outcomes as standard laparoscopy and with added benefits of cosmesis and quicker convalescence. LESS donor nephrectomy is a technically feasible procedure; current status of procedure needs to be proved with randomised controlled studies. PMID- 22837595 TI - Veress needle insertion through left lower intercostal space for creating pneumoperitoneum: Experience with 75 cases. AB - CONTEXT: Veress needle insertion (VNI) at sub-umbilical fold (SUF) midline is associated with serious intra-abdominal injuries. AIM: The aim of this study has been to evaluate the safety and efficacy of lower left intercostal space (LICS) for VNI. SETTINGS AND DESIGN: This prospective observational study was conducted in three parts in Surgery-II, Department of Surgery, GTBH-UCMS, Delhi. MATERIALS AND METHODS: In part one, skin fold thickness (SFT) was measured in 32 patients at SUF, LICS, right iliac fossa (RIF) and Palmer's point. As part two, in these patients, VNI was carried out from LICS under laparoscopic guidance. As part three, same technique of VNI was employed in 43 patients with suspected intra abdominal adhesions undergoing laparoscopy for various reasons. Observations were made regarding ease of insertion, attempts needed for successful entry, loudness or clarity of give-way feeling of Veress needle, intra-abdominal bleeding at point of emergence of Veress needle, hemopneumothorax, bowel or vascular injury. STATISTICAL ANALYSIS USED: SFT was expressed as mean (SD), and one-way ANOVA followed by Tukey's test were employed to find the statistical significance. RESULTS: SFT at LICS was significantly less as compared to SUF and Palmer's point. VNI at LICS was easy to carry out; it could be successfully done in first attempt in all patients, and was associated with very clear and loud give-way feeling. There were no instances of intra-abdominal bleeding at point of emergence of Veress needle, hemopneumothorax, bowel or vascular injury. CONCLUSIONS: VNI at LICS as described here is safe and effective. PMID- 22837596 TI - Laparoscopic elective cholecystectomy with and without drain: A controlled randomised trial. AB - BACKGROUND: Laparoscopic cholecystectomy is the main method of treatment of symptomatic gallstones. Routine drainage after laparoscopic cholecystectomy is an issue of considerable debate. Therefore, a controlled randomised trial was designed to assess the value of drains in elective laparoscopic cholecystectomy. MATERIALS AND METHODS: During a two-year period (From April 2008 to January 2010), 80 patients were simply randomised to have a drain placed (group A), an 8 mm pentose tube drain was retained below the liver bed, whereas 80 patients were randomised not to have a drain (group B) placed in the subhepatic space. End points of this trial were to detect any differences in morbidity, postoperative pain, wound infection and hospital stay between the two groups. RESULTS: There was no mortality in either group and no statistically significant difference in postoperative pain, nausea and vomiting, wound infection or abdominal collection between the two groups. However, hospital stay was longer in the drain group than in group without drain and it is appearing that the use of drain delays hospital discharge. CONCLUSION: The routine use of a drain in non-complicated laparoscopic cholecystectomy has nothing to offer; in contrast, it is associated with longer hospital stay. PMID- 22837597 TI - Laparoscopic vertical sleeve gastrectomy after open gastric banding in a patient with situs inversus totalis. AB - While several equivalent alternatives are available in the bariatric algorithm, more recently the laparoscopic sleeve gastrectomy (SG) has been gaining traction as an effective means of weight loss in patients with morbid obesity. We present the case of a 39-year-old woman with situs inversus totalis, who was taken to the operating room for laparoscopic SG. The patient had previously undergone a failed open gastric banding procedure 20 months earlier. Awareness of the inherited condition before performing the operation allows for advanced planning and preparation. Subsequent modifications to the standard trocar placement help make the procedure more technically feasible. To our knowledge, this is the first published report of a laparoscopic SG after open gastric banding in a patient with situs inversus totalis. After encountering the initial disorientation, we believe experienced laparoscopic surgeons can perform this procedure successfully and safely. PMID- 22837598 TI - Laparoscopic excision of hepatoduodenal ligament cyst. AB - Hepatoduodenal ligament cysts are rare. These may be confused with hepatic cysts even on advanced investigative modalities like Computerized tomography scanning or Magnetic Resonance Imaging. Diagnosis is often an intraoperative surprise. Laparoscopic treatment of such hepatoduodenal cysts is not described in available medical literature. We report one such case treated laparoscopically. PMID- 22837599 TI - Transhepatic metallic stenting for hepaticojejunostomy stricture following laparoscopic cholecystectomy biliary injury: A case of successful 20 years follow up. AB - Laparoscopic cholecystectomy is still associated with a considerable rate of biliary injuries and related strictures. Advances in interventional endoscopy and percutaneous techniques have made stenting a preferred treatment modality for the management of these strictures. We report successful 20 years of follow-up of a case of trans-hepatic metallic stenting (2 Gianturco((r)) prostheses, 5 cm long, 2 cm in diameter) done for stenosed hepatico-jejunostomy anastomosis after laparoscopic CBD injury. Percutaneous transhepatic stenting and long-term placement of metallic stents need to be re-evaluated as a minimally invasive definitive treatment option for benign biliary strictures in patients with altered anatomy such as hepatico-jejunostomy or in whom re-operation involves high risk. PMID- 22837600 TI - Laparoscopic management of chyle leak after Nissen fundoplication. AB - A 41-year-old man presented with chylous ascites 6 weeks after a laparoscopic Nissen fundoplication. The chyle leak was successfully treated with laparoscopic ligation of the leaking duct at the right crus. We would now recommend early consideration of this as a treatment option for this rare complication. PMID- 22837601 TI - Herbal enema: At the cost of colon. AB - Various colonic side-effects of herbal enema have been reported in literature ranging from mild abdominal discomfort to self-limiting haemorrhagic colitis. It rarely requires blood transfusion or subtotal colectomy. We report a 57-year-old male patient developing severe ileo-colitis with persistent massive rectal bleeding immediately after herbal enema administration for the treatment of chronic constipation and was resistant to conservative management. Patient was managed successfully with emergency total laparoscopic colectomy. Post-operative recovery of the patient was excellent. PMID- 22837602 TI - Ultrasound-guided antegrade access during laparoscopic pyeloplasty in infants less than one year of age: A point of technique. AB - BACKGROUND: Access to urethras and ureters of infants may be hazardous and injurious through an endoscopic route. Placement and removal of stents in infants requires anaesthesia and access through these small caliber urethras. We describe our technique of placing antegrade splint during a laparoscopic pyeloplasty in these infants. MATERIALS AND METHODS: An ultrasound-guided percutaneous renal access is obtained. Telescopic metal two part needle is passed into the kidney over a guide wire. A second guide wire is passed through the telescopic metal two part needle. The tract is dilated with 14 Fr screw dilator. Over one guide wire, a 5 Fr ureteric catheter is passed and coiled in the renal pelvis. Over the other wire, a 14 Fr malecot catheter is placed as nephrostomy. Laparoscopic pyeloplasty is then done. During pyelotomy, the ureteric catheter is pulled and advanced through the ureter before the pyeloplasty is completed. The ureteric catheter thus acts as a splint across the anastomosis. Ureteric catheter is removed on the 3(rd) post operative day and nephrostomy is clamped. Nephrostomy is removed on 4(th) post operative day if child is asymptomatic. The modified technique was successfully done in five patients aged less than one year old. All patients tolerated the procedure well. Post operative period was uneventful in all. CONCLUSION: Ultrasound-guided ante grade nephroureteral ureteral splint for infant laparoscopic pyeloplasty is safe. It avoids the need for urethral instrumentation for insertion and removal of stents in these small patients. PMID- 22837603 TI - Pseudomonas bronchopulmonary infections in a palliative care setting. AB - Blood stream infections and pneumonia caused by Pseudomonas aeruginosa is associated with high mortality, especially in an immunocompromised host. A large section of the palliative care patient population has varied forms of compromised immunity due to advanced cancer or cancer treatment, organ failures, chronic autoimmune disorders, degenerative conditions, and acquired immunodeficiency syndrome. The lung is one of the most frequently involved organs in a variety of complications in an immunocompromised host and infection is the most common complication. P. aeruginosa is one of the most common pathogens associated with bronchopulmonary infections in an immunocompromised host. Routine radiological tests like chest X-ray may often be unyielding and an early and a prompt initiation of treatment reduces mortality and morbidity risk. PMID- 22837604 TI - Palliative care for patients with chronic obstructive pulmonary disease: current perspectives. AB - Chronic obstructive pulmonary disease (COPD) is a chronic respiratory illness with a myriad of disabling symptoms and a decline in the functional parameters that affect the quality of life. The mortality and morbidity associated with severe COPD is high and the patients are mostly housebound and in need of continuous care and support. The uncertain nature of its prognosis makes the commencement of palliative care and discussion of end-of-life issues difficult even in the advanced stage of the disease. This is often compounded by inadequate communication and counseling with patients and their relatives. The areas that may improve the quality of care include the management of dyspnea, oxygen therapy, nutritional support, antianxiety, and antidepressant treatment, and advance care planning. Hence, it is necessary to pursue a holistic care approach for palliative care services along with disease-specific medical management in all such patients to improve the quality of life in end-stage COPD. PMID- 22837605 TI - Oral health in children with leukemia. AB - Leukemia is one of the most common malignancies affecting children in India. These children usually suffer from various oral complications, which may be due to the leukemia or due to the chemotherapeutic agents and/or radiotherapy. The complications may include some of the opportunistic infections like candidiasis, herpes simplex; hemorrhage, mucositis, taste alterations and increased incidence of dental caries etc. These complications can cause significant morbidity and mortality in the patients. The aim of this review is to summarize the various oral complications in these children and the methods of prevention and management. PMID- 22837606 TI - Oral health care needs in the dependant elderly in India. AB - There is a sudden blast of the "65 plus" population in the last decade, and India is no exception to that. A continuing progress in the medical field has raised the longevity of life. This changing face of population offers the oral professionals to observe unique challenges to treat the rapidly growing segment of the elderly and the dependant overage population- the Homebound residents and the Nursing homebound residents. The old age of the residents is compounded with chronic medical problems they are suffering from and the medications they are taking. This cohort is characteristically different from other elderly due to their dependency to carry even the routine activities such as tooth cleaning which results in increased risk towards the oral ailments. As very few surveys are done regarding the oral health status among this section, the prevalence of oral and dental problems in them is under a cloud. "Dental care at home or at destinations of residents" is yet a novel concept in India, hence not only there is a need to reach to the residents but also to treat them in the holistic manner. The purpose of this paper is to review the existing oral health conditions in the elderly in India. PMID- 22837607 TI - A Prospective Survey of Patient Drop-outs in a Palliative Care Setting. AB - AIM: A prospective survey of patient drop-outs was carried out in a palliative care setting to understand the background of patients in the drop-out category. This was to understand the background of patients who drop out and why they drop out. MATERIALS AND METHODS: The survey was conducted on 425 patients who had registered in the clinic in 2009 and subsequently persistently dropped out. Patients were classified on the basis of age, gender, education, disease, socioeconomic class, distance from clinic to home, family size, general health on the basis of symptoms on first arrival, reasons subsequently found for missing the appointment, primary caregiver details, and social support. The data were collected, and analyzed statistically using chi-square tests and percentages. RESULTS: Majority of patients presented in the 41- to 60-year age group had secondary level education, with a family size of four. The drop-out rate was 25.06%. There was a significant association (P = 0.026) between reasons for dropping out and social support. A P-value < 0.05 shows that these are two related attributes. Yule's coefficient of association shows a negative correlation. When social support increases, the drop-out rate decreases. Majority of patients discontinued because a similar facility became available nearer their residence. CONCLUSION: A number of palliative care clinics have been created in the district and this has resulted in the significant drop-out rate. PMID- 22837608 TI - Feeding Tube-related Complications and Problems in Patients Receiving Long-term Home Enteral Nutrition. AB - AIM: The aim of this study was to evaluate the long-term complications and problems related to gastrostomy and jejunostomy feeding tubes used for home enteral nutrition support and the effect these have on health care use. MATERIALS AND METHODS: The medical records of 31 patients having gastrostomy (27 patients) and jejunostomy (4) feeding tubes inserted in our Department were retrospectively studied. All were discharged on long-term (>3 months) enteral nutrition and followed up at regular intervals by a dedicated nurse. Any problem or complication associated with tube feeding as well as the intervention, if any, that occurred, was recorded. Data were collected and analyzed. RESULTS: All the patients were followed up for a mean of 17.5 months (4-78). The most frequent tube-related complications included inadvertent removal of the tube (broken tube, plugged tube; 45.1%), tube leakage (6.4%), dermatitis of the stoma (6.4%), and diarrhea (6.4%). There were 92 unscheduled health care contacts, with an average rate of such 2.9 contacts over the mean follow-up time of 17.5 months. CONCLUSION: In patients receiving long-term home enteral nutrition, feeding tube related complications and problems are frequent and result in significant health care use. Further studies are needed to address their optimal prevention modalities and management. PMID- 22837609 TI - Effectiveness of Two High-dose-rate Intraluminal Brachytherapy Schedules for Symptom Palliation in Carcinoma Esophagus: A Tertiary Care Center Experience. AB - AIM: The aim was to analyze different radiation schedules with high-dose-rate (HDR) brachytherapy in patients with unresectable carcinoma esophagus in terms of dysphagia-free survival (DyFS), local control (LC), disease-free survival (DFS), and complications. MATERIALS AND METHODS: Eighty-six patients were studied under three different radiation schedules: Schedule A - radiation 35 Gy/15# followed by HDR brachytherapy 6 Gy each in two sessions; schedule B - chemoradiation 35 Gy/15# with weekly injection cisplatin 30 mg/m(2) infusion and 5-fluorouracil 325 mg/m(2) bolus followed by HDR brachytherapy 6 Gy each in two sessions; and schedule C - same chemoradiation dose followed by HDR brachytherapy three sessions of 4.68 Gy each. The median follow-up was 12.1 months. RESULTS: Treatment compliance was good. There were no significant differences in the incidence of acute toxicities across the three schedules. No grade III toxicities were noted. At 1 month, 27 patients had dysphagia improvement, which was not different across the three schedules. At 6 months, schedule C showed a trend toward better symptom control of dysphagia (dysphagia free=55%). The 2-year DyFS reached 49.5% in schedule C. Two-year LC rates were approximating 89% in both chemoradiation schedules versus 67.6% in schedule A. The 2-year DFS was also high in chemoradiation schedules. Major complications like ulceration and tracheoesophageal fistulas were more often seen with schedule B with a higher dose per fraction of the brachytherapy schedule. CONCLUSION: In unresectable carcinoma esophagus, radiation-only schedules are associated with lower LC and DFS rates. Concurrent chemoradiation followed by a brachytherapy boost is feasible in suitable patients with a good Karnofsky performance score and are associated with higher DyFS, LC, and DFS with acceptable toxicities. Still there is a need for the standardization of HDR brachytherapy schedules with chemoradiation protocols. PMID- 22837610 TI - Should Blood Cultures be Performed in Terminally Ill Cancer Patients? AB - BACKGROUND: No evidence-based guidelines or protocols to treat the infection related symptoms in cancer patients with terminal stages have been established. MATERIALS AND METHODS: We retrospectively analyzed all the patients with terminal stage cancer who died between April 2009 and March 2010. The patients' background, the prevalence of infection and clinical outcomes, pathogens isolated, antibiotics used, and whether blood cultures and some of examinations were performed or not were evaluated. RESULTS: A total of 62 (44 males and 18 females) patients were included in this study. The median age was 73 years (35-98 years). The most common cancer was that of the lung (n =59, 95.2%). A total of 32 patients were diagnosed with the following infections: Infection of respiratory tract in 27 (84.4%), of urinary tract in 4 (12.5%), and cholangitis in 1 (3.1%). Two cases (6.3%) had pneumonia complicated with urinary tract infection. Blood cultures and antibiotic therapies were performed in 28 and 30 cases, respectively. Four (14.3%) positive cultures were isolated from the blood obtained from 28 individual patients. As for clinical course, 3 (10%) of them experienced improved symptoms after antibiotic therapy. Twenty-seven (90%) patients were not confirmed as having any symptom improvement. CONCLUSIONS: Blood cultures and antibiotic therapy were limited, and might not be effective in terminally ill cancer patients with lung cancer. We suggest that administering an antibiotic therapy without performing a blood culture would be one of choices in those with respiratory tract infections if patients' life expectancy is short. PMID- 22837611 TI - Effect of the perioperative infusion of dexmedetomidine on chronic pain after breast surgery. AB - BACKGROUND: This prospective double-blind trial was undertaken to analyze the role of perioperatively administered dexmedetomidine on the occurrence of chronic pain in cases undergoing surgery for breast cancer. SUBJECTS AND METHODS: Eighty six cases were randomly assigned to two groups to receive either dexmedetomidine (2 MUg/ml) in group D or saline in group C, in a loading dose of 0.5 ml/kg, intravenous (IV), 30 min prior to induction, followed by a continuous infusion of 0.25 ml/kg/h IV till the completion of surgery, and then the dose tapered to 0.1 ml/kg/h for up to 24 h. The standardized questionnaires that measured chronic pain (Brief Pain Inventory, BPI; Short Form McGill Pain Questionnaire, SF-MPQ2) and quality of life (Quality of Life Scale, QOLS) were gathered after 3 months of surgery as a primary outcome. Pain (verbal numerical score, VNS), sedation scores (Ramsay scoring), and analgesic requirements were also assessed for 72 h postoperatively. RESULTS: In total, 84 cases (n=42) were analyzed for acute pain and 69 (34 in group D and 35 in group C) for chronic pain. The consumption of isoflurane/fentanyl intra-operatively and paracetamol postoperatively was significantly lower in Group D. The sedation scores were non-significant between the groups. The VNS at rest and after movement was significantly lower in group D at corresponding times (except at 60 min) throughout the assessment period. The BPI and SF-MPQ2 scores were significantly lower in group D in most of the factors. The QOLS score was significantly better in group D in all items except for relationships, friends, and learning. CONCLUSION: The perioperative infusion of dexmedetomidine has a pivotal role in attenuating the incidence and severity of chronic pain and improving the quality of life in cases undergoing breast cancer surgery. PMID- 22837612 TI - Should Patients and Family be Involved in "Do Not Resuscitate" Decisions? Views of Oncology and Palliative Care Doctors and Nurses. AB - BACKGROUND: "Do not resuscitate" (DNR) orders are put in place where cardiopulmonary resuscitation is inappropriate. However, it is unclear who should be involved in discussions and decisions around DNR orders. AIM: The aim was to determine the views of oncology and palliative care doctors and nurses on DNR orders. MATERIALS AND METHODS: A questionnaire survey was conducted on 146 doctors and nurses in oncology and palliative care working within a tertiary specialist cancer center in Singapore. RESULTS: Perceived care differences as a result of DNR determinations led to 50.7% of respondents reporting concerns that a DNR order would mean that the patient received a substandard level of care. On the matter of DNR discussions, majority thought that patients (78.8%) and the next of kin (78.1%) should be involved though with whom the ultimate decision lay differed. There was also a wide range of views on the most appropriate time to have a DNR discussion. CONCLUSIONS: From the viewpoint of oncology and palliative care healthcare professionals, patients should be involved at least in discussing if not in the determination of DNR orders, challenging the norm of familial determination in the Asian context. The varied responses highlight the complexity of decision making on issues relating to the end of life. Thus, it is important to take into account the innumerable bio-psychosocial, practical, and ethical factors that are involved within such deliberations. PMID- 22837614 TI - Breast Self-examination: Knowledge, Attitude, and Practice among Female Dental Students in Hyderabad City, India. AB - AIM: The aim was to assess the knowledge, attitude, and practice (KAP) regarding breast self-examination (BSE) in a cohort of Indian female dental students. MATERIALS AND METHODS: A cross-sectional descriptive questionnaire study was conducted on dental students at Panineeya Institute of Dental Sciences, Hyderabad, Andhra Pradesh, India. Data were analyzed using SPSS software (version 12). Chi-square test was used for analysis of categorical variables. Correlation was analyzed using Karl Pearson's correlation coefficient. The total scores for KAP were categorized into good and poor scores based on 70% cut-off point out of the total expected score for each. P-value of <0.05 was considered statistically significant. RESULTS: This study involved a cohort of 203 female dental students. Overall, the total mean knowledge score was 14.22 +/- 8.04 with the fourth year students having the maximum mean score (19.98 +/- 3.68). The mean attitude score was 26.45 +/- 5.97. For the practice score, the overall mean score was 12.64 +/- 5.92 with the highest mean score noted for third year 13.94 +/- 5.31 students. KAP scores upon correlation revealed a significant correlation between knowledge and attitude scores only (P<0.05). CONCLUSION: The study highlights the need for educational programs to create awareness regarding regular breast cancer screening behavior. PMID- 22837613 TI - Reporting of "quality of life": a systematic review and quantitative analysis of research publications in palliative care journals. AB - CONTEXT: Palliative care clinical practice depends upon an evidence-based decision-making process which in turn is based upon current research evidence. One of the most important goals in clinical palliative care is to improve patients' quality of life (QoL). AIM: This study aimed to perform a quantitative analysis of research publications in palliative care journals for reporting characteristics of articles on QoL. SETTINGS AND DESIGN: This was a systematic review of palliative care journals. MATERIALS AND METHODS: Twelve palliative care journals were searched for articles with "QoL" in the title of the articles published from 2006 to 2010. The reporting rates of all journals were compared. The selected articles were categorized into assessment and treatment, and subsequently grouped into original and review articles. The original articles were subgrouped into qualitative and quantitative studies, and the review articles were grouped into narrative and systematic reviews. Each subgroup of original article category was further classified according to study designs. STATISTICAL ANALYSIS USED: Descriptive analysis using frequencies and percentiles was done using SPSS for Windows, version 11.5. RESULTS: The overall reporting rate among all journals was 1.95% (71/3634), and Indian Journal of Palliative Care (IJPC) had the highest reporting rate of 5.08% (3/59), followed by Palliative Medicine (PM) with 3.71% (20/538), and Palliative and Supportive Care (PSC) with 3.64% (9/247) reporting. CONCLUSIONS: The overall reporting rate for QoL articles in palliative care journals was 1.95% and there were very few randomized clinical trials and systematic reviews found. The study findings indicate further high-quality research to establish an adequate evidence base for QoL. PMID- 22837615 TI - Palliative sedation at home. AB - Patients with advanced cancer often suffer from multiple intractable physical symptoms. Though majority of the symptoms can be controlled, in some of the patients these symptoms remain refractory and uncontrolled till the end. Palliative sedation (PS) is one of the ways to relieve intractable suffering of the dying cancer patients. The main concern while using PS is its life-shortening effect. This case report describes the feasibility of administering PS in Indian home settings. PMID- 22837616 TI - Custom ocular prosthesis: a palliative approach. AB - The goal of palliative care is the achievement of the best quality of life for patients and their families. Eyes are generally the first features of the face to be noticed. Loss of an eye is a traumatic event which has a crippling effect on the psychology of the patient. Several ocular and orbital disorders require surgical intervention that may result in ocular defects. An ocular prosthesis is fabricated to restore the structure, function, and cosmetics of the defects created by such conditions. Although an implant eye prosthesis has a superior outcome, due to economic factors it may not be a feasible option for all patients. Therefore, a custom-made ocular prosthesis is a good alternative. This case report presents a palliative treatment for a patient with an enucleated eye by fabricating a custom ocular prosthesis which improved his psychological, physical, social, functional, emotional and spiritual needs. PMID- 22837617 TI - Ophthalmology: now and then. PMID- 22837618 TI - Incidence and natural course of symptomatic central serous chorioretinopathy in pregnant women in a maternity hospital in Kuwait. AB - PURPOSE: To report the incidence, clinical features and natural course of central serous chorioretinopathy (CSR) in pregnant women in Kuwait. MATERIALS AND METHODS: Patients were actively recruited from a private maternity hospital. Out of the 17,000 pregnant women who visited the antenatal care clinics (Al-Orf Hospital, Kuwait) over 3 years, 900 had visual complaints. Patients with visual complaints underwent complete ophthalmological assessment. Medical records of patients with CSR were reviewed, and a full clinical ophthalmological assessment was performed including measurement of best corrected visual acuity, intraocular pressure, slit lamp biomicroscopy, dilated indirect ophthalmoscopy and Amsler grid screening, color and red free fundus photography and retinal optical coherence tomography. All patients were evaluated throughout the course of pregnancy and for 6 months after delivery. RESULTS: Four patients had CSR among the 17,000 pregnant women reviewed over 3 years corresponding to an incidence of 0.008 % per year. Two patients (50%) had CSR with white subretinal exudates and 2 (50%) had no exudates. There was complete resolution in all patients (100%) within 3 months after delivery. CONCLUSIONS: In pregnant women, CSR can present with or without retinal exudates and completely resolves in either case. Further studies with a larger sample size are warranted to investigate the risk factors in pregnant women. PMID- 22837619 TI - Screening for retinopathy of prematurity in South of Iran. AB - PURPOSE: The purpose of this study is to report the screening data for retinopathy of prematurity (ROP) at a screening center in Southern Iran. MATERIALS AND METHODS: A chart review was performed of all screened neonates who were referred to Poostchi screening center affiliated to Shiraz University of Medical Sciences from February 2006 to January 2010. Statistical analysis of data was performed with the Chi-square and independent t-test where appropriate. A P < 0.05 was considered statistically significant. RESULTS: Of 787 infants referred, 293 (37.2%) had some form of ROP and 77 cases (9.8%) had plus disease, only 6 (2%) patients progressed to advanced ROP stages 4 and 5. The mean gestational age (GA) of patients with ROP (ROP group) was statistically significantly lower at 29.46 +/- 2.31 weeks compared to patients without ROP (non-ROP group) (31.56 +/- 2.03 weeks) (P < 0.05). The mean GA of patients with plus disease was statistically significantly lower at 28.92 +/- 2.18 weeks compared to patients without plus disease (30.98 +/- 2.30 weeks) (P < 0.05). The mean birth weight in the ROP group was statistically significantly lower at 1248.46 +/- 301.75 g compared to the non-ROP group (1485.79 +/- 268.66 g) (P < 0.05). The mean birth weight of patients with plus disease was statistically significantly lower at 1207.92 +/- 334.79 g compared to patients without plus disease (417.99 +/- 293.19 g) (P < 0.05). There was no difference in the occurrence of ROP or plus disease between single or multiple births, normal vaginal delivery, and caesarian section and between clomiphene users and nonusers (P > 0.05, all cases). CONCLUSION: Greater cooperation between ophthalmologists, neonatologists, gynecologists, and health policy makers is necessary to optimize ROP screening programs. Data from this study can be used by health policy makers for implementation of health programs. These programs must include screening guidelines and effective coordination among the screening centers, antenatal, obstetric, and neonatal care services. PMID- 22837620 TI - Cataract blindness, surgical coverage, outcome, and barriers to uptake of cataract services in Plateau State, Nigeria. AB - PURPOSE: The purpose was to estimate the prevalence of blindness due to cataract, assess visual outcomes of cataract surgery, and determine the cataract surgical coverage rate and barriers to uptake of services among individuals aged 50 years or older in Plateau State, Nigeria. MATERIALS AND METHODS: A population-based, cross-sectional survey of 4200 adults 50 years or older was performed. Multistage stratified random sampling, with probability proportional to size was used to select a representative sample. The Rapid Assessment of Cataract Surgical Services protocol was used. Statistical significance was indicated by (P < 0.05). RESULTS: The cohort comprised 4115 subjects (coverage: 98%). The prevalence of bilateral blindness due to cataract was 2.1%, [95% confidence intervals (CI): 1.7 2.5%] in the entire cohort, 2.4% in females (95% CI: 1.8-3.8%); and 1.8% in males (95% CI: 1.2-2.4%) (chi(2) = 0.85, P > 0.05). The prevalence of monocular blindness due to cataract was 5.9% (95% CI: 5.2-6.6%). The cataract surgical coverage for subjects with visual acuity (VA) less 3/60 was 53.8% in the entire cohort; 60.5% for males and 48% for females (chi(2) = 2.49, P > 0.05). The couching coverage for subjects who were blind was 12%. A total of 180 eyes underwent surgical intervention (surgery or couching) for cataract, of which, 48 (26.7%) eyes underwent couching. The prevalence of bilateral (pseudo) aphakia was 1.5%, (95% CI: 1.2-1.9%) and 2.7% (95% CI: 2.2-3.2%) for unilateral (pseudo) aphakia. Visual outcomes of the 180 eyes that underwent surgical intervention were good (VA >= 6/18) in 46 (25.6%) eyes and poor (VA < 6/60) in 105 (58.3%) eyes. Uncorrected aphakia was the most common cause of poor outcome (65.1%). Most subjects who underwent cataract surgery were not using spectacles 74 (71.2%). Cost and lack of awareness were the main barriers to uptake of cataract surgery services. CONCLUSION: Couching remains a significant challenge in Nigeria. The outcomes of cataract surgery are poor with the lack of aphakic correction being the main cause of the poor outcomes. PMID- 22837621 TI - Retinopathy of prematurity: a study of prevalence and risk factors. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a serious complication of prematurity treatment and can lead to blindness unless recognized and treated early. OBJECTIVE: The objective was to estimate the prevalence of ROP in preterm infants in the Neonatal Intensive Care Unit (NICU), to identify the risk factors which predispose to ROP, and to assess the outcome of these cases. MATERIALS AND METHODS: A ROP prospective screening survey was performed enrolling all prematures admitted to the NICU from January 2009 to December 2010, with a gestational age of 32 weeks or less at birth and a birth weight of 1500 g or less. Infants whose gestational age was >32 weeks or birth weight was >1500 g were included if they were exposed to oxygen therapy for more than 7 days. A total of 172 infants (84 males and 88 females) had retinal evaluation by indirect ophthalmoscopy from the fourth postnatal week and followed up periodically. Perinatal risk factors for ROP were assessed using univariate and multivariate analysis. Infants who progressed to stage 3 ROP were given laser therapy. RESULTS: Out of the studied 172 infants, 33 infants (19.2%) developed ROP in one or both eyes; 18 (54.5%) cases stage 1, 9 (27.3%) cases stage 2, and 6 (18.2%) cases stage 3. None of the studied neonates presented ROP at stages 4 or 5. The six cases diagnosed as ROP stage 3 underwent laser ablative therapy. Univariate analysis showed that there was a significant relationship between the occurrence of ROP and gestational age (P = 0.000), sepsis (P = 0.004), oxygen therapy (P = 0.018), and frequency of blood transfusions (P = 0.030). However, an insignificant relationship was found between the occurrence of ROP and sex, mode of delivery, birth weight, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, hypotension, phototherapy, duration of oxygen therapy, mechanical ventilation, and CPAP (all P > 0.05). Gestational age, sepsis, oxygen therapy, and frequency of blood transfusions remained significant variables after logistic regression analysis. CONCLUSION: The prevalence of ROP in this study was 19.2%; low gestational age, sepsis, oxygen therapy, and frequent blood transfusions were significant risk factors for ROP. Laser was effective in treatment and decreasing the progression of ROP. As this is a unit based study, a comprehensive countrywide survey on ROP in Egypt is recommended to determine any regional differences in disease prevalence. PMID- 22837622 TI - Screening for diabetic retinopathy: the first telemedicine approach in a primary care setting in Bahrain. AB - PURPOSE: To develop an integrated diabetic retinopathy screening program that uses telemedicine. MATERIALS AND METHODS: In this evaluation of diagnostic technology, six telemedical screening units were established to cover all regions of Bahrain. The units were equipped with a digital fundus camera at the primary health care clinic. Fundus photographs were transmitted via the Internet to a centralized reading center. A retinal specialist at the reading center assessed the images. RESULTS: From 2003 to 2009, 17,490 diabetic patients were screened. Of the screened patients, 20% were diagnosed with diabetic retinopathy. Of these cases, 31% required treatment. CONCLUSION: Telemedicine-based screening program is a feasible and efficient means of detecting diabetic retinopathy and providing treatment. PMID- 22837623 TI - Selective laser trabeculoplasty in Egyptian patients with primary open-angle glaucoma. AB - PURPOSE: To assess the change in intraocular pressure (IOP) in Egyptian patients after selective laser trabeculoplasty (SLT) as a primary or adjunctive treatment for primary open-angle glaucoma (POAG). MATERIALS AND METHODS: One hundred and six eyes with POAG were enrolled in this prospective study. Patients were divided into two groups: recently diagnosed cases with no preoperative medications (group 1) and; patients with confirmed glaucoma on medical therapy (group 2). All patients underwent 360 degrees SLT. Patients were evaluated to 18 months postoperatively. Data were analyzed on postoperative changes in IOP, number of medications and complications. A P-value less than 0.05 was statistically significant. RESULTS: A statistically significant drop in IOP occurred, from 19.55 +/- 4.8 mmHg preoperatively, to 16.03 +/- 2.8 mmHg postoperatively (P < 0.001). Each group had a statistically significant drop in IOP (P < 0.001). There was a statistically significant decrease in the number of medications in group 2 from 2.25 +/- 0.97 medications preoperatively to 1.0 +/- 1.3 medications postoperatively (P = 0.004). No serious complications occurred for the duration of the study. CONCLUSION: SLT can be safely and effectively used as primary or adjunctive therapy for the treatment of POAG. PMID- 22837624 TI - Efficacy, predictability, and safety of laser-assisted subepithelial keratectomy for the treatment of myopia and myopic astigmatism. AB - PURPOSE: The purpose was to report the refractive and visual outcomes of laser assisted subepithelial keratectomy (LASEK) for the treatment of myopia. MATERIALS AND METHODS: A retrospective, noncomparative consecutive case series of 173 of 91 patients who had undergone LASEK is presented. Primary outcome variables included uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), manifest refraction, epithelialization time, pain, haze, and complications. RESULTS: Preoperatively, the mean spherical equivalent (SE) was -3.71 +/- 1.63 D (range, -0.875 D to 8.25 D), and the mean LogMAR BSCVA was -0.0374 +/- 0.0767 D (range, -0.47 D to 0.00 D). On the final visit, the mean SE was -0.05 +/- 0.335 D (range, -1.63 D to 1.00 D), the mean LogMAR UCVA was 0.04674 +/- 0.0771 D (range, -0.3010 D to 0.1249 D) and the mean LogMAR BSCVA was -0.0164 +/- 0.0497 (range 0.3010 to 0.124). All eyes achieved vision of 20/40 or better, and 83.2% of the eyes achieved a vision of 20/25 or better. One 64 (94.94%) and all the eyes were within +/- 0.50 D and +/- 1.00 D of the attempted correction respectively. Complete epithelialization occurred in 4.70 +/- 2.09 days (range, 2-10 days). At the final visit, 79.7% of eyes had a clear cornea. Grade 1 haze developed in 17.34% of the eyes, grade 2 haze developed in 2.89% of eyes developed; no eyes developed grade 3 or 4 haze. CONCLUSIONS: LASEK is a safe, effective, and predictable method for the treatment of myopia and myopic astigmatism. PMID- 22837625 TI - Development and validation of an Arabic version of the Visual Functioning Index VF-14 for cataract patients. AB - PURPOSE: To develop and validate an Arabic version of the Visual Functioning Index (VF-14) for patients with cataracts. MATERIALS AND METHODS: The VF-14 was translated into Arabic by an epidemiologist and an ophthalmologist, both fluent in Arabic and English. The VF-14 was administered to patients diagnosed with cataract at two hospitals in Egypt and two hospitals in Saudi Arabia. Patients were also administered three other forms; the cataract symptoms score (CSS); global measure of vision; and cataract medical form. Internal reliability and external validity were measured. Index sensitivity to visual acuity was detected and potential effective factors were investigated. Correlation analyses were performed. A p value less than 0.05 was considered statistically significant. RESULTS: The translated VF-14 was consistent and reliable (sigma = 0.763, p < 0.0001). It was also statistically significantly sensitive to vision (p < 0.0001). The mean calculated index was 62.18 +/- 19.34, and was highly correlated with; CSS and other scores (p < 0.0001, all cases). Factors that may affect the index are; age, sex, vision, wearing glasses, type, position, and severity of cataract. CONCLUSION: The Arabic VF 14 is a reliable and valid tool for evaluation of both visual functioning and quality of visual life among cataract patients. It is also sensitive to changes in visual acuity, demographic, and clinical characteristics. PMID- 22837627 TI - Olive-harvesting eye injuries. AB - PURPOSE: To document the types of ocular trauma that occurs during the olive harvesting season in a region of the Middle East. MATERIALS AND METHODS: Ophthalmic assessments of all patients were performed by one ophthalmologist. Examinations included visual acuity, slit-lamp evaluation of the anterior segment, intraocular pressure measurement and posterior segment assessment after pupil dilatation. RESULTS: The study cohort comprised 119 patients who presented for ocular injury due to olive harvesting. Seven patients (5.9%) had severe ocular trauma. Two of these patients presented with corneal perforation, and five with retinal edema. Six patients with severe ocular injury were male. CONCLUSIONS: Ocular injuries are common when olives were harvested manually or with sticks. A preventive program to reduce injury should consider environmental and cultural factors. PMID- 22837626 TI - Effects of inhaled fluticasone on intraocular pressure and central corneal thickness in asthmatic children without a family history of glaucoma. AB - PURPOSE: The aim of this study is to report the effects of fluticasone-inhaled corticosteroid on intraocular pressure (IOP) and central corneal thickness (CCT) of asthmatic children without a family history of glaucoma. MATERIALS AND METHODS: In this prospective study, 93 children were divided into two groups: 69 asthmatic children with no family history of glaucoma who were taking inhaled fluticasone propionate 250 MUg daily for at least 6 months (Group 1) and 24 age matched control subjects without asthma (Group 2). Three measurements each, of IOP and CCT, were performed with a hand-held noncontact tonometer and a noncontact specular microscope, respectively, over a 12-week period. The order of IOP and CCT measured were randomized at each visit. Between-group comparison and the relationship between CCT and IOP measurements were investigated. P < 0.05 was statistically significant. RESULTS: The mean age was 8 +/- 2.4 years (range, 5-15 years) and 9 +/- 2.9 years (range, 5-15 years) for Groups 1 and 2, respectively (P = 0.1337). The mean IOP was 14 +/- 3.3 mmHg (range, 10-24 mmHg) and 14 +/- 2.9 mmHg (range, 11-22 mmHg) for Groups 1 and 2, respectively (P = 0.3626). The mean CCT was 531 +/- 30.1 MUm (range, 467-601 MUm) and 519 +/- 47.0 MUm (range, 415589 MUm) for Groups 1 and 2, respectively (P = 0.1625). There was a weak but statistically significant correlation between IOP and CCT in Group 1 (Pearson's R = 0.3580, P = 0.0025). CONCLUSIONS: Inhaled fluticasone at the regular dose used in this study over a short period (6-24 months) was not associated with a significant effect on CCT and IOP measured with noncontact devices in asthmatic children between 5 and 15 years, without a family history of glaucoma. A weak correlation between IOP and CCT values in asthmatic children did exist. PMID- 22837628 TI - Changing indications and surgical techniques for corneal transplantation between 2004 and 2009 at a tertiary referral center. AB - PURPOSE: The aim of this study is to report the indications, techniques, and clinical outcomes of corneal transplantation and investigate any changing trends in surgical techniques over a 6 year period. MATERIALS AND METHODS: Records of patients who had undergone any kind of corneal transplantation at Labbafinejad Medical Center, Tehran, Iran, from January 2004 to December 2009 were reviewed to determine the indications and types of corneal transplantation. Postoperative best-corrected visual acuity, refractive error, graft clarity, and complications were reported. RESULTS: During this period, 1859 eyes of 1624 patients with a mean age of 41.3 +/- 21.3 years underwent corneal transplantation. The most common indication was keratoconus (38.4%) followed by aphakic/pseudophakic bullous keratopathy (11.7%), previous failed grafts (10.6%), infectious corneal ulcers (10.1%), non-herpetic corneal scars (7.6%), trachoma keratopathy (4.7%), stromal corneal dystrophies (4.6%), post-herpetic corneal scar (3.7%), Fuchs' endothelial dystrophy (0.8%), and congenital hereditary endothelial dystrophy (0.4%). Techniques of corneal transplantation included penetrating keratoplasty (PKP; 70.9%), deep anterior lamellar keratoplasty (DALK; 20.1%), conventional lamellar keratoplasty (LKP; 4.4%), and Descemet's stripping automated endothelial keratoplasty (DSAEK; 2.3%). Over the study period, there was a significant increase in the relative frequency of infectious corneal ulcers, failed grafts, and trachoma keratopathy. Additionally, a significant reduction was observed in PKP and LKP procedures, and volume of DALK and DSAEK increased significantly. At final follow-up, 69.0% of grafts were clear in the PKP group. This figure was 82.6%, 82.7%, and 97.6% in the DALK, LKP, and DSAEK groups, respectively. CONCLUSION: Keratoconus was the most common indication and PKP was the most prevalent technique used for corneal transplantation. However, significant changes in the indications and surgical techniques were observed from 2004 to 2009. PMID- 22837629 TI - Comparison of levobupivacaine 0.5% or bupivacaine 0.5% both in a mixture with lidocaine 2% for superficial extraconal blockade. AB - PURPOSE: To evaluate the quality and efficacy of Peribulbar blockade for superficial extraconal anesthesia with levobupivacaine 0.5% versus bupivacaine 0.5%, both combined with lidocaine 2% for patients undergoing phacoemulsification. MATERIALS AND METHODS: In this prospective, double blind study, 150 patients were randomly divided into two groups: group-1 received a Peribulbar block (PB) with a mixture of evobupivacaine 0.5% and lidocaine 2% while group-2 received a PB with a mixture of bupivacaine 0.5% and lidocaine 2%. The block was performed by insertion of a short needle (15 mm) in infra-temporal space just above inferior orbital notch. An initial volume of 6 9 ml of either mixture was injected until total upper eyelid drop. Akinesia score was assessed at 2, 5, and 10 min after the block. The degree of pain was assessed by a verbal rating scale immediately after block, at the end of surgery and 4 h postoperatively. The patients and surgeons were asked to rate their satisfaction level of the quality of block postoperatively. Data were analyzed with the unpaired, two-tailed t-test and the Chi-square test as appropriate. P < 0.05 was considered statistically significant. RESULTS: There were no significant differences between groups with respect to the akinesia score (P = 0.2) at 2, 5, and 10 min, the number of supplementary injections (P = 0.84) and initial and total required volume of local anesthetics (P = 0.80 and 0.81, respectively). There was no significant difference between the groups regarding surgeon and patient satisfaction (P = 0.53 and P = 0.74, respectively). Similarly the verbal rating scales assessed at three different occasions were not significantly different between the groups (P > 0.05 all cases). The need for additional intra operative topical anesthetic was also similar between the groups. (P = 0.69). CONCLUSIONS: Superficial extra-conal block with a mixture of levobupivicaine 0.5% and lidocaine 2% or bupivicaine 0.5% and lidocaine 2% provides similar block quality and efficacy. PMID- 22837630 TI - Bilateral traumatic expulsive aniridia after phacoemulsification. AB - We report a case of bilateral traumatic expulsive aniridia after uneventful phacoemulsification through small clear corneal incisions. Phacoemulsification was performed 8 and 13 months prior to the trauma in the left and right eyes, respectively. In both eyes, the intraocular lens and capsular bag were undisturbed after trauma. After resolution of hyphema, transient elevated intraocular pressure, and anterior chamber inflammation, best corrected visual acuity returned to 20/25 in each eye 6 months later. Self-sealing clear corneal wounds likely serve as a decompression valve during blunt trauma, thus preventing devastating intraocular damage and globe rupture. The intraocular lens may absorb the external force, therefore preventing damage to the capsular bag and zonules as well as preventing prolapse of posterior structures. A review of previously reported cases of traumatic aniridia is also presented. PMID- 22837631 TI - Imaging studies in a case of infectious scleritis after pterygium excision. AB - A 44-year-old woman presented with a painful red eye for 2 weeks. Ultrasound biomicroscopy and optical coherence tomography were instrumental in the diagnosis and management of this case of infectious scleritis associated with previous pterygium excision complicated by choroidal and retinal detachments. PMID- 22837632 TI - Optic nerve thickening and infarction as the first evidence of orbital involvement with mucormycosis. AB - We report a 53-year-old female with uncontrolled diabetes mellitus who presented with decreased vision in the right eye for a few hours duration. Orbital computed tomography and magnetic resonance imaging were performed at presentation and showed a thickening and infarction of the right optic nerve with no other orbital abnormalities. A few days later, the patient developed necrosis in the region of the right medial canthus and nasal mucosa. Tissue biopsy confirmed the diagnosis of mucormycosis. PMID- 22837633 TI - Spontaneous, uncomplicated dissolution of a large cotton fiber in the laser in situ keratomileusis interface. AB - In this article, we report the spontaneous dissolution of a long cotton thread in the laser in situ keratomileusis (LASIK) flap interface. In this observational case report, sequential follow-up of a post-LASIK eye with a long cotton fiber noticed in the LASIK interface was performed. The postoperative course was uneventful, with no evidence of infection, uveitis, or any other complications. The cotton thread underwent spontaneous dissolution. Conservative management of a cotton fiber, not causing any symptoms and noticed after the immediate postoperative follow-up period is over, seems to be a possible alternative to flap relift and intervention. PMID- 22837634 TI - Vitreous asteroid hyalosis prolapse into the anterior chamber simulating iris metastasis. AB - Two asymptomatic elderly women who underwent cataract extraction 7 or more years previously and with intraocular lens placement presented with a linear bead-like white multinodular mass in the inferior angle simulating iris metastasis versus large inflammatory precipitates. There was no iris infiltration. In the first case, the posterior lens capsule was intact and there was no evidence of gelatinous vitreous in the anterior chamber, whereas in the second case, the capsule was open and there was gelatinous vitreous prolapse. In both cases, there was asteroid hyalosis in the vitreous. Both patients were diagnosed with prolapsed vitreous asteroid hyalosis into the anterior chamber and managed with observation. Vitreous asteroid hyalosis can prolapse into the anterior chamber of pseudophakic elderly patients with or without capsular opening and can simulate an intraocular tumor. PMID- 22837635 TI - Dirofilaria in the anterior chamber: a rare occurrence. AB - Dirofilariasis is a parasitic infection of the carvivores that may present as a zoonotic infestation in humans. Systemic involvement in man is subcutaneous, pulmonary, or ocular. We report a rare occurrence of ocular dirofilariasis in a 25-year-old male patient who presented with pain and redness in the eye. A live, white, coiled, and highly motile worm was present in the anterior chamber. The worm, however, could not be detected in the anterior chamber, posterior segment, or the angle of the anterior chamber when the patient was taken to the operating room for surgical removal of the worm. The patient was made to lie prone till the worm reappeared in the anterior chamber and was removed by paracentesis. The worm was identified as Dirofilaria repens on the basis of microscopic and histopathological examination. PMID- 22837636 TI - Successful removal of a conjunctival myxoma. AB - A 45-year-old woman presented with conjunctival myxoma in the right eye. A mixture of healon and trypan blue solution 0.06 mg was injected through a 27 gauge needle into the conjunctiva to delineate the lesion to achieve complete removal. This technique is effective in delineating the myxoma while preserving its integrity during removal. It may also help in lowering recurrence. PMID- 22837637 TI - Breadth of Extracurricular Participation and Adolescent Adjustment Among African American and European-American Youth. AB - We examined the linear and nonlinear relations between breadth of extracurricular participation in 11th grade and developmental outcomes at 11th grade and 1 year after high school in an economically diverse sample of African-American and European-American youth. In general, controlling for demographic factors, children's motivation, and the dependent variable measured 3 years earlier, breadth was positively associated with indicators of academic adjustment at 11th grade and at 1 year after high school. In addition, for the three academic outcomes (i.e., grades, educational expectations, and educational status) the nonlinear function was significant; at high levels of involvement the well-being of youth leveled off or declined slightly. In addition, breadth of participation at 11th grade predicted lower internalizing behavior, externalizing behavior, alcohol use, and marijuana use at 11th grade. Finally, the total number of extracurricular activities at 11th grade was associated with civic engagement 2 years later. PMID- 22837638 TI - Predicting Positive Citizenship from Adolescence to Young Adulthood: The Effects of a Civic Context. AB - Researchers have theorized that programs to promote positive citizenship should begin with an opportunity for adolescents to participate in civic activities, such as community service or political volunteering. In this article we extend the theory by arguing that a more systemic approach is needed, in which a civic context is developed to promote citizenship. We hypothesize that living within a consistent civic context leads to civic engagement in late adolescence and into young adulthood. We use a diverse, longitudinal dataset to test this hypothesis. We find that social interactions with peers, parent modeling of civic behaviors, and cultural factors, such as ethnicity-specific practices, cumulatively result in a higher level of civic activities among youth and that a continued context that includes these factors results in a higher level of civic activities into adulthood. The implications of our findings are discussed with regard to program and policy development. PMID- 22837639 TI - Circulating Immune Complex Levels are Associated with Disease Severity and Seasonality in Children with Malaria from Mali. AB - Complement receptor one (CR1) is essential for removing circulating immune complexes (CIC), with malaria infection contributing to the formation of large amounts of CIC. We investigated CIC levels in children with malaria, of varying severity and seasonality. Two hundred age and sex-matched severe and mild malaria cases were studied during and after active disease. Pediatric controls had increased CIC levels (mean = 32 MUg mEq/mL) compared to adult controls (mean = 26.9 MUg mEq/mL). The highest levels of CIC were reported in severe malaria (mean = 39 MUg mEq/mL). Higher levels of CIC were recorded in younger children and those with low E-CR1 copy numbers. Our data suggest that low levels of E-CR1 copy numbers, found in children with severe malaria, may adversely affect the ability to remove IC. Furthermore, the high background for circulating immune complex imply that Malian children are under constant assault by other pathogens that evoke a strong immune response. PMID- 22837640 TI - Biomarkers of disease and treatment in murine and cynomolgus models of chronic asthma. AB - BACKGROUND: Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. OBJECTIVE: Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. METHODS: The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. RESULTS: Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3gamma, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. CONCLUSIONS AND CLINICAL RELEVANCE: These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination. PMID- 22837641 TI - A calculation model for serum ionized calcium based on an equilibrium equation for complexation. AB - Measurement of ionized calcium is more important than measurement of total calcium in serum samples. In the present study, equations were derived from complexation and acid dissociation equilibrium equations, and were used to determine the concentration of ionized calcium from the observed serum concentrations of total calcium, albumin, total protein, and inorganic phosphate. The ionized calcium concentration was calculated in 67 serum samples from healthy subjects and 34 outpatients previously identified as having abnormal serum calcium levels. The correlation coefficient between our method (y) and the calcium-ion-selective electrode method (x) was 0.953 and the linear regression equation was y = 0.97x at pH 7.4 with a factor of alpha = 0.21, which was based on the differences between the concentrations of calcium phosphorus compounds obtained by the electrode method and by calculation. The developed calculation is as useful and accurate as the electrode method, and therefore extremely useful for clinical diagnoses. PMID- 22837643 TI - Simple f test reveals gene-gene interactions in case-control studies. AB - Missing heritability is still a challenge for Genome Wide Association Studies (GWAS). Gene-gene interactions may partially explain this residual genetic influence and contribute broadly to complex disease. To analyze the gene-gene interactions in case-control studies of complex disease, we propose a simple, non parametric method that utilizes the F-statistic. This approach consists of three steps. First, we examine the joint distribution of a pair of SNPs in cases and controls separately. Second, an F-test is used to evaluate the ratio of dependence in cases to that of controls. Finally, results are adjusted for multiple tests. This method was used to evaluate gene-gene interactions that are associated with risk of Type 2 Diabetes among African Americans in the Howard University Family Study. We identified 18 gene-gene interactions (P < 0.0001). Compared with the commonly-used logistical regression method, we demonstrate that the F-ratio test is an efficient approach to measuring gene-gene interactions, especially for studies with limited sample size. PMID- 22837642 TI - DNA structural properties in the classification of genomic transcription regulation elements. AB - It has been long known that DNA molecules encode information at various levels. The most basic level comprises the base sequence itself and is primarily important for the encoding of proteins and direct base recognition by DNA-binding proteins. A more elusive level consists of the local structural properties of the DNA molecule wherein the DNA sequence only plays an indirect supportive role. These properties are nevertheless an important factor in a large number of biomolecular processes and can be considered as informative signals for the presence of a variety of genomic features. Several recent studies have unequivocally shown the benefit of relying on such DNA properties for modeling and predicting genomic features as diverse as transcription start sites, transcription factor binding sites, or nucleosome occupancy. This review is meant to provide an overview of the key aspects of these DNA conformational and physicochemical properties. To illustrate their potential added value compared to relying solely on the nucleotide sequence in genomics studies, we discuss their application in research on transcription regulation mechanisms as representative cases. PMID- 22837644 TI - Insulin-like growth factor 1 gene polymorphism and breast cancer risk among arab omani women: a case-control study. AB - Breast cancer is the most common cancer worldwide with significant global burden. Insulin-like growth factor 1 (IGF1) is an important regulator of cellular growth, differentiation, and apoptosis and mitogenic and antiapoptotic activities. Some studies suggested an association between cytosine adenine (CA) repeats gene polymorphisms of IGF1 and the risk of developing breast cancer while other studies did not find such an association. This study aims investigate the role of IGF1 (CA) repeats gene polymorphisms in the risk of developing breast cancer among Omani women. METHODS: We analyzed (CA) repeats gene polymorphisms of IGF1 by extraction of genomic DNA from the peripheral blood of 147 patients with breast cancer and 134 control participants and performed genotyping using DNA sequencing. RESULTS: Approximately 46% of patients carried the IGF (CA)(19) repeat allele, with 31.3% carrying two copies of this allele and 50% of controls carried the IGF (CA)(19) repeat allele with 30.1% carrying two copies of this allele. The difference of the IGF CA repeat groups was significant between cases and controls with (P =0.02). In contrast, there was no difference in the distribution of (CA)(19) repeat allele, (CA)(18) repeat allele and (CA)(19) repeat allele between cases and controls. The difference of the CA groups was significant between cases and controls among postmenopausal women with (P =0.026), whereas no difference was observed among postmenopausal subjects (P =0.429). In both pre- and postmenopausal groups there was no difference in the distribution of (CA)(19) repeat allele, (CA)(18) repeat allele and (CA)(20) repeat allele between patients and control subjects. On further IGF1 genotypes classification, we found an association between progesterone receptor status and the genotypes group where the non carrier of (CA)(19) repeat group was compared to (CA)(19) repeat carrier group (OR =2.482; 95% CI =1.119-5.503; P value =0.023). CONCLUSION: Overall there was no association between the IGF (CA)(19) repeat and breast cancer in Omani females. PMID- 22837646 TI - Kikuchi fujimoto disease. AB - In order to determine the clinical significance of Kikuchi Fujimoto Disease (histiocytic necrotizing lymhadenitis) and to review the literature available on this condition, we selected the Medicine research papers in English language published between the years 1972 to 2011.Kikuchi Fujimoto Disease (KFD) is an uncommon, cosmopolitan, benign and self-limiting condition with higher Japanese and Asian prevalence. Most of the sufferers of KFD are young people who seek treatment because of having acute tender cervical lymphadenopathy, low grade fever and night sweats. Coagulative necrosis with ample karyorrhetic debris in paracortical areas of the involved lymph nodes is the characteristic histologic feature of KFD. Diagnosing KFD is crucial as it can be mistaken for malignant lymphoma and SLE.KFD was put forth first time in 1972 by Dr. Masahiro Kikuchi and by Funimoto as lymphadenitis with reticular proliferation, histiocytes and abundant nuclear debris. It is a rare benign condition of lymph nodes and most of the clinicians and pathologists are unfamiliar with it. KFD is self-limiting disease (within 1 to 4 months), however, patients should be followed up regularly as it may crop up again or progress to SLE. Analgesics and antipyretics help to ameliorate the symptoms. PMID- 22837645 TI - Kynurenine Pathway in Skin Cells: Implications for UV-Induced Skin Damage. AB - The kynurenine pathway (KP) is the principle route of catabolism of the essential amino acid tryptophan, leading to the production of several neuroactive and immunoregulatory metabolites. Alterations in the KP have been implicated in various neuropsychiatric and neurodegenerative diseases, immunological disorders, and many other diseased states. Although the role of the KP in the skin has been evaluated in small niche fields, limited studies are available regarding the effect of acute ultra violet exposure and the induction of the KP in human skin derived fibroblasts and keratinocytes. Since UV exposure can illicit an inflammatory component in skin cells, it is highly likely that the KP may be induced in these cells in response to UV exposure. It is also possible that some KP metabolites may act as pro-inflammatory and anti-inflammatory mediators, since the KP is important in immunomodulation. PMID- 22837647 TI - Violence Exposure and the Development of School-Related Functioning: Mental Health, Neurocognition, and Learning. AB - The relation between history of violence exposure and the development of academic and mental health problems is explored. Violence exposed children have an increased risk of developing school-related problems including: mental health problems, learning disabilities, language impairments, and other neurocognitive problems. These problems interact to create a complex web of deficits and disabilities where intervention access points are difficult to assess. Often mental health problems and academic problems develop in parallel. Timing of violence exposure and the developmental stage of the child during exposure complicate our understanding of the underlying mechanism. A model is presented that explores pathways linking violence exposure to aspects of school-related functioning, both academically and behaviorally. Early life stress, in the form of violence exposure, is related to neurocognitive deficits, including executive functioning and problems in self-regulation. Deficits in self-regulation at the level of behavior, and cognitive control and executive functioning, at the level of brain processing, are related to both academic and mental health problems, suggesting a possible psychological mechanism. Biological mechanisms are also included in the model to illustrate the contribution of the stress response, neuroendocrine system response, and neuroanatomical structural and functional impairments associated with violence exposure. PMID- 22837648 TI - Influence of "glow discharge plasma" as an external stimulus on the self assembly, morphology and binding affinity of gold nanoparticle-streptavidin conjugates. AB - In this study, we investigate the influence of glow discharge plasma (GDP) on the self-assembly, morphology and binding affinity of streptavidin coated gold nanoparticles (Au-NP-SV) and biotinylated antibody (bAb) adsorbed on a highly oriented pyrolytic graphite (HOPG) substrate. Atomic force microscope (AFM) was used to image the pre- and post-GDP treated samples. The analysis of the AFM images showed a considerable change in the aggregation and morphology of Au-NP conjugates after treatment with GDP. To our knowledge, this is the first report on using GDP to enhance and speed-up the aggregation (sintering) of adsorbed NP biomolecular conjugates. These results show a promising route that could be generalized for other NPs and their conjugates. It can also be considered as an alternative and cheap aggregation method for controlling the binding affinity of biomolecular species on different surfaces with interesting applications. PMID- 22837649 TI - Apoptosis signaling is altered in CD4+CD25+FoxP3+ T regulatory lymphocytes in pre eclampsia. AB - The aim of our study was to estimate the surface expressions of CD95 (APO-1/Fas) antigen and the intracellular expressions of anti-apoptotic protein Bcl-2 and pro apoptotic protein Bax in CD4(+)CD25(+)FoxP3(+) T regulatory lymphocytes (Tregs) as well as the percentage of CD8(+)CD28(+) T cytotoxic cells in peripheral blood of patients with pre-eclampsia in comparison with healthy pregnant women in the third trimester of physiological pregnancy. Twenty-four women with pre-eclampsia and 20 normal third trimester pregnant women were included in the study. The lymphocytes were isolated from peripheral blood samples and labeled with monoclonal antibodies. The expressions of surface antigens and intracellular proteins were estimated using flow cytometry. The population of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower in peripheral blood of patients with pre-eclampsia when compared to normal third trimester pregnant women. The percentages of CD4(+)CD25(+)FoxP3(+) Treg cells that express Bcl-2 protein were significantly lower in peripheral blood of patients with pre eclampsia when compared to healthy pregnant women, whereas the percentages of CD4(+)CD25(+)FoxP3(+) Treg cells with the expressions of Bax protein did not differ in both groups. Moreover, the mean fluorescence intensity (MFI) of Bcl-2 protein in CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower and MFI of Bax protein significantly higher in pre-eclampsia when compared to the control group. The percentage of CD8(+)CD28(+) T cells did not differ in both studied groups but MFI of CD28 antigen on T CD8(+) cells was significantly higher in pre eclampsia when compared to the control group. The obtained results suggest that the deficit of CD4(+)CD25(+)FoxP3(+) Treg lymphocytes which is observed in pre eclampsia may be associated with altered apoptosis signaling in Tregs. PMID- 22837650 TI - State of the art in silico tools for the study of signaling pathways in cancer. AB - In the last several years, researchers have exhibited an intense interest in the evolutionarily conserved signaling pathways that have crucial roles during embryonic development. Interestingly, the malfunctioning of these signaling pathways leads to several human diseases, including cancer. The chemical and biophysical events that occur during cellular signaling, as well as the number of interactions within a signaling pathway, make these systems complex to study. In silico resources are tools used to aid the understanding of cellular signaling pathways. Systems approaches have provided a deeper knowledge of diverse biochemical processes, including individual metabolic pathways, signaling networks and genome-scale metabolic networks. In the future, these tools will be enormously valuable, if they continue to be developed in parallel with growing biological knowledge. In this study, an overview of the bioinformatics resources that are currently available for the analysis of biological networks is provided. PMID- 22837651 TI - Identification of Late Embryogenesis Abundant (LEA) protein putative interactors using phage display. AB - Arabidopsis thaliana seeds without functional SEED MATURATION PROTEIN1 (SMP1), a boiling soluble protein predicted to be of intrinsic disorder, presumed to be a LATE EMBRYOGENESIS ABUNDANT (LEA) family protein based on sequence homology, do not enter secondary dormancy after 3 days at 40 degrees C. We hypothesized that SMP1 may protect a heat labile protein involved in the promotion of secondary dormancy. Recombinant SMP1 and GmPM28, its soybean (Glycine max), LEA4 homologue, protected the labile GLUCOSE-6-PHOSPHATE DEHYROGENASE enzyme from heat stress, as did a known protectant, Bovine Serum Albumin, whether the LEA protein was in solution or attached to the bottom of microtiter plates. Maintenance of a biological function for both recombinant LEA proteins when immobilized encouraged a biopanning approach to screen for potential protein interactors. Phage display with two Arabidopsis seed, T7 phage, cDNA libraries, normalized for transcripts present in the mature, dehydrated, 12-, 24-, or 36-h imbibed seeds, were used in biopans against recombinant SMP1 and GmPM28. Phage titer increased considerably over four rounds of biopanning for both LEA proteins, but not for BSA, at both 25 and at 41 degrees C, regardless of the library used. The prevalence of multiple, independent clones encoding portions of specific proteins repeatedly retrieved from different libraries, temperatures and baits, provides evidence suggesting these LEA proteins are discriminating which proteins they protect, a novel finding. The identification of putative LEA-interacting proteins provides targets for reverse genetic approaches to further dissect the induction of secondary dormancy in seeds in response to heat stress. PMID- 22837652 TI - Effect of calcium and potassium on antioxidant system of Vicia faba L. Under cadmium stress. AB - Cadmium (Cd) in soil poses a major threat to plant growth and productivity. In the present experiment, we studied the effect of calcium (Ca(2+)) and/or potassium (K(+)) on the antioxidant system, accumulation of proline (Pro), malondialdehyde (MDA), and content of photosynthetic pigments, cadmium (Cd) and nutrients, i.e., Ca(2+) and K(+) in leaf of Vicia faba L. (cv. TARA) under Cd stress. Plants grown in the presence of Cd exhibited reduced growth traits [root length (RL) plant(-1), shoot length (SL) plant(-1), root fresh weight (RFW) plant(-1), shoot fresh weight (SFW) plant(-1), root dry weight (RDW) plant(-1) and shoot dry weight (SDW) plant(-1)] and concentration of Ca(2+), K(+), Chlorophyll (Chl) a and Chl b content, except content of MDA, Cd and (Pro). The antioxidant enzymes [peroxidase (POD) and superoxide dismutase (SOD)] slightly increased as compared to control under Cd stress. However, a significant improvement was observed in all growth traits and content of Ca(2+), K(+), Chl a, Chl b, Pro and activity of antioxidant enzymes catalase (CAT), POD and SOD in plants subjected to Ca(2+) and/or K(+). The maximum alleviating effect was recorded in the plants grown in medium containing Ca(2+) and K(+) together. This study indicates that the application of Ca(2+) and/or K(+) had a significant and synergistic effect on plant growth. Also, application of Ca(2+) and/or K(+) was highly effective against the toxicity of Cd by improving activity of antioxidant enzymes and solute that led to the enhanced plant growth of faba bean plants. PMID- 22837653 TI - Pharmacophore and molecular docking guided 3D-QSAR study of bacterial enoyl-ACP reductase (FabI) Inhibitors. AB - Enoyl acyl carrier protein (ACP) reductase (FabI) is a potential target for the development of antibacterial agents. Three-dimensional quantitative structure activity relationships (3D-QSAR) for substituted formamides series of FabI inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore and molecular docking methods were used for construction of the molecular alignments. A training set of 36 compounds was performed to create the 3D-QSAR models and their external predictivity was proven using a test set of 11 compounds. Graphical interpretation of the results revealed important structural features of the formamides related to the active site of FabI. The results may be exploited for further optimization of the design of new potent FabI inhibitors. PMID- 22837654 TI - Synthesis and characterization of polyethylene glycol mediated silver nanoparticles by the green method. AB - The roles of green chemistry in nanotechnology and nanoscience fields are very significant in the synthesis of diverse nanomaterials. Herein, we report a green chemistry method for synthesized colloidal silver nanoparticles (Ag NPs) in polymeric media. The colloidal Ag NPs were synthesized in an aqueous solution using silver nitrate, polyethylene glycol (PEG), and beta-D-glucose as a silver precursor, stabilizer, and reducing agent, respectively. The properties of synthesized colloidal Ag NPs were studied at different reaction times. The ultraviolet-visible spectra were in excellent agreement with the obtained nanostructure studies performed by transmission electron microscopy (TEM) and their size distributions. The Ag NPs were characterized by utilizing X-ray diffraction (XRD), zeta potential measurements and Fourier transform infrared (FT IR). The use of green chemistry reagents, such as glucose, provides green and economic features to this work. PMID- 22837655 TI - Proximate composition and antioxidant potential of leaves from three varieties of Mulberry (Morus sp.): a comparative study. AB - In this study, leaves of three indigenous varieties of Mulberry namely, Morus alba L., Morus nigra L. and Morus rubra L. were investigated for their antioxidant potential and their proximate composition was determined. The yields of 80% methanolic extracts ranged between 8.28-13.89%. The contents of total phenolics (TPC), total flavonoids (TFC) and ascorbic acid (AA) ranged between 16.21-24.37 mg gallic acid equivalent (GAE)/g, 26.41-31.28 mg rutin equivalent (RE)/g and 0.97-1.49 mg/g, respectively. The antioxidant activity of leaf extracts was evaluated by measuring 1,1-diphenyl-2-picrylhydrazyl (DPPH(*)) radical scavenging actity, 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid (ABTS(*+)) radical cation scavenging capacity and ferric ion reducing power and values ranged between 1.89-2.12, 6.12-9.89 and 0.56-0.97 mM Trolox equivalent/g of dried leaves, respectively. The investigated features reveal good nutritive and antioxidant attributes of all the varieties with mutually significant differences. PMID- 22837656 TI - Pharmacological classification and activity evaluation of furan and thiophene amide derivatives applying semi-empirical ab initio molecular modeling methods. AB - Pharmacological and physicochemical classification of the furan and thiophene amide derivatives by multiple regression analysis and partial least square (PLS) based on semi-empirical ab initio molecular modeling studies and high-performance liquid chromatography (HPLC) retention data is proposed. Structural parameters obtained from the PCM (Polarizable Continuum Model) method and the literature values of biological activity (antiproliferative for the A431 cells) expressed as LD(50) of the examined furan and thiophene derivatives was used to search for relationships. It was tested how variable molecular modeling conditions considered together, with or without HPLC retention data, allow evaluation of the structural recognition of furan and thiophene derivatives with respect to their pharmacological properties. PMID- 22837657 TI - Intravascular targets for molecular contrast-enhanced ultrasound imaging. AB - Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, which provide contrast during ultrasound imaging, can be targeted to specific molecular markers. These microbubbles accumulate in tissue with target (over) expression, thereby significantly increasing the ultrasound signal. This concept offers safe and low-cost imaging with high spatial resolution and sensitivity. It is therefore considered to have great potential in cancer imaging, and early phase clinical trials are ongoing. In this review, we summarize the current literature on targets that have been successfully imaged in preclinical models using molecularly targeted ultrasound contrast agents. Based on preclinical experience, we discuss the potential clinical utility of targeted microbubbles. PMID- 22837658 TI - Perforin expression by CD4+ regulatory T cells increases at multiple sclerosis relapse: sex differences. AB - Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ T(Reg) in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (T(Reg)) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ T(Reg) in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ T(Reg) playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ T(Reg) in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ T(Reg) in MS, and contributes to the understanding of MS pathophysiology. PMID- 22837659 TI - 8-oxoguanine DNA glycosylases: one lesion, three subfamilies. AB - Amongst the four bases that form DNA, guanine is the most susceptible to oxidation, and its oxidation product, 7,8-dihydro-8-oxoguanine (8-oxoG) is the most prevalent base lesion found in DNA. Fortunately, throughout evolution cells have developed repair mechanisms, such as the 8-oxoguanine DNA glycosylases (OGG), which recognize and excise 8-oxoG from DNA thereby preventing the accumulation of deleterious mutations. OGG are divided into three subfamilies, OGG1, OGG2 and AGOG, which are all involved in the base excision repair (BER) pathway. The published structures of OGG1 and AGOG, as well as the recent availability of OGG2 structures in both apo- and liganded forms, provide an excellent opportunity to compare the structural and functional properties of the three OGG subfamilies. Among the observed differences, the three-dimensional fold varies considerably between OGG1 and OGG2 members, as the latter lack the A domain involved in 8-oxoG binding. In addition, all three OGG subfamilies bind 8 oxoG in a different manner even though the crucial interaction between the enzyme and the protonated N7 of 8-oxoG is conserved. Finally, the three OGG subfamilies differ with respect to DNA binding properties, helix-hairpin-helix motifs, and specificity for the opposite base. PMID- 22837660 TI - Rapid synthesis and antiviral activity of (quinazolin-4-ylamino)methyl phosphonates through microwave irradiation. AB - This study describes the simple synthesis of new (quinazolin-4-ylamino) methylphosphonates via microwave irradiation. Substituted-2-aminobenzonitrile reacted with 1,1-dimethoxy-N,N-dimethylmethanamine at a reflux condition to obtain N'-(substituted-2-cyanophenyl)-N,N-dimethylformamidine (1). The subsequent reaction of this intermediate product with alpha-aminophosphonate (2) in a solution containing glacial acetic acid in 2-propanol through microwave irradiation resulted in the formation of (quinazolin-4-ylamino)methyl-phosphonate derivatives 3a to 3x, which were unequivocally characterized by the spectral data and elemental analysis. The influence of the reaction conditions on the yield of 3a was investigated to optimize the synthetic conditions. The relative optimal conditions for the synthesis of 3a include a 1:1 molar ratio of N'-(2 cyanophenyl)-N,N-dimethylformamidine to diethyl amino(phenyl)methylphosphonate and a 4:1 volume ratio of isopropanol to HOAc in the solvent mixture, at a reaction temperature of 150 degrees C, with a microwave power of 100 W and a corresponding pressure of 150 psi for 20 min in the microwave synthesizer. The yield of 3a was approximately 79%, whereas those of 3b to 3x were approximately 77% to 86%. Some of the synthesized compounds displayed weak to good anti-Tobacco mosaic virus (TMV) activity. PMID- 22837661 TI - Opuntia humifusa supplementation increased bone density by regulating parathyroid hormone and osteocalcin in male growing rats. AB - We investigated the effect of Opuntia humifusa (O. humifusa) supplementation on bone density and related hormone secretion in growing male rats. Sixteen six-week old male Sprague-Dawley rats were randomly divided into two groups; control diet group (CG, n = 8), and experimental diet group (EG, n = 8). The rats in the CG were given a control diet and those in the EG were given 5% O. humifusa added to the control diet for eight weeks. The serum OC level of the EG was significantly higher than that of the CG, and the serum parathyroid hormone (PTH) level of EG was significantly lower than that of the CG. In addition, the femoral and tibial BMD of the EG were significantly higher values than those of the CG, and the tibial BMC of the EG was significantly higher than that of the CG. These results suggest that O. humifusa supplementation has a positive effect on bone density by suppressing PTH and increasing the OC level in growing male rats. PMID- 22837662 TI - Effects of 3beta-acethyl tormentic acid (3ATA) on ABCC proteins activity. AB - Multidrug resistance (MDR) is considered the main cause of cancer chemotherapy failure and patient relapse. The active drug efflux mediated by transporter proteins of the ABC (ATP-binding cassette) family is the most investigated mechanism leading to MDR. With the aim of inhibiting this transport and circumventing MDR, a great amount of work has been dedicated to identifying pharmacological inhibitors of specific ABC transporters. We recently showed that 3beta-acetyl tormentic acid (3ATA) had no effect on P-gp/ABCB1 activity. Herein, we show that 3ATA strongly inhibited the activity of MRP1/ABCC1. In the B16/F10 and Ma104 cell lines, this effect was either 20X higher or similar to that observed with MK571, respectively. Nevertheless, the low inhibitory effect of 3ATA on A549, a cell line that expresses MRP1-5, suggests that it may not inhibit other MRPs. The use of cells transfected with ABCC2, ABCC3 or ABCC4 showed that 3ATA was also able to modulate these transporters, though with an inhibition ratio lower than that observed for MRP1/ABCC1. These data point to 3ATA as a new ABCC inhibitor and call attention to its potential use as a tool to investigate the function of MRP/ABCC proteins or as a co-adjuvant in the treatment of MDR tumors. PMID- 22837664 TI - The kiss-and-run model of intra-Golgi transport. AB - The Golgi apparatus (GA) is the main station along the secretory pathway. Mechanisms of intra-Golgi transport remain unresolved. Three models compete with each other for the right to be defined as the paradigm. The vesicular model cannot explain the following: (1) lipid droplets and aggregates of procollagen that are larger than coatomer I (COPI)-dependent vesicles are transported across the GA; and (2) most anterograde cargoes are depleted in COPI vesicles. The compartment progression/maturation model has the following problems: (1) most Golgi-resident proteins are depleted in COPI vesicles; (2) there are no COPI vesicles for the recycling of the resident proteins in the trans-most-Golgi cisterna; and (3) different proteins have different rates of intra-Golgi transport. The diffusion model based on permanent inter-cisternal connections cannot explain the existence of lipid, ionic and protein gradients across the Golgi stacks. In contrast, the kiss-and-run model has the potential to explain most of the experimental observations. The kiss-and-run model can be symmetric when fusion and then fission occurs in the same place, and asymmetric when fusion takes place in one location, whereas fission takes place in another. The asymmetric kiss-and-run model resembles the carrier maturation mechanism, and it can be used to explain the transport of large cargo aggregates. PMID- 22837665 TI - Ontogenic expression pattern and genetic polymorphisms of the fatty acid transport protein 4 (FATP4) gene in Chinese chicken populations. AB - In the current research, the polymorphism of FATP4 gene was analyzed in Erlang Mountainous chickens. A total of nine genetic variants were identified by FATP4 gene sequencing analysis across the chicken samples. Significant associations (p < 0.05) were observed for two SNPs (g.5608778C>T and g.5608814G>A in exon 6) with certain carcass traits (such as live weight, carcass weight, eviscerated weight) in S01 and S05 populations, respectively. Meanwhile, in S05 population, haplotype 3 (T-G) and haplotype 2 (C-A) were associated with higher and lower partial carcass traits such as live weight, carcass weight, eviscerated weight and semi eviscerated weight, respectively. Moreover, we investigated the expression profile of this gene during ontogenesis in Mountainous black-boned chicken. Quantitative real-time PCR analysis showed that FATP4 mRNA had the highest expression level in small intestine tissue over all other tissues examined. The FATP4 mRNA levels presented remarkable developmental changes with age in the various tissues. These results suggested that the FATP4 gene might play an important role in controlling chicken carcass traits. PMID- 22837663 TI - Mechanistic insights into neurotoxicity induced by anesthetics in the developing brain. AB - Compelling evidence has shown that exposure to anesthetics used in the clinic can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthestics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life. In this paper, we reviewed the possible mechanisms of anesthetic-induced neurotoxicity based on new in vitro and in vivo findings. Also, we discussed ways to protect against anesthetic-induced neurotoxicity and their implications for exploring cellular and molecular mechanisms of neuroprotection. These findings help in improving our understanding of developmental neurotoxicology and in avoiding adverse neurological outcomes in anesthesia practice. PMID- 22837666 TI - Polymorphism in self-assembled structures of 9-anthracene carboxylic acid on Ag(111). AB - Surface self-assembly process of 9-anthracene carboxylic acid (AnCA) on Ag(111) was investigated using STM. Depending on the molecular surface density, four spontaneously formed and one annealed AnCA ordered phases were observed, namely a straight belt phase, a zigzag double-belt phase, two simpler dimer phases, and a kagome phase. The two high-density belt phases possess large unit cells on the scale length of 10 nm, which are seldom observed in molecular self-assembled structures. This structural diversity stems from a complicated competition of different interactions of AnCA molecules on metal surface, including intermolecular and molecular-substrate interactions, as well as the steric demand from high molecular surface density. PMID- 22837667 TI - Role of helicity on the anticancer mechanism of action of cationic-helical peptides. AB - In the present study, the 26-residue amphipathic alpha-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of alpha helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing d-amino acids to replace the original l-amino acids on the non-polar face or the polar face of the helix. Peptide helicity was measured by circular dichroism spectroscopy and was demonstrated to correlate with peptide hydrophobicity and the number of d-amino acid substitutions. Biological studies showed that strong hemolytic activity of peptides generally correlated with high hydrophobicity and helicity. Lower helicity caused the decrease of anti-HeLa activity of peptides. By introducing d-amino acids to replace the original l amino acids on the non-polar face or the polar face of the helix, we improved the therapeutic index of A12L/A20L against HeLa cells by 9-fold and 22-fold, respectively. These results show that the helicity of anticancer peptides plays a crucial role for biological activities. This specific rational approach of peptide design could be a powerful method to improve the specificity of anticancer peptides as promising therapeutics in clinical practices. PMID- 22837668 TI - Determination of aniline and its derivatives in environmental water by capillary electrophoresis with on-line concentration. AB - This paper describes a simple, sensitive and environmentally benign method for the direct determination of aniline and its derivatives in environmental water samples by capillary zone electrophoresis (CZE) with field-enhanced sample injection. The parameters that influenced the enhancement and separation efficiencies were investigated. Surprisingly, under the optimized conditions, two linear ranges for the calibration plot, 1-50 ng/mL and 50-1000 ng/mL (R > 0.998), were obtained. The detection limit was in the range of 0.29-0.43 ng/mL. To eliminate the effect of the real sample matrix on the stacking efficiency, the standard addition method was applied to the analysis of water samples from local rivers. PMID- 22837669 TI - Inflammation amplification by Versican: the first mediator. AB - The effects of inflammation may not always benefit the individual. Its amplifying nature represents a highly regulated biological program, and the inflammatory microenvironment is its essential component. Growing evidence suggests that the ECM (extracellular matrix) is important for the early steps of inflammation. Versican, a ubiquitous component of the ECM, contributes to the formation of the inflammatory response and is highly regulated by cytokines. Certain cytokines exert their initial effects on versican to alter the homeostasis of the inflammatory milieu, and inappropriate production of versican may promote the next inflammatory response. Therefore, versican could be the first step in the amplification of the inflammatory response, and ongoing research of this molecule may help to explain the pathogenesis of inflammation. PMID- 22837670 TI - Fragment C of tetanus toxin: new insights into its neuronal signaling pathway. AB - When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C) can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP 2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport. PMID- 22837671 TI - By-passing large screening experiments using sequencing as a tool to identify scFv fragments targeting atherosclerotic lesions in a novel in vivo phage display selection. AB - Atherosclerosis is a chronic, progressive inflammatory disease that may develop into vulnerable lesions leading to thrombosis. To interrogate the molecular components involved in this process, single-chain variable fragments (scFvs) from a semi-synthetic human antibody library were selected on the lesions induced in a rabbit model of atherosclerosis after two rounds of in vivo phage display. Homing Phage-scFvs were isolated from (1) the injured endothelium, (2) the underlying lesional tissue and (3) the cells within the intima. Clones selected on the basis of their redundancy or the presence of key amino acids, as determined by comparing the distribution between the native and the selected libraries, were produced in soluble form, and seven scFvs were shown to specifically target the endothelial cell surface and inflamed intima-related regions of rabbit tissue sections by immunohistology approaches. The staining patterns differed depending on the scFv compartment of origin. This study demonstrates that large-scale scFv binding assays can be replaced by a sequence-based selection of best clones, paving the way for easier use of antibody libraries in in vivo biopanning experiments. Future investigations will be aimed at characterizing the scFv/target couples by mass spectrometry to set the stage for more accurate diagnostic of atherosclerosis and development of therapeutic strategies. PMID- 22837672 TI - Development of classification models for identifying "true" P-glycoprotein (P-gp) inhibitors through inhibition, ATPase activation and monolayer efflux assays. AB - P-glycoprotein (P-gp) is an efflux pump involved in the protection of tissues of several organs by influencing xenobiotic disposition. P-gp plays a key role in multidrug resistance and in the progression of many neurodegenerative diseases. The development of new and more effective therapeutics targeting P-gp thus represents an intriguing challenge in drug discovery. P-gp inhibition may be considered as a valid approach to improve drug bioavailability as well as to overcome drug resistance to many kinds of tumours characterized by the over expression of this protein. This study aims to develop classification models from a unique dataset of 59 compounds for which there were homogeneous experimental data on P-gp inhibition, ATPase activation and monolayer efflux. For each experiment, the dataset was split into a training and a test set comprising 39 and 20 molecules, respectively. Rational splitting was accomplished using a sphere-exclusion type algorithm. After a two-step (internal/external) validation, the best-performing classification models were used in a consensus predicting task for the identification of compounds named as "true" P-gp inhibitors, i.e., molecules able to inhibit P-gp without being effluxed by P-gp itself and simultaneously unable to activate the ATPase function. PMID- 22837673 TI - Reference gene selection in the desert plant Eremosparton songoricum. AB - Eremosparton songoricum (Litv.) Vass. (E. songoricum) is a rare and extremely drought-tolerant desert plant that holds promise as a model organism for the identification of genes associated with water deficit stress. Here, we cloned and evaluated the expression of eight candidate reference genes using quantitative real-time reverse transcriptase polymerase chain reactions. The expression of these candidate reference genes was analyzed in a diverse set of 20 samples including various E. songoricum plant tissues exposed to multiple environmental stresses. GeNorm analysis indicated that expression stability varied between the reference genes in the different experimental conditions, but the two most stable reference genes were sufficient for normalization in most conditions. EsEF and Esalpha-TUB were sufficient for various stress conditions, EsEF and EsACT were suitable for samples of differing germination stages, and EsGAPDHand EsUBQ were most stable across multiple adult tissue samples. The Es18S gene was unsuitable as a reference gene in our analysis. In addition, the expression level of the drought-stress related transcription factor EsDREB2 verified the utility of E. songoricum reference genes and indicated that no single gene was adequate for normalization on its own. This is the first systematic report on the selection of reference genes in E. songoricum, and these data will facilitate future work on gene expression in this species. PMID- 22837674 TI - A novel chemometric method for the prediction of human oral bioavailability. AB - Orally administered drugs must overcome several barriers before reaching their target site. Such barriers depend largely upon specific membrane transport systems and intracellular drug-metabolizing enzymes. For the first time, the P glycoprotein (P-gp) and cytochrome P450s, the main line of defense by limiting the oral bioavailability (OB) of drugs, were brought into construction of QSAR modeling for human OB based on 805 structurally diverse drug and drug-like molecules. The linear (multiple linear regression: MLR, and partial least squares regression: PLS) and nonlinear (support-vector machine regression: SVR) methods are used to construct the models with their predictivity verified with five-fold cross-validation and independent external tests. The performance of SVR is slightly better than that of MLR and PLS, as indicated by its determination coefficient (R(2)) of 0.80 and standard error of estimate (SEE) of 0.31 for test sets. For the MLR and PLS, they are relatively weak, showing prediction abilities of 0.60 and 0.64 for the training set with SEE of 0.40 and 0.31, respectively. Our study indicates that the MLR, PLS and SVR-based in silico models have good potential in facilitating the prediction of oral bioavailability and can be applied in future drug design. PMID- 22837675 TI - O6-Methylguanine-methyltransferase (MGMT) promoter methylation status in glioma stem-like cells is correlated to temozolomide sensitivity under differentiation promoting conditions. AB - Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to tumor recurrence and TMZ resistance. Recently isolated, glioma stem-like cells (GSCs) are thought to represent the population of tumorigenic cells responsible for GBM resistance and recurrence following surgery and chemotherapy. In addition, MGMT (O6 methylguanine-methyltransferase) methylation is considered as one of the principal mechanisms contributing to TMZ sensitivity of GBM. In this study we have isolated GSCs from 10 adult GBM patients and investigated the relationship between MGMT methylation status and Temozolomide (TMZ) sensitivity of these lines grown either in stem-like or differentiation promoting conditions. Sensitivity to TMZ was significantly associated with MGMT methylation status in cells committed to differentiation but not in stem-like cells. In addition, patients harboring highly methylated MGMT promoters had a longer overall survival. These results reveal the importance of the differentiation process when considering the predictive value of MGMT status in GSCs for clinical response to TMZ. PMID- 22837677 TI - Toward the prediction of FBPase inhibitory activity using chemoinformatic methods. AB - Currently, Chemoinformatic methods are used to perform the prediction for FBPase inhibitory activity. A genetic algorithm-random forest coupled method (GA-RF) was proposed to predict fructose 1,6-bisphosphatase (FBPase) inhibitors to treat type 2 diabetes mellitus using the Mold(2) molecular descriptors. A data set of 126 oxazole and thiazole analogs was used to derive the GA-RF model, yielding the significant non-cross-validated correlation coefficient r(2) (ncv) and cross validated r(2) (cv) values of 0.96 and 0.67 for the training set, respectively. The statistically significant model was validated by a test set of 64 compounds, producing the prediction correlation coefficient r(2) (pred) of 0.90. More importantly, the building GA-RF model also passed through various criteria suggested by Tropsha and Roy with r(2) (o) and r(2) (m) values of 0.90 and 0.83, respectively. In order to compare with the GA-RF model, a pure RF model developed based on the full descriptors was performed as well for the same data set. The resulting GA-RF model with significantly internal and external prediction capacities is beneficial to the prediction of potential oxazole and thiazole series of FBPase inhibitors prior to chemical synthesis in drug discovery programs. PMID- 22837678 TI - Generation of a highly reactive chicken-derived single-chain variable fragment against Fusarium verticillioides by phage display. AB - Fusarium verticillioides is the primary causal agent of Fusarium ear and kernel rot in maize, producing fumonisin mycotoxins that are toxic to humans and domestic animals. Rapid detection and monitoring of fumonisin-producing fungi are pivotally important for the prevention of mycotoxins from entering into food/feed products. Chicken-derived single-chain variable fragments (scFvs) against cell wall-bound proteins from F. verticillioides were isolated from an immunocompetent phage display library. Comparative phage enzyme-linked immunosorbant assays (ELISAs) and sequencing analyses identified four different scFv antibodies with high sensitivity. Soluble antibody ELISAs identified two highly sensitive scFv antibodies, FvCA3 and FvCA4, with the latter being slightly more sensitive. Three dimensional modeling revealed that the FvCA4 may hold a better overall structure with CDRH3, CDRL1 and CDRL3 centered in the core region of antibody surface compared with that of other scFvs. Immunofluorescence labeling revealed that the binding of FvCA4 antibody was localized to the cell walls of conidiospores and hyphae of F. verticillioides, confirming the specificity of this antibody for a surface target. This scFv antibody was able to detect the fungal mycelium as low as 10(-2) MUg/mL and contaminating mycelium at a quantity of 10(-2) mg/g maize. This is the first report that scFv antibodies derived from phage display have a wide application for rapid and accurate detection and monitoring of fumonisin producing pathogens in agricultural samples. PMID- 22837676 TI - Neuroglobin, a novel target for endogenous neuroprotection against stroke and neurodegenerative disorders. AB - Brain neurons and tissues respond to sublethal injury by activating endogenous protective pathways. Recently, following the failure of a large number of clinical trials for protective strategies against stroke that aim to inhibit a specific ischemia response pathway, endogenous neuroprotection has emerged as a more promising and hopeful strategy for development of therapeutics against stroke and neurodegenerative disorders. Neuroglobin (Ngb) is an oxygen-binding globin protein that is highly and specifically expressed in brain neurons. Accumulating evidence have clearly demonstrated that Ngb is an endogenous neuroprotective molecule against hypoxic/ischemic and oxidative stress-related insults in cultured neurons and animals, as well as neurodegenerative disorders such as Alzheimer's disease, thus any pharmacological strategy that can up regulate endogenous Ngb expression may lead to novel therapeutics against these brain disorders. In this review, we summarize recent studies about the biological function, regulation of gene expression, and neuroprotective mechanisms of Ngb. Furthermore, strategies for identification of chemical compounds that can up regulate endogenous Ngb expression for neuroprotection against stroke and neurodegenerative disorders are discussed. PMID- 22837679 TI - A computational study on thiourea analogs as potent MK-2 inhibitors. AB - Mitogen-activated protein kinase-activated protein kinase 2 (MK-2) has been identified as a drug target for the treatment of inflammatory diseases. Currently, a series of thiourea analogs as potent MK-2 inhibitors were studied using comprehensive computational methods by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in activities. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r(2) (ncv), q(2) values of 0.974, 0.536 for the internal validation, and r(2) (pred), r(2) (m) values of 0.910, 0.723 for the external validation and Roy's index, respectively. In addition, more rigorous validation criteria suggested by Tropsha were also employed to check the built models. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules: (i) The substituent with a bulky size and electron-rich group at the C5 position of the pyrazine ring is required to enhance the potency; (ii) The H-bond acceptor group in the C3 position of the pyrazine ring is likely to be helpful to increase MK-2 inhibition; (iii) The small and electropositive substituent as a hydrogen bond donor of the C2 position in the oxazolone ring is favored; In addition, several important amino acid residues were also identified as playing an important role in MK-2 inhibition. The agreement between 3D-QSAR, molecular docking and molecular dynamics simulations also proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential MK-2 inhibitors. PMID- 22837680 TI - Development of 101 gene-based single nucleotide polymorphism markers in sea cucumber, Apostichopus japonicus. AB - Single nucleotide polymorphisms (SNPs) are currently the marker of choice in a variety of genetic studies. Using the high resolution melting (HRM) genotyping approach, 101 gene-based SNP markers were developed for Apostichopus japonicus, a sea cucumber species with economic significance for the aquaculture industry in East Asian countries. HRM analysis revealed that all the loci showed polymorphisms when evaluated using 40 A. japonicus individuals collected from a natural population. The minor allele frequency ranged from 0.035 to 0.489. The observed and expected heterozygosities ranged from 0.050 to 0.833 and 0.073 to 0.907, respectively. Thirteen loci were found to depart significantly from Hardy Weinberg equilibrium (HWE) after Bonferroni corrections. Significant linkage disequilibrium (LD) was detected in one pair of markers. These SNP markers are expected to be useful for future quantitative trait loci (QTL) analysis, and to facilitate marker-assisted selection (MAS) in A. japonicus. PMID- 22837681 TI - Genome-wide DNA methylation changes between the superficial and deep backfat tissues of the pig. AB - Adipose tissue is not only a storage organ involved in fuel metabolism, but also an endocrine organ involved in the regulation of insulin sensitivity, thermogenesis, immunity, and inflammation. There are anatomical, cellular, molecular and physiological differences among adipose tissues deposited in different body sites. However, current understanding of the intrinsic differences between the sub-compartments of the subcutaneous adipose tissue remains rudimentary. Here, we analyzed the genome-wide DNA methylation differences between the porcine superficial and deep backfat tissues using methylated DNA immunoprecipitation combined with high-throughput sequencing. We show that the genes with differentially methylated regions in their promoter are mainly involved in the processes of "lipid metabolism" and "regulation of immune-related cytokines". Compared with the deep backfat tissue, the promoters of genes related to the 'positive regulation of cytokine production' were significantly hypermethylated in the superficial backfat tissue, which reflects the intrinsic functional and metabolic differences between the sub-compartments of the subcutaneous adipose tissue. This study provides epigenetic evidence for functionally relevant methylation differences between different layers of porcine backfat tissues. PMID- 22837683 TI - Target molecular simulations of RecA family protein filaments. AB - Modeling of the RadA family mechanism is crucial to understanding the DNA SOS repair process. In a 2007 report, the archaeal RadA proteins function as rotary motors (linker region: I71-K88) such as shown in Figure 1. Molecular simulations approaches help to shed further light onto this phenomenon. We find 11 rotary residues (R72, T75-K81, M84, V86 and K87) and five zero rotary residues (I71, K74, E82, R83 and K88) in the simulations. Inclusion of our simulations may help to understand the RadA family mechanism. PMID- 22837682 TI - Structural analysis of hypothetical proteins from Helicobacter pylori: an approach to estimate functions of unknown or hypothetical proteins. AB - Helicobacter pylori (H. pylori) have a unique ability to survive in extreme acidic environments and to colonize the gastric mucosa. It can cause diverse gastric diseases such as peptic ulcers, chronic gastritis, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric cancer, etc. Based on genomic research of H. pylori, over 1600 genes have been functionally identified so far. However, H. pylori possess some genes that are uncharacterized since: (i) the gene sequences are quite new; (ii) the function of genes have not been characterized in any other bacterial systems; and (iii) sometimes, the protein that is classified into a known protein based on the sequence homology shows some functional ambiguity, which raises questions about the function of the protein produced in H. pylori. Thus, there are still a lot of genes to be biologically or biochemically characterized to understand the whole picture of gene functions in the bacteria. In this regard, knowledge on the 3D structure of a protein, especially unknown or hypothetical protein, is frequently useful to elucidate the structure-function relationship of the uncharacterized gene product. That is, a structural comparison with known proteins provides valuable information to help predict the cellular functions of hypothetical proteins. Here, we show the 3D structures of some hypothetical proteins determined by NMR spectroscopy and X-ray crystallography as a part of the structural genomics of H. pylori. In addition, we show some successful approaches of elucidating the function of unknown proteins based on their structural information. PMID- 22837685 TI - Antioxidant activities of extract and fractions from receptaculum nelumbinis and related flavonol glycosides. AB - The antioxidant activities of ethanolic crude extract (ECE) and its four different solvent sub-fractions (namely, petroleum ether fraction (PEF), ethyl acetate fraction (EAF), n-butanol fraction (BF) and the aqueous fraction (AF) from the receptacles of Nelumbo nucifera Gaertn. (Receptaculum Nelumbinis) were investigated using two in vitro antioxidant assays. BF showed the highest total phenolic content (607.6 mg/g gallic acid equivalents), total flavonoid content (862.7 mg/g rutin equivalents) and total proanthocyanidin content (331.0 mg/g catechin equivalents), accompanied with the highest antioxidant activity compared to other fractions through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging assays. Five flavonol glycosides, namely hyperoside (1), isoquercitrin (2), quercetin-3-O beta-d-glucuronide (3), isorhamnetin-3-O-beta-d-galactoside (4) and syringetin-3 O-beta-d-glucoside (5) were isolated from the Receptaculum Nelumbinis. Compounds 2-5 were isolated for the first time from the Receptaculum Nelumbinis. The five isolated flavone glycosides, particularly compounds 1-3, demonstrated significant DPPH and ABTS radical scavenging activity, with IC(50) values of 8.9 +/- 0.2, 5.2 +/- 0.2, 7.5 +/- 0.1 for DPPH and 114.2 +/- 1.7, 112.8 +/- 0.8, 172.5 +/- 0.7 MUg/mL for ABTS, respectively. These results suggest that Receptaculum Nelumbinis has strong antioxidant potential and may be potentially used as a safe and inexpensive bioactive source of natural antioxidants. PMID- 22837684 TI - Structural DNA nanotechnology: from design to applications. AB - The exploitation of DNA for the production of nanoscale architectures presents a young yet paradigm breaking approach, which addresses many of the barriers to the self-assembly of small molecules into highly-ordered nanostructures via construct addressability. There are two major methods to construct DNA nanostructures, and in the current review we will discuss the principles and some examples of applications of both the tile-based and DNA origami methods. The tile-based approach is an older method that provides a good tool to construct small and simple structures, usually with multiply repeated domains. In contrast, the origami method, at this time, would appear to be more appropriate for the construction of bigger, more sophisticated and exactly defined structures. PMID- 22837686 TI - Pu-erh tea reduces nitric oxide levels in rats by inhibiting inducible nitric oxide synthase expression through toll-like receptor 4. AB - Pu-erh tea undergoes a unique fermentation process and contains theabrownins, polysaccharides and caffeine; although it is unclear about which component is associated with the down regulation of nitric oxide levels or how this process is mediated. To address this question we examined the effects of pu-erh tea on nitric oxide synthase (NOS) genes. Cohorts of rats were separately given four week treatments of water as control, pu-erh tea, or the tea components: theabrownins, caffeine or polysaccharides. Five experimental groups were injected with lipopolysaccharides (LPS) to induce nitric oxide (NO) production, while the corresponding five control groups were injected with saline as a negative control. The serum and liver NO concentrations were examined and the NOS expression of both mRNA and protein was measured in liver. The results showed that the rats which were fed pu-erh tea or polysaccharides had lower levels of NO which corresponded with the down-regulation of inducible nitric oxide synthase (iNOS) expression. We further demonstrate that this effect is mediated through reduction of Toll-like receptor 4 (TLR4) signaling. Thus we find that the polysaccharide components in pu-erh tea reduce NO levels in an animal model by inhibiting the iNOS expression via signaling through TLR4. PMID- 22837687 TI - Fly ash-based geopolymer lightweight concrete using foaming agent. AB - In this paper, we report the results of our investigation on the possibility of producing foam concrete by using a geopolymer system. Class C fly ash was mixed with an alkaline activator solution (a mixture of sodium silicate and NaOH), and foam was added to the geopolymeric mixture to produce lightweight concrete. The NaOH solution was prepared by dilute NaOH pellets with distilled water. The reactives were mixed to produce a homogeneous mixture, which was placed into a 50 mm mold and cured at two different curing temperatures (60 degrees C and room temperature), for 24 hours. After the curing process, the strengths of the samples were tested on days 1, 7, and 28. The water absorption, porosity, chemical composition, microstructure, XRD and FTIR analyses were studied. The results showed that the sample which was cured at 60 degrees C (LW2) produced the maximum compressive strength for all tests, (11.03 MPa, 17.59 MPa, and 18.19 MPa) for days 1, 7, and 28, respectively. Also, the water absorption and porosity of LW2 were reduced by 6.78% and 1.22% after 28 days, respectively. The SEM showed that the LW2 sample had a denser matrix than LW1. This was because LW2 was heat cured, which caused the geopolymerization rate to increase, producing a denser matrix. However for LW1, microcracks were present on the surface, which reduced the compressive strength and increased water absorption and porosity. PMID- 22837688 TI - Rapid development of microsatellite markers with 454 pyrosequencing in a vulnerable fish, the mottled skate, Raja pulchra. AB - The mottled skate, Raja pulchra, is an economically valuable fish. However, due to a severe population decline, it is listed as a vulnerable species by the International Union for Conservation of Nature. To analyze its genetic structure and diversity, microsatellite markers were developed using 454 pyrosequencing. A total of 17,033 reads containing dinucleotide microsatellite repeat units (mean, 487 base pairs) were identified from 453,549 reads. Among 32 loci containing more than nine repeat units, 20 primer sets (62%) produced strong PCR products, of which 14 were polymorphic. In an analysis of 60 individuals from two R. pulchra populations, the number of alleles per locus ranged from 1-10, and the mean allelic richness was 4.7. No linkage disequilibrium was found between any pair of loci, indicating that the markers were independent. The Hardy-Weinberg equilibrium test showed significant deviation in two of the 28 single-loci after sequential Bonferroni's correction. Using 11 primer sets, cross-species amplification was demonstrated in nine related species from four families within two classes. Among the 11 loci amplified from three other Rajidae family species; three loci were polymorphic. A monomorphic locus was amplified in all three Rajidae family species and the Dasyatidae family. Two Rajidae polymorphic loci amplified monomorphic target DNAs in four species belonging to the Carcharhiniformes class, and another was polymorphic in two Carcharhiniformes species. PMID- 22837689 TI - Nec-1 enhances shikonin-induced apoptosis in leukemia cells by inhibition of RIP 1 and ERK1/2. AB - Necrostatin-1 (Nec-1) inhibits necroptosis by allosterically inhibiting the kinase activity of receptor-interacting protein 1 (RIP1), which plays a critical role in necroptosis. RIP1 is a crucial adaptor kinase involved in the activation of NF-kappaB, production of reactive oxygen species (ROS) and the phosphorylation of mitogen activated protein kinases (MAPKs). NF-kappaB, ROS and MAPKs all play important roles in apoptotic signaling. Nec-1 was regarded as having no effect on apoptosis. Here, we report that Nec-1 increased the rate of nuclear condensation and caspases activation induced by a low concentration of shikonin (SHK) in HL60, K562 and primary leukemia cells. siRNA-mediated knockdown of RIP1 significantly enhanced shikonin-induced apoptosis in K562 and HL60 cells. Shikonin treatment alone could slightly inhibit the phosphorylation of ERK1/2 in leukemia cells, and the inhibitory effect on ERK1/2 was significantly augmented by Nec-1. We also found that Nec-1 could inhibit NF-kappaB p65 translocation to the nucleus at a later stage of SHK treatment. In conclusion, we found that Nec-1 can promote shikonin-induced apoptosis in leukemia cells. The mechanism by which Nec-1 sensitizes shikonin-induced apoptosis appears to be the inhibition of RIP1 kinase dependent phosphorylation of ERK1/2. To our knowledge, this is the first study to document Nec-1 sensitizes cancer cells to apoptosis. PMID- 22837690 TI - Biosysthesis of corn starch palmitate by lipase Novozym 435. AB - Esterification of starch was carried out to expand the usefulness of starch for a myriad of industrial applications. Lipase B from Candida antarctica, immobilized on macroporous acrylic resin (Novozym 435), was used for starch esterification in two reaction systems: micro-solvent system and solvent-free system. The esterification of corn starch with palmitic acid in the solvent-free system and micro-solvent system gave a degree of substitution (DS) of 1.04 and 0.0072 respectively. Esterification of corn starch with palmitic acid was confirmed by UV spectroscopy and IR spectroscopy. The results of emulsifying property analysis showed that the starch palmitate with higher DS contributes to the higher emulsifying property (67.6%) and emulsion stability (79.6%) than the native starch (5.3% and 3.9%). Modified starch obtained by esterification that possesses emulsifying properties and has long chain fatty acids, like palmitic acid, has been widely used in the food, pharmaceutical and biomedical applications industries. PMID- 22837691 TI - Plants versus fungi and oomycetes: pathogenesis, defense and counter-defense in the proteomics era. AB - Plant-fungi and plant-oomycete interactions have been studied at the proteomic level for many decades. However, it is only in the last few years, with the development of new approaches, combined with bioinformatics data mining tools, gel staining, and analytical instruments, such as 2D-PAGE/nanoflow-LC-MS/MS, that proteomic approaches thrived. They allow screening and analysis, at the sub cellular level, of peptides and proteins resulting from plants, pathogens, and their interactions. They also highlight post-translational modifications to proteins, e.g., glycosylation, phosphorylation or cleavage. However, many challenges are encountered during in planta studies aimed at stressing details of host defenses and fungal and oomycete pathogenicity determinants during interactions. Dissecting the mechanisms of such host-pathogen systems, including pathogen counter-defenses, will ensure a step ahead towards understanding current outcomes of interactions from a co-evolutionary point of view, and eventually move a step forward in building more durable strategies for management of diseases caused by fungi and oomycetes. Unraveling intricacies of more complex proteomic interactions that involve additional microbes, i.e., PGPRs and symbiotic fungi, which strengthen plant defenses will generate valuable information on how pathosystems actually function in nature, and thereby provide clues to solving disease problems that engender major losses in crops every year. PMID- 22837692 TI - Evaluation of the antioxidant capacity of synthesized coumarins. AB - Coumarins are secondary metabolites that are widely distributed within the plant kingdom, some of which have been extensively studied for their antioxidant properties. The antioxidant activity of coumarins assayed in the present study was measured by different methods, namely the 1,1-diphenyl-2-picryl-hydrazyl (DPPH(*)) method, cyclic voltammetry and the antioxidant capacity against peroxyl radicals (ACAP) method. The 7,8-dihydroxy-4-methylcoumarin (LaSOM 78), 5-carboxy 7,8-dihydroxy-4-methylcoumarin (LaSOM 79), and 6,7-dihydroxycoumarin (Esculetin) compounds proved to be the most active, showing the highest capacity to deplete the DPPH radicals, the highest antioxidant capacity against peroxyl radicals, and the lowest values of potential oxidation. PMID- 22837693 TI - Oral administration of apigenin inhibits metastasis through AKT/P70S6K1/MMP-9 pathway in orthotopic ovarian tumor model. AB - Apigenin, a flavonoid commonly present in the daily diet, is known for its potential anti-tumor properties. However, the effect of apigenin via oral administration on tumor growth and metastasis remains unknown. In this study we developed an orthotopic ovarian tumor model in nude mice to test the effect of apigenin oral administration, and showed that apigenin inhibited the micrometastasis of cancer cells in the animal tumor model. To understand the mechanism of apigenin in inhibiting metastasis, we found that apigenin greatly inhibited MMP-9 expression and p-AKT and p-p70S6K1 levels in the tumor tissues compared to the control group. We further demonstrated that the downregulation of MMP-9 by apigenin was mediated by the AKT/p70S6K1 pathway. These findings help to address the question with common interests to the public of whether oral uptake of flavonoids is effective in preventing cancer. Our results demonstrate for the first time that oral uptake of apigenin can inhibit tumor metastasis through MMP 9 expression using the orthotopic ovarian tumor model. PMID- 22837694 TI - Function prediction and analysis of mycobacterium tuberculosis hypothetical proteins. AB - High-throughput biology technologies have yielded complete genome sequences and functional genomics data for several organisms, including crucial microbial pathogens of humans, animals and plants. However, up to 50% of genes within a genome are often labeled "unknown", "uncharacterized" or "hypothetical", limiting our understanding of virulence and pathogenicity of these organisms. Even though biological functions of proteins encoded by these genes are not known, many of them have been predicted to be involved in key processes in these organisms. In particular, for Mycobacterium tuberculosis, some of these "hypothetical" proteins, for example those belonging to the Pro-Glu or Pro-Pro-Glu (PE/PPE) family, have been suspected to play a crucial role in the intracellular lifestyle of this pathogen, and may contribute to its survival in different environments. We have generated a functional interaction network for Mycobacterium tuberculosis proteins and used this to predict functions for many of its hypothetical proteins. Here we performed functional enrichment analysis of these proteins based on their predicted biological functions to identify annotations that are statistically relevant, and analysed and compared network properties of hypothetical proteins to the known proteins. From the statistically significant annotations and network information, we have tried to derive biologically meaningful annotations related to infection and disease. This quantitative analysis provides an overview of the functional contributions of Mycobacterium tuberculosis "hypothetical" proteins to many basic cellular functions, including its adaptability in the host system and its ability to evade the host immune response. PMID- 22837696 TI - Herbicide-intercalated zinc layered hydroxide nanohybrid for a dual-guest controlled release formulation. AB - Herbicides, namely 4-(2,4-dichlorophenoxy) butyrate (DPBA) and 2-(3 chlorophenoxy) propionate (CPPA), were intercalated simultaneously into the interlayers of zinc layered hydroxide (ZLH) by direct reaction of zinc oxide with both anions under aqueous environment to form a new nanohybrid containing both herbicides labeled as ZCDX. Successful intercalation of both anions simultaneously into the interlayer gallery space of ZLH was studied by PXRD, with basal spacing of 28.7 A and supported by FTIR, TGA/DTG and UV-visible studies. Simultaneous release of both CPPA and DPBA anions into the release media was found to be governed by a pseudo second-order equation. The loading and percentage release of the DPBA is higher than the CPPA anion, which indicates that the DPBA anion was preferentially intercalated into and released from the ZLH interlayer galleries. This work shows that layered single metal hydroxide, particularly ZLH, is a suitable host for the controlled release formulation of two herbicides simultaneously. PMID- 22837697 TI - Development and characterization of new single nucleotide polymorphism markers from expressed sequence tags in common carp (Cyprinus carpio). AB - The common carp (Cyprinus carpio) is an important aquaculture fish worldwide but only limited single nucleotide polymorphism (SNP) markers are characterized from expressed sequence tags (ESTs) in this species. In this study, 1487 putative SNPs were bioinformatically mined from 14,066 online ESTs mainly from the European common carp, with the occurrence rate of about one SNP every 173 bp. One hundred and twenty-one of these SNPs were selected for validation using PCR fragment sequencing, and 48 out of 81 primers could amplify the expected fragments in the Chinese common carp genome. Only 26 (21.5%) putative SNPs were validated, however, 508 new SNPs and 68 indels were identified. The ratios of transitions to transversions were 1.77 for exon SNPs and 1.05 for intron SNPs. All the 23 SNPs selected for population tests were polymorphic, with the observed heterozygosity (Ho) ranging from 0.053 to 0.526 (mean 0.262), polymorphism information content (PIC) from 0.095 to 0.357 (mean 0.246), and 21 SNPs were in Hardy-Weinberg equilibrium. These results suggest that different common carp populations with geographic isolation have significant genetic variation at the SNP level, and these new EST-SNP markers are readily available for genetics and breeding studies in common carp. PMID- 22837695 TI - The toxicity of amyloid beta oligomers. AB - In this review, we elucidate the mechanisms of Abeta oligomer toxicity which may contribute to Alzheimer's disease (AD). In particular, we discuss on the interaction of Abeta oligomers with the membrane through the process of adsorption and insertion. Such interaction gives rises to phase transitions in the sub-structures of the Abeta peptide from alpha-helical to beta-sheet structure. By means of a coarse-grained model, we exhibit the tendency of beta sheet structures to aggregate, thus providing further insights to the process of membrane induced aggregation. We show that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels. Other pathological progressions to AD due to Abeta oligomers are also covered, such as their interaction with the membrane receptors, and their direct versus indirect effects on oxidative stress and intraneuronal accumulation. We further illustrate that the molecule curcumin is a potential Abeta toxicity inhibitor as a beta-sheet breaker by having a high propensity to interact with certain Abeta residues without binding to them. The comprehensive understanding gained from these current researches on the various toxicity mechanisms show promises in the provision of better therapeutics and treatment strategies in the near future. PMID- 22837698 TI - Solution NMR structure of hypothetical protein CV_2116 encoded by a viral prophage element in Chromobacterium violaceum. AB - CV_2116 is a small hypothetical protein of 82 amino acids from the Gram-negative coccobacillus Chromobacterium violaceum. A PSI-BLAST search using the CV_2116 sequence as a query identified only one hit (E = 2e(-07)) corresponding to a hypothetical protein OR16_04617 from Cupriavidus basilensis OR16, which failed to provide insight into the function of CV_2116. The CV_2116 gene was cloned into the p15TvLic expression plasmid, transformed into E. coli, and (13)C- and (15)N labeled NMR samples of CV_2116 were overexpressed in E. coli and purified for structure determination using NMR spectroscopy. The resulting high-quality solution NMR structure of CV_2116 revealed a novel alpha + beta fold containing two anti-parallel beta-sheets in the N-terminal two-thirds of the protein and one alpha-helix in the C-terminal third of the protein. CV_2116 does not belong to any known protein sequence family and a Dali search indicated that no similar structures exist in the protein data bank. Although no function of CV_2116 could be derived from either sequence or structural similarity searches, the neighboring genes of CV_2116 encode various proteins annotated as similar to bacteriophage tail assembly proteins. Interestingly, C. violaceum exhibits an extensive network of bacteriophage tail-like structures that likely result from lateral gene transfer by incorporation of viral DNA into its genome (prophages) due to bacteriophage infection. Indeed, C. violaceum has been shown to contain four prophage elements and CV_2116 resides in the fourth of these elements. Analysis of the putative operon in which CV_2116 resides indicates that CV_2116 might be a component of the bacteriophage tail-like assembly that occurs in C. violaceum. PMID- 22837699 TI - Role of microglia in oxidative toxicity associated with encephalomycarditis virus infection in the central nervous system. AB - The single-stranded RNA encephalomyocarditis virus (EMCV) can replicate in the central nervous system (CNS) and lead to prominent brain lesions in the stratum pyramidale hippocampus and the stratum granulosum cerebelli. Activated microglia cells infected by EMCV produce a massive burst of reactive oxygen species (ROS) via NADPH oxidase 2 (NOX2) activation, leading to neuronal death. Balancing this effect is mechanisms by which ROS are eliminated from the CNS. Cellular prion protein (PrP(C)) plays an important antioxidant role and contributes to cellular defense against EMCV infection. This review introduces recent knowledge on brain injury induced by EMCV infection via ROS generation as well as the involvement of various mediators and regulators in the pathogenesis. PMID- 22837700 TI - New antifungal pyranoisoflavone from Ficus tikoua Bur. AB - Considering the undesirable attributes of synthetic fungicides and the availability of Ficus species in China, the stem of Ficus tikoua Bur. was investigated. One new antifungal pyranoisoflavone, 5,3',4'-trihydroxy-2",2" dimethylpyrano (5",6":7,8) isoflavone (1), together with two known isoflavones, wighteone (2) and lupiwighteone (3) (with previously reported antifungal activities), were isolated from ethyl acetate extract by bioassay-guided fractionation. Their structures were determined by spectroscopic analysis, such as NMR ((1)H-(1)H COSY, HMQC, HMBC and NOESY), IR, UV and HRMS, as well as ESI MS(n) analyses. The antifungal activities of 1-3 against Phytophthora infestans were evaluated by direct spore germination assay, and the IC(50) values were 262.442, 198.153 and 90.365 MUg.mL(-1), respectively. PMID- 22837701 TI - Aroma volatile compounds from two fresh pineapple varieties in China. AB - Volatile compounds from two pineapples varieties (Tainong No.4 and No.6) were isolated by headspace solid phase microextraction (HS-SPME) and identified and quantified by gas chromatography-mass spectrometry (GC/MS). In the Tainong No. 4 and No. 6 pineapples, a total of 11 and 28 volatile compounds were identified according to their retention time on capillary columns and their mass spectra, and quantified with total concentrations of 1080.44 MUg.kg(-1) and 380.66 MUg.kg( 1) in the Tainong No.4 and No. 6 pineapples, respectively. The odor active values (OAVs) of volatile compounds from pineapples were also calculated. According to the OAVs, four compounds were defined as the characteristic aroma compounds for the Tainong No. 4 pineapple, including furaneol, 3-(methylthio)propanoic acid methyl ester, 3-(methylthio)propanoic acid ethyl ester and delta-octalactone. The OAVs of five compounds including ethyl-2-methylbutyrate, methyl-2-methylbutyrate, 3-(methylthio)propanoic acid ethyl ester, ethyl hexanoate and decanal were considered to be the characteristic aroma compounds for the Tainong No. 6 pineapple. PMID- 22837702 TI - Hierarchical assembly of multifunctional oxide-based composite nanostructures for energy and environmental applications. AB - Composite nanoarchitectures represent a class of nanostructured entities that integrates various dissimilar nanoscale building blocks including nanoparticles, nanowires, and nanofilms toward realizing multifunctional characteristics. A broad array of composite nanoarchitectures can be designed and fabricated, involving generic materials such as metal, ceramics, and polymers in nanoscale form. In this review, we will highlight the latest progress on composite nanostructures in our research group, particularly on various metal oxides including binary semiconductors, ABO(3)-type perovskites, A(2)BO(4) spinels and quaternary dielectric hydroxyl metal oxides (AB(OH)(6)) with diverse application potential. Through a generic template strategy in conjunction with various synthetic approaches- such as hydrothermal decomposition, colloidal deposition, physical sputtering, thermal decomposition and thermal oxidation, semiconductor oxide alloy nanowires, metal oxide/perovskite (spinel) composite nanowires, stannate based nanocompostes, as well as semiconductor heterojunction-arrays and networks have been self-assembled in large scale and are being developed as promising classes of composite nanoarchitectures, which may open a new array of advanced nanotechnologies in solid state lighting, solar absorption, photocatalysis and battery, auto-emission control, and chemical sensing. PMID- 22837703 TI - Dietary supplementations as neuroprotective therapies: focus on NT-020 diet benefits in a rat model of stroke. AB - Stroke remains the number one cause of disability in the adult population. Despite scientific progress in our understanding of stroke pathology, only one treatment (tissue plasminogen activator or tPA) is able to afford benefits but to less than 3% of ischemic stroke patients. The development of experimental dietary supplement therapeutics designed to stimulate endogenous mechanisms that confer neuroprotection is likely to open new avenues for exploring stroke therapies. The present review article evaluates the recent literature supporting the benefits of dietary supplementation for the therapy of ischemic stroke. This article focuses on discussing the medical benefits of NT-020 as an adjunct agent for stroke therapy. Based on our preliminary data, a pre-stroke treatment with dietary supplementation promotes neuroprotection by decreasing inflammation and enhancing neurogenesis. However, we recognize that a pre-stroke treatment holds weak clinical relevance. Thus, the main goal of this article is to provide information about recent data that support the assumption of natural compounds as neuroprotective and to evaluate the therapeutic effects of a dietary supplement called NT-020 as in a stroke model. We focus on a systematic assessment of practical treatment parameters so that NT-020 and other dietary supplementations can be developed as an adjunct agent for the prevention or treatment of chronic diseases. We offer rationale for determining the optimal dosage, therapeutic window, and mechanism of action of NT-020 as a dietary supplement to produce neuroprotection when administered immediately after stroke onset. We highlight our long-standing principle in championing both translational and basic science approaches in an effort to fully reveal the therapeutic potential of NT-020 as dietary supplementation in the treatment of stroke. We envision dietary supplementation as an adjunct therapy for stroke at acute, subacute, and even chronic periods. PMID- 22837704 TI - Identification of intensity ratio break points from photon arrival trajectories in ratiometric single molecule spectroscopy. AB - We describe a statistical method to analyze dual-channel photon arrival trajectories from single molecule spectroscopy model-free to identify break points in the intensity ratio. Photons are binned with a short bin size to calculate the logarithm of the intensity ratio for each bin. Stochastic photon counting noise leads to a near-normal distribution of this logarithm and the standard student t-test is used to find statistically significant changes in this quantity. In stochastic simulations we determine the significance threshold for the t-test's p-value at a given level of confidence. We test the method's sensitivity and accuracy indicating that the analysis reliably locates break points with significant changes in the intensity ratio with little or no error in realistic trajectories with large numbers of small change points, while still identifying a large fraction of the frequent break points with small intensity changes. Based on these results we present an approach to estimate confidence intervals for the identified break point locations and recommend a bin size to choose for the analysis. The method proves powerful and reliable in the analysis of simulated and actual data of single molecule reorientation in a glassy matrix. PMID- 22837705 TI - Vibrational stark effect of the electric-field reporter 4-mercaptobenzonitrile as a tool for investigating electrostatics at electrode/SAM/solution interfaces. AB - 4-mercaptobenzonitrile (MBN) in self-assembled monolayers (SAMs) on Au and Ag electrodes was studied by surface enhanced infrared absorption and Raman spectroscopy, to correlate the nitrile stretching frequency with the local electric field exploiting the vibrational Stark effect (VSE). Using MBN SAMs in different metal/SAM interfaces, we sorted out the main factors controlling the nitrile stretching frequency, which comprise, in addition to external electric fields, the metal-MBN bond, the surface potential, and hydrogen bond interactions. On the basis of the linear relationships between the nitrile stretching and the electrode potential, an electrostatic description of the interfacial potential distribution is presented that allows for determining the electric field strengths on the SAM surface, as well as the effective potential of zero-charge of the SAM-coated metal. Comparing this latter quantity with calculated values derived from literature data, we note a very good agreement for Au/MBN but distinct deviations for Ag/MBN which may reflect either the approximations and simplifications of the model or the uncertainty in reported structural parameters for Ag/MBN. The present electrostatic model consistently explains the electric field strengths for MBN SAMs on Ag and Au as well as for thiophenol and mercaptohexanoic acid SAMs with MBN incorporated as a VSE reporter. PMID- 22837706 TI - Optimization of glutamine peptide production from soybean meal and analysis of molecular weight distribution of hydrolysates. AB - The process parameters of enzymatic hydrolysis and molecular weight distribution of glutamine (Gln) peptides from soybean meal were investigated. The Protamex((r)) hydrolysis pH of 6.10, temperature of 56.78 degrees C, enzyme to substrate ratio (E/S) of 1.90 and hydrolysis time of 10.72 h were found to be the optimal conditions by response surface methodology (RSM) for a maximal degree of hydrolysis (DH) value of 16.63% and Gln peptides content at 5.95 mmol/L. The soybean meal was hydrolyzed by a combination of Protamex((r)) and trypsinase so that DH and Gln peptides would reach 22.02% and 6.05 mmol/mL, respectively. The results of size exclusion chromatography indicated that the relative proportion of the molecular weight <1000 Da fraction increased with DH values from 6.76%, 11.13%, 17.89% to 22.02%, most notably the 132-500 Da fractions of hydrolysates were 42.14%, 46.57%, 58.44% and 69.65%. High DH values did not lead to high Gln peptides content of the hydrolysate but to the low molecular weight Gln peptides. PMID- 22837707 TI - Simulated gastrointestinal pH condition improves antioxidant properties of wheat and rice flours. AB - The present study was conducted to evaluate the antioxidant properties of wheat and rice flours under simulated gastrointestinal pH condition. After subjecting the wheat and rice flour slurries to simulated gastrointestinal pH condition, both slurries were centrifuged to obtain the crude phenolic extracts for further analyses. Extraction yield, total contents of phenolic and flavonoids were determined as such (untreated) and under simulated gastrointestinal pH condition (treated). 1,1-diphenyl-2-picrylhydrazyl radical (DPPH(*)) scavenging activity, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) radical cation (ABTS(*+)) scavenging activity, ferric reducing antioxidant power (FRAP), beta-carotene bleaching (BCB) and iron chelating activity assays were employed for the determination of antioxidant activity of the tested samples. In almost all of the assays performed, significant improvements in antioxidant properties (p < 0.05) were observed in both flours after treatment, suggesting that wheat and rice flours contain considerably heavy amounts of bound phenolics, and that their antioxidant properties might be improved under gastrointestinal digestive conditions. PMID- 22837708 TI - The effect of toll-like receptor 4 on macrophage cytokines during endotoxin induced uveitis. AB - Toll-like receptor 4 (TLR4) signal activation of macrophages can lead to endotoxin-induced uveitis (EIU). Previously, our research group has demonstrated a higher expression of TLR4 in vivo during EIU than normal. In this study, we analyzed levels of peritoneal macrophage cytokines from C3H/HeN mice with LPS stimulation in vitro to elucidate the effect of TLR4 on cytokines during EIU. PMID- 22837709 TI - Mechanism of cellular oxidation stress induced by asymmetric dimethylarginine. AB - The mechanism by which asymmetric dimethylarginine (ADMA) induces vascular oxidative stress is not well understood. In this study, we utilized human umbilical vein endothelial cells (HUVEC) to examine the roles of ADMA cellular transport and the uncoupling of endothelial nitric oxide synthase (eNOS) in contributing to this phenomenon. Dihydroethidium (DHE) fluorescence was used as an index of oxidative stress. Whole cells and their isolated membrane fractions exhibited measureable increased DHE fluorescence at ADMA concentrations greater than 10 MUM. ADMA-induced DHE fluorescence was inhibited by co-incubation with L lysine, tetrahydrobiopterin (BH(4)), or L-nitroarginine methyl ester (L-NAME). Oxidative stress induced in these cells by angiotensin II (Ang II) were unaffected by the same concentrations of L-lysine, L-NAME and BH(4). ADMA-induced reduction in cellular nitrite or nitrite/nitrate production was reversed in the presence of increasing concentrations of BH(4). These results suggest that ADMA induced DHE fluorescence involves the participation of both the cationic transport system in the cellular membrane and eNOS instead of the Ang II-NADPH oxidase pathway. PMID- 22837710 TI - Prediction of a new ligand-binding site for type 2 motif based on the crystal structure of ALG-2 by dry and wet approaches. AB - ALG-2 is a penta-EF-hand Ca(2+)-binding protein and interacts with a variety of intracellular proteins. Two types of ALG-2-binding motifs have been determined: type 1, PXYPXnYP (X, variable; n = 4), in ALIX and PLSCR3; type 2, PXPGF, in Sec31A and PLSCR3. The previously solved X-ray crystal structure of the complex between ALG-2 and an ALIX peptide containing type 1 motif showed that the peptide binds to Pocket 1 and Pocket 2. Co-crystallization of ALG-2 and type 2 motif containing peptides has not been successful. To gain insights into the molecular basis of type 2 motif recognition, we searched for a new hydrophobic cavity by computational algorithms using MetaPocket 2.0 based on 3D structures of ALG-2. The predicted hydrophobic pocket designated Pocket 3 fits with N-acetyl ProAlaProGlyPhe-amide, a virtual penta-peptide derived from one of the two types of ALG-2-binding sites in PLSCR3 (type 2 motif), using the molecular docking software AutoDock Vina. We investigated effects of amino acid substitutions of the predicted binding sites on binding abilities by pulldown assays using glutathione-S-transferase -fused ALG-2 of wild-type and mutant proteins and lysates of cells expressing green fluorescent protein -fused PLSCR3 of wild-type and mutants. Substitution of either L52 with Ala or F148 with Ser of ALG-2 caused loss of binding abilities to PLSCR3 lacking type 1 motif but retained those to PLSCR3 lacking type 2 motif, strongly supporting the hypothesis that Pocket 3 is the binding site for type 2 motif. PMID- 22837711 TI - Effect of ZnO on the physical properties and optical band gap of soda lime silicate glass. AB - This manuscript reports on the physical properties and optical band gap of five samples of soda lime silicate (SLS) glass combined with zinc oxide (ZnO) that were prepared by a melting and quenching process. To understand the role of ZnO in this glass structure, the density, molar volume and optical band gaps were investigated. The density and absorption spectra in the Ultra-Violet-Visible (UV Visible) region were recorded at room temperature. The results show that the densities of the glass samples increased as the ZnO weight percentage increased. The molar volume of the glasses shows the same trend as the density: the molar volume increased as the ZnO content increased. The optical band gaps were calculated from the absorption edge, and it was found that the optical band gap decreased from 3.20 to 2.32 eV as the ZnO concentration increased. PMID- 22837712 TI - DNA polymorphisms of the lipoprotein lipase gene and their association with coronary artery disease in the Saudi population. AB - Coronary heart disease (CHD) is a major health problem and a major cause of death in most countries. Evidence has been presented that gene polymorphisms (HindIII, PvuII and Ser447Ter) of lipoprotein lipase (LPL) are risk factors of coronary artery disease (CAD). AIM: Our objective of the present investigation was to determine whether 3 LPL polymorphisms (LPL-HindIII, LPL-PvuII and LPL-Ser447Ter) can be considered as independent risk factors for CAD in the Saudi population. METHODS: We recruited 120 CAD subjects, confirmed angiographically with identical ethnic backgrounds and 65 control subjects. Polymerase chain reaction-restriction fragment length polymorphisms (RFLP) technique was used to detect the polymorphisms of the LPL gene. RESULTS AND CONCLUSION: For the HindIII genotype, within the CAD group, the frequencies of the H(+)H(+) were found in 50.8%, whereas 44.2% carried the H(-)H(+) genotype, and 5% carried the H(-)H(-) genotype. Within the control group, the H(+)H(+) genotype was found in 44.6%, whereas 35.4% carried the H(-)H(+) genotype, 20% carried the H(-)H(-) genotype. The odds ratio (OR) of HindIII genotype H(+)H(+)vs. H(-)H(-) genotype at 95% Confidence Interval (CI) were 4.6 (1.57-13.2) and p < 0.005, hence showing no significant association with CAD. For the PvuII genotype, within the CAD group the frequencies of the P(+)P(+) found in 41.7% whereas 43.3.2% carried the P( )P(+) genotype, and 15% carried the P(-)P(-) genotype. Within the control group the P(+)P(+) was found in 38.5%, 43.0% carried the P(-)P(+) genotype, and 18.5% carried the P(-)P(-) genotype. The OR of PvuII genotype P(+)P(+)vs. P(-)P(-) genotypes (95% CI) is 1.33 and p = 0.52; hence, it was also insignificant to show association with the disease. For the Ser447Ter genotype, within the CAD group, the frequencies of the C/C found in 83.3%, whereas 16.7% carried the C/G genotype. Within the control group, the C/C was found in 87.7% and 12.3% carried the C/G genotype. We did not get any GG genotypes in control as well as patients for this gene. It can be concluded that C allele of gene masks the presence of G allele in the Saudi population. The OR of CG + GG vs. CC (95% CI) is 1.43 from 0.59 to 3.44 which is insignificant. Hence this gene also has no significant association with CAD in the Saudi population. PMID- 22837713 TI - Carrier injection and transport in blue phosphorescent organic light-emitting device with oxadiazole host. AB - In this paper, we investigate the carrier injection and transport characteristics in iridium(III)bis[4,6-(di-fluorophenyl)-pyridinato-N,C2']picolinate (FIrpic) doped phosphorescent organic light-emitting devices (OLEDs) with oxadiazole (OXD) as the bipolar host material of the emitting layer (EML). When doping Firpic inside the OXD, the driving voltage of OLEDs greatly decreases because FIrpic dopants facilitate electron injection and electron transport from the electron transporting layer (ETL) into the EML. With increasing dopant concentration, the recombination zone shifts toward the anode side, analyzed with electroluminescence (EL) spectra. Besides, EL redshifts were also observed with increasing driving voltage, which means the electron mobility is more sensitive to the electric field than the hole mobility. To further investigate carrier injection and transport characteristics, FIrpic was intentionally undoped at different positions inside the EML. When FIrpic was undoped close to the ETL, driving voltage increased significantly which proves the dopant-assisted-electron injection characteristic in this OLED. When the undoped layer is near the electron blocking layer, the driving voltage is only slightly increased, but the current efficiency is greatly reduced because the main recombination zone was undoped. However, non-negligible FIrpic emission is still observed which means the recombination zone penetrates inside the EML due to certain hole-transporting characteristics of the OXD. PMID- 22837714 TI - Isolation and characterization of Simple Sequence Repeats (SSR) Markers from the moss genus Orthotrichum using a small throughput pyrosequencing machine. AB - Here, we report the results of next-generation sequencing on the GS Junior system to identify a large number of microsatellites from the epiphytic moss Orthotrichum speciosum. Using a combination of a total (non-enrichment) genomic library and small-scale 454 pyrosequencing, we determined 5382 contigs whose length ranged from 103 to 5445 bp. In this dataset we identified 92 SSR (simple sequence repeats) motifs in 89 contigs. Forty-six of these had flanking regions suitable for primer design. We tested PCR amplification, reproducibility, and the level of polymorphism of 46 primer pairs for Orthotrichum speciosum using 40 individuals from two populations. As a result, the designed primers revealed 35 polymorphic loci with more than two alleles detected. This method is cost- and time-effective in comparison with traditional approaches involving cloning and sequencing. PMID- 22837715 TI - Density functional theory (DFT) study of edaravone derivatives as antioxidants. AB - Quantum chemical calculations at the B3LYP/6-31G* level of theory were employed for the structure-activity relationship and prediction of the antioxidant activity of edaravone and structurally related derivatives using energy (E), ionization potential (IP), bond dissociation energy (BDE), and stabilization energies (DeltaE(iso)). Spin density calculations were also performed for the proposed antioxidant activity mechanism. The electron abstraction is related to electron-donating groups (EDG) at position 3, decreasing the IP when compared to substitution at position 4. The hydrogen abstraction is related to electron withdrawing groups (EDG) at position 4, decreasing the BDE(CH) when compared to other substitutions, resulting in a better antioxidant activity. The unpaired electron formed by the hydrogen abstraction from the C-H group of the pyrazole ring is localized at 2, 4, and 6 positions. The highest scavenging activity prediction is related to the lowest contribution at the carbon atom. The likely mechanism is related to hydrogen transfer. It was found that antioxidant activity depends on the presence of EDG at the C(2) and C(4) positions and there is a correlation between IP and BDE. Our results identified three different classes of new derivatives more potent than edaravone. PMID- 22837716 TI - Ultrasound-assisted extraction of syringin from the bark of Ilex rotunda thumb using response surface methodology. AB - In this work, a rapid extraction method based on ultrasound-assisted extraction (UAE) of syringin from the bark of Ilex rotunda Thumb using response surface methodology (RSM) is described. The syringin was analyzed and quantified by high performance liquid chromatography coupled with UV detection (HPLC-UV). The extraction solvent, extraction temperature and extraction time, the three main factors for UAE, were optimized with Box-Behnken design (BBD) to obtain the highest extraction efficiency. The optimal conditions were the use of a sonication frequency of 40 kHz, 65% methanol as the solvent, an extraction time of 30 min and an extraction temperature of 40 degrees C. Using these optimal conditions, the experimental values agreed closely with the predicted values. The analysis of variance (ANOVA) indicated a high goodness of model fit and the success of the RSM method for optimizing syringin extraction from the bark of I. rotunda. PMID- 22837717 TI - Biodegradation study of microcrystalline chitosan and microcrystalline chitosan/beta-TCP complex composites. AB - Bone repair or regeneration is a common and complicated clinical problem in orthopedic surgery. The importance of natural polymers, such as microcrystalline chitosan, and minerals such as HAp and beta-TCP, has grown significantly over the last two decades due to their renewable and biodegradable source, increasing the knowledge and functionality of composites in technological and biomedical applications. This study compares the biodegradation process, bioactivity, structure, morphology, and mechanical properties of microcrystalline chitosan and microcrystalline chitosan/beta-TCP complex; the latter according to the new method of preparation. The complex showed a homogeneous network structure with regular pores, good bioactivity, even after 60 days of conducting the hydrolytic and enzymatic degradation process, showing a bacteriostatic and bactericidal activity. The complex indicates that it could be used successfully as a base for implants and scaffolds production in orthopedic surgery. PMID- 22837719 TI - Supercritical fluid extraction of Eucalyptus globulus bark-A promising approach for triterpenoid production. AB - Eucalyptus bark contains significant amounts of triterpenoids with demonstrated bioactivity, namely triterpenic acids and their acetyl derivatives (ursolic, betulinic, oleanolic, betulonic, 3-acetylursolic, and 3-acetyloleanolic acids). In this work, the supercritical fluid extraction (SFE) of Eucalyptus globulus deciduous bark was carried out with pure and modified carbon dioxide to recover this fraction, and the results were compared with those obtained by Soxhlet extraction with dichloromethane. The effects of pressure (100-200 bar), co solvent (ethanol) content (0, 5 and 8% wt), and multistep operation were studied in order to evaluate the applicability of SFE for their selective and efficient production. The individual extraction curves of the main families of compounds were measured, and the extracts analyzed by GC-MS. Results pointed out the influence of pressure and the important role played by the co-solvent. Ethanol can be used with advantage, since its effect is more important than increasing pressure by several tens of bar. At 160 bar and 40 degrees C, the introduction of 8% (wt) of ethanol greatly improves the yield of triterpenoids more than threefold. PMID- 22837718 TI - WIP remodeling actin behind the scenes: how WIP reshapes immune and other functions. AB - Actin polymerization is a fundamental cellular process regulating immune cell functions and the immune response. The Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor, which is exclusively expressed in hematopoietic cells, where it plays a key regulatory role in cytoskeletal dynamics. WASp interacting protein (WIP) was first discovered as the binding partner of WASp, through the use of the yeast two hybrid system. WIP was later identified as a chaperone of WASp, necessary for its stability. Mutations occurring at the WASp homology 1 domain (WH1), which serves as the WIP binding site, were found to cause the Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). WAS manifests as an immune deficiency characterized by eczema, thrombocytopenia, recurrent infections, and hematopoietic malignancies, demonstrating the importance of WIP for WASp complex formation and for a proper immune response. WIP deficiency was found to lead to different abnormalities in the activity of various lymphocytes, suggesting differential cell-dependent roles for WIP. Additionally, WIP deficiency causes cellular abnormalities not found in WASp-deficient cells, indicating that WIP fulfills roles beyond stabilizing WASp. Indeed, WIP was shown to interact with various binding partners, including the signaling proteins Nck, CrkL and cortactin. Recent studies have demonstrated that WIP also takes part in non immune cellular processes such as cancer invasion and metastasis, in addition to cell subversion by intracellular pathogens. Understanding of numerous functions of WIP can enhance our current understanding of activation and function of immune and other cell types. PMID- 22837720 TI - Expression of Sox2 and Oct4 and their clinical significance in human non-small cell lung cancer. AB - Sox2 and Oct4 are transcription factors with the characteristics of regulating self-renewal and differentiation of embryonic stem cell. The aim of this study was to detect the expression of Sox2 and Oct4 and analyze their clinical significance in human non-small-cell lung cancer (NSCLC). Expression of Sox2 and Oct4 were assayed in cancer tissues and their corresponding paracancerous tissues from 44 patients with NSCLC and 21 patients with benign tumors using immunohistochemistry, Western blot, reverse transcription polymerase chain reaction (RT-PCR). The correlation between the expression of Sox2 and Oct4 and tumor type, grade and prognosis and the utility of the two genes in discriminating between benign and malignant tumors were analyzed as well. The results showed that Sox2 and Oct4 positive staining was only seen in the nuclei of cancer cells but not in either the precancerous tissues or benign tumor tissues by immunohistochemistry (p < 0.01). Furthermore, in the lung cancer tissue, the positive rate for Sox2 and Oct4 was 70.5% and 54.5%, respectively. Meanwhile, clinicopathological correlations showed that the Oct4 expression level was significantly associated with poorer differentiation and higher TNM stage of the cancer (p < 0.05). Western blot and RT-PCR analysis showed similar results to immunohistochemistry. Follow-up analysis revealed that expression of Oct4 was significantly associated with poor prognosis of lung cancer. The conclusion is that Sox2 and Oct4 may act as the promising unit markers in directing NSCLC diagnosis and therapy. Also, Oct4 can be regarded as a novel predictor of poor prognosis for NSCLC patients undergoing resection. PMID- 22837721 TI - Proteomic analysis of cerebrospinal fluid in a fulminant case of multiple sclerosis. AB - Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient's death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject. PMID- 22837722 TI - The role of PPARalpha in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats. AB - Metformin, an anti-diabetic drug, exerts cardioprotection against ischemia reperfusion (IR) through the activation of AMPK. However, the molecular mechanisms underlying these beneficial effects remain elusive. In this study, we examined the role of PPARalpha in mediating cardioprotective effects of metformin on mitochondria. Hearts of male Sprague-Dawley rats perfused by Langendorff were subjected to IR in the presence or absence of metformin and the PPARbeta inhibitor, GW6471. IR reduced cardiac function and compromised the structural integrity of cardiac cells evidenced by increased LDH release from the hearts. In addition, IR induced mitochondrial dysfunction as evidenced by reduced respiration and increased mitochondrial permeability transition pore (PTP) opening. However, metformin-treated hearts demonstrated improved post-ischemic recovery of cardiac function and reduced cell death that were associated with increased state 3 respiration at complexes I and II (by 27% and 32%, respectively, both p < 0.05) and decreased PTP opening (by 27%, p < 0.05) compared to untreated hearts. The protective effects of metformin on cardiac function and mitochondria were blocked by GW6471. Thus, our results demonstrate that inhibition of PPARalpha attenuates the beneficial effects of metformin on mitochondria in acute IR. PMID- 22837723 TI - Effects of methylmercury contained in a diet mimicking the Wayana Amerindians contamination through fish consumption: mercury accumulation, metallothionein induction, gene expression variations, and role of the chemokine CCL2. AB - Methylmercury (MeHg) is a potent neurotoxin, and human beings are mainly exposed to this pollutant through fish consumption. We addressed the question of whether a diet mimicking the fish consumption of Wayanas Amerindians from French Guiana could result in observable adverse effects in mice. Wayanas adult men are subjected to a mean mercurial dose of 7 g Hg/week/kg of body weight. We decided to supplement a vegetarian-based mice diet with 0.1% of lyophilized Hoplias aimara fish, which Wayanas are fond of and equivalent to the same dose as that afflicting the Wayanas Amerindians. Total mercury contents were 1.4 +/- 0.2 and 5.4 +/- 0.5 ng Hg/g of food pellets for the control and aimara diets, respectively. After 14 months of exposure, the body parts and tissues displaying the highest mercury concentration on a dry weight (dw) basis were hair (733 ng/g) and kidney (511 ng/g), followed by the liver (77 ng/g). Surprisingly, despite the fact that MeHg is a neurotoxic compound, the brain accumulated low levels of mercury (35 ng/g in the cortex). The metallothionein (MT) protein concentration only increased in those tissues (kidney, muscles) in which MeHg demethylation had occurred. This can be taken as a molecular sign of divalent mercurial contamination since only Hg(2+) has been reported yet to induce MT accumulation in contaminated tissues. The suppression of the synthesis of the chemokine CCL2 in the corresponding knockout (KO) mice resulted in important changes in gene expression patterns in the liver and brain. After three months of exposure to an aimara-containing diet, eight of 10 genes selected (Sdhb, Cytb, Cox1, Sod1, Sod2, Mt2, Mdr1a and Bax) were repressed in wild-type mice liver whereas none presented a differential expression in KO Ccl2(-/-) mice. In the wild-type mice brain, six of 12 genes selected (Cytb, Cox1, Sod1, Sod2, Mdr1a and Bax) presented a stimulated expression, whereas all remained at the basal level of expression in KO Ccl2(-/-) mice. In the liver of aimara-fed mice, histological alterations were observed for an accumulated mercury concentration as low as 32 ng/g, dw, and metal deposits were observed within the cytoplasm of hepatic cells. PMID- 22837725 TI - Preparation of porous scaffolds from silk fibroin extracted from the silk gland of Bombyx mori (B. mori). AB - In order to use a simple and ecofriendly method to prepare porous silk scaffolds, aqueous silk fibroin solution (ASF) was extracted from silk gland of 7-day-old fifth instar larvae of Bombyx mori (B. mori). SDS-page analysis indicated that the obtained fibroin had a molecular weight higher than 200 kDa. The fabrication of porous scaffolds from ASF was achieved by using the freeze-drying method. The pore of porous scaffolds is homogenous and tends to become smaller with an increase in the concentration of ASF. Conversely, the porosity is decreased. The porous scaffolds show impressive compressive strength which can be as high as 6.9 +/- 0.4 MPa. Furthermore, ASF has high cell adhesion and growth activity. It also exhibits high ALP activity. This implies that porous scaffolds prepared from ASF have biocompatibility. Therefore, the porous scaffolds prepared in this study have potential application in tissue engineering due to the impressive compressive strength and biocompatibility. PMID- 22837724 TI - Clinical neuroprotective drugs for treatment and prevention of stroke. AB - Stroke is an enormous public health problem with an imperative need for more effective therapies. In therapies for ischemic stroke, tissue plasminogen activators, antiplatelet agents and anticoagulants are used mainly for their antithrombotic effects. However, free radical scavengers, minocycline and growth factors have shown neuroprotective effects in the treatment of stroke, while antihypertensive drugs, lipid-lowering drugs and hypoglycemic drugs have shown beneficial effects for the prevention of stroke. In the present review, we evaluate the treatment and prevention of stroke in light of clinical studies and discuss new anti-stroke effects other than the main effects of drugs, focusing on optimal pharmacotherapy. PMID- 22837727 TI - Plasma depolymerization of chitosan in the presence of hydrogen peroxide. AB - The depolymerization of chitosan by plasma in the presence of hydrogen peroxide (H(2)O(2)) was investigated. The efficiency of the depolymerization was demonstrated by means of determination of viscosity-average molecular weight and gel permeation chromatography (GPC). The structure of the depolymerized chitosan was characterized by Fourier-transform infrared spectra (FT-IR), ultraviolet spectra (UV) and X-ray diffraction (XRD). The results showed that chitosan can be effectively degradated by plasma in the presence of H(2)O(2). The chemical structure of the depolymerized chitosan was not obviously modified. The combined plasma/H(2)O(2) method is significantly efficient for scale-up manufacturing of low molecular weight chitosan. PMID- 22837726 TI - Polydatin attenuates hypoxic pulmonary hypertension and reverses remodeling through protein kinase C mechanisms. AB - Hypoxic pulmonary hypertension is a life-threatening emergency if untreated. Consistent pulmonary hypertension also leads to arteries and ventricular remodeling. The clinical therapeutic strategy for pulmonary hypertension and the corresponding remodeling mainly interacts with NO, angiotensin II (Ang II) and elevated endothelin (ET) targets. In the present study, we evaluated the effects of polydatin on hypoxia-induced pulmonary hypertension. It was observed that polydatin attenuated hypoxic pulmonary hypertension, reversed remodeling, and regulated NO, Ang II, ET contents in the serum and lung samples. However, forced activation of PKC signaling by its selective activator thymeleatoxin (THX) could abate the effects of polydatain. These results suggest that polydatin might be a promising candidate for hypoxic pulmonary treatment through interaction with PKC mechanisms. PMID- 22837730 TI - Diffusivity maximum in a reentrant nematic phase. AB - We report molecular dynamics simulations of confined liquid crystals using the Gay-Berne-Kihara model. Upon isobaric cooling, the standard sequence of isotropic nematic-smectic A phase transitions is found. Upon further cooling a reentrant nematic phase occurs. We investigate the temperature dependence of the self diffusion coefficient of the fluid in the nematic, smectic and reentrant nematic phases. We find a maximum in diffusivity upon isobaric cooling. Diffusion increases dramatically in the reentrant phase due to the high orientational molecular order. As the temperature is lowered, the diffusion coefficient follows an Arrhenius behavior. The activation energy of the reentrant phase is found in reasonable agreement with the reported experimental data. We discuss how repulsive interactions may be the underlying mechanism that could explain the occurrence of reentrant nematic behavior for polar and non-polar molecules. PMID- 22837731 TI - Intake_epis_food(): An R Function for Fitting a Bivariate Nonlinear Measurement Error Model to Estimate Usual and Energy Intake for Episodically Consumed Foods. AB - We consider a Bayesian analysis using WinBUGS to estimate the distribution of usual intake for episodically consumed foods and energy (calories). The model uses measures of nutrition and energy intakes via a food frequency questionnaire (FFQ) along with repeated 24 hour recalls and adjusting covariates. In order to estimate the usual intake of the food, we phrase usual intake in terms of person specific random effects, along with day-to-day variability in food and energy consumption. Three levels are incorporated in the model. The first level incorporates information about whether an individual in fact reported consumption of a particular food item. The second level incorporates the amount of intake from those individuals who reported consumption of the food, and the third level incorporates the energy intake. Estimates of posterior means of parameters and distributions of usual intakes are obtained by using Markov chain Monte Carlo calculations. This R function reports to users point estimates and credible intervals for parameters in the model, samples from their posterior distribution, samples from the distribution of usual intake and usual energy intake, trace plots of parameters and summary statistics of usual intake, usual energy intake and energy adjusted usual intake. PMID- 22837728 TI - Spatial simulations in systems biology: from molecules to cells. AB - Cells are highly organized objects containing millions of molecules. Each biomolecule has a specific shape in order to interact with others in the complex machinery. Spatial dynamics emerge in this system on length and time scales which can not yet be modeled with full atomic detail. This review gives an overview of methods which can be used to simulate the complete cell at least with molecular detail, especially Brownian dynamics simulations. Such simulations require correct implementation of the diffusion-controlled reaction scheme occurring on this level. Implementations and applications of spatial simulations are presented, and finally it is discussed how the atomic level can be included for instance in multi-scale simulation methods. PMID- 22837729 TI - Mitogen-Activated Protein (MAP) kinases in plant metal stress: regulation and responses in comparison to other biotic and abiotic stresses. AB - Exposure of plants to toxic concentrations of metals leads to disruption of the cellular redox status followed by an accumulation of reactive oxygen species (ROS). ROS, like hydrogen peroxide, can act as signaling molecules in the cell and induce signaling via mitogen-activated protein kinase (MAPK) cascades. MAPK cascades are evolutionary conserved signal transduction modules, able to convert extracellular signals to appropriate cellular responses. In this review, our current understanding about MAPK signaling in plant metal stress is discussed. However, this knowledge is scarce compared to research into the role of MAPK signaling in the case of other abiotic and biotic stresses. ROS production is a common response induced by different stresses and undiscovered analogies may exist with metal stress. Therefore, further attention is given to MAPK signaling in other biotic and abiotic stresses and its interplay with other signaling pathways to create a framework in which the involvement of MAPK signaling in metal stress may be studied. PMID- 22837732 TI - Seprafilm(r) adhesion barrier: (1) a review of preclinical, animal, and human investigational studies. AB - The aim of this study was to provide a single site resource for investigators, clinicians, and others seeking preclinical, animal, and human investigational studies concerning the postsurgical, anti-adhesion barrier SeprafilmTM (Genzyme Corporation, Cambridge, MA). All published preclinical, animal, human extra abdominal research as of July 2011 have been summarized and included in this document. Searches of Medline and EMBASE Drugs and Pharmaceuticals databases were conducted for original preclinical, animal, and human extra-abdominal studies involving Seprafilm. Preclinical, animal, and extra-abdominal human investigational studies are the study selection for this manuscript. Intraabdominal use is discussed in the accompanying manuscript. Data extraction includes systematic manuscript review. Summary of preclinical, animal, and extra abdominal human investigational use of Seprafilm by surgical discipline were gathered for data synthesis. The clinical use of Seprafilm, which was approved by the FDA for intra-abdominal procedures, is supported by preclinical and animal studies relating to general surgical and obstetrical/gynecological applications. Findings from preclinical, animal, and human investigational studies at other sites throughout the body raises the potential for additional human clinical trials to assess efficacy and safety following surgical procedures at non abdominal locations. PMID- 22837733 TI - Seprafilm((r)) adhesion barrier: (2) a review of the clinical literature on intraabdominal use. AB - This study seeks to provide a review of the clinical data published as of July 2011 concerning the postsurgical adhesion barrier, Seprafilm (chemically modified hyaluronic acid and carboxymethylcelulose; Genzyme Corporation, Cambridge, MA). Included articles detail the application of Seprafilm for intraabdominal uses that have been approved (on-label) and those considered investigational (off label) by the FDA. Medline and EMBASE Drugs and Pharmaceuticals databases were searched for all original clinical Seprafilm research published as of July 2011. All human Seprafilm intraabdominal clinical reports and studies, excluding those related to prosthetic mesh were included. Data extraction involved the systematic review of each article. The data synthesis is the summary of Seprafilm human intraabdominal clinical reports and studies describing safety and/or efficacy. The safety and efficacy of Seprafilm in reducing postoperative adhesions has been clearly demonstrated in abdominal and pelvic laparotomy. While reports have described the safe and successful use of Seprafilm following laparoscopy, pediatric laparotomy, and in patients with malignancy and/or infection, the safety and efficacy of Seprafilm use in these procedures has not been definitively established in randomized controlled trials. PMID- 22837734 TI - Patient safety risk factors in minimally invasive surgery: a validation study. AB - This study was conducted to adapt and validate a patient safety (PS) framework for minimally invasive surgery (MIS) as a first step in understanding the clinical relevance of various PS risk factors in MIS. Eight patient safety risk factor domains were identified using frameworks from a systems approach to patient safety. A questionnaire was drafted containing 34 questions. Three experts in the field of patient safety critically reviewed the questionnaire on clinical relevance and completeness. The questionnaire was distributed among known patient safety experts in person and also sent electronically. A total of 41 questionnaires were distributed and the response rate was 71%. The intraclass correlation coefficient was 0.42 representing moderate agreement. For seven of nine risk domains, Cronbach's alpha was sufficient (alpha > 0.7). Mean scores of the risk domains showed the following order of influence on patient safety from high to low: surgeon's experience [6.6, standard deviation (SD) 0.5], technical skills surgeon (6.6, SD 0.7), technology (5.9, SD 1.1), complications (5.9, SD 1.2), social interaction (5.0, SD 1.0), leadership surgeon (5.4, SD 1.2), blood loss (5.0, SD 1.2), length of surgery (5.0, SD 1.3), surgical team (4.9, SD 1.3), fallibility (4.9, SD 1.3), patient (4.5, SD 1.5), safety measures (4.4, SD 1.5), and finally environment(3.9, SD 1.5). This study is an initiative to give insight into clinical relevance of the maze of PS risk factors in MIS. All investigated risk domains were considered to be of noticeable influence on PS. Nevertheless, it is possible to prioritize various risk domains. In fact, experience and technical skills of the surgeon, technology, and complications are rated as the most important risk factors, closely followed by social interaction and leadership of the surgeon. Patient, safety measures, and environment are rated as the least important risk factors. PMID- 22837735 TI - A multidisciplinary evidence-based guideline for minimally invasive surgery.: Part 1: entry techniques and the pneumoperitoneum. AB - The Dutch Society for Endoscopic Surgery together with the Dutch Society of Obstetrics and Gynecology initiated a multidisciplinary working group to develop a guideline on minimally invasive surgery to formulate multidisciplinary agreements for minimally invasive surgery aiming towards better patient care and safety. The guideline development group consisted of general surgeons, gynecologists, an anesthesiologist, and urologist authorized by their scientific professional association. Two advisors in evidence-based guideline development supported the group. The guideline was developed using the "Appraisal of Guidelines for Research and Evaluation" instrument. Clinically important aspects were identified and discussed. The best available evidence on these aspects was gathered by systematic review. Recommendations for clinical practice were formulated based on the evidence and a consensus of expert opinion. The guideline was externally reviewed by members of the participating scientific associations and their feedback was integrated. Identified important topics were: laparoscopic entry techniques, intra-abdominal pressure, trocar use, electrosurgical techniques, prevention of trocar site herniation, patient positioning, anesthesiology, perioperative care, patient information, multidisciplinary user consultation, and complication registration. The text of each topic contains an introduction with an explanation of the problem and a summary of the current literature. Each topic was discussed, considerations were evaluated and recommendations were formulated. The development of a guideline on a multidisciplinary level facilitated a broad and rich discussion, which resulted in a very complete and implementable guideline. PMID- 22837736 TI - Arthroscopic capsular shift technique and volume reduction. AB - Multidirectional instability is very complex pathology. Excessively redundant capsule is one of the important reasons causing symptomatic laxity in multiple planes. Arthroscopic techniques are not able to reproduce the potential of open methods to reduce the joint volume. Most of the studies based their measurements on cadaver model. The aim of the study was to develop simple and reproducible technique to perform arthroscopic capsular shift and measure its volume reduction potential in both cadaveric and clinical setting. Technique is described in the paper. Capsular shift was applied both in cadaver and clinical scenario. Based on group of 5 cadaver shoulder specimen, glenohumeral joint volume was reduced from average of 19.4 +/- 7.8 ml to 11.9 +/- 4.5 ml following arthroscopic capsular shift (37.9% volume reduction). Clinical material consisted of 12 consecutive patients shoulder with instability and joint laxity undergoing the arthroscopic capsular shift. Average glenohumeral volume before capsular shift was 43.5 +/- 10 ml and was reduced to 17.5 +/- 4.3 ml (58.8% volume reduction). Arthroscopic capsular shift presented in this paper seems to be relatively easy to perform and safe procedure. The technique provides significant decrease in joint volume in both cadaveric and clinical parts of the study. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00590-011-0865-z) contains supplementary material, which is available to authorized users. PMID- 22837737 TI - Letter to the editor. PMID- 22837738 TI - Modulation of mood States as a major factor in relapse to substance use. PMID- 22837739 TI - Subpopulations of somatostatin-immunoreactive non-pyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: evidence for the existence of GABAergic projection neurons in the cortical nuclei and basolateral nuclear complex. AB - The hippocampus and amygdala are key structures of the limbic system whose connections include reciprocal interactions with the basal forebrain (BF). The hippocampus receives both cholinergic and GABAergic afferents from the medial septal area of the BF. Hippocampal projections back to the medial septal area arise from non-pyramidal GABAergic neurons that express somatostatin (SOM), calbindin (CB), and neuropeptide Y (NPY). Recent experiments in our lab have demonstrated that the basolateral amygdala, like the hippocampus, receives both cholinergic and GABAergic afferents from the BF. These projections arise from neurons in the substantia innominata (SI) and ventral pallidum (VP). It remained to be determined, however, whether the amygdala has projections back to the BF that arise from GABAergic non-pyramidal neurons. This question was investigated in the present study by combining Fluorogold (FG) retrograde tract tracing with immunohistochemistry for GABAergic non-pyramidal cell markers, including SOM, CB, NPY, parvalbumin, calretinin, and glutamic acid decarboxylase (GAD). FG injections into the BF produced a diffuse array of retrogradely labeled neurons in many nuclei of the amygdala. The great majority of amygdalar FG+ neurons did not express non-pyramidal cell markers. However, a subpopulation of non-pyramidal SOM+ neurons, termed "long-range non-pyramidal neurons" (LRNP neurons), in the external capsule, basolateral amygdala, and cortical and medial amygdalar nuclei were FG+. About one-third of the SOM+ LRNP neurons were CB+ or NPY+, and one-half were GAD+. It remains to be determined if these inhibitory amygdalar projections to the BF, like those from the hippocampus, are important for regulating synchronous oscillations in the amygdalar-BF network. PMID- 22837740 TI - Neural mechanisms underlying the effects of face-based affective signals on memory for faces: a tentative model. AB - In our daily lives, we form some impressions of other people. Although those impressions are affected by many factors, face-based affective signals such as facial expression, facial attractiveness, or trustworthiness are important. Previous psychological studies have demonstrated the impact of facial impressions on remembering other people, but little is known about the neural mechanisms underlying this psychological process. The purpose of this article is to review recent functional MRI (fMRI) studies to investigate the effects of face-based affective signals including facial expression, facial attractiveness, and trustworthiness on memory for faces, and to propose a tentative concept for understanding this affective-cognitive interaction. On the basis of the aforementioned research, three brain regions are potentially involved in the processing of face-based affective signals. The first candidate is the amygdala, where activity is generally modulated by both affectively positive and negative signals from faces. Activity in the orbitofrontal cortex (OFC), as the second candidate, increases as a function of perceived positive signals from faces; whereas activity in the insular cortex, as the third candidate, reflects a function of face-based negative signals. In addition, neuroscientific studies have reported that the three regions are functionally connected to the memory related hippocampal regions. These findings suggest that the effects of face based affective signals on memory for faces could be modulated by interactions between the regions associated with the processing of face-based affective signals and the hippocampus as a memory-related region. PMID- 22837742 TI - Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. AB - Considerable evidence suggests that transmission at hypocretin-1 (orexin-1) receptors (Hcrt-R1) plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV) cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg) dose-dependently decreased cocaine (0.5 mg/kg/infusion) self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg) also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg) on brain reward systems, as measured by reversal of cocaine induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts. PMID- 22837743 TI - Resilience in migraine brains: decrease of coherence after photic stimulation. AB - BACKGROUND: During migraine attacks, patients generally have photophobia and phonophobia and seek for environments with less sensorial stimulation. Present work aimed to quantify cortical partial directed coherence (PDC) of electroencephalographic (EEG) recordings from migraine patients and controls in occipital, parietal, and frontal areas with or without photic stimulation. Our hypothesis is that migraine patients with visual aura might have neuronal networks with higher coherence than controls even in interictal periods due to a predisposition in sensory cortical processing. METHODS: Eleven adult women with migraine with visual aura (at least 48 h without previous attacks) and seven healthy adult woman were submitted to EEG recording in basal state and during photic stimulation. RESULTS: When compared to healthy volunteers, migraine patients show different coherence profiles. Migraine patients had greater coherence than controls during the basal period (without photic stimulation), showing predisposition for sensory processing in many frequency ranges. After photic stimulation, patients showed a decrease in cortical coherence while controls had an increase. CONCLUSIONS: When compared to healty subjects, migraineurs show increased cortical coherence before photic stimulation, but a decrease when stimulation starts. This may be the expression of a resilience mechanism that allows migraineurs the interictal period. The PDC analysis permits to address a patient coherence profile, or "coherence map," that can be utilized for management of the headache disorder or following up treatments. PMID- 22837744 TI - The two-brain approach: how can mutually interacting brains teach us something about social interaction? AB - Measuring brain activity simultaneously from two people interacting is intuitively appealing if one is interested in putative neural markers of social interaction. However, given the complex nature of interactions, it has proven difficult to carry out two-person brain imaging experiments in a methodologically feasible and conceptually relevant way. Only a small number of recent studies have put this into practice, using fMRI, EEG, or NIRS. Here, we review two main two-brain methodological approaches, each with two conceptual strategies. The first group has employed two-brain fMRI recordings, studying (1) turn-based interactions on the order of seconds, or (2) pseudo-interactive scenarios, where only one person is scanned at a time, investigating the flow of information between brains. The second group of studies has recorded dual EEG/NIRS from two people interacting, in (1) face-to-face turn-based interactions, investigating functional connectivity between theory-of-mind regions of interacting partners, or in (2) continuous mutual interactions on millisecond timescales, to measure coupling between the activity in one person's brain and the activity in the other's brain. We discuss the questions these approaches have addressed, and consider scenarios when simultaneous two-brain recordings are needed. Furthermore, we suggest that (1) quantification of inter-personal neural effects via measures of emergence, and (2) multivariate decoding models that generalize source-specific features of interaction, may provide novel tools to study brains in interaction. This may allow for a better understanding of social cognition as both representation and participation. PMID- 22837745 TI - Parametric models to relate spike train and LFP dynamics with neural information processing. AB - Spike trains and local field potentials (LFPs) resulting from extracellular current flows provide a substrate for neural information processing. Understanding the neural code from simultaneous spike-field recordings and subsequent decoding of information processing events will have widespread applications. One way to demonstrate an understanding of the neural code, with particular advantages for the development of applications, is to formulate a parametric statistical model of neural activity and its covariates. Here, we propose a set of parametric spike-field models (unified models) that can be used with existing decoding algorithms to reveal the timing of task or stimulus specific processing. Our proposed unified modeling framework captures the effects of two important features of information processing: time-varying stimulus-driven inputs and ongoing background activity that occurs even in the absence of environmental inputs. We have applied this framework for decoding neural latencies in simulated and experimentally recorded spike-field sessions obtained from the lateral intraparietal area (LIP) of awake, behaving monkeys performing cued look-and-reach movements to spatial targets. Using both simulated and experimental data, we find that estimates of trial-by-trial parameters are not significantly affected by the presence of ongoing background activity. However, including background activity in the unified model improves goodness of fit for predicting individual spiking events. Uncovering the relationship between the model parameters and the timing of movements offers new ways to test hypotheses about the relationship between neural activity and behavior. We obtained significant spike-field onset time correlations from single trials using a previously published data set where significantly strong correlation was only obtained through trial averaging. We also found that unified models extracted a stronger relationship between neural response latency and trial-by-trial behavioral performance than existing models of neural information processing. Our results highlight the utility of the unified modeling framework for characterizing spike-LFP recordings obtained during behavioral performance. PMID- 22837741 TI - Effects of acetylcholine on neuronal properties in entorhinal cortex. AB - The entorhinal cortex (EC) receives prominent cholinergic innervation from the medial septum and the vertical limb of the diagonal band of Broca (MSDB). To understand how cholinergic neurotransmission can modulate behavior, research has been directed toward identification of the specific cellular mechanisms in EC that can be modulated through cholinergic activity. This review focuses on intrinsic cellular properties of neurons in EC that may underlie functions such as working memory, spatial processing, and episodic memory. In particular, the study of stellate cells (SCs) in medial entorhinal has resulted in discovery of correlations between physiological properties of these neurons and properties of the unique spatial representation that is demonstrated through unit recordings of neurons in medial entorhinal cortex (mEC) from awake-behaving animals. A separate line of investigation has demonstrated persistent firing behavior among neurons in EC that is enhanced by cholinergic activity and could underlie working memory. There is also evidence that acetylcholine plays a role in modulation of synaptic transmission that could also enhance mnemonic function in EC. Finally, the local circuits of EC demonstrate a variety of interneuron physiology, which is also subject to cholinergic modulation. Together these effects alter the dynamics of EC to underlie the functional role of acetylcholine in memory. PMID- 22837746 TI - Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments. AB - Several independent studies show that accumulation of beta-amyloid (Abeta) peptides, one of the characteristic hallmark of Alzheimer's Disease (AD), can affect normal neuronal activity in different ways. However, in spite of intense experimental work to explain the possible underlying mechanisms of action, a comprehensive and congruent understanding is still lacking. Part of the problem might be the opposite ways in which Abeta have been experimentally found to affect the normal activity of a neuron; for example, making a neuron more excitable (by reducing the A- or DR-type K(+) currents) or less excitable (by reducing synaptic transmission and Na(+) current). The overall picture is therefore confusing, since the interplay of many mechanisms makes it difficult to link individual experimental findings with the more general problem of understanding the progression of the disease. This is an important issue, especially for the development of new drugs trying to ameliorate the effects of the disease. We addressed these paradoxes through computational models. We first modeled the different stages of AD by progressively modifying the intrinsic membrane and synaptic properties of a realistic model neuron, while accounting for multiple and different experimental findings and by evaluating the contribution of each mechanism to the overall modulation of the cell's excitability. We then tested a number of manipulations of channel and synaptic activation properties that could compensate for the effects of Abeta. The model predicts possible therapeutic treatments in terms of pharmacological manipulations of channels' kinetic and activation properties. The results also suggest how and which mechanisms can be targeted by a drug to restore the original firing conditions. PMID- 22837747 TI - Parametric computation predicts a multiplicative interaction between synaptic strength parameters that control gamma oscillations. AB - Gamma oscillations are thought to be critical for a number of behavioral functions, they occur in many regions of the brain and through a variety of mechanisms. Fast repetitive bursting (FRB) neurons in layer 2 of the cortex are able to drive gamma oscillations over long periods of time. Even though the oscillation is driven by FRB neurons, strong feedback within the rest of the cortex must modulate properties of the oscillation such as frequency and power. We used a highly detailed model of the cortex to determine how a cohort of 33 parameters controlling synaptic drive might modulate gamma oscillation properties. We were interested in determining not just the effects of parameters individually, but we also wanted to reveal interactions between parameters beyond additive effects. To prevent a combinatorial explosion in parameter combinations that might need to be simulated, we used a fractional factorial design (FFD) that estimated the effects of individual parameters and two parameter interactions. This experiment required only 4096 model runs. We found that the largest effects on both gamma power and frequency came from a complex interaction between efficacy of synaptic connections from layer 2 inhibitory neurons to layer 2 excitatory neurons and the parameter for the reciprocal connection. As well as the effect of the individual parameters determining synaptic efficacy, there was an interaction between these parameters beyond the additive effects of the parameters alone. The magnitude of this effect was similar to that of the individual parameters, predicting that it is physiologically important in setting gamma oscillation properties. PMID- 22837748 TI - Learning tactile skills through curious exploration. AB - We present curiosity-driven, autonomous acquisition of tactile exploratory skills on a biomimetic robot finger equipped with an array of microelectromechanical touch sensors. Instead of building tailored algorithms for solving a specific tactile task, we employ a more general curiosity-driven reinforcement learning approach that autonomously learns a set of motor skills in absence of an explicit teacher signal. In this approach, the acquisition of skills is driven by the information content of the sensory input signals relative to a learner that aims at representing sensory inputs using fewer and fewer computational resources. We show that, from initially random exploration of its environment, the robotic system autonomously develops a small set of basic motor skills that lead to different kinds of tactile input. Next, the system learns how to exploit the learned motor skills to solve supervised texture classification tasks. Our approach demonstrates the feasibility of autonomous acquisition of tactile skills on physical robotic platforms through curiosity-driven reinforcement learning, overcomes typical difficulties of engineered solutions for active tactile exploration and underactuated control, and provides a basis for studying developmental learning through intrinsic motivation in robots. PMID- 22837749 TI - Translational research models and methods for mother-infant interactions and developmental studies. PMID- 22837750 TI - Memory's Malleability: Its Role in Shaping Collective Memory and Social Identity. PMID- 22837751 TI - From simple receptors to complex multimodal percepts: a first global picture on the mechanisms involved in perceptual binding. AB - The binding problem in perception is concerned with answering the question how information from millions of sensory receptors, processed by millions of neurons working in parallel, can be merged into a unified percept. Binding in perception reaches from the lowest levels of feature binding up to the levels of multimodal binding of information coming from the different sensor modalities and also from other functional systems. The last 40 years of research have shown that the binding problem cannot be solved easily. Today, it is considered as one of the key questions to brain understanding. To date, various solutions have been suggested to the binding problem including: (1) combination coding, (2) binding by synchrony, (3) population coding, (4) binding by attention, (5) binding by knowledge, expectation, and memory, (6) hardwired vs. on-demand binding, (7) bundling and binding of features, (8) the feature-integration theory of attention, and (9) synchronization through top-down processes. Each of those hypotheses addresses important aspects of binding. However, each of them also suffers from certain weak points and can never give a complete explanation. This article gives a brief overview of the so far suggested solutions of perceptual binding and then shows that those are actually not mutually exclusive but can complement each other. A computationally verified model is presented which shows that, most likely, the different described mechanisms of binding act (1) at different hierarchical levels and (2) in different stages of "perceptual knowledge acquisition." The model furthermore considers and explains a number of inhibitory "filter mechanisms" that suppress the activation of inappropriate or currently irrelevant information. PMID- 22837752 TI - A Model for Mild Traumatic Brain Injury that Induces Limited Transient Memory Impairment and Increased Levels of Axon Related Serum Biomarkers. AB - Mild traumatic brain injury (mTBI) is one of the most common neuronal insults and can lead to long-term disabilities. mTBI occurs when the head is exposed to a rapid acceleration-deceleration movement triggering axonal injuries. Our limited understanding of the underlying pathological changes makes it difficult to predict the outcome of mTBI. In this study we used a scalable rat model for rotational acceleration TBI, previously characterized for the threshold of axonal pathology. We have analyzed whether a TBI just above the defined threshold would induce any detectable behavioral changes and/or changes in serum biomarkers. The effect of injury on sensory motor functions, memory and anxiety were assessed by beam walking, radial arms maze and elevated plus maze at 3-7 days following TBI. The only behavioral deficits found were transient impairments in working and reference memory. Blood serum was analyzed at 1, 3, and 14 days after injury for changes in selected protein biomarkers. Serum levels of neurofilament heavy chain and Tau, as well as S100B and myelin basic protein showed significant increases in the injured animals at all time points. No signs of macroscopic injuries such as intracerebral hematomas or contusions were found. Amyloid precursor protein immunostaining indicated axonal injuries at all time points analyzed. In summary, this model mimics some of the key symptoms of mTBI, such as transient memory impairment, which is paralleled by an increase in serum biomarkers. Our findings suggest that serum biomarkers may be used to detect mTBI. The model provides a suitable foundation for further investigation of the underlying pathology of mTBI. PMID- 22837754 TI - An assembly model of rift valley Fever virus. AB - Rift Valley fever virus (RVFV) is a bunyavirus endemic to Africa and the Arabian Peninsula that infects humans and livestock. The virus encodes two glycoproteins, Gn and Gc, which represent the major structural antigens and are responsible for host cell receptor binding and fusion. Both glycoproteins are organized on the virus surface as cylindrical hollow spikes that cluster into distinct capsomers with the overall assembly exhibiting an icosahedral symmetry. Currently, no experimental three-dimensional structure for any entire bunyavirus glycoprotein is available. Using fold recognition, we generated molecular models for both RVFV glycoproteins and found significant structural matches between the RVFV Gn protein and the influenza virus hemagglutinin protein and a separate match between RVFV Gc protein and Sindbis virus envelope protein E1. Using these models, the potential interaction and arrangement of both glycoproteins in the RVFV particle was analyzed, by modeling their placement within the cryo-electron microscopy density map of RVFV. We identified four possible arrangements of the glycoproteins in the virion envelope. Each assembly model proposes that the ectodomain of Gn forms the majority of the protruding capsomer and that Gc is involved in formation of the capsomer base. Furthermore, Gc is suggested to facilitate intercapsomer connections. The proposed arrangement of the two glycoproteins on the RVFV surface is similar to that described for the alphavirus E1-E2 proteins. Our models will provide guidance to better understand the assembly process of phleboviruses and such structural studies can also contribute to the design of targeted antivirals. PMID- 22837753 TI - BRET and Time-resolved FRET strategy to study GPCR oligomerization: from cell lines toward native tissues. AB - The concept of oligomerization of G protein-coupled receptor (GPCR) opens new perspectives regarding physiological function regulation. The capacity of one GPCR to modify its binding and coupling properties by interacting with a second one can be at the origin of regulations unsuspected two decades ago. Although the concept is interesting, its validation at a physiological level is challenging and probably explains why receptor oligomerization is still controversial. Demonstrating direct interactions between two proteins is not trivial since few techniques present a spatial resolution allowing this precision. Resonance energy transfer (RET) strategies are actually the most convenient ones. During the last two decades, bioluminescent resonance energy transfer and time-resolved fluorescence resonance energy transfer (TR-FRET) have been widely used since they exhibit high signal-to-noise ratio. Most of the experiments based on GPCR labeling have been performed in cell lines and it has been shown that all GPCRs have the propensity to form homo- or hetero-oligomers. However, whether these data can be extrapolated to GPCRs expressed in native tissues and explain receptor functioning in real life, remains an open question. Native tissues impose different constraints since GPCR sequences cannot be modified. Recently, a fluorescent ligand-based GPCR labeling strategy combined to a TR-FRET approach has been successfully used to prove the existence of GPCR oligomerization in native tissues. Although the RET-based strategies are generally quite simple to implement, precautions have to be taken before concluding to the absence or the existence of specific interactions between receptors. For example, one should exclude the possibility of collision of receptors diffusing throughout the membrane leading to a specific FRET signal. The advantages and the limits of different approaches will be reviewed and the consequent perspectives discussed. PMID- 22837755 TI - Genetic manipulation of Methanosarcina spp. AB - The discovery of the third domain of life, the Archaea, is one of the most exciting findings of the last century. These remarkable prokaryotes are well known for their adaptations to extreme environments; however, Archaea have also conquered moderate environments. Many of the archaeal biochemical processes, such as methane production, are unique in nature and therefore of great scientific interest. Although formerly restricted to biochemical and physiological studies, sophisticated systems for genetic manipulation have been developed during the last two decades for methanogenic archaea, halophilic archaea and thermophilic, sulfur-metabolizing archaea. The availability of these tools has allowed for more complete studies of archaeal physiology and metabolism and most importantly provides the basis for the investigation of gene expression, regulation and function. In this review we provide an overview of methods for genetic manipulation of Methanosarcina spp., a group of methanogenic archaea that are key players in the global carbon cycle and which can be found in a variety of anaerobic environments. PMID- 22837756 TI - Quantification of ammonia oxidation rates and the distribution of ammonia oxidizing Archaea and Bacteria in marine sediment depth profiles from Catalina Island, California. AB - Microbial communities present in marine sediments play a central role in nitrogen biogeochemistry at local to global scales. Along the oxidation-reduction gradients present in sediment profiles, multiple nitrogen cycling processes (such as nitrification, denitrification, nitrogen fixation, and anaerobic ammonium oxidation) are active and actively coupled to one another - yet the microbial communities responsible for these transformations and the rates at which they occur are still poorly understood. We report pore water geochemical (O(2), [Formula: see text], and [Formula: see text]) profiles, quantitative profiles of archaeal and bacterial amoA genes, and ammonia oxidation rate measurements, from bioturbated marine sediments of Catalina Island, California. Across triplicate sediment cores collected offshore at Bird Rock (BR) and within Catalina Harbor (CH), oxygen penetration (0.24-0.5 cm depth) and the abundance of amoA genes (up to 9.30 * 10(7) genes g(-) (1)) varied with depth and between cores. Bacterial amoA genes were consistently present at depths of up to 10 cm, and archaeal amoA was readily detected in BR cores, and CH cores from 2008, but not 2007. Although detection of DNA is not necessarily indicative of active growth and metabolism, ammonia oxidation rate measurements made in 2008 (using isotope tracer) demonstrated the production of oxidized nitrogen at depths where amoA was present. Rates varied with depth and between cores, but indicate that active ammonia oxidation occurs at up to 10 cm depth in bioturbated CH sediments, where it may be carried out by either or both ammonia-oxidizing archaea and bacteria. PMID- 22837757 TI - HTLV-1 uveitis. AB - Human T cell lymphotropic virus type 1 (HTLV-1) is the first retrovirus described as a causative agent of human disease. Following adult T cell leukemia/lymphoma and HLTV-1-associated myelopathy/tropical spastic paraparesis, HTLV-1 uveitis (HU) has been established as a distinct clinical entity caused by HTLV-1 based on seroepidemiological, clinical, and virological studies. HU is one of the most common causes of uveitis in endemic areas of Japan and can be a problematic clinical entity all over the world. HU occurs with a sudden onset of floaters and foggy vision, and is classified as an intermediate uveitis. Analysis of infiltrating cells in eyes with HU revealed that the majority of infiltrating cells were CD3(+) T cells, but not malignant cells or leukemic cells based on their T cell receptor usage. HTLV-1 proviral DNA, HTLV-1 protein, and viral particles were detected from infiltrating cells in eyes with HU. HTLV-1-infected CD4(+) T cell clones established from infiltrating cells in eyes with HU produced large amounts of various inflammatory cytokines, such as IL-1, IL-6, IL-8, TNF alpha, and interferon-gamma. Taken together, HU is considered to be caused by inflammatory cytokines produced by HTLV-1-infected CD4(+) T cells that significantly accumulate in eyes; therefore, topical and/or oral corticosteroid treatment is effective to treat intraocular inflammation in patients with HU. Further investigation is needed to establish a specific treatment for HU. PMID- 22837758 TI - Autoimmune cytopenias in common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20-50%; Chapel et al., 2008; Cunningham-Rundles, 2008), autoimmune cytopenias are by far the most common occurring variably in 4-20% (Michel et al., 2004; Chapel et al., 2008) of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia, and neutropenia. While it may seem paradoxical "prima facie" that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21 low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID. PMID- 22837759 TI - A new paradigm for an old story: the role of regulatory B cells in cancer. PMID- 22837760 TI - Antimicrobial activities of chemokines: not just a side-effect? AB - The large family of chemoattractant cytokines (chemokines) embraces multiple, in part unrelated functions that go well beyond chemotaxis. Undoubtedly, the control of immune cell migration (chemotaxis) is the single, unifying response mediated by all chemokines, which involves the sequential engagement of chemokine receptors on migrating target cells. However, numerous additional cellular responses are mediated by some (but not all) chemokines, including angiogenesis, tumor cell growth, T-cell co-stimulation, and control of HIV-1 infection. The recently described antimicrobial activity of several chemokines is of particular interest because antimicrobial peptides are thought to provide an essential first line defense against invading microbes at the extremely large body surfaces of the skin, lungs, and gastrointestinal-urinary tract. Here we summarize the current knowledge about chemokines with antimicrobial activity and discuss their potential contribution to the control of bacterial infections that may take place at the earliest stage of antimicrobial immunity. In the case of homeostatic chemokines with antimicrobial function, such as CXCL14, we propose an immune surveillance function in healthy epithelial tissues characterized by low-level exposure to environmental microbes. Inflammatory chemokines, i.e., chemokines that are produced in tissue cells in response to microbial antigens (such as pathogen-associated molecular patterns) may be more important in orchestrating the cellular arm in antimicrobial immunity. PMID- 22837761 TI - Stroma cell priming in enteric lymphoid organ morphogenesis. AB - The lymphoid system is equipped with a network of specialized platforms located at strategic sites, which grant strict immune-surveillance and efficient immune responses. The development of these peripheral secondary lymphoid organs (SLO) occurs mainly in utero, while tertiary lymphoid structures can form in adulthood generally in response to persistent infection and inflammation. Regardless of the lymphoid tissue and intrinsic cellular and molecular differences, it is now well established that the recruitment of fully functional lymphoid tissue inducer (LTi) cells to presumptive lymphoid organ sites, and their consequent close and reciprocal interaction with resident stroma cells, are central to SLO formation. In contrast, the nature of events that initially prime resident sessile stroma cells to recruit and retain LTi cells remains poorly understood. Recently, new findings revealed early phases of SLO development putting emphasis on mesenchymal and lymphoid tissue initiator cells. Herein we discuss the main tenets of enteric lymphoid organs genesis and focus in the most recent findings that open new perspectives to the understanding of the early phases of lymphoid morphogenesis. PMID- 22837762 TI - MAP Kinase Cascades in Arabidopsis Innate Immunity. AB - Plant mitogen-activated protein kinase (MAPK) cascades generally transduce extracellular stimuli into cellular responses. These stimuli include the perception of pathogen-associated molecular patterns (PAMPs) by host transmembrane pattern recognition receptors which trigger MAPK-dependent innate immune responses. In the model Arabidopsis, molecular genetic evidence implicates a number of MAPK cascade components in PAMP signaling, and in responses to immunity-related phytohormones such as ethylene, jasmonate, and salicylate. In a few cases, cascade components have been directly linked to the transcription of target genes or to the regulation of phytohormone synthesis. Thus MAPKs are obvious targets for bacterial effector proteins and are likely guardees of resistance proteins, which mediate defense signaling in response to the action of effectors, or effector-triggered immunity. This mini-review discusses recent progress in this field with a focus on the Arabidopsis MAPKs MPK3, MPK4, MPK6, and MPK11 in their apparent pathways. PMID- 22837765 TI - A classification of pulmonary nodules by CT scan. AB - This Image Report aims to briefly describe, giving some imaging examples, the radiological definition of the features of lung nodules as commonly used by radiologists. We hope thus to improve communication and mutual understanding between radiologists and clinicians. PMID- 22837764 TI - Methods for nutrition monitoring in cancer patients: a cognitive perspective. AB - In the present medical context, the evaluation and the monitoring of factors other than mere physical symptoms are an urgent demand. In particular, the issue of quality of life (QoL) has become a relevant target in the treatment of cancer. However, the approach towards these aspects is not well standardized and the actual applications in a concrete setting are fragmented, left to personal or local initiative. If this is true for QoL in general, it is particularly relevant in the specific field of nutrition. Indeed, though the growing awareness of a correlation between chronic diseases and dietary habits has led to an increased interest in nutrition, both before and after cancer, very little is still known about the methods that measure this important variable of the QoL. Indeed, good nutrition may have a relevant impact on QoL, positively affecting both the physical and psychological well-being. Targeting this issue implies using proper instruments to both monitor and educate the patients. Hence, we argue that it is vital for oncologists to be able to individuate the best tool available in a specified context, so as to achieve an important goal with little effort, also adopting standardized strategies proved to be efficacious. In this framework, we briefly reviewed the tools more frequently reported in the scientific literature. We suggest that through a cognitive approach, it is possible to achieve important clinical targets, initially by understanding the patients' needs, values, and psychosocial factors involved in nutritional behaviour and food-related decisions, in order to develop a personalized approach. Hence, this is the only way to support concrete actions for promoting healthier diets, thus preventing recurrences, monitoring chronic conditions, and supporting a good QoL. PMID- 22837763 TI - Are kinesins required for organelle trafficking in plant cells? AB - Plant cells exhibit active movement of membrane-bounded materials, which is more pronounced in large cells but is also appreciable in medium-sized cells and in tip-growing cells (such as pollen tubes and root hairs). Trafficking of organelles (such as Golgi bodies, endoplasmic reticulum, peroxisomes, and mitochondria) and vesicles is essential for plant cell physiology and allows a more or less homogeneous distribution of the cell content. It is well established that the long-range trafficking of organelles is dependent essentially on the network of actin filaments and is powered by the enzyme activity of myosins. However, some lines of evidence suggest that microtubules and members of the kinesin microtubule-based motor superfamily might have a role in the positioning and/or short-range movement of cell organelles and vesicles. Data collected in different cells (such as trichomes and pollen tubes), in specific stages of the plant cell life cycle (for example, during phragmoplast development) and for different organelle classes (mitochondria, Golgi bodies, and chloroplasts) encourage the hypothesis that microtubule-based motors might play subtle yet unclarified roles in organelle trafficking. In some cases, this function could be carried out in cooperation with actin filaments according to the model of "functional cooperation" by which motors of different families are associated with the organelle surface. Since available data did not provide an unambiguous conclusion with regard to the role of kinesins in organelle transport, here we want to debate such hypothesis. PMID- 22837766 TI - A pilot investigation of quality of life and lung function following choral singing in cancer survivors and their carers. AB - BACKGROUND: The diagnosis of cancer creates a wide range of social and emotional problems to patients and carers. However, delivering effective psychological, emotional, and social support remains a challenge. This pilot study evaluated quality of life (QoL) and lung function before and after three months of choral singing in cancer survivors and their carers. METHODS: At baseline, 30 cancer survivors and their carers, mean (standard deviation) age 60 (10), completed questions about QoL (SF-36), anxiety and depression, and the multidimensional fatigue score. Lung function was measured by spirometry, and respiratory musclestrength (maximal inspiratory pressure, MIP; maximal expiratory pressure, MEP) was also measured. Assessments were repeated after three months of singing in the choir, and 10 participants completed semi-structured interviews to explore their experience of the choir. RESULTS: After three months of choral singing, 20 subjects repeated the assessments. Several domains of the SF-36 improved, including vitality, social functioning, mental health, and bodily pain. There was also a trend of reduced anxiety and depression, despite no change in fatigue. Spirometric measures of lung function were unchanged; however, there was a trend of increased MEP. Themes from the interviews revealed that the choir provided a focus, so the future participants felt uplifted and had greater confidence and self-esteem. CONCLUSIONS: This pilot project provides preliminary data which suggest choral singing may improve QoL and depression, despite no physiological change in cancer survivors and their carers. Choral groups offer a support mechanism applicable to cancer patients, carers, and supporters, and may be relevant to other chronic conditions. Further research examining the efficacy of this intervention in a larger controlled study is warranted. PMID- 22837767 TI - Pediatric spinal schwannomas: An institutional study. AB - OBJECTIVE: The objective was to analyze the demography, clinical presentation, and management of spinal intradural schwannomas in pediatric population. MATERIALS AND METHODS: This retrospective study includes 21 pediatric patients (under 18 years of age) who underwent surgery for spinal intradural schwannomas from January 1998 to April 2008. The medical records were reviewed retrospectively and the information regarding clinical presentation, tumor location, operative findings, and postoperative status and functional outcome were analyzed. RESULTS: A total of 21 patients (14 females and 7 males) were operated for spinal schwannomas. Six patients had associated neurofibromatosis (five were NF I and one was NF II) at presentation. The most common presenting symptom was progressive myelopathy (86%). The tumor location was either cervical or dorsal in 18 cases. All patients underwent surgery. Gross total excision was achieved in 20 cases. The median follow-up was 38 months. All the patients had neurological improvement in both power and bladder symptoms. CONCLUSION: Pediatric spinal neurofibromas/schwannomas are an uncommon but completely treatable group of tumors. Complete surgical excision gives excellent outcome. PMID- 22837768 TI - Role of hyperbaric oxygen therapy in severe head injury in children. AB - AIM: A brain injury results in a temporary or permanent impairment of cognitive, emotional, and/or physical function. Predicting the outcome of pediatric brain injury is difficult. Prognostic instruments are not precise enough to reliably predict individual patient's mortality and long-term functional status. The purpose of this article is to provide a guide to the strengths and limitations of the use of hyperbaric oxygen therapy (HBOT) in treating pediatric patients with severe brain injury. MATERIALS AND METHODS: We studied total 56 patients of head injury. Out of them 28 received HBOT. Only cases with severe head injury [Glasgow Coma Scale (GCS) < 8] with no other associated injury were included in the study group. After an initial period of resuscitation and conservative management (10 12 days), all were subjected to three sessions of HBOT at 1-week interval. This study group was compared with a control group of similar severity of head injury (GCS < 8). RESULTS: The study and control groups were compared in terms of duration of hospitalization, GCS, disability reduction,and social behavior. Patients who received HBOT were significantly better than the control group on all the parameters with decreased hospital stay, better GCS, and drastic reduction in disability. CONCLUSION: In children with traumatic brain injury, the addition of HBOT significantly improved outcome and quality of life and reduced the risk of complications. PMID- 22837769 TI - Role of electroencephalogram and neuroimaging in first onset afebrile and complex febrile seizures in children from Kashmir. AB - OBJECTIVES: (1) To determine the frequency of abnormal neuroimaging in children with new-onset afebrile and complex febrile seizures; (2) to draw a correlation between Electroencephalogram (EEG) and neuroimaging. STUDY DESIGN: A hospital based prospective study. MATERIALS AND METHODS: A total of 276 children (6 months to 14 years of age), who presented with new-onset afebrile or complex febrile seizures, underwent EEG and neuroimaging [Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI)]. RESULTS: Generalized seizures constituted the major seizure group in our study - 116/276 (42%) - followed by partial seizures 86/276 (31.2%) and complex febrile seizure in 64/276 (23.2%). Generalized as well as partial seizures were more common in children aged 6-14 years, while complex febrile seizures were predominantly seen in children less than 6 years old. Most of the patients with generalized and partial seizures had EEG abnormalities, while EEG abnormalities were uncommon in patients with complex febrile seizures. A total of 27/276 (9.8%) patients with seizure disorder had abnormal CT scans and this abnormality was more common in patients with partial seizures. CT abnormality was seen more commonly in those patients who had an abnormal EEG. EEG and CT correlation showed that patients with abnormal EEG had higher rates of CT abnormality, ie, 16.1% (25/155). Abnormal MRI was seen in 32/157 (20.4%) of patients; accuracy of picking abnormality by MRI, when EEG was abnormal, was 24.8% (P<0.05). CONCLUSION: Our findings indicate that clinical examination and EEG results are good indicators for neuroimaging, and these can be used as one of the criteria for ordering neuroimaging in new-onset seizures. PMID- 22837770 TI - Evaluation of a parent-based behavioral intervention program for children with autism in a low-resource setting. AB - BACKGROUND: Intensive behavioral intervention programs are recommended for children with autism. However, in resource-constraint settings, such programs are largely inaccessible, and there is an urgent need for development of low-cost interventions. AIM: To evaluate the efficacy of a parent-based behavioral intervention program in Indian autistic children. MATERIALS AND METHODS: Sixteen children with autistic disorder undergoing the intervention for at least six months were enrolled. The mean development, social, expressive, and receptive language quotients, and the Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC) scores were compared before and after the intervention. RESULTS: The average duration of therapy was 19.5+/-11.78 months. There was a significant improvement in the development quotient (P=0.015), social quotient (P=0.004), expressive language quotient (P=0.03), CARS (P=0.001), and ABC (P=0.014) scores. CONCLUSION: Parent-based behavioral intervention programs have a promising role in management of children with autism in resource-constraint settings. PMID- 22837771 TI - The efficacy and side effects of levetiracetam on refractory epilepsy in children. AB - OBJECTIVE: To evaluate the efficacy and tolerability of levetiracetam (LEV) add on therapy in children with refractory epilepsy. MATERIALS AND METHODS: We evaluated 102 children (56 boys, 46 girls, mean age 96.00 +/- 31.15 months) with refractory epilepsy. Patients received LEV as add-on therapy. Changes in seizure frequency and adverse events were observed. Follow-up was conducted at least 6 months after treatment. RESULTS: In total, 46 (45.1%) of the 102 children achieved more than 50% seizure frequency reduction, and 16 (15.6%) of these were seizure free. LEV reduced seizure frequency by at least 50% in 58.3% of patients with partial seizures, in 32.0% of patients with primary generalized seizures, and in 17.6% of patients with both partial and generalized seizures. CONCLUSION: Our results confirm that LEV, as add-on therapy, was effective in reducing seizure frequency in a variety of seizure types but seems most effective for partial-onset seizures. LEV was also well-tolerated in children. PMID- 22837772 TI - Surgery for brain abscess in children with cyanotic heart disease: An anesthetic challenge. AB - CONTEXT: Patients with cyanotic congenital heart disease (cCHD) are prone to develop frequent brain abscesses. Surgery for these abscesses is often limited to aspiration under local anesthesia because excision under general anesthesia (GA) is considered a riskier option. Perioperative hemodynamic instability, cyanotic spells, coagulation defects, electrolyte and acid base imbalance, and sudden cardiac arrest are among the major anesthetic concerns. Most of our current knowledge in this area has been gained from a neurosurgical standpoint while there is a paucity of corresponding anesthesia literature. AIMS: To highlight the anesthesia issues involved in cCHD children undergoing brain abscess excision under GA. SETTINGS AND DESIGN: Retrospective study of our institutional experience over a 5 year period. MATERIALS AND METHODS: Of all the children with cCHD who underwent brain abscess surgery from January 2005 to December 2009, only 4 were operated under GA. Surgery was done after correcting fever, dehydration, electrolyte imbalance, coagulopathy and acid-base abnormalities, and taking appropriate intraoperative steps to maintain hemodynamic stability and prevent cyanotic spells and arrhythmias. RESULTS: All 4 patients had a successful abscess excision though with varying degrees of intraoperative problems. There was one death, on postoperative day 34, due to septicemia. CONCLUSIONS: Brain abscess excision under GA in children of cCHD can be safely carried out with proper planning and attention to detail. PMID- 22837773 TI - Magnetic resonance imaging in pantothenate kinase-2-associated neurodegeneration. AB - Pantothenate kinase-2-associated neurodegeneration (PKAN) is a rare autosomal recessive pediatric neurodegenerative disorder characterized by rigidity, dystonia, impaired postural reflexes, and progressive dementia. On T2-weighted magnetic resonance imaging images, marked low signal intensity is seen in the globus pallidus. This low signal intensity surrounds a central region of high signal intensity in the anteromedial globus pallidus, giving an eye-of-the-tiger appearance. PMID- 22837774 TI - Severe anemia causing cerebral venous sinus thrombosis in an infant. AB - Iron deficiency anemia is a common pediatric problem affecting up to 25% children worldwide. It has been linked with cerebral venous sinus thrombosis in the literature. We describe a 9-month-old child who had severe iron deficiency anemia and developed acute venous sinus thrombosis associated with minor infection. Treatment with anticoagulation was partially successful with persistent thrombosis after 3 months. We reviewed the current literature highlighting the association of anemia as a risk factor for development of stroke in children. PMID- 22837775 TI - Traumatic rupture of arachnoid cyst with subdural hygroma. AB - Intracranial arachnoid cysts developing in relation to the cerebral hemispheres and middle cranial fossa are usually incidental or asymptomatic. However, most of the clinically active cysts present with seizures because of chronic compression. Presentation as raised intracranial pressure due to cyst rupture into the subdural space is a rare clinical entity. We herein present a case of an asymptomatic arachnoid cyst with rupture into the subdural space bilaterally and presenting as raised intracranial pressure. PMID- 22837776 TI - Alveolar soft part sarcoma of the frontal calvarium and adjacent frontal lobe. AB - Alveolar soft part sarcoma is a rare tumor affecting mainly adolescent and young children. It presents as a slowly growing tumor and is usually overlooked due to lack of symptoms. Early metastasis is a characteristic feature of this tumor and, in a good number of cases, metastasis to the lung or brain is the first manifestation of the disease. In this report, we present a case of alveolar soft part sarcoma predominantly located in the right frontal bone with dural breach and contiguous right frontal lobe involvement in a 17-year-old girl without any evident primary or other secondaries. A brief review of literature is also presented. PMID- 22837777 TI - Management problems in a case of third ventricular choroid plexus papilloma. AB - A rare case of third ventricular choroid plexus papilloma and associated complication of shunt ascites is described. We propose to convert shunt into ventricular drain in such a situation and reassess the requirement of shunt after complete tumor removal. PMID- 22837778 TI - Metachronous occurrence of nonradiation-induced brain cavernous hemangioma and medulloblastoma in a child with neurofibromatosis type I phenotype. AB - Cavernous hemangioma (CH) is a sporadic vascular malformation occurring either as an autosomal dominant condition or as a well-known complication of radiation exposure. Medulloblastoma is a primitive neuroectodermal tumor common in children and currently treated with surgical resection, chemotherapy, and radiotherapy. Neurofibromatosis is the most common single-gene disorder of the central nervous system. Posterior fossa malignant tumors in the context of neurofibromatosis type I (NF1) are very infrequent. This is the first documented case of an unusual metachronous occurrence of non-radiation-induced CH and medulloblastoma in a child with NF1 phenotype. We report the case of a 13-month-old boy with cafe-au lait skin lesions associated with NF1-like phenotype who underwent surgical resection of a single CH in the temporal lobe due to recurrent seizures. Four years later he presented with signs of raised intracranial pressure associated with a posterior fossa tumor and hydrocephalus, thus requiring gross total resection of the lesion. Histological analysis revealed a medulloblastoma. After being treated with radiotherapy and chemotherapy, he achieved total remission. Six years later a massive recurrence of the tumor was observed and the child eventually died. The interest in this case lies in the rarity of NF1-like phenotype associated with a non-radiation-induced brain CH and medulloblastoma in a child. PMID- 22837779 TI - Recurrent meningitis due to epidermoid. AB - Aseptic meningitis is characterized by noninfective serous inflammation of the meninges. It can occur in a recurrent fashion when associated with dermoid and epidermoid cysts due to rupture of cyst contents into subarachnoid space resulting in aseptic chemical meningitis. Bacterial meningitis in association with these tumors is commonly related to a coexisting dermal sinus tract and the most common organism is Staphylococcus aureus. PMID- 22837780 TI - Pseudotumoral hemicerebellitis with hemorrhage. AB - Acute cerebellitis is an inflammatory syndrome occurring most commonly in young children. It is caused by a variety of insults and is usually bilateral. Pseudotumoral hemicerebellitis is an exceptionally rare unilateral presentation of acute cerebellitis mimicking a tumor. Magnetic resonance imaging (MRI) reveals a diffusely swollen cerebellar hemisphere, but with the lack of a well-defined mass, which is hyperintense in T2-weighted images and with pial enhancement in post-contrast images. It typically has a benign course with regression in follow up scans, thus distinguishing it from a tumor. Recognizing this entity is important because erroneous diagnosis may lead to needless surgical intervention. We present a case of pseudotumoral hemicerebellitis in a 12-year-old boy with coagulopathy, with follow-up MRI depicting hemorrhage, and discuss the pathogenesis. PMID- 22837781 TI - Concurrent infection of Japanese encephalitis and mixed plasmodium infection. AB - Japanese encephalitis (JE) and malaria would coexist in the areas where both illnesses are endemic with overlapping clinical pictures, especially in a case of febrile encephalopathy with hepatosplenomegaly. However, there are no published data till date showing concurrent infection of these two agents despite both diseases being coendemic in many areas. We report a case of concurrent infection of JE and mixed plasmodium infection, where the case, initially diagnosed as cerebral malaria did not improve on antimalarials and alternative diagnosis of JEV encephalitis was thought which was confirmed by a serological test. To the best of our knowledge, this is the first case report of concurrent Japanese encephalitis with mixed plasmodium infection. We report a case of 3-year-old male child, who presented with febrile encephalopathy with hepatosplenomegaly. Based on a rapid diagnostic test and peripheral smear examination, a diagnosis of mixed P.Vivax and P.falciparum infection was made and the patient was treated with quinine and doxycycline. However, besides giving antimalarials the patient did not improve and an alternative diagnosis of JE was considered as the patient was from the endemic zone of Japanese encephalitis. Cerebrospinal fluid (CSF) of the patient was sent for a virological study which came out to be positive for JE IgM in CSF, which is confirmatory of JE infection. In a patient with febrile encephalopathy with hepatosplenomegaly especially in areas coendemic for JE and malaria, the possibility of mixed infection should be kept in mind. PMID- 22837782 TI - Childhood disintegrative disorder. AB - We are presenting a case of a 10-year-old female child who presented with normal development till 5 years of age followed by deterioration in previously acquired language and social skills with stereotypic hand movements suggestive of childhood disintegrative disorder. This case is reported as this condition is very rare. PMID- 22837783 TI - Infected dermoid tumor causing tethered cord after myelomeningocele repair. AB - Intramedulary dermoid tumors are rare tumors mostly found associated with dermal sinus tracts. Spinal dermoid tumor can occur after myelomeningocele repair. Infected dermoid tumors are reported in patients with dermal sinus tracts as well, but have never been reported subsequent to myelomeningocele surgery. Here, we report a rare association of infected dermoid tumor with tethered cord without dermal sinus tract in a child who had been operated for myelomeningocele during infancy. PMID- 22837784 TI - Intramedullary tubercular abscess with syrinx formation. AB - Intramedullary spinal cord tubercular abscess with involvement of whole cord is a rare entity that too with syrinx formation following disseminated meningitis. Accurate diagnosis requires a high index of suspicion with clinical history and imaging features for a favorable outcome. Here-in we present a similar case with tubercular etiology which was also associated with syrinx formation and has not been reported previously in the literature up to the author's knowledge. PMID- 22837785 TI - Primary Ewing's sarcoma of the spine presenting as acute paraplegia. AB - Ewing's sarcoma is a primary bone malignancy with the highest incidence in the second decade of life. Although it mostly affects the metaphyseal region of long growing bones, involvement of spine is not very uncommon especially the sacrum. Nonsacral spinal Ewing's sarcoma is rarer and often mimics a benign condition before spreading extensively. They present with neurologic deficits due to spinal cord compression, but acute onset paraplegia has not been previously reported. A high index of clinical suspicion can clinch the diagnosis early in the course of the disease. A prompt intervention is required to keep neurological damage to a minimum, and a correct combination of surgery, chemotherapy, and radiotherapy is required for better long-term patient outcome. We report a 16-year-old female who presented with acute paraplegia and had an excellent postoperative outcome after radical excision of a D9 Ewing's sarcoma. PMID- 22837786 TI - Primary spinal intramedullary primitive neuroectodermal tumor. AB - Though primitive neuroectodermal tumor has been considered to arise from a neoplastic transformation of primitive neuroepithelial cells with propensity to involve any part of the central nervous system, a primary intramedullary spinal primitive neuroectodermal tumor is very unusual. The authors describe a case of an 18-year-old female with conus intramedullary tumor diagnosed to be primary spinal primitive neuroectodermal tumor following histopathological examination after surgery. The diagnosis of such a tumor is very crucial as the management strategies for these are relatively unclear and are associated with a poorer outcome compared to the other common intramedullary spinal tumors. PMID- 22837787 TI - A reminder of the dangers of trampolining: Spinal cord infarction secondary to hyperextension injury during trampolining. PMID- 22837788 TI - Choroid plexus carcinoma: Case report and review of literature. PMID- 22837789 TI - Rare case of hemorrhagic brain metastasis from hepatoblastoma. PMID- 22837790 TI - Cerebello pontine angle lipoma in a child. PMID- 22837791 TI - A rare case of spontaneous bilateral extradural hematoma in a sickle cell disease child. PMID- 22837792 TI - Posterior fossa dermoid cyst. PMID- 22837793 TI - Synthesis and comparative study on the antimicrobial activity of hybrid materials based on silver nanoparticles (AgNps) stabilized by polyvinylpyrrolidone (PVP). AB - Hybrid materials based on polyvinylpyrrolidone (PVP) with silver nanoparticles (AgNps) were synthesized applying two different strategies based on thermal or chemical reduction of silver ions to silver nanoparticles using PVP as a stabilizer. The formation of spherical silver nanoparticles with diameter ranging from 9 to 16 nm was confirmed by TEM analysis. UV-vis and FTIR spectroscopy were also applied to confirm the successful formation of AgNps. The antibacterial activity of the synthesized AgNPs/PVP against etalon strains of three different groups of bacteria-Staphylococcus aureus (S. aureus; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria), Pseudomonas aeruginosa (P. aeruginosa; non-ferment gram-negative bacteria), as well as against spores of Bacillus subtilis (B. subtilis) was studied. AgNps/PVP were tested for the presence of fungicidal activity against different yeasts and mold such as Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Aspergillus brasiliensis. The hybrid materials showed a strong antimicrobial effect against the tested bacterial and fungal strains and therefore have potential applications in biotechnology and biomedical science. PMID- 22837794 TI - School-Based Racial and Gender Discrimination among African American Adolescents: Exploring Gender Variation in Frequency and Implications for Adjustment. AB - The present study examined school-based racial and gender discrimination experiences among African American adolescents in Grade 8 (n = 204 girls; n = 209 boys). A primary goal was exploring gender variation in frequency of both types of discrimination and associations of discrimination with academic and psychological functioning among girls and boys. Girls and boys did not vary in reported racial discrimination frequency, but boys reported more gender discrimination experiences. Multiple regression analyses within gender groups indicated that among girls and boys, racial discrimination and gender discrimination predicted higher depressive symptoms and school importance and racial discrimination predicted self-esteem. Racial and gender discrimination were also negatively associated with grade point average among boys but were not significantly associated in girls' analyses. Significant gender discrimination X racial discrimination interactions resulted in the girls' models predicting psychological outcomes and in boys' models predicting academic achievement. Taken together, findings suggest the importance of considering gender- and race-related experiences in understanding academic and psychological adjustment among African American adolescents. PMID- 22837795 TI - Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). AB - The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Myalgic Encephalomyelitis/Fatigue Syndrome are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented. We performed an audit of 138 patients (ages 18 65) diagnosed with ME/CFS and attending a private practice. The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell free DNA in plasma, were made. The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction. Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range. The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria. The ATP Profile is a valuable diagnostic tool for the clinical management of ME/CFS. PMID- 22837796 TI - Induced PDK1 kinase activity suppresses apoptosis in intestinal epithelial cells by activating Akt signaling following polyamine depletion. AB - Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is highly regulated by numerous factors including polyamines. Decreasing cellular polyamines promotes the resistance of intestinal epithelial cells (IECs) to apoptosis by increasing Akt kinase activity, but the exact mechanisms by which polyamine depletion activates Akt remain unknown. 3-phosphoinositide-dependent protein kinase-1 (PDK1), functions as a downstream of phosphatidylinositol-3 kinase (PI3K) and upstream of Akt and serves as a major regulator of Akt activity. The current study determined if polyamines regulate Akt activity by altering PDK1. Studies were conducted in IEC-6 cells, derived from rat small intestinal crypts. Depletion of cellular polyamines induced PDK1 phosphorylation and increased its kinase activity, which were prevented by exogenous polyamine putrescine. Induced PDK1 activation following polyamine depletion was associated with an increase in phosphorylated Akt (pAkt) and Akt kinase activity. In contrast, polyamine depletion did not alter levels of total PDK1 and Akt proteins. PDK1 silencing in polyamine-deficient cells not only prevented the induced Akt activation but also blocked the increased resistance to apoptosis. These results indicate that polyamine depletion enhanced Akt phosphorylation by increasing PDK1 kinase activity, thereby protecting IECs against apoptosis. PMID- 22837797 TI - Serum insulin-like growth factor binding protein 6 (IGFBP6) is increased in patients with type 1 diabetes and its complications. AB - Insulin-like growth factor binding proteins (IGFBPs) are associated with insulin resistance and accelerated micro- and macro-vascular complications of diabetes. We investigated the relationship between serum levels of IGFBP6 in type-1 diabetes (T1D) patients and diabetic complications. In this study, IGFBP6 was measured in the sera from 697 T1D patients and 681 healthy controls using a Luminex assay. Mean serum levels of IGFBP6 were higher in T1D patients than controls matched for sex and age (119.7 vs 130.6 ng/ml, p < 10(-4)). Subject age, sex and duration of disease have a significant impact on serum IGFBP6 levels in both T1D patients and healthy controls. Patients with complications have significantly higher mean serum IGFBP6 than patients without any complication (p = 3.5x10(-6)). More importantly, conditional logistic regression analysis suggested that T1D patients are more likely to have very high levels of serum IGFBP6 (in the 4(th) quartile) (OR = 1.7) than healthy controls. Furthermore, T1D patients with various complications are more likely to have very high levels of serum IGFBP6 (in the 4(th) quartile) than patients without any complication (OR = 1.7 - 22.9). These results indicate the clinical importance of measuring IGFBP6 to the better management of T1D patients. PMID- 22837798 TI - Multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a double-blind placebo-controlled study. AB - AIM: To investigate the effect of bifid triple viable capsule, a multistrain probiotic preparation on symptoms of irritable bowel syndrome (IBS), and the amount of fecal Bifidobacterium spp. and Lactobacillus spp. of IBS patients before and after treatment. METHODS: A total of 60 IBS patients who met Rome III criteria were included in this double-blind, randomized, and placebo-controlled study. The patients were randomly assigned to receive composite probiotics or placebo for four weeks. The IBS symptoms of participants were surveyed using a questionnaire, and the amount of fecal Bifidobacterium spp. and Lactobacillus spp. was determined by quantitative Real-time PCR pre- and post-intervention. RESULTS: During the four week intervention period, the patients receiving probiotic preparation showed a significantly greater improvement in the symptom severity score of IBS, severity and frequency of pain or discomfort, abdominal distention and satisfaction with bowel habits. The symptom subtypes revealed that low amounts of both Bifidobacterium spp. and Lactobacillus spp. were present in the samples of diarrhea-predominant IBS patients, while the alternating predominant IBS patients had only low amounts of Bifidobacterium spp. Post intervention for diarrhea-predominant IBS patients with lower symptom severity score showed even lower amounts of Bifidobacterium spp. and Lactobacillus spp. CONCLUSION: Bifid triple viable capsule supplement may benefit patients with IBS. Multistrain probiotic preparation may be a promising candidate for IBS therapy, although the mechanism needs to be further studied. PMID- 22837799 TI - Changes in mitochondrial DNA and its encoded products in alcoholic cirrhosis. AB - The purpose of this study was to investigate hepatic mitochondrial DNA (mtDNA) damage and changes in its encoded products in patients with alcoholic cirrhosis (AC) in order to understand disease pathogenesis. We enrolled 23 patients with AC, 26 alcoholics without cirrhosis, and 25 normal subjects in this study. Hepatic mtDNA deletions were positioned using a combination of long and accurate polymerase chain reaction (LA PCR) and gene sequencing. The mtDNA copy number was measured using real-time quantitative PCR. The expression of the mtDNA-encoded cytochrome c oxidase 2 (cox2) was detected by western blotting. A large deletion of bases located at positions 749-15486 was identified in hepatic mtDNA from AC patients. Moreover, the mtDNA copy number was significantly reduced (P<0.05), and its encoded product, cox2, was significantly downregulated (P<0.05). Collectively, our results suggest that specific deletions and reduced copy numbers of hepatic mtDNA in patients with AC is an important pathogenetic factor. PMID- 22837800 TI - Evaluation of relationship between grading of fatty liver and severity of atherosclerotic finding. AB - PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a feature of metabolic syndrome and has a high prevalence in the general population. OBJECTIVE: To determine the severity of atherosclerotic finding in various grade of NAFLD. MATERIAL AND METHODS: We examined 250 consecutive patients with various grade of NAFLD and 85 control subjects matched for age, gender, to determine carotid intima-media thickness (CIMT) in each groups. RESULTS: The mean CIMT in patients with G1, G2 and G3 NAFLD were 0.78+/-0.15 mm, 0.82+/-0.11mm and 0.85+/-0.16mm respectively. The differences in CIMT between the various grades of NAFLD were statistically significant (p=0.01). CONCLUSION: According to our study results the presence of NAFLD; severity of atherosclerosis will be higher parallel with severity of fatty liver infiltration. Therefore, Patients with NAFLD especially high-grade fatty liver may be candidate to be investigated for the presence CAD. PMID- 22837801 TI - Lateral fold and partial nail bed excision for the treatment of recurrent ingrown toenails. AB - BACKGROUND: Ingrown toenail is one of the most common nail complaints. Although some surgical treatments have been described for relapse cases, frequent recurrence of pain, infection, and poor cosmetic results prompted us to search for an appropriate treatment. OBJECTIVE: This study was aimed at evaluation of our surgical technique of lateral fold and partial nail bed excision for the treatment of recurrent ingrown toenails. MATERIALS AND METHODS: We retrospectively reviewed the charts of 138 patients who underwent surgery by lateral fold and partial nail bed excision from 2009 to 2011. The operative technique, results, and long-term outcomes were recorded. RESULTS: 131 patients were followed up. 121 patients (92.37%) were cured. 10 patients (7.63%) had recurrent problems in 12 digits (7.06%). Of these, only 6 patients underwent surgery again. CONCLUSIONS: Lateral fold and partial nail bed excision is a simple, safe, and effective technique for treatment of recurrent ingrown toenails with a low risk of relapse. PMID- 22837802 TI - A rare case of acquired hemophilia A associated with myelodysplastic syndrome. AB - 84 year old male with past medical history of myelodysplastic syndrome (MDS) presented with progressive subcutaneous and muscle bleed in the right forearm and arm. Workup revealed elevated activated partial thromboplastin time (aPTT) - 71.8 seconds (normal 23 - 32 seconds) which was persistently elevated after mixing study (37.1 seconds immediately and 51.1 seconds after 1 hour). Further laboratory work up revealed low factor VIII level (3%) and elevated factor VIII inhibitor by Bethesda assay (3 units/ml of blood). Acquired hemophilia A (AHA) diagnosis was established and patient was treated with recombinant factor VIIa (rFVlla) to control the bleeding and also prednisone for immunosuppression. Subsequent monitoring suggested reduction of factor VIII inhibitor - antibody levels to undetectable level in 3 days and increase of factor VIII level from 3% to 50% in 5 days. Despite of improvement in the laboratory values he continued to have progression of his bleeding which involved posterior chest wall and also left arm. Due to the progression of the condition and prior expressed wish family decided to stop the aggressive treatment and patient died nine days after the diagnosis. The case report describes a rare presentation of AHA in MDS (With bone marrow cytogenetics abnormality) patient with fatal outcome. PMID- 22837803 TI - Early-onset breast disease: case of a Grave condition with a favorable prognosis. AB - BACKGROUND: The relationship between thyroid and breast diseases has been well documented, but the clinical impact of Graves' disease on breast tissue is not clear. PATIENT FINDINGS: Twenty-seven year-old African American female patient who presented with multiple bilateral breast masses and skin thickening and ulcerations. Biopsy of the breast masses demonstrated fat necrosis. During her initial evaluation, she was found to be hyperthyroid and was ultimately diagnosed with Graves' disease. Her abnormal breast changes resolved within several months of her medical treatment for Graves' disease. SUMMARY: Graves' disease may present with acute-onset breast changes without personal history of trauma or family history of breast abnormalities. CONCLUSIONS: Interactions between thyroid and estrogen hormones should be studied further to determine their exact clinical and pathologic implications. Medical or surgical management of Graves' disease may reverse associated pathologic breast changes. PMID- 22837804 TI - Recurrence after treatment success in pulmonary multidrug-resistant tuberculosis: predication by continual PCR positivity. PMID- 22837805 TI - Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists. AB - BACKGROUND/AIMS: Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the alpha-melanocyte stimulating hormone derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), gamma-melanocyte stimulating hormone (gamma-MSH), suppress inflammation in immortalised human bronchial airway epithelium. METHODS: TNFalpha and rhino syncitial virus (RSV)-evoked nuclear factor-kappaB (NFkappaB) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o ) in response to KPV and gammaMSH. Cellular and systemic inflammatory signaling was measured by NFkappaB reporter gene and chemokine (IL8, eotaxin) secretion, respectively. RESULTS: KPV and gammaMSH evoked a dose-dependent inhibition of NFkappaB, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, IkappaBalpha stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp-alpha3 binding site on p65RelA which may involve blockade of the importin-alpha armadillo domain 7 and 8. In contrast, the gammaMSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo. CONCLUSION: KPV and gammaMSH respectively suppress NFkappaB signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease. PMID- 22837806 TI - Proteomic analysis of 14-3-3 zeta binding proteins in the mouse hippocampus. AB - 14-3-3 proteins are ubiquitous molecular chaperones with important roles in brain development and neuronal function. Altered expression of 14-3-3 proteins has been reported in several neurologic and neurodegenerative disorders and identifying 14 3-3 binding proteins may provide important insights into the physiologic and pathophysiologic roles of these proteins. Particular interest has emerged on 14-3 3 zeta (zeta) in the setting of neuronal injury because reducing 14-3-3zeta levels triggers an endoplasmic reticulum stress-like response in neurons and increases vulnerability to excitotoxicity. Here we examined the subcellular distribution of 14-3-3zeta in the mouse hippocampus. We then used recombinant His tagged 14-3-3zeta to pull-down interacting proteins from the mouse hippocampus followed by identification by liquid chromatography-mass spectrometry. 14-3-3zeta protein was present in the cytoplasm, microsomal compartment, nucleus and mitochondrial fractions of the mouse hippocampus. Recombinant 14-3-3zeta eluted 13 known 14-3-3 binding partners, including three other 14-3-3 isoforms, and 16 other proteins which have not previously been reported to bind 14-3-3zeta. The present study identifies potentially novel 14-3-3zeta binding proteins and contributes to defining the 14-3-3zeta interactome in the mouse brain. PMID- 22837807 TI - Inhibition of human acid-sensing ion channel 1b by zinc. AB - Acid-sensing ion channel 1b (ASIC1b) is expressed in peripheral sensory neurons and has been implicated in nociception. Understanding the modulation of ASIC1b will provide important insight into how ASIC1b contributes to pain sensation. In our previous study, we showed that zinc, an important modulator of pain sensation, reduces rat ASIC1b current. However, rat ASIC1b shows several important differences from its recently identified human homolog. Most noticeably, human ASIC1b (hASIC1b) has a sustained component, which may play a role in persistent pain. Therefore, we tested here the hypothesis that zinc modulates the current properties of hASIC1b. Bath application of zinc suppressed the peak amplitude of hASIC1b currents, with a half-maximum inhibitory concentration of 37 MUM. However, zinc did not affect the sustained component of hASIC1b currents. The effect of zinc was independent of pH-dependent activation, steady-state desensitization, and extracellular Ca(2+), suggesting noncompetitive mechanisms. Further, we found that extracellular site(s) of the hASIC1b subunit is important for the effect of zinc. Mutating cysteine 196, but not cysteine 309, in the extracellular domain of the hASIC1b abolished the zinc inhibition. These results suggest that, through modulating cysteine196, zinc may have a modulatory role in acute pain. PMID- 22837808 TI - Intra-ventrolateral preoptic nucleus injection of gamma-aminobutyric acid induces sedation in rats. AB - The ventrolateral preoptic nucleus (VLPO) plays a critical role in regulating and maintaining sleep-awake cycle. It receives both excitatory and inhibitory inputs and regulates the activity of tuberomamillary nucleus and other monoaminergic nuclei, which in turn determines the alternation between wakefulness and non rapid eye movement sleep. Although a previous study has shown that systematic administration of GABAergic anesthetic agents activated VLPO neurons, which is believed to be responsible for the sedative effects of these agents, it is unknown whether a direct administration of gamma-Aminobutyric acid (GABA) into the VLPO can induce sedation. Here we report that rats that received intra-VLPO infusion of GABA demonstrated sustained reduction in locomotion, most significantly during the 10-40th min period after infusion. Conversely, rats that received intra-VLPO infusion of noradrenaline demonstrated a sustained increase in locomotion from 20(th) min after infusion. By contrast, no appreciable change was observed in rats that received intra-VLPO infusion of glycine. This result demonstrates that exogenous GABA may activate sleep-active neurons in the VLPO and promote sedation. PMID- 22837809 TI - Selective toxicity of rose bengal to ovarian cancer cells in vitro. AB - Rose bengal (RB) has been utilized as a photodynamic agent for the targeted killing of cancer cells. Recent data suggest that intralesional RB alone may be effective in chemoablating locoregional and metastatic melanomas. The ability of RB to induce direct and bystander melanoma cell death led to the speculation that it may be similarly effective in the treatment of other neoplasms. The objective of this study was to determine whether RB can limit the growth, or kill, ovarian cancer cells in vitro. Ovarian carcinoma cells with or without a germline BRCA1 mutation were cultured with up to 800 MUM RB for one hour or four days, after which their ability to proliferate was assessed using the MTT assay. Control cells included an embryonic kidney cell line transformed with adenovirus, and normal human fibroblasts. Ovarian cancer cells exhibited significant dose dependent suppression of growth in response to RB; this suppression was similar to that seen with carboplatin. RB treated ovarian cancer cells appeared rounded, shrunken, and damaged. RB also inhibited the growth of kidney tumor cells but was much less effective in slowing the growth of normal human fibroblasts suggesting that RB-mediated growth suppression might be tumor cell specific. Ovarian cancer cells treated with RB displayed a significant increase in apoptosis that peaked at approximately four times the levels seen in untreated control cells. Furthermore, RB exposure resulted in the intracellular generation of reactive oxygen species (ROS) at levels that were significantly greater than in untreated cells and similar to levels seen in cells treated short term with H(2)O(2). These data suggest that RB may not only suppress ovarian cancer cell growth but also induce their apoptotic cell death, justifying the further investigation of the effects of RB in an animal model of ovarian cancer. PMID- 22837810 TI - Roles of oxidative stress in synchrotron radiation X-ray-induced testicular damage of rodents. AB - Synchrotron radiation (SR) X-ray has characteristic properties such as coherence and high photon flux, which has excellent potential for its applications in medical imaging and cancer treatment. However, there is little information regarding the mechanisms underlying the damaging effects of SR X-ray on biological tissues. Oxidative stress plays an important role in the tissue damage induced by conventional X-ray, while the role of oxidative stress in the tissue injury induced by SR X-ray remains unknown. In this study we used the male gonads of rats as a model to study the roles of oxidative stress in SR X-ray-induced tissue damage. Exposures of the testes to SR X-ray at various radiation doses did not significantly increase the lipid peroxidation of the tissues, assessed at one day after the irradiation. No significant decreases in the levels of GSH or total antioxidation capacity were found in the SR X-ray-irradiated testes. However, the SR X-ray at 40 Gy induced a marked increase in phosphorylated H2AX - a marker of double-strand DNA damage, which was significantly decreased by the antioxidant N acetyl cysteine (NAC). NAC also attenuated the SR X-ray-induced decreases in the cell layer number of seminiferous tubules. Collectively, our observations have provided the first characterization of SR X-ray-induced oxidative damage of biological tissues: SR X-ray at high doses can induce DNA damage and certain tissue damage during the acute phase of the irradiation, at least partially by generating oxidative stress. However, SR X-ray of various radiation doses did not increase lipid peroxidation. PMID- 22837811 TI - Discovery of Imidazoquinolines with Toll-Like Receptor 7/8 Independent Cytokine Induction. AB - Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8 which in turn induce cytokine production as part of the innate immune response. Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR 7/8 activity. Data is presented that shows this analog not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1beta, a key cytokine involved in activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analog. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production. PMID- 22837812 TI - Chiral cyclohexane 1,3-diones as inhibitors of mutant SOD1-dependent protein aggregation for the treatment of ALS. AB - Cyclohexane 1,3-diones were identified as a class of molecules exhibiting a protective effect against mutant SOD1 induced toxicity in PC-12 cells, but an optimized analogue had little or no effect on life extension in the G93A SOD1 mouse model for amyotrophic lateral sclerosis (ALS). Additional testing showed that these compounds were inactive in neurons and further analogue synthesis was carried out to identify compounds with neuronal activity. Starting from two racemic derivatives that were active in cortical neurons, two potent analogues (1b and 2b) were resolved, which were protective against mutant SOD1 induced toxicity in PC-12 cells. Both compounds were found to be active in cortical neurons and presented good ADME profiles in vitro. On the basis of these results, an ALS mouse trial with 1b was carried out, which showed slightly greater life extension than the FDA-approved ALS drug riluzole, thereby validating cyclohexane 1,3-diones as a novel therapeutic class for the treatment of ALS. PMID- 22837813 TI - Measuring the evolution of contemporary western popular music. AB - Popular music is a key cultural expression that has captured listeners' attention for ages. Many of the structural regularities underlying musical discourse are yet to be discovered and, accordingly, their historical evolution remains formally unknown. Here we unveil a number of patterns and metrics characterizing the generic usage of primary musical facets such as pitch, timbre, and loudness in contemporary western popular music. Many of these patterns and metrics have been consistently stable for a period of more than fifty years. However, we prove important changes or trends related to the restriction of pitch transitions, the homogenization of the timbral palette, and the growing loudness levels. This suggests that our perception of the new would be rooted on these changing characteristics. Hence, an old tune could perfectly sound novel and fashionable, provided that it consisted of common harmonic progressions, changed the instrumentation, and increased the average loudness. PMID- 22837814 TI - Binding mode of CpG oligodeoxynucleotides to nanoparticles regulates bifurcated cytokine induction via Toll-like receptor 9. AB - The interaction of cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) with Toll-like receptor 9 (TLR9) activates the immune system. Multimeric class A CpG ODNs induce interferon-alpha (IFN-alpha) and, to a lesser extent, interleukin 6. By contrast, monomeric class B CpG ODNs induce interleukin-6 but not IFN alpha. This difference suggests that the multimerization of CpG ODN molecules is a key factor in IFN-alpha induction. We multimerized class B CpG ODN2006x3-PD molecules that consist entirely of a phosphodiester backbone onto quantum dot silicon nanoparticles with various binding modes. Herein, we present the binding mode-dependent bifurcation of cytokine induction and discuss its possible mechanism of CpG ODN and TLR9 interaction. Our discoveries also suggest that nanoparticles play roles in not only delivery of CpG ODNs but also control of CpG ODN activity. PMID- 22837816 TI - The effect of temperature compensation on the circadian rhythmicity of photosynthesis in Symbiodinium, coral-symbiotic alga. AB - Circadian rhythms, which are found in most eukaryotes, are defined as rhythms that persist under constant conditions with a periodicity close to 24 h. One central key characteristic of all circadian rhythms is "temperature compensation", which allows organisms to maintain robust rhythms with a period close to a diel cycle over a broad range of physiological temperatures. To better understand the response of the circadian clock in corals to temperature elevation, photosynthesis as an output process of the circadian clock was studied both in Stylophora pistillata corals and in cultured Symbiodinium algae. The time period of photosynthesis was not affected by temperature elevation in the cultured algae or in the corals harbouring Symbiodinium. However, the photosynthetic system responded to temperature elevations by adjusting the photosynthetic apparatus. These findings suggest that the endogenous algal circadian clock regulates the photosynthetic rhythm and compensates for temperature elevations that occur in the natural environment. PMID- 22837815 TI - Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice. AB - The aim of this study was to investigate the effects and the mechanism of diosgenin, a famous plant-derived steroidal sapogenin, on memory deficits in Alzheimer's disease (AD) model mice. Diosgenin-treated 5XFAD mice exhibited significantly improved performance of object recognition memory. Diosgenin treatment significantly reduced amyloid plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Degenerated axons and presynaptic terminals that were only observed in regions closely associated with amyloid plaques were significantly reduced by diosgenin treatment. The 1,25D3-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS) was shown to be a target of diosgenin. 1,25D3-MARRS knockdown completely inhibited diosgenin-induced axonal growth in cortical neurons. Treatment with a neutralizing antibody against 1,25D3 MARRS diminished the axonal regeneration effect of diosgenin in Abeta(1-42) induced axonal atrophy. This is the first study to demonstrate that the exogenous stimulator diosgenin activates the 1,25D3-MARRS pathway, which may be a very critical signaling target for anti-AD therapy. PMID- 22837817 TI - Proteome of Aedes aegypti in response to infection and coinfection with microsporidian parasites. AB - Hosts are frequently infected with more than one parasite or pathogen at any one time, but little is known as to how they respond to multiple immune challenges compared to those involving single infections. We investigated the proteome of Aedes aegypti larvae following infection with either Edhazardia aedis or Vavraia culicis, and coinfections involving both. They are both obligate intracellular parasites belonging to the phylum microsporidia and infect natural populations of Ae. aegypti. The results found some proteins only showing modified abundance in response to infections involving E. aedis, while others were only differentially abundant when infections involved V. culicis. Some proteins only responded with modified abundance to the coinfection condition, while others were differentially abundant in response to all three types of infection. As time since infection increased, the response to each of the single parasite infections diverged, while the response to the E. aedis and coinfection treatments converged. Some of the proteins differentially abundant in response to infection were identified. They included two vacuolar ATPases, proteins known to have a role in determining the infection success of intracellular parasites. This result suggests microsporidia could influence the infection success of other intracellular pathogens infecting vector species of mosquito, including viruses, Plasmodium and Wolbachia. PMID- 22837818 TI - Selection on plasticity of seasonal life-history traits using random regression mixed model analysis. AB - Theory considers the covariation of seasonal life-history traits as an optimal reaction norm, implying that deviating from this reaction norm reduces fitness. However, the estimation of reaction-norm properties (i.e., elevation, linear slope, and higher order slope terms) and the selection on these is statistically challenging. We here advocate the use of random regression mixed models to estimate reaction-norm properties and the use of bivariate random regression to estimate selection on these properties within a single model. We illustrate the approach by random regression mixed models on 1115 observations of clutch sizes and laying dates of 361 female Ural owl Strix uralensis collected over 31 years to show that (1) there is variation across individuals in the slope of their clutch size-laying date relationship, and that (2) there is selection on the slope of the reaction norm between these two traits. Hence, natural selection potentially drives the negative covariance in clutch size and laying date in this species. The random-regression approach is hampered by inability to estimate nonlinear selection, but avoids a number of disadvantages (stats-on-stats, connecting reaction-norm properties to fitness). The approach is of value in describing and studying selection on behavioral reaction norms (behavioral syndromes) or life-history reaction norms. The approach can also be extended to consider the genetic underpinning of reaction-norm properties. PMID- 22837819 TI - Projected changes in distributions of Australian tropical savanna birds under climate change using three dispersal scenarios. AB - Identifying the species most vulnerable to extinction as a result of climate change is a necessary first step in mitigating biodiversity decline. Species distribution modeling (SDM) is a commonly used tool to assess potential climate change impacts on distributions of species. We use SDMs to predict geographic ranges for 243 birds of Australian tropical savannas, and to project changes in species richness and ranges under a future climate scenario between 1990 and 2080. Realistic predictions require recognition of the variability in species capacity to track climatically suitable environments. Here we assess the effect of dispersal on model results by using three approaches: full dispersal, no dispersal and a partial-dispersal scenario permitting species to track climate change at a rate of 30 km per decade. As expected, the projected distributions and richness patterns are highly sensitive to the dispersal scenario. Projected future range sizes decreased for 66% of species if full dispersal was assumed, but for 89% of species when no dispersal was assumed. However, realistic future predictions should not assume a single dispersal scenario for all species and as such, we assigned each species to the most appropriate dispersal category based on individual mobility and habitat specificity; this permitted the best estimates of where species will be in the future. Under this "realistic" dispersal scenario, projected ranges sizes decreased for 67% of species but showed that migratory and tropical-endemic birds are predicted to benefit from climate change with increasing distributional area. Richness hotspots of tropical savanna birds are expected to move, increasing in southern savannas and southward along the east coast of Australia, but decreasing in the arid zone. Understanding the complexity of effects of climate change on species' range sizes by incorporating dispersal capacities is a crucial step toward developing adaptation policies for the conservation of vulnerable species. PMID- 22837820 TI - Size distributions and dispersions along a 485-year chronosequence for sand dune vegetation. AB - Using a sand dune chronosequence that spans 485 years of primary succession, we collected nearest-neighbor vegetation data to test two predictions associated with the traditional "size-advantage" hypothesis for plant competitive ability: (1) the relative representation of larger species should increase in later stages of succession; and (2) resident species that are near neighbors should, over successional time, become more similar in plant body size and/or seed size than expected by random assembly. The first prediction was supported over the time period between mid to later succession, but the second prediction was not; that is, there was no temporal pattern across the chronosequence indicating that either larger resident species, or larger seeded resident species, increasingly exclude smaller ones from local neighborhoods over time. Rather, neighboring species were generally more different from each other in seed sizes than expected by random assembly. As larger species accumulate over time, some relatively small species are lost from later stages of succession, but species size distributions nevertheless remain strongly right-skewed-even in late succession-and species of disparate sizes are just as likely as in early succession to coexist as immediate neighbors. This local-scale coexistence of disparate sized neighbors might be accounted for-as in traditional interpretations-in terms of species differences in "physical-space-niches" (e.g., involving different rooting depths), combined with possible facilitation effects. We propose, however, that this coexistence may also occur because competitive ability involves more than just a size advantage, with traits associated with survival (tolerance of intense competition) and fecundity (offspring production despite intense competition) being at least equally important. PMID- 22837821 TI - Bacterial beta-glucosidase function and metabolic activity depend on soil management in semiarid rainfed agriculture. AB - Genomic and transcriptomic approaches were used to gain insights into the relationship between soil management and bacterial-mediated functions in an olive orchard agroecosystem. Four management practices were assessed in a 30-year trial in a semiarid Mediterranean region. Transcriptional activity of bacterial 16S rRNA genes increased in noncovered soils, indicating higher microbial maintenance requirements to thrive in less favorable environmental conditions. The 16S rRNA transcript:gene copy ratio confirmed this assumption and pointed toward a much higher constitutive expression from rRNA operons in noncovered soils and to even higher expression levels when spontaneous vegetation was removed chemically. As described for 16S rRNA, potential transcription did not reveal the real transcription of bacterial beta-glucosidase genes, and higher gene expression in noncovered soils plus herbicides was evidenced. Since no relationship between total or soluble organic carbon and bacterial beta-glucosidase transcription was found, the above hypothesis could indicate either that soluble organic carbon is not the main pool of enzyme-inducing substrates or that constitutive production of bacterial beta-glucosidase enzymes increases as soil conditions worsen. PMID- 22837822 TI - Egg incubation temperature differently affects female and male hatching dynamics and larval fitness in a leafhopper. AB - Temperature effects on ectotherms are widely studied particularly in insects. However, the life-history effects of temperature experienced during a window of embryonic development, that is egg stage, have rarely been considered. We simulated fluctuating temperatures and examined how this affects the operational sex ratio (OSR) of hatching as well as nymph and adult fitness in a leafhopper, Scaphoideus titanus. Specifically, after a warm or cold incubation we compared males and females hatching dynamics with their consequences on the sex ratio in the course of time, body size, weight, and developmental rate of the two populations, all reared on the same posthatching temperature. Males and females eggs respond differently, with females more sensitive to variation in incubation temperature. The different responses of both sexes have consequences on the sex ratio dynamic of hatchings with a weaker protandry after warm incubation. Temperatures experienced by eggs have more complex consequences on posthatching development. Later nymphal instars that hatched from eggs exposed to warm temperature were larger and bigger but developmental rate of the two populations was not affected. Our study demonstrates how incubation temperature could affect operational sex ratio and posthatching development in an insect and how this may be critical for population growth. PMID- 22837823 TI - Identifying freshwater mussels (Unionoida) and parasitic glochidia larvae from host fish gills: a molecular key to the North and Central European species. AB - Freshwater mussels (order Unionoida) represent one of the most severely endangered groups of animals due to habitat destruction, introduction of nonnative species, and loss of host fishes, which their larvae (glochidia) are obligate parasites on. Conservation efforts such as habitat restoration or restocking of host populations are currently hampered by difficulties in unionoid species identification by morphological means. Here we present the first complete molecular identification key for all seven indigenous North and Central European unionoid species and the nonnative Sinanodonta woodiana, facilitating quick, low cost, and reliable identification of adult and larval specimens. Application of this restriction fragment length polymorphisms (RFLP) key resulted in 100% accurate assignment of 90 adult specimens from across the region by digestion of partial ITS-1 (where ITS is internal transcribed spacer) polymerase chain reaction (PCR) products in two to four single digestions with five restriction endonucleases. In addition, we provide protocols for quick and reliable extraction and amplification of larval mussel DNA from complete host fish gill arches. Our results indicate that this new method can be applied on infection rates as low as three glochidia per gill arch and enables, for the first time, comprehensive, large-scale assessments of the relative importance of different host species for given unionoid populations. PMID- 22837824 TI - The genetics of phenotypic plasticity. X. Variation versus uncertainty. AB - Despite the apparent advantages of adaptive plasticity, it is not common. We examined the effects of variation and uncertainty on selection for plasticity using an individual-based computer simulation model. In the model, the environment consisted of a linear gradient of 50 demes with dispersal occurring either before or after selection. Individuals consisted of multiple loci whose phenotypic expression either are affected (plastic) or are not affected (nonplastic) by the environment. Typically, evolution occurred first as genetic differentiation, which was then replaced by the evolution of adaptive plasticity, opposite to the evolutionary trend that is often assumed. Increasing dispersal rates selected for plasticity, if selection occurred before dispersal. If selection occurred after dispersal, the highest plasticity was at intermediate dispersal rates. Temporal variation in the environment occurring after development, but before selection, favored the evolution of plasticity. With dispersal before selection, such temporal variation resulted in hyperplasticity, with a reaction norm much steeper than the optimum. This effect was enhanced with negative temporal autocorrelation and can be interpreted as representing a form of bet hedging. As the number of nonplastic loci increased, plasticity was disfavored due to an increase in the uncertainty of the genomic environment. This effect was reversed with temporal variation. Thus, variation and uncertainty affect whether or not plasticity is favored with different sources of variation arising from the amount and timing of dispersal, from temporal variation, and even from the genetic architecture underlying the phenotype-having contrasting, interacting, and at times unexpected effects. PMID- 22837825 TI - Seasonal dynamics of arboreal spider diversity in a temperate forest. AB - Measuring and estimating biodiversity patterns is a fundamental task of the scientist working to support conservation and inform management decisions. Most biodiversity studies in temperate regions were often carried out over a very short period of time (e.g., a single season) and it is often-at least tacitly assumed that these short-term findings are representative of long-term general patterns. However, should the studied biodiversity pattern in fact contain significant temporal dynamics, perhaps leading to contradictory conclusions. Here, we studied the seasonal diversity dynamics of arboreal spider communities dwelling in 216 European beeches (Fagus sylvatica L.) to assess the spider community composition in the following seasons: two cold seasons (I: November 2005-January 2006; II: February-April) and two warm seasons (III: May-July; IV: August-October). We show that the usually measured diversity of the warm season community (IV: 58 estimated species) alone did not deliver a reliable image of the overall diversity present in these trees, and therefore, we recommend it should not be used for sampling protocols aimed at providing a full picture of a forest's biodiversity in the temperate zones. In particular, when the additional samplings of other seasons (I, II, III) were included, the estimated species richness nearly doubled (108). Community I possessed the lowest diversity and evenness due to the harsh winter conditions: this community was comprised of one dominant species together with several species low in abundance. Similarity was lowest (38.6%) between seasonal communities I and III, indicating a significant species turnover due to recolonization, so that community III had the highest diversity. Finally, using nonparametric estimators, we found that further sampling in late winter (February-April) is most needed to complete our inventory. Our study clearly demonstrates that seasonal dynamics of communities should be taken into account when studying biodiversity patterns of spiders, and probably forest arthropods in general. PMID- 22837826 TI - Field-based insights to the evolution of specialization: plasticity and fitness across habitats in a specialist/generalist species pair. AB - Factors promoting the evolution of specialists versus generalists have been little studied in ecological context. In a large-scale comparative field experiment, we studied genotypes from naturally evolved populations of a closely related generalist/specialist species pair (Polygonum persicaria and P. hydropiper), reciprocally transplanting replicates of multiple lines into open and partially shaded sites where the species naturally co-occur. We measured relative fitness, individual plasticity, herbivory, and genetic variance expressed in the contrasting light habitats at both low and high densities. Fitness data confirmed that the putative specialist out-performed the generalist in only one environment, the favorable full sun/low-density environment to which it is largely restricted in nature, while the generalist had higher lifetime reproduction in both canopy and dense neighbor shade. The generalist, P. persicaria, also expressed greater adaptive plasticity for biomass allocation and leaf size in shaded conditions than the specialist. We found no evidence that the ecological specialization of P. hydropiper reflects either genetically based fitness trade-offs or maintenance costs of plasticity, two types of genetic constraint often invoked to prevent the evolution of broadly adaptive genotypes. However, the patterns of fitness variance and herbivore damage revealed how release from herbivory in a new range can cause an introduced species to evolve as a specialist in that range, a surprising finding with important implications for invasion biology. Patterns of fitness variance between and within sites are also consistent with a possible role for the process of mutation accumulation (in this case, mutations affecting shade-expressed phenotypes) in the evolution and/or maintenance of specialization in P. hydropiper. PMID- 22837827 TI - Early stages of divergence: phylogeography, climate modeling, and morphological differentiation in the South American lizard Liolaemus petrophilus (Squamata: Liolaemidae). AB - This study examines the phylogeographic structure within the Patagonian lizard Liolaemus petrophilus and tests for patterns of between-clade morphological divergence and sexual dimorphism, as well as demographic and niche changes associated with Pleistocene climate changes. We inferred intraspecific relationships, tested hypotheses for historical patterns of population expansion, and incorporated ecological niche modeling (ENM) with standard morphological and geometric morphometric analyses to examine between-clade divergence as indirect evidence for adaptation to different niches. The two inferred haploclades diverged during the early Pleistocene with the Southern clade depicting the genetic signature of a recent population increase associated with expanding niche envelope, whereas the Northern clade shows stable populations in a shrinking niche envelope. The combination of molecular evidence for postisolation demographic change and ENM, suggest that the two haploclades have responded differently to Pleistocene climatic events. PMID- 22837828 TI - Aeolian process effects on vegetation communities in an arid grassland ecosystem. AB - Many arid grassland communities are changing from grass dominance to shrub dominance, but the mechanisms involved in this conversion process are not completely understood. Aeolian processes likely contribute to this conversion from grassland to shrubland. The purpose of this research is to provide information regarding how vegetation changes occur in an arid grassland as a result of aeolian sediment transport. The experimental design included three treatment blocks, each with a 25 * 50 m area where all grasses, semi-shrubs, and perennial forbs were hand removed, a 25 * 50 m control area with no manipulation of vegetation cover, and two 10 * 25 m plots immediately downwind of the grass removal and control areas in the prevailing wind direction, 19 degrees north of east, for measuring vegetation cover. Aeolian sediment flux, soil nutrients, and soil seed bank were monitored on each treatment area and downwind plot. Grass and shrub cover were measured on each grass-removal, control, and downwind plot along continuous line transects as well as on 5 * 10 m subplots within each downwind area over four years following grass removal. On grass-removal areas, sediment flux increased significantly, soil nutrients and seed bank were depleted, and Prosopis glandulosa shrub cover increased compared to controls. Additionally, differential changes for grass and shrub cover were observed for plots downwind of vegetation-removal and control areas. Grass cover on plots downwind of vegetation-removal areas decreased over time (2004-2007) despite above average rainfall throughout the period of observation, while grass cover increased downwind of control areas; P. glandulosa cover increased on plots downwind of vegetation-removal areas, while decreasing on plots downwind of control areas. The relationships between vegetation changes and aeolian sediment flux were significant and were best described by a logarithmic function, with decreases in grass cover and increases in shrub cover occurring with small increases in aeolian sediment flux. PMID- 22837829 TI - The evolution of dispersal conditioned on migration status. AB - We consider a model for the evolution of dispersal of offspring. Dispersal is treated as a parental trait that is expressed conditional upon a parent's own "migration status," that is, whether a parent, itself, is native or nonnative to the area in which it breeds. We compare the evolution of this kind of conditional dispersal to the evolution of unconditional dispersal, in order to determine the extent to which the former changes predictions about population-wide levels of dispersal. We use numerical simulations of an inclusive-fitness model, and individual-based simulations to predict population-average dispersal rates for the case in which dispersal based on migration status occurs. When our model predictions are compared to predictions that neglect conditional dispersal, observed differences between rates are only slight, and never exceed 0.06. While the effect of dispersal conditioned upon migration status could be detected in a carefully designed experiment, we argue that less-than-ideal experimental conditions, and factors such as dispersal conditioned on sex are likely to play a larger role that the type of conditional dispersal studied here. PMID- 22837830 TI - Small population size and extremely low levels of genetic diversity in island populations of the platypus, Ornithorhynchus anatinus. AB - Genetic diversity generally underpins population resilience and persistence. Reductions in population size and absence of gene flow can lead to reductions in genetic diversity, reproductive fitness, and a limited ability to adapt to environmental change increasing the risk of extinction. Island populations are typically small and isolated, and as a result, inbreeding and reduced genetic diversity elevate their extinction risk. Two island populations of the platypus, Ornithorhynchus anatinus, exist; a naturally occurring population on King Island in Bass Strait and a recently introduced population on Kangaroo Island off the coast of South Australia. Here we assessed the genetic diversity within these two island populations and contrasted these patterns with genetic diversity estimates in areas from which the populations are likely to have been founded. On Kangaroo Island, we also modeled live capture data to determine estimates of population size. Levels of genetic diversity in King Island platypuses are perilously low, with eight of 13 microsatellite loci fixed, likely reflecting their small population size and prolonged isolation. Estimates of heterozygosity detected by microsatellites (H(E)= 0.032) are among the lowest level of genetic diversity recorded by this method in a naturally outbreeding vertebrate population. In contrast, estimates of genetic diversity on Kangaroo Island are somewhat higher. However, estimates of small population size and the limited founders combined with genetic isolation are likely to lead to further losses of genetic diversity through time for the Kangaroo Island platypus population. Implications for the future of these and similarly isolated or genetically depauperate populations are discussed. PMID- 22837831 TI - Species-rich ecosystems are vulnerable to cascading extinctions in an increasingly variable world. AB - Global warming leads to increased intensity and frequency of weather extremes. Such increased environmental variability might in turn result in increased variation in the demographic rates of interacting species with potentially important consequences for the dynamics of food webs. Using a theoretical approach, we here explore the response of food webs to a highly variable environment. We investigate how species richness and correlation in the responses of species to environmental fluctuations affect the risk of extinction cascades. We find that the risk of extinction cascades increases with increasing species richness, especially when correlation among species is low. Initial extinctions of primary producer species unleash bottom-up extinction cascades, especially in webs with specialist consumers. In this sense, species-rich ecosystems are less robust to increasing levels of environmental variability than species-poor ones. Our study thus suggests that highly species-rich ecosystems such as coral reefs and tropical rainforests might be particularly vulnerable to increased climate variability. PMID- 22837833 TI - RNA/DNA ratios in American glass eels (Anguilla rostrata): evidence for latitudinal variation in physiological status and constraints to oceanic migration? AB - During their larval leptocephalus phase, newly hatched American eels undergo an extensive oceanic migration from the Sargasso Sea toward coastal and freshwater habitats. Their subsequent metamorphosis into glass eel is accompanied by drastic morphological and physiological changes preceding settlement over a wide geographic range. The main objective of this study was to compare RNA/DNA ratios and condition factor among glass eels in order to test the null hypothesis of no difference in physiological status and metabolic activity of glass eels at the outcome of their oceanic migration. This was achieved by analyzing glass eel samples collected at the mouth of 17 tributaries covering a latitudinal gradient across the species distribution range from Florida to Gaspesie (Quebec). Our main observations were (i) a latitudinal increase in mean total length; (ii) a latitudinal variation in mean RNA/DNA ratios, which was best explained by a quadratic model reaching its minimum in the central range of sampling locations; and (iii) a latitudinal variation in Fulton's condition factor, which was best explained by a quadratic model reaching its maximum in the central range of sampling locations. Below we discuss the possible links between latitudinal variation in glass eel physiological status and variable energetic and environmental constraints to oceanic migration as a function of latitudinal distribution. PMID- 22837834 TI - Microsatellite variation and genetic structure of brook trout (Salvelinus fontinalis) populations in Labrador and neighboring Atlantic Canada: evidence for ongoing gene flow and dual routes of post-Wisconsinan colonization. AB - In conservation genetics and management, it is important to understand the contribution of historical and contemporary processes to geographic patterns of genetic structure in order to characterize and preserve diversity. As part of a 10-year monitoring program by the Government of Newfoundland and Labrador, Canada, we measured the population genetic structure of the world's most northern native populations of brook trout (Salvelinus fontinalis) in Labrador to gather baseline data to facilitate monitoring of future impacts of the recently opened Trans-Labrador Highway. Six-locus microsatellite profiles were obtained from 1130 fish representing 32 populations from six local regions. Genetic diversity in brook trout populations in Labrador (average H(E)= 0.620) is within the spectrum of variability found in other brook trout across their northeastern range, with limited ongoing gene flow occurring between populations (average pairwise F(ST)= 0.139). Evidence for some contribution of historical processes shaping genetic structure was inferred from an isolation-by-distance analysis, while dual routes of post-Wisconsinan recolonization were indicated by STRUCTURE analysis: K= 2 was the most likely number of genetic groups, revealing a separation between northern and west-central Labrador from all remaining populations. Our results represent the first data from the nuclear genome of brook trout in Labrador and emphasize the usefulness of microsatellite data for revealing the extent to which genetic structure is shaped by both historical and contemporary processes. PMID- 22837835 TI - Interactive effects of past and present environments on overwintering success-a reciprocal transplant experiment. AB - Life-history traits are influenced by environmental factors throughout the lifespan of an individual. The relative importance of past versus present environment on individual fitness, therefore, is a relevant question in populations that face the challenge of temporally varying environment. We studied the interacting effects of past and present density on body mass, condition, and survival in enclosure populations of the bank vole (Myodes glareolus) using a reciprocal transplant design. In connection with the cyclic dynamics of natural vole populations, our hypothesis was that individuals born in low-density enclosures would do better overwintering in low-density enclosures than in high density enclosures and vice versa. Our results show that the effect of summer (past) density was strong especially on survival and body mass. The response of body mass to summer density was negative in both winter (present) density groups, whereas the response of survival probability was nonlinear and differed between the winter density groups. In particular, our data show a trend for higher overwintering success of individuals originating from the lowest summer densities in low winter density and vice versa. We therefore conclude that the capacity of individuals to respond to a change in density was constrained by the delayed density-dependent effects of environment experienced in the past. These effects have the potential to contribute to vole population dynamics. Possible mechanisms mediating the effects of past environment into present performance include both intrinsic and environmental factors. PMID- 22837836 TI - Phylogeographic insights into an irruptive pest outbreak. AB - Irruptive forest insect pests cause considerable ecological and economic damage, and their outbreaks have been increasing in frequency and severity. We use a phylogeographic approach to understand the location and progression of an outbreak by the MPB (Dendroctonus ponderosae Hopkins), an irruptive bark beetle that has caused unprecedented damage to lodgepole pine forests in western North America and is poised to expand its range across the boreal forest. We sampled MPB populations across British Columbia and Alberta and used phylogeographic methods to describe lineage diversification, characterize population structure, investigate expansion dynamics, and identify source populations of the outbreak. Using 1181 bp of mitochondrial DNA sequence from 267 individuals, we found high haplotype diversity, low nucleotide diversity, and limited lineage diversification. The overall pattern was consistent with isolation by distance at a continental scale, and with reduced diversity and population structure in the northerly, outbreak regions. Post-Pleistocene expansion was detected, however more recent expansion signals were not detected, potentially due to the size and rapid rate of range expansion. Based on the limited genetic structure, there were likely multiple source populations in southern British Columbia, although the magnitude of the demographic expansion and rate of spread have obscured the signature of these source populations. Our data highlight the need for caution in interpreting phylogeographic results for species with similar demographics. PMID- 22837837 TI - Fine scale relationships between sex, life history, and dispersal of masu salmon. AB - Identifying the patterns and processes driving dispersal is critical for understanding population structure and dynamics. In many organisms, sex-biased dispersal is related to the type of mating system. Considerably, less is known about the influence of life-history variability on dispersal. Here we investigated patterns of dispersal in masu salmon (Oncorhynchus masou) to evaluate influences of sex and life history on dispersal. As expected, assignment tests and isolation by distance analysis revealed that dispersal of marine migratory masu salmon was male-biased. However, dispersal of resident and migratory males did not follow our expectation and marine-migratory individuals dispersed more than residents. This may be because direct competition between marine-migratory and resident males is weak or that the cost of dispersal is smaller for marine-migratory individuals. This study revealed that both sex and migratory life-history influence patterns of dispersal at a local scale in masu salmon. PMID- 22837838 TI - Sex, horizontal transmission, and multiple hosts prevent local adaptation of Crithidia bombi, a parasite of bumblebees (Bombus spp.). AB - Local adaptation within host-parasite systems can evolve by several non-exclusive drivers (e.g., host species-genetic adaptation; ecological conditions-ecological adaptation, and time-temporal adaptation). Social insects, especially bumblebees, with an annual colony life history not only provide an ideal system to test parasite transmission within and between different host colonies, but also parasite adaptation to specific host species and environments. Here, we study local adaptation in a multiple-host parasite characterized by high levels of horizontal transmission. Crithidia bombi occurs as a gut parasite in several bumblebee species. Parasites were sampled from five different host species in two subsequent years. Population genetic tools were used to test for the several types of adaptation. Although we found no evidence for local adaptation of the parasite toward host species, there was a slight temporal differentiation of the parasite populations, which might have resulted from severe bottlenecks during queen hibernation. Parasite populations were in Hardy-Weinberg equilibrium and showed no signs of linkage disequilibrium suggesting that sexual reproduction is an alternative strategy in this otherwise clonal parasite. Moreover, high levels of multiple infections were found, which might facilitate sexual genetic exchange. The detection of identical clones in different host species suggested that horizontal transmission occurs between host species and underpins the lack of host-specific adaptation. PMID- 22837839 TI - Adaptation to larval crowding in Drosophila ananassae leads to the evolution of population stability. AB - Density-dependent selection is expected to lead to population stability, especially if r and K tradeoff. Yet, there is no empirical evidence of adaptation to crowding leading to the evolution of stability. We show that populations of Drosophila ananassae selected for adaptation to larval crowding have higher K and lower r, and evolve greater stability than controls. We also show that increased population growth rates at high density can enhance stability, even in the absence of a decrease in r, by ensuring that the crowding adapted populations do not fall to very low sizes. We discuss our results in the context of traits known to have diverged between the selected and control populations, and compare our results with previous work on the evolution of stability in D. melanogaster. Overall, our results suggest that density-dependent selection may be an important factor promoting the evolution of relatively stable dynamics in natural populations. PMID- 22837840 TI - No evidence for niche segregation in a North American Cattail (Typha) species complex. AB - Interspecific hybridization can lead to a breakdown of species boundaries, and is of particular concern in cases in which one of the parental species is invasive. Cattails (Typha spp.) have increased their abundance in the Great Lakes region of North America over the past 150 years. This increase in the distribution of cattails is associated with hybridization between broad-leaved (Typha latifolia) and narrow-leaved cattails (T. angustifolia). The resulting hybrids occur predominantly as F(1)s, which are known as T. * glauca, although later-generation hybrids have also been documented. It has been proposed that in sympatric populations, the parental species and hybrids are often spatially segregated according to growth in contrasting water depths, and that this should promote the maintenance of parental species. In this study, we tested the hypothesis that the two species and their hybrids segregate along a water-depth gradient at sites where they are sympatric. We identified the two parental species and their hybrids using molecular genetic markers (SSR), and measured shoot elevations (a proxy for water depth) at 18 sites in Southern Ontario, Canada. We found no evidence for niche segregation among species based on elevation. Our data indicate that all three lineages compete for similar habitat where they co-occur suggesting that there is potential for an overall loss of biodiversity in the species complex, particularly if the hybrid lineage is more vigorous compared to the parental species, as has been suggested by other authors. PMID- 22837841 TI - Uncontrolled admixture and loss of genetic diversity in a local Vietnamese pig breed. AB - The expansion of intensive livestock production systems in developing countries has increased the introduction of highly productive exotic breeds facilitating indiscriminate crossbreeding with local breeds. In this study, we set out to investigate the genetic status of the Vietnamese Black H'mong pig breed by evaluating (1) genetic diversity and (2) introgression from exotic breeds. Two exotic breeds, namely Landrace and Yorkshire used for crossbreeding, and the H'mong pig population from Ha Giang (HG) province were investigated using microsatellite markers. Within the province, three phenotypes were observed: a White, a Spotted and a Black phenotype. Genetic differentiation between phenotypes was low (0.5-6.1%). The White phenotypes showed intermediate admixture values between exotic breeds and the Black HG population (0.53), indicating a crossbreed status. Management practices were used to predict the rate of private diversity loss due to exotic gene introgressions. After 60 generations, 100% of Black private alleles will be lost. This loss is accelerated if the admixture rate is increased but can be slowed down if the mortality rate (e.g., recruitment rate) is decreased. Our study showed that a large number of markers are needed for accurately identifying hybrid classes for closely related populations. While our estimate of admixture still seems underestimated, genetic erosion can occur very fast even through indiscriminate crossbreeding. PMID- 22837842 TI - The ecological-evolutionary interplay: density-dependent sexual selection in a migratory songbird. AB - Little is understood about how environmental heterogeneity influences the spatial dynamics of sexual selection. Within human-dominated systems, habitat modification creates environmental heterogeneity that could influence the adaptive value of individual phenotypes. Here, we used the gray catbird to examine if the ecological conditions experienced in the suburban matrix (SM) and embedded suburban parks (SP) influence reproductive strategies and the strength of sexual selection. Our results show that these habitats varied in a key ecological factor, breeding density. Moreover, this ecological factor was closely tied to reproductive strategies such that local breeding density predicted the probability that a nest would contain extra-pair offspring. Partitioning reproductive variance showed that while within-pair success was more important in both habitats, extra-pair success increased the opportunity for sexual selection by 39% at higher breeding densities. Body size was a strong predictor of relative reproductive success and was under directional selection in both habitats. Importantly, our results show that the strength of sexual selection did not differ among habitats at the landscape scale but rather that fine-scale variation in an ecological factor, breeding density, influenced sexual selection on male phenotypes. Here, we document density-dependent sexual selection in a migratory bird and hypothesize that coarse-scale environmental heterogeneity, in this case generated by anthropogenic habitat modification, changed the fine-scale ecological conditions that drove the spatial dynamics of sexual selection. PMID- 22837843 TI - Comparison of two views of maximum entropy in biodiversity: Frank (2011) and Pueyo et al. (2007). AB - An increasing number of authors agree in that the maximum entropy principle (MaxEnt) is essential for the understanding of macroecological patterns. However, there are subtle but crucial differences among the approaches by several of these authors. This poses a major obstacle for anyone interested in applying the methodology of MaxEnt in this context. In a recent publication, Frank (2011) gives some arguments why his own approach would represent an improvement as compared to the earlier paper by Pueyo et al. (2007) and also to the views by Edwin T. Jaynes, who first formulated MaxEnt in the context of statistical physics. Here I show that his criticisms are flawed and that there are fundamental reasons to prefer the original approach. PMID- 22837844 TI - Phylogenetic analysis of cryptic speciation in the polychaete Pygospio elegans. AB - Development in marine invertebrate species can take place through a variety of modes and larval forms, but within a species, developmental mode is typically uniform. Poecilogony refers to the presence of more than one mode of development within a single species. True poecilogony is rare, however, and in some cases, apparent poecilogony is actually the result of variation in development mode among recently diverged cryptic species. We used a phylogenetic approach to examine whether poecilogony in the marine polychaete worm, Pygospio elegans, is the result of cryptic speciation. Populations of worms identified as P. elegansooded, and intermediate larvae; these modes are found both within and among populations. We examined sequence variation among partial mitochondrial cytochrome c oxidase subunit I sequences obtained for 279 individual worms sampled across broad geographic and environmental scales. Despite a large number of unique haplotypes (121 haplotypes from 279 individuals), sequence divergence among European samples was low (1.7%) with most of the sequence variation observed within populations, relative to the variation among regions. More importantly, we observed common haplotypes that were widespread among the populations we sampled, and the two most common haplotypes were shared between populations differing in developmental mode. Thus, our results support an earlier conclusion of poecilogony in P elegans. In addition, predominantly planktonic populations had a larger number of population-specific low-frequency haplotypes. This finding is largely consistent with interspecies comparisons showing high diversity for species with planktonic developmental modes in contrast to low diversity in species with brooded developmental modes. PMID- 22837845 TI - Evidence of environmental niche differentiation in the striped mouse (Rhabdomys sp.): inference from its current distribution in southern Africa. AB - The aim of this study was to characterize environmental differentiation of lineages within Rhabdomys and provide hypotheses regarding potential areas of contact between them in the Southern African subregion, including the Republic of South Africa, Lesotho, and Namibia. Records of Rhabdomys taxa across the study region were compiled and georeferenced from the literature, museum records, and field expeditions. Presence records were summarized within a 10 * 10 km grid covering the study area. Environmental information regarding climate, topography, land use, and vegetation productivity was gathered at the same resolution. Multivariate statistics were used to characterize the current environmental niche and distribution of the whole genus as well as of three mitochondrial lineages known to occur in southern Africa. Distribution modeling was carried out using MAXENT in order to generate hypotheses regarding current distribution of each taxa and their potential contact zones. Results indicate that the two species within Rhabdomys appear to have differentiated across the precipitation/temperature gradient present in the region from east to west. R. dilectus occupies the wettest areas in eastern southern Africa, while R. pumilio occupies the warmer and drier regions in the west, but also penetrates in the more mesic central part of the region. We provide further evidence of environmental differentiation within two lineages of R. dilectus. Contact zones between lineages appear to occur in areas of strong environmental gradients and topographic complexity, such as the transition zones between major biomes and the escarpment area where a sharp altitudinal gradient separates coastal and plateau areas, but also within more homogeneous areas such as within grassland and savannah biomes. Our results indicate that Rhabdomys may be more specialized than previously thought when considering current knowledge regarding mitochondrial lineages. The genus appears to have differentiated along two major environmental axes in the study region, but results also suggest dispersal limitations and biological interactions having a role in limiting current distribution boundaries. Furthermore, the projection of the potential geographic distribution of the different lineages suggests several contact zones that may be interesting study fields for understanding the interplay between ecological and evolutionary processes during speciation. PMID- 22837846 TI - Phylogeography of Tibouchina papyrus (Pohl) Toledo (Melastomataceae), an endangered tree species from rocky savannas, suggests bidirectional expansion due to climate cooling in the Pleistocene. AB - Many endemic species present disjunct geographical distribution; therefore, they are suitable models to test hypotheses about the ecological and evolutionary mechanisms involved in the origin of disjunct distributions in these habitats. We studied the genetic structure and phylogeography of Tibouchina papyrus (Melastomataceae), endemic to rocky savannas in Central Brazil, to test hypothesis of vicariance and dispersal in the origin of the disjunct geographical distribution. We sampled 474 individuals from the three localities where the species is reported: Serra dos Pirineus, Serra Dourada, and Serra de Natividade. Analyses were based on the polymorphisms at cpDNA and on nuclear microsatellite loci. To test for vicariance and dispersal we constructed a median-joining network and performed an analysis of molecular variance (AMOVA). We also tested population bottleneck and estimated demographic parameters and time to most recent common ancestor (TMRCA) using coalescent analyses. A remarkable differentiation among populations was found. No significant effect of population expansion was detected and coalescent analyses showed a negligible gene flow among populations and an ancient coalescence time for chloroplast genome. Our results support that the disjunct distribution of T. papyrus may represent a climatic relict. With an estimated TMRCA dated from ~836.491 +/- 107.515 kyr BP (before present), we hypothesized that the disjunct distribution may be the outcome of bidirectional expansion of the geographical distribution favored by the drier and colder conditions that prevailed in much of Brazil during the Pre Illinoian glaciation, followed by the retraction as the climate became warmer and moister. PMID- 22837847 TI - The juvenile social environment introduces variation in the choice and expression of sexually selected traits. AB - The juvenile environment provides numerous cues of the intensity of competition and the availability of mates in the near environment. As research demonstrates that the developing individuals can use these cues to alter their developmental trajectories, and therefore, adult phenotypes, we examined whether social cues available during development can affect the expression and the preference of sexually selected traits. To examine this, we used the Australian black field cricket (Telogryllus commodus), a species where condition at maturity is known to affect both male calling effort and female choice. We mimicked different social environments by rearing juveniles in two different densities crossed with three different calling environments. We demonstrate that the social environment affected female response speed but not preference, and male age-specific calling effort (especially the rate of senescence in calling effort) but not the structural/temporal parameters of calls. These results demonstrate that the social environment can introduce variation in sexually selected traits by modifying the behavioral components of male production and female choice, suggesting that the social environment may be an overlooked source of phenotypic variation. We discuss the plasticity of trait expression and preference in reference to estimations of male quality and the concept of condition dependence. PMID- 22837848 TI - A comparison of four methods for detecting weak genetic structure from marker data. AB - Genetic structure is ubiquitous in wild populations and is the result of the processes of natural selection, genetic drift, mutation, and gene flow. Genetic drift and divergent selection promotes the generation of genetic structure, while gene flow homogenizes the subpopulations. The ability to detect genetic structure from marker data diminishes rapidly with a decreasing level of differentiation among subpopulations. Weak genetic structure may be unimportant over evolutionary time scales but could have important implications in ecology and conservation biology. In this paper we examine methods for detecting and quantifying weak genetic structures using simulated data. We simulated populations consisting of two putative subpopulations evolving for up to 50 generations with varying degrees of gene flow (migration), and varying amounts of information (allelic diversity). There are a number of techniques available to detect and quantify genetic structure but here we concentrate on four methods: F(ST), population assignment, relatedness, and sibship assignment. Under the simple mating system simulated here, the four methods produce qualitatively similar results. However, the assignment method performed relatively poorly when genetic structure was weak and we therefore caution against using this method when the analytical aim is to detect fine-scale patterns. Further work should examine situations with different mating systems, for example where a few individuals dominate reproductive output of the population. This study will help workers to design their experiments (e.g., sample sizes of markers and individuals), and to decide which methods are likely to be most appropriate for their particular data. PMID- 22837849 TI - Host plant defense signaling in response to a coevolved herbivore combats introduced herbivore attack. AB - Defense-free space resulting from coevolutionarily naive host plants recently has been implicated as a factor facilitating invasion success of some insect species. Host plants, however, may not be entirely defenseless against novel herbivore threats. Volatile chemical-mediated defense signaling, which allows plants to mount specific, rapid, and intense responses, may play a role in systems experiencing novel threats. Here we investigate defense responses of host plants to a native and exotic herbivore and show that (1) host plants defend more effectively against the coevolved herbivore, (2) plants can be induced to defend against a newly-associated herbivore when in proximity to plants actively defending against the coevolved species, and (3) these defenses affect larval performance. These findings highlight the importance of coevolved herbivore specific defenses and suggest that naivete or defense limitations can be overcome via defense signaling. Determining how these findings apply across various host herbivore systems is critical to understand mechanisms of successful herbivore invasion. PMID- 22837850 TI - Gene or environment? Species-specific control of stomatal density and length. AB - Stomatal characteristics are used as proxies of paleo-environment. Only a few model species have been used to study the mechanisms of genetic and environmental effects on stomatal initiation. Variation among species has not been quantified. In this paper, results from an in situ reciprocal transplant experiment along an elevation gradient in the northeast Tibetan Plateau are reported, in which the relative effects of genetics (original altitude) and environment (transplant altitude) on stomatal density (SD) and length (SL) were quantified. In Thalictrum alpinum, only the environment significantly influenced SD, with the variance component ([Formula: see text]) of the environment found to be much greater than that of genetics ([Formula: see text]) ([Formula: see text]). In Kobresia humillis, only genetics significantly influenced SD and SL, with the genetics variance component found to be greater than that of the environment ([Formula: see text], for SD). These results suggest that the extent to which genetics and the environment determine stomatal initiation and development is species specific. This needs to be considered when studying genetic or environmental controls of stomatal initiation, as well as when SD and SL are used as proxies for ancient climate factors (e.g., CO(2) concentration). PMID- 22837851 TI - The role of endosymbionts in the evolution of haploid-male genetic systems in scale insects (Coccoidea). AB - There is an extraordinary diversity in genetic systems across species, but this variation remains poorly understood. In part, this is because the mechanisms responsible for transitions between systems are often unknown. A recent hypothesis has suggested that conflict between hosts and endosymbiotic microorganisms over transmission could drive the transition from diplodiploidy to systems with male haploidy (haplodiploidy, including arrhenotoky and paternal genome elimination [PGE]). Here, we present the first formal test of this idea with a comparative analysis across scale insects (Hemiptera: Coccoidea). Scale insects are renowned for their large variation in genetic systems, and multiple transitions between diplodiploidy and haplodiploidy have taken place within this group. Additionally, most species rely on endosymbiotic microorganisms to provide them with essential nutrients lacking in their diet. We show that species harboring endosymbionts are indeed more likely to have a genetic system with male haploidy, which supports the hypothesis that endosymbionts might have played a role in the transition to haplodiploidy. We also extend our analysis to consider the relationship between endosymbiont presence and transitions to parthenogenesis. Although in scale insects there is no such overall association, species harboring eukaryote endosymbionts were more likely to be parthenogenetic than those with bacterial symbionts. These results support the idea that intergenomic conflict can drive the evolution of novel genetic systems and affect host reproduction. PMID- 22837853 TI - Science is an endless frontier: Encouraging translational research in pulmonary vascular disease. PMID- 22837854 TI - Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic, progressive disease of the pulmonary vasculature with a high morbidity and mortality. Its pathobiology involves at least three interacting pathways - prostacyclin (PGI(2)), endothelin, and nitric oxide (NO). Current treatments target these three pathways utilizing PGI(2) and its analogs, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE-5) inhibitors. Inhaled nitric oxide (iNO) is approved for the treatment of hypoxic respiratory failure associated with pulmonary hypertension in term/near-term neonates. As a selective pulmonary vasodilator, iNO can acutely decrease pulmonary artery pressure and pulmonary vascular resistance without affecting cardiac index or systemic vascular resistance. In addition to delivery via the endotracheal tube, iNO can also be administered as continuous inhalation via a facemask or a pulsed nasal delivery. Consistent with a deficiency in endogenously produced NO, long-term pulsed iNO dosing appears to favorably affect hemodynamics in PAH patients, observations that appear to correlate with benefit in uncontrolled settings. Clinical studies and case reports involving patients receiving long-term continuous pulsed iNO have shown minimal risk in terms of adverse events, changes in methemoglobin levels, and detectable exhaled or ambient NO or NO(2). Advances in gas delivery technology and strategies to optimize iNO dosing may enable broad-scale application to long-term treatment of chronic diseases such as PAH. PMID- 22837855 TI - Severe pulmonary hypertension: The role of metabolic and endocrine disorders. AB - Pulmonary arterial hypertension (PAH) is a multi-factorial condition and the underlying pulmonary vascular disease is shaped by the combined action of genetic, epigenetic and immune-related factors. Whether and how gender, obesity and the metabolic syndrome modify PAH and associated right heart failure is under intense investigation. Estrogens may enhance the process of pulmonary angioproliferation, but may also protect the right ventricle under pressure. Obesity may affect the pulmonary circulation via interactions with inflammatory cells and mediators, or via alterations in endocrine signaling. Obesity is a major risk factor for pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved LV ejection fraction. Given the overlap between PAH and autoimmune diseases, hypothyroidism in patients with PAH is commonly considered a consequence of an autoimmune thyroiditis. In the clinical setting of hyperthyroidism, severe pulmonary hypertension may develop due to a hyperdynamic circulation, but a more complex situation presents itself when hyperthyroidism is associated with PAH. We recently showed in a relevant animal model of severe PAH that thyroid hormone, via its endothelial cell-proliferative action, can be permissive and drive angioproliferation. Signaling via the integrin alphavbeta3 and FGF receptors may participate in the formation of the lung vascular lesions in this model of PAH. Whether thyroid hormones in euthyroid PAH patients play a pathobiologically important role is unknown- as we also do not know whether the commonly diagnosed hypothyroidism in patients with severe PAH is cardioprotective. This brief review highlights some recent insights into the role of metabolic and endocrine disorders in PAH. PMID- 22837856 TI - Evaluation of patients with chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy. AB - Pulmonary hypertension as a result of chronic thromboembolic disease (CTEPH) is potentially curable with pulmonary endarterectomy surgery. Consequently, correctly diagnosing patients with this type of pulmonary hypertension and evaluating these patients with the goal of establishing their candidacy for surgical intervention is of utmost importance. And as advancements in surgical techniques have allowed successful resection of segmental-level chronic thromboembolic disease, the number of CTEPH patients that are deemed suitable surgical candidates has expanded, making it even more important that the evaluation be conducted with greater precision. This article will review a diagnostic approach to patients with suspected chronic thromboembolic disease with an emphasis on the criteria considered in selecting patients for pulmonary endarterectomy surgery. PMID- 22837857 TI - Diagnosis and management of pulmonary hypertension associated with left ventricular diastolic dysfunction. AB - Pulmonary hypertension (PH) is commonly seen in patients who present with left ventricular diastolic dysfunction (LVDD) and is considered a marker of poor prognosis. While PH in this setting is thought to result from pulmonary venous congestion, there is a subset of patients in which pulmonary pressures fail to improve with appropriate management of diastolic heart failure and go on to develop a clinical picture similar to that of patients with pulmonary arterial hypertension (PAH). Despite the utility of Doppler echocardiography and exercise testing in the initial evaluation of patients with suspected PH-LVDD, the diagnosis can only be confirmed using right heart catheterization. Management of PH-LVDD centers on both optimizing fluid management and afterload reduction to reducing left ventricular diastolic pressures and also increase pulmonary venous return. To date, there is no clear evidence that addition of PH-specific drugs can improve clinical outcomes, and their use should only be considered in the setting of clinical trials. In conclusion, PH-LVDD remains a challenging clinical entity that complicates the management of left ventricular dysfunction and significantly contributes to its morbidity and mortality. Determination of the optimal diagnostic and treatment strategies for this form of PH should be the goal of future studies. PMID- 22837858 TI - Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. AB - Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperoxia-induced BPD and PH. Newborn mice were exposed to hyperoxia (FiO(2)=0.75) for two weeks, were then treated with one intravenous dose of CM from either MSCs or primary mouse lung fibroblasts (MLFs), and placed in room air for two to four weeks. Histological analysis of lungs harvested at four weeks of age was performed to determine the degree of alveolar injury, blood vessel number, and vascular remodeling. At age six weeks, pulmonary artery pressure (PA acceleration time) and right ventricular hypertrophy (RVH; RV wall thickness) were assessed by echocardiography, and pulmonary function tests were conducted. When compared to MLF-CM, a single dose of MSC-CM-treatment (1) reversed the hyperoxia-induced parenchymal fibrosis and peripheral PA devascularization (pruning), (2) partially reversed alveolar injury, (3) normalized lung function (airway resistance, dynamic lung compliance), (4) fully reversed the moderate PH and RVH, and (5) attenuated peripheral PA muscularization associated with hyperoxia-induced BPD. Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases. PMID- 22837859 TI - Group V phospholipase A(2) increases pulmonary endothelial permeability through direct hydrolysis of the cell membrane. AB - Acute lung injury (ALI) is characterized by inflammatory disruption of the alveolar-vascular barrier, resulting in severe respiratory compromise. Inhibition of the intercellular messenger protein, Group V phospholipase A(2) (gVPLA(2)), blocks vascular permeability caused by LPS both in vivo and in vitro. In this investigation we studied the mechanism by which recombinant gVPLA(2) increases permeability of cultured human pulmonary endothelial cells (EC). Exogenous gVPLA(2) (500 nM), a highly hydrolytic enzyme, caused a significant increase in EC permeability that began within minutes and persisted for >10 hours. However, the major hydrolysis products of gVPLA(2) (Lyso-PC, Lyso-PG, LPA, arachidonic acid) did not cause EC structural rearrangement or loss of barrier function at concentrations <10 MUM. Higher concentrations (>= 30 MUM) of these membrane hydrolysis products caused some increased permeability but were associated with EC toxicity (measured by propidium iodide incorporation) that did not occur with barrier disruption by gVPLA(2) (500 nM). Pharmacologic inhibition of multiple intracellular signaling pathways induced by gVPLA(2) activity (ERK, p38, PI3K, cytosolic gIVPLA(2)) also did not prevent EC barrier disruption by gVPLA(2). Finally, pretreatment with heparinase to prevent internalization of gVPLA(2) did not inhibit EC barrier disruption by gVPLA(2). Our data thus indicate that gVPLA(2) increases pulmonary EC permeability directly through action as a membrane hydrolytic agent. Disruption of EC barrier function does not depend upon membrane hydrolysis products, gVPLA(2) internalization, or upregulation of downstream intracellular signaling. PMID- 22837860 TI - Furegrelate, a thromboxane synthase inhibitor, blunts the development of pulmonary arterial hypertension in neonatal piglets. AB - The development of pulmonary arterial hypertension (PAH) in pediatric patients has been linked to the production of the arachidonic acid metabolite, thromboxane A(2) (TxA(2)). The present study evaluated the therapeutic effect of furegrelate sodium, a thromboxane synthase inhibitor, on the development of PAH in a neonatal piglet model. Three-day-old piglets were exposed to 21 days of normoxia (N; 21% F(I)O(2)) or chronic hypoxia (CH; 10% F(I)O(2)). A third group of piglets received the oral TxA(2) synthase inhibitor, furegrelate (3 mg/kg, 2 or 3 times daily) at the induction of CH. In vivo hemodynamics confirmed a 2.55-fold increase of the pulmonary vascular resistance index (PVRI) in CH piglets (104+/-7 WU) compared to N piglets (40+/-2 WU). The CH piglets treated twice daily with furegrelate failed to show improved PVRI, but furegrelate three times daily lowered the elevated PVRI in CH piglets by 34% to 69+/-5 WU and ameliorated the development of right ventricular hypertrophy. Microfocal X-ray computed tomography (CT) scanning was used to estimate the diameter-independent distensibility term, alpha (% change in diameter per Torr). Pulmonary arterial distensibility in isolated lungs of CH piglets (alpha=1.0+/-0.1% per Torr) was lower than that of N piglets (alpha=1.5+/-0.1% per Torr) indicative of vascular remodeling. Arterial distensibility was partially restored in furegrelate-treated CH piglets (alpha =1.2+/-0.1% per Torr) and microscopic evidence showing muscularization of small pulmonary arteries also was less prominent in these animals. Finally, isolated lungs of furegrelate-treated piglets showed lower basal and vasodilator-induced transpulmonary pressures compared to CH animals. These findings suggest that pharmacological inhibition of TxA(2) synthase activity by furegrelate blunts the development of hypoxia-induced PAH in an established neonatal piglet model primarily by preserving the structural integrity of the pulmonary vasculature. PMID- 22837861 TI - Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming. AB - Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose homeostasis. We hypothesized that analysis of the entire metabolome in PAH would reveal multiple other metabolic changes relevant to disease pathogenesis and possible treatment. Layered transcriptomic and metabolomic analyses of human pulmonary microvascular endothelial cells (hPMVEC) expressing two different disease-causing mutations in the bone morphogenetic protein receptor type 2 (BMPR2) confirmed previously described increases in aerobic glycolysis but also uncovered significant upregulation of the pentose phosphate pathway, increases in nucleotide salvage and polyamine biosynthesis pathways, decreases in carnitine and fatty acid oxidation pathways, and major impairment of the tricarboxylic acid (TCA) cycle and failure of anaplerosis. As a proof of principle, we focused on the TCA cycle, predicting that isocitrate dehydrogenase (IDH) activity would be altered in PAH, and then demonstrating increased IDH activity not only in cultured hPMVEC expressing mutant BMPR2 but also in the serum of PAH patients. These results suggest that widespread metabolic changes are an important part of PAH pathogenesis, and that simultaneous identification and targeting of the multiple involved pathways may be a more fruitful therapeutic approach than targeting of any one individual pathway. PMID- 22837862 TI - Leptin levels predict survival in pulmonary arterial hypertension. AB - Evidence suggests that leptin is involved in relevant processes in the cardiovascular system. Low serum leptin levels have been associated with increased cardiovascular events and mortality in patients with coronary artery, diabetes, or chronic kidney disease. We hypothesized that leptin is increased in pulmonary arterial hypertension (PAH) and provides prognostic information. We correlated leptin levels with clinical data and assessed its association with survival. Sixty-seven patients with PAH and 29 healthy controls were studied. Plasma leptin levels were nonlinearly associated with BMI. Leptin level <15 MUg/l was associated with higher mortality in PAH patients, with an adjusted (age, gender, BMI, and smoking status) hazard ratio of 3.8 (95% CI: 1.3-11.2), P=0.016. Similarly, PAH patients with leptin/BMI ratio <0.5 MUg * m(2)/kg * l had worse survival than those with a level >0.5 MUg * m(2)/ kg * l (P=0.046 by log-rank test). Two-year mortality in PAH patients was 24%. A receiver operating characteristic curve using leptin/BMI ratio as the test variable and 2-year mortality as the state variable showed an area under the curve of 0.74 (95% CI: 0.62-0.86). A leptin/BMI ratio cut-off of 0.6 had a high sensitivity (94%) and negative predictive value (96%) for predicting death of any cause at 2 years. In PAH, plasma leptin levels are directly associated with BMI. Lower leptin levels, when adjusted by BMI, are associated with an increased overall mortality and leptin/BMI ratio has high negative predictive value for mortality at 2 years. PMID- 22837863 TI - Mast cell number, phenotype, and function in human pulmonary arterial hypertension. AB - A proliferation of mast cells around the small pulmonary blood vessels and the alveolar septae has been noted in models of pulmonary hypertension, and in plexiform lesions of pulmonary arterial hypertension (PAH) in patients. Here, we hypothesize that total mast cell numbers and activation are increased in PAH and that they contribute to vascular remodeling through cellular and soluble proangiogenic effectors. To test this, blood and urine were collected from patients with PAH (N=44), asthma (N=18) and healthy controls (N=29) to quantitate biomarkers of total body mast cell numbers and activation (total and mature tryptase, N-methyl histamine, leukotriene LTE(4) and prostaglandin PGD-M). Serum total tryptase was higher in PAH than that in controls suggesting greater numbers of mast cells, but indicators of mast cell activation (mature tryptase, LTE(4) and PGD-M) were similar among PAH, asthma, and controls. Immunohistochemistry of lung tissues identified mast cells as primarily perivascular and connective tissue chymase(+) type in PAH, rather than mucosal phenotype. Intervention with mast cell inhibitors cromolyn and fexofenadine was performed in 9 patients for 12 weeks to identify the influence of mast cell products on the pathologic proangiogenic environment. Treatment decreased total tryptase and LTE-4 levels over time of treatment. This occurred in parallel to a drop in vascular endothelial growth factor (VEGF) and circulating proangiogenic CD34+CD133+ progenitor cells, which suggests that mast cells may promote vascular remodeling and dysfunction. In support of this, levels of exhaled nitric oxide, a vasodilator that is generally low in PAH, increased at the end of the 12-week mast cell blockade and antihistamine. These results suggest that mast cells might contribute to the pulmonary vascular pathologic processes underlying PAH. More studies are needed to confirm their potential contribution to the disease. PMID- 22837864 TI - Activation of the unfolded protein response is associated with pulmonary hypertension. AB - Pulmonary hypertension remains an important cause of morbidity and mortality. Although there is currently no cure, descriptions of defective intracellular trafficking and protein misfolding in vascular cell models of pulmonary hypertension have been recently reported. We tested the hypothesis that activation of the unfolded protein response (UPR) would be associated with the development of severe PH. We investigated activation of the UPR in archival tissues from patients with severe PH, and in the monocrotaline-induced rat model of severe PH. We tested the ability of a pharmacologic agent capable of modulating the UPR to prevent and reverse pulmonary hypertension. We found evidence of an active UPR in archival tissue from humans with PH, but not in control lungs. Similarly, monocrotaline-treated rats demonstrated a significant difference in expression of each of the major arms of the UPR compared to controls. Interestingly, the UPR preceded the appearance of macrophages and the development of lung vascular remodeling in the rats. Treatment of monocrotaline rats with salubrinal, a modulator of the PERK arm of the UPR, attenuated PH and was associated with a decrease in lung macrophages. In culture, pulmonary artery smooth muscle cells with UPR induction produced IL-6 and CCL-2/MCP-1, and stimulated macrophage migration. These effects were abolished by pretreatment of cells with salubrinal. These data support the hypothesis that the UPR may play a role in the pathogenesis of inflammatory vascular remodeling and PH. As such, understanding the functional contributions of the UPR in the setting of PH may have important therapeutic implications. PMID- 22837865 TI - Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema. AB - We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension. PMID- 22837866 TI - Partial anomalous pulmonary venous return presenting with adult-onset pulmonary hypertension. AB - Partial anomalous pulmonary venous return (PAPVR) is a rare cause of adult onset pulmonary arterial hypertension (PAH) that can present with a wide spectrum of severity from early childhood throughout adult life. We present two patients with PAH secondary to PAPVR who reflect this range of disease. The diagnosis and treatment of PAPVR and its role in pulmonary vascular disease is discussed. Cardiac and pulmonary physicians should be aware of this entity and its diagnosis and management options. PMID- 22837867 TI - Massive dilatation of the pulmonary artery in association with pulmonic stenosis and pulmonary hypertension. AB - Congenital pulmonary valve stenosis has been associated with the development of massive pulmonary arterial (PA) dilatation. Over time, this dilatation may distort surrounding structures and lead to compression of the left main coronary artery (LMCA) or the left mainstem bronchus. In this report, we describe a patient with a history of chronic thromboembolic pulmonary hypertension (CTEPH) and congenital pulmonic stenosis with massive PA dilatation. He develops exertional chest pain, presenting an unusual differential diagnosis. Novel diagnostic testing was performed to help narrow the differential diagnosis, and the patient responded well to pulmonary vasodilator treatment for progressive pulmonary hypertension. PMID- 22837868 TI - Critical care rehabilitation - is it the answer for reducing morbidity in ARDS survivors? Regarding "Acute respiratory distress syndrome: A clinical review". PMID- 22837869 TI - Atypical symptoms are related to typical symptoms rather than histologic and endoscopic esophagitis. PMID- 22837870 TI - Silent gastroesophageal reflux disease. PMID- 22837871 TI - Investigating functional dyspepsia in Asia. AB - The diagnosis of functional dyspepsia (FD) is challenging since it depends largely on symptoms which are often heterogeneous and overlapping. This is particularly so in Asia with many different cultures and languages. Symptom-based diagnosis of FD based on Rome III criteria has not been fully validated and it may not be suitable in some Asian populations. Clinicians often assume that investigations in FD are not rewarding and physiological tests are often not available unless in the research setting. Investigation of alarm features and role of Helicobacter pylori in FD remain controversial but experts agreed that both should be tested. Physiological tests including gastric accommodation and chemical hypersensitivity tests are underutilized in Asia and available studies were few. While experts do not recommend routine clinical use of gastric accommodation tests but they agree that these tests can be advocated if clinically indicated. Empiric therapeutic trial is not currently a diagnostic option. The pathogenesis of FD is still poorly understood and there is a substantial placebo response. As a conclusion, a diagnosis of FD is challenging especially so in the context of Asia and despite the limitations of available physiological tests experts agreed that these tests can be advocated if and when clinically indicated. PMID- 22837872 TI - Mechanism of interdigestive migrating motor complex. AB - Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This review article discussed the mechanism of gastrointestinal MMC. Luminal administration of 5 hydroxytryptamine (5-HT) initiates duodenal phase II followed by gastrointestinal phase III with a concomitant increase of plasma motilin release in conscious dogs. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces gastrointestinal phase III. 5-HT(4) antagonists significantly inhibits both of gastric and intestinal phase III, while 5-HT(3) antagonists inhibited only gastric phase III. These suggest that gastrointestinal MMC cycle is mediated via the interaction between motilin and 5-HT by the positive feedback mechanism. Gastric MMC is regulated via vagus, 5-HT(3/4) receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons and 5-HT(4) receptors. Stress is highly associated with the pathogenesis of functional dyspepsia. Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity and increased sympathetic activity. It has been shown that subset of functional dyspepsia patients show reduced vagal activity and impaired gastric phase III. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Thus, maintaining gastric MMC in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms. PMID- 22837875 TI - Atypical symptoms in patients with gastroesophageal reflux disease. AB - BACKGROUND/AIMS: Atypical symptoms are common in gastroesophageal reflux disease (GERD). Patients with non-erosive reflux disease (NERD) and erosive reflux disease (ERD) exhibit different clinical characteristics and responses to acid suppression treatment. We aimed to compare atypical characteristics in patients with NERD and ERD. We also investigated the presence of histological esophagitis in patients with NERD and ERD. METHODS: Eligible patients completed a questionnaire regarding reflux symptoms and concomitant atypical symptoms. Endoscopic biopsies with histological examination were performed. RESULTS: Of the 210 patients with GERD, 90 patients with ERD and 120 patients with NERD were studied. ERD patients were characterized by higher prevalence of hiatal hernia (P = 0.001) and smoking (P = 0.047). The prevalence of GERD was greater in the age group between 41 and 60 years regardless of endoscopic finding. There was no difference in the prevalence of atypical symptoms or histological esophagitis between NERD and ERD. In all subjects, heartburn was associated with dysphagia (r = 0.16, P = 0.01), dyspepsia (r = 0.22, P = 0.008) and hiccup (r = 0.19, P = 0.003), whereas acid regurgitation was associated with dyspepsia (r = 0.21, P = 0.014), belching (r = 0.15, P = 0.018) and hiccup (r = 0.19, P = 0.002). CONCLUSIONS: Atypical symptoms did not correlate with the presence of histological esophagitis. Atypical symptoms were equally prevalent in patients with NERD and ERD. The existence of atypical symptoms appears to be associated with the presence of typical reflux symptoms irrespective of endoscopic and histological reflux esophagitis. PMID- 22837874 TI - Physiological and functional evaluation of the transposed human pylorus as a distal sphincter. AB - BACKGROUND/AIMS: Studies evaluating the human pylorus as a sphincter are scanty and contradictory. Recently, we have shown technical feasibility of transposing the human pylorus for end-stage fecal incontinence. This unique cohort of patients provided us an opportunity to study the sphincter properties of the pylorus in its ectopic position. METHODS: Antro-pylorus transposition on end sigmoid colostomies (n = 3) and in the perineum (n = 15) was performed for various indications. Antro-pylorus was assessed functionally (digital examination, high resolution spatiotemporal manometry, barium retention studies and colonoscopy) and by imaging (doppler ultrasound, MRI and CT angiography) in its ectopic position. RESULTS: The median resting pressure of pylorus on colostomy was 30 mmHg (range 28-38). In benign group, median resting pressure in perineum was 12.5 mmHg (range 6-44) that increased to 21.5 mmHg (range 12-29) (P = 0.481) and 31 mmHg (range 16-77) (P = 0.034) on first and second follow-up, respectively. In malignant group, median post-operative pressures were 20 mmHg (range 14-36) and 21 mmHg (range 18-44) on first and second follow-up, respectively. A definite tone and gripping sensation were felt in all the patients on digital examination. On distal loopogram, performed through the diverting colostomies, barium was retained proximal to the neo-pyloric valve. Both perineal ultrasound and MRI showed viable transposed graft. CT angiography and color doppler studies confirmed vascular flow in the transposed position. CONCLUSIONS: The human pyloric valve can function as a tonic sphincter when removed from the gastroduodenal continuity. PMID- 22837876 TI - The relationship between existence of typical symptoms and psychological factors in patients with erosive esophagitis. AB - BACKGROUND/AIMS: In Asian countries including Korea, the prevalence of gastroesophageal reflux disease (GERD) is on the rise and its clinical impact has been emphasized. The purpose of this study was to investigate the clinical characteristics of esophagitis patients with or without symptoms, and their association with psychological factors. METHODS: Subjects diagnosed as erosive esophagitis of Los Angeles-A or more in screening by upper gastrointestinal endoscopy were enrolled. Questionnaires regarding GERD symptoms and Symptom Checklist-90-Revision were used to identify the presence of psychological symptoms. RESULTS: There was no difference between the subjects' general characteristics (gender, age, body mass index, smoking and alcohol intake) according to the existence of typical symptoms in these patients with erosive esophagitis. Patients with typical GERD symptoms were more likely to have atypical symptoms, dyspepsia and higher scores on psychological symptoms (somatization, obsessive-compulsiveness and phobic anxiety) than those without. CONCLUSIONS: Psychological symptoms and other gastrointestinal symptoms should be considered in the patients with erosive esophagitis. PMID- 22837877 TI - Role of Acid and weakly acidic reflux in gastroesophageal reflux disease off proton pump inhibitor therapy. AB - BACKGROUND/AIMS: Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. METHODS: We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. RESULTS: Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [< 1%]). Acid reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. CONCLUSIONS: In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus. PMID- 22837873 TI - An Update on Post-infectious Irritable Bowel Syndrome: Role of Genetics, Immune Activation, Serotonin and Altered Microbiome. AB - The literature on post-infectious irritable bowel syndrome (IBS) is reviewed with special emphasis on recent new data. Further accounts of this phenomenon continue to be reported following a range of infections including giardiasis as well as viral and bacterial gastroenteritis. Risk factors such as severity of initial illness, female gender together with adverse psychological factors have been confirmed. Recent evidence of a genetic predisposition needs replication. Animal studies suggest activation of mast cells and inflammation driven impairment of serotonin transporter may be important, which are findings supported by some recent human studies in IBS with diarrhoea. Experimentally induced inflammation leads to damage and remodelling of enteric nerves. Similar changes have been reported in IBS patients with increase in nerves expressing transient receptor potential cation channel V1. While changes in microbiota are very likely this area has yet to be explored using modern techniques. Since the prognosis is for slow improvement, treatments should currently target the key symptoms of diarrhoea and abdominal pain. Future therapies aimed at correcting underlying mechanisms including immune activation and serotonin excess are currently being explored and may provide better treatments in the future. PMID- 22837878 TI - Subtypes and Symptomatology of Irritable Bowel Syndrome in Children and Adolescents: A School-based Survey Using Rome III Criteria. AB - BACKGROUND/AIMS: This study was conducted with objectives of assessing subtypes of irritable bowel syndrome (IBS) in children aged 10-16 years, their symptomatology and gender differences. METHODS: For this survey, 107 children who fulfilled Rome III criteria for IBS and 1,610 healthy controls were recruited from 8 randomly selected schools, in 4 provinces in Sri Lanka. Data was collected using a previously validated, self administered questionnaire. RESULTS: Constipation predominant, diarrhea predominant and mixed type IBS were almost equally distributed (27%-28%), while unsubtyped IBS had a lower prevalence (17.8%). IBS was more common in girls (59.8% vs 40.2% in boys, P = 0.001). Bloating, flatulence, burping, headache and limb pain were significantly higher in affected children (P < 0.05). CONCLUSIONS: This study highlights the distribution of IBS subtypes among Sri Lankan children and adolescents and its female preponderance. This study also shows a higher prevalence of other intestinal-related and extraintestinal somatic symptoms among affected children. PMID- 22837879 TI - Does acupuncture therapy alter activation of neural pathway for pain perception in irritable bowel syndrome?: a comparative study of true and sham acupuncture using functional magnetic resonance imaging. AB - BACKGROUND/AIMS: Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. METHODS: Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. RESULTS: Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. CONCLUSIONS: We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus. PMID- 22837880 TI - Efficacy of Solifenacin on Irritable Bowel Syndrome With Diarrhea: Open-label Prospective Pilot Trial. AB - BACKGROUND/AIMS: Solifenacin, a muscarinic type 3 receptor antagonist, is used to treat overactive bladder in adults. The aim of this study is to examine the efficacy of solifenacin on the symptomatic relief of diarrhea predominant irritable bowel syndrome (IBS-D). METHODS: A total of 20 patients with IBS-D were enrolled. After a 2-week observation period, all participants received solifenacin for 6 weeks. Subsequently, the administration of solifenacin was discontinued and ramosetron, a serotonin 3 receptor antagonist, was administered for 4 weeks. Overall improvement, the IBS-symptom severity scale (IBS-SSS), and frequency of defecation were assessed. RESULTS: Six weeks after initiation of solifenacin treatment and 4 weeks after initiation of ramosetron treatment, overall improvement was observed in 19 out of 20 (95%) and 17 out of 20 (85%) participants, respectively. At 2 weeks after initiation of solifenacin, overall improvement was observed in 16 out of 20 participants (80%). Total IBS-SSS scores at 2 and 6 weeks after the administration of solifenacin, and at 4 weeks after administration of ramosetron, were significantly lower than those at week 0. Compared to before administration, the participants' quality of life and frequency of defecation were significantly lower in all participants at 2 and 6 weeks after the administration of solifenacin and at 4 weeks after administration of ramosetron. CONCLUSIONS: The efficacy of solifenacin in the treatment of IBS with diarrhea was not inferior to that of ramosetron. Further placebo-controlled parallel studies are needed. PMID- 22837881 TI - Psychiatric, somatic and other functional gastrointestinal disorders in patients with irritable bowel syndrome at a tertiary care center. AB - BACKGROUND/AIMS: To study the prevalence of somatic and psychiatric co morbidities in the patients of irritable bowel syndrome (IBS) and to assess the quality of life (QOL) of these patients. METHODS: One hundred and eighty-four IBS patients and 198 controls were included. Diagnosis of IBS, its sub-classification and assessment of other functional gastrointestinal disorders (FGIDs) was made on basis of Rome III criteria. Severity of IBS was assessed using IBS severity scoring system. Psychiatric evaluation was done using Patient Heath Questionnaire. QOL was evaluated using WHO QOL-BREF. RESULTS: One hundred and forty-seven (79.9%) and 158 (85.9%) patients with IBS had at least one other FGID or at least one somatic co-morbidity, respectively. Higher number of patients had at least one psychiatric co-morbidity compared to controls (79.9% vs 34.3%; P < 0.001). Major depressive syndrome (47.3% vs 5.1%; P < 0.001), somatoform disorder (50% vs 14.6%; P < 0.001) and panic syndrome (44% vs 11.6%; P < 0.001) were more common in IBS than controls. Only 14 (7.6%) patients were receiving drug treatment for their psychiatric illness. Severe IBS symptoms were present in significantly higher number of patients with constipation predominant IBS than diarrhea predominant IBS. Those with severe disease had higher prevalence of psychiatric (95.1%) and somatic (96.7%) co-morbidities compared with mild disease. QOL of IBS patients was significantly lower in all four domains compared to controls. Presence of at least one other FGID was significantly associated with presence of one or more psychiatric co-morbidity (P < 0.001). CONCLUSIONS: Majority of IBS patients presenting to a tertiary care center had associated psychiatric, somatic co-morbidities and reduced QOL. Very few of them received specific psychiatric treatment. PMID- 22837882 TI - How to interpret a functional or motility test - slow nutrient drinking test. AB - The gastric barostat study is the gold standard method for evaluating gastric perception and accommodation. This technique has serious drawbacks, such as expense and invasiveness. Several drinking tests have been developed as noninvasive methods. Such tests are easily performed without special instruments and are well tolerated. We have reported that (1) a threshold volume inducing mild bloating in the slow nutrient drinking test might be an alternative parameter of gastric accommodation volume as determined by the barostat method and (2) the maximum satiety volume in the drinking test correlated positively with the pressure to induce severe discomfort in healthy volunteers, indicating that the slow nutrient drinking test may be useful for evaluating accommodation volume and the threshold to induce severe discomfort. However, the correlation between the maximum satiety drinking volume and accommodation volume as measured by the barostat study has been controversial. Therefore, validation of a certain nutrient drink test for measuring gastroduodenal function might be recommended in each institution. PMID- 22837883 TI - Typical Finding of Mechanical Obstruction Suggested in High-resolution Manometry. PMID- 22837884 TI - High-resolution Manometry for Oropharyngeal Dysphagia in a Patient With Large Cervical Osteophytes. PMID- 22837885 TI - A new concept for pacemaker activity in the human stomach (j physiol 2011:589[pt 24];6105-6118). PMID- 22837886 TI - What is the profiles for predicting treatment responsiveness in gastroesophageal reflux disease? (Gut 2012;61:501-506). PMID- 22837887 TI - Constipation is also an important cause of fecal incontinence in old people. PMID- 22837888 TI - Constipation Is Also an Important Cause of Fecal Incontinence in Old People: Author's Reply. PMID- 22837889 TI - Is There Enough Evidence for the Association of GNbeta3 C825T Polymorphism With Functional Dyspepsia and Irritable Bowel Syndrome? PMID- 22837890 TI - Is There Enough Evidence for the Association of GNbeta3 C825T Polymorphism With Functional Dyspepsia and Irritable Bowel Syndrome?: Author's Reply. PMID- 22837891 TI - What's new in critical illness and injury science? Preventing surgical infections requires the right antibiotic for the right duration. PMID- 22837892 TI - Compliance with the Eastern Association for the Surgery of Trauma guidelines for prophylactic antibiotics after open extremity fracture. AB - CONTEXT: Prophylactic antibiotics, paired with wound care and surgical intervention, is considered the standard of care for patients with open fracture. Guidelines from the Eastern Association for the Surgery of Trauma (EAST) recommend specific prophylactic antimicrobial therapy based on the type of open fracture. AIMS: We quantified adherence to EAST guideline recommendations and documented the incidence of infection in patients with open fracture. SETTINGS AND DESIGN: A retrospective, observational study of all patients with open fracture admitted to our facility from January 2004 to December 2008 was conducted. MATERIALS AND METHODS: Patients were divided into compliant and noncompliant groups according to the EAST guideline recommendations. Compliance was defined as an appropriate spectrum of therapy for guideline suggested duration. We assessed for surgical and non-surgical site infections, and morbidity outcomes. STATISTICAL ANALYSIS: Nominal data were explored using summary measures. Continuous variables were compared using the Student t-test or the Mann-Whitney U-test. Dichotomous data were compared using chi(2) statistic or Fisher's exact test. RESULTS: The final analysis included 214 patients. Prophylactic antibiotics were guideline compliant in 28.5% of patients, and ranged from 10.0% in type 3b fractures to 52.7% in type 1 fractures. The most common reason for non-compliance was the use of guideline recommended coverage that exceeded the suggested duration (71.2%). Patients who received non-compliant therapy required prolonged hospital lengths of stay (6 vs. 3 days, P = 0.0001). The overall incidence of infection was similar regardless of guideline compliance (17.0% vs. 11.5%, P = 0.313). CONCLUSIONS: Prophylactic antibiotics for open fracture frequently exceeded guideline recommendations in duration and spectrum of coverage, especially in more severe fracture types. Non-compliance with EAST recommendations was associated with increased in-hospital morbidity. PMID- 22837893 TI - Prevention of hypotension and prolongation of postoperative analgesia in emergency cesarean sections: A randomized study with intrathecal clonidine. AB - BACKGROUND AND CONTEXT: Different adjuvants been tried out for neuraxial anesthesia in emergency caesarean section so that the dose of the local anesthetic can be reduced and hypotension thereby prevented. AIMS AND OBJECTIVES: The present study was carried out in patients presenting for emergency lower segment caesarean section (LSCS) to establish the dose of intrathecal clonidine that would allow reduction of the dose of local anesthetic (thereby reducing the incidence and magnitude of hypotension) while at the same time providing clinically relevant prolongation of spinal anesthesia without significant side effects. MATERIALS AND METHODS: This randomized clinical study was carried out in our institution among 100 pregnant females who underwent emergency caesarean section. The participants were divided randomly into four groups: A, B, C, and D, each comprising 25 parturients. Subarachnoid block was performed using a 26G Quincke needle, with 12 mg of hyperbaric bupivacaine (LA) in group A, 9 mg of LA + 30 MUg of clonidine in group B, LA + 37.5 MUg of clonidine in group C, and LA + 45 MUg of clonidine in group D. The solution was uniformly made up to 2.2 mL with normal saline in all the groups. Onset of analgesia at T(10) level, sensory and motor blockade levels, maternal heart rate and blood pressure, neonatal Apgar scores, postoperative block characteristics, and adverse events were looked for and recorded. Statistical analysis was carried out with SPSS((r)) version 10.0 for Windows((r)), using the ANOVA test with post hoc significance, the Chi-square test, and the Mann-Whitney U test. P<.05 was considered significant and P<.0001 as highly significant. RESULTS: One hundred patients were enrolled for this study. The four groups were comparable with regard to demographic data and neonatal Apgar scores. Onset and establishment of sensory and motor analgesia was significantly shorter in groups C and D, while hypotension (and the use of vasopressors) was significantly higher in groups A and D. Perioperative shivering, nausea, and vomiting were significantly higher in groups A and D, while incidence of dry mouth was significantly higher in group D. CONCLUSIONS: The addition of 45 MUg, 37.5 MUg, and 30 MUg of clonidine to hyperbaric bupivacaine results in more prolonged complete and effective analgesia, allowing reduction of up to 18% of the total dose of hyperbaric bupivacaine. From the results of this study, 37.5 MUg of clonidine seems to be the optimal dose. PMID- 22837894 TI - Evaluation of long-term infusion of dexmedetomidine in critically ill patients: A retrospective analysis. AB - BACKGROUND: Dexmedetomidine is an alpha2-receptor agonist used for sedation in the intensive care unit (ICU). It is currently FDA indicated for short-term use (i.e., less than 24 h). OBJECTIVES: To compare the safety and efficacy of dexmedetomidine if given long- term (>24 h) to short-term infusion (up to 24 h) for mechanically ventilated critically ill patients. MATERIALS AND METHODS: The medical records of 73 patients were evaluated. Primary outcomes were significant changes in blood pressure or heart rate. Secondary outcomes included hospital and intensive care unit (ICU) length of stay (LOS), ventilator time, rate of reintubation, and rate of death. STATISTICAL ANALYSIS: Pair wise comparisons were based on independent student t-test for continuous data and Chi-square test for categorical data. Statistical difference was defined as P value < 0.05. RESULTS: Of the patients evaluated, 50 received dexmedetomidine for more than 24 h and 23 patients received this agent for 24 h. Patients were similar at baseline except for age. Patients who received dexmedetomidine for more than 24 h were similar to the short-infusion arm in terms of the rate of bradycardia (8.6% vs10%; P = 0.22), hypotension episodes (30.4% vs 28%; P= 0.2), requirement of treatment for those episodes (37% vs 42%; P= 0.43), hospital LOS (30 days vs 38 days; P = 0.45), ICU LOS (14 days vs 19 days; P = 0.44), ventilation days (8 days vs 14 days; P =0.58), rate of reintubation (4% vs 10%; P = 0.79) and mortality (P = 0.2). CONCLUSION: Long-term dexmedetomidine infusion (> 24 h) had similar safety and clinical outcomes in patients receiving this agent for short-term. Due to the retrospective nature of our investigation, more well-designed studies are needed to confirm these findings. PMID- 22837895 TI - Immunoregulation of bone remodelling. AB - Remodeling, a continuous physiological process maintains the strength of the bones, which maintains a delicate balance between bone formation and resorption process. This review gives an insight to the complex interaction and correlation between the bone remodeling and the corresponding changes in host immunological environment and also summarises the most recent developments occuring in the understanding of this complex field. T cells, both directly and indirectly increase the expression of receptor activator of nuclear factor kB ligand (RANKL); a vital step in the activation of osteoclasts, thus positively regulates the osteoclastogenesis. Though various cytokines, chemikines, transcription factors and co-stimulatory molecules are shared by both skeletal and immune systems, but researches are being conducted to establish and analyse their role and / or control on this complex but vital process. The understanding of this part of research may open new horizons in the management of inflammatory and autoimmune diseases, resulting into bone loss and that of osteoporosis also. PMID- 22837897 TI - Negative pressure pulmonary edema with laryngeal mask airway use: Recognition, pathophysiology and treatment modalities. AB - Negative pressure pulmonary edema (NPPE) following the use of the laryngeal mask airway (LMA) is an uncommon and under-reported event. We present a case of a 58 year-old male, who developed NPPE following LMA use. After biting vigorously on his LMA, the patient developed stridor upon emergence, with concurrent appearance of blood-tinged, frothy sputum and pulmonary edema. He subsequently required three days of mechanical ventilation. After discontinuation of mechanical ventilation the patient continued to require additional pulmonary support using continuous positive airway pressure, with a full facemask, to correct the persistent hypoxemia. His roentgenographic findings demonstrated an accelerated improvement with judicious administration of intravenous furosemide. PMID- 22837898 TI - Ultrasound in the diagnosis of Fournier's gangrene. AB - Fournier's gangrene (FG) is a life-threatening, rapidly progressive necrotizing infection. If not recognized and treated early, it is associated with high morbidity and mortality. The classic physical exam findings of crepitus are seen in approximately two-thirds of patients during the early stages of FG. Focused bedside sonography performed in cases of suspected gangrene represents an excellent adjunct in confirming the presence of subcutaneous gas and other signs of necrotizing infection. We present an illustrative case of a patient with FG who was evaluated with focused bedside ultrasonography. PMID- 22837896 TI - Infections of the nervous system. AB - Glycemic control is an important aspect of patient care in the surgical Infections of the nervous system are among the most difficult infections in terms of the morbidity and mortality posed to patients, and thereby require urgent and accurate diagnosis. Although viral meningitides are more common, it is the bacterial meningitides that have the potential to cause a rapidly deteriorating condition that the physician should be familiar with. Viral encephalitis frequently accompanies viral meningitis, and can produce focal neurologic findings and cognitive difficulties that can mimic other neurologic disorders. Brain abscesses also have the potential to mimic and present like other neurologic disorders, and cause more focal deficits. Finally, other infectious diseases of the central nervous system, such as prion disease and cavernous sinus thrombosis, are explored in this review. PMID- 22837899 TI - Massive postoperative cerebral swelling following cranioplasty. PMID- 22837900 TI - Status of pre-hospital care among injury cases admitted to a Tertiary hospital in South India. PMID- 22837901 TI - Developmental origins of adult metabolic disease: The Indian scenario, driving toward a unified hypothesis. PMID- 22837902 TI - Metformin and the promise of geroprotection. PMID- 22837903 TI - South Asian Consensus Guideline: Use of insulin in diabetes during Ramadan. AB - A person with diabetes mellitus (DM) has every right to perform the ritual of fasting during Ramadan. In daily practice we come across both type 1 and type 2 DM who wish to fast. This Consensus Statement describes the pre-Ramadan assessment, planning, prescription, management, and monitoring of patients on insulin, who wish to fast. PMID- 22837904 TI - Role of oral hypoglycemic agents in the management of type 2 diabetes mellitus during Ramadan. AB - It is obligatory for all adult Muslims to observe fast during the holy month of Ramadan, but sick individuals including those with diabetes mellitus are exempted from the duty of fasting. Specific medical advice must be provided to individual patients concerning the potential risks they must accept if they decide to fast. Any alteration in medications deemed necessary to provide an effective and safe antidiabetic regimen should be instituted well before the start of Ramadan. Diet controlled patients and those well controlled on insulin sensitizers have low risk of hypoglycemia and may safely fast with some modification in the timing of the doses. Newer generation sulfonylureas (gliclazide MR and glimepiride) have reasonable safety profile during Ramadan fasting and are economical options for a large number of diabetics worldwide, especially in the developing countries; older, long acting sulfonylureas like glibenclamide and chlorpropamide should be avoided during fasting. Oral DPP-IV inhibitors are important substitutes to sulfonylureas for patients with diabetes mellitus during fasting owing to their glucose-dependent mechanism of action, efficacy, and tolerability. This group of drugs causes a moderate A1c reduction, are weight neutral, and have a very low risk of hypoglycemia. Short-acting insulin secretagogues are an option in the subset of fasting diabetic patients who have predominantly post-prandial hyperglycemia. PMID- 22837905 TI - South Asian consensus statement on women's health and Ramadan. AB - Fasting during Ramadan, the holy month of Islam, is mandatory for all healthy adult Muslims. It is estimated that there are 1.1-1.5 billion Muslims worldwide, comprising 18-25% of the world population. About 62% of the world's Muslim population resides in Asia. Women comprise approximately 50% of this population. There is great religious fervor and enthusiasm in the majority of Muslims the world over for observing the religious fasting. Many of the Muslim women perhaps due to the family and societal pressures or lack of proper information hesitate and fail to avail themselves of the generous provisions of temporary or permanent exemptions from fasting available in Islam. It is therefore important that medical professionals as well as the general population be aware of potential risks that may be associated with fasting during Ramadan. This familiarity and knowledge is as important in South Asia and the Middle East as it is in Europe, North America, New Zealand, and Australia. There has not yet been any statement of consensus regarding women's health issues during Ramadan, namely menstruation, sexual obligations of married life, pregnancy, and lactation. This document aims to put forward some of the general guidelines for these issues especially for the South Asian Muslim women. PMID- 22837906 TI - Diabetic emergencies including hypoglycemia during Ramadan. AB - Majority of physicians are of the opinion that Ramadan fasting is acceptable for well-balanced type 2 patients conscious of their disease and compliant with their diet and drug intake. Fasting during Ramadan for patients with diabetes carries a risk of an assortment of complications. Islamic rules allow patients not to fast. However, if patient with diabetes wish to fast, it is necessary to advice them to undertake regular monitoring of blood glucose levels several times a day, to reduce the risk of hypoglycemia during day time fasting or hyperglycemia during the night. Patient with type 1 diabetes who fast during Ramadan may be better managed with fast-acting insulin. They should have basic knowledge of carbohydrate metabolism, the standard principles of diabetes care, and pharmacology of various antidiabetic drugs. This Consensus Statement describes the management of the various diabetic emergencies that may occur during Ramadan. PMID- 22837907 TI - Fasting guidelines for diabetic children and adolescents. AB - Fasting during the month of Ramadan, the ninth month of Islamic lunar calendar, is obligatory for all healthy adult and adolescent Muslims from the age of 12 years. Fasting starts from early dawn (Sohur/Sehri) till sunset (Iftar). During this period one has to abstain from eating and drinking. Islam has allowed many categories of people to be exempted from fasting, for example, young children, travelers, the sick, the elderly, pregnant, and lactating women. According to expert opinion, patients with type 1 diabetes (type 1 DM) who fast during Ramadan are at a very high risk to develop adverse events. However, some experienced physicians are of the opinion that fasting during Ramadan is safe for type 1 DM patients, including adolescents and older children, with good glycemic control who do regular self-monitoring and are under close professional supervision. The strategies to ensure safety of type 1 diabetic adolescents who are planning to fast include the following: Ramadan-focused medical education, pre-Ramadan medical assessment, following a healthy diet and physical activity pattern, modification in insulin regimen, and blood glucose monitoring as advised by the physician. PMID- 22837908 TI - Guidelines regarding management of adrenal insufficiency in the Holy month of Ramadan. AB - Adrenal insufficiency is a life-threatening event, so it is recommended for patients with known adrenal insufficiency to be properly educated regarding sick day management. In the month of Ramadan, people refrain from eating and drinking during daylight hours. It is very important for patients with adrenal insufficiency, who wish to keep a fast, to be well aware of the disease, the suitable drug to be used for that particular period, warning signs, sick-day management, physical activity, and dietary limits. This article describes guidelines for the sick-day management of patients with adrenal insufficiency, in the month of Ramadan. PMID- 22837909 TI - Thyroid diseases and Ramadan. AB - In the month of Ramadan, patients with thyroid diseases, most of the time, do not need treatment adjustments and can fast safely without any health hazards. Patients with hypothyroidism taking thyroxine can take their tablets on an empty stomach at bedtime instead of half an hour before Sehr. Patients with hyperthyroidism, on methimazole/carbimazole can continue their dose in once or twice daily regimes, while those on propylthiouracil need to be switched. Hyperthyroid patients with severe symptoms should start treatment immediately and can avoid fast for few days after a consultation with their religious scholar. PMID- 22837910 TI - South Asian Consensus Guideline: Use of GLP-1 analogue therapy in diabetes during Ramadan. AB - Ramadan is a lunar based month, during which Muslims across the world observe the ritual fast. This provides a challenge not only to the diabetic patient who wishes to observe the fast but also to the health care professional managing his diabetes. The challenge is to use therapies which are effective in maintaining good glycemic control and at the same time have a low propensity to cause hypoglycemia during the several hours of no calorie intake. The GLP-1 analogues are unique agents which are effective in providing glycemic reduction with a very low risk of hypoglycemia and hence find an important place in the management of diabetes during Ramadan. This Consensus Statement describes the pre-Ramadan assessment, planning, prescription and management and monitoring of patients who are on GLP-1 analogues, with or without other antidiabetic therapies. PMID- 22837911 TI - Drugs affecting HbA1c levels. AB - Glycated hemoglobin (HbA1c) is an important indicator of glycemic control in diabetes mellitus, based on which important diagnostic and therapeutic decisions are routinely made. However, there are several situations in which the level of HbA1c may not faithfully reflect the glycemic control in a given patient. Important among these is the use of certain non-diabetic medications, which can affect the HbA1c levels in different ways. This review focuses on the non diabetic medications which can inappropriately raise or lower the HbA1c levels, and the postulated mechanisms for the same. PMID- 22837913 TI - Geriatric thyroidology: An update. AB - Thyroid anatomy and physiology change in the elderly with age-related fibrosis and atrophy in the thyroid gland and changes in thyroid hormones. The incidence of thyroid nodules increases with age, making the thyroid more nodular. Hypothyroidism is common in the elderly and, if untreated, is associated with significant morbidity. Elderly patients are sensitive to iatrogenic hyperthyroidism, especially with preexisting cardiac disease. Hence, treatment of hypothyroidism should be individualized and should be started with low doses and titrated according to response. Hyperthyroidism, although less common in the elderly if present, is associated with significant cardiac morbidity and mortality. Radioiodine therapy is considered a safe primary treatment in the elderly with hyperthyroidism. Management of subclinical hypo- and hyperthyroidism is still controversial. The incidence of thyroid tumors increase with age. Thyroid malignancy in the elderly is considered as a more advanced disease compared with the young, and aggressive management is recommended. PMID- 22837914 TI - Menopause and the oral cavity. AB - Menopause is associated with a large number of symptoms ranging from physical to psychological. These symptoms may unfavorably affect oral health and treatment needs requiring dentists to be aware of the symptoms and health care needs of peri-menopausal/menopausal/postmenopausal women. This article attempts to provide an insight into the multifarious oral manifestations at menopause along with the relevant prosthodontic implications. PMID- 22837912 TI - Developmental origins of adult diseases. AB - There is considerable evidence for the fact that early life environment in human beings are associated with future development of various metabolic diseases. Fetal programming and perinatal events appear to exert effects on later life that are independent of environmental risk factors in adults. Our understanding of the underlying mechanisms are limited and remains unclear. However several animal models and epidemiological studies have shown this association, and it is assumed secondary to the penalties of developmental plasticity. In this review, we amalgamate facts from several disciplines to support this hypothesis. PMID- 22837915 TI - A prospective assessment of dietary patterns in Muslim subjects with type 2 diabetes who undertake fasting during Ramadan. AB - AIMS: The aim was to assess the dietary pattern during Ramadan season among type 2 diabetic Muslim subjects who underwent fasting and intensive dietary counseling. MATERIALS AND METHODS: The study was conducted among 70 Muslim subjects with type 2 diabetes mellitus who undertook fasting during Ramadan and was part of a randomized control trial using pioglitazone published previously. All subjects were subjected to a dietary assessment and counseling at three stages, i.e., initiation of the study, mid-Ramadan and post-Ramadan, by a trained dietician. Dietary assessment was done by the 24-hour dietary recall method and the food frequency questionnaire. Diabetic diet sheets were dispensed to subjects based on their body mass index (BMI), daily activity, and needs. RESULTS: The mean caloric intake between pre-Ramadan (before fasting) and mid-Ramadan (15 days after fasting) were 1506.80 kcal and 1614.29 (P = 0.001) respectively. The distribution of active components pre and during Ramadan were: carbohydrates (g) 260.76 and 265.35 g (P = 0.001), proteins (g) 43.64 and 46.19 (P = 0.001) and fat (g) was 32.88 and 44.16 (P = 0.0001) respectively. The percentage of energy from dietary carbohydrate prior to fasting (64.11 +/- 6.73) and during fasting (68.41 +/- 4.41) remained almost unchanged but statistically significant when compared at different intervals before and during fasting. Fat intake increased significantly during fasting (P = < 0.001). CONCLUSIONS: The dietary composition in a type 2 diabetic Muslim population who undertook fasting during Ramadan showed a mean increase in consumption of all components of diet during the period of fasting. Nutritional compliance during such a time seems to be difficult and warrants repeated counseling and regular follow-up to achieve targets. PMID- 22837916 TI - Profile of Nigerians with diabetes mellitus - Diabcare Nigeria study group (2008): Results of a multicenter study. AB - BACKGROUND: Diabetes Mellitus is the commonest endocrine-metabolic disorder in Nigeria similar to the experience in other parts of the world. The aim was to assess the clinical and laboratory profile, and evaluate the quality of care of Nigerian diabetics with a view to planning improved diabetes care. MATERIALS AND METHODS: In a multicenter study across seven tertiary health centers in Nigeria, the clinical and laboratory parameters of diabetic out-patients were evaluated. Clinical parameters studied include type of diabetes, anthropometry, and blood pressure (BP) status, chronic complications of diabetes, and treatment types. Laboratory data assessed included fasting plasma glucose (FPG), 2-h post-prandial (2-HrPP) glucose, glycated hemoglobin (HbA1c), urinalysis, serum lipids, electrolytes, urea, and creatinine. RESULTS: A total of 531 patients, 209 (39.4%) males and 322 (60.6%) females enrolled. The mean age of the patients was 57.1 +/- 12.3 years with the mean duration of diabetes of 8.8 +/- 6.6 years. Majority (95.4%) had type 2 diabetes mellitus (DM) compared to type 1 DM (4.6%), with P < 0.001. The mean FPG, 2-HrPP glucose, and HbA1c were 8.1 +/- 3.9 mmol/L, 10.6 +/- 4.6 mmol/L, and 8.3 +/- 2.2%, respectively. Only 170 (32.4%) and 100 (20.4%) patients achieved the ADA and IDF glycemic targets, respectively. Most patients (72.8%) did not practice self-monitoring of blood glucose. Hypertension was found in 322 (60.9%), with mean systolic BP 142.0 +/- 23.7 mmHg, and mean diastolic BP 80.7 +/- 12.7 mmHg. Diabetic complications found were peripheral neuropathy (59.2%), retinopathy (35.5%), cataracts (25.2%), cerebrovascular disease (4.7%), diabetic foot ulcers (16.0%), and nephropathy (3.2%). CONCLUSION: Most Nigerian diabetics have suboptimal glycemic control, are hypertensives, and have chronic complications of DM. Improved quality of care and treatment to target is recommended to reduce diabetes-related morbidity and mortality. PMID- 22837917 TI - Linear growth and neurodevelopmental outcome of children with congenital hypothyroidism detected by neonatal screening: A controlled study. AB - INTRODUCTION: Different growth and neuro-developmental outcomes have been associated with different doses of thyroxine given to infants with congenital hypothyroidism (CH). MATERIALS AND METHODS: We studied the longitudinal growth pattern and assessed the neurodevelopment of 45 children with CH(25 girls, 20 boys) diagnosed through the national screening program in Qatar, for 6 years or more to examine the effects of initial T4 dosage (50 MUg/day) with adjustment of T4 dose to maintain serum free T4 concentrations within the upper quartile of normal range and thyroid stimulating hormone < 4 mIU/mLThe birth size of newborns with CH diagnosed through the screening program before January 2003, was recorded and their growth in weight and stature was monitored every 3 months for at least 6 years of life. The IQ of children was assessed between 3 and 6 years of age using The Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). RESULTS: Birth weight, length, and head circumference of patients (3.21 +/- 0.43 kg, 50.5 +/- 3.21 cm and 34.1 +/- 1.5 cm, respectively) did not differ than those for 10,560 normal newborns with normal thyroid function (3.19 +/- 0.59 kg, 50.5 +/- 2.2 cm and 34.2 +/- 1.7 cm). During the first year CH children growth (25.8 +/- 2.8 cm/year) was similar to those for normal infants (25.5 +/- 0.75 cm/year). During the first 6 years, stature growth was normal in all children with CH versus Center for disease control and prevention (CDC) data. The mean height standard deviation score (HtSDS) of children with CH showed adjustment (+/- 0.5 SD) toward their mid-parental height SDS (MPHtSDS) only during the second year of life. The children's mean HtSDS was higher by an average of 0.4 SD between the 2(nd) and 7(th) year of life. CONCLUSION: These data proved that effective screening and treatment completely assures normal neurodevelopment and linear growth in patients with CH. The data showed that their HtSDS slightly exceeds their MPHtSDS during childhood. PMID- 22837918 TI - Prevalence of systemic lupus erythematosus among patients of hypothyroidism in a tertiary care center. AB - CONTEXT: Hypothyroidism is a common public health problem in India. With iodine sufficiency, autoimmune thyroiditis is becoming the most important etiology of hypothyroidism. Often, thyroiditis is associated with other systemic autoimmune diseases. AIMS: We undertook thisobservational study to find the prevalence of systemic lupus erythematosus (SLE) amongst the hypothyroid patients at our Institution. SETTINGS AND DESIGN: This is probably the first study of its kind from India. MATERIALS AND METHODS: 185 patients with diagnosed hypothyroidism were included and screening for SLE was done by standard epidemiological criteria. Majority of the patients (63.8%) were young adults (20-40 years). STATISTICAL ANALYSIS USED: Two by two contingency tables were analyzed by Chi square test or Fisher's exact test as needed. Logistic regression model was used considering the presence of SLE as a dependent variable. RESULTS: Eleven (5.94%) patients were found to have SLE. However, anti nuclear factor was positive in 145 cases (78.4%). Of the patients with SLE, 8 (72.7%) were found to be anti TPO positive, but the titers of ANF and anti TPO did not correlate. Presence of discoid rash, haematological criteria and presence of antibodies like anti-dsDNA were significantly correlated with the presence of SLE in hypothyroid patients. Presence of ANF was also correlated with the grade of goiter (r=0.62; P<0.05). Also four patients with SLE had a positive family history (OR=9.37). Logistic regression model showed anti-TPO has OR=1.54 (P=0.02) for the development of SLE. CONCLUSIONS: Prevalence of SLE in hypothyroid patients is high compared to the general population, especially, as thyroiditis is very common in SLE. PMID- 22837919 TI - Thyroid function and bone mineral density among Indian subjects. AB - BACKGROUND: Thyroid hormones affect bone remodeling in patients with thyroid disease by acting directly or indirectly on bone cells. In view of limited information on correlation of thyroid function with bone mineral density (BMD) in euthyroid subjects, we undertook this study to evaluate the correlation between thyroid function with BMD in subjects with normal thyroid function and subclinical hypothyroidism. MATERIAL AND METHODS: A total of 1290 subjects included in this cross sectional study, were divided in Group-1 with normal thyroid function and Group-2 with subclinical hypothyroidism. Fasting blood samples were drawn for the estimation of serum 25(OH)D, intact parathyroid hormone, total and ionized calcium, inorganic phosphorus, and alkaline phosphatase. BMD at lumbar spine, femur, and forearm was measured. RESULTS: BMD at all sites (radius, femur, and spine) were comparable in both groups. There was no difference in BMD when subjects were divided in tertiles of TSH in either group. In group-1, FT4 and TSH were positively associated with BMD at 33% radius whereas FT3 was negatively associated with BMD at femoral neck in multiple regression analysis after adjustment for age, sex, BMI, 25(OH)D and PTH levels. In group-2, there was no association observed between TSH and BMD at any site. Amongst all study subjects FT4 and FT3 were positively correlated with BMD at lumbar spine and radius respectively among all subjects. CONCLUSION: TSH does not affect BMD in euthyroid subjects and subjects with subclinical hypothyroidism. Thyroid hormones appear to have more pronounced positive effect on cortical than trabecular bone in euthyroid subjects. PMID- 22837920 TI - Polymorphisms of the human IL-1 receptor antagonist gene and forearm bone mineral density in postmenopausal women. AB - CONTEXT: Studies on the human interleukin 1 receptor antagonist (IL-1RA) gene polymorphism have provided conflicting data regarding the bone mass and quality. AIM AND DESIGN: The objective of this case-control study was to investigate the association between the forearm bone mineral density (BMD) and the IL1RA gene polymorphisms. MATERIALS AND METHODS: A total of 400 postmenopausal Bulgarian women participated in this study. BMD was measured at the forearm by X-ray absorptiometry on a DTX-100 device (Osteometer Meditech, USA). A PCR product was isolated. The alleles were scored according to their length: A1 - 410 bp - 4 repeats; A2 - 240 bp - 2 repeats; A3 - 500 bp - 5 repeats; A4 - 325 bp - 3 repeats; A5 - 595 bp - 6 repeats. All analyses were evaluated for statistical significance (chi(2)-test and T-test). RESULTS: Four alleles were observed - A1, A2, A3, and A4. The A1A1 genotype was more common in cases with low BMD than in controls with normal BMD (95% vs. 90%, chi(2)P < 0.01). The A2A2 genotype was equally distributed among cases and controls (both 5%). The other two genotypes (A3A3 and A4A4) as well as A1A3 were present only in controls with normal BMD. The A2A2 genotype was associated with higher BMD and the A1A1 - with lower BMD at both forearm sites. The odds ratio for low BMD in the presence of the A1A1 genotype was 2.11. The etiological factor reflecting the association between the polymorphism and the disease was 0.50. In our study sample the IL1RA genetic polymorphisms were associated with the forearm BMD. CONCLUSION: This genetic polymorphism may become a useful genetic marker for the study of osteoporosis. PMID- 22837921 TI - Dyslipidemia in racially admixtured children with cystic fibrosis. AB - OBJECTIVES: There are few studies reporting lipid profile in cystic fibrosis (CF) and most of them are in adult Caucasians. Therefore, the aim of this study was to evaluate the lipid profile of racially admixtured youths with CF. MATERIALS AND METHODS: A cross-sectional survey conducted between August and September 2009 at a reference service for CF, evaluating clinical and laboratory data. RESULTS: Forty-six patients aged from 6 years to 16 years and 2 months (median: 9 years and 10 months; 65.2% males) were evaluated. Of these, 26% were Whites, 54.4% Mulattoes and 19.6% Blacks. There were no diabetics, one patient had glucose intolerance and three had insulin resistance. Pancreatic sufficiency was present in 74% and malnutrition in 26% of the patients. The lipid profile revealed hypertriglyceridemia in 56%, hypercholesterolemia in 17.4% and hypocholesterolemia in 46.5%. In 30.4% of the patients, hypertriglyceridemia and hypocholesterolemia was observed. The serum levels of high density lipoprotein (HDL) were low in 56.5% and the low density lipoprotein (LDL) elevated in 15.2% of the patients. CONCLUSIONS: The lipid profile of this sample of Brazilian racially admixtured patients with CF showed a higher prevalence of hypertriglyceridemia and hypocholesterolemia. There was no association of dyslipidemia with the various racial groups, nutritional status, pancreatic sufficiency or glucose tolerance. PMID- 22837923 TI - Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages. AB - INTRODUCTION: Children with congenital adrenal hyperplasia (CAH) provide us an opportunity to study the clinical effects of androgen excess in humans. We studied the sequence of pubertal development in girls with congenital adrenal hyperplasia initiated on treatment at different ages, to assess the effects of androgen exposure on the Hypothalamic-Pituitary-Ovarian (HPO) axis. MATERIALS AND METHODS: Girls more than 18 years of age, with CAH, on follow-up at this hospital were the subjects for this study. Details of history, physical findings, laboratory evaluation, and medication were noted from their case records and verified from the patients and their / parents, in addition to assessment of their present health status. RESULT: We studied 24 patients of classical CAH (SW 2, SV-22, average age - 24.5 +/- 6.6 years). All had varying degrees of genital ambiguity (Prader stage 3 (n = 13), Prader stage 2 (n = 10), Prader stage 1 (n = 1). Among them were13 girls, who were started on steroids after eight years of age. Girls who received treatment from infancy and early childhood had normal pubertal development (mean age at menarche 11.4 +/- 1.7 years). Hirsutism was not a problem among them. Untreated children had progressive clitoral enlargement throughout childhood, developed pubic hair at around three to six years of age, and facial hair between nine and eleven years. Plasma testosterone ranged from 3 to 6 ng / ml prior to treatment. Six of the 13 untreated CAH girls had subtle breast development starting at ages 11 - 16 years and three had spontaneous infrequent vaginal bleeding starting at ages 11 - 17. Steroid supplementation initiated pubertal changes in older girls in two-to-six months' time. CONCLUSION: There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation. PMID- 22837922 TI - Ileal interposition with sleeve gastrectomy for treatment of type 2 diabetes mellitus. AB - AIM: Combination of laparoscopic ileal interposition (II) with sleeve gastrectomy (SG) is an upcoming procedure, which offers good metabolic improvement and weight reduction without causing significant malabsorption. The objective of this study was to evaluate the results of this novel procedure for control of type 2 diabetes, obesity, hypertension, and related metabolic abnormalities. MATERIALS AND METHODS: The II and SG was performed in 43 patients (M:F = 25:18) from February 2008. Participants had a mean age of 47.2 +/- 8.2 years (range 29-66 years), mean duration of diabetes of 10.1 +/- 9.2 years (range 1-32 years), and mean preoperative body mass index (BMI) of 33.2 +/- 7.8 kg/m2. All patients had poorly controlled type 2 diabetes mellitus (DM) [mean glycated hemoglobin (HbA1C) 9.6 +/- 2.1%] despite use of oral hypoglycemic agents (OHAs) and/or insulin. Thirty (70%) patients had hypertension, 20 (46%) had dyslipidemia, and 18 (42%) had significant microalbuminuria. The primary outcome was remission of diabetes (HbA1C < 6.5% without OHAs/insulin) and the secondary outcomes were reduction in antidiabetic agent requirement and components of metabolic syndrome. RESULTS: Mean follow-up was for 20.2 +/- 8.6 months (range 4-40 months). Postoperatively, glycemic parameters (fasting and post-lunch blood sugar, HbA1C improved in all patients (P < 0.05) at all intervals. Twenty (47%) patients had remission in diabetes and the remaining patients showed significantly decreased OHA requirement. All patients had weight loss between 15 and 30% (P < 0.05). Twenty seven (90%) patients had remission in hypertension. At 3 years, the mean fall in HbA1C (34%) was more than reduction in BMI (25%). There was a declining trend in lipids and microalbuminuria postoperatively, though it was significant for microalbuminuria only. CONCLUSIONS: The laparoscopic II with SG seems to be a promising procedure for control of type 2 DM, hypertension, weight reduction, and associated metabolic abnormalities. A multicenter study with larger number of patients and a longer follow-up period is needed to substantiate our preliminary findings. PMID- 22837924 TI - Isolated postprandial hyperglycemia in type 2 diabetic patients in a Nigerian Tertiary Health Center. AB - BACKGROUND: Postprandial hyperglycemia has been shown to be an independent cardiovascular risk factor. Some studies have reported that postprandial hyperglycemia is common and can occur even in patients with normal fasting glucose levels. This has been referred to as isolated postprandial hyperglycemia. OBJECTIVES: This study sets out to estimate the prevalence of isolated postprandial hyperglycemia in a cohort of patients with type 2 diabetes and to identify their clinical characteristics. MATERIALS AND METHODS: Ninety patients being managed for type 2 diabetes were recruited consecutively as they attended the diabetes clinic for follow-up. The patients were assessed with questionnaires, to obtain the demographic data. Their body mass index (BMI) was calculated. Fasting blood samples were collected for analysis of fasting plasma glucose (FPG). Patients were given their usual drugs and then served a standard meal calculated to contain 50 g of carbohydrate, providing 500 kcal. Blood samples were collected two hours after the start of the meal for postprandial glucose levels. RESULTS: The mean age of the patients was 57.7 +/- 10.8 years with a male : female ratio of 2 : 3. The mean duration of diabetes was 6.77 +/- 6.53 years. The mean BMI was 27.54 +/- 6.01 kg / m(2). The mean FPG and two hour postprandial glucose were 7.51 +/- 3.39 mmol / l and 11.02 +/- 4.03 mmol / L, respectively, and the mean HBA1c was 9.0 +/- 2.5%. The prevalence of isolated postprandial hyperglycemia was 24.4%. Elevated postprandial glucose was seen in 41.7% of the patients at target glycated hemoglobin levels. The patients with isolated postprandial hyperglycemia tended to be older and less obese. CONCLUSION: There was poor glycemic control in the patients generally; however, a significant proportion of patients, with apparently good glycemic control, had isolated postprandial hyperglycemia. PMID- 22837925 TI - A comparative study of antioxidant potential of low density lipoprotein in type 2 diabetic men and women. AB - BACKGROUND: Hyperglycemia plays an important role in etiology of vascular complications like atherosclerosis in diabetes. Oxidative modification of low density lipoprotein (LDL) plays an important role in the progression of atherosclerosis. The aim of the present study is to compare the antioxidant potential (AOP) of LDL in type 2 diabetic men and women. MATERIALS AND METHODS: The study was carried out in 80 diabetic subjects and 80 control subjects. The men (40) and women (40) in the diabetic groups were studied separately and matched for age (50-60 years), body mass index (BMI), duration of diabetes, glycosylated hemoglobin, and lipid profile. LDL from the serum sample was precipitated by heparin citrate precipitation method. For the measurement of AOP in LDL, we used xanthine-xanthine oxidase method. RESULTS: Our results showed that AOP value was significantly low in diabetic women (P < 0.05) in comparison with diabetic men. CONCLUSION: It is therefore suggested that LDL from type 2 diabetic women is more prone for oxidation. PMID- 22837926 TI - Occurrence of symptomatic meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine. AB - Occurrence of second tumors has been seen in patients with papillary and follicular thyroid cancer. We studied the occurrence of meningioma as a second neoplasm in patients with differentiated thyroid cancer treated with radioiodine at our institution. PMID- 22837928 TI - Virilizing adrenocortical carcinoma in a child: A rare enigma. AB - Adrenocortical carcinomas are rare tumors with an incidence of one to two cases per million population and are still more rarer in the pediatric age group. Adrenocortical carcinomas can be functional or may be unassociated with syndromes of hormone overproduction. It is very important to differentiate an adrenocortical adenoma from a carcinoma, as both share a large number of phenotypic features, and assess their prognosis, as adrenocortical carcinoma may need an adjuvant therapy. In this communication, we describe the case of a two year-old boy, who presented with iso-sexual precocious puberty, having features of virilization, which included growth of facial and pubic hair, deepening of voice, and penile growth. PMID- 22837927 TI - Necrobiosis lipoidica diabeticorum: A case-based review of literature. AB - Necrobiosis lipoidica diabeticorum (NLD) is a rare chronic and granulomatous skin disorder that affects 0.3% of diabetic patients. Although the etiology and pathogenesis of NLD is still controversial, it is thought that microangiopathy has an important role. The legs are the most common site for NLD, but involvement of other areas such as the abdomen, upper extremities and scalp has been reported. There is no rational therapy. However, benefit has been reported from different treatment regimens such as drugs acting on the hemostatic mechanisms, corticosteroid therapy (topical, intralesional and systemic), enhancers of wound healing, surgery and immunomodulating therapies (including photochemotherapy). We report a 59-year-old female, who was a diabetic patient with multiple, disseminated lesions on the legs, which tended to disappear as the glycemic control was achieved. Hereby, we also review the existing literature for the evolving aspects of etiopathogenesis and treatment. PMID- 22837929 TI - Hyperphagic short stature: A case report and review of literature. AB - A 51/2-year-old adopted girl was referred to us in view of short stature. After ruling out systemic illness, she was evaluated for growth hormone deficiency (GHD) by stimulation tests. The peak value was 3.47 ng/ml. She was then started on growth hormone (GH). At the end of 6 months of GH therapy, her height velocity was only 3 cm/year. There was a lack of attachment between the mother and the child. She had history of hyperphagia, stealing, and hoarding food. Psychiatry consultation confirmed that the child had appetite disorder, and hence was diagnosed as hyperphagic short stature (HSS). The girl and her parents are undergoing psychiatric therapy for the same. Psychosocial dwarfism seems to originate from serious disturbances in the mother-child relationship. These children mimic patients with GHD, but have poor response to GH therapy. This case underscores the importance of social environment in the growth of the individual. PMID- 22837930 TI - Central precocious puberty due to hypothalamic hamartoma in a six-month-old infant girl. AB - Precocious puberty defined as an onset of puberty below eight years in girls and nine years in boys, has an incidence of approximately 1 / 5,000 - 1 / 10,000 subjects with a female / male ratio of 20: 1. It is etiologically classified broadly as central and peripheral. We present to you a case of isosexual (central), precocious puberty in a 16-month-old girl, who was symptomatic since the age of six months, and was later, diagnosed to have hypothalamic hamartoma. It is one of the earliest case records ever in the medical literature of menarche, at an extremely early age (six-month-old child) secondary to a central cause. PMID- 22837931 TI - Incidental detection of hyperfunctioning thyroid cancer metastases in patients presenting with thyrotoxicosis. AB - Thyrotoxicosis due to functioning metastases from thyroid cancer is rare. It also presents a therapeutic challenge, as both the metastatic cancer and thyrotoxicosis need to be treated. We present here two cases of thyrotoxicosis which on a routine (99m)Tc-pertechnetate thyroid scan showed extrathyroidal foci of uptake. Two patients who initially presented with thyrotoxicosis underwent a routine thyroid scan. Abnormal uptake in the shoulder was incidentally noted, which prompted us to do a whole body pertechnetate scan in the same sitting, which revealed extensive hyperfunctioning metastases in the lungs and bones. We also discuss the 'Flip Flop' phenomenon in thyroid cancer, which was seen in our case. This report emphasizes the importance of evaluating the abnormal foci of uptake seen on a routine thyroid scan. PMID- 22837932 TI - Turner's syndrome presenting as metabolic bone disease. AB - Turner's syndrome is a genetic disorder with a complete or partial absence of one X chromosome with characteristic phenotypic features. The prevalence of renal anomalies in turner syndrome is 30-40%. However, the renal function is usually normal. We report a case of Turner's syndrome presenting with chronic kidney disease and renal osteodystrophy. PMID- 22837933 TI - True hermaphrodite presenting as primary amenorrhea. AB - True hermaphrodite is one of the rare variety of disorders of sex development. Most of them are genotypically females (46 XX) and present as under virilized males. Features of hyperandrogenism are present in those reared as females. The commonest histological variety of gonad found in them is ovotestis, which is at risk for malignancy. We report a girl with 46 XY true hermaphrodite without ovotestis presenting as primary amenorrhea and isolated clitoromegaly in the absence of any other features of virilization. PMID- 22837934 TI - Homozygous familial hypercholesterolemia. AB - Familial hypercholesterolema (FH) is an inherited autosomal dominant disorder of lipid metabolism. We report a 3 years old female child who presented with multiple eruptive xanthomatosis of skin since 6 months of age and had deranged lipid profile consistent with FH. PMID- 22837935 TI - Thiamine responsive megaloblastic anemia syndrome associated with patent ductus arteriosus: First case report from Kashmir Valley of the Indian subcontinent. AB - Thiamine responsive megaloblastic anemia syndrome, an autosomal recessive inherited disorder characterized by a triad of anemia, diabetes mellitus and sensorineural deafness is caused by a deficiency of a thiamine transporter protein. The disorder is rare and has not been reported from our community which has high background of consanguinity. We report a six years old girl who presented with diabetes mellitus which remitted after thiamine replacement. The girl in addition had sensorineural deafness, reinopathy, atrial septal defect and megaloblastic anemia which responded to high doses of thymine. This is the first case reported from Kashmir valley and third from India. The presentation and management in such cases is discussed. PMID- 22837936 TI - Nodular goiter with multiple cystic and solid swellings. AB - Thyroid nodules are very common in the general population, but only 5% are malignant. We report the case of a man presenting with nodular goiter, and multiple swellings over the scalp and arm, with pathological fractures. On evaluation by fine needle aspiration, these swellings were found to be metastases from follicular thyroid carcinoma. The patient underwent total thyroidectomy, radioiodine ablation, resection of the bone lesion, and L-thyroxine suppressive therapy, with no recurrence / metastasis over a five-year follow-up. PMID- 22837937 TI - Radioiodine treatment in McCune-Albright syndrome with hyperthyroidism. AB - McCune-Albright syndrome (MAS) is a sporadic disease characterized by polyostotic fibrous dysplasia, "cafe-au-lait" spots and hyperfunctional endocrinopathies. Pathophysiological basis is activating mutation of the gene that encodes the alpha subunit of Gs membrane protein that stimulates the intracellular production of cAMP, conferring autonomous secretion of the gland in particular. One of the uncommon endocrine manifestations is hyperthyroidism. We present a patient who had cafe-au-lait spots, polyostotic fibrous dysplasia and hyperthyroidism. She was treated with radioactive iodine for the symptoms of hyperthyroidism and subsequently relieved from hyperthyroid features. PMID- 22837938 TI - Artifactually lowered glycosylated hemoglobin (HbA1c %) in patient with diabetes on dapsone. PMID- 22837939 TI - Unexpectedly low HbA1c levels in two diabetes patients following dapsone use. PMID- 22837940 TI - Does Vitamin D therapy affect hematological indices in adolescents with vitamin D deficiency? PMID- 22837941 TI - Block and replace therapy using propylthiouracil and levothyroxine for Graves' disease during pregnancy. PMID- 22837942 TI - Self-medication with herbal remedies amongst patients of type 2 diabetes mellitus: A preliminary study. PMID- 22837943 TI - Need for Ramadan guidelines in various aspects of health. PMID- 22837944 TI - Massive multinodular goiter with stridor. PMID- 22837945 TI - Gingival crevicular blood glucose assessment as a chairside test for diabetic patients with chronic periodontitis: A clinical study. PMID- 22837946 TI - Hungry bone disease in a pregnant woman with parathyroid adenoma. PMID- 22837947 TI - Toxic thyroid carcinoma: A new case. PMID- 22837948 TI - The many lives of mifepristone: Multi-glandular exaptation of an endocrine molecule. PMID- 22837949 TI - Hypertriglyceridemia-induced acute pancreatitis treatment with insutin and heparin. PMID- 22837950 TI - Melatonin: Miracles far beyond the pineal gland. PMID- 22837951 TI - Diabetes in the time of HIV. PMID- 22837952 TI - Remarks in metformin and sleep disorders in diabetic patients. PMID- 22837953 TI - Society of Pharmaceutical Education and Research: 1(st) Annual Conference: DIPSAR, New Delhi, India. PMID- 22837954 TI - Herbal drug development from natural sources. PMID- 22837955 TI - Biophytum sensitivum: Ancient medicine, modern targets. AB - Research on medicinal plants began to focus on discovery of natural products as potential active principles against various diseases. Medicinal plants are very interesting, have the ability to produce remarkable chemical structures with diverse biological activities. Biophytum sensitivum is used as traditional medicine to cure variety of diseases. During the last few decades, extensive research has been carried out to elucidate the chemistry, biological activities, and medicinal applications of B. sensitivum. Phytochemical analysis have shown that the plant parts are rich in various beneficial compounds which include amentoflavone, cupressuflavone, and isoorientin. Extracts and its bioactive compounds have been known to possess antibacterial, anti-inflammatory, antioxidant, antitumor, radioprotective, chemoprotective, antimetastatic, antiangiogenesis, wound-healing, immunomodulation, anti-diabetic, and cardioprotective activity. The present review has been carried out to shed light on the diverse role of this plant in the management of various ailments facing us. PMID- 22837956 TI - Hydroxamic acid - A novel molecule for anticancer therapy. AB - Hydroxamic acid is a potent moiety not only in the field of cancer therapy but also as a mutagenic agent. Among the various derivatives of hydroxamic acid, SAHA (Suberoylanilide Hydroxamic Acid) is considered as a potent anticancer agent. Scientists from the different corner synthesized different hydroxamic acid moieties with some straight chain oxazole, thiadiazole, biphenyl moieties in the terminal position. Acetylation and deacetylation of histones of the core proteins of nucleosomes in chromatin play an important role in the regulation of gene expression. The level of acetylation of histones is established and maintained by two classes of enzymes, histone acetyltransferase and histone deacetylases, which have been identified as transcriptional coactivators and transcriptional corepressors, respectively. There is increasing evidence that aberrant histone acetylation has been linked to various malignant diseases. Great efforts are currently underway for the design of more potent and less toxic candidates for the treatment of cancer. In recent years, hydroxamic acid derivatives have attracted increasing attention for their potential as highly efficacious in combating various etiological factors associated with cancer. Our main intention to draw an attention is that this single functional moiety has not only fit in the receptor but also create a diversified activity. PMID- 22837957 TI - Effect of hydroxyapatite on the physicochemical characteristics of a gentamicin loaded monoolein gel intended to treat chronic osteomyelitis. AB - Many works have demonstrated the real potential of gentamicin-monoolein-water formulations as bioresorbable and sustained-release implants for the local treatment of the chronic osteomyelitis. In order to improve the efficacy of this type of implant, the incorporation of hydroxyapatite, a well-known osteointegrator material, is thought to be an interesting approach. Five formulations incorporating 0, 2.5, 5, 10, and 20% of hydroxyapatite were examined with regard to their physicochemical and in vitro drug release characteristics. The rheological, thermal (differential scanning calorimetric and thermogravimetric diffraction analysis), X-ray diffraction, and dissolution studies have showed that the presence of hydroxyapatite does not dramatically disturb the cubic liquid crystalline structure of the monoolein-water gel and their ability to progressively release the antibiotic. Implant 20% that was capable to release gentamicin sulfate over a period of four weeks without marked burst effect could be used as a more suitable biodegradable delivery system for the local management of chronic osteomyelitis. PMID- 22837958 TI - Development and evaluation of antimicrobial herbal formulations containing the methanolic extract of Samadera indica for skin diseases. AB - Samadera indica Gaetrn (Simaroubaceae) is claimed to possess various pharmacological activities like antioxidant, antifungal, antitumor, antiviral, and so on, but its taste is bitter. The aim of the present study is to investigate the toxicity of the methanolic extract and to develop suitable herbal formulations of the methanolic extract of Samadera indica, having efficient antimicrobial activity. The methanolic extract prepared from the dried leaves of Samadera indica by continuous hot percolation, were used to examine the toxicity, according to the OECD 423 guidelines, in Swiss Albino mice. Topical formulations were prepared by incorporating Samadera indica (5% w / w) in an emulsifying ointment and a carbopol gel base and evaluated for physical parameters and in vitro antimicrobial activity (S. aureus, P. aeruginosa and C. albicans). The study reveals that no animals under the study showed any clinical signs of toxicity or mortality when administered a dose of 5 - 2000 mg / kg body weight. Therefore, the maximum tolerated dose of the methanolic extract of Samadera indica was above 2000 mg / kg body weight. The formulated ointment and gel had acceptable physical parameters that showed that they were compatible with the skin, and in addition to this, these formulations passed the short-term stability studies. The in-vitro antimicrobial activity studies showed that the formulated ointment showed significantly strong (p < 0.05) activity against S. aureus, P. aeruginosa and C. albicans than the formulated gel. Thus, the present study concludes that the formulated ointment and gel are safe and efficient antimicrobial formulations for the topical delivery of the methanolic extract of Samadera indica. PMID- 22837959 TI - Effect of permeation enhancers on the penetration mechanism of transfersomal gel of ketoconazole. AB - The aim of the present research work was to investigate the potential of transfersome formulations for transdermal delivery of Ketoconazole (KTZ). KTZ is a broad-spectrum antifungal agent that is active against a wide variety of fungi and yeasts. It is readily but incompletely absorbed after oral dosing and is highly variable. The transfersomes were formulated by lipid film hydration technique using Rotary vacuum Evaporator. The prepared transfersomes were converted into suitable gel formulation and is evaluated for their gel characteristics like pH, viscosity, spreadability, extrudability, homogeneity, drug content, etc. Suitable essential oils acting as natural permeation enhancers were added to the transfersomal formulation of KTZ for their release studies. Studies proved that addition of suitable permeation enhancers to the transfersomal formulation improved the release and permeation of KTZ, which showed that the permeation enhancers modify the barrier to penetration present in skin without itself undergoing any change. From the various essential oils which are used as permeation enhancers, the formulation containing Eucalyptus oil showed better in vitro release and permeation as compared with other formulations containing different permeation enhancers. PMID- 22837960 TI - Acute, sub-chronic oral toxicity studies and evaluation of antiulcer activity of Sooktyn in experimental animals. AB - Sooktyn (SKN), mineralo-herbal drug which is being used largely by the patients for its extremely good therapeutic value to treat the gastric ulcers. The present study was undertaken to evaluate the toxicity studies and antiulcer activity of SKN. Acute and sub-chronic toxicities were studied in male and female Wistar rats. A single acute SKN of 2 000 mg/kg was administered by oral gavage for acute toxicity. Sub-chronic doses were 400 and 800 mg/kg/day. The major toxicological end points examined included animal body weight and food intake, selected tissue weights, and detailed gross necropsy. In addition, we examined blood elements: hematocrit, hemoglobin concentration, erythrocyte count, total leukocyte count and MCH, MCHC and platelets as well as biochemical parameters: urea, sugar, alanine transaminase, aspartate transaminase, alkaline phosphatase, total proteins, and creatinine. Also, anti-ulcer activity was carried out by employing indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models. LD(50) may be greater than 2 000 mg/kg (orally) for SKN and there were no signs of toxicity on 28 days sub-chronic oral administration of 400 and 800 mg/kg of SKN in rats on the basis of blood elements and biochemical parameters. The ulcer indices decrease in all ulcer models with 66.62%, 61.24%, 80.18%, and 74.76% in indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models, respectively. The results suggest that SKN has no signs of toxicity at 2 000 mg/kg body weight of rats orally; sub-chronically. The drug is safe and has antiulcer activity. PMID- 22837961 TI - Development and evaluation of microporous osmotic tablets of diltiazem hydrochloride. AB - Microporous osmotic tablet of diltiazem hydrochloride was developed for colon targeting. These prepared microporous osmotic pump tablet did not require laser drilling to deliver the drug to the specific site of action. The tablets were prepared by wet granulation method. The prepared tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan coating process. The incorporation of sodium lauryl sulfate (SLS), a leachable pore-forming agent, could form in situ delivery pores while coming in contact with gastrointestinal medium. The effect of formulation variables was studied by changing the amounts of sodium alginate and NaCMC in the tablet core, osmogen, and that of pore-forming agent (SLS) used in the semipermeable coating. As the amount of hydrophilic polymers increased, drug release rate prolonged. It was found that drug release was increased as the concentration of osmogen and pore former was increased. Fourier transform infrared spectroscopy and Differential scanning calorimetry results showed that there was no interaction between drug and polymers. Scanning electron microscopic studies showed the formation of pores after predetermined time of coming in contact with dissolution medium. The formation of pores was dependent on the amount of pore former used in the semipermeable membrane. in vitro results showed acid-resistant, timed release at an almost zero order up to 24 hours. The developed osmotic tablets could be effectively used for prolonged delivery of Diltiazem HCl. PMID- 22837962 TI - Development and validation of a HPLC method for the determination of trans resveratrol in spiked human plasma. AB - A simple, accurate, precise, sensitive, and reproducible high-performance liquid chromatography method was developed for the determination of Resveratrol (trans 3, 4',5-trihydroxystilbene) in human plasma using liquid-liquid extraction. Caffeine was employed as an internal standard (IS). However, little information is known about its distribution in the organism generally because of the lack of accurate and precise detection methods. The chromatographic separation was achieved on a Phenomenex C18 column (250 mm * 4.6 mm, 5 MUm) at room temperature in isocratic mode, and the column effluent was monitored by UV detector at 306 nm. The mobile phase used was methanol: phosphate buffer (pH 6.8 adjusted with 0.5% (v/v) orthophosphoric acid solution in Milli-Q water) (63:37%, v/v) at a flow rate of 1.0 ml/min. Nominal retention times of trans-resveratrol and IS were 3.94 and 7.86 minutes, respectively. Limits of detection and Limits of quantification of trans-resveratrol were 0.006 MUg/ml and 0.008 MUg/ml, respectively. This method was linear over the range of 0.010 to 6.4 MUg/ml with regression coefficient greater than 0.9998. The inter- and intra-day precisions in the samples, 0.010, 3.2 and 6.4 MUg/ml of trans-resveratrol was in the range 0.63 to 2.12% relative standard deviation (RSD) and 0.46 to 1.02% RSD, respectively. Resveratrol was found to be stable for a period of 15 days on storage at -20 degrees C. The method was found to be precise, accurate, and specific during the study. PMID- 22837963 TI - Evaluation of anti-inflammatory effects of green tea and black tea: A comparative in vitro study. AB - The present study was conducted to evaluate and compare the anti-inflammatory effects of aqueous extracts of green tea and black tea leaves (Camellia sinensis) against the denaturation of protein in vitro. The test extracts at different concentrations were incubated with egg albumin under controlled experimental conditions and subjected to determination of absorbance to assess the anti inflammatory property. Diclofenac sodium was used as the reference drug. The present results exhibited a concentration-dependent inhibition of protein (albumin) denaturation by both the tea extracts. From the present findings it can be concluded that both green and black tea leaves possessed a marked anti inflammatory effect against the denaturation of protein, in vitro. Green tea was found to be more active than black tea, plausibly due to the higher flavonoid contents of green tea. PMID- 22837964 TI - The effect of combined therapy of exercise and nootropic agent on cognitive function in focal cerebral infarction rat model. AB - OBJECTIVE: To investigate the effect of combined therapy of exercise and nootropic agent on cognitive function in a focal cerebral infarction rat model. METHOD: Forty 10-week old male Sprague-Dawley rats were subjected to photothrombotic cerebral infarction of the left parietal lobe. All rats were randomly divided into 4 groups: group A was photothrombotic cerebral infarction rats without any treatment (n=10); group B was photothrombotic cerebral infarction rats with swimming exercise (n=10); group C was photothrombotic cerebral infarction rats with oral administration of acetyl-L-carnitine (n=10); group D was photothrombotic cerebral infarction rats with swimming exercise and oral administration of acetyl-L-carnitine (n=10). Cognitive function was evaluated using the Morris water maze test on the 1st day, and the 1st, 2nd, and 4th week after the induction of cerebral infarction. The activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA) in the hippocampus were measured. The neuronal cells of the hippocampus were histopathologically evaluated. RESULTS: The escape latency was shorter in groups B, C, and D than in group A. However, the differences were not statistically significant at the 1st, 2nd and 4th week. The activity of SOD was the highest in group D. The level of MDA was the lowest in group D. We observed more normal neuronal cells in groups B, C, and D. CONCLUSION: The combined therapy of exercise and nootropic agent was helpful in ameliorating oxidative stress in the focal cerebral infarction rat model. However, the effect did not translate into improvement of cognitive function. PMID- 22837965 TI - Effect of magnetic stimulation in spinal cord on limb angiogenesis and implication: a pilot study. AB - OBJECTIVE: To investigate the effect of repetitive magnetic stimulation (rMS) of the spinal cord on limb angiogenesis in healthy rats and explore its implication for the treatment of lymphedema. METHOD: Twelve adult male Sprague-Dawley rats were divided into four groups as follows: sham rMS followed by tissue harvest 5 minutes later (group 1, n=2), 1 Hz rMS and tissue harvest 5 minutes later (group 2, n=3), 20 Hz rMS and tissue harvest 5 minutes later (group 3, n=3), 20 Hz rMS and tissue harvest 30 minutes later (group 4, n=4). Animals were treated with 20 minute rMS with 120% of the motor threshold on their left side of upper lumbar spinal cord. Expression of angiogenic factors, that is, Akt, phospho-Akt (pAkt), endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS) were measured by western blot. Bilateral hindlimb muscles (quadriceps and gastrocnemius) were harvested. RESULTS: Expression of Akt in left quadriceps increased in group 4 compared with group 2 and 3 (3.4 and 5.3-fold each, p=0.026). Expression of eNOS in left plus right quadriceps markedly increased in group 3 and 4 compared with group 1 and 2 (p=0.007). Expressions of eNOS, Akt and p-eNOS, pAkt in gastrocnemius were not comparable between four groups (p>0.05). CONCLUSION: Repetitive magnetic stimulation of the spinal cord may exert an angiogenic effect closely linked to lymphangiogenesis. It has clinical implication for the possible therapy of lymphedema caused by breast, cervical or endometrial cancer operation. Future studies with the specific lymphatic endothelial cell markers are required to confirm the effect of rMS on lymphangiogenesis. PMID- 22837966 TI - Magnetic resonance imaging as a determinant for surgical release of congenital muscular torticollis: correlation with the histopathologic findings. AB - OBJECTIVE: (1) To present the magnetic resonance imaging (MRI) findings of congenital muscular torticollis (CMT) of subjects who underwent surgical release and subjects who showed a good prognosis with stretching exercises and (2) to correlate the MRI findings with the histopathologic findings of CMT for subjects who underwent surgical release in order to examine the hypothesis that the MRI findings of CMT can be used as a determinant to perform surgical release of CMT. METHOD: The neck MRI findings of 33 subjects who underwent surgical release for CMT were compared with those of 18 subjects who were successfully managed only with conservative management. The MRI findings were correlated with the histopathologic sections of the CMT mass. RESULTS: All 33 subjects (100%) who underwent surgical release showed one or more low signal intensities within the involved sternocleidomastoid muscle (SCM) on the T1- and T2-weighted images of neck MRI. The eighteen non-surgical candidates showed only enlargement of the SCM without low signal intensity within the SCM. The histopathologic findings showed interstitial fibrosis and/or the presence of aberrant tendon-like excessive dense connective tissue that was either well-arranged or disorganized. CONCLUSION: The histopathologic findings and MRI findings showed good correlation in terms of the amount of fibrosis and aberrant dense connective tissue within the SCM. If multiple or large low signal intensities within the SCM are noted, we think that surgical release should be considered. PMID- 22837967 TI - Spinal Cord Atrophy and Early Motor Recovery following Transverse Myelitis in Pediatric Patients. AB - OBJECTIVE: To compare the motor recovery following transverse myelitis in pediatric patients with and without spinal cord atrophy. METHOD: From January 1995 through December 2009, twenty children (8 boys and 12 girls with an onset at 5.7+/-3.8 years) that were diagnosed with transverse myelitis at a Children's Hospital in Korea, and undertaken an initial and follow-up spine magnetic resonance image (MRI) were included. Medical records and spine MRI scans were reviewed retrospectively. An initial MRI was taken 5.1+/-8.7 days after the onset. The interval between an initial and follow-up MRIs was 33.4+/-23.0 days. The motor recovery differences between subjects with and without spinal cord atrophy on follow-up MRIs were determined. Motor recovery was defined as the elevation of one or more grades of manual muscle tests of the Medical Research Council. RESULTS: Eight patients had developed spinal cord atrophies and 12 patients had not. Of the 8 patients with spinal cord atrophy, 7 showed no motor improvement. Among the 12 patients without atrophy, 11 had motor improvement. Spinal cord atrophy on follow-up MRIs were related to the risk of no motor improvement (odds ratio=77.0, 95% confidence interval [4.114-1441.049], p value=0.001). CONCLUSION: Children with transverse myelitis who had developed spinal cord atrophy on follow-up MRIs had poor motor recovery than those who had not. The appearance of spinal cord atrophy on follow-up MRI could be an indicator of poor prognosis in pediatric transverse myelitis. PMID- 22837968 TI - Clinical characteristics of children with rett syndrome. AB - OBJECTIVE: To identify the clinical characteristics and investigate function related aspects of Korean children with Rett syndrome. METHOD: A total of 26 patients diagnosed as Rett syndrome were clinically observed until the age of five or over. We surveyed past history, developmental history, and presence of typical clinical features of Rett syndrome. Furthermore, we investigated differences in clinical characteristics according to functional status and changes in clinical features related to growth. RESULTS: There were no problems related to gestational, perinatal or neonatal history. Only 12 patients had an ultimate head circumference of less than 3 percentile. Developmental regression was definite in all patients. At final assessment, only 14 patients were able to walk. Twenty patients had an epileptic history requiring medication. Sixteen patients with scoliosis showed progression during serial follow-up. The percentage of patients who were able to walk before 16 months was higher in the high function group than the low function group. The age of regression was 5.4 and 4.0 years in the high and low function group respectively, but the difference was not statistically significant. Scoliosis was more severe and seizure onset age was younger in the low function group. CONCLUSION: We investigated 26 clinical characteristics in Korean children with Rett syndrome. Their clinical features change according to age, and we believe such knowledge could be utilized in rehabilitation to minimize their disabilities. PMID- 22837969 TI - Effect of botulinum toxin a injection into the salivary glands for sialorrhea in children with neurologic disorders. AB - OBJECTIVE: To determine the 9 month period effect of botulinum toxin A (BoNT-A) injection into the salivary gland in children with neurologic disorders and sialorrhea by qualified parent/caregiver-administered questionnaires. METHOD: A total of 17 patients (age 7.6+/-4.24 years) were enrolled in this study. The degree of sialorrhea was assessed at the baseline, 2 weeks, 1, 2, 4, 6 and 9 months after injection. The Drooling Count (DC) was assessed as an objective measurement. The Drooling Frequency and Severity Scale (DFS) and the Teacher Drooling Scale (TDS) were evaluated as a subjective measurement. BoNT-A (0.5 unit/kg) was injected into each submandibular and parotid gland under ultrasonography-guidance. RESULTS: DC, DFS and TDS showed significant improvement at 2 weeks, 1, 2, 4, 6, and 9 months follow-up (p<0.05). Twelve of 17 cases (70.5%) showed more than 50% reduction in DC from the baseline value. CONCLUSION: Ultrasonography-guided BoNT-A injection into the submandibular and parotid gland was a safe and effective method to treat sialorrhea in children with neurologic disorders. PMID- 22837970 TI - Correlation between Location of Brain Lesion and Cognitive Function and Findings of Videofluoroscopic Swallowing Study. AB - OBJECTIVE: To investigate whether patterns of swallowing difficulties were associated with the location of the brain lesion, cognitive function, and severity of stroke in stroke patients. METHOD: Seventy-six patients with first time acute stroke were included in the present investigation. Swallowing-related parameters, which were assessed videofluoroscopically, included impairment of lip closure, decreased tongue movement, amount of oral remnant, premature loss of food material, delay in oral transit time, laryngeal elevation, delay in pharyngeal triggering time, presence of penetration or aspiration, and the amount of vallecular and pyriform sinus remnants. The locations of brain lesions were classified into the frontal, parietotemporal, subcortical, medulla, pons, and cerebellum. The degree of cognitive impairment and the severity of stroke were assessed by the Mini Mental Status Examination (MMSE) and the National Institute of Health Stroke Scale (NIHSS), respectively. RESULTS: An insufficient laryngeal elevation, the amount of pyriform sinus, and vallecular space remnant in addition to the incidence of aspiration were correlated with medullary infarction. Other swallowing parameters were not related to lesion topology. Lip closure dysfunction, decreased tongue movement, increased oral remnant and premature loss were associated with low MMSE scores. A delayed oral transit time were associated with NIHSS scores. CONCLUSION: In-coordination of the lip, the tongue, and the oropharynx were associated with the degree of cognitive impairment and the stroke severity rather than with the location of the lesion, whereas incomplete laryngeal elevation and aspiration were predominant in medullary lesions. PMID- 22837971 TI - Effect of decannulation on pharyngeal and laryngeal movement in post-stroke tracheostomized patients. AB - OBJECTIVE: To investigate effects of tracheostomy tube on the movement of the hyoid bone and larynx during swallowing by quantitative analysis of videofluoroscopic swallowing study. METHOD: 19 adult stroke patients with tracheostomies, who met the criteria of decannulation participated. Serial videofluroscopic swallowing studies were done over 14 days before decannulation, within 24 hours before decannulation, within 24 hours after decannulation, and over 14 days after decannulation. The kinematic parameter such as pharyngeal transition time, stage transition duration, maximal hyoid bone movement, and maximal laryngeal prominence movement were obtained by 2-D quantitative analysis of videofluoroscopic swallowing study. RESULTS: Pharyngeal transition time and stage transition duration were not significantly changed all the time. The maximal hyoid bone movement and maximal laryngeal prominence just after decannulation were improved significantly compared to just before decannulation (p<0.05), especially on vertical movement. CONCLUSION: The hypothesis that a tracheostomy tube disturbs the hyoid bone and laryngeal movement during swallowing may be supported by this study. PMID- 22837972 TI - The influence of sour taste on Dysphagia in brain injury: blind study. AB - OBJECTIVE: To verify the influence of sour taste on swallowing and the presence of reflex cough when sour material was swallowed in patients with dysphagia secondary to brain injury. METHOD: Fifty dysphagic brain injury patients who underwent videofluoroscopic swallowing study (VFSS) were recruited. The patients who had shown severe aspiration at 2 ml of liquid were excluded. The dysphagic patients were given 5 ml each of a sour tasting liquid (SOUR) and a thin liquid barium (LIQUID) in random order. An expert analyzed the result of VFSS by reviewing recorded videotapes. Analysis components consisted of the Penetration Aspiration-Scale (PAS) score, oral transit time (OTT), pharyngeal transit time (PTT), pharyngeal delay time (PDT) and the reflex cough presence. RESULTS: The PAS score for SOUR was significantly lower than the one for LIQUID (p=0.03). The mean OTT for SOUR was significantly shortened compared to that for LIQUID (p=0.03). The mean PTT and PDT were also shortened in SOUR, although the differences were not statistically significant (p=0.26 and p=0.32, respectively). There was no significant difference between SOUR and LIQUID regarding the presence of reflex cough (p=1.00). CONCLUSION: The sour taste could enhance sensorimotor feedback in the oropharynx, thus lowering the chances of penetration aspiration caused by shortening of the oropharyngeal passage times. There was no significant difference in the presence of reflex cough produced between LIQUID and SOUR. PMID- 22837973 TI - Bowel dysfunction and colon transit time in brain-injured patients. AB - OBJECTIVE: To report the defecation patterns of brain-injured patients and evaluate the relationship between functional ability and colon transit time (CTT) in stroke patients. METHOD: A total of 55 brain-injured patients were recruited. Patient interviews and medical records review of pattern of brain injury, anatomical site of lesion, bowel habits, constipation score, and Bristol scale were conducted. We divided the patients into constipation (n=29) and non constipation (n=26) groups according to Rome II criteria for constipation. The CTTs of total and segmental colon were assessed using radio-opaque markers Kolomark(r) and functional ability was evaluated using the functional independence measure (FIM). RESULTS: Constipation scores in constipation and non constipation groups were 7.32+/-3.63 and 5.04+/-2.46, respectively, and the difference was statistically significant. The CTTs of the total colon in both groups were 46.6+/-18.7 and 32.3+/-23.5 h, respectively. The CTTs of total, right, and left colon were significantly delayed in the constipation group (p<0.05). No significant correlation was found between anatomical location of brain injury and constipation score or total CTT. Only the CTT of the left colon was delayed in the patient group with pontine lesions (p<0.05). CONCLUSION: The constipation group had significantly elevated constipation scores and lower Bristol stool form scale, with prolonged CTTs of total, right, and left colon. In classification by site of brain injury, we did not find significantly different constipation scores, Bristol stool form scale, or CTTs between the groups with pontine and suprapontine injury. PMID- 22837974 TI - Development of a motor driven rowing machine with automatic functional electrical stimulation controller for individuals with paraplegia; a preliminary study. AB - OBJECTIVE: To examine the cardiorespiratory responses of patients with spinal cord injury (SCI) paraplegia using a motor driven rowing machine. METHOD: Ten SCI patients with paraplegia [A (n=6), B (n=1), and C (n=3) by the American Spinal Injury Association impairment scale] were selected. Two rowing techniques were used. The first used a fixed seat with rowing achieved using only upper extremity movement (fixed rowing). The second used an automatically moving seat, facilitating active upper extremity movement and passive lower extremity movement via the motorized seat (motor rowing). Each patient performed two randomly assigned rowing exercise stress tests 1-3 days apart. The work rate (WR), time, respiratory exchange ratio (R), oxygen consumption (VO(2)), heart rate (HR), metabolic equivalents (METs), and rating of perceived exertion (RPE) were recorded. RESULTS: WR, time, VO(2), and METs were significantly higher after the motor rowing test than after fixed motor rowing test (p<0.05). HR after motor rowing was significantly lower than fixed rowing (p<0.05). CONCLUSION: Cardiorespiratory responses as VO(2), HR and METs can be elicited by the motor rowing for people with paraplegic SCI. PMID- 22837975 TI - Effect of lower limb strength on falls and balance of the elderly. AB - OBJECTIVE: To assess the effect of lower limb strength on falls and balance in community-dwelling elderly persons by a health status questionnaire, evaluation of lower limb strength and balance. METHOD: A total of 86 subjects (age 69.8+/ 5.3) were categorized into one of two groups, "Fallers" and "Non-fallers". Thirty one participants who had reported the experience of having fallen unexpectedly at least once in the past year were assigned into the group "Fallers", and the remaining 55 subjects having no fall history in the past year, "Non-fallers". A self-assessment questionnaire was taken. Lower limb strength was measured by a "Chair stand test". Balance was measured by the stability index of the fall risk test protocol of Balance System SD(r) (Biodex, New York, USA). The differences between the two groups were compared and the correlation between lower limb strength and balance were analyzed. RESULTS: The questionnaire demonstrated no significant differences between two groups. The "Chair stand test" showed a significantly less for the "Fallers" (p<0.05). The stability index was significantly greater in the "Fallers" group (p<0.05). There was a moderate negative correlation between the "Chair stand test" and the "Stability index" (R= 0.576, p<0.01). CONCLUSION: This study suggests that the "Chair stand test" is a useful screening process for lower limb strength which correlates to risk for falls and balance in the elderly. PMID- 22837976 TI - Reliability of the pinch strength with digitalized pinch dynamometer. AB - OBJECTIVE: To examine the intra-rater, inter-rater, and inter-instrumental reliability of the digitalized pinch muscle strength dynamometer. METHOD: Thirty normal subjects were examined for pinch strength, using both the Preston pinch gauge and the digitalized pinch dynamometer. The participants performed all pinch strength tests in the seated position as recommended by the American Society of Hand Therapists (ASHT). Three successive measurements were taken for each hand. The mean of the three trials was used for data analysis. The pinch strength tests performed used a repeated measure design and measurements were taken by each rater. RESULTS: The relationship between the Preston pinch gauge and the digitalized pinch dynamometer in pinch strength was reliable (the ICC were 0.821 and 0.785 in rater 1 and rater 2 respectively). The relationship between the first session and second session in pinch strength using the digitalized pinch dynamometer was reliable (the ICC were 0.872 and 0.886 in rater A and rater B respectively). The relationship between rater A and rater B in pinch strength using the digitalized pinch dynamometer was reliable (the ICC was 0.754). CONCLUSION: The pinch strength measurement using the digitalized pinch dynamometer is reliable within the rater and between raters. Thus, the Preston pinch gauge and the digitalized dynamometer measure grip strength equivalently, and can be used interchangeably. PMID- 22837977 TI - The change of intrinsic stiffness in gastrocnemius after intensive rehabilitation with botulinum toxin a injection in spastic diplegic cerebral palsy. AB - A recent study claimed that botulinum toxin A (BTX-A) injection into the calf muscle of cerebral palsy (CP) children did not change the intrinsic stiffness. Contrary to this recent report, in our case, decreased muscle spasticity, which was measured using a modified Ashworth scale, and increased Gross Motor Function Measure score were demonstrated at 4 weeks after intensive rehabilitation treatment (IRT) with BTX-A injection to the medial gastrocnemius muscle in a child with spastic CP. Additionally, we indentified decreased muscle stiffness which was demonstrated by a decrease in the color-coded scale and shear velocity, and an increase in the strain ratio using dynamic sonoelastography. PMID- 22837978 TI - Sonographically guided alcohol injection in painful stump neuroma. AB - Stump neuroma is a common cause of pain from disorganized proliferation of nerve fascicles occurring after limb amputation. Ultrasound guided alcohol injection in painful stump neuroma has been tried as a new treatment approach. Herein, we report 2 male patients, who had traumatic amputation and claimed severe and diffuse burning pain in the stump area. Neuroma at the distal end of an amputated nerve was clearly identified on sonography. The patients gradually developed increasing severe pain that could not be managed with conservative care. They were treated with neurolysis using alcohol solution. Using ultrasonographical guidance, 1.2 ml of 100% dehydrated alcohol was injected into the nerves proximal to neuroma. No complications occurred. The patients were initially pain free. After a few months, however, their stump pain recurred slightly. Repeat neurolysis was performed using 0.3 ml of 100% dehydrated alcohol. During the three months follow-up period, mild stump pain occurred but the patients did not require any analgesics. PMID- 22837979 TI - Neuromuscular Electrical Stimulation Therapy for Dysphagia Caused by Wilson's Disease. AB - Wilson's disease is an autosomal recessive disorder of abnormal copper metabolism. Although dysphagia is a common complaint of patients with Wilson's disease and pneumonia is an important cause of death in these patients, management of swallowing function has rarely been reported in the context of Wilson's disease. Hence, we report a case of Wilson's disease presenting with dysphagia. A 33-year-old man visited our hospital with a complaint of difficulty in swallowing, since about last 7 years and which had worsened since the last 2-3 months. He was diagnosed with Wilson's disease about 13 years ago. On the initial VFSS, reduced hyoid bone movement, impaired epiglottic movement and moderate amount of residue in the valleculae during the pharyngeal phase were noted. After 10 sessions of neuromuscular electrical stimulation for 1 hour per day, decreased amount of residue was observed in the valleculae during the pharyngeal phase on the follow-up VFSS. PMID- 22837980 TI - Multivessel thromboembolism associated with dysfunction of protein s. AB - Protein S is a vitamin K-dependent coagulation factor that acts as an anticoagulant. Deficiency of protein S increases the risk of thromboembolic events. We report a case of isolated protein S deficiency in a 39-year-old woman suffering arterial occlusion in both lower legs. She underwent a surgical procedure using thrombectomy and balloon angioplasty of her left lower extremity. Later, she had right trans-tibial amputation because of the reperfusion injury. Throughout the evaluation of thromboembolic events, we diagnosed a large thrombus in the right atrium and an asymptomatic pulmonary thromboembolism. The patient was successfully treated with right atrial thrombectomy and systemic anticoagulation. Careful evaluation for protein S levels may be necessary in patients with arterial thromboembolic events, especially young adults. PMID- 22837981 TI - Amyotrophic lateral sclerosis with an acute hypertensive crises. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving the systemic motor neurons, but autonomic nervous function is relatively well preserved. A few studies related to autonomic dysfunction have been reported, but autonomic dysfunction is rare in ALS. Moreover, dysautonomia symptoms are not prominent in patients with ALS. We present a 55-year-old male patient with ALS, who had acute severe hypertension and tachycardia crises, as well as sudden falls in his blood pressure. After he was diagnosed with ALS, he suddenly collapsed and was placed under mechanical ventilation. Several hypertensive attacks and dysautonomic signs then occurred. We successfully controlled the dysautonomia using diazepam and doxazocin mesylate, an alpha receptor antagonist. PMID- 22837982 TI - Dementia due to Meningovascular Syphilis in Medial Temporal Lobe and Cognitive Rehabilitation. AB - The temporal lobe is essential in saving declarative memory and plays an important role along with the cerebral neocortex in creating and maintaining long term memory. Damage to the temporal lobe is expected to result in cognitive impairment or dementia, which has characteristic symptoms such as cognitive and behavioral dysfunction and decreasing self-reliance in activities of daily living. We report on a patient, who suffered from dementia due to meningovascular syphilis affecting the medial temporal lobe, and on the outcome of cognitive rehabilitation. PMID- 22837983 TI - A Learning Set Up for Detecting Minimally Conscious State (MCS). AB - Detecting signs of learning in persons diagnosed to be in a post-coma vegetative state and minimally conscious state (MCS) may modify their diagnosis. We report the case of a 65-year-old female in a vegetative state. We used microswitch-based technology that is based on patient response to eye-blinking. We followed an ABABCB design, in which A represented baseline periods, B intervention periods with stimuli contingent on the responses, and C a control condition with stimuli presented non-contingently. We observed the level of response during the B phases was higher than the level of A and C phases. This indicated the patient showed signs of learning. This state was confirmed by an evaluation through the Coma Recovery Scale-Revised (CRSR) score, and after completion of this study her CRSR score changed from 4 to 10. We believe microswitch technology may be useful to make a diagnosis of MCS and offer new opportunities for education to MCS patients. PMID- 22837984 TI - The non-death role of metacaspase proteases. AB - The activation of caspase proteases and the targeting of protein substrates act as key steps in the engagement and conduct of apoptosis/programmed cell death. However, the discovery of caspase involvement in diverse non-apoptotic cellular functions strongly suggests that these proteins may have evolved from a core behavior unrelated to the induction of cell death. The presence of similar proteases, termed metacaspases, in single cell organisms supports the contention that such proteins may have co-evolved or derived from a critical non-death function. Indeed, the benefit(s) for single cell life forms to retain proteins solely dedicated to self destruction would be countered by a strong selection pressure to curb or eliminate such processes. Examination of metacaspase biology provides evidence that these ancient protease forerunners of the caspase family also retain versatility in function, i.e., death and non-death cell functions. Here, we provide a critical review that highlights the non-death roles of metacaspases that have been described thus far, and the impact that these observations have for our understanding of the evolution and cellular utility of this protease family. PMID- 22837987 TI - Challenging the conventional wisdom of primary care medicine. PMID- 22837986 TI - Non-targeted effects of photon and particle irradiation and the interaction with the immune system. AB - Ionizing irradiation is an important clinical approach to treat solid tumors. Modern radiation technologies aim to selectively kill tumor cells and protect the surrounding normal tissue. The standard paradigm for radiation effects in cellular systems involves damage of the DNA including DNA double-strand breaks, which are considered as most effective in destroying tumor cells. Due to their enhanced physical and radiobiological properties, high-linear energy transfer radiation qualities are of special interest in tumor therapy. Future radiation therapy strategies aim to utilize carbon ions to effectively treat highly aggressive tumors. More recently, evidence is emerging for non-DNA targeted effects of radiation, including mutations, chromosomal aberrations, and changes in gene expression, which can occur in cells that were not directly exposed to radiation. Radiation oncologists are only gradually beginning to appreciate the clinical relevance of radiation-induced bystander effects, genomic instability, and abscopal effects. Since these effects are sensed by the immune system, a combination of immunotherapy and irradiation presents a new therapeutic opportunity in the future. PMID- 22837985 TI - Adhesion receptors as therapeutic targets for circulating tumor cells. AB - Metastasis contributes to >90% of cancer-associated mortality. Though primary tumors can be removed by surgical resection or chemo/radiotherapy, metastatic disease is a great challenge to treatment due to its systemic nature. As metastatic "seeds," circulating tumor cells (CTCs) are believed to be responsible for dissemination from a primary tumor to anatomically distant organs. Despite the possibility of physical trapping of CTCs in microvessels, recent advances have provided insights into the involvement of a variety of adhesion molecules on CTCs. Such adhesion molecules facilitate direct interaction with the endothelium in specific tissues or indirectly through leukocytes. Importantly, significant progress has been made in understanding how these receptors confer enhanced invasion and survival advantage during hematogenous circulation of CTCs through recruitment of macrophages, neutrophils, platelets, and other cells. This review highlights the identification of novel adhesion molecules and how blocking their function can compromise successful seeding and colonization of CTCs in new microenvironment. Encouraged by existing diagnostic tools to identify and isolate CTCs, strategic targeting of these adhesion molecules to deliver conventional chemotherapeutics or novel apoptotic signals is discussed for the neutralization of CTCs in the circulation. PMID- 22837988 TI - The elution of colistimethate sodium from polymethylmethacrylate and calcium phosphate cement beads. AB - Gram-negative bacilli resistance to all antibiotics, except for colistimethate sodium (CMS), is an emerging healthcare concern. Incorporating CMS into orthopedic cement to treat bone and soft-tissue infections due to these bacteria is attractive, but the data regarding the elution of CMS from cement are conflicting. The in vitro analysis of the elution of CMS from polymethylmethacrylate (PMMA) and calcium phosphate (CP) cement beads is reported. PMMA and CP beads containing CMS were incubated in phosphate-buffered saline and the eluate sampled at sequential time points. The inhibition of the growth of a strain of Acinetobacter baumannii complex by the eluate was measured by disk diffusion and microbroth dilution assays, and the presence of CMS in the eluate was measured by mass spectroscopy. Bacterial growth was inhibited by the eluate from both PMMA and CP beads. Mass spectroscopy demonstrated greater elution of CMS from CP beads than PMMA beads. The dose of CMS in PMMA beads was limited by failure of bead integrity. CMS elutes from both CP and PMMA beads in amounts sufficient to inhibit bacterial growth in vitro. The clinical implications of these findings require further study. PMID- 22837989 TI - Physical examination and radiographic interpretation of carpal anatomy in orthopedic residents and emergency medicine physicians. AB - The purpose of this study was to evaluate carpal anatomy proficiency in orthopedic residents as well as emergency medicine physicians. Orthopedic surgery residents and emergency medicine physicians were tested on their understanding of normal carpal anatomy using a Wrist Anatomy Assessment (WAA) score, which consists of both palpation of carpal bony landmarks and radiographic interpretation of the carpal bones. There were 89 participants in this study. Cohorts of orthopedic residents (n = 20), emergency medicine residents (n = 21), emergency medicine attending physicians (n = 26), and 4th-year medical students (22) were used. Group size was based on 100% orthopedic resident involvement. Total WAA scores (score of 17 = 100% correct) ranged from 2 to 16, with a mean of 8.6. Carpal palpation and radiographic interpretation means were both significantly better in the orthopedic resident cohort (total WAA score, 13.8), compared with either of the emergency medicine groups (resident total WAA score, 7.5; attending total WAA score, 7.2). Orthopedic residents have a better understanding of the clinical and radiographic anatomy of the carpal bones than emergency medicine residents and attending physicians. Future research to test educational interventions to improve carpal anatomy education is warranted. PMID- 22837990 TI - Measurement of anterior cruciate ligament angles in single-bundle reconstruction using the anteromedial portal. AB - The purpose of this study was to measure the graft angles of reconstructed anterior cruciate ligament (ACL) with anteromedial (AM) portal technique in single-bundle reconstruction. Between October 2007 and October 2009, a total of 53 consecutive patients receiving arthroscopic ACL reconstruction with AM portal technique were enrolled in this cohort study. The placement of ACL femoral tunnel was within the femoral footprint of ACL. All the patients underwent postoperative computed tomography scan, magnetic resonance imaging, and radiological examinations, as well as clinical evaluations. Both knees of these patients were measured to compare the ACL angles. The mean sagittal ACL angle in operated knees was 52.88 degrees +/-2.78 degrees , compared with 51.89 degrees +/-1.95 degrees in the contralateral knees (P>.05). The mean ACL-Blumensaat line angle was 4.96 degrees +/-0.77 degrees in operated knees and 4.49 degrees +/ 0.83 degrees in contralateral knees (P>.05). The computed tomography value (32.8%+/-5.6%) was also close to the position of the native femoral tunnel. Drilling the femoral tunnel through the AM portal can place the entry point of femoral tunnel precisely in the footprint, resembling the orientation of a native ACL. PMID- 22837991 TI - Suprapatellar pouch ganglion cyst managed with arthroscopic excision: a case report. AB - This report highlights the first known case of an intra-articular ganglion cyst of the suprapatellar pouch. The patient presented with insidious-onset medial knee pain, swelling, and progressive dysfunction. Initial imaging was negative for pathology. More extensive thigh imaging led to the diagnosis. The patient was treated successfully with arthroscopic excision and was symptom-free at final follow-up. PMID- 22837992 TI - Glenohumeral joint sepsis after magnetic resonance imaging arthrogram. AB - A 65-year-old patient presented with right shoulder pain that had increased in severity over the preceding 2 days. The pain began after the patient had a gadolinium arthrogram for magnetic resonance imaging for rotator cuff evaluation. Examination and laboratory test findings were consistent with a septic glenohumeral joint and emergent arthroscopic irrigation and debridement were performed. Streptococcus sanguinis was isolated from the intraoperative culture, and the infection resolved after a course of antibiotics. PMID- 22837993 TI - Alternative bearings in total knee arthroplasty. AB - Total knee arthroplasty (TKA) is durable and reliable to relieve pain and improve function in patients with end stage arthritis of the knee joint. However, the demographics of patients undergoing TKA is changing; younger and more active patients are electing to undergo knee replacement surgery. In recent years, improvements in design, polyethelyne, and materials promise to reduce wear and improve the durability of TKA further. In this article we review these improvements, including cross-linked polyethelyne, mobile bearings, and alternative bearing surfaces used in TKA. PMID- 22837994 TI - Technical pearls for hip arthroscopy in the management of synovial chondromatosis. AB - Synovial chondromatosis of the hip is often underdiagnosed. A high index of suspicion and good quality imaging studies are therefore essential. A wide array of long and curved instrumentation is needed at surgery. Efficient use of time and an organized surgical approach are critical to decrease joint distraction time and potential complications. A successful outcome, with pain relief and return of joint function and range of motion, is predicated on incremental follow up. PMID- 22837995 TI - D-dimer as an applicable test for detection of posttraumatic deep vein thrombosis in lower limb fracture. AB - Measuring the plasma levels of D-dimer is an accurate and easy modality to detect deep vein thrombosis (DVT) in nontraumatic settings. However, the diagnostic reliability of D-dimer assays in detecting posttraumatic DVT among patients with lower limb fracture undergoing orthopedic surgery is not validated. In this study, 141 patients with lower limb fracture admitted through the emergency department and undergoing orthopedic surgery were enrolled. Postoperative venous blood samples for D-dimer assay were taken on the 1st, 7th, and 28th postoperative days. Color Doppler sonography examination of both lower limbs was performed at the same time as a standard test. Eight out of the 141 patients (6%) had acute DVT based on Color Doppler sonography. Mean D-dimer was 2160 ng/mL in DVT positive patients and 864 in DVT negative patients. D-dimer levels greater than 1000 ng/mL were 100% sensitive and 71% specific for detecting postoperative DVT. D-dimer assay is a useful and sensitive test for detecting posttraumatic DVT. PMID- 22837996 TI - Correlation between cervical spine sagittal alignment and clinical outcome after anterior cervical discectomy and fusion. AB - Studies have shown that maintenance of lordosis improves outcomes after anterior cervical discectomy and fusion (ACDF). The relationship between maintenance or restoration of lordosis after ACDF and health-related quality of life (HRQOL) measures has not been evaluated. Preoperative and 2-year postoperative cervical lordosis (C2-C7) and segmental lordosis were measured from upright lateral cervical spine radiographs in patients who had ACDF. Data on the Neck Disability Index (NDI), Short- Form-36 Physical Composite Summary Score, arm, and neck pain scores were also collected. Paired t-tests were used to compare preoperative and 2-year postoperative radiographic measures and HRQOL measures. Receiver operating characteristic curves were constructed to identify sagittal parameters that predict achievement of a Minimum Clinically Important Difference (MCID) in outcome measures. One hundred one patients (75 female; mean age, 52 years) were included. There was improvement in all HRQOL measures from preoperative to 2 years postoperative. There was no significant difference in preoperative and 2-year postoperative sagittal alignment. Receiver operating characteristic curve analysis showed that a postoperative cervical lordosis of at least 6 degrees predicted achievement of MCID for NDI (8 point change in NDI). This suggests that maintenance or restoration of overall cervical lordosis is important in achieving a successful result after ACDF. PMID- 22837997 TI - Traumatic C4-C5 unilateral facet dislocation with posterior disc herniation above a prior anterior fusion. AB - We report the case of a unilateral cervical facet dislocation above the level of a prior non-instrumented cervical discectomy and fusion, resulting in incomplete neurologic injury. Pre-reduction imaging demonstrated a large posterior disk extrusion. This finding altered our management approach from closed reduction to urgent anterior cervical discectomy, open anterior reduction, and fusion. The patient had excellent neurologic recovery and outcome at 12 months postoperative follow-up. PMID- 22837998 TI - What is the role of autologous blood transfusion in major spine surgery? AB - Major spine surgery is associated with significant blood loss, which has numerous complications. Blood loss is therefore an important concern when undertaking any major spine surgery. Blood loss can be addressed by reducing intraoperative blood loss and replenishing perioperative blood loss. Reducing intraoperative blood loss helps maintain hemodynamic equilibrium and provides a clearer operative field during surgery. Homologous blood transfusion is still the mainstay for replenishing blood loss in major spine surgery across the world, despite its known adverse effects. These significant adverse effects can be seen in up to 20% of patients. Autologous blood transfusion avoids the risks associated with homologous blood transfusion and has been shown to be cost-effective. This article reviews the different methods of autologous transfusion and focuses on the use of intraoperative cell salvage in major spine surgery. Autologous blood transfusion is a proven alternative to homologous transfusion in major spine surgery, avoiding most, if not all of these adverse effects. However, autologous blood transfusion rates in major spine surgery remain low across the world. Autologous blood transfusion may obviate the need for homologous transfusion completely. We encourage spine surgeons to consider autologous blood transfusion wherever feasible. PMID- 22837999 TI - Oral parafunction, pain, and the dental occlusion. PMID- 22838000 TI - Occlusal factors are not related to self-reported bruxism. AB - AIMS: To estimate the contribution of various occlusal features of the natural dentition that may identify self-reported bruxers compared to nonbruxers. METHODS: Two age- and sex-matched groups of self-reported bruxers (n = 67) and self-reported nonbruxers (n = 75) took part in the study. For each patient, the following occlusal features were clinically assessed: retruded contact position (RCP) to intercuspal contact position (ICP) slide length (< 2 mm was considered normal), vertical overlap (< 0 mm was considered an anterior open bite; > 4 mm, a deep bite), horizontal overlap (> 4 mm was considered a large horizontal overlap), incisor dental midline discrepancy (< 2 mm was considered normal), and the presence of a unilateral posterior crossbite, mediotrusive interferences, and laterotrusive interferences. A multiple logistic regression model was used to identify the significant associations between the assessed occlusal features (independent variables) and self-reported bruxism (dependent variable). RESULTS: Accuracy values to predict self-reported bruxism were unacceptable for all occlusal variables. The only variable remaining in the final regression model was laterotrusive interferences (P = .030). The percentage of explained variance for bruxism by the final multiple regression model was 4.6%. This model including only one occlusal factor showed low positive (58.1%) and negative predictive values (59.7%), thus showing a poor accuracy to predict the presence of self reported bruxism (59.2%). CONCLUSION: This investigation suggested that the contribution of occlusion to the differentiation between bruxers and nonbruxers is negligible. This finding supports theories that advocate a much diminished role for peripheral anatomical-structural factors in the pathogenesis of bruxism. PMID- 22838001 TI - Effects of experimental occlusal interferences in individuals reporting different levels of wake-time parafunctions. AB - AIMS: To test the hypothesis that the effects of an experimental occlusal interference differ between individuals reporting a high or low frequency of wake time oral parafunctions. METHODS: Study participants reporting very high (HFP group; n = 10) or very low (LFP group; n = 10) levels of oral parafunctions were selected by means of a questionnaire administered to 200 medical students. The selected participants wore an experimental occlusal interference in a single blind longitudinal study, which comprised different occlusal conditions: interference free (IFC) and active occlusal interference (AIC). Assessments included clinical examination, measurements of nonfunctional tooth contacts, state and trait anxiety, and visual analog scale scores for occlusal discomfort, masticatory muscle pain, and headache. Data were analyzed by repeated measures twoway analysis of variance on ranked data, followed by calculation of within- and between-group differences using Friedman tests and Mann-Whitney tests, respectively. RESULTS: During AIC, the frequency of nonfunctional tooth contacts significantly decreased in both groups (median [interquartile range, IQR]: in HFP from 55.3% [60.0%] to 31.1% [33.5%], P = .03; in LFP from 31.8% [32.4%] to 14.0% [22.8%], P < .01), the decrease being more pronounced in LFP than in HFP (P < .01). Trait anxiety was significantly higher (P = .01) in the HFP group (median, IQR = 22.5, 9.0) than in the LFP group (median, IQR = 19.0, 3.0). The interference caused more occlusal discomfort in the HFP group than in the LFP group (P = .02) and was associated with a significant increase of masticatory muscle pain (P = .05) and headache (P = .04) only in the HFP group. CONCLUSION: The application of an experimental occlusal interference has a different effect in individuals reporting a high or low frequency of oral parafunctions. PMID- 22838002 TI - Tooth contact versus clenching: oral parafunctions and facial pain. AB - AIMS: To test the hypothesis that estimates of time spent in tooth contact are significantly greater than estimates of time spent clenching, and to test the hypothesis that tooth contact is greater in pain patients, particularly those reporting facial or head pain, than those with pain elsewhere in the body. METHODS: An anonymous, voluntary, confidential questionnaire was administered to 235 patients seeking care at a general medical clinic. The questionnaire assessed demographic variables, presence and location of pain, and percentage of time spent in tooth contact and in clenching. Analysis of variance was used to examine differences among groups of patients; logistic regression was used to identify significant predictors of pain. RESULTS: All patients reported that the percentage of time spent in tooth contact was significantly greater than the time spent clenching. The same pattern of results emerged for those with and without head pain, and those with and without any chronic pain problem. Both tooth contact and clenching were significantly associated with head pain. CONCLUSION: Results from the logistic regressions provide convergent validity on the importance of oral parafunctions, specifically tooth contact and clenching, to facial/head pain. For assessment of oral parafunctional behaviors, inquiries that utilize clear behavioral referents (tooth contact versus clenching) are likely to result in more accurate estimates than behaviors with unclear definitions. PMID- 22838003 TI - Stress-related adaptive versus maladaptive coping and temporomandibular disorder pain. AB - AIMS: To test whether patients with temporomandibular disorder (TMD) pain differ from subjects from the general population with regard to their stress-related coping styles. METHODS: Consecutive adult TMD patients (n = 70) and adult subjects of a regional general population sample (n = 868), examined according to the German version of the Research Diagnostic Criteria for TMD (RDC/TMD), were included in this study. The inclusion criterion for TMD patients was at least one pain-related diagnosis according to the RDC/ TMD, while general-population subjects were excluded if they had any pain-related TMD diagnosis. Coping styles were assessed using a common and well-accepted German 114-item stress-coping questionnaire ("Stressverarbeitungsfragebogen" SVF 114). The coping style-TMD pain relationship was investigated using logistic regression analyses adjusted for possible confounders (age, sex, level of education), as well as the influence of psychosocial measures (RDC/TMD Axis II). Odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Study participants who used fewer adaptive coping styles (OR = 0.47, CI: 0.26-0.83) and more maladaptive coping styles (OR = 1.55, CI: 1.05-2.29) were at greater risk for TMD pain. After adjustment for sociodemographic confounders, the coping style-TMD pain relationship changed only slightly in magnitude. In an analysis adjusted for sociodemographic confounders and psychosocial RDC/TMD Axis II measures, adaptive coping styles were even more profoundly related to TMD pain (OR: 0.27, 95 CI: 0.09-0.83), but maladaptive coping styles were less related to TMD pain (OR: 1.17, 95% CI: 0.51-2.72). CONCLUSION: Differences in the applied stress-related coping styles of TMD patients and subjects without TMD may have implications for clinical decision making and choosing among treatment alternatives. PMID- 22838004 TI - Experimental stressors alter hypertonic saline-evoked masseter muscle pain and autonomic response. AB - AIMS: To test in a randomized controlled trial, if hypertonic saline (HS)-evoked pain and autonomic function are modulated by either a cold pressor test (CPT) or mental arithmetic stress induced by a paced auditory serial addition task (PASAT). METHODS: Fourteen healthy women participated in three sessions. Pain was induced by two 5% HS infusions (5 minutes each, 30 minutes apart) infused into the masseter muscle. During the second HS infusion, pain was modulated by PASAT, CPT, or control (HS alone). HS-evoked pain intensity was scored on a 0 to 10 numeric rating scale (NRS). Heart rate variability (HRV) and hemodynamic measures were recorded noninvasively (Task Force Monitor). Data were analyzed using repeated measurements ANOVAs and Spearman correlation analysis. RESULTS: HS evoked pain was significantly and similarly reduced by both PASAT (30.8 +/- 27.6%; P < .001) and CPT (35.8 +/- 26.6%; P < .001) compared with the control session (9.0 +/- 30.5%; P > .05). PASAT and CPT increased the heart rate compared with control (P <.001). CPT reduced measures of vagal activity: Root mean square successive difference, high-frequency (HF) power, and coefficient of HF component variance compared with an internal control, ie, the first HS infusion (P < .05), while PASAT did not alter any of these HRV measures (P > .05). CONCLUSION: CPT and PASAT reduced HS-evoked masseter muscle pain and altered the autonomic response. The increase in heart rate following CPT and PASAT may be caused by different mechanisms. CPT reduced measures of efferent cardiac vagal (parasympathetic) activity, while the PASAT-induced increase in heart rate, but unchanged HRV, may suggest neurohumoral activation. PMID- 22838005 TI - Care seeking for orofacial pain. AB - AIMS: To determine the contribution of a wide range of factors to care-seeking behavior in orofacial pain patients, expressed as (A) decision to seek care and (B) number of health care practitioners visited. METHODS: Subjects with orofacial pain complaints were recruited in seven TMD clinics and from a nonclinical population sample. They received a questionnaire including a wide range of possible predictors. To study which predictive variables were associated with the decision to seek care and with the number of health care practitioners visited, multiple regression models were built. RESULTS: Two hundred three persons with orofacial pain participated in the study. Of these participants, 169 (140 females) had visited at least one health care practitioner (care seekers), while the other 34 persons (25 females) did not (non-care seekers). The decision to seek care was not only associated with the pain intensity (P < .05), but, in women, also with fear of jaw movements (P < .01): Women with more fear of jaw movements were more likely to seek care. Pain intensity and disability were not associated with the number of health care practitioners visited. Instead, the main predictors were catastrophizing (P = .004) and the use of painkillers (P = .008). CONCLUSIONS: Pain intensity and fear of jaw movements play an important role in the decision to seek care for orofacial pain. The continuous search for help is associated with catastrophizing and the use of painkillers. PMID- 22838006 TI - Self-reported impact on daily life activities related to temporomandibular disorders, headaches, and neck-shoulder pain among women in a Sami population living in Northern Sweden. AB - AIMS: To analyze the influence of frequency, intensity, and duration of temporomandibular disorders (TMD), headaches, and neckshoulder pain (NSP) on Sami women's daily life. A further aim was to analyze the relationship between these symptoms and age. METHODS: All 751 Sami women 21 to 70 years old registered in either the Swedish Sami Parliament's electoral register or registered as reindeer owners or herders and living north of the Arctic Circle in Sweden were sent a questionnaire regarding TMD symptoms, NSP, and headaches. In total, 487 women (65%) participated. The questionnaire focused on symptom frequency, duration, and intensity and whether these symptoms influenced activities of daily life. The symptom's interference with daily life activities was measured, respectively, with a numerical rating scale (NRS). The statistical analyses included multiple logistic regression analysis and Chi-square test. A P value < .05 was considered statistically significant. RESULTS: Seventeen percent of the women reported that symptoms in the jaw-face region to some degree disturbed their daily life, and for 6%, the interference was significant (>= 5 on NRS). Duration of jaw pain, troublesome impaired jaw opening, and neck pain, together with a low education level, affected reports of whether symptoms of TMD influenced daily life. Almost half of the study population reported that headaches had a negative impact on their life. A similar pattern was reported for NSP. The prevalence of frequent and troublesome symptoms of TMD and headaches, but not NSP, showed a declining trend with age. CONCLUSION: TMD symptoms, headaches, and NSP negatively influence many Sami women's daily life. Factors related to pain had the greatest influence when these Sami women rated the related impairment. PMID- 22838007 TI - Comparison of techniques for evaluation of deep pain sensitivity in the craniofacial region. AB - AIMS: To determine whether a new palpometer and manual palpation can detect site to-site differences in human craniofacial pain sensitivity in a similar pattern to that of an electronic pressure algometer and subsequently to compare between session and within-session variability of palpometer and manual palpation. METHODS: Sixteen volunteers participated. Experiment 1 was carried out in two sessions. In session 1, pressure pain thresholds (PPT) were determined with a pressure algometer at nine craniofacial sites. Manual palpation and the palpometer were then applied to all sites, and subjects scored perceived pressure/pain on a 0 to 100 numerical rating scale (NRS). Mean scores were compared using analysis of variance (ANOVA). Ten of the volunteers were recalled for a second session and the same protocol was carried out except for assessment of PPTs to establish between-session variability. In experiment 2, three craniofacial sites were examined using the palpometer and manual palpation. Both techniques were repeated 10 times at each site and coefficient of variation (CV) was compared to determine within-session variability. RESULTS: There were no significant differences in NRS scores evoked by manual palpation or palpometer at any test site between repeated sessions. The CV varied between techniques, with lower within-session variability for the palpometer compared with manual palpation (P = .03). CONCLUSION: The palpometer and manual palpation could detect differences in craniofacial sensitivity in healthy subjects, with no significant differences between repeated sessions. All techniques showed the highest sensitivity at the retromandibular site and the lowest at the temporalis muscle site. The palpometer had lower within-session variability compared with manual palpation. PMID- 22838008 TI - Does hypoxia-reperfusion injury occur in osteoarthritis of the temporomandibular joint? AB - AIMS: To determine the available evidence in the literature for whether hypoxia reperfusion injury plays a role in the pathogenesis of joint diseases in general and of osteoarthritis (OA) of the temporomandibular joint (TMJ) in particular. METHODS: The electronic databases CENTRAL, PubMed, and EMBASE were systematically searched. The search strategy combined thesaurus terms "reperfusion injury" and "joints" and excluded "tourniquet," which possibly induces iatrogenic reperfusion injury. Inclusion and exclusion criteria were applied, data were extracted, and quality was assessed. RESULTS: Four studies could be included, investigating four different aspects of the hypoxia-reperfusion mechanism in joints. All studies investigated several arthritides in the knee or shoulder joint and were observational studies, except for one section of one of the studies, which was a randomized controlled trial. These studies do not provide any evidence to support or reject the hypothesis that hypoxia reperfusion occurs in TMJ OA. Positive but weak evidence is provided to support the hypothesis that hypoxia-reperfusion injury occurs in OA of the knee joint. Furthermore, some results of the included studies suggest differences between OA and other types of arthritis in relation to the hypoxia-reperfusion mechanism. CONCLUSION: There is no evidence to support or reject the hypothesis that hypoxia reperfusion occurs in TMJ OA, and limited evidence is provided to support that hypoxia-reperfusion injury occurs in OA of the knee joint. Since the studies suggest differences between OA and other types of arthritis in relation to hypoxia-reperfusion mechanisms, further research in this field needs to distinguish OA from other types of arthritis. PMID- 22838009 TI - Case report: an orofacial pain patient with spots on the brain-multiple sclerosis versus central systemic lupus erythematosus. AB - Orofacial pain bridges an important gap between medicine and dentistry. This article presents the case of a man who reported preauricular pain, tinnitus, and vertigo that began after extraction of an impacted third molar and who was sent for evaluation of a possible temporomandibular joint disorder. However, he was subsequently found to have markers and imaging results consistent with recurrent and more centralized lupus and/or multiple sclerosis. PMID- 22838010 TI - Accreditation scheme for online retailers of veterinary medicines. PMID- 22838011 TI - Vet checks to continue, says Kennel Club. PMID- 22838012 TI - IAH awarded L38 million as part of strategic research programme. PMID- 22838013 TI - Call for human factors to be considered in animal disease outbreaks. PMID- 22838014 TI - International award for FMD researcher. PMID- 22838015 TI - France recalls certain tick and flea collars for pets. PMID- 22838017 TI - Northern Ireland disease surveillance, January to March 2012. PMID- 22838018 TI - Clinical Cardiology began as a family affair. AB - Richard Conti steps down as editor-in-chief and ushers in a new phase of the journal's history under the leadership of John Camm. PMID- 22838019 TI - Clinical development of catheter-based therapy for arterial hypertension. AB - Prof. Ulf Landmesser briefly discusses the latest news for this new treatment modality for hypertension. PMID- 22838020 TI - Should cardiologists tell patients to brush their teeth? PMID- 22838021 TI - The discovery of troponin: its consequences and benefits. AB - Profs Hugo Katus and Christian Hamm discuss with Emma Wilkinson how their work on troponin has improved the diagnosis and treatment of acute coronary syndromes. PMID- 22838022 TI - How the UK is attempting to boost its life sciences industry and speed up the adoption of innovation at the bedside. PMID- 22838024 TI - Year-class coexistence in biennial plants. AB - I extend the well known and biologically well motivated Skellam model of plant population dynamics to biennial plants. The model has two attractors: either one year class competitively excludes the other, resulting in 2-cycles with only vegetative vs only flowering plants in alternating years, or the two year classes coexist at an interior equilibrium. Contrary to earlier models, these two attractors can exist also simultaneously. I investigate the robustness of the model by including delayed flowering, a common phenomenon in plants, and provide a full numerical bifurcation analysis of the generalized model. High fecundity implies strong competition within year classes and promotes coexistence, whereas high survival results in strong competition between year classes and promotes competitive exclusion. Delayed flowering tends to stabilize the interior equilibrium, but (unlike in density-independent matrix models) the population cycles are robust with respect to some delay in flowering. PMID- 22838025 TI - Clines with partial panmixia in an unbounded unidimensional habitat. AB - In geographically structured populations, global panmixia can be regarded as the limiting case of long-distance migration. The effect of incorporating partial panmixia into diallelic single-locus clines maintained by migration and selection in an unbounded unidimensional habitat is investigated. Migration and selection are both weak. The former is homogenous and isotropic; the latter has no dominance. The population density is uniform. A simple, explicit formula is derived for the maximum value beta(0) of the scaled panmictic rate beta for which a cline exists. The former depends only on the asymptotic values of the scaled selection coefficient. If the two alleles have the same average selection coefficient, there exists a unique, globally asymptotically stable cline for every beta >= 0. Otherwise, if beta >= beta(0), the allele with the greater average selection coefficient is ultimately fixed. If beta < beta(0), there exists a unique, globally asymptotically stable cline, and some polymorphism is retained even infinitely far from its center. The gene frequencies at infinity are determined by a continuous-time, two-deme migration-selection model. An explicit expression is deduced for the monotone cline in a step-environment. These results differ fundamentally from those for the classical cline without panmixia. PMID- 22838023 TI - Individual versus collective fibroblast spreading and migration: regulation by matrix composition in 3D culture. AB - Extracellular matrix (ECM) supplies both physical and chemical signals to cells and provides a substrate through which fibroblasts migrate during wound repair. To directly assess how ECM composition regulates this process, we used a nested 3D matrix model in which cell-populated collagen buttons were embedded in cell free collagen or fibrin matrices. Time-lapse microscopy was used to record the dynamic pattern of cell migration into the outer matrices, and 3D confocal imaging was used to assess cell connectivity and cytoskeletal organization. Corneal fibroblasts stimulated with PDGF migrated more rapidly into collagen as compared to fibrin. In addition, the pattern of fibroblast migration into fibrin and collagen ECMs was strikingly different. Corneal fibroblasts migrating into collagen matrices developed dendritic processes and moved independently, whereas cells migrating into fibrin matrices had a more fusiform morphology and formed an interconnected meshwork. A similar pattern was observed when using dermal fibroblasts, suggesting that this response is not unique to corneal cells. We next cultured corneal fibroblasts within and on top of standard collagen and fibrin matrices to assess the impact of ECM composition on the cell spreading response. Similar differences in cell morphology and connectivity were observed - cells remained separated on collagen but coalesced into clusters on fibrin. Cadherin was localized to junctions between interconnected cells, whereas fibronectin was present both between cells and at the tips of extending cell processes. Cells on fibrin matrices also developed more prominent stress fibers than those on collagen matrices. Importantly, these spreading and migration patterns were consistently observed on both rigid and compliant substrates, thus differences in ECM mechanical stiffness were not the underlying cause. Overall, these results demonstrate for the first time that ECM protein composition alone (collagen vs. fibrin) can induce a switch from individual to collective fibroblast spreading and migration in 3D culture. Similar processes may also influence cell behavior during wound healing, development, tumor invasion and repopulation of engineered tissues. PMID- 22838026 TI - Movement patterns, social dynamics, and the evolution of cooperation. AB - The structure of social interactions influences many aspects of social life, including the spread of information and behavior, and the evolution of social phenotypes. After dispersal, organisms move around throughout their lives, and the patterns of their movement influence their social encounters over the course of their lifespan. Though both space and mobility are known to influence social evolution, there is little analysis of the influence of specific movement patterns on evolutionary dynamics. We explored the effects of random movement strategies on the evolution of cooperation using an agent-based prisoner's dilemma model with mobile agents. This is the first systematic analysis of a model in which cooperators and defectors can use different random movement strategies, which we chose to fall on a spectrum between highly exploratory and highly restricted in their search tendencies. Because limited dispersal and restrictions to local neighborhood size are known to influence the ability of cooperators to effectively assort, we also assessed the robustness of our findings with respect to dispersal and local capacity constraints. We show that differences in patterns of movement can dramatically influence the likelihood of cooperator success, and that the effects of different movement patterns are sensitive to environmental assumptions about offspring dispersal and local space constraints. Since local interactions implicitly generate dynamic social interaction networks, we also measured the average number of unique and total interactions over a lifetime and considered how these emergent network dynamics helped explain the results. This work extends what is known about mobility and the evolution of cooperation, and also has general implications for social models with randomly moving agents. PMID- 22838028 TI - Implementing geriatric models of care: a role of the gerontological clinical nurse specialist-part I. PMID- 22838029 TI - The evolution of the GNP-NCGNP the second decade -- the 1990s. PMID- 22838027 TI - A universal scaling law determines time reversibility and steady state of substitutions under selection. AB - Monomorphic loci evolve through a series of substitutions on a fitness landscape. Understanding how mutation, selection, and genetic drift drive this process, and uncovering the structure of the fitness landscape from genomic data are two major goals of evolutionary theory. Population genetics models of the substitution process have traditionally focused on the weak-selection regime, which is accurately described by diffusion theory. Predictions in this regime can be considered universal in the sense that many population models exhibit equivalent behavior in the diffusion limit. However, a growing number of experimental studies suggest that strong selection plays a key role in some systems, and thus there is a need to understand universal properties of models without a priori assumptions about selection strength. Here we study time reversibility in a general substitution model of a monomorphic haploid population. We show that for any time-reversible population model, such as the Moran process, substitution rates obey an exact scaling law. For several other irreversible models, such as the simple Wright-Fisher process and its extensions, the scaling law is accurate up to selection strengths that are well outside the diffusion regime. Time reversibility gives rise to a power-law expression for the steady-state distribution of populations on an arbitrary fitness landscape. The steady-state behavior is dominated by weak selection and is thus adequately described by the diffusion approximation, which guarantees universality of the steady-state formula and its applicability to the problem of reconstructing fitness landscapes from DNA or protein sequence data. PMID- 22838030 TI - A clearer national picture of assisted living. PMID- 22838031 TI - Improving health care of older adults: continuing the journey 2012 NICHE Conference. PMID- 22838032 TI - [Tuberculosis annual report 2010--(1) Summary of tuberculosis notification statistics in 2010]. AB - Annual reports of tuberculosis (TB) statistics in Japan have been compiled mainly from the database of the nationwide computerized tuberculosis surveillance system, which has been in operation since 1987. This system has been revised several times. The latest revision was conducted in 2007, and much new information was added. This summary of tuberculosis notification statistics is the first report of a new series for the Tuberculosis Annual Report 2010. The statistics are summarized as follows: The TB notification rate fell below 20 per 100,000 in 2007 and continued to decline, reaching 18.2 in 2010. However, there were still 23,261 TB patients newly notified in 2010. For sputum-smear positive pulmonary TB, the patient count was 9,019, with an incidence rate of 7.0 per 100,000 in 2010. Since June 2007, it has been compulsory to notify patients with latent TB infections (LTBI) requiring treatment; the number notified in 2010 was 4,930. PMID- 22838033 TI - Top 50 largest nursing facility companies. 2012. Ancillary services still growing. PMID- 22838034 TI - Top 40 assisted living companies. 2012. Most offer independent living. PMID- 22838035 TI - Non-surgical valve replacement may be better than standard therapy. Patients too sick for surgery can benefit from a catheter-based procedure. PMID- 22838036 TI - Treat atrial fibrillation to reduce cognitive dysfunction risks. Reducing the amount of time spent in AFib is the key. PMID- 22838037 TI - Losing belly fat helps improve blood vessel function. A recent study suggests that the type of diet is less important to heart health than the weight-loss result. PMID- 22838038 TI - Bariatric surgery may improve and reverse diabetes. Cleveland Clinic study shows procedure can lead to fewer medications. PMID- 22838039 TI - Research explains how sleep duration affects the heart. Even sleeping too many hours a night can be hazardous. PMID- 22838040 TI - I have arthritis in my spine and severe scoliosis, which keeps me bent over and not as active as I'd like. Any advice on how to exercise more when I can barely stand without support, and any special precautions I should take? I'm 80 and have a pacemaker, and have had several surgeries in the last 15 years, but I know physical activity is still important for good health. PMID- 22838041 TI - I used to take a statin, but developed myopathy and stopped. That was two years ago, but I still have muscle pain and weakness in my legs. Is there a solution or is this permanent damage? PMID- 22838042 TI - Cerebral sinus thrombosis in the 1st trimester of pregnancy. PMID- 22838043 TI - Nearly four million Californians are food insecure. AB - Food insecurity has increased significantly among low-income Californians over the last decade. According to data from the 2009 California Health Interview Survey, 3.8 million adults in households with incomes at or below 200% of the Federal Poverty Level (FPL) could not afford enough food at least once in the previous year. Low-income households with children and Spanish-speaking households suffered from the worst levels of food insecurity. Expanding nutrition assistance programs, such as the Supplemental Nutrition Assistance Program, could help reduce high rates of food insecurity among the low-income population. PMID- 22838044 TI - Reducing prenatal smoking: the role of state policies. PMID- 22838045 TI - State health insurance exchange laws: the first generation. AB - Health insurance exchanges are the centerpiece of the private health insurance reforms included in the Patient Protection and Affordable Care Act. As of May 2012, 13 states, together with the District of Columbia, had taken legal action to establish exchanges, through legislation or executive order. State implementing laws are essential to the translation of broad federal policies into specific state and market practices. Overall, the laws in the 14 jurisdictions vary, but they tend to show a common approach of according exchanges much flexibility in how they will operate and what standards they will apply to the insurance products sold. In all states, these "threshold policies" will be followed by policy decisions, expressed through regulations, guidelines, and health plan contracting and performance standards. PMID- 22838046 TI - Function of microRNA-346 and its roles in human diseases. PMID- 22838048 TI - Findings of research misconduct. PMID- 22838047 TI - Correlation between dental traumatic injuries and overjet among 11 to 17 years Indian girls with Angle's class I molar relation. AB - AIM: The present study was conducted to assess the correlation of traumatic dental injuries and overjet among school going girls of age 11 to 17 years in Pune, India. MATERIALS AND METHODS: A cross-sectional survey was carried out with 2045 school girls aged 11 to 17 years, attending public elementary schools in Pune, India. The traumatic dental injuries were assessed according to Ellis and Davey's criteria. Occlusion was recorded according to Angle's classification and overjet was measured using a WHO 621 probe. The data obtained was subjected to statistical analysis using Mann-Whitney test. RESULTS: There was a significant (Z -2.785) association between increase in overjet and occurrence of trauma. Children with increased overjet were 3.09 times more likely to have dental injuries. CONCLUSION: It can be concluded from the present study that a significant correlation exists between amount of overjet and prevalence of traumatic injuries among children. The percentage of trauma prevalence increases with the increase of overjet. CLINICAL SIGNIFICANCE: Traumatic dental injury is not a result of disease but a consequence of several factors that will accumulate throughout life if not properly treated. One of the most important factors significantly contributing to traumatic dental injuries is the anterior overjet. Hence, correction of increased anterior overjet may help in prevention of traumatic injuries. PMID- 22838049 TI - [Chronic inflammation and diseases of internal medicine. Conclusion]. PMID- 22838050 TI - Study: ED-based care coordination interventions need to fit unique needs of ED settings, providers. AB - Most health policy experts recognize that effective care coordination between the ED and other providers has the potential to improve health and reduce costs. However, researchers have found that ED-based interventions have differing rates of success, depending on the unique characteristics of the work environment, as well as the providers involved. With these caveats in mind, researchers combing through the literature on this topic have found that making care coordinators available to older patients, and having mechanisms in place to automatically set up follow-up appointments for ED patients, have demonstrated some success at improving follow-up care and reducing repeat ED utilization. Also, a new model that is just getting underway in Buffalo, NY, aims to improve care coordination through the use of community health workers who will be embedded in two metro area EDs. The approach, which has just received federal grant funding, aims to save more than $6 million over a period of three years. In anticipation of new payment models that will reward effective care coordination, experts advise ED managers to begin forming links with outside providers and organizations. Recognize that outside organizations and providers need to be willing to connect with the ED in an effective way for care coordination efforts to succeed. Consider methods for connecting high-ED utilizers with primary care as well as social services that can help patients with socioeconomic, environmental, or mental health issues. PMID- 22838051 TI - With aligned incentives, effective care coordination across multiple settings is easier to achieve. PMID- 22838052 TI - Lean-driven improvements slash wait times, drive up patient satisfaction scores. AB - Administrators at LifePoint Hospitals, based in Brentwood, TN, used lean manufacturing techniques to slash wait times by as much as 30 minutes and achieve double-digit increases in patient satisfaction scores in the EDs at three hospitals. In each case, front-line workers took the lead on identifying opportunities for improvement and redesigning the patient-flow process. As a result of the new efficiencies, patient volume is up by about 25% at all three hospitals. At each hospital, the improvement process began with Kaizen, a lean process that involves bringing personnel together to flow-chart the current system, identify problem areas, and redesign the process. Improvement teams found big opportunities for improvement at the front end of the flow process. Key to the approach was having a plan up front to deal with non-compliance. To sustain improvements, administrators gather and disseminate key metrics on a daily basis. PMID- 22838053 TI - Symposium introduction: Assessing multiple dimensions of collaboration. PMID- 22838054 TI - Testing a model of county government influence on health care safety-nets. AB - In the United States, health care is not equitably distributed. As indicated in the literature, age, income, and other socio-economic indicators contribute to substantial differences in the variety and scope of health services. The 2010 Affordable Care Act illustrates the United States' effort to bring balance and equity to the health care system. In the meantime, county governments are struggling with rising health care costs on their budgets (Eaton, 2009; Phaup, 2009; Clark, 2003), particularly health care for low-income residents (Benton, Byers, Cigler, Klase, Menzel, Salant, Streib, Svara, & Waugh, 2008). However, as learned in this study, county governments across the country continue to address the health care needs of uninsured and underinsured citizens through participation in health care safety nets. This research identifies possible county government influences on health care safety-nets. This study analyzed 123 responses from county government administrators and elected officials along with secondary data from the U.S. Census Bureau and the International City/County Manager Association using a variety of statistical techniques, culminating in structural equation modeling. These analyses provided reasonable explanation for the variation among the variables leading to network performance improvement in meeting the health care needs of uninsured and underinsured people as well as the significant influence of county government involvement. PMID- 22838055 TI - Commentary: County government influence on health care safety-nets. PMID- 22838056 TI - Inter-organizational relationships of health partnerships: characteristics of the Fulton County SPARC Program. AB - Local governments have long used partnerships and collaborations with the nonprofit and private sectors to improve services, support innovation, and save cost. Nowhere is this more evident than in the public health and human services sectors. This case study follows up on an earlier report on the attributes of a collaborative public/private-nonprofit health partnership; Fulton County, Georgia's Sickness Prevention Achieved Through Regional Collaboration program, (SPARC). Fulton County has been able to sustain its SPARC partnership despite the demise of similar efforts within the region. This study examines the characteristics of the Fulton County SPARC partnership that may have contributed to its endurance. A series of interviews and surveys were administered to Fulton County SPARC partners in 2009 and 2011 to capture operational characteristics of the partnership and the degree to which partners interacted among themselves. Results indicate that despite changes thought to strengthen the partnership, the developmental stages of partnerships and collaborations are shown to be non linear; therefore, movement from one stage to the other is not guaranteed thus warranting leaders' regular attention to both individual and organizational commitment to collaboration dynamics. PMID- 22838057 TI - Commentary: Interorganizational relationships in program delivery. PMID- 22838058 TI - From threat to opportunity: a Head Start program's response to state-funded pre K. AB - Early childhood education and childcare have traditionally been dominated by nonprofit and other grant-funded agencies. However, public education agencies are increasingly involved with early childhood education through state funded pre-K program initiatives. As public pre-school programming has steadily expanded, programs such as Head Start have to compete for enrollment. As funds for these programs are tied directly to enrollment, the sustainability of these programs is uncertain. Not all such agencies view state funded pre-K as a threat however. Some have seized this as an opportunity to improve service delivery through interagency collaboration. This case study examines the partnership between an urban school district and its local Head Start program. Responding, in part, to the potential threat from state-funded Pre-K, Head Start partnered with the school district to provide enhanced services to Head Start eligible children in the district's early childhood education programs. Through an examination of secondary data and staff surveys, the collaboration is first evaluated in terms of the use of best practices. The success of the collaboration is measured through teacher and administrator perceptions. From these results, specific recommendations for early education and childcare providers are offered. PMID- 22838059 TI - Commentary: A Head Start program's response to state-funded pre-K. PMID- 22838060 TI - Human service delivery in a multi-tier system: the subtleties of collaboration among partners. AB - This article examines the nature of interorganizational relationships that are formed within a multi-tier human service delivery system. Taking into account the hierarchical structure of a statewide initiative to support early childhood education, the study investigates the differences in the relationships between organizations at the service and administrative levels of the system. Forty-nine administrative level and 146 service delivery level relationships are evaluated. Findings indicate that organizations involved in direct service delivery form more collaborative relationships. Thus, when government provides funding for human services, policymakers must seek to balance public accountability with the advantages believed to be inherent in devolved service delivery. Furthermore, practitioners who appreciate the importance and nuances of interorganizational relationships will be in a position to better manage their organizations in an environment of increased collaborative activity and joint delivery of services. Going forward, human service systems will continue to involve organizations from the public, nonprofit, and private sector. A better understanding of how these organizations work together is crucial to the effective delivery of these essential services. PMID- 22838061 TI - Commentary: Human service delivery and interorganizational relationships. PMID- 22838062 TI - Symposium conclusion: Future research on the dimensions of collaboration. PMID- 22838063 TI - Multilayer film applications in drug delivery: what's new and where to next? PMID- 22838064 TI - The drug-delivery system could be an important factor in improving antidepressant medication compliance in primary care. PMID- 22838065 TI - Tools for eradicating HIV in the brain: prodrug dimeric inhibitors of P-gp. AB - Despite positive developments with the use of combination antiretroviral therapy, a major impediment to limiting the neurocognitive effects of HIV and eradicating HIV brain reservoirs is the penetration of these therapies across the blood-brain barrier (BBB). The focus of our work, therefore, has been to develop tools to significantly improve the penetration of antiretroviral agents to sites of HIV reservoirs, with an emphasis on the CNS. To this end, we have developed an innovative chemical approach--dimeric prodrugs of the antiretroviral agents themselves with a traceless tether. These dimeric prodrugs were designed to serve two purposes: inhibition of P-gp, the major drug efflux protein at the BBB, by occupying two substrate binding sites in the transporter; and prodrug dimers that gain entry into the endothelial cells at the BBB would revert to their monomeric forms in the reducing environment of the cytosol due to breakdown of the traceless tether, thus delivering the therapy. We have demonstrated the feasibility of this design by dimerizing the P-gp substrate and antiviral agent abacavir with a traceless tether. Abacavir dimers displayed potent inhibition of P-gp in two different cellular settings and reverted to active abacavir in the reducing environment of HIV-infected T cells, also leading to antiviral activity. Overall, these experiments point to the excellent promise for future use of dimeric prodrug inhibitors of P-gp for brain penetration of a wide range of CNS active agents that are substrates of P-gp. PMID- 22838067 TI - Novel lipoidal amine-based nanocarrier formulations for siRNA delivery. AB - BACKGROUND: Lack of safe and efficient delivery of siRNA remains the greatest hurdle for the therapeutic application of siRNA. This article reports synthesis and evaluation of novel lipoidal amine-based nanocarrier (LANC) formulations for siRNA delivery. METHOD: Physicochemical properties were analyzed for LANC formulations. siRNA delivery efficiency of LANC-siRNA complexes was determined using a luciferase reporter gene assay. Cytotoxicity of the LANC-siRNA complexes was measured by the MTS assay. Finally, cellular uptake and cytoplasmic release of siRNA were analyzed using flow cytometry. CONCLUSION: The LANC formulation facilitated siRNA uptake and release into the cytoplasm, mediating significant luciferase knockdown (70% inhibition). PMID- 22838068 TI - Distribution of effervescent inhalable nanoparticles after pulmonary delivery: an in vivo study. AB - BACKGROUND: Effervescent inhalable nanoparticles (NPs) have previously been shown to be a promising alternative to conventional lung cancer treatment in animals. This study investigates the biodistribution of effervescent inhalable NPs after a single dose administration via pulmonary route in lung cancer-bearing mice. METHODS & RESULTS: Whole-body autoradiography and confocal laser-scanning microscopy (CLSM) were used to investigate the distribution of inhalable NPs loaded in an effervescent microcarrier. Inhalable doxorubicin-loaded NPs were tagged with 14C for whole-body autoradiography, or with fluorescein isothiocyanate for CLSM imaging. After pulmonary delivery, NPs were widely disseminated in the lungs with a long retention time (24 h). The heart was radioactivity free at all time points of the study. CLSM images showed that inhalable NPs were taken up by cells and that doxorubicin was released to the cell nuclei. CONCLUSION: This is the first study to investigate the distribution of inhalable NPs in a lung cancer-bearing animal model. Inhalable NPs achieved deep lung deposition, were actively released from microcarrier particles, spread to different parts of the lung and released doxorubicin in vivo. These NP characteristics contribute to the efficacy of effervescent inhalable NPs as a lung cancer treatment. PMID- 22838069 TI - Organic cation transporters in the blood-air barrier: expression and implications for pulmonary drug delivery. AB - Studies concerning the impact that hepatic, renal and intestinal transporters have on drug disposition have been frequently reported in the literature. Surprisingly, however, little is known regarding the distribution and function of drug-transporter proteins of the lung epithelium. Many drugs (delivered to the lung) have a net positive charge and, thus, are potential substrates of organic cation transporters; currently marketed compounds (e.g., bronchodilators), as well as novel drug candidates in development, are such substrates. It is the aim of this review to summarize the current state of organic cation-transporter expression analysis in the lung and in in vitro models of bronchial and alveolar barriers. Moreover, activity of selected transporters in lung epithelium in situ and in vitro will be highlighted, and their potential role in pulmonary drug disposition will be addressed. One example included here is the transporter dependent absorption of beta2-agonists in respiratory epithelial cells. PMID- 22838066 TI - Therapeutic angiogenesis: controlled delivery of angiogenic factors. AB - Therapeutic angiogenesis aims at treating ischemic diseases by generating new blood vessels from existing vasculature. It relies on delivery of exogenous factors to stimulate neovasculature formation. Current strategies using genes, proteins and cells have demonstrated efficacy in animal models. However, clinical translation of any of the three approaches has proved to be challenging for various reasons. Administration of angiogenic factors is generally considered safe, according to accumulated trials, and offers off-the-shelf availability. However, many hurdles must be overcome before therapeutic angiogenesis can become a true human therapy. This article will highlight protein-based therapeutic angiogenesis, concisely review recent progress and examine critical challenges. We will discuss growth factors that have been widely utilized in promoting angiogenesis and compare their targets and functions. Lastly, since bolus injection of free proteins usually result in poor outcomes, we will focus on controlled release of proteins. PMID- 22838070 TI - Overview and outlook of Toll-like receptor ligand-antigen conjugate vaccines. AB - The discovery of Toll-like receptors (TLRs) facilitated our understanding of the innate and adaptive immune systems, and has raised the potential to develop novel methods of vaccine and immunotherapy. For effective vaccination, antigens and adjuvants must be administered simultaneously via the same route. Many studies have demonstrated that TLR ligands covalently coupled to the antigens have several benefits over nonconjugated antigens. This review introduces the applications of TLR ligands as vaccine adjuvants, focusing on the development of vaccines composed of antigen and TLR ligand in single molecules (TLR ligand antigen conjugates) using Pam3/2Cys, lipid A analogues, recombinant flagellin, imidazoquinoline analogues and unmethylated CpG motifs to activate immune systems through TLR2, TLR4, TLR5, TLR7/8 and TLR9, respectively. PMID- 22838071 TI - Stem cells in alginate bioscaffolds. AB - The immobilization of cells into polymeric scaffolds releasing therapeutic factors, such as alginate microcapsules, has been widely employed as a drug delivery system for numerous diseases for many years. As a result of the potential benefits stem cells offer, during recent decades, this type of cell has gained the attention of the scientific community in the field of cell microencapsulation technology and has opened many perspectives. Stem cells represent an ideal tool for cell immobilization and so does alginate as a biomaterial of choice in the elaboration of these biomimetic scaffolds, offering us the possibility of benefiting from both disciplines in a synergistic way. This review intends to give an overview of the many possibilities and the current situation of immobilized stem cells in alginate bioscaffolds, showing the diverse therapeutic applications they can already be employed in; not only drug-delivery systems, but also tissue engineering platforms. PMID- 22838072 TI - Hydrogels as drug-delivery platforms: physicochemical barriers and solutions. AB - The properties of hydrogels, in particular their high biocompatibility and water sorption uptake, make hydrogels very attractive in drug delivery and biomedical devices. These favorable features of hydrogels are compromised by certain structural limitations such as those associated with their low mechanical strength in the swollen state. This review highlights the most important challenges that may seriously affect the practical implementation of hydrogels in clinical practice and the solutions that may be applied to overcome these limitations. PMID- 22838073 TI - Hot-melt extrusion technology and pharmaceutical application. AB - The use of hot-melt extrusion (HME) within the pharmaceutical industry is steadily increasing, due to its proven ability to efficiently manufacture novel products. The process has been utilized readily in the plastics industry for over a century and has been used to manufacture medical devices for several decades. The development of novel drugs with poor solubility and bioavailability brought the application of HME into the realm of drug-delivery systems. This has specifically been shown in the development of drug-delivery systems of both solid dosage forms and transdermal patches. HME involves the application of heat, pressure and agitation through an extrusion channel to mix materials together, and subsequently forcing them out through a die. Twin-screw extruders are most popular in solid dosage form development as it imparts both dispersive and distributive mixing. It blends materials while also imparting high shear to break up particles and disperse them. HME extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier, increasing dissolution rates and bioavailability. The most common difficulty encountered in producing such dispersions is stabilization of amorphous drugs, which prevents them from recrystallization during storage. Pharmaceutical industrial suppliers, of both materials and equipment, have increased their development of equipment and chemicals for specific use with HME. Clearly, HME has been identified as an important and significant process to further enhance drug solubility and solid dispersion production. PMID- 22838074 TI - [Detection of FADD gene amplification in oral leukoplakia]. AB - The Fas-associated death domain containing protein, FADD, is an adaptor for relaying apoptotic signals. However, recent studies have shown that FADD also plays an important role in the growth and regulation of the cell cycle, and FADD gene amplifications were observed in oral squamous cell carcinoma (OSCC). The purpose of this study was to elucidate the role of FADD in oral leukoplakia, known as potentially malignant disorder. METHODS: The gene amplifications of FADD from the fresh-frozen tissues and the formalin-fixed paraffin-embedded tissues of 51 patients who underwent biopsy or surgical resection of oral leukoplakia were detected: singleplex and multiplex assays were employed. RESULTS: The gene amplifications of FADD were detected in the samples of 3 patients who were diagnosed pathologically with severe epithelial dysplasia or early invasive carcinoma. CONCLUSION: Because the gene amplifications of FADD were observed in early invasive carcinoma rather than precancerous lesions, the FADD gene amplification was not useful for the predictive marker of cancerization and is possibly related to the malignancy of OSCC including metastatic potential. PMID- 22838075 TI - Insights into a successful dual scientific career and partnership. PMID- 22838076 TI - Isolation and molecular characterization of a novel infectious pancreatic necrosis virus strain in returning Atlantic salmon Salmo salar from the Connecticut River, USA. AB - After 22 years of negative viral screening results, the viral pathogen infectious pancreatic necrosis virus (IPNV) was isolated from the ovarian fluid of two pooled samples of returning Connecticut River Atlantic salmon Salmo salar during the 2007 spawning season at Richard Cronin National Salmon Station (RCNSS), Hadley, Massachusetts. Cytopathic effect was observed in Chinook salmon embryo (CHSE-214) cells, and IPNV was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR). Sequence analysis conducted by the U.S. Geological Survey's Western Fisheries Research Center determined that the isolate closely resembled the Canada_3 strain, falling into Genogroup 4 rather than Genogroup 1, which is more common in the United States. This allowed us to speculate that the Atlantic salmon were not infected during their freshwater life stage in the Connecticut River watershed but somewhere on their migratory route or feeding grounds in the Northwest Atlantic. On November 20, 2007, the Connecticut River Atlantic Salmon Commission voted to depopulate the infected stock at RCNSS and the entire suspect egg lots held at White River National Fish Hatchery, Vermont. Approximately one and a half months later, the 121 Connecticut River Atlantic salmon were euthanized and sampled for a follow-up investigation to determine the prevalence of infection. Only one kidney-spleen homogenate (male) was confirmed IPNV positive via cell culture and RT-PCR. A total of 2,983 base pairs from segment A of the RNA genome were sequenced from this fish and determined to be from a new strain (Connecticut-1) of IPNV that closely resembles Canada_2 and Canada_3 in Genogroup 4. The new strain is genetically identical to one of the first ovarian fluid isolates over a shared 130-nucleotide region, possibly indicating original transmission from a single source. The absence of IPNV from the Connecticut River's subsequent four returning Atlantic salmon year-classes may indicate that the aggressive corrective action was prudent. PMID- 22838077 TI - Effects of metomidate hydrochloride sedation on blood glucose and marketability of transported threespot gourami Trichogaster trichopterus. AB - Our objectives were to determine whether sedation with metomidate hydrochloride (hereafter, "metomidate") during transportation of threespot gourami Trichogaster trichopterus would prevent an increase in blood glucose levels and improve fish marketability (i.e., based on appearance and behavior) in comparison with unsedated controls. Threespot gourami are obligate air-breathers that possess a labyrinth organ, enabling the fish to respire air above the water surface; these fish should be lightly sedated during transport. Fish were transported for approximately 24 h via truck and domestic airline. Blood was sampled at 0, 2, 6, and 12 h posttransport ation, and appearance and behavior were observed at 0, 2, 4, 6, and 12 h and 7 d posttransportation. Metomidate concentrations tested were 0.0 (control), 0.1, 0.2, 0.3, and 0.4 mg/L. At the concentrations tested, metomidate neither inhibited elevations in blood glucose nor improved marketability. Fish that were transported with 0.3-mg/L metomidate were less marketable based on behavioral indices, and fish that were transported with 0.4 mg/L metomidate had higher glucose levels than control fish. Use of metomidate as a transport sedative for threespot gourami should be considered with caution and may be problematic at the concentrations tested; however, further research examining additional indices of stress may clarify metomidate use for this species. PMID- 22838078 TI - Edwardsiella ictaluri as the causative agent of mortality in cultured Nile tilapia. AB - Edwardsiella ictaluri was consistently isolated from the spleens, livers, and head kidneys of diseased Nile tilapia Oreochromis niloticus from a farm experiencing mortality events in several culture ponds. We describe the first published outbreak of E. ictaluri-induced edwardsiellosis in Nile tilapia. Pure cultures of the isolated bacteria were characterized both biochemically and molecularly. Biochemical analysis was performed using the API-20E and RapID One systems, and antimicrobial susceptibility was determined by the broth microdilution method. Molecular analysis involved sequencing of the 16S rRNA gene, species-specific real-time polymerase chain reaction (PCR), and PCR mediated genomic fingerprinting (rep-PCR). Pairwise sequence analysis of the 16S rRNA gene identified the case isolates to be a 100% match to E. ictaluri cultured from channel catfish in the southeastern United States. However, rep-PCR analysis identified the case isolates to be genetically different from representative strains isolated from disease outbreaks in cultured channel catfish in Mississippi. Infectivity challenges (intraperitoneal injection and immersion) demonstrated that a representative E. ictaluri strain isolated from tilapia was pathogenic to naive tilapia, reproducing clinical signs and mortality, thereby establishing Koch's postulates. PMID- 22838079 TI - A single sea lamprey attack causes acute anemia and mortality in lake sturgeon. AB - The effects of sea lamprey Petromyzon marinus parasitism on hematological variables have not been quantified for lake sturgeon Acipenser fulvescens. Our study objectives were to (1) assess changes in lake sturgeon hematology immediately after a single sea lamprey attack and after a 2-week recovery period and (2) assess changes in the histological condition of major hematopoietic organs. Lake sturgeon from four size-groups (470-570, 570-650, 650-760, and 950 1,500 mm fork length) were individually subjected to a sea lamprey attack in a series of 55 experimental trials. Survival of lake sturgeon after a single sea lamprey attack was size dependent, with fish in smaller size-groups exhibiting higher direct and indirect mortality than individuals in larger size-classes. The most sensitive blood chemistry variable was hematocrit: each 1% decline in hematocrit resulted in a 5.1% increase in mortality risk. Other important variables were plasma protein level, with a 10-g/dL decline resulting in a 4.2% increase in mortality risk; and hemoglobin, with a 1-g/dL decline resulting in a 2.9% increase in mortality risk. Most of the surviving lake sturgeon were unable to restore hemoglobin, hematocrit, and plasma protein to pre-attack levels by the end of the 2-week recovery period. We developed an index of histological spleen condition, which indicated that short-duration (< 5-d) sea lamprey attachments depleted red blood cell reserves faster than longer-duration attacks. Our study results indicate that sea lamprey parasitism has the potential to induce acute anemia in lake sturgeon and that nonlethal attacks on smaller (< 760-mm) fish can have serious physiological implications. PMID- 22838080 TI - Correlation of parasites with growth of yellow perch. AB - The possible influence of parasites on the short-term and long-term growth and condition of yellow perch Perca flavescens was examined by investigating correlations between parasite abundance and specific growth variables. The following parasites were enumerated in age-1 yellow perch collected from Lake St. Pierre in June 2008: Apophallus brevis, Diplostomum spp., Ichthyocotylurus spp., Tylodelphys scheuringi, Phyllodistomum superbum, and Raphidascaris acus. Short term growth was estimated using RNA/DNA ratios and long-term growth via the total length and condition as measured by the Fulton index. No correlation was found between parasite abundance and short-term growth, but a negative influence of combined infections of T. scheuringi and P. superbum on long-term growth was detected. In addition, the abundance of Ichthyocotylurus spp. was positively correlated with the condition of the yellow perch. Together these results suggest that limited or subtle pathogenic effects in juvenile fish are not discernable in recent growth but only in long-term growth indices. Furthermore, in future studies examination of parasite effects on fish growth should account for multiple infections. PMID- 22838081 TI - Determination of the median lethal dose of botulinum serotype E in channel catfish fingerlings. AB - The median lethal dose of botulinum serotype E in 5.3-g channel catfish Ictalurus punctatus fingerlings was determined. Five tanks (five fish/tank) were assigned to each of the following treatment groups: 70, 50, 35, 25, or 15 pg of purified botulinum serotype E. Fish were injected intracoelomically and observed for 96 h. Administration of the toxin resulted in initial hyperactivity followed by erratic swimming, paresis, and death. The cumulative mortality by treatment group was 100% at 70 pg, 96% at 50 pg, 100% at 35 pg, 88% at 25 pg, and 56% at 15 pg. The median lethal dose was calculated as 13.7 pg/fish (equivalent to a 0.81 median lethal dose for mice Mus musculus) using a logistic regression model. All fish were necropsied; lesions included exophthalmia, ascites, splenic congestion, intussusception of the intestines, congested spleen, and blanching of the intestinal tract. The resultant clinical signs and lesions were similar to those noted in the syndrome of visceral toxicosis of catfish. This study indicates that channel catfish are more sensitive to the effects of botulinum serotype E than laboratory mice, and the signs and lesions of visceral toxicosis of catfish were replicated by injecting catfish with the toxin. PMID- 22838082 TI - Comparison of hatchery and field performance between a whirling-disease-resistant strain and the Ten Sleep strain of rainbow trout. AB - A whirling-disease-resistant strain of rainbow trout Oncorhynchus mykiss (GRHL strain) derived from a backcross of an F1 hybrid of two strains (German strain x Harrison Lake strain) with German strain females, was compared with the Ten Sleep (TS) strain of rainbow trout. The GRHL strain had consistently superior growth and feed conversion in two consecutive hatchery trials. Hatching and mortality rates were similar between strains. Both strains were stocked into two Utah reservoirs (Hyrum, Porcupine), and a third, Causey Reservoir, was monitored as a control for seasonal variation in prevalence of Myxobolus cerebralis. A total of 1,323 salmonids captured by gill net in spring and fall sampling between 2006 and 2008 were tested for M. cerebralis via pepsin-trypsin digest methods. Only eight of these (< 1% per species) had clinical signs consistent with whirling disease. In both reservoirs, GRHL survived better than the TS and had higher growth rates. The prevalence of M. cerebralis was significantly lower for GRHL (18.1%) than TS (50.0%) in Porcupine Reservoir. In Hyrum Reservoir the trend was similar, but prevalence was lower and did not significantly differ between GRHL (9.6%) and TS (23.1%). For infected fish, no significant differences were observed between strains in myxospore counts in either Hyrum (GRHL = 911-28,244 spores/fish [spf], TS = 1,822-155,800 spf) or Porcupine (GRHL = 333-426,667spf, TS = 333-230,511 spf) reservoirs. Unmarked rainbow trout in both reservoirs had significantly higher myxospore counts than stocked fish of either strain. There were significant differences in M. cerebralis prevalence and myxospore loads among other naturally reproducing salmonids in the reservoirs. The trend in susceptibility was cutthroat trout Oncorhynchus clarkii > kokanee Oncorhynchus nerka > brown trout Salmo trutta. The GRHL performed well in both hatchery and field settings and is recommended for stocking programs. PMID- 22838083 TI - Oxytetracycline pharmacokinetics in rainbow trout during and after an orally administered medicated feed regimen. AB - The pharmacokinetic-pharmacodynamic predictor of antimicrobial activity for tetracyclines is reported to be the area under the concentration-time curve at steady state (AUC(ss)) divided by the minimal inhibitory concentration of the targeted pathogen. Here, we estimate AUC(ss) values for oxytetracycline (OTC) in serum of rainbow trout Oncorhynchus mykiss by using a destructive sampling study design. Seventy-two rainbow trout were fed OTC-medicated feed at 74.7 +/- 1.5 mg/kg (mean +/- SD) body weight (BW) by oral gavage for 10 consecutive days. Serum was collected from nine fish at 1, 3, 6, 8, 10, 12, 15, and 22 d after dosing began. Serum OTC concentrations were measured by high-performance liquid chromatography with a 0.01-microg/mL limit of detection. The average OTC AUC(ss) was 29.2 microg x h/mL and was estimated using nonlinear mixed-effects modeling and bootstrap resampling techniques. The elimination half-life was estimated as 85.0 h, and the fraction of steady state achieved was estimated as 0.85. The calculated AUC(ss) (24.8 microg x h/mL) following 10 d of oral dosing with 75 mg OTC/kg BW was less than the estimated AUC(ss). Results suggest that the pharmacokinetics of OTC exposure, including the AUC(ss), is better evaluated by using multiday dosimetry than by using a standard single-dose protocol. PMID- 22838084 TI - Ozone disinfection of eggs from gilthead seabream Sparus aurata, sea bass Dicentrarchus labrax, red porgy, and common dentex Dentex dentex. AB - The risk of fish pathogen transmission via eggs can be reduced by disinfection in ozonated seawater. The aim of this study was to determine the suitable conditions for ozone disinfection of the eggs of gilthead seabream Sparus aurata, sea bass Dicentrarchus labrax, red porgy Pagrus pagrus, and common dentex Dentex dentex. The eggs were disinfected with a concentration (C) of 0.5 mg of ozone/L of water at four different exposure times (T = 2, 4, 8, and 16 min). The hatching rate was determined in triplicate for each treatment. Bacterial colonies were counted on tryptic soy agar and thiosulfate-citrate-bile salts-sucrose agar. At the end of the experiment, bacterial load and hatching rate were assessed together to determine the optimal ozone treatment values, which were estimated in CT units (i.e., C [= 0.5 mg/L] x T [min]). Optimal values were CT 2-4 (T = 4-8 min; 18 degrees C) for gilthead seabream and red porgy, CT 2 (T = 4 min; 18 degrees C) for common dentex, and CT 4 (T = 8 min; 15 degrees C) for sea bass. PMID- 22838085 TI - Vitamin D and skin of color: a call to action. AB - Knowledge regarding the determination, measurement, and supplementation of vitamin D in skin of color patients is evolving. At this time, it is believed that the majority of the skin of color population in the United States is vitamin D insufficient, which is particularly concerning given the possible links to disease states. However, further supporting evidence of insufficiency is required given recent questions regarding genetics and the applicability of normal levels across racial and ethnic groups. Finally, it is important for healthcare providers treating skin of color patients to recognize, educate, and promote the investigation of issues regarding vitamin D insufficiency and deficiency. PMID- 22838086 TI - What is your diagnosis? Urticaria multiforme. PMID- 22838087 TI - The best diagnosis is: pancreatic panniculitis. PMID- 22838088 TI - Reactive benign follicular mucinosis: a report of 2 cases. AB - We report 2 cases of adolescents who developed follicular mucinosis following cutaneous infections. A 17-year-old adolescent boy was evaluated for a 2-week history of erythematous papules and plaques on his face and neck. One month prior to presentation a culture was taken that was positive for methicillin-sensitive Staphylococcus aureus-associated impetigo. Biopsies from 2 representative lesions demonstrated follicular mucinosis without evidence of folliculotropism or T cell gene rearrangements. A separate case involved a 17-year-old adolescent girl who presented with an edematous plaque on her right preauricular region and scattered erythematous papules and small annular plaques over her face 2 weeks following a herpes simplex virus type 2 (HHV-2) infection. on her face. Biopsy showed follicular mucinosis without evidence of epidermotropism or lymphocyte atypia. There was no herpesvirus cytopathic effect. The first case rapidly responded to an oral prednisone taper and the second case resolved over several weeks without further treatment. PMID- 22838089 TI - An atypical presentation of a Pasteurella multocida infection following a cat bite: a case report. AB - Pasteurella multocida is a bacterial organism that commonly causes cellulitis after animal bites, especially cat bites. We report an unusual vesiculopustular infection of the hand following a domestic cat bite. Pasteurella multocida and Staphylococcus aureus were cultured from the wound and the patient was treated with amoxicillin-clavulanate potassium. Further history revealed that the patient's cat had nibbled on her hand. Pasteurella usually is resistant to many of the typical empiric antibiotics used to treat skin infections. Amoxicillin clavulanate potassium (500 mg 3 times daily) is the treatment of choice for patients who have an infected cat or dog bite with no known bacterial cause. A thorough patient history is needed to promptly arrive at a proper diagnosis for an atypical presentation of a common disease. PMID- 22838090 TI - Development of squamous cell carcinoma on an inflammatory linear verrucous epidermal nevus in the genital area. AB - Inflammatory linear verrucous epidermal nevus is a rare cutaneous disorder characterized by pruritic, erythematous, and verrucous papules and plaques along the lines of Blaschko. Histopathologically, there is a benign verrucous proliferation of keratinocytes together with alternating parakeratosis and orthokeratosis as well as inflammatory changes. We report a patient who developed squamous cell carcinoma (SCC) on an inflammatory linear verrucous epidermal nevus and we discuss the importance of regular follow-up of patients with epidermal nevi. PMID- 22838091 TI - Imiquimod reactivation of lichen planus. AB - A 44-year-old man who was previously diagnosed with actinic cheilitis was prescribed imiquimod cream 5%, which resulted in thick hemorrhagic crusting of the lower lip after 4 applications. He subsequently noted the development of lichen planus lesions on his arms and legs for the first time in 15 years following imiquimod use. On follow-up he also was noted to have characteristic Wickham striae on his lower lip. Lichen planus is an autoimmune inflammatory condition in which autoreactive T lymphocytes attack keratinocytes. The mechanism of action for imiquimod is upregulation of IFN-alpha and IFN-beta. Treatment with clobetasol cream 0.05% led to resolution of his lichen planus lesions. PMID- 22838092 TI - CD4+ CD56+ hematodermic neoplasm and plasmacytoid dendritic cell tumor: case report and review of the literature. AB - CD4+ CD56+ hematodermic neoplasm (HN) is a rare and aggressive neoplasm that has raised controversy regarding its etiology. CD4+ CD56+ HN is thought to be derived from plasmacytoid dendritic cells (pDCs) and most commonly stains with CD4, CD56, CD123, and T-cell leukemia/lymphoma 1 (TCL1). Skin manifestations usually are the presenting signs and vary in appearance. Lymph node involvement also is common at the time of presentation, and the natural course of the disease is a progression to leukemia. Treatment of CD4+CD56+ HN focuses on multiple chemotherapeutic regimens but none have been proven to successfully impact overall survival. PMID- 22838093 TI - Acetaminophen-induced exanthem of the breasts. AB - We describe an unusual case of a maculopapular exanthem secondary to acetaminophen use that presented on the breasts and anterior pelvis in regions of pressure from the patient's undergarments. A review of the literature regarding exanthematous drug eruptions secondary to acetaminophen use also is presented. PMID- 22838094 TI - A multicenter, double-blind study to evaluate the efficacy and safety of 2 treatments in participants with mild to moderate acne vulgaris. AB - Acne treatment regimens have changed due to the recent over-the-counter (OTC) switch of all prescription benzoyl peroxide (BPO) topical preparations. The elimination of prescription single-agent BPO products means that dermatologists must select from a variety of OTC formulations to utilize the time-tested efficacy of BPO in the treatment of mild to moderate acne. Our research compared the efficacy and safety of an OTC BPO 5.5% formulation with lipohydroxy acid and tretinoin cream 0.025% with prescription clindamycin 1%-BPO 5% gel and tretinoin cream 0.025%. Parity was demonstrated between the 2 treatment regimens at 12 weeks. PMID- 22838095 TI - What is the role of field-directed therapy in the treatment of actinic keratosis? Part 2: Commonly used field-directed and lesion-directed therapies. AB - Actinic keratosis (AK) constitutes the initial epidermal lesion in a disease continuum that may potentially progress to invasive squamous cell carcinoma (SCC). A number of treatment options are available to clear lesions and thus reduce the risk for progression to SCC. Field-directed therapies are primarily used to clear multiple AKs and subclinical lesions. Part 1 of this review explaining the role of field-directed therapy for the treatment of AK discussed the unmet needs with current therapies and the investigational agents that are being developed to fill treatment gaps. Part 2 will mainly focus on field directed therapies that currently are available for AK, such as resurfacing procedures, patient-administered topical therapy, and photodynamic therapy (PDT), as well as lesion-directed therapy, which is used to clear discrete lesions in relatively small numbers. PMID- 22838096 TI - The birth of ATLANTIC DIP: an overview. PMID- 22838097 TI - Atlantic DIP: subject recruitment, data collection, missing data management and analysis procedures. AB - This paper describes the experiences related to the universal screening study for gestational diabetes mellitus (GDM) with reference to the subject recruitment process, data collection processes, (data entry, editing, quality assurance) and statistical analysis including the importance of missing data. PMID- 22838098 TI - ATLANTIC DIP: pregnancy outcomes for women with type 1 and type 2 diabetes. AB - ATLANTIC DIP prospectively evaluated the perinatal and maternal outcomes of pregnancies complicated by Type 1 and Type 2 diabetes during 2006/2007 in 5 antenatal centres. All women with established diabetes for at least 6 months prior to the index pregnancy and booking for antenatal care between 1/1/2006 and 31/12/2007 were included in the study. Results were collected electronically via the DIAMOND Diabetes Information System. Pregnancy outcome was compared with that of the background population receiving antenatal care in the region during the same time. There were 104 singleton pregnancies during the period of study. The stillbirth rate (SBR) of 25/1000 was 5 times greater than that reported in the background population at 5/1000 and the perinatal mortality rate (PMR) of 25/1000 was 3.5 times greater than background 7/1000. The congenital malformation rate (CMR) of 24/1000 was twice that observed in the background population. Women were not well prepared for pregnancy with 28% receiving pre pregnancy care (PPC), 43% receiving pre pregnancy folic acid and 51% achieving a HbA1C < = 7% at first antenatal visit. Pregnancy induced hypertension (PIH) and/or pre eclampsia toxaemia (PET) were three times more common than in women in the background population. In conclusion women are not well prepared for pregnancy. Maternal and infant morbidity and infant mortality are greater in women with diabetes. A regional pre pregnancy care (PPC) programme and centralised glucose management are urgently needed. PMID- 22838099 TI - Changing clinical practice can improve clinical outcomes for women with pre gestational diabetes mellitus. AB - Prospective evaluation of pregnancy outcomes in women with pre-gestational diabetes over 6 years. The ATLANTIC Diabetes in Pregnancy group represents 5 antenatal centres along the Irish Atlantic seaboard, providing care for women with diabetes throughout pregnancy. In 2007 the group published a report that recognised that women were poorly prepared for pregnancy and that outcomes were sub-optimal. A change in practice occurred, offering women specialist-led, evidence-based care, both pre-pregnancy and combined antenatal/diabetes clinics during pregnancy. We now compare outcomes from 2005-2007 with 2008-2010. There was an increase in the numbers attending pre-conception care. Glycemic control before and throughout pregnancy improved. There was an overall increase in live births and decrease in perinata mortality rate. There was a decrease in large-for gestational-age babies in mothers with Type 1 Diabetes. Elective Caesarean section rates increased while emergency section rates decreased. More women had Type 2 diabetes over time and these women were more likely to be obese. Changing the process of clinical care delivery can improve outcomes in for women with pre gestational diabetes. PMID- 22838100 TI - A regional pre-pregnancy care (PPC) programme for women with type 1 and type 2 diabetes. AB - Unfortunately the risks associated with pregnancy in a woman with Diabetes (Type 1 and Type 2) continue to be high. However these risks can be reduced significantly with pregnancy planning and pre-pregnancy care. We report here the establishment of a regional pre pregnancy service and the interim results of its benefits. Pre pregnancy care is as vital as combined diabetes antenatal care for women with diabetes and must become the norm for this population. PMID- 22838101 TI - Atlantic DIP: the prevalence and consequences of gestational diabetes in Ireland. AB - ATLANTIC DIP carried out a universal screening programme for gestational diabetes mellitus (GDM) along the Irish Atlantic seaboard. Using a 75g OGTT and new International Association of Diabetes in Pregnancy Study Groups (IADPSG) cut off points for diagnosis we found the prevalence of GDM to be 12.4%. Pregnancies complicated by GDM displayed increased morbidities for mother and infant when compared to women who had normal glucose tolerance. With rising obesity levels and older age of mothers, both risk factors for GDM, these results would support a national universal screening programme. PMID- 22838102 TI - New estimates of the costs of universal screening for gestational diabetes mellitus in Ireland. AB - The new International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria have been predicted to increase the prevalence of gestational diabetes mellitus 2-to-3 fold and will have important resource implications for healthcare systems. A bottom-up, prevalence-based analysis was undertaken to estimate the costs of universal screening for gestational diabetes mellitus in Ireland using the new criteria. Healthcare activity was identified from the Atlantic Diabetes in Pregnancy database and grouped into five categories: (i) screening and testing, (ii) GDM treatment, (iii) prenatal care, (iv) delivery care, and (v) neonatal care. When individual resource components were valued using unit cost data and aggregated, the total healthcare cost was estimated at Euro 46,311,301 (95% CI: Euro 36,381,038, Euro 68,007,432). The average cost per case detected was Euro 351 (95% CI: (Euro 126, Euro 558) and the average total cost per case detected and treated was Euro 9,325 (95% CI: Euro 5,982, Euro 13,996). Further research is required to determine the cost effectiveness of screening in the region with a view to improving resource allocation in this area in the future. PMID- 22838103 TI - The impact of travel distance on the decision to attend for screening for gestational diabetes mellitus. AB - This paper estimates the impact of travel distance on the decision to attend for screening for gestational diabetes mellitus (GDM), controlling for a range of personal, clinical and lifestyle characteristics. The results suggest that women who live further away from a screening site are less likely to attend for screening. In particular, the probability of attending for screening is reduced by 1.8% [95% CI: 1.2% to 2.4%] for every additional 10 kms of travel. This is consistent wth previous research that shows geographic inequalities in access to GDM screening in Ireland. We also find that older women, those with a family history of diabetes, and those who are obese are more likely to accept the screening offer, suggesting that certain higher-risk groups may be either self selecting into the screening programme or are being targeted by health care professionals through specific initiatives. PMID- 22838104 TI - Is there a socioeconomic gradient in the prevalence of gestational diabetes mellitus? AB - Previous studies have shown an association between Type 2 diabetes and lower socioeconomic status. This link is less clear in those with gestational diabetes mellitus (GDM). We test for a socioeconomic gradient in the prevalence of GDM by analysing data on 9,842 pregnant women who were offered testing for GDM in the Atlantic Diabetes in Pregnancy universal screening programme. A bivariate probit model relating GDM prevalence to socioeconomic status was estimated, controlling for variation in screening uptake rates across socioeconomic groups. The estimated increased prevalence of GDM is 8.6% [95% CI 2.7%-12.0%] for women in the lowest socioeconomic group when compared to the highest, suggesting a strong socioeconomic gradient in the prevalence of GDM. This gradient is found to be driven by differences in personal, clinical and lifestyle factors across socioeconomic groups. PMID- 22838106 TI - Psychological stress associated with diabetes during pregnancy: a pilot study. AB - Gestational Diabetes Mellitus (GDM) affects approximately 12% of women. The impact of a diagnosis of GDM may lead to increased stress in pregnancy due to the demands of adherence to a treatment regimen and maternal concern about adverse outcomes for the mother and baby. We examined the psychosocial profile of 25 women with gestational diabetes mellitus (GDM) and compared them to 25 non diabetic pregnant women. Measures administered included the Pregnancy Experiences Scale (PES), the Depression, Anxiety Stress Scale (DASS), the Problem Areas in Diabetes Scale (PAID-5) and the Perceived Social Support Scale (PSSS). The GDM group reported a significantly greater ratio of pregnancy 'hassles' to pregnancy 'uplifts'. The GDM group also had a significantly higher Depression score and were twice as likely to score above the cut-off for possible depression. Elevated levels of diabetes-related distress were found in 40% of women with GDM. In addition, the GDM group reported less social support from outside the family. Our preliminary study indicates that the experience of GDM appears to be associated with increased psychological distress in comparison to the experience of non diabetic pregnant women. This may indicate the need for psychological screening in GDM and the provision of psychological support in some cases. PMID- 22838105 TI - The impact of maternal obesity on gestational outcomes. AB - To investigate the effects of raised maternal BMI on pregnancy outcome in glucose tolerant women, using the IADPSG criteria. Prospective observational study of fetal and maternal outcome in a cohort of pregnant women recruited to a universal screening programme for gestational diabetes under the ATLANTIC-DIP partnership. Maternal outcomes included glucose, delivery mode, pregnancy induced hypertension (PIH), preeclampsia (PET), antepartum hemorrhage (APH) and postpartum hemorrhage (PPH). Fetal outcomes included birthweight, congenital malformation, fetal death, neonatal jaundice, hypoglycemia and respiratory distress. Increasing maternal BMI was associated with adverse pregnancy outcomes: higher cesarean section rates, pre-eclamptic toxemia, pregnancy induced hypertension, increased birth weight and congenital malformation. There was also an association between normal range glucose and emergency cesarean section, hypertension of pregnancy and birthweight. In spite of tightening criteria for hyperglycemia during pregnancy, raised BMI is associated with adverse pregnancy outcome. PMID- 22838107 TI - Trimester-specific reference intervals for IFCC standardised haemoglobin A(1c): new criterion to diagnose gestational diabetes mellitus (GDM)? AB - We established trimester-specific reference intervals for IFCC standardised HbA(1c) in 311 non-diabetic Caucasian pregnant women (n = 246) and non-pregnant women (n = 65). A selective screening strategy based on risk factors for gestational diabetes was employed. Pregnancy trimester was defined as trimester 1 (T1, n = 40) up to 12 weeks + 6 days, trimester 2 (T2, n = 106) 13 to 27 weeks + 6 days, trimester 3 (T3, n = 100) > 28 weeks to delivery. The normal HbA(1c) reference interval for Caucasian non-pregnant women was 29-37 mmol/mol (DCCT: 4.8 5.5%), T1: 24-36 mmol/mol (DCCT: 4.3-5.4%), T2: 25-35 mmol/mol (DCCT: 4.4-5.4%), and T3: 28-39 mmol/mol (DCCT: 4.7-5.7%). HbA(1c) was significantly decreased in trimesters 1 (P < 0.01) and 2 (P < 0.001) compared to non-pregnant women. Retrospective application of selective screening to Caucasian women of the Atlantic DIP cohort determined that 5,208 met the criteria. 945 of those women (18.1%) were diagnosed with Gestational Diabetes Mellitus (GDM) using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) glucose concentration thresholds. HbA(1c) measurement within 2 weeks of the diagnostic Oral Glucose Tolerance Test (OGTT) was available in 622 of 945 (66%). Applying the decision threshold for T2: HbA(1c) > 35 mmol/mol (DCCT > 5.4%) identified 287 of 622 (46%) of those with GDM. HbA(1c) measurement in T2 (13 to 27 weeks) should be included in the diagnostic armamentarium for GDM. This would reduce the need for diagnostic OGTT in a significant number of women. PMID- 22838108 TI - Breast-feeding is associated with reduced postpartum maternal glucose intolerance after gestational diabetes. AB - Gestational diabetes mellitus (GDM) is associated with adverse foetal and maternal outcomes, and identifies women at risk of future Type 2 Diabetes Mellitus (T2DM). Breast-feeding may improve postpartum maternal glucose tolerance. We prospectively examined the prevalence of postpartum dysglycaemia after GDM and examined the effect of lactation on postpartum glucose tolerance. We compared postpartum 75g oral glucose tolerance test (OGTT) results from 300 women with GDM and 220 controls with normal gestational glucose tolerance (NGT). Breast-feeding data was collected at time of OGTT. Postpartum OGTT results were classified as normal [fasting plasma glucose (FPG) < 5.6mmol/l, 2-h < 7.8 mmol/l] and abnormal [impaired fasting glucose (IFG), FPG 5.6-6.9 mmol/l; impaired glucose tolerance (IGT), 2-h glucose 7.8-11 mmol/l; IFG+IGT; T2DM, FPG > or = 7 mmol/l +/- 2h glucose > or = 11.1 mmol/l]. 6 (2.7%) with NGT in pregnancy had postpartum dysglycaemia compared to 57 (19%) with GDM in index pregnancy (p < 0.001). Non-European ethnicity (OR 3.40, 95% CI 1.45-8.02, p = 0.005), family history of T2DM (OR 2.14, 95% CI 1.06-4.32, p = 0.034) and gestational insulin use (OR 2.62, 95% CI 1.17-5.87 p = 0.019) were associated with persistent dysglycaemia. The prevalence of persistent hyperglycaemia was significantly lower in women who breast-fed versus bottle-fed postpartum (8.2% v 18.4%, p < 0.001). Breast-feeding may confer beneficial metabolic effects after GDM and should be encouraged. PMID- 22838109 TI - [Warning against uncritical use of overweight surgery in type 2 diabetes]. PMID- 22838110 TI - [The risk behavior of drug addicts requires holistic approach from the society. Syringe exchange and methadone-/buprenorphine treatment are important elements]. PMID- 22838111 TI - [Widespread risk behavior among injecting drug users. Over 80 percent HCV infected--7 percent have HIV, as demonstrated by the first baseline study]. PMID- 22838112 TI - [Risk of prolactinoma growth during pregnancy. Visual field tests required in macroadenoma, small risk in microadenomas]. PMID- 22838113 TI - [The HUS epidemic in the summer of 2011 was severe. German and Swedish experiences of the EHEC outbreak]. PMID- 22838114 TI - [On diseases in the neck and upper musculoskeletal system: Too low scientific quality in the SBU report]. PMID- 22838115 TI - [Watch out for the patient]. PMID- 22838116 TI - [Long term ECG findings. Acute soccer fever]. PMID- 22838117 TI - [Intravenous infusions as IGeL service. How are material costs billed properly?]. PMID- 22838118 TI - [Bureaucracy and mouse clicks. Who or what aggravates us more: our boards or our pcs?]. PMID- 22838119 TI - [GKV study. Too many operations just for the money?]. PMID- 22838120 TI - [A study with dynamite. Stable coronary heart disease: does a stent really have advantages?]. PMID- 22838121 TI - [Flying with lung disease. Can your patient still hyperventilate?]. PMID- 22838122 TI - [What amateur athletes must consider so that they will surface again in good health]. PMID- 22838123 TI - [Altitude sickness. Too quickly too high]. PMID- 22838124 TI - [Unexpected etiology for nausea and leg edema. "Cerebral gyri" in gastroscopy]. PMID- 22838125 TI - [Breakthrough pain in a patient with bronchial carcinoma. Oral morphine hardly possible - what can help?]. PMID- 22838126 TI - [Patient without pathological findings. What is causing the chronic diarrhea?]. PMID- 22838127 TI - [When pediatric joints hurt. These questions can generate further leads]. PMID- 22838128 TI - [Hypertension in an 80-year-old patient. To treat or not to treat?]. PMID- 22838129 TI - [Thrombosis reveals a neoplasm. "This cancer is especially aggressive" (interview by Dr. Beate Schumacher)]. PMID- 22838130 TI - [Vaccinations for children and for adults]. PMID- 22838131 TI - [Vaccinations in the 21st century]. PMID- 22838132 TI - [Vaccination strategies for adults]. PMID- 22838133 TI - [Vaccination of patients with immune deficiency]. PMID- 22838134 TI - [Attack of gout]. PMID- 22838135 TI - [Diabetes and thyroid dysfunction]. PMID- 22838136 TI - [Isolated fear of frogs and toads--a case of bufono-ranophobia]. PMID- 22838137 TI - [Exertional compartment syndrome caused by overstress]. PMID- 22838138 TI - [Hearing loss--what to do if the patient does not understand you]. PMID- 22838139 TI - [Mild heart failure. With hawthorn fit again in routine exertion]. PMID- 22838140 TI - Emotional alignment. PMID- 22838141 TI - Altogether now: Blazing a trail toward lower costs and better care. PMID- 22838142 TI - No free lunch: Physicians getting extra pay for added administrative duties. PMID- 22838143 TI - Truth be told: Give it to me straight, Doc. PMID- 22838144 TI - Patients on the lookout. PMID- 22838145 TI - Automated drug alerts. PMID- 22838146 TI - Documentation. AB - For hospitals to get properly reimbursed under the new coding system, they must make sure physicians document medical activities better. Engaging them can be tricky. PMID- 22838147 TI - Population health's tipping point. Interview by Haydn Bush. PMID- 22838148 TI - Wireless devices incite 'medical spring'. AB - A new breed of medical technology is emerging to make diagnosis and treatment more targeted, effective and efficient. How can hospitals harness all that potential? PMID- 22838149 TI - Smart pain management makes good business sense. AB - Controlling patients' pain is now a key factor in HCAHPS scores--and reimbursement. This Clinical Management installment looks at hospitals that are stepping up to the plate. PMID- 22838151 TI - A straightforward philosophy: 'do what's right'. PMID- 22838150 TI - Data standards in the supply chain. PMID- 22838152 TI - Keeping pharmacy costs in check. PMID- 22838153 TI - Assessment and statistical modeling of the relationship between remotely sensed aerosol optical depth and PM2.5 in the eastern United States. AB - Research in scientific, public health, and policy disciplines relating to the environment increasingly makes use of high-dimensional remote sensing and the output of numerical models in conjunction with traditional observations. Given the public health and resultant public policy implications of the potential health effects of particulate matter (PM*) air pollution, specifically fine PM with an aerodynamic diameter < or = 2.5 pm (PM2.5), there has been substantial recent interest in the use of remote-sensing information, in particular aerosol optical depth (AOD) retrieved from satellites, to help characterize variability in ground-level PM2.5 concentrations in space and time. While the United States and some other developed countries have extensive PM monitoring networks, gaps in data across space and time necessarily occur; the hope is that remote sensing can help fill these gaps. In this report, we are particularly interested in using remote-sensing data to inform estimates of spatial patterns in ambient PM2.5 concentrations at monthly and longer time scales for use in epidemiologic analyses. However, we also analyzed daily data to better disentangle spatial and temporal relationships. For AOD to be helpful, it needs to add information beyond that available from the monitoring network. For analyses of chronic health effects, it needs to add information about the concentrations of long-term average PM2.5; therefore, filling the spatial gaps is key. Much recent evidence has shown that AOD is correlated with PM2.5 in the eastern United States, but the use of AOD in exposure analysis for epidemiologic work has been rare, in part because discrepancies necessarily exist between satellite-retrieved estimates of AOD, which is an atmospheric-column average, and ground-level PM2.5. In this report, we summarize the results of a number of empirical analyses and of the development of statistical models for the use of proxy information, in particular satellite AOD, in predicting PM2.5 concentrations in the eastern United States. We analyzed the spatiotemporal structure of the relationship between PM2.5 and AOD, first using simple correlations both before and after calibration based on meteorology, as well as large-scale spatial and temporal calibration to account for discrepancies between AOD and PM2.5. We then used both raw and calibrated AOD retrievals in statistical models to predict PM2.5 concentrations, accounting for AOD in two ways: primarily as a separate data source contributing a second likelihood to a Bayesian statistical model, as well as a data source on which we could directly regress. Previous consideration of satellite AOD has largely focused on the National Aeronautics and Space Administration (NASA) moderate resolution imaging spectroradiometer (MODIS) and multiangle imaging spectroradiometer (MISR) instruments. One contribution of our work is more extensive consideration of AOD derived from the Geostationary Operational Environmental Satellite East Aerosol/Smoke Product (GOES GASP) AOD and its relationship with PM2.5. In addition to empirically assessing the spatiotemporal relationship between GASP AOD and PM2.5, we considered new statistical techniques to screen anomalous GOES reflectance measurements and account for background surface reflectance. In our statistical work, we developed a new model structure that allowed for more flexible modeling of the proxy discrepancy than previous statistical efforts have had, with a computationally efficient implementation. We also suggested a diagnostic for assessing the scales of the spatial relationship between the proxy and the spatial process of interest (e.g., PM2.5). In brief, we had little success in improving predictions in our eastern-United States domain for use in epidemiologic applications. We found positive correlations of AOD with PM2.5 over time, but less correlation for long-term averages over space, unless we used calibration that adjusted for large-scale discrepancy between AOD and PM2.5 (see sections 3, 4, and 5). Statistical models that combined AOD, PM2.5 observations, and land-use and meteorologic variables were highly predictive of PM2.5 observations held out of the modeling, but AOD added little information beyond that provided by the other sources (see sections 5 and 6). When we used PM2.5 data estimates from the Community Multiscale Air Quality model (CMAQ) as the proxy instead of using AOD, we similarly found little improvement in predicting held-out observations of PM2.5, but when we regressed on CMAQ PM2.5 estimates, the predictions improved moderately in some cases. These results appeared to be caused in part by the fact that large-scale spatial patterns in PM2.5 could be predicted well by smoothing the monitor values, while small-scale spatial patterns in AOD appeared to weakly reflect the variation in PM2.5 inferred from the observations. Using a statistical model that allowed for potential proxy discrepancy at both large and small spatial scales was an important component of our modeling. In particular, when our models did not include a component to account for small-scale discrepancy, predictive performance decreased substantially. Even long-term averages of MISR AOD, considered the best, albeit most sparse, of the AOD products, were only weakly correlated with measured PM2.5 (see section 4). This might have been partly related to the fact that our analysis did not account for spatial variation in the vertical profile of the aerosol. Furthermore, we found evidence that some of the correlation between raw AOD and PM2.5 might have been a function of surface brightness related to land use, rather than having been driven by the detection of aerosol in the AOD retrieval algorithms (see sections 4 and 7). Difficulties in estimating the background surface reflectance in the retrieval algorithms likely explain this finding. With regard to GOES, we found moderate correlations of GASP AOD and PM2.5. The higher correlations of monthly and yearly averages after calibration reflected primarily the improved large-scale correlation, a necessary result of the calibration procedure (see section 3). While the results of this study's GOES reflectance screening and surface reflection correction appeared sensible, correlations of our proposed reflectance-based proxy with PM2.5 were no better than GASP AOD correlations with PM2.5 (see section 7). We had difficulty improving spatial prediction of monthly and yearly average PM2.5 using AOD in the eastern United States, which we attribute to the spatial discrepancy between AOD and measured PM2.5, particularly at smaller scales. This points to the importance of paying attention to the discrepancy structure of proxy information, both from remote-sensing and deterministic models. In particular, important statistical challenges arise in accounting for the discrepancy, given the difficulty in the face of sparse observations of distinguishing the discrepancy from the component of the proxy that is informative about the process of interest. Associations between adverse health outcomes and large-scale variation in PM2.5 (e.g., across regions) may be confounded by unmeasured spatial variation in factors such as diet. Therefore, one important goal was to use AOD to improve predictions of PM2.5 for use in epidemiologic analyses at small-to-moderate spatial scales (within urban areas and within regions). In addition, large-scale PM2.5 variation is well estimated from the monitoring data, at least in the United States. We found little evidence that current AOD products are helpful for improving prediction at small-to moderate scales in the eastern United States and believe more evidence for the reliability of AOD as a proxy at such scales is needed before making use of AOD for PM2.5 prediction in epidemiologic contexts. While our results relied in part on relatively complicated statistical models, which may be sensitive to modeling assumptions, our exploratory correlation analyses (see sections 3 and 5) and relatively simple regression-style modeling of MISR AOD (see section 4) were consistent with the more complicated modeling results. When assessing the usefulness of AOD in the context of studying chronic health effects, we believe efforts need to focus on disentangling the temporal from the spatial correlations of AOD and PM2.5 and on understanding the spatial scale of correlation and of the discrepancy structure. While our results are discouraging, it is important to note that we attempted to make use of smaller-scale spatial variation in AOD to distinguish spatial variations of relatively small magnitude in long-term concentrations of ambient PM2.5. Our efforts pushed the limits of current technology in a spatial domain with relatively low PM2.5 levels and limited spatial variability. AOD may hold more promise in areas with higher aerosol levels, as the AOD signal would be stronger there relative to the background surface reflectance. Furthermore, for developing countries with high aerosol levels, it is difficult to build statistical models based on PM2.5 measurements and land-use covariates, so AOD may add more incremental information in those contexts. More generally, researchers in remote sensing are involved in ongoing efforts to improve AOD products and develop new approaches to using AOD, such as calibration with model-estimated vertical profiles and the use of speciation information in MISR AOD; these efforts warrant continued investigation of the usefulness of remotely sensed AOD for public health research. PMID- 22838154 TI - A new perspective on maternal ill-health and its consequences. PMID- 22838155 TI - Maternal morbidity and disability and their consequences: neglected agenda in maternal health. PMID- 22838156 TI - Profile of maternal and foetal complications during labour and delivery among women giving birth in hospitals in Matlab and Chandpur, Bangladesh. AB - Worldwide, for an estimated 358,000 women, pregnancy and childbirth end in death and mourning, and beyond these maternal deaths, 9-10% of pregnant women or about 14 million women per year suffer from acute maternal complications. This paper documents the types and severity of maternal and foetal complications among women who gave birth in hospitals in Matlab and Chandpur, Bangladesh, during 2007-2008. The Community Health Research Workers (CHRWs) of the icddr,b service area in Matlab prospectively collected data for the study from 4,817 women on their places of delivery and pregnancy outcomes. Of them, 3,010 (62.5%) gave birth in different hospitals in Matlab and/or Chandpur and beyond. Review of hospital records was attempted for 2,102 women who gave birth only in the Matlab Hospital of icddr,b and in other public and private hospitals in the Matlab and Chandpur area. Among those, 1,927 (91.7%) records were found and reviewed by a physician. By reviewing the hospital-records, 7.3% of the women (n=1,927) who gave birth in the local hospitals were diagnosed with a severe maternal complication, and 16.1% with a less-severe maternal complication. Abortion cases--either spontaneous or induced--were excluded from the analysis. Over 12% of all births were delivered by caesarean section (CS). For a substantial proportion (12.5%) of CS, no clear medical indication was recorded in the hospital-register. Twelve maternal deaths occurred during the study period; most (83%) of them had been in contact with a hospital before death. Recommendations include standardization of the hospital record-keeping system, proper monitoring of indications of CS, and introduction of maternal death audit for further improvement of the quality of care in public and private hospitals in rural Bangladesh. PMID- 22838157 TI - Occurrence and determinants of postpartum maternal morbidities and disabilities among women in Matlab, Bangladesh. AB - The burden of maternal ill-health includes not only the levels of maternal mortality and complications during pregnancy and around the time of delivery but also extends to the standard postpartum period of 42 days with consequences of obstetric complications and poor management at delivery. There is a dearth of reliable data on these postpartum maternal morbidities and disabilities in developing countries, and more research is warranted to investigate these and further strengthen the existing safe motherhood programmes to respond to these conditions. This study aims at identifying the consequences of pregnancy and delivery in the postpartum period, their association with acute obstetric complications, the sociodemographic characteristics of women, mode and place of delivery, nutritional status of the mother, and outcomes of birth. From among women who delivered between 2007 and 2008 in the icddr,b service area in Matlab, we prospectively recruited all women identified with complicated births (n=295); a perinatal mortality (n=182); and caesarean-section delivery without any maternal indication (n=147). A random sample of 538 women with uncomplicated births, who delivered at home or in a facility, was taken as the control. All subjects were clinically examined at 6-9 weeks for postpartum morbidities and disabilities. Postpartum women who had suffered obstetric complications during birth and delivered in a hospital were more likely to suffer from hypertension [adjusted odds ratio (AOR)=3.44; 95% confidence interval (CI)=1.14-10.36], haemorrhoids (AOR=1.73; 95% CI=1.11-3.09), and moderate to severe anaemia (AOR=7.11; 95% CI=2.03-4.88) than women with uncomplicated normal deliveries. Yet, women who had complicated births were less likely to have perineal tears (AOR=0.05; 95% CI=0.02-0.14) and genital prolapse (AOR=0.22; 95% CI=0.06-0.76) than those with uncomplicated normal deliveries. Genital infections were more common amongst women experiencing a perinatal death than those with uncomplicated normal births (AOR=1.92; 95% CI=1.18-3.14). Perineal tears were significantly higher (AOR=3.53; 95% CI=2.32-5.37) among those who had delivery at home than those giving birth in a hospital. Any woman may suffer a postpartum morbidity or disability. The increased likelihood of having hypertension, haemorrhoids, or anaemia among women with obstetric complications at birth needs specific intervention. A higher quality of maternal healthcare services generally might alleviate the suffering from perineal tears and prolapse amongst those with a normal uncomplicated delivery. PMID- 22838158 TI - An examination of women experiencing obstetric complications requiring emergency care: perceptions and sociocultural consequences of caesarean sections in Bangladesh. AB - Little is known about the physical and socioeconomic postpartum consequences of women who experience obstetric complications and require emergency obstetric care (EmOC), particularly in resource-poor countries such as Bangladesh where historically there has been a strong cultural preference for births at home. Recent increases in the use of skilled birth attendants show socioeconomic disparities in access to emergency obstetric services, highlighting the need to examine birthing preparation and perceptions of EmOC, including caesarean sections. Twenty women who delivered at a hospital and were identified by physicians as having severe obstetric complications during delivery or immediately thereafter were selected to participate in this qualitative study. Purposive sampling was used for selecting the women. The study was carried out in Matlab, Bangladesh, during March 2008-August 2009. Data-collection methods included in-depth interviews with women and, whenever possible, their family members. The results showed that the women were poorly informed before delivery about pregnancy-related complications and medical indications for emergency care. Barriers to care-seeking at emergency obstetric facilities and acceptance of lifesaving care were related to apprehensions about the physical consequences and social stigma, resulting from hospital procedures and financial concerns. The respondents held many misconceptions about caesarean sections and distrust regarding the reason for recommending the procedure by the healthcare providers. Women who had caesarean sections incurred high costs that led to economic burdens on family members, and the blame was attributed to the woman. The postpartum health consequences reported by the women were generally left untreated. The data underscore the importance of educating women and their families about pregnancy related complications and preparing families for the possibility of caesarean section. At the same time, the health systems need to be strengthened to ensure that all women in clinical need of lifesaving obstetric surgery access quality EmOC services rapidly and, once in a facility, can obtain a caesarean section promptly, if needed. While greater access to surgical interventions may be lifesaving, policy-makers need to institute mechanisms to discourage the over medicalization of childbirth in a context where the use of caesarean section is rapidly rising. PMID- 22838159 TI - Obstetric complications and psychological well-being: experiences of Bangladeshi women during pregnancy and childbirth. AB - Women in developing countries experience postnatal depression at rates that are comparable with or higher than those in developed countries. However, their personal experiences during pregnancy and childbirth have received little attention in relation to postnatal depression. In particular, the contribution of obstetric complications to their emotional well-being during the postpartum period is still not clearly understood. This study aimed to (a) describe the pregnancy and childbirth experiences among women in Bangladesh during normal childbirth or obstetric complications and (b) examine the relationship between these experiences and their psychological well-being during the postpartum period. Two groups of women--one group with obstetric complications (n=173) and the other with no obstetric complications (n=373)--were selected from a sample of women enrolled in a community-based study in Matlab, Bangladesh. The experiences during pregnancy and childbirth were assessed in terms of a five-point rating scale from 'severely uncomfortable=1' to 'not uncomfortable at all=5'. The psychological status of the women was assessed using a validated local version of the Edinburgh Postnatal Depression Scale (EPDS) at six weeks postpartum. Categorical data were analyzed using the chi-square test and continuous data by analysis of variance. Women with obstetric complications reported significantly more negative experiences during their recent childbirth [95% confidence interval (CI) 1.36-1.61, p<0.001] compared to those with normal childbirth. There was a significant main effect on emotional well-being due to experiences of pregnancy [F (4,536)=4.96, p=0.001] and experiences of childbirth [F (4,536)=3.29, p=0.01]. The EPDS mean scores for women reporting severe uncomfortable pregnancy and childbirth experiences were significantly higher than those reporting no such problems. After controlling for the background characteristics, postpartum depression was significantly associated with women reporting a negative childbirth experience. Childbirth experiences of women can provide important information on possible cases of postnatal depression. PMID- 22838160 TI - Violence against women with chronic maternal disabilities in rural Bangladesh. AB - This study explored violence against women with chronic maternal disabilities in rural Bangladesh. During November 2006-July 2008, in-depth interviews were conducted with 17 rural Bangladeshi women suffering from uterine prolapse, stress incontinence, or fistula. Results of interviews showed that exposure to emotional abuse was almost universal, and most women were sexually abused. The common triggers for violence were the inability of the woman to perform household chores and to satisfy her husband's sexual demands. Misconceptions relating to the causes of these disabilities and the inability of the affected women to fulfill gender role expectations fostered stigma. Emotional and sexual violence increased their vulnerability, highlighting the lack of life options outside marriage and silencing most of them into accepting the violence. Initiatives need to be developed to address misperceptions regarding the causes of such disabilities and, in the long-term, create economic opportunities for reducing the dependence of women on marriage and men and transform the society to overcome rigid gender norms. PMID- 22838161 TI - Association of postpartum maternal morbidities with children's mental, psychomotor and language development in rural Bangladesh. AB - Little is known from developing countries about the effects of maternal morbidities diagnosed in the postpartum period on children's development. The study aimed to document the relationships of such morbidities with care-giving practices by mothers, children's developmental milestones and their language, mental and psychomotor development. Maternal morbidities were identified through physical examination at 6-9 weeks postpartum (n=488). Maternal care-giving practices and postnatal depression were assessed also at 6-9 weeks postpartum. Children's milestones of development were measured at six months, and their mental (MDI) and psychomotor (PDI) development, language comprehension and expression, and quality of psychosocial stimulation at home were assessed at 12 months. Several approaches were used for identifying the relationships among different maternal morbidities, diagnosed by physicians, with children's development. After controlling for the potential confounders, maternal anaemia diagnosed postpartum showed a small but significantly negative effect on children's language expression while the effects on language comprehension did not reach the significance level (p=0.085). Children's development at 12 months was related to psychosocial stimulation at home, nutritional status, education of parents, socioeconomic status, and care-giving practices of mothers at six weeks of age. Only a few mothers experienced each specific morbidity, and with the exception of anaemia, the sample-size was insufficient to make a conclusion regarding each specific morbidity. Further research with a sufficient sample-size of individual morbidities is required to determine the association of postpartum maternal morbidities with children's development. PMID- 22838162 TI - Costs of maternal health-related complications in Bangladesh. AB - This paper assesses both out-of-pocket payments for healthcare and losses of productivity over six months postpartum among women who gave birth in Matlab, Bangladesh. The hypothesis of the study objective is that obstetric morbidity leads women to seek care at which time out-of-pocket expenditure is incurred. Second, a woman may also take time out from employment or from doing her household chores. This loss of resources places a financial burden on the household that may lead to reduced consumption of usual but less important goods and use of other services depending on the extent to which a household copes up by using savings, taking loans, and selling assets. Women were divided into three groups based on their morbidity patterns: (a) women with a severe obstetric complication (n=92); (b) women with a less-severe obstetric complication (n=127); and (c) women with a normal delivery (n=483). Data were collected from households of these women at two time-points--at six weeks and six months after delivery. The results showed that maternal morbidity led to a considerable loss of resources up to six weeks postpartum, with the greatest financial burden of cost of healthcare among the poorest households. However, families coped up with loss of resources by taking loans and selling assets, and by the end of six months postpartum, the households had paid back more than 40% of the loans. PMID- 22838163 TI - Early postpartum maternal morbidity among rural women of Rajasthan, India: a community-based study. AB - The first postpartum week is a high-risk period for mothers and newborns. Very few community-based studies have been conducted on patterns of maternal morbidity in resource-poor countries in that first week. An intervention on postpartum care for women within the first week after delivery was initiated in a rural area of Rajasthan, India. The intervention included a rigorous system of receiving reports of all deliveries in a defined population and providing home-level postpartum care to all women, irrespective of the place of delivery. Trained nurse-midwives used a structured checklist for detecting and managing maternal and neonatal conditions during postpartum-care visits. A total of 4,975 women, representing 87.1% of all expected deliveries in a population of 58,000, were examined in their first postpartum week during January 2007-December 2010. Haemoglobin was tested for 77.1% of women (n=3,836) who had a postnatal visit. The most common morbidity was postpartum anaemia--7.4% of women suffered from severe anaemia and 46% from moderate anaemia. Other common morbidities were fever (4%), breast conditions (4.9%), and perineal conditions (4.5%). Life-threatening postpartum morbidities were detected in 7.6% of women--9.7% among those who had deliveries at home and 6.6% among those who had institutional deliveries. None had a fistula. Severe anaemia had a strong correlation with perinatal death [p<0.000, adjusted odds ratio (AOR)=1.99, 95% confidence interval (CI) 1.32 2.99], delivery at home [p<0.000, AOR=1.64 (95% CI 1.27-2.15)], socioeconomically underprivileged scheduled caste or tribe [p<0.000, AOR=2.47 (95% CI 1.83-3.33)], and parity of three or more [p<0.000, AOR=1.52 (95% CI 1.18-1.97)]. The correlation with antenatal care was not significant. Perineal conditions were more frequent among women who had institutional deliveries while breast conditions were more common among those who had a perinatal death. This study adds valuable knowledge on postpartum morbidity affecting women in the first few days after delivery in a low-resource setting. Health programmes should invest to ensure that all women receive early postpartum visits after delivery at home and after discharge from institution to detect and manage maternal morbidity. Further, health programmes should also ensure that women are properly screened for complications before their discharge from hospitals after delivery. PMID- 22838164 TI - Consequences of maternal complications in women's lives in the first postpartum year: a prospective cohort study. AB - Maternal complications are common during and following childbirth. However, little information is available on the psychological, social and economic consequences of maternal complications on women's lives, especially in a rural setting. A prospective cohort study was conducted in southern Rajasthan, India, among rural women who had a severe or less-severe, or no complication at the time of delivery or in the immediate postpartum period. In total, 1,542 women, representing 93% of all women who delivered in the field area over a 15-month period and were examined in the first week postpartum by nurse-midwives, were followed up to 12 months to record maternal and child survival. Of them, a subset of 430 women was followed up at 6-8 weeks and 12 months to capture data on the physical, psychological, social, or economic consequences. Women with severe maternal complications around the time of delivery and in the immediate postpartum period experienced an increased risk of mortality and morbidity in the first postpartum year: 2.8% of the women with severe complications died within one year compared to none with uncomplicated delivery. Women with severe complications also had higher rates of perinatal mortality [adjusted odds ratio (AOR)=3.98, confidence interval (CI) 1.96-8.1, p=0.000] and mortality of babies aged eight days to 12 months (AOR=3.14, CI 1.4-7.06, p=0.004). Compared to women in the uncomplicated group, women with severe complications were at a higher risk of depression at eight weeks and 12 months with perceived physical symptoms, had a greater difficulty in completing daily household work, and had important financial repercussions. The results suggest that women with severe complications at the time of delivery need to be provided regular follow-up services for their physical and psychological problems till about 12 months after childbirth. They also might benefit from financial support during several months in the postpartum period to prevent severe economic consequences. Further research is needed to identify an effective package of services for women in the first year after delivery. PMID- 22838165 TI - [Diagnostic relevance of fine needle aspiration cytology in nodular thyroid lesions]. AB - BACKGROUND/AIM: Fine needle aspiration cytology (FNAC) of the thyroid gland has been used as an initial investigative procedure of thyroid nodule(s) in the Department of Pathology at the Institute of Oncology of Vojvodina for more than 20 years. This procedure is rapid, inexpensive and technologically simple, yet it has found only limited, albeit increasing acceptance in medical practice in Serbia. The aim of the study was to evaluate our FNAC findings by correlating cytological results with histological diagnosis and to define the sensitivity, diagnostic accuracy and positive predictive value of FNAC. METHODS: A total of 266 patients with thyroid swellings were aspirated in one year investigated period at our Institute out of whom 69 underwent surgery between May 2008 and May 2009. The cytological results correlated with clinical features, ultrasound investigations (US) and subsequent histopathological examination of the resected tissue. RESULTS: By the use of cytology we found out thyroid carcinoma in 10 patients, and by histopathological examination in 12. We obtained 83% sensitivity, 100% specificity and 97% of diagnostic accuracy of FNAC. CONCLUSION: The obtained results confirm the importance of FNAC in preoperative assesment of thyroid nodule. PMID- 22838166 TI - [Fracture toughness of zirconia ceramic crowns made by feather-edge tooth preparation design]. AB - BACKGROUND/AIM: Fracture toughness determines functional crown strenght and prevents damages on ceramics during mastication. There is a lack of relevant literature data about fracture toughness of crowns made by feather-edge preparation. Mechanical testing of ceramic samples is supposed to show if feather edge tooth preparation is a successful method for making ceramic crowns without any risk of reduction of their mechanical properties. This research was done to establish effects of feather-edge tooth preparation on fracture toughness of single zirconia ceramic crowns. METHODS: The research was performed as an experimental study. Sixty (60) ceramic crowns were made on non-carious extracted human premolars. Thirty (30) crowns were made on the basis of feather-edge preparation (experimental group I). The group II included 30 crowns made on 1 mm rounded shoulder. Crowns fabrication was executed on a copy mill production system "Zirkonzahn" (Zirkonzahn GMBH, Gais, Germany). The spherical compression test was used to determine fracture toughness, using 6 mmn diameter ceramic ball. Fracture load for damaging ceramic crown was recorded on a universal testing machine--Zwick, type 1464, with the speed of 0.05 mm/min. RESULTS: The results of this research introduced significant differences between fracture toughness of ceramic samples in every examined group. However, fracture toughness of crowns from both group was above 2000 N, what was double beyond a recommended value. The mean value of fracture toughness in the feather-edge group was 2090 N, and in shoulder group it was 2214 N. CONCLUSION: This research showed a high fracture toughness of zirconia crowns made on feather-edge preparation. The examined crowns showed a fracture resistance at a sufficient distance in relation to the minimum values of functional loads. Further research of functional loads of these crown is necessary, as well as research of marginal adaptation of cemented crowns and gingival inflammatory response. PMID- 22838167 TI - [Different insulin treatment regimens in patient with diabetes mellitus type 1: effects on quality of life]. AB - BACKGROUND/AIM: Despite of contemporary diabetes mellitus (DM) treatment, one half of patients do not achieve an optimal metabolic control. Considering great psychological burden of diabetic patients, the purpose of this study was to assess the effect of different insulin treatment regimens, glycemic control and the presence of vascular complications on self-reported well-being and quality of life (QoL) of subjects with type 1 DM. METHODS: The patients with type 1 DM (n=122) recruited from the outpatient Diabetes Endocrinology Clinic of Zvezdara University Medical Center were divided into 4 groups according to the specific treatment regimen: 26 were on continuous subcutaneous insulin infusion (CSII), 30 on conventional insulin therapy, 33 on multiple daily injections (MDI) with human insulins, and 33 on MDI with insulin analogues. QoL was assesed by self-reported well-being with the following questionnaires: WHO-5 item well being index (WHO 5), 36 item short form (SF-36) survey, and insulin treatment appraisal scale (ITAS). Objective metabolic control was assessed by glycosylated hemoglobin (HbA1c), lipid levels and the presence of vascular complications. Statistical analyses used in this cross-sectional study included: descriptive statistics, student's t-test, chi-sqare test, contingency tables, ANOVA and correlation methods. RESULTS: The patients on CSII had significantly better metabolic control than all other treatment groups, especially when compared to the one on conventional therapy (CSII HbA1c 7.07 +/- 1.48% vs. conventional therapy, HbA1c 10.04 +/- 1.44; p = 0.000). No significant difference in glycemic control was observed between patients on MDI with human insulins and insulin analogues. Good glycemic control significantly influenced the reported QoL. The patients with retinopathy and nephropathy reported significantly lower physical well-being, and the patients with polyneuropathy and cardiovascular complications reported also lower psychological well being. CONCLUSIONS: Insulin treatment regiment selection affects not only objective metabolic control, but also QoL. PMID- 22838168 TI - [The influence of the morphometric parameters of the intercondylar notch on rupture of the anterior cruciate ligament]. AB - BACKGROUND/AIM: Morpohometric parameters of the intercondylar notch of femur present one of the substantial risk factors for rupture of the anterior cruciate ligament (ACL). In morphometric studies of the knee the most often referred indexes are notch width index and notch shape index. The aim of this study was to identificate the morphometric parameters of the intercondylar notch as risk factors for ACL rupture. METHODS: This study included 99 patients divided into two groups: the study group (n=57) composed of patients with chronic instability of the knee because of previos rupture of the ACL, and the control group (n=42) composed of patients with lesion of the knee, but without rupture of the ACL. Measuring the width and height of intercondylar notch and epicondylar width was observed on a horizontal MR section. According to these values notch width and notch shape indexes were calculated. RESULTS: The study group had statistically significantly higher (p < 0.05) intercondylar notch and lesser notch shape index than the control group (p < 0.05). The difference was highly statistically significant (p < 0.01) only in males, but not in females (p > 0.05). Absolute dimensions of the morphometric parameters of the distal part of the femur had highly statatistically significant larger values (p < 0.01) in males than females, exept in case of the intercondilar height in the control group (p > 0.05). CONCLUSION: Enhanced height of the intercondylar notch as well as lesser value of the notch shape index are associated with rupture of the ACL in males but not in females. PMID- 22838169 TI - Histochemical and immunohistochemical analyses of the myocardial scar fallowing acute myocardial infarction. AB - BACKGROUND/AIM: The heart has traditionally been considered as a static organ without capacity of regeneration after trauma. Currently, the more and more often asked question is whether the heart has any intrinsic capacities to regenerate myocytes after myocardial infarction. The aim of this study was to present the existence of the preserved muscle fibers in the myocardial scar following myocardial infarction as well as the presence of numerous cells of various size and form that differently reacted to the used immunohistochemical antibodies. METHODS: Histological, histochemical and immunohistochemical analyses of myocardial sections taken from 177 patients who had died of acute myocardial infarction and had the myocardial scar following myocardial infarction, were carried out. More sections taken both from the site of acute infarction and scar were examined by the following methods: hematoxylin-eosin (HE), periodic acid schiff (PAS), PAS-diastasis, Masson trichrom, Malory, van Gieson, vimentin, desmin, myosin, myoglobin, alpha actin, smoth muscle actin (SMA), p53, leukocyte common antigen (LCA), proliferating cell nuclear antigen (PCNA), Ki-67, actin HHF35, CD34, CD31, CD45, CD45Ro, CD8, CD20. RESULTS: In all sections taken from the scar region, larger or smaller islets of the preserved muscle fibers with the signs of hypertrophy were found. In the scar, a large number of cells of various size and form: spindle, oval, elongated with abundant cytoplasm, small with one nucleus and cells with scanty cytoplasm, were found. The present cells differently reacted to histochemical and immunohistochemical methods. Large oval cells showed negative reaction to lymphocytic and leukocytic markers, and positive to alpha actin, actin HHF35, Ki-67, myosin, myoglobin and desmin. Elongated cells were also positive to those markers. Small mononuclear cells showed positive reaction to lymphocytic markers. Endothelial and smooth muscle cells in the blood vessel walls were positive to CD34 and CD31, and smooth muscle cells to SMA. Oval and elongated cells were positive to PCNA and Ki-67. The preserved muscle fibers in the scar were positive to myosin, myoglobin and desmin as well as elongated and oval cells. Other cells were negative to these markers. CONCLUSION: Our findings speak that myocardial regeneration is maybe possible and develops in human ischemic heart damages and that the myocardium is not a static organ without capacity of cell regeneration. PMID- 22838170 TI - Dystocia as a cause of untimely cesarean section. AB - BACKGROUND/AIM: One of the most frequent indications for cesarean section is dystocia. It is impossible to predict, difficult to identify and coincident with the rapid expiry of the expected time, so it is important to point out some mistakes in expecting vaginal delivery. The aim of this study was to examine the frequency and the length of dystocia-related cesarean delivery, as well as the vitality of the newborn immediately after birth. METHODS: A prospective 3-year study was conducted including a total number of 6470 deliveries regardless of whether they were completed using cesarean section after an unsuccessful attempt of spontaneous vaginal delivery or not. The Apgar score, a proved useful tool for the assessment of the vitality of newborn children in the first minute, was used. RESULTS: On the basis of the established indications, 653 (10.10%) of deliveries were completed using cesarean section. Dystocia was the third most common indication for cesarean section (16.38%). Deliveries in which dystocia was established as a diagnosis lasted much longer (p = 0.030) which resulted in weaker vitality of newborn children (p = 0.000) compared to the deliveries ended by spontaneous vaginal delivery. CONCLUSION: This study shows that deliveries caused by dystocia last much longer and newborn children are of weaker vitality compared to other deliveries caused not by dystocia. Decisions concerning cesarean section must be made in a timely fashion. PMID- 22838171 TI - Collateral branches of the brachial plexus as donors in nerve transfers. AB - BACKGROUND/AIM: Nerve transfers in cases of directly irreparable, or high level extensive brachial plexus traction injuries are performed using a variety of donor nerves with various success but an ideal method has not been established. The purpose of this study was to analyze the results of nerve transfers in patients with traction injuries to the brachial plexus using the thoracodorsal and medial pectoral nerves as donors. METHODS: This study included 40 patients with 25 procedures using the thoracodorsal nerve and 33 procedures using the medial pectoral nerve as donors for reinnervation of the musculocutaneous or axillary nerve. The results were analyzed according to the donor nerve, the age of the patient and the timing of surgery. RESULTS: The total rate of recovery for elbow flexion was 94.1%, for shoulder abduction 89.3%, and for shoulder external rotation 64.3%. The corresponding rates of recovery using the thoracodorsal nerve were 100%, 93.7% and 68.7%, respectively. The rates of recovery with medial pectoral nerve transfers were 90.5%, 83.3% and 58.3%, respectively. Despite the obvious differences in the rates of recovery, statistical significance was found only between the rates and quality of recovery for the musculocutaneous and axillary nerve using the thoracodorsal nerve as donor. CONCLUSION: According to our findings, nerve transfers using collateral branches of the brachial plexus in cases with upper palsy offer several advantages and yield high rate and good quality of recovery. PMID- 22838172 TI - [Clinical presentation of different severities of hemorrhagic fever with renal syndrome: how to recognise it]. AB - BACKGROUND/AIM: Besides viral serotype, HLA haplotype and cytokine genes polymorphism are associated with clinical presentation of hemorrhagic fever with renal syndrome. Since these analyses are unavailable in routine clinical practice, the aim of this study was to assess clinical, laboratory and radiographic findings associated with clinical presentation of disease severity. METHODS: A total of 30 patients (27 men and 3 women), average age 40 +/- 14.9 years, treated for hemorrhagic fever with renal syndrome from January 1, 1999 to December 31, 2009 in Clinical Center of Serbia, were included in the study. Nine patients (30%) had mild, 14 (46.7%) moderate and 7 (23.3%) severe form of the disease; 24 (800%) recovered, 6 (20%) died in the acute phase of the illness, and 19 patients (63.3%) required hemodialysis. RESULTS: The average titer of antiviral antibodies in patients infected with Belgrade serotype virus were significantly higher in those with severe clinical presentation. Hypotension, anuria, macrohaematuria, pulmonary infiltration, pleural effusion, hepatomegalia and positive meningeal signs were more frequent in the patients with severe form of the disease. Statistically significant differences between groups with mild, moderate and severe clinical picture were found in serum total protein, albumin, calcium, glutamate pyruvate and glutamate oxaloacetate transaminase on admittance; serum creatinine and phosphorus concentration on day 14 and day 21; serum sodium and calciums on day 14; hemoglobine concentration on day 21. A statistically significant correlation was found between clinical presentation of the disease severity and platelet count, white blood cell count, hemoglobine concentration, serum calcium and serum transaminases on admittance. Multivariate analysis identified variables' combinations associated with clinical presentation of the disease. CONCLUSION: Our study confirmed that we can distinguish patients who will manifest different severities of the disease on the basis of careful consideration of laboratory and clinical findings on admission. PMID- 22838173 TI - Model of psychotherapeutic crisis intervention following suicide attempt. PMID- 22838174 TI - Are the carotid kinking and coiling underestimated entities? PMID- 22838175 TI - Fabry disease, do we think enough about this multisystemic disorder? A presentation of three cases in a Serbian family. AB - BACKGROUND: Fabry Disease is a rare, X-chromosomal inherited lysosomal storage disease with a consequent intracellular accumulation of neutral glycosphingolipids in various tissues. This can cause skin and ocular lessions, progressive renal, cardiac or cerebrovascular disorders. If a person in a family has Fabry disease, other family members including even extended relatives, may also be at risk. CASE REPORT: We presented three cases pointed out various manifestation of Fabry disease, that illustrate a possible cause for otherwise unexplained cardiac hypertrophy and various rhythm and conduction abnormalities. CONCLUSION: Although most symptoms begin in childhood, various manifestations often lead to misdiagnosis and clinical diagnosis is frequently delayed for many years, even decades. Enzyme replacement therapy has become available, pointing out the importance of early diagnosis so that treatment can be initiated before irreversible organ damage. PMID- 22838176 TI - Portal hypertension caused by postoperative superior mesenteric arteriovenous fistula. AB - INTRODUCTION: Arteriovenous fistula of the superior mesenteric blood vessels is a rare complicaton in abdominal surgery. CASE REPORT: We presented a 49-year-old man with cramp-like abdominal pain, abdominal distension and weight loss symptoms, with a history of previous small bowel resection and right colectomy, due to Crohn disease, 16 years ago. Clinical examination revealed a paraumbilical pulsation with systolic murmur and thrill. Ultrasonography and computed tomography revealed cystic dilatation of the superior mesenteric vein, hepatomegaly and ascites. Upper endoscopy revealed grade I esophageal varices with portal hypertensive gastropathy. The diagnosis of arteriovenous fistula between superior mesenteric artery and vein was confirmed by angiogram of the superior mesenteric vessels and resection of the fistula was performed. Control examination after nine months showed no signs of portal hypertension. CONCLUSION: Early diagnosis and treatment of mesenteric blood vessel arteriovenous fistula prevents portal hypertension development and its complications. PMID- 22838177 TI - Tolosa-Hunt syndrome--diagnostic problem of painful ophthalmoplegia. AB - BACKGROUND: Tolosa-Hunt syndrome (THS) is an uncommon disease caused by non specific inflammation of the cavernous sinus, superior orbital fissure and the apex of the orbit. The disease is characterized by periorbital pain, paresis of the bulbomotor and quick response to steroid treatment. The orbital process may lead to optic nerve atrophy. According to the International Headache Society Classification of 2004, the diagnostic protocol includes magnetic resonance imaging (MRI) and biopsy. CASE REPORTS: We presented 46-year old male patient, with THS. The patient had unilateral periorbital pain, inflammatory process in the cavernous sinus, the apex of the orbit and the paranasal sinuses. Inflammatory process had spread into the fascia of the bulbomotor and performed compression to the optic nerve, causing paresis of the bulbomotor, protrusion of the eyeball and atrophy of the optic nerve. Pulse doses of corticosteroids were effective. Regarding the presented patient, diagnostic dilemmas arose from nonspecific sinusitis. The initial ophthalmological diagnosis, based on periorbital pain, drop in visual acuity and the narrow chamber angle was angular glaucoma, which resulted in a delayed diagnosis of THS and the beginning of the treatment. MRI and positive response to the treatment with corticosteroids were relevant for making the diagnosis. CONCLUSION: According to the International Headache Society Classification of 2004, THS is an entity that occurs rarely, its etiopathogenesis is unknown, it is manifested clinically by unilateral orbital pain associated with simple or multiple oculomotor paralyses, which resolves spontaneously but may recur. MRI orbital phlebography and biopsy are the recommended methods for making diagniosis. In our patient MRI findings and positive response to the corticosteroide treatment were relevant for making the diagnosis. PMID- 22838179 TI - A doctor, actor and hypochondriac: a fancy mixture. PMID- 22838178 TI - Primary leptomeningeal melanocytosis--a case report with an autopsy diagnosis. AB - INTRODUCTION: Primary melanocytosis of the leptomeninges is a rare tumor, most likely originating from the melanocytes in the leptomeninges. The average survival is only about 5 months. CASE REPORT: A 61-years-old woman presented with headache, amaurosis and hallucinations lasted for two months, and she had been treated at the Clinic for Psychiatry and Clinic for Infectious Diseases. The cerebrospinal fluid analysis showed a lower level of glucose and a higher level of proteins. Small shaded areas of basal leptomeninges and hydrocephalus were found by computed tomography and magnetic resonance imaging. The autopsy showed a dark brown mass on basal leptomeninges with blurred boundaries. No pigmented skin lesions were found. Histopathological analysis revealed a primary leptomeningeal melanocytosis. CONCLUSION: Primary leptomeningeal melanocytosis is a rare tumor, difficult to diagnose. This case is being presented for its specificity, since this diagnosis is not frequently seen in practice. PMID- 22838180 TI - Preanalytical phase--a continuous challenge for laboratory professionals. AB - Preanalytical phase is the most vulnerable part of the total testing process and is considered to be among the greatest challenges to the laboratory professionals. However, preanalytical activities, management of unsuitable specimens and reporting policies are not fully standardized, nor harmonized worldwide. Several standards related to blood sampling and sample transportation and handling are available, but compliance to those guidelines is low, especially outside the laboratory and if blood sampling is done without the direct supervision of the laboratory staff. Furthermore, for some most critical procedures within the preanalytical phase, internationally accepted guidelines and recommendations as well as related quality measures are unfortunately unavailable. There is large heterogeneity in the criteria for sample rejection, the different strategies by which unacceptable samples are managed, processed and test results reported worldwide. Management of unacceptable specimens warrants therefore immediate harmonization. Alongside the challenging and long road of patient safety, preanalytical phase offers room for improvement, and Editors at Biochemia Medica Journal definitely hope to continue providing a respective mean for reporting studies on different preanalytical phase topics. With pleasure and delight we invite potential future authors to submit their articles examining the quality of various preanalytical activities to Biochemia Medica. We will keep nurturing this topic as our prominent feature and by this we hope to be able to deliver valid evidence for some future guidelines and recommendations. PMID- 22838181 TI - Analysis of censored data. AB - Analyzing events over time is often complicated by incomplete, or censored, observations. Special non-parametric statistical methods were developed to overcome difficulties in summarizing and comparing censored data. Life-table (actuarial) method and Kaplan-Meier method are described with an explanation of survival curves. For the didactic purpose authors prepared a workbook based on most widely used Kaplan-Meier method. It should help the reader understand how Kaplan-Meier method is conceptualized and how it can be used to obtain statistics and survival curves needed to completely describe a sample of patients. Log-rank test and hazard ratio are also discussed. PMID- 22838182 TI - Insights into complexity of congenital disorders of glycosylation. AB - Biochemical and biological properties of glycoconjugates are strongly determined by the specific structure of its glycan parts. Glycosylation, the covalent attachment of sugars to proteins and lipids, is very complex and highly coordinated process involving > 250 gene products. Deficiency of glycosylation enzymes or transporters results in impaired glycosylation, and consequently pathological modulation of many physiological processes. Inborn defects of glycosylation enzymes, caused by the specific mutations, lead to the development of rare, but severe diseases - congenital disorders of glycosylation (CDGs). Up today, there are more than 45 known CDGs. Their clinical manifestations range from very mild to extremely severe (even lethal) and unfortunately, only three of them can be effectively treated nowadays. CDG symptoms highly vary, though some are common for several CDG types but also for other unrelated diseases, especially neurological ones, leaving the possibility that many CDGs cases are under- or misdiagnosed. Glycan analysis of serum transferrin (by isoelectric focusing or more sophisticated methods, such as HPLC (high-performance liquid chromatography) or MALDI (matrix-assisted laser desorption/ionization)) or serum N-glycans (by MS), enzyme activity assays and DNA sequence analysis are the most frequently used methods for CDG screening and identification, since no specific tests are available yet. In this review we summarize the current knowledge on the clinical, biochemical and genetic characteristic of distinct CDGs, as well as existing diagnostic and therapeutic procedures, aiming to contribute to the awareness on the existence of these rare diseases and encourage the efforts to elucidate its genetic background, improve diagnostics and develop new strategies for their treatment. PMID- 22838183 TI - Macroprolactinemia: new insights in hyperprolactinemia. AB - Hypersecretion of prolactin by lactotroph cells of the anterior pituitary may lead to hyperprolactinemia in physiological, pathological and idiopathic conditions. Most patients with idiopathic hyperprolactinemia may have radiologically undetected microprolactinomas, but some may present other causes of hyperprolactinemia described as macroprolactinemia. This condition corresponds to the predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa), that have been postulated to represent prolactin monomer complexed with anti-prolactin immunoglobulins or autoantibodies. The prevalence of macroprolactinemia in hyperprolactinemic populations between 15-46% has been reported. In the pathophysiology of macroprolactinemia it seems that pituitary prolactin has antigenicity, leading to the production of anti-prolactin autoantibodies, and these antibodies reduce prolactin bioactivity and delay prolactin clearance. Antibody-bound prolactin is big enough to be confined to vascular spaces, and therefore macroprolactinemia develops due to the delayed clearance of prolactin rather than increased production. Although the clinical symptoms are less frequent in macroprolactinemic patients, they could not be differentiated from true hyperprolactinemic patients, on the basis of clinical features alone. Although gel filtration chromatography (GFC) is known to be the gold standard for detecting macroprolactin, the polyethylene glycol precipitation (PEG) method has offered a simple, cheap, and highly suitable alternative. In conclusion, macroprolactinemia can be considered a benign condition with low incidence of clinical symptoms and therefore hormonal and imaging investigations as well as medical or surgical treatment and prolonged follow-up are not necessary. PMID- 22838184 TI - Preanalytical management: serum vacuum tubes validation for routine clinical chemistry. AB - INTRODUCTION: The validation process is essential in accredited clinical laboratories. Aim of this study was to validate five kinds of serum vacuum tubes for routine clinical chemistry laboratory testing. MATERIALS AND METHODS: Blood specimens from 100 volunteers in five different serum vacuum tubes (Tube I: VACUETTE, Tube II: LABOR IMPORT, Tube III: S-Monovette, Tube IV: SST and Tube V: SST II) were collected by a single, expert phlebotomist. The routine clinical chemistry tests were analyzed on cobas 6000 module. The significance of the differences between samples was assessed by paired Student's t-test after checking for normality. The level of statistical significance was set at P < 0.005. Finally, the biases from Tube I, Tube II, Tube III, Tube IV and Tube V were compared with the current desirable quality specifications for bias (B), derived from biological variation. RESULTS AND CONCLUSIONS: Basically, our validation will permit the laboratory or hospital managers to select the brand's vacuum tubes validated according him/her technical or economical reasons, in order to perform the following laboratory tests: glucose, total cholesterol, high density lipoprotein-cholesterol, triglycerides, total protein, albumin, blood urea nitrogen, uric acid, alkaline phosphatise, aspartate aminotransferase, gamma glutamyltransferase, lactate dehydrogenase, creatine kinase, total bilirubin, direct bilirubin, calcium, iron, sodium and potassium. On the contrary special attention will be required if the laboratory already performs creatinine, amylase, phosphate and magnesium determinations and the quality laboratory manager intend to change the serum tubes. We suggest that laboratory management should both standardize the procedures and frequently evaluate the quality of in vitro diagnostic devices. PMID- 22838185 TI - The effects of different syringe volume, needle size and sample volume on blood gas analysis in syringes washed with heparin. AB - INTRODUCTION: We evaluated the effect of different syringe volume, needle size and sample volume on blood gas analysis in syringes washed with heparin. MATERIALS AND METHODS: In this multi-step experimental study, percent dilution ratios (PDRs) and final heparin concentrations (FHCs) were calculated by gravimetric method for determining the effect of syringe volume (1, 2, 5 and 10 mL), needle size (20, 21, 22, 25 and 26 G) and sample volume (0.5, 1, 2, 5 and 10 mL). The effect of different PDRs and FHCs on blood gas and electrolyte parameters were determined. The erroneous results from nonstandardized sampling were evaluated according to RiliBAK's TEa. RESULTS: The increase of PDRs and FHCs was associated with the decrease of syringe volume, the increase of needle size and the decrease of sample volume: from 2.0% and 100 IU/mL in 10 mL-syringe to 7.0% and 351 IU/mL in 1 mL-syringe; from 4.9% and 245 IU/mL in 26G to 7.6% and 380 IU/mL in 20 G with combined 1 mL syringe; from 2.0% and 100 IU/mL in full filled sample to 34% and 1675 IU/mL in 0.5 mL suctioned sample into 10 mL syringe. There was no statistical difference in pH; but the percent decreasing in pCO2,, K+, iCa2+, iMg2+; the percent increasing in pO2 and Na+ were statistical significance compared to samples full-filled in syringes. The all changes in pH and pO2 were acceptable; but the changes in pCO2, Na+, K+ and iCa2+ were unacceptable according to TEa limits except fullfilled-syringes. CONCLUSIONS: The changes in PDRs and FHCs due nonstandardized sampling in syringe washed with liquid heparin give rise to erroneous test results for pCO2 and electrolytes. PMID- 22838186 TI - Stability studies of common biochemical analytes in serum separator tubes with or without gel barrier subjected to various storage conditions. AB - INTRODUCTION: The collected and shipped blood samples are exposed to a various extra-analytical factors prior to analysis. The aim of the study was to determine the stability of analytes in serum gel tubes and plain tubes exposed to a range of storage temperatures and times after centrifugation. MATERIALS AND METHODS: Fifteen healthy volunteers were recruited and venous blood was collected into four tubes, two with and two without gel separator. Analyzing the baseline samples in 30 min, all were stored at 4 degrees C or 24 degrees C for 6, 12, 18, 24, 30, 36, 48 and 72 hours and 1 week. Sixteen biochemical anaytes were measured on each sample. Variations remained under the desirable bias considered as clinically insignificant. RESULTS: On day three, most analytes remained stable including albumin, protein, creatinine, cholesterol, triglycerides, gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), creatine kinase (CK), lactate dehydrogenase (LD) regardless of tube types. Glucose concentration decreased markedly (P = 0.001) beginning from the first hours of storage in plain serum. The stability maximized for the analytes including glucose, total bilirubin, urea nitrogen (BUN), uric acid stored at 4 degrees C in gel tubes. Aspartate aminotransferase (AST) activity increased significantly (P = 0.002) up to 48-h, however bias was not significant clinically. High density lipoprotein (HDL) concentration was stable in gel tubes at 24 degrees C, in plain tubes at 4 degrees C stored up to 36-h. CONCLUSION: Serum gel or non-gel tubes might be used interchangeably for 11 analytes chilled or at 24 degrees C, whereas some restrictions must be applied for glucose, AST, BUN, HDL, and uric acid. PMID- 22838187 TI - FABP2 gene polymorphism and metabolic syndrome in elderly people of croatian descent. AB - INTRODUCTION: Metabolic syndrome (MetS) is a multifactorial disorder in which dyslipidemia plays an important role. Fatty acid-binding protein 2 (FABP 2) is responsible for transport of free fatty acids in the intestinal endothelium cells. FABP2-genetic variants might affect plasma lipid concentrations and intracellular lipid transport. The aim of this study was to investigate the association between FABP2 Ala54Thr genetic polymorphism and metabolic syndrome and some biochemical and anthropological parameters in elderly subjects. MATERIALS AND METHODS: This cross-sectional study included 140 men and 176 women older than 70 years. Fasting serum concentration of glucose, lipid parameters, total proteins and C-reactive protein were determined by standardized methods. Presence (MetS(+)) or absence (MetS(-)) of MetS was determined according to criteria of the International Diabetes Federation. FABP2 genetic polymorphism Ala54Thr (rs1799883) was genotyped with PCR-RFPL. RESULTS: The genotype frequencies for Ala/Ala, Ala/Thr and Thr/Thr genotype were 60, 36 and 6 in MetS( ), and 131, 70 and 13 in MetS(+), respectively, without statistical significance (P = 0.567). Ala/Ala genotype was a subgroup of non-carriers, while Ala/Thr and Thr/Thr genotypes were Thr54-carriers. Median triglyceride concentration was significantly lower in carriers then in non-carriers for whole MetS(+) group (P = 0.050); there were no significant difference between men with MetS (P = 0.144), but there was a difference between women with MetS (P = 0.020). T-test showed that mean HDL cholesterol concentrations in MetS(+) group for Thr54-carriers was significantly higher in whole group (P = 0.001), and for both genders (men P = 0.039; women P = 0.004) as compared to non-carriers. CONCLUSIONS: FABP2 genetic polymorphism is associated with lower triglyceride and higher HDL-cholesterol concentrations in elderly subjects with MetS. This genetic variation might be a useful marker for understanding dyslipidemia in MetS. PMID- 22838188 TI - Diagnostic accuracy of heart fatty acid binding protein (H-FABP) and glycogen phosphorylase isoenzyme BB (GPBB) in diagnosis of acute myocardial infarction in patients with acute coronary syndrome. AB - INTRODUCTION: This study aimed to assess whether heart fatty acid-binding protein (H-FABP) and glycogen phosphorylase isoenzyme BB (GPBB) could be used for the accurate diagnosis of acute myocardial infarction (AMI) in acute coronary syndrome (ACS) patients. MATERIALS AND METHODS: The study included 108 ACS patients admitted to a coronary unit within 3 h after chest pain onset. AMI was distinguished from unstable angina (UA) using a classical cardiac troponin I (cTnI) assay. H-FABP and GPBB were measured by ELISA on admission (0 h) and at 3, 6, 12, and 24 h after admission; their accuracy to diagnose AMI was assessed using statistical methods. RESULTS: From 92 patients with ACS; 71 had AMI. H-FABP and GPBB had higher peak value after 3 h from admission than cTnI (P = 0.001). Both markers normalized at 24 h. The area under the receiver operating characteristic curves was significantly greater for both markers in AMI patients than in UA patients at all time points tested, including admission (P < 0.001). At admission, the H-FABP (37%) and GPBB (40%) sensitivities were relatively low. They increased at 3 and 6 h after admission for both markers and decreased again after 24 h. It was 40% for H-FABP and approximately 2-times lower for GPBB (P < 0.01). In AMI patients, both biomarkers had similar specificities, positive- and negative-predictive values, positive and negative likelihood ratios, and risk ratios for AIM. CONCLUSION: H-FABP and GPBB can contribute to early AMI diagnosis and can distinguish AMI from UA. PMID- 22838190 TI - The most common nonconformities encountered during the assessments of medical laboratories in Hong Kong using ISO 15189 as accreditation criteria. AB - INTRODUCTION: ISO 15189 was a new standard published in 2003 for accrediting medical laboratories. We believe that some requirements of the ISO 15189 standard are especially difficult to meet for majority of laboratories. The aim of this article was to present the frequency of nonconformities to requirements of the ISO 15189 accreditation standard, encountered during the assessments of medical laboratories in Hong Kong, during 2004 to 2009. MATERIALS AND METHODS: Nonconformities reported in assessments based on ISO 15189 were analyzed in two periods - from 2004 to 2006 and in 2009. They are categorized according to the ISO 15189 clause numbers. The performance of 27 laboratories initially assessed between 2004 and 2006 was compared to their performance in the second reassessment in 2009. RESULTS: For management requirements, nonconformities were most frequently reported against quality management system, quality and technical records and document control; whereas for technical requirements, they were reported against examination procedures, equipment, and assuring quality of examination procedures. There was no major difference in types of common nonconformities reported in the two study periods. The total number of nonconformities reported in the second reassessment of 27 laboratories in 2009 was almost halved compared to their initial assessments. The number of significant nonconformities per laboratory significantly decreased (P = 0.023). CONCLUSION: Similar nonconformities were reported in the two study periods though the frequency encountered decreased. The significant decrease in number of significant nonconformities encountered in the same group of laboratories in the two periods substantiated that 15015189 contributed to quality improvement of accredited laboratories. PMID- 22838189 TI - Cardiac indexes, cardiac damage biomarkers and energy expenditure in professional cyclists during the Giro d'Italia 3-weeks stage race. AB - INTRODUCTION: The study of cardiac response to strenuous and continuous exercise is crucial to understanding the physiology of endurance. N-terminal proB-type natriuretic peptide (NT-proBNP) is a potential marker for monitoring myocardial wall stress, and troponins (TnT and TnI) are widely used in the diagnosis of cardiac ischemia and infarction. Strenuous exercise may generate transitory ischemia, myocardial stress, and diastolic left ventricular dysfunction, inducing the increased production of both these biomarkers. We measured changes in NT proBNP and TnT in elite cyclists during a 3-week stage race, a model of strenuous exercise. MATERIALS AND METHODS: The study population was 9 professional cyclists participating in the 2011 Giro d'Italia. Pre-analytical and analytical phases scrupulously followed official recommendations. Anthropometric data, net energy expenditure and cardiac indexes (rate, diastolic and systolic blood pressure) were recorded. Blood samples were drawn pre-race (day - 1) and at days 12 and 22; NT-proBNP and highly sensitive-troponin (Hs-TnT) concentrations were assayed and corrected for plasma volume changes. RESULTS: Body-mass index decreased and energy expenditure increased by 52% during the race. NT-proBNP concentrations increased [day -1:23.52 ng/L (9.67-34.33); day 12:63.46 ng/L (22.15-93.31); P = 0.039; day 22:89.26 ng/L (34.66-129.78) vs.day -1; P < 0.001] and correlated with heart rate (r = -0.51; P = 0.006), systolic pressure (r = 0.39; P = 0.046) and energy expenditure (r = 0.70; P < 0.001). TnT concentrations did not vary, but a widened TnT amplitude distribution was observed. CONCLUSIONS: Increases in NT proBNP correlated with higher energy expenditure over a 3-week cycling stage race, possibly indicating myocardial stress. PMID- 22838191 TI - [Epigenetics and long-term memory formation]. AB - Mechanisms underlying long-term memory formation are one of the hottest topics in neurobiology. It was shown that gene expression is needed for the long-term memory formation. Profiles of expressed genes and their regulation are intensively studied. Multi componential regulatory mechanisms make this task even more difficult. Till now have been described a number of DNA binding transcription factors involved in gene expression regulation during learning. However activation of transcription factors is not sufficient for the induction of gene expression, and for this process chromatin modification (remodeling) is necessary. Processes of chromatin remodeling are considered to be epigenetical (on top of genome). Histone phosphorylation, methylation and acetylation, as well as DNA methylation play the most important role in chromatin remodeling. Dysfunction of these processes leads to the inability to form long-term memory. In this review we will describe role of transcription factors and chromatin modifications in the long-term memory formation of invertebrates and vertebrates. Additionally we will discuss perspectives of memory improvement through the modifications of the epigenetic mechanisms. PMID- 22838192 TI - [Inhibitory regulation of glutamate receptors in the frog motoneuron]. AB - The interaction of exogenously applied excitatory (glutamate and their agonists NMDA, AMPA, kainate) and inhibitory (glycine and GABA) amino acid effects was studied intracellularly in the motoneurones of the isolated frog spinal cord. During simultaneous glycine or GABA bath applications GLU-, AMPA-, KA- and NMDA evoked responses were, respectively, decreased up to 45.8 +/- 2.9% (n = 12) and 67.8 +/- 3.9% (n = 16), 13.9 +/- 4.3% (n = 9) and 32.1 +/- 8.3% (n = 12), 36.8 +/ 8.2% (n = 7) and 48.0 +/- 11.8% (n = 6), 7.7 +/- 3.5% (n = 9) and 18.1 +/- 3.8% (n = 14) from the control. Sequential applications of EAA after glycine or GABA as well as the applications of EAA-agonist and glycine (GABA) mixture demonstrated similar results. The decrease of EAA-responses by glycine and GABA was abolished by selective GlyR antagonist strychnine (1 microM) and the selective GABAR antagonist SR95531 (gabazine, 20 MM), respectively. The data revealed differences in inhibitory effect of glycine and GABA on the excitation responses mediated by different types of glutamate receptors in the frog motoneurones: the predominant inhibitory effect of glycine and GABA on NMDA responses and weak inhibitory effect on KA- and GLU-responses. Inhibitory effect of glycine was twice as much as that of GABA at the same concentration. PMID- 22838193 TI - [The adrenergic mechanisms are involved in the pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits]. AB - In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of alpha adrenoreceptors by phentolamine or N-cholinoreceptors of autonomic ganglia by hexamethonium. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was elevated not significantly, the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of alpha adrenoreceptors the pulmonary artery flow and cardiac output decreased in the same level and the pulmonary vascular resistance was decreased. In these conditions the pulmonary artery pressure decreased more than in control animals, meanwhile the pulmonary artery flow was decreased in the same level as in the last case. Following myocardial ischemia after the blockade of N-cholinoreceptors the pulmonary hemodynamics changes were the same as they were following myocardial ischemia in the control rabbits, the cardiac output decreased more than pulmonary artery flow. The disbalance of the cardiac output and pulmonary artery flow changes in the case of myocardial ischemia was caused by the pulmonary vessel reactions following activations of the humoral adrenergic mechanisms. PMID- 22838194 TI - [Respiratory responses to microinjections of gastrin-releasing peptide into the solitary tract nucleus]. AB - In acute experiments on urethane-anesthetized rats, the respiratory effects ofmicroinjections of 10(-5), 10(-8) and 10(-10) M gastrin-releasing peptide (GRP) into the solitary tract nucleus were investigated. It was found that microinjections of the neuropeptide induced an increase in tidal volume, amplitude of diaphragm and external intercostal muscles firing activity and in expiratory duration. The most obvious respiratory responses observed when 10(-8) M GRP was used, while 10(-10) M GRP appeared to be sub-threshold and didn't alter the breathing pattern and activity of inspiratory muscles. In some experiments, where the blood pressure and the heart rate was monitored alone with breathing pattern, these parameters did not change after GRP microinjections into the solitary tract nucleus. The obtained data together with particularities of the distribution of GRP receptors in the brainstem suggest the possibility of GRP involvement into the respiratory control mechanisms at the level of solitary tract nucleus. PMID- 22838195 TI - [Effect of sodium nitroprusside on hemoglobin oxygen binding properties of the blood during hepatic ischemia-reperfusion in rabbits]. AB - The parameters of blood oxygen transport were determined in rabbits during the hepatic ischemia/reperfusion (HIR) with or without sodium nitroprusside (SNP) administration. Hepatic ischemia was induced for 30 min by a. hepatica propria clamping, reperfusion lasted 120 min. Indices of blood oxygen transport (hemoglobin-oxygen affinity index (p50), pO2, pH, pCO2, HCO3-, TCO2, ABE, etc.) and nitrite/nitrate (NO(x)) amounts were measured in blood during HIR. Animals were subdivided into two groups: 1st group--HIR; 2nd--HIR plus SNP infusion (SNP, Sigma, i.v. 10 mcmol/kg). The experiments had shown that HIR led to significant acidic changes in the acid-base balance and high blood p50. The SNP infusion in the 2nd group led to less changing in the p50 values during HIR which were accompanied with high NO(x) levels. We conclude that oxyhemoglobin dissociation curve shift leftwards after SNP administration promotes the maintenance liver during ischemia-reperfusion. PMID- 22838196 TI - [Respiratory reactions on microinjections of GABA and baclofen into the Botzinger complex and the pre-Botzinger complex in rats]. AB - In adult anaesthetized rats the respiratory reactions to microinjections of GABA (10(-5) M) and baclofen (10(-6) M) into Botzinger complex (BC) and pre-Botzinger complex (PBC) were investigated. It was shown, that GABA microinjections into BC shortened inspiratory time and extended expiratory time while respiratory rate was not changed essentially, under this conditions the tidal volume and ventilation were increased. GABA microinjections into PBC significantly inhibited respiratory rhythm due to inspiratory and expiratory time prolongations and reduced tidal volume. The microinjections of baclofen into BC reduced expiration time and ventilation, and increased respiratory frequency whereas microinjections into PBC increased tidal volume without respiratory rate and expiratory time changes. It is suggested that the reactions observed demonstrate the various contribution of GABAergic mechanisms, including GABA(B)-receptors within BC and PBC, in control of respiratory pattern parameters. PMID- 22838197 TI - [Influence of corticotropin-releasing factor fragment CRF4-6 on metabolism in rats]. AB - Influence of corticotropin-releasing factor fragment CRF4-6 on metabolism in the rat was investigated in this study. Tripeptide (10 mkg/rat) after intracerebroventricular infusion to anesthetized animals increased metabolic rate, not affecting the respiratory ratio, induced hyperglycemia and hyperthermia. Synchronously with that heart rate and arterial pressure did also increase. Changes in energy metabolism induced by CRF4-6 closely resemble the effect of untruncated corticotropin-releasing factor molecule. Results of this study and the range of tripeptide effects described previously evidence that CRF4 6 is a physiologically active regulatory molecule, a derivative of corticotropin releasing factor, that expands and prolongs effects of the parent molecule. PMID- 22838198 TI - [Effect of estradiol on food intake, glucose and fat metabolism in mice C57BL/6J with mutation yellow at the agouti locus]. AB - Mutation yellow at the agouti locus in mice (A(y)/a-mice) causes the increase of food intake and development of obesity and type 2 diabetes. In A(y)/a-females the disturbances of glucose and fat metabolisms occur after puberty. We have assumed that the mutation yellow violates the regulatory effect of estradiol on glucose and fat metabolism in mice. We investigated the effects of ovariectomy and estradiol treatment on body weight, food intake, glucose tolerance, plasma levels of glucose, insulin and etherified fatty acids in A(y)/a-females. C57Bl/6J females, not carrying yellow mutation at the agouti locus (a/a-mice), were used as a control. The data suggest that the yellow mutation did not affect estradiol regulation of food intake and glucose blood levels after a night of fasting, but, apparently, prevented estradiol participation in the regulation of glucose and fat metabolisms in the muscle and fat tissues. PMID- 22838199 TI - [Long-term effects of stress in critical periods of development on reactivity of adult female rats]. AB - Effects of stress during different periods of ontogeny, namely, the prenatal, prepubertal, or their combination (prenatal+prepubertal), on the indices of psychoemotional and tonic pain-related behaviors, as well as corticosterone reactivity after pain behavior were investigated in adult 90-day-old female Wistar rats. Our data show for the first time, the similarity of effects of prenatal (immobilization stress of a rat dam during the last week of pregnancy) and prepubertal (forced swimming, pain-related response in the formalin test) stresses on the indices under study, an increase in the time of immobility and in licking duration, but the difference between effects of combined stress on these indices. Pain-related response increased corticosterone in prepubertally stressed rats while in prenatally stressed rats, decreased it. In rats experienced combined stress, formalin-induced pain increased corticosterone as compared with that in prenatally, but not in prepubertally stressed rats. A positive correlation between pain-related reaction and stressed hormonal response was revealed in prepubertally stressed animals. So, long-term effects of stress during critical periods of ontogeny determine stress reactivity of behavioral and hormonal responses in adult female rats. PMID- 22838200 TI - [Study of parvocellular and magnocellular visual channels in normal subjects and in patients with psychopathology]. AB - We measured susceptibility to the Muller-Lyer illusion in schizophrenic patients and normal observers. The images of the Muller-Lyer figure were digitally filtered in a high-frequency and low-frequency band by wavelet filter. Patients with schizophrenia are more susceptible to Muller-Lyer illusion, than mentally healthy examinees. The images of the Muller-Lyer figure with low spatial frequency were perceived in a similar way by the schizophrenic patients on the initial stage of disease and the control subjects. Patients with schizophrenia were more sensitive to the Muller-Lyer illusion when the image contained only high or medium spatial frequency. Schizophrenic patients in advanced stage were more susceptible to the illusion while presented with all types of images of the Muller-Lyer figure than the control group. It is hypothesized that those differences arise from the mismatch work of the magnocellular and parvocellular systems. It is known that images with the high spatial frequencies are most relevant for the parvocellular visual channels. The magnocellular visual channels are most sensitive to the images with the low spatial frequencies. Thus these findings demonstrate a significant impairment in parvocellular pathway function in patients on initial stage of schizophrenia. The patients on advanced stage of schizophrenia demonstrate impairment of both the parvocellular and magnocellular systems. PMID- 22838201 TI - [Erythropoietin level in tear and blood plasma of people with myopia including those who wear soft contact lens]. AB - Erythropoietin level was evaluated in tear film and blood plasma of 63 people with emmetropia (30 people) and myopia (33 people). 17 myopic volunteers wear soft contact lens. There were no statistically significant differences between erythropoietin level in tear samples of emmetropic people, myopic people, and people who wear soft contact lens. Physiological level of erythropoietin in tear of myopic volunteers wearing soft contact lens was established. PMID- 22838202 TI - Tuberculosis prevention: an enigma worth unravelling. PMID- 22838203 TI - Contributions of the Tuberculosis Research Centre, Chennai in the field of epidemiology of tuberculosis (a review over 50 years). PMID- 22838204 TI - Multi-antigen and antibody assays (SEVA TB ELISA) for the diagnosis of tuberculous pleural effusion. AB - OBJECTIVE: Prospective evaluation of inhouse developed SEVA TB ELISA using cocktail of Mycobacterial antigens ES-31 and EST-6 (containing ES-38 and ES-41) and their specific antibodies in the diagnosis of Tuberculous pleural effusion was done in a tertiary care hospital. METHODS: Detection of circulating free and immune-complexed (IC) antigens and antibody by sandwich and indirect peroxidase ELISA respectively was done in pleural fluid and sera specimens. Total 33 patients with pleural effusion, including 24 patients diagnosed as tuberculous pleural effusion based on clinico-radiological, microbiological and biochemical profile (protein, LDH and ADA) of pleural effusion and nine patients with non tuberculous pleural effusion, were studied. RESULTS: Pleural fluid showing either antigen or immune-complexed antigen or antibody positive was considered as ELISA positive for tuberculous pleural effusion. Multi antigen and antibody assay (SEVATB ELISA) showed 100% specificity and 83% sensitivity in pleural fluid while 78% specificity and 92% sensitivity in serum of tuberculous pleuritis patients. CONCLUSION: This study showed usefulness of SEVATB ELISA, using cocktail of ES-31 and EST-6 antigens and their antibodies for antibody and antigen detection respectively in analysis of either sera or pleural fluid samples of suspected tuberculous pleuritis patients as an adjunct test to clinical diagnosis. PMID- 22838205 TI - Morbidity and mortality at five years after initiating Category I treatment among patients with new sputum smear positive pulmonary tuberculosis. AB - BACKGROUND: Evaluation of disease outcome is central to the assessment of tuberculosis control programmes. Most of the follow up studies in RNTCP are short term. Five year follow up studies have not been done previously in this region. The objective of the present study is to [corrected] evaluate the outcome of Category I treatment in smear positive tuberculosis, five years after treatment in terms of relapse, sequelae and death and to know the associated factors. MATERIAL AND METHODS: Patients who had registered for Category 1 treatment during the period 2002 - 2004 were followed up at five years with clinical evaluation, Chest X-ray, ESR and sputum AFB smear. RESULTS: Of the 224 patients who were studied, 81% patients were males. Addictions, including smoking and alcoholism, were prevalent in 136 patients (61%). Treatment success rate at six months was 94.2%. At the end of five years, 124 patients (57.9%) were symptomatic, 59% patients had radiological sequelae, relapse in 10 patients (4.5%), and mortality in 12 (5.4%) patients. Diabetes mellitus was the most common comorbid illness. Smoking and age > or = 45 years were associated with radiological sequelae. Smoking was significantly associated with mortality. Smokers had worse outcomes in all parameters. CONCLUSIONS: Relapse rate was 4.5% and overall mortality was 5.4% at the end of five years. Significant proportion of patients has radiological sequelae. Smoking was the preventable risk factor associated with sequelae, relapse and mortality. PMID- 22838206 TI - Utility of MPT 64 antigen detection assay for rapid characterization of mycobacteria in a resource constrained setting. AB - INTRODUCTION: Important reasons for the negligible numbers of laboratories performing characterization of Mycobacteria in resource constrained settings are requirement of biosafety measures, longer turnaround time and laborious nature of tests. A rapid, accurate and simple test for characterization is required. "SD BIOLINE TB Ag MPT 64 Rapid" is a rapid immunochromatographic test for differentiation of Mycobacteria into M. tuberculosis Complex (MTBC) and nontuberculous mycobacteria (NTM). AIM: To evaluate a commercial assay, SD TB Ag MPT64 Rapid for characterization of Mycobacteria isolated on Lowenstein Jensen (LJ) medium. MATERIAL AND METHODS: 150 non duplicate isolates which were previously characterized as MTBC or NTM based on standard phenotypic characteristics were tested by the commercial assay after blinding. The result of the conventional phenotypic test and the commercial assay was compared. Any discordant result was referred for confirmation by genotypic Mycobacterium CM assay (Hain's life sciences, Germany). Sensitivity and specificity of the commercial assay was calculated using the results of conventional phenotypic and genotypic tests as gold standard. RESULTS: Phenotypically, 124 isolates were characterized as MTBC and 26 as NTM. The commercial assay gave concordant results for 149 isolates. One MTBC isolate did not demonstrate a band. The sensitivity, specificity, PPV and NPV was 99.19%, 100%, 100% and 97.3% respectively. The total turnaround time for the rapid assay was 30 minutes compared to a few hours to days for phenotypic and genotypic method. CONCLUSION: "SD BIOLINE TB Ag MPT 64 Rapid" is a simple, rapid and reliable test to differentiate MTBC from NTM. PMID- 22838207 TI - Multiple visceral abscesses due to tuberculosis. AB - Tuberculosis is a global epidemic, especially in India. In immuno-competent host, abdominal tuberculosis most commonly presents as ileo-caecal tuberculosis and ascitis. Presented is a rare case of immuno-competent host with abdominal tuberculosis in the form of multiple visceral abscess. PMID- 22838208 TI - Seizures with single therapeutic dose of isoniazid. AB - Isoniazid (INH) is an integral component of treatment of tuberculosis. An acute overdose is potentially fatal and is characterised by the clinical triad of repetitive seizures unresponsive to the usual anticonvulsants, metabolic acidosis with a high anion gap and coma. A case of isoniazid induced seizures after therapeutic dose of 600 mg. as a part of CAT I thrice weekly intermittent anti tuberculosis regimen for pulmonary tuberculosis is reported. The frequency of the usage of Isoniazid as antituberculosis therapy requires that physicians be aware of such toxicity. PMID- 22838209 TI - Encephalopathy due to tubercular otitis media. AB - Middle ear infection due to Mycobacterium tuberculosis has been reduced from 3-5% to 0.05-0.9% in the last century due to advent of effective anti-tuberculosis therapy. On the other side, this decrease in frequency of tuberculous otitis media along with indistinguishable signs and symptoms of frequently occurring non tuberculous otitis media makes clinicians vulnerable to delayed or misdiagnosis of the disease. A case of tubercular otitis media with atypical clinical manifestations in the form of encephalopathy is presented. PMID- 22838210 TI - Status report on RNTCP. PMID- 22838211 TI - Fate of sputum samples transported in bottles containing cetylpyridinium chloride and sodium chloride: a national reference laboratory study. AB - The transportation of sputum samples may sometimes take more than one week which results in an increased contamination rate and loss of positive cultures. The current study was planned to analyze the recovery rate of mycobacteria from transported samples with and without Cetylpyridinium chloride (CPC). Addition of CPC is useful for isolation of M. tuberculosis from sputum subjected to long-term storage. PMID- 22838212 TI - Changing trends of cutaneous tuberculosis in the era of DOTS strategy. PMID- 22838213 TI - Influence of salinity upon the phenotypic expression of antibiotic resistance in nonhalophilic and halophilic vibrios. AB - The purpose of the present work is to demonstrate the influence of different NaCI concentrations included in the Mueller Hinton medium, upon the antibiotic susceptibility of 10 non-halophilic and 28 halophilic Vibrio strains. The highest number of resistance aspects were recorded at 1% NaCl concentration for V. cholerae O1/non O1 strains and at 3% for V. parahaemolyticus, V. algynolyticus, V. vulnificus, V. fisheri, V. anguillarum and V. metschnikovii. PMID- 22838214 TI - Generation of some new mutant xylitol producing yeast strains. AB - Xylitol, a sugar alcohol with various utilisations in food, pharmaceutical and cosmetics industry can be produced by yeasts via biotechnologies far more economically efficient and environmentally friendly than chemical separation from natural sources. The present paper reports on a successful attempt to identify high performance xylitol producers among the representatives of the Candida and Rhodotorula genera, followed by the enhancement of their capacities by mutagenesis. The strain designated as C. boidinii ICCF-UV10 was finally selected as the best xylitol producer from the parental and mutant strains. PMID- 22838215 TI - The tip of the iceberg: quinolone-resistance conferred by mutations in gyrA gene in non-typhoidal Salmonella strains. AB - Food-borne infections due to Salmonella spp. seldom require antimicrobial therapy, but this is compulsory in systemic salmonellosis. Salmonella resistance to a large panel of antibiotics has been described worldwide. Since the introduction of nalidixic acid in therapy, Salmonella spp. have steadily developed resistance, especially over the last three decades. The source of quinolone resistance is thought to be the selective pressure determined by the use of quinolones in both human and veterinary practices. Resistance acquisition of Salmonella strains is a stepwise process. Several mechanisms are described, which can lead to the development of quinolone resistance. The main mechanism is considered to be linked with mutations in the quinolone-resistance determining region (QRDR) of the target genes (gyrA and gyrB encoding DNA gyrase, and parC and parE encoding topoisomerase IV). This first step in mutational resistance usually determines a rise in the nalidixic acid minimal inhibitory concentration (MIC). The most common amino acid substitutions in the GyrA subunit, resulting in varied degrees of quinolone resistance, occur at codons Ser83 and Asp87. Higher levels of resistance may occur by further mutational steps, with amino acid changes in the same or a different target enzyme. Other mechanisms are as well involved, like increased efflux or plasmid-mediated resistance. Acknowledgement of the epidemiology and the onset mechanisms of quinolone resistance in Salmonella spp. is compulsory, and surveillance for resistant bacteria among human, animal and food sources remains critical. PMID- 22838216 TI - The adenoviral infections in children admitted to hospital with pneumonia, acute bronchiolitis or respiratory viral infections. AB - The objective of this study was to investigate the percent of infections with adenovirus (ADV) in children who had pneumonia, acute bronchiolitis or viral respiratory infections and were admitted to two pediatrics hospitals in Bucharest (Grigore Alexandrescu Hospital and Alfred Rusescu Hospital). MATERIALS AND METHODS: SUBJECTS: 70 children aged one month - five years, admitted to the above mentioned pediatrics hospitals in Bucharest, who were negative for the Respiratory Syncytial Virus (RSV) and the human Metapneumovirus (hMPV) by Reverse Transcription -Polymerase Chain Reaction (RT-PCR). 48 of them presented pneumonia upon admission to hospital, 6--acute bronchiolitis and 16 respiratory viral infections. Samples (nasal swabs) were taken from patients and introduced in viral transport medium. DIAGNOSTIC METHODS: RT-PCR for RSV and hMPV, Multiplex PCR by seeplex multi-detection system with Seeplex RV/PB 18 ASE Detection for detection of 5 pneumonial bacteria and Real-Time PCR, Duplica Real Time Adenovirus Detection for ADV. RESULTS: Of the total 70 patients negative for RSV, hMPV and 5 pneumonial bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila), 10 were ADV positive; none of the children < 6 months (N = 16) presented ADV infection. In the 6 months - 2 years group (N = 35), 6 were ADV positive. In the 2 - 5 years group (N = 19), 4 were ADV positive. CONCLUSIONS: The percent of ADV infections in children hospitalized with acute respiratory infections (ARI) caused by neither RSV or hMPV is 14.2%. ADV is most frequently encountered in the 6 months 2 years and then 2 - 5 years groups, but the most severe pneumonia forms can be seen in the 6 months - 2 years group. In children < 6 months with acute bronchiolitis ADV was not found to be an etiologic agent. PMID- 22838217 TI - Human MECP2 gene at Q28 arm of X chromosome as a suitable target for monitoring PCR inhibition in a nested, multiplexed HIV-1 DNA detection protocol. AB - Human MECP2 gene located at q28 arm of X chromosome was identified as target for thermal co-amplification with HIV-1 proviral DNA of infected individuals. The selected MECP2 gene-specific primers functioned at a wide range of annealing temperature, extension time and exhibited no significant interaction with pathogen specific primers. A 466 bp PCR amplicon originating from human MECP2 gene was found to be diagnostic for inhibition-free PCR reaction when co amplified with the HIV-1 target gene in a multiplexed, nested PCR reaction. The 5' end of the MECP2 primers were engineered to position an EcoRI restriction endonuclease site to facilitate rapid cloning in various DNA vector molecules at the corresponding EcoRI sites. Cell mass of Escherichia coli (XL1Blue) harboring the recombinant plasmid when added to pleural fluid of HIV-1 infected individuals co-infected with Mycobacterium tuberculosis, generated the diagnostic 466 bp MECP2 PCR amplicon as well as the 194 bp PCR amplicon of target gene from M. tuberculosis. The experiment underlined potential of the region spanning nucleotide position 4118099 to 4118552 of human MECP2 gene (NCBI accession number NT_011726.13) as a reliable target for multiplex PCR to accommodate a wide range of thermal cycling and multiplex reaction conditions. In both cases of this study, electrophoresis-based separation of the 466 bp MECP2 fragment and the 232 bp and 194 bp HIV-1 and M. tuberculosis fragments respectively was distinct and unambiguous. The potential of this human MECP2 gene available from human genome or recombinant plasmid as a potent target to monitor PCR inhibition for a range of different PCR reactions is discussed. PMID- 22838218 TI - Evaluation of UVB light efficacy for inducing apoptosis in Candida albicans cultures. AB - BACKGROUND: Candida albicans is known as part of human's skin normal flora; but simultaneously, is the most common opportunistic fungal pathogen of human which can cause a variety of infections including cutaneous candidiasis. Because of the importance of superficial infections like cutaneous candidiasis, we tried to use Ultraviolet B light as a method of phototherapy for inducing apoptosis in irradiated colonies of Candida albicans. MATERIALS AND METHODS: The Ultraviolet B with the wavelength of 302 nanometer was used for irradiating the colonies of Candida albicans. For detecting the eventual apoptotic reactions, the DNA of irradiated colonies as well as control colonies were extracted and then were run in 1% agarose gel electrophoresis containing ethidium bromide to observe luminescent DNA bands. RESULTS: Despite irradiating of Ultraviolet B to yeast cells, no abnormalities including DNA laddering bands or smears were detected in bands formed by total genomic DNA. DISCUSSION: The applied irradiation protocol in this investigation was not successful to induce apoptotic reactions in Ultraviolet-exposed colonies. Maybe, Heat shock proteins as the important part of fungal protein pool, inhibit the inducing pathway of apoptosis in irradiated colonies of Candida albicans. PMID- 22838219 TI - Identification of four Treponema species in subgingival samples by nested-PCR and their correlation with clinical diagnosis. AB - The relationship between different species of oral Treponemas and inflammation in periodontal disease progression is complex. The purpose of this study was to analyze and compare the subgingival plaque samples collected from periodontally healthy subjects and from chronic gingivitis and periodontitis patients in order to detect the presence of T. denticola, T. pectinovorum, T. socranskii and T. vincentii using nested-PCR technology. After DNA extraction from the samples using QIAmp DNA Mini Kit (QIAGEN, the four Treponema species were determined with nested-polymerase chain reaction which requires two sets of primers to amplify a specific DNA fragment in two separate runs of PCR. Pearson chi-square was implemented to compare the three groups as to the presence of four Treponema species. Results of this investigation showed significant differences between groups regarding subject proportion of T. denticola, T. socranskii, T. pectinovorum, T. vincentii, with a higher percentage of patients from associated disease groups of patients harboring these four species than healthy subjects. These differences were more pronounced in presence of Treponema denticola and Treponema socranskii. Our findings suggest that Treponema denticola and Treponema socranskii concurrent presence indicate more accurately the association with chronic gingivitis and periodontitis. PMID- 22838220 TI - Etiology of pneumonia in children in the absence of pneumococcal and antihaemophilus vaccines. AB - Childhood pneumonia represents an important pathology, a cause of morbidity and mortality worldwide. Our study aims to determine etiology of pneumonia in hospitalized children using several laboratory methods. We performed a prospective study that enrolled 560 children age 1 up to 18 years old all diagnosed with pneumonia by clinical and radiological features. We applied various laboratory methods (serologic, bacteriologic: bronchial aspirate, sputum, pleural effusion and blood culture) in order to identify a pathogen agent that caused pneumonia. Statistics used Statistical Package for Social Science. An etiology was established in 68.92% of all cases included in the study, as follows: in 33.93% viral etiology, in 25.13% we identified Streptococcus pneumoniae, in 20.2% Mycoplasma pneumoniae, Klebsiella pneumoniae in 8.29%, Staphylococcus aureus in 7.51%, Haemophilus influenzae in 4.92%. Mixed bacterial and viral infection was identified in 4.40% of all cases. A potential causative agent of childhood pneumonia was determined in most cases, S. pneumoniae being the main agent involved in community acquired childhood pneumonia in our country. PMID- 22838221 TI - Prevalence of hepatitis B virus in chronic hepatitis B patients. AB - The aim of the current study was to detect HBV by Real time - PCR in chronic hepatitis B patients. Fifty-eight sera of chronic hepatitis B patients were subjected during the period March 2009 to April 2010 in Ilam cities in West of Iran. Sera assayed by real-time PCR and ELISA methods. Twenty serum samples from healthy volunteers and non-hepatitis B patients and negative for hepatitis B seromarkers served as negative controls for the study. Among fifty-eight sera, ELISA showed fifty-five (94.8%) of the samples were positive for HBsAg and three (5.2%) negative results obtained while real-time PCR specified fifty-eight (100%) positive results in chronic hepatitis B patients. HBsAg status did not necessarily reflect HBV DNA level in the serum, as 5.2% of chronic Hepatitis B patients were positive for HBV DNA but negative for HBsAg. HBV DNA was not found to be positive amongst any of the negative controls. Real time - PCR is a sensitive and reproducible assay for HBV DNA quantization. PMID- 22838222 TI - Dental adhesion: mechanism, techniques and durability. AB - Contemporary dental adhesives show favorable immediate results in terms of bonding effectiveness. However, the durability of resin-dentin bonds is their major problem. It appears that simplification of adhesive techniques is rather detrimental to the long-term stability of resin-tooth interface. The hydrostatic pulpal pressure, the dentinal fluid flow and the increased dentinal wetness in vital dentin can affect the intimate interaction of certain dentin adhesives with dentinal tissue. Bond degradation occurs via water sorption, hydrolysis of ester linkages of methacrylate resins, and activation of endogenous dentin matrix metalloproteinases. The three-step etch-and-rinse adhesives still remain the gold standard in terms of durability. This review discusses the fundamental process of adhesion to enamel and dentin with different adhesive techniques, factors affecting the long-term bonding performance of modern adhesives and addresses the current perspectives for improving bond durability. PMID- 22838223 TI - A delayed hypersensitivity reaction to a stainless steel crown: a case report. AB - Stainless steel crowns are commonly used to restore primary or permanent teeth in pediatric restorative dentistry. Here, we describe a case of a delayed hypersensitivity reaction, which manifested itself as perioral skin eruptions, after restoring the decayed first permanent molar tooth of a 13-year-old Caucasian girl with a preformed stainless steel crown. The eruptions completely healed within one week after removal of the stainless steel crown. The decayed tooth was then restored with a bis-acryl crown and bridge. Since no perioral skin eruptions occurred during the six-month follow-up, we presume that the cause of the perioral skin eruptions was a delayed hypersensitivity reaction, which was triggered by the nickel in the stainless steel crown. PMID- 22838224 TI - Comparison of the antibacterial effect of modified 3-mix paste versus Ultrapex over anaerobic microorganisms from infected root canals of primary teeth: an in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate in vitro the antimicrobial efficacy of a modified 3-mix paste and to compare it with an iodoform paste (Ultrapex) against anaerobic microorganisms isolated from root canals of infected or necrotic primary teeth. STUDY DESIGN: An in vitro experimental assay was performed over isolated and identified anaerobic microorganisms of 21 samples, in order to compare the antimicrobial ability of both root canal filling materials, using a disc-diffusion method. RESULTS: A total of 21 microbial samples (15 polymicrobial and 6 monomicrobial) were obtained, from which 19 different strains were identified. Modified 3-mix paste showed an excellent antimicrobial effect against most of both kinds of microbial samples, although some of them exhibited resistance; on the other hand, Ultrapex showed only minimal antimicrobial ability (null or low categories). Clostridium ramosum exhibited the most resistance to both materials. CONCLUSION: The bactericidal effect of the modified 3-mix paste was superior to Ultrapex, with a statistically significant difference, against anaerobic microorganisms isolated from infected root canals of primary teeth. PMID- 22838225 TI - Mandibular block or maxillary infiltration: does it influence children's opposition to a subsequent dental visit? AB - PURPOSE: Local anesthesia by mandibular block or maxillary infiltration is commonly administered to children receiving dental treatment of primary molars. Discomfort, when presenting, most often involves the lower lip. The purpose of this study was to investigate whether children would be more opposed to attending a dental treatment following anesthesia by mandibular block than by maxillary infiltration. METHODS: Each of 102 children in two age groups: 3 to 5 years, and 6 to 9 years, received the two types of local anesthesia at dental appointments one week apart. Their opposition to attending a subsequent appointment was assessed by parent report. RESULTS: More adverse reactions were observed during and following anesthesia with mandibular block than with maxillary infiltration. Few of the children in either age group expressed opposition to attend a dental visit after receiving mandibular block or maxillary infiltration in the previous visit. CONCLUSIONS: Though more adverse reactions were observed in children following mandibular block than maxillary infiltration, this did not result in increased opposition to attend a subsequent dental appointment. PMID- 22838226 TI - Validity and reliability of Oral Impacts on Daily Performances Frequency Scale: a cross-sectional survey among adolescents. AB - AIM: To examine reliability and validity of an abbreviated version of Oral Impacts on Daily Performances (OIDP) questionnaire and to analyze the interrelationship among OIDP scores, socio-demographic characteristics and oral health status among 12-15 year old adolescents in Davanagere city, Karnataka, India. METHOD: The descriptive cross-sectional survey was conducted among 900 adolescents aged between 12-15 years. The study subjects were randomly selected from six high schools. Selected subjects completed a survey instrument designed to measure subjective oral health indicators including the eight-item OIDP frequency scores. The study participants were clinically examined for dental caries and completed a self-administered questionnaire about demographic information and oral behaviors. RESULTS: 44% of the students reported at least one oral impact in the last six months. Cronbach's alpha for the OIDP frequency items was 0.81. Eating was the most common performance affected (33%) followed by cleaning teeth (22%) and speaking (20%). The severity of impacts was low for relaxing and carrying out works. CONCLUSION: The OIDP frequency score have acceptable psychometric properties in the context of an oral health survey among 12-15 year old adolescents. PMID- 22838227 TI - Analysis of root canal treated primary incisor after trauma: two year outcomes. AB - BACKGROUND: The low number of clinical studies of traumatized teeth submitted to root canal treatment is completely out of proportion to the seriousness that dental trauma imposes on children in early years. AIM: This study evaluates the outcomes of root canal treatment (RCT) in traumatized primary incisors and identifies the predisposing factors associated with therapy success. METHODS: This is a retrospective study conducted with all dental records of 704 patients who had one or more teeth with traumatic injuries. Patients with irreversible pulp changes in primary teeth leading to RCT with a 24 month follow-up met the inclusion criteria. RESULTS: Twenty-five maxillary incisors of 17 children were evaluated. The children's age at the time of therapy ranged from 24 to 72 months (mean 47.3). Pulp necrosis was the most common disorder (84.0%) and pre-operative periapical lesions were observed in 52.0%. Coronal discoloration was found in 48.0%. The roots were filled with ZOE paste (68.0%) or Guedes-Pinto paste (32.0%). Overall RCT success rate was 68.0%. The absence of pre-operative periapical lesions (p = 0.02) and pathological root resorption (p = 0.02) presented positive association with therapy success. Success was not associated to filling paste (p = 0.49), filling extent (p = 0.44), of discoloration (p = 0.39) nor the patients' age (p = 0.59). CONCLUSIONS: RCT was considered successful in 68.0% of the cases at the 24 month follow-up. Failure of RCT in traumatized primary incisors was associated with pre-operatory periapical lesions and pathological root resorption. The filling paste, the filling extent and the patient's age were unrelated with therapy success. PMID- 22838228 TI - Apexification of anterior teeth: a comparative evaluation of mineral trioxide aggregate and calcium hydroxide paste. AB - PURPOSE: This study was undertaken to compare the clinical and radiographic effectiveness of Mineral Trioxide Aggregate (MTA) and Calcium Hydroxide in apexification of traumatized young permanent incisors. METHODS: Thirty permanent incisors with necrotic pulps and open apices were evenly divided into two groups- Group I (MTA group) & Group II (Calcium Hydroxide group) and treated by apexification. The time taken for apical barrier formation was analyzed. In MTA group, obturation using gutta-percha points was done after 24 hours, whereas in Calcium Hydroxide group obturation was carried out after radiographic confirmation of an apical barrier. Follow up evaluation (clinical and radiographic) was carried out at- 3, 6, 9 and 12 months. RESULTS: The mean time taken for barrier in Group I was 4.50 +/- 1.56 months whereas for Group II was 7.93 +/- 2.53 months (p value- 0.0002). Radiographic evidence of mean time taken for completion of lamina dura in Group I was 4.07 +/- 1.49 months whereas the time period for Group II was 6.43 +/- 2.59 months (p value- 0.0067). CONCLUSION: MTA demonstrated good success and an effective option for apexification with the advantage of reduced treatment time, good sealing ability, biocompatible and provides barrier for immediate obturation. PMID- 22838229 TI - In vitro biocompatibility tests of glass ionomer cements impregnated with collagen or bioactive glass to fibroblasts. AB - AIM AND DESIGN: To evaluate the biocompatibility of glass ionomer cement (GIC) impregnated with collagen or bioactive glass to BHK-21 fibroblasts in vitro. Mineral Trioxide Aggregate was used as the standard for comparison. Human maxillary central incisors (n = 70) were instrumented with a rotary NiTi system and filled. Following resection of the apical 3mm, root end cavities were prepared and restored with conventional GIC (group 1) or GIC with 0.01%, 0.1% or 1% collagen (groups 2, 3, 4 respectively) or, 10%, 30% or 50% bioactive glass (groups 5, 6, 7 respectively), or Mineral Trioxide Aggregate (group 8). The root slices were incubated in tissue culture plates with BHK-21 fibroblast cell line. Phase contrast and scanning electron microscopes were used to score cell quantity, morphology and cell attachment. The data were statistically analyzed by one way ANOVA with Post Hoc Tukey HSD test (p = 0.05). RESULTS AND CONCLUSIONS: Group 5 showed the highest scores which was significantly higher than all other groups (p < 0.05) except group 8, with which there was no significant difference (p > 0.05). Glass ionomer cement with 10% bioactive glass showed better adhesion and spreading of cells than glass ionomer cement with 0.01% collagen. The biocompatibility of collagen and bioactive glass was concentration dependent. The addition of bioactive glass improved the biocompatibility of glass ionomer cement to fibroblasts better than addition of collagen. PMID- 22838230 TI - Evaluation of short-term fluoride release from fluoride varnishes. AB - OBJECTIVE: The aim of this study was to compare the rate of fluoride release from fluoride varnishes over a 48-hour period and ascertain the time at which a plateau occurred. This data provides clinically relevant time points to resume tooth brushing after fluoride varnish application. STUDY DESIGN: Four commercially available fluoride varnishes, Premier Enamel ProVarnish (EP), Colgate PreviDent (CP), Omni Vanish (OV) and Omni VanishXT (OVXT) were applied on 40 extracted permanent human teeth. Ten teeth served as controls. The teeth were immersed in artificial saliva. At 1, 2, 4, 8, 12, 24 and 48 hours, the teeth were sequentially transferred to new vials. TISAB III and ion selective electrode was used to measure fluoride release. Statistical tools were used to compare the rates of fluoride release and plateau of fluoride release. RESULTS: CP, EP and OV showed a plateau of fluoride release after 4 hours. OVXT did not show a significant change in fluoride release at any time point. EP had the highest fluoride release in the first 8 hours. CONCLUSIONS: CP, EP and OV released maximum rate of fluoride release in the first 4 hours whereas OVXT did not have a plateau. The studied varnishes released different concentrations of fluoride despite the fact that they all contained 5% sodium fluoride. PMID- 22838231 TI - The effects of surface pretreatment on the microleakage of resin-modified glass ionomer cement restorations. AB - OBJECTIVE: To evaluate the effect of different surface pretreatments on the marginal microleakage of Vitremer restorations. STUDY DESIGN: Class V cavities were prepared on the labial and lingual surfaces of extracted human third molar teeth. Cavities were randomly distributed into six groups according to surface treatment, as follows: Group NC (negative control): no surface treatment; Group VP (positive control): Vitremer Primer; Group PA: 32% phosphoric acid; Group PAA: 20% polyacrylic acid; Group PLP: self-etch adhesive (Prompt L Pop); Group PB: etch & rinse adhesive (Prime & Bond NT). All cavities were restored with Vitremer. Teeth were thermocycled, stained with 0.5% basic fuchsin dye and sectioned. Microleakage values were quantitatively assessed by linear measurement of dye penetration using image-analyzing software. Differences between occlusal and gingival microleakage values within groups were evaluated using paired t tests, and differences among groups were analysed using one-way analysis of variance (ANOVA) and Tukey tests. RESULTS: There were statistically significant differences between the occlusal and gingival microleakage values for all groups (p < 0.05). Microleakage differed significantly among surface pretreatment groups (p < 0.001). The negative control and PLP groups showed similar microleakage values, but were significantly higher than other groups for both margins. Although there were no statistically significant differences between positive control and PA, PAA, PB groups, microleakage values of positive control group were smaller than all other experimental groups except for PB group. CONCLUSIONS: Vitremer restorations require surface pretreatment to prevent excessive microleakage. Pretreatment with etch & rinse adhesives and Vitremer Primer may reduce microleakage of Vitremer restorations. PMID- 22838232 TI - Salivary parameters and caries indices in children with black tooth stains. AB - OBJECTIVE: Black tooth stain in children has been associated commonly with a low caries experience. The present study aimed to to compare salivary factors and caries indices in children with and without black tooth stain and to investigate the relationship between caries and caries associated salivary factors in these children. STUDY DESIGN: Salivary flow rate, pH, buffering capacity, total calcium and phosphorus were determined. Calcium and phosphorus levels were assayed by Inductive Coupled Plasma with Atomic Emission Spectrometry. DMFT and dft indices were evaluated according to WHO criteria. RESULTS: Significantly higher levels of salivary buffering capacity and calcium, and lower flow rate were found in children with black tooth stain compared with those of without black tooth stain (p < 0.01, p = 0.044 and p = 0.037, respectively). The differences in phosphorus and pH were not significant between the groups. The dft index was found to be significantly lower in children with black tooth stain than children without black tooth stain (p = 0.030). However, DMFT did not change between the groups. There is no relationship between salivary parameters and caries indices in children with black tooth stain. CONCLUSION: It is suggested that low caries tendency seen in children with black tooth stain may be associated with high salivary calcium and buffering capacity. PMID- 22838233 TI - Extensive idiopathic external apical root resorption on a 13 year old child. AB - External root resorption in permanent teeth can occur as a result of a multitude of local and systemic factors. Root resorption that is idiopathic or occurring without any identifiable underlying cause is an unusual phenomenon, especially in children. This article describes a rare case of extensive external apical root resorption affecting multiple teeth and occurring concomitantly with localized periodontitis in a 13 year-old child. No significant systemic, local or familial findings could be identified as a plausible cause for the root resorption. PMID- 22838234 TI - Salivary sialic acid levels and dental health in children with congenital heart disease. AB - Congenital cardiac disease is one of the most common developmental anomalies in children. Higher caries prevalence and gingivitis compared to healthy children have been shown in children with congenital heart disease which has a significant implication in the medical care of these patients associated with bacteraemia and endocarditis. Sialic acids being terminal sugar components and marker of chronic inflammatory response are found to be present at higher levels in children with poor oral health status. So the present study aimed to evaluate the oral health status and salivary sialic acid levels among the children with congenital heart disease and normal healthy siblings. A total of 71 children with heart diseases aged 6-10 years attending various heart institutes were examined for oral hygiene status, gingival status and dental caries status by using modified WHO oral assessment form. A case-matched control group of 50 children were also examined. Salivary flow rate, pH and sialic acid levels were measured after saliva collection. The results were subjected to Unpaired t test and Pearson's Correlation Coefficient Test. The salivary pH, salivary flow rate, dental caries status, oral hygiene and the gingival status were significantly compromised with a positive correlation with the sialic acid levels in saliva, leading to increased treatment needs in the study group. Therefore the amount of sialic acid in the saliva can be a useful index of the severity of oral disease. PMID- 22838235 TI - Zimmermann-Laband syndrome: a case report. AB - Zimmermann-Laband syndrome is a very rare disorder characterized by gingival fibromatosis, abnormalities of soft cartilages of the nose and/or ears, hypoplastic or absent nails and terminal phalanges, joint hypermobility, hypatoslenomegaly, mild hirsutism and learning difficulties. Early presentation of Zimmermann-Laband syndrome in a newborn has rarely been described. This paper describes a newborn patient with Zimmermann-Laband syndrome. PMID- 22838236 TI - Periodontal condition and orofacial changes in patients with thalassemia major: a clinical and radiographic overview. AB - OBJECTIVE: To assess the prevalence of periodontal disease, orofacial changes and craniofacial abnormalities in patients with thalassemia major (TM). Dental management is discussed STUDY DESIGN: The sample consisted of 54 patients with TM, 31 males and 23 females aged 5.5 to 18.3 years, with the mean age (+/- SD) of 1.6 +/- 3.2 years. The sample was divided into two subgroups according to age. A similar number of unaffected control group matched by age and sex served as a control. Clinical and radiographic examinations were carried out to assess the prevalence of changes caused by this disorder. Student's t-test was used to compare the means between thalassemic group and the control group. The Chi-square test was employed to determine statistical differences in frequencies between the two groups. RESULTS: Poor oral hygiene and gingivitis were observed in 61.1% and 43.0% of the thalassemic patients, respectively. The overall mean plaque score was 1.66 +/- 0.51 and gingival score 1.43 +/- 0.59. In all tested periodontal parameters, a higher frequency and severity were noted in the thalassemic patients compared with controls. More than half of the patients exhibited frontal bossing, saddle nose and to less extent maxillary protrusion; giving in severe cases (16.7%) a "chipmunk" like appearance. Dental discoloration and pallor oral mucosa were noted in 44.4% and 38.9%, respectively. Dental/jaw pain was reported by 40.0% and headache by 29.6% of the patients. Increased overjet was evident in 25.9% of the patients. The majority of the patients had thickened frontal bone (66.7%), and thinned inferior border of the mandible (64.6%). Widened dipolic spaces and spiky roots and were observed in one-third of the patients. The ramus length and width in the patients were significantly smaller than in controls (P < 0.001). CONCLUSION: TM may particularly diagnose through orofacial abnormalities. Dentists required understanding the complications and management of the disease. PMID- 22838237 TI - Correlation of dental maturity with skeletal maturity from radiographic assessment: a review. AB - There have been many attempts to correlate dental development with skeletal growth. The relationship is generally considered to be moderate at best. However, there is evidence that hand-wrist radiographic interpretation of remaining growth can be augmented by taking into account the developing dentition. In addition, the practicality of evaluating routine dental radiographs and avoiding additional radiation is advantageous. To this point, no system has been described to match apical development by Demirjian's stages and compare it to skeletal development and remaining growth. This study reviewed articles pertinent to the relationship between developing teeth and skeletal maturity and remaining growth, and a system is proposed to give practitioners an additional assessment for growth and development. PMID- 22838238 TI - Well-being of Hispanic children in the United States. AB - The availability of general information about the economic, health and social well being of Hispanic children in the United States is essential for dental and other health practitioners. Only recently have government and private agencies moved beyond the standard presentation of information by traditional "white, black and other" groupings. The need is to develop an increased awareness of the different factors which affect children in general, and in particular Hispanic children. An overview is carried out to stimulate such an effort. PMID- 22838239 TI - Risk factors associated with caries experience in children and adolescents with intellectual disabilities. AB - PURPOSE: The purpose of this study was to examine caries experience and associated risk factors in children and adolescents with intellectual disability (ID). METHODS: A total of 86 participants aged 3-13 years (33 with ID and 53 healthy) were included in the study. Participants received an oral examination and their caregivers completed a questionnaire. Caregivers were required to determine the "level of function" of their children with regards to performing self care daily activities (brushing teeth, feeding and self dressing, walking and performing toilet activities). Four levels of function were determined; (A) being completely independent, (D) completely dependent, (B) and (C) partially dependent on caregivers. RESULTS: In healthy participants the mean dft score was 8.83 +/- 4.99 whereas in those with ID the mean dft score was 6.81 +/- 6.11. The mean DFT score in healthy participants was 2.32 +/- 2.98 while the mean DFT in those with ID was 0.92 +/- 1.57. Both dft and DFT scores were significantly different between participants with ID and healthy ones (p = 0. 042, p = 0.044 respectively). Caries status was not associated with gender, age or caregivers' education in the study sample. Significant associations were found between caries experience in participants with ID and their type of school (p = 0.01), nature of diet (p = 0.001) and "level of function" (p = 0.007). CONCLUSIONS: The type of school, nature of diet and "level of function" may be considered as influential risk factors associated with caries experience in children and adolescents with ID. PMID- 22838240 TI - Initial presenting features in gestational trophoblastic neoplasia: does a decade make a difference? AB - OBJECTIVE: To compare the initial clinical presentation of patients who were treated at our center for gestational trophoblastic neoplasia (GTN) between 1996 and 1998 and between 2006 and 2008. STUDY DESIGN: All patients seen at Weston Park Hospitalfor GTN (excluding placental site trophoblastic tumor [PSTT]) between 1996 and 1998 (total, 79) and between 2006 and 2008 (total, 139) were identified and their medical records reviewed. Features from when they first presented with gestational trophoblastic disease (GTD), excluding PSTT, were recorded. During those time periods 1,391 and 1,623 patients, respectively, were registered at our center with GTD. RESULTS: The following results were noted: abnormal vaginal bleeding remains the most common presentation; the proportion of abnormal ultrasound scans at initial diagnosis has risen from 1% to 12%; the mean gestational age of the antecedent pregnancy has dropped from 11.3 to 10.1 weeks; the mean number of evacuations has fallen from 1.9 to 1.2, and the proportion of patients having 2 evacuations has more than halved; and the proportion of patients presenting with GTD requiring chemotherapy for GTN was 4.2% (59 of 1,391) for 1996-1998 and 6.7% (109 of 1,623) for 2006-2008. CONCLUSION: An improvement in ultrasound technology and expertise in early pregnancy is likely to have contributed to a trend toward a lower gestational age at diagnosis of GTD. We noted a major shift in practice towards a higher threshold for repeat evacuations and an increased proportion of patients with GTN receiving chemotherapy. PMID- 22838241 TI - Actinomycin D for methotrexate-failed low-risk gestational trophoblastic neoplasia. AB - OBJECTIVE: To determine outcomes and factors associated with failure of 5-day actinomycin D for treatment of methotrexate-failed low-risk gestational trophoblastic neoplasia (GTN). STUDY DESIGN: We reviewed the records of 358 patients treated with methotrexate 0.4 mg/kg (max 25 mg) IV push q.d. x 5 d every 14 d for FIGO-defined, low-risk GTN between 1979 and 2009. Actinomycin D 0.5 mg IV push q.d. x 5 d every 14 d was given to 64 of 68 patients (18%) who failed methotrexate: 48 (75%) for resistance and 16 (25%) for toxicity. Adjuvant surgery was used in selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: The complete response rate to secondary chemotherapy with actinomycin D for failed methotrexate treatment of low-risk GTN was 75% (48/64), including 71% (34/48) for methotrexate resistance and 88% (14/16) for methotrexate toxicity. All 20 patients (6%) who failed sequential single-agent chemotherapy with methotrexate and actinomycin D were placed into permanent remission with the use of multiagent chemotherapy with or without surgery. The only factor significantly associated with resistance to secondary actinomycin D chemotherapy was clinicopathologic diagnosis of choriocarcinoma versus postmolar GTN (56% versus 20%, p = 0.025). CONCLUSION: Actinomycin D 0.5 mg IV q.d. x 5 d every 14 d used as secondary therapy in methotrexate-failed low-risk GTN resulted in a 75% complete response rate and eventual 100% cure with subsequent multiagent chemotherapy with or without surgery. Resistance to sequential methotrexate and actinomycin D chemotherapy was significantly associated with original FIGO score > or = 3 and clinicopathologic diagnosis of choriocarcinoma. PMID- 22838242 TI - Brain metastasis in gestational trophoblastic neoplasia: an update. AB - OBJECTIVE: To update the treatment of brain metastases in gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center, comparing treatment and outcomes from 1995-2009 with those from 1962-1994. STUDY DESIGN: Thirty-seven patients with GTN who had brain metastases at presentation (25, 68%) or who developed brain metastases during treatment (12, 32%) were treated with chemotherapy and brain irradiation at the Brewer Center between 1962 and 2009 (26 prior to 1995 and 11 since 1995). Patients underwent whole brain irradiation (2400-4000 cGy in 200-300 cGy fractions prior to 1995, and 2400-3000 cGy in 200 cGy fractions since 1995) +/- radiosurgery. RESULTS: Of 11 patients with GTN treated for brain metastases since 1995, 7 (64%) are alive, and 4 died. Six (55%) of the 11 patients treated after 1995 were diagnosed with brain metastases during treatment, 3 (50%) of whom were cured, compared to 6 (23%) of the 26 patients treated before 1995, only 1 (17%) of whom was cured. CONCLUSION: The overall survival for all 37 patients with GTN who had brain metastases from 1962-2009 was 51% (19/37): 46% (12/26) before 1995 and 64% (7/11) after 1995. Survival was significantly influenced by symptoms at presentation: 100% (8/8) for asymptomatic patients versus 41% (7/17) for symptomatic patients (p=0.0005). No patient who died had uncontrolled brain metastases. In our experience, therefore, brain metastases in GTN are curable with a combination of systemic multiagent chemotherapy and whole brain irradiation. PMID- 22838243 TI - Deaths from gestational trophoblastic neoplasia: any lessons to be learned? AB - OBJECTIVE: To review retrospectively the causes of death in unselected patients with gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Between 1975 and 2010, 905 patients with GTN were treated at the Sheffield Centre. Twenty-four of them died. The medical records of these patients were reviewed. RESULTS: Of the 24 patients, 11 died during initial treatment. A further 8 died from disease relapse and progression of the disease. The cause of death was unrelated in the other 5, who were excluded from analysis. For the remaining 19 patients, death was due to metastatic tumor in 13 and was treatment related in 6. Adverse prognostic features for death from GTN included histology (7 were placental site trophoblastic tumor [PSTT]), risk score (15 were high risk) and chemotherapy resistance. All 5 of the patients who died of acute treatment-related complications (invariably sepsis and/or multiorgan failure) still had active GTN at the time of death; all were treated prior to 1987. One multitreated patient died of acute myeloid leukemia 3 years posttreatment. CONCLUSION: Metastatic multidrug-resistant PSTT was and still is the single most important cause of death. Death from choriocarcinoma was with nonpulmonary metastases not responding to initial treatment. Early treatment-related death (from sepsis) is nowadays avoidable. PMID- 22838244 TI - Ectopic gestational trophoblastic disease: a case series review. AB - OBJECTIVE: To highlight the clinical presentation, treatment, histological review and outcome of patients referred to the Sheffield Centre with possible ectopic gestational trophoblastic disease (GTD). STUDY DESIGN: A retrospective case note review of patients with possible ectopic GTD referred to the Sheffield Centre between 1997 and 2010 was performed. RESULTS: During the 13 years of this retrospective study 6,708 patients were registered at the Centre with GTD, of whom 42 had possible ectopic GTD. Most patients presented with abdominal pain and/or vaginal bleeding (67%). Ectopic pregnancy was diagnosed by ultrasound scan in 19%. Laparoscopic removal of ectopic pregnancy was carried out in 50% of cases; the rest underwent laparotomy for removal of ectopic conceptus. Histological review of slides was performed in 19 cases for whom there was clinical concern. This resulted in 12 confirmed cases of ectopic GTD: 4 choriocarcinomas, 5 partial moles and 3 complete moles. No evidence of metastasis was recorded in any of the cases. Three patients diagnosed with ectopic choriocarcinoma needed chemotherapy. Two responded to methotrexate and 1 needed second-line chemotherapy. All patients are alive and free of disease. CONCLUSION: Ectopic GTD is rare and still overdiagnosed. Presentation is the same as for conventional ectopic pregnancy. Central review of the histology should be undertaken, especially in cases where there is clinical, hCG level or histopathologic concern. Conventional chemotherapy for gestational trophoblastic neoplasia is effective. Prognosis remains excellent. PMID- 22838245 TI - Complete hydatidiform mole coexisting with a normal fetus delivered at 33 weeks of gestation and involving maternal lung metastasis: a case report. AB - BACKGROUND: Complete mole and coexisting fetus is rare. The incidence is 1 in 22,000-100,000 pregnancies. The optimal management of complete mole and coexisting fetus is uncertain because of severe maternal complications. The decision to continue or discontinue a current pregnancy is difficult. We report a case of complete mole and coexisting fetus delivered at 33 weeks of gestation with maternal lung metastases development. CASE: A 36-year-old female, G2 P1 A1, was sent to us for further evaluation at 15 weeks of gestation with a placental abnormality. Ultrasonography revealed that the fetal growth was normal, however, the placenta consisted of two parts. One part indicated a normal placenta and the other showed a typical classic molar pattern. Urine hCG was 440,000 mIU/mL and chest X-ray showed no metastatic finding. Genetic amniocentesis showed that the fetal karyotype was normal 46,XY. Diagnosis was determined to be a complete mole and coexisting fetus. Extensive informed consent was obtained from the parents, and they decided to continue the current pregnancy. We carefully monitored the patient, and periodic hCG measurement and chest X-ray were done at every prenatal check. At 32 weeks chest X-ray showed suddenly multiple lung metastases confirmed by CT scan. At 33 weeks and 4 days labor occurred spontaneously, and a newborn, 1,830-g male infant was delivered without any difficulty. Two days after delivery we started single-agent chemotherapy with dactinomycin. Lung metastases disappeared and the patient achieved remission. CONCLUSION: It is possible to achieve a healthy newborn in cases of complete mole and coexisting fetus in spite of subsequent gestational trophoblastic neoplasia. Patients should be carefully monitored and receive thorough informed consent. PMID- 22838246 TI - Influence of hydatidiform mole follow-up setting on postmolar gestational trophoblastic neoplasia outcomes: a cohort study. AB - OBJECTIVE: To assess the influence of hydatidiform mole (HM) management setting (reference center versus other institutions) on gestational trophoblastic neoplasia (GTN) outcomes. METHODS: This cohort study included 270 HM patients attending Botucatu Trophoblastic Diseases Center (BTDC, Sao Paulo State University, Brazil) between January 1990 and December 2009 (204 undergoing evacuation and entire postmolar follow-up at BTDC and 66 from other institutions [OIs]). GTN characteristics and outcomes were analyzed and compared according to HM management setting. The confounding variables assessed included age, gravidity, parity, number of abortions and HM type (complete or partial). Postmolar GTN outcomes were compared using Mann-Whitney's test, chi2 test or Fisher's exact test. RESULTS: Postmolar GTN occurred in 34 (34/204 = 16.7%) BTDC patients and in 27 (27/66 = 40.9%) of those initially treated in other institutions. BTDC patients showed lower metastasis rate (5.8% vs. 48%, p = 0.003) and lower median FIGO (2002) score (2.00 [1.00, 3.00] vs. 4.00 [2.00, 7.00], p = 0.003]. Multiagent chemotherapy to treat postmolar GTN was required in 2 BTDC cases (5.9%) and in 8 OI cases (29.6%) (p = 0.017). Median time interval between molar evacuation and chemotherapy onset was shorter among BTDC patients (7.0 [6.0, 10.0] vs. 10.0 [7.0, 16.0], p = 0.040). CONCLUSION: BTDC patients showed GTN characteristics indicative of better prognosis. This underscores the importance of GTD specialist centers. PMID- 22838247 TI - Clinical epidemiology and management of gestational trophoblastic neoplasia in Hungary in the past 34 years. AB - OBJECTIVE: To review our clinical experience in the treatment of patients with gestational trophoblastic neoplasia (GTN) over the past 34 years in our national trophoblastic disease center. STUDY DESIGN: Between January 1, 1977, and December 31, 2010, 331 patients with low-risk GTN and 174 patients with high-risk GTN (altogether 505) were treated. The patients were directed to the national trophoblastic disease center from all parts of Hungary. The patients were between 14 and 54 years of age, with an average age of 28.7 years. Primary chemotherapy was selected based upon the patient's stage and prognostic score of GTN. RESULTS: Among 237 low-risk patients, 228 (96.2%) achieved remission as a result of primary methotrexate (MTX) therapy. Out of 94 low-risk patients 90 (95.7%) achieved remission as a result of primary actinomycin-D (Act-D) therapy. MTX, Act D and cyclophosphamide (MAC) as a primary therapy was used in 118 high-risk cases, and 110 (93.2%) patients achieved complete remission. A total of 32 high risk patients were treated with the etoposide, high-dose MTX/folinic acid, Act-D, cyclophosphamide and vincristine (EMA-CO) regimen, and of 26 primary therapies complete remission was achieved in 21 (80.8%) cases. Primary cisplatin, etoposide and bleomycin (CEB) therapy was successful in 16 of 17 high-risk cases (94.1%). Metastases were found in 47.3% (239/505) of the patients. Hysterectomy was performed in 68 of 505 (13.5%) cases. Chemotherapy, surgical intervention or other supplementary treatments resulted in 100% remission in cases of nonmetastatic and metastatic low-risk disease. Comparison of mean prognostic scores resulted in significant differences between CEB and MAC, CEB and EMA-CO, and MAC and EMA-CO. CONCLUSION: Our data indicate that MTX/folinic acid or Act-D should be the primary treatment in patients with nonmetastatic or metastatic low risk GTN. Patients with high-risk metastatic GTN should be treated primarily with combination chemotherapy. Our data support the effectiveness of MAC, EMA-CO and CEB regimens. Results also show that patient care under the direction of experienced clinicians serves to optimize the opportunity for cure and minimize morbidity. PMID- 22838248 TI - Embolization of uterine arteriovenous malformations in patients with gestational trophoblastic tumors: a review of patients at Charing Cross Hospital, 2000-2009. AB - OBJECTIVE: To review the indications, efficacy and follow-up for gestational trophoblastic tumor (GTT) patients treated for uterine arteriovenous vascular malformations (AVMs) and bleeding vaginal metastases with modern polyvinyl alcohol particle (PVA)-based radiological embolization. STUDY DESIGN: GTT patients undergoing embolization were identified from the Charing Cross Hospital database. The patients' records were assessed for indication, technique used, primary and overall success in controlling bleeding, complications and subsequent pregnancy outcome. RESULTS: During the period 2000-2009, 19 patients were treated for persistent or life-threatening bleeding by PVA-based uterine artery embolization performed via the femoral artery approach. Embolization resulted in control of hemorrhage in 18 of the 19 patients; 15 achieved control after the first procedure, with only 4 patients requiring a second procedure. In 1 case surgical intervention was required to control bleeding. The most frequent morbidity from the procedure was pelvic pain, requiring opiate administration; there were no other regular complications. The fertility outcome for these 19 patients indicates that 9 women have gone on to deliver a total of 12 healthy infants postembolization. CONCLUSION: For GTT patients with heavy bleeding from AVMs, uterine artery embolization is a safe and effective treatment with low short-term toxicity and no obvious detrimental effect on future fertility. PMID- 22838249 TI - Complicating preeclampsia as a predictor of poor survival of the fetus in complete hydatidiform mole coexistent with twin fetus. AB - OBJECTIVE: To examine whether preeclampsia is a predictive factor for fetal prognosis in complete hydatidiform mole coexistent with twin fetus (CHMCF). STUDY DESIGN: We performed a retrospective chart review for 17 cases of definitive CHMCF managed in our hospital between 1991 and 2011. RESULTS: Fifteen patients chose expectant management and the remaining 2 selected termination of the pregnancy. During expectant management 6 patients displayed hypertension with proteinuria, representing preeclampsia, by the 2nd trimester (11-24 weeks) and the other 9 did not (nonpreeclamptic). No babies from preeclamptic mothers survived, with 5 intrauterine fetal deaths at 16-29 weeks and 1 neonatal death at 22 weeks. By contrast, 5 babies from 9 nonpreeclamptic mothers (1 preterm delivery at 29 weeks and 4 term deliveries) survived, while 4 pregnancies were lost by spontaneous abortion at 11-19 weeks. Low-risk gestational trophoblastic neoplasia (GTN) eventually occurred in both preeclamptic (4 of 6) and nonpreeclamptic (4 of 11) cases. Complicating preeclampsia correlated significantly with fetal demise and an increasing trend in serum hCG level but not with postmolar GTN. CONCLUSION: Complicating preeclampsia predicts poor survival of the fetus, but not subsequent GTN, in CHMCF. PMID- 22838250 TI - Hydatidiform mole in ectopic pregnancy: clinical, imaging, pathological and immunohistochemical characteristics. AB - OBJECTIVE: To determine the clinical, pathological, immunohistochemical and imaging characteristics of hydatidiform mole in ectopic pregnancy (HMEP) in all the cases admitted to the Department of Obstetrics and Gynecology, University Hospital of Caracas (HUC), Central University of Venezuela. STUDY DESIGN: Retrospective and comparative study, based on clinical records review of 2 groups: 10 cases with a diagnosis of HMEP and 20 cases with intrauterine hydatidiform mole (IUHM) admitted to the Obstetrics and Gynecology Department of HUC from 1996 to 2010. Clinical, pathological, immunohistochemical and imaging features were analyzed. RESULTS: The prevalence of HMEP in this study was 0.14:1,000 pregnancies; in this group the mean age was 28.8 years, and the mean gestational age at admission was 8.6 weeks. Both groups (HMEP and IUHM) were comparable in these last variables. Abdominal pain and genital bleeding were the most common clinical symptoms in the HMEP group, while it was vaginal bleeding in the IUHM group. Ultrasound findings were similar to those traditionally described in nonmolar ectopic pregnancy. Histology and immunohistochemistry showed that all cases of HMEP were partial mole. CONCLUSION: Although in this study the prevalence of HMEP was high, the size of the sample limits definitive conclusions. This study concludes that all cases of HMEP are partial mole. PMID- 22838251 TI - PTEN and MDM2 expression in the prediction of postmolar gestational trophoblastic neoplasia. AB - OBJECTIVE: To investigate the role of PTEN and MDM2 expression in hydatidiform mole in the prediction of postmolar gestational trophoblastic neoplasia (GTN). STUDY DESIGN: A total of 145 cases of hydatidiform mole were diagnosed at the King Chulalongkorn Memorial Hospital from 1999 to 2010. Patients were classified into 2 groups: spontaneous remission and patients with postmolar GTN. Clinicopathologic features and immunohistochemical staining by PTEN and MDM2 were reviewed. The results were analyzed in correlation to the clinical characteristics and outcomes. RESULTS: Of 145 recruited cases, 128 (88.3%) cases were complete hydatidiform mole (CHM) and 17 (11.7%) cases were partial hydatidiform mole (PHM). Postmolar GTN was clinically diagnosed in 42 cases (28.9%). The incidences of postmolar GTN following CHM and PHM were 29.7% and 23.5%, respectively. Mean age of the postmolar GTN group was significantly older than that of the remission group (31.2 vs. 27.8, p = 0.04). There was no significant difference of pathologic features between cases with remission and postmolar GTN. Immunoreactivity of PTEN and MDM2 were similarly present in trophoblastic cells of both CHM and PHM groups without significantly different patterns. CONCLUSION: Immunohistochemical expression of PTEN and MDM2 in hydatidiform mole cannot predict molar malignant transformation. PMID- 22838252 TI - Gestational trophoblastic disease: a 21-year review of the clinical experience at an Argentinean public hospital. AB - OBJECTIVE: To analyze the clinical trends of gestational trophoblastic disease (GTD) in a public hospital of Buenos Aires, Argentina. STUDY DESIGN: A review of the clinical records of 358 patients with a diagnosis of GTD admitted to Durand Trophoblastic Disease Center between 1990 and February 2011 was performed. Features of diagnosis, treatment and follow-up were analyzed. RESULTS: A total of 358 cases of GTD were reviewed. Hydatidiform mole was diagnosed in 340 patients; of those 223 (66%) experienced spontaneous remission after evacuation. Of the 135 patients with persistent gestational trophoblastic neoplasia (GTN), 99 (73%) had low-risk GTN, 32 (26%) had high-risk GTN and 4 had either placental site trophoblastic disease or epithelioid trophoblastic tumor. In the low-risk group the first-line treatment was methotrexate and the second-line treatment was actinomycin D, etoposide, cytoxan, and oncovin (EMA/CO), with a complete response rate of 100%. High-risk patients whose WHO prognostic scores were 7-13 were treated initially with EMA/CO. Patients whose scores were >13 were treated with EMA/PE, where platinum and etoposide replaced oncovin and cytoxan. Salvage therapy in patients with relapse or resistant disease were treated with a wide variety of chemotherapy regimens. The complete response rate was 98.2%. Compliance was 100%. Three patients died. In all cases the outcome was related with inadequate initial treatment. CONCLUSION: This protocol is in agreement with international consensus. It was useful, safe and feasible in our population. The compliance with international guidelines allows reach a successful treatment and follow-up in one Latin-American population. PMID- 22838253 TI - Role of thoracotomy and metastatectomy in gestational trophoblastic neoplasia: a single center experience. AB - Gestational trophoblastic neoplasia (GTN) is a rare collection of malignancies which are usually curable with modern chemotherapy. Lung metastasis is a relatively common feature of these malignancies and is not considered an adverse prognostic feature. Occasionally, however, the management of these patients necessitates adjuvant thoracic surgery, either to establish the diagnosis or to potentially provide a curative resection of drug-resistant foci of disease. This case series highlights 5 such cases in which thoracic surgery has significantly contributed to the management and outcome of complicated GTN patients, and suggests when thoracic surgery should be considered in this rare group of patients. PMID- 22838255 TI - Did failure of nurse to return call result in footdrop? Kellon v. Lee, W2011 00195-COA-R3-CV TN-CV (5/21/2012)-TN. PMID- 22838254 TI - Role of hysterectomy in the management of patients with gestational trophoblastic neoplasia: importance of receiving treatment in reference centers. AB - OBJECTIVE: To evaluate hysterectomy prevalence, indications and impact on clinical outcomes in a reference center in southern Brazil. STUDY DESIGN: Institutional Ethical Committee approval was granted for this study. In a cohort study spanning 21 years, all patients who underwent hysterectomy for gestational trophoblastic neoplasia (GTN) were included, and technical differences between hysterectomy performed in the reference center and those performed elsewhere were evaluated as well. RESULTS: Of 1,023 patients with gestational trophoblastic disease, 57 (5.6%) underwent hysterectomy (95% CI, 4.3-7.1). Hysterectomy incidence in 230 GTN patients was 17.7% (95%CI, 15.1-23.3). Indications for 41 hysterectomies in the reference center were as follows: primary treatment in 14 (34.1%) cases and secondary treatment in 27 (65.9%); of these, the main indications were GTN recurrence (7 [25.9%] cases), hemorrhage (6 [22.2%]), resistance to single-agent chemotherapy in patients who refused more aggressive treatment (6 [22.2%]), and tumor mass reduction (5 [18.5%]). Twelve (92.3%) of the 13 hysterectomies with bilateral oophorectomy were performed elsewhere (p < 0.001). Thirty-five (85.4%) patients had no complications, and median hospitalization time was short (3 +/- 4 days). None of the 4 deaths were associated with hysterectomy. In the reference center, when associated with hysterectomy, GTN cure rates reached 93% after 63 +/- 87 months of follow-up. CONCLUSION: When treatment is in a reference center, hysterectomy frequency and morbidity may be low, and indications due to hemorrhage are significantly lower. Furthermore, at a reference center there is significantly greater ovarian preservation at the time of hysterectomy, and significantly more patients who undergo hysterectomy have low-risk GTN. PMID- 22838256 TI - No recovery for damage done to mother during childbirth & post natal care. Case on point: Wilkins v. Connecticut Chldbirth and Womens Ctr., AC 32172 (5/22/2012) CT. PMID- 22838257 TI - CT: Nursing home patient contracts MRSA: failure to allege 'med-mal' doomed pt.'s case. Jefferson v. Waveny Care Center, Inc., AC 33097 CTCOA (4/10/2012)-CT. PMID- 22838259 TI - Caveat for nurses serving as jurors in cases involving medical care. Case on point: Ledbetter v. Howard, 2012 OK 39 (4/24/2012)-OK. PMID- 22838258 TI - MO: Nurse stabbed repeatedly: sues officials: appellate court reversed dismissal of suit. Spero v. Mason, WD740167 MOCA (4/24/2012)-MO. PMID- 22838260 TI - [For a large national museum of history of health!]. PMID- 22838261 TI - [Pregnancy at all cost!]. PMID- 22838262 TI - [Extrapulmonary multifocal tuberculosis in an immunocompetent patient]. PMID- 22838263 TI - [Current status of leprosy]. AB - Leprosy, known since antiquity, is a world infectious disease due to Mycobacterium leprae. The transmission is probably via nasal droplets. The clinical range, from tuberculoid to lepromatous leprosy is a result of variation in the cell-mediated immune response, with a chronic inflammation in skin and peripheral nerves. Diagnosis of leprosy is clinical with anesthetic skin lesion and skin smears detect acid fast bacilli. Besides the classification of patients due to the Ridley scale which is clinically useful, WHO proposed is a simple field classification based on the number of skin patches (paucibacillary or multibacillary). Despite an effective multidrug therapy, leprosy has not been eliminated and remains an important health problem. PMID- 22838264 TI - [How to complete a death certificate?]. AB - The death certificate, an obligatory civil act, engaging the practitioner's responsability, and with administrative, judicial, familial and statistical issues, often raises problems for the physician. We will see in this article how to avoid any error and/or approximation, basing these advices and comments on a retrospective study on 100 analyzed certificates, and 30 interviewed practitioners. PMID- 22838265 TI - [Eruptive pseudoangiomatosis]. PMID- 22838266 TI - [Identify and treat subjects at high cardiovascular risk should be a priority!]. PMID- 22838267 TI - [Distribution of coronary risk in the population]. AB - Of all cardiovascular deaths, those from coronary origin are preponderant. Therefore the reduction of cardiovascular mortality requires improving substantially coronary prevention. Three categories of coronary risk (probability of hard coronary event at 10 years; low <10%, intermediate 10 to 20%, high > 20%) are identifiable via scoring procedure integrating multiple traditional risk factors. Risk is also high, independent of score value, in the case of coexisting major risk factor (diabetes, severe hypertension or hypercholesterolemia) and/or clinically overt coronary, peripheral or cerebral vascular disease. The knowledge of the distribution of coronary risk categories within the population allows defining preventives strategies and estimating needs and costs. Such distribution is pyramidal with the majority of the population at low or intermediate risk while only 15% at high risk. Although largely in minority, the latter convey an important proportion of coronary accidents so justifying the priority given to detection and intensive treatment of high coronary risk condition. PMID- 22838268 TI - [Cardiovascular risk as assessed by traditional risk factors]. AB - Although traditional cardiovascular risk factors play a proven aetiologic role in atherosclerosis-related cardiovascular disease, they fail to predict the occurrence of future clinical events, and, taken separately, they provide useful therapeutic target rather than diagnostic tools. Apart from the situation of severe monorisk, more frequent is the presentation of one individual with numerous moderate risk factors, the resulting global risk of whom being estimated by risk scores, such as the Framingham risk score or its derivatives. These models suffer various limitations, including the lack of applicability depending on geographic zones, and the lack of discrimination in the intermediate risk category, as compared to a better predictive value in the low risk and high risk categories. This lack is partially overcome by models that include complementary risk factors, requiring the need for other tools of reclassification, including the detection of subclinical atherosclerosis. PMID- 22838269 TI - [How to requalify the intermediate coronary risk in high risk?]. PMID- 22838270 TI - [New biomarkers for cardiovascular risk evaluation]. AB - Biomarkers aim at refining risk prediction and at better identifying individuals at high cardiovascular risk. To be recommended in clinical practice, a novel biomarker should be simple to measure, non-invasive, cost-effective, reproducible, and should provide a predictive and discriminative value independently of, and beyond existing risk scores. In addition, it should offer a favourable impact on morbidity, mortality and disability of the disease. Among the hundreds of candidate circulating biomarkers, certain have shown solid statistical associations with the incidence of future events, as is the case for high-sensitivity C-reactive protein. However, contrary to subclinical atherosclerosis assessment, they offer only a modest increase in the predictive value of current scores. To date, the main interest of cardiovascular biomarkers in primary prevention is to better understand pathophysiological mechanisms of atherosclerosis in the research setting. PMID- 22838271 TI - [Is the exercise electrocardiogram still useful in the evaluation of high cardiovascular risk of asymptomatic patients?]. PMID- 22838272 TI - [Means and objectives of primary prevention in patients at high cardiovascular risk]. AB - Since thirty years, cardiovascular mortality fell. That is linked, on the one hand, to an earlier and a more harsh care of the acute accident, and on the other hand, to development of the prophylactic treatment. But cardiovascular diseases stay the main cause of death in the most of western countries, in France in women, and in subjects over 65 years. That's why it is necessary to detect people with a high cardio-vascular risk before any complications so that they can be treated earlier and with an intensive mode. It relates to a global risk which is multifactorial, conducting to a treatment based on the evidence based medicine but also fitting to each patient and which requires his participation to the prevention. This is a 4P physical medicine: predictive, preventive, personalized and participative. PMID- 22838273 TI - [Public health implications of high cardiovascular risk screening]. PMID- 22838274 TI - [Major topic and explosion]. PMID- 22838275 TI - [National organization of forensic medicine in France]. AB - Forensic medicine has long been characterized, in France, by diverse medical practices, which affected its recognition and development. A change was needed, Harmonization procedure includes the development of professional guidelines and allows forensic medicine to look at itself. However, the implementation of the recommendations is still far from complete. A national reform came into effect on 15 January 2011 and has defined a national reform of forensic medicine which includes funding by global budgets instead of fee-for-service. This reform allows easier organization and identification of forensic medicine units. One year later, tangible results are mixed. Forensic medicine is now more clearly identified but properly defined funding criteria are still lacking. PMID- 22838276 TI - [Determination of the total work incapacity]. AB - At the request of the patient or required by a requisition, the physician may be asked to deliver medical certificates with determination of total work incapacity (TWI). This is an attestation of what he has observed and incurs his penal, civil and ethical responsability. The drafting of such certificates implies not only the doctor and the patient, but also the judicial authorities and the alleged offender or offenders. The impact of the determination of the TWI is important to know in order to write "good" certificates before justifying TWI. PMID- 22838277 TI - [Psychological assessment of victims]. AB - The so called "psychological impact examination" (PIE) evaluates the potential psychological impact of an attack. It is conducted by highly specialized psychiatrists in medical and legal area. One of the PIE objectives is for the victim to be recognized by the legal system, the recognition includes not only the physical trauma but also and as importantly the psychological trauma. The exact evaluation of the psychological trauma is however challenging mainly because of the difficulty in predicting the long term psychological sequelae. The other objective of the PIE is to inform the victim of the mental health care and legal assistance available. PMID- 22838278 TI - [Examination and care of sexual assault victims]. AB - Any general practitioner might have to examine and care for a sexual assault victim in their professional practice. Taking time to listen to the victim's story is essential to direct the examination and sample collection. The general physical examination screens for physical injuries. Perineal examination is specialized, and should be performed within a very short period of time in the event of a recent assault with sexual penetration. The purpose of further examination is to collect evidence and identify the victim's sexually transmitted disease status to screen for any seroconversion during follow-up. Preventive measures should be considered on an individual basis: contragestion, triple antiretroviral therapy, immunoglobulins and hepatitis B immunization. Lastly, referrals to social or psychotherapeutic services and/or associations are extremely helpful to the victim. PMID- 22838279 TI - [The associations work with victims of sexual assault]. PMID- 22838280 TI - [The reception of sexual assault victim in a police district]. PMID- 22838281 TI - [What should a physician do facing drug facilitated crimes?]. AB - Chemical submission is the administration, for criminal purposes, of psychoactive substances to an individual without their knowledge. It is clear that general practitioners remain helpless against such a phenomenon. Most of the time, diagnosis is negatively affected by delayed management, due to omitted diagnosis or inappropriate samples. The purpose of our paper is therefore to provide a few simple recommendations. A victim suspecting of being drugged without knowing should be adequately interviewed, examined and informed about the possibility of pressing charges. A quick referral to an emergency unit or a forensic medicine unit is necessary to collect biological samples for toxicological testing as promptly as possible. In the event of a prosecution, these samples will be submitted for toxicological analysis, a critical step in identifying the psychoactive substance used. PMID- 22838282 TI - [Doctor's attendance in police custody]. AB - Medical examination is a right for every person detained in police custody in France. Examination of detainees usually takes place in the police station so that the doctor can assess the conditions in which the detainee is being held. In some cases, such as type I diabetes care, detainees need to be examined and treated in a hospital. Doctors are subject to a duty of care and prevention. Description of recent traumatic injuries is part of the doctor's mission. They should prescribe any ongoing treatment which needs to be continued, as well as any emergency treatment required. Custody officers may monitor the detainee and administer medication. Doctor's opinion should be given in a national standard document. If the doctor considers that the custody conditions are disgraceful, they may refuse to express an opinion as to whether the detainee is fit for custody. PMID- 22838283 TI - [Multidisciplinary protocols for multimorbidity patients]. PMID- 22838284 TI - [Abuse and children at risk: why recognize, how to support?]. PMID- 22838285 TI - [Screening studies of lung cancer: implications for monitoring of pulmonary nodules]. PMID- 22838286 TI - [Metabolic and respiratory acidosis: physiopathology, diagnosis and treatment]. PMID- 22838287 TI - [Angioedema and anaphylaxis]. PMID- 22838288 TI - [Management, substitutive therapy and withdrawal: tobacco, alcohol, psycho-active and illicit substances. Tobacco addiction]. PMID- 22838289 TI - [Medical file, information, medical secrecy]. PMID- 22838290 TI - [Prescription and monitoring of anticoagulant therapies]. PMID- 22838291 TI - [Type 2 diabetes of the child and the adult. Complications]. PMID- 22838292 TI - [Analgesic and anesthetic plants in Roman antiquity]. PMID- 22838293 TI - Preventive medicine for health care workers. PMID- 22838294 TI - Fitness for work in health care workers from the prospective of ethics, science and good practices. AB - Fitness for work (FFW) is the final task of both risk assessment and health surveillance, aimed at protecting workers' health and working capacity. There are numerous specific concerns regarding health care workers. In particular: i) the frequent difficulty in determining at pre-employment/pre-placement examinations the specific task that the individual worker will perform; ii) the prevalence of female workers and the contemporary presence of numerous occupational risk factors that are a potential cause of harmful effects on women's reproductive health; iii) the progressive aging of the staff especially nurses; iv) the risk to third parties, with particular reference to the issues of biological risk and substance abuse, also in relation to shift work, fatigue and occupational stress; v) the increasing number of immigrant workers among support staff In such cases the occupational physician, respecting both ethical principles and regulations and with an appropriate balance between scientific evidence and the precautionary principle, should express a FFW judgment that allows both the adaptation of work to the worker and vice versa, as recommended by the World Health Organization (WHO) and the International Commission on Occupational Health (ICOH). Proper FFW judgment also permits the expected benefits to be achieved, not only for the workers but also for employers, companies and society. PMID- 22838295 TI - Fitness for work in health care workers: biological risk. AB - The aim of this contribution is to propose good medical practice in formulating and managing fitness for work (FFW) for health care workers exposed to biological agents. A literature review was conducted, together with a critical analysis of available scientific evidence and presentation of practical examples taken from the Italian multicentric study in which the authors have been participating since 2008. Within the health care sector and with special reference to biological risk, making and subsequently managing a FFW for a specific job is in fact a particularly arduous task for the occupational physician and for the entire hospital management system. The process that leads to issuing a FFW needs to follow the appropriate guidelines and good technical and scientific practice and also take into careful consideration current legislation (national, regional, etc); it is the result of a well grounded balance between professional ethics, rights and duties of the worker and patient, but also of the employer and of all those involved. All these aspects need to be adapted to the single work situations, applying the principle of precaution and careful flexibility in management, with accurate evaluation of each individual clinical case with its peculiarities and referral, where necessary, to expert opinion. It is also indispensable to have in place a clear and jointly agreed hospital management policy where co-responsibility is taken by each single actor, always with due respect for specific roles, so that the Occupational Physician and employers are not left to manage the issue alone. PMID- 22838296 TI - Occupational diseases due to allergic and toxic chemicals in health care workers: fitness for work. AB - The purpose of this review is to suggest job fitness criteria for health care workers exposed to sensitizing or chemical agents. These recommendations are derived from a comparison between previous documents on prevention and management of allergic and chemical risks in health care settings and updated evidence; the job fitness criteria and the main documents on these topics are summarized in tables. Glove allergy, in particular latex allergy, is still a significant problem but we should remember that a wide choice of alternative materials is now easily available; many different alternative health products are also currently available when an allergy to disinfectants or detergents is diagnosed. Hence the prevention of allergic diseases is mostly based on an appropriate choice and use of the gloves and health products according to the specific tasks and possible individual susceptibility; this meets the requirements of the "good health care organization", which translates into lower costs, if possible, as well as the best protection of worker's health. Concerning chemical risk, it should be remembered that during the last 20 years the improvements made in work environments have profoundly changed the mode and the levels of exposure to chemical substances and the current recommendations concerning the management of workers exposed to anesthetic gases, antineoplastic agents and sterilizers/disinfectants significantly differ from those of early 1990s. However, the past prudential guidelines are still valid for formaldehyde. PMID- 22838297 TI - Assessment of fitness for work in health care workers: biomechanical risk factors. AB - In current practice the assessment of fitness for work in health care workers exposed to biomechanical risk factors is often based on conventional approaches rather than on evidence-based guidelines. However, an accurate evaluation of worker's psychophysical resources compared to job demand and potential occupational risk factors is essential in order to properly assess fitness for work. The latest published guidelines on the management of patients suffering from back pain reported that the evidence-based approach can minimize the period of inactivity by encouraging return to work (and to other non-dangerous physical activities) in a relatively short period of time. As for carpal tunnel syndrome, there is no scientific evidence supporting a restriction of physical activities requiring forceful movements of the hand/wrist. PMID- 22838298 TI - Fitness for work in health care workers: state of the art and possible operational recommendations for its formulation and management in relationship to alcohol and drug addiction. AB - Both chronic and acute alcohol or drug consumption have severe health consequences, alter the subject's cognitive functions and work performance and increase the risk of work-related accidents, for the worker and for third parties (e.g., co-workers and other people subject to negative impact of worker's actions). Limited scientific evidence has suggested that some working conditions present in the health care sector (e.g., high levels of responsibility, competitiveness, burnout, shiftwork, work-related stress) may favour alcohol and drug abuse. The aim of the present report is to describe the problem of alcohol and drug consumption among health care professionals and to evaluate the problem of related fitness for work. The magnitude of this problem remains unclear; recent estimates have reported alcohol abuse and addiction problems in 1-14% and psychotropic, illicit and non-illicit, substance abuse in 6-15% of health care workers. The prevalence of tranquilizer and sedative/hypnotic drug use is high, particularly among physicians. However, it remains unclear whether the incidence of workplace accidents and injuries is higher among drug abusers, and whether the statutory introduction of prevention programmes has led to actual control of this problem in the workplace. Italian legislation identifies the occupational physician as a key figure to prevent psychotropic substance abuse in some work activities, but some difficulties in its application remain. Legislators should issue simple norms that clearly define the responsibilities and skills of each actor involved in safeguarding workplace health and safety, as well as clearly outlining workplace monitoring procedures. PMID- 22838299 TI - Health protection of health care workers from the prospective of ethics, science and good medical practice. Opinions from stakeholders in health care settings. AB - Fitness for work (FFW) in health care workers poses multidisciplinary challenges because of management problems scientific and ethical implications and the implementation of preventive interventions in health care settings. All the relevant stakeholders, including the General Manager, Medical Director, worker's representative, the person responsible for prevention and protection, forensic medicine expert, the person responsible for prevention and health safety at public administration level, commented on: danger to third parties; FFW formulation; human resource management; stress; professional independence; role of the person responsible for prevention and protection and of the person responsible for prevention at public administration level; professional responsibilities. Opinions are reported regarding the main problems related to the role of the Occupational Physician in FFW formulation, such as the difficult balance between autonomy and independence, limited turnover and aging of workforce, need of confidentiality and respect for professional status of the HCW prevalence of susceptibility conditions, rights and duties of stakeholders. The most significant result was the request by the Lombardy Region for more quality in risk assessment and health surveillance; to maintain uniform conduct over all the local health authorities, to allow the board in charge of examining appeals against FFW to fully cooperate with the occupational physician; due attention to the person/worker; the opportunity to convene referral boards for complex FFW management; the challenge of stress management and the need for an observatory for psychological discomforts; the importance of the ICOH Code of Ethics and avoidance of conflicts of interests; the need for individual risk assessment and risk management; the concept of sharing responsibilities and of a real multidisciplinary approach. PMID- 22838300 TI - Assessment of efficacy and safety of pandemic A/H1N1/2009 influenza vaccine in a group of health care workers. AB - INTRODUCTION: The development in an extremely short time of an efficacious and safe vaccine against the pandemi A/H1N1 virus was a challenge that involved the entire scientific community. AIMS: To assess the immunological and clinical efficacy of the new H1N1v monovalent influenza vaccine (Focetria Novartis Vaccines, Siena, Italy) in a group of health care workers (HCWs). METHODS: A total of 148 volunteer HCWs were enrolled between Mid-Novembre 2009 and December 2009. After measuring antibody titers, a single intramuscular dose of 7.5 microg of Focetria monovalent vaccine against A/H1N1/2009 influenza virus with MF59C.1 adjuvant was administered. RESULTS: Antibody titers (median value) before and after a single dose of vaccine, measured by means of standard beam-agglutination inhibition test (HAI), increased from 32 to 256 (p < 0.001). After vaccination, 79.7% of the subjects showed antibody seroconversion, and in 97.3% seroprotection was achieved. The ratio between the geometric means of antibody titers (GMTR) was 6.69. For the 3 subjects who reported symptoms of ILI (Influenza-like illness), a regular nasal-pharyngeal swab sample was taken to identify the virus type by RT PCR, the laboratory results of tests performed on these samples were negative for pandemic A/H1N1/2009 virus. During the entire follow-up period of 6 months no severe adverse events occurred. CONCLUSIONS: The vaccine against pandemic A/H1N1/2009 virus provided protection against the virus and not only contributed to a significant immunization (according to EMEA criteria), but kept all 148 subjects under study free from A/H1N1/2009 influenza illness. PMID- 22838301 TI - Features of registered occupational diseases in Greece: a veil of ignorance. AB - INTRODUCTION: BACKGROUND: Under-registration of occupational diseases is a global problem. OBJECTIVES: The aim of this study was to describe the characteristics of the reported cases of occupational diseases, in the context of the largest insurance scheme in Greece. METHODS: Socio-demographic characteristics related to the identified cases of occupational diseases were collected from the archives of the special medical committee of the Social Insurance Institute (Idrima Koininikon Asfaliseon, IKA) for the year 1999. This year was chosen given that it largely represents the highest number of registered occupational diseases in comparison to the period 2000-2009. RESULTS: Sixty-seven (67) occupational diseases were recognized (3.4 cases/100,000 employees). There were 32 new cases (incidence rate: 1.64/100,000 employees). Occupational skin conditions and diseases of the respiratory system accounted for 85% of all diagnoses. Builders and unskilled blue collar workers were the most frequent occupational groups affected. CONCLUSIONS: These findings indicate a high rate of under-registration of occupational diseases in Greece, compared to data from the European Union. This under-registration could be attributed to a variety of limitations related to the current model of occupational health in Greece. The present pattern of registered occupational morbidity reflects the under development of occupational health in Greece and stresses the need for further and intensified work in order to create modern occupational health services in this country. PMID- 22838302 TI - The contribution of occupational medicine to the origins of paralympics. PMID- 22838303 TI - Mentorship: mutual benefits for ASL students and gifted students (part 1). AB - Postsecondary American Sign Language (ASL) students are capable of teaching short lessons related to sign language and deaf culture to gifted students in elementary school. College students who work as interest-area mentors benefit gifted students while building their own academic discipline and professional skills. In Part 1 of a 2-part series of articles, the authors explain the unique needs shared by students in gifted education programs (GEPs), the concept of interest-area mentorship, and how mentors help meet the needs of gifted students in light of National Association for Gifted Children standards. Benefits for ASL students, gifted students, and GEP teachers are discussed. College instructors also benefit, because mentoring experiences help make mentors better students and professionals. Additionally, mentoring in gifted classes facilitates recruiting of the next generation of professionals. In this case, recruiting occurs with the best and brightest: gifted students. PMID- 22838305 TI - Educational programs for deaf students. PMID- 22838304 TI - College collaboration with gifted programs: deaf studies unit (part 2). AB - The present article is the second in a 2-part series. Part 1 explained the needs of students in gifted education programs (GEPs), the concept of interest-area mentorship, and how mentors help meet gifted elementary-school students' needs in light of National Association for Gifted Children standards. Part 2 explains that the goals and standards GEPs must address not only cover academics but also intellectual and affective categories. Once college instructors understand these goals and standards, they can initiate collaboration with GEP teachers and provide mentors to GEP classrooms. Deaf studies' diverse topics lend themselves to teaching, research, and discussion-perfect qualifications for GEP curricula. Examples show the "fit" between gifted education and a unit on Deaf studies. By delineating the roles of the GEP teacher, the mentor, and the college instructor, the authors provide an understanding that can enable implementation of broadly beneficial mentorship programs. PMID- 22838306 TI - University and college programs for personnel in deafness. PMID- 22838307 TI - Programs for deaf-blind children and adults. PMID- 22838309 TI - Research on deafness. PMID- 22838308 TI - Advocacy, support, and rehabilitation programs. PMID- 22838310 TI - Enlargement of halloysite clay nanotube lumen by selective etching of aluminum oxide. AB - Halloysite clay tubes have 50 nm diameter and chemically different inner and outer walls (inner surface of aluminum oxide and outer surface of silica). Due to this different chemistry, the selective etching of alumina from inside the tube was realized, while preserving their external diameter (lumen diameter changed from 15 to 25 nm). This increases 2-3 times the tube lumen capacity for loading and further sustained release of active chemical agents such as metals, corrosion inhibitors, and drugs. In particular, halloysite loading efficiency for the benzotriazole increased 4 times by selective etching of 60% alumina within the tubes' lumens. Specific surface area of the tubes increased over 6 times, from 40 to 250 m(2)/g, upon acid treatment. PMID- 22838382 TI - A cloud computing based 12-lead ECG telemedicine service. AB - BACKGROUND: Due to the great variability of 12-lead ECG instruments and medical specialists' interpretation skills, it remains a challenge to deliver rapid and accurate 12-lead ECG reports with senior cardiologists' decision making support in emergency telecardiology. METHODS: We create a new cloud and pervasive computing based 12-lead Electrocardiography (ECG) service to realize ubiquitous 12-lead ECG tele-diagnosis. RESULTS: This developed service enables ECG to be transmitted and interpreted via mobile phones. That is, tele-consultation can take place while the patient is on the ambulance, between the onsite clinicians and the off-site senior cardiologists, or among hospitals. Most importantly, this developed service is convenient, efficient, and inexpensive. CONCLUSIONS: This cloud computing based ECG tele-consultation service expands the traditional 12 lead ECG applications onto the collaboration of clinicians at different locations or among hospitals. In short, this service can greatly improve medical service quality and efficiency, especially for patients in rural areas. This service has been evaluated and proved to be useful by cardiologists in Taiwan. PMID- 22838383 TI - Evidence of an increased pathogenic footprint in the lingual microbiome of untreated HIV infected patients. AB - BACKGROUND: Opportunistic oral infections can be found in over 80% of HIV + patients, often causing debilitating lesions that also contribute to deterioration in nutritional health. Although appreciation for the role that the microbiota is likely to play in the initiation and/or enhancement of oral infections has grown considerably in recent years, little is known about the impact of HIV infection on host-microbe interactions within the oral cavity. In the current study, we characterize modulations in the bacterial composition of the lingual microbiome in patients with treated and untreated HIV infection. Bacterial species profiles were elucidated by microarray assay and compared between untreated HIV infected patients, HIV infected patients receiving antiretroviral therapy, and healthy HIV negative controls. The relationship between clinical parameters (viral burden and CD4+ T cell depletion) and the loss or gain of bacterial species was evaluated in each HIV patient group. RESULTS: In untreated HIV infection, elevated viremia was associated with significantly higher proportions of potentially pathogenic Veillonella, Prevotella, Megasphaera, and Campylobacter species in the lingual microbiome than observed in healthy controls. The upsurge in the prevalence of potential pathogens was juxtaposed by diminished representation of commensal Streptococcus and Veillonella species. Colonization of Neisseria flavescens was lower in the lingual microbiome of HIV infected patients receiving antiretroviral therapy than in uninfected controls. CONCLUSIONS: Our findings provide novel insights into the potential impact of HIV infection and antiretroviral therapy on the community structure of the oral microbiome, and implicate potential mechanisms that may increase the capacity of non-commensal species to gain a stronger foothold. PMID- 22838385 TI - Mimicking the biomolecular control of calcium oxalate monohydrate crystal growth: effect of contiguous glutamic acids. AB - Scanning confocal interference microscopy (SCIM) and molecular dynamics (MD) simulations were used to investigate the adsorption of the synthetic polypeptide poly(l-glutamic acid) (poly-glu) to calcium oxalate monohydrate (COM) crystals and its effect on COM formation. At low concentrations (1 MUg/mL), poly-glu inhibits growth most effectively in ?001? directions, indicating strong interactions of the polypeptide with {121} crystal faces. Growth in <010> directions was inhibited only marginally by 1 MUg/mL poly-glu, while growth in <100> directions did not appear to be affected. This suggests that, at low concentrations, poly-glu inhibits lattice-ion addition to the faces of COM in the order {121} > {010} >= {100}. At high concentrations (6 MUg/mL), poly-glu resulted in the formation of dumbbell-shaped crystals featuring concave troughs on the {100} faces. The effects on crystal growth indicate that, at high concentrations, poly-glu interacts with the faces of COM in the order {100} > {121} > {010}. This mirrors MD simulations, which predicted that poly-glu will adsorb to a {100} terrace plane (most calcium-rich) in preference to a {121} (oblique) riser plane but will adsorb to {121} riser plane in preference to an {010} terrace plane (least calcium-rich). The effects of different poly-glu concentration on COM growth (1-6 MUg/mL) may be due to variations between the faces in terms of growth mechanism and/or (nano)roughness, which can affect surface energy. In addition, 1 MUg/mL might not be adequate to reach the critical concentration for poly-glu to significantly pin step movement on {100} and {010} faces. Understanding the mechanisms involved in these processes is essential for the development of agents to reduce recurrence of kidney stone disease. PMID- 22838384 TI - Gauging the flexibility of the active site in soybean lipoxygenase-1 (SLO-1) through an atom-centered density matrix propagation (ADMP) treatment that facilitates the sampling of rare events. AB - We present a computational methodology to sample rare events in large biological enzymes that may involve electronically polarizing, reactive processes. The approach includes simultaneous dynamical treatment of electronic and nuclear degrees of freedom, where contributions from the electronic portion are computed using hybrid density functional theory and the computational costs are reduced through a hybrid quantum mechanics/molecular mechanics (QM/MM) treatment. Thus, the paper involves a QM/MM dynamical treatment of rare events. The method is applied to probe the effect of the active site elements on the critical hydrogen transfer step in the soybean lipoxygenase-1 (SLO-1) catalyzed oxidation of linoleic acid. It is found that the dynamical fluctuations and associated flexibility of the active site are critical toward maintaining the electrostatics in the regime where the reactive process can occur smoothly. Physical constraints enforced to limit the active site flexibility are akin to mutations and, in the cases studied, have a detrimental effect on the electrostatic fluctuations, thus adversely affecting the hydrogen transfer process. PMID- 22838386 TI - Feeding of the probiotic bacterium Enterococcus faecium NCIMB 10415 differentially affects shedding of enteric viruses in pigs. AB - Effects of probiotic bacteria on viral infections have been described previously. Here, two groups of sows and their piglets were fed with or without feed supplementation of the probiotic bacterium Enterococcus faecium NCIMB 10415. Shedding of enteric viruses naturally occurring in these pigs was analyzed by quantitative real-time RT-PCR. No differences between the groups were recorded for hepatitis E virus, encephalomyocarditis virus and norovirus. In contrast, astrovirus was exclusively detected in the non-supplemented control group. Rotavirus was shedded later and with lower amounts in the probiotic piglet group (p < 0.05); rotavirus-shedding piglets gained less weight than non-infected animals (p < 0.05). Serum titres of anti-rotavirus IgA and IgG antibodies were higher in piglets from the control group, whereas no difference was detected between sow groups. Phenotype analysis of immune cell antigens revealed significant differences of the CD4 and CD8beta (p < 0.05) as well as CD8alpha and CD25 (p < 0.1) T cell populations of the probiotic supplemented group compared to the non-supplemented control group. In addition, differences were evident for CD21/MHCII-positive (p < 0.05) and IgM-positive (p < 0.1) B cell populations. The results indicate that probiotic bacteria could have effects on virus shedding in naturally infected pigs, which depend on the virus type. These effects seem to be caused by immunological changes; however, the distinct mechanism of action remains to be elucidated. PMID- 22838387 TI - Oxidative coupling of 1,7,8-unsubstituted BODIPYs: synthesis and electrochemical and spectroscopic properties. AB - We report the synthesis of BODIPYs with unsubstituted 1,7,8-positions and their dimerization by oxidative coupling with phenyliodine(III)-bis(trifluoroacetate) (PIFA). This dimerization was achieved for BODIPYs substituted in the 3,5 positions with either methyl or thienyl groups. The position and the type of the linkage in the resulting dimers depended on the nature of the substituent. The 3,5-dimethyl-BODIPY dyes were linked either via direct 1,1'-pyrrole-pyrrole coupling or via a 1,3'-methylene bridge. The 3,5-dithienyl-BODIPY dyes provided, in excellent yields, unique compounds linked exclusively via the alpha-thienyl positions. All dyes were unreactive in the 8-position. Electrochemical and spectroscopic measurements on the monomers and dimers provided evidence of interactions between the two halves of the dimers. Thus, oxidation and reduction potentials were split by up to 210 mV, and modest excitonic coupling and an internal charge transfer were observed in some cases. PMID- 22838388 TI - Tunability of band gaps in metal-organic frameworks. AB - The tunability of the band gaps in Zn-based metal-organic frameworks (MOFs) has been experimentally demonstrated via two different approaches: changing the cluster size of the secondary building unit (SBU) or alternating the conjugation of the organic linker. PMID- 22838389 TI - SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer. AB - BACKGROUND: Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations. METHODS: We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients' survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells. RESULTS: We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients' survival, when analyzing the entire patients' cohort. An increased risk for a shorter metastasis free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation. CONCLUSION: In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients' survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed. PMID- 22838390 TI - Preparation of polymer-based magnetic resonance imaging contrast agent to visualize therapeutic angiogenesis. AB - The objective of this study was to design and prepare a new contrast agent of magnetic resonance (MR) imaging for the evaluation of therapeutic angiogenesis. Diethylenetriaminepentaacetic acid (DTPA) residue of a chelator was chemically introduced to dextran with a molecular weight of 74,000 (dextran-DTPA). Cyclic peptide containing an arginine-glycine-aspartic acid (RGD) sequence (cyclic RGD) with an inherent affinity for the alpha(v)beta(3) integrin was then introduced to dextran-DTPA (Cyclic RGD-dextran-DTPA). Gd(3+) was added to cyclic RGD-dextran DTPA to prepare a dextran-based MR contrast agent (Cyclic RGD-dextran-DTPA-Gd). Cyclic RGD-dextran-DTPA-Gd had affinity for cells expressing the alpha(v)beta(3) integrin and showed a higher longitudinal relaxivity compared with DTPA-Gd of an MR contrast agent clinically used. Right femoral, external iliac, and deep femoral and circumflex arteries and veins were surgically ligated to prepare a mouse model of hindlimb ischemia. A laser Doppler analysis and histological evaluation confirmed that hindlimb ischemia healed naturally and was accompanied by angiogenesis, while alpha(v)beta(3) integrin was expressed in the ischemic angiogenic region without any treatment. Mice at 7 days after vascular ligation were used as an angiogenesis model. When intravenously injected into mice with hindlimb ischemia, cyclic RGD-dextran-DTPA accumulated in the ischemic-angiogenic region and showed the MR ability to detect the ischemic-angiogenic region. It is concluded that cyclic RGD-dextran-DTPA-Gd is a promising material for evaluation of therapeutic angiogenesis. PMID- 22838391 TI - Can exhaled NO fraction predict radiotherapy-induced lung toxicity in lung cancer patients? AB - BACKGROUND: A large increase in nitric oxide fraction (FeNO) after radiotherapy (RT) for lung cancer may predict RT-induced lung toxicity. METHODS: In this study, we assessed the relationships between FeNO variations and respiratory symptoms, CT scan changes or dose volume histogram (DVH) parameters after RT. We measured FeNO before RT, 4, 5, 6, 10 weeks, 4 and 7.5 months after RT in 65 lung cancer patients. RESULTS: Eleven lung cancer patients (17%) complained of significant respiratory symptoms and 21 (31%) had radiation pneumonitis images in > 1/3 of the irradiated lung after RT. Thirteen patients (20%) showed increases in FeNO > 10 ppb. The sensitivity and specificity of a > 10 ppb FeNO increase for the diagnosis of RT-associated respiratory symptoms were 18% and 83%, respectively. There was no correlation between DVH parameters or CT scan changes after RT and FeNO variations. Three patients (5%) showed intriguingly strong (2 or 3-fold, up to 55 ppb) and sustained increases in FeNO at 4 and 5 weeks, followed by significant respiratory symptoms and/or radiation-pneumonitis images. CONCLUSION: Serial FeNO measurements during RT had a low ability to identify lung cancer patients who developed symptoms or images of radiation pneumonitis. However, three patients presented with a particular pattern which deserves to be investigated. PMID- 22838392 TI - Determinant factors of pregnant mothers' knowledge on mother to child transmission of HIV and its prevention in Gondar town, North West Ethiopia. AB - BACKGROUND: Mother-to-child transmission of HIV is a very important mode of HIV transmission for children. Well-functioning and accessible health facility and knowledge on mother to child transmission of HIV are a prerequisite for a successful mother to child transmission prevention of HIV. However, the determinant factors of pregnant mothers' knowledge towards mother to child transmission of HIV and its prevention is not well studied in Ethiopia and particularly in the present study area. METHODS: Cross-sectional health institution based study was conducted in Gondar town from July 22-August 18, 2011. A total of 400 pregnant women attending antenatal care (ANC) were involved in the study using stratified sampling technique. Data were collected by using structured questionnaire and multiple logistic regression analysis was used. RESULTS: A total of 400 pregnant women actively participated in this study and 354 (88.5%) of them knew mother to child transmission of HIV and 334(83.5%) of them knew mother to child transmission of HIV is preventable. Having knowledge on mother to child transmission of HIV was positively associated with attending antenatal care visits in hospitals [Adj. OR (95%CI) = 4.49 (1.003, 20.06)], residing in urban areas [Adj. OR (95%CI) = 2.46 (1.19, 5.09)] and having education level of secondary and above [Adj. OR (95%CI) = 6.85 (1.96, 24.01)], but negatively associated with increased maternal age. Knowledge on prevention of mother to child transmission of HIV was positively associated with accessibility of health facility [Adj. OR (95%CI) = 2.16 (1.03, 4.57)], having perceived risk of HIV [Adj. OR (95%CI) = 2.61 (1.32, 5.17)], having comprehensive knowledge on HIV [Adj. OR (95%CI) = 2.86 (1.41, 5.82)], having education level of secondary and above [Adj. OR (95%CI) = 6.15 (1.75, 21.66)] and residing in urban areas [Adj. OR (95%CI) = 3.62 (1.73, 7.59)] but negatively associated with increased maternal age. CONCLUSION: Most of the study participants in this study knew that HIV could be transmitted from an infected mother to her baby. There should be well functioning and accessible health facilities with Prevention of mother to child transmission service in the country especially in the rural areas. PMID- 22838393 TI - Validity and reliability of the Caregiver Reaction Assessment scale among primary informal caregivers for older persons in Singapore. AB - Previous studies evaluating the validity and reliability of the Caregiver Reaction Assessment (CRA) scale (24 items; five subscales: schedule, health, finances, family support, and esteem) in different countries are not fully congruent. This article assesses the validity and reliability of the CRA among informal caregivers of older persons in Singapore. Data from a national survey of 1190 primary informal caregivers of Singaporeans aged >=75 years with >=1 activity of daily living limitation was analyzed. Fit of the five-factor model was tested in half of the sample using confirmatory factor analysis (CFA) and the other half subjected to exploratory factor analysis (EFA). The CRA was modified accordingly and again subjected to CFA. The CRA's measurement equivalence/invariance (ME/I) across language of administration (Chinese/English/Malay) was assessed. CFA showed a poor fit for the five-factor model. EFA suggested the presence of four factors, three items to have neither sufficient nor unique factor loadings and items on two of the subscales to load on a single factor. CFA of the 'modified' CRA (21 items; four subscales: schedule and health, finances, family support, and esteem) suggested a better fit for the four-factor model than for the five-factor model. ME/I analysis supported partial invariance of the CRA across language of administration. The CRA scale should be assessed for relevance in Asian settings. With the suggested modifications, it is suitable for assessing negative and positive effects of caregiving among informal caregivers of older persons with activity limitations in Singapore. PMID- 22838394 TI - Three new diarylbutane lignans from the resin of Bursera fagaroides. AB - Three new diarylbutane lignans, named 9-acetyl-9'-pentadecanoil-dihydroclusin (1), 2,3-demethoxy-secoisolintetralin monoacetate (4) and dihydroclusin monoacetate (5), have been isolated from the resin of Bursera fagaroides, together with two known ones, 2,3-demethoxy-secoisolintetralin diacetate (2) and dihydroclusin diacetate (3). The complete structure assignments were obtained by means of (1)H and (13)C NMR spectra. PMID- 22838395 TI - Immunoediting: evidence of the multifaceted role of the immune system in self metastatic tumor growth. AB - BACKGROUND: The role of the immune system in tumor progression has been a subject for discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. METHODS: We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. RESULTS: A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. CONCLUSIONS: Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion. PMID- 22838396 TI - Delusion or obsession: clinical dilemma. AB - BACKGROUND: A 52-year old lady presented for admission with severe depression characterised by suicidal ideation and delusional belief. CASE PRESENTATION: Her treatment regime was reviewed and modified. The dilemma was whether she suffered from a psychotic depression with delusion or an obsessional disorder. She responded well to change of antipsychotic medication. CONCLUSIONS: Her depression went in remission and her delusional belief decreased in intensity. She also gained reasonable insight into her problem. She is currently being followed up in the psychiatric outpatient clinic. PMID- 22838397 TI - A novel Kluyveromyces marxianus strain with an inducible flocculation phenotype. AB - Flocculation is a very useful phenotype for industrial yeast strains, since it facilitates cell harvest and represents an easy way of cell immobilization in continuous fermentation processes. The present work represents the first time that an inducible flocculation phenotype has been generated in a non flocculent strain of Kluyveromyces marxianus. This was accomplished by expressing Saccharomyces cerevisiae FLO5 gene in K. marxianus CECT 11769 strain. The FLO 5 gene was placed under the control of an EPG promoter, not repressed by glucose and induced by anoxia. Our experimental approach successfully generated two novel K. marxianus flocculent phenotypes: one inducible and one constitutive. The constitutive phenotype originated from deletions in the FLO5 promoter region, indicating the existence of putative upstream repressor site involved in oxygen regulation of the EPG1 promoter. The novel strains here generated had a unique set of characteristics that provided an advantage, over the wild-type strain, for the industrial co-production of ethanol and polygalacturonase. PMID- 22838398 TI - Predicted HIV-1 coreceptor usage among Kenya patients shows a high tendency for subtype d to be cxcr4 tropic. AB - BACKGROUND: CCR5 antagonists have clinically been approved for prevention or treatment of HIV/AIDS. Countries in Sub-Saharan Africa with the highest burden of HIV/AIDS are due to adopt these regimens. However, HIV-1 can also use CXCR4 as a co-receptor. There is hence an urgent need to map out cellular tropism of a country's circulating HIV strains to guide the impending use of CCR5 antagonists. OBJECTIVES: To determine HIV-1 coreceptor usage among patients attending a comprehensive care centre in Nairobi, Kenya. METHODS: Blood samples were obtained from HIV infected patients attending the comprehensive care centre, Kenyatta National Hospital in years 2008 and 2009. The samples were separated into plasma and peripheral blood mononuclear cells (PBMCs). Proviral DNA was extracted from PBMCs and Polymerase Chain reaction (PCR) done to amplify the HIV env fragment spanning the C2-V3 region. The resultant fragment was directly sequenced on an automated sequencer (ABI, 3100). Co-receptor prediction of the env sequences was done using Geno2pheno [co-receptor], and phylogenetic relationships determined using CLUSTALW and Neighbor Joining method. RESULTS: A total of 67 samples (46 treatment experienced and 21 treatment naive) were successfully amplified and sequenced. Forty nine (73%) sequences showed a prediction for R5 tropism while 18(27%) were X4 tropic. Phylogenetic analysis showed that 46(69%) were subtype A, 11(16%) subtype C, and 10(15%) subtype D. No statistical significant associations were observed between cell tropism and CD4+ status, patient gender, age, or treatment option. There was a tendency for more X4 tropic strains being in the treatment experienced group than the naive group: Of 46 treatment experiencing participants, 14(30%) harboured X4, compared with 4(19%) of 21 of the treatment naive participants, the association is however not statistically significant (p = 0.31). However, a strong association was observed between subtype D and CXCR4 co- receptor usage (p = 0.015) with 6(60%) of the 10 subtype D being X4 tropic and 4(40%) R5 tropic. CONCLUSION: HIV-1 R5 tropic strains were the most prevalent in the study population and HIV infected patients in Kenya may benefit from CCR5 antagonists. However, there is need for caution where subtype D infection is suspected or where antiretroviral salvage therapy is indicated. PMID- 22838399 TI - Hurdles in tissue engineering/regenerative medicine product commercialization: a pilot survey of governmental funding agencies and the financial industry. AB - The Tissue Engineering and Regenerative Medicine International Society of the Americas (TERMIS-AM) Industry Committee conducted a semiquantitative opinion survey in 2010 to delineate potential hurdles to commercialization perceived by the TERMIS constituency groups that participate in the stream of technology commercialization (academia, start-up companies, development-stage companies, and established companies). A significant hurdle identified consistently by each group was access to capital for advancing potential technologies into development pathways leading to commercialization. A follow-on survey was developed by the TERMIS-AM Industry Committee to evaluate the financial industry's perspectives on investing in regenerative medical technologies. The survey, composed of 15 questions, was developed and provided to 37 investment organizations in one of three sectors (governmental, private, and public investors). The survey was anonymous and confidential with sector designation the only identifying feature of each respondent's organization. Approximately 80% of the survey was composed of respondents from the public (n=14) and private (n=15) sectors. Each respondent represents one investment organization with the potential of multiple participants participating to form the organization's response. The remaining organizations represented governmental agencies (n=8). Results from this survey indicate that a high percentage (<60%) of respondents (governmental, private, and public) were willing to invest >$2MM into regenerative medical companies at the different stages of a company's life cycle. Investors recognized major hurdles to this emerging industry, including regulatory pathway, clinical translation, and reimbursement of these new products. Investments in regenerative technologies have been cyclical over the past 10-15 years, but investors recognized a 1-5-year investment period before the exit via Merger and Acquisition (M&A). Investors considered musculoskeletal products and their top technology choice with companies in the clinical stage of development being the most preferred investment targets. All sectors indicated a limited interest in early-stage start up companies potentially explaining why start-up companies have struggled to access to capital and investors based their investment on the stage of a company's life cycle, reflecting each sector's risk tolerance, exit strategy, time of holding an investment, and investment strategy priorities. Investors highlighted the limited number of regenerative medical companies that have achieved commercial status as a basis for why public investors have been approached by so few companies. Based on respondents to this survey, regenerative medical sponsors seeking capital from the financial industry must keep the explanation of their technology simple, since all sectors considered regenerative medical technology as difficult to evaluate. This survey's results indicate that under the current financial environment, many regenerative medical companies must consider codevelopment or even M&A as nondilutive means of raising capital. The overall summary for this survey highlights the highly varied goals and motivations for the various sectors of the government and financial industries. PMID- 22838400 TI - Visual exploration and action processing in schizophrenia. AB - INTRODUCTION: Visual scanning is widely reported to be abnormal in schizophrenia. The majority of eye movement studies in schizophrenic patients have used pictures of a face in isolation in free viewings. This study was designed to examine whether attentional control, through instructions, modulates the visuomotor behaviour in schizophrenia with pictures presenting a face accompanied by its body, and to investigate the ability of schizophrenic patients to recognise others' actions. METHOD: Visual scan paths were monitored in 26 schizophrenic patients and 26 controls. Participants performed three tasks in which they were asked either to look at the picture in any way they liked, to determine the character's gender, or to recognise the action that the character was making with an object. RESULTS: Patients explored less the pictures than controls in the free viewing. Their scan paths did not differ from that of controls in the active viewings, though patients tended to "avoid" looking at the character's face in the action recognition task. CONCLUSION: The results show that patients are able to normalise their pattern of exploration as a function of task demands. The results are discussed in relation to attentional control, cognitive flexibility, dopamine, and processing of context information. PMID- 22838401 TI - A qualitative investigation of the impact of multimorbidity on GP diagnosis and treatment of depression in Australia. AB - Primary care providers often struggle to identify depression, with patients with multiple chronic conditions presenting additional unique challenges. Whilst the diagnosis and treatment of depression has been explored in a range of contexts in the literature, there is a paucity of information on the impact of multimorbidity on general practitioners (GPs) attempting to diagnose and manage depression in primary care. Eight GPs with multiple referrals to a multidisciplinary clinic engaged in a semi-structured interview to discuss the impact of multimorbidity on the diagnosis and detection of depression. Interviews were transcribed and thematic analysis was used to identify key themes. Grounded theory was generated from data relating to the role of multimorbidity. Participants described multimorbidity as obscuring symptom causation, but also creating time to investigate causation and negotiate the depression diagnosis with the patient, and generating relationship through frequent presentations. Knowledge of the patient impacted on intervention recommendations, and trust facilitated patient receptivity. Treatment was affected by a range of variables, and included medical and social interventions. GP process for multimorbid patients is similar to that of patients with chronic illness. Further research is needed to know whether different processes or diagnostic categories are warranted where multiple chronic illnesses are present. Also, GPs recommend social interventions where medical interventions are perceived as inappropriate. Research into the efficacy of social interventions in multimorbid patients is needed. PMID- 22838402 TI - "Schizophrenic" hemocompatible copolymers via switchable thermoresponsive transition of nonionic/zwitterionic block self-assembly in human blood. AB - "Schizophrenic" diblock copolymers containing nonionic and zwitterionic blocks were prepared with well-controlled molecular weights via atom-transfer radical polymerization (ATRP). In this work, we report a systematic study of how morphological changes of poly(N-isopropylacrylamide)-block-poly(sulfobetaine methacrylate) (PNIPAAm-b-PSBMA) copolymers affect hemocompatibility in human blood solution. The "schizophrenic" behavior of PNIPAAm-b-PSBMA was observed by (1)H NMR, dynamic light scattering (DLS), and turbidity measurement with double morphological transition, exhibiting both lower critical solution temperature (LCST) and upper critical solution temperature (UCST) in aqueous solution. Below the UCST of PSBMA block, micelles were obtained with a core of insoluble PSBMA association and a shell of soluble PNIPAAm, whereas the opposite micelle structure was observed above the LCST of PNIPAAm block. In between the UCST and LCST, unimers with both soluble blocks were detected. Hydrodynamic size of prepared polymers and copolymers is determined to illustrate the correlations between intermolecular nonionic/zwitterionic associations and blood compatibility of PNIPAAm, PNIPAAm-b-PSBMA, and PSBMA suspension in human blood. Human fibrinogen adsorption onto the PNIPAAm-b-PSBMA copolymers from single-protein solutions was measured by DLS to determine the nonfouling stability of copolymer suspension. The new nonfouling nature of PNIPAAm-b-PSBMA copolymers was demonstrated to show extremely high anticoagulant activity and antihemolytic activity in human blood over a wide range of explored temperatures from 4 to 40 degrees C. The temperature-independent blood compatibility of nonionic/zwitterionic block copolymer along with their schizophrenic phase behavior in aqueous solution suggests their potential in blood-contacting applications. PMID- 22838403 TI - Identifying factors associated with experiences of coronary heart disease patients receiving structured chronic care and counselling in European primary care. AB - BACKGROUND: Primary care for chronic illness varies across European healthcare systems. In patients suffering from coronary heart disease (CHD), factors associated with patients' experiences of receiving structured chronic care and counselling at the patient and practice level were investigated. METHODS: In an observational study comprising 140 general practices from five European countries (Austria, Germany, the Netherlands, Switzerland and the United Kingdom), 30 patients with Coronary Heart Disease (CHD) per practice were chosen at random to partake in this research. Patients were provided with a questionnaire and the Patient Assessment of Chronic Illness Care (PACIC-5A) - instrument. Practice characteristics were assessed through a practice questionnaire and face to face interviews. Data were aggregated to obtain two practice scores representing quality management and CHD care, respectively. A hierarchical multilevel analysis was performed to examine the impact of patient and practice characteristics on PACIC scores. RESULTS: The final sample included 1745 CHD-patients from 131 general practices with a mean age of 67.8 (SD 9.9) years. The overall PACIC score was 2.84 (95%CI: 2.79; 2.89) and the 5A score reflecting structured lifestyle counselling was 2.75 (95% CI: 2.69; 2.79). At the patient level, male gender, more frequent practice contact and fewer related or unrelated conditions were associated with higher PACIC scores. At the practice level, performance scores reflecting quality management (p = 0.013) and CHD care (p = 0.009) were associated with improved assessment of the structured chronic care and counselling received. CONCLUSIONS: Patients' perceived quality of care varies. However, good practice management and organisation of care were positively reflected in patients' assessments of receiving structured chronic illness care. This highlights the importance of integrating patient experiences into quality measurements to provide feedback to health care professionals. PMID- 22838404 TI - WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless) signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken. METHODS: Tissue samples from the Lung Tissue Research Consortium (LTRC) of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP) and 19 normal patients were examined for the immunolocalization of Wnt7B. RESULTS: In normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls. CONCLUSIONS: The results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF. PMID- 22838405 TI - Studies on the selectivity between nickel-catalyzed 1,2-cis-2-amino glycosylation of hydroxyl groups of thioglycoside acceptors with C2-substituted benzylidene N phenyl trifluoroacetimidates and intermolecular aglycon transfer of the sulfide group. AB - The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2 amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high alpha-selectivity in the formation of 1,2-cis-2 amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and alpha selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors. PMID- 22838406 TI - Essential oil composition and antimicrobial activity of wild and cultivated mint timija (Mentha suaveolens subsp. timija (Briq.) Harley), an endemic and threatened medicinal species in Morocco. AB - The hydro-distilled essential oils obtained from aerial parts of the wild (w) and cultivated (c) mint timija (Mentha suaveolens subsp. timija), an endemic medicinal species of Morocco, have been analyzed by GC-MS and screened for antimicrobial activity. In total, 35 compounds representing more than 98% of the oils were identified. Menthone (39.4(w)-10.8(c)%), pulegone (62.3(c)-34.3(w)%) and isomenthone (9.3(c)-7.8(w)%) were found as the main components for the two oils. The volatiles of the wild and cultivated material differed significantly in both the percentage of the main components and antimicrobial effect. Pulegone was more dominant in cultivated mint timija (62.3%) than in wild one (34.3%), while menthone was more abundant in the wild material (39.4%). In the antimicrobial assays, both oils displayed good to excellent activity against all microorganisms tested with the oil of the cultivated form being more active. PMID- 22838408 TI - Oxidation of myofibrillar proteins and impaired functionality: underlying mechanisms of the carbonylation pathway. AB - The potential impact of protein oxidation on the functional properties of myofibrillar proteins (MP) was investigated in the present study. To accomplish this purpose, myofibrillar proteins were oxidized in vitro for 12 days at 37 degrees C in the presence of Cu(2+), Fe(3+), and Mb in combination with H(2)O(2) and analyzed at sampling times for chemical changes induced by oxidative reactions and functional properties. The oxidation measurements included specific protein carbonyls (alpha-aminoadipic semialdehyde, AAS), advanced lysine oxidation products (alpha-aminoadipic acid, AAA, and Schiff bases), and thiobarbituric acid-reactive substances (TBARS). The factors and mechanisms involved in the oxidative degradation of lysine residues through the carbonylation pathway are precisely described. According to the present results, intense lipid and protein carbonylation, principally induced by Cu(2+)/systems, leads to a fast and severe loss of MP functionality, including impaired water holding, foaming, and gelling capacities. The implication of Mb in the oxidation events enhances the production of AAA and Schiff bases, compromising to a larger extent the solubility of MP and worsening the aggregation and the gelling capacity. The connection between the oxidation-induced chemical changes and the loss of protein functionality is thoroughly discussed. PMID- 22838407 TI - Nutrition deficiency increases the risk of stomach cancer mortality. AB - BACKGROUND: The purpose of the study is to determine whether exposure to malnutrition during early life is associated with increased risk of stomach cancer in later life. METHODS: The design protocol included analyzing the trend of gastric cancer mortality and nutrition and evaluating the association between nutrient deficiency in early life and the risk of gastric cancer by hierarchical age-period-birth cohort (APC) analysis using general log-linear Poisson models and to compare the difference between birth cohorts who were exposed to the 1959 1961 Chinese famine and those who were not exposed to the famine. Data on stomach cancer mortality from 1970 to 2009 and the dietary patterns from 1955 to 1985 which included the 1959-1961 Chinese famine period in the Zhaoyuan County population were obtained. The nutrition information was collected 15 years prior to the mortality data as based on the latest reference of disease incubation. RESULTS: APC analysis revealed that severe nutrition deficiency during early life may increase the risk of stomach cancer. Compared with the 1960-1964 birth cohort, the risk for stomach cancer in all birth cohorts from 1900 to 1959 significantly increased; compared with the 1970-1974 cohort, the risk for stomach cancer in the 1975-1979 cohort significantly increased, whereas the others had a steadily decreased risk; compared with 85-89 age group in the 2005-2009 death survey, the ORs decreased with younger age and reached significant levels for the 50-54 age group after adjusting the confounding factors. The 1930 to 1964 group (exposed to famine) had a higher mortality rate than the 1965 to 1999 group (not exposed to famine). For males, the relative risk (RR) was 2.39 and the 95% confidence interval (CI) was 1.51 to 3.77. For females, RR was 1.64 and 95% CI was 1.02 to 2.62. CONCLUSION: The results of the present study suggested that prolonged malnutrition during early life may increase the risk of stomach cancer mortality in later life. PMID- 22838409 TI - Simple theory for salt effects on the solubility of amide. AB - Elucidating the interactions of cosolvents and cosolutes, for example, urea and inorganic salts, with proteins plays a very important role in understanding protein structure formation, solubility, and dynamics. In a recent study, we rationalized the experimentally observed salt effects on water/air surface tension and showed the potential importance of cation/anion association/cooperativity. In this paper, we focus on salt effects on the solvation of simple model compounds such as peptides and benzene, hoping to obtain a more general and simple understanding of the Hofmeister series. We show here that preferred cation binding to the carbonyl and anion to the apolar surface of model polypeptides can help explain the experimentally observed salt effects on polypeptide activity coefficient in water. The effects of ions on the solvation of amide group can be both direct and indirect, which together attribute to an effective change of the proton donor/acceptor equilibrium in aqueous solutions. We show that such an argument can be used to understand not only the salt effects on solubility of amides but also why some organic compounds are protein secondary structure denaturants whereas others are protectants. PMID- 22838491 TI - Direct visualization of molecule deprotonation on an insulating surface. AB - Elucidating molecular-scale details of basic reaction steps on surfaces is decisive for a fundamental understanding of molecular reactivity within many fields, including catalysis and on-surface synthesis. Here, the deprotonation of 2,5-dihydroxybenzoic acid (DHBA) deposited onto calcite (101;4) held at room temperature is followed in situ by noncontact atomic force microscopy. After deposition, the molecules form two coexisting phases, a transient striped phase and a stable dense phase. A detailed analysis of high-resolution noncontact atomic force microscopy images indicates the transient striped phase being a bulk like phase, which requires hydrogen bonds between the carboxylic acid moieties to be formed. With time, the striped phase transforms into the dense phase, which is explained by the deprotonation of the molecules. In the deprotonated state, the molecules can no longer form hydrogen bonds, but anchor to the surface calcium cations with their negatively charged carboxylate group. The deprotonation step is directly confirmed by Kelvin probe force microscopy images that unravel the change in the molecular charge. PMID- 22838492 TI - Quantification of echodensities in tuberculous pericardial effusion using fractal geometry: a proof of concept study. AB - BACKGROUND: The purpose of this study was to quantify the heterogeneous distribution of echodensities in the pericardial fluid of patients with tuberculous pericarditis using echocardiography and fractal analysis, and to determine whether there were differences in the fractal dimensions of effusive constrictive and effusive non-constrictive disease. METHODS: We used fractal geometry to quantify the echocardiographic densities in patients who were enrolled in the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry. Sub-costal and four chamber images were included in the analysis if a minimum of two clearly identified fibrin strands were present and the quality of the images were of a standard which allowed for accurate measurement of the fractal dimension. The fractal dimension was calculated as follows: D(f) = limlog N(s)/[log (l/s)], where D(f) is the box counting fractal dimension of the fibrin strand, s is the side length of the box and N(s) is the smallest number of boxes of side length s to cover the outline of the object being measured. We compared the fractal dimension of echocardiographic findings in patients with effusive constrictive pericarditis to effusive non-constrictive pericardial effusion using the non-parametric Mann-Whitney test. RESULTS: Of the 14 echocardiographs from 14 participants that were selected for the study, 42.8% (6/14) of images were subcostal views while 57.1% (8/14) were 4-chamber views. Eight of the patients had tuberculous effusive constrictive pericarditis while 6 had tuberculous effusive non-constrictive pericarditis. The mean fractal dimension D(f) was 1.325 with a standard deviation (SD) of 0.146. The measured fibrin strand dimension exceeded the topological dimension in all the images over the entire range of grid scales with a correlation coefficient (r2) greater than 0.8 in the majority. The fractal dimension of echodensities was 1.359 +/- 0.199 in effusive constrictive pericarditis compared to 1.330 +/- 0.166 in effusive non constrictive pericarditis (p = 0.595). CONCLUSIONS: The echocardiographic densities in tuberculous pericardial effusion have a fractal geometrical dimension which is similar in pure effusive and effusive constrictive disease. PMID- 22838493 TI - Total skin electron beam therapy as palliative treatment for cutaneous manifestations of advanced, therapy-refractory cutaneous lymphoma and leukemia. AB - BACKGROUND: To retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia. PATIENTS AND METHODS: Treatment results of 25 patients (median age 63 years; 5 female, 20 male) with cutaneous manifestations of advanced and therapy refractory CL (n = 21; T-cell lymphomas n = 18, B-cell lymphomas n = 3) stage IIB IV or leukemia (n = 4; AML n = 2, CLL n = 1, PDC n = 1) treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each. RESULTS: The median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1-18 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1-46 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%). CONCLUSION: For palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option. PMID- 22838494 TI - Seed storage proteins of the globulin family are cleaved post-translationally in wheat embryos. AB - BACKGROUND: The 7S globulins are plant seed storage proteins that have been associated with the development of a number of human diseases, including peanut allergy. Immune reactivity to the wheat seed storage protein globulin-3 (Glo-3) has been associated with the development of the autoimmune disease type 1 diabetes in diabetes-prone rats and mice, as well as in a subset of human patients. FINDINGS: The present study characterized native wheat Glo-3 in salt soluble wheat seed protein extracts. Glo-3-like peptides were observed primarily in the wheat embryo. Glo-3-like proteins varied significantly in their molecular masses and isoelectric points, as determined by two dimensional electrophoresis and immunoblotting with anti-Glo-3A antibodies. Five major polypeptide spots were identified by mass spectrometry and N-terminal sequencing as belonging to the Glo 3 family. CONCLUSIONS: These results in combination with our previous findings have allowed for the development of a hypothetical model of the post translational events contributing to the wheat 7S globulin profile in mature wheat kernels. PMID- 22838495 TI - Diversity and specificity of microsatellites within Aspergillus section Fumigati. AB - BACKGROUND: Microsatellites (or short tandem repeats, STRs) are the genetic markers of choice for studying Aspergillus fumigatus molecular epidemiology due to its reproducibility and high discrimination power. However, the specificity of these markers must be investigated in a group of isolates from closely related species. The aim of this work was to test a microsatellite-based PCR multiplex previously designed for A. fumigatus in a set of species belonging to section Fumigati, namely Aspergillus fumigatiaffinis, Aspergillus lentulus, Aspergillus novofumigatus, Aspergillus unilateralis, Aspergillus viridinutans, Neosartorya fischeri, Neosartorya hiratsukae, Neosartorya pseudofischeri and Neosartorya udagawae. RESULTS: The reference A. fumigatus strain ATCC 46645 was easily genotyped in standard conditions showing a final electrophoretic profile of 8 expected peaks corresponding to each microsatellite locus. Inversely, no peaks were observed for all other species from section Fumigati, with an exception for marker MC6b in A. unilateralis. By screening the genome sequence of Neosartorya fischeri NRRL 181, the results showed that MC3, MC6a and MC7 might be employed for N. fischeri genotyping since these markers present several repeats of each motif. The accumulation of insertions and deletions was frequently observed in the genomic regions surrounding the microsatellites, including those where the A. fumigatus primers are located. The amplification of microsatellite markers in less stringent amplification conditions resulted in a distinct electrophoretic profile for species within section Fumigati. CONCLUSIONS: Therefore, the microsatellite-based PCR multiplex allow simple identification of A. fumigatus and, with a slight modification of temperature conditions, it also allows discriminating other pathogenic species within section Fumigati, particularly A. fumigatiaffinis, N. fischeri and N. udagawae. PMID- 22838496 TI - Cleavable cationic antibacterial amphiphiles: synthesis, mechanism of action, and cytotoxicities. AB - The development of novel antimicrobial agents having high selectivity toward bacterial cells over mammalian cells is urgently required to curb the widespread emergence of infectious diseases caused by pathogenic bacteria. Toward this end, we have developed a set of cationic dimeric amphiphiles (bearing cleavable amide linkages between the headgroup and the hydrocarbon tail with different methylene spacers) that showed high antibacterial activity against human pathogenic bacteria (Escherichia coli and Staphylococcus aureus) and low cytotoxicity. The Minimum Inhibitory Concentrations (MIC) were found to be very low for the dimeric amphiphiles and were lower or comparable to the monomeric counterpart. In the case of dimeric amphiphiles, MIC was found to decrease with the increase in the spacer chain length (n = 2 to 6) and again to increase at higher spacer length (n > 6). It was found that the compound with six methylene spacers was the most active among all of the amphiphiles (MICs = 10-13 MUM). By fluorescence spectroscopy, fluorescence microscopy, and field-emission scanning electron microscopy (FESEM), it was revealed that these cationic amphiphiles interact with the negatively charged bacterial cell membrane and disrupt the membrane integrity, thus killing the bacteria. All of the cationic amphiphiles showed low hemolytic activity (HC(50)) and high selectivity against both gram-positive and gram-negative bacteria. The most active amphiphile (n = 6) had a 10-13-fold higher HC(50) than did the MIC. Also, this amphiphile did not show any cytotoxicity against mammalian cells (HeLa cells) even at a concentration above the MIC (20 MUM). The critical micellar concentration (CMC) values of gemini surfactants were found to be very low (CMC = 0.30-0.11 mM) and were 10-27 times smaller than the corresponding monomeric analogue (CMC = 2.9 mM). Chemical hydrolysis and thermogravimetric analysis (TGA) proved that these amphiphiles are quite stable under both acidic and thermal conditions. Collectively, these properties make the newly synthesized amphiphiles potentially superior disinfectants and antiseptics for various biomedical and biotechnological applications. PMID- 22838498 TI - Coordination chemistry with f-element complexes for an improved understanding of factors that contribute to extraction selectivity. AB - Here, we highlight some recent accomplishments in f-element coordination chemistry aimed at probing the fundamental chemical differences between the 4f elements, lanthanides, and the 5f elements, actinides. The studies of particular interest are those that target improving our knowledge of fundamental chemistry to aid in increased selectivity for extractions of actinides. Two components key to understanding the challenges of actinide separations are detailed here, namely, previously described separation methods and recent investigations into the fundamental coordination chemistry of actinides. Both are aimed at probing the critical features necessary for improved selectivity of separations. This is considered a critical goal in the safe remediation of contaminated sites and reprocessing of nuclear fuel sources used in either civilian and noncivilian energy production. PMID- 22838497 TI - Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy. AB - IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade. PMID- 22838499 TI - Automatic artefact removal in a self-paced hybrid brain- computer interface system. AB - BACKGROUND: A novel artefact removal algorithm is proposed for a self-paced hybrid brain-computer interface (BCI) system. This hybrid system combines a self paced BCI with an eye-tracker to operate a virtual keyboard. To select a letter, the user must gaze at the target for at least a specific period of time (dwell time) and then activate the BCI by performing a mental task. Unfortunately, electroencephalogram (EEG) signals are often contaminated with artefacts. Artefacts change the quality of EEG signals and subsequently degrade the BCI's performance. METHODS: To remove artefacts in EEG signals, the proposed algorithm uses the stationary wavelet transform combined with a new adaptive thresholding mechanism. To evaluate the performance of the proposed algorithm and other artefact handling/removal methods, semi-simulated EEG signals (i.e., real EEG signals mixed with simulated artefacts) and real EEG signals obtained from seven participants are used. For real EEG signals, the hybrid BCI system's performance is evaluated in an online-like manner, i.e., using the continuous data from the last session as in a real-time environment. RESULTS: With semi-simulated EEG signals, we show that the proposed algorithm achieves lower signal distortion in both time and frequency domains. With real EEG signals, we demonstrate that for dwell time of 0.0s, the number of false-positives/minute is 2 and the true positive rate (TPR) achieved by the proposed algorithm is 44.7%, which is more than 15.0% higher compared to other state-of-the-art artefact handling methods. As dwell time increases to 1.0s, the TPR increases to 73.1%. CONCLUSIONS: The proposed artefact removal algorithm greatly improves the BCI's performance. It also has the following advantages: a) it does not require additional electrooculogram/electromyogram channels, long data segments or a large number of EEG channels, b) it allows real-time processing, and c) it reduces signal distortion. PMID- 22838501 TI - Effect of residential proximity to major roadways on cystic fibrosis exacerbations. AB - Ambient air pollution has been attributed with an increase in exacerbation frequencies among the cystic fibrosis (CF) population. This study correlates exacerbation frequency with proximity to roadways and two criteria air pollutants. Clinical data was extracted from the Cystic Fibrosis Foundation National Patient Registry and Electronic Medical Records at Children's Hospital Los Angeles (CHLA). Average annual air pollutant levels were obtained from selected US Environmental Protection Agency's monitoring stations. Geographic proximity to monitoring stations and roadways were analyzed using spatial mapping software. A total of 145 patients from the CHLA's CF center were characterized by a dichotomous exacerbation category. No significant association was determined between the frequency of exacerbations and exposure to fine particulate matter and ozone levels. Residential proximity to US-designated highways and freeways also did not achieve significance (p = 0.3777) but was noted to be correlated with major arterial roadways (p = 0.0420). Associations of environmental exposures may have important implications for future predictive models of CF clinical outcomes. PMID- 22838500 TI - Investigation of neovascularization in three-dimensional porous scaffolds in vivo by a combination of multiscale photoacoustic microscopy and optical coherence tomography. AB - It is a grand challenge to visualize and assess in vivo neovascularization in a three-dimensional (3D) scaffold noninvasively, together with high spatial resolution and deep penetration depth. Here we used multiscale photoacoustic microscopy (PAM), including acoustic-resolution PAM (AR-PAM) and optical resolution PAM (OR-PAM), to chronically monitor neovascularization in an inverse opal scaffold implanted in a mouse model up to 6 weeks by taking advantage of the optical absorption contrast intrinsic to hemoglobin molecules in red blood cells. By combining with optical coherence tomography (OCT) based on optical scattering contrast, we also demonstrated the capability to simultaneously image and analyze the vasculature and the scaffold in the same mouse. The hybrid system containing OR-PAM and OCT offered a fine lateral resolution of ~5 MUm and a penetration depth of ~1 mm into the scaffold/tissue construct. AR-PAM further extended the penetration depth up to ~3 mm at a lateral resolution of ~45 MUm. By quantifying the 3D PAM data, we further examined the effect of pore size (200 vs. 80 MUm) of a scaffold on neovascularization. The data collected from PAM were consistent with those obtained from traditional invasive, labor-intensive histologic analyses. PMID- 22838502 TI - Ten-year trends in intoxications and requests for emergency ambulance service. AB - BACKGROUND: Intoxication, whether from alcohol, drugs, or alcohol and drugs in combination, remains a challenging burden on emergency departments. The increasing alcohol consumption among adolescents and young adults, particularly heavy episodic drinking, and the resulting increase in the use of health care resources for alcohol intoxication has been a widely discussed topic. OBJECTIVE: The aim of our study was to assess and characterize the use of emergency ambulance services that was required as a result of alcohol and drug intoxication in a major metropolitan area. METHODS: We conducted a retrospective, longitudinal study over a 10-year period in the greater metropolitan area of Zurich, Switzerland. The study population included intoxicated patients assessed and initially treated by paramedics of the emergency ambulance service. Data were extracted from the ambulance service reports. The primary outcomes measured were trends over time in the numbers and types of intoxication and trends with respect to gender and age distributions of intoxicated patients. RESULTS: An annual increase of about 5% in the number of intoxicated patients requiring emergency ambulance service was observed over the study period. Alcohol use was present in 73% of the cases. The highest number of cases was among patients 25-44 years of age. The greatest increase in the number of cases over time was among patients under 25 years of age. Women comprised 41% of the patients under 25 years of age but only about 35% of older patients. The number of severe injuries and suicide attempts was small, but the number of suicide attempts increased at a higher rate than the overall number of cases of intoxication. There was a significant increase (17.64% per year on average) in the incidence of aggressive behavior toward paramedics from intoxicated patients, although still small in numbers. CONCLUSIONS: Our findings suggest two main vulnerable groups: young persons under 25 years of age, with a particular focus on women, having the greatest increase over time, and middle-aged men, having the greatest proportion among all cases observed. Intervention efforts should include a high-risk approach to reduce alcohol-related problems. Key words: alcohol intoxication; substance-related disorders; aggression; injuries; emergency medical services. PMID- 22838503 TI - Service provision and barriers to care for homeless people with mental health problems across 14 European capital cities. AB - BACKGROUND: Mental health problems are disproportionately higher amongst homeless people. Many barriers exist for homeless people with mental health problems in accessing treatment yet little research has been done on service provision and quality of care for this group. The aim of this paper is to assess current service provision and identify barriers to care for homeless people with mental health problems in 14 European capital cities. METHOD: Two methods of data collection were employed; (i) In two highly deprived areas in each of the 14 European capital cities, homeless-specific services providing mental health, social care or general health services were assessed. Data were obtained on service characteristics, staff and programmes provided. (ii) Semi-structured interviews were conducted in each area with experts in mental health care provision for homeless people in order to determine the barriers to care and ways to overcome them. RESULTS: Across the 14 capital cities, 111 homeless-specific services were assessed. Input from professionally qualified mental health staff was reported as low, as were levels of active outreach and case finding. Out-of hours service provision appears inadequate and high levels of service exclusion criteria were evident. Prejudice in the services towards homeless people, a lack of co-ordination amongst services, and the difficulties homeless people face in obtaining health insurance were identified as major barriers to service provision. CONCLUSIONS: While there is variability in service provision across European capital cities, the reported barriers to service accessibility are common. Homeless-specific services are more responsive to the initial needs of homeless people with mental health problems, while generic services tend to be more conducive to long term care. Further research is needed to determine the effectiveness of different service delivery models, including the most effective coordination of homeless specific and generic services. PMID- 22838505 TI - A Bayesian method for comparing and combining binary classifiers in the absence of a gold standard. AB - BACKGROUND: Many problems in bioinformatics involve classification based on features such as sequence, structure or morphology. Given multiple classifiers, two crucial questions arise: how does their performance compare, and how can they best be combined to produce a better classifier? A classifier can be evaluated in terms of sensitivity and specificity using benchmark, or gold standard, data, that is, data for which the true classification is known. However, a gold standard is not always available. Here we demonstrate that a Bayesian model for comparing medical diagnostics without a gold standard can be successfully applied in the bioinformatics domain, to genomic scale data sets. We present a new implementation, which unlike previous implementations is applicable to any number of classifiers. We apply this model, for the first time, to the problem of finding the globally optimal logical combination of classifiers. RESULTS: We compared three classifiers of protein subcellular localisation, and evaluated our estimates of sensitivity and specificity against estimates obtained using a gold standard. The method overestimated sensitivity and specificity with only a small discrepancy, and correctly ranked the classifiers. Diagnostic tests for swine flu were then compared on a small data set. Lastly, classifiers for a genome-wide association study of macular degeneration with 541094 SNPs were analysed. In all cases, run times were feasible, and results precise. The optimal logical combination of classifiers was also determined for all three data sets. Code and data are available from http://bioinformatics.monash.edu.au/downloads/. CONCLUSIONS: The examples demonstrate the methods are suitable for both small and large data sets, applicable to the wide range of bioinformatics classification problems, and robust to dependence between classifiers. In all three test cases, the globally optimal logical combination of the classifiers was found to be their union, according to three out of four ranking criteria. We propose as a general rule of thumb that the union of classifiers will be close to optimal. PMID- 22838504 TI - Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer. AB - BACKGROUND: S100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression. METHODS: S100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated. RESULTS: S100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells. CONCLUSIONS: Our results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis. PMID- 22838506 TI - Role of the subunit interactions in the conformational transitions in adult human hemoglobin: an explicit solvent molecular dynamics study. AB - Hemoglobin exhibits allosteric structural changes upon ligand binding due to the dynamic interactions between the ligand binding sites, the amino acids residues and some other solutes present under physiological conditions. In the present study, the dynamical and quaternary structural changes occurring in two unligated (deoxy-) T structures and two fully ligated (oxy-) R, R2 structures of adult human hemoglobin were investigated with molecular dynamics. It is shown that, in the submicrosecond time scale, there is no marked difference in the global dynamics of the amino acid residues in both the oxy- and the deoxy-forms of the individual structures. In addition, the R, R2 are relatively stable and do not present quaternary conformational changes within the time scale of our simulations, while the T structure is dynamically more flexible and exhibited the T -> R quaternary conformational transition, which is propagated by the relative rotation of the residues at the alpha(1)beta(2) and alpha(2)beta(1) interface. PMID- 22838507 TI - Expressed emotion-criticism and risk of depression onset in children. AB - The primary goal of the current study was to examine the impact of maternal criticism (expressed emotion-criticism; EE-Crit) on the prospective development of depressive episodes in children. In addition to examining baseline levels of EE-Crit, we also sought to determine whether distinct subgroups (latent classes) of mothers could be identified based on the levels of EE-Crit they exhibited over a multiwave assessment and whether that latent class membership would predict depression onset in children. Finally, we examined whether EE-Crit and maternal depression would independently predict children's depression risk or whether EE Crit would moderate the link between maternal depression and children's depression onset. Children of mothers with or without a history of major depression (N = 100) were assessed 5 times over 20 months. Children completed the Children's Depression Inventory and mothers completed the Five Minute Speech Sample and the Beck Depression Inventory at the baseline assessment, and at 2-, 4 , and 6-month follow-up assessments. Children and mothers completed diagnostic interviews assessing children's onsets of depressive episodes at the 20-month follow-up. Latent class analysis of the 4 waves of EE-Crit assessments revealed two distinct groups, exhibiting relatively lower versus higher levels of EE-Crit across the first 6 months of follow-up. EE-Crit latent class membership predicted children's depression onset over the subsequent 14 months. This finding was maintained after controlling for mother's and children's depressive symptoms during the initial 6 months of follow-up. Finally, maternal depression did not moderate the link between EE-Crit and childhood depression onset. Continued exposure to maternal criticism appears to be an important risk factor for depression in children, risk that is at least partially independent of the risk conveyed by maternal depression. These results highlight the importance of a modifiable risk factor for depression-repeated exposure to maternal criticism. PMID- 22838508 TI - Robust surface doping of Bi2Se3 by rubidium intercalation. AB - Rubidium adsorption on the surface of the topological insulator Bi(2)Se(3) is found to induce a strong downward band bending, leading to the appearance of a quantum-confined two-dimensional electron gas state (2DEG) in the conduction band. The 2DEG shows a strong Rashba-type spin-orbit splitting, and it has previously been pointed out that this has relevance to nanoscale spintronics devices. The adsorption of Rb atoms, on the other hand, renders the surface very reactive, and exposure to oxygen leads to a rapid degrading of the 2DEG. We show that intercalating the Rb atoms, presumably into the van der Waals gaps in the quintuple layer structure of Bi(2)Se(3), drastically reduces the surface reactivity while not affecting the promising electronic structure. The intercalation process is observed above room temperature and accelerated with increasing initial Rb coverage, an effect that is ascribed to the Coulomb interaction between the charged Rb ions. Coulomb repulsion is also thought to be responsible for a uniform distribution of Rb on the surface. PMID- 22838509 TI - Antiproliferative activity and apoptosis induction of Eucalyptus Citriodora resin and its major bioactive compound in melanoma B16F10 cells. AB - Antiproliferative activity and apoptosis induction of ethyl acetate of Eucalyptus citriodora resin (EAEER), and its major bioactive compound in melanoma B16F10 cells were investigated. 6-[1-(p-Hydroxy-phenyl)ethyl]-7-O-methyl aromadendrin (HEMA), a flavanol derivative, was isolated from EAEER and identified on the basis of its mass and NMR spectra. The results from MTT assay showed high antiproliferative effects of EAEER and HEMA on B16F10 cells. Moreover, EAEER- and HEMA-induced cell apoptosis was association with the decrease in the mitochondrial transmembrane potentials (Deltapsi(m)), increase in Bax/Bcl-2 ratio, and activation of caspase-3. Cells treated with EAEER and HEMA generated intracellular reactive oxygen species (ROS) and nitric oxide (NO), indicating that ROS and RNS play important roles in the induction of apoptosis in B16F10 cells. Taken together, EAEER and its major bioactive compound, HEMA, inhibited the proliferation of B16F10 cells via apoptosis and may be a potential antimelanoma agent. PMID- 22838632 TI - Room temperature copper(II)-catalyzed oxidative cyclization of enamides to 2,5 disubstituted oxazoles via vinylic C-H functionalization. AB - A copper(II)-catalyzed oxidative cyclization of enamides to oxazoles via vinylic C-H bond functionalization at room temperature is described. Various 2,5 disubstituted oxazoles bearing aryl, vinyl, alkyl, and heteroaryl substituents could be synthesized in moderate to high yields. This reaction protocol is complementary to our previously reported iodine-mediated cyclization of enamides to afford 2,4,5-trisubstituted oxazoles. PMID- 22838633 TI - IL-3 and TNFalpha increase Thymic Stromal Lymphopoietin Receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) and eosinophils are prominent components of allergic inflammation. Therefore, we sought to determine whether TSLP could activate eosinophils, focusing on measuring the regulation of TSLPR expression on eosinophils and degranulation in response to TSLP, as well as other eosinophil activation responses. METHODS: Eosinophil mRNA expression of TSLPR and IL-7Ralpha was examined by real-time quantitative PCR of human eosinophils treated with TNFalpha and IL-5 family cytokines, and TSLPR surface expression on eosinophils was analyzed by flow cytometry. Eosinophils were stimulated with TSLP (with and without pre-activation with TNFalpha and IL-3) and evaluated for release of eosinophil derived neurotoxin (EDN), phosphorylation of STAT5, and survival by trypan blue exclusion. A blocking antibody for TSLPR was used to confirm the specificity of TSLP mediated signaling on eosinophil degranulation. RESULTS: Eosinophil expression of cell surface TSLPR and TSLPR mRNA was upregulated by stimulation with TNFalpha and IL-3. TSLP stimulation resulted in release of EDN, phosphorylation of STAT5 as well as promotion of viability and survival. TSLP-stimulated eosinophil degranulation was inhibited by a functional blocking antibody to TSLPR. Pre-activation of eosinophils with TNFalpha and IL-3 promoted eosinophil degranulation at lower concentrations of TSLP stimulation. CONCLUSIONS: This study demonstrates that eosinophils are activated by TSLP and that eosinophil degranulation in response to TSLP may be enhanced on exposure to cytokines present in allergic inflammation, indicating that the eosinophil has the capacity to participate in TSLP-driven allergic responses. PMID- 22838634 TI - Analysis of beta-lactamase phenotypes and carriage of selected beta-lactamase genes among Escherichia coli strains obtained from Kenyan patients during an 18 year period. AB - BACKGROUND: Although beta-lactam antibiotics are heavily used in many developing countries, the diversity of beta-lactamase genes (bla) is poorly understood. We screened for major beta-lactamase phenotypes and diversity of bla genes among 912 E. coli strains isolated from clinical samples obtained between 1992 and 2010 from hospitalized and non-hospitalized patients. RESULTS: None of the isolates was resistant to carbapenems but 30% of all isolates were susceptible to cefepime, cephamycins and piperacillin-tazobactam. Narrow spectrum beta-lactamase (NSBL) phenotype was observed in 278 (30%) isolates that contained bla(TEM-1) (54%) or bla(SHV-1) (35%) or both (11%). Extended Spectrum beta-lactamase (ESBL) phenotype was detected in 247 (27%) isolates which carried blaCTX-M-14 (29%), bla(CTX-M-15) (24%), bla(CTX-M-9) (2%), bla(CTX-M-8) (4%), bla(CTX-M-3) (11%), bla(CTX-M-1) (6%), blaSHV-5 (3%), bla(SHV-12) (5%), and bla(TEM-52) (16%). Complex Mutant TEM-like (CMT) phenotype was detected in 220 (24%) isolates which carried bla(TEM-125) (29%), while bla(TEM-50), bla(TEM-78), bla(TEM-109), bla(TEM -152) and bla(TEM-158) were detected in lower frequencies of between 7% and 11%. Majority of isolates producing a combination of CTX-M-15 + OXA-1 + TEM-1 exhibited resistance phenotypes barely indistinguishable from those of CMT producers. Although 73 (8%) isolates exhibited Inhibitor Resistant TEM-like (IRT) phenotype, bla(TEM-103) was the only true IRT-encoding gene identified in 18 (25%) of strains with this phenotype while the rest produced a combination of TEM 1 + OXA-1. The pAmpCs-like phenotype was observed in 94 (10%) isolates of which 77 (82%) carried bla(CMY-2) while 18% contained blaCMY-1.Isolates from urine accounted for 53%, 53%, 74% and 72% of strains exhibiting complex phenotypes such as IRT, ESBL, CMT or pAmpC respectively. On the contrary, 55% isolates from stool exhibited the relatively more susceptible NSBL-like phenotype. All the phenotypes, and majority of the bla genes, were detected both in isolates from hospitalized and non-hospitalized patients but complex phenotypes were particularly common among strains obtained between 2000 and 2010 from urine of hospitalized patients. CONCLUSIONS: The phenotypes and diversity of bla genes in E. coli strains implicated in clinical infections in non-hospitalized and hospitalized patients in Kenya is worryingly high. In order to preserve the efficacy of beta-lactam antibiotics, culture and susceptibility data should guide therapy and surveillance studies for beta-lactamase-producers in developing countries should be launched. PMID- 22838635 TI - Serum proteomic, peptidomic and metabolomic profiles in myasthenia gravis patients during treatment with Qiangji Jianli Fang. AB - BACKGROUND: Qiangji Jianli Fang (QJF) has been used for treatment of myasthenia gravis (MG) in China. However, our understanding of the effects of QJF against MG at the molecular level is limited. This study aims to investigate the effects of QJF treatment of MG patients on the protein, peptide and metabolite levels in serum. METHODS: High-throughput proteomic, peptidomic and metabolomic techniques were applied to investigate serum samples from 21 healthy individuals and 47 MG patients before and after QJF treatment via two-dimensional gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry, respectively. RESULTS: After QJF treatment, the expression levels of peptides m/z 1865.019, 2021.128 and 1211.668 of complement C3f increased (P = 0.004, P = 0.001 and P = 0.043, respectively), while that of peptide m/z 1739.931 of component C4b decreased (P = 0.043), in the serum of MG patients. The levels of gamma-aminobutyric acid (P = 0.000) and coenzyme Q4 (P = 0.000) resumed their normal states. CONCLUSION: QJF could inhibit the activity of the complement system and restore the normal levels of metabolites. PMID- 22838636 TI - Autoantibody profiling to follow evolution of lupus syndromes. AB - INTRODUCTION: Identification of patients who are in early stages of lupus is currently done through clinical evaluation and is not greatly facilitated by available diagnostic tests. Profiling for patient characteristics and antibody specificities that predict disease would enhance the ability of physicians to identify and treat early cases prior to onset of organ damaging illness. METHODS: A group of 22 patients with 4 or fewer diagnostic criteria for lupus were studied for changes in clinical and autoantibody profiles after a mean follow up period of 2.4 years. An array with more than 80 autoantigens was used to profile immunoglobulin G (IgG) and immunoglobulin M (IgM) autoantibodies. Correlations with clinical disease progression were examined. RESULTS: 3 of the 22 patients (14%) added sufficient criteria during follow up to satisfy a diagnosis of systemic lupus erythematosus (SLE) or to acquire a diagnosis of SLE renal disease. Patients who progressed were all females and were younger than those who did not progress (P=0.00054). IgG but not IgM autoreactivity showed greater increases in the progressor group than in the non-progressor group (P=0.047). IgG specificities that were higher at baseline in progressors included proliferating cell nuclear antigen (PCNA), beta 2 microglobulin, C1q and hemocyanin (P<0.019). Progressors had significant increases in La/SSB and liver cytosol type 1 (LC1) IgG autoantibodies over the period of evaluation (P<=0.0072). A quantitative risk profile generated from baseline demographic and autoantibody variables yielded highly different scores for the progressor and non-progressor groups (P=1.38 * 10 7) CONCLUSIONS: In addition to demographic features, autoantibody profiles using an expanded array of specificities were correlated with the risk of progressive disease in patients with lupus. These findings suggest the feasibility of developing a simple diagnostic that could be applied by nonspecialists to screen for lupus and permit effective triage for specialty care. PMID- 22838637 TI - Investigation of the role of FcgammaR and FcRn in mAb distribution to the brain. AB - To evaluate the role of Fc receptors (FcR) on IgG distribution to the brain, the disposition of 8C2, a murine monoclonal IgG1 antibody, was investigated after intravenous administration in FcRn alpha-chain knockout mice, FcgammaRIIb knockout mice, FcgammaRI/RIII knockout mice, and C57BL/6 control mice. (125)I-8C2 was co-administered with (51)Cr-labeled red blood cells to allow accurate assessment of residual blood content in brain samples. Blood and brain tissues were harvested from subgroups of three mice at several time-points up to 10 days, and radioactivity was counted. The blood and brain areas under 8C2 concentration vs time curves (AUCs) were calculated using the linear trapezoidal rule, and the associated standard deviations (SD) were assessed using a modified Bailer method. Concentration data were also analyzed with a semiphysiological population pharmacokinetic model. The brain/blood AUC ratios were comparable across all strains of mice (ratios +/- SD): 0.00774 +/- 0.000452, 0.00841 +/- 0.000535, 0.00636 +/- 0.000548, and 0.00917 +/- 0.000478 for C57BL/6 control mice, FcgammaRI/RIII knockouts, FcgammaRIIb knockouts, and FcRn alpha-chain knockout mice (p > 0.05). Statistically significant improvement in model fitting of the data was shown with incorporation of a strain-specific parameter for antibody clearance for FcRn knockout mice; however, no significant improvements in model fitting were found for strain effects on any other parameter, including the brain uptake clearance or efflux clearances for 8C2. The predicted 8C2 brain efflux clearance was found to be ~135-fold faster than the brain uptake clearance, consistent with the observed low ratio of brain-blood exposure. The experimental results and modeling results indicate that, in mice, FcRn and FcgammaR do not contribute to the "blood-brain barrier" that limits mAb uptake into the brain. PMID- 22838638 TI - Design and evaluation of a new mechatronic platform for assessment and prevention of fall risks. AB - BACKGROUND: Studying the responses in human behaviour to external perturbations during daily motor tasks is of key importance for understanding mechanisms of balance control and for investigating the functional response of targeted subjects. Experimental platforms as far developed entail a low number of perturbations and, only in few cases, have been designed to measure variables used at run time to trigger events during a certain motor task. METHODS: This work introduces a new mechatronic device, named SENLY, that provides balance perturbations while subjects carry out daily motor tasks (e.g., walking, upright stance). SENLY mainly consists of two independently-controlled treadmills that destabilize balance by suddenly perturbing belts movements in the horizontal plane. It is also provided with force sensors, which can be used at run time to estimate the ground reaction forces and identify events along the gait cycle in order to trigger the platform perturbation. The paper also describes the customized procedures adopted to calibrate the platform and the first testing trials aimed at evaluating its performance. RESULTS: SENLY allows to measure both vertical ground reaction forces and their related location more precisely and more accurately than other platforms of the same size. Moreover, the platform kinematic and kinetic performance meets all required specifications, with a negligible influence of the instrumental noise. CONCLUSION: A new perturbing platform able to reproduce different slipping paradigms while measuring GRFs at run time in order to enable the asynchronous triggering during the gait cycle was designed and developed. Calibration procedures and pilot tests show that SENLY allows to suitably estimate dynamical features of the load and to standardize experimental sessions, improving the efficacy of functional analysis. PMID- 22838639 TI - The prevalence of pre-hypertension and its association to established cardiovascular risk factors in south of Iran. AB - BACKGROUND: Pre-hypertension is associated with an increased risk of the development of hypertension and subsequent cardiovascular disease and raises mortality risk. The aim of this study was to determine the prevalence of pre hypertension and to explore the associations between pre-hypertension and established cardiovascular risk factors in a population-based sample of Iranian adults. METHODS: In this cross-sectional study a representative sample of 892 participants aged >= 30 years was selected using a multistage cluster sampling method. After completion of a detailed demographic and medical questionnaire (gender, age, history of diabetes mellitus and hypertension, taking antihypertensive or hypoglycemic agents and history of smoking), all participants were subjected to physical examination, blood lipid profile, blood glucose, anthropometric and smoking assessments, during the years 2009 and 2010. Variables were considered significant at a p-value <= 0.05. Statistical analysis was performed using SPSS version 11.5 software. RESULTS: Pre-hypertension was observed among 300 (33.7%) subjects, 36.4% for men and 31.4% for women (p > 0.05). The pre-hypertensive group had higher levels of blood glucose and triglycerides, higher body mass index and lower percentage of smoking than did the normotensive group. Multivariate logistic regression analysis showed that obesity and overweight were the strongest predictors of pre-hypertension [odds ratio, 2.74: 95% CI (Confidence Interval), 1.62 to 4.62 p < 0.001; odds ratio, 2.56, 95% CI, 1.74 to 3.77, p < 0.001 respectively]. CONCLUSIONS: Overweight and obesity are major determinants of the high prevalence rate of pre-hypertension detected in Iranian population. Therefore, primary prevention strategies should concentrate on reducing overweight and obesity if the increased prevalence of pre hypertension is to be diminished in Iranian adults. PMID- 22838640 TI - Cancer hospitalizations in rural-urban areas in relation to carcinogenic discharges from Toxics Release Inventory facilities. AB - This paper examines whether carcinogenic pollutants discharged from US Toxics Release Inventory (TRI) facilities are related to cancer hospitalization rates among the general population in rural and urban areas. We analyzed cancer hospitalizations (N = 440,061) across 20 states to find age- and sex-adjusted population cancer hospitalization rates. Multiple regression models were used to determine whether cancer hospitalization rates at the county level (N = 1102 counties) were associated with higher levels of carcinogenic discharges from TRI facilities, controlling for other risks. Significantly higher hospitalization rates were found in relation to higher TRI discharges for several cancer types that varied from urban to rural setting. Carcinogenic discharges from TRI facilities were associated with excess inpatient cancer treatment costs of $902.8 million in 2009. Future research may strive to move beyond ecological designs to examine cancer risks from TRI releases to better our understanding of cancer etiology and to establish appropriate environmental safeguards as indicated by the evidence. PMID- 22838642 TI - Normalized median fluorescence: an alternative flow cytometry analysis method for tracking human embryonic stem cell states during differentiation. AB - Human embryonic stem cells (hESCs) are a promising cell source for tissue engineering and regenerative medicine, but before they can be used in therapies, we must be able to accurately identify the state and progeny of hESCs. One of the most commonly used methods for identification is flow cytometry. Many flow cytometry applications use antibodies to detect the amount of antigen present on/in a cell. This allows for the identification of unique cell populations or the tracking of expression changes within a population during differentiation. The results are typically presented as a percentage of positively expressing cells (%Pos) for a marker of choice, relative to a negative control. However, this reporting term is vulnerable to distortion from outliers and inaccuracy from loss of information about the population's fluorescence intensity. In this article, we describe an alternate strategy that uses the normalized median fluorescence intensity (nMFI), in which the MFI of the stained sample is normalized to the MFI of the negative control, as the reporting term to more accurately describe a population of cells in culture. We observed that nMFI provides a more accurate representation for the quality of a starting population and comparing data of different experimental runs. In addition, we demonstrated that the nMFI is a more sensitive measure of pluripotent and differentiation markers expression changes during hESC differentiation into three germ layer lineages. PMID- 22838641 TI - Trends of population-based breast cancer survival in Germany and the US: decreasing discrepancies, but persistent survival gap of elderly patients in Germany. AB - BACKGROUND: Studies have revealed both higher cancer survival in the US than in Germany and substantial improvement of cancer survival in the past in these countries. This population-based study aims at comparing most recent 5-year relative survival of breast cancer patients and preceding trends in both countries. METHODS: Women with a first invasive breast cancer diagnosed and followed up between 1988 and 2008 from Germany and the US (utilizing data from the Saarland Cancer Registry and the Surveillance, Epidemiology, and End Results Program, respectively) were included. Period analysis was used to derive most up to-date 5-year relative survival and preceding survival trends according to age and stage. RESULTS: Since 1993, age standardized relative survival has steadily improved in Germany and the US to 83% and 88%, respectively. In the period 2005 08, relative survival of localized cancer was above 97% in both countries, and 79% and 83% for locally/regionally spread breast cancer, respectively. Prognosis of metastasized disease has remained very poor overall, with improvement essentially being restricted to younger patients. The proportion of patients diagnosed with localized breast cancer was consistently higher in the US. If adjusted for stage, the differences in relative survival between both countries diminished over time and eventually disappeared. CONCLUSIONS: Similar survival is now observed in both countries for patients below the age of 70 years, but in Germany survival is still much lower for elderly patients. The observed trends point to treatment advances as a major cause for improved survival. However, substantial differences in mammography usage existed between both countries and might probably also account for the observed differences (to a lesser extent, also differences in health care systems, and delivery of cancer care). Encouraging, survival of breast cancer patients has improved in Germany to a much greater extent than in the US, albeit the persisting survival gap for elderly patients in Germany requires particular attention by researchers, public health authorities, and clinicians. PMID- 22838643 TI - A recipe for geometry optimization of diradicalar singlet states from broken symmetry calculations. AB - The equilibrium geometries of the singlet and triplet states of diradicals may be somewhat different, which may have an influence on their magnetic properties. The single-determinantal methods, such as Hartree-Fock or Kohn-Sham density functional theory, in general rely on broken-symmetry solutions to approach the singlet-state energy and geometry. An approximate spin decontamination is rather easy for the energy of this state but is rarely performed for its geometry optimization. We suggest simple procedures to estimate the optimized geometry and energy of a spin-decontaminated singlet, the accuracies of which are tested on a few organic diradicals. This technique can be generalized to interactions between higher-spin units or to multispin systems. PMID- 22838644 TI - Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer. AB - PURPOSE: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer. METHODS: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety. RESULTS: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3-4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months. CONCLUSIONS: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer. PMID- 22838646 TI - Enhanced siRNA delivery and silencing gold-chitosan nanosystem with surface charge-reversal polymer assembly and good biocompatibility. AB - A simple nanocarrier coated with chitosan and the pH-responsive charge-reversible polymer, PAH-Cit, was constructed using layer-by-layer assembly to deliver siRNA. Gold nanoparticles (AuNPs) were di-rectly reduced and stabilized by chitosan (CS), forming a positively charged AuNP-CS core. Charge-reversible PAH-Cit and polyethylenimine (PEI) were sequentially deposited onto the surface of AuNP-CS through electrostatic interaction, forming a PEI/PAH-Cit/AuNP-CS shell/core structure. After loading siRNA, the cytotoxicity of siRNA/PEI/PAH-Cit/AuNP-CS against HeLa and MCF-7R cells was negligible. This vehicle completely protected siRNA against enzymatic degradation at vector/RNA mass ratios of 2.5:1 and above. An in vitro release profile demonstrated an efficient siRNA release (79%) from siRNA/PEI/PAH-Cit/AuNP-CS at pH 5.5, suggesting a pH-induced charge-reversing action of PAH-Cit. This mechanism also worked in vivo and facilitated the escape of siRNA from endosomes. Using this carrier, the uptake of cy5-siRNA by HeLa cells was significantly increased compared to PEI, an efficient polycationic transfection reagent. In drug-resistant MCF-7 cells, specific gene silencing effectively reduced expression of MDR1, the gene encoding the drug exporter P-gp, and consequently promoted the uptake of doxorubicin. This simple charge-reversal polymer assembly nanosystem has three essential benefits (protection, efficient uptake, and facilitated escape) and provides a safe strategy with good biocompatibility for enhanced siRNA delivery and silencing. PMID- 22838645 TI - Connecting [NiFe]- and [FeFe]-hydrogenases: mixed-valence nickel-iron dithiolates with rotated structures. AB - New mixed-valence iron-nickel dithiolates are described that exhibit structures similar to those of mixed-valence diiron dithiolates. The interaction of tricarbonyl salt [(dppe)Ni(pdt)Fe(CO)(3)]BF(4) ([1]BF(4), where dppe = Ph(2)PCH(2)CH(2)PPh(2) and pdt(2-) = -SCH(2)CH(2)CH(2)S-) with P-donor ligands (L) afforded the substituted derivatives [(dppe)Ni(pdt)Fe(CO)(2)L]BF(4) incorporating L = PHCy(2) ([1a]BF(4)), PPh(NEt(2))(2) ([1b]BF(4)), P(NMe(2))(3) ([1c]BF(4)), P(i-Pr)(3) ([1d]BF(4)), and PCy(3) ([1e]BF(4)). The related precursor [(dcpe)Ni(pdt)Fe(CO)(3)]BF(4) ([2]BF(4), where dcpe = Cy(2)PCH(2)CH(2)PCy(2)) gave the more electron-rich family of compounds [(dcpe)Ni(pdt)Fe(CO)(2)L]BF(4) for L = PPh(2)(2-pyridyl) ([2a]BF(4)), PPh(3) ([2b]BF(4)), and PCy(3) ([2c]BF(4)). For bulky and strongly basic monophosphorus ligands, the salts feature distorted coordination geometries at iron: crystallographic analyses of [1e]BF(4) and [2c]BF(4) showed that they adopt "rotated" Fe(I) centers, in which PCy(3) occupies a basal site and one CO ligand partially bridges the Ni and Fe centers. Like the undistorted mixed-valence derivatives, members of the new class of complexes are described as Ni(II)Fe(I) (S = 1/2) systems according to electron paramagnetic resonance spectroscopy, although with attenuated (31)P hyperfine interactions. Density functional theory calculations using the BP86, B3LYP, and PBE0 exchange-correlation functionals agree with the structural and spectroscopic data, suggesting that the spin for [1e](+) is mostly localized in a Fe(I)-centered d(z(2)) orbital, orthogonal to the Fe-P bond. The PCy(3) complexes, rare examples of species featuring "rotated" Fe centers, both structurally and spectroscopically incorporate features from homobimetallic mixed-valence diiron dithiolates. Also, when the NiS(2)Fe core of the [NiFe]-hydrogenase active site is reproduced, the "hybrid models" incorporate key features of the two major classes of hydrogenase. Furthermore, cyclic voltammetry experiments suggest that the highly basic phosphine ligands enable a second oxidation corresponding to the couple [(dxpe)Ni(pdt)Fe(CO)(2)L](+/2+). The resulting unsaturated 32e(-) dications represent the closest approach to modeling the highly electrophilic Ni-SI(a) state. In the case of L = PPh(2) (2-pyridyl), chelation of this ligand accompanies the second oxidation. PMID- 22838647 TI - Poly(vinyl alcohol) oligomer in dilute aqueous solution: a comparative molecular dynamics simulation study. AB - Molecular dynamics (MD) simulations of a poly(vinyl alcohol), PVA, oligomer in very diluted aqueous solution have been carried out, at the 2-fold aim to investigate structural and dynamical features of this system and to comparatively test the robustness of G45A3 and G45A4 GROMOS force fields in modeling PVA in aqueous environment. An atactic PVA chain of 30 repeating units in water at concentration of 3% (w/w) has been simulated at 293, 303, and 323 K. The trajectory analysis has focused on the temperature influence on chain size, conformational properties and intramolecular hydrogen bonding of PVA. The PVA water interaction and the polymer induced modifications of water properties have been also investigated. Simulation results have been compared with available experimental data on PVA aqueous solutions, in order to evaluate the reliability of these force fields in the MD simulation of PVA-based systems in aqueous environment. Findings obtained from the simulations with the G45A4 force field have shown a better agreement with experimental results and have highlighted peculiar structural and dynamical characteristics of PVA in dilute aqueous solution. In particular, the simulation has shown a heterogeneity in the overall chain structure, not affected by temperature, and the absence of intrachain hydrogen bonds between nonadjacent residues. The trajectory analysis has revealed that the polymer influence on water structure and dynamics involves about six water molecules per PVA residue. PMID- 22838648 TI - Baicalein protects against 6-OHDA-induced neurotoxicity through activation of Keap1/Nrf2/HO-1 and involving PKCalpha and PI3K/AKT signaling pathways. AB - Baicalein, one of the major flavonoids found in Scutellaria baicalensis Georgi, displays neuroprotective effects on experimental models of Parkinson's disease (PD) in vitro and in vivo. Although the antioxidative and/or anti-inflammatory activity of baicalein likely contributes to these neuroprotective effects, other modes of action remain largely uncharacterized. In the present study, baicalein pretreatment significantly prevented cells from 6-hydroxydopamine (6-OHDA) induced damage by attenuating cellular apoptosis. However, post-treatment with baicalein did not show any restorative effect against 6-OHDA-induced cellular damage. We found that baicalein increased transcriptional factor NF-E2-related factor 2 (Nrf2)/hemo oxygenase 1(HO-1) protein expression and decreased Kelch like ECH-associated protein 1 (Keap1) in a time- and concentration-dependent manner in PC12 cells. In addition, baicalein induced Nrf2 nuclear translocation and enhanced antioxidant response element (ARE) transcriptional activity, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, we demonstrated that cytoprotective effects of baicalein could be attenuated by Nrf2 siRNA transfection and the HO-1 inhibitor zinc protoporphyrin (Znpp) as well as the proteasome inhibitor MG132. Furthermore, PKCalpha and AKT protein phosphorylation were up-regulated by baicalein pretreatment, and selective inhibitors targeted to PKC, PI3K, and AKT could block the cytoprotective effects of baicalein. Taken together, our results indicate that baicalein prevented PC12 cells from 6-OHDA-induced oxidative damage via the activation of Keap1/Nrf2/HO-1, and it also involves the PKCalpha and PI3K/AKT signaling pathway. Ultimately, the neuroprotective effects of baicalein may endue baicalein as a promising candidate for the prevention of PD. PMID- 22838649 TI - Examining characteristics, knowledge and regulatory practices of specialized drug shops in Sub-Saharan Africa: a systematic review of the literature. AB - BACKGROUND: Specialized drug shops such as pharmacies and drug shops are increasingly becoming important sources of treatment. However, knowledge on their regulatory performance is scarce. We set out to systematically review literature on the characteristics, knowledge and practices of specialized drug shops in Sub Saharan Africa. METHODS: We searched PubMed, EMBASE, WEB of Science, CAB Abstracts, PsycINFO and websites for organizations that support medicine policies and usage. We also conducted open searches using Google Scholar, and searched manually through references of retrieved articles. Our search included studies of all designs that described characteristics, knowledge and practices of specialized drug shops. Information was abstracted on authors, publication year, country and location, study design, sample size, outcomes investigated, and primary findings using a uniform checklist. Finally, we conducted a structured narrative synthesis of the main findings. RESULTS: We obtained 61 studies, mostly from Eastern Africa, majority of which were conducted between 2006 and 2011. Outcome measures were heterogeneous and included knowledge, characteristics, and dispensing and regulatory practices. Shop location and client demand were found to strongly influence dispensing practices. Whereas shops located in urban and affluent areas were more likely to provide correct treatments, those in rural areas provided credit facilities more readily. However, the latter also charged higher prices for medicines. A vast majority of shops simply sold whatever medicines clients requested, with little history taking and counseling. Most shops also stocked popular medicines at the expense of policy recommended treatments. Treatment policies were poorly communicated overall, which partly explained why staff had poor knowledge on key aspects of treatment such as medicine dosage and side effects. Overall, very little is known on the link between regulatory enforcement and practices of specialized drug shops. CONCLUSIONS: Evidence suggests that characteristics and practices of specialized drug shops differ across rural and urban locations, and that these providers are highly responsive to client demand. However, there is a dearth in knowledge on how regulatory enforcement influences their characteristics and practices, and what strategies can be employed to strengthen the governance of the retail pharmaceutical sector. PMID- 22838650 TI - Physical activity and quality of life in severely obese individuals seeking bariatric surgery or lifestyle intervention. AB - BACKGROUND: Given that bariatric surgery (BS) and lifestyle intervention (LI) represent two vastly different approaches to treating severe obesity, there is growing interest in whether individuals who seek BS versus LI also differ on weight-related behaviors. In the present study, we compared BS- and LI-seekers on physical activity (PA) and sedentary behaviors (SB), and examined between-group differences in health-related quality of life (HRQoL), while controlling for PA. FINDINGS: A sample of 34 LI-seekers were matched with 34 BS-seekers on gender, age, BMI, and PA monitor-daily wear time (age: 42.1+/-10.0 years; BMI: 45.6+/-6.5 kg/m2). PA and SB were assessed over a 7-day period via the SenseWear Armband (SWA). HRQoL was measured using the SF-36, with scores standardized to a population normal distribution (M=50, SD=10). Participants wore the SWA for 13.7+/-1.6 h/day. BS-seekers did not differ from LI-seekers on average min/d over the wear period spent in SB (641+/-117.1 vs. 638.4+/-133.4, p=0.62) or light (136.4+/-76.1 vs. 145.5+/-72.5, p=0.59) and moderate-to-vigorous (>1-min bouts=36.4+/-26.2 vs. 40.2+/-31.3, p=0.59; >=10-min bouts=5.7+/-8.3 vs. 10.2+/ 17.0, p=0.17) PA. BS-seekers reported significantly lower SF-36 physical functioning (42.4+/-10.9 vs. 49.0+/-6.8, p=0.004) and physical component summary (43.9+/-10.1 vs. 48.9+/-7.0) scores versus LI-seekers. BS-seeker group status was related to lower physical functioning (beta=0.30, p=0.009), independent of gender, age, BMI, and daily PA. CONCLUSIONS: Findings suggest that seeking BS versus LI is not related to patterns of PA or SB, and that lower subjective physical functioning is not associated with lower overall PA levels in BS seekers. PMID- 22838725 TI - Visual detection of the human metapneumovirus using reverse transcription loop mediated isothermal amplification with hydroxynaphthol blue dye. AB - BACKGROUND: Human metapneumovirus (hMPV) is a major cause of acute respiratory infections ranging from wheezing to bronchiolitis and pneumonia in children worldwide. The objective of this study is to develop a visual reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the detection of hMPV and applied to the clinical samples. RESULTS: In this study, visual RT-LAMP assay for hMPV was performed in one step with the addition of hydroxynaphthol blue (HNB), and were used to detect respiratory samples. Six primers, including two outer primers (F3 and B3), two inner primers (FIP, BIP) and two loop primers (LF and LB), were designed for hMPV N gene by the online software. Moreover, the RT-LAMP assay showed good specificity and no cross reactivity was observed with human rhinovirus (HRV), human respiratory syncytial Virus (RSV), or influenza virus A/PR/8/34 (H1N1). The detection limit of the RT LAMP assay was approximately ten viral RNA copies, lower than that of traditional reverse transcriptase polymerase chain reaction (RT-PCR) 100 RNA copies. In the 176 nasopharyngeal samples, 23 (13.1%) were conformed as hMPV positive by RT LAMP, but 18 (10.2%) positive by RT-PCR. CONCLUSION: Compared with conventional RT-PCR, the visual hMPV RT-LAMP assay performed well in the aspect of detect time, sensitivity, specificity and visibility. It is anticipated that the RT-LAMP will be used for clinical tests in hospital or field testing during outbreaks and in emergency. PMID- 22838726 TI - Isolation and characterization of ZZ1, a novel lytic phage that infects Acinetobacter baumannii clinical isolates. AB - BACKGROUND: Acinetobacter baumannii, a significant nosocomial pathogen, has evolved resistance to almost all conventional antimicrobial drugs. Bacteriophage therapy is a potential alternative treatment for multidrug-resistant bacterial infections. In this study, one lytic bacteriophage, ZZ1, which infects A. baumannii and has a broad host range, was selected for characterization. RESULTS: Phage ZZ1 and 3 of its natural hosts, A. baumanni clinical isolates AB09V, AB0902, and AB0901, are described in this study. The 3 strains have different sensitivities to ZZ1, but they have the same sensitivity to antibiotics. They are resistant to almost all of the antibiotics tested, except for polymyxin. Several aspects of the life cycle of ZZ1 were investigated using the sensitive strain AB09V under optimal growth conditions. ZZ1 is highly infectious with a short latent period (9 min) and a large burst size (200 PFU/cell). It exhibited the most powerful antibacterial activity at temperatures ranging from 35 degrees C to 39 degrees C. Moreover, when ZZ1 alone was incubated at different pHs and different temperatures, the phage was stable over a wide pH range (4 to 9) and at extreme temperatures (between 50 degrees C and 60 degrees C). ZZ1 possesses a 100 nm icosahedral head containing double-stranded DNA with a total length of 166,682 bp and a 120-nm long contractile tail. Morphologically, it could be classified as a member of the Myoviridae family and the Caudovirales order. Bioinformatic analysis of the phage whole genome sequence further suggested that ZZ1 was more likely to be a new member of the Myoviridae phages. Most of the predicted ORFs of the phage were similar to the predicted ORFs from other Acinetobacter phages. CONCLUSION: The phage ZZ1 has a relatively broad lytic spectrum, high pH stability, strong heat resistance, and efficient antibacterial potential at body temperature. These characteristics greatly increase the utility of this phage as an antibacterial agent; thus, it should be further investigated. PMID- 22838727 TI - Prevalence of multiple antibiotic-resistant Gram-negative bacteria on bagged, ready-to-eat baby spinach. AB - In this study, multiple antibiotic-resistant (MAR) Gram-negative bacteria (GNB) were isolated from triple-washed, bagged, ready-to-eat (RTE) baby spinach. Biochemical identification of randomly selected bacterial colonies showed the predominance of cytochrome oxidase-positive Pseudomonas species. Among the GNB, a higher prevalence of resistance was observed against cefoxitin (93.1%) followed by ampicillin (79.4%), chloramphenicol (72.6%), ceftizoxime (65.7%), aztreonam (64.9%), cefotaxime (53.6%), imipenem (38.3%), ceftazidime (33.5%), gentamicin (32.6%), tetracycline (22.2%), and ciprofloxacin (19.8%). Multiple antibiotic resistance (MAR) linked to two or more antibiotics was found in 95.3% of isolates, and resistance was transferable in the strains tested. These findings confirm the presence of MAR bacteria on RTE baby spinach and suggest that human consumption of this produce would amplify the MAR gene pool via conjugal transfer of MAR genes to commensal gut microflora and bacterial pathogens. PMID- 22838728 TI - Bioinspired enhancement of superexchange: from 1,3,5-trihydroxybenzene-bridged to 1,3,5-trimercaptobenzene-bridged trinuclear copper(II) complexes. AB - An unprecedented trinucleating ligand with a central 1,3,5-trimercaptobenzene unit and its trinuclear Cu(II)(3) complex are presented. The high covalency of the difficult-to-realize Cu(II)-SR bond provides an order of magnitude increase in the superexchange interaction in comparison to its oxygen analogue. PMID- 22838729 TI - Electroacupuncture at the ST36 acupoint increases interleukin-4 responsiveness in macrophages, generation of alternatively activated macrophages and susceptibility to Leishmania major infection. AB - BACKGROUND: Electroacupuncture (EA) has been used to treat inflammatory diseases. Alternatively activated macrophages (AAMo) stimulated by cytokines such as interleukin (IL)-4, IL-10 and IL-13 are anti-inflammatory and mildly microbicidal. This study aimed to evaluate whether EA at the Zusanli acupoint (ST36) would change the profile of healthy murine macrophages, particularly the generation of AAMo and susceptibility to Leishmania major infection. METHODS: BALB/c mice were treated with EA (15/30 Hz) at the ST36 acupoint for 20 min/d for 5 d. After the final EA session, the mice were euthanized and their peritoneal cells were harvested and counted for determination of arginase activity, nitric oxide (NO) production and microbicidal activity after culture in the presence or absence of IL-4, interferon-gamma (IFNgamma) or lipopolysaccharide (LPS) or both IFNgamma and LPS. Twelve mice were infected with L. major promastigotes into the footpads after the final EA session and the infection course was monitored. RESULTS: Peritoneal cells freshly obtained from EA-treated mice had similar arginase and microbicidal activities to cells from sham-treated mice. After culture with IL-4, cells from EA-treated mice exhibited significant increases in the arginase activity (sham: 58 +/- 11.3 vs. EA: 80.7 +/- 4.6%, P = 0.025) and number of parasites/infected cell (sham: 2.5 +/- 0.4 vs. EA: 4.3 +/- 0.8 cells, P = 0.007). The NO production was lower in cells from EA-treated mice cultured in the presence of a combination of IFNgamma and LPS (sham: 31.6 +/- 6.5 vs. EA: 22.3 +/- 2.1 MUM, P = 0.025). The lesion size in mice infected with L. major promastigotes was larger in EA-treated mice (sham: 3.26 +/- 0.29 vs. EA: 2.23 +/- 0.4 mm, P = 0.039). CONCLUSION: EA at the ST36 acupoint increases IL-4 responsiveness in macrophages, Generation of AAMo and susceptibility to L. major infection. PMID- 22838730 TI - Determination of main categories of components in corn steep liquor by near infrared spectroscopy and partial least-squares regression. AB - Corn steep liquor (CSL) is an important raw material that has a high nutritional value and serves as a nitrogen source. This study aimed to develop a fast, versatile, cheap, and environmentally safe analytical method of quantifying the total acidity (TA) of CSL as well as its contents of dry matter (DM), total sugars (TS), total reducing sugars (TRS), total free amino acids (TFAA), total nitrogen (TN), and total sulfite (TSu). The near-infrared (NIR) spectroscopy measurements of 66 samples (22 batches) of CSL were analyzed by partial least squares regression using several spectral preprocessing methods. Multivariate models developed in the NIR area showed good predictive abilities for DM, TA, TS, TRS, TFAA, TN, and TSu determination. These results confirm the feasibility of the multivariate spectroscopic approach as a replacement for expensive and time consuming conventional chemical methods. Thus, a convenient and feasible method for the quality control of fermentation raw materials for food additives and fine chemicals, especially in CSL, is established. PMID- 22838731 TI - International collaborative project to compare and track the nutritional composition of fast foods. AB - BACKGROUND: Chronic diseases are the leading cause of premature death and disability in the world with over-nutrition a primary cause of diet-related ill health. Excess quantities of energy, saturated fat, sugar and salt derived from fast foods contribute importantly to this disease burden. Our objective is to collate and compare nutrient composition data for fast foods as a means of supporting improvements in product formulation. METHODS/DESIGN: Surveys of fast foods will be done in each participating country each year. Information on the nutrient composition for each product will be sought either through direct chemical analysis, from fast food companies, in-store materials or from company websites. Foods will be categorized into major groups for the primary analyses which will compare mean levels of saturated fat, sugar, sodium, energy and serving size at baseline and over time. Countries currently involved include Australia, New Zealand, France, UK, USA, India, Spain, China and Canada, with more anticipated to follow. DISCUSSION: This collaborative approach to the collation and sharing of data will enable low-cost tracking of fast food composition around the world. This project represents a significant step forward in the objective and transparent monitoring of industry and government commitments to improve the quality of fast foods. PMID- 22838732 TI - Blood flow and associated pathophysiology of uterine cervix cancers: characterisation and relevance for localised hyperthermia. AB - Cervical cancers exhibit substantial intra- and inter-tumour heterogeneities in blood flow prior to treatment, reflecting similar variability in vascularisation. When clinically relevant hyperthermia is applied as an adjuvant to established treatment modalities, blood flow may change in non-predictable directions, extents and durations, indicating subsequent variability in heat dissipation and in flow-associated parameters of the tumour microenvironment. Before heating, locally advanced cervical cancers are mostly hypoxic, acidic, exhibit substrate and energy deprivation and show lactate accumulation, which is spatially and temporally heterogeneous. Additionally a relatively homogeneous interstitial hypertension is observed. Most probably, metabolic parameters of the hostile microenvironment are able to greatly modulate the thermosensitivity of cancer cells. Adequate information concerning changes upon heat treatment is not available so far. Due to this lack of proven data for cervical cancers upon heat treatment, clinical studies are urgently needed in order to judge the possible impact of blood flow and the above-mentioned microenvironmental parameters. PMID- 22838733 TI - Monocyte populations as markers of response to adalimumab plus MTX in rheumatoid arthritis. AB - INTRODUCTION: The treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNFalpha) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment. METHODS: This prospective work investigated the number of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNFalpha treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control. RESULTS: Non responder patients with RA show an increased number of monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNFalpha treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders. CONCLUSIONS: The absolute number of circulating monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNFalpha treatment in patients with RA. PMID- 22838734 TI - Knowledge sharing among healthcare infection preventionists: the impact of public health professionals in a rural state. AB - BACKGROUND: Healthcare-associated infections are a major source of morbidity and mortality in the United States. Infection Preventionists (IPs) are healthcare workers tasked at overseeing the prevention and control of these infections, but they may have difficulties obtaining up-to-date information, primarily in rural states. The objective of this study was to evaluate the importance of public health involvement on the knowledge-sharing network of IPs in a rural state. FINDINGS: A total of 95 attendees completed our survey. The addition of public health professionals increased the density of the network, reduced the number of separate components of the network, and reduced the number of key players needed to contact nearly all of the other network members. All network metrics were higher for public health professionals than for IPs without public health involvement. CONCLUSIONS: The addition of public health professionals involved in healthcare infection prevention activities augmented the knowledge sharing potential of the IPs in Iowa. Rural states without public health involvement in healthcare-associated infection (HAI) prevention efforts should consider the potential benefits of adding these personnel to the public health workforce to help facilitate communication of HAI-related information. PMID- 22838735 TI - A general approach to one-pot fabrication of crumpled graphene-based nanohybrids for energy applications. AB - Crumpled graphene oxide (GO)/graphene is a new type of carbon nanostructure that has drawn growing attention due to its three-dimensional open structure and excellent stability in an aqueous solution. Here we report a general and one-step approach to produce crumpled graphene (CG)-nanocrystal hybrids, which are produced by direct aerosolization of a GO suspension mixed with precursor ions. Nanocrystals spontaneously grow from precursor ions and assemble on both external and internal surfaces of CG balls during the solvent evaporation and GO crumpling process. More importantly, CG-nanocrystal hybrids can be directly deposited onto various current-collecting substrates, enabling their tremendous potential for energy applications. As a proof of concept, we demonstrate the use of hybrid electrodes of CG-Mn(3)O(4) and CG-SnO(2) in an electrochemical supercapacitor and a lithium-ion battery, respectively. The performance of the resulting capacitor/battery is attractive and outperforms conventional flat graphene-based hybrid devices. This study provides a new and facile route to fabricating high performance hybrid CG-nanocrystal electrodes for various energy systems. PMID- 22838737 TI - Neurosurgical management of frontal lobe epilepsy in children. AB - OBJECT: Pediatric frontal lobe epilepsy (FLE) remains a challenging condition for neurosurgeons and epileptologists to manage. Postoperative seizure outcomes remain far inferior to those observed in temporal lobe epilepsies, possibly due to inherent difficulties in delineating and subsequently completely resecting responsible epileptogenic regions. In this study, the authors review their institutional experience with the surgical management of FLE and attempt to find predictors that may help to improve seizure outcome in this population. METHODS: All surgically treated cases of intractable FLE from 1990 to 2008 were reviewed. Demographic information, preoperative and intraoperative imaging and electrophysiological investigations, and follow-up seizure outcome were assessed. Inferential statistics were performed to look for potential predictors of seizure outcome. RESULTS: Forty patients (20 male, 20 female) underwent surgical management of FLE during the study period. Patients were an average of 5.6 years old at the time of FLE onset and 11.7 years at the time of surgery; patients were followed for a mean of 40.25 months. Most patients displayed typical FLE semiology. Twenty-eight patients had discrete lesions identified on MRI. Eight patients underwent 2 operations. Cortical dysplasia was the most common pathological diagnosis. Engel Class I outcome was obtained in 25 patients (62.5%), while Engel Class II outcome was observed in 5 patients (12.5%). No statistically significant predictors of outcome were found. CONCLUSIONS: Control of FLE remains a challenging problem. Favorable seizure outcome, obtained in 62% of patients in this series, is still not as easily obtained in FLE as it is in temporal lobe epilepsy. While no statistically significant predictors of seizure outcome were revealed in this study, patients with FLE continue to require extensive workup and investigation to arrive at a logical and comprehensive neurosurgical treatment plan. Future studies with improved neuroimaging and advanced invasive monitoring strategies may well help define factors for success in this form of epilepsy that is difficult to control. PMID- 22838736 TI - Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. METHODS: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). RESULTS: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. CONCLUSION: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization. PMID- 22838738 TI - Novel pathological abnormalities of deep brain structures including dysplastic neurons in anterior striatum associated with focal cortical dysplasia in epilepsy. AB - OBJECT: Some patients are not seizure free even after epileptogenic cortical resection. The authors recently described a case of frontal lobe epilepsy cured after the resection of periventricular white matter and striatum, in which dysplastic neurons were revealed. The authors attempted to confirm similar cases. METHODS: They reviewed the records of 8 children with frontal lobe epilepsy who had daily (7) or monthly (1) seizures and underwent resections including deep brain structures. RESULTS: Five patients underwent multiple resections. Neuroimaging of the deep structures showed the transmantle sign in 3 patients, ictal hyperperfusion in 6, reduced iomazenil uptake in 2, and spike dipole clustering in 6. All patients became seizure free postoperatively. Focal cortical dysplasia of various types was diagnosed in all patients. Dysmorphic neurons were found in the cortex and subcortical white matter of 5 patients. The striatum was verified in 3 patients in whom dysmorphic neurons were scattered. In the periventricular white matter, prominent astrocytosis was evident in all cases. CONCLUSIONS: Pathological abnormalities such as dysmorphic neurons and astrocytosis in deep brain structures would play a key role in epileptogenesis. PMID- 22838739 TI - Self-assembly of a mixture system containing polypeptide graft and block copolymers: experimental studies and self-consistent field theory simulations. AB - Self-assembly behavior of mixture systems containing poly(gamma-benzyl-L glutamate)-poly(ethylene glycol) graft (PBLG-g-PEG) and block (PBLG-b-PEG) copolymers in aqueous solution was investigated by both experiments and computer simulations. Pure graft copolymers self-assembled into vesicles, and pure block copolymers aggregated into spherical micelles or vesicles, while, for the mixture systems, hybrid cylindrical micelles were observed. In addition to the experimental observations, self-consistent field theory (SCFT) simulations were performed on the self-assembly behavior of graft/block copolymer mixtures. Simulation results reproduced the morphological transitions observed in the experiments. Moreover, from the SCFT simulations, the chain distributions of copolymers in the aggregates were obtained. For the hybrid cylindrical micelles, block copolymers were found to mainly locate at the ends of aggregates, which prevents the fusion of cylinders to vesicles. By combining experimental findings with simulation results, the mechanism regarding the morphological transition of the aggregates formed by graft/block copolymer mixtures is proposed. PMID- 22838740 TI - Improvement of health-related quality of life in depression after transcranial magnetic stimulation in a naturalistic trial is associated with decreased perfusion in precuneus. AB - BACKGROUND: Assessing Health-related Quality of life (HRQoL) is necessary to evaluate care and treatments provided to patients with major depressive disorder (MDD), in addition to the traditional assessment of clinical outcomes. However, HRQoL remains under-utilized to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in research or in a routine clinical setting. The primary objective of this exploratory study on MDD was to investigate the impact of low-frequency rTMS on HRQoL using the SF-36 questionnaire. A secondary objective was to study the functional neural substrate underlying HRQoL changes using neuroimaging. METHODS: Fifteen right-handed patients who met DSM-IV criteria for MDD participated in the study. HRQoL was assessed using the SF-36, and regional cerebral blood (rCBF) flow using 99mTc-ECD SPECT. Voxel based correlation was searched between concomitant changes in rCBF and in HRQoL after rTMS. RESULTS: Role-Physical Problems dimension showed a statistical significant improvement of 73.2% (p = 0.001) and an effect size (Cohen's d) of 0.43, indicating moderate effect. Five SF-36 dimension scores and the two composite scores showed effect sizes ranged from 0.28 to 0.43. Improvement of Mental Composite Score (MCS)-SF-36 after rTMS was correlated with a concomitant decrease of precuneus perfusion (p < 0.001). Post-hoc analyses confirmed that decreased perfusion in precuneus was correlated with improvement of HRQoL, especially for MCS (r = -0.71; p < 0.001), Mental Health (r = -0.81; p < 0.001) and Social Functioning (r = -0.57; p = 0.026) dimensions. CONCLUSIONS: This study suggests low-frequency rTMS can improve HRQoL, through its role physical problems dimension, in patients with MDD. This improvement is associated with a decreased perfusion of the precuneus, a brain area involved in self-focus and self-processing, arguing for a neural substrate to the impact of rTMS on HRQoL. PMID- 22838741 TI - Use of general practice, diagnostic investigations and hospital services before and after cancer diagnosis - a population-based nationwide registry study of 127,000 incident adult cancer patients. AB - BACKGROUND: Knowledge of patterns in cancer patients' health care utilisation around the time of diagnosis may guide health care resource allocation and provide important insights into this groups' demand for health care services. The health care need of patients with comorbid conditions far exceeds the oncology capacity and it is therefore important to elucidate the role of both primary and secondary care. The aim of this paper is to describe the use of health care services amongst incident cancer patients in Denmark one year before and one year after cancer diagnosis. METHODS: The present study is a national population-based case-control (1:10) registry study. All incident cancer patients (n = 127,210) diagnosed between 2001 and 2006 aged 40 years or older were identified in the Danish Cancer Registry. Data from national health registries were provided for all cancer patients and for 1,272,100 controls. Monthly consultation frequencies, monthly proportions of persons receiving health services and three-month incidence rate ratios for one year before and one year after the cancer diagnosis were calculated. Data were analysed separately for women and men. RESULTS: Three months before their diagnosis, cancer patients had twice as many general practitioner (GP) consultations, ten to eleven times more diagnostic investigations and five times more hospital contacts than the reference population. The demand for GP services peaked one month before diagnosis, the demand for diagnostic investigations one month after diagnosis and the number of hospital contacts three months after diagnosis. The proportion of cancer patients receiving each of these three types of health services remained more than 10% above that of the reference population from two months before diagnosis until the end of the study period. CONCLUSIONS: Cancer patients' health service utilisation rose dramatically three months before their diagnosis. This increase applied to all services in general throughout the first year after diagnosis and to the patients' use of hospital contacts in particular. Cancer patients' heightened demand for GP services one year after their diagnosis highlights the importance of close coordination and communication between the primary and the secondary healthcare sector. PMID- 22838834 TI - The Rift Valley Fever virus protein NSm and putative cellular protein interactions. AB - Rift Valley Fever is an infectious viral disease and an emerging problem in many countries of Africa and on the Arabian Peninsula. The causative virus is predominantly transmitted by mosquitoes and high mortality and abortion rates characterize outbreaks in animals while symptoms ranging from mild to life threatening encephalitis and hemorrhagic fever are noticed among infected humans. For a better prevention and treatment of the infection, an increased knowledge of the infectious process of the virus is required. The focus of this work was to identify protein-protein interactions between the non-structural protein (NSm), encoded by the M-segment of the virus, and host cell proteins. This study was initiated by screening approximately 26 million cDNA clones of a mouse embryonic cDNA library for interactions with the NSm protein using a yeast two-hybrid system. We have identified nine murine proteins that interact with NSm protein of Rift Valley Fever virus, and the putative protein-protein interactions were confirmed by growth selection procedures and beta-gal activity measurements. Our results suggest that the cleavage and polyadenylation specificity factor subunit 2 (Cpsf2), the peptidyl-prolyl cis-trans isomerase (cyclophilin)-like 2 protein (Ppil2), and the synaptosome-associated protein of 25 kDa (SNAP-25) are the most promising targets for the NSm protein of the virus during an infection. PMID- 22838836 TI - Optimal experiment selection for parameter estimation in biological differential equation models. AB - BACKGROUND: Parameter estimation in biological models is a common yet challenging problem. In this work we explore the problem for gene regulatory networks modeled by differential equations with unknown parameters, such as decay rates, reaction rates, Michaelis-Menten constants, and Hill coefficients. We explore the question to what extent parameters can be efficiently estimated by appropriate experimental selection. RESULTS: A minimization formulation is used to find the parameter values that best fit the experiment data. When the data is insufficient, the minimization problem often has many local minima that fit the data reasonably well. We show that selecting a new experiment based on the local Fisher Information of one local minimum generates additional data that allows one to successfully discriminate among the many local minima. The parameters can be estimated to high accuracy by iteratively performing minimization and experiment selection. We show that the experiment choices are roughly independent of which local minima is used to calculate the local Fisher Information. CONCLUSIONS: We show that by an appropriate choice of experiments, one can, in principle, efficiently and accurately estimate all the parameters of gene regulatory network. In addition, we demonstrate that appropriate experiment selection can also allow one to restrict model predictions without constraining the parameters using many fewer experiments. We suggest that predicting model behaviors and inferring parameters represent two different approaches to model calibration with different requirements on data and experimental cost. PMID- 22838835 TI - miRNA regulation in the early development of barley seed. AB - BACKGROUND: During the early stages of seed development many genes are under dynamic regulation to ensure the proper differentiation and establishment of the tissue that will constitute the mature grain. To investigate how miRNA regulation contributes to this process in barley, a combination of small RNA and mRNA degradome analyses were used to identify miRNAs and their targets. RESULTS: Our analysis identified 84 known miRNAs and 7 new miRNAs together with 96 putative miRNA target genes regulated through a slicing mechanism in grain tissues during the first 15 days post anthesis. We also identified many potential miRNAs including several belonging to known miRNA families. Our data gave us evidence for an increase in miRNA-mediated regulation during the transition between pre storage and storage phases. Potential miRNA targets were found in various signalling pathways including components of four phytohormone pathways (ABA, GA, auxin, ethylene) and the defence response to powdery mildew infection. Among the putative miRNA targets we identified were two essential genes controlling the GA response, a GA3oxidase1 and a homolog of the receptor GID1, and a homolog of the ACC oxidase which catalyses the last step of ethylene biosynthesis. We found that two MLA genes are potentially miRNA regulated, establishing a direct link between miRNAs and the R gene response. CONCLUSION: Our dataset provides a useful source of information on miRNA regulation during the early development of cereal grains and our analysis suggests that miRNAs contribute to the control of development of the cereal grain, notably through the regulation of phytohormone response pathways. PMID- 22838837 TI - Abundance and community composition of ammonia-oxidizing archaea and bacteria in two different zones of Lake Taihu. AB - The abundance and community composition of ammonia-oxidizing archaea and ammonia oxidizing bacteria in the surface sediments of 2 different zones (Meiliang Bay and Eastern Lake Taihu) of Lake Taihu were investigated using real-time quantitative polymerase chain reaction and clone libraries. The amoA gene copy numbers in the surface sediment of Meiliang Bay ranged from 4.91 * 10(5) to 8.65 * 10(6) copies/g dry sediment for the archaeal amoA gene and from 3.74 * 10(4) to 3.86 * 10(5) copies/g dry sediment for the bacterial amoA gene, which were significantly higher than those of Eastern Lake Taihu (P < 0.05). Concentrations of ammonia (NH(4)(+)), total nitrogen, organic matter, and pH of the sediments exhibited significantly negative correlations with the abundance of ammonia oxidizing archaea or ammonia-oxidizing bacteria (P < 0.05 or P < 0.01, respectively). The potential nitrification rates show remarkable correlations with the copy numbers of the archaeal amoA gene. Diversity of the archaeal amoA gene in Eastern Lake Taihu was significantly higher than that of Meiliang Bay, whereas the bacterial amoA gene diversity was comparable for the 2 lake zones. The data obtained in this study would be useful to elucidate the role of ammonia oxidizing archaea and ammonia-oxidizing bacteria in the nitrogen cycle of freshwater ecosystems. PMID- 22838838 TI - Chemical and biological characterization of sclerosin, an antifungal lipopeptide. AB - Pseudomonas sp. strain DF41 produces a lipopeptide, called sclerosin that inhibits the fungal pathogen Sclerotinia sclerotiorum . The aim of the current study was to deduce the chemical structure of this lipopeptide and further characterize its bioactivity. Mass spectrometry analysis determined the structure of sclerosin to be CH(3)-(CH(2))(6)-CH(OH)-CH(2)-CO-Dhb-Pro-Ala-Leu/Ile-Ala-Val Val-Dhb-Thr-Val-Leu/Ile-Dhp-Ala-Ala-Ala-Val-Dhb-Dhb-Ala-Dab-Ser-Val-OH, similar to corpeptins A and B of the tolaasin group, differing by only 3 amino acids in the peptide chain. Subjecting sclerosin to various ring opening procedures revealed no new ions, suggesting that this molecule is linear. As such, sclerosin represents a new member of the tolaasin lipopeptide group. Incubation of S. sclerotinia ascospores and sclerotia in the presence of sclerosin inhibited the germination of both cell types. Sclerosin also exhibited antimicrobial activity against Bacillus species. Conversely, this lipopeptide demonstrated no zoosporicidal activity against the oomycete pathogen Phytophthora infestans . Next, we assessed the effect of DF41 and a lipopeptide-deficient mutant on the growth and development of Caenorhabditis elegans larvae. We discovered that sclerosin did not protect DF41 from ingestion by and degradation in the C. elegans digestive tract. However, another metabolite produced by this bacterium appeared to shorten the life-span of the nematode compared to C. elegans growing on Escherichia coli OP50. PMID- 22838839 TI - PlantID - DNA-based identification of multiple medicinal plants in complex mixtures. AB - BACKGROUND: An efficient method for the identification of medicinal plant products is now a priority as the global demand increases. This study aims to develop a DNA-based method for the identification and authentication of plant species that can be implemented in the industry to aid compliance with regulations, based upon the economically important Hypericum perforatum L. (St John's Wort or Guan ye Lian Qiao). METHODS: The ITS regions of several Hypericum species were analysed to identify the most divergent regions and PCR primers were designed to anneal specifically to these regions in the different Hypericum species. Candidate primers were selected such that the amplicon produced by each species-specific reaction differed in size. The use of fluorescently labelled primers enabled these products to be resolved by capillary electrophoresis. RESULTS: Four closely related Hypericum species were detected simultaneously and independently in one reaction. Each species could be identified individually and in any combination. The introduction of three more closely related species to the test had no effect on the results. Highly processed commercial plant material was identified, despite the potential complications of DNA degradation in such samples. CONCLUSION: This technique can detect the presence of an expected plant material and adulterant materials in one reaction. The method could be simply applied to other medicinal plants and their problem adulterants. PMID- 22838840 TI - Psychosocial factors associated with becoming a young father in Finland: a nationwide longitudinal study. AB - BACKGROUND: Little is known about the characteristics of boys who become fathers at young age. Some studies have suggested that antisocial adolescents are more likely to be young fathers. The aim of this study was to examine the associations of psychosocial factors in childhood with becoming a young father, and to assess if they are independent of criminal behavior in adolescence. METHODS: The baseline assessment in 1989 included 2,946 boys born in 1981. Information about psychiatric symptoms at age eight was collected with Rutter questionnaires from parents and teachers and with the Child Depression Inventory from the children themselves. Data on criminal offenses at age 16-20 was collected from a police register. Register-based follow-up data on becoming a father under the age of 22 was available for 2,721 boys. RESULTS: The factors measured at age eight, which were associated with becoming a young father independently of adolescent criminality, were conduct problems, being born to a young father and having a mother with a low educational level. Having repeatedly committed criminal offences in adolescence was associated with becoming a young father independently of psychosocial factors in childhood. CONCLUSIONS: Antisocial tendencies both in childhood and adolescence are associated with becoming a young father. They should be taken into consideration when designing preventive or supportive interventions. PMID- 22838841 TI - The saw-tooth sign as a clinical clue for intrathoracic central airway obstruction. AB - BACKGROUND: The saw-tooth sign was first described by Sanders et al in patients with obstructive sleep apnea syndrome as one cause of extrathoracic central airway obstruction. The mechanism of the saw-tooth sign has not been conclusively clarified. The sign has also been described in various extrathoracic central airway diseases, such as in burn victims with thermal injury to the upper airways, Parkinson's disease, tracheobronchomalacia, laryngeal dyskinesia, and pedunculated tumors of the upper airway. CASE PRESENTATION: A 61-year-old man was referred to our hospital with a two-month history of persistent dry cough and dyspnea. He was diagnosed with lung cancer located in an intrathoracic central airway, which was accompanied by the saw-tooth sign on flow-volume loops. This peculiar sign repeatedly improved and deteriorated, in accordance with the waxing and waning of central airway stenosis by anti-cancer treatments. CONCLUSION: This report suggests that the so-called saw-tooth sign may be found even in intrathoracic central airway obstruction due to lung cancer. PMID- 22838842 TI - Quantitative Raman spectrum and reliable thickness identification for atomic layers on insulating substrates. AB - We demonstrate the possibility in quantifying the Raman intensities for both specimen and substrate layers in a common stacked experimental configuration and, consequently, propose a general and rapid thickness identification technique for atomic-scale layers on dielectric substrates. Unprecedentedly wide-range Raman data for atomically flat MoS(2) flakes are collected to compare with theoretical models. We reveal that all intensity features can be accurately captured when including optical interference effect. Surprisingly, we find that even freely suspended chalcogenide few-layer flakes have a stronger Raman response than that from the bulk phase. Importantly, despite the oscillating intensity of specimen spectrum versus thickness, the substrate weighted spectral intensity becomes monotonic. Combined with its sensitivity to specimen thickness, we suggest this quantity can be used to rapidly determine the accurate thickness for atomic layers. PMID- 22838843 TI - AB0 blood group and prognosis in patients with pancreatic cancer. AB - BACKGROUND: Although blood group 0 is associated with a reduced risk of pancreatic cancer, little is known about the role of AB0 blood group antigens in disease progression. We assessed the prognostic relevance of AB0 blood status in a large cohort of patients with resected pancreatic cancer. METHODS: A total of 627 patients, who underwent resection for pancreatic ductal adenocarcinoma between October 2001 and December 2008 were enrolled. The relationship between AB0 blood group status and outcome was analyzed using univariate and multivariate Cox regression analyses. RESULTS: In patients with pancreatic cancer the incidence of blood group 0 (31%) was lower compared to 13.044 patients without pancreatic cancer (38%) (p = 0.0005). There were no significant differences in clinicopathologic characteristics among patients with different AB0 blood groups. The 3-year and 5-year overall survival rates were 29% and 14%. On univariate analysis AB0 blood group status did not correlate with survival (p = 0.39). Multivariate analysis, however, revealed a favorable and independent impact of blood group 0 on survival (Hazard ratio 0.78; 95% confidence interval 0.62 - 0.99; p = 0.037). CONCLUSION: AB0 blood group status is associated independently with the prognosis of patients with resected pancreatic cancer. PMID- 22838844 TI - Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. AB - Noninvasive drug delivery to the brain remains a major challenge for the treatment of neurological disorders. Transcranial focused ultrasound combined with lipid-coated gas microspheres injected into the bloodstream has been shown to increase the permeability of the blood-brain barrier locally and transiently. Coupled with magnetic resonance imaging, ultrasound can be guided to allow therapeutics administered in the blood to reach brain regions of interest. Using this approach, we perform gene transfer from the blood to specific regions of the mouse brain. Focused ultrasound was targeted to the right hemisphere, at multiple foci, or restricted to one focal point of the hippocampus or the striatum. Doses from 5 * 10(8) to 1.25 * 10(10) vector genomes per gram (VG/g) of self complementary adeno-associated virus serotype 9 carrying the green fluorescent protein were injected into the tail vein. A dose of 2.5 * 10(9) VG/g was optimal to express the transgene, 12 days later, in neurons, astrocytes, and oligodendrocytes in brain regions targeted with ultrasound, while minimizing the infection of peripheral organs. In the hippocampus and striatum, predominantly neurons and astrocytes were infected, respectively. Transcranial focused ultrasound applications could fulfill a long-term goal of gene therapy: delivering vectors to diseased brain areas directly from the circulation, in a noninvasive manner. PMID- 22838845 TI - Carbonic anhydrase I (CA1) is involved in the process of bone formation and is susceptible to ankylosing spondylitis. AB - INTRODUCTION: Ankylosing spondylitis (AS) is characterized by abnormal bone formation in the spine and the sacroiliac joints. In vitro assays demonstrate that carbonic anhydrase I (CA1) promotes calcium precipitation. This study investigated the function of CA1 for bio-mineralization and determined if common polymorphisms in the CA1 gene might contribute to AS risk. METHODS: Calcification was induced in Saos-2 cells, a human osteosarcoma cell line, with ascorbic acid and beta-glycerophosphate. Calcification was determined by Alizarin Red-S (AR-S) staining. Expressions of CA1, alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN), osterix (OSX) and runt-related transcription factor-2 (Runx2) were determined by real-time PCR and western blotting. The cells were also treated with acetazolamide, an anti-carbonic anhydrase drug. Genotyping was performed using Illumina VeraCode microarray in a case-control study including 51 AS patients, 267 rheumatoid arthritis (RA) patients and 160 healthy controls. The result was confirmed by Taqman assay, including 258 AS patients, 288 RA patients and 288 healthy controls. RESULTS: Following the induction of calcification, Saos 2 cells produced large amounts of calcium-rich deposits. Increased transcriptions of CA1, ALP, BSP, OCN, OSX and Runx2, essential genes for ossification, were detected in the cultured cells. Following treatmen with acetazolamide, the expression of CA1 obviously declined and mineralized nodule formation was also decreased. Illumina microarray indicates that SNP at rs7841425 also showed significant differences in allelic frequency (P = 0.01396) and genotypic frequency (P = 0.005902) between AS cases and controls. In addition, SNP at rs7827474 showed significant differences in allelic frequency (P = 5.83E-04) and genotypic frequency (P = 0.000186) between RA cases and controls (P values were adjusted to multiple comparisons). The Taqman assay revealed that rs725605 demonstrated statistically significant evidence of allele frequency (P = 0.022307) and gene frequency (P = 0.007731) for association with AS. This SNP did not show significant differences in allelic frequencies and gene frequencies between RA patients and controls. CONCLUSIONS: CA1 may play an essential role in bio-mineralization and new bone formation. The gene encoding CA1 is susceptible to AS. PMID- 22838847 TI - Molecular and system parameters governing mass and charge transport in polar liquids and electrolytes. AB - Onsager's model of the dielectric constant is used to provide a molecular-level picture of how the dielectric constant affects mass and charge transport in organic liquids and organic liquid electrolytes. Specifically, the molecular and system parameters governing transport are the molecular dipole moment MU and the solvent dipole density N. The compensated Arrhenius formalism (CAF) writes the temperature-dependent ionic conductivity or diffusion coefficient as an Arrhenius like expression that also includes a static dielectric constant (epsilon(s)) dependence in the exponential prefactor. The temperature dependence of epsilon(s) and therefore the temperature dependence of the exponential prefactor is due to the quantity N/T, where T is the temperature. Using the procedure described in the CAF, values of the activation energy can be obtained by scaling out the N/T dependence instead of the epsilon(s) dependence. It has been previously shown that a plot of the prefactors versus epsilon(s) results in a master curve, and here it is shown that a master curve also results by plotting the prefactors against N/T. Therefore, the CAF can be applied by using temperature-dependent density data instead of temperature-dependent dielectric constant data. This application is demonstrated for diffusion data of n-nitriles, n-thiols, n acetates, and 2-ketones, as well as conductivity data for dilute tetrabutylammonium triflate-nitrile electrolytes. PMID- 22838846 TI - The heat-induced protein aggregate correlated with trypsin inhibitor inactivation in soymilk processing. AB - Kunitz trypsin inhibitor (KTI) and Bowman-Birk inhibitor (BBI) have trypsin inhibitor activities (TIA), which could cause pancreatic disease if at a high level. It is not clear why some KTI and BBI lose TIA and some does not in the soymilk processing. This would be examined in this study. TIA assay showed residual TIA was decreased with elevated temperature and TIA was decreased quickly in the beginning and then slowly in boiling water bath. Interestingly, ultracentrifugation showed low residual TIA soymilk had more precipitate than high residual TIA soymilk and soymilk TIA loss had a high correlation coefficient (R(2) > 0.9) with precipitate amount. In addition, the TIAs of floating, supernatant, and precipitate obtained by ultracentrifugation were assayed and >80% residual TIA was concentrated in the supernatant. Tricine-SDS-PAGE showed KTI in supernatant was mainly a noncovalent bound form which might exist as itself and/or incorporated into a small protein aggregate, while KTI in precipitate was incorporated into a protein aggregate by disulfide and/or noncovalent bonds. Chymotrypsin inhibitor activity (CIA) assay showed about 89% of the original CIA remained after 100 degrees C for 15 min. Ultracentrifugation showed that >90% residual CIA was concentrated in supernatant. Tricine-SDS-PAGE showed soymilk (100 degrees C, 15 min) BBI mainly existed in supernatant but not in precipitate. It was considered that BBI tended to exist as itself with its natural conformation. Thus, it was suggested residual TIA was mainly from the free BBI and TIA inactivation was mainly from KTI incorporation into protein aggregate. This study is meaningful for a new strategy for low TIA soymilk manufacture based on the consideration of promoting protein aggregate formation. PMID- 22838848 TI - TDDFT and CIS studies of optical properties of dimers of silver tetrahedra. AB - The absorption spectra for dimers of Ag(4)(+2) and Ag(8) clusters at various interparticle distances are examined using time-dependent density functional theory (TDDFT) and configuration interaction singles (CIS) calculations. With TDDFT calculations employing the SAOP functional, minor peaks for Ag(4)(+2) and Ag(8) dimers appear as the interparticle distance decreases; these peaks are suggested to be charge transfer artifacts on the basis of CIS and TDDFT (CAM B3LYP) calculations. The relationship of the absorption peak locations to the distance and orientation between T(d) Ag(20) dimers is also investigated. TDDFT calculations using the SAOP functional are used to determine excitation absorption spectra for eight different orientations of Ag(20) dimers. Although the Ag(20)T(d) monomer has a sharp peak, each dimer absorption spectrum is split due to lower symmetry. This splitting increases as the center of mass distance decreases. As the interparticle distance between the monomers decreases, the initially strong peaks decrease in intensity and red or blue shift depending on symmetry, while the minor peaks increase in intensity and red shift. PMID- 22838849 TI - Formation of heterocyclic amines during cooking of duck meat. AB - Heterocyclic amines (HAs) are an important class of food mutagens and carcinogens produced in meat cooked at high temperature. In the present study, the effects of various cooking methods: boiling, microwave cooking, charcoal-grilling, roasting, deep-frying and pan-frying on the formation of HAs in duck breast were studied. The various HAs formed during cooking were isolated by solid-phase extraction and analysed by HPLC. Results showed that both the varieties and contents of HAs and the cooking loss of duck breast increase along with increasing cooking temperature and time. Pan-fried duck breasts contained the highest amount of total HAs, followed by charcoal-grilling, deep-frying, roasting, microwave cooking and boiling. 9H-pyrido[3,4-b]indole (norharman) and 1-methyl-9H pyrido[3,4-b]indole (harman) were detected in all of the cooked duck meat, with levels in the range of 0.1-33 ng g-1. 2-Amino-1-methyl-6-phenylimidazo[4,5 f]pyridine (PhIP) was formed easily in duck meat cooked by pan-frying and charcoal-grilling in the range of 0.9-17.8 ng g-1. 2-Amino-3-methylimidazo[4,5 f]quinoline (IQ) was identified in duck meat cooked by charcoal-grilling and pan frying, in the range of 0.4-4.2 ng g-1. 2-Amino-3,8-dimethyl-imidazo[4,5 f]quinoxaline (MeIQx) was detected in amounts below 4.5 ng g-1 in duck meat cooked by charcoal-grilling, roasting, deep-frying and pan-frying. The other HAs were detected in amounts below 10 ng g-1. Colour development increased with cooking temperature, but no correlation with HAs' content was observed. PMID- 22838940 TI - Parental stress when caring for a child with cancer in Jordan: a cross-sectional survey. AB - BACKGROUND: Most studies report that being parents of a child with cancer is a stressful experience, but these have tended to focus on mothers and few have included both parents. Moreover, studies have focussed on families in Western countries and none have been published examining the psychological outcomes for parents living in an Arabic country.This research explores the stress levels of Jordanian parents caring for a child with cancer in order to identify the psychological needs of parents in this environment and to explore how mothers and fathers stress levels might differ. METHODS: The study was carried out in Jordan using the Perceived Stress Scale 10-items (PSS10). The questionnaire was completed by 300 couples with a child who has cancer and a comparison group of 528 couples where the children do not have any serious illness. Multivariate backward regression analysis was carried out. RESULTS: Analysis adjusting for spousal stress and sociodemographic predictors revealed that stress levels of mothers with a child who had cancer remained significantly higher than mothers whose children did not have any serious illness (p < 0.001). However, having a child with cancer did not show a significant association with the fathers' reported stress scores (p = 0.476) when spousal stress was in the model, but was highly significant once that was removed (p < 0.001).Parental stress was analysed for those with a child who has cancer and in models which included spouse's stress scores, sociodemographic and cancer-related predictors 64 % of the variance was explained for mothers (adjusted R2 = 0.64, p < 0.001) and fathers (adjusted R2 = 0.64, p < 0.001). Models excluding spousal stress scores explained just 26 % of the variance for fathers and 22 % for mothers. CONCLUSIONS: This is the first study into the psychological outcomes for parents living in an Arabic country who care for a child with cancer. Both mothers and fathers with a child diagnosed with cancer reported higher stress levels than those from the normal Jordanian parent population. Mothers and fathers of children with cancer reported significantly different levels of stress to each other but models reveal significant contributions of the stress score of fathers upon mothers, and vice versa. The findings provide evidence of the need for psychological support to be developed for families caring for a child with cancer in Jordan. PMID- 22838942 TI - Can pharmacogenomics guide effective anticancer therapy in pancreatic ductal adenocarcinoma? PMID- 22838941 TI - Analysis of pan-African Centres of excellence in health innovation highlights opportunities and challenges for local innovation and financing in the continent. AB - A pool of 38 pan-African Centres of Excellence (CoEs) in health innovation has been selected and recognized by the African Network for Drugs and Diagnostics Innovation (ANDI), through a competitive criteria based process. The process identified a number of opportunities and challenges for health R&D and innovation in the continent: i) it provides a direct evidence for the existence of innovation capability that can be leveraged to fill specific gaps in the continent; ii) it revealed a research and financing pattern that is largely fragmented and uncoordinated, and iii) it highlights the most frequent funders of health research in the continent. The CoEs are envisioned as an innovative network of public and private institutions with a critical mass of expertise and resources to support projects and a variety of activities for capacity building and scientific exchange, including hosting fellows, trainees, scientists on sabbaticals and exchange with other African and non-African institutions. PMID- 22838943 TI - Phenocopy and phenoconversion: do they complicate association studies? PMID- 22838944 TI - Pharmacogenetics to screen for drug-induced osteonecrosis of the jaw. PMID- 22838945 TI - Identification of a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy. PMID- 22838946 TI - Genetic variants in the human SLCO1B1 gene and individual variations in methotrexate clearance. PMID- 22838947 TI - Conference Scene: Pharmacogenomic highlights of the DGPT Annual Congress. PMID- 22838948 TI - Genetic variants of thiopurine and folate metabolic pathways determine 6-MP mediated hematological toxicity in childhood ALL. AB - AIM: The rationale of this study was to explore the contribution of genetic variants of the folate pathway to toxicity of 6-mercaptopurine (6-MP)-mediated hematological toxicity in children with acute lymphoblastic leukemia (ALL) and to explore the interaction of these variants with TPMT and ITPA haplotypes using multifactor dimensionality reduction analysis. MATERIALS & METHODS: Children with ALL (n = 96) were screened for GCPII C1561T, RFC1 G80A, cSHMT C1420T, TYMS 5'-UTR 2R3R, TYMS 3'-UTR ins6/del6, MTHFR C677T, MTR A2756G polymorphisms using PCR-RFLP and PCR-amplified fragment length polymorphism techniques. RESULTS: GCPII C1561T showed independent association with toxicity. The following synergetic interactions appeared to increase the toxicity of 6-mercaptopurine: TPMT*12 * RFC1 G80A; TPMT CTTAT haplotype * RFC1 G80A; TPMT CTTAT haplotype * RFC1 G80A * TYMS 2R3R. The genetic variants of thiopurine and folate pathway cumulatively appeared to increase the predictability of toxicity (r(2) = 0.41) in a multiple linear regression model. For the observed toxicity grades of 1, 2, 3 and 4, the respective predicted toxicity grades were 1.65 +/- 0.29, 1.68 +/- 0.24, 2.56 +/- 0.58 and 2.99 +/- 1.03, p(trend) < 0.0001. CONCLUSION: Gene-gene interaction between thiopurine and folate pathways inflate the 6-MP-mediated toxicity in Indian children with ALL illustrating the importance of ethnicity in the toxicity of 6-MP. PMID- 22838949 TI - Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors. AB - AIM: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy. MATERIALS & METHODS: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics. RESULTS: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2',2'-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2',2'-difluoro 2'-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1. CONCLUSION: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients. PMID- 22838950 TI - Effect of genetic polymorphisms on therapeutic response and clinical outcomes in pancreatic cancer patients treated with gemcitabine. AB - AIM: Gemcitabine is the first chemotherapeutic agent to show clinical benefits in pancreatic cancer patients. While interindividual variability in chemoresponse is observed, genetic factors that affect drug metabolism have not been clearly defined. The purpose of this study is to evaluate the relationships between genetic polymorphisms and therapeutic efficacy in pancreatic cancer patients treated with gemcitabine. PATIENTS & METHODS: The study population consisted of 102 pancreatic cancer patients who had been treated with a gemcitabine-based chemotherapeutic regimen. 102 genetic polymorphisms were selected from 23 genes involved in the metabolism and action sites of gemcitabine and screened for polymorphisms using the MassARRAY((r)) system. The polymorphisms and haplotypes were analyzed in relation to overall survival (OS), time-to-progression (TTP) and disease progression. RESULTS: CMPK1 360C>T was significantly associated with OS, TTP and disease progression (p = 0.042, 0.007 and 0.040, respectively, in a dominant genetic model). Additionally, CMPK1 240G>T was correlated with OS and TTP. The frequencies of the haplotypes for the CMPK1, SLC28A1, DCTD and TLE4 genes differed according to disease progression. CONCLUSION: Genetic polymorphisms in genes related to metabolism and action sites of gemcitabine showed associations with the therapeutic efficacy, in terms of OS, TTP and disease progression in pancreatic cancer patients treated with gemcitabine-based chemotherapy. In particular, polymorphisms of the CMPK1 gene seem to provide important prognostic information. PMID- 22838951 TI - Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration. AB - Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions. PMID- 22838952 TI - Functional impact and prevalence of polymorphisms involved in the hepatic glucuronidation of valproic acid. AB - Metabolism of valproic acid, a widely used drug, is only partially understood. It is mainly metabolized through glucuronidation and acts as a substrate for various UDP-glucuronosyltransferases (UGTs). UGTs metabolizing valproic acid in the liver are UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, with UGT1A6 and UGT2B7 being the most prominent. Polymorphisms in genes expressing these enzymes may have clinical consequences, regarding dosing, blood levels of the drug and adverse reactions. Not all genes are well studied and studies, where they exist, report conflicting results. Prevalence of polymorphisms and various haplotypes is also of great importance, as it may suggest different therapeutic approaches in various populations. Presented here is a review of currently known polymorphisms, their functional impact, when known, and their prevalence in different populations, highlighting the current state of understanding and areas where there is a lack of data and suggesting new perspectives for further research. PMID- 22838953 TI - Pharmacogenetics of conventional chemotherapy in non-small-cell lung cancer: a changing landscape? AB - Pharmacogenetics might be used to select patients who may benefit from specific chemotherapy that best matches the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. Even if most studies in non-small cell lung cancer yielded contradictory results, several potential biomarkers for sensitivity/resistance to platinum compounds, gemcitabine, taxanes and pemetrexed have been proposed. However, these markers need to be validated within larger prospective randomized trials of customized chemotherapy in homogeneous populations. Other critical points include the optimization/standardization of technical procedures, and further studies to unravel the extremely complex regulation of gene function. From this perspective, the evaluation of key factors influencing genotype-phenotype relationships, such as miRNAs, and functional studies to clarify pharmacokinetic/pharmacodynamic interactions, are fundamental for the pharmacogenetic optimization of cancer chemotherapy. Finally, limitation of the traditional pharmacogenetic approach relying only on candidate genes suspected of affecting drug response is now being overcome by the use of novel genome-wide studies. PMID- 22838954 TI - Clinical pharmacogenetic model to predict response of MTX monotherapy in patients with established rheumatoid arthritis after DMARD failure. AB - BACKGROUND: The performance of a clinical pharmacogenetic model to predict nonresponse of methotrexate (MTX) monotherapy in patients with established rheumatoid arthritis (RA) and failure of disease-modifying antirheumatic drugs (DMARDs) was studied. METHODS: For 75 RA patients receiving MTX monotherapy for 6 months, DNA and clinical data were available. Risk scores for nonresponse at 6 months (disease activity score >2.4), were calculated using the pharmacogenetic prediction model utilizing four clinical factors and four polymorphisms in the genes MTHFD1, AMPD1, ITPA and ATIC. RESULTS: At 6 months, there were 25 responders and 50 nonresponders. Using the clinical pharmacogenetic prediction model, 75% (56 out of 75) were categorized into predicted responders (risk score <= 3.5) and predicted nonresponders (risk score >= 6). At 6 months, the negative predictive value was 81% (21 out of 26) and the positive predictive value was 47% (14 out of 30). CONCLUSION: The pharmacogenetic model predicts nonresponse to MTX monotherapy, but performs better in DMARD naive recent-onset RA patients than in patients with preceding DMARD failure. PMID- 22838956 TI - Molecular characterization of totiviruses in Xanthophyllomyces dendrorhous. AB - BACKGROUND: Occurrence of extrachromosomal dsRNA elements has been described in the red-yeast Xanthophyllomyces dendrorhous, with numbers and sizes that are highly variable among strains with different geographical origin. The studies concerning to the encapsidation in viral-like particles and dsRNA-curing have suggested that some dsRNAs are helper viruses, while others are satellite viruses. However, the nucleotide sequences and functions of these dsRNAs are still unknown. In this work, the nucleotide sequences of four dsRNAs of the strain UCD 67-385 of X. dendrorhous were determined, and their identities and genome structures are proposed. Based on this molecular data, the dsRNAs of different strains of X. dendrorhous were analyzed. RESULTS: The complete sequences of L1, L2, S1 and S2 dsRNAs of X. dendrorhous UCD 67-385 were determined, finding two sequences for L1 dsRNA (L1A and L1B). Several ORFs were uncovered in both S1 and S2 dsRNAs, but no homologies were found for any of them when compared to the database. Instead, two ORFs were identified in each L1A, L1B and L2 dsRNAs, whose deduced amino acid sequences were homologous with a major capsid protein (5'-ORF) and a RNA-dependent RNA polymerase (3'-ORF) belonging to the Totiviridae family. The genome structures of these dsRNAs are characteristic of Totiviruses, with two overlapped ORFs (the 3'-ORF in the -1 frame with respect to the 5'-ORF), with a slippery site and a pseudoknot in the overlapped regions. These structures are essential for the synthesis of the viral polymerase as a fusion protein with the viral capsid protein through -1 ribosomal frameshifting. In the RNase protection analysis, all the dsRNAs in the four analyzed X. dendrorhous strains were protected from enzymatic digestion. The RT-PCR analysis revealed that, similar to strain UCD 67-385, the L1A and L1B dsRNAs coexist in the strains VKM Y-2059, UCD 67-202 and VKM Y-2786. Furthermore, determinations of the relative amounts of L1 dsRNAs using two-step RT-qPCR revealed a 40-fold increment of the ratio L1A/L1B in the S2 dsRNA-cured strain compared to its parental strain. CONCLUSIONS: Three totiviruses, named as XdV-L1A, XdV-L1B and XdV-L2, were identified in the strain UCD 67-385 of X. dendrorhous. The viruses XdV-L1A and XdV-L1B were also found in other three X. dendrorhous strains. Our results suggest that the smaller dsRNAs (named XdRm-S1 and XdRm-S2) of strain UCD 67-385 are satellite viruses, and particularly that XdRm-S2 is a satellite of XdV L1A. PMID- 22838958 TI - Cross-species testing and utility of microsatellite loci in Indirana frogs. AB - BACKGROUND: Microsatellite loci are widely used in population and conservation genetic studies of amphibians, but the availability of such markers for tropical and subtropical taxa is currently very limited. In order to develop resources for conservation genetic studies in the genus Indirana, we tested amplification success and polymorphism in 62 previously developed microsatellite loci, in eight Indirana species - including new candidate species. Developing genomic resources for this amphibian taxon is particularly important as it is endemic to the Western Ghats biodiversity hotspot, and harbours several endangered species. FINDINGS: The cross-species amplification success rate varied from 11.3 % to 29.0 % depending on the species, with 29 - 80 % of the amplifying loci being polymorphic. A strong negative correlation between cross-species amplification success (and polymorphism) and genetic distance separating target from source species was observed. CONCLUSIONS: Our results provide additional genetic support for the existence of genetically divergent cryptic species within the genus Indirana. The tested markers should be useful for population and conservation genetic studies in this genus, and in particular, for species closely related to the source species, I. beddomii. PMID- 22838957 TI - How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer. AB - BACKGROUND: Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women's treatment choices - treatment-focused genetic testing 'TFGT' - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service. DESIGN/METHODS: In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals' attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention. DISCUSSION: This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed. PMID- 22838959 TI - Road traffic related mortality in Vietnam: evidence for policy from a national sample mortality surveillance system. AB - BACKGROUND: Road traffic injuries (RTIs) are among the leading causes of mortality in Vietnam. However, mortality data collection systems in Vietnam in general and for RTIs in particular, remain inconsistent and incomplete. Underlying distributions of external causes and body injuries are not available from routine data collection systems or from studies till date. This paper presents characteristics, user type pattern, seasonal distribution, and causes of 1,061 deaths attributable to road crashes ascertained from a national sample mortality surveillance system in Vietnam over a two-year period (2008 and 2009). METHODS: A sample mortality surveillance system was designed for Vietnam, comprising 192 communes in 16 provinces, accounting for approximately 3% of the Vietnamese population. Deaths were identified from commune level data sources, and followed up by verbal autopsy (VA) based ascertainment of cause of death. Age standardised mortality rates from RTIs were computed. VA questionnaires were analysed in depth to derive descriptive characteristics of RTI deaths in the sample. RESULTS: The age-standardized mortality rates from RTIs were 33.5 and 8.5 per 100,000 for males and females respectively. Majority of deaths were males (79%). Seventy three percent of all deaths were aged from 15 to 49 years and 58% were motorcycle users. As high as 80% of deaths occurred on the day of injury, 42% occurred prior to arrival at hospital, and a further 29% occurred on-site. Direct causes of death were identified for 446 deaths (42%) with head injuries being the most common cause attributable to road traffic injuries overall (79%) and to motorcycle crashes in particular (78%). CONCLUSION: The VA method can provide a useful data source to analyse RTI mortality. The observed considerable mortality from head injuries among motorcycle users highlights the need to evaluate current practice and effectiveness of motorcycle helmet use in Vietnam. The high number of deaths occurring on-site or prior to hospital admission indicates a need for effective pre-hospital first aid services and timely access to emergency facilities. In the absence of standardised death certification, sustained efforts are needed to strengthen mortality surveillance sites supplemented by VA to support evidence based monitoring and control of RTI mortality. PMID- 22838960 TI - Follicular ovarian torsion in an ostrich (Struthio camelus). PMID- 22838961 TI - Mammographic density as a mediator for breast cancer risk: analytic approaches. AB - Mammographic breast density has been found to be associated with breast cancer risk. Many of the traditional risk factors for breast cancer are themselves associated with mammographic breast density. A natural question that arises in this setting is the extent to which the effects of breast cancer risk factors are mediated by breast density and the extent to which such effects are through other pathways. We discuss analytic approaches to address these questions of mediation and also discuss how such approaches can accommodate potential interaction between risk factors and mammographic density and can accommodate case-control study designs. PMID- 22838962 TI - Harmonic bath averaged Hamiltonian: an efficient tool to capture quantum effects of large systems. AB - Starting from a reaction path Hamiltonian, a suitably reduced harmonic bath averaged Hamiltonian is derived by averaging over all the normal mode coordinates. Generalization of the harmonic bath averaged Hamiltonian to any dimensions are performed and the feasibility to use a linear reaction path/surface are investigated and discussed. By use of a harmonic bath averaged Hamiltonian, the tunneling splitting and proton transfer dynamics of malonaldehyde is briefly discussed and shows that the harmonic bath averaged Hamiltonian is an efficient tool to capture quantum effects in larger systems. PMID- 22838963 TI - Metabolic fingerprints of serum, brain, and liver are distinct for mice with cerebral and noncerebral malaria: a 1H NMR spectroscopy-based metabonomic study. AB - Cerebral malaria (CM) is a life-threatening disease in humans caused by Plasmodium falciparum, leading to high mortality. Plasmodium berghei ANKA (PbA) infection in C57Bl/6 mice induces pathologic symptoms similar to that in human CM. However, experimental CM incidence in mice is variable, and there are no known metabolic correlates/fingerprints for the animals that develop CM. Here, we have used (1)H NMR-based metabonomics to investigate the metabolic changes in the mice with CM with respect to the mice that have noncerebral malaria (NCM) of the same batchmates with identical genetic backgrounds and infected simultaneously. The metabolic profile of the infected mice (both CM and NCM) was separately compared with the metabolite profile of uninfected control mice of same genetic background. The objective of this study was to search for metabolic changes/fingerprints of CM and identify the pathways that might be differentially altered in mice that succumbed to CM. The results show that brain, liver, and sera exhibit unique metabolic fingerprints for CM over NCM mice. Some of the major fingerprints are increased level of triglycerides, VLDL-cholesterol in sera of CM mice, and decreased levels of glutamine in the sera concomitant with increased levels of glutamine in the brain of the mice with CM. Moreover, glycerophosphocholine is decreased in both the brain and the liver of animals with CM, and myo-inositol and histamine are increased in the liver of CM mice. The metabolic fingerprints in brain, sera, and liver of mice with CM point toward perturbation in the ammonia detoxification pathway and perturbation in lipid and choline metabolism in CM specifically. The study helps us to understand the severity of CM over NCM and in unrevealing the specific metabolic pathways that are compromised in CM. PMID- 22838964 TI - Inhibitory effect of luteolin on estrogen biosynthesis in human ovarian granulosa cells by suppression of aromatase (CYP19). AB - Inhibition of aromatase, the key enzyme in estrogen biosynthesis, is an important strategy in the treatment of breast cancer. Several dietary flavonoids show aromatase inhibitory activity, but their tissue specificity and mechanism remain unclear. This study found that the dietary flavonoid luteolin potently inhibited estrogen biosynthesis in a dose- and time-dependent manner in KGN cells derived from human ovarian granulosa cells, the major source of estrogens in premenopausal women. Luteolin decreased aromatase mRNA and protein expression in KGN cells. Luteolin also promoted aromatase protein degradation and inhibited estrogen biosynthesis in aromatase-expressing HEK293A cells, but had no effect on recombinant expressed aromatase. Estrogen biosynthesis in KGN cells was inhibited with differing potencies by extracts of onion and bird chili and by four other dietary flavonoids: kaempferol, quercetin, myricetin, and isorhamnetin. The present study suggests that luteolin inhibits estrogen biosynthesis by decreasing aromatase expression and destabilizing aromatase protein, and it warrants further investigation as a potential treatment for estrogen-dependent cancers. PMID- 22838965 TI - Integrating gene expression and protein-protein interaction network to prioritize cancer-associated genes. AB - BACKGROUND: To understand the roles they play in complex diseases, genes need to be investigated in the networks they are involved in. Integration of gene expression and network data is a promising approach to prioritize disease associated genes. Some methods have been developed in this field, but the problem is still far from being solved. RESULTS: In this paper, we developed a method, Networked Gene Prioritizer (NGP), to prioritize cancer-associated genes. Applications on several breast cancer and lung cancer datasets demonstrated that NGP performs better than the existing methods. It provides stable top ranking genes between independent datasets. The top-ranked genes by NGP are enriched in the cancer-associated pathways. The top-ranked genes by NGP-PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2 might coordinate to promote cell cycle related processes in cancer but not normal cells. CONCLUSIONS: In this paper, we have developed a method named NGP, to prioritize cancer-associated genes. Our results demonstrated that NGP performs better than the existing methods. PMID- 22838966 TI - Global transcriptome analysis reveals distinct expression among duplicated genes during sorghum-interaction. AB - BACKGROUND: Sorghum (Sorghum bicolor L. Moench) is a rich source of natural phytochemicals. We performed massive parallel sequencing of mRNA to identify differentially expressed genes after sorghum BTx623 had been infected with Bipolaris sorghicola, a necrotrophic fungus causing a sorghum disease called target leaf spot. RESULT: Seventy-six-base-pair reads from mRNAs of mock- or pathogen-infected leaves were sequenced. Unannotated transcripts were predicted on the basis of the piling-up of mapped short reads. Differentially expressed genes were identified statistically; particular genes in tandemly duplicated putative paralogs were highly upregulated. Pathogen infection activated the glyoxylate shunt in the TCA cycle; this changes the role of the TCA cycle from energy production to synthesis of cell components. The secondary metabolic pathways of phytoalexin synthesis and of sulfur-dependent detoxification were activated by upregulation of the genes encoding amino acid metabolizing enzymes located at the branch point between primary and secondary metabolism. Coordinated gene expression could guide the metabolic pathway for accumulation of the sorghum specific phytochemicals 3-deoxyanthocyanidin and dhurrin. Key enzymes for synthesizing these sorghum-specific phytochemicals were not found in the corresponding region of the rice genome. CONCLUSION: Pathogen infection dramatically changed the expression of particular paralogs that putatively encode enzymes involved in the sorghum-specific metabolic network. PMID- 22838968 TI - Staff characteristics and attitudes towards the sexuality of people with intellectual disability. AB - BACKGROUND: The identification of individual staff characteristics that have a relationship with specific attitudes of staff caring for people with intellectual disability (ID) may enable targeted training and better support. METHOD: Sixty six participants from services for people with ID in metropolitan Melbourne, Australia, completed a survey, including the Attitudes to Sexuality Questionnaire (Individuals with an Intellectual Disability; Cuskelly & Gilmore, 2007). RESULTS: Staff attitudes towards the sexuality of people with ID were quite positive. Age, program agency position, and training uptake were all associated with positive staff attitudes. CONCLUSION: Targeted training programs in sexuality can benefit direct care workers in general, and older staff more specifically. Emphasis is warranted in the area of training for managing male sexual behaviours. PMID- 22838967 TI - Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. AB - BACKGROUND: Pro-inflammatory stimuli, including cytokines like Interleukin-1beta, Interleukin-6 and Interferon-gamma, in the brain have been proposed to exacerbate existing Alzheimer's disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Abeta accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Abeta. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques. RESULTS: mIL-4 expression resulted in establishment of an "M2-like" phenotype in the brain and was accompanied by exacerbated Abeta deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Abeta. mIL-4 treatment attenuates soluble Abeta40 uptake by microglia but does not affect aggregated Abeta42 internalization by microglia or soluble Abeta40 internalization by astrocytes. CONCLUSIONS: Short term focal mIL 4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side effects of anti-inflammatory therapies for neurodegenerative diseases, including AD. PMID- 22838969 TI - Response of C57Bl/6 mice to a carbohydrate-free diet. AB - High fat feeding in rodents generally leads to obesity and insulin resistance whereas in humans this is only seen if dietary carbohydrate is also high, the result of the anabolic effect of poor regulation of glucose and insulin. A previous study of C57Bl/6 mice (Kennedy AR, et al.: Am J Physiol Endocrinol Metab (2007) 262 E1724-1739) appeared to show the kind of beneficial effects of calorie restriction that is seen in humans but that diet was unusually low in protein (5%). In the current study, we tested a zero-carbohydrate diet that had a higher protein content (20%). Mice on the zero-carbohydrate diet, despite similar caloric intake, consistently gained more weight than animals consuming standard chow, attaining a dramatic difference by week 16 (46.1 +/- 1.38 g vs. 30.4 +/- 1.00 g for the chow group). Consistent with the obese phenotype, experimental mice had fatty livers and hearts as well as large fat deposits in the abdomino pelvic cavity, and showed impaired glucose clearance after intraperitoneal injection. In sum, the response of mice to a carbohydrate-free diet was greater weight gain and metabolic disruptions in distinction to the response in humans where low carbohydrate diets cause greater weight loss than isocaloric controls. The results suggest that rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans. PMID- 22838970 TI - Gender disparities in diabetes and coronary heart disease medication among patients with type 2 diabetes: results from the DIANA study. AB - BACKGROUND: Coronary heart disease (CHD) is one of the most common long-term complications in people with type 2 diabetes. We analyzed whether or not gender differences exist in diabetes and CHD medication among people with type 2 diabetes. METHODS: The study was based on data from the baseline examination of the DIANA study, a prospective cohort study of 1,146 patients with type 2 diabetes conducted in South-West Germany. Information on diabetes and CHD medication was obtained from the physician questionnaires. Bivariate and multivariate analyses using logistic regression were employed in order to assess associations between gender and prescribed drug classes. RESULTS: In total, 624 men and 522 women with type 2 diabetes with a mean age of 67.2 and 69.7 years, respectively, were included in this analysis. Compared to women, men had more angiopathic risk factors, including smoking, alcohol consumption and worse glycemic control, and had more often a diagnosed CHD. Bivariate analyses showed higher prescription of thiazolidinediones and oral combination drugs as well as of angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers and aspirin in men than in women. After full adjustment, differences between men and women remained significant only for ACE inhibitors (OR=1.44; 95%-confidence interval (CI): 1.11-1.88) and calcium channel blockers (OR=1.42, 95%-CI: 1.05 1.91). CONCLUSIONS: These findings contribute to current discussions on gender differences in diabetes care. Men with diabetes are significantly more likely to receive oral combination drugs, ACE inhibitors and calcium channel blockers in the presence of coronary heart disease, respectively. Our results suggest, that diabetic men might be more thoroughly treated compared to women. Further research is needed to focus on reasons for these differences mainly in treatment of cardiovascular diseases to improve quality of care. PMID- 22839094 TI - Cyclophosphamide-based in vivo T-cell depletion for HLA-haploidentical transplantation in Fanconi anemia. AB - Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine (FLU)-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced dose cyclophosphamide (CY) to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at 1 month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pretransplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, are transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality of life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced dose CY for in vivo T-cell depletion can correct life-threatening aplasia in FA patients. PMID- 22839095 TI - Identification of variables contributing to superovulation efficiency for production of transgenic prairie voles (Microtus ochrogaster). AB - BACKGROUND: The prairie vole (Microtus ochrogaster) is an emerging animal model for biomedical research because of its rich sociobehavioral repertoire. Recently, lentiviral transgenic technology has been used to introduce the gene encoding the green fluorescent protein (GFP) into the prairie vole germline. However, the efficiency of transgenesis in this species is limited by the inability to reliably produce large numbers of fertilized embryos. Here we examined several factors that may contribute to variability in superovulation success including, age and parentage of the female, and latency to mating after being placed with the male. METHODS: Females produced from 5 genetically distinct breeder lines were treated with 100 IU of pregnant mare serum gonadotrophin (PMSG) and immediately housed with a male separated by a perforated Plexiglas divider. Ovulation was induced 72 hr later with 30 IU of human chorionic gonadotropin (hCG) and 2 hrs later mating was allowed. RESULTS: Superovulation was most efficient in young females. For example, females aged 6-11 weeks produced more embryos (14 +/- 1.4 embryos) as compared to females aged 12-20 weeks (4 +/- 1.6 embryos). Females aged 4-5 weeks did not produce embryos. Further, females that mated within 15 min of male exposure produced significantly more embryos than those that did not. Interestingly, there was a significant effect of parentage. For example, 12 out of 12 females from one breeder pair superovulated (defined as producing 5 or more embryos), while only 2 out of 10 females for other lines superovulated. CONCLUSIONS: The results of this work suggest that age and genetic background of the female are the most important factors contributing to superovulation success and that latency to mating is a good predictor of the number of embryos to be recovered. Surprisingly we found that cohabitation with the male prior to mating is not necessary for the recovery of embryos but is necessary to recover oocytes. This information will dramatically reduce the number of females required to generate embryos for transgenesis in this species. PMID- 22839097 TI - Complete calvarial agenesis in conjunction with a Tessier 1-13 facial cleft. AB - Amniotic band sequence (ABS) is a condition in which rupture of the amniotic sac leads to the development of a broad spectrum of fetal anomalies. A newborn male presented at term with multiple craniofacial and skeletal anomalies, including attachment of the placenta to the head, a paramedian facial cleft, and multiple skeletal anomalies. The patient has undergone several operations to date. The initial operation was performed to remove the attached placenta off the underlying dura, which was with a collagen matrix bound to a silicone membrane. The patient subsequently underwent split-thickness skin grafting with complete survival of the graft. PMID- 22839096 TI - Gremlin in the pathogenesis of hepatocellular carcinoma complicating chronic hepatitis C: an immunohistochemical and PCR study of human liver biopsies. AB - BACKGROUND: The possible role of secretory products of fibrous tissue in the development of hepatocellular carcinoma (HCC) complicating chronic hepatitis C was investigated. Our hypothesis was that gremlin, secreted by fibroblasts, inhibited bone morphogenic protein (BMP), which mediates stem cell maturation into adult functioning hepatocytes, and thus, arrest stem cell maturation and promoted their proliferation in an immature state possibly culminating into development of HCCs. RESULTS: Protein expression of cytokeratin 19 (CK19) and fibroblast growth factor 2 (FGF-2), and mRNA expression of gremlin and BMP-7 were studied in 35 cases of chronic hepatitis, cirrhosis and HCC complicating chronic hepatitis C. CK19 expression was higher in cases of cirrhosis (0.004), which correlated with the grade (r = 0.64, p = 0.009) and stage (r = 0.71, p = 0.001). All HCCs were negative for CK19. Stem cell niche activation (as indicated as a ductular reaction) was highest in cases of cirrhosis (p = 0.001) and correlated with CK19 expression (r = 0.42, p = 0.012), the grade(r = 0.56, p = 0.024) and stage (0.66, p = 0.006). FGF-2 expression was highest in HCCs and correlated with the grade (r = 0.6, p = 0.013), stage (0.72, p = 0.002), CK19 expression (r = 0.71, p = 002) and ductular reaction (0.68, p = 0.004) in hepatitis cases. Higher numbers of cirrhosis cases and HCCs (p = 0.009) showed gremlin expression, which correlated with the stage (r = 0.7, p = 0.002). Gremlin expression correlated with that of CK19 (r = 0.699, p = 0.003) and FGF2 (r = 0.75, p = 0.001) in hepatitis cases. CONCLUSIONS: Fibrosis promotes carcinogenesis by fibroblast secreted gremlin that blocks BMP function and promotes stem cell activation and proliferation as well as possibly HCC development. PMID- 22839100 TI - Conformational analysis of quinine and its pseudo enantiomer quinidine: a combined jet-cooled spectroscopy and vibrational circular dichroism study. AB - Laser-desorbed quinine and quinidine have been studied in the gas phase by combining supersonic expansion with laser spectroscopy, namely, laser-induced fluorescence (LIF), resonance-enhanced multiphoton ionization (REMPI), and IR-UV double resonance experiments. Density funtional theory (DFT) calculations have been done in conjunction with the experimental work. The first electronic transition of quinine and quinidine is of pi-pi* nature, and the studied molecules weakly fluoresce in the gas phase, in contrast to what was observed in solution (Qin, W. W.; et al. J. Phys. Chem. C2009, 113, 11790). The two pseudo enantiomers quinine and quinidine show limited differences in the gas phase; their main conformation is of open type as it is in solution. However, vibrational circular dichroism (VCD) experiments in solution show that additional conformers exist in condensed phase for quinidine, which are not observed for quinine. This difference in behavior between the two pseudo enantiomers is discussed. PMID- 22839099 TI - Overexpression of cell cycle regulator CDCA3 promotes oral cancer progression by enhancing cell proliferation with prevention of G1 phase arrest. AB - BACKGROUND: Cell division cycle associated 3 (CDCA3), part of the Skp1-cullin-F box (SCF) ubiquitin ligase, refers to a trigger of mitotic entry and mediates destruction of the mitosis inhibitory kinase. Little is known about the relevance of CDCA3 to human malignancy including oral squamous cell carcinoma (OSCC). We aimed to characterize the expression state and function of CDCA3 in OSCC. METHODS: We evaluated CDCA3 mRNA and protein expression in both OSCC-derived cell lines and primary OSCCs and performed functional analyses of CDCA3 in OSCC derived cells using the shRNA system. RESULTS: The CDCA3 expression at both the mRNA and protein levels was frequently up-regulated in all cell lines examined and primary tumors (mRNA, 51/69, 74 %; protein, 79/95, 83 %) compared to normal controls (p < 0.001). In contrast, no significant level of CDCA3 protein expression was seen in oral premalignant lesions (OPLs) (n = 20) compared with the expression in OSCCs. Among the clinical variables analyzed, the CDCA3 expression status was closely related to tumor size (p < 0.05). In addition, suppression of CDCA3 expression with shRNA significantly (p < 0.05) inhibited cellular proliferation compared with the control cells by arresting cell-cycle progression at the G1 phase. Further, there was up-regulation of the cyclin dependent kinase inhibitors (p21(Cip1), p27(Kip1), p15(INK4B), and p16(INK4A)) in the knockdown cells. CONCLUSION: The current results showed that overexpression of CDCA3 occurs frequently during oral carcinogenesis and this overexpression might be associated closely with progression of OSCCs by preventing the arrest of cell-cycle progression at the G1 phase via decreased expression of the cyclin dependent kinase inhibitors. PMID- 22839101 TI - The negative impact of living environment on intelligence quotient of primary school children in Baghdad City, Iraq: a cross-sectional study. AB - BACKGROUND: Environmental factors play a very important role in the child development process, especially in a situation like that of Iraq. Thirteen years of economic sanctions followed by the 2003 war and 8 years of unstable security have affected the daily life of Iraqi families and children. The objective of this study was to assess the associations between living environment domains and child intelligence quotient (IQ) score. METHODS: A cross-sectional survey was conducted among 529 children aged 7-8 years from five primary schools in Baghdad during September-October, 2011. The five schools represent people living a range of conditions, and include of both high and low socio-economic groups. Living environment was assessed by 13 questionnaire items, consists of three domains: physical safety , mental stress and public services. While IQ was assessed by Raven Colored progressive matrices. RESULTS: Among the participants, 22% were of low intelligence versus 77% of high intelligence and 19% lived in a poor environment. There were significant associations between the mental stress and service living environment domains and child IQ (p = 0.009 and p = 0.001, respectively). CONCLUSION: In Iraq, child IQ was found to be associated with the mental stress and service domains of the living environment. This study findings will help authorities in their efforts to improve living environment. PMID- 22839102 TI - Steaming-induced chemical transformations and holistic quality assessment of red ginseng derived from Panax ginseng by means of HPLC-ESI-MS/MS(n)-based multicomponent quantification fingerprint. AB - The purpose of this study is to evaluate the steaming-induced chemical transformation of red ginseng manufactured from fresh ginseng by means of simultaneous quantitative and qualitative analyses with a combinative high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI MS/MS(n)) technique. Thirty-six ginsenosides were identified in red ginseng and white ginseng by comparing the mass spectrum and/or matching the empirical molecular formula with that of known published compounds, and 11 of them were determined to be newly generated during the red ginseng preparatory process. The mechanisms involved were further deduced to be hydrolysis, dehydration, isomerization, and decarboxylation at C-20, and hydrolysis also occurs at C-3 or C-6 of the original ginsenosides through the mimic process of steaming and heating in laboratory. The multicomponent quantification fingerprint of ginseng was also established by HPLC-UV method, and the contents of 12 ginsenosides in red and white ginsengs from different sources were determined simultaneously. The ratio of the total content of determined malonyl ginsenosides to the corresponding neutral ginsenosides (T(m-PPD)/T(PPD)) in white ginseng ranged from 0.46 to 0.62 and from 0 to 0.19 in red ginseng. The validated method is expected to provide an effective approach to standardize the processing procedures of ginseng products and regulate the usage of ginseng in Traditional Chinese Medical prescription. PMID- 22839103 TI - The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition. AB - INTRODUCTION: Gene expression data derived from clinical cancer specimens provide an opportunity to characterize cancer-specific transcriptional programs. Here, we present an analysis delineating a correlation-based gene expression landscape of breast cancer that identifies modules with strong associations to breast cancer specific and general tumor biology. METHODS: Modules of highly connected genes were extracted from a gene co-expression network that was constructed based on Pearson correlation, and module activities were then calculated using a pathway activity score. Functional annotations of modules were experimentally validated with an siRNA cell spot microarray system using the KPL-4 breast cancer cell line, and by using gene expression data from functional studies. Modules were derived using gene expression data representing 1,608 breast cancer samples and validated in data sets representing 971 independent breast cancer samples as well as 1,231 samples from other cancer forms. RESULTS: The initial co-expression network analysis resulted in the characterization of eight tightly regulated gene modules. Cell cycle genes were divided into two transcriptional programs, and experimental validation using an siRNA screen showed different functional roles for these programs during proliferation. The division of the two programs was found to act as a marker for tumor protein p53 (TP53) gene status in luminal breast cancer, with the two programs being separated only in luminal tumors with functional p53 (encoded by TP53). Moreover, a module containing fibroblast and stroma-related genes was highly expressed in fibroblasts, but was also up regulated by overexpression of epithelial-mesenchymal transition factors such as transforming growth factor beta 1 (TGF-beta1) and Snail in immortalized human mammary epithelial cells. Strikingly, the stroma transcriptional program related to less malignant tumors for luminal disease and aggressive lymph node positive disease among basal-like tumors. CONCLUSIONS: We have derived a robust gene expression landscape of breast cancer that reflects known subtypes as well as heterogeneity within these subtypes. By applying the modules to TP53-mutated samples we shed light on the biological consequences of non-functional p53 in otherwise low-proliferating luminal breast cancer. Furthermore, as in the case of the stroma module, we show that the biological and clinical interpretation of a set of co-regulated genes is subtype-dependent. PMID- 22839104 TI - Percutaneous intrarenal marsupialization of symptomatic peripelvic renal cysts: a single-centre experience in China. AB - OBJECTIVE.The aim of this study was to report the authors' experience with percutaneous intrarenal marsupialization of symptomatic peripelvic renal cysts. MATERIAL AND METHODS: Thirty-one patients (16 male and 15 female, with a mean age of 49 years) with a peripelvic renal cyst associated with chronic flank or lumbar pain or urinary infection were selected for percutaneous intrarenal marsupialization with a 2 MUm laser in the authors' centre from January 2005 to December 2010. Cyst size ranged from 4.5 to 10.5 (mean 6.0) cm. The cysts were punctured by a percutaneous technique guided by ultrasonography, a 20.8 F nephroscope was introduced and the whole internal surface of the cyst was inspected. Methylene blue was injected through the ureteral catheter to help identify the collecting system. A 1.5-4 cm incision was made at the avascular area of the cystic wall by the 2 MUm laser to achieve intrarenal marsupialization of the cyst into the renal collecting system. One or two 6 F double-J stents were placed with the proximal end in the cyst for 2-3 months. RESULTS: The mean operation time was 50 (25-120) min. No serious complications such as massive bleeding, urine leak or infected haematoma occurred. The patients were followed up for a mean of 12 (range 3-36) months. All patients were relieved of their symptoms. Eighteen cysts disappeared after surgery, while 13 cysts reduced in size by over one-third and communicated with the renal collecting system. No enlargement of cysts was observed. CONCLUSIONS: Percutaneous intrarenal marsupialization with a 2 MUm laser is an effective and safe procedure and may offer a minimally invasive alternative for the management of symptomatic peripelvic renal cysts. PMID- 22839105 TI - Fludarabine and cladribine induce changes in surface proteins on human B-lymphoid cell lines involved with apoptosis, cell survival, and antitumor immunity. AB - Fludarabine and cladribine are purine analogues used to treat hematological malignancies. Alone or in combination with therapeutic antibodies, they are effective in treating patients with chronic lymphocytic leukemia and non Hodgkin's lymphoma. However, the mechanisms of action of these drugs are not well understood. Plasma membrane proteins perform a variety of essential functions that can be affected by malignancy and perturbed by chemotherapy. Analysis of surface proteins may contribute to an understanding of the mechanisms of action of purine analogues and identify biomarkers for targeted therapy. The surface of human cells is rich in N-linked glycoproteins, enabling use of a hydrazide coupling technique to enrich for glycoproteins, with iTRAQ labeling for quantitative comparison. A number of plasma membrane proteins on human leukemia and lymphoma cells were affected by treatment with a purine analogue, including decreases in CD22 (an adhesion and signaling molecule) and increases in CD205 (a "damaged cell marker") and CD80 and CD50 (T-cell interaction molecules). Purine analogues may affect B-cell receptor (BCR) signaling and costimulatory molecules, leading to multiple signals for apoptosis and cell clearance. Fludarabine and cladribine induce differential effects, with some cell survival proteins (ECE-1 and CD100) more abundant after fludarabine treatment. Cell surface proteins induced by fludarabine and cladribine may be targets for therapeutic antibodies. PMID- 22839107 TI - Special series on positive behaviour support--efficacy: research agenda. PMID- 22839106 TI - Short-read reading-frame predictors are not created equal: sequence error causes loss of signal. AB - BACKGROUND: Gene prediction algorithms (or gene callers) are an essential tool for analyzing shotgun nucleic acid sequence data. Gene prediction is a ubiquitous step in sequence analysis pipelines; it reduces the volume of data by identifying the most likely reading frame for a fragment, permitting the out-of-frame translations to be ignored. In this study we evaluate five widely used ab initio gene-calling algorithms-FragGeneScan, MetaGeneAnnotator, MetaGeneMark, Orphelia, and Prodigal-for accuracy on short (75-1000 bp) fragments containing sequence error from previously published artificial data and "real" metagenomic datasets. RESULTS: While gene prediction tools have similar accuracies predicting genes on error-free fragments, in the presence of sequencing errors considerable differences between tools become evident. For error-containing short reads, FragGeneScan finds more prokaryotic coding regions than does MetaGeneAnnotator, MetaGeneMark, Orphelia, or Prodigal. This improved detection of genes in error containing fragments, however, comes at the cost of much lower (50%) specificity and overprediction of genes in noncoding regions. CONCLUSIONS: Ab initio gene callers offer a significant reduction in the computational burden of annotating individual nucleic acid reads and are used in many metagenomic annotation systems. For predicting reading frames on raw reads, we find the hidden Markov model approach in FragGeneScan is more sensitive than other gene prediction tools, while Prodigal, MGA, and MGM are better suited for higher-quality sequences such as assembled contigs. PMID- 22839108 TI - Birth defects in Iraq and the plausibility of environmental exposure: A review. AB - An increased prevalence of birth defects was allegedly reported in Iraq in the post 1991 Gulf War period, which was largely attributed to exposure to depleted uranium used in the war. This has encouraged further research on this particular topic. This paper reviews the published literature and provided evidence concerning birth defects in Iraq to elucidate possible environmental exposure. In addition to published research, this review used some direct observation of birth defects data from Al-Ramadi Maternity and Paediatric Hospital in Al-Anbar Governorate in Iraq from1st July 2000 through 30th June 2002. In addition to depleted uranium other war-related environmental factors have been studied and linked directly or indirectly with the increasing prevalence of birth defects. However, the reviewed studies and the available research evidence do not provide a clear increase in birth defects and a clear indication of a possible environmental exposure including depleted uranium although the country has been facing several environmental challenges since 1980. PMID- 22839109 TI - Experimental determination of the respiratory tract deposition of diesel combustion particles in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Air pollution, mainly from combustion, is one of the leading global health risk factors. A susceptible group is the more than 200 million people worldwide suffering from chronic obstructive pulmonary disease (COPD). There are few data on lung deposition of airborne particles in patients with COPD and none for combustion particles. OBJECTIVES: To determine respiratory tract deposition of diesel combustion particles in patients with COPD during spontaneous breathing. METHODS: Ten COPD patients and seven healthy subjects inhaled diesel exhaust particles generated during idling and transient driving in an exposure chamber. The respiratory tract deposition of the particles was measured in the size range 10-500 nm during spontaneous breathing. RESULTS: The deposited dose rate increased with increasing severity of the disease. However, the deposition probability of the ultrafine combustion particles (< 100 nm) was decreased in COPD patients. The deposition probability was associated with both breathing parameters and lung function, but could be predicted only based on lung function. CONCLUSIONS: The higher deposited dose rate of inhaled air pollution particles in COPD patients may be one of the factors contributing to their increased vulnerability. The strong correlations between lung function and particle deposition, especially in the size range of 20-30 nm, suggest that altered particle deposition could be used as an indicator respiratory disease. PMID- 22839110 TI - Increased expression of the yeast multidrug resistance ABC transporter Pdr18 leads to increased ethanol tolerance and ethanol production in high gravity alcoholic fermentation. AB - BACKGROUND: The understanding of the molecular basis of yeast tolerance to ethanol may guide the design of rational strategies to increase process performance in industrial alcoholic fermentations. A set of 21 genes encoding multidrug transporters from the ATP-Binding Cassette (ABC) Superfamily and Major Facilitator Superfamily (MFS) in S. cerevisiae were scrutinized for a role in ethanol stress resistance. RESULTS: A yeast multidrug resistance ABC transporter encoded by the PDR18 gene, proposed to play a role in the incorporation of ergosterol in the yeast plasma membrane, was found to confer resistance to growth inhibitory concentrations of ethanol. PDR18 expression was seen to contribute to decreased 3H-ethanol intracellular concentrations and decreased plasma membrane permeabilization of yeast cells challenged with inhibitory ethanol concentrations. Given the increased tolerance to ethanol of cells expressing PDR18, the final concentration of ethanol produced during high gravity alcoholic fermentation by yeast cells devoid of PDR18 was lower than the final ethanol concentration produced by the corresponding parental strain. Moreover, an engineered yeast strain in which the PDR18 promoter was replaced in the genome by the stronger PDR5 promoter, leading to increased PDR18 mRNA levels during alcoholic fermentation, was able to attain a 6 % higher ethanol concentration and a 17 % higher ethanol production yield than the parental strain. The improved fermentative performance of yeast cells over-expressing PDR18 was found to correlate with their increased ethanol tolerance and ability to restrain plasma membrane permeabilization induced throughout high gravity fermentation. CONCLUSIONS: PDR18 gene over-expression increases yeast ethanol tolerance and fermentation performance leading to the production of highly inhibitory concentrations of ethanol. PDR18 overexpression in industrial yeast strains appears to be a promising approach to improve alcoholic fermentation performance for sustainable bio-ethanol production. PMID- 22839111 TI - T2* MRI in regularly transfused children with thalassemia intermedia: serum ferritin does not reflect liver iron stores. AB - Nontransfused patients with thalassemia intermedia (TI) accumulate iron due to increased gastrointestinal absorption of iron. Recent studies using T2* MRI revealed that serum ferritin does not reflect the severity of iron overload in nontransfused TI patients. We evaluated the iron overload status in TI children on monthly transfusion. Based on serum ferritin levels, 11 such patients (mean age 13.18 +/- 4.09 years), were classified into two groups, group 1 (six patients) and group 2 (five patients) with serum ferritin levels below and above 1000 ng/mL, respectively. T2* MRI assessments were done for evaluation of hepatic and cardiac iron status. Group 1 and group 2 had mean serum ferritin levels of 817.300 +/- 244.690 ng/mL and 1983.80 +/- 662.862 ng/mL, respectively (P = .003). T2* MRI showed comparable moderate to severe hepatic iron overload status in both. None of the patients had myocardial iron deposition. We conclude that serum ferritin does not reflect the hepatic iron overload status in our patients with TI on regular transfusion. PMID- 22839197 TI - Translation of tobacco policy into practice in disadvantaged and marginalized subpopulations: a study of challenges and opportunities in remote Australian Indigenous communities. AB - BACKGROUND: In Australia generally, smoking prevalence more than halved after 1980 and recently commenced to decline among Australia's disadvantaged Indigenous peoples. However, in some remote Indigenous Australian communities in the Northern Territory (NT), extremely high rates of up to 83% have not changed over the past 25 years. The World Health Organisation has called for public health and political leadership to address a global tobacco epidemic. For Indigenous Australians, unprecedented policies aim to overcome disadvantage and close the 'health gap' with reducing tobacco use the top priority. This study identifies challenges and opportunities to implementing these important new tobacco initiatives in remote Indigenous communities. METHODS: With little empirical evidence available, we interviewed 82 key stakeholders across the NT representing operational- and management-level service providers, local Indigenous and non Indigenous participants to identify challenges and opportunities for translating new policies into successful tobacco interventions. Data were analysed using qualitative approaches to identify emergent themes. RESULTS: The 20 emergent themes were classified using counts of occasions each theme occurred in the transcribed data as challenge or opportunity. The 'smoke-free policies' theme occurred most frequently as opportunity but infrequently as challenge while 'health workforce capacity' occurred most frequently as challenge but less frequently as opportunity, suggesting that policy implementation is constrained by lack of a skilled workforce. 'Smoking cessation support' occurred frequently as opportunity but also frequently as challenge suggesting that support for individuals requires additional input and attention. CONCLUSIONS: These results from interviews with local and operational-level participants indicate that current tobacco policies in Australia targeting Indigenous smoking are sound and comprehensive. However, for remote Indigenous Australian communities, local and operational-level participants' views point to an 'implementation gap'. Their views should be heard because they are in a position to provide practical recommendations for effective policy implementation faithful to its design, thereby translating sound policy into meaningful action. Some recommendations may also find a place in culturally diverse low- and middle-income countries. Key words: tobacco policy implementation, challenges, opportunities, remote Indigenous Australian communities. PMID- 22839198 TI - A national survey into perioperative anesthetic management of patients with a fractured neck of femur. AB - BACKGROUND: We made a survey among Finnish anesthesiologists concerning the current perioperative anesthetic practice of hip fracture patients for further development in patient care. METHODS: All members of the Finnish Society of Anesthesiologists with a known e-mail address (786) were invited to participate in an internet-based survey. RESULTS: The overall response rate was 55% (423 responses); 298 respondents participated in the care of hip fracture patients. Preoperative analgesia was mostly managed with oxycodone and paracetamol; every fifth respondent applied an epidural infusion. Most respondents (98%) employed a spinal block with or without an epidural catheter for intraoperative anesthesia. Midazolam, propofol and/or fentanyl were used for additional sedation. General anesthesia was used rarely. Postoperatively, paracetamol and non-steroidal anti inflammatory drugs and occasionally peroral oxycodone, were prescribed in addition to epidural analgesia. CONCLUSIONS: The survey suggests that the impact of more individualised analgesia regimens, both preoperatively and postoperatively, should be investigated in further studies. PMID- 22839199 TI - BetaSearch: a new method for querying beta-residue motifs. AB - BACKGROUND: Searching for structural motifs across known protein structures can be useful for identifying unrelated proteins with similar function and characterising secondary structures such as beta-sheets. This is infeasible using conventional sequence alignment because linear protein sequences do not contain spatial information. beta-residue motifs are beta-sheet substructures that can be represented as graphs and queried using existing graph indexing methods, however, these approaches are designed for general graphs that do not incorporate the inherent structural constraints of beta-sheets and require computationally expensive filtering and verification procedures. 3D substructure search methods, on the other hand, allow beta-residue motifs to be queried in a three-dimensional context but at significant computational costs. FINDINGS: We developed a new method for querying beta-residue motifs, called BetaSearch, which leverages the natural planar constraints of beta-sheets by indexing them as 2D matrices, thus avoiding much of the computational complexities involved with structural and graph querying. BetaSearch exhibits faster filtering, verification, and overall query time than existing graph indexing approaches whilst producing comparable index sizes. Compared to 3D substructure search methods, BetaSearch achieves 33 and 240 times speedups over index-based and pairwise alignment-based approaches, respectively. Furthermore, we have presented case-studies to demonstrate its capability of motif matching in sequentially dissimilar proteins and described a method for using BetaSearch to predict beta-strand pairing. CONCLUSIONS: We have demonstrated that BetaSearch is a fast method for querying substructure motifs. The improvements in speed over existing approaches make it useful for efficiently performing high-volume exploratory querying of possible protein substructural motifs or conformations. BetaSearch was used to identify a nearly identical beta residue motif between an entirely synthetic (Top7) and a naturally-occurring protein (Charcot-Leyden crystal protein), as well as identifying structural similarities between biotin-binding domains of avidin, streptavidin and the lipocalin gamma subunit of human C8. PMID- 22839200 TI - Clinical outcomes of HER2-positive metastatic breast cancer patients with brain metastasis treated with lapatinib and capecitabine: an open-label expanded access study in Korea. AB - BACKGROUND: To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP). METHODS: LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m(2) daily in two divided doses, days 1-14, every 21 days and lapatinib 1250 mg once daily. RESULTS: Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P = 0.88). In patients with BM, brain response was synchronized with systemic responses (P = 0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P = 0.23). Multivariable analysis found hormone receptor positivity (P = 0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P < 0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P = 0.03) and longer trastuzumab use (P = 0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM. CONCLUSION: Lapatinib plus capecitabine is equally effective in patients with or without BM. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00338247). PMID- 22839201 TI - Optimal control simulation of field-free molecular orientation: alignment enhanced molecular orientation. AB - Nonresonant optimal control simulation is applied to a CO molecule to design two color phase-locked laser pulses (800 nm + 400 nm) with the aim of orienting the molecule under the field-free condition. The optimal pulse consists of two subpulses: the first subpulse aligns the molecule and the second one orients it. The molecular alignment induced by the first subpulse considerably enhances the degree of orientation, the value of which is close to an ideal value at temperature T = 0 K. To confirm the effectiveness of this alignment-enhanced orientation mechanism, we adopt a set of model Gaussian pulses and calculate the maximum degrees of orientation as a function of the delay time and the intensity. In finite-temperature (T = 3.0 K and T = 5.0 K) cases, although the alignment subpulse can improve the degree of orientation, the control achievement decreases with temperature rapidly; this decrease can be attributed to the initial-state dependent (phase-shifted) rotational wave packet motion. PMID- 22839202 TI - Computational modeling of the bHLH domain of the transcription factor TWIST1 and R118C, S144R and K145E mutants. AB - BACKGROUND: Human TWIST1 is a highly conserved member of the regulatory basic helix-loop-helix (bHLH) transcription factors. TWIST1 forms homo- or heterodimers with E-box proteins, such as E2A (isoforms E12 and E47), MYOD and HAND2. Haploinsufficiency germ-line mutations of the twist1 gene in humans are the main cause of Saethre-Chotzen syndrome (SCS), which is characterized by limb abnormalities and premature fusion of cranial sutures. Because of the importance of TWIST1 in the regulation of embryonic development and its relationship with SCS, along with the lack of an experimentally solved 3D structure, we performed comparative modeling for the TWIST1 bHLH region arranged into wild-type homodimers and heterodimers with E47. In addition, three mutations that promote DNA binding failure (R118C, S144R and K145E) were studied on the TWIST1 monomer. We also explored the behavior of the mutant forms in aqueous solution using molecular dynamics (MD) simulations, focusing on the structural changes of the wild-type versus mutant dimers. RESULTS: The solvent-accessible surface area of the homodimers was smaller on wild-type dimers, which indicates that the cleft between the monomers remained more open on the mutant homodimers. RMSD and RMSF analyses indicated that mutated dimers presented values that were higher than those for the wild-type dimers. For a more careful investigation, the monomer was subdivided into four regions: basic, helix I, loop and helix II. The basic domain presented a higher flexibility in all of the parameters that were analyzed, and the mutant dimer basic domains presented values that were higher than the wild type dimers. The essential dynamic analysis also indicated a higher collective motion for the basic domain. CONCLUSIONS: Our results suggest the mutations studied turned the dimers into more unstable structures with a wider cleft, which may be a reason for the loss of DNA binding capacity observed for in vitro circumstances. PMID- 22839204 TI - Relationship between colon and kidney: a critical point for percutaneous procedures. AB - OBJECTIVE: The aim of this study was to determine the frequency of anatomical variations of the colon associated with the kidney. MATERIAL AND METHODS: A retrospective analysis was performed on 1000 consecutive abdominal computed tomography (CT) scans performed between July 2010 and September 2011. A line parallel to the horizontal plane was drawn through the posterior edge of each kidney at three renal levels: upper, middle and lower pole. The bowel between the psoas muscle and the kidney was determined as the interposition of the colon. The amount of perinephric fat was estimated and graded. RESULTS: The total number of patients undergoing CT scans was 1000 (male/female = 510/490). The mean age of patients was 42.2 years. Seventeen patients (1.7%) had retrorenal colon, of which 12 (1.2%) were on the left side, three (0.3%) on the right side and two (0.2%) were bilateral. Of these 17 cases, 11 were found at the lower, two at the middle and four at the upper pole of the kidney. There was grade I perirenal fat tissue in 13 and grade II in four cases. Interposition of the colon was detected in 32 (3.2%) patients, 30 (3%) on the right and two (0.2%) on the left. The grade of perirenal fat tissue in patients with colon interposition was as follows: 25 patients grade I, six patients grade II and one patient grade III. CONCLUSIONS: In accessing the lower pole of the kidney, especially on the left side, the risk of colonic injury should be taken into consideration during percutaneous procedures, regardless of the patient's age and gender. PMID- 22839206 TI - Quantity of documentation of maltreatment risk factors in injury-related paediatric hospitalisations. AB - BACKGROUND: While child maltreatment is recognised as a global problem, solid epidemiological data on the prevalence of child maltreatment and risk factors associated with child maltreatment is lacking in Australia and internationally. There have been recent calls for action to improve the evidence-base capturing and describing child abuse, particularly those data captured within the health sector. This paper describes the quantity of documentation of maltreatment risk factors in injury-related paediatric hospitalisations in Queensland, Australia. METHODS: This study involved a retrospective medical record review, text extraction and coding methodology to assess the quantity of documentation of risk factors and the subsequent utility of data in hospital records for describing child maltreatment and data linkage to Child Protection Service (CPS). RESULTS: There were 433 children in the maltreatment group and 462 in the unintentional injury group for whom medical records could be reviewed. Almost 93% of the maltreatment code sample, but only 11% of the unintentional injury sample had documentation identified indicating the presence of any of 20 risk factors. In the maltreatment group the most commonly documented risk factor was history of abuse (41%). In those with an unintentional injury, the most commonly documented risk factor was alcohol abuse of the child or family (3%). More than 93% of the maltreatment sample also linked to a child protection record. Of concern are the 16% of those children who linked to child protection who did not have documented risk factors in the medical record. CONCLUSION: Given the importance of the medical record as a source of information about children presenting to hospital for treatment and as a potential source of evidence for legal action the lack of documentation is of concern. The details surrounding the injury admission and consideration of any maltreatment related risk factors, both identifying their presence and ruling them out are required for each and every case. This highlights the need for additional training for clinicians to understand the importance of their documentation in child injury cases. PMID- 22839205 TI - Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. AB - BACKGROUND: Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1) in oxaliplatin-induced acute hypersensitivity was investigated in mice. RESULTS: A single intraperitoneal administration of oxaliplatin (1-10 mg/kg) induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg), also induced acute cold hypersensitivity, while another platinum based chemotherapeutic agent, cisplatin (5 mg/kg), or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg) failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg) and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl isothiocyanate (AITC; TRPA1 agonist) were significantly enhanced in mice treated for 2 h with oxaliplatin (1-10 mg/kg) in a dose-dependent manner, while capsaicin (TRPV1 agonist)-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist)-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG) neurons with oxaliplatin (30-300 MUM) for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons. CONCLUSIONS: Taken together, these results suggest that a brief treatment with oxaliplatin or its metabolite oxalate is sufficient to enhance the responsiveness of TRPA1 but not that of TRPM8 and TRPV1 expressed by DRG neurons, which may contribute to the characteristic acute peripheral neuropathy induced by oxaliplatin. PMID- 22839207 TI - Permissive hypofiltration. AB - Acute kidney injury (AKI) is a syndrome with a multitude of causes and is associated with high mortality and a permanent loss of renal function. Our current understanding of the most common causes of AKI is limited, and thus a silver bullet therapy remains elusive. A change in the approach to AKI that shifts away from the primary composite endpoint of death/dialysis, and instead focuses on improving survival and mitigating permanent renal damage, is likely to be more fruitful. We suggest that the current approach of augmenting renal function by increasing the renal blood flow or glomerular filtration rate during AKI may actually worsen outcomes. Analogous to the approach towards adult respiratory distress syndrome that limits ventilator-induced lung injury, we propose the concept of permissive hypofiltration. The primary goals of this approach are: resting the kidney by providing early renal replacement therapy, avoiding the potentially injurious adverse events that occur during AKI (for example, fluid overload, hypophosphatemia, hypothermia, and so forth), and initiating therapies focused on improving survival and mitigating permanent loss of kidney function. PMID- 22839208 TI - Investigation of antibacterial properties silver nanoparticles prepared via green method. AB - BACKGROUND: This study aims to investigate the influence of different stirring times on antibacterial activity of silver nanoparticles in polyethylene glycol (PEG) suspension. The silver nanoparticles (Ag-NPs) were prepared by green synthesis method using green agents, polyethylene glycol (PEG) under moderate temperature at different stirring times. Silver nitrate (AgNO3) was taken as the metal precursor while PEG was used as the solid support and polymeric stabilizer. The antibacterial activity of different sizes of nanosilver was investigated against Gram-positive [Staphylococcus aureus] and Gram-negative bacteria [Salmonella typhimurium SL1344] by the disk diffusion method using Mueller-Hinton Agar. RESULTS: Formation of Ag-NPs was determined by UV-vis spectroscopy where surface plasmon absorption maxima can be observed at 412-437 nm from the UV-vis spectrum. The synthesized nanoparticles were also characterized by X-ray diffraction (XRD). The peaks in the XRD pattern confirmed that the Ag-NPs possessed a face-centered cubic and peaks of contaminated crystalline phases were unable to be located. Transmission electron microscopy (TEM) revealed that Ag-NPs synthesized were in spherical shape. The optimum stirring time to synthesize smallest particle size was 6 hours with mean diameter of 11.23 nm. Zeta potential results indicate that the stability of the Ag-NPs is increases at the 6 h stirring time of reaction. The Fourier transform infrared (FT-IR) spectrum suggested the complexation present between PEG and Ag-NPs. The Ag-NPs in PEG were effective against all bacteria tested. Higher antibacterial activity was observed for Ag-NPs with smaller size. These suggest that Ag-NPs can be employed as an effective bacteria inhibitor and can be applied in medical field. CONCLUSIONS: Ag NPs were successfully synthesized in PEG suspension under moderate temperature at different stirring times. The study clearly showed that the Ag-NPs with different stirring times exhibit inhibition towards the tested gram-positive and gram negative bacteria. PMID- 22839210 TI - Interference of the surface of the solid on the performance of tethered molecular catalysts. AB - The catalytic performance of cinchonidine in the promotion of thiol additions to conjugated ketones was used as a probe to assess the tethering of molecular functionality onto solid surfaces using well-known "click" chemistry involving easy-to-react linkers. It has been assumed in many applications that the tethered molecules retain their chemical properties and dominate the chemistry of the resulting solid systems, but it is shown here that this is not always the case. Indeed, a loss of enantioselectivity was observed upon tethering, which could be accounted for by a combination of at least three effects: (1) the nonselective catalytic activity of the surface of the solid itself; (2) the activity of the OH species generated by hydrolysis of some of the Si-alkoxy groups in the trialkoxy moieties used to bind many linkers to oxide surfaces; and (3) the bonding of the molecule to be tethered directly to the surface. Several ideas were also tested to minimize these problems, including the silylation of the active OH groups within the surface of the oxide support, the selection of solvents to optimize silane polymerization and minimize their breaking up via hydrolysis or alcoholysis reactions, and the linking at defined positions in the molecule to be tethered in order to minimize its ability to interact with the surface. PMID- 22839209 TI - Molecular epidemiology of drug resistance markers of Plasmodium falciparum in Yunnan Province, China. AB - BACKGROUND: The mutations in Plasmodium falciparum chloroquine resistance transporter (pfcrt), multidrug resistance 1 (pfmdr1), dihydrofolate reductase (pfdhfr), dihydropteroate synthase (pfdhps) and ATPase (pfatp6) genes were associated with anti-malaria drug resistance. The aim of this study was to investigate the prevalence of polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps and pfatp6 in Yunnan Province. Finger-prick blood samples were collected from malaria positive patients from Yunnan Province in 2009-2010. Single-nucleotide polymorphisms (SNPs) in the resistance-related genes were analysed by various PCR based methods. RESULTS: A total of 108 blood samples were collected. Although chloroquine has not been used to treat falciparum malaria for nearly 30 years, 95.3% of the parasites still carried the pfcrt K76T mutation, whereas the majority of isolates displayed the wild-type pfmdr1 N86 and D1246 sequences. The molecular level of sulphadoxine-pyrimethamine resistance in P. falciparum was high. The most prevalent mutation was pfdhfr C59R (95.9%), whereas the frequencies of the quadruple, triple and double mutants were 22.7% (N51I/C59R/S108N/I164L), 51.5% (N51I/C59R/S108N, N51I/C59R/I164L and C59R/S108N/ I164L) and 21.6% (N51I/ C59R, C59R/S108N and C59R/I164L), respectively. A437G (n = 77) and K540E (n = 71) were the most prevalent mutations in pfdhps, and 52.7% of the samples were double mutants, among which A437G/K540E was the most common double mutation (37/49). Quadruple mutants were found in 28.0% (26/93) of samples. A total of 8.6% of isolates (8/93) carried the S436A/A437G/A581G triple mutation. No mutations were found in pfatp6 codons 623 or 769, but another two mutations (N683K and R756K) were found in 4.6% (3/97) and 9.2% (6/97) of parasite isolates, respectively. CONCLUSIONS: This study identified a high frequency of mutations in pfcrt, pfdhfr and pfdhps associated with CQ and SP resistance in P. falciparum and no mutations linked to artemisinin resistance (pfatp6). Molecular epidemiology should be included in routine surveillance protocols and used to provide complementary information to assess the appropriateness of the current national anti-malarial drug policy. PMID- 22839211 TI - Reusable nanostencils for creating multiple biofunctional molecular nanopatterns on polymer substrate. AB - In this paper, we demonstrate a novel method for high throughput patterning of bioprobes with nanoscale features on biocompatible polymer substrate. Our technique, based on nanostencil lithography, employs high resolution and robust masks integrated with array of reservoirs. We show that the smallest pattern size can reach down to 100 nm. We also show that different types of biomolecules can be patterned on the same substrate simultaneously. Furthermore, the stencil can be reused multiple times to generate a series of identical patterns at low cost. Finally, we demonstrate that biomolecules can be covalently patterned on the surface while retaining their biofunctionalities. By offering the flexibility on the nanopattern design and enabling the reusability of the stencil, our approach significantly simplifies the bionanopatterning process and therefore could have profound implications in diverse biological and medical applications. PMID- 22839212 TI - Diversity of anopheline species and their Plasmodium infection status in rural Bandarban, Bangladesh. AB - BACKGROUND: Historically, the Chittagong Hill Tracts (CHT) of Bangladesh was considered hyperendemic for malaria. To better understand the contemporary malaria epidemiology and to develop new and innovative control strategies, comprehensive epidemiologic studies are ongoing in two endemic unions of Bandarban district of CHT. Within these studies entomological surveillance has been undertaken to study the role of the existing anopheline species involved in the malaria transmission cycle throughout the year. METHODS: CDC miniature light traps were deployed to collect anopheline mosquitoes from the sleeping room of the selected houses each month in a single union (Kuhalong). Molecular identification was carried out for available Anopheles species complexes. Circumsporozoite proteins (CSP) for Plasmodium falciparum, Plasmodium vivax-210 (Pv-210) and Plasmodium vivax-247(Pv-247) were detected by Enzyme-linked immunosorbent assay (ELISA) from the female anopheline mosquitoes. To confirm CSP ELISA results, polymerase chain reaction (PCR) was also performed. RESULTS: A total of 2,837 anopheline mosquitoes, of which 2,576 were female, belonging to 20 species were collected from July 2009-June 2010. Anopheles jeyporiensis was the most abundant species (18.9%), followed by An. vagus (16.8%) and An. kochi (14.4%). ELISA was performed on 2,467 female mosquitoes of 19 species. 15 (0.6%) female anophelines belonging to eight species were found to be positive for Plasmodium infection by CSP-ELISA. Of those, 11 (0.4%) mosquitoes were positive for P. falciparum and four (0.2%) for Pv-210. No mosquito was found positive for Pv-247. An. maculatus (2.1%, 2/97) had the highest infection rate followed by An. umbrosus (1.7%, 2/115) and An. barbirostris (1.1%, 2/186). Other infected species were An. nigerrimus, An. nivipes, An. jeyporiensis, An. kochi, and An. vagus. Out of 11 P. falciparum CSP positive samples, seven turned out to be positive by PCR. None of the samples positive for Pv-210 was positive by PCR. In terms of abundance and incrimination, the results suggest that An. maculatus, An. jeyporiensis and An. nivipes play important roles in malaria transmission in Kuhalong. CONCLUSION: The findings of this study suggest that even in the presence of an insecticide impregnated bed-net intervention, a number of Anopheles species still play a role in the transmission of malaria. Further investigations are required to reveal the detailed biology and insecticide resistance patterns of the vector mosquito species in endemic areas in Bangladesh in order to assist with the planning and implementation of improved malaria control strategies. PMID- 22839213 TI - Association of postmenopausal endogenous sex hormones with global methylation level of leukocyte DNA among Japanese women. AB - BACKGROUND: Although global hypomethylation of leukocyte DNA has been associated with an increased risk of several sites of cancer, including breast cancer, determinants of global methylation level among healthy individuals remain largely unexplored. Here, we examined whether postmenopausal endogenous sex hormones were associated with the global methylation level of leukocyte DNA. METHODS: A cross sectional study was conducted using the control group of a breast cancer case control study in Nagano, Japan. Subjects were postmenopausal women aged 55 years or over who provided blood samples. We measured global methylation level of peripheral blood leukocyte DNA by luminometric methylation assay; estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate, testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex-hormone binding globulin by immunoradiometric assay. A linear trend of association between methylation and hormone levels was evaluated by regression coefficients in a multivariable liner regression model. A total of 185 women were included in the analyses. RESULTS: Mean global methylation level (standard deviation) was 70.3% (3.1) and range was from 60.3% to 79.2%. Global methylation level decreased 0.27% per quartile category for estradiol and 0.39% per quartile category for estrone while it increased 0.41% per quartile category for bioavailable estradiol. However, we found no statistically significant association of any sex hormone level measured in the present study with global methylation level of leukocyte DNA. CONCLUSIONS: Our findings suggest that endogenous sex hormones are not major determinants of the global methylation level of leukocyte DNA. PMID- 22839214 TI - Upregulation of SATB1 is associated with the development and progression of glioma. AB - BACKGROUND: Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be expressed in several human cancers and may have malignant potential. This study was aimed at investigating the expression and potential role of SATB1 in human glioma. METHOD: The relationship between SATB1 expression, clinicopathological parameters, Ki67 expression and MGMT promoter methylation status was evaluated, and the prognostic value of SATB1 expression in patients with gliomas was analyzed. SATB1-specific shRNA sequences were synthesized, and U251 cells were transfected with SATB1 RNAi plasmids. Expression of SATB1 mRNA and protein was investigated by RT-PCR and immunofluoresence staining and western blotting. The expression of c-Met, SLC22A18, caspase-3 and bcl-2 protein was determined by western blotting. U251 cell growth and adherence was detected by methyl thiazole tetrazolium assay. The apoptosis of U251 cells was examined with a flow cytometer. The adherence, invasion, and in vitro angiogenesis assays of U251 cells were done. The growth and angiogenesis of SATB1 low expressing U251 cells was measured in an in vivo xenograft model. RESULTS: Of 70 tumors, 44 (62.9%) were positive for SATB1 expression. SATB1 expression was significantly associated with a high histological grade and with poor survival in univariate and multivariate analyses. SATB1 expression was also positively correlated with Ki67 expression but negatively with MGMT promoter methylation in glioma tissues. SATB1 shRNA expression vectors could efficiently induce the expression of SLC22A18 protein, increase the caspase-3 protein, inhibit the expression of SATB1, c-Met and bcl-2 protein, the growth, invasion, metastasis and angiogenesis of U251 cells, and induce apoptosis in vitro. Furthermore, the tumor growth of U251 cells expressing SATB1 shRNA were inhibited in vivo, and immunohistochemical analyses of tumor sections revealed a decreased vessel density in the animals where shRNA against SATB1 were expressed. CONCLUSIONS: SATB1 may have an important role as a positive regulator of glioma development and progression, and that SATB1 might be a useful molecular marker for predicting the prognosis of glioma. PMID- 22839216 TI - Are we growing more picky, more careless or simply under more pressure? PMID- 22839215 TI - Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: gene-environmental interaction with alcohol consumption. AB - BACKGROUND: Genetic variants near/within the ALDH2 gene encoding the mitochondrial aldehyde dehydrogenase 2 have been associated with blood pressure and hypertension in several case-control association studies in East Asian populations. METHODS: Three common tag single nucleotide polymorphisms (tagSNP) in the ALDH2 gene were genotyped in 1,134 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. We examined whether the ALDH2 SNP genotypes predicted the development of hypertension in the prospective SAPPHIRe cohort. RESULTS: Over an average follow-up period of 5.7 years, carriers homozygous for the rs2238152 T allele in the ALDH2 gene were more likely to progress to hypertension than were non-carriers (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.06-7.84, P = 0.03), corresponding to a population attributable risk of ~7.1%. The risk associated with the rs2238152 T allele were strongest in heavy/moderate alcohol drinkers and was reduced in non-drinkers, indicating an interaction between ALDH2 genetic variants and alcohol intake on the risk of hypertension (P for interaction = 0.04). The risk allele was associated with significantly lower ALDH2 gene expression levels in human adipose tissue. CONCLUSION: ALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption. PMID- 22839297 TI - Colon carcinoma in a child treated with oxaliplatin and antiangiogenic treatment regimens. AB - Colorectal carcinoma is an extremely rare tumor in childhood. Therefore, the role of adjuvant chemotherapy has not been adequately evaluated in children leading to limited data on safety profile and treatment response after application of novel drugs and novel targeted agents. In this report, we describe a case of colon adenocarcinoma in a 13-year-old girl treated with standard adult treatment as well as novel targeted therapy. This case report illustrates initial good disease control with FOLFOX therapy. On the other hand, targeted therapy revealed no improvement in disease control and good safety profile without significant adverse effects. PMID- 22839298 TI - Mesenchymal stem cells from the retropatellar fat pad and peripheral blood stimulate ACL fibroblast migration, proliferation, and collagen gene expression. AB - Mesenchymal stem cells (MSCs) have been of recent interest as adjuncts for ligament repair. However, the effect of these cells on the resident ligament fibroblasts has not yet been defined. In this study, we hypothesized that co culture of MSCs and ligament fibroblasts would result in increases in the proliferative rate of the ligament fibroblasts and their expression of collagen related genes, as well as differentiation of the MSCs down a fibroblastic pathway. In addition, we hypothesized that these effects would be dependent on the source of the MSCs. Porcine MSCs were isolated from both the retro-patellar fat pad (ADSCs) and the peripheral blood (PBMCs) and co-cultured with porcine anterior cruciate ligament (ACL) fibroblasts. Fibroblast migration, proliferation, and collagen gene expression were evaluated at time points up to 14 days. ADSCs had a greater effect on stimulating ACL-fibroblast proliferation and procollagen production, while PBMCs were more effective in stimulating ligament fibroblast migration. In addition, co-culture with the ACL fibroblasts led to significant increases in collagen gene expression for ADSCs, suggesting a differentiation of these cells down a fibroblastic pathway during the co-culture period. This was not seen for the PBMCs. Thus, the effects of MSCs on in situ ACL fibroblasts were found to be source dependent, and the choice of MSC source should take into account the different performance characteristic of each type of MSC. PMID- 22839299 TI - Dedifferentiated follicular granulosa cells derived from pig ovary can transdifferentiate into osteoblasts. AB - Transdifferentiation is the conversion of cells from one differentiated cell type into another. How functionally differentiated cells already committed to a specific cell lineage can transdifferentiate into other cell types is a key question in cell biology and regenerative medicine. In the present study we show that porcine ovarian follicular GCs (granulosa cells) can transdifferentiate into osteoblasts in vitro and in vivo. Pure GCs isolated and cultured in Dulbecco's modified Eagle's medium supplemented with 20% FBS (fetal bovine serum) proliferated and dedifferentiated into fibroblast-like cells. We referred to these cells as DFOG (dedifferentiated follicular granulosa) cells. Microarray analysis showed that DFOG cells lost expression of GC-specific marker genes, but gained the expression of osteogenic marker genes during dedifferentiation. After osteogenic induction, DFOG cells underwent terminal osteoblast differentiation and matrix mineralization in vitro. Furthermore, when DFOG cells were transplanted subcutaneously into SCID mice, these cells formed ectopic osteoid tissue. These results indicate that DFOG cells derived from GCs can differentiate into osteoblasts in vitro and in vivo. We suggest that GCs provide a useful model for studying the mechanisms of transdifferentiation into other cell lineages in functionally differentiated cells. PMID- 22839300 TI - Study protocol of a parent-focused child feeding and dietary intake intervention: the feeding healthy food to kids randomised controlled trial. AB - BACKGROUND: Poor childhood nutrition is a more pervasive and insidious risk factor for lifestyle-related chronic disease than childhood obesity. Parents find it difficult to address the reported barriers to optimal child feeding, and to improve child dietary patterns. To impact at the population level, nutrition interventions need to be easy to disseminate, have a broad reach and appeal to parents while overcoming the barriers parents face when trying to improve child feeding behaviours. The Feeding Healthy Food to Kids (FHFK) Randomised Control Trial (RCT) examines the impact of providing low cost, self-directed nutrition and parenting resources to rural parents, on child dietary intake and parent child feeding practices. METHODS/DESIGN: Up to 150 parents of two-to-five year old children will be recruited in five rural Australian towns. Eligible, consenting parents will be randomly allocated to intervention or 12-month wait list control groups. Intervention group parents will receive an interactive nutrition CD and parenting DVD, and be provided with instructions for optimal resource utilisation. Intervention and control group participants will also receive a generic nutrition and physical activity brochure and a physical activity resource to blind participants to group allocation. Primary outcome measures are dietary intake of vegetables (serves/day), fruit and energy dense nutrient poor foods (serves/day and %Energy). Secondary outcome measures are total energy (kCal), other food groups (serves/day and %Energy), key nutrients (mg/day), child feeding domains and parenting style domains.Analysis of dietary outcome measures, child feeding and parenting domains will be conducted on an intention-to-treat basis and compared at baseline, three and 12 months using the random effects model, using STATA software. Details of the methodological aspects of recruitment, inclusion criteria, randomisation and statistical analysis are described. DISCUSSION: This paper will add to existing research examining child feeding practices and dietary intake of young children, by specifically focusing on the efficacy of an RCT that has the potential to be implemented at a population level. The correlation of the RCT outcomes with parents' perceptions about child feeding practices and children's dietary intake of their children in a subsequent qualitative study will further contribute to this emerging area of research. TRIAL REGISTRATION: Australian Clinical Trials Registration Number: ACTRN12609000356268. PMID- 22839301 TI - Functional divergence of gene duplicates - a domain-centric view. AB - BACKGROUND: Gene duplicates have been shown to evolve at different rates. Here we further investigate the mechanism and functional underpinning of this phenomenon by assessing asymmetric evolution specifically within functional domains of gene duplicates. RESULTS: Based on duplicate genes in five teleost fishes resulting from a whole genome duplication event, we first show that a Fisher Exact test based approach to detect asymmetry is more sensitive than the previously used Likelihood Ratio test. Using our Fisher Exact test, we found that the evolutionary rate asymmetry in the overall protein is largely explained by the asymmetric evolution within specific protein domains. Moreover, among cases of asymmetrically evolving domains, for the gene copy containing a fast evolving domain, the non-synonymous substitutions often cluster within the fast evolving domain. We found that rare substitutions were preferred within asymmetrically evolving domains suggestive of functional divergence. While overall ~32 % of the domains tested were found to be evolving asymmetrically, certain protein domains such as the Tyrosine and Ser/Thr Kinase domains had a much greater prevalence of asymmetric evolution. Finally, based on the spatial expression of Zebra fish duplicate proteins during development, we found that protein pairs containing asymmetrically evolving domains had a greater divergence in gene expression as compared to the duplicate proteins that did not exhibit asymmetric evolution. CONCLUSIONS: Taken together, our results suggest that the previously observed asymmetry in the overall duplicate protein evolution is largely due to divergence of specific domains of the protein, and coincides with divergence in spatial expression domains. PMID- 22839302 TI - Clinical review: Traumatic brain injury in patients receiving antiplatelet medication. AB - As the population ages, emergency physicians are confronted with a growing number of trauma patients receiving antithrombotic and antiplatelet medication prior to injury. In cases of traumatic brain injury, pre-injury treatment with anticoagulants has been associated with an increased risk of posttraumatic intracranial haemorrhage. Since high age itself is a well-recognised risk factor in traumatic brain injury, this population is at special risk for increased morbidity and mortality. The effects of antiplatelet medication on coagulation pathways in posttraumatic intracranial haemorrhage are not well understood, but available data suggest that the use of these agents increases the risk of an unfavourable outcome, especially in cases of severe traumatic brain injury. Standard laboratory investigations are insufficient to evaluate platelet activity, but new assays for monitoring platelet activity have been developed. Commonly used interventions to restore platelet activity include platelet transfusion and application of haemostatic drugs. Nevertheless, controlled clinical trials have not been carried out and, therefore, clinical practice guidelines are not available. In addition to the risks of the acute trauma, patients are at risk for cardiac events such as life-threatening stent thrombosis if antiplatelet therapy is withdrawn. In this review article, we summarize the pathophysiologic mechanisms of the most commonly used antiplatelet agents and analyse results of studies on the effects of this treatment on patients with traumatic brain injury. Additionally, we focus on opportunities to counteract antiplatelet effects in those patients as well as on considerations regarding the withdrawal of antiplatelet therapy. In those chronically ill patients, an interdisciplinary approach involving intensivists, neurosurgeons as well as cardiologists is often mandatory. PMID- 22839303 TI - Ice growth from supercooled aqueous solutions of benzene, naphthalene, and phenanthrene. AB - Classical molecular dynamics (MD) were performed to investigate the growth of ice from supercooled aqueous solutions of benzene, naphthalene, or phenanthrene. The main objective of this study is to explore the fate of those aromatic molecules after freezing of the supercooled aqueous solutions, i.e., if these molecules become trapped inside the ice lattice or if they are displaced to the QLL or to the interface with air. Ice growth from supercooled aqueous solutions of benzene, naphthalene, or phenanthrene result in the formation of quasi-liquid layers (QLLs) at the air/ice interface that are thicker than those observed when pure supercooled water freezes. Naphthalene and phenanthrene molecules in the supercooled aqueous solutions are displaced to the air/ice interface during the freezing process at both 270 and 260 K; no incorporation of these aromatics into the ice lattice is observed throughout the freezing process. Similar trends were observed during freezing of supercooled aqueous solutions of benzene at 270 K. In contrast, a fraction of the benzene molecules become trapped inside the ice lattice during the freezing process at 260 K, with the rest of the benzene molecules being displaced to the air/ice interface. These results suggest that the size of the aromatic molecule in the supercooled aqueous solution is an important parameter in determining whether these molecules become trapped inside the ice crystals. Finally, we also report potential of mean force (PMF) calculations aimed at studying the adsorption of gas-phase benzene and phenanthrene on atmospheric air/ice interfaces. Our PMF calculations indicate the presence of deep free energy minima for both benzene and phenanthrene at the air/ice interface, with these molecules adopting a flat orientation at the air/ice interface. PMID- 22839305 TI - Prophylactic treatment of flea-infested cats with an imidacloprid/flumethrin collar to forestall infection with Dipylidium caninum. AB - BACKGROUND: The objective of the study was to determine the sustained effectiveness of 10% imidacloprid (w/w) and 4.5% flumethrin (w/w) incorporated in a slow-release matrix collar in preventing Dipylidium caninum infection in cats following repeated laboratory-infestations with fleas infected with metacestodes. METHODS: Efficacy against infection with D. caninum was evaluated by infesting 16 cats with the flea Ctenocephalides felis felis infected with metacestodes of the tapeworm. Medicated collars were fitted to 8 of the cats and infestation of each cat with 200 fleas from a suitably infected batch commenced 7 days later and continued at weekly intervals until Day 28. Efficacy against fleas was evaluated 24 h after each infestation. Infection of the cats with D. caninum was verified by daily examination of the cats' faeces and immediate surroundings for proglottids from Day 21 to Day 60. Calculation of the prophylactic effectiveness of the collars in preventing infection of the cats with D. caninum was based on the difference in the geometric mean number of scoleces recovered from the gastrointestinal tracts of collared compared to untreated cats at necropsy on Day 61. RESULTS: Efficacy of the collars against infestation of the cats with fleas was 99.9% on Day 7 and 100% at each subsequent weekly assessment. Infection of the fleas with metacestodes was >=40% in 7 to 13 day old fleas, but progressively decreased thereafter. At necropsy all the control cats were infected with D. caninum and harboured between 19 and 346 scoleces with a geometric mean of 58.3. A single treated cat was infected and harboured 2 scoleces. Effective prevention of infection with D. caninum, based on a comparison of the geometric mean numbers of scoleces recovered from control and treated cats, was 99.7%. CONCLUSION: The insecticidal components of the medicated collars are capable of rapidly eliminating newly-acquired infestations of fleas that are infected with the metacestodes of D. caninum, thus preventing infection with the cestode in collared cats. PMID- 22839306 TI - Morphology and thermodynamic properties of a copolymer with an electronically conducting block: poly(3-ethylhexylthiophene)-block-poly(ethylene oxide). AB - We report on the synthesis and morphology of a block copolymer, poly(3-(2' ethylhexyl)thiophene)-b-poly(ethylene oxide) (P3EHT-b-PEO), that conducts both electrons and ions. We show that in the melt state the P3EHT-b-PEO chains self assemble to produce traditional nanoscale morphologies such as lamellae and gyroid. This is in contrast to a majority of previous studies on copolymers with electronically conducting blocks wherein a nanofibrillar morphology is obtained. Our approach enables estimation of the Flory-Huggins interaction parameter, chi. The segregation strength between the two blocks is controlled through the addition of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI). For the salt free sample, the gyroid morphology, obtained in the melt state, is transformed into lamellae below the melting temperature of the P3EHT block. This is due to the "breaking out" of the crystalline phase. For the salt-containing sample, P3EHT-b-PEO has a lamellar morphology in both melt and crystalline states (confined crystallization). PMID- 22839304 TI - Peripheral nerve injury increases glutamate-evoked calcium mobilization in adult spinal cord neurons. AB - BACKGROUND: Central sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We used Fura-2 AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ to test the hypotheses that: 1. Exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice; 2. Glutamate-evoked Ca2+ mobilization is associated with spontaneous and/or evoked action potentials; 3. Glutamate acts at glutamate receptor subtypes to evoked Ca2+ transients; and 4. The magnitude of glutamate-evoked Ca2+ responses increases in the setting of peripheral neuropathic pain. RESULTS: Bath-applied glutamate robustly increased [Ca2+]i in 14.4 +/- 2.6 cells per dorsal horn within a 440 x 330 um field-of view, with an average time-to-peak of 27 s and decay of 112 s. Repeated application produced sequential responses of similar magnitude, indicating the absence of sensitization, desensitization or tachyphylaxis. Ca2+ transients were glutamate concentration-dependent with a Kd = 0.64 mM. Ca2+ responses predominantly occurred on neurons since: 1) Over 95% of glutamate-responsive cells did not label with the astrocyte marker, SR-101; 2) 62% of fura-2 AM loaded cells exhibited spontaneous action potentials; 3) 75% of cells that responded to locally-applied glutamate with a rise in [Ca2+]i also showed a significant increase in AP frequency upon a subsequent glutamate exposure; 4) In experiments using simultaneous on-cell recordings and Ca2+ imaging, glutamate elicited a Ca2+ response and an increase in AP frequency. AMPA/kainate (CNQX)- and AMPA (GYKI 52466)-selective receptor antagonists significantly attenuated glutamate-evoked increases in [Ca2+]i, while NMDA (AP-5), kainate (UBP-301) and class I mGluRs (AIDA) did not. Compared to sham controls, peripheral nerve injury significantly decreased mechanical paw withdrawal threshold and increased glutamate-evoked Ca2+ signals. CONCLUSIONS: Bulk-loading fura-2 AM into spinal cord slices is a successful means for determining glutamate-evoked Ca2+ mobilization in naive adult dorsal horn neurons. AMPA receptors mediate the majority of these responses. Peripheral neuropathic injury potentiates Ca2+ signaling in dorsal horn. PMID- 22839307 TI - Inhibition of Listeria monocytogenes ATCC 19115 on ham steak by tea bioactive compounds incorporated into chitosan-coated plastic films. AB - BACKGROUND: The consumer demands for better quality and safety of food products have given rise to the development and implementation of edible films. The use of antimicrobial films can be a promising tool for controlling L. monocytogenes on ready to eat products. The aim of this study was to develop effective antimicrobial films incorporating bioactive compounds from green and black teas into chitosan, for controlling L. monocytogenes ATCC 19115 on vacuum-packaged ham steak. The effectiveness of these antimicrobial films was evaluated at room temperature (20 degrees C) for 10 days and at refrigerated temperature (4 degrees C) for 8 weeks. RESULTS: The HPLC results clearly show that relative concentrations of catechins and caffeine in green tea ranked EGCG>EGC>CAF>ECG>EC>C while in black tea extracts ranked CAF>EGCG>ECG>EGC>EC>C. The chitosan-coated plastic films incorporating green tea and black tea extracts shows specific markers identified by FTIR. Incorporating natural extracts into chitosan showed that the growth of L monocytogenes ATCC 19115 was inhibited. The efficacy of antimicrobial effect of tea extracts incorporated into chitosan coated plastic film was dose dependent. However, chitosan-coated films without addition of tea extracts did not inhibit the growth of L. monocytogenes ATCC 19115. Chitosan-coated plastic films incorporating 4% Green tea extract was the most effective antimicrobial, reducing the initial counts from 3.2 to 2.65 log CFU/cm2 during room temperature storage and from 3.2 to 1-1.5 log CFU/cm2 during refrigerated storage. CONCLUSIONS: Incorporation of tea extracts into the chitosan-coated films considerably enhanced their effectiveness against L. monocytogenes ATCC 19115. 4% Green tea incorporated into chitosan-coated plastic film had a better antilisterial effect than 2% green tea or 2% and 4% black tea. Data from this study would provide new formulation options for developing antimicrobial packaging films using tea extracts to improve the microbiological safety and quality of ham steak during room and refrigerated storage. PMID- 22839351 TI - The economic benefits of malaria elimination: do they include increases in tourism? AB - BACKGROUND: Policy makers have speculated that one of the economic benefits of malaria elimination includes increases in foreign direct investment, particularly tourism. METHODS: This study examines the empirical relationship between the demand for travel and malaria cases in two countries with large tourism industries around the time in which they carried out malaria-elimination campaigns. In Mauritius, this analysis examines historical, yearly tourist arrivals and malaria cases from 1978-1999, accounting for the background secular trend of increasing international travel. In Dominican Republic, a country embarking upon malaria elimination, it employs a time-series analysis of the monthly, international tourist arrivals from 1998-2010 to determine whether the timing of significant deviations in tourist arrivals coincides with malaria outbreaks. RESULTS: While naive relationships exist in both cases, the results show that the relationships between tourist arrivals and malaria cases are relatively weak and statistically insignificant once secular confounders are accounted for. CONCLUSIONS: This suggests that any economic benefits from tourism that may be derived from actively pursuing elimination in countries that have high tourism potential are likely to be small when measured at a national level. Rather, tourism benefits are likely to be experienced with greater impact in more concentrated tourist areas within countries, and future studies should seek to assess these relationships at a regional or local level. PMID- 22839352 TI - High-performance graphene-titania platform for detection of phosphopeptides in cancer cells. AB - Phosphopeptides play a crucial role in many biological processes and constitute some of the most powerful biomarkers in disease detection. However they are often present in very low concentration, which makes their detection highly challenging. Here, we demonstrate the use of a solution-dispersible graphene titania platform for the selective extraction of phosphopeptides from peptide mixtures. This is followed by direct analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The efficient charge and energy exchange between graphene and TiO(2) during laser irradiation in SELDI-TOF MS promotes the soft ionization of analytes and affords a detection limit in the attomole range, which is 10(2)-10(5) more sensitive than conventional platforms. The graphene-titania platform can also be used for detecting phosphopeptides in cancer cells (HeLa cells), where it shows high specificity (94%). An expanded library of 967 unique phosphopeptides is detected using significantly reduced loading of extraction matrixes compared to conventional TiO(2) bead-based assays. PMID- 22839353 TI - Social organization of self-management support of persons with diabetes: a health systems comparison. AB - OBJECTIVE: Identify important organizational elements for providing self management support (SMS). DESIGN: Semi-structured qualitative interviews conducted in two healthcare systems. SETTING: Kaiser Permanente Northern California and the Danish Health Care System. SUBJECTS: 36 managers and healthcare professionals in the two healthcare systems. MAIN OUTCOME MEASURES: Elements important to providing self-management support to persons with diabetes. RESULTS: Healthcare professionals' provision of SMS was influenced by healthcare system organization and their perceptions of SMS, the capability and responsibility of healthcare systems, and their roles in the healthcare organization. Enabling factors for providing SMS included: strong leadership; aligned incentives; use of an integrated health information technology (HIT) system; multidisciplinary healthcare provider teams; ongoing training for healthcare professionals; outreach; and quality goals. Barriers to providing SMS included lack of collaboration between providers and skeptical attitudes towards prevention and outreach. CONCLUSIONS AND IMPLICATIONS: Implementation of SMS can be improved by an understanding of the elements that enhance its provision: (1) initiatives seeking to improve collaboration and integration between providers; (2) implementation of an integrated HIT system; and (3) ongoing training of healthcare professionals. PMID- 22839354 TI - Remarkably robust monomeric alkylperoxyzinc compounds from tris(oxazolinyl)boratozinc alkyls and O2. AB - Metal alkylperoxides are remarkable, highly effective, yet often thermally unstable, oxidants that may react through a number of possible pathways including O-O homolytic cleavage, M-O homolytic cleavage, nucleophilic O-atom transfer, and electrophilic O-atom transfer. Here we describe a series of zinc alkyl compounds of the type To(M)ZnR (To(M) = tris(4,4-dimethyl-2-oxazolinyl)phenylborate; R = Et, n-C3H7, i-C3H7, t-Bu) that react with O2 at 25 degrees C to form isolable monomeric alkylperoxides To(M)ZnOOR in quantitative yield. The series of zinc alkylperoxides is crystallographically characterized, and the structures show systematic variations in the Zn-O-O angle and O-O distances. The observed rate law for the reaction of To(M)ZnEt (2) and O2 is consistent with a radical chain mechanism, where the rate-limiting SH2 step involves the interaction of (*)OOR and To(M)ZnR. In contrast, To(M)ZnH and To(M)ZnMe are unchanged even to 120 degrees C under 100 psi of O2 and in the presence of active radical chains (e.g., (*)OOEt). This class of zinc alkylperoxides is unusually thermally robust, in that the compounds are unchanged after heating at 120 degrees C in solution for several days. Yet, these compounds are reactive as oxidants with phosphines. Additionally, an unusual alkylperoxy group transfer to organosilanes affords To(M)ZnH and ROOSiR3'. PMID- 22839355 TI - Discontinued drugs 2011: pulmonary, allergy, gastrointestinal and arthritis. AB - This is the annual perspective paper on the discontinued drugs in the field of pulmonary allergy, gastrointestinal, and arthritis conditions. It is part of series of papers discussing drugs discontinued from clinical development in the previous year and presented according to therapeutic indication. Specifically, this paper presents the 23 compounds developed for various inflammatory conditions and 10 pulmonary drugs which were discontinued in 2011. Information for this perspective was derived from a search of the Pharmaprojects database for drugs discontinued after reaching Phase-I - III clinical trials. PMID- 22839356 TI - Evaluating current automatic de-identification methods with Veteran's health administration clinical documents. AB - BACKGROUND: The increased use and adoption of Electronic Health Records (EHR) causes a tremendous growth in digital information useful for clinicians, researchers and many other operational purposes. However, this information is rich in Protected Health Information (PHI), which severely restricts its access and possible uses. A number of investigators have developed methods for automatically de-identifying EHR documents by removing PHI, as specified in the Health Insurance Portability and Accountability Act "Safe Harbor" method.This study focuses on the evaluation of existing automated text de-identification methods and tools, as applied to Veterans Health Administration (VHA) clinical documents, to assess which methods perform better with each category of PHI found in our clinical notes; and when new methods are needed to improve performance. METHODS: We installed and evaluated five text de-identification systems "out-of the-box" using a corpus of VHA clinical documents. The systems based on machine learning methods were trained with the 2006 i2b2 de-identification corpora and evaluated with our VHA corpus, and also evaluated with a ten-fold cross validation experiment using our VHA corpus. We counted exact, partial, and fully contained matches with reference annotations, considering each PHI type separately, or only one unique 'PHI' category. Performance of the systems was assessed using recall (equivalent to sensitivity) and precision (equivalent to positive predictive value) metrics, as well as the F(2)-measure. RESULTS: Overall, systems based on rules and pattern matching achieved better recall, and precision was always better with systems based on machine learning approaches. The highest "out-of-the-box" F(2)-measure was 67% for partial matches; the best precision and recall were 95% and 78%, respectively. Finally, the ten-fold cross validation experiment allowed for an increase of the F(2)-measure to 79% with partial matches. CONCLUSIONS: The "out-of-the-box" evaluation of text de identification systems provided us with compelling insight about the best methods for de-identification of VHA clinical documents. The errors analysis demonstrated an important need for customization to PHI formats specific to VHA documents. This study informed the planning and development of a "best-of-breed" automatic de-identification application for VHA clinical text. PMID- 22839357 TI - Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula. AB - BACKGROUND: Carotid cavernous fistulas are abnormal communications between the cavernous sinus and the external or internal carotid arteries. Although rare, closure of carotid cavernous fistulas can lead to immediate ocular complications. To our knowledge, our case represents the first report of worsening angle closure glaucoma and choroidal detachments over an extended period of two months subsequent to closure of a carotid cavernous fistula. CASE PRESENTATION: A 70 year-old female with a history of primary angle closure glaucoma presented with 4 mm of proptosis, resistance to retropulsion, tortuous corkscrew blood vessels and an orbital bruit of the right eye. Diagnostic cerebral angiogram showed a small indirect Barrow type D right carotid cavernous fistula. Transarterial embolization was planned but repeat cerebral angiography prior to the procedure demonstrated spontaneous partial closure of the carotid cavernous fistula and the procedure was aborted. One month later, our patient was noted to have worsening vision and choroidal detachments of the right eye. She declined further testing and was thus started on self-administered manual carotid jugular compressions. One month later, she developed progressive worsening of her choroidal detachments and angle closure. She eventually opted for surgical intervention but repeat cerebral angiography showed significant thrombosis of the carotid cavernous fistula and no intervention was warranted. Examination two months later showed complete resolution of the choroidal detachments and open angles of both eyes. CONCLUSIONS: Our patient demonstrated worsening angle closure glaucoma and choroidal detachments after spontaneous closure of her carotid cavernous fistula had been noted. Ocular complications, including acute angle closure, have been reported to occur immediately after closure of carotid cavernous fistulas, but not over months as in our patient. It is imperative that individuals who have undergone apparent closure of a carotid cavernous fistula be carefully monitored for worsening ocular complications. PMID- 22839358 TI - Prognostic significance of c-KIT in vulvar cancer: bringing this molecular marker from bench to bedside. AB - BACKGROUND: Vulvar carcinomas are rare tumors, and there is limited data regarding molecular alterations. To our knowledge there are no published studies on c-KIT and squamous cell carcinomas of the vulva (VSCC). Although there are a significant number of other tumor types which express c-KIT, there remains controversy as to its relationship to patient outcome. Thus, we wished to investigate such controversial findings to determine the prognostic importance of c-KIT by evaluating its protein and mRNA expression in VSCCs, correlating these findings with clinicopathological features and Human Papillomavirus (HPV) infection. METHODS: c-KIT expression was scored by immunohistochemistry (IHC) as positive or negative in 139 formalin-fixed paraffin-embedded (FFPE) cases of vulvar carcinomas arrayed in a tissue microarray (TMA) using the DAKO A4502 rabbit polyclonal c-KIT antibody (diluted 1:100). c-KIT mRNA was evaluated by qRT PCR in 34 frozen samples from AC Camargo Hospital Biobank (17 tumoral and 17 non tumoral samples) using TaqMan probes-Applied Biosystems [Hs00174029_m1]. HPV genotyping was assessed in 103 samples using Linear Array(r) HPV Genotyping Test kit (Roche Molecular Diagnostics, Basel, Switzerland). All results obtained were correlated with clinical and pathological data of the patients. RESULTS: c-KIT protein was positive by immunohistochemistry in 70.5% of the cases and this was associated with a higher global survival (p = 0.007), a higher recurrence-free survival (p < 0.0001), an absence of associated lesions (p = 0.001), lymph node metastasis (p = 0.0053), and HPV infection (p = 0.034). Furthermore, c-KIT mRNA quantitation revealed higher levels of transcripts in normal samples compared to tumor samples (p = 0,0009). CONCLUSIONS: Our findings indicate that those vulvar tumors staining positively for c-KIT present better prognosis. Thus, positivity of c-KIT as evaluated by IHC may be a good predictor for use of more conservative surgery techniques and lymph node dissection in vulvar cancer. So part of the essence of our study is to see the possibility of translating our current results from the bench to the bedside. This will help provide patients a more appropriate, less mutilating treatment, in order to keep the maximum physical and psychic quality as possible to these women. PMID- 22839359 TI - Sociodemographic and socioeconomic differences in sleep duration and insomnia related symptoms in Finnish adults. AB - BACKGROUND: Poor sleep tends to be patterned by sociodemographic and socioeconomic factors. The aim of this study was to examine the associations of sociodemographic and socioeconomic factors with sleep duration and insomnia related symptoms across life course. METHODS: We used cross-sectional Health 2000 Survey (2000-2001) among a total of 5,578 adult Finns, aged 30-79 years, representative of adult Finnish population. Data about sociodemographic and socioeconomic circumstances, insomnia-related symptoms over the previous month as well as average sleep duration were collected by questionnaires. Multinomial logistic regression models were adjusted first for gender and age, second for sociodemographic factors, third additionally for socioeconomic factors, and fourth for all covariates and self-perceived health simultaneously. RESULTS: On average 70% of Finnish adults slept 7-8 hours a day. Frequent insomnia-related symptoms were more prevalent among women (14%) than men (10%). Not being married, not having children, having low education, low income, being unemployed, and being a disability retiree were associated with frequent insomnia-related symptoms. Similar factors were associated with short and long sleep duration. However, childhood socioeconomic position was mostly unrelated to sleep in adulthood except parental education had some associations with short sleep duration. CONCLUSIONS: Disadvantaged socioeconomic position in adulthood, in particular income and employment status, is associated with poorer sleep. When promoting optimal sleep duration and better sleep quality, families with low incomes, unemployed people, and disability retirees should be targeted. PMID- 22839360 TI - Molecular structure of human GM-CSF in complex with a disease-associated anti human GM-CSF autoantibody and its potential biological implications. AB - Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1lambda autoantibody-binding fragment (Fab) at 1.9 A (1 A=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody. PMID- 22839362 TI - Patterning of two-level topographic cues for observation of competitive guidance of cell alignment. AB - Cells display contact guidance when cultured on topographical cues. By combining standard photolithography, nanoimprint lithography, and soft lithography, we produced sophisticated patterns on two levels, including crossing microgrooves with different depth/spacing and microgrooves with superimposed submicrometer features. The results show that for narrowly spaced microgrooves, the contact guidance is more significant to the change of groove depth than to other geometry parameters. For crossing microgrooves, the shallow grooves take over the influence on cell alignment when the deeper grooves are well separated. Finally, the superimposed submicrometer features on the groove ridges decrease the efficiency of the contact guidance of microgrooves, due to increased adhesion of cells on patterned surfaces. PMID- 22839361 TI - Evolution of specifier proteins in glucosinolate-containing plants. AB - BACKGROUND: The glucosinolate-myrosinase system is an activated chemical defense system found in plants of the Brassicales order. Glucosinolates are stored separately from their hydrolytic enzymes, the myrosinases, in plant tissues. Upon tissue damage, e.g. by herbivory, glucosinolates and myrosinases get mixed and glucosinolates are broken down to an array of biologically active compounds of which isothiocyanates are toxic to a wide range of organisms. Specifier proteins occur in some, but not all glucosinolate-containing plants and promote the formation of biologically active non-isothiocyanate products upon myrosinase catalyzed glucosinolate breakdown. RESULTS: Based on a phytochemical screening among representatives of the Brassicales order, we selected candidate species for identification of specifier protein cDNAs. We identified ten specifier proteins from a range of species of the Brassicaceae and assigned each of them to one of the three specifier protein types (NSP, nitrile-specifier protein, ESP, epithiospecifier protein, TFP, thiocyanate-forming protein) after heterologous expression in Escherichia coli. Together with nine known specifier proteins and three putative specifier proteins found in databases, we subjected the newly identified specifier proteins to phylogenetic analyses. Specifier proteins formed three major clusters, named AtNSP5-cluster, AtNSP1-cluster, and ESP/TFP cluster. Within the ESP/TFP cluster, specifier proteins grouped according to the Brassicaceae lineage they were identified from. Non-synonymous vs. synonymous substitution rate ratios suggested purifying selection to act on specifier protein genes. CONCLUSIONS: Among specifier proteins, NSPs represent the ancestral activity. The data support a monophyletic origin of ESPs from NSPs. The split between NSPs and ESPs/TFPs happened before the radiation of the core Brassicaceae. Future analyses have to show if TFP activity evolved from ESPs at least twice independently in different Brassicaceae lineages as suggested by the phylogeny. The ability to form non-isothiocyanate products by specifier protein activity may provide plants with a selective advantage. The evolution of specifier proteins in the Brassicaceae demonstrates the plasticity of secondary metabolism within an activated plant defense system. PMID- 22839363 TI - Influence of pH and oxidation state on the interaction of arsenic with struvite during mineral formation. AB - Struvite (MgNH(4)PO(4).6H(2)O) precipitated from animal and human wastes may be a sustainable source of fertilizer. However, arsenic, present in some wastes, may be removed with struvite. Here the sorption of As with struvite during mineral formation at pH 8-11 was assessed. The yield of struvite increased with pH, and was highest at pH 10. For recovered struvite, XRD indicated reduced crystallinity and particle size, and FT-IR suggested less distortion of phosphate tetrahedra with increased pH. The As impurity did not affect the crystallinity or particle size, but did contribute to phosphate distortion. Sorption of As(V) was observed at all pH values, and was highest at pH 10. As(III) sorption was consistently lower than that of As(V), but increased with pH. XAFS suggested coprecipitation of As(V), and adsorption of As(III) as the potential sorption mechanisms. Solids derived from As(III) solutions exhibited dual mechanisms due to the partial oxidation of As(III) to As(V) in solution prior to sorption. For struvite recovery in the presence of As, optimizing the pH to improve yields may increase the As content. Adsorbed As(III) could be removed prior to fertilizer application, however coprecipitated As(V) will release upon mineral decomposition, linking its cycling to that of phosphorus. PMID- 22839364 TI - An analysis of Sorghum halepense's behavior in presence of tropane alkaloids from Datura stramonium extracts. AB - BACKGROUND: This study aimed to quantify the allelopathic potential of Datura stramonium (Jimson weed). Sorghum halepense (Johnsongrass) tolerance was assessed by germinating, seed and growing seedlings, dosing of photo-synthesis pigments, followed by treatment with D. stramonium extract tropane alkaloids. RESULTS: Preliminary chemical analysis of the extracts showed the presence of alkaloids.The presence of alkaloids was confirmed through HPLC-UV system analysis. Various concentrations of analytic purity alkaloids had similar effects on germination and development of S. halepense's root systems with those of extracts from of D. stramonium. Germination was not affected by any of the tested extracts, but growth was inhibited by the presence of tropane alkaloids. Extracts had effects at higher alkaloid concentrations. Seedlings of S. halepense developed toxicity symptoms in the presence of alkaloid extracts, but the occurrence of several chlorotic and necrotic areas was noticed in the flower extract biotest. CONCLUSIONS: Results show that the tested species is sensitive to alkaloids in their growth environment. This research justifies the fact that aqueous extracts from D. stramonium are adequate to the situations in which S. halepense becomes damaging. PMID- 22839365 TI - Canine and feline parasitic zoonoses in China. AB - Canine and feline parasitic zoonoses have not been given high priority in China, although the role of companion animals as reservoirs for zoonotic parasitic diseases has been recognized worldwide. With an increasing number of dogs and cats under unregulated conditions in China, the canine and feline parasitic zoonoses are showing a trend towards being gradually uncontrolled. Currently, canine and feline parasitic zoonoses threaten human health, and cause death and serious diseases in China. This article comprehensively reviews the current status of major canine and feline parasitic zoonoses in mainland China, discusses the risks dogs and cats pose with regard to zoonotic transmission of canine and feline parasites, and proposes control strategies and measures. PMID- 22839366 TI - Syphilis in pregnancy in Tuscany, description of a case series from a global health perspective. AB - OBJECTIVE: To estimate the epidemiological impact of syphilis in pregnancy and congenital syphilis in Tuscany and to better delineate their determinants in this region. METHODS: Features of pregnant women with syphilis attending the Tuscany Reference Center for Infectious Diseases in Pregnancy between 2000 and 2010 and their infants were retrospectively reviewed. RESULTS: One hundred and eighty seven pregnancies were observed. The number of pregnancies evaluated increased steadily from 24 in 2000-2002 to 70 in 2009-2010. The majority of women were Italian (20.32%) and East European (44.39%). Eight cases of congenital syphilis were diagnosed (5.60% of pregnancies with known outcome). Italian women had more often an early stage of syphilis (11.76 vs. 1.34%; p = 0.016), an rapid plasma regain (RPR) title >= 1:8 (15.79 vs. 5.37%; p = 0.041) and a partner with positive test (60.00 vs. 21.69%; p < 0.001) compared with migrant women. Migrant women received treatment after the first trimester more often compared with Italian ones (40.94 vs. 18.42%; p = 0.013). CONCLUSIONS: Syphilis in pregnancy is emerging in Tuscany. Italian and migrant women with syphilis show two different "risk patterns" of vertical transmission. An additional screening test for syphilis in the third trimester and educational campaigns about maternal and sexual health could be effective in combating congenital syphilis in Italy. PMID- 22839367 TI - Youth sexual health improvement in Estonia, 1990-2009: the role of sexuality education and youth-friendly services. AB - OBJECTIVES: A new school curriculum was introduced in Estonia in 1996 comprising for the first time sexuality education (SE) topics. The first youth counselling centres (YCCs) addressing sexual health matters were set up in 1991-1992. This study describes the development of school-based SE and YCCs in 1992 - 2009, and explores the concurrent changes in sexuality-related knowledge, behaviour, and sexual health indicators. METHODS: The analyses are based on 12 population-based surveys. Data on births, abortions and sexually transmitted infections, including HIV, are taken from national registers. RESULTS: By the middle of the past decade SE was well established. There has been a trend towards younger age at first sexual intercourse, and increased usage of condoms and reliable contraceptive methods. The abortion rate among 15-19-year-olds declined by 61% and their fertility rate by 59%. The annual number of registered new HIV cases among 15-19 year-olds dropped from 560 in 2001 to 25 in 2009, new syphilis cases from 116 in 1998 to two in 2009, and gonorrhoea cases from 263 in 1998 to 20 in 2009. CONCLUSIONS: This study documents considerable improvements in sexual health indicators of youths, and indicates that these run parallel to the development of school-based SE and YCCs. PMID- 22839412 TI - Microwave spectra and barriers to internal rotation of Z- and E-1-propenyl isocyanide. AB - A synthetic procedure yielding a mixture of Z- and E-1-propenyl isocyanide (CH(3)CH?CHNC) is described. The microwave spectrum of this mixture has been recorded in the 12-100 GHz spectral range, and the spectra of the Z and E isomers have been assigned for the first time. Most transitions of the Z form were split into two components of equal intensity due to tunneling of the methyl group, which allowed the barrier to internal rotation of this group to be determined as 4.0124(12) kJ/mol by fitting 568 transitions with a maximum value of J = 46 using the computer program Xiam. This fit had a root-mean-square deviation as large as 4.325. The same transitions were therefore fitted anew using the more sophisticated program Erham. This fit has a rms deviation marginally better (4.136) than the Xiam fit. No split MW lines were found for E-1-propenyl isocyanide. The absence of splittings is ascribed to a barrier to internal rotation of the methyl group that is significantly higher than the barrier of the Z isomer. It is concluded that the barrier must be larger than 6 kJ/mol for the E form. The experimental work was augmented by quantum chemical calculations at CCSD/cc-pVTZ, B3LYP/cc-pVTZ, and MP2/cc-pVTZ levels of theory. The CCSD method predicts rotational constants of the Z and E forms well. The B3LYP barriers to internal rotation of a series of substituted propenes were calculated and found to be in good agreement with experiments. Calculations of the quartic centrifugal distortion constants of the two 1-propenyl isocyanides by the B3LYP and MP2 methods were less successful. PMID- 22839368 TI - Evaluation of peripapillary choroidal thickness in patients with normal-tension glaucoma. AB - BACKGROUND: To compare peripapillary choroidal thickness measurements between normal and normal-tension glaucoma eyes. METHODS: Cross-sectional comparative study. 50 normal and 52 normal-tension glaucoma subjects were enrolled in the study. Peripapillary choroidal thickness was measured with spectral-domain optical coherence tomography and enhanced depth imaging. After obtaining circular B-scans around the disc, choroidal thicknesses were calculated based on the exported segmentation values. Visual fields were measured using automated perimetry. Difference in peripapillary choroidal thickness between the normal subjects and the patients with normal-tension glaucoma was analyzed. RESULTS: There were no significant differences in age, axial length, or refraction between the two groups. Peripapillary choroidal thickness was inversely correlated with age in both the normal (r = -0.287, P = 0.04) and normal and normal-tension glaucoma (r = -0.322, P = 0.02) groups. Peripapillary choroidal thickness of inferonasal (125 vs 148 MUm, P < 0.05), inferior (101 vs 122 MUm, P < 0.05), or inferotemporal (100 vs 127 MUm, P < 0.05) regions were significantly thinner in the normal-tension glaucoma group as compared to normal subjects. Superior visual hemifield defect was significantly worse than inferior visual hemifield defect in normal and normal-tension glaucoma patients. CONCLUSION: As compared to normal subjects, peripapillary choroidal thickness was significantly thinner in the normal and normal-tension glaucoma patients, at least in some locations. PMID- 22839413 TI - Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care. AB - Erythropoietin (EPO) is known to have numerous biological functions. Its primary function in the body is to increase red blood cell numbers by way of preventing the apoptosis of erythroid progenitor cells via the homodimeric EPO receptor. The discovery that the local production of EPO within the brain in response to hypoxia or ischemia protects neurons against injury via an anti-apoptotic effect formed the basis of the hypothesis that the local generation of EPO limits the extent of injury. Although the hypothesis proved to be true in pre-clinical models of ischemia/reperfusion injury and inflammation, the randomized, controlled clinical trials that followed demonstrated serious adverse events of EPO due to activation of the hematopoietic system. Consequently, derivatives of EPO that lacked erythropoietic activity were discovered to reduce injury in many pre-clinical models associated with ischemia and inflammation. Unfortunately, there are no published clinical trials to determine the efficacy of non erythropoietic derivatives of EPO in humans. PMID- 22839415 TI - Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats. AB - BACKGROUND: The neural mobilization technique is a noninvasive method that has proved clinically effective in reducing pain sensitivity and consequently in improving quality of life after neuropathic pain. The present study examined the effects of neural mobilization (NM) on pain sensitivity induced by chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted thereafter to 10 sessions of NM, each other day, starting 14 days after the CCI injury. Over the treatment period, animals were evaluated for nociception using behavioral tests, such as tests for allodynia and thermal and mechanical hyperalgesia. At the end of the sessions, the dorsal root ganglion (DRG) and spinal cord were analyzed using immunohistochemistry and Western blot assays for neural growth factor (NGF) and glial fibrillary acidic protein (GFAP). RESULTS: The NM treatment induced an early reduction (from the second session) of the hyperalgesia and allodynia in CCI-injured rats, which persisted until the end of the treatment. On the other hand, only after the 4th session we observed a blockade of thermal sensitivity. Regarding cellular changes, we observed a decrease of GFAP and NGF expression after NM in the ipsilateral DRG (68% and 111%, respectively) and the decrease of only GFAP expression after NM in the lumbar spinal cord (L3-L6) (108%). CONCLUSIONS: These data provide evidence that NM treatment reverses pain symptoms in CCI-injured rats and suggest the involvement of glial cells and NGF in such an effect. PMID- 22839414 TI - Using two on-going HIV studies to obtain clinical data from before, during and after pregnancy for HIV-positive women. AB - BACKGROUND: The UK Collaborative HIV Cohort (UK CHIC) is an observational study that collates data on HIV-positive adults accessing HIV clinical care at (currently) 13 large clinics in the UK but does not collect pregnancy specific data. The National Study of HIV in Pregnancy and Childhood (NSHPC) collates data on HIV-positive women receiving antenatal care from every maternity unit in the UK and Ireland. Both studies collate pseudonymised data and neither dataset contains unique patient identifiers. A methodology was developed to find and match records for women reported to both studies thereby obtaining clinical and treatment data on pregnant HIV-positive women not available from either dataset alone. RESULTS: Women in UK CHIC receiving HIV-clinical care in 1996-2009, were found in the NSHPC dataset by initially 'linking' records with identical date-of birth, linked records were then accepted as a genuine 'match', if they had further matching fields including CD4 test date. In total, 2063 women were found in both datasets, representing 23.1% of HIV-positive women with a pregnancy in the UK (n = 8932). Clinical data was available in UK CHIC following most pregnancies (92.0%, 2471/2685 pregnancies starting before 2009). There was bias towards matching women with repeat pregnancies (35.9% (741/2063) of women found in both datasets had a repeat pregnancy compared to 21.9% (1502/6869) of women in NSHPC only) and matching women HIV diagnosed before their first reported pregnancy (54.8% (1131/2063) compared to 47.7% (3278/6869), respectively). CONCLUSIONS: Through the use of demographic data and clinical dates, records from two independent studies were successfully matched, providing data not available from either study alone. PMID- 22839416 TI - Plasmodium vivax malaria relapses at a travel medicine centre in Rio de Janeiro, a non-endemic area in Brazil. AB - BACKGROUND: Malaria is a potentially severe disease widely distributed in tropical and subtropical regions worldwide. Clinically, the progression of the disease can be life-threatening if it is not promptly diagnosed and properly treated. Through treatment, the radical cure of Plasmodium vivax infection can be achieved, thus preventing potential relapses and the emergence of new cases outside the Amazon region in Brazil. Surveillance for therapeutic failure in non endemic areas is advantageous, as it is unlikely that recurrence of the disease can be attributed to a new malaria infection in these regions. METHODS: An observational study of 53 cases of P. vivax and mixed (P. vivax and Plasmodium falciparum) malaria was conducted at a travel medicine centre between 2005 and 2011 in Rio de Janeiro and a descriptive analysis of the potential factors related to recurrence of P. vivax malaria was performed. Groups with different therapeutic responses were compared using survival analysis based on the length of time to recurrence and a set of independent variables thought to be associated with recurrence. RESULTS: Twenty-one relapses (39.6%) of P. vivax malaria were observed. The overall median time to relapse, obtained by the Kaplan-Meier method, was 108 days, and the survival analysis demonstrated an association between non-weight-adjusted primaquine dosing and the occurrence of relapse (p < 0.03). Primaquine total dose at 3.6 mg/kg gave improved results in preventing relapses. CONCLUSIONS: A known challenge to individual cure and environmental control of malaria is the possibility of an inappropriate, non-weight-based primaquine dosing, which should be considered a potential cause of P. vivax malaria relapse. Indeed, the total dose of primaquine associated with non occurrence of relapses was higher than recommended by Brazilian guidelines. PMID- 22839417 TI - Left ventricular remodeling and hypertrophy in patients with aortic stenosis: insights from cardiovascular magnetic resonance. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) is the gold standard non invasive method for determining left ventricular (LV) mass and volume but has not been used previously to characterise the LV remodeling response in aortic stenosis. We sought to investigate the degree and patterns of hypertrophy in aortic stenosis using CMR. METHODS: Patients with moderate or severe aortic stenosis, normal coronary arteries and no other significant valve lesions or cardiomyopathy were scanned by CMR with valve severity assessed by planimetry and velocity mapping. The extent and patterns of hypertrophy were investigated using measurements of the LV mass index, indexed LV volumes and the LV mass/volume ratio. Asymmetric forms of remodeling and hypertrophy were defined by a regional wall thickening >= 13 mm and >1.5-fold the thickness of the opposing myocardial segment. RESULTS: Ninety-one patients (61 +/- 21 years; 57 male) with aortic stenosis (aortic valve area 0.93 +/- 0.32 cm2) were recruited. The severity of aortic stenosis was unrelated to the degree (r2=0.012, P=0.43) and pattern (P=0.22) of hypertrophy. By univariate analysis, only male sex demonstrated an association with LV mass index (P=0.02). Six patterns of LV adaption were observed: normal ventricular geometry (n=11), concentric remodeling (n=11), asymmetric remodeling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). Asymmetric patterns displayed considerable overlap in appearances (wall thickness 17 +/- 2mm) with hypertrophic cardiomyopathy. CONCLUSIONS: We have demonstrated that in patients with moderate and severe aortic stenosis, the pattern of LV adaption and degree of hypertrophy do not closely correlate with the severity of valve narrowing and that asymmetric patterns of wall thickening are common. PMID- 22839418 TI - Factors associated with complete immunization coverage in children aged 12-23 months in Ambo Woreda, Central Ethiopia. AB - BACKGROUND: Vaccination is a proven tool in preventing and eradicating communicable diseases, but a considerable proportion of childhood morbidity and mortality in Ethiopia is due to vaccine preventable diseases. Immunization coverage in many parts of the country remains low despite the efforts to improve the services. In 2005, only 20% of the children were fully vaccinated and about 1 million children were unvaccinated in 2007. The objective of this study was to assess complete immunization coverage and its associated factors among children aged 12-23 months in Ambo woreda. METHODS: A cross-sectional community-based study was conducted in 8 rural and 2 urban kebeles during January- February, 2011. A modified WHO EPI cluster sampling method was used for sample selection. Data on 536 children aged 12-23 months from 536 representative households were collected using trained nurses. The data collectors assessed the vaccination status of the children based on vaccination cards or mother's verbal reports using a pre-tested structured questionnaire through house-to-house visits. Bivariate and multivariate logistic regression analyses were used to assess factors associated with immunization coverage. RESULTS: About 96% of the mothers heard about vaccination and vaccine preventable diseases and 79.5% knew the benefit of immunization. About 36% of children aged 12-23 months were fully vaccinated by card plus recall, but only 27.7% were fully vaccinated by card alone and 23.7% children were unvaccinated. Using multivariate logistic regression models, factors significantly associated with complete immunization were antenatal care follow-up (adjusted odds ratio(AOR = 2.4, 95% CI: 1.2- 4.9), being born in the health facility (AOR = 2.1, 95% CI: 1.3-3.4), mothers' knowledge about the age at which vaccination begins (AOR = 2.9, 95% CI: 1.9-4.6) and knowledge about the age at which vaccination completes (AOR = 4.3, 95% CI: 2.3-8), whereas area of residence and mother's socio-demographic characteristics were not significantly associated with full immunization among children. CONCLUSION: Complete immunization coverage among children aged 12-23 months remains low. Maternal health care utilization and knowledge of mothers about the age at which child begins and finishes vaccination are the main factors associated with complete immunization coverage. It is necessary that, local interventions should be strengthened to raising awareness of the community on the importance of immunization, antenatal care and institutional delivery. PMID- 22839419 TI - Entangling single photons from independently tuned semiconductor nanoemitters. AB - Quantum communication systems based on nanoscale semiconductor devices is challenged by inhomogeneities from device to device. We address this challenge using ZnMgSe/ZnSe quantum-well nanostructures with local laser-based heating to tune the emission of single impurity-bound exciton emitters in two separate devices. The matched emission in combination with photon bunching enables quantum interference from the devices and allows the postselection of polarization entangled single photons. The ability to entangle single photons emitted from nanometer-sized sources separated by macroscopic distances provides an essential step for a solid-state realization of a large-scale quantum optical network. This paves the way toward measurement-based entanglement generation between remote electron spins localized at macroscopically separated fluorine impurities. PMID- 22839420 TI - William A. Bernhard (1942-2012). PMID- 22839421 TI - Directional liquid spreading over chemically defined radial wettability gradients. AB - We investigate the motion of liquid droplets on chemically defined radial wettability gradients. The patterns consist of hydrophobic fluorinated self assembled monolayers (SAMs) on oxidized silicon substrates. The design comprises a central hydrophobic circle of unpatterned SAMs surrounded by annular regions of radially oriented stripes of alternating wettability, i.e., hydrophilic and hydrophobic. Variation in the relative width of the stripes allows control over the macroscopic wettability. When a droplet is deposited in the middle, it will start to move over to the radially defined wettability gradient, away from the center because of the increasing relative surface area of hydrophilic matter for larger radii in the pattern. The focus of this article is on a qualitative description of the characteristic motion on such types of anisotropic patterns. The influence of design parameters such as pattern dimensions, steepness of the gradient, and connection between different areas on the behavior of the liquid are analyzed and discussed in terms of advancing and receding contact lines, contact angles, spatial extent, and overall velocity of the motion. PMID- 22839422 TI - Hepatitis C virus infection in a child with autoimmune polyendocrine syndrome type 2: a case report. AB - INTRODUCTION: Autoimmune polyendocrine syndrome type 2 is a rare disorder. Its prevalence in western populations has been reported as 1.5 to 4.5/100,000. On the other hand, its prevalence in Egypt is unknown. It is characterized by the association of autoimmune Addison's disease with thyroid autoimmune diseases and/or type I diabetes mellitus. Hepatitis C virus infection is an important public health issue worldwide. Egypt has the highest prevalence of hepatitis C virus infection of any country in the world. It is estimated to be 8% in urban and 25% in rural areas. We present the case of an Egyptian child with autoimmune polyendocrine syndrome type 2 associated with chronic hepatitis C infection. CASE PRESENTATION: A 14-year-old Egyptian boy with type 1 diabetes mellitus was referred to our institution for an evaluation of recurrent attacks of hypoglycemia of two months duration. The initial clinical examination revealed hypotension as well as vitiligo of the skin. He had high potassium, low sodium, low cortisol, high adrenocorticotropic hormone, slightly high thyroid stimulating levels with strong positivity of anti-thyroglobulin and anti-thyroid peroxidase antibodies. The hepatitis C antibody and hepatitis C virus-polymerase chain reaction were positive. Based on these findings, a diagnosis of autoimmune polyendocrine syndrome type 2 with chronic hepatitis C was made. He was started on hydrocortisone (10mg twice daily), fludrocortisone (0.1mg twice daily) and multiple daily doses of insulin. He showed great improvement of his symptoms on the prescribed treatment. CONCLUSIONS: The importance of the early diagnosis of autoimmune polyendocrine syndrome type 2 and the possibility of its association with chronic hepatitis C infection should be considered in order to implement the proper management of such cases. PMID- 22839423 TI - Cholestatic hepatic injury due to a thyroid storm: a case report from a resource limited setting. AB - INTRODUCTION: Thyroid storm is an endocrinological emergency caused by an exacerbation of the hyperthyroid state and is characterized by multi organ dysfunction. Liver dysfunction or injury predominantly of a cholestatic type is one of the atypical manifestations of thyroid storm and has been previously described in literature. However, there have been few published case reports among African patients and from resource limited settings. CASE REPORT: We report a case of a 21 year old Ugandan female patient who presented with a thyroid storm due to untreated Graves' disease complicated by cholestatic hepatic injury, congestive heart failure and acute kidney injury. CONCLUSION: This case highlights the varied multi organ dysfunctions seen in a patient with thyroid storm with emphasis on liver injury mainly to increase awareness among clinicians in resource limited settings. Mechanisms of liver injury due to thyroid storm or hyperthyroidism are discussed in the literature review. PMID- 22839428 TI - Newly evolved introns in human retrogenes provide novel insights into their evolutionary roles. AB - BACKGROUND: Retrogenes generally do not contain introns. However, in some instances, retrogenes may recruit internal exonic sequences as introns, which is known as intronization. A retrogene that undergoes intronization is a good model with which to investigate the origin of introns. Nevertheless, previously, only two cases in vertebrates have been reported. RESULTS: In this study, we systematically screened the human (Homo sapiens) genome for retrogenes that evolved introns and analyzed their patterns in structure, expression and origin. In total, we identified nine intron-containing retrogenes. Alignment of pairs of retrogenes and their parents indicated that, in addition to intronization (five cases), retrogenes also may have gained introns by insertion of external sequences into the genes (one case) or reversal of the orientation of transcription (three cases). Interestingly, many intronizations were promoted not by base substitutions but by cryptic splice sites, which were silent in the parental genes but active in the retrogenes. We also observed that the majority of introns generated by intronization did not involve frameshifts. CONCLUSIONS: Intron gains in retrogenes are not as rare as previously thought. Furthermore, diverse mechanisms may lead to intron creation in retrogenes. The activation of cryptic splice sites in the intronization of retrogenes may be triggered by the change of gene structure after retroposition. A high percentage of non-frameshift introns in retrogenes may be because non-frameshift introns do not dramatically affect host proteins. Introns generated by intronization in human retrogenes are generally young, which is consistent with previous findings for Caenorhabditis elegans. Our results provide novel insights into the evolutionary role of introns. PMID- 22839429 TI - Spatial and temporal assessment of mercury and organic matter in thermokarst affected lakes of the Mackenzie Delta uplands, NT, Canada. AB - We examined dated sediment cores from 14 thermokarst affected lakes in the Mackenzie Delta uplands, NT, Arctic Canada, using a case-control analysis to determine how retrogressive thaw slump development from degrading permafrost affected the delivery of mercury (Hg) and organic carbon (OC) to lakes. We show that sediments from the lakes with retrogressive thaw slump development on their shorelines (slump-affected lakes) had higher sedimentation rates and lower total Hg (THg), methyl mercury (MeHg), and lower organic carbon concentrations compared to lakes where thaw slumps were absent (reference lakes). There was no difference in focus-corrected Hg flux to sediments between reference lakes and slump affected lakes, indicating that the lower sediment Hg concentration in slump affected lakes was due to dilution by rapid inorganic sedimentation in the slump affected lakes. Sedimentation rates were inversely correlated with THg concentrations in sediments among the 14 lakes considered, and explained 68% of the variance in THg concentration in surface sediment, further supporting the dilution hypothesis. We observed higher S2 (algal-derived carbon) and particulate organic carbon (POC) concentrations in sediment profiles from reference lakes than in slump lakes, likely because of dilution by inorganic siliciclastic matter in cores from slump-affected lakes. We conclude that retrogressive thaw slump development increases inorganic sedimentation in lakes, and decreases concentrations of organic carbon and associated Hg and MeHg in sediments. PMID- 22839430 TI - Bilateral macular thickening in mild unilateral anterior uveitis: is HLA-B27 involved? AB - BACKGROUND: Macular thickening (MT) without clinically recognized macular edema has been described in anterior uveitis (AU). Although fellow-eyes of patients have been used as controls in several studies, little is known about macular thickness in these eyes. We studied the rate and extent of MT in both AU-affected and quiescent fellow-eyes of phakic AU patients with good visual acuity (VA). We also assessed macular thickness related to HLA-B27 presence and to recurrence, since these issues have been almost unexplored by previous optical coherence tomography (OCT) studies. METHODS: Patients with AU were prospectively included and macular thickness was measured with OCT initially and on follow up. Macular thickness in patients' affected eyes (n = 30) as well as in their quiet fellow eyes (n = 28) was compared with eyes of age- and gender matched controls. Inter ocular differences in macular thickness between AU affected eyes and their fellow eyes were assessed in patients (n = 28), also in a subgroup with visual acuity >= 0.8 (n = 23) by one-sample Student's t-tests. Inter-ocular differences were also assessed related to HLA-B27 presence and related to the status of current AU episode (initial or relapse). RESULTS: Subclinical MT is present in both quiet fellow-eyes and AU-affected eyes of patients. MT was found in most cases of AU, even in phakic eyes with good VA. There was a larger increase in macular thickness in HLA-B27-positive than in HLA-B27-negative patients. No differences in macular thickness were found between patients with their first AU episode and patients with recurrent episodes. CONCLUSIONS: MT probably reflects systemic immune-mediated response to the inflammatory disorder in AU, and it is possible that HLA-B27-related factors are involved in the pathogenesis of AU. These observations are in line with and extend the current understanding of the mechanisms behind MT in AU. PMID- 22839431 TI - Choice of glucocorticoid in HELLP syndrome - dexamethasone versus betamethasone: revisiting the dilemma. AB - OBJECTIVE: Maternal corticosteroid administration has been reported to improve the blood pressure, urine output, laboratory values of liver enzymes and platelets in HELLP syndrome. In this controversial subject, recently, Cochrane Database had updated its systematic review and in the subgroup analysis they indicated that dexamethasone was superior to betamethasone for the improvement of platelet counts and liver enzymes. However, there are several issues which need to be clarified about the subgroup analysis and the consequent conclusion. METHODS: Systematic review and re-analysis of the indicated studies. RESULTS: In the subgroup analysis two studies were included, which had used non-parametric methods for statistical analysis and yielded insignificant p-values that showed indifference between betamethasone and dexamethasone. However, the Cochrane meta analysis had used parametric methods in contradistinction to the included studies and indicated significant difference between two steroids. Accordingly, results and conclusions of the Cochrane meta-analysis in this subgroup analysis cannot be justified with the indicated two studies. CONCLUSION: Here we can only urge further studies to provide frank evidence about the comparison of dexamethasone and betamethasone in HELLP syndrome. Until shown to be true, we doubt the credibility of the subgroup analysis results of the Cochrane review and the application of these subgroup results into clinical practice. PMID- 22839432 TI - Funding for malaria control 2006-2010: a comprehensive global assessment. AB - BACKGROUND: The last decade has seen a dramatic increase in international and domestic funding for malaria control, coupled with important declines in malaria incidence and mortality in some regions of the world. As the ongoing climate of financial uncertainty places strains on investment in global health, there is an increasing need to audit the origin, recipients and geographical distribution of funding for malaria control relative to populations at risk of the disease. METHODS: A comprehensive review of malaria control funding from international donors, bilateral sources and national governments was undertaken to reconstruct total funding by country for each year 2006 to 2010. Regions at risk from Plasmodium falciparum and/or Plasmodium vivax transmission were identified using global risk maps for 2010 and funding was assessed relative to populations at risk. Those nations with unequal funding relative to a regional average were identified and potential explanations highlighted, such as differences in national policies, government inaction or donor neglect. RESULTS: US$8.9 billion was disbursed for malaria control and elimination programmes over the study period. Africa had the largest levels of funding per capita-at-risk, with most nations supported primarily by international aid. Countries of the Americas, in contrast, were supported typically through national government funding. Disbursements and government funding in Asia were far lower with a large variation in funding patterns. Nations with relatively high and low levels of funding are discussed. CONCLUSIONS: Global funding for malaria control is substantially less than required. Inequity in funding is pronounced in some regions particularly when considering the distinct goals of malaria control and malaria elimination. Efforts to sustain and increase international investment in malaria control should be informed by evidence-based assessment of funding equity. PMID- 22839434 TI - Comparison of endotracheal intubation using direct and video laryngoscopes in the ICU. PMID- 22839433 TI - Patient perceptions of innovative longitudinal integrated clerkships based in regional, rural and remote primary care: a qualitative study. AB - BACKGROUND: Medical students at the University of Wollongong experience continuity of patient care and clinical supervision during an innovative year long integrated (community and hospital) clinical clerkship. In this model of clinical education, students are based in a general practice 'teaching microsystem' and participate in patient care as part of this community of practice (CoP). This study evaluates patients' perceptions of the clerkship initiative, and their perspectives on this approach to training 'much-needed' doctors in their community. METHODS: Semi-structured, face-to-face, interviews with patients provided data on the clerkship model in three contexts: regional, rural and remote health care settings in Australia. Two researchers independently thematically analysed transcribed data and organised emergent categories into themes. RESULTS: The twelve categories that emerged from the analysis of transcribed data were clustered into four themes: learning as doing; learning as shared experience; learning as belonging to a community; and learning as 'becoming'. Patients viewed the clerkship learning environment as patient- and student-centred, emphasising that the patient-student-doctor relationship triad was important in facilitating active participation by patients as well as students. Patients believed that students became central, rather than peripheral, members of the CoP during an extended placement, value-adding and improving access to patient care. CONCLUSIONS: Regional, rural and remote patients valued the long-term engagement of senior medical students in their health care team(s). A supportive CoP such as the general practice 'teaching microsystem' allowed student and patient to experience increasing participation and identity transformation over time. The extended student-patient-doctor relationship was seen as influential in this progression. Patients revealed unique insights into the longitudinal clerkship model, and believed they have an important contribution to make to medical education and new strategies addressing mal distribution in the medical workforce. PMID- 22839435 TI - Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4 dideoxy-1,4-imino-D-mannitol. AB - Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine. PMID- 22839437 TI - [Prognostic value of markers of inflammation in patients with stable ischemic heart disease after implantation of stents with drug covering at the background of long-term therapy with statins (inhospital period)]. AB - The objective of this study was to examine the prognostic value of C-reactive protein, erythrocyte sedimentation rate (ESR), white blood count, phospholipase A2 in patients with stable ischemic disease on long-term statin therapy undergoing percutaneous coronary intervention (PCI) with drug-eluting stent implantation. In the interim analysis in- hospital outcomes were assessed a total of 602 patients from December 2009 through December 2010 underwent successful PCI with at least one DES implanted. They were prospectively followed before discharge. MACE (death, myocardial infarction [MI], stroke, stent thrombosis [ST] which did not lead to MI) occurred in 10,6% of the patients. There was no death or stroke before discharge. MI (including 0,3% of Q-MI) occurred in 10,3% of the patients. 6 patients had verified ST. Multivariate logistic regression identified ESR level before PCI and total length of stents implanted as independent predictors of MACE. PMID- 22839436 TI - Cardiac output and cardiac index measured with cardiovascular magnetic resonance in healthy subjects, elite athletes and patients with congestive heart failure. AB - BACKGROUND: Cardiovascular Magnetic Resonance (CMR) enables non-invasive quantification of cardiac output (CO) and thereby cardiac index (CI, CO indexed to body surface area). The aim of this study was to establish if CI decreases with age and compare the values to CI for athletes and for patients with congestive heart failure (CHF). METHODS: CI was measured in 144 healthy volunteers (39 +/- 16 years, range 21-81 years, 68 females), in 60 athletes (29 +/- 6 years, 30 females) and in 157 CHF patients with ejection fraction (EF) below 40% (60 +/- 13 years, 33 females). CI was calculated using aortic flow by velocity-encoded CMR and is presented as mean +/- SD. Flow was validated in vitro using a flow phantom and in 25 subjects with aorta and pulmonary flow measurements. RESULTS: There was a slight decrease of CI with age in healthy subjects (8 ml/min/m2 per year, r2 = 0.07, p = 0.001). CI in males (3.2 +/- 0.5 l/min/m2) and females (3.1 +/- 0.4 l/min/m2) did not differ (p = 0.64). The mean +/- SD of CI in healthy subjects in the age range of 20-29 was 3.3 +/- 0.4 l/min/m2, in 30-39 years 3.3 +/- 0.5 l/min/m2, in 40-49 years 3.1 +/- 0.5 l/min/m2, 50-59 years 3.0 +/- 0.4 l/min/m2 and >60 years 3.0 +/- 0.4 l/min/m2. There was no difference in CI between athletes and age-controlled healthy subjects but HR was lower and indexed SV higher in athletes. CI in CHF patients (2.3 +/- 0.6 l/min/m2) was lower compared to the healthy population (p < 0.001). There was a weak correlation between CI and EF in CHF patients (r2 = 0.07, p < 0.001) but CI did not differ between patients with NYHA-classes I-II compared to III-IV (n = 97, p = 0.16) or patients with or without hospitalization in the previous year (n = 100, p = 0.72). In vitro phantom validation showed low bias ( 0.8 +/- 19.8 ml/s) and in vivo validation in 25 subjects also showed low bias (0.26 +/- 0.61 l/min, QP/QS 1.04 +/- 0.09) between pulmonary and aortic flow. CONCLUSIONS: CI decreases in healthy subjects with age but does not differ between males and females. We found no difference in CI between athletes and healthy subjects at rest but CI was lower in patients with congestive heart failure. The presented values can be used as reference values for flow velocity mapping CMR. PMID- 22839438 TI - [Assessment of therapeutic equivalence of original bisoprolol and its generics in patients with ischemic heart disease with concomitant chronic obstructive pulmonary disease]. AB - Therapeutic equivalence of original bisoprolol (Concor) and its two generics (Biprol and Biol) was studied in 102 patients with ischemic heart disease (IHD) combined with chronic obstructive pulmonary disease (COPD). Concor, Biprol and Biol were given for 12 weeks to 36, 36, and 30 patients, respectively. Methods comprised test with endothelium dependent vasodilation, 24-hour ECG monitoring, pulmonary ventilation tests, and measurement of blood concentrations of nitrous oxide metabolites. Hypotensive and antiischemic effects were similar in all groups. However significant improvement of endothelial function occurred only among Concor treated patients. No negative changes of parameters of pulmonary ventilation took place after 4 weeks of therapy but after 12 weeks their significant lowering was observed among Biprol treated patients. We conclude that in this study on patients with IHD and COPD original bisoprolol demonstrated higher clinical efficacy and better tolerability than its generics. PMID- 22839439 TI - [Value of allele gene polymorphism of the inflammation system for prognosis of patients with myocardial infarction]. AB - In recent years levels of a number of inflammatory markers namely C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF) etc. are measured for the purpose of postinfarction risk evaluation. Dynamics of inflammatory markers concentrations can reflect processes occurring in atherosclerotic plaque and coronary arteries. Concentrations of inflammatory markers depend particularly on genetic factors affecting transcription levels of individual genes. This data suggest that genotypes which determine increased inflammatory markers levels in blood can increase risk of unfavorable events after myocardial infarction. STUDY PURPOSES: Analysis of influence of allelic polymorphisms C1444T of CRP gene (rs1130864), G(-174)A of IL6 gene (rs1800795), A(-308)G of TNF gene (rs1800629), G252A of LTA gene (rs909253), (-509) of TGFB1 gene (rsl800469) and delta32 (w/d) of CCR5 gene (rs333) on development of cardiac unfavorable events in Russian patients with MI during two years follow-up. 211 Russian patients were included (52.3+/-10.3 years), 160 men (50.1+/-10.6 years) and 51 women (55.2+/-10.1 years). After two years of follow-up patients were examined in hospital, or telephon call occurred for determination of patient's condition or end point assessment. The end points were cardiac death, recurrent MI, recurrent hospitalization with unstable angina or stroke, CABG or PTCA performing. The genotyping was performed by methods based on polymerase chain reaction (PCR): PCR-SSP and PCR-RFLP. Analysis revealed association of allele T (p=0.036, OR=1.6, 95%CI: 1.052.6) and of allele T carriage (genotypes CT+TT) (p=0.046, OR=1.9, 95%CI: 1.053.6) of polymorphism C1444T of CRP gene with unfavorable events development. Analysis of survival rate by Kaplan-Meier estimation showed that cumulative part of patients without unfavorable events was significantly lower among allele T carriers than among carriers of genotype C/C of polymorphism C1444T CRP. Allele A of polymorphism A252G of LTA gene was also associated with unfavorable events risk (p=0.034, OR=1.96, 95%CI: 1.073.06). There was no association of polymorphisms delta 32 (w/d) of CCR5 gene, A(-308)G of TNF gene, G(-174)C of IL-6 gene, C(-509)T of TGFB1 gene with unfavorable events development. PMID- 22839440 TI - [The state of carotid arteries in young men with arterial hypertension]. AB - PURPOSE: To study elastic properties of carotid arteries in young men with arterial hypertension (AH). MATERIAL AND METHODS: We examined men aged 18-25 years (mean 21.1+/-0.14 years): 36 with normal blood pressure (BP), 123 with stable and 51 with unstable AH. Parameters studied comprised intima-media thickness (IMT) of carotid arteries, their M-mode measured maximal systolic and minimal diastolic diameters (Ds and Dd), stiffness of common carotid artery (CCA) wall determined on the basis of analysis of elasticity and distensibility coefficients (CC and DC), Peterson's and Young's modules of elasticity (Ep and E), and index of flow deformation (CS). RESULTS: Compared with young men with normal BP and unstable AH patients with stable AH had abnormal elastic properties of CCA and increased IMT. CONCLUSIONS: Stable AH in young men is associated with signs of remodeling of CCA walls and increase of their rigidity. PMID- 22839441 TI - [Comparison of effectiveness of radiofrequency catheter ablation of left arterial isthmuses for treatment of postablational perimitral atrial flutter]. AB - AIM: To compare results of radiofrequency (RF) ablation (A) of mitral and inferior septal isthmuses in the left atrium for the treatment of perimitral atrial flutter (AF) in patients with atrial fibrillation previously subjected to RF isolation of pulmonary veins and modification of the left atrial anatomical arrhythmia substrate. MATERIAL AND METHODS: We treated 20 patients (3 women, mean age 57.1+/-9.3 years) with recurrent postablational perimitral AF verified by 3 dimensional reconstruction of left and right atrial activation by nonfluoroscopic mapping and pacing techniques of entrainment into tachycardia cycle. At first stage RFA was carried out in the region of mitral isthmus (its endocardial parts). At second stage RFA was performed in the region of coronary sinus (CS) roof (epicardial portions of the mitral isthmus). At the third stage RFA influences were applied in the region of inferior septal isthmus (endocardial portions of the inferioseptal isthmus). At the fourth stage RFA was applied in the region of roof of proximal CS (epicardial portions of inferioseptal isthmus). RESULTS: Application of RF influences to endocardial parts of the mitral isthmus resulted in sinus rhythm (SR) restoration in 6 cases. Change of length of the tachycardia cycle was noted in 5cases. SR restoration was observed after RFA in the region of the roof of distal CS in 3 cases and change of length of the tachycardia cycle was noted in 2 more cases. RFA of epicardial parts of the inferioseptal isthmus resulted in SR restoration in 3 cases and in increase of atypical AF cycle length in 6 cases. In 12 cases SR was restored during RFA application in the region of the roof of proximal CS parts. RF influences in the region of endocardial (stage 1) and epicardial (stage 2) parts of the mitral isthmus resulted in SR restoration in 9 cases while continuation of RFA in the region of endocardial (stage 3) and epicardial (stage 4) parts of the inferioseptal isthmus led to SR restoration in the remaining 15 cases (p<0.05). CONCLUSION: RFA of endocardial and epicardial parts of the inferioseptal isthmus significantly more often led to termination of perimitral atypical AF in patients previously operated because of atrial fibrillation. PMID- 22839442 TI - [Vitamin D in the treatment of cardiorenal syndrome in patients with chronic nephropathy]. AB - AIM: To determine place of vitamin D in prevention and treatment of cardiorenal syndrome (CRS) and chronic allograft nephropathy (CAN) in the aspect of myocardial and renal reparation. METHODS AND MATERIAL: In Russia and the Netherlands we included in a randomized placebo controlled study 120 vitamin D deficient [25(OH) vitamin D<40 mol/l] recipients of asystolic and cadaveric donors. Patients were divided in 4 groups: paricalcitol (2-4 g/day) group (n=28), calcitriol (1-6 g/day orally) group (n=28), diet (1200-1800 IU/day of vitamin D with multivitamins and from foodstuffs) group (n=26), placebo with diet control group (n=27). RESULTS: After 180 days degree of CAN according to the Banff classification was 1.24 and 1.22 in paricalcitol and calcitriol groups, respectively, compared with 1.43 and 1.68 in diet and placebo groups, respectively (p<0.05). Glomerular filtration rate (GFR) changed from 46.7 to 84.4, 81.4, 76.8, and 54.5 ml/min/1.73 m3 in paricalcitol, calcitriol, diet and placebo groups, respectively. Fluorescence activated cell scanning (FACS) analysis allowed to detect quantitative induction of SP+ cells amounting 7.4, 2.9 and 1.2%; 7.2, 2.7; and 1.1%; 6.1, 2.9 and 1.2%; 9.3, 1.3 and 0.7% of peripheral blood progenitors, renal epithelial cells, and cardiomyocytes in paricalcitol, calcitriol, diet and placebo groups, respectively. Levels of CD133, CD34, CD73, and CD105 were significantly elevated in patients of paricalcitol (median 161, range 0-834 copies), calcitriol (163, 0-721), and diet (119, 0-401) groups, compared with the placebo group (0,0-41), p<0.01. Level of nuclear vitamin D receptor (VDR) protein in renal tissue homogenizate and myocardium achieved 584, 599, 478, and 333 mole VRD/mg and 801, 715, 654, and 389 Phimole VRD/mg of protein in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). Circulating progenitor stem cells demonstrated comparatively high level of VDR expression--529, 526, 401, and 211 mole VRD/mg in CD133, CD34 cells; 432, 414, 303, and 290 mole VRD/mg in CD73, CD105 cells; 549, 558, 442, and 302 phimole VRD/mg in SP+ cells in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.05). Hypercalcemia was detected in 4(14%) patients in calcitriol group (p<0.001). Under influence of antihypertensive therapy arterial pressure decreased after transplantation from 180/101 to 143/87, 141/94, 147,102, and 165/101 mm Hg in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). NYHA heart failure functional class changed from 2.3 to 1.8, 1.9, 1.9, and 2.5 in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). In 6 months after transplantation average CCS scores were 533 (0-998), 611 (0-1712), 524 (122-1278) and 990 (120-1800) cells in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.05). CONCLUSIONS: Vitamin D is an effective mean of prevention and treatment of CRS and CAN, stimulator of reparation of renal and myocardial tissues. Optimal for wide clinical practice is the use of active vitamin D analog paricalcitol (2-4 g/day) as well as special diet with multivitamins (up to 1800 IU of cholecalciferol). PMID- 22839443 TI - [Galectin 3--a new biomarker for diagnostics and outcome of chronic heart failure]. AB - Galectins--lectins binding beta-galactosides their properties and biological role have been described. Galectines family in mammalians consists of 15 members. Galectin-3 is atypical specimen of galectins family. Its participation in fibrosis, cardiac remodeling, immune and inflammation responses have been shown. Employment galectin-3 as new independent biomarker for diagnosis of acute heart failure and outcome predictor in patients with chronic heart failure (HF) are discussed. Diagnostic and prognostic values of galectin-3 are compared with famous and wide using HF marker NT-proBNP. Combined employing biomarkers for diagnostic and prognostic purpose of HF have been discussed. Using galectin-3 as therapeutic target in treatment of chronic HF in future is suggested. PMID- 22839444 TI - [Heart failure: the pathogenetic continuum and biomarkers]. AB - Molecular aspects of pathogenesis of cardiac failure touching on transmission of pathological signals through the transduction system, involvement of mechanisms of transcriptional reprogramming and metabolic changes in the myocardium, as well as processes of aging and inflammation in the pathogenetic continuum are considered in this paper. Data on markers of early diagnosis, prognosis and progression of heart failure and perspectives of discovery of its pathogenesis within framework of developing system biology integrating analysis of multiple different in their nature biomarkers are also presented. PMID- 22839445 TI - [31P magnetic-resonance spectroscopy in cardiac diseases]. AB - Magnetic Resonant spectroscopy (MRS) in the nuclei of phosphorus is the only noninvasive method of studying the state of myocardial energy metabolism does not require the introduction of radiopharmaceuticals. This method uses the signals from the nuclei of 31P contained in such mattered phosphates like phosphocreatine and adenosine triphosphate. MRS can provide an answer to a variety of theoretical and clinical issues in the study of various cardiac diseases. The first is ischemic heart disease, as well as heart failure, hypertrophy of various origins, etc. In addition, the method can be used to control the various treatments, including therapeutic, interventional or surgical. Combined with magnetic resonance imaging of the heart gives information on the anatomy, size, function, perfusion defects, structural changes of the myocardium, as well as about the state of energy metabolism of myocardium. PMID- 22839446 TI - [Vasovagal syncope or epilepsy: how to avoid errors in diagnosis]. AB - Transitory loss of consciousness might have multiple mechanisms of development among which vasovagal syncope and epilepsy have the greatest significance. It is thought that in every forth patient the initial diagnosis is erroneous because of similarity of clinical picture and even well prepared specialists are not secured against mistakes. Aim of this review is to stress key points of diagnosis from the point of view of a cardiologist and epileptologist. PMID- 22839447 TI - [Comparative antiplatelet efficacy of prasugrel and high-dose clopidogrel in patients with coronary heart disease including acute coronary syndrome]. AB - A number of randomized double-blind studies have been conducted for comparative assessment of the pharmacodynamic properties of high loading and maintenance doses of clopidogrel (600-900 mg loading dose and 150 mg maintenance dose) and standard dose of prasugrel (60 mg loading dose and 10 mg maintenance dose) in patients with coronary heart disease, including those with acute coronary syndrome. This review briefly discusses the trials ACAPULCO and PRINCIPLE-TIMI 44. Compared with high dose clopidogrel, prasugrel inhibited P2Y12-mediated platelet aggregation faster and to a greater extent. A difference between effects of clopidogrel and prasugrel emerged as soon as at 30 minutes after the loading dose. Antiplatelet effects of prasugrel were greater than those of clopidogrel both during first 2-4 hours after administration of loading dose, and during maintenance dosing. This may have important clinical implications. PMID- 22839448 TI - [The relationship of cardiovascular disease and metabolic disorders caused by magnesium deficiency]. PMID- 22839449 TI - [Made in Russia system for facilitated external counterpulsation: development and first experience of clinical application]. PMID- 22839450 TI - Reversible Kirkwood-Alder transition observed in Pt3Cu2 nanoctahedron assemblies under controlled solvent annealing/drying conditions. AB - We report a Kirkwood-Alder transition in a system of nonspherical Pt(3)Cu(2) nanoctahedra coated with oleic acid and oleylamine ligands. Using both transmission electron microscopy tomography with 3D reconstruction analysis and synchrotron-based in-situ grazing-incidence small-angle X-ray scattering (GISAXS) techniques, we specifically determined that these nanoctahedra can assemble into an open structure in which the nanoctahedra are arranged tip-to-tip to form a bcc superlattice with a low packing efficiency. Using in-situ and real-time GISAXS, we further observed a "nanoctahedron crystallization" as a soft Kirkwood-Alder transition, that is, the soft nanoactahedra crystallize at a critical concentration and possess continuous crystalline states during a period of solvent evaporation. Finally, we found a reversible change of the superlattice constant during the solvent annealing and evaporation/drying processes. PMID- 22839451 TI - The changing landscape of global public health. PMID- 22839452 TI - Increased risk of cancer in patients with type 2 diabetes mellitus: a retrospective cohort study in China. AB - BACKGROUND: Previous studies indicated that type 2 diabetes mellitus (T2DM) might be associated with the risk of cancer. The aim of this study was to investigate the association between T2DM and the risk of developing common cancers in a Chinese population. METHODS: A population-based retrospective cohort study was carried out in the Nan-Hu district of Jiaxing city, Zhejiang province, China. The incidence of cancer cases among type 2 diabetic patients were identified through record-linkage of the Diabetic Surveillance and Registry Database with the Cancer Database from January 2002 to June 2008. The standardized incidence ratio (SIR) and 95% confidence interval (CI) were estimated for the risk of cancer among the patients with type 2 diabetes. RESULTS: The overall incidence of cancer was 1083.6 per 10(5) subjects in male T2DM patients and 870.2 per 105 in females. Increased risk of developing cancer was found in both male and female T2DM patients with an SIR of 1.331 (95% CI = 1.143-1.518) and 1.737 (1.478-1.997), respectively. As for cancer subtypes, both male and female T2DM patients had a significantly increased risk of pancreatic cancer with the SIRs of 2.973 (1.73 4.21) and 2.687 (1.445-3.928), respectively. Elevated risk of liver and kidney cancers was only found in male T2DM patients with SIRs of 1.538 (1.005-2.072) and 4.091 (1.418-6.764), respectively. Increased risks of developing breast cancer [2.209 (1.487-2.93)] and leukemia SIR: [4.167 (1.584- 6.749) ] were found in female patients. CONCLUSIONS: These findings indicated that patients with T2DM have an increased risk of developing cancer. Additional cancer screening should be employed in the management of patients with T2DM. PMID- 22839453 TI - A pilot randomised controlled trial of negative pressure wound therapy to treat grade III/IV pressure ulcers [ISRCTN69032034]. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is widely promoted as a treatment for full thickness wounds; however, there is a lack of high-quality research evidence regarding its clinical and cost effectiveness. A trial of NPWT for the treatment of grade III/IV pressure ulcers would be worthwhile but premature without assessing whether such a trial is feasible. The aim of this pilot randomised controlled trial was to assess the feasibility of conducting a future full trial of NPWT for the treatment of grade III and IV pressure ulcers and to pilot all aspects of the trial. METHODS: This was a two-centre (acute and community), pilot randomised controlled trial. Eligible participants were randomised to receive either NPWT or standard care (SC) (spun hydrocolloid, alginate or foam dressings). Outcome measures were time to healing of the reference pressure ulcer, recruitment rates, frequency of treatment visits, resources used and duration of follow-up. RESULTS: Three hundred and twelve patients were screened for eligibility into this trial over a 12-month recruitment period and 12/312 participants (3.8%) were randomised: 6 to NPWT and 6 to SC. Only one reference pressure ulcer healed (NPWT group) during follow-up (time to healing 79 days). The mean number of treatment visits per week was 3.1 (NPWT) and 5.7 (SC); 6/6 NPWT and 1/6 SC participants withdrew from their allocated trial treatment. The mean duration of follow-up was 3.8 (NPWT) and 5.0 (SC) months. CONCLUSIONS: This pilot trial yielded vital information for the planning of a future full study including projected recruitment rate, required duration of follow-up and extent of research nurse support required. Data were also used to inform the cost-effectiveness and value of information analyses, which were conducted alongside the pilot trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN69032034. PMID- 22839497 TI - Photoinduced carbene generation from diazirine modified task specific phosphonium salts to prepare robust hydrophobic coatings. AB - 3-Aryl-3-(trifluormethyl)diazirine functionalized highly fluorinated phosphonium salts (HFPS) were synthesized, characterized, and utilized as photoinduced carbene precursors for covalent attachment of the HFPS onto cotton/paper to impart hydrophobicity to these surfaces. Irradiation of cotton and paper, as proof of concept substrates, treated with the diazirine-HFPS leads to robust hydrophobic cotton and paper surfaces with antiwetting properties, whereas the corresponding control samples absorb water readily. The contact angles of water were determined to be 139 degrees and 137 degrees for cotton and paper, respectively. In contrast, water placed on the untreated or the control samples (those treated with the diazirine-HFPS but not irradiated) is simply absorbed into the surface. Additionaly, the chemically grafted hydrophobic coating showed high durability toward wash cycles and sonication in organic solvents. Because of the mode of activation to covalently tether the hydrophobic coating, it is amenable to photopatterning, which was demonstrated macroscopically. PMID- 22839499 TI - Vasa previa is not infrequent. AB - OBJECTIVE: To clarify certain frequency of vasa previa using ultrasonography. METHODS: Umbilical cord insertion site were examined prospectively by the ultrasound during first trimester in 3647 cases between 2006 and 2011. RESULTS: 10 cases (1: 365) of vasa previa were found. All cases with vasa previa at the delivery had been diagnosed as a lower cord insertion in the uterine cavity in the first trimester, whereas we do not have any misdiagnosed cases. CONCLUSION: Although it is believed that the incidence of vasa previa is very rare, according to our ultrasonographic evaluation vasa previa is not infrequent. Additional systematic identification of umbilical cord abnormalities from early gestation is recommended. PMID- 22839498 TI - Physical activity and fat mass gain in Mexican school-age children: a cohort study. AB - BACKGROUND: In Mexico, the prevalence of unhealthy weight increased from 24% at 6 y to 33% at 12 y of age, opening a window of opportunity to better understand the pathogenesis of obesity. The objective of this study was to explore the association between time spent on medium, vigorous physical activity (MVPA) and concurrent gains in BMI, fat mass (FM) and fat-free mass (FFM), alternately, in a cohort of Mexican children followed from kindergarten (baseline) to 2nd grade elementary school (endline). METHODS: The MVPA (5-d accelerometry), BMI, FM and FFM (air displacement plethysmography) were measured at baseline and endline. Associations between gains in BMI, FM and FFM and changes in MVPA were examined using lagged and dynamic regression models, controlling for energy intake and demographic variables. RESULTS: A total of 205 children were analyzed. Gender affected the effect of MVPA on FM gain. In girls, a high baseline MVPA predicted a lower FM gain (-0.96 kg, p=0.025) compared to low/medium MVPA. Increasing, decreasing or having a persistently high MVPA predicted a lower FM gain (range 1.6 to -1.03 kg, p<0.05) compared to persistently low MVPA. In boys, increases in MVPA were associated with higher gains in BMI (+0.76 kg/m2, p=0.04) and FFM (+1.1 kg, p=0.01) compared to persistently low MVPA. CONCLUSION: These results support a protective role of MVPA on FM gain in girls, suggesting that it may play a crucial role in the development of obesity. Further research on the gender effect of MVPA is warranted to better understand its role in the prevention and control of overweight and obesity. PMID- 22839500 TI - How to find a needle (or anything else) in a haystack: two-dimensional correlation spectroscopy-filtering with iterative random sampling applied to pharmaceutical heparin. AB - Risks of contamination of the major clinical anticoagulant heparin can arise from deliberate adulteration with unnatural or natural polysaccharides, including heparin from other animal sources, other natural products, or artifacts of manufacture, and these can escape detection by conventional means. Currently, there is no generally applicable, objective test recommended by regulators that can detect these in pharmaceutical heparin, and this continues to leave heparin exposed to contamination risks. Two-dimensional correlation spectroscopic filtering with iterative random sampling (2D-COS-firs) is reported. It employs a difference covariance matrix with iterative random sampling, and is capable of revealing contamination in pharmaceutical heparin to a high level of sensitivity irrespective of the nature of those features. The technique is suitable to any situation in which a comparison of a single entity to a family of heterogeneous entities, particularly natural products and biosimilars, needs to be made, and will find application in pharmaceutical monitoring, manufacturing quality control, materials science, biotechnology, and metabolomic investigations. PMID- 22839501 TI - Molecular functions of metallothionein and its role in hematological malignancies. AB - Metallothionein (MT) was reported to be a potential negative regulator of apoptosis, and various reports have suggested that it may play roles in carcinogenesis and drug resistance, in at least a portion of cancer cells. The author summarizes the current understanding of the molecular functions of MT for tumor cell growth and drug resistance. These activities are regulated through intracellular metal ion modulation and free radical scavenging. Compared with analyses of solid tumors, few studies have analyzed the roles of MT in hematological malignancies. This review mainly describes the functions of MT in hematopoietic cells. Furthermore, through expression analyses of leukemias and lymphomas, the roles of MT in the biology of these diseases are particularly focused upon. PMID- 22839502 TI - PGASO: A synthetic biology tool for engineering a cellulolytic yeast. AB - BACKGROUND: To achieve an economical cellulosic ethanol production, a host that can do both cellulosic saccharification and ethanol fermentation is desirable. However, to engineer a non-cellulolytic yeast to be such a host requires synthetic biology techniques to transform multiple enzyme genes into its genome. RESULTS: A technique, named Promoter-based Gene Assembly and Simultaneous Overexpression (PGASO), that employs overlapping oligonucleotides for recombinatorial assembly of gene cassettes with individual promoters, was developed. PGASO was applied to engineer Kluyveromycesmarxianus KY3, which is a thermo- and toxin-tolerant yeast. We obtained a recombinant strain, called KR5, that is capable of simultaneously expressing exoglucanase and endoglucanase (both of Trichodermareesei), a beta-glucosidase (from a cow rumen fungus), a neomycin phosphotransferase, and a green fluorescent protein. High transformation efficiency and accuracy were achieved as ~63% of the transformants was confirmed to be correct. KR5 can utilize beta-glycan, cellobiose or CMC as the sole carbon source for growth and can directly convert cellobiose and beta-glycan to ethanol. CONCLUSIONS: This study provides the first example of multi-gene assembly in a single step in a yeast species other than Saccharomyces cerevisiae. We successfully engineered a yeast host with a five-gene cassette assembly and the new host is capable of co-expressing three types of cellulase genes. Our study shows that PGASO is an efficient tool for simultaneous expression of multiple enzymes in the kefir yeast KY3 and that KY3 can serve as a host for developing synthetic biology tools. PMID- 22839503 TI - Long-term effects of high nitrogen loads on cation and carbon riverine export in agricultural catchments. AB - The intensification of agriculture in recent decades has resulted in extremely high nitrogen inputs to ecosystems. One effect has been H(+) release through NH(4)(+) oxidation in soils, which increases rock weathering and leads to acidification processes such as base-cation leaching from the soil exchange complex. This study investigated the evolution of cation concentrations over the past 50 years in rivers from the Armorican crystalline shield (Brittany, western France). On a regional scale, acidification has resulted in increased base-cation riverine exports (Ca(2+), Mg(2+), Na(+), K(+)) correlated with the increased NO(3)(-) concentration. The estimated cation increase is 0.7 mmol(+)/L for Ca(2+) + Mg(2+) and 0.85 mmol(+)/L for total cations. According to mass balance, cation loss represents >30% of the base-cation exchange capacity of soils. Long-term acidification thus contributes to a decline in soil productivity. Estimates of the total organic nitrogen annually produced worldwide indicate that acidification may also constitute an additional carbon source in crystalline catchments if compensated by liming practices. PMID- 22839504 TI - Effects of endotoxin on lactate metabolism in humans. AB - INTRODUCTION: Hyperlactatemia represents one prominent component of the metabolic response to sepsis. In critically ill patients, hyperlactatemia is related to the severity of the underlying condition. Both an increased production and a decreased utilization and clearance might be involved in this process, but their relative contribution remains unknown. The present study aimed at assessing systemic and muscle lactate production and systemic lactate clearance in healthy human volunteers, using intravenous endotoxin (LPS) challenge. METHODS: Fourteen healthy male volunteers were enrolled in 2 consecutive studies (n = 6 in trial 1 and n = 8 in trial 2). Each subject took part in one of two investigation days (LPS-day with endotoxin injection and placebo-day with saline injection) separated by one week at least and in a random order. In trial 1, their muscle lactate metabolism was monitored using microdialysis. In trial 2, their systemic lactate metabolism was monitored by means of a constant infusion of exogenous lactate. Energy metabolism was monitored by indirect calorimetry and glucose kinetics was measured with 6,6-H2 glucose. RESULTS: In both trials, LPS increased energy expenditure (p = 0.011), lipid oxidation (p<0.0001), and plasma lactate concentration (p = 0.016). In trial 1, lactate concentration in the muscle microdialysate was higher than in blood, indicating lactate production by muscles. This was, however, similar with and without LPS. In trial 2, calculated systemic lactate production increased after LPS (p = 0.031), while lactate clearance remained unchanged. CONCLUSIONS: LPS administration increases lactatemia by increasing lactate production rather than by decreasing lactate clearance. Muscle is, however, unlikely to be a major contributor to this increase in lactate production. TRIAL REGISTRATION: ClinicalTrials.gov NCT01647997. PMID- 22839505 TI - CD44/CD24 expression in recurrent gastric cancer: a retrospective analysis. AB - BACKGROUND: To correlate CD44/CD24 expression with gastric cancer recurrence and prognosis. Gastric cancer is the second leading cause of cancer mortality due to the high recurrence rate, of which the molecular signature has not yet been identified. METHODS: We retrospectively reviewed the hospital records of patients with gastric cancer. Among 500 patients receiving curative resection, 95 patients had recurrence. Twenty patients from the recurrence group (95 patients) and 20 patients from the non-recurrence group (405 patients) were randomly selected and identified as "study" and "control" groups, respectively. We reviewed patients' histological study of CD44/CD24 expression by performing immunohistochemistry and recurrence rate. RESULTS: Study group had higher TNM stage (III-IV) than control group (80% vs. 25%, P = 0.001). Proportion of lymph node metastasis was significantly higher in study group than that in control group (90% vs. 45%, P = 0.002), and proportion of patients with 5 or more metastatic lymph nodes was also significantly higher in study group than in control group (45% vs. 15%, P = 0.007). Univariate analysis revealed no difference in risk of gastric cancer recurrence between CD44+ and CD44- patients (OR = 1.00, 95% CI: 0.29-3.45, P =1.000). CD24+ patients showed no greater significance of gastric cancer recurrence than CD24- patients (OR = 1.86, 95% CI: 0.52-6.61, P = 0.339). After adjusting for other risk factors, the association of CD44 expression (aOR = 0.66, 95% CI: 0.10-4.26, P = 0.658), CD24 expression (aOR = 0.09, 95% CI: 0.01-1.35, P = 0.081) or combined (CD44/CD24) with gastric cancer recurrence were not significant. CONCLUSION: Neither individual expression of CD24 or CD44, nor combined expression of CD44/CD24 was associated with recurrence of gastric carcinoma. PMID- 22839506 TI - A multi-gene phylogeny of Cephalopoda supports convergent morphological evolution in association with multiple habitat shifts in the marine environment. AB - BACKGROUND: The marine environment is comprised of numerous divergent organisms living under similar selective pressures, often resulting in the evolution of convergent structures such as the fusiform body shape of pelagic squids, fishes, and some marine mammals. However, little is known about the frequency of, and circumstances leading to, convergent evolution in the open ocean. Here, we present a comparative study of the molluscan class Cephalopoda, a marine group known to occupy habitats from the intertidal to the deep sea. Several lineages bear features that may coincide with a benthic or pelagic existence, making this a valuable group for testing hypotheses of correlated evolution. To test for convergence and correlation, we generate the most taxonomically comprehensive multi-gene phylogeny of cephalopods to date. We then create a character matrix of habitat type and morphological characters, which we use to infer ancestral character states and test for correlation between habitat and morphology. RESULTS: Our study utilizes a taxonomically well-sampled phylogeny to show convergent evolution in all six morphological characters we analyzed. Three of these characters also correlate with habitat. The presence of an autogenic photophore (those relying upon autonomous enzymatic light reactions) is correlated with a pelagic habitat, while the cornea and accessory nidamental gland correlate with a benthic lifestyle. Here, we present the first statistical tests for correlation between convergent traits and habitat in cephalopods to better understand the evolutionary history of characters that are adaptive in benthic or pelagic environments, respectively. DISCUSSION: Our study supports the hypothesis that habitat has influenced convergent evolution in the marine environment: benthic organisms tend to exhibit similar characteristics that confer protection from invasion by other benthic taxa, while pelagic organisms possess features that facilitate crypsis and communication in an environment lacking physical refuges. Features that have originated multiple times in distantly related lineages are likely adaptive for the organisms inhabiting a particular environment: studying the frequency and evolutionary history of such convergent characters can increase understanding of the underlying forces driving ecological and evolutionary transitions in the marine environment. PMID- 22839507 TI - Oral delivery of near-infrared quantum dot loaded micelles for noninvasive biomedical imaging. AB - The purpose of this study is to design, develop, and characterize an optical imaging agent for oral administration. The hydrophobic, nanosized (7 nm), near infrared (NIR) quantum dots (QDs) have been loaded into deoxycholic acid (DOCA) conjugated low molecular weight heparin (LMWH) micelles. The QD-loaded LMWH-DOCA (Q-LHD) nanoparticles have been characterized by electrophoretic light scattering (ELS) and a transmission electron microscope (TEM) which shows the average particle size was 130-220 nm in diameter. The Q-LHD nanoparticles also show the excellent stability in different pH conditions, and the release profile demonstrates the slow release of QDs after 5 days of oral administration. Concfocal laser microscopic scanning images show that the Q-LHD nanoparticles penetrate the cell membrane and are located inside the cell membrane. The real time pharmacokinetics studies show the absorption, distribution, metabolism, and elimination profile of Q-LHD nanoparticles, observed by the Kodak molecular imaging system (KMIS). This study has demonstrated that the orally administered Q LHD nanoparticles are absorbed in the small intestine through the bile acid transporter and eliminated through the kidneys. PMID- 22839508 TI - Artemisinin resistance containment project in Thailand. (I): Implementation of electronic-based malaria information system for early case detection and individual case management in provinces along the Thai-Cambodian border. AB - BACKGROUND: The Bureau of Vector-borne Diseases, Ministry of Public Health, Thailand, has implemented an electronic Malaria Information System (eMIS) as part of a strategy to contain artemisinin resistance. The attempt corresponds to the WHO initiative, funded by the Bill & Melinda Gates Foundation, to contain anti malarial drug resistance in Southeast Asia. The main objective of this study was to demonstrate the eMIS' functionality and outputs after implementation for use in the Thailand artemisinin-resistance containment project. METHODS: The eMIS had been functioning since 2009 in seven Thai-Cambodian border provinces. The eMIS has covered 61 malaria posts/clinics, 27 Vector-borne Disease Units covering 12,508 hamlets at risk of malaria infections. The eMIS was designed as an evidence-based and near real-time system to capture data for early case detection, intensive case investigation, monitoring drug compliance and on/off site tracking of malarial patients, as well as collecting data indicating potential drug resistance among patients. Data captured by the eMIS in 2008-2011 were extracted and presented. RESULTS: The core functionalities of the eMIS have been utilized by malaria staff at all levels, from local operational units to ministerial management. The eMIS case detection module suggested decreasing trends during 2009-2011; the number of malaria cases detected in the project areas over the years studied were 3818, 2695, and 2566, with sero-positive rates of 1.24, 0.98, and 1.16%, respectively. The eMIS case investigation module revealed different trends in weekly Plasmodium falciparum case numbers, when classified by responsible operational unit, local and migrant status, and case detection type. It was shown that most Thai patients were infected within their own residential district, while migrants were infected either at their working village or from across the border. The data mapped in the system suggested that P. falciparum-infected cases and potential drug-resistant cases were scattered mostly along the border villages. The mobile technology application has detected different follow-up rates, with particularly low rates among seasonal and cross border migrants. CONCLUSION: The eMIS demonstrated that it could capture essential data from individual malaria cases at local operational units, while effectively being used for situation and trend analysis at upper-management levels. The system provides evidence-based information that could contribute to the control and containment of resistant parasites. Currently, the eMIS is expanding beyond the Thai-Cambodian project areas to the provinces that lie along the Thai-Myanmar border. PMID- 22839509 TI - A general method for palladium-catalyzed direct carbonylation of indole with alcohol and phenol. AB - A novel strategy involving a first oxidative iodination and subsequent Pd(0) catalyzed carbonylation to yield indole-3-carboxylate has been developed. It showed perfect generality to indole, alcohol, and phenol. The current methodology could also be conveniently applied to the synthesis of biologically active tropisetron from simple indole and tropine. PMID- 22839510 TI - [Prognostic power of various models in determination of level of coronary risk in patients with non ST-elevation acute coronary syndrome]. AB - The GRACE prognostic scale appeared ineffective for prognostication of deaths and sum of deaths and myocardial infarctions (MI) during hospitalization and demonstrated moderate level of prognostic value during 6 months of observation. TIMI model gave similar result relative to prediction of death/MI/refractory ischemia during 14 days and 12 months of observation. PURSUIT risk model showed very good level of prognostic significance during 30 days and 12 months of observation. Comparison of GRACE and PURSUIT models relative to all cause death and composite of death and MI showed that PURSUITd scale had better accuracy of predictions. PMID- 22839511 TI - [Transthoracic dopllerographic assessment of the relative coronary reserve in the norm and in the presence of isolated hemodynamically significant stenoses of the left anterior descending coronary artery]. AB - Comparison of velocity parameters of blood flow and absolute coronary reserve (absCR) in the left anterior descending and posterior interventricular coronary arteries (ADCA and PICA) with calculation of relative coronary reserve (relCR) and determination of its normative values was carried out with the help of transthoracic echocardiography in 29 healthy volunteers (mean age 40+/-13 years). Assessment of the role of absCR and relCR in ADCA in diagnostics of hemodynamically significant stenoses of this vessel was performed in 88 patients with syndrome of cardiac pain (mean age 40+/-12 years). Coronary angiography was used as a reference method. Coronary blood flow in distal segments of ADCA and PICA was measured at baseline and during infusion of a vasodilator (dipyridamole up to 0.84 mg/kg as intravenous infusion). AbsCR for each of these arteries was determined as ratio of hyperemic peak diastolic blood flow velocity and its baseline value. Lowering of absCR was diagnosed at its level <2.0). RelCR was calculated only for ADCA as ratio of absCR of ADCA and PICA. It was established that parameters of coronary blood flow and absCR level in healthy volunteers in ADA and PICA had no significant differences. Therefore these vessels were considered referent for each other. In the norm relCR in ADA was 1.09+/-0.36 (95% confidence interval from 0.95 to 1.23). We proved that ADA abs CR in <2.0 served as predictor of ADA stenosis >50% with sensitivity 89% and specificity 85%. However 22% of subjects with lowering of absCR had ADA stenoses <50%, microvascular involvement, or belonged to the group of healthy volunteers. It was established that ADA relCR <0.80 in patients with ADA absCR <2.0 was a sensitive and specific sign of isolated ADA stenosis >50%. PMID- 22839512 TI - [CYP2C19 gene polymorphism in patients with myocardial infarction who use clopidogrel]. AB - One of the foundations of the modern treatment of myocardial infarction (MI) is a combination antiplatelet therapy consisting of acetylsalicylic acid (ASA) and clopidogrel. Pharmacodynamic and clinical studies have demonstrated that the polymorphism CYP2C19 (CYP2C19*2 allele) is associated with a reduced antiplatelet effect of clopidogrel and an increase in the incidence of severe cardiovascular complications. The study included 97 patients with MI. Coronary angiography was performed with subsequent standard treatment of MI, including stenting of the infarct-related coronary artery. CYP2C19 polymorphism was determined by polymerase chain reaction. At 6months, outcomes were determined. The frequency of allele CYP2C19*2 was 22.7%. We found statistically insignificant differences in the prevalence of CYP2C19 gene polymorphism in different forms of myocardial infarction. In contrast to the authors, who previously published data on the effect of CYP2C19 gene polymorphism on cardiovascular complications, we found no differences according to genotype. CYP2C19 gene polymorphism does not influence the prognosis for the next six months, if to patient follow medical recommendations, including the regular use of clopidogrel. PMID- 22839513 TI - [Risk factors of development of left ventricular hypertrophy in patients with hypertensive disease with high compliance to treatment]. AB - Aim of the study was to assess rate of development of left ventricular hypertrophy (LVH) and its risk factors in patients with hypertensive disease (HD) without target organs damage with high compliance to treatment. We included in this prospective cohort study 428 patients with HD without target organs damage. Duration of follow-up was 8.8+/-2.6 years. Rate of LVH development was 36.9%. It was more frequent in men (41.3%) than in women (32.7%). Intensity of antihypertensive therapy was higher in a group of patients with with left ventricular remodeling. Risk of development of LVH was associated with age especially in men older than 55 years, duration of hypertension, body mass, initial level of diastolic blood pressure, pulse blood pressure, level of low density lipoprotein cholesterol, and fasting level of glucose in blood plasma. Thus in patients with HD rate of LVH development at the background of high compliance to treatment is lower than in total population and has definite specific patterns. PMID- 22839514 TI - [Advantages of quinapril therapy in patients with arterial hypertension and functional class III chronic heart failure with preserved left ventricular ejection fraction]. AB - AIM: To determine advantages of therapy of functional class (FC) I-II chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction in patients with hypertensive disease (HD) with metoprolol succinate or quinapril and to assess their effect on regulatory-adaptive status. METHODS: Two hundred patients with I-II FC CHF and LVEF >50% at the background of stage I-II hypertensive disease participated in this study. They were randomized into 2 groups. Group I comprised 104 patients (mean age 52.8+1.9 years) who were prescribed metoprolol succinate 87.7+/-7.6 mg/day. Patients of group 2 (n=96, mean age 55.0+/-1.4 years) were prescribed quinapril 21.0+55 mg/day. Examination at baseline and after 6 months of therapy included 6 min walk test, treadmillometry with assessment of maximal oxygen consumptiion (VO2max), echocardiography, 24 hour blood pressure monitoring, measurement of N-terminal precursor of brain natriuretic peptide (NT-proBNP); test of cardio-respiratory synchronism was used for objective qualitative determination of the state of the ,renin-angiotensin system. RESULTS: Both drugs improved parameters of LV diastolic function, but only quinapril effectively changed LV structural geometric parameters and systolic function. Only treatment with quinapril was associated with improvement of RAS, elevation of tolerance to physical effort, and increased VO2max. Quinapril more substantially lowered level of NT-proBNP. CONCLUSION: Quinapril has an advantage over metoprolol succinate in therapy of patients with FC I-II CHF and preserved LF EF at the background of stage I-II HD. PMID- 22839515 TI - [Cryoballoon ablation for pulmonary vein isolation to treat atrial fibrillation: first experience in Russian Federation]. AB - Cryoballon ablation (CBA) for pulmonary vein (PV) isolation is a new method for catheter-based treatment of patients with atrial fibrillation (AF). The purpose of our work is to describe the CBA technique and to report its short-term results. Methods. CBA was performed in 12 patients (8 men; age 53.1+/-5.7 years) with highly symptomatic drug-refractory AF. Paroxysmal AF was present in 11 and persistent AF - in 1 patient. CBA procedure was carried out under general anesthesia with intubation in 6 and under light sedation in 6 patients. After transseptal access and direct PV angiography, 28 mm-cryoballoon was introduced into the left atrium, and more or equal 2 cryoapplications were delivered to each PV, once good PV occlusion was obtained. PV isolation was verified utilizing a circular mapping catheter. Arrhythmia recurrences were monitored every 3 months after ablation using 24-hour Holter, and additional ECG registrations. Holter monitoring was also performed in a case of symptoms. Results. Complete electrical PV isolation was achieved by only cryoballoon ablation in 11 patients, and additional cryocatheter touch-up ablation was required in left PVs in 1 patient. Total procedure time was 203.1+/-34.2 min, fluoroscopy time - 50.5+/-14.0 min. There were no complications. During a mean follow-up period of 136.8+/-59.8 days 9 (75%) patients were free from arrhythmia recurrence after a single procedure. Redo ablation was required in 1 patient, in whom electrical reconnection to all PVs was documented. Conclusion. CBA is a novel promising technique for treatment of patients with AF, and now is available in Russian Federation. The method standardizes and facilitates interventional AF treatment with acute isolation of 96% PVs. The short-term follow-up shows freedom from atrial tachyarrhythmias in 75% of patients. PMID- 22839516 TI - [Spherical remodeling of left atrium in hypertrophic nonobstructive cardiomyopathy]. AB - We examined 86 patients with various forms and variants of hypertrophic cardiomyopathy (HCM). Examination of 69 patients with nonobstructive form of the disease included echocardiography. The state of left atrium (LA) was studied by measurement of its systolic and diastolic longitudinal and transversal dimensions with calculation of main parameters of contractility. In 60% of patients with HCM including those with nonobstuctive form we found spherical remodeling of LA with lowering of its contractility. Coefficient of remodeling was suggested as ratio of transversal and longitudinal dimensions of its cavity. PMID- 22839517 TI - [The contribution of parameters of subclinical artery wall damage in the evaluation of cardiovascular risk]. AB - AIM: To assess contribution of such parameters as intima-media thickness (IMT), presence of carotid plagues (ab), pulse wave velocity (abPWV) and ankle-brachial index (ABI) to asessment of cardiovascular risk in patients who were initially assigned to the group of low and moderate risk according to the SCORE scale. SUBJECTS AND METHODS: 600 patients with low and moderate cardiovascular risk according to "SCORE" scale were selected: 445 women and 155 men in the age 30-65 years. We used color duplex ultrasound imaging (DUI) of carotid arteries (CA),. computer sphigmography (CS), biochemical tests (lipid profile. MDRD. glucose). RESULTS: The contribution of studied methods to risk stratification was compared: DUI of CA allowed to find patients with subclinical artery wall damage in 96%, CS abPWV - in 39%, and ABI only - in 5% of cases. After adding abPWV to patient examination 61% remained in the low risk group and 17% were converted into the high risk group. At the same time after adding DUI of CA only 37% of patients remained in the low risk group and 36% (almost every third) were converted to more high risk group. CONCLUSION: The most sensitive method of detection subclinical artery wall damages is duplex ultrasound imaging of CA. The abPWV also has some diagnostic value and can be recommended to find out this kind of damage due to its simplicity and convenience. PMID- 22839518 TI - [Acetylsalicylic acid in patients with planned (elective) interventions on the coronary arteries. Risks and benefits]. AB - In a review of the literature describes the risks and benefits of surgical interventions, in particular, coronary artery bypass grafting in patients with coronary artery disease receiving antiplatelet therapy with no cancellation or late withdrawal of acetylsalicylic acid (ASA). The data supporting a moderate - without increasing the frequency of reoperation and blood transfusion - an increased risk of perioperative bleeding in cases where operations are conducted against a background of aspirin therapy. At the same time showed a significant reduction in the risk of perioperative cardiovascular complications and improve survival after intervention, which did not occur before the removal of the drug ASA. PMID- 22839519 TI - [Indirect anticoagulants in the prevention of thromboembolic complications after myocardial infarction]. PMID- 22839520 TI - [The role of direct-acting P2Y12 inhibitors in acute coronary syndrome]. AB - P2Y12 receptor inhibitors are recommended for treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention as a part of dual antiplatelet therapy. While thienopyridine group of P2Y12 inhibitors remains to be widely used treatment for patients with ACS, there are still complications for its application. Emerging antiplatelet treatments expand therapy strategies for management of ACS. The purpose of this article is to define the developing role of novel non-thienopyridine reversible P2Y12 inhibitor ticagrelor to present its pharmacokinetic, pharmacodynamic, and pharmacogenetic characteristics, based on current evidence. PMID- 22839521 TI - [Omega-3-polyunsaturated fatty acids: profs of benefit and perspectives of application]. PMID- 22839522 TI - [Arrhythmogenic right ventricular dysplasia: polymorphism of clinical manifestations]. AB - We observed 15 patients with arrhythmogenic right ventricular dysplasia (ARVD): 9 with definite and 5 with probable ARVD (modified European Criteria, 2010). Eight patients had typical ARVD (frequent right ventricular extrasystoles, nonsustained right ventricular tachycardia without heart failure with or without myocarditis). Five patients had ARVD with progressive heart failure (right- or biventricular with or without myocarditis). Two patients had full scale arrhythmic form (sustained right ventricular tachycardia without or with right ventricular dilation, with or without myocarditis). In 3 cases diagnosis was confirmed morphologically or with DNA-diagnostics. This material allowed us to highlight the following specific points related to diagnostics of ARVD. Detection of fat at MRT is not obligatory for diagnosis, fat can be detected by MSCT; ventricular arrhythmias can move backwards in the picture of the disease; leading clinical manifestation can be unexplained right ventricular insufficiency; ARVD can be combined with other genetic cardiomyopathies as well as with infectious immune myocarditis (up to 50% of patients); elevated titer of anticardiac antibodies is not characteristic for isolated ARVD; myocardial biopsy allows to verify both ARVD and concomitant myocarditis. The paper also contains discussion of the role of myocarditis in various forms of ARVD and possibilities of its diagnosis and treatments. PMID- 22839523 TI - [Termination of paroxysm of atrial fibrillation conversion using oral propafenone after unsuccessful electrical cardioversion]. PMID- 22839524 TI - Observation of single metal nanoparticle collisions by open circuit (mixed) potential changes at an ultramicroelectrode. AB - Single nanoparticle (NP) collisions were successfully observed by a potentiometric measurement. The open circuit potential (OCP) of a measuring Au ultramicroelectrode (UME) changes when Pt NPs collide with the UME in a hydrazine solution. The OCP change is related to the redox processes, the concentration of particles, particle size, and electrode size. Compared with the amperometric technique, this approach has several advantages: higher sensitivity, simpler apparatus, fewer problems with NP decomposition, and contamination. PMID- 22839525 TI - Global public health leadership for the twenty-first century: towards improved health of all populations. AB - We are at an unprecedented moment in history in terms of the health of populations around the world. New and old problems all require both short- and long-term solutions, at the individual, community, national and global levels. Unique solutions for each challenge may not be feasible or adequately effective or cost-effective. We are confronted by health systems that are not well matched to current and future needs, both for sustained prevention and chronic care. Moving forward effectively as a field will benefit from a focus on the changing needs of global health, and on how changing conditions, globally, should define the next generation of public health leadership so as to best accomplish global health goals. PMID- 22839526 TI - Myocardial scarring on cardiovascular magnetic resonance in asymptomatic or minimally symptomatic patients with "pure" apical hypertrophic cardiomyopathy. AB - BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) enables state-of-the-art in vivo evaluations of myocardial fibrosis. Although LGE patterns have been well described in asymmetrical septal hypertrophy, conflicting results have been reported regarding the characteristics of LGE in apical hypertrophic cardiomyopathy (ApHCM). This study was undertaken to determine 1) the frequency and distribution of LGE and 2) its prognostic implication in ApHCM. METHODS: Forty patients with asymptomatic or minimally symptomatic pure ApHCM (age, 60.2 +/- 10.4 years, 31 men) were prospectively enrolled. LGE images were acquired using the inversion recovery segmented spoiled gradient echo and phase-sensitive inversion recovery sequence, and analyzed using a 17-segment model. Summing the planimetered LGE areas in all short axis slices yielded the total volume of late enhancement, which was subsequently presented as a proportion of total LV myocardium (% LGE). RESULTS: Mean maximal apical wall thickness was 17.9+/-2.3 mm, and mean left ventricular (LV) ejection fraction was 67.7 +/- 8.0%. All but one patient presented with electrocardiographic negative T wave inversion in anterolateral leads, with a mean maximum negative T wave of 7.2 +/- 4.7 mm. Nine patients (22.5%) had giant negative T waves, defined as the amplitude of >= 10 mm, in electrocardiogram. LGE was detected in 130 segments of 30 patients (75.0%), occupying 4.9 +/- 5.5% of LV myocardium. LGE was mainly detected at the junction between left and right ventricles in 12 (30%) and at the apex in 28 (70%), although LGE-positive areas were widely distributed, and not limited to the apex. Focal LGE at the non-hypertrophic LV segments was found in some ApHCM patients, even without LGE of hypertrophied apical segments. Over the 2-year follow-up, there was no one achieving the study end-point, defined as all cause death, sudden cardiac death and hospitalization for heart failure. CONCLUSIONS: LGE was frequently observed not only in the thickened apex of the heart but also in other LV segments, irrespective of the presence or absence of hypertrophy. The simple presence of LGE on CMR was not representative of adverse prognosis in this population. PMID- 22839527 TI - A summary index of infant and child feeding practices is associated with child growth in urban Shanghai. AB - BACKGROUND: Recently, an infant and child feeding index (ICFI) constructed on brief recalls of breastfeeding, feeding frequency and food diversification was assumed to provide long-term prediction about child feeding practices. The aim of this study was to investigate the association between the cross-sectional ICFI (CS-ICFI) or longitudinal ICFI (L-ICFI) and child anthropometric indices in downtown Shanghai, China. METHODS: The prospective cohort study included 180 infants aged 5-7 mo with their main caregivers who were visited 3 times every 6 months over 12 months. A CS-ICFI was constructed for each visit by using data on feeding practices based on 24-h and 7-d recalls. An L-ICFI was constructed with use of the 3 CS-ICFIs. The associations between ICFI and length-for-age z score (LAZ), weight-for-age z score (WAZ), and weight-for-length z score (WLZ) were examined. The stability of the CS-ICFI was assessed by using repeatability coefficient (RC). RESULTS: The L-ICFI was positively associated with LAZ and WAZ at Visit 3(beta = 0.151, P = 0.040 and beta = 0.173, P = 0.024, respectively). Moreover, the CS-ICFI at Visit 1 was positively associated with LAZ, WAZ and WLZ (beta = 0.160, P = 0.029; beta = 0.191, P = 0.009; beta = 0.176, P = 0.020) at Visit 3, and the CS-ICFI at Visit 3 was also positively associated with LAZ (beta = 0.176, P = 0.016). Stability of the CS-ICFI was shown by the value of 0.14 (95% CI: 0.07, 0.31) of the RC, which differed significantly from 0 (P < 0.05). CONCLUSIONS: The ICFI constructed on brief recalls based on cross-sectional studies can be used to evaluate the effects of child feeding practice on child growth. PMID- 22839528 TI - Diagnosis and treatment of chronic cough in China: an insight into the status quo. AB - Chronic cough is a very common complaint in clinics throughout China. Clinical and basic science research on chronic cough started late, but in recent years the effort has yielded promising findings regarding the etiological diagnosis, treatment and pathogenesis. We found that inflammation in nonasthmatic eosinophilic bronchitis has some similarities to cough variant asthma but also a number of distinct differences. Recent evidence has also suggested a mechanistic link between airway neurogenic inflammation and and gastroesophageal reflux cough (GERC). Cough-related animal models have been developed, including models for esophageal reflux, nonasthmatic eosinophilic bronchitis and allergic rhinitis. Normal reference values for differential cell counts in induced sputum, cough sensitivity and esophageal 24-h pH monitoring in Chinese healthy subjects have been established. By using a modified algorithm for the etiological diagnosis of chronic cough, the causes of chronic cough have been investigated across a number of cities in China. The most common causes of chronic cough are cough variant asthma, eosinophilic bronchitis, upper airway cough symptoms, atopic cough and GERC, however, there are some regional variations. The Chinese National Guidelines on Diagnosis and Management of Chronic Cough were drafted in 2005, updated in 2009, and have been widely publicized and disseminated through many channels since their publication. PMID- 22839529 TI - Thermoascus aurantiacus is a promising source of enzymes for biomass deconstruction under thermophilic conditions. AB - BACKGROUND: Thermophilic fungi have attracted increased interest for their ability to secrete enzymes that deconstruct biomass at high temperatures. However, development of thermophilic fungi as enzyme producers for biomass deconstruction has not been thoroughly investigated. Comparing the enzymatic activities of thermophilic fungal strains that grow on targeted biomass feedstocks has the potential to identify promising candidates for strain development. Thielavia terrestris and Thermoascus aurantiacus were chosen for characterization based on literature precedents. RESULTS: Thermoascus aurantiacus and Thielavia terrestris were cultivated on various biomass substrates and culture supernatants assayed for glycoside hydrolase activities. Supernatants from both cultures possessed comparable glycoside hydrolase activities when incubated with artificial biomass substrates. In contrast, saccharifications of ionic liquid pretreated switchgrass (Panicum virgatum) revealed that T. aurantiacus enzymes released more glucose than T. terrestris enzymes over a range of protein mass loadings and temperatures. Temperature-dependent saccharifications demonstrated that the T. aurantiacus proteins retained higher levels of activity compared to a commercial enzyme mixture sold by Novozymes, Cellic CTec2, at elevated temperatures. Enzymes secreted by T. aurantiacus released glucose at similar protein loadings to CTec2 on dilute acid, ammonia fiber expansion, or ionic liquid pretreated switchgrass. Proteomic analysis of the T. aurantiacus culture supernatant revealed dominant glycoside hydrolases from families 5, 7, 10, and 61, proteins that are key enzymes in commercial cocktails. CONCLUSIONS: T. aurantiacus produces a complement of secreted proteins capable of higher levels of saccharification of pretreated switchgrass than T. terrestris enzymes. The T. aurantiacus enzymatic cocktail performs at the same level as commercially available enzymatic cocktail for biomass deconstruction, without strain development or genetic modifications. Therefore, T. aurantiacus provides an excellent platform to develop a thermophilic fungal system for enzyme production for the conversion of biomass to biofuels. PMID- 22839570 TI - Risk of viral acute gastrointestinal illness from nondisinfected drinking water distribution systems. AB - Acute gastrointestinal illness (AGI) resulting from pathogens directly entering the piping of drinking water distribution systems is insufficiently understood. Here, we estimate AGI incidence from virus intrusions into the distribution systems of 14 nondisinfecting, groundwater-source, community water systems. Water samples for virus quantification were collected monthly at wells and households during four 12-week periods in 2006-2007. Ultraviolet (UV) disinfection was installed on the communities' wellheads during one study year; UV was absent the other year. UV was intended to eliminate virus contributions from the wells and without residual disinfectant present in these systems, any increase in virus concentration downstream at household taps represented virus contributions from the distribution system (Approach 1). During no-UV periods, distribution system viruses were estimated by the difference between well water and household tap virus concentrations (Approach 2). For both approaches, a Monte Carlo risk assessment framework was used to estimate AGI risk from distribution systems using study-specific exposure-response relationships. Depending on the exposure response relationship selected, AGI risk from the distribution systems was 0.0180 0.0661 and 0.001-0.1047 episodes/person-year estimated by Approaches 1 and 2, respectively. These values represented 0.1-4.9% of AGI risk from all exposure routes, and 1.6-67.8% of risk related to drinking water exposure. Virus intrusions into nondisinfected drinking water distribution systems can contribute to sporadic AGI. PMID- 22839571 TI - Vapor-phase detection of trinitrotoluene by AIEE-active hetero-oligophenylene based carbazole derivatives. AB - New AIEE-active hetero-oligophenylene carbazole derivatives 3 and 4 have been synthesized and serve as fluorescent probes for the selective detection of 2,4,6 trinitrotoluene (TNT) in the vapor phase, the solid phase, and aqueous media. In addition, paper strips prepared by dip-coating a solution of aggregates of derivatives 3 and 4 can provide a simple, portable, sensitive, selective, low cost method for the detection of TNT on the picogram level. PMID- 22839530 TI - Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequently-occurring malignant neoplasm in children, but the pathogenesis of the disease remains unclear. In a microarray assay using samples from 100 children with ALL, SFRS1 was found to be up-regulated. Serine/arginine-rich splicing factor 1 (SRSF1, also termed SF2/ASF), encoded by the SFRS1 gene, had been shown to be a pro oncoprotein. Our previous study indicated that SRSF1 can be methylated by protein arginine methyltransferase 1 (PRMT1) in vitro; however, the biological function of SRSF1 and PRMT1 in pediatric ALL are presently unknown. METHODS: Matched, newly diagnosed (ND), complete remission (CR) and relapse (RE) bone marrow samples from 57 patients were collected in order to evaluate the expression patterns of SRSF1 and PRMT1. The potential oncogenic mechanism of SRSF1 and PRMT1 in leukemogenesis was also investigated. RESULTS: We identified significant up regulation of SRSF1 and PRMT1 in the ND samples. Importantly, the expression of SRSF1 and PRMT1 returned to normal levels after CR, but rebounded in the RE samples. Our observation that SRSF1 could predict disease relapse was of particular interest, although the expression patterns of SRSF1 and PRMT1 were independent of the cytogenetic subtypes. In pre-B-cell lines, both SRSF1 and PRMT1 expression could be efficiently attenuated by the clinical chemotherapy agents arabinoside cytosine (Ara-c) or vincristine (VCR). Moreover, SRSF1 and PRMT1 were associated with each other in leukemia cells in vivo. Knock-down of SRSF1 resulted in an increase in early apoptosis, which could be further induced by chemotherapeutics. CONCLUSIONS: Our results indicate that SRSF1 serves as an anti-apoptotic factor and potentially contributes to leukemogenesis in pediatric ALL patients by cooperating with PRMT1. PMID- 22839572 TI - Evaluation of patient satisfaction of an outpatient gastroscopy service in an Asian tertiary care hospital. AB - BACKGROUND: There are limited published studies on patient satisfaction towards endoscopy from Asian countries. Different methods of evaluation of patient satisfaction may yield different results and there is currently no study to compare results of on-site versus phone-back interviews. METHOD: On-site followed by phone-back interviews were carried out on consecutive patients attending the outpatient gastroscopy service of University of Malaya Medical Centre between July 2010 and January 2011 using the modified Group Health Association of America 9 (mGHAA-9) questionnaire. The question on technical skill of endoscopist was replaced with a question on patient comfort during endoscopy. RESULTS: Seven hundred patients were interviewed. Waiting times for appointment and on gastroscopy day, and discomfort during procedure accounted for over 90% of unfavorable responses. Favorable response diminished to undesirable level when waiting times for appointment and on gastroscopy day exceeded 1 month and 1 hour, respectively. Satisfaction scores were higher for waiting time for appointment but lower for personal manner of nurses/staff and explanation given during phone back interview. There was no significant difference in satisfaction scores for other questions, including overall rating between the two methods. CONCLUSION: Waiting times and discomfort during procedure were main causes for patient dissatisfaction. Phone-back interview may result in different scores for some items compared with on-site interview and should be taken into account when comparing results using the different methods. PMID- 22839573 TI - Bridging bronchus--a rare cause of recurrent wheezy bronchitis. AB - BACKGROUND: Wheezing is a common symptom in infants and toddlers. Usually it occurs due to viral infection of the lower airways and no further diagnostic procedures are necessary. However in rare cases, other reasons such as anatomical malformation have to be considered. CASE PRESENTATION: We report about an infant with recurrent episodes of wheezy bronchitis, which persisted despite adequate therapy. Bronchoscopy and computed tomography of the lung with three-dimensional reconstruction revealed a rare bronchial branching anomaly - the so called "bridging bronchus". In contrast to previous case reports, this infant showed no additional malformations, which seems to be important for the prognosis. CONCLUSION: To the best of our knowledge this is the first report about a patient with a bridging bronchus in its "original form" without associated anomalies of the trachea-bronchial system or other organs. PMID- 22839574 TI - Therapeutic electric stimulation does not affect immune status in healthy individuals - a preliminary report. AB - BACKGROUND: Neuromuscular electric stimulation is widely used for muscle strengthening in clinical practice and for preventative purposes. However, there are few reports on the effects of electric stimulation on the immune response of the organism, and even those mainly describe the changes observed immediately after the electrotherapeutic procedures. The objective of our study was to examine the possible immunological consequences of moderate low-frequency transcutaneous neuromuscular electric stimulation for quadriceps muscle strengthening in healthy individuals. METHODS: The study included 10 healthy volunteers (5 males, 5 females, mean age 37.5 years). At the beginning and after a two-week electric stimulation program, muscle strength was measured and peripheral blood was collected to analyse white blood cells by flow cytometry for the expression of cell surface antigens (CD3, CD19, CD4, CD8, CD4/8, DR/3, NK, Th reg, CD25 + CD3+, CD25 + CD4+, CD25 + CD8+, CD69 + CD3+, CD69 + CD4+, CD69 + CD8+) and phagocytosis/oxidative killing function. RESULTS: Muscle strength slightly increased after the program on the dominant and the nondominant side. No statistically or clinically significant difference was found in any of the measured blood and immune cells parameters as well as phagocytosis and oxidative burst function of neutrophil granulocytes and monocytes one day after the program. CONCLUSIONS: The program of transcutaneous low-frequency electric stimulation slightly strengthened the quadriceps femoris muscle while producing no changes in measured immunological parameters. Hence, therapeutic low-frequency electric stimulation appears not to be affecting the immune response of healthy persons. PMID- 22839575 TI - Non-invasive prenatal screening of fetal sex chromosomal abnormalities: perspective of pregnant women. AB - OBJECTIVE: To study whether pregnant women would like to be informed if sex chromosomal abnormalities (SCA) were suspected with the non-invasive prenatal diagnosis of fetal Down syndrome (the NIFTY) test. METHODS: Two hundred and one patients carried a singleton pregnancy requesting the NIFTY test were invited to give their preferences if there was suspicion of SCA by the NIFTY test. RESULTS: Over 93.5% were ethnic Chinese, with a mean age of 36. Prior Down screening was positive in 66 (32.8%). Over 50% of subjects considered SCA to be better in terms of disability compared to Down syndrome, and only 5.2% considered SCA to be worse. Yet, the majority (198, 98.5%) indicated that they wanted to be informed if there was suspicion of SCA. Of whom 34.8% would have an amniocentesis for confirmation, while 57.1% were not certain, indicating the possibility of accepting these conditions. CONCLUSION: Besides screening Down syndrome by NIFTY, most pregnant women would also like to be informed if there was suspicion of SCA. Those screened positive should be counseled by those with experience in genetics to avoid unnecessary pregnancy termination. PMID- 22839576 TI - Genome-wide identification of significant aberrations in cancer genome. AB - BACKGROUND: Somatic Copy Number Alterations (CNAs) in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC), a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1) exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2) performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3) iteratively detecting Significant Copy Number Aberrations (SCAs) and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. RESULTS: We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS) on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma). When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC) or tumor suppressor genes (e.g., CDKN2A/B). Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. CONCLUSIONS: Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes. Open-source and platform-independent SAIC software is implemented using C++, together with R scripts for data formatting and Perl scripts for user interfacing, and it is easy to install and efficient to use. The source code and documentation are freely available at http://www.cbil.ece.vt.edu/software.htm. PMID- 22839578 TI - [Disturbances of heart rhythm in patients after myocardial infarction with obstructive sleep apnea during outpatient rehabilitation]. AB - We studied specific features of heart rhythm disturbances observed during outpatient rehabilitation of 432 patients after first myocardial infarction. In 94 of these patients (21.8%) we diagnosed obstructive sleep apnea syndrome (OSAS). We noted substantial preponderance of pathologic ectopy related to OSAS with most significant detection of frequent ventricular extrasystoles. Their paired variant and polymorphic forms in patients with OSAS were 3.4 and 7.4 times, respectively, more frequent than in patients without OSAS. Frequency of ventricular ectopy rose with increase of severity of OSAS and was maximal during nocturnal hours. Analysis of correlations revealed association between OSAS and frequencies of ventricular and supraventricular extrasystoles. CONCLUSION: After myocardial infarction patients should be thoroughly examined for timely detection of OSAS and corresponding correction of their rehabilitation program. PMID- 22839579 TI - [Acute kidney injury in patients with myocardial infarction and efficacy of thrombolytic therapy]. AB - Aim of the study was to assess rate and severity of acute kidney injury (AKJ) (RIFLE and AKIN criteria) in patients with ST-elevation myocardial infarction (STEMI), to determine relationship between AKJ, mortality and effectiveness of thrombolytic therapy (TLT). We examined 146 patients (117 men, 29 women, mean age 56.7+/-10.8 ) with STEMI subjected to TLT with streptokinase. AKJ was diagnosed and classified according to RIFLE and AKIN criteria by creatinine (RIFLECr, AKINCr) and diuresis (RIFLEou, AKINou). TLT was effective in 104(71%) patients. AKJ was found in 74 (51%) according to RIFLECr and in 86 (59%) - AKINCr, in 51 (35%) - RIFLEou and AKINou criteria. Eight patients 8 (5%) died. Results of logistic regression analysis showed that AKJ according to RIFLEou or AKINou irrespective of sex, age, and time after appearance of symptoms to hospitalization, was associated with mortality (relative risk [RR] 12.9, 95% confidence interval [95%CI] 1.45-115,58, p=0.002). Thus more than 50% of STEMI patients have AKJ according to RIFLECr AKINCr criteria. Frequency of AKJ according to RIFLEou and AKINou was by 40% and one third less than that according to AKINCr and RIFLECr, respectively. Presence of AKJ was associated with TLT inefficacy and elevation of mortality. PMID- 22839577 TI - Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury - a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts. AB - INTRODUCTION: Acute kidney injury (AKI) is associated with a high mortality of up to 60%. The mode of renal replacement therapy (intermittent versus continuous) has no impact on patient survival. Sustained low efficiency dialysis using a single-pass batch dialysis system (SLED-BD) has recently been introduced for the treatment of dialysis-dependent AKI. To date, however, only limited evidence is available in the comparison of SLED-BD versus continuous veno-venous hemofiltration (CVVH) in intensive care unit (ICU) patients with AKI. METHODS: Prospective, randomized, interventional, clinical study at a surgical intensive care unit of a university hospital. Between 1 April 2006 and 31 January 2009, 232 AKI patients who underwent renal replacement therapy (RRT) were randomized in the study. Follow-up was assessed until 30 August 2009. Patients were either assigned to 12-h SLED-BD or to 24-h predilutional CVVH. Both therapies were performed at a blood flow of 100 to 120 ml/min. RESULTS: 115 patients were treated with SLED-BD (total number of treatments n = 817) and 117 patients with CVVH (total number of treatments n = 877).The primary outcome measure, 90-day mortality, was similar between groups (SLED: 49.6% vs. CVVH: 55.6%, P = 0.43). Hemodynamic stability did not differ between SLED-BD and CVVH, whereas patients in the SLED-BD group had significantly fewer days of mechanical ventilation (17.7 +/- 19.4 vs. 20.9 +/- 19.8, P = 0.047) and fewer days in the ICU (19.6 +/- 20.1 vs. 23.7 +/- 21.9, P = 0.04). Patients treated with SLED needed fewer blood transfusions (1,375 +/- 2,573 ml vs. 1,976 +/- 3,316 ml, P = 0.02) and had a substantial reduction in nursing time spent for renal replacement therapy (P < 0.001) resulting in lower costs. CONCLUSIONS: SLED-BD was associated with reduced nursing time and lower costs compared to CVVH at similar outcomes. In the light of limited health care resources, SLED-BD offers an attractive alternative for the treatment of AKI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00322530. PMID- 22839580 TI - [Cystatin C and bleedings during hospitalization of noninvasively treated patients with acute coronary syndromes]. AB - PURPOSE: To assess relationship between blood level of a marker of renal function cystatin C (CC) and bleeding events in patients with acute coronary syndromes (ACS). MATERIAL AND METHODS: CC level was measured in 160 patients from the ACS registry conducted in a noninvasive hospital in Moscow. Each month we included in this registry 25 consecutively hospitalized patients and recorded deaths and bleeding events (major and moderate by TIMI and/or GUSTO criteria) during hospitalization. CC measurement was made by ELISA in stored blood samples taken within first 24 hours after admission. The cut-off level for CC (> 1.53 mg/l) was established by ROC analysis. RESULTS: There were 10 deaths (6.3%) and 11 bleeding events (6.9%) during hospitalization (median 20 days). Inhospital mortality was 45.5 and 3.4% % among patients with and without bleeding, respectively (=0.0001). Bleeding events occurred significantly more often among patients with CC level >1.53 mg/l compared to those with CC level less or equal 1.53 mg/l (13.8 and 2.1%; respectively, p=0.008). Multifactorial regression analysis identified the following independents predictors of bleeding: thrombolysis at admission (odds ratio [OR] 9.32; 95% confidence interval [95%CI] 1.96-44.29; =0.005), CC level >1.53 mg/l (OR 7.96; 95% CI 1.34-47.26; p=0.023), initial white blood cells count (OR 1.31; 95%CI 1.10-1.57; =0.003). When CC was excluded from regression analysis creatinine clearance entered the list of independent predictors of bleeding (OR 0.95; 95% CI 0.90-0.99; =0.023). CONCLUSION: In this group of noninvasively treated patients with ACS high CC level (>1.53 mg/l) was independently related to major and moderate bleedings during hospitalization. If CC was excluded from analysis, another marker of renal function (creatinine clearance) became an independent predictor of inhospital bleeding. PMID- 22839581 TI - [Association of 2B-adrenergic receptor gene polymorphism with disturbances of cardiac conduction]. AB - In this work we for the first time revealed on clinical - genetic material association between hereditary disturbances of cardiac conduction and polymorphism of 2-adrenergic receptor gene. PMID- 22839582 TI - [Clinico-economical aspects of cardioversion of paroxysmal atrial fibrillation at phehospital stage and during hospitalization]. AB - We carried out clinico-economical analysis of 2 tactics of rhythm restoration in patients with paroxysmal atrial fibrillation (AF) lasting less than 48 hours: cardioversion at prehospital stage with intravenous procainamide and inhospital cardioversion with any method. This retrospective study was based on the data from department of urgent aid of an outpatient clinic. The results showed that within 48 hours inhospital was a was more effective, safe, and more economically profitable compared with administration of procainamide at prehospital stage. Intravenous procainamide resulted in effective cardioversion in 70.6% of patients. It was associated with arterial hypotension and proarrhythmogenic action in 14,7% of cases. Patients with effective cardioversion with procainamide had lesser mean values of left ventricular anterior-posterior dimension (echocardiography) and shorter duration of arrhythmia. PMID- 22839583 TI - [Asymptomatic ventricular pre-excitation in children: a 17 year follow-up study]. AB - Results of long term clinic-electrophysiological follow-up of a large group of children with Wolf-Parkinson-White (WPW) phenomenon are present. From 1993 to 2011 we examined 176 children - 117 boys (66,5%) and 59 girls (33,5%) - with manifesting type of WPW. Age at first examination was 12.5+/-3.2 ( 0.1 18 ). In 66.5% of children WPW phenomenon was present in the age from 10 to 18 . Hundred fifty nine children (104 [65.4%] boys and 55 [34.6%] girls) were followed up for 0.5-17 years (mean 7.4+/-4.5 years). During follow-up spontaneous attacs of atrioventricular reciprocal tachycardia appeared in 13 children (8.2%, 95% confidence interval [CI] 4.4-13.6%). Spontaneous disappearance of signs of ventricular pre-excitation on electrocardiogram and transition to intermittent form of WPW were registered in 14(8.8%, 95%CI 4.9-14.3%) and 12 children (7.5%, 95% CI 3.9-12.8%). Short lasting syncopal states were observed in 15 children (8.4%). In 3 of them atrial fibrillation with high rate of venricular rhytm was induced during transesophageal electrophysiological study. Two (1.3%) children had history of clinical death. In one of them WPW phenomenon was combined with hypertrophic cardiomyopathy and polymorphic ventricular tachycardia. This child died at the age of 11 years. One (0.6%) boy with WPW phenomenon died suddenly in 3 years after initial examination. Thus, children with WPW phenomenon are at risk of development of life threatening states and sudden cardiac death. Stratification of risk of sudden death is necessary at examination of such children. PMID- 22839584 TI - [Inflammatory-destructive biomarkers of atherosclerotic plaques instability. Study of arterial wall and blood]. AB - Concentrations of tumor necrosis factor, interleukin 1- and its receptor antagonist, IL-6, IL-8, IL-18, IL-2, ligand of CD40 receptor (CD40L), high sensitive C-reactive protein (hsCRP), monocyte chemotactic protein -1, endothelial monocyte activating protein II, adhesive molecules (sICAM-1 and sVCAM 1), matrix metalloproteinase (MMP-3, MMP-7, MMP-9), tissue inhibitor of metalloproteinase (TIMP-1) and endothelin-1 were studied in blood and in coronary artery intima/media of men with coronary atherosclerosis without acute coronary syndrome. Blood levels of hsCRP, IL-8, IL-6 and CD40L were higher, while blood levels of sVCAM and TIMP-1 were lower in men with prevalence of unstable atherosclerotic plaques compared to men with prevalence of stable atherosclerotic plaques in coronary arteries. Blood levels of hsCRP, IL-6 and IL-8 correlated with characteristics of coronary artery atherosclerotic plaques instability. Correlation between hsCRP blood level and hsCRP concentration in coronary artery intima/media material was also revealed. PMID- 22839585 TI - [Isolated elevation of troponin-T level after percutaneous coronary interventions: clinical significance]. AB - Relationship between isolated elevation of troponin-T (Tn-T) level after percutaneous coronary interventions (PCI) and remote outcomes was studied in 124 patients with ischemic heart disease with normal level of creatine kinase MB fraction after elective PCI. Blood samples for measurement of markers of myocardial necrosis were taken before, and in 8 and 24 hours after PCI. Patients were divided into 2 groups: without (n=58, group 1) and with (n=54, group 2) postprocedural elevation of Tn-T level above upper limit of normal ( more or equal 0.03 hg/ml). During follow-up we registered primary end points (cardiac deaths, nonfatal myocardial infarctions [MI]) and composite criterion comprising first occurrence of either of these outcomes. We also assessed 1, 2, 3, 4 and 5 year survival. There were no inhospital deaths and no significant differences between groups in rate of nonfatal MI (2 vs 0%) and occurrence of composite criterion (2 vs 0%). During long term follow-up Tn-T elevation also was not associated with increased number of deaths. However nonfatal MIs were more frequent and risk of death/MI higher in group 2 compared with group 1(6.5 vs 9.3%, p>0.05 and 15.5 vs 16.7%; p>0.05, respectively). Five year survival of patients with elevated Tn-T was not lower compared with patients of group 1. PMID- 22839586 TI - [Clinical features and history of vasovagal syncope]. AB - Aim of this investigation was to study special characteristics of natural course of vasovagal syncope (VVS). During 3 years we examined 212 patients (44% men) in accordance with recommendations of European Society of Cardiology using tilt tests according to Westminster or Italian protocols for confirmation of vasovagal genesis. Depending on results of initial investigation patients were divided into 2 groups: group 1 comprised 144 patients (68%) satisfying criteria of VVS; group 2 comprised other patients (n=41, 19%) with transitory loss of consciousness of unclear origin. Patients with VVS were significantly younger (mean age 35.1+/ 13.6 and 44.4+/-13.,9 years, respectively; <0.01) with earlier appearance of first episode of fainting (16 vs. 39 years; <0,01). In most cases VVS appeared in the age younger than 35 years. Accuracy of anamnestic method for diagnosis of VVS was 99%. Forty one percent of patients with classical VVS had several potential causes of fainting (situational syncope, paroxysms of tachyarrhythmia, epilepcy). This could lead to mistakes at initial stage of diagnostics. Progressive clinical course was observed in 15% of patients and was associated either with syncopi of other, including nonvagal origin, or with increased frequency of previously stereotypical attacks. In every second patient with initially frequent recurrences of VVS we observed long spontaneous remissions. Nondrug methods of treatment were effective in 43% of these patients. Tilt test had high informative power for diagnostics of VVS. With this its informativity was low in patients with onset of fainting attacks in middle age and with atypical clinical picture. PMID- 22839587 TI - [Epidemiology of dilation cardiomyopathy]. PMID- 22839588 TI - [Alcohol, cardiovascular disease and physical health]. PMID- 22839589 TI - [Propafenone in the treatment of cardiac arrhythmias]. PMID- 22839590 TI - [Broadened indications for the use of selective beta-adrenoblockers]. AB - Broadened Indications to the prescription of selective -adrenoblockers in international and European recommendations are considered in this review. Selective beta-adrenoblockers have been shown to possess both good antihypertensive and neutral metabolic actions. Bisoprolol does not worsen lipid, carbohydrate metabolisms, and sexual function in men. Antiischemic activity of bisoprolol exceeds that of calcium channel blocker nifedipine. Generic preparation of bisoprolol according to a series of clinical studies can be successfully used both in patients with arterial hypertension and concomitant diseases and in patients with ischemic heart disease. PMID- 22839591 TI - [Pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery]. AB - More than 230 million surgical operations are performed yearly in the world and this number is continually growing. Thirty days mortality in moderate and high risk non-cardiac surgery is about 2% and exceeds 5% in patients with high cardiac risk. European Society of Cardiology (ESC) issued specific guidelines in 2009. ESC experts created clear stepwise algorithm for assessment of risk of cardiac complications in preoperative period and use of diagnostic and curative procedures aimed at its lowering. This allows to avoid unjustified investigations and drug therapy in operations with low cardiac risk and stresses significance of perioperative medical treatment. This review contains an analysis questioning some statements of the novel ESC guidelines such as reduction of preoperative cardiac tests and prophylactic revascularization of coronary arteries before operations with intermediate and high risk of cardiac complications. PMID- 22839592 TI - [Actual problems of the treatment of arterial hypertension (according to materials of European congresses of 2010 year)]. AB - The review is devoted to actual questions of successful control of arterial hypertension discussed at European cardiological congresses in 2010. Problems of therapeutic inertia, timing of initiation of antihypertensive therapy, necessity of treatment of prehypertension, and expediency of early starting combination drug therapy are considered. PMID- 22839593 TI - Palladium-catalyzed nitromethylation of aryl halides: an orthogonal formylation equivalent. AB - An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation. The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method that is compatible with many functional groups. PMID- 22839594 TI - High performance cellulose nanocomposites: comparing the reinforcing ability of bacterial cellulose and nanofibrillated cellulose. AB - This work investigates the surface and bulk properties of nanofibrillated cellulose (NFC) and bacterial cellulose (BC), as well as their reinforcing ability in polymer nanocomposites. BC possesses higher critical surface tension of 57 mN m(-1) compared to NFC (41 mN m(-1)). The thermal degradation temperature in both nitrogen and air atmosphere of BC was also found to be higher than that of NFC. These results are in good agreement with the higher crystallinity of BC as determined by XRD, measured to be 71% for BC as compared to NFC of 41%. Nanocellulose papers were prepared from BC and NFC. Both papers possessed similar tensile moduli and strengths of 12 GPa and 110 MPa, respectively. Nanocomposites were manufactured by impregnating the nanocellulose paper with an epoxy resin using vacuum assisted resin infusion. The cellulose reinforced epoxy nanocomposites had a stiffness and strength of approximately ~8 GPa and ~100 MPa at an equivalent fiber volume fraction of 60 vol.-%. In terms of the reinforcing ability of NFC and BC in a polymer matrix, no significant difference between NFC and BC was observed. PMID- 22839595 TI - Physical inactivity and arterial dysfunction in patients with rheumatoid arthritis. AB - OBJECTIVES: The increased risk of cardiovascular (CV) disease associated with rheumatoid arthritis (RA) is partly attributable to chronic inflammation, but traditional CV risk factors such as physical inactivity are also likely to be important. This study assessed the cross-sectional relationship between physical activity (PA) and arterial dysfunction in patients with RA. METHODS: Participants free of overt arterial disease aged 40-65 years were recruited from a consecutive series of RA patients attending a rheumatology clinic. A research nurse measured the 'augmentation index' (AIX%) on a single occasion (a higher AIX% indicates arterial dysfunction) using SphygmoCor radial pulse wave analysis (PWA) according to current recommendations. Participants provided a fasting blood sample and self completed a patient questionnaire that included the modified Godin PA score (mGPAS). Analysis was adjusted for age, sex, CV and rheumatological factors using multiple linear regression. RESULTS: Among 114 patients (mean age 54 years, median arthritis duration 10 years, 82% women), mean AIX% was 31.5 (SD 7.7) and median mGPAS 15 (IQR 10-35). AIX% was correlated with mGPAS (rho -0.21, p = 0.02). AIX% decreased with more frequent vigorous PA. On unadjusted analysis, a 10-point higher mGPAS was associated with a -0.9 [95% confidence interval (CI) 1.3 to -0.4, p = 0.0005] lower AIX%. On adjusted analysis, the reduction was attenuated to -0.5 (95% CI -0.8 to -0.1, p = 0.03). CONCLUSIONS: A higher level of self-reported PA in RA patients is associated with a lower level of arterial dysfunction independently of other CV and rheumatological factors. Longitudinal studies are required to demonstrate that increased PA improves arterial dysfunction in RA patients. PMID- 22839596 TI - Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS. AB - BACKGROUND: It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO). RESULTS: We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR) method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs). Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA) method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the alpha = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the alpha = 0.05 level. A GO category was determined to replicate if that category was significant at the alpha = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, 'Regulation of Cellular Component Organization and Biogenesis', a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, 'Actin Cytoskeleton', a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. CONCLUSIONS: Pathway analysis of pairwise genetic associations in two GWAS of sporadic ALS revealed a set of genes involved in cellular component organization and actin cytoskeleton, more specifically, that were not reported by prior GWAS. However, prior biological studies have implicated actin cytoskeleton in ALS and other motor neuron diseases. This study supports the idea that pathway-level analysis of GWAS data may discover important associations not revealed using conventional one-SNP-at-a-time approaches. PMID- 22839598 TI - Production of aqueous spherical gold nanoparticles using conventional ultrasonic bath. AB - A conventional ultrasonic bath was used to examine the feasibility of forming aqueous spherical gold nanoparticles (GNPs) under atmospheric conditions. The effects of ultrasonic energy on the size and morphology of GNPs were also investigated. Highly monodispersed spherical GNPs were successfully synthesised by sodium citrate reduction in a conventional ultrasonic bath, without an additional heater or magnetic stirrer, as evidenced by ultraviolet-visible spectra and transmission electron microscopy. Ultrasonic energy was shown to be a key parameter for producing spherical GNPs of tunable sizes (20 to 50 nm). A proposed scheme for understanding the role of ultrasonic energy in the formation and growth of GNPs was discussed. The simple single-step method using just a conventional ultrasonic bath as demonstrated in this study offers new opportunities in the production of aqueous suspensions of monodispersed spherical GNPs. PMID- 22839597 TI - Prevalence of psychological distress and associated factors in tuberculosis patients in public primary care clinics in South Africa. AB - BACKGROUND: Psychological distress has been rarely investigated among tuberculosis patients in low-resource settings despite the fact that mental ill health has far-reaching consequences for the health outcome of tuberculosis (TB) patients. In this study, we assessed the prevalence and predictors of psychological distress as a proxy for common mental disorders among tuberculosis (TB) patients in South Africa, where over 60 % of the TB patients are co-infected with HIV. METHODS: We interviewed 4900 tuberculosis public primary care patients within one month of initiation of anti-tuberculosis treatment for the presence of psychological distress using the Kessler-10 item scale (K-10), and identified predictors of distress using multiple logistic regressions. The Kessler scale contains items associated with anxiety and depression. Data on socio-demographic variables, health status, alcohol and tobacco use and adherence to anti-TB drugs and anti-retroviral therapy (ART) were collected using a structured questionnaire. RESULTS: Using a cut off score of >=28 and >=16 on the K-10, 32.9 % and 81 % of tuberculosis patients had symptoms of distress, respectively. In multivariable analysis older age (OR = 1.52; 95 % CI = 1.24-1.85), lower formal education (OR = 0.77; 95 % CI = 0.65-0.91), poverty (OR = 1.90; 95 % CI = 1.57 2.31) and not married, separated, divorced or widowed (OR = 0.74; 95 % CI = 0.62 0.87) were associated with psychological distress (K-10 >=28), and older age (OR = 1.30; 95 % CI = 1.00-1.69), lower formal education (OR = 0.55; 95 % CI = 0.42 0.71), poverty (OR = 2.02; 95 % CI = 1.50-2.70) and being HIV positive (OR = 1.44; 95 % CI = 1.19-1.74) were associated with psychological distress (K-10 >=16). In the final model mental illness co-morbidity (hazardous or harmful alcohol use) and non-adherence to anti-TB medication and/or antiretroviral therapy were not associated with psychological distress. CONCLUSIONS: The study found high rates of psychological distress among tuberculosis patients. Improved training of providers in screening for psychological distress, appropriate referral to relevant health practitioners and providing comprehensive treatment for patients with TB who are co-infected with HIV is essential to improve their health outcomes. It is also important that structural interventions are promoted in order to improve the financial status of this group of patients. PMID- 22839643 TI - Noncovalent template-assisted mimicry of multiloop protein surfaces: assembling discontinuous and functional domains. AB - We report here a novel noncovalent synthetic strategy for template-assembled de novo protein design. In this approach, a peptide was first conjugated with two oligoguanosine strands via click chemistry and the conjugates were then self assembled in the presence of metal ions. G-quadruplex formation directs two peptide strands to assemble on one face of the scaffold and form an adjacent two loop surface. This approach can be used to rapidly prepare multiple two-loop structures with both homo- and heterosequences. PMID- 22839645 TI - Wildlife and the coal waste policy debate: proposed rules for coal waste disposal ignore lessons from 45 years of wildlife poisoning. AB - This analysis examines wildlife poisoning from coal combustion waste (CCW) in the context of EPA's proposed policy that would allow continued use of surface impoundments as a disposal method. Data from 21 confirmed damage sites were evaluated, ranging from locations where historic poisoning has led to corrective actions that have greatly improved environmental conditions to those where contamination has just recently been discovered and the level of ecological impacts has yet to be determined. The combined direct and indirect cost of poisoned fish and wildlife exceeds $2.3 billion, which is enough money to construct 155 landfills with state-of-the-art composite liners and leachate collection systems. This cost is projected to increase by an additional $3.85 billion over the next 50 years, an amount that would construct 257 landfills. Evidence revealed through this study indicates the following: (1) for the past 45 years, environmental damage has been a recurring theme with surface impoundment of CCW, (2) the National Pollutant Discharge Elimination System has not been effective in preventing serious environmental damage from CCW, (3) EPA's Regulatory Impact Analysis of the costs and benefits of pollution control options fails to include benefits of avoided damages to natural resources, specifically, poisoned fish and wildlife, and (4) surface impoundments pose unacceptably high ecological risks regardless of location or design. Regulators should no longer ignore rigorous science and the lessons from multiple case examples. EPA and the United States need to show leadership on this issue by prohibiting surface impoundments, particularly since the rise in coal use in developing countries is leading to the same CCW pollution problems on a global scale. PMID- 22839644 TI - A tale of 10 European centres - 2010 APOSSM travelling fellowship review in ACL surgery. AB - The purpose of ESSKA- APOSSM Travelling fellowship is to better understand the epidemiology, management and surgical techniques for sports across continents. There has been a progressive evolution in ACL reconstruction and there is variation in technique in ACL reconstruction amongst the most experienced surgeons in different continents. During this one month fellowship, we saw various ACL reconstruction techniques using different graft sources, with a variety of graft fixation methods, with the common aim of recreating an anatomical ACL reconstruction. PMID- 22839646 TI - A high throughput DNA extraction method with high yield and quality. AB - BACKGROUND: Preparation of large quantity and high quality genomic DNA from a large number of plant samples is a major bottleneck for most genetic and genomic analyses, such as, genetic mapping, TILLING (Targeting Induced Local Lesion IN Genome), and next-generation sequencing directly from sheared genomic DNA. A variety of DNA preparation methods and commercial kits are available. However, they are either low throughput, low yield, or costly. Here, we describe a method for high throughput genomic DNA isolation from sorghum [Sorghum bicolor (L.) Moench] leaves and dry seeds with high yield, high quality, and affordable cost. RESULTS: We developed a high throughput DNA isolation method by combining a high yield CTAB extraction method with an improved cleanup procedure based on MagAttract kit. The method yielded large quantity and high quality DNA from both lyophilized sorghum leaves and dry seeds. The DNA yield was improved by nearly 30 fold with 4 times less consumption of MagAttract beads. The method can also be used in other plant species, including cotton leaves and pine needles. CONCLUSION: A high throughput system for DNA extraction from sorghum leaves and seeds was developed and validated. The main advantages of the method are low cost, high yield, high quality, and high throughput. One person can process two 96-well plates in a working day at a cost of $0.10 per sample of magnetic beads plus other consumables that other methods will also need. PMID- 22839647 TI - Correlations of coronary plaque wall thickness with wall pressure and wall pressure gradient: a representative case study. AB - BACKGROUND: There are two major hemodynamic stresses imposed at the blood arterial wall interface by flowing blood: the wall shear stress (WSS) acting tangentially to the wall, and the wall pressure (WP) acting normally to the wall. The role of flow wall shear stress in atherosclerosis progression has been under intensive investigation, while the impact of blood pressure on plaque progression has been under-studied. METHOD: The correlations of wall thickness (WT) with wall pressure (WP, blood pressure on the lumen wall) and spatial wall pressure gradient (WPG) in a human atherosclerotic right coronary artery were studied. The pulsatile blood flow was simulated using a three dimensional mathematical model. The blood was treated as an incompressible viscous non-Newtonian fluid. The geometry of the artery was re-constructed using an in vivo intravascular ultrasound (IVUS) 44-slice dataset obtained from a patient with consent obtained. The WT, the WP and the WPG were averaged on each slice, respectively, and Pearson correlation analysis was performed on slice averaged base. Each slice was then divided into 8 segments and averaged vessel WT, WP and WPG were collected from all 352 segments for correlation analysis. Each slice was also divided into 2 segments (inner semi-wall of bend and outer semi-wall of bend) and the correlation analysis was performed on the 88 segments. RESULTS: Under mean pressure, the Pearson coefficient for correlation between WT and WP was r = - 0.52 (p < 0.0001) by 2-segment analysis and r = - 0.81 (p < 0.0001) by slice averaged analysis, respectively. The Pearson coefficient for correlation between WT and WPG was r = 0.30 (p = 0.004) by 2-segment analysis and r = 0.45 (p = 0.002) by slice averaged analysis, respectively. The r-values corresponding to systole and diastole pressure conditions were similar. CONCLUSIONS: Results from this representative case report indicated that plaque wall thickness correlated negatively with wall pressure (r = -0.81 by slice) and positively with wall pressure gradient (r = 0.45). The slice averaged WT has a strong linear relationship with the slice averaged WP. Large-scale patient studies are needed to further confirm our findings. PMID- 22839648 TI - Control of alpha-calcium sulfate hemihydrate morphology using reverse microemulsions. AB - Alpha calcium sulfate hemihydrate (alpha-HH) is an important class of cementitious material and exhibits considerable morphology-dependent properties. In the reverse microemulsions of water/n-hexanol/cetyltrimethylammonium bromide (CTAB)/sodium dodecyl sulfonate (SDS), the morphology and aspect ratio of alpha HH are successfully controlled by adjusting the mass ratio of CTAB/H(2)O and the concentration of SDS. As the ratio of CTAB/H(2)O is increased from 1.3 to 4.5, the crystal length decreases from 120 to 150 MUm to 0.5-1.2 MUm with the corresponding aspect ratio reduced sharply from 180 to 250 to 2-7. With increasing SDS concentration, the crystal morphology gradually changes from submicrometer-sized long column to rod, hexagonal plate, and even nanogranule. The preferential adsorption of CTAB on the side facets and SDS on the top facets contributes to the morphology control. This work presents a simple, versatile, highly efficient approach to controlling the morphology of alpha-HH on a large scale and will offer more opportunities for alpha-HH multiple applications. PMID- 22839650 TI - Direct synthesis of beta-alkyl N-aryl aza Baylis-Hillman adducts via nitroso-ene reaction. AB - A new approach for the direct Fe-catalyzed synthesis of beta-alkyl N-aryl aza Baylis-Hillman (ABH) adducts is reported. This approach involves the formation of a C-N bond via a nitroso-ene reaction. This is a simple, fast, and best alternate method to overcome the substrate scope limitations of the ABH reaction, which converts allyl esters and carbonyl compounds to novel ABH adducts. A variety of arylhydroxylamines reacted with esters, aldehydes, ketone, and nitriles to yield the corresponding products in moderate to excellent yields. PMID- 22839649 TI - A novel method of selective removal of human DNA improves PCR sensitivity for detection of Salmonella Typhi in blood samples. AB - BACKGROUND: Enteric fever is a major public health problem, causing an estimated 21million new cases and 216,000 or more deaths every year. Current diagnosis of the disease is inadequate. Blood culture only identifies 45 to 70% of the cases and is time-consuming. Serological tests have very low sensitivity and specificity. Clinical samples obtained for diagnosis of enteric fever in the field generally have <1 organism/ml of blood, so that even PCR-based methods, widely used for detection of other infectious diseases, are not a straightforward option in typhoid diagnosis. We developed a novel method to enrich target bacterial DNA by selective removal of human DNA from blood samples, enhancing the sensitivity of PCR tests. This method offers the possibility of improving PCR assays directly using clinical specimens for diagnosis of this globally important infectious disease. METHODS: Blood samples were mixed with ox bile for selective lysis of human blood cells and the released human DNA was then digested with addition of bile resistant micrococcal nuclease. The intact Salmonella Typhi bacteria were collected from the specimen by centrifugation and the DNA extracted with QIAamp DNA mini kit. The presence of Salmonella Typhi bacteria in blood samples was detected by PCR with the fliC-d gene of Salmonella Typhi as the target. RESULTS: Micrococcal nuclease retained activity against human blood DNA in the presence of up to 9% ox bile. Background human DNA was dramatically removed from blood samples through the use of ox bile lysis and micrococcal nuclease for removal of mammalian DNA. Consequently target Salmonella Typhi DNA was enriched in DNA preparations and the PCR sensitivity for detection of Salmonella Typhi in spiked blood samples was enhanced by 1,000 fold. CONCLUSIONS: Use of a combination of selective ox-bile blood cell lysis and removal of human DNA with micrococcal nuclease significantly improves PCR sensitivity and offers a better option for improved typhoid PCR assays directly using clinical specimens in diagnosis of this globally important infection disease which we believe could be of importance in improving clinical care and providing effective evaluation of novel vaccines. PMID- 22839651 TI - Long-term radiosurgery effects in the treatment of temporal lobe epilepsy. AB - Epilepsy surgery is an effective treatment for medically resistant temporal lobe epilepsy (TLE). To minimize complication rates and potentially improve neuropsychology outcomes, stereotactic radiosurgery (SRS) has been explored as an alternative. Two pilot trials have demonstrated the effectiveness of SRS for the treatment of medically resistant TLE, with seizure-free outcomes for approximately 65% of patients at last follow-up. Despite encouraging results, no conclusive long-term outcomes are available for SRS. This article discusses a single patient who presented with recurrent seizures, worsening headaches, and persistent abnormal MRI findings 7 years and 8 months after SRS. This 29-year old woman with a history of medically refractory complex partial seizures since childhood was referred for evaluation. Medical management had failed in this patient. The workup was compatible with left mesial temporal lobe onset, with MRI findings suggestive of mesial temporal sclerosis. In 2003, at the age of 23 years, she underwent Gamma Knife surgery (GKS) targeting the left temporal mesial area with a dose of 24 Gy at the 50% marginal isodose line. After GKS, the patient's seizures decreased in frequency over several months, but auras were persistent. Nine months after treatment, she developed worsening headaches. A follow-up MRI study demonstrated a thick, irregular, enhancing lesion in the medial part of the temporal lobe. She was placed on corticosteroids, with resolution of her headaches. Her seizures and headaches recurred in March 2010. An MRI study showed a 2.2-cm, ill-defined, enhancing cystic lesion in the left mesial temporal lobe with T2 and FLAIR hyperintensity, which was presumably radiation induced. At that time, the patient opted for left temporal lobe resection to control her seizures. Histological examination showed moderately severe, remote, longstanding sclerosis at the level of the hippocampus. A vascular lesion was identified, and it was most consistent with radiation-induced capillary hemangioma. The entorhinal region was severely damaged, with hemorrhage, necrosis, neuronal loss, astrogliosis, and hemosiderin deposition. There was evidence of radiation vasculopathy. Radiation-induced lesions after SRS for the treatment of epilepsy are not well documented. Although GKS is a promising technique for the treatment of medically resistant TLE, the ideal candidate is not yet well defined. The selection of the appropriate technical parameters to obtain a desirable functional effect without histological damage to the surrounding neural tissue remains a challenge. This case illustrates the need for long-term follow-up when radiosurgery is used for epilepsy. PMID- 22839652 TI - Editorial: hypothermia. PMID- 22839653 TI - Letter to the Editor: Venous thromboembolism. PMID- 22839654 TI - A radiopathological classification of dural tail sign of meningiomas. AB - OBJECT: The completeness of meningioma resection depends on the resection of dura mater invaded by the tumor. The pathological changes of the dura around the tumor can be interpreted by evaluating the dural tail sign (DTS) on MRI studies. The goal of this study was to clarify the pathological characteristics of the DTSs, propose a classification based on the histopathological and radiological correlation, and identify the invasive range of tumor cells in different types of DTS. METHODS: The authors retrospectively reviewed 179 patients with convexity meningiomas who underwent Simpson Grade I resection. All patients underwent an enhanced MRI examination preoperatively. The convexity meningiomas were dichotomized into various subtypes in accordance with the 2007 WHO classification of tumors of the CNS, and the DTS was identified based on the Goldsher criteria. The range of resection of the involved dura was 3 cm from the base of the tumor, which corresponded with the length of DTS on MRI studies. Histopathological examination of dura at 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 cm from the base of the tumor was conducted, and the findings were correlated with the preoperative MRI appearance of the DTS. RESULTS: A total of 154 (86%) of 179 convexity meningiomas were classified into WHO Grade I subtype, including transitional (44 [28.6%] of 154), meningothelial (36 [23.4%] of 154), fibrous (23 [14.9%] of 154), psammomatous (22 [14.3%] of 154), secretory (10 [6.5%] of 154), and angiomatous (19 [12.3%] of 154). The other 25 (14%) were non-Grade I (WHO) tumors, including atypical (12 [48%] of 25), anaplastic (5 [20%] of 25), and papillary (8 [32%] of 25). The DTS was classified into 5 types: smooth (16 [8.9%] of 179), nodular (36 [20.1%] of 179), mixed (57 [31.8%] of 179), symmetrical multipolar (15 [8.4%] of 179), and asymmetrical multipolar (55 [30.7%] of 179). There was a significant difference in distribution of DTS type between Grade I and non-Grade I tumors (p = 0.004), whereas the difference was not significant among Grade I tumors (0.841) or among non-Grade I tumors (p = 0.818). All smooth-type DTSs were encountered in Grade I tumors, and the mixed DTS (52 [33.8%] of 154) was the most common type in these tumors. Nodular-type DTS was more commonly seen in non-Grade I tumors (12 [48%] of 25). Tumor invasion was found in 88.3% (158 of 179) of convexity meningiomas, of which the range of invasion in 82.3% (130 of 158) was within 2 cm and that in 94.9% (150 of 158) was within 2.5 cm. The incidence of invasion and the range invaded by tumor cells varied in different types of DTS, and differences were statistically significant (p < 0.001). CONCLUSIONS: Nodular-type DTS on MRI studies might be associated with non-Grade I tumors. The range of dural resection for convexity meningiomas should be 2.5 cm from the tumor base, and if this extent of resection is not feasible, the type of DTS should be considered. However, for skull base meningiomas, in which mostly Simpson Grade II resection is achieved, the use of this classification should be further validated. The classification of DTS enables the surgeon to predict preoperatively and then to achieve the optimal range of dural resection that might significantly reduce the recurrence rate of meningiomas. PMID- 22839655 TI - Editorial: dural tail sign. PMID- 22839656 TI - Early induction of hypothermia for evacuated intracranial hematomas: a post hoc analysis of two clinical trials. AB - OBJECT: The authors hypothesized that cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury and, if so, further hypothesized that hypothermia induction before or soon after craniotomy should be associated with improved outcomes. METHODS: The National Acute Brain Injury Study: Hypothermia I (NABIS:H I) was a randomized multicenter clinical trial of 392 patients with severe brain injury treated using normothermia or hypothermia for 48 hours with patients reaching 33 degrees C at 8.4 +/- 3 hours after injury. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) was a randomized, multicenter clinical trial of 97 patients with severe brain injury treated with normothermia or hypothermia for 48 hours with patients reaching 35 degrees C within 2.6 +/- 1.2 hours and 33 degrees C within 4.4 +/- 1.5 hours of injury. Entry and exclusion criteria, management, and outcome measures in the 2 trials were similar. RESULTS: In NABIS:H II among the patients with evacuated intracranial hematomas, outcome was poor (severe disability, vegetative state, or death) in 5 of 15 patients in the hypothermia group and in 9 of 13 patients in the normothermia group (relative risk 0.44, 95% CI 0.22-0.88; p = 0.02). All patients randomized to hypothermia reached 35 degrees C within 1.5 hours after surgery start and 33 degrees C within 5.55 hours. Applying these criteria to NABIS:H I, 31 of 54 hypothermia-treated patients reached a temperature of 35 degrees C or lower within 1.5 hours after surgery start time, and the remaining 23 patients reached 35 degrees C at later time points. Outcome was poor in 14 (45%) of 31 patients reaching 35 degrees C within 1.5 hours of surgery, in 14 (61%) of 23 patients reaching 35 degrees C more than 1.5 hours of surgery, and in 35 (60%) of 58 patients in the normothermia group (relative risk 0.74, 95%, CI 0.49-1.13; p = 0.16). A meta-analysis of 46 patients with hematomas in both trials who reached 35 degrees C within 1.5 hours of surgery start showed a significantly reduced rate of poor outcomes (41%) compared with 94 patients treated with hypothermia who did not reach 35 degrees C within that time and patients treated at normothermia (62%, p = 0.009). CONCLUSIONS: Induction of hypothermia to 35 degrees C before or soon after craniotomy with maintenance at 33 degrees C for 48 hours thereafter may improve outcome of patients with hematomas and severe traumatic brain injury. Clinical trial registration no.: NCT00178711. PMID- 22839657 TI - Development of a universal colorimetric indicator for G-quadruplex structures by the fusion of thiazole orange and isaindigotone skeleton. AB - The rapid and convenient method for identification of all kinds of G-quadruplex is highly desirable. In the present study, a novel colorimetric indicator for a vast variety of G-quadruplex was designed and synthesized on the basis of thiazole orange and isaindigotone skeleton. Its distinct color change enables label-free visual detection of G-quadruplexes, which is due to the disassembly of dye H-aggregates to monomers. This specific detection of G-quadruplex arises from its end-stacking interaction with G-quartet. On the basis of this universal indicator, a facile approach for large-scale identification of G-quadruplex was developed. PMID- 22839658 TI - Balancing noise and plasticity in eukaryotic gene expression. AB - BACKGROUND: Coupling the control of expression stochasticity (noise) to the ability of expression change (plasticity) can alter gene function and influence adaptation. A number of factors, such as transcription re-initiation, strong chromatin regulation or genome neighboring organization, underlie this coupling. However, these factors do not necessarily combine in equivalent ways and strengths in all genes. Can we identify then alternative architectures that modulate in distinct ways the linkage of noise and plasticity? RESULTS: Here we first show that strong chromatin regulation, commonly viewed as a source of coupling, can lead to plasticity without noise. The nature of this regulation is relevant too, with plastic but noiseless genes being subjected to general activators whereas plastic and noisy genes experience more specific repression. Contrarily, in genes exhibiting poor transcriptional control, it is translational efficiency what separates noise from plasticity, a pattern related to transcript length. This additionally implies that genome neighboring organization -as modifier- appears only effective in highly plastic genes. In this class, we confirm bidirectional promoters (bipromoters) as a configuration capable to reduce coupling by abating noise but also reveal an important trade-off, since bipromoters also decrease plasticity. This presents ultimately a paradox between intergenic distances and modulation, with short intergenic distances both associated and disassociated to noise at different plasticity levels. CONCLUSIONS: Balancing the coupling among different types of expression variability appears as a potential shaping force of genome regulation and organization. This is reflected in the use of different control strategies at genes with different sets of functional constraints. PMID- 22839659 TI - Preparation and properties of electrospun soy protein isolate/polyethylene oxide nanofiber membranes. AB - Soy protein isolate (SPI) and polyethylene oxide (PEO) were dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and nonwoven nanofiber membranes were prepared from the solution by electrospinning. PEO functioned as a cospinning polymer in the process to improve the spinnability of SPI. The ratio of SPI to PEO was varied and the rest spinning conditions remained unchanged. The morphology of the nanofiber membranes, SPI and PEO distribution and phase structure in the fiber, crystallization and interaction between SPI and PEO, thermal properties and wettability of the membranes were studied. The results showed that the diameter of most of the nanofibers was in the range of 200-300 nm. SPI and PEO showed high compatibility in the fiber and SPI was homogeneously dispersed at nanoscale. Crystallization of SPI and PEO in the fiber was significantly different from that of their pure forms. All the nanofiber membranes showed superhydrophilicity. These nanofiber membranes can find importance in filtration and biomedical applications. PMID- 22839661 TI - 'Wagon-wheel' mask as a tool to study anisotropy of porous silicon formation rate. AB - Relationship between the rate of electrochemical formation of mesoporous Si and the crystallographic directions has been studied by local anodization of wafers through a mask having the form of narrow long wedges radiating from the center in all directions ('wagon-wheel' mask). The etching rates were found from the side etching under the thin transparent n-Si mask. On p+-substrates of various orientation diagrams characterizing the distribution of pore formation rates over different directions in the wafer plane were constructed for the first time. The wagon-wheel method was applied to study the current dependence of the anisotropy. It was found that the orientation-related difference between the pore formation rates is 5% to 25%, depending on the crystallographic direction and the etching current density. At a current density of approximately 9 mA/cm2, the etching rates are related as V100:V113:V110:V112:V111 = 1.000:0.900:0.836:0.824:0.750. A general tendency is observed toward weakening of the anisotropy with increasing current. The highest rate always corresponds to the <100 > direction, and the rate ratio between the other directions varies with increasing current, which leads to a change of their sequence. PMID- 22839660 TI - A note on the graphical presentation of prediction intervals in random-effects meta-analyses. AB - BACKGROUND: Meta-analysis is used to combine the results of several related studies. Two different models are generally applied: the fixed-effect (FE) and random-effects (RE) models. Although the two approaches estimate different parameters (that is, the true effect versus the expected value of the distribution of true effects) in practice, the graphical presentation of results is the same for both models. This means that in forest plots of RE meta-analyses, no estimate of the between-study variation is usually given graphically, even though it provides important information about the heterogeneity between the study effect sizes. FINDINGS: In addition to the point estimate of the between study variation, a prediction interval (PI) can be used to determine the degree of heterogeneity, as it provides a region in which about 95% of the true study effects are expected to be found. To distinguish between the confidence interval (CI) for the average effect and the PI, it may also be helpful to include the latter interval in forest plots. We propose a new graphical presentation of the PI; in our method, the summary statistics in forest plots of RE meta-analyses include an additional row, '95% prediction interval', and the PI itself is presented in the form of a rectangle below the usual diamond illustrating the estimated average effect and its CI. We then compare this new graphical presentation of PIs with previous proposals by other authors. The way the PI is presented in forest plots is crucial. In previous proposals, the distinction between the CI and the PI has not been made clear, as both intervals have been illustrated either by a diamond or by extra lines added to the diamond, which may result in misinterpretation. CONCLUSIONS: To distinguish graphically between the results of an FE and those of an RE meta-analysis, it is helpful to extend forest plots of the latter approach by including the PI. Clear presentation of the PI is necessary to avoid confusion with the CI of the average effect estimate. PMID- 22839662 TI - [Predictors of non-fulfillment of reperfusion therapy in patients with ST elevation acute coronary syndrome]. AB - At present reperfusion therapy in ST-elevation (STE) acute coronary syndrome (ACS) is carried out in majority of countries not more than in 70% of cases. We analyzed predictors of non-fulfillment of reperfusion therapy in patients with STEACS included into ACS registry conducted in the Kemerovo cardiological dispensary. Reperfusion therapy was not carried out in 154 patients with STEACS (36.2%). Main predictors of non-fulfillment of reperfusion were age older than 75 years (odds ratio [OR] 47.97, 95% confidence interval [CI] 19.47-118.21), admission later than in 12 hours after onset of disease (OR 4.29, 95%CI 1.52 12.13), history of myocardial infarction (OR 2.68, 95%CI 1.11-6.48). Thus there are factors including subjective ones which preclude full-fledged use of contemporary recommendations on the management of patients with STEACS. PMID- 22839663 TI - [Prehospital thrombolysis acute coronary syndrome in patients with acute left bundle branch block]. AB - Analyzed 30-days survival in 18 patients after a system of dark prehospital thrombolysis performed for an acute coronary syndrome (ACS) with acute left bundle branch block (LBBB). Survival after thrombolytic therapy (TLT) was 4 times higher than in patients with acute coronary syndrome and acute blockade LBBB without TLT. It is concluded that thrombolytic therapy leads to a reduction of the QRS complex in 66% of patients. PMID- 22839664 TI - [Prognostic significance of platelet metabolism in patients with cerebrovascular complications of hypertension in combination with coronary heart disease]. AB - The study of hemostasis and NAD(P)-dependent platelet dehydrogenases activity was made in 90 patients with cerebrovascular complications (development of ischemic stroke) of hypertension and coronary heart disease. On the basis of NADP dependent platelet dehydrogenases activity we suggested a mode of prognostication a development of repeated cerebrovascular complications of thrombotic nature (the acute stroke, transitory ischemic attack, acute myocardial infarction, cardiovascular death). The proposed prognostic factor has heightened sensibility and specificity. PMID- 22839665 TI - [Relationship between the structure-functional state of the heart and brain natriuretic peptide level in patients with arterial hypertension]. AB - We studied relationship between structure-functional parameters of left and right cardiac chambers and N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 118 patients with arterial hypertension (AH) (35 men, 83 women) and 17 healthy volunteers. Methods comprised 24-hour arterial pressure monitoring (APM), two dimensional echocardiography (echoCG), Doppler echoCG, and tissue echoCG of mitral and tricuspid atrioventricular annuli, treadmill test, 6-min walk test, and measurement of NT-proBNP level in blood plasma. In patients with AH blood plasma NT-proBNP level was significantly higher than in a group of healthy persons of similar age. Elevation of this biochemical marker was accompanied by significant change of characteristics of remodeling of left and right parts of the heart, abnormalities of left ventricular diastolic function according to transmitral blood flow, disturbances of left ventricular diastolic and systolic function according to tissue Doplerography data. Comparative analysis of structure-functional parameters of the heart and NT-proBNP level in patients with AH allowed to reveal more significant changes of parameters of diastolic and systolic remodeling, local and global diastolic and systolic left ventricular function in patients with NT-proBNP levels more than 306 mol/ml. Factors determining NT-proBNP level in patients with AH were age, free right ventricular wall thickness, and body mass index. PMID- 22839666 TI - [Endogenous sex hormone testosterone and haemostatic factors in young men after myocardial infarction]. AB - OBJECTIVES: To compare levels of haemostatic factors and sex hormones in young men after myocardial infarction, to study relationship between sex hormones and factors of hemostasis. METHODS: We studied 32 men aged 30-50 years with diagnosis of myocardial infarction. Patients were divided into 2 groups according to age: group 1 - 11 patients aged 30-39 years, group 2 - 21 patients aged of 40-50 years. Levels of sex hormones were measured by IFA. Level of fibrinogen, prothrombin index, plasma recalcification time, fibrinolytic activity, indices of aggregation and disaggregation were also determined. RESULTS: Testosterone level in the group I was more decreased in comparison with the Group 2 and level of fibrinogen was higher in the group 1 (3.9+/-0,7) in comparison with the group II (3.1+/-0.8; p<0.05). Pearsons correlation between estradiol and fibrinogen in the group 1 was 0.613 (p<0.05). No such relationship was found in the group 2. Pearsons correlation between testosterone and prothrombin index was 0,477 (p<0.009). CONCLUSION: Endogenous testosterone level is one of the factors which influence haemostatic system, but this effect is not well-defined and requires further study. PMID- 22839667 TI - [Prevalence of multifocal atherosclerosis in different age groups]. AB - Aim of the study was to assess prevalence of lesions in several arterial beds in patients with atherosclerosis of various localization in the clinic of cardiovascular surgery. We examined 1018 patients (825 men and 193 women, aged 31 78 years, mean age 59+/-12 years) in the period of preparation to elective surgical interventions on coronary arteries or other arterial beds. All patients were divided into 4 age groups: group 1 - younger than 60 years (n=542), group 2 - 60-64 years (n=215), group 3 - 65-69 years (n=141), group 4-70 years and older (n=120). All patients were subjected to coronary angiography and Doppler ultrasound investigation (USI) of extracranial arteries. USI of arteries of lower extremities and angiography of peripheral arteries were carried out if indicated. Presence of 50% or greater stenosis was considered a criterion of involvement of an arterial vascular bed. Lesions in 2 or more beds were found in 321 patients (31.5%). Stenoses in 2 and 3 arterial beds were revealed in 24 and 3.5%, respectively, of patients in group 1, and in 31.8 and 10%, respectively, of patients in group 4 (p=0.008). Purposeful diagnostics of multifocal atherosclerosis in patients of the given category apparently should not be limited by older age groups. PMID- 22839668 TI - [Periportal cardiomyopathy. Some peculiarities of clinical picture and course of the disease]. AB - Results of the study of special characteristics of the course of chronic heart failure (CHF) in women with periportal cardiomyopathy (PCMP) are presented. We have found that prevalence of PCMP in the structure of dilated cardiomyopathy is 9.5%. PCMP compared with idiopathic cardiomyopathy is characterized by less pronounced dilation of left cardiac chambers, relative preservation of left ventricular contractile function, more favorable course of CHF with lower frequency of destabilizations of clinical state. PCMP has developed mainly during postportal period and in women with preexisting anemia and chronic viral diseases. PMID- 22839669 TI - [Analysis of causes of pulmonary artery embolism hypodiagnostics at prehospital stage]. AB - Aim of the study was to analyze causes of pulmonary artery thromboembolism (PATE) hypodiagnostics at prehospital stage. We compared clinical and electrocardiographic picture of acute period of the disease in groups of patients with diagnosed (n=61) and undiagnosed (n=22) PATE at prehospital stage. We also assessed retrospectively probability of PATE according to Revised Geneva Score. In 49 cases we analyzed dynamics of the acute period of PATE. The analysis showed that in more than 50% of cases hypodiagnostics of PATE was caused by similarity of observed clinical and electrocardiographical picture and that of acute coronary syndrome. There were no differences between groups in Revised Geneva Score. PMID- 22839670 TI - [Effect of short term graded physical exercise on the level of glycemia in children and adolescents with type 1 diabetes mellitus: data of long term ECG monitoring and registration of motor activity]. AB - Study aim was to elucidate effect of graded physical exercise on glycemia level and interval QT duration in children and adolescents with type 1 diabetes mellitus. We carried out 25-hours parallel monitoring of glycemia, ECG and physical activity in 15 children and adolescents aged 9-17 years. During monitoring these patients performed an exercise test (PWC170). We found that there were two periods of significant and prolonged lowering of glycemia: in 120 420 min and 19-21 hours after exercise. Lowering of glycemia after physical exercise was associated with prolongation of QT interval. Registration of motor activity allowed to exclude changes of glycemia due to physical activity unrelated to graded exercise. PMID- 22839671 TI - [Assessment of vasovagal origin of syncope based on history features]. AB - Study aim was to elaborate questionnaire for diagnostics of vasovagal syncope (VVS) based on data of anamnesis. We examined 182 patients (mean age 37.1+/-14.3 years, 78 men, 104 women). Initial examination included anamnesis, physical examination, electrocardiography at rest, measurement of blood pressure in orthostasis. Each patient was asked 82 questions describing duration of symptoms, characteristics of episodes of loss of consciousness, symptoms of prodromal period before loss on consciousness and in the period of recovery. As a standard method of VVS diagnostics of we used tilt test (TT) according to Westminster or Italian protocols. Using methods of statistical analysis we created questionnaire for diagnostics of VVS. Tilt-positive group comprised 108 patients (age 35.9+/ 14.6 years, 45% men), tilt-negative group comprised 74 patients (age 36.1+/-14.3 years, 39% men). Of 82 testing questions 8 had probability ratio (PR) >1 and were significant predictors (<0.05) of positive TT. Seven questions had <1 and were significant predictors (<0.05) of negative TT. These questions were included into logistical regression analysis. The final variant of the questionnaire comprises 15 vasovagal origin questions. Total score necessary for diagnosis of VVS is more or equal 1. Sensitivity of questionnaire for prediction of positive result of TT was 95%, specificity - 57%. This allows to using it as a screening test for selection of further method of investigation in patients with episodes of loss of consciousness. PMID- 22839672 TI - [The role of oxidative processes in augmentation of atherogenity of low density lipoprotein particles]. AB - We investigated action of natural dicarbonyl compounds which are formed in atherosclerosis and diabetes on properties of low density lipoproteins (LDL) such as surface charge, conformational changes of apoB100, susceptibility to oxidation. and aggregation rate. It was found that malonic dialdehyde (MDA) compared with glyoxal and methylglyoxal is more effective modificating agent of protein part of LDL particle. Nevertheless glyoxal and methylglyoxal-dependent modification of LDL can accelerate processes of further free radical peroxidation increasing atherogenity of LDL particles. PMID- 22839673 TI - [Remodeling of vascular bed in patients with arterial hypertension: possibilities of diagnostics and correction]. AB - Arterial hypertension determines the remodeling of the vascular bed at all levels, resulting in a high risk of developing cardiovascular complications. Recent studies performed on the basis of evidence-based medicine, demonstrated the high efficiency of the combination drug therapy with perindopril and amlodipine in preventing such complications. This may be due to the positive influence of a fixed combination of these drugs on the parameters of the state of the microcirculatory level of the vascular bed. PMID- 22839674 TI - [Diagnostic value of small concentrations of troponin in patients with myocardial infarction]. AB - We have reviewed here studies of measurement of small concentrations of troponin in patients with myocardial infarction conducted in 2010-2011 which were most significant for the clinic. Troponin is a most specific and sensitive cardiomarker appearance of which in blood serum evidence for a necrotic process in cardiac muscle. We discuss the problem of interpretation of small troponin concentrations by clinicians as well as the states in which appearance of the cardiomarker in blood serum has noncardiac origin. We also discuss novel possibilities of application of troponin as a prognostic marker in patients with stable or unstable angina after revascularization procedures. PMID- 22839675 TI - [Bisoprolol: opportunities in the treatment of hypertension]. AB - Bisoprolol (bisoprolol fumarate) - -cardioselective blocker, does not possess intrinsic sympathomimetic and membrane stabilizing activity. The main indications for bisoprolol are arterial hypertension (AH) and heart failure. This article provides an overview of the literature on the potential uses of bisoprolol in the treatment of hypertension. The features of the pharmacokinetics of the drug. The data on the effectiveness of bisoprolol in hypertension and tolerability in patients with concomitant disorders: diabetes, chronic obstructive pulmonary disease, peripheral atherosclerosis. Proofs of the high efficiency of antianginal bisoprola and justified the use of the drug in patients with hypertension and coronary heart disease. The capabilities of bisoprolol in the perioperative correction of hypertension. The data and pharmacoeconomic properties of bisoprolol generic counterparts. PMID- 22839676 TI - [beta-adrenoblockers in the treatment of arrythmias]. PMID- 22839677 TI - [Cardiac angiosarcoma in a pregnant women]. AB - We present a case of cardiac angiosarcoma in a pregnant women. Clinical manifestations of angiosarcoma were unspecific and progressed rapidly as hemopericardium, cardiac tamponade, heart failure, fever, chest pain. Pregnancy was interrupted at 22-nd week. The patient died in 6 months after appearance of first symptoms. PMID- 22839678 TI - Free energy relationships for reactions of substituted benzhydrylium ions: from enthalpy over entropy to diffusion control. AB - Second-order rate constants k(2) for the reactions of various donor- and acceptor substituted benzhydrylium ions Ar(2)CH(+) with pi-nucleophiles in CH(2)Cl(2) were determined by laser flash irradiation of benzhydryl triarylphosphonium salts Ar(2)CH-PAr(3)(+)X(-) in the presence of a large excess of the nucleophiles. This method allowed us to investigate fast reactions up to the diffusional limit including reactions of highly reactive benzhydrylium ions with m-fluoro and p (trifluoromethyl) substituents. The rate constants determined in this work and relevant literature data were jointly subjected to a correlation analysis to derive the electrophilicity parameters E for acceptor-substituted benzhydrylium ions, as defined by the linear free energy relationship log k(2)(20 degrees C) = s(N)(N + E). The new correlation analysis also leads to the N and s(N) parameters of 18 pi-nucleophiles, which have only vaguely been characterized previously. The correlations of log k(2) versus E are linear well beyond the range where the activation enthalpies DeltaH(++) of the reactions are extrapolated to reach the value of DeltaH(++) = 0, showing that the change from enthalpy control to entropy control does not cause a bend in the linear free energy relationship, a novel manifestation of the compensation effect. A flattening of the correlation lines only occurs for k(2) > 10(8) M(-1) s(-1) when the diffusion limit is approached. PMID- 22839679 TI - Tetranuclear d-f metallostars: synthesis, relaxometric, and luminescent properties. AB - A novel ditopic ligand DTPA-ph-phen, based on 1,10-phenanthroline and diethylenetriaminepentaacetic acid (DTPA) units, has been designed and fully characterized by (1)H, (13)C, and 2D-COSY NMR spectroscopy, IR and electrospray ionization mass spectrometry (ESI-MS) techniques. The DTPA core of the ligand specifically binds Ln(III) ions (Ln = Eu, Gd) resulting in formation of the [Ln{DTPA-ph-phen}(H(2)O)](-) complex. The photophysical properties of the Eu(III) compound have been investigated, and the complex shows characteristic red luminescence with an overall quantum yield of 2.2%. Reaction of [Gd{DTPA-ph phen}(H(2)O)](-) with Ru(II) leads to further self-assembly into a heterobimetallic metallostar complex containing Gd(III) and Ru(II) in a 3:1 ratio. This tetranuclear [(Gd{DTPA-ph-phen})(3)(H(2)O)(3)Ru](-) complex (Gd(3)Ru), formed by the coordination of Ru(II) to the 1,10-phenanthroline unit, has been characterized by a range of experimental techniques and evaluated toward its feasibility as a potential bimodal optical/MRI agent. The Gd(3)Ru metallostar shows intense metal-to-ligand charge transfer (MLCT) transition resulting in intense light absorption in the visible spectral region. Upon irradiation into this MLCT band at 450 nm, the Gd(3)Ru complex exhibits red broad-band luminescence in the range of 550-800 nm centered at 610 nm with a quantum yield of 4.8%. Proton nuclear magnetic relaxation dispersion (NMRD) measurements indicate that the Gd(3)Ru complex exhibits an enhanced relaxivity value r(1) of 36.0 s(-1) mM(-1) per metallostar molecule at 20 MHz and 310 K. The ability of the complex to noncovalently bind to human serum albumin (HSA) was investigated, but no significant interaction was detected. PMID- 22839680 TI - Using metagenomic analyses to estimate the consequences of enrichment bias for pathogen detection. AB - BACKGROUND: Enriching environmental samples to increase the probability of detection has been standard practice throughout the history of microbiology. However, by its very nature, the process of enrichment creates a biased sample that may have unintended consequences for surveillance or resolving a pathogenic outbreak. With the advent of next-generation sequencing and metagenomic approaches, the possibility now exists to quantify enrichment bias at an unprecedented taxonomic breadth. FINDINGS: We investigated differences in taxonomic profiles of three enriched and unenriched tomato phyllosphere samples taken from three different tomato fields (n = 18). 16S rRNA gene meteganomes were created for each of the 18 samples using 454/Roche's pyrosequencing platform, resulting in a total of 165,259 sequences. Significantly different taxonomic profiles and abundances at a number of taxonomic levels were observed between the two treatments. Although as many as 28 putative Salmonella sequences were detected in enriched samples, there was no significant difference in the abundance of Salmonella between enriched and unenriched treatments. CONCLUSIONS: Our results illustrate that the process of enriching greatly alters the taxonomic profile of an environmental sample beyond that of the target organism. We also found evidence suggesting that enrichment may not increase the probability of detecting a target. In conclusion, our results further emphasize the need to develop metagenomics as a validated culture independent method for pathogen detection. PMID- 22839681 TI - Prognostic significance of functional somatic symptoms in adolescence: a 15-year community-based follow-up study of adolescents with depression compared with healthy peers. AB - BACKGROUND: There is a lack of population-based long-term longitudinal research on mental health status and functional physical/somatic symptoms. Little is known about the long-term mental health outcomes associated with somatic symptoms or the temporal relationship between depression and such symptoms. This 15-year study followed up adolescents with depression and matched controls, screened from a population-based sample, who reported different numbers of somatic symptoms. METHODS: The total population of 16-17-year-olds in Uppsala, Sweden, was screened for depression in 1991-1993. Adolescents who screened positive and an equal number of healthy controls took part in a semi-structured diagnostic interview. In addition, 21 different self-rated somatic symptoms were assessed. Sixty-four percent of those adolescents participated in a follow-up structured interview 15 years later. RESULTS: Somatic symptoms in adolescence predicted depression and other adult mental disorders regardless of the presence of adolescent depression. In adolescents with depression, the number of functional somatic symptoms predicted, in a dose response relationship, suicidal behavior, bipolar episodes, and psychotic episodes as well as chronic and recurrent depression. Contrary to expectations, the somatic symptoms of abdominal pain and perspiration without exertion better predicted depression than all DSM-IV depressive symptoms. Abdominal pain persisted as an independent strong predictor of depression and anxiety, even after controlling for other important confounders. CONCLUSIONS: Somatic symptoms in adolescence can predict severe adult mental health disorders. The number of somatic symptoms concurrent with adolescent depression is, in a stepwise manner, linked to suicidal attempts, bipolar disorders, psychotic disorders, and recurrent and chronic depression. These findings can be useful in developing treatment guidelines for patients with somatic symptoms. PMID- 22839682 TI - The comparative economic burden of mild, moderate, and severe fibromyalgia: results from a retrospective chart review and cross-sectional survey of working age U.S. adults. AB - BACKGROUND: Patients with fibromyalgia report persistent widespread pain, fatigue, and substantial functional limitations, which may lead to high health resource use (HRU) and lost productivity. Previous analyses of the U.S. population have not examined the direct and indirect costs of fibromyalgia by severity level. OBJECTIVES: To assess (a) HRU, direct and indirect costs associated with fibromyalgia in routine clinical practice in the United States using a patient-centric approach, and (b) the relationship of fibromyalgia severity level to HRU and costs. METHODS: This study recruited a nonprobability convenience sample of 203 subjects aged 18 through 65 years between August 2008 and February 2009 from 20 U.S. community-based physician offices. Subjects had a prior diagnosis of fibromyalgia by a rheumatologist, neurologist, or pain specialist; received treatment at the enrolling physician's practice for at least 3 months; experienced widespread pain for at least 3 months; and experienced pain in the previous 24 hours. Subjects completed a 106-item patient questionnaire that included 5 validated health-related quality-of-life instruments and study specific questions about demographics; clinical history; overall health; treatment satisfaction; and impact of fibromyalgia on cognitive function, daily activities, and employment status. Subjects also self-reported hours of unpaid informal caregiver time because of inability to perform daily activities (e.g., housework, child care), out-of-pocket expenses for medical and nonmedical services, and lost productivity related to fibromyalgia for the previous 4 weeks. The 20-item Fibromyalgia Impact Questionnaire total score was used to stratify subjects into fibromyalgia severity groups (0 to less than 39 = mild, 39 to less than 59 = moderate, 59 to 100 = severe). Staff at each site recorded clinical characteristics, HRU, and medication use attributable to fibromyalgia on a paper clinical case report form (CRF) based on a 3-month retrospective medical chart review. Unit costs for 2009 were assigned to the 3-month HRU data reported on the CRF and 4-week subject-reported lost productivity. Costs were then annualized and reported in the following categories: direct medical, direct nonmedical, and indirect. Differences across severity levels were evaluated using the Kruskal Wallis test (continuous measures) and Pearson chi-square or Fisher's exact tests (categorical measures) at the 0.05 alpha level. RESULTS: Of the 203 subjects, 21 (10.3%) had mild, 49 (24.1%) had moderate, and 133 (65.5%) had severe fibromyalgia. For subjects with mild, moderate, and severe fibromyalgia, respectively, the number of fibromyalgia-related medications (3-month means: 1.8, 2.3, and 2.8, P = 0.011) and office visits to health care providers (3-month means: 2.7, 5.2, and 6.9, P < 0.001) significantly differed across severity levels. Across severity levels, total medical and nonmedical out-of-pocket costs also differed (P = 0.025). Mean [median] 3-month total direct costs (including payer costs for HRU and out-of-pocket costs for medical and nonmedical services) were $1,213 [$1,150], $1,415 [$1,215], and $2,329 [$1,760] for subjects with mild, moderate, and severe fibromyalgia, respectively (P = 0.002); and mean [median] 3-month indirect costs (including subject-reported absenteeism, unemployment, disability, and the estimated value of unpaid informal care) were $1,341 [$0], $5,139 [$1,680], and $8,285 [$7,030] (P < 0.001). Mean total indirect costs accounted for 52.5%, 78.4%, and 78.1% of mean total costs for subjects with mild, moderate, and severe fibromyalgia, respectively. CONCLUSIONS: Direct and indirect costs related to fibromyalgia are higher among subjects with worse fibromyalgia severity. Indirect costs account for a majority of fibromyalgia-related costs at all fibromyalgia severity levels. PMID- 22839683 TI - Adverse drug reactions for CAM and conventional drugs detected in a network of physicians certified to prescribe CAM drugs. AB - BACKGROUND: Within recent years, the increasing popularity of complementary and alternative medicine (CAM) has led health care authorities to focus on the safety of these drugs. One reason for the low awareness of adverse drug reactions (ADRs) associated with CAM might be that users and physicians believe that there are no risks associated with CAM drugs. Recent studies have shown that ADRs are under reported and are considered a leading cause of morbidity and mortality. The Evaluation of Anthroposophical Medicine (EvaMed) Pharmacovigilance Network was formed in 2004 at the Havelhoehe Research Institute in Berlin and is composed of 38 CAM physicians located in 12 of the 16 federal states in Germany for the purpose of using EvaMed data to evaluate the prescribing patterns, effectiveness, and safety of CAM therapies. OBJECTIVE: To describe and quantify the volume and severity of ADRs for CAM and conventional (CON) drugs in a proprietary database created from prescriptions and patient data of primary care CAM physicians who participate in the EvaMed Network. METHODS: This was a prospective, multicenter, observational study based on the ADR reports and electronic prescription data of 38 individual physicians (21 general practitioners, 9 pediatricians, 4 internists, 2 gynecologists, 1 dermatologist, and 1 neurologist) participating in the EvaMed Network. In addition to standard medical education, all physicians had 5 years practical experience and an additional qualification for anthroposophic medicine, which is a subcategory of CAM. All 38 physicians documented ADRs deemed serious, defined as life threatening or resulting in death, disability/incapacity, or inpatient hospital days. Due to the time-consuming nature of documenting ADRs, only a subgroup of 7 physicians (4 in general practice and 1 each in internal medicine, pediatrics, and gynecology) agreed to report both nonserious and serious ADRs. Therefore, the incidence and frequency of ADRs were evaluated in this subgroup. The study period was January 2004 through June 2009. ADRs were documented by the physicians using an electronic case report form in the EvaMed software, which was linked to the physicians' existing electronic medical record (EMR) systems and incorporated into their daily routines to avoid missing data or double entries. The participating physicians were compensated ?15 (approximately US$20) for each ADR report. All ADR reports were monitored at the Havelhoehe Research Institute by 2 physicians who evaluated patient characteristics, present visit diagnosis, target drugs, associated drug classes and type of drugs, type of ADR, actions taken for the ADR, and outcome of the ADR. RESULTS: There were 1,018,626 drugs (54.8% CAM) prescribed by the 38 physicians for 88,431 patients, and 412 ADRs reported for 389 patients; 124 (30.1%) ADRs were for CAM drugs. The majority were reported in children (69.2%, n = 285) and females (56.3%, n = 232). All serious ADRs (n = 14) were associated with CON drugs. In the subgroup of 7 physicians who agreed to report all ADRs, a total of 327 serious and nonserious ADRs were reported for 392,243 prescribed drugs (0.08%) and for 308 of 25,966 patients (1.2%). ADRs were reported for 241 of 16,032 children (aged 17 years or younger; 1.5%) versus 67 of 9,934 adults (0.7%). Of the 327 total ADRs, 10 (3.1%) were serious. There were 95 ADRs for 213,900 CAM prescriptions (4.4 per 10,000) versus 232 for 178,343 CON prescriptions (13.0 per 10,000). The CAM drug with the highest frequency of ADRs was Pelargonium sidoides root (0.21%, 4 of 1,940 prescriptions). The most frequently reported ingredient in CAM was ivy leaves with an ADR frequency of 0.17% (n = 11 of 6,575 prescriptions). The most reported drug connected with ADRs was amoxicillin (1.36%, n = 31 of 2,276 prescriptions). The most common ADR medical management was withdrawal of the drug (82.3% overall, 83.9% CAM, 81.6% CON). CONCLUSIONS: A sample of 38 CAM physicians reported the occurrence of at least 1 ADR for 0.4% of treated patients in a 5.5-year study period. There were no serious ADRs reported for CAM drugs. In a subsample of 7 physicians who agreed to report all nonserious and serious ADRs, 1.2% of patients experienced at least 1 ADR; rates of ADRs per 10,000 prescriptions were 4.4 for CAM drugs and 13.0 for CON drugs. PMID- 22839684 TI - Analysis of liquid medication dose errors made by patients and caregivers using alternative measuring devices. AB - BACKGROUND: Patients use several types of devices to measure liquid medication. Using a criterion ranging from a 10% to 40% variation from a target 5 mL for a teaspoon dose, previous studies have found that a considerable proportion of patients or caregivers make errors when dosing liquid medication with measuring devices. OBJECTIVE: To determine the rate and magnitude of liquid medication dose errors that occur with patient/caregiver use of various measuring devices in a community pharmacy. METHODS: Liquid medication measurements by patients or caregivers were observed in a convenience sample of community pharmacy patrons in Korea during a 2-week period in March 2011. Participants included all patients or caregivers (N = 300) who came to the pharmacy to buy over-the-counter liquid medication or to have a liquid medication prescription filled during the study period. The participants were instructed by an investigator who was also a pharmacist to select their preferred measuring devices from 6 alternatives (etched-calibration dosing cup, printed-calibration dosing cup, dosing spoon, syringe, dispensing bottle, or spoon with a bottle adapter) and measure a 5 mL dose of Coben (chlorpheniramine maleate/phenylephrine HCl, Daewoo Pharm. Co., Ltd) syrup using the device of their choice. The investigator used an ISOLAB graduated cylinder (Germany, blue grad, 10 mL) to measure the amount of syrup dispensed by the study participants. Participant characteristics were recorded including gender, age, education level, and relationship to the person for whom the medication was intended. RESULTS: Of the 300 participants, 257 (85.7%) were female; 286 (95.3%) had at least a high school education; and 282 (94.0%) were caregivers (parent or grandparent) for the patient. The mean (SD) measured dose was 4.949 (0.378) mL for the 300 participants. In analysis of variance of the 6 measuring devices, the greatest difference from the 5 mL target was a mean 5.552 mL for 17 subjects who used the regular (etched) dosing cup and 4.660 mL for the dosing spoon (n = 10; P < 0.001). Doses were within 10% of the 5 mL target volume for 88.7% (n = 266) of the participant samples. Only 34 cases (11.3%) had dose errors greater than 10%, and only 6 cases (2.0%) had a variance of more than 20% from the 5 mL target volume. Dose errors greater than 10% of the target volume were more common for the etched dosing cup (47.1%, n = 8), the dosing spoon (50.0%, n = 5), and the printed dosing cup (30.8%, n = 4), but these 3 devices were used by only 13.3% of the study participants. CONCLUSIONS: Approximately 1 in 10 participants measured doses of liquid medication with a volume error greater than 10%, and these dose errors were more common with the etched dosing cup, the dosing spoon, and the printed dosing cup. Pharmacists have an opportunity to counsel patients or caregivers regarding the appropriate use of measuring devices for liquid medication. PMID- 22839685 TI - Opinions of a small sample of pharmacists about pharmacy setting and patient adherence to antiretroviral therapy. PMID- 22839686 TI - Usefulness of blood pressure measurement by community pharmacists in the management of hypertension. PMID- 22839687 TI - Application of decision-analytic models in personalized medicine for CML treatment decisions made by payers, providers, and patients. PMID- 22839688 TI - Insulin-like growth factor-1 gene polymorphism in rheumatoid arthritis patients. AB - OBJECTIVES: Insulin-like growth factor-1 (IGF-1) regulates several biological functions, and low plasma levels of IGF-1 are known to contribute towards the pathogenesis of rheumatoid arthritis (RA). In view of the biological significance of IGF-1, we investigated the association of RA with the polymorphism of a 192-bp allele which is cytosine-adenosine repeat located 1 kb upstream from the IGF-1 gene transcription site and is known to regulate serum IGF-1 levels. METHODS: Blood samples were collected from 52 healthy controls (HC) and 68 RA patients to measure the levels of IGF-1 and to isolate genomic DNA. Polymorphism of the IGF-1 gene was examined using polymerase chain reaction (PCR). Disease severity, duration, and activity were recorded for all RA patients. RESULTS: We observed that 97% of all the subjects who participated in this study showed the presence of a 192-bp allele of the IGF-1 gene. All healthy controls exhibited the presence of 192-bp wild-type allele. All non-carriers of the 192-bp allele were Arabs and had RA. Gender correlated significantly with allele frequencies as 14% of the male and only 2% of the female RA patients were non-carriers of 192-bp allele. Plasma IGF-1 levels were significantly lower (p < 0.01) in RA patients compared to HC, and all RA patients who were non-carriers of the 192-bp allele had a significantly high disease activity score. No correlation was found between the duration of RA and the presence or absence of this allele. CONCLUSIONS: This study suggests a possible association of the IGF-1 gene polymorphism with developing RA, particularly in males as non-carriers of the 192-bp allele. PMID- 22839689 TI - Prediction of severe community-acquired pneumonia: a systematic review and meta analysis. AB - INTRODUCTION: Severity assessment and site-of-care decisions for patients with community-acquired pneumonia (CAP) are pivotal for patients' safety and adequate allocation of resources. Late admission to the intensive care unit (ICU) has been associated with increased mortality in CAP. We aimed to review and meta-analyze systematically the performance of clinical prediction rules to identify CAP patients requiring ICU admission or intensive treatment. METHODS: We systematically searched Medline, Embase, and the Cochrane Controlled Trials registry for clinical trials evaluating the performance of prognostic rules to predict the need for ICU admission, intensive treatment, or the occurrence of early mortality in patients with CAP. RESULTS: Sufficient data were available to perform a meta-analysis on eight scores: PSI, CURB-65, CRB-65, CURB, ATS 2001, ATS/IDSA 2007, SCAP score, and SMART-COP. The estimated AUC of PSI and CURB-65 scores to predict ICU admission was 0.69. Among scores proposed for prediction of ICU admission, ATS-2001 and ATS/IDSA 2007 scores had better operative characteristics, with a sensitivity of 70% (CI, 61 to 77) and 84% (48 to 97) and a specificity of 90% (CI, 82 to 95) and 78% (46 to 93), but their clinical utility is limited by the use of major criteria. CONCLUSIONS: New severity scores for predicting the need for ICU or intensive treatment in patients with CAP, such as ATS/IDSA 2007 minor criteria, SCAP score, and SMART-COP, have better discriminative performances compared with PSI and CURB-65. High negative predictive value is the most consistent finding among the different prediction rules. These rules should be considered an aid to clinical judgment to guide ICU admission in CAP patients. PMID- 22839691 TI - Study of surface reaction of spinel Li4Ti5O12 during the first lithium insertion and extraction processes using atomic force microscopy and analytical transmission electron microscopy. AB - Spinel lithium titanate (Li(4)Ti(5)O(12), LTO) is a promising anode material for a lithium ion battery because of its excellent properties such as high rate charge-discharge capability and life cycle stability, which were understood from the viewpoint of bulk properties such as small lattice volume changes by lithium insertion. However, the detailed surface reaction of lithium insertion and extraction has not yet been studied despite its importance to understand the mechanism of an electrochemical reaction. In this paper, we apply both atomic force microscopy (AFM) and transmission electron microscopy (TEM) to investigate the changes in the atomic and electronic structures of the Li(4)Ti(5)O(12) surface during the charge-discharged (lithium insertion and extraction) processes. The AFM observation revealed that irreversible structural changes of an atomically flat Li(4)Ti(5)O(12) surface occurs at the early stage of the first lithium insertion process, which induces the reduction of charge transfer resistance at the electrolyte/Li(4)Ti(5)O(12) interface. The TEM observation clarified that cubic rock-salt crystal layers with a half lattice size of the original spinel structure are epitaxially formed after the first charge-discharge cycle. Electron energy loss spectroscopy (EELS) observation revealed that the formed surface layer should be alpha-Li(2)TiO(3). Although the transformation of Li(4)Ti(5)O(12) to Li(7)Ti(5)O(12) is well-known as the lithium insertion reaction of the bulk phase, the generation of surface product layers should be inevitable in real charge-discharge processes and may play an effective role in the stable electrode performance as a solid-electrolyte interphase (SEI). PMID- 22839690 TI - Biological activities of extracts from Chenopodium ambrosioides Lineu and Kielmeyera neglecta Saddi. AB - BACKGROUND: Chenopodium ambrosioides and Kielmeyera neglecta are plants traditionally used in Brazil to treat various infectious diseases. The study of the biological activities of these plants is of great importance for the detection of biologically active compounds. METHODS: Extracts from these plants were extracted with hexane (Hex), dichloromethane (DCM), ethyl acetate (EtOAc) and ethanol (EtOH) and assessed for their antimicrobial properties, bioactivity against Artemia salina Leach and antifungal action on the cell wall of Neurospora crassa. RESULTS: Extracts from C. ambrosioides (Hex, DCM and EtOH) and K. neglecta (EtOAc and EtOH) showed high bioactivity against A. salina (LD50 < 1000 MUg/mL), which might be associated with cytotoxic activity against cancer cells. C. ambrosioides Hex and DCM showed specific activity against yeasts, highlighting the activity of hexanic extract against Candida krusei (MIC = 100 MUg/mL). By comparing the inhibitory concentration of 50% growth (IC 50%) with the growth control, extracts from K. neglecta EtOAc and EtOH have shown activities against multidrug-resistant bacteria (Enterococcus faecalis ATCC 51299 and Staphylococcus aureus ATCC 43300), with IC 50% of 12.5 MUg/mL The assay carried out on N. crassa allowed defining that extracts with antifungal activity do not have action through inhibition of cell wall synthesis. CONCLUSIONS: Generally speaking, extracts from C. ambrosioides and K. neglecta showed biological activities that have made the search for bioactive substances in these plants more attractive, illustrating the success of their use in the Brazilian folk medicine. PMID- 22839692 TI - Difficulties in demonstrating long term immunity in FeLV vaccinated cats due to increasing age-related resistance to infection. AB - BACKGROUND: Feline leukaemia virus (FeLV) is a pathogen causing fatal illness in cats worldwide, and as such there is a high demand for products to protect against disease. The duration of immunity provided by an inactivated FeLV vaccine, Versifel FeLV, when administered to cats of the target age was determined. Kittens received two vaccinations when aged 7 to 9 weeks old, and were subsequently challenged up to 36 months later with the FeLV-A Glasgow isolate. RESULTS: In all studies, all of the younger aged control kittens showed persistent FeLV p27 antigenaemia confirming that the challenge virus was severe and efficacious. In contrast, the control cats did not show the required level of persistent antigenaemia, with a maximum of 45% cats affected in the middle duration study and only 10% in the longer study. However, apart from one animal in the short duration study, all of the cats vaccinated with Versifel FeLV were negative for persistent antigenaemia and can be considered treatment successes. CONCLUSION: In conclusion, we have shown that although age-related resistance to infection with a virulent FeLV challenge is evident from as early as 10 months of age, vaccination with Versifel FeLV may aid in the protection of cats from FeLV related disease up to three years after primary vaccination as kittens. PMID- 22839693 TI - The role of diabetes co-morbidity for tuberculosis treatment outcomes: a prospective cohort study from Mwanza, Tanzania. AB - BACKGROUND: Due to the association between diabetes and pulmonary tuberculosis (TB), diabetes may threaten the control of TB. In a prospective cohort study nested in a nutrition trial, we investigated the role of diabetes on changes in anthropometry, grip strength, and clinical parameters over a five months follow up period. METHODS: Among pulmonary TB patients with known diabetes status, we assessed anthropometry and clinical parameters (e.g. haemoglobin) at baseline and after two and five months of TB treatment. A linear mixed-effects model (repeated measurements) was used to investigate the role of diabetes during recovery. RESULTS: Of 1205 TB patients, the mean (standard deviation) age was 36.6 (13.0) years, 40.9% were females, 48.9% were HIV co-infected, and 16.3% had diabetes. TB patients with diabetes co-morbidity experienced a lower weight gain at two (1.3 kg, CI95% 0.5; 2.0, p = 0.001) and five months (1.0 kg, CI95% 0.3; 1.7, p = 0.007). Similarly, the increase in the level of haemoglobin was lower among TB patients with diabetes co-morbidity after two (Delta 0.6 g/dL, CI95% 0.3; 0.9 p < 0.001) and five months (Delta 0.5 g/dL, CI95% 0.2; 0.9 p = 0.004) of TB treatment, respectively. CONCLUSION: TB patients initiating TB treatment with diabetes co-morbidity experience delayed recovery of body mass and haemoglobin, which are important for the functional recovery from disease. PMID- 22839694 TI - Local and circulating levels of adipocytokines in obese and normal weight individuals with chronic periodontitis. AB - BACKGROUND: The aim of this study is to evaluate the local and circulating levels of adipocytokines (resistin, adiponectin, leptin, tumor necrosis factor [TNF] alpha, and interleukin [IL]-6) in individuals who are obese and individuals who are normal weight (NW) with chronic periodontitis (CP). METHODS: Periodontal and anthropometric examinations were performed. Based on these measurements, the individuals were divided into one of the following groups: NW non-periodontitis (NP) (NWNP; n = 20); NWCP (n = 20); obese NP (ONP; n = 18); and obese CP (OCP; n = 20). The levels of adipocytokines were evaluated in the serum and gingival crevicular fluid of shallow and deep sites by enzyme-linked immunosorbent assay. RESULTS: In serum, resistin levels were higher whereas adiponectin levels were lower in periodontitis than in NP groups (P <0.05). The NWNP group presented the lowest serum leptin levels (P <0.05). The ONP and OCP groups demonstrated higher TNF-alpha levels in periodontal sites than the NWNP and NWCP groups (P <0.05). Serum levels of IL-6 (P = 0.04) and leptin (P = 0.01) were correlated with the OCP group, with odds ratios of 0.99 (95% confidence interval [CI]: -0.01 to 0.00) and 0.99 (95% CI: -0.00 to -0.00), respectively. CONCLUSIONS: Periodontitis mainly influenced the circulating levels of resistin and adiponectin, whereas both obesity and periodontitis affected the circulating levels of leptin in favor of proinflammation. In addition, obesity upregulated the local levels of TNF alpha. PMID- 22839695 TI - Bone morphogenic protein-2 induces apoptosis and cytotoxicity in periodontal ligament cells. AB - BACKGROUND: Periodontal ligament (PDL) expresses endogenous growth factors, such as bone morphogenic proteins (BMPs), which facilitate maintenance of tissue homeostasis. Inflammatory conditions, such as chronic periodontitis, could disrupt this homeostasis, and physiologic levels of growth factors may be insufficient to maintain tissue homeostasis. BMPs facilitate periodontal bone regeneration but also are implicated in causing tooth ankylosis and root resorption. The underlying mechanism of tooth ankylosis is unclear. However, there is evidence that BMPs induce apoptosis in progenitor cells. Little is known about BMP-induced cytotoxicity in PDL cells, which contain a population of progenitor cells. The aim of this study is to determine BMP2-induced osteogenic mediators and cytotoxic effects in PDL cells and compare these cells to osteoblasts. METHODS: Human PDL cells and primary osteoblasts were stimulated with doses of 1 to 200 ng/mL BMP2. Expression of alkaline phosphatase (ALP), in vitro mineralization along with osteonectin expression, induction of apoptosis, and cytotoxicity assays were performed. RESULTS: PDL cells and osteoblasts upregulated ALP and in vitro mineralization in a dose-dependent manner with BMP2 stimulation. However, at BMP2 concentrations >10 ng/mL, ALP, in vitro mineralization, and osteonectin were downregulated in PDL cells. Relative to osteoblasts, PDL cells were susceptible to apoptosis and cytotoxicity with 10 times lower concentration of BMP2. CONCLUSIONS: Relative to osteoblasts, PDL cells are susceptible to BMP2-induced cytotoxicity. BMP-induced tooth ankylosis is controversial and is poorly understood. Disruption of PDL homeostasis by BMP induced apoptosis could play a role in tooth ankylosis. PMID- 22839696 TI - 'Female condoms give women greater control': a qualitative assessment of the experiences of commercial sex workers in Swaziland. AB - OBJECTIVES: To explore commercial sex workers' experiences with the female condom in Swaziland. METHODS: This is a qualitative study that draws on two focus group discussions and ten individual in-depth interviews with female commercial sex workers in Lavumisa, Swaziland. RESULTS: The findings suggest that the majority of female sex workers prefer to use the female condom with their clients because it offers them greater control over the sexual encounter. Other factors that facilitate its use include the absence of side effects, the enhancement of sexual pleasure and protection against the risk of STIs (including HIV). In addition, the women reported that the female condom is stronger and more resistant to breakage than the male condom. Moreover, the female condoms can be inserted well in advance of sexual intercourse. Difficulties of insertion, partner objection and limited product availability were some of the barriers to the use of the device. There was also a tendency to reuse the female condoms because of lack of product availability and privacy to insert it. CONCLUSION: Although female condom use involves negotiation with clients, the fact that it offers sex workers an independent method of protection gives them more power and also, increases their ability to control their sexual and reproductive health. PMID- 22839697 TI - Intervertebral disk width in dogs with and without clinical signs of disk associated cervical spondylomyelopathy. AB - BACKGROUND: Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological disorder in which progressive caudal cervical spinal cord compression is mainly caused by one or more intervertebral disk protrusions. The Doberman pinscher breed seems predisposed for this condition. The underlying cause and pathophysiology of DA-CSM are currently unknown. Recently, wider intervertebral disks have been put forward as a risk factor for development of clinically relevant DA-CSM. However, little is known about other factors affecting intervertebral disk width. Therefore the aim of this study was to assess the association between intervertebral disk width, measured on magnetic resonance imaging (MRI), and clinical status, age, gender and intervertebral disk location in dogs with and without clinical signs of DA-CSM. METHODS: Doberman pinschers with clinical signs of DA-CSM (N=17),clinically normal Doberman pinschers (N=20), and clinically normal English Foxhounds (N=17), underwent MRI of the cervical vertebral column. On sagittal T2-weighted images, intervertebral disk width was measured from C2-C3 to C6-C7. Intra -and interobserver agreement were assessed on a subset of 20 of the 54 imaging studies. RESULTS: Intervertebral disk width was not significantly different between Doberman pinschers with clinical signs of DA-CSM, clinically normal Doberman pinschers or clinically normal English Foxhounds (p=0.43). Intervertebral disk width was positively associated with increasing age (p=0.029). Each monthly increase in age resulted in an increase of disk width by 0.0057 mm. Intervertebral disk width was not significantly affected by gender (p=0.056), but was significantly influenced by intervertebral disk location (p <0.0001). The assessed measurements were associated with a good intra -and interobserver agreement. CONCLUSIONS: The present study does not provide evidence that wider intervertebral disks are associated with clinical status in dogs with and without DA-CSM. Instead, it seems that cervical intervertebral disk width in dogs is positively associated with increase in age. PMID- 22839699 TI - Correlative analyses of nitric oxide generation rates and nitric oxide synthase levels in individual cells using a modular cell-retaining device. AB - Nitric oxide (NO) is recognized as one of the major immune system agents involved in the pathogenesis and control of various diseases that may benefit from novel drug development, by exploiting NO signaling pathways and targets. This calls for detection of both intracellular levels of NO and expression of its synthesizing enzymes (NOS) in individual, intact, living cells. Such measurements are challenging, however, due to short half-life, low and fluctuating concentrations of NO, cellular heterogeneity, and inability to trace the same cells over time. The current study presents a device and methodology for correlative analysis of NO generation rates and NOS levels in the same individual cells, utilizing fluorescent imaging followed by immunohistochemistry (IHC). U937 promonocyte cell populations demonstrated significant heterogeneity in their baseline levels, in NO-generation kinetics, and in their response rates to stimuli. Individual cell analysis exposed cell subgroups which showed enhanced NO production upon stimulation, concomitantly with significant up-regulation of inducible NOS (iNOS) levels. Exogenous NO modulated the expression of iNOS in nondifferentiated cells within 1 h, in a dose-dependent manner, while treatment with lysophosphatidylcholine (LPC) enhanced the expression of iNOS, demonstrating a nondependence on NO production. PMID- 22839698 TI - Analysis of lead toxicity in human cells. AB - BACKGROUND: Lead is a metal with many recognized adverse health side effects, and yet the molecular processes underlying lead toxicity are still poorly understood. Quantifying the injurious effects of lead is also difficult because of the diagnostic limitations that exist when analyzing human blood and urine specimens for lead toxicity. RESULTS: We analyzed the deleterious impact of lead on human cells by measuring its effects on cytokine production and gene expression in peripheral blood mononuclear cells. Lead activates the secretion of the chemokine IL-8 and impacts mitogen-dependent activation by increasing the secretion of the proinflammatory cytokines IL-6 and TNF-alpha and of the chemokines IL-8 and MIP1 alpha in the presence of phytohemagglutinin. The recorded changes in gene expression affected major cellular functions, including metallothionein expression, and the expression of cellular metabolic enzymes and protein kinase activity. The expression of 31 genes remained elevated after the removal of lead from the testing medium thereby allowing for the measurement of adverse health effects of lead poisoning. These included thirteen metallothionein transcripts, three endothelial receptor B transcripts and a number of transcripts which encode cellular metabolic enzymes. Cellular responses to lead correlated with blood lead levels and were significantly altered in individuals with higher lead content resultantly affecting the nervous system, the negative regulation of transcription and the induction of apoptosis. In addition, we identified changes in gene expression in individuals with elevated zinc protoporphyrin blood levels and found that genes regulating the transmission of nerve impulses were affected in these individuals. The affected pathways were G-protein mediated signaling, gap junction signaling, synaptic long-term potentiation, neuropathic pain signaling as well as CREB signaling in neurons. Cellular responses to lead were altered in subjects with high zinc protoporphyrin blood levels. CONCLUSIONS: The results of our study defined specific changes in gene and protein expression in response to lead challenges and determined the injurious effects of exposures to lead on a cellular level. This information can be used for documenting the health effects of exposures to lead which will facilitate identifying and monitoring efficacious treatments for lead-related maladies. PMID- 22839700 TI - Substance use and risky sexual behaviours among sexually experienced Ghanaian youth. AB - BACKGROUND: The association between risky sexual behaviours and substance uses among Ghanaian youth were investigated. METHODS: An in-school cross-sectional representative survey was conducted among 12-18-year- old youth in Ghana in 2008 (N = 1195, response rate =90%). Logistic regression analyses were employed to investigate the association between substance use (tobacco use, drunkenness, marijuana use and other drug uses) and risky sexual behaviours (sexual debut, condom use and number of sexual partners). RESULTS: Of all youth, 25% (28% boys and 23% girls) were sexually experienced. The mean age for first sexual intercourse was 14.8 years (14.4 years for boys and 15.1 years for girls). Among the sexually experienced, 31% had multiple sexual partners. Older age (OR = 3.4, 95% CI = 1.7-3.4) and rural residency (OR = 1.5, 95% CI = 1.1-2.1) were independently associated with sexual debut while only older age (OR = 2.4, 95% CI = 1.7-3.4) was associated with condom use. Additionally, smoking (OR = 3.7, 95% CI = 2.0-6.8), tawa use (OR = 2.4, 95% CI = 1.3-4.7), tobacco use (OR = 2.8, 95% CI = 1.7-4.7) drunkenness (OR = 1.7, 95% CI = 1.1-2.8) and marijuana use (OR = 3.3, 95% CI = 1.6-7.0) were independently associated with sexual debut. Furthermore, all substance uses studied were associated with having one or multiple sexual partners. CONCLUSION: Substance use seems to be a gateway for risky sexual behaviours among Ghanaian youth. Public health interventions should take into account the likelihood of substance use among sexually experienced youth. PMID- 22839701 TI - Disruption of Yarrowia lipolytica biofilms by rhamnolipid biosurfactant. AB - BACKGROUND: Yarrowia lipolytica is an ascomycetous dimorphic fungus that exhibits biofilm mode of growth. Earlier work has shown that biosurfactants such as rhamnolipids are efficient dispersants of bacterial biofilms. However, their effectiveness against fungal biofilms (particularly Y. lipolytica) has not been investigated. The aim of this study was to determine the effect of rhamnolipid on a biofilm forming strain of Y. lipolytica. Two chemical surfactants, cetyl trimethyl ammonium bromide (CTAB) and sodium dodecyl sulphate (SDS) were used as controls for comparison. RESULTS: The methylene blue dye exclusion assay indicated an increase in fungal cell permeability after rhamnolipid treatment. Microtiter plate assay showed that the surfactant coating decreased Y. lipolytica biofilm formation by 50%. Rhamnolipid treatment disrupted pre-formed biofilms in a more effective manner than the other two surfactants. Confocal laser scanning microscopic studies showed that biofilm formation onto glass surfaces was decreased by 67% after sub-minimum inhibitory concentration (sub-MIC) treatment with rhamnolipids. The disruption of biofilms after rhamnolipid treatment was significant (P<0.05) when compared to SDS and CTAB. CONCLUSION: The results indicate a potential application of the biological surfactant to disrupt Y. lipolytica biofilms. PMID- 22839702 TI - Permission to enter cell by shape: nanodisk vs nanosphere. AB - Changing polystyrene nanoparticles from three-dimensional spherical shape to two dimensional disk shape promotes their cell surface binding with significant reduction of cell uptake. As a result of lower cell uptake, nanodisks show very little perturbations on cell functions such as cellular ROS generation, apoptosis and cell cycle progression compared to nanospheres. Therefore, disk-shaped nanoparticles may be a promising template for developing cell membrane-specific and safer imaging agents for a range of biomedical applications such as molecular imaging, tissue engineering, cell tracking, and stem cell separation. PMID- 22839704 TI - The electronic and magnetic properties of functionalized silicene: a first principles study. AB - Based on first-principles calculations, we study the structural, electronic, and magnetic properties of two-dimensional silicene saturated with hydrogen and bromine atoms. It is found that the fully saturated silicene exhibits nonmagnetic semiconducting behavior, while half-saturation on only one side with hydrogen or bromine results in the localized and unpaired electrons of the unsaturated Si atoms, showing ferromagnetic semiconducting or half-metallic properties, respectively. Total energy calculations show that the half-hydrogenated silicene exhibits a ferromagnetic order, while the half-brominated one exhibits an antiferromagnetic behavior. PMID- 22839703 TI - Multicomponent assembly of proposed DNA precursors in water. AB - We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and beta-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from beta-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form. PMID- 22839705 TI - Achieving treat to target in gout: a clinical practice improvement project. AB - OBJECTIVE: Gout care is suboptimal because of lack of translation of knowledge into real-world practice, despite evidence-based guidelines. We have developed processes to ensure systematic care for gout patients and determined the predictors for achievement of a target serum uric acid (SUA) concentration of < 360 MUmol/L in a prospective cohort of Asian gout patients requiring allopurinol therapy. METHODS: A 1-year clinical practice improvement project was undertaken using evidence-based guidelines and quality planning tools. Interventions included comprehensive patient education, enhanced telephone access, reappointments and refills, upward titration of allopurinol with no limitation specified by renal function, and increased frequency of visits until the target SUA concentration was achieved. The primary outcome was the time to achieve an SUA level of <360 MUmol/L. RESULTS: We recruited 126 gout patients. The median time to achieving the target SUA concentration was 36.9 weeks [95% confidence interval (CI) 29.3-44.4]. Based on survival analysis, the proportion of patients achieving the target was 8.1% (95% CI 3.2-13.0), 40.6% (95% CI 31.4-50.8), and 72.0% (95% CI 61.2-82.8) at 3, 6, and 12 months, respectively. On average, our patients who achieved the target were seen once every 2 months and achieved the target after a mean of 2.5 (SD = 1.1) visits. Frequency of follow-up visits and older patients not taking aspirin were independent predictors associated with achieving the target outcome, regardless of renal function. CONCLUSIONS: Optimization of control of SUA is achievable, even in the setting of renal impairment, by redesigning and implementing processes involving changes in physician prescribing habits, enhanced nursing interventions, and patient empowerment and education. PMID- 22839706 TI - The aging epigenome: DNA methylation from the cradle to the grave. AB - Whole-genome methylation analysis of newborns and centenarians reveals widespread epigenetic alterations, and provides new insight into age-related methylation pattern changes. PMID- 22839707 TI - [Clinical and prognostic significance of multifocal atherosclerosis in patients with acute coronary syndromes without ST-segment elevation]. AB - Aim of the study was to determine incidence of multifocal atherosclerosis (MFA), to assess its clinical and prognostic significance in the hospital phase in patients with non-ST elevation acute coronary syndrome (NSTEACS). We studied data from 225 patients with duration of NSTEACS 48 hours or less, who along with usual examination were subjected to coronary angiography and color duplex scanning of extracranial arteries and arteries of lower extremities. As lesions we considered any stenosis irrespective of intima media thickness. MFA was detected in 43.6% of cases. Patients with MFA were older, they more often had history of myocardial infarction, had lower creatinine clearance, and left ventricular ejection fraction. Presence of artery stenoses in 3 vascular regions was associated with multivessel coronary artery disease. Inhospital "endpoints" (myocardial infarction, stroke, death) occurred more frequently in patients with MFA. Patients with lesions in 2 and 3 vascular beds were characterized by maximal Grace score, while those without coronary and peripheral artery involvement- by minimal Grace score. The presence of MFA in patients with NSTEACS was associated with unfavourable course of the disease. Thus ptatients with MFA were characterized by high average rating on Grace scale; involvement of three vascular beds was associated with high mortality. PMID- 22839708 TI - [Efficacy of early invasive strategy of diagnostics and treatment of unstable angina at the background of preexisting ischemic heart disease]. AB - Study aim was assessment of efficacy of early invasive tactics of treatment of patients with various forms of unstable angina at the background of preexisting ischemic heart disease. We compared noninvasive and invasive estimation of risk in 354 patients admitted to the N.V.Sklifosofsky Institute of Urgent Aid in 2002 to 2008. Percutaneous coronary interventions on infarct related artery (IRA) during 1 procedure were carried out in 144 patients (41%), indications to coronary artery (CA) bypass surgery were found in 167 patients (47%), 43 patients (12%) were treated conservatively. Coronary angiography performed in the first 48 hours gives an opportunity to determine indications to myocardial revascularization, to avoid discrepancy between choice of treatment tactics and noninvasive assessment of risk. The latter can be used with the aim of optimization of timing of early invasive strategy. In high risk it is expedient to employ it immediately, in medium - without delay allowed in recommended time intervals. Rentgenoendovascular restoration of IRA conducted during one procedure is an optimal type of myocardial revascularization in many patients including those with multiple CA involvement. Method of choice in patients with stenoses of left CA trunk or its equivalents is surgical revascularization of the myocardium. Detection of indications for myocardial revascularization in patients with unstable angina including those at medium and low risk confirms necessity of application of early invasive strategy as conventional strategy ensuring timeliness of pathogenetic treatment. Absence of indications to myocardial revascularization in a limited group of patients gives an opportunity to clarify diagnosis, prescribe drug therapy and prevent unjustified hospitalizations. PMID- 22839709 TI - [Effect of omega-3 polyunsaturated fatty acids on predictors of sudden cardiac death in patients with ischemic heart disease and ventricular rhythm disturbances]. AB - OBJECTIVE: To assess the dynamics of non-invasive electrophysiologic (ventricular arrhythmias, HRV, HRT, mTWA) and humoral (red blood cells omega-3 index) SCD predictors at the background of therapy with omega-3 PUFA in patients with iscemic heart disease and ventricular arrhythmias. MATERIALS AND METHODS: The study included 80 patients. Inclusion criteria were: documented IHD (history of myocardial infarction, stable angina, previous surgical intervention on coronary arteries (coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI]), positive stress tests, signs of IHD in coronary angiography or computer tomography of coronary arteries; ventricular arrhythmias, according to registered Holter monitoring (PVCs in the number of 250 or more per day and /or intermittent ventricular tachycardia paroxysms); continuous antiarrhytmic therapy for at least 1 month before inclusion (omega-blockers and /or amiodarone), 4) informed consent to participate in the study. RESULTS: All criteria for a good anti-arrhythmic effect (reducing the number of PVCs by 75% and more, paired PVCs by 90% or more, the complete elimination of unstable ventricular tachycardia paroxysms) after 3 months of therapy were observed in 16% of patients, and 6 months after - in 46%. A small but significant increase in the number of PVCs, paired PVCs and ventricular tachycardia paroxysms was noted in the control group. As a result, after 6 months of observation the mean SDNN in patients taking omega-3 PUFA, significantly exceeded the value of the one in the control group. Six months after, the mean value of TO was significantly lower and the mean value of TS - higher than in the control group. After 6 months of therapy with omega-3 PUFA it a significant increase of red blood cells omega-3 index was show by increasing the value of both EPA (an average of 78%) and DHA (an average of 42 %). CONCLUSION: 6 months supplementation with 1 g/day omega-3 PUFA for 6 months in patients with IHD improves the effect of standard antiarrhythmic therapy, reducing the number of isolated and paired PVCs, the number of unstable ventricular tachycardia paroxysms, improves HRT, HRV, increases red blood cells omega-3 index. The long-term (more than 3 months) omega 3 PUFA supplementation must consider be taken into in mTWA assessment to avoid false-positive findings in the SCD risk stratification. PMID- 22839710 TI - [Complex of genotypes of cytokines as a genetic factor of risk of development of myocardial infarction of in Europien population of Russia men]. AB - Cytokines as regulators of activity of inflammation play significant role in mechanisms of formation of atherosclerotic plaques and in processes of their destabilization. One of leading genetic factors determining level of their production appears to be polymorphism of cytokine genes structure at their promoter loci. We have conducted an analysis of distribution in groups of healthy male and female survivors of myocardial infarction (MI) of combined genetic signs represented as a complex of genotypes of a number of studied cytokine genes : TNF A863C; TNF-A308G; TNF-A238G; IL1B-C511T; IL1B-C-31T; IL4-C590T; IL6-C174G; IL10A 1082G IL10-A592C. Among these homozygous combinations of cytokine genotypes characterizing a group of men who have lived up to middle and old age without development of MI there are widely represented genotypes associated with high levels of production of both cytokines with pronounced proinflammatory (IL-1) and antiinflammatory (IL-4, IL-10) activity. Absence of such multidirectional combinations in genome of patients with myocardial infarction can be considered one of genetic factors of risk of development of acute distirbances of coronary circulation. PMID- 22839711 TI - [24-Hour arterial pressure variability and 24-hour variability of pulse carries unidirectional character and is not associated with left ventricular hypertrophy (results of population study)]. AB - Alternative prognostic interpretation of variability of arterial pressure (AP) and pulse seems contradictory if one considers classical conceptions of close physiological connection between AP and pulse. It is logical to expect that elevated variability of AP should be associated with elevated variability of pulse and vice versa. Within framework of the project EPOCH we examined a populational sample of inhabitants of Novosibirsk (129 men and 170 women) formed according to the family principle. Ambulatory 24-hour registration of AP and pulse was carried out with 15-30 minutes interval. Variability of AP turned out to be unidirectionally interconnected with variability of pulse and was not an independent marker of hypertrophy of the left ventricle but was associated with it at the account of concealed dependence on mean 24-hour AP. Cornell voltage index in persons with normal AP, "white coat" arterial hypertension (AH), "masked" AH was comparable and significantly lower than in subjects with sustained AH. PMID- 22839712 TI - [Vegetative status in pregnant and perimenopausal women with hypertension]. AB - We observed 137 patients, 72 of whom (53%) had hypertension in II trimester of pregnancy, and 65 patients (47%) who had hypertension in perimenopausal period. The comprehensive clinical and instrumental examination was carried out in all patients, including simultaneous 24-hour ambulatory blood pressure (BP) recording (with BP pattern), assessment of vegetative tone using the vegetative index (index Kerdo). Sympathetic/adrenergic activity (SAA) was quantified as beta receptor binding (beta-RB). Hypertension in pregnant women is associated with increased activity of the sympathetic-adrenal system, as evidenced by high values of beta-ARM, the Kerdo index and the presence of correlation between these parameters. Parasympathicotonia in perimenopausal women prevails. PMID- 22839713 TI - [Association of parameters of heart rate variability with severity of bronchial obstruction and presence of pulmonary hypertension in patients with chronic obstructive pulmonary disease]. AB - With the aim of assessing parameters of heart rate variability (HRV) and heart rhythm turbulence (HRT) in patients with chronic obstructive pulmonary disease (COPD) in dependence on severity of the course of this disease and presence of pulmonary hypertension (PH) we examined 73 patients (28 with COPD and 45 healthy subjects). Invasive measurement of central hemodynamics was conducted. Compared with the control group in patients with COPD we revealed lowering of temporal as well as frequency HRV parameters. No significant changes of HRV parameters depended on severity of COPD course. However a tendency to maximal lowering of HRV parameters was noted in the group of patients with COPD with first sec forced expiratory volume <50%. Comparison of patients with and without PH with controls revealed tendency to maximal lowering of HRV parameters in the PH group. Thus measurement of HRV can be used for supplementary assessment of severity of the disease and detection of PH. PMID- 22839714 TI - [Comparison of the effectiveness of pulmonary veins isolation vs linear radiofrequency ablation in paroxysmal atrial fibrillation patients using either mathematical scanning or clinical approach]. AB - AIM: to compare clinical results of linear ablation vs. PVI approach in patients with paroxysmal AF and to estimate theoretical probability of 4-waves re-entry to eliminate as a results of the both ablative techniques formatting by means left atrial geometry two-dimensional mathematical modeling. MATERIAL AND METHODS: Clinical phase. Study was conducted on 20 pts (6 women, 51,4+/-13,6 years of age) with paroxysmal AF underwent index RFA. All pts were divided into two age-sex arrhythmia history duration-antiarrhythmic drugs (AAD)-matched groups. The first group consisted of 10 pts (3 women, mean age - 51,1+/-11,9, history of arrhythmia - 3,2+/-1,2 years) in whom ablation strategy consisted of PVI using LASSO technique. The second group concluded of 10 pts (3 women, mean age - 51,1+/-12,9, history of arrhythmia- 3,1+/-1,1 years) in whom ablation strategy consisted of wide-area circumferential lines application around pulmonary veins, combined to roof line and mitral isthmus RFA using three-dimensional mapping system. Mathematical phase. As the first step numeric reconstruction of the autowave process in excitable tissues of the left atrium and the simulation of AF was performed. Fitzhugh-Nagumo equation was used for simulation to enabled us to take into account the electrical inhomogeneity of the atria (pulmonary vein ostia). A special scanning method was used for calculating characteristics of autowave processes in a two-dimensional mathematical model of the atrium. As the second step simulation of circular (corresponding to LASSO approach) and linear ablation (corresponding to 3D approach) was performed. RESULTS: Clinical phase. There were no complications associated with RFA. 7 pts of the first group vs 4 pts of the second subgroup had early recurrences of arrhythmia. AAD free sinus rhythm incidence in the first/second groups was 80%/20% at 12 months respectively (p=0,003). Mathematical phase. While circular LASSO-like ablation pattern was used, there was no elimination of 4-waves re-entry turning around the pulmonary veins ostia and vortex waves caused by them in a distributed two-dimensional atrial medium after time period equal to the re-entry period. Thus, the circular ablation formatting does not affect peripulmonary veins re-entry and, therefore, does not suppress AF. In contrast, linear ablation patterns suppress arrhythmias caused by 4-waves re-entry in two-dimensional mathematical modeling of the left atrium. CONCLUSION: Mathematical approach using linear ablation to simulate suppressed 4-waves re-entry more effectively comparing to PVI only. Clinical results are consistent with ablation formatting data obtained by means of 4-waves re-entry simulation in a two-dimensional mathematical modeling of the left atrium. PMID- 22839715 TI - [Comparison of three methods of antithrombotic therapy in elderly patients with nonvalvular atrial fibrillation]. AB - We compared efficacy and safety of warfarin, direct thrombin inhibitor dabigatran and clopidogrel in prevention of stroke in 210 patients with nonvalvular atrial fibrillation (AF) aged 65-80 years. The use of dabigatran (110 mg twice daily) for 12 months or warfarin was associated with similar rate of ischemic stroke but caused less bleeding (2.8 vs. 16.9%, p<0.05). Treatment with clopidogrel prevented stroke no less successfully, than those with warfarin and dabigatran and turned out to be sufficiently safe. When chosing antithrombotic therapy in gerontological patients with nonvalvular AF dabigatran and clopidogrel can be considered acceptable alternative to warfarin. PMID- 22839716 TI - [Heart rate variability in the prognosis of tilt-testing results]. AB - Study aim was assessment of dynamics of spectral parameters of heart rate variability (HRV) during the Westminster and Italian protocols of tilt-test (TT). We included in this study 114 patients with recurrent vasovagal syncope (VVS). Basing on TT results we distinguished 4 groups of patients: with positive result of the Westminster protocol (WPTT) (group 1, n=30); with negative result of WPTT (group 2, n=23); with positive result of the Italian protocol (IPTT) (group 3, n=44); with negative result of IPTT (group 4, n=11). Control group comprised 14 healthy persons without history of syncope. Spectral parameters of HRV were analyzed in 3 five minutes intervals (before TT in horizontal position, during first and last 5 minutes of orthostasis). Structure of vasovagal responses was similar for all TT protocols used. In lying position in patients of groups 1-3 lower values of LF1 and LF1/HF1 were registered, as well as high values of HF1 compared with the control group and patients with negative results of IPTT. Initial stage of TT in patients with positive result of WPTT (group 1) was characterized by almost twofold increase of LF values (n.u.) and decrease of HF parameters (n.u.) compared with other patients. In the group 1 during the second period. PMID- 22839717 TI - [Prevalence and diagnosis of dilated cardiomyopathy. Results of the registry of dilated cardiomyopathy in the Russian Federation]. PMID- 22839718 TI - [The experience of the application of ascorbinic acid as antioxidant after coronary artery surgery with use of cardiopulmonary bypass]. AB - We have studied the role of oxidant stress in development of rhythm disturbances in early postoperative period after coronary artery bypass grafting and possibilities of their prevention with preparations of ascorbinic acid. It was shown that the use of beta-adrenoblockers allows to prevent arrhythmia on first day after operation only in 80% of cases. Patients with developed disturbances of cardiac rhythm were characterized by high parameters of lipid peroxidation (LPO) and substantial changes of activity of antioxidant enzyme catalase. Administration of ascorbinic acid at the stage of preparation of patients to surgery and in first 24 hours after operation allowed to effectively prevent development of oxidative stress and disturbances of cardiac rhythm. A conclusion was made that inclusion of ascorbinic acid in drug therapy of patients with ischemic heart disease could be recommended for prevention of arrhythmia in postoperative period. PMID- 22839719 TI - [The problem of bone marrow fatty transformation]. PMID- 22839720 TI - [Atorvastatin or rosuvastatin? Select from the perspective of evidence-based medicine]. PMID- 22839721 TI - [Histiocytoid cardiomyopathy in an infant]. AB - We present a description of a clinical observation of a histiocytoid cardiomyopathy in a female patient aged 4 months. This pathology is rare in pediatric cardiology. Its etiology is linked with mutation of the gene encoding mitochondrial cytochrome B (mitochondrial transport of electrons). This mutation leads to a specific morphological and functional abnormalities of cardiomyocytes. Purkinje cells and cells of conduction system at microscopy appear as histiocytolike foam cells cytoplasm of which contain large amount of lipids and glycogen. Girls prevail among those affected. The case reflects clinical picture characteristic for this nosology: malignant arrhythmia and cardiomegaly with fatal outcome. PMID- 22839722 TI - Quantitative detection of zeta-chain-associated protein 70 expression in chronic lymphocytic leukemia. AB - Overexpression of zeta-chain-associated protein 70 (ZAP-70) was recently recognized as an independent prognostic marker for the aggressive form of chronic lymphocytic leukemia (CLL). The objective of this study was to demonstrate the feasibility and implementation of quantitative detection of ZAP-70 protein in B cells to clearly distinguish patients with CLL with the aggressive form of the disease. B cells were isolated from patient blood and lysed. Released ZAP-70 protein was detected using an immunomagnetic fluorescence assay. The assay protocol was developed using Jurkat cells and recombinant ZAP-70 (rZAP-70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP-70 protein. The signal response was linear over a wide dynamic range, from 125 to 40 000 Jurkat cells per test (R(2) = 0.9987) and from 0 to 40 000 pg rZAP 70 protein per test (R(2) = 0.9928). The results from 20 patients with CLL correlated strongly with flow cytometry analysis. Concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. The assay reported here is a simple, reliable and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention. PMID- 22839723 TI - Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin. AB - Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses. PMID- 22839724 TI - Hydroxy decenoic acid down regulates gtfB and gtfC expression and prevents Streptococcus mutans adherence to the cell surfaces. AB - BACKGROUND: 10-Hydroxy-2-decenoic acid, an unsaturated fatty acid is the most active and unique component to the royal jelly that has antimicrobial properties. Streptococcus mutans is associated with pathogenesis of oral cavity, gingivoperiodontal diseases and bacteremia following dental manipulations. In the oral cavity, S. mutans colonize the soft tissues including tongue, palate, and buccal mucosa. When considering the role of supragingival dental plaque in caries, the proportion of acid producing bacteria (particularly S. mutans), has direct relevance to the pathogenicity of the plaque. The genes that encode glucosyltransferases (gtfs) especially gtfB and gtfC are important in S. mutans colonization and pathogenesis. This study investigated the hydroxy-decenoic acid (HDA) effects on gtfB and gtfC expression and S. mutans adherence to cells surfaces. METHODS: Streptococcus mutans was treated by different concentrations of HPLC purified HDA supplied by Iran Beekeeping and Veterinary Association. Real time RT-PCR and western blot assays were conducted to evaluate gtfB and gtfC genes transcription and translation before and after HDA treatment. The bacterial attachment to the cell surfaces was evaluated microscopically. RESULTS: 500 MUg ml-1 of HDA inhibited gtfB and gtfC mRNA transcription and its expression. The same concentration of HDA decreased 60% the adherence of S. mutans to the surface of P19 cells. CONCLUSION: Hydroxy-decenoic acid prevents gtfB and gtfC expression efficiently in the bactericide sub-concentrations and it could effectively reduce S. mutans adherence to the cell surfaces. In the future, therapeutic approaches to affecting S. mutans could be selective and it's not necessary to put down the oral flora completely. PMID- 22839725 TI - Characterisation of a natural variant of the gamma-butyrolactone signalling receptor. AB - BACKGROUND: The control of antibiotic production in Streptomyces coelicolor A3(2) involves complicated regulatory networks with multiple regulators controlling the expression of antibiotic biosynthetic pathways. One such regulatory network is that of the gamma-butyrolactones, the so-called S. coelicolor butanolide (SCB) system. The gamma-butyrolactones in this system serve as signalling molecules and bind to the receptor protein ScbR, releasing the repression of its target genes. The resulting expression changes affect the production of the two pigmented antibiotics Act and Red, as well as the transcription of the cpk antibiotic biosynthesis gene cluster and the synthesis of the gamma-butyrolactones themselves. RESULTS: We identified a natural variant of ScbR in S. coelicolor (ScbRM600) that differs from ScbR in the genome-sequenced strain M145 (ScbRM145) by a single amino acid change, R120S. ScbRM600 is impaired in its DNA binding ability and alters the expression of the pathway-specific regulatory genes of the red and cpk antibiotic biosynthesis gene clusters. Also, expression of the gamma butyrolactone biosynthesis gene scbA and production of the signalling molecules is slightly reduced. CONCLUSIONS: The gamma-butyrolactone receptor, ScbR, plays a key role in the SCB regulatory cascade and in determining the onset of the expression of the antibiotic regulatory genes. PMID- 22839727 TI - Nine diiron(II) complexes of three bis-tetradentate pyrimidine based ligands with NCE (E = S, Se, BH3) coligands. AB - Three bis-tetradentate acyclic amine ligands differing only in the arm length of the pyridine pendant arms attached to the 4,6-positions of the pyrimidine ring, namely, 4,6-bis[N,N-bis(2'-pyridylethyl)aminomethyl]-2-phenylpyrimidine (L(Et)), 4,6-bis[N,N-bis(2'-pyridylmethyl)aminomethyl]-2-phenylpyrimidine (L(Me)), and 4,6 [(2'-pyridylmethyl)-2'-pyridylethyl)aminomethyl]-2-phenylpyrimidine (L(Mix)) have been used to synthesize nine air-sensitive diiron(II) complexes: [Fe(II)(2)L(Et)(NCS)(4)].MeOH.3/4H(2)O (1.MeOH.3/4H(2)O), [Fe(II)(2)L(Et)(NCSe)(4)].H(2)O (2.H(2)O), [Fe(II)(2)L(Et)(NCBH(3))(4)].(5/2)H(2)O (3.(5/2)H(2)O), [Fe(II)(2)L(Me)(NCS)(4)].1/2H(2)O (4.1/2H(2)O), [Fe(II)(2)L(Me)(NCSe)(4)] (5), [Fe(II)(2)L(Me)(NCBH(3))(4)].(3/2)H(2)O (6.(3/2)H(2)O), [Fe(II)(2)L(Mix)(NCS)(4)].1/2H(2)O (7.1/2H(2)O), [Fe(II)(2)L(Mix)(NCSe)(4)].(3/2)H(2)O (8.(3/2)H(2)O), and [Fe(II)(2)L(Mix)(NCBH(3))(4)].(3/2)H(2)O (9.(3/2)H(2)O). Complexes 3.(5/2)H(2)O, 4.1/2H(2)O, 5, 6.(3/2)H(2)O, and 8.(3/2)H(2)O were structurally characterized by X-ray crystallography, revealing, in all cases, both of the iron(II) centers in an octahedral environment with two NCE (E = S, Se, or BH(3)) anions in a cis position relative to one another. Variable temperature magnetic susceptibility measurements showed that all nine diiron(II) complexes are stabilized in the [HS HS] state from 300 K to 4 K, and exhibit weak antiferromagnetic coupling. Mossbauer spectroscopy confirmed the spin and oxidation states of eight of the nine complexes (the synthesis of air-sensitive complex 3 was not readily reproduced). PMID- 22839726 TI - The copycat phenomenon after two Finnish school shootings: an adolescent psychiatric perspective. AB - BACKGROUND: Two school shootings with altogether 18 victims took place in Finland in November 2007 and September 2008. Homicides and suicides are both associated with the copycat phenomenon. The aim of the present study was to characterize adolescent copycats who had threatened to carry out a school massacre. METHODS: The nation-wide study evaluated 77 13- to 18-year-old adolescents who were sent for adolescent psychiatric evaluations between 8.11.2007 and 30.6.2009, one of the reasons for evaluation being a threat of massacre at school. The medical files of the copycats were retrospectively analysed using a special data collection form. Data on demographics, family- and school-related issues, previous psychiatric treatment and previous delinquency, current symptoms, family adversities and psychiatric diagnoses were collected. The severity of the threat expressed and the risk posed by the adolescent in question were evaluated. The Psychopathy Checklist Youth Version was used to assess psychopathic traits. RESULTS: All of the copycats were native Finns with a mean age of 15.0 years. Almost two thirds of them had a history of previous mental health treatment before the index threat. Almost two thirds of the copycats suffered from anxiety and depressive symptoms, and almost half of the sample expressed either suicidal ideation or suicidal plans. Behavioural problems including impulse control problems, aggressive outbursts, the destruction of property as well as non physical and physical violence against other persons were common. The diagnosis groups highlighted were behavioural and emotional disorders, mood disorders as well as schizophrenia-related disorders. The prevalence of pervasive developmental disorders was high. Only one of the copycats was assessed as expressing high traits of psychopathy. CONCLUSION: The copycats with school massacre threats were characterized with a high prevalence of mental and behavioural disorders. Like actual school shooters, they showed psychotic symptoms and traumatic experiences, but unlike the shooters, the copycats were not psychopathic. PMID- 22839729 TI - Nanoparticle-induced morphology and hydrophilicity of structured surfaces. AB - Nanoparticles have been applied into the construction of micro- and nanoscaled surface structures with extreme wettability over the past few years. However, the details of processing and employing colloidal nanosuspensions for this purpose have not yet been fully investigated. In this work, we study the surface structures formed via nanosuspensions, in which nanoparticles of solid phase are presented, and the caused surface wettability. We disperse silica nanoparticles with different sizes into pure ethanol to prepare nanosuspensions with a series of concentrations. The suspensions are ultrasonically processed to prompt uniform distribution of nanoparticles before application. The deposited nanosuspensions are thermally treated to assist the regulation of surface patterns based on nanoparticles. Hence, the investigation explores a variety of experimental conditions that will lead to distinctive surface structures and wettabilities. Accordingly, the wettability of the induced surfaces is investigated using contact angle measurement, and the structures of those surfaces are mainly revealed by atomic force microscopy (AFM). Superhydrophilicity is observed on many of such formed surfaces, and the pattern of surface structures in micro- and nanoscale is closely related to the processing conditions and the size of nanoparticles. Thus, we report the characteristics of the surface patterns based on nanoparticles and the formed wettability. PMID- 22839728 TI - Cervical human papillomavirus infection among young women engaged in sex work in Phnom Penh, Cambodia: prevalence, genotypes, risk factors and association with HIV infection. AB - BACKGROUND: Although cervical cancer is the leading cancer in Cambodia, most women receive no routine screening for cervical cancer and few treatment options exist. Moreover, nothing is known regarding the prevalence of cervical HPV or the genotypes present among women in the country. Young sexually active women, especially those with multiple sex partners are at highest risk of HPV infection. We examine the prevalence and genotypes of cervical HPV, as well as the associated risk factors among young women engaged in sex work in Phnom Penh, Cambodia. METHODS: We conducted a cross-sectional study among 220 young women (15 29 years) engaged in sex work in different venues including brothels or entertainment establishments, and on a freelance basis in streets, parks and private apartments. Cervical specimens were collected using standard cytobrush technique. HPV DNA was tested for by polymerase chain reaction (PCR) and genotyping using type-specific probes for 29 individual HPV types, as well as for a mixture of 10 less common HPV types. All participants were also screened for HIV status using blood samples. Multivariate logistic regression analyses were conducted to assess risk factors for any or multiple HPV infection. RESULTS: The prevalence of cervical HPV 41.1%. HPV 51 and 70 were the most common (5.0%), followed by 16 (4.6%), 71 (4.1%) and 81 (3.7%). Thirty-six women (16.4%) were infected with multiple genotypes and 23.3% were infected with at least one oncogenic HPV type. In multivariate analyses, having HIV infection and a higher number of sexual partners were associated with cervical HPV infection. Risk factors for infection with multiple genotypes included working as freelance female sex workers (FSW) or in brothels, recent binge use of drugs, high number of sexual partners, and HIV infection. CONCLUSIONS: This is the first Cambodian study on cervical HPV prevalence and genotypes. We found that HPV infection was common among young FSW, especially among women infected with HIV. These results underscore the urgent need for accessible cervical cancer screening and treatment, as well as for a prophylactic vaccine that covers the HPV subtypes present in Cambodia. PMID- 22839730 TI - Promoting contraceptive use among female rural-to-urban migrants in Qingdao, China: a comparative impact study of worksite-based interventions. AB - BACKGROUND: We conducted a comparative study in worksites to assess the impact of sexual health promoting interventions on contraceptive use among female rural-to urban migrants. STUDY DESIGN: In Qingdao ten manufacturing worksites were randomly allocated to a standard package of interventions (SPI) and an intensive package of interventions (IPI). The interventions ran from July 2008 to January 2009. Cross-sectional surveys at baseline and end line assessed the sexual behaviour of young female migrants. To evaluate the impact of the interventions we assessed pre- and post-time trends. RESULTS: From the SPI group 721 (baseline) and 615 (end line) respondents were considered. Out of the IPI group we included 684 and 603 migrants. Among childless migrants, self-reported contraceptive use increased significantly after SPI and IPI (adjusted odds ratio [aOR] = 3.23; 95% confidence interval [CI] = 1.52-6.84; p < 0.01 and aOR = 5.81; 95% CI = 2.63 12.80; p < 0.001, respectively). Childless migrants older than 22 years reported a greater use after IPI than after SPI. CONCLUSION: Implementing current Chinese sexual health promotion programmes at worksites is likely to have a positive impact on migrant women working in the manufacturing industry of Qingdao. More comprehensive interventions seem to have an added value if they are well targeted to specific groups. PMID- 22839731 TI - Consideration of the influence of place on access to employment for persons with serious mental illness in northeastern Ontario. AB - INTRODUCTION: Despite increasing attention to employment within the mental health sector, reports indicate that people with serious mental illness (SMI) continue to experience limited employment success in the province of Ontario, Canada. Research specifies that people with SMI who live in rural places are less likely than those living in urban centers to have access to satisfactory employment services or to become gainfully employed. The objective of this study was to examine access to employment from the perspectives of people with SMI, mental health and vocational service providers, and decision-makers, and to explore whether place influenced their access to work in northeastern Ontario. METHODS: A qualitative case study using community-based participatory research methods was chosen to examine the experience of access to competitive employment in two northeastern Ontario communities. The cases selected for study were two geographic areas in northeastern Ontario which provided best-practice, mental health services to persons with SMI. Community-based site partners advertised and recruited participants, and a consumer advisory provided input on key stakeholders, questions, findings and the study action plan. The study findings were informed by individual and group interviews conducted with 46 individuals who resided in both rural and urban settings in the case communities, and feedback from 49 participants who attended town hall forums for presentation of study findings and development of an action plan. The qualitative data was supported by a secondary data source reporting on the employment outcomes of 4112 people with SMI who received disability income support and who resided in the case communities. Qualitative data were analyzed inductively, and categories and themes were developed. Findings were member checked with all informants and town hall participants in each case community. RESULTS: This article draws on the findings of a larger study and reports on the influence of place to the low employment success experienced by people with SMI who reside in the case communities; 91.3% of those receiving disability income support are unemployed, and rural residents experience higher levels of unemployment than those in urban places. Place was found to influence access to employment in five ways: by limited access to employment support services in rural places, and to recommended ratios in urban places; by the use of different models and practices that were inconsistent with best practices for people with SMI; by the lack of a plan for the implementation of employment services in the case communities; by limited use of the available, dedicated vocational resources for employment purposes; and by inadequate supports provided to persons with SMI who wish to enter the workforce. The results also underscore how people with SMI continue to be perceived negatively regarding their capacity for employment. Such stereotypical attitudes additionally contributed to employment marginalization of people with SMI from the workforce, especially in rural communities. CONCLUSIONS: The study highlights the influence of geography and human resources to the implementation of best practice employment services and supports for persons with SMI. Important policy implications include the need to consider place when implementing evidence-based practices in places where geography, distance and human health resources limit the communities' capacity to successfully do so. The study also underscores the need to build community capacity for supported employment, especially in rural places, in order to improve the participation of people with SMI in employment, and subsequently, to help shift the communities' thinking about their capacity for work. PMID- 22839732 TI - A blinded randomised controlled trial to determine the effect of enteric coating on enzyme treatment for canine exocrine pancreatic efficiency. AB - BACKGROUND: Enzyme treatment is the mainstay for management of exocrine pancreatic insufficiency (EPI) in dogs. 'Enteric-coated' preparations have been developed to protect the enzyme from degradation in the stomach, but their efficacy has not been critically evaluated. The hypothesis of the current study was that enteric coating would have no effect on the efficacy of pancreatic enzyme treatment for dogs with EPI.Thirty-eight client-owned dogs with naturally occurring EPI were included in this multicentre, blinded, randomised controlled trial. Dogs received either an enteric-coated enzyme preparation (test treatment) or an identical preparation without the enteric coating (control treatment) over a period of 56 days. RESULTS: There were no significant differences in either signalment or cobalamin status (where cobalamin deficient or not) between the dogs on the test and control treatments. Body weight and body condition score increased in both groups during the trial (P<0.001) but the magnitude of increase was greater for the test treatment compared with the control treatment (P<0.001). By day 56, mean body weight increase was 17% (95% confidence interval 11-23%) in the test treatment group and 9% (95% confidence interval 4-15%) in the control treatment group. The dose of enzyme required increased over time (P<0.001) but there was no significant difference between treatments at any time point (P=0.225). Clinical disease severity score decreased over time for both groups (P=0.011) and no difference was noted between groups (P=0.869). No significant adverse effects were reported, for either treatment, for the duration of the trial. CONCLUSIONS: Enteric coating a pancreatic enzyme treatment improves response in canine EPI. PMID- 22839734 TI - Quantitative aspects of ohmic microscopy. AB - The potential difference between two microreference electrodes, Deltaphi(sol), immersed in an aqueous sulfuric acid solution was monitored while performing conventional cyclic voltammetric experiments with a Pt disk electrode embedded in an insulating surface in an axisymmetric cell configuration. The resulting Deltaphi(sol) vs E curves, where E is the potential applied to the Pt disk electrode were remarkably similar to the voltammograms regardless of the position of the microreference probes. Most importantly, the actual values of Deltaphi(sol) were in very good agreement with those predicted by the primary current distribution using Newman's formalism (Newman, J. J. Electrochem. Soc. 1966, 113, 501-502). These findings afford a solid basis for the development of ohmic microscopy as a quantitative tool for obtaining spatially resolved images of electrodes displaying nonhomogenous surfaces. PMID- 22839733 TI - 2C-Methyl-d-erythritol 4-phosphate enhances and sustains cyclodiphosphate synthase IspF activity. AB - There is significant progress toward understanding catalysis throughout the essential MEP pathway to isoprenoids in human pathogens; however, little is known about pathway regulation. The present study begins by testing the hypothesis that isoprenoid biosynthesis is regulated via feedback inhibition of the fifth enzyme cyclodiphosphate synthase IspF by downstream isoprenoid diphosphates. Here, we demonstrate recombinant E. coli IspF is not inhibited by downstream metabolites isopentenyl diphosphate (IDP), dimethylallyl diphosphate (DMADP), geranyl diphosphate (GDP), and farnesyl diphosphate (FDP) under standard assay conditions. However, 2C-methyl-d-erythritol 4-phosphate (MEP), the product of reductoisomerase IspC and first committed MEP pathway intermediate, activates and sustains this enhanced IspF activity, and the IspF-MEP complex is inhibited by FDP. We further show that the methylerythritol scaffold itself, which is unique to this pathway, drives the activation and stabilization of active IspF. Our results suggest a novel feed-forward regulatory mechanism for 2C-methyl-d erythritol 2,4-cyclodiphosphate (MEcDP) production and support an isoprenoid biosynthesis regulatory mechanism via feedback inhibition of the IspF-MEP complex by FDP. The results have important implications for development of inhibitors against the IspF-MEP complex, which may be the physiologically relevant form of the enzyme. PMID- 22839735 TI - Reversible O-O bond scission of peroxodiiron(III) to high-spin oxodiiron(IV) in dioxygen activation of a diiron center with a bis-tpa dinucleating ligand as a soluble methane monooxygenase model. AB - The conversion of peroxodiiron(III) to high-spin S = 2 oxodiiron(IV) via reversible O-O bond scission in a diiron complex with a bis-tpa dinucleating ligand, 6-hpa, has been characterized by elemental analysis; kinetic measurements for alkene epoxidation; cold-spray ionization mass spectrometry; and electronic absorption, Mossbauer, and resonance Raman spectroscopy to gain insight into the O(2) activation mechanism of soluble methane monooxygenases. This is the first synthetic example of a high-spin S = 2 oxodiiron(IV) species that oxidizes alkenes to epoxides efficiently. The bistability of the peroxodiiron(III) and high-spin S = 2 oxodiiron(IV) moieties is the key feature for the reversible O-O bond scission. PMID- 22839736 TI - Relationship between smoking and a new index of arterial stiffness, the cardio ankle vascular index, in male workers: a cross-sectional study. AB - BACKGROUND: Cigarette smoking is one of the major factors that increases arterial stiffness. The purpose of this study was to examine further the relationship between smoking status and arterial stiffness using a new index, the cardio-ankle vascular index (CAVI), in male Japanese workers. METHODS: This cross-sectional study included 4,729 male Japanese workers undergoing annual health checkups. CAVI was measured at the time of the annual health checkup between April 2007 and March 2008. The subjects were divided into three groups, smokers (n = 1,913), former smokers (n = 1,481) and non-smokers (n = 1,348) according to their responses to a questionnaire. We compared the CAVI in the three groups after adjusting for age. Multiple regression analysis was used to examine the association between CAVI and the number of cigarettes smoked per day in order to examine whether there was a dose-response relationship between smoking and CAVI. RESULTS: The mean CAVI for each group was 7.81 +/- 0.02 for smokers, 7.70 +/- 0.02 for former smokers and 7.64 +/- 0.02 for non-smokers. A significant difference was observed between each group. According to the results of multiple regression analysis, the standardized beta of the number of cigarettes smoked per day was 0.09 (p < 0.01). This confirmed a positive association with CAVI. CONCLUSIONS: Our study demonstrated that there is a significant association between the number of cigarettes smoked per day and arterial stiffness, as measured by CAVI. PMID- 22839738 TI - Net financial benefits of averting HIV infections among people who inject drugs in Urumqi, Xinjiang, Peoples Republic of China (2005-2010). AB - BACKGROUND: To quantify the contribution of locally implemented prevention programmes in contributing to reductions in treatment and care costs by averting HIV infections among those who inject drugs this study calculates net financial benefit of providing harm reduction programmes using information from services being implemented in Urumqi, Xinjiang Uighur Autonomous Region of China ( between 2005 and 2010). METHODS: Information was collected to assess cost of providing methadone treatment (MMT) and needle and syringe programmes (NSP). HIV incidence was estimated among people who inject drugs (PWID). HIV infections averted were calculated. Net benefit was assessed by estimating costs of providing prevention programmes and comparing these to the costs of providing care. RESULTS: An estimated 5678 (range 3982-7599) HIV infections were averted between 2005 and 2010 and the net financial benefit of providing harm reduction programmes compared to treatment and care costs for HIV infections averted was USD 4.383 million during the same time period. CONCLUSION: These results demonstrate the net and accumulating benefit of investing in harm reduction programmes for PWID in Urumqi. The return on investment progressively increased during the time period studied and it is clear that these cost savings will continue to accrue with the continued implementation of HIV prevention interventions in the community that include harm reduction programmes targeted at PWID. PMID- 22839737 TI - Microbial transformation from normal oral microbiota to acute endodontic infections. AB - BACKGROUND: Endodontic infections are a leading cause of oro-facial pain and tooth loss in western countries, and may lead to severe life-threatening infections. These infections are polymicrobial with high bacterial diversity. Understanding the spatial transition of microbiota from normal oral cavities through the infected root canal to the acute periapical abscess can improve our knowledge of the pathogenesis of endodontic infections and lead to more effective treatment. We obtained samples from the oral cavity, infected root canal and periapical abscess of 8 patients (5 with localized and 3 with systemic infections). Microbial populations in these samples were analyzed using next generation sequencing of 16S rRNA amplicons. Bioinformatics tools and statistical tests with rigorous criteria were used to elucidate the spatial transition of the microbiota from normal to diseased sites. RESULTS: On average, 10,000 partial 16S rRNA gene sequences were obtained from each sample. All sequences fell into 11 different bacterial phyla. The microbial diversity in root canal and abscess samples was significantly lower than in the oral samples. Streptococcus was the most abundant genus in oral cavities while Prevotella and Fusobacterium were most abundant in diseased samples. The microbiota community structures of root canal and abscess samples were, however, more similar to each other than to the oral cavity microbiota. Using rigorous criteria and novel bioinformatics tools, we found that Granulicatella adiacens, Eubacterium yurii, Prevotella melaninogenica, Prevotella salivae, Streptococcus mitis, and Atopobium rimae were over represented in diseased samples. CONCLUSIONS: We used a novel approach and high throughput methodologies to characterize the microbiota associated normal and diseased oral sites in the same individuals. PMID- 22839739 TI - Genetic parameters of infectious bovine keratoconjunctivitis and its relationship with weight and parasite infestations in Australian tropical Bos taurus cattle. AB - BACKGROUND: Infectious bovine keratoconjunctivitis (IBK) or 'pinkeye' is an economically important ocular disease that significantly impacts animal performance. Genetic parameters for IBK infection and its genetic and phenotypic correlations with cattle tick counts, number of helminth (unspecified species) eggs per gram of faeces and growth traits in Australian tropically adapted Bos taurus cattle were estimated. METHODS: Animals were clinically examined for the presence of IBK infection before and after weaning when the calves were 3 to 6 months and 15 to 18 months old, respectively and were also recorded for tick counts, helminth eggs counts as an indicator of intestinal parasites and live weights at several ages including 18 months. RESULTS: Negative genetic correlations were estimated between IBK incidence and weight traits for animals in pre-weaning and post-weaning datasets. Genetic correlations among weight measurements were positive, with moderate to high values. Genetic correlations of IBK incidence with tick counts were positive for the pre-weaning and negative for the post-weaning datasets but negative with helminth eggs counts for the pre weaning dataset and slightly positive for the post-weaning dataset. Genetic correlations between tick and helminth eggs counts were moderate and positive for both datasets. Phenotypic correlations of IBK incidence with helminth eggs per gram of faeces were moderate and positive for both datasets, but were close to zero for both datasets with tick counts. CONCLUSIONS: Our results suggest that genetic selection against IBK incidence in tropical cattle is feasible and that calves genetically prone to acquire IBK infection could also be genetically prone to have a slower growth. The positive genetic correlations among weight traits and between tick and helminth eggs counts suggest that they are controlled by common genes (with pleiotropic effects). Genetic correlations between IBK incidence and tick and helminth egg counts were moderate and opposite between pre weaning and post-weaning datasets, suggesting that the environmental and (or) maternal effects differ between these two growth phases. This preliminary study provides estimated genetic parameters for IBK incidence, which could be used to design selection and breeding programs for tropical adaptation in beef cattle. PMID- 22839740 TI - Care redesign--a path forward for providers. PMID- 22839741 TI - Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. AB - Although mesenchymal stem cells (MSCs) have been increasingly trialed to treat a variety of diseases, the underlying mechanisms remain still elusive. In this study, human umbilical cord (UC)-derived MSCs were stimulated by hypoxia, and the membrane microvesicles (MVs) in the supernatants were collected by ultracentrifugation, observed under an electron microscope, and the origin was identified with the flow cytometric technique. The results showed that upon hypoxic stimulus, MSCs released a large quantity of MVs of ~100 nm in diameter. The MVs were phenotypically similar to the parent MSCs, except that the majority of them were negative for the receptor of platelet-derived growth factor. DiI labeling assay revealed that MSC-MVs could be internalized into human UC endothelial cells (UC-ECs) within 8 h after they were added into the culture medium. Carboxyfluorescein succinimidyl ester-labeling technique and MTT test showed that MSC-MVs promoted the proliferation of UC-ECs in a dose-dependent manner. Further, MVs could enhance in vitro capillary network formation of UC-ECs in a Matrigel matrix. In a rat hindlimb ischemia model, both MSCs and MSC-MVs were shown to improve significantly the blood flow recovery compared with the control medium (P<0.0001), as assessed by laser Doppler imaging analysis. These data indicate that MV releasing is one of the major mechanisms underlying the effectiveness of MSC therapy by promoting angiogenesis. PMID- 22839743 TI - Understanding complex traits: from farmers to pharmas. AB - A report on the 4th International Conference on Quantitative Genetics (ICQG4), Edinburgh, UK, June 17-22, 2012. PMID- 22839742 TI - Does the choice of neighbourhood supermarket access measure influence associations with individual-level fruit and vegetable consumption? A case study from Glasgow. AB - BACKGROUND: Previous studies have provided mixed evidence with regards to associations between food store access and dietary outcomes. This study examines the most commonly applied measures of locational access to assess whether associations between supermarket access and fruit and vegetable consumption are affected by the choice of access measure and scale. METHOD: Supermarket location data from Glasgow, UK (n = 119), and fruit and vegetable intake data from the 'Health and Well-Being' Survey (n = 1041) were used to compare various measures of locational access. These exposure variables included proximity estimates (with different points-of-origin used to vary levels of aggregation) and density measures using three approaches (Euclidean and road network buffers and Kernel density estimation) at distances ranging from 0.4 km to 5 km. Further analysis was conducted to assess the impact of using smaller buffer sizes for individuals who did not own a car. Associations between these multiple access measures and fruit and vegetable consumption were estimated using linear regression models. RESULTS: Levels of spatial aggregation did not impact on the proximity estimates. Counts of supermarkets within Euclidean buffers were associated with fruit and vegetable consumption at 1 km, 2 km and 3 km, and for our road network buffers at 2 km, 3 km, and 4 km. Kernel density estimates provided the strongest associations and were significant at a distance of 2 km, 3 km, 4 km and 5 km. Presence of a supermarket within 0.4 km of road network distance from where people lived was positively associated with fruit consumption amongst those without a car (coef. 0.657; s.e. 0.247; p0.008). CONCLUSIONS: The associations between locational access to supermarkets and individual-level dietary behaviour are sensitive to the method by which the food environment variable is captured. Care needs to be taken to ensure robust and conceptually appropriate measures of access are used and these should be grounded in a clear a priori reasoning. PMID- 22839744 TI - Symptoms of depression in ICU physicians. AB - BACKGROUND: Work and family are the two domains from which most adults develop satisfaction in life. They also are responsible for stressful experiences. There is a perception in the community that work is increasingly the source of much of our stress and distress. Depressive symptoms may be related to repeated stressful experiences. Intensive care unit (ICU) physicians are exposed to major stressors. However, the existence of depressive symptoms in these doctors has been poorly studied. This study was designed to evaluate the prevalence and associated risk factors of depressive symptoms in junior and senior ICU physicians. METHOD: A one day national survey was conducted in adult intensive care units (ICU) in French public hospitals. Symptoms of depression were assessed using the Centers of Epidemiologic Studies Depression Scale (CES-D). RESULTS: A total of 189 ICUs participated, and 901 surveys were returned (75.8% response rate). Symptoms of depression were found in 23.8% of the respondents using the CES-D scale. Fifty eight percent of these intensivists presenting symptoms of depression wished to leave their job compared with only 33% of those who did not exhibit signs of depression as assessed by the CES-D scale (p < 0.0001). Multiple logistic regression showed that organizational factors were associated with the presence of depressive symptoms. Workload (long interval since the last nonworking weekend, absence of relief of service until the next working day after a night shift) and impaired relationships with other intensivists were independently associated with the presence of depressive symptoms. A high level of burnout also was related to the presence of depressive symptoms. In contrast, no demographic factors regarding ICU physicians and no factor related to the severity of illness of patients were retained by the model. The quality of relationships with other physicians (from other departments) was associated with the absence of depressive symptoms (protective effect). CONCLUSIONS: Approximately one of four intensivists presented symptoms of depression. The next step could be to test whether organization modification is associated with less depressive symptoms and less desire to leave the job. PMID- 22839745 TI - Laparoscopic versus open catheter placement in peritoneal dialysis patients: a systematic review and meta-analysis. AB - BACKGROUND: Peritoneal dialysis has been proven to be a safe and effective mode of renal replacement therapy for patients with end-stage renal disease. The usage of laparoscopic catheter placement technique was increased in recent years. But the advantages and disadvantages between the laparoscopic catheter placement technique and open laparotomy technique were still http://in controversy. The objective of this study is to access the operation-related data and complications of catheter placement for peritoneal dialysis (PD) patients, Then to determine the better method for catheter insertion. METHODS: We performed a systematic review and meta-analysis on published studies identified by the databases PubMed, EMBASE, Highwire, and the Cochrane Library. Analysis was performed using the statistical software Review Manager Version 5.0. RESULTS: We assessed the operation-related data and complications of four randomized controlled trials (RCTs) and ten observational studies. The available data showed that laparoscope prolonged the time for catheter insertion in PD patients, however, the two groups did not significantly differ in hospital stays, early and late complications, including infection, dialysate leaks, catheter migration, pericannular bleeding, blockage and hernia. CONCLUSIONS: The data showed that Laparoscopic catheter placement had no superiority to open surgery. However, this treatment still needs to be confirmed in a large, multi-center, well-designed RCT. PMID- 22839746 TI - Redox routes to substitution of aluminum(III): synthesis and characterization of (IP-)2AlX (IP = alpha-iminopyridine, X = Cl, Me, SMe, S2CNMe2, C=CPh, N3, SPh, NHPh). AB - Redox active ligands are shown to facilitate a variety of group transfer reactions at redox inert aluminum(III). Disulfides can be used as a two-electron group transfer reagent, and we show that (IP(-))(2)AlSR can be formed by reaction of [(THF)(6)Na][(IP(2-))(2)Al] (1c) with disulfides RSSR (where X = C(S)NMe(2), 4; SMe, 5). In a more general redox route to substitution of aluminum bis(iminopyridine) complexes, we report zinc(II) salts as a group transfer reagent. Reaction of [((R)IP(2-))(2)Al](-) (R = H, 1c; Me, 1d) with ZnX(2) affords ((R)IP(-))(2)AlX (where IP = iminopyridine, R = H, and X = Cl, 2; CCPh, 6; N(3), 7; SPh, 8; or R = Me and X = NHPh, 9). Single crystal X-ray diffraction analysis of the complexes reveal that each of the five coordinate complexes reported here has a trigonal bipyramidal geometry with tau = 0.668 - 0.858. We observed a correlation between the greatest deviations from ideal trigonal bipyramidal symmetry (lowest tau values), the bond lengths consistent with smallest degree of ligand reduction, and the least polarizable X ligand in (IP( ))(2)AlX. Complex 4 is six-coordinate and is best described as distorted octahedral. Variable temperature magnetic susceptibility measurements indicate that each of the complexes 3-9 has a biradical electronic structure similar to previously reported 2. Magnetic exchange coupling constants in the range J = -94 to -212 cm(-1) were fit to the data for 2-9 to describe the energy of antiferromagnetic interaction between ligand radicals assuming a spin Hamiltonian of the form H = -2JS(L(1)).S(L(2)). The strongest coupling occurs when the angle between the ligand planes is smallest, presumably to afford good overlap with the Al-X sigma* orbital. Electrochemical properties of the complexes were probed using cyclic voltammetry and each of 3-9 displayed a reversible two-electron reduction and two quasi-reversible one-electron oxidation processes. The energy of the ligand based redox processes for 2-9 differ by about 150 mV over all complexes and show a correlation with the degree of IP(-) reduction observed crystallographically; more reduced IP(-) ligands require higher potentials for further reduction. Comproportionation constants that describe the equilibrium for the reaction (IP(-))(2)AlX + (IP)(2)AlX <-> (IP(-))(IP)AlX fall in the range of K(c) = 10(5.7) to 10(7.9) for 3-9. PMID- 22839747 TI - The association between online gaming, social phobia, and depression: an internet survey. AB - BACKGROUND: Online gaming technology has developed rapidly within the past decade, and its related problems have received increasing attention. However, there are few studies on the psychiatric symptoms associated with excessive use of online games. The aim of this study is to investigate the characteristics of online gamers, and the association between online gaming hours, social phobia, and depression using an internet survey. METHODS: An online questionnaire was designed and posted on a popular online game websites, inviting the online gamers to participate the survey. The content of the questionnaire included demographic data, profiles of internet usage and online gaming, and self-rating scales of Depression and Somatic Symptoms Scale (DSSS), Social Phobia Inventory (SPIN), and Chen Internet Addiction Scale (CIAS). RESULTS: A total of 722 online gamers with a mean age of 21.8 +/- 4.9 years completed the online survey within one month. 601 (83.2%) participants were male, and 121 (16.8%) were female. The mean weekly online gaming time was 28.2 +/- 19.7 hours, which positively associated with history of online gaming (r = 0.245, p < 0.001), total DSSS (r = 0.210, p < 0.001), SPIN (r = 0.150, p < 0.001), and CIAS (r = 0.290, p < 0.001) scores. The female players had a shorter history of online gaming (6.0 +/- 3.1 vs. 7.2 +/- 3.6 years, p = 0.001) and shorter weekly online gaming hours (23.2 +/- 17.0 vs. 29.2 +/- 20.2 hours, p = 0.002), but had higher DSSS (13.0 +/- 9.3 vs. 10.9 +/- 9.7, p = 0.032) and SPIN (22.8 +/- 14.3 vs. 19.6 +/- 13.5, p = 0.019) scores than the male players. The linear regression model showed that higher DSSS scores were associated with female gender, higher SPIN scores, higher CIAS scores, and longer weekly online gaming hours, with controlling for age and years of education. CONCLUSION: The online gamers with longer weekly gaming hours tended to have a longer history of online gaming, and more severe depressive, social phobic, and internet addiction symptoms. Female online gamers had fewer weekly online gaming hours and a shorter previous online gaming history, but tended to have more severe somatic, pain, and social phobic symptoms. The predictors for depression were higher social phobic symptom, higher internet addiction symptoms, longer online gaming hours, and female gender. PMID- 22839748 TI - Transition-metal-free superbase-promoted stereoselective alpha-vinylation of ketones with arylacetylenes: a general strategy for synthesis of beta,gamma unsaturated ketones. AB - A wide variety of beta,gamma-unsaturated ketones of E configuration have been obtained in good to excellent yields via KO(t)Bu/DMSO promoted alpha-vinylation of aliphatic, cycloaliphatic, and alkyl aromatic (heteroaromatic) ketones with diverse arylacetylenes. PMID- 22839750 TI - Microstructural reorganization and cargo release in pyrene urethane methacrylate random copolymer hollow capsules. AB - We report the synthesis of polymer microcapsules by direct one-pot free radical random copolymerization approach. Urethane methacrylate comb monomers having pendant pyrene (Py) and 3-pentadecyl phenol (PDP) units were copolymerized in a random manner using benzoyl peroxide (BPO) as free radical initiator in dimethylformamide (DMF) as solvent. These copolymers and corresponding homopolymers spontaneously self-organized into microspheres upon drop casting from solvents like DMF and tetrahydrofuran (THF). Stable microspheres were obtained in water by dialyzing THF solution of the polymers against water in dialysis bags with molecular weight cutoff of ~2000. The hollow nature of the spheres was confirmed by rhodamine B (RhB) encapsulation followed by Forster resonance energy transfer (FRET) based fluorescence emission from RhB upon exciting pyrene. The microenvironment inside the capsule was probed by following the I(1)/I(3) ratio of pyrene emission as well as RhB release as a function of temperature. The RhB encapsulated in the pyrene homopolymer PIHP-100Py capsules experienced strong donor-acceptor interaction and did not undergo complete release even at high temperature (85 degrees C). The encapsulated RhB from the copolymers with low pyrene incorporation was released almost fully upon heating beyond 50 degrees C. Pyrene moieties in the PIHP-100Py were shielded from surrounding water and experienced a hydrophobic environment, whereas in the low pyrene incorporated copolymer the PDP units were better shielded from the hydrophilic environment. This work represents a simple approach to produce polymer hollow capsules, and the varying pyrene incorporation was used to trace the microenvironment inside the capsules. PMID- 22839749 TI - Acute HIV-1 infection in the Southeastern United States: a cohort study. AB - In 1998 a collaboration between Duke University and the University of North Carolina, Chapel Hill (UNC) was founded to enhance identification of persons with acute HIV-1 infection (AHI). The Duke-UNC AHI Research Consortium Cohort consists of patients >=18 years old with a positive nucleic acid amplification test (NAAT) and either a negative enzyme immunoassay (EIA) test or a positive EIA with a negative/indeterminate Western blot. Patients were referred to the cohort from acute care settings and state-funded HIV testing sites that use NAAT testing on pooled HIV-1 antibody-negative samples. Between 1998 and 2010, 155 patients with AHI were enrolled: 81 (52%) African-Americans, 63 (41%) white, non-Hispanics, 137 (88%) males, 108 (70%) men who have sex with men (MSM), and 18 (12%) females. The median age was 27 years (IQR 22-38). Most (n=138/155) reported symptoms with a median duration of 17.5 days. The median nadir CD4 count was 408 cells/mm(3) (IQR 289-563); the median observed peak HIV-1 level was 726,859 copies/ml (IQR 167,585 3,565,728). The emergency department was the most frequent site of initial presentation (n=55/152; 3 missing data). AHI diagnosis was made at time of first contact in 62/137 (45%; 18 missing data) patients. This prospectively enrolled cohort is the largest group of patients with AHI reported from the Southeastern United States. The demographics reflect the epidemic of this geographic area with a high proportion of African-Americans, including young black MSM. Highlighting the challenges of diagnosing AHI, less than half of the patients were diagnosed at the first healthcare visit. Women made up a small proportion despite increasing numbers in our clinics. PMID- 22839751 TI - P+ state of nitrogenase p-cluster exhibits electronic structure of a [Fe4S4]+ cluster. AB - Mo nitrogenase consists of two component proteins: the Fe protein, which contains a [Fe(4)S(4)] cluster, and the MoFe protein, which contains two different classes of metal cluster: P-cluster ([Fe(8)S(7)]) and FeMoco ([MoFe(7)S(9)C.homocitrate]). The P-cluster is believed to mediate the electron transfer between the Fe protein and the MoFe protein via interconversions between its various oxidation states, such as the all-ferrous state (P(N)) and the one- (P(+)) and two-electron (P(2+)) oxidized states. While the structural and electronic properties of P(N) and P(2+) states have been well characterized, little is known about the electronic structure of the P(+) state. Here, a mutant strain of Azotobacter vinelandii (DJ1193) was used to facilitate the characterization of the P(+) state of P-cluster. This strain expresses a MoFe protein variant (designated DeltanifB beta-188(Cys) MoFe protein) that accumulates the P(+) form of P-cluster in the resting state. Magnetic circular dichroism (MCD) spectrum of the P-cluster in the oxidized DeltanifB beta-188(Cys) MoFe protein closely resembles that of the P(2+) state in the oxidized wild-type MoFe protein, except for the absence of a major charge-transfer band centered at 823 nm. Moreover, magnetization curves of DeltanifB beta-188(Cys) and wild-type MoFe proteins suggest that the P(2+) species in both proteins have the same spin state. MCD spectrum of the P(+) state in the DeltanifB beta-188(Cys) MoFe protein, on the other hand, is associated with a classic [Fe(4)S(4)](+) cluster, suggesting that the P-cluster could be viewed as two coupled 4Fe clusters and that it could donate either one or two electrons to FeMoco by using one or both of its 4Fe halves. Such a mode of action of P-cluster could provide energetic and kinetic advantages to nitrogenase in the complex mechanism of N(2) reduction. PMID- 22839752 TI - Palladium-catalyzed oxidation of unsaturated hydrocarbons using molecular oxygen. AB - Oxidation reactions are central components of organic chemistry, and modern organic synthesis increasingly requires selective and mild oxidation methods. Although researchers have developed new organic oxidation methods in recent years, the chemistry community faces continuing challenges to use "green" reagents and maximize atom economy. Undoubtedly, with its low cost and lack of environmentally hazardous byproducts, molecular oxygen (O(2)) is an ideal oxidant. However, relatively limited methodologies are available that use O(2) efficiently in selective organic transformations. Recently, the use of metal catalysts coupled with the reduction of O(2) has become an attractive approach for aerobic oxidation. In particular, Pd complexes have shown great potential for the development of versatile aerobic reactions because of their ability to directly couple O(2) reduction. As a result, these complexes have attracted tremendous research attention and afford new opportunities for selective oxidation chemistry. In this Account we highlight some of our progress toward the synthetic goal to functionalize the unsaturated hydrocarbons largely through the appropriate choice of Pd catalysts and O(2). We have focused on developing simple and efficient methods to construct new carbon-carbon and carbon-heteroatom bonds with O(2) as the oxidant and/or reactant. We have demonstrated Pd-catalyzed oxidation of carbon-carbon double bonds, Pd-catalyzed oxidation of carbon-carbon triple bonds, and Pd-catalyzed oxidative cross-coupling reactions of alkenes and/or alkynes with high selectivity. O(2) plays a critical role in the success of these transformations. Most of the reactions can tolerate a range of functional groups, and some can occur under aqueous conditions. Depending on the specific process, we propose several mechanistic scenarios that describe the in situ generation of different intermediates and discuss the plausible reaction pathways. These methods provide new strategies for the green synthesis of diverse 1,2-diols, carbonyls, lactones, conjugated dienes, trienes, and aromatic rings. These products have potential applications in natural product synthesis, materials science, and bioorganic chemistry. Given our new mechanistic understanding, we are optimistic that additional Pd-catalyzed aerobic oxidative transformations will be developed that are both more economical and environmentally friendly. PMID- 22839753 TI - Amniote phylogeny and the position of turtles. AB - The position of turtles among amniotes remains in dispute, with morphological and molecular comparisons giving different results. Morphological analyses align turtles with either lizards and their relatives, or at the base of the reptile tree, whereas molecular analyses, including a recent study by Chiari et al. in BMC Biology, place turtles with birds and crocodilians. Molecular studies have not wavered as the numbers of genes and species have increased, but morphologists have been reluctant to embrace the molecular tree. PMID- 22839754 TI - Minimal invasive surgery for unicameral bone cyst using demineralized bone matrix: a case series. AB - BACKGROUND: Various treatments for unicameral bone cyst have been proposed. Recent concern focuses on the effectiveness of closed methods. This study evaluated the effectiveness of demineralized bone matrix as a graft material after intramedullary decompression for the treatment of unicameral bone cysts. METHODS: Between October 2008 and June 2010, twenty-five patients with a unicameral bone cyst were treated with intramedullary decompression followed by grafting of demineralized bone matrix. There were 21 males and 4 female patients with mean age of 11.1 years (range, 3-19 years). The proximal metaphysis of the humerus was affected in 12 patients, the proximal femur in five, the calcaneum in three, the distal femur in two, the tibia in two, and the radius in one. There were 17 active cysts and 8 latent cysts. Radiologic change was evaluated according to a modified Neer classification. Time to healing was defined as the period required achieving cortical thickening on the anteroposterior and lateral plain radiographs, as well as consolidation of the cyst. The patients were followed up for mean period of 23.9 months (range, 15-36 months). RESULTS: Nineteen of 25 cysts had completely consolidated after a single procedure. The mean time to healing was 6.6 months (range, 3-12 months). Four had incomplete healing radiographically but had no clinical symptom with enough cortical thickness to prevent fracture. None of these four cysts needed a second intervention until the last follow-up. Two of 25 patients required a second intervention because of cyst recurrence. All of the two had a radiographical healing of cyst after mean of 10 additional months of follow-up. CONCLUSIONS: A minimal invasive technique including the injection of DBM could serve as an excellent treatment method for unicameral bone cysts. PMID- 22839756 TI - Hybrid dynamic stabilization: a biomechanical assessment of adjacent and supraadjacent levels of the lumbar spine. AB - OBJECT: The object of this study was to evaluate the effect of hybrid dynamic stabilization on adjacent levels of the lumbar spine. METHODS: Seven human spine specimens from T-12 to the sacrum were used. The following conditions were implemented: 1) intact spine; 2) fusion of L4-5 with bilateral pedicle screws and titanium rods; and 3) supplementation of the L4-5 fusion with pedicle screw dynamic stabilization constructs at L3-4, with the purpose of protecting the L3-4 level from excessive range of motion (ROM) and to create a smoother motion transition to the rest of the lumbar spine. An industrial robot was used to apply continuous pure moment (+/- 2 Nm) in flexion-extension with and without a follower load, lateral bending, and axial rotation. Intersegmental rotations of the fused, dynamically stabilized, and adjacent levels were measured and compared. RESULTS: In flexion-extension only, the rigid instrumentation at L4-5 caused a 78% decrease in the segment's ROM when compared with the intact specimen. To compensate, it caused an increase in motion at adjacent levels L1-2 (45.6%) and L2-3 (23.2%) only. The placement of the dynamic construct at L3-4 decreased the operated level's ROM by 80.4% (similar stability as the fusion at L4-5), when compared with the intact specimen, and caused a significant increase in motion at all tested adjacent levels. In flexion-extension with a follower load, instrumentation at L4-5 affected only a subadjacent level, L5-sacrum (52.0%), while causing a reduction in motion at the operated level (L4-5, 76.4%). The dynamic construct caused a significant increase in motion at the adjacent levels T12-L1 (44.9%), L1-2 (57.3%), and L5-sacrum (83.9%), while motion at the operated level (L3-4) was reduced by 76.7%. In lateral bending, instrumentation at L4-5 increased motion at only T12-L1 (22.8%). The dynamic construct at L3-4 caused an increase in motion at T12-L1 (69.9%), L1-2 (59.4%), L2-3 (44.7%), and L5-sacrum (43.7%). In axial rotation, only the placement of the dynamic construct at L3-4 caused a significant increase in motion of the adjacent levels L2-3 (25.1%) and L5-sacrum (31.4%). CONCLUSIONS: The dynamic stabilization system displayed stability characteristics similar to a solid, all-metal construct. Its addition of the supraadjacent level (L3-4) to the fusion (L4-5) did protect the adjacent level from excessive motion. However, it essentially transformed a 1-level lumbar fusion into a 2-level lumbar fusion, with exponential transfer of motion to the fewer remaining discs. PMID- 22839755 TI - Constitutive phosphorylation of the mTORC2/Akt/4E-BP1 pathway in newly derived canine hemangiosarcoma cell lines. AB - BACKGROUND: Canine hemangiosarcoma (HSA) is a malignant tumor with poor long-term prognosis due to development of metastasis despite aggressive treatment. The phosphatidyl-inositol-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is involved in its endothelial pathologies; however, it remains unknown how this pathway plays a role in canine HSA. Here, we characterized new canine HSA cell lines derived from nude mice-xenografted canine HSAs and investigated the deregulation of the signaling pathways in these cell lines. RESULTS: Seven canine HSA cell lines were established from 3 xenograft canine HSAs and showed characteristics of endothelial cells (ECs), that is, uptake of acetylated low density lipoprotein and expression of canine-specific CD31 mRNA. They showed varied morphologies and mRNA expression levels for VEGF-A, bFGF, HGF, IGF-I, EGF, PDGF-B, and their receptors. Cell proliferation was stimulated by these growth factors and fetal bovine serum (FBS) in 1 cell line and by FBS alone in 3 cell lines. However, cell proliferation was not stimulated by growth factors and FBS in the remaining 3 cell lines. Phosphorylated p44/42 Erk1/2 was increased by FBS stimulation in 4 cell lines. In contrast, phosphorylation of Akt at Ser473, mTOR complex 1 (mTORC1) at Ser2448, and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) at Ser65 was high in serum-starved condition and not altered by FBS stimulation in 6 cell lines, despite increased phosphorylation of these residues in normal canine ECs. This suggested that the mTORC2/Akt/4E-BP1 pathway was constitutively activated in these 6 canine HSA cell lines. After cell inoculation into nude mice, canine HSA tumors were formed from 4 cell lines and showed Akt and 4E-BP1 phosphorylation identical to the parental cell lines. CONCLUSIONS: Our findings suggest that the present cell lines may be useful tools for investigating the role of the mTORC2/Akt/4E-BP1 pathway in canine HSA formation both in vivo and in vitro. PMID- 22839757 TI - Evaluating alternate models to estimate genetic parameters of calving traits in United Kingdom Holstein-Friesian dairy cattle. AB - BACKGROUND: The focus in dairy cattle breeding is gradually shifting from production to functional traits and genetic parameters of calving traits are estimated more frequently. However, across countries, various statistical models are used to estimate these parameters. This study evaluates different models for calving ease and stillbirth in United Kingdom Holstein-Friesian cattle. METHODS: Data from first and later parity records were used. Genetic parameters for calving ease, stillbirth and gestation length were estimated using the restricted maximum likelihood method, considering different models i.e. sire (-maternal grandsire), animal, univariate and bivariate models. Gestation length was fitted as a correlated indicator trait and, for all three traits, genetic correlations between first and later parities were estimated. Potential bias in estimates was avoided by acknowledging a possible environmental direct-maternal covariance. The total heritable variance was estimated for each trait to discuss its theoretical importance and practical value. Prediction error variances and accuracies were calculated to compare the models. RESULTS AND DISCUSSION: On average, direct and maternal heritabilities for calving traits were low, except for direct gestation length. Calving ease in first parity had a significant and negative direct maternal genetic correlation. Gestation length was maternally correlated to stillbirth in first parity and directly correlated to calving ease in later parities. Multi-trait models had a slightly greater predictive ability than univariate models, especially for the lowly heritable traits. The computation time needed for sire (-maternal grandsire) models was much smaller than for animal models with only small differences in accuracy. The sire (-maternal grandsire) model was robust when additional genetic components were estimated, while the equivalent animal model had difficulties reaching convergence. CONCLUSIONS: For the evaluation of calving traits, multi-trait models show a slight advantage over univariate models. Extended sire models (-maternal grandsire) are more practical and robust than animal models. Estimated genetic parameters for calving traits of UK Holstein cattle are consistent with literature. Calculating an aggregate estimated breeding value including direct and maternal values should encourage breeders to consider both direct and maternal effects in selection decisions. PMID- 22839758 TI - Solution structure of the second RRM domain of RBM5 and its unusual binding characters for different RNA targets. AB - The RNA binding motif protein 5 (RBM5), also known as LUCA15 or H37, containing two RNA recognition motifs, is a component of the spliceosome A complex. Previously, it has been reported that RBM5 bound to a U/C-rich sequence upstream of the In100 element at intron 9 of caspase2 pre-mRNA that enhanced the formation of proapoptotic caspase-2L isoform. In the present study, we solved the solution structure of the RBM5 RRM2 core domain and characterized its unusual binding capability for different RNA sequences. We found that the RBM5 RRM2 could preferentially bind to both CU rich and GA rich sequences with affinity in 10(-5) molar range. Further NMR experiments revealed that the dual RNA molecules could be accommodated on almost the same region of the protein's beta-sheet surface and that both the N- and C-terminal regions of the protein were involved in the recognition. Our studies provide evidence for the RBM5 sequence specific interaction with the cis-acting element in pre-mRNA regulating alternative splicing. PMID- 22839759 TI - Endoscopic submucosal dissection as a treatment for gastric adenomatous polyps: predictive factors for early gastric cancer. AB - OBJECTIVE: Endoscopic forceps biopsy (EFB) sampling of gastric adenoma may provide inadequate specimens for a correct diagnosis and lead to inappropriate follow-up strategies for adenomas or missed carcinoma foci. The aim of this study was to determine the diagnostic concordance between an EFB and resected gastric adenomatous polyps by endoscopic submucosal dissection (ESD) and to know the efficacy of ESD for the treatment of gastric adenomatous polyps. MATERIAL AND METHODS: Between November 2008 and May 2011, 413 ESDs were carried out at Pusan National University Yangsan Hospital. After exclusion, 282 cases were enrolled. The clinicopathological features, complete resection rate, procedure time, complication rate and associated factors for early gastric cancer (EGC) prediction were analyzed. RESULTS: The mean age was 62.13 +/- 8.91 years. Submucosal dissection results showed that the discrepancy rate between endoscopic biopsy and pathology of resected specimens was 32.9% (93/282). Additionally, 71 cases (25.2%) were adenocarcinomas. Among low-grade dysplasia (LGD) from EFB, 23 cases (11.8%) were adenocarcinomas after ESD. Among high-grade dysplasia (HGD) from EFB, 48 cases (55.2%) were adenocarcinomas after ESD. EFB procedure times were longer in the HGD group than in the LGD group (24.90 vs. 29.88 min, p = 0.017). In multivariate analysis, HGD from EFB, surface redness and lesion diameter were the significant predictive factors for EGC. CONCLUSIONS: Gastric adenomatous polyps should be removed by endoscopic resection regardless of histopathological type. ESD is a useful method for complete resection of gastric adenomas, regardless of size and location. PMID- 22839760 TI - Integrative analysis of single nucleotide polymorphisms and gene expression efficiently distinguishes samples from closely related ethnic populations. AB - BACKGROUND: Ancestry informative markers (AIMs) are a type of genetic marker that is informative for tracing the ancestral ethnicity of individuals. Application of AIMs has gained substantial attention in population genetics, forensic sciences, and medical genetics. Single nucleotide polymorphisms (SNPs), the materials of AIMs, are useful for classifying individuals from distinct continental origins but cannot discriminate individuals with subtle genetic differences from closely related ancestral lineages. Proof-of-principle studies have shown that gene expression (GE) also is a heritable human variation that exhibits differential intensity distributions among ethnic groups. GE supplies ethnic information supplemental to SNPs; this motivated us to integrate SNP and GE markers to construct AIM panels with a reduced number of required markers and provide high accuracy in ancestry inference. Few studies in the literature have considered GE in this aspect, and none have integrated SNP and GE markers to aid classification of samples from closely related ethnic populations. RESULTS: We integrated a forward variable selection procedure into flexible discriminant analysis to identify key SNP and/or GE markers with the highest cross-validation prediction accuracy. By analyzing genome-wide SNP and/or GE markers in 210 independent samples from four ethnic groups in the HapMap II Project, we found that average testing accuracies for a majority of classification analyses were quite high, except for SNP-only analyses that were performed to discern study samples containing individuals from two close Asian populations. The average testing accuracies ranged from 0.53 to 0.79 for SNP-only analyses and increased to around 0.90 when GE markers were integrated together with SNP markers for the classification of samples from closely related Asian populations. Compared to GE only analyses, integrative analyses of SNP and GE markers showed comparable testing accuracies and a reduced number of selected markers in AIM panels. CONCLUSIONS: Integrative analysis of SNP and GE markers provides high-accuracy and/or cost-effective classification results for assigning samples from closely related or distantly related ancestral lineages to their original ancestral populations. User-friendly BIASLESS (Biomarkers Identification and Samples Subdivision) software was developed as an efficient tool for selecting key SNP and/or GE markers and then building models for sample subdivision. BIASLESS was programmed in R and R-GUI and is available online at http://www.stat.sinica.edu.tw/hsinchou/genetics/prediction/BIASLESS.htm. PMID- 22839763 TI - On how to increase safety innovations. AB - In this action research study, we show by several cases that a synthetic innovation style in combination with an entrepreneurial culture might increase innovations for safety. Rational decisions and early product specifications were replaced by a natural selection of ideas in an acting reality to have the most fitted ideas among the actors. The forthcoming ideas actually ruled the development of the process and the business set-up like in an entrepreneurial culture. With financial support from the Swedish research funds, Vinnova and SBUF, a laboratory for both research and innovation was implemented at the Karolinska Institutet. The laboratory emanated from an initiative of Professor Leif Svanstrom in developing a multidisciplinary collaboration on design and consumer safety. In this review, we present our promising findings. PMID- 22839762 TI - Changing patterns in the association between regional socio-economic context and dental caries experience according to gender and age: a multilevel study in Korean adults. AB - BACKGROUND: Little is known about the effects of socio-environmental factors on dental caries in different demographic situations in Asian populations. We investigated whether the nature of the association between regional socio economic context and dental caries experience differed according to gender and age groups in Korean adults. METHODS: We obtained a linked data set containing individual information from the 2000 Korean National Oral Health Survey and regional information from the "Major statistical indices of Si-Gun-Gu" (city county-ward), published by the Korean Statistical Office. We stratified participants into women and men and into four 10-year-interval age groups (19-34, 35-44, 45-54, and 55-64 years) and analysed the linked data using a multilevel analysis. In total, 5,259 individuals were included in the final study population. RESULTS: Regional socio-economic context was significantly associated with dental caries experience in men, but not in women. The patterns of the association between regional contextual variables and dental caries experience differed among age groups. People 35-44 years of age living in areas less dependent on the manufacturing industry and those 45-54 years of age living in areas where local government was relatively poor were more prone to have caries experience. CONCLUSIONS: The results of this study indicated that socio-economic factors affecting residents' dental health status may operate through different mechanisms or degrees according to geographic location, suggesting that some gender- and age-defined subgroups may be likely to benefit from different types of intervention, including the development of specific health policies. PMID- 22839761 TI - Does Beta-lactam Pharmacokinetic Variability in Critically Ill Patients Justify Therapeutic Drug Monitoring? A Systematic Review. AB - The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When "standard" beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and individualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required. PMID- 22839764 TI - Health and aging in elderly farmers: the AMI cohort. AB - BACKGROUND: The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. METHODS/DESIGN: The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson's disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry...). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). DISCUSSION: AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach. PMID- 22839766 TI - Homoleptic pnictogen-chalcogen coordination complexes. AB - The synthesis and structural characterization of dicationic selenium and tellurium analogues of the carbodiphosphorane and triphosphenium families of compounds are reported. These complexes, [Ch(dppe)][OTf](2) [Ch = Se, Te; dppe = 1,2-bis(diphenylphosphino)ethane; OTf = trifluoromethanesulfonate], are formed using [Ch](2+) reagents via a ligand-exchange protocol and represent extremely rare examples of homoleptic pnictogen -> chalcogen coordination complexes. The corresponding arsenic compounds were also prepared, [Ch(dpAse)][OTf](2) [Ch = Se, Te; dpAse = 1,2-bis(diphenylarsino)ethane], exhibiting the first instance of an arsenic -> chalcogen dative bond. The electronic structures of these unique compounds were determined and compared to previously reported chalcogen dications. PMID- 22839765 TI - Changes in the gene expression programs of renal mesangial cells during diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy is the leading cause of end stage renal disease. All three cell types of the glomerulus, podocytes, endothelial cells and mesangial cells, play important roles in diabetic nephropathy. In this report we used Meis1-GFP transgenic mice to purify mesangial cells from normal mice and from db/db mice, which suffer diabetic nephropathy. The purpose of the study is to better define the unique character of normal mesangial cells, and to characterize their pathogenic and protective responses during diabetic nephropathy. METHODS: Comprehensive gene expression states of the normal and diseased mesangial cells were defined with microarrays. By comparing the gene expression profiles of mesangial cells with those of multiple other renal cell types, including podocytes, endothelial cells and renal vesicles, it was possible to better define their exceptional nature, which includes smooth muscle, phagocytic and neuronal traits. RESULTS: The complete set of mesangial cell expressed transcription factors, growth factors and receptors were identified. In addition, the analysis of the mesangial cells from diabetic nephropathy mice characterized their changes in gene expression. Molecular functions and biological processes specific to diseased mesangial cells were characterized, identifying genes involved in extracellular matrix, cell division, vasculogenesis, and growth factor modulation. Selected gene changes considered of particular importance to the disease process were validated and localized within the glomuerulus by immunostaining. For example, thrombospondin, a key mediator of TGFbeta signaling, was upregulated in the diabetic nephropathy mesangial cells, likely contributing to fibrosis. On the other hand the decorin gene was also upregulated, and expression of this gene has been strongly implicated in the reduction of TGFbeta induced fibrosis. CONCLUSIONS: The results provide an important complement to previous studies examining mesangial cells grown in culture. The remarkable qualities of the mesangial cell are more fully defined in both the normal and diabetic nephropathy diseased state. New gene expression changes and biological pathways are discovered, yielding a deeper understanding of the diabetic nephropathy pathogenic process, and identifying candidate targets for the development of novel therapies. PMID- 22839767 TI - An imprinted IMAGe: insights into growth regulation through genomic analysis of a rare disease. AB - Missense mutations in the imprinted gene that encodes cyclin-dependent kinase inhibitor 1C (CDKN1C, also called p57Kip2) result in a rare disorder associated with prenatal growth retardation (IMAGe syndrome). Loss-of-function mutations in CDKN1C have been previously described in the congenital overgrowth syndrome Beckwith-Wiedemann syndrome and some cancers. In contrast, a recent study by Arboleda et al. proposes that the CDKN1C mutations associated with IMAGe syndrome have a gain-of-function effect. These findings highlight how rare genetic disorders can provide important insights into the regulation of critical processes such as regulation of cell growth. PMID- 22839768 TI - Synthesis of [2]catenanes by template-directed clipping approach. AB - A series of [2]catenanes were efficiently synthesized in high yields by a template-directed clipping approach with the formation of one macrocycle around another macrocycle containing a dialkylammonium recognition site. Their structures were identified by the NMR spectra and ESI mass spectrometry, and their geometries were investigated by the theoretical calculation. PMID- 22839769 TI - Periodontopathogens around the surface of mini-implants removed from orthodontic patients. AB - OBJECTIVE: To verify if mini-implant mobility is affected by the presence of periodontopathogens, frequently associated with peri-implantitis. MATERIALS AND METHODS: The surfaces of 31 mini-implants used for skeletal anchorage in orthodontic patients were evaluated. Polymerase chain reaction was used for identification of the presence of DNA from three different periodontopathogens ( P. intermedia [ Pi ], A. actinomycetemcomitans [ Aa ], and P. gingivalis [ Pg ]) in 16 mini-implants without mobility (control group) and 15 mini-implants with mobility (experimental group). RESULTS: The results showed that Pi was present in 100% of the samples, from both groups: Aa was found in 31.3% of the control group and in 13.3% of the experimental group. Pg was detected in 37.4% of the control group and in 33.3% of the experimental group. The Fisher exact test and the odds ratio (OR) values for Aa and Pg (OR = 0.34; 95% confidence interval [CI]: 0.05 2.10 and OR = 0.61; 95% CI: 0.13-2.79, respectively) showed no significant association (P > .05) between the periodontopathogens studied and the mobility of the mini-implants. CONCLUSIONS: It can be concluded that the presence of Aa , Pi , and Pg around mini-implants is not associated with mobility. PMID- 22839772 TI - A tribute to the past and a look to the future. PMID- 22839773 TI - Re: Gummy smile and facial profile correction using miniscrew anchorage. Angle Orthod. 2012;82(1):170-177. By Masato Kaku, Shunichi Kojima, Hiromi Sumi, et al. PMID- 22839776 TI - Cationic polythiophene-surfactant self-assembly complexes: phase transitions, optical response, and sensing. AB - The absorption and photoluminescence spectra of the cationic conjugated polyelectrolyte poly[3-(6-trimethylammoniumhexyl)thiophene] (P3TMAHT) were observed to be dramatically altered in the presence of anionic surfactants due to self-assembly through ionic complex formation. Small-angle neutron scattering (SANS), UV/vis, and photoluminescence spectroscopy were used to probe the relationship between the supramolecular complex organization and the photophysical response of P3TMAHT in the presence of industrially important anionic surfactants. Subtle differences in the surfactant mole fraction and chemical structure (e.g., chain length, headgroup charge density, perfluorination) result in marked variations in the range and type of complexes formed, which can be directly correlated to a unique colorimetric and fluorimetric fingerprint. Our results show that P3TMAHT has potential as an optical sensor for anionic surfactants capable of selectively identifying distinct structural subgroups through dual mode detection. PMID- 22839777 TI - Patterns and architecture of genomic islands in marine bacteria. AB - BACKGROUND: Genomic Islands (GIs) have key roles since they modulate the structure and size of bacterial genomes displaying a diverse set of laterally transferred genes. Despite their importance, GIs in marine bacterial genomes have not been explored systematically to uncover possible trends and to analyze their putative ecological significance. RESULTS: We carried out a comprehensive analysis of GIs in 70 selected marine bacterial genomes detected with IslandViewer to explore the distribution, patterns and functional gene content in these genomic regions. We detected 438 GIs containing a total of 8152 genes. GI number per genome was strongly and positively correlated with the total GI size. In 50% of the genomes analyzed the GIs accounted for approximately 3% of the genome length, with a maximum of 12%. Interestingly, we found transposases particularly enriched within Alphaproteobacteria GIs, and site-specific recombinases in Gammaproteobacteria GIs. We described specific Homologous Recombination GIs (HR-GIs) in several genera of marine Bacteroidetes and in Shewanella strains among others. In these HR-GIs, we recurrently found conserved genes such as the beta-subunit of DNA-directed RNA polymerase, regulatory sigma factors, the elongation factor Tu and ribosomal protein genes typically associated with the core genome. CONCLUSIONS: Our results indicate that horizontal gene transfer mediated by phages, plasmids and other mobile genetic elements, and HR by site-specific recombinases play important roles in the mobility of clusters of genes between taxa and within closely related genomes, modulating the flexible pool of the genome. Our findings suggest that GIs may increase bacterial fitness under environmental changing conditions by acquiring novel foreign genes and/or modifying gene transcription and/or transduction. PMID- 22839778 TI - Anticancer peptide SVS-1: efficacy precedes membrane neutralization. AB - Anticancer peptides are polycationic amphiphiles capable of preferentially killing a wide spectrum of cancer cells relative to noncancerous cells. Their primary mode of action is an interaction with the cell membrane and subsequent activation of lytic effects; however, the exact mechanism responsible for this mode of action remains controversial. Using zeta potential analyses we demonstrate the interaction of a small anticancer peptide with membrane model systems and cancer cells. Electrostatic interactions have a pivotal role in the cell killing process, and in contrast to the antimicrobial peptides action cell death occurs without achieving full neutralization of the membrane charge. PMID- 22839780 TI - Selective localization of preformed nanoparticles in morphologically controllable block copolymer aggregates in solution. AB - The development of nanodevices currently requires the formation of morphologically controlled or highly ordered arrays of metal, semiconducting, or magnetic nanoparticles. In this context, polymer self-assembly provides a powerful bottom-up approach for constructing these materials. The self-assembly of block copolymers (BCPs) in solution is a facile and popular method for the preparation of aggregates of controllable morphologies, including spherical micelles, cylindrical micelles, vesicles (or polymersomes), thin films, and other complex structures that range from zero to three dimensions. Researchers can generally control the morphology of the aggregates by varying copolymer composition or environmental parameters, including the copolymer concentration, the common solvent, the content of the precipitant, or the presence of additives such as ions, among others. For example, as the content of the hydrophilic block in amphiphilic copolymers decreases, the aggregates formed from the copolymers can change from spherical micelles to cylindrical micelles and to vesicles. The aggregates of various morphologies provide excellent templates for the organization of the nanoparticles. The presence of various domains, such as cores, interfaces, and coronas, in BCP aggregates allows for selective localization of nanoparticles in different regions, which may critically affect the resulting properties and applications of the nanoparticles. For example, the incorporation of quantum dots (QDs) into micelle cores solves many problems encountered in the utilization of QDs in biological environments, including enhancement of water solubility, aggregation prevention, increases in circulation or retention time, and toxicity clearance. Simultaneously it preserves the unique optical performance of QDs compared with those of organic fluorophores, such as size-tunable light emission, improved signal brightness, resistance against photobleaching, and simultaneous excitation of multiple fluorescence colors. Therefore, many studies have focused on the selective localization of nanoparticles in BCP aggregates. This Account describes the selective localization of preformed spherical nanoparticles in different domains of BCP aggregates of controllable morphologies in solution, including spherical micelles, cylindrical micelles, and vesicles. These structures offer many potential applications in biotechnology, biomedicine, catalysis, etc. We also introduce other types of control, including interparticle spacing, particle number density, or aggregate size control. We highlight examples in which the surface coating, volume fraction, or size of the particles was tailored to precisely control incorporation. These examples build on the thermodynamic considerations of particle-polymer interactions, such as hydrophobic interactions, hydrogen bonding, electrostatic interactions, and ligand replacement, among others. PMID- 22839779 TI - VtaA8 and VtaA9 from Haemophilus parasuis delay phagocytosis by alveolar macrophages. AB - Haemophilus parasuis, a member of the family Pasteurellaceae, is a common inhabitant of the upper respiratory tract of healthy pigs and the etiological agent of Glasser's disease. As other virulent Pasteurellaceae, H. parasuis can prevent phagocytosis, but the bacterial factors involved in this virulence mechanism are not known. In order to identify genes involved in phagocytosis resistance, we constructed a genomic library of the highly virulent reference strain Nagasaki and clones were selected by increased survival after incubation with porcine alveolar macrophages (PAM). Two clones containing two virulent associated trimeric autotransporter (VtaA) genes, vtaA8 and vtaA9, respectively, were selected by this method. A reduction in the interaction of the two clones with the macrophages was detected by flow cytometry. Monoclonal antibodies were produced and used to demonstrate the presence of these proteins on the bacterial surface of the corresponding clone, and on the H. parasuis phagocytosis-resistant strain PC4-6P. The effect of VtaA8 and VtaA9 in the trafficking of the bacteria through the endocytic pathway was examined by fluorescence microscopy and a delay was detected in the localization of the vtaA8 and vtaA9 clones in acidic compartments. These results are compatible with a partial inhibition of the routing of the bacteria via the degradative phagosome. Finally, antibodies against a common epitope in VtaA8 and VtaA9 were opsonic and promoted phagocytosis of the phagocytosis-resistant strain PC4-6P by PAM. Taken together, these results indicate that VtaA8 and VtaA9 are surface proteins that play a role in phagocytosis resistance of H. parasuis. PMID- 22839962 TI - Commentary on "ICF from an occupational therapy perspective in adult care: an integrative literature review". AB - This letter to the editor is in response to the article by Pettersson, Pettersson and Frisk entitled, "ICF from an occupational therapy perspective in adult care: an integrative literature review". Given the breadth of this topic, the authors have done an admirable job in their survey of the topic. One area we felt deserved additional attention was the inadequate way the ICF classification system codes mobility assistive technology use. We also offer a point of clarification about the Wheelchair Outcome Measure, which was identified incorrectly as the only wheelchair specific measure that could measure activity and participation. PMID- 22839781 TI - Phylogenomic analyses support the position of turtles as the sister group of birds and crocodiles (Archosauria). AB - BACKGROUND: The morphological peculiarities of turtles have, for a long time, impeded their accurate placement in the phylogeny of amniotes. Molecular data used to address this major evolutionary question have so far been limited to a handful of markers and/or taxa. These studies have supported conflicting topologies, positioning turtles as either the sister group to all other reptiles, to lepidosaurs (tuatara, lizards and snakes), to archosaurs (birds and crocodiles), or to crocodilians. Genome-scale data have been shown to be useful in resolving other debated phylogenies, but no such adequate dataset is yet available for amniotes. RESULTS: In this study, we used next-generation sequencing to obtain seven new transcriptomes from the blood, liver, or jaws of four turtles, a caiman, a lizard, and a lungfish. We used a phylogenomic dataset based on 248 nuclear genes (187,026 nucleotide sites) for 16 vertebrate taxa to resolve the origins of turtles. Maximum likelihood and Bayesian concatenation analyses and species tree approaches performed under the most realistic models of the nucleotide and amino acid substitution processes unambiguously support turtles as a sister group to birds and crocodiles. The use of more simplistic models of nucleotide substitution for both concatenation and species tree reconstruction methods leads to the artefactual grouping of turtles and crocodiles, most likely because of substitution saturation at third codon positions. Relaxed molecular clock methods estimate the divergence between turtles and archosaurs around 255 million years ago. The most recent common ancestor of living turtles, corresponding to the split between Pleurodira and Cryptodira, is estimated to have occurred around 157 million years ago, in the Upper Jurassic period. This is a more recent estimate than previously reported, and questions the interpretation of controversial Lower Jurassic fossils as being part of the extant turtles radiation. CONCLUSIONS: These results provide a phylogenetic framework and timescale with which to interpret the evolution of the peculiar morphological, developmental, and molecular features of turtles within the amniotes. PMID- 22839963 TI - Eczema in early childhood is strongly associated with the development of asthma and rhinitis in a prospective cohort. AB - BACKGROUND: This study aimed to estimate the association between eczema in early childhood and the onset of asthma and rhinitis later in life in children. METHODS: A total of 3,124 children aged 1-2 years were included in the Dampness in Building and Health (DBH) study in the year 2000, and followed up 5 years later by a parental questionnaire based on an International Study of Asthma and Allergies in Childhood protocol. The association between eczema in early childhood and the incidence of asthma and rhinitis later in life was estimated by univariable and multivariable logistic regression modelling. RESULTS: The prevalence of eczema in children aged 1-2 years was 17.6% at baseline. Children with eczema had a 3-fold increased odds of developing asthma (adjusted odds ratio [aOR], 3.07; 95% confidence interval (CI) 1.79-5.27), and a nearly 3-fold increased odds of developing rhinitis (aOR, 2.63; 1.85-3.73) at follow-up compared with children without eczema, adjusted for age, sex, parental allergic disease, parental smoking, length of breastfeeding, site of living, polyvinylchloride flooring material, and concomitant allergic disease. When eczema was divided into subgroups, moderate to severe eczema (aOR, 3.56; 1.62 7.83 and aOR, 3.87; 2.37-6.33, respectively), early onset of eczema (aOR, 3.44; 1.94-6.09 and aOR, 4.05; 2.82-5.81; respectively), and persistence of eczema (aOR, 5.16; 2.62-10.18 and aOR, 4.00; 2.53-6.22, respectively) further increased the odds of developing asthma and rhinitis. Further independent risk factors increasing the odds of developing asthma were a parental history of allergic disease (aOR, 1.83; 1.29-2.60) and a period of breast feeding shorter than 6 months (aOR, 1.57; 1.03-2.39). The incidence of rhinitis was increased for parental history of allergic disease (aOR, 2.00; 1.59-2.51) and polyvinylchloride flooring (aOR, 1.60; 1.02-2.51). CONCLUSION: Eczema in infancy is associated with development of asthma and rhinitis during the following 5-year period, and eczema is one of the strongest risk factors. Early identification is valuable for prediction of the atopic march. PMID- 22839964 TI - Stem cells from human exfoliated deciduous tooth-derived conditioned medium enhance recovery of focal cerebral ischemia in rats. AB - Regenerative therapy using stem cells is a promising approach for the treatment of stroke. Recently, we reported that dental pulp stem cells (DPSC) ameliorated ischemic tissue injury in the rat brain and accelerated functional recovery after middle cerebral artery occlusion (MCAO). In this study, we investigated the effects of stem cells from human exfoliated deciduous tooth (SHED)-derived conditioned medium (SHED-CM) on permanent MCAO (pMCAO). Adult male Sprague-Dawley rats were subjected to pMCAO. SHED-CM were then administered intranasally, and the motor function and infarct volume were evaluated. Neurogenesis and vasculogenesis were determined using immunochemical markers. The SHED-CM group had more positive signals than the Dulbecco's modified Eagle's medium group, with doublecortin (DCX), neurofilament H, neuronal nuclei, and rat endothelial cell antigen observed in the peri-infarct area. Migration of neuronal progenitor cells (NPC) with DCX from the subventricular zone to the peri-infarct area was observed on days 6 and 16, with migration on day 6 being the most prominent. In conclusion, SHED-CM promoted the migration and differentiation of endogenous NPC, induced vasculogenesis, and ameliorated ischemic brain injury after pMCAO as well as transplantation of DPSC. PMID- 22839965 TI - 99Tc and Re incorporated into metal oxide polyoxometalates: oxidation state stability elucidated by electrochemistry and theory. AB - The radioactive element technetium-99 ((99)Tc, half-life = 2.1 * 10(5) years, beta(-) of 253 keV), is a major byproduct of (235)U fission in the nuclear fuel cycle. (99)Tc is also found in radioactive waste tanks and in the environment at National Lab sites and fuel reprocessing centers. Separation and storage of the long-lived (99)Tc in an appropriate and stable waste-form is an important issue that needs to be addressed. Considering metal oxide solid-state materials as potential storage matrixes for Tc, we are examining the redox speciation of Tc on the molecular level using polyoxometalates (POMs) as models. In this study we investigate the electrochemistry of Tc complexes of the monovacant Wells-Dawson isomers, alpha(1)-P(2)W(17)O(61)(10-) (alpha1) and alpha(2)-P(2)W(17)O(61)(10-) (alpha2) to identify features of metal oxide materials that can stabilize the immobile Tc(IV) oxidation state accessed from the synthesized Tc(V)O species and to interrogate other possible oxidation states available to Tc within these materials. The experimental results are consistent with density functional theory (DFT) calculations. Electrochemistry of K(7-n)H(n)[Tc(V)O(alpha(1) P(2)W(17)O(61))] (Tc(V)O-alpha1), K(7-n)H(n)[Tc(V)O(alpha(2)-P(2)W(17)O(61))] (Tc(V)O-alpha2) and their rhenium analogues as a function of pH show that the Tc containing derivatives are always more readily reduced than their Re analogues. Both Tc and Re are reduced more readily in the lacunary alpha1 site as compared to the alpha2 site. The DFT calculations elucidate that the highest oxidation state attainable for Re is VII while, under the same electrochemistry conditions, the highest oxidation state for Tc is VI. The M(V)-> M(IV) reduction processes for Tc(V)O-alpha1 are not pH dependent or only slightly pH dependent suggesting that protonation does not accompany reduction of this species unlike the M(V)O alpha2 (M = (99)Tc, Re) and Re(V)O-alpha1 where M(V/IV) reduction process must occur hand in hand with protonation of the terminal M?O to make the pi*(M?O) orbitals accessible to the addition of electrons. This result is consistent with previous extended X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) data that reveal that the Tc(V) is "pulled" into the alpha1 framework and that may facilitate the reduction of Tc(V)O-alpha1 and stabilize lower Tc oxidation states. This study highlights the inequivalency of the two sites, and their impact on the chemical properties of the Tc substituted in these positions. PMID- 22839966 TI - Profile of native cellulosomal proteins of Clostridium cellulovorans adapted to various carbon sources. AB - We performed a focused proteome analysis of cellulosomal proteins predicted by a genome analysis of Clostridium cellulovorans [Tamaru, Y., et al.. 2010. J. Bacteriol. 192:901-902]. Our system employed a long monolithic column (300 cm), which provides better performance and higher resolution than conventional systems. Twenty-three cellulosomal proteins were, without purification, identified by direct analysis of the culture medium. Proteome analysis of the C. cellulovorans cellulosome after culture in various carbon sources demonstrated the production of carbon source-adapted cellulosome components. PMID- 22839967 TI - Implementation Science six years on--our evolving scope and common reasons for rejection without review. AB - Implementation Science has been published for six years and over that time has gone from receiving 100 articles in 2006 to receiving 354 in 2011; our impact factor has risen from 2.49 in June 2010 to 3.10 in June 2012. Whilst our article publication rate has also risen, it has risen much less slowly than our submission rate--we published 29 papers in 2006 and 134 papers in 2011 and we now publish only around 40 % of submissions. About one-half of submitted manuscripts are rejected without being sent out for peer review; it has become clear that there are a number of common issues that result in manuscripts being rejected at this stage. We hope that by publishing this editorial on our common reasons for rejection without peer review we can help authors to better judge the relevance of their papers to Implementation Science. PMID- 22839968 TI - Nanoscale topography mediates the adhesion of F-actin. AB - Using a controllable nanoengineered surface that alters the dynamics of filamentous actin (F-actin) adhesion, we studied the tunability of biomolecular surface attachment. By grafting aminated nanoparticles, NPs, with diameters ranging from 12 to 85 nm to a random copolymer film, precise control over surface roughness parameters is realized. The ability to selectively generate monodisperse or polydisperse features of varying size and areal density leads to immobilized, side-on wobbly, or end-on F-actin binding as characterized by total internal reflection fluorescence (TIRF) microscopy. The interaction between the surface and actin is explained by a worm-like chain model that balances the bending energy penalty required for actin to conform to topographical features with the electrostatic attraction engineered into the surface. A Myosin V motility assay demonstrates that electrostatically immobilized actin retains its ability to direct myosin motion, indicating that nanoengineered surfaces are attractive candidates for biomolecular device fabrication. PMID- 22839970 TI - Effectiveness of antibiotic prophylaxis in cholecystectomy: a prospective population-based study of 1171 cholecystectomies. AB - BACKGROUND: The aim of this study was to assess the benefit from antibiotic prophylaxis (AP) during cholecystectomy in a population-based cohort study. METHODS: All cholecystectomies performed in Uppsala County, 2003-2005, were registered prospectively according to a standardized protocol. High-risk procedures (HP) were defined as operations for acute cholecystitis and procedures including exploration of the common bile duct. Infections requiring surgical or percutaneous drainage and non-surgical infections that prolonged hospital stay were defined as major infectious complications (IC). RESULTS: Altogether 1171 patients underwent cholecystectomy. AP was given to 130 of 867 (15%) of the patients undergoing low-risk procedures (LP) and 205 of 304 (67%) of those undergoing H-R P. Major IC were seen in 6 of 205 (3%) of the patients undergoing H-R P with AP and 1 of 99 of the patients undergoing H-R P without AP. No major IC was seen after L-R P. Minor IC were seen after 5 of 205 (2%) HP with AP, 1 of 99 (1%) HP without AP, 0 of 130 (0%) LP with AP, and 2 of 737 (0.3%) LP without AP. In univariate logistic analysis, the overall risk for IC was found to be higher with AP (p < 0.05), but the increase did not remain significant if adjusting for age, gender, ASA class, H-R P/L-R P and surgical approach or limiting the analysis to major IC. CONCLUSION: There is no benefit from AP in uncomplicated procedures. The effectiveness of antibiotic prophylaxis in complicated cholecystectomy must be evaluated in randomized controlled trials. PMID- 22839971 TI - Dynamics of water/methanol mixtures at functionalized chromatographic interfaces. AB - Fully atomistic simulations of water/methanol mixtures of varying compositions (80/20 and 50/50) at chromatographic interfaces with different functionalizations are presented. The dynamical properties in terms of equilibration times and solvent exchange dynamics are characterized and found to depend on the different systems on the nanosecond time scale. The solvent density profile and the structuring of the stationary phase differ for derivatizations including (-CN, NO(2), -NH(2), -C(6)H(5)) of the C(18) chain. The time scale and intensity of the water exchange dynamics differs for the different realizations of the chromatographic systems and ranges from 200 to 500 ps. Water exchange rates depend on solvent composition as well as on the functionalization of alkyl chains. Simulations with acridine as a probe molecule provide atomistic insight into the slot model. PMID- 22839969 TI - Nucleotide release sequences in the protein kinase SRPK1 accelerate substrate phosphorylation. AB - Protein kinases are essential signaling enzymes that transfer phosphates from bound ATP to select amino acids in protein targets. For most kinases, the phosphoryl transfer step is highly efficient, while the rate-limiting step for substrate processing involves slow release of the product ADP. It is generally thought that structural factors intrinsic to the kinase domain and the nucleotide binding pocket control this step and consequently the efficiency of protein phosphorylation for these cases. However, the kinase domains of protein kinases are commonly flanked by sequences that regulate catalytic function. To address whether such sequences could alter nucleotide exchange and, thus, regulate protein phosphorylation, the presence of activating residues external to the kinase domain was probed in the serine protein kinase SRPK1. Deletion analyses indicate that a small segment of a large spacer insert domain and a portion of an N-terminal extension function cooperatively to increase nucleotide exchange. The data point to a new mode of protein kinase regulation in which select sequences outside the kinase domain constitute a nucleotide release factor that likely interacts with the small lobe of the kinase domain and enhances protein substrate phosphorylation through increases in ADP dissociation rate. PMID- 22839972 TI - Asymmetric synthesis of enaminophosphines via palladacycle-catalyzed addition of Ph2PH to alpha,beta-unsaturated imines. AB - A highly reactive, chemo- and enantioselective addition of diphenylphosphine to alpha,beta-unsaturated imines catalyzed by a palladacycle has been developed, thus providing the access to a series of chiral tertiary enaminophosphines in high yields. A putative catalytic cycle has also been proposed. PMID- 22839976 TI - A 'horrible cycle' with PM stickers. PMID- 22839979 TI - Ten questions with ... Gene Moy. PMID- 22839974 TI - UCHL1 S18Y variant is a risk factor for Parkinson's disease in Japan. AB - BACKGROUND: A recent meta-analysis on the UCHL1 S18Y variant and Parkinson's disease (PD) showed a significant inverse association between the Y allele and PD; the individual studies included in that meta-analysis, however, have produced conflicting results. We examined the relationship between UCHL1 S18Y single nucleotide polymorphism (SNP) and sporadic PD in Japan. METHODS: Included were 229 cases within 6 years of onset of PD, defined according to the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 357 inpatients and outpatients without neurodegenerative disease. Adjustment was made for sex, age, region of residence, smoking, and caffeine intake. RESULTS: Compared with subjects with the CC or CA genotype of UCHL1 S18Y SNP, those with the AA genotype had a significantly increased risk of sporadic PD: the adjusted OR was 1.57 (95 % CI: 1.06 - 2.31). Compared with subjects with the CC or CA genotype of UCHL1 S18Y and the CC or CT genotype of SNCA SNP rs356220, those with the AA genotype of UCHL1 S18Y and the TT genotype of SNP rs356220 had a significantly increased risk of sporadic PD; the interaction, however, was not significant. Our previous investigation found significant inverse relationships between smoking and caffeine intake and PD in this population. There were no significant interactions between UCHL1 S18Y and smoking or caffeine intake affecting sporadic PD. CONCLUSIONS: This study reveals that the UCHL1 S18Y variant is a risk factor for sporadic PD. We could not find evidence for interactions affecting sporadic PD between UCHL1 S18Y and SNCA SNP rs356220, smoking, or caffeine intake. PMID- 22839973 TI - Getting personalized cancer genome analysis into the clinic: the challenges in bioinformatics. AB - Progress in genomics has raised expectations in many fields, and particularly in personalized cancer research. The new technologies available make it possible to combine information about potential disease markers, altered function and accessible drug targets, which, coupled with pathological and medical information, will help produce more appropriate clinical decisions. The accessibility of such experimental techniques makes it all the more necessary to improve and adapt computational strategies to the new challenges. This review focuses on the critical issues associated with the standard pipeline, which includes: DNA sequencing analysis; analysis of mutations in coding regions; the study of genome rearrangements; extrapolating information on mutations to the functional and signaling level; and predicting the effects of therapies using mouse tumor models. We describe the possibilities, limitations and future challenges of current bioinformatics strategies for each of these issues. Furthermore, we emphasize the need for the collaboration between the bioinformaticians who implement the software and use the data resources, the computational biologists who develop the analytical methods, and the clinicians, the systems' end users and those ultimately responsible for taking medical decisions. Finally, the different steps in cancer genome analysis are illustrated through examples of applications in cancer genome analysis. PMID- 22839982 TI - More than make believe: the power and promise of simulation. PMID- 22839983 TI - 'We've got you covered': how to create a team atmosphere at work. PMID- 22839984 TI - Monitor alarm fatigue: an integrative review. AB - Alarm fatigue is a national problem and the number one medical device technology hazard in 2012. The problem of alarm desensitization is multifaceted and related to a high false alarm rate, poor positive predictive value, lack of alarm standardization, and the number of alarming medical devices in hospitals today. This integrative review synthesizes research and non-research findings published between 1/1/2000 and 10/1/2011 using The Johns Hopkins Nursing Evidence-Based Practice model. Seventy-two articles were included. Research evidence was organized into five main themes: excessive alarms and effects on staff; nurse's response to alarms; alarm sounds and audibility; technology to reduce false alarms; and alarm notification systems. Non-research evidence was divided into two main themes: strategies to reduce alarm desensitization, and alarm priority and notification systems. Evidence-based practice recommendations and gaps in research are summarized. PMID- 22839985 TI - Keeping data secure: protected health information and medical equipment. PMID- 22839986 TI - Simulation director envisions greater use for training tool. PMID- 22839987 TI - Partnership with college solves staff shortage problem. PMID- 22839988 TI - The importance of leadership in HTM programs. PMID- 22839989 TI - The fundamentals of ...liquid chromatography systems. PMID- 22839990 TI - Surgical tables and video integration. PMID- 22839991 TI - Simulation of medical device network performance and requirements for an integrated clinical environment. PMID- 22839993 TI - A 'risky' conversation with your boss is vital. PMID- 22839994 TI - Reimbursement agreements may restrict career opportunities. PMID- 22839995 TI - A Multilocus Sequence Typing System (MLST) reveals a high level of diversity and a genetic component to Entamoeba histolytica virulence. AB - BACKGROUND: The outcome of an Entamoeba histolytica infection is variable and can result in either asymptomatic carriage, immediate or latent disease (diarrhea/dysentery/amebic liver abscess). An E. histolytica multilocus genotyping system based on tRNA gene-linked arrays has shown that genetic differences exist among parasites isolated from patients with different symptoms however, the tRNA gene-linked arrays cannot be located in the current assembly of the E. histolytica Reference genome (strain HM-1:IMSS) and are highly variable. RESULTS: To probe the population structure of E. histolytica and identify genetic markers associated with clinical outcome we identified in E. histolytica positive samples selected single nucleotide polymorphisms (SNPs) by multiplexed massive parallel sequencing. Profile SNPs were selected which, compared to the reference strain HM-1:IMSS sequence, changed an encoded amino acid at the SNP position, and were present in independent E. histolytica isolates from different geographical origins. The samples used in this study contained DNA isolated from either xenic strains of E. histolytica trophozoites established in culture or E. histolytica positive clinical specimens (stool and amebic liver abscess aspirates). A record of the SNPs present at 16 loci out of the original 21 candidate targets was obtained for 63 of the initial 84 samples (63% of asymptomatically colonized stool samples, 80% of diarrheal stool, 73% of xenic cultures and 84% of amebic liver aspirates). The sequences in all the 63 samples both passed sequence quality control metrics and also had the required greater than 8X sequence coverage for all 16 SNPs in order to confidently identify variants. CONCLUSIONS: Our work is in agreement with previous findings of extensive diversity among E. histolytica isolates from the same geographic origin. In phylogenetic trees, only four of the 63 samples were able to group in two sets of two with greater than 50% confidence. Two SNPs in the cylicin-2 gene (EHI_080100/XM_001914351) were associated with disease (asymptomatic/diarrhea p = 0.0162 or dysentery/amebic liver abscess p = 0.0003). This study demonstrated that there are genetic differences between virulent and avirulent E. histolytica strains and that this approach has the potential to define genetic changes that influence infection outcomes. PMID- 22839996 TI - Silencing of Apoptosis-Inducing factor and poly(ADP-ribose) glycohydrolase reveals novel roles in breast cancer cell death after chemotherapy. AB - BACKGROUND: Cell death induced by poly(ADP-ribose) (PAR) and mediated by apoptosis-inducing factor (AIF) is well-characterized in models of ischemic tissue injury, but their roles in cancer cell death after chemotherapy are less understood. METHODS: Here we investigated the roles of PAR and AIF by RNA interference (RNAi) in MDA-MB-231 and MCF-7 breast adenocarcinoma cells after chemotherapy. Differences in effects were statistically tested by analysis-of variance and unpaired student's t-test. RESULTS: Silencing of AIF by RNAi led to decreased MDA-MB-231 and MCF-7 breast cancer cell death after chemotherapy, which demonstrates a critical role for AIF. RNAi silencing of PAR glycohydrolase (PARG), the primary enzyme that catalyzes the hydrolysis of PAR, led to increased PAR levels but decreased cell death. Further investigation into the possible role of PAR in apoptosis revealed decreased caspase-3/7/8/9 activity in PARG-null cells. Interestingly, the pharmacologic inhibition of caspase activity in PARG silenced breast cancer cells led to increased cell death after chemotherapy, which indicates that an alternative cell death pathway is activated due to elevated PAR levels and caspase inhibition. AIF silencing in these cells led to profound protection from chemotherapy, which demonstrates that the increased cell death after PARG silencing and caspase inhibition was mediated by AIF. CONCLUSIONS: The results show a role for AIF in breast cancer cell death after chemotherapy, the ability of PAR to regulate caspase activity, and the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases. Thus, the induction of cell death by PAR/AIF may represent a novel strategy to optimize the eradication of breast tumors by activating an alternative cell death pathway. PMID- 22839998 TI - Microfibrillated cellulose - its barrier properties and applications in cellulosic materials: a review. AB - Interest in microfibrillated cellulose (MFC) has been increasing exponentially. During the last decade, this bio-based nanomaterial was essentially used in nanocomposites for its reinforcement property. Its nano-scale dimensions and its ability to form a strong entangled nanoporous network, however, have encouraged the emergence of new high-value applications. In previous years, its mode of production has completely changed, as many forms of optimization have been developed. New sources, new mechanical processes, and new pre- and post treatments are currently under development to reduce the high energy consumption and produce new types of MFC materials on an industrial scale. The nanoscale characterization possibilities of different MFC materials are thus increasing intensively. Therefore, it is critical to review such MFC materials and their properties. Moreover, very recent studies have proved the significant barrier properties of MFC. Hence, it is proposed to focus on the barrier properties of MFC used in films, in nanocomposites, or in paper coating. PMID- 22839997 TI - Solid organ transplant-associated lymphocytic choriomeningitis, United States, 2011. AB - Three clusters of organ transplant-associated lymphocytic choriomeningitis virus (LCMV) transmissions have been identified in the United States; 9 of 10 recipients died. In February 2011, we identified a fourth cluster of organ transplant-associated LCMV infections. Diabetic ketoacidosis developed in the organ donor in December 2010; she died with generalized brain edema after a short hospitalization. Both kidneys, liver, and lung were transplanted to 4 recipients; in all 4, severe posttransplant illness developed; 2 recipients died. Through multiple diagnostic methods, we identified LCMV infection in all persons, including in at least 1 sample from the donor and 4 recipients by reverse transcription PCR, and sequences of a 396-bp fragment of the large segment of the virus from all 5 persons were identical. In this cluster, all recipients developed severe illness, but 2 survived. LCMV infection should be considered as a possible cause of severe posttransplant illness. PMID- 22840000 TI - Effect of Renshen polysaccharides on oxidative injury in kidney IR rabbits. AB - There is increasing evidence to suggest that reactive oxygen metabolites (ROMs) play a role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to determine the possible protective effect of Renshen polysaccharides (RSP) on renal ischemia/reperfusion (I/R) injury. Results showed that the polysaccharides of Renshen consisted mainly of glucose (29.21%), mannose (6.54%), rhamnose (4.34%), arabose (6.92%), galactose (18.41%). In addition, kidney lipid peroxidation level in IR rabbits were markedly increased, whereas antioxidant enzymes activities were significantly decreased. Renshen polysaccharides pre-treatment could decrease oxidative injury in kidney of IR rabbits. PMID- 22839999 TI - S-protected thiolated chitosan: synthesis and in vitro characterization. AB - Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6 mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. PMID- 22840001 TI - Study of the reaction of grafting acrylamide onto xanthan gum. AB - The present study aimed to study the reaction conditions of grafting of acrylamide on xanthan gum. It was analyzed the influence of reaction conditions, mainly type of initiator activation, initiator concentration and initiator/acrylamide ratio, on graft parameters and copolymer properties. Potassium persulfate was employed as an initiator and heating or N,N,N',N' tetramethylethylenediamine was used to activate the initiator. Reaction time and initiator concentration were varied and final values for grafting percentage and grafting efficiency were the same for both methods, whereas speed in reaching these values differs from one technique to another. We found that reaction time was inversely proportional to intrinsic viscosity, likely due to main chain degradation promoted by potassium persulfate (KPS); furthermore, the increasing in the KPS concentration lowers grafting percentage, acrylamide conversion and chain degradation, possibly as a result of O(2) formation at high KPS concentrations. PMID- 22840002 TI - Polyacrylamide grafted Agar: synthesis and applications of conventional and microwave assisted technique. AB - Polyacrylamide grafted Agar (Ag-g-PAM) has been successfully synthesized by conventional method and microwave assisted method. The former method employs ceric ammonium nitrate (CAN) as the free radical initiator while the latter uses the combination of ceric ammonium nitrate (CAN) and microwave irradiation. The synthesized graft copolymers have been characterized by elemental analysis (C, H, N, O and S), FTIR spectroscopy, intrinsic viscosity measurement and scanning electron micrograph (SEM); taking agar as a reference. Flocculation efficacy of synthesized graft copolymers was studied in kaolin suspension and in waste water through 'Jar test' procedure. In the present investigation, we have observed that polyacrylamide grafted agar synthesized by microwave assisted technique shows superior properties than conventional technique. These properties are reported in terms of intrinsic viscosity, flocculation efficacy and pollutant load reduction of waste water. PMID- 22840003 TI - Catalytic conversion of cellulose to 5-hydroxymethyl furfural using acidic ionic liquids and co-catalyst. AB - Efficient catalytic conversion of microcrystalline cellulose (MCC) to 5 hydroxymethyl furfural (HMF), is achieved using acidic ionic liquids (ILs) as the catalysts and metal salts as co-catalysts in the solvent of 1-ethyl-3 methylimidazo-lium acetate ([emim][Ac]). A series of acidic ILs has been synthesized and tested in conversion of MCC to HMF. The effect of reaction conditions, such as reaction time, temperature, catalyst dosage, metal salts, water dosage, Cu(2+) concentration and various acidic ILs are investigated in detail. The results show that CuCl(2) in 1-(4-sulfonic acid) butyl-3 methylimidazolium methyl sulfate ([C(4)SO(3)Hmim][CH(3)SO(3)]), is found to be an efficient catalyst for catalytic conversion of MCC to HMF, and 69.7% yield of HMF is obtained. A mechanism to explain the high activity of CuCl(2) in [C(4)SO(3)Hmim][CH(3)SO(3)] is proposed. To the best of our knowledge, this report first proposes that the Cu(2+) and [C(4)SO(3)Hmim][CH(3)SO(3)] show better catalytic performance in catalytic conversion of MCC to HMF. PMID- 22840004 TI - Synthesis and characterization of a novel boronic acid-functionalized chitosan polymeric nanosphere for highly specific enrichment of glycopeptides. AB - In this study we describe a method for highly specific enrichment of glycopeptides with boronic acid-functionalized chitosan polymeric nanospheres and matrix assisted laser desorption-ionization mass spectrometry (MALDI-MS). This is the first time chitosan has been used to create nanosphere support material for selective enrichment of glycopeptides by modification with glycidyl methacrylate (GMA) and derivatization with 3-aminophenylboronic acid (APB). Due to their multifunctional chemical moieties, these 20-100 nm chitosan-GMA-APB nanospheres have unique properties, such as good dispersibility, good biocompatibility and chemical stability, as well as augmented specificity with glycopeptides. Enrichment conditions were optimized by using trypsin digested glycoprotein horseradish peroxidase. The high specificity of chitosan-GMA-APB nanospheres was demonstrated by effectively enriching glycopeptides from a digest mixture of horseradish peroxidase and nonglycoproteins (bovine serum albumin (BSA)). PMID- 22840005 TI - Mild pretreatment and enzymatic saccharification of cellulose with recycled ionic liquids towards one-batch process. AB - The development of second-generation bioethanol involves minimizing the energy input throughout the processing steps. We report here that efficient ionic liquid pretreatments of cellulose can be achieved with short duration times (20 min) at mild temperature (45 degrees C) with [Emim](+)[MeO(H)PO(2)](-) and at room temperature (25 degrees C) with [Emim](+)[CH(3)COO](-). In these conditions, yields of glucose were increased by a factor of 3. In addition, the recycling of these two imidazolium-based ILs can be performed in maintaining their efficiency to pretreat cellulose. The short time and mild temperature of cellulose solubilization allowed a one-batch processing of [Emim](+)[MeO(H)PO(2)](-) IL pretreatment and saccharification. In the range from 0 to 100% IL in an aqueous enzymatic medium, the glucose yields were improved at IL proportions between 10 and 40%. The maximum yield at 10% IL is very promising to consider one batch process as efficient as two-step process. PMID- 22840006 TI - Chemical and biological properties of a highly branched beta-glucan from edible mushroom Pleurotus sajor-caju. AB - Hot aqueous extraction of the basidiocarps of the mushroom Pleurotus sajor-caju provided a cold water-soluble, gel-like glucan, which was characterized chemically, and its effects on RAW 264.7 cell line (mouse leukaemic monocyte macrophage) activation were determined. NMR spectroscopy, HPSEC, methylation analysis, and a controlled Smith degradation showed it to have a branched structure with a (1->3)-linked beta-Glcp main-chain, substituted at O-6 by single unit beta-Glcp side-chains, on the average of two to every third residues of the backbone, with a molar mass of 9.75 * 10(5) g mol(-1). In macrophage cell culture, the beta-glucan induced production of NO and the cytokines TNF-alpha, IL 1beta, these effects being very similar as those of Escherichia coli serotype 0111:B4 Sigma-Aldrich lipopolysaccharide (LPS), although not modifying the response of LPS-activated macrophages. The results suggest that the (1->3), (1 >6)-linked beta-glucan from P. sajor-caju may have potential for immunological activities, although additional experiments are necessary for a better understanding of the mechanisms involved. PMID- 22840007 TI - Sugarcane bagasse derivative-based superabsorbent containing phosphate rock with water-fertilizer integration. AB - To improve the water-fertilizer utilization ratio and mitigate the environmental contamination, an eco-friendly superabsorbent polymer (SPA), modified sugarcane bagasse/poly (acrylic acid) embedding phosphate rock (MSB/PAA/PHR), was prepared. Ammonia, phosphate rock (PHR) and KOH were admixed in the presence of acrylic acid to provide nitrogen (N), phosphorus (P) and potassium (K) nutrients, respectively. Impacts on water absorption capacity of the superabsorbent polymer (SAP) were investigated. The maximum swelling capacity in distilled water and 0.9 wt.% (weight percent) NaCl solution reached 414 gg(-1) and 55 gg(-1) (water/prepared SAP), respectively. The available NPK contents of the combination system were 15.13 mgg(-1), 6.93 mgg(-1) and 52.05 mgg(-1), respectively. Moreover, the release behaviors of NPK in the MSB/PAA/PHR were also studied. The results showed that the MSB/PAA/PHR has outstanding sustained-release plant nutrients property. PMID- 22840008 TI - Isolation and structural characterization of the water-extractable polysaccharides from Cassia obtusifolia seeds. AB - The seed of Cassia obtusifolia is a food or herbal medicine used for improving eyesight, treating constipation and other disorders, and polysaccharides have been implicated in these pharmacological activities. The endosperm of the seeds, Cassia gum, is a commercial thickening or gelling agent, composed mainly of galactomannans. However, the whole seeds of C. obtusifolia, rather than the endosperm, are used in folk medicine or food, which might contain more complex constituents of polysaccharides. In this study, the whole seeds of C. obtusifolia were extracted with boiling water, and from the water extract, three homogeneous fractions were isolated, designated CFAA-1, CFAA-3, and CFBB2, respectively, after treatment with Fehling solution followed by anion-exchange and gel permeation chromatography. Using chemical and spectroscopic methods, CFAA-1, and CFAA-3 were elucidated to be both branched galactomannans with different molecular weights, consisting of 1,4-linked beta-d-mannopyranosyl backbone with single-unit alpha-d-galactopyranosyl branches attached to O-6 of mannose, while CFBB2 was shown to be a linear (1->4)-alpha-polygalacturonic acid. PMID- 22840010 TI - Residual keratan sulfate in chondroitin sulfate formulations for oral administration. AB - Chondroitin sulfate is a biomedical glycosaminoglycan (GAG) mostly used as a dietary supplement. We undertook analysis on some formulations of chondroitin sulfates available for oral administration. The analysis was based on agarose-gel electrophoresis, strong anion-exchange chromatography, digestibility with specific GAG lyases, uronic acid content, NMR spectroscopy, and size-exclusion chromatography. Keratan sulfate was detected in batches from shark cartilage, averaging ~16% of the total GAG. Keratan sulfate is an inert material, and hazardous effects due to its presence in these formulations are unlikely to occur. However, its unexpected high percentage compromises the desired amounts of the real ingredient specified on the label claims, and forewarns the pharmacopeias to update their monographs. The techniques they recommended, especially cellulose acetate electrophoresis, are inefficient in detecting keratan sulfate in chondroitin sulfate formulations. In addition, this finding also alerts the manufacturers for improved isolation procedures as well as the supervisory agencies for better audits. Analysis based on strong anion-exchange chromatography is shown to be more reliable than the methods presently suggested by standard pharmacopeias. PMID- 22840009 TI - Rheological characterization of the galactomannan from Leucaena leucocephala seed. AB - A water soluble galactomannan isolated from Leucaena leucocephala seeds gave an intrinsic viscosity of 3.5 dl/g and viscosity average molecular mass, M(v), of 6.98 * 10(5) g/mol. This was in reasonably good agreement with the value of the weight average molecular mass, M(w), of 5.44 +/- 0.20 * 10(5) g/mol determined by GPC-MALLS coupled to RI. The onset of polymer coil overlap occurred at c*[eta] of 2.1, with slope of 3.0 above and 1.3 below the point of polymer coil overlap. The shear viscosity of the polysaccharide was temperature dependent and decreased with increasing temperature. The activation energy for viscous flow of 3.0% polysaccharide concentration obtained by Arrhenius plot of zero shear viscosity as a function of temperature was 26.4 kJ/mol. Both the storage modulus (G') and loss modulus (G") showed strong dependence on frequency indicating the presence of entangled coils. The Cox-Merz plot gave close superimposition of the complex and shear viscosities. PMID- 22840011 TI - Preparation and NMR characterization of glucosamine oligomers bearing an azide function using chitosan. AB - In this study, a procedure to produce glucosamine oligomers with the amino functions transformed into azido groups was optimized, and HPLC purification afforded to the isolation of nine different oligosaccharides derivatives, with the reducing end transformed in alditol. These oligomers differed for the degree of polymerization and for the type of alditol at the reducing end. The first group comprehended species from di- to hexasaccharide, with all the amino functions converted into an azido group. The second and the third groups were isolated in minor yields, and were both constituted from tri- and tetrasaccharides; the difference between the two groups regarded exclusively the type of alditol found at the reducing end, which was a glucosaminitol in the first case, or a N-acetylglucosaminitol in the other. Products were fully characterized by 2D NMR spectroscopy. The azido moieties installed on these oligosaccharides can be further exploited in Cu(I) catalyzed azido-alkyne cycloaddition reactions. PMID- 22840012 TI - Sodium alginate/Na+-rectorite composite microspheres: preparation, characterization, and dye adsorption. AB - Sodium alginate/Na(+)-rectorite (SA/Na(+)REC) intercalated nano-composite microspheres were prepared in an inverse suspension system. The effect of the preparation conditions of SA/Na(+)REC composite microspheres on adsorption capacity for Basic Blue 9 was investigated. The structure and morphology were analyzed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscope (SEM). The results showed that the optimal condition was that the amount of Na(+)-rectorite was 2wt%, the amount of cross linker was 0.384% and the amount of the initiator was 8%. SEM showed that it is porous products with spherical particulate surface. XRD showed that intercalation is formed between Na(+)-rectorite and sodium alginate. The adsorption capacity of SA/Na(+)REC was investigated in comparison with Na(+)-rectorite and sodium alginate using different cationic dyes. The SA/Na(+)REC composite microspheres showed the highest adsorption capacity. The reason lies in the existence of intercalated sodium alginate. It could enlarge the pore structure of microspheres, facilitating the penetration of macromolecular dyes. PMID- 22840015 TI - Fixed-bed column studies on a modified chitosan hydrogel for detoxification of aqueous solutions from copper (II). AB - A new efficient, low cost chitosan based biosorbent was successfully prepared and employed for the biosorption of copper ions from an aqueous solution using a fixed bed column. Pyromellitic dianhydride crosslinked chitosan as the new adsorbent was characterized by SEM, FTIR spectroscopy, X-ray diffraction, thermogravimetric analysis and solid state (13)C NMR analysis. Scanning electron microscopy coupled with an X-ray energy dispersed analysis for the copper equilibrated biomass confirmed the presence of Cu(II) ions on the surface of the hydrogel. Thermogravimetric analysis showed a significant improvement in the thermal stability of the new hydrogel compared to pure chitosan. Kinetic models were applied to predict the breakthrough curves. This study shows that the prepared hydrogel based on modified chitosan could be utilized as an efficient bioadsorbent for the removal of copper ions from wastewater. PMID- 22840014 TI - Antitumor and immunomodulatory activity of water-soluble polysaccharide from Inonotus obliquus. AB - The medicinal mushroom Inonotus obliquus has been used as a folk remedy for a long time in Russia and East-European countries to treat gastrointestinal cancer, cardiovascular disease and diabetes. In our study, a water-soluble polysaccharide (ISP2a) was successfully purified from I. obliquus by DEAE-Sepharose CL-6B and Sepharose CL-6B column chromatography. In vivo ISP2a had not only shown antitumor activity, but also could significantly enhance the immune response of tumor bearing mice. In addition, ISP2a significantly enhanced the lymphocyte proliferation and increased the production of TNF-alpha. Results of these studies demonstrated that ISP2a had a potential application as natural antitumor agent with immunomodulatory activity. PMID- 22840013 TI - A versatile method for functionalization and grafting of 2-hydroxyethyl cellulose (HEC) via Click chemistry. AB - This article describes a versatile method for the modification of 2-hydroxyethyl cellulose (HEC) involving azide-alkyne cycloaddition reaction to impart neutral (ester) and ionic (carboxylic acid and 1(ry) amine) functionalities. The synthetic approach involved, first the introduction of the azide functionality to HEC and then followed by its cycloaddition reaction with several alkyne terminated compounds: namely ethyl propiolate, 5-hexynoic acid and propargyl amine. Sequential Click reactions were also demonstrated to be feasible by the successful synthesis of polydimethylsiloxane (PDMS) grafted HEC containing neutral (ester) and ionic (carboxylic acid and 1(ry) amine) functionalities. The Click chemistry was then further utilized similarly to graft poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) segments to HEC to access its hydrophobic and hydrophilic analogs, respectively. AFM analysis revealed that while HEC itself formed uniform oval features, the PLA grafted HEC exhibited a brushlike architecture. The formation of these brushlike structures suggested that the HEC backbone exhibits an extended conformation with the side chains stretched out. The resulting polymeric materials were characterized by solution and solid state (13)C NMR and FTIR spectroscopy. PMID- 22840016 TI - Efficient removal of both cationic and anionic dyes from aqueous solutions using a novel amphoteric straw-based adsorbent. AB - In the current paper, a novel amphoteric straw-based adsorbent was prepared and applied to adsorb various dyes from aqueous solutions. The amphoteric adsorbent was proven effective in eliminating both cationic and anionic dyes (methylene blue and acid green 25), especially at corresponding favored pH conditions. The fundamental adsorption behavior of the adsorbent on removing various dyes was also investigated at different temperatures. The adsorption isotherms were all best-fitted by the Langmuir equation, whereas the adsorption kinetics was well described by both the pseudo-second order model and the Elovich model. The experimental result revealed that the adsorption mechanism followed the monolayer chemical adsorption with an ion-exchange process. PMID- 22840017 TI - Rheological, water uptake and controlled release properties of a novel self gelling aldehyde functionalized chitosan. AB - In this work, aldehyde-functionalized chitosan was used to prepare gels through Schiff base formation between the aldehyde and the free amine groups. The gels, which were formed in situ without an external crosslinker, were characterized in respect to their rheological properties and water uptake capacity. In addition, the potential use of these gels as drug carriers was investigated using metronidazole (Mw 171 Da), FTIC-dextran (Mw 40 kDa) and bovine serum albumin (Mw 66 kDa), as the model drugs. Higher concentrations of the aldehyde-functionalized chitosan originated more rigid gels, as evidenced by the higher values of complex modulus (G*). The highly porous structure of these gels allowed for more than 400% of water uptake. The release of the model drugs followed a near zero-order release profile. The molecular size as well as the pH of the medium influenced the amount of drug released, where the higher the pH, the slower the resulting drug release. PMID- 22840018 TI - Synthesis of graft copolymer (CgOH-g-AGA): physicochemical properties, characterization and application. AB - A graft copolymer of kappa-carrageenan and 2-acrylamidoglycolic acid (CgOH-g-AGA) was synthesized via free radical polymerization initiated by potassium peroxymonosulphate/malonic acid redox pair. For affording maximum percentage of grafting, optimum conditions were determined by varying the concentrations of kappa-carrageenan, 2-acrylamidoglycolic acid, potassium peroxymonosulphate, malonic acid, hydrogen ion, time and temperature. The swelling, metal ion uptake and flocculation studies were investigated with water, three metals (Ni(2+), Pb(2+) and Zn(2+)) solutions, coal (coking and non-coking) suspensions, respectively. Both, polymer backbone and its corresponding graft copolymer samples were characterized by Fourier transform infrared spectroscopy and thermogravimetric analysis. PMID- 22840019 TI - Functionalization of cellulose-containing fabrics by plasma and subsequent metal salt treatments. AB - In order to upgrade the UV-protection and antibacterial functional properties of cotton/polyester (80/20), cotton/linen (50/50) and linen/viscose-polyester (50/50) fabric blends, they were treated with different plasma gases (oxygen, air, and argon) followed by subsequent treatment with certain metal salts namely Zn-acetate, Cu-acetate, Al-chloride, and Zr-oxychloride. The obtained results show that the type of plasma gas, the kind of metal salt as well as the nature of the treated substrate play an important role in the extent of enhancing the demanded functional properties. Oxygen plasma treatment followed by Cu-acetate or Zn-acetate treatment gives the best UV-protection or antibacterial activity respectively, keeping other parameters constant. The surface morphology of some untreated and plasma-treated samples was also analyzed by SEM. PMID- 22840020 TI - Bio-synthesis and applications of silver nanoparticles onto cotton fabrics. AB - Recently, biosynthesis of metal nanoparticles has drawn considerable attention due to environment-ecofriendly and sustainable methods. Herein, fungus Fusarium solani was selected as candidate for biosynthesis of silver nanoparticles (AgNPs). Factors affecting the biomass concentration, pH of the reaction medium, AgNO(3) concentration and the ratio of AgNO(3) to biomass concentration on the production of AgNPs were extensively studied. Optimum conditions for biosynthesis of AgNPs could be attained using biomass of F. solani (10 g/100ml); AgNO(3) (0.078 g/100 ml); pH, 12; temperature, 25 degrees C and duration, 24h. Under these conditions, the maximum concentration of well stabilized AgNPs obtained was 2000 ppm with a mean diameter range of 8-15 nm. Such solution is unequivocally feasible for industrial applications. A diluted solution containing 50 ppm AgNPs was applied to cotton fabrics which imparts antibacterial activity to the fabric with 97% and 91% reduction of Staphylococcus aureus and Escherichia coli, respectively. PMID- 22840021 TI - Optimization and characterization of a polysaccharide produced by Pseudomonas fluorescens WR-1 and its antioxidant activity. AB - The extracellular polysaccharide produced by a newly isolated strain Pseudomonas fluorescens WR-1 was purified and characterized and its production was optimized using response surface methodology. The results showed that the strain WR-1 produced one kind of EPS that was composed of arabinose, glucose and uronic acid. The molecular weight of the EPS was determined to be 6.78 * 10(6)Da. The preferable culture conditions for EPS production were pH 7.0, temperature 28 degrees C for 72 h with peptone and maltose as best N and C sources, respectively. The model predicted that the maximum EPS production (39.6 gL(-1)) was appeared with maltose 48.65 gL(-1), Mn(2+) 1118 MUM and Zn(2+) 901 MUM. The EPS also showed good H(2)O(2) scavenging activity while moderate free radical scavenging activity and reductive ability were determined. The EPS from WR-1 may be a new source of natural antioxidants with potential value for health, food and industry. PMID- 22840022 TI - Preparation and characterization of poly(acrylic acid)-hydroxyethyl cellulose graft copolymer. AB - Poly(acrylic acid) hydroxyethyl cellulose [poly(AA)-HEC] graft copolymer was prepared by polymerizing acrylic acid (AA) with hydroxyethyl cellulose (HEC) using potassium bromate/thiourea dioxide (KBrO(3)/TUD) as redox initiation system. The polymerization reaction was carried out under a variety of conditions including concentrations of AA, KBrO(3) and TUD, material to liquor ratio and polymerization temperature. The polymerization reaction was monitored by withdrawing samples from the reaction medium and measuring the total conversion. The rheological properties of the poly(AA)-HEC graft copolymer were investigated. The total conversion and rheological properties of the graft copolymer depended on the ratio of KBrO(3) to TUD and on acrylic acid concentration as well as temperature and material to liquor ratio. Optimum conditions of the graft copolymer preparation were 30 mmol KBrO(3) and 30 mmol TUD/100g HEC, 100% AA (based on weight of HEC), duration 2h at temperature 50 degrees C using a material to liquor ratio of 1:10. PMID- 22840023 TI - Ca2+ sorption on regenerated cellulose fibres. AB - High calcium content in cellulose materials can cause considerable problems in pulp processing, textile chemical treatment and consumer use, e.g. dyeing operations or household laundry. The Ca(2+) binding capacity of cellulose also is of relevance in food and medical applications. Through their carboxyl group content regenerated cellulose fibres can act as weak anion exchangers, thus all types of regenerated cellulose fibres such as lyocell, viscose and modal fibres, show a distinct ability to bind Ca(2+) ions. The binding capacity is limited by the carboxyl group content, which was determined with 15 mmol/kg for lyocell fibres and 20 mmol/kg for viscose fibres, using the Methylene Blue sorption method. The presence of bound Ca(2+) also was demonstrated by complex formation with alizarin. The molar ratio between carboxylic group content and bound Ca(2+) ions was one Ca(2+) ion for a single carboxyl group. As a result of Ca(2+) sorption a positive net charge of the cellulose results and another anion has to be bound as counter ion for reasons of charge neutralisation. Results of potentiometric titrations indicate HCO(3)(-) to be present as counter ion in the Ca(2+) cellulose system. Thus under the experimental conditions studied, bound Ca(2+) is proposed to be present in the form COO(-)Ca(2+)HCO(3)(-). PMID- 22840024 TI - Pharmacological evaluation of tea polysaccharides with antioxidant activity in gastric cancer mice. AB - Tea polysaccharides were fractionated by Sephadex G-100 gel permeation chromatography. The results showed that tea polysaccharides were mainly composed of TF-1, TF-2 and TF-3. The average molecular weights of TF-1, TF-2 and TF-3 determined by high-performance gel permeation chromatography (HPGPC) and high performance liquid chromatography-evaporative light scattering detector (HPLC ELSD) were 231,568 Da, 46,278 Da and 7251 Da, respectively. The monosaccharide composition of Renshen polysaccharides was evaluated by GC. TF-1 was composed of glucose, mannose, xylose with molar ratio of 1:3.2:1.4. TF-2 and TF-3 consisted of glucose, xylose and glucose, xylose, arabinose with molar ratios of 1:1.7 and 1:2.5:0.9, respectively. TF-1 contained mannose as main sugar component and TF-2 was rich in xylose, whereas TF-3 was rich in xylose. In addition, tea polysaccharides could decrease stomach malondialdehyde (MDA) level, serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels, increased serum immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10) levels, and stomach antioxidant enzymes activities in gastric cancer mice. PMID- 22840026 TI - LBL fabricated biopolymer-layered silicate based nanofibrous mats and their cell compatibility studies. AB - N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) was synthesized from chitosan (CS). Organic rectorite (OREC) added into cellulose acetate (CA) was used to fabricate electrospun nanofibrous mats with improved thermal properties, as a result of depositing multilayers of the positively charged HTCC-OREC composites and the negatively charged sodium alginate (ALG) via layer-by-layer (LBL) technique. The morphology was affected by the number of deposition bilayers and the component of the outmost layer. Observed from the field emission scanning electron microscopy (FE-SEM) images, the LBL structured nanofibrous mats had much larger fiber sizes than CA-OREC nanofibrous mats. X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) results further confirmed that HTCC-OREC was assembled on nanofibrous mats. Additionally, cell experiments and MTT results demonstrated that OREC had little effect on the cytotoxicity of LBL template, but obviously affected both the cytotoxicity and the cell compatibility of LBL structured mats when OREC was in the deposition films. PMID- 22840025 TI - Effects of modified cellulose nanocrystals on the barrier and migration properties of PLA nano-biocomposites. AB - The aim of this paper is to report the impact of the addition of cellulose nanocrystals on the barrier properties and on the migration behaviour of poly(lactic acid), PLA, based nano-biocomposites prepared by the solvent casting method. Their microstructure, crystallinity, barrier and overall migration properties were investigated. Pristine (CNC) and surfactant-modified cellulose nanocrystals (s-CNC) were used, and the effect of the cellulose modification and content in the nano-biocomposites was investigated. The presence of surfactant on the nanocrystal surface favours the dispersion of CNC in the PLA matrix. Electron microscopy analysis shows the good dispersion of s-CNC in the nanoscale with well defined single crystals indicating that the surfactant allowed a better interaction between the cellulose structures and the PLA matrix. Reductions of 34% in water permeability were obtained for the cast films containing 1 wt.% of s CNC while good oxygen barrier properties were detected for nano-biocomposites with both 1 wt.% and 5 wt.% of modified and un-modified cellulose nanocrystals, underlining the improvement provided by cellulose on the PLA films. Moreover, the migration level of the studied nano-biocomposites was below the overall migration limits required by the current normative for food packaging materials in both non polar and polar simulants. PMID- 22840027 TI - Preparation of microcapsules with multi-layers structure stabilized by chitosan and sodium dodecyl sulfate. AB - The microcapsules with oil core and multi-layers shell were developed from poly cationic chitosan (CS) and anionic SDS in multistep electrostatic layer by layer deposition technique combined with oil in water emulsification process. The net charge of microcapsules determined by zeta potential indicated that microcapsules are highly positive charged because of poly-cationic nature of CS, and charge neutralization of microcapsules occurred after alkali treatment. The granulometry measurement showed increase in average diameter of microcapsules by alkali treatment suggesting swelling or formation of small aggregates. The morphology analysis of microcapsules by optical microscopy corroborated the results of granulometry, and diameter of microcapsules was found to be decreased in multistep process due to tight packing of layers in outer shell of microcapsules. The alkali treatment of microcapsules to solidify outer shell was optimized with 0.02 N NaOH to reduce microcapsules aggregation and gel formation by CS chains as found in optical micrographs. PMID- 22840028 TI - TG/DTG/DTA evaluation of flame retarded cotton fabrics and comparison to cone calorimeter data. AB - Unbleached cotton fabrics (UCF) with 12.5% polypropylene scrim treated with two phosphate-urea based fire-retardant (FR) formulations were evaluated for FR properties using thermogravimetry/differential thermogravimetry/differential thermal analysis (TG/DTG/DTA) method. In addition to testing the two FR-treated unbleached cotton fabrics (CF-FR1 and CF-FR2), bleached cotton fabric (BCF) treated with the two FR formulations (BCF-FR1 and BCF-FR2) was evaluated. Both formulations were washable with add-on of FR chemicals at 18.7% (FR1) or 17.4% (FR2) for UCF and 22.5% (FR1) or 24.9% (FR2) for BCF. The decreasing order of sums at maximal rates of samples degradation in air environment according to DTG method was: BCF (21.40%/min)>UCF (12.91%/min)>BCF-FR2 (12.83%/min)>BCF-FR1 (11.68%/min)>CF-FR2 (10.20%/min)>CF-FR1 (9.73%/min). It indicates that both formulations cause the decrease of thermooxidation of the products at slower rates than the starting material. Several endo- and exothermic peaks observed by DTA in inert and oxidative environment gives additional information about the degradation process. The order of decreasing thermal responses of the studied samples based on sums of DTA peak values of endothermic and exothermic peaks in air environment is: UCF (0.597 degrees C/mg)>BCF (0.120 degrees C/mg)>CF-FR1 (0.089 degrees C/mg)>BCF-FR1 (0.077 degrees C/mg)>CF-FR2 (0.062 degrees C/mg)>BCF-FR2 (0.053 degrees C/mg). This is in agreement with the cone calorimeter results according to which the flammability properties are improving with the decreasing heat release rates or ignition time prolongation in order: UCF>CF-FR1>CF-FR2. The advantage of TG/DTG/DTA method is slower linear heating rate, which allows the more detailed evaluation of the light and flammable cotton fabric. PMID- 22840029 TI - Solution blowing of submicron-scale cellulose fibers. AB - Solution blowing is an innovative process for spinning micro-/nano-fibers from polymer solutions using high-velocity gas flow as fiber forming driving force. Submicron-scale cellulose fibers were successfully solution blown by two improvement measures. First, cellulose solution was directly blown to fibers of 260-1900 nm in diameter by raising the air temperature along the spinning line which was proved to accelerate the evaporation of solvent and fiber forming. Second, coaxial solution blowing technique was established with cellulose solution and polyethylene oxide (PEO) solution used as core and shell liquids, respectively. The core-shell structures of the fibers were examined by SEM and TEM. Cellulose fibers with diameter between 160 nm and 960 nm were further obtained after removing PEO shell. X-ray diffraction studies showed that the two kinds of submicron-scale cellulose fibers are mostly amorphous. PMID- 22840030 TI - Modification of hydroxypropyl guar gum with ethanolamine. AB - A new guar gum derivative containing amino group was synthesized through nucleophilic substitution of p-toluenesulfonate activated hydroxypropyl guar gum with ethanolamine. For the preparation of p-toluenesulfonate esters hydroxypropyl guar gum, the results showed that the reaction rate was optimal at 25 degrees C and the reaction could reach equilibrium state when it was carried out for 10h at 25 degrees C. For the nucleophilic substitution of tosyl group with ethanolamine, the reaction was completed after 10h reaction at 50 degrees C. The structures of products were characterized by NMR and FT-IR spectroscopy. The results showed that the p-toluenesulfonate esters can be effectively substituted by ethanolamine to form the hydroxyethyl amino hydroxypropyl guar gum (EAHPG). The content of nitrogen of EAHPG was determined by acid-base titration and element analysis. PMID- 22840031 TI - ESIMS analysis of fucoidan preparations from Costaria costata, extracted from alga at different life-stages. AB - Four fucoidan fractions from brown alga Costaria costata, collected at different life-stages: vegetative, May (5F2 and 5F3) and generative, July (7F1 and 7F2) collections were characterized. It was found that seaweed synthesizes different set of fucoidans - one with high fucose content and substantial percentage of hexoses and uronic acid and lower sulfate content (7F1, 5F2 and 5F3) and other - highly sulfated galactofucan (7F2). Structural features of fractions 7F2 and 5F3 were predominantly determined by mass spectrometric analysis of low-molecular weight (LMW) oligosaccharide fragments, obtained by autohydrolysis of 7F2 and mild acid hydrolysis of 5F3 fucoidans. It was found that oligosaccharides from 7F2 fractions were mainly built up of sulfated at C-2 and/or at C-2/C-4 (1->3) linked alpha-l-fucopyranose residues. d-Galactose residues, sulfated either at C 2 or C-6, were found as parts of mixed di- and trisaccharides at both termini and, probably, internal. Fucose residues in 5F3 fucoidan fragments were sulfated at C-2 and sometimes at C-4. Galactose residues were sulfated at C-4 and less frequently at C-2. Resistant to hydrolysis fraction was probably a core, built up with fucose, mannose and glucuronic acid. Presumably, oligosaccharide fragments were branches at C-4 of GlcA. They were sulfated at C-2 and sometimes at C-4 (1 >3)- and/or (1->4)-linked fucooligosaccharides (sometimes terminated with (1->3) linked galactose) and sulfated at C-4 or C-2 (1->4)- or, probably, (1->6)-linked galactooligosaccharides, probably, with own branches, formed by (1->2)-linked galactose residues. Unsulfated xylose residues were probably terminal in chains built up of fucose. It was confirmed, that monosaccharide content and structure of fucoidans of vegetative algae changed following its life stage. Generative alga in general produced highly sulfated galactofucan having lower MW along with less sulfated mannoglucuronofucan with higher MW, which was extensively synthesized by vegetative algae. PMID- 22840032 TI - Structural and electrical properties of paper-polyaniline composite. AB - Conducting polymers have generated a great deal of interest because of their physical and chemical properties as well as their potential application in industry particularly in packaging applications. However one of short comings of most conducting polymer is that they are often formed as intractable films that are difficult to process. To overcome this problem we have incorporated conducting polymer, namely polyaniline into sheets of paper in order to create new composite material which combine the universal properties of paper product with the chemical and electrically conducting properties of the conducting polymer. Paper conducting polymer composite have been prepared by polymerizing aniline directly onto the paper sheet using ammonium peroxydisulfate (APS) as an oxidant at different temperatures. The prepared composite was characterized by FT IR and SEM. The thermo-oxidative degradation was studied by thermo gravimetric analysis (TGA); electrical conductivities measurements of the composites were significantly increased over those of the precursor paper. PMID- 22840033 TI - Preparation of cellulose derived from corn stalk and its application for cadmium ion adsorption from aqueous solution. AB - Cellulose was isolated from corn stalk and modified by graft copolymerization to produce an absorbent material (AGCS-cell), which was characterized by scanning electron microscope and energy disperse spectroscopy (SEM-EDS), X-ray diffraction (XRD) and solid-state CP/MAS (13)C NMR. The results showed that AGCS-cell had better adsorption potential for cadmium ion than unmodified cellulose because of the addition of functional groups (CN and OH groups) and the lower crystallinity. The Langmuir isotherms gave the best fit to the data and gave an adsorption capacity was 21.37 mg g(-1), which was close to unpurified cellulose (AGCS) and reflected the feasibility of using AGCS-cell as an adsorbent to remove cadmium ions. PMID- 22840034 TI - Modified coaxial electrospinning for the preparation of high-quality ketoprofen loaded cellulose acetate nanofibers. AB - This study investigates the use of a modified coaxial electrospinning process in the production of drug-loaded cellulose acetate (CA) nanofibers. With CA employed as a filament-forming matrix and ketoprofen (KET) as an active pharmaceutical ingredient, modified coaxial processes using sheath fluids comprising only mixed solvents were undertaken. With a sheath-to-core flow rate ratio of 0.2:1, the nanofibers prepared from the coaxial process had a smaller average diameter, narrower size distribution, more uniform structures, and smoother surface morphologies than those generated from single fluid electrospinning. In addition, the coaxial fibers provided a better zero-order drug release profile. The use of a sheath solvent means that the core jet is subjected to electrical drawing for a longer period, facilitating homogeneous core jet solidification and retarding the formation of wrinkles on the surface of the nanofibers. This modified coaxial electrospinning protocol allows the systematic fabrication of functional polymer nanofibers with improved quality. PMID- 22840035 TI - In vivo evaluation of in situ polysaccharide based hydrogel for prevention of postoperative adhesion. AB - In this paper, the carboxymethyl chitosan/oxidized dextran hydrogel was developed and its potency application in the prevention of postoperative adhesion was investigated. The developed hydrogel showed porous and interconnected interior structure with pore size about 250 MUm, which was sensitive to lysozymic solution (1.5 MUg/ml) with almost complete degradation after 4 weeks of in vitro incubation. In vivo study suggested that the developed hydrogel showed the great capacity on the prevention of postoperative adhesions in rat model. According to the result of histopathological examination, it clearly showed that the mesothelial cell layer of abdominal wall and cecum were completely recovered after 7 days of surgery in 3% carboxymethyl chitosan/oxidized dextran hydrogel group, while obvious adhesion between abdominal wall and cecum was observed as treatment with saline solution or 3% carboxymethyl chitosan solution after 1 day of surgery. All these results suggested that the developed biodegradable hydrogel might have potential application in the prevention of postoperative adhesion. PMID- 22840036 TI - Effect of waxy rice flour and cassava starch on freeze-thaw stability of rice starch gels. AB - Repeatedly frozen and thawed rice starch gel affects quality. This study investigated how incorporating waxy rice flour (WF) and cassava starch (CS) in rice starch gel affects factors used to measure quality. When rice starch gels containing 0-2% WF and CS were subjected to 5 freeze-thaw cycles, both WF and CS reduced the syneresis in first few cycles. However CS was more effective in reducing syneresis than WF. The different composite arrangement of rice starch with WF or CS caused different mechanisms associated with the rice starch gel retardation of retrogradation, reduced the spongy structure and lowered syneresis. Both swollen granules of rice starch and CS caused an increase in the hardness of the unfrozen and freeze-thawed starch gel while highly swollen WF granules caused softer gels. These results suggested that WF and CS were effective in preserving quality in frozen rice starch based products. PMID- 22840037 TI - Enzymatic hydrolysis and characterization of lignocellulosic biomass exposed to electron beam irradiation. AB - Pretreatment of lignocellulosic biomass has been taken up as a global challenge as it comprises a large renewable source of fermentable sugars. In this study, effect of electron beam irradiation (EBI) on a hybrid grass variety investigated as a biomass pretreatment method. Dry biomass samples after characterization were exposed to EBI doses of 0, 75, 150 and 250 kGy. The pretreated biomass samples were enzymatically hydrolyzed using Trichoderma reesei ATCC 26921 cellulase for 144 h. The enzyme loadings were 15 and 30 FPU/g of biomass. The structural changes and degree of crystallinity of the pretreated biomass were studied by FTIR, XRD and SEM analyses. The lignocellulosic biomass sample showed 12.0% extractives, 36.9% cellulose, 28.4% hemicellulose, 11.9% lignin and 8.6% ash. Significant improvements in the reducing sugar and glucose yields were observed in the hydrolysate of EBI pretreated biomass compared to the control. In 250 kGy exposed samples 79% of the final reducing sugar yield was released within 48 h of hydrolysis at an enzyme loading rate of 30FPU/g of biomass. The IR crystallinity index calculated from the FTIR data and degree of crystallinity (XRD) decreased in the EBI treated samples. A significant negative correlation was observed between degree of crystallinity and the glucose yield from enzymatic hydrolysis. PMID- 22840038 TI - Multi-morphological self-assembled structures in water of a biodegradable beta cyclodextrin-based copolymer. AB - A rigid-coil beta-cyclodextrin-poly (E-caprolactone) (CD-PCL) copolymer was synthesized in which biodegradable flexible multi PCL arms were selectively connected onto the wide side of the rigid torus-shaped beta-CD through ring opening polymerization (ROP) of E-caprolactone (CL) and protection/deprotection technique of beta-cyclodextrin (beta-CD) via trimethylsilyl groups. (1)H NMR, FT IR, and GPC analysis confirmed the "jellyfish-like" branched architecture of CD PCL copolymers. The self-assembled structures in water of the amphiphilic CD-PCL copolymer were investigated by transmission electron microscopy (TEM), dynamic light scattering (DLC) and viscometry. The results showed that CD-PCL could self assemble into multi-morphological aggregates such as spheres, rods, vesicles, vesicular clusters and vesicular network in water. Interestingly, hierarchical stripe structure was observed in the formed vesicular network, which was driven by the crystallization of PCL segment in micelles. Moreover, the inclusion ability of copolymer micelles with ferrocenecarboxylic acid was investigated by UV. PMID- 22840039 TI - Astragalus polysaccharide and sulfated epimedium polysaccharide synergistically resist the immunosuppression. AB - The immunoenhancement of compound polysaccharides, APS-sEPS composed with astragalus polysaccharide (APS) and sulfated epimedium polysaccharide (sEPS), was observed in immunosuppressed model chicken induced by cyclophosphamide (Cy). 11 day-old chickens were injected with Cy once a day for three successive days except vaccine control group. At day-14-old, all chickens were vaccinated with ND vaccine, and in experimental groups simultaneously administrated with APS-sEPS at three dosages, APS and sEPS once a day for three successive days. On days 7, 14, 21 and 28 after the administration, the peripheral T-lymphocyte proliferation, serum antibody titers, IFN-gamma, IL-2, IgG and IgM were determined. The results displayed that APS-sEPS could overcome Cy-induced immunosuppression, significantly promote T-lymphocyte proliferation and raised serum antibody titers, IFN-gamma, IL-2, IgG and IgM levels, its high and medium doses were superior to single APS or sEPS. This demonstrated that APS and sEPS could synergistically resist the immunosuppression and APS-sEPS was an effective immunopotentiator. PMID- 22840040 TI - Synthesis of a new amphiphilic glycodendrimer with antiviral functionality. AB - A new third generation amphiphilic glycodendrimer was synthesized from a stearylamide lysine dendrimer by condensation of the oligosaccharide moiety. By stepwise condensation and deprotection of di-boc lysine from a core of stearyl amide lysine, a third-generation stearylamide lysine dendrimer was constructed. Acetyl cellobiose and glucose units with the carboxylic acid at the end of alkyl chain attached to the reducing end of the sugar moiety was condensed with surface amino groups of the third generation lysine dendrimer, respectively, to give a new stearylamide acetylcellobiose and acetylglucose lysine dendrimers. The structural analysis was carried out using NMR, IR, and matrix-associated laser desorption/ionization time-of-flight (MALDI TOF) mass spectroscopies. After deacetylation to recover hydroxyl groups and subsequent sulfation, the third generation sulfated cellobiose stearylamide lysine dendrimer was preliminarily found to have high anti-HIV activity at a 50% effective concentration (EC(50)) as low as 6.4 MUg/ml and low cytotoxicity at a 50% cytotoxic concentration (CC(50)) as high as 1000 MUg/ml, indicating that the dendrimer gave the enhancement of the functionality of oligosaccharides with low molecular weights. The glycodendrimer with a hydrophobic stearyl chain is immobilized on hydrophobic surfaces by hydrophobic interaction and is expected to provide a new biomedical material with the surface functionality of hydrophilic sulfated oligosaccharides. PMID- 22840041 TI - Carboxymethyl chitin/organic rectorite composites based nanofibrous mats and their cell compatibility. AB - In this study, carboxymethyl chitin (CMC) - organic rectorite (OREC)/poly (vinyl alcohol) (PVA) composite nanofibrous mats were successfully prepared via electrospinning. SAXRD pattern showed that the interlayer distance of OREC was increased from 3.68 to 4.08nm, which verified that polymer chains were intercalated into the interlayer of OREC. Field emission scanning electron microscopy, Fourier transform infrared spectra and energy-dispersive X-ray spectroscopy were used to characterize the morphology and microcosmic structure of nanofibrous mats. Thermal properties of mats were determined by differential scanning calorimetry. To evaluate the cell compatibility of mats, mouse lung fibroblast (L929) was chosen for cell attachment and spreading assay. The results shows that nanofibrous mats contained OREC have better thermal properties. Besides, the addition of OREC has little effect on the cell compatibility of nanofibrous mats. PMID- 22840042 TI - Cellulose nanowhiskers extracted from TEMPO-oxidized jute fibers. AB - Cellulose nanowhiskers is a kind of renewable and biocompatible nanomaterials evoke much interest because of its versatility in various applications. Here, for the first time, a novel controllable fabrication of cellulose nanowhiskers from jute fibers with a high yield (over 80%) via a 2,2,6,6-tetramethylpiperidine-1 oxyl radical (TEMPO)/NaBr/NaClO system selective oxidization combined with mechanical homogenization is reported. The versatile jute cellulose nanowhiskers with ultrathin diameters (3-10 nm) and high crystallinity (69.72%), contains C6 carboxylate groups converted from C6 primary hydroxyls, which would be particularly useful for applications in the nanocomposites as reinforcing phase, as well as in tissue engineering, pharmaceutical and optical industries as additives. PMID- 22840043 TI - Properties of cellulose/pectins composites: implication for structural and mechanical properties of cell wall. AB - The primary cell wall of dicotyledonous plants can be considered as a concentrated polymer assembly, containing in particular polysaccharides among which cellulose and pectins are known to be the major components. In order to understand and control the textural quality of plant-derived foods, it is highly important to elucidate the rheological and microstructural properties of these components, individually and in mixture, in order to define their implication for structural and mechanical properties of primary plant cell wall. In this study, the rheological and microstructural properties of model systems composed of sugar beet microfibrillated cellulose and HM pectins from various sources, with varied degrees of methylation and containing different amounts of neutral sugar side chains, were investigated. The influence of the presence of calcium and/or sodium ions and the biopolymer concentrations on the properties of the mixed systems were also studied. The characterizations of the mixed system, considered as a simplified model of primary plant cell wall, showed that whatever the structural characteristics of the pectins, the ionic conditions of the medium and the biopolymer concentrations, the gelation of the composite was mainly controlled by cellulose. Thus, the cellulose network would be the principal component governing the mechanical properties of the cell walls. However, the neutral sugar side chains of the pectins seem to play a part in the interactions with cellulose, as shown by the interesting viscoelastic properties of cellulose/apple HM pectins systems. The rigidity of cellulose/pectins composite was strongly influenced by the structural characteristics of pectins. The particular properties of primary plant cell walls would thus result from the solid viscoelastic properties of cellulose, its interactions with pectins according to their structural characteristics (implication of the neutral sugar side chains and the specific potential calcic interactions) and of the distribution of the components in separate phases. PMID- 22840044 TI - Chain length distribution and aggregation of branched (1->3)-beta-D-glucans from Saccharomyces cerevisae. AB - Water-soluble (1->3)-beta-D-glucans with 1,6-linked branches (SBG), originally isolated from the cell walls of Saccharomyces cerevisiae and partially depolymerised for optimal performance in wound healing applications, were studied by size exclusion chromatography (SEC) with multi-angle laser light scattering (MALLS) detector and a viscosity detector at both high and ambient column temperatures. The strongly aggregating materials could be dispersed as single chains in water following partial carboxymethylation (degree of substitution (DS) 0.51 or higher). Lower DS (0.23) also dispersed as single chains provided a column temperature of 80 degrees C was applied. Reduction of reducing ends prior to carboxymethylation was required to avoid alkaline peeling and hence to obtain correct molecular weight distributions of the native material. DS was determined using (13)C NMR and potentiometric titration (range 0.23-0.91). Further analysis of CM-SBG in the single chain state suggested a randomly coiled behaviour with marginal influence of the branches in terms of macromolecular dimensions, which were close to those of CM-curdlan. The result of the investigation is a simple and reliable protocol for preparing undegraded and un-aggregated SBG derivatives, which are well suited as a standard analysis of the molecular weight distribution of SBG-like molecules. PMID- 22840045 TI - Application of a novel plasma-induced CD/MWCNT/iron oxide composite in zinc decontamination. AB - Herein, beta-cyclodextrin (beta-CD) was grafted onto magnetic MWCNT/iron oxide particles by using low temperature plasma-induced technique to synthesize a novel nanocomposite. The prepared composite (denoted as CD/MWCNT/iron oxide) exhibited high magnetic property (saturation magnetization M(s)=37.8 emu/g) and good dispersion property in aqueous solution. Batch experiments were conducted to evaluate the application potential of CD/MWCNT/iron oxide in the decontamination of Zn(II) from aqueous solutions. The sorption amount of Zn(II) on CD/MWCNT/iron oxide was higher than that of Zn(II) on MWCNT/iron oxides and oxidized MWCNTs, indicating that the grafted beta-CD could enhance the sorption capacity of CD/MWCNT/iron oxide composite toward Zn(II) by providing multiple hydroxyl functional groups. Due to its high magnetic, CD/MWCNT/iron oxide could be easily separated from aqueous solution with an external magnetic field. Regeneration studies suggested that CD/MWCNT/iron oxide can support long term use as a cost effective material in sewage treatment with minimum replacement costs. PMID- 22840048 TI - Synthesis and thermal characterization of xylan-graft-polyacrylonitrile. AB - In this study emulsion polymerization of acrylonitrile using xylan from agricultural waste material (corn cob) and cerium ammonium nitrate was investigated in terms of catalyst acid. Stock ceric solutions were prepared using either nitric or perchloric acid as catalyst. Optimum conditions were determined using different parameters such as reaction time, temperature, and component concentrations. Nitric acid catalyzed reactions resulted in maximum conversion ratio (96%) at 50 degrees C, 1 h where ceric ion, acrylonitrile, xylan, and catalyst concentrations were 21.7 mmol l(-1), 0.5 mol l(-1), 0.2% (w/v), and 0.1 mol l(-1), respectively. However, 83% conversion was obtained with perchloric acid catalysis at 27 degrees C, 1 h where concentrations were 5.4 mmol l(-1), 0.8 mol l(-1), 0.5% (w/v), and 0.2 mol l(-1), respectively. Copolymer synthesis using perchloric acid was realized at milder conditions than using nitric acid. Thermal analyses of obtained polymers were conducted to characterize copolymers. Results showed that calculated activation energy, maximum degradation temperature, and heat of thermal decomposition changed relying mainly on molecular weight. PMID- 22840046 TI - Xylitol production from corncob hydrolysate using polyurethane foam with immobilized Candida tropicalis. AB - Polyurethane foam (PUF) was used as a carrier for Candida tropicalis (C. tropicalis) in the multi-batches fermentation of xylitol from xylose-containing corncob hemicellulose hydrolysate. After washing and sterilization, PUF (density of 320 kgm(-3), specific surface area of 1.5-2.0 * 10(5) m(2) m(-3), average porosity of 95%, pore diameter of 0.03 mm and cubic length of 5mm) was mixed with the culture medium at appropriate proportion followed by the inoculation. The fermentation parameters such as initial cell concentration, PUF dosage, pH value and temperature were controlled to study the effects on xylitol fermentation. In the 21-day durability tests, the optimal xylitol yield and volumetric productivity reached to 71.2% and 2.10 gL(-1)h(-1) respectively. Moreover, the average xylitol yield and volumetric productivity were 66.3% and 1.90 gL(-1)h(-1) for ten batchwise operations. The current research demonstrated that the PUF immobilization could serve as an efficient method for improving the cells vitality and enzyme reactivity in the continuous operation of fermentation. PMID- 22840050 TI - Photocrosslinkable gellan gum film as an anti-adhesion barrier. AB - The purpose of this study was to develop a gellan gum-based film which could be photocrosslinked for medical applications. Gellan gum was grafted with cinnamate to yield the photo crosslinkable polymer (gellan gum-cin). This material had 14.7% of its D-galacturonic residues reacted with cinnamate groups and displayed maximum absorption at 254 nm. Investigation of the photochemical properties showed that the crosslinking efficiency was 82% after 16 min of UV irradiation. The anti-adhesion films prepared from gellan gum-cin polymers exhibited high gel contents (88 +/- 2%) and suitable mechanical properties. When implanted into rats, the gellan gum-cin film exhibited the most promising anti-adhesion potential in 2 out of 10 rats without forming any tissue adhesion. Furthermore, the gellan gum-cin film could effectively inhibit inflammation in rats based on the results of fluid leukocyte analyses. The gellan gum-cin film thus has potential in clinical applications. PMID- 22840049 TI - Extraction, purification and antitumor activity of a water-soluble polysaccharide from the roots of Polygala tenuifolia. AB - One polysaccharide PTP was isolated and purified from the roots of Polygala tenuifolia. It consisted of galactose, glucose and galactose in the ratio of 3.1:3.7:2.5, and a small amount of rhamnose, mannose and xylose. 17 general amino acids were identified to be components of the protein-bound polysaccharide analyzed by automatic amino acid analyzer. In order to test the anti-cancer activity of PTP, we investigated its effect against the growth of human ovarian cancer cells SKOV3 in vitro and in ovarian cancer rats. The intracellular reactive oxygen species (ROS) and glutathione (GSH) in SKOV3 cells following PTP treatment were also quantified to explore the possible mechanism underlying the antitumor activity of the polysaccharide. The result showed that PTP is effective on inhibiting the proliferation of SKOV3 cells in a concentration-dependent manner. Furthermore, treatment with PTP caused a rapid depletion of intracellular GSH content and accumulation of intracellular ROS, thus resulting in the apoptosis, which may prove to be a pivotal mechanism for its cancer protection action. In addition, a significant tumor growth inhibition effect was observed in nude mice after PTP administration for 7 weeks. All above indicated PTP could be beneficial towards ovarian cancer therapy. PMID- 22840047 TI - A polysaccharide from Sargassum fusiforme protects against immunosuppression in cyclophosphamide-treated mice. AB - A water-soluble polysaccharide (SFPS) isolated from Sargassum fusiforme was purified by DEAE-52 cellulose anion-exchange and Sephadex G-200 gel filtration chromatography. The high performance gel permeation chromatography (HPGPC) analysis showed that the average molecular weight (Mw) of SFPS was 299 kDa. The SFPS was composed of D-fucose, L-xylose, D-mannose and D-galactose in a molar ratio of 5.9:1.0:2.3:2.2. The results showed that SFPS stimulated proliferation and the cytokines (IL-2, IL-6 and IFN-gamma) secretion of splenic lymphocytes in cyclophosphamide-induced immunosuppressed mice. SFPS markedly increased the phagocytic rates and cytokines (IL-2, IL-6 and TNF-alpha) secretion of peritoneal macrophages. Administration of SFPS significantly raised spleen index. It could act as an efficacious adjacent immunopotentiating therapy or an alternative means in lessening chemotherapy-induced immunosuppression, and also can be utilized as immunostimulants for food and pharmaceutical industries. PMID- 22840053 TI - Synthesis of diethylaminoethyl dextran hydrogel and its heavy metal ion adsorption characteristics. AB - Epichlorohydrin-crosslinked diethylaminoethyl dextran (DEAE-D/ECH) hydrogel was synthesized by intermolecular side-chain reaction of DEAE-D hydroxyl groups with monomeric crosslinking agent, ECH. Swelling ability, adsorption capacity and metal removal of the hydrogel were profoundly determined and some structural parameters for the hydrogel such as volume of non-swollen gel, percentages of gellation, swelling ratio and equilibrium water content were evaluated in this study. The ability of removing heavy metal ions from Orontes River by the synthesized hydrogel, thoroughly characterized by photometric spectrometer and the adsorption characteristics of metal ions, was investigated as well as surface morphologies of the hydrogel before and after metal adsorption were examined by SEM. Structure of DEAE-D/ECH gel was analyzed by FTIR, TGA, and DSC. Gellation point of binary system reaction between DEAE-D and ECH was determined via monitoring viscosity changes during reaction. The order of affinity based on amount of metal ion uptake was found as follows: Zn(2+)>Mn(2+)>Pb(2+)>Cd(2+). PMID- 22840052 TI - Physical properties of emulsion-based hydroxypropyl methylcellulose films: effect of their microstructure. AB - The initial characteristics of emulsions and the rearrangement of the oil droplets in the film matrix during film drying, which defines its microstructure, has an important role in the physical properties of the emulsion-based films. The objective of this work was to study the effect of the microstructure (two droplet size distributions) and stability (with or without surfactant) of HPMC oil-in water emulsions over physical properties of HPMC emulsion-based edible films. HPMC was used to prepare sunflower oil-in-water emulsions containing 0.3 or 1.0% (w/w) of oil with or without SDS, as surfactant, using an ultrasonic homogenizer. Microstructure, rheological properties and stability of emulsions (creaming) were measured. In addition, microstructure, coalescence of oil droplets, surface free energy, optical and mechanical properties and water vapor transfer of HPMC films were evaluated. Image analysis did not show differences among droplet size distributions of emulsions prepared at different oil contents; however, by using SDS the droplet size distributions were shifted to lower values. Volume mean diameters were 3.79 and 3.77 MUm for emulsions containing 0.3 and 1.0% without surfactant, respectively, and 2.72 and 2.71 MUm for emulsions with SDS. Emulsions formulated with 1.0% of oil presented higher stability, with almost no change during 5 and 3 days of storage, for emulsions with and without SDS, respectively. Internal and surface microstructure of emulsion-based films was influenced by the degree of coalescence and creaming of the oil droplets. No effect of microstructure over the surface free energy of films was found. The incorporation of oil impaired the optical properties of films due to light scattering of light. Addition of oil and SDS decreased the stress at break of the emulsion-based films. The replace of HPMC by oil and SDS produce a lower "amount" of network structure in the films, leading to a weakening of their structure. The oil content and SDS addition had an effect over the microstructure and physical properties of HPMC-based emulsions which lead to different microstructures during film formation. The way that oil droplets were structured into the film had an enormous influence over the physical properties of HPMC films. PMID- 22840054 TI - Hyaluronan regulates PPARgamma and inflammatory responses in IL-1beta-stimulated human chondrosarcoma cells, a model for osteoarthritis. AB - The carbohydrate polymer, hyaluronan, is a major component of the extracellular matrix in animal tissues. Exogenous hyaluronan has been used to treat osteoarthritis (OA), a degenerative joint disease involving inflammatory changes. The underlying mechanisms of hyaluronan in OA are not fully understood. Pro inflammatory interleukin (IL)-1beta downregulates peroxisome proliferator activated receptor gamma (PPARgamma), and increases expression of matrix metalloproteinases (MMPs) which are responsible for the degeneration of articular cartilage. The effects of low- and high-molecular-weight hyaluronan (oligo-HA and HMW-HA) on the inflammatory genes were determined in human SW-1353 chondrosarcoma cells. HMW-HA antagonized the effects of IL-1beta by increasing PPARgamma and decreasing cyclooxygenase (COX)-2, MMP-1, and MMP-13 levels. It promoted Akt, but suppressed mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NFkappaB) signaling, indicating anti-inflammatory effects. In contrast, the cells had overall opposite responses to oligo-HA. In conclusion, HMW-HA and oligo HA exerted differential inflammatory responses via PPARgamma in IL-1beta-treated chondrosarcoma cells. PMID- 22840056 TI - A short synthesis of highly soluble chemoselective chitosan derivatives via "click chemistry". AB - A short synthesis of chemoselective chitosan derivatives was achieved by copper catalyzed Huisgen cycloaddition, which is an ideal reaction for click chemistry, by using N-(4-azidophthaloyl)-chitosan. N-(4-azidophthaloyl)-chitosan was prepared through chemoselective N-bromophthaloylation of chitosan in acidic water and subsequent azidation. The obtained N-(4-bromopthaloyl)-chitosan had higher solubility in common solvents than conventional phthaloyl chitosan. N-(4 azidophthaloyl)-chitosan was successfully converted with ethynyl derivatives having functional groups (hydroxymethyl, phenyl, and methyl ester) in the presence of copper(II) sulfate, sodium ascorbate and/or trimethylamine. FT-IR spectra, elemental analyses, and (1)H and (13)C NMR spectra supported that the desired chitosan derivatives were chemoselectively transferred by these groups with a 1,4-triazole linker. PMID- 22840051 TI - Viscoelastic properties and antimicrobial activity of cellulose fiber sheets impregnated with Ag nanoparticles. AB - A silver nanoparticle colloid was prepared by a modified Tollens method using d glucose as the reduction agent. The obtained nanoparticles were used for the modification of pine, linter and recycled cellulose fibers. Although the silver contents were relatively low (0.05-0.13 wt.%), the cellulose-sheets prepared from the modified fibers show improved mechanical and viscoelastic properties. The tensile index (strength) increased with up to 30% in comparison to the index of the sheets obtained from the untreated fibers. The influence of the nanoparticles on the viscoelastic properties of the cellulose sheets was investigated by dynamic mechanical analysis (DMA) in the temperature range from -120 to 20 degrees C and with a force frequency of 100 Hz. A broad relaxation transition positioned at -80 degrees C was observed in the loss modulus spectrum of all the cellulose sheets, while the Ag-modified sheets exhibited higher storage moduli values in the whole temperature range. The antimicrobial activity tests show that the pine, silver and recycled cellulose fiber sheets with silver nanoparticles can be successfully employed to prevent the viability and growth of the common pathogens Staphylococcus aureus, Escherichia coli and Candida albicans. PMID- 22840057 TI - Expression patterns of chitinase produced from Paenibacillus chitinolyticus with different two culture media. AB - To investigate the expression patterns of chitinase isozymes on native-PAGE and SDS-PAGE gels Paenibacillus chitinolyticus MP-306 was cultured on culture media with and without chitin substrate. P. chitinolyticus MP-306 had a strong chitinolytic activity on colloidal chitin medium. Chitinase isozymes of MP-306 were expressed as six bands (CN1-CN6) on native-PAGE gels and thirteen bands (CS1 CS13) on SDS-PAGE gels after incubation in chitin medium. Three bands (CN1, CN2, and CN3) of chitinase isozymes of MP-306 on native-PAGE gels were expressed as nine bands (CS1, CS2, CS3, CS4, CS5, CS6, CS8, CS10, and CS13) of chitinase isozymes on SDS-PAGE gels. Three bands (CN4, CN5, and CN6) of chitinase isozymes of MP-306 were strongly inhibited by metal ions on native-PAGE and SDS-PAGE gels. PMID- 22840055 TI - Carboxyalkylation of chitosan in the gel state. AB - This study presents a new approach for direct carboxyalkylation of chitosan in the gel state by using aza-Michael addition and substitution reactions. Various reagents were applied including acrylic and crotonic acids, and alpha-, beta-, gamma-, delta-, and E-halocarboxylic acids. The reaction of chitosan with gamma- and delta-halocarboxylic acids showed no target product formation either in solution or in the gel state. In the case of acrylic, crotonic, alpha- and beta halocarboxylic acids, the reaction performed in the gel state (concentration of chitosan 20-40%) shows higher degree of substitution at lower reaction time and temperature than in diluted solutions (concentration of chitosan 0.5-2%). The results were discussed in terms of kinetics of the target and side reactions. (1)H and (13)C NMR confirmed that in all cases the carboxyalkylation of chitosan proceeds exclusively at the amino groups. PMID- 22840058 TI - Preparation of the beta-cyclodextrin-vitamin C (beta-CD-Vc) inclusion complex under high hydrostatic pressure (HHP). AB - In this study, a novel high hydrostatic pressure (HHP) technique was used to prepare the beta-cyclodextrin-vitamin C (beta-CD-Vc) inclusion complex. The inclusion ratio was positively correlated with the pressure under 300 MPa and remained at above 50.0% when the pressure was more than 300 MPa. Fourier transform infrared spectroscopy (FI-IR) and UV-visible spectroscopy (UV-vis) analysis showed that characteristic absorption bands and the absorption peak of Vc disappeared in the spectra of the beta-CD-Vc inclusion complex. Furthermore, differential scanning calorimetry (DSC) data revealed that only one endothermic peak appeared at about 138 degrees C in the DSC curve of the beta-CD-Vc inclusion complex. These results indicate that the HHP treatment effectively induces the formation of beta-CD-Vc inclusion complex. PMID- 22840059 TI - A case report: Giant cystic parathyroid adenoma presenting with parathyroid crisis after Vitamin D replacement. AB - BACKGROUND: Parathyroid adenoma with cystic degeneration is a rare cause of primary hyperparathyroidism. The clinical and biochemical presentation may mimic parathyroid carcinoma. CASE PRESENTATION: We report the case of a 55 year old lady, who had longstanding history of depression and acid peptic disease. Serum calcium eight months prior to presentation was slightly high, but she was never worked up. She was found to be Vitamin D deficient while being investigated for generalized body aches. A month after she was replaced with Vitamin D, she presented to us with parathyroid crisis. Her corrected serum calcium was 23.0 mg/dL. She had severe gastrointestinal symptoms and acute kidney injury. She had unexplained consistent hypokalemia until surgery. Neck ultrasound and CT scan revealed giant parathyroid cyst extending into the mediastinum. After initial medical management for parathyroid crisis, parathyroid cystic adenoma was surgically excised. Her serum calcium, intact parathyroid hormone, creatinine and potassium levels normalized after surgery. CONCLUSION: This case of parathyroid crisis, with very high serum calcium and parathyroid hormone levels, is a rare presentation of parathyroid adenoma with cystic degeneration. This case also highlights that Vitamin D replacement may unmask subclinical hyperparathyroidism. Consistent hypokalemia until surgery merits research into its association with hypercalcemia. PMID- 22840182 TI - Live-cell, temporal gene expression analysis of osteogenic differentiation in adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) are a widely investigated type of mesenchymal stem cell with great potential for musculoskeletal regeneration. However, use of ASCs is complicated by their cellular heterogeneity, which exists at both the population and single-cell levels. This study demonstrates a live-cell assay to investigate gene expression in ASCs undergoing osteogenesis using fluorescently tagged DNA hybridization probes called molecular beacons. Three molecular beacons were designed to target mRNA sequences for alkaline phosphatase, type I collagen, and osteocalcin (ALPL, COL1A1, and BGLAP), genes characteristically expressed during osteogenesis. The percentage of cells expressing these genes in a population was monitored daily to quantify the uniformity of the differentiation process. Differentiating ASC populations were repeatedly measured in a nondestructive fashion over a 21-day period to obtain temporal gene expression data. Results showed consistent expression patterns for the investigated osteogenic genes in response to induction medium. Peak expression was observed at days 3-4 for ALPL, day 14 for COL1A1, and day 21 for BGLAP. Additionally, the differentiation response of sample populations became more uniform after 2 weeks in osteogenic induction medium, suggesting a syncing of ASCs occurs over time. These findings are consistent with previous studies of osteogenic differentiation and suggest that molecular beacons are a viable means to monitor the spatiotemporal gene expression of live, differentiating ASCs. PMID- 22840183 TI - Hepatitis E virus in pork food chain, United Kingdom, 2009-2010. AB - We investigated contamination by hepatitis E virus (HEV) in the pork production chain in the United Kingdom. We detected HEV in pig liver samples in a slaughterhouse, in surface samples from a processing plant, and in pork sausages and surface samples at point of sale. Our findings provide evidence for possible foodborne transmission of HEV during pork production. PMID- 22840184 TI - Zinc finger arrays binding human papillomavirus types 16 and 18 genomic DNA: precursors of gene-therapeutics for in-situ reversal of associated cervical neoplasia. AB - BACKGROUND: Human papillomavirus (HPV) types 16 and 18 are the high-risk, sexually transmitted infectious causes of most cervical intraepithelial neoplasias (CIN) or cancers. While efficacious vaccines to reduce the sexual acquisition of these high-risk HPVs have recently been introduced, no virus targeted therapies exist for those already exposed and infected. Considering the oncogenic role of the transforming (E6 and E7) genes of high-risk HPVs in the slow pathogenesis of cervical cancer, we hypothesize that timely disruption or abolition of HPV genome expression within pre-cancerous lesions identified at screening may reverse neoplasia. We aimed to derive model zinc finger nucleases (ZFNs) for mutagenesis of the genomes of two high-risk HPV (types 16 & 18). METHODS AND RESULTS: Using ZiFiT software and the complete genomes of HPV types16 and 18, we computationally generated the consensus amino acid sequences of the DNA-binding domains (F1, F2, & F3) of (i) 296 & 327 contextually unpaired (or single) three zinc-finger arrays (sZFAs) and (ii) 9 & 13 contextually paired (left and right) three- zinc-finger arrays (pZFAs) that bind genomic DNA of HPV types 16 and 18 respectively, inclusive of the E7 gene (s/pZFAHpV/E7). In the absence of contextually paired three-zinc-finger arrays (pZFAs) that bind DNA corresponding to the genomic context of the E6 gene of either HPV type, we derived the DNA binding domains of another set of 9 & 14 contextually unpaired E6 gene-binding ZFAs (sZFAE6) to aid the future quest for paired ZFAs to target E6 gene sequences in both HPV types studied (pZFAE6). This paper presents models for (i) synthesis of hybrid ZFNs that cleave within the genomic DNA of either HPV type, by linking the gene sequences of the DNA-cleavage domain of the FokI endonuclease FN to the gene sequences of a member of the paired-HPV-binding ZFAs (pZFAHpV/E7 + FN), and (ii) delivery of the same into precancerous lesions using HPV-derived viral plasmids or vectors. CONCLUSIONS: With further optimization, these model ZFNs offer the opportunity to induce target-mutagenesis and gene therapeutic reversal of cervical neoplasia associated with HPV types 16 & 18. PMID- 22840185 TI - AwareCare: a pilot randomized controlled trial of an awareness-based staff training intervention to improve quality of life for residents with severe dementia in long-term care settings. AB - BACKGROUND: The extent to which care home residents with severe dementia show awareness is influenced by the extent to which the environment provides opportunities for engagement and by the way in which care staff interact with them. We aimed to establish whether training care staff to observe and identify signs of awareness in residents with severe dementia resulted in improved quality of life for residents. METHODS: In this pilot cluster randomized trial, care staff in four homes (n = 32) received training and supervision and carried out structured observations of residents using the AwareCare measure (n = 32) over an eight-week period, while staff in four control homes (n = 33) had no training with regard to their residents (n = 33) and no contact with the research team. The primary outcome was resident quality of life. Secondary outcomes were resident well-being, behavior and cognition, staff attitudes and well-being, and care practices in the home. RESULTS: Following intervention, residents in the intervention group had significantly better quality of life as rated by family members than those in the control group, but care staff ratings of quality of life did not differ. There were no other significant between-group differences. Staff participating in the intervention identified benefits in terms of their understanding of residents' needs. CONCLUSIONS: Staff were able to use the observational measure effectively and relatives of residents in the intervention homes perceived an improvement in their quality of life. PMID- 22840186 TI - Main extracts and hypolipidemic effects of the Bauhinia racemosa Lam. leaf extract in HFD-fed hamsters. AB - The lipid lowering effects of ethanolic extract (BR) obtained from leaves of Bauhinia racemosa on hyperlipidemic hamsters were examined. BR showed significant lowering of lipid profile at a dose of 250 mg kg(-1) body-wt of hamster. Chloroform fraction (F2) obtained from BR showed pronounced activity at lower dose of 100 mg kg(-1). F2 gave two most active fractions (L and T) whose chromatographic separations led to the isolation of constituents 1-5, which are being reported for the first time from this natural source. The results of activity profile of the plant were found to be better than the standard drug lovastatin. PMID- 22840187 TI - Prenatal management and perinatal outcome in giant placental chorioangioma complicated with hydrops fetalis, fetal anemia and maternal mirror syndrome. AB - BACKGROUND: Giant placental chorioangiomas have been associated with a number of severe fetal complications and high perinatal mortality. CASE PRESENTATION: We report a case of giant chorioangioma with fetal hydrops, additionally complicated by severe anemia, mild cardiomegaly with hyperdinamic heart circulation and maternal mirror syndrome. Intrauterine blood transfusion and amniodrainage was performed at 29 weeks. Worsening of the fetal and maternal condition prompted us to proceed with delivery at 29 + 5 weeks. The newborn died 3 hours later due to pulmonary hypoplasia and hemodynamic failure. Maternal course was favourable, mirror syndrome resolved in the second day and the patient was discharged four days following delivery. CONCLUSIONS: In the case described here, fetal condition got worse despite of the anemia correction and amniodrainage. Our outcome raises the issue whether additional intrauterine clinical intervention, as intersticial laser, should have been performed to stop further deterioration of the fetal condition when progressive severe hydrops develops. PMID- 22840188 TI - Entrepreneurship, resource management, organizational culture, and other "business" factors influencing pharmacy practice change. PMID- 22840189 TI - Gold(I)-catalyzed addition of thiols and thioacids to 3,3-disubstituted cyclopropenes. AB - Gold(I)-catalyzed reactions of thiols, thiophenols, and thioacids with 3,3 disubstituted cyclopropenes occur in a regioselective and chemoselective manner to produce either vinyl thioethers or primary allylic thioesters in good yields. A survey of commonly used gold(I) catalysts shows Echavarren's cationic gold(I) catalyst to be most tolerant of deactivation by sulfur. A novel digold with bridging thiolate complex is characterized by X-ray crystallography, shedding light on a possible deactivation pathway. PMID- 22840190 TI - Socioeconomic status and the prevalence of fever in children under age five: evidence from four sub-Saharan African countries. AB - BACKGROUND: The burden of fevers remains enormous in sub-Saharan Africa. While several efforts at reducing the burden of fevers have been made at the macro level, the relationship between socioeconomic status and fever prevalence has been inconclusive at the household and individual levels. The purpose of this study was to examine how individual and household socioeconomic status influences the prevalence of fever among children under age five in four sub-Saharan African countries. METHODS: The study used data from the 2008 Demographic and Health Survey (DHS) from Ghana, Nigeria, Kenya and Sierra Leone with a total of 38,990 children below age five. A multi-level random effects logistic model was fitted to examine the socioeconomic factors that influence the prevalence of fever in the two weeks preceding the survey. Data from the four countries were also combined to estimate this relationship, after country-specific analysis. RESULTS: The results show that children from wealthier households reported lower prevalence of fever in Ghana, Nigeria and Kenya. Result from the combined dataset shows that children from wealthier households were less likely to report fever. In general, vaccination against fever-related diseases and the use of improved toilet facility reduces fever prevalence. The use of bed nets by children and mothers did not show consistent relationship across the countries. CONCLUSION: Poverty does not only influence prevalence of fever at the macro level as shown in other studies but also the individual and household levels. Policies directed towards preventing childhood fevers should take a close account of issues of poverty alleviation. There is also the need to ensure that prevention and treatment mechanisms directed towards fever related diseases (such as malaria, pneumonia, measles, diarrhoea, polio, tuberculosis etc.) are accessible and effectively used. PMID- 22840191 TI - Paragonimus kellicotti flukes in Missouri, USA. AB - Paragonimiasis is an infection caused by lung flukes of the genus Paragonimus. In Asia, P. westermani infections are relatively common because of dietary practices. However, in North America, cases of paragonimiasis, which are caused by P. kellicotti flukes, are rare. Only 7 autochthonous cases of paragonimiasis were reported during 1968-2008. In 2009, we reported 3 new case-patients with paragonimiasis who had been seen at our medical center over an 18-month period. Six additional case-patients were identified in St. Louis, Missouri, USA, and treated at Washington University-affiliated health centers in 2009-2010. We report detailed descriptions of these case-patients, which includes unusual clinical manifestations. We also describe public health interventions that were undertaken to inform the general public and physicians about the disease and its mode of transmission. PMID- 22840192 TI - Molecular typing and epidemiological investigation of clinical populations of Pseudomonas aeruginosa using an oligonucleotide-microarray. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen which has the potential to become extremely harmful in the nosocomial environment, especially for cystic fibrosis (CF) patients, who are easily affected by chronic lung infections. For epidemiological purposes, discriminating P.aeruginosa isolates is a critical step, to define distribution of clones among hospital departments, to predict occurring microevolution events and to correlate clones to their source. A collection of 182 P. aeruginosa clinical strains isolated within Italian hospitals from patients with chronic infections, i.e. cystic fibrosis (CF) patients, and with acute infections were genotyped. Molecular typing was performed with the ArrayTube (AT) multimarker microarray (Alere Technologies GmbH, Jena, Germany), a cost-effective, time-saving and standardized method, which addresses genes from both the core and accessory P.aeruginosa genome. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were employed as reference genotyping techniques to estimate the ArrayTube resolution power. RESULTS: 41 AT-genotypes were identified within our collection, among which 14 were novel and 27 had been previously described in publicly available AT-databases. Almost 30% of the genotypes belonged to a main cluster of clones. 4B9A, EC2A, 3C2A were mostly associated to CF-patients whereas F469, 2C1A, 6C22 to non CF. An investigation on co-infections events revealed that almost 40% of CF patients were colonized by more than one genotype, whereas less than 4% were observed in non CF patients. The presence of the exoU gene correlated with non-CF patients within the intensive care unit (ICU) whereas the pKLC102-like island appeared to be prevalent in the CF centre. The congruence between the ArrayTube typing and PFGE or MLST was 0.077 and 0.559 (Adjusted Rand coefficient), respectively.AT typing of this Italian collection could be easily integrated with the global P. aeruginosa AT-typed population, uncovering that most AT-genotypes identified (> 80%) belonged to two large clonal clusters, and included 12 among the most abundant clones of the global population. CONCLUSIONS: The ArrayTube (AT) multimarker array represented a robust and portable alternative to reference techniques for performing P. aeruginosa molecular typing, and allowed us to draw conclusions especially suitable for epidemiologists on an Italian clinical collection from chronic and acute infections. PMID- 22840193 TI - Teaching methods in Hawler College of Medicine in Iraq: a qualitative assessment from teachers' perspectives. AB - BACKGROUND: Medical education in Iraq is poorly assessed and there is a general lack of documented knowledge about the challenges facing this field and the needs for its development. This study aimed to assess the existing teaching methods in the Hawler College of Medicine, Iraq from teaching staff perspectives and assess the knowledge of the teaching staff about student-centred learning. METHODS: A qualitative study based on a self-administered questionnaire survey of a purposive sample of 83 teaching staff in Hawler Medical University was conducted. The questionnaire addressed the participants' view on the positive aspects and problems of the current teaching methods and priorities to change it. The qualitative data analysis comprised thematic analysis. RESULTS: The study revealed significant problems facing the existing teaching methods including having large number of students in the lecture hall (45.0 %), having focus on teacher-centred teaching (45.0 %) and lack of infrastructures and facilities suitable for proper teaching (26.7 %). The priorities for improving the quality of teaching methods included adoption of small group teaching strategy in all study years (34.6 %), improving the infrastructure and facilities for teaching in the college (34.6 %) and provision of continuous academic development programs for the teaching staff (24.3 %). CONCLUSIONS: The existing medical education system face significant problems and it needs important and comprehensive improvements in different areas. There is a need for further research in this field to explore the identified problems in a more in-depth manner in order to better understand of the problems and needs of this important area of education. PMID- 22840194 TI - CoMFA QSAR models of camptothecin analogues based on the distinctive SAR features of combined ABC, CD and E ring substitutions. AB - Quantitative Structure-Activity Relationship (QSAR) paradigm has proved to be useful in understanding the requirements of physicochemical properties of the molecular substituents in many key locations as well as molecules as a whole. The knowledge of Structure-Activity Relationship (SAR), together with the generation of QSAR, constitutes a large body of evidence that may assist in the development of new molecules with excellent biological activity and low toxicity. The camptothecin (CPT) analogues are emerging as a promising group of chemotherapeutic agents. The SAR of these molecules provide insight into the mechanism of topoisomerase I inhibition and help in the synthesis of various CPT analogues by modifying the different rings of the original CPT molecule, giving each analogue a unique property. Here we have demonstrated the Comparative Molecular Force field Analysis (CoMFA) QSAR models for ABC-ring, CD-ring and E ring substitution of CPT in comparison with the traditional 2D-QSAR model. The 3D QSAR model gave convincing (standard deviation) r2 values of 0.99, 0.99 and 0.996 as against 2D-QSAR r2 values of 0.83, 0.97 and 0.90 for ABC-Ring, CD-Ring and E Ring analogues, respectively. In this model special emphasis was given to the contribution of steric and electrostatic force fields in predicting biological activity of CPT derivatives and they were found to improve the QSAR model and make it more precisely predictive. PMID- 22840195 TI - Reactive iron and its buffering capacity towards dissolved sulfide in sediments of Jiaozhou Bay, China. AB - Reactive iron (Fe) oxides in marine sediments play a critical role in removal of free sulfide. In this study, 0.5 and 6 N HCl-extractable Fe, acid volatile sulfide (AVS), and pyrite were examined in sediments at three sites of eutrophic Jiaozhou Bay to investigate the interactions of sulfur and Fe and possible influences of eutrophication on free sulfide removal. The results indicate that formation and accumulation of AVS and pyrite are limited by low availability of labile organic matter, despite eutrophication of the bay water. Quick buffering of free sulfide proceeded mainly via consumption of 0.5 N HCl-extractable Fe (labile Fe), however, the consumption did not result in a depletion of the Fe pool. High residual buffering capacity enables a quick removal of free sulfide in porewater, and thereby it is difficult for sulfide to accumulate and to cause detrimental effects on benthic organisms at the present steady state. Significant effects of eutrophication on Fe and sulfur geochemistry is restricted only to the estuarine sediments which were subject to direct wastewater discharges, whereas no such effects were observed in other sediments of the bay. PMID- 22840196 TI - Autochthonous infections with hepatitis E virus genotype 4, France. AB - During January-March 2011, diagnoses of hepatitis E virus (HEV) infection increased in Marseille University hospitals in southeastern France. HEV genotype 4, which is described almost exclusively in Asia, was recovered from 2 persons who ate uncooked pork liver sausage. Genetic sequences were 96.7% identical to those recently described in swine in Europe. PMID- 22840198 TI - The use of the Revised Trauma Score as an entry criterion in traumatic hemorrhagic shock studies: data from the DCLHb clinical trials. AB - INTRODUCTION: The Revised Trauma Score (RTS) has been proposed as an entry criterion to identify patients with mid-range survival probability for traumatic hemorrhagic shock studies. HYPOTHESIS/PROBLEM: Determination of which of four RTS strata (1-3.99, 2-4.99, 1-4.99, and 2-5.99) identifies patients with predicted and actual mortality rates near 50% for use as an entry criterion in traumatic hemorrhagic shock clinical trials. METHODS: Existing database analysis in which demographic and injury severity data from two prior international Diaspirin Cross Linked Hemoglobin (DCLHb) clinical trials were used to identify an RTS range that could be an optimal entry criterion in order to find the population of trauma patients with mid-range predicted and actual mortality rates. RESULTS: Of 208 study patients, the mean age was 37 years, 65% sustained blunt trauma, 49% received DCLHb, and 57% came from the European Union study arm. The mean values were: ISS, 31 (SD = 18); RTS, 5.6 (SD = 1.8); and Glasgow Coma Scale (GCS), 10.4 (SD = 4.8). The mean TRISS-predicted mortality was 34% and the actual 28-day mortality was 35%. The initially proposed 1-3.99 RTS range (n = 41) had the highest predicted (79%) and actual (71%) mortality rates. The 2-5.99 RTS range (n = 79) had a 62% predicted and 53% actual mortality, and included 76% blunt trauma patients. Removal of GCS <5 patients from this RTS 2-5.99 subgroup caused a 48% further reduction in eligible patients, leaving 41 patients (20% of 208 total patients), 66% of whom sustained a blunt trauma injury. This subgroup had 54% predicted and 49% actual mortality rates. Receiver operator curve (ROC) analysis found the GCS to be as predictive of mortality as the RTS, both in the total patient population and in the RTS 2-5.99 subgroup. CONCLUSION: The use of an RTS 2-5.99 inclusion criterion range identifies a traumatic hemorrhagic shock patient subgroup with predicted and actual mortality that approach the desired 50% rate. The exclusion of GCS <5 from this RTS 2-5.99 subgroup patients yields a smaller, more uniform patient subgroup whose mortality is more likely related to hemorrhagic shock than traumatic brain injury. Future studies should examine whether the RTS or other physiologic criteria such as the GCS score are most useful as traumatic hemorrhagic shock study entry criteria. PMID- 22840197 TI - Relating human genetic variation to variation in drug responses. AB - Although sequencing a single human genome was a monumental effort a decade ago, more than 1000 genomes have now been sequenced. The task ahead lies in transforming this information into personalized treatment strategies that are tailored to the unique genetics of each individual. One important aspect of personalized medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses. Additionally, we discuss the major challenges in translating this knowledge into a systems-level understanding of drug physiology, with the ultimate goal of developing more effective personalized clinical treatment strategies. PMID- 22840199 TI - Pelargonium graveolens L'Her. and Artemisia arborescens L. essential oils: chemical composition, antifungal activity against Rhizoctonia solani and insecticidal activity against Rhysopertha dominica. AB - The chemical composition of the Pelargonium graveolens essential oil allowed the identification of 15 compounds (93.86% of the total essential oil). The major fractions were citronellol (35%) and geraniol (28.8%). The chemical composition of the Artemisia arborescens essential oil revealed twenty-one compounds representing 93.57% of the total essential oil. The main compounds were chamazulene (31.9%) and camphor (25.8%). The insecticidal effects were tested towards the insect Rhysopertha dominica. Results revealed that these two essential oils were highly effective against R. dominica at the dose of 50 uL on Petri dish of 8.5 cm of diameter. The antifungal activity was evaluated against Rhizoctonia solani and results showed that both of the essential oils were highly active at a dose of 12.5 uL/20 mL of PDA. Moreover, the inhibitory effect of P. graveolens essential oil was evidenced as stronger than that of the A. arborescens oil for all the tested doses. PMID- 22840200 TI - The effects of torrefaction on compositions of bio-oil and syngas from biomass pyrolysis by microwave heating. AB - Microwave pyrolysis of torrefied Douglas fir sawdust pellet was investigated to determine the effects of torrefaction on the biofuel production. Compared to the pyrolysis of raw biomass, the increased concentrations of phenols and sugars and reduced concentrations of guaiacols and furans were obtained from pyrolysis of torrefied biomass, indicating that torrefaction as a pretreatment favored the phenols and sugars production. Additionally, about 3.21-7.50 area% hydrocarbons and the reduced concentration of organic acids were obtained from pyrolysis of torrefied biomass. Torrefaction also altered the compositions of syngas by reducing CO2 and increasing H2 and CH4. The syngas was rich in H2, CH4, and CO implying that the syngas quality was significantly improved by torrefaction process. PMID- 22840201 TI - Removal of off-flavors from sea tangle (Laminaria japonica) extract by fermentation with Aspergillus oryzae. AB - This study was conducted to reduce off-flavors from sea tangle (Laminaria japonica) extract since the typical odor of seaweed is an impediment to consumption of seaweed products. Fifty-six odor compounds emitted from the extract were identified using a thermal desorbor and gas chromatography-mass spectrometry. On the basis of expected odor intensity (EOI), isovaleric acid (41.2%), allyl isothiocyanate (22.6%), octanal (11.1%) and acetaldehyde (10.6%) were responsible for about 85.5% of total odor strength in the extract, suggesting that the odor of the extract might mainly be attributed to these compounds. The EOIs of odor compounds were dramatically reduced or disappeared during fermentation by Aspergillus oryzae. Total EOI of the odor compounds decreased about four-fold, compared with that of the raw extract (control) after the four days of fermentation at 30 degrees C with agitation at 120 rpm. These results indicate that microbial fermentation may be a good strategy to reduce off flavors of seaweeds. PMID- 22840203 TI - Evolution of rural-urban health gaps in Morocco: 1992-2011. AB - BACKGROUND: Moroccan authorities carry out regular surveys on population and family health (NSFFP 1980, NSPH 1992, SPFH 2004, NSPFH 2011). These surveys constitute valuable resources for monitoring socio-economic and health indicators. They provide an evidence base for health decision makers to help them to optimize health strategies in order to improve the health conditions of the whole population. They also provide updated measures on geographic disparities, socio-economic inequalities and health inequity. The most recent Moroccan population and family health survey (NSPFH 2011) was carried out between November 2010 and March 2011. The final report and the database are not yet accessible, but a preliminary report was released early March 2012. This report does not allow for a complete evaluation of the present health situation in Morocco. A partial equity analysis can, however, be devoted to the comparison of health indicators especially in terms of rural-urban gaps. RESULTS: The 2011 survey shows that Moroccan population is in the last phase of the demographic transition. The total fertility rate decreased from 5.6 children per woman in 1980 to 2.5 per woman in 2011. The mean age of first marriage increased from 24 years for men and 17.5 years for women in 1960 to 31.5 years and 26.3 years in 2011 for men and women, respectively. The age structure shows a trend of ageing population. A comparison with the 1992 NSPH indicates that adult illiteracy has decreased from 53% in 1992 to 37.6% in 2011.During the same time period, women's access to maternal care and health services improved significantly. For instance, the proportion of deliveries assisted by skilled health personnel increased from 31% in 1992 to 73.6% in 2011. Between 1992 and 2011, neonatal, postnatal, infant and under-five mortality rates were reduced by 44%, 65%, 54% and 64%, respectively. CONCLUSION: This paper shows that average health indicators improved noticeably during the last two decades but rural-urban disparities are still a challenge for health decision makers. Socio-economic indicators, like illiteracy rate and unemployment, also demonstrate large gender inequalities. This preliminary analysis is designed to assist Moroccan health authorities to evaluate the current health situation in order to adopt cost-effective strategies that improve "health for all" and reduce the gaps between advantaged and disadvantaged populations. PMID- 22840202 TI - Hepatitis E virus genotype 3 in wild rats, United States. AB - The role of rodents in the epidemiology of zoonotic hepatitis E virus (HEV) infection has been a subject of considerable debate. Seroprevalence studies suggest widespread HEV infection in commensal Rattus spp. rats, but experimental transmission has been largely unsuccessful and recovery of zoonotic genotype 3 HEV RNA from wild Rattus spp. rats has never been confirmed. We surveyed R. rattus and R. norvegicus rats from across the United States and several international populations by using a hemi-nested reverse transcription PCR approach. We isolated HEV RNA in liver tissues from 35 of 446 rats examined. All but 1 of these isolates was relegated to the zoonotic HEV genotype 3, and the remaining sequence represented the recently discovered rat genotype from the United States and Germany. HEV-positive rats were detected in urban and remote localities. Genetic analyses suggest all HEV genotype 3 isolates obtained from wild Rattus spp. rats were closely related. PMID- 22840204 TI - How appropriately is blood ordered in a rural hospital? AB - BACKGROUND: Blood products are a limited resource particularly in a rural setting and their appropriate use is important to maintain patient safety and minimise costs. OBJECTIVE: To assess the appropriateness of transfusion practices in a rural hospital. DESIGN/DATA SOURCES: A retrospective medical record audit of packed red blood cell (PRBC) use. SETTING: A rural hospital 300 km northwest of Melbourne. PARTICIPANTS: All patients in Wimmera Base Hospital who had a PRBC crossmatch request from October 2010 to March 2011 inclusive. MAIN OUTCOME MEASURES: Proportion of appropriate transfusions and crossmatch to transfusion ratios. RESULTS: A total of 257 patients and 657 PRBC units were cross-matched during the study period. Of these patients, 28.4% had pre-procedure (elective) cross-matches. Of the elective cross-matches, 27.4% were inappropriate, compared with 16.1% of emergency cross-matches. The cross-match to transfusion ratio (C:T) was 1.59 for emergency requests and 5.96 for elective requests. The C:T ratio was high in the surgical and obstetrics and gynaecology departments. 16.3% of all transfusions were single-unit transfusions. CONCLUSIONS: Emergency requests were predominantly appropriate but a significant proportion of elective requests were inappropriate, suggesting changes in elective crossmatch request protocols, and increased education regarding ordering blood in a rural setting. PMID- 22840205 TI - Risk factors for superficial digital flexor tendinopathy in Thoroughbred racehorses in steeplechase starts in the United Kingdom (2001-2009). AB - The objective of this study was to identify risk factors for superficial digital flexor (SDF) tendinopathy in Thoroughbred horses in steeplechase races in the United Kingdom. Potential risk factors for SDF tendinopathy were studied between 1st January 2001 and 31st December 2009 using a cohort study design with 648 injuries sustained in 102,894 starts. Potential risk factors were screened using univariable logistic regression prior to multivariable model building. In the final multivariable model, 12 statistically significant risk factors were identified. Variables that increased the odds of SDF tendinopathy included firmer going, increased horse age, and racing in the summer compared to other seasons. Variables that decreased the odds included having a higher official rating and the number of starts in the preceding days. Fewer and different risk factors were identified than in an equivalent model of SDF tendinopathy in hurdle racing, highlighting potential differences between these disciplines. Further collection of training and racecourse information would be beneficial and may help to explain further some of the associations identified in this study. The results will facilitate the development of strategies to improve overall safety of horses in UK steeplechase racing. PMID- 22840206 TI - A miniature lighted stylet for fast oral endotracheal intubation in rabbits. AB - Efficient oral endotracheal intubation of laboratory animals is a challenging technique in veterinary research. This study introduces a miniaturized lighted stylet for rabbit intubation. An experiment with repeated measures on two factors was used to assess the feasibility and efficacy of this method. The first factor compared stylet intubation vs. laryngoscopic intubation. The second compared three practitioners, one with prior experience and two without. Success rates on the initial attempt were not statistically different (chi(2)=2.46, P=0.12). The time difference between methods was significant (F=41.007, P<0.001), although the effect of practitioners was not (F=1.038, P=0.365). The mean+/-SD of the intubation time, combining results from the three practitioners, was 20.34+/ 17.15s for the stylet method and 57.58+/-64.21s for the laryngoscopic method. The results of this study demonstrate that lighted stylet intubation is efficient, robust, and independent of practitioner experience. PMID- 22840207 TI - Characterization of oral double balloon endoscopy in the dog. AB - Exploration of the canine small intestine using conventional endoscopy is restricted to the duodenum and/or the ileum. Double balloon endoscopy (DBE) is a 'push and pull' technique that has been described in humans and permits a complete exploration of the small intestine. In this study, oral DBE was performed on 12 healthy dogs (10-34kg) to characterize for the first time the efficiency, exploration dynamics and safety of the technique. DBE was successful in 83% of dogs; the average estimated insertion depth of the endoscope was 287+/ 36cm, and the average duration of the exploration was 84+/-8min. No complications or relevant adverse clinical effects were observed, and there was no indication of post-procedure pancreatitis based on serology of two specific markers of pancreatitis (amylase and lipase) and the immediate nonspecific inflammatory mediator C-reactive protein. The study showed that oral DBE is viable and safe in the dog, allowing for the diagnosis and treatment of gastrointestinal diseases deep in the small intestine to an extent that has not previously been possible using conventional endoscopy. PMID- 22840208 TI - Molecular and histological evidence of brown adipose tissue in adult cats. AB - Brown adipose tissue (BAT) can influence glucose, lipid, and energy metabolism in rodents. Active BAT is now known to be present in adult humans, and interventions targeting BAT are being investigated for the treatment of human obesity and disorders of glucose and lipid metabolism. Domestic cats, like humans, are at increasing risk for obesity and diabetes but little is known about the presence and role of BAT in adult cats. The purpose of this study was to determine if brown adipocytes, identifiable by histological features and molecular markers, were present in the fat depots of adult cats. Adipose tissue samples from intrascapular, perirenal, and subcutaneous depots of eleven 8-12 year old cats (6 lean, 5 obese), were analyzed by real-time PCR for brown adipocyte markers uncoupling protein 1 (UCP1) and Type II iodothyronine 5'deiodinase (D2), by histological examination and by immunohistochemistry for UCP1. UCP1 mRNA was detectable in interscapular and subcutaneous depots in all cats, and in the perirenal depot in 10/11 cats. D2 mRNA was detectable in all depots from all cats. Multilocular adipocytes were identified in the interscapular depots of 4/11 cats and these were positive for UCP1 immunoreactivity. The results demonstrate that UCP1-expressing brown adipocytes are present in multiple depots of adult lean and long-term obese cats, even at 8-12 years of age. It is possible that dietary components or pharmacological agents that influence brown fat activity could exert a relevant biological effect in cats. PMID- 22840209 TI - Potential predictive biomarkers of obesity in Burmese cats. AB - Australian Burmese cats are predisposed to diabetes mellitus and, compared to other breeds, have delayed triglyceride clearance that may result in subtle changes within cells and tissues that trigger specific alterations in gene expression within peripheral blood leucocytes (PBLs). Expression of genes involved in energy metabolism (glucose-6-phosphate dehydrogenase and malate dehydrogenase), lipogenesis (ATP citrate lyase [ACL], fatty acid synthase [FAS] and sterol regulatory binding protein-1c [SREBP-1c]), and insulin signalling (insulin receptor substrates 1 and 2, and phosphatidylinositol-3 kinase), as well as cholesterol lipoprotein subfraction profiling were carried out on PBLs from lean Burmese cats and compared with similar profiles of age and gender matched lean and obese Australian domestic shorthaired cats (DSHs) in an attempt to identify possible biomarkers for assessing obesity. For the majority of the genes examined, the lean Burmese cats demonstrated similar PBL gene expression patterns as age and gender matched obese Australian DSH cats. Lean Burmese had increased expression of ACL and FAS, but not SREBP-1c, a main upstream regulator of lipid synthesis, suggesting possible aberrations in lipogenesis. Moreover, lean Burmese displayed a 3- to 4-fold increase in the very low density cholesterol fraction percentage, which was double that for obese DSH cats, indicating an increased degree of lipid dysregulation especially in relation to triglycerides. The findings suggest that Burmese cats may have a particular propensity for dysregulation in lipid metabolism. PMID- 22840210 TI - Retrospective comparison of prednisolone and ursodeoxycholic acid for the treatment of feline lymphocytic cholangitis. AB - A retrospective study was performed to evaluate the effect of treatment with prednisolone or ursodeoxycholic acid (UDCA) on the survival times of 26 cats with lymphocytic cholangitis, and to determine prognostic factors. Most affected cats were males (76.9%, P=0.006) and a breed predisposition for the Norwegian Forest Cat was demonstrated (P=0.021). Clinical signs included weight loss, icterus, anorexia, vomiting, and listlessness. Blood analyses revealed elevated hepatic enzymes, bile acids and hypergammaglobulinaemia. Breed, sex, and therapeutic regimen were significantly associated with survival times. Prednisolone treatment resulted in a statistically longer survival time compared to UDCA. PMID- 22840211 TI - The validity of Iran's national university entrance examination (Konkoor) for predicting medical students' academic performance. AB - BACKGROUND: In Iran, admission to medical school is based solely on the results of the highly competitive, nationwide Konkoor examination. This paper examines the predictive validity of Konkoor scores, alone and in combination with high school grade point averages (hsGPAs), for the academic performance of public medical school students in Iran. METHODS: This study followed the cohort of 2003 matriculants at public medical schools in Iran from entrance through internship. The predictor variables were Konkoor total and subsection scores and hsGPAs. The outcome variables were (1) Comprehensive Basic Sciences Exam (CBSE) scores; (2) Comprehensive Pre-Internship Exam (CPIE) scores; and (3) medical school grade point averages (msGPAs) for the courses taken before internship. Pearson correlation and regression analyses were used to assess the relationships between the selection criteria and academic performance. RESULTS: There were 2126 matriculants (1374 women and 752 men) in 2003. Among the outcome variables, the CBSE had the strongest association with the Konkoor total score (r = 0.473), followed by msGPA (r = 0.339) and the CPIE (r = 0.326). While adding hsGPAs to the Konkoor total score almost doubled the power to predict msGPAs (R2 = 0.225), it did not have a substantial effect on CBSE or CPIE prediction. CONCLUSIONS: The Konkoor alone, and even in combination with hsGPA, is a relatively poor predictor of medical students' academic performance, and its predictive validity declines over the academic years of medical school. Care should be taken to develop comprehensive admissions criteria, covering both cognitive and non-cognitive factors, to identify the best applicants to become "good doctors" in the future. The findings of this study can be helpful for policy makers in the medical education field. PMID- 22840212 TI - A re-parameterisation of the Power Model of the relationship between the speed of traffic and the number of accidents and accident victims. AB - This paper presents a re-analysis of the Power Model of the relationship between the mean speed of traffic and road safety. Past evaluations of the model, most recently in 2009, have broadly speaking supported it. However, the most recent evaluation of the model indicated that the relationship between speed and road safety depends not only on the relative change in speed, as suggested by the Power Model, but also on initial speed. This implies that the exponent describing, for example, a 25% reduction in speed will not be the same when speed changes from 100km/h to 75km/h as it will when speed changes from 20km/h to 15km/h. This paper reports an analysis leading to a re-parameterisation of the Power Model in terms of continuously varying exponents which depend on initial speed. The re-parameterisation was accomplished by fitting exponential functions to data points in which changes in speed and accidents were sorted in groups of 10km/h according to initial speed, starting with data points referring to the highest initial speeds. The exponential functions fitted the data extremely well and imply that the effect on accidents of a given relative change in speed is largest when initial speed is highest. PMID- 22840213 TI - Road rage among drug dependent patients. AB - The consumption of alcohol, cocaine and cannabis is associated with aggressive behaviour, being a victim of injuries from various causes, and suffering traffic accidents. On the other hand, there is a significant association between road rage and traffic accidents, yet this has not been studied in persons suffering a substance dependence disorder. This study analyses the prevalence of road rage in substance dependent patients undergoing treatment. 100 patients randomly selected at an outpatient treatment centre were included in the study. 63% of the patients had experienced road rage in the year prior to the interview, and 18% were serious perpetrators. There was a higher frequency among drivers and those who were starting treatment for cocaine and cocaine+heroin. The study shows that road rage is very frequent among patients with disorders due to substance dependence who are undergoing treatment, in particular the most severe form ("serious perpetrators"). Special attention should be addressed to the issue of driving and road rage during the treatment of these patients. PMID- 22840214 TI - Putative novel genotype of avian hepatitis E virus, Hungary, 2010. AB - To explore the genetic diversity of avian hepatitis E virus strains, we characterized the near-complete genome of a strain detected in 2010 in Hungary, uncovering moderate genome sequence similarity with reference strains. Public health implications related to consumption of eggs or meat contaminated by avian hepatitis E virus, or to poultry handling, require thorough investigation. PMID- 22840215 TI - Spiritual well-being in patients with advanced heart and lung disease. AB - OBJECTIVE: The purpose of this study was to evaluate levels of spiritual well being over time in populations with advanced congestive heart failure (CHF) or chronic obstructive lung disease (COPD). METHOD: In a prospective, longitudinal study, patients with CHF or COPD (each n = 103) were interviewed at baseline and every 3 months for up to 30 months. At each interview, patients completed: the basic faith subscale of the Functional Assessment of Chronic Illness Therapy Spiritual Well-Being (FACIT-Sp) questionnaire, the Memorial Symptom Assessment Scale (MSAS), the Rand Mental Health Inventory (MHI), the Multidimensional Index of Life Quality (MILQ), the Sickness Impact Profile (SIP), and the Short Portable Mental Health Questionnaire (SPMSQ). RESULT: The mean age was 65 years, 59% were male, 78% were Caucasian, 50% were married, 29% lived alone, and there was no significant cognitive impairment. Baseline median FACIT-Sp score was 10.0 on a scale of 0-16. FACIT-Sp scores did not change over time and multivariate longitudinal analysis revealed higher scores for black patients and lower scores for those with more symptom distress on the MSAS-Global Distress Index (GDI) (both p = 0.02). On a separate multivariate longitudinal analysis, MILQ scores were positively associated with the FACIT-Sp and the MHI, and negatively associated with the MSAS-GDI and the SIP (all p-values < 0.001). SIGNIFICANCE OF RESULTS: In advanced CHF and COPD, spiritual well-being remains stable over time, it varies by race and symptom distress, and contributes to quality of life, in combination with symptom distress, mental health and physical functioning. PMID- 22840217 TI - Secoiridoids from the stem barks of Fraxinus rhynchophylla with pancreatic lipase inhibitory activity. AB - Pancreatic lipase digests dietary fats by hydrolysis, which is a key enzyme for lipid absorption. Therefore, reduction of fat absorption by the inhibition of pancreatic lipase is suggested to be a therapeutic strategy for obesity. From the EtOAc-soluble fraction of the stem barks of Fraxinus rhynchophylla (Oleaceae), four secoiridoids such as ligstroside (1), oleuropein (2), 2"-hydroxyoleuropein (3) and hydroxyframoside B (4) were isolated. The inhibitory activity of these compounds on pancreatic lipase was assessed using porcine pancreatic lipase as an in vitro assay system. Compound 4 showed the strongest inhibition on pancreatic lipase, which followed by compounds 1-3. In addition, compound 4 exerted inhibitory effect on pancreatic lipase in a mixed mechanism of competitive and noncompetitive manner. Taken together, F. rhynchophylla and its constituents might be beneficial to obesity. PMID- 22840216 TI - Hepatitis E virus strains in rabbits and evidence of a closely related strain in humans, France. AB - Hepatitis E virus (HEV) strains from rabbits indicate that these mammals may be a reservoir for HEVs that cause infection in humans. To determine HEV prevalence in rabbits and the strains' genetic characteristics, we tested bile, liver, and additional samples from farmed and wild rabbits in France. We detected HEV RNA in 7% (14/200) of bile samples from farmed rabbits (in 2009) and in 23% (47/205) of liver samples from wild rabbits (in 2007-2010). Full-length genomic sequences indicated that all rabbit strains belonged to the same clade (nucleotide sequences 72.2%-78.2% identical to HEV genotypes 1-4). Comparison with HEV sequences of human strains and reference sequences identified a human strain closely related to rabbit strain HEV. We found a 93-nt insertion in the X domain of open reading frame 1 of the human strain and all rabbit HEV strains. These findings indicate that the host range of HEV in Europe is expanding and that zoonotic transmission of HEV from rabbits is possible. PMID- 22840218 TI - Physicians reading and writing practices: a cross-sectional study from Civil Hospital, Karachi, Pakistan. AB - BACKGROUND: To determine the behavior of physicians regarding medical literature reading and participation in research activities at one of the largest teaching hospitals in Pakistan. METHOD: This descriptive, cross-sectional study was conducted by interviewing the house officers, residents and fellows of six major specialties (Medicine, Surgery, Pediatrics, Psychology, Obstetrics & Gynecology and Anesthesia) in Civil Hospital, Karachi between August and December, 2011. The questionnaire elicited responses regarding the reading habits of physicians, preferred sources of information, their participation in research activities (publication & supervision) and views regarding journal club. SPSS 17.0 was used for data entry and analysis. RESULT: A total of 259 completely filled questionnaires were returned with a response rate of 85.19%. Mean age of the participants was 29.67 +/- 7.65 years. Books were selected by 71.4% doctors as their preferred source of information, regardless of their clinical specialties. (p < 0.05). E-journals were preferred by 75.7% of the doctors over printed journals. This holds true for doctors from all specialties (p < 0.05). The ease of searching for relevant articles was the major contributor (50.5%) in preference of e-journals. 137 (52.9%) doctors read 5 or less articles per week. 30 (11.6%) doctors have subscription of journals (printed or electronic). At least one research paper has been published by 151 (58.3%) of the physicians interviewed. Most common reason for not participating in research activities was busy schedule (56.4%). Almost half (49.4%) doctors reported lack of journal club in their units. Of these, majority (88.35%) wanted a journal club in their respective units. CONCLUSION: Urgent intervention is required to promote healthcare literature reading and writing practice in our physicians. Easy access to workplace computers with internet and subscription of paid journals will facilitate physicians. Lack of supervisors and busy schedule were reported to be important contributors for not participating in research. Addressing these issues will encourage doctors to participate more in research activities. PMID- 22840219 TI - Improved survival of patients with coronary artery disease and low ejection fraction with ICD implantation versus conventional therapy in a real world survey. AB - BACKGROUND: Coronary artery disease (CAD) is associated with an increased risk for sudden cardiac death. Randomized controlled trials have shown that implantable cardioverter defibrillators (ICD) improve life expectancy unless they are implanted within the first days after an acute myocardial infarction and guidelines recommend their use. We aimed to validate that these results also apply to patients of a typical community hospital in Germany. METHODS: This was a retrospective analysis of patients undergoing coronary angiography in the Lippe Detmold Hospital between 2003 and 2006. They had to have significant CAD and an ejection fraction (EF) <= 35% and no acute myocardial infarction within 28 days of implantation and no history of ventricular fibrillation. RESULTS: 213 patients were included; 70 of which received an ICD. Patients with an ICD implantation were younger (64.8 +/- 9.9 vs. 67.9 +/- 9.8 years; p = 0.034), had single vessel CAD more frequently (22.9 vs. 11.2%; p = 0.025) and a lower EF (26.7 +/- 6.3 vs. 29.1 +/- 4.6%; p = 0.006). Hospital readmissions were comparable between the ICD and the control group (68.6 vs. 72.0%; p = 0.602). ICD therapy was associated with a considerable survival benefit compared to conventional therapy (HR 0.52; 95%CI 0.29-0.93; p = 0.027) in a Cox-Proportional Hazards Regression analysis. CONCLUSIONS: Appreciating the potential limitations of retrospective studies, we found that ICD use was associated with improved survival in patients with significant CAD and an EF <= 35% typical for a large tertiary hospital. PMID- 22840220 TI - Novel hepatitis E virus in ferrets, the Netherlands. PMID- 22840221 TI - Hepatitis E virus in pork production chain in Czech Republic, Italy, and Spain, 2010. AB - We evaluated the prevalence of hepatitis E virus (HEV) in the pork production chain in Czech Republic, Italy, and Spain during 2010. A total of 337 fecal, liver, and meat samples from animals at slaughterhouses were tested for HEV by real-time quantitative PCR. Overall, HEV was higher in Italy (53%) and Spain (39%) than in Czech Republic (7.5%). HEV was detected most frequently in feces in Italy (41%) and Spain (39%) and in liver (5%) and meat (2.5%) in Czech Republic. Of 313 sausages sampled at processing and point of sale, HEV was detected only in Spain (6%). HEV sequencing confirmed only g3 HEV strains. Indicator virus (porcine adenovirus) was ubiquitous in fecal samples and absent in liver samples and was detected in 1 slaughterhouse meat sample. At point of sale, we found porcine adenovirus in sausages (1%-2%). The possible dissemination of HEV and other fecal viruses through pork production demands containment measures. PMID- 22840222 TI - Microfabrication of proangiogenic cell-laden alginate-g-pyrrole hydrogels. AB - Cells have been extensively studied for their uses in various therapies because of their capacities to produce therapeutic proteins and recreate new tissues. It has often been suggested that the efficacy of cell therapies can greatly be improved through the ability to localize and regulate cellular activities at a transplantation site; however, the technologies for this control are lacking. Therefore, this study reports a cell-Laden hydrogel patch engineered to support the proliferation and angiogenic growth factor expression of cells adhered to their surfaces, and to further promote neovascularization. Hydrogels consisting of alginate chemically linked with pyrrole units, termed alginate-g-pyrrole, were prepared through an oxidative cross-linking reaction between pyrrole units. Fibroblasts adhered to the alginate-g-pyrrole hydrogels, and exhibited increased proliferation and overall vascular endothelial growth factor (VEGF) expression, compared to those on pyrrole-free hydrogels. Furthermore, the alginate-g-pyrrole hydrogel surfaces were modified to present microposts, subsequently increasing the amount of pyrrole units on their surfaces. Cells adhered to the microfabricated gel surfaces exhibited increased proliferation and overall VEGF expression proportional to the density of the microposts. The resulting micropatterned alginate-g-pyrrole hydrogels exhibited increases in the size and density of mature blood vessels when implanted on chick chorioallantoic membranes (CAMs). The hydrogel system developed in this study will be broadly useful for improving the efficacy of a wide array of cell-based wound healing and tissue regenerative therapies. PMID- 22840223 TI - Influence of polymer architecture on antigens camouflage, CD47 protection and complement mediated lysis of surface grafted red blood cells. AB - Hyperbranched polyglycerol (HPG) and polyethylene glycol (PEG) polymers with similar hydrodynamic sizes in solution were grafted to red blood cells (RBCs) to investigate the impact of polymer architecture on the cell structure and function. The hydrodynamic sizes of polymers were calculated from the diffusion coefficients measured by pulsed field gradient NMR. The hydration of the HPG and PEG was determined by differential scanning calorimetry analyses. RBCs grafted with linear PEG had different properties compared to the compact HPG grafted RBCs. HPG grafted RBCs showed much higher electrophoretic mobility values than PEG grafted RBCs at similar grafting concentrations and hydrodynamic sizes indicating differences in the structure of the polymer exclusion layer on the cell surface. PEG grafting impacted the deformation properties of the membrane to a greater degree than HPG. The complement mediated lysis of the grafted RBCs was dependent on the type of polymer, grafting concentration and molecular size of grafted chains. At higher molecular weights and graft concentrations both HPG and PEG triggered complement activation. The magnitude of activation was higher with HPG possibly due to the presence of many hydroxyl groups per molecule. HPG grafted RBCs showed significantly higher levels of CD47 self-protein accessibility than PEG grafted RBCs at all grafting concentrations and molecular sizes. PEG grafted polymers provided, in general, a better shielding and protection to ABO and minor antigens from antibody recognition than HPG polymers, however, the compact HPGs provided greater protection of certain antigens on the RBC surface. Our data showed that HPG 20 kDa and HPG 60 kDa grafted RBCs exhibited properties that are more comparable to the native RBC than PEG 5 kDa and PEG 10 kDa grafted RBCs of comparable hydrodynamic sizes. The study shows that small compact polymers such as HPG 20 kDa have a greater potential in the generation of functional RBC for therapeutic delivery applications. The intermediate sized polymers (PEG or HPG) which showed greater antigen camouflage at lower grafting concentrations have significant potential in transfusion as universal red blood donor cells. PMID- 22840224 TI - Radiopaque fluorescence-transparent TaOx decorated upconversion nanophosphors for in vivo CT/MR/UCL trimodal imaging. AB - To address the intractable issues such as the low performance or biocompatibility frequently encountered in previous CT, magnetic resonance (MR) and fluorescence trimodal imaging nanoprobes, a nanocomposite has been constructed by decorating gadolinium ions doped upconversion nanoparticle (Gd-doped UCNP) with radiopaque but fluorescence-transparent tantalum oxide (TaO(x), x ~ 1). The as-synthesized water-soluble nanoparticle showed a litchi-like shape with an average size of ~30 nm and demonstrated extraordinarily high longitudinal and transverse relaxivity values (r(1) = 11.45 mM(-1)s(-1) and r(2) = 147.3 mM(-1)s(-1)) compared with the reported Gd-doped UCNPs to date. Obvious CT contrast enhancement was obtained by the combined effect between the radiopaque TaO(x) shell and the Gd-doped UCNP inner core. Strong upconversion luminescence (UCL) signal could unobstructedly penetrate out in virtue of high transparency of the TaO(x) shell. No mutual interference among different modalities of the upconversion nanolitchi (UCNL) was found, which ensured that the individual merits of every imaging modality could be brought into full play, demonstrated by in vitro and in vivo imagings. Furthermore, UCNLs showed only a slight effect on macrophages and RBCs in vitro and tissue in vivo. PMID- 22840225 TI - PET imaging of tumor associated macrophages using mannose coated 64Cu liposomes. AB - Macrophages within the tumor microenvironment (TAMs) have been shown to play a major role in the growth and spread of many types of cancer. Cancer cells produce cytokines that cause macrophages to express scavenger receptors (e.g. the mannose receptor) and factors that facilitate tissue and blood vessel growth, suppress T cell mediated anti-tumor activity, and express enzymes that can break down the extracellular matrix, thereby promoting metastasis. We have designed a mannosylated liposome (MAN-LIPs) and show that it accumulates in TAMs in a mouse model of pulmonary adenocarcinoma. These liposomes are loaded with (64)Cu to allow tracking by PET imaging, and contain a fluorescent dye in the lipid bilayer permitting subsequent fluorescence microscopy. We injected these liposomes into a mouse model of lung cancer. In vivo PET images were acquired 6 h after injection followed by the imaging of select excised organs. MAN-LIPs accumulated in TAMs and exhibited little accumulation in remote lung areas. MAN-LIPs are a promising new vehicle for the delivery of imaging agents to lung TAMs. In addition to imaging, MAN-LIPs hold the potential for delivery of therapeutic agents to the tumor microenvironment. PMID- 22840226 TI - The effect of octadecyl chain immobilization on the hemocompatibility of poly (2 hydroxyethyl methacrylate). AB - Albumin-scavenging surfaces decorated with n-alkyl chains represent an established strategy for blood-contacting applications. To evaluate this concept, a set of poly (2-hydroxyethyl methacrylate) (pHEMA) films modified with different amounts of octadecyl isocyanate (C18) was investigated in an in vitro hemocompatibility assay using freshly drawn human whole blood. In addition, the hydrogel materials were thoroughly characterized with respect to changes in wettability and elasticity, which accompanied the gradual chemical modification of pHEMA. An increase of the surface C18 content induced enhanced hydrophobicity and stiffness. Immobilization of C18 chains was found to substantially reduce the coagulation activation and the complement activation by the pHEMA films. Platelet adhesion and degranulation (PF4 release) were similar on the modified and the unmodified pHEMA. Platelet adhesion to pHEMA hydrogels was lower than the polytetrafluoroethylene reference. We conclude that the immobilization of octadecyl chains improved the hemocompatibility of pHEMA materials under conditions that might be encountered in low shear blood flow. PMID- 22840228 TI - A mother's love. PMID- 22840227 TI - Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape. AB - The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Deltapsim after treatment with PEG-PEI MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy. PMID- 22840229 TI - A new cyclonerol derivative from a marine-derived fungus Ascotricha sp. ZJ-M-5. AB - A new sesquiterpene, ascotrichic acid (1), was isolated from a marine-derived fungus Ascotricha sp., together with the other two known analogues, cyclonerodiol (2) and 10(Z)-cyclonerotriol (3). Its structure was established by spectroscopic methods (1D and 2D NMR, HR-ESI-MS). PMID- 22840230 TI - Epidemic Clostridium difficile ribotype 027 in Chile. PMID- 22840231 TI - Influence of perioperative oxygen fraction on pulmonary function after abdominal surgery: a randomized controlled trial. AB - BACKGROUND: A high perioperative inspiratory oxygen fraction (FiO2) may reduce the frequency of surgical site infection. Perioperative atelectasis is caused by absorption, compression and reduced function of surfactant. It is well accepted, that ventilation with 100% oxygen for only a few minutes is associated with significant formation of atelectasis. However, it is still not clear if a longer period of 80% oxygen results in more atelectasis compared to a low FiO2.Our aim was to assess if a high FiO2 is associated with impaired oxygenation and decreased pulmonary functional residual capacity (FRC). METHODS: Thirty-five patients scheduled for laparotomy for ovarian cancer were randomized to receive either 30% oxygen (n = 15) or 80% oxygen (n = 20) during and for 2 h after surgery. The oxygenation index (PaO2/FiO2) was measured every 30 min during anesthesia and 90 min after extubation. FRC was measured the day before surgery and 2 h after extubation by a rebreathing method using the inert gas SF6. RESULTS: Five min after intubation, the median PaO2/FiO2 was 69 kPa [53-71] in the 30%-group vs. 60 kPa [47-69] in the 80%-group (P = 0.25). At the end of anesthesia, the PaO2/FiO2 was 58 kPa [40-70] vs. 57 kPa [46-67] in the 30%- and 80%-group, respectively (P = 0.10). The median FRC was 1993 mL [1610-2240] vs. 1875 mL [1545-2048] at baseline and 1615 mL [1375-2318] vs. 1633 mL [1343-1948] postoperatively in the 30%- and 80%-group, respectively (P = 0.70). CONCLUSION: We found no significant difference in oxygenation index or functional residual capacity between patients given 80% and 30% oxygen for a period of approximately 5 hours. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00637936. PMID- 22840232 TI - The effect of a nuclear localization sequence on transfection efficacy of genes delivered by cobalt(II)-polybenzimidazole complexes. AB - We have demonstrated that the metal complexes of polybenzimidazoles are emerging likely as a new type of gene-delivery systems based on their strong DNA condensing ability. However, the in vitro transfection efficacy of the DNA condensates formed with the metal complexes was relatively low. The positively charged peptides, such as cell-penetrating peptides and nuclear localization sequences (NLSs), have been reported to be capable of enhancing expression of the transgenes, likely as they promote entrance of their electrostatic complexes with DNA into the nuclear through nuclear pores. Here, we explored expression of the genes transferred by a series of Co(II) complexes in the presence of NLS (PKKKRKV) in normal and cancer cell lines. The results showed that the Co(II) complexes lead to the more pronounced DNA condensation in the presence of NLS than that in the absence of NLS. The binding of NLS prior to addition of the Co complexes can significantly reduce both the size and the population of the condensates at the given Co complexes/DNA ratios, compared with the NLS-free condensates. Meanwhile, the binding of NLS can considerably increase surface positive charges on the DNA nanoparticles. The suitable sizes and high surface positive charges facilitate the entrance of the nanoparticles into cells. Luciferase activity assay indicated that the transfection efficacy of the NLS bound condensates was five-fold of that of the NLS-free ones in different cell lines, and comparable to that of the condensate formed with the commercially available carrier PEI. Moreover, cell viability assay of the NLS-bound condensates showed lower cytotoxicity than the NLS-free ones. Thus, the combination of NLS and cationic metal complexes might offer a new type of ternary delivery systems. PMID- 22840233 TI - Controlling Pseudomonas aeruginosa persister cells by weak electrochemical currents and synergistic effects with tobramycin. AB - It is well recognized that bacterial populations commonly contain a small percentage of phenotypic variants, known as persister cells, which are dormant and extremely tolerant to antibiotics. When the antibiotic treatment is stopped, surviving persister cells can regenerate the bacterial population with a similar percentage of persister cells. Such persistence presents a great challenge to curing chronic infections, such as those associated with implanted medical devices. In this study, we report that bacterial persister cells can be effectively eliminated by low-level direct currents (DCs); e.g. treatment with 70 MUA/cm(2) DC for 1 h using stainless steel (SS) 304 reduced the number of viable planktonic persister cells of Pseudomonas aeruginosa PAO1 by 98% compared to the untreated control. In addition to persister killing by applying DC alone, synergistic effects were observed when treating persister cells with 70 MUA/cm(2) DC and 1.5 MUg/mL tobramycin together using SS304 electrodes. The same level of DC was also found to be cidal to biofilms-associated persister cells of P. aeruginosa PAO1. These results are helpful for developing more effective methods to control chronic infections associated with implanted medical devices. PMID- 22840235 TI - When the belief in a miracle is the last thread of hope. PMID- 22840234 TI - [Meticillin resistant Staphylococcus aureus bacteremia of respiratory origin]. PMID- 22840236 TI - Impact of visceral fat on laparoscopy-assisted distal gastrectomy. AB - BACKGROUND: Obesity is known to be a preoperative risk factor for gastric cancer surgery. However, the influence of obesity on laparoscopy-assisted distal gastrectomy (LADG) remains controversial. In the present study, we evaluated several obesity parameters and investigated the influence of obesity on the surgical outcomes of LADG for gastric cancer. MATERIALS AND METHODS: Between January 2010 and July 2011, 84 patients who underwent LADG for gastric cancer were enrolled. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured in cross-sectional CT scan using SlimVision((r)) software. Patients were classified into two groups by the degree of BMI or VFA. Surgery time and blood loss were compared between each two groups. Predictive factors for perioperative complications were assessed by univariate and multivariate analyses. RESULTS: There were no significant differences in surgery time or blood loss between patients with high and low BMIs. In contrast, high VFA patients had significantly longer surgery times (p=0.0047) and higher estimated blood loss (p=0.0034) than low VFA patients. By univariate and multivariate analyses, only a high VFA significantly predicted perioperative complications (p=0.0162, p=0.0288). CONCLUSIONS: We suggest that VFA is more accurate than BMI in predicting surgery time, blood loss, and perioperative complications associated with LADG for gastric cancer. The visceral fat area could be efficiently assessed before laparoscopic surgery for gastric cancer in obese patients. PMID- 22840237 TI - ortho Substituent effects on the anticonvulsant properties of 4-hydroxy trifluoroethyl phenols. AB - 2,6-Dialkylphenols with isopropyl and sec-butyl substituent are well known anesthetic compounds. The 4-substitution with 1-hydroxy-2,2,2-trifluoroethyl (4 HTFE) group in these compounds led to the discovery of compounds with anticonvulsant activity in the 6 Hz (32 mA) model of partial epilepsy. In the present study a series of 2-alkyl-4-HTFE phenols with the 6-position being replaced with either hydrogen and bromine were designed, synthesized and tested to evaluate the effect of ortho-substitution on the anticonvulsant property. The studies show that 2-substituted branched alkyl chain (iso-propyl and sec-butyl) is necessary for the anti-seizure effect. Phenols with 2-substituted linear alkyl groups (methyl, ethyl and n-propyl) having no substitution at 6-position were found to be devoid of antiseizure effects. The 6-substitution with bromine moderately reduces the anticonvulsant effect in the compounds with branched alkyl chains, but led to enhanced anticonvulsant effect in the compound with a linear alkyl chain. This study shows that 4-HTFE phenols having isopropyl or sec-butyl ortho groups produce good antiseizure protection in the 6 Hz therapy-resistant mouse model. PMID- 22840238 TI - Glucose uptake stimulatory effect of 4-hydroxypipecolic acid by increased GLUT 4 translocation in skeletal muscle cells. AB - Peganum harmala Linn, commonly known as 'harmal' belonging to the family Zygophyllaceae, is one of the most important medicinal plants of India. In continuation of our drug development program on Indian medicinal plants we discovered antihyperglycemic activity in 4-hydroxypipecolic acid (4-HPA), isolated from the seed of P. harmala. Effect of 4-HPA on glucose uptake and glucose transporter-4 (GLUT-4) translocation was investigated in L6 skeletal muscle cell lines. Treatment with 4-HPA stimulated both glucose uptake and GLUT4 translocation from intracellular to cell surface in skeletal muscle cells in a concentration-dependent manner, which might be leading to antihyperglycemic effect. PMID- 22840239 TI - Pregnancy loss after frozen-embryo transfer--a comparison of three protocols. AB - OBJECTIVE: To compare the reproductive outcome of three protocols for frozen ET treatment. DESIGN: Retrospective follow-up study. SETTING: Two public clinics and one private clinic. PATIENT(S): Four thousand four hundred seventy frozen ET cycles between 2006 and 2010. INTERVENTION(S): Thawing of embryos and ET. MAIN OUTCOME MEASURE(S): Pregnancy test rate, clinical pregnancy rate, and pregnancy loss rate. RESULT(S): The natural cycle followed by P (NC + P) was used in 26% of cycles, the natural cycle with hCG (NC + hCG) in 10%, and the substituted cycle with estrogen and P (E + P) in 64% of cycles. The rate of transfers after thawing was similar in all groups (87.2%, 73.9%, and 87.2%, respectively). There was a significantly higher positive pregnancy test rate in the E + P (34.3%) and NC + hCG (35.5%) cycles as compared with the NC + P cycles (26.7%). However, the clinical pregnancy rate was similar in all groups (27.7%, 29.1%, and 24.3%, respectively). Moreover, no differences were seen between groups regarding the live-birth rate (20.1%, 23.5%, and 20.7%, respectively). A logistic regression analysis showed that the type of protocol was the only predictor of pregnancy loss, while age, irregular cycles, endometrial thickness, number, and quality of embryos transferred did not correlate to pregnancy loss. CONCLUSION(S): A higher positive pregnancy test rate was obtained in E + P frozen ET cycles in comparison with other protocols; however, due to an increased preclinical and clinical pregnancy loss, comparable clinical pregnancy, and delivery rates are reported for the three protocols. PMID- 22840240 TI - Recruiting egg donors online: an analysis of in vitro fertilization clinic and agency websites' adherence to American Society for Reproductive Medicine guidelines. AB - OBJECTIVE: To examine compliance with ethical guidelines of the American Society for Reproductive Medicine (ASRM) regarding trait-based payment variation, presentation of risks, and minimum recruitment age. DESIGN: In June 2010, we systematically examined 207 websites, of which 102 were egg donor agency or IVF clinic websites that both recruited online and displayed compensation amounts. SETTING: The Internet. PATIENT(S): None. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Mention of increased payment for particular donor traits, recruitment age less than 21 years, noting risks to donors. RESULT(S): Of the 102 sites, considerable numbers were noncompliant with ASRM's guidelines that prohibit varying compensation based on a donor's traits (34%), and recommend an age of 21 years or older (41%), and presentation of risks alongside compensation (56%). Trait-based payment variation was associated with being an agency rather than a clinic, location in the West, not being endorsed by ASRM or Society of Assisted Reproductive Technology (SART), and referring to ASRM's guidelines about compensation. Of sites mentioning traits, prior donation success was the most commonly paid for trait (64%). CONCLUSION(S): Our data, the first to systematically analyze agency and clinic websites reveal that many do not follow ASRM's guidelines. These data have critical implications for policy, practice, and research, suggesting needs for consideration of possible changes in guidelines, and/or improvements in compliance and monitoring by ASRM or others. PMID- 22840242 TI - Inpatient dermatology consultation in a Spanish tertiary care hospital: a prospective cohort study. AB - BACKGROUND AND OBJECTIVE: Although dermatology has traditionally been practiced through outpatient consultation, hospitalized patients often have dermatologic problems. The aim of this study was to describe and quantify the volume of interdepartmental consultation of the dermatology department of Hospital Universitario Virgen del Rocio. MATERIAL AND METHODS: In this year-long prospective observational cohort study of 429 patients we used a specific data collection form to record information on consultations for patients admitted between July 2010 and June 2011. RESULTS: The 429 consultations over the 12 months of study accounted for 1.56% of all first consultations with a dermatologist during the period. A mean of 1.75 new patients were attended each day. The mean (SD) age of the patients was 52.63 (19) years, and the ratio of men to women was 1.21. Immunocompromised patients accounted for more than a third of the cohort. The medical specialties consulting most often were internal medicine (n=115) and hematology (n=66). The most frequent diagnoses were inflammatory skin conditions (36.2%) and infectious skin diseases (26.5%). DISCUSSION AND CONCLUSIONS: To date, the role of interdepartmental consultation in dermatology has been little studied. Our results suggest that dermatology plays a fundamental role within the hospital. We have identified the most common skin problems in hospitalized patients and their clinical course. PMID- 22840241 TI - Altered resting brain function and structure in professional badminton players. AB - Neuroimaging studies of professional athletic or musical training have demonstrated considerable practice-dependent plasticity in various brain structures, which may reflect distinct training demands. In the present study, structural and functional brain alterations were examined in professional badminton players and compared with healthy controls using magnetic resonance imaging (MRI) and resting-state functional MRI. Gray matter concentration (GMC) was assessed using voxel-based morphometry (VBM), and resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity. Results showed that the athlete group had greater GMC and ALFF in the right and medial cerebellar regions, respectively. The athlete group also demonstrated smaller ALFF in the left superior parietal lobule and altered functional connectivity between the left superior parietal and frontal regions. These findings indicate that badminton expertise is associated with not only plastic structural changes in terms of enlarged gray matter density in the cerebellum, but also functional alterations in fronto-parietal connectivity. Such structural and functional alterations may reflect specific experiences of badminton training and practice, including high-capacity visuo-spatial processing and hand-eye coordination in addition to refined motor skills. PMID- 22840245 TI - Adherence to environmental control measures. PMID- 22840244 TI - PAR-2 triggers placenta-derived protease-induced altered VE-cadherin reorganization at endothelial junctions in preeclampsia. AB - PAR-2 is a G-protein coupled protease receptor whose activation in endothelial cells (ECs) is associated with increased solute permeability. VE-cadherin is an endothelial-specific junction protein, which exhibits a disorganized distribution at cell junction during inflammation and is a useful indicator of endothelial barrier dysfunction. In the present study, we tested the hypothesis that PAR-2 activation mediates placenta-derived chymotrypsin-like protease (CLP)-induced endothelial junction disturbance and permeability in preeclampsia (PE). PAR-2 and VE-cadherin were examined by immunofluorescent staining. Specific CLP induced PAR 2 activation and altered VE-cadherin distribution was assessed following depletion of protease chymotrypsin in the placental conditioned medium and after PAR-2 siRNA. VE-cadherin assembly was determined by treating cells with protease chymotrypsin and/or the specific PAR-2 agonist SLIGKV-NH2. Our results showed: 1) placental conditioned medium not only disturbed VE-cadherin distribution at cell junctions but also activated PAR-2 in ECs; 2) PAR-2 siRNA blocked the placental conditioned medium induced PAR-2 upregulation and disorganization of VE-cadherin at cell junctions; 3) PAR-2 agonist induced PAR-2 activation and VE-cadherin reorganization were dose-dependent; and 4) PAR-2 agonist could stimulate ERK1/2 activation. These results strongly suggest that proteases produced by the placenta elicit endothelial barrier dysfunction via a PAR-2 signaling regulatory mechanism in PE. PMID- 22840246 TI - What will allergen immunotherapy look like in the future? PMID- 22840247 TI - Improving patient adherence with asthma self-management practices: what works? PMID- 22840248 TI - Farming-associated environmental exposures and effect on atopic diseases. PMID- 22840249 TI - Telephone-based environmental control interventions in asthmatic patients: what are patients willing to do? AB - BACKGROUND: Environmental control education is recommended for allergic patients with persistent asthma, but patients may not be willing to comply with recommendations. In a prior study from our group, only 24% of patients reported making any recommended environmental changes. OBJECTIVE: To determine what environmental changes allergic asthmatic patients say they would be willing to make and what changes they actually make. METHODS: Asthmatic patients with known perennial aeroallergen sensitization were asked by telephone to rate on a 1- to 5 point Likert scale their willingness to make specific environmental changes. Items with mean scores of 3 or higher were used to formulate a practical set of recommendations to be given to patients in stage 2 of the study. Stage 2 patients were given the advice formulated in stage 1 and then telephoned 2 months later to see what changes they actually made. RESULTS: Stage 1 patients (n = 60) were willing to institute 14 of the 18 proposed allergen-specific recommendations. Of 36 stage 2 patients who were allergic to mite, mold, and/or dander, 29 (80.6%) reported that they complied with at least 1 of the recommendations made in this study. Patients who owned their own home were significantly (P < .05) more likely (91.3%) to make at least 1 change than patients who rented their home (63.6%). CONCLUSION: Pending additional information, we suggest that environmental control recommendations for mite, mold, and dander emphasize those used in this study because they appear to be practical for a substantial proportion of patients, especially if they own their home. PMID- 22840250 TI - Understanding the relationship among pharmacoadherence measures, asthma control test scores, and office-based spirometry. AB - BACKGROUND: This study used accepted asthma metrics and pharmaceutical claim data to develop a new asthma metric as a possible surrogate for spirometry and to better assess asthma control. OBJECTIVE: To develop and validate a new asthma metric called the Rescue Index (RI) based on beta(2)-agonist dispensings and to test the feasibility of a multivariate model to construct a global asthma metric called the Asthma Control Index (ACI). METHODS: This prospective, observational, multicenter cohort study was conducted at the Naval Medical Center San Diego (NMCSD) and at the Phoenix VA Health Care System (PVAHCS). Pharmacy claim data were correlated with the ACT, Medication Adherence Report Scale for Asthma (MARS A), and spirometry using univariate and multivariate analyses. RESULTS: A total of 263 individuals enrolled in the study, and 95 (PVAHCS) and 156 (NMCSD) individuals completed the study. In the PVAHCS, the ACT correlated with the asthma medication ratio (AMR) (rho = 0.37, P < .001) and inversely correlated with the RI (rho = -0.33, P = .001), the RI inversely correlated with forced expiratory volume in 1 second (FEV(1)) (rho = -0.22, P = .03) and the FEV(1) to forced vital capacity ratio (rho = 0.22, P = .03). In the NMCSD population, the ACT correlated with the MARS-A (rho = 0.23, P = .006), FEV(1) did not correlate with ACT (rho = 0.09, P = .25) or MARS-A (rho = 0.16, P = .047) but directly correlated with the RI (rho = 0.19, P = .03). The AMR was strongly inversely correlated with RI in both populations (-0.74, P < .001 in the PVAHCS group and 0.78, P < .001 in the NMCSD group). When multivariate models were applied to the NMCSD and PVAHCS groups, the combination of RI and MARS-A was the best predictor of spirometry. CONCLUSION: The RI shows promise as a new asthma metric because it correlated with AMR in both cohorts. However, because RI correlated with adult spirometry and ACT only, further validation studies are needed before RI may be included in an ACI metric. PMID- 22840251 TI - Cut points for Asthma Control Tests in Mexican children in Orange County, California. AB - BACKGROUND: The Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT) are validated measures of asthma control in which a score of 19 is defined as uncontrolled according to published reports. However, different cut points may exist in different ethnic populations. OBJECTIVE: To determine the cut point for uncontrolled asthma in a Mexican descent population from Orange Country, California, compared with an age- and asthma severity-matched non-Hispanic cohort. METHODS: The C-ACT (in children 6-11 years old) and ACT (in children 12 17 years old) scores were collected from 151 children of Mexican descent and 48 non-Hispanic controls with mild-to-moderate asthma who lived in Orange County. Physicians were masked to C-ACT and ACT scores while assessing control based on National Asthma Education and Prevention program guidelines. The receiver operating characteristic method was used to examine the screening accuracy of the tests to detect uncontrolled asthma. The optimal cut points were selected by maximizing the total sensitivity and specificity. RESULTS: Cronbach alpha values for the C-ACT (0.76) and the ACT (0.80) confirmed that both tests were reliable in our study population. The C-ACT and ACT scores were statistically higher in children of Mexican descent than non-Hispanic children (P = .008). A cut point of 22 was optimal to detect uncontrolled asthma in children of Mexican descent 6 to 11 years old (group 1: sensitivity, 0.74; specificity, 0.86; area under the curve [AUC], 0.83) and children 12 to 17 years old (group 3: sensitivity, 0.78; specificity, 0.68; AUC, 0.79). For non-Hispanic controls, a cut point of 20 were optimal to detect uncontrolled asthma in children 6 to 11 years old (group 2: sensitivity, 0.70; specificity, 0.91; AUC, 0.86) and children 12 to 17 years old (group 4: sensitivity, 0.83; specificity, 0.87; AUC, 0.91). CONCLUSION: In this cross-ethnic validation study, children of Mexican descent in Orange County seem to underreport asthma symptoms compared with a non-Hispanic population and may require higher C-ACT and ACT cut points to detect uncontrolled asthma. PMID- 22840252 TI - Lung function and biomarkers of airway inflammation during and after hospitalization for acute exacerbations of childhood asthma associated with viral respiratory symptoms. AB - BACKGROUND: There are limited data assessing relationships between biomarkers of inflammation and lung function after hospitalization for asthma exacerbations in children. OBJECTIVE: To assess the associations in asthmatic children among changes in lung function, fraction of exhaled nitric oxide (FENO), and cysteinyl leukotrienes (CysLTs) in exhaled breath condensate (EBC) after hospitalization for acute asthma. METHODS: Spirometry and FENO were measured and EBC collected for CysLT measurement from 40 children during and 1, 2, and 4 weeks after hospitalization for an asthma exacerbation and during a single-study visit for 40 healthy children. RESULTS: Enrollment FENO and EBC CysLT concentrations were higher in the children with asthma than in healthy individuals (mean FENO, 31.6 vs 7 ppb; P < .0001; mean EBC CysLT, 7.9 vs 4.9 ppb; P = .03). Among children with asthma, improvement in lung function reached a plateau within 2 weeks after hospital discharge. The EBC CysLT concentrations were not associated with changes in lung function, use of albuterol, or use of inhaled corticosteroids (ICSs). Among asthmatic children enrollment FENO was not associated with changes in lung function during follow-up. However, among children who had an elevated enrollment FENO (>=25 ppb), patients who did not use ICSs after hospital discharge had lower end-of-study lung function than those who used ICSs. At 2 and 4 weeks after hospital discharge, FENO was higher among patients who reported albuterol use more than twice weekly and among patients who reported no ICS use. CONCLUSION: FENO measured at hospital discharge among children hospitalized with acute asthma may be useful in identifying patients who will respond to ICS therapy. PMID- 22840253 TI - Recruitment, asthma characteristics, and medication behaviors in Midwestern Puerto Rican youth: data from Project CURA. AB - BACKGROUND: Puerto Rican children have the highest prevalence of asthma, but detailed descriptions of this population have been limited to the island of Puerto Rico and the northeastern United States. OBJECTIVE: To describe the asthma characteristics of this urban Midwest cohort of Puerto Rican youth, focusing on medication behaviors, and to test whether their asthma outcomes are associated with their demographic and psychosocial variables. METHODS: Data are from the baseline cohorts of a randomized controlled trial designed to improve medication adherence in Puerto Rican youth. Recruitment used a community-based participatory research approach. Data were collected in the home. Medications and medication technique were visually assessed, and adherence was determined using electronic medication monitors or counters. Data on asthma symptoms and morbidity, demographics, and psychosocial factors were collected. RESULTS: The recruitment of 101 participants (51 in elementary school and 50 in high school) was completed in 14 months. Despite overall high asthma severity and poor asthma control, 20% of participants had no reliever medicine in their home. Self-report of controller use was higher than actual controller medications visualized in the home. For those who had an inhaled corticosteroid medicine (only 45% of elementary school participants and 12% of high school participants), median adherence was 1.0 doses per day. Rates of depression and stress were very high among both caregivers and children. CONCLUSION: Puerto Rican youth in the Midwest bear a significant asthma burden in addition to other stressors, including depression. Visual inspection of medications and monitoring of adherence are critical for understanding asthma morbidity in this high-risk population. PMID- 22840254 TI - Modifiable factors associated with severe asthma exacerbations in urban patients. AB - BACKGROUND: Rates of asthma morbidity, mortality, and resource use are highest among African American individuals residing in inner-city locations, yet factors associated with adverse outcomes are not well established. OBJECTIVE: To identify modifiable factors associated with asthma exacerbations. METHODS: A total of 104 adult patients who presented to an inner-city hospital or emergency department (ED) with an asthma exacerbation from October 1, 2009, through June 31, 2010, completed surveys of clinical status, acute events, sociodemographic characteristics, current asthma knowledge, self-efficacy, attitudes toward asthma self-management, and perceived barriers to asthma care questionnaires. Associations with asthma hospitalizations and ED visits were assessed. RESULTS: The mean age of the patients was 42 years, 91% were African American, 33% were insured, 57% were taking a controller medication, and 63% had an income level below the federal poverty line. On bivariate analysis, males, years of asthma, history of smoking, self-classification of asthma severity, history of admission to intensive care unit or intubation, use of peak flow meter or asthma action plan, controller medication use, and history of oral corticosteroid bursts were positively associated, whereas self-efficacy was negatively associated with number of ED visits or hospitalizations. No association was found for asthma knowledge, perceived barriers to care, or attitudes toward asthma management. On multivariate analysis, low self-efficacy remained associated with both asthma hospitalizations and ED visits. CONCLUSION: Short-term use of health services for asthma is negatively associated with asthma self-efficacy. Self-management programs that enhance self-efficacy, rather than those that focus on knowledge or attitudes, may be effective in reducing adverse asthma outcomes for inner-city, predominantly African American populations. PMID- 22840255 TI - Anaphylaxis in the community setting: determining risk factors for admission. AB - BACKGROUND: Although the identification and management of anaphylaxis in an emergency department setting has been well studied, our understanding of the risk factors for admission in a community-based hospital is lacking. OBJECTIVE: To determine the demographics and the predictors of hospitalization, in patients presenting with anaphylaxis to a community-based emergency department (ED). METHODS: We performed a five-year retrospective chart review of all patients seen in the ED of Winthrop University Hospital, a community-based institution, with an International Classification of Diseases, 9(th)Edition code related to anaphylaxis. RESULTS: Fifty-eight visits met inclusion criteria, of which 34% resulted in hospital admission (95% CI: 22-48%). Univariate predictors for admission included (1) the involvement of 2, 3, and 4 organ systems (26%, 55%, and 75%, respectively; P < .02); (2) gastrointestinal symptoms vs no symptoms (59% vs 24%, P < .02); (3) non-sting (ingested and other allergens) vs insect sting allergen (50% vs 12.5%, P < .005); and (4) a history of an ED visit for anaphylaxis vs none (67% vs 30%, P < .05). Multivariate analysis (logistic regression) confirmed non-sting allergens (p < 0.02) and number of organ systems involved (P < .05) as independent predictors of hospitalization. CONCLUSION: In our study population, the involvement of multiple organ systems, particularly gastrointestinal involvement, a history of ED visits for anaphylaxis, and involvement of ingested or other allergens (non-sting) demonstrated higher admission rates. PMID- 22840256 TI - Allergy alerts in electronic health records for hospitalized patients. AB - BACKGROUND: Electronic health records (EHRs) are used to register important health-related information, such as allergic conditions, and contribute to the safety and quality of medical care. OBJECTIVES: To evaluate the use of allergy alert entries in EHRs and to establish the allergy profile of hospitalized patients. METHODS: Allergy data recorded in EHRs were analyzed in a cross sectional, observational, descriptive study of patients admitted to the hospital from January 1 through June 30, 2011. RESULTS: A total of 15,534 patients were admitted to the hospital during the study period. The rate of inclusion of allergy information in the EHRs was 64.4%. In 2,106 patients an alert was activated to declare an allergy, intolerance, or any other type of adverse reaction. Drugs were the most common responsible agent (74.4%), followed by foods (12.6%) and materials (4.8%). Entries for drug allergy or intolerance were more common in females (64.8%) than males, with a significant statistical difference (P < .01), and increased proportionally with age. Entries for food allergy or intolerance were also more common in females (58.0%) than males (P < .01), but this trend was reversed in the 0- to 15-year-old age group. By contrast, the entries for food allergy or intolerance decreased proportionally with age. In 7,907 cases the EHRs revealed that patients were free of allergies, intolerances, or any other type of adverse reactions. CONCLUSION: Drug allergy was the most frequently reported allergic condition, followed by foods and materials. Allergy alerts vary depending on age and sex. The proper use of a system for allergy alerts included in EHRs provides valuable information about hospitalized patients, contributing to the improvement of clinical practice. PMID- 22840257 TI - Nasal corticosteroid treatment reduces substance P levels in tear fluid in allergic rhinoconjunctivitis. AB - BACKGROUND: The mechanisms underlying conjunctival symptom reduction by nasal corticosteroids in allergic rhinoconjunctivitis are unknown. A naso-ocular reflex may be present. OBJECTIVE: To study the effects of nasal fluticasone furoate (FF) on conjunctival symptoms and substance P and histamine levels in tear fluid after nasal grass pollen provocation (GPP). METHODS: A double-blind placebo-controlled study was performed in 26 grass pollen-allergic patients. A selective GPP was performed during the grass pollen season after 2 weeks of FF or placebo treatment. Nasal and conjunctival symptoms were scored using a visual analog scale (VAS), and tear fluid was collected for measuring substance P and histamine using an enzyme-linked immunosorbent assay. RESULTS: Compared with placebo, FF reduced conjunctival symptom scores during the pollen season (-1.75 [-2.75, 0.20] vs 0.0 [0.0, 0.0]; P = .01) and after GPP at 15 minutes (0.05 [-0.42, 1.52] vs 2.05 [0.62, 3.62]; P < .001) and 1 hour (-0.45 [-1.75, 0.1] vs 0.05 [-0.97, 1.85]; P < .01). Treatment with FF decreased substance P levels in tear fluid (44.11 [32.81, 61.02] vs 65.26 [48.62, 79.73] pg/mg protein; P = .0098). Histamine levels in tear fluid showed a GPP-induced increase in the placebo group (7.26 [3.12, 9.69] vs 5.71 [2.05, 7.00] ng/mg protein; P = .02), but not in the FF group (6.77 [3.43, 13.00] vs 5.24 [3.18, 7.06] ng/mg protein; P = .08). CONCLUSION: FF nasal spray reduced conjunctival symptoms in grass pollen-allergic patients in parallel with lower substance P levels in tear fluid. These data help in understanding the reduction of conjunctival symptoms by intranasal anti inflammatory therapy. PMID- 22840258 TI - Chronic urticaria with monoclonal IgG gammopathy: a clinical variant of Schnitzler syndrome? PMID- 22840259 TI - What should drive the choice of allergen for immunotherapy in polysensitized patients? PMID- 22840260 TI - Hereditary angioedema: implications of treating a rare disease. PMID- 22840263 TI - Expanding access to medical abortion: perspectives of women and providers in developing countries. PMID- 22840262 TI - Allergen of the month--downy chess. PMID- 22840264 TI - Knowledge of medical abortion among Brazilian medical students. AB - OBJECTIVE: To assess the knowledge of Brazilian medical students regarding medical abortion (MA) and the use of misoprostol for MA, and to investigate factors influencing their knowledge. METHODS: All students from 3 medical schools in Sao Paulo State were invited to complete a pretested structured questionnaire with precoded response categories. A set of 12 statements on the use and effects of misoprostol for MA assessed their level of knowledge. Of about 1260 students invited to participate in the study, 874 completed the questionnaire, yielding a response rate of 69%. The chi(2) test was used for the bivariate analysis, which was followed by multiple regression analysis. RESULTS: Although all students in their final year of medical school had heard of misoprostol for termination of pregnancy, and 88% reported having heard how to use it, only 8% showed satisfactory knowledge of its use and effects. Academic level was the only factor associated with the indicators of knowledge investigated. CONCLUSION: The very poor knowledge of misoprostol use for MA demonstrated by the medical students surveyed at 3 medical schools makes the review and updating of the curriculum urgently necessary. PMID- 22840265 TI - Women's experiences of and perspectives on abortion at public facilities in Mexico City three years following decriminalization. AB - OBJECTIVE: To understand the experiences of women undergoing legal first trimester abortion through Mexico City's Ministry of Health (MOH) services. Aims included comparing satisfaction with medical and surgical abortion services; drawing evidence-based recommendations for program improvement; and measuring contraceptive uptake following abortion. METHODS: A total of 350 women completed a 65-item survey questionnaire at 2 main MOH abortion facilities. Moreover, a subset of 20 participated in an in-depth interview. Multivariate analysis was performed to investigate satisfaction with abortion care and in-depth interview (IDI) data were analyzed. RESULTS: The participants overwhelmingly reported satisfaction with the care they received, with no significant differences between the medical and surgical abortion groups. However, qualitative data revealed a need for a more sympathetic staff, reduced waiting times, more comprehensive information on surgical abortion, and counseling that includes psychosocial issues. Postabortion contraception uptake was high, with most women opting for the intrauterine device. CONCLUSION: The quantitative analysis suggests that although most women were satisfied with the services, some areas were identified as requiring improvement. The IDI data suggest that women wanted counseling to better address psychosocial needs and allow for discussion on a wider range of contraceptive methods. PMID- 22840266 TI - Improving care of women at risk of unsafe abortion: implementing a risk-reduction model at the Uruguayan-Brazilian border. AB - OBJECTIVE: To describe the initial stages of the implementation of a risk reduction model designed by Iniciativas Sanitarias to shield women from unsafe abortion in a traditional community on the Uruguay-Brazil border. METHODS: This mixed-design study was conducted first between 22 and 26 March 2010, and then between 2 and 7 May 2011, in Rivera, Uruguay, to gather information from women seen at health centers, healthcare providers, and local policy makers before the project started and midway through the project. RESULTS: At baseline most women and providers considered abortion justifiable only on narrow grounds, yet favored the implementation of a risk-reduction model that would include preabortion as well as postabortion counseling, the former providing information on different abortion methods and their risks. By the midterm assessment, the counseling service had assisted 87 women with unwanted pregnancies. Of the 52 who came for a postabortion visit, 50 had self-administered misoprostol, with no complications. Women were highly satisfied with the counseling. At baseline, misoprostol seemed to be available from both pharmacists and informal sellers. At midterm, it was still available from informal vendors but pharmacists said they did not provide misoprostol. The risk-reduction initiative heightened public attention to the abortion issue but the controversy it generated did not seriously impede its implementation. CONCLUSION: It is feasible to implement the proposed risk reduction model in a traditional community such as Rivera, not only in Uruguay but in any country irrespective of its abortion laws. PMID- 22840267 TI - Study of knowledge and attitudes on medical abortion among Chinese health providers. AB - OBJECTIVE: To investigate providers' knowledge and attitudes about medical abortion (MA) and their views regarding the main challenges to expanding the use of MA in urban and rural areas in China. METHODS: A total of 658 abortion providers were surveyed from November 7, 2009, to May 29, 2010. RESULTS: The providers' knowledge about MA was relatively poor, and most thought the risks of severe complications of MA were much higher than they are. Urban nonphysician providers were the least informed about MA. Most providers thought that the main challenges to an expanded use of MA were its lesser effectiveness in comparison to surgical abortion and women's lack of knowledge about it. In rural areas many providers thought that deficiencies of clinics, such as limited bed space and inadequate toilets and washing facilities, also posed serious obstacles to expanding MA use. CONCLUSION: Abortion providers, especially urban nonphysician providers, need refresher training to strengthen their knowledge of the approved protocol for providing MA in China, and also of the indications, contraindications, and safety and efficacy of the method. Deficiencies at abortion facilities should be addressed as well, and they are more numerous in rural areas. PMID- 22840268 TI - Medical abortion: understanding perspectives of rural and marginalized women from rural South India. AB - OBJECTIVE: To understand how rural and other groups of marginalized women define safe abortion; their perspectives and concerns regarding medical abortion (MA); and what factors affect their access to safe abortion. METHODS: Focus group discussions were held with various groups of rural and marginalized women in Tamil Nadu to understand their perspectives and concerns on abortion, especially MA. RESULTS: Nearly a decade after mifepristone was approved for abortion in India, most study participants had never heard of MA. When they learned of the method, most preferred it over other methods of abortion. The women also had questions and concerns about the method and recommendations on how services should be provided. Their definition of a "safe abortion" included criteria beyond medical safety. They placed a high priority on "social safety," including confidentiality and privacy. In their view, factors affecting access to safe abortion and choice of provider included cost, assurance of secrecy, promptness of service provision, and absence of provider gatekeeping and provider-imposed conditions for receiving services. CONCLUSION: Women's preference for MA shows the potential of this technology to address the problem of unsafe abortion in India. Women need better access to information and services to realize this potential, however. Women's preferences regarding information dissemination and service provision need to be taken into account if policies and programs are to be truly responsive to the needs of marginalized women. PMID- 22840269 TI - Hidden realities: What women do when they want to terminate an unwanted pregnancy in Bolivia. AB - OBJECTIVE: To explore women's experience of unwanted pregnancy and induced abortion in Bolivia, where nearly all induced abortions are carried out in clandestine, unregulated, and unsafe conditions. METHODS: Qualitative and quantitative research methods, including focus group discussions, in-depth interviews and a structured survey of women of reproductive age, were used to explore the experience of unwanted pregnancy and induced abortion in poor urban areas of 5 Bolivian cities. RESULTS: Of the 1175 sexually experienced women surveyed, 13% reported having had an induced abortion. The methods they tried included surgical abortion, taking misoprostol, drinking herbal and chemical preparations, and inflicting physical trauma on themselves. Many women made multiple attempts before successfully terminating a pregnancy. Lack of knowledge and confusion about how to use misoprostol may have contributed to the complications that resulted in seeking postabortion care. CONCLUSION: Increased access to accurate information and counseling about abortion options are paramount if women are to make informed decisions and minimize health risks. PMID- 22840270 TI - Knowledge, attitudes, and practices of certified providers of medical abortion: evidence from Bihar and Maharashtra, India. AB - OBJECTIVE: To explore Indian abortion providers' knowledge of medical abortion (MA), their personal experiences and practices of providing medical abortion, and their attitudes toward providing MA to eligible women who were poor, uneducated, and/or from rural areas. METHODS: In selected districts of India's Bihar and Maharashtra states, interviews were conducted with 270 physicians who were certified as abortion providers, using a structured questionnaire. RESULTS: The providers' knowledge of the gestational limit, the recommended doses of mifepristone and misoprostol, and other aspects of the approved protocol was far from universal. Only about two-thirds of these physicians authorized to perform MA actually performed it. Although they all counseled women about the procedure before they took mifepristone, the matters discussed were often limited to pain management and possible complications. Contraception was usually not discussed until the follow-up visit. Most providers thus missed the opportunity to provide sustained counseling to their MA patients, and did not counsel them about the need to protect themselves in the 2 weeks following the administration of mifepristone. Moreover, many providers were reluctant to offer MA to poor, uneducated, and/or rural women. CONCLUSIONS: These findings shed light on the need to raise awareness and dispel misgivings about MA among certified providers of abortion services. By placing emphasis on the method's safety and effectiveness, additional training to these would increase their confidence about offering MA to eligible women. PMID- 22840271 TI - Adoption and continuation of contraception following medical or surgical abortion in Bihar and Jharkhand, India. AB - OBJECTIVE: This study was carried out to explore whether the rates of postabortion adoption of a contraceptive method, and continuation of contraception over 6 months, differ among women undergoing medical abortion (MA) or surgical abortion by manual vacuum aspiration (MVA). METHODS: The study was conducted in Bihar and Jharkhand, 2 of the least-developed states of India. The analysis focused on 679 married women who were followed up 6 months after they underwent MA (n=308) or MVA (n=371) at clinics run by Janani, a nonprofit organization. RESULTS: The rates of adoption and continuation of contraception were similar in the 2 groups, although with some notable distinctions in the timing of adoption of contraception and the method of contraception adopted. While the women who underwent MA were significantly less likely to adopt contraception in the month following abortion (58% vs 86%), this difference had narrowed considerably by the end of the second month (82% vs 91%); and by the end of the sixth month (89% vs 94%), respectively. There were no significant differences between the MA and the MVA groups with respect to the continuation of reversible contraception. CONCLUSIONS: The findings indicate that, in a setting that offers comprehensive counseling and a range of contraceptive methods, and where adoption of contraception is voluntary, a large majority of women will adopt and continue to use a method of contraception after an abortion even in these less developed parts of India. PMID- 22840272 TI - Factors associated with choice of medical or surgical abortion among women in Nepal. AB - OBJECTIVE: To investigate factors associated with women's choice of medical abortion (MA) or manual vacuum aspiration (MVA) in Nepal, where the government recently began offering MA services. METHODS: Structured exit interviews were conducted between January 19 and May 21, 2010, with women with a pregnancy of 63 days or less who underwent abortions at 7 clinics in 3 districts of Nepal. All those who accepted MA, and 1 in each 4 or 5 of those who underwent MVA, were invited for an interview. Of those interviewed, 499 chose MA and 542 underwent MVA. RESULTS: Many women were not aware of both abortion methods before they came to the clinic. The odds of choosing MA were more than 3 times as high among those who knew about both methods as among those who did not. Of those who had decided on MVA prior to receiving information at the clinic, 29% chose MA. In contrast, only 10% of those who intended to accept MA opted for MVA after receiving information and counseling. Women who had more education, were of the upper Hindu caste, or resided in urban areas were more likely to choose MA. CONCLUSION: Information and counseling have a large impact on the women's choice of an abortion method. To expand access to MA and to ensure that women can make an informed choice, it is essential that the government of Nepal create positions for trained counselors at all public abortion clinics. PMID- 22840273 TI - Introducing medical abortion in Turkey: perspectives of physicians. AB - OBJECTIVE: To better understand the knowledge, attitudes, and perspectives on medical abortion (MA) held by physicians in Turkey. METHODS: The study was conducted in 4 provinces. Pretested, structured, self-administered questionnaires were answered by 187 obstetricians-gynecologists (ob-gyns) and 268 general physicians (GPs). RESULTS: Although MA is not yet available at reproductive health facilities in Turkey, 96% of the ob-gyns and 82% of the GPs said they had heard about it. Moreover, 60% of the former and 5% of the latter said they had performed MAs, most commonly using misoprostol alone. More than 90% of the ob gyns and 13% of the GPs had performed surgical abortions, and most (71% and 78%) thought that MA should be offered in the country. CONCLUSION: Most physicians in Turkey are aware of MA, with a large majority supporting its wider use. However, their concerns about the method and the incorrect understanding of its risks and possible complications may explain the reluctance of some physicians to provide MA services. These issues should be covered in physician training programs before the formal introduction of MA, while advocacy efforts press for registering mifepristone and misoprostol for its use. PMID- 22840275 TI - Hashimoto encephalopathy presenting as progressive myoclonus epilepsy syndrome. AB - We report an 11 year old girl with multi-focal spontaneous myoclonus, generalized seizures and behavioural changes. She was found to have sub-clinical hypothyroidism and elevated anti-thyroid peroxidase antibodies. A diagnosis of Hashimoto encephalopathy (or Steroid Responsive Encephalopathy with Autoimmune Thyroiditis) was made in view of consistent clinical and laboratory features. The patient showed and maintained significant improvement with valproate, clonazepam and long term prednisolone. Other findings included mild cerebral cortical grey matter atrophy on brain magnetic resonance imaging and intermittent slowing with generalized poly-spike-and-wave discharges on electroencephalography. Other causes of progressive myoclonus epilepsy (PME) syndrome including subacute sclerosing panencephalitis, Lafora body disease, Juvenile Neuronal Ceroid Lipofuscinosis, Late onset gangliosidosis, Sialidosis, mitochondrial disorders and coeliac disease were ruled out by appropriate investigations. No other auto immune abnormality was detected. This case emphasizes that Hashimoto encephalopathy should be considered in the etiologies of PME syndrome in adolescents since it is a treatable entity. PMID- 22840274 TI - Factors related to increasing prevalence of resistance to ciprofloxacin and other antimicrobial drugs in Neisseria gonorrhoeae, United States. AB - Using data from the Gonococcal Isolate Surveillance Project, we studied changes in ciprofloxacin resistance in Neisseria gonorrhoeae isolates in the United States during 2002-2007. Compared with prevalence in heterosexual men, prevalence of ciprofloxacin-resistant N. gonorrhoeae infections showed a more pronounced increase in men who have sex with men (MSM), particularly through an increase in prevalence of strains also resistant to tetracycline and penicillin. Moreover, that multidrug resistance profile among MSM was negatively associated with recent travel. Across the surveillance project sites, first appearance of ciprofloxacin resistance in heterosexual men was positively correlated with such resistance for MSM. The increase in prevalence of ciprofloxacin resistance may have been facilitated by use of fluoroquinolones for treating gonorrhea and other conditions. The prominence of multidrug resistance suggests that using other classes of antimicrobial drugs for purposes other than treating gonorrhea helped increase the prevalence of ciprofloxacin-resistant strains that are also resistant to those drugs. PMID- 22840276 TI - Can we safely avoid fasting before abortions with low-dose procedural sedation? A retrospective cohort chart review of anesthesia-related complications in 47,748 abortions. AB - BACKGROUND: Some licensing authorities require fasting before abortions under intravenous sedation to avoid aspiration of gastric contents. This study was conducted to estimate the incidence of anesthesia-related complications in women undergoing abortions without preprocedure fasting. STUDY DESIGN: This is a retrospective cohort chart review of patients having abortions with both fentanyl and midazolam at two urban free-standing abortion clinics with routine policy of advising women to eat a light meal before the procedure. RESULTS: There were no reports of anesthesia-related complications in the 47,748 charts reviewed from 1998 to 2010. Applying Hanley's formula for rare events that have not occurred, the upper 95% confidence interval for the true incidence of anesthesia-related complications for women having abortion under low-dose procedural sedation without fasting was estimated to be 0.00006%. CONCLUSIONS: This large retrospective cohort chart review identified no complications related to low-dose procedural sedation in over 47,000 consecutive nonfasting patients having abortions through 18 weeks' gestation. Eliminating the requirement to fast would decrease unnecessary stress and unpleasant symptoms without increase in the anesthesia-related complications for women having abortions. PMID- 22840277 TI - Revisiting optimal hormonal contraception following bariatric surgery. PMID- 22840279 TI - Estimating contraceptive efficacy: the case of spermicides. PMID- 22840278 TI - A randomized controlled study of two educational interventions on adherence with oral contraceptives and condoms. AB - BACKGROUND: The study was conducted to examine the effectiveness of two different interventions on oral contraception (OC) adherence and condom use. STUDY DESIGN: A total of 1,155 women 16-24 years of age requesting OC were randomized to receive either face-to-face behavioral counseling and education at their baseline clinic visit (C group; n=383) or this same intervention followed by monthly phone calls for 6 months (C+P group; n=384) or standard care (S group; n=388). Phone interviews at 3, 6 and 12 months after the initial visit as well as a medical record review assessed OC continuation, condom use and several other secondary and clinically meaningful outcomes such as pregnancy and sexually transmitted infection (STI) rates and correct use of pills. RESULTS: The interventions did not have a significant effect on OC continuation after 3 (C+P: 58%; C: 50%; S: 55%), 6 (39%; 32%; 37%) or 12 months (20%; 18%; 20%) (p>.05). Condom use at last sexual intercourse did not differ by intervention methods (p>.05). Moreover, no effect was observed on pregnancy [S=48 (12.4%), C =63 (16.5%), C+P=52 (13.5%); p=.22] and STI [S=18 (4.6%), C=12 (3.1%), C+P=13 (3.4%); p=.50] rates, and mean number of correctly used pill packs (p=.06). However, those randomized to C+P were more likely than C and S patients to identify a cue and report that the cue worked as a reminder to take their OC on time based on 3 and 6 months follow-up information (p<.01 for all relationships). CONCLUSIONS: Neither intervention in this study improved OC adherence among young women. PMID- 22840280 TI - Extending contraceptive coverage under the Affordable Care Act saves public funds. AB - BACKGROUND: The Affordable Care Act (ACA) will expand health care coverage to low income Americans. Contraception services are a mandated component of ACA plans. STUDY DESIGN: A decision-analytic model was developed to compare the costs and outcomes of the current versus the proposed plan for contraceptive coverage (Federal Poverty Level=185% vs. 399%, respectively) over 5 years. The perspective adopted was that of Oregon state insurance providers. The primary outcomes were number of pregnancies averted, health costs and quality adjusted life years (QALYs). Contraceptive failure rates, costs, projected insurance coverage, contraception use and pregnancy outcome data were obtained from the published literature. Sensitivity analyses were performed for all variables. RESULTS: Extending contraceptive coverage both saves money and improves outcomes for Oregon state insurance plan providers. The proposed policy would prevent an additional 72 pregnancies per 1000 women over 5 years. Extending coverage is cost effective, saving an additional $489 per woman enrolled over 5 years while increasing QALYs. CONCLUSIONS: Expanding contraceptive coverage under the Affordable Health Act is cost-effective for Oregon state insurance providers. PMID- 22840281 TI - The development of an automatic recognition system for earmark and earprint comparisons. AB - The value of earmarks as an efficient means of personal identification is still subject to debate. It has been argued that the field is lacking a firm systematic and structured data basis to help practitioners to form their conclusions. Typically, there is a paucity of research guiding as to the selectivity of the features used in the comparison process between an earmark and reference earprints taken from an individual. This study proposes a system for the automatic comparison of earprints and earmarks, operating without any manual extraction of key-points or manual annotations. For each donor, a model is created using multiple reference prints, hence capturing the donor within source variability. For each comparison between a mark and a model, images are automatically aligned and a proximity score, based on a normalized 2D correlation coefficient, is calculated. Appropriate use of this score allows deriving a likelihood ratio that can be explored under known state of affairs (both in cases where it is known that the mark has been left by the donor that gave the model and conversely in cases when it is established that the mark originates from a different source). To assess the system performance, a first dataset containing 1229 donors elaborated during the FearID research project was used. Based on these data, for mark-to-print comparisons, the system performed with an equal error rate (EER) of 2.3% and about 88% of marks are found in the first 3 positions of a hitlist. When performing print-to-print transactions, results show an equal error rate of 0.5%. The system was then tested using real-case data obtained from police forces. PMID- 22840282 TI - Are there population differences in minutiae frequencies? A comparative study of two Argentinian population samples and one Spanish sample. AB - In recent years, both scientific and judicial sources have highlighted the need for more knowledge about minutiae variability, in order to improve their statistical application to fingerprint identification. In line with this trend toward improving our knowledge of this subject, the aim of the present study was to calculate the frequency with which 20 types of minutiae appeared in 2780 fingerprint impressions obtained from 278 individuals from two Argentinian population samples (100 individuals from Ramal and 178 from Puna-Quebrada). The different types of minutiae were located, identified, and quantified visually in two areas on the fingerprint, the inside and outside of a circle, the radius of which cut fifteen ridges perpendicularly, starting from the center cut of the axes defining the sectors. The non-equiprobability found in both population samples for the different minutiae types studied demonstrated that the evidential weight provided by these characteristics is not the same when applied in identification processes, whether used quantitatively (numerical standard) or qualitatively (holistic method). The results obtained for both populations were compared statistically with those published previously for a Spanish population sample, which had been collected using the same methodology. This comparison has enabled us to demonstrate, for the first time, the existence of significant differences between populations in minutiae frequencies, independently from the main pattern type. PMID- 22840283 TI - Nanotechnology for forensic sciences: analysis of PDMS replica of the case head of spent cartridges by optical microscopy, SEM and AFM for the ballistic identification of individual characteristic features of firearms. AB - A novel application of replica molding to a forensic problem, viz. the accurate reproduction of the case head of gun and rifle cartridges, prior and after been shot, is presented. The fabrication of an arbitrary number of identical copies of the region hit by the firing pin and by the breech face is described. The replicas can be (i) handled without damaging the original evidence, (ii) distributed to different law enforcement agencies for comparison against other evidences found on crime scenes or ballistic tests of seized firearms, (iii) maintained on a file by the laboratories. A detailed analysis of the morphological features of the replicas has been carried out by standard microscopy techniques as well as by advanced microscopy such as scanning probe and scanning electron leading to a quantitative morphological characterization of the case heads down to the nanometer scale. The assignment of the cartridge replicas to the shooting weapon is demonstrated to hold below the micron scale, while it is hindered at the nanometer level both by the manufacturing differences and by eventual modifications occurring on the firing pin. PMID- 22840284 TI - Zoonotic pathogens among white-tailed deer, northern Mexico, 2004-2009. PMID- 22840285 TI - Total palliative care for a patient with multiple cerebral infarctions that occurred repeatedly in association with gastric cancer (Trousseau's syndrome). AB - OBJECTIVE: Malignancy-related thromboembolism, also referred to as Trousseau's syndrome, can present as acute cerebral infarction, nonbacterial thrombotic endocarditis (NBTE), and migratory thrombophlebitis. Therefore, many physical, neurological, and psychological symptoms associated with Trousseau's syndrome may occur in the clinical course. METHOD: To illustrate this, we report a case of a male patient in his 50s with carcinomatous peritonitis caused by gastric cancer, with multiple cerebral infractions that developed during disease progression. The patient was admitted to our hospital for the treatment of side effects of chemotherapy, although he strongly hoped to go home as soon as possible. In addition to making social supports plans, we were required to perform intensive total palliative care, because of his physical pain, general fatigue, anorexia, abdominal and neck pain, and psychological issues (insomnia, delirium, depression, suicidal thoughts, self-mutilation, panic attacks, agoraphobia, fear of death, and feelings of hopelessness). RESULTS: To the best of our knowledge, based on the literature search, this is the first reported case of Trousseau's syndrome described in the context of total palliative care, especially psychological care. SIGNIFICANCE OF RESULTS: We propose that neurological symptoms of Trousseau's syndrome cause these extensive mental disorders. Furthermore, because of the prognosis of Trousseau's syndrome, we should utilize our expertise fulfill the patient's wishes. PMID- 22840286 TI - The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy. AB - The mechanism underlying the weight gain due to treatment with olanzapine and other second generation antipsychotics has not been fully understood. To examine olanzapine's weight gain effects, we accepted first attack psychotic patients with no medication (pre-treatment) (n=22) and the healthy control group (n=26) in this study. After patients diagnosis, they were hospitalized and then treated for four weeks with olanzapine (post-treatment). We used case-control association design to test body mass index (BMI) and biochemical changes in each group. We also investigated peripheral leptin and neuropeptides/hormones namely, pro opiomelanocortin (POMC), cocaine and amphetaime regulated transcript (CART), and neuropeptide Y (NPY) levels. These neuropeptides which are synthesized/secreted from arcuate nucleus of hypothalamus affect food intake and therefore, body weight. After 4 weeks of olanzapine treatment; BMI (body mass index), waist circumference, blood triglyceride, total cholesterol, and very low density lipoprotein (VLDL) levels were increased significantly in patients compared to their pre-treatment baseline. In pre-treatment, patients' NPY levels were significantly lower while alpha-MSH, the anorexigenic product of POMC levels were significantly higher vs. control. Both leptin and NPY levels were significantly increased in patients after the treatment but the NPY levels were also significantly lower in post-treatment vs. the control group. The CART levels did not change after the treatment. We may presume that the antagonist effect of olanzapine on the serotonin (5HT2CR and 5HT1BR) receptors of the arcuate hypothalamic neurons may be a basis for a deregulation of the neurohormones secretion. PMID- 22840287 TI - Associations between cognitive performance and cortisol reaction to the DEX/CRH test in patients recovered from depression. AB - BACKGROUND: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depression (MDD) is one of the most reliably reported neurobiological characteristics of affective disorders. Whether these alterations in HPA axis regulation are limited to the acute stage of MDD or whether they persist after recovery, remains ambiguous. A relationship between hypercortisolemia and cognitive dysfunction in acutely depressed patients has been repeatedly observed and it was also demonstrated in a number of studies that a discrete cognitive impairment often persists in the remitted state of depression. In the present study we were interested, whether these subtle impairments in cognitive functioning observed in patients recovered from depression compared to healthy control subjects are associated with HPA axis feedback sensitivity. METHODS: In 20 recovered patients and 20 matched healthy controls we assessed HPA axis feedback sensitivity with the combined dexamethasone suppression/corticotropin releasing-hormone (DEX/CRH) challenge test. Furthermore cognitive performance was investigated with respect to the following domains: verbal memory (Auditory Verbal Learning Test, VLMT), attention and executive control (Trail Making Test, TMT-A/B) as well as verbal fluency (Controlled Oral Word Association Test, COWAT). RESULTS: Recovered patients showed a significantly poorer cognitive performance compared to healthy controls (all p<.05). With regard to HPA-axis activity, no overall difference was observed in the DEX/CRH test between recovered patients and controls. In recovered patients however, a significant association was observed between cortisol response and verbal memory (main effect VLMT trial 1-5: p=.046), attention (main effect TMT-A: p=.015) and executive functioning in terms of set shifting (interaction samples*TMT-B: p=.018). Poorer test performance was related to increased cortisol levels in response to challenge. CONCLUSIONS: The present findings suggest that patients recovered from MDD are especially vulnerable toward detrimental effects of subtle HPA axis disturbances on cognitive performance. PMID- 22840288 TI - Key messages from the conference master-classes. PMID- 22840289 TI - Health and wellbeing: the 21st century agenda. PMID- 22840290 TI - Balloon-assisted enteroscopy in patients with surgically altered anatomy: a liver transplant center experience (with video). PMID- 22840291 TI - Segmental increases in force application during colonoscope insertion: quantitative analysis using force monitoring technology. AB - BACKGROUND: Colonoscopy is a frequently performed procedure that requires extensive training and a high skill level. OBJECTIVE: Quantification of forces applied to the external portion of the colonoscope insertion tube during the insertion phase of colonoscopy. DESIGN: Observational cohort study of 7 expert and 9 trainee endoscopists for analysis of colonic segment force application in 49 patients. Forces were measured by using the colonoscopy force monitor, which is a wireless, handheld device that attaches to the insertion tube of the colonoscope. SETTING: Academic gastroenterology training programs. PATIENTS: Patients undergoing routine screening or diagnostic colonoscopy with complete segment force recordings. MAIN OUTCOME MEASUREMENTS: Axial and radial force and examination time. RESULTS: Both axial and radial force increased significantly as the colonoscope was advanced from the rectum to the cecum. Analysis of variance demonstrated highly significant operator-independent differences between segments of the colon (zones) in all axial and radial forces except average torque. Expert and trainee endoscopists differed only in the magnitude of counterclockwise force, average push/pull force rate used, and examination time. LIMITATIONS: Small study, observational design, effect of prototype device on insertion tube manipulation. CONCLUSION: Axial and radial forces used to advance the colonoscope increase through the segments of the colon and are operator independent. PMID- 22840292 TI - Endoscopic retrograde appendicitis therapy: a pilot minimally invasive technique (with videos). AB - BACKGROUND: Inspired by the success of ERCP for the treatment of suppurative cholangitis, we investigated a new minimally invasive method for the treatment of acute uncomplicated appendicitis, which we call endoscopic retrograde appendicitis therapy. OBJECTIVE: To investigate the feasibility and efficacy of endoscopic retrograde appendicitis therapy for the treatment of acute uncomplicated appendicitis. DESIGN AND SETTING: A retrospective, single-center study at an academic medical center. PATIENTS: Four patients with acute uncomplicated appendicitis. INTERVENTIONS: There were 5 steps after insertion of a colonoscope into the cecum and identification of the appendiceal orifice: (1) endoscopic appendiceal intubation; (2) appendiceal decompression; (3) retrograde appendicography; (4) stent drainage; and (5) cleansing the appendiceal lumen. MAIN OUTCOME MEASUREMENTS: The rate of successful endoscopic intubation and decompression, the time to symptom relief, the time to disappearance of signs, increased white blood cell count, procedure-related complications, and recurrence, if any. RESULTS: All 4 endoscopic appendiceal intubations were successful. Pain was relieved immediately after endoscopic decompression and stent drainage. Leukocytosis returned to normal within 24 hours. There were no complications and no recurrences during 4 to 19 months of follow-up. LIMITATIONS: Small sample size, single-center study without controls. CONCLUSION: Endoscopic retrograde appendicitis therapy is a feasible and effective endoscopic treatment modality for acute uncomplicated appendicitis. PMID- 22840293 TI - Intragastric balloon significantly improves nonalcoholic fatty liver disease activity score in obese patients with nonalcoholic steatohepatitis: a pilot study. AB - BACKGROUND: There is no satisfactory treatment for nonalcoholic steatohepatitis (NASH). The Bioenterics intragastric balloon (BIB) can be an effective treatment for weight reduction in obese patients. OBJECTIVE: We evaluated the efficacy of the BIB in improving the histology of NASH in obese patients. DESIGN: Randomized, controlled study. SETTING: University hospital. PATIENTS: Obese patients with body mass indexes (BMI) >=27 kg/m(2) and who had histologic evidence of NASH were recruited. INTERVENTION: Patients were randomly assigned to a step 1 American Heart Association (AHA) diet plus exercise and BIB placement or step 1 AHA diet plus exercise and sham BIB placement for a period of 6 months. MAIN OUTCOME MEASUREMENTS: Liver histology was the primary outcome measure recorded before and after treatment. RESULTS: A total of 18 patients completed the study. Baseline characteristics of the BIB and sham groups were similar. At 6 months, a significant reduction in the mean BMI was seen in the BIB group (1.52 vs 0.8; P = .0008). The median nonalcoholic fatty liver disease activity scores at the end of treatment were significantly lower in the BIB-treated compared with the sham treated groups (2 [0.75] vs 4 [2.25]; P = .03). There was a trend toward improvement in the median steatosis scores (1 [0.75] vs 1 [1]; P = .075). There was no change in the median loblular inflammation, hepatocellular ballooning, or fibrosis scores in both groups after treatment. LIMITATIONS: Pilot study with small numbers and short duration. CONCLUSION: Results from this pilot study demonstrated that addition of BIB for 6 months provided a greater loss of BMI and improvement in 2 of 5 histologic parameters of nonalcoholic fatty liver disease. A longer study with larger numbers will be required to prove whether or not the therapy is meaningful in the treatment of NASH. PMID- 22840294 TI - Endoscopic duodenal variceal ligation: a series of 4 cases and review of the literature (with video). PMID- 22840295 TI - Impact of patient education with cartoon visual aids on the quality of bowel preparation for colonoscopy. AB - BACKGROUND: High-quality bowel preparation is a prerequisite for colonoscopy. Few studies have evaluated visual aids as a means of improving the quality of bowel preparation. OBJECTIVE: To assess the effect of patient education by using cartoon visual aids on the quality of bowel preparation. DESIGN: An endoscopist blinded, randomized, controlled trial. SETTING: Tertiary referral center. SUBJECTS: Patients scheduled for screening colonoscopy in a health examination center. INTERVENTIONS: Patients were assigned to receive the existing verbal and written instructions (group A) or a new cartoon visual educational instruction (group B) for colonoscopy. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the quality of bowel preparation, assessed by using the Boston Bowel Preparation Scale (BBPS). Secondary endpoints were the quality of bowel preparation assessed by using the Universal Preparation Assessment Scale; insertion, withdrawal, and workup times; and polyp detection rates in the 2 groups. Logistic regression analysis was performed to determine the factors associated with poor bowel preparation according to a BBPS score less than 5. RESULTS: Group B exhibited better bowel preparation than group A according to BBPS scores (mean BBPS score, 6.12 +/- 2.19 vs 7.44 +/- 1.87, P <= .01; median BBPS score, 6.00 +/- 0.00 vs 9.00 +/- 0.00, P <= .01; good bowel preparation for colonoscopy, BBPS score >=5, 81.6% vs 93.1%, P = .02). Multivariate analysis revealed that older age (odds ratio 1.07, P <= .01) and no use of visual aids (odds ratio 3.08, P = .02) were independent factors associated with poor bowel preparation. LIMITATIONS: Single center study. CONCLUSIONS: Patient education with cartoons effectively improved bowel preparation for colonoscopy. PMID- 22840296 TI - Inherent propensity of amnion-derived mesenchymal stem cells towards endothelial lineage: vascularization from an avascular tissue. AB - One of the most pressing problems in injury is wound healing and blood vessel formation. The amniotic membrane is important in clinical applications as it is pro-angiogenic, anti-fibrotic and anti-scarring and has low immunogenicity. In this study, we characterized amniotic membrane mesenchymal stem cells (AMMSCs) by their trademark mesenchymal stem cell (MSC) signature and profiled for embryonic pluripotency markers namely alkaline phosphatase, Oct4, Sox2, Nanog, SSEA3 and 4, and Klf4 by RT-PCR and nuclear localization of Oct4 and Nanog by immunocytochemistry. The amnion, although avascular, contains pro-angiogenic factors such as type I, III, IV and V collagen, laminin, and fibronectin in the extra cellular matrix. We, therefore, hypothesized that AMMSCs is pro-angiogenic. Thus, we demonstrate that MSCs derived from the amnion have a natural ability to initiate endothelialization and angiogenesis in vitro. Our results using a wound scratch assay and angiogenesis on Matrigel suggest a pro-angiogenic property of AMMSCs. We also show that native, uninduced AMMSCs are able to form endothelial rings in Matrigel. Further evidence was provided by RT-PCR showing the expression of pro-angiogenic factors such as Tie2, Ang1, VEGF, VEGFR, vWF, KDR and Flt4 in native AMMSCs. Taken together, our results suggest that MSCs from an avascular amnion have an inherent propensity for promoting angiogenesis and could be an ideal choice in wound healing, stroke and ischemic diseases that require rapid vascularization and tissue restoration. PMID- 22840298 TI - The evolutionary significance of placental interdigitation in mammalian reproduction: contributions from comparative studies. AB - The placenta is fundamental to mammalian reproduction and is surprisingly diverse in gross morphology among species. Whether and how this diversity affects maternal investment and fetal growth is still poorly understood. Contrary to suggestions that highly invasive hemochorial placentation is beneficial to fetal development, recent comparative studies have revealed that interdigitation - the degree of contact between maternal and fetal tissues at the area of exchange - strongly influences fetal growth rates. Species with labyrinthine placentae give birth to neonates of similar size to those of species with villous or trabecular placentae but in less than half the time. These findings suggest that there might be tradeoffs between fetal growth rates (higher with greater interdigitation) and gestation time (shorter with greater interdigitation), in association with type of interdigitation. Such tradeoffs might be the results of maternal-offspring conflict over the allocation of maternal resources, with paternal genes favouring greater interdigitation and so higher fetal growth, and maternal genes responding by reducing gestation time. These results emphasize the role of interdigitation as a means to increase the surface area for exchange, and are consistent with within species studies demonstrating that a higher surface area for exchange is associated with heavier neonates. Further studies could investigate the role of other traits in the evolution of placental diversity and their impact on fetal development. PMID- 22840297 TI - MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. AB - Preeclampsia (PE) affects 5-8% of all pregnancies and is associated with significant maternal and fetal morbidity and mortality. Placental mitochondrial dysfunction has been reported in PE. MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression through mRNA degradation and translational repression. MiR-210 has been previously shown to be upregulated in placentas from pregnancies complicated by PE. We hypothesized that placental mitochondrial dysfunction during PE can be mediated by miR-210. Placentas were collected at term from normotensive pregnancies (CTRL) and those complicated by severe PE (n = 6 each) following c-section (no labor). Villous tissue from PE showed significantly increased levels of HIF-1alpha compared to CTRL with no change in corresponding mRNA expression but with reduced DNA-binding activity. Mitochondrial complex III was significantly decreased in PE along with significantly reduced protein expression in complex I and IV during PE. Among the four miRNAs tested, miR-210 showed significant up regulation in PE and significant downregulation of its target, ISCU mRNA. To understand the role of miR-210 in PE, loss- and gain-of-function studies were performed using primary trophoblasts. Trophoblasts were transfected with miR-210 inhibitor or pre-miR-210 and mitochondrial function was measured using Seahorse Extracellular Flux Analyzer. Cells transfected with pre-miR-210 showed significant reduction in oxygen consumption. In contrast, transfection of trophoblast with AntagomiR-210 was sufficient to prevent the DFO-mediated respiratory deficiency. These data collectively suggest that miR-210 overexpression during PE could be responsible for placental mitochondria dysfunction. PMID- 22840299 TI - Combined use of rapid pacing and adenosine facilitates catheter based correction of severe bileaflet prolapse with the MitraClip system. AB - The results of the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) II trial have demonstrated that percutaneous mitral valve repair using the MitraClip in high-risk patients was associated favourable outcomes. However, commonly accepted contraindications for the standard MitraClip procedure include extensively prolapsed valves and flail leaflets. We report on the management of a patient not amenable to standard interventional procedure. PMID- 22840300 TI - Anticoagulation management pre- and post atrial fibrillation ablation: a survey of canadian centres. AB - BACKGROUND: Anticoagulation in patients undergoing atrial fibrillation (AF) ablation is crucial to minimize the risk of thromboembolic complications. There are broad ranges of approaches to anticoagulation management pre and post AF ablation procedures. The purpose of this study was to determine the anticoagulation strategies currently in use in patients peri- and post AF ablation in Canada. METHODS: A Web-based national survey of electrophysiologists performing AF ablation in Canada collected data regarding anticoagulation practice prior to ablation, periprocedural bridging, and duration of postablation anticoagulation. RESULTS: The survey was completed by 36 (97%) of the 37 electrophysiologists performing AF ablation across Canada. Prior to AF ablation, 58% of electrophysiologists started anticoagulation for patients with paroxysmal AF CHADS(2) scores of 0 to 1, 92% for paroxysmal AF CHADS(2) scores >= 2, 83% for persistent AF CHADS(2) scores of 0 to 1, and 97% for persistent AF CHADS(2) scores >= 2. For patients with CHADS(2) 0 to 1, warfarin was continued for at least 3 months by most physicians (89% for paroxysmal and 94% for persistent AF). For patients with CHADS(2) >= 2 and with no recurrence of AF at 1 year post ablation, 89% of physicians continued warfarin. CONCLUSIONS: Although guidelines recommend long-term anticoagulation in patients with CHADS(2) >= 2, 11% of physicians would discontinue warfarin in patients with no evidence of recurrent AF 1 year post successful ablation. Significant heterogeneity exists regarding periprocedural anticoagulation management in clinical practice. Clinical trial evidence is required to guide optimal periprocedural anticoagulation and therapeutic decisions regarding long-term anticoagulation after an apparently successful catheter ablation for AF. PMID- 22840301 TI - Clinical equivalence of proprietary and generic atorvastatin in lipid clinic patients. AB - BACKGROUND: The loss of patent protection for proprietary statins offers affordability advantages to payers, but some clinicians still question the efficacy of generic formulations in real-world clinical applications. METHODS: In this retrospective cohort study, we examined the effects of generic atorvastatin substitution on relevant biochemical parameters in 85 dyslipidemic patients who had been previously maintained on stable doses of proprietary atorvastatin from 2009 to 2011. For comparison, we studied 143 patients who were continuously prescribed stable doses of rosuvastatin, which was only available in its proprietary formulation over the same time period. RESULTS: We found that substitution of generic for proprietary atorvastatin was not associated with significant changes in plasma levels of total or low-density lipoprotein cholesterol, or triglycerides, but was associated with a small but significant increase in high-density lipoprotein cholesterol. Plasma levels of aspartate aminotransferase and creatine kinase were also unchanged. Additionally, the changeover to generic atorvastatin was not associated with increased switching to another statin or more frequent changes in other lipid-lowering medications compared with the proprietary rosuvastatin group. CONCLUSIONS: Substituting generic for proprietary atorvastatin in lipid clinic patients was not associated with significant changes in efficacy, adverse events, or patient management. PMID- 22840302 TI - The challenge of timing surgery in a complex case of endocarditis. AB - While the results of clinical trials are useful in guiding management of the "average" patient, physicians are often left to their own devices when confronted with cases that neither fulfil the entrance criteria for clinical trials nor conveniently match evidence-based guidelines. We present a teaching exercise, built around a complex case of endocarditis, in a branched self-assessment format that challenges the reader's clinical judgement. The case involves a woman aged 45 years with decompensated liver cirrhosis who presents with endocarditis complicated by heart failure and multiple systemic emboli. The risk-to-benefit ratio for urgent surgical intervention tilts as the complications accumulate. PMID- 22840303 TI - Patient satisfaction after total knee and hip arthroplasty. AB - Patient satisfaction is an important outcome measurement in TKA/THA surgery. Patient satisfaction can be evaluated from 2 perspectives, determinants of satisfaction and components of satisfaction.(5) In total joint arthroplasty, improvements in satisfaction can be achieved by examining these perspectives. Patient satisfaction is one of the many PROMs used in orthopedic surgery and is an integral part of the growing sentiment to evaluate surgery from the patient's perspective as well as from the surgeon's. The importance of measuring outcomes from the patient perspective is integral to today's patient-centered models of care. PMID- 22840304 TI - Patient-reported outcomes for total hip and knee arthroplasty: commonly used instruments and attributes of a "good" measure. AB - Although the effectiveness of THA and TKA as interventions for end-stage degenerative joint disease has been well established, the use of instruments that measure outcome from the patient's perspective are relatively poorly investigated. Considering the increasing prevalence, associated risks, and high personal and financial cost associated with THA and TKA, patient-reported outcomes are required to ensure optimal selection of patients, and that postoperative outcomes outweigh the burden associated with surgical procedures. It is clear from the information presented that clinicians need to consider a number of factors when selecting a "good" patientreported outcome for use in their TJA patients. Not only does the instrument need to measure dimensions appropriate for THA and TKA patients, but it also needs to have minimal administrative burden, accessibility to a variety of clinicians and patients, reliability, validity, and responsiveness to change. Furthermore, knowledge regarding the minimal score that patients deem to be meaningful is useful in interpreting whether a patient has experienced real improvement in their condition after surgery. It is clear that further studies are required, particularly to fill some of the gaps regarding known psychometric properties of patient-reported outcomes for THA and TKA. Based on data acquired in THA and TKA patients for the instruments reviewed, it appears that OA-specific and TJA specific measures for which patients have been involved in the developmental process (HOOS, KOOS, WOMAC, Oxford Hip and Knee Scores) can more consistently be considered "good" patient-reported outcomes for THA and TKA. Clinicians wishing to evaluate a broader range of dimensions may choose to complement these with one of the generic measures evaluated, bearing in mind the practical issues and psychometric limitations of these instruments when applied to THA and TKA patients. PMID- 22840305 TI - Health-related quality of life after total joint arthroplasty: a scoping review. AB - A scoping review was completed to summarize the change in health status after THA and TKA. Although a recent study has performed a systematic review of functional recovery after THA,(61) we reviewed a broad topic of HRQL changes after total joint arthroplasty. This scoping review was not restricted by study design; however, the majority of studies were prospective single group, observational studies so that change over time could be reported. A variety of HRQL measures were used, including disease-specific, generic, and utility measures. We reported on 33 studies that met our inclusion criteria. Most studies' primary outcomes were disease-specific measures. Not surprisingly, MCIDs were reported with recovery both short term and long term. These clinically relevant changes were accompanied with large effect sizes for pain and function using disease-specific measures such as the WOMAC. In general, smaller changes were reported with joint stiffness; however, this may also be related to inherent measurement properties of the WOMAC in that it uses two questions to evaluate stiffness. Overall, large effect sizes, in excess of 1.0, were seen not only short term but also long term, that is, more than a year after surgery. The changes may also be reflected in the low rate of complications reported with total joint arthroplasty.(62) The generic health measures showed a smaller magnitude of change, which is to be expected given the construct of these measures evaluate overall health and includes the effect of other health conditions. That being said, the largest changes were seen in those domains that were primary to total joint arthroplasty, pain and physical function. A challenge of evaluating change of health status after total joint arthroplasty is that each measure has individual strengths and limitations. This review introduced the measures and the MCIDs when available to evaluate clinical change. The derived MCIDs should be considered carefully because these values are dependent on a number of features such as the study setting, methodology used to derive the values, baseline scores, and severity of the disease.(63) Change over time was also presented by the effect sizes. The effect size provided another perspective to measuring recovery after total joint arthroplasty in which comparison across measures can be made. Regardless of the type of outcome measure, large effect sizes are seen with total joint arthroplasty both over short-term and long-term outcomes. Because a number of HRQL measures are used to evaluate the outcomes after total joint arthroplasties, comparisons can be challenging. This review summarized published findings to help place the magnitude of change seen with total joint arthroplasty in perspective. Changes seen with HRQL are one aspect of evaluating outcomes from a patient perspective; however, recovery is a complex concept(64) that needs many clinical and research oriented measures to evaluate the full spectrum of recovery. PMID- 22840306 TI - Revision total hip and knee replacement. AB - The number of primary and revision total joint arthroplasty procedures is increasing exponentially with time. It is anticipated that there will be a huge expected demand for revision knee surgery over the next 2 decades. Knee revisions alone are projected to increase by 601% between 2005 and 2030 in the United States.(2) Awareness is needed by both general practitioner and physician for the signs of failure of these implants and when to refer to the surgeon. Infection remains the primary cause to exclude first. Unless the surgeon accurately identifies the mode of failure, successful treatment becomes very unlikely; an increasing physical burden on the patient and financial burden on hospital trusts ensues. In comparison with primary joint arthroplasty, complication rates after revision surgery are significantly increased, and outcome is less assured. PMID- 22840307 TI - Minimally invasive total hip and knee arthroplasty-implications for the elderly patient. AB - Overall, it can be concluded that because of the aging society, an increasing number of elderly people will be undergoing total joint arthroplasty. These elderly patients have an increased risk for serious complications after primary THA or TKA. However, the overall complication rates remain low. The use of MIS total joint arthroplasty is also increasing, although its risks and benefits are still an ongoing issue of debate in the orthopedic community. MIS total joint arthroplasty aims at decreasing the surgical incision and minimizing damage to the underlying soft tissue to accelerate postoperative recovery and an earlier return to normal function. A critical look at the literature on MIS shows that the term minimally invasive is often used for a conventional total joint arthroplasty performed through a smaller skin incision. Research has shown promising results of using MIS in elderly patients; it seems that compared with younger patients, elderly patients benefit more from a minimally invasive approach. PMID- 22840308 TI - Pharmacologic pain management before and after total joint replacement of the hip and knee. AB - There are many effective treatment measures for OA of the hip or knee, with varying degrees of effectiveness. Nonoperative measures include patient education, physical therapy, activity modification, weight loss, and medications. Pharmacologic strategies include acetaminophen, NSAIDs, injections of cortisone or viscosupplementation, and, less commonly, tramadol or other pain relievers. In patients who may be candidates for TJR, narcotic medications should be avoided to preserve their benefits for the postoperative period. Over the past 20 years, multimodal pain management has been beneficial to the patient undergoing TJR surgery. Studies have shown this form of pain management decreases postoperative opioid consumption and the related adverse effects. Research is warranted in the areas of postoperative pain scores and patient satisfaction as institutional multimodal protocols continue to evolve. PMID- 22840309 TI - Perioperative complications following total joint replacement. AB - Total joint arthroplasty is a safe and highly effective treatment for moderate to severe osteoarthritic symptoms and other causes of joint derangement in the elderly population. Significant improvements in pain, function, and quality of life are nearly universal, with a low rate of complications and adverse outcomes. Because of its success and cost-effectiveness, the rate of utilization of TJR is increasing, and all health care providers must be familiar with the potential complications and perioperative management of these patients. Elderly patients may be at a higher risk for postoperative medical complications; however, the majority of these complications are minor and many are avoidable with appropriate preoperative screening and careful postoperative management. As with all patients undergoing TJR, patients should be prophylactically treated for infection and thromboembolism and carefully followed for the development of these potential complications as well as fracture, hip dislocation, and neurovascular dysfunction. Postoperative delirium may be minimized and prophylactically treated in appropriate elderly patients to maximize recovery and promote safety. PMID- 22840310 TI - Rehabilitation and total joint arthroplasty. AB - The long-term outcomes following primary TJA for OA are favorable. However, surgery alone fails to fully restore physical function and address longstanding impairments associated with chronic joint disease. Older adults undergoing TJA can gain similar benefits as those who are younger; however, the elderly are at increased risk for adverse events. Frailty, more so than age, is related to suboptimal outcomes. To what extent appropriate and sufficient rehabilitation can further improve health outcomes including activity and participation and positively impact prosthesis survival and need for revision is still unclear. There is evidence to suggest that evaluation and management of perioperative psychosocial and other patient factors are important in enhancing outcomes after TJA. Further, there is a growing body of research that points to the importance of progressive resistance training after TJA to address the muscle weakness associated with aging and end-stage hip and knee OA, and secondary to the surgery itself, and to optimize functional outcomes. With the projected increases in number of individuals undergoing TJA over the next two decades, it becomes even more critical to develop cost-effective rehabilitation strategies and identify individuals who would most benefit from such interventions. PMID- 22840311 TI - Physical activity participation among patients after total hip and knee arthroplasty. PMID- 22840312 TI - Race/ethnicity and use of elective joint replacement in the management of end stage knee/hip osteoarthritis: a review of the literature. AB - Although much research has documented disparities exist for utilization of TJA, additional studies have shown that we have not narrowed the gap. Because multiple studies have shown that insurance and access to care are not necessarily underlying causes for these disparities, other studies have shown that there are real and significant differences between racial/ethnic groups in preferences for and expectations of joint arthroplasty. Additional research has established there are racial differences in certain postoperative processes and outcomes. Reasons have not been elucidated, but highlight the need for more research to understand these differences, their causes, and then to design interventions to minimize these inequalities. PMID- 22840313 TI - Preface. Total joint arthroplasty. PMID- 22840314 TI - Comparison of enzootic risk measures for predicting West Nile disease, Los Angeles, California, USA, 2004-2010. AB - In Los Angeles, California, USA, 2 epidemics of West Nile virus (WNV) disease have occurred since WNV was recognized in 2003. To assess which measure of risk was most predictive of human cases, we compared 3 measures: the California Mosquito-Borne Virus Surveillance and Response Plan Assessment, the vector index, and the Dynamic Continuous-Area Space-Time system. A case-crossover study was performed by using symptom onset dates from 384 persons with WNV infection to determine their relative environmental exposure to high-risk conditions as measured by each method. Receiver-operating characteristic plots determined thresholds for each model, and the area under the curve was used to compare methods. We found that the best risk assessment model for human WNV cases included surveillance data from avian, mosquito, and climate sources. PMID- 22840315 TI - Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia. AB - Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)~24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy. PMID- 22840316 TI - Pregnancy in a patient with anterior sacral meningocele and bicornuate uterus. PMID- 22840317 TI - Expression of KITENIN and its association with tumor progression in oral squamous cell carcinoma. AB - OBJECTIVE: KAI1 COOH-terminal interacting tetraspanin (KITENIN) contributes to tumor invasion and metastasis in various cancers. The aim of this study was to investigate expression of KITENIN in patients with oral cavity squamous cell carcinoma (SCC) and to determine whether KITENIN affects tumor cell behavior in oral cavity SCC cell line. METHODS: Western blotting and immunohistochemistry was used to assess alteration of KITENIN expression in human oral cavity SCC and normal oral cavity mucosa. To evaluate the impact of KITENIN knockdown, the cell invasion assay and cell migration assay using small-interfering RNA were performed. RESULTS: KITENIN protein expression was significantly increased in human oral cavity SCC tissues than in normal oral cavity mucosa by Western blotting. KITENIN immunoreactivity was strongly identified in human oral cavity SCC relative to adjacent normal tissue. Knockdown of KITENIN resulted in significantly reduced cell invasion in human oral cavity SCC cells (p=0.001). Cell migration showed a marked decrease in KITENIN knockdown oral cavity SCC cells compared to the negative control oral cavity SCC cells (p=0.01). CONCLUSION: KITENIN is associated with tumor invasiveness and metastasis in human oral cavity SCC. PMID- 22840318 TI - Clinical characteristics and outcome in patients with isolated sphenoid sinus aspergilloma. AB - OBJECTIVE: Isolated sphenoid sinus aspergilloma (ISSA) is a rare disorder that is difficult to diagnose in a timely manner. These lesions can also extend to adjacent structures and thereby cause severe complications. ISSA patients with orbital complications typically have a poor prognosis even when surgical interventions have been successful. We here reviewed 30 ISSA cases with respect to clinical characteristics and treatment outcomes. METHODS: A group of 30 patients diagnosed with ISSA between January 1990 and October 2010 were retrospectively reviewed in terms of clinical manifestations, endoscopic findings, radiologic imaging data, and treatment results. We also compared the clinical manifestations and treatment results between patients with and without orbital complications. RESULTS: Old age (median, 55 years) and a female predominance (23 women in the study) were noted. The most commonly reported symptom was headache (80%) and the average duration of the symptoms before diagnosis was 8.1 months. On radiologic examination, including CT and MRI scans, 13 patients showed bony wall erosions and five patients demonstrated orbital complications including diplopia and visual loss. The appearance of a bony wall erosion on a CT scan and the acute onset of ISSA symptoms were found to be significant factors in the onset of orbital complications (P=0.003 in each case). Endoscopic sphenoidotomy was performed in all 30 cases. Most of the preoperative symptoms among the patients, including headache, facial pain, and postnasal drip, were improved after surgery. Among the five patients in the study group with orbital complications, diplopia was completely resolved after surgery in each case but there was no improvement in visual loss. CONCLUSIONS: An early diagnosis of ISSA, although not easy, is important to prevent complications arising from extensions of these lesions beyond the sphenoid sinus. Our present study demonstrates that ISSA could be effectively treated with an endoscopic sphenoidotomy, and that timely intervention is needed in patients with a sinus bony wall to prevent irreversible complications such as visual loss. PMID- 22840319 TI - Residual tinnitus after the medical treatment of sudden deafness. AB - OBJECTIVES: Some patients with sudden sensorineural hearing loss (SSNHL) are frustrated by residual tinnitus even after accomplishment of the treatment for SSNHL. In the present prospective study, we examined patients' backgrounds of sex, laterality and age together with changes in hearing level and the tinnitus score after the onset of SSHNL to determine the prognostic factors of residual tinnitus after the final day of medical treatment for SSNHL. METHODS: Forty-four patients with SSNHL were all treated with systemic administration of steroids for 2 weeks and oral intake of vasoactive drugs and vitamin B12 for 6 months before accomplishment of the treatment for SSNHL. The hearing improvement rate (HIR) was determined by comparing the hearing level before and 6 months after the start of treatment. Tinnitus was subjectively evaluated by the tinnitus scoring questionnaire before, 6 and 24 months after the start of treatment. The score of a five-step evaluation of subjective tinnitus feelings, "loudness", "duration" and "annoyance", was recorded. RESULTS: HIR was significantly correlated with tinnitus score improvement (TSI) in "duration" at 6 months after the start of treatment compared with before treatment. The tinnitus score of all 3 items was significantly improved 6 months after the start of treatment compared with that before treatment but it was not significantly changed between 6 and 24 months after the start of treatment. TSI in "duration" between 6 and 24 months was significantly correlated with the patients' age and HIR using multiple regression analysis. CONCLUSION: According to the tinnitus scoring questionnaire, "duration" is the most reliable item for subjective evaluation of tinnitus accompanied by SSNHL. Generally, subjective feelings for residual tinnitus 6 months after the start of treatment for SSNHL are supposed to be almost the same, even at the 24th post-treatment month. Especially, younger patients with better hearing improvement are predicted to achieve further improvement of tinnitus between 6 and 24 months after the start of treatment. PMID- 22840320 TI - KIs virus and blood donors, France. PMID- 22840321 TI - Use of mobility aids reduces attentional demand in challenging walking conditions. AB - While mobility aids (e.g., four-wheeled walkers) are designed to facilitate walking and prevent falls in individuals with gait and balance impairments, there is evidence indicating that walkers may increase attentional demands during walking. We propose that walkers may reduce attentional demands under conditions that challenge balance control. This study investigated the effect of walker use on walking performance and attentional demand under a challenged walking condition. Young healthy subjects walked along a straight pathway, or a narrow beam. Attentional demand was assessed with a concurrent voice reaction time (RT) task. Slower RTs, reduced gait speed, and increased number of missteps (>92% of all missteps) were observed during beam-walking. However, walker use reduced attentional demand (faster RTs) and was linked to improved walking performance (increased gait speed, reduced missteps). Data from two healthy older adult cases reveal similar trends. In conclusion, mobility aids can be beneficial by reducing attentional demands and increasing gait stability when balance is challenged. This finding has implications on the potential benefit of mobility aids for persons who rely on walkers to address balance impairments. PMID- 22840322 TI - Differential responses to salinity of two Atriplex halimus populations in relation to organic solutes and antioxidant systems involving thiol reductases. AB - Atriplex halimus L. is a xero-halophyte species widespread in the Mediterranean basin. The tolerance to water stress and high salinity of two Atriplex populations from semi-arid (Djelfa) and arid saline (Laghouat) Algerian regions has been investigated in relation with organic solutes and antioxidant systems. Whereas no noticeable difference was observed between the two populations under water stress resulting from withholding watering or PEG treatment, Laghouat plants display significantly higher fresh and dry weights than Djelfa plants when exposed to high salinity. At 300mM NaCl, Laghouat plants exhibit higher concentrations in Na(+), proline and quaternary ammonium compounds, and a higher catalase activity than Djelfa plants. We then analysed the involvement of recently characterized plastidial thiol reductases, peroxiredoxins (Prxs) and methionine sulphoxide reductases (MSRs), key enzymes scavenging organic peroxides and repairing oxidized proteins, respectively. Upon salt treatment (300mM NaCl), we observed higher amounts of PrxQ and over-oxidized 2-Cys Prx in Laghouat than in Djelfa. An increased abundance of plastidial MSRA and a higher total MSR activity were also noticed in Laghouat plants treated with 300mM NaCl compared to Djelfa ones. We propose that mechanisms based on organic solutes and antioxidant enzymes like catalases, peroxiredoxins and MSRs party underlie the better tolerance of the Laghouat population to high salt. PMID- 22840323 TI - The calcium-dependent protein kinase (PnCDPK1) is involved in Pharbitis nil flowering. AB - Signaling pathways, and specifically the signaling pathway of calcium, have been widely implicated in the regulation of a variety of signals in plants. Calcium dependent protein kinases (CDPKs) are essential sensor-transducers of calcium signaling pathways, the functional characterization of which is of great interest because they play important roles during growth and in response to a wide range of environmental and developmental stimuli. Here, we report the first evidence of transient and specific elevation of PnCDPK1 transcript level and enzyme activity following conversion of a leaf bud to a flower bud, as well as participation of PnCDPK1 in evocation and flower morphogenesis in Pharbitis nil. Fluorescence microscopy immunolocalization and biochemical analysis confirmed the presence of CDPK in shoot apexes. The protein level was low in leaves, vegetative apexes and increased significantly in apexes after a flowering long-induction night. In the vegetative apex, a very weak PnCDPK1 protein signal was accumulated prominently in the zone of the ground meristem and in external layers of tissues of the cortex. After the dark treatment, the signal in cells of the ground meristem was still present, but a significantly stronger signal appeared in epidermal cells, cortex tissue, and leaf primordium. At the onset of flower meristem development, the PnCDPK1 level diverged significantly. PnCDPK1 mRNA, protein level and enzyme activity were very low at the beginning of flower bud development and gradually increased in later stages, reaching the highest level in a fully open flower. Analysis of flower organs revealed that PnCDPK1 was accumulated mainly in petals and sepals rather than in pistils and stamens. Our results clearly indicate that PnCDPK1 is developmentally regulated and may be an important component in the signal transduction pathways for flower morphogenesis. Findings from this research are important for further dissecting mechanisms of flowering and functions of CDPKs in flowering plants. PMID- 22840324 TI - Day light quality affects the night-break response in the short-day plant chrysanthemum, suggesting differential phytochrome-mediated regulation of flowering. AB - Chrysanthemum (Chrysanthemum morifolium) is a short-day plant, which flowers when the night length is longer than a critical minimum. Flowering is effectively inhibited when the required long-night phase is interrupted by a short period of exposure to red light (night break; NB). The reversal of this inhibition by subsequent exposure to far-red (FR) light indicates the involvement of phytochromes in the flowering response. Here, we elucidated the role of light quality in photoperiodic regulation of chrysanthemum flowering, by applying a range of different conditions. Flowering was consistently observed under short days with white light (W-SD), SD with monochromatic red light (R-SD), or SD with monochromatic blue light (B-SD). For W-SD, NB with monochromatic red light (NB-R) was most effective in inhibiting flowering, while NB with monochromatic blue light (NB-B) and NB with far-red light (NB-FR) caused little inhibition. In contrast, for B-SD, flowering was strongly inhibited by NB-B and NB-FR. However, when B-SD was supplemented with monochromatic red light (B+R-SD), no inhibition by NB-B and NB-FR was observed. Furthermore, the inhibitory effect of NB-B following B-SD was partially reversed by subsequent exposure to a FR light pulse. The conditions B-SD/NB-B (no flowering) and B+R-SD/NB-B (flowering) similarly affected the expression of circadian clock-related genes. However, only the former combination suppressed expression of the chrysanthemum orthologue of FLOWERING LOCUS T (CmFTL3). Our results suggest the involvement of at least 2 distinct phytochrome responses in the flowering response of chrysanthemum. Furthermore, it appears that the light quality supplied during the daily photoperiod affects the light quality required for effective NB. PMID- 22840325 TI - Stomatal density and metabolic determinants mediate salt stress adaptation and water use efficiency in basil (Ocimum basilicum L.). AB - Increasing salinity tolerance and water-use efficiency in crop plants are two major challenges that agriculture must face in the next decades. Many physiological mechanisms and molecular components mediating crop response to environmental stresses have been identified. However, the functional inter-links between stress adaptation responses have not been completely understood. Using two basil cultivars (Napoletano and Genovese) with contrasting ability to respond to salt stress, here we demonstrate that reduced stomatal density, high ascorbate level and polyphenol oxidase (PPO) activity coordinately contribute to improve basil adaptation and water use efficiency (WUE) in saline environment. The constitutively reduced stomatal density was associated with a "delayed" accumulation of stress molecules (and growth inhibiting signals) such as abscisic acid (ABA) and proline, in the more tolerant Genovese. Leaf volatile profiling also revealed cultivar-specific patterns, which may suggest a role for the volatile phenylpropanoid eugenol and monoterpenes in conferring stress tolerance via antioxidant and signalling functions. PMID- 22840326 TI - Hsp90 binds microtubules and is involved in the reorganization of the microtubular network in angiosperms. AB - Microtubules (MTs) are essential for many processes in plant cells. MT-associated proteins (MAPs) influence MT polymerization dynamics and enable them to perform their functions. The molecular chaperone Hsp90 has been shown to associate with MTs in animal and plant cells. However, the role of Hsp90-MT binding in plants has not yet been investigated. Here, we show that Hsp90 associates with cortical MTs in tobacco cells and decorates MTs in the phragmoplast. Further, we show that tobacco Hsp90_MT binds directly to polymerized MTs in vitro. The inhibition of Hsp90 by geldanamycin (GDA) severely impairs MT re-assembly after cold-induced de polymerization. Our results indicate that the plant Hsp90 interaction with MTs plays a key role in cellular events, where MT re-organization is needed. PMID- 22840327 TI - Possible therapeutic potential of berberine in diabetic osteopathy. AB - Diabetic osteopathy is a complication that leads to decreased bone mineral density, bone formation and having high risk of fractures that heals slowly. Diabetic osteopathy is a result of increase in osteoclastogenesis and decrease in osteoblastogenesis. Various factors viz., oxidative stress, increased inflammatory markers, PPAR-gamma activation in osteoblast, activation of apoptotic pathway, increased glucose levels and inhibitory effect on parathyroid hormone etc. are mainly responsible for decreased bone mineral density. Berberine is an isoquinoline alkaloid widely used in Asian countries as a traditional medicine. Berberine is extensively reported to be an antioxidant, anti inflammatory, antidiabetic, and having potential to treat diabetic complications and glucocorticoid induced osteoporosis. The osteoclastogenesis decreasing property of berberine can be hypothesized for inhibiting diabetic osteopathy. In addition, chronic treatment of berberine will be helpful for increasing the osteoblastic activity and expression of the modulators that affect osteoblastic differentiation. The apoptotic pathways stimulated due to increased inflammatory markers and nucleic acid damages could be reduced due to berberine. Another important consideration that berberine is having stimulatory effect on glucagon like peptide release and insulin sensitization that will be helpful for decreasing glucose levels and therefore, may exerts osteogenesis. Thiazolidinediones show bone loss due to activation of PPAR-gamma in osteoblasts, whereas berberine stimulates PPAR-gamma only in adipocytes and not in osteoblasts, and therefore the decreased bone loss due to use of thiazolidinediones may not be observed in berberine treatment conditions. Berberine decreases the advanced glycation end-products (AGE) formation in diabetic condition which will be ultimately helpful to decrease the stiffness of collagen fibers due to AGE-induced cross linking. Lastly, it is also reported that berberine has inhibitory effect on parathyroid hormone and enhances marker genes like osteocalcin, which are responsible for the osteoblastic activity. From these evidences, we hypothesized that berberine may have potential in the treatment of diabetic osteopathy. PMID- 22840328 TI - Adoptive transfer of naive dendritic cells in resolving post-sepsis long-term immunosuppression. AB - Following initial episode of sepsis, survivors suffer an increased risk of mortality that persists long-term and remains a significant health care problem. Opportunistic infections and neoplasms are more frequent partially accounting for shorter life expectancy. This suggests that during sepsis the immune system becomes aberrant and is unable to restore its optimal function after the initial insult. Dendritic cells (DC) or their precursors are frequently affected during the initial episode of sepsis as well as after the resolution of symptom. Considering these cells' pivotal role in regulating innate and acquired immune, they are promising candidates for therapeutic manipulation. Sepsis induces several changes in the populations of DCs via epigenetic, and/or other, mechanisms. Here, we propose that transplantation of 'naive dendritic cells' (DCs which are never exposed to sepsis) can reverse several aspects of the long-term post-sepsis immunosuppression. Furthermore, we present advantages of the presented therapeutic approach. PMID- 22840329 TI - The label free picomolar detection of insulin in blood serum. AB - Insulin, a polypeptide hormone secreted by pancreatic cells, is a key regulator in glucose homeostasis. Its deficiency leads to insulin-dependent (type I) diabetes whereas resistance to insulin is common in type II diabetes, obesity and a range of endocrine disorders. Its determination is of considerable value, particularly in the clinical diagnosis of diabetes mellitus and the doping control of athletes. It has, additionally, been noted as a potential breast cancer marker (serum insulin levels being found to be raised in comparison to control patients). Electrochemical assays are potentially very cheap, highly sensitive, and very readily transposed to a point of care. Though there exist numerous examples of label free impedimetric or capacitative assaying of biomolecules, these are rarely demonstrated to be effective in complex biological mixtures or to be applicable to low molecular weight targets (since they operate through the interfacial displacement of water/ions and/or the steric blocking of a redox probe). We report herein an ultrasensitive electrochemical and label-free biosensor for insulin in blood serum with a clinically relevant linear range and detection limit of 1.2pM. The transducing surfaces, based on readily prepared, antibody modified, polyethylene glycol monolayer modified polycrystalline gold surfaces, respond in a highly specific and re-useable manner to the target in up to 50% blood serum. PMID- 22840330 TI - Ultrasensitive and selective detection of copper (II) and mercury (II) ions by dye-coded silver nanoparticle-based SERS probes. AB - A simple and distinctive method for the ultrasensitive detection of Cu(2+) and Hg(2+) based on surface-enhanced Raman scattering (SERS) using cysteine functionalized silver nanoparticles (AgNPs) attached with Raman-labeling molecules was developed. The glycine residue in a silver nanoparticle-bound cysteine can selectively bind with Cu(2+) and Hg(2+) and form a stable inner complex. Silver nanoparticles co-functionalized with cysteine and 3,5-Dimethoxy-4 (6'-azobenzotriazolyl)phenol (AgNP conjugates) can be used to detect Cu(2+) and Hg(2+) based on aggregation-induced SERS of the Raman tags. The addition of SCN( ) to the analyte can successfully mask Hg(2+) and allow for the selective detection of Cu(2+). This SERS-based assay showed an unprecedented limit of detection (LOD) of 10pM for Cu(2+) and 1pM for Hg(2+); these LODs are a few orders of magnitude more sensitive than the typical colorimetric approach based on the aggregation of noble nanoparticles. The analysis of real water samples diluted with pure water was performed and verified this conclusion. We envisage that this SERS-based assay may provide a general and simple approach for the detection of other metal ions of interest, which can be adopted from their corresponding colorimetric assays that have already been developed with significantly improved sensitivity and thus have wide-range applications in many areas. PMID- 22840331 TI - Polymorphisms of the bovine WNT10B gene and their associations with growth traits. AB - Wingless-type MMTV integration site family, member 10B (WNT10B) may play an important role in inhibiting differentiation of preadipocytes in vitro and impairing adipose development in vivo. In this study, based on DNA sequencing and PCR-RFLP methods, we attempted to characterize the associations between common genetic polymorphisms in WNT10B and growth traits of 435 female cattle from three breeds (Jiaxian, Qinchuan and Luxi cattle). The results indicated that g.220A>G was in the intron 1, and g.1617C>T, g.3980G>T, g.4711G>C were in the coding region. At the g.3980G>T locus, Jiaxian cattle individuals with genotype TT had greater body length than those with genotypes GG and GT (P<0.05). At the g.220A>G locus, Qinchuan cattle individuals with genotype GG had greater growth traits than those with genotype AA and AG (P<0.05 or P<0.01). These statistical results showed that the WNT10B gene might be a potential candidate gene for marker assisted selection (MAS). PMID- 22840332 TI - Cytotoxicity and genotoxicity of 1,4-bisdesoxyquinocetone, 3-methylquinoxaline-2 carboxylic acid (MQCA) in human hepatocytes. AB - Quinoxaline-1,4-dioxides, widely used as medicinal feed additives as antibacterial growth promoters, have been shown to exert diverse toxicities. Their toxicities are hypothesized to be closely related to the formation of N oxide reductive metabolites. 1,4-Bisdesoxyquinocetone and MQCA are important N oxide reductive metabolites of quinocetone or olaquindox. In this study, we evaluated the cytotoxicity and genotoxicity of the metabolites, 1,4 bisdesoxyquinocetone and MQCA, as well as their parental drugs (quinocetone and olaquindox) in two human hepatocyte cell lines, L-02 and Chang liver cells. All these compounds inhibited the growth of cells in a dose-dependent and time dependent manner by the MTT assay. Hormesis effects were found in L-02 cells treated with quinocetone at low doses. In the comet assay, although the two metabolites induced dose-related DNA damage in both cell lines, the levels of damage were less than that demonstrated for the parent drugs. The flow cytometric analysis showed that only the two metabolites induced cell cycle arrest at the S phase, and a decrease in the G0/G1, G2/M phase of Chang liver cells, which was not found for the L-02 cells treated with any compounds. The results indicate that 1,4-bisdesoxyquinocetone and MQCA are toxic to L-02 and Chang liver cells, and provide important new information towards understanding the olaquindox and quinocetone toxic mechanisms. PMID- 22840333 TI - LKTA and PlpE small fragments fusion protein protect against Mannheimia haemolytica challenge. AB - Bovine respiratory disease (BRD) complex is a major cause of economic losses for the cattle backgrounding and feedlot industries. Mannheimia haemolytica is considered the most important pathogen associated with this disease. Vaccines against M. haemolytica have been prepared and used for many decades, but traditional bacterins have failed to demonstrate effective protection and their use has often exacerbated disease in vaccinated animals. Thus, the BRD complex continues to exert a strong adverse effect on the health and wellbeing of stocker and feeder cattle. Therefore, generation of recombinant proteins has been helpful in formulating enhanced vaccines against M. haemolytica, which could confer better protection against BRD. In the present study, we formulated a vaccine preparation enriched with recombinant small fragments of leukotoxin A (LKTA) and outer-membrane lipoprotein (PlpE) proteins, and demonstrated its ability to generate high antibody titers in rabbits and sheep, which protected against M. haemolytica bacterial challenge in mice. PMID- 22840334 TI - Evaluation of a Serpens species bacterin for treatment of digital dermatitis in dairy cattle. AB - Digital dermatitis is a major cause of lameness in many dairy herds and represents a detriment to milk production, reproductive efficiency, productive lifespan and welfare. The purpose of this study was to evaluate the therapeutic use of a Serpens species bacterin in a dairy herd known to have a significant prevalence of lameness due to digital dermatitis. Seventy-six mature lactating Holsteins were enrolled in this study. Group 1 (n=38) received three injections of a Serpens species bacterin at four-week intervals (weeks 0, 4, and 8) while group 2 (n=38) received only adjuvant. Blood samples were obtained prior to the first injection at week 0 and again at week 12 to evaluate antibody responses. Locomotion and digital dermatitis lesion measurements were performed at weeks 0, 12 and 18. Although Serpens-associated antibody titers increased from week 0 to 12 in vaccinated cows; the prevalence of digital dermatitis, the percentage of cows identified as clinically lame and the average width of digital dermatitis lesions did not differ from week 0 to 12 or from week 0 to 18 between groups. The results of this study indicate a lack of any clinical efficacy associated with vaccination in this herd, although inoculation with the bacterin did stimulate a measurable antibody response. PMID- 22840335 TI - Evaluation of serological cross-reactivity between canine visceral leishmaniasis and natural infection by Trypanosoma caninum. AB - In order to evaluate if the presence of Trypanosoma caninum can lead to a confuse diagnosis of canine visceral leishmaniasis (CVL), we investigated the serological status of dogs infected by T. caninum and assessed the serological cross reactivity with CVL. A set of 117 serum samples from dogs infected by T. caninum, Leishmania chagasi and not infected dogs (n=39 in each group) was tested using commercial kits--indirect immunofluorescence (IFI-LVC), ELISA (EIE-LVC) and immunochromatographic test (DPP)--and in house tests with T. caninum (IIF-Tc and ELISA-Tc) and L. chagasi antigens (IIF-Lc and ELISA-Lc). IIF-Tc and ELISA-Tc presented sensitivity of 64.1% and 94.9% and specificity of 23.1% and 35.9%, respectively. The sensitivity of the IFI-LVC, EIE-LVC and DPP tests was 100% and the specificity was 70.5%, 68% and 97.5% respectively. The concordance between the tests was considered as satisfactory. The specificities of IFI-LVC, EIE-LVC and DPP were higher when the group Tc was excluded, with significant values for IFI-LVC (chi2=4.36, P-value=0.036), thus suggesting that the infection by T. caninum can confuse the diagnosis of CVL. PMID- 22840336 TI - Neural activities during affective processing in people with Alzheimer's disease. AB - This study examined brain activities in people with Alzheimer's disease when viewing happy, sad, and fearful facial expressions of others. A functional magnetic resonance imaging and a voxel-based morphometry methodology together with a passive viewing of emotional faces paradigm were employed to compare the affective processing in 12 people with mild Alzheimer's disease and 12 matched controls. The main finding was that the clinical participants showed reduced activations in regions associated with the motor simulation system (the ventral premotor cortex) and in regions associated with emotional simulation-empathy (the anterior insula and adjacent frontal operculum). This regional decline in blood oxygen level-dependent signals appeared to be lateralized in the left hemisphere and was not related to any structural degeneration in the clinical participants. Furthermore, the regions that showed changes in neural activity differed for the 3 emotional facial expressions studied. Findings of our study indicate that neural changes in regions associated with the motor and emotional simulation systems might play an important role in the development of Alzheimer's disease. PMID- 22840337 TI - The journal in evolution. PMID- 22840338 TI - Hydrogen sulfide as a regulator of calcium channels. AB - An increasing body of evidence suggests the involvement of hydrogen sulfide (H(2)S) in different physiological and pathological processes. Similarly to the other gasotransmitters nitric oxide (NO) and carbon monoxide (CO), this bioactive compound is rapidly diffusible through the biological membranes and acts in a paracrine fashion. Despite the large amount of biological actions observed in vitro and in vivo upon stimulation with H(2)S donors, as well as by interfering with its synthesis, the molecular targets and mechanisms through which it exerts its intracellular effects are only partially known. A number of proteins are covalently modified by H(2)S through sulfhydration of specific cysteine residues. However, only in few cases their identity has been discovered and the functional role of this post-translational modification needs to be investigated in more detail. Great attention has been devoted to potassium channels, particularly K(ATP), as they are considered key mediators of H(2)S-induced effects, and their sulfhydration has been clearly demonstrated. Recently, different authors reported the ability of H(2)S to interfere with calcium homeostasis in neurons, cardiomyocytes and endothelial cells. Since calcium signaling is involved in all cell processes, these observations attracted increasing attention from basic biology and medicine. Although some effects of H(2)S on calcium signals can be ascribed to K(ATP) modulation, there is growing consensus about the existence of other targets for the gasotransmitter. Some of them are Ca(2+)-permeable channels. In this review we discuss the state of the art in this specific field, providing an updated report of H(2)S interaction with Ca(2+) channels and its functional outcomes. PMID- 22840339 TI - Medical student career survey--vascular surgery awareness initiative. AB - BACKGROUND: The objectives of this survey were to identify medical students' general knowledge of vascular surgery as a career choice on entrance to medical school, and how student perspectives change during their exposure to clinical disciplines. Furthermore, we sought to determine which factors may influence the choice of a particular career path, and to apply this knowledge to improve the recruitment process of medical students into the specialty of vascular surgery. METHODS: A one-time anonymous questionnaire consisting of 21 open and multiple choice questions was distributed to first- (MS1), second- (MS2), and third-year (MS3) medical students at a large single-campus medical school. Responses were collected and subjected to analysis. RESULTS: Three hundred thirty-eight medical students responded to the survey (110 MS1, 126 MS2, and 102 MS3). Two hundred thirty-six MS1 and MS2 students had no clinical exposure to vascular surgery. Of 102 MS3 students having completed a general surgery rotation, 38 had exposure to vascular surgery. Of MS1 and MS2 students, 49% would consider vascular surgery. An additional 19% were willing to consider vascular surgery if the length of training was reduced. Twenty-six percent of the clinical students rotated on a vascular surgery service during their clinical general surgery rotation, of which 78% reported a positive experience. Only 26% (10 of 38) still considered vascular surgery as a career at the MS3 level. Thirty-four percent of students would consider vascular surgery if the training was reduced from 7 to 5 years. However, only 5% of MS1 and MS2 (11 of 236) and 9% of MS3 (9 of 102) students were aware of the 0 + 5 training program. As students advanced in medical school, lifestyle (31% MS1 vs. 63% MS3, P < 0.001) and length of training (19% MS1 and 2 vs. 34% MS3, P < 0.001) became a more critical factor in their career choice decision making. CONCLUSIONS: Medical students have minimal knowledge of vascular surgery on entry to medical school; however, many are willing to consider vascular surgery as a career. Lack of exposure in the first 2 years of medical school and lifestyle considerations may be deterrents for students to choosing vascular surgery as a career. To improve the recruitment process, focused education and interaction with preclinical medical students are needed. PMID- 22840340 TI - Anastomoses in the common femoral artery, vascular clips or sutures? A feasibility study. AB - BACKGROUND: The Vessel Closure System (VCS) is commercially available since 1997. This clip system has proven to be successful for vascular anastomoses in access surgery. There is little experience with the VCS in peripheral vascular surgery. METHODS: A trial was conducted for patients with peripheral arterial disease, who required either a femoral artery endarterectomy or a peripheral bypass procedure. Patients were randomized into two groups: a VCS group, in which the proximal anastomoses were made using VCS clips; and a control group, in which both proximal and distal anastomoses were performed using Prolene sutures. Outcomes assessed were the speed of anastomosis and patency. Adverse events were monitored. RESULTS: In the VCS group, 12 patients underwent anastomoses using VCS clips. In the control group, 12 patients underwent vascular reconstruction using sutures. In the VCS group, the mean speed of anastomosis was 1.9 mm/min, whereas the mean speed in the control group was 2.5 mm/min; this was not significantly different (P = 0.096). After a follow-up of 12 months, there was no difference in patency. In the VSC group, two serious adverse events occurred, which required emergency surgery. CONCLUSION: Anastomosis in the femoral artery using VCS clips is not faster than that using running Prolene sutures, and in our small sample, two serious adverse events in the VCS group were observed. These results do not support the further use of vascular clips in peripheral vascular surgery. PMID- 22840341 TI - Technique of aortic replacement through endovascular stenting before aortic wall resection for primary leiomyosarcoma of the abdominal aorta. AB - Tumors involving the aorta represent a challenging situation because the surgical approach can lead to blood loss and/or clamping-related complications such as ischemia, thrombosis, or reperfusion syndromes. We describe the technique of aortic endograft placement to cover part of the abdominal aorta and provide conditions for extensive aortic wall resection, without clamping or blood loss, followed immediately by aortic reconstruction with bovine pericardium. This technique also allows the surgeon to wait for the results of freeze biopsy without additional clamping time, thus avoiding the risk of leaving residual tumor cells in the aortic wall. PMID- 22840342 TI - Identifying the incidence of and risk factors for reamputation among patients who underwent foot amputation. AB - BACKGROUND: Many patients who have lower-extremity amputations secondary to peripheral vascular disease or diabetes require reamputation eventually. This study was designed to identify the incidence of and risk factors for ipsilateral reamputation after forefoot amputation, to evaluate whether postoperative infection increases the risk of reamputation, and to evaluate whether the risk of reamputation was reduced by the duration of antimicrobial therapy after amputation. METHODS: A retrospective analysis of patients who underwent foot amputation for nontraumatic reason from January 2002 to December 2004 at the Veterans Affairs Pittsburgh Healthcare System was performed. RESULTS: Among 116 patients, 57 (49.1%) had ipsilateral reamputation within 3 years after their first surgeries; 78.9% received reamputation in the first 6 months; 53 (45.7%) died within 3 years; and 16 (13.8%) developed postoperative infections. Upper level of amputation, long duration of hospitalization, insulin-dependent diabetes, and gangrene on physical examination on admission were risk factors for reamputation in univariate analysis. Gangrene (odds ratio: 3.81, 95% confidence interval: 1.60-9.12, P = 0.003) and insulin-dependent diabetes (odds ratio: 2.93, 95% confidence interval: 1.26-6.78, P = 0.012) were risk factors in multivariate analysis. Postoperative infection did not increase the risk of reamputation. Longer than 2-week course of antibiotic use after amputation did not prevent reamputation. CONCLUSIONS: Approximately one-half of patients required ipsilateral reamputation and died in 3 years. Gangrene on admission and history of insulin-dependent diabetes were significant risk factors (P = 0.003, P = 0.028). Long duration of antibiotic use after amputation and postoperative infection did not change the risk of reamputation. PMID- 22840343 TI - [Takotsubo cardiomyopathy in a cardiology department]. AB - Takotsubo cardiomyopathy, also known as transient left ventricular apical ballooning syndrome, stress-induced cardiomyopathy and broken heart syndrome, is characterized by transient left ventricular dysfunction in the absence of obstructive coronary artery disease. It was first described in 1990 in Japan, and gained worldwide recognition following the publication of several series of case reports. Its prevalence is estimated to be 1.7-2.2% of suspected acute coronary syndromes. Although takotsubo cardiomyopathy has been progressively better characterized, certain aspects remain to be clarified, and it is still under study. In this article, we report a series of ten cases of takotsubo cardiomyopathy admitted to a cardiology department, and compare the clinical, laboratory, electrocardiographic and imaging characteristics, therapeutic regimens and follow-up of these patients with those described in the latest scientific reviews. PMID- 22840345 TI - Molecular epidemiologic investigation of an anthrax outbreak among heroin users, Europe. AB - In December 2009, two unusual cases of anthrax were diagnosed in heroin users in Scotland. A subsequent anthrax outbreak in heroin users emerged throughout Scotland and expanded into England and Germany, sparking concern of nefarious introduction of anthrax spores into the heroin supply. To better understand the outbreak origin, we used established genetic signatures that provided insights about strain origin. Next, we sequenced the whole genome of a representative Bacillus anthracis strain from a heroin user (Ba4599), developed Ba4599-specific single-nucleotide polymorphism assays, and genotyped all available material from other heroin users with anthrax. Of 34 case-patients with B. anthracis-positive PCR results, all shared the Ba4599 single-nucleotide polymorphism genotype. Phylogeographic analysis demonstrated that Ba4599 was closely related to strains from Turkey and not to previously identified isolates from Scotland or Afghanistan, the presumed origin of the heroin. Our results suggest accidental contamination along the drug trafficking route through a cutting agent or animal hides used to smuggle heroin into Europe. PMID- 22840346 TI - Atherosclerotic risk factors and their association with hospital mortality among patients with first myocardial infarction (from the National Registry of Myocardial Infarction). AB - Few studies have examined associations between atherosclerotic risk factors and short-term mortality after first myocardial infarction (MI). Histories of 5 traditional atherosclerotic risk factors at presentation (diabetes, hypertension, smoking, dyslipidemia, and family history of premature heart disease) and hospital mortality were examined among 542,008 patients with first MIs in the National Registry of Myocardial Infarction (1994 to 2006). On initial MI presentation, history of hypertension (52.3%) was most common, followed by smoking (31.3%). The least common risk factor was diabetes (22.4%). Crude mortality was highest in patients with MI with diabetes (11.9%) and hypertension (9.8%) and lowest in those with smoking histories (5.4%) and dyslipidemia (4.6%). The inclusion of 5 atherosclerotic risk factors in a stepwise multivariate model contributed little toward predicting hospital mortality over age alone (C statistic = 0.73 and 0.71, respectively). After extensive multivariate adjustments for clinical and sociodemographic factors, patients with MI with diabetes had higher odds of dying (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.20 to 1.26) than those without diabetes and similarly for hypertension (OR 1.08, 95% CI 1.06 to 1.11). Conversely, family history (OR 0.71, 95% CI 0.69 to 0.73), dyslipidemia (OR 0.62, 95% CI 0.60 to 0.64), and smoking (OR 0.85, 95% CI 0.83 to 0.88) were associated with decreased mortality (C-statistic = 0.82 for the full model). In conclusion, in the setting of acute MI, histories of diabetes and hypertension are associated with higher hospital mortality, but the inclusion of atherosclerotic risk factors in models of hospital mortality does not improve predictive ability beyond other major clinical and sociodemographic characteristics. PMID- 22840347 TI - Meta-analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia. AB - Addition of fenofibrate to statin therapy might represent a viable treatment option for patients whose high risk for coronary heart disease is not controlled by a statin alone. However, safety of coadministration of statin with fenofibrate has been a great concern. The present study tested the safety of coadministration of statin with fenofibrate. We systematically searched the literature to identify randomized controlled trials examining safety of coadministration of statin with fenofibrate. A meta-analysis was performed to estimate safety of coadministration of statin with fenofibrate using fixed-effects models. There were 1,628 subjects in the identified 6 studies. Discontinuation attributed to any adverse events (4.5% vs 3.1%, p = 0.20), any adverse events (42% vs 41%, p = 0.82), adverse events related to study drug (10.9% vs 11.0%, p = 0.95), and serious adverse events (2.0% vs 1.5%, p = 0.71) were not significantly different in the 2 arms. Incidence of alanine aminotransferase and/or aspartate aminotransferase >=3 times upper limit of normal in the combination therapy arm was significantly higher than in the statin monotherapy arm (3.1% vs 0.2%, p = 0.0009). In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. In conclusion, statin-fenofibrate combination therapy was tolerated as well as statin monotherapy. Physicians should consider statin-fenofibrate combination therapy to treat patients with mixed dyslipidemia. PMID- 22840348 TI - Understanding the substrate specificity of the heparan sulfate sulfotransferases by an integrated biosynthetic and crystallographic approach. AB - Heparan sulfates (HSs) have potential therapeutic value as anti-inflammatory and antimetastasis drugs, in addition to their current use as anticoagulants. Recent advances in chemoenzymatic synthesis of HS provide a way to conveniently produce homogenous HS with different biological properties. Crystal structures of sulfotransferases involved in this process are providing atomic detail of their substrate binding clefts and interactions with their HS substrates. In theory, the flexibility of this method can be increased by modifying the specificities of the sulfotransferases based on the structures, thereby producing a new array of products. PMID- 22840350 TI - A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis. AB - CONTEXT: Nocturia is a common urologic symptom that has been covered in a variety of reported studies in the literature but is not specifically covered in current guidelines. OBJECTIVE: To comprehensively review the literature pertaining to the definition, etiologies, and consequences of nocturia and assess the evidence supporting the use of conservative medical and interventional therapy. EVIDENCE ACQUISITION: A literature search was conducted using the keyword nocturia, restricted to articles in the English language, after 2000 and before April 2012, in PubMed/Medline, Embase, Scopus, Web of Science, and Cochrane Library databases. Regarding treatment modalities, studies were included only if nocturia was a primary end point and if the studies were designed as randomized controlled trials without limit of date. When suitable, a meta-analysis was conducted. Papers covering treatment options for nocturia specifically related to nonurologic conditions were excluded. EVIDENCE SYNTHESIS: Nocturia is still defined as the symptom of wakening from sleep once or more often to void. The prevalence is high in both genders and increases with age. Frequency-volume charts, which are the pivotal tool of clinical assessment, detect 24-h polyuria, nocturnal polyuria (NP), or reduced nocturnal bladder capacity and help to target specific nonurologic etiologies. Nocturia is a morbid condition that significantly affects quality of life and increases mortality. Besides behavioral measures, validated treatment options include oral desmopressin, which is superior to placebo in treating NP. While the level of evidence for desmopressin is high, limited data support the use of alpha1-blockers and antimuscarinics; however, only rarely has nocturia been a primary end point when studying these drug classes, and studies have not consistently controlled for the effect of NP. CONCLUSIONS: Our knowledge of nocturia, its etiology, and its management has substantially improved in recent years. The evidence available on the management of nocturia remains limited; contributory factors include (1) the complexity of associated conditions, (2) the underuse of objective evaluation tools, and (3) the lack of specific focus on nocturia in clinical trials. PMID- 22840351 TI - Salvage cryosurgery of the prostate for failure after primary radiotherapy or cryosurgery: long-term clinical, functional, and oncologic outcomes in a large cohort at a tertiary referral centre. AB - BACKGROUND: Salvage cryosurgery (SC) is a recognised option for patients who fail either primary radiation or cryosurgery. OBJECTIVE: To report outcomes of patients undergoing SC. DESIGN, SETTING, AND PARTICIPANTS: A consecutive series of 396 patients who had failed either primary radiotherapy or cryosurgery underwent SC between October 1994 and August 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Demographic and clinical parameters before primary and salvage treatment were evaluated; disease-free-survival (DFS), overall-survival (OS), disease-specific-survival (DSS), and complications were assessed. RESULTS AND LIMITATIONS: Sufficient follow-up data were available for 328 patients. Median age was 65.8 yr (range: 45-81 yr), median serum prostate-specific antigen (PSA) level was 8.0 ng/ml (range: 0.6-290.0 ng/ml). After primary treatment, median time to recurrence was 55 mo (range: 0.0-183.6 mo). SC was performed at a median of 67.5 mo (range: 7.0-212.7 mo) later; median pre-SC PSA level was 4.0 ng/ml (range: 0.1-112.4 ng/ml). Median PSA nadir was 0.2 ng/ml (range: 0.01-70.70 ng/ml), reached after a median of 2.6 mo (range: 2.0-67.3 mo) after SC. Median follow-up was 47.8 mo (range: 1.6-203.5 mo). Respective 5- and 10-yr DFS was 63% and 35%; OS: 74% and 45%; and DSS: 91% and 79%. In univariate analyses, time from primary treatment to SC or recurrence, PSA level before SC, and PSA nadir after SC were all significant predictors of recurrence (p <= 0.01). PSA before SC and time to recurrence were also predictive of DSS (p=0.003 and p=0.01, respectively). In multivariate analyses, only PSA nadir after SC was predictive of recurrence and DSS (p<0.001 and p=0.012, respectively). Complications were rare (range: 0.6-4.6%). Fifty-five patients (16.7%) underwent focal SC. Median PSA nadir after focal SC was 0.44 ng/ml (range: 0.04-20.1 ng/ml). Twenty-seven patients (49%) experienced recurrence. Respective 5- and 10-yr DFS was 47% and 42%; OS: 87% and 81%; and DSS: 100% and 83%. CONCLUSIONS: Our analysis confirms SC as an effective treatment option for patients failing primary therapy. Patients experienced excellent survival outcome and minimal associated morbidity after SC. Focal SC is an efficacious treatment for properly selected patients. PMID- 22840352 TI - Uptake of laparoscopic radical nephroureterectomy in France: a 2003-2011 national practice report. PMID- 22840353 TI - Randomised controlled trial comparing laparoscopic and robot-assisted radical prostatectomy. AB - BACKGROUND: The advantages of robot-assisted radical prostatectomy (RARP) over laparoscopic radical prostatectomy (LRP) have rarely been investigated in randomised controlled trials. OBJECTIVE: To compare RARP and LRP in terms of the functional, perioperative, and oncologic outcomes. The main end point of the study was changes in continence 3 mo after surgery. DESIGN, SETTING, AND PARTICIPANTS: From January 2010 to January 2011, 120 patients with organ-confined prostate cancer were enrolled and randomly assigned (using a randomisation plan) to one of two groups based on surgical approach: the RARP group and the LRP group. INTERVENTION: All RARP and LRP interventions were performed with the same technique by the same single surgeon. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The demographic, perioperative, and pathologic results, such as the complications and prostate-specific antigen (PSA) measurements, were recorded and compared. Continence was evaluated at the time of catheter removal and 48 h later, and continence and potency were evaluated after 1, 3, 6, and 12 mo. The student t test, Mann-Whitney test, chi(2) test, Pearson chi(2) test, and multiple regression analysis were used for statistics. RESULTS AND LIMITATIONS: The two groups (RARP: n=60; LRP: n=60) were comparable in terms of demographic data. No differences were recorded in terms of perioperative and pathologic results, complication rate, or PSA measurements. The continence rate was higher in the RARP group at every time point: Continence after 3 mo was 80% in the RARP group and 61.6% in the LRP group (p=0.044), and after 1 yr, the continence rate was 95.0% and 83.3%, respectively (p=0.042). Among preoperative potent patients treated with nerve-sparing techniques, the rate of erection recovery was 80.0% and 54.2%, respectively (p=0.020). The limitations included the small number of patients. CONCLUSIONS: RARP provided better functional results in terms of the recovery of continence and potency. Further studies are needed to confirm our results. PMID- 22840354 TI - Usefulness of school absenteeism data for predicting influenza outbreaks, United States. PMID- 22840355 TI - Prognostic factors and treatment options for paediatric ependymomas. AB - The aim of this study was to determine factors of prognostic relevance for paediatric ependymomas, and evaluate the efficacy of treatment modalities. This is a retrospective study of 43 patients with ependymoma (<18 years) who underwent a combination of surgical excision, chemotherapy, and/or radiotherapy treatment at The Prince of Wales Cancer Centre between 1969 and 2009. Statistical analysis was performed to assess the prognostic relevance of various parameters affecting the two-year and five-year overall survival (OS) and progression-free survival (PFS). The five-year OS and PFS were 50.3% and 44.8% respectively (median follow up 50 months). Eighteen patients (41.9%) experienced tumour recurrence: 13 had a local recurrence (LR) and five had both LR and distant recurrence. On univariate analysis, a more favourable prognosis in terms of both OS and PFS was evident for supratentorial tumours compared to infratentorial tumours (OS p=0.007, PFS p=0.045), stereotactic radiosurgery/ fractionated stereotactic radiotherapy compared to craniospinal irradiation or local posterior fossa/local brain+/-boost radiotherapy modalities (OS p=0.047, PFS p=0.031), total radiotherapy dose >50 Gy compared to <=50 Gy (OS p=0.008, PFS p=0.005), and in patients with no tumour recurrence compared to those with recurrence (OS p=0.03, PFS p<0.001). Although not statistically significant, a more favourable multivariate outcome was evident in patients who underwent complete surgical resection. Chemotherapy treatment and histopathological grade, however, were not relevant to prognosis. This study supports the need to pursue more aggressive treatment for infratentorial and/or recurrent tumours. Ideal treatment involves maximal surgical resection, followed by adjuvant radiotherapy (>50 Gy). PMID- 22840356 TI - [Transcatheter aortic valve prostheses: an open future]. PMID- 22840357 TI - Salt-stressed fresh cut leek accelerates CO2 and C2H4 production and enhances the development of quality characteristics of traditional Greek sausages during storage. AB - Fresh cut leek was mixed with salt for 0.5 (IM) and 5 (LM) min or remained untreated (control) and stored alone or mixed with minced meat and seasonings, cased and stored at 15 degrees C for 7 days. The fresh cut leek and sausage metabolics and sausage microbiological and physicochemical traits were measured during storage. Sausages with LM leek had significantly higher counts of lactic acid bacteria, faster rates of pH drop and dehydration and increased red color compared with the other treatments. Sausage to fresh cut leek peaks of CO2 or C2H4 production was 5 or 2 fold higher in LM than the other treatments indicating that the sausage flora was the source of both. The use of salt-stressed fresh cut leek before manufacture of sausages enhances microbial activity as well as its stability and shortens the necessary storage time needed for the development of the quality characteristics of Greek traditional sausages. PMID- 22840358 TI - Effect of dietary supplementation with olive pomaces on the performance and meat quality of growing rabbits. AB - The aim was to investigate the effects of three types (A, B and C) of stoned and dehydrated olive pomaces (OPs), differing in olive cultivar, on productive performance and meat quality of growing rabbits. The inclusion of OPs (5%) negatively affected the performance of rabbits as it reduced the feed intake, growth rate, carcass weight and dressing out percentage (P<0.05). Compared with the control, the meat of OP rabbits had a greater amount of monounsaturated and a lower amount of polyunsaturated fatty acids (P<0.05), independent of the type of OP used. Oxidative processes in the meat of OPA and OPB were higher (P<0.05), whereas OPC showed the same levels as the control group. This was due to the higher total polyphenol concentration and to the concomitant lower peroxide value of OPC. These results recommend the use of OP in rabbit diet with caution, taking into account the quality of the by-product in terms of oxidative status. PMID- 22840359 TI - The effect of kimchi on the microbiological stability of fermented sausage. AB - The effects of kimchi and freeze-dried kimchi-powder added to raw meat mixtures on the microbiological quality of fermented sausage were studied. The results clearly demonstrated that the lactic acid bacteria (LAB) integrated via the addition of kimchi as well as kimchi-powder were well adapted to the new habitat of fermenting sausage, reaching maximum numbers of 8.65-8.80 log10 cfu/g after 1 2 days of fermentation. In all kimchi and kimchi-powder sausages, the growth of Enterobacteriaceae was completely inhibited throughout the processing period (<2 log10 cfu/g). The sausage batches containing more than 10% kimchi and 2% kimchi powder showed no growth of S. aureus, whereas the control and another kimchi sausage batch reflected the growth of S. aureus (3.68-4.72 log10 cfu/g). As a result, the addition of kimchi (>=10%) and kimchi-powder to the sausage mixture prior to fermentation produced the microbiological stability required for fermented sausages. PMID- 22840360 TI - Joint editorial. PMID- 22840362 TI - Rituximab in combination with high-dose dexamethasone for the treatment of relapsed/refractory chronic lymphocytic leukemia. AB - BACKGROUND: High-dose methylprednisolone is active in treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but infectious toxicity is serious. The aim of this project was to retrospectively assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in this setting. PATIENTS AND METHODS: We treated 54 patients (pts) with relapsed/refractory CLL using R-dex regimen at two tertiary centers. Two schedules of rituximab were used (not randomized - based on the choice of the center): group 1, rituximab 500 mg/m(2)day 1, 8, 15, 22 (375 mg/m(2) in 1st dose) every 4 weeks (n=29); group 2, 500 mg/m(2)day 1 (375 mg/m(2) in 1st cycle) repeated every 3 weeks (n=25). The target dose of dexamethasone was 40 mg on days 1-4 and 10-13 or 15-18. Rai III/IV stages were present in 82%, unmutated IgVH genes in 82%, del 11q in 38% and del 17p in 19% pts; 46% had bulky lymph nodes; 82% were pretreated with fludarabine and 29% with alemtuzumab. RESULTS: Overall response rate/complete remissions were 62/21% (Group 1) and 72/4% (Group 2). In three patients, R-dex was successfully used for debulking before nonmyeloablative allogeneic stem cell transplantation. R-dex was particularly effective in improvement of anemia and thrombocytopenia (p=0.0055 and p=0.0036); B-symptoms resolved after treatment in 11/17 pts. Hematological toxicity was mild. Serious infections occurred in 32% pts. At the median follow-up of 9 and 10 months, median progression-free survival was 6 months in Group 1 and 6.9 months in Group 2 (p=ns); median overall survival was 14.1 months in Group 1 vs. not reached in Group 2 (p=ns). CONCLUSIONS: R-dex appears to be an active and feasible treatment for relapsed/refractory CLL. Infectious toxicity remains an important issue. Further investigation of this regimen in larger studies appears fully warranted. PMID- 22840363 TI - Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome is caused by a POC1A mutation. AB - Disproportionate short stature refers to a heterogeneous group of hereditary disorders that are classified according to their mode of inheritance, clinical skeletal and nonskeletal manifestations, and radiological characteristics. In the present study, we report on an autosomal-recessive osteocutaneous disorder that we termed SOFT (short stature, onychodysplasia, facial dysmorphism, and hypotrichosis) syndrome. We employed homozygosity mapping to locate the disease causing mutation to region 3p21.1-3p21.31. Using whole-exome-sequencing analysis complemented with Sanger direct sequencing of poorly covered regions, we identified a homozygous point mutation (c.512T>C [p.Leu171Pro]) in POC1A (centriolar protein homolog A). This mutation was found to cosegregate with the disease phenotype in two families. The p.Leu171Pro substitution affects a highly conserved amino acid residue and is predicted to interfere with protein function. Poc1, a POC1A ortholog, was previously found to have a role in centrosome stability in unicellular organisms. Accordingly, although centrosome structure was preserved, the number of centrosomes and their distribution were abnormal in affected cells. In addition, the Golgi apparatus presented a dispersed morphology, cholera-toxin trafficking from the plasma membrane to the Golgi was aberrant, and large vesicles accumulated in the cytosol. Collectively, our data underscore the importance of POC1A for proper bone, hair, and nail formation and highlight the importance of normal centrosomes in Golgi assembly and trafficking from the plasma membrane to the Golgi apparatus. PMID- 22840364 TI - POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism. AB - Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing. In three families affected by a distinct form of PD, we identified a founder truncating mutation in POC1A. This gene is one of two vertebrate paralogs of POC1, which encodes one of the most abundant proteins in the Chlamydomonas centriole proteome. Cells derived from the index individual have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis. siRNA knockdown of POC1A in fibroblast cells recapitulates this ciliogenesis defect. Our findings highlight a human ciliopathy syndrome caused by deficiency of a major centriolar protein. PMID- 22840366 TI - What can we make with this national programme? PMID- 22840365 TI - Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements. AB - We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels were detected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and in silico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements. PMID- 22840367 TI - The evolving role of the Portuguese Journal of Pulmonology: "Gardens are not made by sitting in the shade". PMID- 22840369 TI - Array CGH and PIK3CA/AKT1 mutations to drive patients to specific targeted agents: a clinical experience in 108 patients with metastatic breast cancer. AB - Breast cancer includes high number of molecular entities targetable by specific agents. In this study, array CGH and PIK3CA/AKT1 mutations were used to drive patients into targeted therapy. A prospective molecular analysis was offered to metastatic breast cancer patients for whom samples were collected prospectively or retrospectively either from frozen or paraffin-embedded tissue. Analyses were performed using array CGH (Agilent platform) and PIK3CA (exon 10 and 21) and AKT1 mutations were explored by standard Sanger sequencing. One hundred and eight patients were included. Good quality CGH was obtained in 79% cases and was better for frozen samples. Genomic alterations were identified in 50% of patients including 11 PIK3CA and 8 AKT1 mutations. Eighteen treatments (17 patients) were administered according to their molecular profile with evidence of activity in nine. Reasons for not providing a genomic-driven treatment included absence of progressive disease (38%), investigator's choice (9%), rapid PD (19%), and no drug access (21%). Array CGH correctly identified Her2 status in 97% cases; failures were related to low % of tumour cells. Our study showed that array CGH is feasible in the context of daily practice and, in combination with PIK3CA/AKT1 mutations, identifies a significant number of actionable molecular alterations that allow driving patients into specific targeted agents. PMID- 22840370 TI - Rhodococcus erythropolis encephalitis in patient receiving rituximab. PMID- 22840368 TI - Insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3) is a marker of unfavourable prognosis in colorectal cancer. AB - BACKGROUND: Evidence suggests that insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3, also known as IMP3) represents a promising cancer biomarker. However, the clinical, pathological, molecular and prognostic features of IGF2BP3-positive colorectal cancers remain uncertain. MATERIALS AND METHODS: We evaluated IGF2BP3 expression by immunohistochemistry in 671 rectal and colon cancer cases that form part of a molecular pathological epidemiology database. Cox proportional hazards regression models were used to compute mortality hazard ratio (HR), adjusting for clinical, pathological and molecular features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation and KRAS, BRAF and PIK3CA mutations. RESULTS: Among 671 colorectal cancers, 234 (35%) tumours were positive for IGF2BP3. In contrast, normal colorectal epithelium was negative for IGF2BP3 in all 403 specimens of normal mucosa adjacent to carcinoma. IGF2BP3 positivity was associated with poor differentiation (p=0.0003), stage III-IV disease (p=0.0081), BRAF mutation (p=0.031), and LINE-1 hypomethylation (p=0.020). IGF2BP3 positivity was significantly associated with shorter colorectal cancer-specific [log-rank p<0.0001; multivariate HR, 1.37; 95% confidence interval (CI), 1.02-1.84] and overall survival (log-rank p=0.0004; multivariate HR, 1.32; 95% CI, 1.05-1.66). CONCLUSIONS: IGF2BP3 expression in colorectal cancer is associated with adverse clinical outcome. Our findings support a role for IGF2BP3 as a diagnostic and/or prognostic biomarker in colorectal cancer. PMID- 22840371 TI - Posteromedial ankle dislocation without malleolar fracture: a report of six cases. AB - Posteromedial ankle dislocation without malleolar fracture is a rare injury. Six patients who suffered from this injury were reviewed. The deltoid ligament was not at risk in this particular type of dislocation. Those patients without chondral lesion have a good long-term prognosis if prompt reduction is performed. Associated chondral lesion is a significant contributing factor to late development of ankle osteoarthrosis. PMID- 22840372 TI - A study of time harmonic guided Lamb waves and their caustics in composite plates. AB - Spatial steady-state Lamb wave propagation in an anisotropic composite plate excited by harmonic surface sources is modeled using a Green's matrix representation in a frequency-wavenumber domain. An approach based on a residue integration technique for two dimensional wavenumber integrals for the computation of displacements outside an excitation source is presented in this paper. In the far-field zone of the excitation source, the method of stationary phase is used, which gives an asymptotic expansion of the displacement vector as a sum of cylindrical waves. Near caustic directions, a far-field solution is computed in terms of Airy functions. The results obtained applying residue integration technique and asymptotic expansion are found to be coinciding with the results of the computation by using the adaptive quadratures. Moreover, these approaches agree well with experimental data. Then, the advantages and disadvantages of the various methods applied for modeling of Lamb wave propagation are discussed in this paper. Focussing and other properties of Lamb waves are studied using numerical examples. PMID- 22840373 TI - Investigation of surface acoustic waves propagating in ZnO-SiO2-Si multilayer structure. AB - The investigations of the propagation of the SAW in the multilayered structures have been of great interest since the combination of the surface acoustic wave (SAW) technology with the microelectromechanical system (MEMS) technology comes true. In this paper, the recursive asymptotic method (RAM) is applied to analysis the propagation of the SAW in the ZnO-SiO(2)-Si multilayered structure. The influences of the ZnO layer thickness and the SiO(2) layer thickness to the phase velocity and the electro-mechanical coupling coefficient for the Rayleigh wave and Love wave are discussed. The Love mode wave is found to be predominantly generated since the c-axis of the ZnO film is generally perpendicular to the substrate. In order to prove the theoretical results, a series of Love mode SAW devices based on the ZnO-SiO(2)-Si multilayered structure is fabricated by micromachining, and their frequency responses are detected. The experimental results are found to be mainly consistent with the theoretical ones except the little larger velocities induced by the residual stresses produced in the fabrication process of the films. The deviation of the experimental results from the theoretical ones is reduced by thermal annealing. PMID- 22840375 TI - Escherichia coli O104 associated with human diarrhea, South Africa, 2004-2011. AB - To determine the origin of >4,000 suspected diarrheagenic Escherichia coli strains isolated during 2004-2011 in South Africa, we identified 7 isolates as serotype O104; 5 as enteroaggregative E. coli O104:H4, and 2 as enteropathogenic E. coli O104:non-H4. Pulsed-field gel electrophoresis showed that these isolates were unrelated to the 2011 E. coli O104:H4 outbreak strain from Germany. PMID- 22840376 TI - Absence of deletion and duplication of MLL2 and KDM6A genes in a large cohort of patients with Kabuki syndrome. AB - Kabuki syndrome is a rare, multiple congenital anomaly/mental retardation syndrome caused by MLL2 point mutations and KDM6A microdeletions. We screened a large cohort of MLL2 mutation-negative patients for MLL2 and KDM6A exon(s) microdeletion and microduplication. Our assays failed to detect such rearrangements in MLL2 as well as in KDM6A gene. These results show that these genomic events are extremely rare in the Kabuki syndrome, substantiating its genetic heterogeneity and the search for additional causative gene(s). PMID- 22840377 TI - Quantitative and qualitative QuantiFERON((r))-TB gold in-tube results among groups with varying risks of exposure to tuberculosis. AB - OBJECTIVE: We sought to describe qualitative and borderline quantitative QuantiFERON((r))-TB Gold In-Tube (QFT-IT; Cellestis, Valencia, CA) results among persons screened in the context of routine reasons, employment, contact investigation, high-risk foreign-born arrivals in the United States <= 5 years, and high-risk United States residents >5 years. METHODS: We performed a retrospective review of 3288 QFT-IT results from a clinical laboratory in the Pacific Northwest from January 2, 2008 to June 5, 2009. Interferon-gamma (IFN gamma) responses were quantified as low, borderline, or high for tuberculosis (TB) antigens (IFN-gamma [TB]) and a positive mitogen control (IFN-gamma [mitogen]), after subtracting a background control (IFN-gamma [nil]). Qualitative results were categorized as negative, positive, or indeterminate. RESULTS: Quantitative values categorized as borderline, well above, or well below the cut point were associated with qualitative results for IFN-gamma (TB-nil) (chi(2) = 2913.178, degrees of freedom [df] = 4, P < .001) and IFN-gamma (mitogen-nil) values (chi(2) = 2559.758, df = 4, P < .001). CONCLUSION: Quantitative data enhance the interpretation of qualitative QFT-IT results for persons with varying risks of exposure. PMID- 22840378 TI - Pulse duration and energy dependence of photodamage and lethality induced by femtosecond near infrared laser pulses in Drosophila melanogaster. AB - The potential application of nonlinear optical imaging diagnosis and treatment using femtosecond laser pulses in humans accentuates the need for studies carried out in whole organisms instead of single cells or cell cultures. While there is a general consensus that in order to minimize the level of photodamage the excitation power has to be kept as low as possible, it has yet to be determined if shorter pulses have greater benefit than longer pulses. Here we evaluate the rate of death in Drosophila melanogaster as the integral parameter related to photodamage resulting from femtosecond near infrared (NIR) laser irradiation under conditions comparable to those used in two-photon excited fluorescence (TPEF) microscopy. We found that the lethality (resulting from photodamage) as a function of laser energy fluence fits a 3-region dose-response curve. The lethality was accompanied with development of necrosis and apoptosis in irradiated tissues. Quantitative analysis showed that the damage has a mostly linear character on energy fluence per pulse, and for a given TPEF signal, shorter (37 fs) pulse duration results in lower lethality than longer (100 fs) pulse duration. These results have important implications for the use of femtosecond NIR laser pulses in microscopy as well as in vivo medical imaging. PMID- 22840379 TI - Recognizing the limitations of a meta-analysis. PMID- 22840381 TI - The ultrashort flare GnRH-agonist/GnRH-antagonist protocol enables cycle programming and may overcome the "detrimental effect" of the oral contraceptive. PMID- 22840382 TI - Patient radiation exposure tracking: worldwide programs and needs--results from the first IAEA survey. AB - The purpose of this study was to assess the current status of patient radiation exposure tracking internationally, gauge interest and develop recommendations for implementation. A survey questionnaire was distributed to representatives of countries to obtain information, including the existence of a patient exposure tracking program currently available in the country, plans for future programs, perceived needs and goals of future programs, which examinations will be tracked, whether procedure tracking alone or dose tracking is planned, and which dose quantities will be tracked. Responses from 76 countries, including all of the six most populous countries and 16 of the 20 most populous, showed that although no country has yet implemented a patient exposure tracking program at a national level, there is increased interest in this issue. Eight countries (11%) indicated that such a program is actively being planned and 3 (4%) stated that they have a program for tracking procedures only, but not for dose. Twenty-two (29%) feel that such a program will be "extremely useful", 46 (60%) "very useful" and 8 (11%) "moderately useful", with no respondents stating "Mildly useful" or "Not useful". Ninety-nine percent of countries indicated an interest in developing and promoting such a program. In a first global survey covering 76 countries, it is clear that no country has yet achieved exposure tracking at a national level, although there are successful examples at sub-national level. Almost all have indicated interest and some have plans to achieve dose tracking in the near future. PMID- 22840383 TI - Midterm follow-up after DC-BEADTM-TACE of hepatocellular carcinoma (HCC). AB - AIM: To determine local response, its predictors and survival and complication rates after DC-BeadTM-TACE in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: DC-BeadsTM are non-resorbable, polyvinyl-alcoholic hydrophilic microspheres. They release high amounts of chemotherapeutics directly into the tumour. Delivery is sustained over time, tumour feeders are embolised. We used beads from 100-300 to 500-700 MUm loaded with Doxorubicin (max. 150 mg/4ml). Fifty patients (mean age: 68.5 +/- 8.8 years) with HCC were analysed. DC BeadTM-TACE was performed once or repeated in two-month intervals. Imaging scans (CT or MRI) were done one-month following each procedure. To evaluate tumour response EASL and RECIST criteria was applied. If eligible, every patient received a non-selective TACE. RESULTS: 128 DC-BeadTM sessions were performed: 127 showed technical success, 120 successful stasis. Complications occurred in 7% (9/128): active bleeding into the tumour (n=1), liver failure (n=1), liver abscess (n=1) ascites (n=3), pleural effusion (n=1), false aneurysm (n=1) and hypoglycaemia (n=1). At imaging after the 1st, 2nd, 3rd and 4th-8th session, objective response (complete+partial) was 49%, 67%, 67% and 31%, progressive disease was seen in n=11/50. Baseline diameter and differentiation significantly impacted response. Median overall survival was 25.1 months (95% [CI]: 18.3-31.9) with an estimated cumulative survival rate at one and two-to-four years of 66.7% and 45.7%, respectively. CONCLUSION: DC-BeadsTM can be safely and effectively control HCC. Survival and response rates are encouraging, complications are low. Many factors are involved in response to treatment like liver function or child state. PMID- 22840384 TI - Identification of fungal diseases at necropsy. AB - The purpose of the Death Verification Service is to elucidate the causes of deaths that occur without medical assistance and of ill-defined deaths. In recent decades, the epidemiological reality of fungal infections has changed due to the rise in opportunistic infections chiefly in immunocompromised patients. A study of fungal diseases in autopsies performed in the Death Verification Service of the Medicine School in Sao Jose do Rio Preto between January 2000 and December 2009 was made. Sixty-seven cases of fungal disease, most involving men (70%), were found in 4824 autopsies. Cryptococcosis was the most prevalent (45%), followed by paracoccidioidomycosis, candidiasis, histoplasmosis, aspergillosis and mucormycosis. Associations between AIDS (n=14) and fungal diseases were identified for cryptococcosis (36%), candidiasis (28.5%) and histoplasmosis (28.5%). Pneumonia, AIDS and fungal diseases were evident in 26% of the cases, with the most prevalent etiologies being Cryptococcus neoformans (55.5%) and Histoplasma capsulatum (22%). Pneumonia alone occurred in 43% of cases, with cryptococcosis (53%) and paracoccidioidomycosis (33%) being the main infectious agents. Diabetes mellitus was associated with candidiasis in two cases and aspergillosis in one. One case of renal transplantation linked to paracoccidioidomycosis and one case of bone marrow aplasia with mucormycosis were reported. Despite the reduction in the number of autopsies over recent decades, these findings suggest that this procedure is useful to provide additional data on the etiology, underlying disease and specific risk factors, essential for quality control and to improve treatment protocols. PMID- 22840385 TI - [Surgical aspects of living donor nephrectomy]. AB - CONTEXT: Living donor renal transplant surgery has evolved from the classical nephrectomy by lumbotomy to less invasive surgery, the laparoscopic and robotic nephrectomy currently being the most important. It is important to know the available evidence on whether nephrectomy in patients with multiple arteries, right kidney and in obese patients can be performed safely when there is a correct indication. OBJECTIVE: To perform a review of the different surgical techniques in living donor nephrectomy, adapted to the current surgical evidence and other aspects related to the indication. EVIDENCE ACQUISITION: A systematic review was made in PubMed (1997-2011). This included previous reviews randomized controlled clinical studies, cohort studies, and meta-analyses of this surgical aspects of living donor nephrectomy. CONCLUSIONS: Currently, there is sufficient evidence to consider living donor laparoscopic nephrectomy as the technique of choice, although the role of hand-assisted retroperitoneoscopic technique is still not totally clear. Open surgery techniques using mini-incision are an acceptable alternative for the sites that have not yet implemented laparoscopic surgery. Right kidney nephrectomy, of those cases that present multiple pedicles and in obese donors, is justified in selected cases. PMID- 22840386 TI - Curcumin attenuates rat thoracic aortic aneurysm formation by inhibition of the c Jun N-terminal kinase pathway and apoptosis. AB - OBJECTIVE: Recent studies have suggested that c-Jun N-terminal kinase (JNK) plays an important role in the formation of abdominal aortic aneurysms, and that direct blockade of JNK by specific inhibitors can effectively prevent the progression of aortic aneurysms. A study has demonstrated that curcumin can suppress the development of experimental abdominal aortic aneurysms by inhibiting inflammation. We sought to investigate whether curcumin could inhibit JNK pathways and apoptosis in thoracic aortic aneurysms. METHODS: We used a rat model of a CaCl2-induced thoracic aortic aneurysm followed by daily oral gavage with curcumin 100 mg/kg or vehicle alone. After treatment for 4 wk, tissue specimens were obtained for histologic assessments, and tissue composition was evaluated using immunohistochemistry, western blotting, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. RESULTS: Curcumin significantly suppressed the CaCl2-induced expansion of the thoracic aortic diameter and the structural preservation of medial elastin fibers. Most importantly, curcumin treatment significantly inhibited the phosphorylation of JNK and c-Jun, accompanied by less cell apoptosis in thoracic aortic aneurysm tissues. Furthermore, the expression levels of caspase-3 and the Bax/Bcl-2 ratio were significantly decreased in the aortic walls of curcumin-treated rats. CONCLUSION: The present study indicates that the beneficial effect of curcumin on degenerative aortic aneurysms is related to the inhibition of JNK and apoptosis in the walls of thoracic aortic aneurysms. PMID- 22840387 TI - Which are more important: prebiotics or probiotics? PMID- 22840388 TI - Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. AB - OBJECTIVE: Most aggressive cancers demonstrate a positive positron emission tomographic (PET) result using 18F-2-fluoro-2-deoxyglucose (FDG), reflecting a glycolytic phenotype. Inhibiting insulin secretion provides a method, consistent with published mechanisms, for limiting cancer growth. METHODS: Eligible patients with advanced incurable cancers had a positive PET result, an Eastern Cooperative Oncology Group performance status of 0 to 2, normal organ function without diabetes or recent weight loss, and a body mass index of at least 20 kg/m2. Insulin inhibition, effected by a supervised carbohydrate dietary restriction (5% of total kilocalories), was monitored for macronutrient intake, body weight, serum electrolytes, beta-hydroxybutyrate, insulin, and insulin-like growth factors-1 and -2. An FDG-PET scan was obtained at study entry and exit. RESULTS: Ten subjects completed 26 to 28 d of the study diet without associated unsafe adverse effects. Mean caloric intake decreased 35 +/- 6% versus baseline, and weight decreased by a median of 4% (range 0.0-6.1%). In nine patients with prior rapid disease progression, five with stable disease or partial remission on PET scan after the diet exhibited a three-fold higher dietary ketosis than those with continued progressive disease (n = 4, P = 0.018). Caloric intake (P = 0.65) and weight loss (P = 0.45) did not differ in those with stable disease or partial remission versus progressive disease. Ketosis was associated inversely with serum insulin levels (P = 0.03). CONCLUSION: Preliminary data demonstrate that an insulin-inhibiting diet is safe and feasible in selected patients with advanced cancer. The extent of ketosis, but not calorie deficit or weight loss, correlated with stable disease or partial remission. Further study is needed to assess insulin inhibition as complementary to standard cytotoxic and endocrine therapies. PMID- 22840389 TI - Sterols with antileishmanial activity isolated from the roots of Pentalinon andrieuxii. AB - A new cholesterol derivative, pentalinonsterol (cholest-4,20,24-trien-3-one, 1), and a new polyoxygenated pregnane sterol glycoside, pentalinonside (2), together with 18 known compounds, including 14 sterols (3-16), three coumarins (17-19), and a triterpene (20), were isolated from a n-hexane partition of a methanol extract of the roots of the Mexican medicinal plant Pentalinon andrieuxii. Structure elucidation of compounds 1 and 2 was accomplished by spectroscopic data interpretation. All isolates were evaluated in vitro for their antileishmanial activity. Among these compounds, 6,7-dihydroneridienone (15) was found to be the most potent principle against promastigotes of Leishmania mexicana (L. mexicana). The cholesterol analogue, pentalinonsterol (1), together with two known sterols, 24-methylcholest-4,24(28)-dien-3-one (3) and neridienone (16), also exhibited significant leishmanicidal activity in this same bioassay. Compounds 1, 3, 15, 16, cholest-4-en-3-one (4), and cholest-5,20,24-trien-3beta-ol (7), showed strong antileishmanial activity against amastigotes of L. mexicana, and 4 was found to be the most potent agent with an IC(50) value of 0.03MUM. All the isolates were also evaluated for their cytotoxicity in non-infected bone marrow-derived macrophages, but none of these compounds was found active towards this cell line. The intracellular parasites treated with compounds 1, 3, 4, 15, and 16 were further studied by electron microscopy; morphological abnormalities and destruction of the amastigotes were observed, as a result of treatment with these compounds. PMID- 22840390 TI - Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA. AB - One puzzling observation in patients affected with Hutchinson-Gilford progeria syndrome (HGPS), who overall exhibit systemic and dramatic premature aging, is the absence of any conspicuous cognitive impairment. Recent studies based on induced pluripotent stem cells derived from HGPS patient cells have revealed a lack of expression in neural derivatives of lamin A, a major isoform of LMNA that is initially produced as a precursor called prelamin A. In HGPS, defective maturation of a mutated prelamin A induces the accumulation of toxic progerin in patient cells. Here, we show that a microRNA, miR-9, negatively controls lamin A and progerin expression in neural cells. This may bear major functional correlates, as alleviation of nuclear blebbing is observed in nonneural cells after miR-9 overexpression. Our results support the hypothesis, recently proposed from analyses in mice, that protection of neural cells from progerin accumulation in HGPS is due to the physiologically restricted expression of miR-9 to that cell lineage. PMID- 22840391 TI - MicroRNA-9 Modulates Hes1 ultradian oscillations by forming a double-negative feedback loop. AB - Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate. PMID- 22840392 TI - Nuclear RNase P of Trypanosoma brucei: a single protein in place of the multicomponent RNA-protein complex. AB - RNase P is the endonuclease that removes 5' extensions from tRNA precursors. In its best-known form, the enzyme is composed of a catalytic RNA and a protein moiety variable in number and mass. This ribonucleoprotein enzyme is widely considered ubiquitous and apparently reached its highest complexity in the eukaryal nucleus, where it is typically composed of at least ten subunits. Here, we show that in the protist Trypanosoma brucei, two proteins are the sole forms of RNase P. They localize to the nucleus and the mitochondrion, respectively, and have RNase P activity each on their own. The protein-RNase P is, moreover, capable of replacing nuclear RNase P in yeast cells. This shows that complex ribonucleoprotein structures and RNA catalysis are not necessarily required to support tRNA 5' end formation in eukaryal cells. PMID- 22840393 TI - Conservation of a triple-helix-forming RNA stability element in noncoding and genomic RNAs of diverse viruses. AB - Abundant expression of the long noncoding (lnc) PAN (polyadenylated nuclear) RNA by the human oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) depends on a cis-element called the expression and nuclear retention element (ENE). The ENE upregulates PAN RNA by inhibiting its rapid nuclear decay through triple-helix formation with the poly(A) tail. Using structure-based bioinformatics, we identified six ENE-like elements in evolutionarily diverse viral genomes. Five are in double-stranded DNA viruses, including mammalian herpesviruses, insect polydnaviruses, and a protist mimivirus. One is in an insect picorna-like positive-strand RNA virus, suggesting that the ENE can counteract cytoplasmic as well as nuclear RNA decay pathways. Functionality of four of the ENEs was demonstrated by increased accumulation of an intronless polyadenylated reporter transcript in human cells. Identification of these ENEs enabled the discovery of PAN RNA homologs in two additional gammaherpesviruses, RRV and EHV2. Our findings demonstrate that searching for structural elements can lead to rapid identification of lncRNAs. PMID- 22840394 TI - Selective activation of cholinergic interneurons enhances accumbal phasic dopamine release: setting the tone for reward processing. AB - Dopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior. PMID- 22840395 TI - Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons. AB - Neurotrophin signaling is crucial for neuron growth. While the "signaling endosomes" hypothesis is one of the accepted models, the molecular machinery that drives retrograde axonal transport of TrkB signaling endosomes is largely unknown. In particular, mechanisms recruiting dynein to TrkB signaling endosomes have not been elucidated. Here, using snapin deficient mice and gene rescue experiments combined with compartmentalized cultures of live cortical neurons, we reveal that Snapin, as a dynein adaptor, mediates retrograde axonal transport of TrkB signaling endosomes. Such a role is essential for dendritic growth of cortical neurons. Deleting snapin or disrupting Snapin-dynein interaction abolishes TrkB retrograde transport, impairs BDNF-induced retrograde signaling from axonal terminals to the nucleus, and decreases dendritic growth. Such defects were rescued by reintroducing the snapin gene. Our study indicates that Snapin-dynein coupling is one of the primary mechanisms driving BDNF-TrkB retrograde transport, thus providing mechanistic insights into the regulation of neuronal growth and survival. PMID- 22840397 TI - First exon length controls active chromatin signatures and transcription. AB - Here, we explore the role of splicing in transcription, employing both genome wide analysis of human ChIP-seq data and experimental manipulation of exon-intron organization in transgenic cell lines. We show that the activating histone modifications H3K4me3 and H3K9ac map specifically to first exon-intron boundaries. This is surprising, because these marks help recruit general transcription factors (GTFs) to promoters. In genes with long first exons, promoter-proximal levels of H3K4me3 and H3K9ac are greatly reduced; consequently, GTFs and RNA polymerase II are low at transcription start sites (TSSs) and exhibit a second, promoter-distal peak from which transcription also initiates. In contrast, short first exons lead to increased H3K4me3 and H3K9ac at promoters, higher expression levels, accuracy in TSS usage, and a lower frequency of antisense transcription. Therefore, first exon length is predictive for gene activity. Finally, splicing inhibition and intron deletion reduce H3K4me3 levels and transcriptional output. Thus, gene architecture and splicing determines transcription quantity and quality as well as chromatin signatures. PMID- 22840396 TI - Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure. AB - Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture. PMID- 22840398 TI - Genomic imprinting absent in Drosophila melanogaster adult females. AB - Genomic imprinting occurs when expression of an allele differs based on the sex of the parent that transmitted the allele. In D. melanogaster, imprinting can occur, but its impact on allelic expression genome-wide is unclear. Here, we search for imprinted genes in D. melanogaster using RNA-seq to compare allele specific expression between pools of 7- to 10-day-old adult female progeny from reciprocal crosses. We identified 119 genes with allelic expression consistent with imprinting, and these genes showed significant clustering within the genome. Surprisingly, additional analysis of several of these genes showed that either genomic heterogeneity or high levels of intrinsic noise caused imprinting-like allelic expression. Consequently, our data provide no convincing evidence of imprinting for D. melanogaster genes in their native genomic context. Elucidating sources of false-positive signals for imprinting in allele-specific RNA-seq data, as done here, is critical given the growing popularity of this method for identifying imprinted genes. PMID- 22840399 TI - An olfactory subsystem that mediates high-sensitivity detection of volatile amines. AB - Olfactory stimuli are detected by over 1,000 odorant receptors in mice, with each receptor being mapped to specific glomeruli in the olfactory bulb. The trace amine-associated receptors (TAARs) are a small family of evolutionarily conserved olfactory receptors whose contribution to olfaction remains enigmatic. Here, we show that a majority of the TAARs are mapped to a discrete subset of glomeruli in the dorsal olfactory bulb of the mouse. This TAAR projection is distinct from the previously described class I and class II domains, and is formed by a sensory neuron population that is restricted to express TAAR genes prior to choice. We also show that the dorsal TAAR glomeruli are selectively activated by amines at low concentrations. Our data uncover a hard-wired, parallel input stream in the main olfactory pathway that is specialized for the detection of volatile amines. PMID- 22840400 TI - Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. AB - In neurons, transmembrane proteins are targeted to dendrites in vesicles that traffic solely within the somatodendritic compartment. How these vesicles are retained within the somatodendritic domain is unknown. Here, we use a novel pulse chase system, which allows synchronous release of exogenous transmembrane proteins from the endoplasmic reticulum to follow movements of post-Golgi transport vesicles. Surprisingly, we found that post-Golgi vesicles carrying dendritic proteins were equally likely to enter axons and dendrites. However, once such vesicles entered the axon, they very rarely moved beyond the axon initial segment but instead either halted or reversed direction in an actin and Myosin Va-dependent manner. In contrast, vesicles carrying either an axonal or a nonspecifically localized protein only rarely halted or reversed and instead generally proceeded to the distal axon. Thus, our results are consistent with the axon initial segment behaving as a vesicle filter that mediates the differential trafficking of transport vesicles. PMID- 22840401 TI - Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules neurexin and neuroligin. AB - Polymorphic adhesion molecules neurexin and neuroligin (NL) mediate asymmetric trans-synaptic adhesion, which is crucial for synapse development and function. It is not known whether or how individual synapse function is controlled by the interactions between variants and isoforms of these molecules with differing ectodomain regions. At a physiological concentration of Ca(2+), the ectodomain complex of neurexin-1 beta isoform (Nrx1beta) and NL1 spontaneously assembled into crystals of a lateral sheet-like superstructure topologically compatible with transcellular adhesion. Correlative light-electron microscopy confirmed extracellular sheet formation at the junctions between Nrx1beta- and NL1 expressing non-neuronal cells, mimicking the close, parallel synaptic membrane apposition. The same NL1-expressing cells, however, did not form this higher order architecture with cells expressing the much longer neurexin-1 alpha isoform, suggesting a functional discrimination mechanism between synaptic contacts made by different isoforms of neurexin variants. PMID- 22840402 TI - The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. AB - Genome-wide studies have identified thousands of long noncoding RNAs (lncRNAs) lacking protein-coding capacity. However, most lncRNAs are expressed at a very low level, and in most cases there is no genetic evidence to support their in vivo function. Malat1 (metastasis associated lung adenocarcinoma transcript 1) is among the most abundant and highly conserved lncRNAs, and it exhibits an uncommon 3'-end processing mechanism. In addition, its specific nuclear localization, developmental regulation, and dysregulation in cancer are suggestive of it having a critical biological function. We have characterized a Malat1 loss-of-function genetic model that indicates that Malat1 is not essential for mouse pre- and postnatal development. Furthermore, depletion of Malat1 does not affect global gene expression, splicing factor level and phosphorylation status, or alternative pre-mRNA splicing. However, among a small number of genes that were dysregulated in adult Malat1 knockout mice, many were Malat1 neighboring genes, thus indicating a potential cis-regulatory role of Malat1 gene transcription. PMID- 22840403 TI - Infection-induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus. AB - Infection leads to heightened activation of natural killer (NK) cells, a process that likely involves direct cell-to-cell contact, but how this occurs in vivo is poorly understood. We have used two-photon laser-scanning microscopy in conjunction with Toxoplasma gondii mouse infection models to address this question. We found that after infection, NK cells accumulated in the subcapsular region of the lymph node, where they formed low-motility contacts with collagen fibers and CD169(+) macrophages. We provide evidence that interactions with collagen regulate NK cell migration, whereas CD169(+) macrophages increase the activation state of NK cells. Interestingly, a subset of CD169(+) macrophages that coexpress the inflammatory monocyte marker Ly6C had the most potent ability to activate NK cells. Our data reveal pathways through which NK cell migration and function are regulated after infection and identify an important accessory cell population for activation of NK cell responses in lymph nodes. PMID- 22840404 TI - Age-related oxidative stress compromises endosomal proteostasis. AB - A hallmark of aging is an imbalance between production and clearance of reactive oxygen species and increased levels of oxidatively damaged biomolecules. Herein, we demonstrate that splenic and nodal antigen-presenting cells purified from aging mice accumulate oxidatively modified proteins with side-chain carbonylation, advanced glycation end products, and lipid peroxidation. Furthermore, we show that the endosomal accumulation of oxidatively modified proteins interferes with the efficient processing of exogenous antigens and degradation of macroautophagy-delivered proteins. In support of a causative role for oxidized products in the inefficient immune response, a decrease in oxidative stress improved the adaptive immune response to immunizing antigens. These findings underscore a previously unrecognized negative effect of age-dependent changes in cellular proteostasis on the immune response. PMID- 22840406 TI - A theory of germinal center B cell selection, division, and exit. AB - High-affinity antibodies are generated in germinal centers in a process involving mutation and selection of B cells. Information processing in germinal center reactions has been investigated in a number of recent experiments. These have revealed cell migration patterns, asymmetric cell divisions, and cell-cell interaction characteristics, used here to develop a theory of germinal center B cell selection, division, and exit (the LEDA model). According to this model, B cells selected by T follicular helper cells on the basis of successful antigen processing always return to the dark zone for asymmetric division, and acquired antigen is inherited by one daughter cell only. Antigen-retaining B cells differentiate to plasma cells and leave the germinal center through the dark zone. This theory has implications for the functioning of germinal centers because compared to previous models, high-affinity antibodies appear one day earlier and the amount of derived plasma cells is considerably larger. PMID- 22840405 TI - Operator sequence alters gene expression independently of transcription factor occupancy in bacteria. AB - A canonical quantitative view of transcriptional regulation holds that the only role of operator sequence is to set the probability of transcription factor binding, with operator occupancy determining the level of gene expression. In this work, we test this idea by characterizing repression in vivo and the binding of RNA polymerase in vitro in experiments where operators of various sequences were placed either upstream or downstream from the promoter in Escherichia coli. Surprisingly, we find that operators with a weaker binding affinity can yield higher repression levels than stronger operators. Repressor bound to upstream operators modulates promoter escape, and the magnitude of this modulation is not correlated with the repressor-operator binding affinity. This suggests that operator sequences may modulate transcription by altering the nature of the interaction of the bound transcription factor with the transcriptional machinery, implying a new layer of sequence dependence that must be confronted in the quantitative understanding of gene expression. PMID- 22840408 TI - Genome-wide analysis reveals extensive functional interaction between DNA replication initiation and transcription in the genome of Trypanosoma brucei. AB - Identification of replication initiation sites, termed origins, is a crucial step in understanding genome transmission in any organism. Transcription of the Trypanosoma brucei genome is highly unusual, with each chromosome comprising a few discrete transcription units. To understand how DNA replication occurs in the context of such organization, we have performed genome-wide mapping of the binding sites of the replication initiator ORC1/CDC6 and have identified replication origins, revealing that both localize to the boundaries of the transcription units. A remarkably small number of active origins is seen, whose spacing is greater than in any other eukaryote. We show that replication and transcription in T. brucei have a profound functional overlap, as reducing ORC1/CDC6 levels leads to genome-wide increases in mRNA levels arising from the boundaries of the transcription units. In addition, ORC1/CDC6 loss causes derepression of silent Variant Surface Glycoprotein genes, which are critical for host immune evasion. PMID- 22840407 TI - An in vivo platform for rapid high-throughput antitubercular drug discovery. AB - Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here, we develop a model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of concept that both traditional bacterial-targeting antitubercular drugs and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model's utility for the identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial- and host-targeting compounds. Thus, the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small-molecule screens for other infectious and noninfectious diseases. PMID- 22840410 TI - Microsuture after benign vocal fold lesion removal: a randomized trial. AB - PURPOSE: Removal of benign vocal fold lesions results in small to moderate-sized mucosal defect on vocal fold, which heals by secondary intention. Microsuturing this defect leads to primary wound healing with fastened recovery and less scar. However, its value has not been determined. MATERIALS AND METHODS: This is prospective, randomized, and controlled study performed in university hospital. Forty adults with vocal polyp, cyst, and Reinke's edema were included. Preoperatively, all patients completed VHI (Voice Handicap Index)-30, had acoustic analysis with continuous /a/ and videolaryngostroboscopy (VLS). The patients were randomly assigned to study group (with 1 or 2 6/0 vicryl suture) (n = 20) or control group (n = 20). Postoperative follow-up was done at the first, second, and fourth weeks. During follow-up examinations, VLS was repeated; the patients completed VHI-30 and had an acoustic analysis again. RESULTS: All patients recovered with normal VLS and without complications; all were satisfied with the treatment result. The VHI results and acoustic analysis parameters of the study group were statistically significantly better than those of the control group at the first postoperative week (P < .05) but not at the second and fourth weeks (P > .05). Normal VLS was obtained significantly more early in the study group compared with the control group (P < .05). CONCLUSIONS: Microlaryngoscopic removal of benign vocal fold lesions is a safe, satisfying procedure with excellent to good results if done according to its principles. Microsuturing of the mucosal defect helps to speed up recovery, although final result remains to be clinically unchanged. It may be beneficial for professional voice users by making early return of vocal fold function possible. PMID- 22840411 TI - Reprint of: Factor VIIa-AT complex plasma levels and arterial thrombosis. PMID- 22840409 TI - ChAP-MS: a method for identification of proteins and histone posttranslational modifications at a single genomic locus. AB - The field of epigenomics has been transformed by chromatin immunoprecipitation approaches that provide for the localization of a defined protein or posttranslationally modified protein to specific chromosomal sites. While these approaches have helped us conceptualize epigenetic mechanisms, the field has been limited by the inability to define features such as the proteome and histone modifications at a specific genomic locus in an unbiased manner. We developed an unbiased approach whereby a unique native genomic locus was isolated, which was followed by high-resolution proteomic identification of specifically associated proteins and histone posttranslational modifications. This chromatin affinity purification with mass spectrometry (ChAP-MS) technique was used to specifically enrich a ~1,000 base pair section of GAL1 chromatin under transcriptionally active and repressive conditions, as well as to identify the specifically bound proteins and histone posttranslational modifications. ChAP-MS should yield insight into the regulatory mechanisms of transcription and help identify factors that epigenetically control chromatin function. PMID- 22840412 TI - New directions in the diagnosis and treatment of pulmonary embolism in pregnancy. AB - The diagnosis and management of pulmonary embolism in pregnancy is difficult, because diagnostic procedures and the use of anticoagulants potentially can expose mother and fetus to adverse effects. This article reviews evidence for current best practice and emerging novel techniques for the diagnosis of pulmonary embolism in pregnancy and includes clinical prediction models, biomarkers, and diagnostic imaging that may offer improvement in the diagnosis and investigation of pulmonary embolism in pregnancy in the future. The usefulness of new anticoagulant agents (fondaparinux, rivaroxaban, and dabigatran) in managing pulmonary embolism in future pregnancies is also explored. PMID- 22840413 TI - Randomized trial of transversus abdominis plane block at total laparoscopic hysterectomy: effect of regional analgesia on quality of recovery. AB - OBJECTIVE: The objective of the study was to determine whether transversus abdominis plane (TAP) block improves the early postoperative quality of recovery (QoR-40). The secondary objectives measured postoperative pain, length of stay, and narcotic use. STUDY DESIGN: This was a randomized, single-blinded trial of TAP block versus no block on women undergoing laparoscopic hysterectomy. TAP block patients received 20 mL of 0.5% ropivacaine with epinephrine 1:200,000 placed under ultrasound guidance on each side. The outcomes were measured using validated quality of recovery questionnaires (QoR-40), visual analog scales (VAS) for pain, and documented narcotic use in the electronic medical record. RESULTS: In 58 women, no differences in demographics were noted between groups. Comparisons of pain and recovery between the 2 groups showed no differences. There was no decrease in narcotic use or length of stay among those who received the TAP block. CONCLUSIONS: TAP block does not improve postoperative QoR-40 scores or VAS pain scores following laparoscopic hysterectomy, nor does it decrease narcotic pain medication use. PMID- 22840414 TI - What is the best treatment of drug-resistant trigeminal neuralgia in patients affected by multiple sclerosis? A literature analysis of surgical procedures. AB - OBJECTIVE: Drug-resistant trigeminal neuralgia (TN) can complicate the clinical course of patients affected by multiple sclerosis (MS). Various surgical procedures have been reported for the treatment of this condition, but there is no agreement on the best management of these patients. To our knowledge, there is no critical literature analysis focusing on this particular topic. The aim of this study was to evaluate the clinical outcome of different surgical procedures utilized for drug-resistant TN in MS patients. METHODS: We reviewed the literature about the studies reporting on surgical treatment of drug-resistant TN in MS patients. Case reports and case series less than 4 patients were excluded from the analysis. Nineteen studies were selected for the statistical analysis. To reduce the variability of the data, the selected studies were evaluated for the following outcome parameters: acute pain relief rate (APR), rate of recurrence (RR), pain free at follow-up rate (PF at FU) and complication rate (CR). For the statistical analysis, chi-square statistic, using the Fisher's exact test was utilized. RESULTS: There was no procedure statistically superior in terms of APR rate in MS patients following the surgical treatment of TN. The highest RR was observed for percutaneous balloon compression (PBC) (60.2+/ 14.4%). This result was statistically significant when compared to gamma knife surgery (GKS) (p=0.0129) and microvascular decompression (MVD) (p=0.0281). MVD together with percutaneous radiofrequency rhizothomy (PRR) was associated with a statistically better PF at FU rate (56.5+/-16.8% and 73.5+/-14.2%, respectively). However PBC and MVD showed statistical significant minor CR compared to other techniques (no complications and 18.7+/-17.4%, respectively). CONCLUSION: Our study shows no differences in the short term results among different procedures for TN in MS patients. Each technique demonstrate advantages and limits in terms of long term pain, recurrence rate and complication rate. Each patient should be accurately informed on pros and cons of each procedure in order to be involved in the most appropriate choice. PMID- 22840415 TI - Prevalence and subtypes of radiological cerebrovascular disease in late-onset isolated seizures and epilepsy. AB - BACKGROUND: Late-onset epilepsy (LOE), onset over 60, is often attributed to cerebrovascular disease (CVD), and is associated with increased stroke risk. We investigated the radiological prevalence of CVD in LOE. METHODS: We undertook a retrospective case-control study of patients with LOE and age and sex-matched controls, also matched for imaging modality. Radiological CVD was recorded, with radiological findings by an experienced consultant neuroradiologist usi a structured proforma. RESULTS: 105 cases and 105 controls were studied, comprising 61 (58.1%) males, mean (+/-SD) age (years) 72.7+/-7.48 (cases), 72.4+/-7.02 (controls). 9 cases had isolated seizures rather than LOE. Imaging modality (in cases and controls) was CT in 59 and MRI in 46. Radiological CVD was more prevalent amongst cases (65.7%) than controls (33.3%) (p<0.0001, Chi-square), odds ratio 3.83 (95% CI 2.16-6.79). Large vessel disease (LVD) (single or multiple cortical or subcortical infarcts>1.5 cm) was present in 23 (21.9%) cases and 2 (1.9%) (p<0.001) controls, with small vessel disease (SVD) (periventricular or subcortical white matter lesions (WMLs), including leukoaraiosis (LA)) present in 52 (49.5%) cases (LA in 4) and 34 (32.3%) controls (LA in 0) (p<0.05). When WMLs were rated using a semiquantitative visual rating scale, a trend towards greater severity was observed amongst cases compared to controls. CONCLUSIONS: Radiological CVD is significantly more prevalent in patients with LOE than controls, including signs of both LVD and SVD. SVD also appears to be of greater severity. Further studies are needed in this area. PMID- 22840416 TI - L-2 hydroxyglutaric aciduria as a rare cause of leukencephalopathy in adults. PMID- 22840417 TI - Benzimidazole bearing oxadiazole and triazolo-thiadiazoles nucleus: design and synthesis as anticancer agents. AB - Two new series of benzimidazole bearing oxadiazole[1-(1H-benzo[d]imidazol-2-yl)-3 (5-substituted-1,3,4-oxadiazol-2-yl)propan-1-ones (4a-l)] and triazolo thiadiazoles[1-(1H-benzo[d]imidazol-2-yl)-3-(6-(substituted)-[1,2,4]triazolo[3,4 b][1,3,4]thiadiazol-3-yl)propan-1-one (7a-e)] have been synthesized successfully from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide (3) with an aim to produce promising anticancer agents. In vitro anticancer activities of synthesized compounds were screened at the National Cancer Institute (NCI), USA, according to their applied protocol against full NCI 60 human cell lines panel; results showed good to remarkable anticancer activity. Among them, compound (4j, NCS: 761980) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 MUM) with GI(50) values ranging from 0.49 to 48.0 MUM and found superior for the non-small cell lung cancer cell lines like HOP-92 (GI(50) 0.49, TGI 19.9,LC(50) >100 and Log(10)GI(50) -6.30, Log(10)TGI -4.70, Log(10)LC(50) >-4.00). PMID- 22840418 TI - Extraction, isolation, and purification of analytes from samples of marine origin -a multivariate task. AB - The development of a multivariate study for a quantitative analysis of six different polybrominated diphenyl ethers (PBDEs) in tissue of Atlantic Salmo salar L. is reported. An extraction, isolation, and purification process based on an accelerated solvent extraction system was designed, investigated, and optimized by means of statistical experimental design and multivariate data analysis and regression. An accompanying gas chromatography-mass spectrometry analytical method was developed for the identification and quantification of the analytes, BDE 28, BDE 47, BDE 99, BDE 100, BDE 153, and BDE 154. These PBDEs have been used in commercial blends that were used as flame-retardants for a variety of materials, including electronic devices, synthetic polymers and textiles. The present study revealed that an extracting solvent mixture composed of hexane and CH2Cl2 (10:90) provided excellent recoveries of all of the six PBDEs studied herein. A somewhat lower polarity in the extracting solvent, hexane and CH2Cl2 (40:60) decreased the analyte %-recoveries, which still remain acceptable and satisfactory. The study demonstrates the necessity to perform an intimately investigation of the extraction and purification process in order to achieve quantitative isolation of the analytes from the specific matrix. PMID- 22840419 TI - Factors influencing emergence of tularemia, Hungary, 1984-2010. PMID- 22840420 TI - Optic neuropathy after vitrectomy for retinal detachment: clinical features and analysis of risk factors. AB - PURPOSE: To describe the clinical characteristics of and risk factors for the development of optic neuropathy after pars plana vitrectomy (PPV) for macula sparing primary rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective case-control study. PARTICIPANTS: Seven patients who underwent PPV for macula-sparing primary RRD with subsequent development of optic neuropathy and 42 age- and gender-matched control patients undergoing PPV for macula-sparing primary RRD. METHODS: Retrospective chart review of medical and surgical records. MAIN OUTCOME MEASURES: Clinical features of patients who developed optic neuropathy after PPV for macula-sparing RRD and analysis of potential risk factors (age, gender, medical history, surgical technique, intraoperative ocular perfusion pressure [OPP], and operative time). RESULTS: At last follow-up, all 7 patients with optic neuropathy had visual acuity less than 20/200, relative afferent pupillary defects, optic nerve pallor, and visual field defects. A total of 5 of 7 patients (71%) demonstrated intraoperative reduced OPP with associated systemic hypotension compared with 7 of 42 patients (17%) in the control cohort (P = 0.01). CONCLUSIONS: Optic neuropathy after PPV for macula-sparing primary RRD is a rare but potentially devastating complication. Although the cause is often unclear, reduced ocular perfusion due to intraoperative systemic hypotension may be a contributing risk factor in some eyes. PMID- 22840422 TI - Subspecialization in glaucoma surgery. AB - PURPOSE: To evaluate trends in glaucoma surgery subspecialization. DESIGN: Population-based analysis of incisional glaucoma surgery and laser trabeculoplasty practice patterns among all ophthalmologists in Ontario, Canada, from 1995 through 2010. PARTICIPANTS: All ophthalmologists in Ontario, Canada, providing universal health care for the provincial population of approximately 12 million. METHODS: The province of Ontario provides government-funded universal health care insurance to all citizens through the Ontario Health Insurance Plan (OHIP). Anonymized physician services data were obtained from the OHIP database, which has excellent accuracy for procedure performance. MAIN OUTCOME MEASURES: Proportion of ophthalmologists providing incisional glaucoma surgery and laser trabeculoplasty and the distribution of these surgical and laser procedures among ophthalmologists. RESULTS: Between 1995 and 2010, the median number of ophthalmologists in Ontario was 427 (35.1 per 1 million population), ranging from 417 to 453 (32.9-40.3 per 1 million population). The percentage of ophthalmologists providing incisional glaucoma surgery dropped from 35% in 1995 to 19% in 2010, a 47% decline. Over the same period, the mean number of incisional glaucoma surgeries performed per surgeon doubled, and the percentage of incisional glaucoma operations provided by high-volume surgeons rose from 23% to 59%. The percentage of ophthalmologists performing laser trabeculoplasty was relatively stable (48% in 1995 to 50% in 2010). CONCLUSIONS: Over the past 16 years, the proportion of ophthalmologists providing incisional glaucoma surgery has declined significantly. At the same time, the proportion of incisional glaucoma surgery provided by high-volume glaucoma surgeons has more than doubled. These trends will have important implications for stakeholders from policy makers and hospitals to academic departments and residency education programs. PMID- 22840421 TI - The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). AB - PURPOSE: The Age-Related Eye Disease Study (AREDS) demonstrated beneficial effects of oral supplementation with antioxidant vitamins and minerals on the development of advanced age-related macular degeneration (AMD) in persons with at least intermediate AMD (bilateral large drusen with or without pigment changes). Observational data suggest that other oral nutrient supplements might further reduce the risk of progression to advanced AMD. The primary purpose of the Age Related Eye Disease Study 2 (AREDS2) is to evaluate the efficacy and safety of lutein plus zeaxanthin (L+Z) and/or omega-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation in reducing the risk of developing advanced AMD. The study also assesses the reduction in zinc and the omission of beta-carotene from original AREDS formulation. DESIGN: Multicenter, phase III, randomized, controlled clinical trial. PARTICIPANTS: Persons aged 50 to 85 with bilateral intermediate AMD or advanced AMD in 1 eye. METHODS: All participants were randomly assigned to placebo (n = 1012), L+Z (10 mg/2 mg; n = 1044), omega-3 LCPUFAs (eicosapentaenoic acid + docosahexaenoic acid [650 mg/350 mg]; n = 1069), or the combination of L+Z and omega-3 LCPUFAs (n = 1078). All participants were offered a secondary randomization to 1 of 4 variations of the original AREDS formulation keeping vitamins C (500 mg) and E (400 IU) and copper (2 mg) unchanged while varying zinc and beta-carotene as follows: Zinc remains at the original level (80 mg), lower only zinc to 25 mg, omit beta-carotene only, or lower zinc to 25 mg and omit beta-carotene. MAIN OUTCOME MEASURES: Progression to advanced AMD determined by centralized grading of annual fundus photographs. RESULTS: We enrolled 4203 participants at 82 clinical centers located in the United States. Population characteristics at baseline were as follows: Mean age, 74 years; 57% female; 97% white; 7% current smokers; 19% with prior cardiovascular disease; and 44% and 50% taking statin-class cholesterol-lowering drugs and aspirin, respectively. Ocular characteristics include 59% with bilateral large drusen, 32% with advanced AMD in 1 eye and mean visual acuity of 20/32 in eyes without advanced AMD. CONCLUSIONS: This report presents the AREDS2 study design and the participants' baseline demographic and ocular characteristics. PMID- 22840423 TI - Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration. AB - PURPOSE: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. DESIGN: Case series study. PARTICIPANTS: A cohort of 420 eyes of 397 neovascular AMD patients. METHODS: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models. MAIN OUTCOME MEASURES: The VA change after 3 ranibizumab injections and the age of neovascular disease onset. RESULTS: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001). CONCLUSIONS: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. PMID- 22840424 TI - Vertical transmission of Babesia microti, United States. AB - Babesiosis is usually acquired from a tick bite or through a blood transfusion. We report a case of babesiosis in an infant for whom vertical transmission was suggested by evidence of Babesia spp. antibodies in the heel-stick blood sample and confirmed by detection of Babesia spp. DNA in placenta tissue. PMID- 22840426 TI - Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study. AB - AIMS: Hypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults. METHODS: We analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30-45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile. RESULTS: In bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P<0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P<0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve >= 0.37). CONCLUSION: PAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis. PMID- 22840425 TI - JC virus agnoprotein enhances large T antigen binding to the origin of viral DNA replication: evidence for its involvement in viral DNA replication. AB - Agnoprotein is required for the successful completion of the JC virus (JCV) life cycle and was previously shown to interact with JCV large T-antigen (LT-Ag). Here, we further characterized agnoprotein's involvement in viral DNA replication. Agnoprotein enhances the DNA binding activity of LT-Ag to the viral origin (Ori) without directly interacting with DNA. The predicted amphipathic alpha-helix of agnoprotein plays a major role in this enhancement. All three phenylalanine (Phe) residues of agnoprotein localize to this alpha-helix and Phe residues in general are known to play critical roles in protein-protein interaction, protein folding and stability. The functional relevance of all Phe residues was investigated by mutagenesis. When all were mutated to alanine (Ala), the mutant virus (F31AF35AF39A) replicated significantly less efficiently than each individual Phe mutant virus alone, indicating the importance of Phe residues for agnoprotein function. Collectively, these studies indicate a close involvement of agnoprotein in viral DNA replication. PMID- 22840427 TI - Acute effects of cigarette smoking on insulin resistance and arterial stiffness in young adults. AB - BACKGROUND: It is unclear whether changes in insulin sensitivity or arterial stiffness in cigarette smokers could explain the link between cigarette smoking and diabetes mellitus. The purpose of the study was to evaluate the acute effects of cigarette smoking on insulin resistance and arterial stiffness in a cohort of young healthy adults. METHODS: Metabolic risk components, hemodynamic parameters, plasma nitrite/nitrate and high-sensitivity C-reactive protein (hsCRP) levels, were compared between smokers and age- and gender-matched controls (non-smokers). In smokers, these levels were determined 8-h following cigarette abstinence and an hour after smoking. RESULTS: One hundred nineteen smokers and age-matched non smokers (mean age, 32 years; 83% men) were included in this study. Compared with non-smokers, smokers had a significantly higher number of abnormal metabolic risk components, HOMA-IR index and total nitrite/nitrate levels. There were no differences in brachial/central blood pressure, augmentation index and hsCRP between smokers and non-smokers. An hour after smoking, smokers had significantly higher levels of HOMA-IR, total nitrite/nitrate, hsCRP and heart rate compared with baseline levels. By contrast, brachial/central blood pressure and augmentation index were unchanged after cigarette smoking. Baseline vascular and insulin resistance status predicted the extent of rise in the HOMA-IR and augmentation indices acutely after cigarette smoking (adjusted R(2) 0.358 and 0.124, p < 0.001 respectively). CONCLUSIONS: Individuals with more advanced vascular damage and insulin resistance are vulnerable to the acute effects of cigarette smoking. PMID- 22840428 TI - Can premenstrual syndrome affect arterial stiffness or blood pressure? AB - OBJECTIVE: We tested the hypotheses that monthly fluctuations in markers of arterial stiffness and blood pressure hemodynamics differ between women with and without premenstrual syndrome. We also assessed hypertension prevalence and arterial stiffening in postmenopausal women with or without history of premenstrual symptoms. METHODS: Twenty one pre-menopausal women with premenstrual syndrome and 15 women without were prospectively examined in three distinct phases of their menstrual cycle (menses, late follicular and luteal phase). Pulse wave velocity and analysis were used to assess arterial stiffness and wave reflection indices, respectively. Endothelial function was evaluated by flow mediated vasodilation. In a cross-sectional substudy, 156 postmenopausal women were assessed for possible associations between retrospectively reported PMS symptoms and hypertension. RESULTS: In women with premenstrual syndrome, arterial stiffness significantly increased during the luteal and menses phase (late follicular: 6.48 +/- 1.07, luteal: 7.1 +/- 1.26, menstruation: 7.12 +/- 1.19 m/s, p = 0.003), while blood pressure peaked at the menses phase. Significant interactions between PMS and changes in arterial stiffness and blood pressure but not endothelial function, were observed. Changes in PWV were significantly associated with concomitant changes in blood pressure, C-reactive protein and the severity of PMS symptoms. The prevalence of hypertension (20.9% vs. 40.9%, p = 0.041) and pulse-wave velocity values (8.64 +/- 1.52 vs. 9.37 +/- 1.1, p = 0.046) were higher in postmenopausal women with 7 or more reported PMS symptoms. Arterial stiffness differences remained significant after adjustment for confounding factors. CONCLUSION: These results imply that PMS may affect arterial stiffness and BP monthly variability. Whether PMS is associated with new onset hypertension later in life needs further evaluation. PMID- 22840429 TI - Non-alcoholic fatty liver disease and cardiovascular disease. PMID- 22840430 TI - Metabolic phenotype of rats exposed to heroin and potential markers of heroin abuse. AB - BACKGROUND: Metabolomics allows the high-throughput analysis of low molecular mass compounds in biofluids, which can reflect the metabolic response of the body to heroin exposure and potentially reveal biomarkers of heroin abuse. METHODS: Heroin was administered to Sprague-Dawley rats in increasing doses from 3 to 16.5 mg kg(-1)d(-1) (i.p.) for 10 days, then withdrawn and re-administered for 4 days. The analytes in serum and urine were profiled using gas chromatography-mass spectrometry, and metabolic patterns were evaluated based on the metabolomics data. RESULTS: Both the administration and withdrawal of heroin resulted in aberrant behaviour in the rats; however, the rats gradually became adapted to heroin. Metabolomics data showed that heroin administration caused deviations in the metabolic patterns, whereas heroin withdrawal restored the metabolic patterns towards baseline. Re-administration of heroin caused the metabolic patterns to deviate again. Analysis of the metabolites revealed that heroin induced an acceleration of the tricarboxylic acid cycle and the metabolism of free fatty acids that may contribute to the reduction in observed body weight in the heroin group. Heroin administration decreased tryptophan and 5-hydroxytryptamine levels in peripheral serum but increased urinary tryptophan and 5-hydroxyindoleacetate. Withdrawal of heroin for 4 days efficiently restored all metabolites to baseline, except serum myo-inositol-1-phosphate, threonate, and hydroxyproline in the urine. CONCLUSIONS: Heroin administration significantly perturbed metabolic pathways, elevated energy metabolism, whereas heroin withdrawal restored all but a few metabolites to baseline. These peripheral metabolites were indicated as the surrogates characterising the metabolic effect of heroin on central nervous system function. PMID- 22840431 TI - [Quality of life of males with spinal cord injury and sexual dysfunction]. AB - AIMS: the aims of this study are to assess the quality of life (QOL) of males with spinal cord injury (SCI) and to know their sexual health. We also analyze the links among clinic and sociodemographic variables, the sexual health of males with SCI and their QOL. METHOD: This is a transversal cross-sectional study that was made in the hospital of Paraplegics of Toledo. The sample included 45 men presenting SCI and sexual dysfunction. Life Satisfaction Checklist and Sexual Health Measurement Scale were used to gather data. RESULTS: The 97, 8% of all participants are interested in having sexual relationships; the 70% of all participants have a steady sexual couple while the 51% often maintain sexual relations. The 86% of the sample admit to suffer from erectile dysfunction and the 71% can't ejaculate. The score of the group which has erectile dysfunction are significantly low in sexual QOL (p t-Student 0.000) and in general QOL (p t Student 0.001). The sample had an average in general QOL of 34,27 (standard deviation: 2,8), in social QOL 20,16 (SD:2,7), in sexual QOL 7,62 (SD:2,7) and in economic QOL 7,71 (SD:2,6). There isn't a significant relationship among the QOL and the etiology, the degree and the time of evolution of the SCI. CONCLUSIONS: The individuals who have participated in this study generally experienced a good general QOL, but their sexual life is the aspect which causes them a greater dissatisfaction. In fact, those who suffer from erectile dysfunction show less satisfaction with their general and sexual QOL. PMID- 22840432 TI - [The sense of coherence among nurses]. AB - Through the construct "The sense of coherence" (SOC), the salutogenic model explains why people subjected to stressors are able to maintain good health. The SOC was defined by Antonovsky as a global orientation that expresses the extent to which a person has a highly internalized, permanent - but at the same time dynamic - feeling of confidence; this feeling of confidence is predictable and leads to a high probability that events will turn out well. The present article reviews the literature on the SOC in the nursing profession. The results show that the SOC is a protective factor against stressors in the work environment and in the work-life balance. Low SOC levels are associated with health problems such as burnout or depression, as well as certain personality traits. PMID- 22840433 TI - [Determination of ankle-brachial index using a portable doppler and a blood pressure measuring device in diabetic patients]. AB - Peripheral arterial disease (PAD) is one of the systemic manifestations of atherothrombosis. The subjects with atherosclerosis in a particular vascular bed are at increased risk of cardiovascular and cerebrovascular complications. The diagnostic methods currently available in Primary Care (PC) for the diagnosis of PAD are pedal pulse palpation, oscillometry and Doppler. We designed a descriptive study to determine the prevalence of PAD in diabetic patients by calculating their ankle-brachial index (ABI) using portable Doppler HADECO SMARTDOP 30EX and OMRON automatic blood pressure by two previously trained investigators-examiners, a doctor and a nurse. It was also intended to compare the results obtained with both diagnostic methods and learn the predictive value of a vascular event with an abnormal ABI. The prevalences of PAD measured with portable Doppler and automatic sphygmomanometer were 29.3 (95% CI; 23.3 to 35.8) and 15.3 (95% CI; 10.2 to 20.5), respectively. The intraclass correlation coefficient (ICC) showed an acceptable match of results obtained with the ABI automatic blood pressure compared to Doppler technique. We found in our study that the history variables of PAD, age, duration of diabetes, and sex showed statistical significance with PAD. The correlation coefficients of both ABI measurement with the existence of a cardiovascular event proved to be significant for patients with levels below 0.9 with a chi-squared P<.05. Early detection of PAD in the clinic enables preventive strategies to be established and to intensify the treatment in these cases. PMID- 22840434 TI - [The vision of the other and conflicts in the relationship between nurses and muslim patients]. AB - OBJECTIVES: -To find out the views of nurses on Muslim patients and to determine whether these views are related to the existence of, or lack of conflicts. - To determine what the Muslim patients think of the nurses who look after them, and to see whether this is related to the existence of, or lack of conflicts. - To look for similarities or differences in the "vision of the other" in the nurse Muslim patient relationship. METHOD: Grounded Theory, using in-depth interviews. INFORMANTS: Nurses (N=32), men and women of Muslim tradition who have been hospitalized in one of the public hospitals in the province of Almeria (N=37) RESULTS: The nurses. In the discourses there were numerous stereotypes and prejudices towards patients of Muslim tradition. This negative view was in contrast with the lack of conflicts with this type of patient. The patients. These patients gave a positive opinion of the nurses, stressing in particular, their professional attitude and the confidence they install in them. They tended to play down any negative experience with the nursing professionals. CONCLUSIONS: In spite of this stereotyped and prejudiced "vision of the other" on the part of the nurses, the relationship is not affected from the point of view of the Muslim patients. It is necessary to be aware of this negative vision that the nursing professionals have, and of the need to work actively to modify it, promoting cultural knowledge and respect through specific training in this field. PMID- 22840435 TI - An investigation of a genomewide supported psychosis variant in ZNF804A and white matter integrity in the human brain. AB - ZNF804A, a genomewide supported susceptibility gene for schizophrenia and bipolar disorder, has been associated with task-independent functional connectivity between the left and right dorsolateral prefrontal cortices. Several lines of evidence have converged on the hypothesis that this effect may be mediated by structural connectivity. We tested this hypothesis using diffusion tensor magnetic resonance imaging in three samples: one German sample of 50 healthy individuals, one Scottish sample of 83 healthy individuals and one Scottish sample of 84 unaffected relatives of bipolar patients. Voxel-based analysis and tract-based spatial statistics did not detect any fractional anisotropy (FA) differences between minor allele carriers and individuals homozygous for the major allele at rs1344706. Similarly, region-of-interest analyses and quantitative tractography of the genu of the corpus callosum revealed no significant FA differences between the genotype groups. Examination of effect sizes and confidence intervals indicated that this negative finding is very unlikely to be due to a lack of statistical power. In summary, despite using various analysis techniques in three different samples, our results were strikingly and consistently negative. These data therefore suggest that it is unlikely that the effects of genetic variation at rs1344706 on functional connectivity are mediated by structural integrity differences in large, long range white matter fiber connections. PMID- 22840436 TI - Annual resuscitation competency assessments: a review of the evidence. AB - BACKGROUND: Australian critical care nurses generally undertake assessment of resuscitation competencies on an annual or biannual basis. International resuscitation evidence and guidelines released in 2010 do not support this practice, instead advocating more frequent retraining. AIM: To review the evidence for annual assessment of resuscitation knowledge and skills, and for the efficacy of resuscitation training practices. METHODS: A search of the Medline and CINAHL databases was conducted using the key search words/terms 'resuscitation' 'advanced life support' 'advanced cardiac life support' 'assessment' 'cardiac arrest', 'in-hospital cardiac arrest', 'competence', 'training', 'ALS', 'ACLS' 'course' and 'competency'. The search was limited to English language publications produced during the last 10 years. The International Liaison Committee On Resuscitation worksheets were reviewed for key references, as were the reference lists of articles from the initial search. RESULTS: There is little evidence to support the current practice of annual resuscitation competency assessments. Theoretical knowledge has no correlation with resuscitation performance, and current practical assessment methods are problematic. Both knowledge and skills decline well before the 12-month mark. There is emerging support in the literature for frequent practice sessions using simulation technology. CONCLUSION: The current practice of annual assessments is not supported by evidence. Emerging evidence for regular resuscitation practice is not conclusive, but it is likely to produce better outcomes. Changing practice in Australia also represents an opportunity to generate data to inform practice further. PMID- 22840437 TI - Sorption behavior of sulfamethazine on unamended and manure-amended soils and short-term impact on soil microbial community. AB - In this study we investigated the sorption of sulfamethazine (SMZ) in two soils with different physico-chemical properties and the sulfonamide short-term influence on the microbial community structure and function. The presence of manure increased the SMZ sorption, the uppermost level being measured on soil with the lower pH and the higher manure content allowed by the Italian regulation. The sulfonamide desorption was hysteretic on both soils. SMZ addition to soil at the concentration of 53.6 MUg/g had a significant short-term negative impact on readily culturable bacteria, potential metabolic activity (Biolog CLPP) and soil enzyme activity. Moreover, a shift of the culturable microbial populations towards a lower bacteria/fungi ratio was observed after SMZ addition. Despite the observed SMZ effects disappeared almost completely after 7 day, structural changes of microbial communities were still present in SMZ-treated soils. The results presented are remarkable since previous studies addressing the SMZ impact on soil microbial parameters failed to highlight any significant effect of the sulfonamide on microbial abundance and diversity. PMID- 22840439 TI - Health care-associated infections studies project: an American Journal of Infection Control and National Healthcare Safety Network data quality collaboration case study 8. PMID- 22840438 TI - [Consumption of alcohol and other drugs by the active population in Spain]. AB - OBJECTIVE: To describe consumption patterns of alcohol and other drugs in the active population in Spain by gender. METHODS: Based on 15,082 active persons selected from the Domiciliary Survey of Alcohol and Drugs (Encuesta Domiciliaria de Alcohol y Drogas [EDADES]) 2007, we estimated prevalences for high-risk alcohol consumption (>50 g/day in males, >30 g/day in females), daily intake of tranquilizers, cannabis consumption in the last 30 days, and consumption of any other illegal drug in the last 12 months, by employment status, economic sector and occupational categories. Odds ratios (OR) and their confidence intervals (95% CI) were estimated by logistic regression models. RESULTS: The following prevalences were found: high-risk alcohol consumption, 3.4%; daily use of tranquilizers, 2.3%; cannabis consumption in the last 30 days, 7.9%; and consumption of any illegal drug in the last 12 months, 11.9%. Except for tranquilizer use, prevalences were higher in men than in women. Consumption of tranquilizers (OR = 1.68; 95%CI: 1.04-2.73), cannabis and other illegal drugs were all higher in unemployed men than in employed men, while only tranquilizer consumption was higher in unemployed women (OR = 1.70; 95% CI: 1.23-2.34). High risk alcohol consumption was greater among men engaged in the catering, primary production and construction sectors in comparison to manufacturing industries: OR = 1.63 (95% CI: 1.11-2.38), OR = 1.52 (95% CI: 1.04-2.20), and OR = 1.50 (95% CI: 1.10-2.04), respectively. For women, those in catering showed higher consumptions of cannabis (OR = 2.34; 95% CI: 1.28-4.27) and of other illegal drugs (OR = 2.85; 95% CI: 1.71-4.76); the latter were also higher in commerce, transport and administration sectors than in manufacturing industries. CONCLUSIONS: These findings could serve as a useful reference for companies wanting to carry out preventive programs, and also for future studies assessing the impact of preventive measures. PMID- 22840440 TI - Why do cyclists infringe at red lights? An investigation of Australian cyclists' reasons for red light infringement. AB - This study investigated the behavioural, attitudinal and traffic factors contributing to red light infringement by Australian cyclists using a national online survey. The survey was conducted from February to May 2010. In total, 2061 cyclists completed the survey and 37.3% reported that they had ridden through a signalised intersection during the red light phase. The main predictive characteristics for infringement were: gender with males more likely to offend than females (OR: 1.54, CI: 1.22-1.94); age with older cyclists less likely to infringe compared to younger cyclists 18-29 years (30-49 yrs: OR: 0.71, CI: 0.52 0.96; 50+ yrs: OR: 0.51, CI: 0.35-0.74), and; crash involvement with cyclists more likely to infringe at red lights if they had not previously been involved in a bicycle-vehicle crash while riding (OR: 1.35; CI: 1.10-1.65). The main reasons given for red light infringement were: to turn left (32.0%); because the inductive loop detector did not detect their bike (24.2%); when there was no other road users present (16.6%); at a pedestrian crossing (10.7%); and 'Other' (16.5%). A multinomial logistic regression model was constructed to examine the associations between cyclist characteristics and reasons for infringement. Findings suggest that some cyclists are motivated to infringe by their perception that their behaviour is safe and that infrastructure factors were associated with infringement. Ways to manage this, potentially risky, behaviour including behaviour programmes, more cyclist-inclusive infrastructure and enforcement are discussed. PMID- 22840441 TI - Advancing fertility-sparing treatments in cervical cancer: where is the limit? PMID- 22840442 TI - Changes in characteristics of inmates with latent tuberculosis infection. AB - OBJECTIVES: Health and social characteristics place prisoners at high risk for progression from latent tuberculosis infection (LTBI) to tuberculosis (TB), but completion of LTBI therapy is low with many patients lost to follow-up after release. Despite decreases in active TB, demographic characteristics of active cases have remained relatively unchanged. This study investigated whether characteristics have changed in inmates diagnosed with LTBI in San Francisco, CA, USA. STUDY DESIGN: Cross-sectional. METHODS: Data from baseline interviews of randomized trials conducted in 1998-1999 and 2004-2007 were compared. RESULTS: In both time periods, most subjects with LTBI (>60%) were Latinos, while the proportion in both the jail and San Francisco remained at 15-20%. Overall, the prisoners interviewed in 2004-2007 were less likely to have been on medication for LTBI previously, and expressed more likelihood of finishing their medication compared with those interviewed in 1998-1999. In 2004-2007, the foreign-born subjects were more likely to prefer English to Spanish, to have been in stable housing and to have been employed before jail compared with 1998-1999, while no such changes were seen between the two time periods for US-born subjects. CONCLUSIONS: The pool of TB-infected individuals coming from a jail is not static, and understanding the changes over time is of importance for targeted programmes. Given the high infection rate and the predominance of foreign-born individuals who may have received bacillus Calmette-Guerin vaccination, screening with interferon-gamma release assay may be beneficial to identify those with true infection. PMID- 22840443 TI - Prevention and care - uneasy bedfellows. PMID- 22840444 TI - Erythrocyte invasions and receptor heterogeneity in field isolates of Nanay river basin Iquitos. AB - OBJECTIVE: To determine whether the requirements for sialic acid varies and whether several types of silaic acid independent receptors utilized for invasion mechanisms of fresh filed isolates collected around Nanay river basin, Iquitos. METHODS: The field isolates were cultured as described previously by Jensen and Trager and MR4 protocol with little modifications. The erythrocytes preparation and subsequent enzyme treatment was done as described previously by Sharma. with little modification. Invasion assay was performed as described previously by Sharma et al with little modification. RESULTS: The Nanay river basin isolates showed five types of invasion mechanisms or types of receptors-ligand interactions. Here we observed that an equal numbers of neuraminidase sensitive and resistant invasion receptor-ligand interaction profiles as the most common receptor-ligand invasion profiles. Neuraminidase resistance trypsin sensitive chymotrypsin sensitive (NM(R)T(S)CT(S)) invasion of receptor-ligand interaction profile was found in seven isolates, Five field isolates and one reference strain showed neuraminidase sensitive, trypsin sensitive and chymotrypsin resistant (NM(S)T(S)CT(R)) invasion of receptor-ligand interactions, six isolates including one reference strains dd2 showed neuraminidase sensitive, trypsin and chymotrypsin resistance (NM(S)T(R)CT(R)) indicating its dependence on sialic acids and independence of trypsin and chymotrypsin sensitive proteins. Four isolates showed neuraminidase sensitive, trypsin sensitive and chymotrypsin sensitive (NM(S)T(S)CT(S)) invasion of receptor-ligand interactions, seven isolates were neuraminidase resistant, trypsin sensitive and chymotrypsin resistance (NM(R)T(S)CT(R)) invasion of receptor-ligand interactions, indicating its dependence on trypsin sensitive proteins. CONCLUSIONS: The Nanay river basin isolates showed five types of invasion mechanisms or types of receptors-ligand interactions. A full understanding of theses invasion mechanisms may allow the development of novel prophylactic and therapeutic strategies that block erythrocyte receptor-ligand invasion mechanisms. PMID- 22840445 TI - Lethal effect of Streptomyces citreofluorescens against larvae of malaria, filaria and dengue vectors. AB - OBJECTIVE: To investigate lethal effect of culture filtrates of Streptomyces citreofluorescens (S. citreofluorescens) against Anopheles stephensi (An. stephensi), Culex quinquefasciatus (Cx. quinquefasciatus), and Aedes aegypti (Ae. aegypti) larvae vectors for malaria, filarial and dengue. METHODS: The culture filtrates obtained from S. citreofluorescens 2528 was grown in Potato Dextrose Broth (PDB), filtrated and used for the bioassay after a growth of 15 days. RESULTS: The results demonstrated that the An. stephensi shows mortalities with LC(50), LC(90) values of first instar 46.8 MUL/mL, 79.5 MUL/mL, second instar 79.0 MUL/mL, 95.6 MUL/mL, third instar 79.0 MUL/mL, 136.9 MUL/mL, and fourth instar 122.6 MUL/mL, 174.5 MUL/mL. Whereas, The Cx. quinquefasciatus were found effective on first instar 40.0 MUL/mL, 138.03 MUL/mL, second instar 80.0 MUL/mL, 181.97 MUL/mL, third instar 100.0 MUL/mL, 309.2 MUL/mL, and fourth instar 60.0 MUL/mL, 169.82 MUL/mL. The Ae. aegypti were successfully achieved susceptible with higher concentrations in comparisons of An. stephensi and Cx. quinquefasciatus larvae. These outcomes of the investigations have compared with the Chitinase of Streptomyces griseus (S. griseus) C6137 that shows 90%-95% mortality. CONCLUSIONS: These new findings significantly permitted that the culture filtrates of S. citreofluorescens can be used as bacterial larvicides. This is an environmentally safe approach to control the vectors of malaria, dengue and filariasis of tropical areas. PMID- 22840446 TI - Larvicidal, ovicidal and pupicidal activities of Gliricidia sepium (Jacq.) (Leguminosae) against the malarial vector, Anopheles stephensi Liston (Culicidae: Diptera). AB - OBJECTIVE: To investigate the potentiality of mosquitocidal activity of Gliricidia sepium (G. sepium) (Jacq.) (Leguminosae). METHODS: Twenty five early third instar larvae of Anopheles stephensi (An. stephensi) were exposed to various concentrations (50-250 ppm) and the 24 h LC(50) values of the G. sepium extract was determined by probit analysis. The ovicidal activity was determined against An. stephensi to various concentrations ranging from 25-100 ppm under laboratory conditions. The eggs hatchability was assessed 48 h post treatment. The pupicidal activity was determined against An. stephensi to various concentrations ranging from 25-100 ppm. Mortality of each pupa was recorded after 24 h of exposure to the extract. RESULTS: Results pertaining to the experiment clearly revealed that ethanol extract showed significant larvicidal, ovicidal and pupicidal activity against the An. stephensi. Larvicidal activity of ethanol extracts of G. sepium showed maximum mortality in 250 ppm concentration (96.0+/ 2.4)%. Furthermore, the LC(50) was found to be 121.79 and the LC(90) value was recorded to be 231.98 ppm. Ovicidal activity of ethanol extract was assessed by assessing the egg hatchability. Highest concentration of both solvent extracts exhibited 100% ovicidal activity. Similarly, pupae exposed to different concentrations of ethanol extract were found dead with 58.10% adult emergence when it was treated with 25 ppm concentration. Similarly, 18.36 (n=30; 61.20%); 21.28(70.93) and 27.33(91.10) pupal mortality was recorded from the experimental pupae treated with 50, 75 and 100 ppm concentration of extracts. Three fractions have been tested for their larvicidal activity of which the Fraction 3 showed the LC(50) and LC(90) values of 23.23 and 40.39 ppm. With regard to the ovicidal effect fraction 3 showed highest ovicidal activities than the other two fractions. Furthermore, there were no hatchability was recorded above 50 ppm (100% egg mortality) in the experimental group. Statistically significant pupicidal activity was recorded from 75 ppm concentration. CONCLUSIONS: From the results it can be concluded the crude extract of G. sepium is an excellent potential for controlling An. stephensi mosquito. It is apparent that, fraction 3 possess a novel and active principle which could be responsible for those biological activities. PMID- 22840447 TI - Current status of the efficacy and effectiveness of albendazole and mebendazole for the treatment of Ascaris lumbricoides in North-Western Indonesia. AB - OBJECTIVE: To investigate the efficacy and effectiveness of albendazole and mebendazole in the treatment of Ascaris lumbricoides (A. lumbricoides) in the North-Western Indonesia. METHODS: 229 primary school children who were positive for A. lumbricoides in their stool were recruited in the study. 123 children received single-dose of 400 mg albendazole and 106 children received single-dose 500 mg of mebendazole. After 1 week, their stools were examined for the cure rate (CR) and egg reduction rate (ERR). Egg culture was also performed and observation was made on week-1, -3, -4. RESULTS: have shown a non-significant difference in CR 96.7%vs. 100% and ERR of 99.3%vs. 100.0% for albendazole and mebendazole groups respectively (P>0.05). In-vitro egg culture has shown trends of decrease in the percentage of the unfertilized eggs and in >= 2 cell eggs in both treatment groups (P<0.05). The embryonated eggs from the albendazole groups has shown an increase from 7.3% on week-1 to 13.8% on week-4, whilst the mebendazole group has shown a constant increase during the whole 4 weeks of culture from 7.5% to 28.3% (P<0.01). CONCLUSIONS: No evidence of drug resistance is noted so far from the area of North-Western part of Indonesia. In addition, although both drugs showed incomplete ovicidal effects, single-dose albendazole is better than mebendazole in sterilizing A. lumbricoides eggs. PMID- 22840448 TI - Protective effect of Luffa acutangula extracts on gastric ulceration in NIDDM rats: role of gastric mucosal glycoproteins and antioxidants. AB - OBJECTIVE: To study the comparative gastroprotective effect of Luffa acutangula methanolic extract (LAM) and aqueous extract (LAW) on type II diabetes rats. METHODS: Streptozotocin (65 mg/kg, i.p.) along with nicotinamide (120 mg/kg, i.p.) was used to induce non insulin dependent diabetes mellitus (NIDDM) in rats. A daily oral dose of aspirin (200 mg/kg, i.p.) was administered for initial seven days to induce gastric ulcerations in the diabetic rats. LAM and LAW were administered orally in the doses of 100, 200 and 400 mg/kg once daily for 21 days. Glibenclamide and ranitidine were used as standards for comparing the antidiabetic and antiulcer effect respectively. RESULTS: LAM significantly (P<0.01) increased mucosal glycoprotein and antioxidant enzyme level in gastric mucosa of diabetic rats than LAW (P <0.05). LAM was efficient in reversing the delayed healing of gastric ulcer in diabetic rats close to the normal level. LAM exhibited better ulcer healing effect than glibenclamide and LAW, because of its both antihyperglycemic and mucosal defensive actions. CONCLUSIONS: Thus, LAM is proved to be a better alternative for treating gastric ulcers co-occurring with diabetes. PMID- 22840449 TI - Preliminary study on antifertility activity of Enicostemma axillare leaves and Urena lobata root used in Indian traditional folk medicine. AB - OBJECTIVE: To evaluate the possible antifertility activity of Enicostemma axillare (E. axillare) leaves and Urena lobata (U. lobata) root in adult male Wistar albino rats. METHODS: Six groups of rats were treated with ethanolic (70%v/v) extracts of E. axillare (375 and 750 mg/kg body weight) and U. lobata root (300 and 600 mg/kg body weight) once daily for 55 days. Control groups received the distilled water and vehicle. All the treated rats had corresponding recovery groups. At the end of each treatment periods, animals were killed and organ weights, sperm characteristics, testicular and epididymal biochemicals as well as testicular enzymes were assessed. RESULTS: The E. axillare and U. lobata at tested doses did not decrease body weight, whereas the weight of testes, epididymides and seminal vesicles were significantly (P<0.01) reduced. Significantly (P<0.01) more reductions in the sperm motility, viability and counts, epididymal and testicular protein contents were noted in the rats treated with higher dose of both the plants. Both the plants at the higher dose caused a marked increase (P<0.01) in sperm morphological abnormalities, testicular cholesterol and ascorbic acid contents were remarkably increased (P<0.01), while, the activities of testicular glucose-6-phosphate dehydrogenase (G-6-PDH) and Delta(5)-3beta-hydroxy steroid dehydrogenase (Delta(5)-3beta-HSD) were significantly reduced (P<0.01). However, reversal of these changes occurred after 55 days of treatment withdrawal. CONCLUSIONS: This study suggests that the E. axillare leaves and U. lobata root reversibly inhibited spermatogenesis and steroidogenesis indicating reversible antifertility activity which could partially support the traditional of these plants as male contraceptives. PMID- 22840450 TI - Evaluation of chemopreventive effect of Fumaria indica against N nitrosodiethylamine and CCl4-induced hepatocellular carcinoma in Wistar rats. AB - OBJECTIVE: To investigation the chemopreventive potential of Fumaria indica (F. indica) extract (FIE) on N-nitrosodiethylamine and CCl(4)-induced hepatocarcinogenesis in Wistar rats. METHODS: The experimental animals were divided into six groups (n=6). Hepatocellular carcinoma was induced by single intraperitoneal injection of N-nitrosodiethylamine (NDEA) in normal saline at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CCl(4)(3 mL/kg/week) for 6 weeks, as the promoter of carcinogenic effect. After administration of the carcinogen, 200 and 400 mg/kg of FIE were administered orally once a day throughout the study. At the end of 20 weeks, the body weight, liver weight and relative liver weight were measured. The percentage of nodule incidence and liver cancer markers such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (gamma GT), total bilirubin level (TBL), alpha-feto protein (AFP) and carcinoembryonic antigen were estimated along with histopathological investigation in experimental groups of rats. RESULTS: Obtained results demonstrated that the cotreatment with FIE significantly prevented the decrease of the body weight and also increased in relative liver weight caused by NDEA. The treatment with FIE significantly reduced the nodule incidence and nodule multiplicity in the rats after NDEA administration. The levels of liver cancer markers such as AST, ALT, ALP, gamma glutamyl transferase, TBL, AFP and carcinoembryonic antigen were substantially increased by NDEA treatment. However, FIE treatment significantly reduced the liver injury and restored the entire liver cancer markers. Histological observations of liver tissues too correlated with the biochemical observations. CONCLUSIONS: These finding powerfully supports that F. indica exert chemopreventive effect by suppressing the tumor burden and restoring the activities of hepatic cancer marker enzymes on NDEA and CCl(4)-induced hepatocarcinogenesis in Wistar rats. PMID- 22840451 TI - Antidiarrhoeal efficacy of Mangifera indica seed kernel on Swiss albino mice. AB - OBJECTIVE: To examine the antidiarrhoeal activity of alcoholic and aqueous seed kernel extract of Mangifera indica (M. indica) on castor oil-induced diarrhoeal activity in Swiss albino mice. METHODS: Mango seed kernels were processed and extracted using alcohol and water. Antidiarrhoeal activity of the extracts were assessed using intestinal motility and faecal score methods. RESULTS: Aqueous and alcoholic extracts of M. indica significantly reduced intestinal motility and faecal score in Swiss albino mice. CONCLUSIONS: The present study shows the traditional claim on the use of M. indica seed kernel for treating diarrhoea in Southern parts of India. PMID- 22840452 TI - Aqueous extract of Ocimum tenuiflorum decreases levels of blood glucose in induced hyperglycemic tilapia (Oreochromis niloticus). AB - OBJECTIVE: To evaluate, in hyperglycemic tilapia [Oreochromis niloticus (O. niloticus)], the effect of this aqueous extract on blood glucose levels. METHODS: The hyperglycemia in O. niloticus was induced by adding glucose to fish pond water. An aqueous extract of Ocimum tenuiflorum (O. tenuiflorum) was prepared by boiling fresh leaves and the doses of 0, 40, 80, 200 and 400 mg per liter of pond water were tested. RESULTS: The blood sugar concentration for tilapia with hyperglycemic induced was an average of 50% higher than the control group. The blood glucose levels in tilapia after the induction of hyperglycemia were higher than the control group for 90 min after the treatment. The treatment with the aqueous extract of O. tenuiflorum dropped the serum glucose level of hyperglycemic tilapia until it was similar to that of the control group and was dose dependent. CONCLUSIONS: The results indicated that O. tenuiflorum was endowed with anti-hyperglycemic activity. To our knowledge, this is the first report on the use of fish as a diabetes model to test natural extracts from plants. PMID- 22840453 TI - Role of mechanical stretching and lipopolysaccharide in early apoptosis and IL-8 of alveolar epithelial type II cells A549. AB - OBJECTIVE: To investigate the effects of mechanical stretching and lipopolysaccharide (LPS) on the early apoptosis and IL-8 production of alveolar epithelial type II cells A549. METHODS: The experimental matrix consisted of three integrated studies. In the first study, A549 cells were subjected to different stretching strain frequency and duration time to see the effects on the early apoptosis. In the second study, A549 cells were subjected to mechanical stretch (15% 4 h, 0.5 Hz) and LPS (1 or 100 ng/mL) to see whether mechanical strain and LPS also have an addictive effect on the early apoptosis. In the third study to investigate whether this addictive effect could be induced by LPS and mechanical stretch on IL-8 production, A549 cells were subjected to LPS (100 ng/mL) and mechanical strain (15%, 0.5 Hz, 4 h). Real time PCR and enzyme linked immunosorbent assay were used to measure mRNA and protein level of IL-8. The early apoptosis was detected by flow cytometry. RESULTS: Mechanical stretch induced the early apoptosis in a force and frequency and time-dependent manner. In the presence of LPS, mechanical stretch enhanced LPS-induced early apoptosis, especially in 100 ng/mL LPS group compared with 1 ng/mL LPS and the control group. Mechanical stretch increased IL-8 production and enhanced LPS-induced IL-8 screation both in mRNA and protein levels. CONCLUSIONS: Mechanical stretch can induce the early apoptosis and IL-8 secretion. Mechanical stretch and LPS have an addictive effect on the early apoptosis and IL-8 production in alveolar type 2 cells, which is one of the mechanisms of ventilator-induced lung injury. PMID- 22840454 TI - Inhibition of Pim-1 attenuates the proliferation and migration in nasopharyngeal carcinoma cells. AB - OBJECTIVE: To explore the role of proto-oncogene Pim-1 in the proliferation and migration of nasopharyngeal carcinoma (NPC) cells. METHODS: Pim-1 expressions in NPC cell lines CNE1, CNE1-GL, CNE-2Z and C666-1 were examined by RT-PCR, western blotting and immunoflucesence, respectively. After CNE1, CNE1-GL and C666-1 cells were treated with different concentrations of Pim-1 special inhibitor, quercetagetin, the cell viability, colony formation rate and migration ability were analyzed. RESULTS: Pim-1 expression was negative in well-differentiated CNE1 cells, whereas expressed weakly positive in poor-differentiated CNE-2Z cells and strongly positive in undifferentiated C666-1 cells. Interestingly, CNE1-GL cells that derived from CNE1 transfected with an Epstein Barr virus latent membrane protein-1 over-expression plasmid displayed stronger expression of Pim-1. Treatment of CNE1-GL and C666-1 cells with quercetagetin significantly decreased the cell viability, colony formation rate and migration ability but not the CNE1 cells. CONCLUSIONS: These findings suggest that Pim-1 overexpression contributes to NPC proliferation and migration, and targeting Pim-1 may be a potential treatment for anti-Pim-1-expressed NPCs. PMID- 22840455 TI - Establishment and expression of recombinant human glial cell line-derived neurotrophic factor and TNF alpha receptor in human neural stem cells. AB - OBJECTIVE: To investigate the interference and expression of human glial cell line-derived neurotrophic factor (hGDNF) and soluble TNF alpha (sTNFR I) receptor genes in neural stem cells and to evaluate the roles of these proteins in the genetic treatment of spinal cord injury. METHODS: Full-length of GDNF cDNA (558 bp) and sTNFR I cDNA (504 bp) were inserted into the early 1 region of adenovirus genomic DNA respectively and were immediated by the human cytomegalovirus (gene promoter/enhancer). These adenoviruses were propagated in HEK293 cells via homologous recombination for 7-10 days in vivo, then they were used to infect human neural stem cells. The infection and expression of gene were tested under immunofluorescence, ELISA and Western-blot after 48 hours. RESULTS: Almost all the cultured cells showed the nestin immunofluorescence positive staining, which was the characteristics of neural stem cell. A great quantity of EGFP and RFP were observed in neural stem cells, which indicated the expression of GDNF and sTNFR I. After transfection of GDNF and sTNFR I genes, many neural stem cells show GFAP and tubulin immunofluorescence positive staining, which meant that most neural stem cells differentiated into neuron at that condition. CONCLUSIONS: The infective efficiency of adenovirus is greatly acceptable to neural stem cell, thus adenovirus provide a useful vector for exogenous GDNF and sTNFR I genes expressing in neural stem cells, which is useful for differentiation of neural stem cell. PMID- 22840456 TI - Combined APACH II score and arterial blood lactate clearance rate to predict the prognosis of ARDS patients. AB - OBJECTIVE: To explore the easily applicable indicators of practical value to evaluate the prognosis of acute respiratory distress syndrome (ARDS). METHODS: Blood and biochemical tests and blood-gas analyses were performed upon entry into the ICUs, 12 h, 24 h, 48 h and 72 h after that in 72 ARDS patients (who were admitted to the ICUs of our hospital from January 2000 to December 2009). Then APACHE II scores were achieved by combining relevant physiological parameters and laboratory results. RESULTS: There was a statistical difference between the death group and survival group at different time points upon entering the ICUs in terms of APACHE II score, alveolar-arterial oxygen difference and arterial blood lactate clearance rate. PaO(2)/FiO(2) values were recorded to be statistically different between the death group and survival group 24 h, 48 h and 72 h, respectively after entry into the ICUs. In addition, registered linear regression existed between APACHE II score, alveolar-arterial oxygen difference or PaO(2)/FiO(2) value and time. APACHE II score 24 h and 72 h after entering ICUs predicted mortality with an area under the ROC curve (AUC) standing respectively at 0.919 and 0.955. Arterial blood lactate clearance rate 12 h, 24 h, 48 h and 72 h after entering ICUs predicted mortality with an area under the ROC curve (AUC) at 0.918, 0.918, 0.909 and 0.991, respectively. CONCLUSIONS: APACHE II score applied in combination with arterial blood lactate clearance rate is of clinical significance in assessing the prognosis of ARDS patients. PMID- 22840457 TI - Effect of Western medicine therapy assisted by Ginkgo biloba tablet on vascular cognitive impairment of none dementia. AB - OBJECTIVE: To discuss the clinical effects of Western medicine therapy assisted by Ginkgo biloba tablet (GBT) on patients with vascular cognitive impairment of none dementia (VCIND). METHODS: A total of 80 patients with VCIND were divided into two groups randomly: Conventional treatment group (control group) and combined treatment group. Conventional treatment group was given conventional treatment with anti-platelet aggregation. In this group, 75 mg aspirin was given three times a day for 3 months. While in combined treatment group, 19.2 mg GBT was given three times a day for 3 months together with conventional treatment (anti-platelet aggregation drugs). Montreal cognitive assessment (MoCA) and transcranial Doppler (TCD) were used to observe changes of cognitive ability and cerebral blood flow in VCIND patients before and after treatment in both groups. Then the clinical data were analyzed so as to compare the efficacy in two groups. RESULTS: After 3 month-treatment in combined treatment group, the scores of executive ability, attention, abstract, delayed memory, orientation in the MoCA were significantly increased compared with those before treatment and those in control group after treatment. Besides, blood flow velocity of anterior cerebral artery increased significantly than that before treatment and that in control group after treatment. CONCLUSIONS: GBT tablet can improve the therapeutic efficacy as well improve cognitive ability and cerebral blood flow supply of patients with VCIND. PMID- 22840458 TI - Vivax malaria: a rare cause of thalamic bleed. AB - Most common cause of thalamic bleed is hypertension; other causes are arteriovenous malformation, aneurysm, bleeding diathesis, drugs, amyloid angiopathy, tumor etc. We present a case of Plasmodium vivax (P. vivax) malaria with unusual site of bleeding i.e. left thalamus of brain. To the best of our knowledge, this is the first reported case of thalamic bleed caused by vivax malaria in absence of severe thrombocytopenia/disseminated intravascular coagulation (DIC). PMID- 22840459 TI - Refractory hypocalcemia precipitated by dual infection with typhoid fever and hepatitis A in a patient with congenital hypoparathyroidism. AB - We present this rare occurrence of a 17 yr old boy, a known case of congenital hypoparathyroidism, who presented with fever and jaundice for 8 days and 2 episodes of generalised tonic-clonic seizures. Premorbidly patient was on regular oral calcium supplementations with normal serum calcium levels. Investigations revealed severe hypocalcaemia (3.2 mg/dL), low 25 hydroxyvitamin D levels and hypomagnesaemia. The marked elevation of serum bilirubin was accompanied by derangement of liver enzymes. Microbiological investigations were confirmatory for both hepatitis A and typhoid fever. In spite of the aggressive management with intravenous calcium gluconate infusion, refractory hypocalcaemia persisted with recovery only after gradual decline in the bilirubin levels. We inferred that the cholestatic process produced by both acute viral hepatitis A and typhoid fever precipitated this state of refractory hypocalcaemia in the previously well preserved patient. PMID- 22840460 TI - A case of advanced mycosis fungoides with comprehensive skin and visceral organs metastasis: sensitive to chemical and biological therapy. AB - Mycosis fungoides is a common cutaneous T-cell lymphoma, which is usually characterized by chronic, indolence progression, with absence of typical symptoms in early stage, metastasis to lymph nodes, bone marrow and visceral organs in later stage and ultimately progression to systemic lymphoma. It can result in secondary skin infection which is a frequent cause of death. At present, no curative therapy existed. Therapeutic purpose is to induce remission, reduce tumor burden and protect immune function of patients. A case of patient with advanced severe mycosis fungoides receiving CHOP plus interferon alpha-2a was reported here, with disease-free survival of 7 months and overall survival of over 17.0 months, and current status as well as developments of mycosis fungoides were briefly introduced. PMID- 22840461 TI - Klebsiella pneumoniae Carbapenemase-producing enterobacteria in hospital, Singapore. PMID- 22840462 TI - Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer. AB - BACKGROUND: To quantify tumour angiogenesis, microvessel density (MVD) has been widely used. We here present a novel angiogenesis marker, microvessel proliferation (MVP), based on dual immunohistochemical staining of nestin and Ki 67. Immature endothelial cells express nestin, and when co-expressed with the proliferation marker Ki-67, the number of proliferating immature blood vessels can be measured. MATERIALS AND METHODS: Microvessel proliferation was evaluated in 178 breast cancer samples and estimated by vascular proliferation index (VPI), the ratio between the number of vessels containing proliferating endothelial cells and the total number of immature vessels. RESULTS: High VPI was strongly associated with several markers of aggressive breast cancer, such as negative oestrogen receptor (ER) status (p = 0.003), high tumour cell proliferation by Ki 67 (p = 0.004), high p53 expression (p = 0.001), and five profiles for the basal like phenotype (odds ratios (OR); range 3.4-6.3). Also, high VPI was significantly associated with interval detected breast cancer compared with screening detected lesions (p < 0.0005), and adverse outcome in univariate and multivariate survival analysis (p = 0.034 and p = 0.022, respectively). CONCLUSION: Microvessel proliferation is a novel marker of ongoing angiogenesis and was associated with aggressive tumour features, basal-like phenotypes, interval presentation, and prognosis in this series of breast cancer. PMID- 22840463 TI - DSM-IV 12-month and lifetime major depressive disorder and romantic relationships among African Americans. AB - BACKGROUND: This brief report examines the association between marital and relationship status and 12-month and lifetime prevalence of major depressive disorder (MDD) among African Americans. Previous work has found that adults with major depressive disorder are less likely to be married or in a cohabiting relationship. This report extends previous research by investigating whether unmarried, non-cohabiting African Americans with depression are also less likely to be involved in a romantic relationship. METHODS: Data are from the African American sub-sample (n=3570) of the National Survey of American Life (NSAL; 2001 2003). The DSM-IV World Mental Health Composite International Diagnostic Interview was used to assess 12-month and lifetime MDD. Weighted logistic regression was used. RESULTS: The findings indicate that for both 12-month and lifetime major depressive disorder, African Americans who are depressed are not only less likely to be married; they are also significantly less likely to be involved in a romantic relationship. This is particularly the case for 12-month depression. LIMITATIONS: Due to limitations in the number of cohabiting respondents, currently married and cohabiting respondents were combined into a single category. CONCLUSION: The findings of this brief report highlight the importance of changes in marital and relationship circumstances of the U.S. population for research and practice on depression and other psychiatric disorders. Our study provides evidence for a more nuanced approach in which examining marital and romantic relationship status together promotes a better understanding of the impact of major depression on romantic unions. PMID- 22840464 TI - Predicting outcomes of mood, anxiety and somatoform disorders: the Leiden routine outcome monitoring study. AB - BACKGROUND: Mood, anxiety and somatoform (MAS) disorders are highly prevalent disorders with substantial mutual comorbidity and a large disease burden. Early identification of patients at risk for poor outcome in routine clinical practice is of clinical importance. The purpose of this study was to predict outcomes in outpatients with MAS disorders using routine outcome monitoring (ROM) data. METHODS: We conducted a cohort study of 892 adult MAS patients in a naturalistic outpatient psychiatric specialty care setting and validated our results in a replication cohort of 1392 patients. Poor outcome was defined as a <50% reduction (compared to baseline) on the self-report brief symptom inventory (BSI) or a score of >=3 on the observer-rated clinical global impression severity scale (CGI S). During a follow-up of up to 2 years, Cox regression models were used to analyze the independent baseline predictors for poor outcome. RESULTS: In multivariable Cox regression models, independent and replicated predictors for poor outcome were higher age (overall p<0.001 for combined cohorts in multivariable Cox regression model), having comorbid MAS disorders or a somatoform disorder (<0.001), dysfunctional personality traits (i.e., tendency to self-harm [p<0.001], intimacy problems [p<0.001] and affective lability [p<0.001]), and a low reported general health status (p<0.001). LIMITATIONS: Detailed treatment information was not available. CONCLUSIONS: MAS patients meeting the profile of being elderly, suffering from comorbid MAS disorders or a somatoform disorder, with cluster B personality traits, and a poor reported general health may need special preventive measures to minimise the risk of poor outcome. PMID- 22840465 TI - Longitudinal risk profiling for suicidal thoughts and behaviours in a community cohort using decision trees. AB - BACKGROUND: While associations between specific risk factors and subsequent suicidal thoughts or behaviours have been widely examined, there is limited understanding of the interplay between risk factors in the development of suicide risk. This study used a decision tree approach to develop individual models of suicide risk and identify the risk factors for suicidality that are important for different subpopulations. METHODS: In a population cohort of 6656 Australian adults, the study examined whether measures of mental health, physical health, personality, substance use, social support, social stressors and background characteristics were associated with suicidal ideation and suicidal behaviours after four-year follow-up. RESULTS: Previous suicidality, anxiety symptoms, depression symptoms, neuroticism and rumination were the strongest predictors of suicidal ideation and behaviour after four years. However, divergent factors were predictive of suicidal thoughts and behaviours across the spectrum of mental health. In particular, substance use was only associated with suicidal thoughts and behaviours in those with moderate levels of anxiety or depression. LIMITATIONS: Most of the measurements were based on self-report. Further research is required to assess whether changes in risk factors lead to changes in suicidality. CONCLUSIONS: Examining suicide risk factors using decision trees is a promising approach for developing individualised assessments of suicide risk and tailored intervention programs. PMID- 22840466 TI - Deficit status in bipolar disorder: investigation on prevalence rate and description of seven cases. AB - OBJECTIVE: While the Kraepelinian dichotomy explicitly distinguishes between schizophrenia and bipolar disorder, it remains unclear as to whether a deficit form of bipolar disorder exists. METHOD: We conducted a study to investigate the prevalence rate of the deficit form of bipolar disorder; the criteria of which were basically adopted by the original proposal for schizophrenia that described the predominance of negative symptoms for over a year. Moreover, we presented a series of cases with "deficit" bipolar disorder to characterize its clinical pictures in detail. RESULTS: Consecutive outpatients who visited one psychiatric hospital in Tokyo, Japan in March 2007 were evaluated cross-sectionally. Additionally, medical charts of inpatients who were hospitalized in the same hospital between April 2006 and March 2007 were also thoroughly reviewed. Of 494 patients, 7 patients (1.4%; 10.9% of 64 bipolar cases) fulfilled the criteria for bipolar disorder with deficit syndrome. Seven "deficit" cases had a mean+/-SD age of 61+/-5 year-old with the age at onset being 25+/-8 year-old. In addition to pervasive negative symptoms, they exhibited evidence of cognitive impairments close to the magnitude of what is usually noted in schizophrenia (i.e. a mean+/ SD total IQ score of 80+/-9 in the Wechsler Adult Intelligence Scale and 0.4+/ 0.5 in the Wisconsin Card Sorting Test, categories achieved). CONCLUSION: Although preliminary, the evidence on deficit status in patients with bipolar disorder that we found in this study appears more consistent with recent evidence and challenges the Kraepelinian dichotomy that reserves deficit status solely to schizophrenia patients. PMID- 22840468 TI - Assessing DSM-IV symptoms of panic attack in the general population: an item response analysis. AB - BACKGROUND: Unexpected panic attacks may represent a non-specific risk factor for future depression and anxiety disorders. The examination of panic symptoms and associated latent severity levels may lead to improvements in the identification, prevention, and treatment of panic attacks and subsequent psychopathology for 'at risk' individuals in the general population. METHODS: The current study utilised item response theory to assess the DSM-IV symptoms of panic in relation to the latent severity level of the panic attack construct in a sample of 5913 respondents from the National Epidemiologic Survey on Alcohol and Related conditions. Additionally, differential item functioning (DIF) was assessed to determine if each symptom of panic targets the same level of latent severity between different sociodemographic groups (male/female, young/old). RESULTS: Symptoms indexing 'choking', 'fear of dying', and 'tingling/numbness' are some of the more severe symptoms of panic whilst 'heart racing', 'short of breath', 'tremble/shake', 'dizzy/faint', and 'perspire' are some of the least severe symptoms. Significant levels of DIF were detected in the 'perspire' symptom between males and females and the 'fear of dying' symptom between young and old respondents. LIMITATIONS: The current study was limited to examining cross sectional data from respondents who had experienced at least one panic attack across their lifetime. CONCLUSIONS: The findings of the current study provide additional information regarding panic symptoms in the general population that may enable researchers and clinicians to further refine the detection of 'at risk' individuals who experience threshold and sub-threshold levels of panic. PMID- 22840467 TI - Validity of an interviewer-administered patient health questionnaire-9 to screen for depression in HIV-infected patients in Cameroon. AB - BACKGROUND: In high-income countries, depression is prevalent in HIV patients and is associated with lower medication adherence and clinical outcomes. Emerging evidence from low-income countries supports similar relationships. Yet little research has validated rapid depression screening tools integrated into routine HIV clinical care. METHODS: Using qualitative methods, we adapted the Patient Health Questionnaire-9 (PHQ-9) depression screening instrument for use with Cameroonian patients. We then conducted a cross-sectional validity study comparing an interviewer-administered PHQ-9 to the reference standard Composite International Diagnostic Interview in 400 patients on antiretroviral therapy attending a regional HIV treatment center in Bamenda, Cameroon. RESULTS: The prevalence of major depressive disorder (MDD) in the past month was 3% (n=11 cases). Using a standard cutoff score of >=10 as a positive depression screen, the PHQ-9 had estimated sensitivity of 27% (95% confidence interval: 6-61%) and specificity of 94% (91-96%), corresponding to positive and negative likelihood ratios of 4.5 and 0.8. There was little evidence of variation in specificity by gender, number of HIV symptoms, or result of a dementia screen. LIMITATIONS: The low prevalence of MDD yielded very imprecise sensitivity estimates. Although the PHQ-9 was developed as a self-administered tool, we assessed an interviewer administered version due to the literacy level of the target population. CONCLUSION: The PHQ-9 demonstrated high specificity but apparently low sensitivity for detecting MDD in this sample of HIV patients in Cameroon. Formative work to define the performance of proven screening tools in new settings remains important as research on mental health expands in low-income countries. PMID- 22840469 TI - The effect of premenstrual dysphoric disorder and menstrual cycle phase on brain activity during response inhibition. AB - BACKGROUND: Premenstrual dysphoric disorder (PMDD) has generally not been associated with impulsive behavior. However, some studies suggest that women with PMDD have higher impulsivity scores than healthy controls and that brain activity during response inhibition may vary across the menstrual cycle. Therefore, our aim was to unravel potentially important cognitive aspects of PMDD by investigating brain activity during response inhibition in women with PMDD and healthy controls in relation to menstrual cycle phase. METHODS: Fourteen PMDD patients and 13 healthy controls performed a Go/NoGo task to measure brain activity during response inhibition by use of event-related functional magnetic resonance imaging. RESULTS: Women with PMDD displayed decreased activity during both menstrual cycle phases compared to healthy controls in several task-related parietal areas. A significant group by phase interactions was found in the left insula, driven by enhanced activity among healthy controls in the follicular phase and by enhanced insula activity during the luteal phase among PMDD patients. LIMITATIONS: The limitations of the present study are the relatively limited sample size, the relatively small number of NoGo trials and the lack of a baseline contrast for the NoGo trials. CONCLUSIONS: During response inhibition women with PMDD have reduced activity in areas associated with attention and motor function which is unrelated to menstrual cycle phase. Insular cortex activity, involved in both affective and cognitive processing, was significantly activated during the luteal phase among PMDD women. These findings are relevant for the understanding of how ovarian steroids influence mood symptoms in women. PMID- 22840470 TI - How to get exogenous DNA to cross the cell membrane of plants: Comment on "Physical methods for genetic transformation in plants" by Rivera et al. PMID- 22840471 TI - Comment on "Physical methods for genetic plant transformation" by Rivera et al. PMID- 22840472 TI - A delay decomposition approach to robust stability analysis of uncertain systems with time-varying delay. AB - This paper is concerned with delay-dependent robust stability for uncertain systems with time-varying delays. The proposed method employs a suitable Lyapunov Krasovskii's functional for new augmented system. Then, based on the Lyapunov method, a delay-dependent robust criterion is devised by taking the relationship between the terms in the Leibniz-Newton formula into account. By developing a delay decomposition approach, the information of the delayed plant states can be taken into full consideration, and new delay-dependent sufficient stability criteria are obtained in terms of linear matrix inequalities (LMIs) which can be easily solved by various optimization algorithms. Numerical examples are included to show that the proposed method is effective and can provide less conservative results. PMID- 22840473 TI - Klebsiella pneumoniae in gastrointestinal tract and pyogenic liver abscess. AB - To determine the role of gastrointestinal carriage in Klebsiella pneumoniae liver abscess, we studied 43 patients. Bacterial isolates from liver and fecal samples from 10 patients with this condition and 7 healthy carriers showed identical serotypes and genotypes with the same virulence. This finding indicated that gastrointestinal carriage is a predisposing factor for liver abscess. PMID- 22840474 TI - Variability of invertebrate abundance in drinking water distribution systems in the Netherlands in relation to biostability and sediment volumes. AB - A survey of invertebrates in drinking water from treatment works, internal taps and hydrants on mains was carried out by almost all water companies in the Netherlands from September 1993 to August 1995. Aquatic sow bugs (Asellidae, 1-12 mm) and oligochaeta worms (Oligochaeta, 1-100 mm), both known to have caused rare though embarrassing consumer complaints, were found to form 98% of the mean biomass in water flushed from mains. Their numbers in the mains water ranged up to 1500 (mean 37) Asellidae m(-3) and up to 9900 (mean 135) Oligochaeta m(-3). Smaller crustaceans (0.5-2 mm) dominated the numbers in water from mains. e.g. water fleas (Cladocera and Copepoda up to 14,000 m(-3)). Common invertebrates in treated water and in tap water were Rotifera (<1 mm) and nematode worms (Nematoda, <2 mm). No Asellidae, large Oligochaeta (>5 mm) or other large invertebrates were found in 1560 samples of 200 l treated water or tap water. Large variations in invertebrate abundance were found within and between distribution systems. Of the variability of mean biomass in mains per system, 55%, 60% and 63% could statistically be explained by differences in the Biofilm Formation Rate, non-particulate organic matter and the permanganate index of the treated water of the treatment works respectively. A similar correlation was found between mean invertebrate biomass and mean sediment volumes in the distribution systems (R(2) = 52%). PMID- 22840475 TI - Interspinous bursitis and chondrocalcinosis. PMID- 22840476 TI - Is routine ankle-brachial pressure index evaluation useful in rheumatoid arthritis? PMID- 22840477 TI - Large paralabral cyst in the axilla. PMID- 22840478 TI - Recurrent orbital myositis in undifferentiated connective tissue disease. PMID- 22840479 TI - Erosive hand osteoarthritis and systemic sclerosis: a casual association? AB - To describe an unexpected association between a patient affected with erosive hand osteoarthritis (EHOA) and systemic sclerosis (SSc). We report a case of SSc presenting typical radiological findings of EHOA in a 60-year-old woman referred to our outpatient Rheumatology Unit. Physical examination revealed puffy hands with sclerodactyly and concomitant adduction of the thumb and subluxation of the first carpometacarpal (CMC) and metacarpophalangeal (MCP) joints bilaterally and nodose deformities of the distal interphalangeal (DIP). Hand X-rays showed joint space narrowing, osteophytosis and bone sclerosis of the proximal interphalangeal (PIP) joints. The DIP joints showed central bone erosion, collapse of the subchondral bone plate and typical "gull-wing" type deformity. EHOA is a particularly aggressive subset of osteoarthritis (OA). In light of its still unclear pathogenesis, peculiarities in the disease characteristics may be useful to better define the EHOA patient profile. One of these is an unexpected association with some autoimmune diseases. EHOA and SSc in the same patient is not uncommon, and it could speculate that there may be a genetic and autoimmune involvement. PMID- 22840480 TI - Reduced-fluence photodynamic therapy for subfoveal serous pigment epithelial detachment with choroidal vascular hyperpermeability. AB - PURPOSE: To evaluate the efficacy of reduced-fluence photodynamic therapy (PDT) for treating symptomatic subfoveal serous pigment epithelial detachments (PEDs) with hyperfluorescence on late-phase indocyanine green angiography (ICGA) without choroidal neovascularization (CNV). DESIGN: Retrospective, interventional case series. METHODS: Fifteen eyes of 15 patients (mean age, 55.3 years) with a serous PED were included. Baseline ICGA showed hyperpermeable choroidal vessels but no CNV in any eyes. Reduced-fluence PDT was applied and included treatment of hyperfluorescent areas on late-phase ICGA. We evaluated changes in the PEDs and hyperfluorescence on late-phase ICGA at baseline and 3 months after PDT. We compared the subfoveal choroidal thickness and best-corrected visual acuity (BCVA). RESULTS: The baseline ICGA showed mild to intense hyperfluorescence at the PED with hyperpermeable choroidal vessels. One month after reduced-fluence PDT, the PED resolved in 14 eyes (93%) and decreased in height in 1 eye. The PED flattening continued for more than 3 months. The baseline hyperfluorescence on ICGA decreased at month 3 except for 1 eye. The subfoveal choroidal thickness decreased significantly (P < .0001) from 297 to 238 MUm; the BCVA significantly (P = .019) improved from 0.08 to -0.01 between baseline and month 3. The month-3 BCVA was significantly associated with the baseline BCVA and the duration and size of the PED. No PEDs recurred or complications developed, such as secondary CNV or retinal pigment epithelial tears. CONCLUSION: Serous PEDs accompanying hyperfluorescence on ICGA are considered a variant of central serous chorioretinopathy. Reduced-fluence PDT is beneficial for resolving PEDs. PMID- 22840481 TI - Quantifying changes in corneal neovascularization using fluorescein and indocyanine green angiography. AB - PURPOSE: To quantify changes in corneal neovascularization in patients with active keratitis after treatment using color imaging, fluorescein angiography (FA), and indocyanine green angiography (ICGA). DESIGN: Prospective, interventional case series. METHODS: Twelve consecutive patients were studied. A comparison of corneal neovascularization parameters was undertaken before and after resolution of the keratitis. A slit-lamp digital camera acquired images of the neovascularization using color imaging, FA, and ICGA. The best-quality images were selected using a grading system, and the neovascular regions of interest were analyzed using automated in-house software. The parameters of analysis were vessel area, diameter, tortuosity, and FA dye leakage. RESULTS: There was a significant reduction in the area of neovascularization after treatment on color imaging (0.78 mm(2); P < .05), FA (2.33 mm(2); P < .01), and ICGA (2.07 mm(2); P < .01). There was also a significant reduction in mean vessel diameter across the region of interest for each patient, more marked on FA (42.74 to 32.52 MUm; P < .01) and ICGA (44.77 to 33.29 MUm; P < .01) than on color imaging (29.10 to 25.17 MUm; P < .01). A significant change in vessel tortuosity was not observed. There was a significant increase in FA dye leakage time (12.41 seconds; P < .05) after treatment. CONCLUSIONS: We demonstrate application of an objective method for analyzing changes in corneal neovascularization. The excellent vessel delineation with ICGA even in the presence of stromal scars makes it an ideal agent for measurement of vessel parameters. FA is useful at detecting vessel leakage, and the time to leakage provides a possible measure of vessel staging. PMID- 22840482 TI - Retinal vascular fractal dimension and its relationship with cardiovascular and ocular risk factors. AB - PURPOSE: To examine the influence of a range of cardiovascular risk factors and ocular conditions on retinal vascular fractal dimension in the Singapore Malay Eye Study. DESIGN: Population-based cross-sectional study. METHODS: Fractal analysis of the retinal vessels is a method to quantify the global geometric complexity of the retinal vasculature. Retinal vascular fractal dimension (D(f)) and caliber were measured from retinal photographs using a computer-assisted program. D(f) and arteriolar caliber were combined to form a retinal vascular optimality score (ranging from 0 to 3). Data on cardiovascular and ocular factors were collected from all participants based on a standardized protocol. RESULTS: Two thousand nine hundred thirteen (88.8% of 3280 participants) persons had retinal photographs of sufficient quality for the measurement. The mean D(f) was 1.405 (standard deviation, 0.046; interquartile range, 1.243 to 1.542). In the multiple linear regression analysis, after controlling for gender, serum glucose, intraocular pressure, anterior chamber depth, and retinal vascular caliber, smaller D(f) was associated independently with older age (standardized regression coefficient [sbeta] = -0.311; P < .001), higher mean arterial blood pressure (sbeta = -0.085; P < .001), a more myopic spherical equivalent (sbeta = 0.152; P < .001), and presence of cataract (sbeta = -0.107; P < .001). Retinal vascular optimality score was associated significantly with higher mean arterial blood pressure (P > .001 for trend). CONCLUSIONS: Age, blood pressure, refractive error, and lens opacity had significant influence on retinal vascular fractal measurements. A new score of retinal vascular optimality combining fractals and caliber showed strong association with blood pressure. Quantitative analysis of retinal vasculature therefore may provide additional information on microvascular architecture and optimality. PMID- 22840483 TI - The international council of ophthalmology: vision for ophthalmic education in an interdependent world. AB - PURPOSE: To describe the emerging strategic global perspective of the International Council of Ophthalmology (ICO) efforts in ophthalmic education. DESIGN: A global perspective describing how the development of sophisticated educational tools in tandem with information technology can revolutionize ophthalmic education worldwide. METHODS: Review of ICO educational tools, resources, and programs that are available to ophthalmic educators across the globe. RESULTS: With the explosive growth of the Internet, the ability to access medical information in the most isolated of locations is now possible. Through specific ICO initiatives, including the ICO curricula, the "Teaching the Teachers" program, and the launching of the new ICO Center for Ophthalmic Educators, the ICO is providing ophthalmic educators across the globe with access to standardized but customizable educational programs and tools to better train ophthalmologists and allied eye care professionals throughout the world. CONCLUSION: Access to educational tools and strengthening of global learning will help providers meet the goals of VISION 2020 and beyond in eliminating avoidable blindness. It is the intent of the ICO that its programs for ophthalmic educators, including conferences, courses, curricula, and online resources, result in better-trained ophthalmologists and eye care professionals worldwide. PMID- 22840484 TI - Estimating the rate of retinal ganglion cell loss in glaucoma. AB - PURPOSE: To present and evaluate a new method of estimating rates of retinal ganglion cell (RGC) loss in glaucoma by combining structural and functional measurements. DESIGN: Observational cohort study. METHODS: The study included 213 eyes of 213 glaucoma patients followed up for an average of 4.5 +/- 0.8 years with standard automated perimetry visual fields and optical coherence tomography. A control group of 33 eyes of 33 glaucoma patients underwent repeated tests over a short period to test the specificity of the method. An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 +/- 0.7 years was used to estimate age-related losses of RGCs. Estimates of RGC counts were obtained from standard automated perimetry and optical coherence tomography, and a weighted average was used to obtain a final estimate of the number of RGCs for each eye. The rate of RGC loss was calculated for each eye using linear regression. Progression was defined by a statistically significant slope faster than the age-expected loss of RGCs. RESULTS: From the 213 eyes, 47 (22.1%) showed rates of RGC loss that were faster than the age-expected decline. A larger proportion of glaucomatous eyes showed progression based on rates of RGC loss rather than based on isolated parameters from standard automated perimetry (8.5%) or optical coherence tomography (14.6%; P < .01), while maintaining similar specificities in the stable group. CONCLUSIONS: The rate of RGC loss estimated from combining structure and function performed better than either isolated structural or functional measures for detecting progressive glaucomatous damage. PMID- 22840485 TI - Icare ONE rebound versus Goldmann applanation tonometry in children with known or suspected glaucoma. AB - PURPOSE: To compare Icare ONE tonometry by clinic examiner and parent/guardian to Goldmann applanation in children with known/suspected glaucoma; to evaluate the trend in intraocular pressure (IOP) with 4 repeated measurements using Icare ONE; and to evaluate the feasibility of instructing parents on the use of the Icare ONE device in the clinic setting. DESIGN: Nonrandomized, prospective clinical study. METHODS: Patients with known or suspected glaucoma were recruited from the Duke pediatric glaucoma clinic. Parent(s) of all subjects gave informed consent (and children gave assent) for participation in this research study. IOP was measured using Icare ONE by clinic examiner and parent/guardian, then using Goldmann applanation (masked physician). Each parent/guardian completed an ease of-use survey. RESULTS: Sixty eyes (60 children) were included. Absolute value of mean IOP difference (ICare ONE clinic examiner vs Goldmann applanation) was 3.3 +/- 4.0 mm Hg (P = .001). Icare ONE IOP by clinic examiner was within 3 mm Hg of Goldmann applanation in 68% (n = 41 eyes). In eyes with >3 mm Hg difference, Icare ONE was higher than Goldmann applanation in 84%. IOP demonstrated a statistically significant downward trend with repeated sequential measurements with Icare ONE (P = .0053, r(2) = 0.9894). All parents accomplished Icare ONE tonometry on at least 1 eye; 98% reported it was "easy to learn to use." CONCLUSION: Icare ONE tonometry appears accurate and well-tolerated compared to Goldmann applanation, and holds promise for clinic and home tonometry in children. IOP trends downward with successive measurements using Icare ONE, demonstrating a possible effect from presumed patient relaxation. PMID- 22840486 TI - Genetic investigation into the endophenotypic status of central corneal thickness and optic disc parameters in relation to open-angle glaucoma. AB - PURPOSE: To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to disc ratio (VCDR) also are associated with open-angle glaucoma (OAG). DESIGN: Retrospective case-control genetic association study. METHODS: A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia. RESULTS: Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 * 10(-06); odds ratio, 1.38; 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 * 10(-05); odds ratio, 0.74; 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG. CONCLUSIONS: The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG. PMID- 22840487 TI - Course and outcome of accidental sodium hydroxide ocular injury. AB - PURPOSE: To evaluate the course and outcome of patients with accidental ocular alkali burns. DESIGN: Prospective, interventional case series. METHODS: Study of a cohort of 16 patients (31 eyes) who sustained concomitant accidental sodium hydroxide ocular burns and received appropriate treatment at a tertiary care eye hospital in India. The patients were followed up for 1 year, and parameters including best-corrected visual acuity, epithelial defect area, conjunctival and limbal involvement, and injury-related complications were evaluated. RESULTS: Severe sodium hydroxide exposure of a mean duration of 12 +/- 2.5 minutes and delay in specialist eye care caused moderate to severe injury (grade II, 19% [n = 6]; grade III, 19% [n = 6]; grade IV, 10% [n = 3]; and grade VI, 52% [n = 16]). Median best-corrected visual acuity at presentation was 1.0 logarithm of the minimal angle of resolution (logMAR) units (range, 0.3 to 1.9 logMAR units), and at 1 year, it was 1.0 logMAR units (range, 0 to 1.9 logMAR units; P = .121). The median initial epithelial defect was 100 mm(2) (range, 18 to 121 mm(2)), which healed in all eyes by 3.5 months. Initial median limbal involvement was 12 clock hours (range, 3 to 12 clock hours), resulting in a residual limbal stem cell deficiency of 6 clock hours (range, 0 to 12 clock hours) at 1 year. Most common complications were glaucoma and cataract. Corneal ulcers developed in 2 eyes, and keratolimbal graft was performed in 1 patient. Grade VI injuries had significantly worse outcome than the lower-grade injuries. CONCLUSIONS: The course and outcome of ocular alkali burns depends on effective first aid (including a thorough eyewash), age, initial grade of injury, response to treatment, prevention of secondary infection, and control of glaucoma. Despite appropriate treatment, these eyes responded poorly and carried a guarded visual prognosis. PMID- 22840489 TI - The failure response of the human cervical facet capsular ligament during facet joint retraction. AB - Studies implicate the cervical facet joint and its capsule as a primary anatomical site of injury during whiplash exposures to the neck. Although the facet joint is known to undergo stretch as the superior vertebra is retracted relative to the inferior vertebra during the whiplash kinematic, the response of the facet capsular ligament and its microstructure during failure in joint retraction is unknown. Polarized light imaging and vector correlation analysis were used to measure the collagen fiber alignment in the human capsular ligament, together with traditional mechanical metrics, during joint retraction sufficient to induce ligament failure. Anomalous fiber realignment occurs at 2.95+/-1.66mm of displacement, which is not different from the displacement when the ligament first yields (2.77+/-1.55mm), but is significantly lower (p=0.016) than the displacement at tissue failure (5.40+/-1.65mm). The maximum principal strain at the first detection of anomalous fiber realignment (0.66+/-0.39) also is significantly lower (p=0.046) than the strain at failure (1.39+/-0.64), but is not different from the strains at yield or partial failure. The onset of collagen fiber realignment determined in this study corresponds to the ligament's yielding and supports assertions that the facet capsule can undergo tissue injury during joint retraction. Further, such microstructural responses may indicate tissue damage in the absence of rupture. PMID- 22840488 TI - In vivo patellar tracking and patellofemoral cartilage contacts during dynamic stair ascending. AB - The knowledge of normal patellar tracking is essential for understanding the knee joint function and for diagnosis of patellar instabilities. This paper investigated the patellar tracking and patellofemoral joint contact locations during a stair ascending activity using a validated dual-fluoroscopic imaging system. The results showed that the patellar flexion angle decreased from 41.9 degrees to 7.5 degrees with knee extension during stair ascending. During first 80% of the activity, the patella shifted medially about 3.9 mm and then slightly shifted laterally during the last 20% of the ascending activity. Anterior translation of 13 mm of the patella was measured at the early 80% of the activity and the patella slightly moved posteriorly by about 2mm at the last 20% of the activity. The path of cartilage contact points was slightly lateral on the cartilage surfaces of patella and femur. On the patellar cartilage surface, the cartilage contact locations were about 2mm laterally from heel strike to 60% of the stair ascending activity and moved laterally and reached 5.3mm at full extension. However, the cartilage contact locations were relatively constant on the femoral cartilage surface (~5mm lateral). The patellar tracking pattern was consistent with the patellofemoral cartilage contact location pattern. These data could provide baseline knowledge for understanding of normal physiology of the patellofemoral joint and can be used as a reference for clinical evaluation of patellofemoral disorders. PMID- 22840490 TI - Multiple-step model-experiment matching allows precise definition of dynamical leg parameters in human running. AB - The spring-loaded inverted pendulum (SLIP) model is a well established model for describing bouncy gaits like human running. The notion of spring-like leg behavior has led many researchers to compute the corresponding parameters, predominantly stiffness, in various experimental setups and in various ways. However, different methods yield different results, making the comparison between studies difficult. Further, a model simulation with experimentally obtained leg parameters typically results in comparatively large differences between model and experimental center of mass trajectories. Here, we pursue the opposite approach which is calculating model parameters that allow reproduction of an experimental sequence of steps. In addition, to capture energy fluctuations, an extension of the SLIP (ESLIP) is required and presented. The excellent match of the models with the experiment validates the description of human running by the SLIP with the obtained parameters which we hence call dynamical leg parameters. PMID- 22840491 TI - Computational pharmacokinetics of solute penetration into human intervertebral discs - effects of endplate permeability, solute molecular weight and disc size. AB - A finite element model is developed to predict the penetration time-history of three different solutes into the human lumbar disc following intravenous injection. Antibiotics are routinely administered intravenously in spinal surgery to prevent disc infection. Successful prophylaxis requires antibiotics to reach adequate inhibitory levels. Here, the transient diffusion of cephazolin is investigated over 10h post-injection in a human disc model subject to reported concentrations in the blood stream as the prescribed boundary sources. Post injection variation of cephazolin concentrations in the disc adjacent to supply sources closely followed the decay curve in the blood stream and fell sharply with time. Much lower concentrations were computed in the inner annulus and nucleus; much of the disc (80% at 1h and 49% at 4h) experienced concentrations below required inhibitory level of 1mg/L in agreement with measurements. Changes in endplate permeability, disc size, and solute molecular weight had profound effects on concentration profiles at all times and regions, especially in the disc centre, demonstrating their crucial roles on the adequate delivery of drugs. Larger solutes markedly slow transport into the disc. The failure to reach critical therapeutic levels in the central disc regions, especially when endplates calcify and in larger discs, raises concerns and calls for caution in attempts to extrapolate findings of studies on animals with much smaller and non degenerate discs to the human discs. The current study also demonstrates the capability of computational models in predicting the transport of intravenously injected solutes into the disc. PMID- 22840492 TI - Mechanistic insights from comparing intrinsic clearance values between human liver microsomes and hepatocytes to guide drug design. AB - Metabolic stability of drug candidates are often determined in both liver microsome and hepatocyte assays. Comparison of intrinsic clearance values between the two assays provides additional information to guide drug design. Intrinsic clearance values from human liver microsomes and hepatocytes were compared for a set of commercial drugs with known metabolic pathways and transporter characteristics. The results showed that for compounds that were predominately metabolized by CYP mediated mechanisms, the intrinsic clearance values from the two assays were comparable. For compounds with non-CYP pathways, such as UGT and AO, intrinsic clearance was faster in hepatocytes than in microsomes. Substrates of uptake or efflux transporters in this study did not have significant differences of intrinsic clearance between microsomes and hepatocytes, when uptake into the hepatocytes was not the rate-limiting step. When hepatic uptake was rate limiting, intrinsic clearance in microsomes was faster than that in hepatocytes, which was more prevalent for compounds with rapid metabolism. Low passive permeability can limit the exposure to drug molecules to the metabolizing enzymes in the hepatocytes in relationship to the rate of metabolism. The faster the rate of metabolism, the higher permeability is needed for molecule to enter the cells and not becoming rate-limiting. The findings are very useful for drug discovery programs to gain additional insights on mechanistic information to help drug design without added experiments. Follow-up studies can then be designed to address specific questions. PMID- 22840493 TI - Semi-synthesis and anti-tumor evaluation of novel 25-hydroxyprotopanaxadiol derivatives. AB - 30 novel compounds have been synthesized from 25-hydroxyprotopanaxadiol (25-OH PPD) and their in vitro anti-tumor activities were tested on three cancer cell lines and one normal cell line (IOSE144) by standard MTT assay. The results showed that compound 27 exhibited the best anti-tumor activity in the in vitro assays. Compounds 1, 2, 16, 17, 18, 27, 28 and 29 have better anti-tumor activities against MCF-7 and A549 cancer cell lines than 25-OH-PPD, together with low toxicity in the normal cell. The results may provide useful data for researching and developing new antitumor agents. PMID- 22840494 TI - Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non steroidal anti-inflammatory agents with favorable gastrointestinal tolerance. AB - In an effort to establish new candidates with improved analgesic and anti inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b] 1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1 methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs. PMID- 22840495 TI - Synthesis and biological evaluation of some novel 1-indanone thiazolylhydrazone derivatives as anti-Trypanosoma cruzi agents. AB - A series of novel 4-arylthiazolylhydrazones (TZHs) derived from 1-indanones were synthesized in good yields (66-92%) in a simple procedure using microwave irradiation and then characterized by spectroscopy studies. The compounds were evaluated for their in vitro anti-Trypanosoma cruzi activity against the epimastigote, trypomastigote and amastigote forms of the parasite. Most TZHs displayed excellent activity, and were more potent and selective than the reference drug Benznidazole, used in the current chemotherapy. Analysis of the free sterols from parasite incubated with the compounds showed that inhibition of ergosterol biosynthesis is a possible target for the action of these new TZHs. In particular, TZH 9 emerged as a promising antichagasic compound to be evaluated in animal models. PMID- 22840496 TI - IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. AB - OBJECTIVE: Interleukin 22 (IL-22), a relatively new cytokine has been found to induce significant proliferation of human keratinocytes and fibroblast like synoviocytes (FLS) and thus plays an important role in the pathogenesis of autoimmune diseases like psoriasis and rheumatoid arthritis (RA) which are characterized by hyperproliferation of keratinocytes and FLS respectively. PI3K/Akt/mTOR signaling cascade plays crucial role in cell growth and survival. Therefore our objective was to see the regulatory role of PI3K/Akt/mTOR signaling cascade in IL-22 induced proliferation of keratinocytes and FLS. METHODS: Normal human epidermal keratinocytes (NHEK) and FLS were isolated from skin of healthy volunteer's undergone plastic surgery and synovial tissue of psoriatic arthritis (PsA) and RA patients respectively. IL-22 induced proliferation of NHEK and FLS was measured by MTT assay. Phosphorylation of Akt/mTOR was determined by western blot assay and further confirmed by real time polymerase chain reaction (RT-PCR). RESULTS: We observed that IL-22 induced significant proliferation of NHEK and FLS which was effectively inhibited by dual kinase (PI3K/mTOR) inhibitor, NVP-BEZ235 and specific mTOR inhibitor, Rapamycin. In NHEK and FLS, IL-22 significantly induced phosphorylation of Akt and mTOR which was effectively blocked by Rapamycin and NVP-BEZ235. Further we did RT-PCR in NHEK and found that IL-22 significantly upregulated AKT1 and MTOR gene. CONCLUSION: These results show that IL-22 induced proliferation of NHEK and FLS is dependent on PI3K/Akt/mTOR signaling pathway. This novel observation provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR signaling pathway in autoimmune diseases like psoriasis and rheumatoid arthritis. PMID- 22840497 TI - HIV-1 diseases progression associated with loss of Th17 cells in subtype 'C' infection. AB - Th17 cells play a crucial role in host immune response. We examined the role of Th17 cells in HIV-1 'subtype-C' infection and report that HIV-1 specific Th17 cells are induced in early infection and slow progressors but are significantly reduced at late stage of infection. There was a further decline in Th17 cells in late stage subjects with gastrointestinal infections. Additionally, we observed expanded population of IL-21 (needed for Th17 population expansion) producing CD4 T cells in early and slow progressors compared to subjects with late stage infection. A significant positive correlation existed between virus specific IL 17 and IL-21 producing CD4 T cells suggesting that HIV-1 infection induces a demand for Th17 cells. A significant negative correlation between virus specific Th17 cells and HIV-1 plasma viral load (pVL) was also observed, indicating a gradual loss of Th17 cells with HIV-1 disease progression. PMID- 22840498 TI - Serum amyloid A measurements in saliva and serum in growing pigs affected by porcine respiratory and reproductive syndrome in field conditions. AB - The response of serum amyloid A (SAA) concentrations in serum and saliva during a natural porcine respiratory and reproductive syndrome (PRRS) outbreak was investigated. Basal levels of SAA were reliably determined and significant differences in SAA were found between diseased and healthy pigs in both sample types (serum SAA medians 78.3 vs. 55.74 mg/L, respectively; salivary SAA medians 8.97 vs. 2.52 mg/L, respectively; P<0.001). In serum, an SAA cut-off value of 66.4 mg/L showed 68.9% sensitivity and 68.09% specificity, while in saliva an SAA cut-off value of 5.59 mg/mL showed a sensitivity-specificity pair of 69-66%. Furthermore, it was observed that the growth stage of animals should be accounted to correctly interpret SAA measurements, since more accurate cut-off values could be determined and a particular behaviour of salivary SAA was identified in post weaning pigs. Salivary and serum SAA measurements can therefore be confirmed as a valuable tool to consistently discriminate between healthy and PRRS-affected pigs. PMID- 22840499 TI - Heavy metal characterization of circulating fluidized bed derived biomass ash. AB - Although the direct combustion of biomass for energy that applies circulating fluidized bed (CFB) technology is steadily expanding worldwide, only few studies have conducted an environmental assessment of biomass ash thus far. Therefore, this study aims to integrate information on the environmental effects of biomass ash. We investigated the concentration of heavy metal in biomass ash samples (bottom ash, cyclone ash, and filter ash) derived from a CFB boiler that combusted agricultural and forest residues at a biomass power plant (2*12 MW) in China. Ash samples were gathered for the digestion and leaching test. The heavy metal content in the solution and the leachate was studied via an inductively coupled plasma-mass spectrometer and a Malvern Mastersizer 2000 mercury analyzer. Measurements for the chemical composition, particle size distribution, and the surface morphology were carried out. Most of the metals in cyclone ash particles were enriched, whereas Ti and Hg were enriched in filter ash. Residence time contributed most to heavy metal enrichment. Under HJ/T 300 conditions, the heavy metals showed serious leaching characteristics. Under EN 12457-2 conditions, leaching behavior was hardly detected. PMID- 22840500 TI - Removal of pharmaceuticals, polybrominated flame retardants and UV-filters from sludge by the fungus Trametes versicolor in bioslurry reactor. AB - Conventional wastewater treatments are inefficient in the removal of many organic pollutants. The presence of these contaminants in the final sludge represents a source of environmental pollution due to the increasing use of biosolids in land application. A biotechnological approach which employed the fungus Trametes versicolor in a sludge-bioslurry reactor was assessed in order to remove several groups of emerging pollutants. Biological fungal activity was monitored by means of ergosterol and laccase determinations. Fifteen out of 24 detected pharmaceuticals were removed at efficiencies over 50% after the treatment, including eight completely degraded. Removal ranged between 16-53% and 22-100% for the brominated flame retardants and the UV-filters, respectively. Only two of all the detected compounds remained unchanged after the treatment. Although elimination results are promising, the toxicity of the final sludge increased after the treatment. This finding is contrary to the toxicity results obtained in similar treatments of sludge with T. versicolor in solid-phase. PMID- 22840501 TI - Collaborating for a diverse workforce and membership. PMID- 22840502 TI - A legacy of legendary leadership. PMID- 22840503 TI - Staged separation of craniopagus conjoined twins: a multidisciplinary approach. AB - During 2003 and 2004, a multidisciplinary team at the Children's Hospital at Montefiore, Bronx, New York, successfully separated twin infants who presented with a total craniopagus vertical O'Connell type 1 conjoining. The twins underwent a series of four staged separation procedures over 10 months. The first three stages involved performing gradual circumferential craniotomies, dividing the dura, ligating large and small bridging veins, separating abutting brains, and inserting skin expanders. The fourth stage involved dividing the remaining dura and veins, transecting shared brain tissue not detected in preoperative imaging, replacing dura in twin B, and replacing skin over native dura in twin A. Planning and carrying out separation of the conjoined twins required organization and cooperation of all the disciplines involved to prepare the children preoperatively, care for them perioperatively and postoperatively, and support the mother during the process. PMID- 22840504 TI - Uphill grime: process improvement in surgical instrument cleaning. AB - After its investigation of cross-contamination from arthroscopic shavers, the US Food and Drug Administration issued an alert to hospitals about medical device reprocessing methods. In response to this, a team of risk management and instrument room personnel at a university hospital undertook a project that tested the manufacturer's recommended cleaning methods for surgical instruments with the objective of determining the efficacy of automated instrument reprocessing and identifying a process that would produce a verifiably clean instrument after the cleaning process is performed. The quality improvement project focused on suction tips because they are used in most surgical procedures, are exposed to high levels of organic debris, and are difficult to clean. A variety of suction tips were cleaned and tested with a variety of processes and products to determine best instrument cleaning practices. Results of the project were eye-opening--debris was found where debris should not be, and the manufacturer's recommended cleaning methods--the current practices-were not effective. PMID- 22840505 TI - A magnetic approach to treating progressive early-onset scoliosis. AB - Early-onset scoliosis presents at birth and up to five years of age. Growing rods are a treatment option when early-onset scoliosis cannot be controlled by serial casts or braces. The function of a growing rod is to allow a child's spine to continue to grow under controlled conditions until a definitive correction can be made when the patient nears skeletal maturity. This article presents two case reports describing the use of an expandable magnetic growing rod in children with progressive, early-onset scoliosis. After implantation, caregivers expand the rod nonsurgically using an external magnet to obtain and maintain correction while the child grows. The first case report describes the use of a magnetic growing rod in a patient with a rigid spinal curve and a significant rotational deformity; the second case report describes a patient with a more flexible neuromuscular curve. These were the first two patients to be offered treatment with an expandable rod in North America after the surgeon obtained approval to use the device based on compassionate grounds from the US Food and Drug Administration and institutional review board consent and approval for both surgeries. PMID- 22840506 TI - Fetal myelomeningocele repair: a new standard of care. AB - Myelomeningocele, also known as spina bifida, is one of the most common congenital anomalies of the central nervous system and the most common open, prenatally repaired birth defect. The Management of Myelomeningocele Study (MOMS), which compared the results of prenatal and postnatal myelomeningocele repair, found prenatal surgery to be much more effective than postnatal surgery. During surgery, the surgeon makes a hysterotomy and repairs the fetal myelomeningocele without removing the fetus from the uterus. After the repair is completed, the surgeon closes the uterus. The obstetric team monitors the mother closely with a goal of performing a cesarean delivery at 37 weeks' gestation. The fetal surgery nursing team used innovative simulation teaching methods to establish and maintain fetal surgery team member competence, resulting in a successful program with good outcomes. PMID- 22840507 TI - Global collaboration in disaster nursing. PMID- 22840508 TI - Using clinical peer coaching for patient safety. PMID- 22840510 TI - Are we pushing graduate nurses too fast? PMID- 22840511 TI - Aerobic exercise training during pregnancy increases antioxidant status in nulliparous women: secondary analysis of a controlled clinical trial. PMID- 22840512 TI - How multivariate ejaculate traits determine competitive fertilization success in Drosophila melanogaster. AB - Success in sperm competition, occurring whenever females mate with multiple males, is predicted to be influenced by variation in ejaculate quality and interactions among competing sperm. Yet, apart from sperm number, relevant ejaculate characteristics and sperm-sperm interactions are poorly understood, particularly within a multivariate framework and the natural selective environment of the female reproductive tract. Here, we used isogenic lines of Drosophila melanogaster with distinguishable sperm to demonstrate and partition genetic variation in multiple sperm quality and performance traits. Next, by competing males from different lines, we show how rival sperm significantly influence each other's velocity and reveal that males with relatively slow and/or long sperm better displace rival sperm and resist displacement, thus avoiding ejection by the female from her reproductive tract. Finally, we establish fitness consequences of genetic variation in sperm quality and its role in securing a numerical advantage in storage by showing that offspring paternity is determined strictly by the representation of stored, competing sperm. These results provide novel insight into complex postcopulatory processes, illustrate that different ejaculate traits are critical at different biologically relevant time-points, and provide a critical foundation for elucidating the role of postcopulatory sexual selection in trait diversification and speciation. PMID- 22840513 TI - Contributions of turgor pressure, the contractile ring, and septum assembly to forces in cytokinesis in fission yeast. AB - A paradigm of cytokinesis in animal cells is that the actomyosin contractile ring provides the primary force to divide the cell. In the fission yeast Schizosaccharomyces pombe, cytokinesis also involves a conserved cytokinetic ring, which has been generally assumed to provide the force for cleavage (see also [5]). However, in contrast to animal cells, cytokinesis in yeast cells also requires the assembly of a cell wall septum, which grows centripetally inward as the ring closes. Fission yeast, like other walled cells, also possess high (MPa) turgor pressure. Here, we show that turgor pressure is an important factor in the mechanics of cytokinesis. Decreasing effective turgor pressure leads to an increase in cleavage rate, suggesting that the inward force generated by the division apparatus opposes turgor pressure. The contractile ring, which is predicted to provide only a tiny fraction of the mechanical stress required to overcome turgor, is largely dispensable for ingression; once septation has started, cleavage can continue in the absence of the contractile ring. Scaling arguments and modeling suggest that the large forces for cytokinesis are not produced by the contractile ring but are driven by the assembly of cell wall polymers in the growing septum. PMID- 22840514 TI - Supernumerary centrosomes nucleate extra cilia and compromise primary cilium signaling. AB - The primary cilium is a nexus of cell signaling, and ciliary dysfunction is associated with polycystic kidney disease, retinal degeneration, polydactyly, neural tube defects, and obesity (ciliopathies). Signaling molecules for cilium associated pathways are concentrated in the cilium, and this is essential for efficient signaling. Cilia are nucleated from centrioles, and aberrant centriole numbers are seen in many cancers and in some ciliopathies. We tested the effect of supernumerary centrioles on cilium function and found that cells with extra centrioles often formed more than one cilium, had reduced ciliary concentration of Smoothened in response to Sonic hedgehog stimulation, and reduced Shh pathway transcriptional activation. This ciliary dilution phenotype was also observed with the serotonin receptor Htr6, fibrocystin PKHD1, and Arl13b. The presence of extra centrioles and cilia disrupted epithelial organization in 3D spheroid culture. Cells mutant for the tuberous sclerosis gene Tsc2 also had extra cilia and diluted ciliary protein. In most cells, extra cilia were clustered and shared the same ciliary pocket, suggesting that the ciliary pocket is the rate-limiting structure for trafficking of ciliary proteins. Thus, extra centrioles and cilia disrupt signaling and may contribute to disease phenotypes. PMID- 22840515 TI - Homeodomain-interacting protein kinase regulates Hippo pathway-dependent tissue growth. AB - The Salvador-Warts-Hippo (SWH) pathway is an evolutionarily conserved regulator of tissue growth that is deregulated in human cancer. Upstream SWH pathway components convey signals from neighboring cells via a core kinase cassette to the transcription coactivator Yorkie (Yki). Yki controls tissue growth by modulating activity of transcription factors including Scalloped (Sd). To date, five SWH pathway kinases have been identified, but large-scale phosphoproteome studies suggest that unidentified SWH pathway kinases exist. To identify such kinases, we performed an RNA interference screen and isolated homeodomain interacting protein kinase (Hipk). Unlike previously identified SWH pathway kinases, Hipk is unique in its ability to promote, rather than repress, Yki activity and does so in parallel to the Yki-repressive kinase, Warts (Wts). Hipk is required for basal Yki activity and is likely to regulate Yki function by promoting its accumulation in the nucleus. Like many SWH pathway proteins, Hipk's function is evolutionarily conserved as its closest human homolog, HIPK2, promotes activity of the Yki ortholog YAP in a kinase-dependent fashion. Further, HIPK2 promotes YAP abundance, suggesting that the mechanism by which HIPK2 regulates YAP has diverged in mammals. PMID- 22840516 TI - Optogenetically induced behavioral and functional network changes in primates. AB - Optogenetics is currently the state-of-the-art method for causal-oriented brain research. Despite an increasingly large number of invertebrate and rodent studies showing profound electrophysiological and behavioral effects induced by optogenetics, only two primate studies have reported modulation of local single cell activity but with no behavioral effects. Here, we show that optogenetic stimulation of cortical neurons within rhesus monkey arcuate sulcus, during the execution of a visually guided saccade task, evoked significant and reproducible changes in saccade latencies as a function of target position. Moreover, using concurrent optogenetic stimulation and opto-fMRI), we observed optogenetically induced changes in fMRI activity in specific functional cortical networks throughout the monkey brain. This is critical information for the advancement of optogenetic primate research models and for initiating the development of optogenetically based cell-specific therapies with which to treat neurological diseases in humans. PMID- 22840517 TI - Gaze stabilization by efference copy signaling without sensory feedback during vertebrate locomotion. AB - BACKGROUND: Self-generated body movements require compensatory eye and head adjustments in order to avoid perturbation of visual information processing. Retinal image stabilization is traditionally ascribed to the transformation of visuovestibular signals into appropriate extraocular motor commands for compensatory ocular movements. During locomotion, however, intrinsic "efference copies" of the motor commands deriving from spinal central pattern generator (CPG) activity potentially offer a reliable and rapid mechanism for image stabilization, in addition to the slower contribution of movement-encoding sensory inputs. RESULTS: Using a variety of in vitro and in vivo preparations of Xenopus tadpoles, we demonstrate that spinal locomotor CPG-derived efference copies do indeed produce effective conjugate eye movements that counteract oppositely directed horizontal head displacements during undulatory tail-based locomotion. The efference copy transmission, by which the extraocular motor system becomes functionally appropriated to the spinal cord, is mediated by direct ascending pathways. Although the impact of the CPG feedforward commands matches the spatiotemporal specificity of classical vestibulo-ocular responses, the two fundamentally different signals do not contribute collectively to image stabilization during swimming. Instead, when the CPG is active, horizontal vestibulo-ocular reflexes resulting from head movements are selectively suppressed. CONCLUSIONS: These results therefore challenge our traditional understanding of how animals offset the disruptive effects of propulsive body movements on visual processing. Specifically, our finding that predictive efference copies of intrinsic, rhythmic neural signals produced by the locomotory CPG supersede, rather than supplement, reactive vestibulo-ocular reflexes in order to drive image-stabilizing eye adjustments during larval frog swimming, represents a hitherto unreported mechanism for vertebrate ocular motor control. PMID- 22840518 TI - Hawkmoth pollinators decrease seed set of a low-nectar Petunia axillaris line through reduced probing time. AB - Although deception of floral pollinators is well known among orchids, the majority of animal-pollinated plants secure pollination by nectar rewards. The costs and benefits of nectar production remain poorly understood. Here, we developed a crossing design to introgress a low-nectar-volume locus of Petunia integrifolia into the genetic background of P. axillaris. The resulting introgression line resembled P. axillaris but produced only one-third of the nectar volume. When exposed simultaneously to low-nectar and wild-type P. axillaris plants, hawkmoth pollinators reduced their probing duration on low nectar plants but otherwise did not show any signs of discrimination against these plants. However, reduced probing duration resulted in reduced seed production in the low-nectar plants despite their higher reproductive potential as evidenced by hand pollination. In line with this interpretation, we found a positive correlation between probing duration and seed set, and hawkmoth pollination of low-nectar plants that were manually supplemented with nectar to parental levels yielded seed sets similar to hand pollination. Thus, a simple self-serving pollinator behavior--the adjustment of probing time in response to nectar volume--may select against reducing nectar and protect many plant pollinator mutualisms against a drift toward parasitism. PMID- 22840519 TI - Differential representations of prior and likelihood uncertainty in the human brain. AB - BACKGROUND: Uncertainty shapes our perception of the world and the decisions we make. Two aspects of uncertainty are commonly distinguished: uncertainty in previously acquired knowledge (prior) and uncertainty in current sensory information (likelihood). Previous studies have established that humans can take both types of uncertainty into account, often in a way predicted by Bayesian statistics. However, the neural representations underlying these parameters remain poorly understood. RESULTS: By varying prior and likelihood uncertainty in a decision-making task while performing neuroimaging in humans, we found that prior and likelihood uncertainty had quite distinct representations. Whereas likelihood uncertainty activated brain regions along the early stages of the visuomotor pathway, representations of prior uncertainty were identified in specialized brain areas outside this pathway, including putamen, amygdala, insula, and orbitofrontal cortex. Furthermore, the magnitude of brain activity in the putamen predicted individuals' personal tendencies to rely more on either prior or current information. CONCLUSIONS: Our results suggest different pathways by which prior and likelihood uncertainty map onto the human brain and provide a potential neural correlate for higher reliance on current or prior knowledge. Overall, these findings offer insights into the neural pathways that may allow humans to make decisions close to the optimal defined by a Bayesian statistical framework. PMID- 22840520 TI - A superfamily of actin-binding proteins at the actin-membrane nexus of higher plants. AB - Complex animals use a wide variety of adaptor proteins to produce specialized sites of interaction between actin and membranes. Plants do not have these protein families, yet actin-membrane interactions within plant cells are critical for the positioning of subcellular compartments, for coordinating intercellular communication, and for membrane deformation. Novel factors are therefore likely to provide interfaces at actin-membrane contacts in plants, but their identity has remained obscure. Here we identify the plant-specific Networked (NET) superfamily of actin-binding proteins, members of which localize to the actin cytoskeleton and specify different membrane compartments. The founding member of the NET superfamily, NET1A, is anchored at the plasma membrane and predominates at cell junctions, the plasmodesmata. NET1A binds directly to actin filaments via a novel actin-binding domain that defines a superfamily of thirteen Arabidopsis proteins divided into four distinct phylogenetic clades. Members of other clades identify interactions at the tonoplast, nuclear membrane, and pollen tube plasma membrane, emphasizing the role of this superfamily in mediating actin-membrane interactions. PMID- 22840521 TI - Cursive writing with smooth pursuit eye movements. AB - The eyes never cease to move: ballistic saccades quickly turn the gaze toward peripheral targets, whereas smooth pursuit maintains moving targets on the fovea where visual acuity is best. Despite the oculomotor system being endowed with exquisite motor abilities, any attempt to generate smooth eye movements against a static background results in saccadic eye movements. Although exceptions to this rule have been reported, volitional control over smooth eye movements is at best rudimentary. Here, I introduce a novel, temporally modulated visual display, which, although static, sustains smooth eye movements in arbitrary directions. After brief training, participants gain volitional control over smooth pursuit eye movements and can generate digits, letters, words, or drawings at will. For persons deprived of limb movement, this offers a fast, creative, and personal means of linguistic and emotional expression. PMID- 22840522 TI - Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth. AB - The Hippo (Hpo) tumor suppressor pathway regulates tissue size by inhibiting cell proliferation and promoting apoptosis. The core components of the pathway, Hpo, Salvador, Warts (Wts), and Mats, form a kinase cascade to inhibit the activity of Yorkie (Yki), the transcriptional effector of the pathway. Homeodomain interacting protein kinases (Hipks) are a family of conserved serine/threonine kinases that function as regulators of various transcription factors to regulate developmental processes including proliferation, differentiation, and apoptosis. Hipk can induce tissue overgrowth in Drosophila. We demonstrate that Hipk is required to promote Yki activity. Hipk affects neither Yki stability nor its subcellular localization. Moreover, hipk knockdown suppresses the overgrowth and target gene expression caused by hyperactive Yki. Hipk phosphorylates Yki and in vivo analyses show that Hipk's regulation of Yki is kinase-dependent. To our knowledge, this is the first kinase identified to positively regulate Yki. PMID- 22840523 TI - Comparing scaffold-free and fibrin-based adipose-derived stromal cell constructs for adipose tissue engineering: an in vitro and in vivo study. AB - Success of adipose tissue engineering for soft tissue repair has been limited by insufficient adipogenic differentiation, an unfavorable host response, and insufficient vascularization. In this study, we examined how scaffold-free spheroid and fibrin-based environments impact these parameters in human adipose derived stromal cell (ASC)-based adipose constructs. ASCs were differentiated in spheroids or fibrin-based constructs. After 7 days, conditioned medium was collected and spheroids/fibrin-based constructs were either harvested or implanted subcutaneously in athymic mice. Following 7 days of implantation, the number of blood vessels in fibrin-based constructs was significantly higher than in spheroids (93+/-45 vs. 23+/-11 vessels/mm(2)), and the inflammatory response to fibrin-based constructs was less severe. The reasons for these results were investigated further in vitro. We found that ASCs in fibrin-based constructs secreted significantly higher levels of the angiogenic factors VEGF and HGF and lower levels of the inflammatory cytokine IL-8. Furthermore, ASCs in fibrin-based constructs secreted significantly higher levels of leptin and showed a 2.5-fold upregulation of the adipogenic transcription factor PPARG and a fourfold to fivefold upregulation of the adipocyte-specific markers FABP4, perilipin, and leptin. These results indicate that fibrin-based ASC constructs are potentially more suitable for ASC-based adipose tissue reconstruction than scaffold-free spheroids. PMID- 22840524 TI - The Patient Assessment Questionnaire: initial validation of a measure of treatment effectiveness for patients with schizophrenia and schizoaffective disorder. AB - Investigation of patients' subjective perspective regarding the effectiveness - as opposed to efficacy - of antipsychotic medication has been hampered by a relative shortage of self-report measures of global clinical outcome. This paper presents data supporting the feasibility, inter-item consistency, and construct validity of the Patient Assessment Questionnaire (PAQ)-a self-report measure of psychiatric symptoms, medication side effects and general wellbeing, ultimately intended to assess effectiveness of interventions for schizophrenia-spectrum patients. The original 53-item instrument was developed by a multidisciplinary team which utilized brainstorming sessions for item generation and content analysis, patient focus groups, and expert panel reviews. This instrument and additional validation measures were administered, via Audio Computer-Assisted Self-Interviewing (ACASI), to 300 stable, medicated outpatients diagnosed with schizophrenia or schizoaffective disorder. Item elimination was based on psychometric properties and Item-Response Theory information functions and characteristic curves. Exploratory factor analysis of the resulting 40-item scale yielded a five factor solution. The five subscales (General Distress, Side Effects, Psychotic Symptoms, Cognitive Symptoms, Sleep) showed robust convergent (beta's=0.34-0.75, average beta=0.49) and discriminant validity. The PAQ demonstrates feasibility, reliability, and construct validity as a self-report measure of multiple domains pertinent to effectiveness. Future research needs to establish the PAQ's sensitivity to change. PMID- 22840525 TI - Genetic testing in Brugada syndrome. PMID- 22840526 TI - Use of the implantable cardioverter-defibrillator in patients with coronary artery spasm as the apparent cause of spontaneous life-threatening ventricular tachycardia or ventricular fibrillation: crossing the spasm sudden death chasm. PMID- 22840527 TI - Clinical implications of an implantable cardioverter-defibrillator in patients with vasospastic angina and lethal ventricular arrhythmia. AB - OBJECTIVES: The present study was performed to investigate the clinical implications of an implantable cardioverter-defibrillator (ICD) in patients with vasospastic angina (VSA) resuscitated from lethal ventricular arrhythmia. BACKGROUND: The prognosis of VSA is known to be good with medication; however, ventricular arrhythmia and cardiopulmonary arrest are rare but life-threatening complications of this disease. The ICD is a proven modality for patients with ventricular arrhythmia, but the clinical implications in this population remain to be elucidated. METHODS: We conducted a retrospective, observational, multicenter study involving patients with an ICD due to documented ventricular arrhythmia and VSA diagnosed by acetylcholine provocation test. All patients were followed up for appropriate ICD therapy, sudden cardiac arrest, or death from all causes. RESULTS: Twenty-three patients were included in the present study and completely followed up. All patients are still alive. During a follow-up of 2.9 years (median 2.1 years), 4 ventricular fibrillations and 1 episode of pulseless electrical activity occurred in 5 patients (21.7%). There were no statistically significant differences in patient characteristics between the recurrence and nonrecurrence groups, including medication, smoking status, and whether the patient was or was not free of symptoms after ICD implantation. CONCLUSIONS: Patients with VSA and lethal ventricular arrhythmia are a population at high risk for recurrence of cardiopulmonary arrest, and there is no reliable indicator for predicting recurrence of ventricular arrhythmia. Insertion of an ICD with medication for VSA is appropriate for this high-risk population. PMID- 22840529 TI - Exploring the risk of unintended consequences of quality improvement efforts. PMID- 22840528 TI - Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing. AB - OBJECTIVES: The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients. BACKGROUND: BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events. METHODS: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12 susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only). RESULTS: Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men<20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval. CONCLUSIONS: We identified putative pathogenic mutations in ~20% of our BrS cohort, with BrS genes 2 through 12 accounting for <5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval. PMID- 22840531 TI - Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure. AB - Cardiorenal syndrome (CRS) type 1 is characterized as the development of acute kidney injury (AKI) and dysfunction in the patient with acute cardiac illness, most commonly acute decompensated heart failure (ADHF). There is evidence in the literature supporting multiple pathophysiological mechanisms operating simultaneously and sequentially to result in the clinical syndrome characterized by a rise in serum creatinine, oliguria, diuretic resistance, and in many cases, worsening of ADHF symptoms. The milieu of chronic kidney disease has associated factors including obesity, cachexia, hypertension, diabetes, proteinuria, uremic solute retention, anemia, and repeated subclinical AKI events all work to escalate individual risk of CRS in the setting of ADHF. All of these conditions have been linked to cardiac and renal fibrosis. In the hospitalized patient, hemodynamic changes leading to venous renal congestion, neurohormonal activation, hypothalamic-pituitary stress reaction, inflammation and immune cell signaling, systemic endotoxemic exposure from the gut, superimposed infection, and iatrogenesis all contribute to CRS type 1. The final common pathway of bidirectional organ injury appears to be cellular, tissue, and systemic oxidative stress that exacerbate organ function. This review explores in detail the pathophysiological pathways that put a patient at risk and then effectuate the vicious cycle now recognized as CRS type 1. PMID- 22840530 TI - Pre-hospital electrocardiography by emergency medical personnel: effects on scene and transport times for chest pain and ST-segment elevation myocardial infarction patients. AB - OBJECTIVES: This study sought to measure the impact of pre-hospital (PH) electrocardiography (ECG) on scene-to-hospital time for patients with chest pain of cardiac origin and those with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Pre-hospital ECG decreases door-to balloon (D2B) time for STEMI patients. However, obtaining a PH ECG might prolong scene time. We investigated the impact of obtaining a PH ECG on both scene and transport times for patients with chest pain suspected of cardiac origin. METHODS: City of San Diego Emergency Medical System runsheets of patients with chest pain from January 2003 to April 2008 were analyzed. The scene times and transport times were compared before (from January 2003 to December 2005) and after (from January 2006 to April 2008) implementation of the PH ECG. Among patients with a PH ECG, median scene times and transport times were compared in patients with and without STEMI. RESULTS: There were 21,742 patients evaluated for chest pain during the study period. Implementation of PH ECG resulted in minimal increases in median scene time (19 min, 10 s vs. 19 min, 28 s, p = 0.002) and transport time (13 min, 16 s vs. 13 min, 28 s, p = 0.007). However, compared with chest pain patients, in STEMI patients (n = 303), shorter median scene time (17 min, 51 s vs. 19 min, 31 s, p < 0.001), transport time (12 min, 34 s vs. 13 min, 31 s, p = 0.006), and scene-to-hospital time was observed (30 min, 45 s vs. 33 min, 29 s, p < 0.001). CONCLUSIONS: Obtaining a PH ECG for patients with chest pain minimally prolongs scene and transport times. Further, for STEMI patients, both scene times and transport times are actually reduced leading to a potential reduction in total ischemic time. PMID- 22840532 TI - bla(NDM-1)-positive Klebsiella pneumoniae from environment, Vietnam. PMID- 22840533 TI - Effective collection of hydrophobic organic pollutants in water with aluminum hydroxide and hydrophobically modified polyacrylic acid. AB - Polyacrylic acid was hydrophobically modified with dodecylamine and used as a coagulant for coprecipitation of hydrophobic organic pollutants from water. The polymer coagulant induced effective aggregation of aluminum hydroxide having hydrophobic regions which are essential for the incorporation of hydrophobic organic pollutants. Recoveries of the organic pollutants increased with increasing the dodecylamine content, which indicated that the dodecylamine moiety played an important role in the formation of hydrophobic area on the precipitate. Different hydrophobic organic pollutants that had hardly been removed by the conventional coprecipitation were successfully collected by the proposed method. PMID- 22840534 TI - Lindane removal by pure and mixed cultures of immobilized actinobacteria. AB - Lindane (gamma-HCH) is an organochlorine insecticide that has been widely used in developing countries. It is known to persist in the environment and can cause serious health problems. One of the strategies adopted to remove lindane from the environment is bioremediation using microorganisms. Immobilized cells present advantages over free suspended cells, like their high degradation efficiency and protection against toxins. The aims of this work were: (1) To evaluate the ability of Streptomyces strains immobilized in four different matrices to remove lindane, (2) To select the support with optimum lindane removal by pure cultures, (3) To assay the selected support with consortia and (4) To evaluate the reusability of the immobilized cells. Four Streptomyces sp. strains had previously shown their ability to grow in the presence of lindane. Lindane removal by microorganisms immobilized was significantly higher than in free cells. Specifically immobilized cells in cloth sachets showed an improvement of around 25% in lindane removal compared to the abiotic control. Three strains showed significantly higher microbial growth when they were entrapped in silicone tubes. Strains immobilized in PVA-alginate demonstrated lowest growth. Mixed cultures immobilized inside cloth sachets showed no significant enhancement compared to pure cultures, reaching a maximum removal of 81% after 96 h for consortium I, consisting of the four immobilized strains together. Nevertheless, the cells could be reused for two additional cycles of 96 h each, obtaining a maximum removal efficiency of 71.5% when each of the four strains was immobilized in a separate bag (consortium III). PMID- 22840535 TI - Persistent organic pollutants (POPs) in human milk: a biomonitoring study in rural areas of Flanders (Belgium). AB - To collect information on the concentrations of persistent organic pollutants (POPs) in the rural areas in Flanders (Belgium), 84 breastfeeding mothers were recruited in rural communities in East and West Flanders and Flemish Brabant in 2009-2010. Polychlorinated biphenyl (PCB) congeners, organochlorine pesticides, brominated flame retardants, perfluorinated compounds, polychlorinated dibenzodioxines and dibenzofurans, and dioxin-like PCBs were measured in individual milk samples and in a pooled milk sample, while some additional pollutants were only measured in the pooled sample. For most pollutants, the concentrations in this study were lower or comparable to the concentrations measured in the pooled Belgian sample of the WHO human milk study of 2006, except for the pesticides dichlorodiphenyltrichloroethane DDT (+25% for SigmaDDT and metabolites) and trans-nonachlor (+94%), and for the brominated flame retardant hexachlorocyclododecane HBCD (+153%). Perfluorinated compounds were for the first time determined in human milk samples from Belgium and the concentrations were comparable to those from other European countries. Also, interesting associations were found between the concentrations of POPs measured in human milk and personal characteristics as well as dietary habits of the study population. PFOS en PFOA concentrations were significantly higher in milk of primiparous participants compared to mothers who gave birth to their second child. Lower brominated PBDE congeners increased with increasing BMI of the mothers (p=0.01 for BDE 47, p=0.02 for BDE 99 and p=0.02 for BDE 100). Participants consuming milk or dairy products daily had significant higher concentrations of SigmaDDTs (p=0.03) and oxychlordane (p=0.047) in their human milk samples. PMID- 22840536 TI - Occurrence, compositional patterns, and possible sources of polybrominated diphenyl ethers in agricultural soil of Shanghai, China. AB - The present study analyzed surface soil collected from agricultural region of Shanghai to determine the occurrence, compositional patterns and possible sources of polybrominated diphenyl ethers (PBDEs). The results showed that 32 PBDEs were detected among 44 target PBDEs. Total PBDE concentrations ranged from 129 to 1245 ng kg(-1) with a mean of 429 ng kg(-1). BDE209 was the predominant congener in a range of 33.2-796 ng kg(-1) with a mean of 254 ng kg(-1). Meanwhile, BDE47, BDE49, BDE153, BDE190, and BDE99 have the most abundant with high concentrations and detectable frequencies. PBDE congeners and homologues analysis and principal component analysis (PCA) also revealed that the major source of PBDE in the soil samples was associated with the prevalent use of technical decabromodiphenyl ether (Deca-BDE) and pentabromodiphenyl ether (Penta-BDE). The correlation analysis proved that there was a significant correlation between total organic carbon (TOC) and lower brominated PBDEs, indicating the significant diffuse nature of the sources of these congeners. PMID- 22840537 TI - Effect of organics and alkalinity on the sulfur oxidizing bacteria (SOB) biosensor. AB - The environmental risk assessment of toxic chemicals in stream water requires the use of a low cost standardized toxicity bioassay. Here, a biosensor for detection of toxic chemicals in stream water was studied using sulfur oxidizing bacteria (SOB) in continuous mode. The biosensor depends on the ability of SOB to oxidize sulfur particles under aerobic conditions to produce sulfuric acid. The reaction results in an increase in electrical conductivity (EC) and a decrease in pH. The biosensor is based on the inhibition of SOB in the presence of toxic chemicals by measuring changes in EC and pH. We found that the SOB biosensor can detect Cr(6+)at a low concentration (50 ppb) which is lower than many whole-cell biosensors. The effect of organic material in real stream water on SOB activity was studied. Due to the presence of mixotrophic SOB, we found that the presence of organic matter increases SOB activity which decreases the biosensor start up period. Low alkalinity (22 mg L(-1) CaCO(3)) increased effluent EC and decreased effluent pH which is optimal for biosensor operation. While at high alkalinity (820 mg L(-1) CaCO(3), the activity of SOB little decreased. We found that system can detect 50 ppb of Cr(6+) at low alkalinity (22 mg L(-1) CaCO(3)) in few hours while, complete inhibition was observed after 35 h of operation at high alkalinity (820 mg L(-1) CaCO(3)). PMID- 22840538 TI - Modulation of immune-associated parameters and antioxidant responses in the crab (Scylla serrata) exposed to mercury. AB - Organic and inorganic contaminants can suppress immune function in molluscs and crustaceans. It was postulated that metals could modulate immune function in marine crabs. To test this hypothesis, sublethal effects of mercury (Hg) on cellular immune and biochemical responses of crabs were determined. When crabs were exposed for 14 d to environmentally-relevant concentrations of Hg, changes in immune-associated parameters including, total haemocyte count, lysosomal membrane stability, phenoloxidase, super oxide generation and phagocytosis were observed. Oxidative stress, as measured by lipid peroxidation, antioxidant responses, including superoxide dismutase and catalase activities and glutathione mediated antioxidant enzymes in serum, haemocyte lysate, gills, hepatopancreas and muscle were assessed in crabs exposed to Hg. Exposure to Hg resulted in significantly lesser immune-associated parameters in haemolymph and antioxidants in all tissues studied. Conversely, GST and phenoloxidase activity, were greater in crabs exposed to Hg. Responses of antioxidant parameters (SOD, CAT and GP(x)) were positively correlated with immune responses, including THC, superoxide and phagocytosis. These results were postulated to be due to an immediate response of antioxidant defense to oxygen radicals generated. Overall, the results suggest that 14 d exposure to environmentally realistic concentrations of Hg causes immunomodulation and potentially harmful lessened antioxidant defenses of crabs. PMID- 22840539 TI - 6:2 fluorotelomer alcohol biotransformation in an aerobic river sediment system. AB - The 6:2 FTOH [F(CF(2))(6)CH(2)CH(2)OH] is a major raw material being used to replace 8:2 FTOH [F(CF(2))(8)CH(2)CH(2)OH] to make FTOH-based products for industrial and consumer applications. A novel aerobic sediment experimental system containing 20 g wet sediment and 30 mL aqueous solution was developed to study 6:2 FTOH biotransformation in river sediment. 6:2 FTOH was dosed into the sediment to follow its biotransformation and to analyze transformation products over 100 d. The primary 6:2 FTOH biotransformation in the aerobic sediment system was rapid (T(1/2)<2d). 5:3 acid [F(CF(2))(5)CH(2)CH(2)COOH] was observed as the predominant polyfluorinated acid on day 100 (22.4 mol%), higher than the sum of perfluoropentanoic acid (10.4 mol%), perfluorohexanoic acid (8.4 mol%), and perfluorobutanoic acid (1.5 mol%). Perfluoroheptanoic acid was not observed during 6:2 FTOH biotransformation. The 5:3 acid can be further degraded to 4:3 acid [F(CF(2))(4)CH(2)CH(2)COOH, 2.7 mol%]. This suggests that microbes in the river sediment selectively degraded 6:2 FTOH more toward 5:3 and 4:3 acids compared with soil. Most of the observed 5:3 acid formed bound residues with sediment organic components and can only be quantitatively recovered by post treatment with NaOH and ENVI-CarbTM carbon. The 6:2 FTCA [F(CF(2))(6)CH(2)COOH], 6:2 FTUCA [F(CF(2))(5)CF=CHCOOH], 5:2 ketone [F(CF(2))(5)C(O)CH(3)], and 5:2 sFTOH [F(CF(2))(5)CH(OH)CH(3)] were major transient intermediates during 6:2 FTOH biotransformation in the sediment system. These results suggest that if 6:2 FTOH or 6:2 FTOH-based materials were released to the river or marine sediment, poly- and per-fluorinated carboxylates could be produced. PMID- 22840540 TI - Serum concentrations of persistent organic pollutants (POPs) in the inhabitants of a Sicilian city. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine pesticides are common environmental contaminants that have been associated with human health problems. OBJECTIVES: To assess serum concentrations of several organochlorine contaminants in general population living in a city with an ancient agricultural tradition and to identify possible exposure sources in Sicily. METHODS: A cross sectional study was conducted on 101 individuals. Each participant answered a face-to-face questionnaire submitted by well-trained personnel and provided a serum sample which was analyzed for the concentrations of PCBs, HCB, HCHs and DDTs by using gas-chromatography coupled with mass spectrometry. RESULTS: HCB, p,p'-DDE, PCB 138, PCB 153 and PCB 180 were detected in more than 80% of the study participants. The ng g(-1) lipid median concentrations were: 18.6 for HCB; 175.1 for p,p'-DDE; 22. for PCB 138; 32.5 for PCB 153 and 23.0 for PCB 180. PCB 153 and PCB 138, PCB 138 and PCB 180, PCB 153 and PCB 180, and p,p'-DDE and HCB showed a high correlation each other (p<0.05). HCB and p,p'-DDE concentrations were significantly higher in subjects >49 years old (adj-p=0.03 in 50-69 years old and adj-p<0.001 in >69 years old, respectively) whereas PCB 138, PCB 153 and PCB 180 concentrations were higher in males (adj-p=0.03), in subjects >69 years old (adj-p=0.04) and in current smokers (adj-p=0.04). CONCLUSIONS: The present study shows that serum concentrations of organochlorine compounds detected in subjects living in a small Sicilian city with ancient agricultural tradition are similar to those found in subjects living in urban areas of other countries. However, further investigations are needed to compare data from rural/urban areas in the same country, assessing correlations between serum concentrations of several chemical compounds and potential health effects in general population. PMID- 22840541 TI - Metal-induced decomposition of perchlorate in pressurized hot water. AB - Decomposition of perchlorate (ClO(4)(-)) in pressurized hot water (PHW) was investigated. Although ClO(4)(-) demonstrated little reactivity in pure PHW up to 300 degrees C, addition of zerovalent metals to the reaction system enhanced the decomposition of ClO(4)(-) to Cl(-) with an increasing order of activity of (no metal)~Al < Cu < Zn < Ni << Fe: the addition of iron powder led to the most efficient decomposition of ClO(4)(-). When the iron powder was added to an aqueous ClO(4)(-) solution (104 MUM) and the mixture was heated at 150 degrees C, ClO(4)(-) concentration fell below 0.58 MUM (58 MUg L(-1), detection limit of ion chromatography) in 1 h, and Cl(-) was formed with the yield of 85% after 6 h. The decomposition was accompanied by transformation of the zerovalent iron to Fe(3)O(4). This method was successfully used in the decomposition of ClO(4)(-) in a water sample contaminated with this compound, following fireworks display at Albany, New York, USA. PMID- 22840542 TI - Identification of biofilm formation by Mycoplasma gallisepticum. AB - Mycoplasma gallisepticum is the causative agent of chronic respiratory disease in chickens and of infectious sinusitis in turkeys, chickens, game birds, pigeons, and passerine birds of all ages. This study investigated the biofilm-producing ability of M. gallisepticum strains in an attempt to explain its intriguing persistence in commercial flocks. Eleven strains of M. gallisepticum were investigated for their biofilm formation, which varied considerably. Strains Nobilis MG 6/85, S(6) (P(5) and P(20)), D(9604), and SU(15) were strong biofilm producers. Strains R(low) (P(10) and P(100)), NCL, CG(5), YL(4), and F were weak biofilm producers. Strains Vaxsafe MG ts-11 and F(36) did not produce biofilm as verified using a crystal violet staining assay. In addition, highly differentiated biofilm structures of strain Nobilis MG 6/85 with characteristic stacks and channels were observed under confocal scanning laser microscopy and scanning electron microscopy. The carbohydrates (sucrose, glucose), disodium ethylenediaminetetraacetic acid (EDTA), antibiotics (tetracycline, gentamicin), or detergent (Triton X-100) were further used to determine their effects on biofilm formation. Biofilm formation was significantly inhibited by 5% sucrose and 5 mmol/L EDTA. Compared with the planktonic mycoplasma, these biofilm-grown cultures were more resistant to tetracycline, gentamicin, and Triton X-100 treatments. Furthermore, real-time reverse transcriptase-polymerase chain reaction was performed to investigate the transcription of several genes that may be associated with biofilm formation. The results indicated that the transcriptions of some genes in the biofilm-grown cells were markedly decreased, including vlhA3.03, csmC, hatA, gapA, neuraminidase, and mgc2. Our results will benefit further research on the persistence of M. gallisepticum infections. PMID- 22840543 TI - In this issue/abstract thinking: Inflaming findings: brain and body outcomes of early adversity. PMID- 22840544 TI - New developments in medical student education: opportunities for child and adolescent psychiatrists. PMID- 22840545 TI - Gender bias, female resilience, and the sex ratio in autism. PMID- 22840546 TI - Fixing a broken system: the story of autism, one state at a time. PMID- 22840547 TI - Longitudinal studies using a "natural experiment" design: the case of adoptees from Romanian institutions. AB - OBJECTIVE: To summarize the advantages and limitations of general population, high-risk and "natural experiment" longitudinal studies for studying psychological change. The English and Romanian Adoptees study is used as an example of a "natural experiment," and detailed findings are provided. METHOD: What is new is a focus on the young people who spent the whole of their life in institutional care up to the time of adoption and who did not show subnutrition. The results were compared with a composite comparison group who had not experienced institutional care or who were adopted before the age of 6 months. The outcomes were assessed in terms of previously established deprivation specific patterns (DSPs). RESULTS: "Pure" psychosocial deprivation was associated with a substantial increase in the rate of DSPs. It was not associated with significantly impaired head growth if institutional care lasted less than 6 months, whereas thereafter there was a 2.5 standard deviation reduction. Subnutrition differed in being accompanied by impaired head and body growth even with institutional care lasting less than 6 months. In the pure psychosocial deprivation group, 45.5% showed a DSP at 15 years compared with 1.3% in the comparison group. CONCLUSION: "Pure" psychosocial deprivation (in the absence of subnutrition) had a profound effect on psychological functioning in the form of DSPs. Subnutrition had a surprisingly small effect on DSPs. PMID- 22840548 TI - Impact of a private health insurance mandate on public sector autism service use in Pennsylvania. AB - OBJECTIVE: Many states have implemented regulations (commonly referred to as waivers) to increase access to publicly insured services for autism spectrum disorders (ASD). In recent years, several states have passed legislation requiring improved coverage for ASD services by private insurers. This study examines the impact of such legislation on use of Medicaid-funded ASD services. METHOD: We used Medicaid claims data from July 1, 2006, through June 30, 2010, to identify children with ASD and to assess their use of behavioral health services and psychotropic medications. Service and medication use were examined in four consecutive 12-month periods: the 2 years preceding passage of the legislation, the year after passage but before implementation, and the year after implementation. We examined differences in use of services and medications, and used growth rates from nonwaiver children to estimate the impact of the legislation on Medicaid spending for waiver-eligible children with ASD. RESULTS: The number of children with ASD receiving Medicaid services increased 20% from 2006-2007 to 2009-2010. The growth rate among children affected by the legislation was comparable to that of other groups before passage of the legislation but decreased after the legislation's passage. We project that, without the legislation, growth in this population would have been 46% greater in 2009-2010 than observed, associated with spending of more than $8 million in 2009 2010. CONCLUSIONS: Passage of legislation increasing private insurance coverage of ASD services may decrease the number of families seeking eligibility to obtain Medicaid-funded services, with an associated substantial decrease in Medicaid expenditures. PMID- 22840549 TI - Randomized trial of the Availability, Responsiveness, and Continuity (ARC) organizational intervention with community-based mental health programs and clinicians serving youth. AB - OBJECTIVE: Evidence-based Practice (EBP) implementation is likely to be most efficient and effective in organizations with positive social contexts (i.e., organizational culture, climate, and work attitudes of clinicians). The study objective was to test whether an organizational intervention labeled Availability, Responsiveness and Continuity (ARC) could improve the organizational social contexts of community-based mental health programs for youth. METHOD: The study randomly assigned 26 community-based mental health programs for youth to ARC or control conditions. The organizational cultures, climates, and work attitudes of clinicians (n = 197) in the programs were assessed with the Organizational Social Context (OSC) measure for mental health services at baseline and following the 18-month ARC intervention. RESULTS: Hierarchical linear models (HLM) analyses indicated that organizational culture, climate, and work attitudes were significantly improved in the ARC condition after 18 months. Clinicians in programs assigned to ARC reported less rigid, less centralized and less apathetic organizational cultures, more engaged and functional organizational climates with less role conflict, and work attitudes with improved morale, job satisfaction, and organizational commitment. CONCLUSIONS: ARC improved the organizational social contexts of clinicians in community-based mental health programs for youth. Results suggest that organizational intervention strategies can be used to create the types of organizational social contexts that are believed to be necessary for EBP implementation and other service innovations in mental health programs. PMID- 22840550 TI - How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? AB - OBJECTIVE: This study aimed to explore sex differences in autistic traits in relation to diagnosis, to elucidate factors that might differentially impact whether girls versus boys meet diagnostic criteria for autism or a related autism spectrum disorder (ASD). METHOD: Data from a large population-based sample of children were examined. Girls and boys (aged 10-12 years) meeting diagnostic criteria for an ASD were compared with those failing to meet diagnostic criteria despite very high scores on a trait measure of ASD, the Childhood Autism Spectrum Test (CAST). Information about behavioral difficulties as reported by teachers, and early estimates of intellectual functioning, were compared. RESULTS: Girls, but not boys, meeting diagnostic criteria for ASD showed significantly more additional problems (low intellectual level, behavioral difficulties) than peers with similarly high CAST scores who did not meet diagnostic criteria. CONCLUSIONS: These data suggest that, in the absence of additional intellectual or behavioral problems, girls are less likely than boys to meet diagnostic criteria for ASD at equivalently high levels of autistic-like traits. This might reflect gender bias in diagnosis or genuinely better adaptation/compensation in girls. PMID- 22840551 TI - Synchrony and specificity in the maternal and the paternal brain: relations to oxytocin and vasopressin. AB - OBJECTIVE: Research on the neurobiology of parenting has defined biobehavioral synchrony, the coordination of biological and behavioral responses between parent and child, as a central process underpinning mammalian bond formation. Bi parental rearing, typically observed in monogamous species, is similarly thought to draw on mechanisms of mother-father synchrony. METHOD: We examined synchrony in mothers' and fathers' brain response to ecologically valid infant cues. Thirty mothers and fathers, comprising 15 couples parenting 4- to 6-month-old infants, were visited at home, and infant play was videotaped. Parents then underwent functional magnetic resonance imaging scanning while observing own-infant compared with standard-infant videos. Coordination in brain response between mothers and fathers was assessed using a voxel-by-voxel algorithm, and gender specific activations were also tested. Plasma oxytocin and arginine vasopressin, neuropeptides implicated in female and male bonding, were examined as correlates. RESULTS: Online coordination in maternal and paternal brain activations emerged in social-cognitive networks implicated in empathy and social cognition. Mothers showed higher amygdala activations and correlations between amygdala response and oxytocin. Fathers showed greater activations in social-cognitive circuits, which correlated with vasopressin. CONCLUSIONS: Parents coordinate online activity in social-cognitive networks that support intuitive understanding of infant signals and planning of adequate caregiving, whereas motivational-limbic activations may be gender specific. Although preliminary, these findings demonstrate synchrony in the brain response of two individuals within an attachment relationship, and may suggest that human attachment develops within the matrix of biological attunement and brain-to-brain synchrony between attachment partners. PMID- 22840552 TI - Acute stress symptoms in children: results from an international data archive. AB - OBJECTIVE: To describe the prevalence of acute stress disorder (ASD) symptoms and to examine proposed DSM-5 symptom criteria in relation to concurrent functional impairment in children and adolescents. METHOD: From an international archive, datasets were identified that included assessment of acute traumatic stress reactions and concurrent impairment in children and adolescents 5 to 17 years of age. Data came from 15 studies conducted in the United States, United Kingdom, Australia, and Switzerland and included 1,645 children and adolescents. Dichotomized items were created to indicate the presence or absence of each of the 14 proposed ASD symptoms and functional impairment. The performance of a proposed diagnostic criterion (number of ASD symptoms required) was examined as a predictor of concurrent impairment. RESULTS: Each ASD symptom was endorsed by 14% to 51% of children and adolescents; 41% reported clinically relevant impairment. Children and adolescents reported from 0 to 13 symptoms (mean = 3.6). Individual ASD symptoms were associated with greater likelihood of functional impairment. The DSM-5 proposed eight-symptom requirement was met by 202 individuals (12.3%) and had low sensitivity (0.25) in predicting concurrent clinically relevant impairment. Requiring fewer symptoms (three to four) greatly improved sensitivity while maintaining moderate specificity. CONCLUSIONS: This group of symptoms appears to capture aspects of traumatic stress reactions that can create distress and interfere with children's and adolescents' ability to function in the acute post-trauma phase. Results provide a benchmark for comparison with adult samples; a smaller proportion of children and adolescents met the eight-symptom criterion than reported for adults. Symptom requirements for the ASD diagnosis may need to be lowered to optimally identify children and adolescents whose acute distress warrants clinical attention. PMID- 22840554 TI - Theory of mind and the brain in anorexia nervosa: relation to treatment outcome. AB - OBJECTIVE: Converging evidence suggests deficits in theory-of-mind (ToM) processing in patients with anorexia nervosa (AN). The present study aimed at elucidating the neural mechanisms underlying ToM-deficits in AN. METHOD: A total of 19 adolescent patients with AN and 21 age-matched controls were investigated using functional magnetic resonance imaging during performance of a ToM-task at two time points (in-patients: admission to hospital and discharge after weight recovery). Clinical outcomes in patients were determined 1 year after admission. RESULTS: Irrespective of the time point, AN patients showed reduced activation in middle and anterior temporal cortex and in the medial prefrontal cortex. Hypoactivation in the medial prefrontal cortex at admission to hospital (T1) was correlated with clinical outcome at follow-up. CONCLUSIONS: Hypoactivation in the brain network supporting theory of mind may be associated with a social-cognitive endophenotype reflecting impairments of social functioning in anorexia nervosa which is predictive for a poor outcome at 1-year follow-up. PMID- 22840553 TI - Abnormal amygdala and prefrontal cortex activation to facial expressions in pediatric bipolar disorder. AB - OBJECTIVE: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses. METHOD: A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces). RESULTS: There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group * Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group. CONCLUSIONS: These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD. PMID- 22840556 TI - Initial predictors associated with outcome in injured multiple traumatic limb amputations: a Kandahar-based combat hospital experience. AB - INTRODUCTION: Improvised explosive devices (IEDs) are the defining mechanism of injury during Operation Enduring Freedom. This is a retrospective analysis of initial management for IED blast injuries presenting with bilateral, traumatic, lower-extremity (LE) amputations with and without pelvic and perineal involvement. METHODS: A database of trauma admissions presenting to a North Atlantic Treaty Organization (NATO) Role 3 combat hospital in southern Afghanistan over a 7-month period was created to evaluate the care of this particular injury pattern. Patients were included if they were received from point of injury with at least bilateral traumatic LE amputations and had vital signs with initial resuscitation efforts. RESULTS: Thirty-two presented with double LE amputations (36%) and nine with triple amputations (10%). After excluding 10 patients who failed to meet the inclusion criteria, 22 patients were analysed. The mean age was 29 years, and the average ISS and admission haemoglobin were 22 and 11.3mgl(-1), respectively. Patients received an average of 54 units of blood products and underwent 1.6 operations with a mean operative time of 142.5min. The pattern of injury was associated with an increase in the total blood products required for resuscitation (pelvis n=12, p=0.028, gastrointestinal tract (GI) n=14, p=0.02, perineal n=15, p=0.036). There was no relationship between ISS or admission haemoglobin and the need for massive transfusion. Low Glasgow Coma Scale (GCS) was associated with increased 30-day mortality. Hollow viscus injury and operative hemipelvectomy were also associated with mortality. CONCLUSIONS: Early 30-day follow-up demonstrated that IED injuries with bilateral LE amputations with and without pelvic and perineal involvement are survivable injuries. Standard measures of injury and predictors of survival bore little relationship to observed outcomes and may need to be re evaluated. Long-term follow-up is needed to assess the extent of functional recovery and overall morbidity and mortality. PMID- 22840557 TI - Evaluating the tibial and femoral insertion site of the anterior cruciate ligament using an objective coordinate system: a cadaver study. AB - PURPOSE: The purpose of this study was to evaluate the tibial and femoral insertion site of the anterior cruciate ligament (ACL) using an objective coordinate system in a cadaver study in order to confirm radiological assumptions of previous investigators who identified the tibial footprint (T) of the ACL on T (5.3; 5.5) and the femoral footprint (F) on F (2.9; 3.5). METHODS: The tibial and femoral insertion site of the ACL was analysed on 30 human cadaver knee joints preserved according to the technique by Thiel. Thirty femora and tibiae were photographed under standardised methods and measured on a coordinate system twice by two examiners with respect to the ACL's footprint. We evaluated these measurements by use of the Cohen's kappa inter- and intraobserver coefficient for two observers. RESULTS: The photographs and tibial and femoral measurements were achieved with an almost perfect and a substantial agreement of inter- and intraobserver coefficients. Further, we could demonstrate that assumptions of anatomic points in previous radiological investigations were correct. CONCLUSIONS: Our findings confirmed the anatomic tibial and femoral ACL footprint of a previous investigation and further the reproducibility of our coordinate system as an objective method for graft placement evaluation. PMID- 22840559 TI - Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study. AB - Inflammatory mechanisms, like microglial activation, could be involved in the pathogenesis of Alzheimer's disease (AD). (R)-[(11)C]PK11195 (1-(2-chlorophenyl) N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide), a positron emission tomography (PET) ligand, can be used to quantify microglial activation in vivo. The purpose of this study was to assess whether increased (R)-[(11)C]PK11195 binding is present in AD and mild cognitive impairment (MCI), currently also known as "prodromal AD." METHODS: Nineteen patients with probable AD, 10 patients with prodromal AD (MCI), and 21 healthy control subjects were analyzed. Parametric images of binding potential (BP(ND)) of (R)-[(11)C]PK11195 scans were generated using receptor parametric mapping (RPM) with supervised cluster analysis. Differences between subject groups were tested using mixed model analysis, and associations between BP(ND) and cognition were evaluated using Pearson correlation coefficients. RESULTS: Voxel-wise statistical parametric mapping (SPM) analysis showed small clusters of significantly increased (R) [(11)C]PK11195 BP(ND) in occipital lobe in AD dementia patients compared with healthy control subjects. Regions of interest (ROI)-based analyses showed no differences, with large overlap between groups. There were no differences in (R) [(11)C]PK11195 BP(ND) between clinically stable prodromal AD patients and those who progressed to dementia, and BP(ND) did not correlate with cognitive function. CONCLUSION: Microglial activation is a subtle phenomenon occurring in AD. PMID- 22840558 TI - Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. AB - Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers. PMID- 22840560 TI - A non-invasive Cochlear Microphonic measurement system. AB - The Cochlear Microphonic is one of the electrical potentials generated by the ear in response to audible stimuli. It is very difficult to measure the CM non invasively because it has a very small magnitude (less than 1 MUV). A high Common Mode Rejection Ratio (CMRR) and very large bandwidth (5 Hz-20 kHz) biomedical amplifier system is presented to measure the signal. The system also uses a driven right leg circuit to increase the CMRR. PMID- 22840561 TI - Patients affected by metabolic syndrome show decreased levels of circulating platelet derived growth factor (PDGF)-BB. AB - BACKGROUND & AIMS: The development and/or progression of metabolic syndrome (MetS) in overweight and obese individuals have been associated to low-grade inflammation, but few studies have simultaneously analyzed the circulating levels of several cytokines. METHODS: In this pilot study, a group of 27 cytokines and growth factors was analyzed in the serum of obese patients (n=40) diagnosed for MetS in comparison with sex- and age-matched control subjects without MetS (n=53) by using a multiplex immunoassay. Release of cytokines was measured in culture supernatants of human primary endothelial cells, THP-1 macrophagic cells and HuH 7 hepatoma cells upon exposure to a high fat mixture. RESULTS: While the majority of cytokines did not show significant differences between the investigated groups, the circulating levels of CXCL10/IP-10 and IL-6 were higher in the MetS group versus overweight control group. In contrast, PDGF-BB serum levels were significantly decreased in MetS patients. The in vitro addition of a high fat mixture increased the release of IL-6 and/or CXCL10/IP-10 in the culture supernatant of human primary endothelial cells and THP-1 macrophagic cells, while the same mixture significantly decreased the release of PDGF-BB by human THP-1 macrophagic and HuH-7 hepatoma cells. CONCLUSIONS: The current demonstration that MetS is associated with decrease of the pro-fibrotic PDGF cytokine is a completely novel finding, which adds complexity to the interplay between inflammation and fibrosis in patients affected by MetS. PMID- 22840562 TI - Third-generation cephalosporin-resistant Vibrio cholerae, India. AB - Vibrio cholerae resistance to third-generation cephalosporins is rarely reported. We detected a strain that was negative for extended-spectrum beta-lactamase and positive for the AmpC disk test, modified Hodge test, and EDTA disk synergy test and harbored the blaDHA-1 and blaNDM-1 genes. The antimicrobial drug susceptibility profile of V. cholerae should be monitored. PMID- 22840563 TI - Treatment of panic in chest pain patients from emergency departments: efficacy of different interventions focusing on panic management. AB - OBJECTIVE: The aim was to assess the efficacy of two brief cognitive-behavioral therapy (CBT)-based interventions (7*1-h sessions and 1*2-h session) and a pharmacological treatment (paroxetine), compared to supportive usual care, initiated in the emergency department (ED) for individuals suffering from panic disorder (PD) with a chief complain of noncardiac chest pain (NCCP). We hypothesized that the interventions would be more efficacious than supportive usual care on all outcomes. METHOD: A 12-month follow-up study of patients who received a diagnosis of NCCP in the ED and who met diagnostic criteria for PD (n=71) was performed. Assessments included several psychological questionnaires and a structured interview. A series of repeated-measures analyses of variances, using a split-plot design, were conducted, as well as planned comparisons to examine the differences. RESULTS: The seven-session CBT (n=19), one-session panic management (n=24) and pharmacotherapy (n=13) led to greater improvements in PD severity (primary outcome) compared to supportive usual care (n=15) at posttest, and no significant difference was noted between the three active interventions. On the other measures, patients improved in all conditions, and the therapeutic gains were maintained up to 1 year following the visit to the ED. CONCLUSIONS: These results suggests that early intervention, in particular seven sessions of CBT, one session of PM or pharmacotherapy (generic paroxetine), should be considered for the treatment of PD patients consulting the ED with a discharge diagnosis of NCCP. PMID- 22840564 TI - The effects of memantine on a patient having preclinical dementia with Lewy bodies. AB - OBJECTIVE: Memantine has been reported to have positive effects on visual hallucinations and cognition in patients with dementia with Lewy bodies (DLB). We hypothesized that memantine would have similar effects on a patient having Charles Bonnet syndrome, preclinical DLB. METHOD: We evaluated the effect of memantine on visual hallucination, cognitive abilities and so on from baseline to 4 months after the start of medication. RESULTS: Treatment of the patient with memantine resulted in the disappearance of visual hallucinations but could not stop the progression to dementia. CONCLUSIONS: Our results suggested that, for a patient having preclinical DLB, memantine had some degree of positive effects, but the mechanism remains to be revealed. PMID- 22840565 TI - [Induced membrane technique in oral & maxillofacial reconstruction]. AB - Maxillofacial defects reconstruction represents a formidable challenge to achieve both functional and aesthetic goals. To succeed, numerous parameters must be taken into account: patient's general conditions, defect's location, width and type of the defect and eventual donor sites which can provide the tissues. Routine reconstructions include bone transplantation (autologous, homologous or heterologous), implantation of biomaterials and osteogenic distraction. The advantages of these techniques are evident, but they are usually limited by their complexity in patients with bad general health. The technique of induced membranes needs to be more known in maxillofacial surgery. PMID- 22840567 TI - The Global Rating Scale in clinical practice: a comprehensive quality assurance programme for endoscopy departments. AB - BACKGROUND: The Global Rating Scale is an endoscopy quality assurance programme, successfully implemented in England. It remains uncertain whether it is applicable in another health care setting. AIM: To assess the applicability of the Global Rating Scale as benchmark tool in an international context. METHODS: Eleven Dutch endoscopy departments were included for a Global Rating Scale census, performed as a cross-sectional evaluation, July 2010. Two Global Rating Scale-dimensions - 'clinical quality' and 'patient experience' - were assessed across six items using a range of levels: from level-D (basic) to level-A (excellent). Construct validity was assessed by comparing department-specific colonoscopy audit data to GRS-levels. RESULTS: For 'clinical quality', variable scores were achieved in items 'safety' (9%=B, 27%=C, 64%=D) and 'communication' (46%=A, 18%=C, 36%=D). All departments achieved a basic score in 'quality' (100%=D). For 'patient experience', variable scores were achieved in 'timeliness' (18%=A, 9%=B, 73%=D) and 'booking-choice' (36%=B, 46%=C, 18%=D). All departments achieved basic scores in 'equality' (100%=D). Departments obtaining level-C or above in 'information', 'comfort', 'communication', 'timeliness' and 'aftercare', achieved significantly better audit outcomes compared to those obtaining level-D (p<0.05). CONCLUSION: The Global Rating Scale is appropriate to use outside England. There was significant variance across departments in dimensions. Most Global Rating Scale-levels were in line with departments' audit outcomes, indicating construct validity. PMID- 22840568 TI - Chronic opioid therapy and its utility in different populations. PMID- 22840571 TI - Association between co-morbidities and labour force participation amongst persons with back problems. AB - There are few studies that have looked at the occurrence of co-morbid conditions amongst patients with back problems. This study assesses the association between of a range of co-morbidities and the labour force participation rates of 45- to 64-year-old Australians with back problems. Logistic regression models were applied to the 2003 Survey of Disability, Ageing and Carers (SDAC) data to look at the relationship between chronic back problems, labour force participation and comorbidities. For some conditions, there is a significant increase in the chance of an individual being out of the labour force, relative to those with back problems alone. For example, an individual with back problems and heart disease is more than 10 times more likely to be out of the labour force than those with back problems alone (OR=10.90, 95% CI=2.91-40.79, P=.0004). Amongst conditions that have a significant impact on labour force participation rates, back problems and multiple co-morbidities are significantly more likely to cause persons with these conditions to be out of the labour force than those with back problems alone or those with no chronic health condition. It is important to consider which co-morbidities an individual has when assessing the impact of back problems on labour force participation, as co-morbid conditions vary in their association with labour force participation. PMID- 22840572 TI - First hominine remains from a ~1.0 million year old bone bed at Cornelia-Uitzoek, Free State Province, South Africa. AB - We report here on evidence of early Homo around 1.0 Ma (millions of years ago) in the central plains of southern Africa. The human material, a first upper molar, was discovered during the systematic excavation of a densely-packed bone bed in the basal part of the sedimentary sequence at the Cornelia-Uitzoek fossil vertebrate locality. We dated this sequence by palaeomagnetism and correlated the bone bed to the Jaramillo subchron, between 1.07 and 0.99 Ma. This makes the specimen the oldest southern African hominine remains outside the dolomitic karst landscapes of northern South Africa. Cornelia-Uitzoek is the type locality of the Cornelian Land Mammal Age. The fauna contains an archaic component, reflecting previous biogeographic links with East Africa, and a derived component, suggesting incipient southern endemism. The bone bed is considered to be the result of the bone collecting behaviour of a large predator, possibly spotted hyaenas. Acheulian artefacts are found in small numbers within the bone bed among the fossil vertebrates, reflecting the penecontemporaneous presence of people in the immediate vicinity of the occurrence. The hominine tooth was recovered from the central, deeper part of the bone bed. In size, it clusters with southern African early Homo and it is also morphologically similar. We propose that the early Homo specimen forms part of an archaic component in the fauna, in parallel with the other archaic faunal elements at Uitzoek. This supports an emergent pattern of archaic survivors in the southern landscape at this time, but also demonstrates the presence of early Homo in the central plains of southern Africa, beyond the dolomitic karst areas. PMID- 22840570 TI - Predictors of postoperative movement and resting pain following total knee replacement. AB - This study determined preoperative predictors of movement and resting pain following total knee replacement (TKR). We hypothesized that younger patients with higher preoperative pain intensity, pain sensitivity, trait anxiety, pain catastrophizing, and depression would be more likely to experience higher postoperative movement pain than older patients with lower scores on these variables prior to surgery, and that predictors would be similar for resting pain. Demographics, analgesic intake, anxiety, depression, pain catastrophizing, resting pain, movement pain (ie, during active knee range of motion), and quantitative sensory tests were performed preoperatively on 215 participants scheduled for a unilateral TKR. On postoperative day 2, analgesic intake, resting pain, and movement pain were again assessed. Significant predictors of moderate or severe movement pain were higher preoperative movement pain, von Frey pain intensity, and heat pain threshold. People with severe movement pain preoperatively were 20 times more likely to have severe movement pain postoperatively. When the influence of preoperative movement pain was removed, depression became a predictor. Significant predictors of moderate to severe resting pain were higher preoperative resting pain, depression, and younger age. These results suggest that patients with higher preoperative pain and depression are more likely to have higher pain following TKR, and younger patients may have higher resting pain. Cutaneous pain sensitivity predicted movement pain but not resting pain, suggesting that mechanisms underlying movement pain are different from resting pain. Aggressive management of preoperative pain, pain sensitivity, and depression prior to surgery may facilitate postoperative recovery. PMID- 22840573 TI - Rickettsia felis in fleas, southern Ethiopia, 2010. PMID- 22840574 TI - Outline of the report on cardiovascular disease in China, 2010. AB - Major and profound changes have taken place in China over the past 30 years. Rapid socioeconomic progress has exerted a great impact on lifestyle, ranging from food, clothing, working and living conditions, and means of transportation to leisure activities and entertainment. At the same time, new health problems have emerged, and health services are facing new challenges. Presently, cardiovascular diseases (CVD) are among the top health problems of the Chinese people, and pose a serious challenge to all engaged in the prevention and control of these diseases. An epidemic of CVD in China is emerging as a result of lifestyle changes, urbanization and longevity. Both national policy decision making and medical practice urgently need an authoritative report which comprehensively reflects the trends in the epidemic of CVD and current preventive measures. Since 2005, guided by the Bureau of Disease Prevention of the Ministry of Health of the People's Republic of China and the National Center for Cardiovascular Diseases of China, nationwide experts in the fields of epidemiology, clinical medicine and health economics in the realms of CVD, cerebrovascular disease, diabetes and chronic kidney disease, completed the Report on Cardiovascular Diseases in China every year. The report aims to provide a timely review of the trend of the epidemic and to assess the progress of prevention and control of CVD. In addition, as the report is authoritative, representative and readable, it will become an information platform in the CVD field and an important reference book for government, academic institutes, medical organizations and clinical physicians. This publication is expected to play a positive role in the prevention and control of CVD in China. We present an abstract from the Report on Cardiovascular Diseases in China (2010), including trends in CVD, morbidity and mortality of major CVDs, up-to-date assessment of risk factors, as well as health resources for CVD, and a profile of medical expenditure, with the aim of providing evidence for decision-making in CVD prevention and control programs in China, and of delivering the most authoritative information on CVD prevention and control for all citizens. PMID- 22840576 TI - A survey of 16 rare Earth elements in the major foods in China. AB - OBJECTIVE: The aim of this survey was to investigate the level of contamination of the most consumed foods in China with 16 rare earth elements (REEs), and to provide the basic data for establishing and revising food safety standards for REEs. METHODS: Sixteen REEs in foods were measured by inductively coupled plasma mass spectrometry (ICP-MS) in the labs of the Centers for Disease Control and Prevention of four provinces and two municipalities, during 2009-2010. RESULTS: 1 231 samples were analyzed and 19 121 concentration data of 16 REEs were collected. The REEs levels in the investigated foods varied significantly. The concentrations of cerium (Ce), dysprosium (Dy), yttrium (Y), lanthanum (La), and neodymium (Nd) were relatively high, while the remaining eleven REEs were at low levels. The mean values of total rare earth element oxides (REOs) in cereals, fresh vegetables, fresh aquatic products, fresh meats and eggs varied from 0.052 mg/kg to 0.337 mg/kg. CONCLUSION: 16 REEs in the major foods were at very low contamination levels in the investigated regions. PMID- 22840575 TI - High sensitivity C-reactive protein associated with different health predictors in middle-aged and oldest old Chinese. AB - OBJECTIVE: To describe the distribution of plasma high sensitivity C-reactive protein (hsCRP) and explore the relationship between hsCRP and metabolic risk factors among residents living in longevity areas of China. METHODS: 268 individuals aged between 40 and 59 years and 506 individuals aged over 90 years were selected from 5 longevity areas of China to participate in a cross section longitudinal cohort study. The participants were interviewed with general health related questionnaire to collect their demographic, behavioral and lifestyle data, as well as their chronic conditions, and meanwhile their physical and biomedical parameters including waist circumference (WC), blood pressure (BP), hsCRP, plasma lipids, and fasting blood glucose (FBG) were measured. RESULTS: The median of hsCRP was 0.99 mg/L in the middle-aged group and 1.76 mg/L in the oldest old group. No significant gender difference was observed between the above two groups. Among the oldest old individuals, 36.56% had an hsCRP level >3.0 mg/L. The prevalence of high hsCRP was 16.79% in the middle-aged group. The results of stepwise multiple linear regression analyses showed that HDL-C was independently associated with ln (hsCRP) concentration in the middle-aged group, whereas ln (TG), HDL-C and FBG were correlated after adjustment for gender, study site, smoking, drinking, education and BMI in the oldest old group. CONCLUSION: HDL-C is a stronger predictor of elevated hsCRP than other metabolic factors in the middle-aged population. For the oldest old persons, high TG, low HDL-C, and FBG predict elevated plasma hsCRP. PMID- 22840577 TI - Chemotherapy-based control of ascariasis and hookworm in highly endemic areas of China: field observations and a modeling analysis. AB - OBJECTIVE: Our objective was to systematically evaluate chemotherapy-based control of ascariasis and hookworm infection and make predictions of the effectiveness of repeated mass treatment at different levels of coverage in highly endemic areas of China. METHODS: Field surveys were carried out to acquire the ascariasis and hookworm prevalence and intensity (mean worm burden) at baseline, one month and one year later. We calculated model parameters based on the survey data, then incorporated them into a quantitative framework to predict the prevalence and intensity one year later. Sensitivity analyses were performed to assess the influence of the chemotherapy measures on prevalence and intensity, and model simulations were performed to evaluate the feasibility of achieving the proposed transmission control criteria under different chemotherapy measures. RESULTS: The predicted prevalence and intensity one year from baseline were within the 95% confidence interval of actual values. As treatment frequency or coverage increased, the prevalence and intensity decreased. Model simulations show that many rounds of treatment are needed to maintain the prevalence at a low level in highly endemic areas of China. CONCLUSION: We should select different combinations of treatment frequency, coverage and drug efficacy according to available resources and practical attainable conditions. Mathematical modeling could be used to help optimize the chemotherapeutic scheme aiming at specific parasitic species and areas, and to direct the establishment of soil-transmitted helminthiasis control criteria in China. PMID- 22840578 TI - Comparison of lipopolysaccharide and protein immunogens from pathogenic Yersinia enterocolitica bio-serotype 1B/O:8 and 2/O:9 using SDS-PAGE. AB - OBJECTIVE: Yersinia enterocolitica is an extracellular pathogen and its related antigens interact with the host immune system. We investigated the difference in immunological characteristics between a highly pathogenic and poorly pathogenic strain of Y. enterocolitica. METHODS: We used SDS-PAGE and western blotting to characterize lipopolysaccharide (LPS), Yersinia outer membrane proteins (Yops), membrane proteins, and whole-cell proteins from poorly pathogenic Y. enterocolitica bio-serotype 2/O:9, isolated from China, and highly pathogenic bio serotype 1B/O:8, isolated from Japan. RESULTS: These two strains of Y. enterocolitica had different LPS immune response patterns. Comparison of their Yops also showed differences that could have accounted for their differences in pathogenicity. The membrane and whole-cell proteins of both strains were similar; immunoblottting showed that the 35 kD and perhaps the 10 kD proteins were immunogens in both strains. CONCLUSION: The major antigens of the two strains eliciting the host immune response were the LPS and membrane proteins, as shown by comparing protein samples with reference and purified preparations. PMID- 22840580 TI - Epidemiological characteristics of Japanese encephalitis in Guizhou Province, China, 1971-2009. AB - OBJECTIVE: The aim of the study was to establish the contemporary epidemiological characteristics of Japanese encephalitis (JE) in Guizhou Province. METHODS: A retrospective study of National Notifiable Disease Reporting System (NNDRS) data from 1971 through 2009, was conducted to ascertain the geographical, seasonal, and age distributions of JE incidence in Guizhou Province, China. RESULTS: A total of 68 425 JE cases were reported in Guizhou from 1971-2009. The JE cases occurred sporadically in all 9 prefectures of Guizhou, mostly among residents of rural areas. Seasonal distribution of JE remained consistent over the period from 1971-2009 with the main transmission season starting from June to September and peaking in August. JE occurred mainly in children under the age of 15 years with peak incidence in the 0-6-year age group. Pearson's correlation analysis showed that JE vaccine distribution had a negative correlation with JE incidence rates during 1971-2009 (coefficient of correlation=-0.475, P<0.01). CONCLUSION: Over the period of 1971-2009, the JE incidence rate had declined dramatically in terms of geographical and age distributions due to JE vaccination to children at risk. PMID- 22840579 TI - Influence of polluted SY River on child growth and sex hormones. AB - OBJECTIVE: To investigate the influence of the polluted SY River on children's growth and sex hormones, and provide scientific data for assessment of the polluted status of the SY River. METHODS: The study areas were selected randomly from the SY River Basin. Lead (Pb), mercury (Hg), arsenic (As), phthalates (DEP, DBP, DMP, DEHP), and bisphenol A (BPA) were measured both in the river water and in the drinking water. School children were selected by cluster sampling (n=154). Physical development indexes (height, weight, bust-circumference, and skinfold thickness) and sex hormones [testosterone (T) and estradiol (E2)] were measured for all the children. RESULTS: The contents of Pb and Hg exceeded Class V standards of surface water quality in each section of the river and other indicators exceeded Class III. Compared to the control area, the concentrations of Pb, Hg, As, BPA, DEP, and DBP in the drinking water were significantly higher than in the polluted area (P<0.05). Children from the control area had significantly lower E2 and T than children from the polluted area (P<0.05). Among anthropometric results, only skinfold thickness had statistically significant difference between the two groups (P<0.05), while the other indexes showed no significant differences between the two groups (P>0.05). CONCLUSION: The drinking water has been polluted by the SY River and affected serum sex hormone levels of children living in the polluted area. PMID- 22840581 TI - Relationship between dyslipidemia and gene polymorphism in Tibetan population. AB - OBJECTIVE: To investigate the relationship between SNPs reported in previous studies and the blood lipid level in the Tibetan population. METHODS: Random cluster sampling was employed in 5 areas (Lhasa, Shigatse, Shannan, Nagqu, and Nyingchi). The levels of cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from blood samples were determined and DNA was extracted for genotyping and statistical analyses. RESULTS: Among 1 318 subjects aged >18 years enrolled in this study, 367 had dyslipidemia with a prevalence of 27.8%, of whom dyslipidemia males accounted for 33.1% and dyslipidemia females -24.5%. Results of the correlation analysis between all SNPs and TG showed that the SNPs of rs714052 and rs964184 were related to the serum TG level. Subjects with rs714052 CC genotype had the lowest TG level, and the highest TG level was found in those with rs714052 TT genotype. The serum TG level in individuals with TC genotype lied in between the above two population groups. Subjects with rs964184 CC genotype had the lowest TG level, and the highest serum TG level was noted in those with rs964184 GG genotype. CONCLUSION: Several SNPs were found to be related to the serum TG level in the Tibetan population. The APOA5 gene and MLXIPL gene may be closely associated with the serum TG level in this ethnic population group. PMID- 22840582 TI - Hyperglycemic effects of a periocular dexamethasone injection in diabetic patients after vitreoretinal surgery. AB - OBJECTIVE: To examine the hyperglycemic effects of periocular dexamethasone injection in type 2 diabetic patients after vitreoretinal surgery (VRS). METHODS: This was a retrospective non-randomized controlled trial. Twenty consecutive hospitalized patients with type 2 diabetes and ocular inflammatory reaction after VRS were enrolled in this study. Ten patients received 2.5 mg dexamethasone and 10 patients received 5 mg dexamethasone. Fourteen consecutive type 2 diabetic patients without ocular inflammatory reaction after VRS were used as control group. We measured fasting blood glucose (FBG) and at 2 h after each meal (post prandial glucose, PBG; 09:00, 13:00, and 19:00 h) after periocular dexamethasone injection. Differences among three groups were determined by q tests. RESULTS: The PBG levels in both dexamethasone-treated groups started to increase within 5 h after injection (i.e., PBG at 13:00 h), and were significantly increased at 19:00 h after injection (P<0.05). BG levels were almost 2-fold higher than at baseline and compared with the control group. The BG values declined gradually by 24 h to 48 h after injection. There were no differences in BG levels between the two dexamethasone-treated groups (P>0.05), except for PBG at 19:00 h on day 2 after injection (P<0.05). CONCLUSION: Periocular dexamethasone injection can cause transient hyperglycemia in diabetic patients after VRS. BG monitoring should be performed following such injection. PMID- 22840583 TI - Effects of short-term forest bathing on human health in a broad-leaved evergreen forest in Zhejiang Province, China. AB - OBJECTIVE: To investigate the effects of short-term forest bathing on human health. METHODS: Twenty healthy male university students participated as subjects and were randomly divided into two groups of 10. One group was sent on a two night trip to a broad-leaved evergreen forest, and the other was sent to a city area. Serum cytokine levels reflecting inflammatory and stress response, indicators reflecting oxidative stress, the distribution of leukocyte subsets, and plasma endothelin-1 (ET-1) concentrations were measured before and after the experiment to evaluate the positive health effects of forest environments. A profile of mood states (POMS) evaluation was used to assess changes in mood states. RESULTS: No significant differences in the baseline values of the indicators were observed between the two groups before the experiment. Subjects exposed to the forest environment showed reduced oxidative stress and pro inflammatory level, as evidenced by decreased malondialdehyde, interleukin-6, and tumor necrosis factor a levels compared with the urban group. Serum cortisol levels were also lower than in the urban group. Notably, the concentration of plasma ET-1 was much lower in subjects exposed to the forest environment. The POMS evaluation showed that after exposure to the forest environment, subjects had lower scores in the negative subscales, and the score for vigor was increased. CONCLUSION: Forest bathing is beneficial to human health, perhaps through preventive effects related to several pathological factors. PMID- 22840584 TI - Television news coverage of obesity in China, 1982-2009. AB - OBJECTIVE: The purpose of this study was to explore how obesity was covered in television news in China, including the trends over time and the characteristics of obesity-related news. METHODS: The frame analysis was adopted to assess the content of obesity-related news broadcasted in China Central Television (CCTV) from 1982 to 2009. To investigate the characteristics of the news, the obesity related news was divided into subgroups according to populations concerned, as well as the period in which the news was broadcasted. The differences between subgroups were examined. RESULTS: A total of 1 599 pieces of news reported obesity, in which 1 278 pieces (79.92%) aired in "wealthy" period (2006-2009). More news was concerned with adults (1 134, 70.92%). "Individual behavior" dominated most of the cause frames (389, 24.33%), solution frames (522, 32.65%), and responsibility frames (860, 53.78%). There was more news mentioning individual factors in news aired in "wealthy" period and news concerning children. The coverage of social-structure causes was higher in news concerning children, while the coverage of social-structure solutions was higher in news concerning children and news aired in "wealthy" period. CONCLUSION: Although the coverage of obesity was modest, it showed an incremental trend as the economy grew. Obesity was mostly depicted as an individual problem in terms of responsibility, causes and solutions. PMID- 22840585 TI - In vitro refolding process of bovine allergen beta-lactoglobulin by Multispectroscopic method. AB - OBJECTIVE: To characterize the relationship between the refolding process of recombinant bovine beta-lactoglobulin and its immunoreactivity for clinical purposes. To establish a spectral method which examine the extent of recombinant allergen renaturation. METHODS: The refolding process of recombinant bovine beta lactoglobulin was investigated by using circular dichroism, fluorescence and synchronous fluorescence spectra. IgE-binding capacity of recombinant protein was analyzed by ELISA. In addition, bioinformatic methods were used to explain the spectral characteristics and analyze the relationship between the conformational changes and the immunoreactivity of the protein during renaturation in vitro. RESULTS: Renaturation of recombinant bovine beta-lactoglobulin resulted in a more compact structure resembling the natural counterpart with stronger IgE-binding capacity. CONCLUSION: The degree of protein renaturation correlated with the IgE binding capacity of the protein. Results from this study may be of help for food allergy therapy and development of vaccination in the future. PMID- 22840586 TI - Dimethoate induced oxidative damage and histopathological changes in lung of adult rats: modulatory effects of selenium and/or vitamin E. AB - OBJECTIVE: To determine the efficiency of selenium and/or vitamin E to alleviate lung oxidative damage induced by dimethoate, an organophosphorus compound. METHODS: Adult Wistar rats were exposed during 30 days either to dimethoate (0.2 g/L of drinking water), dimethoate+selenium (0.5 mg/kg of diet), dimethoate+vitamin E (100 mg/kg of diet), or dimethoate+selenium+vitamin E. RESULTS: Exposure to dimethoate caused oxidative stress in lung evidenced by an increase of malondialdehyde, protein carbonyl groups and advanced oxidation protein products. An increase in glutathione peroxidase, superoxide dismutase, catalase and a decrease in acetylcholinesterase and butyrylcholinesterase activities, glutathione, non-protein thiols and vitamins C levels were observed. Histopathological changes in lung tissue were noted as emphysema, hemorrhages and hemosiderin deposits. Co-administration of selenium or vitamin E to the diet of dimethoate treated rats ameliorated the biochemical parameters as well as histological impairments. The joint effect of these elements was more powerful in antagonizing dimethoate-induced lung oxidative damage. CONCLUSION: We concluded that selenium and vitamin E ameliorated the toxic effects of this pesticide in lung tissue suggesting their role as potential antioxidants. PMID- 22840587 TI - Echinococcus granulosus 14-3-3 protein: a potential vaccine candidate against challenge with Echinococcus granulosus in mice. AB - OBJECTIVE: To investigate the protective immunity against Echinococcus granulosus in mice immunized with rEg14-3-3. METHODS: ICR mice were subcutaneously immunized three times with rEg14-3-3, followed by the challenge with Echinococcus granulosus protoscoleces intraperitoneally and then sacrificed after six months of post-challenge to detect the proliferation of splenocytes by MTT assay, and to measure the secretion of IL-2, IL-4, IL-10, and IFN-gamma by ELISA. The rate of reduced hydatid cyst and the levels of IgE, IgG and IgG subclasses in sera were examined. RESULTS: Mice vaccinated with rEg14-3-3 and challenged with protoscoleces revealed significant protective immunity of 84.47%. ELISA analysis indicated that the immunized mice generated specific high levels of IgG and the prevailing isotypes of IgG were IgG1 and IgG2a. Splenocytes from mice immunized with rEg14-3-3 showed a significant proliferation response. The secretion of IFN gamma and IL-2 increased significantly in the vaccinated mice whereas there was no significant difference in IL-4 and IL-10 levels between vaccinated and control mice. CONCLUSION: The results indicate that the rEg14-3-3 vaccine could induce a high level of protective immunity as a promising vaccine candidate to prevent cystic echinococcosis. PMID- 22840588 TI - Prediction of ocular irritancy of 26 chemicals and 26 cosmetic products with isolated rabbit eye (IRE) test. AB - OBJECTIVE: This study aims to establish and evaluate the methodology of isolated rabbit eye (IRE) test. METHODS: IRE test was performed according to modifications of the in vitro toxicology (INVITTOX) Protocol No.85: Rabbit enucleated eye test by European Centre for the Validation of Alternative Methods (ECVAM), and then 26 chemicals and 26 cosmetic products were tested in both in vitro IRE and in vivo Draize tests. A statistical analysis was conducted to determine the relevance of the IRE test to the data generated in the Draize test. RESULTS: IRE test was established successfully in our laboratory. It was shown that ranking correlation and class concordance were fairly well between the IRE test and the Draize test for 26 reference chemicals (Fisher's Exact Test chi(2)=51.314, P<0.001; McNemar P=0.261; Gamma=0.960, P<0.001; Kappa=0.843, P<0.001) and 26 cosmetic products (Fisher's Exact Test chi(2)=15.522, P<0.001; McNemar P=0.311; Gamma=0.967, P<0.001; Kappa=0.611, P<0.001). CONCLUSION: IRE test was established successfully for in vitro testing of eye irritation as an alternative to Draize test. PMID- 22840589 TI - Rapid detection of Haemophilus influenzae and Haemophilus parainfluenzae in nasopharyngeal swabs by multiplex PCR. AB - OBJECTIVE: To establish multiplex PCR-based assays for detecting H.influenzae and H.parainfluenzae. And the PCR-based assays were applied to detect the carriage rates of H.influenzae and H.parainfluenzae in nasopharyngeal swab specimens which were collected from healthy children. METHODS: Multiplex primers for species specific PCR were designed by using DNAstar soft based on the sequences of 16S rRNA genes from genus Haemophilus to detect H.influenzae and H.parainfluenzae. RESULTS: The sensitivity of the 16S rRNA PCR assay for detecting H.influenzae and H.parainfluenzae was 97.53% and 100% respectively, and the specificity was 95.89% and 96.63% respectively. Youden's Index on the ability to detect H.influenzae and H.parainfluenzae was 0.9342 and 0.9663 respectively. 666 nasopharyngeal swab specimens were collected from healthy children. The detection rates of H.influenzae and H.parainfluenzae were 14.11% and 16.07% respectively by using isolation and culture methods. The detection rates of H.influenzae and H.parainfluenzae were 43.54% and 57.96% respectively by 16S rRNA PCR assays. The carriage rates of serotypes a, b, c, d, e, f and non-typeable isolates were 0% (0/666), 0.15% (1/666), 1.20% (8/666), 0.15% (1/666), 1.20% (8/666), 1.80% (12/666), 95.50% (636/666) respectively. CONCLUSION: The multiplex PCR assays were very rapid, reliable and feasible methods for detection of H.influenzae and H.parainfluenzae in pharyngeal swab specimens which were compared to conventional isolation and culture methods. 95.5% of H.influenzae strains in healthy children were nontypeable. The encapsulated or typable strains were mainly three serotypes which was c, e, and f serotype. PMID- 22840590 TI - Evaluation of cytokines and hormones in dogs before and after treatment of diabetic ketoacidosis and in uncomplicated diabetes mellitus. AB - In human beings, diabetes mellitus (DM) and diabetic ketoacidosis (DKA) are recognized as proinflammatory states and dysregulation of cytokines has been linked to some potentially fatal complications. Cytokine profiles of dogs with DM or DKA have not been reported. The objectives of this study were to compare cytokine and hormone concentrations in dogs with DKA before and after resolution of ketoacidosis, to compare these concentrations before treatment of DKA to those measured in dogs with uncomplicated DM and healthy dogs, and to compare concentrations in dogs with uncomplicated DM to those measured in healthy dogs. 27 dogs were included in this prospective clinical study. 18 dogs had naturally occurring disease (9 DKA and 9 DM) and 9 dogs were healthy. Serum GMCSF, IL-2, IL 4, IL-6, IL-7, CXCL8, IL-10, IL-15, IL-18, IFNgamma, IP-10, TNFalpha, Monocyte Chemoattractant Protein-1 (MCP-1), Keratinocyte Chemoattractant (KC), glucagon, leptin, adiponectin, and resistin were assayed using Milliplex MAP Canine kits.(2)(,)(3) IL-18, resistin, and GMCSF concentrations were significantly higher in dogs with DKA before treatment compared to after resolution of ketoacidosis. CXCL8, MCP-1, KC, and resistin were significantly higher in DKA dogs compared to healthy controls, and KC was also significantly higher in DKA compared to DM dogs. Additionally, CXCL8 and MCP-1 were significantly higher in dogs with DM compared to healthy controls. Significant differences were not detected in concentrations of the other measured analytes, including glucagon. It is concluded that IL-18, resistin, GMCSF, and KC may be involved in the pathogenesis of canine DKA, and their importance in this pathogenesis may be as great as that of glucagon. Dysregulation of CXCL8 and MCP-1 may be involved in the pathogenesis of DM in dogs. PMID- 22840591 TI - Cytokine profiles in various graft-versus-host disease target organs following hematopoietic stem cell transplantation. AB - Previous studies using genetic-deficient murine models suggest that different T helper subsets may contribute to different types of tissue damages in graft versus-host disease (GvHD). However, there is limited information available on the distribution of T-helper cytokines in the various GvHD target tissues. In the current study, an acute GvHD murine model was set up to directly assess the in situ cytokine profiles in various GvHD tissue lesions; in addition, we also studied GvHD tissues from patients who had undergone bone marrow transplantation procedures. We observed that interferon-gamma (IFN-gamma was dominant in murine liver and gastrointestinal tissue lesions, whereas IFN-gamma and interleukin 17 (IL-17) were abundant in murine skin lesions. Furthermore, in human GvHD tissues, interleukin 4 (IL-4) and IFN-gamma were predominant in liver lesions and colon lesions, respectively, while no specific cytokine was prevalent in human GvHD skin lesions. In addition, a low ratio of CD4(+) T helper (Th) versus CD8(+) T cytotoxic (Tc) cells in human GvHD tissue lesions, especially in the liver, was detected, and this contrasts with the situation in murine GvHD tissues where CD4(+) Th cells were predominant. Dual staining for CD markers and cytokine expression showed that IFN-gamma-secreting T cells were enriched in all murine GvHD target tissue lesions, and Tc1 and Tc2 cells were predominant in human GvHD colon and liver sections, respectively. However, IFN-gamma(+) Th1, IL-17(+) Th17, IFN-gamma(+) Tc1, and IL-17(+) Tc17 cells were slightly more frequent in human skin lesions compared to IL-4(+) Th2 and IL-4(+) Tc2 cells. To sum up, these results suggest that differences in cytokine imbalances may significantly contribute to tissue-specific pathogenesis in GvHD target organs, and CD8(+) Tc cells may play an important role in human GvHD induction. PMID- 22840592 TI - [Effects of surface electrical stimulation in older women with stress urinary incontinence: a randomized controlled pilot study]. AB - OBJECTIVE: The objective of this study was to evaluate the effects of surface electrical stimulation in elderly women with stress urinary incontinence (SUI) as compared to no treatment. MATERIALS AND METHODS: This randomized controlled pilot study included women over the age of 60 years, with at least one episode of stress urinary leakage during the previous month. Fourteen women were allocated according to a computer generated randomization list in two groups: surface electrical stimulation (SES), and control group (CG). The women in the SES group were treated with surface electrical stimulation using four electrodes, during six weeks with two weekly sessions of 20 minutes each. They were evaluated before and after treatment primary outcome, urinary leakage, and secondary outcomes, King's Health Questionnaire, pressure perineometry, and subjective satisfaction. RESULTS: For the urinary leakage, there was a significant decrease in SES group after treatment (P=.017). Significant differences were observed between the SES group and CG in the evaluation after treatment (P<.01; effect size: -1,38; 95% confidence interval from 1,18 to 14,14). No significant differences were observed in both groups for the outcome pelvic floor muscle pressure. In the evaluation of quality of life, a significant reduction of score in the gravity domain was observed for the SES group after treatment (P=.017). CONCLUSION: The results of this study showed that surface electrical stimulation in elderly women with SUI can be an effective method for the improvement of urinary leakage. PMID- 22840593 TI - Letter from the editors: PET/CT in radiation oncology. PMID- 22840594 TI - Technical aspects of positron emission tomography/computed tomography in radiotherapy treatment planning. AB - The usage of functional data in radiation therapy (RT) treatment planning (RTP) process is currently the focus of significant technical, scientific, and clinical development. Positron emission tomography (PET) using ((18)F) fluorodeoxyglucose is being increasingly used in RT planning in recent years. Fluorodeoxyglucose is the most commonly used radiotracer for diagnosis, staging, recurrent disease detection, and monitoring of tumor response to therapy (Lung Cancer 2012;76:344 349; Lung Cancer 2009;64:301-307; J Nucl Med 2008;49:532-540; J Nucl Med 2007;48:58S-67S). All the efforts to improve both PET and computed tomography (CT) image quality and, consequently, lesion detectability have a common objective to increase the accuracy in functional imaging and thus of coregistration into RT planning systems. In radiotherapy, improvement in target localization permits reduction of tumor margins, consequently reducing volume of normal tissue irradiated. Furthermore, smaller treated target volumes create the possibility of dose escalation, leading to increased chances of tumor cure and control. This article focuses on the technical aspects of PET/CT image acquisition, fusion, usage, and impact on the physics of RTP. The authors review the basic elements of RTP, modern radiation delivery, and the technical parameters of coregistration of PET/CT into RT computerized planning systems. PMID- 22840595 TI - Motion management in positron emission tomography/computed tomography for radiation treatment planning. AB - Hybrid positron emission tomography (PET)/computed tomography (CT) scanners combine, in a unique gantry, 2 of the most important diagnostic imaging systems, a CT and a PET tomograph, enabling anatomical (CT) and functional (PET) studies to be performed in a single study session. Furthermore, as the 2 scanners use the same spatial coordinate system, the reconstructed CT and PET images are spatially co-registered, allowing an accurate localization of the functional signal over the corresponding anatomical structure. This peculiarity of the hybrid PET/CT system results in improved tumor characterization for oncological applications, and more recently, it was found to be also useful for target volume definition (TVD) and treatment planning in radiotherapy (RT) applications. In fact, the use of combined PET/CT information has been shown to improve the RT treatment plan when compared with that obtained by a CT alone. A limiting factor to the accuracy of TVD by PET/CT is organ and tumor motion, which is mainly due to patient respiration. In fact, respiratory motion has a degrading effect on PET/CT image quality, and this is also critical for TVD, as it can lead to possible tumor missing or undertreatment. Thus, the management of respiratory motion is becoming an increasingly essential component in RT treatment planning; indeed, it has been recognized that the use of personalized motion information can improve TVD and, consequently, permit increased tumor dosage while sparing surrounding healthy tissues and organs at risk. This review describes the methods used for motion management in PET/CT for radiation treatment planning. The article covers the following: (1) problems caused by organ and lesion motion owing to respiration, and the artifacts generated on CT, PET, and PET/CT images; (2) data acquisition and processing techniques used to manage respiratory motion in PET/CT studies; and (3) the use of personalized motion information for TVD and radiation treatment planning. PMID- 22840596 TI - The role of positron emission tomography/computed tomography in radiation therapy planning for patients with lung cancer. AB - Positron emission tomography (PET)/computed tomography (CT) has rapidly assumed a critical role in the management of patients with locoregionally advanced lung cancers who are candidates for definitive radiation therapy (RT). Definitive RT is given with curative intent, but can only be successful in patients without distant metastasis and if all gross tumor is contained within the treated volume. An increasing body of evidence supports the use of PET-based imaging for selection of patients for both surgery and definitive RT. Similarly, the use of PET/CT images for accurate target volume definition in lung cancer is a dynamic area of research. Most available evidence on PET staging of lung cancer relates to non-small cell lung cancer (NSCLC). In general clinical use, (18)F fluorodeoxyglucose (FDG) is the primary radiopharmaceutical useful in NSCLC. Other tracers, including proliferation markers and hypoxia tracers, may have significant roles in future. Much of the FDG-PET literature describing the impact of PET on actual patient management has concerned candidates for surgical resection. In the few prospective studies where PET was used for staging and patient selection in NSCLC candidates for definitive RT, 25%-30% of patients were denied definitive RT, generally because PET detected unsuspected advanced locoregional or distant metastatic disease. PET/CT and CT findings are often discordant in NSCLC but studies with clinical-pathological correlation always show that PET-assisted staging is more accurate than conventional assessment. In all studies in which "PET-defined" and "non-PET-defined" RT target volumes were compared, there were major differences between PET and non-PET volumes. Therefore, in cases where PET-assisted and non-PET staging are different and biopsy confirmation is unavailable, it is rational to use the most accurate modality (namely PET/CT) to define the target volume. The use of PET/CT in patient selection and target volume definition is likely to lead to improvements in outcome for patients with NSCLC. PMID- 22840597 TI - The evolving role of positron emission tomography-computed tomography in organ preserving treatment of head and neck cancer. AB - The introduction of image-guided radiation therapy and intensity-modulated radiation therapy has led to unparalleled advances in achieving precise dose conformality in radiation therapy and ushered in new possibilities in organ preservation. Without the ability to meticulously delineate radiation treatment volumes, these advantages would be clinically irrelevant. Positron emission tomography (PET)/computed tomography (CT) has revolutionized the management of head and neck cancers in all areas, including diagnosis, staging, radiation treatment planning, and response evaluation. It has been shown to have a superior sensitivity for defining primary disease and both higher sensitivity and specificity for nodal disease in comparison with CT or magnetic resonance imaging during treatment planning. Thus, PET/CT frequently leads to an alteration of gross tumor volume/clinical target volume/planning target volume and often changes a patient's tumor, nodes, metastases staging. According to our data, the addition of PET to CT alone led to a modification in treatment planning in 55% of patients studied. PET/CT also helps to standardize radiation therapy between institutions and decreases interobserver variability. PET/CT is a powerful predictor of outcome after treatment. Although technical obstacles do exist and PET/CT does have small inherent inaccuracies, these can usually be overcome with careful planning and specification of setup error/margins, thereby allowing PET/CT to remain an essential and necessary tool in our fight against head and neck cancers. PMID- 22840599 TI - Hypoxia imaging markers and applications for radiation treatment planning. AB - Tumor hypoxia presents a unique therapeutic challenge in the treatment of solid malignancies. Not only does the presence of hypoxia compromise the efficacy of locally-directed therapies, such as radiotherapy, but the proteomic and genomic changes activated by hypoxia can promote malignant progression and systemic dissemination. In an effort to improve therapeutic ratios and treatment outcomes, therapies that specifically target areas of hypoxia are actively being investigated. Therefore, functional noninvasive methods of assessing tumor hypoxia, such as imaging via positron emission tomography/computed tomography, are warranted. Multiple imaging agents are currently being used or investigated to evaluate hypoxia status before therapy and to measure changes in oxygenation during treatment, as a means to optimizing therapeutic regimens. Advances in therapeutic radiation delivery, such as intensity-modulated radiation therapy, and proton therapy now allow for differential targeting of tumor areas, with potential dose escalation via dose painting to areas of greatest treatment resistance. The incorporation of novel imaging markers into the multimodal treatment paradigm, whether with radiation dose escalation or in concert with agents that reverse tumor hypoxia, hypoxic radiosensitizers, or hypoxic cytotoxins, will be a vital component of advancing clinical individualized cancer care and improving cure rates. PMID- 22840600 TI - The use of a rotational bladder flap for the repair of recurrent mixed trigonal supratrigonal vesicovaginal fistulas. AB - OBJECTIVE: To describe an approach for managing 10 patients with complex, mixed trigonal-supratrigonal vesiocovaginal fistulas (VVFs) using the rotational bladder flap technique. METHODS: The 10 patients were undergoing their second to fourth repair of a mixed trigonal-supratrigonal VVF. The fistula was approached transabdominally, the bladder was opened along the sagittal plane and a bladder flap was rotated downward and medially to fill the fistula defect. First, the vaginal defect was repaired as usual; then, an omental flap was interposed and fixed between the vagina and bladder; finally, the fistula and posterior wall of the bladder were meticulously sutured in 1 layer. RESULTS: Fistula closure was unsuccessful in 1 patient, in whom the corrugated drain had entered the bladder via the suture line. The fistulas were repaired successfully in the 9 remaining patients, with no recurrence or surgical reintervention for any reason for the follow-up duration. CONCLUSION: The rotational bladder flap technique is safe and effective for the repair of complex, mixed trigonal-supratrigonal VVFs which always require tension-free approximation. PMID- 22840601 TI - Arts and health as a practice of liminality: managing the spaces of transformation for social and emotional wellbeing with primary school children. AB - Intervention to enhance wellbeing through participation in the creative arts has a transformative potential, but the spatialities to this are poorly theorised. The paper examines arts-based interventions in two primary schools in which small groups of children are taken out of their everyday classrooms to participate in weekly sessions. The paper argues that such intervention is usefully seen as a practice of liminality, a distinct time and space that needs careful management to realise a transformative potential. Such management involves negotiating multiple sources of tension to balance different modes of power, forms of art practices and permeability of the liminal time-space. PMID- 22840598 TI - Functional imaging for prostate cancer: therapeutic implications. AB - Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities computed tomography (CT) or magnetic resonance imaging (single photon emission computed tomography [SPECT]/CT, positron emission tomography [PET]/CT, and PET/magnetic resonance imaging), are promising tools for the management of prostate cancer, particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regard to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, although the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging, including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects. PMID- 22840603 TI - WITHDRAWN: Endoscopic Radial Artery Harvesting: Long-Term Results and Graft Patency Rate. AB - This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy. This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. PMID- 22840602 TI - Seroprevalence and cross-reactivity of human polyomavirus 9. AB - Many humans have antibodies against simian lymphotropic polyomavirus (LPyV), but its DNA has not been found in humans. Identification of human polyomavirus 9 (HPyV9) led us to compare the seroprevalence and cross-reactivity of LPyV and HpyV9. Results could indicate that humans who have antibodies against LPyV are infected by HPyV9. PMID- 22840604 TI - Simulation of reflex late decelerations in labor with a mathematical model. AB - Fetal welfare during labor and delivery is commonly monitored through the cardiotocogram (CTG), the combined registration of uterus contractions and fetal heart rate (FHR). From the CTG, the fetal oxygen state is estimated as the main indicator of the fetal condition, but this estimate is difficult to make, due to the complex relation between CTG and oxygen state. Mathematical models can be used to assist in the interpretation of the CTG, since they enable quantitative modeling of the flow of events through which uterine contractions affect fetal oxygenation and FHR. We propose a mathematical model to simulate reflex 'late decelerations', i.e. variations in FHR originating from uteroplacental flow reduction during uterine contractions and mediated by the baroreflex and the chemoreflex. Results for the uncompromised fetus show that partial oxygen pressures reduce in relation to the strength and duration of the contraction. Above a certain threshold, hypoxemia will evoke a late deceleration. Results for uteroplacental insufficiency, simulated by reduced uterine blood supply or reduced placental diffusion capacity, demonstrated lower baseline FHR and smaller decelerations during contraction. Reduced uteroplacental blood volume was found to lead to deeper decelerations only. The model response in several nerve blocking simulations was similar to experimental findings by Martin et al. [18], indicating a correct balance between vagal and sympathetic reflex pathways. PMID- 22840607 TI - Reappraising the relationship between maternal age and postpartum depression according to the evolutionary theory: Empirical evidence from a survey in primary health services. AB - BACKGROUND: Postpartum depression (PPD) is a widespread worldwide phenomenon, but its etiology remains unclear. This study reappraised how evolutionary theory could explain PPD as an adaptation through investigating the relationship between maternal age and PPD, and if this relationship is modified according to the number of children at home. METHODS: A cross-sectional study carried out in five primary health care units included 811 participants randomly selected among mothers of children up to five postpartum months in Rio de Janeiro, Brazil. Postpartum depression was defined by scores above 11 on Edinburgh Postnatal Depression Scale (EPDS), and statistical analysis was based on multivariate logistic regression models. RESULTS: One hundred and ninety-seven (24.3%, CI 95% 21.3-27.2) participants were classified as PPD positives. Maternal age was significantly associated to PPD (OR=0.96, p-value=0.019) independently of socioeconomic and reproductive characteristics, conjugal status or substance consumption by the couple. Thus, for each additional year, a reduction of 4% in the chance of developing PPD could be anticipated, effect which was not modified by the number of children at home (p-value=0.602). LIMITATIONS: Information on social support was not included in this analysis since its relationship with maternal mental health would be better evaluated in a prospective fashion. CONCLUSIONS: These findings suggest that adaptive mechanisms shaped through human generations persist contributing to the development of PPD in contemporary societies. According to this evolutionary approach, as maternal age advances the reproductive potential diminishes and, consequently, mothers are less prone to develop PPD and reduce investment in new offspring. PMID- 22840608 TI - Psychiatrists' perceptions of potential reasons for non- and partial adherence to medication: results of a survey in bipolar disorder from eight European countries. AB - BACKGROUND: Partial/non-adherence to medication by patients with bipolar disorder is associated with exacerbation of symptoms, neurocognitive decline and increased risk of suicide and has a major influence on patient outcomes. Understanding psychiatrists' views on the causes and management of non-adherence are vital to address adherence problems effectively. METHODS: A 15-question survey was conducted of 2448 psychiatrists treating patients with bipolar disorder in eight European countries to ascertain their perceptions of the level and causes of non adherence, and their preferred methods by which to assess it. RESULTS: A majority of patients (57%) were estimated to be partially/non-adherent. Three in four psychiatrists responded that most patients who deteriorated after stopping medication were unable to attribute this to non-adherence. An irregular daily routine/living circumstance affecting adherence was considered the most important reason for patients discontinuing medication. Only 4% of psychiatrists deemed intolerable side effects had led to most patients stopping their medication; 11% responded that drug/alcohol consumption may have impacted on adherence to medication for the majority of patients. LIMITATIONS: The survey was not distributed to all psychiatrists in the countries and the impact on the results, of any difference in the demographics of the respondents with respect to the population of psychiatrists across the eight countries, is not known. CONCLUSIONS: Partial/non-adherence remains a considerable problem amongst patients with bipolar disorder. There is a need for increased knowledge concerning partial/non-adherence at the level of the clinician-patient interaction, to reduce its impact and bring about improved clinical outcomes. PMID- 22840605 TI - Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis. AB - BACKGROUND: Very low birth weight neonates (<= 1500 g, VLBWs) have a high rate of infection and distinct baseline immune function compared with more mature populations. In critically ill children and adults, sepsis increases subsequent infection risk. It is unknown whether sepsis modifies the risk of subsequent infection in VLBWs. METHODS: We conducted a retrospective cohort study of VLBWs<=32weeks of gestation at birth cared for in 312 neonatal intensive care units in the United States from 1997 to 2011 (n=103,376). Early-onset sepsis (EOS, culture-positive only) and late-onset sepsis (LOS, culture-positive or clinical) cases were identified. Cox proportional hazard models were used to control for clinical variables between neonates with and without EOS to determine if EOS modified risk of LOS, necrotizing enterocolitis (NEC), or death. RESULTS: LOS occurred in 12,112/102,317 (11.8%) neonates without EOS and in 133/1059 (12.6%) of those with EOS. After adjustment for clinical variables, the risk of LOS was not different between neonates with or without a history of EOS (hazard ratio [HR]=0.92; 95% confidence interval [CI] 0.74, 1.16). EOS increased the risk of 120-day mortality (HR=1.78; 95% CI 1.49, 2.13). CONCLUSIONS: In contrast to findings in children and adults, EOS was not associated with an increased risk of LOS in this cohort. Age-specific investigations are needed to determine if post sepsis immunologic alterations are present. PMID- 22840606 TI - A novel coding-region RNA element modulates infectious dengue virus particle production in both mammalian and mosquito cells and regulates viral replication in Aedes aegypti mosquitoes. AB - Dengue virus (DENV) is an enveloped flavivirus with a positive-sense RNA genome transmitted by Aedes mosquitoes, causing the most important arthropod-borne viral disease affecting humans. Relatively few cis-acting RNA regulatory elements have been described in the DENV coding-region. Here, by introducing silent mutations into a DENV-2 infectious clone, we identify the conserved capsid-coding region 1 (CCR1), an RNA sequence element that regulates viral replication in mammalian cells and to a greater extent in Ae. albopictus mosquito cells. These defects were confirmed in vivo, resulting in decreased replication in Ae. aegypti mosquito bodies and dissemination to the salivary glands. Furthermore, CCR1 does not regulate translation, RNA synthesis or virion retention but likely modulates assembly, as mutations resulted in the release of non-infectious viral particles from both cell types. Understanding the role of CCR1 could help characterize the poorly-defined stage of assembly in the DENV life cycle and uncover novel anti viral targets. PMID- 22840609 TI - A tomato-rich diet is related to depressive symptoms among an elderly population aged 70 years and over: a population-based, cross-sectional analysis. AB - BACKGROUND: Enhanced oxidative stress or defective anti-oxidant defenses are related to the pathogenesis of depressive symptoms. Lycopene is the most powerful antioxidant amongst the carotenoids. The aim of this study was to investigate the relationship between different vegetables, including tomatoes/tomato products (a major source of lycopene), and depressive symptoms in a community-based elderly population. METHODS: We analyzed a cross-sectional survey including 986 community dwelling elderly Japanese individuals aged 70 years and older. Dietary intake was assessed using a valid self-administered diet-history questionnaire, and depressive symptoms were evaluated using the 30-item Geriatric Depression Scale with 2 cut-off points: 11 (mild and severe) and 14 (severe) or use of anti depressive agents. RESULTS: The prevalence of mild and severe and severe depressive symptoms was 34.9% and 20.2%, respectively. After adjustments for potentially confounding factors, the odds ratios of having mild and severe depressive symptoms by increasing levels of tomatoes/tomato products were 1.00, 0.54, and 0.48 (p for trend <0.01). Similar relationships were also observed in the case of severe depressive symptoms. In contrast, no relationship was observed between intake of other kinds of vegetables and depressive symptoms. LIMITATIONS: This is a cross-sectional study, and not for making a clinical diagnosis of depressive episodes. CONCLUSIONS: This study demonstrated that a tomato-rich diet is independently related to lower prevalence of depressive symptoms. These results suggest that a tomato-rich diet may have a beneficial effect on the prevention of depressive symptoms. Further studies are needed to confirm these findings. PMID- 22840610 TI - The relevance of oxidative stress status in first episode and recurrent depression. AB - Oxidative and nitrosative stress (O&NS) could play an important role in the pathophysiology of major depression (MDD). The aim of the present work was to evaluate the specific activity of the main peripheral antioxidant defences (superoxide dismutase--SOD and glutathione peroxidase--GPX) and the level of malondialdehyde--MDA (a lipid peroxidation maker), in depressed patients, as compared to an age-matched control group. Also, we were interested to see if there are any differences between first episode vs. recurrent depression groups, in terms of oxidative stress markers. Additionally, we want it to investigate the effects of different antidepressant medication (mirtazapine, venlafaxine, tianeptine and escitalopram) on oxidative status of depressed patients. Our results showed an increased oxidative stress status in the serum of patients with MDD, expressed by a significant decrease of both SOD and GPX specific activities and a significant increase of the lipid peroxidation marker MDA, as compared to the control group. When we analyzed the oxidative stress status in depressed patients based on chronicity we observed significant decrease of SOD and GPX specific activities in recurrent depression group, as compared to the first episode group. Moreover, a very significant increase in MDA concentration was observed in recurrent depression patients, as compared to the first episode group. Our work provides additional evidences of increased oxidative stress in MDD, expressed by altered antioxidant enzyme activity and increased levels of lipid peroxidation. Also, it seems that sub-classifying depression into different subtypes, based on chronicity, can predict differences in the levels of some various oxidative stress markers. PMID- 22840611 TI - Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment. AB - BACKGROUND: Glutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls. METHODS: Eighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment. RESULTS: Patients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients. LIMITATIONS: There was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures. CONCLUSION: Although no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment. PMID- 22840612 TI - Effectiveness of a universal school-based programme for preventing depression in Chinese adolescents: a quasi-experimental pilot study. AB - BACKGROUND: Evidence of the effectiveness, rather than efficacy, of universal school-based programmes for preventing depression among adolescents is limited. This study examined the effectiveness of a universal depression prevention programme, "The Little Prince is Depressed" (LPD), which adopted the cognitive behavioural model and aimed to reduce depressive symptoms and enhance protective factors of depression among secondary school students in Hong Kong. METHODS: A quasi-experimental design was adopted for this pilot study. Thirteen classes were assigned to the intervention or control conditions according to the deliberation of the programme administrator of the four participating schools. Implementation was carried out in two phases, with a professional-led first phase and teacher led programme second phase. LPD consisted of a 12-week school-based face-to-face programme with psycho-educational lessons and homework assignments. RESULTS: Students completed the programme generally showed positive development in help seeking attitudes and self-esteem. For students who had more depressive symptoms at pre-assessment, the programme was found to be significant in enhancing cognitive-restructuring skills and support-seeking behaviours. The programme was not, however, found to be statistically significant in reducing depressive symptoms of the participants over the study period. LIMITATIONS: A small sample size, a high attrition rate, and a short follow-up time frame. CONCLUSIONS: The LPD programme was successful in building resilience of the students in general and enhancing the cognitive-behavioural skills of students with depressive symptoms. While we did not find sufficient evidence for concluding that the LPD was effective in reducing depressive symptoms, we believe that these results highlight the challenges of implementing evidence-based practices generated from highly controlled environments in real-life settings. PMID- 22840613 TI - Hypomanic symptoms assessed by the HCL-32 in patients with major depressive disorder: a multicenter trial across China. AB - AIM: To investigate the results of the Hypomania Checklist-32 (HCL-32) administered as a screening instrument in clinical settings to mood disorders patients in the depressive phase. METHODS: A total of 1487 patients diagnosed and being treated for major depressive disorder (MDD) in 13 mental health centers across China were self-rated by the HCL-32 and independently examined by the Mini International Neuropsychiatric Interview (MINI). RESULTS: After examination by the MINI, 309 (20.8%) of the 1487 patients clinically diagnosed as having MDD satisfied DSM-IV criteria for bipolar disorder (BD): 118 (7.9%) for bipolar I disorder (BD-I) and 191 (12.8%) for bipolar II disorder (BD-II). The mean HCL-32 score of the BD patients was statistically higher than that of patients with unipolar depression (UD, major depressive disorder), BD-II higher than UD, while no significant difference between BD-I and BD-II. The HCL-32 distinguished between BD and UD (best cutoff score 14), between BD-II and UD (best cutoff 12). At the optimum cutoff of 12 between BD and UD, the sensitivity was 0.86, specificity 0.69. LIMITATIONS: No standardized instruments were used to measure the severity of depressive symptoms. Depressed patients with a previous history of BD were excluded from this study. CONCLUSIONS: The HCL-32 results in this multicenter study of patients in the depressive phase were similar to those of earlier, generally smaller-scale studies which subjects could be in any mood phases. A score of 12 could be used as the optimum cutoff between BD and UD to improve screening for BD-II if the HCL-32 was applied in clinical settings in China. PMID- 22840614 TI - The dominance behavioral system and manic temperament: motivation for dominance, self-perceptions of power, and socially dominant behaviors. AB - The dominance behavioral system has been conceptualized as a biologically based system comprising motivation to achieve social power and self-perceptions of power. Biological, behavioral, and social correlates of dominance motivation and self-perceived power have been related to a range of psychopathological tendencies. Preliminary evidence suggests that mania and risk for mania (manic temperament) relate to the dominance system. METHOD: Four studies examine whether manic temperament, measured with the Hypomanic Personality Scale (HPS), is related to elevations in dominance motivation, self-perceptions of power, and engagement in socially dominant behavior across multiple measures. In Study 1, the HPS correlated with measures of dominance motivation and the pursuit of extrinsically-oriented ambitions for fame and wealth among 454 undergraduates. In Study 2, the HPS correlated with perceptions of power and extrinsically-oriented lifetime ambitions among 780 undergraduates. In Study 3, the HPS was related to trait-like tendencies to experience hubristic (dominance-related) pride, as well as dominance motivation and pursuit of extrinsically-oriented ambitions. In Study 4, we developed the Socially Dominant Behavior Scale to capture behaviors reflecting high power. The scale correlated highly with the HPS among 514 undergraduates. LIMITATIONS: The studies rely on self-ratings of manic temperament and dominance constructs, and findings have not yet been generalized to a clinical sample. CONCLUSIONS: Taken together, results support the hypothesis that manic temperament is related to a focus on achieving social dominance, ambitions related to achieving social recognition, perceptions of having achieved power, tendencies to experience dominance-related pride, and engagement in social behaviors consistent with this elevated sense of power. PMID- 22840615 TI - Neurocognitive alterations in first degree relatives of suicide completers. AB - BACKGROUND: Suicide aggregates within families and the relatives of suicide completers are at an increased risk for suicide. Though neurocognitive changes are gaining increasing attention as part of the vulnerability for suicide, the literature on neurocognitive alterations among suicide relatives as possible endophenotypes of suicide is sparse. METHOD: Normothymic first-degree relatives (n=14) of suicide completers without personal histories of suicide attempts were compared to individuals without family histories of suicide (n=14) matched for age-, sex- and education. Participants completed the Wisconsin card sorting test, a well validated test of cognitive control in a changing environment. RESULTS: First-degree relatives of suicide completers made significantly more perseverative errors and have a lower level of conceptual responses than comparison subjects. CONCLUSION: Alterations found in first-degree relatives of suicide completers suggest a decreased responsiveness to changing, yet unambiguous, conditions. These neurocognitive impairments are similar to deficits observed among individuals engaging in suicide attempts. Neurocognitive impairments revealed by the Wisconsin card sorting test may represent a neurocognitive endophenotype of suicide. PMID- 22840616 TI - Health Belief Model deterrents of social support seeking among people coping with eating disorders. AB - BACKGROUND: Eating disorders have the highest mortality rates of any psychiatric diagnosis (Sullivan, 1995). Understanding what prevents people from seeking or accessing that which can help them manage these disorders is critical to improving eating disorder outcomes. This study identifies specific barriers and deterrents individuals living with eating disorders perceive when deciding if and when they will seek eating disorder-specific social support. METHODS: 34 men and women living with eating disorders were recruited and interviewed regarding their experiences with managing their disorders, including reasons why they may forego seeking social support to help cope with these conditions. RESULTS: Participant reported reasons as to why they would forego seeking social support for the management of their eating disorders were framed against the five main constructs of the Health Belief Model. These include (a) perceived susceptibility to a health threat, (b) perceived severity of the health threat, (c) perceived benefit of protective health behaviors, (d) perceived self-efficacy with these protective behaviors, and (e) perceived barriers to performing these behaviors. LIMITATIONS: It could be argued that since this study does not focus solely on one type of eating disorder, such as anorexia or bulimia, the barriers to social support may differ depending upon the characteristics inherent to the specific disorders. CONCLUSIONS: Findings can be used to inform and improve therapeutic interventions to produce better long-term outcomes among people struggling with eating disorders. PMID- 22840617 TI - Social cognition and interaction training (SCIT) for outpatients with bipolar disorder. AB - INTRODUCTION: Patients with bipolar disorder show social cognition deficits during both symptomatic and euthymic phases of the illness, partially independent of other cognitive dysfunctions and current mood. Previous studies in schizophrenia have revealed that social cognition is a modifiable domain. Social cognition and interaction training (SCIT) is an 18-week, manual-based, group treatment designed to improve social functioning by way of social cognition. METHOD: 37 outpatients with DSM-IV-TR bipolar and schizoaffective disorders were randomly assigned to treatment as usual (TAU)+SCIT (n=21) or TAU (n=16). Independent, blind evaluators assessed subjects before and after the intervention on Face Emotion Identification Task (FEIT), Face Emotion Discrimination (FEDT), Emotion Recognition (ER40), Theory of Mind (Hinting Task) and Hostility Bias (AIHQ). RESULTS: Analysis of covariance revealed significant group effects for emotion perception, theory of mind, and depressive symptoms. The SCIT group showed a small within-group decrease on the AIHQ Blame subscale, a moderate decrease in AIHQ Hostility Bias, a small increase in scores on the Hinting Task, a moderate increase on the ER40, and large increases on the FEDT and FEIT. There was no evidence of effects on aggressive attributional biases or on global functioning. LIMITATION: No follow up assessment was conducted, so it is unknown whether the effects of SCIT persist over time. CONCLUSION: This trial provides preliminary evidence that SCIT is feasible and may improve social cognition for bipolar and schizoaffective outpatients. PMID- 22840618 TI - A Chinese Chan-based mind-body intervention for patients with depression. AB - BACKGROUND: Given the recent growing interest and encouraging findings in studies of alternative treatments for depression, the present randomized controlled trial study aimed to compare the effect of a newly developed Chinese Chan-based Dejian Mind-Body Intervention (DMBI) with the Cognitive Behavioral Therapy (CBT) on improving depressive symptoms in patients with depression. METHODS: Seventy-five participants diagnosed with major depressive disorder were randomly assigned to receive either 10-session CBT or DMBI, or placed on a waitlist. Pre-post measurements included record of anti-depressants treatment, ratings by psychiatrists who were blinded to the experimental design and self-report on mood measures, and performance in a cognitive test tapping concentration ability. RESULTS: Both the CBT and DMBI groups demonstrated significantly reduced overall depressive syndrome after intervention at large effect size (0.93-1.10). Furthermore, the DMBI group (p<0.05), but not the CBT or waitlist groups, demonstrated significant reduction in intake of anti-depressants, and significant improvement in specific depression-related symptoms including difficulty in concentration (p=0.002), and problems in gastrointestinal health (p=0.02) and overall sleep quality (p<0.001). LIMITATIONS: This study has provided some evidence for the short-term effect of the DMBI on Chinese population. Its long term effect on a larger sample and on Caucasian population warrants further investigation. CONCLUSIONS: The present findings suggest that a Chinese Chan based Mind-Body intervention has positive effects on improving mood and health conditions of individuals with depression. PMID- 22840619 TI - Star-crossed? The association of the 5-HTTLPR s allele with season of birth in a healthy female population, and possible consequences for temperament, depression and suicide. AB - BACKGROUND: Birth season has well-known effects on neuropsychiatric disorders, and may also influence genotype distribution by possibly influencing chance of conception via parental idiosyncratic conception patterns or survival of foetuses or infants. The 5-HTTLPR is associated with phenomena including affective temperaments or suicide which are also associated with birth season. Our aim was to investigate the association of 5-HTTLPR genotype and birth season in a healthy female population. METHODS: Birth date and 5-HTTLPR genotype was determined for 327 psychiatrically healthy women. The association between presence of s allele and time of birth was analysed using generalized linear models. RESULTS: A significant association between s allele frequency and time of birth was detected. S allele carrier frequency was marginally significantly higher in July borns and significantly lower in autumn borns. LIMITATIONS: We investigated an adult sample so genotype frequency data do not reflect birth frequencies. Our sample consisted exclusively of females. CONCLUSIONS: There is no clear explanation for the observed association, although idiosyncratic parental conception patterns, the association of 5-HTTLPR with sudden infant/intrauterine death, or other s allele-mediated behaviours may play a role. Our results are strikingly parallel with earlier data reporting a higher risk of completed suicide in July borns, and higher scores of July borns and lower scores of autumn borns on certain affective temperament scales, both of which are also associated with the s allele of 5-HTTLPR. Thus our results may add to the growing body of evidence regarding the etiological background of affective disorders. PMID- 22840620 TI - A systematic review of cognitive remediation for schizo-affective and affective disorders. AB - BACKGROUND: Cognitive remediation is accepted as an important therapeutic intervention in schizophrenia, but few studies provide data on whether the benefits extend to affective disorders. OBJECTIVES: To review quantitatively studies of cognitive remediation with samples that included cases of schizoaffective disorder, affective psychosis, unipolar and/or bipolar disorders. METHODS: Twenty one studies met preliminary inclusion criteria, comprising a total of 940 participants of which 35% had an affective or schizoaffective disorder. Effect sizes (ES) for pre- to post-intervention change in cognitive performance were estimated. RESULTS: A meta-analysis of 16 studies gave a pooled ES for change in cognitive function of 0.32 (95% Confidence Intervals 0.20 to 0.43) and produced statistical homogeneity. Overall, ES were significantly positively correlated with higher proportion of schizo-affective and affective cases (r=0.61; p=0.007), even when age, gender and duration of therapy were included as covariates in the analysis (r=.59, p=0.017). LIMITATIONS: The quality of and small number of affective disorder only studies mean the findings must be treated with caution. CONCLUSIONS: The estimated ES reflect those reported in the literature on cognitive remediation for schizophrenia. As such a conservative interpretation is that cognitive remediation has at least equivalent benefits in affective and schizo-affective disorder as demonstrated in schizophrenia. Further studies are urgently required to examine the durability of any gains with cognitive remediation in affective populations and to determine if any changes in cognitive deficits lead to improvements in symptoms or functioning and/or whether post-intervention cognitive changes differ in character or magnitude from those reported in schizophrenia. PMID- 22840621 TI - Randomized non-invasive sham-controlled pilot trial of electroacupuncture for postpartum depression. AB - BACKGROUND: Postpartum depression affects 10-15% of mothers. Although acupuncture was efficacious for major depressive disorder in pregnancy and in women outside the perinatal period, there has been no randomized controlled study on the feasibility, tolerability, and efficacy of acupuncture for postpartum depression. METHODS: This was a randomized, subject- and assessor-blind, parallel-group, sham controlled trial. Twenty women within six months postpartum with DSM-IV-diagnosed major depressive disorder of mild severity, defined as a 17-item Hamilton Depression Rating Scale (HDRS(17)) score of 12 to 19, were randomly assigned to either electroacupuncture or non-invasive sham acupuncture two sessions weekly for four weeks. RESULTS: There was significant reduction in HDRS(17) score from baseline to 4-week posttreatment in both groups, with an effect size 1.4 and 1.8 for electroacupuncture and sham acupuncture, respectively. Improvement was observed as early as two weeks after commencing acupuncture. The response and remission rate in the electroacupuncture group at 4-week posttreatment was 33% and 44%, respectively; for the sham acupuncture group, it was 60% and 50%, respectively. There was no significant between-group difference in all outcome measures, including the HDRS(17), Edinburgh Postnatal Depression Scale, Hospital Anxiety and Depression Scale, Clinical Global Impression, and Sheehan Disability Scale. Treatment credibility, success of blinding, and adverse events were similar between groups. LIMITATION: Small sample size and high attrition rate. No waiting list observation group. CONCLUSION: Both electroacupuncture and non invasive sham acupuncture were effective for postpartum depression. Further studies utilizing larger sample size, better recruitment strategies, and home based acupuncture treatment are warranted. CLINICAL TRIAL INFORMATION: Pilot Study on the Use of Acupuncture for Postpartum Depression; ClinicalTrials.gov Registration #NCT01178008; URL - http://clinicaltrials.gov/ct2/show/NCT01178008?term=postpartum+acupuncture&rank=1 PMID- 22840622 TI - Does the stress generation hypothesis apply to eating disorders?: an examination of stress generation in eating, depressive, and anxiety symptoms. AB - BACKGROUND: The stress generation hypothesis posits that individuals actively contribute to stress in their lives. Although stress generation has been studied frequently in the context of depression, few studies have examined whether this stress generation process is unique to depression or whether it occurs in other disorders. Although evidence suggests that stress contributes to the development of eating disorders, it is unclear whether eating disorders contribute to subsequent stress. METHODS: A prospective design was used to examine the influence of eating disorder symptoms on negative life stressors. Two hundred and ninety female undergraduates completed questionnaires at two time points that examined eating disorder, depressive and anxiety symptoms and the presence of negative life events. RESULTS: Regression analyses found that while eating disorder symptoms (i.e. bulimic symptoms and drive for thinness) were independent, significant predictors of negative life events, they did not predict negative life events above and beyond symptoms of depression. LIMITATIONS: Limitations include the use of self-report measures and a college-based sample, which may limit generalizability of the results. CONCLUSIONS: Findings suggest that if stress generation is present in individuals with symptoms of eating disorders, it is likely attributable to symptoms of depression. Thus, it may be important for clinicians to target depressive symptoms in order to reduce the frequency of negative life stressors among individuals with eating disorders. PMID- 22840623 TI - Automated hippocampal subfields segmentation in late life depression. AB - Although a few automated hippocampal subfields segmentation methods have been developed, there has been no in vivo Magnetic Resonance Imaging (MRI) study on the hippocampal subfields volumes of Late Life Depression (LLD). The aim of this study was to investigate the hippocampal subfields volume differences between LLD subjects and healthy elderly controls using an automated hippocampal subfields segmentation technique. Thirty subjects with LLD and 30 group-matched healthy control subjects underwent 3T MRI scanning, and hippocampal subfields volumes were measured and compared between the groups. Subjects with LLD exhibited significant hippocampal volume reductions in the total hippocampus, subiculum, and Cornu Ammonis (CA) 2-3 areas compared with healthy subjects (uncorrected, p<0.001). This study is the first to elaborate the subfields volume differences of both hippocampi between controls and LLD patients. These structural changes in the hippocampal presubiculum, subiculum, and CA2-3 areas might be at the core of the underlying neurobiological mechanisms of hippocampal dysfunction in LLD. PMID- 22840624 TI - High sex ratio as a correlate of depression in Chinese men. AB - BACKGROUND: There is a large and increasing excess of men in China, especially in poor rural areas, with millions now unable to marry. The study aimed to determine whether these high sex ratios influence the prevalence of depression. METHODS: The study was a cross-sectional survey, using a self-completion questionnaire, administered to adults of reproductive age in localities with widely varying sex ratios in three provinces: Zhejiang, Yunnan and Guizhou. Depression was measured using the Chinese version of the Beck Depression Inventory (BDI). RESULTS: A total of 7435 men and women aged 19-40 completed questionnaires. Moderate or severe depression was found in 17.6% of men and 17.0% of women, and suicide thoughts and wishes in 18.0% and 20.0% respectively. Independent correlates for depression and suicide ideation in men were high local sex ratio, rural residence, low education and poor economic status. Very high local sex ratio was the strongest independent determinant of depression in men. LIMITATIONS: These include (1) selection bias: with just three provinces and a purposive sampling strategy, (2) reporting bias: the BDI score is arguably a crude measure for a complex psychological condition, and the veracity of responses to sensitive questions cannot be guaranteed, (3) information bias: county-level sex ratio figures may underestimate the actual sex ratio, especially in rural areas. CONCLUSION: Very high sex ratios in parts of China are contributing to depression and suicidal tendencies in men, and women, but especially unmarried men. Proactive measures need to be taken to identify and treat vulnerable individuals. PMID- 22840625 TI - Enhancing attributional style as a protective factor in suicide. AB - BACKGROUND: We applied Needles and Abramson (1990) recovery model of cognitive vulnerability to the suicide. Previous research has found that individuals who make global and stable attributions to positive events (an enhancing attributional style) are more resilient to depression and recover faster if they do become depressed. Building upon past research, we hypothesized that an enhancing attributional style would buffer the relationship between depressive symptoms and suicidal ideation. We also explored possible mediators of this effect. Specifically, we hypothesized that the reduction in suicidal ideation may be due to changes in depressive symptoms. METHOD: Two hundred and nine diverse undergraduates participated in a four-week prospective study. RESULTS: Results of a moderated Poisson regression analysis demonstrate that enhancing attributional style buffers the relationship between baseline depressive symptoms and followup suicidal ideation, controlling for baseline depressive symptoms. A mediated moderation analysis using structural equation modeling did not support the hypothesis that the reduction in suicidal ideation was due to a reduction in depressive symptoms. LIMITATIONS: Limitations include an unselected college sample with a low base rate of suicidal ideation, the use of self-report measures, and assessing only suicidal ideation not behaviors. CONCLUSIONS: Results suggest that enhancing attributional style is a viable protective factor in suicide. Moreover, the buffering effect is due to direct reduction in suicidal ideation, rather than simply a reduction in depressive symptoms. Since attributional styles are modifiable, findings suggest that modifying negative attributional styles can be useful to prevent suicide in a clinical setting. PMID- 22840627 TI - Natural course of depressive symptoms in late life. An 8-year population-based prospective study. AB - AIMS: The aim of the study was to follow the natural course of late-life depressive symptoms within a German population-based study. METHODS: Within the Leipzig Longitudinal Study of the Aged (LEILA 75+), a representative sample of 1265 individuals aged 75 years and older were interviewed every 1.5 years over 8 years. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D, German-specific cut-off score >=23). RESULTS: The incidence of depressive symptoms was 34 per 1000 person-years (95% confidence interval 31-37). In a multivariate regression model, female gender, poor self rated health status, stroke, risky alcohol consumption, a poor social network, higher number of specialist visits, functional impairment, and CES-D score at baseline were significant risk factors of future depressive symptoms. We observed remission in 60%, an intermittent course in 17% and a chronic course in 23% of the participants. No baseline characteristic distinguished the remission group from the persistently depressed. CONCLUSION: Depressive symptoms in late life are common and highly persistent. In the present study encountered risk factors entailed potentialities for secondary prevention. PMID- 22840626 TI - Fluctuations of suicidality in the aftermath of a marital separation: 6-month follow-up observations. AB - BACKGROUND: There is a lack of understanding of how the changing nature of the separation process impacts on suicidality. AIMS: This paper aims to identify factors contributing to fluctuations in suicidality during the process of marital/de facto separation along a 6-month follow-up. METHOD: Separated persons who had contacted relationship-counselling services, help-line services, and variety of support and self-help groups were asked to participate in the first assessment. A 'Follow-Up Questionnaire' was sent 6 months later. Participants were required to be 18 years or older and separated from their married/de facto partner within the previous 18 months but not yet divorced. RESULTS: Overall, in the first assessment, separated females presented lower levels of suicidality than males. During the follow-up suicidality decreased. There were some gender differences in terms of predictors of changes in suicidality. Separated males who showed an increase or stability in suicidality were more affected by stressful experiences such as legal negotiations on obtaining a divorce, feelings of loss and loneliness, loss of social networks and financial difficulties than males who were not suicidal in either assessment. Separated males and females who remained suicidal were more likely to report different mental and physical illnesses. LIMITATIONS: Relatively low response rates of the follow-up (60%) limited our statistical analyses as some of the groups were too small and did not enable modelling. CONCLUSIONS: Suicidality decreased, which seems to indicate that individuals adjusted to their new life circumstances. However, persons whose suicidality remained or increased reported more frequently stressful life events, physical and mental illnesses. PMID- 22840628 TI - PTSD symptoms in a cohort of National Guard soldiers deployed to Iraq: evidence for nonspecific and specific components. AB - BACKGROUND: There is evidence that some of the symptoms included under the current diagnostic criteria for PTSD are not unique to PTSD and instead represent general distress. This study attempted to delineate the nonspecific and specific components of PTSD by examining the relation of PTSD symptoms to trauma exposure and demoralization in a cohort of National Guard soldiers deployed to Iraq. METHODS: Data were collected from a cohort of 348 combat deployed National Guard soldiers participating in the readiness and resilience in National Guard soldiers (RINGS) study. Current DSM-IV PTSD diagnoses and trauma exposure were determined 6 to 12 months following soldiers' return from deployment using the Clinician Administered PTSD Scale. Level of trauma exposure (as measured by a combat exposure scale), demoralization and self-reported PTSD symptoms were assessed with self-report questionnaires. RESULTS: Dysphoria symptoms had the weakest relation with trauma exposure and the strongest relation with demoralization. In addition, these symptoms had high rates of endorsement in a group of soldiers without trauma exposure. Intrusions were strongly related to trauma and were significantly higher in the group with trauma exposure compared to the no-trauma group. LIMITATIONS: These findings may not generalize to survivors of other types of trauma, service members from other era's, or even service members from different regions or military branches who have different demographic and duty characteristics. CONCLUSIONS: Emphasizing symptoms of PTSD that are strongly related to trauma exposure will be important for the differential diagnosis of PTSD. PMID- 22840629 TI - Amygdala dysfunction attenuates frustration-induced aggression in psychopathic individuals in a non-criminal population. AB - BACKGROUND: Individuals with psychopathy have an increased tendency toward certain types of aggression. We hypothesized that successful psychopaths, who have no criminal convictions but can be diagnosed with psychopathy in terms of personality characteristics, are skilled at regulating aggressive impulses, compared to incarcerated unsuccessful psychopaths. METHODS: In this block designed functional magnetic resonance imaging (fMRI) study, we sought to clarify the neural mechanisms underlying differences in frustration-induced aggression as a function of psychopathy in non-criminal populations. Twenty male undergraduate students who completed a self-report psychopathy questionnaire were scanned while they completed a task in which they either could or could not punish other individuals who made unfair offers of monetary distribution. RESULTS: Individuals with high psychopathic tendencies were less likely to make a decision to inflict costly punishment on people proposing unfair offers. During this decision-making, psychopathy was associated with less amygdala activity in response to the unfairness of offers. Moreover, the amygdala dysfunction in psychopathic individuals was associated with reduced functional connectivity with dopaminergic related areas, including the striatum, when punishment was available compared to when it was unavailable. LIMITATIONS: The possibility that levels of psychopathic traits in a regular population were milder than in incarcerated populations cannot be ruled out. CONCLUSIONS: The findings indicate that amygdala dysfunction underlies affective deficits of psychopathy. We propose that the insensitivity of the amygdala to the affective significance of social stimuli contributes to an increased risk of violation of social norms, but enhances the ability to attenuate impulses toward maladaptive aggression in successful psychopaths. PMID- 22840630 TI - The impact of cyclothymic temperament in adult ADHD. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder in children and adults. Many ADHD patients experience affective symptoms that resemble the cyclothymic temperament trait, which is suggested to be a part of the bipolar spectrum. However, the relationship between adult ADHD and cyclothymic temperament has never been systematically studied. METHODS: A sample of 586 clinically diagnosed Norwegian adult ADHD patients and 721 population derived controls responded to the 21-item cyclothymic subscale of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego auto questionnaire (TEMPS-A). Self-reported data on psychiatric symptoms, comorbidity, educational and occupational level, and known comorbidity in family members, including bipolar disorder, was also obtained. RESULTS: The mean TEMPS-A scores were 13.0 for patients and 4.6 for controls (p<0.001), and 71% of the patients compared to 13% of the controls were classified as having a cyclothymic temperament (TEMPS score >=11 points). Among ADHD patients, cyclothymic temperament was strongly associated with more childhood and adult ADHD symptoms, lower educational and occupational achievements and increased psychiatric comorbidity, including bipolar disorder (10%). In addition, 49% screened positive on the Mood Disorder Questionnaire. LIMITATIONS: Although the cyclothymic TEMPS-A scale has been used in clinical settings in Norway for many years, it has not yet been officially validated. CONCLUSIONS: Cyclothymic temperament is highly prevalent in adults with ADHD, and this characterises a subgroup of more psychiatrically impaired individuals, possibly reflecting an underlying affective instability with a pathophysiology closer to the bipolar spectrum disorders. PMID- 22840632 TI - Response to antidepressants in major depressive disorder with melancholic features: the CRESCEND study. AB - BACKGROUND: This study aimed to determine whether major depressive disorders with melancholic and without melancholic features differ with respect to their responses to treatment with antidepressants. METHODS: From a nationwide sample of 18 hospitals in South Korea, 559 presenting patients with major depressive disorder were recruited. The DSM-IV based Structured Clinical Interview was administered for confirmatory diagnoses and depression subtypes with/without melancholic features. After baseline evaluation, they received naturalistic clinician-determined antidepressant interventions. Assessment scales for evaluating depression (HAMD), anxiety (HAMA), global severity (CGI-s), and functioning (SOFAS) were administered at baseline and re-evaluated at 1, 2, 4, 8, and 12 weeks later. RESULTS: At baseline, the 243 (43.5%) participants with melancholic features were more likely to have a previous history of depression, and had higher HAMA and lower SOFAS scores. After adjustment for baseline status, participants with melancholic features were more likely to achieve and to experience shorter times to CGI-s remission and associated with an enhanced global symptomatic remission with any antidepressant treatment. They were more likely to achieve and to experience shorter times to CGI-s remission and this difference was strongest in those receiving selective serotonin reuptake inhibitor (SSRI) antidepressants treatment. LIMITATIONS: The study was observational, and the treatment modality was naturalistic. CONCLUSIONS: These findings suggest a faster and more evident global response to pharmacotherapy in melancholia compared to other depressive syndromes, particularly where SSRI agents are used. PMID- 22840631 TI - Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder. AB - BACKGROUND: There is inconsistent evidence of interaction between stressful events and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. Recent studies have indicated that the moderating effect of 5-HTTLPR may be strongest when adverse experiences have occurred in childhood and the depressive symptoms persist over time. However, it is unknown whether this gene environment interaction is present for recurrent depressive disorder and different forms of maltreatment. Therefore, patients with recurrent clinically diagnosed depression and controls screened for the absence of depression were utilised to examine the moderating effect of 5-HTTLPR on associations between specific forms of childhood adversity and recurrent depression. METHOD: A sample of 227 recurrent unipolar depression cases and 228 never psychiatrically ill controls completed the Childhood Trauma Questionnaire to assess exposure to sexual, physical and emotional abuse, physical and emotional neglect in childhood. DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS: All forms of childhood maltreatment were reported as more severe by cases than controls. There was no direct association between 5-HTTLPR and depression. Significant interactions with additive and recessive 5-HTTLPR genetic models were found for overall severity of maltreatment, sexual abuse and to a lesser degree for physical neglect, but not other maltreatment types. LIMITATIONS: The cross-sectional design limits causal inference. Retrospective report of childhood adversity may have reduced the accuracy of the findings. CONCLUSIONS: This study provides support for the role of interplay between 5-HTTLPR and a specific early environmental risk in recurrent depressive disorder. PMID- 22840633 TI - Cognitive processes and attitudes in bipolar disorder: a study into personality, dysfunctional attitudes and attention bias in patients with bipolar disorder and their relatives. AB - BACKGROUND: Research in cognitive processes and attitudes in bipolar disorder is scarce and has provided mixed findings, possibly due to differences in current mood state. It is unclear whether alterations in cognitive processes and attitudes are only related to the depressive mood states of bipolar patients or also represent a vulnerability marker for the development of future (depressive) episodes. This was investigated in the current study. METHODS: Both implicit (attentional bias for emotional words) and explicit (dysfunctional attitudes and personality characteristics) measures of cognitive processes and attitudes were assessed in 77 bipolar patients with varying levels of depressive symptoms (depressed=17, euthymic n=60), their healthy first-degree relatives (n=39) and a healthy control group (n=61). Analyses of variance were used to investigate differences between groups. RESULTS: Mildly depressed patients with bipolar disorder demonstrated an attentional bias away from positive emotional words and showed increased dysfunctional attitudes and higher levels of neuroticism. Euthymic patients were largely comparable to healthy controls and only differed from controls in higher levels of neuroticism. Relatives were similar to controls on all measures, although they significantly differed from bipolar patients in displaying less neuroticism and more extraversion. LIMITATIONS: No firm conclusions regarding causality can be drawn from the associations that were found between cognitive processes and attitudes and the evolution of mood symptoms in bipolar disorder. CONCLUSION: Alterations in cognitive processes and attitudes in bipolar patients appear to be mostly related to the expression of mood symptomatology rather than to the vulnerability for bipolar disorder. PMID- 22840634 TI - Sympathetic system modulation to treat post-traumatic stress disorder (PTSD): a review of clinical evidence and neurobiology. AB - A review of clinical evidence and neurobiology on the effects of modulation of sympathetic system modulation to treat post-traumatic stress disorder (PTSD) is being presented . The review provides an overview of currently available treatments followed by efficacy of orally effective sympathetic blocking agents. The main focus of the review is the application of stellate ganglion blocks (SGBs) or a local anesthetic blockade of the sympathetic ganglion in the neck. PMID- 22840635 TI - Patient-practitioner relationships desired by overweight/obese adults. AB - OBJECTIVE: This study investigated the characteristics of the patient practitioner relationship desired by overweight/obese individuals in weight management. The aim was to identify characteristics of the relationship which empower patients to make lifestyle changes. METHODS: Grounded theory was used inductively to build a model of the patient-practitioner relationship based on the perspectives of 21 overweight/obese adults. RESULTS: Emerging from the match between patient and practitioner characteristics, collaboration was the key process explicitly occurring in the patient-practitioner relationship, and was characterised by two subcategories; perceived power dimensions and openness. Trust emerged implicitly from the collaborative process, being fostered by relational, informational, and credible aspects of the interaction. Patient trust in their practitioner consequently led to empowering outcomes including goal ownership and perceiving the utility of changes. CONCLUSION: An appropriate match between patient and practitioner characteristics facilitates collaboration which leads to trust, both of which appear to precede empowering outcomes for patients such as goal ownership and perceiving the utility of changes. Collaboration is an explicit process and precedes the patient trusting their practitioner. PRACTICE IMPLICATIONS: Practitioners should be sensitive to patient preferences for collaboration and the opportunity to develop trust with patients relationally, through information provision, and modelling a healthy lifestyle. PMID- 22840636 TI - Persistent toxic substances released from uncontrolled e-waste recycling and actions for the future. AB - The Basel Convention on the Control of Transboundary Movement of Hazardous Wastes and their Disposal was adopted on March 22, 1989 and enforced on May 5, 1992. Since then, the USA, one of the world's largest e-waste producers, has not ratified this Convention or the Basel Ban Amendment. Communities are still debating the legal loophole, which permits the export of whole products to other countries provided it is not for recycling. In January 2011, China's WEEE Directive was implemented, providing stricter control over e-waste imports to China, including Hong Kong, while emphasizing that e-waste recycling is the producers' responsibility. China is expected to supersede the USA as the principal e-waste producer, by 2020, according to the UNEP. Uncontrolled e-waste recycling activities generate and release heavy metals and POPs into the environment, which may be re-distributed, bioaccumulated and biomagnified, with potentially adverse human health effects. Greater efforts and scientific approaches are needed for future e-product designs of minimal toxic metal and compound use, reaping greater benefits than debating the definition and handling responsibilities of e-waste recycling. PMID- 22840637 TI - Development of a stream-aquifer numerical flow model to assess river water management under water scarcity in a Mediterranean basin. AB - Stream flow, as a part of a basin hydrological cycle, will be sensible to water scarcity as a result of climate change. Stream vulnerability should then be evaluated as a key component of the basin water budget. Numerical flow modeling has been applied to an alluvial formation in a small mountain basin to evaluate the stream-aquifer relationship under these future scenarios. The Arbucies River basin (116 km(2)) is located in the Catalan Inner Basins (NE Spain) and its lower reach, which is related to an alluvial aquifer, usually becomes dry during the summer period. This study seeks to determine the origin of such discharge losses whether from natural stream leakage and/or induced capture due to groundwater withdrawal. Our goal is also investigating how discharge variations from the basin headwaters, representing potential effects of climate change, may affect stream flow, aquifer recharge, and finally environmental preservation and human supply. A numerical flow model of the alluvial aquifer, based on MODFLOW and especially in the STREAM routine, reproduced the flow system after the usual calibration. Results indicate that, in the average, stream flow provides more than 50% of the water inputs to the alluvial aquifer, being responsible for the amount of stored water resources and for satisfying groundwater exploitation for human needs. Detailed simulations using daily time-steps permit setting threshold values for the stream flow entering at the beginning of the studied area so surface discharge is maintained along the whole watercourse and ecological flow requirements are satisfied as well. The effects of predicted rainfall and temperature variations on the Arbucies River alluvial aquifer water balance are also discussed from the outcomes of the simulations. Finally, model results indicate the relevance of headwater discharge management under future climate scenarios to preserve downstream hydrological processes. They also point out that small mountain basins could be self-sufficient units so long as the response of the main hydrological components to external forces that produce water scarcity, as climate change or human pressures, is appropriately considered in water resource planning. PMID- 22840638 TI - Identification of cause of posttransplant cachexia by PCR. PMID- 22840639 TI - Behavioural intervention to increase physical activity among patients with coronary heart disease: protocol for a randomised controlled trial. AB - BACKGROUND: Although physical activity has significant health benefits in the treatment of patients with coronary heart disease, patients often do not follow prescribed physical activity recommendations. Behavioural strategies have been shown to be efficacious in increasing physical activity among those patients with coronary heart disease who are attending structured cardiac rehabilitation programmes. Research has also shown that tailoring consultation according to patients' needs and sending motivational reminders are successful ways of motivating patients to be physically active. However, there is a lack of evidence for the efficacy of behavioural interventions based on individualised consultation in promoting physical activity among those patients with coronary heart disease who are not attending structured physical activity programmes. OBJECTIVE: This paper outlines the study protocol for a trial which is currently underway, to examine the effect of a behavioural change intervention delivered through individualised consultation calls and motivational reminder text messages on the level of physical activity among patients with coronary heart disease. SETTING: Two large hospitals in Jordan. PARTICIPANTS: Eligible patients aged between 18 and 70 years, who are clinically stable, are able to perform physical activity and who have access to a mobile telephone have been randomly allocated to control or intervention group. DESIGN AND METHODS: Two-group randomised controlled trial. Behavioural intervention will be compared with usual care in increasing physical activity levels among patients with coronary heart disease. The control group (n=85) will receive advice from their doctors about physical activity as they would in usual practice. The intervention group (n=71) will receive the same advice, but will also receive behavioural change intervention (goal-setting, feed-back, self-monitoring) that will be delivered over a period of six months. Intervention will be delivered through individually tailored face to-face and telephone consultations, supported by motivational SMS text messages to encourage and remind patients to attain these goals. The participants and the researcher delivering the intervention are not blinded to group assignment. RESULTS: Recruitment started in February 2012 and preliminary findings are expected in November 2012. CONCLUSION: It is hypothesised that behavioural intervention delivered through tailored individualised consultation supported by motivational SMS text message reminders will help CHD patients to increase their level of PA. TRIAL REGISTRATION: The study is registered as a clinical trial at ISRCTN register (ISRCTN48570595). PMID- 22840640 TI - [Detection of sexual dysfunction in primary care]. PMID- 22840641 TI - The role of several ABC transporter genes in ivermectin resistance in Caenorhabditis elegans. AB - The functions of nine ATP-binding cassette (ABC) transporter genes, mrp-1, mrp-4, mrp-6, pgp-2, pgp-3, pgp-4, pgp-5, haf-2 and haf-9, in an ivermectin (IVM) resistant strain of Caenorhabditis elegans were screened by comparing transcription levels between the resistant (IVR10) and wild-type (Bristol N2) strains, and by measuring the effects of RNA interference (RNAi) on the IVM resistant strain, on motility, pharyngeal pumping, egg production and death in the presence or varying concentrations of IVM (0-20 ng/ml). mRNA levels of mrp-1, 2, 4, 5, 6, 7, pgp-1, 2, 4, 12, 14, haf-1, 2 and 3 were significantly increased in IVR10 compared with the N2 strain. At 15 or 20 ng/ml IVM, down regulation of mrp-1, pgp-4, haf-2 and haf-9 significantly increased the effect of IVM to reduce egg production. At low to moderate IVM concentrations, down regulation of mrp-1 and haf-2 reduced the motility of C. elegans. However, at high IVM concentrations motility was increased by down regulation of transcription of pgp-3, pgp-4 and haf-9. Down regulation of expression of mrp-1, pgp-2 and pgp-5 resulted in reduced pharyngeal pumping in the presence of varying concentrations of IVM, while down regulation of mrp-6 and haf-2 increased pharyngeal pumping of the resistant strain irrespective of the IVM concentration used. Although the IVR10 strain was markedly resistant to IVM, compared with the unselected N2 strain, IVM led to the death of the C. elegans in a concentration dependent manner. However, differences in the IVM induced death rate, following RNAi, were not significantly different from the IVR10 strain without RNAi. The study shows that different ABC transporter genes may play a role in modulating the effects of IVM on pharyngeal pumping, motility and egg production, with down regulation of mrp-1 and haf-2 perhaps having the greatest effects. However, down regulation of expression of no individual ABC transporter gene profoundly affected the effect of IVM on mortality in the IVR10 strain. This suggests that some of these ABC transporter genes and their products may play a role in modulating the effects of IVM, but are not, individually, the critical gene responsible for IVM resistance. This study provides a model that may help to understand drug resistance in parasitic nematodes. PMID- 22840642 TI - Virulence potential of Metarhizium anisopliae s.l. isolates on Rhipicephalus (Boophilus) microplus larvae. AB - The use of entomopathogenic fungi to control arthropods has been reported worldwide for decades. The aim of the present study was to evaluate the virulence of 30 Metarhizium anisopliae s.l. Brazilian isolates from different geographical regions, hosts or substrates on the larvae of Rhipicephalus (Boophilus) microplus ticks under in vitro conditions to the selection of virulent isolates in order to be further used in biological control programs. The current study confirmed the lethal action of M. anisopliae s.l. isolates on R. (B.) microplus larvae with different mortality levels, usually directly proportional to the conidia concentration. No relationship was found between the origin of the isolate and its virulence potential or between the virulence potential and conidia production. Three isolates (CG 37, CG 384 and IBCB 481) caused a high percentage of larval mortality, reaching LC(50) at 10(6) conidia ml(-1), thus requiring a lower conidia concentration to cause an approximately 100% larval mortality. The results of this study suggest that these three isolates are the most promising for use in programs aimed at microbial control in the field. PMID- 22840643 TI - A diagnostic study of Echinococcus multilocularis in red foxes (Vulpes vulpes) from Great Britain. AB - Alveolar echinococcosis is caused by a parasitic tapeworm Echinococcus multilocularis and is a serious disease with high fatality in humans. The definitive primary host is the red fox (Vulpes vulpes) but domestic animals (dogs and to a lesser extent cats) as well as several genera of rodents can also be infected with the parasite. There is, to date, no evidence of indigenous cases of E. multilocularis in Great Britain (GB) but in most of continental Europe the parasite is considered to be endemic and/or slowly spreading. All pet dogs entering the United Kingdom (UK) under the pet travel scheme (PETS) are therefore currently treated with an anthelmintic effective against Echinococcus spp. Surveillance of red foxes is required to demonstrate disease freedom and maintain this regulation to prevent further geographical spread of the parasite to free areas within the EU. A study of 588 wild red foxes collected from across Great Britain (GB) between October 1999 and November 2000 found no Echinococcus spp. This report describes a further study of GB foxes collected predominately during 2005 and 2006. Fox faecal samples (n=384) were examined for both E. multilocularis and Echinococcus granulosus using an egg isolation procedure followed by PCR method, based on published primer sets. A non-specific primer set that amplifies Taenia spp. as well as Mesocestoides, Dipylidium and Diphyllobothrium was also included in the assay to validate the test procedure as these parasites are expected to be more common in wild fox populations. All faecal samples tested negative for both E. multilocularis and E. granulosus but results for approximately 35% of the samples indicated the presence of Taenia spp. or other closely related cestodes. This data contributes to the evidence that suggests that E. multilocularis is not present in mainland Britain and justifies the requirement for ongoing surveillance to demonstrate disease freedom. PMID- 22840644 TI - Miniaturization through lab-on-a-chip: utopia or reality for routine laboratories? A review. AB - Micro total analysis (MUTAS), also called "lab-on-a-chip (LOC)" technology, promises solutions for high throughput and highly specific analysis for chemistry, biology and medicine, while consuming only tiny amounts of samples, reactants and space. This article reports selected contributions of LOC, which represent clear practical approaches for routine work, or presenting potentiality to be transferred to routine analytical laboratories. Taking into account the present LOC state-of-the-art, we identify various reasons for its scarce implementation in routine analytical laboratories despite its high analytical potential, as well as the probably main "niche" for successfully practical developments is suggested. PMID- 22840645 TI - Instrument and process independent binning and baseline correction methods for liquid chromatography-high resolution-mass spectrometry deconvolution. AB - Setting appropriate bin sizes to aggregate hyphenated high-resolution mass spectrometry data, belonging to similar mass over charge (m/z) channels, is vital to metabolite quantification and further identification. In a high-resolution mass spectrometer when mass accuracy (ppm) varies as a function of molecular mass, which usually is the case while reading m/z from low to high values, it becomes a challenge to determine suitable bin sizes satisfying all m/z ranges. Similarly, the chromatographic process within a hyphenated system, like any other controlled processes, introduces some process driven systematic behavior that ultimately distorts the mass chromatogram signal. This is especially seen in liquid chromatogram-mass spectrometry (LC-MS) measurements where the gradient of the solvent and the washing step cycle-part of the chromatographic process, produce a mass chromatogram with a non-uniform baseline along the retention time axis. Hence prior to any automatic signal decomposition techniques like deconvolution, it is a equally vital to perform the baseline correction step for absolute metabolite quantification. This paper will discuss an instrument and process independent solution to the binning and the baseline correction problem discussed above, seen together, as an effective pre-processing step toward liquid chromatography-high resolution-mass spectrometry (LC-HR-MS) data deconvolution. PMID- 22840646 TI - Random frog: an efficient reversible jump Markov Chain Monte Carlo-like approach for variable selection with applications to gene selection and disease classification. AB - The identification of disease-relevant genes represents a challenge in microarray based disease diagnosis where the sample size is often limited. Among established methods, reversible jump Markov Chain Monte Carlo (RJMCMC) methods have proven to be quite promising for variable selection. However, the design and application of an RJMCMC algorithm requires, for example, special criteria for prior distributions. Also, the simulation from joint posterior distributions of models is computationally extensive, and may even be mathematically intractable. These disadvantages may limit the applications of RJMCMC algorithms. Therefore, the development of algorithms that possess the advantages of RJMCMC methods and are also efficient and easy to follow for selecting disease-associated genes is required. Here we report a RJMCMC-like method, called random frog that possesses the advantages of RJMCMC methods and is much easier to implement. Using the colon and the estrogen gene expression datasets, we show that random frog is effective in identifying discriminating genes. The top 2 ranked genes for colon and estrogen are Z50753, U00968, and Y10871_at, Z22536_at, respectively. (The source codes with GNU General Public License Version 2.0 are freely available to non commercial users at: http://code.google.com/p/randomfrog/.). PMID- 22840647 TI - High-performance liquid chromatography with fast-scanning fluorescence detection and multivariate curve resolution for the efficient determination of galantamine and its main metabolites in serum. AB - Based on green analytical chemistry principles, an efficient approach was applied for the simultaneous determination of galantamine, a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease, and its major metabolites in serum samples. After a simple serum deproteinization step, second-order data were rapidly obtained (less than 6 min) with a chromatographic system operating in the isocratic regime using ammonium acetate/acetonitrile (94:6) as mobile phase. Detection was made with a fast-scanning spectrofluorimeter, which allowed the efficient collection of data to obtain matrices of fluorescence intensity as a function of retention time and emission wavelength. Successful resolution was achieved in the presence of matrix interferences in serum samples using multivariate curve resolution-alternating least-squares (MCR-ALS). The developed approach allows the quantification of the analytes at levels found in treated patients, without the need of applying either preconcentration or extraction steps. Limits of detection in the range between 8 and 11 ng mL(-1), relative prediction errors from 7 to 12% and coefficients of variation from 4 to 7% were achieved. PMID- 22840648 TI - A high-throughput approach for the determination of pesticide residues in cucumber samples using solid-phase microextraction on 96-well plate. AB - A high-throughput solid-phase microextraction (SPME) on 96-well plate together with gas chromatography-mass spectrometry (GC-MS) was developed for the determination of some selected pesticides in cucumber samples. Pieces with the length of 1.0 cm of silicon tubing were precisely prepared and then coated on the end part of stainless steel wires. The prepared fibers were positioned in a home made polytetrafluoroethylene (PTFE)-based constructed ninety-six holes block to have the possibility of simultaneous immersion of the SPME fibers into the center of individual wells. Pesticides such as diazinon, penconazol, tebuconazol, bitertanol, malathion, phosalone and chlorpyrifos-methyl were selected for their highly application in cucumber field. The performances of the SPME fibers, such as intra and inter-fibers reproducibility, were evaluated and the results showed a good similarity in extraction yields. A volume of 1 mL of the aquatic supernatant of the cucumber samples was transferred into the 96-well plate and the array of SPME fibers was applied for the extraction of the selected pesticides. The important parameters influencing the whole extraction process including, organic solvent percent, salt addition, dilution factor, stirring rate and extraction time were optimized. The inter- and intra-day RSD% were found to be less than 15.4%. Limits of detection (LOD) and limits of quantification (LOQ) were below 60 and 180 MUg kg(-1), respectively. The coefficient of determination was satisfactory (r(2)>0.99) for all the studied analytes. The developed method was successfully applied to the monitoring of several samples gathered from local markets. PMID- 22840649 TI - Multiresidue determination of pesticides from aquatic media using polyaniline nanowires network as highly efficient sorbent for microextraction in packed syringe. AB - A simple, rapid and sensitive method based on microextraction in packed syringe (MEPS), in combination with gas chromatography-mass spectrometry (GC-MS) was developed. Polyaniline (PANI) nanowires network was synthesized and used as sorbent of MEPS for the multiresidue determination of selected analytes from triazine, organochlrorine and organophosphorous pesticides in aqueous samples. The PANI nanowires network was prepared using soft template technique and its characterization was studied by scanning electron microscopy (SEM). The presence of micelles in this methodology showed to be an important parameter in shaping the growing polymer. Hexadecyltrimethylammonium bromide (HTAB) was used as structure directing agent in PANI preparation procedure and this was led to the formation of nanowires with diameters ranging from 35 nm to 45 nm. The synthesized PANI nanowires network showed higher extraction capability in comparison with the bulk PANI. Important parameters influencing the extraction and desorption processes including desorption solvent, elution volume, draw-eject cycles of sample, draw-eject mode, pH effect and amount of sorbent were optimized. Limits of detection were in the range of 0.07-0.3 ng mL(-1) using time scheduled selected ion monitoring (SIM) mode. The linearity of method was in the range from 0.5-200 ng mL(-1) to 0.2-1000 ng mL(-1). The method precision (RSD %) with three replicates were in the range of 5.3-18.4% at the concentration level of 5 ng mL(-1). The developed method was successfully applied to the Zayandeh rood river water samples and the matrix factor obtained for the spiked real water samples were in the range of 0.79-0.94. PMID- 22840650 TI - Ion-pair sorptive extraction of perfluorinated compounds from water with low-cost polymeric materials: polyethersulfone vs polydimethylsiloxane. AB - A method for the determination of seven perfluorinated carboxylic acids and perfluorooctane sulphonate (PFOS) in aqueous samples using low-cost polymeric sorptive extraction as sample preparation technique, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) determination has been developed and validated. Simplicity of the analytical procedure, low volume of solvent and sample required, low global price and a good selectivity providing cleaner extracts are the main advantages of this extraction technique. Polydimethylsiloxane (PDMS) and polyethersulfone (PES) materials were evaluated and compared to achieve the best extraction efficiencies. Hence, different variables have been optimized, viz.: sample pH, concentration of an ion-pairing agent (tetrabutylammonium), ionic strength, sample volume, extraction time, desorption solvent volume, desorption time and the need for auxiliary desorption techniques (sonication). Overall, PES leaded to a better sensitivity than PDMS, particularly for the most polar compounds, reaching detection limits (LODs) in the 0.2-20 ng L(-1) range. The precision of the method, expressed as relative standard deviation (RSD), was lower than 16%. Finally, the PES material was employed for the analysis of sea, sewage and fresh water samples. Perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were detected in all the analyzed influent samples reaching levels of up to 401 ng L(-1). In surface water, perfluorohexanoic acid (PFHxA) exhibited the highest concentrations, up to 137 ng L(-1). PMID- 22840651 TI - Comparison of three different enrichment strategies for serum low molecular weight protein identification using shotgun proteomics approach. AB - Serum low-molecular weight (LMW) proteins potentially contain useful biological information and their identification can be used to discover novel potential biomarkers. Given the high complexity of serum samples, in the last years several different prefractionation and enrichment strategies have been developed. In this study three different methods, i.e. hydrogel nanoparticles, Proteominer((r)) peptide ligand affinity beads and Sartorius Vivaspin((r)) centrifugal ultrafiltration device, were compared and evaluated in order to select the best strategy for the enrichment and prefractionation of LMW proteins. A shotgun proteomics approach was adopted, with in-solution proteolytic digestion of the whole protein mixture and determination of the resulting peptides by nanoHPLC coupled with a high-resolution Orbitrap LTQ-XL mass spectrometer. Data analysis, focusing on the LMW proteome (MW <= 40 kDa), has shown that the hydrogel nanoparticles performed better in enriching the LMW protein profiles, with 115 proteins identified against 93 and 95 for Proteominer((r)) beads and Sartorius Vivaspin((r)) device, respectively. PMID- 22840652 TI - Evaluating the complexation behavior and regeneration of boron selective glucaminium-based ionic liquids when used as extraction solvents. AB - Glucaminium-based ionic liquids are a new class of solvents capable of extracting boron-species from water with high efficiency. The complexation behavior of these ILs with borate was thoroughly studied using (11)B NMR. Two different complexes, namely, monochelate complex and bischelate complex, were observed. (11)B NMR was used extensively to determine the formation constants for monochelate and bischelate complexes. The IL concentration was observed to have a significant effect on the IL-borate complexes. Using an in situ dispersive liquid-liquid microextraction (in situ DLLME) method, the extraction efficiency for boron species was increased dramatically when lithium bis[(trifluoromethyl)sulfonyl]imide (LiNTf(2)) was used as the metathesis salt in an aqueous solution containing 0.1M sodium chloride. IL regeneration after extraction was achieved using 0.1M hydrochloric acid. The extraction efficiency of boron species was consistent when the IL was employed after three regeneration cycles. The selectivity of the IL for boron species in synthetic seawater samples was similar to performing the same extraction from Milli-Q water samples. PMID- 22840653 TI - A naked-eye based strategy for semiquantitative immunochromatographic assay. AB - It is critical to develop a cost-effective quantitative/semiquantitative assay for rapid diagnosis and on-site detection of toxic or harmful substances. Here, a naked-eye based semiquantitative immunochromatographic strip (NSI-strip) was developed, on which three test lines (TLs, TL-I, TL-II and TL-III) were dispensed on a nitrocellulose membrane to form the test zone. Similar as the traditional strip assay for small molecule, the NSI-strip assay was also based on the competitive theory, difference was that the analyte competed three times with the capture reagent for the limited number of antibody binding sites. After the assay, the number of TLs developed in the test zone was inversely proportional to the analyte concentration, thus analyte content levels could be determined by observing the appeared number of TLs. Taking aflatoxin B(1) as the model analyte, visual detection limit of the NSI-strip was 0.06 ng mL(-1) and threshold concentrations for TL-I-III were 0.125, 0.5, and 2.0 ng mL(-1), respectively. Therefore, according to the appeared number of TLs, the following concentration ranges would be detectable by visual examination: 0-0.06 ng mL(-1) (negative samples), and 0.06-0.125 ng mL(-1), 0.125-0.5 ng mL(-1), 0.5-2.0 ng mL(-1) and >2.0 ng mL(-1) (positive samples). That was to say, compared to traditional strips the NSI-strip could offer more parameter information of the target analyte content. In this way, the NSI-strip improved the qualitative presence/absence detection of traditional strips by measuring the content (range) of target analytes semiquantitatively. PMID- 22840654 TI - Photoluminescent and electrochemiluminescent dual-signaling probe for bio-thiols based on a ruthenium(II) complex. AB - Photoluminescence (PL) and electrochemiluminescence (ECL) detection techniques are highly sensitive and widely used methods for clinical diagnostics and analytical biotechnology. In this work, a unique ruthenium(II) complex, [Ru(bpy)(2)(DNBSO-bpy)](PF(6))(2) (bpy: 2,2'-bipyridine; DNBSO-bpy: 2,4 dinitrobenzenesulfonate of 4-(4-hydroxyphenyl)-2,2'-bipyridine), has been designed and synthesized as a highly sensitive and selective PL and ECL dual signaling probe for the recognition and detection of bio-thiols in aqueous media. As a thiol-responsive probe, the complex can specifically and rapidly react with bio-thiols in aqueous solutions to yield a bipyridine-Ru(II) complex derivative, [Ru(bpy)(2)(HP-bpy)](2+) (HP-bpy: 4-(4-hydroxyphenyl)-2,2'-bipyridine), accompanied by the remarkable PL and ECL enhancements. The complex was used as a probe for the PL and ECL detections of cysteine (Cys) and glutathione (GSH) in aqueous solutions. The dose-dependent PL and ECL enhancements showed good linear relationships against the Cys/GSH concentrations with the detection limits at nano-molar concentration level. Moreover, the complex-loaded HeLa cells were prepared for PL imaging of the endogenous intracellular thiols. The results demonstrated the practical utility of the complex as a cell-membrane permeable probe for PL imaging detection of bio-thiols in living cells. PMID- 22840655 TI - A graphene-based real-time fluorescent assay of deoxyribonuclease I activity and inhibition. AB - Using the remarkable difference in the affinity of graphene oxide (GO) with double strand DNA (dsDNA) and short DNA fragments, we report for the first time a GO-based nonrestriction nuclease responsive system. Our system was composed of GO and a fluorescent dye fluorescein amidite (FAM)-labeled dsDNA substrate (F dsDNA). At first, the fluorescence of this F-dsDNA substrate was quenched upon addition of GO. When nuclease was added to the mixture of dsDNA and GO, hydrolysis of dsDNA was initiated and small DNA fragments were produced. As a result, the short FAM-linked DNA fragments were released from GO due to the weak affinity of GO with short DNA fragments, and the fluorescence got a restoration. At present, many sensing systems are based on the fact that GO prefers to bind long single strand DNA (ssDNA) over dsDNA or short ssDNA. As for our system, GO has a prior binding with dsDNA over short DNA fragments. Compared with previous methods, this assay platform has some advantages. First, since GO can be prepared in large quantities from graphite available at very low cost, this method shows advantages of simplicity and cost efficiency. Besides, the proposed GO-based nuclease assay provides high sensitivity due to the super quenching capacity of GO. Using deoxyribonuclease I (DNase I) as a model system, DNase I activity can be quantitatively analyzed by the velocity of the enzymatic reaction, and 1.75 U mL(-1) DNase I can be significantly detected. Moreover, the fluorescent intensity with various concentrations of nuclease becomes highly discriminating after 3-8 min. Thus, it is possible to detect nuclease activity within 3-8 min, which demonstrates another advantage of quick response of the present system. Finally, use of dsDNA as substrate, our method can achieve real-time nuclease activity/inhibition assay, which is time-saving and effortless. PMID- 22840657 TI - Lack of evidence for Schmallenberg virus infection in highly exposed persons, Germany, 2012. AB - Schmallenberg virus, a novel orthobunyavirus, is spreading among ruminants, especially sheep, throughout Europe. To determine the risk for human infection, we conducted a survey among shepherds to assess possible exposure and symptoms. We also performed serologic and molecular assays. No evidence of transmission to humans was detected. PMID- 22840656 TI - Determination of polycyclic aromatic hydrocarbons and their oxy-, nitro-, and hydroxy-oxidation products. AB - A sensitive method has been developed for the trace analysis of PAHs and their oxidation products (i.e., nitro-, oxy-, and hydroxy-PAHs) in air particulate matter (PM). Following PM extraction, PAHs, nitro-, oxy-, and hydroxy-PAHs were fractionated using solid phase extraction (SPE) based on their polarities. Gas chromatography-mass spectrometry (GC-MS) conditions were optimized, addressing injection (i.e., splitless time), negative-ion chemical ionization (NICI) parameters, i.e., source temperature and methane flow rate, and MS scanning conditions. Each class of PAH oxidation products was then analyzed using the sample preparation and appropriate ionization conditions (e.g., nitro-PAHs exhibited the greatest sensitivity when analyzed with NICI-MS while hydroxy-PAHs required chemical derivatization prior to GC-MS analysis). The analyses were performed in selected-ion-total-ion (SITI) mode, combining the increased sensitivity of selected-ion monitoring (SIM) with the identification advantages of total-ion current (TIC). The instrumental LODs determined were 6-34 pg for PAHs, 5-36 pg for oxy-PAHs, and 1-21 pg for derivatized hydroxy-PAHs using electron ionization (GC-EI-MS). NICI-MS was found to be a useful tool for confirming the tentative identification of oxy-PAHs. For nitro-PAHs, LODs were 1 10 pg using negative-ion chemical ionization (GC-NICI-MS). The developed method was successfully applied to two types of real-world PM samples, diesel exhaust standard reference material (SRM 2975) and wood smoke PM. PMID- 22840658 TI - Physical activity and biomarkers in breast cancer survivors: a systematic review. AB - Breast cancer is the most common cancer among women. The number of breast cancer survivors has increased due to screening and improved treatment methods, which makes it important to increase knowledge on their health and well-being. Physical activity has been reported to improve quality of life, decrease fatigue and reduce all-cause and breast cancer-specific mortality in breast cancer survivors. The beneficial effects of physical activity may manifest themselves in circulating levels of insulin, insulin-growth factors (IGFs) I and II and their binding proteins (IGFBPs), or inflammatory biomarkers. The aim of this report was to review available randomized controlled trials (RCTs) on the effects of physical activity on biomarkers in breast cancer survivors. We identified 12 publications based on nine RCTs that fulfilled our inclusion criteria published until 19th June 2012. The RCTs were small (16-101 breast cancer survivors); mean BMI was >=25 and the mean age in 8 out of 9 RCTs was approximately 50 years. Five RCTs reported statistically significant effects of physical activity on insulin, IGF-I, IGF-II and IGFBP-3 in breast cancer survivors, but the results were not consistent. None of four RCTs found any evidence for a role of investigated interleukines. One trial reported some evidence that exercise may decrease C reactive protein levels. In conclusion, available RCTs have produced some evidence that physical activity may result in beneficial changes in levels of insulin, IGFs, IGFBPs, and inflammatory biomarkers in breast cancer survivors. However, further larger RCTs on physical activity and biomarkers in breast cancer survivors are warranted. PMID- 22840659 TI - Performance of a large building rainwater harvesting system. AB - Rainwater harvesting is increasingly becoming an integral part of the sustainable water management toolkit. Despite a plethora of studies modelling the feasibility of the utilisation of rainwater harvesting (RWH) systems in particular contexts, there remains a significant gap in knowledge in relation to detailed empirical assessments of performance. Domestic systems have been investigated to a limited degree in the literature, including in the UK, but there are few recent longitudinal studies of larger non-domestic systems. Additionally, there are few studies comparing estimated and actual performance. This paper presents the results of a longitudinal empirical performance assessment of a non-domestic RWH system located in an office building in the UK. Furthermore, it compares actual performance with the estimated performance based on two methods recommended by the British Standards Institute - the Intermediate (simple calculations) and Detailed (simulation-based) Approaches. Results highlight that the average measured water saving efficiency (amount of mains water saved) of the office based RWH system was 87% across an 8-month period, due to the system being over sized for the actual occupancy level. Consequently, a similar level of performance could have been achieved using a smaller-sized tank. Estimated cost savings resulted in capital payback periods of 11 and 6 years for the actual over sized tank and the smaller optimised tank, respectively. However, more detailed cost data on maintenance and operation is required to perform whole life cost analyses. These findings indicate that office-scale RWH systems potentially offer significant water and cost savings. They also emphasise the importance of monitoring data and that a transition to the use of Detailed Approaches (particularly in the UK) is required to (a) minimise over-sizing of storage tanks and (b) build confidence in RWH system performance. PMID- 22840660 TI - Bloodstream infection, venous thrombosis, and peripherally inserted central catheters: reappraising the evidence. AB - The widespread use of peripherally inserted central catheters (PICCs) has transformed the care of medical and surgical patients. Whereas intravenous antibiotics, parenteral nutrition, and administration of chemotherapy once necessitated prolonged hospitalization, PICCs have eliminated the need for such practice. However, PICCs may not be as innocuous as once thought; a growing body of evidence suggests that these devices also have important risks. This review discusses the origin of PICCs and highlights reasons behind their rapid adoption in medical practice. We evaluate the evidence behind 2 important PICC-related complications--venous thrombosis and bloodstream infections--and describe how initial studies may have led to a false sense of security with respect to these outcomes. In this context, we introduce a conceptual model to understand the risk of PICC-related complications and guide the use of these devices. Through this model, we outline recommendations that clinicians may use to prevent PICC-related adverse events. We conclude by highlighting important knowledge gaps and identifying avenues for future research in this area. PMID- 22840661 TI - Cardiac evaluation of collegiate student athletes: a medical and legal perspective. AB - Physicians participate in the screening, routine medical supervision, and disqualification process of collegiate student athletes today. Physicians and universities evaluating collegiate student athletes for athletic participation should understand the meticulous medical process necessary to make eligibility/disqualification decisions and the associated liability issues. It is the responsibility of a team physician to take the lead role in the college sports medical evaluation process. The first duty of a team physician and institution is to protect the health and well-being of their collegiate student athletes. The potential liability associated with the evaluation process requires institutions of higher education and physicians to develop sound and reasonable administrative strategies regarding college athletes and their participation in intercollegiate athletics. Reducing this liability risk requires an understanding of the evolving judicial framework and compliance with standard case law and available guidelines. As medical professional standards evolve, so will responsibilities under legal standards. PMID- 22840662 TI - Pustular eruption in the ICU. PMID- 22840663 TI - A real exercise stress test. PMID- 22840664 TI - Risk of falls and major bleeds in patients on oral anticoagulation therapy. AB - BACKGROUND: The risk of falls is the most commonly cited reason for not providing oral anticoagulation, although the risk of bleeding associated with falls on oral anticoagulants is still debated. We aimed to evaluate whether patients on oral anticoagulation with high falls risk have an increased risk of major bleeding. METHODS: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants. The outcome was the time to a first major bleed within a 12-month follow-up period adjusted for age, sex, alcohol abuse, number of drugs, concomitant treatment with antiplatelet agents, and history of stroke or transient ischemic attack. RESULTS: Among the 515 enrolled patients, 35 patients had a first major bleed during follow-up (incidence rate: 7.5 per 100 patient-years). Overall, 308 patients (59.8%) were at high risk of falls, and these patients had a nonsignificantly higher crude incidence rate of major bleeding than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P=.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed (hazard ratio 1.09; 95% confidence interval, 0.54-2.21). Overall, only 3 major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). CONCLUSIONS: In this prospective cohort, patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. These findings suggest that being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients. PMID- 22840665 TI - CRP level and HDL cholesterol concentration jointly predict mortality in a Korean population. AB - BACKGROUND: C-reactive protein (CRP) and high-density lipoprotein (HDL) cholesterol are well-known cardiovascular predictors. However, the joint effect of these parameters on long-term mortality has not been established. METHODS: We studied a total of 92,500 subjects older than 20 years who underwent routine health examination at the three health care centers affiliated with Seoul National University. High-sensitivity CRP and the lipid profile were obtained at baseline. Subjects were followed for a median of 45.5 months. Mortality data were obtained from the National Statistics Office of Korea. RESULTS: There were 649 deaths (0.7%) during the follow-up. The leading cause of death was cancer. The subjects who died were significantly older, had a male predominance, and had increased levels of inflammatory markers. A significant mortality difference was identified according to the CRP and HDL cholesterol levels. Considering both parameters jointly, subjects with a CRP >=1.4 mg/L (highest quartile) and HDL cholesterol <45 mg/dL (lowest quartile) were at the highest risk for all-cause mortality, even after adjusting for covariates (hazard ratio 2.29, 95% confidence interval, 1.83~2.87). After matching on the propensity score, 6304 subjects with a high CRP and low HDL cholesterol were at high risk of death (hazard ratio 2.52, 95% confidence interval, 1.59~4.01). Interestingly, the joint effect of CRP and HDL cholesterol was observed for cardiovascular as well as cancer-related mortality prediction. CONCLUSIONS: Elevated CRP and low HDL cholesterol jointly contribute to the prediction of all-cause, cancer, and cardiovascular mortality in Koreans. The interactive relationship between them in mediating inflammatory processes might explain these results. PMID- 22840666 TI - Placebo adherence and mortality in the Heart and Estrogen/Progestin Replacement Study. AB - BACKGROUND: Analyses from double-blind randomized trials have reported lower mortality among participants who were more adherent to placebo compared with those who were less adherent. We explored this phenomenon by analyzing data from the placebo arm of the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, double-blind, placebo-controlled trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the HERS. Secondary aims included assessment of the association between placebo adherence and cause-specific morbidity and mortality. METHODS: Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication during each individual's participation in the study, whereas those with "lower placebo adherence" took less than 75%. The primary outcome was in-study all-cause mortality. RESULTS: More adherent participants had significantly lower total mortality compared with less adherent participants (hazard ratio, 0.52; 95% confidence interval, 0.29-0.93). Adjusting for available confounders did not change the magnitude or significance of the estimates. Analyses revealed that the association of higher adherence and mortality might be explained, in part, by time-dependent confounding. CONCLUSIONS: Analyses of the HERS data support a strong association between adherence to placebo study medication and mortality. Although probably not due to simple confounding by healthy lifestyle factors, the underlying mechanism for the association remains unclear. Further analyses of this association are necessary to explain this observation. PMID- 22840667 TI - Eplerenone is not superior to older and less expensive aldosterone antagonists. AB - INTRODUCTION: Eplerenone is publicized to be extremely effective in reducing mortality from heart failure, with a reasonable side-effect profile. However, it is much more expensive compared with older aldosterone antagonists. We reviewed available evidence to assess whether increased expense was justified with outcomes data. METHODS AND RESULTS: The authors searched the PubMed, CENTRAL, CINAHL, and EMBASE databases for randomized controlled trials from 1966 through July 2011. Interventions included aldosterone antagonists (Aldactone [Pfizer, NY, NY], canrenone, eplerenone) in systolic heart failure. The comparator included standard medical therapy or placebo, or both. Outcomes assessed were mortality in the intervention versus the comparator groups, and rates of adverse events at the end of at least 8 weeks of follow-up. Event rates were compared using a forest plot of relative risk (RR) (95% confidence interval [CI]) using a random-effects model (Mantel-Haenszel) between the aldosterone antagonists and controls. We included 13 studies for aldosterone antagonists other than eplerenone, and 3 studies for eplerenone. There was significant reduction of mortality with all aldosterone antagonists, but eplerenone (15% mortality relative reduction; RR 0.85; 95% CI, 0.77-0.93; P=.0007) was outperformed by other aldosterone antagonists, namely, spironolactone and canrenone (26% mortality relative reduction; RR 0.74; 95% CI, 0.66-0.83; P <.0001). Reduction in cardiovascular mortality with eplerenone was 17% (RR 0.83; 95% CI, 0.75-0.92; P=.0005), while that with other aldosterone antagonists was 25% (RR 0.75; 95% CI, 0.67-0.84, P <.0001), without contributing significantly to an improved side-effect profile. CONCLUSION: Eplerenone does not appear to be more effective in reducing clinical events compared with older, less expensive aldosterone antagonists. PMID- 22840669 TI - Quality improvement and patient safety activities in academic departments of medicine. PMID- 22840668 TI - A rare hematological adverse event induced by bevacizumab: severe thrombocytopenia. AB - BACKGROUND: Bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, is approved for the treatment of various malignancies, and its hematological toxicities are considered infrequent. METHODS: A colorectal cancer patient receiving chemotherapy (5-fluorouracil and oxaliplatin) plus bevacizumab developed acute, severe thrombocytopenia. We postulated that this thrombocytopenia could be directly triggered by bevacizumab. RESULTS: A man with stage IV colorectal cancer and synchronous liver metastasis had received 10 cycles of FOLFOX plus bevacizumab (5 mg/kg) without significant hematological toxicity. Due to thrombocytopenia, oxaliplatin was withdrawn after cycle 11. On cycle 12, shortly after bevacizumab infusion and before 5-fluorouracil infusion, the patient developed fever, lower limbs purpura, grade 1 proctorrhagia, and epistaxis. Platelets had decreased from 105,000/mm(3) to 3000/mm(3) within 1 hour after bevacizumab infusion. Flow cytometry identified platelet-associated immunoglobulins. Despite 2 apheresis-derived platelet transfusions, oral corticotherapy, and gamma globulin infusions, thrombocytopenia persisted, but was finally successfully treated with a peptibody thrombopoietin mimetic, which was introduced 28 days after the last bevacizumab infusion. CONCLUSIONS: Clinicians should keep in mind that bevacizumab can induce acute and potentially severe immune-mediated thrombocytopenia. PMID- 22840670 TI - The lived experiences of chronic pain. PMID- 22840672 TI - Bedside assessment of cardiac hemodynamics: role of the simple Valsalva maneuver. PMID- 22840674 TI - Recertification: is the pass/fail approach right? PMID- 22840676 TI - Risk of thiazide-induced hyponatremia in patients with hypertension. PMID- 22840677 TI - Thiazide-induced hyponatremia is predictable. PMID- 22840678 TI - Casebook consults: improving outcomes in gout (multimedia activity). AB - Gout is a chronic, potentially debilitating condition characterized by an inflammatory process in the joints or periarticular tissues that results from the deposition of monosodium urate crystals. Underdiagnosis and undertreatment can lead to the development of tophi and chronic arthropathy. A presumptive diagnosis of gout can be made on the basis of the clinical presentation as well as risk factors such as metabolic syndrome. Key conditions to rule out in the differential diagnosis are septic arthritis, calcium pyrophosphate deposition disease (pseudogout), fracture, and rheumatoid arthritis. Acute flares of gout should be managed with nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or corticosteroids. With a diagnosis of gout, if urate-lowering therapy (ULT) is required, prophylaxis should be considered with low-dose colchicine or an NSAID, followed by the addition of ULT. The goal of ULT is to reach a serum uric acid (SUA) level <=6.0 mg/dL. Measurements of SUA should be obtained after resolution of an acute attack, then periodically to facilitate titration of the ULT dose to achieve the target SUA level. Studies have confirmed significant reductions in gout attacks among patients who have attained SUA levels <=6.0 mg/dL with ULT. Patient education concerning the disease and its treatment is essential to ensure close adherence with recommended therapies. Patients should also understand that ULT is intended as long-term, and for most patients, lifelong therapy to maximize the prospects for control of the disease. Clinicians should feel confident in making a presumptive diagnosis and choosing a therapeutic regimen for gout while effectively communicating with and educating patients about their disease. PMID- 22840681 TI - Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. AB - Recent advancements in fetal imaging and antenatal care have enabled identification of numerous anomalies including agenesis of corpus callosum and posterior fossa abnormalities. One of the important determinants of long-term prognosis in these conditions is the presence of central nervous system (CNS) and extra-CNS anomalies. The difficulty in confirming the isolated nature of these conditions antenatally and the lack of clear information regarding long-term prognoses makes it difficult for the clinician to provide accurate information to the parents antenatally. Caring for these families would require input from a multidisciplinary team involving obstetricians, geneticists, neurologists, radiologists and neonatologists. PMID- 22840680 TI - Early labour services: changes, triggers, monitoring and evaluation. AB - OBJECTIVES: to identify the changes to early labour services, their triggers and monitoring. DESIGN AND SETTING: a mixed methods approach in two stages, firstly a postal questionnaire survey of Heads of Midwifery (HoM) services in NHS Trusts in England (cover sheet to each HoM and questionnaire for each unit in their jurisdiction) and, secondly, semi-structured telephone interviews with a purposive sample of senior midwives. The interviews sought further information about reasons for change; the impact of changes and explored the unit's particular innovations. PARTICIPANTS AND RESPONSE RATE: 145 (89%) NHS Trusts provided data (cover sheet and/or questionnaire); responses were received from all areas and types of unit. Seventeen HoMs or designated senior midwives were interviewed. FINDINGS: 83 of 170 units (49%) had made changes to early labour service provision during the past 5 years, including home assessment; the introduction of triage units and telephone assessment tools. Changes were more likely in high volume units and in consultant units with midwifery-led care areas. Further changes were planned by 93/178 (25%) units. Triggers for changes to early labour services comprised local or unit-based factors, including Category X (non-labour) admissions, response to service users and research evidence. The impact of Category X admissions on workload contributed to the triggers for change. Fifty-six (31%) could provide a confirmed figure or estimate for category X admissions. Experiences of introducing change included issues related to engagement of the workforce and the contribution of clinical leadership. Thirty-eight (48%) units did not routinely monitor use of early labour services. Overall monitoring of services was not significantly more likely in units that had made changes. Audit activity was reported more frequently in units that had made changes to their early labour services. CONCLUSIONS: early labour services had undergone significant changes following a range of triggers but the extent of change was not reflected in monitoring and evaluation activity. IMPLICATIONS FOR PRACTICE: Changes to service provision should be accompanied by monitoring and evaluation. Changes to services require utilisation of appropriate change management strategies. PMID- 22840682 TI - Murine typhus in drug detoxification facility, Yunnan Province, China, 2010. PMID- 22840683 TI - Twelve-month results of the EverFlex stent in the superficial femoral artery. AB - PURPOSE: To evaluate the clinical efficacy of EverFlex stents (length, 6-20 cm) for the treatment of peripheral artery disease (PAD) in the superficial femoral artery (SFA). MATERIAL AND METHODS: Over a period of 18 months, 56 SFA lesions in 53 patients were treated with an EverFlex stent. The following parameters were documented before the intervention, immediately afterward, and 12 months later: clinical stage, ankle-brachial index, and peak systolic velocity ratio (PSVR). The primary study endpoint was the primary patency rate after 12 months (defined as a PSVR < 2.5). RESULTS: In 18% of the 56 lesions, complete occlusions were present. Mean lesion length was 9.4 cm +/- 5.3, and mean stent length was 12.6 cm +/- 5.6. Of the 53 patients enrolled in the study, a 12-month follow-up was performed in 46. The primary patency rate after 12 months was 71.7%. In-stent restenosis or occlusion occurred in 13 patients. Compared with the total study group, the mean stent length in these 13 patients was greater (14.0 cm +/- 7.3) and the incidence of de novo lesions was lower. In the patient group with stents less than 10 cm in length (n = 24), six patients (25%) required a repeat intervention, compared with seven patients (32%) in the group with stents longer than 12 cm. CONCLUSIONS: Although the primary patency rate associated with the EverFlex stent is comparable to those in published data, the present results demonstrate a higher percentage of in-stent stenoses in patients in whom longer SFA stents were implanted. PMID- 22840684 TI - Radiation exposure in vascular angiographic procedures. AB - PURPOSE: To evaluate dose reduction in vascular angiographic procedures by using fluoroscopy capture instead of digital subtraction angiography frames for documentation. MATERIALS AND METHODS: A total of 764 consecutive vascular interventional procedures performed over a period of 1 year were retrospectively analyzed with respect to the fluoroscopy time and the resulting dose-area product (DAP), the DAP of the radiographic frames, and the overall DAP. RESULTS: A total of 70% of the total DAP was a result of the acquisition of radiographic frames, leaving only 30% being applied by fluoroscopy. CONCLUSIONS: Fluoroscopy capture should be used for documentation whenever possible. A registry of radiation exposure should not only comprise a sufficiently large number of interventions but also different intervention types to allow the development of interventional reference levels. PMID- 22840685 TI - Discontinuation of beta-blockers in cardiovascular disease: UK primary care cohort study. AB - AIMS: The present study aims to investigate patterns of beta-blocker usage in a national primary care cohort. METHODS AND RESULTS: This is a retrospective cohort study utilising the UK General Practice Research Database from 2004 to 2008. Inclusion criteria were (i) a first diagnosis of chronic heart failure (CHF), myocardial infarction (MI) or angina, and (ii) first-ever prescription of beta blocker on or after 1st April 2004. Outcome measures were discontinuation of beta blockers over time, initiation dosages, titration patterns, incidence of adverse events (AEs) and associated prescribing actions. A total of 12,493 patients (68.0% male; mean age 58.0 +/- SD 17.6 years) were included. Of these, 27% had discontinued beta-blockers within 1 year of initiation, increasing to 39% by 2 years and 50% by 3 years. Persistence appeared to be greater in the MI cohort compared with angina or CHF cohorts. Beta-blocker dose at initiation averaged approximately 33% of guideline recommended target, rising to 40% in those who continued with therapy. Dyspnoea, fatigue and dizziness were the most common incident AEs at 98, 53 and 49 per 1000 patient years, with little difference between indications. CONCLUSION: A quarter of patients with cardiovascular disease who are commenced on a beta-blocker are no longer taking the drug by one year. This rises to 50% by three years, a finding that is consistent irrespective of whether the prescription is for prognostic (CHF or post MI) or symptomatic (angina) benefit. There is an urgent need to understand and address the prescribing difficulties of beta-blockers in these at-risk patients. PMID- 22840686 TI - Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis. AB - INTRODUCTION: Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40 mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE. METHODS: A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220 mg qd versus enoxaparin 40 mg qd in patients with a normal body mass index (BMI) of >20-25 kg/m(2), pre-obese patients (BMI >25-30 kg/m(2)) and obese patients (BMI >30 kg/m(2)). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events. RESULTS: The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9 kg/m(2). Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24-0.97, P=0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups. CONCLUSIONS: Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI >25 kg/m(2) do not differ from the overall population. PMID- 22840687 TI - Effect of quality chronic disease management for alcohol and drug dependence on addiction outcomes. AB - We examined the effect of the quality of primary care-based chronic disease management (CDM) for alcohol and/or other drug (AOD) dependence on addiction outcomes. We assessed quality using (1) a visit frequency based measure and (2) a self-reported assessment measuring alignment with the chronic care model. The visit frequency based measure had no significant association with addiction outcomes. The self-reported measure of care-when care was at a CDM clinic-was associated with lower drug addiction severity. The self-reported assessment of care from any healthcare source (CDM clinic or elsewhere) was associated with lower alcohol addiction severity and abstinence. These findings suggest that high quality CDM for AOD dependence may improve addiction outcomes. Quality measures based upon alignment with the chronic care model may better capture features of effective CDM care than a visit frequency measure. PMID- 22840688 TI - Sexual dimorphism of abdominal aortic aneurysms: a striking example of "male disadvantage" in cardiovascular disease. AB - The abdominal aortic aneurysm (AAA) is a permanent, localised, dilation of the abdominal aorta that causes death in 80% of patients if left untreated. An apparent male predominance in AAA has been observed in most studies, with a male: female gender ratio of ~6:1 between the ages 60 years-64 years. The majority of risk factors for AAA exhibit sexual dimorphism but no single risk factor shows a higher magnitude of "male disadvantage" than AAA itself. This in turn suggests that the additive effects of risk factors may better explain the higher prevalence of AAA in men than women compared to each individual factor. Amongst others, sex steroids and sex chromosomes have been hypothesised to act as the drivers of this sexual dimorphism. Future research should focus on the major biological differences between the sexes identifying why men are at more risk of AAA than women. PMID- 22840689 TI - Influence of mild-to-moderate alcohol consumption on cardiovascular diseases in men from the general population. AB - BACKGROUND AND METHODS: There is controversy about the association between mild to-moderate alcohol consumption and a reduced risk of cardiovascular diseases. The relationships between daily alcohol consumption and the incidence of acute myocardial infarction (MI) or ischemic stroke (IS) were examined in men in a community-based, prospective cohort study (n = 8014, age 40-80 years, mean age = 64.1 years). Alcohol consumption was categorized into 3 groups (A1, none or occasional; A2, <=25 g/day; A3, >25 g/day as ethanol) at baseline. RESULTS: During the mean follow-up of 5.5 years, 53 MIs and 186 ISs occurred. On Cox regression analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking index, and body mass index (BMI), the hazard ratio (HR) for incident MI was significantly lower in the A2 group than in the A1 group (HR = 0.49, p = 0.043). The HR for incident MI in the A3 group tended to be lower than in the A1 group (HR = 0.53, p = 0.10). In obese subjects, while a significantly lower HR for incident MI in the A2 group was retained (HR = 0.29, p = 0.049), no significant difference in the HR of the A3 group compared with the A1 group was found. No significant differences were found in the IS-free curve among the 3 groups of alcohol consumption. CONCLUSIONS: Alcohol consumption may have a protective effect on the onset of MI but not on IS in the general population. A U shaped relation between alcohol consumption and incident MI was found in obese subjects. An appropriate limit for daily alcohol consumption, depending on the risk of ischemic heart disease, may need to be established. PMID- 22840690 TI - SCM-198 attenuates early atherosclerotic lesions in hypercholesterolemic rabbits via modulation of the inflammatory and oxidative stress pathways. AB - OBJECTIVE: To investigate SCM-198 (also known as "leonurine"), a compound in Herba leonuri, as well as its effect on the progression of atherosclerosis in hypercholesterolemic rabbits and underlying mechanisms. METHODS: Thirty New Zealand male White rabbits (5 groups, n = 6) were fed either a normal diet or a high-cholesterol diet (1%). The rabbits on the high-cholesterol diet received treatments of low, moderate, and high doses of SCM-198 and placebo concurrently. Eight weeks later, the animals underwent ultrasonographic imaging. They were then sacrificed for further pathological and molecular biological analysis. RESULTS: SCM-198-treated rabbits showed a significant alleviation in the development of atherosclerosis in a dose-dependent manner. The lesions were smaller after the SCM-198 treatments. In addition, the elasticity of the arteries and hemodynamic status improved, accompanied with a decrease in smooth muscle cell migration and, macrophage infiltration, as well as the expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) in the aortas. Marginal changes in the lipid parameters were found in the SCM-198-treated rabbits, with high-density lipid cholesterol (HDL-C) elevation and triglyceride (TG) reduction at the high dose. SCM-198 treatment dose-dependently reduced levels of serum soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM 1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as the mRNA levels of VCAM-1, IL-6, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), iNOS and MMP-9 in the aorta. In addition, SCM-198 also dose-dependently increased the total antioxidant capacities and in parallel decreased the lipid peroxidation levels in the serum and liver. The antioxidant effects of SCM-198 were implicated by the enhanced activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of glutathione (GSH) in the liver, as well as the mRNA levels of CAT, SOD-1 and GPx in the aorta. CONCLUSIONS: In a rabbit atherosclerotic model, SCM-198 dose-dependently ameliorated the progression of atherosclerotic lesions and vascular dysfunction accompanied by the suppression of inflammatory factors and oxidative stress. These findings suggested that SCM-198 might be a potential agent for the treatment of atherosclerosis. PMID- 22840691 TI - Oxidized LDL to autoantibodies against oxLDL ratio - the new biomarker associated with carotid atherosclerosis and cardiovascular complications in dialyzed patients. AB - OBJECTIVE: To investigate the role of autoantibodies against oxidized LDL (oxLDL Ab) in clearing of oxLDL from circulation in dialyzed uremic patients, as well as the significance of this process in the carotid atherosclerosis and cardiovascular complications. METHODS: oxLDL, oxLDL-Ab and intima-media thickness (IMT) were measured in 132 uremic patients on hemodialysis (HD), peritoneal dialysis (PD) or conservative treatment both with and without cardiovascular disease (CVD) and in 29 healthy controls. The ratio of oxLDL to oxLDL-Ab (oxLDL/oxLDL-Ab), reflecting the balance between in vivo oxidative LDL modification and the clearance of oxLDL from circulation was also calculated. RESULTS: oxLDL were lower, whereas oxLDL-Ab were higher in patients without CVD compared to those with CVD. oxLDL/oxLDL-Ab ratio was also significantly lower in dialyzed subjects without CVD compared to their counterparts with CVD and healthy controls. IMT values were significantly higher in uremic patients compared with controls, and patients with CVD had particularly elevated IMT compared with those without CVD. The inverse correlation was between IMT and oxLDL-Ab, whereas the IMT was strongly and positively associated with oxLDL/oxLDL-Ab ratio. There was the weak inverse relationship between oxLDL and oxLDL-Ab levels in dialyzed patients. Multiple stepwise regression analysis identified oxLDL/oxLDL-Ab ratio as one of the predictors of IMT in the whole dialyzed group. CONCLUSIONS: oxLDL/oxLDL-Ab ratio could be a new biomarker significantly and independently associated with carotid atherosclerosis in dialyzed patients. A titer of oxLDL-Ab and oxLDL/oxLDL-Ab ratio seem to play an important role for distinguishing patients with and without cardiovascular complications. PMID- 22840692 TI - Increased levels of the homeostatic chemokine CXCL13 in human atherosclerosis - Potential role in plaque stabilization. AB - OBJECTIVES: Based on the newly recognized role of the homeostatic chemokines in inflammation, we hypothesized that CXCL13 could modulate atherogenesis and plaque destabilization. METHODS: The study included in vivo analyses in patients with carotid atherosclerosis and in vitro experiments in cells involved in atherogenesis (ie, monocytes/macrophages, vascular smooth muscle cells [SMC], and platelets). RESULTS: Our main findings were: (i) Patients with carotid atherosclerosis (n = 130) had increased plasma levels of CXCL13 with particularly high levels in symptomatic disease. (ii) CXCL13 showed increased expression within atherosclerotic carotid plaques as compared with non-atherosclerotic vessels. (iii) Within the atherosclerotic lesions, CXCR5 and CXCL13 were expressed by macrophages and SMC in all stages of plaque progression. (iv) Releasate from activated platelets and toll-like receptor activation enhanced the expression of CXCL13 in THP-1 monocytes and primary monocytes. (v) In vitro, CXCL13 exerted anti-apoptotic effects in primary monocytes, THP-1 macrophages, and vascular SMC. (vi) CXCL13 increased arginase-1, transforming growth factor beta, and interleukin-10 expression in THP-1 cells and in samples from isolated carotid plaques. CONCLUSION: Levels of CXCL13 are increased in carotid atherosclerosis both systemically and within the atherosclerotic lesion. Based on our in vitro findings, we hypothesize a potential plaque stabilizing effects of CXCL13-CXCR5 interaction. PMID- 22840693 TI - Can C-reactive protein predict cardiovascular events in asymptomatic patients? Analysis based on plaque characterization. AB - OBJECTIVE: High-sensitivity C-reactive protein (hsCRP) and coronary artery plaque characteristics have been separately evaluated as prognosticators of adverse cardiovascular events; however, their relationship remains unclear. We therefore evaluated the prognostic value of hsCRP in relation to plaque subtypes in predicting adverse cardiovascular outcome in asymptomatic patients without known coronary artery disease. METHODS: A total of 4690 asymptomatic patients who underwent coronary computed tomography angiography for screening purposes were included. HsCRP was categorized as <1 mg/L, 1-3 mg/L and >3 mg/L. Cardiovascular events were defined as cardiovascular death, acute coronary syndrome, and stroke. RESULTS: During follow-up (median 49 months, interquartile range 34-59 months), adverse cardiovascular events were observed in 56 (1.2%) patients. Higher hsCRP was associated with poor outcome in overall patients (OR 2.716, 95% CI 1.512 4.880, p = 0.001 for hsCRP 1-3 mg/L, OR 2.705, 95% CI 1.239-5.908, p = 0.013 for hsCRP > 3 mg/L, hsCRP <1 mg/L as reference). When patients were evaluated according to plaque subtype, hsCRP > 3 mg/L was a significant predictor of poor outcome only in patients with noncalcified plaques (NCP; p = 0.038). After adjusting for Framingham risk and coronary artery calcium score, hsCRP > 3 mg/L was a significant predictor of adverse outcomes in the presence of NCP (p = 0.048) but not in the presence of CP or MCP (p = 0.742). CONCLUSION: Elevated hsCRP is a predictor of adverse cardiovascular events in asymptomatic patients with NCP. After adjusting for Framingham risk and coronary artery calcium scores, hsCRP > 3 mgL remained an independent predictor of risk in patients with NCP but not in patients with CP or MCP. PMID- 22840694 TI - Synthesis, characterization and structure optimization of a series of thiazolidinone derivatives as Entamoeba histolytica inhibitors. AB - A series of thiazolidinone derivatives were synthesized by sodium acetate assisted cyclization of 1-isobutyl-3-phenylthiourea with chloroacetic acid followed by the piperidine facilitated substitution of the resulting thiazolidinone with different substituted aldehydes. The ethene and imine double bonds adopt (Z,Z) configuration as indicated by (1)H-(1)H COSY and 2D-NOESY (1)H NMR and further confirmed by the crystal structure studies. The in vitro antiamoebic activity of these compounds was evaluated against HM1:IMSS strain of Entamoeba histolytica. Eight compounds exhibited promising activity with IC(50) values (0.11-0.172 MUM) lower than the standard drug metronidazole (IC(50) 1.64 MUM). In vitro cytotoxicity results revealed low cytotoxic up to the concentration of 25 MUM. PMID- 22840695 TI - Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5 yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine. AB - We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K(+) channel inhibition (IC(50) = 4.7 MUM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F(po) = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain. PMID- 22840696 TI - Synthesis, DNA binding and antileishmanial activity of low molecular weight bis arylimidamides. AB - The effects of reducing the molecular weight of the antileishmanial compound DB766 on DNA binding affinity, antileishmanial activity and cytotoxicity are reported. The bis-arylimidamides were prepared by the coupling of aryl S-(2 naphthylmethyl)thioimidates with the corresponding amines. Specifically, we have prepared new series of bis-arylimidamides which include 3a, 3b, 6, 9a, 9b, 9c, 13, and 18. Three compounds 9a, 9c, and 18 bind to DNA with similar or moderately lower affinity to that of DB766, the rest of these compounds either show quite weak binding or no binding at all to DNA. Compounds 9a, 9c, and 13 were the most active against Leishmania amazonensis showing IC(50) values of less than 1 MUM, so they were screened against intracellular Leishmania donovani, showing outstanding activity with IC(50) values of 25-79 nM. Despite exhibiting little in vitro cytotoxicity these three compounds were quite toxic to mice. PMID- 22840697 TI - A review of the treatment of endocrine responsive metastatic breast cancer in postmenopausal women. AB - Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) - anastrozole, exemestane, letrozole - and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC. PMID- 22840699 TI - Sorbent materials for separation and preconcentration of gold in environmental and geological samples--a review. AB - Determination of gold in environmental and geological samples requires very often preconcentration and separation due to the high concentration of interfering matrix components and the low content of this metal. Solid phase extraction technique with different kind of solid sorbents offers for this purpose high enrichment factor, rapid phase separation and the ability of combination with different detection techniques. It can be easily implemented and controlled in flow systems, The recent developments in this area are presented and discussed. PMID- 22840698 TI - A new application of scanning electrochemical microscopy for the label-free interrogation of antibody-antigen interactions: Part 2. AB - Within this paper we describe the use of scanning electrochemical microscopy (SECM) to fabricate a dotted array of biotinylated polyethyleneimine which was then used to immobilise first neutravidin and then a biotinylated antibody towards a relevant antigen of interest (PSA, NTx, ciprofloxacin). These antigens were selected both for their clinical relevance but also since they display a broad range of molecular weights, to determine whether the size of the antigen used effects the sensitivity of this approach. The SECM was then used to image the binding of both complementary and non-complementary antigens in a label-free assay. Imaging of the arrays before and following exposure to various concentrations of antigen in buffer showed clear evidence for specific binding of the complementary antigens to the antibody functionalised dots. Non-specific binding was also quantified by control experiments with other antigens. This demonstrated non-specific binding across the whole of the substrate, thereby confirming that specific binding does occur between the antibody and antigen of interest at the surface of the dots. The binding of ciprofloxacin was investigated both in simple buffer solution and in a more complex media, bovine milk. PMID- 22840701 TI - A highly accurate method for determination of dissolved oxygen: gravimetric Winkler method. AB - A high-accuracy Winkler titration method has been developed for determination of dissolved oxygen concentration. Careful analysis of uncertainty sources relevant to the Winkler method was carried out and the method was optimized for minimizing all uncertainty sources as far as practical. The most important improvements were: gravimetric measurement of all solutions, pre-titration to minimize the effect of iodine volatilization, accurate amperometric end point detection and careful accounting for dissolved oxygen in the reagents. As a result, the developed method is possibly the most accurate method of determination of dissolved oxygen available. Depending on measurement conditions and on the dissolved oxygen concentration the combined standard uncertainties of the method are in the range of 0.012-0.018 mg dm(-3) corresponding to the k=2 expanded uncertainty in the range of 0.023-0.035 mg dm(-3) (0.27-0.38%, relative). This development enables more accurate calibration of electrochemical and optical dissolved oxygen sensors for routine analysis than has been possible before. PMID- 22840700 TI - Simultaneous determination of ascorbic acid, dopamine, uric acid and tryptophan on gold nanoparticles/overoxidized-polyimidazole composite modified glassy carbon electrode. AB - A novel electrode was developed through electrodepositing gold nanoparticles (GNPs) on overoxidized-polyimidazole (PImox) film modified glassy carbon electrode (GCE). The combination of GNPs and the PImox film endowed the GNPs/PImox/GCE with good biological compatibility, high selectivity and sensitivity and excellent electrochemical catalytic activities towards ascorbic acid (AA), dopamine (DA), uric acid (UA) and tryptophan (Trp). In the fourfold co existence system, the peak separations between AA-DA, DA-UA and UA-Trp were large up to 186, 165 and 285 mV, respectively. The calibration curves for AA, DA and UA were obtained in the range of 210.0-1010.0 MUM, 5.0-268.0 MUM and 6.0-486.0 MUM with detection limits (S/N=3) of 2.0 MUM, 0.08 MUM and 0.5 MUM, respectively. Two linear calibrations for Trp were obtained over ranges of 3.0-34.0 MUM and 84.0 464.0 MUM with detection limit (S/N=3) of 0.7 MUM. In addition, the modified electrode was applied to detect AA, DA, UA and Trp in samples using standard addition method with satisfactory results. PMID- 22840702 TI - Sensitive and robotic determination of bromate in sea water and drinking deep-sea water by headspace solid-phase micro extraction and gas chromatography-mass spectrometry. AB - A robotic method has been established for the determination of bromate in sea water and drinking deep-sea water. Bromate in water was converted into volatile derivative, which was measured with headspace solid-phase micro extraction and gas chromatography-mass spectrometry (HS-SPME GC-MS). Derivatization reagent and the HS-SPME parameters (selection of fibre, extraction/derivatization temperature, heating time and; the morality of HCl) were optimized and selected. Under the established conditions, the detection and the quantification limits were 0.016 MUg L(-1) and 0.051 MUg L(-1), respectively, and the intra- and inter day relative standard deviation was less than 7% at concentrations of 1.0 and 10.0 MUg L(-1). The calibration curve showed good linearity with r(2)=0.9998. The common ions Cl(-), NO(3)(-), SO(4)(2-), HPO(4)(2-), H(2)PO(4)(-), K(+), Na(+), NH(4)(+), Ca(2+), Mg(2+), Ba(2+), Mn(4+), Mn(2+), Fe(3+) and Fe(2+) did not interfere even when present in 1000-fold excess over the active species. The method was successfully applied to the determination of bromate in sea water and drinking deep-sea water. PMID- 22840703 TI - Membrane-based microchannel device for continuous quantitative extraction of dissolved free sulfide from water and from oil. AB - Underground fluids are important natural sources of drinking water, geothermal energy, and oil-based fuels. To facilitate the surveying of such underground fluids, a novel microchannel extraction device was investigated for in-line continuous analysis and flow injection analysis of sulfide levels in water and in oil. Of the four designs investigated, the honeycomb-patterned microchannel extraction (HMCE) device was found to offer the most effective liquid-liquid extraction. In the HMCE device, a thin silicone membrane was sandwiched between two polydimethylsiloxane plates in which honeycomb-patterned microchannels had been fabricated. The identical patterns on the two plates were accurately aligned. The extracted sulfide was detected by quenching monitoring of fluorescein mercuric acetate (FMA). The sulfide extraction efficiencies from water and oil samples of the HMCE device and of three other designs (two annular and one rectangular channel) were examined theoretically and experimentally. The best performance was obtained with the HMCE device because of its thin sample layer (small diffusion distance) and large interface area. Quantitative extraction from both water and oil could be obtained using the HMCE device. The estimated limit of detection for continuous monitoring was 0.05 MUM, and sulfide concentrations in the range of 0.15-10 MUM could be determined when the acceptor was 5 MUM FMA alkaline solution. The method was applied to natural water analysis using flow injection mode, and the data agreed with those obtained using headspace gas chromatography-flame photometric detection. The analysis of hydrogen sulfide levels in prepared oil samples was also performed. The proposed device is expected to be used for real time survey of oil wells and groundwater wells. PMID- 22840704 TI - Silica nanoparticles pre-spotted onto target plate for laser desorption/ionization mass spectrometry analyses of peptides. AB - We report on the simple deposition of Stober silica nanoparticles (SiO(2) NPs) on conventional MALDI target plate for high throughput laser desorption/ionization mass spectrometry (LDI-MS) analyses of peptide mixtures with sensitivity in the femtomolar range. This low-cost easily prepared material allowed straightforward LDI experiments by deposition of the studied samples directly onto a pre-spotted MALDI plate. This analytical strategy can be performed in any laboratory equipped with a MALDI-TOF instrument. All key benefits of organic matrix-free technologies were satisfied while maintaining a high level of detection performances (sensitivity and reproducibility/repeatability). In particular, sample preparation was simple and detection in the low mass range was not hampered by matrix ions. Imaging studies were undertaken to query sample dispersion into the inert SiO(2) NPs and to help into the search of the best experimental conditions producing homogeneous analyte distribution within the deposit. In contrast to commercial disposable LDI targets designed for single use and requiring an adaptor such as NALDITM, the proposed SiO(2) NPs pre-spotting on a MALDI target plate allowed very easily switching between MALDI and LDI experiments. They can be conducted either simultaneously (positions with an organic matrix or SiO(2) NPs) or in the row (support prepared in advance, stored and washed after use). The overall cost and versatility of the methodology made it very attractive to MALDI users in many domains (peptidomics, proteomics, metabolomics). PMID- 22840705 TI - A direct assessment of mycotoxin biomarkers in human urine samples by liquid chromatography tandem mass spectrometry. AB - Detection of mycotoxin biomarkers in urine of humans and animals provides a direct approach for assessing exposure to these mycotoxins as opposed to the indirect approach of food analysis, which in most cases is affected by the heterogeneity of the toxin in the food samples. Seven (7) mycotoxins and their metabolites (total 18 analytes) were selected and an LC-MS/MS method for their determination in human urine was developed and validated. The method consisted of direct analysis of two mycotoxin conjugates, deoxynivalenol-glucuronide and zearalenone-glucuronide without beta glucuronidase digestion of the urine samples. Since high method sensitivity is of utmost importance in such study, critical factors which could improve the analyte recovery and method sensitivity were investigated by a D-optimal experimental design. Urine samples (10 mL) were first extracted with 15 mL ethyl acetate/formic acid (99/1, v/v) followed by SAX SPE clean-up of the acidified aqueous fraction. Both extracts were combined and analyzed using an LC-MS/MS system operated in the positive ionization mode. A total run time of 28 min was adopted with all the 18 analytes eluting within 15 min. The method was validated by taking into consideration the guidelines specified in Commission Decision 2002/657/EC and 401/2006/EC. Forty samples obtained from volunteers within the laboratory research group were analyzed as part of a pilot study. All results were expressed per mg creatinine. A total of 9 samples were found contaminated with one or more of the following analytes: DON, OTA, OTalpha, 4-OH OTA, ZEN, CIT and beta-ZOL. One-eighth (5/40) of the samples were contaminated with DON in the range of 3.7-67 ng mg(-1) creatinine. Samples with detectable levels of DON did not show any co-occurrence of DON-3Glu. One sample was found to be contaminated with 4-OH OTA ( C capsular switching. This study identified B -> C switches within the sequence type 32 complex. Substantial disease related to capsular switching emphasizes the need for surveillance of circulating meningococcal strains to optimize disease control. PMID- 22840714 TI - A geometric morphometric analysis of hominin upper second and third molars, with particular emphasis on European Pleistocene populations. AB - The study of dental morphology by means of geometric morphometric methods allows for a detailed and quantitative comparison of hominin species that is useful for taxonomic assignment and phylogenetic reconstruction. Upper second and third molars have been studied in a comprehensive sample of Plio- and Pleistocene hominins from African, Asian and European sites in order to complete our analysis of the upper postcanine dentition. Intraspecific variation in these two molars is high, but some interspecific trends can be identified. Both molars exhibit a strong reduction of the distal cusps in recent hominin species, namely European Homo heidelbergensis, Homo neanderthalensis and Homo sapiens, but this reduction shows specific patterns and proportions in the three groups. Second molars tend to show four well developed cusps in earlier hominin species and their morphology is only marginally affected by allometric effects. Third molars can be incipiently reduced in earlier species and they evince a significant allometric component, identified both inter- and intraspecifically. European Middle Pleistocene fossils from Sima de los Huesos (SH) show a very strong reduction of these two molars, even more marked than the reduction observed in Neanderthals and in modern human populations. The highly derived shape of SH molars points to an early acquisition of typical Neanderthal dental traits by pre-Neanderthal populations and to a deviation of this population from mean morphologies of other European Middle Pleistocene groups. PMID- 22840715 TI - A comparative study of the trabecular bony architecture of the talus in humans, non-human primates, and Australopithecus. AB - This study tested the hypothesis that talar trabecular microarchitecture reflects the loading patterns in the primate ankle joint, to determine whether talar trabecular morphology might be useful for inferring locomotor behavior in fossil hominins. Trabecular microarchitecture was quantified in the anteromedial, anterolateral, posteromedial, and posterolateral quadrants of the talar body in humans and non-human primates using micro-computed tomography. Trabecular bone parameters, including bone volume fraction, trabecular number and thickness, and degree of anisotropy differed between primates, but not in a manner entirely consistent with hypotheses derived from locomotor kinematics. Humans have highly organized trabecular struts across the entirety of the talus, consistent with the compressive loads incurred during bipedal walking. Chimpanzees possess a high bone volume fraction, consisting of plate-like trabecular struts. Orangutan tali are filled with a high number of thin, connected trabeculae, particularly in the anterior portion of the talus. Gorillas and baboons have strikingly similar internal architecture of the talus. Intraspecific analyses revealed no regional differences in trabecular architecture unique to bipedal humans. Of the 22 statistically significant regional differences in the human talus, all can also be found in other primates. Trabecular thickness, number, spacing, and connectivity density had the same regional relationship in the talus of humans, chimpanzees, gorillas, and baboons, suggesting a deeply conserved architecture in the primate talus. Australopithecus tali are human-like in most respects, differing most notably in having more oriented struts in the posteromedial quadrant of the body compared with the posterolateral quadrant. Though this result could mean that australopiths loaded their ankles in a unique manner during bipedal gait, the regional variation in degree of anisotropy was similar in humans, chimpanzees, and gorillas. These results collectively suggest that the microarchitecture of the talus does not simply reflect the loading environment, limiting its utility in reconstructing locomotion in fossil primates. PMID- 22840716 TI - Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. AB - This study estimated the cumulative incidence and risk ratio for osteonecrosis of the jaw (ONJ) after tooth extraction in patients with and without administration of bisphosphonates (BP) and identified potential risk factors for bisphosphonate induced osteonecrosis of the jaw (BIONJ). A cohort study was conducted in all patients undergoing tooth extraction at a university hospital in Japan from April 2006 to June 2009. Of 3216 patients, 126 had BP administration, of whom 5 (3.9%, 95% confidence interval (CI): 1.2-9.2) developed ONJ, versus 1 (0.032%, 95% CI: 0.00081-0.18) among 3090 patients without BP administration. BP administration was associated with the development of ONJ after tooth extraction, with an unadjusted risk ratio of 122.6 (95% CI: 14.4-1041.8). When stratified by age and route of BP administration, the risk ratio for ONJ patients aged 65 years or older with intravenous BP administration compared to those without was 200.2 (95% CI: 23.8-1679.4, P<0.001). Patients receiving BP showed a significant association between the incidence of BIONJ and alveolar bone loss score. The risk of ONJ is higher in patients with than without BP administration, particularly intravenous administration. Severe periodontitis might be a risk factor for BIONJ. PMID- 22840717 TI - Obstetrician/gynecologist hospitalists: can we improve safety and outcomes for patients and hospitals and improve lifestyle for physicians? AB - Over the last 5 years, a new obstetric-gynecologic hospitalist model has emerged rapidly, the primary focus of which is the care and safety of the laboring patient. The need for this type of practitioner has been driven by a number of factors: various types of patient safety programs that require a champion and organizer; the realization that bad outcomes and malpractice lawsuits often result from the lack of immediate availability of a physician in the labor and delivery suite; the desire for many younger practicing physicians to seek a balance between their personal and professional lives; the appeal of shift work as opposed to running a busy private practice; the waning amount of training that new residency graduates receive in critical skills that are needed on labor and delivery; the void in critical care of the laboring patient that is created by the outpatient focus of many physicians in maternal-fetal medicine; the need for hospitals to have a group of physicians to implement protocols and policies on the unit, and the need for teaching in all hospitals, not just academic centers. By having a dedicated group of physicians whose practice is limited mostly to the care of the labor and delivery aspects of patient care, there is great potential to address many of these needs. There are currently 164 known obstetrician/gynecologist hospitalist programs across the United States, with 2 more coming on each month; the newly formed Society of Obstetrician/Gynecologist Hospitalists currently has >80 individual members. This article addresses the advantages, challenges, and variety of Hospitalist models and will suggest that what may be considered an emerging trend is actually a sustainable model for improved patient care and safety. PMID- 22840719 TI - Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification. AB - OBJECTIVE: The aim of the present study was to differentiate and specify the subtypes of adenomyosis. STUDY DESIGN: Surgically treated adenomyosis (n = 152) was subcategorized retrospectively into 4 subtypes on the basis of magnetic resonance imaging geography. Subtype I (n = 59) consisted of adenomyosis that occurs in the uterine inner layer without affecting the outer structures. Subtype II (n = 51) consisted of adenomyosis that occurs in the uterine outer layer without affecting the inner structures. Subtype III (n = 22) consisted of adenomyosis that occurs solitarily without relationship to structural components. Adenomyosis that did not satisfy these criteria composed subtype IV (n = 20). Stepwise logistic regression analysis was used for specification of the subtypes. RESULTS: Subtypes I-III were suggested as a product of direct endometrial invasion, endometriotic invasion from the outside, and de novo metaplasia, respectively. Subtype IV was a heterogeneous mixture of far advanced disease. CONCLUSION: Adenomyosis appears to consist of 3 distinct subtypes of different causes and an additional subtype of indeterminate cause. PMID- 22840720 TI - Neonatal mortality by attempted route of delivery in early preterm birth. AB - OBJECTIVE: We sought to study neonatal outcomes in early preterm births by delivery route. STUDY DESIGN: Delivery precursors were analyzed in 4352 singleton deliveries, 24 0/7 to 31 6/7 weeks' gestation. In a subset (n = 2906) eligible for a trial of labor, neonatal mortality in attempted vaginal delivery (VD) was compared to planned cesarean delivery stratified by presentation. RESULTS: Delivery precursors were classified as maternal or fetal conditions (45.7%), preterm premature rupture of membranes (37.7%), and preterm labor (16.6%). For vertex presentation, 79% attempted VD and 84% were successful. There was no difference in neonatal mortality. For breech presentation, at 24 0/7 to 27 6/7 weeks' gestation, 31.7% attempted VD and 27.6% were successful; neonatal mortality was increased (25.2% vs 13.2%, P = .003). At 28 0/7 to 31 6/7 weeks' gestation, 30.5% attempted VD and 17.2% were successful; neonatal mortality was increased (6.0% vs 1.5%, P = .016). CONCLUSION: Attempted VD for vertex presentation has a high success rate with no difference in neonatal mortality unlike breech presentation. PMID- 22840721 TI - Outcomes associated with a structured prenatal counseling program for shoulder dystocia with brachial plexus injury. AB - OBJECTIVE: We examined outcomes that were associated with a novel program to identify patients who are at high risk for shoulder dystocia with brachial plexus injury. STUDY DESIGN: The program included a checklist of key risk factors and a multifactorial algorithm to estimate risk of shoulder dystocia with brachial plexus injury. We examined rates of cesarean delivery and shoulder dystocia in 8767 deliveries by clinicians who were enrolled in the program and in 11,958 patients of clinicians with no access to the program. RESULTS: Key risk factors were identified in 1071 of 8767 mothers (12.2%), of whom 40 of 8767 women (0.46%) had results in the high-risk category. The rate of primary cesarean delivery rate was stable (21.2-20.8%; P = .57). Shoulder dystocia rates fell by 56.8% (1.74 0.75%; P = .002). The rates of shoulder dystocia and cesarean birth showed no changes in the group with no access to the program. CONCLUSION: With the introduction of this program, overall shoulder dystocia rates fell by more than one-half with no increase in the primary cesarean delivery rate. PMID- 22840722 TI - Timing of delivery following selective laser photocoagulation for twin-to-twin transfusion syndrome. AB - OBJECTIVE: We sought to compare intrauterine risks with postnatal outcome in monochorionic pregnancies operated by fetoscopic laser surgery for twin-to-twin transfusion syndrome. STUDY DESIGN: A cohort of 602 consecutive cases was analyzed. Unexpected prenatal adverse events were identified when a fatal or potentially fatal event occurred that could have been avoided by timely delivery. RESULTS: The prospective risk of an unexpected adverse event dropped from 16.8% (95% confidence interval [CI], 13.6-20.5%) to 0% (95% CI, 0-11%) between 26-36 weeks. At 32 weeks, the residual risk was 1 in 17 (95% CI, 1/28-1/11). The perinatal rate of death or severe brain lesions dropped from 35% (25-47%) in infants delivered at 26-28 weeks down to 3% (1-6%) at 34-36 weeks. CONCLUSION: Our results did not identify an optimal cut-off for elective preterm delivery in laser-operated twin-to-twin transfusion syndrome. Perinatal morbidity appears low from >=32 weeks and the decision for elective delivery should be based upon medical history, parental demand, and expert assessment. PMID- 22840723 TI - Maternal obesity and contraction strength in the first stage of labor. AB - OBJECTIVE: The purpose of this study was to determine whether maternal obesity is associated with cesarean delivery and decreased contraction strength in the first stage of labor. STUDY DESIGN: We studied a retrospective cohort of women who delivered within a single healthcare system from 2007-2009; we included 5410 women with an intrauterine pressure catheter during the last 2 hours of the first stage of labor and who either had a vaginal delivery or cesarean delivery for dystocia. Logistic regression was used to determine how body mass index was associated with cesarean delivery or mean Montevideo units of >=200. RESULTS: Although obese women were at significantly greater odds of cesarean delivery than normal-weight women (odds ratio, 2.4; 95% confidence interval, 1.9-3.1), they were equally able to achieve Montevideo units of >=200. Among women with a vaginal delivery, obese women had a longer first stage of labor compared with normal-weight women (597 vs 566 min; P = .003). CONCLUSION: Obese women have longer labors but are equally able to achieve adequate Montevideo units as normal weight women. PMID- 22840724 TI - Vascular limb occlusion in twin-twin transfusion syndrome (TTTS): case series and literature review. AB - OBJECTIVE: The purpose of this study was to evaluate the phenomenon of vascular ischemic limb necrosis in twin-twin transfusion syndrome (TTTS). STUDY DESIGN: This was a multicenter retrospective review of ischemic limb necrosis in patients with TTTS. RESULTS: Twenty cases of fetal ischemic limb necrosis in association with TTTS were identified from 10 fetal medicine centers. The recipient was affected in 19 cases, and the lower limb was affected in 17 cases. The extent of the damage correlated with TTTS severity. Eighty percent of limb defects (16/20) clearly were unrelated to laser treatment (3 cases untreated, 7 cases after amnioreduction, 6 cases present at time of laser). The recipient was relatively polycythemic in 5 of 7 cases in which neonatal or fetal hemoglobin/hematocrit levels were available. CONCLUSION: Ischemic limb necrosis is a rare complication of TTTS. The lesion is unrelated to therapy and may be the result of polycythemia, hypertension, and vasoconstriction. PMID- 22840725 TI - A randomized trial of birthing with and without stirrups. AB - OBJECTIVE: The objective of the study was to determine whether bed delivery without stirrups reduces the incidence of perineal lacerations compared with delivery in stirrups. STUDY DESIGN: In this randomized trial, we compared bed delivery without stirrups with delivery in stirrups in nulliparous women. The primary outcome was any perineal laceration (first through fourth degree). RESULTS: One hundred eight women were randomized to delivery without stirrups and 106 to stirrups. A total of 82 women randomized to no stirrups (76%) sustained perineal lacerations compared with 83 in women allocated to stirrups (78%) (P = .8). There was no significant difference in the severity of lacerations or in obstetric outcomes such as prolonged second stage of labor, forceps delivery, or cesarean birth. Similarly, infant outcomes were unaffected. CONCLUSION: Our results do not incriminate stirrups as a cause of perineal lacerations. Alternatively, our findings of no difference in perineal lacerations suggest that delivering in bed without stirrups confers no advantages or disadvantages. PMID- 22840726 TI - Tissue factor-dependent thrombin generation across pregnancy. AB - OBJECTIVE: Normal pregnancy results in a prothrombotic state. Studies that have investigated the capacity of pregnant women to generate thrombin are limited. Our aim was to evaluate thrombin generation longitudinally from the preconception period, through pregnancy, and after pregnancy. STUDY DESIGN: We evaluated young, healthy nulligravid women (n = 20) at 4 time points and compared the data with 10 control women at 2 time points. Coagulation was initiated with tissue factor in contact pathway inhibited plasma, and thrombin generation was determined in the presence of a fluorogenic substrate. RESULTS: The maximum level and rate of thrombin generation increased during pregnancy; the highest level and rate occurred in late pregnancy compared with prepregnancy (P < .001). Subsequently, thrombin generation decreased in the postpregnancy samples that included maximum level, rate, and area under the curve (P < .001). CONCLUSION: Our data provide evidence for an increase in tissue factor-dependent thrombin generation with pregnancy progression, followed by a return to prepregnancy thrombin levels. PMID- 22840727 TI - Endothelial microparticles and the antiangiogenic state in preeclampsia and the postpartum period. AB - OBJECTIVE: We sought to determine if endothelial microparticles (EMPs), markers of endothelial damage, are associated with soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin, and placental growth factor (PlGF) in women with preeclampsia. STUDY DESIGN: A prospective cohort study was conducted on 20 preeclamptic women and 20 controls. EMPs by flow cytometry, sFlt1, soluble endoglin, and PlGF were measured at time of enrollment, 48-hours postpartum, and 1-week postpartum. RESULTS: Preeclamptic CD31(+)/42(-), CD62E(+), and CD105(+) EMP levels were significantly elevated in preeclamptics vs controls at time of enrollment. The sFlt1:PlGF ratio was correlated with CD31(+)/42(-) and CD105(+) EMPs (r = 0.69 and r = 0.51, respectively) in preeclampsia. Levels of CD31(+)/42( ) EMPs remained elevated 1-week postpartum (P = .026). CONCLUSION: EMPs are elevated in preeclampsia. The correlation of EMPs and the sFlt1:PlGF ratio suggests that antiangiogenesis is related to apoptosis of the endothelia. Endothelial damage persists 1 week after delivery. PMID- 22840728 TI - Proangiogenic immature myeloid cells populate the human placenta and their presence correlates with placental and birthweight. AB - OBJECTIVE: To determine whether proangiogenic immature myeloid cells are present in human placentas. STUDY DESIGN: Biopsies were obtained from 61 placentas of term pregnancies. Percentage of CD45(+)CD33(+)LIN2(-)HLADR(-) immature myeloid cells of total CD45(+) hematopoietic cells was determined by flow cytometry. Location of immature myeloid cells in the placenta was identified using confocal microscopy. The proangiogenic potential of immature myeloid cells was analyzed by endothelial tube formation. RESULTS: Immature myeloid cells comprise ~25% of human placental CD45(+) hematopoietic cells and infiltrate placentas in proximity of blood vessels. The percentage of immature myeloid cells correlated positively with placental weight (r(2) = 0.108, P = .01) and birthweight (r(2) = 0.087, P = .02). Endothelial tube formation was increased in the presence of immature myeloid cells as compared with the presence of CD45(+)LIN2(+) control cells. CONCLUSION: Human placentas are populated by immature myeloid cells in the proximity of blood vessels. Consistent with their involvement in angiogenesis, immature myeloid cells accelerated endothelial tube formation. The presence of immature myeloid cells in pathologic pregnancies warrants further studies. PMID- 22840729 TI - Fetoplacental biometry and umbilical artery Doppler velocimetry in the overnourished adolescent model of fetal growth restriction. AB - OBJECTIVE: The purpose of this study was to evaluate ultrasonographically fetal growth trajectories, placental biometry, and umbilical artery (UA) Doppler indices in growth-restricted pregnancies of overnourished adolescent ewes and normally developing pregnancies of control-fed ewes. STUDY DESIGN: Singleton pregnancies were established using embryo transfer in 42 adolescent ewes that were overnourished (n = 27) or control-fed (n = 15) and were scanned at weekly intervals from 83-126 days' gestation and necropsied at 131 days' gestation (term = 145 days). RESULTS: Ultrasonographic placental measurements were reduced and UA Doppler indices were increased from 83 days' gestation; measurements of fetal abdominal circumference and femur length, renal volume and tibia length, and biparietal diameter were reduced from 98, 105, and 112 days' gestation, respectively, in overnourished vs control-intake pregnancies. CONCLUSION: Overnourishment of adolescent sheep dams produced late-onset asymmetric fetal growth restriction that was commensurate with brain sparing. Ultrasonographic placental biometry was already reduced and UA Doppler indices increased by mid gestation in overnourished pregnancies, preceding reduced fetal growth velocity and indicating an early nutritionally mediated insult on placental development. PMID- 22840730 TI - Clear cell carcinoma arising in the abdominal wall: two case reports and literature review. AB - Clear cell carcinoma originating in the abdominal wall is rare and usually develops within endometriotic implants in the scar. We describe 2 patients: a 42 year old with a 15 cm mass on the abdominal wall treated with neoadjuvant chemotherapy and excision and a 51 year old with a 6 cm abdominal mass treated with excision and adjuvant radiotherapy. PMID- 22840731 TI - Effects of hip extensor fatigue on lower extremity kinematics during a jump landing task in women: a controlled laboratory study. AB - BACKGROUND: Lower extremity kinematics may change as a result of impaired hip muscle function, thereby placing athletes at increased risk of injury. The purpose of this study was to examine whether experimentally-induced hip extensor fatigue alters lower extremity kinematics during a jump-landing task in women. METHODS: Forty healthy women were randomly assigned to an experimental group in which participants performed modified Biering-Sorenson tests to fatigue the hip extensors or to a sham control group in which participants performed repeated push-ups to exhaustion. Three-dimensional hip and knee kinematics and gluteus maximus electromyography (EMG) signals were measured during jump-landing tests to examine the effects of hip extensor fatigue. FINDINGS: Hip extension strength decreased in the experimental group by 25% following the intervention, thereby confirming effects of the fatigue intervention. No group*time interactions in hip and knee motions were statistically significant, indicating that hip and knee kinematics did not change following the fatigue-inducing intervention. Gluteus maximus recruitment during the post-fatigue test, however, increased by 55% in the experimental group. INTERPRETATION: A 25% reduction in hip extensor strength did not lead to changes in hip or knee kinematics. Rather, participants accommodated for the loss of strength by recruiting more Gmax activation to complete the task. Gmax recruitment may compensate when hip extensor strength is impaired, suggesting that improved neuromuscular control can influence motor performance when strength is diminished. PMID- 22840732 TI - Right atrial chromaffin paraganglioma in a dog. AB - Cardiac neoplasia is relatively uncommon in canine patients, with the most common neoplasms including right atrial hemangiosarcoma and paragangliomas occurring at the heart base (i.e. chemodectomas or aortic body tumors). Intracardiac paragangliomas are rare neoplasms in humans and have seldom been documented in the veterinary literature. This report describes the clinical course and histopathological findings in an adult canine patient with an intracardiac chromaffin paraganglioma (non-adrenal pheochromocytoma) of the right atrium. PMID- 22840733 TI - Involvement of the choroid plexus in the inflammatory response after acute spinal cord injury in dogs: an immunohistochemical study. AB - The choroid plexus (CP) is increasingly recognized as an important contributor to central nervous system (CNS) inflammation by recruitment of inflammatory cells and release of inflammatory cytokines. Here we investigate the role of the CP epithelium (CPE) as a source of three pro-inflammatory molecules of potential importance in inflammation after acute spinal cord injury (SCI): IL-1beta, TNF alpha, and hsp70. Immunohistochemical (IHC) staining for these three proteins was performed on 4th ventricular CPE from 4 dogs euthanized 12-48 h after spontaneous acute SCI, and from 4 neurologically normal dogs euthanized for other reasons. IHC staining was quantified using Aperio ImageScope software. IHC staining in the CPE of dogs with acute SCI was 2.2, 1.6 and 1.5 times higher than that of normal dogs, for IL-1beta, TNF-alpha, and hsp70, respectively. Increases were statistically significant (p<0.1) for IL-1beta and TNF-alpha, and closely approached significance for hsp70. These findings indicate that the CPE could serve as an important source of these inflammatory mediators after SCI. There was also an inverse correlation between IL-1beta and hsp70 staining and duration of clinical signs in acute SCI, suggesting that increased expression of these proteins by the CPE may be of particular importance in the immediate-early inflammatory response after acute SCI. PMID- 22840734 TI - Moving along the mental time line influences the processing of future related words. AB - Abstract concepts like numbers or time are thought to be represented in the more concrete domain of space and the sensorimotor system. For example, thinking of past or future events has a physical manifestation in backward or forward body sway, respectively. In the present study, we investigated the reverse effect: can passive whole-body motion influence the processing of temporal information? Participants were asked to categorize verbal stimuli to the concepts future or past while they were displaced forward and backward (Experiment 1), or upward and downward (Experiment 2). The results showed that future related verbal stimuli were categorized faster during forward as compared to backward motion. This finding supports the view that temporal events are represented along a mental time line and that the sensorimotor system is linked to that representation. We showed that body motion is not just an epiphenomenon of temporal thoughts. Passive whole-body motion can influence higher-order temporal cognition. PMID- 22840735 TI - Introduction of laser technology and procedure use for benign prostatic hyperplasia: data from Florida. AB - OBJECTIVE: To examine the association of laser technology adoption in a market with surgery rates for benign prostatic hyperplasia. METHODS: Using the Florida files from the State Ambulatory and Inpatient Surgery Databases (2001-2009), we identified all patients who underwent transurethral surgery for benign prostatic hyperplasia. We calculated rates of benign prostatic hyperplasia surgery for all markets within the state (defined by Hospital Service Area) over time. Markets were split into 3 categories: (1) Always offering, (2) never offering, or (3) initially not offering but adopting laser prostatectomy after 2001. We used multivariable regression models to estimate surgery rates adjusted for other market characteristics. Interaction terms were included in the models to examine differences in time trends between market categories. RESULTS: After adjusting for market characteristics, time trends differed by market category (P < .001). Surgery rates decreased from 318 to 248 procedures per 100,000 men in markets always offering laser prostatectomy (P < .001). Markets never offering laser surgery had much lower rates that remained stable (180-187 procedures per 100,000 men, P = .805). In markets adopting laser technology, rates increased from 268 to 296 procedures per 100,000 men after adoption (P = .044), such that 4 years after adoption these markets had the highest rates among the 3 categories. CONCLUSION: Adoption of laser technology is associated with rising rates of surgical intervention for benign prostatic hyperplasia. This trend appears to be induced by the introduction of laser surgery. PMID- 22840737 TI - Flow-diverting stents for the treatment of arterial aneurysms. AB - BACKGROUND: Anatomic factors may limit the application of stent grafts for the treatment of arterial aneurysms. Flow- diverting stents (FDSs) are specially designed to reduce flow velocity in the aneurysm sac and promote thrombosis while maintaining flow in the main artery and branch vessels. FDSs include the Pipeline Embolization Device (ev3, Plymouth, Minn), the SILK Arterial Reconstruction Device (Balt Extrusion, Montmorency, France), and the Cardiatis Multilayer Stent (Cardiatis, Isnes, Belgium). The first two have been mainly used for the treatment of intracranial aneurysms. The aim of this study was to review the current role of FDSs in the treatment of extracranial arterial aneurysms. METHODS: A systematic electronic health database search was conducted using PubMed, Ovid, Medline, and the Cochrane Database on all accessible published articles through March 2012. An additional search for abstracts presented in international congresses for vascular surgery was also performed. Full-text articles and abstracts were analyzed separately due to the heterogeneity of the data. RESULTS: Results of the use of FDSs in arterial aneurysms were reported in 12 full-text articles including 35 patients (26 men, age 65.4) with 38 aneurysms. The aneurysms were located in the hepatic (n = 12), splenic (n = 6), renal (n = 5), celiac (n = 4), superior mesenteric (n = 3), subclavian (n = 2), gastroduodenal (n = 1), and popliteal arteries (n = 1) and in the descending thoracic (n = 1), suprarenal (n = 1) and infrarenal aorta (n = 2). The 30-day mortality was 5.7% (2 of 35 patients). Three stent thromboses occurred (8.3%), none of them with clinical consequences. Thirty patients with 33 aneurysms and patent FDSs were monitored for an average of 9.2 months. Thrombosis occurred in 90.6%, and volume reduction was observed in 81% of the aneurysms. No branch vessel occlusion occurred. Twelve abstracts were identified, including 133 patients (mean age, 64.7 years). They included 62 peripheral, 28 visceral, and 43 abdominal and thoracoabdominal aneurysms. The Cardiatis Multilayer Stent was used in all cases. Thrombosis was achieved in all but two peripheral and visceral aneurysms. Volume reduction was observed in 82.7%, and no branch vessel occlusion occurred. In aortic aneurysms, better results regarding aneurysm thrombosis, reduction of the volume, and patency of collateral branches were reported at 12 months rather than at 6 months postoperatively. No aneurysm rupture has yet been described. CONCLUSIONS: Initial clinical experience with the use of FDSs in the treatment of visceral and peripheral aneurysms yielded satisfactory results in technical success, aneurysm thrombosis and shrinkage, and in patency of branch vessels. The results in aortic aneurysms are still under investigation. No aneurysm rupture has yet been described. There is a significant incidence of FDS thrombosis. Volume reduction of the aneurysm is a clearer evidence of the clinical success after treatment with FDSs than aneurysm thrombosis. PMID- 22840738 TI - Comparison of vein valve function following pharmacomechanical thrombolysis versus simple catheter-directed thrombolysis for iliofemoral deep vein thrombosis. AB - BACKGROUND: Successful catheter-directed thrombolysis (CDT) for iliofemoral deep vein thrombosis (IFDVT) reduces post-thrombotic morbidity and is a suggested treatment option by the American College of Chest Physicians for patients with IFDVT. Pharmacomechanical thrombolysis (PMT) is also suggested to shorten treatment time and reduce the dose of plasminogen activator. However, concern remains that mechanical devices might damage vein valves. The purpose of this study is to examine whether PMT adversely affects venous valve function compared to CDT alone in IFDVT patients treated with catheter-based techniques. METHODS: Sixty-nine limbs in 54 patients (39 unilateral, 15 bilateral) who underwent catheter-based treatment for IFDVT form the basis of this study. Lytic success and degree of residual obstruction were analyzed by reviewing postprocedural phlebograms. All patients underwent bilateral postprocedure duplex to evaluate patency and valve function. Phlebograms and venous duplex examinations were interpreted in a blinded fashion. Limbs were analyzed based on the method of treatment: CDT alone (n = 20), PMT using rheolytic thrombolysis (n = 14), and isolated pharmacomechanical thrombolysis (n = 35). The validated outcome measures were compared between the treatment groups. RESULTS: Sixty-nine limbs underwent CDT with or without PMT. The average patient age was 47 years (range, 16-78). Venous duplex was performed 44.4 months (mean) post-treatment. Of the limbs treated with CDT with drip technique, 65% demonstrated reflux vs 53% treated with PMT (P = .42). There was no difference in long-term valve function between patients treated with rheolytic and isolated pharmacomechanical thrombolysis. In the bilateral group, 87% (13/15) demonstrated reflux in at least one limb. In the unilateral group, 64% (25/39) had reflux in their treated limb and 36% (14/39) in their contralateral limb. There was no correlation effect of residual venous obstruction on valve function, although few patients had >50% residual obstruction. CONCLUSIONS: In patients undergoing catheter-based intervention for IFDVT, PMT does not adversely affect valve function compared with CDT alone. A higher than expected number of patients had reflux in their uninvolved limb. PMID- 22840739 TI - Preoperative prediction of mortality within 1 year after elective thoracic endovascular aortic aneurysm repair. AB - OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) is known to have a survival benefit over open repair in patients with descending thoracic aneurysms and has become a mainstay of therapy. Because death before 1 year after TEVAR likely indicates an ineffective therapy, we have created a predictive model for death within 1 year using factors available in the preoperative setting. METHODS: A registry of 526 TEVARs performed at the University of Florida between September 2000 and November 2010 was queried for patients with degenerative descending thoracic aneurysm as their primary pathology. Procedures with emergent or urgent indications were excluded. Preoperatively available variables, such as baseline comorbidities, anatomic-, and procedure-specific planning details, were recorded. Univariate predictors of death were analyzed with multivariable Cox proportional hazards to identify independent predictors of 30-day (death within 30 days) and 1 year mortality (death within 1 year) after TEVAR. RESULTS: A total of 224 patients were identified and evaluated. The 30-day mortality rate was 3% (n = 7) and the 1-year mortality rate was 15% (n = 33). Multivariable predictors of 1 year mortality (hazard ratios [95% confidence interval]) included: age >70 years (5.8 [2.1-16.0]; P = .001), adjunctive intraoperative procedures (eg, brachiocephalic or visceral stents, or both, concomitant arch debranching procedures; 4.5 [1.9-10.8]; P = .001), peripheral arterial disease (3.0 [1.4 6.7]; P = .006), coronary artery disease (2.4 [1.1-4.9]; P = .02), and chronic obstructive pulmonary disease (1.9 [1.0-3.9]; P = .06). A diagnosis of hyperlipidemia was protective (0.4 [0.2-0.7]; P = .006). When patients were grouped into those with one, two, three, or four or more of these risk factors, the predicted 1-year mortality was 1%, 3%, 10%, 27%, and 54%, respectively. CONCLUSIONS: Factors are available in the preoperative setting that are predictive of death within 1 year after TEVAR and can guide clinical decision making regarding the timing of repair. Patients with multiple risk factors, such as age >= 70 years, coronary artery disease, chronic obstructive pulmonary disease, and a need for an extensive procedure involving adjunctive therapies, have a high predicted mortality within 1 year and may be best served by waiting for a larger aneurysm size to justify the risk of intervention. PMID- 22840741 TI - The role of dynamic contrast-enhanced magnetic resonance imaging in the diagnosis and management of patients with vascular malformations. AB - OBJECTIVE: Vascular malformations are uncommon but may confer significant morbidity. Limitations in diagnosis and treatment result from inadequate classification schema and diagnostic algorithms. The crucial distinction is between high-flow and low-flow lesions because this informs prognosis and treatment. This study assessed the utility of dynamic contrast-enhanced magnetic resonance imaging (dceMRI) in distinguishing high-flow from low-flow lesions, a technique that has previously not been widely applied or evaluated in this patient population. METHODS: A prospective database of all patients referred to the multidisciplinary vascular malformation team at our institution was reviewed from January 2006 to June 2010. dceMRI was obtained on each patient to determine flow characteristics and lesion extent. Additional studies were used as indicated. Catheter-based arteriography was performed when high-flow lesions were identified with the intention of intervening or to distinguish between high-flow and low-flow lesions when MRI was indeterminate. A triage algorithm was used to stratify patients and formulate therapeutic goals. We analyzed the accuracy of dceMRI in identifying high-flow and low-flow lesions. RESULTS: The study included 122 patients (aged <1 to 70 years) comprising 52 males (42.6%) and 70 females (57.4%). Pain (72 patients; 59%) and swelling (88 patients; 72.1%) were the most common presenting symptoms. All patients underwent dceMRI. Of these, 68 had confirmatory imaging (n = 15) or intervention (n = 53). The dceMRI was able to definitively and correctly distinguish high-flow from low-flow lesions in 57 studies, for an accuracy rate of 83.8%. In the remaining 11 studies, dceMRI correctly queried flow status but not definitively, and confirmatory angiography was required. CONCLUSIONS: Using a diagnostic tool designed to identify key clinical characteristics, we were able to successfully distinguish between high flow and low-flow vascular malformations using dceMRI alone in 83.8% of patients, minimizing the need for unnecessary invasive catheter-based procedures. PMID- 22840742 TI - Contralateral occlusion is not a clinically important reason for choosing carotid artery stenting for patients with significant carotid artery stenosis. AB - OBJECTIVE: Contralateral carotid artery occlusion by itself carries an increased risk of stroke. Carotid endarterectomy (CEA) in the presence of contralateral carotid artery occlusion has high reported rates of perioperative morbidity and mortality. Our objective was to determine if there is a clinical benefit to patients who receive carotid artery stenting (CAS) compared to CEA in the presence of contralateral carotid artery occlusion. METHODS: We conducted a retrospective medical chart review over a 4.5-year institutional experience of persons with contralateral carotid artery occlusion and ipsilateral carotid artery stenosis who underwent CAS or CEA. The main outcome measures were 30-day cardiac, stroke, and mortality rate, and midterm mortality. RESULTS: Of a total of 713 patients treated for carotid artery stenosis during this time period, 57 had contralateral occlusion (~8%). Thirty-nine of these patients were treated with CAS, and 18 with CEA. The most common indications for CAS were prior neck surgery (18), contralateral internal carotid occlusion (nine), and prior neck radiation (seven). The average age was 70 +/- 8.5 for CEA and 66.7 +/- 9.3 for CAS (P = .20). Both groups were predominantly men (CEA 12 of 18; CAS 28 of 39; P = .76), with similar prevalence of symptomatic lesions (CEA 8 of 18, CAS 20 of 39; P = .77). Two patients died within 30 days in the CAS group (5%). No deaths occurred within 30 days in the CEA group (P = .50); the mortality rate for CAS and CEA combined was 3.5%. No perioperative strokes or myocardial infarction occurred in either group. Two transient ischemic attacks occurred after CAS. At mean follow-up of 29.4 +/- 16 months (CEA) and 28 +/- 14.4 months (CAS; range, 1.5-48.5 months), seven deaths occurred in the CAS group and one in the CEA group (17.9% vs 5.5%; P = .40). There were two reinterventions in the CAS group for in stent restenosis and there were no reoperations in the CEA group. CONCLUSIONS: Although CEA and CAS can both be performed with good perioperative results and acceptable midterm mortality, the observed outcomes do not support use of contralateral carotid artery occlusion as a selection criterion for CAS over CEA in the absence of other indications. PMID- 22840743 TI - Hsp90 modulation for the treatment of Alzheimer's disease. AB - Hsp90 serves as the master regulator of the prosurvival, heat shock response. Upon exposure to cellular stress or small molecule inhibitors of Hsp90, various heat shock proteins are induced to assist in the rematuration of misfolded proteins. Several neurodegenerative diseases, including Alzheimer's disease, manifest through the accumulation of misfolded proteins, suggesting that induction of the heat shock response may provide a viable approach toward the management of such diseases. In this chapter, the rationale for such an approach and potential therapeutics are discussed. PMID- 22840746 TI - gamma-Secretase as a target for Alzheimer's disease. AB - gamma-Secretase is a protease complex responsible for cutting the transmembrane domain of the amyloid beta-protein precursor (APP) to form the amyloid beta protein (Abeta), an aggregation-prone product that accumulates in the brain in Alzheimer's disease. As evidence suggests that Abeta is critical to Alzheimer pathogenesis, gamma-secretase is considered a key target for the development of disease-modifying therapeutics. The protease complex cuts many other substrates, and some of these proteolytic events are part of signaling pathways or other important cellular functions. Among these, proteolysis of the Notch receptor is essential for signaling that is involved in a number of cell-fate determinations. Many inhibitors of gamma-secretase have been identified, but it is clear that drug candidates for Alzheimer's disease should have minimal effects on the Notch signaling pathway, as serious safety issues have arisen with nonselective inhibitors. Two types of promising candidates that target this protease complex have emerged: the so-called "Notch-sparing" gamma-secretase inhibitors, which block cleavage of APP selectively over that of Notch, and gamma-secretase modulators, which shift the proportion of Abeta peptides produced in favor of shorter, less aggregation-prone species. The current status and prospects for these two general types of candidates will be discussed. PMID- 22840747 TI - Altering mitochondrial dysfunction as an approach to treating Alzheimer's disease. AB - Mitochondrial dysfunction appears to be a precipitating or exacerbating factor in both familial and late stage Alzheimer's disease. This chapter summarizes various mechanisms by which dysfunction of mitochondrial metabolism can be involved in loss of cognitive function as well as in the exacerbation of structural changes in the signature pathology of Alzheimer's disease. Although currently few in number, a number of mitochondrially directed/metabolic approaches are now being tried that include limiting the damage caused by dysfunctional oxidative metabolism. There is a clear need to identify and test specific targets to take advantage of a growing understanding in this field. The eventual successful approach to meaningfully treat Alzheimer's disease will likely include treatments aimed at correction of the mitochondrial dysfunction component. PMID- 22840749 TI - Beyond amyloid: the future of therapeutics for Alzheimer's disease. AB - Currently, the field is awaiting the results of several pivotal Phase III clinical Alzheimer's disease (AD) trials that target amyloid-beta (Abeta). In light of the recent biomarker studies that indicate Abeta levels are at their most dynamic 5-10 years before the onset of clinical symptoms, it is becoming uncertain whether direct approaches to target Abeta will achieve desired clinical efficacy. AD is a complex neurodegenerative disease caused by dysregulation of numerous neurobiological networks and cellular functions, resulting in synaptic loss, neuronal loss, and ultimately impaired memory. While it is clear that Abeta plays a key role in the pathogenesis of AD, it may be a challenging and inefficient target for mid-to-late stage AD intervention. Throughout the course of AD, multiple pathways become perturbed, presenting a multitude of possible therapeutic avenues for design of AD intervention and prophylactic therapies. In this chapter, we sought to first provide an overview of Abeta-directed strategies that are currently in development, and the pivotal Abeta-targeted trials that are currently underway. Next, we delve into the biology and therapeutic designs associated with other key areas of research in the field including tau, protein trafficking and degradation pathways, ApoE, synaptic function, neurotrophic/neuroprotective strategies, and inflammation and energy utilization. For each area we have provided a comprehensive and balanced overview of the therapeutic strategies currently in preclinical and clinical development, which will shape the future therapeutic landscape of AD. PMID- 22840748 TI - scyllo-Inositol, preclinical, and clinical data for Alzheimer's disease. AB - Preclinical development of scyllo-inositol for the treatment of Alzheimer's disease (AD) has been investigated in both in vitro and in vivo models with positive results. scyllo-Inositol stabilized a small conformer of Abeta42 in vitro, neutralized cell derived Abeta trimers and promoted low molecular weight Abeta species in vivo. These interactions resulted in decreased neuronal toxicity, increased long-term potentiation (LTP) and ablation of cognitive deficits in multiple mouse models of AD. scyllo-Inositol bioavailability, pharmacokinetics, and small animal toxicology studies demonstrated the potential for translation to human patients. The results of Phase I and Phase II clinical trials for AD are presented. Furthermore, the use of this compound for imaging and other amyloid related disorders is discussed. PMID- 22840744 TI - Using Pittsburgh Compound B for in vivo PET imaging of fibrillar amyloid-beta. AB - The development of Abeta-PET imaging agents has allowed for detection of fibrillar Abeta deposition in vivo and marks a major advancement in understanding the role of Abeta in Alzheimer's disease (AD). Imaging Abeta thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other non-Abeta causes in patients presenting with mild or atypical symptoms or confounding comorbidities (in which the distinction is difficult to make clinically). From a research perspective, imaging Abeta allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to mild cognitive impairment (MCI) to AD; and to monitor the effectiveness of anti-Abeta drugs and relate them to neurodegeneration and clinical symptoms. Here, we will discuss the application of one of the most broadly studied and widely used Abeta imaging agents, Pittsburgh Compound-B (PiB). PMID- 22840750 TI - Activation of protein kinase C isozymes for the treatment of dementias. AB - Memories are much more easily impaired than improved. Dementias, a lasting impairment of memory function, occur in a variety of cognitive disorders and become more clinically dominant as the population ages. Protein kinase C is one of the "cognitive kinases," and plays an essential role in both memory acquisition and maintenance. Deficits in protein kinase C (PKC) signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and other types of memory impairment, including those related to cerebral ischemia and ischemic stroke. Inhibition or impairment of PKC activity results in compromised learning and memory, whereas an appropriate activation of certain PKC isozymes leads to an enhancement of learning and memory and/or antidementic effects. In preclinical studies, PKC activators have been shown to increase the expression and activity of PKC isozymes, thereby restoring PKC signaling and downstream activity, including stimulation of neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas. PKC activators also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation and support anti apoptotic processes in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of effective cognition-enhancing therapeutics for the treatment of dementias. PMID- 22840745 TI - Mitochondrial abnormalities in Alzheimer's disease: possible targets for therapeutic intervention. AB - Mitochondria from persons with Alzheimer's disease (AD) differ from those of age matched control subjects. Differences in mitochondrial morphology and function are well documented, and are not brain-limited. Some of these differences are present during all stages of AD, and are even seen in individuals who are without AD symptoms and signs but who have an increased risk of developing AD. This chapter considers the status of mitochondria in AD subjects, the potential basis for AD subject mitochondrial perturbations, and the implications of these perturbations. Data from multiple lines of investigation, including epidemiologic, biochemical, molecular, and cytoplasmic hybrid studies, are reviewed. The possibility that mitochondria could potentially constitute a reasonable AD therapeutic target is discussed, as are several potential mitochondrial medicine treatment strategies. PMID- 22840751 TI - Striatal-enriched protein tyrosine phosphatase in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia among the elderly, affecting millions of people worldwide and representing a substantial economic burden. AD is a progressive disease associated with memory loss and impaired cognitive function. The neuropathology is characterized by cortical accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are small, aggregated peptides called beta amyloid (Abeta) and NFTs are aggregates of hyperphosphorylated Tau protein. Because Abeta disrupts multiple intracellular signaling pathways, resulting in some of the clinical symptoms of AD, understanding the underlying molecular mechanisms has implications for the diagnosis and treatment of AD. Recent studies have demonstrated that Abeta regulates striatal-enriched protein tyrosine phosphatase (STEP) (PTPN5). Abeta accumulation is associated with increases in STEP levels and activity that in turn disrupts glutamate receptor trafficking to and from the neuronal membrane. These findings indicate that modulating STEP levels or inhibiting its activity may have beneficial effects for patients with AD, making it an important target for drug discovery. This article reviews the biology of STEP and its role in AD as well as the potential clinical applications. PMID- 22840753 TI - Carpal tunnel syndrome with paracoccidioidomycosis. PMID- 22840754 TI - Aqueous salt transport through soft contact lenses: an osmotic-withdrawal mechanism for prevention of adherence. AB - In addition to improving oxygen permeability, modern silicone-hydrogel (SiHy) soft contact lenses (SCLs) exceed a limiting diffusive ion permeability to aqueous sodium chloride. Below the ion-permeability threshold, siloxane-based SCLs are prone to bind against the corneal epithelium. Salt permeability is argued to reflect indirectly water hydraulic permeability. However, no quantitative explanation is available to date for a threshold salt permeability. We hypothesize that molecular salt diffusion through a SCL supports the postlens tear film (PoLTF) by enhancing water flow into the PoLTF from the cornea. Higher salt concentrations in the PoLTF raise the osmotic pressure there relative to that in the cornea increasing osmotic water withdrawal from the cornea. The proposed osmotic-withdrawal mechanism successfully predicts a self-consistent threshold lens salt permeability when thin-film attractive binding forces are introduced. For the first time, we present a quantitative picture for the possible origin of a threshold salt permeability in SCL manufacture. PMID- 22840755 TI - Cutaneous vascular calcifications secondary to treatment with teriparatide. PMID- 22840756 TI - Simulation of the effects of different pilot helmets on neck loading during air combat. AB - New generation pilot helmets with mounted devices enhance the capabilities of pilots substantially. However, the additional equipment increases the helmet weight and shifts its center of mass forward. Two helmets with different mass properties were modeled to simulate their effects on the pilot's neck. A musculoskeletal computer model was used, with the methods of inverse dynamics and static optimization, to compute the muscle activations and joint reaction forces for a given range of quasi-static postures at various accelerations experienced during air combat. Head postures which induce much higher loads on the cervical spine than encountered in a neutral position could be identified. The increased weight and the forward shift of the center of mass of a new generation helmet lead to higher muscle activations and higher joint reaction loads over a wide range of head and neck movements. The muscle activations required to balance the head and neck in extreme postures increased the compressive force at the T1-C7 level substantially, while in a neutral posture the muscle activations remained low. The lateral neck muscles can reach activations of 100% and cause compressive joint forces up to 1100N during extensive rotations and extensions at high 'vertical' accelerations (Gz). The calculated values have to be interpreted with care as the model has not been validated. Nevertheless, this systematic analysis could separate the effects of head posture, acceleration and helmet mass on neck loading. More reliable data about mass properties and muscle morphometry with a more detailed motion analysis would help to refine the existing model. PMID- 22840757 TI - Muscle and prosthesis contributions to amputee walking mechanics: a modeling study. AB - Unilateral, below-knee amputees have altered gait mechanics, which can significantly affect their mobility. Below-knee amputees lose the functional use of the ankle muscles, which are critical during walking to provide body support, forward propulsion, leg-swing initiation and mediolateral balance. Thus, either muscles must compensate or the prosthesis must provide the functional tasks normally provided by the ankle muscles. Three-dimensional (3D) forward dynamics simulations of amputee and non-amputee walking were generated to identify muscle and prosthesis contributions to amputee walking mechanics, including the subtasks of body support, forward propulsion, leg-swing initiation and mediolateral balance. Results showed that the prosthesis provided body support in the absence of the ankle muscles. The prosthesis contributed to braking from early to mid stance and propulsion in late stance. The prosthesis also functioned like the uniarticular soleus muscle by transferring energy from the residual leg to the trunk to provide trunk propulsion. The residual-leg vasti and rectus femoris reduced their contributions to braking in early stance, which mitigated braking from the prosthesis during this period. The prosthesis did not replace the function of the gastrocnemius, which normally generates energy to the leg to initiate swing. As a result, lower overall energy was delivered to the residual leg. The prosthesis also acted to accelerate the body laterally in the absence of the ankle muscles. These results provide further insight into muscle and prosthesis function in below-knee amputee walking and can help guide rehabilitation methods and device designs to improve amputee mobility. PMID- 22840758 TI - The influence of a unilateral fixed ankle on metabolic and mechanical demands during walking in unimpaired young adults. AB - The plantarflexors provide a major source of propulsion during walking. When mechanical power generation from the plantarflexor muscles is limited, other joints may compensate to maintain a consistent walking velocity, but likely at increased metabolic cost. The purpose of this study was to determine how a unilateral reduction in ankle plantarflexor power influences the redistribution of mechanical power generation within and across limbs and the associated change in the metabolic cost of walking. Twelve unimpaired young adults walked with an ankle brace on the dominant limb at 1.2m/s on a dual-belt instrumented treadmill. Lower extremity kinematics and kinetics as well as gas exchange data were collected in two conditions: (1) with the brace unlocked (FREE) and (2) with the brace locked (FIXED). The brace significantly reduced ankle plantarflexion excursion by 12.96+/-3.60 degrees (p<0.001) and peak ankle mechanical power by 1.03+/-0.51W/kg (p<0.001) in the FIXED versus FREE condition. Consequently, metabolic power (W/kg) of walking in the FIXED condition increased by 7.4% compared to the FREE condition (p=0.03). Increased bilateral hip mechanical power generation was observed in the FIXED condition (p<0.001). These results suggest that walking with reduced ankle power increases metabolic demand due to the redistribution of mechanical power generation from highly efficient ankle muscle tendons to less efficient hip muscle-tendons. A within and across limb redistribution of mechanical workload represents a potential mechanism for increased metabolic demand in pathological populations with plantarflexion deficits or those that walk with an ankle-foot orthosis that restricts range of motion. PMID- 22840752 TI - Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of beta-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy. PMID- 22840759 TI - Interleukin-18 gene polymorphisms in Egyptian patients with allergic diseases. AB - BACKGROUND: Allergic diseases, such as allergic rhinitis (AR) and atopic dermatitis (AD), affect a large proportion of people worldwide. Both have environmental and genetic predisposing factors. Single nucleotide polymorphisms (SNPs) in interleukin (IL)-18, may play a direct role in the disease pathogenesis. This study was designed to investigate the association of the IL-18 gene SNPs (-137 G/C [rs187238], and -140 C/G [rs360721]) with AR and AD, as well as their relations to the diseases' severity. METHODS: Seventy-five individuals were enrolled in the study including, 25 AD children, 25 AR patients, and 25 unrelated healthy adult volunteers who served as controls. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: AR and AD patients showed no significant differences in the genotype distribution and allele frequencies of -137 G/C and 140 C/G SNPs when compared independently with the control group. However, the 140 GG genotype and the -140 G allele were more often associated with severe AD compared with mild and moderate phenotypes (p = 0.01 and 0.001, respectively; odds ratios [ORs], 14.25 [95% CI, 1.48-143.2] and 16 [95% CI, 2.8-90.46], respectively). Moreover, the -137 G allele was associated with moderate/severe AR (p = 0.019; OR, 6.1 [95% CI, 1.34-28.1]). CONCLUSION: This preliminary study indicates that the studied polymorphisms do not confer susceptibility to allergy in Egyptian patients but may be related to the disease phenotype. However, the role of IL-18 in allergy may be too complex to be reflected in a simple association study. PMID- 22840760 TI - Gray matter correlates of posttraumatic stress disorder: a quantitative meta analysis. AB - BACKGROUND: Since the inception of the diagnosis posttraumatic stress disorder (PTSD), attempts have been undertaken to understand why only a subpopulation of individuals exposed to trauma develops PTSD. Cerebral gray matter reductions have been suggested to be a crucial pathobiological marker of PTSD. However, a quantitative meta-analysis of whole-brain voxel-based morphometry studies is lacking. METHODS: Here, we investigated concurrence across voxel-based morphometry studies in PTSD compared with trauma-exposed individuals without PTSD (all together nine studies with 319 subjects) by means of activation likelihood estimation. RESULTS: We identified brain regions of consistent gray matter reduction in anterior cingulate cortex, ventromedial prefrontal cortex, left temporal pole/middle temporal gyrus, and left hippocampus in PTSD patients compared with individuals exposed to trauma without PTSD. CONCLUSIONS: This is the first quantitative whole-brain meta-analysis showing brain structure deficits in traumatized subjects with PTSD compared with trauma-exposed healthy control subjects. The gray matter deficit profile overlaps with brain networks of emotion processing, fear extinction, and emotion regulation known to be affected in PTSD. Although the data cannot clarify if this is a predisposition or a consequence of the disease, the results may facilitate the need to control for structural characteristics in future functional brain studies. PMID- 22840761 TI - Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. AB - BACKGROUND: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Asberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 +/- 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine. PMID- 22840762 TI - Reduced neuronal activity in language-related regions after transcranial magnetic stimulation therapy for auditory verbal hallucinations. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) is a novel therapeutic approach, used in patients with pharmacoresistant auditory verbal hallucinations (AVH). To investigate the neurobiological effects of TMS on AVH, we measured cerebral blood flow with pseudo-continuous magnetic resonance-arterial spin labeling 20 +/- 6 hours before and after TMS treatment. METHODS: Thirty patients with schizophrenia or schizoaffective disorder were investigated. Fifteen patients received a 10-day TMS treatment to the left temporoparietal cortex, and 15 received the standard treatment. The stimulation location was chosen according to an individually determined language region determined by a functional magnetic resonance imaging language paradigm, which identified the sensorimotor language area, area Spt (sylvian parietotemporal), as the target region. RESULTS: TMS treated patients showed positive clinical effects, which were indicated by a reduction in AVH scores (p <= .001). Cerebral blood flow was significantly decreased in the primary auditory cortex (p <= .001), left Broca's area (p <= .001), and cingulate gyrus (p <= .001). In control subjects, neither positive clinical effects nor cerebral blood flow decreases were detected. The decrease in cerebral blood flow in the primary auditory cortex correlated with the decrease in AVH scores (p <= .001). CONCLUSIONS: TMS reverses hyperactivity of language regions involved in the emergence of AVH. Area Spt acts as a gateway to the hallucination-generating cerebral network. Successful therapy corresponded to decreased cerebral blood flow in the primary auditory cortex, supporting its crucial role in triggering AVH and contributing to the physical quality of the false perceptions. PMID- 22840763 TI - Single-cell technologies highlight heterogeneity among cells. PMID- 22840764 TI - Babysitting flavin for biosynthesis. AB - Enzymes involved in natural product biosynthesis employ a variety of cofactors, reaction mechanisms, and substrate preferences to achieve remarkable chemical diversity found in nature. In this issue of Chemistry & Biology, Goldman and colleagues show how cofactor (FAD) binding affinity impacts the reaction mechanism and outcome of two related proteins, RebC and StaC, involved in indolocarbazoles biosynthesis. PMID- 22840765 TI - New mechanisms of 5-nitrofuran toxicity. AB - Phenotypic screens and the target identification that follows can lead to surprising new connections between small molecules and targets. In this issue of Chemistry & Biology, Zhou and colleagues seek to understand the pigmentation of fish skin and end up uncovering an interesting clinical hypothesis about the trypanocidal compound nifurtimox. PMID- 22840766 TI - Visualizing individual sodium channels on the move. AB - Visualization of voltage-gated sodium channels at work is an important requirement for the understanding of rapid electrical signaling in nerve cells. In this issue of Chemistry & Biology, Ondrus and colleagues have mastered this challenge by chemical synthesis of a fluorescent antagonist and by monitoring single sodium channels in living cells with unprecedented optical resolution. PMID- 22840767 TI - Chemical ecology of endophytic fungi: origins of secondary metabolites. AB - Endophytes constitute a remarkably multifarious group of microorganisms ubiquitous in plants and maintain an imperceptible association with their hosts for at least a part of their life cycle. Their enormous biological diversity coupled with their capability to biosynthesize bioactive secondary metabolites has provided the impetus for a number of investigations on endophytes. Here, we highlight the possible current and future strategies of understanding the chemical communication of endophytic fungi with other endophytes (fungi and bacteria) and with their host plants, which might not only allow the discovery and sustainable production of desirable natural products but also other mostly overlooked bioactive secondary metabolites. PMID- 22840768 TI - Clofarabine targets the large subunit (alpha) of human ribonucleotide reductase in live cells by assembly into persistent hexamers. AB - Clofarabine (ClF) is a drug used in the treatment of leukemia. One of its primary targets is human ribonucleotide reductase (hRNR), a dual-subunit, (alpha(2))(m)(beta(2))(n), regulatory enzyme indispensable in de novo dNTP synthesis. We report that, in live mammalian cells, ClF targets hRNR by converting its alpha-subunit into kinetically stable hexamers. We established mammalian expression platforms that enabled isolation of functional alpha and characterization of its altered oligomeric associations in response to ClF treatment. Size exclusion chromatography and electron microscopy documented persistence of in-cell-assembled-alpha(6). Our data validate hRNR as an important target of ClF, provide evidence that in vivo alpha's quaternary structure can be perturbed by a nonnatural ligand, and suggest small-molecule-promoted, persistent hexamerization as a strategy to modulate hRNR activity. These studies lay foundations for documentation of RNR oligomeric state within a cell. PMID- 22840769 TI - HNF4alpha antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. AB - Hepatocyte nuclear factor (HNF)4alpha is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic beta cells. Although fatty acids were found to occupy the HNF4alpha ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4alpha ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4alpha antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4alpha with high affinity and modulated the expression of known HNF4alpha target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4alpha raises the possibility that diseases involving HNF4alpha, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4alpha activity. PMID- 22840770 TI - Arginine topology controls escape of minimally cationic proteins from early endosomes to the cytoplasm. AB - Proteins represent an expanding class of therapeutics, but their actions are limited primarily to extracellular targets because most peptidic molecules fail to enter cells. Here we identified two small proteins, miniature protein 5.3 and zinc finger module ZF5.3, that enter cells to reach the cytosol through rapid internalization and escape from Rab5+ endosomes. The trafficking pathway mapped for these molecules differs from that of Tat and Arg(8), which require transport beyond Rab5+ endosomes to gain cytosolic access. Our results suggest that the ability of 5.3 and ZF5.3 to escape from early endosomes is a unique feature and imply the existence of distinct signals, encodable within short sequences, that favor early versus late endosomal release. Identifying these signals and understanding their mechanistic basis will illustrate how cells control the movement of endocytic cargo and may allow researchers to engineer molecules to follow a desired delivery pathway for rapid cytosolic access. PMID- 22840771 TI - Cellular uptake mechanisms and endosomal trafficking of supercharged proteins. AB - Supercharged proteins (SCPs) can deliver functional macromolecules into the cytoplasm of mammalian cells more potently than unstructured cationic peptides. Thus far, neither the structural features of SCPs that determine their delivery effectiveness nor their intracellular fate postendocytosis, has been studied. Using a large set of supercharged GFP (scGFP) variants, we found that the level of cellular uptake is sigmoidally related to net charge and that scGFPs enter cells through multiple pathways, including clathrin-dependent endocytosis and macropinocytosis. SCPs activate Rho and ERK1/2 and also alter the endocytosis of transferrin and EGF. Finally, we discovered that the intracellular trafficking of endosomes containing scGFPs is altered in a manner that correlates with protein delivery potency. Collectively, our findings establish basic structure-activity relationships of SCPs and implicate the modulation of endosomal trafficking as a determinant of macromolecule delivery efficiency. PMID- 22840772 TI - Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening. AB - Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery, but subsequent target elucidation often proves difficult. Conditional mutants that underexpress essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA), and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered mutants hypersensitive to target specific inhibitors. Stable reporter strains were generated for use in high throughput screening, and their utility was demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. PMID- 22840773 TI - An unusual role for a mobile flavin in StaC-like indolocarbazole biosynthetic enzymes. AB - The indolocarbazole biosynthetic enzymes StaC, InkE, RebC, and AtmC mediate the degree of oxidation of chromopyrrolic acid on route to the natural products staurosporine, K252a, rebeccamycin, and AT2433-A1, respectively. Here, we show that StaC and InkE, which mediate a net 4-electron oxidation, bind FAD with a micromolar K(d), whereas RebC and AtmC, which mediate a net 8-electron oxidation, bind FAD with a nanomolar K(d) while displaying the same FAD redox properties. We further create RebC-10x, a RebC protein with ten StaC-like amino acid substitutions outside of previously characterized FAD-binding motifs and the complementary StaC-10x. We find that these mutations mediate both FAD affinity and product specificity, with RebC-10x displaying higher StaC activity than StaC itself. X-ray structures of this StaC catalyst identify the substrate of StaC as 7-carboxy-K252c and suggest a unique mechanism for this FAD-dependent enzyme. PMID- 22840774 TI - Design and application of in vivo FRET biosensors to identify protein prenylation and nanoclustering inhibitors. AB - Protein prenylation is required for membrane anchorage of small GTPases. Correct membrane targeting is essential for their biological activity. Signal output of the prenylated proto-oncogene Ras in addition critically depends on its organization into nanoscale proteolipid assemblies of the plasma membrane, so called nanoclusters. While protein prenylation is an established drug target, only a handful of nanoclustering inhibitors are known, partially due to the lack of appropriate assays to screen for such compounds. Here, we describe three cell based high-throughput screening amenable Forster resonance energy transfer NANOclustering and Prenylation Sensors (NANOPS) that are specific for Ras, Rho, and Rab proteins. Rab-NANOPS provides the first evidence for nanoclustering of Rab proteins. Using NANOPS in a cell-based chemical screen, we now identify macrotetrolides, known ionophoric antibiotics, as submicromolar disruptors of Ras nanoclustering and MAPK signaling. PMID- 22840775 TI - Identification of exosite-targeting inhibitors of anthrax lethal factor by high throughput screening. AB - Protease inhibitor discovery has focused almost exclusively on compounds that bind to the active site. Inhibitors targeting protease exosites, regions outside of the active site that influence catalysis, offer potential advantages of increased specificity but are difficult to systematically discover. Here, we describe an assay suitable for detecting exosite-targeting inhibitors of the metalloproteinase anthrax lethal factor (LF) based on cleavage of a full-length mitogen-activated protein kinase kinase (MKK) substrate. We used this assay to screen a small-molecule library and then subjected hits to a secondary screen to exclude compounds that efficiently blocked cleavage of a peptide substrate. We identified a compound that preferentially inhibited cleavage of MKKs compared with peptide substrates and could suppress LF-induced macrophage cytolysis. This approach should be generally applicable to the discovery of exosite-targeting inhibitors of many additional proteases. PMID- 22840776 TI - ALDH2 mediates 5-nitrofuran activity in multiple species. AB - Understanding how drugs work in vivo is critical for drug design and for maximizing the potential of currently available drugs. 5-nitrofurans are a class of prodrugs widely used to treat bacterial and trypanosome infections, but despite relative specificity, 5-nitrofurans often cause serious toxic side effects in people. Here, we use yeast and zebrafish, as well as human in vitro systems, to assess the biological activity of 5-nitrofurans, and we identify a conserved interaction between aldehyde dehydrogenase (ALDH) 2 and 5-nitrofurans across these species. In addition, we show that the activity of nifurtimox, a 5 nitrofuran anti-trypanosome prodrug, is dependent on zebrafish Aldh2 and is a substrate for human ALDH2. This study reveals a conserved and biologically relevant ALDH2-5-nitrofuran interaction that may have important implications for managing the toxicity of 5-nitrofuran treatment. PMID- 22840777 TI - Analyzing fission yeast multidrug resistance mechanisms to develop a genetically tractable model system for chemical biology. AB - Chemical inhibitors can help analyze dynamic cellular processes, particularly when probes are active in genetically tractable model systems. Although fission yeast has served as an important model system, which shares more cellular processes (e.g., RNAi) with humans than budding yeast, its use for chemical biology has been limited by its multidrug resistance (MDR) response. Using genomics and genetics approaches, we identified the key transcription factors and drug-efflux transporters responsible for fission yeast MDR and designed strains sensitive to a wide-range of chemical inhibitors, including commonly used probes. We used this strain, along with acute chemical inhibition and high-resolution imaging, to examine metaphase spindle organization in a "closed" mitosis. Together, our findings suggest that our fission yeast strains will allow the use of several inhibitors as probes, discovery of new inhibitors, and analysis of drug action. PMID- 22840778 TI - Fluorescent saxitoxins for live cell imaging of single voltage-gated sodium ion channels beyond the optical diffraction limit. AB - A desire to better understand the role of voltage-gated sodium channels (Na(V)s) in signal conduction and their dysregulation in specific disease states motivates the development of high precision tools for their study. Nature has evolved a collection of small molecule agents, including the shellfish poison (+) saxitoxin, that bind to the extracellular pore of select Na(V) isoforms. As described in this report, de novo chemical synthesis has enabled the preparation of fluorescently labeled derivatives of (+)-saxitoxin, STX-Cy5, and STX-DCDHF, which display reversible binding to Na(V)s in live cells. Electrophysiology and confocal fluorescence microscopy studies confirm that these STX-based dyes function as potent and selective Na(V) labels. The utility of these probes is underscored in single-molecule and super-resolution imaging experiments, which reveal Na(V) distributions well beyond the optical diffraction limit in subcellular features such as neuritic spines and filopodia. PMID- 22840779 TI - Effects of orthopedic maxillary expansion on nasal cavity size in growing subjects: a low dose computer tomography clinical trial. AB - OBJECTIVE: The aim of this retrospective clinical trial was to evaluate the effects of rapid maxillary expansion on skeletal nasal cavity size in growing subjects by use of low dose computer tomography. METHODS: Eight Caucasian children (three male; five female) with a mean age of 9.7 years (SD+/-1.41) were the final sample of this research that underwent palatal expansion as a first phase of orthodontic treatment. The maxillary expander was banded to the upper first molars and was activated according a rapid maxillary expansion protocol. Low-dose computer tomography examinations of maxilla and of the low portion of nasal cavity were performed before inserting the maxillary expander (T0) and at the end of retention (T1), 7 months later. A low-dose computer tomography protocol was applied during the exams. Image processing was achieved in 3 steps: reslicing; dental and skeletal measurements; skeletal nasal volume computing. A set of reproducible skeletal and dental landmarks were located in the coronal passing through the first upper right molar furcation. Using the landmarks, a set of transverse linear measurements were identified to estimate maximum nasal width and nasal floor width. To compute the nasal volume the lower portion of the nasal cavity was set as region of interest. Nasal volume was calculated using a set of coronal slices. In each coronal slice, the cortical bone of the nasal cavity was identified and selected with a segmentation technique. Dependent t-tests were used to evaluate changes due to expansion. For all tests, a significance level of P<0.05 was used. RESULTS: Rapid maxillary expansion produced significant increases of linear transverse skeletal measurements, these increments were bigger in the lower portion of the nasal cavities: nasal floor width (+3.15 mm; SD +/- 0.99), maximum nasal width (+2.47 mm; SD +/- 0.99). Rapid maxillary expansion produced significant increment of the total nasal volume (+1.27 cm(3) +/- SD 0.65). The anterior volume increase was 0.58 cm(3) while the posterior one was 0.69 cm(3). CONCLUSION: In growing subjects RME is able to significantly enlarge the dimension of nasal cavity. The increment is bigger in the lower part of the nose and equally distributed between the anterior e the posterior part of the nasal cavity. PMID- 22840780 TI - Eosinophils and risk stratification of patients treated by coronary stenting. PMID- 22840781 TI - Is there any need for a TAFI(a) inhibitor as thrombolytic drug? PMID- 22840782 TI - Avian influenza and ban on overnight poultry storage in live poultry markets, Hong Kong. AB - We analyzed ~ 12 years of surveillance data on avian influenza in Hong Kong live poultry markets. A ban on keeping live poultry overnight in these markets reduced virus isolation rates by 84% in chickens (p = 0.006) and 100% (p = 0.01) in minor poultry. PMID- 22840784 TI - Honorary note: John Ralston, AO. PMID- 22840783 TI - Genetic variability in glutamic acid decarboxylase genes: associations with post traumatic seizures after severe TBI. AB - Post traumatic seizures (PTS) occur frequently after traumatic brain injury (TBI). Since gamma-amino butyric acid (GABA) neurotransmission is central to excitotoxicity and seizure development across multiple models, we investigated how genetic variability for glutamic acid decarboxylase (GAD) influences risk for PTS. Using both a tagging and functional single nucleotide polymorphism (SNP) approach, we genotyped the GAD1 and GAD2 genes and linked them with PTS data, regarding time to first seizure, obtained for 257 adult subjects with severe TBI. No significant associations were found for GAD2. In the GAD1 gene, the tagging SNP (tSNP) rs3828275 was associated with an increased risk for PTS occurring <1 wk. The tSNP rs769391 and the functional SNP rs3791878 in the GAD1 gene were associated with increased PTS risk occurring 1 wk-6 mo post-injury. Both risk variants conferred an increased susceptibility to PTS compared to subjects with 0 1 risk variant. Also, those with haplotypes having both risk variants had a higher PTS risk 1 wk-6 mo post-injury than those without these haplotypes. Similarly, diplotype analysis showed those with 2 copies of the haplotype containing both risk alleles were at the highest PTS risk. These results implicate genetic variability within the GABA system in modulating the development of PTS. PMID- 22840785 TI - Overcoming resistance to EGFR inhibitor in head and neck cancer: a review of the literature. AB - Head and neck squamous cell carcinoma (HNSCC) affects over half a million people worldwide. Despite advances in therapy, only half of the patients are alive in 5 years. Epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of the tumors, and it is correlated with poor response to treatment and worse outcome. Multiple therapies targeting this pathway have been tested. Cetuximab is the only EGFR inhibitor approved in HNSCC, but response rates are low. More recently, significant interest has focus on identifying mechanisms of acquired and de novo EGFR blockage resistance. Here we review some of these mechanisms and describe strategies to overcome that resistance. PMID- 22840786 TI - Implications of morphologic patterns of intraepithelial microvasculature observed by narrow-band imaging system in cases of oral squamous cell carcinoma. AB - PURPOSE: To investigate the intraepithelial microvascular morphology of oral squamous cell carcinoma (OSCC) by using narrow-band imaging (NBI) and analyze whether the intraepithelial papillary capillary loop (IPCL) patterns correlate with infiltration depth and disease severity in OSCC. METHODS: The clinicopathologic data, morphology of vascular architecture as observed by NBI, and histopathology of patients with OSCC were retrospectively reviewed and analyzed. RESULTS: A total of 80 patients, including 73 males and 7 females with an average age of 54.18+/-12.23 years, were enrolled. Three patterns of intraepithelial microvasculature were revealed by NBI and differences in these three patterns were significant with regard to pathologic T-classification (p<0.0001), N-classification (p=0.00022), TNM stage (p<0.0001), lymphovascular invasion (p<0.0001), perineural invasion (p=0.000299), depth of tumor infiltration (p<0.0001), and tumor differentiation (p<0.0001). A cut-off point of tumor infiltration of 10.012 mm was best predicted for the destructive pattern of IPCL (sensitivity=100%, specificity=90.0%). CONCLUSIONS: Three different patterns of IPCL, showing step-wise increased severity according to pathologic parameters, were observed by NBI in cases of OSCC. The pattern indicating IPCL destruction with angiogenesis was associated with more advanced disease stage. PMID- 22840787 TI - Trends over three decades of the risk of second primary cancer among patients with head and neck cancer. AB - OBJECTIVES: Patients with a head and neck squamous cell carcinoma (HNSCC) carry a high risk of second primary cancer (SPC). In recent years, a rise in incidence of human papillomavirus (HPV)-associated HNSCC has been recorded. Moreover, tobacco and alcohol consumption levels have changed and major advances have been made in radiation treatment approaches. This raises the question of a modification to the risk of SPC, taking into account variations of patient characteristics related to the HPV-cancer epidemic. MATERIALS AND METHODS: All patients with a first HNSCC diagnosed between 1975 and 2006 in the French Bas-Rhin region were followed up for 10 years. Multivariate Poisson regression models were used to model standardized incidence rates and excess absolute risks (EARs) over years of diagnosis, taking into account confounders such as sex, age, subsite of first HNSCC and follow-up. RESULTS: Among these 6258 patients, 1326 presented with a SPC. High EAR values were observed for SPC of lung, head and neck, and esophagus sites (EAR of 172.8, 159.3 and 72.5 excess cancers per 10,000 person-years, respectively). Multivariate analysis showed that the excess risk of SPC of head and neck (P<.001) and esophagus (P=.029) sites decreased, with 53% lower EARs values in 2000-2006 compared to 1975-1979. In contrast, the excess risk of SPC of the lung did not change significantly (P=.174). CONCLUSIONS: Efforts made by public health policy-makers and oncology care providers should be sustained to develop effective smoking cessation interventions, as the excess risk of lung SPC remains high and unchanged. PMID- 22840789 TI - Physiologic adaptations to pregnancy. AB - Pregnancy leads to diverse physiologic changes to accommodate the demands of the developing fetoplacental unit, which affect many major organ systems. Understanding these physiologic adaptations to pregnancy is important for all clinicians because they have important implications for the diagnosis and management of various disorders. This article provides a brief overview of the most notable of these adaptations, including cardiovascular, hematologic, respiratory, renal, immunologic, and gastrointestinal. Clinical correlate of pharmacokinetics and a patient case study are included. PMID- 22840788 TI - Positive and negative regulation of podoplanin expression by TGF-beta and histone deacetylase inhibitors in oral and pharyngeal squamous cell carcinoma cell lines. AB - OBJECTIVES: Podoplanin, a transmembrane sialomucin-like glycoprotein, is known to express at high frequency in oral squamous cell carcinomas (OSCC) and possess metastasis-promoting activity such as increased invasion and platelet-aggregating activity. However, the regulatory mechanism of podoplanin expression in OSCC remains unknown. MATERIALS AND METHODS: In the present study, we investigated the podoplanin expression in both clinical specimens from total 80 patients (50 OSCC and 30 pharyngeal SCC) and in 4 OSCC cell lines in vitro. RESULTS: Immunohistochemical analysis of surgically resected specimens of OSCC revealed podoplanin expression in 70% of OSCC cases with localization primarily in the basal layer of squamous cancer nest and the expression was inversely correlated with squamous cell differentiation. In vitro analysis of OSCC cell lines revealed 36 that podoplanin expression was decreased in response to the squamous cell differentiation (Cytokeratin 10 expression as a marker) induced by treatment with histone deacetylase (HDAC) inhibitors such as sodium butyrate and trichostatin. Furthermore, transforming growth factor-beta (TGF-beta) significantly enhanced podoplanin expression in OSCC cell lines in line with increased phosphorylation of Smad2. A TGF-beta type I receptor inhibitor (SB431542) significantly inhibited such induction of podoplanin expression by TGF-beta at both the protein and mRNA level. However, in a subset of OSCC cell line, its expression was only weakly dependent on TGF-beta and squamous differentiation. CONCLUSION: These results suggest that regulation of podoplanin is not simple, but in the majority of OSCC cell lines, its expression is positively and negatively regulated by TGF-beta receptor/Smad signaling pathway and epigenetic mechanism leading to squamous differentiation, respectively. PMID- 22840790 TI - Imaging of neurologic conditions during pregnancy and the perinatal period. AB - Throughout pregnancy and the puerperium, a variety of hormonal and physiologic changes occur that are associated with pregnancy-specific neurologic conditions, which may also influence known preexisting medical conditions or bring previously unknown neurologic conditions to clinical attention. This article reviews the imaging of a spectrum of neurologic conditions that may be encountered in the pregnant or puerperal patient, the key physiologic changes that are most germane to the imaging of neurologic conditions, and the important safety considerations that are made when choosing and performing a diagnostic imaging test for the pregnant and puerperal patient. PMID- 22840791 TI - Neurologic complications in the patient receiving obstetric anesthesia. AB - Neurologic deficits during or following labor and delivery often occur as a result of obstetric trauma. They can also be caused by neuraxial (epidural or spinal) anesthesia. The incidence of obstetric anesthesia neuropathy is unknown. Anesthesia can cause neurologic injury, although the mechanisms for these injuries are different from those of obstetric injury. Injury can result from direct trauma to the spinal cord, epidural hematoma, as well as other causes that are discussed in this article. These injuries are less common than those of birth trauma. PMID- 22840792 TI - Headache in pregnancy. AB - Primary headaches are most common in women during their reproductive years and are affected by the hormonal fluctuations during pregnancy. Most headaches follow a benign course during pregnancy, although migraine is associated with increased risk of hypertensive disorders of pregnancy and stroke. Management of primary headaches during pregnancy is essentially similar to management in the nonpregnant state, with a few exceptions. This article reviews the epidemiology, prognosis, and management of primary headaches during pregnancy and lactation, and considers secondary headaches that are important to exclude. PMID- 22840793 TI - The postpartum period in women with epilepsy. AB - For women with epilepsy (WWE), the postpartum period is a vulnerable time owing to medication alterations, disrupted sleep, increased stress, and the challenges of breastfeeding. Sleep deprivation and the stress of having a new child can be challenging for WWE. Concerns over antiepileptic drugs (AEDs) in breast milk and sleep disruption associated with breastfeeding leads some WWE to discontinue breastfeeding. Adjustment of AEDs in the postpartum period can lead to difficulties in seizure control. Postpartum depression is increased in WWE, and patient education about newborn safety remains a concern. This article covers these important topics in postpartum WWE. PMID- 22840794 TI - Pregnancy and multiple sclerosis. AB - Pregnancy is a major concern in multiple sclerosis (MS), because the typical patient is a young woman of childbearing age. This article reviews the impact of pregnancy on MS. Disease activity decreases, particularly during the last trimester. There is a temporary rebound of disease activity in the 3 months postpartum. Pregnancy and the postpartum period have many implications for counseling and for therapeutic decision making in MS. PMID- 22840795 TI - Neuromuscular disorders in pregnancy. AB - Preexisting and coincident neuromuscular disorders in pregnancy are challenging for clinicians because of the heterogeneity of disease and the limited data in the literature. Many questions arise regarding the effect of disease on the pregnancy, delivery, and newborn in addition to the effect of pregnancy on the course of disease. Each disorder has particular considerations and possible complications. An interdisciplinary team of physicians is essential. This article discusses the most recent literature on neuromuscular disorders in pregnancy including acquired root, plexus, and peripheral nerve lesions; acquired and inherited neuropathies and myopathies; disorders of the neuromuscular junction; and motor neuron diseases. PMID- 22840796 TI - Stroke and pregnancy. AB - Strategies for stroke prevention should take into account the competing risks to mother and fetus. Treatment of acute stroke in pregnant women is still controversial, but not strictly contraindicated. Several case reports have documented successful reperfusion, in addition to satisfactory maternal and fetal outcomes. Aspirin and warfarin are safe in the second and third trimesters. There are no trials of anticoagulation or antiplatelet therapies of stroke prevention in pregnancy. PMID- 22840797 TI - Sleep disorders in pregnancy: implications, evaluation, and treatment. AB - The dynamic changes across pregnancy affect sleep and wakefulness producing sleep disturbances, which causes sleep disorders in some cases. This review will identify common sleep disorders in pregnancy, related maternal-fetal outcomes, pathophysiologic mechanisms, and potential therapies to guide clinicians in serving this population. PMID- 22840798 TI - Pregnancy and brain tumors. AB - This article discusses the clinical presentation, diagnosis, and treatment of the pregnant patient with an intracranial mass. Common manifestations, pitfalls, and guidelines for management are discussed. PMID- 22840799 TI - Many neurologists have little experience with evaluating, diagnosing, and managing a pregnant woman. Introduction. PMID- 22840800 TI - Society of Interventional Radiology 2012 Presidential Address. PMID- 22840802 TI - In vitro analysis of polymer candidates for the development of absorbable vascular filters. AB - PURPOSE: To test absorbable materials as a prelude to development of an absorbable vena cava filter for the prevention of pulmonary embolism (PE). MATERIALS AND METHODS: Three absorbing polymer candidates, poliglecaprone (Monocryl; sizes 4-0 and 1), polyglactin (Vicryl; sizes 4-0 and 1), and polydioxanone (PDSII; sizes 4-0, 2-0, 0, and 1), were fabricated into vascular filters and evaluated in an engineered closed circulation system that replicated human physiologic characteristics. Material performance was determined over a period of 10 weeks via weekly tensile testing, yielding stress-versus-strain parameters. Control samples of the same absorbable polymers were also tested in a static buffer. RESULTS: PDSII (size 2-0) retained 69% strength in circulation versus 86% in control at 6 weeks (P < .0001) and 11% strength in circulation versus 51% in control at 10 weeks (P < .001). It was fully absorbed in circulation by 22 weeks. In contrast, Monocryl and Vicryl absorbed much faster, with Monocryl possessing 6% strength at 2 weeks in circulation and Vicryl reaching 0% strength at 4 weeks. CONCLUSIONS: Polydioxanone appears to be a strong candidate for novel absorbable vascular filters for PE prevention, with sufficient strength retention to catch emboli for at least 6 weeks and sequentially absorb via hydrolysis into CO(2) and H(2)O within 22 weeks. PMID- 22840803 TI - Computed tomographic appearance of lung tumors treated with percutaneous cryoablation. AB - PURPOSE: To describe the computed tomographic (CT) appearance of lung tumors treated with cryoablation to establish a reliable reference profile. MATERIALS AND METHODS: CT images of 56 patients who underwent follow-up CT for at least 1 year for treatment with cryoablation of 79 tumors from 2003 to 2010 were retrospectively reviewed. Patients had a follow-up CT scan immediately after the procedure; 1 day, 1 week (two-phase dynamic CT), and 1 month later; and then at 3 month intervals. The appearance of ablation zones on CT images was classified into five patterns, and bidimensional diameters and other imaging features were evaluated. RESULTS: Seventy-eight percent of ablation zones (62 of 79) showed transformation similar to the following: a consolidation or nodular pattern was seen within the 1-week follow-up, involution and a "stripe" pattern was shown at 1 month or later, and zones later became indistinct. Eighty percent of cases of local progression (eight of 10) arose from the stripe pattern on follow-up CT 6 months or later, after the ablation zones showed a transformation opposite the aforementioned pattern. Ice balls could not always be visualized exactly because of dense peritumoral hemorrhage. Internal and marginal enhancement of the ablation zone within the 3-month follow-up did not show a direct relationship with local progression. In total, cavitation and peritumoral ground-glass opacity were seen in 35% (n = 28) and 85% (n = 66) of ablation zones, respectively. CONCLUSIONS: The reference profile of CT appearance, which is mandatory for follow-up, has been established. No single indicator of complete ablation was proven throughout this study. Careful long-term follow-up with CT is indispensable. PMID- 22840804 TI - Single-center experience in endovascular treatment for infrainguinal bypass obstructions. AB - PURPOSE: To evaluate patency and clinical efficacy of endovascular therapy for infrainguinal bypass obstructions. MATERIALS AND METHODS: Patients were categorized with regard to symptoms (asymptomatic/intermittent claudication [IC] vs critical limb ischemia [CLI]), bypass graft material used (autologous vs prosthetic graft), and localization of distal anastomoses (femoropopliteal vs femorodistal bypass). Primary patency was defined as absence of sonographically verified stenosis greater than 50%. Assisted primary patency was applied to secondary revisions to prevent impending occlusion. Secondary patency refers to repeat interventions aimed at restoring bypass patency after occlusion. Primary sustained clinical improvement in IC was defined as an upward shift of at least one category per Rutherford classification, accordingly to a level of claudication in patients with CLI. RESULTS: A total of 54 patients (54 limbs, 12 with CLI) were included. At 1 year, primary patency rates were 74% in IC and 27% in CLI (P = .001), primary assisted patency rates were 85% in IC and 68% in CLI (P = .05), and secondary patency rates were 89% in IC and 100% in CLI (P = .32). Accordingly, primary sustained clinical improvement rates were 64% in IC and 25% in CLI (P = .018). After adjustment for confounding factors, CLI (hazard ratio [HR], 7.8; 95% CI, 2.3-26.32; P = .001) and impaired patent runoff (ie, less than three crural runoff vessels; HR, 0.16; 95% CI, 0.03-0.96; P = .045) were independently associated with impaired primary patency. CONCLUSIONS: Endovascular revascularization is a reasonable treatment option to prevent impending bypass occlusion. Presence of CLI and impaired crural runoff are independent risk factors for lower patency rates. PMID- 22840805 TI - Optimal treatment of failing and failed lower-extremity bypass grafts: the jury is still out. PMID- 22840801 TI - Guidelines for the prevention of intravascular catheter-related infections: recommendations relevant to interventional radiology for venous catheter placement and maintenance. PMID- 22840806 TI - Cryoablation of recurrent sacrococcygeal tumors. AB - PURPOSE: To review the safety and efficacy of cryoablation of recurrent sacrococcygeal tumors. MATERIALS AND METHODS: The radiology departmental ablation database was retrospectively searched for cases of cryoablation performed to treat recurrences of sacrococcygeal tumors between January 1, 2010, and August 1, 2011. Patient demographics, procedure technical parameters, and patient outcomes were reviewed. RESULTS: Five cases of recurrent chordoma and one recurrent myxopapillary ependymoma were treated with cryoablation in six patients whose ages ranged from 31 to 80 years. The tumors measured 14-39 mm in maximal dimension. Cryoablation was performed with the use of computed tomography guidance (n = 5) or a combination of ultrasound and magnetic resonance imaging guidance (n = 1). Sterile fluid was instilled to displace adjacent bowel and/or vagina in four cases, and electromyography monitoring was performed in two cases with adjacent nerve roots. Two patients with recurrent chordoma were treated for palliation of pain, with complete pain relief in one patient (pain recurred after 6 wk) and immediate reduction in pain from a score of six to a score of two on a 10-point scale in the other (pain recurred after 7 mo). Four tumors were treated for local control, with no evidence of recurrence on follow-up imaging at 3, 6, 12, and 15 months. No serious complication occurred. CONCLUSIONS: Limited results suggest cryoablation to be a safe and relatively effective means of treating recurrent sacrococcygeal neoplasms for local control or palliation of pain in this small series with short-term follow-up. PMID- 22840807 TI - Endoluminal dilation technique to remove "stuck" tunneled hemodialysis catheters. AB - Most tunneled catheters can be easily removed after the retention cuff is dissected. Occasionally, these catheters can become resistant to removal even after application of potentially hazardous forceful traction. In addition, an infected catheter may cause life-threatening septicemia. Several methods have been described for their extraction, some of which may be available only in tertiary-care facilities. The present report describes the successful extraction of five such "stuck" catheters by using a recently described technique of endoluminal dilation. The technique appears safe and straightforward and can be performed in any interventional suite while allowing preservation of venous access. PMID- 22840808 TI - Image-guided cryoablation for metastatic diaphragmatic thymoma. PMID- 22840809 TI - Neurologic complication after use of a percutaneous vascular closure device. PMID- 22840810 TI - Successful iterative percutaneous cryoablation of multiple extraabdominal desmoid tumors in a patient with Gardner syndrome. PMID- 22840811 TI - Necrotizing fasciitis following endovenous laser treatment and stab avulsions of lower-limb varicose veins. PMID- 22840812 TI - Is it time to include radiation risks in the consent discussion for interventional radiology procedures? PMID- 22840813 TI - Effective treatment of a 13-year-old boy with steroid-dependent ocular myasthenia gravis using tacrolimus. AB - Over the past several years, tacrolimus has attracted attention as a new therapeutic drug for myasthenia gravis (MG), but few reports have considered its use for MG in pediatric patients, and most of these have focused on severe systemic MG. In this case report, we used tacrolimus to successfully treat a 13 year-old boy with ocular MG who had suffered from severe steroid complications, including a failure of thrive and osteoporosis. He first showed symptoms of ocular MG at age 2 years 3 months. At age 13 years, he was receiving PSL (3.75 mg/day), but the symptoms of ocular MG recurred. We increased the dosage of oral PSL up to 30 mg/day, and three courses of mPSL pulse therapy were applied, but these therapies had only limited effect, and his symptoms worsened. Tacrolimus was started at 0.4 mg/day (0.011 mg/kg/day), and every 2 weeks the dose was gradually increased by 0.2 mg/day. His symptoms of MG began to improve 3 weeks after the initial administration of tacrolimus. Approximately 3 months after the start of tacrolimus administration, PSL was discontinued. Currently, at 1 year and 4 months after the start of tacrolimus administration, while slight ptosis is observed in the evening, it does not influence his daily life, and his condition remains comparable to that when he stopped taking PSL. No adverse effects of tacrolimus have been recognized. In pediatric patients with steroid-dependent ocular MG without thymectomy, tacrolimus may be a safe and effective alternative to steroid and thymectomy. PMID- 22840814 TI - Alcohol use, alcohol problems, and problem behavior engagement among students at two schools in northern Mexico. AB - This study examined the association between alcohol-use problem severity, defined by number of DSM-IV alcohol Abuse and Dependence symptoms and frequency of alcohol use, and problem behavior engagement among Mexican students. A confidential survey was administered to 1229 students in grades 7-12 at two schools in a northern border city in Mexico. Youths were categorized into five groups based on their alcohol use frequency and symptoms of DSM-IV alcohol Abuse and Dependence, specifically: no lifetime alcohol use, lifetime alcohol use but none in the past year, past year alcohol use, one or two alcohol Abuse or Dependence symptoms, and three or more alcohol Abuse or Dependence symptoms. The association between five levels of alcohol-use problem severity and three problem behaviors, lifetime marijuana use, lifetime sexual intercourse, and past year arrest/law trouble, was examined using chi-square or Fisher's exact tests. Several alcohol-use problem severity categories were significantly different with respect to rates of lifetime marijuana use, lifetime sexual intercourse, and past year arrest/law trouble. Higher alcohol-use problem severity was associated with greater endorsement of problem behaviors. Knowing about variations in adolescent alcohol use and alcohol problems may be instrumental in determining if youths are also engaging in a range of other risk behaviors. Considering varying levels of alcohol use and alcohol problems is important for effective targeted prevention and treatment interventions. PMID- 22840815 TI - Opportunities for prevention of alcohol-related death in primary care: results from a population-based cross-sectional study. AB - The mortality rate from alcohol-related conditions has risen sharply in the United Kingdom and it is not known whether opportunities for preventive interventions could be improved. The purpose of our study was to identify opportunities to detect, assess, and manage alcohol problems in primary care according to evidence-based guidelines. We carried out a cross-sectional study on patients who died from alcohol-related conditions in the calendar year 2003 within National Health Service Greater Glasgow Health Board area, Scotland (population 920,000). We described patient characteristics and care recorded in health service records, comparing it with best evidence-based practice in Scottish Intercollegiate Guidelines Network and Health Technology Board for Scotland recommendations on the management of harmful drinking and alcohol dependence. 501 deaths occurred from an alcohol-related cause. The mean age at death was 57.5 years and 72% were male. The most common causes of death, recorded by the International Classification of Diseases, revision 10, excluding accidents, were alcoholic liver disease (290, 57.9%) and mental and behavioural disorders due to alcohol (70, 14.0%). Lifetime mean consultations at primary care general practitioner and hospital outpatient departments were 24 in males and 5 in females. All individuals who died from an alcohol-related cause had at least one biochemical or physical indicator suggestive of alcohol misuse. 21% (95% CI 13-33%) had no record of having been advised to abstain from alcohol and 23% (95% CI 15-35%) had received brief interventions. 58% (95% CI 46-70%) had been referred to specialist alcohol services but a third of them did not attend. The majority of patients (83%, 95% CI 72-90%) had no evidence of shared health service and social work care. We concluded that individuals who died from alcohol related conditions were usually in contact with statutory and voluntary services but further efforts were required to use these opportunities to detect, assess, and manage serious alcohol problems according to evidence-based guidelines. PMID- 22840817 TI - Theoretical study of using simulated moving bed chromatography to separate intermediately eluting target compounds. AB - This study deals with the separation of ternary mixtures based on Simulated Moving Bed chromatography to isolate target components with intermediate adsorption strength. To overcome the limitations of conventional SMB systems, which are designed for binary separations and unable to perform center-cut separations, several modifications have been proposed. The purpose of this study was to provide a theoretical comparison of several of advanced SMB configurations capable to separate ternary mixtures. Emphasis is given to those techniques, which have already been used in practice, and to those having potential for future industrial application. SMB cascades connected in series via the extract or raffinate ports of the first unit are analyzed and compared are as well as an integrated 8-zone SMB unit with internal recycle. Additionally, the commercialized pseudo SMB process (JO process) was evaluated. The performance of these modified SMB systems was investigated based on the assumption of linear adsorption isotherms for all three components considering three separation problems characterized by different separation difficulty. Besides the influence of separation factors, the concentrations of the impurities in the feed mixture and the purity requirements for the target product were studied systematically. PMID- 22840816 TI - Ethanol-induced disruption of Golgi apparatus morphology, primary neurite number and cellular orientation in developing cortical neurons. AB - Prenatal ethanol exposure disrupts cortical neurite initiation and outgrowth, but prior studies have reported both ethanol-dependent growth promotion and inhibition. To resolve this ambiguity and better approximate in vivo conditions, we quantitatively analyzed neuronal morphology using a new, whole hemisphere explant model. In this model, Layer 6 (L6) cortical neurons migrate, laminate and extend neurites in an organotypic fashion. To selectively label L6 neurons, we performed ex utero electroporation of a GFP expression construct at embryonic day 13 and allowed the explants to develop for 2 days in vitro. Explants were exposed to (400 mg/dL) ethanol for either 4 or 24 h prior to fixation. Complete 3-D reconstructions were made of >80 GFP-positive neurons in each experimental condition. Acute responses to ethanol exposure included compaction of the Golgi apparatus accompanied by elaboration of supernumerary primary apical neurites, as well as a modest (~15%) increase in higher order apical neurite length. With longer exposure time, ethanol exposure leads to a consistent, significant disorientation of the cell (cell body, primary apical neurite, and Golgi) with respect to the pial surface. The effects on cellular orientation were accompanied by decreased expression of cytoskeletal elements, microtubule-associated protein 2 and F-actin. These findings indicate that upon exposure to ethanol, developing L6 neurons manifest disruptions in Golgi apparatus and cytoskeletal elements which may in turn trigger selective and significant perturbations to primary neurite formation and neuronal polarity. PMID- 22840818 TI - Development of a two-dimensional high-performance liquid chromatography system coupled with on-line reduction as a new efficient analytical method of 3 nitrobenzanthrone, a potential human carcinogen. AB - 3-Nitrobenzanthrone (3-NBA) is an extremely strong mutagen and carcinogen in rats inducing squamous cell carcinoma and adenocarcinoma. We developed a new sensitive analytical method, a two-dimensional HPLC system coupled with on-line reduction, to quantify non-fluorescent 3-NBA as fluorescent 3-aminobenzanthrone (3-ABA). The two-dimensional HPLC system consisted of reversed-phase HPLC and normal-phase HPLC, which were connected with a switch valve. 3-NBA was purified by reversed phase HPLC and reduced to 3-ABA with a catalyst column, packed with alumina coated with platinum, in ethanol. An alcoholic solvent is necessary for reduction of 3-NBA, but 3-ABA is not fluorescent in the alcoholic solvent. Therefore, 3-ABA was separated from alcohol and impurities by normal-phase HPLC and detected with a fluorescence detector. Extracts from surface soil, airborne particles, classified airborne particles, and incinerator dust were applied to the two dimensional HPLC system after clean-up with a silica gel column. 3-NBA, detected as 3-ABA, in the extracts was found as a single peak on the chromatograms without any interfering peaks. 3-NBA was detected in 4 incinerator dust samples (n=5). When classified airborne particles, that is, those <1.1, 1.1-2.0, 2.0-3.3, 3.3 7.0, and >7.0 MUm in size, were applied to the two-dimensional HPLC system after purified using a silica gel column, 3-NBA was detected in those particles with particle sizes <1.1 and 1.1-2.0 MUm and the particle-size distribution ratios were 84% and 16%, respectively. This is the first report on the particle-size distribution of 3-NBA in airborne particles and the detection of 3-NBA in incinerator dust. PMID- 22840819 TI - Determination of pharmaceutically related compounds by suppressed ion chromatography: IV. Interfacing ion chromatography with universal detectors. AB - This work forms the final part of a study investigating gradient elution ion exchange chromatography of pharmaceutically relevant compounds, aiming at achieving complementary selectivity to reversed-phase HPLC. In this study the coupling of three universal detectors (electro-spray ionisation mass spectrometer (ESI-MS); corona charged aerosol detector (CAD); and evaporative light scattering detector (ELSD)) to suppressed IC using complex elution profiles with potassium hydroxide eluents is demonstrated. The non-volatile ions were removed from the eluent by the suppressor prior to detection, thus allowing a stable detector response, especially with the prototype electrolytic suppressor. The detector response for ten weakly anionic pharmaceuticals followed the expected models and the limits of detection obtained were not compromised by the use of a suppressor, yielding values below 50 ng/mL with MS, low to sub MUg/mL levels with CAD and 2 20 MUg/mL with ELSD (25 MUL injections). When coupled to MS and CAD, the prototype electrolytic suppressor showed percentage relative standard deviations (%RSDs) in peak areas of 0.4-2.5% on average, compared to the chemical suppressor which yielded 1.5-3 fold higher %RSD values for the test analytes. The prototype electrolytic suppressor also generally exhibited wider linear response ranges than the chemical suppressor. PMID- 22840820 TI - Evaporative light scattering detector in normal-phase high-performance liquid chromatography determination of FAME oxidation products. AB - The use of an ELS detector in NP-HPLC for quantitative analysis of oxidation products in FAME obtained from oils is evaluated in this study. The results obtained have shown that the ELS detector enables the quantitative determination of the hydroperoxides of oleic and linoleic acid methyl esters as a whole, and connected in series with a UV detector makes it possible to determine both groups of compounds by difference, providing useful complementary information. The limits of detection (LOD) and quantification (LOQ) found for hydroperoxides were respectively 2.5 and 5.7 MUg mL-1 and precision of quantitation expressed as coefficient of variation was lower than 10%. Due to a low sensitivity the ELS detector shows limitations to determine the low contents of secondary oxidation products in the direct analysis of FAME oxidized at low or moderate temperature. Analysis of FAME samples obtained either from high linoleic sunflower oil (HLSO) or high oleic sunflower oil (HOSO) and oxidized at 80 degrees C showed that only ketodienes formed from methyl linoleate can be determined in samples with relatively high oxidation, being the LOD and LOQ 0.2 and 0.4 mg/g FAME, respectively, at the analytical conditions applied. The ELS detector also enabled the determination of methyl cis-9,10-epoxystearate and methyl trans-9,10 epoxystearate, which were resolved at the chromatographic conditions applied. Results showed that these compounds, which are formed from methyl oleate, were not detected in the high-linoleic sample, but occurred at non-negligible levels in the oxidized FAME obtained from HOSO. PMID- 22840821 TI - Evaluation of an isotope dilution liquid chromatography tandem mass spectrometry method for pharmaceuticals in fish. AB - An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was successfully developed and applied for analysis of 15 pharmaceuticals and 2 pharmaceutically active metabolites in fish tissues. This method relied on electrospray ionization (ESI), for which the influence of sample matrix on analyte ionization efficiencies remains a persistent challenge to environmental analysis. Statistically derived method detection limits (MDLs) for most analytes ranged from 1 to 10 ng/g, independent of sample matrix, and were as low as 0.04 ng/g for the most sensitive compounds in fillet tissue. MDLs for fish fillets were determined for both 10 MUL and 100 MUL injection volumes; however, results showed that detection limits did not scale linearly with injection volume. Direct comparison of spike recoveries from fish liver demonstrated that isotope dilution was superior to matrix-matched calibration in compensating for matrix interference. Spike recoveries for the isotope dilution approach generally ranged from 91 to 112%, independent of tissue (i.e., fillet or liver). The developed method was applied to examine target analytes in brown trout (Salmo trutta), collected upstream and downstream from a municipal effluent discharge to East Canyon Creek, Park City, UT, USA. Though no pharmaceuticals were detected in fish samples from the upstream location, 3 and 10 compounds (out of 17 target analytes) were detected in fish fillet and liver samples, respectively, from the downstream sampling site. Pharmaceuticals in fish fillets were observed at concentrations ranging from 0.14 to 12 ng/g, while levels were markedly higher in liver tissues (range: 0.27-600 ng/g). PMID- 22840823 TI - Infectious disease transmission during organ and tissue transplantation. AB - Infectious disease transmission through organ and tissue transplantation has been associated with severe complications in recipients. Determination of donor derived infectious risk associated with organ and tissue transplantation is challenging and limited by availability and performance characteristics of current donor epidemiologic screening (e.g., questionnaire) and laboratory testing tools. Common methods and standards for evaluating potential donors of organs and tissues are needed to facilitate effective data collection for assessing the risk for infectious disease transmission. Research programs can use advanced microbiological technologies to define infectious risks posed by pathogens that are known to be transplant transmissible and provide insights into transmission potential of emerging infectious diseases for which transmission characteristics are unknown. Key research needs are explored. Stakeholder collaboration for surveillance and research infrastructure is required to enhance transplant safety. PMID- 22840824 TI - Analysis of semi-volatile organic compounds in indoor suspended particulate matter by thermal desorption coupled with gas chromatography/mass spectrometry. AB - People are exposed to multiple pollutants, especially indoors. In the perspective of a cumulative risk assessment, a multi-residue analytical method was developed to assess the contamination of indoor suspended particulate matter by 55 semi volatile organic compounds (SVOCs) including musk fragrances, organochlorines (OCs), organophosphates (OPs), polycyclic aromatic hydrocarbons (PAHs), polybromodiphenylethers (PBDEs), polychlorobiphenyls (PCBs), phthalates and pyrethroids. It is based on thermal desorption (TD) coupled with gas chromatography/mass spectrometry (GC/MS). Once the thermal desorption conditions were optimized, the method was validated in terms of quantification limits and accuracy using a standard reference material (SRM 2585). Instrumental quantification limits were 10 pg (some OCs, some pyrethroids, musk fragrances, OPs, PAHs, PBDEs and PCBs), 100 pg (phthalates and other OCs) and 1000 pg (other pyrethroids) corresponding respectively to method quantification limits of 1, 10, and 100 pg/m3 for a sampled air volume of 20 m3. Calibration quadratic curves for ranges of 10-1000, 100-10,000, and 1000-100,000 pg, depending on the substance, exhibit determination coefficients above 0.999. Recoveries were between 61 and 96% for chlorinated pesticides, PAHs, PBDEs and PCBs present in the SRM 2585. A test of the method on indoor particulate matter samples (PM10) collected on quartz fiber filters in French dwellings demonstrated its ability to quantify SVOCs from a small amount of PM. PMID- 22840822 TI - Advanced proteomic liquid chromatography. AB - Liquid chromatography coupled with mass spectrometry is the predominant platform used to analyze proteomics samples consisting of large numbers of proteins and their proteolytic products (e.g., truncated polypeptides) and spanning a wide range of relative concentrations. This review provides an overview of advanced capillary liquid chromatography techniques and methodologies that greatly improve separation resolving power and proteomics analysis coverage, sensitivity, and throughput. PMID- 22840825 TI - Analysis of phenolic pollutants in human samples by high performance capillary electrophoresis based on pretreatment of ultrasound-assisted emulsification microextraction and solidification of floating organic droplet. AB - A novel, simple and rapid method, termed ultrasound-assisted emulsification microextraction and solidification of floating organic droplet (UAEM-SFO) coupled to high performance capillary electrophoresis (HPCE), was developed for preconcentration and analysis of five phenolic compounds (PCs) in human urine and blood samples. The proposed method is based on microextraction of target analytes in less-toxic organic solvent under assistance of ultrasound. A micro-droplet of less-toxic organic solvent floating on the surface of liquid samples in a sealed vial can be dispersed into sample solutions under the ultrasound frequency, solidified under ice bath, collected with a medicine spatula, molten at ambient temperature, and finally subjected to HPCE analysis. The parameters of UAEM-SFO procedure including type and volume of extraction solvent, extraction temperature, time of ultrasound-assisted extraction and centrifugation, sample pH, and ionic strength were optimized. The influence parameters on HPCE resolution such as pH, concentration of running buffer, applied voltage and injection time were also investigated. This method requires only 40 MUL of 2 dodecanol extraction solvent and 8 min of pretreatment time. The enrichment factors of analytes were in the range of 114-172 and extraction recoveries (69 86%) were obtained. Good linearity was achieved for five analytes in the range of 0.05-100 MUg L-1 and the correlation coefficients ranged from 0.9934 to 0.9999. The limits of detection were 0.01 MUg L-1 for triclosan (TCS) and biophenol A (BPA), and 0.02 MUg L-1 for pentachlorophenol (PCP), 2,4-dichlorophenol (2,4-DCP) and 4-nonylphenol (4-NP) in urine samples, and 0.02 MUg L-1 for TCS and BPA, 0.04 MUg L-1 for PCP, 2,4-DCP and 4-NP in blood samples. The developed UAEM-SFO-HPCE method has a great potential in routine residual analysis of trace PCs in biological samples. PMID- 22840826 TI - Randomized controlled trial of peer mentoring for individuals with traumatic brain injury and their significant others. AB - OBJECTIVES: To examine the efficacy of a peer-mentoring program for persons with traumatic brain injury (TBI) and their significant others, and to determine the relationship of this mentoring program to 3 main outcomes: (1) emotional well being; (2) post-TBI quality of life; and (3) community integration. DESIGN: Randomized controlled trial. SETTING: Midwestern rehabilitation hospital. PARTICIPANTS: Persons with TBI (n=96) and significant others/caregivers (n=62). INTERVENTIONS: Persons with TBI and friends/caregivers who knew the person prior to their injury were randomly assigned to a treatment (mentored) or no-treatment (no mentoring) control group immediately prior to discharge from the rehabilitation unit and were mentored for up to 2 years. MAIN OUTCOME MEASURES: Peer Mentoring Questionnaire; Brief Symptom Inventory-18; Family Assessment Device; Coping Inventory for Stressful Situations; Short Michigan Alcohol Screening Test; Medical Outcomes Study 12-Item Short-Form Health Survey; and Community Integration Measure. RESULTS: Eighty-eight percent of individuals who were involved in the mentoring program reported positive experiences. t tests revealed that among persons with TBI, individuals who received mentoring had significantly better behavioral control and less chaos in the living environment (P=.04), lower alcohol use (P=.01), less emotion-focused (P=.04) and avoidance coping (P=.03), and good physical quality of life (P=.04) compared with those who did not receive mentoring. Among significant others, mentored individuals demonstrated greater community integration (P=.03) than the nonmentored control group. CONCLUSIONS: Mentoring can be an effective way to benefit mood and healthy coping after TBI, and it can help to prevent maladaptive behaviors, such as substance abuse and behavioral dyscontrol, in the living situation. PMID- 22840827 TI - Change in inpatient rehabilitation admissions for individuals with traumatic brain injury after implementation of the Medicare inpatient rehabilitation facility prospective payment system. AB - OBJECTIVE: To evaluate the impact of Medicare's inpatient rehabilitation facility (IRF) prospective payment system (PPS) on use of inpatient rehabilitation for individuals with traumatic brain injury (TBI). DESIGN: Retrospective cohort study of patients with TBI. SETTING: One hundred twenty-three level I and II trauma centers across the U.S. who contributed data to the National Trauma Data Bank. PARTICIPANTS: Patients (N=135,842) with TBI and an Abbreviated Injury Score of the head of 2 or greater admitted to trauma centers between 1995 and 2004. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Discharge location: IRF, skilled nursing facility, home, and other hospitals. RESULTS: Compared with inpatient rehabilitation admissions before IRF PPS came into effect, demographic characteristics of admitted patients changed. Those admitted to acute care trauma centers after PPS was enacted (January 2002) were older and nonwhite. No differences were found in rates of injury between men and women. Over time, there was a significant drop in the percent of patients being discharged to inpatient rehabilitation, which varied by region, but was found across all insurance types. In a logistic regression, after controlling for patient characteristics (age, sex, race), injury characteristics (cause, severity), insurance type, and facility, the odds of being discharged to an IRF after a TBI decreased 16% after Medicare's IRF PPS system was enacted. CONCLUSIONS: The enactment of the Medicare PPS appears to be associated with a reduction in the chance that patients receive inpatient rehabilitation treatment after a TBI. The impact of these changes on the cost, quality of care, and patient outcome is unknown and should be addressed in future studies. PMID- 22840828 TI - Association of sleep and co-occurring psychological conditions at 1 year after traumatic brain injury. AB - OBJECTIVES: To compare individuals' sleep 1 year after traumatic brain injury (TBI) with that of a healthy comparison group, and examine the relationship between sleep, co-occurring conditions, and functional status in those with TBI. DESIGN: Longitudinal assessment of a prospectively studied sample of individuals with moderate to severe TBI. Assessment of sleep occurred at 1 year after TBI. SETTING: Inpatient acute rehabilitation for TBI and community follow-up at 1 year postinjury. PARTICIPANTS: Individuals with TBI (N=174) were recruited from consecutive admissions to an inpatient rehabilitation unit and enrolled into the TBI Model Systems study. Participant mean age was 38, and mean Glasgow Coma Scale score on admission was 9.3. Seventy-eight percent of the sample were men. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI). Depression, anxiety, and pain were measured with the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 Scale, and an analog pain rating scale, respectively. RESULTS: Participants with TBI reported significantly greater sleep difficulties than the healthy comparison group. Forty-four percent of participants with TBI reported significant sleep problems (PSQI>5). Participants with 1 or more co-occurring conditions (depression, pain, or anxiety) had significantly worse sleep than those without such a condition. The highest level of sleep problems was reported by participants with multiple co-occurring conditions. Sleep problems were also associated with poor functional status. CONCLUSIONS: Sleep difficulties are a frequent problem at 1 year after TBI, and often co-occur with depression, anxiety, and pain. Assessment and treatment of sleep difficulties should be included in clinical practice. Future research on the potential causal relationship among co-occurring conditions may assist in additional intervention planning. PMID- 22840829 TI - Benefits of exercise maintenance after traumatic brain injury. AB - OBJECTIVE: To examine the effect of exercise intervention on exercise maintenance, depression, quality of life, and mental health at 6 months for people with traumatic brain injury (TBI) with at least mild depression. DESIGN: Treatment group participants were assessed at baseline, after a 10-week exercise intervention, and 6 months after completion of the intervention. SETTING: Community. PARTICIPANTS: Participants (N=40) with self-reported TBI from 6 months to 5 years prior to study enrollment and a score of 5 or greater on the Patient Health Questionnaire-9. INTERVENTIONS: Ten-week exercise intervention program consisting of supervised weekly 60-minute sessions and unsupervised 30 minutes of aerobic exercises 4 times each week. Telephone follow-up was conducted every 2 weeks for an additional 6 months to promote exercise maintenance for individuals randomized to the intervention group. MAIN OUTCOME MEASURE: Beck Depression Inventory (BDI) comparing participant outcomes over time. Post hoc analyses included comparison among those who exercised more or less than 90 minutes per week. RESULTS: Participants reduced their scores on the BDI from baseline to 10 weeks and maintained improvement over time. Many participants (48%) demonstrated increased physical activity at 6 months compared with baseline. Those who exercised more than 90 minutes had lower scores on the BDI at the 10-week and 6 month assessments and reported higher perceived quality of life and mental health. CONCLUSIONS: Exercise may contribute to improvement in mood and quality of life for people with TBI and should be considered as part of the approach to depression treatment. PMID- 22840830 TI - Preinjury predictors of life satisfaction at 1 year after traumatic brain injury. AB - OBJECTIVE: To investigate the predictive value of preinjury factors for satisfaction with life (SWL) at 1-year posttraumatic brain injury (TBI). DESIGN: Secondary analysis of prospective, longitudinal registry using data collected during inpatient rehabilitation and at 1-year post-TBI. SETTING: Fifteen specialized brain injury units providing acute rehabilitation care as part of the Traumatic Brain Injury Model Systems (TBIMS) program. PARTICIPANTS: Community dwelling persons (N=444) with moderate to severe TBI aged 16 to 64 years enrolled in the TBIMS program between October 2007 and October 2008 with 1-year follow-up data. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Satisfaction With Life Scale (SWLS). RESULTS: Hierarchical stepwise linear regression revealed that injury-related and demographic variables did not contribute significantly to the explained variance in SWLS scores. In contrast, the preinjury functioning (education, productivity/employment) and preinjury condition (psychiatric and substance use problems, severe sensory dysfunction, learning problems, prior TBI) blocks each contributed significantly to the explained variance in SWLS scores. Preinjury functioning accounted for 2.9% of the variance and preinjury conditions for 3.8%. CONCLUSIONS: Although their contributions are small, preinjury functioning and preinjury conditions are important to consider in the prediction of SWL post-TBI. Educational level and history of psychiatric and other premorbid difficulties are particularly important for clinicians to consider when implementing or developing interventions for persons with moderate to severe TBI. PMID- 22840831 TI - Sexual functioning 1 year after traumatic brain injury: findings from a prospective traumatic brain injury model systems collaborative study. AB - OBJECTIVE: To investigate the incidence and types of sexual difficulties in men and women with traumatic brain injury (TBI) 1 year after injury, as well as their comfort level in discussing problems with health care professionals. DESIGN: Prospective cohort study. SETTING: Community. PARTICIPANTS: Persons with TBI (N=223; 165 men and 58 women) who had been treated at 1 of 6 participating TBI Model Systems inpatient rehabilitation units and were living in the community. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Derogatis Interview for Sexual Functioning-self-report (DISF-SR); Global Sexual Satisfaction Index (GSSI); structured interview regarding changes in sexual functioning; and comfort level discussing sexuality with health care professionals. RESULTS: Women with TBI scored significantly below the normative sample for all subscales of the DISF-SR, including sexual cognition/fantasy, arousal, sexual behavior/experience, and orgasm. Men scored significantly below the normative sample on all scales except arousal. Women reported greater dysfunction than men for sexual cognition/fantasy and arousal. Twenty-nine percent of participants reported dissatisfaction with sexual functioning on the GSSI, with a greater percentage of men reporting dissatisfaction. Sixty-eight percent of participants indicated that they would spontaneously raise issues of sexual difficulties with health care professionals, while the remainder would either bring it up only if directly asked or would not discuss it at all. CONCLUSIONS: Sexual difficulties were present in a substantial portion of community-dwelling people with TBI at 1 year after injury. Educational interventions to increase awareness among people with TBI and rehabilitation professionals are warranted, as well as interventions to improve sexual functioning. PMID- 22840832 TI - Comorbid disease in persons with traumatic brain injury: descriptive findings using the modified cumulative illness rating scale. AB - OBJECTIVE: To provide descriptive findings regarding the overall health status and prevalence of medical comorbidities experienced by traumatic brain injury (TBI) patients. DESIGN: Inception cohort design with cross-sectional follow-up at 1 to 15 years. SETTING: Rehabilitation hospital. PARTICIPANTS: Adults (N=258) with moderate to severe TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Modified Cumulative Illness Rating Scale is a 14-item rating scale used to indicate health status by rating impairment across 14 different domains. RESULTS: The TBI sample had lower rates of comorbidities compared with other rehabilitation populations, including stroke and orthopedic samples. The most commonly encountered medical conditions within our sample were eyes, ears, nose, and throat problems, psychiatric or behavioral disturbances, hypertension, and musculoskeletal injury at mild to moderate severity. Prevalence of conditions did not differ by sex, race, or cause of TBI. CONCLUSIONS: The current TBI sample was relatively healthy with few medical comorbidities. Further, the Modified Cumulative Illness Rating Scale may better be used as a standardized checklist to assess for the presence of co-occurring conditions, given the near absence of conditions in the higher range of severity. PMID- 22840833 TI - A longitudinal study of major and minor depression following traumatic brain injury. AB - OBJECTIVE: To examine patterns of change and factors associated with change in depression, both major (major depressive disorder [MDD]) and minor, between 1 and 2 years after traumatic brain injury (TBI). DESIGN: Observational prospective longitudinal study. SETTING: Inpatient rehabilitation centers, with 1- and 2-year follow-up conducted primarily by telephone. PARTICIPANTS: Persons with TBI (N=1089) enrolled in the Traumatic Brain Injury Model Systems database, followed at 1 and 2 years postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Patient Health Questionnaire-9. RESULTS: Among participants not depressed at 1 year, close to three fourths remained so at 2-year follow-up. However, 26% developed MDD or minor depression between the first and second years postinjury. Over half of participants with MDD at year 1 also reported MDD the following year, with another 22% reporting minor depression; thus three fourths of those with MDD at year 1 experienced clinically significant symptoms at year 2. Almost one third of those with minor depression at year 1 traversed to MDD at year 2. Polytomous logistic regression confirmed that worse depression at year 1 was associated with higher odds of depression a year later. For those without depression at year 1, symptom worsening over time was related to year 2 problematic substance use and lower FIM motor and cognitive scores. For those with depression at year 1, worsening was associated with lower cognitive FIM, poor social support, and preinjury mental health issues including substance abuse. CONCLUSIONS: Major and minor depression exist on a continuum along which individuals with TBI may traverse over time. Predictors of change differ according to symptom onset. Results highlight importance of long-term monitoring for depression, treating minor as well as major depression, and developing interventions for comorbid depression and substance abuse. PMID- 22840834 TI - Use of neighborhood characteristics to improve prediction of psychosocial outcomes: a traumatic brain injury model systems investigation. AB - OBJECTIVE: To determine whether use of neighborhood characteristics derived from U.S. Census Bureau information contributes to the prediction of outcomes after traumatic brain injury (TBI) beyond the variance accounted for by individual characteristics. DESIGN: Cross-sectional analysis of follow-up interviews conducted 1, 2, and 5 years postinjury. SETTING: Twelve Traumatic Brain Injury Model Systems (TBIMS) centers. PARTICIPANTS: Patients 16 years of age and older with moderate or severe TBI enrolled in the TBIMS National Database (N=472). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Satisfaction With Life Scale and Participation Assessment with Recombined Tools-Objective. RESULTS: Individual characteristics alone accounted for 26% and 48% of variance in life satisfaction and participation, respectively; neighborhood characteristics alone accounted for 6% and 9% of variance, respectively. Models combining both types of characteristics included significant neighborhood and individual predictors for participation but not life satisfaction; however, for participation, prediction only improved beyond that found for individual characteristics alone by 1.2%. CONCLUSIONS: The results did not support the hypotheses that characteristics of a person's neighborhood would increase outcome prediction beyond that which can be accomplished based on characteristics of the individual alone. Though neighborhood characteristics were statistically significant in prediction models, the improvement in percent of variance accounted for was negligible. Refinements in conceptualization and methodology are suggested for continued exploration of the contribution of neighborhood characteristics to TBI outcomes. PMID- 22840835 TI - T cell assays and MIATA: the essential minimum for maximum impact. PMID- 22840836 TI - Professional cross-presenting CD8alpha-type CD141(hi) dendritic cells: we have got you in our skin! AB - In this issue of Immunity, Haniffa et al. (2012) identify the presence of professional cross-presenting human dendritic cells in the skin, the liver, and the lung and also presented comparative genomics to align human and mouse dendritic cell types across tissues. PMID- 22840837 TI - Regulating with Reg proteins: a new role in Th17 cell-mediated skin inflammation. AB - The mechanisms linking skin inflammation and observed defects in skin barrier function and integrity need further elucidation. In this issue of Immunity, Lai et al. (2012) identify REG3A as a downstream mediator of interleukin 17A that enhances keratinocyte proliferation and downmodulates keratinocyte differentiation. PMID- 22840838 TI - Brain autoimmunity: the CD8 question(s). AB - In this issue of Immunity, Na et al. (2012) show that the purging of central nervous system (CNS)-specific CD8(+) T cell repertoire requires direct contact with antigen expressing oligodendrocytes and inflammation tips the balance toward autoimmunity. PMID- 22840839 TI - Maintaining poise: commensal microbiota calibrate interferon responses. AB - The mechanisms of how commensal bacteria impact systemic immunity are unclear. In this issue of Immunity, Abt et al. (2012) and Ganal et al. (2012) demonstrate that microbiota poise macrophages for induction of the type I interferon pathway after virus infection. PMID- 22840840 TI - Widespread immunological functions of mast cells: fact or fiction? AB - Immunological functions of mast cells are currently considered to be much broader than the original role of mast cells in IgE-driven allergic disease. The spectrum of proposed mast cell functions includes areas as diverse as the regulation of innate and adaptive immune responses, protective immunity against viral, microbial, and parasitic pathogens, autoimmunity, tolerance to graft rejection, promotion of or protection from cancer, wound healing, angiogenesis, cardiovascular diseases, diabetes, obesity, and others. The vast majority of in vivo mast cell data have been based on mast cell-deficient Kit mutant mice. However, work in new mouse mutants with unperturbed Kit function, which have a surprisingly normal immune system, has failed to corroborate some key immunological aspects, formerly attributed to mast cells. Here, we consider the implications of these recent developments for the state of the field as well as for future work, aiming at deciphering the physiological functions of mast cells. PMID- 22840841 TI - Developmental origin and functional specialization of mast cell subsets. AB - Mast cells (MCs) are constitutively present in most tissues and a distinct subset of MCs can also be induced upon host responses to inflammation. The hematopoietic lineage development of tissue MCs is unique compared to other myeloid-derived cells because it is early lineage progenitors, undetectable by histochemistry, that leave the bone marrow to enter the circulation. These immature lineage MCs immediately undergo transendothelial recruitment into peripheral tissues wherein the appearance of secretory granules with a particular protease phenotype is regulated by the peripheral tissue. In this Perspective, we discuss our current understanding of how these unique immunocytes arise, traffic to various sites, and may or may not mature into tissue-directed granulated phenotypes and query whether a granulated end stage is their only intended role. PMID- 22840842 TI - The NLRP12 inflammasome recognizes Yersinia pestis. AB - Yersinia pestis, the causative agent of plague, is able to suppress production of inflammatory cytokines IL-18 and IL-1beta, which are generated through caspase-1 activating nucleotide-binding domain and leucine-rich repeat (NLR)-containing inflammasomes. Here, we sought to elucidate the role of NLRs and IL-18 during plague. Lack of IL-18 signaling led to increased susceptibility to Y. pestis, producing tetra-acylated lipid A, and an attenuated strain producing a Y. pseudotuberculosis-like hexa-acylated lipid A. We found that the NLRP12 inflammasome was an important regulator controlling IL-18 and IL-1beta production after Y. pestis infection, and NLRP12-deficient mice were more susceptible to bacterial challenge. NLRP12 also directed interferon-gamma production via induction of IL-18, but had minimal effect on signaling to the transcription factor NF-kappaB. These studies reveal a role for NLRP12 in host resistance against pathogens. Minimizing NLRP12 inflammasome activation may have been a central factor in evolution of the high virulence of Y. pestis. PMID- 22840843 TI - Cytomegalovirus impairs antiviral CD8+ T cell immunity by recruiting inflammatory monocytes. AB - Inflammatory monocytes are key early responders to infection that contribute to pathogen-host interactions in diverse ways. Here, we report that the murine cytomegalovirus-encoded CC chemokine, MCK2, enhanced CCR2-dependent recruitment of these cells to modulate antiviral immunity, impairing virus-specific CD8(+) T cell expansion and differentiation into effector cytotoxic T lymphocytes, thus reducing the capacity to eliminate viral antigen-bearing cells and slowing viral clearance. Adoptive transfer of inflammatory monocytes into Ccr2(-/-)Ccl2(-/-) mice impaired virus antigen-specific clearance. Cytomegalovirus therefore enhances a natural CCR2-dependent immune regulatory network to modulate adaptive immunity via nitric oxide production, reminiscent of the monocytic subtype of myeloid-derived suppressor cells primarily implicated in cancer immunomodulation. PMID- 22840845 TI - Antithrombotic strategies to reduce adverse clinical outcomes in patients with acute coronary syndrome. AB - Acute coronary syndromes (ACSs), which include ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina, present a considerable burden to the health care system. Furthermore, many patients with a first ACS event will develop another event within 1 year. To prevent this, higher-risk patients with ACS are revascularized when possible after presentation and then prescribed ongoing treatments to prevent recurrent vascular events. These include agents that prevent platelet aggregation and subsequent coronary thrombosis. However, some patients will develop a recurrent event despite treatment with these drugs, prompting a search for additional strategies to augment the effectiveness of current therapies. One such approach is add-on therapy with oral anticoagulant drugs. These agents may act synergistically with antiplatelet agents in preventing thrombosis. In conclusion, new oral anticoagulants might represent an attractive therapeutic strategy if they do not result in unacceptable bleeding. PMID- 22840844 TI - Spectral decomposition of P50 suppression in schizophrenia during concurrent visual processing. AB - Reduced suppression of the auditory P50 event-related potential has long been associated with schizophrenia, but the mechanisms associated with the generation and suppression of the P50 are not well understood. Recent investigations have used spectral decomposition of the electroencephalograph (EEG) signal to gain additional insight into the ongoing electrophysiological activity that may be reflected by the P50 suppression deficit. The present investigation extended this line of study by examining how both a traditional measure of sensory gating and the ongoing EEG from which it is extracted might be modified by the presence of concurrent visual stimulation - perhaps better characterizing gating deficits as they occur in a real-world, complex sensory environment. The EEG was obtained from 18 patients with schizophrenia and 17 healthy control subjects during the P50 suppression paradigm and while identical auditory paired-stimuli were presented concurrently with affectively neutral pictures. Consistent with prior research, schizophrenia patients differed from healthy subjects in gating of power in the theta range; theta activity also was modulated by visual stimulation. In addition, schizophrenia patients showed intact gating but overall increased power in the gamma range, consistent with a model of NMDA receptor dysfunction in the disorder. These results are in line with a model of schizophrenia in which impairments in neural synchrony are related to sensory demands and the processing of multimodal information. PMID- 22840846 TI - Risk factors for bradycardia requiring pacemaker implantation in patients with atrial fibrillation. AB - Symptomatic bradycardia may complicate atrial fibrillation (AF) and necessitate a permanent pacemaker. Identifying patients at increased risk for symptomatic bradycardia may reduce associated morbidities and health care costs. The aim of this study was to investigate predictors for developing bradycardia requiring a permanent pacemaker in patients with AF. The records of all patients treated for AF or atrial flutter in an academic hospital's emergency department from August 1, 2005, to July 31, 2008, were reviewed. Survival and the presence of a pacemaker as of November 1, 2011, were determined. Cases were defined as patients with pacemakers placed for bradycardia after their AF diagnoses. Patients without pacemakers who were followed constituted the control group. Variables for the logistic regression analysis were identified a priori. A post hoc model was fit adjusting for AF type and atrioventricular nodal blocker use. Of the 362 patients in the cohort, 119 cases had permanent pacemakers implanted for bradycardia after AF diagnosis, and 243 controls were alive without pacemakers. The median follow up time was 4.5 years (interquartile range 3.8 to 5.4). Odds ratios were determined for age at the time of AF diagnosis (1.02, 95% confidence interval [CI] 1 to 1.04), female gender (1.58, 95% CI 0.95 to 2.63), previous heart failure (2.72, 95% CI 1.47 to 5.01), and African American race (0.33, 95% CI 0.12 to 0.94). The post hoc model identified permanent AF (odds ratio 2.99, 95% CI 1.61 to 5.57) and atrioventricular nodal blocker use (odds ratio 1.43, 95% CI 0.85 to 2.4). In conclusion, in patients with AF, heart failure and permanent AF each nearly triple the odds of developing bradycardia requiring a permanent pacemaker; although not statistically significant, our results suggest that women are more likely and African Americans less likely to develop bradycardia requiring pacemaker implantation. PMID- 22840847 TI - Comparison between transradial and transfemoral percutaneous coronary intervention in acute ST-elevation myocardial infarction. AB - Transradial (TR) access is increasingly being used in percutaneous coronary intervention (PCI). However, its role in PCI for ST-segment elevation myocardial infarction remains controversial because of concerns of procedural complexity adversely affecting the promptness of reperfusion. In this study, 150 consecutive patients who underwent PCI for acute ST-segment elevation myocardial infarction over a period of 24 months were prospectively evaluated; 46 had TR access (31%) and 104 (69%) had transfemoral (TF) access. All patients received thienopyridines, aspirin, and heparin per routine management. There were no significant differences between the TR access and TF access groups with respect to age (62.2 +/- 11.6 vs 64.7 +/- 14.1, p = 0.28), gender (76.1% vs 72.1% men, p = 0.69), or incidence of diabetes (23.9% vs 26.9%, p = 0.84). The TR and TF access groups were comparable with respect to door-to-balloon time (79.2 +/- 32.3 vs 86.8 +/- 51.8 minutes, p = 0.67) and amount of contrast used (190.5 +/- 101.5 vs 172.2 +/- 81.7 ml, p = 0.24). Total fluoroscopy time was longer in the TR access group compared to the TF access group (21.7 +/- 12.7 vs 14.4 +/- 10.4 minutes, p <0.0001). Postprocedural Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow was comparable for the 2 groups (87% for the TF group and 96% for the TR group, p = 0.15). There were no vascular complications in the TR access group compared to the TF access group (0% vs 5.8%, p = 0.18). In conclusion, this single-center observational study shows that TR access for PCI in STEMI is feasible and that it has fewer vascular complications and shorter length of hospital stay than the TF approach. PMID- 22840848 TI - Drug-resistant tuberculosis transmission and resistance amplification within families. AB - Drug-resistant tuberculosis is caused by transmission of resistant strains of Mycobacterium tuberculosis and by acquisition of resistance through inadequate treatment. We investigated the clinical and molecular features of the disease in 2 families after drug-resistant tuberculosis was identified in 2 children. The findings demonstrate the potential for resistance to be transmitted and amplified within families. PMID- 22840849 TI - A segmentation framework towards automatic generation of boost subvolumes for FDG PET tumors: a digital phantom study. AB - Potential benefits of administering nonuniform radiation dose to heterogeneous tumors imaged with FDG-PET have been widely demonstrated; whereas the number of discrete dose levels to be utilized and corresponding locations for prescription inside tumors vary significantly with current existing methods. In this paper, an automated and unsupervised segmentation framework constituted mainly by an image restoration mechanism based on variational decomposition and a voxel clustering scheme based on spectral clustering was presented towards partitioning FDG-PET imaged tumors into subvolumes characterized with the total intra-subvolume activity similarity and the total inter-subvolume activity dissimilarity being simultaneously maximized. Experiments to evaluate the proposed system were carried out with using FDG-PET data generated from a digital phantom that employed SimSET (Simulation System for Emission Tomography) to simulate PET acquisition of tumors. The obtained results show the feasibility of the proposed system in dividing FDG-PET imaged tumor volumes into subvolumes with intratumoral heterogeneity being properly characterized, irrespective of variation in tumor morphology as well as diversity in intratumoral heterogeneity pattern. PMID- 22840850 TI - Amikacin-induced drug reaction with eosinophilia and systemic symptoms syndrome: delayed skin test and ELISPOT assay results allow the identification of the culprit drug. PMID- 22840851 TI - Ambient pollen concentrations and emergency department visits for asthma and wheeze. AB - BACKGROUND: Previous studies report associations between aeroallergen exposure and asthma exacerbations. Aeroallergen burdens and asthma prevalence are increasing worldwide and are projected to increase further with climate change, highlighting the importance of understanding population-level relationships between ambient pollen concentrations and asthma. OBJECTIVE: We sought to examine short-term associations between ambient concentrations of various pollen taxa and emergency department (ED) visits for asthma and wheeze in the Atlanta metropolitan area between 1993 and 2004. METHODS: We assessed associations between the 3-day moving average (lag 0-1-2) of Betulaceae (except Alnus species), Cupressaceae, Quercus species, Pinaceae (except Tsuga species), Poaceae, and Ambrosia species pollen concentrations and daily asthma and wheeze ED visit counts, controlling for covarying pollen taxa and ambient pollutant concentrations. RESULTS: We observed a 2% to 3% increase in asthma- and wheeze related ED visits per SD increase in Quercus species and Poaceae pollen and a 10% to 15% increased risk on days with the highest concentrations (comparing the top 5% of days with the lowest 50% of days). An SD increase in Cupressaceae concentrations was associated with a 1% decrease in ED visits. The association for Quercus species pollen was strongest for children aged 5 to 17 years. Effects of Ambrosia species pollen on asthma exacerbations were difficult to assess in this large-scale temporal analysis because of possible confounding by the steep increase in circulating rhinoviruses every September. CONCLUSION: Poaceae and Quercus species pollen contribute to asthma morbidity in Atlanta. Altered Quercus species and Poaceae pollen production caused by climate change could affect allergen-induced asthma morbidity in the southeastern United States. PMID- 22840853 TI - Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-gamma and IL-4. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far. OBJECTIVE: We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS. METHODS: Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-gamma, IL-4, and IL-17 on ALI cultures was assessed. RESULTS: A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-gamma and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity. CONCLUSION: A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-gamma and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS. PMID- 22840852 TI - Staphylococcus aureus alpha-toxin modulates skin host response to viral infection. AB - BACKGROUND: Patients with atopic dermatitis (AD) with a history of eczema herpeticum have increased staphylococcal colonization and infections. However, whether Staphylococcus aureus alters the outcome of skin viral infection has not been determined. OBJECTIVE: We investigated whether S aureus toxins modulated host response to herpes simplex virus (HSV) 1 and vaccinia virus (VV) infections in normal human keratinocytes (NHKs) and in murine infection models. METHODS: NHKs were treated with S aureus toxins before incubation of viruses. BALB/c mice were inoculated with S aureus 2 days before VV scarification. Viral loads of HSV 1 and VV were evaluated by using real-time PCR, a viral plaque-forming assay, and immunofluorescence staining. Small interfering RNA duplexes were used to knockdown the gene expression of the cellular receptor of alpha-toxin, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 protein and alpha-toxin heptamers were detected by using Western blot assays. RESULTS: We demonstrate that sublytic staphylococcal alpha-toxin increases viral loads of HSV-1 and VV in NHKs. Furthermore, we demonstrate in vivo that the VV load is significantly greater (P < .05) in murine skin inoculated with an alpha-toxin-producing S aureus strain compared with murine skin inoculated with the isogenic alpha-toxin deleted strain. The viral enhancing effect of alpha-toxin is mediated by ADAM10 and is associated with its pore-forming property. Moreover, we demonstrate that alpha-toxin promotes viral entry in NHKs. CONCLUSION: The current study introduces the novel concept that staphylococcal alpha-toxin promotes viral skin infection and provides a mechanism by which S aureus infection might predispose the host toward disseminated viral infections. PMID- 22840854 TI - Colloidal interactions between monoclonal antibodies in aqueous solutions. AB - Colloidal interactions between proteins determine the behavior and stability of globular proteins such as monoclonal antibodies (mAbs) against their propensity to cluster formation in solution. We study interactions between these proteins through their dilute solution behavior. Experiments to quantify intermolecular interactions were done using Dynamic and Static Light Scattering (DLS and SLS) in a high-throughput manner in parallel with zeta potential measurements with Laser Doppler Electrophoresis method (M3-PALS). This approach offers a rapid indirect determination of colloidal interactions through their measured second virial coefficient. Electrostatic part of the DLVO interaction was conveniently parameterized via the corresponding surface charge and/or surface potential, while the van der Waals interactions were parameterized via their Hamaker coefficient, both as functions of ionic strength and pH of the bathing solution. This parametrization of protein-protein interactions improves our understanding of mAb assembly and provides a means for its control by solution parameter variation. Additionally, our results also provide a consistency check and validation of applicability of the DLVO theory in mAbs solution assembly processes. PMID- 22840855 TI - Genetic variability of the SNPforID 52-plex identification SNP panel in Italian population samples. PMID- 22840856 TI - A cautionary note on switching mitochondrial DNA reference sequences in forensic genetics. PMID- 22840857 TI - Robotic management of benign mid and distal ureteral strictures and comparison with laparoscopic approaches at a single institution. AB - OBJECTIVE: To present our experience and outcomes with robotic mid and distal ureteral reconstruction and to compare these results with our previous laparoscopic series. METHODS: In an institutional review board-approved retrospective study, 16 patients underwent robotic mid and distal ureteral repair (13 ureteral reimplantations and 3 ureteroureterostomies) at our institution from August 2008 to September 2011. Proximal ureteral stricture, extrinsic obstruction, and ureteropelvic junction obstruction cases were excluded. The demographic, perioperative, and postoperative data were reviewed in the reimplantation and ureteroureterostomy robotic groups. These data were compared with the outcomes from our previously published series on laparoscopic ureteral reimplantation. RESULTS: The data from 16 robotic procedures were included in the present study, including 2 open conversions because of excessive scar tissue. A symptomatic bowel injury (Clavien grade IIIb) occurred in 1 case. In our previous series, 5 of the 6 laparoscopic procedures were performed completely laparoscopically with 1 open conversion for anastomosis completion. No major complications occurred. The mean robotic surgery time was 258.6 minutes (range 146-450) compared with 276.5 minutes (range 180-360) for the laparoscopic group. The mean robotic hospital stay was 2.5 days (range 1-8) compared with 2.7 days (range 2-5) for the laparoscopic group. The mean robotic estimated blood loss was 171 mL (range 30-500) compared with 150 mL (range 50-250) for the laparoscopic group. All cases were clinically and radiographically successful at the last follow-up examination. CONCLUSION: Although early in our experience, the robotic repair of mid and distal ureteral strictures appears to be an efficacious approach comparable to laparoscopy for such conditions. PMID- 22840858 TI - Effects of sildenafil citrate, isoniazid, and streptomycin on testicular tissue and epididymal semen quality in rats. AB - OBJECTIVE: To evaluate the effects of isoniazid (INH) and streptomycin (STR) on epididymal semen quality and testicular tissue, and to evaluate the protective effect of sildenafil citrate (SC) on possible testicular toxicity induced by STR and INH in rats. METHODS: Eighty adult male Sprague-Dawley rats were divided randomly into 8 groups including control, SC, INH, STR, STR+INH, SC+INH, SC+STR, and SC+INH+STR. After 45 days of treatment, the reproductive organ weights, epididymal semen quality, testicular histopathological findings, levels of serum nitric oxide, testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were investigated. RESULTS: SC significantly increased the epididymal sperm motility and concentration, and the levels of FSH, LH, and testosterone. The STR group had a significantly higher percentage of sperm head defect than the control group (P < .05). The INH group had lower Johnsen Testicular Biopsy Score than the control group (P < .001). Although SC and INH treatment alone did not affect the epididymal semen quality negatively, the SC+INH group had significantly higher spermatozoon tail and total morphologic defect ratios than the control group (P < .05). CONCLUSION: It has been concluded from this study that (1) SC has positive effects on spermatogenesis, sperm production, and semen quality; (2) STR affected the testicular biopsy score and spermatozoon head morphology negatively, but positively affected the other spermatologic traits; (3) INH did not effect the epididymal semen quality negatively, but decreased testicular biopsy score; and (4) SC can prevent the spermatozoon head defects induced by STR and can decrease the testicular toxicity induced by INH. PMID- 22840859 TI - Potential role of prokineticin 2 in experimental varicocele-induced rat testes. AB - OBJECTIVE: To determine the possible role of prokineticin 2 in varicocele by inducing varicoceles in adult rats. METHODS: Forty male Sprague-Dawley rats were used for sham operation (n = 10) and varicocele (n = 30) groups. Experimental varicocele was induced by partial ligation of the left renal vein in the varicocele, whereas the sham operation group only received a sham induction of varicocele. Left testes were harvested for real-time quantitative polymerase chair readtion analysis 2, 4, and 8 weeks after the induction of varicocele. RESULTS: The expression of prokineticin 2 mRNA in 8-week varicocele-induced rats was significantly higher (P < .05) than that in the sham operation group. CONCLUSION: The present study suggests that prokineticin 2 expression is increased by varicocele induction and it may have a role in varicocele-induced infertility. PMID- 22840860 TI - Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis. AB - OBJECTIVE: To present a systematic review to assess efficacy and safety of tramadol for premature ejaculation. METHODS: A literature search was performed using the Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. Literature reviewed included meta-analyses and randomized and nonrandomized prospective studies. End points included intravaginal ejaculation latency time (in minutes), adverse events, and patient-reported outcome assessments. We used mean difference to measure intravaginal ejaculation latency time and odds ratio to measure adverse events rates. These odds ratios were pooled using a random or fixed effects model and were tested for heterogeneity. We used the Cochrane Collaboration's Review manager (RevMan) 5.1 software for statistical analysis. RESULTS: We identified 7 publications that strictly met our eligibility criteria. Meta-analysis of extractable data showed that tramadol was associated with a 3 minute intravaginal ejaculation latency time increasing (mean difference 2.77 minutes; 95% CI 1.12-4.47; P = .001) and significantly more patients with adverse events rates compared with placebo (odds ratio 2.89; 95% CI 1.88-4.43; P < .0001). There were no differences between the tramadol and the paroxetine of intravaginal ejaculation latency time (mean difference -0.44; 95% CI -5.07 to 4.18; P = .85). In addition, patients saw significantly greater improvement in patient-reported outcome. CONCLUSION: In this diverse population, tramadol is an effective and safety pharmacologic therapy for premature ejaculation. PMID- 22840861 TI - Anastomosing hemangioma arising from the adrenal gland. PMID- 22840862 TI - Diagnostic significance of overexpression of Golgi membrane protein 1 in prostate cancer. AB - OBJECTIVE: To investigate the diagnostic significance of Golgi membrane protein 1 (GOLM1) expression in prostate cancer. METHODS: The localization of GOLM1 in prostate cancer cells was detected by immunofluorescence. The GOLM1 expression in prostate cancer cells at the mRNA and protein level was determined by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. A prostate cancer tissue microarray was used to analyze GOLM1 protein expression by immunohistochemistry. RESULTS: The immunofluorescence results demonstrated that GOLM1 was located at the cis-Golgi in the DU145 cells. GOLM1 transcripts and protein were overexpressed in a wide variety of prostate cancer cell lines (DU145, 22RV1, PC-3, and LNCaP). Tissue microarray immunohistochemistry demonstrated that GOLM1 protein staining was occasionally found in the normal prostate gland and benign prostatic hyperplasia, whereas that in prostate cancer was predominantly observed in the cytoplasm of tumor cells. GOLM1 protein was strongly expressed in prostate cancer tissues, and there was a significant difference compared with the normal prostate and benign prostatic hyperplasia cases (P < .05). There were no significant differences between GOLM1 overexpression and pathologic variables of prostate cancer, including histologic grade and pathologic stage (P > .05). CONCLUSION: Our results suggest that GOLM1 protein is significantly expressed in prostate cancer in comparison with the normal prostate gland and benign prostatic hyperplasia. These findings may suggest that GOLM1 is useful in the diagnosis or therapy of prostate cancer. However, GOLM1 overexpression is not associated with disease stage and grade. PMID- 22840864 TI - Editorial comment. PMID- 22840865 TI - Effect of testicular germ cell tumor therapy on renal function. AB - OBJECTIVE: To assess the pre- and post-therapy glomerular filtration rate in patients with testicular germ cell tumors to determine its effect on the natural history of renal function. METHODS: We reviewed an institutional database of patients with testicular germ cell tumor, with pre- and post-therapy serum creatinine levels available. The renal function was estimated using a calculated glomerular filtration rate. We compared the patients treated without chemotherapy (orchiectomy with or without radiotherapy or retroperitoneal lymph node dissection) with those who received systemic chemotherapy. We analyzed the data for the outcome of new-onset chronic kidney disease (CKD) stage 3 between these groups. Kaplan-Meier curves were constructed and compared using a log-rank test. RESULTS: A total of 144 patients were reviewed. The testicular germ cell tumor stage distribution was stage I in 78 (54.2%), stage II in 28 (19.4%), and stage III in 38 (26.4%). Overall, the median creatinine and estimated glomerular filtration rate at diagnosis was 0.9 mg/dL (range 0.5-1.5) and 104.0 mL/min/1.73 m(2) (range 58.7-235), respectively. Of the 144 patients, 102 (70.8%) had CKD stage 0-1, 41 (28.5%) stage 2, and 1 (0.7%) stage 3. The median creatinine and estimated glomerular filtration rate at the last follow-up visit was 1.0 mg/dL (range 0.6-2.6) and 95.5 mL/min/1.73 m(2) (range 31.5-167.6), respectively. This difference between the pre- and post-therapy estimated glomerular filtration rate was significant (P < .01). A total of 81 patients (56.3%) received chemotherapy (median 4 cycles, range 1-12), and 63 (43.7%) were treated without chemotherapy. Of the 81 patients who received chemotherapy, 8 (9.9%) developed new-onset CKD 3 compared with none in the nonchemotherapy group (P = .01). CONCLUSION: Patients with testicular germ cell tumor receiving chemotherapy experienced a significant decrease in the estimated glomerular filtration rate and had a significantly increased risk of developing CKD stage 3 compared with those treated without chemotherapy. These findings offer insight into the long-term risks of testicular germ cell tumor survivorship and will be useful in counseling patients. PMID- 22840866 TI - Assessment of tamsulosin as a potential male contraceptive in healthy volunteers. AB - OBJECTIVE: To investigate the efficacy and safety of tamsulosin, an alpha(1A) adrenoceptor antagonist, as a potential male contraceptive. METHODS: Forty healthy male volunteers were equally divided into 2 groups, each of which received placebo and tamsulosin sequentially in a crossover manner. Ejaculatory profile was examined 4 to 6 hours after administration and adverse effects were noted. RESULTS: Anejaculation occurred in all subjects after taking 0.8-mg of tamsulosin. Total functional sperm count was significantly reduced in subjects after taking 0.4-mg of tamsulosin. Six subjects receiving 0.8-mg of tamsulosin complained of tolerated discomfort, which disappeared 10 hours after administration. CONCLUSION: When administered at 0.8 mg, tamsulosin can cause anejaculation with some transient side effects. Our results imply that tamsulosin and related drugs might potentially be used as male contraceptive agents in the future, which needs more studies to verify. PMID- 22840867 TI - A new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". AB - OBJECTIVE: To investigate the prognostic factors associated with the treatment efficacy of retrograde intrarenal surgery (RIRS) and develop a scoring system for predicting the stone-free rate after this surgery. METHODS: We performed a retrospective analysis of 207 patients who underwent RIRS for renal stones between January 2009 and September 2011. Patient age, gender, body mass index, stone size, stone side, stone location, stone composition, number of stones, lower pole infundibulopelvic angle, using anticoagulant therapy, abnormal skeletal anatomy, and abnormal renal anatomy were investigated as potential preoperative predictive factors. RESULTS: The present study included 111 (53.6%) men and 96 (46.4%) women. Mean patient age was 32.9 +/- 18.8 years (range 1-74) and mean stone size was 16.2 +/- 4.1 mm (range 8-40). Overall, 178 of the 207 (86%) patients were stone free after the initial treatment. Univariate analysis showed that stone size (P <.001), stone location (P = .025), stone composition (P = .01), stone number (P = .049), renal malformations (P = .042), and lower pole infundibulopelvic angle (P = .003) had significant influence on the stone-free rate after RIRS. Multivariate analysis excluded stone location from the logistic regression model, whereas other factors maintained their statistically significant effect on success rate, indicating that they were independent predictors. CONCLUSION: Our study demonstrated that stone size, stone number, stone composition, infundibulopelvic angle, and renal malformations are significant predictors of RIRS outcome. A scoring system based on these factors helps separate patients into outcome groups and facilitates treatment planning. PMID- 22840868 TI - Use of near infrared spectroscopy as an alternative to videourodynamics to detect detrusor overactivity in women with the overactive bladder syndrome. AB - OBJECTIVE: To evaluate near infrared spectroscopy as a noninvasive alternative to cystometry for detecting detrusor overactivity in women with overactive bladder (OAB). Although cystometry is considered the "gold standard" investigation for the lower urinary tract, it is invasive. Recently, a noninvasive form of assessment of the lower urinary tract has been introduced using near infrared spectroscopy. METHODS: This was a prospective pilot study. Women with symptoms of OAB, referred to a tertiary referral one-stop urodynamics clinic were studied. A urodynamic diagnosis was made according to the International Continence Society guidelines. The near infrared spectroscopy monitoring results were analyzed by an independent near infrared spectroscopy Clinical Research Assessor. Both the urodynamics and near infrared spectroscopy assessors reported whether detrusor overactivity was present. Primary outcome measurement was the performance of near infrared spectroscopy as a new diagnostic test. We evaluated the performance of this by calculating the sensitivity and specificity. The clinical usefulness of near infrared spectroscopy was evaluated using positive and negative predictive values. RESULTS: One hundred patients were recruited of whom 95 had traces that could be interpreted. Thirty-one patients were found to have detrusor overactivity on cystometry. Twenty-five of these patients (26%) had detrusor overactivity on near infrared spectroscopy analysis. In 6% of these cases, no near infrared spectroscopy changes identified as suggestive of detrusor overactivity were seen. No detrusor overactivity was detected by cystometry in 64 patients, and in 19% of cases by near infrared spectroscopy. Forty-six patients (48%) had near infrared spectroscopy monitoring events identified as detrusor overactivity but no cystometry changes diagnostic of detrusor overactivity. CONCLUSION: The results of our study suggest that near infrared spectroscopy is an unreliable method for detecting detrusor overactivity in women with OAB symptoms. PMID- 22840869 TI - Urethral-sparing histotripsy of the prostate in a canine model. AB - OBJECTIVE: To evaluate the feasibility and healing response to urethral-sparing prostate histotripsy using a canine model of benign prostatic hypertrophy. METHODS: Histotripsy was performed on 10 canines using a 750-kHz piezoelectric ultrasound transducer targeting the prostatic parenchyma while avoiding the urethra. Periprocedure prostatic urethral integrity was evaluated with serial cystourethroscopy. Evolution of histotripsy treatment effect and subjects' response to urethral sparing was evaluated with serial ultrasound and laboratory evaluation, respectively. The dogs were euthanized acutely or chronically and findings were confirmed histologically. RESULTS: Bilateral treatment was possible in 8/10 subjects, whereas unilateral treatment was performed in 2/10. Failure to spare the urethra was observed in 2/18 treatments-one acutely and one chronically, despite normal cystourethroscopy for the first week. Modest prostatic volume reduction was seen in subjects survived to 8 weeks post histotripsy. Laboratory studies revealed transient perioperative increases in mean white blood cell count, C-reactive protein, and lactate dehydrogenase. On histology, 80% of successful urethral sparing treatment cavities were completely epithelialized, containing simple fluid with minimal cellular debris at 8 weeks despite no communication with the urethra. CONCLUSION: Urethral-sparing histotripsy of the prostate is feasible and well tolerated in a canine model, resulting in modest volume reduction and prompt resorption of homogenized tissue debris. Human studies to evaluate the clinical utility and symptomatic response of urethral sparing are needed. PMID- 22840870 TI - Large cystocele with spontaneous vesicovaginal fistula. AB - Vesicovaginal fistulae (VVF) caused by cystoceles are very rare. To date, there are no documented cases in English literature. A 77-year-old woman presented with near total incontinence. On physical examination, she was found to have severe vaginal atrophy and pressure necrosis of the anterior vaginal wall, which caused partial thickness erosion and breakdown of the mucosa. A fistula had formed but there was no obvious full thickness necrosis. She underwent a combined vesicovaginal fistula repair with pubovaginal sling. PMID- 22840871 TI - Giant benign adrenal adenoma. PMID- 22840872 TI - Challenges in childhood urinary tract infection/vesicoureteral reflux investigation and management: calming the storm. PMID- 22840873 TI - Controlled synthesis and investigation of the mechanism of formation of hollow hemispherical protrusions on laurate anion-intercalated Zn/Al layered double hydroxide hybrid films. AB - Films of laurate (La) anion-intercalated zinc-aluminum layered double hydroxides (ZnAl-La-LDHs) with hollow hemispherical protrusions on the surface of the hybrid film have been conveniently prepared by an ion-exchange reaction of a nitrate containing LDH film previously grown in situ on a porous anodic alumina/aluminum (PAO/Al) substrate. No template is required to form the hemispherical protrusions, thus avoiding a complicated template removal process. The dimensions, morphology, and resistance to bursting of the hollow hemispherical protrusions can be easily tuned by varying the experimental conditions such as sodium laurate concentration, reaction time, and reaction temperature. The evolution of the hollow protrusions was investigated by scanning electron microscopy (SEM), and a "bubble template-reconfiguration assembly" mechanism, in which air bubbles on the film surface act as a template, has been proposed to explain their formation. When the ion-exchange reaction was carried out on a film that had been treated by ultrasound to eliminate surface air bubbles, no hemispherical protrusions were formed, which is consistent with the proposed mechanism. PMID- 22840874 TI - Chitosan adsorption on hydroxyapatite and its role in preventing acid erosion. AB - Polymer adsorption onto an artificial saliva (AS) layer is investigated using quartz-crystal microbalance with dissipation (QCM-D) and chitosan as the model polymer. QCM-D is utilized in an innovative manner to monitor in situ adsorption of chitosan (CH) onto a hydroxyapatite (HA) coated crystal and to examine the ability of the adsorbed layer to "protect" the HA upon sequential exposure to acidic solutions. After deposition of a thin AS layer (16 nm), the total thickness on the HA substrate increases to 37 nm upon exposure to CH at pH 5.5 for 10 min. Correspondingly, the surface charge changes from negative (i.e., AS) to positive, consistent with the adsorption the polycationic CH onto or into the AS layer. Upon exposure to an oxidizing agent, the chitosan cross-links and collapses as noted by a decrease in thickness to 10 nm and an increase in the shear modulus by an order of magnitude. Atomic force microscopy (AFM) is used to determine the surface morphology and RMS roughness of the coated and HA surfaces after citric acid challenges. Both physisorbed and cross-linked chitosan are demonstrated to limit and prevent the erosion of HA, respectively. PMID- 22840875 TI - Biphasic synthesis of colloidal mesoporous silica nanoparticles using primary amine catalysts. AB - A new type of colloidal mesoporous silica nanoparticles (MSNs) is synthesized in liquid-liquid biphasic systems consisting of tetraethoxysilane (TEOS) and water in the presence of primary amines and cationic surfactants (cetyltrimethylammonium chloride, CTAC) under controlled pH conditions (pH 11.1 11.5). The obtained MSNs are characterized by scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), X-ray diffraction (XRD), and nitrogen adsorption-desorption. The results show that the colloidal MSNs with an average diameter in the range of 28-54 nm and a size polydispersity below ca. 15% have been obtained. Importantly, each MSN is composed of a number of tiny primary silica nanoparticles (PSNPs) forming 3D connected pore structure. The pore size of the MSNs can be tuned from 2.5 to 3.0 nm by changing the pH of catalyst stock solution, and larger pore sizes (3.1-4.5 nm) can be achieved by using pore swelling agent. The Brunauer-Emmett-Teller (BET) surface areas and total pore volumes vary from 550 to 750 m(2)g(-1) and from 1.2 to 1.7 cm(3)g(-1), respectively. Compared with conventional MCM-41-type MSNs, our new MSNs show outstanding colloidal and hydrothermal stabilities. They are colloidally stable at room temperature over 1 year, and their mesostructure was retained even after hydrothermal treatment at 120 degrees C for 24h. Finally, based on the analysis of the morphology and structure of MSNs, a formation scheme based on the cooperative self-assembly of PSNPs and surfactant molecules is proposed. PMID- 22840876 TI - Influence of natural organic matter on the transport and deposition of zinc oxide nanoparticles in saturated porous media. AB - The significance of natural organic matter (NOM, both humic acid and alginate) on the transport and deposition kinetics of ZnO nanoparticles (NPs) in irregular quartz sand was examined by direct comparison of both breakthrough curves and retained profiles with NOM present in NPs suspension versus those obtained without NOM. Packed column experiments were conducted in both NaCl and CaCl(2) solutions under a series of environmentally relevant ionic strengths. Under all examined conditions, breakthrough plateaus with NOM even at concentration as low as 1 mg L(-1) of total organic carbon (TOC) were higher than those without NOM, indicating that presence of NOM in NPs suspensions enhanced ZnO NPs transport. Although hyper-exponential retained profiles were observed both in the presence and absence of NOM, the amount of retained ZnO NPs acquired in the presence of NOM decreased slowly as the transport distance increased. Straining induced by concurrent aggregation is found to cause the hyper-exponential decrease. In the presence of NOM, electrosteric interaction effectively reduced the ZnO NPs deposition on collector surfaces and NPs-NPs aggregation. Subsequently, the amount of NPs that jammed in the column inlet in the absence of NOM were markedly decreased, which therefore exhibited as flatter retained profiles. PMID- 22840877 TI - Prognostication and prediction using gene expression profiling in oesophageal cancer. AB - AIM: To evaluate current literature on gene expression profiling in oesophageal cancer. METHODS: We performed a review of the literature (2000-2010) on prognostication and prediction using gene expression analysis in oesophageal cancer. RESULTS: Seventeen papers comprising 638 patients were included. Gene expression profiles studied in relation to survival, lymph node metastasis and response to neoadjuvant therapy. Most studies included a limited number of patients. Several prognostic and predictive gene signatures were identified with different accuracies. In only one study, the gene signature was validated in a large, independent patient cohort. CONCLUSION: Gene expression profiling has potential clinical applications in oesophageal cancer. Especially a signature which is predictive for response to neoadjuvant treatment could be of great clinical value. To date, most published studies suffer from an underpowered training cohort or lack adequate validation. Clinicians should put effort in the collection of high quality tissue samples and should participate in biobank initiatives, considering the increasing availability and possibilities of sequencing technology. PMID- 22840878 TI - Design and implementation of clinical trials in rehabilitation research. AB - The growth of evidence-based medicine means that both researchers and clinicians must grasp the complex issues involved in implementing clinical trials, which are especially challenging for the behavioral (experience-based) treatments that predominate in rehabilitation. In this article we discuss selected issues germane to the design, implementation, and analysis of group-level clinical trials in rehabilitation. We review strengths, weaknesses, and best applications of 1 sample, between-subjects, and within-subjects study designs, including newer models such as practical clinical trials and point-of-care trials. We also discuss the selection of appropriate control conditions against which to test rehabilitation treatments, as well as issues related to trial blinding. In a section on treatment definition, we discuss the challenges of specifying the active ingredients in the complex interventions that are widely used in rehabilitation, and present an illustration of 1 approach to defining treatments via the learning mechanisms that underlie them. Issues related to treatment implementation are also discussed, including therapist allocation and training, and assessment of treatment fidelity. Finally we consider 2 statistical topics of particular importance to many rehabilitation trials: the use of multiple or composite outcomes, and factors that must be weighed in estimating sample size for clinical trials. PMID- 22840879 TI - Practice-based evidence research in rehabilitation: an alternative to randomized controlled trials and traditional observational studies. AB - Sound rigorous methods are needed by researchers and providers to address practical questions about risks, benefits, and costs of interventions as they occur in routine clinical practice such as: Are treatments used in daily practice associated with intended outcomes? For whom does an intervention work best? With limited clinical resources, what are the best interventions to use for specific types of patients? Answers to such questions can help clinicians, patients, researchers, and health care administrators learn from, and improve, real-world everyday clinical practice. In this article, we describe existing research designs to demonstrate clinical usefulness and comparative effectiveness of rehabilitation treatments. We compare randomized controlled trials and observational cohort studies of various types, including those that use instrumental variables or propensity scores to control for potential patient or treatment selection effects. We argue that practice-based evidence (PBE) study designs include features that address limitations inherent in both randomized trials and traditional observational studies, and also reduce the need for instrumental variables and propensity scores methods. We give examples of how PBE designs have been used in various rehabilitation areas to determine better treatments for specific types of patients. PMID- 22840880 TI - Developing and evaluating prediction models in rehabilitation populations. AB - This article presents a 3-part framework for developing and evaluating prediction models in rehabilitation populations. First, a process for developing and refining prognostic research questions and the scientific approach to prediction models is presented. Primary components of the scientific approach include the study design and sampling of patients, outcome measurement, selecting predictor variable(s), minimizing methodologic sources of bias, assuring a sufficient sample size for statistical power, and selecting an appropriate statistical model. Examples focus on prediction modeling using samples of rehabilitation patients. Second, a brief overview for statistically building and validating multivariable prediction models is provided, which includes the following 7 steps: data inspection, coding of predictors, model specification, model estimation, model performance, model validation, and model presentation. Third, we propose a set of primary considerations for evaluating prediction model studies using specific quality indicators as criteria to help stakeholders evaluate the quality of a prediction model study. Lastly, we offer perspectives on the future development and use of rehabilitation prediction models. PMID- 22840881 TI - Improving measurement methods in rehabilitation: core concepts and recommendations for scale development. AB - Validated measurement scales are essential to evaluating clinical outcomes and conducting meaningful and reliable research. The purpose of this article is to present the clinician and researcher with a contemporary 8-stage framework for measurement scale development based on a mixed-methods qualitative and quantitative approach. Core concepts related to item response theory are presented. Qualitative methods are described to conceptualize scale constructs; obtain patient, family, and other stakeholder perspectives; and develop item pools. Item response theory statistical methodologies are presented, including approaches for testing the assumptions of unidimensionality, local independence, monotonicity, and indices of model fit. Lastly, challenges faced by scale developers in implementing these methodologies are discussed. While rehabilitation research has recently started to apply mixed-methods qualitative and quantitative methodologies to scale development, these approaches show considerable promise in advancing rehabilitation measurement. PMID- 22840882 TI - Conducting systematic evidence reviews: core concepts and lessons learned. AB - A systematic review (SR) is an essential component of evidence-based practice, because it synthesizes information on a particular topic that is necessary to inform health-related decision making. The purpose of this article is to document the process of producing a high-quality SR within the field of rehabilitation in contrast to other fields (eg, pharmaceutic research). We describe the notable methodologic challenges to producing high-quality SRs for rehabilitation researchers. Broadly, we outline how the quality of SRs is evaluated and suggest mechanisms for researchers to address potential pitfalls. Because meaningful SRs can and should be conducted in this field, we provide practical guidance regarding how to conduct such an SR. We outline a series of 8 important steps in the production of an SR: forming a committee, creating a development plan, conducting a literature review, selecting articles for inclusion, extracting data, preparing tables of evidence, facilitating external review and publication, and forming conclusions and recommendations. For each step of the SR process, we provide detailed description about the methodologic decisions involved and recommended strategies that researchers can implement to produce a high-quality SR. Using these preestablished steps and procedures as a guideline will not only help to increase the efficiency of the SR process, but also to improve the quality. The availability of high-quality SRs with plain language summaries promotes access to the best quality information for all involved in decision making. PMID- 22840883 TI - Toward improved evidence standards and methods for rehabilitation: recommendations and challenges. AB - Interventions and programs for people with disability should be based on the best -the most discriminating and rigorous--methods of systematic review and knowledge translation possible. Extant systems for systematic review and practice recommendations have excellent features but severe difficulties are encountered when attempting to apply them to disability and rehabilitation. This article identifies issues in evidence synthesis and linked practice recommendations and describes both new and long-tested methods to address them. Evidence synthesis in disability and rehabilitation can be improved by: explicating criteria for evaluating nonrandomized evidence, including the regression discontinuity, interrupted time series, and single-subject designs, as well as state-of-the-art methods of analysis of observational studies; greater use of meta-analysis; considering effect size, direction of biases, and dose-response relationships; employing more discriminating methods of evaluating flaws in masking, considering also measurement reliability and objectivity; considering overall biases and conflicts of interest; increased attention to composition of review panels; and greater transparency in reporting of the bases of reviewers' judgments. Review methods need to be developed for assistive technology and for measurement procedures. Application to practice can be improved by attention to treatment alternatives, explicit evaluation of generalizability, synthesizing clinical experience as a source of evidence, and a focus on the best--rather than the ideally most-rigorous--evidence. Study outcomes should be measured and reviewed in terms meaningful to persons served. In sum, methods are available to improve evidence synthesis and the application of resulting knowledge. We recommend that these methods be employed. PMID- 22840884 TI - Obesity and food insecurity at the same table: how head start programs respond. AB - INTRODUCTION: Head Start is a federally funded early childhood education program that serves just over 900,000 US children, many of whom are at risk for obesity, are living in food insecure households, or both. The objective of this study was to describe Head Start practices related to assessing body mass index (BMI), addressing food insecurity, and determining portion sizes at meals. METHODS: A survey was mailed in 2008 to all eligible Head Start programs (N = 1,810) as part of the Study of Healthy Activity and Eating Practices and Environments in Head Start. We describe program directors' responses to questions about BMI, food insecurity, and portion sizes. RESULTS: The response rate was 87% (N = 1,583). Nearly all programs (99.5%) reported obtaining height and weight data, 78% of programs calculated BMI for all children, and 50% of programs discussed height and weight measurements with all families. In 14% of programs, directors reported that staff often or very often saw children who did not seem to be getting enough to eat at home; 55% saw this sometimes, 26% rarely, and 5% never. Fifty-four percent of programs addressed perceived food insecurity by giving extra food to children and families. In 39% of programs, staff primarily decided what portion sizes children received at meals, and in 55% the children primarily decided on their own portions. CONCLUSION: Head Start programs should consider moving resources from assessing BMI to assessing household food security and providing training and technical assistance to help staff manage children's portion sizes. PMID- 22840885 TI - Integrating tobacco cessation quitlines into health care: Massachusetts, 2002 2011. AB - QuitWorks is a Massachusetts referral program that links health care organizations, providers, and patients to the state's tobacco cessation quitline and provides feedback reporting. Designed collaboratively with all major Massachusetts health plans, QuitWorks was launched in April 2002. In 2010, approximately 340 institutions and practices used QuitWorks. Between April 2002 and March 2011, approximately 3,000 unique providers referred patients and 32,967 tobacco users received referrals. An analysis of QuitWorks data showed 3 phases in referrals between April 2002 and March 2011: referrals increased from April 2002 through November 2005, plateaued during December 2005 through January 2009, then substantially increased during February 2009 through March 2011. Factors responsible include partnerships with stakeholders, periodic program promotions, hospital activities in response to Joint Commission tobacco use measures, service evolutions, provision of nicotine replacement therapy for referred patients, and electronic referral options. QuitWorks' history demonstrates that tobacco cessation referral programs can be successfully sustained over time; reach substantial numbers of tobacco users, benefit providers and health care organizations; and contribute to sustainable systems-level changes in health care. PMID- 22840886 TI - Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. AB - The objective of this population-based study was to evaluate the incidence of vaginitis (females) and balanitis (males) among a cohort of type 2 diabetes patients and compare this risk to patients without diabetes. The study population included 125,237 female patients and 146,603 males identified from GPRD. All patients were followed for 1-year from their study index date for the first record of an infection or a censored event. Among patients with diabetes the incidence of vaginitis was 21.0/1000PY (95% CI 19.8-22.1) with the risk being 1.81 (95% CI 1.64-2.00) greater that patients without diabetes. The incidence of balanitis among diabetes patients was 8.4/1000PY (95% CI 7.8-9.1) with a relative risk of 2.85 (2.39-3.39) compared to patients without diabetes. Additional analyses were performed by HbA1c level. Results from this large population-based study indicate that patients with diabetes are at an increased risk of being diagnosed with infections of the genital tract and patients with poorly controlled diabetes have higher risks. PMID- 22840887 TI - Analysis of genetic variants of class II cytokine and their receptor genes in psoriasis patients of two ethnic groups from the Volga-Ural region of Russia. AB - BACKGROUND: The molecular basis of pathogenesis of psoriasis remains unclear, but one unifying hypothesis of disease aetiology is the cytokine network model. The class II cytokines (CF2) and their receptors (CRF2) are all involved in the inflammatory processes and single nucleotide polymorphisms (SNPs) in respective genes have been associated with psoriasis in a previous study of the Estonian population. OBJECTIVE: We performed a replication study of 47 SNPs in CF2 and CRF2 genes in independent cohorts of psoriasis patients of two ethnic groups (Russians and Bashkirs) from the Volga-Ural region of Russia. METHODS: DNA was obtained from 395 psoriasis patients of two ethnic groups from the Volga-Ural region of Russia and 476 ethnically matched controls. 47 SNPs in the loci of the genes encoding Class II cytokines and their receptors were selected by SNPbrowser version 3.5. Genotyping was performed using the SNPlexTM (Applied Biosystems) platform. RESULTS: The genetic variant rs30461 previously associated in original case-control study in Estonians, was also associated in Russians (corrected P value (Pc=0.008, OR=0.44), but did not reach statistical significance in the Bashkir population. Additionally, the haplotype analysis provided that CC haplotype formed by the SNPs rs30461 and rs955155 had a protective effect in Russians (Pc=0.0024, OR=0.44), supporting the involvement of this locus in the protection against psoriasis. Combined meta-analysis of three populations, including 943 psoriasis patients and 812 healthy controls, showed that the IL29 rs30461 C-allele was not associated with decreased risk of psoriasis (P=0.165, OR=0.68). Moreover, stratification of studies by ethnicity revealed a significant association in the European cohort (P=9.506E-006, OR=0.53). CONCLUSION: Therefore, there is no overall evidence of association between psoriasis and SNP rs30461 of the IL29 gene, but there is some evidence to suggest that an association exists in Europeans. However, this current concept should be considered as preliminary and the results need to be confirmed in future independent studies. PMID- 22840889 TI - Quantification of myocardial area at risk: validation of coronary angiographic scores with cardiovascular magnetic resonance methods. AB - INTRODUCTION AND OBJECTIVES: Quantification of myocardial area-at-risk after acute myocardial infarction has major clinical implications and can be determined by cardiovascular magnetic resonance. The Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index (BARI) and Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) angiographic scores have been widely used for rapid myocardial area-at-risk estimation but have not been directly validated. Our objective was to compare the myocardial area-at-risk estimated by BARI and APPROACH angiographic scores with those determined by cardiovascular magnetic resonance. METHODS: In a prospective study, cardiovascular magnetic resonance was performed in 70 patients with a first successfully-reperfused ST-segment elevation acute myocardial infarction in the first week after percutaneous coronary intervention. Myocardial area-at-risk was obtained both by analysis of T2-short tau inversion recovery sequences and calculation of infarct endocardial surface area with late enhancement sequences. These results were compared with those of BARI and APPROACH scores. RESULTS: BARI and APPROACH showed a statistically significant correlation with T2-short tau inversion recovery for myocardial area-at-risk estimation (BARI, intraclass correlation coefficient=0.72; P<.001; APPROACH, intraclass correlation coefficient=0.69; P<.001). Better correlations were observed for anterior acute myocardial infarction than for other locations (BARI, intraclass correlation coefficient=0.73 vs 0.63; APPROACH, intraclass correlation coefficient=0.68 vs 0.50). Infarct endocardial surface area showed a good correlation with both angiographic scores (BARI, intraclass correlation coefficient=0.72; P<.001; with APPROACH, intraclass correlation coefficient=0.70; P<.001). CONCLUSIONS: BARI and APPROACH angiographic scores allow reliable estimation of myocardial area-at-risk in current clinical practice, particularly in anterior infarctions. Full English text available from:www.revespcardiol.org. PMID- 22840888 TI - Chloroquine-resistant malaria in travelers returning from Haiti after 2010 earthquake. AB - We investigated chloroquine sensitivity to Plasmodium falciparum in travelers returning to France and Canada from Haiti during a 23-year period. Two of 19 isolates obtained after the 2010 earthquake showed mixed pfcrt 76K+T genotype and high 50% inhibitory concentration. Physicians treating malaria acquired in Haiti should be aware of possible chloroquine resistance. PMID- 22840890 TI - Late arterial switch, without previous preparation or extracorporeal membrane oxygenation back-up. PMID- 22840891 TI - Characterization of gait pattern by 3D angular accelerations in hemiparetic and healthy gait. AB - Characterization of gait pattern is of interest for clinical gait assessment. Past developments of ambulatory measurement systems have still limitations for daily usage in the clinical environment. This study investigated the potential of 3D angular accelerations of foot, shank, and thigh to characterize gait events and phases of ten healthy and ten hemiparetic subjects. The key feature of the system was the use of angular accelerations obtained by differential measurement. Further, the effect of sensor position and walking cadence on the signal was investigated. We found that gait phases are characterized as modulated amplitudes of angular accelerations of foot, shank, and thigh. Increasing the gait cadence from 70 steps/min to 100 steps/min caused an amplitude increase of the magnitude of the vector, summing all 3D angular accelerations on the sensor position (p<0.001). Comparison of healthy and hemiparetic gait showed a lower mean of the magnitude of the vector during the loading response in the hemiparetic gait (p<0.05), while during pre-swing and swing no significant differences between healthy and hemiparetic gait were observed. A comparison of the tangential acceleration component in the frontal plane showed no statistically significant difference between healthy and hemiparetic gait. Further, no statistically significant difference between the tangential components was found for both groups. This method demonstrated promising results for a possible use for gait assessment. PMID- 22840892 TI - Speed-dependent temporospatial gait variability and long-range correlations in cerebellar ataxia. AB - OBJECTIVE: This study investigated the influence of impaired cerebellar locomotion function on the magnitude and structure of stride-to-stride fluctuations in the walking pattern. On the basis of studies reporting a dependency of variability magnitude and structure on the walking speed, we hypothesized that patients with cerebellar ataxia (CA) would show alterations of gait variability in a speed-dependent manner. METHODS: 11 patients with CA [7 idiopathic sporadic ataxia, 4 inherited spinocerebellar ataxia] and 11 healthy subjects (HS) walked on a treadmill for 5-min periods at their preferred walking speed and at 20%, 40%, 70%, and 80% of maximal walking speed. The variability magnitude of stride time, stride length and base width was calculated, and long range correlations were detected by a detrended fluctuation analysis. RESULTS: Both temporal and spatial gait variability were impaired in CA. Variability magnitude and structure of all examined parameters depended on the walking speed. The preferred walking speed of patients was linked to minimal levels of stride time and stride length variability magnitude and to the strongest correlations within the fluctuations of these parameters. Long-range correlations were present for all examined gait parameters in patients and HS. Compared to HS, patients showed alterations in the speed dependency of stride time and stride length variability, with increased variability occurring at slow and maximal pace, whereas base width variability remained unaffected. CONCLUSIONS: Gait variability and therefore walking stability is critically dependent on the walking speed in patients with CA. At preferred walking speed, however, variability is minimal and similar to HS. PMID- 22840893 TI - Path integration: effect of curved path complexity and sensory system on blindfolded walking. AB - Path integration refers to the ability to integrate continuous information of the direction and distance traveled by the system relative to the origin. Previous studies have investigated path integration through blindfolded walking along simple paths such as straight line and triangles. However, limited knowledge exists regarding the role of path complexity in path integration. Moreover, little is known about how information from different sensory input systems (like vision and proprioception) contributes to accurate path integration. The purpose of the current study was to investigate how sensory information and curved path complexity affect path integration. Forty blindfolded participants had to accurately reproduce a curved path and return to the origin. They were divided into four groups that differed in the curved path, circle (simple) or figure eight (complex), and received either visual (previously seen) or proprioceptive (previously guided) information about the path before they reproduced it. The dependent variables used were average trajectory error, walking speed, and distance traveled. The results indicated that (a) both groups that walked on a circular path and both groups that received visual information produced greater accuracy in reproducing the path. Moreover, the performance of the group that received proprioceptive information and later walked on a figure-eight path was less accurate than their corresponding circular group. The groups that had the visual information also walked faster compared to the group that had proprioceptive information. Results of the current study highlight the roles of different sensory inputs while performing blindfolded walking for path integration. PMID- 22840894 TI - Molecular quantification of environmental DNA using microfluidics and digital PCR. AB - Real-time PCR has been widely used to evaluate gene abundance in natural microbial habitats. However, PCR-inhibitory substances often reduce the efficiency of PCR, leading to the underestimation of target gene copy numbers. Digital PCR using microfluidics is a new approach that allows absolute quantification of DNA molecules. In this study, digital PCR was applied to environmental samples, and the effect of PCR inhibitors on DNA quantification was tested. In the control experiment using lambda DNA and humic acids, underestimation of lambda DNA at 1/4400 of the theoretical value was observed with 6.58 ng MUL(-1) humic acids. In contrast, digital PCR provided accurate quantification data with a concentration of humic acids up to 9.34 ng MUL(-1). The inhibitory effect of paddy field soil extract on quantification of the archaeal 16S rRNA gene was also tested. By diluting the DNA extract, quantified copy numbers from real-time PCR and digital PCR became similar, indicating that dilution was a useful way to remedy PCR inhibition. The dilution strategy was, however, not applicable to all natural environmental samples. For example, when marine subsurface sediment samples were tested the copy number of archaeal 16S rRNA genes was 1.04*10(3) copies/g-sediment by digital PCR, whereas real-time PCR only resulted in 4.64*10(2) copies/g-sediment, which was most likely due to an inhibitory effect. The data from this study demonstrated that inhibitory substances had little effect on DNA quantification using microfluidics and digital PCR, and showed the great advantages of digital PCR in accurate quantifications of DNA extracted from various microbial habitats. PMID- 22840896 TI - Invited commentary. PMID- 22840895 TI - Vaccination of health care workers to protect patients at increased risk for acute respiratory disease. AB - Health care workers (HCWs) may transmit respiratory infection to patients. We assessed evidence for the effectiveness of vaccinating HCWs to provide indirect protection for patients at risk for severe or complicated disease after acute respiratory infection. We searched electronic health care databases and sources of gray literature by using a predefined strategy. Risk for bias was assessed by using validated tools, and results were synthesized by using a narrative approach. Seventeen of the 12,352 identified citations met the full inclusion criteria, and 3 additional articles were identified from reference or citation tracking. All considered influenza vaccination of HCWs, and most were conducted in long-term residential care settings. Consistency in the direction of effect was observed across several different outcome measures, suggesting a likely protective effect for patients in residential care settings. However, evidence was insufficient for us to confidently extrapolate this to other at-risk patient groups. PMID- 22840897 TI - Comparison of initial hemodynamic response after endovascular therapy and open surgical bypass in patients with diabetes mellitus and critical limb ischemia. AB - BACKGROUND: While endovascular (ENDO) therapy has increasingly become the initial intervention of choice to treat lower extremity peripheral arterial disease, reported outcomes for ENDO in patients with critical limb ischemia (CLI) and diabetes have been reported to be inferior compared to open bypass surgery (OPEN). Objective data assessing the hemodynamic success of ENDO compared to the established benchmark of OPEN are sparse. We therefore evaluated and compared early hemodynamic outcomes of ENDO and OPEN in patients with diabetes with CLI at a single academic center. METHODS: We studied 85 consecutive patients with diabetes and CLI who underwent 109 interventions, either ENDO (n = 78) or OPEN (n = 31). The mean patient age was 69 years; 62% were men. All patients presented with either rest pain and/or ulcer/gangrene. Per protocol, all were assessed using ankle brachial index (ABI) and toe pressure (TP) determinations before and early postintervention. RESULTS: Both ENDO (DeltaABI = 0.36 +/- 0.24, P < .0001; DeltaTP = 35.6 +/- 24.1, P < .0001) and OPEN (DeltaABI = 0.39 +/- 0.17, P < .0001; DeltaTP = 34.3 +/- 24.0, P < .0001) resulted in significant hemodynamic improvement. There was no statistically significant initial difference between the two types of intervention (ABI, P = .6; TP, P = .6). CONCLUSIONS: These data suggest that with appropriate patient selection, each intervention is similarly efficacious in initially improving hemodynamics. If the intermediate or long-term results of ENDO for CLI in people with diabetes are inferior, the problem is not one of initial hemodynamic response, but more likely due to differing patient characteristics or durability of the intervention. PMID- 22840900 TI - Endovascular repair of a proximal aortic arch aneurysm with extrathoracic debranching. PMID- 22840901 TI - Ruptured splenic artery aneurysm masquerading as a gastric hemorrhage. PMID- 22840902 TI - Questions remain about quality of life after abdominal aortic aneurysm repair. AB - INTRODUCTION: Morbidity and mortality have traditionally been used as key markers of surgical outcome. However, as complication rates associated with abdominal aortic aneurysm (AAA) repair decrease, subjective measures, such as quality of life (QOL), are increasingly recognized as important indicators of treatment efficacy and quality of care. This review presents the existing evidence relating to QOL changes in patients undergoing AAA repair by open repair (OR) and endovascular techniques (EVAR) and challenges current misconceptions about the relative effect of these two procedures. METHODS: A comprehensive literature search was performed to identify studies relating to QOL or health status in AAA repair. Quality of included studies was assessed according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Twenty-three studies satisfied the inclusion criteria. Preoperative QOL in AAA patients has been previously suggested as being worse than that of the general population, that OR patients have a worse QOL in the early postoperative period, and that EVAR patients have a worse QOL in the longer term. None of these assertions is uniformly supported in the literature. From the existing evidence, no clear conclusions can be drawn about the relative QOL benefits of OR vs EVAR. CONCLUSIONS: There are a paucity of good-quality data relating to health status and QOL in patients undergoing AAA repair. Little is known about the prevalence of preoperative or postoperative symptoms and the degree to which these influence patient well-being. Further investigation is needed to clarify health status and QOL changes in these patients and allow clinicians to make targeted improvements in practice. PMID- 22840903 TI - Medical expert witness litmus. AB - Several years ago, Dr G. Breaking was the foremost proponent of a new surgical procedure, which was named after him. At a recent national meeting, he discussed a paper that modified the procedure and criticized the presenter's revisions as dangerous--risking increased paralysis. GB's unedited comments were published last month in the specialty's leading journal. Today, an attorney called the office representing a surgical patient who suffered paralysis after undergoing the modified procedure. GB has unremittingly avoided involvement in litigation. The plaintiff's attorney asks him to serve as an expert witness against the surgeon. What should GB do? PMID- 22840904 TI - How educational theory can inform the training and practice of vascular surgeons. AB - The past decade has seen the beginning of a revolution in the way in which surgeons learn their craft. As technology has become increasingly sophisticated, and care more accountable, traditional methods of skill acquisition are no longer optimal as sole training modalities. Against this backdrop, there has been a shift toward competency-based training programs reflecting the growing emphasis on outcomes-based medical education. The modern vascular specialist needs to possess a thorough understanding of the pathophysiology of vascular disease, imaging modalities, and the nonoperative and operative management of the vascular patient. Surgical educators are therefore compelled to develop practical training programs that can teach each of these skills in a safe, learner-centric manner. This report highlights how an understanding of pedagogy or the principles of adult learning can aid this endeavor. Key models of educational theory are presented and their application to vascular training and the development of expertise are highlighted. The report concludes with recommendations for surgical educators to build assessments of competence using these theoretic principles to optimize the training of the next generation of vascular surgeons. PMID- 22840905 TI - Lower extremity bypass vs endovascular therapy for young patients with symptomatic peripheral arterial disease. AB - The uncertainty continues over the best approach to patients with symptomatic peripheral arterial disease. Medical therapy and risk factor modification is part of any treatment regimen; with this there is little disagreement. However, with the introduction of lesser invasive percutaneous technologies, the discussion regarding surgical and endovascular therapies has become more and more complicated. Unfortunately, there is a relative shortage of robust outcomes data to support many of our specific treatment recommendations. Younger patients are an especially troublesome patient cohort. They have consistently shown poorer outcomes after any intervention compared with older patients and may represent a subset of more aggressive atherosclerotic disease. Our debaters will discuss their preferred approaches to these difficult patients in the context of the currently available supporting literature. PMID- 22840906 TI - Editors' commentary. PMID- 22840907 TI - Natural history of thoracic aortic aneurysms. AB - Understanding the natural history of thoracic aortic aneurysms (TAAs) is essential to patient care and surgical decision making. In this evidence summary we discuss some of the most clinically relevant features of the disease. The true incidence of TAAs is likely to be higher than currently reported because of the inherently silent nature of TAAs. However, TAAs can become rapidly lethal once dissection or rupture occurs, highlighting the need for more robust screening. The impressive discovery of familial patterns and novel genetic loci for TAAs challenges the idea that most TAAs are simply sporadic. Although the aorta grows in an indolent manner, its rate of growth and its current diameter both have important clinical implications. Biomechanical studies have supported clinical findings of 6.0 cm as a dangerous threshold. Surgical extirpation of TAAs is currently the mainstay of effective treatment. Although endovascular TAA repair is becoming increasingly common, long-term safety remains unproven. We still need more data to support the concept that any medical therapy is effective. PMID- 22840909 TI - Regarding "Results of endovascular aortic aneurysm repair with general, regional, and local/monitored anesthesia care in the American College of Surgeons National Surgical Quality Improvement Program database". PMID- 22840911 TI - Regarding "Association of Program Directors in Vascular Surgery (APDVS) survey of program selection, knowledge acquisition, and education provided as viewed by vascular trainees from two different training paradigms". PMID- 22840912 TI - Regarding "New routine alternative for proximal anterior tibial artery bypass in patients with Buerger disease". PMID- 22840915 TI - Skin patch, polyneuropathy, and paraproteinemia. PMID- 22840916 TI - Are patients with inflammatory bowel disease at increased risk of coronary artery disease? AB - The inflammatory state of atherosclerosis has been established as those with chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, who are at increased risk of coronary artery disease. A systematic search was conducted to retrieve high-quality, peer-reviewed studies of inflammatory bowel disease and coronary artery disease. Recent literature supports an association between inflammatory bowel disease and coronary artery disease. While hypertension increases the risk of coronary artery disease in inflammatory bowel disease patients, other typical risk factors have not been confirmed, and markers of inflammation may predict coronary artery disease risk in this population. Common cardiovascular drugs such as statins and angiotensin converting enzyme inhibitors may have dual potential for controlling inflammatory bowel disease and preventing or treating coronary artery disease. Large, prospective, longitudinal studies can help to determine the true prevalence of coronary artery disease in this population and confirm risk factors. In the absence of such evidence, physicians should be cognizant of increased coronary artery disease risk in inflammatory bowel disease patients without traditional risk factors and consider primary preventive strategies. PMID- 22840918 TI - Autonomous learning derived from experimental modeling of physical laws. AB - This article deals with experimental description of physical laws by probability density function of measured data. The Gaussian mixture model specified by representative data and related probabilities is utilized for this purpose. The information cost function of the model is described in terms of information entropy by the sum of the estimation error and redundancy. A new method is proposed for searching the minimum of the cost function. The number of the resulting prototype data depends on the accuracy of measurement. Their adaptation resembles a self-organized, highly non-linear cooperation between neurons in an artificial NN. A prototype datum corresponds to the memorized content, while the related probability corresponds to the excitability of the neuron. The method does not include any free parameters except objectively determined accuracy of the measurement system and is therefore convenient for autonomous execution. Since representative data are generally less numerous than the measured ones, the method is applicable for a rather general and objective compression of overwhelming experimental data in automatic data-acquisition systems. Such compression is demonstrated on analytically determined random noise and measured traffic flow data. The flow over a day is described by a vector of 24 components. The set of 365 vectors measured over one year is compressed by autonomous learning to just 4 representative vectors and related probabilities. These vectors represent the flow in normal working days and weekends or holidays, while the related probabilities correspond to relative frequencies of these days. This example reveals that autonomous learning yields a new basis for interpretation of representative data and the optimal model structure. PMID- 22840917 TI - Extended-release niacin acutely suppresses postprandial triglyceridemia. AB - OBJECTIVE: Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides by restricting free fatty acids. Immediate release niacin reduced postprandial triglycerides, but extended-release niacin failed to do so when dosed the night before a fat challenge. The study aims were to determine whether extended-release niacin dosed before a fat challenge suppresses postprandial triglycerides and whether postprandial triglycerides are related to free fatty acid restriction. METHODS: A double-blinded, placebo controlled, random-order crossover experiment was performed, in which healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours and report triglycerides and free fatty acid as means +/- standard deviation for incremental area under the curve (AUC) and nadir. RESULTS: By combining 43 fat challenges from 22 subjects, postprandial triglycerides incremental AUC was +312 +/- 200 mg/dL*h on placebo versus +199 +/- 200 mg/dL*h on extended-release niacin (33% decrease, P=.02). The incremental nadir for free fatty acid was -0.07 +/- 0.15 mmol/L on placebo versus -0.27 +/- 0.13 mmol/L on extended-release niacin (P<.0001), and free fatty acid incremental AUC decreased from +2.9 +/- 1.5 mmol/L*h to +1.5 +/- 1.5 mmol/L*h on extended release niacin (20% decrease, P=.0015). The incremental AUC for triglycerides was strongly related to the post-dose decrease in free fatty acid (r = +0.58, P=.0007). CONCLUSIONS: Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial triglycerides suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked free fatty acid restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy. PMID- 22840919 TI - Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. AB - Synaptic plasticity, such as long-term potentiation and long-term depression (LTD), is believed to underlie learning and memory processes in vivo. The cerebellum is an ideal brain region to obtain definitive proof for this hypothesis. The current belief is that the acquisition of motor learning is stored by LTD at the parallel fiber (PF)-Purkinje cell synapse in the cerebellar cortex. Recently, however, several lines of mutant mice that display normal motor learning in the absence of cerebellar LTD have been reported. A similar dichotomy between synaptic plasticity at the circuitry level and learning at the behavioral level has also been reported in the hippocampus. One possible explanation for this dichotomy is that compensatory pathways at the molecular and circuitry levels play an important role in mice that have been genetically modified for their entire lives. Mice that are genetically modified to be deficient in or to express mutant versions of the delta2 glutamate receptor (GluD2) serve as an interesting model due to the predominant expression of GluD2 at PF-Purkinje cell synapses. Furthermore, two major functions of GluD2-PF synapse formation and LTD induction-can be mechanistically dissociated so that the role of LTD in motor learning can be investigated in the absence of morphological abnormalities caused by altered synapse formation. Therefore, genetic manipulations of GluD2 will help to clarify the relationship between LTD and motor learning in the cerebellum. PMID- 22840921 TI - Treatment for patients with catecholaminergic polymorphic ventricular tachycardia: are we in need of randomized trials? PMID- 22840920 TI - Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. AB - To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at > 60* coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height. PMID- 22840922 TI - Intermittent capture of the right ventricular outflow tract by atrial pacing in a patient with a dual-chamber pacemaker. AB - We describe a previously unreported phenomenon of intermittent outflow right ventricular tract capture from the atrial lead of a dual-chamber pacemaker. This was more obvious at slower paced atrial rates and disappeared by decreasing the atrial pulses voltage. Electroanatomical mapping showed that the onset of activation was nearly simultaneous at the insertion site of the atrial lead and at an intermediate level of the right ventricular outflow tract. This exceptional finding might be erroneously diagnosed as due to pseudo-pseudo fusion beats. PMID- 22840923 TI - Limitations of the negative concordance pattern in the diagnosis of broad QRS tachycardia. PMID- 22840924 TI - Percutaneous reduction of an isolated zygomatic fracture using a wire suture. PMID- 22840925 TI - "In vitro" azathioprine-induced changes in peripheral T cell apoptosis and IFN gamma production associate with drug response in patients with Crohn's Disease. AB - BACKGROUND AND AIM: The use of the highly effective thiopurines as early therapeutic option in Crohn's Disease (CD) may be discouraged by the long time interval required to obtain clinical efficacy as also by their potential side effects. The development of non-invasive markers of responsiveness to thiopurines represents a major attempt in the clinical management of CD patients. Azathioprine is able to induce apoptosis of T cells. We studied the effect of thiopurines on "in vitro" T cell apoptosis, IFN-gamma and IL-10 production in a group of CD patients with known response to a previous treatment with AZA. METHODS: Heparinized blood samples were drawn from 25 CD patients showing or not a previous responsiveness to a conventional azathioprine treatment (n=17 and n=8, respectively). CD4+ T cells were stimulated "in vitro" with aCD3/28 mAbs in the presence or absence of azathioprine, 6-mercaptopurine or 6-thioguanine. Apoptosis was assessed using Annexin V staining, and IFN-gamma and IL-10 production in cell culture supernatants was evaluated by ELISA. RESULTS: Apoptosis stimulation index (% of apoptotic cells in the presence of thiopurine/% of apoptotic cells in the absence of thiopurine) and IFN-gamma stimulation index (IFN-gamma production in the presence of thiopurine/IFN-gamma production in the absence of thiopurine) were, respectively, significantly lower and higher in non-responder when compared to responder patients. No variation was observed in IL-10 production. CONCLUSIONS: Evaluation of apoptosis and IFN-gamma stimulation index of peripheral CD4+ T cell may be useful for a proper selection of CD patients candidate to thiopurine treatment. PMID- 22840926 TI - The neurobiology of speech perception and production--can functional imaging tell us anything we did not already know? AB - Our understanding of the neurobiological basis for human speech production and perception has benefited from insights from psychology, neuropsychology and neurology. In this overview, I outline some of the ways that functional imaging has added to this knowledge and argue that, as a neuroanatomical tool, functional imaging has led to some significant contributions. PMID- 22840927 TI - [Is it still time to save the antibiotics?]. PMID- 22840928 TI - [Evaluation of residency training and needs of fellowships by anaesthesia and intensive care residents of Ile-de-France]. PMID- 22840929 TI - [Ultrasound-guided interscalene block]. PMID- 22840930 TI - [Infection control in ultrasound guided regional anaesthesia]. PMID- 22840931 TI - Running the gamut from teen sexuality to abnormal uterine bleeding. PMID- 22840932 TI - Platelet function disorders and menorrhagia in adolescents: a review of laboratory diagnosis. AB - This article provides an overview of the prevalence and pathophysiology of platelet function disorders (PFDs) in adolescents with menorrhagia. In addition, this article reviews the various testing modalities employed for diagnosing PFDs including platelet aggregometry, platelet function analyzer (PFA-100), platelet electron microscopy (EM), flow cytometry, and thromboelastography (TEG), discuss their utility and drawbacks, and allude to the recent recommendations and consensus statements about some of these modalities. Finally, the authors have sketched out a diagnostic algorithm for platelet function testing, which will guide treating physicians to a step-wise approach while evaluating adolescents with menorrhagia for PFDs. PMID- 22840933 TI - Pregnancy, contraception and emergency contraception: the language of urban adolescent young women. AB - OBJECTIVE: We sought to characterize how a group of urban adolescent females understands the domains of pregnancy, contraception, and emergency contraception (EC). DESIGN: We used the research strategy of freelisting as part of an in-depth interview study. SETTING AND PARTICIPANTS: Urban adolescent females presenting to a Pediatric Emergency Department. Participants were enrolled using a purposive sampling strategy if they were black, English-speaking females, 15-19 years old, who resided in 1 of 11 zip codes surrounding the hospital. MAIN OUTCOME MEASURE: Smith's saliency score. Freelists were analyzed for the entire sample, as well as for subgroups. RESULTS: Thirty adolescents completed the interview. We found that this group of adolescents uses different words to characterize the domains of pregnancy, contraception, and EC. The only overlapping salient term was "abortion," which appeared in the overall lists for pregnancy and EC and in the younger group's list for contraception. In addition, lack of knowledge was cited as an important factor related to contraception. CONCLUSIONS: Adolescent patients may not fully understand the concepts of contraception and EC. Providers should consider the potential need to provide an explanation for terms used, and they should consider explicitly differentiating between routine forms of contraception and EC, as well as between EC and abortion. PMID- 22840934 TI - Psychological problems sequalae in adolescents after artificial abortion. AB - STUDY AND OBJECTIVES: Controversy exists over psychological risks associated with unwanted pregnancy and consecutive abortion. The aim of this study was to assess the psychological health of female adolescents following artificial abortion up to 12(th) week of pregnancy. DESIGN: The control case study. SETTING: The study was carried out in the Department of Gynecology and Obstetrics, University Clinical Center Tuzla, in Bosnia-Herzegovina. PARTICIPANTS: We assessed 120 female adolescents. The mean (SD) age of the patients was 17.7 (1.5) years experiencing sexual intercourse in the age of 14-19 years for trauma experiences, presence of posttraumatic stress symptoms, depression and anxiety as state, and anxiety as trait. Sixty adolescents had intentional artificial abortion and 60 had sexual intercourse but did not become pregnant. MAIN OUTCOME MEASURES: We used the PTSD Questionnaire, the Beck Depression Inventory, and the Spielberger State Trait Anxiety Inventory (Form Y) for assessment of anxiety in adolescents. Basic socio-demographic data were also collected. RESULTS: PTSD presented significantly more often in adolescents who aborted pregnancy (30%), than in adolescents who did not abort (13.3%) (odds ratio = 4.91 (95%CI 0.142-0.907) P = 0.03). Anxiety as state and as trait were significantly higher in the abortion group, as the mean (SD) anxiety score of patients was 59.8 (8.9), 57.9 (9.7) respectively, than in non-abortion group 49.5 (8.8), 47.3 (9.9) respectively (t = 6.392, P < 0.001; t = 5.914, P < 0.001, respectively). Adolescents who aborted pregnancy had significantly higher depression symptoms severity 29.2 (5.6) than controls 15.2 (3.3) (t = 8.322, P < 0.001), and they presented significantly more often depression (75%), than adolescents who did not abort (10%) (chi(2) = 53.279, P < 0.001). Logistic regression showed that only experience of life threatening(s) and injury of other person(s) reliably predicted PTSD, whereas abortion and experience of life threatening(s) reliably predicted depression. CONCLUSION: Adolescents who aborted pregnancy presented significantly greater prevalence of PTSD and depression, and significantly greater depression severity and anxiety as state and trait than those who did not abort. Abortion predicted depression only, and did not predict PTSD. PMID- 22840935 TI - A comparison of bone mineral density in normal weight and obese adolescents with polycystic ovary syndrome. AB - STUDY OBJECTIVE: To evaluate whether there are any differences in bone mineral density (BMD) between normal weight and obese adolescents suffering from polycystic ovary syndrome (PCOS) with oligo/amenorrhea. DESIGN: Prospective cohort study. SETTING: Adolescent gynecology clinic in a general service hospital. PARTICIPANTS: Subjects consisted of adolescents between 16 to 18 years of age presenting with oligo/ amenorrhea with ultrasound morphology of polycystic ovaries +/- evidence of hyperandrogenism over 24 months. Controls consisted of consecutive eumenorrheic patients within the same age group. INTERVENTIONS: All underwent full hormonal profile assessment, and dual energy X-ray absorptiometry and peripheral quantitative computed tomography scans. MAIN OUTCOME MEASURES: Areal and volumetric BMD parameters. RESULTS: Of 37 adolescents with PCOS, 12 (32%) were obese with BMI >=25, of which 9/12 (75%) were hyperandrogenic. The control group consisted of 40 normal weight eumenorrheic girls. The PCOS group overall had lower lumbar spine BMD values as compared to the controls (0.91 vs 0.97 g/ cm(2), P = 0.033). The normal weight PCOS group had lower BMD at the spine (0.90 vs 0.97 g/ cm(2), P = 0.027), trochanter (0.66 vs 0.71 g/ cm(2), P = 0.039) as well as volumetric distal tibial core sites (268 vs 296 mg/ cm(3)) as compared to eumenorrheic controls, but there were no significant BMD differences between the obese PCOS group and the eumenorrheic controls. CONCLUSIONS: Normal weight PCOS adolescents with oligo/amenorrhea have marginally lower BMD values than controls, but obese PCOS adolescents have BMD values compatible with eumenorrheic adolescents. PMID- 22840936 TI - Clinical variability in approaches to polycystic ovary syndrome. AB - STUDY OBJECTIVE: The objective of this study was to evaluate methods of initial diagnosis and management of polycystic ovary syndrome (PCOS) among members of the North American Society for Pediatric and Adolescent Gynecology (NASPAG) to assess the degree of practice heterogeneity among specialist providers of adolescent care. DESIGN: Cross-sectional, anonymous, internet survey PARTICIPANTS: NASPAG membership (N = 326; Respondents = 127 (39%)) RESULTS: Percentage of respondents who incorporated specific tests at initial diagnosis was highly variable ranging from 87% (thyroid stimulating hormone) to 17% (sex hormone binding globulin). Oral contraceptives and diet modification/exercise were the most common therapies recommended by 98% and 90% of respondents respectively. CONCLUSION: Considerable practice heterogeneity was present with regards to diagnostic testing for suspected PCOS. Recommendations for first-line therapy were more consistent. Future studies should clarify the clinical utility of specific diagnostic tests for adolescents, such that selection of diagnostic testing is evidence based. PMID- 22840937 TI - Ameliorative effects of resveratrol on acute ovarian toxicity induced by total body irradiation in young adult rats. AB - OBJECTIVE: The purpose of this study was to investigate the ovarian protective effects of resveratrol in rats exposed to total body irradiation. DESIGN: Experimental study. SETTINGS: University hospital. PARTICIPANTS AND INTERVENTIONS: Thirty female rats were randomized into four groups: (1) control group (n = 7); (2) low-dose (10 mg/kg) resveratrol group (n = 8); (3) high-dose (100 mg/kg) resveratrol group (n =7); and (4) sham irradiation group (n = 8). The drugs were administered intraperitoneally as single doses, and the rats were exposed to total body radiation 24 h after the treatment. The animals were sacrificed the following day, and their ovaries were excised for histopathological and biochemical analysis. MAIN OUTCOME MEASURES: The ovarian follicle counts were calculated, and irradiation-dependent ovarian damage and tissue levels of antioxidant enzymes were evaluated. RESULTS: Group 2 and Group 3 showed significantly higher numbers of total follicle counts compared with Group 1 (P < 0.01). The low-dose resveratrol treatment was associated with significantly higher numbers of primary follicles than the high-dose group. The tissue activities of glutathione peroxidase (GsH-Px) and catalase (CAT) were significantly elevated in the resveratrol-treated animals. Evaluation of ovarian histology revealed no remarkable changes in fibrosis and leucocyte infiltration among the resveratrol-treated and control rats; however, vascularity was significantly reduced in the high-dose group (P = 0.014). CONCLUSION: Resveratrol attenuated irradiation-dependent ovarian damage, suggesting that this natural antioxidant is effective in reducing the follicle loss induced by ionizing radiation. PMID- 22840938 TI - Perceptions among adolescent girls and their mothers regarding tampon use. AB - STUDY OBJECTIVE: To explore the perceptions of perimenarchal females and their mothers regarding tampons and tampon use. DESIGN: Descriptive study; convenience sample survey. SETTING: Diverse pediatric practice setting. PARTICIPANTS: 139 females 11-18 years of age and 129 of their mothers/female guardians. INTERVENTION: Survey. MAIN OUTCOME MEASURES: Frequencies, chi-square tests, t tests. RESULTS: Most adolescents (38%-55%) respond "don't know" to various attitude and knowledge items pertaining to tampon use. Adolescent-mother pairs report similar perceptions about tampon use for adolescents. Mothers and adolescents who have "ever tried" tampons (including 68% and 56% of respondents, respectively) have more favorable attitudes about tampons than those who have not tried tampons. Adolescent females list their mothers as the primary source of tampon information; 70% of adolescents and 66% of mothers report that no doctor has spoken to them about tampon use for the daughter. CONCLUSIONS: There is a vast educational deficit among both adolescent females and their mothers regarding the use of tampons among youth. Adolescents and their mothers note that few providers have educated 11- to 18-year-old females or their parents about tampons. Providers have the opportunity to influence adolescent health choices and quality of life associated with tampon use. PMID- 22840939 TI - Status of cis and trans fatty acids in Brazilian adolescent mothers and their newborns. AB - STUDY OBJECTIVE: The objective was to quantify cis and trans fatty acids in maternal plasma and infant cord plasma from adolescent mothers. DESIGN: From 80 adolescent healthy mothers, we sampled postpartum maternal blood and umbilical cord blood at birth. Trans fatty acids (tFAs), linoleic (18:2), and arachidonic (AA, 20:4) acids of the n-6 family, and alpha-linolenic (18:3), eicosapentaenoic (20:5) and docosahexaenoic (22:6) acids of the n-3 family were analyzed by gas liquid chromatography. Results were expressed as a percentage of total fatty acids. RESULTS: Linoleic fatty acid was present in greater proportions in the maternal plasma than in that of the umbilical cord, whereas AA was present in greater proportions in the total lipids of umbilical cord blood. Docosahexaenoic acid was the long-chain polyunsaturated fatty acid of the n-3 family that was predominant in both maternal and umbilical cord plasma. The tFAs in the maternal plasma had a negative correlation with oleic acid and linoleic acid. Linolenic acid had a positive correlation with cephalic perimeter upon birth. A tendency for a negative correlation between trans isomers and gestational age at birth (P = .05) was observed. CONCLUSIONS: Long-chain polyunsaturated fatty acids, which are important to fetal growth and development, were found in greater quantities in the cord blood of newborns of adolescents than in the maternal blood, indicating a priority of transfer of AA and docosahexaenoic fatty acids to the fetus. Despite the lower levels of tFAs found in maternal blood, we verified potential risk for premature birth. PMID- 22840940 TI - High level of agreement between clinician-collected and self-collected samples for HPV detection among South African adolescents. PMID- 22840941 TI - Hypertrophic donavanosis in a young pregnant woman. AB - BACKGROUND: Donovanosis is a chronic bacterial illness, progressive and indolent, which normally attacks the skin and mucous membranes in the genital and perigenital regions. CASE: An 18-year-old pregnant female presented with large, hypertrophic lesions in the ano-genital region. HIV serology was negative. Pap smear revealed a CIN 1 associated with HPV infection. Biopsy yielded macrophages laden with Gram-negative Donovan bodies. SUMMARY AND CONCLUSION: A diagnosis of vulvar and perianal donovanosis was reached; the patient decided to terminate the pregnancy and was treated with azithromycin, which led to clinical resolution. PMID- 22840943 TI - A minimally invasive approach to an iatrogenic pelvic mass. AB - A case report describing an unusual complication following a 17-week elective termination of pregnancy in a pediatric patient that was managed laparoscopically. PMID- 22840942 TI - Recurrent ovarian torsion due to paratubal cysts in an adolescent female. AB - BACKGROUND: Though paratubal and paraovarian cysts are rare in adolescent females, the influence of post-menarchal hormonal stimulation on these tubal derivates can produce large and clinically significant adnexal pathology. Ovarian torsion secondary to paratubal cysts is rare due to the cyst's location and ipsilateral recurrence is uncommon. CASE: We report a case of an 11-year-old female with a large right paratubal cyst causing ovarian torsion on two separate occasions within one year and our approach to surgical management. CONCLUSION: Excision of a paratubal or paraovarian cyst that causes ovarian torsion is necessary to decrease the risk of cyst recurrence and ovarian torsion in the future. Timely diagnosis and treatment of ovarian torsion enables preservation of ovarian function and patient fertility. PMID- 22840944 TI - Primary vulvar Ewing sarcoma/primitive neuroectodermal tumor: a report of one case and review of the literature. AB - BACKGROUND: Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) are aggressive malignancies characterized by translocation involving the EWS gene. Primary extraskeletal ES/PNET rarely affects the female genital tract. CASE: We report the case of a 20-year-old female, who presented with a rapidly growing painful mass arising from the left labium majus for six months. Multiple lesions in bones and nodules in lungs were considered metastasis. The diagnosis was established by immunohistochemical stain and reverse transcriptase polymerase chain reaction analysis. The patient ceased treatment and died of respiratory failure one month after discharge. CONCLUSION: Vulvar ES/PNET mainly affects adolescent females. ES/PNET should be considered in the differential diagnosis of tumors involving the lower gynecologic tract in adolescent female. PMID- 22840945 TI - Severe hyperandrogenemia and insulin resistance in a 12-year-old girl. AB - BACKGROUND: Signs of androgen excess are common complaints of adolescents and young adults. Rapid onset/progression of hyperandrogenism or virilization should prompt further investigation to exclude an androgen-secreting tumor. CASE: We report the case of an obese young adolescent girl who presented with hirsutism, deepened voice, oligomenorrhea, marked acanthosis nigricans, and rapidly increasing testosterone and insulin levels. Imaging studies were negative for both ovarian and adrenal masses. She was successfully treated with continuous combined oral contraceptives. Investigation, treatment, and outcome are reviewed. SUMMARY AND CONCLUSION: This case demonstrates that patients with PCOS may present with a testosterone > 200 ng/dL and that severe hyperinsulinemia can be associated with rapid progression of hyperandrogenism. PMID- 22840946 TI - The promise of rapidly acting antidepressants: challenges and opportunities. PMID- 22840948 TI - Adult neurogenesis: nature versus nurture. PMID- 22840947 TI - Fibroblast growth factor-2: an endogenous antidepressant and anxiolytic molecule? PMID- 22840949 TI - [Relationship of acromial morphology and rotator cuff tears]. AB - PURPOSE OF THE STUDY: To evaluate the effect of acromial morphology, as assessed on radiographs, on rotator cuff tears. MATERIAL: A total of 200 patients surgically treated for shoulder disorders were enrolled. All were older than 40 years and had good quality shoulder radiographs. Two groups were composed: First, a clinical model group of 136 patients to be investigated for three parameters of rotator cuff injury that was divided into two subgroups. One included 68 patients, with an average age of 53.5 years, in whom surgery revealed no injury to the rotator cuff; the other subgroup of 68 patients, with an average age of 58 years, had a ruptured supraspinatus tendon. Subsequently, a control group of 64 patients (32 with rotator cuff injury and 32 without it) was used to verify the results of the model group. METHODS: Three parameters describing the acromion, i.e., acromion index (AI), lateral acromion angle and acromial slope, were measured on standard radiographs. Tangential antero-posterior and scapular "Y" (supraspinatus outlet) views were taken, the images were digitalised and evaluated using a TomoCon 3.0 Viewer programme, and the results of the two groups were statistically analysed and compared. RESULTS: The difference between the patients with rotator cuff injury and those without it was best shown, in both groups, by significant differences in the acromion index. This was true for both the men and women. The AI values for the patients with rotator cuff injury were 0.66 and 0.65 in the model and control groups, respectively. The same AI value of 0.76 was found for uninjured rotator cuffs in both groups. The two other parameters investigated did not appear to be of any significant validity for assessment of rotator cuff tears. DISCUSSION: The aetiology of injury to the rotator cuff has not been fully understood yet but, undoubtedly, the causes will be many. The shape of the acromion is regarded as one of the important factors. We agree with Nyffeler et al. that a lateral extension of the acromion is most often associated with rotator cuff tears and that the acromion index proposed by these authors is a good parameter to assess this morphological change. CONCLUSIONS: A lateral extension of the acromion plays an important role in the aetiology of degenerative tears of the supraspinatus tendon. The acromion index appears to be the best instrument for assessing this morphological change. PMID- 22840950 TI - Management of hemodynamic unstable patients "in extremis" with pelvic ring fractures. AB - The hemodynamic status in patients with pelvic ring injuries is a major prognostic factor of an immediate mortality risk. Especially, patients "in extremis" are of high risk to die. This patient group is characterized by absent vital signs or being in severe shock with initial systolic blood pressure .70 mm Hg and/or requiring mechanical resuscitation or catecholamines despite >12 blood transfusions within the first two hours after admission. The sources of pelvic bleeding is in approximately 80-90% of venous origin and relevant arterial bleeding accounts for 10-20%. Important parts of the initial treatment treatment concept include mechanical pelvic ring stabilization combined with hemorrhage control concepts. Mechanical stabilization is performed non-invasively by pelvic binder application or invasively by classical anterior pelvic fixation or posterior pelvic C-clamp, depending on the local available resources. In patients "in extremis" the concept of direct extraperitoneal pelvic packing is recommended, whereas in moderately unstable patients or in patients where persistant hemodynamic instability occurs despite shock therapy and mechanical stabilization and pelvic packing, arterial injury is ruled out by angiography followed by selected embolization of pelvic vessels. PMID- 22840951 TI - Current concepts review - fractures in the region of the elbow. AB - Elbow injuries continue to rise with increased athletic activity and life expectancy. Knowledge of anatomy and biomechanics of this sophisticated joint, various injury patterns, and the implication of injury to the static and dynamic stabilizers will result in improvement in specific diagnosis, and therapy. The surgical treatment of trauma to the adult elbow has evolved rapidly in recent years and many useful concepts and techniques have been established. This paper reviews the published scientific data and current opinion available to guide patient care. PMID- 22840952 TI - [Current knowledge on the effect of technology and sterilization on the structure, properties and longevity of UHMWPE in total joint replacement]. AB - Ultrahigh molecular weight polyethylene (UHMWPE) is the most frequently used bearing surface in currently used total joint replacements (TJR). According to the literature available, UHMWPE is the best polymer material, in terms of biocompatibility, mechanical properties and wear resistance, for this application. In spite of this fact, UHMWPE wear (i.e., release of microscopic particles from the polymer surface) remains one of the main reasons of TJR failures. Consequently, the wear of UHMWPE is a subject of intensive study by both materials scientists and orthopaedic surgeons. The structure and properties of UHMWPE strongly depend on the way of processing and post-processing modifications. The processing includes polymer resin preparation (microparticles about 100 em in size) and resin consolidation (forming bulk material). Post processing modifications aim at increasing wear resistance and oxidation stability which are regarded as major factors involved in TJR failure. In order to maintain high purity materials for medical application, it is not allowed to use additional chemicals during the modification processes. The only exception is the use of vitamin E, a natural stabilizer and antioxidant. Considering all the above mentioned facts, the modifications can be based on (I) ionizing radiation such as gamma rays or accelerated electrons, (II) thermal modification, (III) additional stabilization with vitamin E, and (IV) sterilization. According to the modifications, we usually differentiate three generations of UHMWPE. The 1st generation UHMWPE is not modified except for obligatory sterilization. The sterilization procedures based on chemical procedures (formaldehyde vapours, hot water) have lately been forbidden, abandoned and replaced by gamma-irradiation with doses of 25-45 kGy. In the course of time, sterilization by means of gamma irradiation showed to be unsuitable due to oxidative degradation of UHMWPE, which resulted in lower wear resistance, worse material properties and a decrease in longevity of joint replacements. The 2nd generation UHMWPE or highly cross-linked UHMWPE is material treated with ionizing radiation (gamma-rays or accelerated electrons) at higher doses (usually 50-100 kGy). The irradiation is followed by thermal treatment in order to eliminate residual radicals and limit oxidative degradation that occurs in the 1st generation UHMWPE types. Finally, the material is sterilized usually by modern procedures using ethylene oxide or gas plasma neither of which causes oxidative degradation (as opposed to gamma-irradiation sterilization). The 3rd generation UHMWPE is basically the same as that of the 2nd generation. The main difference consists in slightly better mechanical properties (strength, fatigue) and further stabilization to oxidative degradation. This is achieved by special procedures, some of which are either controversial (sequential irradiation) or well-accepted by a great majority of the orthopaedic community (vitamin E stabilization). Only the future will show whether the difference between the 2nd and 3rd generations of UHMWPE will play any role in increasing TJR longevity and therefore the quality of its performance. The final objective of all of UHMWPE modifications is, as already mentioned, to increase wear resistance, oxidative resistance and mechanical performance of the polymer. These changes, especially an increase in wear resistance, have been confirmed to prolong the longevity of total joint replacements based on UHMWPE. PMID- 22840953 TI - [Release of the lateral structures of the first metatarsophalangeal joint during hallux valgus surgery]. AB - PURPOSE OF THE STUDY: Operations of hallux valgus deformity are very well known in orthopaedic surgery. The important part of these procedures is the release of soft tissue on the lateral side of the first metatarsophalangeal joint. Soft tissue procedures became routinely used in the 1920s and 1930s and several techniques of soft tissue release have been published in the past seventy years. We found several inaccuracies between the anatomy published and the routine clinical performance. The purpose of the study was to describe the anatomy of the first metatarsophalangeal joint's lateral part, especially the adductor hallucis muscle attachment, and to assess to what extent the lateral structures of the first metatarsophalangeal joint should be released to correct hallux valgus deformity. MATERIAL: We described and compared the anatomy of the lateral part of the first metatarsophalangeal joint on 30 dissected specimens obtained from cadavers that met the criteria of hallux valgus deformity. METHODS: The standard preparation method was used for anatomical dissection; whole leg specimens including the pelvic girdle were fixed in formaldehyde, acetone, ethyl-alcohol and glycerol. The detailed course and shape of the adductor muscle attachment was described as well as its relation to the lateral sesamoid bone, lateral portion of the flexor hallucis brevis and the transverse metatarsal ligament. Dissection of the joint's lateral capsule was used to show the course of the lateral collateral ligament, sesamoid ligament and conjoined tendon of the adductor hallucis and flexor hallucis brevis muscles. Subsequently, we released the lateral sesamoid ligament with a standard longitudinal cut and then released the conjoined tendon and lateral collateral ligament at the level of the joint gap in the frontal plane. We evaluated the proposed technique in terms of the extent of soft tissue release and the size of tenotomy necessary to correct the deformity. RESULTS: The mean valgus deformity was 32 degrees (range, 18 degrees to 50 degrees ). We were not able to define space between the medial border of the adductor hallucis and the flexor hallucis brevis in 23 cases (77%). The mean size of release was 6.4 mm (range, 5 to 15 mm) and the width of a conjoined tendon at the level of release was 11.2 mm (range, 8 to 15 mm). We did not achieve satisfactory release with our technique in two cases (7%, deviation 45 degrees and 50 degrees ). DISCUSSION: We compared our results with those of similar anatomical studies. We found several inaccuracies in anatomical descriptions of the adductor hallucis attachment. We confirmed the difficulty in separation of the adductor hallucis from the lateral head of the flexor hallucis brevis in total tenotomy of the adductor. Our technique was successful in releasing the first metatarsophalangeal joint's lateral structures. CONCLUSIONS: Our study showed than even partial tenotomy of the conjoined tendon of the adductor hallucis and flexor hallucis brevis muscles is successful in correcting hallux valgus deformity. The release has to be combined with release of the lateral sesamoid ligament. PMID- 22840954 TI - [Arthroscopically-assisted osteosynthesis of calcaneal fractures: clinical and radiographic results of a prospective study]. AB - PURPOSE OF THE STUDY: The aim of this prospective study was to evaluate the clinical and radiographic results in a group of patients with calcaneal fractures treated by means of minimally invasive, arthroscopically-assited osteosynthesis. MATERIAL AND METHODS: A total of 175 calcaneal fractures in 154 patients were treated surgically at the Trauma Centre of Masaryk Hospital between January 2006 and August 2010. Twenty-six patients were enrolled in this prospective study. They had a total of 30 calcaneal fractures, of which 28 were managed by minimally invasive, arthroscopically-assisted osteosynthesis. The patient's records included demographic data, relevant medical history, fracture type by Sander's classification, associated injuries, time to surgery, length of surgery, post operative quality of reduction, Bohler's angle before and after surgery, healing complications, hospitalisation time, follow-up period, bone union, functional outcome in Rowe score and hardware removal. The patients underwent minimally invasive osteosynthesis under arthroscopic and radiographic guidance. For this procedure, patients with Sanders type IIa and IIb fractures were predominantly indicated. The group also included patients older than 60 years, smokers, patients addicted to alcohol, a diabetic patient, a dialysed patient and a patient with chronic lower-limb lymphoedema. RESULTS: The patient group included 21 men with 25 fractures (83.5%) and five women with five fractures (16.5%). Nine men (42.9%) were heavy smokers; three men (14.3%) and one woman (20 %) were addicted to alcohol. All fractures were closed and, according to the Sanders system, were classified as follows: 16 fractures as type IIa (57.1%); eight fractures as IIb (28.6%); two fractures as IIIab (7.1%) and one IIIac and IIIbc (3.6% respectively). Six patients (23.1%) sustained bilateral fractures of the lower-limb. In the post-operative period, no disturbance of soft tissue healing and no superficial or deep wound infection were observed. The outcome of fracture reduction assessed by CT examination was excellent in 24 fractures (85.6%), satisfactory in one (3.6%) and poor in one fracture (3.6%). The mean Bohler's angle was +7.2 degrees pre-operatively and +35.4 degrees post-operatively. In all patients bone union was achieved within 3 months; hardware was removed in 19 fractures (67.9%). Functional outcomes according to the Rowe score were very good in 18 (69.2%), good in four (15.4%) and satisfactory in four (15.4%) patients. There were no poor results. The mean Rowe score for the whole patient group was 86 points. DISCUSSION: The demographic data are in agreement with the recent literature data. However, most studies have not included smokers and people addicted to alcohol, therefore, no comparison can be made. The comparison with studies on ORIF-treated fractures is also difficult, because our study included a higher number of less severe fracture types. The surgical technique is demanding and was, at the beginning, associated with intra-operative errors. The post operative values of Bohler's angle are comparable to the results of ORIF techniques, but this does not mean that this technique could substitute the use of ORIF in complex fractures. The absence of any soft- or bone-tissue healing problems is a very good result, considering the number of risk factors in our patient group. The good functional outcomes according to the Rowe score can be attributed to a higher proportion of less complex fractures in the group. CONCLUSIONS: In our group of patients with predominantly less severe types of calcaneal fractures, the quality of post-operative fracture reduction, as a result of minimally invasive, arthroscopically-assisted osteosynthesis, appeared to be comparable with open techniques. The observed complete bone healing and absence of soft-tissue problems could present a surgical option to treatment nihilism in patients contraindicated for ORIF techniques. PMID- 22840955 TI - [Timing of surgical intervention in acute spinal cord injury and post-operative neurological recovery]. AB - PURPOSE OF THE STUDY: The effect of an early surgical intervention in the traumatised spine on resolution of neurological deficit still remains a topic of professional discussions. The aim of this retrospective study was to find a correlation between the length of an injury-to-surgery interval and the development of a post-operative neurological deficit, and thus to answer the question of whether early surgical decompression and stabilization gives better chance of neurological recovery. MATERIAL AND METHODS: Medical records of consecutive surgical patients admitted between 2007 and 2010 with traumatic spinal cord injury were reviewed and the injury-to-surgery interval and post operative development of neurological deficit at a minimum follow-up of 6 months was evaluated. The initial neurological finding and the finding at 6 months of follow-up were classified on the Frankel scale and the outcome was assessed as improved or unimproved. The patients were allocated to four subgroups according to the time that elapsed between injury and surgery, i.e., time up to 24 h, 24-72 h, 72 h -1 week, and longer than 1 week. The percentage of improved patients was calculated in each subgroup and the results were statistically evaluated using the Kruskal-Wallis test at a significance level of 0.1. RESULTS: Out of the total number of 32 evaluated patients, 28 had at least partial neurological recovery. In the subgroup treated within first 24 h, improvement was found in 93 % of the patients, in the 24-72 h subgroup it was 80%, in the 72 h-1 week subgroup it was 60% and surgery later than a week after injury resulted in improvement in 42% of the patients. Based on statistical evaluation, the time between injury and surgery appeared to be a significant prognostic factor. When a paired comparison of subgroups was made, the only significant difference was found between the subgroup treated within 24 hours of injury and that operated on later than a week after injury. The other paired comparisons failed to show a significant difference due to a small number of patients; however, a tendency to better functional results was observed in all earlier- treated subgroups. DISCUSSION: The authors are aware of few limitations of the study. Its retrospective character, a relatively small number of patients and a single institution setup may limit the interpretation. Despite this fact, the message is clear. Similar studies carried out prospectively at several institutions may, however, provide results with a higher validity. CONCLUSIONS: Patients with traumatic spinal cord injury who undergo early decompression and stabilisation have a higher chance of at least partial neurological recovery. PMID- 22840956 TI - [The results of ulnar nerve decompression in Guyon's canal syndrome]. AB - PURPOSE OF THE STUDY: The aim of the study was to evaluate a group of patients treated for Guyon's canal syndrome with analysis of the cause for and outcome of surgery. MATERIAL AND METHODS: The group comprised 13 patients operated on for compressive neuropathies of the ulnar nerve in the canal of Guyon in the period from 2007 to 2010. The clinical parameters evaluated were the adduction strength of the fifth digit, degree of interosseous primus muscle hypotrophy and degree of hypoesthesia in the area innervated by the ulnar nerve. EMG parameters included motor and sensory nerve conduction through Guyon's canal. Patients' subjective evaluations of the treatment outcomes were also recorded. The results were not compared with a control group. RESULTS: Post-operative improvements in all clinical and EMG parameters were significant (p=0.02-0.003). All but one patient (90%) reported an improved subjective condition after surgery; on the other hand, pre-operative severe impairment of motor nerve conduction highly affected the post-operative motor function. Guyon's canal syndrome accounted for 0.8% of all compressive neuropathies of the upper extremity in our patients. DISCUSSION: Ulnar nerve compression at the wrist is a relatively rare condition amongst the compressive neuropathies of the upper extremity, and literature data concerning this disease are very few. Although many causes of ulnar nerve compression at the wrist have been reported, only one of our patients had ganglion. We conclude that the majority of cases can be diagnosed as a "neuritis" due to chronic microtrauma produced by pressure of a hypertrophic palmar ligament. CONCLUSIONS: Syndrome of Guyon's canal can easily be treated by surgery. As in other compression syndromes, the sooner a surgical decompression is performed, the better outcomes are achieved. PMID- 22840957 TI - [Magnetic resonance imaging in the diagnosis of intra-articular lesions of the knee]. AB - PURPOSE OF THE STUDY: Magnetic resonance imaging (MRI) has the highest sensitivity of all methods for the diagnosis of intra-articular knee injuries. In spite of this, its benefit for the decision-making algorithm is questionable. The aim of this study was to evaluate the real situation in our regional conditions. MATERIAL AND METHODS: The medical records of the patients who underwent knee arthroscopy in 2008 and 2009, and had pre-operative MRI examination, were retrospectively reviewed. The group included 92 patients (46 women and 46 men; average age, 41.7 years) of whom 49 had knee injury in their medical history. RESULTS: In medial meniscus (MM) injuries, the MRI examination had a sensitivity of 0.92 and a specificity of 0.44, and the congruence of MRI and arthroscopic findings was 0.73. In lateral meniscus (LM) tears, the values were 0.70 for sensitivity, 0.81 for specificity and 0.87 for congruence. In injury to the anterior cruciate ligament (ACL), MRI sensitivity was 0.66, specificity was 0.85 and congruence was 0.79. In evaluation of articular chondral lesions, the values were 0.45 for sensitivity, 0.87 for specificity and 0.60 for congruence. DISCUSSION: In our examination of knee structures for MM, LM, ACL and cartilage injuries, the diagnostic value of MRI was lowest for cartilage damage, with sensitivity being only 0.45. This was in agreement with the findings of other authors. Although this fact is known, our arthroscopic findings in patients with no MRI evidence of injury were very high: 22 knees with grade III or grade IV chondral lesions. Therefore, MRI examination is not considered to be sensitive enough to replace arthroscopy in the diagnosis of cartilage injuries. MRI examination is most frequently indicated in suspected meniscal damage. Its sensitivity reported in the literature varies; generally, it is about 0.90 in MM injuries, and about 0.75 in LM lesions, and this is in agreement with our results. However, in view of our previous experience, the high sensitivity of MRI in the diagnosis of MM lesions was an unexpected finding. A detailed statistical analysis showed that its high value was at the expense of a relatively high negative positivity (0.56) and a low predictive value of the positive test (0.65). In LM injuries these values were even worse: in addition to low sensitivity (0.70), the predictive value of the positive test was only 0.50. In the diagnosis of ACL injuries, MRI examination is reported to have a high sensitivity ranging from 0.85 to 0.90. This study showed poorer results; sensitivity was 0.66 and the predictive value of the positive test was 0.62. For injuries in which the orthopaedist is sure about the diagnosis and indicates arthroscopy, it is doubtful to indicate also MRI examination. This should be reserved for clinical presentations that are not clear, for post-operative conditions, serious knee injuries or combined injuries. However, patients with chronic problems and unclear clinical presentations should benefit from MRI examination which can make the diagnosis more accurate and thus reduce the number of arthroscopic procedures done entirely for diagnostic purposes. CONCLUSIONS: There is no consensus regarding the role of MRI in the diagnosis of intra articular lesions of the knee. To a certain extent, its use is related to local conditions. It can be concluded that MRI examination is not currently as important for the diagnosis of knee injuries as expected by both medical and lay communities. PMID- 22840958 TI - [Validation of the DTP-3 system for noninvasive spinal shape measurement by comparison with X-ray examination]. AB - PURPOSE OF THE STUDY: Repeated measurements of the spine are absolutely necessary in children and adolescents affected by spinal deformities especially during their growing-up periods. To avoid risks of tissue damage from x-ray exposure, several methods for non-invasive measurement of the spinal curvature have been developed. One of them is the DTP-3 position system allowing for a three dimensional measurement of anatomical landmarks (spinous processes) and the calculation of curvature angles in both the frontal and sagittal planes. We were interested to know whether the DTP-3 was precise enough to determine the true spinal curvature. MATERIAL AND METHODS: To determine the precision of the DTP-3 system, we constructed a model of the spine. The model was then repeatedly investigated by both the noninvasive and x-ray methods. The distortion of x-ray images caused by the central projection mechanism was considered and included in the calculation. In addition, a group of patients with scoliosis up to 40 degrees was evaluated by both the DTP-3 system and x-ray (the latter according to Cobb's method). RESULTS: Differences in spatial coordinates between DTP-3 and x-ray examinations reached 20.9 mm in the frontal plane and 67.3 mm in the sagittal plane without distortion correction of x-ray images. The differences decreased below 1.5 mm after image distortion correction in each plane. Distortion correction had not the same effect for angle parameters as for coordinates. Differences between the DTP-3 angle parameters and Cobb's x-ray angles were below 4.7 degrees , both without correction and after correction. The difference between DTP-3 angle parameters and Cobb's x-ray angles was -1.8 degrees +/- 3.0 degrees (mean +/- standard deviation) when measurement was performed on the patients with scoliosis. DISCUSSION: The goal of any clinical examination is to obtain data applicable to decision-making analysis. In the case of scoliosis it is necessary to report results in terms of Cobb's angle, which is the problem for all surface-dependent methods, especially in patients with double curves. A solution may be to define the maximal difference between noninvasive and x-ray methods that could be acceptable for good clinical practice. CONCLUSIONS: In this study we report good concordance between noninvasive and x-ray examinations of a modeled spinal deformity in terms of both angle and linear measurements. The same results were obtained for angle measurements in a group of patients with scoliosis up to 40 degrees . Based on this study and our previous data we believe that the DTP-3 system can be introduced into clinical practice. PMID- 22840959 TI - [Micturition, sexual and defecation disorders in middle-aged women after pelvic fractures. A comparative study]. AB - PURPOSE OF THE STUDY: To present the results of a three-year study on micturition, defecation, gynecological and sexual disorders in middle-aged women who sustained pelvic fractures. MATERIAL AND METHODS: A group of 33 female patients who were treated for unstable pelvic fractures (AO types B or C) in the 2004-2009 period were evaluated (treated group) and compared with 31 women who had given vaginal birth at least once and went to see a urologist because of urinary problems in the period from 2009 to 2010 (control group). The questionnaires used in the study included ICIQ, UIQ, UDI and PISQ12 instruments. Urodynamic tests included flow cystometry, urethral pressure profile at rest and under stress and uroflowmetry. For a comparison of continuous variables of normal distribution, the t-test for independent samples was used. In the questionnaire study when responses were classified as nominal-ordinal variables, the Mann Whitney U-test was used. Differences between the two patient groups in qualitative variables were tested by Pearson s 2 test. When the expected number of answers in contingency table was lower than 5, Fisher s exact test was used; when the number of answers was 0, Haldane s correction was employed. The results in all tests were considered significant when the level of significance was lower than 5%, i.e. p-value < 0.05. RESULTS: The age of patients in the treated group ranged from 17 to 55 years (average, 32 years), the age in the control group was between 30 and 78 years (average, 58 years). The difference was significant (p<0.001). The control group patients had significantly more serious urination disorders than the treated group patients. Some micturition problems were reported by 25 patients (75%) of the treated group and by all patients of the control group (p<0.001). Intestinal disorders were more frequent in the treated group, in which 19 (61%) patients reported problems as against seven (21%) in the control group. Gynaecological problems involving feelings of genital prolapse had 13 (39%) control patients (p = 0.041). Sexual disorders were markedly worse in the treated group, with 16 (52%) of the patients having problems in comparison with only seven (21%) in the control group. DISCUSSION: A comparison of patient groups composed using the method described here is disputable. The first difficulty lay with a low compliance of the treated patients, of whom only 33 underwent examination out of 52 originally enrolled. The other problem was the necessity of having an exactly defined control group of patients willing to undergo urological and gynaecological examination including urodynamic testing. The groups composed by our method were comparable only in the micturition disorder characteristic. A significantly higher age of the control group affected the comparison of defecation, gynaecological and sexual problems. CONCLUSIONS: The results of this study showed a high occurrence of micturition, defecation and sexual disorders in middle-aged women after pelvic injury. However, the problems are usually not serious enough to make the patients seek help of a specialist. The authors recommend that these problems should be looked for by disorder directed inquiry in the final period of pelvic fracture treatment and help of a specialist in urology, gynaecology, sexuology or proctology should be offered to the patients in whom disorders have been identified. Key words: urinary incontinence, voiding dysfunction, stool incontinence, obstipation, unstable pelvic fracture. PMID- 22840960 TI - [Epidemiological, morphological and clinical aspects of ankle fractures]. AB - PURPOSE OF THE STUDY: The study presents the evaluation and comparison of two groups of patients surgically treated for ankle fractures at our department in 2007 and in 2010, respectively. Our analysis included patients' age, the mechanism of injury, fracture morphology and the method of osteosynthesis. The aim of the comparison was to ascertain recent trends in the development of the selected characteristics. MATERIAL AND METHODS: The 2007 group comprised 62 patients, 31 men and 32 women, the 2010 group had 123 patients, 55 men and 68 women. The ankle fractures were classified according to the Weber and Lauge Hansen systems. The selected characteristics were analysed in each group and the results were compared to obtain information on changes during the interval of 4 years. The data were evaluated using the methods of descriptive statistics; categorical data were analysed by the chi-square test with the level of significance set at 5%. RESULTS: The average age was 44 years in men and 59 in women in the 2007 group and 40 years in men and 56 in women in the 2010 group; in the whole patient group, the average age decreased from 52 years in 2007 to 47 years in 2010. Based on the Weber classification, the incidence of fractures in 2007 and 2010 was as follows; type A, 5% in both years; type B, 68% and 72%; type C, 27% and 23%. There was no significant difference between the groups in the incidence of either type B or type C fractures (p = 0.823 and p = 0.659, respectively). The majority of fractures were caused by low-energy mechanisms. High-energy injuries due to falls from a height or traffic accidents did not exceed 6 %. In men, who sustained sports-related injury more often, fractures were found in 23% and 16% in 2007 and 2010, respectively; this difference approached statistical significance (p = 0.050). Most of the fibular fractures were managed by plate osteosynthesis, often in combination with lag screws. Medial malleolar fractures were usually fixed with two cancellous screws, or with a screw and a K-wire. The number of surgical inspections of the medial structures of an injured ankle with no medial malleolar fracture decreased from 68% in 2007 to 37% in 2010. Osteosynthesis of a fractured posterior margin of the distal tibia was carried out in 7% of the patients in 2007 and in 23% in 2010. DISCUSSION: The morphological and epidemiological characteristics described were selected to obtain a comprehensive notion of the patients studied. Only the patients who had surgery were included. An increase in the number of ankle fractures managed surgically during a four-year period of our study was due to a growing number of patients and the fact that surgery was indicated more frequently because stricter criteria for assessment of post-reduction findings or secondary displacement were adopted. In surgical treatment, the recent trend preferring primary osteosynthesis to transfixation or external fixation has been evident because it allows for early rehabilitation and return to normal activities. CONCLUSIONS: The number of ankle fractures treated by primary osteosynthesis grew between 2007 and 2010. There was also an increase in the number of fractured posterior margins of the distal tibia managed by osteosynthesis. The results of the Weber and Lauge-Hansen classifications were in agreement with the relevant literature data. In the majority of cases the ankle fracture occurred as a single trauma. PMID- 22840961 TI - Osteoid osteoma of the femoral neck mimicking monarthritis and causing femoroacetabular impingement. AB - Different aetiologies including the femoroacetabular impingement (FAI) may cause a painful hip, especially in young pa - tients. Two general types of femoroacetabular impingement have been described, the pincer- and the cam type impingement. The latter is characterized by a femoral deformity, usually a bump on the head-and-neck junction that impinges on the acetabular rim. The authors describe the case of a 21-year-old male, bodybuilder, suffering from progressive hip pain with impairment of exercise tolerance, gait and other daily activities. Besides limitation of hip internal rotation physical examination was normal. He had a transitory response to non-steroid anti-inflammatory drugs. Initially performed MRI of the pelvis shows predominant inflammation of the hip joint. In external performed arthroscopy the biopsies of the capsule demonstrated chronic synovitis. In the follow up hip pain remains, however, diagnosis was still unclear. Re-evaluation of the formerly performed and a follow up MRI, and of an additional CT, the findings were compatible with an osteoid osteoma in the femoral cervico-cephalic transition causing itself a cam impingement and monarthritis. The adopted therapeutic strategy consisted on arthroscopic excision of the nidus and trimming of the femoral neck, with clinical recovery after surgical intervention. PMID- 22840962 TI - [Inveterate dislocation fracture of the sternoclavicular joint]. AB - We present the case report of a 21-year-old man with a late diagnosis of retrosternal dislocation of the sternoclavicular joint with a fractured sternal end of the clavicle. The first symptom leading to the diagnosis was dysphagia associated with physical activity. The diagnosis was based on computed tomography examination. In the first place, the fragment of the medial clavicular end was fixed with two screws. During surgery the sternoclavicular joint was wrongly identified; this fact was revealed by the following radiographic examination. On revision surgery, the sternoclaviculr ligament was reconstructed using a semitendinosus tendon graft. The reconstructed ligament was augmented with two Orthocord sutures running between the clavicle and the first rib. At 2 years after surgery the functional outcome and sternoclavicular joint stability were excellent. PMID- 22840963 TI - Finite mixture regression model analysis on antipsychotics induced weight gain: investigation of the role of the serotonergic genes. AB - Antipsychotics-induced weight gain is a complex phenomenon with a relevant underlying genetic basis. Polymorphisms of serotonin receptors and related proteins were genotyped in 139 schizophrenia patients and incorporated as covariates in a mixture regression model of weight gain in combination with clinical covariates. The HTR1D rs6300 polymorphism was showing a slight significance conferring risk for obesity (heavy weight gain group) under additive model. After correcting for multiple testing all the genetic predictors were non significant, however the clinical predictors were associated with the risk of heavy weight gain. These findings suggest a role of ethnicity and olanzapine in increasing the risk for obesity in the heavy weight gain group and haloperidol protecting against heavy weight gain. The mixture regression model appears to be a useful strategy to highlight different weight gain subgroups that are affected differently by clinical and genetic predictors. PMID- 22840964 TI - New variants of porcine epidemic diarrhea virus, China, 2011. AB - In 2011, porcine epidemic diarrhea virus (PEDV) infection rates rose substantially in vaccinated swine herds. To determine the distribution profile of PEDV outbreak strains, we sequenced the full-length spike gene from samples from 9 farms where animals exhibited severe diarrhea and mortality rates were high. Three new PEDV variants were identified. PMID- 22840965 TI - Significance of seizure in cerebral venous sinus thrombosis. AB - PURPOSE: To report the frequency and predictors of presenting seizures in cerebral venous sinus thrombosis (CVST) and their influence on seizure recurrence and outcome. METHODS: This retrospective study, between 1995 and 2011, included 90 consecutive patients with CVST diagnosed using magnetic resonance imaging (MRI) and magnetic resonance venography (MRV). Clinical parameters like frequency, type (presenting, early, and late), and duration of seizures, precipitating causes of CVST, and underlying prothrombotic conditions, were recorded. The location of infarction on MRI and the number of sinuses involved on MRV, were noted. The patients were prescribed anticoagulants, and those with seizures were prescribed antiepileptic drugs. The patients were followed up at 3, 6, and 12 months. The functional outcome at 6 months was categorized into death, poor, partial and complete recovery. RESULTS: A total of 42 patients with CVST presented with seizures (focal 11, focal with secondary generalized 19, and generalized tonic clonic 16), of whom 10 had status epilepticus. On univariate analysis, supratentorial lesion (P=0.005), frontal (P=0.02) or parietal lobe (P=0.04) involvement and haemorrhagic lesion (P=0.002) were associated with higher risk of presenting seizure. On multivariate analysis, only supratentorial parenchymal lesion on MRI (odds ratio [OR]=4.67, 95% confidence interval [CI] 1.51-15.08, P=0.005) was independently associated with higher risk of presenting seizure. Only 4 patients had early seizures and none had late seizures. At 6 months, 10 patients died and 73 patients had complete recovery. Seizures were not associated with death (P=1.00) and 6-month functional outcome (P=0.66). CONCLUSION: About half the patients with CVST had presenting seizures which was independently related to supratentorial lesion. However, seizures were not related to death or 6-month outcome. PMID- 22840966 TI - Guards of the great wall: bacterial lysozyme inhibitors. AB - Peptidoglycan is the major structural component of the bacterial cell wall. It provides resistance against turgor and its cleavage by hydrolases such as lysozymes results in bacteriolysis. Most, if not all, animals produce lysozymes as key effectors of their innate immune system. Recently, highly specific bacterial proteinaceous lysozyme inhibitors against the three major animal lysozyme families have been discovered in bacteria, and these may represent a bacterial answer to animal lysozymes. Here, we will review their properties and phylogenetic distribution, present their structure and molecular interaction mechanism with lysozyme, and discuss their possible biological functions and potential applications. PMID- 22840967 TI - A case of bilateral ureteric obstruction in an allogeneic stem cell transplant recipient. PMID- 22840968 TI - Come fly with me: review of clinically important arboviruses for global travelers. AB - Western tourists are increasingly traveling to exotic locations often located in tropical or subtropical regions of the world. The magnitude of international travel and the constantly changing dynamics of arbovirus diseases across the globe demand up-to-date information about arbovirus threats to travelers and the countries they visit. In this review, the current knowledge on arbovirus threats to global travelers is summarized and prioritized per region. Based on most common clinical syndromes, currently known arboviruses can be grouped to develop diagnostic algorithms to support decision-making in diagnostics. This review systematically combines and structures the current knowledge on medically important travel-related arboviruses and illustrates the necessity of a detailed patient history (travel history, symptoms experienced, vaccination history, engaged activities, tick or mosquito bite and use of repellent and onset of symptoms), to guide the diagnosis. PMID- 22840969 TI - VIM-2-producing multidrug-resistant Pseudomonas aeruginosa ST175 clone, Spain. AB - A total of 183 patients were colonized or infected with multidrug-resistant Pseudomonas aeruginosa isolates at a hospital in Spain during 2007-2010; prevalence increased over this period from 2.8% to 15.3%. To characterize these isolates, we performed molecular epidemiologic and drug resistance analysis. Genotyping showed that 104 (56.8%) isolates belonged to a single major clone (clone B), which was identified by multilocus sequence typing as sequence type (ST) 175. This clone was initially isolated from 5 patients in 2008, and then isolated from 23 patients in 2009 and 76 patients in 2010. PCR analysis of clone B isolates identified the bla(VIM-2) gene in all but 1 isolate, which harbored bla(IMP-22). ST175 isolates were susceptible to only amikacin (75%) and colistin (100%). Emergence of the ST175 clone represents a major health problem because it compromises therapy for treatment of P. aeruginosa nosocomial infections. PMID- 22840970 TI - Genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway as potential risk factors of menopausal hot flashes. AB - OBJECTIVE: We sought to determine if genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway are associated with menopausal hot flashes via hormone levels. STUDY DESIGN: Women (n = 639) aged 45-54 years completed a study survey and provided blood for genetic and hormone analyses. The associations were analyzed using multivariable logistic regression and generalized linear models. RESULTS: Women carrying CYP1B1 (rs1800440) GG genotype had 3-fold greater odds of experiencing hot flashes for >=1 year compared to the AA genotype (adjusted odds ratio [OR], 3.05; 95% confidence interval [CI], 1.12 8.25). Adding serum estradiol concentrations to the confounder-adjusted model resulted in a nonsignificant association (adjusted OR, 2.59; 95% CI, 0.91-7.18). Carriers of both CYP1B1 (rs1800440) G and CYP1B1 (rs1058636) G alleles had higher odds of experiencing hot flashes for >=1 year compared to women homozygous for the major alleles (adjusted OR, 1.77; 95% CI, 1.06-2.96), even after adjustment for serum estradiol. CONCLUSION: CYP1B1 is associated with menopausal hot flashes via pathways that may involve changes in serum estradiol concentration. PMID- 22840971 TI - Improved climate, culture, and communication through multidisciplinary training and instruction. AB - OBJECTIVE: The objective of the study was to determine the effectiveness of multidisciplinary team training on organizational culture and team communication. STUDY DESIGN: The training included a 6-step protocol: (1) a pretest survey assessing cultural attitudes and perceptions, (2) a baseline high-fidelity simulation session, (3) invitational medical rhetoric instruction, (4) a second high-fidelity simulation session, (5) a posttest survey assessing changed cultural attitudes and perceptions, and (6) a debriefing with participants. Teams of 4 physicians trained together: 2 obstetricians and 2 anesthesiologists. Forty four physicians completed the training protocol during 2010 and 2011. RESULTS: Paired-sample t tests demonstrated significant decreases in autonomous cultural attitudes and perceptions (t = 8.23, P < .001) and significant increases in teamwork cultural attitudes and perceptions (t = -4.05, P < .001). Paired-sample t tests also demonstrated significant increases in communication climate that invited participation and integrated information from both medical services (t = 5.80, P < .001). CONCLUSION: The multidisciplinary team training program specified in this report resulted in increased teamwork among obstetricians and anesthesiologists. PMID- 22840972 TI - Gestational diabetes screening with the new IADPSG guidelines: a cost effectiveness analysis. AB - OBJECTIVE: This study investigates the cost effectiveness of gestational diabetes mellitus screening using the new International Association of Diabetes in Pregnancy Study Group (IADPSG) guidelines. STUDY DESIGN: A decision analytic model was built comparing routine screening with the 2-hour (2h) oral glucose tolerance test (OGTT) vs the 1-hour glucose challenge test. All probabilities, costs, and benefits were derived from the literature. Base case, sensitivity analyses, and a Monte Carlo simulation were performed. RESULTS: Screening with the 2h OGTT was more expensive, more effective, and cost effective at $61,503/quality-adjusted life year. In a 1-way sensitivity analysis, the more inclusive IADPSG diagnostic approach remained cost effective as long as an additional 2.0% or more of patients were diagnosed and treated for gestational diabetes mellitus. CONCLUSION: Screening at 24-28 weeks' gestational age under the new IADPSG guidelines with the 2h OGTT is expensive but cost effective in improving maternal and neonatal outcomes. How the health care system will provide expanded care to this group of women will need to be examined. PMID- 22840974 TI - Does the presence of adenomyosis and lymphovascular space invasion affect lymph node status in patients with endometrioid adenocarcinoma of the endometrium? AB - OBJECTIVE: We sought to determine the prevalence of adenomyosis and assess its effect on lymph node status in endometrioid adenocarcinoma of the endometrium (EAC). STUDY DESIGN: Hysterectomy specimens from a single institution were reviewed for the presence of adenomyosis, lymphovascular space invasion (LVSI), tumor grade, histology, and lymph node status. Standard statistical analysis was used to compare variables. RESULTS: Adenomyosis was present in 42% of total and 66% of malignant hysterectomy specimens (P = .009). Adenomyosis was most commonly associated with EAC histology (P = .023). LVSI was found to be an independent predictor of lymph node metastasis in EAC patients without adenomyosis, but not in those with coexisting adenomyosis (odds ratio, 58.7; P = .03; and odds ratio, 4.98; P = .15; respectively). CONCLUSION: Adenomyosis was associated with a lower risk of lymph node metastasis in EAC patients with LVSI. Further studies are needed to investigate the role of adenomyosis in lymphatic tumor infiltration. PMID- 22840973 TI - Effects of antenatal corticosteroids on the hypothalamic-pituitary-adrenocortical axis of the fetus and newborn: experimental findings and clinical considerations. AB - The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine pathway that modulates the stress response. The glucocorticoid, cortisol, is the principal end product of the HPA axis in humans and plays a fundamental role in maintaining homeostasis and in fetal maturation and development. Antenatal administration of synthetic glucocorticoids (GCs) accelerates fetal lung maturation and has significantly decreased neonatal mortality and morbidity in infants born before 34 weeks of gestation. Exposure to excess levels of endogenous GCs and exogenous GCs (betamethasone and dexamethasone) has been shown to alter the normal development trajectory. The development and regulation of the fetal HPA axis is discussed and the experimental animal evidence presented suggests long-term adverse consequences of altered HPA function. The clinical data in infants exposed to GCs also suggest altered HPA axis function over the short term. The longer-term consequences of antenatal GC exposure on HPA axis function and subtler neurodevelopmental outcomes including adaptation to stress, cognition, behavior, and the cardiovascular and immune responses are poorly understood. Emerging clinical strategies and interventions may help in the selection of mothers at risk for preterm delivery who would benefit from existing or future formulations of antenatal GCs with a reduction in the associated risk to the fetus and newborn. Detailed longitudinal long-term follow-up of those infants exposed to synthetic GCs are needed. PMID- 22840976 TI - Fathers' knowledge about and attitudes towards breast feeding in Manisa, Turkey. AB - OBJECTIVE: to determine the extent of knowledge fathers of newborns have about breast feeding and lactation and to examine their attitudes regarding breast feeding. DESIGN: a descriptive, cross-sectional study. SETTING: Manisa Maternity and Children's Hospital. PARTICIPANTS: 203 fathers of newborn infants. FINDINGS: although a wide majority of the participants (92.1%) expressed a desire to have their infants breastfed, it was found that only 58.6% discussed this with their partners. It was discovered that 88.7% of the fathers were happy to help with the housework so that their wives could breast feed while 57.6% stated that breast feeding would be psychologically beneficial to both the mother and the baby. Approximately half of the study subjects (48.8%) expressed an interest in attending an educational programme on breast feeding for fathers. The study also showed that the fathers' level of education, the type of family they were a part of and previously received education on lactation and breast feeding had an effect on their knowledge and attitudes toward breast feeding (p<0.05). CONCLUSION: it was seen that fathers were eager to have their infants breastfed but unable to adequately share such thoughts with their wives. It was also observed that their knowledge about breast feeding and lactation was limited, leading to the conclusion that fathers may benefit from a supportive educational programme on breast feeding. PMID- 22840977 TI - A criterion for assessing homogeneity distribution in hyperspectral images. Part 2: application of homogeneity indices to solid pharmaceutical dosage forms. AB - This article is the second of a series of two articles detailing the application of mixing index to assess homogeneity distribution in oral pharmaceutical solid dosage forms by image analysis. Chemical imaging (CI) is an emerging technique integrating conventional imaging and spectroscopic techniques with a view to obtaining spatial and spectral information from a sample. Near infrared chemical imaging (NIR-CI) has proved an excellent analytical tool for extracting high quality information from sample surfaces. The primary objective of this second part was to demonstrate that the approach developed in the first part could be successfully applied to near infrared hyperspectral images of oral pharmaceutical solid dosage forms such as coated, uncoated and effervescent tablets, as well as to powder blends. To this end, we assessed a new criterion for establishing mixing homogeneity by using four different methods based on a three-dimensional (M*N*lambda) data array of hyperspectral images (spectral standard deviations and correlation coefficients) or a two-dimensional (M*N) data array (concentration maps and binary images). The four methods were used applying macropixel analysis to the Poole (M(P)) and homogeneity (H%(Poole)) indices. Both indices proved useful for assessing the degree of homogeneity of pharmaceutical samples. The results testify that the proposed approach can be effectively used in the pharmaceutical industry, in the finished products (e.g., tablets) and in mixing unit operations for example, as a process analytical technology tool for the blending monitoring (see part 1). PMID- 22840978 TI - Effect of laser irradiation on the stability of a photo-sensitive active pharmaceutical ingredient by Raman microscopy. AB - This study was conducted to investigate the effect of laser beam irradiation from a novel non-confocal laser Raman microscope on the stability of a photo-sensitive drug. The non-confocal Raman microscopy, which irradiates a low-power unfocused laser beam on the surface of the samples by controlling of optical system, was applied to characterize the stability of nifedipine as a photo-sensitive drug model. The time-dependent changes in the Raman spectra of nifedipine were monitored in order to evaluate the degradation of nifedipine during laser irradiation. The results were compared with the Raman spectra measured by using the confocal laser Raman microscopy which irradiates a low-power focused laser beam. The intensity of some peaks in the confocal Raman spectra significantly decreased depending on the irradiation-time length, compared to the non-confocal Raman macroscopic analysis. The photodegradation of nifedipine caused by the laser irradiation followed the first-order kinetics. The degradation rate constants of nifedipine with the non-confocal analysis were lower than those of nifedipine with the confocal analysis. Thus, the novel non-confocal laser Raman microscopy can be applied to reduce the degradation of the photo-sensitive drug during laser irradiation, and the results suggest that the non-confocal laser Raman microscopy will be a useful technique for the measuring of Raman spectra of photo-sensitive materials with a long-term exposure. PMID- 22840975 TI - Sexual activity and function in women more than 2 years after midurethral sling placement. AB - OBJECTIVE: The purpose of this study was to assess prospectively the effects of midurethral sling surgery on sexual function and activity. STUDY DESIGN: Sexual activity and function was assessed in 597 women with stress urinary incontinence who were enrolled in a randomized equivalence trial of retropubic compared with transobturator midurethral slings. Repeated measures analysis of variance was used to assess changes in Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire scores over a 2-year period. RESULTS: Significant, similar improvements in sexual function were seen in both midurethral sling groups. Mean Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire scores increased from 32.8 at baseline to 37.6 at 6 months and 37.3 at 24 months (P < .0001). Dyspareunia, incontinence during sex, and fear of incontinence during sex each significantly improved after surgery. Preoperative urge incontinence was associated with abstinence after surgery (P = .02); postoperative urge incontinence negatively impacted sexual function (P = .047). CONCLUSION: Midurethral sling surgery for stress urinary incontinence significantly improves sexual function, although coexistent urge incontinence has a negative impact. PMID- 22840979 TI - Isolation and characterization of propoxyphenyl linked sildenafil and thiosildenafil analogues in health supplements. AB - Two new phosphodiesterase-5 inhibitors (PDE-5) which consist of one sildenafil analogue and one thiosildenafil analogue have been found in heath supplements. The structural properties of these analogues have been elucidated by NMR, high resolution MS, MS(2), UV and IR spectroscopy. The sildenafil analogue is very similar to aildenafil and the thiosildenafil analogue is similar to thioaildenafil, except the ethoxy group bonded to phenyl ring is replaced by a propoxy group. Hence, the sildenafil analogue is named as propoxyphenyl aildenafil or propoxyphenyl methisosildenafil and the thiosildenafil analogue as propoxyphenyl thioaildenafil or propoxyphenyl thiomethisosildenafil. PMID- 22840980 TI - Liquid chromatography tandem mass spectrometry determination of chemical markers and principal component analysis of Vitex agnus-castus L. fruits (Verbenaceae) and derived food supplements. AB - A validated analytical method for the quantitative determination of seven chemical markers occurring in a hydroalcoholic extract of Vitex agnus-castus fruits by liquid chromatography electrospray triple quadrupole tandem mass spectrometry (LC/ESI/(QqQ)MSMS) is reported. To carry out a comparative study, five commercial food supplements corresponding to hydroalcoholic extracts of V. agnus-castus fruits were analysed under the same chromatographic conditions of the crude extract. Principal component analysis (PCA), based only on the variation of the amount of the seven chemical markers, was applied in order to find similarities between the hydroalcoholic extract and the food supplements. A second PCA analysis was carried out considering the whole spectroscopic data deriving from liquid chromatography electrospray linear ion trap mass spectrometry (LC/ESI/(LIT)MS) analysis. High similarity between the two PCA was observed, showing the possibility to select one of these two approaches for future applications in the field of comparative analysis of food supplements and quality control procedures. PMID- 22840981 TI - Precision versus accuracy: a case for common sense. PMID- 22840982 TI - Surgical access warming blanket to prevent hypothermia after hip arthroscopy. PMID- 22840984 TI - The changing role of acromioplasty. PMID- 22840986 TI - American Academy of Orthopaedic Surgeons Rotator Cuff Clinical Practice Guideline. PMID- 22840987 TI - A randomized clinical trial evaluating plasma rich in growth factors (PRGF Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. AB - PURPOSE: This multicenter, double-blind clinical trial evaluated and compared the efficacy and safety of PRGF-Endoret (BTI Biotechnology Institute, Vitoria Gasteiz, Spain), an autologous biological therapy for regenerative purposes, versus hyaluronic acid (HA) as a short-term treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 176 patients with symptomatic knee osteoarthritis to receive infiltrations with PRGF-Endoret or with HA (3 injections on a weekly basis). The primary outcome measure was a 50% decrease in knee pain from baseline to week 24. As secondary outcomes, we also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index; the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety. RESULTS: The mean age of the patients was 59.8 years, and 52% were women. Compared with the rate of response to HA, the rate of response to PRGF-Endoret was 14.1 percentage points higher (95% confidence interval, 0.5 to 27.6; P = .044). Regarding the secondary outcome measures, the rate of response to PRGF-Endoret was higher in all cases, although no significant differences were reached. Adverse events were mild and evenly distributed between the groups. CONCLUSIONS: Plasma rich in growth factors showed superior short-term results when compared with HA in a randomized controlled trial, with a comparable safety profile, in alleviating symptoms of mild to moderate osteoarthritis of the knee. LEVEL OF EVIDENCE: Level I, randomized controlled multicenter trial. PMID- 22840988 TI - The effect of graft tissue on anterior cruciate ligament outcomes: a multicenter, prospective, randomized controlled trial comparing autograft hamstrings with fresh-frozen anterior tibialis allograft. AB - PURPOSE: To compare the results and outcome of anterior cruciate ligament (ACL) reconstruction using autogenous hamstring tendon versus fresh-frozen allograft anterior tibialis tendon. METHODS: A prospective randomized study was conducted from September 2002 to October 2006. We randomized 147 patients to undergo ACL reconstruction with either autogenous hamstring or fresh-frozen allograft anterior tibialis tendon. Of these patients, 102 (69%) completed a minimum of 2 years' follow-up. There were 54 patients in the hamstring group (73% of those originally enrolled in the group) and 48 patients in the allograft group (66%). All patients underwent standardized subjective and objective evaluation with functional outcome assessments (International Knee Documentation Committee [IKDC]), and standardized radiographs were also obtained. RESULTS: The mean age was 32.0 years for the autograft group and 33.3 years for the allograft group. There was no difference in stability between the 2 groups (P > .05). The mean IKDC subjective score was 91.0 for the autograft group and 90.9 for the allograft group (P > .05). The functional IKDC scores for the autograft group were normal in 46 patients (85%), nearly normal in 7 patients (13%), and severely abnormal in 1 patient. For the allograft group, the functional IKDC scores were normal in 43 patients (90%) and nearly normal in 5 (10%) (P > .05). There were 4 reoperations in the allograft group and 3 reoperations in the autograft group. No patient underwent revision ACL surgery or planned to undergo revision surgery because of instability in either group during the study period despite the 1 patient in the autograft group with a pivot shift and a maximum manual KT measurement (MEDmetric, San Diego, CA) of 5 mm. CONCLUSIONS: The use of fresh-frozen anterior tibialis allograft (non-treated) for ACL reconstruction produced similar subjective and functional outcomes at 24 months' minimal follow-up compared with patients undergoing ACL reconstruction with autograft hamstring tendon. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 22840989 TI - Osteochondral allograft transplantation from a living donor. AB - Treatment of extended and massive osteochondral defects is a real challenge for an orthopaedic practice. Osteochondral allograft transplantation is a possible solution for such lesions. Transplantation of osteochondral allografts has undergone extensive experimental and limited clinical study during recent decades. Graft availability, sizing, technical issues, and viral transmission represent the most problematic points. Because interest in this technique is gaining, more and more countries face the problem of a lack of tissue banks where fresh osteochondral allografts are available. We investigated the advantages of the so-called living donor transplantation of the grafts under programmed surgical conditions. We demonstrate a technique that allows the transplantation of osteochondral allografts without the need for a tissue bank. The radiologic and histologic results regarding the quality of the transplanted cartilage are presented. PMID- 22840990 TI - Hip labral cyst caused by psoas impingement. AB - Hip labral impingement can cause labral tears and secondary paralabral cyst formation. Femoroacetabular impingement is the main cause of labral impingement, but other conditions such as iliopsoas tendon impingement are described. There is no description of labral cyst resulting from psoas impingement treated arthroscopically in the literature. We present the case of a young sportsman with groin pain caused by psoas impingement with a labral tear and secondary paralabral cyst who was treated arthroscopically by cyst debridement, psoas tenotomy, and labral repair. PMID- 22840991 TI - Autoantibodies in Sjogren's syndrome: clinical presentation and regulatory mechanisms. AB - Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease mostly affecting the exocrine glands. A large number of autoantibodies have been detected in the serum of patients with pSS. Among them, anti-Ro/SSA and anti La/SSB autoantibodies are the most common; they serve as disease markers and are involved in the pathogenesis of neonatal lupus syndrome (NLS). Other autoantibodies are associated with significant clinical phenotypes, such as cryoglobulins with development of non-Hodgkin's lymphoma, anti-centromere antibodies with Raynaud's phenomenon and anti-mitochondrial antibodies with liver pathology. As a result, pSS patients can be schematically categorized in subgroups according to their serological profile. Although the clinical utility of these autoantibodies is appreciated, little is known about the mechanisms related to their production and the regulation of the autoimmune response. In the present review, the clinical subsets of patients with pSS related to different autoantibodies as well as the regulating mechanisms of their production with special emphasis on idiotypic/anti-idiotypic network are discussed. PMID- 22840992 TI - Central and peripheral neurological complications of primary Sjogren's syndrome. AB - Primary Sjogren's syndrome (pSS) is an autoimmune inflammatory disorder characterized by lymphocytic infiltration of exocrine glands, mainly the lacrimal and salivary glands leading to a chronic sicca syndrome. However, extraglandular organ systems may frequently be involved, including both central and peripheral nervous systems. Clinically significant neurologic manifestations affect approximately 20% of patients and may be the first manifestation of the disease in at least 25% of the cases. The spectrum of pSS-related neuropathies is wide including sensory neuropathies, neuronopathies, sensory-motor neuropathies, mononeuritis multiplex related to vasculitis... Central nervous system involvement is composed by multiple sclerosis-like manifestations including acute and chronic myelopathies and by more diffuse manifestations (cognitive dysfunction, subacute aseptic meningitis, encephalopathy, psychiatric symptoms, chorea, seizures...). The diagnosis and treatment of such pSS-related manifestations must be optimized in order to avoid severe disability. PMID- 22840993 TI - [Paraneoplastic cutaneous leukocytoclastic vasculitis disclosing IgA multiple myeloma]. PMID- 22840994 TI - Do we need new diagnostic criteria for Sjogren's syndrome? AB - Diagnostic and classification criteria for Sjogren's syndrome (SS) continue to evolve as more is learned about SS and about autoimmune diseases in general. Among diagnostic or classification criteria for SS that are in current use, most include various and variable combinations of results from questions about symptoms and objective tests, many of which are not specific to SS. Given the rapid increase of genetic knowledge about other autoimmune diseases and the potential of finding and testing new biological agents to treat SS, selection of patients who have as uniform a disease process as possible becomes an important goal to better understand and treat this prevalent autoimmune disease. Such is the goal and promise of the latest entry into the SS classification criteria field. PMID- 22840995 TI - Two Fe-superoxide dismutase families respond differently to stress and senescence in legumes. AB - Three main families of SODs in plants may be distinguished according to the metal in the active center: CuZnSODs, MnSOD, and FeSOD. CuZnSODs have two sub-families localized either in plant cell cytosol or in plastids, the MnSOD family is essentially restricted to mitochondria, and the FeSOD enzyme family has been typically localized into the plastid. Here, we describe, based on a phylogenetic tree and experimental data, the existence of two FeSOD sub-families: a plastidial localized sub-family that is universal to plants, and a cytosolic localized FeSOD sub-family observed in determinate-forming nodule legumes. Anti-cytosolic FeSOD (cyt_FeSOD) antibodies were employed, together with a novel antibody raised against plastidial FeSOD (p_FeSOD). Stress conditions, such as nitrate excess or drought, markedly increased cyt_FeSOD contents in soybean tissues. Also, cyt_FeSOD content and activity increased with age in both soybean and cowpea plants, while the cyt_CuZnSOD isozyme was predominant during early stages. p_FeSOD in leaves decreased with most of the stresses applied, but this isozyme markedly increased with abscisic acid in roots. The great differences observed for p_FeSOD and cyt_FeSOD contents in response to stress and aging in plant tissues reveal distinct functionality and confirm the existence of two immunologically differentiated FeSOD sub-families. The in-gel FeSOD activity patterns showed a good correlation to cyt_FeSOD contents but not to those of p_FeSOD. This indicates that cyt_FeSOD is the main active FeSOD in soybean and cowpea tissues. The diversity of functions associated with the complexity of FeSOD isoenzymes depending of the location is discussed. PMID- 22840996 TI - Electron paramagnetic resonance (EPR) spectroscopy characterization of wheat grains from plants of different water stress tolerance. AB - Grains of five genotypes of wheat (four Polish and one Finnish), differing in their tolerance to drought stress were chosen for this investigation. Electron paramagnetic resonance spectroscopy allowed observation of transition metal ions (Mn, Fe, Cu) and different types of stable radicals, including semiquinone centers, present in seed coats, as well as several types of carbohydrate radicals found mainly in the inner parts of grains. The content of paramagnetic metal centers was higher in sensitive genotypes (Radunia, Raweta) than in tolerant ones (Parabola, Nawra), whereas the Finnish genotype (Manu) exhibited intermediate amounts. Similarly, the concentrations of both types of radicals, carbohydrates and semiquinone were significantly higher in the grains originating from more sensitive wheat genotypes. The nature of carbohydrate radicals and their concentrations were confronted with the kinds and amounts of sugars found by the biochemical analyses and microscopy observations. It is suggested that some long lived radicals (semiquinone and starch radicals) occurring in grains could be indicators of stress resistance of wheat plants. PMID- 22840997 TI - Ventilatory efficiency in juvenile elite cyclists. AB - OBJECTIVES: Ventilation ( [Formula: see text] ) as a function of CO2 output, and oxygen uptake ( [Formula: see text] ) as a function of [Formula: see text] , define cardio-respiratory efficiency, although few data compare efficiency with maximum oxygen uptake ( [Formula: see text] ), or consider reproducibility. Currently there are no data for trained juveniles. DESIGN: Twenty-five trained juvenile cyclists (mean age 14.7 years), performed maximal exercise testing on two occasions, separated by 16 weeks. METHODS: [Formula: see text] vs. [Formula: see text] slope, oxygen uptake efficiency slope, and [Formula: see text] were measured during cycle ergometer exercise to volitional exhaustion on two occasions, 16 weeks apart. RESULTS: Mean (SD) [Formula: see text] vs. [Formula: see text] slope, oxygen uptake efficiency slope, and [Formula: see text] were 28.14 (3.89), 4.16 (0.73), and 75.4 (8.9) mlkg(-1)min(-1) on visit 1, and 27.92 (4.63), 4.22 (0.76), and 73.6 (9.3) mlkg(-1)min(-1) on visit 2. Good reproducibility (differences <=2.4%), but poor correlations (r<=0.29) between efficiency and [Formula: see text] were recorded. CONCLUSIONS: Reproducibility of efficiency measures was comparable to [Formula: see text] , however, poor associations between efficiency and [Formula: see text] suggested independence. Efficient ventilation may be of limited importance in determining the [Formula: see text] in a trained juvenile cyclist. PMID- 22840998 TI - Making a noisy gene: HDACs turn up the static. AB - In this issue of Molecular Cell, Weinberger et al. (2012) find that particular histone deacetylases (HDACs) regulate distinct stages of transcription, implicating chromatin dynamics in the generation of gene-specific noise within populations of genetically identical cells. PMID- 22840999 TI - Should I stay or should I go? Chromodomain proteins seal the fate of heterochromatic transcripts in fission yeast. AB - In this issue of Molecular Cell, Ishida et al. (2012) and Keller et al. (2012) show distinct outcomes for heterochromatic RNAs that bind different chromodomain proteins; Chp1 tethers transcripts to centromeres, whereas Swi6(HP1)-bound transcripts are evicted from chromatin and destroyed. PMID- 22841000 TI - TOR-tured yeast find a new way to stand the heat. AB - In this issue, Takahara and Maeda (2012) discover that together, Pbp1 and sequestration of the TORC1 complex in cytoplasmic mRNP stress granules provides a negative regulatory mechanism for TORC1 signaling during stress. PMID- 22841001 TI - Clocks, metabolism, and the epigenome. AB - Many behaviors and physiological activities in living organisms display circadian rhythms, allowing the organisms to anticipate and prepare for the diurnal changes in the living environment. In this way, metabolic processes are aligned with the periodic environmental changes and behavioral cycles, such as the sleep/wake and fasting/feeding cycles. Disturbances of this alignment significantly increase the risk of metabolic diseases. Meanwhile, the circadian clock receives signals from the environment and feedback from metabolic pathways, and adjusts its activity and function. Growing evidence connects the circadian clock with epigenomic regulators. Here we review the recent advances in understanding the crosstalk between the circadian clock and energy metabolism through epigenomic programming and transcriptional regulation. PMID- 22841002 TI - DNA sequence preferences of transcriptional activators correlate more strongly than repressors with nucleosomes. AB - Transcription factors (TFs) and histone octamers are two abundant classes of DNA binding proteins that coordinate the transcriptional program in cells. Detailed studies of individual TFs have shown that TFs bind to nucleosome-occluded DNA sequences and induce nucleosome disruption/repositioning, while recent global studies suggest this is not the only mechanism used by all TFs. We have analyzed to what extent the intrinsic DNA binding preferences of TFs and histones play a role in determining nucleosome occupancy, in addition to nonintrinsic factors such as the enzymatic activity of chromatin remodelers. The majority of TFs in budding yeast have an intrinsic sequence preference overlapping with nucleosomal histones. TFs with intrinsic DNA binding properties highly correlated with those of histones tend to be associated with gene activation and might compete with histones to bind to genomic DNA. Consistent with this, we show that activators induce more nucleosome disruption upon transcriptional activation than repressors. PMID- 22841004 TI - Mitochondrial gene expression. PMID- 22841003 TI - Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase. AB - DNA double-strand breaks are repaired by two main pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). The choice between these pathways depends on cell-cycle phase; however the continuous effect of cell cycle on the balance between them is still unclear. We used live cell imaging and fluorescent reporters for 53BP1, Rad52, and cell cycle to quantify the relative contribution of NHEJ and HR at different points of the cell cycle in single cells. We found that NHEJ is the dominant repair pathway in G1 and G2 even when both repair pathways are functional. The shift from NHEJ to HR is gradual, with the highest proportion of breaks repaired by HR in mid S, where the amount of DNA replication is highest. Higher proportions of HR also strongly correlate with slower rates of repair. Our study shows that the choice of repair mechanism is continuously adjusted throughout the cell cycle and suggests that the extent of active replication, rather than the presence of a sister chromatid influences the balance between the two repair pathways in human cells. PMID- 22841005 TI - Outbreak of extended-spectrum beta-lactamase-producing Klebsiella oxytoca infections associated with contaminated handwashing sinks(1). AB - Klebsiella oxytoca is primarily a health care-associated pathogen acquired from environmental sources. During October 2006-March 2011, a total of 66 patients in a hospital in Toronto, Ontario, Canada, acquired class A extended-spectrum beta lactamase-producing K. oxytoca with 1 of 2 related pulsed-field gel electrophoresis patterns. New cases continued to occur despite reinforcement of infection control practices, prevalence screening, and contact precautions for colonized/infected patients. Cultures from handwashing sinks in the intensive care unit yielded K. oxytoca with identical pulsed-field gel electrophoresis patterns to cultures from the clinical cases. No infections occurred after implementation of sink cleaning 3*/day, sink drain modifications, and an antimicrobial stewardship program. In contrast, a cluster of 4 patients infected with K. oxytoca in a geographically distant medical ward without contaminated sinks was contained with implementation of active screening and contact precautions. Sinks should be considered potential reservoirs for clusters of infection caused by K. oxytoca. PMID- 22841006 TI - Click-based synthesis of triazolobithiazole DeltaF508-CFTR correctors for cystic fibrosis. AB - Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1H-1,2,3-triazol-1-yl)-4,5'-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr-4a, improved logP values (4.5 vs 5.96). PMID- 22841007 TI - Severe human granulocytic anaplasmosis transmitted by blood transfusion. AB - A 36-year-old woman acquired severe human granulocytic anaplasmosis after blood transfusion following a cesarean section. Although intensive treatment with mechanical ventilation was needed, the patient had an excellent recovery. Disease caused by Anaplasma phagocytophilum infection was confirmed in 1 blood donor and in the transfusion recipient. PMID- 22841008 TI - A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. PMID- 22841010 TI - Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever. AB - BACKGROUND: IgE sensitization against grass pollen is a cause of seasonal allergic rhinitis. OBJECTIVE: We sought to investigate the evolution at the molecular level and the preclinical predictive value of IgE responses against grass pollen. METHODS: The German Multicentre Allergy Study examined a birth cohort born in 1990. A questionnaire was administered yearly, and blood samples were collected at 1, 2, 3, 5, 6, 7, 10, and 13 years of age. Grass pollen-related seasonal allergic rhinitis (SARg) was diagnosed according to nasal symptoms in June/July. Serum IgE antibodies to Phleum pratense extract and 8 P pratense molecules were tested with immune-enzymatic singleplex and multiplex assays, respectively. RESULTS: One hundred seventy-seven of the 820 examined children had SARg. A weak monomolecular/oligomolecular IgE response to P pratense was observed very frequently before SARg onset. These initial IgE responses increased in concentration and molecular complexity during the preclinical and clinical process. A typical progression of IgE sensitization was observed: Phl p 1 (initiator in >75% of cases); then Phl p 4 and Phl p 5; then Phl p 2, Phl p 6, and Phl p 11; and then Phl p 12 and Phl p 7. At age 3 years, IgE sensitization predicted SARg by age 12 years (positive predictive value, 68% [95% CI, 50% to 82%]; negative predictive value, 84% [95% CI, 80% to 87%]). At this preclinical prediction time, the number of recognized molecules and the serum levels of IgE to P pratense were significantly lower than at 3 or more years after SARg onset. CONCLUSIONS: The IgE response against grass pollen molecules can start years before disease onset as a weak monosensitization or oligosensitization phenomenon. It can increase in serum concentration and complexity through a "molecular spreading" process during preclinical and early clinical disease stages. Testing IgE sensitization at a preclinical stage facilitates prediction of seasonal allergic rhinitis at its molecular monosensitization or oligosensitization stage. PMID- 22841011 TI - When Mr Yuck meets Mr Bubble: a primer on pediatric decontamination. PMID- 22841009 TI - Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. AB - BACKGROUND: IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T(H)2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both T(H)2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. OBJECTIVE: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. METHODS: The role of PARP-14 and its enzyme activity in AAD and T(H)2 differentiation were examined by using a murine model of AAD and in vitro T(H) cell differentiation. RESULTS: PARP-14-deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a T(H)2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. CONCLUSION: PARP-14 and the catalytic activity associated with it promote T(H)2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma. PMID- 22841013 TI - Conflicting priorities: emergency nurses perceived disconnect between patient satisfaction and the delivery of quality patient care. AB - INTRODUCTION: As hospitals compete for patients and their healthcare dollars, the emergency nurse is being asked to provide excellent nursing care to "customers" rather than patients. This has changed the approach in delivering quality care and has created favorable conditions for conflict as the nurse tries to achieve specific patient satisfaction goals. METHODS: A sample of 9 emergency nurses from 2 hospitals in northern New Jersey participated in focus groups designed to learn about the types of conflict commonly encountered, and to identify the attitudes and understanding of the emergency nurses experiencing conflict and how interpersonal conflict is dealt with. RESULTS: Thematic content analysis identified an overarching theme of conflicting priorities that represented a perceived disconnect between the priority of the ED leadership to achieve high patient satisfaction scores and nurses' priority to provide quality care. Three interacting sub-themes were identified: (1) staffing levels, (2) leaders don't understand, and (3) unrealistic expectations. The study also found that avoidance was the approach to manage conflict. DISCUSSION: The core conflict of conflicting priorities was based on the emergency nurses' perception that while patient satisfaction is important, it is not necessarily an indicator of quality of care. Interacting sub-themes reflect the way in which conflict priorities were influenced by patient satisfaction and the nurses' ability to provide quality care. Avoidant conflict management style was used to resolve conflicting priorities because nurses perceive that there is not enough time to address conflict even though it could impact on work stress and patient care. PMID- 22841012 TI - Nurses' knowledge and attitudes toward pain in the emergency department. AB - INTRODUCTION: The purpose of this study was to investigate emergency nurses' knowledge and attitudes about pain. METHODS: A descriptive design was used for this study. A validated tool, the Knowledge and Attitudes Survey Regarding Pain (KASRP), was administered to nurses working in 5 U.S. emergency departments. Demographic data also were collected from each participant. RESULTS: Ninety-one emergency nurses completed the survey. The mean total KASRP score was 76%. No significant differences were found in mean total scores by age, education level, years of nursing experience, or years of ED experience. Eight questions were answered incorrectly by more than 50% of participants. Five of these questions were related to opioid pharmacology and dosage, 2 concerned understanding of addiction and dependence, and one was linked to nurse assessment and patient report of pain level. Analysis of these 8 questions revealed that higher education levels had a weak positive association with correct answers. DISCUSSION: Participants taking the survey scored comparably or better than participants in other reported studies using the KASRP. Years of nursing experience was not correlated with correct responses. Findings from this study underscore the Institute of Medicine's Pain in America recommendation to increase pain management education for all providers. PMID- 22841014 TI - Progressive meningoencephalitis due to neurosarcoidosis. PMID- 22841015 TI - Nutritional status and postoperative outcome after pneumonectomy for lung cancer. AB - BACKGROUND: The influence of nutritional status on outcome after major lung resection remains controversial. Nutritional assessment is not included as a major recommendation in lung cancer guidelines. The purpose of this study was to assess the nutritional status of patients referred for pneumonectomy and to assess the predictive value of malnutrition in determining the surgical outcome. METHODS: This study was a multicenter observational trial. The eligibility criterion for participants was pneumonectomy for lung cancer. Criteria for group classification according to nutritional status were albumin and transthyretin levels. Predicted outcomes were major infectious and noninfectious complications and 90-day mortality. Univariate analysis identified independent variables for the predictive model of age, sex, induction chemotherapy, extended resections, treatment side, smoking, and malnutrition. Predictive variables were then included in a logistic regression model. RESULTS: Between January 2010 and December 2011, 86 (mean age, 61.5 years) consecutive patients referred for pneumonectomy (left side, n = 58; right side, n = 28) at 4 thoracic surgery centers were included. The malnutrition group included 33 patients (39%) and the normal nutritional status group included 53 patients. Univariate analysis elected malnutrition, recent active smoking, and extended resection to be included in a multivariate analysis. Multivariate analysis identified malnutrition, recent smoking, and extended resection as predictive variables for major complications and mortality. CONCLUSIONS: The frequency of malnutrition detected by biological markers was dramatically high. Malnutrition, as well as recent active smoking and extended resection, is a predictive factor for infectious complications and mortality after pneumonectomy. Nutritional assessment with appropriate markers should be considered before pneumonectomy. PMID- 22841016 TI - Single-center experience of arch reconstruction in the setting of Norwood operation. AB - BACKGROUND: Arch reconstruction is a key part of the Norwood operation for hypoplastic left heart syndrome and is related to late morbidity. Since 2003, our surgical technique has been standardized to a right ventricle to pulmonary artery conduit, arch reconstruction with homograft patch, and Damus-Kaye-Stansel anastomosis onto homograft patch, with partial or complete resection of any coarctation ridge. We studied the impact of the surgical approach on arch reinterventions and outcome. METHODS: A retrospective review of echocardiogram, catheterizations, and hospital records of patients who underwent stage1 reconstruction from January 2003 to December 2010 was performed. RESULTS: A total of 289 patients underwent stage 1 reconstruction during this period. Age and body weight at operation were 9.3 +/- 25 days and 3.1 +/- 0.6 kg. Early survival was 86%. Seventy-three patients (25%) underwent intervention for recoarctation: balloon angioplasty (n = 68) or surgical intervention (n = 11). Eighteen patients underwent multiple interventions for recoarctation. Size of ascending aorta and incomplete resection of ductal tissue were risk factors for reintervention (p = 0.01 and p = 0.02). Patients with an ascending aorta diameter less than 2 mm had significantly higher reintervention rates (p = 0.01). CONCLUSIONS: Our standard technique for the Norwood operation has good results but further intervention for recoarctation is common. Size of ascending aorta and incomplete resection of coarctation tissue were risk factors for recoarctation. Complete resection of coarctation tissue may reduce the incidence of recoarctation. A small ascending aorta may predict late arch problems. PMID- 22841017 TI - Perioperative serum aspartate aminotransferase level as a predictor of survival after coronary artery bypass grafting. AB - BACKGROUND: Elevated cardiac enzymes after coronary artery bypass grafting (CABG) surgery have been identified as a risk factor for worse postoperative outcome. Cardiac enzymes play an important role in the diagnosis of perioperative myocardial infarction. This study aims to investigate the predictive value of aspartate aminotransferase (AST) with respect to early and late mortality after CABG. METHODS: Patients undergoing isolated CABG in a single center between January 1998 and December 2010 were prospectively enrolled in our database. Patients were arbitrarily divided into 4 groups according to the postoperative AST level: group 1 (AST < 50 U/L), group 2 (AST = 51 to 100 U/L), group 3 (AST = 101 to 200 U/L), group 4 (AST = 201 to 300 U/L), and group 5 (AST > 300 U/L). The impact of biomedical variables on early mortality was determined using univariate and multivariate logistic regression analyses. Risk factors for late mortality were identified using Cox proportional hazard regression analyses. RESULTS: The study population consisted of 13,505 patients who underwent isolated CABG. Postoperative AST level was identified as a risk factor for early (odds ratio = 3.6 [2.5 to 5.4], p < 0.0001) and late mortality (hazard ratio = 1.4 [1.2 to 1.7], p < 0.001). After correction for other risk factors, AST level was an independent predictor of worse survival. CONCLUSIONS: Elevated postoperative AST level is an independent predictor of early and late mortality after CABG. Although it is not a specific indicator for cardiac damage, it can reflect ischemic effects on the other organs as an indirect sign of depressed cardiac function. PMID- 22841018 TI - Correlation between prostate brachytherapy-related urethral stricture and peri apical urethral dosimetry: a matched case-control study. AB - BACKGROUND AND PURPOSE: Radiation dose to the bulbomembranous urethra has been shown to correlate with urethral stricture formation. This retrospective case control study was designed to explore the relationship between dose to the apical/peri-apical regions of the urethra and development of brachytherapy (BXT) related urethral stricture. MATERIALS AND METHODS: Cases were patients who developed urethral stricture after treatment with BXT as monotherapy and who had urethral dosimetry post-implant. Each case was matched with a control that had not developed urethral stricture. Dosimetry was compared between cases and controls. RESULTS: Twenty-three cases were pair matched with 23 controls. There were no significant differences between the two groups in terms of age, presenting Prostate Specific Antigen (PSA), International Prostate Symptom Score (IPSS) or Gleason score. The dose delivered to the peri-apical and apical urethra was significantly higher for cases when compared with controls (peri-apical urethra: mean V(150) 1.1 Vs 0.8 cc [p=0.02]; apical urethra: mean dose 200 Vs 174 Gy [p=0.01]). The distance from the prostate apex to isodose lines was also found to be significant in predicting stricture formation. CONCLUSION: There was evidence to suggest that the development of BXT-related stricture was associated with radiation dose at the apical and peri-apical urethra. Attention to the dose delivered to those areas may minimise the risk of developing such morbidity. PMID- 22841019 TI - Reproducibility and genital sparing with a vaginal dilator used for female anal cancer patients. AB - PURPOSE: Acute vulvitis, acute urethritis, and permanent sexual dysfunction are common among patients treated with chemoradiation for squamous cell carcinoma of the anal canal. Avoidance of the genitalia may reduce sexual dysfunction. A vaginal dilator may help delineate and displace the vulva and lower vagina away from the primary tumor. The goal of this study was to evaluate the positional reproducibility and vaginal sparing with the use of a vaginal dilator. MATERIALS AND METHODS: Ten female patients treated with IMRT for anal cancer were included in this study. A silicone vaginal dilator measuring 29 mm in diameter and 114 mm in length was inserted into the vagina before simulation and each treatment. The reproducibility of dilator placement was investigated with antero-posterior and lateral images acquired daily. Weekly cone beam CT (CBCT) imaging was used to confirm coverage of the GTV, which was typically posterior and inferior to the dilator apex. Finally, a planning study was performed to compare the vaginal doses for these 10 patients to a comparable group of 10 female patients who were treated for anal cancer with IMRT without vaginal dilators. RESULTS: The absolute values of the location of the dilator apex were 7.0 +/- 7.8mm in the supero inferior direction, 7.5 +/- 5.5 mm in the antero-posterior, and 3.8 +/- 3.1mm in the lateral direction. Coverage of the GTV and CTV was confirmed from CBCT images. The mean dose to the vagina was lower by 5.5 Gy, on average, for the vaginal dilator patients, compared to patients treated without vaginal dilators. CONCLUSION: The vaginal dilator tended to be inserted more inferiorly during treatment than during simulation. For these ten patients, this did not compromise tumor coverage. Combined with IMRT treatment planning, use of a vaginal dilator could allow for maximum sparing of female genitalia for patients undergoing radiation therapy for anal cancer. PMID- 22841020 TI - Modulation of radiation-induced oral mucositis (mouse) by selective inhibition of beta1 integrin. AB - INTRODUCTION: Oral mucositis is a severe side effect of radio(chemo)therapy for head and neck tumors, for which beta1 integrins have been proposed as potential therapeutic targets. The present study was initiated to determine the effect of selective inhibition of beta1 integrin on the oral epithelial radiation response. MATERIALS AND METHODS: Daily fractionated irradiation was given with 5 * 3 Gy/week over 1 or 2 weeks with/without the beta1 integrin-inhibiting monoclonal antibody AIIB2 or an IgG control. Each protocol was terminated by graded test doses to generate full dose-effect curves for mucosal ulceration. The same technique was used for single dose irradiation. RESULTS: Combined single dose irradiation plus AIIB2 resulted in a significant decrease of the ED50 compared to irradiation alone or control IgG. No effect of AIIB2 was found with fractionated irradiation over 1 week. With 2 weeks of fractionation, AIIB2 induced a significant increase in the ED50 for the terminating test irradiation when administered in week 2. The time course of the response was largely unaffected by beta1 integrin inhibition. CONCLUSIONS: A reduction of mucosal reactions by beta1 integrin inhibition later in a course of fractionation was observed, i.e. when epithelial repopulation processes were active. Further mechanistic studies are required. PMID- 22841021 TI - Impact of negative margin width on local recurrence in breast conserving therapy. AB - BACKGROUND AND PURPOSE: This study aims to explain the unexpected weak association between the width of the negative surgical margin and the risk of local recurrence in breast conserving therapy. MATERIALS AND METHODS: We utilized a classical tumor-control probability (TCP) model to estimate the risk of local recurrence, considering the heterogeneity of microscopic disease spread observed around the invasive index tumor in a pathology dataset (N=60). The estimated result was compared with the true risk observed in the EORTC boost-versus-no boost trial (N=1616). RESULTS: The disease volume beyond any given distance from the edge of the index tumor varied considerably among patients. Adopting this disease volume variation in the TCP model accurately reproduced the local recurrence rate as function of surgical margin width in the boost-versus-no-boost trial (Pearson's correlation coefficients are 0.652 and 0.862, and significant at the 0.05 and 0.01 level for absence and presence of a radiation boost, respectively). CONCLUSIONS: The impact of a negative margin width on local recurrence is limited due to the large variation of microscopic disease that can reach large quantities beyond any given distance from the edge of the index tumor across the patient population of breast-conserving therapy. PMID- 22841022 TI - Henoch-Schonlein purpura nephritis in a patient with IgG4-related disease: a possible association. AB - We report a case of Henoch- Schonlein purpura nephritis (HSPN) associated with tubulointerstitial nephritis (TIN) and chronic sclerosing sialoadenitis. The patient is a 75-year-old Japanese woman who had bilateral submandibular gland swelling, palpable purpura on the lower legs, and decreased renal function with hematoproteinuria and marked hypocomplementemia, but no skin lesion suggestive of systemic lupus erythematosus (SLE), and did not fulfill the classification criteria for SLE. Her serum IgG4 level was high and immunostaining of renal biopsies revealed marked infiltration by IgG4-positive plasma cells in the interstitium, confirming the diagnosis of IgG4- related disease. On the other hand, glomeruli showed endocapillary proliferative glomerulonephritis with mesangial IgA and C3 deposition demonstrated by immunofluorescence staining, which were typical glomerular lesions for HSPN. The glomerular and tubulointerstitial lesions responded to steroid therapy dramatically, and her renal function recovered to within the normal range within a month. This case suggests a possible new association between HSPN and IgG4-related disease. PMID- 22841024 TI - Heritability in chronic insomnia: commentary on Yun-Kwok Wing et al. familial aggregation and heritability of insomnia in a community-based study Sleep Med 2012. PMID- 22841025 TI - Efficiency of invasive mechanical ventilation during sleep in Duchenne muscular dystrophy. AB - OBJECTIVE: Inspiratory unintentional leaks (IULs) during noninvasive ventilation (NIV) adversely affect the sleep and the effectiveness of mechanical ventilation (MV). The aim of this study was to assess the effects of nocturnal IULs in Duchenne muscular dystrophy (DMD) patients with a tracheostomy and uncuffed tube comparatively with NIV patients. METHODS: Polysomnography with transcutaneous partial pressure of carbon dioxide (PtcCO(2)) recording and blood gas measurement was performed in 26 stable tracheostomized DMD patients using home MV, among whom 11 were matched with NIV patients. RESULTS: IULs occurred during 29.4% [1.7 61.9%] (median [IQR]) of the total sleep time. By univariate regression analysis, the closest correlation with IUL duration was for daytime base excess (r(2)=0.69, P<0.0001), followed by daytime bicarbonate level. In a stepwise multiple regression analysis, only base excess remained significantly correlated. Sleep and respiratory parameters improved in the four patients who agreed to use cuffed tubes. Tracheostomized patients had lower maximal PtcCO(2) (P=0.02) and base excess values (P=0.045) compared to NIV controls. CONCLUSION: Tracheostomy does not guarantee that MV is effective during sleep, as IULs may occur, but ensures better nocturnal gas exchanges than NIV. DMD patients should be evaluated using at least blood gas measurement, nocturnal oximetry, and PtcCO(2) monitoring. PMID- 22841026 TI - Does rapid eye movement sleep behavior disorder exist in psychiatric populations? A clinical and polysomnographic case-control study. AB - OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) has been increasingly reported in patients with psychiatric disorders (pRBD). Although a close association with the usage of psychotropics has been postulated, it remains elusive whether psychotropics are the only causative factor of RBD symptoms in psychiatric populations. Moreover, there is limited literature documenting and quantifying the clinical and polysomnographic features in this population. METHODS: A case-control study comparing the clinical and polysomnographic features of 31 pRBD patients with: (1) Age-, sex-, and psychiatric diagnoses matched controls; and (2) Typical idiopathic RBD (tRBD) patients. RESULTS: Despite being prescribed with similar psychotropics, pRBD patients had more dream enacting behaviors (p<0.01), sleep-related injuries (p<0.01), and nightmares (p<0.01) than the psychiatric controls. pRBD patients were younger with more females, but they had comparable sleep-related injuries to tRBD. Both tRBD and pRBD had more REM-related muscle activity than controls (p<0.01) and the effect remained significant after adjusting for age, gender, and use of antidepressants. CONCLUSIONS: Our study suggests that pRBD had comparable clinical features and consequences to those of tRBD. The occurrence of RBD symptoms in these patients may be related to a constellation of factors, including individual predisposition, depressive illness, antidepressants, and other clinical factors. Given the association of RBD and neurodegeneration in tRBD, further prospective follow-up of these patients is warranted. PMID- 22841027 TI - Health, social, and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. AB - OBJECTIVE: Despite the fact that narcolepsy is a chronic disorder affecting younger people, there is insufficient information about its societal burden, time course, and familiar effect. We aimed to estimate the factual direct and indirect costs of narcolepsy patients and their families in a national sample using a controlled study design. PATIENTS/METHODS: Using records from the Danish National Patient Registry (1997-2009), all 816 narcolepsy patients and their partners were identified and compared with 3254 randomly chosen controls matched for age, gender, geographic area, and civil status. Direct and indirect costs, including frequencies of primary and secondary sector contacts' and procedures, medication, labor supply, and social transfer payments were extracted from the national databases. RESULTS: Fewer patients (46.7%) than controls (51.4%) were married or cohabiting. Patients with narcolepsy had significantly higher rates of health related contact, medication use, and a higher socioeconomic cost. Furthermore, they had lower employment rates, and those in employment had a lower income level than control subjects. Partners presented higher public health insurance and public transfers and lower income from employment. In all, the annual mean excess health-related cost, including social transfers, was ?9572 for patients with narcolepsy and ?3606 for their partners (both p<0.001). Patient consequences could be identified up to 11 years before first diagnosis and became more pronounced as the disease advanced. CONCLUSION: Narcolepsy causes socioeconomic consequences, not only for patients, but also for their partners, which is present years prior to disease diagnosis, confirming a diagnostic delay. PMID- 22841029 TI - Sleep duration and central obesity in women - differences between short sleepers and long sleepers. AB - OBJECTIVE: To assess characteristics of short sleepers and long sleepers and to assess association between sleep duration and central obesity in a population based sample of women. METHOD: Non-pregnant women >=20 years that were randomly selected from the population-registry of Uppsala, Sweden, answered a questionnaire (n=6461) including questions on sleeping habits and somatic disorders. RESULTS: There was a U-shaped association between sleep duration and waist circumference. Short sleeping women (<5 h) had a waist circumference of 89.2+/-14.9 cm (mean+/-SD) decreasing to 82.9+/-11.9 cm for women sleeping 7-<8 h and increasing to 89.0+/-16.7 cm for women sleeping >=10 h. Both short sleepers and long sleepers were more often physically inactive, smokers, ill or taking medication, and psychologically distressed than normal sleepers (6-<9 h). In women <50 years both short and long sleep duration were risk factors for central obesity. Short sleep duration remained a risk factor for central obesity, whereas the association with long sleep duration did not reach statistical significance after adjustments. CONCLUSIONS: Short sleepers and long sleepers showed differences in characteristics compared to normal sleepers. Furthermore, we showed an independent association between short sleep duration and central obesity, which was strongest in younger women. It is important to identify short sleepers, especially in younger women. PMID- 22841028 TI - Sleep-disordered breathing symptoms among African-Americans in the Jackson Heart Study. AB - BACKGROUND: Sleep-disordered breathing (SDB) is an increasingly recognized risk factor for cardiovascular disease (CVD). Limited data are available from large African American cohorts. METHODS: We examined the prevalence, burden, and correlates of sleep symptoms suggestive of SDB and risk for obstructive sleep apnea (OSA) in the Jackson Heart Study (JHS), an all-African-American cohort of 5301 adults. Data on selected daytime and nighttime sleep symptoms were collected using a modified Berlin questionnaire during the baseline examination. Risk of OSA was calculated according to published prediction model. Age and multivariable adjusted logistic regression models were used to examine the associations between potential risk factors and measures of sleep. RESULTS: Sleep symptoms, burden, and risk of OSA were high among men and women in the JHS and increased with age and obesity. Being married was positively associated with sleep symptoms among women. In men, poor to fair perceived health and increased levels of stress were associated with higher odds of sleep burden, whereas prevalent hypertension and CVD were associated with higher odds of OSA risk. Similar associations were observed among women with slight variations. Sleep duration <7h was associated with increased odds of sleep symptoms among women and increased sleep burden among men. Moderate to severe restless sleep was consistently and positively associated with odds of adverse sleep symptoms, sleep burden, and high risk OSA. CONCLUSIONS: Sleep symptoms in JHS had a strong positive association with features of visceral obesity, stress, and poor perceived health. With increasing obesity among younger African Americans, these findings are likely to have broad public health implications. PMID- 22841031 TI - A two-year follow-up study on the symptoms of sleep disturbances/insomnia and their effects on daytime functioning. AB - OBJECTIVE: This study attempts to identify changes in the symptoms of sleep disturbances/insomnia over a two-year course and their effects on daytime functioning. METHODS: We administered two population-based epidemiological surveys in 2005 and 2007 to participants from rural Japan. RESULTS: In the first survey, 30.7% of the subjects reported sleep disturbances/insomnia. Among them, 60.9% reported sleep problems at the two-year follow-up. A comparison of sleep disturbances/insomnia, and subjective daytime functioning measures between the new incident cases and persistent poor sleepers revealed that the total score of persistent poor sleepers was significantly lower than that of new incident cases on the Pittsburgh Sleep Quality Index and physical quality of life (QoL) but not mental QoL. Longitudinal comparisons of the symptoms of sleep disturbances/insomnia in persistent poor sleepers revealed that sleep efficiency was significantly worse at follow-up. Exacerbation of the symptoms of sleep disturbances/insomnia at follow-up was observed in mild but not severe cases. CONCLUSIONS: Sleep efficiency progressively worsens over time, and physical QoL can deteriorate as sleep disturbances/insomnia become chronic. Since the symptoms of sleep disturbances/insomnia and their daytime effects are exacerbated even in mild cases, early intervention and treatment are necessary. PMID- 22841030 TI - Capturing PLMS and their variability in children with sickle cell disease: does ankle activity monitoring measure up to polysomnography? AB - OBJECTIVES: To test agreement and define differences in periodic limb movements in sleep (PLMS) measured by polysomnography and an ankle activity monitor, and to describe PLMS variability across nights, feasibility of home monitoring, and correlates of PLMS in children with sickle cell disease (SCD). METHODS: Twenty children with SCD and restless legs syndrome (RLS) symptoms or polysomnography documented PLMS underwent concurrent attended polysomnography and ankle activity monitoring over one to two nights and home activity monitoring for three nights. Serum iron and ferritin were measured pre- and post-polysomnography. RESULTS: Adequate sensitivity (1.00), specificity (0.69), and mean bias (5.0+/-7.4 PLMS/h) for identifying elevated PLMS by activity monitor were obtained when scoring the period from sleep onset to offset rather than time in bed per manufacturer recommendation, and using a cut-point of 10 PLMS/h. Compared to activity monitor, only polysomnographic PLMS demonstrated periodicity, at inter-movement intervals (IMI) 20-35 s; the activity monitor overscored PLMS at the beginning and end of sleep and at shorter IMI (5-15s; p<=0.003), suggesting misclassification of nonperiodic leg movements as PLMS by activity monitor. PLMS varied across four nights by 16.1+/-13.4 PLMS/h. Post-polysomnography ferritin was associated (positively) with PLMS (p=0.034); RLS symptoms were not. CONCLUSIONS: Ankle activity monitoring is a valid screening measure for PLMS in children with SCD and can readily be performed at home. Interpretation should incorporate a threshold for elevated PLMS of 10/h and scoring from sleep onset to offset, which could be identified with concurrent wrist actigraphy, to better account for true PLMS. PMID- 22841032 TI - The association between sleep duration and weight in treatment-seeking preschoolers with obesity. AB - OBJECTIVE: To examine the association between nocturnal sleep duration and weight and caloric intake outcomes among preschool-aged children who are obese and enrolled in a family-based weight management program. METHODS: Forty-one preschool-aged children who were obese (BMI >= 95th percentile) and enrolled in a weight management program completed pre- and posttreatment assessments of body mass, caloric intake, and sleep. Separate linear regression analyses examined the relationship between nocturnal sleep duration and posttreatment body mass index relative to age- and sex-linked norms (BMIz) and caloric intake. RESULTS: After controlling for pretreatment BMIz, longer posttreatment nocturnal sleep was significantly associated with lower posttreatment BMIz (beta=-0.21, p=0.02) and explained a significant proportion of unique variance in posttreatment BMIz (DeltaR(2)=0.04). Similarly, after controlling for pretreatment caloric intake, longer nocturnal sleep duration at posttreatment was significantly associated with lower caloric intake at posttreatment (beta=-0.45, p=0.003) and explained a significant proportion of unique variance in posttreatment caloric intake (DeltaR(2)=0.19). CONCLUSIONS: These findings extend the literature on the sleep and weight relationship and suggest that adequate sleep may be an important element in interventions for preschoolers with obesity. PMID- 22841033 TI - The relationship between psychotic-like experiences and sleep disturbances in adolescents. AB - OBJECTIVE: We investigated the relationships between sleep disturbances and psychotic-like experiences (PLEs) among adolescents. METHODS: A total of 8530 students (grades 7-11) were recruited in the Republic of Korea, and 7172 students who completed all of the relevant questionnaires participated in the current study. The survey included the Eppendorf Schizophrenia Inventory (ESI), the Youth Psychosis At Risk Questionnaire (Y-PARQ), the Beck Depression Inventory (BDI), the Epworth Sleepiness Scale and questionnaires about sleep disturbances (insomnia, cataplexy and snoring). RESULTS: Subjects with insomnia, excessive daytime somnolence (EDS), or probable cataplexy had higher ESI and Y-PARQ scores after controlling for age, sex and BDI scores (all p<0.001). Insomnia (OR=4.40), EDS (OR=3.84) and probable cataplexy (OR=2.97) predicted clinical high risk of psychosis. Insomnia, EDS and probable cataplexy remained as significant predictors of clinical high risk for psychosis, even after controlling for depressive symptoms or when analyses were confined to non-depressive adolescents. CONCLUSIONS: Insomnia and EDS were found to predict PLEs in adolescents, independent of depression. Our findings suggest that adolescents complaining of insomnia or sleepiness may require further assessment regarding potential risk of psychosis. PMID- 22841034 TI - Acupressure, reflexology, and auricular acupressure for insomnia: a systematic review of randomized controlled trials. AB - Previous randomized controlled trials (RCTs) have shown that acupuncture may be efficacious for insomnia. Instead of needling, acupressure, reflexology, and auricular acupressure are procedures involving physical pressure on acupoints or reflex areas. These variants of acupuncture are gaining popularity, perhaps due to their non-invasive nature. A systematic review has therefore been conducted to examine their efficacy and safety for insomnia. Two independent researchers searched five English and 10 Chinese databases from inception to May 2010. Forty RCTs were identified for analysis. Only 10 studies used sham controls, four used double-blind design, nine studies scored three or more by the Jadad scale, and all had at least one domain with high risk of bias. Meta-analyses of the moderate quality RCTs found that acupressure as monotherapy fared marginally better than sham control. Studies that compared auricular acupressure and sham control showed equivocal results. It was also found that acupressure, reflexology, or auricular acupressure as monotherapy or combined with routine care was significantly more efficacious than routine care or no treatment. Owing to the methodological limitations of the studies and equivocal results, the current evidence does not allow a clear conclusion on the benefits of acupressure, reflexology, and auricular acupressure for insomnia. PMID- 22841035 TI - Sleep-related eating disorder versus sleepwalking: a controlled study. AB - BACKGROUND/OBJECTIVE: Sleep-related eating disorder (SRED) may have some common clinical features with sleepwalking and with eating behavior disorders. The objective of this study was to compare clinical, sleep, and eating behavior measures in patients with SRED vs. sleepwalkers and controls. METHODS: Overall, 15 patients with SRED, 21 sleepwalkers, and 20 age- and sex-matched healthy volunteers underwent interviews, completed sleep, anxiety, depression, and eating behavior scales, and had a night-time videopolysomnography. RESULTS: Patients with SRED were mainly women, had disease onset in adulthood, suffered nightly episodes and insomnia, and had more frequent eating problems in childhood and higher current anorexia scores than sleepwalkers and controls. Unlike controls, they shared several commonalities with sleepwalkers, including a high frequency (66%) of past or current sleepwalking, a similar timing of parasomnia episodes during the first half of the night, numerous arousals from stage N3, and a similarly altered level of daytime sleepiness and anxiety, but higher awareness during parasomnia episodes. Conversely, only 10% of sleepwalkers ate during their sleepwalking episodes. On videopolysomnography, the eating episodes occurred mostly within 1min after awakening from stage N2 (n=9) or stage N3 (n=6). The frequencies of restless legs syndrome, periodic leg movements, and sleep apnea were similar across the three groups. CONCLUSIONS: Patients with SRED share several clinical commonalities with sleepwalkers (although their level of awareness is higher) plus former or current eating behavior problems. It suggests that they have specialized a former sleepwalking behavior toward sleep-related eating because they are more vulnerable to eating behavior problems during the daytime. PMID- 22841036 TI - Sleep disordered breathing in patients with primary Sjogren's syndrome: a group controlled study. AB - OBJECTIVE: Patients with primary Sjogren's syndrome (pSS) have higher fatigue levels and also suffer from excessive day time sleepiness. The underlying mechanisms for this are not fully understood. Knowing that these patients have higher salivary surface tension, we postulated that sleep disordered breathing (SDB) would be more common and would be a contributor to these symptoms amongst pSS patients. We investigated the prevalence of SDB in pSS patients and its relationship to their symptoms of fatigue and excessive daytime sleepiness. METHODS: This was an observational study of 28 pSS patients (mean+/-SEM age, 58.7+/-1.9) and 18 healthy subjects (mean+/-SEM age, 55.8+/-3.4) matched for age, sex, and BMI. All the participants underwent an overnight polysomnography. The two groups were compared for fatigue, sleepiness, anxiety, and depression scores, and for the frequency of obstructive apneas and hypopneas during sleep. Correlation analyses were used to explore relationships between sleep study variables and excess sleepiness and fatigue. RESULTS: Fatigue, sleepiness, anxiety and depression symptoms, and sleep onset latency were significantly greater in pSS patients than controls. pSS patients had twice the frequency of obstructive apneas and hypopneas compared with control subjects (median[IQR],18.6/h [10.4-40.1] vs. 9.9/h [6.5-23.4]; p=0.032) and OSA defined as an apnea-hypopnea index >15 events/h of sleep was more prevalent amongst pSS patients than controls (64% vs. 28%; p=0.033). While no significant correlations were found between parameters of sleep disordered breathing and sleepiness scores or fatigue scores in the pSS group, CPAP treatment in a small subset of the pSS who were more severely affected by OSA suggested significant symptomatic benefit. CONCLUSION: OSA appears to be increased in pSS and may be a useful therapeutic target to improve the quality of life of these patients. PMID- 22841037 TI - Prevalence of and risk factors for obstructive sleep apnea syndrome in Brazilian railroad workers. AB - OBJECTIVE: This study evaluated the prevalence of, and the risk factors for, obstructive sleep apnea syndrome (OSAS) among Brazilian railroad workers. METHODS: Male railroad workers (745) from a railway company in Brazil were analyzed after responding to questionnaires about their demographics, sleep habits, excessive daytime sleepiness (Epworth), and the likelihood of having apnea (Berlin). We also performed polysomnography and measured anthropometric data for all of the railroad workers. RESULTS: The results showed that 261 (35.03%) of the railroad workers presented with OSAS. These railroad workers were older (OSAS: 38.53+/-10.08 versus non-OSAS: 33.99+/-8.92 years), more obese according to body mass index (27.70+/-4.38 versus 26.22+/-3.92 kg/m(2)), and employed for a longer period of time (14.32+/-9.13 years) compared with those without OSAS (10.96+/-7.66 years). Among those with OSAS, 9.5% were smokers and 54.7% reported alcohol use. The associated risk factors were age (OR=2.51, 95% CI=1.76-3.57), BMI (OR=1.56, 95% CI=1.04-2.34), alcohol use (OR=1.28, 95% CI=0.90 1.81), and a high chance of having sleep apnea, as assessed by the Berlin questionnaire (OR=2.19, 95% CI=1.49-3.21). CONCLUSION: The prevalence of OSAS in Brazilian railroad workers was higher than that observed in the general population but similar to that found in the population of the city of Sao Paulo, Brazil. These results suggest that age, BMI, a high risk of developing apnea through subjective self-reporting (Berlin), and alcohol use are associated with a higher risk of developing OSAS. These data reinforce the need to be more attentive to this population because they have a higher propensity for accidents. PMID- 22841038 TI - Is portable monitoring accurate in the diagnosis of obstructive sleep apnea syndrome in chronic pulmonary obstructive disease? AB - BACKGROUND: No scientific evidence supports the use of portable devices to diagnose obstructive sleep apnea syndrome (OSAS) in patients with co-morbities. Our aim was to evaluate the accuracy of a portable monitoring device (Stardust - STD) in the detection of patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD and clinical suspicion of OSAS were recruited for a prospective randomized study. The STD was used on two different nights: (1) at home (STDHome) and (2) at the sleep laboratory simultaneous with polysomnography (PSG-STDLab). RESULTS: A total of 72 patients underwent the proposed recordings. Forty-six volunteers were excluded due to recording problems, and data from 26 subjects were analyzed. The mean age was (mean+/-SD) 62.8+/-8.5 years, 50% were male, and the mean forced expiratory volume in the first second was 55+/-11%. Significant intraclass correlation was observed between apnea-hypopnea index (AHI)-PSG vs. AHI-STDLab (r=0.61, p<0.0001) and AHI STDHome (r=0.47, p<0.007). Kappa analysis also showed a significant agreement for severe group. CONCLUSION: Despite the agreement found in a small number of patients between AHI, a large number of failures in the recording limits the use of this portable device for the diagnosis of OSAS in patients with COPD. PMID- 22841039 TI - The relationship between psychotic-like experiences and attention deficits in adolescents. AB - OBJECTIVE: The present study focused on the relationship between psychotic-like experiences (PLEs) and attention deficits in adolescents. METHODS: A total of 2325 students, ages 14-19 years, across eight high schools in the Republic of Korea were recruited. Students performed the computerized Comprehensive Attention Test (CAT), which measures sustained and divided attention, and completed the Eppendorf Schizophrenia Inventory (ESI) and Beck Depression Inventory (BDI). One hundred sixty-six participants were excluded from the present study due to incomplete answers on the ESI; thus, data from 2159 students were included in the final analysis. RESULTS: Higher ESI scores predicted more omission and commission errors in divided-attention tasks after controlling for age, sex, and depressed mood (p = 0.024; p = 0.001, respectively). Attention and speech impairments on the ESI were the most frequent predictors of an increased number of errors in the attention tasks. All four ESI domains predicted the number of commission errors in divided-attention tasks (p < 0.001, p = 0.040, p = 0.046, and p = 0.013, respectively). In the high-risk group for psychosis (ESI >= 29), higher scores on the ideas of reference subscale were significantly associated with a higher number of both omission and commission errors in divided-attention tasks (p = 0.006, p = 0.017, respectively). CONCLUSIONS: PLEs during adolescents were associated with impaired attention on the divided-attention task, which demands increased attentional effort. Attention deficits in adolescents prone to psychosis may be related to thought-content disturbances rather than to cognitive and perceptual symptoms. PMID- 22841040 TI - A review on creatinine measurement techniques. AB - This paper reviews the entire recent global tendency for creatinine measurement. Creatinine biosensors involve complex relationships between biology and micro mechatronics to which the blood is subjected. Comparison between new and old methods shows that new techniques (e.g. Molecular Imprinted Polymers based algorithms) are better than old methods (e.g. Elisa) in terms of stability and linear range. All methods and their details for serum, plasma, urine and blood samples are surveyed. They are categorized into five main algorithms: optical, electrochemical, impedometrical, Ion Selective Field-Effect Transistor (ISFET) based technique and chromatography. Response time, detection limit, linear range and selectivity of reported sensors are discussed. Potentiometric measurement technique has the lowest response time of 4-10 s and the lowest detection limit of 0.28 nmol L(-1) belongs to chromatographic technique. Comparison between various techniques of measurements indicates that the best selectivity belongs to MIP based and chromatographic techniques. PMID- 22841041 TI - High-speed cryo-focusing injection for gas chromatography: reduction of injection band broadening with concentration enrichment. AB - In order to maximize peak capacity and detection sensitivity of fast gas chromatography (GC) separations, it is necessary to minimize band broadening, and in particular due to injection since this is often a major contributor. A high speed cryo-focusing injection (HSCFI) system was constructed to first cryogenically focus analyte compounds in a 6 cm long section of metal MXT column, and second, reinject the focused analytes by rapidly resistively heating the metal column via an in-house built electronic circuit. Since the cryogenically cooled section of column is small (~750 nl) and the direct resistive heating is fast (~6000 degrees C/s), HSCFI is demonstrated to produce an analyte peak with a 6.3 ms width at half height, w(1/2). This was achieved using a 1m long column with a 180 MUm inner diameter (i.d.) operated at an absolute head pressure of 55 psi and an oven temperature of 60 degrees C, with a 10 V pulse applied to the metal column for 50 ms. HSCFI was also used to demonstrate the head space sampling and fast GC analysis of an aqueous solution containing six test analytes (acetone, methanol, ethanol, toluene, chlorobenzene, pentanol). Using Henry's law constants for each of the analytes, injected mass limits of detection (LODs) were typically in the low pg levels (e.g., 1.2 pg for acetone) for the high speed separation. Finally, to demonstrate the use of HSCFI with a complex sample, a gasoline was separated using a 20 m * 100 MUm i.d. column and the stock GC oven for temperature programming, which provided a separation time of 200 s and an average peak width at the base of 440 ms resulting in a total peak capacity of 460 peaks (at unit resolution). PMID- 22841042 TI - Ultrasonic assisted synthesis of adenosine triphosphate capped manganese-doped ZnS quantum dots for selective room temperature phosphorescence detection of arginine and methylated arginine in urine based on supramolecular Mg(2+) adenosine triphosphate-arginine ternary system. AB - An ultrasonic assisted approach was developed for rapid synthesis of highly water soluble phosphorescent adenosine triphosphate (ATP)-capped Mn-doped ZnS QDs. The prepared ATP-capped Mn-doped ZnS QDs allow selective phosphorescent detection of arginine and methylated arginine based on the specific recognition nature of supramolecular Mg(2+)-ATP-arginine ternary system in combination with the phosphorescence property of Mn-doped ZnS QDs. The developed QD based probe gives excellent selectivity and reproducibility (1.7% relative standard deviation for 11 replicate detections of 10 MUM arginine) and low detection limit (3 s, 0.23 MUM), and favors biological applications due to the effective elimination of interference from scattering light and autofluorescence. PMID- 22841043 TI - Micellar electrokinetic chromatography method for the simultaneous determination of furanic compounds in honey and vegetable oils. AB - A simple micellar electrokinetic chromatography (MEKC) method for the simultaneous determination of 2-furfural (2-F), 3-furfural (3-F), 5 methylfurfural (5-MF), 5-hydroxymethylfurfural (5-HMF), 2-furoic acid (2-FA) and 3-furoic acid (3-FA) in honey and vegetable oils is described. Parameters affecting the separation such as pH, buffer and surfactant concentrations, applied voltage, capillary temperature, injection time and capillary length were studied and optimized. The separation was carried out in normal polarity mode at 20 degrees C, 22 kV and using hydrodynamic injection (17 s). The separation was achieved in a bare fused-silica capillary (46 cm * 50 MUm i.d.) with a background electrolyte of 75 mM phosphoric acid (pH 7.3), containing 200 mM of sodium dodecyl sulphate (SDS). The detection wavelengths were at 200 nm (2-FA and 3-FA) and 280 nm (2-F, 3-F, 5-MF, 5-HMF). The furfurals were well separated in less than 20 min. The method was validated in terms of linearity, limit of detection and quantitation, precision and recoveries. Calibration curves of the six furfurals were well correlated (r(2)>0.991) within the range 1-25 MUg mL(-1). Relative standard deviations of intra- and inter-day migration times and corrected peak areas <=9.96% were achieved. The limit of detection (signal:noise, 3) was 0.33-0.70 MUg mL(-1) whereas the limit of quantitation (signal:noise, 10) was 1.00-2.12 MUg mL(-1). The method was applied to the determination of furanic compounds in honeys and vegetable oils (palm, walnut, grape seed and rapeseed). The effects of thermal treatment and gamma irradiation on the formation of the furanic compounds in honey were also investigated. PMID- 22841045 TI - Sensitive chemiluminescent immunoassay of triclopyr by digital image analysis. AB - An image based detection of chemiluminescence enzyme-linked immunosorbent assay (CL-ELISA) for the quantification of triclopyr has been developed. The immunoassay was an indirect competitive immunoassay with an anti-rabbit secondary antibody conjugated to horseradish peroxidase (HRP). Chemiluminescence was produced by the luminol/H(2)O(2)/HRP reaction, detected by a monochrome video CCD camera and digitized with an Imagraph IC-PCI frame grabber using a custom program developed in C(++) (Microsoft Visual C(++) 6.0). Two main improvements are reported in the data processing software: the implementation of a circular mesh covering the perimeter of each well, eliminating diffuse light from the neighboring wells, and the use of volume (the integration of light intensity of all pixels that define a well) as an analytical signal instead of CL intensity or area (as usual in commercial plate readers) to improve precision for normalization of the total light output. The standard curve was produced for 0.01 10 ng/L triclopyr. The limit of detection was 0.8 ng/L and the variation coefficient was 3.07% (n=10, P=0.05). PMID- 22841044 TI - Development of a liquid chromatography-tandem mass spectrometry method for the determination of sulfonamides, trimethoprim and dapsone in honey and validation according to Commission Decision 2002/657/EC for banned compounds [corrected]. AB - This work reports a sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method for identification and quantification of seven sulfonamides, trimethoprim and dapsone in honey. The method is based on a solid-phase extraction (SPE) step of the target analytes with Oasis HLB cartridges after acidic hydrolysis of the honey sample to liberate the sugar-bound sulfonamides. Analysis was performed using liquid chromatography-tandem mass spectrometry (LC MS/MS) in the positive electro-spray ionization (ESI) mode with two different isotopically labeled internal standards with the view to improve the quantitative performance of the method. The method validation has been performed according to the Commission Decision 2002/657/EC; the average recoveries, measured at three concentration levels (1.5, 2.5 and 5.0 MUg kg(-1)), have been estimated in the range 70 to 106% while the respective % relative standard deviations of the within-laboratory reproducibility ranged from 6 to 18%. Mean values of the expanded uncertainties calculated were in the range 22-41% at the 99% confidence level. Decision limit (CCalpha) and detection capability (CCbeta) values were in the ranges 0.4-0.9 and 0.7-1.4 MUg kg(-1), respectively. Matrix effects have been investigated demonstrating a moderate signal suppression/enhancement for most of the target compounds. The method described has been successfully applied to the analysis of honey samples; sulfamethoxazole, sulfathiazole and trimethoprim were detected in some cases. PMID- 22841046 TI - An integrated lab-on-a-disc for automated cell-based allergen screening bioassays. AB - We have utilized various valving scheme to leverage purely rotation-regulated flow control to enable comprehensive cell-based bioassays (CBBs) on centrifuge based lab-on-a-disc (LOAD). A LOAD has been developed to examine allergic degranulation from live basophils for allergens screening for the first time, which can also be adjusted to suit a wide range of CBBs. In this system, controlled allergic reaction together with mediator separation from basophils using siphon valving and centrifugal sedimentation are realized inside microstructured network. The entire degranulation analysis process including on demand release of samples, reaction and degranulation, allergic mediator separation and detection is executed in an automatic sequence within a single run. To validate our cell-based approach, detection of degranulation mediated by known secretagagues, ionomycin or chemotatic peptide formyl-methionine-leucine pheylalanine (fMLP), is first demonstrated. Further experiments using real allergens house dust mite protein (Der p1) and its corresponding human serum IgE also show positive results. The overall efficiency of the assay is 80.6%, which is comparable to other conventional methods. With 4 identical units on a disc running in a parallel format, the device offers the possibility of single-step, multiplexed allergens screening. The device is capable of reporting a result within 30 min. It has many desirable merits including fast and multiplexed analysis, low cost, single-step operation, minimal sample volume, less discomfort and most importantly increased safety as patients are no longer susceptible to possible anaphylactic shock reactions induced by the common skin-prick-test. The flexibility of the flow control within the device makes it suitable to a wide range of CBBs. PMID- 22841047 TI - Aliphatic and aromatic amines in atmospheric aerosol particles: comparison of three ionization techniques in liquid chromatography-mass spectrometry and method development. AB - A complete methodology was developed for the determination of ten aliphatic and nine aromatic amines in atmospheric aerosol particles. Before the liquid chromatography - tandem mass spectrometric separation and determination, the derivatization reaction of the analytes using dansyl chloride was accelerated by ultrasounds. From three different ionization techniques studied electrospray ionization was superior in terms of sensitivity, linearity, repeatability and reproducibility over atmospheric pressure chemical ionization and photoionization for the target analytes. The method developed was validated for the gas phase, 30 nm and total suspended atmospheric aerosol particles. The method quantification limits ranged between 1.8 and 71.7 pg. The accuracy and the potential matrix effects were evaluated using a standard addition methodology. Recoveries from 92.1% to 109.1%, the repeatability from 0.6% to 8.4% and the reproducibility from 2.3% to 9.8% were obtained. The reliability of the methodology was proved by the statistical evaluation. Finally, the developed methodology was applied to the determination of the target analytes in eight size separated ultrafine particulate (Dp=30+/-4 nm) samples and in eight total suspended particulate samples collected at the SMEAR II station. The mean concentrations for aliphatic amines were between 0.01 and 42.67 ng m(-3) and for aromatic amines between 0.02 and 1.70 ng m(-3). Thirteen amines were quantified for the first time in 30 nm aerosol particles. PMID- 22841048 TI - Survey analysis and chemical characterization of solid inhomogeneous samples using a general homogenization procedure including acid digestion, drying, grinding and briquetting together with X-ray fluorescence. AB - A survey analysis and chemical characterization methodology for inhomogeneous solid waste samples of relatively large samples (typically up to 100g) using X ray fluorescence following a general homogenization procedure is presented. By using a combination of acid digestion and grinding various materials can be homogenized e.g. pure metals, alloys, salts, ores, plastics, organics. In the homogenization step, solid material is fully or partly digested in a mixture of nitric acid and hydrochloric acid in an open vessel. The resulting mixture is then dried, grinded, and finally pressed to a wax briquette. The briquette is analyzed using wave-length dispersive X-ray fluorescence with fundamental parameters evaluation. The recovery of 55 elements were tested by preparing samples with known compositions using different alloys, pure metals or elements, oxides, salts and solutions of dissolved compounds. It was found that the methodology was applicable to 49 elements including Na, Mg, Al, Si, P, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, As, Se, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, Te, Cs, Ba, La, Ce, Ta, W, Re, Ir, Pt, Au, Tl, Pb, Bi, and Th, that all had recoveries >0.8. 6 elements were lost by volatilization, including Br, I, Os, and Hg that were completely lost, and S and Ge that were partly lost. Since all lanthanides are chemically similar to La and Ce, all actinides are chemically similar to Th, and Hf is chemically similar to Zr, it is likely that the method is applicable to 77 elements. By using an internal standard such as strontium, added as strontium nitrate, samples containing relatively high concentrations of elements not measured by XRF (hydrogen to fluorine), e.g. samples containing plastics, can be analyzed. PMID- 22841049 TI - Mixture-process variable approach to optimize a microemulsion electrokinetic chromatography method for the quality control of a nutraceutical based on coenzyme Q10. AB - In recent years, multivariate optimization has played an increasing role in analytical method development. ICH guidelines recommend using statistical design of experiments to identify the design space, in which multivariate combinations of composition variables and process variables have been demonstrated to provide quality results. Considering a microemulsion electrokinetic chromatography method (MEEKC), the performance of the electrophoretic run depends on the proportions of mixture components (MCs) of the microemulsion and on the values of process variables (PVs). In the present work, for the first time in the literature, a mixture-process variable (MPV) approach was applied to optimize a MEEKC method for the analysis of coenzyme Q10 (Q10), ascorbic acid (AA), and folic acid (FA) contained in nutraceuticals. The MCs (buffer, surfactant-cosurfactant, oil) and the PVs (voltage, buffer concentration, buffer pH) were simultaneously changed according to a MPV experimental design. A 62-run MPV design was generated using the I-optimality criterion, assuming a 46-term MPV model allowing for special cubic blending of the MCs, quadratic effects of the PVs, and some MC-PV interactions. The obtained data were used to develop MPV models that express the performance of an electrophoretic run (measured as peak efficiencies of Q10, AA, and FA) in terms of the MCs and PVs. Contour and perturbation plots were drawn for each of the responses. Finally, the MPV models and criteria for the peak efficiencies were used to develop the design space and an optimal subregion (i.e., the settings of the mixture MCs and PVs that satisfy the respective criteria), as well as a unique optimal combination of MCs and PVs. PMID- 22841050 TI - Methyl mercury in nail clippings in relation to fish consumption analysis with gas chromatography coupled to inductively coupled plasma mass spectrometry: a first orientation. AB - For the identification of human exposure to one of the most toxic compounds, which is methyl mercury (MeHg(+)), fingernail clippings were selected as the matrix of interest. Within this pilot study, six samples from different origins and from people with different food consumption patterns were chosen. Species analysis of MeHg(+) was performed according to the following procedure: dissolution of the sample material in tetramethylammonium hydroxide (TMAH), derivatisation of MeHg(+) with sodium tetraethylborate (NaBEt(4)), extraction into iso-octane and measurement with gas chromatography hyphenated to inductively coupled plasma mass spectrometry (GC-ICPMS) for the quantification MeHg(+). PMID- 22841051 TI - Preparation and characterization of magnetic nanocomposite of Schiff base/silica/magnetite as a preconcentration phase for the trace determination of heavy metal ions in water, food and biological samples using atomic absorption spectrometry. AB - A versatile and robust solid phase with both magnetic property and a very high adsorption capacity is presented on the basis of modification of iron oxide silica magnetic particles with a newly synthesized Schiff base (Fe(3)O(4)/SiO(2)/L). The structure of the resulting product was confirmed by Fourier transform infrared (FT-IR) spectra, X-ray diffraction (XRD) spectrometry and transmission electron microscopy (TEM). We developed an efficient and cost effective method for the preconcentration of trace amounts of Pb(II), Cd(II) and Cu(II) in environmental and biological samples using this novel magnetic solid phase. Prepared magnetic solid phase is an ideal support because it has a large surface area, good selectivity and can be easily retrieved from large volumes of aqueous solutions. The possible parameters affecting the enrichment were optimized. Under the optimal conditions, the method detection limit was 0.14, 0.19 and 0.12 MUg L(-1) for Pb(II), Cd(II) and Cu(II) ions, respectively. The established method has been successfully applied to analyze real samples, and satisfactory results were obtained. All these indicated that this magnetic phase had a great potential in environmental and biological fields. PMID- 22841052 TI - Novel multi walled carbon nanotubes/beta-cyclodextrin based carbon paste electrode for flow injection potentiometric determination of piroxicam. AB - A novel carbon paste electrode based on functionlized multi-walled carbon nanotubes/beta-cyclodextrin composite (FMWCNTs/beta-CD-CPE) is described for potentiometric determination of piroxicam (PXM). Improved sensitivity and selectivity was achieved by application of CDs as molecular host-guest recognition elements and MWCNTs. The electrochemical performance of carbon paste electrodes incroporated with FMWCNTs/beta-CD composite was compared to those incroporated with MWCNTs and free CDs. Matrices compositions of each electrode are optimized on the basis of nature and content of the modifier, ionic sites and selected plasticizer. CPEs containing FMWCNTs/beta-CD composite, hyamine (Hy) and 2-fluorophenyl 2-nitrophenyl ether (f-NPE) as electrode plasticizer, work satisfactory in the concentration range from 10(-6) to 10(-2) mol L(-1) with Nernstain compliance (58.7+/-0.9 mV decade(-1) activity) with fast response time of about 2s and exhibit adequate operational lifetime (16 weeks). The developed electrodes have been applied for the potentiometric determination of PXM in pharmaceutical formulation under batch and flow injection analysis (FIA). FIA allows the analysis of 120 samples h(-1) with the advantage of simplicity, accuracy and automation feasibility. PMID- 22841053 TI - Comparison of fatty acid analysis methods for assessing biorefinery applicability of wastewater cultivated microalgae. AB - In this study, we compared the performances of four different gas chromatography (GC) based microalgal fatty acid analysis methods that are typically applied to biorefinery research using wastewater-adapted microalgae. Compared with the HP-5 type non-polar column, WAX-type polar columns exhibited excellent abilities to quantitatively separate C(16)-C(18) polyunsaturated fatty acids (PUFAs) from selected wastewater-adapted microalgae (Chlorella vulgaris, Ankistrodesmus gracilis and Scenedesmus quadricauda) isolates. GC-mass spectroscopy (MS) using the WAX-type polar column provided the strongest detection sensitivity among the tested methods by lowest detection limit, and GC-flame ionized detector (FID) with the same polar column exhibited nearly consistent results to GC-MS analysis. Our statistical comparison of microalgal fatty acid composition profiles generated using various GC methods, microalgal resources and culture media (wastewater, BG11 and nitrogen limitation) suggested that an appropriate GC method and algal resource choice are more important than the optimization of culture conditions to evaluate the applicability of microalgal biorefinery using wastewater resources. PMID- 22841054 TI - A new ion pair receptor fulfilling a dual function as a chromogenic molecular switch for F- and ratiometric selective recognition of HSO4(-). AB - A new ditopic ion pair receptor 1 containing two biindole moieties and a bis benzocrown ether unit shows a remarkable color switching (ON- and -OFF) function induced by anion (F(-)) and cation (K(+)) recognition. The ditopic receptor 1 binds in a cooperative fashion to HSO(4)(-) in the presence of 1.K(+) and acts as a selective ditopic receptor to recognize ion pairs with a wavelength-ratiometric manner. PMID- 22841056 TI - Use of tetraethylenepentamine-functional Fe3O4 magnetic polymers for matrix solid phase dispersion extraction and preconcentration of Cr(VI) in water samples at ultratrace levels. AB - A new method that utilizes tetraethylenepentamine-functional Fe(3)O(4) magnetic polymers (TEPA-NMPs) as a solid-phase extractant for matrix solid phase dispersion extraction (MSPD) has been developed for preconcentration of Cr(VI) at ultratrace levels prior to the measurement by flame atomic absorption spectroscopy (FAAS). The separation/preconcentration conditions of Cr(VI) was investigated, including the pH value, shaking time, adsorption temperature, sample volume, desorption conditions and interfering ions. The results showed the adsorption properties of the TEPA-NMPs were highly pH dependent. The data of adsorption kinetics obeyed pseudo-second-order rate mechanism well. Adsorption thermodynamic studies suggested that the adsorption processes of Cr(VI) onto the TEPA-NMPs was endothermic and entropy favored in nature. Under the best experimental conditions, the enhancement factor was 125 times, the detection limit of the method was 0.16 MUg L(-1) and the relative standard deviation was 1.9% (n=7). Furthermore, the developed method was validated by comparing with Graphite Furnace atomic absorption spectrometry (GF-AAS) method, and has been applied for the determination of ultratrace Cr(VI) ions in the river and tap water samples with satisfactory results, which revealed the sensitivity of the proposed TEPA-NMPs MSPD-FAAS method was comparable with that of GF-AAS method. PMID- 22841055 TI - Pretreatment of whole blood using hydrogen peroxide and UV irradiation. Design of the advanced oxidation process. AB - A new process to pretreat blood samples has been developed. This process combines the Advanced Oxidation Process (AOP) treatment (using H(2)O(2) and UV irradiation) with acid deactivation of the enzyme catalase in blood. A four-cell reactor has been designed and built in house. The effect of pH on the AOP process has been investigated. The kinetics of the pretreatment process shows that at high C(H(2)O(2),t=0), the reaction is zeroth order with respect to C(H(2)O(2)) and first order with respect to C(blood). The rate limiting process is photon flux from the UV lamp. Degradation of whole blood has been compared with that of pure hemoglobin samples. The AOP pretreatment of the blood samples has led to the subsequent determination of chromium and zinc concentrations in the samples using electrochemical methods. PMID- 22841057 TI - Simultaneous determination of organophosphorus, organochlorine, pyrethriod and carbamate pesticides in Radix astragali by microwave-assisted extraction/dispersive-solid phase extraction coupled with GC-MS. AB - A simple, rapid and reliable method was proposed for the simultaneous determination of 27 pesticides (organophosphorus, organochlorine, pyrethroid and carbamate pesticides) in Radix astragali. The pesticides were extracted by acetonitrile and the experimental variables, such as temperature, extraction time and volume of acetonitrile, were optimized through orthogonal array experimental design. Cleanup of extracts was performed with dispersive-solid phase extraction using primary secondary amine (PSA) as the sorbent. The determination of pesticides in the final extracts was carried out by gas chromatography-mass spectrometry in selected ion monitoring mode (GC-MS, SIM). The linearity of the calibration curves is good in matrix-matched standard, and yields the coefficients of determination (R(2))>=0.99 for approximately 96% of the target analytes. Under optimized conditions, the average recoveries (six replicates) for most pesticides (spiked at 0.02, 0.1 and 0.2 mg kg(-1)) range from 70% to 120%, and RSDs are less than 17.2%. PMID- 22841058 TI - A fast and sensitive method for the determination of nitrite in human plasma by capillary electrophoresis with fluorescence detection. AB - Analysis of nitrite, the indicator of nitric oxide (NO) generation in vivo, provides a useful tool to study NO synthesis in vivo. A fast and sensitive fluorometric CE method was developed for determination of nitrite in human plasma through its derivatization with 2,3-diaminonaphthalene (DAN). Nitrite in human plasma was easily reacted with DAN under acid conditions to yield the highly fluorescent 2,3-naphthotriazole (NAT). Fluorescence detection was optimized to achieve subnanomolar detection which allows a direct analysis of plasma samples unlike most CE-UV methods using sample stacking. Acetonitrile was used to remove the protein. Short-end injection and a high voltage (-30 kV) were used to shorten the analysis time. The good separation was achieved with 20 mM borate buffer at pH 9.23. The separation of NAT was obtained within 1.4 min. The deproteinized plasma sample was injected hydrodynamically for 5s at -50 mbar into a 60 cm * 75 MUm internal diameter uncoated fused-silica capillary. Excitation wavelength was selected with a broad-band filter (240-400 nm), and the emitted light was measured at 418 nm by the use of a cutoff filter. A good linearity (R(2)=0.9975) was obtained in the range from 2 to 500 nM. The detection limit of nitrite was 0.6 nM in original plasma samples, which is 750 times lower than our previous CE UV method. The developed fluorometric CE method offers the advantages of more simple system and lower cost compared with the current fluorometric HPLC methods without losing sensitivity. The detected mean nitrite concentration in human plasma by this method was consistent with the most frequently reported values. PMID- 22841059 TI - Determination of deoxynivalenol and nivalenol by liquid chromatography and fluorimetric detection with on-line chemical post-column derivatization. AB - A rapid, sensitive and selective analytical method was developed for the quantitative determination of deoxynivalenol (DON) and nivalenol (NIV) in cereals intended for human and animal consumption. The method, based on liquid chromatography and fluorescence detection, involves an automated 2 channel post column derivatization, performed with sodium hydroxide, methyl acetoacetate and ammonium acetate. The chromatographic separation was accomplished using a C18 column eluted in isocratic mode with a mixture of 0.01% acetic acid and acetonitrile. Optimal fluorescence detection was obtained by an excitation and emission wavelength of 360 nm and 470 nm, respectively. The sample preparation required a rapid extraction of mycotoxins with water and a purification step by hydrophilic-lipophilic balance column clean-up. Under the optimized experimental conditions, a complete separation of DON and NIV was obtained in less than 20 min. The on-line post-column derivatization ensures excellent results in terms of simplicity and sensitivity, with limits of detection down to 0.014 mg/kg. The proposed method was extensively validated and the analytical performances of linearity (correlation coefficient of 0.9998), selectivity, precision (intra-day precision lower than 8%) and recovery (ranging from 89% to 101%) were evaluated, demonstrating the method feasibility in accurate confirmation analyses. PMID- 22841060 TI - A simple way to configure on-line two-dimensional liquid chromatography for complex sample analysis: acquisition of four-dimensional data. AB - An on-line comprehensive two-dimensional liquid chromatography (HPLC*UPLC-TOF MS) was set up just using the injection valve of the ultra performance liquid chromatography (UPLC) as the interface through which the effluent of high performance liquid chromatography (HPLC) was injected automatically to UPLC coupled to time-of-flight mass spectrometry (TOF MS). As a demonstrative application, a complex sample of Traditional Chinese Medicine, Qingkailing was analyzed. As a result, a four-dimensional (4D) data containing 2D retention times, peak intensity and m/z ratios was plotted, where 398 peaks were counted and low concentration components were distinguished from the high concentration ones with a total peak capacity of 1090. Comparing with traditional 3D data acquired by HPLC*HPLC, the 4D data generated by HPLC*UPLC-TOF MS can increase the number of recognized components by three times, reduce the analysis time by 75%. Such a configuration of HPLC*UPLC-TOF MS can realize easily upon commercial chromatographs while exhibited enhanced separation efficiency, high sensitivity, huge peak capacity and great potential in complex sample analysis. PMID- 22841061 TI - Reagentless and calibrationless silicate measurement in oceanic waters. AB - Determination of silicate concentration in seawater without addition of liquid reagents was the key prerequisite for developing an autonomous in situ electrochemical silicate sensor (Lacombe et al., 2007) [11]. The present challenge is to address the issue of calibrationless determination. To achieve such an objective, we chose chronoamperometry performed successively on planar microelectrode (ME) and ultramicroelectrode (UME) among the various possibilities. This analytical method allows estimating simultaneously the diffusion coefficient and the concentration of the studied species. Results obtained with ferrocyanide are in excellent agreement with values of the imposed concentration and diffusion coefficient found in the literature. For the silicate reagentless method, successive chronoamperometric measurements have been performed using a pair of gold disk electrodes for both UME and ME. Our calibrationless method was tested with different concentrations of silicate in artificial seawater from 55 to 140*10(-6) mol L(-1). The average value obtained for the diffusion coefficient of the silicomolybdic complex is 2.2+/-0.4*10(-6) cm(2) s(-1), consistent with diffusion coefficient values of molecules in liquid media. Good results were observed when comparing known concentration of silicate with experimentally derived ones. Further work is underway to explore silicate determination within the lower range of oceanic silicate concentration, down to 0.1*10(-6) mol L(-1). PMID- 22841062 TI - Real-time determination of critical quality attributes using near-infrared spectroscopy: a contribution for Process Analytical Technology (PAT). AB - Process Analytical Technology (PAT) is playing a central role in current regulations on pharmaceutical production processes. Proper understanding of all operations and variables connecting the raw materials to end products is one of the keys to ensuring quality of the products and continuous improvement in their production. Near infrared spectroscopy (NIRS) has been successfully used to develop faster and non-invasive quantitative methods for real-time predicting critical quality attributes (CQA) of pharmaceutical granulates (API content, pH, moisture, flowability, angle of repose and particle size). NIR spectra have been acquired from the bin blender after granulation process in a non-classified area without the need of sample withdrawal. The methodology used for data acquisition, calibration modelling and method application in this context is relatively inexpensive and can be easily implemented by most pharmaceutical laboratories. For this purpose, Partial Least-Squares (PLS) algorithm was used to calculate multivariate calibration models, that provided acceptable Root Mean Square Error of Predictions (RMSEP) values (RMSEP(API)=1.0 mg/g; RMSEP(pH)=0.1; RMSEP(Moisture)=0.1%; RMSEP(Flowability)=0.6 g/s; RMSEP(Angle of repose)=1.7 degrees and RMSEP(Particle size)=2.5%) that allowed the application for routine analyses of production batches. The proposed method affords quality assessment of end products and the determination of important parameters with a view to understanding production processes used by the pharmaceutical industry. As shown here, the NIRS technique is a highly suitable tool for Process Analytical Technologies. PMID- 22841063 TI - Salt release monitoring with specific sensors in "in vitro" oral and digestive environments from soft cheeses. AB - The objective of the present work is to demonstrate the interest and the feasibility of the measurement of NaCl concentrations in soft cheeses and in particular an in vitro digestion process by the use of chemical sensors. The analyzed matrices were the commercial Italian mozzarella cheeses and domestic cheese base models. The classification of mozzarellas was performed according to their salinity, while the breakdown of cheese base models has been followed both at initial steps of digestion in artificial mouth dispositive mimicking the oral sphere and in a gut-imitating digester (TIM-1). During the breakdown of soft cheese in the digester, the estimated values for Na(+) concentration using mono Na-ISEs showed correlation coefficients values about 0.907 and 0.832 compared to Ionic Chromatography (IC) reference values, with an important relative error (about 30-40%). The use of ISE array system combining several electrodes, in particular electrodes showing more selectivity to Cl(-) and Na(+) ions, showed the best results for Na(+) concentration estimation, with good correlations both in calibration (R=0.962) and in validation (R=0.952) steps. For cheese digestion in the artificial mouth, good correlations for Na(+) concentration were observed using single Na-ISE compared to IC with coefficients ranking between 0.93 and 0.96 for both the calibration and validation steps. Moreover, a fair correlation between chloride ions measured with Cl-ISE2 and Na(+) (R=0.96) was found. The best results were obtained with the use of ISEs array combining, in particular, Cl(-) and Na(+) detections. The salinity of commercial mozzarella cheese samples, as far as originally utilized milk type (cow or buffalo), were also satisfactory determined with developed ISE array. PMID- 22841064 TI - Study of bond Elut(r) PlexaTM PCX cation exchange resin in flow injection column preconcentration system for metal determination by flame atomic absorption spectrometry. AB - A simple and sensitive on-line solid-phase extraction methodology for preconcentration and determination of trace amounts of Cd(II), Pd(II) and Cu(II) in natural water samples has been developed using the strong cation exchange capability of Bond Elut((r)) PlexaTM PCX polymer resin. Plexa PCX is a mixed-mode sorbent, commercially available in a cartridge format and as far as we know, there is no application into the field of metal determination. The analytes were retained on the resin, eluted with 1 mol L(-1) hydrochloric acid and subsequently directed to FAAS for quantification. The influence of chemical and flow variables which affect the performance of the system have been studied, providing the appropriate conditions for the analysis of real samples. For preconcentration time of 90 s, an enrichment factor of 90, 95 and 95 and a detection limit (3 s) of 0.1, 1.8 and 0.5 MUg L(-1) for Cd(II), Pb(II) and Cu(II), respectively were obtained along with a sampling frequency of 30 h(-1). The accuracy of the proposed method was evaluated by analyzing certified reference materials. This procedure was successfully applied for metal determination in environmental and biological samples. PMID- 22841065 TI - Determination of mercury in indoor dust samples by ultrasonic probe microextraction and stripping voltammetry on gold nanoparticles-modified screen printed electrodes. AB - A miniaturized, fast, and efficient ultrasonic probe assisted method for Hg(II) extraction from indoor dust samples, in hydrochloric acid medium, was developed. The combination of the extraction method with the electrochemical determination of mercury by square-wave anodic stripping voltammetry (SWASV) on gold nanoparticles-modified screen-printed carbon electrodes (AuNPs-SPCEs) resulted in a convenient method for rapid, sensitive, and reliable mercury monitoring. Parameters involved in the extraction such as acid concentration, sonication amplitude, and sonication time were optimized using a Face-centered cube Central Composite Design. ICP-MS was also used to contrast the methodology and good agreement with electrochemical results was verified. Optimization and validation of the procedure were carried out by using NIST Standard Reference Material((r)) 2583 Trace Elements in Indoor Dust. Finally, the proposed methodology was successfully applied for Hg(II) determination in dust samples collected at different indoor ambients. PMID- 22841066 TI - Sensitive and selective capillary electrophoretic analysis of proteins by zirconia nanoparticle-enhanced copper (II)-catalyzed luminol-hydrogen peroxide chemiluminescence. AB - We report herein a sensitive, selective, convenient CE determination of heme proteins in complex matrices by a sodium-dodecyl-sulfate-assisted, zirconia nanoparticle-enhanced copper (II)-catalyzed luminol-hydrogen peroxide chemiluminescence (CCLHPCL). Introducing a segment of sodium dodecyl sulfate to the capillary after sample injection not only rendered selective detection by quenching the luminescence signals from the non-heme proteins but also owning to the suppressed protein adsorption, led to significant improvement in separation efficiency and detection sensitivity. The signals were further improved by addition of ZrO(2) nanoparticles to the chemiluminescence solution. Compared with the conventional CCLHPCL, the detection limits (S/N=3) were improved by 10.2-22.0 folds, with 7.8*10(-9), 3.3*10(-9) and 1.5*10(-9) M for three model proteins, viz, myoglobin, hemoglobin and cytochrome C, respectively. Because the method did not require sophisticated pretreatment, it was convenient to analyze heme proteins in complex matrices, as demonstrated, hemoglobin in human blood and spiked human urine samples. PMID- 22841067 TI - A new method for determining the acid number of biodiesel based on coulometric titration. AB - A new method is proposed for determining the acid number (AN) of biodiesel using coulometric titration with potentiometric detection, basically employing a potentiostat/galvanostat and an electrochemical cell containing a platinum electrode, a silver electrode, and a combination pH electrode. The method involves a sequential application of a constant current between the platinum (cathode) and silver (anode) electrodes, followed by measuring the potential of the combination pH electrode, using an isopropanol/water mixture as solvent and LiCl as the supporting electrolyte. A preliminary evaluation of the new method, using acetic acid for doping a biodiesel sample, showed an average recovery of 100.1%. Compared to a volumetric titration-based method for determining the AN of several biodiesel samples (ranging from about 0.18 to 0.95 mg g(-1)), the new method produced statistically similar results with better repeatability. Compared to other works reported in the literature, the new method presented an average repeatability up to 3.2 times better and employed a sample size up to 20 times smaller. PMID- 22841068 TI - Effect of organic solvents on peroxidases from rice and horseradish: prospects for enzyme based applications. AB - A feasibility test for rice peroxidase (RP) enzyme as a substitute for horseradish peroxidase (HRP) was carried out. The activity of HRP was maximum at 30 degrees C with pH 6.0-7.0. The purified rice peroxidase showed optimum activity at 30 degrees C with pH 7-8 and was thermostable till 68 degrees C, which is higher than the temperature reported for HRP. RP obeyed Michaelis-Menten kinetics. With increasing substrate concentrations, RP and HRP had V(max) as 8.23 MUM min(-1) and 4.21 MUM min(-1) and K(m) as 5.585 and 3.662 mM, respectively. In 10% 1,4-dioxane and ethanol, RP exhibited 2 and 1.3 times higher activity, respectively than HRP. Shelf life studies show RP to be significantly stable till 60 h in 20% 1,4-dioxane and till 12 h in ethanol. The activity of RP/HRP increased gradually with 0%-40% ethanol or 0%-30% 1,4-dioxane till 20 h with a sharp decline thereafter. The stability of HRP and RP reduced with increasing storage period. Enzyme efficiencies compared as V(m)/K(m) showed water miscible organic solvents, viz.1,4-dioxane and ethanol, to exhibit a regular decrease in V(m)/K(m) with increase in organic solvent concentration whereas, a reverse trend was observed with water-immiscible solvent like chloroform. The relative activity of RP and HRP enzymes upon immobilization on poly-5-carboxy-indole shows increasing enzyme activity with time and with guaiacol/dopamine hydrochloride as substrates. Immobilized RP had a better relative activity with dopamine as substrate than immobilized HRP, whereas with guaiacol both RP and HRP had a comparable activity upon immobilization. Results suggest rice peroxidase to be a cheaper and convenient enzyme system for immobilization using organic solvents. The high thermal stability, more stability in organic solvents and longer shelf life of RP over the immobilizing matrix suggest conducting polyindole having carboxyl functional groups to be a suitable matrix for the covalent entrapment of rice peroxidase through amide linkage. Good sensitivity and fast response to dopamine makes RP a suitable enzyme system for monitoring dopamine levels in aqueous medium. PMID- 22841069 TI - Optimization of solid-phase extraction using artificial neural networks and response surface methodology in combination with experimental design for determination of gold by atomic absorption spectrometry in industrial wastewater samples. AB - Solid-phase extraction (SPE) is often used for preconcentration and determination of metal ions from industrial and natural samples. A traditional single variable approach (SVA) is still often carried out for optimization in analytical chemistry. Since there is always a risk of not finding the real optimum by single variation method, more advanced optimization approaches such as multivariable approach (MVA) should be applied. Applying MVA optimization can save both time and chemical materials, and consequently decrease analytical costs. Nowadays, using artificial neural network (ANN) and response surface methodology (RSM) in combination with experimental design (MVA) are rapidly developing. After prediction of model equation in RSM and training of artificial neurons in ANNs, the products were used for estimation of the response of the 27 experimental runs. In the present work, the optimization of SPE using single variation method and optimization by ANN and RSM in combination with central composite design (CCD) are compared and the latter approach is practically illustrated. PMID- 22841070 TI - Optical nanobiosensor: a new analytical tool for monitoring carboplatin-DNA interaction in vitro. AB - The interaction of DNA and Carboplatin was studied with DNA labeled gold nanoparticles (AuNPs) based optical nanobiosensor. Carboplatin, a cytotoxic drug, is responsible for producing nephrotoxicity at effective dose. Thus, we have developed optical nanobiosensor for monitoring carboplatin-DNA interaction based on Fluorescence Resonance Energy Transfer (FRET) phenomenon. Paracetamol, an analgesic agent, was used as controlled drug in this study. The DNA labeled AuNPs, exposed to carboplatin, a binding event among the DNA and carboplatin takes place, resulting in a conformational change within the biosensor complex which decreases the distance among the fluorescent molecules or the fluorescent/quencher molecules. As the carboplatin interact with DNA, an increase in fluorescence intensity was observed. So, the major difference in increased fluorescence intensity between carboplatin-DNA and paracetamol-DNA interaction shows significant observations. Results have demonstrated that Optical sensor is able to rapidly and effectively monitor carboplatin-DNA interaction with a detection limit up to 0.45 MUg/ml. This suggests that the developed optical nanobiosensor was ideal for monitoring Drug-DNA interaction studies while performing combinatorial synthesis for new drug development. PMID- 22841071 TI - Determination of diethylstilbestrol in milk using carbon nanotube-reinforced hollow fiber solid-phase microextraction combined with high-performance liquid chromatography. AB - Carbon nanotube-reinforced hollow fiber solid-phase microextraction (CNTs-HF SPME) combined with high-performance liquid chromatography (HPLC) was used to extract and determine diethylstilbestrol (DES) in milk products. Wall pores of the hollow fiber were filled with multi-walled carbon nanotubes (MWCNTs) using sol-gel technology. In the proposed method, DES was selectively extracted by MWCNTs, desorbed to methanol, and analyzed by HPLC. The parameters affecting the efficiency of CNTs-HFSPME, such as the length of the hollow fiber, extraction and desorption times, extraction temperature, stirring rate, pH of the sample solution, and the amount of organic solvent and salt in the sample solution, were investigated and optimized. Under the optimized extraction conditions, the method showed good linearity (24-960 MUg L(-1)), a low method detection limit (MDL, 5.1 MUg L(-1)), and good recoveries at four different concentrations. It was proven to be simple, rapid, sensitive, and solvent free for the analysis of DES in dairy products. PMID- 22841072 TI - Multivariate optimization on flow-injection electrochemical hydride generation atomic absorption spectrometry of cadmium. AB - A novel electrochemical hydride generation (ECHG) system working in flow injection (FI) mode was developed for determination of cadmium coupled to an electrically heated quartz tube atomizer (QTA) by atomic absorption spectrometry (AAS). A Plackett-Burman experimental design for screening has been used to evaluate the influence of several variables on the analytical response. Then, the significant parameters such as the concentration of NaCl in catholyte, applied electrolytic current and flow rate of carrier gas have been simultaneously optimized using a central composite design (CCD). Under the optimized conditions, the detection limit (3sigma(b), n=9) was found to be 0.51 ng mL(-1) Cd and the relative standard deviation (RSD) for nine replicate analyses of 20 ng mL(-1) Cd was 6.5%. The calibration curve was linear in the range of 2-50 ng mL(-1) of Cd. The potential interferences from various ions were also evaluated. The analysis of a reference material showed good agreement with the certified value. The proposed method was successfully applied to the determination of Cd in tap water sample. PMID- 22841073 TI - Optimized ultrasound-assisted emulsification microextraction for simultaneous trace multielement determination of heavy metals in real water samples by ICP OES. AB - Ultrasonic-assisted emulsification microextraction (USAEME) combined with inductively coupled plasma-optical emission spectrometry (ICP-OES) was used for preconcentration and determination of aluminum, bismuth, cadmium, cobalt, copper, iron, gallium, indium, nickel, lead, thallium and zinc in real water samples. Ammonium pyrrolidine dithiocarbamate (APDC) and carbon tetrachloride (CCl(4)) were used as the chelating agent and extraction solvent, respectively. The effective parameters (factors) of the extraction process such as volume of extraction solvent, pH, sonication time, and concentration of chelating agent were optimized by a small central composite design (CCD). The optimum conditions were found to be 98 MUL for extraction solvent, 1476 mg L(-1) for chelating agent, 3.8 for pH and 9 min for sonication time. Under the optimal conditions, the limits of detection (LODs) for Al, Bi, Cd, Co, Cu, Fe, Ga, In, Ni, Pb, Tl and Zn were 0.13, 0.48, 0.19, 0.28, 0.29, 0.27, 0.27, 0.38, 0.44, 0.47, 0.52 and 0.17 MUg L(-1), respectively. The linear dynamic range (LDR) was 1-1000 MU gL(-1) with determination coefficients of 0.991-0.998. Relative standard deviations (RSDs, C=200 MUg L(-1), n=6) were between 1.87%-5.65%. The proposed method was successfully applied to the extraction and determination of heavy metals in real water samples and the satisfactory relative recoveries (90.3%-105.5%) were obtained. PMID- 22841074 TI - Uncovering interactions in Plackett-Burman screening designs applied to analytical systems. A Monte Carlo ant colony optimization approach. AB - Screening of relevant factors using Plackett-Burman designs is usual in analytical chemistry. It relies on the assumption that factor interactions are negligible; however, failure of recognizing such interactions may lead to incorrect results. Factor associations can be revealed by feature selection techniques such as ant colony optimization. This method has been combined with a Monte Carlo approach, developing a new algorithm for assessing both main and interaction terms when analyzing the influence of experimental factors through a Plackett-Burman design of experiments. The results for both simulated and analytically relevant experimental systems show excellent agreement with previous approaches, highlighting the importance of considering potential interactions when conducting a screening search. PMID- 22841075 TI - Fast screening of rice knockout mutants by multi-channel microchip electrophoresis. AB - A multi-channel microchip electrophoresis (MC-ME) system with a laser-induced fluorescence detector was developed for the fast simultaneous detection of rice knockout mutants in genetically modified (GM) rice. In addition, three parallel separation channels were fabricated on a glass microchip to investigate the possibility of high-throughput screening of amplified-polymerase chain reaction products representing wild-type rice and mutants. The MC-ME system was developed to simultaneously record data on all channels using specifically designed electrodes for an even distribution of electric fields, an expanded laser beam for excitation, a 10* objective lens to capture emissions, and a charge coupled device camera for detection. Under a programmed electric field strength and a sieving gel matrix of 0.7% poly(ethylene oxide) (M(r)=8,000,000), T-DNA-inserted rice mutants, two standard wild-type rice lines, and six rice knockout mutants were analyzed within 4 min using three parallel channels on the microchip. Compared to conventional microchip electrophoresis, the MC-ME method is a valid and practical way to effectively analyze multiple samples in parallel for the identification of GM rice without any loss of resolving power or reproducibility. The MC-ME method was more than 15 times faster than traditional slab gel electrophoresis and proved to be a powerful tool for high-throughput screening of GM rice with high sensitivity, efficiency, and reproducibility. PMID- 22841076 TI - A new method for quantifying N-nitrosamines in wastewater samples by gas chromatography-triple quadrupole mass spectrometry. AB - We developed a methodology for the separation, identification, and quantification of eight N-nitrosamines. For a range of wastewater samples, including raw sewage and final-discharge wastewater, the methodology, which was based on solid-phase extraction (SPE) and a purification technique followed by analysis using a gas chromatograph equipped with a triple-quadrupole mass spectrometer, gave effective separation of the targeted compounds. The limits of detection of this method for N-nitrosamines in wastewaters ranged from 0.1 to 1.0 ng L(-1) and the limits of quantification ranged from 0.4 to 3.3 ng L(-1). As a result of preliminary recovery testing, we decided on a combination of two types of sorbent cartridges for SPE-one was aminoprophyl for sample purification and the other was activated charcoal for analyte concentration-that gave excellent recovery rates (98% to 152%) of three deuterided nitrosamines (surrogates). Using this combination of SPE, internal surrogates, and an injection surrogate, we obtained good recovery rates (80% to 131%) with low relative standard deviations (1% to 14%, n=3) for eight N-nitrosamines in all samples of influent, secondary effluent, and final discharge. We applied the newly developed pre-treatment method to an influent wastewater samples. All of the N-nitrosamines except two (NMEA and NDPA) were detected in the influent sample, at 1 to 1057 ng L(-1). PMID- 22841078 TI - Simple flow injection for screening of total antioxidant capacity by amperometric detection of DPPH radical on carbon nanotube modified-glassy carbon electrode. AB - An amperometric flow injection (FI) method suitable for evaluation of 'total antioxidant capacity' (TAC) is presented. In this method, a carrier stream of a solution of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)) continuously flows through an electrochemical cell, furnished with a carbon nanotube modified-glassy carbon electrode (CNT/GC) as the working electrode. At the applied voltage of 0.05V (vs. Ag/AgCl), DPPH(*) is reduced resulting in a constant electric current. For measurement of the TAC, a sample zone containing antioxidant(s) is injected into the carrier stream therein reduction reaction of DPPH(*) occurring within the sample zone. The decreased amount of the radical in the sample zone leads to a drop of the amperometric signal at the CNT/GC electrode. We have also compared the performance of the CNT/GC electrode to the unmodified GC electrode using cyclic voltammetry. The sensitivity of the CNT/GC electrode was more than twenty five times greater than the bare GC electrode. The study of the sweep rate dependence showed that the cathodic and anodic current of 0.1mM DPPH solution varied linearly (r(2)=0.998) with the square root of the scan rate, from 0.02 to 0.12 Vs(-1). These results demonstrated that the CNT/GC electrode is appropriate for the quantitation of antioxidants via amperometric detection of the residual concentration of non-reacted DPPH(*). We obtained linear calibrations for all the antioxidants tested including gallic acid, catechin, quercetin, caffeic acid and Trolox. The system offers rapid sample throughput (45 samples h(-1)) and good precision of 3.2% R.S.D., for 20 MUL-injection of 2.5 MUM Trolox (n=30). This method was applied to evaluate the TAC of extracts of some Thai indigenous vegetables. PMID- 22841077 TI - Immunochromatographic assay of cadmium levels in oysters. AB - Oysters are one of foodstuffs containing a relatively high amount of cadmium. Here we report on establishment of an immunochromatographic assay (ICA) method of cadmium levels in oysters. Cadmium was extracted with 0.l mol L(-1) HCl from oysters and cleaned up from other metals by the use of an anion-exchange column. The behavior of five metals Mn, Fe, Cu, Zn, and Cd was monitored at each step of extraction and clean-up procedure for the ICA method in an inductively coupled plasma-mass spectrometry (ICP-MS) analysis. The results revealed that a simple extraction method with the HCl solution was efficient enough to extract almost all of cadmium from oysters. Clean-up with an anion-exchange column presented almost no loss of cadmium adsorbed on the column and an efficient removal of metals other than cadmium. When a spiked recovery test was performed in the ICA method, the recovery ranged from 98% to 112% with relative standard deviations between 5.9% and 9.2%. The measured values of cadmium in various oyster samples in the ICA method were favorably correlated with those in ICP-MS analysis (r(2)=0.97). Overall results indicate that the ICA method established in the present study is an adequate and reliable detection method for cadmium levels in oysters. PMID- 22841079 TI - Determination of chemical oxygen demand by a flow injection method based on microwave digestion and chromium speciation coupled to inductively coupled plasma optical emission spectrometry. AB - The present paper evaluates the applicability of a new FIA system for COD determination. The new system, flow injection microwave solid phase extraction by means of activated carbon (FI-MW-SPE), consists of a digestion circuit, placed in a home MW oven, coupled to an ICP-OES spectrophotometer. Doehlert experimental design was used to speed up the optimization of different experimental variables studied for assisted digestion methods. The method provided a high throughput of about 18 samples h(-1). To assess the accuracy of analytical methods linear regression, elliptic joint confidence region (EJCR) was used. A large linear range of 2.78-850 mg O(2) L(-1) with an excellent detection limit of 0.94 mg O(2) L(-1) was obtained. The interference by high chloride concentration was studied, and values below 3000 mg Cl(-) ions L(-1), allowed the estimation of COD load without any masking agents. COD values for various types of wastewater samples were correlated with those obtained by standard manual methods. Moreover, interferences due to matrix nature are absent; since matrix is washed out of the column before Cr (III) is eluted. This method reduces the time, reagent volume, hazardous emission, external contamination, with a good reproducibility and accuracy. PMID- 22841080 TI - Rapid analysis of chlorinated anilines in environmental water samples using ultrasound assisted emulsification microextraction with solidification of floating organic droplet followed by HPLC-UV detection. AB - The present study demonstrates a simple, rapid and efficient method for the determination of chlorinated anilines (CAs) in environmental water samples using ultrasonication assisted emulsification microextraction technique based on solidification of floating organic droplet (USAEME-SFO) coupled with high performance liquid chromatography-ultraviolet (HPLC-UV) detection. In this extraction method, 1-dodecanol was used as extraction solvent which is of lower density than water, low toxicity, low volatility, and low melting point (24 degrees C). After the USAEME, extraction solvent could be collected easily by keeping the extraction tube in ice bath for 2 min and the solidified organic droplet was scooped out using a spatula and transferred to another glass vial and allowed to thaw. Then, 10 MUL of extraction solvent was diluted with mobile phase (1:1) and taken for HPLC-UV analysis. Parameters influencing the extraction efficiency, such as the kind and volume of extraction solvent, volume of sample, ultrasonication time, pH and salt concentration were thoroughly examined and optimized. Under the optimal conditions, the method showed good linearity in the concentration range of 0.05-500 ng mL(-1) with correlation coefficients ranging from 0.9948 to 0.9957 for the three target CAs. The limit of detection based on signal to noise ratio of 3 ranged from 0.01 to 0.1 ng mL(-1). The relative standard deviations (RSDs) varied from 2.1 to 6.1% (n=3) and the enrichment factors ranged from 44 to 124. The proposed method has also been successfully applied to analyze real water samples and the relative recoveries of environmental water samples ranged from 81.1 to 116.9%. PMID- 22841081 TI - In situ digestion for the determination of Ca in beverages by tungsten coil atomic emission spectrometry. AB - Tungsten coil atomic emission spectrometry (WCAES) is employed for the determination of calcium in juice, mineral and coconut water samples. A sample aliquot of 20 MUL is placed directly on the coil and a constant-voltage power source is used to dry and atomize the sample, as well as to promote Ca atomic emission. Analytical signals are resolved and detected using a Czerny-Turner spectrometer and a charge coupled device detector. Some experimental parameters such as coil position related to the spectrometer entrance slit and integration time are critically evaluated. A heating program with relatively constant drying temperatures is used in all measurements. An in situ digestion procedure is used to partially decompose organic matrices and improve WCAES precision and accuracy. By adding an oxidizing mixture to the sample and including a digestion step in the heating cycle, no statistical difference was observed between WCAES and ICP OES results for Ca in juice and coconut water samples. Mineral water samples were simply diluted with 1% vv(-1) HNO(3) before analysis and no significant interference was observed for concomitants such as Na and K. Despite severe positive interference caused by Mg, good agreement was obtained between WCAES and ICP OES results for Ca in several mineral water samples. Limits of detection and quantification obtained were 0.02 and 0.07 mg L(-1), respectively. The method precision, calculated as the relative standard deviation for 10 consecutive measurements of a 2.5 mg L(-1) Ca solution, is 3.8%. PMID- 22841082 TI - Simultaneous voltammetric determination of synthetic colorants in food using a cathodically pretreated boron-doped diamond electrode. AB - Differential pulse voltammetry (DPV) and a cathodically pretreated boron-doped diamond (BDD) electrode were used to simultaneously determine two pairs of synthetic food colorants commonly found mixed in food products: tartrazine (TT) and sunset yellow (SY) or brilliant blue (BB) and sunset yellow (SY). In the DPV measurements using the BDD electrode, the reduction peak potentials of TT and SY or BB and SY were separated by about 150 mV. The detection limit values obtained for the simultaneous determination of TT and SY or BB and SY were 62.7 nmol L(-1) and 13.1 nmol L(-1) or 143 nmol L(-1) and 25.6 nmol L(-1), respectively. The novel proposed voltammetric method was successfully applied in the simultaneous determination of these synthetic colorants in food products, with results similar to those obtained using a HPLC method at 95% confidence level. PMID- 22841083 TI - Application of near infrared spectroscopy technology for the detection of fungicide treatment on durum wheat samples. AB - The feasibility of Near Infrared Spectroscopy to detect fungicide treatment on wheat samples was assessed. A total of 213 durum wheat samples from four different trial sites in Andalusia (southern Spain), with different agroclimatic conditions (soil, temperature, rainfall) were selected for been analyzed on VIS+NIR (400 nm-2500 nm) and NIR (1100 nm-2500 nm). Different mathematical pre treatment on the signal (scatter correction and derivatives) were evaluated for their discrimination accuracies. Using MPLS, the selected models obtained 84% of well classified samples. PMID- 22841084 TI - Inductively coupled plasma mass spectrometry in comparison with neutron activation and ion chromatography with UV/VIS detection for the determination of lanthanides in plant materials. AB - Analytical performance of inductively coupled plasma mass spectrometry (ICP-MS) for determination of lanthanides in plant materials was investigated and compared with neutron activation analysis (NAA) as well as ion chromatography (IC) with UV VIS detection. Two sample preparation protocols were tested: (i) microwave assisted digestion by concentrated nitric acid; (ii) microwave digestion involving silica and fluoride removal, followed by the selective and quantitative lanthanides group separation from the plant matrix. Several Certified Reference Materials (CRM) of plant origin were used for the evaluation of the accuracy of the applied analytical procedures. The consistency of results, obtained by various methods, enabled to establish the tentative recommended values (TRV) for several missing elements in one of CRMs. The ICP-MS, due to its very high sensitivity, has the potential to contribute to this aim. The discrepancy of the results obtained by various methods was discussed in a view of possible matrix effects related to the composition of investigated materials. PMID- 22841085 TI - Mechanism change in estimating of antioxidant activity of phenolic compounds. AB - The 2,2'-diphenyl-1-picrylhydrazyl (DPPH(*)) method is commonly applied for the estimation of antioxidant activity of single compounds and plant extracts. In this method, the amount of disappeared DPPH(*) in the examined system, determined spectrophotometrically, is a measure of the antioxidative (hydrogen-donating) activity of compounds. The present paper discusses the influence of buffer components on the estimation of antioxidant activity of phenolic compounds by this method. According to the obtained results, the change of hydrogen ion concentration changes the mechanism of scavenging process of DPPH radicals by phenolic antioxidants, and the introduction of metal ions into measuring system blocks the scavenging process of DPPH radicals. Both factors depend on the anion type used in the measuring system. The presented results may be especially important for the researches examining plant extract which differ in the content and composition of natural acids and metal ions, and for those who investigate the mechanisms of the reaction applied for the estimation of antioxidant properties. PMID- 22841086 TI - Humidity effect on ammonia sensing properties of substituted and unsubstituted cobalt phthalocyanines. AB - In this paper, we studied the effect of humidity on the response of cobalt phthalocyanine-containing resistors to ammonia, in the ppm range. We pointed out the fact that, when alternating exposure periods with recovery periods, the humidity effect had to be carefully studied, in correlation with the flow variation. Thus, for a sulfonated cobalt phthalocyanine, the effect of NH(3) was totally screened as soon as the relative humidity (RH) was above 10%. On the contrary, when using unsubstituted cobalt phthalocyanine (CoPc) as sensing material, the sensors' response to NH(3) appears to be quite stable in a wide RH range, allowing a discrimination between 12, 25 and 50 ppm of NH(3) over the 10 70% RH range. Finally, CoPc offers a promising perspective as sensing material for air quality control applications, even at relatively high humidity levels. PMID- 22841087 TI - Differentiation of mangoes (Magnifera indica L.) conventional and organically cultivated according to their mineral content by using support vector machines. AB - Mangoes of uniform genetics (Lippens variety) cultivated in the Gomera Island (Canary Islands) by conventional and organic farming were used to analyze the mineral content in order to differentiate crops cultivated in the same geographic area by the cultivation practices. Farming differences as well as soil differences may be reflected in the mineral content of the mangoes cultivated in these extensions. Concentration metal profiles consisting of the content of Ca, Co, Cu, Fe, K, Mg, Mn, Na, Ni and Zn in mangoes were obtained by using atomic absorption spectrometry (AAS). Pattern recognition classification procedures were applied for discriminating purposes. Linear discriminant analysis (LDA) allows to a classification performance of about 73% and support vector machines (SVM) found up to a 93% of prediction ability. The classification success when applying support vector machines techniques is due to their ability for modeling non linear class boundaries. PMID- 22841088 TI - Colorimetric detection of Mn2+ using silver nanoparticles cofunctionalized with 4 mercaptobenzoic acid and melamine as a probe. AB - A facile, selective and highly sensitive method is proposed for colorimetric detection of manganese ions using 4-mercaptobenzoic acid (4-MBA) and melamine (MA) modified silver nanoparticles (AgNPs). The presence of Mn(2+) induces the aggregation of AgNPs through cooperative metal-ligand interaction, resulting in a color change from bright yellow to purple. The cofunctionalized AgNPs showed obvious advantages over the ones functionalized only by 4-MBA or MA in terms of selectivity. Mn(2+) could be monitored by colorimetric response of AgNPs by a UV vis spectrophotometer or even naked eyes. The absorbance ratio (A(550 nm)/A(408 nm)) is linear with the concentration of Mn(2+) ranging from 5*10(-7) mol/L to 1*10(-5) mol/L with a correlation coefficient of 0.993, and the detection limit is as low as 5*10(-8) mol/L. Particularly, this cost-effective process also allowed rapid and simple determination of the Mn(2+) in drinking water. PMID- 22841089 TI - Nanobeads-based rapid magnetic solid phase extraction of trace amounts of leuco malachite green in Chinese major carps. AB - A proof-of-concept for the use of oleic acid coated magnetic nanobeads (OA-MNBs) for the magnetic solid phase extraction (MSPE) of trace amounts of leuco malachite green (LMG) from fish samples was developed. The OA-MNBs were prepared by covalently conjugating oleic acid on amino-modified magnetic polystyrene beads. The OA-MNBs were characterized with transmission electron microscopy, Fourier transform infrared spectroscopy and zeta-potential analyzer. The optimized parameters for MSPE with OA-MNBs of LMG from fish muscle involved a combination of pH 10.0 in 10% acetonitrile, 1.5 M sodium chloride as an adsorption solution, and an extraction procedure involving 6 mg OA-MNBs in 18 mL LMG adsorption solution. This was optimized for 0.5 g fish muscles with an incubation period of 10 min using 200 MUL acetonitrile for elution. Using the optimized parameters, the performance of MSPE with OA-MNBs was evaluated by analyzing LMG-spiked fish extracts with liquid chromatography-mass spectrometry (LC-MS/MS) method. The results indicated that recoveries of LMG (from 0.1 to 2 ng/g) ranged from 71.2%-112.6% with relative standard deviations as low as 0.6%. Out of 57 field fish samples, eight LMG positive samples were confirmed using MSPE with OA-MNBs. Compared with traditional liquid-liquid extraction methods, the results showed that MSPE with OA-MNBs had a higher sensitivity for samples with low LMG concentration. Furthermore, the MSPE with OA-MNB took only 40 min to perform without the need for time consuming sample-pretreatment process. Therefore, MSPE with OA-MNBs holds promise for rapid, sensitive, and cost effective screening for LMG in fish samples. PMID- 22841090 TI - A simple sensitive colorimetric/fluorometric probe for iodide. AB - A simple fluorene oligomer 7, 7'-bis(9, 9-bis(6-(9H-carbazol-9-yl)hexyl)-9H fluoren-2-yl)-9,9,9',9'-tetrakis(6-(9H-carbazol-9-yl)hexyl)-9H, 9'H-2, 2' bifluorene (OCZ) with peripheral carbazole side chains is synthesized and used to detect iodide (I(-)) as colorimetric/fluorometric probe. It shows high fluorescence quenching sensitivity and selectivity towards I(-). When OCZ acted as the colorimetric probe, the color change is observed with naked eyes at a very low concentration of 0.1 mM, which is among the best reported performances. The good sensitivity and selectivity may be due to the wide range of electron-rich carbazole groups. PMID- 22841091 TI - Ionic liquids with amino acids as cations: novel chiral ligands in chiral ligand exchange capillary electrophoresis. AB - Ionic liquids (ILs) with L-proline (L-Pro) as cations have been developed for the novel chiral ligands coordinated with Cu(II) in chiral ligand exchange capillary electrophoresis (CLE-CE). Four kinds of amino acid ionic liquids (AAILs), including [L-Pro][CF(3)COO], [L-Pro][NO(3)], [L-Pro][BF(4)] and [L Pro(2)][SO(4)], were successfully synthesized. Among them, [L-Pro][CF(3)COO] was selected as the model ligand to optimize the separation conditions. The influences of AAIL concentration, pH, and methanol concentration on efficiency of chiral separation were investigated. Then it has been testified that the optimal buffer solution consisted of 25.0mM Cu(Ac)(2), 50.0 mM AAIL and 20% (v/v) methanol at pH 4.0. The interesting thing is well enantioresolution could be observed with [L-Pro][CF(3)COO] as the new chiral ligand and nine pairs of labeled D,L-AAs were successfully separated with the resolution ranging from 0.93 to 6.72. Meanwhile, the baseline separation of labeled D,L-AAs could be achieved with the other three kinds of AAILs as ligands. The results have demonstrated the good applicability of AAILs with AAs as cations for chiral separation in CLE-CE system. In addition, comparative study was also conducted for exploring the mechanism of the AAILs as new ligands in CLE-CE. PMID- 22841092 TI - Determination of n-octanol/water partition coefficients of weak ionizable solutes by RP-HPLC with neutral model compounds. AB - The utilization of neutral compounds as model compounds is put forward for determination of the n-octanol/water partition coefficient (K(ow)) of highly hydrophobic, weak acidic compounds by reversed-phase high performance liquid chromatography (RP-HPLC). It is based on a linear relationship between the logarithm of apparent n-octanol/water partition coefficient (log K(ow)"), expressing hydrophobicity of acidic solutes more accurately, and the logarithm of RP-HPLC retention factor of the solutes corresponding to the neat aqueous fraction of mobile phase (log k(w)). The availability of neutral model compounds was theoretically tested for this novel protocol. Moreover, a high consistency of linear log K(ow)"-log k(w) correlations was demonstrated between a mixed training set of neutral and acidic model compounds, and a training set of neutral model compounds. It is proved in theory that for a certain set of compounds investigated, all derived linear relationships between log K(ow)" and log k(w) have a unit slope and the same intercept, regardless of mobile phase pH. This model was applied to measure log K(ow) of lipophilic aristolochic acid I (AA I) and aristolochic acid II (AA II). Log K(ow) values for AA I and AA II are 4.45+/ 0.07 and 3.99+/-0.06, respectively. To the best of our knowledge, this is the first report on experimental log K(ow) data for AAs. The proposed strategy solves the problem of lacking suitable acidic model compounds with reliable experimental K(ow) in determining K(ow) of lipophilic acidic solutes by RP-HPLC. PMID- 22841093 TI - Screening alpha-glucosidase inhibitors from mulberry extracts via DOSY and relaxation-edited NNR. AB - Inhibition of the alpha-glucosidase activity is a therapeutic approach for diabetes. In this study, an effective strategy for screening alpha-glucosidase inhibitors based on Nuclear magnetic resonance (NMR) techniques was developed to screen and identify alpha-glucosidase inhibitors from Mulberry leaf extract. As a result, deoxynojirimycin, as a potential alpha-glucosidase inhibitor, was found. The study suggested that our strategy was a powerful tool for screening and identification of alpha-glucosidase inhibitors in complex samples. Furthermore the interaction between alpha-glucosidase and its inhibitor was studied by NMR. PMID- 22841094 TI - A SERS and fluorescence dual mode cancer cell targeting probe based on silica coated Au@Ag core-shell nanorods. AB - We report a dual mode cancer cell targeting probe based on CdTe quantum dots (QDs) conjugated, silica coated Au@Ag core-shell nanorods (Au@Ag NRs), which can generate both surface enhanced Raman scattering (SERS) and fluorescence signals. In such a probe, folic acid (FA) is used as a targeting ligand for folate receptors (FRs) overexpressed cancer cells. To synthesize the probe, Au@Ag NRs were first prepared to serve as the SERS substrates by coating an Ag shell on the gold nanorods. Then the Au@Ag NRs were labeled with 4-mercaptobenzoic acid (4MBA) to generate SERS signals, followed by being coated with a silica shell through a modified Stober method. Finally, CdTe QDs and FA were conjugated to the silica coated Au@Ag NRs by the carbodiimide chemistry to yield fluorescence and the targeting ability, respectively. To validate the targeting capability of the probe, in vitro experiments were conducted, using HeLa cells with overexpressed FRs as the model target cells and MRC-5 cells with a low folate receptor expression level as the negative control. Both the fluorescence imaging and the SERS mapping results confirmed that the proposed probe can be used as an efficient cancer cell targeting agent. This kind of multifunctional probe has great potential in the diagnosis and therapeutics of cancerous diseases due to its specific targeting and multiplex imaging abilities, especially in the simultaneous tracking of multiple components in a hybrid bio-system. PMID- 22841095 TI - The dual role of deposited microbead plug (DMBP): a blood filter and a conjugate reagent carrier toward point-of-care microfluidic immunoassay. AB - To set up a point-of-care whole-blood immunoassay system, sample preparation and on-chip storage of conjugate reagents are indispensable functional units. Here, we merge these functions into a deposited microbead plug (DMBP) to simultaneously play the roles of a blood filter and a conjugate reagent carrier. The DMBP was easily fabricated by the use of natural deposition of beads without the need of weirs. Conjugate reagents (FITC labeled antibodies used here) were incorporated into the DMBP during the assembly of the DMBP. To demonstrate the ability of the DMBP, we constructed a DMBP-based microfluidic chip and used it for the detection of human IgG (hIgG). The DMBP enabled to remove blood cells from whole blood and provide the pure plasma for the downstream on-chip immunoreactions. The release of reconstituted FITC labeled antibodies from the DMBP was controlled in a passive fashion. Dry FITC labeled antibodies retained at least 81% of their activity after 60 days of storage at the room temperature. The DMBP presented here makes an important step towards the development of the self-contained, integrated, sample-to-answer microfluidic chips for point-of-care diagnostics. PMID- 22841096 TI - On-line extractive separation in flow injection analysis based on polymer inclusion membranes: a study on membrane stability and approaches for improving membrane permeability. AB - The effect of temperature on the sensitivity and sampling rate is studied for a flow injection analysis (FIA) system that uses a membrane separation cell fitted with a polymer inclusion membrane (PIM) for the determination of Zn(II). A temperature of 50 degrees C for the flowing donor and acceptor solutions and the membrane separation cell improves the sensitivity and the sampling rate relative to 20 degrees C up to 10-fold and 2-fold, respectively. Studies on the stability of the PIM are reported that show a limited loss of the membrane liquid phase into the aqueous phases used in the FIA system but this has exhibited a negligible effect on the amount of Zn(II) transported across the membrane. Most importantly, the extent of leaching of the PIM components is shown to depend on the nature of the aqueous phase with the membrane eventually reaching a stable composition. It is also shown that the application of ultrasound to the membrane separation cell leads to a slight increase in sensitivity without affecting the long term membrane stability. PMID- 22841097 TI - Simple and rapid colorimetric detection of Hg(II) by a paper-based device using silver nanoplates. AB - This work combines lab-on-paper methodology with nanoparticle science to develop a new tool for the simple and rapid determination of Hg(II). The resulting paper based device enables measurement of Hg(II) from only 2 MUL of sample solution. The color of the nanosilver in the test area immediately changes in the presence of Hg(II), and this change can be monitored by the naked eye. This method exhibits superior selectivity towards Hg(II) compared with the other metal ions tested. Furthermore, the results show a significant increase in the Hg(II) analytical signal when Cu(II) is added to the Ag Nanoplates at the test zone. With digital camera imaging and software processing, which are shown to further improve the quantitative capability of this technique, the linear detection range is 5-75 ppm Hg(II) with a limit of detection of 0.12 ppm. Using a pre concentration scheme (based on repeated 2 MUL applications of the test Hg(II) solution onto the same test zone) reduces the limit of detection to 2 ppb. The technique developed by this study provides a rapid, sensitive and selective detection method for aqueous Hg(II) samples and is especially suitable for remote field and environmental analysis. PMID- 22841098 TI - Thermospray flame furnace atomic absorption spectrometry for determination of silver in biological materials. AB - A method for silver determination without concentration steps is described using thermospray flame furnace atomic absorption spectrometry. Carrier type and flow rate, sample volume, flame conditions (acetylene and air flow rate), water flow rate in the nebulizer, metallic tube and type and concentration of the acid diluent of the analyte are the parameters evaluated in the optimization of the method. Using the optimized conditions, eleven elements are evaluated as concomitants. The limits of detection and quantification are 0.15 MUg L(-1) and 0.50 MUg L(-1), respectively. The linear range is from 0.50 MUg L(-1) to 40 MUg L(-1) and the accuracy of the method is obtained through two certified reference materials: MA-A-2 (fish flesh homogenate) and SRM 1643e (trace elements in water). PMID- 22841099 TI - Combined corona discharge and UV photoionization source for ion mobility spectrometry. AB - An ion mobility spectrometer is described which is equipped with two non radioactive ion sources, namely an atmospheric pressure photoionization and a corona discharge ionization source. The two sources cannot only run individually but are additionally capable of operating simultaneously. For photoionization, a UV lamp was mounted parallel to the axis of the ion mobility cell. The corona discharge electrode was mounted perpendicular to the UV radiation. The total ion current from the photoionization source was verified as a function of lamp current, sample flow rate, and drift field. Simultaneous operation of the two ionization sources was investigated by recording ion mobility spectra of selected samples. The design allows one to observe peaks from either the corona discharge or photoionization individually or simultaneously. This makes it possible to accurately compare peaks in the ion mobility spectra from each individual source. Finally, the instrument's capability for discriminating two peaks appearing in approximately identical drift times using each individual ionization source is demonstrated. PMID- 22841100 TI - Conjugates of graphene oxide covalently linked ligands and gold nanoparticles to construct silver ion graphene paste electrode. AB - We reported on the synthesis and application of ionophore-gold nanoparticle conjugates in Ag(+) graphene paste electrode. Ionophore was a novel graphene oxide nanosheets (NGO) covalently grafted 2-thiophenecarboxylic (TPC) hybrid material. The hybrid material NGO-TPC decorated with gold nanoparticles was used as both a receptor and an ion-to-electron transducer to fabricate Ag(+) graphene paste electrode. The developed electrode was highly selective to Ag(+) over other tested cations and exhibited an excellent Nernstian slope of 59.3 mV dec(-1) ranging from 8.4*10(-7) to 1.0*10(-) M with a detection limit of 6.3*10(-7) M. Moreover, it also showed a fast response time and a long lifetime. Importantly, the new method of immobilizing ligands on NGO nanosheets to construct electrode successfully solved the universal problem of the electrode components loss from ion-selective electrode. PMID- 22841101 TI - Critical assessment of graphene as ion-to-electron transducer for all-solid-state potentiometric sensors. AB - Carboxy-functionalized graphene was used as a solid contact for potassium ion selective electrodes with poly(vinyl chloride) based membrane. Transducer layers were obtained simply by application of a dispersion of graphene derivative in water. Analytical performance of thus obtained sensors was compared with that of all-solid-state sensors with typical transducer materials: poly(octylthiophene) applied as chloroform solution, conducting polymers available as aqueous dispersions of poly(3,4-ethylenedioxythiophene) doped with poly(4 styrenesulfonate) ions or polyaniline. It was found that all sensors tested were characterized with similar analytical parameters. Carboxy-functionalized graphene contact layer was in some respect similar to polyaniline one, what most probably results from the presence of pH sensitive groups in both materials. PMID- 22841102 TI - Separation of olive proteins by capillary gel electrophoresis. AB - Olive proteins are not well known and there are still a lot of unknown information requiring further studies focused on the determination and characterization of these proteins. Despite the widely use of gel electrophoresis, this is the first time that capillary gel electrophoresis (CGE) is applied to separate proteins extracted from olive fruits. Seven common peaks were identified in the twenty olive varieties studied in this work. According to their migration times, these seven peaks could correspond to molecules with molecular masses of 11.0+/-0.4, 13.9+/-0.5, 16.3+/-0.8, 22.1+/-0.6, 30+/-1, 48+/ 1, and 53+/-2 kDa. All of the determined molecular masses could be attributed to proteins and four of them have been previously observed by SDS-PAGE. The electrophoretic profiles were also evaluated for their capability to differentiate olive varieties according to their presumed geographical origin. Results demonstrated that this method could successfully classify the studied olive varieties by its combination with multivariate chemometrics tools. PMID- 22841103 TI - HRMAS NMR as a tool to study metabolic responses in heart clam Ruditapes decussatus exposed to Roundup(r). AB - The essence of this study was to investigate the metabolic responses of heart tissues of carpet-shell clam Ruditapes decussatus after exposure to two doses (0.2 and 1 g/L) of Roundup((r)) during 24 and 72 h. The main metabolic changes after Roundup((r)) exposure were related to disturbance in energy metabolism and metabolic biomarkers such as alanine, succinate, acetate and propionate, suggesting the occcurence of anaerobiosis and the impairment of oxydative metabolism. Results showed also that peak intensities of amino acids used as biomarker of anaerobiosis in molluscs are time and dose dependent. In the opposite, phosphoarginine and ATP level are dependent to Roundup((r)) concentration rather than to the time of exposure. We suggest that changes in energy demands require adjustements in the forward arginine kinase reaction rate. Therefore, the results demonstrate the high applicability of HRMAS NMR to elucidate the mechanism of toxicity of Roundup((r)). In addition, (31)P HRMAS NMR appeared to be an effective and simple method to follow bioaccumulation of Roundup((r)) formulation. PMID- 22841104 TI - Use of flat-sheet membrane extraction with a sorbent interface for solvent-free determination of BTEX in water. AB - An analytical method for solvent-free determination of benzene, toluene, ethylbenzene, and xylenes (BTEX) in water using flat-sheet membrane extraction with a sorbent interface (MESI) coupled to GC-MS was established by optimizing the flow rates of the donor (20 ml water) and acceptor (helium) phases and extraction temperature. BTEX compounds permeated through a nonporous silicone membrane and evaporated into the acceptor phase were purged into a cryofocusing trap (-30 degrees C) with helium gas. Enriched compounds were thermally desorbed into a capillary gas chromatograph and detected with a mass spectrometer. The optimum flow rates of the donor and acceptor phases were set at 1.5 and 55 ml min(-1), respectively, and the temperature of the membrane extraction module was maintained within the 28-30 degrees C range. The method as established showed low method detection limits (MDLs:~0.1 MUg l(-1)) and highly linear calibration curves (r(2)>0.998) for all of the four compounds. High repeatability (relative standard deviation <~5%) and a reasonably high extraction recovery (62-78%), after a single pass of the sample through the extraction module, also were established. Further, the method's high compatibility with the purge and trap (P&T) method indicates its applicability to field measurement. Other advantages include rapidity, simplicity, and a ready extendibility to automated on-line monitoring. PMID- 22841105 TI - Efficient immobilization of glucose oxidase by in situ photo-cross-linking for glucose biosensing. AB - A glucose biosensor was fabricated based on electrostatic self-assembly in combination with in situ photo-cross-linking of glucose oxidase (GOx) and diazoresin-chitosan (DAR-CS) on Prussian blue deposited multi-walled carbon nanotubes (PB-MWNTs) backbone. It was demonstrated that GOx was initially ionically deposited and subsequently covalently photo-cross-linked onto the PB MWNTs backbone using photosensitive DAR-CS as the assembly interlayer. The modified electrode exhibited good electrical conductivity and effective electron transfer mediation toward H(2)O(2) reduction due to the employment of PB-MWNTs as the fabrication backbone. The biosensor showed high sensitivity of 77.9 MUA mM( 1) cm(-2) to glucose in the linear concentration range from 1.0*10(-5) to 1.1*10( 3) M with fast response time of 10s, detection limit of 3.1*10(-6) M, and good anti-interference ability. More importantly, the biosensor exhibited greatly improved biosensing stability in comparison with the non-photo-cross-linked biosensor attributed to the conversion of weak ionic bonds to strong covalent ones for enzyme immobilization by the proposed strategy. The results for glucose determination in real serum samples with the biosensor were found to be in good agreement with those obtained by the conventional clinical procedure. PMID- 22841106 TI - Compound-specific isotope analysis for aerobic biodegradation of phthalate acid esters. AB - The degradation of three phthalic acid esters (PAEs) (dimethyl phthalate (DMP), diethyl phthalate (DEP) and di-n-butyl phthalate (DBP)) by natural microbial community under aerobic condition and their isotope fractionation were compared by using a laboratory microcosm system with natural marine sediment overlying with natural seawater. The results showed that the degradation of the three tested PAEs followed a first-order kinetics, with rate constants of 0.0541, 0.0352 and 0.00731 day(-1) for DMP, DBP and DOP, respectively, indicating that the degradation rate of PAEs is a inverse function of the length of the alkyl side chain: the longer the side chain, the slower the rate is. (13)C isotope enrichment of the three residual PAEs were evaluated with compound-specific isotope analysis (CSIA). A relatively obvious (13)C enrichment, with maximum delta(13)C shifts of Deltadelta(13)C(DMP)=2.05+/-0.210/00 (f=0.17) and Deltadelta(13)C(DBP)=1.92+/-0.230/00 (f=0.08) in the residual DMP and DBP, respectively, was observed at an advanced stage of biodegradation. No significant (13)C enrichment occurred in the residual DOP (Deltadelta(13)C(DOP)=0.55+/ 0.210/00, f=0.16) within the accuracy and reproducibility for GC-C-IRMS (+/ 0.50/00). The experimental results indicated that the degree of isotopic fractionation in the three residual PAEs appeared to be related to the number of carbon atoms, which is in the order of DMP>DBP>DOP. PMID- 22841107 TI - Direct determination of deuterium of wide concentration range in water by Nuclear Magnetic Resonance. AB - Based on quantitative (1)H NMR and (2)H NMR techniques, a quantitative method of direct determination of deuterium concentration in water was proposed and validated. This is a simple, rapid, and sensitive method, with minimum sample preparation. The detection range of the proposed method was from natural abundance to nearly 100%, thus satisfying multiple analysis requirements. PMID- 22841108 TI - Novel chitosan-based fluorescent materials for the selective detection and adsorption of Fe3+ in water and consequent bio-imaging applications. AB - A series of fluorescent materials were synthesized by modification of chitosan (CS) with 4-fluoresceincarboxaldehyde (Fluo) and N-methyl-carbazole-3-aldehyde (Cb). Both L-CS-Fluo and L-CS-Cb feature excellent water-solubility and exhibit highly selective fluorescence response to Fe(3+) in environment and biological fields. The high-molecular weight chitosan-based materials: H-CS-Fluo and H-CS-Cb take on doubled absorptivity compared to free chitosan due to the introduction of fluorescence probes. These modified-probe chitosan materials could be regenerated by treating with EDTA. Meanwhile, monomer probes AG-Fluo and AG-Cb linked by D glucosamine were also synthesized to explore the binding efficiency. PMID- 22841109 TI - Simultaneous determination of three beta-blockers at a carbon nanofiber paste electrode by capillary electrophoresis coupled with amperometric detection. AB - In the paper, a novel carbon nanofiber paste electrode (CFPE) was fabricated and firstly used as a sensitive amperometric detector in capillary electrophoresis (CE) for the simultaneous determination of three beta-blockers: sotalol, alprenolol and atenolol. Compared with the bare carbon paste electrode, the CFPE exhibited enhanced oxidation peak current responses to the analytes due to its excellent electrocatalytic activities, high conductivity and large effective surface area. Subsequently, effects of several important factors such as detection potential, pH and concentration of running buffer, separation voltage and injection time on the analysis were investigated. Under the optimum conditions, the three analytes could be separated and detected in a phosphate buffer (pH 8.5) within 11 min. The linear ranges were 0.1-100 MUM for sotalol, 0.2-150 MUM for alprenolol and 0.1-50 MUM for atenolol and the detection limits were as low as 10(-8)M magnitude (S/N=3). Moreover, the CFPE exhibited good repeatability and long-time stability. The proposed method was applied to determine the three beta-blockers in spiked urine samples with satisfactory assay results. The good performance, low cost and straightforward preparation method of CFPE demonstrated that it could be used as a detector for CE-amperometric detection system for drug analysis. PMID- 22841110 TI - Evaluation of industrial cutting fluids using electrochemical impedance spectroscopy and multivariate data analysis. AB - In this paper we explore the combination of electrochemical impedance spectroscopy (EIS) and multivariate data analysis to evaluate the concentration and pH of an industrial cutting fluid. These parameters are vital for the performance of for instance tooling processes, and an on-line quality monitoring system would in such applications be very beneficial. It is shown that both the total impedance and the phase angle contain information that allows the simultaneous discrimination of the concentration and the pH. The final evaluation was conducted using the regression technique partial least squares (PLS), and this approach provided a way to quickly and easily find the correlation between EIS data and the sought parameters. The possibility to estimate both the concentration and pH level clearly indicates the potential of this method to be implemented for on-line evaluation. PMID- 22841111 TI - Rapid assessment of endpoint antioxidant capacity of red wines through microchemical methods using a kinetic matching approach. AB - Antioxidant capacity of food samples is usually assessed by different analytical methods, however the results attained even for the same method are strongly dependent on the selected reaction time and also on the standard compound used. To tackle this problem, we propose here a kinetic matching approach, associated to the conversion of results into equivalents of a common standard compound, as a universal way for expression of results. The methodology proposed was applied to methods based on different chemistries (Folin-Ciocalteu (F-C), CUPRAC, DPPH(*) and ABTS(*+) assays) and red wines (n=40) were chosen as a model of complex food sample. For implementation of the kinetic matching approach, the standard phenolic mixture (caffeic acid, (+)-catechin, hesperetin, morin and (-) epigallocatechin gallate) was chosen for calibration in F-C, CUPRAC and DPPH(*) assays, while tannic acid was suitable for ABTS(*+) assay. Results showed that, for all methods, there was no statistical difference between results attained by the kinetic matching approach (after <10 min of reaction) and that at endpoint conditions (after 60 to 300 min). The repeatability and the reproducibility of the kinetic matching approach was <4.5%, for all antioxidant assays. The sample throughput increases from <18 (endpoint measurements) to >108 h(-1) using the proposed kinetic approach. Moreover, we have established here a way of converting results to equivalents of a common standard, providing values independent of its kinetic profile, by using the ratio between calibration sensitivities performed at endpoint conditions. PMID- 22841112 TI - Biotin determination in food supplements by an electrochemical magneto biosensor. AB - An electrochemical magneto biosensor for the rapid determination of biotin in food samples is reported. The affinity reaction was performed on streptavidin modified magnetic microbeads as a solid support in a direct competitive format. The biotinylated horseradish peroxidase enzyme (biotin-HRP) competes with free biotin in the sample for the binding sites of streptavidin on the magnetic microbeads. The modified magnetic beads were then easily captured by a magneto graphite-epoxy composite electrode and the electrochemical signal was based on the enzymatic activity of the HRP enzyme under the addition of H(2)O(2) as the substrate and o-phenilendiamine as cosubstrate. The response was electrochemically detected by square wave voltammetry. The limit of detection was 8.4*10(-8) mol L(--1) of biotin (20 MUg L(--1)) with a dynamic range from 0.94 to 2.4*10(-7) mol L(--1). Biotin-fortified commercial dietary supplement and infant formula samples were evaluated obtaining good performances in the results. Total time of analysis was 40 min per 20 assays. PMID- 22841113 TI - Measurement of yunaconitine and crassicauline A in small-volume blood serum samples by LC-MS/MS: tracing of aconite poisoning in clinical diagnosis. AB - Aconite poisoning is one of the most serious types of herb-related medical emergencies. In Hong Kong, many if not most of these poisoning cases are due to confusion in herbal species; that is, the wrong herbs are used in prescriptions. Such human errors, while inevitable perhaps, can be serious, and sometimes fatal. The chemical components responsible for aconite poisoning are yunaconitine and crassicauline A. In the present study, a rapid and sensitive method for the screening and quantification of yunaconitine and crassicauline A in human serum, using LC-MS/MS, was developed and validated. Methyllycaconitine was chosen as the internal standard. The limit of detection (LOD) of yunaconitine and crassicauline A were found to be 0.022 and 0.021 ng/mL, respectively. The limit of quantification (LOQ) was 0.1 ng/mL for both yunaconitine and crassicauline A. The recovery of yunaconitine and crassicauline A ranged from 78.6% to 84.9% and 78.3% to 87.2%, respectively. The matrix effect of yunaconitine and crassicauline A ranged from 110.0% to 130.4% and 121.2 to 130.0%, respectively. Both yunaconitine and crassicauline A were stable in serum for at least 3 months at -20 degrees C, and the extracts were stable for at least 7 days. For clinical applications, serum samples of two patients confirmed to have had aconite herbs poisoning in 2008 were quantified using the developed method. The result showed that this method can be utilized in clinical routine applications. This screening method expedites the diagnosis in cases of suspected aconite poisoning, thus enabling doctors to treat the condition more quickly and effectively. PMID- 22841114 TI - Novel automated flow-based immunosensor for real-time measurement of the breast cancer biomarker CA15-3 in serum. AB - A novel automated immunosensor assay has been developed for real-time measurement of the breast cancer biomarker CA15-3 in serum. The assay employed the kinetic exclusion analytical technology of the KinExATM 3200 instrument. Polymethylmethacrylate (PMMA) beads coated with CA15-3 were used as capturing reagent, mouse anti-CA15-3 monoclonal antibody was used as primary antibody, and the fluorescence was monitored and recorded during the flow of the fluorescent labeled antibody through the beads. The fluorescence signal retained on the beads was plotted versus CA15-3 concentration to generate a calibration curve. The concentrations of CA15-3 in the samples were then obtained by interpolation on the curve. The assay limit of detection was 0.2 IU mL(-1). This highly sensitive automated system allowed rapid and reliable quantification of CA15-3 without any matrix effect; analytical recovery of serum-spiked CA15-3 was 90.7%-108.6%+/ 2.05%-7.45%. The precision of the sensor was satisfactory; relative standard deviation (RSD) was 3.8%-5.1% and 5.2%-7.4% for the intra- and inter-assay precision, respectively. The analytical performance of the proposed sensor was superior to the non-competitive sandwich immunoassays for CA15-3. The automated analysis by the sensor facilitated the processing of a large number of specimens, and the new sensor-based assay is anticipated to have a great value in measurement of CA15-3. PMID- 22841115 TI - Simultaneous determination of arsenic, cadmium, copper, chromium, nickel, lead and thallium in total digested sediment samples and available fractions by electrothermal atomization atomic absorption spectroscopy (ET AAS). AB - This study describes the optimization and validation of a quick and simple method for the simultaneous determination of total content and available fractions of As, Cr, Cu, Ni, Pb and Tl in sediments by ET AAS, which has been proved to be useful for environmental research. The optimization was carried out using a 3(3) Box-Behnken factorial design which was applied to matrices of total digestion and to stages 1 and 2 of the modified BCR sequential extraction scheme for sediments in order to determine the appropriate atomization temperatures and masses for the chemical modifiers: Pd(NO(3))(2) and Mg(NO(3))(2). The simultaneous determination of the elements in all matrices considered was performed, without the use of chemical modifiers at atomization temperatures of 1700 degrees C for Cd and Tl, and 2100 degrees C for As, Cu, Cr, Ni and Pb, using a standard calibration curve for calibration purposes. The characteristic masses and limits of detection obtained were 36.5, 1.8, 6.5, 28, 34, 46.5 and 48 rhog and 0.11, 0.001, 0.022, 0.04, 0.2, 0.03 and 0.003 MUg g(-1) for As, Cd, Cr, Cu, Ni, Pb and Tl, respectively. The analytical procedure was validated by analyzing three sediment certified reference materials (CRM NCS DC 73315 and LKSD-4 for total content and BCR 701 for available fractions). Good accuracy was obtained (tested statistically, P=0.05, and shown by the high recovery for each element in each matrix), except for total As in the matrix of total digestion, where losses of the analyte could be attributed to sample treatment with HNO(3). The precision of the procedure was between 0.6% and 6%. PMID- 22841116 TI - Cationic polyelectrolyte copolymer modified polyurethane foam for flow injection preconcentration and separation of trace amounts of beta-lactam antibiotics. AB - A more sensitive flow injection preconcentration method has been developed for the determination of four beta-lactam antibiotics (BLAs) namely cefaclor, cefotaxime, amoxicillin and ampicillin in urine, pharmaceuticals and milk. A mini column packed with PUF functionalized with the cationic polyelectrolyte, poly(N chloranil N,N,N',N'-tetramethylethylene diammonium dichloride) PCTDD, was utilized for selective preconcentration. The detection limits with this method were 3.3, 3.8, 5.1 and 7.0 ng mL(-1) and enrichment factors were 38, 21, 39, and 36 for cefaclor, cefotaxime, amoxicillin and ampicillin, respectively with a sample throughput of 12 h(-1) for all BLAs. Moreover, the BLAs were successfully separated by isocratic elution using a micellar mobile phase. Application of the method developed has resulted in recovery values in the range 95%-109% (RSD<=8.7), 83%-99% (RSD<=9.7) and 91%-103% (RSD<=4.0) for urine, pharmaceuticals and milk samples, respectively. PMID- 22841117 TI - Selective extraction and determination of vitamin B12 in urine by ionic liquid based aqueous two-phase system prior to high-performance liquid chromatography. AB - A rapid and simple extraction technique based on aqueous two-phase system (ATPS) was developed for separation and enrichment of vitamin B(12) in urine samples. The proposed ATPS-based method involves the application of the hydrophilic ionic liquid (IL) 1-hexyl-3-methylimidazolium chloride and K(2)HPO(4). After the extraction procedure, the vitamin B(12)-enriched IL upper phase was directly injected into the high performance liquid chromatography (HPLC) system for analysis. All variables influencing the IL-based ATPS approach (e.g., the composition of ATPS, pH and temperature values) were evaluated. The average extraction efficiency was 97% under optimum conditions. Only 5.0 mL of sample and a single hydrolysis/deproteinization/extraction step were required, followed by direct injection of the IL-rich upper phase into HPLC system for vitamin B(12) determination. A detection limit of 0.09 MUg mL(-1), a relative standard deviation (RSD) of 4.50% (n=10) and a linear range of 0.40-8.00 MUg mL(-1) were obtained. The proposed green analytical procedure was satisfactorily applied to the analysis of samples with highly complex matrices, such as urine. Finally, the IL-ATPS technique could be considered as an efficient tool for the water-soluble vitamin B(12) extraction. PMID- 22841118 TI - On-line measurement of perchlorate in atmospheric aerosol based on ion chromatograph coupled with particle collector and post-column concentrator. AB - An automated analysis system has been developed for measuring perchlorate concentration in atmospheric aerosol. The perchlorate in aerosol sample, which has been collected with water mist in a hydrophobic filter/mist chamber based particle collector, is continuously preconcentrated. The matrix ions such as sulfate are subsequently removed from the preconcentrator. The remaining perchlorate is then analyzed on-line with an ion chromatograph in conjunction with a Nafion membrane tube based post-column concentrator. The sensitivity is increased by a factor of 7.7 with the post-column concentration technique. The proposed system has been successfully operated at Tokushima, Japan. The limit of detection is 0.35 ng/m(3) for 3 h sampling cycle. The perchlorate concentration in the atmospheric aerosol averaged 1.01+/-1.75 ng/m(3) (n=12). PMID- 22841119 TI - Micrococcal nuclease detection based on peptide-bridged energy transfer between quantum dots and dye-labeled DNA. AB - A novel and simple method was presented for micrococcal nuclease (MNase) detection based on fluorescence resonance energy transfer (FRET) realized by electrostatic interaction. In this study, mercaptoacetic acid capped quantum dots (MAA-QDs) and ROX-modified single-stranded DNA (ROX-ssDNA) were chosen as energy donor and acceptor, respectively. At slightly basic pH, the positively charged peptide served as a bridge to bring negatively charged QDs and negatively charged ROX-ssDNA into close contact to energy transfer. When the ROX-ssDNA was cleaved into small fragments by MNase, the relatively weak electrostatic interaction between the fragmented ssDNA chains and the QDs/peptide complex should make the ROX away from the QDs/peptide complex, and thus the FRET efficiency decreased. Consequently, the fluorescence intensity of acceptor decreased and a quantification of the MNase was enabled. Under the optimal conditions, experimental results showed that the fluorescence intensity of acceptor was proportional to the logarithm of MNase concentration in a range of 4.0*10(-3) 8.0*10(-2) U mL(-1). The proposed approach offered adequate sensitivity for the detection of the MNase at 2.9*10(-3) U mL(-1). PMID- 22841121 TI - Evaluation of a titanium dioxide-based DGT technique for measuring inorganic uranium species in fresh and marine waters. AB - A new diffusive gradients in a thin film (DGT) technique for measuring dissolved uranium (U) in freshwater is reported. The new method utilises a previously described binding phase, Metsorb (a titanium dioxide based adsorbent). This binding phase was evaluated and compared to the well-established Chelex-DGT method. Batch experiments showed quantitative uptake (100+/-3%) of dissolved U by Metsorb and an elution efficiency of 95% was obtained using a mixed eluent of 1 mol L(-1) NaOH/1 mol L(-1) H(2)O(2). The mass of U accumulated by Metsorb was linear (R(2)>=0.98) with time across the pH range 3.0-8.1, validating the DGT measurement. The measured effective diffusion coefficients were highly dependent on pH, ranging from 2.74-4.81*10(-6)cm(2)s(-1), which were in reasonable agreement with values from the literature. Ionic strength showed no effect on the uptake of U, and thereby on diffusion coefficients, at NaNO(3) concentrations <=0.01 mol L(-1), but caused the U concentration to be underestimated by 18% and 24% at 0.1 mol L(-1) NaNO(3) and 0.7 mol L(-1) NaNO(3), respectively. Deployment of Metsorb-DGT in synthetic freshwater resulted in reliable measurement of the dissolved U concentration (C(DGT)/C(Sol)=1.05), whereas Chelex-DGT significantly underestimated the dissolved U concentration (C(DGT)/C(Sol)=0.76). Metsorb-DGT was found to give reliable results after 8h deployments in synthetic seawater but experienced competition effects with longer deployments. The Chelex-DGT was unable to measure U at all in synthetic seawater. A field deployment in a freshwater stream (Coomera River) confirmed the utility of the Metsorb-DGT method for measuring U in natural freshwaters, but performance of field deployments may require further evaluation due to the possibility of major changes in uranium speciation with pH and water composition. We recommend a filtered sample, of any water in which DGT measurements are to be made, be used to determine the appropriate diffusion coefficient under controlled laboratory conditions. PMID- 22841120 TI - Identification of multiply charged proteins and amino acid clusters by liquid nitrogen assisted spray ionization mass spectrometry. AB - The development of liquid nitrogen assisted spray ionization mass spectrometry (LNASI MS) for the analysis of multiply charged proteins (insulin, ubiquitin, cytochrome c, alpha-lactalbumin, myoglobin and BSA), peptides (glutathione, HW6, angiotensin-II and valinomycin) and amino acid (arginine) clusters is described. The charged droplets are formed by liquid nitrogen assisted sample spray through a stainless steel nebulizer and transported into mass analyzer for the identification of multiply charged protein ions. The effects of acids and modifier volumes for the efficient ionization of the above analytes in LNASI MS were carefully investigated. Multiply charged proteins and amino acid clusters were effectively identified by LNASI MS. The present approach can effectively detect the multiply charged states of cytochrome c at 400 nM. A comparison between LNASI and ESI, CSI, SSI and V-EASI methods on instrumental conditions, applied temperature and observed charge states for the multiply charged proteins, shows that the LNASI method produces the good quality spectra of amino acid clusters at ambient conditions without applied any electric field and heat. To date, we believe that the LNASI method is the most simple, low cost and provided an alternative paradigm for production of multiply charged ions by LNASI MS, just as ESI-like ions yet no need for applying any electrical field and it could be operated at low temperature for generation of highly charged protein/peptide ions. PMID- 22841122 TI - Electrochemical detection of dopamine in the presence of ascorbic acid using PVP/graphene modified electrodes. AB - Graphene (GR) was synthesized through electrochemical reduction of graphene oxide and characterized by spectroscopic and electrochemical techniques. Polyvinylpyrrolidone (PVP)/graphene modified glassy carbon electrode (PVP/GR/GCE) was prepared and applied for the fabrication of dopamine (DA) sensors without the interference of ascorbic acid (AA). Compared to bare GCE, an increase of current signal was observed, demonstrating that PVP/GR/GCE exhibited favorable electron transfer kinetics and electrocatalytic activity towards the oxidation of dopamine. Furthermore, PVP/GR/GCE exhibited good ability to suppress the background current from large excess ascorbic acid. Amperometric response results show that the PVP based sensor displayed a wide linear range of 5*10(-10) to 1.13*10(-3) mol/L DA with a correlation coefficient of 0.9990 and a detection limit of 0.2 nM (S/N=3). The determination of dopamine in urine and human serum samples were studied. PMID- 22841123 TI - A novel reverse phase stability indicating RP-UPLC method for the quantitative determination of fifteen related substances in Ranolazine drug substance and drug product. AB - A gradient reverse-phase ultra performance liquid chromatographic (RP-UPLC) method was developed for the quantitative determination of Ranolazine and potential process-related impurities (starting materials, positional isomers, degradants and byproducts) at the level of 0.1 MUg mL(-1) to 0.3 MUg mL(-1). Fifteen potential impurities were identified in the crude samples during the process development. Tentative structures for all the impurities were assigned based on m/z values from LC-MS/MS analysis. This method can be used for the quality control of both drug substance and drug product. All these impurities were separated with a gradient UPLC method by using a polar embedded Waters Acquity BEH RP18 100 mm * 2.1 mm,1.7 MUm column, monobasic sodium buffer, a basic organic modifier and acetonitrile in the mobile phase. Further, this method is also capable of separating a major oxidative degradant Di-N-oxide. Impurities having electron donating groups(+I effect) on the phenyl ring increased the retention by improved p-p interactions. The drug was subjected to the International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic and thermal stress conditions. The performance of the method was validated according to the present ICH guidelines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness and robustness. PMID- 22841124 TI - Application of TLC and LA ICP SF MS for speciation of S, Ni and V in petroleum samples. AB - A coupling of thin layer chromatography with laser ablation ICP SF MS was developed for the fractionation of Ni, V, Fe and S in crude oil and its fractions (saturate, aromatic, resin and asphaltene). The detection limits were 18 ng g(-1) and 23 ng g(-1) for nickel and vanadium, respectively, and a sample could be characterized in terms of the metal distribution as a function of species polarity within 10 min. The method was used to characterize the metal distribution in crude oils of different origins and their different fractions. PMID- 22841126 TI - Standardized patient identification and specimen labeling: a retrospective analysis on improving patient safety. AB - BACKGROUND: There is an increased risk of specimen labeling errors with the generation of a high volume of pathology specimens. Measuring specimen labeling accuracy has been suggested as a possible measure for patient safety. OBJECTIVE: We sought to identify operational areas for improvement around specimen handling with the institution of a standardized specimen labeling protocol in the Duke University Medical Center Department of Dermatology. The average rates of specimen labeling events before and after implementation of this protocol were analyzed to determine the efficacy of this systematic approach. METHODS: We collected the monthly aggregated rates of specimen labeling events occurring with skin specimens processed through the Duke University Medical Center Department of Pathology from December 2008 through June 2011. The average monthly rates of events per 1000 cases for the time periods from December 2008 through March 2010 and June 2010 through September 2011 were compared. RESULTS: The data collected showed a statistically significant decline in the average monthly rate of specimen labeling errors after institution of the protocol. Before implementation, specimen labeling events occurred at a rate of 5.79 events per 1000 with a decrease to 3.53 events per 1000 after integration of this system (P = .028). LIMITATIONS: Limitations of this study include possible sampling error and regression toward the mean. CONCLUSIONS: Low-cost, process-driven interventions are effective in the reduction of specimen handling errors. PMID- 22841125 TI - Screening analysis of biodiesel feedstock using UV-vis, NIR and synchronous fluorescence spectrometries and the successive projections algorithm. AB - This paper investigates the use of UV-vis, near infrared (NIR) and synchronous fluorescence (SF) spectrometries coupled with multivariate classification methods to discriminate biodiesel samples with respect to the base oil employed in their production. More specifically, the present work extends previous studies by investigating the discrimination of corn-based biodiesel from two other biodiesel types (sunflower and soybean). Two classification methods are compared, namely full-spectrum SIMCA (soft independent modelling of class analogies) and SPA-LDA (linear discriminant analysis with variables selected by the successive projections algorithm). Regardless of the spectrometric technique employed, full spectrum SIMCA did not provide an appropriate discrimination of the three biodiesel types. In contrast, all samples were correctly classified on the basis of a reduced number of wavelengths selected by SPA-LDA. It can be concluded that UV-vis, NIR and SF spectrometries can be successfully employed to discriminate corn-based biodiesel from the two other biodiesel types, but wavelength selection by SPA-LDA is key to the proper separation of the classes. PMID- 22841128 TI - Tract-based diffusion tensor imaging in patients with schizophrenia and their non psychotic siblings. AB - Structural brain abnormalities have consistently been found in patients with schizophrenia. Diffusion tensor imaging (DTI) has been shown to be a useful method to measure white matter (WM) integrity in this illness, but findings in the earlier disease stages are inconclusive. Moreover, the relationship between WM microstructure and the familial risk for developing schizophrenia remains unresolved. From 126 patients with schizophrenia, 123 of their non-psychotic siblings and 109 healthy control subjects, DTI images were acquired on a 1.5 T MRI scanner. Mean fractional anisotropy (FA) was compared along averaged WM tracts, computed for the genu, splenium, left and right uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, fornix, arcuate fasciculus, and inferior longitudinal fasciculus. Fractional anisotropy (FA) was assessed for its unique environmental and familial (possibly heritable) aspects associated with schizophrenia, using structural equation modeling for these white matter tracts. The results of this study show that young adult (mean age 26.7 years) patients with schizophrenia did not differ in mean FA from healthy controls along WM fibers; siblings of patients showed higher mean FA in the left and right arcuate fasciculus as compared to patients and controls. With increasing age, an excessive decline in mean FA was found in patients as compared to siblings and healthy controls in the genu, left uncinate fasciculus, left inferior fronto occipital fasciculus, and left inferior longitudinal fasciculus. Moreover, symptom severity was negatively correlated to mean FA in the arcuate fasciculus bilaterally in patients with schizophrenia. In young adult patients with schizophrenia integrity of individual tract-based (corticocortical) fibers can (still) be within normal limits. However, changes in the arcuate fasciculus may be relevant to (the risk to develop) psychosis, while a general and widespread loss of fiber integrity may be related to illness progression. PMID- 22841127 TI - Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. AB - BACKGROUND: Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. OBJECTIVE: We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs >=3 patients with CM among first-degree relatives in a family). METHODS: We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. RESULTS: The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. LIMITATIONS: The study was not population based. CONCLUSIONS: This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma. PMID- 22841129 TI - Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics. A meta-analysis of randomized clinical trials in acute mania. AB - BACKGROUND: there is a lack of scientific data regarding speed of action of antimanic treatments, a relevant issue in clinical practice. OBJECTIVE: to assess differences in the speed of onset of antimanic efficacy between haloperidol (as most studied first-generation antipsychotic) and second-generation antipsychotics. EXPERIMENTAL PROCEDURES: meta-analysis of double-blind randomized clinical trials in acute mania, comparing treatment with haloperidol and with second-generation antipsychotics. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). Differences in mania scale score reduction at week 1 were assessed. RESULTS: 8 randomized clinical trials fulfilled inclusion criteria and 1 of them was excluded due to low methodological quality. 2037 Manic patients had been treated with antipsychotics in the 7 trials. Haloperidol was found to be significantly more efficacious in the reduction of the mania scale score at week 1. The effect size was small, the Standardized Mean Difference (SMD) being 0.17, with a 95% Confidence Interval ranging from 0.01 to 0.32. Haloperidol was significantly more efficacious than olanzapine (SMD: 0.40 [0.21, 0.59]) and ziprasidone (0.39 [0.18, 0.61]). A non significant trend towards superiority of haloperidol was found over aripiprazole (SMD: 0.13 [-0.02, 0.19]). There were no significant differences between haloperidol and quetiapine (0.17 [-0.11, 0.44]), and haloperidol and risperidone (SMD: -0.10 [0.30, 0.09]). CONCLUSIONS: haloperidol shows a faster onset of antimanic action than second-generation antipsychotics. This difference may be related to D2 affinity. Haloperidol may be considered a treatment option in severely ill manic patients who require urgent relief of symptoms. PMID- 22841130 TI - Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: a pilot study of six candidate genes. AB - The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR>=2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted. PMID- 22841131 TI - Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive-behavioral therapy in obsessive-compulsive disorder. AB - Nearly one-third of patients with obsessive-compulsive disorder (OCD) fail to respond to adequate therapeutic approaches such as serotonin reuptake inhibitors and/or cognitive-behavioral therapy (CBT). This study investigated structural magnetic resonance imaging (MRI) correlates as potential pre-treatment brain markers to predict treatment response in treatment-naive OCD patients randomized between trials of fluoxetine or CBT. Treatment-naive OCD patients underwent structural MRI scans before randomization to a 12-week clinical trial of either fluoxetine or group-based CBT. Voxel-based morphometry was used to identify correlations between pretreatment regional gray matter volume and changes in symptom severity on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Brain regional correlations of treatment response differed between treatment groups. Notably, symptom improvement in the fluoxetine treatment group (n=14) was significantly correlated with smaller pretreatment gray matter volume within the right middle lateral orbitofrontal cortex (OFC), whereas symptom improvement in the CBT treatment group (n=15) was significantly correlated with larger pretreatment gray matter volume within the right medial prefrontal cortex (mPFC). No significant a priori regional correlations of treatment response were identified as common between the two treatment groups when considering the entire sample (n=29). These findings suggest that pretreatment gray matter volumes of distinct brain regions within the lateral OFC and mPFC were differentially correlated to treatment response to fluoxetine versus CBT in OCD patients. This study further implicates the mPFC in the fear/anxiety extinction process and stresses the importance of lateral portions of the OFC in mediating fluoxetine's effectiveness in OCD. Clinical registration information: http://clinicaltrials.gov-NCT00680602. PMID- 22841132 TI - Penile Crohn's disease resolved by infliximab. AB - Crohn's disease is a chronic relapsing, granulomatous, and inflammatory bowel disorder. Variable extra-intestinal manifestations may occur, which include erythema nodosum, erythema multiforme, pyoderma gangrenosum, and other non specific skin lesions. Here, we present a case of metastatic penile Crohn's disease without scrotal involvement, which was initially approached as a balanoposthitis with penile cellulitis, and completely treated with infliximab infusion in a short time. PMID- 22841133 TI - Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease. AB - Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting. PMID- 22841134 TI - Anti-TNFalpha therapy early improves hemodynamics in local intestinal and extraintestinal circulations in active Crohn's disease. AB - BACKGROUND AND AIMS: Active Crohn's disease affects intestine but may alter other locations as eyes vasculature. Previous studies provide evidence of elevated blood flow velocities (BFv) and volume (BFV) in superior mesenteric artery (SMA). We prospectively studied hemodynamics in feeding arteries of bowel and eyes before and 2 weeks after treatment induction with anti-TNFalpha. METHODS: Fifteen patients (5 females, 10 males, 35.4 +/- 9.0 years, mean +/- SD) with active Crohn's disease for 7.5 +/- 7.7 years were enrolled. Ultrasound imaging was performed before and 2 weeks after treatment in SMA and retrobulbar arteries: central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries. Serum markers of inflammation (CRP and fibrinogen), arterial blood pressures (ABP) and skin flow-mediated dilation (sFMD) were measured and patients were compared to 10 control age- and sex-matched subjects. RESULTS: Before treatment, CRP and fibrinogen plasma concentrations, SMA BFV (339 +/- 100 mL/min) were higher in patients than in controls by 8.5-fold (p<0.001), 1.4-fold (p<0.01) and 1.5-fold, respectively (p<0.01). BFv in CRA (3.5 +/- 0.7 cm/s) and TPCA (4.4 +/- 1.0 cm/s), sFMD (371 +/- 469%) were significantly lower than in controls by 83%, 73% and 52% respectively (p<0.05). Two weeks after treatment, CRP and fibrinogen decreased, SMA BFV was normalized (230 +/- 39L/min, p<0.01), BFv in CRA, TPCA and OA increased respectively to 4.0 +/- 1.1 (p<0.05), 5.2 +/- 1.4 (p<0.001), 8.9 +/- 3 cm/s (p<0.05). ABP and sFMD remained unchanged. CONCLUSIONS: In active Crohn's disease, a first anti-TNFalpha administration rapidly normalized concomitantly plasma inflammatory markers and blood-flows in the mesenteric and retrobulbar arteries without affecting blood pressure and endothelial function. PMID- 22841135 TI - Incorporating cutting-edge analytical science research into anti-doping testing. PMID- 22841136 TI - A simplified clustering method for novice narcotic chemists. AB - Statistical classification remains the most useful statistical tool for forensic chemists to assess the relationships between samples. Many clustering techniques such as principal component analysis and hierarchical cluster analysis have been employed to analyze chemical data for pattern recognition. Due to the feeble foundation of this statistics knowledge among novice drug chemists, a tetrahedron method was designed to simulate how advanced chemometrics operates. In this paper, the development of the graphical tetrahedron and computational matrices derived from the possible tetrahedrons are discussed. The tetrahedron method was applied to four selected parameters obtained from nine illicit heroin samples. Pattern analysis and mathematical computation of the differences in areas for assessing the dissimilarity between the nine tetrahedrons were found to be user convenient and straightforward for novice cluster analysts. PMID- 22841137 TI - The effects of dosed tobacco in evidentiary breath testing using non-drinking subjects. AB - A total of seventeen subjects were administered breath tests with alcohol dosed tobacco to see if there was an interference with the evidentiary breath testing. Fourteen subjects provided one set of two breath samples without the dosed tobacco followed by a set of two breath samples with the dosed tobacco. The other three subjects provided one breath sample without the dosed tobacco and then one breath sample with the dosed tobacco within the same testing sequence. Eight subjects had breath test readings of 0.00g/210L with the dosed tobacco. Mouth alcohol was detected with the dosed tobacco in six of the subjects, and a reading of 0.01g/210L, 0.04g/210L, and 0.05g/210L were found in five of the subjects. If the officer follows the directive of checking the mouth for a foreign substance and following a 15-20min observation/deprivation period, a false positive result will likely be avoided. If the officer does not find tobacco when checking the mouth for a foreign substance, and dosed tobacco is present during the breath test, most likely there would not be a measurable amount of alcohol to report or there would be a mouth alcohol reading from the sample. PMID- 22841138 TI - A methodology for finger mark research. AB - Currently there is no standard way of carrying out research into finger mark enhancement techniques. Individuals, groups or establishments tend to use different methodologies depending on a number of factors, especially finance and time. However, data published in the literature can be misleading to the forensic community if the data generated reflects research involving very few finger marks or if those finger marks have been deliberately doped with an unnatural balance of sweat or an unusual contaminant. This paper presents an experimental methodology which is intended to establish minimum standards for those carrying out finger mark enhancement research (at least within the United Kingdom) and bring some consistency to the process. It will aim to identify the many variables encountered when dealing with finger marks and suggest experimental methods to take these into account. It will also present the key stages of the progression of a process from a laboratory concept to a tool used on operational work. PMID- 22841139 TI - Dichroism measurements in forensic fibre examination: part 5-pigmented fibres. AB - A number of pigmented fibre samples were examined with plane polarized light on their dichroic behaviour by optical light microscopy (OLM) and microspectrophotometry with plane polarized light (MSP-PPL). It was found that about half of the samples show a strong dichroic effect and another 20% have a weak dichroism. Both regular (80%) and inversed dichroic effects (20%) occur. The dichroic characteristics of pigmented fibres can be compared to these of sheet polarizers. It is suggested that the dichroic behaviour of pigmented fibres depends strongly on the crystal structure (shape of the pigment grains) and the draw ratio (orientation of the polymer chains). PMID- 22841140 TI - Controlling the variable of pressure in the production of test footwear impressions. AB - Footwear impression lifting and enhancement techniques may be affected by several variables introduced during the production of test footwear impressions, thus limiting the usefulness of enhancement technique comparisons and the results obtained. One such variable is the force applied when the impressed mark is being made. Producing consistent test impressions for research into footwear enhancement techniques would therefore be beneficial. This study was designed to control pressure in the production of test footwear impressions when mimicking a stamping action. Twenty-seven volunteers were asked to stamp on two different surfaces and the average stamping force was recorded. Information from the data obtained was used to design and build a mechanical device which could be calibrated to consistently deliver footwear impressions with the same force onto a receiving surface. Preliminary experiments using this device and different contaminants on the footwear sole have yielded consistent and repeatable impressions. Controlling the variable of pressure for the production of test impressions in this study demonstrated that the differences observed were visual (due to the amount of contaminant transferred and subsequent enhancement) and did not affect the replication of outer sole characteristics. This paper reports the development of the device and illustrates the quality of the impressions produced. PMID- 22841141 TI - Age estimation through histological study of trabecular volume and cortical bone width of the iliac crest. AB - There have been many methods proposed to estimate the age of human bones in forensic medicine or in forensic anthropology, including those that assess histological structures. In this study, age was evaluated through the histomorphometric study of trabecular volume and cortical width of the right iliac crest. A total of 25 samples A total of 66 samples (42 male and 24 female) were obtained from necropsies of judicial cases, with ages ranging from 13 to 58years, who had died a sudden or violent death. The samples were obtained using Bordier's trocar for bone biopsy, in a period not exceeding 24h after death. The samples were examined without decalcification, with 96 degrees alcohol dehydration, embedding in methyl methacrylate, and sectioned with a microtome Reichert (3MUm). The sections were fixed on microscope slides and stained using toluidine blue, Goldner trichrome and hematoxylin-eosin methods. The samples were studied under a Leica DM LB microscope and the images were digitally captured. The digital images were processed using an image analysis program and data were analyzed using the SPSS statistical package. The results demonstrated that the combination of the trabecular volume and cortical width acted as predictors of the age in subjects which did not suffer from any deterioration of bone and/or mineral metabolism. PMID- 22841142 TI - Palatal rugae as an individualising marker: reliability for forensic odontology and personal identification. AB - Personal identification is based on the comparison between ante mortem and post mortem data which can be considered unique for each individual: palatal rugae represent a useful element for such a comparison, thanks to their apparent low variability with time and unique patterns. Literature however is scarce. This pilot study aims at assessing the reliability of palatal rugae in time and at developing an identification method based on their comparison. Two casts from the upper dental arch of 39 subjects were obtained in different periods of time; at their first cast, 85.2% of patients were less than 16 years old. The second cast was performed after a period of time which varied between 4 and 65 months later than the first cast. The first cast can be taken to simulate ante mortem information, the second post mortem information. Every cast was then digitised with a scanner. In the digital images the palatal rugae were highlighted by using Adobe(r) Photoshop(r) 7.0 software; each image was coded and a comparison between "simulated" ante mortem and post mortem data was performed. In all cases ante mortem and post mortem data from the same individual were correctly matched. The study seems to indicate that this technique is highly reliable and user friendly, even on subadults, where growth processes seem not to affect the specific morphology of palatal rugae. PMID- 22841143 TI - Consideration of the probative value of single donor 15-plex STR profiles in UK populations and its presentation in UK courts. AB - The adoption of new 15 locus STR multiplex systems into UK forensic science would be facilitated by agreed guidelines for reporting the strength of DNA evidence using likelihood ratios. To facilitate such an agreement, we present an analysis of previously published UK allele frequencies for white Caucasian, Afro-Caribbean and Indo-Pakistani populations and investigate their effect on likelihood ratios for single donor profiles. We consider the implication of the five additional loci and suggest a procedure for reporting likelihood ratios for 15-plex STR profiles. PMID- 22841144 TI - Learning about Bayesian networks for forensic interpretation: an example based on the 'the problem of multiple propositions'. AB - Both, Bayesian networks and probabilistic evaluation are gaining more and more widespread use within many professional branches, including forensic science. Notwithstanding, they constitute subtle topics with definitional details that require careful study. While many sophisticated developments of probabilistic approaches to evaluation of forensic findings may readily be found in published literature, there remains a gap with respect to writings that focus on foundational aspects and on how these may be acquired by interested scientists new to these topics. This paper takes this as a starting point to report on the learning about Bayesian networks for likelihood ratio based, probabilistic inference procedures in a class of master students in forensic science. The presentation uses an example that relies on a casework scenario drawn from published literature, involving a questioned signature. A complicating aspect of that case study - proposed to students in a teaching scenario - is due to the need of considering multiple competing propositions, which is an outset that may not readily be approached within a likelihood ratio based framework without drawing attention to some additional technical details. Using generic Bayesian networks fragments from existing literature on the topic, course participants were able to track the probabilistic underpinnings of the proposed scenario correctly both in terms of likelihood ratios and of posterior probabilities. In addition, further study of the example by students allowed them to derive an alternative Bayesian network structure with a computational output that is equivalent to existing probabilistic solutions. This practical experience underlines the potential of Bayesian networks to support and clarify foundational principles of probabilistic procedures for forensic evaluation. PMID- 22841145 TI - A plea for thresholds, i.e., maximal allowed levels for prohibited substances, to prevent questionable doping convictions. AB - With the development of highly sensitive drug testing technologies that can detect a minute quantity of a prohibited substance in an athlete's body, accidental contamination through contact with publicly circulated materials can more readily result in a "positive" reading. To discharge the burden of a positive finding, the athlete must show the "factual circumstances" in which the prohibited substance entered his/her system. In cases of accidental contamination, the athlete generally cannot even know how it occurred, as there are many known and unknown possible sources of contamination. When an athlete does give an account, it cannot generally be proven or disproven. Outside the realm of sports anti-doping, the use of scientifically established thresholds for drug testing is standard practice. Basic logic dictates that thresholds would enable one to differentiate between relevant and irrelevant amounts in the context of a possible sports doping offence. Such a threshold should be functionally motivated, i.e., enable the differentiation between relevant and irrelevant quantities in the context of a possible doping offence, rather than based on instrument performance limits. PMID- 22841146 TI - More on the Bayesian approach and the LR. PMID- 22841148 TI - Is this the end of radiotherapy in early hodgkin lymphoma? PMID- 22841149 TI - Lack of prognostic effect of carbonic anhydrase-9, hypoxia inducible factor 1alpha and bcl-2 in 286 patients with early squamous cell carcinoma of the glottic larynx treated with radiotherapy. AB - AIMS: To evaluate the prognostic significance of potential tumour markers of hypoxia and apoptosis in early squamous cell carcinoma of the glottic larynx managed with radiotherapy. MATERIALS AND METHODS: In total, 382 patients with T1 and T2 squamous cell carcinoma of the glottic larynx (vocal cords) received radical radiotherapy (50-55 Gy, in 16 fractions in 98% of cases). Pre-treatment haemoglobin was available for 328 patients; biopsy samples were available for 286. Immunohistochemistry was carried out for carbonic anhydrase-9 (CA-9), hypoxia inducible factor-1alpha (HIF-1alpha) and Bcl-2. RESULTS: At 5 years, locoregional control was achieved in 88.2%, cancer-specific survival in 95.0% and overall survival in 78.7%. Adverse prognostic factors for locoregional tumour recurrence were pre-treatment haemoglobin <13.0 g/dl (P = 0.035, Log rank test; sensitivity 0.28, specificity 0.84) and stage T2 rather than T1 (P = 0.002). The effect of haemoglobin level on locoregional control was not significant when stratified by the median of 14.2 g/dl (P = 0.43) or as a continuous variable (P = 0.59). High CA-9 (P = 0.11), HIF-1alpha (P = 0.67) and Bcl-2 (P = 0.77) expression had no prognostic significance. CONCLUSIONS: High CA-9, HIF-1alpha and Bcl-2 do not add to the prognostic significance of tumour stage and lower haemoglobin in predicting failure of local control in early glottic larynx squamous cell carcinoma managed with radiotherapy. The effect of haemoglobin was not strong enough to be useful as a prognostic biomarker. PMID- 22841150 TI - Technique of whole brain radiotherapy: conformity index and parotid glands. PMID- 22841151 TI - Cancer risk models and preselection for screening. AB - OBJECTIVE: The invitation to population screening is based on age criteria in many countries. Screening is not offered to younger or older participants, because the benefits in these age groups do not outweigh the harms. One could argue that it is not so much age that determines the benefits but the risk of developing preclinical and treatable cancer. Cancer risk varies with age but is also affected by other factors. METHODS: We performed a systematic review for risk models for the three types of cancer for which population screening programs exist: breast, cervical and colon cancer. We used an evaluation scheme that distinguishes three phases of model development: model derivation, validation and impact analysis. Data were collected in August 2010. RESULTS: We identified two colorectal, four breast and three cervix cancer risk models. One colorectal, four breast and none of the cervix cancer models have been externally validated. We could not identify evaluations of the impact on population screening effectiveness. CONCLUSION: We conclude that risk models for the pre-selection of screening have been developed. These models could improve the pre-selection for screening, help in making personal decisions about participation, and reduce adverse effects of population screening. The validity of this hypothesis, as well as practicalities and issues of equity and reliability, have to be tested in further studies. PMID- 22841152 TI - A longer, better ride with engineered stem cells. PMID- 22841153 TI - Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair. AB - OBJECTIVES: The goal of this study was to demonstrate the enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for the treatment of myocardial infarction. BACKGROUND: Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation, and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration. METHODS: hCPCs isolated from the myocardium of heart failure patients undergoing left ventricular assist device implantation were engineered to express green fluorescent protein (hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential were performed with immunocompromised mice by using intramyocardial adoptive transfer injection after infarction. Myocardial structure and function were monitored by echocardiographic and hemodynamic assessment for 20 weeks after delivery. hCPCe and hCPCeP expressing luciferase were observed by using bioluminescence imaging to noninvasively track persistence. RESULTS: hCPCeP exhibited augmentation of reparative potential relative to hCPCe control cells, as shown by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrated increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe was revealed by bioluminescence imaging at up to 8 weeks post-delivery. CONCLUSIONS: Genetic engineering of hCPCs with Pim-1 enhanced repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of hCPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in pre-clinical settings. PMID- 22841155 TI - Something old holds potential to be something new in heart failure: allopurinol revisited. PMID- 22841156 TI - ESEM modifications to LEO SUPRA 35 VP FESEM. AB - A LEO SUPRA 35 VP FESEM has been modified to significantly improve image quality in the low pressure mode of operation. It is further shown that the same conversion can allow the machine to operate also as a fully fledged environmental scanning electron microscope with specimen chamber pressures in excess of 2000 Pa. This is achieved by a diamagnetic insert with a thin pressure limiting aperture at the bottom of the pole-piece. The insert allows the use of various size apertures in addition to the existing 1 mm differential diaphragm. PMID- 22841154 TI - Population diversity among Bordetella pertussis isolates, United States, 1935 2009. AB - Since the 1980s, pertussis notifications in the United States have been increasing. To determine the types of Bordetella pertussis responsible for these increases, we divided 661 B. pertussis isolates collected in the United States during 1935-2009 into 8 periods related to the introduction of novel vaccines or changes in vaccination schedule. B. pertussis diversity was highest from 1970 1990 (94%) but declined to ~ 70% after 1991 and has remained constant. During 2006-2009, 81.6% of the strains encoded multilocus sequence type prn2-ptxP3 ptxS1A-fim3B, and 64% were multilocus variable number tandem repeat analysis type 27. US trends were consistent with those seen internationally; emergence and predominance of the fim3B allele was the only molecular characteristic associated with the increase in pertussis notifications. Changes in the vaccine composition and schedule were not the direct selection pressures that resulted in the allele changes present in the current B. pertussis population. PMID- 22841157 TI - Transosseous fixation in insertional Achilles tendonitis. AB - The surgical approach of severe insertional Achilles tendonitis involves debridement, repair, and reattachment. Previously described techniques for bone tendon reattachment involved the use of suture anchors in the sparsely trabeculated calcaneus. The following technique tip is a reintroduction of bicortical transosseous fixation previously used in rotator cuff repairs. Bone tunnels are a viable option in the treatment of insertional Achilles tendonitis; however, additional research is necessary to validate its efficacy in this application. PMID- 22841158 TI - Isolated chronic anteroinferior tibiofibular ligament rupture repair. AB - Chronic anteroinferior tibiofibular ligament tears are rarely an isolated pathology. Only a small amount of published, peer-reviewed literature exists describing the isolated repair of the syndesmotic complex in patients who present with chronic ankle pain. We present a technique to restore the anatomic stability of the ligament and syndesmotic complex. The procedure can be easily performed using allogenic semitendinosus tendon graft and stabilized with transyndesmotic screws. The graft can be secured with biotenodesis screws or anchors of the surgeon's preference. The patient described in this report had a successful outcome with no complications. PMID- 22841160 TI - Right sided heart mass reveals hepatocellular carcinoma. PMID- 22841159 TI - Estimated GFR and incident cardiovascular disease events in American Indians: the Strong Heart Study. AB - BACKGROUND: In populations with high prevalences of diabetes and obesity, estimating glomerular filtration rate (GFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation may predict cardiovascular disease (CVD) risk better than by using the Modification of Diet in Renal Disease (MDRD) Study equation. STUDY DESIGN: Longitudinal cohort study comparing the association of GFR estimated using either the CKD-EPI or MDRD Study equation with incident CVD outcomes. SETTING & PARTICIPANTS: American Indians participating in the Strong Heart Study, a longitudinal population-based cohort with high prevalences of diabetes, CVD, and CKD. PREDICTOR: Estimated GFR (eGFR) predicted using the CKD-EPI and MDRD Study equations. OUTCOMES: Fatal and nonfatal cardiovascular events, consisting of coronary heart disease, stroke, and heart failure. MEASUREMENTS: The association between eGFR and outcomes was explored in Cox proportional hazards models adjusted for traditional risk factors and albuminuria; the net reclassification index and integrated discrimination improvement were determined for the CKD-EPI versus MDRD Study equations. RESULTS: In 4,549 participants, diabetes was present in 45%; CVD, in 7%; and stages 3-5 CKD, in 10%. During a median of 15 years, there were 1,280 cases of incident CVD, 929 cases of incident coronary heart disease, 305 cases of incident stroke, and 381 cases of incident heart failure. Reduced eGFR (<90 mL/min/1.73 m2) was associated with adverse events in most models. Compared with the MDRD Study equation, the CKD-EPI equation correctly reclassified 17.0% of 2,151 participants without incident CVD to a lower risk (higher eGFR) category and 1.3% (n=28) were reclassified incorrectly to a higher risk (lower eGFR) category. LIMITATIONS: Single measurements of eGFR and albuminuria at study visits. CONCLUSIONS: Although eGFR based on either equation had similar associations with incident CVD, coronary heart disease, stroke, and heart failure events, in those not having events, reclassification of participants to eGFR categories was superior using the CKD-EPI equation compared with the MDRD Study equation. PMID- 22841162 TI - Characterisation of a remineralising Glass Carbomer(r) ionomer cement by MAS-NMR spectroscopy. AB - OBJECTIVES: The purpose of this study was to characterize commercial glass polyalkenoate cement (GPC) or glass ionomer cement (GIC), Glass Carbomer((r)), which is designed to promote remineralization to fluorapatite (FAp) in the mouth. The setting reaction of the cement was followed using magic angle spinning nuclear magnetic resonance (MAS-NMR) spectroscopy. METHODS: Glass Carbomer((r)) initial glass powder and cements were subjected to (27)Al, (31)P, (19)F and (29)Si MAS-NMR analysis. X-ray powder diffraction (XRD) was employed to determine the presence of crystalline phases. RESULTS: (27)Al MAS-NMR showed the Al to be predominantly four coordinate, Al(IV), and the presence of Al-O-P species in the glass. The proportion of Al(IV) was reduced with setting reaction of the cement and significant amount of six coordinate Al, Al(VI), was found in the cement. The (31)P MAS-NMR spectra showed clearly a decrease of the orthophosphate peak of apatite on initial setting. (19)F MAS-NMR showed only a small fraction of FAp. (29)Si MAS-NMR demonstrated the presence of largely Q(4)(2Al) in the glass which changed only little in the aged cement. SIGNIFICANCE: This study also demonstrated how the setting reaction in Glass Carbomer((r)) cement and other GICs can be followed by (27)Al MAS-NMR examining the conversion of Al(IV) to Al(VI). Our data revealed that the apatite in this cement was not FAp but largely hydroxyapatite, which was partially consumed during the cement formation. PMID- 22841161 TI - The RIG-I-like receptor LGP2 controls CD8(+) T cell survival and fitness. AB - The RIG-I-like receptors (RLRs) signal innate immune defenses upon RNA virus infection, but their roles in adaptive immunity have not been clearly defined. Here, we showed that the RLR LGP2 was not essential for induction of innate immune defenses, but rather was required for controlling antigen-specific CD8(+) T cell survival and fitness during peripheral T cell-number expansion in response to virus infection. Adoptive transfer and biochemical studies demonstrated that T cell-receptor signaling induced LGP2 expression wherein LGP2 operated to regulate death-receptor signaling and imparted sensitivity to CD95-mediated cell death. Thus, LGP2 promotes an essential prosurvival signal in response to antigen stimulation to confer CD8(+) T cell-number expansion and effector functions against divergent RNA viruses, including West Nile virus and lymphocytic choriomeningitis virus. PMID- 22841163 TI - Maternal serum interleukin-33 and soluble ST2 across early pregnancy, and their association with miscarriage. AB - A shift from type 1 to type 2 immune bias is essential for successful implantation and pregnancy. ST2 is a receptor present on type 2 immune cells and IL-33 was recently discovered to be its ligand. We measured serum levels of soluble ST2 (sST2) and IL-33 across the mid-first trimester and examined whether levels were dysregulated among women with a viable fetus but destined to miscarry. While there was no significant change in sST2 or IL-3 across the first trimester, we found that women with live pregnancies destined to fail had dysregulated levels of serum IL-33, and potentially sST2 at six weeks' gestation. PMID- 22841164 TI - Specific decidual CD14(+) cells hamper cognate NK cell proliferation and cytolytic mediator expression after mucin 1 treatment in vitro. AB - Mucin 1 (MUC1) forms a glycocalyx on the surface of decidual epithelial cells that needs to be removed for successful embryo attachment. We investigated whether MUC1 affects human early pregnancy decidual CD14(+) cells and their interactions with cognate decidual natural killer (NK) cells. FITC-dextran internalisation, surface and intracellular antigen levels, and proliferation of CD14(+) and/or CD56(+) cells were analysed by flow cytometry. Magnetic separation was used to purify CD56(+) and CD14(+) cells. Uncultured CD14(+) cells expressed a negligible percentage of CD1a and CD83 molecules. They expressed lower levels of CD16, and higher levels of endocytic mannose receptors (MR), dendritic cell specific intercellular adhesion molecule grabbing non-integrin (DC-SIGN), proinflammatory chemokine CC receptor 5 (CCR5), and CD163 receptor, than their peripheral blood counterparts. Lipopolysaccharide stimulation did not affect FITC dextran internalisation in CD14(+) cells. MUC1 bound and internalised, in a dose dependent manner, the carbohydrate recognition domain of MR, increasing the decoy IL-1 receptor type II and decreasing IL-15 expression in CD14(+) cells. In the presence of MUC1-treated macrophages, the expression levels of the proliferation and cytotoxic mediators (perforin, Fas ligand and TNF-related activation-induced ligand or TRAIL) was attenuated, while that of the anti-inflammatory chemokine CCL17 was increased, in NK cells compared with untreated macrophages. In conclusion, MUC1 supports the alternative activation of tissue-specific CD14(+) cells, and may restrict proliferation of NK cells and regulate their content of cytotoxic mediators. Based on the experiments with first-trimester decidual cells in vitro, we conclude that removing MUC1 from decidual tissue might help control trophoblast invasion by NK cells. PMID- 22841165 TI - Effect of preoperative renal function on long-term survival after cardiac surgery. AB - OBJECTIVES: The study objective was to investigate the effect of renal failure on intermediate-term survival in cardiac surgery patients. METHODS: All patients aged 18 years or older undergoing coronary artery bypass grafting, valvular surgery, thoracic aortic surgery, or a combination of these from January 1, 2002 to December 1, 2005 were included. Data were obtained from the cardiac surgery and intensive care databases. Using a matching algorithm, the date of death was obtained from the National Death Index. The simplified Medical Diet for Renal Disease formula was used to calculate the estimated glomerular filtration rate, and the patients were stratified accordingly. An estimation of the effect of the preoperative renal function on the interval to death was determined using Cox regression analysis with and without cubic splines and polynomial regression. The long-term survival was described using the Kaplan-Meier product limit method. RESULTS: A total of 5297 patients were included in the present study. The vital status of all patients was obtained at a mean of 2.9 years (range, 1-5) postoperatively. The actuarial 1-year survival rate was 96% +/- 1%, and the 3 year survival rate was 92% +/- 1%. The greatest early mortality occurred in the severe renal dysfunction group; however, the dialysis-dependent renal failure group showed increased mortality over time compared with the other groups. The lowest risk of death (longest interval to death) occurred with an estimated glomerular filtration rate of approximately 90 mL/min/1.73 m(2). CONCLUSIONS: The results of our study have shown that preoperative renal dysfunction is an independent predictor of long-term mortality in cardiac surgery patients. PMID- 22841166 TI - Brain natriuretic peptide and risk of atrial fibrillation after thoracic surgery. AB - OBJECTIVES: Postoperative atrial fibrillation (POAF) complicating general thoracic surgery is a marker of increased morbidity and stroke risk. Our goal was to determine whether increased preoperative brain natriuretic peptide (BNP) levels are able to stratify patients by the risk of POAF. METHODS: Using a prospective database of 415 patients aged 60 years or older, who had undergone lung or esophageal surgery during a 1-year period, the preoperative clinical data, including BNP levels, were compared between patients who developed POAF lasting longer than 5 minutes during hospitalization and those who did not. RESULTS: POAF occurred in 65 (16%) of the 415 patients and was more frequent among patients who had undergone esophagectomy or anatomic lung resection (22% or 58 of 269) compared with those who did not (5% or 7 of 146; P < .0001). After esophagectomy or anatomic lung resection, 46 (34%) of the 135 patients with BNP levels greater than the median (>= 30 pg/mL) developed POAF compared with only 12 (9%) of 134 patients with BNP levels less than 30 pg/mL (P < .0001). The rates of POAF in patients undergoing other thoracic procedures were low and not associated with the BNP levels. Multivariate logistic regression analysis showed that in patients undergoing esophagectomy or anatomic lung resection, older age (5-year increments, odds ratio [OR], 1.28; 95% confidence interval [CI], 1.01-1.61; P = .04), male gender (OR, 2.61; 95% CI, 1.12-4.17; P = .02), and BNP level 30 pg/mL or greater (OR, 4.52; 95% CI, 2.19-9.32; P < .0001) were independent risk factors for POAF. The length of hospital stay was significantly increased in patients who developed POAF compared with those who did not (P < .0001). CONCLUSIONS: Among patients undergoing anatomic lung resection or esophagectomy, increased age, male gender, and preoperative BNP level of 30 pg/mL or greater were significant risk factors for the development of POAF. The identification of patients who are more likely to develop POAF will allow the development of trials assessing prevention strategies aimed at reducing this complication. PMID- 22841167 TI - Preoperative multidetector computed tomograpy angiography for planning of minimally invasive robotic mitral valve surgery: impact on decision making. AB - BACKGROUND: Minimally invasive mitral valve (MV) surgeries (ie, right thoracotomy and robotic approaches) are preferred for degenerative mitral regurgitation because these procedures result in reduced surgical trauma and recovery time. However, because of peripheral cardiopulmonary bypass, there is risk of embolic complications. We sought to use the strengths of 3-dimensional multidetector computed tomography (MDCT) in assessing aortoiliac atherosclerosis and mitral annular calcification (MAC) and its influence on decision for approach in MV surgery. METHODS: We included 141 patients with isolated grade 3 or 4+ mitral regurgitation who underwent contrast-enhanced MDCT of the chest, abdomen, and pelvis. Aortoiliac atherosclerosis was measured as circumferentiality (0 = none, 1 = less than one third, 2 = one third to two thirds, and 3 = more than two thirds) and thickness (0 = none or <1 mm, 1 = 1 to 2.9 mm, 2 = 3 to 5 mm, and 3 = >5 mm). Significant atherosclerosis was defined as circumferentiality score >= 1 and/or thickness score >= 1. Circumferentiality of MAC was also measured in a similar manner. Change in surgical approach was considered if a full/partial sternotomy was performed or surgical procedure was cancelled. RESULTS: One hundred eleven (79%) patients (mean age, 54 +/- 11 years; 67% men) underwent minimally invasive MV repair, whereas 30 patients (21%) had surgical approach changed (1 surgical cancellation). Of 111 patients who underwent minimally invasive repair, 4 (3.6%) patients had significant atherosclerosis/MAC, whereas 26 (87%) patients had evidence of significant atherosclerosis/MAC in the changed approach group. CONCLUSIONS: In patients undergoing minimally invasive MV surgery, there is a strong association between presence of significant aortoiliac atherosclerosis, as determined by MDCT and/or MAC and change in surgical approach. PMID- 22841168 TI - Does new-onset postoperative atrial fibrillation after coronary artery bypass grafting affect postoperative quality of life? AB - OBJECTIVES: New-onset postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery. We investigated the effect of POAF on quality of life after coronary artery bypass grafting. METHODS: All patients who underwent nonemergency coronary artery bypass grafting between March 2009 and January 2011 were requested to complete a Short Form-36 Health Survey before and 6 months after the procedure. Norm-based scores of 8 health status domains and 2 component summary scores were calculated. Only patients undergoing first-time coronary artery bypass grafting, with no history of atrial fibrillation, were included in the analyses. RESULTS: Of 1608 patients, 360 (22.4%) had POAF diagnosed. Twenty-eight patients died within half a year after the procedure (1.7% in the no POAF group and 1.8% in the POAF group; P = .90). After excluding these patients, data from 1580 patients were analyzed. Preoperative questionnaires were returned by 66% of the patients and postoperative questionnaires by 65%. Preoperative scores did not differ between patients with and without POAF in any subcategory (0/10). After the procedure, 4 of 10 scores were worse in the group with POAF compared to patients without POAF. Patients without POAF improved in all subcategories (10/10) after the procedure, whereas those with POAF did so in only 7 of 10. Multilinear regression showed POAF to be an independent negative predictor for improved quality of life 6 months postoperatively in 7 of 10 subcategories, including both mental and physical component summary scores. CONCLUSIONS: New-onset POAF does affect 6-month postoperative mental and physical health, possibly warranting more aggressive POAF treatment. PMID- 22841169 TI - Use of continuous flow ventricular assist devices in patients with heart failure and a normal ejection fraction: a computer-simulation study. AB - OBJECTIVES: Continuous flow left ventricular assist devices are used in end-stage systolic heart failure. However, about one half of the patients with heart failure exhibit diastolic dysfunction with a normal ejection fraction. In the present study, the possible hemodynamic consequences of continuous flow left ventricular assist devices use for these patients were investigated. METHODS: A previously developed cardiovascular model was modified to reproduce the peculiar hemodynamics of heart failure with a normal ejection fraction. The model was based on and validated with patient data derived from the published data. A continuous flow left ventricular assist device model was included and the hemodynamic effects of pump support evaluated at rest and during exercise. RESULTS: The model accurately reproduced the published data both at rest and during exercise, leading to simulated hemodynamic values within the standard deviations of patient variability. At rest, pump support decreased the end diastolic left ventricular pressure (6 vs 15 mm Hg) and volume (88 vs 135 mL). During exercise, maximal pump support substantially unloaded the left ventricle (end-diastolic pressure, 14 vs 35 mm Hg; volume, 133 vs 158 mL) and the pulmonary venous circulation (left atrial pressure, 12 vs 24 mm Hg) and resulted in a slight increase in cardiac output (11.7 vs 9.9 L/min). CONCLUSIONS: The simulation results suggested that continuous flow left ventricular assist devices improve the hemodynamics in patients with heart failure and a normal ejection fraction. For an optimal use of continuous flow left ventricular assist devices, low speeds should be maintained at rest, to avoid suction. However, during physical activity, higher speeds are needed to prevent an abnormal increase in the ventricular filling pressures typical of patients with heart failure and a normal ejection fraction. PMID- 22841170 TI - Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. AB - OBJECTIVE: The mammalian target of rapamycin signaling pathway has been implicated in therapeutic resistance in several types of cancer. However, the significance of mammalian target of rapamycin activation in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma treated with chemoradiotherapy remain unknown. However, this pathway is of particular interest because an effective inhibitor is available. METHODS: By using immunohistochemistry, phosphorylated mammalian target of rapamycin expression was examined in 77 patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy followed by surgery between 1999 and 2009, and correlated with treatment outcome. With the use of CE81T/VGH and TE2 cell lines, cells were treated with chemotherapy, temsirolimus (mammalian target of rapamycin inhibitor), or a combination of chemotherapy and temsirolimus, and investigated by 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: Pathologic complete response rates were 42% and 16% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .01). The 3-year overall survivals were 57% and 30% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .005). Positive phosphorylated mammalian target of rapamycin expression was independently associated with inferior overall and disease-free survival. In patients who did not achieve pathologic complete response, postchemoradiotherapy esophagectomy specimens showed significantly higher phosphorylated mammalian target of rapamycin expression than pretreatment biopsy specimens. In cell lines, concomitant administration of temsirolimus enhanced the effect of chemotherapy. CONCLUSIONS: Phosphorylated mammalian target of rapamycin expression is independently associated with the response to chemoradiotherapy and prognosis of patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy. Mammalian target of rapamycin inhibition can sensitize esophageal cancer cells to chemotherapy. Our results suggest the potential for mammalian target of rapamycin as a therapeutic target for patients with esophageal squamous cell carcinoma who receive multimodality treatment. PMID- 22841171 TI - Bioengineered human and allogeneic pulmonary valve conduits chronically implanted orthotopically in baboons: hemodynamic performance and immunologic consequences. AB - OBJECTIVE: This study assesses in a baboon model the hemodynamics and human leukocyte antigen immunogenicity of chronically implanted bioengineered (decellularized with collagen conditioning treatments) human and baboon heart valve scaffolds. METHODS: Fourteen baboons underwent pulmonary valve replacement, 8 with decellularized and conditioned (bioengineered) pulmonary valves derived from allogeneic (N = 3) or xenogeneic (human) (N = 5) hearts; for comparison, 6 baboons received clinically relevant reference cryopreserved or porcine valved conduits. Panel-reactive serum antibodies (human leukocyte antigen class I and II), complement fixing antibodies (C1q binding), and C-reactive protein titers were measured serially until elective sacrifice at 10 or 26 weeks. Serial transesophageal echocardiograms measured valve function and geometry. Differences were analyzed with Kruskal-Wallis and Wilcoxon rank-sum tests. RESULTS: All animals survived and thrived, exhibiting excellent immediate implanted valve function by transesophageal echocardiograms. Over time, reference valves developed a smaller effective orifice area index (median, 0.84 cm(2)/m(2); range, 1.22 cm(2)/m(2)), whereas all bioengineered valves remained normal (effective orifice area index median, 2.45 cm(2)/m(2); range, 1.35 cm(2)/m(2); P = .005). None of the bioengineered valves developed elevated peak transvalvular gradients: 5.5 (6.0) mm Hg versus 12.5 (23.0) mm Hg (P = .003). Cryopreserved valves provoked the most intense antibody responses. Two of 5 human bioengineered and 2 of 3 baboon bioengineered valves did not provoke any class I antibodies. Bioengineered human (but not baboon) scaffolds provoked class II antibodies. C1q(+) antibodies developed in 4 recipients. CONCLUSIONS: Valve dysfunction correlated with markers for more intense inflammatory provocation. The tested bioengineering methods reduced antigenicity of both human and baboon valves. Bioengineered replacement valves from both species were hemodynamically equivalent to native valves. PMID- 22841172 TI - The utility of adding expiratory or decubitus chest radiographs to the radiographic evaluation of suspected pediatric airway foreign bodies. AB - STUDY OBJECTIVE: This study aimed to compare test characteristics of standard (lateral and posteroanterior or anteroposterior) chest radiographs with and without special views (expiratory or bilateral decubitus) in the emergency department evaluation of children with suspected airway foreign bodies. METHODS: From 1997 to 2008, 328 patients with a suspected airway foreign body had standard and special view chest radiographs: 192 with left and right decubitus views, 133 with expiratory views, and 3 with both. Patients were excluded for cardiorespiratory disease, chest wall deformity, visible airway foreign bodies on standard views, or spontaneously expelled airway foreign bodies. After blinded radiologist review, standard plus special view test characteristics were compared to standard views. RESULTS: Nine upper airway and 70 tracheobronchial airway foreign bodies were identified by direct visualization or bronchoscopy, and the remainder were ruled out by bronchoscopy (50 patients) or clinically (199 patients). The sensitivity and specificity of the radiographs were, respectively, decubitus cohort, standard views, 56% and 79% and standard+decubitus views, 56% and 64%; expiratory radiograph cohort, standard views, 33% and 70% and standard+expiratory views, 62% and 72%. For standard plus decubitus views versus standard views alone, the relative sensitivity was 1.0 (0.56/0.56; 95% confidence interval [CI] 0.81 to 1.23) and the relative 1-specificity was 1.76 (0.36/0.21; 95% CI 1.3 to 2.37). For standard plus expiratory views versus standard views alone, the relative sensitivity was 1.87 (0.62/0.33; 95% CI 1.23 to 2.83) and the relative 1-specificity was 0.93 (0.28/0.3; 95% CI 0.6 to 1.44). CONCLUSION: The addition of decubitus to standard views increases false positives without increasing true positives and lacks clinical benefit. The addition of expiratory to standard views increases true positives without increasing false positives, but test accuracy remains low and the clinical benefit is uncertain. PMID- 22841173 TI - Performance of the Canadian Triage and Acuity Scale for children: a multicenter database study. AB - STUDY OBJECTIVE: We evaluate the association between triage levels assigned using the Canadian Triage and Acuity Scale and surrogate markers of validity for real life children triaged in multiple emergency departments (EDs). METHODS: This was a retrospective cohort study evaluating the triage assessment and outcomes of all children presenting to 12 pediatric EDs, all of which are members of the Pediatric Emergency Research Canada group, during a 1-year period (2010 to 2011). Anonymous data were retrieved from the ED computerized databases. The primary outcome measure was the proportion of children hospitalized for each triage level. Other outcomes were ICU admission, proportion of patients who left without being seen by a physician, and length of stay in the ED. Evaluation of all children visiting these EDs during 1 year was expected to provide more than 1,000 patients in each triage category. RESULTS: A total of 550,940 children were included. Pooled data demonstrated hospitalization proportions of 61%, 30%, 10%, 2%, and 0.9% for patients in Canadian Triage and Acuity Scale levels 1, 2, 3, 4, and 5, respectively. There was a strong association between triage level and admission to the ICU, probability of leaving without being seen by a physician, and length of stay. CONCLUSION: The strong association between triage level and multiple markers of severity in 12 Canadian pediatric EDs suggests validity of the Canadian Triage and Acuity Scale for children. PMID- 22841174 TI - The spectrum and frequency of critical procedures performed in a pediatric emergency department: implications of a provider-level view. AB - STUDY OBJECTIVE: We seek to provide current, comprehensive, and physician-level data for critical procedures performed in a high-volume pediatric emergency department (ED). METHODS: We conducted a retrospective study of all critical procedures performed in the ED of a tertiary care pediatric institution. Data were collected from written records of resuscitative care provided. The primary outcome measure was the cumulative frequency of each critical procedure during 12 consecutive months. Additional outcome measures included the number of critical procedures performed by pediatric emergency medicine faculty and fellows and a description of the other physician types performing each procedure. RESULTS: Two hundred sixty-one critical procedures were performed during 194 patient resuscitations, which represented 0.22% of all ED patient evaluations. Sixty-one percent of pediatric emergency medicine faculty did not perform a single critical procedure. Orotracheal intubation occurred 147 times and represented 56% of all critical procedures, yet 63% of pediatric emergency medicine faculty did not perform a single successful orotracheal intubation. Pediatric emergency medicine fellows performed a median of 3 critical procedures. CONCLUSION: Critical procedures were rarely performed in a large, academic pediatric ED. Pediatric emergency medicine faculty are at significant risk for skill deterioration, and pediatric emergency medicine fellows are unlikely to achieve competence in the performance of critical procedures if clinical exposure is the sole basis for the attainment and maintenance of skill. PMID- 22841175 TI - Don't hyperventilate over triage respiratory rates. PMID- 22841176 TI - The effect of abdominal pain duration on the accuracy of diagnostic imaging for pediatric appendicitis. AB - STUDY OBJECTIVE: Advanced imaging with computed tomography (CT) or ultrasonography is frequently used to evaluate for appendicitis. The duration of the abdominal pain may be related to the stage of disease and therefore the interpretability of radiologic studies. Here, we investigate the influence of the duration of pain on the diagnostic accuracy of advanced imaging in children being evaluated for acute appendicitis. METHODS: A secondary analysis of a prospective multicenter observational cohort of children aged 3 to 18 years with suspected appendicitis who underwent CT or ultrasonography was studied. Outcome was based on histopathology or telephone follow-up. Treating physicians recorded the duration of pain. Imaging was coded as positive, negative, or equivocal according to an attending radiologist's interpretation. RESULTS: A total of 1,810 children were analyzed (49% boys, mean age 10.9 years [SD 3.8 years]); 1,216 (68%) were assessed by CT and 832 (46%) by ultrasonography (238 [13%] had both). The sensitivity of ultrasonography increased linearly with increasing pain duration (test for trend: odds ratio=1.39; 95% confidence interval 1.14 to 1.71). There was no association between the sensitivity of CT or specificity of either modality with pain duration. The proportion of equivocal CT readings significantly decreased with increasing pain duration (test for trend: odds ratio=0.76; 95% confidence interval 0.65 to 0.90). CONCLUSION: The sensitivity of ultrasonography for appendicitis improves with a longer duration of abdominal pain, whereas CT demonstrated high sensitivity regardless of pain duration. Additionally, CT results (but not ultrasonographic results) were less likely to be equivocal with longer duration of abdominal pain. PMID- 22841177 TI - How accurate are rapid influenza diagnostic tests? PMID- 22841178 TI - How accurate is ultrasonography for excluding pneumothorax? PMID- 22841179 TI - Assessing the accuracy of diagnostic imaging for pediatric appendicitis during the course of illness. PMID- 22841180 TI - Clinical decisions for pediatric Fever-still a hot mess? PMID- 22841181 TI - Can quality-adjusted life-years and subgroups help us decide whether to treat late-arriving stroke patients with tissue plasminogen activator? PMID- 22841182 TI - Balancing the potential risks and benefits of out-of-hospital intubation in traumatic brain injury: the intubation/hyperventilation effect. PMID- 22841183 TI - Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion. AB - We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized. PMID- 22841184 TI - Visceral obesity assessed by computed tomography predicts cardiovascular events in chronic kidney disease patients. AB - BACKGROUND AND AIM: Cardiovascular disease is the leading cause of death among patients with chronic kidney disease (CKD). Although there is emerging evidence that excess visceral fat is associated with a cluster of cardiometabolic abnormalities in these patients, the impact of visceral obesity evaluated by a gold-standard method on future outcomes has not been studied. We aimed to investigate whether visceral obesity assessed by computed tomography was able to predict cardiovascular events in CKD patients. METHODS AND RESULTS: We studied 113 nondialyzed CKD patients [60% men; 31% diabetics; age 55.3 +/- 11.3 years; body mass index (BMI) 27.2 +/- 5.3 kg/m(2); estimated glomerular filtration rate (GFR) 33.7 +/- 13.6 ml/min/1.73 m(2)]. Visceral and subcutaneous abdominal fat were assessed by computed tomography at L4-L5. Visceral to subcutaneous fat ratio >0.55 (highest tertile cut-off) was defined as visceral obesity. Cardiovascular events including acute myocardial infarction, angina, arrhythmia, uncontrolled blood pressure, stroke and cardiac failure were recorded during 24 months. Cardiovascular events were 3-fold higher in patients with visceral obesity than in those without visceral obesity. The Kaplan-Meier analysis indicated that patients with visceral obesity had shorter cardiovascular event-free time than those without visceral obesity (P = 0.021). In the univariate Cox analysis, visceral obesity was associated with higher risk of cardiovascular events (hazard ratio = 3.4; 95% confidence interval = 1.1-10.5; P = 0.03). The prognostic power of visceral obesity for cardiovascular events remained significant after adjustments for sex, age, diabetes, previous cardiovascular disease, smoking, sedentary lifestyle, BMI, GFR, hypertension, dyslipidemia and inflammation. CONCLUSION: Visceral obesity assessed by computed tomography was a predictor of cardiovascular events in CKD patients. PMID- 22841185 TI - Low glycaemic index diets and blood lipids: a systematic review and meta-analysis of randomised controlled trials. AB - AIMS: Low glycaemic index (GI) diets are beneficial in the management of hyperglycemia. Cardiovascular diseases are the major cause of mortality in diabetes therefore it is important to understand the effects of GI on blood lipids. The aim was to systematically review randomised controlled trials (RCTs) of low GI diets on blood lipids. DATA SYNTHESIS: We searched OVID Medline, Embase and Cochrane library to March 2012. Random effects meta-analyses were performed on twenty-eight RCTs comparing low- with high GI diets over at least 4 weeks (1272 participants; studies ranged from 6 to 155 participants); one was powered on blood lipids, 3 had adequate allocation concealment. Low GI diets significantly reduced total (-0.13 mmol/l, 95%CI -0.22 to -0.04, P = 0.004, 27 trials, 1441 participants, I(2) = 0%) and LDL-cholesterol (-0.16 mmol/l, 95%CI 0.24 to -0.08, P < 0.0001, 23 trials, 1281 participants, I(2) = 0%) compared with high GI diets and independently of weight loss. Subgroup analyses suggest that reductions in LDL-C are greatest in studies of shortest duration and greatest magnitude of GI reduction. Furthermore, lipid improvements appear greatest and most reliable when the low GI intervention is accompanied by an increase in dietary fibre. Sensitivity analyses, removing studies without adequate allocation concealment, lost statistical significance but retained suggested mean falls of ~0.10 mmol/l in both. There were no effects on HDL-cholesterol (MD -0.03 mmol/l, 95%CI -0.06 to 0.00, I(2) = 0%), or triglycerides (MD 0.01 mmol/l, 95%CI -0.06 to 0.08, I(2) = 0%). CONCLUSIONS: This meta-analysis provides consistent evidence that low GI diets reduce total and LDL-cholesterol and have no effect on HDL cholesterol or triglycerides. PMID- 22841186 TI - 23rd Congress of the Spanish Liver Transplantation Society (SETH). Preface. PMID- 22841187 TI - Donation after cardiac death: where, when, and how? AB - The continuing shortage of donors has led to the increasing use of marginal grafts. Surgical techniques such as split, domino, and living donations have not been able to decrease waiting list mortality. Donation after cardiac death (DCD) was the only source of grafts prior to the establishment of brain death criteria in 1968. Thereafter, donation after brain death emerged as the leading source of grafts. The context in which irreversible cessation of circulatory and respiratory functions happens was the cornerstone to definite the four categories of DCD by the First International Workshop on DCD held in Maastricht in 1995. Controlled (CDCD) and uncontrolled (UDCD) categories now account for 10%-20% of the donor pool in several countries. Despite initial high rates of primary nonfunction and ischemic-type biliary lesions, refinements in protocols and surgical techniques have led to excellent 1- and 3-year graft survivals of 80% and 70%, respectively with PNF and ITBL rates below 3%. The institution of UDCD and CDCD depends on legal considerations of presumed consent and withdrawal of maneuvers, respectively. The potential for DCD programs is huge; it may be the only real, effective way to increase the grafts pool, both in adult and pediatric populations. Recent advances in perfusion machines will surely optimize this donor pool and allow new therapies for graft resuscitation. PMID- 22841188 TI - Liver transplantation from anti-hepatitis C virus-positive donors: our experience. AB - BACKGROUND: Hepatitis C (HCV) is among the most common causes of end-stage liver disease worldwide. The donor shortage leads us to consider alternative organ sources such as HCV-positive donors. The outcomes of these transplants must be evaluated thoroughly since there is universal recurrence of disease among HCV positive liver transplant recipients. METHODS: From January 2005 to April 2011, we performed 143 liver transplants (OLT) to treat end-stage liver disease secondary to HCV infection. Thirteen patients (9,1%) received livers from HCV positive donors. A control group consisted of 130 HCV-positive patients who underwent OLT during the same period with organs from HCV-negative donors. Donor HCV status was assessed by 2 tests: HCV antibodies and viral load. Not only recipient and graft survivals were analyzed, but also frequency, timing and severity of hepatitis recurrence. RESULTS: Among 143 transplants performed in HCV positive recipients during a 6-year period from January 1, 2005, to April 30, 2011, 9.1% of patients received an organ from an anti-HCV-positive donor, 72.7% of whom showed a negative viral load. The vast majority (80%) of our patients suffered hepatitis during their follow-up, 22.4% of which were severe cases. CONCLUSIONS: No significant difference in patient or graft survival was observed between the 2 groups. A high percentage of grafts with initial positive serology for HCV showed no viral replication. Grafts from HCV-positive donors can be considered to be a safe, effective source for liver donation. PMID- 22841189 TI - Multivariate analysis to determine the factors affecting the attitudes toward organ donation of healthcare assistants in Spanish and Mexican healthcare centers. AB - BACKGROUND: Healthcare assistants are an important group of workers who can influence public opinion. Their attitudes toward organ donation may influence public awareness of healthcare matters; negative attitudes toward donation and transplantation could have a negative impact on public attitudes. Our objective was analyze the attitudes of healthcare assistants, in Spanish and Mexican healthcare centers toward organ donation and determine factors affecting them using a multivariate analysis. MATERIAL AND METHODS: As part of the "International Collaborative Donor Project," 32 primary care centers and 4 hospitals were selected in Spain and 5 hospitals in Mexico. A randomized sample of healthcare assistants was stratified according to healthcare services. Attitudes were evaluated using a validated questionnaire of the psychosocial aspects of donation, which was self-completed anonymously by the respondent. Statistical analysis used the chi-square test, Student t test, and logistic regression analysis. RESULTS: Of 532 respondents, 66% in favored donation and 34% were against it or undecided. Upon multivariate analysis, the following variables had the most weight: 1) country of origin (Mexicans were more in favor than Spanish; odds ratio [OR]) = 1.964; P = .014); 2) a partner with a favorable attitude (OR = 2.597; P = .013); 3) not being concerned about possible bodily mutilation after donation (OR = 2.631; P = .006); 4) preference for options apart from burial for handling the body after death (OR = 4.694; P < .001) and 5) accepting an autopsy if one was needed (OR = 3.584; P < .001). CONCLUSIONS: The attitudes of healthcare assistants toward organ donation varied considerably according to the respondent's country of origin. The psycho-social profile of a person with a positive attitude to donation was similar to that described within the general public. PMID- 22841190 TI - Multivariate analysis of the factors affecting attitude toward living liver donation among workers in surgical services in Spanish, Mexican, and Cuban hospitals. AB - INTRODUCTION: Current liver donation rates are insufficient to cover transplant needs. Therefore, it is essential to promote living liver donation (LLD) given the ever decreasing morbidity and mortality in the donor and the improving results in the recipient. LLD is becoming increasingly accepted. However, in the health care system, a percentage of the personnel are not in favor. OBJECTIVE: To analyze the attitude of personnel in surgical services in Spain and Latin-America hospitals toward LLD. MATERIALS AND METHODS: As part of the "International Collaborative Donor Project," a random sample was taken and stratified according to surgical service and job category in 10 hospitals; three in Spain, five in Mexico, and two in Cuba (n = 496). Attitude was evaluated using a validated survey that was completed anonymously and self-administered. RESULTS: Eighty-six percent (n = 425) of respondents were in favor of related living liver donation, and 30% (n = 147) were in favor if it were not related. According to country, 88% of the Mexican respondents were in favor of living liver donation, 85% of the Cubans, and 82% of the Spanish (P > .05). In the multivariate analysis of the variables with most weight affecting attitude toward LLD, the following significant associations were found: (1) a favourable attitude toward living kidney donation (odds ratio [OR] = 91; P < .001); (2) acceptance of a donated living liver if one were needed (OR = 11; P < .001); and (3) family discussion about donation and transplantation (OR = 2.581; P = .037). CONCLUSIONS: Attitude toward related living liver donation was very favorable among hospital personnel in Spanish and Latin American surgical services. PMID- 22841191 TI - Knowledge of the brain-death concept among secondary school teachers. AB - INTRODUCTION: The concept of brain death (BD) is not very well known in the population, and its unknown nature is one of the main factors that could lead to an attitude against organ donation. The teaching sector has an important influence on the education of adolescents, and for this reason the teacher's knowledge of these concepts is fundamental to spread the correct meaning of the concept to young people. OBJECTIVE: To analyze the concept of BD among teachers of compulsory secondary education (CSE) in southeast Spain and to determine teachers' influence on attitude toward organ donation. MATERIALS AND METHODS: Ten CSE level schools were selected and stratified according to geographical location in southeast spain. A random sample was taken of CSE teachers. The knowledge of the concept of BD and attitude toward donation were analyzed using a validated questionnaire, which was self-administered and completed anonymously. RESULTS: Sixty-four percent (n = 180) of respondents knew the BD concept and they considered it to be the death of an individual. Of the rest, 34% (n = 95) did not know this concept, and the remaining 3% (n = 8) believed it did not mean a person's death. Those who understood the concept of BD were more in favor of deceased donation than those who held the wrong concept (82% versus 75%; P < .01). The knowledge of the concept of BD is associated with variables directly and indirectly related with donation and transplantation (P < .05). CONCLUSIONS: A third of the CSE teaching staff did not know or understand the BD concept as the death of an individual. The knowledge of BD positively affects attitude toward organ donation. Given that teachers are a source of information, the basic training of CSE teaching staff in basic concepts such as BD would be important. PMID- 22841193 TI - Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients. AB - The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis. Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis (n=5). Selected genes up-regulated before transplantation were: TNFRSF9 (tumor necrosis factor [TNF] receptor superfamily, member 9); IL2RB (interleukin-2 receptor beta); BCL2L2 (BCL2-like 2); NOX5 (NADPH) oxidase, EF-hand calcium binding domain 5); PEX5 (peroxisomal biogenesis factor 5); PPARG (peroxisome proliferator activated receptor gamma); NIBP (IKK2 binding protein); NKIRAS2 (NFKappaBeta inhibitor interacting Ras-like 2); IL4 (interleukin-4); IL-4R (interleukin 4 receptor); ADH1A (alcohol dehydrogenase 1A, class 1); ALDH1L1 (aldehyde dehydrogenase 1 family, member L1); MPO (myeloperoxidase); NPPA (natriuretic peptide precursor A); BCL2A1 (BCL2-related protein A1); GADD45A (growth arrest and DNA-damage-inducible alpha); TEGT (Bax inhibitor 1); PIK3CA (phosphoinositide 3-kinase, catalytic, alpha polypeptide); IFNGR2 (interferon gamma receptor 2); JAK2 (Janus Kinase 2); FAS (Fas, TNF receptor superfamily, member 6); TANK (TRAF family member-associated NFKB activator); TTRAP (TRAF and TNF receptor-associated protein); and ANXA5 (annexin A5). PMID- 22841192 TI - Evaluation of attitude toward living organ donation among adolescents in Southeast Spain. AB - INTRODUCTION: The infant and youth population constitutes a sector in which early awareness is important to increase favorable attitudes toward donation. Objectives were as follows: (1) to analyze the attitudes of adolescents toward living organ donation; and (2) to determine the psychosocial variables affecting them. MATERIALS AND METHODS: In Southeast of Spain a random sample was stratified according to Compulsory Secondary Education (CSO) school. In the 10 selected schools we performed a random sampling of each of the classes from the first to the fourth year of CSO. Attitudes were evaluated using a validated questionnaire lowering psychosocial aspects of donation. The self-administered questionnaire was completed anonymously. Statistical analyses employed Student t test and the chi(2) test. RESULTS: Regarding living kidney donation, 89% (n = 3146) of adolescents favored it, although only 29% (n = 1035) in unrelated cases. For living liver donation, 78% (n = 2753) were in favor of related donation, but only 19% (n = 668) were in favor if it was unrelated. The favorable attitude toward living donation was mainly associated with the following variables: (1) being a woman; (2) having previous experience with the donation-transplantation process; (3) having spoken about the matter of donation and transplantation with family and friends; (4) a favorable attitude of one's mother and father; (5) concern about possible bodily mutilation after donation; and (6) having performed pro social type activities (P < .05). CONCLUSIONS: Related living donation is well accepted among adolescents on the Southeast of Spain. There was a high acceptance of unrelated living donation compared with studies published in other geographic areas. PMID- 22841194 TI - Prevalence and characteristics of bone disease in cirrhotic patients under evaluation for liver transplantation. AB - BACKGROUND: We performed a retrospective study to examine the prevalence of bone disease (BD) among cirrhotic patients being evaluated for liver transplantation (OLT) using bone densitometry dual-energy x-ray absorptiometry in the hip/femoral neck and lumbar spine. The associations of BD with demographic and clinical data, disease etiology and liver function were studied by univariate and multivariate logistic regression analyses. Osteopenia and osteoporosis were defined by World Health Organization criteria. RESULTS: We included 486 patients (79% men of mean age, 53 +/- 8.8 years (range, 21-69) who included 62.6% smoker and 23.7% diabetic subjects. Body mass index (BMI) was 28.8 +/- 5.7 kg/m(2) (range, 16-43). The liver disease was Child-Pugh class A (22%), B (51%), or C (27%); the Model for End-Stage Liver Disease (MELD) score was 14.6 +/- 5.4 (range, 7-33). The disease etiology was alcohol (59%), hepatitis C (32%), hepatitis B (10%), primary biliary cirrhosis (PBC) (2.3%), secondary biliary cirrhosis, (2%) or other causes (10%). In all, 350 patients (72%) had BD in the hip/femoral neck and/or lumbar spine: Global hip, 26% (osteopenia, 22%; osteoporosis, 4%); femoral neck, 48% (osteopenia, 43%; osteoporosis, 5%) and lumbar spine, 63% (osteopenia, 40%; osteoporosis, 23%). Univariate analysis showed the BD risk to increase with the following variables: Female gender (odds ratio [OR], 1.88; P = .023) and lower BMI (OR, 0.95; P = .012). Upon multivariate analysis, female gender (OR, 2.43; P = .004), lower BMI (OR, 0.96; P = .016), and tobacco use (OR, 1.59; P = .043) were significant. PBC showed BD in 100% of cases. By adjusting bone mineral density (BMD) values to age (Z-score) in relation to that defined by T-score, we observed a decrease in BD prevalence in both the femoral neck (20% vs 48%) and the lumbar spine (44% vs 63%). CONCLUSION: BD, especially in the lumbar spine, is common among cirrhotic patients under evaluation for OLT. Cirrhosis is a major BD risk factor that remains even when BMD values are adjusted for age. Female gender, lower BMI, and tobacco consumption are major risk factors for BD in cirrhotic patients. Bone densitometry must be included in the OLT evaluation of all patients. PMID- 22841195 TI - Response to vaccination against hepatitis B virus with a schedule of four 40-MUg doses in cirrhotic patients evaluated for liver transplantation: factors associated with a response. AB - We performed a retrospective study to evaluate the rate of and factors associated with a response to recombinant hepatitis B virus (HBV) vaccination using 4 intramuscular doses (40 MUg) administered at 0, 1, 2, and 6 months among 278 cirrhotic patients being evaluated for orthotopic liver transplantation (OLT). We re-vaccinated 57 non-responders with the same schedule. The 39.2% overall response rate to vaccination included 36% after three and 40.7% after four doses, namely, a median anti-HBs level of 100 IU/mL (range, 10 to 1000 IU/mL). The 51% revaccination response rate achieved a median hepatitis B surface antibody (anti HBs) level of 99 IU/mL (range, 11 to >1000 IU/mL). Upon univariate analysis, variables associated with a higher response were: better liver function (Child Pugh class [A, 53.8% B, 33.3%, C, 30.1%; P = .002), Model for End-stage Liver Disease (MELD) score (11.4 versus 13.6; P = .001]), absence of diabetes (43.6% versus 20.8%; P = .002), presence of isolated hepatitis B core antibody (anti HBc) positivity (80% versus 37.7%; P = .007), and younger age (< 45 years, 52.2%; range, 45 to 55 years, 40.4%; > 55 years, 34.1%; P = .031). Upon multivariate logistic regression analysis, lower MELD score (odds ratio [OR]: 0.922; P = .046), absence of diabetes (OR:0.359; P = .008) and isolated anti-HBc positivity (OR:5.826; P = .034) were associated with a higher response. No differences were observed to be associated with gender, weight, body mass index, etiology or tobacco consumption. Among the same patient cohort (n = 79), the responses after the third and fourth doses were 36.7% and 51.9% respectively. In conclusion, the response rate to HBV vaccination in cirrhotic patients evaluated for OLT reached more than 35% among those who received at least 3 doses. It was higher among patients who showed isolated anti-HBc positivity, better liver function, younger age, and non-diabetic status. The fourth dose only increased the response rate by 24% over that obtained after the first three doses, whereas a revaccination achieved a 50% response rate, which probably accounts for revaccination after no response to 3 doses. Vaccination should be introduced against HBV in the early stages of the disease. PMID- 22841196 TI - Prevalence of hepatitis B and A virus markers and vaccination indication in cirrhotic patients evaluated for liver transplantation in Spain. AB - In the absence of immunity, vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is recommended for patients with chronic liver disease and those evaluated for liver transplantation (OLT) HAV and HBV infections after OLT which are frequent in this setting, are associated with a worse prognosis. The aim of this study was to estimate the need for vaccination against HBV and HAV among cirrhotic patients who were candidates for OLT and associations with gender, age, and etiologic factors. HBV and HAV serological markers HBsAg, anti HBc, antiHBs, immunoglobulin G (IgG)-anti-HAV were investigated among 568 patients, including 75% men. The overall mean age was 53.6 +/- 8.9 years range 17 69, and 20% were diabetic. This etiologies were alcohol (68%), hepatitis C virus (35%) or other causes (10.4%). Child-Pugh classes were: A (26%), B (44%), and C (30%). In contrast with 359 patients (63.2%) who had negative HBV markers, 209 (36.8%) were positive: HBsAg (+), 43 (7.6%), isolated anti-HBc (+), 57 (10%), isolated anti-HBs (+), 19 (3.3%), anti-HBc (+)/anti-HBs (+), 90 (15.8%). HBV vaccine indication was performed in 416 patients (73.2%) who either had negative HBV markers or isolated anti-HBc (+). It was more frequently performed in women (82.3% versus 70.3%, P = .005), albeit with no differences according to age or etiology. There were only 8.2% (44/538) IgG-anti-HAV-negative, an indication for vaccination against HAV, which was more frequent affecting patients who were younger [<= 45 years (27.6%), 46-55 (7.2%), >55 (2.6%); P < .0001)]; nondiabetic (9.5% versus 2.8%, P = .023); nonalcoholic (11.4% versus 6.6%, P = .056); and displayed negative HBV markers (10.2% versus 4.6%, P = .023). Only three patients with IgG-anti- HAV (-) were over 60 years. In conclusion, there is a frequent indication for HBV vaccination among cirrhotic and especially HAV vaccine for under 45 year old patients undergoing evaluation for OLT. PMID- 22841197 TI - Does the transjugular intrahepatic portosystemic influence the outcome of liver transplantation? PMID- 22841198 TI - Hepatopulmonary syndrome among cirrhotic candidates for liver transplantation. AB - This study assess of hepatopulmonary syndrome (HPS) prevalence and the influence of etiology among cirrhotic patients due to an alcoholic or viral etiology. We examined the records of patients were distributed as Group 1, alcoholic (n = 40) and Group 2, hepatic cirrhosis of viral etiology (n = 35). Hepatic cirrhosis status was estimated by CHILD and MELD scores. Presence of clinical ascites spell out was noted as well as size and diastolic functions of the cardiac chambers using two-dimensional transthoracic echocardiography in M mode and by Doppler. HPS was studied with agitated saline serum and intravenous contrast administration. HPS was considered to be present when serum or contrast passed to the left chamber before the 5th cardiac cycle. There was no significant differences among related to sex, age, cirrhosis status or ascites. HPS frequency was 35% in Group 1 versus 64.7% among Group 2-Patients (P = .01). Taking into account the results, we concluded that HPS frequency was related to cirrhotic etiology. Upon multivariate analysis a patients with cirrhosis from viral etiology showed significantly increased HPS frequency compared with those displaying cirrhosis of an alcoholic etiology. PMID- 22841199 TI - Emotional-type psychopathologic symptoms among patients with terminal chronic alcohol-induced liver cirrhosis. AB - INTRODUCTION: Patients with toxic substance abuse syndrome, such as alcohol abuse, have elevated psychopathologic morbidity and mortality such as mood disorders. OBJECTIVE: To evaluate the emotional-type psychopathologic symptoms in patients with alcohol-induced hepatic cirrhosis on the liver transplant waiting list. MATERIALS AND METHODS: Patients with alcoholic liver cirrhosis who were candidates for liver transplant (n = 41) completed the SA-45 questionnaire (Gonzalez y Cuevas; 88), which assesses nine dimensions: somatizations, obsessive compulsivity, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. A control group consisted of patients with chronic nonalcoholic terminal hepatopathies (n = 22). RESULTS: Seventy-six percent of patients had some kind of psychopathologic symptom compared to 68% of the patients in the control group with other nonalcoholic etiologies (P > .05). The emotional-type clinical symptoms were: (1) somatizations: 37% of patients with alcoholic cirrhosis had this type of clinical symptoms compared to 32% of the control group (P > .05); (2) obsessive compulsivity: 56% versus 46%, respectively (P > .05); (3) interpersonal sensitivity: 19% versus 9%, respectively (P > .05); (4) depression: 54% versus 27%, respectively (P = .045); (5) anxiety: 59% versus 46%, respectively (P > .05); (6) hostility: 29% versus 5%, respectively (P = .021); (7) phobic anxiety: 10% versus 14%, respectively (P > .05); (8) paranoid Ideation: 7% versus 5%, respectively (P > .05); (9) psychoticism: 5% versus 4%, respectively (P > .05). CONCLUSIONS: The patients with alcoholic liver cirrhosis on the liver transplant waiting list had elevated psychopathologic symptoms. Depressive- and hostile-type emotional alterations were most frequent in this type of patients. PMID- 22841200 TI - Split liver transplantation: where? when? how? AB - Donor scarcity is among the greatest concerns in the transplantation community. Dividing a liver graft theoretically offers a double benefit for candidates on the waiting list. Split liver transplantation entails a higher logistic and technical complexity that is extensively compensated, not only with an increase in the accessibility for child and adult candidates on the liver transplant waiting list, but also acceptable survival results. PMID- 22841201 TI - Statistical quality control charts for liver transplant process indicators: evaluation of a single-center experience. AB - Liver transplantation, the best option for many end-stage liver diseases, is indicated in more candidates than the donor availability. In this situation, this demanding treatment must achieve excellence, accessibility and patient satisfaction to be ethical, scientific, and efficient. The current consensus of quality measurements promoted by the Sociedad Espanola de Trasplante Hepatico (SETH) seeks to depict criteria, indicators, and standards for liver transplantation in Spain. According to this recommendation, the Canary Islands liver program has studied its experience. We separated the 411 cadaveric transplants performed in the last 15 years into 2 groups: The first 100 and the other 311. The 8 criteria of SETH 2010 were correctly fulfilled. In most indicators, the outcomes were favorable, with an actuarial survivals at 1, 3, 5, and 10 years of 84%, 79%, 76%, and 65%, respectively; excellent results in retransplant rates (early 0.56% and long-term 5.9%), primary nonfunction rate (0.43%), waiting list mortality (13.34%), and patient satisfaction (91.5%). On the other hand, some indicators of mortality were worse as perioperative, postoperative, and early mortality with normal graft function and reoperation rate. After the analyses of the series with statistical quality control charts, we observed an improvement in all indicators, even in the apparently worst, early mortality with normal graft functions in a stable program. Such results helped us to discover specific areas to improve the program. The application of the quality measurement, as SETH consensus recommends, has shown in our study that despite being a consuming time process, it is a useful tool. PMID- 22841202 TI - Coagulopathy management in liver transplantation. AB - Risk of bleeding and transfusion in liver transplantation is determined by age, severity of liver disease, as well as hemoglobin and plasma fibrinogen values. During the hepatectomy and the anhepatic phase, the coagulopathy is related to a decrease in clotting factors caused by surgical bleeding, facilitated by the increased portal hypertension and esophageal-gastric venous distension. Corrections of hematologic disturbances by administration of large volumes of crystalloid, colloid, or blood products may worsen the coagulopathy. Also, impaired clearance of fibrinolytic enzymes released from damaged cells can lead to primary fibrinolysis. At time of graft reperfusion further deterioration may occur as characterized by global reduction among all coagulation factors, decreased plasminogen activator inhibitor factors, and simultaneous generation of tissue plasminogen activator. In situations with inherent risk of bleeding, hypofibrinogenemia must be corrected. Concern about unwanted events is a major limitation of preventive therapy. There is some evidence for the efficacy of antifibrinolytic drugs to reduce red blood cell requirements. A guide for antifibrinolytic therapy are clot firmness in trhomboelastometry or alternatively, diffuse bleeding associated to a fibrinogen value less than 1 g/L. Because thrombin generation is limited in severe thrombocytopenia, platelet administration is recommended when active bleeding coexists with a platelet count below 50,000/mm(3). When the administration of hemoderivates and antifibrinolytic drugs does not correct severe bleeding, consumption coagulopathy and secondary fibrinolysis should be suspected. Treatment of affected patients should be based upon correcting the underlying cause, mostly related to tissue hypoxia due to critical hypoperfusion. PMID- 22841203 TI - Have we changed the liver retransplantation survival? AB - INTRODUCTION: Orthotropic liver retransplantation (RT) is the therapeutic option for the failure of an allograft. Patient and graft survival rates after RT are inferior to primary liver transplantation (OLT). Because of the limited number of donors, it is essential that we optimize their use. We reviewed 68 consecutive retransplantations to evaluate their results. MATERIALS AND METHODS: Using registry data from our Liver Transplantation Unit, we performed a retrospective cohort study of adult RT between 1991 and 2010. Patients were divided into 2 groups (urgent vs elective RT) to compare the utility of RT. We also analyzed data collected at the time of RT, including age, gender, indications for primary OLT and RT (hepatitis C virus [HCV]+ and HCV-). At various stages (1991-2000, 2001-2006, and 2007-2010), we calculated probability survival curves according to the Kaplan-Meier method with comparisons using the log-rank test. RESULTS: Among 771 adult liver transplantations, 68 (8.8%) underwent late secondary OLT. 21 (31%) cases were urgent and 47 elective RT (69%). Vascular complications was the most common cause for urgent RT, and chronic rejection, for elective RT. Differences were also detected in the overall survival of RT patients; mortality was significantly lower among the urgent procedures (15% vs 47.8%). Significantly differences were also detected in overall survival for RT patients between 2007 and 2010 (81.7% with urgent RT and 76.5% with elective situations). CONCLUSION: These data confirmed the utility of RT in elective and emergency situations. Overall survival of elective RT patients has improved in recent years. Liver RT requires a multidisciplinary team to decide the inclusion and prioritization of elective RT cases on the OLT waiting list. PMID- 22841204 TI - What do we know about the clinical impact of complete withdrawal of immunosuppression in liver transplantation? AB - The liver is a privileged organ with a lower incidence of rejection than other organs. However, immunosuppressive regimens are still required to control the alloreactive T-lymphocyte response after transplantation. These treatments may lead to severe complications, such as infectious diseases, cancers, cardiovascular diseases, and chronic renal insufficiency. In clinical transplantation, there is increasing evidence that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting that tolerance is already present. This strategy is feasible in 25% to 33% of liver transplant recipients. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression (IS) withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with it. In preliminary studies, IS withdrawal was safely achieved in selected liver transplant patients, and improved not only kidney function, but also other IS-associated side-effects such as hypercholesterolemia, hyperuricemia, hypertension, and diabetes control. However, longer follow-up periods are needed to confirm the benefits of IS withdrawal in liver transplant patients. PMID- 22841205 TI - Serum levels of interleukin-9 during acute rejection in liver transplantation. AB - INTRODUCTION: Interleukin-9 (IL-9) has been cast as a player in autoimmunity, but its role in liver transplantation remains to be clarified. The aim of our study was to investigate the time course of IL-9 serum levels during hepatic allograft rejection. METHODS: IL-9 serum levels were determined in 34 healthy subjects and 50 hepatic transplant recipients. The patients were divided into two groups: group I was composed of 15 patients with acute rejection episodes, and group II, 35 patients free of this problem. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy. RESULTS: The concentrations of IL-9 were similar in the rejection and nonrejection groups over the entire postoperative period. The whole transplant group, including those with stable graft function, showed higher IL-9 serum levels than the controls at all times after liver transplantation. CONCLUSIONS: These preliminary results suggest a lack of participation of IL-9 in human liver allograft rejection. PMID- 22841206 TI - Interleukin-9 in stable liver transplant recipients. AB - INTRODUCTION: Interleukin-9 (IL-9) has recently been described to be involved in the maintenance of a tolerant environment, but there is no evidence of its role in human liver transplantation. The aim of our study was to measure the serum levels of IL-9 in stable liver transplant recipients and examine their influence on immunosuppressant load. METHODS: Serum IL-9 levels were determined in 34 healthy subjects and 30 stable liver transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the blood levels of calcineurin inhibitors (CNIs) at the time of the study: 13 patients showed high concentrations of either cyclosporine or tacrolimus (high CNI: cyclosporine > 80 ng/mL or tacrolimus > 5 ng/mL) and another 17 patients showed low CNI levels. RESULTS: The concentrations of IL-9 were significantly higher among liver transplant recipients compared with healthy subjects. In addition, patients with low CNI blood levels showed higher serum levels of IL-9, an effect that was greater with tacrolimus, albeit not significantly. CONCLUSIONS: These preliminary results indicated that increased serum IL-9 concentrations accompanied a lower immunosuppressive load. It remains to be established whether this relates to induction of tolerance in liver transplantation. PMID- 22841208 TI - Perioperative levels of glutathione reductase in liver transplant recipients with hepatitis C virus cirrhosis. AB - Surgical intervention causes oxidative stress leading to an adaptive responses by the body. To evaluate changes in the defense capacity of antioxidant enzymes, we determined the activity of glutathione reductase (GR) levels among liver transplant recipients with due to hepatitis C virus cirrhosis. The study was performed in 22 patients (16 males and 6 females) of average ages 52.63 +/- 5.49 years for males and 59.67 +/- 5.65 years for females. Blood samples for glutathione reductase activity were drawn on admission before as well as at 1, 6, and 12 h and 1, 2, 3, 5 and 7 days after the liver transplantation. Perioperative glutathione reductase levels were significant (P = .014) over the period using Bonferroni tests. GR activity reached a maximum (15.6112 +/- 6.56035 nmol/mg protein) at 3 days after liver transplantation (T3d) (P = .001). The increased GR activity values detected perioperatively indicated scavenging of reactive oxygen species generated after liver transplantation of hepatitis C virus cirrhosis patients. PMID- 22841207 TI - Limitations of use of the noninvasive clearance of indocyanine green as a prognostic indicator of graft function in liver transplantation. AB - AIM: To assess the prognostic value of noninvasive indocyanine green (ICG) clearance (ICG-pulse-densitometric method [PDR]) for the outcome of liver grafts after transplantation. METHODS: ICG-PDR, hepatic artery resistance index, cardiac output, transaminases, prothrombin time, bilirubin, albumin, hematocrit at 48 to 72 hours after transplantation were analyzed with reference to outcome among 59 liver graft recipients. RESULTS: Two grafts were lost at 10 and 88 days during the initial hospitalization. These two patients only differed from the other recipients in the need for packing (1/2 versus 3/57) and degree of hypoproteinemia (46 +/- 0 versus 51 +/- 7.8 g/L), whereas they had similar ICG PDR values (16.7%/min and 21.8%/min versus 17.3%/min +/- 7.2%/min). Seven patients showed an ICG-PDR <= 8.8%/min, a previously identified cutoff for early postoperative complications. These patients versus the other 52 significantly differed in prothrombin index (47.9% +/- 15.9% versus 64.3% +/- 11.7%, P = .001) and bilirubin (8.3 +/- 3.2 versus 3.3 +/- 2.9 mg/dL, P = .0001). Early postoperative complications--primary graft nonfunction, hepatic artery thrombosis, or septic shock--responsible for an ICG-PDR <= 8.8%/min were observed in 2/7 patients. Interestingly, six cases developed an early (range: 3-15 days) rejection episode. In all the cases rejection suspected by analytical abnormalities was confirmed by liver biopsy. Among the overall series of patients, ICG-PDR significantly correlated with serum albumin (r = 0.345; P = .007), bilirubin (r = -0.514; P = .0001), and hematocrit (r = 0.462; P = .0001) but not with transaminases, prothrombin index, cardiac output, or hepatic artery resistance index. Actuarial 72-month probability of graft survival was 75%. Overall, 14 grafts were lost over a median follow-up of 78 months (range 1-99 m). There were no significant differences among early ICG-PDR values among grafts lost vs retained upon follow-up. CONCLUSION: ICG-PDR measured once early after liver transplantation did not offer relevant information to predict individual patient outcomes in the immediate postoperative phase. This lack of prognostic value may have been due to the multiple confounding factors involved in ICG metabolism after liver transplantation. PMID- 22841209 TI - Biliary complications after orthotopic liver transplantation: a review of incidence and risk factors. AB - Biliary complications (BCs) are a common source of morbidity after liver transplantation, leading to long-term and repeated therapies. The incidence of BCs currently ranges from 5% and 25%. Biliary strictures and leaks are the most common complications after deceased donor liver transplantation (DDLT), occurring in 9%-12% and 5%-10% of cases, respectively. Hepatic artery complications are recognized as the major risk factor for BCs; however, other circumstances such as advanced donor age, prolonged cold and warm ischemia times, grafts from donors after cardiac death, occurrence of a previous bile leak, T-tube use, cytomegalovirus infection, or graft steatosis have also been reported to be potential risk factors. Use of various preservation solutions has not significantly improved the biliary complication rate after DDLT. Technical modifications in biliary reconstruction have been proposed to improve outcomes after DDLT; the use of a T-tube for biliary reconstruction continues to be controversial. Non anastomotic strictures (NAS) are recognized to be different from anastomotic strictures. Although they have been associated with ischemic or immunological mechanisms, bile salt toxicity has recently been recognized as a potential factor for NAS. Donation after cardiac death is a significant source of organs that has been associated with decreased graft survival due to the increased BCs. PMID- 22841210 TI - Laparoscopic treatment of biliary peritonitis after removal of T-tube in liver transplant patients. AB - INTRODUCTION: T-tube removal in liver transplant patients can occasionally cause a massive biliary leak and may require surgical treatment for its resolution. We present our experience with a laparoscopic approach to biliary peritonitis in liver transplant patients after the removal of a T-tube. PATIENTS AND METHODS: From January 2003 until February 2010, we performed 351 liver transplantations in 313 recipients, including 135 with a T-tube. After its removal 31 biliary leaks developed (23%); 12 were massive and required surgery, which utilized a laparoscopic approach. RESULTS: The mean length of the intervention was 72.9 +/- 12.87 minutes (range = 55-95), without any complications during the procedure, and no need to convert to a laparotomy. Mean hospital stay after the intervention was 6.75 +/- 3.88 days (range 4-18). There was no mortality from the procedure. CONCLUSION: The laparoscopic approach for biliary leakage after T-tube removal is indicated when large diffuse acute peritonitis is established a few hours postremoval of the T-tube. This safe procedure treats the complication without the need for another laparotomy. PMID- 22841211 TI - Biliary complications in orthotopic liver transplantation using choledochocholedochostomy with a T-tube. AB - Despite significant advances in orthotopic liver transplantation (OLT), biliary tract reconstruction is still a major source of complications. Choledochocholedochostomy with a T-tube used to be the standard procedure for biliary reconstruction after OLT. However, many centers currently avoid use of the T-tube because of the high incidence of complications. Our aim was to study the biliary complications occurring at our center when end-to-end choledochocholedochostomy (EE-CC) over a T-tube was used as the standard procedure for biliary reconstruction. A retrospective review was conducted of all patients who underwent liver transplantation from February 1, 1996, to April 30, 2010. Only patients requiring any therapy to treat biliary complications were considered, whereas those with concomitant hepatic artery complications were excluded. The study cohort consisted of 743 patients who had EE-CC with a T-tube. Of these, 73 patients (9.8%) experienced any biliary complication. Anastomotic strictures occurred in 17 patients (2.3%), and non-anastomotic strictures in 2 (0.3%). Fifteen patients with anastomotic strictures were successfully treated by dilatation and stenting. Bile leakage was diagnosed in 39 patients (5.2%). Leakage occurred at the anastomosis in 15 patients (2%), and at the exit site of the T-tube in 24 patients (3.2%). Tube opening was the only treatment used in 30 patients with bile leakage (76.9%). Seven patients experienced leaks after elective T-tube removal (1%). Overall, repeat surgery to manage biliary complications was needed in 9 patients (1.2%). The mortality rate from biliary complications was 0.13%. In conclusion, EE-CC with a T-tube was followed by a low incidence of biliary complications. The complication rate after elective T-tube removal and the repeat surgery rate were extremely low. These results might challenge the current trend to avoid T-tube stenting in OLT. PMID- 22841212 TI - Surgical treatment of biliary tract complications after liver transplantation. AB - OBJECTIVE: Biliary strictures are the most common biliary tract complication after liver transplantation. There are scarce data on the results of hepaticojejunostomy (HJ) in the management of biliary complications after orthotopic liver transplantation (OLT). Thus, the role of surgery in this setting remains to be established. The aim of this study was to evaluate the results of surgical treatment of patients with biliary complications at our institution. PATIENTS AND METHODS: We reviewed 1000 consecutive liver transplantations performed at our institution from 1984 to 2007. We used a prospectively recorded database to identify patients who underwent HJ to treat any biliary tract complication. RESULTS: Overall, 62 patients (6.2%) underwent HJ, 40 for an anastomotic and 7 for a non-anastomotic stricture as well as 15 for biliary leaks. Postoperative morbidity was 16%, and postoperative mortality 1.6%. There were 7 cases of anastomotic stenosis (11.3%). Four patients (5%) required retransplantation. CONCLUSIONS: HJ is a safe procedure to manage biliary complications after OLT. It may be the first treatment choice especially for cases with anastomotic strictures. PMID- 22841213 TI - Efficacy of laparoscopic approach in the management of early liver transplant complications. AB - The use of the laparoscopic approach in managing early liver transplant complications has been shown to be safe and feasible in various settings with the advantages of shorter recovery period, decreased postoperative pain, and rapid functional recovery. The laparoscopic approach has been used to resolve postoperative complications in kidney and pancreas recipients and less often in orthotopic liver transplantation (OLT) recipients, most of them in the late period (> 1 month posttransplantation). We herein describe our experience with the laparoscopic management of early complications after liver transplantation. From May 2009 to May 2011, we successfully treated three patients with early abdominal complications after OLT using a laparoscopic approach. Three patients two with intraabdominal bleedings and one with a small bowel obstruction were treated successfully, thereby avoiding risks of a relaparotomy. In addition to these benefits, the laparoscopic approach causes less tissue injury and consequently evokes a minor innate immune response. PMID- 22841214 TI - Cutaneous mucormycosis infection by Absidia in two consecutive liver transplant patients. AB - Mucormycosis, although an infrequent fungal infection, has a high mortality in patients undergoing orthotopic liver transplantation. We present two cases of cutaneous Absidia mucormycosis in two successive patients undergoing liver transplantation in our hospital. In our literature search, we encountered only one published case of Absidia infection in liver transplantation. PMID- 22841215 TI - Late recurrence of hepatocellular carcinoma after liver transplantation: is an active surveillance for recurrence needed? AB - INTRODUCTION: Liver transplantation (OLT) is considered the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rates, when restrictive selection criteria are applied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usually occurs within 2 years following OLT, having a major negative impact on prognosis. The efficacy of active posttransplantation surveillance for recurrence has not been demonstrated, due to the poor prognosis of recipients with recurrences. AIM: To analyze the clinical, pathological, and prognostic consequences of late recurrence (>5 years after OLT). METHOD: We analyzed the clinical records of 165 HCC patients including 142 males of overall mean age of 58 +/- 6.9 years who underwent OLT between July 1994 and August 2011. RESULTS: Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years, respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a major predictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10 years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 years after OLT. Three recipients (100% males, aged 54-60 years) showed late recurrences after 7, 9, and 10 years. In only one case were Milan criteria surpassed after the examination of explanted liver; no vascular invasion was detected in any case. Recurrence sites were peritoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosuppression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor. We surgically resected the extrahepatic recurrences. The remaining recipient was treated with transarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis after diagnosis of recurrence was poor with median a survival of 278 days (range, 114-704). CONCLUSIONS: Global survival, recurrence rate, and pattern of recurrence were similar to previously reported data. Nevertheless, in three patients recurrence was diagnosed >5 years after OLT. Although recurrence was limited and surgically removed in two cases, disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence beyond 5 years after OLT may be not useful to provide a survival benefit for these patients. PMID- 22841216 TI - Subsequent nonmelanoma skin cancer after liver transplantation. AB - BACKGROUND: Liver transplant recipients have a high risk of developing nonmelanoma skin cancer (NMSC). Some develop multiple NMSC. METHODS: Patients with a follow-up of >1 year have been prospectively followed to detect NMSC. We studied the risk of developing >1 NMSC. RESULTS: After a follow-up of 2658 patient-years (mean, 8.5 years per patient), 59/312 (19%) patients were diagnosed with NMSC. Twenty-five had >1 NMSC. The 5-year risk of developing 1 NMSC, >1 NMSC, and a subsequent NMSC (a new NMSC after a first one) were 15%, 5.5%, and 46.5%, respectively. Age >60 years and transplantation for hepatocellular carcinoma were independently associated with a higher risk of developing >1 NMSC. CONCLUSION: NMSC are frequent complications after liver transplantation and they may show a high rate of recurrence. Older age and hepatocellular carcinoma were related to the development of multiple NMSC. PMID- 22841217 TI - Early and extended therapy for recurrent hepatitis C after liver transplantation. AB - BACKGROUND: End-stage cirrhosis due to hepatitis C virus (HCV) is one of the most common indications for orthotopic liver transplantation (OLT). Recurrence is universal and more aggressive than before OLT. The aim of this study was to evaluate the efficacy and tolerability of antiviral therapy in recurrent HCV after OLT. Therapy was started even with mild fibrosis (F < 2) and extended until 72 weeks, if it was possible. METHODS: Between November 2001 and December 2010, 279 OLTs were performed in 262 patients in our hospital; 81 (31%) for HCV-related cirrhosis. Nineteen patients were excluded because they died in the first 6 months. We treated 28 of 62 HVC patients. RESULTS: Twenty-eight patients met the indication for antiviral therapy: 21 male (75%) and 7 female (25%), with a mean age of 56 years (range, 40 to 68 years). All the patients had histologically proven recurrence liver disease: F1, 19 patients (68%); F2, 4 patients (14%), and F3, 45 patients (18%). The mean time to recurrence was 23 months, with a range of 3 to 90 months. Adverse effects (leukopenia in 82% and anemia in 79%) were treated with granulocyte colony-stimulating factor (GCSF) and erythropoietin (EPO), and dose reduction. Four patients (14%) were withdrawn from the treatment because of adverse effects. Nineteen patients achieved early virologic response (68%), and the sustained virologic response was 54% (15 of 28 patients). Five patients died (18%). CONCLUSION: Improving sustained virologic response in HCV liver transplant patients is a key goal. Antiviral therapy is safe and effective treating HCV recurrence after OLT. Starting this therapy in an early stage of hepatitis C recurrence, extending antiviral therapy (72 weeks), and avoiding dose reduction of antiviral drugs could help to achieve higher rates of sustained virological response. PMID- 22841218 TI - Generation of human-to-pig chimerism to induce tolerance through transcutaneous in utero injection of cord blood-derived mononuclear cells or human bone marrow mesenchymals cells in a preclinical program of liver xenotransplantation: preliminary results. AB - OBJECTIVE: Using a percutaneous ecoguided injection system to obtain chimeric piglets through a less invasive and traumatic technique than previously reported. MATERIALS AND METHODS: The two types of human cells included umbilical cord blood mononuclear elements and mesenchymal stem cells cultured from bone marrow. Four sows at gestational day 50 were anesthetized. A needle was inserted through the skin and uterine wall to reach the peritoneal cavity of the fetuses under continuous ultrasound guidance. Fourteen piglets were injected with various cell concentrations. RESULTS: All sows carried pregnancies to term yielding 69 piglets, among which 67 were alive and two mummified. Two piglets died during the first 48 hours of life. Chimerism was detected using flow cytometry and by quantitative polymerase chain reaction (q-PCR) to detect Alu gene in blood or tissues samples. The analysis detected blood chimerism in 13 piglets (21%) by flow cytometry and the presence of the human Alu gene in 33 (51%) by q-PCR. The results suggest cell trafficking between littermates after in utero injection. CONCLUSIONS: Transcutaneous echo-guided injection succeeded to produce chimeric piglets without disadvantages to the sow or the fetuses and avoiding abortions or fetal death. PMID- 22841219 TI - Analysis of tissue bioimpedance as a measurement of liver steatosis: experimental model in large animals. AB - BACKGROUND: Electrical bioimpedance (BI) has been used to indirectly measure steatosis. This method has not yet been established in the clinics thus experimental studies are needed in big animals. We assessed BI to measure liver steatosis in porcine animals. METHODS: Twelve large-white * Landrace pigs weighing 35 kg were allocated to a study (n = 9) and a control group (n = 3). A special diet was used to promote steatosis among the study group: methionine deficient and choline-restricted diet that contains supplements of cholesterol, collate and excess of saturated fat. Control group animals were fed a normal diet. A new tetrapolar electrode model was used for BI measurement, which were performed during open laparotomy by inserting a probe into one of the lobes. Measurements were done in the third and fourth segments of the pig liver, placing the probe either on the surface or inserted into the parenchyma of the liver. Open biopsies were obtained at the end of the measurements. Histological samples were processed and stained with hematoxylin-eosin to estimate macrosteatosis. Pearson correlation coefficient between BI and percentage steatosis were calculated at different frequencies. RESULTS: After 4 months of the special diet all the animals in the study group developed steatosis (90% to 20%), whereas none of the control group was affected. Pearson correlation coefficients between BI and percentage of steatosis were significant (0.877-0.878) with the best correlations obtained with a probe placed on the fourth segment of the liver surface and the best frequency to perform the measurements being 50 and 75 kHz. CONCLUSIONS: BI is an accurate, fast method for steatosis measurements, that is easier and cheaper than either open or needle biopsy. PMID- 22841221 TI - 8th Congress of the Turkish Transplantation Centers Coordination Association (TTCCA) 2011. Preface. PMID- 22841222 TI - International Registry in Organ Donation and Transplantation 2010. AB - The International Registry in Organ Donation and Transplantation (IRODaT) seeks to support the transplant community by providing up-to-date data on organ donation and transplantation worldwide at three different levels: national, regional, and Hospital. The database provides up-to-date information provided by a network of professionals directly involved in the various stages of the donation and transplantation process. All collected data are made public online, so professionals can use them as descriptive and epidemiological references. The registry provides numbers on donors after brain death, donors after cardiac death, and living donors, as well as on specific organ transplantation activities related to the three types of organ donation. A subregistry on tissue and cell donation has been made available as well. All numbers are continuously checked, updated, and validated and, when needed, responsible representatives are contacted for the required statistics. Data on organ donation and transplantation from 2009 and 2010 have been collected from 63 countries. The information reveals a remarkable increase in the donation rate in some countries such as Croatia, Italy, Slovenia, Czech Republic, Germany, Hungary, Australia, Luxemburg, Poland, Brazil, Singapore, Iran, Saudi Arabia, Venezuela, Romania, Bulgaria, Mexico, Russia, and Argentina. IRODaT provides data concerning the organ donation and transplantation activities for the general public and professionals around the world. National and comparative statistics generated on an international basis can be provided that is of extreme value to scientific programs and social and governmental bodies because they can support different initiatives of current practices in organ and tissue donation in any country or region of the world. PMID- 22841220 TI - Assessment of in vitro heparin complement regulation capacity during real-time cell analyzer antibody-mediated cytolysis assay: compatibility studies for pig-to baboon xenotransplantation. AB - OBJECTIVE: To assess the effect of sodium heparin concentrations on antibody- and complement-mediated cytolysis by means of a real-time cell analyzer system (RTCA) investigating the complement regulation ability of heparin to reduce or prevent hyperacute in an in vitro model of pig-to-baboon xenotransplantation. MATERIALS AND METHODS: Fibroblasts isolated from the skin of two transgenic pigs were cultured in microelectronic 96-well plates for 9 hours. Then, we added 20 MUL of normal sera from two healthy adult olive baboons (Papio anubis) or two volunteer healthy humans. Simultaneous cultures had added heparin at 3.5, 5, 7.5, 15, and 30 IU. Moreover, rabbit complement was added for the exogenous complement group (ExC) versus the other group only with the complement present in the sera as an endogenous complement group (EnC). Cellular cultures were monitored over 150 hours after challenge. With cellular index (CI) data recorded by the xCELLigence software system, we calculate area under the curve versus concentration (AUC) and minimum CI (CImin) versus concentration. RESULTS: All cultures showed decreased CI after challenge with human or baboon sera. There was a high correlation for AUC (r(2) > 0.90) and CImin versus concentration (r(2) > 0.970) during the first 40 hours postchallenge among the EnC group, regardless of human or baboon sera. However, there was no correlation for AUC and CImin for the ExC group. There was a reduction of CImin related to increased heparin concentrations. CONCLUSIONS: The addition of heparin did not reduce antibody- and complement-mediated cytolysis assessed in vitro by RTCA in pig-to-baboon compatibility assays. PMID- 22841223 TI - What kind of changes occurred in clinical characteristics of deceased kidney donor recipients after national allocation system in Turkey? A single-center retrospective analysis. AB - OBJECTIVE: Clinical characteristics of recipients of deceased donor renal transplantations were evaluated in the period before versus after implementation of The National Allocation System (NAS). PATIENTS AND METHODS: We evaluated retrospectively clinical profiles of the 42 after NAS (June 2008-December 2010) versus 42 consecutive deceased donor renal transplantation patients before NAS. Patient and graft survival rates were assessed using the Kaplan-Meier method; graft function was assessed based on creatinine clearance with the Cockcroft Gault equation. Patient and donor data were obtained from medical records. RESULTS: Recipients were older in the pre-NAS group (39 +/- 8 vs 33 +/- 8 years, respectively; P = .001) and median duration of preoperative dialysis was longer in the post-NAS group (103 +/- 61 months vs 50 +/- 36 months, respectively; P = .000). The average number of human leukocyte antigen-mismatched antigens were pre NAS 3.4 +/- 1.0 versus post-NAS 3.9 +/- 1.2 (P = .05). Considering the recipients serological status 9 were hepatitis C virus (HCV)(+) and 2 hepatitis B virus (HBV)(+) among the post-NAS versus no HBV(+) and only 1 HCV(+) patient pre-NAS. Kaplan-Meier analysis of graft survival rates showed 90% at 1 and 85% at 3 years pre-NAS. Similar to 95% at 1 and 86% at 3 years for the post-NAS group (P > .05). Likewise, patient survival rates for both groups at 1 and 3 years were 97%. The mean parameter of donor age, allograft loss, cold ischemia time, patient death, number of retransplantations, HBV(+) patients, and delayed graft function were similar between groups (P > .05). DISCUSSION: After NAS the transplant recipients were older, had a longer duration of dialysis, greater number of HLA mismatched antigens and, more HCV(+). No differences were observed in short-term patient and graft survival rates. PMID- 22841224 TI - Use of kidney donors with hepatitis B, hepatitis C, or brain tumor: a single center experience. AB - INTRODUCTION: With the rapid increase in the number of patients on the waiting lists, the idea of using organs from donors who were previously classified as "marginal" has emerged. The aim of this study was to evaluate the clinical outcomes of the patients who received kidneys from donors with hepatitis B, hepatitis C, or brain tumors. PATIENTS AND METHOD: Between 2003 and 2010, 27 transplantations were performed from donors with hepatitis B, hepatitis C or brain tumors between 2003 and 2010. Demographic and clinical characteristics of donors and recipients were retrospectively collected from medical files. RESULTS: Fifteen patients received kidneys from donors with hepatitis B: 9 from deceased donors having a positive hepatitis B surface antigen (HBsAg) and six from living donors with positive HBsAg having negative results of qualitative hepatitis B DNA analysis. Two of the fifteen recipients were previously diagnosed with chronic active mild hepatitis B infection. The remaining 13, who were HBsAg (-)/anti HBs(+) at the time of transplantation, underwent hepatitis B immune globulin and lamivudine therapy. Median follow up time was 40 +/- 35 months. One patient developed decompensated liver disease owing to noncompliance to lamivudine therapy. Five patients who received grafts from anti-HCV(+) deceased donors were anti-HCV(+) at the time of transplantation with alanine aminotransferase (ALT) levels <40 U/L. All grafts remained functional at a median of 70 months. Seven subjects received grafts from deceased donors with brain tumors, none of whom had a history of a craniotomy or a ventriculoperitoneal shunt. All recipients had serious vascular access problems. No graft loss or de novo malignancies was observed among these patients after a median follow-up of 69 +/- 26 months. CONCLUSION: With appropriate patient selection, the donated organ pool can be expanded by addition of donors with hepatitis or brain tumors. PMID- 22841226 TI - Dyadic adjustment and psychological concordance of kidney transplant recipients and donors after spousal transplantation. AB - The aim of this study was to compare depression and anxiety levels of kidney transplant recipients and of their donor spouses seeking to show whether their dyadic adjustment levels related to their psychological states in the posttransplantation period. We selected 30 donor-recipient pairs who underwent spousal kidney transplantation. The study was performed while participants were in the hospital for routine examinations. Both donors and recipients were administered The Dyadic Adjustment Scale, The Hospital Anxiety and Depression Scale, and The Beck Depression Inventory. Our results showed correlations between donor and recipient postoperative depression levels (P < .01). For donors, dyadic adjustment and depression levels were correlated, but not for recipients. Pretransplantation psychological assessment of a spousal donor is necessary to provide pretransplantation interventions for possible depressive disorders and marital dysfunction. In this way, recipient depression and anxiety levels may be reduced in the posttransplantation period with better treatment compliance and improved graft survival. PMID- 22841225 TI - Donor complications among 500 living donor liver transplantations at a single center. AB - INTRODUCTION: Living donor liver transplantation (LDLT) has become necessary because of the shortage of cadaveric organs. We retrospectively analyzed 500 living donor hepatectomies using the Clavien classification system for complications to grade their severity. MATERIALS AND METHODS: We retrospectively identified and applied the Clavien classification to 500 consecutive donors who underwent right for LDLT left hepatectomy between January 2007 and August 2011. RESULTS: The 149 complications were observed in 93 of 500 (18.6%) donors who were followed for a mean 30 months. There wan no donor mortality. Complications developed in 85 (18.6%) right 5 (35.7%) left, and 3 (10%) left lateral segment hepatectomy donors. The overall incidence of reoperations was 7.2%. Seventy-seven of 149 complications were grade I (51.6%) or 9 grade II (6%). The major complications consisted of 27 (18.1%) grade IIIa, 35 (23.4%) grade IIIb, and 1 (0.6%) grade IVa. Grade IVb and grade V complications did not occur. The most common problems were biliary complications in 14 of 181 donors (7.7%). CONCLUSION: Donors for LDLT experienced a range of complications. PMID- 22841227 TI - The assessment of long-term clinic and laboratory data of living related kidney donors. AB - Living-donor kidney transplantations are more common in Turkey. The present study, therefore, investigated the structural changes in the remaining kidney and their impacts on the outcomes of 71 donors who underwent nephrectomy. Among 123 screened living-donor transplantations performed between 2001 and 2008, information was available on 71. The study group included 37 female and 34 male donors with ages ranging between 20 and 68 years (mean, 45 +/- 9 years). The donors had a median follow-up of 7.2 years. We investigated renal function and creatinine clearance as well as the presence of proteinuria and/or hypertension before versus after nephrectomy. Healthy individuals referred to our blood center were included as the control group. A comparison of pre- versus post-nephrectomy with control group data did not show any significant correlations between serum creatinine levels, creatinine clearances, and the presence of proteinuria relative to post-donation years. In contrast, we identified an increased prevalence of hypertension: Stage 1 in 4 patients before versus 22 subjects after nephrectomy. A key finding of this study was the slight increase in the number of hypertensive donors. Hypertension is, therefore, the most critical parameter to monitor donors in countries with a high proportion of living donors. PMID- 22841228 TI - Avoiding abdominal flank bulge after lumbotomy incision: cadaveric study and ultrasonographic investigation. AB - OBJECTIVE: The object of this study was to better define the relevant anatomy and innervation of the anterolateral abdominal wall musculature seeking to avoid abdominal wall complication after open donor nephrectomy. We dissected four cadavers and retrospectively assessed donor ultrasonographic imaging of anterolateral abdominal muscle atrophy after donor nephrectomy with a lumbotomy incision. METHODS: Anatomic study was performed on four cadavers using bilateral dissections. The 8th, 9th, 10th, 11th, and 12th (subcostal) intercostal nerves were dissected from the intercostal space to the rectus sheath. With the experience gained from anatomic study, we performed 40 living donor incisions 1.5 to 2 cm medial to the tip of 12th rib, toward the lateral border of the rectus muscle and the umbilicus. Donors were invited to the hospital at 1 year postoperative to examine abdominal wall complications. Ultrasonography (USG) was performed to assess the thickness of the abdominal wall muscles bilaterally to ascertain whether there was atrophy. RESULTS: All distal intercostal nerves ran as multiple mixed segmental nerves, communicating with each other widely within the neurovascular plane. The thick 12th nerve was located at 1.5 to 2 cm medial and under the tip of the 12th rib, running to the suprapubic area. Postoperative USG confirmed that the mean percent thickness of the abdominal muscles of the operative side was not significantly different from the other side (P < .05). CONCLUSION: Most significant intercostal nerve contributions to the anterolateral abdominal wall arise from T12. Damage to the intercostal nerves will be minimal if the lombotomy incision is performed above the safe line between the tip of the 12th rib and the umbilicus. PMID- 22841229 TI - A possible system for optimal donor kidney exchange in Turkey. AB - The lack of available deceased donors and the immunological incompatibility between the patients and their voluntary donor candidates make kidney exchange among donor-patient pairs a preferable solution performed locally by many organ transplantation centers in Turkey. However, maximum benefit from kidney exchange can only be achieved when the donor patient pool is maximized using a nationwide kidney exchange program. This work discusses kidney exchange practices worldwide to develop a nationwide exchange program in Turkey and related challenges. PMID- 22841230 TI - Comparison of paired exchange kidney transplantations with living related kidney transplantations. AB - OBJECTIVE: Paired-exchange kidney transplantation (PETx) gains an importance because it is difficult to find suitable organs. The aim of this study was to compare biochemical and clinical parameters of PETx with those of living-related kidney transplantation (LRTx). METHOD: The 57 PETx included 18 female and 39 male recipients among 1081 LRTx in 360 females and 721 males (N = 1138) whose operations were performed between November 21, 2008, and March 1, 2011. These two groups were compared for graft and patient survival, rejections, serum creatinine levels, glomerular filtration rates (GFRs), and other biochemical parameters. RESULTS: The PETx patients were older than the LRTx patients (45.4 +/- 13.2 years versus 40.9 +/- 13.5 years; P = .014). HLA mismatch was higher in the PETx group (4.7 +/- 0.7 versus 3.56 +/- 1.6; P = .000). First- and second-year serum creatinine and GFR values were similar between the two groups. Acute rejection episodes (PETx: 13/57; LRTx: 226/1081, P = .925), patient loss (0/57 versus 34/1081; P = .174) and graft loss (1/57 versus 55/1081; P = .257) were similar between the two groups. CONCLUSION: Our study showed similar biochemical and clinical findings of PETx versus LRTx over 2 years posttransplantation. PMID- 22841231 TI - Hepatitis B surface antigen positivity is not a contraindication for living kidney donation. AB - Because of the organ shortage, the number of patients awaiting kidney transplantation has increased rapidly requiring physicians to implement new methods to increase the number of grafts. In this study, we compared clinical and biochemical parameters of patients who received kidneys from hepatitis B surface antigen-positive (group 1) versus other living related kidney donors (group 2). The study included 414 female (15 group 1 and 399 group 2) and 816 male (20 group 1 and 796 group 2) donors for 1195 living related kidney transplantations performed between April 21, 2008 and March 1, 2011. Group 1 kidney transplantations were undertaken only if the recipient displayed a hepatitis B antibody titer >10 mIU/mL and donor hepatitis B virus (HBV) DNA was negative. Demographic characteristics, 1- and 2-year serum creatinine levels, glomerular filtration rates (GFR), and liver function test results were similar between the 2 groups. There were no new HBV infections throughout the study period. Acute rejection rates (7/35 in group 1 vs 232/1195 in group 2; P = .988), graft loss (1/35 in group 1 vs 55/1195 in group 2; P = .624), and patient loss (0/35 in group 1 vs 34/1195; P = .311) were similar between the 2 groups. Our study showed that hepatitis B surface antigen positivity was not a contraindication to living kidney donation. PMID- 22841232 TI - Incidental appendectomy in donors undergoing hepatectomy for living-donor liver transplantation. AB - BACKGROUND: The aim of this study was to investigate the morbidity associated with appendectomy in living liver donors undergoing hepatectomy. METHODS: The medical records of 338 donors who underwent hepatectomies for living-donor liver transplantation between 2008 and 2010 were reviewed retrospectively. The patients were divided into 2 groups on the basis of appendectomy: patients in group A (n = 126) received incidental appendectomies in conjunction with donor hepatectomy, and those in group B (n = 212) underwent hepatectomy alone. RESULTS: No significant difference in age, gender, or body mass index was found between groups. The wound infection rate (P = .037) and length of hospital stay (P = .0038) were higher in group A than in group B. Intraoperative findings in 126 donors in group A were subserosal (n = 4), retrocecal (n = 6), or hard nodular (n = 11) appendix; hyperemic appendix with edema (n = 9); appendix length >= 8 cm (n = 18); and palpable fecalith (n = 78). Histopathologic examination of appendix specimens revealed lymphoid hyperplasia with a fecalith (n = 32), fecalith only (n = 32), acute appendicitis (n = 20), normal anatomy (n = 18), fibrous obliteration (n = 9), lymphoid hyperplasia (n = 9), Enterobius vermicularis (n = 3), appendiceal neuroma (n = 1), carcinoid tumor (n = 1), and mucoceles (n = 1). CONCLUSION: Although incidental appendectomy increased the wound infection rate and length of hospital stay, this procedure is necessary for the prevention of potential complications due to appendicitis when the exploration of the ileocecal region in patients undergoing donor hepatectomy reveals one or more of the following: appendix length >= 8 cm; dropsical, hyperemic, subserosal, nodular, and/or retrocecal appendix; and/or palpable fecaloma. PMID- 22841234 TI - Can an extended right lobe be harvested from a donor with Gilbert's syndrome for living-donor liver transplantation? Case report. AB - Gilbert's syndrome (GS) is a common cause of inherited benign unconjugated hyperbilirubinemia that occurs in the absence of overt hemolysis, other liver function test abnormalities, and structural liver disease. GS may not affect a patient's selection for living-donor liver transplantation (LDLT). Between February 2005 and April 2011, 446 LDLT procedures were performed at our institution. Two of the 446 living liver donors were diagnosed with GS. Both donors underwent extended right hepatectomies, and donors and recipients experienced no problem in the postoperative period. Their serum bilirubin levels returned to the normal range within 1-2 weeks postoperatively. In our opinion, extended right hepatectomy can be performed safely in living liver donors with GS if appropriate conditions are met and remnant volume is >30%. Livers with GS can be used successfully as grafts in LDLT recipients. PMID- 22841233 TI - Effects of desflurane and isoflurane on hepatic and renal functions and coagulation profile during donor hepatectomy. AB - We compared the effect of two inhalation anesthetics desflurane and isoflurane on postoperative hepatic and renal functions as well as coagulation profiles in living donors undergoing right hepatectomy. This study was performed on 80 patients who were randomly allocated to group D (desflurane, n = 40) or group I (isoflurane, n = 40) after Faculty Ethics Committee approval. After induction, isoflurane or desflurane was used with air/oxygen for anesthetic maintenance. The isoflurane or desflurane concentration was set at one minimum alveolar concentration (MAC). Remifentanil was infused for analgesia as well as cisatracurium. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ratio (INR), albumin, total bilirubin, blood urea nitrogen, creatinine, platelet count, and hemoglobin levels were analyzed preoperatively at end of the operation, and on postoperative days (PODs) 1, 2, 3, 5, 7, and 30. Both AST and ALT differed significantly and continually except on POD 30. AST showed significant elevations from the end of the operation to POD 2 and ALT, from the end of the operation to POD 5 in group I compared with group D. INR was significantly higher from the end of the operation to POD 3 in group I and to POD 2 in group D. At the end of the operation as well as on POD 1 and POD 2, INR was significantly increased in group I compared with group D. Albumin level was significantly lower at the end of the operation in both groups, but it was not different. No patient developed hepatic or renal failure. Our study showed better postoperative hepatic tests and INR using desflurane than isoflurane at equivalent doses of 1 MAC in living donors undergoing right hepatectomy. PMID- 22841235 TI - Is routine sternotomy necessary for organ recovery from deceased donors? A comparative retrospective study. AB - BACKGROUND: Traditionally, sternotomy and laparotomy are performed to recover thoracoabdominal organs from deceased donors; however, recovering abdominal organs without sternotomy is possible. We evaluated and compared organ recovery from deceased donors, with and without sternotomy. METHODS: Between February 2006 and November 2011, organ recovery was performed in 68 deceased donors by our transplantation team. The recovery procedure was carried out using standard techniques in 31 donors (with sternotomy; Group A) and with modified techniques in 37 donors (without sternotomy; Group B). Average age, gender, body mass index (BMI), and time to cold ischemia were compared retrospectively in both groups. The demographic and clinical parameters were compared using a Student t test and chi-square test. The level of statistical significance was set at P < .05. RESULTS: Organ recovery was performed on 31 of 67 (45.6%) deceased donors with sternotomy (Group A) and 37 of 67 (54.4%) without sternotomy (Group B). Thirty six donors were male and 32 were female. The average donor age was 40.4 +/- 3.4 years in Group A and 52.4 +/- 4.6 years in Group B (P < .02). The average BMI of donors was 26.2 +/- 0.8 kg/m(2) in Group A and 23.9 +/- 0.8 kg/m(2) in Group B. The average time to cold ischemia was 127 +/- 6.2 minutes in Group A and 47.5 +/- 1.8 minutes in Group B (P < .0001). CONCLUSION: The transition time to cold ischemia can be shortened by harvesting organs without sternotomy in unstable donors, or under conditions in which intrathoracic organs are not recovered. PMID- 22841236 TI - Recent developments in desensitization of crossmatch-positive kidney transplant recipients. AB - Currently, there are two major options for the successful and timely transplantation of sensitized kidney transplant recipients: (1) avoidance of the sensitization barrier using special allocation programs, or (2) desensitization. In the case of broadly sensitized kidney patients, a combination of both options might be necessary. This review focuses on new advances in desensitization of crossmatch-positive kidney transplant recipients which include immunoadsorption and the administration of new substances such as the complement C5 inhibitor eculizumab. Finally, integrated algorithms that combine different measures are acknowledged. PMID- 22841237 TI - Serum flow cytometric C1q binding antibody analysis of renal recipients with low levels of sensitization. AB - AIM: Patients displaying flow cytometric crossmatch results within the grey zone of positivity are hard to evaluate, especially if they are undergoing their first transplantation. For these patients assays of donor-specific anti-HLA (human leukocyte antigen) antibodies with complement-fixing properties to cause cell lysis are important for antibody-mediated rejection and graft failure. The aim of this study was to detect the relevance of serum C1q-binding antibodies detected in renal recipients with grey zone crossmatch reactivity who were considered to show low levels of sensitization against their potential donors. METHOD: This study includes 114 patients who were admitted for their first renal transplantation between September 2009 and August 2011, including 33 subjects considered by flow cytometric cross-match to be the sensitized group, whereas the remaining 81 recipients had negative results. We analyzed the accumulation of serum the immunoglobulin (Ig)G bound C1q on HLA-coated flow cytometric panel reactive antibody (FlowPRA) beads. The serum samples were retrospectively analyzed with [C1q]FlowPRA (HLA class I and II), which were collected during the pretransplantation period every 6 months and every week posttransplantation within the first month and every 3 months thereafter. All serum samples were analyzed for the presence of anti-FlowPRA IgG alloantibody. We compared the C1q FlowPRA-positive and-negative groups for the number of posttransplantation days that the serum creatinine level was below <2 mg/dL as a metric of graft function. RESULTS: With a mean follow-up of 492 +/- 84 days, there was a significant difference between flow cytometric crossmatch results and creatinine decrease rate (P = .02). The serum creatinine decrease rates of the 9 C1q-positive versus the 15 C1q-negative subjects showed significant difference (P < .05). CONCLUSION: C1q-binding antibody analysis shows the presence of serum antibodies capable of complement binding and antibody-mediated rejection, which could be useful to assess rejection risk among the "grey zone" of renal recipients with low levels of sensitization against their donors. PMID- 22841238 TI - Flow cytometric evaluation of pregnancy-induced anti-donor immunization. AB - BACKGROUND: Living donor kidneys from spouses and children (from offspring to parents) are currently considered to be important organ sources. However, pregnancy-induced alloimmunization may provoke acute rejection episodes after kidney transplantation. being flow cytometry cross-match (FCXM) we studied donor specific antibodies (DSAs) in the sera of recipients planned for living kidney transplantation from their spouse or children. When the FCXM was positive, we confirmed the existence of anti-human leukocyte antigen (HLA) antibodies using flow cytometry panel-reactive antibody (flow-PRA). PATIENTS AND METHODS: Between March 2005 and November 2010, we tested 85 pretransplantation sera from renal transplant recipients for DSAs. The recipients included 37 wives (group I) and 48 husbands (group II). FCXM-positive sera were tested using a flow-PRA screening method using HLA class I and class II antigen-coated beads. The mean recipient age was 48.1 +/- 9.8 (range, 28-69) years and the mean donor age was 45.1 +/- 11.1 (range, 23-69 years). RESULTS: Among group I were 18 (48.6%) FCXM-positive cross-matches; for group II, 5 (10.4%) cases (P = .001). Sensitized patients were 37.9% FCXM-positive, whereas nonsensitized patients were 3.7% positive (P = .001). FCXM-positive patients were re-evaluated for anti-HLA antibodies using flow-PRA. Seventeen of 18 group I tests (94.4%) were FCXM-positive, whereas 3 of 5 (60%) were positive among group II. CONCLUSIONS: We concluded that flow cytometry-based cross-match and PRA techniques can be used to detect anti-HLA antibodies using spousal or children donors for kidney transplantation. PMID- 22841239 TI - Human leukocyte antigen and major histocompatibility complex class I-related chain A antibodies after kidney transplantation in Turkish renal transplant recipients. AB - BACKGROUND: This study was designed to determine whether human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related A (MICA) antibody (Ab) production during the first 6 months posttransplantation correlated with long-term graft survival and rejection rate. The study group included 147 first transplantations from either living related (LRDs) or deceased donors (DDs) who were divided into two subgroups: rejection (RG, n = 28) and nonrejection (NRG, n = 119). Serum samples (n = 441) collected from each patient on posttransplant days 30, 90, and 180 were tested for HLA and MICA Ab using the Luminex technique. RESULTS: Among 82 Ab-positive patients (55.8%), 40 had both HLA and MICA, 33 only HLA, and 9 only MICA Ab in the posttransplant period. The rates of HLA class I, class II, or both Ab positivities were greater in the RG than the NRG (P = .011, .037, and .0275, respectively). At 180 days posttransplant, 64.3% of patients in the RG had Ab and 41.2% in the NRG (P = .0349). The data for the LRD (n = 116) group were similar to those for the entire group; whereas there was no significant difference in Ab positivity between RG and NRG patients who received organs from DDs. There was no significant difference with respect to HLA class II and/or MICA Ab positivity between RG and NRG among patients who lacked HLA class I Ab. DISCUSSION: We confirmed that HLA and MICA Ab may be harmful posttransplant, promoting rejection processes and representing an important cause of graft failure. HLA class II and MICA Ab positivities were only important predictors of graft failure when present together with HLA class I positivity. Patients who developed HLA alone or both HLA and MICA Ab rejected their grafts more frequently than Ab-negative recipients. PMID- 22841240 TI - The presence of donor-specific antibodies in renal transplantation. AB - Determining the presence of anti-HLA antibodies before transplantation is an important factor to prevent loss of function among renal transplantations. In addition, recent studies have shown that not only the pretransplantation existence of anti-HLA antibody but also posttransplantation donor-specific antibodies (DSA) and non-donor-specific antibodies are significantly associated with allograft rejection or loss of graft function. This study presented DSA among patients after renal transplantation together with graft function and survival. PMID- 22841241 TI - Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors. AB - BACKGROUND: Certain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection episodes or graft outcomes. We sought to evaluate the relationships between gene polymorphisms and acute rejection episodes (RG, n = 19) versus stable graft function (NRG, n = 71) in transplant recipients compared with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. Using polymerase chain reaction sequence-specific primers with the Heidelberg kit we genotyped 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes. RESULTS: Interleukin (IL)-2 TT/GT haplotype was found in 36.8% of RG patients and 6.7% of HCG but not among the NRG (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and nine HCG patients (P = .007); the IL-2 GG/GG haplotype, 18.7% HCG and 4.2% NRG patients (P = .0033); and the IL-2 TT/TT haplotype, five NRG and eight HCG patients, but none of the RG cohort (P > .05). The transforming-growth factor beta 1 CG/CC haplotype was noted in 15 NRG (21.1%) and four HCG but no RG patients (P < .0001). The IL-2 +166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 -330 GG genotype was demonstrated in 32 healthy controls and three nonrejection transplant patients (P = .0007). Significant differences were concluded between NRG and HCG for IL-6 565 AG, IL-1beta -511 TT and +3962 CC/CT/TT genotypes. DISCUSSION: We observed significant differences among the frequencies of IL-2 gene polymorphisms among RG and NRG subjects, which agreed with previous clinical, but not in vitro studies. PMID- 22841242 TI - The effect of glutathion S-transferase polymoprhisms and anti-GSTT1 antibodies on allograft functions in recipients of renal transplant. AB - The balance between oxidative stress and anti-oxidant defense systems after renal transplantation may explain the development and progression of allograft dysfunction. Glutathione S-transferase (GST) decreases the damage from oxidative stress. In contrast, recipient antibodies against GSTT1 expressed on the graft are believed to cause its dysfunction. The aim of our research was to study the probable relationship to rejection between GST gene polymorphisms and anti-GSTT1 antibodies. We included 122 patients transplantations from living donors and 51 healthy individuals as controls group in our study. The patient groups were comprised of 57 patients who did and 65 who did not experienced rejection episode. Polymerase chain reactions were used to detect GSTM1 and GSTT1 polymorphisms, whereas PCR-RFLP (restriction fragment length polymorphism), for GSTP1 polymorphism. An enzyme-linked immunosorbent assay method was used for anti GSTT1 antibody scans. There was no significant difference between the groups for allele and genotype frequencies of GSTT1, GSTM1, GSTP1 polymorphisms of the recipients, donors, and controls. Within the rejection group the frequency of patients with the GSTM1 null genotype was higher among subjects prescribed cyclosporine A versus tacrolimus (P = .029). Among the entire patient group, 46 subjects with GSTT1 null genotype were scanned for anti-GSTT1 antibody which was detected in 5 of 8 patients with an acute rejection episode (P = .04). Anti-GSTT1 antibody was observed more frequently albeit not significantly, among the cyclosporine versus tacrolimus patient group (P = .16). This study suggested that GSTM1 genotype may be important for cyclosporine detoxification and for allograft outcomes due to drug nephrotoxicity. After transplantation, antigens distinct from the HLA system such as GSTT1 protein may also be targets for alloimmune responses. PMID- 22841243 TI - A kidney transplant center's initial experiences in eastern Turkey. AB - OBJECTIVES: Kidney transplantation is the best treatment method associated with improved quality of life and better survival for patients with end-stage renal disease. We started performing kidney transplantations in November 2010. We have performed 19 kidney transplantations so far. Fourteen of these were from living donors and five from deceased donors. Here, we present our initial experiences with 14 kidney transplant recipients from living donor kidney transplantations. MATERIALS AND METHODS: All recipients and their donors underwent detailed clinical history and examination. Recipients and their donors were followed in the transplant clinic during hospitalization. RESULTS: The male-to-female ratio was 11:3 in recipients. The mean age of recipients was 27.8 years (range 4-58 years). The number of the related, emotionally related, and unrelated transplantations were 9, 3, 2, respectively. The mean warm ischemic time was 95.7 seconds (range 52-168 seconds). Urine output started immediately after vascular anastomosis in all. The mean time of discharge from hospital was postoperative day 8 (range 4-18 days). The mean flow up was 125 days (range 18-210 days). Graft survival was 100% in this period, but one patient died from sepsis after 56 days. No kidney was lost from rejection, technical causes, infection, or recurrent disease. CONCLUSION: If transplant centers are as equipped and experienced as ours, kidney transplant programs should be started immediately so that they can reduce the number of the patients in waiting list for kidney transplantation. PMID- 22841244 TI - Is heparinization necessary in the early postoperative period of renal transplantation from cadaveric donors? AB - INTRODUCTION: Venous thromboemboli and bleeding are the complications that threaten the graft and patient's life in the early postoperative period after cadaveric renal transplantation. For this reason, heparin administration after renal transplantation should be administered carefully. The aim of this study was to evaluate the necessity for heparinization after cadaveric renal transplantation. METHODS: Between March 2009 and October 2010, we formed 2 study groups among 50 recipients who underwent either cadaveric (n = 25) or living donor transplantations (n = 25). We did not observe any risk factors for thromboembolism while group 1 did not undergo heparinization, group 2 received a prophylactic dose of low-molecular weight heparin for 1 week. Doppler ultrasonography (USG) was performed between postoperative 24-48 hours to examine the transplanted kidney vessels, and in one group 1 case for a bilateral lower extremity venous system examination. We were also compared postoperative thromboembolic and hemorrhagic complications, lymphorrhagia, and serum creatinine levels. RESULTS: The female/male ratios in group 1 and 2 were 14/11 and 8/17 with mean ages of 36.7 (range, 17-51) and 35.9 (range, 17-59) years, respectively. The mean preoperative serum creatinine levels were 7.9 +/- 2.9 mg/dL and 6.8 +/- 2.4 mg/dL, and at postoperative week 1, they were 5.1 +/- 4.3 mg/dL and 1.2 +/- 0.5 mg/dL, respectively. We did not encounter any partial or total thrombus upon doppler USG studies for renal and lower extremity venous systems. No clinical symptoms of pulmonary emboli were detected in any patients. Only 1 subject group 2 experienced massive postoperative bleeding. CONCLUSION: Herein, we have reported that, except for the patients with risk factors for venous thromboemboli, heparinization was not necessary in the early postoperative period and did not add benefits to outcomes of cadaveric renal transplant recipients. PMID- 22841245 TI - The impact of C4d staining as a humoral injury marker. AB - PURPOSE: Acute and chronic humoral injuries in renal transplant recipients are the main reasons for graft rejection and failure. Histological and clinical characteristics of humoral rejection and symptoms are variable and not always helpful for differential diagnosis. Clinical monitoring of the allograft, an elevated serum panel-reactive antibody (PRA), and the presence of donor-specific antibody (DSA) during immune monitoring as well as C4d staining of biopsy material can establish the differential diagnosis. Even without a cellular component, humoral rejection reaction is serious because the target tissue is the graft endothelium. Because the kidney graft has a rich vascular structure this attack causes permanent injury to the kidney in the long term. Graft dysfunction in this setting is usually more severe, requiring dialysis therapy, compared with acute cellular reactions. Positive C4d staining of peritubular capillaries in biopsy material represent a hallmark of complement-dependent cytotoxicity, supporting the diagnosis of humoral rejection. We analyzed C4d staining as a hallmark of humoral rejection. METHODS: From 2009 to 2011, we analyzed the relationship between pathological findings of C4d immunohistochemistry staining and the clinical outcomes of 45 kidney transplant recipients who underwent a kidney biopsy because of graft dysfunction due to possible humoral rejection. RESULTS: Biopsy specimens of 15 patients stained C4d positive; the remaining 30 showed negative results. Intravenous steroids, PP + IVIG with or without antithymocyte globulin (ATG), was administered for treatment. Sixty six percent (n = 10) of patients were C4d positive with 16% (n = 5) of those showing C4d negative biopsy results, losing their grafts, and returning to hemodialysis. CONCLUSIONS: C4d staining refractory humoral rejection injury was related to poor graft outcomes. PMID- 22841246 TI - Long-term outcomes of kidney transplants with multiple renal arteries: a retrospective study. AB - OBJECTIVE: The aim of this study was to investigate whether kidney transplantations performed using grafts with multiple arteries negatively affected renal function or increased the risk of vascular or urologic complications. METHODS: Among 249 kidney transplant patient followed for at least 1 year between 2000 and 2005, we retrospectively evaluated their donor renal artery anatomy to compare postoperative vascular and urologic complications: creatinine clearance at 1, 2, and 5 years, as well as graft survival at 3 and 5 years. RESULTS: While 214 (85.9%) displayed a single artery (group 1), 35 (14.1%) showed multiple renal arteries (group 2). Thirty-one of the group 2 allografts had two, three donors had three, and one had four arteries. The postoperative vascular and urologic complications and the creatinine clearance values at 1, 2, and 5 years of both groups were similar. The 3- and 5-year graft survivals among group 1 were 95% and 90%, whereas those of group 2 were 94% and 91% respectively (P < .05). CONCLUSION: Our study indicated that multiple renal arteries did not adversely affect postoperative urologic or vascular complications or kidney allograft or patient survival compared with single renal artery cases. PMID- 22841247 TI - En bloc and dual kidney transplantation: two initial cases from a new kidney transplantation center. AB - AIM: The aim of this study was to share our initial successful experiences with en bloc dual kidney transplantation. CASES: En bloc kidney were obtained, for case 1 from a 3-year-old deceased pediatric donor who had undergone cadaveric liver transplantation due to fulminant hepatitis A virus infection 1 week prior. The donor length was 97 cm and weight 13 kg. According to the age and weight of the donor, we selected a 50-year-old respectively. For case 2, a kidney was retrieved from a 20-month-old pediatric donor after development of hypoxic brain injury secondary to status epilepticus. The donor length and weight were 75 cm and 13 kg respectively. A 30-year-old female patient was of 162 cm and 59 kg. The suprarenal aorta, suprarenal vena cava, and caval and aortic lumbar branches were closed with running sutures during the backtable procedures. After the classic Gibson incision, the donor aorta was anastomosed to the recipient right common iliac artery, and the donor inferior vena cava to the recipient right common iliac vein in end-to-side fashion. The ureters were implanted with mucosa-to mucosa ureteroneocystostomies separately according to the Lich-Gregoir technique. After the vascular anastomoses the kidneys had immediate good perfusion in both cases. Postoperative recovery was rapid, the recipients were discharged uneventfullly. CONCLUSION: En bloc dual kidney transplantation from young pediatric patients to adult recipients can be performed with low mortality and morbidity even by new centers. PMID- 22841248 TI - ABO-incompatible kidney transplantation: first cases in Turkey. AB - INTRODUCTION: ABO compatibility has been believed to be necessary in kidney transplantation (Ktx) to prevent acute antibody-mediated rejection. However, developments in immunosuppression and immunoadsorption techniques have overcome acute antibody-mediated rejection caused by ABO incompatibility. Herein, we have presented the first ABO-incompatible Ktx cases in Turkey. All recipients did not have an ABO-compatible donor but presented significant dialysis inadequacy due to vascular access problems. METHOD: Five dialysis patients with blood groups O or B underwent kidney transplantation from living related donors of blood group type A1 or AB between march 23, 2007 and August 16, 2007. All patients received Rituximab (375 mg/m(2)) at 3-4 weeks before the Ktx. Additionally, we started tacrolimus (0.15 mg/kg), mycophenolate mofetil (2 * 1 g), and simvastatin (1 * 20 mg) 1 week before the operation. Immunoadsorption therapy employing a specific filter (Glycosorbs) to remove anti-A or anti-B antibodies was continued until the titers were <1/4. After the Ktx, we again performed immunoadsorption if the anti A or the anti-B antibody titer was >1/8 during the first postoperative week and >1/16 at the second postoperative week. We used 2 standard hemodialysis machines with a connection line to perform immunoabsorption and dialysis during the same session. RESULTS: Acute humoral and cellular rejection was not detected. During the follow-up 1 patient was lost due to a cardiovascular complication. Mean creatinine level was 1.1 +/- 0.3 mg/dL. These first ABO-incompatible transplantation cases in Turkey suggest that this source may represent an effective approach to overcome the organ shortage. PMID- 22841249 TI - Flow cytometric detection of anti-AB antibody titers in blood group O recipients of blood group A2 donor kidneys. AB - AIM: ABO-incompatible kidney transplantation has been accepted for end-stage renal failure patients who have no ready opportunity for a deceased or living donor. Antibody titration for ABO-incompatible renal transplantation is not only difficult but also lacks conformity among laboratories. Herein we analyzed 20 living related renal transplant couples to detect recipient anti-A2 antibody using flow cytometric analysis. MATERIALS AND METHODS: Patients were admitted to our center for renal transplantation between January 1999 and December 2010. All but four of them had undergone a previous renal transplantation from an ABO compatible donor but experienced graft failure. All donor blood groups were subtyped by our blood bank using a lectin-based dilution assay. To detect recipient anti-A2 antibody titers we used a tube hemagglutination method. A/B antibody titer analysis by flow cytometry incubated serially diluted serum samples with donor erythrocytes. Each analysis was repeated three times over a 2 week period using an older and the last sera simultaneously. RESULTS: The 13 male and 7 female patients showed our overall mean age of 32 +/- 12 years. All patients had panel-reactive antibody levels below 15%. The level of flow cytometric antibody titers did not vary upon repeated analysis (P = .01). When compared with the tube method there was a discrepancy of the level at which the antibody titer became negative. DISCUSSION: Flow cytometric antibody titration is a practical and rapid technique to determine the amount of anti-A2 antibody in renal recipients. PMID- 22841250 TI - Spousal versus living unrelated renal transplantation: a retrospective analysis of allograft outcomes. AB - OBJECTIVE: To compare the outcomes of spousal and living unrelated donor (LUD) allografts. PATIENTS AND METHODS: The 378 ABO-compatible living and cadaveric kidney transplantations between February 2005 and August 2010 included 25 wife-to husband (group 1), 15 husband-to-wife (group 2), and 20 LUD cases (group 3). Donor nephrectomy was performed by open surgery. Induction therapy with antithymocyte globulin or anti-interleukin-2 receptor antibody was followed by maintenance regimens using cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) and corticosteroids. We compared spousal donor and LUDs in terms of clinical characteristics as well as graft and patient survival rates. RESULTS: Fifty-six (93.3%) patients underwent induction therapy with either antithymocyte globulin (n = 30) or anti-interleukin-2 receptor antibody (n = 26). Maintenance immunosuppression was administered with Tac + MMF (n = 37; 61.6%) or CsA + MMF (n = 23; 38.4) with corticosteroids. Mean follow-up was 34 +/ 16 months. There were four graft losses and five patient deaths. There were no significant differences between spousal and living unrelated transplants in terms of clinical characteristics or biopsy-proven acute rejection episodes. The Kaplan Meier analysis showed 3-year patient survival rates of 94%, 100%, and 88% in group 1, group 2, and group 3, respectively (P > .05). Overall graft survival rates were 94%, 100%, and 77% in group 1, group 2, and group 3, respectively (P > .05). Graft and patient survival rates were similar at 3 years for wife-to husband, husband-to-wife, or LUDs. CONCLUSION: In conclusion, family members should be encouraged as LUD or spousal donors, based on similar patient and graft survival rates. PMID- 22841251 TI - Living donor liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Liver transplantation is a widely accepted modality in the treatment of hepatocellular carcinoma (HCC). In our center, patients with HCC limited to the liver without macrovascular invasion are accepted as candidates for living donor liver transplantation (LDLT). The aim of this study was to describe the patient characteristics and outcomes at a single institution to analyze the impact of our criteria on the survival of HCC patients. PATIENTS AND METHODS: We reviewed the medical records of all HCC (n = 105) patients who underwent liver transplantation in our institution. We excluded deaths in the early postoperative period and deceased donor liver transplantation (DDLT) patients, leaving 74 subjects (65 males and 9 female). Their median age was 53 years (range, 19-69). Univariate Kaplan-Meier and multivariate Cox proportional hazards models were used to analyze overall and disease-free survivals. RESULTS: Thirty-two (43%) patients were within the Milan criteria, and 42 (57%) exceeded them. One- and 2 year overall survival rates for patients within versus exceeding the Milan criteria were 72% versus 68% and 61% versus 58%, respectively. One- and 2-year disease-free survival rates for patients within versus exceeding the Milan criteria were 72% versus 68% and 60% versus 55%, respectively (P > .05). Tumor recurrence rates for patients within versus exceeding the Milan criteria were 0% versus 36%, respectively (P = .0002). Alpha-fetoprotein level was the only predictor of overall survival; alpha-fetoprotein level and tumor differentiation were predictors of disease-free survival. CONCLUSION: Although higher recurrence rates have been observed among patients exceeding the Milan criteria, LDLT is the only treatment option for the patients in countries with limited sources of cadaveric organs. As a general principle, we believe that the use of cadaveric donor liver grafts is not suitable for patients who exceed these criteria. PMID- 22841252 TI - Comparison of harmonic scalpel versus conventional knot tying for transection of short hepatic veins at liver transplantation: prospective randomized study. AB - The objective of this study was to compare harmonic scalpel for short hepatic vein transection with conventional ligation during recipient hepatectomy with caval preservation. Sixteen patients undergoing elective living donor liver transplantation were randomized into 2 groups. We recorded number, diameter, and location of each short hepatic vein, procedure time, central venous pressure, and degree of liver failure (Child-Pugh and Model for End stage Liver Disease scores). As an end point, we observed the intraoperative and postoperative bleeding rates of the transected veins. We transected 144 veins of mean diameter of 2.6 +/- 1.8 mm (range, 1-12 mm). Mean number of short hepatic veins in each person was 9 (range, 5-16). Harmonic scalpel was safe for veins with a diameter <= 2 mm; these veins were more prone to bleeding with conventional ligation. Bleeding rate was higher after ligation of veins in the upper half than the lower half of the cava (37% vs 21%; P = .04). Both total and per vessel procedure time did not differ between the groups. No postoperative bleeding complications occurred. Transection of veins with a diameter <= 2 mm by harmonic scalpel was as safe as conventional ligation. Harmonic scalpel transection of small hepatic veins (<= 2 mm) can be even safer than conventional control by knot tying, particularly in narrow areas. PMID- 22841253 TI - Liver transplantation following blunt liver trauma. AB - Due to developing medical technology worldwide, an increasing number of liver transplantations are performed for various indications. Liver transplantation has a limited but important role in specific life-threatening liver trauma cases, when initial therapeutic options fail to control the bleeding or when liver failure ensues. Herein we have reported a patient who required liver transplantation at 18 days after blunt liver trauma with acute liver failure. This case report suggested that liver transplantation is a potential treatment modality for a selected group of patients including pedratric cases who experience acute or subacute liver failure secondary to blunt trauma. PMID- 22841255 TI - New circulatory support system: heartware. AB - INTRODUCTION: Through the new developments in medicine, heart failure therapy has advanced to mechanical circulatory support systems. The HeartWare Ventricular Assist System HVAD; HeartWare, Inc.; Miramar, Fla, USA) is a new device that is a centrifugal, intracorporeal, miniaturized and continuous flow pump that serves simple patient use and enhanced life quality. This article reports the midterm results of patients who underwent the heartware support system. MATERIALS AND METHODS: We retrospectively compiled our data from December 2010, including 10 patients of mean age 51.8 years with 90% males, 70% of the overall patient cohort had dilated cardiomyopathy and remaining ones, ischemic disease. Mean left ventricular ejection fraction was 20.1% and mean systolic pulmonary artery pressure was 49.2 mm Hg. A single patient was grade 1; seven were grade 2; and remaining ones, grade 3 according to the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) scale. All patients were operated with cardiopulmonary bypass (CPB) with moderate hypothermia. Tricuspid ring annuloplasty was performed in 3 (30%) patients. In one patient we removed a left ventricular thrombus. In a case with severe aortic regurgitation, we placed a simple coaptation stitch at the central portion of the three aortic cusps under the aortic cross clamp. The mean CPB duration was 95.5 minutes. RESULTS: There was no operative or in-hospital mortality. Mean support time was 250.67 days. During the early postoperative period, one patient experienced a minor hemorrhagic neurological event also requiring a tracheostomy due to pneumonia. This patient has completely healed and on follow-up continues a normal life. All patients were asymptomatic regarding heart failure. One patient unfortunately died because of possible pancreatic cancer and sepsis. Two patients underwent transplantations on days 159 and 172 of support. CONCLUSION: The HVAD system provided effective circulatory support for patients with end-stage heart failure with low adverse event rates. Long-term results are needed particularly for destination therapy candidates. PMID- 22841254 TI - To bridge or not to bridge? AB - OBJECTIVE: Ventricular assist devices (VAD) are an important therapy that saves the lives of candidates a waiting heart transplantation (HTx). However, there are questions about posttransplantation effects of VADs. METHODS: Seventy-four patients with end-stage heart failure who underwent HTx in our clinic between February 2007 and July 2011 were divided into two groups; a bridge cohort (n = 28) and a nonbridge group comprising 46 who underwent HTx without mechanical circulatory support. There mean ages were 39.89 +/- 15.66 and 38.33 +/- 16.23 years respectively. Significantly more patients in the bridge group, were man displayed anemia, were treated with anticoagulation therapy, and underwent a resternotomy. In the nonbridge group, more patients needed preoperative inotropic support. RESULTS: Multiple logistic regression analysis revealed preoperative renal failure (P = .007, odds ratio [OR] 27) and inotropic support (P = .006, OR: 10,222) as well as longer cardiopulmonary bypasses (>= 130 minutes, P = .001, OR: 11,24) to be risk factors for in-hospital mortality, which was 15.2% in nonbridge and 10.7% in bridge subjects, P = .733). Major adverse events, such as renal failure, pulmonary failure, right ventricular failure, neurological event, and reoperation due to bleeding, shown similar incidences between the groups. The amount of blood transfusion was significantly higher in the bridge group (2.34 U versus 3.56 U, P = .037). The preoperative incidence of human leukocyte antigen sensitization (panel reactive antibody >= 10%) and grade 2R were rejection episodes in the early period were similar. CONCLUSION: Early posttransplant results were not adversely or beneficially influenced by the use of VADs. Similar to other types of cardiac surgery, a patients preoperative condition seemed to be the major factor affecting mortality. PMID- 22841256 TI - Changing face of heart failure surgery. AB - BACKGROUND: Heart failure is a serious disease ending with death if untreated. Although heart transplantation is the best therapy for end-stage heart failure, most candidates die in the waiting period due to the lack of donor organs. This condition represent a new era of heart failure surgery. METHODS: We retrospectively investigated 159 patients from 1998 to 2011 with a mean age of 40.0 years (range = 5-65), who were mostly diagnosed as dilated cardiomyopathy (n = 113). After April 2007, 67 patients underwent vascular assist device (VAD) implantation surgery for acute or chronic end-stage heart failure. We performed 69 heart transplantation with 27 on VAD systems before transplantation. RESULTS: Early mortality was 13.3% with 21 patients after the heart transplantation. The 67 patients supported with VAD did not experience an intraoperative death. The mean support time was 214 days (range = 3-1035). Twenty-four patients (35.8%) are still on pump support. The overall survival until transplantation or weaning was 77.6% at mean of 250.7 days survival reached 90% with Heartware (Hartware Inc, Miramar, Fla, USA) continuous flow pumps. CONCLUSION: After the introduction of VAD in 2007, the overall picture has been restructured radically for heart failure surgery, reducing patient loss on the waiting list. Especially, since 2009 nearly 80% of donor hearts were used for patients on mechanical circulatory support. PMID- 22841257 TI - Valvular procedures during ventricular assist device implantation. AB - BACKGROUND: Increased experience and success with ventricular assist devices (VAD) has permitted more aggressive use in patients formerly believed to be inappropriate for mechanical circulatory support (MCS). There is no clearly proven policy to manage end-stage heart failure patients with valvular pathologies. The aim of this report was to analysis our experience with combined approach of VAD implantation and valvular procedures among patients with valvular heart disease and end-stage heart failure. METHODS: We evaluated the clinical records of 67 patients who underwent MCS from April 2007 to September 2011. We identified 12 patients (17.9%) who received concomitant valvular procedures, four of whom had significant aortic insufficiency and received a simple coaptation stitch at the center to approximate the fibrous nodules of Arantius. The mechanical aortic valve was replaced with a stentless bioprosthesis in three patients. Mitral valve commissurotomy was performed in one patient with mitral stenosis and seven patients underwent tricuspit valve repair using an annuloplasty ring. RESULTS: All 12 patients were males, of mean age 50.3 +/- 11.5 years (range = 25-66). Eleven of them (91.6%) survived the early and late postoperative periods. Ten subjects (83.3%) continue to be supported with VAD; 1 (8.3%) was successfully bridged to transplantation. Each study participant regression of the valvular pathologies by early echocardiography demonstrated. CONCLUSION: Concomitant valve surgery during VAD implantation appeared to be a reasonable option in end-stage heart failure patients with valvular heart disease. PMID- 22841259 TI - Cilostazol and diltiazem attenuate cyclosporine-induced nephrotoxicity in rats. AB - AIM: Cyclosporine (CsA), an important agent used in organ transplantation to prevent rejection, displays nephrotoxicity as the most important side effect limiting usage. In this study, we sought to evaluate the effects of cilostazol and diltiazem to counter the nephrotoxicity induced by the calcineurin inhibitor CsA. MATERIALS AND METHODS: Animals were randomly divided into seven groups, each consisting of eight animals: sham, controls, cilostazol, diltiazem, CsA, CsA plus diltiazem, and CsA plus cilostazol treatment. At the end of a 60-minute ischemic period, we administered the drugs after reperfusion for 7 days thereafter. CsA (10 mg/kg/d) was intraperitoneally for 7 days; cilostazol (10 mg/kg/d) orally by catheter for 7 days; diltiazem (5 mg/kg/d) intraperitoneally for 7 days. At the end of the 7-day treatment period, blood and tissue samples were harvested for biochemical, and serological evaluation. RESULTS: Ischemia-reperfusion injury significantly increased malondialdehyde (MDA) levels as well as decreased catalase (CAT) activities and superoxide dysmutase (SOD) content. The lowest MDA mean level was observed in the diltiazem and, the highest in the control group. The lowest CAT mean levels were noted in the CsA and diltiazem groups with highest CAT content was in the CsA and cilostazol groups. The lowest SOD mean level occurred in the sham group; the highest, in the CsA group. CONCLUSION: Cilostazol and especially diltiazem were effective to mitigate renal ischemia reperfusion injury. PMID- 22841258 TI - Evaluation of changes in quality of life among Turkish patients undergoing ventricular assist device implantation. AB - BACKGROUND: Ventricular assist device (VAD) application has become an increasingly common method to treatment end-stage heart failure. In this study we evaluated the effect of VAD implantation upon the quality of life among Turkish patients with end-stage heart failure. METHODS: Twenty-eight VAD implantation patients included 3 (10.7%) with biventricular support using the Berlin Heart Excor; 15 (53.6%), left ventricular support with the Berlin Heart Excor; and 10 (35.7%), Heartware implantation for left ventricular support. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short Form 36 (SF-36) Health Questionnaire were used to assess changes in the quality of life (QOL). RESULTS: Of the 28 patients, 2 were females (7.1%) and 26 were males (92.9%) of overall mean age of 44.6 +/- 15.3 years (range, 8-66). Preoperative mean score of MLHFQ was significantly improved at 200.4 +/- 147.4 days follow-up (72.8 +/- 11.5 vs 13.7 +/- 10.5; P < .05). SF-36 physical scores and mental scores were improved postoperatively (physical scores, 20.0 +/- 24.4 vs 70.2 +/- 19.9; mental scores, 38.4 +/- 18.8 vs 73.9 +/- 15.7; P < .05). No significant relation was observed between the postoperative scores of questionnaires and type of surgery. More improvement in postoperative MLHFQ scores was seen in patients younger than 45 years of age (P = .027). The severity of chronic heart failure (CHF) regressed from New York Heart Association (NYHA) class IV to NYHA class II in 26 and to NYHA class III in 2 patients (P = .000). CONCLUSION: The QOL among patients with end-stage heart failure improved dramatically soon after VAD implantation. PMID- 22841260 TI - No harmful effect of mycophenolate mofetil on liver regeneration: an experimental study. AB - AIM: The aim of this experimental study was to examine the effects of mycophenolate mofetil (MMF) on liver regeneration in a partial hepatectomy model. METHODS: Rats were divided into 3 groups immediately following partial liver resection: saline, controls intraperitoneally (MMF; Group 1); MMF (15 mg/kg/d; Group II), and MMF (30 mg/kg/d; Group III). On days 3 and 7 following liver resection we humanely killed half of the rats in each group to measure alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and to evaluate Ki-67 using immunohistochemistry. We calculated liver regeneration rates. RESULTS: The difference between ALT levels on days 3 and 7 was not significantly different among the groups (P = .157; P = .292; P > .05, respectively). The AST levels were significantly different at 3 days (P = .018) but not 7 days (P = .385). The Ki-67 level were different among groups at day 3 (P = .002) but not at day 7 (P = .290). Liver regeneration rates were not different among the groups either at 3 or at 7 days (P = .264 and P = .925, respectively). CONCLUSION: MMF stimulates mitosis but its effect on regeneration is not clear. MMF appeared to show no adverse effects on liver regeneration. PMID- 22841261 TI - Sildenafil accelerates liver regeneration after partial hepatectomy in rats. AB - OBJECTIVE: The regeneration process causes the liver to achieve an adequate volume and function after major hepatectomy or living donor liver transplantation. Sildenafil, a selective phosphodiesterase-5 inhibitor used for erectile dysfunction, impacts the liver by enhancing the effects of nitric oxide. The aim of this study was to investigate the influence of sildenafil on liver regeneration in rats after partial hepatectomy. METHODS: Sixty young female Wistar Albino rats were randomly divided into three equal groups before 70% hepatectomy. Thereafter, we administered intraperitoneal saline to the control group (G1); 10 MUg/kg sildenafil to the low-dose group (G2) and 100 MUg/kg to the high-dose sildenafil group (G3). Half of the rats per group were sacrificed on the first and the other half on the fifth postoperative day after partial hepatectomy. Regeneration was assessed using three methods: (1) the formula described by Kwon et al formula, (2) the average number of mitotic figures in 10 microscopic fields, and (3) the average of Ki-67-positive nuclei in 1000 cells using immunohistochemistry. RESULTS: Although, the hepatic regeneration and mitosis rates were similar in all three groups, Ki-67 levels were significantly higher in both G2 and G3 than the control group on the first postoperative day. Hepatic regeneration was significantly greater in G2 and G3 than the control group as was the mitosis rate in the G2 group versus the two groups. By the 5th postoperative day Ki-67 levels were similar in the three groups. CONCLUSION: Sildenafil treatment accelerated hepatic regeneration after partial hepatectomy in rats. PMID- 22841262 TI - Chronic graft-versus-host disease after liver transplantation: a case report. AB - Graft-versus-host disease (GVHD) after orthotopic liver transplantation (OLT) is a rare but significant complication, occurring in 1%-2% of cases with a mortality rate of 85%- 90%. It occurs when donor passenger lymphocytes mount an alloreactive response against the host's histocompatibility antigens. It presents as fever, rash, and diarrhea with or without pancytopenia. Between March 2002 and September 2011, among 656 OLT patients 1 (0.15%) had acute GVHD. A biopsy at the 7th posttransplantation month revealed chronic GVHD. Consequently, in the cases that had fever, rash, and/or desquamation of the any part of body after liver transplantation, GVHD must be considered and skin biopsies must be planned for the diagnosis. PMID- 22841263 TI - Hepatic vein stenosis developed during living donor hepatectomy and corrected with peritoneal patch technique: a case report. AB - An 18-year-old male living donor for his father with end-stage liver cirrhosis due to hepatitis B underwent an extended right lobe donor hepatectomy. The middle hepatic vein was visualised on the cut surface of the graft and dissected up to the confluence of the middle and left hepatic veins. After vascular clamping, right and middle hepatic veins were cut to removed the graft. While starting the stump closure, the clamp over the middle hepatic vein slipped and the vein stump sutured quickly under suboptimal exposure. Soon after this closure, the remnant liver showed increasing congestion. Intraoperative Doppler ultrasound revealed obstruction of venous outflow at the remnant left liver due to stenosis in the left hepatic vein. Under total hepatic vascular occlusion, the sutures were removed from the narrowed left hepatic vein. A 2 * 2 cm peritoneal patch from the subcostal area that was prepared to close the defect was sutured to the edges of the left hepatic vein defect. Venous congestion of the liver disappeared when the clamps were removed. Intraoperative Doppler ultrasound confirmed normal hepatic venous flow. The postoperative course of the donor was uneventful. There was no clinical, biochemical, or radiological problems at 47 months of follow-up. An autogenous peritoneal patch may be a good option to repair vascular defects, which are not suitable for primary sutures, due to easy accessibility and size adjustment, cost effectiveness, as well as relatively low risk of infection and thrombosis. Close dissection of the left hepatic vein during parenchymal transection over the middle hepatic vein can result in narrowing, particularly at the bifurcation of the middle/left hepatic veins that can cause congestion in the remnant liver. When we include the middle hepatic vein with the right graft, we now believe that dissection away from the left hepatic vein seems much more secure for donors. PMID- 22841264 TI - Replacement of the vena cava with aortic graft for living donor liver transplantation in Budd-Chiari syndrome associated with hydatid cyst surgery: a case report. AB - A 12-year-old girl, operated because of a hydatid cyst of the liver, with Budd Chiari syndrome was evaluated for postoperative development of ascites and paraumbilical varicose veins. A vena caval stent was placed for the relief of inferior vena caval obstruction. The patient was admitted because of progressive deterioration in ascites and liver functions. Imaging techniques showed degeneration adjacent to the right hepatic vein in liver segments 7 to 8, a partially calcified 5-cm hydatid cyst, and a thrombosis in the inferior vena cava was that addressed with a 10-cm metal stent. A living donor segments 2 to 3 liver transplantation was obtained from the patient's mother. After completion of the donor operation without complications, the vena caval stent was removed following the recipient hepatectomy. Suprarenal flow continued after resection of the fibrotic vena cava and placement of a cadaveric cryopreserved aortic graft for the vena cava, anastomosed between the suprarenal and subdiaphragmatic segments of the vena cava. An end-to-side anastomosis was performed between the left hepatic vein of the donor liver and the aortic graft. There was no complication and the patient was discharged on postoperative day 19. Follow-up Doppler ultrasonography showed the aortic vena caval graft to be open, along with the hepatic/portal vein and hepatic artery. This case demonstrated that operations for liver hydatid cyst surgeries can iatrogenically induce Budd-Chiari syndrome; a cryopreserved aortic graft can be an alternative to ensure the continuity of the vena cava in living donor liver transplantation. PMID- 22841265 TI - Cardiac arrest that developed during liver transplantation and intervention with cardiopulmonary bypass: case report. PMID- 22841266 TI - Living donor liver transplantation in the absence of inferior vena cava: a case report. AB - Because of difficulties in the supply of cadaveric organs, of living donor liver transplantations are performed in increasing numbers. Congenital hepatic fibrosis associated with fibrosis and atrophy of the inferior vena cava were present in a potential recipient of living donor liver transplantation. This case report documented living donor liver transplantation as a treatment modality for a patient with absence of the inferior vena cava due to chronic liver failure. PMID- 22841267 TI - Successful kidney transplantation from a cadaveric donor unsuitable for other centers due to acute renal failure: a case report. AB - The demand for kidney transplantation due to improved recipient outcomes has stimulated surgeons to expand the criteria for usable donors, but still the use of organs from deceased donors with terminal acute renal failure is uncommon. We report 2 kidney transplant recipients from a cadaveric donor who was not accepted by other centers because of acute renal failure. The donor, a 24-year-old man with an intracerebral hemorrhage, displayed a serum creatinine (SCr) value of 0.6 mg/dL on hospital admission, which increased to 7.3 mg/dL on the fourth hospital day. After the diagnosis of brain death and refusal of the kidneys by other regional centers, we decided to transplant the 2 kidneys. Recipient 1, a 31-year old man on an 11-year dialysis program, discontinued hemodialysis after 7 days of delayed graft function. The SCr level decreased gradually and was stable at 1.08 mg/dL on postoperative day (POD) 45. The contralateral graft was transplanted into a 30-year-old man (recipient 2) undergoing dialysis treatment for 7 years. After 10 days of delayed graft function, the SCr decreased gradually with continued hemodialysis until POD 24. The SCr level has been stable at 1.34 mg/dL on POD 52. At the end of the third month the SCr levels in recipients 1 and 2 were 1.1 mg/dL and 1.4 mg/dL, respectively. In conclusion, one may safely expand the donor pool with kidneys from deceased donors with acute renal failure (ARF) with good short-term outcomes. PMID- 22841268 TI - Is flow cytometry crossmatch analysis using sera with different dilutions important for pretransplant analysis? A case report. AB - The most effective form of treatment for chronic renal failure is kidney transplantation from a cadaver or a living donor. For a kidney transplant to be successful, tissue compatibility and a lack of donor-specific anti-human leukocyte antigen (HLA) antibodies in the circulation of the patient are vital, in addition to ABO blood group compatibility. The presence of anti-HLA antibodies is assayed before transplantation using various methods, but because organ rejections have been observed in previous studies, different techniques are required to detect anti-HLA antibodies. Today, flow cytometry crossmatching is one of the most important and effective techniques in testing for donor-specific anti-HLA antibodies (DSAs). If weakly positive serum is assayed after serial dilution, it can yield high positivity. Herein, we describe the differences between the results for diluted and undiluted weakly positive sera studied using the flow cytometry crossmatch (FCXM) technique. In a recent study, the sera of weakly FCXM-positive patients were diluted 1/50, and the FCXM test was repeated. The use of diluted serum eliminated the effect of the prozone so that the DSAs could be detected. PMID- 22841269 TI - Urological knowledge before and after transplantation is of central importance, as donors and recipients are getting older and as kidney recipients may develop urological problems after transplantation. Preface. PMID- 22841270 TI - Xeno-kidney transplantation: from idea to reality. AB - Although kidney transplantation is a widely used therapy for chronic renal failure, not all patients can be transplanted due to the limited numbers of organ donations. A possible solution could be xenogenic kidney transplantation. Herein we have described the present state, problems and possible solutions using xenograft treatments. PMID- 22841271 TI - Ischemic postconditioning protects renal function after 24 hours of cold preservation in a canine autotransplantation model. AB - OBJECTIVES: Ischemia-reperfusion (I/R) injury is the most common cause of renal dysfunction. Ischemic postconditioning (IPO) is a phenomenon by which intermittent interruptions of blood flow in the early phase of reperfusion protect an organ from I/R injury. In the present study, we investigated the effects of IPO on renal I/R injury using a canine autotransplantation model. MATERIALS AND METHODS: Fifty adult male mongrel dogs were randomly divided into five groups of 10 animals each. The animals underwent a left nephrectomy followed by flushing and static preservation of the kidney in University of Wisconsin solution for 24 hours. IPO was performed by six cycles of 10 or 30 seconds or three cycles of 1-minute I/R before final reperfusion. All dogs underwent a right nephrectomy 24 hours later followed by autotransplantation of the preserved left kidney. Blood and urine were collected at various reperfusion times (24, 48, and 72 hours). We assayed blood urea nitrogen and creatinine levels, as well as urine N-acetyl-beta-D-glucosaminidase levels. Kidney samples were harvested after I/R to measured renal superoxide dismutase (SOD), malondialdehyde (MDA), and myeloperoxidase (MPO) concentrations. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assays of tissue samples. RESULTS: Compared with the sham group, I/R resulted in renal dysfunction with decreased SOD and increased MDA and MPO levels, as well as increased apoptosis indices. However, IPO attenuated the above effects, particularly the six cycles of 10-second I/R. CONCLUSIONS: IPO exerted protective effects on renal I/R injury. PMID- 22841272 TI - Donors with malignancies-risk or chance? AB - The disparity between organ demand and organ supply in renal transplantation has led transplant physicians to pursue a variety of options for increasing the number of donor kidneys. One option is to use kidneys from living or deceased donors who have been diagnosed with a malignant tumor, either of the kidney itself or of other origin. Today, there is an increasing body of evidence in favor of accepting kidneys from donors with renal or ureteral malignancy. This review article, based on a Medline and PubMed search, presents options and strategies for deciding under which circumstances these kidneys may be considered for transplantation. The decision depends on donor tumor characteristics and recipient issues but also on surgical and urological knowledge. PMID- 22841273 TI - Living donor nephrectomy--quantifying the risk for the donor. AB - Living kidney donation is on the rise, either due to cultural or ethical reasons or due to a lack of deceased donor kidneys. For adequately counseling of a potential living kidney donor, medical professionals must know not only the immediate risks of kidney donation but also possible long-term effects of kidney donation on the donor's physical and psychological well-being. This also includes a range of aspects such as quality of life, insurance issues, and family planning following kidney donation. This review article is based on a Medline and PubMed search and elucidates the risks living kidney donors face with regard to all aspects just mentioned. Living kidney donation does not end with the operative procedure--long-term cost-free physical and psychological follow-up should be offered to each donor for the gift he or she is willing to give to the recipient. PMID- 22841274 TI - Paired kidney donation: outcomes, limitations, and future perspectives. AB - It has been calculated that approximately one-third of willing, otherwise appropriate donor-recipient pairs are biologically incompatible due to blood group differences or positive crossmatches therefore cannot proceed to living donor transplantation. Paired kidney donation (KPD) may overcome this problem. Several types of KPD are in practice today and is a good alternative for incompatible donor-recipient couples. According to the existing data, KPD can increase the number of kidney transplants form living donors while providing excellent clinical results. This is also a cost-effective treatment as compared with dialysis and desensitization protocols. However, there are several barriers and limitations of this program. This article analyzed the advantages as well as the drawbacks and shortcomings of KPD programs. PMID- 22841275 TI - Incentives for organ donation: pros and cons. AB - Altruism still remains the main principle of organ donation worldwide. However, since the current practices has not met the demand for organs, new strategies should be found to encourage organ donation. Implementation of financial incentives in transplantation is a matter of debate among experts in the fields of transplantation, ethics, law, and economics. It should be acknowledged that donors incur many expenses while participating in the transplant process, which seems unfair. Various forms of incentives have been suggested and are currently used worldwide. This article describes current attitudes toward incentives for in transplantation used in different countries, arguing in favor as well as against them. PMID- 22841276 TI - Long-term outcome of single institutional experience with conservative and surgical management for renal artery aneurysm. AB - BACKGROUND: Spontaneous rupture risk of a renal artery aneurysm (RAA) is extremely low. Indications for surgical repair of RAA remain uncertain. OBJECTIVE: Long-term outcomes of conservative therapy and surgical repair were evaluated. PATIENTS: The study included 58 patients (17 males, 41 females) who were diagnosed with RAA during the last 21 years. Median age at the time of diagnosis was 62 (19-85) years, and the median follow-up 69 months (range 3-216). METHODS: The patients were divided into two groups, conservative group (n = 30) who had been followed with blood pressure control, and treatment group (n = 29), who underwent an intervention. RESULTS: Multiple efferent aneurysmal branches were observed in seven conservative and 16 treatment cases (P = .002). The median maximum diameter of the aneurysm was lower in the conservative than the treatment group (15 versus 25 mm, P = .005). Two conservative group cases showed increases in aneurysm size during follow-up. The hypertensive state showed essentially no change in either group during the follow-up. Renal function decreased with age similarly both in conservative and treatment groups. CONCLUSIONS: Our conservative management criteria for RAA are justifiable and even too strict. PMID- 22841277 TI - Do intraoperative hemodynamic factors of the recipient influence renal graft function? AB - PURPOSE: To assess the importance of intraoperative management of recipient hemodynamics for immediate versus delayed graft function. METHODS: The retrospective study of 1966 consecutive renal transplants performed in our department between June 1980 and December 2009 analyzed several perioperative hemodynamic factors: central venous pressure (CVP), mean arterial pressure (MAP) as well as volumes of fluids, fresh frozen plasma (FFP), albumin, and whole blood transfusions. We examined their influence on renal graft function parameters: immediate diuresis, serum creatinine levels, acute rejection, chronic transplant dysfunction, and graft survival. RESULTS: Mean CVP was 9.23 +/- 2.65 mm Hg and its variations showed no impact on graft function. We verified a twofold greater risk of chronic allograft dysfunction among patients with CVP >= 11 mm Hg (P < .001). Mean MAP was 93.74 +/- 13.6 mm Hg; graft survivals among subjects with MAP >= 93 mm Hg were greater than those of patients with MAP < 93 mm Hg (P = .04). On average, 2303.6 +/- 957.4 mL of saline solutions were infused during surgery. Patients who received whole blood transfusions (48%) showed a greater incidence of acute rejection episodes (ARE) (P = .049) and chronic graft dysfunction (P < .001). Patients who received FFP (55.7%), showed a higher incidence of ARE (P < .001). Only 4.6% of patients (n = 91) received human albumin with a lower incidence of ARE (P = .045) and chronic graft dysfunction (P = .024). Logistic binary regression analysis revealed that plasma administration was an independent risk factor for ARE (P < .001) and chronic dysfunction (P = .028). Volume administration (>= 2500 mL) was also an independent risk factor for chronic allograft dysfunction (P = .016). Using Cox regression, we verified volume administration >= 2500 mL to be the only independent risk factor for graft failure (P < .001). CONCLUSION: MAP >= 93 mm Hg and perioperative fluid administration <2500 mL were associated with greater graft survival. Albumin infusion seemed to be a protective factor, while CVP >= 11 mm Hg, whole blood, and FFP transfusions were associated with higher rates of ARE and chronic graft dysfunction. PMID- 22841278 TI - Renal replacement and male sexuality. AB - End-stage renal disease (ESRD) and dialysis have negative impact on lifestyle. Renal transplantation improves many facets of daily life. Male sexuality is a significant predictor of quality of life. This brief review summarizes the impacts of ESRD and renal replacement on a range of sexual domains as presented at the European Association of Urology meeting in Vienna. PMID- 22841279 TI - Synthesis and antiproliferative evaluation of some new amidino-substituted bis benzothiazolyl-pyridines and pyrazine. AB - Novel diamidino substituted conformationally restricted derivatives of bis benzothiazolyl-pyridines and pyrazine were synthesized and their antiproliferative activity against several human cancer cell lines were determinated. The synthetic approach used for preparation of isomeric amidinobenzotiazolyl disubstituted pyridines 3a-3k and pyrazine 3l was achieved by condenzation reaction of commercially available pyridine and pyrazine dicarboxylic acids with amidino- 2a and 2-imidazolinyl-substituted 2 aminothiophenol 2b in polyphosphoric acid in moderate to good yield. The condenzation reaction was greatly optimized. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. Antiproliferative assays revealed significant differences in antiproliferative activities of diamidino- and diimidazolinyl-derivatives, the latter exerting stronger concentration-dependent antiproliferative effects on tested tumor cell lines and thus being a prominent compound class for further chemical optimization and biological studies. Biological studies on SW620 cell line and BJ fibroblasts performed for the diimidazolinyl-derivative 3b revealed oxidative stress as a possible mechanism of antiproliferative action and predicted antineoplastic properties for this class of compounds. PMID- 22841280 TI - The synthesis and biological evaluation of novel Danshensu-cysteine analog conjugates as cardiovascular-protective agents. AB - A series of novel amide and thioester conjugates between Danshensu and cysteine derivatives have been designed and synthesized based on the strategy of "medicinal chemical hybridization". Pharmacological evaluation indicated that the amide conjugates 3a/4a/17a and thioester conjugates 6a-d exhibited obvious protective effects on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs). Pretreated with these conjugates could increase glutathione (GSH) activity and decrease malondialdehyde (MDA) level. Further study on mechanism of compound 4a revealed that it was related to its mitochondrial-protective effect and regulation of apoptosis-related proteins expression (Bax, p53, PARP, caspase 3, caspase-9 and Bcl-2). These results indicate that these Danshensu-cysteine analog conjugates possess significant cardiovascular-protective effects and merit further investigation. PMID- 22841281 TI - Synthesis, visible light photocleavage, antiproliferative and cellular uptake properties of ruthenium complex [Ru(phen)2(mitatp)]2+. AB - A new ruthenium complex [Ru(phen)(2)(mitatp)](2+) (phen = 1,10-phenanthroline, mitatp = 5-methoxy-isatino[1,2-b]-1,4,8,9-tetraazatriphenylene) has been synthesized and characterized. The interaction of the complex with DNA has been studied and the results indicate that [Ru(phen)(2)(mitatp)](2+) could efficiently photocleave pBR322 DNA under irradiation at visible light and the singlet oxygen (1)O(2) was proved to be reactive species in the photocleavage process. The cytotoxicity has also been evaluated by MTT method, and [Ru(phen)(2)(mitatp)](2+) shows prominent anticancer activity against various cancer cells. Live cell imaging study and flow cytometric analysis demonstrate that the complex could cross cell membrane accumulating in the nucleus and inducing cell death by induction of G0/G1 cells cycle arrest and apoptosis. PMID- 22841282 TI - Synthesis and in vitro antibacterial activity of gemifloxacin derivatives containing a substituted benzyloxime moiety. AB - A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested gram-positive strains including MRSA and MRSE (MIC: <0.008-8 MUg/mL), although they are generally less active than the references against the gram-negative strains. In particular, compound 11l (MIC: <0.008-4 MUg/mL) was found to be 8-2048 and 2-128 times more potent than levofloxacin (LVFX) and GMFX against the gram-positive strains, respectively. Moreover, against MRSA clinical isolates, 11l (MIC(90): 1 MUg/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC(90): 4 MUg/mL). PMID- 22841283 TI - Segment I intrahepatic biliary cystadenocarcinoma impinging on the hepatic vein. AB - BACKGROUND: Biliary cystadenoma is a rare cystic tumor; prognosis is dependent on the completeness of the surgical resection. CASE REPORT: The case of a 65-year old woman with a multilocular cystic hepatic tumor is reported. Radiological and laboratory findings suggested the diagnosis of cystadenoma with localized malignant degeneration. RESULTS: A surgical resection of hepatic Segment I was performed, requiring total vascular exclusion (TVE) of the liver and a needle aspiration of a non-degenerated cyst to permit total resection. CONCLUSIONS: TVE and decompression of a cyst presumed to be benign may be warranted to achieve a safe and complete resection of biliary cystadenoma. PMID- 22841284 TI - New classes of antibiotics. AB - Several novel chemical classes of antibiotics are currently in human clinical studies. While most are narrow spectrum agents that inhibit unexploited targets, the susceptible pathogens are clinically important, including staphylococci, pseudomonads, and mycobacteria. Given the paucity of antibacterial agents consisting of novel chemical scaffolds that act on established targets, these new antibacterial scaffolds, which are active against new targets, represent an important advance in the battle against antibiotic resistance. Indeed, most of these compounds are unlikely to be subject to existing compound-based or target based resistance mechanisms. PMID- 22841285 TI - Inhibition of experimental neointimal hyperplasia and neoatherosclerosis by local, stent-mediated delivery of everolimus. AB - INTRODUCTION: A novel self-expanding, drug-eluting stent (DES) was designed to slowly release everolimus in order to prevent restenosis after percutaneous peripheral intervention. The purpose of this experimental animal study was to test the hypothesis that long-term local, stent-mediated delivery of everolimus would reduce neointimal hyperplasia in porcine iliac arteries. METHODS: The iliac arteries of 24 Yucatan mini-swine were percutaneously treated with overlapping 8- * 28-mm self-expanding nitinol stents loaded with everolimus (225 MUg/cm2 stent surface area) formulated in a poly(ethylene-co-vinyl alcohol) copolymer intended to deliver the drug in a sustained fashion over about 6 months (DES). Bare nitinol self-expanding stents (bare metal stent [BMS]) were implanted in an identical fashion on the contralateral side to serve as controls. After 3, 6, or 12 months, the animals were sacrificed and the stented arteries perfusion-fixed for histomorphometric analysis. RESULTS: The chronic presence of everolimus in arterial tissue reduced stent-induced inflammation after 3 months (inflammation score: BMS 2.29+/-0.44 vs DES 0.17+/-0.17; P=.001) and 6 months (BMS 2.06+/-0.43 vs DES 0.50+/-0.5; P=.007), although some late inflammation was observed after drug exhaustion (BMS 1.00+/-0.25 vs DES 2.56+/-0.62 after 12 months; P=not significant [NS]). Treatment with locally delivered everolimus significantly reduced neointimal hyperplasia after 3 months (neointimal thickness: BMS 0.79+/ 0.20 vs DES 0.37+/-0.04 mm; P=.03) and 6 months (BMS 0.73+/-0.14 vs DES 0.41+/ 0.08 mm; P=.05), although the effect had dissipated after 12 months (BMS 0.68+/ 0.11 vs DES 0.67+/-0.11 mm; P=NS). Remarkably, stent-induced neoatherosclerosis, characterized by the histologic presence of foamy macrophages and cholesterol clefts, was significantly attenuated by treatment with everolimus (atherogenic change scores at 3 months: BMS 0.56+/-0.15 vs DES 0.04+/-0.04; P=.003; 6 months: BMS 0.84+/-0.23 vs DES 0.00+/-0.00; P=.004; and 12 months: BMS 0.09+/-0.10 vs DES 0.19+/-0.19; P=NS). CONCLUSIONS: In this experimental animal model, local arterial stent-mediated delivery of everolimus inhibited the formation of neointimal hyperplasia and neoatherosclerosis during the first 6 months. The effect was transient, however, as arterial morphology and histology appeared similar to control stented arteries after 12 months. PMID- 22841286 TI - Brain computed tomography perfusion may help to detect hemodynamic reconstitution and predict intracerebral hemorrhage after carotid stenting. AB - OBJECTIVE: We wanted to examine whether brain computed tomography (CT) perfusion can help to detect the reconstitution of cerebral hemodynamics and predict intracerebral hemorrhage (ICH) after carotid stenting. METHODS: From September 2002 to October 2009, data of 114 patients with carotid intervention were prospectively collected, and we retrospectively identified a total of 108 consecutive patients with unilateral carotid stenting. Brain CT perfusion was studied at three time points: 1 week before, and 1 week and 6 months after stenting. Cerebral blood volume (CBV), cerebral blood flow, and time to peak (TTP) of brain CT perfusion were examined at cortical and subcortical areas of middle cerebral artery (MCA) and posterior cerebral artery territory. The CBV, cerebral blood flow, and TTP ratios of stenting side/nonstenting side were used for comparison. The flow direction of ophthalmic artery was detected by sonography, and the presence of anterior communicating artery was examined on prestenting cerebral angiogram. RESULTS: After carotid stenting, CBV and TTP ratios improved significantly in both MCA cortical and subcortical areas in patients with unilateral carotid stenosis (P < .01) but not in patients with bilateral carotid stenosis. Patients with reversed ophthalmic flow had better improvement of TTP in both MCA and posterior cerebral artery territories (P < .05) than patients with forward flow. However, no significant difference was found between patients with and patients without anterior communicating artery collateral (P > .05). The prestenting TTP ratio in MCA subcortical area was significantly higher in patients with poststenting ICH than patients without ICH (P = .0191). CONCLUSIONS: Cerebral hemodynamics can be reconstituted within a few days after carotid revascularization, especially in patients with reversed ophthalmic flow. Prolonged TTP in prestenting MCA subcortical area may suggest a high risk of poststenting ICH. PMID- 22841287 TI - Vascular distribution of stroke and its relationship to perioperative mortality and neurologic outcome after thoracic endovascular aortic repair. AB - OBJECTIVE: This study assessed the vascular distribution of stroke after thoracic endovascular aortic repair (TEVAR) and its relationship to perioperative death and neurologic outcome. METHODS: A retrospective review was performed for patients undergoing TEVAR between 2001 and 2010. Aortic arch hybrid and abdominal debranching cases were excluded. Demographics, operative variables, and neurologic complications were examined. Stroke was defined as any new focal or global neurologic deficit lasting>24 hours with radiographic confirmation of acute intracranial pathology. RESULTS: Perioperative stroke occurred in 20 of 530 patients (3.8%) undergoing TEVAR. The cohort was 55% male and a mean age of 75.2+/-8.9 years (range, 57-90 years). Among patients with perioperative strokes, the indication for surgery was degenerative aneurysm in 14 (mean diameter, 6.8 cm), acute type B dissection in four, penetrating atherosclerotic aneurysm in one, and aortic transection in one. Cases were performed urgently or as an emergency in 60%. The proximal landing zone was zone 2 in 11 or zone 3 in nine. All strokes were embolic. The vascular distribution of stroke involved the anterior cerebral (AC) circulation in eight (zone 2, n=5) and the posterior cerebral (PC) circulation in 12 (zone 2, n=6). Laterality of cerebral infarction included five right-sided, eight left-sided, and seven bilateral strokes. Nine strokes were diagnosed<24 hours after operation. There was no difference in baseline demographics, aortic pathology, acuity, zone coverage, preoperative left subclavian artery revascularization, number of stents, or estimated blood loss between stroke groups based on vascular distribution. Independent risk factors for any perioperative stroke were chronic renal insufficiency (odds ratios [OR], 4.65; 95% confidence interval [CI], 1.22-17.7; P=.02) and history of prior stroke (OR, 4.92; 95% CI, 1.69-14.4; P=.004); the risk factor for AC stroke was prior stroke (OR, 7.67; 95% CI, 1.25-46.9; P=.03) and the risk factors for PC stroke were age (OR, 1.11; 95% CI, 1.00-1.23; P=.04), prior stroke (OR, 7.53; 95% CI, 1.78-31.8; P=.006), zone 2 coverage (OR, 6.11; 95% CI, 1.15-32.3; P=.03), and penetrating atherosclerotic ulcer (OR, 32.7; 95% CI, 1.33-807.2; P=.03). Overall in-hospital mortality was 20% (n=4), with those sustaining PC strokes observed to trend toward increased mortality (33% vs 0%; P=.12). Patients with AC strokes were more likely than those with PC strokes to achieve complete recovery of neurologic deficits before discharge (75% vs 17%; P=.02). CONCLUSIONS: Perioperative stroke after TEVAR is primarily an embolic event. Although infrequent, stroke was associated with significant morbidity and death, particularly among those with strokes involving the PC circulation. PMID- 22841289 TI - Liver fat quantification by dual-echo MR imaging outperforms traditional histopathological analysis. AB - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the accuracy of dual-echo (DE) magnetic resonance imaging (MRI) with and without fat and water separation for the quantification of liver fat content (LFC) in vitro and in patients undergoing liver surgery, with comparison to histopathologic analysis. MATERIALS AND METHODS: MRI was performed on a 1.5-T scanner using a three dimensional DE MRI sequence with automated reconstruction of in-phase (IP) and out-of-phase (OP) and fat-signal-only and water-signal-only images. LFC was estimated by fat fractions from IP and OP images (MRI(IP/OP)) and from Dixon based fat-only and water-only images (MRI(DIxON)). Seven phantoms containing a titrated mixture of liver and fat from 0% to 50% were examined. Forty-three biopsies in 22 patients undergoing liver surgery were prospectively evaluated by a pathologist by traditional determination of the cell-count fraction and by a computer-based algorithm, the latter serving as the reference standard. RESULTS: In vitro, both MRI(IP/OP) and MRI(DIxON) were significantly correlated with titrated LFC (r = 0.993, P < .001), with a smaller measurement bias for MRI(IP/OP) (+2.6%) than for MRI(DIxON) (+4.5%). In vivo, both MRI(IP/OP) and MRI(DIxON) from DE MRI were correlated significantly better with computer-based histologic results (P < .001) and showed significantly smaller measurement bias (4.8% vs 21.1%) compared to histologic cell-count fraction (P < .001). Measurement bias was significantly smaller for MRI(IP/OP) than for MRI(DIxON) (P < .001). CONCLUSIONS: DE MRI allows the accurate quantification of LFC in a surgical population, outperforming traditional histopathologic analysis. DE MRI without fat and water separation shows the highest accuracy and smallest measurement bias for the quantification of LFC. PMID- 22841288 TI - Evaluation of hepatic tumor response to yttrium-90 radioembolization therapy using texture signatures generated from contrast-enhanced CT images. AB - RATIONALE AND OBJECTIVES: The aim of this study was to explore the use of texture features generated from liver computed tomographic (CT) datasets as potential image-based indicators of patient response to radioembolization (RE) with yttrium 90 ((90)Y) resin microspheres, an emerging locoregional therapy for advanced stage liver cancer. MATERIALS AND METHODS: Overall posttherapy survival and percent change in serologic tumor marker at 3 months posttherapy represent the primary clinical outcomes in this study. Thirty advanced-stage liver cancer cases (primary and metastatic) treated with RE over a 3-year period were included. Texture signatures for tumor regions, which were delineated to reveal boundaries with normal regions, were computed from pretreatment contrast-enhanced liver CT studies and evaluated for their ability to classify patient serologic response and survival. RESULTS: A series of systematic leave-one-out cross-validation studies using soft-margin support vector machine (SVM) classifiers showed hepatic tumor texton and local binary pattern (LBP) signatures both achieve high accuracy (96%) in discriminating subjects in terms of their serologic response. The image based indicators were also accurate in classifying subjects by survival status (80% and 93% accuracy for texton and LBP signatures, respectively). CONCLUSIONS: Hepatic texture signatures generated from tumor regions on pretreatment triphasic CT studies were highly accurate in differentiating among subjects in terms of serologic response and survival. These image-based computational markers show promise as potential predictive tools in candidate evaluation for locoregional therapy such as RE. PMID- 22841290 TI - Probability and surprisal in auditory comprehension of morphologically complex words. AB - Two auditory lexical decision experiments document for morphologically complex words two points at which the probability of a target word given the evidence shifts dramatically. The first point is reached when morphologically unrelated competitors are no longer compatible with the evidence. Adapting terminology from Marslen-Wilson (1984), we refer to this as the word's initial uniqueness point (UP1). The second point is the complex uniqueness point (CUP) introduced by Balling and Baayen (2008), at which morphologically related competitors become incompatible with the input. Later initial as well as complex uniqueness points predict longer response latencies. We argue that the effects of these uniqueness points arise due to the large surprisal (Levy, 2008) carried by the phonemes at these uniqueness points, and provide independent evidence that how cumulative surprisal builds up in the course of the word co-determines response latencies. The presence of effects of surprisal, both at the initial uniqueness point of complex words, and cumulatively throughout the word, challenges the Shortlist B model of Norris and McQueen (2008), and suggests that a Bayesian approach to auditory comprehension requires complementation from information theory in order to do justice to the cognitive cost of updating probability distributions over lexical candidates. PMID- 22841293 TI - Information encoded in non-native states drives substrate-chaperone pairing. AB - Many proteins refold in vitro through kinetic folding intermediates that are believed to be by-products of native-state centric evolution. These intermediates are postulated to play only minor roles, if any, in vivo because they lack any information related to translation-associated vectorial folding. We demonstrate that refolding intermediate of a test protein, generated in vitro, is able to find its cognate chaperone, from the whole complement of Escherichia coli soluble chaperones. Cognate chaperone-binding uniquely alters the conformation of non native substrate. Importantly, precise chaperone targeting of substrates are maintained as long as physiological molar ratios of chaperones remain unaltered. Using a library of different chaperone substrates, we demonstrate that kinetically trapped refolding intermediates contain sufficient structural features for precise targeting to cognate chaperones. We posit that evolution favors sequences that, in addition to coding for a functional native state, encode folding intermediates with higher affinity for cognate chaperones than noncognate ones. PMID- 22841292 TI - Cas5d protein processes pre-crRNA and assembles into a cascade-like interference complex in subtype I-C/Dvulg CRISPR-Cas system. AB - Clustered regularly interspaced short palindromic repeats (CRISPRs), together with an operon of CRISPR-associated (Cas) proteins, form an RNA-based prokaryotic immune system against exogenous genetic elements. Cas5 family proteins are found in several type I CRISPR-Cas systems. Here, we report the molecular function of subtype I-C/Dvulg Cas5d from Bacillus halodurans. We show that Cas5d cleaves pre crRNA into unit length by recognizing both the hairpin structure and the 3' single stranded sequence in the CRISPR repeat region. Cas5d structure reveals a ferredoxin domain-based architecture and a catalytic triad formed by Y46, K116, and H117 residues. We further show that after pre-crRNA processing, Cas5d assembles with crRNA, Csd1, and Csd2 proteins to form a multi-sub-unit interference complex similar to Escherichia coli Cascade (CRISPR-associated complex for antiviral defense) in architecture. Our results suggest that formation of a crRNA-presenting Cascade-like complex is likely a common theme among type I CRISPR subtypes. PMID- 22841294 TI - Structural modeling of heteromeric protein complexes from disassembly pathways and ion mobility-mass spectrometry. AB - Structure determination of macromolecular protein assemblies remains a challenge for well-established methods. Here, we provide an assessment of an emerging structural technique, ion mobility-mass spectrometry (IM-MS), and examine the use of collision cross-sections (CCSs), derived from IM-MS, as restraints for structure characterization of heteromeric protein assemblies. Using 15 complexes selected from the Protein Data Bank, we validate the use of low-resolution models by comparing their CCSs with those calculated for all-atom structures. We then select six heteromeric complexes, disrupting them in solution to form subcomplexes. Experimental and calculated CCSs reveal close similarity for 18 of the 21 (sub)complexes. Exploring the use of CCS as a restraint, we incorporate it into a scoring function and show good correlation between the score and similarity to the native structure for heteromers, especially when an additional symmetry restraint was introduced. PMID- 22841291 TI - beta-Barrel mobility underlies closure of the voltage-dependent anion channel. AB - The voltage-dependent anion channel (VDAC) is the major protein in the outer mitochondrial membrane, where it mediates transport of ATP and ADP. Changes in its permeability, induced by voltage or apoptosis-related proteins, have been implicated in apoptotic pathways. The three-dimensional structure of VDAC has recently been determined as a 19-stranded beta-barrel with an in-lying N-terminal helix. However, its gating mechanism is still unclear. Using solid-state NMR spectroscopy, molecular dynamics simulations, and electrophysiology, we show that deletion of the rigid N-terminal helix sharply increases overall motion in VDAC's beta-barrel, resulting in elliptic, semicollapsed barrel shapes. These states quantitatively reproduce conductance and selectivity of the closed VDAC conformation. Mutation of the N-terminal helix leads to a phenotype intermediate to the open and closed states. These data suggest that the N-terminal helix controls entry into elliptic beta-barrel states which underlie VDAC closure. Our results also indicate that beta-barrel channels are intrinsically flexible. PMID- 22841295 TI - Characterization of radioactive contaminants and water treatment trials for the Taiwan Research Reactor's spent fuel pool. AB - There were approximately 926 m(3) of water contaminated by fission products and actinides in the Taiwan Research Reactor's spent fuel pool (TRR SFP). The solid and ionic contaminants were thoroughly characterized using radiochemical analyses, scanning electron microscopy equipped with an energy dispersive spectrometer (SEM-EDS), and inductively coupled plasma optical emission spectrometry (ICP-OES) in this study. The sludge was made up of agglomerates contaminated by spent fuel particles. Suspended solids from spent ion-exchange resins interfered with the clarity of the water. In addition, the ionic radionuclides such as (137)Cs, (90)Sr, U, and alpha-emitters, present in the water were measured. Various filters and cation-exchange resins were employed for water treatment trials, and the results indicated that the solid and ionic contaminants could be effectively removed through the use of <0.9 MUm filters and cation exchange resins, respectively. Interestingly, the removal of U was obviously efficient by cation exchange resin, and the ceramic depth filter composed of diatomite exhibited the properties of both filtration and adsorption. It was found that the ceramic depth filter could adsorb beta-emitters, alpha emitters, and uranium ions. The diatomite-based ceramic depth filter was able to simultaneously eliminate particles and adsorb ionic radionuclides from water. PMID- 22841296 TI - Application of linear free energy relationships to characterizing the sorptive characteristics of organic contaminants on organoclays from water. AB - Linear free energy relationships (LFERs) were applied to investigate the sorptive characteristics of organic contaminants (OCs) on organoclays from water. Three cetyltrimethylammonium modified montmorillonites (C-Mts) were selected as representative organoclays. The sorption coefficients (logK(oc)) of OCs on the C Mts were calculated according to the results of batch sorption experiments. Then the LFER equations for OC sorption on C-Mts from water were developed. The results of this study showed that compared with bulk water, water saturated C-Mts are more polarizable, less polar and cohesive, and have stronger H-bond acceptor capacities and weaker H-bond donor capacities. The primary driving forces for the sorption of OCs from water to C-Mts can be ascribed to the weaker cohesive characteristics of C-Mts as well as the stronger nonspecific Van der Waals interaction between OCs and C-Mts. With increasing CTMA loading amount, the interaction between OCs and C-Mts increases whereas the C-Mts become more cohesive. Consequently, the sorption capacity of C-Mts first increases with CTMA loading amount and then decreases with further increased loading amount. PMID- 22841297 TI - Enhanced fluoride adsorption using Al (III) modified calcium hydroxyapatite. AB - Aluminum-modified hydroxyapatite (Al-HAP) was prepared and characterized using XRD and BET analyses. Al-HAP possessed higher defluoridation capacity (DC) of 32.57 mgF(-)/g than unmodified hydroxyapatite (HAP) which showed a DC of 16.38 mgF(-)/g. The effect of Al/Ca atomic ratio in Al-HAP, solution pH and co-existing anions was further studied. The results indicated that the adsorption data could be well described by the Langmuir isotherm model and the adsorption kinetic followed the pseudo-second-order model. The pH changes during the adsorption process suggested that the OH on the surface of Al-HAP was the adsorption sites. The more adsorption sites were formed on Al modified HAP, which possessed abundant surface hydroxyl groups, resulting in higher efficiency of F(-) removal. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were calculated in order to understand the nature of adsorption process. The results revealed that the adsorption reaction was a spontaneous and endothermic process. PMID- 22841298 TI - Pulsation of the nailbed. PMID- 22841299 TI - Neurogenesis interferes with the retrieval of remote memories: forgetting in neurocomputational terms. AB - In contrast to models and theories that relate adult neurogenesis with the processes of learning and memory, almost no solid hypotheses have been formulated that involve a possible neurocomputational influence of adult neurogenesis on forgetting. Based on data from a previous study that implemented a simple but complete model of the main hippocampal circuitry (Weisz & Argibay, 2009), we now test this model under different situations to better study the case of remote memories. The results of this work show that following neurogenesis, the new, ongoing memories in the hippocampus are better retained than when no neurogenesis occurs at all, while the older memories are affected (to a lesser extent) by a special type of interference that is different from interference that occurs with an increasing number of memories per se. This work adds a new point of analysis in support of the interference view that might lead to the forgetting of memories in the hippocampus as they are transferred to neocortex for long-term storage, consistent with the Complementary Learning Systems models of system-level consolidation. Attention should be directed to the specific causes of interference; the results of this work signal a type of distortion of remote memories that is produced by the birth and the growth of new processing units, which results in a subtly impoverished retrieval as new neurons become active. The proposals of this model fit well with some empirical findings that are related to the issue. In the future, as new evidence emerges, we believe that this biological process, which is largely related to learning and memory, will also help to shape our ideas about normal forgetting and its possible contributions to system consolidation. PMID- 22841300 TI - Too much of a good thing: stronger bilingual inhibition leads to larger lag-2 task repetition costs. AB - Inhibitory control and monitoring abilities of Hebrew-English bilingual and English monolingual university students were compared, in a paradigm requiring participants to switch between performing three distinct tasks. Inhibitory control was gauged by lag-2 task repetition costs, namely decreased performance on the final trial of sequences of type ABA relative to CBA, due to persisting inhibition of the recently abandoned task. Bilinguals had larger lag-2 repetition costs, which reflect stronger inhibition of a no-longer relevant task to facilitate a switch into a new task. Monitoring ability was measured by the fadeout effect, which reflects adaptation to simpler task demands when a single task block immediately and unexpectedly follows mixed task blocks. Bilinguals did not differ from monolinguals in the magnitude or trajectory of the fade-out effect. Thus, results support the notion of increased bilingual inhibitory control, even when it is detrimental to performance, and do not demonstrate a specific bilingual advantage in monitoring. These findings are discussed in the context of the recent debate concerning the locus of bilingual advantages. PMID- 22841301 TI - Reviews on the visual cortex: a tribute to Hubel and Wiesel. PMID- 22841302 TI - David Hubel and Torsten Wiesel. AB - While attending medical school at McGill, David Hubel developed an interest in the nervous system during the summers he spent at the Montreal Neurological Institute. After heading to the United States in 1954 for a Neurology year at Johns Hopkins, he was drafted by the army and was assigned to the Neuropsychiatry Division at the Walter Reed Hospital, where he began his career in research and did his first recordings from the visual cortex of sleeping and awake cats. In 1958, he moved to the lab of Stephen Kuffler at Johns Hopkins, where he began a long and fruitful collaboration with Torsten Wiesel. Born in Sweden, Torsten Wiesel began his scientific career at the Karolinska Institute, where he received his medical degree in 1954. After spending a year in Carl Gustaf Bernhard's laboratory doing basic neurophysiological research, he moved to the United States to be a postdoctoral fellow with Stephen Kuffler. It was at Johns Hopkins where he met David Hubel in 1958, and they began working together on exploring the receptive field properties of neurons in the visual cortex. Their collaboration continued until the late seventies. Hubel and Wiesel's work provided fundamental insight into information processing in the visual system and laid the foundation for the field of visual neuroscience. They have had many achievements, including- but not limited to--the discovery of orientation selectivity in visual cortex neurons and the characterization of the columnar organization of visual cortex through their discovery of orientation columns and ocular-dominance columns. Their work earned them the Nobel Prize for Physiology or Medicine in 1981, which they shared with Roger Sperry. PMID- 22841303 TI - The bionic retina: a small molecule with big potential for visual restoration. AB - In this issue of Neuron, Polosukhina et al. (2012) intravitreally deliver the light-activatable molecule acrylamide-azobenzene-quaternary ammonium (AAQ) to the eyes of mice with end-stage retinal degeneration. Results show that, with the appropriate illumination, AAQ restores light sensitivity and visual behavior. PMID- 22841304 TI - Have you heard? Viral-mediated gene therapy restores hearing. AB - Genetic loss of VGLUT3 in cochlear inner hair cells results in profound deafness. In this issue of Neuron, Akil et al. (2012) show that AAV-mediated introduction of wild-type VGLUT3 in the genetically deaf mouse cochlea results in significantly improved hearing. PMID- 22841305 TI - Dendritic ventriloquism: inhibitory synapses throw their voices. AB - In a theoretical study in this issue of Neuron,Gidon and Segev (2012) identify several new principles governing how inhibition interacts with excitation in active dendrites. They show that inhibitory synapses can interact with excitability at a distance, effectively "throwing their voices" in the dendritic tree, such that distributed inhibitory synapses can act synergistically to provide a global veto of dendritic excitability. PMID- 22841306 TI - Mechanisms of neuronal computation in mammalian visual cortex. AB - Orientation selectivity in the primary visual cortex (V1) is a receptive field property that is at once simple enough to make it amenable to experimental and theoretical approaches and yet complex enough to represent a significant transformation in the representation of the visual image. As a result, V1 has become an area of choice for studying cortical computation and its underlying mechanisms. Here we consider the receptive field properties of the simple cells in cat V1--the cells that receive direct input from thalamic relay cells--and explore how these properties, many of which are highly nonlinear, arise. We have found that many receptive field properties of V1 simple cells fall directly out of Hubel and Wiesel's feedforward model when the model incorporates realistic neuronal and synaptic mechanisms, including threshold, synaptic depression, response variability, and the membrane time constant. PMID- 22841307 TI - From functional architecture to functional connectomics. AB - "Receptive Fields, Binocular Interaction and Functional Architecture in the Cat's Visual Cortex" by Hubel and Wiesel (1962) reported several important discoveries: orientation columns, the distinct structures of simple and complex receptive fields, and binocular integration. But perhaps the paper's greatest influence came from the concept of functional architecture (the complex relationship between in vivo physiology and the spatial arrangement of neurons) and several models of functionally specific connectivity. They thus identified two distinct concepts, topographic specificity and functional specificity, which together with cell-type specificity constitute the major determinants of nonrandom cortical connectivity. Orientation columns are iconic examples of topographic specificity, whereby axons within a column connect with cells of a single orientation preference. Hubel and Wiesel also saw the need for functional specificity at a finer scale in their model of thalamic inputs to simple cells, verified in the 1990s. The difficult but potentially more important question of functional specificity between cortical neurons is only now becoming tractable with new experimental techniques. PMID- 22841308 TI - Traveling waves in visual cortex. AB - Electrode recordings and imaging studies have revealed that localized visual stimuli elicit waves of activity that travel across primary visual cortex. Traveling waves are present also during spontaneous activity, but they can be greatly reduced by widespread and intensive visual stimulation. In this Review, we summarize the evidence in favor of these traveling waves. We suggest that their substrate may lie in long-range horizontal connections and that their functional role may involve the integration of information over large regions of space. PMID- 22841311 TI - Less is more: expectation sharpens representations in the primary visual cortex. AB - Prior expectations about the visual world facilitate perception by allowing us to quickly deduce plausible interpretations from noisy and ambiguous data. The neural mechanisms of this facilitation remain largely unclear. Here, we used functional magnetic resonance imaging (fMRI) and multivariate pattern analysis (MVPA) techniques to measure both the amplitude and representational content of neural activity in the early visual cortex of human volunteers. We find that while perceptual expectation reduces the neural response amplitude in the primary visual cortex (V1), it improves the stimulus representation in this area, as revealed by MVPA. This informational improvement was independent of attentional modulations by task relevance. Finally, the informational improvement in V1 correlated with subjects' behavioral improvement when the expected stimulus feature was relevant. These data suggest that expectation facilitates perception by sharpening sensory representations. PMID- 22841310 TI - Adult visual cortical plasticity. AB - The visual cortex has the capacity for experience-dependent change, or cortical plasticity, that is retained throughout life. Plasticity is invoked for encoding information during perceptual learning, by internally representing the regularities of the visual environment, which is useful for facilitating intermediate-level vision--contour integration and surface segmentation. The same mechanisms have adaptive value for functional recovery after CNS damage, such as that associated with stroke or neurodegenerative disease. A common feature to plasticity in primary visual cortex (V1) is an association field that links contour elements across the visual field. The circuitry underlying the association field includes a plexus of long-range horizontal connections formed by cortical pyramidal cells. These connections undergo rapid and exuberant sprouting and pruning in response to removal of sensory input, which can account for the topographic reorganization following retinal lesions. Similar alterations in cortical circuitry may be involved in perceptual learning, and the changes observed in V1 may be representative of how learned information is encoded throughout the cerebral cortex. PMID- 22841309 TI - Development and plasticity of the primary visual cortex. AB - Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright. PMID- 22841312 TI - Photochemical restoration of visual responses in blind mice. AB - Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases. PMID- 22841313 TI - Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. AB - Mice lacking the vesicular glutamate transporter-3 (VGLUT3) are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse. Cochlear delivery of VGLUT3 using adeno-associated virus type 1 (AAV1) leads to transgene expression in only inner hair cells (IHCs), despite broader viral uptake. Within 2 weeks of AAV1-VGLUT3 delivery, auditory brainstem response (ABR) thresholds normalize, along with partial rescue of the startle response. Lastly, we demonstrate partial reversal of the morphologic changes seen within the afferent IHC ribbon synapse. These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness. PMID- 22841314 TI - Subcellular knockout of importin beta1 perturbs axonal retrograde signaling. AB - Subcellular localization of mRNA enables compartmentalized regulation within large cells. Neurons are the longest known cells; however, so far, evidence is lacking for an essential role of endogenous mRNA localization in axons. Localized upregulation of Importin beta1 in lesioned axons coordinates a retrograde injury signaling complex transported to the neuronal cell body. Here we show that a long 3' untranslated region (3' UTR) directs axonal localization of Importin beta1. Conditional targeting of this 3' UTR region in mice causes subcellular loss of Importin beta1 mRNA and protein in axons, without affecting cell body levels or nuclear functions in sensory neurons. Strikingly, axonal knockout of Importin beta1 attenuates cell body transcriptional responses to nerve injury and delays functional recovery in vivo. Thus, localized translation of Importin beta1 mRNA enables separation of cytoplasmic and nuclear transport functions of importins and is required for efficient retrograde signaling in injured axons. PMID- 22841315 TI - Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. AB - Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease. PMID- 22841316 TI - Two distinct channels of olfactory bulb output. AB - Rhythmic neural activity is a hallmark of brain function, used ubiquitously to structure neural information. In mammalian olfaction, repetitive sniffing sets the principal rhythm but little is known about its role in sensory coding. Here, we show that mitral and tufted cells, the two main classes of olfactory bulb projection neurons, tightly lock to this rhythm, but to opposing phases of the sniff cycle. This phase shift is established by local inhibition that selectively delays mitral cell activity. Furthermore, while tufted cell phase is unperturbed in response to purely excitatory odorants, mitral cell phase is advanced in a graded, stimulus-dependent manner. Thus, phase separation by inhibition forms the basis for two distinct channels of olfactory processing. PMID- 22841317 TI - Principles governing the operation of synaptic inhibition in dendrites. AB - Synaptic inhibition plays a key role in shaping the dynamics of neuronal networks and selecting cell assemblies. Typically, an inhibitory axon contacts a particular dendritic subdomain of its target neuron, where it often makes 10-20 synapses, sometimes on very distal branches. The functional implications of such a connectivity pattern are not well understood. Our experimentally based theoretical study highlights several new and counterintuitive principles for dendritic inhibition. We show that distal "off-path" rather than proximal "on path" inhibition effectively dampens proximal excitable dendritic "hotspots," thus powerfully controlling the neuron's output. Additionally, with multiple synaptic contacts, inhibition operates globally, spreading centripetally hundreds of micrometers from the inhibitory synapses. Consequently, inhibition in regions lacking inhibitory synapses may exceed that at the synaptic sites themselves. These results offer new insights into the synergetic effect of dendritic inhibition in controlling dendritic excitability and plasticity and in dynamically molding functional dendritic subdomains and their output. PMID- 22841318 TI - Coding of the reach vector in parietal area 5d. AB - Competing models of sensorimotor computation predict different topological constraints in the brain. Some models propose population coding of particular reference frames in anatomically distinct nodes, whereas others require no such dedicated subpopulations and instead predict that regions will simultaneously code in multiple, intermediate, reference frames. Current empirical evidence is conflicting, partly due to difficulties involved in identifying underlying reference frames. Here, we independently varied the locations of hand, gaze, and target over many positions while recording from the dorsal aspect of parietal area 5. We find that the target is represented in a predominantly hand-centered reference frame here, contrasting with the relative code seen in dorsal premotor cortex and the mostly gaze-centered reference frame in the parietal reach region. This supports the hypothesis that different nodes of the sensorimotor circuit contain distinct and systematic representations, and this constrains the types of computational model that are neurobiologically relevant. PMID- 22841320 TI - A social learning perspective on the development of doctors in the UK National Health Service. AB - How best to develop doctors is a problem for many healthcare systems. The current trend towards competence-based models, especially in UK postgraduate medical education, appears to neglect lessons emerging from social learning theories in the workplace. However, social learning itself, especially communities of practice (CoP), also has shortcomings because it needs to take into account broader social, economic and political factors. Our contribution is to show how an extended version of CoP might shed light on the education and development of doctors by drawing on data from a qualitative interview study of participants' experiences of three eras of postgraduate medical education. We also make recommendations for further research and practice in this critical field of healthcare. PMID- 22841319 TI - Diagnosis as a social determinant: the development of prosocial behaviour before and after an autism spectrum diagnosis. AB - Jutel and Nettleton (2011) discuss diagnosis as not only a major classification tool for medicine but also an interactive social process that itself may have ramifications for health. Consideration of diagnosis as a social determinant of health outcomes led to the formulation of our research question: Can we detect a change in the development of prosocial symptoms before and after an Autism Spectrum Disorder (ASD) diagnosis? We examined the developmental trajectory of prosocial skills of children, as impairment in social skills is given as a core symptom for children with ASD. We used a validated scale measuring prosocial behaviour for a sample of 57 children where the measure was repeatedly recorded over ten years. We plotted the developmental trajectory of the prosocial trait in this sample who were enrolled in a longitudinal birth cohort study based in South West England. Multi-factorial fixed effect modelling suggests that the developmental trajectory of this measure of behaviour was not significantly altered by ASD diagnosis, or the consequences of diagnosis, either for better or worse. Further analysis was conducted on a subset of 33 of the children who had both pre-diagnosis and post-diagnosis information, and the same result obtained. The results indicate that prosocial behaviours may be resistant to typical 'treatments': provision of educational and specialist health services triggered by a clinical ASD diagnosis. The implications of this for considering diagnosis as a social determinant are discussed. PMID- 22841321 TI - Effect of preoperational mechanical ventilation on short-term postoperative outcomes in patients with severe tetralogy of Fallot. AB - BACKGROUND: This study is designed to investigate the effect of preoperational mechanical ventilation on the short-term postoperative outcomes following corrective surgery for severe tetralogy of Fallot (TOF). METHODS: Ninety-two patients (58 males, mean age 20.5+/-8.5 months) with severe TOF were randomised into study and control groups. In the study group, mechanical ventilation was performed in PEEP/PRVC mode in the intensive care unit to correct blood gas imbalances for the corrective surgery. In the control group, preoperative oxygen supply was provided via face mask or nasal tubes. RESULTS: The postoperative mechanical ventilation time (14.3+/-1.9 vs 22.5+/-2.2h, p=0.02), intensive care stay (2.3+/-1.2 vs 4.7+/-1.1d, p=0.03) and duration for positive inotropic drug administration (2.5+/-1.1 vs 4.8+/-1.2d, p=0.04) in the study group were shorter than those in the control group. The postoperative capillary leak syndrome in the study group was lower than that in the control group (4.3% vs 23.9%, p=0.006). There was no statistically significant difference in the postoperative mortality between the study and control groups (2.1% vs 6.5%, p=0.606). CONCLUSIONS: Preoperational mechanical ventilation in patients with severe forms of TOF was associated with improved short-term outcomes following the corrective surgery. The effect of the preoperational ventilation on postoperative mortality requires further investigation. PMID- 22841322 TI - Prostate cancer: send away the PSA? PMID- 22841323 TI - Undernutrition holds back progress on child development. PMID- 22841324 TI - New weight-loss drugs and the US obesity epidemic. PMID- 22841325 TI - Looking for a good night's sleep. PMID- 22841327 TI - Subclinical thyroid disorders. PMID- 22841328 TI - Subclinical thyroid disorders. PMID- 22841329 TI - Subclinical thyroid disorders. PMID- 22841332 TI - Suicidality and the economic crisis in Greece. PMID- 22841334 TI - Why a Youth Commission on Global Governance for Health? PMID- 22841333 TI - The interleukin 6 pathway and atherosclerosis. PMID- 22841335 TI - Physics and medicine in the life and work of Bozo Metzger. PMID- 22841336 TI - TDR: a time to live or die? PMID- 22841337 TI - Marketing versus evidence-based medicine. PMID- 22841338 TI - Query rectal bleeding. PMID- 22841340 TI - Educating leaders: insights from John D. Rockefeller. PMID- 22841339 TI - ABO blood group and risk of renal cell cancer. AB - BACKGROUND: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between ABO blood group and risk of various cancers. However, its relationship to RCC remains unclear and no prospective data are available. METHODS: We prospectively followed up 77,242 women in the Nurses' Health Study and 30,071 men in the Health Professionals Follow-Up Study from 1996 to 2008. The information on the ABO blood group was collected from participants' self-reports in 1996. Incidence of pathology-confirmed RCC was compared using hazard ratios (HRs) and 95% confidence intervals (CIs) derived from Cox proportional hazards models. RESULTS: During 12 years of follow-up, 163 cases of incident RCC were documented in women and 88 cases in men. The multivariate HRs between non-O blood group (combined group of A, AB, and B) vs. blood group O were 1.51 (95% CI 1.09-2.09) in women, 1.08 (95% CI 0.70-1.66) in men, and 1.32 (95% CI 0.95-1.82) in the pooled cohorts. The associations between ABO blood group and RCC were consistent across strata of known risk factors for RCC including age, obesity, smoking, and history of hypertension (Pinteraction >= 0.32). CONCLUSIONS: We found a suggestive non significant association between non-O blood group and increased risk of RCC in the pooled cohorts of men and women, and this association was significant in women. Our findings need to be replicated by other prospective studies. PMID- 22841341 TI - Small bowel imaging with MRI. AB - Magnetic resonance imaging (MRI) has evolved as a powerful tool for the assessment of the small bowel. Strengths of MRI include the superb soft-tissue contrast, lack of radiation exposure, and the implementation of fast scanning techniques. Clinically relevant findings such as inflammation and tumor disease can be well-depicted. We describe in this article current techniques of small bowel MRI including its implementation and clinical outcome in comparison to other radiological and endoscopic procedures. PMID- 22841342 TI - Spatiotemporal analysis of normal and pathological human vocal fold vibrations. AB - PURPOSE: For spatiotemporal analysis to become a relevant clinical tool, it must be applied to human vocal fold vibration. Receiver operating characteristic (ROC) analysis will help assess the ability of spatiotemporal parameters to detect pathological vibration. MATERIALS AND METHODS: Spatiotemporal parameters of correlation length and entropy were extracted from high-speed videos of 124 subjects, 67 without vocal fold pathology and 57 with either vocal fold polyps or nodules. Mann-Whitney rank sum tests were performed to compare normal vocal fold vibrations to pathological vibrations, and ROC analysis was used to assess the diagnostic value of spatiotemporal analysis. RESULTS: A statistically significant difference was found between the normal and pathological groups in both correlation length (P < .001) and entropy (P < .001). The ROC analysis showed an area under the curve of 0.85 for correlation length, 0.87 for entropy, and 0.92 when the 2 parameters were combined. A statistically significant difference was not found between the nodules and polyps groups in either correlation length (P = .227) or entropy (P = .943). The ROC analysis showed an area under the curve of 0.63 for correlation length and 0.51 for entropy. CONCLUSIONS: Although they could not effectively distinguish vibration of vocal folds with nodules from those with polyps, the spatiotemporal parameters correlation length and entropy exhibit the ability to differentiate normal and pathological vocal fold vibration and may represent a diagnostic tool for objectively detecting abnormal vibration in the future, especially in neurological voice disorders and vocal folds without a visible lesion. PMID- 22841344 TI - Self-mutilation induced by psychotropic substances: a systematic review. AB - Self-mutilation (SM) not only occurs among patients with schizophrenia, personality disorders or transsexuality but also as a phenomenon induced by psychotropic substances (PS). We intended to find characteristics of patients at risk to perform SM induced by PS (SMIPS), frequent PS within this phenomenon and typical presentations of SMIPS. A systematic review of the literature (including Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Scopus) was conducted. On October 2011 we identified 26 cases (23 publications) of SM related to PS. Majority of patients (85%) was male, mean age was 30 years (median 41 years). Seventy-three percent of patients developed SM subsequent to the use of one PS, 27% presented SM after the use of more than one PS. Alcohol (25%), hallucinogens (25%) and amphetamines (22%) were found most frequently among the reported substances. Major impairment was present in 80%. Our findings suggest male sex, young age, a previous history of abuse of PS and the current use of alcohol, hallucinogens or amphetamines to favour SMIPS. PMID- 22841343 TI - Sensitivity to monetary reward is most severely compromised in recently abstaining cocaine addicted individuals: a cross-sectional ERP study. AB - Recent studies suggest that drug-addicted individuals have a dampened cortical response to non-drug rewards. However, it remains unclear whether recency of drug use impacts this impairment. Therefore, in this event-related potential study, recency of cocaine use was objectively determined by measuring cocaine in urine on study day. Thirty-five individuals with current cocaine use disorder [CUD: 21 testing positive (CUD+) and 14 testing negative (CUD-) for cocaine in urine] and 23 healthy controls completed a sustained attention task with graded monetary incentives (0c, 1c and 45c). Unlike in controls, in both CUD subgroups P300 amplitude was not modulated by the varying amounts of money and the CUD- showed the most severe impairment as documented by the lowest P300 amplitudes and task accuracy. Moreover, while recency of drug use was associated with better accuracy and higher P300 amplitudes, chronic drug use was associated with lower sensitivity to money. These results extend our previous findings of decreased sustained sensitivity to monetary reward in CUD+ to recently abstaining individuals, where level of impairment was most severe. Taken together, these results support the self-medication hypothesis, where CUD may be self administering cocaine to avoid or compensate for underlying cognitive and emotional difficulties albeit with a long-term detrimental effect on sensitivity to non-drug reward. PMID- 22841345 TI - Validation of a clinician questionnaire to assess reasons for antipsychotic discontinuation and continuation among patients with schizophrenia. AB - The Reasons for Antipsychotic Discontinuation Questionnaire (RAD-Q) was designed to assess clinicians' perceptions of reasons for antipsychotic discontinuation or continuation. The current study examined psychometric properties of this instrument and patterns of antipsychotic discontinuation. The sample of 121 patients (81 discontinuation, 40 continuation) with schizophrenia or schizoaffective disorder was 66.9% male, with a mean age of 41.6 years. Treating clinicians reported a mean of 4.1 reasons for discontinuation and 7.5 reasons for continuation. RAD-Q domain scores were derived to quantify the impact of three factors on the decision to discontinue or continue: treatment benefits, adverse events, and distal reasons other than direct effects of the medication. Analysis of inter-rater reliability indicated an acceptable degree of agreement between clinicians (weighted Kappa for discontinuation scores=0.70-0.78). Correlations with symptom measures (Clinical Global Impression-Schizophrenia Scale (CGI-SCH), Positive and Negative Syndrome Scale (PANSS)) supported convergent validity of the benefits domain score (r=0.28-0.47; all p<0.05). Domain scores discriminated among groups of patients differing in clinician and patient-reported clinical variables. Results suggest that the RAD-Q is a useful detailed measure of reasons for antipsychotic discontinuation and continuation. Findings indicate that clinicians usually report multiple reasons for discontinuation, rather than a single reason for each patient. PMID- 22841346 TI - The relation of objective sleep patterns, depressive symptoms, and sleep disturbances in adolescent children and their parents: a sleep-EEG study with 47 families. AB - OBJECTIVES: Numerous studies have shown that the sleep and well-being of children and their parents are closely related. Previous studies have relied on subjective sleep data and have focused mostly on younger preadolescent children. The aim of the present study was therefore to investigate the relationship between the sleep patterns of adolescents and those of their parents using objective assessment of sleep. METHODS: Forty-seven families took part in this study. The sample comprised 80 adolescents (age: 16.3 +/- 2.0 years; 44 males/36 females), 47 mothers (age: 49.5 +/- 4.0 years), and 39 fathers (age: 50.8 +/- 5.1 years). All participants individually completed questionnaires related to psychological functioning and sleep. Sleep-EEGs were assessed for all family members in their homes. RESULTS: Adolescents' and parents' objective sleep patterns were associated. In particular, the sleep continuity and architecture of adolescents and their mothers were strongly related. Additionally, significant relationships between objectively assessed sleep patterns, subjective sleep disturbances, depression scores and family climate held true for equally adolescents and mothers. Also, substantial links were found between adolescents' and parents' subjective sleep disturbances, depressive symptoms, and perceived family climate. CONCLUSION: The present findings document objectively for the first time the existence of relationships between adolescents' sleep and well-being and parents' sleep and well-being. These relationships were apparent regardless of whether subjective or objective sleep data were considered. The overall pattern of results strongly indicates that adolescents' sleep and well-being and family functioning are related. PMID- 22841347 TI - The role of induced pluripotent stem cells in research and therapy of primary immunodeficiencies. AB - The advent of reprogramming technology has greatly advanced the field of stem cell biology and nurtured our hope to create patient specific renewable stem cell sources. While the number of reports of disease specific induced pluripotent stem cells is continuously rising, the field becomes increasingly more aware that induced pluripotent stem cells are not as similar to embryonic stem cells as initially assumed. Our state of the art understanding of human induced pluripotent stem cells, their capacity, their limitations and their promise as it pertains to the study and treatment of primary immunodeficiencies, is the content of this review. PMID- 22841348 TI - Host defenses against bacterial lower respiratory tract infection. AB - Bacterial pneumonia continues to be a significant cause of morbidity and mortality worldwide. Recent studies have shown that lung epithelia signal through pattern recognition receptors to initiate the innate immune response. Other mediators of innate immunity against bacterial pneumonia include transepithelial dendritic cells, alveolar macrophages, and innate produces of IL-17. CD4+ T cells and B cells play a key role in eliminating and preventing the development of bacterial pneumonias. B cell development and maturation can be modulated by the lung epithelia through BAFF and APRIL, furthering our current understanding of the role of epithelial cells in the immune response. PMID- 22841349 TI - A functional framework for interpretation of genetic associations in T1D. AB - Susceptibility to type 1 diabetes is attributable to genes that link disease progression to distinct steps in immune activation, expansion, and regulation. Recent studies illustrate examples of disease-associated variants that function in multiple cell types and independent pathways, some that impact different steps of a single mechanistic pathway, and some that are functionally interactive for deterministic events in setting thresholds for immune response. PMID- 22841350 TI - Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: a fMRI study. AB - Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in "ON" dopaminergic treatment state (DTS) and in "OFF" DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the "motor" theory of verb processing. PMID- 22841351 TI - Time to withdraw AEDs after successful epilepsy surgery. PMID- 22841353 TI - [Axillary nerve block under ultrasonography: review of evidence]. PMID- 22841352 TI - Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study. AB - BACKGROUND: Postoperative antiepileptic drug (AED) withdrawal practices remain debatable and little is known about the optimum timing. We hypothesised that early AED withdrawal does not affect long-term seizure outcome but allows identification of incomplete surgical success earlier than late withdrawal. We aimed to assess the relation between timing of AED withdrawal and subsequent seizure recurrence and long-term seizure outcome. METHODS: TimeToStop included patients aged under 18 years from 15 centres in Europe who underwent surgery between Jan 1, 2000, and Oct 1, 2008, had at least 1 year of postoperative follow up, and who started AED reduction after having reached postoperative seizure freedom. Time intervals from surgery to start of AED reduction (TTR) and complete discontinuation (TTD) were studied in relation to seizure recurrence during or after AED withdrawal, seizure freedom for at least 1 year, and cure (defined as being seizure free and off AEDs for at least 1 year) at latest follow-up. Cox proportional hazards regression models were adjusted for identified predictors of timing intervals. FINDINGS: TimeToStop included 766 children. Median TTR and TTD were 12.5 months (95% CI 11.9-13.2) and 28.8 months (27.4-30.2), respectively. 95 children had seizure recurrence during or after AED withdrawal. Shorter time intervals predicted seizure recurrence (hazard ratio [HR] 0.94, 95% CI 0.89-1.00, p=0.05 for TTR; and 0.90, 0.83-0.98, p=0.02 for TTD). After a mean postoperative follow-up of 61.6 months (SD 29.7), 728 patients were seizure free for at least 1 year. TTR and TTD were not related to regain of seizure freedom after restart of drug treatment (HR 0.98, 95% CI 0.92-1.05, p=0.62; and 0.93, 0.83-1.05, p=0.26, respectively), or to seizure freedom (0.97, 0.89-1.07, p=0.55; and 1.03, 0.93 1.14, p=0.55, respectively) or cure (0.97, 0.97-1.03, p=0.84; and 0.98, 0.94 1.02, p=0.31, respectively) at final follow-up. INTERPRETATION: Early AED withdrawal does not affect long-term seizure outcome or cure. It might unmask incomplete surgical success sooner, identifying children who need continuous drug treatment and preventing unnecessary continuation of AEDs in others. A prospective randomised trial is needed to study the possible cognitive effects and confirm the safety of early AED withdrawal after epilepsy surgery in children. FUNDING: Dutch National Epilepsy Fund. PMID- 22841354 TI - [Ultrasound guidance: Teaching]. PMID- 22841356 TI - [Can we perform an ultrasound-guided regional anesthesia in an anaesthetized patient?]. PMID- 22841355 TI - [Pulmonary embolism and intracranial hemorrhage: is there still an indication for a caval filter placement?]. AB - The treatment of pulmonary embolism is mainly based on anticoagulants and intravenous thrombolysis in case of collapse. The cerebral hemorrhage is the main complication of thrombolysis and contraindicates anticoagulation. We report the case of a patient with a subdural and intraparenchymal hematoma complicating intravenous thrombolysis. The patient had persistent respiratory and hemodynamic instability related to the pursuit of embolic phenomena. The implementation of a cava filter was performed and the patient had a favorable outcome. PMID- 22841357 TI - Decreasing the delay to carotid endarterectomy in symptomatic patients with carotid stenosis--outcome of an intervention. AB - OBJECTIVES: Surgical treatment of carotid stenosis after the onset of ischaemic symptoms should be performed within 2 weeks. This aim was accomplished only in 11% during the years 2007-2008 in the Helsinki University Central Hospital (HUCH) region. Since then, special efforts have been made in order to shorten the delay. The aim of this study was to find out how these changes affected the symptom-to knife time (SKT). MATERIALS AND METHODS: All symptomatic patients (n = 144) who had carotid endarterectomy (CEA, n = 145) in HUCH in 2010 were retrospectively analysed and the SKT was determined. RESULTS: Of the operations, 37% (n = 53) were performed within the recommended 2 weeks. The median SKT was 19 days (1 183). Of the patients who came to HUCH on an emergency basis (n = 80), 55% (n = 45) were operated within 2 weeks and their median SKT was 13 days (1-148). CONCLUSIONS: The changes that were made in 2008-2009 have significantly shortened the delay in the treatment of carotid stenosis, but the desired time frame of 2 weeks was reached far too seldom. The greatest benefit from preventive CEA is achieved when patients are referred emergently to a clinic where neurologist, imaging resources and vascular surgeon are available. PMID- 22841358 TI - Skeletal muscle adaptation in response to supervised exercise training for intermittent claudication. AB - OBJECTIVES: There is evidence that the improvement following supervised exercise for claudication results from skeletal muscle adaptation. The myosin heavy chain (MHC) determines muscle fibre type and therefore efficiency. Immunohistochemical analysis has failed to take account of hybrid MHC expression within myofibres. This study sought evidence of differential MHC protein expression following supervised exercise for claudication. DESIGN: 38 claudicants were recruited. Subjects undertook a three-month supervised exercise programme. Controls were patients awaiting angioplasty for claudication. MATERIALS AND METHODS: Subjects underwent paired gastrocnemius biopsy. Relative expression of MHC proteins was determined by SDS-PAGE electrophoresis. Non-parametric data is presented as median with the inter-quartile range and parametric as the mean +/- standard deviation. RESULTS: Upon completion of the exercise programme there was a 94% increase (124 (106-145) to 241 (193-265) metres, p = 0.002) in maximum walking distance, which was not evident in the control group. An 11.1% (p = 0.02) increase in MHC I expression was observed in the exercise but not the control group (34.3% +/- 6.8 to 45.4% +/- 4.4). There was a positive correlation between the change in MHC I expression and the improvement in claudication distance (r = 0.69, p < 0.05). CONCLUSIONS: Supervised exercise training for claudication results in an increase in the proportion of MHC type I expression within the symptomatic gastrocnemius muscle. PMID- 22841359 TI - To use or not to use heparin during abdominal aortic aneurysm repair? PMID- 22841360 TI - Vitamin D deficiency may be an independent risk factor for arterial disease. AB - OBJECTIVES: The aim of this study was to assess the vitamin D status in patients with occlusive or aneurysmatic arterial disease in relation to clinical cardiovascular risk profiles and markers of atherosclerotic disease. METHODS: We included 490 patients with symptomatic peripheral arterial disease (PAD, n = 254) or aortic aneurysm (n = 236). Cardiovascular risk factors and comorbidities carotid intima-media thickness (CIMT), ankle-brachial index (ABI), serum high sensitive C-reactive protein (hs-CRP) and vitamin D were assessed. Patients were categorised into severely (<=25 nmol l(-1)) or moderately (26-50 nmol l(-1)) vitamin D deficient, vitamin D insufficient (51-75 nmol l(-1)) or vitamin D sufficient (>75 nmol l(-1)). RESULTS: Overall, 45% of patients suffered from moderate or severe vitamin D deficiency. The prevalence of vitamin D deficiency was similar in patients with PAD and those with an aortic aneurysm. Low levels of vitamin D were associated with congestive heart failure and cerebrovascular disease. Adjusting for clinical cardiovascular risk factors, multivariable regression analyses showed that low vitamin D status was associated with higher CIMT (P = 0.001), lower ABI (P < 0.001) and higher hs-CRP (P = 0.022). CONCLUSIONS: The current study shows a strong association between low vitamin D status and arterial disease, independent of traditional cardiovascular risk factors and irrespective of the type of vascular disease, that is, occlusive or aneurysmatic disease. PMID- 22841361 TI - CHIVA effectiveness score: the correct one is below. PMID- 22841362 TI - Using standardized patient with immediate feedback and group discussion to teach interpersonal and communication skills to advanced practice nursing students. AB - BACKGROUND: Interpersonal and communication skills (IPCS) are essential for advanced practice nursing (APN) in our increasingly complex healthcare system. The Standardized Patient (SP) is a promising innovative pedagogy in medical and healthcare education; however, its effectiveness for teaching IPCS to graduate nursing students remains unclear. OBJECTIVES: We examined the effectiveness of using SP with SP feedback and group discussion to teach IPCS in graduate nursing education. DESIGN: Randomized-controlled study. PARTICIPANTS: First-year APN students in Taiwan. METHODS: Participants were randomly assigned to the experimental (SP assessments with SP feedback and group discussion) or control (SP assessments only) group. There were two outcome indicators: IPCS and student learning satisfaction (SLS). The IPCS were assessed before and after the study in interviews with the SPs. SLS was measured when the study ended. RESULTS: All participants expressed high SLS (94.44%) and showed significant (p <= 0.025) improvements on IPCS total scores, interviewing, and counseling. However, there were no significant differences between groups. Qualitative feedback from encounters with SPs is described. CONCLUSIONS: Using SPs to teach IPCS to APN students produced a high SLS. The students learned and significantly improved their IPCS by interviewing SPs, but future studies are needed to confirm the effectiveness of SP feedback and group discussions. PMID- 22841363 TI - A computer simulation model for Doppler ultrasound signals from pulsatile blood flow in stenosed vessels. AB - A computer simulation model based on an analytic flow velocity distribution is proposed to generate Doppler ultrasound signals from pulsatile blood flow in the vessels with various stenosis degrees. The model takes into account the velocity field from pulsatile blood flow in the stenosed vessels, sample volume shape and acoustic factors that affect the Doppler signals. By analytically solving the Navier-Stokes equations, the velocity distributions of pulsatile blood flow in the vessels with various stenosis degrees are firstly calculated according to the velocity at the axis of the circular tube. Secondly, power spectral density (PSD) of the Doppler signals is estimated by summing the contribution of all scatterers passing through the sample volume grouped into elemental volumes. Finally, Doppler signals are generated using cosine-superposed components that are modulated by the PSD functions that vary over the cardiac cycle. The results show that the model generates Doppler blood flow signals with characteristics similar to those found in practice. It could be concluded that the proposed approach offers the advantages of computational simplicity and practicality for simulating Doppler ultrasound signals from pulsatile blood flow in stenosed vessels. PMID- 22841364 TI - Analysis of adductors angle measurement in Hammersmith infant neurological examinations using mean shift segmentation and feature point based object tracking. AB - This paper presents image and video analysis based schemes to automate the process of adductors angle measurement which is carried out on infants as a part of Hammersmith Infant Neurological Examination (HINE). Image segmentation, thinning and feature point based object tracking are used for automating the analysis. Segmentation outputs are processed with a novel region merging algorithm. It is found that the refined segmentation outputs can successfully be used to extract features in the context of the application under consideration. Next, a heuristic based filtering algorithm is applied on the thinned structures for locating necessary points to measure adductors angle. A semi-automatic scheme based on the object tracking of a video has been proposed to minimize errors of the image based analysis. It is observed that the video-based analysis outperforms the image-based method. A fully automatic method has also been proposed and compared with the semi-automatic algorithm. The proposed methods have been tested with several videos recorded from hospitals and the results have been found to be satisfactory in the present context. PMID- 22841365 TI - Simulating a dual-array electrode configuration to investigate the influence of skeletal muscle fatigue following functional electrical stimulation. AB - A novel, anatomically-accurate model of a tibialis anterior muscle is used to investigate the electro-physiological properties of denervated muscles following functional electrical stimulation. The model includes a state-of-the-art description of cell electro-physiology. The main objective of this work is to develop a computational framework capable of predicting the effects of different stimulation trains and electrode configurations on the excitability and fatigue of skeletal muscle tissue. Utilizing a reduced but computationally amenable model, the effects of different electrode sizes and inter-electrode distances on the number of activated muscle fibers are investigated and qualitatively compared to existing literature. To analyze muscle fatigue, the sodium current, specifically the K+ ion concentrations within the t-tubule and the calcium release from the sarcoplasmic reticulum, is used to quantify membrane and metabolic fatigue. The simulations demonstrate that lower stimulation frequencies and biphasic pulse waveforms cause less fatigue than higher stimulation frequencies and monophasic pulses. A comparison between single and dual electrode configurations (with the same overall stimulation surface) is presented to locally investigate the differences in muscle fatigue. The dual electrode configuration causes the muscle tissue to fatigue quicker. PMID- 22841367 TI - Governance and the functions of boards: an empirical study of hospital boards in Norway. AB - OBJECTIVE: This paper describes the implementation of hospital governance under the Norwegian hospital reforms 2001-2008. METHODS: Data are analysed from interviews with key decision makers in hospital boards and among hospital managers (N=13), and a survey among a national sample of board members (N=130). The analysis integrates findings from both the qualitative and quantitative data, which are analysed according to the theoretical framework. RESULTS: The findings indicate a transition of the roles given to the hospital board from a model with professional and autonomous boards towards two different roles. These roles are a mixture between the tasks of a formal decision body and the behaviour of a body to secure the interests of different stakeholders. CONCLUSIONS: The hospital boards have to act in contexts of ambiguity and uncertainty. In such situations, a wide decision space will face the boards with problems related to emotions and opportunism. Thus, the principals in the context of public sector hospitals have to balance among strong political influence, hierarchical modes of governance and discretion given to the boards. PMID- 22841366 TI - Efficient DNA cleavage mediated by mononuclear mixed ligand copper(II) phenolate complexes: the role of co-ligand planarity on DNA binding and cleavage and anticancer activity. AB - The new mononuclear copper(II) complexes [Cu(L)(H(2)O)(2)](+)1 and [Cu(L)(diimine)](+)2-6, where LH=2-[(2-dimethylaminoethylimino)methyl]phenol and diimine=2,2'-bipyridine (bpy) (2), or 1,10-phenanthroline (phen) (3), or dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) (4) or dipyrido[3,2-a:2',3'-c]phenazine (dppz) (5) or 11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine (dmdppz) (6), have been isolated and characterized. The X-ray crystal structures of 2 contains the monomeric complex molecule with a trigonal bipyramidal distorted square pyramidal (TBPDSP) coordination geometry, while 4 and 6 with square pyramidal distorted trigonal bipyramidal (SPDTBP) coordination geometry. The amine nitrogen of NMe(2) group of the tridentate primary ligand is located at one of the corners of the square plane in 2 and 6 but in the axial position in 4. The interaction of the complexes with calf thymus DNA has been investigated using UV-visible and fluorescence spectroscopy, and viscosity measurements to understand the effect of diimine co-ligands on the mode and extent of DNA binding. The complexes 4 and 5 interact with calf thymus DNA more strongly than the other complexes through partial intercalation of the extended planar ring of the dpq (4) and dppz (5) co ligands with the DNA base stack. All the complexes, except 1, effect the double strand DNA cleavage of plasmid DNA and 5 cleaves plasmid DNA in the absence of a reductant at a concentration (40 MUM) lower than 4. It is remarkable that all the complexes display cytotoxicity against human breast cancer cell lines (MCF-7) and human cervical epidermoid carcinoma cell lines (ME 180) with potency higher than the currently used chemotherapeutic agent cisplatin and that 5 exhibits cytotoxicity higher than the other complexes. PMID- 22841368 TI - Nurses' various ways of conceiving their learning process as doctoral students: a phenomenographic study. AB - AIM: The aim was to describe variations in how doctoral students conceive their learning process to become researchers in the light of their professional background as nurses. BACKGROUND: Nursing research is an emerging discipline and the number of nurses who acquire a doctor's degree is increasing. METHOD: The study had a descriptive, qualitative design with a phenomenographic approach and was carried out by means of 20 interviews. RESULTS: Three different description categories emerged: (1) A learning process that provides a synthesis of different parts of the research process aimed at developing preparedness for action within the nursing profession. (2) A learning process where practical problems are integrated with and problematised in relation to scientific theories. (3) A learning process involving the transformation from nurse to researcher. CONCLUSIONS: The description categories revealed that the focus was on solving problems that occur in health care and synthesising them by means of research tools. Furthermore, the doctoral students explored different ways of understanding and developing their awareness of the nature of research. Focus was also on the nursing profession and practice and a shift towards the role of a researcher was evident. PMID- 22841369 TI - Layers of complexity: diverse molecular mechanisms transforming germ layers into organisms. PMID- 22841370 TI - Biglycan: a promising new therapeutic for neuromuscular and musculoskeletal diseases. PMID- 22841371 TI - Association of the presence of bone bars on radiographs and hip fracture in postmenopausal Caucasian women. AB - AIM: To determine whether the presence of bone bars (BB) identified on anteroposterior hip radiographs are more prevalent in patients that have had a hip fracture as compared to patients without a fracture. MATERIALS AND METHODS: Ninety-two Caucasian women with a unilateral proximal femur fracture were retrospectively evaluated and randomly selected using radiology database records to comprise the investigational group. Ninety-eight age-matched Caucasian women without hip fracture were selected as a control group. Anteroposterior hip radiographs were evaluated for the presence of BBs by two musculoskeletal radiologists. Chi-square tests were used to assess whether fractures were more prevalent in patients with BB than those without BB. RESULTS: The patient population was comprised Caucasian women with a mean age of 79.8 +/- 6.4 years in the control group and 79.9 +/- 6.6 years in the investigational group. Regardless of the reader, BB were identified in a significantly higher percentage of women with a fracture (75 versus 39%, p < 0.001 or 53 versus 38%, p = 0.041) as compared to those without a fracture. CONCLUSION: BB are associated with hip fracture. Their presence is a trigger for requesting a dual-energy x-ray absorptiometry (DXA) examination to confirm or refute a diagnosis of low bone mineral density (BMD) and a subsequent increased risk of fracture. PMID- 22841373 TI - 17alpha-hydroxlyase/17, 20-lyase deficiency in three siblings with primary amenorrhea and absence of secondary sexual development. AB - BACKGROUND: 17alpha-hydroxlyase/17, 20-lyase deficiency (17OHD) is a rare phenotype of congenital adrenal hyperplasia that can cause primary amenorrhea. CASE: Three phenotypically female siblings visited the adolescent gynecologic clinic complaining of primary amenorrhea and absence of secondary sexual developments. All had constant high blood pressure and showed a hypergonadotropic hypogonadal state with high progesterone and low testosterone levels. Two were genotypically females and one was genotypically a male; all were confirmed to have 17OHD, and estrogen replacement, glucocorticoids, and antihypertensive drugs were Prescribed to the patients. SUMMARY AND CONCLUSION: Identifying a 17OHD patient complaining of primary amenorrhea in a gynecologic clinic is important for proper management. PMID- 22841374 TI - Herlyn-Werner-Wunderlich syndrome--timely diagnosis is important to preserve fertility. AB - BACKGROUND: Herlyn-Werner-Wunderlich syndrome is an urogenital malformation with uterus didelphys and obstructed hemivagina with ipsilateral renal agenesis. Most of these patients present after the onset of menstruation. We describe two cases diagnosed too late to prevent the complications. CASE: The first patient presented with acute abdomen one year after the onset of menstruation and had salpingectomy due to pyosalpinx. The blind hemivagina was not recognized and she had severe endometriosis. She underwent hysterectomy 8 years later. The second patient presented with foul smelling vaginal discharge when she was 21 years old. She had a simple vaginal septum resection. SUMMARY AND CONCLUSION: In the presence of uterine cavities in a regularly menstruating girl with dysmenorrhea, the presence of both kidneys should be checked. When unilateral renal agenesis and uterus didelphys coexist the first thing that we should remember is to confirm or refute the presence of a blind vagina. PMID- 22841372 TI - Puberty in girls of the 21st century. AB - Several studies have noted contemporary girls are undergoing pubertal maturation at younger ages. During this same time period many Western nations have experienced an obesity epidemic, prompting investigators and public health officials to consider the association of these 2 events, and if other exposures might impact this relationship. There are several potential mechanisms that could impact the relationship of pubertal timing in girls with greater body mass, including direct effects of obesity on pubertal timing as well underlying exposures that impact body mass as well as timing of pubertal maturation. These underlying conditions include chemical compounds that could impact synthesis or action of sex hormones, called endocrine disrupting chemicals (EDs). We examine the decline in the age of breast development and potential genetic and environmental influences, the obesity epidemic in the US and other nations, and potential mechanisms to explain the relationship between greater body mass index with earlier puberty in girls. PMID- 22841375 TI - Precocious puberty in Turner syndrome variant. AB - BACKGROUND: Turner syndrome is due to the absence of all or significant parts of one of the sex chromosomes in females. Turner syndrome is a common cause of ovarian failure, and hypergonadotropic hypogonadism occurs in virtually all affected individuals. One case of a variant Turner syndrome with precocious puberty is presented. CASE: An eight-year-old girl was referred with complaints of short stature and breast budding. A physical examination revealed a Tanner stage III for breast development and her bone age was 11 years. Chromosome analysis showed a karyotype of 46,X,del(x)(p11.2). SUMMARY AND CONCLUSION: To preserve growth potential, careful examinations are recommended for pediatric patients with an unusual growth pattern. PMID- 22841376 TI - [Retractions due to errors and frauds]. AB - Scientific papers disseminate information but they cannot reflect the reality as they sometimes contain errors or fraud. Retractions and errata are the means allowing to correct the literature. The annual retraction rate increased 10 times between 1999 and 2009. Meanwhile, retractions are rare events, concerning 0.02% of the publications. To limit the errors and frauds, we should focus on quality instead of quantity of the literature; we should implement systems able to detect misconduct, and measures of prevention. PMID- 22841377 TI - B-cell populations and sub-populations in Sjogren's syndrome. AB - Sjogren's Syndrome (SS) is a chronic inflammatory disorder affecting exocrine glands, in particular the lacrimal and salivary glands. The disease can be primary (pSS) or secondary to other systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and others. The systemic autoimmune character of pSS is also apparent from the occurrence of (non-organ specific) autoantibodies in this disease. Histopathologically, glandular involvement is characterized by focal accumulation of lymphocytes, particularly around epithelial ducts, with, sometimes, germinal center-like structures. The infiltrates largely consist of T-cells, with a preponderance of CD4-positive T cells. As a result, the pathology in SS was primarily attributed to T cells. However, a break with the fixation on the role of T cells in pSS came when therapeutic B-cell depletion strategies proved remarkably efficacious in this disease, thereby indicating a major role for B-cells in the immunopathogenesis of pSS. In this regard, a closer look at the composition of B-cells and B-cell sub populations, both in the peripheral blood and in target tissues, is worthwhile. In this review, we discuss current data on B-cells in pSS. B-cell depletion offers a unique possibility to study the recurrence of (pathogenic) B-cells and their characteristics in pSS patients treated with rituximab. Data on B-cell sub populations in the peripheral blood and B-cell repertoire in the target tissues following rituximab treatment are discussed as well. We also address their state of activation, repertoire, and relation to B-cell activating factor (BAFF). PMID- 22841378 TI - [Beautification of data: Minimal fraud, incompetence or mixture of both]. AB - The beautification of data is the process of reporting results of a research in a way that does not correspond to reality, in order to present them in a more favorable or attractive way. The border between errors due to methodological ignorance, embellishment of reality and fraud is sometimes difficult to determine. It is the intentional nature and the repetition of these "arrangements" that are the real switch to deliberate fraud. The emergence of regulatory procedures, such as clinical trial registries, "reporting guidelines", improvement of "peer review" and data sharing, are some of the measures used to fight against and improve transparency of clinical research. PMID- 22841379 TI - [Letter on the article: "Stroke in children: a medical emergency"]. PMID- 22841381 TI - Diagnosis of periprosthetic joint infection after unicompartmental knee arthroplasty. AB - The purpose of this multicenter study is to determine the utility of the erythrocyte sedimentation rate, C-reactive protein, and synovial fluid white blood cell (WBC) count and differential for evaluating periprosthetic joint infection (PJI) in patients with a failed unicompartmental knee arthroplasty (UKA). A total of 259 patients undergoing revision of a failed UKA were reviewed; 28 (10.8%) met the study criteria for PJI. The optimal cutoff values were 27 mm/h for the erythrocyte sedimentation rate, 14 mg/L for the C-reactive protein, 6200/MUL for the synovial fluid WBC count, and 60% for the differential. These tests are useful for diagnosing PJI after UKA with optimal cutoff values that are similar to those used for total knee arthroplasty; however, the optimal synovial WBC count was found to be somewhat higher, which may be related to the unresurfaced compartments. In addition, we found that nearly half of patients had suboptimal evaluation for PJI. PMID- 22841382 TI - Hand-assisted laparoscopy leads to efficient colorectal cancer surgery. AB - BACKGROUND: Laparoscopic-assisted (LA) colorectal resections have improved short term outcomes compared with open resections. Lack of tactile feedback, though, has led to lengthy operations and high conversion rates with attendant adverse effects on patients. Hand-assisted laparoscopy (HAL), in contrast, provides tactile feedback while still being minimally invasive. We hypothesize that HAL compared with LA for colorectal cancer resections will be associated with lower conversion rates and decreased operative times, without compromising the advantages of laparoscopy. MATERIALS AND METHODS: We performed a retrospective case-matched study of patients undergoing LA or HAL colorectal cancer resections from 2002 to 2010, using a prospectively maintained colorectal cancer database at a Veterans Affairs Medical Center. Short-term outcomes analyzed (using the Wilcoxon signed rank and McNemar's tests) included operative and perioperative variables and surrogate markers of adequacy of oncologic care. RESULTS: Forty seven LA patients were matched 1:1 by age and resection with 47 HAL patients. Patients in the HAL group had significantly lower blood loss (100 versus 150 cc, P = 0.04), operative times (206 versus 252 min, P = 0.002), and conversion rates (6% versus 38%, P < 0.0005). They also spent fewer days in the intensive care unit (0 versus 1, P = 0.004) and had quicker return of flatus (3 versus 4 d, P = 0.03). HAL resulted in more lymph nodes resected (21 versus 15, P = 0.03) and a more adequate lymph node harvest (98% versus 77%, P = 0.01). CONCLUSIONS: HAL is associated with improved operative efficiency, conversion rates, and lymphadenectomy as compared with LA colorectal cancer resections. HAL should be considered in the management of colorectal cancer patients. PMID- 22841383 TI - Influence of patient age and experience of the surgeon on early complications after surgical closure of the cleft palate--a retrospective cohort study. AB - Comparative studies on timing of palatoplasty are rare. The aim of this retrospective cohort study was to compare the influence of early (<14 months) and later (>14 months) one-step closure of the soft and hard palate on early complications. All non-syndromic patients from 1999 to 2009 were included; 6-14 months n = 41 and 15-24 months n = 53. Each palatoplasty was performed as a single-step procedure using bipedicled flaps by a team of two Maxillofacial Surgeons either supervising or operating. The surgeon was rated as "non experienced" when having performed less than 10 palatoplasties under supervision. Main outcome variable is the occurrence of residual fistula. Fistula occurred in four (4.5%) of the patients. In the multivariate model with respect to the occurrence of fistula neither age, leucocyte count, duration of surgery, nor experience of the surgeon showed a significant influence on the occurrence of a fistula. Only reduced weight contributed to a significantly higher risk of post operative fistula. In conclusion patient age, experience of surgeon, and duration of surgery had no influence on the early outcome. High leucocyte count had a tendency for and reduced weight had a significant influence on fistula occurrence. Long-term outcome on speech development and maxillary growth have to be collected. PMID- 22841384 TI - Global electromagnetic toxicity and frequency-induced diseases: Theory and short overview. AB - The development and implementation of electricity in the modern society have facilitated the survival of mankind in the present, modern ages. However, the health consequences of introducing electricity into the society are poorly studied. Studies of artificial light and non-ionizing radiation are generally low priorities on the agenda of public health organizations, and the reported existing data indicate that there are several unanswered questions to whether humans are negatively affected in electrified environments. This article discusses the potential aspects of the impact of electricity on human health and brain function and introduces a hypothesis. The article furthermore discusses the disturbance of sleep patterns caused by electrified environments, and the increasing absence of natural stimuli to the human brain causing chronic 'digital stress' facilitating pathophysiological development. A significant need to study adverse health effects from non-ionizing radiation and synthetic luminous environments from an environmental toxicological perspective is definitely urged. PMID- 22841385 TI - The response of monocyte derived dendritic cells following exposure to a nematode larval carbohydrate antigen. AB - The glycolipid CarLA (carbohydrate larval antigen) is present on the epicuticle of the infective-stage larvae of gastrointestinal nematode parasites infecting livestock. The molecule is lost from the surface of the larvae in the few days post-ingestion by a host animal, and the resulting anti-CarLA antibody response has been demonstrated to be protective in vivo. Both the anti-CarLA response, and anti-parasite immunity in general, are slow to develop, and several months of natural exposure to ingested larvae is required. The current study was designed to provide information on how the anti-CarLA response develops, and focuses on the initial recognition of the molecule by human monocyte derived dendritic cells (mdDC) in vitro. Immunofluorescence and flow cytometry demonstrated that mdDC recognise and internalise both the purified and the native form of CarLA, in the case of the latter once it is shed from the larval surface. However, the recognition of CarLA did not result in classical maturation of DC, while there was only transient or minor up-regulation of CD86, CD83, HLA-DR and CD40. Exposure of mdDC to purified CarLA resulted in the increased production of the pro-inflammatory cytokines IL-6 and to a lesser extent of IL-8 and TNF-alpha, and a reduced production of the anti-inflammatory cytokine IL-1RA. CarLA therefore has little ability to mature and functionally alter monocyte derived dendritic cell function. PMID- 22841386 TI - Should CITES permit regulations be eased for certain kinds of scientific research? PMID- 22841387 TI - Overview of the 20th century impact of trace metal contamination in the estuaries of Todos os Santos Bay: past, present and future scenarios. AB - This paper discusses the distribution patterns of trace metals in sediments and suspended particulate matter (SPM) in the three main estuaries of the Todos os Santos Bay (BTS), Brazil, during dry and rainy seasons. Data available up to 2012 was also reviewed to assess the status of contamination. For most elements, metal concentrations in sediments decreased from the tidal limits to the lower estuary. Metals in SPM presented more complex distributions along the salinity gradient. Metal variability between rainy and dry conditions was only significant for SPM data. Of the BTS estuaries, the levels of Cd, Zn, Pb and Cu are highest in the Subae estuary, and they seem to be promoting harmful biological effects in macrofauna, and also may pose potential human health risks. Despite the evidence of important localized contamination, much of the data compiled indicates that the bay and its estuaries are still relatively preserved. PMID- 22841388 TI - Prevalence of mitral valve prolapse in residents living at moderately high altitude. AB - OBJECTIVE: Prolapse of mitral valve leaflets is a frequent disorder and the most common cause of severe mitral regurgitation in western countries. However, little is known about the effects of altitude on mitral valve prolapse. We studied the prevalence and echocardiographic characteristics of mitral valve prolapse at moderately high altitude and sea level. METHODS: A total of 936 consecutive subjects who were admitted to 2 study institutions at Kars, Turkey (1750 m) and Istanbul, Turkey (7 m) were enrolled in this study to determine prevalence of mitral valve prolapse. Demographic and 2-dimensional echocardiographic characteristics of participants were recorded. RESULTS: Prevalence of mitral valve prolapse was found to be significantly higher in people living at moderate altitude compared with those living at sea level (6.2% vs 2.0%; P = .007). Overall echocardiographic features regarding valve thickness (4.1 +/- 0.80 mm vs 3.6 +/- 0.66 mm; P = 0.169), maximal valve prolapse (4.6 +/- 2.08 mm vs 3.9 +/- 0.91 mm; P = .093), and frequency of mitral regurgitation (89% vs 73%; P = .65) were similar between groups, although anterior valve prolapse was seen more frequently at moderate altitude (50% vs 11%; P = .056) and posterior leaflet prolapse was significantly more frequent at sea level (66% vs 10%; P = .002). CONCLUSIONS: Mitral valve prolapse is more frequently observed at moderately high altitudes. Further studies are needed to determine clinical importance of our findings. PMID- 22841389 TI - Executive functions in mild cognitive impairment: emergence and breakdown of neural plasticity. AB - INTRODUCTION: Our goal was to test the effect of disease severity on the brain activation associated with two executive processes: manipulation and divided attention. METHOD: This was achieved by administrating a manipulation task and a divided attention task using functional magnetic resonance imaging to 24 individuals with mild cognitive impairment (MCI) and 14 healthy controls matched for age, sex and education. The Mattis Dementia Rating Scale was used to divide persons with MCI into those with better and worse cognitive performances. RESULTS: Both tasks were associated with more brain activation in the MCI group with higher cognition than in healthy controls, particularly in the left frontal areas. Correlational analyses indicated that greater activation in a frontostriatal network hyperactivated by the higher-cognition group was related with better task performance, suggesting that these activations may support functional reorganization of a compensatory nature. By contrast, the lower cognition group failed to show greater cerebral hyperactivation than controls during the divided attention task and, during the manipulation task, and showed less brain activation than controls in the left ventrolateral cortex, a region commonly hypoactivated in patients with Alzheimer's disease. CONCLUSION: These findings indicate that, during the early phase of MCI, executive functioning benefits from neural reorganization, but that a breakdown of this brain plasticity characterizes the late stages of MCI. PMID- 22841390 TI - [Impact of enterobacteriaceae-producing extended-spectrum beta-lactamases (ESBLE) incidence increasing on barrier precautions implementation in a university hospital]. AB - AIM OF THE STUDY: The French national surveillance program of multidrug-resistant bacteria (MDR) shows an increase of enterobacteriaceae-producing extended spectrum beta-lactamases (ESBLE) incidence. The objectives of this study were to assess: the incidence of EBLSE in a large French university hospital between 2005 and 2010, and the difference of barrier precautions implementation between ESBL and other MDR. METHODS: The ESBLE incidence measure used data from the laboratory of bacteriology. The application of isolation and barrier precautions was analyzed from the MRB national surveillance data over a 3-year period from 2006 to 2008. Data were entered and analyzed using Epi Info software. The Chi(2) test was used for the comparison of proportions. RESULTS: The overall incidence of ESBLE was significantly higher in 2010 than in 2005 (0.20/1000 patients-days vs 0.03/1000 patients-days, respectively) (P<0.001). The same was observed for Escherichia coli incidence with rates ranging from 0.02/1000 patients-days in 2005 to 0.15/1000 patients-days in 2010. Isolation precautions for patients with EBLSE were applied in relation for most patients with MRB (ESBLE vs others), without significant difference. CONCLUSION: The surveillance programme of MRB showed a significant increase of ESBLE, especially for E. coli. Isolation and barrier precautions were used for most patients with MRB, including ESBLE. PMID- 22841391 TI - Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice. AB - It is has been hypothesized that methylselenol is a critical selenium metabolite for anticancer activity in vivo. In this study, we used a protein array which contained 112 different antibodies known to be involved in the p53 pathway to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. The array analysis indicated that methylselenol exposure changed the expression of 11 protein targets related to the regulation of cell cycle and apoptosis. Subsequently, we confirmed these proteins with the Western blotting approach, and found that methylselenol increased the expression of GADD 153 and p21 but reduced the level of c-Myc, E2F1 and Phos p38 MAP kinase. Similar to our previous report on human HCT116 colon cancer cells, methylselenol also inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. When the MC26 cells were transplanted to their immune-competent Balb/c mice, methylselenol-treated MC26 cells had significantly less tumor growth potential than that of untreated MC26 cells. Taken together, our data suggest that methylselenol modulates the expression of key genes related to cell cycle and apoptosis and inhibits colon cancer cell proliferation and tumor growth. PMID- 22841392 TI - Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure. AB - Prenatal ethanol exposure (PNEE) causes long-lasting deficits in brain structure and function. In this study, we have examined the effect of PNEE on antioxidant capacity and oxidative stress in the adult brain with particular focus on four brain regions known to be affected by ethanol: cerebellum, prefrontal cortex and hippocampus (cornu ammonis and dentate gyrus subregions). We have utilized a liquid diet model of fetal alcohol spectrum disorders that is supplied to pregnant Sprague-Dawley rats throughout gestation. To examine the therapeutic potential of omega-3 fatty acid supplementation, a subset of animals were provided with an omega-3-enriched diet from birth until adulthood to examine whether these fatty acids could ameliorate any deficits in antioxidant capacity that occurred due to PNEE. Our results showed that PNEE caused a long-lasting decrease in glutathione levels in all four brain regions analyzed that was accompanied by an increase in lipid peroxidation, a marker of oxidative damage. These results indicate that PNEE induces long-lasting changes in the antioxidant capacity of the brain, and this can lead to a state of oxidative stress. Postnatal omega-3 supplementation was able to increase glutathione levels and reduce lipid peroxidation in PNEE animals, partially reversing the effects of alcohol exposure, particularly in the dentate gyrus and the cerebellum. This is the first study where omega-3 supplementation has been shown to have a beneficial effect in PNEE, reducing oxidative stress and enhancing antioxidant capacity. PMID- 22841393 TI - Curcumin induces human cathelicidin antimicrobial peptide gene expression through a vitamin D receptor-independent pathway. AB - The vitamin D receptor (VDR) mediates the pleiotropic biologic effects of 1alpha,25 dihydroxy-vitamin D3. Recent in vitro studies suggested that curcumin and polyunsaturated fatty acids (PUFAs) also bind to VDR with low affinity. As potential ligands for the VDR, we hypothesized that curcumin and PUFAs would induce expression of known VDR target genes in cells. In this study, we tested whether these compounds regulated two important VDR target genes - human cathelicidin antimicrobial peptide (CAMP) and 1,25-dihydroxyvitamin D3 24 hydroxylase (CYP24A1) - in human monocytic cell line U937, colon cancer cell line HT-29 and keratinocyte cell line HaCaT. We demonstrated that PUFAs failed to induce CAMP or CYP24A1 mRNA expression in all three cell lines, but curcumin up regulated CAMP mRNA and protein levels in U937 cells. Curcumin treatment induced CAMP promoter activity from a luciferase reporter construct lacking the VDR binding site and did not increase binding of the VDR to the CAMP promoter as determined by chromatin immunoprecipitation assays. These findings indicate that induction of CAMP by curcumin occurs through a vitamin D receptor-independent manner. We conclude that PUFAs and curcumin do not function as ligands for the VDR. PMID- 22841394 TI - Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis. AB - Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. Due to dismal prognosis and limited therapeutic intervention, chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC. Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties. We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 (Nrf2) mediated antioxidant mechanisms. Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB (NF-kappaB)-regulated inflammatory pathway, our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion (PE) during DENA-induced rat hepatocarcinogenesis. Rats were administered with PE (1 or 10 g/kg) 4 weeks before and 18 weeks following DENA initiation. There was a significant increase in hepatic expressions of inducible nitric oxide synthase, 3 nitrotyrosine, heat shock protein 70 and 90, cyclooxygenase-2 and NF-kappaB in DENA-exposed rat livers. PE dose-dependently suppressed all aforementioned elevated inflammatory markers. A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography. Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-kappaB signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis. Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits, namely, Nrf2-mediated redox signaling and NF kappaB-regulated inflammatory pathway, by pomegranate phytoconstituents to achieve chemoprevention of HCC. PMID- 22841395 TI - Yerba mate extract (Ilex paraguariensis) attenuates both central and peripheral inflammatory effects of diet-induced obesity in rats. AB - To clarify the effects of natural dietary components on the metabolic consequences of obesity, we examined the effects of yerba mate extract Ilex paraguariensis on both central and peripheral inflammatory effects of diet induced obesity and correlated the hypothalamic tumor necrosis factor (TNF)-alpha level with adipose depot weight. Wistar rats were divided into four groups: a control group (CTL) fed with chow diet, a second group fed with chow diet plus yerba mate extract (CTL+E), a third group fed with a high-fat diet rich in saturated fatty acids (HFD) and a fourth group fed with HFD plus yerba mate extract (HFD+E). Enzyme-linked immunosorbent assay, Western blotting, colorimetric method and treatment by gavage were utilized as materials and methods. The HFD groups showed a significant increase in food intake (kcal), body weight, adipose tissue and leptin level in comparison to CTL and CTL+E. HFD leads to increase of both central and peripheral inflammatory effects, and deregulation of insulin pathway. In addition, yerba mate extract intake blunted the proinflammatory effects of diet-induced obesity in rats by reducing the phosphorylation of hypothalamic IKK and NFkappaBp65 expression and increasing the phosphorylation of IkappaBalpha, the expression of adiponectin receptor-1 and consequently the amount of IRS-2. Moreover, the increase in interleukin (IL)-6 levels in the liver and muscle and of the IL-10/TNF-alpha ratio in groups that received yerba mate extract showed the anti-inflammatory effects of this natural substance. Taken together, our data suggest that the use of yerba mate extract may be useful for reducing low-grade obesity-associated inflammation. PMID- 22841396 TI - Supplementation of a gamma-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia. AB - Postprandial hyperglycemia induces oxidative stress responses, impairs vascular endothelial function (VEF) and increases the risk of cardiovascular disease. We hypothesized that the antioxidant and anti-inflammatory activities of a gamma tocopherol-rich mixture of tocopherols (gamma-TmT) would protect against vascular dysfunction that is otherwise caused by postprandial hyperglycemia by decreasing oxidative stress and proinflammatory responses, and improving nitric oxide (NO*) homeostasis. In a randomized, crossover study, healthy men (n=15; 21.8 +/- 0.8 years) completed a fasting oral glucose challenge (75 g) with or without prior supplementation of gamma-TmT (5 days). Brachial artery flow-mediated dilation (FMD), plasma glucose, insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine and asymmetric dimethylarginine (ADMA) were measured at regular intervals during a 3-h postprandial period. Supplementation of gamma-TmT increased (P<.05) plasma gamma-T by threefold and gamma-carboxyethyl hydroxychroman by more than ninefold without affecting alpha-T, glucose, arginine or ADMA. Baseline FMD, MDA, arginine and ADMA were unaffected by gamma-TmT (P>.05). Postprandial FMD decreased 30%-44% (P<.05) following glucose ingestion, but was maintained with gamma-TmT. Supplementation of gamma-TmT also attenuated postprandial increases in MDA that occurred following glucose ingestion. Plasma arginine decreased (P<.05) in both trials to a similar extent regardless of gamma TmT supplementation. However, the ratio of ADMA/arginine increased time dependently in both trials (P<.05), but to a lesser extent following gamma-TmT supplementation (P<.05). Inflammatory proteins were unaffected by glucose ingestion or gamma-TmT. Collectively, these findings support that short-term supplementation of gamma-TmT maintains VEF during postprandial hyperglycemia possibly by attenuating lipid peroxidation and disruptions in NO* homeostasis, independent of inflammation. PMID- 22841397 TI - Effects of biotin supplementation in the diet on insulin secretion, islet gene expression, glucose homeostasis and beta-cell proportion. AB - Besides its role as a carboxylase cofactor, biotin has a wide repertoire of effects on gene expression, development and metabolism. Pharmacological concentrations of biotin enhance insulin secretion and the expression of genes and signaling pathways that favor islet function in vitro. However, the in vivo effects of biotin supplementation on pancreatic islet function are largely unknown. In the present study, we investigated whether in vivo biotin supplementation in the diet has positive effects in rodent pancreatic islets. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet over 8 weeks postweaning and tested for glucose homeostasis, insulin secretion, islet gene expression and pancreatic morphometry. Insulin secretion increased from the islets of biotin-supplemented mice, together with the messenger RNA (mRNA) expression of several transcription factors regulating insulin expression and secretion, including forkhead box A2, pancreatic and duodenal homeobox 1 and hepatocyte nuclear factor 4alpha. The mRNA abundance of glucokinase, Cacna1d, acetyl-CoA carboxylase, and insulin also increased. Consistent with these effects, glucose tolerance improved, and glucose-stimulated serum insulin levels increased in biotin-supplemented mice, without changes in fasting glucose levels or insulin tolerance. Biotin supplementation augmented the proportion of beta cells by enlarging islet size and, unexpectedly, also increased the percentage of islets with alpha cells at the islet core. mRNA expression of neural cell adhesion molecule 1, an adhesion protein participating in the maintenance of islet architecture, decreased in biotin-supplemented islets. These findings provide, for the first time, insight into how biotin supplementation exerts its effects on function and proportion of beta cells, suggesting a role for biotin in the prevention and treatment of diabetes. PMID- 22841398 TI - Association between the plasma proteome and serum ascorbic acid concentrations in humans. AB - Vitamin C has been associated with a reduced risk of chronic diseases, but the biological pathways regulated by vitamin C are not all known. The objective was to use a proteomics approach to identify plasma proteins associated with circulating levels of ascorbic acid. Men and women (n=1022) 20-29 years of age from the Toronto Nutrigenomics and Health Study completed a general health and lifestyle questionnaire and a 196-item food frequency questionnaire and provided a fasting blood sample. Circulating ascorbic acid was analyzed by high performance liquid chromatography, and a mass-spectrometry-based multiple reaction monitoring method was used to measure 54 proteins abundant in plasma that are involved in numerous physiologic pathways. Mean protein concentrations were compared across tertiles of serum ascorbic acid using analysis of covariance adjusted for sex, ethnocultural group, season of blood draw, hormonal contraceptive use among women, waist circumference and tertiles of plasma alpha tocopherol. A Bonferroni significance level of P<.0009 was applied, and analyses were adjusted for multiple comparisons using the Tukey-Kramer procedure. Levels of complement C9, ceruloplasmin, alpha-1-anti-trypsin, angiotensinogen, complement C3, vitamin D binding protein and plasminogen were inversely associated with levels of ascorbic acid. The inverse association between ascorbic acid and vitamin D binding protein was highest in those with higher levels of serum 25-hydroxyvitamin D. In conclusion, several plasma proteins from various physiologic pathways are significantly associated with circulating levels of ascorbic acid. These findings suggest that vitamin C may have novel physiological effects. PMID- 22841399 TI - The sleeve gastrectomy intervention to treat morbid obesity in a Parkinson's disease patient. AB - BACKGROUND & AIMS: Some Parkinson's disease patients may develop morbid obesity, on account of the reduction in exercise and/or of the appearance of compulsive food intake in the first years after diagnosis. The prescription of central appetite suppressants is actually not recommended in Parkinson's disease patients. To the best of our knowledge, no cases of morbidly obese Parkinson's disease patients submitted to bariatric surgery procedures have been reported in literature before. METHODS: We here describe for the first time the outcome of a sleeve gastrectomy intervention in a morbidly obese Parkinson's disease patient, resistant to several non-surgical weight-loss treatments. RESULTS: The outcome of the sleeve gastrectomy intervention was satisfactory in terms of body weight loss, long term weight stabilization and improvement of cardioprotective circulating factors, including adiponectin. Furthermore, the antiparkinson therapy (levodopa) was reduced by 25%. CONCLUSIONS: These observations suggest that morbidly obese Parkinson's disease patients, who are resistant to other dietary treatments, might be candidated for sleeve gastrectomy. PMID- 22841401 TI - Outcome of ureteroscopy for treatment of pediatric ureteral stones. AB - PURPOSE: We assess the efficacy and safety of semirigid ureteroscopy for treatment of ureteral stones in children. MATERIALS AND METHODS: The records of 18 non-consecutive children with symptomatic ureteral stones treated with ureteroscopy in 2008-2010 were reviewed. Mean age was 7.6 years (range 15 months 14 years). A semirigid (8F) ureteroscope was used in all cases. A 0.038-inch floppy-tipped guidewire was passed through the selected ureteric orifice, advanced under direct vision, and monitored fluoroscopically. Dilatation of the ureteral orifice was necessary in 7 cases. Either direct extraction or disintegration using a pneumatic lithotripter was performed. The follow-up period was 6 months. RESULTS: Ureteroscopic procedures were successfully completed in 16 children (89%). Stones were located at the middle ureter in 3 (19%) cases and various levels of the lower third ureter in 13 (81%) cases. Stone size was 4-10 mm (mean 7 mm). Stones were fragmented with pneumatic lithotripsy in 9 (56%) cases and removed by forceps without fragmentation in 7 (44%). Stent was left in place for 3 days to 3 weeks in 12 (75%) cases. Early postoperative complications were insignificant hematuria in 2 patients and renal colic and fever in 3 patients. No complications were observed during the period of follow up. CONCLUSION: Ureteroscopy is a feasible treatment option for ureteral stones in children, when in skilled hands and with the aid of experience gained in the adult population. PMID- 22841400 TI - Waist circumference in children and adolescents correlate with metabolic syndrome and fat deposits in young adults. AB - BACKGROUND & AIMS: To determine the relevance of waist circumference (WC) measurement and monitoring in children and adolescents as an early indicator of overweight, metabolic syndrome (MS) and cardiovascular problems in young adults in comparison with visceral and subcutaneous adiposity. METHODS: A cohort study with 159 subjects (51.6% female) started in 1999 with an average age of 13.2 years. In 1999, 2006 and 2008 weight, height, and WC were evaluated. In 2006 blood samples for laboratory diagnosis of MS were added. In 2008 abdominal computed tomography (ACT) to quantify the fat deposits were also added. RESULTS: The WC measured in children and adolescents was strongly correlated with body mass index (BMI) measured simultaneously. A strong correlation was established between WC in 1999 with measures of WC and BMI as young adults. WC strongly correlated with fat deposits in ACT. The WC in 1999 expressed more subcutaneous fat (SAT), while the WC when young adults expressed strong correlation with both visceral fat (VAT) and SAT. The correlation of WC with fat deposits was stronger in females. WC and not BMI in 1999 was significantly higher in the group that evolved to MS. CONCLUSIONS: The WC in children and adolescents was useful in screening patients for MS. WC expressed the accumulation of abdominal fat; especially subcutaneous fat. PMID- 22841402 TI - Prenatal diagnosis of bladder exstrophy by fetal MRI. AB - PURPOSE: To review our experience with prenatal diagnosis of bladder exstrophy by fetal magnetic resonance imaging (MRI). Bladder exstrophy can be diagnosed by ultrasonography (US) evaluation of the fetus based on absence of bladder filling, low-set umbilicus, small genitalia and lower abdominal mass, although in some instances more accurate anatomical information is desired. MATERIAL AND METHODS: We studied three patients at mean gestational age of 27.3 weeks. The fetal MRI exam was performed on axial, sagittal, coronal planes and echo gradient in the best plan for acquisition of fetus. Images were analyzed by a group of three radiologists with experience in fetal MRI. RESULTS: The MRI defined a lower abdominal mass prolapsing below the umbilical vessels, having the ureters ending on it in an anterior position. A cloacal malformation or a cloacal exstrophy could be excluded, as well as other accompanying spinal abnormalities. The renal system and oligohydramnios could be well documented. CONCLUSIONS: The MRI showed a detailed scenario of the abnormality with advantages over the US evaluation in regard to excluding cloacal anomalies. MRI allowed accurate sexual differentiation and may be indicated after suspected bladder exstrophy on US evaluation. PMID- 22841403 TI - Combined laparoscopic and cystoscopic injection sclerotherapy for bladder venous malformation: a novel technique. AB - Treatment of vascular malformations of the urinary bladder can be challenging. We report a case of bladder venous malformation treated with sodium tetradecyl sulphate (STS 3%) sclerotherapy, using a combined cystoscopic and percutaneous transperitoneal laparoscopy guided approach. When cystoscopic views are poor, the laparoscopic approach is a useful adjunct to aid sclerotherapy of bladder venous malformation. This technique has not been previously described. PMID- 22841404 TI - Isolation and phylogenetic analysis of Bartonella species from wild carnivores of the suborder Caniformia in Japan. AB - The prevalence of Bartonella species was investigated among wild carnivores of the suborder Caniformia, including 15 Japanese badgers (Meles anakuma), 8 Japanese martens (Martes melampus), 2 Japanese weasels (Mustela itatsi), 1 Siberian weasel (Mustela sibirica), 171 raccoon dogs (Nyctereutes procyonoides), and 977 raccoons (Procyon lotor) in Japan. Bartonella bacteria were isolated from one Japanese badger (6.7%) and from one Japanese marten (12.5%); however, no Bartonella species was found in other representatives of Caniformia. Phylogenetic analysis was based on concatenated sequences of six housekeeping genes (16S rRNA, ftsZ, gltA, groEL, ribC, and rpoB) and sequence of the 16S-23S internal transcribed spacer region. The sequence analysis indicated that the isolate derived from the Japanese badger (strain JB-15) can represent a novel Bartonella species and the isolate from the Japanese marten (strain JM-1) was closely related to Bartonella washoensis. This is the first report on isolation of Bartonella from badger and marten. PMID- 22841405 TI - Phylogeny and molecular typing of Mycoplasma agalactiae and Mycoplasma bovis by multilocus sequencing. AB - Mycoplasma agalactiae and Mycoplasma bovis are important pathogens producing similar pathologies in small ruminants and cattle, respectively. They share many phenotypic and genotypic traits and comparison of their 16S rDNA sequences lacks sufficient resolution for phylogenetic analysis. The aim of this study was to develop a multilocus sequence typing (MLST) scheme to analyse the phylogenetic relationships between M. agalactiae and M. bovis and to assess its use for unequivocal strain characterisation and molecular typing. An MLST based on fusA, gyrB, lepA and rpoB was applied to a sample of strains from both species, some of which could not be classified by serology or PCR. A robust phylogenetic tree was inferred, where the two species were clearly resolved. The use of this tool for the molecular typing of M. agalactiae strains was further evaluated on 19 presumably unrelated isolates, resulting in the discrimination of 14 sequence types (ST). The discriminatory power was increased (17 ST) by including an alternative target located in a more variable region. The diversity of M. agalactiae in Turkey (9 strains) and Israel (15 strains) was also assessed. Five closely related ST were evidenced in Turkey and 6 in Israel, with one ST common to both countries. Each country showed a predominant type that persisted over years. The MLST scheme developed here constitutes a universal tool for unequivocal strain characterisation and global, long-term screening of dissemination of M. agalactiae and M. bovis, whereas addition of more variable, non-housekeeping gene targets allows precise epidemiological investigations. PMID- 22841406 TI - Detection of antibodies against classical swine fever virus in fecal samples from wild boar. AB - Classical swine fever (CSF) is a contagious viral disease that affects pigs. Wild boars can play an important epidemiological role in CSF outbreaks. In the past decades, studies conducted in many countries have reported that the CSF virus (CSFV) may persist in wild boar populations. The existence of CSFV in the free ranging wild boar populations was indirectly confirmed by determining the prevalence of antibodies against CSFV in the serum of hunted wild boars. However, analyzing sero-prevalence in hunted wild boars to study the risk of CSF outbreaks is difficult due to insufficient number of samples, limitation of hunting area and biased age distribution of hunted wild boars. To improve this survey method, we collected feces of wild boars from their habitat and tested them using CSFV antibody enzyme-linked immunosorbent assay (ELISA) and CSF virus neutralization (VN) test. In this study, ELISA was found to be highly sensitive for detecting antibodies against CSFV in fecal samples. Most of doubtful or positive results obtained in CSFV ELISA were confirmed by VN tests. Despite the high coincidence rate of antibody-positive samples between CSFV ELISA and VN test, the possibility of false positive reaction should be considered. In the regional distribution, a fact that antibody-positive fecal and serum samples were found in geographically close area was shown. Hence, presence of antibodies in fecal samples may provide vital information regarding the risk of CSF outbreaks in wild boar groups in geographical proximity. PMID- 22841407 TI - Characterization of H10 subtype avian influenza viruses isolated from wild birds in South Korea. AB - A total of 13 avian influenza viruses of the H10 subtype were isolated from wild birds in South Korea over the winter season between July 2008 and July 2011. The HA cleavage site of most of the isolated viruses, PEIMQGR?G was similar to that of H10 viruses (A/turkey/England/384/79 and A/mandarin duck/Singapore/805/93), which are well known to be highly pathogenic in chickens. The exception was the A/mallard/Korea/1242/10(H10N6) virus, which had a PEMMQGR motif. Phylogenetic analysis showed that eight genes of the isolated H10 viruses belonged to the Eurasian lineage, and that the Korean H10 viruses could be divided four genotypes (genotypes A, B, C and D). Chicken challenge studies revealed that most of the H10 viruses did not replicate well through the natural infection route, but a genotype D virus was re-isolated from the brain of a chicken inoculated by the intravenous route. Although H10 viruses have not been isolated from poultry in South Korea, our results emphasize the continuing need to monitor the evolutionary genetics of the influenza virus in wild birds. PMID- 22841409 TI - Pharmacologic management of non-cancer pain among nursing home residents. AB - CONTEXT: Pain is common in nursing home settings. OBJECTIVES: To describe scheduled analgesic use among nursing home (NH) residents experiencing non-cancer pain and evaluate factors associated with scheduled analgesic use. METHODS: We identified 2508 residents living in one of 185 NHs predominantly from one for profit chain, with pain recorded on two consecutive Minimum Data Set assessments. Pharmacy transaction files provided detailed medication information. Logistic regression models adjusted for clustering of residents in NHs identified factors related to scheduled prescription analgesics. RESULTS: Twenty-three percent had no scheduled analgesics prescribed. Those with scheduled analgesics were more likely to have excruciating pain (5.5% vs. 1.2%) and moderate pain documented (64.7% vs. 47.5%) than residents without scheduled analgesics. Hydrocodone (41.7%), short-acting oxycodone (16.6%), and long-acting fentanyl (9.4%) were common, and 13.8% reported any nonsteroidal anti-inflammatory agent use. Factors associated with decreased odds of scheduled analgesics included severe cognitive impairment (adjusted odds ratio [AOR] 0.56; 95% confidence interval [CI] 0.36 to 0.88), age more than 85 years (AOR 0.57; 95% CI 0.41 to 0.80), and Parkinson's disease (AOR 0.55; 95% CI 0.30 to 0.99). Factors associated with increased odds of scheduled analgesic use included history of fracture (AOR 1.79; 95% CI 1.16 to 2.76), diabetes (AOR 1.30; 95% CI 1.02 to 1.66), and higher Minimum Data Set mood scores (AOR 1.11; 95% CI 1.04 to 1.19). CONCLUSION: Some improvements in pharmacologic management of pain in NHs have been realized. Yet, presence of pain without scheduled analgesics prescribed was still common. Evidence-based procedures to assure adherence to clinical practice guidelines for pain management in this setting are warranted. PMID- 22841408 TI - An examination of adherence to pain medication plans in older cancer patients in hospice care. AB - CONTEXT: Timely and appropriate management of pain is essential to promote comfort at the end of life. OBJECTIVES: To determine if pain-related factors and nonpharmacologic interventions affect medication adherence in older cancer patients in community-based hospices. METHODS: The study involved cancer patients aged 55 years and older, newly admitted to one of the 13 community-based hospices in the midwestern U.S. A descriptive design with patients or their proxies providing information during two telephonic interviews and review of their hospice medical records were used. RESULTS: A total sample of 65 patients was obtained, with data directly from 32 patients during Interview 1 (T(1)), 25 during Interview 2 (T(2)), and proxy reports for 33 (T(1)) and 30 (T(2)) patients. The overall mean pain medication adherence scores (maximum 9) for all patients were 8.43 (T(1)) and 8.38 (T(2)). For component analysis (three components; maximum of three points each), patients were the least adherent with opioid orders at both time points (2.65). Patients were the most adherent to nonsteroidal anti-inflammatory/acetaminophen orders at T(1) (2.91) and medications for neuropathic pain at T(2) (2.89). Data provided statistical evidence that patients with more hours of controlled pain in the past 24 hours were more likely to have had better adherence, whereas patients with higher levels of comfort over the last few days were more likely to have had worse adherence. CONCLUSION: This study identified that pain medication adherence among older adults with cancer receiving hospice care is high. However, hospices must be alert to the fact that even as patients become more comfortable, adherence must continue to be emphasized to ensure that pain does not redevelop or exacerbate, if pain relief is a patient priority. PMID- 22841410 TI - Insight into advance care planning for patients on dialysis. AB - CONTEXT: Advance care planning is not included in regular clinical care for patients on dialysis. Insight into life-sustaining treatment preferences and communication about end-of-life care is necessary to develop interventions to improve advance care planning for patients on dialysis. OBJECTIVES: This cross sectional observational study aimed to understand the preferences for life sustaining treatments of outpatients on dialysis and to study the quality of patient-physician communication about end-of-life care and barriers and facilitators to this communication. METHODS: The following outcomes were assessed in 80 clinically stable dialysis patients: demographics, clinical characteristics, life-sustaining treatment preferences (cardiopulmonary resuscitation and mechanical ventilation, and Willingness to Accept Life Sustaining Treatment instrument), preference for site of death, quality of communication (Quality of Communication Questionnaire), and barriers and facilitators to communication about end-of-life care (Barriers and Facilitators Questionnaire). RESULTS: Patients were able to indicate their preferences for life-sustaining treatments and site of death. Preferences for life-sustaining treatments depend on the specific treatment, the expected outcome of treatment, and likelihood of an adverse outcome. Life-sustaining preferences were discussed with the nephrologist by 30.3% of the patients. Quality of the patient-physician communication about end-of-life care was rated poor. This study identified several barriers and facilitators to end-of-life care communication. CONCLUSION: Patients should receive information about treatment burden, expected outcome, and the likelihood of an adverse outcome when discussing life-sustaining treatments. Quality of patient-physician communication about end-of-life care needs to improve. Barriers and facilitators to communication about end-of-life care provide direction for future interventions to facilitate advance care planning for patients on dialysis. PMID- 22841411 TI - Palliative care after attempted suicide in the absence of premorbid terminal disease: a case series and review of the literature. AB - Palliative care involvement in the management of incomplete suicide in patients without terminal illness is rare. This paper documents two such cases and explores some of the clinical and ethical issues raised. PMID- 22841412 TI - Assessment of neutrophil-lymphocyte ratio in ulcerative colitis: a promising marker in predicting disease severity. AB - BACKGROUND AND AIM: In order to diagnosis and monitor the disease activity of ulcerative colitis (UC), serum biomarkers are generally used, but none of them are specific for intestinal inflammation. It is therefore desirable in clinical practice to be able to assess disease activity with simple, inexpensive and objective tools. The objective of the present study was to assess whether the neutrophil-lymphocyte ratio (NLR) would be useful in predicting disease severity in UC patients who had not received corticosteroid or immunosuppressive drugs within a defined period of time. Additionally, a possible relationship of NLR with other inflammatory markers in UC patients was also investigated. METHODS: We designed a retrospective study examining the utility of NLR in estimating disease severity in UC patients admitted to our hospital between 2008 and 2011. In total, 119 patients with active UC and 77 patients with inactive UC were enrolled in the study group, and 59 age and gender matched healthy subjects were included as the control group. Disease activity was assessed using Truelove and Witts criteria. RESULTS: In the active UC group, NLR values were found to be elevated compared to inactive UC patients and controls (3.22 +/- 1.29, 1.84 +/- 0.69 and 2.01 +/- 0.64, respectively). Using ROC statistics, a cut-off value of 2.16 indicated the presence of active disease with a sensitivity of 81.8% and a specificity of 80.5% (positive predictive value [PPV] 86.8%, negative predictive value [NPV] 73.8%). NLR values were found to be correlated with WBC and ESR levels. CONCLUSIONS: The present study revealed that NLR is increased in active UC. Peripheral blood NLR can reflect disease activity and can be used as an additional marker for estimating intestinal inflammation. PMID- 22841413 TI - [Enophtalmos of the anophtalmic socket: incidence of the orbital morphology and therapeutic implications. Clinical study of 86 cases]. AB - AIM OF THE STUDY: From a light asymmetry to a sunken eye aspect, a great disparity between the results after anophtalmic socket rehabilitation is noticeable: what are the factors involved in the degree of residual enophtalmos following excision of the eye? The litterature's response is based on physiopathological considerations around intraorbital architectural disturbance. We propose a geometrical approach related to the existence of different morphological types of orbit. PATIENTS AND METHOD: Eighty-six records of eviscerated and enucleated patients have been studied and submitted to a statistical analysis. A preliminary study has defined four types of orbit depending on the shape and operture of the orbital "window": two opposite types IA and III, a type II intermediate and a particular one, the type IB. A classification of enophtalmos' degree allows to analyze the parameters chosen and to identify the predictive factors. RESULTS: The statistical analysis confirms the incidence of the orbital morphology on the degree of enophtalmos but do not support the theories based on the intraorbital septal architecture changes. Depending on the orbital shape and the container-content relation, the volume loss is more visible on the whole orbitopalpebral surface of opened and high orbit but remains centered on the anteroposterior position of the implant of a closed and lengthened orbit. At the contrary to the type III, the type IA is not favorable for the anophtalmic patient and predispose to a higher degree of enophtalmos. This new approach has therapeutic implications on primary and secondary surgery for volume loss replacement. CONCLUSION: The success of anophtalmic socket rehabilitation is influenced by the orbital morphological type that has to be considered in the therapeutic strategy. PMID- 22841414 TI - Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C]vinpocetine. AB - Although there is increasing evidence for microglial activation after an ischaemic stroke in the infarct core and the peri-infarct region, the "evolution" of the process in stroke patients is poorly known. Using PET and [((11))C]vinpocetine, we measured the regional changes of TSPO in the brain of nine ischaemic stroke patients up to 14weeks after the insult. Already a week after stroke there was an increased radioligand uptake, indicating the up regulation of TSPO and the presence of activated microglia, in both the ischaemic core and the peri-infarct zone. This increased activation showed a steady decrease with post stroke time. The proportion between %SUV values in the peri infarct zone and the ischaemic core increased with time. There were no time dependent TSPO activity changes in other regions, not affected directly by the stroke. The present observations demonstrate that increased regional microglia activation, as a consequence of stroke, can be visualised with PET, using the TSPO molecular imaging biomarker [((11))C]vinpocetine. The evolution of this microglial activation shows a time dependent decrease the gradient of which is different between the peri-infarct zone and the ischaemic core. The findings indicate an increased microglial activation in the peri-stroke region for several weeks after the insult. PMID- 22841415 TI - A high prevalence of autoimmune indices and disorders in primary nummular headache. AB - BACKGROUNDS: Nummular headache (NH) is currently considered a form of peripheral neuralgia originating from the terminal branch in epicranial tissue but its etiopathogenesis is still unknown. Since autoimmune disorders often involve the trigeminosensory nerve to provoke craniofacial pain, we hypothesize that autoimmunity aberration may play a role with regard to NH. METHODS: We examined the antibodies to antinuclear factor, ds-DNA, extracted nuclear antigens, rheumatoid factor, as well as antiphospholipid antibodies, in 23 primary NH patients. RESULTS: Among them were 16 patients (69.6%) found as having at least one abnormal autoimmune index, namely, antibodies to antinuclear factor in 8 patients, SSA/La in 6 patients, rheumatoid factor in 4 patients, SSB/Ro in 2 patients, and ds-DNA in 1 patient. An abnormal increase of blood anti-beta2 glycoprotein I antibody was noted in 4 patients and lupus anticoagulant in 1 patient, whereas HLA-B27 seropositivity was detected in 1 patient. Except for 2 patients positive for antinuclear factor without other associated features, 15 patients (65%) were finally diagnosed as having Sjogren/sicca syndrome, rheumatoid arthritis or antiphospholipid antibody syndrome. CONCLUSIONS: A high prevalence of abnormal autoimmune indices and disorders is present in primary NH patients, suggesting a probable relationship between autoimmunity aberration and epicranial neuralgia in NH. PMID- 22841416 TI - Use of satellite-based aerosol optical depth and spatial clustering to predict ambient PM2.5 concentrations. AB - Satellite-based PM(2.5) monitoring has the potential to complement ground PM(2.5) monitoring networks, especially for regions with sparsely distributed monitors. Satellite remote sensing provides data on aerosol optical depth (AOD), which reflects particle abundance in the atmospheric column. Thus AOD has been used in statistical models to predict ground-level PM(2.5) concentrations. However, previous studies have shown that AOD may not be a strong predictor of PM(2.5) ground levels. Another shortcoming of remote sensing is the large number of non retrieval days (i.e., days without satellite data available) due to clouds and snow- and ice-cover. In this paper we propose statistical approaches to overcome these two shortcomings, thereby making satellite imagery a viable method to estimate PM(2.5) concentrations. First, we render AOD a robust predictor of PM(2.5) mass concentration by introducing an AOD daily calibration approach through the use of mixed effects model. Second, we develop models that combine AOD and ground monitoring data to predict PM(2.5) concentrations during non retrieval days. A key feature of this approach is that we develop these prediction models separately for groups of days defined by the observed amount of spatial heterogeneity in concentrations across the study region. Subsequently, these methodologies were applied to examine the spatial and temporal patterns of daily PM(2.5) concentrations for both retrieval days (i.e., days with satellite data available) and non-retrieval days in the New England region of the United States during the period 2000-2008. Overall, for the years 2000-2008, our statistical models predicted surface PM(2.5) concentrations with reasonably high R(2) (0.83) and low percent mean relative error (3.5%). Also the spatial distribution of the estimated PM(2.5) levels in the study domain clearly exhibited densely populated and high traffic areas. The method we have developed demonstrates that remote sensing can have a tremendous impact on the fields of environmental monitoring and human exposure assessment. PMID- 22841417 TI - Spatial organization of cortical and spinal neurons controlling motor behavior. AB - A major task of the central nervous system (CNS) is to control behavioral actions, which necessitates a precise regulation of muscle activity. The final components of the circuitry controlling muscles are the motorneurons, which settle into pools in the ventral horn of the spinal cord in positions that mirror the musculature organization within the body. This 'musculotopic' motor-map then becomes the internal CNS reference for the neuronal circuits that control motor commands. This review describes recent progress in defining the neuroanatomical organization of the higher-order motor circuits in the cortex and spinal cord, and our current understanding of the integrative features that contribute to complex motor behaviors. We highlight emerging evidence that cortical and spinal motor command centers are loosely organized with respect to the musculotopic spatial-map, but these centers also incorporate organizational features that associate with the function of different muscle groups during commonly enacted behaviors. PMID- 22841418 TI - Engineering tissues for children: building grafts that grow. PMID- 22841420 TI - Growth and differentiation characteristics of equine mesenchymal stromal cells derived from different sources. AB - Multipotent mesenchymal stromal cells (MSCs) are a promising therapeutic tool for the treatment of equine tendon and other musculoskeletal injuries. While bone marrow is considered the 'gold standard' source of these cells, various other tissues contain MSCs with potentially useful features. The aim of this study was to compare clinically relevant characteristics of MSCs derived from bone marrow, umbilical cord blood and tissue and from adipose tissue and tendon. Cell yield, proliferation, migration, tendon marker expression and differentiation into adipocytes, chondrocytes and osteoblasts was assessed, quantified and compared. MSC numbers obtained from adipose, tendon or umbilical cord tissues were 222-fold higher than those obtained from bone marrow or cord blood. Cells derived from tendon and adipose tissues exhibited most rapid proliferation. Osteogenic differentiation was most prominent in MSCs derived from bone marrow, and was weak in MSCs derived from umbilical cord blood and tissue. In contrast, the highest levels of chondrogenic differentiation were observed in MSCs derived from these sources. Collagen 1A2 expression was highest in adipose- and tendon-derived MSCs, while scleraxis expression was highest in cord blood- and in tendon-derived MSCs. The findings indicate that MSCs from different sources display significantly diverse properties that may impact on their therapeutic application. PMID- 22841419 TI - Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. AB - BACKGROUND: Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up. METHODS: A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor beta to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts. FINDINGS: The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school. INTERPRETATION: Follow-up of the first paediatric, stem-cell based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research. FUNDING: Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany. PMID- 22841421 TI - Colonization of termite hindgut walls by oxymonad flagellates and prokaryotes in Incisitermes tabogae, I. marginipennis and Reticulitermes flavipes. AB - We studied the colonization of the paunch wall of three lower termites, Reticulitermes flavipes, Incisitermes tabogae, and Incisitermes marginipennis, by light and electron microscopy. In addition to various prokaryotes, oxymonad flagellates were attached to the wall of the paunch in all three species. The prokaryotic layer found in R. flavipes is relatively thin, since most organisms are attached laterally. Large members of the flagellate genus Pyrsonympha protrude into the gut lumen. The prokaryotes are very abundant on the gut wall in I. tabogae and I. marginipennis, forming a thick carpet of mostly vertically attached rods and wavy spirochetes. The adhering oxymonads are relatively small and almost hidden in the thick bacterial biofilm. Three small morphotypes were seen in I. tabogae; two possessing a short rostellum and one amoeboid. The only oxymonad found in I. tabogae so far, Oxymonas clevelandi, is not identical to any of the present oxymonads. I. marginipennis contains a mid-sized oxymonad with ectobiotic spirochetes, probably identical to Oxymonas hubbardi, and a tiny unknown morphotype. The spatial organization of the pro- and eukaryotic microorganisms on the gut wall of the three termites is described and discussed concerning oxygen stress. PMID- 22841422 TI - AIDing the immune system-DIAbolic in cancer. AB - Activation induced deaminase (AID) has evolved with the immune system to enhance the ability of antibodies to bind and eliminate pathogens. It is a member of the AID/APOBEC family of proteins, which deaminate cytosine (or 5-methyl cytosine) in DNA leading to uracil (thymidine). These base modifications can lead to repair, DNA demethylation, mutagenesis, recombination, or viral/foreign DNA elimination. Because of their physiological function, their ubiquitous expression, and hormonal regulation (e.g. estrogen), these proteins play an important role in oncogenesis, with AID being directly implicated in B cell lymphomas. The targeting preference of each DNA deaminase provides a means to identify their mutation foot-print in tumours, and have implicated them in mutating the genome, including the loci of tumour suppressors, of various cancers (e.g. breast). In this special issue devoted to understanding AID function and regulation, leading members of the field discuss all aspects from AID transcriptional regulation, mRNA turnover, protein expression, modification, and transport, to complex formation, targeting and enzymatic turnover. AID's function will be discussed in context of DNA repair and how changes of key components of each pathway have an influence on the overall efficacy of targeted DNA deamination. PMID- 22841423 TI - "Chemical and biological extraction of metals present in e-waste: a hybrid technology". PMID- 22841424 TI - Clinical language fMRI with real-time monitoring in temporal lobe epilepsy: online processing methods. AB - The increasing demand for clinical fMRI data has resulted in a need to translate research methods to clinical use. Referrals for language lateralization prior to epilepsy surgery are becoming more common, but time constraints make this unachievable in many busy neuroimaging departments. This study examines whether a single covert verbal fluency paradigm with real-time monitoring and online processing (BrainWave) could replace conventional offline processing (SPM) for the purpose of establishing expressive language dominance prior to epilepsy surgery. We analyzed language fMRI results of 30 patients (17 female; 24 right handed; median age: 30.5) with temporal lobe epilepsy. Concordance between visual assessment of SPM and BrainWave was 92.8%. Lateralization indices correlated closely with visual assessments of lateralization with a concordance of 85.7%. BrainWave provided a real-time, fast and accurate display of language lateralization easily applied in a clinical setting using only online image processing. PMID- 22841425 TI - Evaluation of whether intracameral dexamethasone predisposes to glaucoma after pediatric cataract surgery. AB - PURPOSE: To evaluate the effect of intracameral dexamethasone during pediatric cataract surgery on the incidence of postoperative glaucoma. SETTING: Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital, London, United Kingdom. DESIGN: Retrospective case series. METHODS: This case-note review comprised all infants who had cataract surgery with intraocular lenses between January 1, 2007, and December 31, 2008, and were given preservative-free intracameral dexamethasone intraoperatively. The definition of glaucoma was an intraocular pressure (IOP) of 21 mm Hg or greater on more than 2 occasions or moderate or firm digital IOP with 1 of the following: myopic shift, increased cup to-disc ratio, increased horizontal corneal diameter, or corneal edema. RESULTS: Eighteen patients (24 eyes) were included. The median age at surgery was 3 months (mean 4 months +/- 3 (SD); range 1 to 11 months). The median follow-up was 38 months (mean 34 +/- 10 months; range 20 to 48 months). In 4 eyes, transient postoperative antihypertensive medication was used; however, no eye developed glaucoma during the follow-up period. Fifteen eyes had a second procedure to clear the visual axis due to posterior visual axis opacification a mean of 6.4 +/ 3.5 months postoperatively (median 4.8 months; range 3.5 to 14.5 months); however, no eye developed anterior membranes. CONCLUSION: Intracameral preservative-free dexamethasone in infantile cataract surgery did not seem to cause an increased risk for glaucoma and appeared to protect against anterior membrane formation. PMID- 22841426 TI - Real-time intraoperative high-speed imaging during phacoemulsification. AB - We describe the use of high-speed imaging during phacoemulsification in a clinical scenario. Images captured during surgery at high frame rates are converted into a slow-motion film to view and analyze various surgical steps. This technique highlights events that are not captured in a normal-speed video recording. It has obvious applications for understanding surgical techniques and technology. PMID- 22841427 TI - Occlusal risk factors associated with temporomandibular disorders in young adults with normal occlusions. AB - OBJECTIVE: The aim of this study was to characterize occlusal stability in young adults with temporomandibular disorder (TMD). STUDY DESIGN: Thirty-one patients (aged 19-31 years) with complete natural dentition and Angle class I occlusion who exhibited TMD were compared with 31 age- and sex-matched healthy control subjects. The occlusal registrations were performed using the T-Scan II occlusal imaging and analysis system. Center of occlusal force, asymmetry index of occlusal force, maximal movement of COF, premature contacts, clusion time, and disclusion time were recorded. RESULTS: Compared with control subjects, TMD subjects had a significantly higher frequency of premature contacts (16/32, 50.0%) and greater bilateral asymmetry in the occlusal force. Furthermore, prolonged clusion time and disclusion time also were observed in TMD subjects. CONCLUSIONS: These results suggest that a significant association exists between occlusal stability and TMD in young adults. PMID- 22841428 TI - Retrotuberosity versus submentosubmandibular and median submental intubation: patients with maxillofacial surgery. AB - OBJECTIVE: In certain maxillofacial trauma cases, nasotracheal intubation is contraindicated and the standard method of orotracheal intubation interferes with maxillomandibular fixation. In such cases alternative techniques, such as submental, submentosubmandibular, and retromolar intubation have been used. STUDY DESIGN: We reviewed 8 patients who underwent median submental intubation, 7 patients who underwent submentosubmandibular intubation, and 10 patients who underwent a retromolar intubation with an armored endotracheal tube secured in place with a circumdental wire. The tube was positioned in the retromolar region behind the most posterior maxillary tooth. RESULTS: In the group of patients who underwent median submental intubation, 1 presented difficulty in performing a median submental intubation. No complications were recorded in the rest of the patients. CONCLUSIONS: Submental and submentosubmandibular intubation are useful methods with low morbidity. However, both are invasive techniques compared with retrotuberosity intubation secured in place with a circumdental wire placed around the most posterior maxillary tooth. PMID- 22841429 TI - Osteoblast responses to thin nanohydroxyapatite coated on roughened titanium surfaces deposited by an electrochemical process. AB - PURPOSE: The purpose of this study was to investigate in vitro osteoblast responses to the thin nano-hydroxyapatite (HA) coating on porous implant surfaces. MATERIALS AND METHODS: Surface characteristics of nano-HA coating were evaluated by x-ray diffractometer (XRD) and Fourier transform infrared spectroscopy (FTIR). Murine preosteoblast cell (MC3T3-E1) proliferation, alkaline phosphatase (ALP) activity, and osteocalcin release on nano-HA coated surfaces were compared with HA-coated surfaces. RESULTS: The XRD pattern demonstrated that the peak of nano-HA coating matched well with the standard HA patterns. FTIR spectra also showed that the coating consisted of pure HA crystals. Significant increases in cell proliferation, total protein on day 7, ALP activity on day 14 and day 21, and osteocalcin production on day 21 (P < .05) were observed for nano HA coated surfaces. CONCLUSIONS: It was concluded that thin nano-HA coating, deposited by the electrochemical process, improved proliferation and differentiation of osteoblasts. PMID- 22841430 TI - Superior osteogenic capacity of different mesenchymal stem cells for bone tissue engineering. AB - OBJECTIVE: We evaluated the effect of human bone marrow stromal cells (hBMSCs), human adipose tissue-derived mesenchymal stem cells (hAD-MSCs), and umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in bone tissue engineering and identified a reliable cell source. STUDY DESIGN: Alkaline phosphatase (ALP) activity and quantitative polymerase chain reaction were used to evaluate osteogenic in vitro, X-ray and histologic analysis in vivo. RESULTS: hBMSCs exhibited strongest ALP staining, followed by hAD-MSCs and hUC-MSCs. At 7 days, hUC-MSCs and hAD-MSCs had higher expression of collagen type I and Runt-related transcription factor 2 than hBMSCs, and hUC-MSCs showed higher osteopontin expression. Bone structure was observed in the hUC-MSC group. Defects showed good healing in the hBMSC and hAD-MSC groups. Enhanced green fluorescent protein and osteopontin were detected in newly formed bone at 8 weeks. CONCLUSIONS: Our results suggested that hUC-MSCs and hAD-MSCs could be used for bone tissue engineering effectively; hUC-MSCs could serve as a new alternative cell source. PMID- 22841431 TI - Sutures coated with antiseptic pomade to prevent bacterial colonization: a randomized clinical trial. AB - OBJECTIVE: The aim of this study was to assess if an antiseptic pomade could reduce the bacterial colonization on multifilament sutures. STUDY DESIGN: A randomized clinical trial was conducted with 40 volunteer patients of both sexes aged 18-70, randomly separated into experimental (n = 20) and control (n = 20) groups. The experimental group received pomade-coated sutures (iodoform + calendula) and the control group uncoated sutures. Two millimeters of the suture was harvested from each patient from the 1st to the 15th postoperative day. The bacteria that had adhered to them were cultured. The number of colony-forming units per milliliter (CFU/mL) was determined and the groups were compared using the Mann-Whitney statistical test (P < .05). RESULTS: The experimental group showed a significant reduction in bacterial growth compared with the control group (P = .002). CONCLUSIONS: In this experimental model, the antiseptic pomade was effective in reducing bacterial colonization on silk braided sutures. PMID- 22841432 TI - Articaine (4%) with epinephrine (1:100,000 or 1:200,000) in intraosseous injections in symptomatic irreversible pulpitis of mandibular molars: anesthetic efficacy and cardiovascular effects. AB - OBJECTIVE: The aim of this study was to compare the cardiovascular effects and the anesthetic efficacy of intraosseous injections of 4% articaine with 1:100,000 epinephrine (EPI100) or 4% articaine with 1:200,000 epinephrine (EPI200). STUDY DESIGN: In this prospective, randomized, double-blind study, 0.9 mL EPI100 and EPI200 solutions were administered for endodontic treatment of mandibular molars with symptomatic irreversible pulpitis in 60 patients. The anesthetic success and pain during anesthesia were evaluated by visual analog scale. The cardiovascular parameters evaluated were heart rate, diastolic/systolic blood pressure, pulse oximetry, and electrocardiogram changes. RESULTS: Both solutions provided high anesthetic efficacy (96.8% and 93.1% for EPI100 and EPI200, respectively; P > .05), and the cardiovascular parameters showed minimal incidences of significant differences throughout the clinical procedure. CONCLUSIONS: The epinephrine concentration did not affect the efficacy of 4% articaine, and both solutions produced a high success level of pulpal anesthesia. Intraosseous delivery by slow speed of injection did not induce significant clinical changes in cardiovascular parameters. PMID- 22841433 TI - The effects of individual and context on aggression in repeated social interaction. AB - In two studies using variations of the Prisoner's Dilemma game, we explore the impact of individual traits and social context on aggressive behavior. In the first study, we compared defection rates in the Iterated Prisoner's Dilemma when participants were presented with a payoff matrix (Description condition) or learned payoffs through experience (Experience condition). Interpersonal trust and maximizing tendency led to relatively less defection in the Description condition than in the Experience condition, demonstrating that individual characteristics manifest differently depending on the information available to decision-makers. In the second study, we employed a new game paradigm, the Intergroup Prisoner's Dilemma with Intragroup Power Dynamics, to examine the way that power motives influence extreme aggressive behavior. We discovered that certain individuals exhibit very high levels of defection, but only when they play with particular combinations of predefined strategies, further suggesting how the confluence of individual factors and context can induce aggression. PMID- 22841435 TI - Structural and functional inverse cardiac remodeling after cavotricuspid isthmus ablation in patients with typical atrial flutter. AB - INTRODUCTION AND OBJECTIVES: The purpose of the present study is to determine the structural and functional cardiac changes that occur in patients at 1-year follow up after ablation of typical atrial flutter. METHODS: We enrolled 95 consecutive patients referred for cavotricuspid isthmus ablation. Echocardiography was performed at <=6h post-procedure and 1-year follow-up. RESULTS: Of 95 patients initially included, 89 completed 1-year follow-up. Hypertensive cardiopathy was the most frequently associated condition (39%); 24% of patients presented low baseline left ventricular systolic dysfunction. We observed a significant reduction in right and left atrial areas, end-diastolic and end-systolic left ventricular diameters, and interventricular septum. We observed substantial improvement in right atrium contraction fraction and left ventricular ejection fraction, and a reduction in pulmonary hypertension. Changes in diastolic dysfunction pattern were observed: 60% of patients progressed from baseline grade III to grade I; at 1-year follow-up, this improvement was found in 81%. We found no structural differences between paroxysmal and persistent atrial flutter at baseline and 1-year follow-up, exception for basal diastolic function. CONCLUSIONS: In patients with typical atrial flutter undergoing cavotricuspid isthmus catheter ablation, we found inverse structural and functional cardiac remodeling at 1-year follow-up with much improved left ventricular ejection fraction, right atrium contraction fraction, and diastolic dysfunction pattern. Full English text available from:www.revespcardiol.org. PMID- 22841437 TI - Novel anticancer therapeutics targeting telomerase. AB - Telomeres are protective caps at the ends of human chromosomes. Telomeres shorten with each successive cell division in normal human cells whereas, in tumors, they are continuously elongated by human telomerase reverse transcriptase (hTERT). Telomerase is overexpressed in 80-95% of cancers and is present in very low levels or is almost undetectable in normal cells. Because telomerase plays a pivotal role in cancer cell growth it may serve as an ideal target for anticancer therapeutics. Inhibition of telomerase may lead to a decrease of telomere length resulting in cell senescence and apoptosis in telomerase positive tumors. Several strategies of telomerase inhibition are reviewed, including small molecule inhibitors, antisense oligonucleotides, immunotherapies and gene therapies, targeting the hTERT or the ribonucleoprotein subunit hTER. G-quadruplex stabilizers, tankyrase and HSP90 inhibitors targeting telomere and telomerase assembly, and T-oligo approach are also covered. Based on this review, the most promising current telomerase targeting therapeutics are the antisense oligonucleotide inhibitor GRN163L and immunotherapies that use dendritic cells (GRVAC1), hTERT peptide (GV1001) or cryptic peptides (Vx-001). Most of these agents have entered phase I and II clinical trials in patients with various tumors, and have shown good response rates as evidenced by a reduction in tumor cell growth, increased overall disease survival, disease stabilization in advanced staged tumors and complete/partial responses. Most therapeutics have shown to be more effective when used in combination with standard therapies, resulting in concomitant telomere shortening and tumor mass shrinkage, as well as preventing tumor relapse and resistance to single agent therapy. PMID- 22841436 TI - Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors with activity in animal models of schizophrenia. AB - A series of 2-methoxyacylhydrazones were optimized to yield compounds with high affinity for PDE10A. Several compounds demonstrated efficacy in animal models of schizophrenia, including conditioned avoidance response and a pro-psychotic phencyclidine hyperactivity model. PMID- 22841438 TI - Four-dimensional, flow-sensitive magnetic resonance imaging of blood flow patterns in thoracic aortic dissections. AB - OBJECTIVE: The purpose of this study was to evaluate alterations in flow patterns in thoracic aortic dissections using 4-dimensional, flow-sensitive magnetic resonance imaging. METHODS: This prospective study was conducted at 2 academic tertiary referral medical centers. Thirteen 4-dimensional flow magnetic resonance imaging studies were performed in 12 subjects (4 female, aged 25-71 years) with thoracic aortic dissection using 3.0T clinical scanners. Qualitative assessment of flow patterns in the true and false lumina was performed in consensus by 3 cardiovascular radiologists. Quantitative analysis included measurement of net flow, retrograde flow, peak flow, and time-to-peak flow in the true and false lumina in the ascending aorta, aortic arch, and descending aorta. Differences in flow through the true and false lumina at each analysis plane were compared with the 2-tailed, paired Student t test. RESULTS: Flow patterns were significantly altered in association with different extents of disease, vessel dilatation, and post-therapeutic anatomy. Total flow per cardiac cycle and peak flow were higher in the true lumen than in the false lumen (P < .01). Retrograde flow was less in the true lumen than in the false lumen (P <= .01). Time-to-peak flow in the true lumen occurred later than in the false lumen (P = .05-.08). CONCLUSIONS: Four dimensional, flow-sensitive magnetic resonance imaging at 3.0T provided qualitative and quantitative information on alterations of aortic flow in patients with thoracic aortic dissection. Future application of this magnetic resonance flow methodology may help provide insights into the pathophysiology and effects of flow alterations and establish prognostic indicators for the development of complications or aneurysm growth in patients with aortic dissection. PMID- 22841439 TI - A new classification of bronchial anastomosis after sleeve lobectomy. AB - OBJECTIVE: Ischemia and infection of the distal part of the tracheobronchial anastomosis are the leading causes of bronchial anastomotic leakage with a high morbidity and mortality. To improve interpretation of healing of the anastomosis and the consequences, we have developed a classification scheme that allows quality control and defines early and standardized treatment of complications. PATIENTS AND METHOD: We conducted a retrospective analysis of the records of 202 patients treated in our institution between January 1, 2006 and December 31, 2010 after sleeve lobectomy. All patients received prophylactic inhalation with tobramycin 80 mg twice a day. Neoadjuvant treatment was given in 21% of the patients. Routine bronchoscopy on day 7 was performed with classification of the anastomosis as follows: X, unknown; 1, healing well with no fibrin deposits; 2, focal fibrin deposits and superficial (mucosal) necrosis; 3, circular fibrin deposits, superficial (mucosal) necrosis, and/or ischemia of the distal mucosa; 4, transmural necrosis with instability of the anastomosis; and 5, perforation, necrosis of the anastomosis, and insufficiency. RESULTS: The anastomosis was graded as satisfactory (1 and 2) in 86% of the patients. In 14%, it was regarded as critical (>=3-5) leading to systemic antibiotic treatment and control bronchoscopy. The overall 30-day mortality was 1%. CONCLUSIONS: Quality control of the tracheobronchial anastomosis comprised bronchoscopy performed before patients were dismissed. Inasmuch as postoperative bronchoscopy is not always performed by the operating surgeon, this classification is an aid to improve the description of endobronchial healing and to commence treatment of critical bronchial healing. PMID- 22841440 TI - CD recording of clinical consultations in the oncology clinic for subsequent patient use. PMID- 22841441 TI - Bezafibrate can be a new treatment option for mitochondrial fatty acid oxidation disorders: evaluation by in vitro probe acylcarnitine assay. AB - BACKGROUND: The number of patients with mitochondrial fatty acid oxidation (FAO) disorders is recently becoming larger with the spread of newborn mass screening. Despite the advances in metabolic and molecular characterization of FAO disorders, the therapeutic studies are still limited. It was reported recently that bezafibrate (BEZ), an agonist of peroxisome proliferating activator receptor (PPAR), can restore FAO activity in cells from carnitine palmitoyltransferase-2 (CPT2) and very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies as well as clinical symptoms in the adult patients. METHODS: In this study, the therapeutic effect of BEZ was determined by in vitro probe acylcarnitine (IVP) assay using cultured fibroblasts and tandem mass spectrometry on various FAO disorders. The clinical trial of BEZ treatment for a boy with the intermediate form of glutaric acidemia type 2 (GA2) was also performed. RESULTS: The effect of BEZ was proven in cells from various FAO disorders including GA2, deficiencies of VLCAD, medium chain acyl-CoA dehydrogenase, CPT2, carnitine acylcarnitine translocase and trifunctional protein, by the IVP assay. The aberrantly elevated long- or medium chain acylcarnitines that are characteristic for each FAO disorder were clearly corrected by the presence of BEZ (0.4 mmol/L) in culture medium. Moreover, daily administration of BEZ in a 2-year-old boy with GA2 dramatically improved his motor and cognitive skills, accompanied by sustained reduction of C4, C8, C10 and C12 acylcarnitines in blood, and normalized the urinary organic acid profile. No major adverse effects have been observed. CONCLUSION: These results indicate that BEZ could be a new treatment option for FAO disorders. PMID- 22841442 TI - Mutant alpha-galactosidase A with M296I does not cause elevation of the plasma globotriaosylsphingosine level. AB - Recently, plasma globotriaosylsphingosine (lyso-Gb3) has attracted attention as a biomarker of Fabry disease. However, we found a subset of Fabry disease patients who did not show any increase in the plasma lyso-Gb3 concentration, although other patients exhibited apparent enhancement of it. This subset predominantly exhibited the clinical phenotype of later-onset Fabry disease, and gene analysis revealed that the patients harbored the M296I mutation common to Japanese Fabry patients. This amino acid substitution is predicted to cause a small conformational change on the surface of the alpha-galactosidase A molecule, resulting in residual enzyme activity. Plasma lyso-Gb3 is a good biomarker of Fabry disease but care should be taken when it is used for a definitive diagnosis. PMID- 22841443 TI - Step-gate polysilicon nanowires field effect transistor compatible with CMOS technology for label-free DNA biosensor. AB - Currently, detection of DNA hybridization using fluorescence-based detection technique requires expensive optical systems and complex bioinformatics tools. Hence, the development of new low cost devices that enable direct and highly sensitive detection stimulates a lot of research efforts. Particularly, devices based on silicon nanowires are emerging as ultrasensitive electrical sensors for the direct detection of biological species thanks to their high surface to volume ratio. In this study, we propose innovative devices using step-gate polycrystalline silicon nanowire FET (poly-Si NW FETs), achieved with simple and low cost fabrication process, and used as ultrasensitive electronic sensor for DNA hybridization. The poly-SiNWs are synthesized using the sidewall spacer formation technique. The detailed fabrication procedure for a step-gate NWFET sensor is described in this paper. No-complementary and complementary DNA sequences were clearly discriminated and detection limit to 1 fM range is observed. This first result using this nano-device is promising for the development of low cost and ultrasensitive polysilicon nanowires based DNA sensors compatible with the CMOS technology. PMID- 22841444 TI - Micro-fluidic chip platform for the characterization of breast cancer cells using aptamer-assisted immunohistochemistry. AB - We demonstrated a new QIHC (Quantitative Immunohistochemistry) microfluidic PDMS (Polydimethylsiloxane) platform by the introduction of the aptamer specific to the Fc region of the IgG antibody as a reporting probe. The aptamer was designed and synthesized. Various breast cancer cell lines were prepared as paraffin block slides, which were covered by a microfluidic PDMS platform to form a micro reaction chamber. Primary antibodies specific to marker proteins (HER2, ER, PR, and ki-67) for breast cancer characterization were loaded in the micro-fluidic chip prior to the introduction of the aptamer. A master mixture of QNASBA (Quantitative Nucleic Acid Sequence Based Amplification) was used to quantify marker proteins by real time amplification of the aptamers. The quantitative results of aptamer amplification were linearly proportional to the concentrations of 4 different primary antibodies. The characterization results of the aptamer assisted IHC using the microfluidic platform were well-correlated with those of conventional IHC for breast cancer cell lines (SK-BR-3, MCF-7, MDA-MB-231). Objective quantitative evaluations were carried out and compared with conventional results for real clinical samples. PMID- 22841445 TI - Biomimetic sensor for certain catecholamines employing copper(II) complex and silver nanoparticle modified glassy carbon paste electrode. AB - A dimeric Cu(II) complex [Cu(MU(2)-hep)(hep-H)](2).2ClO(4) (1) containing bidentate (hep-H=2-(2-hydroxyethyl)pyridine) ligand was synthesized and characterized by single crystal X-ray diffraction studies. Each Cu-ion in 1 is in a distorted square pyramidal geometry. Further 1 along with silver nanoparticles (SNPs) have been used as modifier in the construction of a biomimetic sensor (1 SNP-GCPE) for determining certain catecholamines viz., dopamine (DA), levodopa (l Dopa), epinephrine (EP) and norepinephrine (NE) using cyclic voltammetry, chronocoulometry, electrochemical impedance spectroscopy and adsorptive stripping square wave voltammetry (AdSSWV). Finally, the catalytic properties of the sensor were characterized by chronoamperometry. Employing AdSSWV, the calibration curves showed linear response ranging between 10(-6) and 10(-9)M for all the four analytes with detection limits (S/N=3) of 8.52*10(-10)M, 2.41*10(-9)M, 3.96*10( 10)M and 3.54*10(-10)M for DA, l-Dopa, EP and NE respectively. The lifetime of the biomimetic sensor was 3 months at room temperature. The prepared modified electrode shows several advantages such as simple preparation method, high sensitivity, high stability, ease of preparation and regeneration of the electrode surface by simple polishing along with excellent reproducibility. The method has been applied for the selective and precise analysis of DA, l-Dopa, EP and NE in pharmaceutical formulations, urine and blood serum samples. PMID- 22841446 TI - Platelet-derived growth factor oncoprotein detection using three-dimensional carbon microarrays. AB - The potential of aptamers as ligand binding molecule has opened new avenues in the development of biosensors for cancer oncoproteins. In this paper, a label free detection strategy using signaling aptamer/protein binding complex for platelet-derived growth factor (PDGF-BB) oncoprotein detection is reported. The detection mechanism is based on the release of fluorophore (TOTO intercalating dye) from the target binding aptamer's stem structure when it captures PDGF. Amino-terminated three-dimensional carbon microarrays fabricated by pyrolyzing patterned photoresist were used as a detection platform. The sensor showed near linear relationship between the relative fluorescence difference and protein concentration even in the sub-nanomolar range with an excellent detection limit of 5pmol. This detection strategy is promising in a wide range of applications in the detection of cancer biomarkers and other proteins. PMID- 22841447 TI - Transmission of Lawsonia intracellularis to weanling foals using feces from experimentally infected rabbits. AB - The aim of this study was to investigate whether feces from rabbits experimentally infected with Lawsonia intracellularis were infectious to foals. Two rabbits were infected with L. intracellularis, while two rabbits served as controls. Eight foals received daily feces from either the infected or the control rabbits. All rabbits and foals were monitored daily for clinical signs for the entire study period (21days for rabbits, 42days for foals). Feces and blood were collected for the PCR detection of L. intracellularis and serologic analysis, respectively. None of the infected rabbits or foals developed clinical signs compatible with proliferative enteropathy. All infected rabbits and foals shed L. intracellularis in their feces and all seroconverted. The results support the role of rabbits as asymptomatic amplifiers of L. intracellularis and their role as sources of infection for susceptible foals. PMID- 22841448 TI - Pyrosequencing of the rabies virus glycoprotein gene to demonstrate absence of vaccine-associated rabies cases following oral vaccination. AB - Replication competent vaccines have been used successfully for the control of terrestrial rabies, mainly in wildlife; however, these vaccine strains occasionally may induce rabies. In this study, a pyrosequencing protocol for the rapid identification of vaccine-associated rabies viruses was applied to the 2008 2011 Italian epidemic. There was no evidence of vaccine-associated rabies cases following oral vaccination of foxes with the SAG2 and SADB19 vaccine strains. PMID- 22841449 TI - Risk factors for insect bite hypersensitivity in Friesian horses and Shetland ponies in The Netherlands. AB - Insect bite hypersensitivity (IBH) is an equine skin allergy caused by bites of Culicoides spp. and impacts on the welfare of affected horses. The aim of this study was to identify and quantify risk factors for IBH. Data from 3453 Friesian horse mares and 7074 Shetland pony mares scored for IBH by inspectors during obligatory foal inspections were analysed using breed-specific multivariable logistic regression models. The combined effect of month and year of scoring, Province and inspector were significantly associated with IBH in both breeds. In Shetland pony mares, withers height and coat colour were also significantly associated with IBH, while body condition had a nearly significant effect. The outcomes from this study on risk factors might contribute to the development of more efficient measures to reduce the prevalence of IBH. PMID- 22841450 TI - Commercial porcine circovirus type 2 vaccines: efficacy and clinical application. AB - Porcine circovirus type 2 (PCV2) is the one of the most economically important pathogens of pigs. After postweaning multisystemic wasting syndrome (PMWS) was first identified and reported in western Canada in 1991, it took 13years for the first commercial PCV2 vaccine to be used under special licence in France and Germany in 2004. Along with PMWS, PCV2 is also associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease (PCVAD). Currently, five commercial vaccines are available on the international market. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. This review focuses on (1) the types of commercial vaccines; (2) the criteria of vaccine efficacy; (3) the clinical, virological, immunological and pathological efficacy of the vaccines; and (4) the use of PCV2 vaccines against different clinical manifestations of PCVAD. PMID- 22841451 TI - Prognostic histopathological and molecular markers in feline mammary neoplasia. AB - Feline mammary tumours comprise approximately 11% of feline non-integumentary neoplasms, are more commonly malignant than benign, and carry a poor prognosis attributable to a high probability of local recurrence and metastasis. This review discusses histopathological and molecular markers that could aid in prognostic discrimination, and draws comparisons with studies examining prognostic markers in breast cancer. Tumour grade and mitotic index correlate with survival data and could be useful for prognostication. Although assessment of Ki67 expression might have prognostic potential, further studies are required to corroborate the correlation between expression and clinical outcome. Additional molecular markers that have been investigated for prognostic potential can be grouped according to the 'hallmarks of cancer'. Many studies utilise 'surrogate markers' of clinical outcome, such as correlation with histological grade, to assess the prognostic value of molecular markers, and further investigation is therefore necessary before reaching firm conclusions regarding the prognostic value of some markers. Feline mammary tumours have been proposed as spontaneous models of breast cancer but might only be suitable models for certain molecular sub-types. Compared to humans, cats tend to have a high percentage of mammary tumours which are oestrogen receptor-negative and they might therefore be suitable models for late stage oestrogen receptor-negative breast cancer. The basal-like properties of feline mammary carcinomas offer another avenue for future research in this field of comparative oncology. PMID- 22841452 TI - Effects on cardiopulmonary function and oxygen delivery of doses of romifidine and xylazine followed by constant rate infusions in standing horses. AB - The objective of this study was to compare the cardiopulmonary effects of a xylazine or romifidine loading-dose, followed by a constant rate infusion (CRI) of the same alpha(2)-agonist. Nine research horses were treated in a randomized, blinded, crossover design with xylazine or romifidine. After instrumentation, a loading dose of intravenous xylazine (1mg/kg) or romifidine (80MUg/kg) was administered, immediately followed by a CRI of xylazine (0.69mg/kg/h) or romifidine (30MUg/kg/h) for a duration of 2h. Cardiopulmonary variables were recorded before bolus administration, during CRI, and for 1h after discontinuing drug administration. A significant decrease in haemoglobin concentration (tHb), arterial oxygen content (CaO(2)), oxygen delivery (DO(2)), mixed venous partial pressure of oxygen, heart rate, and cardiac output (Qt) followed the loading dose with both treatments. Carotid arterial blood pressure (ABP), systemic vascular resistance, and right atrial pressure (RAP) increased significantly. The increased ABP was followed by a significant decrease compared to baseline. Mean pulmonary arterial pressure increased significantly with romifidine only. No significant changes in stroke volume, arterial partial pressure of oxygen, and oxygen consumption were observed. Changes in Qt and RAP were more pronounced with romifidine. During CRI, tHb, and CaO(2) were significantly higher with romifidine, whereas DO(2) did not differ between treatments. Overall, cardiopulmonary effects were more pronounced and lasted longer with romifidine compared to xylazine. However, during CRI, there was no difference in DO(2) between drugs. With both alpha(2)-agonists, cardiovascular effects were most pronounced after loading dose administration and tended to stabilize during CRI. PMID- 22841453 TI - [Constitutional syndrome, fever and systemic embolisms due to two common-origin conditions: the heart]. PMID- 22841455 TI - Effects of alcohol on disinhibition towards alcohol-related cues. AB - BACKGROUND: We investigated (1) the effects of acute alcohol on inhibition of alcohol-related versus neutral cues, (2) the effects of drinking status on inhibition of alcohol-related versus neutral cues, and (3) the similarity of any effects of alcohol or drinking status across two different cue types (lexical versus pictorial). METHODS: Participants received 0.0 g/kg, 0.4 g/kg or 0.6g/kg of alcohol in a between-subjects design. Healthy, heavy and light social alcohol users (n=96) completed both lexical and pictorial cue versions of an alcohol shifting task. Participants were instructed to respond to target stimuli by pressing the spacebar, but to ignore distracter stimuli. Errors towards distracter stimuli were analysed using a series of mixed-model ANOVAs, with between-subjects factors of challenge and drinking status and within-subjects factors of distracter type (alcohol, neutral) and block (shift, non-shift). RESULTS: Lexical commission error data indicated a main effect of distracter (F [1,90]=43.25, p<0.001, eta(2)=0.33), which was qualified by a marginal interaction with challenge condition (F [2,90]=2.77, p=0.068, eta(2)=0.06). Following an acute high dose of alcohol participants made more errors towards alcohol distracters. Pictorial commission error data indicated a significant main effect of distracter (F [1,90]=67.40, p<0.001, eta(2)=0.43), such that all participants made more errors towards neutral image distracters versus alcohol distracter images. CONCLUSIONS: Our results reveal acute alcohol's impairment of inhibitory control may be enhanced when a response towards alcohol-related lexical stimuli is required to be withheld. PMID- 22841456 TI - Neonatal outcomes following in utero exposure to methadone or buprenorphine: a National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009. AB - BACKGROUND: In Norway, most opioid-dependent women are in opioid maintenance treatment (OMT) with either methadone or buprenorphine throughout pregnancy. The inclusion criteria for both medications are the same and both medications are provided by the same health professionals in any part of the country. International studies comparing methadone and buprenorphine in pregnancy have shown differing neonatal outcomes for the two medications. METHOD: This study compared the neonatal outcomes following prenatal exposure to either methadone or buprenorphine in a national clinical cohort of 139 women/neonates from 1996 to 2009. RESULTS: After adjusting for relevant covariates, buprenorphine-exposed newborns had larger head circumferences and tended to be heavier and longer than methadone-exposed newborns. The incidence of neonatal abstinence syndrome (NAS) and length of treatment of NAS did not differ between methadone- and buprenorphine-exposed newborns. There was little use of illegal drugs and benzodiazepines during the pregnancies. However, the use of any drugs or benzodiazepines during pregnancy was associated with longer lasting NAS-treatment of the neonates. CONCLUSIONS: The clinical relevance of these findings is that both methadone and buprenorphine are acceptable medications for the use in pregnancy, in line with previous studies. If starting OMT in pregnancy, buprenorphine should be considered as the drug of choice, due to more favorable neonatal growth parameters. Early confirmation of the pregnancy and systematic follow-up throughout the pregnancy are of importance to encourage the women in OMT to abstain from the use of tobacco, alcohol, illegal drugs or misuse of prescribed drugs. PMID- 22841457 TI - 2012 Beers criteria update: how should practicing nurses use the criteria? PMID- 22841454 TI - The contribution of stress to the social patterning of clinical and subclinical CVD risk factors in African Americans: the Jackson Heart Study. AB - It is often hypothesized that psychosocial stress may contribute to associations of socioeconomic position (SEP) with risk factors for cardiovascular disease (CVD). However, few studies have investigated this hypothesis among African Americans, who may be more frequently exposed to stressors due to social and economic circumstances. Cross-sectional data from the Jackson Heart Study (JHS), a large population-based cohort of African Americans, were used to examine the contributions of stressors to the association of SEP with selected cardiovascular (CVD) risk factors and subclinical atherosclerotic disease. Among women, higher income was associated with lower prevalence of hypertension, obesity, diabetes and carotid plaque and lower levels of stress. Higher stress levels were also weakly, albeit positively, associated with hypertension, diabetes, and obesity, but not with plaque. Adjustment for the stress measures reduced the associations of income with hypertension, diabetes and obesity by a small amount that was comparable to, or larger, than the reduction observed after adjustment for behavioral risk factors. In men, high income was associated with lower prevalence of diabetes and stressors were not consistently associated with any of the outcomes examined. Overall, modest mediation effects of stressors were observed for diabetes (15.9%), hypertension (9.7%), and obesity (5.1%) among women but only results for diabetes were statistically significant. No mediation effects of stressors were observed in men. Our results suggest that stressors may partially contribute to associations of SEP with diabetes and possibly hypertension and obesity in African American women. Further research with appropriate study designs and data is needed to understand the dynamic and interacting effects of stressors and behaviors on CVD outcomes as well as sex differences in these effects. PMID- 22841458 TI - Medication management in assisted living. PMID- 22841459 TI - 18F-FDG-PET/CT in lymphoma: two decades of experience. AB - The use of (18)F-FDG-PET/CT has changed the management of patients with lymphoma for the last two decades. This technique improves initial staging of the disease, making a prognostic approach and appropriate treatment planning, as well as monitoring therapy response of lymphoma. However, there are still controversial issues in medical literature that impact on daily clinical practice. This comprehensive literature review summarizes the current information regarding the potential use of (18)F-FDG-PET/CT in patients with lymphoma, highlighting the main applications and the current dilemmas for the nuclear medicine physicians at the time of the evaluation of these studies, trying to standardize criteria for its assessment, particularly in restaging and therapy monitoring. PMID- 22841460 TI - [Chemical submission and attention in emergency departments]. PMID- 22841461 TI - [Lactic acidosis due to thiamine deficiency]. PMID- 22841462 TI - [Is it dangerous to reduce excessively blood pressure? The J curve]. PMID- 22841463 TI - [Inflammation and oxidative stress in respiratory and limb muscles of patients with severe sepsis]. AB - BACKGROUND AND OBJECTIVE: Oxidative stress and inflammation contribute to the diaphragm contractile dysfunction observed in animal models of sepsis and endotoxemia. In septic patients, molecular events have never been explored in their respiratory muscles. Levels of oxidative stress and inflammation were evaluated in a respiratory muscle, the external intercostal, and a limb muscle, the vastus lateralis, of patients with sepsis. PATIENTS AND METHODS: Levels of oxidized and nitrated proteins, protein adducts of malondialdehyde and hydroxinonenal, antioxidant enzymes catalase and Mn-superoxide dismutase, tumor necrosis factor (TNF)-alpha, TNF-alpha receptors i and ii, interleukin (IL)-1 and IL-6, the panleukocyte marker CD18, and fiber type composition were explored using immunoblotting, real time-polymerase chain reaction, and immunohistochemistry in the external intercostal and vastus lateralis of patients with severe sepsis and/or septic shock. RESULTS: Compared to the controls, in septic patients, levels of oxidized and nitrated proteins were increased in the vastus lateralis, but not in the external intercostal, while those of the antioxidant enzymes did not differ, and the proportions and sizes of the muscle fibers were not significantly different in any muscle between patients and controls. CONCLUSIONS: Differences in activity between the respiratory and limb muscles may account for the differential pattern of oxidative stress and inflammation observed among patients with severe sepsis. These findings may have relevant implications for the clinical and therapeutic management of these patients. PMID- 22841464 TI - [Treatment effect of breast cancer and prostate cancer on bone]. AB - Aromatase inhibitors are used in the treatment of breast cancer and androgen deprivation therapy is used in prostate cancer. Both of them induce bone loss and increase fracture incidence. Early detection is important for patients with increased risk of osteoporotic fractures. In this article we review the available treatments and their indication to prevent the onset of osteoporosis and osteoporotic fractures in this patient group. PMID- 22841465 TI - [Gestational diabetes mellitus and maternal ethnicity: high prevalence of fetal macrosomia in non-Caucasian women]. AB - BACKGROUND AND OBJECTIVE: Differences in perinatal outcomes according to ethnicity have been described in pregnant women with gestational diabetes mellitus (GDM). We analysed the relationship between ethnicity, maternal characteristics and perinatal outcomes in pregnant women with GDM. PATIENTS AND METHODS: Retrospective analysis of women with GDM attended at the centre between 1986 and 2007. We studied 2,543 mother-infant pairs (8.9% multiple pregnancies, 2,480 Caucasian [C] and 63 non-Caucasian [NC] mothers). Maternal characteristics and perinatal outcomes were compared according to maternal ethnicity and multivariable logistic regression analyses (backward method) were performed to predict perinatal outcomes. RESULTS: The groups (C vs NC) differed in previous pregnancies, obstetric history, pregestational body mass index, delay between diagnosis and clinic entry, fasting plasma glucose at diagnosis and both initial and third trimester glycated hemoglobin, with all of them being worse in NC group. As to perinatal outcomes, we also observed differences in the prevalence of macrosomic (4.3 vs 19.4%) and large for gestational age newborns (LGA) (9.5 vs 32.3%), all of them being higher in the NC group. In the logistic regression analyses, NC was an independent predictor of macrosomia, LGA and jaundice with odds ratio ranging from 2.767 (95% confidence interval [95% CI] 1.257-6.091) for LGA and 3.629 (95% CI 0.972-13.548) for neonatal jaundice. CONCLUSIONS: NC-GDM patients had more adverse perinatal outcomes only partially explained by medical history, anthropometric data and maternal glycemic control. NC ethnicity was an independent predictor of poor perinatal outcomes. PMID- 22841466 TI - [Utilization of the extracorporeal membrane oxygenator in myocarditis with refractory cardiogenic shock: preliminary results from a Spanish pioneering experience]. PMID- 22841467 TI - [Metabolic syndrome in patients with schizophrenia and antipsychotic treatment]. AB - Patients with schizophrenia have a shorter life expectancy and their risk of dying from a cardiovascular disease is higher than the general population. Both facts have been attributed to the raised presence of metabolic syndrome. There is a big amount of scientific publications that deals with the relationship between schizophrenia, antipsychotic treatment, and the development of metabolic syndrome. There is also information about recommendations and clinical guides to achieve an adequate prevention, screening, and treatment of the disease. The aim of this review is to update the current information about this issue and to understand related etiologic factors, differences between antipsychotic drugs, and the current recommendations for patient's care. PMID- 22841468 TI - [Evolution of the frequency of congenital defects in newborn infants and fetuses from terminations of pregnancy after prenatal diagnosis in the period 1982-2009]. AB - BACKGROUND AND OBJECTIVE: The study of congenital defects (CD) must include termination of pregnancy (TOP) for CD and evaluate risk factors that modify their frequency. PATIENTS AND METHODS: Consecutive series of 517 newborn and 202 TOP with CD among 38,191 childbirths, between 1982-2009 years. RESULTS: The mean frequency for newborns with CD is 13.540/00 and for newborn and TOP with CD is 18.730/00. Single CD are 61.12% in newborns and 52.17% in TOP. The 18.37% of CD in newborn and 40.58% of TOP are syndromic. Mean gestational age for TOP is 17.92 weeks. Overall frequency of anencephaly is 2.620/00 for newborns and 6.77 for 10,000 for newborns and TOP. Spina bifida is 3.14 for 10,000 newborns and 5.99 for 10,000 newborns and TOP. Overall frequency of Down syndrome (DS) is 10.74 for 10,000 newborns and 22.14 for 10,000 newborns and TOP. The percentage of foreign mothers was 35.9% in 2009 and the mean maternal age significantly increased in this period. CONCLUSION: We observe a significant decrease of CD in newborns but not in their conception. We have not detected primary prevention for neural tube defects. The decrease in DS in newborns is not statistically relevant but ethnic diversity and maternal aging may be modifying the frequency. The 53% of CD were TOP in the period 2007-2009. It is mandatory a complete study for CD in TOP in order to offer serious reproductive counselling. PMID- 22841469 TI - [Management of esophageal squamous cell carcinoma and adenocarcinoma: surgical, endoscopic, and radiotherapeutic options]. PMID- 22841470 TI - [Relevance of diabetes in high cardiovascular risk hypertensive patients]. AB - BACKGROUND AND OBJECTIVE: The aim of this cross-sectional study was to compare the prevalence of target organ damage (TOD) and established cardiovascular disease (CVD) in a cohort of nondiabetic hypertensive patients with 3 or more cardiovascular risk factors (CVRF) against a group of hypertensives with type 2 diabetes. PATIENTS AND METHOD: We included 4,725 hypertensive patients, 62% male, mean age 64 (SD 12) years, with type 2 diabetes mellitus, independently of the number of associated CVRF (N=2,608), or non-diabetics, in which case we required the presence of 3 CVRF (N=2,117). The prevalence of established CVD (clinical interview) and TOD (left ventricular hypertrophy by electrocardiogram, microalbuminuria and estimated glomerular filtration rate) were estimated. RESULTS: Hypertensive patients with type 2 diabetes had an older age and more marked obesity. Furthermore, these patients showed a higher prevalence of micro- and macroalbuminuria, renal failure, left ventricular hypertrophy, atherosclerotic plaques in carotid arteries and CVD compared with nondiabetic hypertensive patients with 3 or more CVRF. Multivariate analysis showed that the risk of TOD or established CVD were associated independently with the presence of diabetes. CONCLUSION: Hypertensive patients with type 2 diabetes have a higher prevalence of LOD and CVD compared to nondiabetic hypertensive patients with 3 or more CVRF. Although both situations are included in the high cardiovascular risk stratum, it would be expected an increased incidence of cardiovascular complications in hypertensive diabetic patients. PMID- 22841471 TI - [Tinea incognito]. PMID- 22841472 TI - A brief educational intervention about pain and aging for older members of the community and health care workers. AB - Developing educational interventions about pain may lead to improved pain management for older people. A public group educational session, entitled "Pain in the Older Person," was presented in 7 cities across Canada (Vancouver, Calgary, London, Toronto, Ottawa, Montreal, and Halifax). The presentation lasted approximately 90 minutes and was followed by a question and answer period of at least 20 minutes. Prior to the educational session, participants provided demographic data and completed measures of pain intensity, frequency, interference, and treatment; of subjective health; and of knowledge about pain. Following the session, participants completed the same knowledge items again as well as items assessing satisfaction. Data were provided by 54 health care workers (HCW) and 54 older community members (66.3 +/- 10.2 years old). Prior to the educational session, knowledge gaps were evident among the older community members, especially about analgesic use. Among the HCW, knowledge gaps were found about addiction and the relationship between pain and aging. Comparison of knowledge scores before and after the educational session revealed that both groups demonstrated significant knowledge gains. Satisfaction scores were very high, with no significant difference between HCW and older community members. This is the first study to show that a brief educational intervention is associated with gains in knowledge about pain and aging among both older community members and HCW. These results suggest that a brief public educational session is a promising method of pain education that may reduce barriers to pain management in older people. PERSPECTIVE: This article describes the results of a brief public educational session about pain and aging attended by older members of the community and health care workers. This intervention could potentially improve pain management for older people. PMID- 22841473 TI - Transient reduction and activation of circulating dendritic cells in patients with acute myocardial infarction. AB - BACKGROUND: Dendritic cells (DCs) are highly potent professional antigen presenting cells that play a central role in initiating the primary immune response. Accumulating evidence suggests that immune-mediated inflammation plays an important role in the pathophysiology of AMI, but the mechanism that triggers such immune responses is unknown. METHODS: Using multi-color flow-cytometry, we determined the numbers of circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with AMI (n = 26) or stable angina pectoris (SAP) (n = 19), and in age-matched control subjects (n = 19). The DC activation markers CD40 and CD83 were also measured. RESULTS: On admission, circulating mDC and pDC counts were significantly lower in AMI patients compared to control subjects and SAP patients (mDC, P < 0.01; pDC, P < 0.05). The activation markers of mDCs in AMI patients were significantly higher and returned to the levels of control subjects or SAP patients 3 days after AMI (mDC, P < 0.05; pDC, P < 0.05). Reductions of circulating mDC and pDC numbers were restored 7 days after the onset of AMI. Furthermore, we found that the recovery of the circulating DC numbers 14 days after AMI was correlated with the alterations of creatine kinase-MB (CK-MB) (mDC, r = 0.48, P < 0.05; pDC, r=0.52, P < 0.01) and brain natriuretic peptide (BNP) (mDC, r = 0.53, P < 0.01; pDC, r = 0.51, P < 0.01). CONCLUSION: Our findings suggest that the transient reduction and activation of circulating DCs may play important roles in the pathophysiology of myocardial injury after AMI. PMID- 22841475 TI - Clinicopathologic and radiologic correlation of ossifying fibroma and juvenile ossifying fibroma--an institutional study of 22 cases. AB - To analyze the clinical, radiographic, and histopathologic features of ossifying fibroma (OF) and juvenile OF (JOF), an archival study of 17 cases of OF and 5 cases of JOF reported over a period of 4.5 years was undertaken to analyze the aforementioned features. Age incidence of OF varied from 8 to 53 years, and JOF was seen in a comparatively younger age of 8 to 28 years. Both tumors were almost equally distributed between men and women. Thirteen cases of OF were found to occur in posterior mandible, whereas JOF was predominant in the anterior maxilla. Radiographically, OF varied from completely radiolucent (n = 7), mixed (n = 5), to completely radiopaque (n = 5), whereas JOF was predominantly radiolucent. Microscopically, stroma in OF varied from fibrous to highly cellular with overlap between various types of calcification. Juvenile OF showed highly cellular stroma and 2 distinct patterns of mineralization-psammomatoid and trabecular with osteoid seams. The origin of OF and JOF seems to be distinct from each other with OF arising from periodontal ligament and JOF arising from precursor myxoid tissue of paranasal sinuses. PMID- 22841474 TI - Epigenetic regulation of miR-34a expression in alcoholic liver injury. AB - Epigenetic changes are associated with the regulation of transcription of key cell regulatory genes [micro RNAs (miRNAs)] during different types of liver injury. This study evaluated the role of methylation-associated miRNA, miR-34a, in alcoholic liver diseases. We identified that ethanol feeding for 4 weeks significantly up-regulated 0.8% of known miRNA compared with controls, including miR-34a. Treatment of normal human hepatocytes (N-Heps) and cholangiocytes [human intrahepatic biliary epithelial cells (HiBECs)] with ethanol and lipopolysaccharide induced a significant increase of miR-34a expression. Overexpression of miR-34a decreased ethanol-induced apoptosis in both N-Heps and HiBECs. In support of the concept that the 5'-promoter region of miR-34a was noted to be embedded within a CpG island, the expression level of miR-34a was significantly increased after demethylation treatment in N-Heps and HiBECs. By methylation-specific PCR, we confirmed that miR-34a activation is associated with ethanol-linked hypomethylation of the miR-34a promoter. A combination of bioinformatics, dual-luciferase reporter assay, mass spectrometry, and Western blot analysis revealed that caspase-2 and sirtuin 1 are the direct targets of miR 34a. Furthermore, modulation of miR-34a also altered expression of matrix metalloproteases 1 and 2, the mediators involved in hepatic remodeling during alcoholic liver fibrosis. These findings provide the basis for an exciting field in which the epigenomic microRNAs of hepatic cells may be manipulated with potential therapeutic benefits in human alcoholic liver diseases. PMID- 22841476 TI - Syndecan and integrin interactomes: large complexes in small spaces. AB - The syndecan family of transmembrane proteoglycans cooperate with integrins to regulate both early and late events in adhesion formation. The heparan sulphate chains substituted on to the syndecan ectodomains are capable of engaging ligands over great distance, while the protein core spans the plasma membrane and initiates cytoplasmic signals through a short cytoplasmic tail. These properties create a spatial paradox. The volume of the heparan sulphate chains greatly exceeds that of the integrins with which it cooperates, while the short cytodomain must bind to multiple cytoplasmic factors, despite being long enough to bind only one or two. In this review we consider the structural rearrangements that a cell undertakes to overcome spatial restrictions and compare the interactomes of syndecans and integrins to gain insight into the composition of adhesions and how they are regulated over time. PMID- 22841477 TI - Maintenance of mitochondrial genome distribution by mitochondrial AAA+ protein ClpX. AB - The segregation of mitochondrial DNA (mtDNA) is important for the maintenance and transmission of the genome between generations. Recently, we clarified that human mitochondrial transcription factor A (TFAM) is required for equal distribution and symmetric segregation of mtDNA in cultured cells; however, the molecular mechanism involved is largely unknown. ClpX is an ATPase associated with various cellular activities (AAA+) proteins that localize to the mitochondrial matrix and is suggested to associate with mtDNA. In this study, we found that RNAi-mediated knockdown of ClpX in HeLa cells resulted in enlarged mtDNA nucleoids, which is very similar to that observed in TFAM-knockdown cells in several properties. The expression of TFAM protein was not significantly reduced in ClpX-knockdown cells. However, the enlarged mtDNA nucleoids caused by ClpX-knockdown were suppressed by overexpression of recombinant TFAM and the phenotype was not observed in knockdown with ClpP, a protease subunit of ClpXP. Endogenous ClpX and TFAM exist in close vicinity, and ClpX enhanced DNA-binding activity of TFAM in vitro. These results suggest that human ClpX, a novel mtDNA regulator, maintains mtDNA nucleoid distribution through TFAM function as a chaperone rather than as a protease and its involvement in mtDNA segregation. PMID- 22841478 TI - Safety and immunogenicity of a freeze-dried, cell culture-derived Japanese encephalitis vaccine (Inactivated) (JEBIK((r))V) in children. AB - Freeze dried, cell culture-derived Japanese encephalitis vaccine (Inactivated) (JEBIK((r))V) is approved for a three-dose primary immunization followed by a one dose booster immunization in Japan. We conducted a multicenter, double-blinded, randomized controlled trial of the safety and immunogenicity of the vaccine in 370 healthy children who received three doses of 5, 2.5 or 1.25 MUg of virus protein per 0.5 mL formulation subcutaneously. Children received two doses of test vaccine 7-28 days apart followed by a dose 6-12 months after the second vaccination. The three-dose regimen showed a good safety profile with no serious vaccine-related adverse events. Fever and reactions at the injection site were common adverse reactions at each dose of vaccine. The seroconversion rates were 100%, 99.2% and 95.0% after two doses in the 5, 2.5 and 1.25 MUg groups, respectively, and 100.0% after three doses in all groups. The geometric mean titers were high for all three formulations after the second and third doses, with a very clear dose-response relationship. These results indicate that JEBIK((r))V is likely to be a useful vaccine. PMID- 22841479 TI - A US postmarketing evaluation of the frequency and safety of live attenuated influenza vaccine use in nonrecommended children younger than 5 years: 2009-2010 season. AB - The 2007 US approval for use of Ann Arbor strain live attenuated influenza vaccine (LAIV) in children aged 24 through 59 months included precautions against use in (1) children <24 months and children aged 24 through 59 months with (2) asthma, (3) recurrent wheezing, and (4) altered immunocompetence. Results from the third season (2009-2010) of a 3-year study postmarketing commitment to monitor LAIV vaccination rates and frequency of hospitalizations or emergency department visits within 42 days after LAIV are reported here. As in the first 2 seasons, LAIV usage in cohorts 1, 2, and 4 were low relative to those in LAIV recommended populations. The only numerically increased risk observed was for respiratory events in children aged <24 months administered LAIV, compared to those administered trivalent inactivated influenza vaccine (TIV). The number of children vaccinated with LAIV was small and precluded precise quantification of rare event. PMID- 22841480 TI - Factors influencing postoperative length of hospital stay after breast cancer surgery. AB - As part of a feasibility study to restructure the breast cancer services in Glasgow, factors influencing 'postoperative length of stay' (LOS) and bed utilisation in patients undergoing surgery for breast cancer were examined. Data for patients admitted at five hospitals between March 2007 and February 2008 was collected prospectively. Age, socio-demographic and clinico-pathologic factors were recorded. Independent affects of variables predicting prolonged LOS were assessed using binary logistic regression analysis. Of the 519 women, 252(49%) had screen-detected cancers with a median LOS of 1 day while 267(51%) had symptomatic cancers with a median LOS of 4 days (p < 0.001). On multivariate analysis, axillary procedure performed independently influenced prolonged LOS in both screen-detected and symptomatic cancers. In symptomatic cancers, comorbidities and deprivation also had some influence. While mastectomy with or without axillary surgery utilised 51% of the bed days, a further 20% were utilised by patients having re-operations. This study has helped in the planning of ambulatory surgery services and inpatient bed requirements for patients undergoing breast cancer surgery in Glasgow. PMID- 22841481 TI - Statistical analysis of surface electromyographic signal for the assessment of rectus femoris modalities of activation during gait. AB - Aim of the present study was to identify the different modalities of activation of rectus femoris (RF) during gait at self-selected speed, by a statistical analysis of surface electromyographic signal from a large number (hundreds) of strides per subject. The analysis of ten healthy adults showed that RF is characterized by different activation modalities within different strides of the same walk. RF most recurrent modality (observed in 53 +/- 6% of total strides) consists of three activations, at the beginning of gait cycle, around foot-off and in the terminal swing. Further two modalities of RF activation differ from the most recurrent one because of the lack of activity around foot-off (26 +/- 6%) or the splitting into two (or three) small activations around stance-to-swing transition (17 +/- 2%). Despite the large variability, our statistical analysis allowed to identify two patterns of activation that characterize completely the behavior of rectus femoris during gait. The first pattern, around stance-to-swing transition, can be monophasic, biphasic or triphasic and is necessary to control knee extension and hip flexion from pre-swing to initial swing. The second pattern, from terminal swing to following mid-stance, is likely due to the contribution of low-level RF activity and cross-talk from surrounding vastii. PMID- 22841482 TI - Influence of stimulus intensity on electromechanical delay and its mechanisms. AB - Electromechanical delay (EMD) is the time lag between muscle activation and force development. Using very high frame rate ultrasound, both electrochemical and mechanical processes involved in EMD can be assessed. Percutaneous electrical stimulations at submaximal intensity are often used to stimulate a specific target muscle. The aim of this study was to determine whether stimulus intensity alters the delay between stimulation and the onset of muscle fascicules motion (Dm), the onset of myotendinous junction motion (Dt), and force production (EMD). Ten participants underwent two electrically evoked contractions, with the probe maintained either the biceps brachii muscle belly or the distal myotendinous junction of the biceps brachii, for six stimulus intensities (30%, 50%, 70%, 90%, 110% and 130% of the lowest intensity inducing the maximal involuntary force production, Imax). In addition, inter-day reliability was tested in nine participants at both 70% and 90% of Imax. Dm, Dt and EMD were significantly longer (p < 0.001) at very low (30% and 50% of Imax) compared to higher intensities (70%, 90%, 110% and 130% of Imax). Inter-day reliability of EMD, Dm, and Dt was good (coefficient of variation ranged from 6.8% to 12.5%, i.e. SEM lower than 0.79 ms). These results indicate that the stimulus intensity needs to be standardized to perform longitudinal evaluation and/or to make between-subject comparisons. PMID- 22841483 TI - A systematic review of 3D scapular kinematics and muscle activity during elevation in stroke subjects and controls. AB - Through the onset of post-stroke motor disorders, the normal scapular function is compromised. As a result, shoulder pain and associated upper limb dysfunctions frequently arise after stroke. This review aimed to provide a systematic overview of available literature on scapular function, i.e. scapular three-dimensional (3D) kinematics and muscle activity during elevation, in healthy persons, persons with primary shoulder disorders and post-stroke patients. 3D scapular kinematics have been widely reported in healthy persons and persons with primary shoulder disorders, whereby a general pattern of upward rotation and posterior tilt during elevation has been agreed upon. Results on scapular internal/external rotation are inconsistent. In a post-stroke population, 3D scapular kinematics are less frequently reported. Scapular muscle activity has thus far been studied to very limited extend and firm conclusions could not be drawn. Although 3D scapular kinematics and muscle activity registrations are being increasingly used, some general methodological aspects should be considered. While the International Society of Biomechanics already proposed recommendations on the definition of upper limb joint coordinate systems and rotation sequences, proper result comparison necessitates further guidelines on other methodological aspects, i.e. data collection, processing, analyzing, and reporting. PMID- 22841484 TI - Dissection of mechanistic principles of a secondary multidrug efflux protein. AB - Multidrug transporters are ubiquitous efflux pumps that provide cells with defense against various toxic compounds. In bacteria, which typically harbor numerous multidrug transporter genes, the majority function as secondary multidrug/proton antiporters. Proton-coupled secondary transport is a fundamental process that is not fully understood, largely owing to the obscure nature of proton-transporter interactions. Here we analyzed the substrate/proton coupling mechanism in MdfA, a model multidrug/proton antiporter. By measuring the effect of protons on substrate binding and by directly measuring proton binding and release, we show that substrates and protons compete for binding to MdfA. Our studies strongly suggest that competition is an integral feature of secondary multidrug transport. We identified the proton-binding acidic residue and show that, surprisingly, the substrate binds at a different site. Together, the results suggest an interesting mode of indirect competition as a mechanism of multidrug/proton antiport. PMID- 22841485 TI - DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. AB - DNA methylation is a mechanism of epigenetic regulation that is common to all vertebrates. Functional studies underscore its relevance for tissue homeostasis, but the global dynamics of DNA methylation during in vivo differentiation remain underexplored. Here we report high-resolution DNA methylation maps of adult stem cell differentiation in mouse, focusing on 19 purified cell populations of the blood and skin lineages. DNA methylation changes were locus specific and relatively modest in magnitude. They frequently overlapped with lineage associated transcription factors and their binding sites, suggesting that DNA methylation may protect cells from aberrant transcription factor activation. DNA methylation and gene expression provided complementary information, and combining the two enabled us to infer the cellular differentiation hierarchy of the blood lineage directly from genome-scale data. In summary, these results demonstrate that in vivo differentiation of adult stem cells is associated with small but informative changes in the genomic distribution of DNA methylation. PMID- 22841486 TI - A central coupler for recombination initiation linking chromosome architecture to S phase checkpoint. AB - Higher-order chromosome structure is assumed to control various DNA-templated reactions in eukaryotes. Meiotic chromosomes implement developed structures called "axes" and "loops"; both are suggested to tether each other, activating Spo11 to catalyze meiotic DNA double-strand breaks (DSBs) at recombination hotspots. We found that the Schizosaccharomyces pombe Spo11 homolog Rec12 and its partners form two distinct subcomplexes, DSBC (Rec6-Rec12-Rec14) and SFT (Rec7 Rec15-Rec24). Mde2, whose expression is strictly regulated by the replication checkpoint, interacts with Rec15 to stabilize the SFT subcomplex and further binds Rec14 in DSBC. Rec10 provides a docking platform for SFT binding to axes and can partially interact with DSB sites located in loops depending upon Mde2, which is indicative of the formation of multiprotein-based tethered axis-loop complex. These data lead us to propose a mechanism by which Mde2 functions as a recombination initiation mediator to tether axes and loops, in liaison with the meiotic replication checkpoint. PMID- 22841488 TI - Antimalarial activity of ellipticine. PMID- 22841487 TI - LincRNA-p21 suppresses target mRNA translation. AB - Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and beta-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation. PMID- 22841489 TI - Leaf curl diseases of two solanaceous species in Southwest Arabia are caused by a monopartite begomovirus evolutionarily most closely related to a species from the Nile Basin and unique suite of betasatellites. AB - The complete genome of 2780 bases was amplified using rolling circle amplification, and cloned, and sequenced for two distinct strains of the monopartite begomovirus Tomato leaf curl Sudan virus (ToLCSDV). The two strains shared 86-91% identity with the previously described ToLCSDV from the Nile Basin, and 90-91% identity with one another. One strain was cloned from symptomatic tomato plants from Tihamah (ToLCSDV-YE[YE:Tih:05]) while the other was cloned from symptomatic tobacco plants collected from Wadi Hadramaut (ToLCSDV YE[YE:Had:89]). A distinct full-length betasatellite molecule (1352 bases) was cloned from the respective field-infected tomato and tobacco plants. Agro inoculation of tomato and Nicotiana benthamiana plants with cloned partial tandem repeats of ToLCSDV-YE[YE:Tih11:05]) and the associated betasatellite, Tomato leaf curl Yemen betasatellite (ToLCYEB-[Tih:tom:137:05]), resulted in the reproduction of leaf curl disease symptoms in test plants like those observed in the field infected plants. The betasatellite contributed to symptom severity in N. benthamiana test plants when it was co-inoculated with ToLCSDV-YE, compared to the milder symptoms that were observed in tobacco plants infected with the helper virus alone. PMID- 22841490 TI - Australian monocot-infecting mastrevirus diversity rivals that in Africa. AB - Monocotyledonous plant infecting mastreviruses (family Geminiviridae) have been found in the Old World. The greatest diversity of these viruses has been found in Africa but this may simply reflect the more extensive sampling that has been done there. To provide a better understanding of mastrevirus diversity in Australia, we have sequenced the genomes of 41 virus isolates found in naturalised and native grasses and identified four new species in addition to the four previously characterised species. Two of these species, which were recovered from a single Sporobolus plant, are highly divergent and are most closely related to the African streak viruses. This, coupled with the discovery of divergent dicotyledonous plant infecting mastreviruses in Australia brings into question the hypothesis that mastreviruses may have originated in Africa. We found that the patterns of inter- and intra-species recombination and the recombination hotspots mirror those found in both their African monocot-infecting counterparts and dicot-infecting mastrevirus. PMID- 22841491 TI - Coordinated and sequential transcription of the cyprinid herpesvirus-3 annotated genes. AB - Cyprinid herpesvirus-3 (CyHV-3) is the cause of a fatal disease in carp and koi fish. The disease is seasonal and appears when water temperatures range from 18 to 28 degrees C. CyHV-3 is a member of the Alloherpesviridae, a family in the Herpesvirales order that encompasses mammalian, avian and reptilian viruses. CyHV 3 is a large double-stranded DNA (dsDNA) herpesvirus with a genome of approximately 295kbp, divergent from other mammalian, avian and reptilian herpesviruses, but bearing several genes similar to cyprinid herpesvirus-1 (CyHV 1), CyHV-2, anguillid herpesvirus-1 (AngHV-1), ictalurid herpesvirus-1 (IcHV-1) and ranid herpes virus-1 (RaHV-1). Here we show that viral DNA synthesis commences 4-8h post-infection (p.i.), and is completely inhibited by pre treatment with cytosine beta-d-arabinofuranoside (Ara-C). Transcription of CyHV-3 genes initiates after infection as early as 1-2h p.i., and precedes viral DNA synthesis. All 156 annotated open reading frames (ORFs) of the CyHV-3 genome are transcribed into RNAs, most of which can be classified into immediate early (IE or alpha), early (E or beta) and late (L or gamma) classes, similar to all other herpesviruses. Several ORFs belonging to these groups are clustered along the viral genome. PMID- 22841492 TI - Down-regulation of the cyprinid herpesvirus-3 annotated genes in cultured cells maintained at restrictive high temperature. AB - Cyprinid herpesvirus-3 (CyHV-3) is a member of the Alloherpesviridae, in the order Herpesvirales. It causes a fatal disease in carp and koi fish. The disease is seasonal and is active when water temperatures ranges from 18 to 28 degrees C. Little is known about how and where the virus is preserved between the permissive seasons. The hallmark of the herpesviruses is their ability to become latent, persisting in the host in an apparently inactive state for varying periods of time. Hence, it could be expected that CyHV-3 enter a latent period. CyHV-3 has so far been shown to persist in fish maintained under restrictive temperatures, while shifting the fish to permissive conditions reactivates the virus. Previously, we demonstrated that cultured cells infected with CyHV-3 at 22 degrees C and subsequently transferred to a restrictive temperature of 30 degrees C preserve the virus for 30 days. The present report shows that cultured carp cells maintained and exposed to CyHV-3 at 30 degrees C are abortively infected; that is, autonomous viral DNA synthesis is hampered and the viral genome is not multiplied. Under these conditions, 91 of the 156 viral annotated ORFs were initially transcribed. These transcripts were down-regulated and gradually shut off over 18 days post-infection, while two viral transcripts encoded by ORFs 114 and 115 were preserved in the infected cells for 18 days p.i. These experiments, carried out in cultured cells, suggest that fish could be infected at a high non-permissive temperature and harbor the viral genome without producing viral particles. PMID- 22841493 TI - On being first in epidemiology. PMID- 22841494 TI - Comment on "Fisheries mismanagement". PMID- 22841495 TI - Long-term monitoring of heavy metals in Chilean coastal sediments in the eastern South Pacific Ocean. AB - Concentrations of seven metals (Al, Cd, Cu, Fe, Pb, Ni, Zn) were determined in 256 surface sediment samples, collected between May 2006 and November 2009, from 15 stations at the mouth of the Itata River and its adjacent marine zone (central southern Chile) as part of an environmental monitoring program. The objectives of the work were to: (i) establish baseline metal concentrations in the sediments of the area and (ii) identify tendencies in the spatial and temporal distribution of the metals in these marine sediments. Concentrations were highest in the north zone of the Itata River mouth (stations E2C, E13C) for all the metals and at the stations farthest offshore from the mouth (E4, E6) for Cu, Fe, Pb, and Ni. The ranges in those concentrations were lower than those reported in other studies performed along the Chilean coast and lower than those observed in most other coastal systems around the world. Based on results of the indices used (geoaccumulation index, enrichment factor), the coastal sediments were not measurably elevated above natural levels. PMID- 22841496 TI - Dogs and horses with antibodies to outer-surface protein C as on-time sentinels for ticks infected with Borrelia burgdorferi in New York State in 2011. AB - Reported cases of Lyme disease (a chronic disease caused by infection with Borrelia burgdorferi) in humans increased more than two-fold between 1992 and 2006 in the United States. Recently, the annual number of reported human Lyme disease cases stabilized (according to the Center for Disease Control and Prevention) but the geographic distribution seemed to increase. In New York (NY) State, USA, a spread from the original Lyme disease focus in southeastern parts of the state has occurred. We determined incidence risks of new companion animal infection in 2011 with B. burgdorferi by county in 451 dog and 2100 horse sera; the samples were non-randomly collected by referring veterinarians in NY State between June 15, 2011 and January 31, 2012 because of suspicion of infection with B. burgdorferi or during annual health checks. All samples were submitted to the New York State Animal Health Center; the samples were submitted from 50 out of 62 counties in the state. Incident infections were determined by measuring antibodies to outer surface protein C (OspC; a marker of early infection that is detectable in serum from 3 weeks to 5 months after infection). Incident infections with B. burgdorferi were detected in 23% (95% confidence interval (CI): 19, 27) of canine samples and in 8% (95%CI: 7, 10) of equine samples. In 21 counties, samples were submitted from only one species (i.e. only dogs or only horses) that indicated incident infection. Recognition of incidence infections in dogs and horses might serve as a sentinel for infected ticks in different NY State counties; detection of the OspC antigen can provide a sensitive, new tool to allow recognition of risk for possible human and animal infection with B. burgdorferi by geographic region. We recommend that both dogs and horses be part of such a passive surveillance system. PMID- 22841497 TI - Phenotypic regional functional imaging patterns during memory encoding in mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Reliable blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) phenotypic biomarkers of Alzheimer's disease (AD) or mild cognitive impairment (MCI) are likely to emerge only from a systematic, quantitative, and aggregate examination of the functional neuroimaging research literature. METHODS: A series of random-effects activation likelihood estimation (ALE) meta-analyses were conducted on studies of episodic memory encoding operations in AD and MCI samples relative to normal controls. ALE analyses were based on a thorough literature search for all task-based functional neuroimaging studies in AD and MCI published up to January 2010. Analyses covered 16 fMRI studies, which yielded 144 distinct foci for ALE meta-analysis. RESULTS: ALE results indicated several regional task-based BOLD consistencies in MCI and AD patients relative to normal control subjects across the aggregate BOLD functional neuroimaging research literature. Patients with AD and those at significant risk (MCI) showed statistically significant consistent activation differences during episodic memory encoding in the medial temporal lobe, specifically parahippocampal gyrus, as well superior frontal gyrus, precuneus, and cuneus, relative to normal control subjects. CONCLUSIONS: ALE consistencies broadly support the presence of frontal compensatory activity, medial temporal lobe activity alteration, and posterior midline "default mode" hyperactivation during episodic memory encoding attempts in the diseased or prospective predisease condition. Taken together, these robust commonalities may form the foundation for a task-based fMRI phenotype of memory encoding in AD. PMID- 22841498 TI - Disruption of microtubule integrity initiates mitosis during CNS repair. AB - Mechanisms of CNS repair have vital medical implications. We show that traumatic injury to the ventral midline of the embryonic Drosophila CNS activates cell divisions to replace lost cells. A pilot screen analyzing transcriptomes of single cells during repair pointed to downregulation of the microtubule stabilizing GTPase mitochondrial Rho (Miro) and upregulation of the Jun transcription factor Jun-related antigen (Jra). Ectopic Miro expression can prevent midline divisions after damage, whereas Miro depletion destabilizes cortical beta-tubulin and increases divisions. Disruption of cortical microtubules, either by chemical depolymerization or by overexpression of monomeric tubulin, triggers ectopic mitosis in the midline and induces Jra expression. Conversely, loss of Jra renders midline cells unable to replace damaged siblings. Our data indicate that upon injury, the integrity of the microtubule cytoskeleton controls cell division in the CNS midline, triggering extra mitosis to replace lost cells. The conservation of the identified molecules suggests that similar mechanisms may operate in vertebrates. PMID- 22841500 TI - gamma oscillations in the human basal ganglia. AB - Interest in beta activity in the basal ganglia has mushroomed since it was first identified in the subthalamic nucleus of patients with Parkinson's disease in Jonathan Dostrovsky's landmark paper (Levy et al., 2000). Here we consider a less explored phenomenon; namely gamma frequency synchronisation of neurons in the basal ganglia. Gamma oscillations have been reported in a distributed network involving the basal ganglia, thalamus and motor cortex, and have been described in a wide range of diseases as well as during increased arousal and voluntary movement. In Parkinson's disease, gamma activity is promoted by dopaminergic therapy. These features suggest that its elevation may be involved in the production of movement and this hypothesis is supported by the correlation between the amplitude of gamma activity and limb kinematics. Here we review these data, discuss the functional anatomy of gamma activity in basal ganglia and question how closely it relates to the coding of movement parameters. PMID- 22841499 TI - Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. AB - X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development. PMID- 22841501 TI - EUS-guided celiac ganglion irradiation with iodine-125 seeds for pain control in pancreatic carcinoma: a prospective pilot study. AB - BACKGROUND: Celiac plexus neurolysis for the palliative reduction of pain in unresectable pancreatic carcinoma (PC) is safe but provides limited relief. In a previous study, we found that EUS-guided implantation of iodine-125 ((125)I) around the celiac ganglia is a safe procedure and can induce apoptosis of local neurons in a porcine model. OBJECTIVE: To evaluate the safety and efficacy of direct celiac ganglion irradiation with (125)I seeds for the relief of moderate to severe pain secondary to unresectable PC. DESIGN: Prospective study. SETTING: Single, tertiary care referral center. PATIENTS: This study enrolled consecutive patients who had moderate to severe pain resulting from biopsy-proven unresectable PC. INTERVENTION: All patients underwent EUS-guided direct celiac ganglion irradiation with (125)I seeds. Follow-up was conducted at least once weekly until death. MAIN OUTCOME MEASUREMENTS: Blood parameters, Visual Analog Scale (VAS) score, mean analgesic (MS Contin [morphine sulfate]) consumption, and complications were evaluated during follow-up. RESULTS: Twenty-three patients with unresectable PC underwent the procedure. The mean number of seeds implanted in the celiac ganglion per patient was 4 (range 2-6). Immediately after the procedure, pain relief and analgesic consumption showed no significant changes compared with preoperative values. Six patients (26%) reported pain exacerbation. Two weeks later, the VAS score and mean analgesic consumption were significantly less than preoperative values. No procedure-related deaths or major complications occurred. LIMITATIONS: Uncontrolled study. CONCLUSIONS: EUS-guided direct celiac ganglion irradiation with (125)I seeds can reduce the VAS score and analgesic drug consumption in patients with unresectable PC. PMID- 22841502 TI - MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines. AB - Metastasis is a complex process facilitated by the action of several genes. Metastasis associated 1 (MTA1) gene is one such gene which assists the process of metastasis by regulating several molecular targets. MTA1 acts as part of a nucleosome remodelling and histone deacetylation complex, which is involved in transcriptional regulation. Expression of MTA1 has been shown to be closely correlated with aggressiveness in several types of cancers, including breast cancer. In the present study we show that MTA1 regulates SMAD7, a component of Transforming growth factor beta (TGFbeta) signalling. TGFbeta signals are transduced to the nucleus by the Smad family of proteins, which includes Smad7, an inhibitory SMAD, which acts as a negative regulator of TGFbeta. On knockdown of MTA1, SMAD7 expression increases. Treating cells with a histone deacetylase inhibitor also increases SMAD7 expression. MTA1 is recruited to SMAD7 promoter region. SMAD7 inhibits activation of SMAD2 and SMAD3 and we show that the levels of these active SMAD proteins are decreased in cells expressing shRNA against MTA1. We further show that on MTA1 knockdown, the expression of downstream targets of SMAD7 is decreased. MTA1 thus appears to regulate a key inhibitor of TGFbeta signalling, SMAD7. By regulating molecules like SMAD7 MTA1 might assist the process of tumourigenesis and metastasis. PMID- 22841503 TI - When should retained Paparella type I tympanostomy tubes be removed in asymptomatic children? AB - OBJECTIVES: Tympanostomy tubes are routinely used for the treatment of otitis media with effusion (OME). There is no definite consensus on the optimal length of the intubation period and the timing of tube removal. This study was designed to determine the appropriate time for tympanostomy tube removal in asymptomatic patients of preschool age. METHODS: A retrospective study was conducted in 336 patients (478 ears) under the age of 7 years old who underwent tympanostomy tube insertion or removal from January 2006 to September 2010 at our institution. The information gathered from chart review included patients' age at the time of tube insertion, duration of intubation, and the presence of complications, such as tube site infection and persistent tympanic membrane perforation. Logistic regression, chi-square test and Fisher's exact test were used to determine the statistical significance of observations. RESULTS: The spontaneous extrusion rate of tympanostomy tubes was about 90% at 18 months and showed a plateau after 18 months. The OME recurrence rate decreased after 12 months of intubation, and complications such as tube site infection and persistent tympanic membrane perforation increased after 15 months of intubation. CONCLUSION: Tympanostomy tubes removed before 12 months showed a high possibility of recurrence. Removal after 15 months showed an increased possibility of complications. Spontaneous extrusion seldom occurred after 18 months. From these findings, we concluded that asymptomatically retained tympanostomy tubes are recommended to remove when a tube is retained for more than 18 months. PMID- 22841504 TI - Designing biological compartmentalization. AB - Intracellular organization is a key factor in cell metabolism. Cells have evolved various organizational systems to solve the challenges of toxic pathway intermediates, competing metabolic reactions, and slow turnover rates. Inspired by nature, synthetic biologists have utilized proteins, nucleic acids, and lipids to construct synthetic organizational systems that mimic natural systems. Many of these systems have been applied to metabolic pathways and shown to significantly increase the production of industrially and commercially important chemicals. Further engineering and characterization of synthetic organizational systems will allow us to better understand native cellular strategies of spatial organization. Here, we discuss recent advances and ongoing efforts in designing and characterizing synthetic compartmentalization systems to mimic natural strategies and increase metabolic yields of engineered pathways. PMID- 22841505 TI - Alkaline phosphatase and risk of stroke among Japanese: the Circulatory Risk in Communities Study (CIRCS). AB - Although serum alkaline phosphatase (ALP) levels have been associated with mortality from all-cause and from either ischemic or hemorrhagic stroke, no study has been published of the associations between ALP and the incidence of stroke. We therefore examined the associations of ALP with risk of stroke among Japanese, stratified by drinking status because ALP is known as an enzyme affected by alcohol consumption. We conducted a prospective cohort study of 10,754 Japanese subjects (4098 men and 6656 women) aged 40-69 years and living in 4 communities under systematic surveillance for stroke incidence. During the 16-year follow-up, we documented 264 strokes (164 ischemic strokes and 69 hemorrhagic strokes) for men and 225 strokes (118 ischemic strokes and 89 hemorrhagic strokes) for women. There was a U-shaped association between ALP level and stroke incidence in both men and women, which was confined primarily to nondrinkers. For nondrinkers, higher ALP levels were associated with an elevated risk of ischemic stroke for men and of hemorrhagic stroke for women, whereas lower ALP levels were associated with elevated risks of ischemic and hemorrhagic strokes in both men and women. Our data indicate that not only higher, but also lower, serum ALP level may be a predictor for the risk of stroke in nondrinking men and women. PMID- 22841506 TI - Exosomal tumor-suppressive microRNAs as novel cancer therapy: "exocure" is another choice for cancer treatment. AB - MicroRNAs (miRNAs) act to fine-tune cellular responses in a variety of biological circumstances such as development, organogenesis, and homeostasis. The dysregulation of miRNA expression accelerates disease progression, including metabolic disease, immunological disease and cancer, through the gene network disorder. Therefore, understanding the miRNA maturation process may unravel the mechanisms of cancer malignancy; however, the life of miRNA has not been clarified. In this article, we summarize the recent findings regarding the novel forms of miRNA, especially secretory miRNAs, focusing on exosomal miRNAs. Recent research has revealed that exosomal miRNAs affect many aspects of physiological and pathological conditions, and may be useful as novel therapy. Here, we propose a method for the delivery of tumor-suppressive miRNAs to desired sites using exosomes, and we named this method "exocure". PMID- 22841507 TI - Impact of atopic dermatitis on health-related quality of life in Spanish children and adults: the PSEDA study. AB - BACKGROUND AND OBJECTIVES: Atopic dermatitis (AD) affects both children and adults. The main symptom of this disease is pruritus, which impacts health related quality of life (HRQOL). The aim of this study was to evaluate the impact of AD on the lives of children and adults with this disease. PATIENTS AND METHODS: This was a multicenter prospective epidemiological study of children (2 17 years) and adults (>= 18 years) with AD selected from dermatology offices in Spain. The patients had all had AD for at least a year and had no other chronic inflammatory skin diseases. In addition to sociodemographic information, the data collected included the clinical features of AD and the results of patient centered questionnaires: the Itch Severity Scale (ISS), the Dermatology Life Quality Index (DLQI), and the children's version of this questionnaire (cDLQI). RESULTS: We studied 151 children and 172 adults. The mean (SD) age of the children was 9.4 (4.5) years and 51.7% were boys. In the case of adults, the mean age was 32.3 (13.4) years and 58.7% were women. Among the children, the ISS score increased with disease severity and in the adults, both the frequency and intensity of pruritus increased with disease severity (P<.05 in both cases); 79% of the children and 87.1% of the adults reported difficulty sleeping. In both populations, overall and subscale DLQI and cDLQI scores varied according to disease severity. CONCLUSIONS: AD affects HRQOL in both children and adults and its impact is correlated with the presence and intensity of pruritus. PMID- 22841509 TI - Submucosal tumor of the stomach? PMID- 22841510 TI - Immune quiescence and hepatitis B virus: tolerance has its limits. PMID- 22841511 TI - Quantification of Yersinia enterocolitica in raw milk using qPCR. AB - This report describes a new, sensitive and specific protocol for rapid detection and quantification of Yersinia enterocolitica in artificially contaminated raw milk samples. The new method is based on an optimized real-time PCR protocol with a TaqMan probe. The primers and probe are based on the chromosomal ail gene. This method was successful for both intended uses: (1) direct detection and quantification of Y. enterocolitica in artificially and naturally contaminated raw milk samples and (2) characterization of growth potential of different serotypes of Y. enterocolitica in raw milk at the most commonly used storage temperatures. The recent method eliminates the pre-PCR enrichment step, which makes it possible to quickly assess milk-related consumer exposure to this pathogen. PMID- 22841512 TI - A novel protease inhibitor in Bombyx mori is involved in defense against Beauveria bassiana. AB - Entomopathogenic fungi, such as Beauveria bassiana, penetrate the insect cuticle using a plethora of hydrolytic enzymes including cuticle-degrading proteases and chitinases, which are important virulence factors. The insect integument and hemolymph contains a relatively high concentration of protease inhibitors, which are closely involved with defense against pathogenic microorganisms. To elucidate the molecular mechanism underlying resistance against entomopathogenic fungi and to identify a new molecular target for improving fungal resistance in the silkworm, Bombyx mori, we cloned and expressed a novel silkworm TIL-type protease inhibitor BmSPI38, which was very stable over a wide range of temperatures and pH values. An activity assay suggested that BmSPI38 potently inactivated the insecticidal cuticle-degrading enzyme (CDEP-1) produced by B. bassiana and subtilisin A produced by Bacillus licheniformis. The melanization of silkworm induced by CDEP-1 protease could also be blocked by BmSPI38. These results provided new insights into the molecular mechanisms whereby insect protease inhibitors provide resistance against entomopathogenic fungi, suggesting the possibility of using fungal biopesticides in sericulture. PMID- 22841513 TI - Cytotoxic and anticancer effects of the triorganotin compound [(C6H5)3Sn(cmbzt)]: an in vitro, ex vivo and in vivo study. AB - Since the initial success of cisplatin, metal complexes and organometallic compounds have been gaining growing interest in cancer therapy. It is well known that organotin(IV) compounds display strong biological activity. The triorganotin compound [(C(6)H(5))(3)Sn(cmbzt)] (cmbzt=5-chloro-2-mercaptobenzothiazole) (SnCMB), was tested for its antiproliferative and antitumour activities. Two sets of experimental procedures were followed: (1) In vitro and ex vivo procedures included the study of the cytotoxic activity of the complex against leiomyosarcoma cells (LMS) and on a normal human fibroblast line (MRC5) by the MTT assay (cell proliferation), colony formation efficiency and flow cytometric analysis with Annexin V-FITC. The anticoagulation properties of the complex were also studied. (2) In vivo procedures included acute toxicity studies and finally administration of the complex to tumour bearing Wistar rats. The results showed that the complex exhibited potent cytotoxic activity (LMS IC(50)=155 nM) and induced significant apoptosis against LMS cells. Acute toxicity studies on Wistar rats presented kidney and liver toxicity at a single dose of 40 mg/kg body wt. Furthermore, antitumour activity studies on sarcoma bearing Wistar rats revealed that SnCMB complex, administrated in two different therapeutic schemes (treated with 4 * 2 mg/kg body wt every 5 days and 3 * 2.67 mg/kg body wt every 10 days of SnCMB complex), prolonged mean survival time (by 50% and 70% respectively), but failed to decrease the mean tumour growth rate (MTGR) compared to the control group (p<0.01). In conclusion, the organic complex SnCMB possess potent cytotoxic and antimetastatic effects, and low toxicity introducing it as possible successor of organometallic compounds used nowadays in chemotherapy. PMID- 22841514 TI - Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia. AB - BACKGROUND: In the orbitofrontal cortex (OFC), reduced gray matter volume and reduced glutamic acid decarboxylase 67kDa isoform (GAD67) messenger (m)RNA are found in schizophrenia; however, how these alterations relate to developmental pathology of interneurons is unclear. The present study therefore aimed to determine if increased interstitial white matter neuron (IWMN) density exists in the OFC; whether gamma-aminobutyric acid (GABA)ergic neuron density in OFC white matter was altered; and how IWMN density may be related to an early-expressed inhibitory neuron marker, Dlx1, in OFC gray matter in schizophrenia. METHODS: IWMN densities were determined (38 schizophrenia and 38 control subjects) for neuronal nuclear antigen (NeuN+) and 65/67 kDa isoform of glutamic acid decarboxylase immunopositive (GAD65/67+) neurons. In situ hybridization was performed to determine Dlx1 and GAD67 mRNA expression in the OFC gray matter. RESULTS: NeuN and GAD65/67 immunopositive cell density was significantly increased in the superficial white matter in schizophrenia. Gray matter Dlx1 and GAD67 mRNA expression were reduced in schizophrenia. Dlx1 mRNA levels were negatively correlated with GAD65/67 IWMN density. CONCLUSIONS: Our study provides evidence that pathology of IWMNs in schizophrenia includes GABAergic interneurons and that increased IWMN density may be related to GABAergic deficits in the overlying gray matter. These findings provide evidence at the cellular level that the OFC is a site of pathology in schizophrenia and support the hypothesis that inappropriate migration of cortical inhibitory interneurons occurs in schizophrenia. PMID- 22841515 TI - Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. AB - BACKGROUND: A need exists to expand the characterization of tetrahydrobiopterin (BH(4)) responsiveness in patients with phenylketonuria (PKU), beyond simply evaluating change in blood phenylalanine concentrations. The clinical interpretation of BH(4) responsiveness should be evaluated within the context of phenylalanine hydroxylase (PAH) genotype. AIM: This investigation seeks to use a modified version of a previously developed PAH genotype severity tool, the assigned value (AV) sum, to assess the molecular basis of responsiveness in a clinical cohort and to explore the tool's ability to differentiate BH(4) responsive groups. METHODS: BH(4) response was previously clinically classified in 58 patients with PKU, with three response groups emerging: definitive responders, provisional responders, and non-responders. Provisional responders represented a clinically ambiguous group, with an initial decrease in plasma phenylalanine concentrations, but limited ability to improve dietary phenylalanine tolerance. In this retrospective analysis, mutations in the PAH gene were identified in each patient. PAH genotype was characterized through the AV sum approach, in which each mutation is given an AV of 1, 2, 4, or 8; the sum of both mutations' AV corresponds to genotype severity, with a lower number representing a more severe phenotype. An AV sum cutoff of 2 (indicative of the most severe genotypes) was used to dichotomize patients and predict BH(4) responsiveness. Provisional responders were classified with the definitive responders then the non-responders to see with which group they best aligned. RESULTS: In 17/19 definitive responders, at least one mutation was mild or moderate in severity (AV sum>2). In contrast, 7/9 provisional responders carried two severe or null mutations (AV sum=2), suggesting little molecular basis for responsiveness. Non-responders represent a heterogeneous group with 15/25 patients carrying two severe mutations (AV sum=2), 5/25 patients carrying one moderate or mild mutation in combination with a severe or null mutation (AV sum>2), and the remaining five patients carrying an uncharacterized mutation in combination with a severe mutation. Predictive sensitivity of the AV sum was maximized (89.5% vs. 67.9%) with limited detriment to specificity (79.4% vs. 80.0%), by classifying provisional responders with the non-responders rather than with the definitive responders. CONCLUSIONS: In our clinical cohort, the AV sum tool was able to identify definitive responders with a high degree of sensitivity. As demonstrated by both the provisional responder group and the substantial number of non-responders with AV sums>2, a potential exists for misclassification when BH(4) response is determined by relying solely on change in plasma phenylalanine concentrations. PAH genotype should be incorporated in the clinical evaluation of BH(4) responsiveness. PMID- 22841516 TI - Optimizing therapy for argininosuccinic aciduria. AB - Argininosuccinic aciduria (ASA) is a urea cycle disorder with a complex phenotype. In spite of a lower risk for recurrent hyperammonemic episodes as compared to the proximal disorders of ureagenesis, subjects with ASA are at risk for long-term complications including, poor neurocognitive outcome, hepatic disease and systemic hypertension. These complications can occur in spite of current standard therapy that includes dietary modifications and arginine supplementation suggesting that the presently available therapy is suboptimal. In this article, we discuss the natural history of ASA and the recent mechanistic insights from animal studies that have shown the requirement of argininosuccinate lyase, the enzyme deficient in ASA, for systemic nitric oxide production. These findings may have therapeutic implications and may help optimize therapy in ASA. PMID- 22841518 TI - Helical tomotherapy for SIB and hypo-fractionated treatments in lung carcinomas: a 4D Monte Carlo treatment planning study. AB - PURPOSE: To evaluate the impact of intra-fraction motion induced by regular breathing on treatment quality for helical tomotherapy treatments. MATERIAL AND METHODS: Four patients treated by simultaneous-integrated boost (SIB) and three by hypo-fractionated stereotactic treatments (hypo-fractionated, 18 Gy/fraction) were included. All patients were coached to ensure regular breathing. For the SIB group, the tumor volume was delineated using CT information only (CTV(CT)) and the boost region was based on PET information (GTV(PET), no CTV extension). In the hypo-fractionated group, a GTV based on CT information was contoured. In both groups, ITVs were defined according to 4D data. The PTV included the ITV plus a setup error margin. The treatment was planned using the tomotherapy TPS on 3D CT images. In order to verify the impact of intra-fraction motion and interplay effects, dose calculations were performed using a previously validated Monte Carlo model of tomotherapy (TomoPen): first on the planning 3D CT ("planned dose") and second, on the 10 phases of the 4D scan. For the latter, two dose distributions, termed "interplay simulated" or "no interplay" were computed with and without beamlet-phase correlation over the 10 phases and combined using deformable dose registration. RESULTS: In all cases, DVHs of "interplay simulated" dose distributions complied within 1% of the original clinical objectives used for planning, defined according to ICRU (report 83) and RTOG (trials 0236 and 0618) recommendations, for SIB and hypo-fractionated groups, respectively. For one patient in the hypo-fractionated group, D(mean) to the CTV(CT) was 2.6% and 2.5% higher than "planned" for "interplay simulated" and "no interplay", respectively. CONCLUSION: For the patients included in this study, assuming regular breathing, the results showed that interplay of breathing and tomotherapy delivery motions did not affect significantly plan delivery accuracy. Hence, accounting for intra-fraction motion through the definition of an ITV volume was sufficient to ensure tumor coverage. PMID- 22841517 TI - Gabapentin's minimal action on markers of rat brain arachidonic acid metabolism agrees with its inefficacy against bipolar disorder. AB - In rats, FDA-approved mood stabilizers used for treating bipolar disorder (BD) selectively downregulate brain markers of the arachidonic acid (AA) cascade, which are upregulated in postmortem BD brain. Phase III clinical trials show that the anticonvulsant gabapentin (GBP) is ineffective in treating BD. We hypothesized that GBP would not alter the rat brain AA cascade. Chronic GBP (10 mg/kg body weight, injected i.p. for 30 days) compared to saline vehicle did not significantly alter brain expression or activity of AA-selective cytosolic phospholipase A(2) (cPLA(2)) IVA or secretory (s)PLA(2) IIA, activity of cyclooxygenase-2, or prostaglandin E(2) or thromboxane B(2) concentrations. Plasma esterified and unesterified AA concentration was unaffected. These results, taken with evidence of an upregulated AA cascade in the BD brain and that approved mood stabilizers downregulate the rat brain AA cascade, support the hypothesis that effective anti-BD drugs act by targeting the brain AA cascade whereas ineffective drugs (such as GBP) do not target this pathway, and suggest that the rat model might be used for screening new anti-BD drugs. PMID- 22841519 TI - Enrichment and identification of large filamentous sulfur bacteria related to Beggiatoa species from brackishwater ecosystems of Tamil Nadu along the southeast coast of India. AB - Beggiatoa species are filamentous sulfide-oxidizing bacteria belonging to the family Beggiatoaceae that contains several largest bacteria known today. These large sulfur bacteria occur in diverse ecosystems and play an important role in the global sulfur, nitrogen and phosphorus cycle. In this study, sediment samples from brackishwater shrimp culture ponds and other brackishwater ecosystems from Tamil Nadu, southeast coast of India, were enriched for Beggiatoa species. Extracted hay medium supplemented with catalase was used and were incubated for two weeks at 28 degrees C. Out of seven set-ups, four yielded positive growth of filamentous sulfide-oxidizing bacteria. The filaments were several millimeters long, ranged in width between 2 and 15 MUm and exhibited typical gliding motility. The 16S rRNA gene of four single filaments representing the four positive enrichments was subjected to PCR-DGGE followed by sequencing. All four filaments were affiliated to the Beggiatoaceae, but showed less than 89% identity with the Beggiatoa type strain Beggiatoa alba and less than 93% identity with any other sequence of the family. One of the four filaments revealed a nearly full length 16S rDNA sequence (1411bp) and it formed a monophyletic cluster with two of the partial DGGE-16S rRNA gene sequences (99-100% identity) within the Beggiatoa species cluster. These organisms could possibly represent a novel genus within the family Beggiatoaceae. The fourth partial sequence affiliated with less than 93% sequence identity to the genera Parabeggiatoa, Thioploca and Thiopilula, and was likewise strongly delineated from any sequence published in the family. PMID- 22841520 TI - The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. AB - OBJECTIVE: This study was designed to investigate whether metformin affects monocyte secretory function in patients with impaired fasting glucose receiving chronic statin therapy. MATERIALS/METHODS: The study included 48 patients with impaired fasting glucose treated for at least three months with simvastatin (40 mg daily). These patients were randomized to either metformin (3 g daily) or placebo, which was administered together with simvastatin for 90 days. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C reactive protein levels were determined before randomization and at the end of the treatment. RESULTS: Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma C reactive protein levels, which were accompanied by an improvement in insulin sensitivity. CONCLUSIONS: The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and metformin. PMID- 22841521 TI - A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance. AB - OBJECTIVE: Insulin resistance (IR) is associated with low adiponectin and elevated high sensitivity C-reactive protein (hsCRP). Osteoprotegerin (OPG) has been shown to be elevated in type 2 diabetes, but whether it reflects underlying IR is unclear. We aimed to compare the ability of serum OPG with adiponectin and hsCRP to act as a marker for IR in individuals with normal and abnormal glucose tolerance. MATERIALS/METHODS: 115 men underwent a 75 g oral glucose tolerance test. OPG, hsCRP and adiponectin were measured using ELISA. IR was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Men with abnormal glucose tolerance (n=38) were older (58.3+/-11.2 vs 47.3+/-11.4 years, P<.001), had higher body mass index (BMI) (31.1+/-2.9 vs 27.9+/-3.2 kg/m(2), P<.001) and were more insulin resistant (median (I.Q.) HOMA-IR 5.88 (3.38) vs 1.13 (1.14), P<.001) than those with normal glucose tolerance (n=77). After adjustment for age and BMI, OPG (6.28 (2.32) vs 5.16 (1.86) pmol/L, P<.001) and hsCRP (2.07 (5.47) vs 0.78 (1.05) mg/L, P<.001) were higher and adiponectin (3.02+/-1.17 vs 4.78+/-2.38 MUg/mL, P<.001) was lower in those with AGT. After adjustment for age and BMI, adiponectin (r=-0.317, P<.001) and hsCRP (r=0.318, P<.001), but not OPG (r=0.126, P=.196) correlated with HOMA-IR. On multiple linear regression analysis, adiponectin and hsCRP but not OPG were independent predictors of HOMA-IR. CONCLUSIONS: OPG is higher in individuals with abnormal glucose tolerance, but unlike adiponectin and hsCRP, does not correlate with HOMA IR, suggesting its elevation within this cohort of individuals is due to factors other than insulin resistance. PMID- 22841523 TI - Increased reticulocyte count from cord blood samples using hypotonic lysis. AB - Human reticulocytes are one of the fundamental components needed to study the in vitro invasion processes of the human malaria parasite Plasmodium vivax. Additionally examinations of reticulocytes and their binding proteins are difficult in areas of the world that do not have access to advanced equipment or stem cell lines. These issues are particularly relevant to malaria vaccine candidate studies that are directed against surface proteins that the parasites use to gain entry into erythrocytes. Described here is a simple and inexpensive method to increase the reticulocyte count of cord blood samples. Exposure of cord blood to hypotonic saline (0.2%) for 5 min selectively lyses the non reticulocytes resulting in an average 3.6-fold increase in reticulocyte count. Our studies show that this enrichment process does not damage the hemoglobin of the remaining erythrocytes which are still capable of supporting Plasmodium falciparum invasion and growth. This economical and rapid method of enrichment could facilitate studies of in vitro laboratory culturing of other malaria parasite species which preferentially invade reticulocytes such as P. vivax. PMID- 22841522 TI - Helicobacter pylori infection in patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: Clinical data regarding Helicobacter pylori (Hp) infection in nonalcoholic fatty liver disease (NAFLD) are limited. The aim was the evaluation of Hp infection in patients with NAFLD and its association with disease severity. METHODS: 28 patients with biopsy-proven NAFLD (15 with simple nonalcoholic fatty liver [NAFL], 13 with nonalcoholic steatohepatitis [NASH]) and 25 matched healthy controls were recruited. Blood samples for anti-Hp Immunoglobulin G (IgG) and standard biochemical tests were obtained after overnight fasting, and (13)C urea breath test was performed before liver biopsy in NAFLD group. RESULTS: Higher rates of anti-Hp IgG (P=.038) were observed in NAFLD compared to control group. Only two NAFLD patients neither were Hp IgG seropositive nor did they have a history of eradication treatment compared to 11 control subjects (P=.002). Both Hp infection (assessed by history of Hp eradication treatment and/or Hp IgG seropositivity) (P=.034) and log(HOMA-IR) (P=.007) could independently predict NAFLD in logistic regression analysis. There were similar rates of Hp IgG seropositivity or positivity in (13)C urea breath test or their combination between NAFL and NASH patients. There were no significant differences in steatosis grade, fibrosis stage, lobular or portal inflammation, or ballooning, when NAFLD patients were divided according to Hp IgG seropositivity or (13)C urea breath test positivity. CONCLUSIONS: Hp infection may represent one more hit contributing to the pathogenesis of NAFL, though not to the progression from NAFL to NASH. These results warrant further validation. If confirmed, eradicating Hp infection may have certain therapeutic perspectives in NAFLD treatment. PMID- 22841524 TI - Algorithms: what computers do best. PMID- 22841525 TI - Lack of evidence for a remote effect of renal ischemia/reperfusion acute kidney injury on outcome from temporary focal cerebral ischemia in the rat. AB - OBJECTIVE: Acute kidney injury (AKI) and ischemic stroke may occur in the same cardiac surgical patient. It is not known if an interaction exists between these organ injuries. Isolated renal ischemia/reperfusion is associated with dysfunction in remote, otherwise normal organs, including the brain. In a rat model of simultaneous bilateral renal artery occlusion (BRAO) and middle cerebral artery occlusion (MCAO), the authors tested the hypothesis that AKI would worsen experimental stroke outcome. DESIGN: Sixty thermoregulated anesthetized rats were randomized to (1) 40-minute BRAO, (2) 80-minute MCAO, or (3) simultaneous BRAO + MCAO. Serum creatinine was measured at baseline and 2 and 7 days after organ reperfusion. Neurologic function and brain and kidney histologies were measured on day 7. In a parallel study, serum cytokines were measured over 16 hours. SETTING: Laboratory. PARTICIPANTS: Male Wistar rats. INTERVENTIONS: Combined or isolated BRAO and MCAO. MEASUREMENTS AND MAIN RESULTS: AKI was similar between the BRAO and BRAO + MCAO groups, with greater 48-hour creatinine increases (p < 0.02) and renal histopathologic scores (p < 0.001) in these groups than with MCAO alone. Neurologic scores correlated with cerebral infarct size (p = 0.0001). There were no differences in neurologic score (p = 0.53) and cerebral infarct volume (p = 0.21) between the MCAO and BRAO + MCAO groups. There was no association between cerebral infarct size or neurologic score and 48-hour creatinine increase. Interleukin-6 was increased during reperfusion (p < 0.0001), but a difference among groups was absent (p = 0.41). CONCLUSIONS: In contrast to the effects reported for AKI on normal remote organs, AKI had no influence on infarct size or neurologic function after experimental ischemic cerebral stroke. PMID- 22841526 TI - Hypertonic solution decreases extravascular lung water in cardiac patients undergoing cardiopulmonary bypass surgery. AB - OBJECTIVE: To test the hypothesis that the infusion of hypertonic solution would decrease extravascular lung water postoperatively and thus improve pulmonary function. DESIGN: Prospective, randomized, blinded trial. SETTING: Tertiary cardiothoracic referral center. PARTICIPANTS: Twenty-six patients with coronary artery disease who underwent surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were allocated randomly to receive 4 mL/kg of 7.2% NaCl/hydroxyethyl starch, 200/0.5 (HSH group) or an equal volume of 0.9% NaCl (control group) for 30 minutes starting after anesthesia induction. The extravascular lung water index, hemodynamic and biochemical data, and the rate of complications were analyzed. MEASUREMENTS AND MAIN RESULTS: The extravascular lung water index was significantly lower (7 v 9.5 mL/kg) in the HSH group at the first postoperative day (p < 0.01). The index of arterial oxygenation efficiency was significantly higher at 5 minutes and 2 and 4 hours after cardiopulmonary bypass (CPB) in the HSH group (p < 0.05). The alveolar-arterial oxygen tension difference was significantly lower at 5 minutes and 2 and 4 hours after CPB in the HSH group (p < 0.01). The cardiac index was significantly higher at 5 minutes after infusion in the HSH group (p < 0.05). CONCLUSIONS: The infusion of HSH leads to significant decreases in the extravascular lung water index during and after cardiac surgery and is associated with better preservation of pulmonary function and transient increases in the cardiac index. Further trials are needed to clarify the clinical advantages of hypertonic solution administration in patients undergoing surgery with CPB. PMID- 22841527 TI - Echocardiographic anatomy of the mitral valve: a critical appraisal of 2 dimensional imaging protocols with a 3-dimensional perspective. AB - OBJECTIVE: To highlight the limitations of traditional 2-dimensional (2D) echocardiographic mitral valve (MV) examination methodologies, which do not account for patient-specific transesophageal echocardiographic (TEE) probe adjustments made during an actual clinical perioperative TEE examination. DESIGN: Institutional quality-improvement project. SETTING: Tertiary care hospital. PARTICIPANTS: Attending anesthesiologists certified by the National Board of Echocardiography. INTERVENTION: Using the technique of multiplanar reformatting with 3-dimensional (3D) data, ambiguous 2D images of the MV were generated, which resembled standard midesophageal 2D views. Based on the 3D image, the MV scallops visualized in each 2D image were recognized exactly by the position of the scan plane. Twenty-three such 2D MV images were created in a presentation from the 3D datasets. Anesthesia staff members (n = 13) were invited to view the presentation based on the 2D images only and asked to identify the MV scallops. Their responses were scored as correct or incorrect based on the 3D image. METHODS AND MAIN RESULTS: The overall accuracy was 30.4% in identifying the MV scallops. The transcommissural view was identified correctly >90% of the time. The accuracy of the identification of A1, A3, P1, and P3 scallops was <50%. The accuracy of the identification of A2P2 scallops was >=50%. CONCLUSION: In the absence of information on TEE probe adjustments performed to acquire a specific MV image, it is possible to misidentify the scallops. PMID- 22841528 TI - [Aeromonas and meningitis: An unusual presentation]. AB - The natural habitat of the genus Aeromonas is an aquatic environment. We describe the case of a patient suffering severe traumatic brain injury and meningitis by A. hydrophyla. PMID- 22841529 TI - Effects of drinking supplementary water at school on cognitive performance in children. AB - We investigated the beneficial effects of drinking supplementary water during the school day on the cognitive performance and transitory subjective states, such as fatigue or vigor, in 168 children aged between 9 and 11years who were living in a hot climate (South Italy, Sardinia). The classes were randomly divided into an intervention group, which received water supplementation, and a control group. Dehydration was determined by urine sampling and was defined as urine osmolality greater than 800mOsm/kg H(2)O (Katz, Massry, Agomn, & Toor, 1965). The change in the scores from the morning to the afternoon of hydration levels, cognitive performance and transitory subjective states were correlated. In line with a previous observational study that evaluated the hydration status of school children living in a country with a hot climate (Bar-David, Urkin, & Kozminsky, 2005), our results showed that a remarkable proportion of children were in a state of mild, voluntary dehydration at the beginning of the school day (84%). We found a significant negative correlation between dehydration and the auditory number span, which indicates a beneficial effect of drinking supplementary water at school on short-term memory. Moreover, there was a positive correlation between dehydration and performance in the verbal analogy task. The results are discussed in the light of the complexity of the neurobiological mechanisms involved in the relationship between hydration status and cognition. PMID- 22841530 TI - Surface topographical factors influencing bacterial attachment. AB - Substratum surface roughness is known to be one of the key factors in determining the extent of bacterial colonization. Understanding the way by which the substratum topography, especially at the nanoscale, mediates bacterial attachment remains ambiguous at best, despite the volume of work available on the topic. This is because the vast majority of bacterial attachment studies do not perform comprehensive topographical characterization analyses, and typically consider roughness parameters that describe only one aspect of the surface topography. The most commonly reported surface roughness parameters are average and root mean square (RMS) roughness (R(a) and R(q) respectively), which are both measures of the typical height variation of the surface. They offer no insights into the spatial distribution or shape of the surface features. Here, a brief overview of the current state of research on topography-mediated bacterial adhesion is presented, as well as an outline of the suite of roughness characterization parameters that are available for the comprehensive description of the surface architecture of a substratum. Finally, a set of topographical parameters is proposed as a new standard for surface roughness characterization in bacterial adhesion studies to improve the likelihood of identifying direct relationships between substratum topography and the extent of bacterial adhesion. PMID- 22841531 TI - Introduction: gene therapy has gone from a pipe dream to clinical reality. PMID- 22841532 TI - Bone properties affect loosening of half-pin external fixators at the pin-bone interface. AB - INTRODUCTION: Local bone yielding at the pin-bone interface of external fixation half-pins has been known to initiate fixator loosening. Deterioration of bone properties due to ageing and disease can lead to an increase in the risk of pin loosening. This study determines the extent, locations and mechanics of bone yielding for unilateral external fixation systems at the tibial midshaft with changes in age-related bone structure and properties. The study also evaluates the effect of the number of pins used in the fixation system and use of titanium pins (in place of steel) on bone yielding. METHODS: We employ nonlinear finite element (FE) simulations. Strain-based plasticity is used to simulate bone yielding within FE analyses. Our analyses also incorporate contact behaviour at pin-bone interfaces, orthotropic elasticity and periosteal-endosteal variation of bone properties. RESULTS: The results show that peri-implant yielded bone volume increases by three times from young to old-aged cases. The use of three, rather than two half-pins (on either side of the fracture), reduces the volume of yielded bone by 80% in all age groups. The use of titanium half-pins resulted in approximately 60-65% greater volumes of yielded bone. CONCLUSIONS: We successfully simulate half-pin loosening at the bone-implant interface which has been found to occur clinically. Yielding across the full cortical thickness may explain the poor performance of these devices for old-aged cases. The models are able to identify patients particularly at risk of half-pin loosening, who may benefit from alternative fixator configurations or techniques such as those using pre-tensioned fine wires. PMID- 22841533 TI - Evaluation of methods and timing in nail dynamisation for treating delayed healing femoral shaft fractures. AB - INTRODUCTION: Dynamisation is a simple method for treating femoral shaft fractures (FSFs) in patients with delayed healing after intramedullary nailing. However, only around half of patients with a slow-healing FSF have been successfully treated with this strategy. Although it is thought that dynamisation with a screw preserved in the dynamic locking hole improves treatment outcome in these patients, to date, no studies have demonstrated empirical evidence supporting this technique. In this study, we investigated the effects of dynamisation with and without rotation and length control as well as timing of dynamisation on treatment outcomes in FSF patients with delayed healing. PATIENTS AND METHODS: Thirty-nine consecutive acute FSF patients with static locking intramedullary nails who subsequently underwent dynamisation were recruited between January 2000 and June 2011. The indication for dynamisation was the presence of gap caused by bone absorption or over-traction at the fracture site when the locking screws were placed. Age, gender, dynamisation method, fracture classification, duration from nail insertion to dynamisation (i.e., timing of dynamisation) and dynamisation outcome were included in the statistical analysis. RESULTS: Patients whose nail was dynamised with a screw preserved in the dynamic locking hole had a significantly higher successful bone union rate (14/15 vs. 14/24, p=0.028) compared with those with all screws removed from one end of the nail. The patients treated in 10-24 weeks had a significantly increased chance of bone union than those treated after 24 weeks (p=0.027). A significantly higher bone union rate (p=0.036) was observed in 10-24 weeks (83.3%) than after 24 weeks (33.3%) in the group of dynamisation with all screws removed from one end of the nail. No statistical difference in bone union success rate was found between patients at 10-24 weeks and after 24 weeks in the group of dynamisation with a screw preserved in the dynamic locking hole. There were no significant differences in outcome based on other variables. CONCLUSION: (1) Dynamisation with a screw preserved in the dynamic locking hole was associated with a higher success rate in bone union than all screws removed from one end of the nail for patients with delayed healing FSFs. (2) Early dynamisation (10-24 weeks) had a better outcome than late dynamisation (>24 weeks). Late dynamisation with all screws removed from one end of the nails resulted in a poor success rate. Alternative treatment should be considered if the latter approach is to be adopted. PMID- 22841534 TI - Slow Calcium-Depolarization-Calcium waves may initiate fast local depolarization waves in ventricular tissue. AB - Intercellular calcium waves in cardiac myocytes are a well-recognized, if incompletely understood, phenomenon. In a variety of preparations, investigators have reported multi-cellular calcium waves or triggered propagated contractions, but the mechanisms of propagation and pathological importance of these events remain unclear. Here, we review existing experimental data and present a computational approach to investigate the mechanisms of multi-cellular calcium wave propagation. Over the past 50 years, the standard modeling paradigm for excitable cardiac tissue has seen increasingly detailed models of the dynamics of individual cells coupled in tissue solely by intercellular and interstitial current flow. Although very successful, this modeling regime has been unable to capture two important phenomena: 1) the slow intercellular calcium waves observed experimentally, and 2) how intercellular calcium events resulting in delayed after depolarizations at the cellular level could overcome a source-sink mismatch to initiate depolarization waves in tissue. In this paper, we introduce a mathematical model with subcellular spatial resolution, in which we allow both inter- and intracellular current flow and calcium diffusion. In simulations of coupled cells employing this model, we observe: a) slow inter-cellular calcium waves propagating at about 0.1 mm/s, b) faster Calcium-Depolarization-Calcium (CDC) waves, traveling at about 1 mm/s, and c) CDC-waves that can set off fast depolarization-waves (50 cm/s) in tissue with varying gap-junction conductivity. PMID- 22841535 TI - Rhynchophylline prevents cardiac dysfunction and improves survival in lipopolysaccharide-challenged mice via suppressing macrophage I-kappaBalpha phosphorylation. AB - Myocardial dysfunction is a common complication during sepsis and significantly contributes to the mortality of patients with septic shock. However, none of the available therapeutic strategies proven to be effective in patients with severe sepsis are designed specifically to target myocardial dysfunction. The purpose of the present study is to investigate the effect of rhynchophylline (Rhy) on LPS induced myocardial dysfunction in mice. We found that pretreatment with Rhy significantly improved cardiac systolic dysfunction, increased stroke volume and cardiac output in mice challenged with LPS. LPS induced cardiac inhibitor kappaBalpha (I-kappaBalpha) phosphorylation, tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta) mRNA expression, and in turn increased cardiac TNF-alpha and IL-1beta protein production, all of which were attenuated by pretreatment with Rhy. Immunohistochemistry revealed that TNF-alpha was found in infiltrated macrophages (F4/80(+)) and myocardium, and Rhy reduced TNF-alpha immunostaining in cardiac infiltrated macrophages in LPS-challenged mice. Furthermore, Rhy inhibited LPS-induced I-kappaBalpha phosphorylation and TNF alpha production in cultured mouse peritoneal macrophages, but not in neonatal mouse cardiomyocytes. Pretreatment with Rhy significantly decreased the mortality of LPS-challenged mice. These results indicate that Rhy reduces cardiac dysfunction and improves survival via suppression of macrophage I-kappaBalpha phosphorylation in LPS-challenged mice, and suggest that Rhy may be a potential agent for the treatment of septic cardiac dysfunction. PMID- 22841536 TI - The analgesic activity and possible mechanisms of deacetyl asperulosidic acid methyl ester from Ji shi teng in mice. AB - Deacetyl Asperulosidic Acid Methyl Ester (DAAME) from Ji shi teng was evaluated on analgesic activity in mice using chemical and thermal models of nociception. Given intraperitoneally, DAAME, at doses of 40 and 80 mg/kg, produced significant inhibitions on chemical nociception induced by intraperitoneal acetic acid, subplantar formalin/capsaicin injections and on thermal nociception in the tail flick test and in the hot plate test. In the open-field test and the rotarod test, DAAME couldn't impair the motor performance, indicating that the observed antinociception was unlikely due to motor abnormality. In a measurement of core body temperature, DAAME (80 mg/kg) did not affect temperature within 80 min. Moreover, DAAME-induced antinociception in the capsaicin test and the hot plate test was significantly antagonized by glibenclamide. The results suggested that DAAME-produced antinociception was possibly involved in the ATP sensitive K+ channels in the capsaicin test and the hot plate test, which merited exploring further. PMID- 22841537 TI - Involvement of dopaminergic system in stress-induced anticonvulsant effect in juvenile mice. AB - Various stresses affect neuronal functions, including the onset and progression of seizures, in animals and humans of all ages. However, the effect of stress on the convulsion in juvenile animals has been rarely investigated. In the present study, we investigated the effect of swim stress on the convulsion threshold in juvenile and adult mice, and the involvement of brain monoaminergic systems in establishing this threshold. In the pentylenetetrazol-induced convulsion model, acute swim stress increased the convulsion threshold in adult mice, whereas repeated swim stress increased it in both juvenile and adult mice. Microdialysis study showed that in the medial prefrontal cortex (mPFC) of juvenile mice, repeated swim stress caused lasting elevation of dopamine (DA) release relative to the basal levels. In contrast, acute swim stress increased noradrenaline release from the mPFC of both juvenile and adult mice compared with the basal levels; the elevation was higher in adult mice. Pretreatment with SCH23390 or haloperidol at low doses suppressed the anticonvulsant effect by repeated swim stress in juvenile mice. Yohimbine clearly abolished the anticonvulsant effect by acute swim stress in adult mice. These results indicated a critical role of brain monoamine in establishing the convulsion threshold. Also, DA system in the mPFC may play an important role in the anticonvulsant effects of repeated swim stress in juvenile mice. PMID- 22841538 TI - Endocannabinoids reduce cerebral damage after hypoxic-ischemic injury in perinatal rats. AB - Hypoxic-ischemic (HI) insult during the perinatal period remains as one of the most common causes of brain injury and produces long-term neurological deficits, and there is a growing need for effective therapies. The aim of the present work was to perform a prospective study designed to assess the possible protector effect of two endocannabinoids: 2-arachidonoylglycerol (2AG) and anandamide (AEA) in the brain after HI injury in perinatal rat model. We evaluate their effects on cell death and check several cellular parameters. 7-days-old Wistar rats were assigned to four different experimental groups (n=7-10): Sham, HI, and HI treated with 2AG or AEA. The injury was induced by the left carotid artery ligature and subsequent exposure to 8% O(2) for 120 min. Immediately after the injury, treated groups received a single dose of 2AG (1mg/kg) or AEA (5mg/kg) and then animals were sacrificed 24, 72 h or 7 days after the HI event. Brains fixed by perfusion were stained with Nissl for morphological studies, and non-fixed brains were dissociated and analyzed by flow cytometry to quantify apoptosis, mitochondrial state, intracellular calcium and reactive oxygen species. Our results show that both 2AG and AEA have beneficial effects after HI injury in this rat model, producing a remarkable amelioration of brain injury, reducing apoptotic cell death, contributing to the maintenance of mitochondrial functionality, and improving cellular parameters such as the influx of calcium and ROS production. PMID- 22841539 TI - The amygdala to periaqueductal gray pathway: plastic changes induced by audiogenic kindling and reversal by gabapentin. AB - Repeated, periodic induction of AGS (AGS kindling) in GEPR-9s increases seizure duration and induces an additional generalized clonus phase [post-tonic clonus (PTC)], which involves expansion of the localized brainstem AGS network to the amygdala. The pathway between central amygdala (CeA) and ventrolateral periaqueductal gray (vlPAG) is implicated in several disorders, including pain and anxiety. This pathway is also implicated in the network of audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR-9s). We examined AGS kindling-induced changes in vlPAG extracellular action potentials evoked by electrical stimuli in CeA in awake, behaving GEPR-9s, using chronically-implanted stimulation electrodes in CeA and microwire recording electrodes in vlPAG. The effect of gabapentin, an anticonvulsant drug that is also effective in pain and anxiety disorders, on the CeA to vlPAG pathway in AGS-kindled GEPR-9s was also evaluated. Electrical stimulation in CeA evoked consistent, short latency and intensity-dependent vlPAG neuronal firing increases. However, in AGS-kindled GEPR 9s these responses showed a precipitous firing increase with increasing stimulus intensity, as compared to non-kindled GEPR-9s. Gabapentin (50mg/kg, i.p.) significantly reduced vlPAG neuronal responses to CeA stimulation to pre-AGS kindled levels and reversibly blocked PTC in AGS-kindled GEPR-9s. These data suggest that the amygdala to vlPAG pathway may be critical in mediating the emergence of PTC during AGS kindling. The ability of gabapentin to suppress this pathway may be important for its anticonvulsant effects in AGS-kindled GEPR-9s, and this effect may contribute to gabapentin's effectiveness in anxiety and pain in which the amygdala to PAG pathway is also implicated. PMID- 22841540 TI - Ursolic acid induces cell death and modulates autophagy through JNK pathway in apoptosis-resistant colorectal cancer cells. AB - Colorectal carcinomas (CRCs) with P53 mutations have been shown to be resistant to chemotherapy with 5-fluorouracil (5-FU), the most widely used chemotherapeutic drug for CRC treatment. Autophagy is emerging as a promising therapeutic target for drug-resistant tumors. In the present study, we tested the effects of ursolic acid (UA), a natural triterpenoid, on cell death mechanisms and its effects in combination with 5-FU in the HCT15 p53 mutant apoptosis-resistant CRC cell line. The involvement of UA in autophagy and its in vivo efficacy were evaluated. Our data show that UA induces apoptosis independent of caspases in HCT15 cells and enhances 5-FU effects associated with an activation of c-jun N-terminal kinase (JNK). In this cell line, where this compound has a more pronounced effect on the induction of cell death compared to 5-FU, apoptosis corresponds only to a small percentage of the total cell death induced by UA. UA also modulated autophagy by inducing the accumulation of LC3 and p62 levels with involvement of JNK pathway, which indicates a contribution of autophagy on JNK-dependent induction of cell death by UA. By using nude mice xenografted with HCT15 cells, we verified that UA was also active in vivo decreasing tumor growth rate. In conclusion, this study shows UA's anticancer potential both in vitro and in vivo. Induction of cell death and modulation of autophagy in CRC-resistant cells were shown to involve JNK signaling. PMID- 22841541 TI - DHA-fluorescent probe is sensitive to membrane order and reveals molecular adaptation of DHA in ordered lipid microdomains. AB - Docosahexaenoic acid (DHA) disrupts the size and order of plasma membrane lipid microdomains in vitro and in vivo. However, it is unknown how the highly disordered structure of DHA mechanistically adapts to increase the order of tightly packed lipid microdomains. Therefore, we studied a novel DHA-Bodipy fluorescent probe to address this issue. We first determined if the DHA-Bodipy probe localized to the plasma membrane of primary B and immortal EL4 cells. Image analysis revealed that DHA-Bodipy localized into the plasma membrane of primary B cells more efficiently than EL4 cells. We then determined if the probe detected changes in plasma membrane order. Quantitative analysis of time-lapse movies established that DHA-Bodipy was sensitive to membrane molecular order. This allowed us to investigate how DHA-Bodipy physically adapted to ordered lipid microdomains. To accomplish this, we employed steady-state and time-resolved fluorescence anisotropy measurements in lipid vesicles of varying composition. Similar to cell culture studies, the probe was highly sensitive to membrane order in lipid vesicles. Moreover, these experiments revealed, relative to controls, that upon incorporation into highly ordered microdomains, DHA-Bodipy underwent an increase in its fluorescence lifetime and molecular order. In addition, the probe displayed a significant reduction in its rotational diffusion compared to controls. Altogether, DHA-Bodipy was highly sensitive to membrane order and revealed for the first time that DHA, despite its flexibility, could become ordered with less rotational motion inside ordered lipid microdomains. Mechanistically, this explains how DHA acyl chains can increase order upon formation of lipid microdomains in vivo. PMID- 22841542 TI - Network analysis of adipose tissue gene expression highlights altered metabolic and regulatory transcriptomic activity in high-fat-diet-fed IL-1RI knockout mice. AB - A subacute inflammatory phenotype is implicated in the pathology of insulin resistance (IR) and type 2 diabetes mellitus. Interleukin (IL)-1alpha and IL 1beta are produced by innate immune cells, including macrophages, and mediate their inflammatory response through the IL-1 type I receptor (IL-IRI). This study sought to understand the transcriptomic signature of adipose tissue in obese IL 1RI(-/-) mice. Following dietary intervention, markers of insulin sensitivity and inflammation in adipose tissue were determined, and gene expression was assessed with microarrays. IL-1RI(-/-) mice fed a high-fat diet (HFD) had significantly lower plasma inflammatory cytokine concentrations than wild-type mice. Metabolic network analysis of transcriptomic effects identified up-regulation and co expression of genes involved in lipolysis, lipogenesis and tricarboxylic acid (TCA) cycle. Further assessment of gene expression in a network of protein interactions related to innate immunity highlighted Stat3 as a potential transcriptional regulator of IL-1 signalling. The complex, downstream effects of IL-1 signalling through the IL-1RI receptor remain poorly defined. Using network based analyses of transcriptomic signatures in IL-1RI(-/-) mice, we have identified expression changes in genes involved in lipid cycling and TCA cycle, which may be more broadly indicative of a restoration of mitochondrial function in the context of HFD. Our results also highlight a potential role for Stat3 in linking IL-1 signalling to adipogenesis and IR. PMID- 22841543 TI - Adjunct therapy of n-3 fatty acids to 5-ASA ameliorates inflammatory score and decreases NF-kappaB in rats with TNBS-induced colitis. AB - 5-aminosalicylic acid (5-ASA) is widely used for the treatment of inflammatory bowel disease (IBD). Recent studies have evaluated the potential of nutritional intervention as adjunct therapy to 5-ASA in IBD. N-3 polyunsaturated fatty acids (PUFA) have shown potent anti-inflammatory properties in gut inflammation. Therefore, we aimed to evaluate the efficacy of the dual therapy (n-3 PUFA plus 5 ASA) in rats with 2, 4, 6-trinitrobenzen sulfonic acid (TNBS)-induced colitis. Colitis was induced by intrarectal injection of TNBS while control rats received the vehicle. Rats received by gavage a fish oil-rich formula (n-3 groups) or an isocaloric and isolipidic oil formula supplemented with 5-ASA for 14 days. A dose response of 5-ASA (5-75 mg. suppression mg kg(-1) d(-1)) was tested. Colitis was evaluated and several inflammatory markers were quantified in the colon. COX-2 expression (P<.05) and pro-inflammatory eicosanoids production of prostaglandin E2 (P<.001) and leukotriene B4 (P<.001) were significantly inhibited by n-3 PUFA or 5-ASA therapy. 5-ASA also reduces mRNA levels of tumor necrosis factor alpha (P<.05). n-3 PUFA or 5-ASA significantly inhibits nuclear factor kappaB (NF kappaB) activation (P<.01 and P<.05, respectively). The dual therapy n-3 PUFA plus 5-ASA also inhibited inflammatory response by lowering NF-kappaB activation (P<.01) or inducing peroxisome proliferator-activated receptor-gamma (PPARgamma) expression (P<.05). These results indicate that 5-ASA plus n-3 PUFAs are more effective than a higher dose of 5-ASA alone to reduce NF-kappaB activation and to induce PPARgamma. By contrast, the dual therapy did not improve the effects of individual treatments on eicosanoids or cytokine production. Use of n-3 PUFA in addition to 5-ASA may reduce dose of standard therapy. PMID- 22841544 TI - Age and sex affect protein metabolism at protein intakes that span the range of adequacy: comparison of leucine kinetics and nitrogen balance data. AB - Research suggests that changes in leucine oxidation (leuox) with feeding may reflect adult protein requirements. We evaluated this possibility by assessing the effects of age, sex, and different protein intakes on whole-body leucine kinetics and nitrogen balance. Thirty-four young (n=18, 22-46 years) and old (n=16, 63-81 years) men and women completed three 18-day trials with protein intakes of 0.50, 0.75 and 1.00 g protein.kg body weight(-1).d(-1). Fasting and fed-state leucine kinetics were quantified on day 12 of each trial using a primed, constant infusion of L-[1-13C]leucine. Protein requirement was estimated using classical nitrogen balance measurements and calculations. Leucine kinetics parameters were influenced by age and sex across all protein intakes. With feeding, leuox increased more in old vs. young adults. Independent of age, fasting and fed-state leuox were lower, and net leucine balance (fasting+fed state) was higher in women vs. men. Among all subjects and protein intakes, nitrogen balance was correlated with fed-state leuox (r=0.39), fed-state leucine balance (r=0.60), net leucine balance (r=0.49) and the change in leuox from the fasting to fed state (r=0.49) (P<.05 for all results). At the highest protein intake, the change in leuox with feeding was inversely correlated with protein requirement (r=-0.39). These findings indicate that leucine kinetics, especially leuox, reflect nitrogen balance-based estimates of the need for dietary protein and generally support the view that protein requirement is comparable between young and old adults. PMID- 22841545 TI - The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response. AB - Selenium induces a senescence response in cells through induction of ataxia telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1 oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response. PMID- 22841547 TI - Is Gram staining a diagnostic tool or a guide for optimal empirical therapy? PMID- 22841546 TI - Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARgamma activation on diet-induced intestine inflammatory response. AB - PFKFB3 is a target gene of peroxisome proliferator-activated receptor gamma (PPARgamma) and encodes for inducible 6-phosphofructo-2-kinase (iPFK2). As a key regulatory enzyme that stimulates glycolysis, PFKFB3/iPFK2 links adipocyte metabolic and inflammatory responses. Additionally, PFKFB3/iPFK2 is involved in the effect of active PPARgamma on suppressing overnutrition-induced adipose tissue inflammatory response, which accounts for the insulin-sensitizing and antidiabetic effects of PPARgamma activation. Using PFKFB3/iPFK2-disrupted mice, the present study investigated the role of PFKFB3/iPFK2 in regulating overnutrition-associated intestine inflammatory response and in mediating the effects of PPARgamma activation. In wild-type mice, intestine PFKFB3/iPFK2 was increased in response to high-fat diet (HFD) feeding compared with that in mice fed a low-fat diet. However, intestine PFKFB3/iPFK2 was decreased in PFKFB3/iPFK2 disrupted mice and did not respond to HFD feeding. Furthermore, on an HFD, PFKFB3/iPFK2-disrupted mice displayed a significant increase in major intestine proinflammatory indicators such as toll-like receptor 4 expression, c-Jun N terminal kinase 1 and nuclear factor kappa B phosphorylation, and proinflammatory cytokine expression compared with wild-type littermates. Upon treatment with rosiglitazone, an agonist of PPARgamma, intestine proinflammatory indicators were markedly decreased in wild-type mice, but to a much lesser degree in PFKFB3/iPFK2 disrupted mice. Overall, the status of HFD-induced intestine inflammatory response in all treated mice correlated inversely with systemic insulin sensitivity, indicated by the homeostasis model assessment of insulin resistance data. Together, these results suggest that PFKFB3/iPFK2 is critically involved in the effect of PPARgamma activation on suppressing diet-induced intestine inflammatory response. PMID- 22841548 TI - Regulation of CLL survival by hypoxia-inducible factor and its target genes. AB - Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is characterized by the progressive accumulation of small mature CD5(+)B lymphocytes in the peripheral blood, lymphoid organs, and bone marrow (BM). The main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells. Appropriate cellular responses to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, are ultimately regulated by the transcription factor, hypoxia-inducible factor (HIF). Unlike their normal counterparts, CLL cells express HIF-1alpha even under normoxia. In addition, overexpression of HIF 1alpha has been observed in leukemic cells in BM specimens from CLL patients. The HIF transcription factor has been implicated in controlling the expression of a wide variety of genes implicated in apoptosis, angiogenesis, invasion, and metastasis. This review describes pathways regulating CLL survival with a focus on HIF-1alpha and its target genes, MIF and Midkine (MK), and the potential cross talk between these factors. PMID- 22841549 TI - Annexin A9 is a periplakin interacting partner in membrane-targeted cytoskeletal linker protein complexes. AB - Periplakin regulates keratin organisation and participates in the assembly of epidermal cornified envelopes. A proteomic approach identified annexin A9 as a novel interacting partner for periplakin N-terminus. The presence of annexin A9 in complexes with periplakin was confirmed by immunoblotting of proteins immunoprecipitated by anti-HA or anti-annexin A9 antibodies. Both endogenous and GFP-tagged annexin A9 co-localise with endogenous periplakin and transfected periplakin N-terminus at MCF-7 cell borders and aggregate after Okadaic acid treatment. Annexin A9 and periplakin co-localise in the epidermis and annexin A9 is up-regulated in differentiating keratinocytes, but the epidermal annexin A9 expression does not require periplakin. PMID- 22841550 TI - Structural and functional characterization of the bacterial translocation inhibitor GE82832. AB - The structure of GE82832, a translocation inhibitor produced by a soil microorganism, is shown to be highly related to that of dityromycin, a bicyclodecadepsipeptide antibiotic discovered long ago whose characterization had never been pursued beyond its structural elucidation. GE82832 and dityromycin were shown to interfere with both aminoacyl-tRNA and mRNA movement and with the Pi release occurring after ribosome- and EF-G-dependent GTP hydrolysis. These findings and the unusual ribosomal localization of GE82832/dityromycin near protein S13 suggest that the mechanism of inhibition entails an interference with the rotation of the 30S subunit "head" which accompanies the ribosome-unlocking step of translocation. PMID- 22841551 TI - Reduction of catheter-related bloodstream infections in preterm infants by the use of catheters with the AgION antimicrobial system. AB - OBJECTIVE: The present study aims to assess if use of a silver zeolite impregnated umbilical catheter (AgION technology) can decrease the occurrence of catheter-related bloodstream infection (CRBSIs) in preterm infants. STUDY DESIGN: Infants with gestational age<30weeks were randomized to receive an AgION impregnated or non-impregnated polyurethane umbilical venous catheter (UVC). The primary endpoint was the incidence of CRBSIs during the time the UVC was in place. RESULTS: We studied 86 infants, 41 of whom received the AgION catheter and 45 the non-impregnated catheter. During umbilical venous catheterization 2% of infants in the AgION group developed CRBSI in comparison with 22% of infants in the control group (p=0.005). AgION catheters were well tolerated and none of the patients showed signs attributable to silver toxicity. CONCLUSIONS: The AgION impregnated UVCs were effective in decreasing the development of CRBSIs in preterm infants compared to non-impregnated polyurethane UVCs. PMID- 22841552 TI - Endonuclease substrate selectivity characterized with full-length PA of influenza A virus polymerase. AB - The influenza A polymerase is a heterotrimer which transcribes viral mRNAs and replicates the viral genome. To initiate synthesis of mRNA, the polymerase binds a host pre-mRNA and cleaves a short primer downstream of the 5' end cap structure. The N-terminal domain of PA has been demonstrated to have endonuclease activity in vitro. Here we sought to better understand the biochemical nature of the PA endonuclease by developing an improved assay using full-length PA protein. This full-length protein is active against both RNA and DNA in a cap-independent manner and can use several different divalent cations as cofactors, which affects the secondary structure of the full-length PA. Our in vitro assay was also able to demonstrate the minimal substrate size and sequence selectivity of the PA protein, which is crucial information for inhibitor design. Finally, we confirmed the observed endonuclease activity of the full-length PA with a FRET-based assay. PMID- 22841553 TI - High-throughput assay for simultaneous quantification of the plasma concentrations of morphine, fentanyl, midazolam and their major metabolites using automated SPE coupled to LC-MS/MS. AB - A rapid LC-MS/MS assay method for simultaneous quantification of morphine, fentanyl, midazolam and their major metabolites: morphine-3-beta-D-glucuronide (M3G), morphine-6-beta-D-glucuronide (M6G), norfentanyl, 1'-hydroxymidazolam (1 OH-MDZ) and 4-hydroxymidazolam (4-OH-MDZ) in samples of human plasma has been developed and validated. Robotic on-line solid phase extraction (SPE) instrumentation was used to elute the eight analytes of interest from polymeric SPE cartridges to which had been added aliquots (150 MUL) of human plasma and aliquots (150 MUL) of a mixture of two internal standards, viz. morphine-d3 (200 ng/mL) and 1'-hydroxymidazolam-d5 (50 ng/mL) in 50 mM ammonium acetate buffer (pH 9.25). Cartridges were washed using 10% methanol in ammonium acetate buffer, pH 9.25 (1 mL, 2 mL/min) before elution with mobile phase comprising 0.1% formic acid in water (A) and acetonitrile (B) with a flow rate of 0.6 mL/min using an 11.5 min run time. The analytes were separated on a C18 X-Terra(r) analytical column. The linear concentration ranges were 0.5-100 ng/mL for fentanyl, norfentanyl and midazolam; 1-200 ng/mL for 4-hydroxymidazolam, 2.5-500 ng/mL for 1'-hydroxymidazolam and 3.5-700 ng/mL for morphine, M3G, and M6G. The method showed acceptable within-run and between-run precision (relative standard deviation (RSD) and accuracy <20%) for quality control (QC) samples spiked at concentrations of 80% and 50% of the ULOQ, 3 times higher than the LLOQ, and also at the LLOQ. Furthermore, analytes were stable in samples (after mixing with internal standard) for at least 48 h in the autosampler (except for 4 hydroxymidazolam which decreased by 22% after 24 h), 5 h at room temperature and after three cycles of freeze and thaw. No autosampler carry-over was observed and the absolute recovery (the area ratio of analyte in plasma relative to that in ammonium acetate buffer 50 mM, pH 9.25) was in the range 40% (midazolam) to 110% (morphine). The assay was applied successfully to the measurement of the analytes of interest in plasma samples from patients on extracorporeal membrane oxygenation (ECMO). PMID- 22841554 TI - Validated determination of primulasaponins in primula root by a high-performance thin-layer-chromatography densitometric approach. AB - A novel HPTLC-densitometric method was developed for separation and quantitation of primulasaponin I and II in different matrices. HPTLC silica gel 60 F254(S), 20 cm * 10 cm, plates with ethyl acetate:water:formic acid (5:1:1 v/v) as the mobile phase were used. Densitometric determinations were performed in reflectance mode at 540 nm after derivatization with vanillin reagent. The method was validated giving rise to a dependable and high throughput procedure well suited to routine applications. Primulasaponins were quantified in the range of 150-450 ng with RSD of repeatability and intermediate precision between 0.8 and 1.4% and accuracy within the acceptance limits. The method was tested on commercial herbal medicinal preparations claiming to contain primula root extract. PMID- 22841555 TI - Design of experiments as a tool for LC-MS/MS method development for the trace analysis of the potentially genotoxic 4-dimethylaminopyridine impurity in glucocorticoids. AB - The present study reports on a liquid chromatography-tandem mass spectrometry (LC MS/MS) method development strategy supported by design of experiments (DoE) for the trace analysis of 4-dimethylaminopyridine (DMAP). The conventional approaches for development of LC-MS/MS methods are usually via trial and error, varying intentionally the experimental factors which is time consuming and interactions between experimental factors are not considered. The LC factors chosen for the DoE study include flow (F), gradient (G) and injection volume (V(inj)) while cone voltage (E(con)) and collision energy (E(col)) were chosen as MS parameters. All of the five factors were studied simultaneously. The method was optimized with respect to four responses: separation of peaks (Sep), peak area (A(peak)), length of the analysis (T) and the signal to noise ratio (S/N). A quadratic model, namely central composite face (CCF) featuring 29 runs was used instead of a less powerful linear model since the increase in the number of injections was insignificant. In order to determine the robustness of the method a new set of DoE experiments was carried out applying robustness around the optimal conditions was evaluated applying a fractional factorial of resolution III with 11 runs, wherein additional factors - such as column temperature and quadrupole resolution - were considered. The method utilizes a Phenomenex Gemini NX C-18 HPLC analytical column with electrospray ionization and a triple quadrupole mass detector in multiple reaction monitoring (MRM) mode, resulting in short analyses with a 10min runtime. Drawbacks of derivatization, namely incomplete reaction and time consuming sample preparation, have been avoided and the change from SIM to MRM mode resulted in increased sensitivity and lower LOQ. The DoE method development strategy led to a method allowing the trace analysis of DMAP at 0.5 ng/ml absolute concentration which corresponds to a 0.1 ppm limit of quantification in 5mg/ml mometasone furoate glucocorticoid. The obtained method was validated in a linear range of 0.1-10 ppm and presented a %RSD of 0.02% for system precision. Regarding DMAP recovery in mometasone furoate, spiked samples produced %recoveries between 83 and 113% in the range of 0.1-2 ppm. PMID- 22841556 TI - Development and validation of a ultra high performance liquid chromatography tandem mass spectrometric method for the direct detection of formoterol in human urine. AB - Formoterol is a long acting beta(2)-agonist and has proven to be a very effective bronchodilating agent. Hence it is frequently applied therapeutically for the treatment of asthma. Because beta(2)-agonists might be misused in sports for the stimulatory effects and for growth-promoting action their use is restricted. Since January 2012, formoterol is prohibited in urinary concentrations higher than 30 ng/mL. The objective of this study was to develop and validate a simple and robust ultra high performance liquid chromatographic-tandem mass spectrometric (UHPLC-MS/MS) method for the direct quantification of formoterol in urine. Sample preparation was limited to an enzymatic hydrolysis step after which 2 MUL was injected in the chromatographic system. Chromatography was performed on a C(8)-column using gradient conditions. The mobile phase consisted of water/methanol (H(2)O/MeOH) both containing 0.1% acetic acid (HOAc) and 1mM ammonium acetate (NH(4)OAc). Calibration curve were constructed between 15 and 60 ng/mL. Validation data showed bias of 1.3% and imprecision of 5.4% at the threshold. Ion suppression/enhancement never exceeded 7%. Calculating measurement uncertainty showed proof of applicability of the method. Stability of formoterol was also investigated at 56 degrees C (accelerated stability test) at pH 1.0/5.2/7.0 and 9.5. At the physiological pH values of 5.2 and 7.0, formoterol showed good stability. At pH 1.0 and 9.5 significant degradation was observed. PMID- 22841557 TI - Photochemical stability of 4'-azido-2'-deoxy-2'-methylcytidine hydrochloride: structural elucidation of major degradation products by LC-MS and NMR analysis. AB - The photochemical stability of (1'R,2'S,3'S,4'R)-4'-azido-2'-deoxy-2' methylcytidine hydrochloride, a new anti-HCV agent, was investigated. Aqueous solutions and bulk drug powder of the drug candidate were exposed to UV-visible light, complying with ICH requirements. The nucleoside analog decomposed via loss of nitrogen to yield products derived from a highly reactive azide intermediate. Major photolysis products were identified by LC-MS and NMR analysis, revealing three main photodegradation pathways. The first one led to the formation of a ring-expanded imidate ester. The other degradation pathways involved exocyclic or endocyclic bond cleavage with imine or imino lactone formation. The latter were prone to rapid hydrolysis, eventually resulting in the release of cytosine, 2 methyl malonaldehyde and (E)-cytosyl-2-methylpropenal. PMID- 22841558 TI - The association between vitamin D levels and recurrent group A streptococcal tonsillopharyngitis in adults. AB - OBJECTIVES: To determine the association between recurrent group A streptococcal (GAS) tonsillopharyngitis and serum 25-hydroxy (25(OH)) vitamin D among adult subjects. METHODS: Adult patients with tonsillopharyngitis between January 2007 and December 2009 were reviewed and identified retrospectively. Cases with a medical history of recurrent GAS tonsillopharyngitis were compared to age- and gender-matched individuals without a medical history of GAS tonsillopharyngitis. Recurrent tonsillopharyngitis was defined as three or more episodes of GAS tonsillopharyngitis per year for a period of two consecutive years. RESULTS: Fifty-four cases with recurrent GAS tonsillopharyngitis and 50 controls were enrolled. There were no significant differences between cases and controls with regard to mean age (41 +/- 13 vs. 42 +/- 12 years; p=0.7) and male gender (55% vs. 54%; p=0.6). Mean serum levels of 25(OH) vitamin D among subjects with recurrent GAS tonsillopharyngitis were significantly lower from the controls (11.5 ng/ml +/- 4.7 vs. 26 ng/ml +/- 7; p=0.001). Multiple regression analysis showed that a serum 25(OH) vitamin D level <20 ng/ml was associated with recurrent GAS tonsillopharyngitis (odds ratio 1.62, 95% confidence interval 1.51 1.76; p < 0.001). CONCLUSIONS: Our findings indicate a link between vitamin D deficiency and the recurrence of GAS tonsillopharyngitis. PMID- 22841559 TI - Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole. AB - BACKGROUND: Voriconazole has been used for prevention and treatment of fungal infections in patients after lung transplantation. We postulate that long-term use of voriconazole may increase the risk of squamous cell carcinoma of the skin in these patients. METHODS: The study included 120 patients who received lung transplantation at UC San Diego Health System between July 2000 and June 2006. All patients received a similar initial immunosuppression regimen, and 43 (35.8%) received voriconazole for treatment or prophylaxis for fungal diseases. In this retrospective study, we compared the incidence of squamous cell carcinoma in lung transplant recipients with or without voriconazole use. RESULTS: Squamous cell carcinomas developed in 39.5% of patients (17 of 43) who received voriconazole for prophylaxis or treatment of fungal disease, compared with 19.5% (15 of 77) who did not receive voriconazole (p = 0.03). Four patients died of metastatic squamous cell carcinoma, all in the voriconazole group. Multiple logistic regression analysis showed older age at the time of transplant (odds ratio [OR], OR (95% CI) 2.8 (1.5-5.5)), skin cancer pre-transplant (OR, 11.0 (1.76-68.4), and longer voriconazole therapy (OR, 1.8 (1.3-2.6)) were independent risk factors for development of skin cancer after transplant. CONCLUSIONS: Our results suggest that long-term use of voriconazole may be associated with development of cutaneous squamous cell carcinoma in patients after lung transplant. Greater clinical aggressiveness of skin cancer was also noted in these patients. PMID- 22841560 TI - [Radio-induced oral and pharyngeal mucositis: management updates]. AB - Mucositis is a major side effect induced by radiotherapy and/or chemotherapy of head and neck cancer. This toxicity impacts patient's quality of life and may compromise optimal treatments. Pathophysiology, risk factors, incidence and consequences of mucositis will be discussed in this review. Its management remains principally supportive (pain medication and nutritional support); however, in recent years several studies have revealed that the use of low level energy laser is particularly useful in the prevention and treatment of chemo- and radio-induced mucositis. PMID- 22841561 TI - Supporting involved health care professionals (second victims) following an adverse health event: a literature review. AB - BACKGROUND: One out of seven patients is involved in an adverse event. The first priority after such an event is the patient and their family (first victim). However the involved health care professionals can also become victims in the sense that they are traumatized after the event (second victim). They can experience significant personal and professional distress. Second victims use different coping strategies in the aftermath of an adverse event, which can have a significant impact on clinicians, colleagues, and subsequent the patients. It is estimated that nearly half of health care providers experience the impact as a second victim at least once in their career. Because of this broad impact it is important to offer support. OBJECTIVE: The focus of this review is to identify supportive interventional strategies for second victims. STUDY DESIGN: An extensive search was conducted in the electronic databases Medline, Embase and Cinahl. We searched from the start data of each database until September 2010. RESULTS: A total of 21 research articles and 10 non-research articles were identified in this literature review. There are numerous supportive actions for second victims described in the literature. Strategies included support organized at the individual, organizational, national or international level. A common intervention identified support for the health care provider to be rendered immediately. Strategies on organizational level can be separated into programs specifically aimed at second victims and more comprehensive programs that include support for all individuals involved in the adverse event including the patient, their family, the health care providers, and the organization. CONCLUSION: Second victim support is needed to care for health care workers and to improve quality of care. Support can be provided at the individual and organizational level. Programs need to include support provided immediately post adverse event as well as on middle long and long term basis. PMID- 22841563 TI - Alcohol depletes coenzyme-Q(10) associated with increased TNF-alpha secretion to induce cytotoxicity in HepG2 cells. AB - Alcohol consumption has been implicated to cause severe hepatic steatosis which is mediated by alcohol dehydrogenase (ADH) activity and CYP(450) 2E1 expression. In this context, the effect of ethanol was studied for its influence on lipogenesis in HepG2 cell which is deficient of ADH and does not express CYP(450) 2E1. The results showed that ethanol at 100mM concentration caused 40% cytotoxicity at 72h as determined by MTT assay. The incorporation of labeled [2 (14)C] acetate into triacylglycerol and phospholipid was increased by 40% and 26% respectively upon 24h incubation, whereas incorporation of labeled [2-(14)C] acetate into cholesterol was not significantly increased. Further, ethanol inhibited HMG-CoA reductase which is a rate-limiting enzyme in the cholesterol biosynthesis. It was observed that, HMG-CoA reductase inhibition was brought about by ethanol as a consequence of decreased cell viability, since incubation of HepG2 cells with mevalonate could not increase the cholesterol content and increase the cell viability. Addition of ethanol significantly increased TNF alpha secretion and depleted mitochondrial coenzyme-Q(10) which is detrimental for cell viability. But vitamin E (10mM) could partially restore coenzyme-Q(10) and glutathione content with decreased TNF-alpha secretion in ethanol treated cells. Further, lipid peroxidation, glutathione peroxidase and superoxide dismutase enzyme activities remained unaffected. Ethanol decreased glutathione content while, GSH/GSSG ratio was significantly higher compared to other groups showing cellular pro-oxidant and antioxidant balance remained intact. Alanine amino transferase activity was increased by 4.85 folds in cells treated with ethanol confirming hepatocyte damage. Hence, it is inferred that ethanol induced cytotoxicity in HepG2 cells due to coenzyme-Q(10) depletion and increased TNF alpha secretion. PMID- 22841564 TI - Application of next generation qPCR and sequencing platforms to mRNA biomarker analysis. AB - Recent years have seen the emergence of new high-throughput PCR and sequencing platforms with the potential to bring analysis of transcriptional biomarkers to a broader range of clinical applications and to provide increasing depth to our understanding of the transcriptome. We present an overview of how to process clinical samples for RNA biomarker analysis in terms of RNA extraction and mRNA enrichment, and guidelines for sample analysis by RT-qPCR and digital PCR using nanofluidic real-time PCR platforms. The options for quantitative gene expression profiling and whole transcriptome sequencing by next generation sequencing are reviewed alongside the bioinformatic considerations for these approaches. Considering the diverse technologies now available for transcriptome analysis, methods for standardising measurements between platforms will be paramount if their diagnostic impact is to be maximised. Therefore, the use of RNA standards and other reference materials is also discussed. PMID- 22841566 TI - Fifteen years of the yeast three-hybrid system: RNA-protein interactions under investigation. AB - In 1996, the Wickens and the Kuhl labs developed the yeast three-hybrid system independently. By expressing two chimeric proteins and one chimeric RNA molecule in Saccharomyces cerevisiae, this method allows in vivo monitoring of RNA-protein interactions by measuring the expression levels of HIS3 and LacZ reporter genes. Specific RNA targets have been used to characterize unknown RNA binding proteins. Previously described RNA binding proteins have also been used as bait to select new RNA targets. Finally, this method has been widely used to investigate or confirm previously suspected RNA-protein interactions. However, this method falls short in some aspects, such as RNA display and selection of false positive molecules. This review will summarize the results obtained with this method from the past 15years, as well as on recent efforts to improve its specificity. PMID- 22841565 TI - Studying protein complexes by the yeast two-hybrid system. AB - Protein complexes are typically analyzed by affinity purification and subsequent mass spectrometric analysis. However, in most cases the structure and topology of the complexes remains elusive from such studies. Here we investigate how the yeast two-hybrid system can be used to analyze direct interactions among proteins in a complex. First we tested all pairwise interactions among the seven proteins of Escherichia coli DNA polymerase III as well as an uncharacterized complex that includes MntR and PerR. Four and seven interactions were identified in these two complexes, respectively. In addition, we review Y2H data for three other complexes of known structure which serve as "gold-standards", namely Varicella Zoster Virus (VZV) ribonucleotide reductase (RNR), the yeast proteasome, and bacteriophage lambda. Finally, we review an Y2H analysis of the human spliceosome which may serve as an example for a dynamic mega-complex. PMID- 22841562 TI - GABA system dysfunction in autism and related disorders: from synapse to symptoms. AB - Autism spectrum disorders (ASDs) are neurodevelopmental syndromes characterised by repetitive behaviours and restricted interests, impairments in social behaviour and relations, and in language and communication. These symptoms are also observed in a number of developmental disorders of known origin, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these conditions have diverse etiologies, and poorly understood pathologies, emerging evidence suggests that they may all be linked to dysfunction in particular aspects of GABAergic inhibitory signalling in the brain. We review evidence from genetics, molecular neurobiology and systems neuroscience relating to the role of GABA in these conditions. We conclude by discussing how these deficits may relate to the specific symptoms observed. PMID- 22841567 TI - The bacterial two-hybrid system based on adenylate cyclase reconstitution in Escherichia coli. AB - The bacterial two-hybrid system based on the reconstitution of adenylate cyclase in Escherichia coli (BACTH) was described 14years ago (Karimova, Pidoux, Ullmann, and Ladant, 1998, PNAS, 95:5752). For microbiologists, it is a practical and powerful alternative to the use of the widely spread yeast two-hybrid technology for testing protein-protein interactions. In this review, we aim at giving the reader clear and most importantly simple instructions that should break any reticence to try the technique. Yet, we also add recommendations in the use of the system, related to its specificities. Finally, we expose the advantages and disadvantages of the technique, and review its diverse applications in the literature, which should help in deciding if it is the appropriate method to choose for the case at hand. PMID- 22841568 TI - Nodular sclerosing Hodgkin's disease mimicking Riedel's invasive fibrous thyroiditis. AB - Riedel's thyroiditis appears in the form of a hard cervical mass with rapid onset, and it is associated with extensive fibrosis that compresses nearby structures, such as the trachea and supra-aortic vessels; its diagnosis is essentially histopathological. Although its histological characteristics have been well established, there are some diagnostic pitfalls. We report here the case of a 37-year-old woman, with clinical and histopathological data suggesting Riedel's disease. Fibrosis regressed after treatment with corticosteroids, relieving the compressed airways. However, in contrast with the latest knowledge on this disease, the IgG4 serum levels were consistently normal, and positron emission tomography in search of extensive fibrosis revealed an abnormal metabolic activity of the bone marrow. The final diagnosis revised by the histopathologist was that of nodular sclerosing Hodgkin's lymphoma. This case allows us to review the diagnostic approach when facing a thyroid mass with extremely rapid evolution. PMID- 22841569 TI - Immunogold TEM of otoconin 90 and otolin - relevance to mineralization of otoconia, and pathogenesis of benign positional vertigo. AB - Implementation of the deep-etch technique enabled unprecedented definition of substructural elements of otoconia, including the fibrillar meshwork of the inner core with its globular attachments. Subsequently the effects of the principal soluble otoconial protein, otoconin 90, upon calcite crystal growth in vitro were determined, including an increased rate of nucleation, inhibition of growth kinetics and significant morphologic changes. The logical next step, ultrastructural localization of otoconin 90, by means of immunogold TEM in young mature mice, demonstrated a high density of gold particles in the inner core in spite of a relatively low level of mineralization. Here gold particles are typically arranged in oval patterns implying that otoconin 90 is attached to a scaffold consisting of the hexagonal fibrillar meshwork, characteristic of otolin. The level of mineralization is much higher in the outer cortex where mineralized fiber bundles are arranged parallel to the surface. Following decalcification, gold particles, as well as matrix fibrils, presumed to consist of a linear structural phenotype of otolin, are aligned in identical direction, suggesting that they serve as scaffold to guide mineralization mediated by otoconin 90. In the faceted tips, the level of mineralization is highest, even though the density of gold particles is relatively low, conceivably due to the displacement by the dense mineral phase. TEM shows that individual crystallites assemble into iso-oriented columns. Columns are arranged in parallel lamellae which convert into mineralized blocks for hierarchical assembly into the complex otoconial mosaic. Another set of experiments based on immunogold TEM in young mice demonstrates that the fibrils interconnecting otoconia consist of the short chain collagen otolin. By two years of age the superficial layer of mouse otoconia (corresponding to mid-life human) has become demineralized resulting in weakening or loss of anchoring of the fibrils interconnecting otoconia. Consequently, otoconia detached from each other may be released into the endolymphatic space by minor mechanical disturbances. In humans, benign positional vertigo (BPV) is believed to result from translocation of otoconia from the endolymphatic space into the semi-circular canals rendering their receptors susceptible to stimulation by gravity causing severe attacks of vertigo. The combinations of these observations in humans, together with the presented animal experiments, provide a tentative pathogenetic basis of the early stage of BPV. PMID- 22841570 TI - Inner hair cells of mice express the glutamine transporter SAT1. AB - Glutamate has been implicated in signal transmission between inner hair cells and afferent fibers of the organ of Corti. The inner hair cells are enriched in glutamate and the postsynaptic membranes express AMPA glutamate receptors. However, it is not known whether inner hair cells contain a mechanism for glutamate replenishment. Such a mechanism must be in place to sustain glutamate neurotransmission. Here we provide RT-PCR and immunofluorescence data indicating that system A transporter 1 (SLC38A1), which is associated with neuronal glutamine transport and synthesis of the neurotransmitters GABA and glutamate in CNS, is expressed in inner hair cells. It was previously shown that inner hair cells contain glutaminase that converts glutamine to glutamate. Thus, our finding that inner hair cells express a glutamine transporter and the key glutamine metabolizing enzyme glutaminase, provides a mechanism for glutamate replenishment and bolsters the idea that glutamate serves as a transmitter in the peripheral synapse of the auditory system. PMID- 22841571 TI - Characterizing the dependence of pure-tone frequency difference limens on frequency, duration, and level. AB - This study examined the relationship between the difference limen for frequency (DLF) of pure tones and three commonly explored stimulus parameters of frequency, duration, and sensation level. Data from 12 published studies of pure-tone frequency discrimination (a total of 583 DLF measurements across 77 normal hearing listeners) were analyzed using hierarchical (or "mixed-effects") generalized linear models. Model parameters were estimated using two approaches (Bayesian and maximum likelihood). A model in which log-transformed DLFs were predicted using a sum of power-law functions plus a random subject- or group specific term was found to explain a substantial proportion of the variability in the psychophysical data. The results confirmed earlier findings of an inverse square-root relationship between log-transformed DLFs and duration, and of an inverse relationship between log(DLF) and sensation level. However, they did not confirm earlier suggestions that log(DLF) increases approximately linearly with the square-root of frequency; instead, the relationship between frequency and log(DLF) was best fitted using a power function of frequency with an exponent of about 0.8. These results, and the comprehensive quantitative analysis of pure tone frequency discrimination on which they are based, provide a new reference for the quantitative evaluation of models of frequency (or pitch) discrimination. PMID- 22841572 TI - Dual role of VAMP8 in regulating insulin exocytosis and islet beta cell growth. AB - Optimal insulin secretion required to maintain glucose homeostasis is the summation of total pancreatic islet beta cell mass and intrinsic secretory capacity of individual beta cells, which are regulated by distinct mechanisms that could be amplified by glucagon-like-peptide-1 (GLP-1). Because of these actions of GLP-1 on islet beta cells, GLP-1 has been deployed to treat diabetes. We employed SNARE protein VAMP8-null mice to demonstrate that VAMP8 mediates insulin granule recruitment to the plasma membrane, which partly accounts for GLP 1 potentiation of glucose-stimulated insulin secretion. VAMP8-null mice also exhibited increased islet beta cell mass from increased beta cell mitosis, with beta cell proliferative activity greatly amplified by GLP-1. Thus, despite the beta cell exocytotic defect, VAMP8-null mice have an increased total insulin secretory capacity, which improved glucose homeostasis. We conclude that these VAMP8-mediated events partly underlie the therapeutic actions of GLP-1 on insulin secretion and beta cell growth. PMID- 22841574 TI - A curvilinear approach to the kinetic analysis of linoleate peroxidation in aqueous liposomes by 2,2'azobis(2-amidoinopropane) dihydrochloride. AB - Lipid peroxidation is a common feature of many chemical and biological processes, and is governed by a complex kinetic scheme. A fundamental stage in kinetic investigations of lipid peroxidation is the accurate determination of the rate of peroxidation, which in many instances is heavily reliant on the method of finite differences. Such numerical approximations of the first derivative are commonly employed in commercially available software, despite suffering from considerable inaccuracy due to rounding and truncation errors. As a simple solution to this, we applied three empirical sigmoid functions (viz. the Prout-Tompkins, Richards & Gompertz functions) to data obtained from the AAPH-mediated peroxidation of aqueous linoleate liposomes in the presence of increasing concentrations of Trolox, evaluating the curve fitting parameters using the widely available Microsoft Excel Solver add-in. We have demonstrated that the five-parameter Richards' function provides an excellent model for this peroxidation, and when applied to the determination of fundamental rate constants, produces results in keeping with those available in the literature. Overall, we present a series of equations, derived from the Richards' function, which enables direct evaluation of the kinetic measures of peroxidation. This procedure has applicability not only to investigations of lipid peroxidation, but to any system exhibiting sigmoid kinetics. PMID- 22841573 TI - Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. AB - Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance. PMID- 22841575 TI - A flow cytometry based competitive fluorescent microsphere immunoassay (CFIA) system for detecting up to six mycotoxins. AB - BACKGROUND: Exposure to multiple mycotoxins through the food chain represents a major potential health hazard to both humans and livestock. They can cause a variety of severe acute as well as chronic diseases. Eliminating mycotoxins from various grain crops is a global health priority. According to the Food and Agriculture Organization (FAO), world food production needs to double by 2050. Innovative solutions will be required to sustain toxin free grain supplies worldwide. METHODS: A competitive flow cytometry based multiplexed assay with fluorescent microspheres has been developed. The new multiplexed method can analyze simultaneously any one or all six major mycotoxins. They include: Ochratoxin A (OTA), Aflatoxin B1 (AFB1), Fumonisin B1 (FB1), T-2 toxin (T-2), Deoxynivalenol (DON) and Zearalenone (ZEA), which are all potential human health hazards. The CFIA described here includes a simplified single extraction step for mycotoxins from specimens and a comprehensive post acquisition software module. The new assay system was developed with a FACSArrayTM BD Bioanalyzer flow cytometer (BD Biosciences, Belgium). RESULTS: The CFIA performs favourably when compared to commercial ELISA. Sensitivity range with CFIA increased between 13% and 100% with an average improvement of 50% for the six mycotoxins. CONCLUSIONS: The multiplexed assay presented here has the unique capacity to quantify up to six mycotoxins simultaneously from a single specimen extraction. CFIA's poly mycotoxin detection sensitivity exceeds standard ELISA. CFIA may be part of a comprehensive assay system that will provide reliable and effective safeguard for agricultural commodities to be free of mycotoxins. PMID- 22841576 TI - Human monocyte-derived dendritic cells from leukoreduction system chambers after plateletpheresis are functional in an in vitro co-culture assay with intestinal epithelial cells. AB - The dendritic cells (DC) found in the intestine are involved both in the maintenance of tolerance towards commensal microbiota, and in the generation of protective immune responses against pathogens, thus contributing to gut immune homeostasis. There is an increasing interest in the use of lactic acid bacteria (LAB) as probiotics; among their beneficial effects we highlight the modulation of the immune system which is one of their fundamental properties. As these effects are strain-dependent, it is important to have in vitro systems that include DC and intestinal epithelial cells (IEC), which are crucial for intestinal homeostasis, to identify candidates by means of bacterial screening. Obtaining enough human cells, necessary to simultaneously test several bacteria, is a major challenge for researchers. In this study we analyzed the usefulness of the cellular fraction retained in leukoreduction system chambers following plateletpheresis (PP) as a source of DC. We compared the capacity of peripheral blood mononuclear cells (PBMC) from buffy coats (BC) or PP to generate DC using a short differentiation protocol. The functionality of the DC obtained was analyzed in co-cultures together with intestinal epithelial HT-29 cells, stimulating with LPS alone or with two LAB commonly used in the food industry, Streptococcus thermophilus and Lactobacillus delbrueckii. DC surface markers CD86, HLA-DR and cytokine production were measured. The behavior of DC derived from PP was similar to the behavior observed for DC derived from BC. When we tested the response of DC to bacteria, we found significant differences in cytokine secretion, especially for IL-10, suggesting that the system has the ability to discriminate LAB with different immunomodulatory properties. We also found that DC derived from both sources displayed a similar ability to phagocyte bacteria. In conclusion, we hereby propose a modification of the two-day protocol for obtaining human DC previously described, using PP as an alternative source of PBMC, to be used in co-culture systems with IEC. The novelty of this protocol is the combination of the blood monocyte source with a simple and fast differentiation method to obtain DC, and their use in a combined culture with IEC and LAB to model microbial-host interaction. Since the initial PP volume is ten times lower than that of BC, the use of PP minimizes biological residue generation and reagent consumption. In addition, monocyte-derived DC from PP were suitable for use in co-culture assays as a first screening step to study the immunomodulatory properties of LAB. PMID- 22841577 TI - Role of monocytes in mediating HIV-specific antibody-dependent cellular cytotoxicity. AB - Antibodies (Abs) that mediate antibody-dependent cellular cytotoxicity (ADCC) activity against HIV-1 are of major interest. A widely used method to measure ADCC Abs is the rapid and fluorometric antibody-dependent cellular cytotoxicity (RFADCC) assay. Antibody-dependent killing of a labelled target cell line by PBMC is assessed by loss of intracellular CFSE but retention of membrane dye PKH26 (CFSE-PKH26+). Cells of this phenotype are assumed to be derived from CFSE+PKH26+ target cells killed by NK cells. We assessed the effector cells that mediate ADCC in this assay. Backgating analysis and phenotyping of CFSE-PKH26+ revealed that the RFADCC assay's readout mainly represents CD3-CD14+ monocytes taking up the PKH26 dye. This was confirmed for 53 HIV+plasma-purified IgG samples when co cultured with PBMC from three separate healthy donors. Emergence of the CFSE PKH26+ monocyte population was observed upon co-culture of targets with purified monocytes but not with purified NK cells. Image flow cytometry and microscopy showed a monocyte-specific interaction with target cells without typical morphological changes associated with phagocytosis, suggesting a monocyte mediated ADCC process. We conclude that the RFADCC assay primarily reflects Ab mediated monocyte function. Further studies on the immunological importance of HIV-specific monocyte-mediated ADCC are warranted. PMID- 22841578 TI - A new method for quantitative analysis of the T cell receptor V region repertoires in healthy common marmosets by microplate hybridization assay. AB - The common marmoset, Callithrix jacchus, is one of the smallest primates and is increasingly used for an experimental nonhuman primate model in many research fields. Analysis of T cell receptor (TCR) repertoires is a powerful tool to investigate T cell immunity in terms of antigen specificity and variability of TCR expression. However, monoclonal antibodies specific for many TCR Valpha or Vbeta chains have not been created. We have recently identified a large number of TCRalpha chain variable (TRAV) and TCRbeta chain variable (TRBV) sequences from a cDNA library of common marmosets. The purpose of this study is to develop a new method for analysis of TCR repertoires in the common marmoset using this sequence information. This method is based on a microplate hybridization technique using 32 TRAV-specific and 32 TRBV-specific oligoprobes following an adaptor-ligation PCR. This enables the easy quantitation of the respective TRAV and TRBV expression levels. No cross-hybridization among specific-oligoprobes and very low variances in repeated measures of the same samples was found, demonstrating high specificity and reproducibility. Furthermore, this method was validated by an antihuman Vbeta23 antibody which specifically bound to marmoset Vbeta23. Using this method, we analyzed TCR repertoires from various tissue samples (PBMCs, spleen, lymph node and thymus) and isolated T cell subpopulations (CD4+CD8+, CD4+CD8- and CD4-CD8+) from the thymus of 10 common marmosets. Neither tissue specific nor T cell subpopulation-specific differences was found in TRAV and TRBV repertoires. These results suggest that, unlike mice, TCR repertoires in the common marmoset are not affected by endogenous superantigens and are conserved among individuals, among tissues, and among T cell subpopulations. Thus, TCR repertoire analysis with high specificity and reproducibility is a very useful technique, with the potential to replace flow cytometric analysis using a panel of TRV-specific antibodies, many of which remain unavailable. PMID- 22841579 TI - Experimental models of dermal fibrosis and systemic sclerosis. AB - Vasculopathy, immunological abnormalities, and fibrosis are the key features in the pathogenesis of systemic sclerosis (SSc). Expression of each of the three pathologic features varies among SSc patients leading to disease heterogeneity and variable organ manifestations. Although the etiology of SSc has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interplay between endothelial cells, immune cells and fibroblasts through cell-cell and cell-matrix interactions and communications. Relevant animal models are essential tools to in depth investigate pathogenesis of SSc. Several murine and avian models are available; however, some models display inflammation followed by fibrosis, whether some others primarily mimic autonomous fibroblast activation. In addition, typical microvascular changes of SSc are only observed in few models. Therefore, none of these animal models encompasses all features of the human disease and a critical selection is mandatory for successful in vivo studies. Hence, we will provide an overview of the most important experimental models of dermal fibrosis and SSc and discuss their respective contribution to the better understanding of SSc pathogenesis. PMID- 22841580 TI - Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what's in a name? PMID- 22841581 TI - The effect on dental enamel of varying concentrations of fluoridated milk with a cariogenic challenge in situ. AB - OBJECTIVES: This study investigated the effect of two concentrations of fluoride in milk, 2.5 and 5.0 ppm, on the prevention of demineralisation with a cariogenic challenge compared with milk with 0 ppm F. METHODS: In a controlled, randomised, cross-over, double-blind in situ study, 23 subjects wore a lower removable appliance with 2 enamel slabs for 21 days during each study arm. Subjects used F free toothpaste and the cariogenic challenge comprised of five 2 min dippings per day in 12% sucrose. The slabs were dipped in 50 ml of milk with 0 ppm, 2.5 ppm or 5.0 ppm F twice daily for 5 min. Subjects drank 100ml twice per day of the same milk. Slabs were analysed with Knoop microhardness to assess changes in mineralisation. RESULTS: Results showed that enamel was softened in all groups but the extent of enamel softness was reduced with an increasing concentration of F in milk, being highly significant for both F groups compared to the control (p<0.0001). 5.0 ppm F group showed a trend towards less softening compared to the 2.5 ppm F but was not statistically significant. CONCLUSIONS: In our in situ model, 2.5 and 5.0 ppm F in milk significantly protected enamel from demineralisation. PMID- 22841582 TI - Effects of ageing on surface textures of veneering ceramics for zirconia frameworks. AB - OBJECTIVES: To evaluate the effects of ageing on surface textures of veneering ceramics for zirconia frameworks. METHODS: Five different veneering ceramics for zirconia frameworks, Vintage ZR (ZR), Cerabien ZR (CZR), VitaVM9 (VM9), Cercon ceram KISS (KISS), and IPS e.max ceram (e.max), and one veneering ceramic with metal frameworks, Vintage MP (MP), were evaluated. Twenty specimens were fabricated from each veneering ceramic. All specimens were divided into two groups, one of which was subjected to accelerated ageing. The other was used as the control. Accelerated ageing was performed on the distilled water for 5h at 200 degrees C and 2 atm. Surface textures were examined using laser profilometry, X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). RESULTS: Compared to unaged specimens, surface roughness parameters (Ra, Rp, Rv) of all aged specimens except e.max were significantly greater (P=0.000). Compared to the unaged specimens, sodium and potassium on the surfaces of all the aged specimens significantly decreased (P<0.05). However, oxygen levels increased significantly (P<0.05). Silicon showed a tendency to decrease in all aged specimens, and that of ZR, KISS and e.max have a significant decrease (P<0.01). Numerous ruffled cracks were observed on the surfaces of all aged specimens, as shown by SEM. The peaks of all crystalline phases on the surfaces of all specimens changed after accelerated ageing. CONCLUSION: Surface textures of all examined veneering ceramics were changed by the accelerated ageing test. PMID- 22841583 TI - Direct transaortic access for transcatheter aortic valve implantations with the self-expanding CoreValve(r) prosthesis: a series of 2 cases. PMID- 22841584 TI - Health care delay times in acute myocardial infarction: differences by gender. PMID- 22841585 TI - Conformational study of the open-chain and furanose structures of D-erythrose and D-threose. AB - The potential energy surfaces for the different configurations of the D-erythrose and D-threose (open-chain, alpha- and beta-furanoses) have been studied in order to find the most stable structures in the gas phase. For that purpose, a large number of initial structures were explored at B3LYP/6-31G(d) level. All the minima obtained at this level were compared and duplicates removed. A further reoptimization of the remaining structures was carried out at B3LYP/6-311++G(d,p) level. We characterized 174 and 170 minima for the open-chain structures of D erythrose and D-threose, respectively, with relative energies that range over an interval of just over 50kJ/mol. In the case of the furanose configurations, the number of minima is smaller by approximately one to two dozen. G3B3 calculations on the most stable minima indicate that the alpha-furanose configuration is the most stable for both D-erythrose and D-threose. The intramolecular interactions of the minima have been analyzed with the Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) methodologies. Hydrogen bonds were classified as 1-2, 1-3 or 1 4, based on the number of C-C bonds (1, 2 and 3, respectively) that separate the two moieties participating in the hydrogen bond. In general, the AIM and NBO methodologies agree in the designation of the moieties involved in hydrogen bond interactions, except in a few cases associated to 1-2 contact which have small OH...O angles. PMID- 22841586 TI - Vibrotactile neurofeedback balance training in patients with Parkinson's disease: reducing the number of falls. AB - The aim of this study was to assess effectiveness of balance training with a vibrotactile neurofeedback system in improving overall stability in patients with Parkinson's disease (PD). Ten patients diagnosed with idiopathic PD were included. Individualization of the rehabilitation program started with a body sway analysis of stance and gait tasks (Standard Balance Deficit Test, SBDT) by using the diagnostic tool of the applied device (Vertiguard((r))-RT). Those tasks with the poorest outcome as related to age- and gender-related controls were included in the training program (not more than six tasks). Improvement of postural stability was assessed by performing SBDT, Sensory Organization Test (SOT) of Computerized Dynamic Posturography (CDP), Dizziness Handicap Inventory (DHI), activity-specific balance confidence scale and recording the number of falls over the past three months. Furthermore, scores of SOT and DHI of 10 PD patients previously trained in an earlier study (by using CDP) were compared with results of those in the present study. After neurofeedback training (NFT), there was a statistically significant improvement in body sway (calculated over all training tasks), number of falls, and scores of SOT, DHI and ABC. In comparison with CDP-training, a statistically significant higher increase of SOT score was observed for patients after NFT with the Vertiguard-RT device compared to CDP training. Our results showed that a free-field vibrotactile NFT with Vertiguard((r))-RT device can improve balance in PD patients in everyday life conditions very effectively, which might led in turn to a reduction of falls. PMID- 22841587 TI - Abnormal loading of the major joints in knee osteoarthritis and the response to knee replacement. AB - Knee osteoarthritis is common and patients frequently complain that they are 'overloading' the joints of the opposite leg when they walk. However, it is unknown whether moments or co-contractions are abnormal in the unaffected joints of patients with single joint knee osteoarthritis, or how they change following treatment of the affected knee. Twenty patients with single joint medial compartment knee osteoarthritis were compared to 20 asymptomatic control subjects. Gait analysis was performed for normal level gait and surface EMG recordings of the medial and lateral quadriceps and hamstrings were used to investigate co-contraction. Patients were followed up 12 months post-operatively and the analysis was repeated. Results are presented for the first 14 patients who have attended follow-up. Pre-operatively, adduction moment impulses were elevated at both knees and the contra-lateral hip compared to controls. Co contraction of hamstrings and quadriceps was elevated bilaterally. Post operatively, moment waveforms returned to near-normal levels at the affected knee and co-contraction fell in the majority of patients. However, abnormalities persisted in the contra-lateral limb with partial or no recovery of both moment waveforms and co-contraction in the majority. Patients with knee osteoarthritis do experience abnormal loads of their major weight bearing joints bilaterally, and abnormalities persist despite treatment of the affected limb. Further treatment may be required if we are to protect the other major joints following joint arthroplasty. PMID- 22841588 TI - Efficacy but side effects of anakinra therapy for chronic refractory gout in a renal transplant recipient with preterminal chronic renal failure. PMID- 22841589 TI - Treatment-related and psychosocial variables in explaining physical activity in women three weeks to six months post-treatment of breast cancer. AB - OBJECTIVE: This study examined treatment-related and psychosocial variables in explaining total and leisure time physical activity in breast cancer survivors three weeks to six months post-treatment. METHODS: A questionnaire was used to measure total and leisure time physical activity and relevant determinants among 464 breast cancer survivors (aged 18-65 years). RESULTS: Personal control was an important overall determinant in explaining physical activity in breast cancer survivors. The impact of treatment-related variables and psychological functioning depended on the working status of the women. Fatigue and poor body image prevented non-working women from being sufficiently physically active. In working women, chemotherapy and arm problems negatively influenced physical activity, whereas therapy side-effects (headaches, hot flashes, feeling unwell) and poor body image positively influenced physical activity. Social support and coping strategies could not explain post-treatment physical activity levels. CONCLUSION: Personal control, treatment-related variables and psychological functioning influenced physical activity after cancer treatment. Relations depended on the working status of the women. PRACTICE IMPLICATIONS: Incorporating self-control methods in physical activity interventions after breast cancer could be helpful. Furthermore, interventions should be tailored to the experienced symptoms (fatigue, arm-problems, body image) and working status of women. PMID- 22841590 TI - Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells. AB - Resistance to chemotherapy is a serious problem for the successful treatment of ovarian cancer patients but signalling pathways that contribute to this chemoinsensitivity are largely unknown. We demonstrate that the chemotherapeutic drug doxorubicin induces activation of the HER3-PI3K-AKT signalling cascade in ovarian cancer cells. We further show that the induction of this anti-apoptotic signalling pathway is based on upregulated expression of HER3 ligands, their shedding by the metalloprotease ADAM17, and is dependent on the HER2 receptor. The doxorubicin-mediated activation of this important survival cascade can be blocked by the kinase inhibitors lapatinib or erlotinib as well as by the therapeutic monoclonal antibody trastuzumab. Inhibition of the doxorubicin induced activation of HER3-PI3K-AKT signalling significantly increased apoptosis of ovarian cancer cells. Besides doxorubicin, treatment of cells with cisplatin resulted in activation of the HER3 receptor whereas other chemotherapeutics did not show this effect. The increase in HER3 phosphorylation was detected in well established ovarian cancer cell lines which originate from patients previously treated with these chemotherapeutic drugs. Based on these results, we postulate that activation of the HER3-PI3K-AKT cascade represents a major mechanism of chemoresistance in ovarian cancer. PMID- 22841591 TI - Natural growth and disease progression of non-small cell lung cancer evaluated with 18F-fluorodeoxyglucose PET/CT. AB - PURPOSE: The aims of this study were to: (1) estimate the volumetric and metabolic growth rate of non-small cell lung cancer (NSCLC), (2) evaluate disease progression prior to treatment, and (3) explore the effects of tumor growth rate and time to treatment (TTT) on survival outcome. METHODS: Patients with inoperable stages I-III NSCLC with serial pre-treatment PET/CT scans were eligible for this study. PET-derived metabolic tumor volumes (PET-MTV) and CT derived gross tumor volumes (CT-GTV) were contoured using PET/CT information. Normalized standardized uptake values (NSUV) in tumors including the NSUVmean and NSUVmax were measured. Tumor growth rates expressed as doubling time (DT) were estimated using an exponential model. Pre-treatment disease progression defined as the development of any new site of disease on PET/CT and change in TNM stage (AJCC 7th ed.) were recorded. Growth rate and tumor progression were analyzed with respect to overall (OS) and progression free survival (PFS). RESULTS: Thirty four patients with a median inter-scan interval (ISI) of 43 days and TTT of 48 days were analyzed. Tumor volumes showed remarkable inter-scan growth while NSUV did not increase significantly. The DT for PET-MTV, CT-GTV, NSUVmean and NSUVmax were 124, 139, 597, and 333 days, respectively. Pre-treatment disease progression occurred in 20.6% patients with longer ISI being a significant risk factor (OR=1.027, p=0.02). The optimal threshold ISI to predict progression was 58 days (4.8% vs. 46.2%, p=0.007). Neither tumor growth rates nor TTT were significantly correlated to OS or PFS. CONCLUSIONS: NSCLC displays rapid tumor volume growth whereas NSUVmean and NSUVmax are relatively stable over the same time period. Longer delays before initiation of treatment are associated with higher risk of pre-treatment disease progression. PMID- 22841592 TI - Ergonomics issues in national identity card for homeland security. AB - Ever since the 9/11 terrorist attack, many countries are considering the use of smart national identity card (SNIC) which has the ability to identify terrorists due to its biometric verification function. However, there are many ergonomics issues in the use of SNIC, e.g. card credibility. This research presents a case study survey of Malaysian users. Although most citizens (>96%) own MyKad (Malaysia SNIC), many do not carry it around and use its applications. This defeats one of its main purposes, i.e. combating terrorism. Thus, the research investigates ergonomics issues affecting the citizens' Intention to Use (ITU) MyKad for homeland security by using an extended technology acceptance model. Five hundred questionnaires were collected and analysed using structural equation modelling. Results show that perceived credibility and performance expectancy are the key issues. The findings provide many countries with insights into methods of addressing ergonomics issues and increasing adoption of SNIC for homeland security. PMID- 22841593 TI - Individual and combined effects of water quality and empty bed contact time on As(V) removal by a fixed-bed iron oxide adsorber: implication for silicate precoating. AB - The individual and combined effects of changes in water quality (i.e. pH, initial concentrations of arsenate (As(V)) and competing ions) and empty bed contact time (EBCT) on As(V) removal performance of a fixed-bed adsorber (FBA) packed with a nanostructured goethite-based granular porous adsorbent were systematically studied under environmentally relevant conditions. Rapid small scale column tests (RSSCTs) were extensively conducted at different EBCTs with synthetic waters in which pH and the concentrations of competing ions (phosphate, silicate, and vanadate) were controlled. In the absence of the competing ions, the effects of initial As(V) concentration, pH, and EBCT on As(V) breakthrough curves were successfully predicted by the homogeneous surface diffusion model (HSDM) with adsorption isotherms predicted by the extended triple layer model (ETLM). The interference effects of silicate and phosphate on As(V) removal were strongly influenced by pH, their concentrations, and EBCT. In the presence of silicate (<=21 mg/L as Si), a longer EBCT surprisingly resulted in worse As(V) removal performance. We suggest this is because silicate, which normally exists at much higher concentration and moves more quickly through the bed than As(V), occupies or blocks adsorption sites on the media and interferes with later As(V) adsorption. Here, an alternative operating scheme of a FBA for As(V) removal is proposed to mitigate the silicate preloading. Silicate showed a strong competing effect to As(V) under the tested conditions. However, as the phosphate concentration increased, its interference effect dominated that of silicate. High phosphate concentration (>100 MUg/L as P), as experienced in some regions, resulted in immediate As(V) breakthrough. In contrast to the observation in the presence of silicate, longer EBCT resulted in improved As(V) removal performance in the presence of phosphate. Vanadate was found to compete with As(V) as strongly as phosphate. This study reveals the competitive interactions of As(V) with the competing ions in actual adsorptive treatment systems and the dependence of optimal operation scheme and EBCT on water quality in seeking improved As(V) removal in a FBA. PMID- 22841594 TI - The effect of zeolite treatment by acids on sodium adsorption ratio of coal seam gas water. AB - Many coal seam gas (CSG) waters contain a sodium ion concentration which is too high relative to calcium and magnesium ions for environment acceptance. Natural zeolites can be used as a cheap and effective method to control sodium adsorption ratio (SAR, which is a measure of the relative preponderance of sodium to calcium and magnesium) due to its high cation exchange capacity. In this study, a natural zeolite from Queensland was examined for its potential to treat CSG water to remove sodium ions to lower SAR and reduce the pH value. The results demonstrate that acid activated zeolite at 30%wt solid ratio can reduce the sodium content from 563.0 to 182.7 ppm; the pH from 8.74 to 6.95; and SAR from 70.3 to 18.5. Based on the results of the batch experiments, the sodium adsorption capacity of the acid-treated zeolite is three times greater than that of the untreated zeolite. Both the untreated and acid-treated zeolite samples were characterized using zeta potential, surface characterization, DTA/TG and particle size distribution in order to explain their adsorption behaviours. PMID- 22841595 TI - Molecular and phylogenetic approaches for assessing sources of Cryptosporidium contamination in water. AB - The high sequence diversity and heterogeneity observed within species or genotypes of Cryptosporidium requires phylogenetic approaches for the identification of novel sequences obtained from the environment. A long-term study on Cryptosporidium in the agriculturally-intensive South Nation River watershed in Ontario, Canada was undertaken, in which 60 sequence types were detected. Of these sequence types 33 were considered novel with no identical matches in GenBank. Detailed phylogenetic analysis identified that most sequences belonged to 17 previously described species: Cryptosporidium andersoni, Cryptosporidium baileyi, Cryptosporidium hominis, Cryptosporidium parvum, Cryptosporidium ubiquitum, Cryptosporidium meleagridis, muskrat I, muskrat II, deer mouse II, fox, vole, skunk, shrew, W12, W18, W19 and W25 genotypes. In addition, two new genotypes were identified, W27 and W28. C. andersoni and the muskrat II genotype were most frequently detected in the water samples. Species associated with livestock made up 39% of the total molecular detections, while wildlife associated species and genotypes accounted for 55% of the Cryptosporidium identified. The human pathogenic species C. hominis and C. parvum had an overall prevalence of 1.6% in the environment, indicating a small risk to humans from the Cryptosporidium present in the watershed. Phylogenetic analysis and knowledge of host-parasite relationships are fundamental in using Cryptosporidium as a source-tracking or human health risk assessment tool. PMID- 22841596 TI - Influence of adsorption and anaerobic granular sludge characteristics on long chain fatty acids inhibition process. AB - The impact of LCFA adsorption on the methanogenic activity was evaluated in batch assays for two anaerobic granular sludges in the presence and absence of bentonite as synthetic adsorbent. A clear inhibitory effect at an oleate (C18:1) concentration of 0.5 g(C18:1) L(-1) was observed for both sludges. Palmitate (C16:0) was confirmed to be the main intermediate of C18:1 degradation in not adapted sludge and its accumulation was further evidenced by fluorescence staining and microscopy techniques. LCFA inhibition could be decreased by the addition of bentonite, reducing the lag-phase and accelerating the kinetics of LCFA degradation, concluding in the importance of the adsorptive nature of the LCFA inhibitory process. Granule morphology and molecular profiling of predominant microorganisms revealed that biomass adaptation to LCFA could modify the intermediates accumulation profiles and process rates. PMID- 22841597 TI - Combined processes of two-stage Fenton-biological anaerobic filter-biological aerated filter for advanced treatment of landfill leachate. AB - There are numerous non-biodegradable organic materials in the mature landfill leachate. To meet the new discharge standard of China, additional advanced treatment is needed for the effluent from the biological treatment processes of leachate. In this study, a combined process including two stages of "Fenton biological anaerobic filter (BANF)-biological aerated filter (BAF)" was evaluated to address the advanced treatment need. The Fenton oxidation was applied to reduce chemical oxygen demand (COD) and enhance biodegradability of refractory organics, and the BANF-BAF process was then applied to remove the total nitrogen (TN). The treatment achieved effluent concentrations of COD<70 mg/L, TN<40 mg/L and NH(3)-N<10 mg/L. The removal efficiency of COD and TN were 96.1% and 95.9%, respectively. The effluent quality met the new discharge standard for Pollution Control on the Landfill Site of Municipal Solid of PR China (GB16889-2008). The operation cost of these processes was about 36.1CHY/t (5.70USD/t). PMID- 22841598 TI - Characterization of olfactory sensory neurons in the white clover seed weevil, Apion fulvipes (Coleoptera: Apionidae). AB - Seed-eating Apion weevils (Coleoptera: Apionidae) cause large economic losses in white and red clover seed production across Europe. Monitoring and control of clover weevils would be facilitated by semiochemical-based methods. Until now, however, nothing was known about physiological or behavioral responses to semiochemicals in this insect group. Here we analyzed the antenna of the white clover (Trifolium repens L.) specialist Apion fulvipes Geoffroy with scanning electron microscopy, and used single sensillum recordings with a set of 28 host compounds to characterize 18 classes of olfactory sensory neurons (OSNs). Nine of the OSN classes responded strongly to synthetic compounds with high abundance in clover leaves, flowers, or buds. Eight classes responded only weakly to the synthetic stimuli, whereas one collective class responded exclusively to volatiles released from a crushed clover leaf. The OSNs showed a remarkable degree of specificity, responding to only one or a few chemically related compounds. In addition, we recorded a marked difference in the temporal dynamics of responses between different neurons, compounds, and doses. The identified physiologically active compounds will be screened for behavioral activity, with the ultimate goal to develop an odor-based control strategy for this pest. PMID- 22841599 TI - Distribution and accumulation of caffeine in rat tissues and its inhibition on semicarbazide-sensitive amine oxidase. AB - Wistar rats were treated with caffeine or 2-bromoethylamine, the effect of caffeine on the activity of semicarbazide-sensitive amine oxidase (SSAO) in rat serum and tissues was studied using various LC-MS methods. Caffeine was found to present in all tissues after administration for 10 days and accumulated for 25 days. The level of caffeine was high in brain and liver, and the SSAO activity in all tissues was found to be inhibited by caffeine. As the concentration of caffeine increased, the SSAO activity decreased. The inhibition ratio was correlated to the levels of caffeine present. We presume that caffeine may treat with SSAO activity associated diseases. PMID- 22841600 TI - Exposure to 2,5-hexanedione can induce neural malformations in chick embryos. AB - Worldwide, n-hexane is an organic solvent widely used in numerous industries such as chemical engineering, pharmaceutical and cosmetic industry. 2,5-Hexanedione (2,5-HD) is the main metabolite of n-hexane. It is now gradually recognized that chronic exposure to n-hexane could harm the health of people. Nevertheless, it is still unclear whether or not 2,5-HD is potentially teratogenic during pregnancies. In this study, we investigated the effects of 2,5-HD exposure on embryonic development in the chick embryo. We first determine the effect of 2,5 HD on neurodevelopment - specifically looking for neural tube defects in the forebrain, midbrain, and also for malformation in the eyes. We established that in the presence of 2,5-HD, the dorsal neural tubes were malformed during the closure of the neural folds. In addition, exposure to 2,5-HD could also inhibit neural differentiation as revealed by immunofluorescent staining for neurofilament (NF). We also demonstrated that the impaired neurodevelopment was attributed to negative effect of 2,5-HD on neurite development and positive effect on apoptosis in developing neurons. Specifically, we found 2,5-HD treatment resulted in fewer neurons and the neurites projecting from the neurons were significantly shorten when compared with control cultures. In addition, MTT and mitochondrial membrane potential (MMP) assays revealed neuron cell viability was reduced by exposure to 2,5-HD in a dose-dependent fashion. In sum, our results suggest that chronic exposure to 2,5-HD is harmful to the developing embryo, especially in the context of neurodevelopment. PMID- 22841601 TI - Evidence of acrylamide induced oxidative stress and neurotoxicity in Drosophila melanogaster - its amelioration with spice active enrichment: relevance to neuropathy. AB - Acrylamide (ACR) intoxication in its monomeric form leads to neuronal damage in both experimental animals and humans. Oxidative stress is one of the principle mechanisms related to the neurotoxicity of ACR exposure. Hence, the present study aimed to recapitulate the potential of ACR to cause oxidative stress and neurotoxic effects in Drosophila melanogaster. Exposure of adult male flies (Oregon K strain) to ACR (1-10 mM, 7 d) in the diet resulted in a concentration and time dependent mortality, while the survivors exhibited significant locomotor deficits. Further, ACR exposure (1-5 mM, 3 d) caused robust oxidative stress as evidenced by markedly elevated levels of reactive oxygen species and hypdroperoxides in head/body regions. Enhanced lipid peroxidation, perturbations in the activities of antioxidant enzymes accompanied with depletion of reduced glutathione levels in head region at high concentrations suggested induction of oxidative stress. Further, marked diminution in the activities of complexes I III, Succinic dehydrogenase, with concomitant reduction in MTT suggested the propensity of ACR to impair mitochondrial function. Furthermore, ACR-induced neurotoxic effects were discernible in terms of diminished ATPase activity, enhanced activity of acetylcholinesterase and dopamine depletion. In a satellite study, employing a co-exposure paradigm, we tested the propensity of spice actives namely eugenol (EU) and isoeugenol (IE) to ameliorate ACR-induced neurotoxicity. EU/IE enriched diet offered marked protection against ACR-induced mortality, locomotor dysfunctions and oxidative stress. Furthermore, the spice actives prevented the depletion of reduced GSH levels, maintained the activity of AChE enzyme and dopamine levels in head region. Collectively, these findings clearly demonstrate that ACR induced neurotoxicity in Drosophila may be mediated through oxidative stress mechanisms and the potential of spice actives to abrogate the condition. These data suggest that Drosophila may serve as a suitable model to understand the possible mechanism/s associated with ACR associated neuropathy. PMID- 22841602 TI - Assessment of the clinical significance of antigenic and functional levels of alpha1-proteinase inhibitor (alpha1-Pi) in infiltrating ductal breast carcinomas. AB - OBJECTIVES: To determine the clinical significance of alpha1-proteinase inhibitor (alpha1-Pi) in infiltrating ductal breast carcinoma patients. DESIGN AND METHODS: Serum levels of alpha1-Pi, tryptic specific inhibitory capacity and alpha1-Pi circulating immune complexes were determined using radial immunodiffusion, BAPNA assays and ELISA, respectively. 2-DE-MS and immunohistochemistry were performed to examine alpha1-Pi protein expression. RESULTS: A decreased serum level of alpha1-Pi was found among breast cancer patients in comparison to controls. In addition, we found a significantly decreased mean level of alpha1-Pi in the node metastatic group when compared to node negative patients. However, the functional activity of the inhibitor did not decrease proportionately. Through 2-DE analyses, a differential expression of alpha1-Pi isoforms according to tumor stage and node metastatic development was found. CONCLUSIONS: Both alpha1-Pi levels and specific activity could be a source of complementary clinical information and may provide useful information for a better understanding of the mechanisms of metastasis. PMID- 22841603 TI - Variability in swimming performance and underlying physiology in rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta). AB - We investigated intra- and interspecific variation in swimming performance and related physiological parameters in two members of the salmonid family. For our comparisons, we sourced juvenile brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss) from one hatchery and a second strain of rainbow trout from another. The hatcheries maintain genetic stocks obtained several decades ago from very different environments. We tested competing hypotheses: that there would be greater interspecific (across species) variation or that there would be greater intraspecific (within species) variation, owing to regional adaptations. To test these hypotheses, individual and small schools of five fish were taken to fatigue using the critical swimming speed test (U(crit)), and three post-exercise physiological metrics, packed red cell volume (hematocrit), citrate synthase and lactate dehydrogenase activity, were assessed. The majority of the results in swimming performance and hematocrit support that intraspecific variation was greater than interspecific variation, i.e. the location had a stronger effect than did genus. Variation in lactate dehydrogenase activity supported neither intra- nor interspecific variation as determining factors. In sum, our findings suggest that the performance of different species of salmonids from the same locale can be more similar than those of the same species from different areas. PMID- 22841604 TI - Molecular cloning, tissue distribution and daily expression of cry1 and cry2 clock genes in European seabass (Dicentrarchus labrax). AB - Biological rhythms are driven by circadian oscillators, which are ultimately controlled by the cyclic expression of clock genes. Cryptochromes (CRY), blue light photoreceptors, belong to the negative elements of the transcriptional feedback loop into the molecular clock. This paper describes the cloning and characterization of two cryptochromes (cry1 and 2) in European seabass, which is considered an interesting chronobiology model due to its dual (diurnal/nocturnal) behavior. The cloned cDNA fragments encoded for two proteins of 567 and 668 amino acids, which included the FAD-binding and the DNA-photolyase domains. Moreover, both proteins had a high homology with cryptochrome proteins (Cry) of other teleost fish. These cry1 and 2 genes were expressed in several tissues of seabass (brain, liver, heart, retina, muscle, spleen, gill and intestine). In addition, the daily expression of cry1 was rhythmic in brain, heart and liver with the acrophase around ZT 03:15 h (after the onset of lights). Similarly, the cry2 daily expression was rhythmic in liver, peaking at ZT 03:28 h, whereas in brain the acrophase was at ZT 11:08 h (shortly prior to the offset of lights). These findings provide new elements to help understanding the functioning of the molecular clock of seabass. PMID- 22841605 TI - Effects of temperature and dietary protein level on hepatic oxidative status of Senegalese sole juveniles (Solea senegalensis). AB - Effects of 55 and 45% dietary protein levels (55P and 45P diets, respectively) and temperature (12 and 18 degrees C) on hepatic activity of superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase (GR), glucose-6-phosphate dehydrogenase and lipid peroxidation (LPO) levels of Solea senegalensis juveniles were studied. Further, effects of acute thermal shocks provoked by a drop (18 degrees C to 12 degrees C) or a rise (12 degrees C to 18 degrees C) of water temperature on sole oxidative state was also evaluated. Dietary protein reduction increased LPO levels though no major alterations were found on antioxidant enzyme activities between dietary treatments. At 12 degrees C GR activity was higher and SOD activity was lower than 18 degrees C but LPO levels were not affected. In both thermal shock cases, LPO levels increased in 55P group, probably due to insufficient antioxidant enzyme activation. In contrast, fish of 45P group under acute exposition to warmer and colder temperature exhibited no substantial changes and a significant decrease on LPO levels, respectively, along with no major changes in antioxidant enzymes. Overall, results suggest that independently of rearing temperatures 45P group was more susceptible to oxidative stress than 55P group. Thermal shock either due to rise or drop of temperature seemed to induce oxidative stress in 55P group. PMID- 22841606 TI - Relationship between oxidative stress and circulating testosterone and cortisol in pre-spawning female brown trout. AB - Reproduction in vertebrates is an energy-demanding process that is mediated by endogenous hormones and potentially results in oxidative stress. The primary aim of this study was to quantify the relationship between oxidative stress parameters (antioxidant capacity and levels of reactive oxygen metabolites) and circulating testosterone and cortisol in a common and widespread teleost fish, the brown trout (Salmo trutta, L.). Results show that trout with higher testosterone levels prior to spawning have higher levels of oxidative damage at the time that they spawn (although by the time of spawning testosterone levels had dropped, leading to a negative relationship between testosterone and oxidative damage at that time). Cortisol levels were not directly related to oxidative damage or antioxidant capacity, but concentrations of this hormone were positively related to levels of fungal infection, which was itself associated both with lower antioxidant capacity and lower levels of oxidative damage. These results highlight the complexity of interactions between different components of the endocrine system and metabolism and suggest that caution be used in interpreting relationships between a single hormone and indicators of oxidative balance or other fitness proxies. PMID- 22841607 TI - Specific antibodies protect gamma-irradiated mice against Francisella tularensis infection. AB - The role of antibodies in the course of Francisella tularensis (F. tularensis) infection is still a subject of debate. The understanding of the poorly described role of humoral immunity is more than important for the effort to develop effective prophylactic procedure against the infection with Francisella virulent strains. We utilized the model of gamma-irradiated mice for the studies of the protective role of anti-F. tularensis antibodies in order to partially eliminate cellular responses. The model of gamma-irradiated mice can also demonstrate the responses of immunocompromised host to intracellular bacterial infection. The gamma-irradiation by doses greater than 3 Gy completely impairs the resistance to infection and causes a disbalance of cytokine production in mice. In this study, we demonstrate that passive transfer of immune sera protected irradiated mice against subsequent infection with strains of F. tularensis subsp. holarctica. Naive mice of BALB/c or C3H/CBi strains were subjected to passive transfer of sera obtained from immunized mice with live vaccine strain (LVS) F. tularensis LVS, F. tularensis subsp. holarctica strain 15, heat-killed F. tularensis LVS, or heat-killed strain 15 two hours before infection with lethal doses of LVS or strain 15. The passive transfer of sera obtained from immunized mice conferred full protection of naive unirradiated as well as sublethally irradiated mice against low lethal doses of infection with F. tularensis LVS or strain 15, in all variants of the experiments. In addition, the passively protected mice that survived the primary infection with F. tularensis LVS were protected also against further secondary challenge with a highly virulent strain of F. tularensis subsp. tularensis SchuS4. Moreover, the first evidence of combination of successful passive transfer of immunity by specific antisera and subsequent active immunization of immunocompromised animals is demonstrated. In summary, we demonstrate that B cell-mediated effector responses together with the induction of T cell-mediated immunity both play an important role in naive and also in immunocompromised mice and this fact it would be appropriate to take into the account in the design of new vaccines. PMID- 22841608 TI - Association between glomerular filtration rate and endothelial function in an elderly community cohort. AB - BACKGROUND: Endothelial dysfunction is prevalent among individuals with chronic kidney disease. However, the association between glomerular filtration rate and endothelial function in the community is unclear and needs to be investigated in the general population. METHODS: In the community-based Prospective Investigation of the Vasculature of Uppsala Seniors study (PIVUS, n = 952, mean age 70, women 49.3%), we investigated cross-sectional associations between estimated cystatin C based glomerular filtration rate (eGFR), and 3 measures representing different aspects of endothelial function (endothelial-dependent vasodilation [EDV], endothelial independent vasodilatation [EIDV], and flow-mediated dilatation [FMD]). We also performed pre-specified sub-group analyses in participants with normal eGFR (>60 ml/min/1.73 m(2)). RESULTS: In the whole cohort, 10 ml/min/1.73 m(2) higher eGFR was associated with 3% higher EDV (p = 0.001) and 2% higher EIDV (p = 0.007), adjusted for age and sex. The associations were attenuated and no longer statistically significant after adjusting for established cardiovascular risk factors. In participants with eGFR >60 ml/min/1.73 m(2), 10 ml higher eGFR was associated with 2% higher EDV (p = 0.04) after adjusting for sex and age. eGFR was not associated to FMD in any model or sub-sample. CONCLUSION: This community-based study suggests that eGFR is associated with endothelial function also in persons with normal kidney function, but that this association is largely explained by confounding by established cardiovascular risk factors. Thus, our data do not support the notion of a direct causal interplay between renal and vascular function prior to the development of CKD. PMID- 22841609 TI - Compliance with barrier precautions during paediatric trauma resuscitations. AB - PURPOSE: Barrier precautions protect patients and providers from blood-borne pathogens. Although barrier precaution compliance has been shown to be low among adult trauma teams, it has not been evaluated during paediatric resuscitations in which perceived risk of disease transmission may be low. The purpose of this study was to identify factors associated with compliance with barrier precautions during paediatric trauma resuscitations. METHODS: Video recordings of resuscitations performed on injured children (<18 years old) were reviewed to determine compliance with an established policy requiring gowns and gloves. Depending on activation level, trauma team members included up to six physicians, four nurses, and a respiratory therapist. Multivariate logistic regression was used to determine the effect of team role, resuscitation factors, and injury mechanism on barrier precaution compliance. RESULTS: Over twelve weeks, 1138 trauma team members participated in 128 resuscitations (4.7% penetrating injuries, 9.4% highest level activations). Compliance with barrier precautions was 81.3%, with higher compliance seen among roles primarily at the bedside compared to positions not primarily at the bedside (90.7% vs. 65.1%, p<0.001). Bedside residents (98.4%) and surgical fellows (97.6%) had the highest compliance, while surgical attendings (20.8%) had the lowest (p<0.001). Controlling for role, increased compliance was observed during resuscitations of patients with penetrating injuries (OR=3.97 [95% CI: 1.35-11.70], p=0.01), during resuscitations triaged to the highest activation level (OR=2.61 [95% CI: 1.34 5.10], p=0.005), and among team members present before patient arrival (OR=4.14 [95% CI: 2.29-7.39], p<0.001). CONCLUSIONS: Compliance with barrier precautions varies by trauma team role. Team members have higher compliance when treating children with penetrating and high acuity injuries and when arriving before the patient. Interventions integrating barrier precautions into the workflow of team members are needed to reduce this variability and improve compliance with universal precautions during paediatric trauma resuscitations. PMID- 22841611 TI - Differences in outcomes between ICU attending and senior resident physician led medical emergency team responses. AB - INTRODUCTION: Although rapid response systems (RRS) have been shown to decrease the incidence of cardiac arrest (CA), there are no studies evaluating optimal staffing. We hypothesize that there are no outcome differences between ICU physician and senior resident led events. METHODS: A retrospective study of the RRS database at a single, academic hospital was performed from July 1, 2006 to May 31, 2010. Surgical patients and those in the ICU were excluded. Daytime (D) was defined as 7 am-5 pm Monday through Friday, and weekends were defined as 5 pm on Friday to 6:59 am on Monday. The nurse to patient ratio is constant during all shifts. An ICU physician leads daytime events on weekdays whereas night/weekend (NW) events are led by residents. NW events were compared against D events using chi square or Fischer's exact test. Significance was defined as p<0.05. RESULTS: A total of 1404 events were reviewed with 534 (38%) D and 870 (62%) NW events. Respiratory and staff concerns were more likely during NW compared to D (50% vs. 39% and 46% vs. 34%, p<0.001, respectively). Following RRS activation, no difference was noted between D and NW periods in the incidence of progression to CA, transfer to ICU, or hospital mortality. Invasive procedures were more common in the NW period. CONCLUSION: Resident-led RRS may have similar outcomes to attending intensivist led events. Prospective studies are needed to determine the ideal team composition. PMID- 22841610 TI - Hyperoxia, hypocapnia and hypercapnia as outcome factors after cardiac arrest in children. AB - PURPOSE: Arterial hyperoxia after resuscitation has been associated with increased mortality in adults. The aim of this study was to test the hypothesis that post-resuscitation hyperoxia and hypocapnia are associated with increased mortality after resuscitation in pediatric patients. METHODS: We performed a prospective observational multicenter hospital-based study including 223 children aged between 1 month and 18 years who achieved return of spontaneous circulation after in-hospital cardiac arrest and for whom arterial blood gas analysis data were available. RESULTS: After return of spontaneous circulation, 8.5% of patients had hyperoxia (defined as PaO(2)>300 mm Hg) and 26.5% hypoxia (defined as PaO(2)<60 mm Hg). No statistical differences in mortality were observed when patients with hyperoxia (52.6%), hypoxia (42.4%), or normoxia (40.7%) (p=0.61). Hypocapnia (defined as PaCO(2)<30 mm Hg) was observed in 13.5% of patients and hypercapnia (defined as PaCO(2)>50 mm Hg) in 27.6%. Patients with hypercapnia or hypocapnia had significantly higher mortality (59.0% and 50.0%, respectively) than patients with normocapnia (33.1%) (p=0.002). At 24h after return of spontaneous circulation, neither PaO(2) nor PaCO(2) values were associated with mortality. Multiple logistic regression analysis showed that hypercapnia (OR, 3.27; 95% CI, 1.62-6.61; p=0.001) and hypocapnia (OR, 2.71; 95% CI, 1.04-7.05; p=0.04) after return of spontaneous circulation were significant mortality factors. CONCLUSIONS: In children resuscitated from cardiac arrest, hyperoxemia after return of spontaneous circulation or 24h later was not associated with mortality. On the other hand, hypercapnia and hypocapnia were associated with higher mortality than normocapnia. PMID- 22841612 TI - [Totally laparoscopic resection of solid hepatic lesions: analysis of a single centre series of 71 cases]. AB - OBJECTIVE: To assess the results of a single-centre series of solid hepatic lesion resections using a totally laparoscopic approach. PATIENTS AND METHOD: A total of 71 solid hepatic lesion resections using a totally laparoscopic approach were performed from November 2002 to February 2012. Of these, 65 were due to malignant disease, and 6 due to benign diseases. A total of 21 hepatocellular carcinomas were removed, 16 on a cirrhotic liver. Limited resections were performed in 52 (73.2%) cases, as well as 14 sectionectomies (3 right posterior and 11 left laterals). Finally, there were 5 major liver resections: 3 left and 2 right hepatectomies. In 14 cases (19.7%) it was combined with some other surgical procedure (cholecystectomy not included). The lesions were located in the anterior segments (SA) in 41 cases (57.7%) and in postero-superior segments (PSS) in 30 cases. RESULTS: There were 2 (2.8%) conversions to open surgery. Five (7%) patients required transfusions during surgery. The median hospital stay was 4 (3 5) days. There was one (1.4%) death, and one patient required further surgery due to esophagojejunal anastomotic leak. The resection margins were tumour-free in 100% of the cases. Combined surgery showed a significant increase in the morbidity rate (35.7 compared to 7%, p=.012). There were no differences in regards to complication rate (p=.28), transfusions (p=.69) or hospital stay (p=.44) with PSS resections when compared to AS resections. CONCLUSION: The totally laparoscopic approach is feasible and safe in the resection of solid liver lesions. Combined surgery can significantly increase the morbidity rate. Resections of lesions situated in PSS can be performed with similar safety to those in SA. PMID- 22841614 TI - Ultrasound promoted Barbier reactions and Csp3-Csp2 Stille coupling for the synthesis of diarylmethanes and substituted benzophenones. AB - Here we present the preparation of a variety of diarylmethanes obtained via ultrasound Stille coupling under palladium catalysis between some substituted aryl compounds and benzyltributyltin compounds generated through sonicated Barbier reaction in a very short time reaction and excellent yield. The study reported below compares different methods to optimize the synthesis of usually unstable benzyltin derivatives and is another contribution to the investigation of Csp(3)-Csp(2) coupling process involving benzyl-aryl reagents. Substituted carboxylated benzophenones were easily prepared in a very good yield by oxidation of some diarylmethanes. PMID- 22841613 TI - Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells. AB - Ultrasound-targeted microbubble destruction (UTMD) technique can be potentially used for non-viral delivery of gene therapy. Targeting wild-type p53 (wtp53) tumor suppressor gene may provide a clinically promising treatment for patients with ovarian cancer. However, UTMD mediated gene therapy typically uses non targeted microbubbles with suboptimal gene transfection efficiency. We synthesized a targeted microbubble agent for UTMD mediated wtp53 gene therapy in ovarian cancer cells. Lipid microbubbles were conjugated with a Luteinizing Hormone-Releasing Hormone analog (LHRHa) via an avidin-biotin linkage to target the ovarian cancer A2780/DDP cells that express LHRH receptors. The microbubbles were mixed with the pEGFP-N1-wtp53 plasmid. Upon exposure to 1 MHz pulsed ultrasound beam (0.5 W/cm(2)) for 30s, the wtp53 gene was transfected to the ovarian cancer cells. The transfection efficiency was (43.90 +/- 6.19)%. The expression of wtp53 mRNA after transfection was (97.08 +/- 12.18)%. The cell apoptosis rate after gene therapy was (39.67 +/- 5.95)%. In comparison with the other treatment groups, ultrasound mediation of targeted microbubbles yielded higher transfection efficiency and higher cell apoptosis rate (p<0.05). Our experiment verifies the hypothesis that ultrasound mediation of targeted microbubbles will enhance the gene transfection efficiency in ovarian cancer cells. PMID- 22841615 TI - [Prehospital analgesia with femoral nerve block following lower extremity injury. A 107 cases survey]. AB - OBJECTIVE: Femoral Nerve Block (FNB) has been proposed for femoral fracture analgesia in a prehospital setting. METHODS: Descriptive case-series survey. All suspected femoral fractures that were managed by our extrahospital service and had a femoral block were prospectively included. The physician was free to choose any block technique (paravascular femoral block [BFPV], nerve stimulation femoral block [BFNS], or fascia iliaca block [BFI]), as well as local anesthetic mixture and volume. Pain was assessed using a simplified verbal scale (0-4) before (T0), 10minutes after block (T1), and at hospital arrival (T2). Demographic values, actual trauma diagnosis, the technique used, the local anesthetic mixture and volume, incidents and complications were recorded. RESULTS: One hundred and seven blocks were included. Eighty-six percent of the blocks were performed by an anesthesiologist, although they represent 50% of the prehospital physician staff. Pain on the simplified verbal scale (EVS) decreased from T0 to both T1 and T2 for the whole population and also in each technique subgroup (eight BFPV, 36 BFNS, and 63 BFI). Two BFI blocks required a re-injection to be successful. Ten blocks failed (eight BFI, and two BFNS). Among those 10 failed blocks, two were first wrongly quoted as successful and two successful BFNS blocks appeared inadequate with regard to the trauma location outside the femoral dermatoma. No complication was observed. CONCLUSION: Prehospital FNB appeared to be efficacious in routine practice. Teaching FNB to non-anesthesiologist physicians is challenging. PMID- 22841616 TI - Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: concept and standards of the EARLYSTIM-study. AB - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (<= 3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors. PMID- 22841617 TI - Target fishing and docking studies of the novel derivatives of aryl aminopyridines with potential anticancer activity. AB - A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation. PMID- 22841618 TI - Recombinant expression and purification of human TATA binding protein using a chimeric fusion. AB - The TATA binding protein (TBP) is the central core protein of the transcription factor II D that binds directly to the TATA box and therefore plays an integral part in eukaryotic transcription. This pivotal position of TBP is underlined by the vast number of interaction partners involved. Expression and purification of human TATA binding protein (hTBP) has remained a challenge due to protein instability and the protein loss during expression and purification involved. Here, we present a novel approach for high yield expression and purification of human TBP core (hTBPc) protein. Protein fold and activity are verified by nuclear magnetic resonance (NMR) spectroscopy and microscale thermophoresis (MST). PMID- 22841619 TI - Intestinal tuberculosis complicated with perforation during anti-tuberculous treatment in a 13-year-old girl with defective mitogen-induced IL-12 production. AB - Interleukin-12 (IL-12) is a cytokine which is secreted by activated phagocytes and dendritic cells and promotes cell-mediated immunity to intracellular pathogens, by inducing type 1 helper T cell (TH1) responses and interferon- gamma (IFN- gamma) production. Defects in the IL-12 may cause selective susceptibility to intracellular pathogens, such as mycobacteria. We herein report on a 13-year old girl with defective mitogen-induced IL-12 production, who developed intestinal tuberculosis with wide dissemination involving the lung and urinary tract. She improved gradually, but developed terminal ileal perforation approximately 6.1 months following initiation of anti-tuberculous treatment. The paradoxical response phenomenon was suspected. The girl subsequently underwent surgical resection of the affected bowel segment with a temporary double barrel stoma, and ileocolonic anastomosis was performed after the completion of the anti tuberculous therapy. The patient remained well, with no evidence of recurrent tuberculosis in the past 5 years. This case illustrates the possibility of underlying primary immunodeficiency in a patient with disseminated tuberculosis; delayed tuberculous intestinal perforation can develop during chemotherapy for tuberculosis. PMID- 22841620 TI - Subcutaneous phaeohyphomycosis caused by Exophiala jeanselmei. AB - Exophiala jeanselmei, a saprobe in the environment, is an opportunistic pathogen. We present a rare case of subcutaneous phaeohyphomycosis caused by E jeanselmei in a man aged 66 years with a 3-month history of a tender swelling on the dorsal area of the left middle finger. Purulent fluid was aspirated from the area, and the culture yielded black colonies composed of conidiophores, phialides, and yeast cells. After sequencing of the rDNA ITS1-5.8S-ITS2 gene, the pathogen was confirmed as E jeanselmei. The patient was cured by surgical excision without any antifungal agents. PMID- 22841621 TI - Human papillomavirus infection in human immunodeficiency virus-positive Taiwanese women incarcerated for illicit drug usage. AB - BACKGROUND: The number of female injection drug users infected with human immunodeficiency virus (HIV) is increasing in Taiwan. Their human papillomavirus (HPV) infection has not been fully discussed. METHODS: A cross-sectional study was conducted in a prison for women. Both HIV-positive and HIV-negative women were enrolled voluntarily. All patients answered self-administered questionnaires, had a Pap smear, and underwent linear array HPV genotype tests. RESULTS: A total of 72 female patients infected with HIV and 76 women who were not infected with HIV were enrolled in this cross-sectional study (mean age, 33.4 years). HPV infection was detected in 63.9% of patients infected with HIV and 47.4% of HIV-negative counterparts (p=0.043). Oncogenic HPV was detected in 41.6% of patients infected with HIV and 28.9% of their counterparts (p=0.10). A mean of 2.41 types of HPV were detected in HIV-positive women and 1.53 types were detected in the HIV-negative counterparts (p=0.014). HPV 52 was the most commonly encountered oncogenic type. Only 10.2% of the patients (10.9% of HIV-positive patients) had vaccine-preventable HPV types. Patients with abnormal cytology (81.3%) tended to have oncogenic types of HPV infection. HIV serostatus was the significant factor associated with oncogenic HPV infection (odds ratio=2.583, 95% confidence interval 1.071-6.231, p=0.0347). CONCLUSION: Drug-using women infected with HIV had significantly higher rates of HPV infections, justifying the aggressive screening for cervical dysplasia. PMID- 22841622 TI - Bacteremia caused by Pantoea agglomerans at a medical center in Taiwan, 2000 2010. AB - BACKGROUND/PURPOSE: There are only three case reports of adult patients with spontaneous Pantoea agglomerans bacteremia in the English literature. The aim of this study was to investigate clinical and microbiologic characteristics patients of P agglomerans bacteremia. METHODS: We studied all adult patients with P agglomerans bacteremia at a medical center from 2000 to 2010. The isolates were identified using two commercial identification systems. RESULTS: Of the 18 patients identified, 72% (n = 13) had active gastroesophageal disease treated with antacids. Two-thirds of patients had indwelling central lines and advanced cancers. None of the removed catheter tips yielded P agglomerans and line persistence was not associated with adverse outcomes. Initial disease severity was low, hypotension was uncommon and no patient died of bacteremia. Recurrence of bacteremia occurred in one patient with deep-seated infection. 16srRNA gene sequencing identified only half of the isolates as P agglomerans. The remaining nine isolates were Enterobacter species for six, Pantoea ananatis for two, and Exiguobacterium profundum for one. There were no significant differences between the characteristics of the subgroup molecularly identified as P agglomernas and the overall group characteristics. Eleven (61%) of the 18 isolates were susceptible to cefazolin, six (33%) susceptible to fosfomycin (MIC <= 64 mg/ml). Two isolates had colistin MICs >= 4 mg/ml. CONCLUSION: Bacteremia caused by P agglomerans is associated with gastroesophageal reflux disease and receipt of antacids. 16srRNA gene sequencing should not be used as the sole basis for its identification and we have highlighted the need for another molecular-based technique to conclusively characterize P agglomerans. PMID- 22841623 TI - Proteomic analysis of dark response in Arabidopsis cell suspension cultures. AB - Despite intense research on light responses in plants, the consequences of a simple shift from light to darkness are largely unexplored. In this research, the physiological outcome and proteomic changes in Arabidopsis cell suspension cultures after switching from light to total darkness were examined. Deprivation of light led to a visible loss of chlorophyll and failure to develop functional chloroplasts that are present in light-grown cells. This response was accompanied by a significant increase in the cell multiplication rate, most likely due to decreased formation of the damaging reactive oxygen species in the dark. Additionally, there were significant changes in the abundance of 46 protein spots (mostly assigned to chloroplasts, mitochondria and membranes) which were resolved by two-dimensional difference gel electrophoresis and mass spectrometric analysis. All identified chloroplast proteins were down-regulated in response to sustained darkness. In contrast, all differentially expressed proteins associated with cell wall biosynthesis were up-regulated by the dark treatment. Changes in the levels of these proteins were consistent with the observed morphological and physiological changes of the cells. These results reveal a comprehensive picture of the dark response in Arabidopsis cells and provide a useful platform for further characterization of gene function and regulation in plant responses to light. PMID- 22841624 TI - Different strategies to achieve Pb-tolerance by the two Trebouxia algae coexisting in the lichen Ramalina farinacea. AB - Lichen thalli are permeable to airborne substances, including heavy metals, which are harmful to cell metabolism. Ramalina farinacea shows a moderate tolerance to Pb. This lichen comprises two Trebouxia phycobionts, provisionally referred to as TR1 and TR9, with distinct physiological responses to acute oxidative stress. Thus, there is a more severe decay in photosynthesis and photosynthetic pigments in TR1 than in TR9. Similarly, under oxidative stress, antioxidant enzymes and HSP70 protein decrease in TR1 but increase in TR9. Since Pb toxicity is associated with increased ROS formation, we hypothesized greater Pb tolerance in this phycobiont. Accordingly, the aim of the present study was to characterize the physiological differences in the responses of TR1 and TR9 to Pb exposure. Liquid cultures of isolated phycobionts were incubated for 7 days in the presence of Pb(NO3)2. Thereafter, extracellular and intracellular Pb accumulation, photosynthetic pigments, and photosynthesis (as modulated chlorophyll fluorescence) were analyzed along with the antioxidant enzymes glutathione reductase (GR), superoxide dismutase (SOD), ascorbate peroxidase (APx), and catalase (CAT), and the stress-related protein HSP70. Pb uptake increased with the amount of supplied Pb in both algae. However, while significantly more metal was immobilized extracellularly by TR9, the amount of intracellular Pb accumulation was three times higher in TR1. In neither of the phycobionts were significant effects on photosynthetic pigments or photosynthetic electron transport observed. While under control conditions GR, SOD, and APx levels were significantly higher in TR1 than in TR9, only in the latter were these enzymes induced by Pb. This resulted in quantitatively similar antioxidant activities in the two algae when exposed to Pb. In conclusion, the phycobionts of R. farinacea make use of two different strategies against stress, in which the integration of distinct anatomical and physiological features affords similar levels of Pb tolerance. PMID- 22841625 TI - Identification and characterization of miRNAs and their potential targets in flax. AB - MicroRNAs (miRNAs) are small non-protein coding regulatory RNAs released after the cleavage of a primary transcript. A computational homology search of expressed sequence tags (ESTs) available in public databases allowed the identification of 20 conserved miRNAs belonging to 13 different families in flax (Linum usitatissimum). Most of the miRNAs were 21 nucleotides-long and carried a uracil at the 5' end. They originated from precursor transcripts that vary greatly in length. A single precursor containing 2 different stem-loop structures, each one carrying a member of the miR398 family, was identified for the first time in plants. qRT-PCR analyses of 4 selected miRNAs indicated that all were differentially expressed in flax tissues. The 20 miRNAs could potentially regulate 112 different targets including genes involved in cell wall metabolism. Analyses of pri-miRNA and potential gene expression profiles in a publically available microarray data set allowed the identification of a number of highly opposite pri-miRNA/target gene profiles potentially involved in regulating plantacyanin levels, F-box mediated signalling processes, protein metabolism and ion homeostasis, as well as 6 unknown processes. PMID- 22841626 TI - Two non-target mechanisms are involved in glyphosate-resistant horseweed (Conyza canadensis L. Cronq.) biotypes. AB - The physiological and biochemical bases for glyphosate resistance and susceptibility in horseweed (Conyza canadensis L. Cronq.) populations collected from Cordoba, Huelva, Malaga, Jaen and Seville in southern Spain were investigated. Screening 25 populations treated with glyphosate (238gacidequivalentha(-1)) at the rosette stage (BBCH 14-15) revealed reductions in fresh weight (fw) of 9-99%. The resistant biotype (R C004) was 6.1 times more resistant than the susceptible biotype (S). Shikimate accumulation in both biotypes increased until 72h after treatment (HAT), and then continued to increase (to 61.2%) in the S biotype, but decreased by 40% in the R (C004) biotype. Differential glyphosate spray retention and foliar uptake of applied (14)C-glyphosate between the R (C004) and S biotype had no effect on resistance to this herbicide. Quantitative and qualitative tests showed greater (14)C glyphosate mobility in the S biotype than in the R (C004) biotype. Glyphosate was metabolized faster in the R (C004) biotype than in the S biotype. The herbicide disappeared completely from the R (C004) biotype by conversion into glyoxylate, sarcosine and aminomethylphosphonic acid within 96 HAT. On the other hand, 41.43nmolg(-1)fw of all glyphosate applied remained in the S biotype and glyoxylate was its only non-toxic metabolite. These results suggest that glyphosate resistance in horseweed is due to two different non-target mechanisms, namely: (a) impaired glyphosate translocation and (b) glyphosate metabolism to other compounds. PMID- 22841627 TI - Activation of germline-specific genes is required for limb regeneration in the Mexican axolotl. AB - The capacity for tissue and organ regeneration in humans is dwarfed by comparison to that of salamanders. Emerging evidence suggests that mechanisms learned from the early phase of salamander limb regeneration-wound healing, cellular dedifferentiation and blastemal formation-will reveal therapeutic approaches for tissue regeneration in humans. Here we describe a unique transcriptional fingerprint of regenerating limb tissue in the Mexican axolotl (Ambystoma mexicanum) that is indicative of cellular reprogramming of differentiated cells to a germline-like state. Two genes that are required for self-renewal of germ cells in mice and flies, Piwi-like 1 (PL1) and Piwi-like 2 (PL2), are expressed in limb blastemal cells, the basal layer keratinocytes and the thickened apical epithelial cap in the wound epidermis in the regenerating limb. Depletion of PL1 and PL2 by morpholino oligonucleotides decreased cell proliferation and increased cell death in the blastema leading to a significant retardation of regeneration. Examination of key molecules that are known to be required for limb development or regeneration further revealed that FGF8 is transcriptionally downregulated in the presence of the morpholino oligos, indicating PL1 and PL2 might participate in FGF signaling during limb regeneration. Given the requirement for FGF signaling in limb development and regeneration, the results suggest that PL1 and PL2 function to establish a unique germline-like state that is associated with successful regeneration. PMID- 22841629 TI - Digital detection and analysis of branching and cell contacts in neural cell cultures. AB - Changes in human/animal behaviour and the involved neural functions are characterized by structural alterations in the brain circuitry. These changes comprise the formation of new synapses and the elimination of existing synapses aside from the modulation of connecting properties within other ones. The mechanisms of neuronal branching and cell contacting regulate and prepare for the processes of synaptic formation. In this study, we present a set of methods to detect, describe and analyse the dynamics attributed to the process of cell contacting in cell cultures in vitro. This involves the dynamics of branching and seeking for synaptic partners. The proposed technique formally distinguishes between the actual formed synapses and the potential synaptic sites, i.e. where cell contacts are likely. The study investigates the dynamic behaviour of these potential synaptic sites within the process of seeking for contacts. The introduced tools use morphological image processing algorithms to automatically detect the sites of interest. Results indicate that the introduced tools can reliably describe experimentally observed branching and seeking for contacts dynamics. Being straightforward in terms of implementation and analysis, our framework represents a solid method for studying the neural preparation phases of synaptic formation via cell contacting in random networks using standard phase contrast microscopy. PMID- 22841628 TI - Disheveled mediated planar cell polarity signaling is required in the second heart field lineage for outflow tract morphogenesis. AB - Disheveled (Dvl) is a key regulator of both the canonical Wnt and the planar cell polarity (PCP) pathway. Previous genetic studies in mice indicated that outflow tract (OFT) formation requires Dvl1 and 2, but it was unclear which pathway was involved and whether Dvl1/2-mediated signaling was required in the second heart field (SHF) or the cardiac neural crest (CNC) lineage, both of which are critical for OFT development. In this study, we used Dvl1/2 null mice and a set of Dvl2 BAC transgenes that function in a pathway-specific fashion to demonstrate that Dvl1/2-mediated PCP signaling is essential for OFT formation. Lineage-specific gene-ablation further indicated that Dvl1/2 function is dispensable in the CNC, but required in the SHF for OFT lengthening to promote cardiac looping. Mutating the core PCP gene Vangl2 and non-canonical Wnt gene Wnt5a recapitulated the OFT morphogenesis defects observed in Dvl1/2 mutants. Consistent with genetic interaction studies suggesting that Wnt5a signals through the PCP pathway, Dvl1/2 and Wnt5a mutants display aberrant cell packing and defective actin polymerization and filopodia formation specifically in SHF cells in the caudal splanchnic mesoderm (SpM), where Wnt5a and Dvl2 are co-expressed specifically. Our results reveal a critical role of PCP signaling in the SHF during early OFT lengthening and cardiac looping and suggest that a Wnt5a-> Dvl PCP signaling cascade may regulate actin polymerization and protrusive cell behavior in the caudal SpM to promote SHF deployment, OFT lengthening and cardiac looping. PMID- 22841630 TI - How many neurons can we see with current spike sorting algorithms? AB - Recent studies highlighted the disagreement between the typical number of neurons observed with extracellular recordings and the ones to be expected based on anatomical and physiological considerations. This disagreement has been mainly attributed to the presence of sparsely firing neurons. However, it is also possible that this is due to limitations of the spike sorting algorithms used to process the data. To address this issue, we used realistic simulations of extracellular recordings and found a relatively poor spike sorting performance for simulations containing a large number of neurons. In fact, the number of correctly identified neurons for single-channel recordings showed an asymptotic behavior saturating at about 8-10 units, when up to 20 units were present in the data. This performance was significantly poorer for neurons with low firing rates, as these units were twice more likely to be missed than the ones with high firing rates in simulations containing many neurons. These results uncover one of the main reasons for the relatively low number of neurons found in extracellular recording and also stress the importance of further developments of spike sorting algorithms. PMID- 22841631 TI - Neurovascular deconvolution of optical signals as a proxy for the true neuronal inputs. AB - Since the Kalman filter and Monte Carlo techniques, much theoretical work has been put into the development of signal deconvolution tools. Among recent developments taking place in neuroscience are Dynamic Expectation Maximization, Generalized Filtering and the Cubature Kalman Filter. While there are exciting prospects to use these tools for Dynamic Causal Modeling and other analyses of networks, there has been comparatively little work to validate the algorithms on controlled experimental data. In this work, the latest evolution of these tools, the square-root cubature Kalman smoother (SCKS), is tested for its effectiveness on multimodal neurovascular data. Multispectral intrinsic optical imaging and electrophysiological measurements of Wistar rats are used in combination with somatosensory stimulation. The Buxton-Friston (B-F) balloon model is then deconvolved with the SCKS algorithm to obtain the estimated neuronal inputs u(t) from the hemodynamic measurements (flow, oxy- and deoxygenated hemoglobin). RESULTS: The estimated neuronal inputs are compared to the stimulation protocol and a sensitivity and specificity analysis is carried out. SCKS succeeds in recovering most of the stimulations. Next, the estimated inputs are compared to actual measures of neuronal activity: local field potentials (LFPs) and multiunit activity (MUA). Good sensitivity of the technique is obtained with both LFPs and MUA over the whole recordings, with the area of the ROC curves favoring LFPs. A weak correlation between SCKS estimated inputs and LFPs is found outside stimulation periods, significant at one standard deviation. Finally, the accuracy of state reconstructions is studied and SCKS reconstructed states are highly concordant with measured states. PMID- 22841632 TI - Fine neurite patterns from photocrosslinking of cell-repellent benzophenone copolymer. AB - We have synthesized photocrosslinkable benzophenone copolymer, Poly(St-co-MBz), and fabricated cell-repellent patterns of Poly(St-co-MBz) on covalently bound poly-D-lysine (PDL) layer via the photocrosslinking. We have successfully obtained fine grid line pattern with line width of 3 MUm and fine neurite, presumably axon, patterns with excellent pattern fidelity. We found that benzophenone unit can be crosslinked under the exposure of UV (with the intensity of ~77 mW/cm2 at 280 nm and ~60 mW/cm2 at 365 nm) without photo-oxidative damage to PDL, poly-L-lysine, and polyethyleneimine. PMID- 22841635 TI - Options for the delivery of anti-pathogen molecules in arthropod vectors. AB - Blood feeding arthropods are responsible for the transmission of a large array of medically important infectious agents that include viruses, bacteria, protozoan parasites and helminths. The recent development of transgenic and paratransgenic technologies have enabled supplementing the immune system of these arthropod vectors with anti-pathogen effector molecules in view of compromising their vector competence for these microbial agents. The characteristics of the selected anti-pathogen compound will largely determine the efficacy and specificity of this approach. Low specificity will generally result in bystander effects, likely having a direct or indirect fitness cost for the arthropod. In contrast, the use of highly specific compounds from the adaptive immune system of vertebrates such as antibody derived fragments is more likely to enable highly specific effects without conferring a selective disadvantage to the (para)transgenic arthropods. Here, Nanobodies(r) are excellent candidates to increase the immune competence of arthropods. Moreover they were shown to exert a novel type of anti-pathogen activity that uniquely depends on their small size. PMID- 22841633 TI - A longitudinal study of occlusal caries in Newark New Jersey school children: relationship between initial dental finding and the development of new lesions. AB - OBJECTIVE: Dental caries is a significant public health problem especially amongst children from low-income backgrounds. This longitudinal study examined the development of new occlusal caries in 227 Newark, NJ children ages 10-18. The role of previous caries experience and the presence of occlusal white and dark lesions in predicting the development of new lesions were examined. DESIGN: At each visit, the patient's teeth were given a visual-tactile examination and the subject's decayed, missing and filled (DMFS) score was determined. Next, molars lacking probeable caries or restorations were examined using transillumination for occlusal white and dark spots. This examination was repeated periodically. A Cox proportional hazard was used to analyse data concerning the development of new occusal caries in molars. RESULTS: The longitudinal data indicates that patients who were caries free at visit-1 developed significantly fewer occlusal caries during the longitudinal study. The hazard ratio for subjects who had first visit caries was 2.27 compared to caries free subjects. Intact molars with occlusal white or dark lesions had caries hazard ratios of 0.78 and 1.49 respectively, compared to molars lacking initial colour changes. CONCLUSION: Having a prior caries history places the subject at increased risk of developing future caries. Teeth with dark lesions but not white lesions are at significantly increased risk for developing decay. White lesions may represent remineralizing or slowly progressing lesions. The results of this study can help identify patients and tooth surfaces at risk for future occlusal decay. PMID- 22841634 TI - Manganese-induced toxicity in normal and human B lymphocyte cell lines containing a homozygous mutation in parkin. AB - Mutations in the parkin gene are linked to development of juvenile onset of Parkinson's disease and recent studies have reported that parkin can protect against increased oxidative stress and mitochondrial dysfunction caused by a variety of oxidative and toxic insults. Overexpression of parkin has also been reported to selectively protect dopaminergic neurons from Mn toxicity. Accordingly, in this paper we compare the effect that mutations in parkin have on Mn toxicity and associated apoptotic signals in normal and human B lymphocyte cell lines containing a homozygous mutation in the gene. Results of these studies reveal that Mn toxicity was similar in both control and mutant parkin lymphocyte cells indicating that cell death caused by Mn was not altered in cells devoid of parkin activity. In contrast, Mn did inhibit mitochondrial function to a greater extent in cells devoid of active parkin as indicated by a decrease in ATP production although mitochondrial membrane potential was essentially unaffected. Consistent with inactive parkin influencing the Mn response is the observation of increased activity in the down-stream apoptotic signal, caspase 3. In summary, results reported in this paper demonstrate that mutations in parkin can lead to functional changes in potential signaling processes known to provoke Mn toxicity. The selectivity and magnitude of this response, however, does not necessarily lead to cell death in lymphocytes which are devoid of dopamine. PMID- 22841637 TI - Insect cell culture: virus replication and applications in biotechnology. AB - Insect cell lines have been initiated since the 1930s and were used to replicate insect baculoviruses as well as arboviruses. Since the latter group of viruses cause serious diseased in man and equines, efforts were expended to characterize the viruses in the new cell lines in attempts to understand the replication cycle at the cellular and molecular levels. Soon it was realized that insect baculoviruses have a potential as viable alternatives to chemicals in the control of agricultural and forest insect pests. The cell lines provided excellent tools to understand the molecular biology of baculoviruses before wide-scale use in the field. During these investigastions, it came to light that baculoviruses can be exploited as vectors for the expression of exogenous proteins and vaccines. The amenability of the virus to genetic modifications and the increasing numbers of permissive cell lines opened new avenues in protein expression. However, not all baculoviruses were able to replicate in cell lines. Indeed, there are no cell lines permissive to viruses belonging to the genera Gammabaculvirus and Deltabaculovirus. Some entomopoxviruses have been replicated in a few cell lines and this paper reports the replication of an entomopoxvirus from the spruce budworm in a homologous cell line. PMID- 22841638 TI - Tsetse-transmitted trypanosomes--their biology, disease impact and control. AB - Tsetse-transmitted trypanosome infections of man and animals occur across large areas of sub-Saharan Africa and are a major cause of ill-health and death. Although many details of the biology of tsetse-transmitted trypanosomes and the diseases they cause have been clearly established their control has proved extremely difficult. In part this is because trypanosomes show amazing antigenic variation of their surface coat and this has prevented the development of an effective vaccine. Also the few drugs which are available for treatment are unsatisfactory and often have severe side-effects. Significant progress has been made through tsetse control but such programmes are expensive and frequently re infestation occurs. There is an urgent need for more effective disease diagnostic methods, new safer drugs and more sustained international support for integrated control programmes. PMID- 22841636 TI - Improving Sterile Insect Technique (SIT) for tsetse flies through research on their symbionts and pathogens. AB - Tsetse flies (Diptera: Glossinidae) are the cyclical vectors of the trypanosomes, which cause human African trypanosomosis (HAT) or sleeping sickness in humans and African animal trypanosomosis (AAT) or nagana in animals. Due to the lack of effective vaccines and inexpensive drugs for HAT, and the development of resistance of the trypanosomes against the available trypanocidal drugs, vector control remains the most efficient strategy for sustainable management of these diseases. Among the control methods used for tsetse flies, Sterile Insect Technique (SIT), in the frame of area-wide integrated pest management (AW-IPM), represents an effective tactic to suppress and/or eradicate tsetse flies. One constraint in implementing SIT is the mass production of target species. Tsetse flies harbor obligate bacterial symbionts and salivary gland hypertrophy virus which modulate the fecundity of the infected flies. In support of the future expansion of the SIT for tsetse fly control, the Joint FAO/IAEA Programme of Nuclear Techniques in Food and Agriculture implemented a six year Coordinated Research Project (CRP) entitled "Improving SIT for Tsetse Flies through Research on their Symbionts and Pathogens". The consortium focused on the prevalence and the interaction between the bacterial symbionts and the virus, the development of strategies to manage virus infections in tsetse colonies, the use of entomopathogenic fungi to control tsetse flies in combination with SIT, and the development of symbiont-based strategies to control tsetse flies and trypanosomosis. The results of the CRP and the solutions envisaged to alleviate the constraints of the mass rearing of tsetse flies for SIT are presented in this special issue. PMID- 22841639 TI - RNAi: future in insect management. AB - RNA interference is a post- transcriptional, gene regulation mechanism found in virtually all plants and animals including insects. The demonstration of RNAi in insects and its successful use as a tool in the study of functional genomics opened the door to the development of a variety of novel, environmentally sound approaches for insect pest management. Here the current understanding of the biogenesis of the two RNAi classes in insects is reviewed. These are microRNAs (miRNAs) and short interfering RNAs (siRNAs). Several other key approaches in RNAi -based for insect control, as well as for the prevention of diseases in insects are also reviewed. The problems and prospects for the future use of RNAi in insects are presented. PMID- 22841640 TI - Phylogeny and evolution of Hytrosaviridae. AB - The Hytrosaviridae comprises a family of dsDNA viruses with a circular genome of 120-190 kb p. They are exclusively associated with Diptera, such as the tsetse fly, the house fly and the Narcissus bulb fly. Hytrosaviruses cause a very unique pathology including hypertrophy of salivary glands as well as testicular and ovarian malformation. On the other hand these viruses share a significant number of gene homologues with other dsDNA viruses, esp. baculoviruses and nudiviruses. These gene homologues include twelve so-called baculovirus core genes involved in transcription, DNA replication and the infection process. Most strikingly, the Musca domestica salivary gland hypertrophy virus (MdSGHV) encodes a homologue of a polyhedrin/granulin gene of Alpha-, Beta-, Gammabaculoviruses. Hence, it is proposed that hytrosaviruses are phylogenetically related to baculoviruses but evolved in a very close association with their dipteran hosts. PMID- 22841641 TI - Recruitment of community pharmacies in a randomized trial to generate patient referrals to the tobacco quitline. AB - BACKGROUND: Community pharmacies have the potential to reduce the prevalence of tobacco use, yet most pharmacies do not integrate cessation activities into routine practice. OBJECTIVES: The objective of this study was to describe the recruitment strategy and participant yield for a 2-state, randomized trial evaluating 2 intervention approaches for increasing pharmacy-based referrals to tobacco quitlines. METHODS: Detailed study recruitment tracking forms were used to document all contact attempts between the study investigators and each potential study site. These data were analyzed to characterize the overall recruitment and consent process for community pharmacies and pharmacy personnel (pharmacists, technicians). RESULTS: Achieving the target sample size of 64 study sites required contacting a total of 150 pharmacies (84 independent and 66 chain). Excluding 22 ineligible pharmacies, participation rates were 49% (32 of 65) for independent pharmacies and 51% (32 of 63) for chain pharmacies (50% overall). Across the 64 participating pharmacies, a total of 124 pharmacists (of 171; 73%) and 127 pharmacy technicians (of 215; 59%) were enrolled in the study. Pharmacies that chose not to participate most often cited time constraints as the primary reason. Overall, combining both the recruitment and consent process, a median of 5 contacts were made with each participating pharmacy (range, 2-19; interquartile range [IQR], 4-7), and the median overall duration of time elapsed from initial contact to consent was 25 days (range, 3-122 days; IQR, 12-47 days). CONCLUSIONS: Results from this study suggest that community pharmacy personnel are receptive to participation in multisite, tobacco cessation clinical research trials. However, execution of a representative sampling and recruitment scheme for a multistate study in this practice setting is a time- and labor-intensive process. PMID- 22841642 TI - The role of Bicoid cooperative binding in the patterning of sharp borders in Drosophila melanogaster. AB - In Drosophila embryonic development, the Bicoid (Bcd) protein establishes positional information of downstream developmental genes like hunchback (hb), which has a strong anterior expression and a sharp on-off boundary in the mid embryo. The role of Bcd cooperative binding in the positioning of the Hb pattern has been previously demonstrated. However, there are discrepancies in the reported results about the role of this mechanism in the sharp Hb border. Here, we determined the Hill coefficient (nH) required for Bcd to generate the sharp border of Hb in wild-type (WT) embryos. We found that an n(H) of approximately 6.3 (s.d. 1.4) and 10.8 (s.d. 4.0) is required to account for Hb sharpness at early and late cycle 14A, respectively. Additional mechanisms are possibly required because the high nH is likely unachievable for Bcd binding to the hb promoter. To test this idea, we determined the nH required to pattern the Hb profile of 15 embryos expressing an hb14F allele that is defective in self activation and found nH to be 3.0 (s.d. 1.0). This result indicates that in WT embryos, the hb self-activation is important for Hb sharpness. Corroborating our results, we also found a progressive increase in the required value of n(H) spanning from 4.0 to 9.2 by determining this coefficient from averaged profiles of eight temporal classes at cycle 14A (T1 to T8). Our results indicate that there is a transition in the mechanisms responsible for the sharp Hb border during cycle 14A: in early stages of this cycle, Bcd cooperative binding is primarily responsible for Hb sharpness; in late cycle 14A, hb self-activation becomes the dominant mechanism. PMID- 22841643 TI - Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3. AB - Anterior-posterior (AP) limb patterning is directed by sonic hedgehog (SHH) signaling from the posteriorly located zone of polarizing activity (ZPA). GLI3 and GLI2 are the transcriptional mediators generally utilized in SHH signaling, and each can function as an activator (A) and repressor (R). Although GLI3R has been suggested to be the primary effector of SHH signaling during limb AP patterning, a role for GLI3A or GLI2 has not been fully ruled out, nor has it been determined whether Gli3 plays distinct roles in limb development at different stages. By conditionally removing Gli3 in the limb at multiple different time points, we uncovered four Gli3-mediated functions in limb development that occur at distinct but partially over-lapping time windows: AP patterning of the proximal limb, AP patterning of the distal limb, regulation of digit number and bone differentiation. Furthermore, by removing Gli2 in Gli3 temporal conditional knock-outs, we uncovered an essential role for Gli2 in providing the remaining posterior limb patterning seen in Gli3 single mutants. To test whether GLIAs or GLIRs regulate different aspects of AP limb patterning and/or digit number, we utilized a knock-in allele in which GLI1, which functions solely as an activator, is expressed in place of the bifunctional GLI2 protein. Interestingly, we found that GLIAs contribute to AP patterning specifically in the posterior limb, whereas GLIRs predominantly regulate anterior patterning and digit number. Since GLI3 is a more effective repressor, our results explain why GLI3 is required only for anterior limb patterning and why GLI2 can compensate for GLI3A in posterior limb patterning. Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors. PMID- 22841644 TI - Regional cell shape changes control form and function of Kupffer's vesicle in the zebrafish embryo. AB - Cilia-generated fluid flow in an 'organ of asymmetry' is critical for establishing the left-right body axis in several vertebrate embryos. However, the cell biology underlying how motile cilia produce coordinated flow and asymmetric signals is not well defined. In the zebrafish organ of asymmetry-called Kupffer's vesicle (KV)-ciliated cells are asymmetrically positioned along the anterior posterior axis such that more cilia are placed in the anterior region. We previously demonstrated that Rho kinase 2b (Rock2b) is required for anteroposterior asymmetry and fluid flow in KV, but it remained unclear how the distribution of ciliated cells becomes asymmetric during KV development. Here, we identify a morphogenetic process we refer to as 'KV remodeling' that transforms initial symmetry in KV architecture into anteroposterior asymmetry. Live imaging of KV cells revealed region-specific cell shape changes that mediate tight packing of ciliated cells into the anterior pole. Mathematical modeling indicated that different interfacial tensions in anterior and posterior KV cells are involved in KV remodeling. Interfering with non-muscle myosin II (referred to as Myosin II) activity, which modulates cellular interfacial tensions and is regulated by Rock proteins, disrupted KV cell shape changes and the anteroposterior distribution of KV cilia. Similar defects were observed in Rock2b depleted embryos. Furthermore, inhibiting Myosin II at specific stages of KV development perturbed asymmetric flow and left-right asymmetry. These results indicate that regional cell shape changes control the development of anteroposterior asymmetry in KV, which is necessary to generate coordinated asymmetric fluid flow and left-right patterning of the embryo. PMID- 22841645 TI - Multinucleated smooth muscles and mononucleated as well as multinucleated striated muscles develop during establishment of the male reproductive organs of Drosophila melanogaster. AB - The adult musculature in D. melanogaster forms during metamorphosis. Much is known about the flight and leg musculature, but not about the muscles surrounding the male reproductive tract. The inner genitalia of males consist of the testes, which emerge from the gonads; the remaining genital organs, i.e., paragonia (or accessory glands), ejaculatory duct, sperm pump, and seminal vesicles, develop out of the genital imaginal disc. We analyzed the myoblasts forming the muscle layers of these organs. In myoblasts derived from the genital imaginal disc, the regulatory region of the transcription factor DMef2 is active. DMef2 is also needed for specification and differentiation of embryonic and adult myoblasts. We could discriminate three different muscle types: (i) multinucleated muscles that resemble vertebrate smooth muscles surround the testes, (ii) multinucleated muscles that resemble striated muscles comprises seminal vesicles and the sperm pump, and (iii) mononucleated striated musculature encloses the paragonia and ejaculatory duct. Members of the immunoglobulin superfamily involved in embryonic myogenesis, Dumbfounded (Duf) and Sticks and Stones (Sns), were also expressed in the genital imaginal disc, in the muscle sheath of the testes during muscle differentiation and in the secretory secondary cells, which are part of the binucleated epithelia enclosing the paragonia. PMID- 22841646 TI - Fibrillin-2b regulates endocardial morphogenesis in zebrafish. AB - scotch tape (sco) is a zebrafish cardiac mutant initially proposed to exhibit a reduced amount of cardiac jelly, the extracellular matrix between the myocardial and endocardial layers. We analyzed sco(te382) mutant hearts in detail using both selective plane illumination microscopy (SPIM) and transmission electron microscopy (TEM), and observed a fascinating endocardial defect. Time-lapse SPIM imaging of wild-type and mutant embryos revealed significant and dynamic gaps between endocardial cells during development. Although these gaps close in wild type animals, they fail to close in the mutants, ultimately leading to a near complete absence of endocardial cells in the atrial chamber by the heart looping stage. TEM analyses confirm the presence of gaps between endocardial cells in sco mutants, allowing the apparent leakage of cardiac jelly into the lumen. High resolution mapping places the sco(te382) mutation within the fbn2b locus, which encodes the extracellular matrix protein Fibrillin 2b (OMIM ID: 121050). Complementation and further phenotypic analyses confirm that sco is allelic to puff daddy(gw1) (pfd(gw1)), a null mutant in fbn2b, and that sco(te382) is a hypomorphic allele of fbn2b. fbn2b belongs to a family of genes responsible for the assembly of microfibrils throughout development, and is essential for microfibril structural integrity. In sco(te382) mutants, Fbn2b is disabled by a missense mutation in a highly conserved cbEGF domain, which likely interferes with protein folding. Integrating data obtained from microscopy and molecular biology, we posit that this mutation impacts the rigidity of Fbn2b, imparting a structural defect that weakens endocardial adhesion thereby resulting in perforated endocardium. PMID- 22841647 TI - Molecular characterization and expression profiles of cdc2 and cyclin B during oogenesis and spermatogenesis in green mud crab (Scylla paramamosain). AB - The maturation promoting factor (MPF) is a key regulator of controlling G2/M phase transition in the meiotic maturation of oocyte and spermatocyte in animals, which is a complex of CDC2 (CDK1) and cyclin B. To better understand the molecular mechanism of oocyte and spermatocyte maturation in mud crab (Scylla paramamosain), the full length cDNA of cdc2 (Sp-cdc2) and cyclin B (Sp-cyclin B) were cloned and characterized. The full length cDNA of Sp-cdc2 gene is of 1593 bp encoding a protein of 299 amino acids. Real-time quantitative PCR analysis revealed that the expression level of Sp-cdc2 in the ovary was higher than in other tissues (P<0.01); and its expression level was not significantly different in different stages of ovary development (P>0.05), meanwhile there was higher expression in T3 stage than in T1 and T2 stages (P<0.05). The full length cDNA of Sp-cyclin B is 1492 bp encoding a protein of 391 amino acids. The real-time PCR results showed that its expression level in the ovary was the highest in all examined tissues (P<0.01), and the gonad expression level in O5 stage was significantly higher than in previous 4 stages and the testis (P<0.05), and was also significantly higher in T2 stage than in T1 stage (P<0.05). In situ hybridization analysis showed that the expressions of Sp-cdc2 and Sp-cyclin B transcripts were presented in similar distribution patterns in different developing stages of ovary and testis. The positive signals of Sp-cdc2 and Sp cyclin B mRNA were detected in the oocytoplasm of oogonia and pre-vitellogenic and primary vitellogenic oocytes, while these two genes had higher expression level in the spermatid and secondary spermatocyte following primary spermatocyte. These results suggested that Sp-cdc2 and Sp-cyclin B may play essential roles in the oogenesis and spermatogenesis of the crab. PMID- 22841648 TI - [Nutcracker syndrome]. PMID- 22841650 TI - Effect of flow pulsatility on modeling the hemodynamics in the total cavopulmonary connection. AB - Total cavopulmonary connection is the result of a series of palliative surgical repairs performed on patients with single ventricle heart defects. The resulting anatomy has complex and unsteady hemodynamics characterized by flow mixing and flow separation. Although varying degrees of flow pulsatility have been observed in vivo, non-pulsatile (time-averaged) boundary conditions have traditionally been assumed in hemodynamic modeling, and only recently have pulsatile conditions been incorporated without completely characterizing their effect or importance. In this study, 3D numerical simulations with both pulsatile and non-pulsatile boundary conditions were performed for 24 patients with different anatomies and flow boundary conditions from Georgia Tech database. Flow structures, energy dissipation rates and pressure drops were compared under rest and simulated exercise conditions. It was found that flow pulsatility is the primary factor in determining the appropriate choice of boundary conditions, whereas the anatomic configuration and cardiac output had secondary effects. Results show that the hemodynamics can be strongly influenced by the presence of pulsatile flow. However, there was a minimum pulsatility threshold, identified by defining a weighted pulsatility index (wPI), above which the influence was significant. It was shown that when wPI<30%, the relative error in hemodynamic predictions using time-averaged boundary conditions was less than 10% compared to pulsatile simulations. In addition, when wPI<50, the relative error was less than 20%. A correlation was introduced to relate wPI to the relative error in predicting the flow metrics with non-pulsatile flow conditions. PMID- 22841651 TI - The use of near-infrared light for safe and effective visualization of subsurface blood vessels to facilitate blood withdrawal in children. AB - Obtaining access to blood vessels can be difficult, especially in children. Visualization of subsurface blood vessels might be a solution. Ultrasound and visible light have been used to this purpose, but have some drawbacks. Near infrared light might be a better option since subsurface blood vessels can be visualized in high contrast due to less absorption and scattering in tissue as compared to visible light. Our findings with a multispectral imaging system support this theory. A device, the VascuLuminator, was developed, based on transillumination of the puncture site with near-infrared light. The VascuLuminator was designed to meet the requirements of compact and safe use. A phantom study showed that the maximum depth of visibility (5.5mm for a 3.6mm blood vessel) is sufficient to visualize blood vessels in typical locations for peripheral venous and arterial access. A quantitative comparison of the VascuLuminator and to two other vessel imaging devices, using reflection of near infrared light instead of transillumination, was conducted. The VascuLuminator is able to decrease failure at first attempt in blood withdrawal in pediatric patients from 10/80 (13%) to 1/45 (2%; P=.05). PMID- 22841652 TI - Digital anthropometric shape analysis of 110 rhinoplasty patients in the Black Sea Region in Turkey. AB - PURPOSE: The aim of the study was to describe the average values of the nasal anthropometric measurements by using the landmark-based geometric morphometric technique in young male patients who applied for rhinoplasty in the Black Sea Region in Turkey. MATERIALS AND METHODS: The study group consisted of 110 healthy male patients all were born in the Black Sea Region, Turkey. The landmark-based geometric morphometric technique was used to analyze the nasal shapes as described in the literature. The mean age was 29 years (ranging from 23 to 35). All patients underwent primary rhinoplasty in our clinic between 2006 and 2011 years. All data were obtained from standardized digital photographic images. Anterior and worm's eye view photos of the patients were analyzed by using standard anthropometric measurement methods. RESULTS: The mean total length and nasal bridge length of the noses were 58.90 and 57.35 mm, respectively. The mean nasal bridge width and the morphologic nose width were 32.65 and 35.50mm, respectively. The average width of the anatomic nose was 26.25 mm. The mean length and width of the ala were 22.72 and 4.73 mm, respectively. The mean length and width of the columella were 11.35 and 5.20mm, respectively. The mean frontonasal angle was 137.88 degrees and the mean nasolabial angle was 87.34 degrees . CONCLUSION: Black Sea nose was characterized by being considerably longer than average in nasal length and columellar height. Also nasolabial angle was found to be more acute than average when compared to other noses. PMID- 22841649 TI - Neurobiological studies of fatigue. AB - Fatigue is a symptom associated with many disorders, is especially common in women and in older adults, and can have a huge negative influence on quality of life. Although most past research on fatigue uses human subjects instead of animal models, the use of appropriate animal models has recently begun to advance our understanding of the neurobiology of fatigue. In this review, results from animal models using immunological, developmental, or physical approaches to study fatigue are described and compared. Common across these animal models is that fatigue arises when a stimulus induces activation of microglia and/or increased cytokines and chemokines in the brain. Neurobiological studies implicate structures in the ascending arousal system, sleep executive control areas, and areas important in reward. In addition, the suprachiasmatic nucleus clearly plays an important role in homeostatic regulation of the neural network mediating fatigue. This nucleus responds to cytokines, shows decreased amplitude firing rate output in models of fatigue, and responds to exercise, one of our few treatments for fatigue. This is a young field but very important as the symptom of fatigue is common across many disorders and we do not have effective treatments. PMID- 22841653 TI - Trichloroacetic acid for the treatment of dysfunctional uterine bleeding: a pilot prospective clinical trial. AB - OBJECTIVE: The aim of the trial was to assess the safety and efficacy of tricholoroacetic acid for the treatment of dysfunctional uterine bleeding using topical versus intrauterine instillation. STUDY DESIGN: In a pilot prospective randomized clinical trial, seventy women were randomly allocated to one of two groups. In Group I, the patients were subjected to intrauterine instillation of 95% tricholoroacetic acid. Group II underwent dilatation and curettage before topical application of 95% tricholoroacetic acid. RESULTS: The groups were similar regarding baseline clinical characteristics. There was a satisfactory clinical reduction of menstrual flow (amenorrhea, hypomenorrhea and eumenorrhea) at a rate of 97.1% (Group I) and 85.7% (Group II) at 6 months. A significant increase was observed in the mean haemoglobin value at 3 and 6 months in both treatment groups (P<0.05). Group I showed a significant increase in haemoglobin level compared to Group II (P<0.05) and a significant reduction of the endometrial thickness compared to Group II (2.21 +/- 0.41 versus 3.03 +/- 3.37). CONCLUSION: Trichloroacetic acid use for treating dysfunctional uterine bleeding seems to be efficient and safe, especially in women who do not require conception. Trichloroacetic acid intrauterine instillation is associated with longer duration of reduced menstrual bleeding than topical application. PMID- 22841654 TI - Learning curve analysis of laparoscopic radical hysterectomy and lymph node dissection in early cervical cancer. AB - OBJECTIVE: We aimed to evaluate the learning curve for laparoscopic radical hysterectomy and lymph node dissection (LRHND) in uterine cervical cancer and to compare the surgicopathologic outcomes of cases treated in the first half of the curve with those treated in the second half of the curve. STUDY DESIGN: The medical records of LRHND patients between August 2004 and April 2011 were reviewed retrospectively. The patients were divided into two groups of the first 35 cases (phase I) and the second 35 cases (phase II). All operations were performed by the same surgeon. Demographic data and surgicopathologic parameters were analyzed. The learning curve was evaluated using the cumulative summation (CUSUM) technique. RESULTS: No difference was found in demographics and histologic type between the two groups. The mean operating time (307.7+/-85.8 min) of phase I was significantly longer than phase II (266.3+/-58.8 min) (P=0.021). The number of complications in phase I patients (N=9) was significantly higher than that (N=1) of phase II patients (P=0.013). There were no significant differences between the two groups with respect to lymph node yield and likelihood of identifying positive lymph nodes, resection margins, parametrium, stromal invasion, and lymphovascular space invasion. Disease-free survival did not differ between the two groups (P=0.142). The learning period for LRHND to reach a turning point was calculated to be 40 cases. CONCLUSIONS: An extended learning period can be required for LRHND, during which survival and pathologic outcome of LRHND may not be adversely affected. PMID- 22841655 TI - [Infective fungal endocarditis in patients with no previous cardiac disease]. AB - Infective endocarditis is a serious and uncommon condition affecting the endocardium. Less than 10% of these cases are of fungal origin. A growing number of individuals are at high risk, due to insertion of central venous catheters, total parenteral nutrition and prolonged exposure to broad-spectrum antibiotics, even without previous heart diseases. We retrospectively analysed the records of six children with Candida endocarditis, reviewing the comorbidities, clinical outcome, and treatment. The antifungal agents used were amphotericin B, 5 fluorocytosine and fluconazole. Patients underwent surgical excision of vegetation, five tricuspid valve repairs and one mitral valve replacement. There were no hospital deaths, and one child needed a new valvuloplasty one year later. The mean follow up was five years, and all have good valvular function without recurrent endocarditis. A combination of synergistic long-term antifungal treatment and early surgical intervention is recommended. PMID- 22841656 TI - Species tree estimation for a deep phylogenetic divergence in the New World monkeys (Primates: Platyrrhini). AB - The estimation of a robust phylogeny is a necessary first step in understanding the biological diversification of the platyrrhines. Although the most recent phylogenies are generally robust, they differ from one another in the relationship between Aotus and other genera as well as in the relationship between Pitheciidae and other families. Here, we used coding and non-coding sequences to infer the species tree and embedded gene trees of the platyrrhine genera using the Bayesian Markov chain Monte Carlo method for the multispecies coalescent (*BEAST) for the first time and to compared the results with those of a Bayesian concatenated phylogenetic analysis. Our species tree, based on all available sequences, shows a closer phylogenetic relationship between Atelidae and Cebidae and a closer relationship between Aotus and the Cebidae clade. The posterior probabilities are lower for these conflictive tree nodes compared to those in the concatenated analysis; this finding could be explained by some gene trees showing no concordant topologies between Aotus and the other genera. Moreover, the topology of our species tree also differs from the findings of previous molecular and morphological studies regarding the position of Aotus. The existence of discrepancies between morphological data, gene trees and the species tree is widely reported and can be related to processes such as incomplete lineage sorting or selection. Although these processes are common in species trees with low divergence, they can also occur in species trees with deep and rapid divergence. The sources of the inconsistency of morphological and molecular traits with the species tree could be a main focus of further research on platyrrhines. PMID- 22841657 TI - Net-like pattern of calcification on plain soft-tissue radiographs in patients with calciphylaxis. AB - BACKGROUND: Calciphylaxis is a rare, life-threatening syndrome marked by vascular calcification and cutaneous necrosis. The role of radiographic imaging in assisting in diagnosis has not been established. OBJECTIVE: To investigate the potential role of plain radiographic imaging in the diagnosis of calciphylaxis. METHODS: We searched for cases of patients at our tertiary referral center with a diagnosis of calciphylaxis between Jan 1, 1996, and Dec 31, 2010. Two control patients receiving dialysis but without calciphylaxis were age- and sex-matched to each study patient. Plain radiographs were obtained from the date closest to diagnosis in patients with calciphylaxis and from matched controls at approximately the same dates. Two radiologists, masked as to cases and controls, read each image together. Size of calcified vessels, pattern and extent of calcifications, presence of net-like or other calcifications, and bone density/mineralization were recorded and analyzed. RESULTS: Twenty-nine patients with calciphylaxis (mean age, 57 years; 21 [72%] women) were identified. Mean age at diagnosis was 57 years (range, 36-75 years). Compared with those of controls, plain radiographs of patients with calciphylaxis had more vascular calcifications, more small-vessel calcifications, and a netlike pattern of calcifications. A netlike pattern of calcifications had considerable strength of association with calciphylaxis (odds ratio, 9.4) and a specificity of nearly 90%. These findings were preserved even if only one image was used per patient. LIMITATIONS: This was a retrospective study. CONCLUSION: A netlike pattern of calcifications on plain radiographs was more common in patients with calciphylaxis and may aid in diagnosis. PMID- 22841658 TI - Intrathecal dihydroergotamine inhibits capsaicin-induced vasodilatation in the canine external carotid circulation via GR127935- and rauwolscine-sensitive receptors. AB - It has been suggested that during a migraine attack trigeminal nerves release calcitonin gene-related peptide (CGRP), producing central nociception and vasodilatation of cranial arteries, including the extracranial branches of the external carotid artery. Since trigeminal inhibition may prevent this vasodilatation, the present study has investigated the effects of intrathecal dihydroergotamine on the external carotid vasodilatation to capsaicin, alpha-CGRP and acetylcholine. Anaesthetized vagosympathectomized dogs were prepared to measure blood pressure, heart rate and external carotid conductance. A catheter was inserted into the right common carotid artery for the continuous infusion of phenylephrine (to restore the carotid vascular tone), whereas the corresponding thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine (which dose-dependently increased the external carotid conductance). Another cannula was inserted intrathecally (C(1)-C(3)) for the administration of dihydroergotamine, the alpha(2)-adrenoceptor antagonist rauwolscine or the serotonin 5-HT(1B/1D) receptor antagonist GR127935 (N-[4 methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol 3-yl)[1,1-biphenyl]-4-carboxamide hydrochloride monohydrate). Intrathecal dihydroergotamine (10, 31 and 100MUg) inhibited the vasodilatation to capsaicin, but not that to alpha-CGRP or acetylcholine. This inhibition was: (i) unaffected by 10MUg GR127935 or 100MUg rauwolscine, but abolished by 31MUg GR127935 or 310MUg rauwolscine at 10MUg dihydroergotamine; and (ii) abolished by the combination 10MUg GR127935+100MUg rauwolscine at 100MUg dihydroergotamine. Thus, intrathecal (C(1)-C(3)) dihydroergotamine seems to inhibit the external carotid vasodilatation to capsaicin by spinal activation of serotonin 5-HT(1B/1D) (probably 5-HT(1B)) receptors and alpha(2) (probably alpha(2A/2C))-adrenoceptors. PMID- 22841660 TI - The human microbiome: a hot spot of microbial horizontal gene transfer. AB - The human body harbors numerous microbes, and here exists a close relationship between microbes and human health. The Human Microbiome Project has generated whole genome sequences of several hundred human microbes. In this study, we identified horizontal gene transfer (HGT) events in human microbes and tried to elucidate the relationships between the gene-transferring microbes. A total of 13,514 high confidence HGT genes were identified in 308 human microbes. The horizontally transferred genes were enriched for Gene Ontology terms pertaining to catalytic functions and metabolic processes. Construction of an HGT event network suggested that the human microbes could be divided into specific communities which only partly overlap their distribution in human body. Our research suggests that human microbiome may facilitate frequent horizontal gene transfer among bacteria in human body. Awareness of HGT in human microbiome may aid our understanding of the relationship between the human microbiome and human health. PMID- 22841659 TI - Laparoscopic nerve-sparing radical vaginectomy in patients with vaginal carcinoma: surgical technique and operative outcomes. AB - STUDY OBJECTIVES: To describe our technique for laparoscopic nerve-sparing radical vaginectomy and to assess the feasibility and safety of the procedure via operative outcomes. DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Major university teaching hospital in Chongqing, China. PATIENTS: Twelve consecutive patients with early stage vaginal carcinoma. INTERVENTIONS: Laparoscopic radical parametrectomy/vaginectomy with pelvic/paraaortic lymphadenectomy. MEASUREMENTS AND MAIN RESULTS: Nerve-sparing radical vaginectomy was completed laparoscopically without conversion to laparotomy in 12 patients with early stage vaginal cancer. Mean (SD) operative time was 158.5 (36.7) minutes, and estimated blood loss was 135.2 (62.8) mL. No intraoperative complications occurred, and no patients required blood transfusion. The number of pelvic nodes obtained was 21.2 (9.8), and of para aortic nodes was 13. All nodes were negative for malignancy. Histologic analysis confirmed the absence of any residual cancer tissue in the margins of the parametrial tissue and vagina. The median (range) time before Foley catheter removal was 9.76 (3-14) days, and bladder void function recovery to grade 0-I was observed in 11 patients (91.7%). Neither long-term bladder voiding dysfunction nor any other long-term complications were reported. The median duration of follow-up was 28 months. One patient with stage II vaginal cancer received pelvic regional radiation therapy; the other patients did not require adjuvant therapy after the operation. All patients were included in the follow-up protocol, and there was no recurrence of disease in any patients. CONCLUSIONS: Laparoscopic radical parametrectomy/vaginectomy with pelvic/para-aortic lymphadenectomy is a therapeutic option for early stage vaginal carcinoma. Nerve-sparing radical surgery in indicated patients may lead to optimal preservation of bladder function. The technique described in this preliminary study seems to be safe and feasible, and was relatively easy to perform in our study population. PMID- 22841661 TI - Regulatory, policy and quality update for venous thromboembolism and stroke in United States hospitals. AB - Stroke and venous thromboembolism (VTE) have a large impact on the United States (US) healthcare system. It is estimated that up to 1.7million new and recurrent stroke and VTE events are occurring in the US on an annual basis with the combined cost approaching over $200billion per year. A significant amount of stroke and VTE are preventable from appropriate antithrombotic use in at-risk patients and the Center for Medicaid and Medicare Services, the Joint Commission, the National Quality Forum and other key quality and regulatory entities have prioritized minimizing the impact of morbidity, mortality and avoidable costs related to these diseases. This review provides a brief history, overview, and update for the development of quality measures, quality systems, and regulatory and policy changes as related to stroke and VTE within the US healthcare system. PMID- 22841662 TI - Unsuspected visceral venous thrombosis, in patients with cancer of the gastrointestinal system. PMID- 22841663 TI - Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice. AB - Intermedin, a novel member of calcitonin gene-related peptide family, is an endogenous cardiovascular-protective peptide. Because intermedin exists in human atherosclerotic plaque, we studied the role of intermedin in macrophage scavenger receptor A (SR-A)-mediated foam-cell formation and atherogenesis. In an in vitro foam-cell formation model (induced by acetylated low-density lipoprotein [AcLDL]) with mouse (C57BL/6J) macrophages, intermedin reduced AcLDL uptake and binding, decreased intracellular cholesterol content, and suppressed both mRNA and protein levels of SR-A. Simultaneously, intermedin increased phosphatase and tensin homolog (PTEN) protein levels by increasing PTEN phosphorylation and inhibiting ubiquitin-mediated PTEN degradation. These effects were blocked by the intermedin receptor antagonist or cAMP-protein kinase A inhibitors. PTEN overexpression mimicked the inhibitory effects of intermedin on SR-A expression and AcLDL uptake. However, knockdown of PTEN by short-hairpin RNA completely blocked all inhibitory effects of intermedin. Furthermore, in apolipoprotein E-deficient (apoE(-/-)) mice, 6-week intermedin infusion reduced AcLDL uptake and SR-A mRNA and protein levels and increased PTEN protein level in peritoneal macrophages. PTEN level was increased and SR-A expression decreased in parallel in macrophages in atherosclerotic lesions. Thus, intermedin inhibited atherosclerosis in apoE(-/ ) mice. Increased stability of PTEN by intermedin leads to SR-A inhibition in macrophages, which ameliorates foam-cell formation and atherosclerosis in apoE(-/ ) mice. PMID- 22841664 TI - Development and validation of a capillary electrophoresis tandem mass spectrometry analytical method for the determination of Leu-Val-Val- and Val-Val hemorphin-7 peptides in cerebrospinal fluid. AB - A CE-tandem MS method was optimised and validated for selective and specific determination of LVV- and VV-hemorphin-7 peptides in cerebrospinal fluid. These two small peptides originate from haemoglobin beta chains. They possess relevant biological activity and recently a potential biomarker role in posterior cranial fossa paediatric brain tumour disease was evidenced. The separation was optimised using formic acid as background electrolyte and a water/methanol mixture, containing 0.1% (v/v) formic acid, as sheath liquid. The two peptides, differing in only one amino acid of the sequence at the N-terminal side were baseline separated in less than 15 min. The method allowed a very reduced and rapid sample pretreatment and was successfully applied to hemorphins determination in patient samples without matrix interferences. The method successfully passed bioanalytical validation showing linearity, accuracy and precision data on cerebrospinal fluid matrix within the acceptable values. The analysis of cerebrospinal fluid of patients affected by different posterior cranial fossa tumour forms confirmed our previous findings showing the absence of hemorphins in the pre-surgical cerebrospinal fluid and their presence in the post-ones and controls. The present method saves costs and time due to capillary electrophoresis miniaturisation and to the absence of chromatographic column and gradient elution and allows numerous injections per sample starting from few microlitres of cerebrospinal fluid. PMID- 22841665 TI - Innovative microwave-assisted oximation and silylation procedures for metabolomic analysis of plasma samples using gas chromatography-mass spectrometry. AB - Analysis of plasma metabolomic samples by gas chromatography-mass spectrometry always requires comprehensive pretreatment including oximation and silylation. Although heating block (HB) is a commonly used method, it is time consuming. This study describes an extremely time-effective microwave-assisted (MA) oximation and silylation approach for metabolomic study of plasma samples. The Box-Behnken design was employed to optimize the MA conditions by means of oximation at 65 W for 100 s and then silylation through 180 s incubation with 230 W microwave irradiation. The results showed that microwave irradiation decreased the sample preparation time from approximately 180 min to 5 min without loss of information for the metabolites in plasma samples. Both the HB method and the developed MA method were applied in plasma metabolomic study of sulfur mustard intoxication. Partial least-squares discriminant analysis (PLS-DA) was used to globally understand the metabolic changes, and multi-criteria assessment was used to select the most significant and reliable variables as potential biomarkers. The data obtained by the MA method were in good correlation with the HB method. Compared with HB method, the newly developed MA oximation and silylation of plasma metabolome samples was more efficient and time-effective and may prove to be an attractive alternative for high-throughput sample preparation in plasma metabolomics. PMID- 22841666 TI - Teneurin protein family: an emerging role in human tumorigenesis and drug resistance. AB - Using a chemoproteomic strategy, we recently demonstrated the expression of teneurin-2, a transmembrane glycoprotein, in the majority of malignant mesothelioma cell lines. This finding was unexpected since no formally organized evidence existed to implicate teneurins in human malignancy. For this reason, here we provide a comprehensive review on the expression of teneurins in human tumors and cell lines. Current evidence supports the aberrant expression of teneurins in various tumor types, their involvement in cancer-related regulatory networks, and their potential participation in drug resistance. Structural attributes of teneurins could enable the detection of shedded forms in body fluids for clinical applications. PMID- 22841667 TI - A-Disintegrin and Metalloprotease (ADAM) 10 and 17 promote self-renewal of brain tumor sphere forming cells. AB - It has been proposed that gliomas contain a subpopulation of 'Brain Tumor Stem Cells' (BTSCs), which demonstrate resistance to conventional therapies. A potential component of the environment governing the behavior of these BTSCs is a class of transmembrane proteins with structural and signaling functions, the A Disintegrin And Metalloproteases (ADAMs). In this study we confirm overexpression of ADAM10 and 17 in human glioma tissue compared to human controls, and especially in tumor sphere cultures thought to enrich for BTSCs. Inhibition of ADAM10/17 function impairs the growth of tumor spheres with evidence of depletion of the sphere forming cell population. This results from a combination of reduced proliferation, cell death and a switch of sphere-forming cells away from symmetric self-renewal division towards neuronal differentiation. A developing appreciation of the role of ADAMs in BTSC promises insights into pathophysiology and potential therapeutic avenues in this intractable group of tumors. PMID- 22841668 TI - Tumor grafts derived from sarcoma patients retain tumor morphology, viability, and invasion potential and indicate disease outcomes in the chick chorioallantoic membrane model. AB - The chick chorioallantoic membrane (CAM) assay was used to evaluate whether xenotransplanted sarcomas retain the histological characteristics and functional behavior of the original tumors. Metabolically active tumor tissue, identified by dynamic-contrast MRI, from 28 patients with a bone or soft-tissue tumors was applied to the CAM. Angiogenesis and graft and host behaviors were evaluated. The essential features and immunohistochemical characteristics of the original tumors were maintained, illustrating the diversity of sarcomas. Graft viability was inversely related to patient survival, but longer follow-up and more patients are needed to relate tumor graft behavior to natural history. We conclude that the CAM assay is a potential prognostic and predictive preclinical xenograft model for tumors that are difficult to culture in vitro, such as sarcomas; therefore, the use of the CAM assay may facilitate personalized medicine. PMID- 22841669 TI - Comparison of Xpert Flu rapid nucleic acid testing with rapid antigen testing for the diagnosis of influenza A and B. AB - Influenza infections are associated with thousands of hospital admissions and deaths each year. Rapid detection of influenza is important for prompt initiation of antiviral therapy and appropriate patient triage. In this study the Cepheid Xpert Flu assay was compared with two rapid antigen tests, BinaxNOW Influenza A & B and BD Directigen EZ Flu A+B, as well as direct fluorescent antibody testing for the rapid detection of influenza A and B. Using real-time, hydrolysis probe based, reverse transcriptase PCR as the reference method, influenza A sensitivity was 97.3% for Xpert Flu, 95.9% for direct fluorescent antibody testing, 62.2% for BinaxNOW, and 71.6% for BD Directigen. Influenza B sensitivity was 100% for Xpert Flu and direct fluorescent antibody testing, 54.5% for BinaxNOW, and 48.5% for BD Directigen. Specificity for influenza A was 100% for Xpert Flu, BinaxNOW, and BD Directigen, and 99.2% for direct fluorescent antibody testing. All methods demonstrated 100% specificity for influenza B. These findings support the use of the Xpert Flu assay in settings requiring urgent diagnosis of influenza A and B. PMID- 22841670 TI - Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. AB - Venenum Bufonis, a traditional Chinese medicine, is widely used in the treatment of liver cancer in modern Chinese medical practices. In our search for anti hepatoma constituents in Venenum Bufonis, bufotalin, bufalin, telocinobufagin and cinobufagin were obtained. Bufotalin was the most potent active compound among these four bufadienolides, and it exerted stronger inhibitory effect on the viability of doxorubicin-induced multidrug resistant liver cancer cells (R-HepG2) than that of their parent cells HepG2. Structure-activity relationship analysis indicated that the acetyl group linked to C-16 of bufadienolides might be useful for increasing anti-hepatoma activity. Further mechanistic studies revealed that bufotalin treatment induced cell cycle arrest at G(2)/M phase through down regulation of Aurora A, CDC25, CDK1, cyclin A and cyclin B1, as well as up regulation of p53 and p21. Bufotalin treatment also induced apoptosis which was accompanied by decrease in mitochondrial membrane potential, increases in intracellular calcium level and reactive oxygen species production, activations of caspase-9 and -3, cleavage of poly ADP-ribose polymerase (PARP) as well as changes in the expressions of bcl-2 and bax. It was also found that the inhibition of Akt expression and phosphorylation was involved in apoptosis induction, and specific Akt inhibitor LY294002 or siRNA targeting Akt can synergistically enhanced bufotalin-induced apoptosis. In vivo study showed that bufotalin significantly inhibited the growth of xenografted R-HepG2 cells, without body weight loss or marked toxicity towards the spleen. These results indicate that bufotalin has a promising potential to become a novel anti-cancer agent for the treatment of liver cancer with multidrug resistance. PMID- 22841673 TI - Systematic review of perioperative and quality-of-life outcomes following surgical management of localised renal cancer. AB - CONTEXT: For the treatment of localised renal cell carcinoma (RCC), uncertainties remain over the perioperative and quality-of-life (QoL) outcomes for the many different surgical techniques and approaches of nephrectomy. Controversy also remains on whether newer minimally invasive nephron-sparing interventions offer better QoL and perioperative outcomes, and whether adrenalectomy and lymphadenectomy should be performed simultaneously with nephrectomy. These non oncological outcomes are important because they may have a considerable impact on localised RCC treatment decision making. OBJECTIVE: To review systematically all the relevant published literature comparing perioperative and QoL outcomes of surgical management of localised RCC (T1-2N0M0). EVIDENCE ACQUISITION: Relevant databases including Medline, Embase, and the Cochrane Library were searched up to January 2012. Randomised controlled trials (RCTs) or quasi-randomised controlled trials, prospective observational studies with controls, retrospective matched pair studies, and comparative studies from well-defined registries/databases were included. The outcome measures were QoL, analgesic requirement, length of hospital stay, time to normal activity level, surgical morbidity and complications, ischaemia time, renal function, blood loss, length of operation, need for blood transfusion, and perioperative mortality. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation. EVIDENCE SYNTHESIS: A total of 4580 abstracts and 380 full-text articles were assessed, and 29 studies met the inclusion criteria (7 RCTs and 22 NRSs). There were high risks of bias and low-quality evidence for studies meeting the inclusion criteria. There is good evidence indicating that partial nephrectomy results in better preservation of renal function and better QoL outcomes than radical nephrectomy regardless of technique or approach. Regarding radical nephrectomy, the laparoscopic approach has better perioperative outcomes than the open approach, and there is no evidence of a difference between the transperitoneal and retroperitoneal approaches. Alternatives to standard laparoscopic radical nephrectomy (LRN) such as hand-assisted, robot-assisted, or single-port techniques appear to have similar perioperative outcomes. There is no good evidence to suggest that minimally invasive procedures such as cryotherapy or radiofrequency ablation have superior perioperative or QoL outcomes to nephrectomy. Regarding concomitant lymphadenectomy during nephrectomy, there were low event rates for complications, and no definitive difference was observed. There was no evidence to base statements about concomitant ipsilateral adrenalectomy during nephrectomy. CONCLUSIONS: Partial nephrectomy results in significantly better preservation of renal function over radical nephrectomy. For tumours where partial nephrectomy is not technically feasible, there is no evidence that alternative procedures or techniques are better than LRN in terms of perioperative or QoL outcomes. In making treatment decisions, perioperative and QoL outcomes should be considered in conjunction with oncological outcomes. Overall, there was a paucity of data regarding QoL outcomes, and when reported, both QoL and perioperative outcomes were inconsistently defined, measured, or reported. The current evidence base has major limitations due to studies of low methodological quality marked by high risks of bias. PMID- 22841674 TI - A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk. AB - BACKGROUND: A rare but recurrent missense mutation (G84E, rs138213197) in the gene homeobox B13 (HOXB13) was recently reported to be associated with hereditary prostate cancer. OBJECTIVE: To explore the prevalence and penetrance of HOXB13 G84E in a general population. DESIGN, SETTING, AND PARTICIPANTS: G84E and 14 additional HOXB13 polymorphisms were genotyped in two population-based, Swedish, case-control samples (Cancer of the Prostate in Sweden [CAPS] and Stockholm-1) comprising 4693 controls and 5003 prostate cancer cases. CAPS collected data on patients and population controls nationally between 2001 and 2003. Stockholm-1 collected data on biopsy-positive patients and biopsy-negative controls in the Stockholm area between 2005 and 2007. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was pathologically verified prostate cancer. Relative and absolute risks among HOXB13 G84E mutation carriers were explored, as was the combined impact on disease risk of G84E and a polygenic score based on 33 established, common, low-risk variants. RESULTS AND LIMITATIONS: HOXB13 G84E was observed in 1.3% of population controls and was strongly associated with prostate cancer risk (CAPS: odds ratio [OR]: 3.4; 95% confidence interval [CI], 2.2-5.4; Stockholm-1: OR: 3.5; 95% CI, 2.4-5.2). The strongest association was observed for young-onset (OR: 8.6; 95% CI, 5.1-14.0) and hereditary (OR: 6.6; 95% CI, 3.3 12.0) prostate cancer. Haplotype analyses supported that G84E is a founder mutation. G84E carriers have an estimated 33% (95% CI, 23-46) cumulative risk to age 80 yr of prostate cancer, compared to 12% (95% CI, 11-13) among noncarriers. For G84E carriers within the top quartile of a polygenic score of established susceptibility variants, the cumulative risk was estimated at 48% (95% CI, 36 64). CONCLUSIONS: HOXB13 G84E is prevalent in >1% of the Swedish population and is associated with a 3.5-fold increased risk of prostate cancer. One-third of G84E carriers will be diagnosed with prostate cancer, which has implications for surveillance in mutation carriers. PMID- 22841675 TI - A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam. AB - BACKGROUND: Inconclusive test results often occur after prostate-specific antigen (PSA)-based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing. OBJECTIVE: To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen. DESIGN, SETTING, AND PARTICIPANTS: We analyzed data from 15 791 screen-negative men aged 55-70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score >= 7 and/or PSA >= 10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening. RESULTS AND LIMITATIONS: Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0-4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, <= 1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, >= 5%) might benefit from immediate retesting. These findings need to be validated externally. CONCLUSIONS: This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa. PMID- 22841676 TI - Sildenafil effect on the human bladder involves the L-cysteine/hydrogen sulfide pathway: a novel mechanism of action of phosphodiesterase type 5 inhibitors. AB - BACKGROUND: Phosphodiesterase type 5 inhibitors (PDE5-Is) are effective in the treatment of lower urinary tract symptom (LUTS), although their mechanism of action is still unclear. PDE5-Is cause bladder detrusor relaxation, and this effect is partially independent of nitric oxide. Hydrogen sulfide (H(2)S) is a newly discovered transmitter with myorelaxant properties. It is predominantly formed from L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine gamma-lyase (CSE). OBJECTIVE: To evaluate whether the L-cysteine/H(2)S pathway contributes to the relaxing effect of sildenafil on the human detrusor dome. DESIGN, SETTING, AND PARTICIPANTS: Samples of bladders obtained from men undergoing open prostatectomy for benign prostatic hyperplasia (BPH) were used. The presence of CBS and CSE enzymes was assessed by western blot. H(2)S production was measured by a colorimetric assay in basal and stimulated conditions with L-cysteine and in response to sildenafil (1, 3, 10, and 30 MUM), 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP; 100 MUM) or dibutyryl cyclic adenosine monophosphate (dibutyryl-cAMP; 100 MUM). A curve concentration effect of sodium hydrosulfide (NaHS), H(2)S donor (0.1 MUM to 10mM), L-cysteine (0.1 MUM to 10mM), and sildenafil (0.1-10 MUM) was performed on precontracted detrusor dome strips. To investigate H(2)S signaling in a sildenafil effect, CBS and CSE inhibitors were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Analysis of variance was used, followed by the Bonferroni post hoc test. RESULTS AND LIMITATIONS: CBS and CSE are present in the human bladder dome and efficiently convert L-cysteine into H(2)S. Both NaHS and L-cysteine relaxed human strips. Sildenafil caused (1) a relaxation of bladder dome strips and (2) a concentration-dependent increase in H(2)S production. Both effects were significantly reduced by CBS and CSE inhibitors. Similar to sildenafil, both 8 bromo-cGMP and dibutyryl-cAMP caused an increase in H(2)S production. CONCLUSIONS: The sildenafil relaxant effect on the human bladder involves the H(2)S signaling pathway. This effect may account in part for the efficacy of PDE5 Is in LUTS. A better definition of the pathophysiologic role of the H(2)S pathway in the human bladder may open new therapeutic approaches. PMID- 22841677 TI - Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. AB - Human Papillomavirus (HPV) related oropharyngeal squamous cell carcinomas (OPSCCs) are reported to have improved prognosis and survival in comparison to other head and neck squamous cell cancers (HNSCCs). This systematic review and meta-analysis examines survival differences in HPV-positive HNSCC and OPSCC subtypes including tonsillar carcinoma in studies not previously investigated. Four electronic databases were searched from their inception till April 2011. A random effects meta-analysis was used to pool study estimates evaluating disease specific (death from HNSCC), overall (all-cause mortality), progression-free and disease-free (recurrence free) survival outcomes in HPV-positive vs. HPV-negative HNSCCs. All statistical tests were two-sided. Forty-two studies were included. Patients with HPV-positive HNSCC had a 54% better overall survival compared to HPV-negative patients HR 0.46 (95% CI 0.37-0.57); the pooled HR for tonsillar cancer and OPSCC was 0.50 (95% CI 0.33-0.77) and HR 0.47 (95% CI 0.35-0.62) respectively. The pooled HR for disease specific survival was 0.28 (95% CI 0.19 0.40); similar effect sizes were found irrespective of the adjustment for confounders, HPV detection methods or study location. Both progression-free survival and disease-free survival were significantly improved in HPV-positive HNSCCs. HPV-positive HNSCCs and OPSCCs patients have a significantly lower disease specific mortality and are less likely to experience progression or recurrence of their cancer than HPV-negative patients; findings which have connotations for treatment selection in these patients. PMID- 22841678 TI - Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. AB - BACKGROUND: Human papillomavirus (HPV) is a cause of oropharyngeal cancer, but a role for HPV in the etiology of oral cavity squamous cell carcinomas (OCSCC) remains uncertain. METHODS: We sought to estimate the etiologic fraction for HPV among consecutive, incident OCSCC diagnosed from 2005 to 2011 at four North American hospitals. DNA and RNA purified from paraffin-embedded tumors were considered evaluable if positive for DNA and mRNA control genes by quantitative PCR. Fifteen high-risk (HR) HPV types were detected in tumors by consensus PCR followed by type-specific HR-HPV E6/7 oncogene expression by quantitative reverse transcriptase PCR. P16 expression was evaluated by immunohistochemistry (IHC). A study of 400 cases allowed for precision to estimate an etiologic fraction of as low as 0% (97.5% confidence interval, 0-0.92%). RESULTS: Of 409 evaluable OCSCC, 24 (5.9%, 95%CI 3.6-8.2) were HR-HPV E6/7 expression positive; 3.7% (95%CI 1.8 5.5) for HPV16 and 2.2% (95%CI 0.8-3.6) for other HR-HPV types. HPV-positive tumors arose from throughout the oral cavity (floor of mouth [n=9], anterior tongue [6], alveolar process [4], hard palate [3], gingiva [1] and lip [1]) and were significantly associated with male gender, small tumor stage, poor tumor differentiation, and basaloid histopathology. P16 IHC had very good-to-excellent sensitivity (79.2%, 95%CI 57.9-92.9), specificity (93.0%, 95%CI 90.0-95.3), and negative-predictive value (98.6%, 95%CI 96.8-99.6), but poor positive-predictive value (41.3%, 95%CI 27.0-56.8) for HR-HPV E6/7 expression in OCSCC. CONCLUSION: The etiologic fraction for HR-HPV in OCSCC was 5.9%. p16 IHC had poor positive predictive value for detection of HPV in these cancers. PMID- 22841679 TI - Mycobacterium tuberculosis modulators of the macrophage's cellular events. AB - A number of mycobacterial macromolecules have been shown to target biological processes within host macrophages; however, the exact mechanism for the majority of these host-pathogen interactions is poorly understood. The following review summarizes current knowledge and expands on a subset of mycobacterial effectors for which a cognate substrate, cellular partner or signaling pathway have been experimentally identified within the human host. PMID- 22841680 TI - Dengue virus infection-enhancing and neutralizing antibody balance in children of the Philippines and Indonesia. AB - Dengue fever and dengue hemorrhagic fever are important diseases worldwide. Although antibody-dependent enhancement of infection has been proposed as a mechanism for increased disease severity, enhancing antibodies in endemic people have not been thoroughly investigated. Recently, we established a serological assay system to measure the balance of enhancing and neutralizing activities, which provides useful information for estimating in vivo antibody status. We measured the balance of these activities against four dengue virus (DENV) types in endemic populations, and analyzed the proportion of sera containing enhancing and neutralizing antibodies. Predominantly healthy Filipino children were used for analysis, although a population of Indonesian children was also investigated. In the Filipino population, the highest proportion of neutralizing activities was shown against DENV2, followed by DENV1. A greater proportion of sera exhibited enhancing rather than neutralizing antibodies against other virus types. Neutralizing activities were complement-dependent, while enhancing activities were complement-independent. The Indonesian population showed a similar dengue antibody status. Our results indicate that a relatively high proportion of endemic children possessed complement-independent enhancing antibodies against some DENV types. PMID- 22841681 TI - Interference of ethylene glycol with lactate measurement: a comparison study on new generation cassette-based blood gas analyzers. PMID- 22841682 TI - Multidrug-resistant Pseudomonas aeruginosa outbreaks in two hospitals: association with contaminated hospital waste-water systems. AB - BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa (MDR-P) expressing VIM metallo-beta-lactamase is an emerging infection control problem. The source of many such infections is unclear, though there are reports of hospital outbreaks of P. aeruginosa related to environmental contamination, including tap water. AIM: We describe two outbreaks of MDR-P, sensitive only to colistin, in order to highlight the potential for hospital waste-water systems to harbour this organism. METHODS: The outbreaks were investigated by a combination of descriptive epidemiology, inspection and microbiological sampling of the environment, and molecular strain typing. FINDINGS: The outbreaks occurred in two English hospitals; each involved a distinct genotype of MDR-P. One outbreak was hospital-wide, involving 85 patients, and the other was limited to four cases in one specialized medical unit. Extensive environmental sampling in each outbreak yielded MDR-P only from the waste-water systems. Inspection of the environment and estates records revealed many factors that may have contributed to contamination of clinical areas, including faulty sink, shower and toilet design, clean items stored near sluices, and frequent blockages and leaks from waste pipes. Blockages were due to paper towels, patient wipes, or improper use of bedpan macerators. Control measures included replacing sinks and toilets with easier-to-clean models less prone to splashback, educating staff to reduce blockages and inappropriate storage, reviewing cleaning protocols, and reducing shower flow rates to reduce flooding. These measures were followed by significant reductions in cases. CONCLUSION: The outbreaks highlight the potential of hospital waste systems to act as a reservoir of MDR-P and other nosocomial pathogens. PMID- 22841683 TI - Deletion of an ATP-binding cassette protein subfamily C transporter in Leishmania donovani results in increased virulence. AB - Genome comparison of Leishmania species sequenced to date has identified several hundred differentially distributed genes which are present as functional genes in some species but as pseudogenes or absent in others. It is not clear whether these differentially distributed genes are important for disease, redundant or even harmful for a particular Leishmania species though a few of these genes have been implicated in Leishmania infection tissue tropism. The L. infantum LinJ.24.1510 gene is an ATP-binding cassette transporter protein subfamily C member which is present in L. donovani complex species and L. mexicana but absent in L. major and L. braziliensis and its substrate is unknown. Experimental deletion of this gene from L. donovani has resulted in an increase in growth as axenic amastigotes and increased virulence in infecting mice. To our knowledge, this is the first gene identified in Leishmania where its deletion results in hypervirulence. PMID- 22841684 TI - A priori and a posteriori approaches for finding genes of evolutionary interest in non-model species: osmoregulatory genes in the kidney transcriptome of the desert rodent Dipodomys spectabilis (banner-tailed kangaroo rat). AB - One common goal in evolutionary biology is the identification of genes underlying adaptive traits of evolutionary interest. Recently next-generation sequencing techniques have greatly facilitated such evolutionary studies in species otherwise depauperate of genomic resources. Kangaroo rats (Dipodomys sp.) serve as exemplars of adaptation in that they inhabit extremely arid environments, yet require no drinking water because of ultra-efficient kidney function and osmoregulation. As a basis for identifying water conservation genes in kangaroo rats, we conducted a priori bioinformatics searches in model rodents (Mus musculus and Rattus norvegicus) to identify candidate genes with known or suspected osmoregulatory function. We then obtained 446,758 reads via 454 pyrosequencing to characterize genes expressed in the kidney of banner-tailed kangaroo rats (Dipodomys spectabilis). We also determined candidates a posteriori by identifying genes that were overexpressed in the kidney. The kangaroo rat sequences revealed nine different a priori candidate genes predicted from our Mus and Rattus searches, as well as 32 a posteriori candidate genes that were overexpressed in kidney. Mutations in two of these genes, Slc12a1 and Slc12a3, cause human renal diseases that result in the inability to concentrate urine. These genes are likely key determinants of physiological water conservation in desert rodents. PMID- 22841685 TI - Repetitive electroacupuncture causes prolonged increased met-enkephalin expression in the rVLM of conscious rats. AB - Enkephalinergic neurons in the rostral ventrolateral medulla (rVLM), an important presympathetic region in the brainstem, are activated by 30 min of low frequency (2 Hz) electroacupuncture (EA) at acupoints P5-P6, which overlie the median nerves. To more closely model the clinical application of acupuncture, we administered EA for 30 min twice over a 72 h period to unsedated conscious rats to examine its prolonged action. We hypothesized that repetitive EA would increase preproenkephalin mRNA and met-enkephalin in the rVLM of unsedated conscious rats. Rats received either EA (1-4 mA, 0.5 ms, 2 Hz) or sham stimulation (needle placement without electrical stimulation) twice at P5-P6 acupoints bilaterally. Preproenkephalin mRNA and its peptide met-enkephalin in the rVLM were measured 24 or 48 h after the final EA or sham procedure. Relative ratios of preproenkephalin mRNA levels (normalized with the 18S housekeeping gene) were almost doubled at 24h compared to sham (6.1 +/- 0.79 vs. 3.1 +/- 0.47). Met-enkephalin measured in rVLM tissue pooled from several rats exposed to the same treatment was increased by repeated EA by 68% after 24h and 51% after 48h, relative to sham. These findings suggest that repeated application of EA in the conscious rats enhances transcription and translation of enkephalin in rVLM for days. Since opioids in the rVLM contribute importantly to the action of EA on sympathetic outflow, this mechanism may contribute to the prolonged action of acupuncture on elevated blood pressure in patients. PMID- 22841686 TI - Parkinson disease: associated disorders in the Norwegian population based incident ParkWest study. AB - Parkinson's disease (PD) may be associated with a number of different diseases due to common risk factors or overlapping symptomatology. We have asked for possible associated disorders in a Norwegian population of incident PD patients and controls, the Norwegian ParkWest study. The patients were diagnosed according to the Gelb criteria. 212 incident PD patients and 175 age and gender matched controls were included. PD patients and controls were asked for information on earlier medical history and family history. PD patients had a higher frequency of self-reported symptoms of depression (p = 0.003) and anxiety disorders (p = 0.004) before baseline. They tended to have a higher frequency of diabetes (p = 0.09) and had a higher frequency of prior stroke or TIA (p = 0.004). PMID- 22841687 TI - In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson's disease. AB - BACKGROUND: Reactive microgliosis, hallmark of neuroinflammation, may contribute to neuronal degeneration, as shown in several neurodegenerative diseases. We in vivo evaluated microglia activation in early dementia with Lewy bodies, still not reported, and compared with early Parkinson's disease, to assess possible differential pathological patterns. METHODS: We measured the [(11)C]-PK11195 binding potentials with Positron Emission Tomography, using a simplified reference tissue model, as marker of microglia activation, and cerebral spinal fluid protein carbonylation levels, as marker of oxidative stress. Six dementia with Lewy bodies and 6 Parkinson's disease patients within a year from the onset, and eleven healthy controls were included. Clinical diagnosis was confirmed at a 4-year follow-up. RESULTS: In dementia with Lewy bodies as well as in Parkinson's disease, we found significant (p < 0.001) [(11)C]-PK11195 binding potential increases in the substantia nigra and putamen. Patients with Lewy bodies dementia had extensive additional microglia activation in several associative cortices. This was evident also at a single subject level. Significant increase of Cerebral Spinal Fluid protein carbonylation was shown in both patients' groups. CONCLUSIONS: [(11)C]-PK11195 Positron Emission Tomography imaging revealed neuroinflammation in dementia with Lewy bodies and Parkinson's disease, mirroring, even at a single subject level, the common and the different topographical distribution of neuropathological changes, yet in the earliest stages of the disease process. Focusing on those events that characterize parkinsonisms and Parkinson's disease may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection. PMID- 22841688 TI - Molecular signature and in vivo behavior of bone marrow endosteal and subendosteal stromal cell populations and their relevance to hematopoiesis. AB - In the bone marrow cavity, hematopoietic stem cells (HSC) have been shown to reside in the endosteal and subendosteal perivascular niches, which play specific roles on HSC maintenance. Although cells with long-term ability to reconstitute full hematopoietic system can be isolated from both niches, several data support a heterogenous distribution regarding the cycling behavior of HSC. Whether this distinct behavior depends upon the role played by the stromal populations which distinctly create these two niches is a question that remains open. In the present report, we used our previously described in vivo assay to demonstrate that endosteal and subendosteal stromal populations are very distinct regarding skeletal lineage differentiation potential. This was further supported by a microarray-based analysis, which also demonstrated that these two stromal populations play distinct, albeit complementary, roles in HSC niche. Both stromal populations were preferentially isolated from the trabecular region and behave distinctly in vitro, as previously reported. Even though these two niches are organized in a very close range, in vivo assays and molecular analyses allowed us to identify endosteal stroma (F-OST) cells as fully committed osteoblasts and subendosteal stroma (F-RET) cells as uncommitted mesenchymal cells mainly represented by perivascular reticular cells expressing high levels of chemokine ligand, CXCL12. Interestingly, a number of cytokines and growth factors including interleukin-6 (IL-6), IL-7, IL-15, Hepatocyte growth factor (HGF) and stem cell factor (SCF) matrix metalloproteases (MMPs) were also found to be differentially expressed by F-OST and F-RET cells. Further microarray analyses indicated important mechanisms used by the two stromal compartments in order to create and coordinate the "quiescent" and "proliferative" niches in which hematopoietic stem cells and progenitors reside. PMID- 22841689 TI - In vivo biomarker expression patterns are preserved in 3D cultures of Prostate Cancer. AB - Here we report that Prostate Cancer (PCa) cell-lines DU145, PC3, LNCaP and RWPE-1 grown in 3D matrices in contrast to conventional 2D monolayers, display distinct differences in cell morphology, proliferation and expression of important biomarker proteins associated with cancer progression. Consistent with in vivo growth rates, in 3D cultures, all PCa cell-lines were found to proliferate at significantly lower rates in comparison to their 2D counterparts. Moreover, when grown in a 3D matrix, metastatic PC3 cell-lines were found to mimic more precisely protein expression patterns of metastatic tumour formation as found in vivo. In comparison to the prostate epithelial cell-line RWPE-1, metastatic PC3 cell-lines exhibited a down-regulation of E-cadherin and alpha6 integrin expression and an up-regulation of N-cadherin, Vimentin and beta1 integrin expression and re-expressed non-transcriptionally active AR. In comparison to the non-invasive LNCaP cell-lines, PC3 cells were found to have an up-regulation of chemokine receptor CXCR4, consistent with a metastatic phenotype. In 2D cultures, there was little distinction in protein expression between metastatic, non invasive and epithelial cells. These results suggest that 3D cultures are more representative of in vivo morphology and may serve as a more biologically relevant model in the drug discovery pipeline. PMID- 22841690 TI - VEA1 is required for cleistothecial formation and virulence in Histoplasma capsulatum. AB - Histoplasma capsulatum is a pathogenic fungus dependent on dimorphism for virulence. Among the four described Velvet family genes, two of them, Ryp2 and Ryp3, have been shown to be required for dimorphism. It is known that Velvet A (VeA) is necessary for sexual development and toxin production in Aspergillus nidulans. However, the role of the VeA ortholog in H. capsulatum has not yet been explored. Vea1, H. capsulatum homolog of VeA, was studied to determine its role in cleistothecial formation, dimorphism, and virulence. H. capsulatum Vea1 restores cleistothecial formation and partially restores sterigmatocystin production in an A. nidulans veA deletion strain. Furthermore, silencing VEA1 in an H. capsulatum strain capable of forming cleistothecia abolishes cleistothecial formation. Silenced strains also switch to mycelial phase faster, and show impaired switching to the yeast phase once in mycelial phase. Virulence in mice and macrophages is attenuated in VEA1 silenced strains and silenced strains demonstrate increased sensitivity during growth under acidic conditions. These results indicate that H. capsulatum Vea1 shares a similar role in development as VeA. H. capsulatum is also more susceptible to growth in acidic conditions when VEA1 is silenced, which may contribute to the silenced strains' attenuated virulence in mice and macrophages. PMID- 22841691 TI - Gating movement of acetylcholine receptor caught by plunge-freezing. AB - The nicotinic acetylcholine (ACh) receptor converts transiently to an open channel form when activated by ACh released into the synaptic cleft. We describe here the conformational change underlying this event, determined by electron microscopy of ACh-sprayed and freeze-trapped postsynaptic membranes. ACh binding to the alpha subunits triggers a concerted rearrangement in the ligand-binding domain, involving an ~1-A outward displacement of the extracellular portion of the beta subunit where it interacts with the juxtaposed ends of alpha-helices shaping the narrow membrane-spanning pore. The beta-subunit helices tilt outward to accommodate this displacement, destabilising the arrangement of pore-lining helices, which in the closed channel bend inward symmetrically to form a central hydrophobic gate. Straightening and tangential motion of the pore-lining helices effect channel opening by widening the pore asymmetrically and increasing its polarity in the region of the gate. The pore-lining helices of the alpha(gamma) and delta subunits, by flexing between alternative bent and straight conformations, undergo the greatest movements. This coupled allosteric transition shifts the structure from a tense (closed) state toward a more relaxed (open) state. PMID- 22841692 TI - Crystal structure of cucumisin, a subtilisin-like endoprotease from Cucumis melo L. AB - Cucumisin is a plant serine protease, isolated as an extracellular glycoprotein from the melon fruit Cucumis melo L. var. Prince. Cucumisin is composed of multiple domain modules, including catalytic, protease-associated, and fibronectin-III-like domains. The crystal structure of cucumisin was determined by the multiwavelength anomalous dispersion method and refined at 2.75A resolution. A structural homology search indicated that the catalytic domain of cucumisin shares structural similarity with subtilisin and subtilisin-like fold enzymes. According to the Z-score, the highest structural similarity is with tomato subtilase 3 (SBT3), with an rmsd of 3.5A for the entire region. The dimer formation mediated by the protease-associated domain in SBT3 is a distinctive structural characteristic of cucumisin. On the other hand, analytical ultracentrifugation indicated that cucumisin is mainly monomeric in solution. Although the locations of the amino acid residues composing the catalytic triad are well conserved between cucumisin and SBT3, a disulfide bond is uniquely located near the active site of cucumisin. The steric circumstances of the active site with this disulfide bond are distinct from those of SBT3, and it contributes to the substrate preference of cucumisin, especially at the P2 position. Among the plant serine proteases, the thermostability of cucumisin is higher than that of its structural homologue SBT3, as determined by their melting points. A structural comparison between cucumisin and SBT3 revealed that cucumisin possesses less surface area and shortened loop regions. Consequently, the higher thermostability of cucumisin is achieved by its more compact structure. PMID- 22841694 TI - Disgust elevates core body temperature and up-regulates certain oral immune markers. AB - Recent findings suggest that disgust can activate particular aspects of the immune system. In this study we examine whether disgust can also elevate core body temperature (BT), a further feature of an immune response to disease. In addition, we also examined whether food based disgust--a core eliciting stimulus- may be a more potent immune stimulus than non-food based disgust. Healthy males were randomly assigned to view one of four sets of images--food disgust, non-food disgust, food control and negative emotion control. Measures of BT, salivary immune and related markers, and self-report data, were collected before, and at two time points after image viewing. Disgust elevated BT relative to the negative emotion control condition, as did food images. Different mechanisms appeared to account for these effects on BT, with higher initial levels of Tumor Necrosis Factor alpha (TNF-a) and disgust, predictive of BT increases in the disgust conditions. Disgust also increased TNF-a, and albumin levels, relative to the control conditions. Type of disgust exerted little effect. These findings further support the idea that disgust impacts upon immune function, and that disgust serves primarily a disease avoidance function. PMID- 22841693 TI - Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. AB - Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood-brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring-similar to those reported for ASD and SZ-that may alter CNS development and behavior. PMID- 22841695 TI - Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions. AB - Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosoma cruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T. cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T. cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive like behavior was triggered only by the type I Colombian T. cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite induced immune dysregulation may contribute to chronic depressive disorder in T. cruzi infection, which opens a new therapeutic pathway to be explored. PMID- 22841696 TI - The effects of morphine on basal neuronal activities in the lateral and medial pain pathways. AB - Numerous studies indicate that morphine suppresses pain-evoked activities in both spinal and supraspinal regions. However, little is known about the effect of morphine on the basal brain activity in the absence of pain. The present study was designed to assess the effects of single-dose morphine on the spontaneous discharge of many simultaneously recorded single units, as well as their functional connections, in the lateral pain pathway, including the primary somatosensory cortex (SI) and ventral posterolateral thalamus (VPL), and medial pain pathway, including the anterior cingulate cortex (ACC) and medial dorsal thalamus (MD), in awake rats. Morphine (5mg/kg) was administered intraperitoneally before the recording. Naloxone plus morphine and normal saline injections were performed respectively as controls. The results showed that morphine administration produced significant changes in the spontaneous neuronal activity in more than one third of the total recorded neurons, with primary activation in the lateral pathway while both inhibition and activation in the medial pathway. Naloxone pretreatment completely blocked the effects induced by morphine. In addition, the correlated activities between and within both pain pathways was exclusively suppressed after morphine injection. These results suggest that morphine may play different roles in modulating neural activity in normal vs. pain states. Taken together, this is the first study investigating the morphine modulation of spontaneous neuronal activity within parallel pain pathways. It can be helpful for revealing neuronal population coding for the morphine action in the absence of pain, and shed light on the supraspinal mechanisms for preemptive analgesia. PMID- 22841697 TI - Effects of ADHD therapeutic agents, methylphenidate and atomoxetine, on hippocampal neurogenesis in the adolescent mouse dentate gyrus. AB - Methylphenidate (MPH) and atomoxetine (ATX) are commonly used as attention deficit/hyperactivity disorder (ADHD) therapeutic agents. In the present study, we investigated the effects of MPH and ATX on cell proliferation and neuronal differentiation in the dentate gyrus (DG) of the adolescent mouse by 5-bromo-2' deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry. BrdU-positive ((+)) cells, DCX(+) cells and BrdU(+)/NeuN(+) neurons (BrdU(+) cells with NeuN immunoreaction) were easily detected in the subgranular zone (SGZ) of the DG in the vehicle-, MPH- and ATX-treated groups. Among them, only in the 10mg/kg MPH treated group, the numbers of BrdU(+), DCX(+) and BrdU(+)/NeuN(+) cells were significantly increased compared to those in the vehicle-treated group. In addition, brain-derived neurotrophic factor (BDNF) level was significantly increased in 10mg/kg MPH-treated group, not in the other experimental groups, compared to the vehicle-treated group. These results indicate that MPH, not ATX, can enhance cell proliferation and neuroblast differentiation in the SGZ of the DG via increasing BDNF level. PMID- 22841698 TI - Balancing a simulated inverted pendulum through motor imagery: an EEG-based real time control paradigm. AB - Most brain-computer interfaces (BCIs) are non-time-restraint systems. However, the method used to design a real-time BCI paradigm for controlling unstable devices is still a challenging problem. This paper presents a real-time feedback BCI paradigm for controlling an inverted pendulum on a cart (IPC). In this paradigm, sensorimotor rhythms (SMRs) were recorded using 15 active electrodes placed on the surface of the subject's scalp. Subsequently, common spatial pattern (CSP) was used as the basic filter to extract spatial patterns. Finally, linear discriminant analysis (LDA) was used to translate the patterns into control commands that could stabilize the simulated inverted pendulum. Offline trainings were employed to teach the subjects to execute corresponding mental tasks, such as left/right hand motor imagery. Five subjects could successfully balance the online inverted pendulum for more than 35s. The results demonstrated that BCIs are able to control nonlinear unstable devices. Furthermore, the demonstration and extension of real-time continuous control might be useful for the real-life application and generalization of BCI. PMID- 22841699 TI - The dynamics of changes in hippocampal GABAergic system in rats exposed to early life hypoxia-induced seizures. AB - Hypoxia-evoked seizures (H/S) early in life lead to multiple chronic neurological deficits. Here, we present the results of studying GABA release and uptake in hippocampal axon terminals of rats exposed to H/S at 10-12 days of age. We characterized (i) exocytotic release of GABA; (ii) the initial rate of GABA uptake; (iii) the regulation of GABA release by presynaptic GABA(B) receptors. Rats were used for experiments 2, 4 and 8 weeks after H/S. We found that exocytotic [(3)H]GABA release was higher in rats exposed to H/S, and a maximal difference in the release was observed between the control and experimental rats tested 2 weeks after H/S. In contrast, the initial rate of GABA uptake decreased with age, and this tendency was more pronounced in rats exposed to H/S. Using (+/ )-baclofen and SKF 97541 as agonists of GABA(B) receptor, we revealed that a significant difference in the auto-inhibition of exocytotic [(3)H]GABA release was detected only between the control and experimental adult rats (8 weeks after hypoxia). The inhibitory effect dropped dramatically in the control adults, but only slightly decreased in adult rats exposed to H/S, thus becoming threefold more potent after hypoxic injury. Together, the results show that H/S affects the dynamics of age-dependent changes in the GABAergic system, and that the enhanced GABA(B) receptor-mediated auto-inhibition can be an important factor in weakening the postsynaptic inhibition and in the development of hyperexcitability in rats exposed to H/S. PMID- 22841700 TI - Therapeutic vaccination against chronic hepatitis C virus infection. AB - Approximately 170 million people worldwide are chronic carriers of Hepatitis C virus (HCV). To date, there is no prophylactic vaccine available against HCV. The standard-of-care therapy for HCV infection involves a combination of pegylated interferon-alpha and ribavirin. This therapy, which is commonly associated with side effects, has a curative rate varying from 43% (HCV genotype 1) to 80% (HCV genotype 2). In 2011, two direct-acting antiviral agents, telaprevir and boceprevir, were approved by the US Food and drug Administration and are now being used in combination with standard-of-care therapy in selected patients infected with HCV genotype 1. Although both drugs are promising, resulting in a shortening of therapy, these drugs also induce additional side effects and have reduced efficacy in patients who did not respond to standard-of-care previously. An alternative approach would be to treat HCV by stimulating the immune system with a therapeutic vaccine ideally aimed at (i) the eradication of HCV-infected cells and (ii) neutralization of infectious HCV particles. The challenge is to develop therapeutic vaccination strategies that are either at least as effective as antiviral drugs but with lower side effects, or vaccines that, when combined with antiviral drugs, can circumvent long-term use of these drugs thereby reducing their side effects. In this review, we summarize and discuss recent preclinical developments in the area of therapeutic vaccination against chronic HCV infection. Although neutralizing antibodies have been described to exert protective immunity, clinical studies on the induction of neutralizing antibodies in therapeutic settings are limited. Therefore, we will primarily discuss therapeutic vaccines which aim to induce effective cellular immune response against HCV. PMID- 22841701 TI - The viral RNA capping machinery as a target for antiviral drugs. AB - Most viruses modify their genomic and mRNA 5'-ends with the addition of an RNA cap, allowing efficient mRNA translation, limiting degradation by cellular 5'-3' exonucleases, and avoiding its recognition as foreign RNA by the host cell. Viral RNA caps can be synthesized or acquired through the use of a capping machinery which exhibits a significant diversity in organization, structure and mechanism relative to that of their cellular host. Therefore, viral RNA capping has emerged as an interesting field for antiviral drug design. Here, we review the different pathways and mechanisms used to produce viral mRNA 5'-caps, and present current structures, mechanisms, and inhibitors known to act on viral RNA capping. PMID- 22841702 TI - Employing the FITT framework to explore HIV case managers' perceptions of two electronic clinical data (ECD) summary systems. AB - PURPOSE: Case managers facilitate continuity of care for persons living with HIV (PLWH) by coordination of resources and referrals to social services and medical care. The complexity of HIV care and associated comorbidities drives the need for medical and psychosocial care coordination, which may be achieved through health information exchange (HIE) systems. However, the use of HIE has not been well studied in the context of HIV services. The purpose of this descriptive qualitative study is to explore factors influencing case managers' adoption of electronic clinical data (ECD) summaries as an HIE strategy in HIV care through application of the "fit between individuals, task and technology" (FITT) framework. METHODS: Focus group methodology was used to gather perceptions from 48 participants who provided direct case management services for PLWH in New York City. Questions addressed current quality and efficiency challenges to HIE utilization in the context of case management of PLWH as well as barriers and enablers to use of an ECD summary. Analysis of the data was guided by the FITT framework. RESULTS: Major themes by interaction type were: (1) task-technology fit - resources, time and workflow; (2) individual-task fit - training and technical support; and 3) individual-technology fit - ECD summary functionality, technical difficulties and the need of a computer for each end-user. CONCLUSIONS: Our findings provide evidence for the applicability of the FITT framework to explore case managers' perceptions of factors influencing the adoption of ECD summary systems for HIV care prior to actual implementation. Assessment of fit among individual, task, and technology and addressing the concerns identified prior to implementation is critical to successful adoption of health information technology as a strategy to improve quality and efficiency in health care. PMID- 22841703 TI - The essential role of reconfiguration capabilities in the implementation of HIV related health information exchanges. AB - PURPOSE: To understand the dynamic capabilities that enabled the six demonstration projects of the Information Technology Networks of Care Initiative to implement health information exchanges (HIEs) tailored to their local HIV epidemics and regional care systems. METHODS: We conducted 111 semi-structured interviews with project staff and information technology (IT) specialists associated with the demonstration projects, staff from community-based organizations and public health agencies collaborating in the design and implementation of the HIEs, and providers who used each HIE. The dynamic capability framework guided analyses. In the context of a HIE, the framework's components include information systems (the actual technological exchange systems and capacity to update them), absorptive capacity (the ability to implement an operating HIE), reconfiguration capacity (the ability to adapt workflows and clinical practices in response to a HIE), and organizational size and human resources (characteristics likely to affect a clinic's ability to respond). RESULTS: Across the projects, we found evidence for the importance of three dynamic capabilities: information systems, reconfiguration capacity, and organizational size and human resources. However, of these three, reconfiguration capacity was the most salient. Implementation outcomes at all six of the projects were shaped substantially by the degree of attention dedicated to reworking procedures and practices so that HIE usage became routine. CONCLUSION: Electronic information exchange offers the promise of improved coordination of care. However, implementation of HIEs goes beyond programing and hardware installation challenges, and requires close attention to the needs of the HIEs end-users. Providers need to discern value from a HIE because their active participation is essential to ensuring that clinic and agency practices and procedures are reconfigured to incorporate new systems into daily work processes. PMID- 22841704 TI - Facile method for large scale synthesis of magnetic inorganic-organic hybrid anisotropic Janus particles. AB - Anisotropic Janus particles with strong magnetic iron oxide domain and polymer microsphere domain were prepared with large scale in one batch through a facile method via the solvothermal method in the presence of poly(methylenebisacrylmide co-methacrylic acid) (P(MBA-co-MAA)) microspheres. The coordination interaction between the carboxyl acid groups and inorganic species played an essential role during the formation of uniform P(MBA-co-MAA)/iron oxide core-shell microspheres via the controlled hydrolysis of ferric chloride in the initial stage. The formation of P(MBA-co-MAA)/Fe(3)O(4) Janus particles may be originated from a thermodynamic incompatibility between the P(MBA-co-MAA) domain and the Fe(3)O(4) domain during the partial reduction and crystallization of inorganic component to lower the interfacial energy change via reducing the interfacial area between the polymeric and inorganic magnetic domain. Further, the sizes of the inorganic magnetite domains were well controlled via altering the ratio of P(MBA-co-MAA) microspheres to ferric chloride inorganic precursors. PMID- 22841705 TI - Hybrid materials: Magnetite-Polyethylenimine-Montmorillonite, as magnetic adsorbents for Cr(VI) water treatment. AB - Hybrid materials formed by the combination of a sodium rich Montmorillonite (MMT), with magnetite nanoparticles (40 nm, Fe(3)O(4) NPs) coated with Polyethylenimine polymer (PEI 800 g/mol or PEI 25000 g/mol) were prepared. The intercalation of the magnetite nanoparticles coated with PEI among MMT platelets was achieved by cationic exchange. The resulting materials presented a high degree of exfoliation of the MMT sheets and a good dispersion of Fe(3)O(4) NPs on both the surface and among the layers of MMT. The presence of amine groups in the PEI structure not only aids the exfoliation of the MMT layers, but also gives to the hybrid material the necessary functionality to interact with heavy metals. These hybrid materials were used as magnetic sorbent for the removal of hexavalent chromium from water. The effect that pH, Cr(VI) concentration, and adsorbent material composition have on the Cr(VI) removal efficiency was studied. A complete characterization of the materials was performed. The hybrid materials showed a slight dependence of the removal efficiency with the pH in a wide range (1-9). A maximum amount of adsorption capacity of 8.8 mg/g was determined by the Langmuir isotherm. Results show that these hybrid materials can be considered as potential magnetic adsorbent for the Cr(VI) removal from water in a wide range of pH. PMID- 22841706 TI - Attractive double-layer forces and charge regulation upon interaction between electrografted amine layers and silica. AB - Amine functionalities have been introduced on glassy carbon surfaces through electrografting of 4-(2-aminoethyl)benzenediazonium tetrafluoroborate. The grafted layers were characterized by ellipsometry and by nanomechanical mapping in air and aqueous solutions using the atomic force microscopy PeakForce QNM mode. The layer was found to be 2.5 nm thick with low roughness, comparable to that of the glassy carbon substrate. However, small semi-spherical features were observed in the topographical image, indicating a clustering of the grafted amine compound. The nanomechanical mapping also demonstrated some swelling of the layer in water and pointed toward an important contribution of electrostatic interactions for the tip-surface adhesion. The forces between an aminated glassy carbon surface and a MUm-sized silica particle in aqueous solutions were measured at different ionic strength and pH-values. The results demonstrate that an attractive double-layer force predominates at large separations, and that the surface charge densities increase as the separation between the surfaces decreases. The degree of charge regulation on the aminated glassy carbon is significant. The relatively low surface charge density of the aminated glassy carbon is attributed to significant incorporation of counterions in the water rich grafted layer. PMID- 22841707 TI - Characterization of poly(2-hydroxyethyl methacrylate) (PHEMA) contact lens using the Langmuir monolayer technique. AB - The behavior of poly(2-hydroxyethyl methacrylate) (PHEMA) polymer monolayer spread on water was studied under various experimental conditions. The influence of subphase pH and temperature, compression speed, elapsed time from the deposit of the monolayer and the recording of the surface pressure-area (pi-A) isotherms, as well as the number of polymer molecules deposited at the air/water surface (surface concentration) was studied. The obtained results show that PHEMA exhibits a very stable monolayer given that it is unaffected by modifications in the majority of these variables. Only the elapsed time between the spreading of the monolayer and the beginning of compression causes a small change in the pi-A isotherms that consists in an increase in the area occupied by the film. This is attributed to the greater unfolding with time of the polymer's monomers at the air/water interface. The plateau that appears on pi-A curves of the PHEMA monolayer is attributed to the reorientation of their hydroxyethyl polar groups through their C-O-C bonds, as well as to the reorientation of the ethylene (CH(2)) groups that link the monomers, which provokes a folding of the polymer's chains causing an accordion configuration. The existence of this structure is confirmed by the presence of numerous noise peaks in the relative thickness versus time curve corresponding to this region. In the same fashion, the images observed from Brewster angle microscopy (BAM) reveal the existence of light-dark "bands" relative to the different regions of this particular structure. PMID- 22841708 TI - The physiological effect of ingested beta-N-methylamino-L-alanine on a glutamatergic synapse in an in vivo preparation. AB - The neurotoxin, BMAA (beta-N-methylamino-L-alanine), may be a risk factor for amyotrophic lateral sclerosis (ALS), Parkinson's (PD) and Alzheimer's (AD) disease. In vivo experiments have demonstrated that BMAA can cause a number of motor dysfunctions if ingested or injected, and in vitro experiments show that this toxin binds to glutamate receptors with deleterious results. Also, BMAA exists in the human food chain worldwide, and has been detected in the brains of ALS and AD patients. This paper offers the first demonstration by intracellular recording of the effect of ingested BMAA on the postsynaptic response of an identified glutamatergic cell in a living, undissected organism (Drosophila melanogaster), and correlates these observations with the specific motor dysfunctions that result from ingestion. The results suggest that BMAA acts as a glutamate agonist, causing NMDA receptor channels to remain open for prolonged periods of time, thereby damaging the cell by excitotoxicity. The effect on the postsynaptic response became apparent days before the function of the postsynaptic cell (wing beat) became affected. Severely depolarized cells were able to fully recover with the removal of BMAA from the food source, suggesting that blocking BMAA binding in the brain might be a good treatment strategy. PMID- 22841709 TI - Does platelet transfusion improve outcomes in patients with spontaneous or traumatic intracerebral hemorrhage? PMID- 22841710 TI - Is water effective for wound cleansing? PMID- 22841711 TI - Arabidopsis Zinc Ribbon 3 is the ortholog of yeast mitochondrial HSP70 escort protein HEP1 and belongs to an ancient protein family in mitochondria and plastids. AB - ZR proteins belong to a phylogenetically conserved family of small zinc-ribbon proteins in plastids and mitochondria of higher plants. The function of these proteins is so far unclear. The mitochondrial proteins share sequence similarities with mitochondrial Hsp70 escort proteins (HEP) from Saccharomyces cerevisiae (HEP1) and human. Expression of the mitochondrial ZR protein from Arabidopsis, ZR3, rescued a hep1 knockout mutant from yeast. Accordingly, ZR3 was found to physically interact with mitochondrial Hsp70 from Arabidopsis. Our findings support the idea that mitochondrial and plastidic ZR proteins from higher plants are orthologs of HEP proteins. PMID- 22841712 TI - Physical and functional interaction of KV10.1 with Rabaptin-5 impacts ion channel trafficking. AB - K(V)10.1 is a potassium channel expressed in brain and implicated in tumor progression. We have searched for proteins interacting with K(V)10.1 and identified Rabaptin-5, an effector of the Rab5 GTPase. Both proteins co-localize on large early endosomes induced by Rab5 hyperactivity. Silencing of Rabaptin-5 induces down-regulation of recycling of K(V)10.1 channel in transfected cells and reduction of K(V)10.1 current density in cells natively expressing K(V)10.1, indicating a role of Rabaptin-5 in channel trafficking. K(V)10.1 co-localizes, but does not physically interact, with Rab7 and Rab11. Our data highlights the complex control of the amount of K(V)10.1 channels on the cell surface. PMID- 22841713 TI - Catalytic promiscuity of a bacterial alpha-N-methyltransferase. AB - The posttranslational methylation of N-terminal alpha-amino groups (alpha-N methylation) is a ubiquitous reaction found in all domains of life. Although this modification usually occurs on protein substrates, recent studies have shown that it also takes place on ribosomally synthesized natural products. Here we report an investigation of the bacterial alpha-N-methyltransferase CypM involved in the biosynthesis of the peptide antibiotic cypemycin. We demonstrate that CypM has low substrate selectivity and methylates a variety of oligopeptides, cyclic peptides such as nisin and haloduracin, and the epsilon-amino group of lysine. Hence it may have potential for enzyme engineering and combinatorial biosynthesis. Bayesian phylogenetic inference of bacterial alpha-N methyltransferases suggests that they have not evolved as a specific group based on the chemical transformations they catalyze, but that they have been acquired from various other methyltransferase classes during evolution. PMID- 22841714 TI - Pilt is a coiled-coil domain-containing protein that localizes at the trans-Golgi complex and regulates its structure. AB - Protein incorporated later into tight junctions (Pilt), also termed tight junction-associated protein 1 or tight junction protein 4, is a coiled-coil domain-containing protein that was originally identified as a human discs large interacting protein. In this study, we identified Pilt as an Arf6-binding protein by yeast two-hybrid screening. By immunocytochemical analysis, Pilt was shown to be predominantly localized at the trans-Golgi complex and to exhibit diffuse cytoplasmic distribution in association with endosomes and plasma membrane in NIH3T3 cells. Silencing of endogenous Pilt disrupted the Golgi structure. The present findings suggest the functional involvement of Pilt in the maintenance of the Golgi structure. PMID- 22841715 TI - MRPS27 is a pentatricopeptide repeat domain protein required for the translation of mitochondrially encoded proteins. AB - Mammalian pentatricopeptide repeat domain (PPR) proteins are involved in regulation of mitochondrial RNA metabolism and translation and are required for mitochondrial function. We investigated an uncharacterised PPR protein, the supernumerary mitochondrial ribosomal protein of the small subunit 27 (MRPS27), and show that it associates with the 12S rRNA and tRNA(Glu), however it does not affect their abundance. We found that MRPS27 is not required for mitochondrial RNA processing or the stability of the small ribosomal subunit. However, MRPS27 is required for mitochondrial protein synthesis and its knockdown causes decreased abundance in respiratory complexes and cytochrome c oxidase activity. PMID- 22841716 TI - Towards an artificial cell. AB - We are on the verge of producing "synthetic cells," or protocells, in which some, many or all of the tasks of a real biological cell are harnessed into a synthetic platform. Such advances are made possible through genetic engineering, microfabrication technologies, and the development of cellular membranes from new surfactants that extend beyond phospholipids in stability and chemical control, and can be used to introduce designer functionality into membranes and cells. We review some of the recent advances in the development of synthetic cells and suggest future exciting directions. PMID- 22841717 TI - Antibody-antigen pair probed by combinatorial approach and rational design: bringing together structural insights, directed evolution, and novel functionality. AB - The unique hypervariability of the immunoglobulin (Ig) superfamily provides a means to create both binding and catalytic antibodies with almost any desired specificity and activity. The diversity of antigens and concept of adaptive response suggest that it is possible to find an antigen pair to any raised Ig. In the current review we discuss combinatorial approaches, which makes it possible to obtain an antibody with predefined properties, followed by 3D structure-based rational design to enhance or dramatically change its characteristics. A similar strategy, but applied to the second partner of the antibody-antigen pair, may result in selection of complementary substrates to the chosen Ig. Finally, 2D screening may be performed solving the "Chicken and Egg" problem when neither antibody nor antigen is known. PMID- 22841718 TI - E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. AB - E-cadherin plays a major role in cell-cell adhesion and inactivating germline mutations in its encoding gene predispose to hereditary diffuse gastric cancer. Evidence indicates that aside from its recognized role in early tumourigenesis, E cadherin is also pivotal for tumour progression, including invasion and metastization. Herein, we discuss E-cadherin alterations found in a cancer context, associated cellular effects and signalling pathways, and we raise new key questions that will impact in the management of GC patients and families. PMID- 22841719 TI - Competitive binding of UBPY and ubiquitin to the STAM2 SH3 domain revealed by NMR. AB - To date, the signal transducing adaptor molecule 2 (STAM2) was shown to harbour two ubiquitin binding domains (UBDs) known as the VHS and UIM domains, while the SH3 domain of STAM2 was reported to interact with deubiquitinating enzymes (DUBs) like UBPY and AMSH. In the present study, NMR evidences the interaction of the STAM2 SH3 domain with ubiquitin, demonstrating that SH3 constitutes the third UBD of STAM2. Furthermore, we show that a UBPY-derived peptide can outcompete ubiquitin for SH3 binding and vice versa. These results suggest that the SH3 domain of STAM2 plays versatile roles in the context of ubiquitin mediated receptor sorting. PMID- 22841720 TI - The strength of the miR398-Csd2-CCS1 regulon is subject to natural variation in Arabidopsis thaliana. AB - miR398 links expression of the three major chloroplast copper proteins, plastocyanin, CCS1 and Csd2, to copper availability. miR398 abundance was stronger plastocyanin-controlled in accessions from cold and continental habitats (Kas-1, Ms-0, WS) than in Cvi-0 and Col-0. Target gene regulation was broken for Csd2 in Cvi-0 upon cold-treatment. Comparison of miR398 levels, target gene regulation as well as Ago1 and miR168 expression demonstrated that the miR398 regulon can be overwritten by accession specific transcriptional regulation in Cvi-0. It is concluded that the escape from the miRNA control of copper homeostasis is linked to adaptation of Cvi-0 to its harsh natural habitat. PMID- 22841721 TI - Control over DNA replication in time and space. AB - DNA replication is precisely regulated in time and space, thereby safeguarding genomic integrity. In eukaryotes, replication initiates from multiple sites along the genome, termed origins of replication, and propagates bidirectionally. Dynamic origin bound complexes dictate where and when replication should initiate. During late mitosis and G1 phase, putative origins are recognized and become "licensed" through the assembly of pre-replicative complexes (pre-RCs) that include the MCM2-7 helicases. Subsequently, at the G1/S phase transition, a fraction of pre-RCs are activated giving rise to the establishment of replication forks. Origin location is influenced by chromatin and nuclear organization and origin selection exhibits stochastic features. The regulatory mechanisms that govern these cell cycle events rely on the periodic fluctuation of cyclin dependent kinase (CDK) activity through the cell cycle. PMID- 22841722 TI - Systems biology of cellular rhythms. AB - Rhythms abound in biological systems, particularly at the cellular level where they originate from the feedback loops present in regulatory networks. Cellular rhythms can be investigated both by experimental and modeling approaches, and thus represent a prototypic field of research for systems biology. They have also become a major topic in synthetic biology. We review advances in the study of cellular rhythms of biochemical rather than electrical origin by considering a variety of oscillatory processes such as Ca++ oscillations, circadian rhythms, the segmentation clock, oscillations in p53 and NF-kappaB, synthetic oscillators, and the oscillatory dynamics of cyclin-dependent kinases driving the cell cycle. Finally we discuss the coupling between cellular rhythms and their robustness with respect to molecular noise. PMID- 22841723 TI - Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. AB - We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-alpha, IL-2, IFN-gamma, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. PMID- 22841725 TI - Iron predicts tolerance in liver transplantation. PMID- 22841724 TI - A proposed protocol for the standardized preparation of PRF membranes for clinical use. AB - Upon clinical application, thick platelet-rich fibrin (PRF) is usually compressed to fit the implantation site. However, it is speculated that the preservation of platelets and plasma content depends on the compression methods used. To accurately evaluate the clinical outcome of PRF, the preparation protocol should be standardized. Freshly prepared PRF clots were compressed into a thin membrane by our novel PRF compression device. The localization of platelets was examined by SEM and immunostaining. Growth factor levels were evaluated by bioassays and cytokine-antibody array techniques. The angiogenic activity was examined by the chick chorioallantoic membrane assay and the scratch assay using HUVEC cultures. Platelets were concentrated on the surface of the region adjacent to the red thrombus and this region was subjected to the experiments. Compared to the PRF membrane compressed by dry gauze (G-PRF), the preservation of the plasma content, 3D-fibrin meshwork, and platelets was more intact in the compressor-prepared PRF membrane (C-PRF). Among the growth factors tested, C-PRF contained PDGF isoforms at higher levels, and significantly stimulated cell proliferation and neovascularization. C-PRF may be useful for grafting while minimizing the loss of bioactive factors. This C-PRF preparation protocol is proposed as a standardized protocol for PRF membrane preparation. PMID- 22841728 TI - An unusual rectal mass. PMID- 22841729 TI - High fructose consumption can induce endotoxemia. PMID- 22841731 TI - Association between higher predicted serum vitamin D levels and reduced incidence of inflammatory bowel diseases. PMID- 22841732 TI - Huge atypical cyst arising from the pancreas. PMID- 22841733 TI - An unusual mass in a cirrhotic liver. PMID- 22841734 TI - Barrett's esophagus: who should receive ablation and how can we get the best results? PMID- 22841735 TI - Dietary fiber and asymptomatic diverticulosis. PMID- 22841736 TI - A rare tumor of the liver with a sudden presentation. PMID- 22841737 TI - The challenging task of treating painful chronic pancreatitis. PMID- 22841738 TI - Improved protocol for the extraction of bacterial mRNA from soils. AB - An improved protocol for extraction of prokaryotic mRNA from soil samples was developed by modifying the extraction procedure to obtain higher yields of mRNA and to reduce co-extraction of humic acids. The modified protocol was found to be more robust and efficient compared to the original protocol by Griffiths et al. (2000) without compromising with the quality and quantity of RNA. PMID- 22841739 TI - A new and efficient method to obtain benzalkonium chloride adapted cells of Listeria monocytogenes. AB - A new method to obtain benzalkonium chloride (BAC) adapted L. monocytogenes cells was developed. A factorial design was used to assess the effects of the inoculum size and BAC concentration on the adaptation (measured in terms of lethal dose 50 -LD50-) of 6 strains of Listeria monocytogenes after only one exposure. The proposed method could be applied successfully in the L. monocytogenes strains with higher adaptive capacity to BAC. In those cases, a significant empirical equation was obtained showing a positive effect of the inoculum size and a positive interaction between the effects of BAC and inoculum size on the level of adaptation achieved. However, a slight negative effect of BAC, due to the biocide, was also significant. The proposed method improves the classical method based on successive stationary phase cultures in sublethal BAC concentrations because it is less time-consuming and more effective. For the laboratory strain L. monocytogenes 5873, by applying the new procedure it was possible to increase BAC-adaptation 3.69-fold in only 33 h, whereas using the classical procedure 2.61 fold of increase was reached after 5 days. Moreover, with the new method, the maximum level of adaptation was determined for all the strains reaching surprisingly almost the same concentration of BAC (mg/l) for 5 out 6 strains. Thus, a good reference for establishing the effective concentrations of biocides to ensure the maximum level of adaptation was also determined. PMID- 22841740 TI - Co-evolution between sociality and dispersal: the role of synergistic cooperative benefits. AB - Explaining the evolution of sociality is challenging because social individuals face disadvantages that must be balanced by intrinsic benefits of living in a group. One potential route towards the evolution of sociality may emerge from the avoidance of dispersal, which can be risky in some environments. Although early studies found that local competition may cancel the benefits of cooperation in viscous populations, subsequent studies have identified conditions, such as the presence of kin recognition or specific demographic conditions, under which altruism will still spread. Most of these studies assume that the costs of cooperating outweigh the direct benefits (strong altruism). In nature, however, many organisms gain synergistic benefits from group living, which may counterbalance even costly altruistic behaviours. Here, we use an individual based model to investigate how dispersal and social behaviour co-evolve when social behaviours result in synergistic benefits that counterbalance the relative cost of altruism to a greater extent than assumed in previous models. When the cost of cooperation is high, selection for sociality responds strongly to the cost of dispersal. In particular, cooperation can begin to spread in a population when higher cooperation levels become correlated with lower dispersal tendencies within individuals. In contrast, less costly social behaviours are less sensitive to the cost of dispersal. In line with previous studies, we find that mechanisms of global population control also affect this relationship: when whole patches (groups) go extinct each generation, selection favours a relatively high dispersal propensity, and social behaviours evolve only when they are not very costly. If random individuals within groups experience mortality each generation to maintain a global carrying capacity, on the other hand, social behaviours spread and dispersal is reduced, even when the latter is not costly. PMID- 22841741 TI - Reproductive hormone profile and pubertal development in 14-year-old boys prenatally exposed to polychlorinated biphenyls. AB - Because polychlorinated biphenyls (PCBs) are thought to cause endocrine disruption, we examined 438 adolescent boys from a birth cohort in the Faroe Islands, where PCB exposures are elevated. We measured PCBs and p,p' dichlorodiphenyldichloroethylene (DDE) in cord blood and in serum from clinical examination at age 14. Higher prenatal PCB exposure was associated with lower serum concentrations of both luteinizing hormone (LH) and testosterone. In addition, sex hormone binding globulin (SHBG) was positively associated with both prenatal and concurrent PCB exposures. The PCB-SHBG association was robust to covariate adjustment. In a structural equation model, a doubling in prenatal PCB exposure was associated with a decrease in LH of 6% (p=0.03). Prenatal exposure to PCB and DDE showed weak, non-significant inverse associations with testicular size and Tanner stage. DDE was highly correlated with PCB and showed slightly weaker associations with the hormone profile. These findings suggest that delayed puberty with low serum-LH concentrations associated with developmental exposure to non dioxin-like PCBs may be due to a central hypothalamo-pituitary mechanism. PMID- 22841742 TI - Comparative analysis of two glyceraldehyde-3-phosphate dehydrogenases from a thermoacidophilic archaeon, Sulfolobus tokodaii. AB - Sulfolobus tokodaii, a thermoacidophilic archaeon, possesses two structurally and functionally different enzymes that catalyze the oxidation of glyceraldehyde-3 phosphate (GAP): non-phosphorylating GAP dehydrogenase (St-GAPN) and phosphorylating GAP dehydrogenase (St-GAPDH). In contrast to previously characterized GAPN from Sulfolobus solfataricus, which exhibits V-type allosterism, St-GAPN showed K-type allosterism in which the positive cooperativity was abolished with concomitant activation by glucose 1-phosphate (G1P). St-GAPDH catalyzed the reversible oxidation of GAP to 1,3 bisphosphoglycerate (1,3-BPG) with high gluconeogenic activity, which was specific for NADPH, while both NAD(+) and NADP(+) were utilized in the glycolytic direction. PMID- 22841743 TI - Determination of phenylbutyric acid and its metabolite phenylacetic acid in different tissues of mouse by liquid chromatography with tandem mass spectrometry and its application in drug tissue distribution. AB - Endoplasmic reticulum (ER) stress is associated with various human diseases. Phenylbutyric acid (PBA) is a well-known chemical chaperone that regulates ER stress. The main objective of this study was to develop a simple, rapid, and sensitive method for the simultaneous determination of phenylbutyric acid and its metabolite, phenylacetic acid (PAA). A LC-MS/MS analysis using negative electrospray ionization was used. Samples were analyzed by multiple reaction monitoring (MRM) in 15 min of total run time, using d11-PBA and d7-PAA as internal standards. The limit of quantification was 1 MUg/g for tissue and 0.8 MUg/mL for plasma. Recoveries for plasma and tissues were higher than 81% for both PBA and PAA. The inter-day and intra-day accuracy and precision were within +/-15%. We then further successfully validated this method by applying it to determine the tissue distribution of PBA and its metabolite PAA after i.p. injection of PBA at a dose of 500 mg/kg in mice. The maximum concentrations of PBA and PAA in plasma and tissues were seen at 15 min and 45 min, respectively. The PBA plasma concentration was 15-fold higher than the concentration in the kidney, whereas the PAA plasma concentration was 6-fold higher than the concentration in the liver. The area under the curve decreased in the order of plasma > kidney > liver > heart > muscle > lung for PBA and plasma > liver > kidney > heart > muscle > lung for PAA. The tissue to plasma ratio ranged from 0.007 to 0.063 for PBA and 0.016 to 0.109 for PAA. In summary, the LC-ESI-MS method developed in this study is simple, sensitive and reliable. PMID- 22841744 TI - Determination of oxyntomodulin, an anorectic polypeptide, in rat plasma using 2D LC-MS/MS coupled with ion pair chromatography. AB - Polypeptide therapeutics present a challenge for quantitative analysis when using immunoassays or recently, liquid chromatography-tandem mass spectrometry because of their structural similarities to endogenous proteins and peptides in plasma. In this assay, a Waters Oasis(r) mixed-mode anion exchange (MAX) microelution modified solid phase extraction (SPE) method coupled with two-dimensional reversed phase ion pair chromatography-tandem mass spectrometry was used for the validation and analysis of oxyntomodulin in rat plasma. Oxyntomodulin (OXM) and its isotope labeled internal standard were extracted from rat plasma and analyzed with a chromatographic run time of 8 min. Modified SPE, two-dimensional liquid chromatography coupled with 3-nitrobenzyl alcohol as a mobile phase additive, and monitoring of multiply charged SRM transitions (+7 charge state) of OXM were necessary to achieve a lower limit of quantification of 1 ng/mL. The method was validated with a linear range of 1-1000 ng/mL, with average R2 of 0.992, and reversed calculated residuals between -8.6% and 6.0%. Precision and accuracy for inter- and intra-day were determined to be +/-17%. Following a complete validation, the method was applied to show utility using rat plasma samples that were intravenously dosed with oxyntomodulin. PMID- 22841745 TI - High performance aptamer affinity chromatography for single-step selective extraction and screening of basic protein lysozyme. AB - A DNA aptamer based high-performance affinity chromatography is developed for selective extraction and screening of a basic protein lysozyme. First, a poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolithic column was synthesized in situ by thermally initiated radical polymerization, and then an anti-lysozyme DNA aptamer was covalently immobilized on the surface of the monolith through a 16-atom spacer arm. The target protein lysozyme but non-target proteins can be trapped by the immobilized anti-lysozyme DNA aptamer. In contrast, lysozyme cannot be trapped by the immobilized oligodeoxynucleotide that does not contain the sequence of the anti-lysozyme DNA aptamer. The study clearly demonstrates the trapping of lysozyme by the immobilized anti-lysozyme DNA aptamer is mainly due to specific recognition rather than simple electrostatic interaction of positively charged protein and the negatively charged DNA. The inter-day precision was determined as 0.8% for migration time and 4.2% for peak area, respectively. By the use of aptamer affinity monolith, a screening strategy is developed to selectively extract lysozyme from chicken egg white, showing the advantages of high efficiency, low cost and ease-of-operation. PMID- 22841746 TI - A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells. AB - Cancer cells increase glucose uptake and reject lactic acid even in the presence of oxygen (Warburg effect). This metabolism reorients glucose towards the pentose phosphate pathway for ribose synthesis and consumes great amounts of glutamine to sustain nucleotide and fatty acid synthesis. Oxygenated and hypoxic cells cooperate and use their environment in a manner that promotes their development. Coenzymes (NAD(+), NADPH,H(+)) are required in abundance, whereas continuous consumption of ATP and citrate precludes the negative feedback of these molecules on glycolysis, a regulation supporting the Pasteur effect. Understanding the metabolism of cancer cells may help to develop new anti-cancer treatments. PMID- 22841747 TI - Improving knowledge management through the support of image examination and data annotation using DICOM structured reporting. AB - An important effort has been invested on improving the image diagnosis process in different medical areas using information technologies. The field of medical imaging involves two main data types: medical imaging and reports. Developments based on the DICOM standard have demonstrated to be a convenient and widespread solution among the medical community. The main objective of this work is to design a Web application prototype that will be able to improve diagnosis and follow-on of breast cancer patients. It is based on TRENCADIS middleware, which provides a knowledge-oriented storage model composed by federated repositories of DICOM image studies and DICOM-SR medical reports. The full structure and contents of the diagnosis reports are used as metadata for indexing images. The TRENCADIS infrastructure takes full advantage of Grid technologies by deploying multi resource grid services that enable multiple views (reports schemes) of the knowledge database. The paper presents a real deployment of such Web application prototype in the Dr. Peset Hospital providing radiologists with a tool to create, store and search diagnostic reports based on breast cancer explorations (mammography, magnetic resonance, ultrasound, pre-surgery biopsy and post-surgery biopsy), improving support for diagnostics decisions. A technical details for use cases (outlining enhanced multi-resource grid services communication and processing steps) and interactions between actors and the deployed prototype are described. As a result, information is more structured, the logic is clearer, network messages have been reduced and, in general, the system is more resistant to failures. PMID- 22841748 TI - Discovering discovery patterns with Predication-based Semantic Indexing. AB - In this paper we utilize methods of hyperdimensional computing to mediate the identification of therapeutically useful connections for the purpose of literature-based discovery. Our approach, named Predication-based Semantic Indexing, is utilized to identify empirically sequences of relationships known as "discovery patterns", such as "drug x INHIBITS substance y, substance y CAUSES disease z" that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature by the SemRep system, and subsequently utilized to direct the search for known treatments for a held out set of diseases. Rapid and efficient inference is accomplished through the application of geometric operators in PSI space, allowing for both the derivation of discovery patterns from a large set of known TREATS relationships, and the application of these discovered patterns to constrain search for therapeutic relationships at scale. Our results include the rediscovery of discovery patterns that have been constructed manually by other authors in previous research, as well as the discovery of a set of previously unrecognized patterns. The application of these patterns to direct search through PSI space results in better recovery of therapeutic relationships than is accomplished with models based on distributional statistics alone. These results demonstrate the utility of efficient approximate inference in geometric space as a means to identify therapeutic relationships, suggesting a role of these methods in drug repurposing efforts. In addition, the results provide strong support for the utility of the discovery pattern approach pioneered by Hristovski and his colleagues. PMID- 22841749 TI - Effect of LED light spectra on starvation-induced oxidative stress in the cinnamon clownfish Amphiprion melanopus. AB - The present study aimed to test starvation-induced oxidative stress in the cinnamon clownfish Amphiprion melanopus illuminated by light-emitting diodes (LEDs): red (peak at 630 nm), green (peak at 530 nm), and blue (peak at 450 nm) within a visible light. We investigated the oxidative stress induced by starvation for 12 days during illumination with 3 LED light spectra through measuring antioxidant enzyme (superoxide dismutase [SOD] and catalase [CAT]) mRNA expression and activity; CAT western blotting; and measuring lipid peroxidation [LPO]), plasma H(2)O(2), lysozyme, glucose, alanine aminotransferase (AlaAT), aspartate aminotransferase (AspAT), and melatonin levels. In green and blue lights, expression and activity of antioxidant enzyme mRNA were significantly lower than those of other light spectra, results that are in agreement with CAT protein expression level by western blot analysis. Also, in green and blue lights, plasma H(2)O(2), lysozyme, glucose, AlaAT, AspAT, and melatonin levels were significantly lower than those in other light spectra. These results indicate that green and blue LEDs inhibit oxidative stress and enhance immune function in starved cinnamon clownfish. PMID- 22841750 TI - Surveillance of human rotaviruses in 2007-2011, Hungary: exploring the genetic relatedness between vaccine and field strains. AB - BACKGROUND: The availability of rotavirus vaccines has resulted in an intensification of post vaccine strain surveillance efforts worldwide to gain information on the impact of vaccines on prevalence of circulating rotavirus strains. OBJECTIVES: In this study, the distribution of human rotavirus G and P types in Hungary is reported. In addition, the VP4 and VP7 genes of G1P[8] strains were sequenced to monitor if vaccine-derived strains were introduced and/or some strains/lineages were selected against. STUDY DESIGN: The study was conducted in 8 geographic areas of Hungary between 2007 and 2011. Rotavirus positive stool samples were collected from diarrheic patients mostly <5 years of age. Viral RNA was amplified by multiplex genotyping RT-PCR assay, targeting the medically most important G and P types. When needed, sequencing of the VP7 and VP4 genes was performed. RESULTS: In total, 2380 strains were genotyped. During the 5-year surveillance we observed the dominating prevalence of genotype G1P[8] (44.87%) strains, followed by G4P[8] (23.4%), G2P[4] (14.75%) and G9P[8] (6.81%) genotypes. Uncommon strains were identified in a low percentage of samples (4.12%). Phylogenetic analysis of 318 G1P[8] strains identified 55 strains similar to the Rotarix strain (nt sequence identities; VP7, up to 97.9%; VP4, up to 98.5%) although their vaccine origin was unlikely. CONCLUSIONS: Current vaccines would have protected against the majority of identified rotavirus genotypes. A better understanding of the potential long-term effect of vaccine use on epidemiology and evolutionary dynamics of co-circulating wild type strains requires continuous strain surveillance. PMID- 22841751 TI - The impact of cytokine gene polymorphisms on Epstein-Barr virus infection outcome in pediatric liver transplant recipients. AB - BACKGROUND: Epstein-Barr virus (EBV) is associated with most cases of the post transplant lymphoproliferative disorders developed during the first year after transplantation. The high EBV DNA load constitutes a major risk for the development of EBV-related lymphoproliferations. However, among transplant recipients there are patients with a chronically high viral load (CHVL) who do not develop lymphoproliferations. The polymorphism within cytokine genes might influence the susceptibility to, and contribute to the pathogenesis of the disease. OBJECTIVES: The aim of this study was to analyze the genetic polymorphism in the selected cytokines with regard to EBV infection outcome in children after liver transplantation (LTx). STUDY DESIGN: Thirteen cytokine/cytokine receptor polymorphisms were genotyped in 170 children after LTx, and related to: EBV DNAemia, CHVL onset and the length of CHVL carriage. RESULTS: The study revealed: the protective effect of rare homozygous and heterozygous IL-1beta-511 and IL-1 receptor antagonist (IL-1RN VNTR) genotypes against viremia within the first year after LTx (OR=0.28, p=0.0007 and OR=0.35, p=0.009, respectively); the protective effect of CC chemokine ligand 2 (CCL2)+1543CT and TT genotypes against CHVL onset (OR=0.38, p=0.042); and the prolonged CHVL-resolution in IL12B 3'untranslated region (3'UTR) AC individuals (p=0.034). CONCLUSIONS: This data suggests that carriage of IL-1beta-511CT/TT and/or IL-1RN VNTR 1.2/2.2 genotype may be beneficial for combating EBV infection. This is the first study reporting the association of CCL2 and IL12B gene polymorphisms with the CHVL carriage in pediatric LTx recipients. PMID- 22841752 TI - Trypanosoma brucei has a canonical mitochondrial processing peptidase. AB - Most mitochondrial matrix and inner membrane proteins have N-terminal presequences which serve as import signals. After import these presequences are cleaved by the heterodimeric mitochondrial processing peptidase. In the parasitic protozoa Trypanosoma brucei mitochondrial protein import relies on presequences that are much shorter than in other eukaryotes. How they are processed is unknown. The trypansomal genome encodes four open reading frames that are annotated as mitochondrial processing peptidase. Here we show that RNAi-mediated ablation of two of these proteins leads to a growth arrest and a concomitant accumulation of mitochondrial precursor proteins inside mitochondria. Import experiments using isolated mitochondria from RNAi cell lines reveals that both proteins are required for efficient import and processing of the tested precursor protein. Reciprocal immunoprecipitation demonstrates that the proteins interact with each other. In summary these results show that we have identified the two subunits of the trypanosomal mitochondrial processing peptidase. PMID- 22841753 TI - Structural and kinetic studies of Schistosoma mansoni adenylate kinases. AB - The human parasite Schistosoma mansoni is totally dependent on the purine salvage pathway in order to supply large quantities of purine precursors for its energy and DNA biosynthetic needs. Adenylate kinase (ADK) is responsible for the conversion of AMP (produced by the adenosine kinase reaction) into ADP, which is subsequently converted into ATP by nucleoside diphosphate kinase (NDPK). ADK and NDPK are the most active enzymes of the pathway, probably reflecting an evolutionary adaptation due to the intense use of the branch in which they participate. However, notwithstanding their importance very little information has been accumulated found regarding these enzymes. In this work two adenylate kinases from S. mansoni were cloned and heterologously expressed in Escherichia coli. The purified products were utilized in activity assays, and displayed kinetic parameters similar to the corresponding human orthologous proteins. The cytosolic S. mansoni ADK was crystallized and its structure solved allowing us to detect a difference in the nucleotide binding site when compared with the human ortholog. PMID- 22841754 TI - Event-rate effects in the flanker task: ERPs and task performance in children with and without AD/HD. AB - Demanding tasks require a greater amount of effort, in which case individuals are required to alter their energetic-state to a level appropriate to perform the task. According to the Cognitive-Energetic Model (CEM), children with AD/HD are unable to effectively modulate their energetic state, leading to task underperformance. Using an Eriksen flanker task with varying event-rates, the current study compared the ability of typically-developing children and children with AD/HD to modulate their energetic state. In line with the CEM, it was predicted that children with AD/HD would underperform in the fast and slow event rates. Results indicated that the groups did not differ in commission errors (i.e., incorrect responses). However, children with AD/HD made more omission errors to incongruent stimuli at the fast and slow event-rates, compared to controls. N2 amplitude was significantly larger for the AD/HD than control group in the slow event-rate. It is concluded that the energetic state modulation dysfunction in children with AD/HD results in an inability to attend to the task, as opposed to an inability to perform the task itself. Furthermore, these task performance differences did not manifest in either the N2 or P3 ERP components. Therefore, inattention in children with AD/HD may have its locus in response preparation, as opposed to stimulus processing, but more research is required to validate these conjectures. PMID- 22841755 TI - Neural correlates of social motivation: an fMRI study on power versus affiliation. AB - Power versus affiliation motivations refer to two different strivings relevant in the context of social relationships. We used functional magnetic resonance imaging (fMRI) to determine neural structures involved in power versus affiliation motivation based on an individual differences approach. Seventeen participants provided self-reports of power and affiliation motives and were presented with love, power-related, and control movie clips. The power motive predicted activity in four clusters within the left prefrontal cortex (PFC), while participants viewed power-related film clips. The affiliation motive predicted activity in the right putamen/pallidum while participants viewed love stories. The present findings extend previous research on social motivations to the level of neural functioning and suggest differential networks for power related versus affiliation-related social motivations. PMID- 22841756 TI - Use of aortic extension cuffs for preserving hypogastric blood flow in endovascular aneurysm repair with aneurysmal involvement of common iliac arteries. AB - BACKGROUND: Intentional hypogastric artery covering during endovascular repair of abdominal aortic aneurysms (EVAR) can carry a non-negligible rate of complications; to preserve pelvic blood flow, several approaches are in use, such as sandwich techniques, branched iliac devices, or the use of aortic extender cuffs in a bell-bottom configuration. We assess the performance of the latter for treatment of common iliac artery aneurysms during EVAR. METHODS: Prospective gathering of data in 21 dilated common iliac arteries (18-25 mm) with coexisting abdominal aorta aneurysm, which were treated from 2005 to 2010 and received a GORE((r)) Excluder endograft and one (n = 14) or several aortic extenders in a bell-bottom configuration. Control group consisted of 136 EVARs performed with the same device in the same time frame. Median follow-up was of 47 months, with contrast-enhanced computed tomography assessment 1 month after the procedure and yearly thereafter. RESULTS: Age and comorbidities were homogeneously distributed among groups, although the aortic aneurysm diameter was lower in the bell-bottom group (50 mm vs. 58.2 mm, P < 0.001). There was no 30-day mortality registered in this group, and only one patient died during follow-up (5.3%), without relation with the aneurysmal disease. No significant differences were found in reintervention (15.8% vs. 14.7%, P = 0.707) or endoleak rates (36.8% vs. 38.9%, Fisher P = 1). There were no type I and four type II endoleaks, two of which precised treatment for sac growth. Endoleak-free survival (P = 0.994) and reintervention-free survival (P = 0.563) did not show differences either. CONCLUSION: Bell-bottom technique is a feasible and safe alternative for preserving hypogastric blood flow, and does not imply a higher risk of reintervention or endoleak at 3-year follow-up. PMID- 22841757 TI - The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals. AB - The harmful consequences of carcinogenic metals, such as nickel, arsenic, and chromium, are thought to be in part due to their ability to induce oxidative stress. The ubiquity of oxidative stress in biological systems has made it a fairly obvious culprit in causing cellular damage and/or development of disease. However, the full extent of oxidative stress-induced damage is not limited to its direct effects on cellular components, such as lipids, proteins, and DNA, but may extend to its ability to alter gene expression. Gene expression regulation is an important component of cellular and/or tissue homeostasis, and its alteration can have detrimental consequences. Therefore, a growing amount of interest is being paid to understanding how oxidative stress can influence gene expression. Oxidative stress-induced epigenetic dysregulation in the form of posttranslational histone modifications, in particular, is a popular topic of research. This review will therefore primarily focus on discussing the role of oxidative stress and hypoxia on histone methylation and/or gene expression alterations. The sources of oxidative stress discussed here are carcinogenic metals, such as, nickel, arsenic, and chromium. PMID- 22841758 TI - Cytochrome c oxidase dysfunction in oxidative stress. AB - Cytochrome c oxidase (CcO) is the terminal oxidase of the mitochondrial electron transport chain. This bigenomic enzyme in mammals contains 13 subunits of which the 3 catalytic subunits are encoded by the mitochondrial genes. The remaining 10 subunits with suspected roles in the regulation, and/or assembly, are coded by the nuclear genome. The enzyme contains two heme groups (heme a and a3) and two Cu(2+) centers (Cu(2+) A and Cu(2+) B) as catalytic centers and handles more than 90% of molecular O(2) respired by the mammalian cells and tissues. CcO is a highly regulated enzyme which is believed to be the pacesetter for mitochondrial oxidative metabolism and ATP synthesis. The structure and function of the enzyme are affected in a wide variety of diseases including cancer, neurodegenerative diseases, myocardial ischemia/reperfusion, bone and skeletal diseases, and diabetes. Despite handling a high O(2) load the role of CcO in the production of reactive oxygen species still remains a subject of debate. However, a volume of evidence suggests that CcO dysfunction is invariably associated with increased mitochondrial reactive oxygen species production and cellular toxicity. In this paper we review the literature on mechanisms of multimodal regulation of CcO activity by a wide spectrum of physiological and pathological factors. We also review an array of literature on the direct or indirect roles of CcO in reactive oxygen species production. PMID- 22841759 TI - Metabolic regulation of oxygen and redox homeostasis by p53: lessons from evolutionary biology? AB - The genetic links between p53 and metabolic processes such as oxidative phosphorylation are being studied with increasing interest given that cellular metabolism seems to play an important role in tumorigenesis. This review focuses on how p53 regulation of various metabolic genes may influence redox homeostasis, as the genome is constantly susceptible to oxidative damage, a consequence of living in an aerobic environment. Because p53-like genetic sequences are also found in life forms that may not necessarily benefit from tumor suppression, an evolutionary introduction is given in an attempt to understand why p53 might regulate a basic cellular activity such as metabolism. The presented epidemiologic and experimental data suggest that one reason may be for the homeostatic regulation of oxygen, the essential substrate for reactive oxygen species generation. PMID- 22841761 TI - The role of pituitary gonadotropins in gonadal sex differentiation in the protogynous Malabar grouper, Epinephelus malabaricus. AB - The aim of this study was to clarify the roles of 2 gonadotropins (GTHs), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), on sex differentiation in the protogynous Malabar grouper, Epinephelus malabaricus. To do this, the mRNA expression patterns of GTH subunits (cga, fshb, and lhb) in the fish pituitary throughout gonadal sex differentiation were investigated. Real time reverse transcriptase (RT)-PCR showed that cga and fshb were present in the undifferentiated and ovarian differentiation stages, and that the expression levels significantly increased after ovarian differentiation (AOD). However, lhb was not expressed before ovarian differentiation (BOD) and was first detected AOD. Next, to investigate the differentiation and distribution of Fshb and Lhb producing cells in the pituitary of fish throughout gonadal sex differentiation, immunohistochemical analysis was used to detect teleost GTH subunits. Positive immunoreactivity against Fshb and Lhb was not detected in the pituitary BOD; Fshb and Lhb-positive cells first appeared in the pituitary AOD. It therefore seems unlikely that pituitary gonadotropins play a major role in the control of gonadal sex differentiation in the Malabar grouper. PMID- 22841762 TI - Hypothalamus-pituitary-adrenal axis activity and the subsequent response to chronic stress differ depending upon life history stage. AB - The hypothalamus-pituitary-adrenal (HPA) axis is modulated seasonally in many species, and chronic stress can alter HPA functioning. However, it is not known how these two factors interact - are there particular life history stages when animals are more or less vulnerable to chronic stress? We captured wild house sparrows (Passer domesticus) in Massachusetts during six different life history stages: early and late winter, pre-laying, breeding, late breeding, and molt. At each time point, we tested HPA function by measuring baseline and stress-induced corticosterone (CORT), negative feedback in response to an injection of dexamethasone, and maximum adrenal response through an injection of adrenocorticotropic hormone. We then brought birds into captivity as a model for chronic stress, and repeated the four tests 5 days later. At capture, all HPA variables varied seasonally. Birds showed increased negative feedback during breeding and late winter compared to pre-laying. Furthermore, birds during the late breeding period had down-regulated their HPA axis, perhaps in preparation for molt. After 5 days of captivity, house sparrows lost ~11% of initial body mass, although birds lost more weight during molt and early winter. Overall, captive sparrows showed elevated baseline CORT and increased negative feedback, although negative feedback did not show a significant increase during any individual life history stage. During most of the year, adrenal sensitivity was unaffected by captivity. However, during late breeding and molt, adrenal sensitivity increased during captivity. Taken together, these data provide further support that HPA function naturally varies throughout the year, with the interesting consequence that molting birds may potentially be more vulnerable to a chronic stressor such as captivity. PMID- 22841760 TI - Knockdown of leptin A expression dramatically alters zebrafish development. AB - Using morpholino antisense oligonucleotide (MO) technology, we blocked leptin A or leptin receptor expression in embryonic zebrafish, and analyzed consequences of leptin A knock-down on fish development. Embryos injected with leptin A or leptin receptor MOs (leptin A or leptin receptor morphants) had smaller bodies and eyes, undeveloped inner ear, enlarged pericardial cavity, curved body and/or tail and larger yolk compared to control embryos of the same stages. The defects persisted in 6-9 days old larvae. We found that blocking leptin A function had little effect on the development of early brain (1 day old), but differentiation of both the morphant dorsal brain and retinal cells was severely disrupted in older (2 days old) embryos. Despite the enlarged pericardial cavity, differentiation of cardiac cells appeared to be similar to control embryos. Formation of the morphants' inner ear is also severely disrupted, which corroborates existing reports of leptin receptor expression in inner ear of both zebrafish and mammals. Co-injection of leptin A MO and recombinant leptin results in partial rescue of the wild-type phenotype. Our results suggest that leptin A plays distinct roles in zebrafish development. PMID- 22841763 TI - Seasonal variation in estrogen receptor ERalpha, but not ERbeta, androgen receptor and aromatase, in the efferent ductules and epididymis of the big fruit eating bat Artibeus lituratus. AB - The efferent ductules (ED) are a major target for estrogens, which act via the estrogen receptors ERalpha (ESR1) and ERbeta (ESR2). ERalpha has been found in the ED of all species studied so far. However, in the epididymis (EP), the expression of ERalpha is controversial, as is data about the occurrence of aromatase in the epithelium lining the excurrent ducts. Therefore, to further investigate this estrogen-responsive system, we used a seasonal breeder, the Neotropical bat, Artibeus lituratus, in which testicular expression of androgen (AR) and estrogen (ER) receptors vary with reproductive phase. The localization of aromatase, ERalpha, ERbeta and AR in the ED and EP of A. lituratus was investigated. The results showed that aromatase, AR and ERbeta were distributed throughout the excurrent ducts and did not vary during the annual reproductive cycle. Conversely, ERalpha was detected primarily in the ED epithelium, had marked seasonal variation and was increased during regression, especially in the EP epithelium. The results suggest that ERalpha may be involved in preparing the male genital tract for recrudescence. Together, the data obtained under natural conditions emphasize that specific segments of the excurrent ducts downstream of the testis are the primary targets for estrogen action via ERalpha, which is similar to previous findings in animals lacking functional ERalpha. PMID- 22841764 TI - Thyroid hormone receptor-beta gene expression in the brain of the frog Pelophylax esculentus: seasonal, hormonal and temperature regulation. AB - Thyroid hormone receptor-beta (trbeta) cDNA was identified in the adult of Pelophylax esculentus (previously: Rana esculenta), a seasonally breeding species, in order to detect spatial brain trbeta expression, its levels through the seasons and in response to 6-n-propyl-2-thiouracil, T(4) and T(3) administrations as well as to thermal manipulations. The deduced amino acid sequence of P. esculentus trbeta showed a high similarity to the homologous of other vertebrates. By in situ hybridization we found trbeta mRNA signal in the anterior preoptic nucleus, the habenulae, the hypothalamic-pituitary region and the ependyma. Brain trbeta transcript levels varied through the seasons, and they were well correlated with brain T(4) levels but only partially with T(3) levels. Experimentally-induced hypothyroidism decreased brain trbeta expression. The administration of exogenous thyroid hormones increased brain trbeta expression, with T(4) appearing more potent than T(3). The experiments of thermal manipulations further strengthen the hypothesis that T(4) is more effective than T(3) in brain trbeta regulation. This study also shows that, as in other vertebrates, deiodinase enzymes could modulate trbeta expression via thyroid hormone regulation. PMID- 22841765 TI - Relaxin-like gonad-stimulating substance in an echinoderm, the starfish: a novel relaxin system in reproduction of invertebrates. AB - Gonad-stimulating substance (GSS) in starfish is the only known invertebrate peptide hormone responsible for final gamete maturation, rendering it functionally analogous to gonadotropins in vertebrates. Recently, GSS was purified from the radial nerves of the starfish Asterina pectinifera and its chemical structure determined. This review summarizes the chemical structure of relaxin-like peptide, GSS, from a starfish as the first identified gonadotropin in invertebrates and its hormonal action on reproduction. The starfish GSS is a relaxin-like heterodimeric peptide composed of two peptides (A- and B-chains) with disulfide cross-linkages. Chemically synthesized GSS induced oocyte maturation and ovulation in vitro and an unique spawning behavior followed by release of gametes in vivo. GSS is a first trigger for oocyte maturation in starfish, but its effect is indirect because GSS acts on the ovary to produce a second mediator, 1-methyladenine (1-MeAde), as a maturation-inducing hormone of starfish. The action of GSS on ovarian follicle cells to produce 1-MeAde is mediated through the activation of its receptor, G-protein, and adenylyl cyclase. In contrast to follicle cells in a fully grown state, GSS fails to induce 1-MeAde production in growing follicle cells because of a lack of Gs-proteins. Thus, relaxin-like GSS is a major factor in the neuroendocrine cascade controlling reproduction in starfish. PMID- 22841766 TI - Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. AB - BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is characterized by relapsing skin swellings, abdominal pain attacks, and, less frequently, potentially life-threatening laryngeal attacks. OBJECTIVE: This study determined the mortality of patients with and without the diagnosis of HAE-C1-INH and analyzed fatal laryngeal attacks. METHODS: A cohort of 728 patients from 182 families with HAE-C1-INH was evaluated for death cases by analyzing pedigrees. Detailed information on fatal laryngeal attacks in 36 patients was obtained by questioning relatives and treating physicians. RESULTS: Of the 214 patients who had died, 70 asphyxiated during a laryngeal attack. Mortality by asphyxiation was higher in patients with undiagnosed HAE-C1-INH (63 cases) than in patients with diagnosed HAE-C1-INH (7 cases). The lifespan of asphyxiated patients with undiagnosed HAE-C1-INH was on average ~31 years shorter than patients with undiagnosed HAE-C1-INH who died of other causes. Three phases were distinguished in the fatal laryngeal attacks. Phase 1, the predyspnea phase, lasted on average for 3.7 +/- 3.2 hours (range, 0-11 hours). Phase 2, the dyspnea phase, lasted on average for 41 +/- 49 minutes (range, 2 minutes to 4 hours). Phase 3, the loss of consciousness phase, lasted on average for 8.9 +/- 5.1 minutes (range, 2-20 minutes). CONCLUSIONS: The high mortality in patients with undiagnosed HAE-C1-INH underscores the need to identify these patients and diagnose their condition. The analysis of fatal laryngeal attacks gives further insight into their course, thus helping to avoid fatalities in the future. PMID- 22841767 TI - Xerosis is latitude dependent and affects the propensity to develop atopic disease. PMID- 22841769 TI - Serum IL-9 and lung function. PMID- 22841770 TI - Donor-derived transplant acceptance-inducing cells in composite tissue allotransplantation. AB - BACKGROUND: Composite tissue allotransplantation (CTA) is a newly emerging field of transplantation. Immunological research in CTA has been intensified due to the recent clinical success of hand and face transplantation. Establishing immunological tolerance by adoptive transfer of ex vivo cultured tolerance inducing cell types is of growing interest. Transplant acceptance-inducing cells (TAICs) are a type of deactivated immunoregulatory macrophages. METHODS: A total of 36 allogeneic hind limb transplantations in the rat were performed in six groups. Group A (Lewis (LW) -> Brown-Norway (BN)) received Lewis-donor-derived TAICs locally (i.m.). Group B (LW -> BN) received Lewis-donor-derived TAICs systemically (i.v.) and group C (Sprague Dawley (Sp-D) -> BN) served as a control group receiving Lewis-donor-derived TAICs systemically (i.v.). Groups D (LW -> BN), E (LW -> BN), and F (BN -> BN) also served as control groups with group D receiving no immunosuppression, group E receiving FK506 and prednisolone and group F receiving no immunosuppression with isograft transplantations (BN -> BN). The timing of rejection was assessed by clinical observation and histological findings. RESULTS: Rejection of the allogeneic hind limb occurred on average 7.7 days after transplantation in group A and 7.4 days in group B. Rejection was significantly delayed (Log-rank test, p < 0.01) compared to groups C and D, where rejection of the allogeneic hind limb occurred on average 5.8 days and 5.6 days after transplantation. No rejection was seen in groups E and F. CONCLUSION: For the first time, TAICs have been applied in a CTA model and demonstrated a significant immunosuppressive effect. Even though the immunomodulatory effect is relatively modest, the results of this study justify subsequent research on TAIC therapy to improve experimental and clinical outcome after CTA. PMID- 22841771 TI - A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the LD50 of polychlorinated biphenyls in avian species. AB - Birds differ in sensitivity to the embryotoxic effects of polychlorinated biphenyls (PCBs), which complicates environmental risk assessments for these chemicals. Recent research has shown that the identities of amino acid residues 324 and 380 in the avian aryl hydrocarbon receptor 1 (AHR1) ligand binding domain (LBD) are primarily responsible for differences in avian species sensitivity to selected dibenzo-p-dioxins and furans. A luciferase reporter gene (LRG) assay was developed in our laboratory to measure AHR1-mediated induction of a cytochrome P450 1A5 reporter gene in COS-7 cells transfected with different avian AHR1 constructs. In the present study, the LRG assay was used to measure the concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and PCBs 126, 77, 105 and 118 on luciferase activity in COS-7 cells transfected with AHR1 constructs representative of 86 avian species in order to predict their sensitivity to PCB-induced embryolethality and the relative potency of PCBs in these species. The results of the LRG assay indicate that the identity of amino acid residues 324 and 380 in the AHR1 LBD are the major determinants of avian species sensitivity to PCBs. The relative potency of PCBs did not differ greatly among AHR1 constructs. Luciferase activity was significantly correlated with embryolethality data obtained from the literature (R(2)>=0.87, p<0.0001). Thus, the LRG assay in combination with the knowledge of a species' AHR1 LBD sequence can be used to predict PCB-induced embryolethality in potentially any avian species of interest without the use of lethal methods on a large number of individuals. PMID- 22841773 TI - Dose-response analysis of phthalate effects on gene expression in rat whole embryo culture. AB - The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing gene expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations. PMID- 22841772 TI - Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries. AB - There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100nmol) exposure of the corneas for 2h (cultured for 24h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2h and every 4h thereafter, for 24h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100MUg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline+dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. PMID- 22841775 TI - DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. AB - Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a negative regulator of this process. PTEN promoter hypermethylation is a major epigenetic silencing mechanism in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in HSC activation and liver fibrosis. Treatment of activated HSCs with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) decreased aberrant hypermethylation of the PTEN gene promoter and prevented the loss of PTEN expression that occurred during HSC activation. Silencing DNA methyltransferase 1 (DNMT1) gene also decreased the PTEN gene promoter methylation and upregulated the PTEN gene expression in activated HSC-T6 cells. In addition, knockdown of DNMT1 inhibited the activation of both ERK and AKT pathways in HSC-T6 cells. These results suggest that DNMT1-mediated PTEN hypermethylation caused the loss of PTEN expression, followed by the activation of the PI3K/AKT and ERK pathways, resulting in HSC activation. PMID- 22841774 TI - Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer. AB - Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1 expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9 fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. PMID- 22841776 TI - Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries. AB - Although estrogen receptor (ER)alpha agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia-reperfusion. The functional mechanisms of ERalpha have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERalpha agonist, selective ER modulators (SERMs) and an ER antagonist on drug induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERalpha-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERalpha in drug induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. PMID- 22841777 TI - An atlas-based geometry pipeline for cardiac Hermite model construction and diffusion tensor reorientation. AB - Here we present a novel atlas-based geometry pipeline for constructing three dimensional cubic Hermite finite element meshes of the whole human heart from tomographic patient image data. To build the cardiac atlas, two superior atria, two inferior ventricles as well as the aorta and the pulmonary trunk are first segmented, and epicardial and endocardial boundary surfaces are extracted and smoothed. Critical points and skeletons (or central-line paths) are identified, following the cardiac topology. The surface model and the path tree are used to construct a hexahedral control mesh via a skeleton-based sweeping method. Derivative parameters are computed from the control mesh, defining cubic Hermite finite elements. The thickness of the atria and the ventricles is obtained using segmented epicardial boundaries or via offsetting from the endocardial surfaces in regions where the image resolution is insufficient. We also develop a robust optical flow approach to deform the constructed atlas and align it with the image from a second patient. This registration method is fully-automatic, and avoids manual operations required by segmentation and path extraction. Moreover, we demonstrate that this method can also be used to deformably map diffusion tensor MRI data with patient geometries to include fiber and sheet orientations in the finite element model. PMID- 22841778 TI - Semiautomatic carotid lumen segmentation for quantification of lumen geometry in multispectral MRI. AB - Quantitative information about the geometry of the carotid artery bifurcation is relevant for investigating the onset and progression of atherosclerotic disease. This paper proposes an automatic approach for quantifying the carotid bifurcation angle, carotid area ratio, carotid bulb size and the vessel tortuosity from multispectral MRI. First, the internal and external carotid centerlines are determined by finding a minimum cost path between user-defined seed points where the local costs are based on medialness and intensity. The minimum cost path algorithm is iteratively applied after curved multi-planar reformatting to refine the centerline. Second, the carotid lumen is segmented using a topology preserving geodesic active contour which is initialized by the extracted centerlines and steered by the MR intensities. Third, the bifurcation angle and vessel tortuosity are automatically extracted from the segmented lumen. The methods for centerline tracking and lumen segmentation are evaluated by comparing their accuracy to the inter- and intra-observer variability on 48 datasets (96 carotid arteries) acquired as part of a longitudinal population study. The evaluation reveals that 94 of 96 carotid arteries are segmented successfully. The distance between the tracked centerlines and the reference standard (0.33 mm) is similar to the inter-observer variation (0.32 mm). The lumen segmentation accuracy (average DSC=0.89, average mean absolute surface distance=0.31 mm) is close to the inter-observer variation (average dice=0.92, average mean surface distance=0.23 mm). The correlation coefficient of manually and automaticly derived bifurcation angle, carotid proximal area ratio, carotid proximal bulb size and vessel totuosity quantifications are close to the correlation of these measures between observers. This demonstrates that the automated method can be used for replacing manual centerline annotation and manual contour drawing for lumen segmentation in MRIs data prior to quantifying the carotid bifurcation geometry. PMID- 22841779 TI - Eradication of iodine deficiency in Spain. Close, but not there yet. PMID- 22841780 TI - An examination of liver offers to candidates on the liver transplant wait-list. AB - BACKGROUND & AIMS: We aimed to characterize offers of organs to candidates awaiting liver transplantation (LT). METHODS: We analyzed data from the United Network for Organ Sharing registry on all US LT candidates with nonfulminant disease who were offered livers from February 1, 2005, to January 31, 2010, and ultimately received transplants. We excluded candidates with a final Model for End-stage Liver Disease score of less than 15. Livers were classified as high quality if they were from donors 18-50 years of age who were >= 170 cm tall, of non-black race, suffered brain death secondary to trauma, hepatitis C antibody negative, not categorized as high risk by the Centers for Disease Control, and locally or regionally located. RESULTS: Of 33,389 candidates for LT, 20% died or were removed from the list and 64% received LT; the median (interquartile range) number of liver offers for all candidates was 5 (range, 2-12). Of those who died or were removed from the list, 84% received 1 or more liver offers. Overall, 55% of those who died or were removed from the list, and 57% of those who received LT, received 1 or more offers of a high-quality liver when they had Model for End stage Liver Disease scores of 15 or greater (P = .005). However, the proportion of last liver offers of high quality to patients who underwent LT was twice that of patients who died or were removed from the list (28% vs 14%; P < .001). Most liver offers (68%) were refused for reasons related to donor quality. CONCLUSIONS: Most candidates for LT who died or were removed from the list received 1 or more offers of a liver beforehand, and 55% received 1 or more offers of a high-quality liver. These findings indicate that a substantial proportion of wait-list mortality results in part from declined livers, rather than lack of opportunity, for transplantation. Understanding the real-time factors involved in the complex decision to accept a liver offer is vital to reducing wait-list mortality for LT candidates. PMID- 22841781 TI - Crypt base columnar stem cells in small intestines of mice are radioresistant. AB - BACKGROUND & AIMS: Adult stem cells have been proposed to be quiescent and radiation resistant, repairing DNA double-strand breaks by nonhomologous end joining. However, the population of putative small intestinal stem cells (ISCs) at position +4 from the crypt base contradicts this model, in that they are highly radiosensitive. Cycling crypt base columnar cells (CBCs) at crypt positions +1-3 recently were defined as an alternative population of ISCs. Little is known about the sensitivity of this stem cell population to radiation. METHODS: Radiation-induced lethality of CBCs was quantified kinetically in Lgr5 lacZ transgenic mice. gamma-H2AX, BRCA1, RAD51, and DNA-PKcs foci were used as DNA repair surrogates to investigate the inherent ability of CBCs to recognize and repair double-strand breaks. 5-ethynyl-2'-deoxyuridine and 5-bromo-2' deoxyuridine incorporation assays were used to study patterns of CBC growth arrest and re-initiation of cell cycling. Apoptosis was evaluated by caspase-3 staining. RESULTS: CBCs are relatively radioresistant, repairing DNA by homologous recombination significantly more efficiently than transit amplifying progenitors or villus cells. CBCs undergo apoptosis less than 24 hours after irradiation (32% +/- 2% of total lethality) or mitotic death at 24-48 hours. Survival of CBCs at 2 days predicts crypt regeneration at 3.5 days and lethality from gastrointestinal syndrome. Crypt repopulation originates from CBCs that survive irradiation. CONCLUSIONS: Adult ISCs in mice can cycle rapidly yet still be radioresistant. Importantly, homologous recombination can protect adult stem cell populations from genotoxic stress. These findings broaden and refine concepts of the phenotype of adult stem cells. PMID- 22841782 TI - Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) have increased activity in the insula and reduced activation of the dorsolateral prefrontal cortex (DLPFC) in response to visceral stimulation. We investigated whether they have latent impairments in cognitive flexibility because of dysfunction in the DLPFC and insula and altered connectivity between brain regions. METHODS: We analyzed data from 30 individuals with IBS (15 men; age, 21.7 +/- 3.0 y) diagnosed based on Rome III criteria, along with 30 individuals matched for age, sex, and education level (controls). Event-related functional magnetic resonance imaging of the brain was performed to evaluate cognitive flexibility and was assessed by the Wisconsin Card Sorting Test, in which subjects are allowed to change choice criteria, defined as set-shifting in response to error feedback. Brain images were analyzed with statistical parametric mapping 5 and 8 software and dynamic causal modeling. RESULTS: Subjects with IBS had significantly more Nelson perseverative errors (P < .05) and set-maintenance difficulties (P < .05) than controls. They also showed significantly decreased activity of the right DLPFC (Brodmann's area 9; P < .001) and right hippocampus (P < .001), and significantly increased activity of the left posterior insula (P < .001) at error feedback during set-shifting. Dynamic causal modeling analysis during set shifting revealed significantly less connectivity from the DLPFC to pre supplementary motor area in subjects with IBS, compared with controls (P = .012). CONCLUSIONS: Individuals with IBS have latent impairments in cognitive flexibility as a result of altered activity of the DLPFC, insula, and hippocampus, and impaired connectivity between the DLPFC and pre-supplementary motor area. PMID- 22841783 TI - Hormone therapy increases risk of ulcerative colitis but not Crohn's disease. AB - BACKGROUND & AIMS: Estrogen has been proposed to modulate gut inflammation through an effect on estrogen receptors found on gastrointestinal epithelial and immune cells. The role of postmenopausal hormone therapy on risk of Crohn's disease (CD) and ulcerative colitis (UC) is unclear. METHODS: We conducted a prospective cohort study of 108,844 postmenopausal US women (median age, 54 years) enrolled in 1976 in the Nurses' Health Study without a prior history of CD or UC. Every 2 years, we have updated information on menopause status, postmenopausal hormone use, and other risk factors. Self-reported diagnoses of CD and UC were confirmed through medical record review by 2 gastroenterologists who were blinded to exposure information. We used Cox proportional hazards models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Through 2008, with more than 1.8 million person-years of follow-up, we documented 138 incident cases of CD and 138 cases of UC. Compared with women who never used hormones, the multivariate-adjusted HR for UC was 1.71 (95% CI, 1.07 2.74) among women who currently used hormones and 1.65 (95% CI, 1.03-2.66) among past users. The risk of UC appeared to increase with longer duration of hormone use (P(trend) = .04) and decreased with time since discontinuation. There was no difference in risk according to the type of hormone therapy used (estrogen vs estrogen plus progestin). In contrast, we did not observe an association between current use of hormones and risk of CD (multivariate-adjusted HR, 1.19; 95% CI, 0.78-1.82). The effect of hormones on risk of UC and CD was not modified by age, body mass index, or smoking. CONCLUSIONS: In a large prospective cohort of women, postmenopausal hormone therapy was associated with an increased risk of UC but not CD. These findings indicate that pathways related to estrogens might mediate the pathogenesis of UC. PMID- 22841785 TI - Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis. AB - BACKGROUND & AIMS: The TOR signaling pathway regulator-like (TIPRL) protein, the mammalian ortholog of yeast TIP41, was identified in an expression profiling screen for factors that regulate human liver carcinogenesis. We investigated the role of human TIPRL protein in hepatocellular carcinoma (HCC). METHODS: We measured the level of TIPRL in HCC and adjacent nontumor tissues from patients. We used small interfering RNAs and zebrafish to study the function of TIPRL. We used annexin V propidium iodide staining and immunoblot analyses to measure apoptosis and activation of apoptotic signaling pathways. We used confocal microscopy, coimmunoprecipitation, and glutathione-S transferase pull-down analyses to determine interactions among mitogen-activated protein kinase kinase 7 (MKK7 or MAP2K7), TIPRL, and the protein phosphatase type 2A (PP2Ac). We studied the effects of TIPRL in tumor xenografts in mice. RESULTS: Levels of TIPRL were higher in HCC tissues and cell lines than nontumor tissues and primary hepatocytes. Knockdown of tiprl expression in zebrafish led to large amounts of apoptosis throughout the embryos. Incubation of HCC cells, but not primary human hepatocytes, with small interfering RNA against TIPRL (siTIPRL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) caused prolonged activation (phosphorylation) of MKK7 and c-Jun N-terminal kinase (JNK) and led to apoptosis, indicated by cleavage of procaspase-8,-3 and of poly-(adenosine diphosphate-ribose) polymerase. TIPRL bound to MKK7 and PP2Ac and promoted the interaction between MKK7 and PP2Ac. In mice, injection of HCC xenograft tumors with siTIPRL and TRAIL led to tumor apoptosis and regression. CONCLUSIONS: TIPRL is highly up-regulated in human HCC samples and cell lines, compared with noncancerous liver tissues. TIPRL prevents prolonged activation of MKK7 and JNK and TRAIL-induced apoptosis by mediating the interaction between MKK7 and PP2Ac. PMID- 22841784 TI - Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. AB - BACKGROUND & AIMS: Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection. METHODS: We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 * 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. RESULTS: In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 * 10(-9) and 1.1 * 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 * 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. CONCLUSIONS: Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis. PMID- 22841786 TI - Proximal and distal colorectal cancer resection rates in the United States since widespread screening by colonoscopy. AB - BACKGROUND & AIMS: Screening decreases colorectal cancer (CRC) incidence and mortality. Colonoscopy has become the most common CRC screening test in the United States, but the degree to which it protects against CRC of the proximal colon is unclear. We examined US trends in rates of resection for proximal vs distal CRC, which reflect CRC incidence, in the context of national CRC screening data, before and since Medicare's 2001 decision to pay for screening colonoscopy. METHODS: We used the Nationwide Inpatient Sample, the largest US all-payer inpatient database, to estimate age-adjusted rates of resection for distal and proximal CRC, from 1993 to 2009, in adults. Temporal trends were analyzed using Joinpoint regression analysis. RESULTS: The rate of resection for distal CRC decreased from 38.7 per 100,000 persons (95% confidence interval [CI], 35.4-42.0) to 23.2 per 100,000 persons (95% CI, 20.9-25.5) from 1993 to 2009, with annual decreases of 1.2% (95% CI, 0.1%-2.3%) from 1993 to 1999, followed by larger annual decreases of 3.8% (95% CI, 3.3%-4.3%) from 1999 to 2009 (P < .001). In contrast, the rate of resection for proximal CRC decreased from 30.0 per 100,000 persons (95% CI, 27.4-32.5) to 22.7 per 100,000 persons (95% CI, 20.6-24.7) from 1993 to 2009, but significant annual decreases of 3.1% (95% CI, 2.3%-4.0%) occurred only after 2002 (P < .001). Rates of resection for CRC decreased for adults ages 50 years and older, but increased for younger adults. CONCLUSIONS: These findings support the hypothesis that population-level decreases in rates of resection for distal CRC are associated with screening, in general, and that implementation of screening colonoscopy, specifically, might be an important factor that contributes to population-level decreases in rates of resection for proximal CRC. PMID- 22841787 TI - Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. AB - BACKGROUND & AIMS: Progression of liver fibrosis in experimental models depends on gut-derived bacterial products, but little is known about mechanisms of disruption of the mucosal barrier or translocation. We used a mouse model of cholestatic liver disease to investigate mechanisms of intestinal barrier disruption following liver injury. METHODS: Liver fibrosis and bacterial translocation were assessed in Toll-like receptor 2 (TLR2)-deficient and tumor necrosis factor receptor I (TNFRI)-deficient mice subjected to bile duct ligation. Epithelial and lamina propria cells were isolated and analyzed by immunoblot analyses and flow cytometry. We analyzed bone marrow chimeras and mice with a conditional gain-of-function allele for the TNFRI receptor. By crossing TNFRI(flxneo/flxneo) mice with mice that expressed the VillinCre transgene specifically in intestinal epithelial cells, we created mice that express functional TNFRI specifically on intestinal epithelial cells (VillinCreTNFRI(flxneo/flxneo) mice). RESULTS: Following bile duct ligation, TLR2 deficient mice had less liver fibrosis and intestinal translocation of bacteria and bacterial products than wild-type mice. Mice with hematopoietic cells that did not express TLR2 also had reduced bacterial translocation, indicating that TLR2 expression by hematopoietic cells regulates intestinal barrier function. The number of TLR2(+) monocytes that produce tumor necrosis factor alpha increased in the intestinal lamina propria of wild-type mice following bile duct ligation; bacterial translocation was facilitated by TNFRI-mediated signals on intestinal epithelial cells. CONCLUSIONS: Intestinal inflammation and bacterial translocation contribute to liver fibrosis via TLR2 signaling on monocytes in the lamina propria and TNFRI signaling on intestinal epithelial cells in mice. Therefore, enteric TNFRI is an important mediator of cholestatic liver fibrosis. PMID- 22841788 TI - NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice. AB - BACKGROUND & AIMS: The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. METHODS: We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. RESULTS: Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate induced activation of NFAT in all organs. A-285222 also reduced taurocholate induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l-arginine induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A 285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. CONCLUSIONS: NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target. PMID- 22841789 TI - Complete chloroplast genome sequence of Elodea canadensis and comparative analyses with other monocot plastid genomes. AB - Elodea canadensis is an aquatic angiosperm native to North America. It has attracted great attention due to its invasive nature when transported to new areas in its non-native range. We have determined the complete nucleotide sequence of the chloroplast (cp) genome of Elodea. Taxonomically Elodea is a basal monocot, and only few monocot cp genomes representing early lineages of monocots have been sequenced so far. The genome is a circular double-stranded DNA molecule 156,700 bp in length, and has a typical structure with large (LSC 86,194 bp) and small (SSC 17,810 bp) single-copy regions separated by a pair of inverted repeats (IRs 26,348 bp each). The Elodea cp genome contains 113 unique genes and 16 duplicated genes in the IR regions. A comparative analysis showed that the gene order and organization of the Elodea cp genome is almost identical to that of Amborella trichopoda, a basal angiosperm. The structure of IRs in Elodea is unique among monocot species with the whole cp genome sequenced. In Elodea and another monocot Lemna minor the borders between IRs and LSC are located upstream of rps 19 gene and downstream of trnH-GUG gene, while in most monocots, IR has extended to include both trnH and rps 19 genes. A phylogenetic analysis conducted using Bayesian method, based on the DNA sequences of 81 chloroplast genes from 17 monocot taxa provided support for the placement of Elodea together with Lemna as a basal monocot and the next diverging lineage of monocots after Acorales. In comparison with other monocots, the Elodea cp genome has gone through only few rearrangements or gene losses. IR of Elodea has a unique structure among the monocot species studied so far as its structure is similar to that of a basal angiosperm Amborella. This result together with phylogenetic analyses supports the placement of Elodea as a basal monocot to the next diverging lineage of monocots after Acorales. So far, only few cp genomes representing early lineages of monocots have been sequenced and, therefore, this study provides valuable information about the course of evolution in divergence of monocot lineages. PMID- 22841790 TI - Steroid 21-hydroxylase gene mutational spectrum in 50 Tunisian patients: characterization of three novel polymorphisms. AB - Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease of steroid biosynthesis in humans. More than 90% of all CAH cases are caused by mutations of the 21-hydroxylase gene (CYP21A2), and approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. In this study, the CYP21A2 gene was genotyped in 50 patients in Tunisia with the clinical diagnosis of 21-hydroxylase deficiency. CYP21A2 mutations were identified in 87% of the alleles. The most common point mutation in our population was the pseudogene specific variant p.Q318X (26%). Three novel single nucleotide polymorphism (SNP) loci were identified in the CYP21A2 gene which seems to be specific for the Tunisian population. The overall concordance between genotype and phenotype was 98%. With this study the molecular basis of CAH has been characterized, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling. PMID- 22841791 TI - BnC15 and BnATA20, the different putative components, control anther development in Brassica napus L. AB - In Brassica napus, male fertility depends on proper cell differentiation in the anther. However, relatively little is known about the genes regulating anther cell differentiation and function. Here, we report two floral organ specific genes, BnC15 and BnATA20, derived from a B. napus two-line Rs1046A/B floral subtractive library. Although BnC15 and BnATA20 genes have a different expression pattern in anthers demonstrated by in situ hybridization and real-time PCR analysis, silencing of both genes in B. napus by antisense suppression resulted in pollen abortion after microspore release. Light and electron microscopy observation revealed the lack of plastoglobuli, lipid bodies and sporopollenin secreted from the tapetum leading to aberrations in exine sculpturing and the formation of a pollen coat. In addition, the microspores were squeezed to the irregular shape in the locule in the end. As shown by gene expression analysis in transgenic plants and the comparison of anther development between bnc15 or bnata20 mutants and Rs1046A, BnC15 and BnATA20 were positively regulated downstream of Rf gene controlling the fertility of Rs1046B in the same pathway. The results support the hypothesis that BnC15 and BnATA20 are crucial components of a genetic network that controls tapetum development and exine sculpturing. PMID- 22841792 TI - Phylogenetic and molecular evolution of the ADAM (A Disintegrin And Metalloprotease) gene family from Xenopus tropicalis, to Mus musculus, Rattus norvegicus, and Homo sapiens. AB - ADAM (a disintegrin and metalloprotease) genes have been identified in various tissues and species, and recently associated with several important human diseases such as tumor and asthma. Although various biological processes have been known for the ADAM family in different species including fertilization, neurogenesis, infection and inflammation, little is known about its detailed phylogenetic and molecular evolutionary history. In this study, the ADAMs of Xenopus (Silurana) tropicalis, Mus musculus, Rattus norvegicus, and Homo sapiens were collected and analyzed by using the Bayesian analysis and gene synteny analysis to establish a comprehensive phylogenetic relationship and evolutionary drive of this gene family. It was found that there were more ADAMs in the two rodents than in the amphibian, suggesting an expansion of the ADAM gene family during the early evolution of mammals. All ADAMs from this expansion were retained in both the rodents, but other duplication events occurred subsequently in the two rodents, respectively, leading to the classification of rodent ADAMs as classes I, II and III. Moreover, these duplicated ADAM genes in the rodents were found to be driven by positive selection, which might be the major force to retain them in the genome. Importantly, it was also found that orthologs of ADAM3 and 5 have been lost in humans. These results not only provide valuable information of the evolution of ADAM genes, but may also help in understanding the role of ADAM genes in the pathobiology of relevant diseases. PMID- 22841794 TI - Cellular and vascular effects of the photodynamic agent temocene are modulated by the delivery vehicle. AB - The effects of the drug delivery system on the PDT activity, localization, and tumor accumulation of the novel photosensitizer temocene (the porphycene analogue of temoporfin or m-tetrahydroxyphenyl chlorin) were investigated against the P815 tumor, both in vitro and in DBA/2 tumor bearing mice. Temocene was administered either free (dissolved in PEG(400)/EtOH mixture), or encapsulated in Cremophor EL micelles or in DPPC/DMPG liposomes, chosen as model delivery vehicles. The maximum cell accumulation and photodynamic activity in vitro was achieved with the free photosensitizer, while temocene in Cremophor micelles hardly entered the cells. Notwithstanding, the micellar formulation showed the best in vivo response when used in a vascular regimen (short drug light interval), whereas liposomes were found to be an efficient drug delivery system for a tumor cell targeting strategy (long drug-light interval). PEG/EtOH formulation was discarded for further in vivo experiments as it provoked lethal toxic effects caused by photosensitizer aggregation. These results demonstrate that drug delivery systems modulate the vascular and cellular outcomes of photodynamic treatments with temocene. PMID- 22841793 TI - The constant region contributes to the antigenic specificity and renal pathogenicity of murine anti-DNA antibodies. AB - Affinity for DNA and cross-reactivity with renal antigens are associated with enhanced renal pathogenicity of lupus autoantibodies. In addition, certain IgG subclasses are enriched in nephritic kidneys, suggesting that isotype may determine the outcome of antibody binding to renal antigens. To investigate if the isotype of DNA antibodies affects renal pathogenicity by influencing antigen binding, we derived IgM, IgG1, IgG2b and IgG2a forms of the PL9-11 antibody (IgG3 anti-DNA) by in vitro class switching or PCR cloning. The affinity and specificity of PL9-11 antibodies for nuclear and renal antigens were analyzed using ELISA, Western blotting, surface plasmon resonance (SPR), binding to mesangial cells, and glomerular proteome arrays. Renal deposition and pathogenicity were assayed in mice injected with PL9-11 hybridomas. We found that PL9-11 and its isotype-switched variants had differential binding to DNA and chromatin (IgG3>IgG2a>IgG1>IgG2b>IgM) by direct and competition ELISA, and SPR. In contrast, in binding to laminin and collagen IV the IgG2a isotype actually had the highest affinity. Differences in affinity of PL9-11 antibodies for renal antigens were mirrored in analysis of specificity for glomeruli, and were associated with significant differences in renal pathogenicity in vivo and survival. Our novel findings indicate that the constant region plays an important role in the nephritogenicity of antibodies to DNA by affecting immunoglobulin affinity and specificity. Increased binding to multiple glomerular and/or nuclear antigens may contribute to the renal pathogenicity of anti-DNA antibodies of the IgG2a and IgG3 isotype. Finally, class switch recombination may be another mechanism by which B cell autoreactivity is generated. PMID- 22841796 TI - Induction of potent CD8+ T cell responses through the delivery of subunit protein vaccines to skin antigen-presenting cells using densely packed microprojection arrays. AB - The generation of both antibody and CD8+ T cell responses against pathogens is considered important for many advanced vaccines for diseases including tuberculosis, HIV and malaria. However, most current vaccines are delivered into muscle by the needle and syringe method and induce protection via humoral (antibody) immune responses. In this paper, we test the hypothesis that delivering a model subunit protein antigen (ovalbumin) to the skin's abundant immune cell population using a densely packed microprojection array (Nanopatch) enhances CD8+ T cell responses. We found that the Nanopatch significantly enhanced the CD8+ T cell responses when compared to intramuscular delivery of both antigen-only and adjuvanted cases (Quil-A and CpG; separately). To our knowledge, this is the first published study demonstrating significantly improved CD8+ T cell responses achieved by delivering subunit vaccines to the skin's abundant immune cell population. Successfully replicating these findings in humans could significantly advance the reach of vaccines. PMID- 22841795 TI - Nano-inside-micro: Disease-responsive microgels with encapsulated nanoparticles for intracellular drug delivery to the deep lung. AB - It is well appreciated that delivery of therapeutic agents through the pulmonary route could provide significant improvement in patient compliance and reduce systemic toxicity for a variety of diseases. Many inhalable drug formulations suffer from low respirable fractions, rapid clearance by alveolar macrophages, target non-specificity, and difficulty in combining aerodynamic properties with efficient cellular uptake. To overcome these challenges, we developed an enzyme responsive, nanoparticle-in-microgel delivery system. This system is designed to provide optimal aerodynamic carrier size for deep lung delivery, improved residence time of carriers in the lungs by avoiding rapid clearance by macrophages, and reduction of side effects and toxicity by releasing encapsulated therapeutics in response to disease-specific stimuli. This unique carrier system is fabricated using a new Michael addition during (water-in-oil) emulsion (MADE) method, especially suitable for biologic drugs due to its gentle fabrication conditions. The resulting microgels have a highly porous internal structure and an optimal aerodynamic diameter for effective deep lung delivery. They also exhibit triggered release of various nanoparticles and biologics in the presence of physiological levels of enzyme. In addition, the nanoparticle-carrying microgels showed little uptake by macrophages, indicating potential for increased lung residence time and minimal clearance by alveolar macrophages. Collectively, this system introduces a rationally designed, disease-specific, multi-tiered delivery system for use as an improved pulmonary carrier for biologic drugs. PMID- 22841798 TI - Production of Japanese encephalitis virus-like particles using the baculovirus insect cell system. AB - The production of a secreted form of Japanese encephalitis (JE) virus-like particles (VLPs) using the baculovirus-insect cell system was investigated. A recombinant baculovirus that contained the JE virus (JEV) prM signal sequence and the genes encoding the precursor (prM) of the viral membrane protein (M) and the envelope glycoprotein (E) was constructed. Western blotting and enzyme-linked immunosorbent assay (ELISA) of the culture supernatant showed that Spodoptera frugiperda Sf9 cells infected with the recombinant baculovirus had secreted the E protein. Sucrose density-gradient sedimentation analysis of the culture supernatant suggested that secreted E antigen molecules were in a particulate form. Baculovirus-infected Sf9 cells produced more than a 10-fold higher yield of E antigen than that produced by previously reported recombinant CHO cells. Following infection with a recombinant baculovirus encoding a form of prM with a pr/M cleavage site mutation designed to suppress cell-fusion activity of E, Sf9 cells showed an E antigen yield comparable to a yield obtained with the baculovirus encoding the authentic form of prM. Baculovirus-infected Trichoplusia ni BTI-TN-5B1-4 (High Five) cells secreted less of the E antigen than Sf9 cells. Moreover, the Drosophila BiP signal sequence gave an E antigen yield comparable to the prM signal sequence, while the honeybee melittin signal sequence and the baculovirus gp64 signal sequence resulted in lower yields of the E antigen. These results provide information important to the development of VLP production processes using the baculovirus-insect cell system. PMID- 22841799 TI - Social status, glucocorticoids, immune function, and health: can animal studies help us understand human socioeconomic-status-related health disparities? AB - For humans in developed nations, socioeconomic status (SES)--relative income, education and occupational position in a society--is a strong predictor of morbidity and mortality rates, with increasing SES predicting longer life span (e.g. Marmot et al., 1991). Mechanisms underlying this relationship have been examined, but the relative role of each mechanism still remains unknown. By understanding the relative role of specific mechanisms that underlie dramatic health disparities between high and low social status individuals we can begin to identify effective, targeted methods to alleviate health disparities. In the current paper, we take advantage of a growing number of animal studies that have quantified biological health-related correlates (glucocorticoid production and immune function) of social status and compare these studies to the current literature on human SES and health to determine if and how animal studies can further our understanding of SES-associated human health disparities. Specifically, we compared social-status related glucocorticoid production and immune function in humans and animals. From the review, we show that our present understanding of the relationships between social status and glucocorticoid production/immune function is still growing, but that there are already identifiable parallels (and non-parallels) between humans and animals. We propose timely areas of future study focused on (1) specific aspects of social status that may influence stress-related physiology, (2) mechanisms underlying long-term influences of social status on physiology and health, and (3) intervention studies to alleviate potentially negative physiological correlates of social status. PMID- 22841800 TI - Detection and identification of Rift Valley fever virus in mosquito vectors by quantitative real-time PCR. AB - Diagnostic methods allowing for rapid identification of pathogens are crucial for controlling and preventing dissemination after disease outbreaks as well as for use in surveillance programs. For arboviruses, detection of the presence of virus in their arthropod hosts is important for monitoring of viral activity and quantitative information is useful for modeling of transmission dynamics. In this study, molecular detection of Rift Valley fever virus (RVFV) in mosquito samples from the 2006 to 2007 East African outbreaks was performed using quantitative real-time PCR assay (qRT-PCR). Specific RVFV sequence-based primer/fluorogenic (TaqMan) probe sets were derived from the L and S RNA segments of the virus. Both primer-probe L and S segment-based combinations detected genomic RVFV sequences, with generally comparable levels of sensitivity. Viral loads from three mosquito species, Aedes mcintoshi, Aedes ochraceus and Mansonia uniformis were estimated and significant differences of between 5- and 1000-fold were detected between Ae. mcintoshi and M. uniformis using both the L and S primer-probe-based assays. The genetic relationships of the viral sequences in mosquito samples were established by partial M segment sequencing and assigned to the two previously described viral lineages defined by analysis of livestock isolates obtained during the 2006 2007 outbreak, confirming that similar viruses were present in both the vector and mammalian host. The data confirms the utility of qRT-PCR for identification and initial quantification of virus in mosquito samples during RVFV outbreaks. PMID- 22841801 TI - Mn-Ce-Co complex oxide nanoparticles: hydrothermal synthesis and their catalytic subcritical oxidation of 4,4'-Dibromobiphenyl. AB - In situ transformation of 4,4'-Dibromobiphenyl (4,4'-DBB) in water was observed with hydrothermal diamond anvil cell (HDAC) up to 633 K. It shows that 4,4'-DBB dissolves in water to form a homogenous phase at the temperature of 588 K and thus subcritical water oxidation of 4,4'-DBB higher than the temperature can be a homogenous phase. To accelerate the oxidative degradation, some Mn-Ce-Co complex oxide nanoparticles of about 100 nm were prepared by co-precipitation hydrothermal method. The nanoparticles show enough stability and catalytic activity for oxidative degradation of 4,4'-DBB in subcritical water. The catalytic activation increases with some Co doping and as for the complex oxides of Mn(1)Ce(1), Mn(0.9)Ce(1)Co(0.1), Mn(0.5)Ce(1)Co(0.5), Mn(0.1)Ce(1)Co(0.9), and Co(1)Ce(1), the Mn(0.9)Ce(1)Co(0.1) presents the best activation. The main intermediate products of degradation are benzoic acid and phenol. The apparent activation energy (E(a)) is 35.92 with 5% Mn(0.9)Ce(1)Co(0.1) as catalyst and 46.69 kJ/mol with no catalyst about the chemical oxygen demand (COD). PMID- 22841802 TI - Life stressors and barriers to timely prenatal care for women with high-risk pregnancies residing in rural and nonrural areas. AB - PURPOSE: To identify the contribution of life stressors and barriers to the untimely initiation of prenatal care for women with high-risk pregnancies living in rural and nonrural areas. METHODS: Data collected in 10 U.S. states by the 2006-2008 Pregnancy Risk Assessment Monitoring System (PRAMS) were used (n = 34,161). Data were weighted to reflect the PRAMS complex survey design. Separate logistic regression models derived adjusted odds ratios for untimely prenatal care initiation based on several life stressors and barriers. RESULTS: Women with high-risk pregnancies living in rural areas were more likely to report late initiation of prenatal care (17.5% vs. 14.6%). The most frequently reported life stressors were the same for both cohorts: Moving, having a very sick family member, arguing more than usual with their partners, and having bills they could not pay. The most frequently cited barriers were also the same for both groups: Not having enough money or insurance for health care visits and not being able to get an appointment when they wanted one. Having two or more barriers increased the risk of late prenatal care initiation by 2.85-fold for rural women and 2.01 fold for nonrural women. CONCLUSION: To increase timely prenatal care initiation, preconception interventions are needed that address common life stressors and barriers shared by women living in rural and nonrural areas. PMID- 22841803 TI - Social determinants of breast cancer screening in urban primary care practices: a community-engaged formative study. AB - BACKGROUND: The recent decline in the breast cancer mortality rate can be attributed to intensive screening and early detection efforts. However, studies have documented a decline in self-reported recent mammography use and interventions to enhance mammography utilization have yielded modest improvements. To address the root causes of breast cancer disparities and improve mammography use, interventions need to address multiple layers of patient, provider, and health system factors. OBJECTIVE: Using community-based participatory research principles, we sought to learn from women receiving care through urban primary care practices about issues surrounding mammography screening and strategies to increase screening. METHODS: We conducted five focus groups among 41 eligible women who were predominantly African American, recruited using nonprobability purposive sampling methods from urban community health centers in Baltimore, Maryland. Data are reported from three focus groups (n = 28) that provided usable data. We used the social determinants of health perspective to conduct a qualitative content analysis and interpretation of the data. RESULTS: Major obstacles to obtaining a screening mammogram were individual level (i.e., pain from the procedure) and structural-level factors (i.e., cost, geography, convenience). Strategies to overcome obstacles could include the creation of structural mechanisms whereby women can receive a host of services during one visit to a healthcare professional's office. Important promoters of screening behavior included social-level factors such as social support, hope, and positive treatment outcomes. CONCLUSION: The social determinants of health perspective provided a unique perspective to frame barriers and promoters of mammography utilization and insights to develop interventions aimed at improving cancer control among women receiving care at urban primary care health centers. PMID- 22841805 TI - Epidemiologically and clinically relevant Group B Streptococcus isolates do not bind collagen but display enhanced binding to human fibrinogen. AB - Group B Streptococcus (GBS) is the leading cause of neonatal septicemia and meningitis. Pili appendages were shown to play a critical role in bacterial adhesion and colonization of human tissues. Recently it was claimed that binding of the pilus-associated adhesin PilA to collagen is a critical, initial step in promoting interactions with the alpha2beta1 integrin expressed on brain endothelial cells. Here we show that strain NCTC10/84 used in this study is not representative for GBS isolates and question the importance of collagen as a critical extracellular matrix component for GBS infections of the central nervous system. PMID- 22841804 TI - Control of innate and adaptive immunity by the inflammasome. AB - The importance of innate immunity lies not only in directly confronting pathogenic and non-pathogenic insults but also in instructing the development of an efficient adaptive immune response. The Nlrp3 inflammasome provides a platform for the activation of caspase-1 with the subsequent processing and secretion of IL-1 family members. Given the importance of IL-1 in a variety of inflammatory diseases, understanding the role of the Nlrp3 inflammasome in the initiation of innate and adaptive immune responses cannot be overstated. This review examines recent advances in inflammasome biology with an emphasis on its roles in sterile inflammation and triggering of adaptive immune responses. PMID- 22841806 TI - Sonic hedgehog in the notochord is sufficient for patterning of the intervertebral discs. AB - The intervertebral discs, located between adjacent vertebrae, are required for stability of the spine and distributing mechanical load throughout the vertebral column. All cell types located in the middle regions of the discs, called nuclei pulposi, are derived from the embryonic notochord. Recently, it was shown that the hedgehog signaling pathway plays an essential role during formation of nuclei pulposi. However, during the time that nuclei pulposi are forming, Shh is expressed in both the notochord and the nearby floor plate. To determine the source of SHH protein sufficient for formation of nuclei pulposi we removed Shh from either the floor plate or the notochord using tamoxifen-inducible Cre alleles. Removal of Shh from the floor plate resulted in phenotypically normal intervertebral discs, indicating that Shh expression in this tissue is not required for disc patterning. In addition, embryos that lacked Shh in the floor plate had normal vertebral columns, demonstrating that Shh expression in the notochord is sufficient for pattering the entire vertebral column. Removal of Shh from the notochord resulted in the absence of Shh in the floor plate, loss of intervertebral discs and vertebral structures. These data indicate that Shh expression in the notochord is sufficient for patterning of the intervertebral discs and the vertebral column. PMID- 22841807 TI - Sex, stress and social status: patterns in fecal testosterone and glucocorticoid metabolites in male Ethiopian wolves. AB - Ethiopian wolves, Canis simensis, live in large multi-male family packs, where males are philopatric and do not disperse. Within a pack, mating and breeding is largely monopolized by the dominant male and female, although extra-pack copulations are common, and subordinate males may sire pups in neighboring packs. Regardless of paternity, all males in a pack help rear the pups. We non invasively studied patterns in fecal testosterone and glucocorticoid metabolite concentrations using radioimmunoassays of fecal samples collected from nine wild male Ethiopian wolves between August 2007 and February 2008. We tested the predictions of the Challenge Hypothesis, namely that fecal testosterone metabolite concentrations would be higher during the annual mating season, which is the portion of the reproductive cycle when mating and increased aggression typically occur, and lower when there were pups in the pack for which to care. Contrary to the predictions of the Challenge Hypothesis, we did not detect patterns in fecal testosterone metabolite concentrations associated with reproductive stage during our study period. Similarly, we found no patterns associated with reproductive stage in male fecal glucocorticoid metabolite concentrations. Dominant males had higher average fecal testosterone and glucocorticoid metabolite concentrations than did subordinates, which may be related to higher rates of aggression and mate guarding in dominant males of group-living canids, a pattern also reported in African wild dogs, Lycaon pictus. PMID- 22841808 TI - Antinociceptive properties of Micrurus lemniscatus venom. AB - The therapeutic potential of snake venoms for pain control has been previously demonstrated. In the present study, the antinociceptive effects of Micrurus lemniscatus venom (MlV) were investigated in experimental models of pain. The antinociceptive activity of MIV was evaluated using the writhing, formalin, and tail flick tests. Mice motor performance was assessed in the rota rod and open field tests. In a screening test for new antinociceptive substances--the writhing test--oral administration of MlV (19.7-1600 MUg/kg) produced significant antinociceptive effect. The venom (1600 MUg/kg) also inhibited both phases of the formalin test, confirming the antinociceptive activity. The administration of MlV (1600 MUg/kg) did not cause motor impairment in the rota rod and open field tests, which excluded possible non-specific muscle relaxant or sedative effects of the venom. The MIV (177-1600 MUg/kg) also increases the tail flick latency response, indicating a central antinociceptive effect for the venom. In this test, the MlV-induced antinociceptive effect was long-lasting and higher than that of morphine, an analgesic considered the gold standard. In another set of experiments, the mechanisms involved in the venom-induced antinociception were investigated through the use of pharmacological antagonists. The MlV (1600 MUg/kg) antinociceptive effect was prevented by naloxone (5 mg/kg), a non selective opioid receptor antagonist, suggesting that this effect is mediated by activation of opioid receptors. In addition, the pre-treatment with the MU-opioid receptor antagonist CTOP (1 mg/kg) blocked the venom antinociceptive effect, while the k-opioid receptor antagonist nor-BNI (0.5 mg/kg) or the delta-opioid receptor antagonist naltrindole (3 mg/kg) only partially reduced the venom induced antinociception. The present study demonstrates, for the first time, that oral administration of M. lemniscatus venom, at doses that did not induce any motor performance alteration, produced potent and long-lasting antinociceptive effect mediated by activation of opioid receptors. PMID- 22841809 TI - Insights into the global molecular epidemiology of carbapenem non-susceptible clones of Acinetobacter baumannii. AB - The global emergence of multidrug resistance (MDR) among Gram-negative bacteria has dramatically limited the therapeutic options. During the last two decades, Acinetobacter baumannii has become a pathogen of increased clinical importance due to its remarkable ability to cause outbreaks of infections and to acquire resistance to almost all currently used antibiotics, including the carbapenems. This review considers the literature on A. baumannii and data from multilocus sequence typing studies to explore the global population structure of A. baumannii and detect the occurrence of clonality, with the focus on the presence of specific resistance mechanisms such as the OXA-carbapenemases. The worldwide dissemination of MDR and carbapenem non-susceptible A. baumannii is associated with diverse genetic backgrounds, but predominated by a number of extensively distributed clones, such as CC92(B)/CC2(P) and CC109(B)/CC1(P), which have frequently been supplemented by acquired OXA-type carbapenemase genes. PMID- 22841810 TI - Potential new targets involved in 1,3-dinitrobenzene induced testicular toxicity. AB - 1,3-Dinitrobenzene (DNB) causes testicular injury, particularly to Sertoli cells, and induces apoptosis in the surrounding germinal cells in rodents; however, the mechanisms causing this toxicity are poorly understood. Our studies, using standard and molecular tools, were conducted to better understand the pathogenesis of the testicular effects. Four daily oral doses of 0.1-8mg/kg/day caused marked testicular lesions in rats from 4mg/kg/day. Global transcriptomics revealed cell cycle and cell death as the major biological processes affected with the expression of genes associated with cell cycle progression ("mitotic roles of polo-like kinase") being particularly altered. In a single dose time course study (4mg/kg), no adverse changes were recorded; however, in contrast to the data from the multiple dose study, plasma testosterone and testicular steroidogenesis-related gene expression were affected. These steroid hormone effects were confirmed in vitro using the H295R steroidogenesis assay. With this global approach we show that DNB not only induces apoptosis and interferes with cell cycle in the testes but that DNB can also modulate steroid hormone biosynthesis, suggesting an interference with the endocrine system. However, the contribution of the endocrine changes to the severe testicular lesions is presently unknown and requires further investigation. PMID- 22841811 TI - Pharmacokinetic change of nanoparticulate formulation "Lactosome" on multiple administrations. AB - Lactosome, which is a polymer micelle composed of poly(lactic acid)-b poly(sarcosine), was applied successfully for solid tumor imaging. Lactosome is considered to escape from the reticuloendothelial system recognition, and shows prolonged in vivo blood clearance time. In vivo disposition of Lactosome, however, changed upon multiple dosages. Lactosome at the 2nd dosage was cleared from the blood stream by trapping at liver. This accelerated blood clearance (ABC) phenomenon is explained by production of anti-Lactosome IgM and IgG(3) through the immune response related with B-lymphocyte cells. The memory effect of B-lymphocyte cells lasted nearly for six months in mouse. The epitope moiety of Lactosome is concluded to be poly(sarcosine) based on the competitive inhibition assay. Since the ABC phenomenon was also reported with PEGylated liposome, nanoparticles in general may be potential in triggering the immune system. PMID- 22841812 TI - Short sleep duration is associated with greater alcohol consumption in adults. AB - The objective of this cross-sectional study was to examine the association between sleep duration and alcohol consumption in adults (301 men and 402 women aged 18-64years) from the greater Quebec City area. Sleep duration (self reported), alcohol consumption (3-day food record and questions on drinking habits), and disinhibition eating behavior trait (score >= 6 on the Three-Factor Eating Questionnaire) were assessed. Participants were categorized as short- ( <= 6h), average- (7-8h) or long- ( >= 9h) duration sleepers. Overall, short-duration sleepers consumed significantly more alcohol than the two other sleep-duration groups. After adjusting for relevant covariates, short sleep duration was associated with an increase in the odds of exceeding the recommendations for sensible weekly alcohol intake of 14 drinks for men and 7 drinks for women compared to those sleeping between 7 and 8h (OR 1.87, 95%CI 1.03-3.54, both sexes combined). In both men and women, daily alcohol intake was significantly higher in short-duration sleepers having a high disinhibition eating behavior trait. However, the prevalence of a binge drinking occasion (i.e. >=5 drinks on one occasion) was more common in men than women. Men sleeping less than 6h per night with a disinhibited eating behavior were more likely to report binge drinking (41% of them). In summary, the combination of short sleep duration with disinhibited eating behavior is associated with greater alcohol intake in adults. PMID- 22841813 TI - Food after deprivation rewards the earlier eating. AB - Food intake can be increased by learning to anticipate the omission of subsequent meals. We present here a new theory that such anticipatory eating depends on an associative process of instrumental reinforcement by the nutritional repletion that occurs when access to food is restored. Our evidence over the last decade from a smooth-brained omnivore has been that food after deprivation rewards intake even when those reinforced ingestive responses occur long before the physiological signals from renewed assimilation. Effects of food consumed after self-deprivation might therefore reward extra eating in human beings, through brain mechanisms that could operate outside awareness. That would have implications for efforts to reduce body weight. This food reward mechanism could be contributing to the failure of the dietary component of interventions on obesity within controlled trials of the management or prevention of disorders such as hypertension, atherosclerosis and type 2 diabetes. PMID- 22841814 TI - Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome. AB - The regulatory peptide ghrelin has been proposed to help mediate both hunger and sleep. The neuroendocrine circadian patterns in the night eating syndrome (NES) have been distinguished by an attenuated nocturnal rise in the plasma concentrations of melatonin and leptin and a greater increase in the concentrations of cortisol. In this study we wanted to test the hypothesis that night eaters have disturbances in the circadian levels of ghrelin, growth hormone (GH) and associated regulatory peptides. In 12 female night eaters (6 normal weight and 6 overweight), and 25 healthy controls (12 normal weight and 13 overweight), blood was sampled over a 24-hour period. Four meals were served from 8 AM to 8 PM, and blood samples were drawn every second hour for determination of plasma ghrelin concentrations and GH by radioimmunoassay (RIA). Analysis of serum GH, IGF-1, IGFBP-3 and prolactin were performed by ELISA. In healthy normal weight subjects there was a slight but non significant nocturnal increase of ghrelin, whereas a more or less flat curve was observed for healthy overweight, NES normal weight and NES overweight patients. The RMANOVA analysis showed a significant independent lowering effect of overweight on the grand mean of ghrelin. No direct effects on NES normal weight and overweight subjects were found, but a near-significant interaction was found between healthy overweight and overweight NES subjects. There were independent significant lowering effects of overweight and NES on the serum GH levels. During the time course no changes in the serum levels of IGF-1 or IGFB-3 were observed. Independent significant lowering effects of overweight and NES on the levels of IGF-1 were detected, whereas a near significant reduction in the global levels of IGFBP-3 was observed in both NES groups. Finally, significant nocturnal changes were observed for serum levels of prolactin in all four subgroups. Grand mean levels tended to be higher in NES subjects whereas the opposite was observed in healthy overweight (ns). We conclude that in both NES groups and in healthy overweight subjects more or less attenuated ghrelin and GH secretions were observed, whereas divergent secretions were observed for prolactin. PMID- 22841815 TI - Consumer understanding, interpretation and perceived levels of personal responsibility in relation to satiety-related claims. AB - The aim of this study was to explore (a) whether and how consumers may (over-) interpret satiety claims, and (b) whether and to what extent consumers recognize that personal efforts are required to realize possible satiety-related or weight loss benefits. Following means-end chain theory, we explored for a number of satiety claims the extent of inference-making to higher-level benefits than actually stated in the claim, using internet-based questions and tasks. Respondents (N=1504) in U.K., France, Italy and Germany participated in the study. The majority of these respondents correctly interpret satiety-related claims; i.e. they largely limit their interpretation to what was actually stated. They do not expect a "magic bullet" effect, but understand that personal efforts are required to translate product attributes into potential weight control benefits. Less-restrained eaters were at lower risk for over-interpreting satiety related claims, whilst respondents with a stronger belief that their weight is something that they can control accept more personal responsibility, and better understand that personal efforts are required to be effective in weight control. Overall, these results indicate there is likely to be a relatively low level of consumer misinterpretation of satiety-related claims on food products. PMID- 22841816 TI - Adrenomedullin inhibits choroidal neovascularization via CCL2 in the retinal pigment epithelium. AB - The molecular mechanism that leads to age-related macular degeneration (AMD) is poorly understood. Gene expression profiling identified adrenomedullin (ADM) as a possible molecular target for the treatment of AMD and expression of ADM was upregulated in eyes with laser-induced choroidal neovascularization (CNV). In vivo experiments strongly indicated that ADM inhibits laser-induced CNV. In vitro tube formation assay demonstrated that neither ADM nor conditioned medium from the retinal pigment epithelial (RPE) cells, D407 cells, treated with ADM affected the capillary-formation of human umbilical vein endothelial cells. In contrast, in vitro macrophage migration assay clearly demonstrated that the conditioned medium of D407 inhibited macrophage migration. Furthermore, the expression of C-C motif chemokine 2 (CCL2) was significantly inhibited in D407 cells after ADM treatment. In vivo experiments using a laser-induced CNV model in ADM(+/-) mice demonstrated that CCL2 expression was upregulated in ADM(+/-) mice with concomitant increase in macrophage migration in the subretinal space. Additionally, the effect of ADM was abrogated in CCL2 knockout mice. These results suggest that administration of ADM inhibits macrophage migration in the subretinal space and leads to the suppression of laser-induced CNV in an animal model. The inhibition of macrophage migration occurred through the CCL2 from RPE. This study provides a novel potential therapeutic target for AMD which does not substantially disrupt VEGF-A signaling mediated vasculogenesis. PMID- 22841817 TI - MutT homolog-1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration. AB - Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro 2'-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP. PMID- 22841818 TI - Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease. AB - Thrombin generation is increased in patients with nonalcoholic fatty liver disease (NAFLD) and in mouse models of diet-induced obesity. Deficiency in the thrombin receptor protease activated receptor-1 reduces hepatic inflammation and steatosis in mice fed a Western diet. However, it is currently unclear whether thrombin inhibitors can modify the pathogenesis of established NAFLD. We tested the hypothesis that thrombin inhibition could reverse hepatic steatosis and inflammation in mice with established diet-induced NAFLD. Low-density lipoprotein receptor-deficient LDLr(-/-) mice were fed a control diet or a Western diet for 19 weeks. Mice were given the direct thrombin inhibitor argatroban ~15 mg/kg/day or its vehicle via a miniosmotic pump for the final 4 weeks of the study. Argatroban administration significantly reduced hepatic proinflammatory cytokine expression and reduced macrophage and neutrophil accumulation in livers of mice fed a Western diet. Argatroban did not significantly impact hepatic steatosis, as indicated by histopathology, Oil Red O staining, and hepatic triglyceride levels. Argatroban reduced serum triglyceride and cholesterol levels in mice fed a Western diet. Argatroban reduced both alpha-smooth muscle actin expression and Type 1 collagen mRNA levels in livers of mice fed a Western diet, indicating reduced activation of hepatic stellate cells. This study indicates that therapeutic intervention with a thrombin inhibitor attenuates hepatic inflammation and several profibrogenic changes in mice fed a Western diet. PMID- 22841819 TI - Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment. AB - X-linked myotubular myopathy is a severe congenital myopathy caused by deficiency of the lipid phosphatase, myotubularin. Recent studies of human tissue and animal models have discovered structural and physiological abnormalities in myotubularin deficient muscle, but the impact of myotubularin deficiency on myogenic stem cells within muscles is unclear. In the present study, we evaluated the viability, proliferative capacity, and in vivo engraftment of myogenic cells obtained from severely symptomatic (Mtm1delta4) myotubularin-deficient mice. Mtm1delta4 muscle contains fewer myogenic cells than wild-type (WT) littermates, and the number of myogenic cells decreases with age. The behavior of Mtm1delta4 myoblasts is also abnormal, because they engraft poorly into C57BL/6/Rag1null/mdx5cv mice and display decreased proliferation and increased apoptosis compared with WT myoblasts. Evaluation of Mtm1delta4 animals at 21 and 42 days of life detected fewer satellite cells in Mtm1delta4 muscle compared with WT littermates, and the decrease in satellite cells correlated with progression of disease. In addition, analysis of WT and Mtm1delta4 regeneration after injury detected similar abnormalities of satellite cell function, with fewer satellite cells, fewer dividing cells, and increased apoptotic cells in Mtm1delta4 muscle. These studies demonstrate specific abnormalities in myogenic cell number and behavior that may relate to the progression of disease in myotubularin deficiency, and may also be used to develop in vitro assays by which novel treatment strategies can be assessed. PMID- 22841820 TI - Soluble human IL-1 receptor type 2 inhibits ectopic endometrial tissue implantation and growth: identification of a novel potential target for endometriosis treatment. AB - Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokine's elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (alphav and beta3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 MUg/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool. PMID- 22841821 TI - Prospective treatment of age-related diseases by slowing down aging. AB - Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age related diseases is that it inhibits the aging process. PMID- 22841822 TI - Leptin deficiency contributes to the pathogenesis of alcoholic fatty liver disease in mice. AB - White adipose tissue (WAT) secretes adipokines, which critically regulate lipid metabolism. The present study investigated the effects of alcohol on adipokines and the mechanistic link between adipokine dysregulation and alcoholic fatty liver disease. Mice were fed alcohol for 2, 4, or 8 weeks to document changes in adipokines over time. Alcohol exposure reduced WAT mass and body weight in association with hepatic lipid accumulation. The plasma adiponectin concentration was increased at 2 weeks, but declined to normal at 4 and 8 weeks. Alcohol exposure suppressed leptin gene expression in WAT and reduced the plasma leptin concentration at all times measured. There is a highly positive correlation between plasma leptin concentration and WAT mass or body weight. To determine whether leptin deficiency mediates alcohol-induced hepatic lipid dyshomeostasis, mice were fed alcohol for 8 weeks with or without leptin administration for the last 2 weeks. Leptin administration normalized the plasma leptin concentration and reversed alcoholic fatty liver. Alcohol-perturbed genes involved in fatty acid beta-oxidation, very low-density lipoprotein secretion, and transcriptional regulation were attenuated by leptin. Leptin also normalized alcohol-reduced phosphorylation levels of signal transducer Stat3 and adenosine monophosphate activated protein kinase. These data demonstrated for the first time that leptin deficiency in association with WAT mass reduction contributes to the pathogenesis of alcoholic fatty liver disease. PMID- 22841823 TI - Mitochondrial heat shock protein-90 modulates vascular smooth muscle cell survival and the vascular injury response in vivo. AB - The healing response of blood vessels from the vascular injury induced by therapeutic interventions is characterized by increased cellularity and tissue remodeling. Frequently, this leads to intimal hyperplasia and lumen narrowing, with significant clinical sequelae. Vascular smooth muscle cells are the primary cell type involved in this process, wherein they express a dedifferentiated phenotype that transiently resembles neoplastic transformation. Recent studies have highlighted the role of mitochondrial proteins, such as the molecular chaperone heat shock protein-90 (Hsp90), in promoting cancer cell survival, which leads to new candidate chemotherapeutic agents for neoplastic disease. Herein, we identify mitochondrial Hsp90 as a key modulator of the vascular injury response. Hsp90 expression is up-regulated in injured arteries and colocalizes with the apoptosis inhibitor, survivin, in vascular smooth muscle cell in vitro and in vivo. By using a proteomic approach, we demonstrate that targeted disruption of mitochondrial Hsp90 chaperone function in vascular smooth muscle cell leads to loss of cytoprotective client proteins (survivin and Akt), induces mitochondrial permeability, and leads to apoptotic cell death. Hsp90 targeting using a cell permeable peptidomimetic agent resulted in marked attenuation of neointimal lesions in a murine arterial injury model. These findings suggest that mitochondrial Hsp90 chaperone function is an important regulator of intimal hyperplasia and may have implications for molecular strategies that promote the long-term patency of cardiovascular interventions. PMID- 22841824 TI - Social context decouples the relationship between a sexual ornament and testosterone levels in a male wild bird. AB - In order to maximise fitness individuals should adjust their level of signalling according to their surrounding social environment. However, field experiments showing such adjustment of current signalling associated to changes in social context are lacking. Here, we manipulated levels of male aggressive- and dominance-related displays in a wild bird in our treated area by increasing testosterone levels using implants in a subset of males. We then compared the expression of sexual signals (i.e. comb size) between non-treated red grouse Lagopus lagopus scoticus males from control and treatment areas. We further explored the potential endocrinological mechanism linking social environment and signal expression by analysing testosterone levels in all males. Our treatment successfully increased overall aggressive- and dominance-related behaviours in the treatment area. Furthermore, testosterone-implanted birds increased their comb size as repeatedly shown in previous studies in male red grouse. Interestingly, untreated males living in the treatment area decreased their comb size, whilst increasing testosterone levels. Since comb size is a signal of dominance, untreated males from the treatment area may have perceived themselves as subordinate individuals and decreased their signalling levels to avoid confrontations with testosterone-treated, dominant individuals. In conclusion, our findings show that social context has the potential to regulate sexual signalling and testosterone levels. Our results highlight the role of social context when exploring the link between testosterone and behaviour, as it may reverse the relationship between both traits. Our results suggest that social context affects signalling and testosterone independently. PMID- 22841825 TI - Processes and outcomes of developing a continuity of care document for use as a personal health record by people living with HIV/AIDS in New York City. AB - PURPOSE: To describe the processes and outcomes of developing and implementing a Continuity of Care Document (CCD), My Health Profile, as a personal health record for persons living with HIV (PLWH) in an HIV/AIDS Special Needs Plan in New York City. METHODS: Multiple qualitative and quantitative data sources were used to describe the processes and outcomes of implementing My Health Profile including focus groups, Audio Computer Assisted Self Interview (ACASI) surveys, administrative databases, chart abstraction, usage logs, and project management records. Qualitative data were thematically analyzed. Quantitative data analytic methods included descriptive and multivariate statistics. Data were triangulated and synthesized using the Reach, Efficacy/Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) Framework. RESULTS: Reach - SNP members are predominantly African American or Hispanic/Latino and about one-third are female. A larger proportion of African Americans and smaller proportions of Hispanics/Latinos and Whites were trained to use My Health Profile.Efficacy/Effectiveness - CCDs were produced for 8249 unique members and updated on a monthly basis, 509 members were trained to use My Health Profile. Total number of member logins for 112 active users was 1808 and the longest duration of use was 1008 days. There were no significant differences between users and non-users of My Health Profile in clinical outcomes, perceptions of the quality of medical care, or health service utilization. Adoption -My Health Profile was well-matched to organizational mission, values, and priorities related to coordination of care for a high-risk population of PLWH. Implementation - Pre-implementation focus group participants identified potential barriers to use of My Health Profile including functional and computer literacy, privacy and confidentiality concerns, potential reluctance to use technology, and cognitive challenges. Key strategies for addressing barriers included a dedicated bilingual coach for recruitment, training, and support; basic computer and My Health Profile training; transparent audit trail revealing clinician and case manager access of My Health Profile, time-limited passwords for sharing My Health Profile with others at the point of need, and emergency access mechanism. Maintenance -My Health Profile was integrated into routine operational activities and its sustainability is facilitated by its foundation on standards for Health Information Exchange (HIE). CONCLUSIONS: Although potential barriers exist to the use of personal health records (PHRs) such as My Health Profile, PLWH with complex medical needs, low socioeconomic status, and limited computer experience will use such tools when a sufficient level of user support is provided and privacy and confidentiality concerns are addressed. PMID- 22841826 TI - One-pot preparation of methyl levulinate from catalytic alcoholysis of cellulose in near-critical methanol. AB - One-pot preparation of methyl levulinate (MLA) from cellulose in near-critical methanol was studied. Acids containing SO(3)H group were proven to be effective catalysts for the production of MLA from cellulose's catalytic alcoholysis. The effects of different reaction conditions, such as an initial cellulose concentration of 10-30 g/L, a temperature range from 170 to 190 degrees C, and a sulfuric acid concentration of 0.01-0.03 mol/L, on the production of MLA were investigated. The results showed the reaction temperature and acid concentration significantly affected the process of cellulose alcoholysis and the yield of MLA. A high yield of up to 55% MLA was achieved at 190 degrees C for 5h, using 0.02 mol/L H(2)SO(4) as a catalyst. PMID- 22841828 TI - Arrhythmogenic mechano-electric heterogeneity in the long-QT syndrome. AB - Since the first linkage of the long-QT syndrome to the Harvey ras-1 gene in 1991 ample research has been performed to decipher the molecular-biophysical basis of congenital repolarization defects and the electrophysiological mechanisms of torsades-de-pointes arrhythmias in this condition. Mechanistic knowledge is mostly derived from cellular experiments (cardiac myocytes, cultured cells), ventricular tissue (including arterially-perfused wedge) preparations and Langendorff-perfused hearts, with relatively little information from in-vivo animal models, and even more scant intact human-heart investigations. Until now, much emphasis has been put on purely membrane-related pathways of arrhythmia initiation with a prominent role for spatiotemporal dispersion of repolarization, early afterdepolarizations and reentrant excitation. Here, we review additional factors that influence the onset of torsades de pointes, notably myocardial Ca2+ (over) loading and spontaneous SR Ca2+ release, occurring particularly during intense sympathetic nervous stimulation and dynamic cycle-length changes. Recent tissue and in-vivo data suggest that spontaneous SR Ca2+ release, underlying aftercontractions in the isolated myocyte, may organize to local myocardial Ca2+ waves and aftercontractions in the intact heart. In the setting of prolonged repolarization and a negative electromechanical window, these spontaneous [Ca2+](cyt)-based events (which often arise during early diastole) may exaggerate repolarization instability via [Ca2+](cyt)-activated inward membrane currents and, as we postulate, via mechano-sensitive ion currents. Future long-QT research should focus on the intact beating heart with preserved autonomic input to examine these arrhythmogenic mechanisms. PMID- 22841827 TI - Cannabinoid 2 receptor- and beta Arrestin 2-dependent upregulation of serotonin 2A receptors. AB - Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP55,940) or selective CB2 receptor agonists (JWH133 or GP1a) upregulate 5-HT(2A) receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT(2A) receptors was prevented in cells stably transfected with either CB2 or beta-Arrestin 2 shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis also prevented the cannabinoid receptor-induced upregulation of 5-HT(2A) receptors. Our results indicate that cannabinoid agonists might upregulate 5-HT(2A) receptors by a mechanism that requires CB2 receptors and beta-Arrestin 2 in cells that express both CB2 and 5 HT(2A) receptors. 5-HT(2A) receptors have been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to some cognitive and mood disorders in humans. PMID- 22841829 TI - Upregulation of temperature susceptibility in Bemisia tabaci upon acquisition of Tomato yellow leaf curl virus (TYLCV). AB - Acquisition of plant viruses has various effects on physiological mechanisms in vector insects. Bemisia tabaci is the only known vector of Tomato yellow leaf curl virus (TYLCV), which is a serious virus affecting tomato cultivars. In this study, the lifespan of Q1 biotype was compared between non-viruliferous (NV) and TYLCV-viruliferous (V) whiteflies. Total lifespan from egg to adult death of NV whiteflies was 62.54 days but 10.64 days shorter in V whiteflies. We investigated the temperature susceptibility of B. tabaci by comparing mortalities as well as heat shock protein (hsp) mRNA levels between NV and V whiteflies. For this, NV and V whiteflies were exposed for either 1 or 3h at 4, 25, and 35 degrees C. The mortality of V whiteflies was higher than NV ones following exposure at either 4 or 35 degrees C, but there was no significant difference at 25 degrees C. Analysis of the expression level of heat shock protein (hsp) genes using quantitative real-time PCR showed that both cold and heat shock treatments stimulated higher expression of hsps (hsp40, hsp70, and hsp90) at various rates in V whiteflies than NV ones, but there was no difference at 25 degrees C. All together, our results show that TYLCV acquisition accelerated the developmental rate and increased susceptibility to thermal stress in B. tabaci. Therefore, this modification may result in reduced vector longevity due to increased metabolic energy utilization. Our results provide insights into the complex interaction between vector fitness and thermal stress in relation to the acquisition and transmission of plant viruses. PMID- 22841831 TI - OxLDL stimulates Id1 nucleocytoplasmic shuttling in endothelial cell angiogenesis via PI3K pathway. AB - Angiogenesis plays remarkable roles in the development of atherosclerotic rupture plaques. However, its essential mechanism remains unclear. The purpose of the study was to investigate whether inhibitor of DNA binding-1 or inhibitor of differentiation 1 (Id1) promoted angiogenesis when exposed to oxidised low density lipoprotein (oxLDL), and to determine the molecular mechanism involved. Using aortic ring assay and tube formation assay as a model system, a low concentration of oxLDL was found to induce angiogenic sprouting and capillary lumen formation of endothelial cell. But the Id1 expression was significantly upregulated by oxLDL at low and high concentrations. The Id1 was localised in the nuclei of the human umbilical vein endothelial cells in the control group and in the high-concentration oxLDL group. Id1 was translocated to the cytoplasm at low oxLDL concentrations. The nucleocytoplasmic shuttling at low oxLDL concentration was inhibited by treatment with the nuclear export inhibitor leptomycin B. Protein kinase A (PKA) inhibitor H89 promoted nuclear export of Id1, and phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 reduced the nuclear export of Id1. PI3K inhibition blocked oxLDL-induced angiogenesis. Low concentrations of oxLDL promoted angiogenic sprouting and capillary formation. And this process depends on nuclear export of Id1, which in turn is controlled by the PI3K pathway. This report presents a new link between oxLDL and Id1 localisation, and may provide a new insight into the interactions of ox-LDL and Id1 in the context of atherosclerosis. PMID- 22841830 TI - Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. AB - Human synovial fluid (SF) provides nutrition and lubrication to the articular cartilage. Particularly in arthritic diseases, SF is extensively accumulating in the synovial junction. During the last decade lipids have attracted considerable attention as their role in the development and resolution of diseases became increasingly recognized. Here, we describe a capillary LC-MS/MS screening platform that was used for the untargeted screening of lipids present in human SF of rheumatoid arthritis (RA) patients. Using this platform we give a detailed overview of the lipids and lipid-derived mediators present in the SF of RA patients. Almost 70 different lipid components from distinct lipid classes were identified and quantification was achieved for the lysophosphatidylcholine and phosphatidylcholine species. In addition, we describe a targeted LC-MS/MS lipid mediator metabolomics strategy for the detection, identification and quantification of maresin 1, lipoxin A(4) and resolvin D5 in SF from RA patients. Additionally, we present the identification of 5S,12S-diHETE as a major marker of lipoxygenase pathway interactions in the investigated SF samples. These results are the first to provide a comprehensive approach to the identification and profiling of lipids and lipid mediators present in SF and to describe the presence of key anti-inflammatory and pro-resolving lipid mediators identified in SF from RA patients. PMID- 22841832 TI - PE-Cy5.5 conjugates bind to the cells expressing mouse DEC205/CD205. AB - DEC205/CD205, an endocytic receptor of C-type multilectin, is expressed highly in dendritic cells (DCs). DEC205 was shown to efficiently deliver vaccine antigens in surrogate ligands to the antigen processing and presentation machinery of DCs, which resulted in the development of DC-targeted vaccines employing anti-DC monoclonal antibodies (mAbs). During our studies to characterize a variety of anti-DC mAbs including anti-DEC205 by flow cytometric analysis, we discovered that a secondary anti-immunoglobulin antibody conjugated with PE-Cy5.5 bound strongly to the cells expressing mouse DEC205 (mDEC205) without incubation of a primary anti-mDEC205 mAb. In the present study we demonstrate that various antibodies and streptavidin conjugated with PE-Cy5.5 bind to the mDEC205 expressing cells including CHO, KIT6, and HEK293 cells. The interaction between the PE-Cy5.5 conjugates and the cells expressing mDEC205 appears distinctive, since none of the PE-Cy5.5 conjugates bind to the cells that express human DEC205 on surface. Besides, only PE-Cy5.5 conjugates bind strongly to mDEC205-expressing cells; PerCP-Cy5.5, APC-Cy5.5, and Cy5.5 conjugates bind weakly; PE, PE-Cy5, Cy5, FITC, or Alexa488 conjugates do not bind to mDEC205-expressing cells. Therefore the use of PE-Cy5.5 conjugates, widely utilized in multicolor flow cytometry, requires precaution against nonspecific binding to mDEC205-positive cells. PMID- 22841833 TI - Oxidative stress and glutathione response in tissue cultures from persons with major depression. AB - There is evidence that major depressive disorder (MDD) is associated with increased peripheral markers of oxidative stress. To explore oxidation and antioxidant response in MDD, we assayed human dermal fibroblast cultures derived from skin biopsies of age-, race-, and sex-matched individuals in depressed and normal control groups (n = 16 each group), cultured in glucose and galactose conditions, for relative protein carbonylation (a measure of oxidative stress), glutathione reductase (GR) expression, and total glutathione concentration. In control-group fibroblasts, galactose induced a significant increase from the glucose condition in both protein carbonylation and GR. The cells from the MDD group showed total protein carbonylation and GR expression in the glucose condition that was significantly higher than control cells in glucose and equivalent to controls in galactose. There was a small decrease in protein carbonylation in MDD cells from glucose to galactose and no significant change in GR. There was no difference in total glutathione among any of the groups. Increased protein carbonylation and GR expression, cellular responses to oxidative stress induced by galactose in control fibroblasts, are present in fibroblasts derived from MDD patients and are not explainable by reduced GR or total glutathione in the depressed patients. These studies support the role of oxidative stress in the pathophysiology of MDD. Further confirmation of these findings could lead to the development of novel antioxidant approaches for the treatment of depression. PMID- 22841834 TI - Netrin ligands and receptors: lessons from neurons to the endothelium. AB - Netrins were initially identified as secreted ligands regulating axon guidance and migration through interaction with canonical receptors. Netrins were then shown to be necessary for development of a range of tissues, including lung, mammary gland, and the vasculature. While new netrin receptors, as well as alternative ligands for classical netrin receptors, were described in the neuronal and epithelial fields, there was a singular focus on canonical netrin receptors in the vascular system, leading to controversy on netrin function and the nature of receptor-mediated netrin signaling in the endothelium. Here, we summarize the current state of knowledge on netrin ligands and receptors and discuss questions, controversies, and perspectives surrounding netrin functions and receptor identity in the vasculature. PMID- 22841836 TI - The emerging role of epigenetic modifiers linking cellular metabolism and gene activity in cardiac progenitor cells. AB - During mammalian heart development, cardiac gene expression is controlled by a complex network consisting of signaling pathways, cardiac transcription factors, and epigenetic modifiers. Emerging evidence suggests that epigenetic modifying enzymes sense and respond to metabolic cues, thereby translating environmental stimuli to cardiac gene expression patterns. Here, we review the impact of metabolic cues on epigenetic changes and survey how epigenetic changes, including DNA modifications, histone modifications, and ATP-dependent chromatin remodeling, affect recruitment of progenitor cells into the cardiac lineage. We reason that a better understanding of epigenetic control mechanisms regulating cardiac gene expression will improve reprogramming strategies to generate cardiovascular cells for therapeutic applications. PMID- 22841835 TI - Pannexin 1 in the regulation of vascular tone. AB - Pannexins are a recently discovered protein family with the isoform Panx1 ubiquitously expressed and therefore extensively studied. Panx1 proteins form membrane channels known to release purines such as ATP. Because ATP and, more generally, purinergic signaling plays an important role in the vasculature, it became evident that Panx1 could have a key role in vascular functions. This article reviews recent findings on the pivotal role of Panx1 in smooth muscle cells in the contraction of arteries as well as recent insights into Panx1 channel regulation. PMID- 22841837 TI - HOXC9: a key regulator of endothelial cell quiescence and vascular morphogenesis. AB - The members of the HOX transcription factor family are important basic regulators of morphogenesis and development and several HOX proteins have also been identified as essential regulators of physiological and pathologic angiogenesis. HOXC9 is highly expressed in quiescent endothelial cells and keeps the vasculature in a resting state via inhibition of interleukin-8 production. HOXC9 overexpression in zebra-fish negatively regulated vascular development which can be rescued by exogenous interleukin-8. The further understanding of the HOXC9-IL 8 signaling axis and the identification of other HOXC9 targets in the vasculature will provide important insights into mechanisms promoting endothelial cell activation during physiological angiogenesis. It will also be beneficial to understand pathophysiological angiogenesis regulation and thus provide important new directions for the development of novel anti-angiogenic therapeutic strategies. PMID- 22841838 TI - On mechanosensation, acto/myosin interaction, and hypertrophy. AB - Current concepts of mechanosensation are general and applicable to almost every cell type. However, striated muscle cells are distinguished by their ability to generate strong forces via actin/myosin interaction, and this process is fine tuned for optimum contractility. This aspect, unique for actively contracting cells, may be defined as "sensing of the magnitude and dynamics of contractility," as opposed to the well-known concepts of the "perception of extracellular mechanical stimuli." The acto/myosin interaction, by producing changes in ATP, ADP, Pi, and force on a millisecond timescale, may be regarded as a novel and previously unappreciated mechanosensory mechanism. In addition, sarcomeric mechanosensory structures, such as the Z-disc, are directly linked to autophagy, survival, and cell death-related pathways. One emerging example is telethonin and its ability to interfere with p53 metabolism and hence apoptosis (mechanoptosis). In this article, we introduce contractility per se as an important mechanosensory mechanism, and we differentiate extracellular from intracellular mechanosensory effects. PMID- 22841839 TI - Target of rapamycin (TOR)-based therapy for cardiomyopathy: evidence from zebrafish and human studies. AB - Rapamycin is a U.S. Food and Drug Administration-approved drug for the prevention of immunorejection following organ transplantation. Pharmacological studies suggest a potential new application of rapamycin in attenuating cardiomyopathy, but the potential for this application is not yet supported by genetic studies of genes in target of rapamycin (TOR) signaling in rodents. Recently, supporting genetic evidence was presented in zebrafish using two adult cardiomyopathy models. By characterizing a heterozygous zebrafish target of rapamycin (ztor) mutant, the therapeutic effect of long-term TOR signaling inhibition was demonstrated. Dose- and stage-dependent functions of TOR signaling provide an explanation for the seemingly contradictory results obtained in genetic studies of TOR components in rodents. The results from the zebrafish studies, together with the supporting preliminary clinical studies, suggested that TOR signaling inhibition should be further pursued as a novel therapeutic strategy for cardiomyopathy. Future directions for developing TOR-based therapy include assessing the long-term benefits of rapamycin as a candidate drug for heart failure patients, defining the dynamic activity of TOR, exploring the impacts of TOR signaling manipulation in different models of cardiomyopathies, and elucidating the downstream signaling branches that confer the therapeutic effects of TOR signaling inhibition. PMID- 22841840 TI - Another view of personalized medicine: optimizing stent selection on the basis of predicted benefit in percutaneous coronary intervention. AB - Drug-eluting stents (DES) decrease the risk of restenosis compared to bare metal stents (BMS) for percutaneous coronary intervention (PCI). However, their use requires patients to take prolonged dual antiplatelet therapy that increases bleeding risk and without which, patients have an increased risk of developing stent thrombosis. In light of these competing risks, understanding which patients derive the greatest benefit of DES compared to BMS is essential for guiding therapy. We review recent efforts to predict the magnitude of the restenosis benefit of DES compared to BMS for individual patients. Understanding and predicting the likelihood of benefit for individual patients is essential to rational decision making with regard to the type of stent to use during PCI and will serve to increase the value of the health care that clinicians deliver. PMID- 22841841 TI - Protective role of natural IgM-producing B1a cells in atherosclerosis. AB - Atherosclerosis initiated by hyperlipidemia is modulated by immune cells in its development, progression, and rupture that results in thrombotic arterial occlusion leading to strokes and myocardial infarction. B cells initially thought to be atheroprotective provide opposing roles by their different subsets. Unlike B2 cells that are atherogenic, serosal B1a cells are atheroprotective by producing natural IgM antibodies that clear modified low-density lipoprotein and apoptotic and necrotic debris. In addition to natural IgM antibodies, B1a cells may act as regulatory B cells by producing the anti-inflammatory cytokine interleukin-10, which inhibits proinflammatory cytokines secreted by activated macrophages and T cells in atherosclerotic lesions. These findings suggest in vivo expansion of atheroprotective B1a cells as a potential therapeutic strategy to augment the benefits of lipid-lowering statin therapy. PMID- 22841842 TI - Age, drugs, or disease: what alters the macrostructure of sleep in Parkinson's disease? AB - OBJECTIVE: To describe the alterations in the macrostructure of sleep in a large cohort of sleep-disturbed patients with Parkinson's disease (PD) and investigate influencing factors. METHODS: A cohort of sleep-disturbed but otherwise unselected PD patients (n=351) was investigated with video-supported polysomnography. We analyzed the influence of age, disease duration, disease severity, and dopaminergic medication on subjective sleep perception, sleep efficiency, the amount of slow wave sleep, awakenings, periodic leg movements in sleep (PLMS), and REM sleep behavior disorder (RBD). RESULTS: Sleep efficiency and slow wave sleep decreased with age (p=0.003 and p=0.041, respectively). The number of awakenings and the frequency of RBD increased with age (p=0.028 and p=0.006, respectively). Higher Hoehn & Yahr stages were associated with more PLMS (p=0.017). A higher daily dose of levodopa corresponded to more RBD (p<0.001). Neither disease duration nor levodopa dosage had any influence on sleep efficiency, slow wave sleep, awakenings, or PLMS. Dopamine agonists increased awakenings (p<0.001) and lowered PLMS (p<0.001). Subjective sleep perception was not influenced by any of the factors analyzed. The only path model that could be replicated identified disease severity and dopamine agonists as interdependent factors influencing awakenings and PLMS. CONCLUSION: Age leads to less sleep and a higher risk for RBD, and disease severity increases motor phenomena such as PLMS; dopamine agonists reduce PLMS but increase awakenings. No single factor analyzed influenced subjective sleep perception in this cohort of sleep disturbed PD patients. PMID- 22841843 TI - Melatonin profile and its relation to circadian rhythm sleep disorders in Angelman syndrome patients. AB - BACKGROUND: Sleep problems are known to be common in Angelman syndrome (AS), a neurodevelopmental disorder which is associated with an abnormality of chromosome 15q11-q13. However, the circadian aspect of sleep disorders in AS and an effective treatment for the disorder have yet to be established. METHODS: We elucidated the sleep-wake patterns of AS patients and its relationship to the serum melatonin levels. The serum melatonin levels of 15 AS patients were measured every 4h for one day and the values were compared with those of age matched controls. We also examined the effectiveness of the oral administration of melatonin on AS patients with circadian rhythm sleep disorders (CRSD). RESULTS: A total of eight of the 15 AS patients had CRSD (irregular sleep-wake type, n=4; free-running type n=2; delayed sleep phase type, n=2). The nighttime serum melatonin levels of the AS patients were significantly lower than those of the controls at the measured time points during the night. The nocturnal melatonin levels were comparably low both in AS patients with and without CRSD except for the cases with delayed sleep phase type, which showed normal but delayed peak melatonin level. Six out of eight CRSD cases were given a daily dose of 1mg of melatonin between 18:00 and 19:00 regularly for three months. After receiving the treatment, the sleep patterns improved in four cases. CONCLUSION: This study revealed a high prevalence of CRSD in AS patients, which may be related to abnormal serum melatonin profiles. PMID- 22841844 TI - HSV IgG antibody inhibits virus detection in CSF. AB - BACKGROUND: Before PCR testing of cerebrospinal fluid (CSF), laboratory diagnosis of herpes encephalitis (HSE) was based on virus isolation from brain biopsy. Viral isolation from CSF has limited clinical value due to low virus recovery; the cause for which has not been demonstrated. OBJECTIVE: To investigate the role of anti-HSV antibodies on recovery of HSV from CSF via cell culture. STUDY DESIGN: HSV-positive CSF samples were evaluated for their ability to neutralize HSV in cell culture. The presence of HSV-specific IgG and IgM antibodies were analyzed using HSV-infected cells. To identify whether HSV-specific IgG is the cause of viral inhibition, IgG was removed using anti-human IgG magnetic beads. Viral inhibition from CSF originating from asymptomatic patients was examined as a comparison. RESULTS: CSF from 13 patients with acute HSV CNS disease was analyzed. All displayed high levels of viral neutralization to both HSV-1 and HSV 2 regardless of the infecting subtype. Interestingly, all the CSF samples stained strongly for anti-IgG antibody but none for anti-IgM antibody. Removal of IgG from CSF eliminated the viral inhibitory activity. Neutralizing IgG antibody was also found to be common in CSF of most patients, even in the absence of HSV disease. CONCLUSIONS: Viral specific IgG is the major determinant of viral inhibition in CSF and prevents virus recovery in cell culture. In CSF from HSE un infected patients, viral inhibitory IgG originates from circulating serum antibody and is commonly present in CSF. However, this inhibitory IgG is not protective for the development of HSV disease. PMID- 22841845 TI - In vitro and in vivo stability and pharmacokinetic profile of unacylated ghrelin (UAG) analogues. AB - Ghrelin, an endocrine hormone predominantly produced by the stomach, exists in acylated and unacylated forms in the circulation. Unacylated ghrelin (UAG), the more abundant form in blood, possesses similar, independent or opposite physiological actions as acylated ghrelin (AG). AZP502, a linear 8-amino acid peptide from the central region of UAG (UAG(6-13)), and its full (AZP531) and partially (AZP533) cyclised derivatives, exhibit the same pharmacological profile as UAG both in vitro and in vivo, independently of AG receptor binding. We investigated the stability of these three fragments in vitro in human blood samples and in vivo after subcutaneous and intravenous injection in rats and dogs using liquid chromatography-mass spectrometry. In both species, AZP502 is rapidly degraded generating two major metabolites. Partial cyclisation of AZP502 and acylation at its N-terminus (AZP533 peptide) improves its stability in human plasma in vitro. Full cyclisation of AZP502 (AZP531 peptide) also completely protects the peptide from peptidase degradation in vitro in human blood samples. Moreover this cyclisation strongly improves the stability and the bioavailability of this peptide in vivo in both dogs and rats (mean bioavailability of 10-15% and 85-95% for AZP502 and AZP531 respectively). Taken together these results support the rationale for developing AZP531 as a long-acting UAG analogue for subcutaneous injection for the treatment of type 2 diabetes mellitus and other metabolic disorders. PMID- 22841846 TI - Experimental and theoretical NMR determination of isoniazid and sodium p sulfonatocalix[n]arenes inclusion complexes. AB - In this work the inclusion complex formation of isoniazid with sodium p sulfonatocalix[n]arenes is reported aiming to improve the physicochemical and biopharmaceutical properties of isoniazid a first line antibuberculosis drug. The architectures of the complexes were proposed according to NMR data Job plot indicating details on the insertion of the isoniazid in the calix[n]arenes cavities. DFT theoretical NMR calculations were also performed for sodium p sulfonatocalix[4]arene complex with isoniazid, with various modes of complexation being considered, to provide support for the experimental proposal. A comparison between experimental and theoretical 1H NMR chemical shifts profiles allowed for the inclusion complex characterization confirming the isoniazid inclusion mode which is preferentially through the hydrazide moiety. The remarkable agreement between experimental and theoretical NMR profiles adds support to their use in the structural characterization of inclusion compounds. Antibacterial activity was evaluated and the results indicated the inclusion complexes as a potential strategy for tuberculosis treatment. PMID- 22841847 TI - Neurobiology of language: highlights from the second annual meeting. PMID- 22841848 TI - Impact of gold nanoparticle coating on redox homeostasis. AB - Gold nanoparticles (AuNP) hold great potential for biomedical applications. This study was aimed at examination of the effect of AuNP coating on the redox status of their environment. Two kinds of AuNP were tested, similar by shape and size, but with different surface coatings: either stabilized with citrate or functionalized with dihydrolipoic acid (Au@DHLA NP). Interestingly, whereas citrate-stabilized AuNP interact in vitro with reduced glutathione (GSH) and S nitrosoglutathione, Au@DHLA NP do not interfere with both biomolecules. Albumin exhibits higher affinity toward citrate-stabilized AuNP than Au@DHLA NP, increasing their hydrodynamic diameter (8.0- and 1.3-fold, respectively). Furthermore, the AuNP coating affects also their internalization by macrophages (which was two fold higher for citrate-stabilized AuNP), following an exposure to a subtoxic NP concentration (10 nM, 80% viability). Citrate-stabilized AuNP were found to decrease the intracellular GSH level (ca. 20%), with no increase in reactive oxygen species production. Furthermore, these AuNP did not induce apoptosis (as shown by caspase-3 activity and nfkb2 transcription factor), and also did not activate gene expression related to oxidative stress (ncf1) and inflammatory response (tnfalpha). The present data highlight that the functionalization of AuNP with DHLA decreases their reactivity with biomolecules and cells, resulting in a promising medical platform. PMID- 22841849 TI - Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery. AB - Nanoparticulate drug delivery system possesses distinct advantages for brain drug delivery. However, its amount that reach the brain is still not satisfied. Cell penetrating peptides (CPPs), short peptides that facilitate cellular uptake of various molecular cargo, would be appropriate candidates for facilitating brain delivery of nanoparticles. However, such effect could be deprived by the rapid systemic clearance of CPPs-functionalized nanoparticles due to their positive surface charge. Penetratin (CPP with relatively low content of basic amino acids) was here functionalized to poly(ethylene glycol)-poly(lactic acid) nanoparticles (NP) to achieve desirable pharmacokinetic and biodistribution profiles for brain drug delivery. The obtained penetratin-NP showed a particle size of 100 nm and zeta potential of -4.42 mV. The surface conjugation of penetratin was confirmed by surface chemical compositions analysis via X-ray photo electron spectroscopy. In MDCK-MDR cell model, penetratin-NP presented enhanced cellular accumulation via both lipid raft-mediated endocytosis and direct translocation processes with the involvement of Golgi apparatus, lysosome and microtubules. In vivo pharmacokinetic and biodistribution studies showed that penetratin-NP exhibited a significantly enhanced brain uptake and reduced accumulation in the non-target tissues compared with low-molecular-weight protamine (CPP with high arginine content)-functionalized nanoparticles. These data strongly implicated that penetratin-NP might represent a promising brain-targeting drug delivery system. The findings also provided an important basis for the optimization of brain drug delivery systems via surface charge modulation. PMID- 22841850 TI - Lectin-coated PLGA microparticles: thermoresponsive release and in vitro evidence for enhanced cell interaction. AB - PLGA-microparticles with 4.7 MUm in diameter were prepared by the double emulsion technique and loaded with 1.7 MUg fluorescein/mg PLGA mimicking a hydrophilic API. In an effort to further elucidate the release and bioadhesive characteristics of lectin-grafted formulations in vitro, the particles were coated with wheat germ agglutinin. The microparticles exhibited thermo-responsive release since no free fluorescein was detected at 4 degrees C or room temperature. At body temperature, however, more than 80% of the payload was released within 48 h. The adhesion of lectin-grafted particles to Caco-2 monolayers, which were applied as a model for the human intestinal epithelium, exceeded that of plain ones 1.5-fold as also observed by fluorescence microscopy. Furthermore, the amount of model drug bound and taken up into the cells was 5.8 fold higher after incubation for 4 h at 37 degrees C as compared to fluorescein in solution. According to fluorescence imaging a considerable amount of the total fluorescein payload was accumulated intracellularily after incubation for 5 h at 37 degrees C. These findings not only confirm the utility of bioadhesives of the second generation for improved absorption of low molecular weight hydrophilic compounds but also indicate storage stability of such suspensions at 4 degrees C and room temperature without any premature loss of API. PMID- 22841851 TI - In vitro antimicrobial activity of nanoconjugated vancomycin against drug resistant Staphylococcus aureus. AB - The mounting problem of antibiotic resistance of Staphylococcus aureus has prompted renewed efforts toward the discovery of novel antimicrobial agents. The present study was aimed to evaluate the in vitro antimicrobial activity of nanoconjugated vancomycin against vancomycin sensitive and resistant S. aureus strains. Folic acid tagged chitosan nanoparticles are used as Trojan horse to deliver vancomycin into bacterial cells. In vitro antimicrobial activity of nanoconjugated vancomycin against VSSA and VRSA strains was determined by minimum inhibitory concentration, minimum bactericidal concentration, tolerance and disc agar diffusion test. Cell viability and biofilm formation was assessed as indicators of pathogenicity. To establish the possible antimicrobial mechanism of nanoconjugated vancomycin, the cell wall thickness was studied by TEM study. The result of the present study reveals that nano-sized vehicles enhance the transport of vancomycin across epithelial surfaces, and exhibits its efficient drug-action which has been understood from studies of MIC, MBC, DAD of chitosan derivative nanoparticle loaded with vancomycin. Tolerance values distinctly showed that vancomycin loaded into nano-conjugate is very effective and has strong bactericidal effect on VRSA. These findings strongly enhanced our understanding of the molecular mechanism of nanoconjugated vancomycin and provide additional rationale for application of antimicrobial therapeutic approaches for treatment of staphylococcal pathogenesis. PMID- 22841852 TI - Preparation, structural analysis, and properties of tenoxicam cocrystals. AB - Cocrystals of tenoxicam, a non-steroidal anti-inflammatory drug, are screened, prepared, and characterized in this study. Nine tenoxicam cocrystals were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Thermal analysis, PXRD, and 1D SSNMR are used to detect solvates and phase mixtures encountered in SDG cocrystal screening. 2D SSNMR methods are then used to confirm cocrystal formation and determine structural aspects for selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid in comparison to Forms I and III of tenoxicam. Molecular association is demonstrated using cross-polarization heteronuclear dipolar correlation (CP HETCOR) methods involving (1)H and (13)C nuclei. Short-range (1)H-(13)C CP-HETCOR and (1)H-(1)H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding, are used to reveal local aspects of the cocrystal structure. (15)N SSNMR is used to assess ionization state and the potential for zwitterionization in the selected cocrystals. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. The four selected cocrystals yielded intrinsic dissolution rates that were similar or reduced relative to tenoxicam Form III. PMID- 22841853 TI - [Course in IPR: method for the identification of patients at risk]. PMID- 22841854 TI - Comparing the donor-site morbidity using DIEP, SIEA or MS-TRAM flaps for breast reconstructive surgery: a meta-analysis. AB - BACKGROUND: Countless studies have compared the use of autologous tissue for breast reconstruction; however, rates of donor-site morbidity differ greatly. This study examined the donor-site morbidity of superficial inferior epigastric artery (SIEA), deep inferior epigastric perforator (DIEP) and muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps when used for unilateral breast reconstruction. METHODS: Searches in PubMed and Medline as well as three manual search strategies for English-language articles published from 1 January 1995 to 1 January 2011 resulted in 2154 publications. Four levels of screening identified five studies suitable for the meta-analysis. StatsDirect software was used to perform the Mantel-Haenszel fixed-effect model. RESULTS: Only one study reported rates of donor-site morbidity for SIEA flaps. It was therefore impossible to perform any analysis regarding SIEA flaps. Five studies reported rates for both DIEP and MS-TRAM flaps and were used to estimate pooled relative risk (RR) and confidence intervals (CIs) of bulging. There was a 20% reduced risk of bulging when DIEP flaps were used compared to MS-TRAM flaps (RR 0.80, 95% CI 0.48-1.35). Subgroup analysis demonstrated that the risk of bulging in DIEP flap patients was one-third of MS-TRAM flap patients (RR 0.29; 95% CI 0.06-1.36), when rates were reported by clinical examinations. However, when rates were reported by surveys there was no difference in bulge formation between DIEP and MS-TRAM flap patients (RR 1.04; 95% CI 0.59-1.79). The adjusted RR of hernia in DIEP flap patients was approximately one-half of MS-TRAM flap patients (RR 0.43; 95% CI 0.07-2.63). CONCLUSION: This analysis demonstrated a clear trend towards a favourable outcome when DIEP flaps were used compared to MS-TRAM flaps. PMID- 22841855 TI - Antimicrobial activity of recombinant Pg-AMP1, a glycine-rich peptide from guava seeds. AB - Antimicrobial peptides (AMPs) are compounds that act in a wide range of physiological defensive mechanisms developed to counteract bacteria, fungi, parasites and viruses. These molecules have become increasingly important as a consequence of remarkable microorganism resistance to common antibiotics. This report shows Escherichia coli expressing the recombinant antimicrobial peptide Pg AMP1 previously isolated from Psidium guajava seeds. The deduced Pg-AMP1 open reading frame consists in a 168 bp long plus methionine also containing a His6 tag, encoding a predicted 62 amino acid residue peptide with related molecular mass calculated to be 6.98 kDa as a monomer and 13.96 kDa at the dimer form. The recombinant Pg-AMP1 peptide showed inhibitory activity against multiple Gram negative (E. coli, Klebsiella pneumonia and Pseudomonas aeruginosa) and Gram positive (Staphylococcus aureus and Staphylococcus epidermides) bacteria. Moreover, theoretical structure analyses were performed in order to understand the functional differences between natural and recombinant Pg-AMP1 forms. Data here reported suggest that Pg-AMP1 is a promising peptide to be used as a biotechnological tool for control of human infectious diseases. PMID- 22841856 TI - Antimicrobial-immunomodulatory activities of zebrafish phosvitin-derived peptide Pt5. AB - A phosvitin (Pv)-derived peptide, Pt5, which consists of the C-terminal 55 residues of Pv in zebrafish, has been shown to function as an antimicrobial agent capable of killing microbes in vitro. However, its in vivo role in zebrafish remains unknown. In this study, we clearly demonstrated that Pt5 protected adult zebrafish from pathogenic Aeromonas hydrophila attack, capable of significantly enhancing the survival rate of zebrafish after the pathogenic challenge. Pt5 also caused a marked decrease in the numbers of A. hydrophila in the blood, spleen, kidney, liver and muscle, suggesting that Pt5 was able to block multiplication/dissemination of A. hydrophila in zebrafish. Additionally, Pt5 markedly suppressed the expression of the proinflammatory cytokine genes IL 1beta, IL-6, TNF-alpha and IFN-gamma in the spleen and head kidney of A. hydrophila-infected zebrafish, but it considerably enhanced the expressions of the antiinflammatory cytokine genes IL-10 and IL-4 in the same tissues. Taken together, these data indicate that Pt5 plays a dual role in zebrafish as an antimicrobial and immunomodulatory agent, capable of protecting zebrafish against pathogenic A. hydrophila through its antimicrobial activity as well as preventing zebrafish from the detrimental effects of an excessive inflammatory response via modulating immune functions. PMID- 22841857 TI - Characterization of a distinctive pattern of periovulatory leptin secretion and its relationship with ovulation rate and luteal function in swine with obesity/leptin resistance. AB - Patterns of leptin secretion during the estrous cycle and the possible relationship of changes in circulating leptin during the periovulatory period with ovarian function in sows of obese (Iberian breed) and lean genotype (Large White x Landrace) were evaluated in two consecutive experiments. Plasma leptin concentrations throughout the estrous cycle in lean sows remain unchanged, but Iberian females showed a periovulatory increase in circulating leptin levels without associated changes in body condition and fatness. In these sows, plasma leptin concentrations at Days -1 and 0 of the cycle were found to be positively correlated with the ovulation rate (r=0.943 and r=0.987, respectively; P<0.05 for both), but the levels of leptin at Day 0 were negatively correlated with the progesterone release from Day 3 (r=-0.557; P<0.05) and, became more evident at Day 5 of the estrous cycle (r=-0.924; P<0.005). Such relationships were not observed in the females of the lean genotype. In conclusion, the present study indicates the existence of a distinctive pattern in the periovulatory leptin secretion in swine with obesity and leptin resistance, which is associated with the number and functionality of the corpora lutea present in the subsequent cycle. PMID- 22841858 TI - The tragedy and horror of human trafficking of children and youth. PMID- 22841859 TI - Reversal of BoNT/A-mediated inhibition of muscle paralysis by 3,4-diaminopyridine and roscovitine in mouse phrenic nerve-hemidiaphragm preparations. AB - Botulinum neurotoxins (BoNTs) comprise a family of neurotoxic proteins synthesized by anaerobic bacteria of the genus Clostridium. Each neurotoxin consists of two polypeptide chains: a 100kDa heavy chain, responsible for binding and internalization into the nerve terminal of cholinergic motoneurons and a 50kDa light chain that mediates cleavage of specific synaptic proteins in the host nerve terminal. Exposure to BoNT leads to cessation of voltage- and Ca(2+) dependent acetylcholine (ACh) release, resulting in flaccid paralysis which may be protracted and potentially fatal. There are no approved therapies for BoNT intoxication once symptoms appear, and specific inhibitors of the light chain developed to date have not been able to reverse the consequences of BoNT intoxication. An alternative approach for treatment of botulism is to focus on compounds that act by enhancing ACh release. To this end, we examined the action of the K(+) channel blocker 3,4-diaminopyridine (3,4-DAP) in isolated mouse hemidiaphragm muscles intoxicated with 5pM BoNT/A. 3,4-DAP restored tension within 1-3min of application, and was effective even in totally paralyzed muscle. The Ca(2+) channel activator (R)-roscovitine (Ros) potentiated the action of 3,4 DAP, allowing for use of lower concentrations of the K(+) channel blocker. In the absence of 3,4-DAP, Ros was unable to augment tension in BoNT/A-intoxicated muscle. This is the first report demonstrating the efficacy of the combination of 3,4-DAP and Ros for the potential treatment of BoNT/A-mediated muscle paralysis. PMID- 22841860 TI - Myostatin as a therapeutic target in Amyotrophic lateral sclerosis. AB - Amyotrophic Lateral Sclerosis is a devastating neurological disease that is inevitably fatal after 3-5years duration. Treatment options are minimal and as such new therapeutic modalities are required. In this review, we discuss the role of the myostatin pathway as a modulator of skeletal muscle mass and therapeutic approaches using biological based therapies. Both monoclonal antibodies to myostatin and a soluble receptor decoy to its high affinity receptor have been used in clinical trials of neuromuscular diseases and while there have been efficacy signals with the latter approach there have also been safety issues. Our approach is to target the high affinity receptor-binding site on myostatin and to develop a next generation set of therapeutic reagents built on a novel protein scaffold. This is the natural single domain VNAR found in sharks which is extremely versatile and has the ability to develop products with superior properties compared to existing therapeutics. PMID- 22841861 TI - Increased tyrosine availability increases brain regional DOPA levels in vivo. AB - Tyrosine hydroxylation is considered to be the rate-limiting step in catecholamine synthesis. It is also assumed that under usual conditions, tyrosine 3-monooxygenase (EC 1.14.16.2) (tyrosine hydroxylase - TH) is close to full saturation with its l-tyrosine substrate and hence that raising the availability of l-tyrosine does not substantially increase 3,4-dihydroxyphenylalanine (DOPA) synthesis. We evaluated this in vivo by reverse dialysis of the aromatic-l-amino acid decarboxylase (EC 4.1.1.28) inhibitor NSD-1015 (20MUM) and selected concentrations of l- or d-tyrosine. In striatum, extracellular DOPA levels increased linearly (maximum 250% control) as l-tyrosine concentrations were raised from 0-1000MUM. In medial prefrontal cortex, DOPA levels reached a maximum (300% control) at l-tyrosine 62.5-125MUM but still remained significantly elevated (200% control) at higher l-tyrosine concentrations (250-500MUM). At the l-tyrosine concentrations tested, DOPA levels were never below those of controls. d-tyrosine (62.5MUM) did not affect DOPA levels. The degree to which the elevation of DOPA levels represents a net increase in tyrosine hydroxylation as opposed to heteroexchange of l-TYR for intracellular DOPA remains to be determined. However, one interpretation of the data is that under usual in vivo conditions brain TH may not be near full saturation with l-tyrosine and that mechanisms other than tyrosine hydroxylation may be more important in the acute regulation of brain catecholamine synthesis than previously appreciated. This would have implications for the pathophysiology and treatment of neuropsychiatric conditions in which dysregulation of DA transmission and l-tyrosine transport have been implicated. PMID- 22841862 TI - Single intravenous low-dose injections of connexin 43 mimetic peptides protect ischemic heart in vivo against myocardial infarction. AB - The opening of unapposed connexin 43 hemichannels (Cx43Hc) under ischemic stress leads to cell death and irreversible tissue injury. Here, we investigate for the first time in vivo the cardioprotective potentials of two unique Cx43 structural mimetic peptides (Cx43MPs) presumed specific blockers of Cx43Hc, Gap26 and Gap27, when injected intravenously using a rat model of myocardial infarction.Sprague Dawley rats were utilized. Myocardial infarction was induced by occluding the left anterior descending coronary for 40 min followed by 2 days of reperfusion. Interestingly, single bolus injections of Gap26 or Gap27 (1 MUg/kg) into the jugular vein caused infarct size reductions by up to 61% with reference to control rats injected with saline at similar timings. Infarct reductions did not vary significantly whether peptides were administered before or after the onset of ischemia. Although the two peptides allegedly interact with distinct structures of Cx43, co-administration of Gap26/Gap27 in equal doses did not confer additive protection to hearts (maximum infarct reduction by 64%). Using patch clamp technique, we provide unique and direct evidence for the inhibitory effect of Cx43MPs on genuine human Cx43Hc transiently expressed in the ion channel-deficient tsA201 cells. In concordance with the cardioprotective effect observed in vivo, co-application of both peptides did not cause cumulative current inhibition. A safety profile of Cx43MPs was also addressed.Our results reveal great therapeutic potential of Cx43MPs in treatment of myocardial infarction. Their practical way and timing of administration and their apparent safe profile make them promising tools to fight ischemic heart disease. PMID- 22841863 TI - Preemptive kidney transplantation: has it come of age? AB - The benefits of preemptive kidney transplantation are manifold. By avoiding complications associated with dialysis, preemptive kidney transplantation offers significant benefits in terms of patient welfare and societal cost-saving. Patients transplanted preemptively also tend to enjoy better patient and graft survival, especially when done with a living-donor organ. While dialysis exposure limited to 6 to 12 months may not significantly impact post-transplant outcomes, longer period of dialysis has been shown to increase the risk of mortality, delayed graft function, acute rejection, and death-censored graft loss. The benefits of preemptive transplantation also extend to different age groups and end-stage kidney disease (ESKD) diagnoses. However, multiple barriers have prevented wider adoption of preemptive transplantation as the primary treatment of ESKD around the world. Timely preparation for ESKD and identification of living donors should be encouraged in all patients with advanced chronic kidney disease to increase the chance of preemptive transplantation. PMID- 22841864 TI - Inflammatory arthritis as a novel risk factor for cardiovascular disease. AB - Cardiovascular disease (CVD) comorbidity is a significant issue for the inflammatory arthritides (IA). There is a wealth of mortality studies showing increased cardiovascular mortality in rheumatoid arthritis (RA) and the evidence suggests that the same is likely to be true of psoriatic arthritis (PsA) and ankylosing spondylitis (AS). CVD co-morbidity is due to ischaemic pathologies driven by accelerated atherosclerosis and relates to the increased prevalence and clustering of classical risk factors, which may also be affected by treatments for IA, and their interplay with novel risk factors, namely systemic inflammation. Currently we are unable to quantify the contribution that classical and novel risk factors make to an individuals' CVD risk and specific algorithms need to be developed and validated in RA, PsA and AS to facilitate clinical management. Furthermore, large clinical trials are required to assess the effect of lifestyle modifications, primary prevention strategies and effective immunosuppression on hard CVD endpoints. However, in the meantime, a pragmatic approach should be adopted towards CVD risk management. Consensus opinion has generated guidelines for the management of CVD risk in IA and we discuss the importance of assessing each individual for CVD risk and establishing a system for routine risk factor identification alongside a commitment to treat identified risk factors to specific targets. PMID- 22841865 TI - Identification of an acetate-tolerant strain of Saccharomyces cerevisiae and characterization by gene expression analysis. AB - A massive screening was performed to identify an acetate-tolerant strain of Saccharomyces cerevisiae. We found that S. cerevisiae ATCC 38555 is acetate tolerant, with a fermentation profile indicating that it has a high level of acetate adaptation. The global gene expression analysis indicated that AFT1- and HAA1-regulated genes are clearly up-regulated. PMID- 22841866 TI - Gene cloning and catalytic characterization of cold-adapted lipase of Photobacterium sp. MA1-3 isolated from blood clam. AB - A lipase-producing Photobacterium strain (MA1-3) was isolated from the intestine of a blood clam caught at Namhae, Korea. The lipase gene was cloned by shotgun cloning and encoded 340 amino acids with a molecular mass of 38,015 Da. It had a very low sequence identity with other bacterial lipases, with the exception of that of Photobacterium lipolyticum M37 (83.2%). The MA1-3 lipase was produced in soluble form when Escherichia coli cells harboring the gene were cultured at 18 degrees C. Its optimum temperature and pH were 45 degrees C and pH 8.5, respectively. Its activation energy was calculated to be 2.69 kcal/mol, suggesting it to be a cold-adapted lipase. Its optimum temperature, temperature stability, and substrate specificity were quite different from those of M37 lipase, despite the considerable sequence similarities. Meanwhile, MA1-3 lipase performed a transesterification reaction using olive oil and various alcohols including methanol, ethanol, 1-propanol, and 1-butanol. In the presence of t butanol as a co-solvent, this lipase produced biodiesel using methanol and plant or waste oils. The highest biodiesel conversion yield (73%) was achieved using waste soybean oil and methanol at a molar ratio of 1:5 after 12 h using 5 units of lipase. PMID- 22841867 TI - A simple fed-batch method for transcription and insect cell-free translation. AB - We tested a one batch reaction method for the transcription and the insect cell free translation from undigested plasmids without any centrifugation steps. The efficiency of protein synthesis reached 74-112% of that achieved using the conventional procedure. This simplified method will help expedite the high throughput insect cell-free protein production. PMID- 22841868 TI - Transcriptional response of Lactobacillus acidophilus L-92 after attachment to epithelial Caco-2 cells. AB - Transcriptome analysis showed that Lactobacillus acidophilus L-92 cells having anti-allergy effects on human up-regulated 41 genes involved permease, ABC transporter, proteinase and transcriptional regulator after attached to epithelial Caco-2 cells. Inversely, 37 genes were down-regulated, including ATP synthases, ABC transporters and transcriptional regulators. PMID- 22841869 TI - Haptoglobin alters oxygenation and oxidation of hemoglobin and decreases propagation of peroxide-induced oxidative reactions. AB - We compared oxygenation and anaerobic oxidation reactions of a purified complex of human hemoglobin (Hb) and haptoglobin (Hb-Hp) to those of uncomplexed Hb. Under equilibrium conditions, Hb-Hp exhibited active-site heterogeneity and noncooperative, high-affinity O(2) binding (n(1/2)=0.88, P(1/2)=0.33 mm Hg in inorganic phosphate buffer at pH 7 and 25 degrees C). Rapid-reaction kinetics also exhibited active-site heterogeneity, with a slower process of O(2) dissociation and a faster process of CO binding relative to uncomplexed Hb. Deoxygenated Hb-Hp had significantly reduced absorption at the lambda(max) of 430 nm relative to uncomplexed Hb, as occurs for isolated Hb subunits that lack T state stabilization. Under comparable experimental conditions, the redox potential (E(1/2)) of Hb-Hp was found to be +54 mV, showing that it is much more easily oxidized than uncomplexed Hb (E(1/2)=+125 mV). The Nernst plots for Hb-Hp oxidation showed no cooperativity and slopes less than unity indicated active site heterogeneity. The redox potential of Hb-Hp was unchanged by pH over the range of 6.4-8.3. Exposure of Hb-Hp to excess hydrogen peroxide (H(2)O(2)) produced ferryl heme, which was found to be more kinetically inert in the Hb-Hp complex than in uncomplexed Hb. The negative shift in the redox potential of Hb Hp and its stabilized ferryl state may be central elements in the protection against Hb-induced oxidative damage afforded by formation of the Hb-Hp complex. PMID- 22841870 TI - Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons. AB - Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is a multifunctional protein critical for cellular survival. Its involvement in adaptive survival responses includes key roles in redox sensing, transcriptional regulation, and repair of DNA damage via the base excision repair (BER) pathway. Ape1 is abundant in most cell types and central in integrating the first BER step catalyzed by different DNA glycosylases. BER is the main process for removal of oxidative DNA lesions in postmitotic brain cells, and after ischemic brain injury preservation of Ape1 coincides with neuronal survival, while its loss has been associated with neuronal death. Here, we report that in cultured primary neurons, diminution of cellular ATP by either oligomycin or H(2)O(2) is accompanied by depletion of nuclear Ape1, while other BER proteins are unaffected and retain their nuclear localization under these conditions. Importantly, while H(2)O(2) induces gammaH2AX phosphorylation, indicative of chromatin rearrangements in response to DNA damage, oligomycin does not. Furthermore, despite comparable diminution of ATP content, H(2)O(2) and oligomycin differentially affect critical parameters of mitochondrial respiration that ultimately determine cellular ATP content. Taken together, our findings demonstrate that in neurons, nuclear compartmentalization of Ape1 depends on ATP and loss of nuclear Ape1 reflects disruption of neuronal energy homeostasis. Energy crisis is a hallmark of stroke and other ischemic/hypoxic brain injuries. In vivo studies have shown that Ape1 deficit precedes neuronal loss in injured brain regions. Thus, our findings bring to light the possibility that energy failure-induced Ape1 depletion triggers neuronal death in ischemic brain injuries. PMID- 22841871 TI - Polymeric black tea polyphenols modulate the localization and activity of 12-O tetradecanoylphorbol-13-acetate-mediated kinases in mouse skin: mechanisms of their anti-tumor-promoting action. AB - Polymeric black tea polyphenols (PBPs) have been shown to possess anti-tumor promoting effects in two-stage skin carcinogenesis. However, their mechanisms of action are not fully elucidated. In this study, mechanisms of PBP-mediated antipromoting effects were investigated in a mouse model employing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Compared to controls, a single topical application of TPA to mouse skin increased the translocation of protein kinase C (PKC) from cytosol to membrane. Pretreatment with PBPs 1-3 decreased TPA-induced translocation of PKC isozymes (alpha, beta, eta, gamma, epsilon) from cytosol to membrane, whereas PBPs 4 and 5 were less effective. The levels of PKCs delta and zeta in cytosol/membrane were similar in all the treatment groups. Complementary confocal microscopic evaluation showed a decrease in TPA-induced PKCalpha fluorescence in PBP-3-pretreated membranes, whereas pretreatment with PBP-5 did not show a similar decrease. Based on the experiments with specific enzyme inhibitors and phosphospecific antibodies, both PBP-3 and PBP-5 were observed to decrease TPA-induced level and/or activity of phosphatidylinositol 3-kinase (PI3K) and AKT1 (pS473). An additional ability of PBP-3 to inhibit site-specific phosphorylation of PKCalpha at all three positions responsible for its activation [PKCalpha (pT497), PKC PAN (betaII pS660), PKCalpha/betaII (pT638/641)] and AKT1 at the Thr308 position, along with a decrease in TPA-induced PDK1 protein level, correlated with the inhibition of translocation of PKC, which may impart relatively stronger chemoprotective activity to PBP-3 than to PBP-5. Altogether, PBP-mediated decrease in TPA-induced PKC phosphorylation correlated well with decreased TPA-induced NF-kappaB phosphorylation and downstream target proteins associated with proliferation, apoptosis, and inflammation in mouse skin. Results suggest that the antipromoting effects of PBPs are due to modulation of TPA-induced PI3K-mediated signal transduction. PMID- 22841872 TI - Recruitment of TRF2 to laser-induced DNA damage sites. AB - Several lines of evidence suggest that the telomere-associated protein TRF2 plays critical roles in the DNA damage response. TRF2 is rapidly and transiently phosphorylated by an ATM-dependent pathway in response to DNA damage and this DNA damage-induced phosphoryation is essential for the DNA-PK-dependent pathway of DNA double-strand break repair (DSB). However, the type of DNA damage that induces TRF2 localization to the damage sites, the requirement for DNA damage induced phosphorylation of TRF2 for its recruitment, as well as the detailed kinetics of TRF2 accumulation at DNA damage sites have not been fully investigated. In order to address these questions, we used an ultrafast femtosecond multiphoton laser and a continuous wave 405-nm single photon laser to induce DNA damage at defined nuclear locations. Our results showed that DNA damage produced by a femtosecond multiphoton laser was sufficient for localization of TRF2 to these DNA damage sites. We also demonstrate that ectopically expressed TRF2 was recruited to DNA lesions created by a 405-nm laser. Our data suggest that ATM and DNA-PKcs kinases are not required for TRF2 localization to DNA damage sites. Furthermore, we found that phosphorylation of TRF2 at residue T188 was not essential for its recruitment to laser-induced DNA damage sites. Thus, we provide further evidence that a protein known to function in telomere maintenance, TRF2, is recruited to sites of DNA damage and plays critical roles in the DNA damage response. PMID- 22841873 TI - Letter to editor. PMID- 22841874 TI - Re: "Chylous ascites: analysis of 24 patients". PMID- 22841875 TI - How insensitive ... how a mutation in the SCN5A voltage sensor leads to clinical arrhythmia. PMID- 22841876 TI - Clinical and procedural outcome of patients implanted with a quadripolar left ventricular lead: early results of a prospective multicenter study. AB - BACKGROUND: Recent studies suggest that cardiac resynchronization therapy (CRT) with a quadripolar left ventricular (LV) lead results in low rates of dislocation and phrenic nerve stimulation (PNS) acutely and at short-term follow-up. Confirmation of these results by long-term observational studies is needed. OBJECTIVE: To evaluate the long-term procedural and clinical outcomes of CRT patients implanted with a quadripolar LV lead. METHODS: A total of 154 consecutive heart failure patients (79% men, age 68 +/- 10 years) having CRT implantation attempts with a quadripolar LV lead were included in this observational registry. Demographic and clinical data were preoperatively collected, and patients were followed up for at least 6 months. RESULTS: The overall implant success rate after coronary sinus cannulation was 97.4%. Mean overall duration and fluoroscopy time of successful procedures was 112 +/- 22 and 16 +/- 8 minutes, respectively, while 17 +/- 13 minutes were necessary for the LV lead placement. After implant, the conventional bipolar configuration was used as the final pacing configuration in 33.3% of the patients. Four lead dislodgments (requiring reoperation) and 9 clinical PNS were reported during follow-up; reprogramming of the device was sufficient to prevent PNS in all patients. Once placed, the LV lead remained stable with excellent pacing thresholds during follow-up (15 +/- 5 months). Overall, there were 71.3% CRT responders as assessed by 6-month echocardiography, and 66% improved at least 1 New York Heart Association class. CONCLUSION: Over the longer term, CRT with the quadripolar LV lead is associated with excellent pacing thresholds, low rates of dislocations, and PNS. PMID- 22841877 TI - Surgical trials for pain relief: in search of better answers. PMID- 22841878 TI - Impaired spatial body representation in complex regional pain syndrome type 1 (CRPS I). AB - Recently, a shift of the visual subjective body midline (vSM), a correlate of the egocentric reference frame, towards the affected side was reported in patients with complex regional pain syndrome (CRPS). However, the specificity of this finding is as yet unclear. This study compares 24 CRPS patients to 21 patients with upper limb pain of other origin (pain control) and to 24 healthy subjects using a comprehensive test battery, including assessment of the vSM in light and dark, line bisection, hand laterality recognition, neglect-like severity symptoms, and motor impairment (disability of the arm, shoulder, and hand). STATISTICS: 1-way analysis of variance, t-tests, significance level: 0.05. In the dark, CRPS patients displayed a significantly larger leftward spatial bias when estimating their vSM, compared to pain controls and healthy subjects, and also reported lower motor function than pain controls. For right-affected CRPS patients only, the deviation of the vSM correlated significantly with the severity of distorted body perception. Results confirm previous findings of impaired visuospatial perception in CRPS patients, which might be the result of the involvement of supraspinal mechanisms in this pain syndrome. These mechanisms might accentuate the leftward bias that results from a right-hemispheric dominance in visuospatial processing and is known as pseudoneglect. Pseudoneglect reveals itself in the tendency to perceive the midpoint of horizontal lines or the subjective body midline left of the centre. It was observable in all 3 groups, but most pronounced in CRPS patients, which might be due to the cortical reorganisation processes associated with this syndrome. PMID- 22841880 TI - The effect of intravenous immunoglobulin on neuromyelitis optica. AB - OBJECTIVE: Evaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). METHODS: Eight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7 g per kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). RESULTS: All 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis. The mean age of onset was 20.5 years (range, 7-31 years) and 87,5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z=2,5, P=.01). The EDSS score fell from 3.3+/-1.3 to 2.6+/-1.5 (z=-2.0, P=.04). CONCLUSIONS: Treatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders. PMID- 22841879 TI - Smoking and air pollution exposure and lung cancer mortality in Zhaoyuan County. AB - BACKGROUND: Simultaneous exposure to high levels of air pollution and high tobacco consumption at the same place is rare. The aim of the present study was to evaluate the impact of the two factors on the risk of developing lung cancer. METHODS: Data on the number of deaths due to lung cancer and on population from 1970 to 2009 were obtained from Zhaoyuan County. Data on the smoking populations were obtained at random sampling survey during the time in Zhaoyuan. Data on the components of atmospheric surveillance were obtained from the local environmental protection offices. Logarithmic linear regression and general log-linear Poisson age-period-cohort (APC) models were used to estimate age, period, cohort, gender, smoking, and air pollution effects on the risk of lung cancer mortality. RESULTS: The standardized mortality rates of lung cancer drastically increased from 8.43 in per 100 000 individuals in the 1970-1974 to 25.67 in per 100 000 individuals in the 2005-2009 death survey. The annual change of lung cancer mortality was 3.20%. In the log linear regression model, the age, proportion of smokers, gender, period, and air pollution are significantly associated with lung cancer mortality. The APC analysis shows that the relative risks (RRs) of gender, smoking, and air pollution are 2.29 (95% confidence interval (CI): 2.16-2.43), 3.05 (95% CI = 2.76-3.36), and 1.42 (95% CI = 1.19-1.69), respectively. Compared with the period 1970-1974, high RRs were found during 1995-2009. Compared with the birth cohort 1950-1954, the RRs increased in the birth cohorts of 1910 to the 1940. Compared the aged 35-59 and 60-84 in the 1980-1984 death survey (not exposed to air pollution) with that in the 2005-2009 death survey (exposed to air pollution), The two age groups exposed to air pollution, 25 years later, had an increased mortality rates for lung cancer by 2.27 and 3.55 times for males and by 1.47 and 3.35 times for females. CONCLUSION: The mortality rates of lung cancer drastically increased in the past 35 years. The trend of lung cancer mortality may be in a great extent possibly due to the effects of combined smoking and air pollution exposure. PMID- 22841881 TI - Drug precipitation-permeation interplay: supersaturation in an absorptive environment. AB - PURPOSE: The present study investigated the interplay between supersaturation, absorption, precipitation, and excipient-mediated precipitation inhibition by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment. Loviride and HPMC-E5 were selected as poorly soluble model drug and precipitation inhibitor, respectively. METHOD: To investigate supersaturation in an absorptive environment, supersaturation was induced at different degrees (DS), using a solvent shift method, in shaken Caco-2 Transwell(r) inserts containing fasted state simulated intestinal fluid (FaSSIF); to simulate a non-absorption environment, the inserts were parafilm-sealed and did not contain a cell monolayer. Donor and acceptor compartments were sampled as a function of time to determine precipitation kinetics and transport, respectively. RESULTS: In absence of precipitation, loviride transport increased proportionally with the initial DS; however, precipitation limited the supersaturation-induced transport enhancement. Loviride precipitation was found to be less extensive in an absorption environment compared to a non-absorption environment. As a result, the optimal DS obtained in a non-absorption environment (highest amount maintained in solution) did not correlate with the highest transport in an absorption environment. In addition, the impact of HPMC-E5 on loviride transport was inferior to its precipitation inhibitory capacity observed in a non-absorption environment. CONCLUSION: For the first time, the present study explicitly demonstrated that implementation of permeation in precipitation assays is critical to predict the impact of supersaturation, precipitation, and precipitation inhibition on the absorption of poorly soluble drugs. PMID- 22841882 TI - Development of a novel mucosal vaccine against strangles by supercritical enhanced atomization spray-drying of Streptococcus equi extracts and evaluation in a mouse model. AB - Strangles is an extremely contagious and sometimes deadly disease of the Equidae. The development of an effective vaccine should constitute an important asset to eradicate this worldwide infectious disease. In this work, we address the development of a mucosal vaccine by using a Supercritical Enhanced Atomization (SEA) spray-drying technique. Aqueous solutions containing the Streptococcus equi extracts and chitosan were converted into nanospheres with no use of organic solvents. The immune response in a mouse model showed that the nanospheres induced a well-balanced Th1 and Th2 response characterized by a unitary ratio between the concentrations of IgG2a and IgG1, together with IgA production. This strategy revealed to be an effective alternative for immunization against S. equi, and therefore, it may constitute a feasible option for production of a strangles vaccine. PMID- 22841883 TI - Detection and forecasting of oyster norovirus outbreaks: recent advances and future perspectives. AB - Norovirus is a highly infectious pathogen that is commonly found in oysters growing in fecally contaminated waters. Norovirus outbreaks can cause the closure of oyster harvesting waters and acute gastroenteritis in humans associated with consumption of contaminated raw oysters. Extensive efforts and progresses have been made in detection and forecasting of oyster norovirus outbreaks over the past decades. The main objective of this paper is to provide a literature review of methods and techniques for detecting and forecasting oyster norovirus outbreaks and thereby to identify the future directions for improving the detection and forecasting of norovirus outbreaks. It is found that (1) norovirus outbreaks display strong seasonality with the outbreak peak occurring commonly in December-March in the U.S. and April-May in the Europe; (2) norovirus outbreaks are affected by multiple environmental factors, including but not limited to precipitation, temperature, solar radiation, wind, and salinity; (3) various modeling approaches may be employed to forecast norovirus outbreaks, including Bayesian models, regression models, Artificial Neural Networks, and process-based models; and (4) diverse techniques are available for near real-time detection of norovirus outbreaks, including multiplex PCR, seminested PCR, real-time PCR, quantitative PCR, and satellite remote sensing. The findings are important to the management of oyster growing waters and to future investigations into norovirus outbreaks. It is recommended that a combined approach of sensor-assisted real time monitoring and modeling-based forecasting should be utilized for an efficient and effective detection and forecasting of norovirus outbreaks caused by consumption of contaminated oysters. PMID- 22841884 TI - A patient with both narcolepsy and multiple sclerosis in association with Pandemrix vaccination. AB - Narcolepsy with cataplexy is caused by a selective loss of hypocretin-producing neurons, but symptomatic narcolepsy can also result from hypothalamic and brainstem lesions caused by multiple sclerosis (MS). We report a previously healthy man who developed clinical and laboratory verified narcolepsy without having any indication of hypothalamic lesions and MS after vaccination against the influenza H1N1 with Pandemrix. HLA typing showed both DRB1*15:01, associated with MS and DQB1*06:02, associated with narcolepsy. The genetic susceptibility in this patient makes it tempting to speculate upon an immune-mediated mechanism and a common etiology for both diseases in this patient. PMID- 22841885 TI - The calcium-sensing receptor: a novel Alzheimer's disease crucial target? AB - Alzheimer's disease (AD) is the most common human neurodegenerative ailment, the most prevalent (>95%) late-onset type of which has a still uncertain etiology. The progressive decline of cognitive functions, dementia, and physical disabilities of AD is caused by synaptic losses that progressively disconnect key neuronal networks in crucial brain areas, like the hippocampus and temporoparietal cortex, and critically impair language, sensory processing, memory, and conscious thought. AD's two main hallmarks are fibrillar amyloid-beta (fAbeta) plaques in extracellular spaces and intracellular accumulation of fAbeta peptides and neurofibrillary tangles (NFTs). It is still undecided whether either or both these AD hallmarks cause or result from the disease. Recently, the dysregulation of calcium homeostasis has been advanced as a novel cause of AD. In this case, a suitable candidate of AD driver would be the Abeta peptides binding/activated calcium-sensing receptor (CaSR), whose intracellular signalling is triggered by Abeta peptides. In this review, we briefly discuss CaSR's roles in normal adult human astrocytes (NAHAs) and their possible impacts on AD. PMID- 22841886 TI - High mobility group box 1 activates Toll like receptor 4 signaling in hepatic stellate cells. AB - AIMS: The aim of the present study was to investigate the effect of high mobility group box 1 (HMGB1), a damage pattern molecule that signals the presence of necrosis, on TLR4 signaling in hepatic stellate cells (HSC). MAIN METHODS: Immortalized mouse HSC lines JS1, JS2, and JS3 that were either TLR4(+/+), TLR4( /-), or MyD88(-/-) were transfected with NF-kappaB or AP-1 responsive luciferase reporter plasmids, followed by stimulation with 100 ng/ml lipopolysacchride (the exogenous TLR4 ligand) or 100 ng/ml HMGB1. The activation of NF-kappaB or AP-1 activities was determined by a dual-luciferase reporter assay system. The cells were also stimulated with LPS or HMGB1 and collected for the determination of chemotactic cytokine MCP-1 mRNA or proteins secretion. In a separate experiment, the cells were co-stimulated with 10 MUg/ml TGF-beta1 and LPS or HMGB1 and collected for assessment of fibrogenic mRNA and protein expression. KEY FINDINGS: HMGB1 stimulation markedly up-regulated MCP-1 mRNA expression and protein secretion, and enhanced TGF-beta1-stimulated collagen alpha2(I) and alpha-SMA expression in JS1 cells. This was associated with enhanced activation of NF kappaB and AP-1 responsive luciferase reporters. On the contrary, JS2 and JS3 cells were hyporesponsive to both LPS and HGMB1 stimulation compared to JS1 cells. SIGNIFICANCE: As an endogenous ligand of TLR4, HMGB1 activates TLR4 signaling in HSCs to enhance their inflammatory phenotype, indicating that TLR4 signaling need not rely solely on gut-derived LPS for activation during liver injury. HMGB1 also has a synergistic effect with TGF-beta1 to stimulate fibrogenic protein expression, which is likely to be TLR4 dependent. PMID- 22841887 TI - Digestion, growth and reproductive performance of the zoophytophagous rove beetle Philonthus quisquiliarius (Coleoptera: Staphylinidae) fed on animal and plant based diets. AB - The zoophytophagous feeding habits of larvae and adults of the rove beetle, Philonthus quisquiliarius (Gyllenhal) (Coleoptera: Staphylinidae), are reported for the first time. This study evaluates the effects of different feeding regimes on its growth and reproductive performance (i.e., larval growth, adult weight gain, consumption, fecundity and fertility) and digestive physiology. Larvae presented similar growth rates when fed on living animal or on green plant material for 48 h. However, higher consumption rates and lower efficiencies of conversion of digested matter to body mass were obtained when leaves were consumed. Adults presented also positive weight gains regardless of the food consumed (plant or animal material). Interestingly, the highest weight gain rate and efficiency of digestion resulted when adults fed on a rearing diet containing nutrients from both animals and plants. Moreover, we have found negative effects upon P. quisquiliarius fecundity and fertility when supplemental plant nutrients were removed from the optimum rearing diet. Physiological adaptations to allow trophic switching between predation and phytophagy have been found, such as the higher ratio of alpha-amylase activity to protease activity to deal with the inverted protein-carbohydrate ratio of plant versus animal tissues. Furthermore, this species has an arsenal of digestive proteases whose activity is affected by the type of diet ingested. All together, our results suggest that P. quisquiliarius needs certain nutrients, which are obtained only from plant material. This knowledge will help to understand the complex trophic interactions that occur in agroecosystems. PMID- 22841888 TI - Gas chromatography-mass spectrometry metabolite profiling of worker honey bee (Apis mellifera L.) hemolymph for the study of Nosema ceranae infection. AB - Here, we are presenting a gas chromatography-mass spectrometry (GC/MS) approach for the study of infection of the worker honey bee (Apis mellifera L.) by the newly emerged obligate intracellular parasite Nosema ceranae based on metabolite profiling of hemolymph. Because of the severity of the disease, early detection is crucial for its efficient control. Results revealed that the parasite causes a general disturbance of the physiology of the honey bee affecting the mechanisms controlling the mobilization of energy reserves in infected individuals. The imposed nutritional and energetic stress to the host was depicted mainly in the decreased levels of the majority of carbohydrates and amino acids, including metabolites such as fructose, l-proline, and the cryoprotectants sorbitol and glycerol, which are implicated in various biochemical pathways. Interestingly, the level of glucose was detected at significantly higher levels in infected honey bees. Metabolomics analyses were in agreement with those of multiplex quantitative PCR analyses, indicating that it can be used as a complementary tool for the detection and the study of the physiology of the disease. PMID- 22841889 TI - Carbohydrate digestion in Lutzomyia longipalpis' larvae (Diptera - Psychodidae). AB - Lutzomyia longipalpis is the principal species of phlebotomine incriminated as vector of Leishmania infantum, the etiological agent of visceral leishmaniasis in the Americas. Despite its importance as vector, almost nothing related to the larval biology, especially about its digestive system has been published. The objective of the present study was to obtain an overview of carbohydrate digestion by the larvae. Taking in account that phlebotomine larvae live in the soil rich in decaying materials and microorganisms we searched principally for enzymes capable to hydrolyze carbohydrates present in this kind of substrate. The principal carbohydrases encountered in the midgut were partially characterized. One of them is a alpha-amylase present in the anterior midgut. It is probably involved with the digestion of glycogen, the reserve carbohydrate of fungi. Two other especially active enzymes were present in the posterior midgut, a membrane bound alpha-glucosidase and a membrane bound trehalase. The first, complete the digestion of glycogen and the other probably acts in the digestion of trehalose, a carbohydrate usually encountered in microorganisms undergoing hydric stress. In a screening done with the use of p-nitrophenyl-derived substrates other less active enzymes were also observed in the midgut. A general view of carbohydrate digestion in L. longipalpis was presented. Our results indicate that soil microorganisms appear to be the main source of nutrients for the larvae. PMID- 22841891 TI - Staurosporine-induced apoptosis presents with unexpected cholinergic effects in a differentiated neuroblastoma cell line. AB - Apoptosis of cholinergic neurons is one of the core hallmarks of Alzheimer's disease. SH-SY5Y neuroblastoma cells differentiated to the cholinergic phenotype were exposed to 100nM staurosporine. Over a treatment period of 24h, the pro- and anti-apoptotic factors, caspase-3 and Bcl-2, as well as LDH release as a measure of cell viability, were assessed in conjunction with the number of apoptotic cells by means of fluorescence-activated cell sorting. Caspase-3 activity and LDH release increased by 30% and 20% over controls, respectively, while Bcl-2 levels rose by 200% over controls. Furthermore, staurosporine treatment resulted in decreased acetylcholinesterase (AChE) enzymatic activity and decreased protein levels of the AChE splice variant tailed AChE (AChE-T). Only a slight increase in levels of readthrough AChE (AChE-R) was observed. Likewise, staurosporine reduced levels and activity of the cholinergic players choline acetyltransferase and high affinity choline uptake. The present study demonstrates that treatment with staurosporine leads to apoptotic events, which, however, are not reflected in the increased AChE activity and the alterations of AChE isoforms expression that are usually seen in apoptotic conditions. The effects of various additional phosphorylation inhibitors on AChE activity suggest that these unexpected cholinergic effects, firstly, are linked to the impact of staurosporine on phosphorylation and, secondly, reveal themselves in a first phase of cellular adaption that precedes neurotoxicity and subsequent cell death. PMID- 22841892 TI - In vivo hippocampal microdialysis reveals impairment of NMDA receptor-cGMP signaling in APP(SW) and APP(SW)/PS1(L166P) Alzheimer's transgenic mice. AB - Transgenic (Tg) mice overexpressing human amyloid precursor protein (APP) mutants reproduce features of early Alzheimer's disease (AD) including memory deficit, presence of beta-amyloid (Abeta) oligomers, and age-associated formation of amyloid deposits. In this study we used hippocampal microdialysis to characterize the signaling of N-methyl-d-aspartic acid receptors (NMDA-Rs) in awake and behaving AD Tg mice. The NMDA-R signaling is central to hippocampal synaptic plasticity underlying memory formation and several lines of evidence implicate the role of Abeta oligomers in effecting NMDA-R dysfunction. CA1 NMDA-Rs were stimulated by NMDA infused through reverse microdialysis while changes in the cyclic guanosine monophosphate (cGMP) concentration in the brain interstitial fluid (ISF) were used to determine NMDA-Rs responsiveness. While 4 months old wild type C57BL/6 mice mounted robust cGMP response to the NMDA challenge, the same stimulus failed to significantly change the cGMP level in 4 and 15 months old APP(SW) and 4 months old APP(SW)/PS1(L166P) Tg mice, which were all on C57BL/6 background. Lack of response to NMDA in AD Tg mice occurred in the absence of changes in expression levels of several synaptic proteins including synaptophysin, NR1 NMDA-R subunit and postsynaptic density protein 95, which indicates lack of profound synaptic degeneration. Abeta oligomers were detected in all three AD Tg mice groups and their concentration in the hippocampus ranged from 40.5+/-3.6ng/g in 4 months old APP(SW) mice to 60.8+/-15.9ng/g in 4 months old APP(SW)/PS1(L166P) mice. Four months old APP(SW) mice had no Abeta amyloid plaques, while the other two AD Tg mice groups showed evidence of incipient Abeta amyloid plaque formation. Our studies describes a novel approach useful to study the function of NMDA-Rs in awake and behaving AD Tg mice and demonstrate impairment of NMDA-R response in the presence of endogenously formed Abeta oligomers but predating onset of Abeta amyloidosis. PMID- 22841893 TI - Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients. AB - We investigated the prevalence and the strength of anti-HLA-Cw and DP antibodies and clinical outcomes in kidney transplant recipients with isolated donor specific anti-HLA-Cw antibodies. Patients on the waiting list were screened by Luminex single antigen beads (One Lambda). The strength of antibodies was determined by mean fluorescence intensity (MFI) values of the beads. Of the 1069 patients on the waiting list, 251 (24%) were sensitized with calculated panel reactive antibody >0%. The frequency and the median MFI values of anti-HLA antibodies to Cw (56%, 4955) and DP (35%, 2945) were lower than anti-HLA-A (79%, 10,194), B (86%, 11,235), DR (66%, 7866) and DQ (69%, 8283) (p<0.01). Among three major sensitizing events, only previous transplant was associated with development of all anti-HLA antibodies and history of pregnancy was associated only with development of anti-HLA-A antibodies. Eight patients with donor specific anti-HLA-Cw antibodies received transplantation. During a median 6 months of follow-up (range 3-24 months), patient and graft survival was 100% without any acute rejection. In summary, the prevalence and the strength of anti HLA-Cw and HLA-DP were lower compared to anti-HLA-A, B, DR, and DQ antibodies and previous organ transplantation was the main sensitizing event in our cohort of patients. PMID- 22841894 TI - Signaling of endothelial cytoprotection in transplantation. AB - A better knowledge of the processes by which endothelium can resist to cell death and adapt to injury by specific intracellular signaling pathways and dedicated protein regulation is a key step to understand how vascular inflammation/injury develops and how it is regulated. This review focuses on signaling pathways and molecular effectors that trigger the balance between endothelial cell activation and dysfunction. In addition to the canonical nuclear factor-kappaB (NF-kappaB), phosphatidyl inositol 3-kinase (PI-3K) and mitogen-activated protein kinases (MAPK) that orchestrated the inflammatory response and its termination we report here additive pathways such as Notch pathway and protein C/protease activated receptor (PAR) pathway that have been also reported to play a role in the control of EC activation and apoptosis. This review also provides an update of the characteristics of some established and novel protective molecules for the endothelium, identified in transplantation. PMID- 22841895 TI - Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase expression by endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress is induced in infectious and inflammatory conditions, but its role in inflammatory responses still remains elusive. In this study we found tunicamycin (TM) and brefeldin A (BFA), two ER stressors, could attenuate lipopolysaccharide (LPS)-elicited inducible nitric oxide synthase (iNOS) gene expression in murine RAW264.7 macrophages, and this effect was not resulting from the effects on IKK or MAPKs activation. However, ER stressors could block NF-kappaB binding to the iNOS promoter in late-phase signaling evoked by LPS. Results indicated that inhibition of RelB nuclear translocation and p300 expression are involved in the anti-inflammatory actions of ER stressors. We also found that ER stressors could block LPS- and IFN (alpha, beta, and gamma) mediated STAT1 phosphorylation. Our results suggest that activation of MKP-1 via a Ca/calmodulin/calcineurin pathway accounts for the inhibitory effect of ER stressors on IFN signaling. MKP-1 was downregulated by IFN-gamma and is a newly identified protein phosphatase targeting STAT1. Taken together, these results indicate that multiple mechanisms are involved in the inhibition of LPS-induced iNOS gene expression by ER stressors. These include downregulation of RelB and p300, upregulation of MKP-1, and inhibition of the JAK/STAT signaling pathway. PMID- 22841896 TI - Anxiolytic effects of standardized extract of Centella asiatica (ECa 233) after chronic immobilization stress in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica has long been used for various neurological disturbances in Southeast Asian countries. The present study aims to demonstrate the anxiolytic effect of ECa 233, a standardized extract of C. asiatica containing triterpenoids not less than 80%, in comparison to diazepam. MATERIALS AND METHODS: The test compound was given orally to non-stressed mice and mice subjected to chronic immobilization stress. Anxiolytic effect was assessed by an elevated plus maze (EPM), a dark-light box and an open-field tests. RESULTS: Anxiolytic effect of ECa 233 was clearly demonstrated in non stressed mice subjected to acute stress in all behavioral tests employed. In the EPM test, chronically stressed mice showed significant decrease in the number of open arm entries, shortening the time spent in open arms and an increase of the latency to leave the central area, suggesting their release from the stress. In addition, ameliorating effect of ECa 233 was observed on the body weight and serum corticosterone which were adversely affected by immobilization stress. Madecassoside and asiaticoside, equal to their respective contents of the effective doses of ECa 233, exclusively presented anxiolytic effects in EPM, while no distinct effect was observed on the body weight and serum corticosterone. CONCLUSIONS: The present study demonstrated anxiolytic effect of ECa 233 in both acutely and chronically stressed animals. These effects could be mainly accounted by madecassoside and asiaticoside, suggesting a possible use of ECa 233 for the treatment of both acute and chronic anxiety in the pathological state. PMID- 22841897 TI - 1alpha,25-Dihydroxyvitamin D(3) inhibits vascular cellular adhesion molecule-1 expression and interleukin-8 production in human coronary arterial endothelial cells. AB - Kawasaki disease is an acute febrile vasculitis of childhood that is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. The production of proinflammatory cytokines and expression of adhesion molecules in human coronary arterial endothelial cells (HCAECs) is regulated by nuclear transcription factor-kappaB (NF-kappaB) activation. We have previously reported that the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)), inhibits tumor necrosis factor-alpha (TNF-alpha) induced NF-kappaB activation. In this study, we examined the anti-inflammatory effects of 1alpha,25-(OH)(2)D(3) on TNF-alpha-induced adhesion molecule expression (vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)) and cytokine production (interleukin-6 (IL-6) and IL-8) in HCAECs. Pretreatment with 1alpha,25-(OH)(2)D(3) significantly inhibited TNF-alpha-induced VCAM-1 expression and IL-8 production in HCAECs. Our results suggest that adjunctive 1alpha,25-(OH)(2)D(3) therapy may modulate the inflammatory response during Kawasaki disease vasculitis. PMID- 22841898 TI - Postthrombotic syndrome: feasibility of a strategy of imaging-guided endovascular intervention. AB - PURPOSE: To describe the short-term efficacy of a strategy of imaging-guided endovascular intervention for the treatment of patients with established postthrombotic syndrome (PTS). MATERIALS AND METHODS: The medical records of 183 patients with venous disease who were seen in a single interventional radiology clinic were retrospectively reviewed. Study inclusion criteria were (i) endovascular intervention performed to treat established PTS from January 1, 2000, to March 10, 2009; (ii) patient age greater than 18 years; and (iii) availability of follow-up records. A total of 44 patients (20 men, 24 women; mean age, 42.2 y +/- 14.1) with PTS who had received 72 interventions (iliac vein stent placement [n = 52] and endovenous laser ablation [EVLA; n = 20]) were identified. A reviewer who did not participate in their care evaluated the follow up records; recorded the presence or absence of pain, swelling, and active ulceration; and categorized the degree of symptom improvement. RESULTS: Of 45 treated limbs in 40 patients with available follow-up, complete, partial, or no improvement of overall symptoms was observed in 46.7%, 33.3%, and 20.0%, respectively. The proportions of limbs with pain (35.0% after treatment vs 82.5% before; McNemar test, P < .01) and swelling (50.0% after treatment vs 90.0% before; P < .01) were significantly reduced after treatment with iliac vein stent placement and/or EVLA. Six of seven ulcerated limbs showed significant healing. CONCLUSIONS: The use of an endovascular strategy to treat patients with established PTS was associated with complete or partial symptom relief in 80% of patients at short-term follow-up. PMID- 22841899 TI - Garland vein: sequela of left innominate occlusion. PMID- 22841900 TI - The interventional radiology business plan. AB - Strategic planning and business planning are processes commonly employed by organizations that exist in competitive environments. Although it is difficult to prove a causal relationship between formal strategic/business planning and positive organizational performance, there is broad agreement that formal strategic and business plans are components of successful organizations. The various elements of strategic plans and business plans are not common in the vernacular of practicing physicians. As health care becomes more competitive, familiarity with these tools may grow in importance. Herein we provide an overview of formal strategic and business planning, and offer a roadmap for an interventional radiology-specific plan that may be useful for organizations confronting competitive and financial threats. PMID- 22841901 TI - Measurements of Brownian relaxation of magnetic nanobeads using planar Hall effect bridge sensors. AB - We compare measurements of the Brownian relaxation response of magnetic nanobeads in suspension using planar Hall effect sensors of cross geometry and a newly proposed bridge geometry. We find that the bridge sensor yields six times as large signals as the cross sensor, which results in a more accurate determination of the hydrodynamic size of the magnetic nanobeads. Finally, the bridge sensor has successfully been used to measure the change in dynamic magnetic response when rolling circle amplified DNA molecules are bound to the magnetic nanobeads. The change is validated by measurements performed in a commercial AC susceptometer. The presented bridge sensor is, thus, a promising component in future lab-on-a-chip biosensors for detection of clinically relevant analytes, including bacterial genomic DNA and proteins. PMID- 22841890 TI - Animal models for medications development targeting alcohol abuse using selectively bred rat lines: neurobiological and pharmacological validity. AB - The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID- 22841902 TI - Resolution of sustained narrow complex ventricular tachycardia and tachycardia induced cardiomyopathy in a Quarter Horse following quinidine therapy. AB - Sustained narrow-QRS tachycardia of three months duration and left ventricular systolic dysfunction were identified in a fifteen-year-old Quarter Horse. No underlying cause for the tachyarrhythmia was found and no predisposing structural cardiac lesions were evident by echocardiography. Intravenous diltiazem and lidocaine were administered without achieving successful conversion of the arrhythmia. Oral quinidine therapy converted the tachyarrhythmia to sinus rhythm. Ventricular systolic dysfunction and chamber dilatation subsequently resolved. As with other species, echocardiographic features of dilated cardiomyopathy can be tachycardia-induced and may resolve following successful control of heart rate and rhythm. PMID- 22841903 TI - Efficacy of two commercially available cardiac pacing catheters for transesophageal atrial pacing in dogs. AB - OBJECTIVE: Compare the efficacy of two cardiac pacing catheters for transesophageal atrial pacing (TAP). ANIMALS: Ten healthy dogs. METHODS: Transesophageal atrial pacing was attempted in left lateral recumbency under general anesthesia. In series, a curved electrophysiologic (EP) catheter and a straight transesophageal pacing (TP) catheter were passed transorally into the distal esophagus, caudal to the heart. Each catheter was slowly withdrawn until pacing was initiated. The catheter continued to be withdrawn in 5 mm increments until capture was no longer achieved at maximal pacing setting creating a total zone of capture (tZOC). Minimum pacing threshold (Th(min)) and degree of extraneous muscle stimulation (EMS) were determined at each site. RESULTS: The EP catheter achieved TAP in 10/10 dogs with a Th(min) of 8.8 +/- 4.8 mA and tZOC of 4.0 +/- 1.7 cm. The TP catheter achieved TAP in 7/10 dogs with a Th(min) of 22.5 +/- 5.6 mA and tZOC of 1.2 +/- 1.6 cm. No EMS was noted during TAP at Th(min) using the EP catheter. Of the 7 dogs in which TAP was successful, 3/7 experienced considerable EMS at Th(min). There was no significant relationship between patient body weight and Th(min) with either catheter (EP catheter P = 0.09; TP catheter P = 0.81). CONCLUSIONS: The electrophysiology catheter captured the atria of more dogs over a larger area without EMS as compared to the TP catheter. The electrophysiology catheter is recommended for transesophageal atrial pacing in dogs. PMID- 22841904 TI - Spirocercosis in owned and stray dogs in Grenada. AB - The aim of this retrospective study was to estimate the prevalence of Spirocerca lupi and its associated lesions in owned and stray dogs in Grenada. During 2001 2011 necropsies were carried out on 1022 owned and 450 stray dogs at the pathology diagnostic laboratory, School of Veterinary Medicine, St. George's University, Grenada. Lesions due to S. lupi characterized by focal to multifocal granulomatous esophagitis with aneurysms, mineralized plaques and nodules in the adjacent thoracic aorta were found in 90 (8.8%; 95% confidence interval, 7.1 10.5%) of owned dogs and 64 (14.2%; 95% CI, 11.2-17.6%) of stray dogs. Stray dogs were significantly more affected by spirocercosis than owned dogs (p=0.0022). Of the 90 owned dogs with spirocercosis, 3 dogs had aberrant migration to the thoracic vertebral column with resultant spondylitis; 1 dog each had aberrant migration involving the stomach and the lung. Two dogs had ruptured aorta with hemothorax. Among the 64 stray dogs with spirocercosis, one dog had an esophageal granuloma that transformed into a fibroblastic osteosarcoma; spondylitis due to aberrant migration of S. lupi and hypertrophic osteopathy. We report spirocercosis for the first time in the dogs from a tropical island of Grenada. PMID- 22841905 TI - Supracoronary ascending aortic replacement in patients with acute aortic dissection type A: what happens to the aortic root in the long run? AB - OBJECTIVE: Our objective was to determine long-term outcome predictors for patients with acute aortic dissection type A (AADA) and aortic root involvement. METHODS: From 2001 through 2009, 119 of 152 patients operated on for AADA at a tertiary medical center underwent supracoronary ascending aortic replacement (52 women; mean age, 61 +/- 15 years). Those with at least 1-year follow-up (n = 97) were retrospectively assessed for preoperative aortic root disease. Follow-up data were assessed for evidence of new-onset aortic root disease by computed tomography and echocardiography, and for reoperation for aortic root disease. RESULTS: Median follow-up was 33.8 months (range, 0-112 months). Twenty-six (27%) patients had new-onset aortic root disease at 4.4 +/- 2.6 years after the initial procedure (range, 1.0-8.2 years) and 10 required aortic root reoperation. Severe aortic dissection with extension to pelvic arteries was an independent predictor for new-onset aortic root disease (P < .01). Dissection of all aortic sinuses during the initial procedure was an independent predictor (P < .05) for aortic root reoperation. Mean rate of aortic root expansion after supracoronary repair was 0.6 +/- 1.1 mm per year. Preoperative aortic root diameter and aortic sinus dissection did not affect survivals. Five-year survivals were similar in patients with and without new-onset aortic root disease (91% vs 89%; P = .79). CONCLUSIONS: In patients with AADA, dissection of 3 aortic sinuses is an independent predictor for need of reoperation, whereas dissection extension into the iliac arteries is a predictor of secondary aortic root disease. Long-term follow-up at close intervals is warranted in patients with supracoronary ascending aortic replacement to reduce mortality caused by new onset of aortic root disease. PMID- 22841907 TI - Surgical management after stent-graft failure during the frozen elephant trunk technique for acute type A aortic dissection. PMID- 22841906 TI - Temporary biventricular pacing decreases the vasoactive-inotropic score after cardiac surgery: a substudy of a randomized clinical trial. AB - OBJECTIVE: Vasoactive medications improve hemodynamics after cardiac surgery but are associated with high metabolic and arrhythmic burdens. The vasoactive inotropic score was developed to quantify vasoactive and inotropic support after cardiac surgery in pediatric patients but may be useful in adults as well. Accordingly, we examined the time course of this score in a substudy of the Biventricular Pacing After Cardiac Surgery trial. We hypothesized that the score would be lower in patients randomized to biventricular pacing. METHODS: Fifty patients selected for increased risk of left ventricular dysfunction after cardiac surgery and randomized to temporary biventricular pacing or standard of care (no pacing) after cardiopulmonary bypass were studied in a clinical trial between April 2007 and June 2011. Vasoactive agents were assessed after cardiopulmonary bypass, after sternal closure, and 0 to 7 hours after admission to the intensive care unit. RESULTS: Over the initial 3 collection points after cardiopulmonary bypass (mean duration, 131 minutes), the mean vasoactive inotropic score decreased in the biventricular pacing group from 12.0 +/- 1.5 to 10.5 +/- 2.0 and increased in the standard of care group from 12.5 +/- 1.9 to 15.5 +/- 2.9. By using a linear mixed-effects model, the slopes of the time courses were significantly different (P = .02) and remained so for the first hour in the intensive care unit. However, the difference was no longer significant beyond this point (P = .26). CONCLUSIONS: The vasoactive-inotropic score decreases in patients undergoing temporary biventricular pacing in the early postoperative period. Future studies are required to assess the impact of this effect on arrhythmogenesis, morbidity, mortality, and hospital costs. PMID- 22841908 TI - Possible application of the Environmental Relative Moldiness Index in France: a pilot study in Brittany. AB - Our goal was to determine if the US Environmental Relative Moldiness Index (ERMI) scale might have application in France. Twenty homes in Brittany, north western region of France were classified by inspection as "Moldy" or "Non-Moldy". Dust and air samples were collected (MiTest sampler or Coriolis sampler, respectively) from each home and analyzed by quantitative polymerase chain reaction (QPCR) for the 36 fungi that make-up the ERMI. Inspection and ERMI values provided a consistent assessment for 90% of the homes. Two homes originally classified as "Non-Moldy" were found to fit better into the "Moldy" category based on the QPCR analysis and the ERMI. Dust and air samples analyzed by QPCR provided similar fungal contamination assessments. In conclusion, a metric like the ERMI describes mold burdens in homes on a continuum, as opposed to the frequently used dichotomous approach (moldy vs. non-moldy). Although a larger, random national sampling of French homes is needed, these results suggest that these same 36 fungi may be useful in creating an ERMI for France. PMID- 22841909 TI - The effect of antifungal agents on surface properties of poly(methyl methacrylate) and its relation to adherence of Candida albicans. AB - PURPOSE: Candida-associated denture stomatitis is the most prevalent form of oral candidosis affecting 65% of denture wearers. Failure of therapy and recurrence of infection are not uncommon and the continuous use of antifungal agents may affect the surface properties of the denture material and may contribute to Candida adhesion. This study aimed to investigate surface properties of poly(methyl methacrylate) PMMA denture material before and after exposure to antifungal agents and its relation to in vitro adhesion of Candida albicans. METHODS: Four groups of acrylic specimens (20 mm * 20 mm * 2.5mm) were prepared (25 specimens in each group). Specimens were immersed in nystatin (group 1), fluconazole (group 2), distilled water (group 3) and group 4 was not exposed. Specimens were tested for surface roughness, contact angle, surface hardness and in vitro Candida adherence to PMMA. RESULTS: The results showed that nystatin had no statistically significant effect on surface hardness (P>0.05), but had a statistically significant effect on surface roughness, contact angle, and Candida adhesion to PMMA (P<0.05). On the other hand, fluconazole had no statistically significant effect on surface hardness or roughness (P>0.05), but had a statistically significant effect on contact angle, and Candida adhesion to PMMA (P<0.05). Distilled water had no statistically significant effect on surface hardness, roughness, contact angle, or Candida adhesion to PMMA (P>0.05). CONCLUSIONS: Exposure of PMMA to nystatin may induce changes in roughness, wettability while exposure to fluconazole may affect surface free energy and therefore may increase Candida adhesion to it. PMID- 22841911 TI - Inducing repetitive action potential firing in neurons via synthesized photoresponsive nanoscale cellular prostheses. AB - Recently we reported an analysis that examined the potential of synthesized photovoltaic functional abiotic nanosystems (PVFANs) to modulate membrane potential and activate action potential firing in neurons. Here we extend the analysis to delineate the requirements on the electronic energy levels and the attendant photophysical properties of the PVFANs to induce repetitive action potential under continuous light, a capability essential for the proposed potential application of PVFANs as retinal cellular prostheses to compensate for loss of photoreceptors. We find that repetitive action potential firing demands two basic characteristics in the electronic response of the PVFANs: an exponential dependence of the PVFAN excited state decay rate on the membrane potential and a three-state system such that, following photon absorption, the electron decay from the excited state to the ground state is via intermediate state(s) whose lifetime is comparable to the refractory time following an action potential. FROM THE CLINICAL EDITOR: In this study, the potential of synthetic photovoltaic functional abiotic nanosystems (PVFANs) is examined under continuous light to modulate membrane potential and activate action potential firing in neurons with the proposed potential application of PVFANs as retinal cellular prostheses. PMID- 22841910 TI - Nanoparticle uptake in tumors is mediated by the interplay of vascular and collagen density with interstitial pressure. AB - Nanoparticle delivery into solid tumors is affected by vessel density, interstitial fluid pressure (IFP) and collagen, as shown in this article by contrasting the in vivo macroscopic quantitative uptake of 40 nm fluorescent beads in three tumor types.The fluorescence uptake was quantified on individual animals by normalization with the transmitted light and then normalized to normal tissue uptake in each mouse. Mean data for uptake in individual tumor lines then showed expected trends with the largest uptake in the most vascularized tumor line. Tumor lines with increased collagen were also consistent with highest interstitial fluid pressure and correlated with lowest uptake of nanoparticles. The data is consistent with a delivery model indicating that while vascular permeability is maximized by neovascular growth, it is inhibited by collagen content and the resulting interstitial pressure. Imaging of these parameters in vivo can lead to better individual noninvasive methods to assess drug penetration in situ. FROM THE CLINICAL EDITOR: In this manuscript the dependence of nanoparticle delivery is addressed from the standpoint of vascular factors (the more vascularized, the better delivery) and as a function of collagen density and interstitial pressure (the higher these are, the worse the delivery). PMID- 22841912 TI - Gold nanocages as contrast agents for two-photon luminescence endomicroscopy imaging. AB - We explored the possibility of using gold (Au) nanocages as a new class of exogenous contrast agents for endomicroscopic nonlinear imaging. The two-photon luminescence cross-section of nanocages was characterized. Two-photon luminescence endomicroscopy imaging of a phantom, cancer cells and biological tissues was performed, demonstrating that Au nanocages can potentially serve as an effective molecular contrast agent for nonlinear endomicroscopy imaging. FROM THE CLINICAL EDITOR: In this study, the utility of Au nanocages is described in a variety of settings as effective molecular contrast agent for nonlinear endomicroscopy imaging. PMID- 22841913 TI - In vivo visualization of gold-loaded cells in mice using x-ray computed tomography. AB - The ability to perform cell tracking using x-ray computed tomography combined with gold nanoparticles has been demonstrated recently on ex vivo samples using different malignant and nonmalignant cell lines. Here we proved the concept of the method for in vivo assessment in a small-animal model of malignant brain tumors. The limitations of the method due to radiation dose constraints were investigated using Monte Carlo simulations. Taking into consideration different x ray entrance doses and the spatial resolution, the visibility of the cell clusters was evaluated. The results of the experiments conducted on mice implanted with F98 tumor cells confirmed the prediction of the Monte Carlo calculations. Small clusters of cells exogenously loaded with gold nanoparticles could be visualized using our in vivo method. FROM THE CLINICAL EDITOR: This article discusses the use of CT-based detection of gold nanoparticle loaded cells of interest in small-animal models of malignant brain tumors, where small clusters of cells loaded with gold nanoparticles could be visualized. PMID- 22841914 TI - RGD-based cell ligands for cell-targeted drug delivery act as potent trophic factors. AB - Integrin-binding, Arg-Gly-Asp (RGD)-containing peptides are the most widely used agents to deliver drugs, nanoparticles, and imaging agents. Although in nature, several protein-mediated signal transduction events depend on RGD motifs, the potential of RGD-empowered materials in triggering undesired cell-signaling cascades has been neglected. Using an RGD-functionalized protein nanoparticle, we show here that the RGD motif acts as a powerful trophic factor, supporting extracellular signal-regulated kinase 1/2 (ERK1/2)-linked cell proliferation and partial differentiation of PC12 cells, a neuronlike model. FROM THE CLINICAL EDITOR: This work focuses on RGD peptides, which are among the most commonly used tags for targeted drug delivery. They also promote protoneurite formation and expression of neuronal markers (MAP2) in model PC12 cells, which is an unexpected but relevant event in the functionalization of drugs and their nanocarriers. PMID- 22841915 TI - Drug transport by Organic Anion Transporters (OATs). AB - Common to all so far functionally characterized Organic Anion Transporters (OATs) is their broad substrate specificity and their ability to exchange extracellular against intracellular organic anions. Many OATs occur in renal proximal tubules, the site of active drug secretion. Exceptions are murine Oat6 (nasal epithelium), human OAT7 (liver), and rat Oat8 (renal collecting ducts). In human kidneys, OAT1, OAT2, and OAT3 are localized in the basolateral membrane, and OAT4, OAT10, and URAT1 in the apical cell membrane of proximal tubule cells, respectively. In rats and mice, Oat1 and Oat3 are located basolaterally, and Oat2, Oat5, Oat9, Oat10, and Urat1 apically. Several classes of drugs interact with human OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, beta-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs. For most drugs, interaction was demonstrated in vitro by inhibition of OAT-mediated transport of model substrates; for some drugs, transport by OATs was directly proven. Based on IC50 values reported in the literature, OAT1 and OAT3 show comparable affinities for diuretics, cephalosporins, and nonsteroidal anti-inflammatory drugs whereas OAT2 has a lower affinity to most of these compounds. Drug-drug interactions at OAT1 and OAT3 may retard renal drug secretion and cause untoward effects. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, and OAT10 to nicotinate absorption. OAT4 is in addition able to release drugs, e.g. diuretics, into the tubule lumen. PMID- 22841916 TI - Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats. AB - Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1 mg/mL drinking solution for 30 days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22841917 TI - Cognitive enhancement by omega-3 fatty acids from child-hood to old age: findings from animal and clinical studies. AB - Omega-(n)-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are major components of neuronal membranes and have a wide range of functions, from modulating synaptic plasticity and neurochemistry, to neuroimmune-modulation and neuroprotection. Thus, it is not surprising that n-3 PUFA are widely acknowledged to have cognitive-enhancing effects. Although clinical evidence is somewhat conflicting, probably in large part due to methodological issues, animal studies have consistently demonstrated that n-3 PUFA are indispensable for proper brain development, may enhance cognitive function in healthy, adult individuals and attenuate cognitive impairment in aging and age-related disorders, such as dementia. This review discusses and integrates up to date evidence from clinical and animal studies investigating the cognitive-enhancing effects of n-3 PUFA during development, child- and adult-hood, as well as old-age with associated neurodegenerative diseases, such as Alzheimer's disease. Furthermore, we cover the major underlying biochemical and neurophysiological mechanisms by which n-3 PUFA mediate these effects on cognition. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22841918 TI - Diazeniumdiolate-doped poly(lactic-co-glycolic acid)-based nitric oxide releasing films as antibiofilm coatings. AB - Nitric oxide (NO) releasing films with a bilayer configuration are fabricated by doping dibutyhexyldiamine diazeniumdiolate (DBHD/N2O2) in a poly(lactic-co glycolic acid) (PLGA) layer and further encapsulating this base layer with a silicone rubber top coating. By incorporating pH sensitive dyes within the films, pH changes in the PLGA layer are visualized and correlated with the NO release profiles (flux vs. time). It is demonstrated that PLGA acts as both a promoter and controller of NO release from the coating by providing protons through its intrinsic acid residues (both end groups and monomeric acid impurities) and hydrolysis products (lactic acid and glycolic acid). Control of the pH changes within the PLGA layer can be achieved by adjusting the ratio of DBHD/N2O2 and utilizing PLGAs with different hydrolysis rates. Coatings with a variety of NO release profiles are prepared with lifetimes of up to 15 d at room temperature (23 degrees C) and 10 d at 37 degrees C. When incubated in a CDC flow bioreactor for a one week period at RT or 37 degrees C, all the NO releasing films exhibit considerable antibiofilm properties against gram-positive Staphylococcus aureus and gram-negative Escherichia coli. In particular, compared to the silicone rubber surface alone, an NO releasing film with a base layer of 30 wt% DBHD/N2O2 mixed with poly(lactic acid) exhibits an ~98.4% reduction in biofilm biomass of S. aureus and ~99.9% reduction for E. coli at 37 degrees C. The new diazeniumdiolate-doped PLGA-based NO releasing coatings are expected to be useful antibiofilm coatings for a variety of indwelling biomedical devices (e.g., catheters). PMID- 22841919 TI - The effect of co-culturing costal chondrocytes and dental pulp stem cells combined with exogenous FGF9 protein on chondrogenesis and ossification in engineered cartilage. AB - Dental pulp stem cells (DPSCs), which arise from cranial neural crest cells, are multipotent, making them a candidate for use in tissue engineering that may be especially useful for craniofacial tissues. Costal chondrocytes (CCs) can be easily obtained and demonstrate higher initial cell yields and expansion than articular chondrocytes. CCs have been found to retain chondrogenic capacity that can effectively repair articular defects. In this study, human CCs were co cultured with human DPSCs, and the results showed that the CCs were able to supply a chondro-inductive niche that promoted the DPSCs to undergo chondrogenic differentiation and to enhance the formation of cartilage. Although CCs alone could not prevent the mineralization of chondro-differentiated DPSCs, CCs combined with exogenous FGF9 were able to simultaneously promote the chondrogenesis of DPSCs and partially inhibit their mineralization. Furthermore, FGF9 may activate this inhibition by binding to FGFR3 and enhancing the phosphorylation of ERK1/2 in DPSCs. Our results strongly suggest that the co culture of CCs and DPSCs combined with exogenous FGF9 can simultaneously enhance chondrogenesis and partially inhibit ossification in engineered cartilage. PMID- 22841920 TI - Cellular uptake and reactive oxygen species modulation of cerium oxide nanoparticles in human monocyte cell line U937. AB - Cerium oxide nanoparticles (nanoceria) are promising materials for intracellular oxygen free radical scavenging providing a potential therapy for reactive oxygen species (ROS)-mediated inflammatory processes. In this study rhombohedral-shaped nanoceria were synthesized by flame spray pyrolysis with tuneable particle diameters between 3 and 94 nm by changing the liquid precursor flow rate. Monocytes and macrophages are major players in inflammatory processes as their production of ROS species has important downstream effects on cell signalling. Therefore, this study examined the ability of the nanoceria to be internalised by the human monocytic cell line, U937, and scavenge intracellular ROS. U937 cells activated in the presence of phorbol 12-myristate 13-acetate (PMA) were found to be more responsive to the nanoceria than U937 cells, which may not be surprising given the role of monocyte/macrophages in phagocytosing foreign material. The smaller particles were found to contain more crystal lattice defects with which to scavenge ROS, however a greater proportion of both the U937 and activated U937 cell populations responded to the larger particles. Hence all nanoceria particle sizes examined in this study were equally effective in scavenging intracellular ROS. PMID- 22841921 TI - Rotavirus capsid surface protein VP4-coated Fe(3)O(4) nanoparticles as a theranostic platform for cellular imaging and drug delivery. AB - The development of a theranostic nanoplatform based on rotavirus structural protein VP4-coated Fe(3)O(4) nanoparticles (NPs) for dual modality magnetic resonance/fluorescence cellular imaging and drug delivery is reported. VP4 protein was obtained from Escherichia coli approach, and then chemically conjugated to Fe(3)O(4) NPs premodified with meso-2,3-dimercaptosuccinnic acid (DMSA) in the presence of 1-ethyl-3-(3-dimethyaminopropyl) carbodiimide (EDC). Next, the VP4-coated Fe(3)O(4) NPs were loaded with doxorubicin (DOX), a typical anticancer drug, via formation of amide bond through the EDC approach. Prussian blue staining analysis reveals that the VP4-coated Fe(3)O(4) NPs can be internalized efficiently by MA104 and HepG2 cells, thereby significantly improving cellular MRI sensitivity, compared with dextran- and BSA-coated Fe(3)O(4) NPs. In addition, DOX loaded on the VP4-coated Fe(3)O(4) NPs exhibits significant cytotoxicity to the cancer cells (HepG2). The current work provides a general approach toward the rational design and synthesis of a versatile theranostic nanoplatform based on functional protein-coated magnetic NPs with good biocompatibility, biodegradability, and capability of simultaneously performing multimodality imaging and therapy for optimal clinical outcomes. PMID- 22841922 TI - Iterative design of peptide-based hydrogels and the effect of network electrostatics on primary chondrocyte behavior. AB - Iterative peptide design was used to generate two peptide-based hydrogels to study the effect of network electrostatics on primary chondrocyte behavior. MAX8 and HLT2 peptides have formal charge states of +7 and +5 per monomer, respectively. These peptides undergo triggered folding and self-assembly to afford hydrogel networks having similar rheological behavior and local network morphologies, yet different electrostatic character. Each gel can be used to directly encapsulate and syringe-deliver cells. The influence of network electrostatics on cell viability after encapsulation and delivery, extracellular matrix deposition, gene expression, and the bulk mechanical properties of the gel cell constructs as a function of culture time was assessed. The less electropositive HLT2 gel provides a microenvironment more conducive to chondrocyte encapsulation, delivery, and phenotype maintenance. Cell viability was higher for this gel and although a moderate number of cells dedifferentiated to a fibroblast-like phenotype, many retained their chondrocytic behavior. As a result, gel-cell constructs prepared with HLT2, cultured under static in vitro conditions, contained more GAG and type II collagen resulting in mechanically superior constructs. Chondrocytes delivered in the more electropositive MAX8 gel experienced a greater degree of cell death during encapsulation and delivery and the remaining viable cells were less prone to maintain their phenotype. As a result, MAX8 gel-cell constructs had fewer cells, of which a limited number were capable of laying down cartilage-specific ECM. PMID- 22841923 TI - Decellularization methods of porcine kidneys for whole organ engineering using a high-throughput system. AB - End-stage renal failure is a devastating disease, with donor organ transplantation as the only functional restorative treatment. The current number of donor organs meets less than one-fifth of demand, so regenerative medicine approaches have been proposed as potential therapeutic alternatives. One such approach for whole large-organ bioengineering is to combine functional renal cells with a decellularized porcine kidney scaffold. The efficacy of cellular removal and biocompatibility of the preserved porcine matrices, as well as scaffold reproducibility, are critical to the success of this approach. We evaluated the effectiveness of 0.25 and 0.5% sodium dodecyl sulfate (SDS) and 1% Triton X-100 in the decellularization of adult porcine kidneys. To perform the decellularization, a high-throughput system was designed and constructed. In this study all three methods examined showed significant cellular removal, but 0.5% SDS was the most effective detergent (<50 ng DNA/mg dry tissue). Decellularized organs retained intact microarchitecture including the renal vasculature and essential extracellular matrix components. The SDS-treated decellularized scaffolds were non-cytotoxic to primary human renal cells. This method ensures clearance of porcine cellular material (which directly impacts immunoreactivity during transplantation) and preserves the extracellular matrix and cellular compatibility of these renal scaffolds. Thus, we have developed a rapid decellularization method that can be scaled up for use in other large organs, and this represents a step toward development of a transplantable organ using tissue engineering techniques. PMID- 22841924 TI - Steadily propagating waves of a chemotaxis model. AB - This paper studies the existence, asymptotic decay rates, nonlinear stability, wave speed and chemical diffusion limits of traveling wave solutions to a chemotaxis model describing the initiation of angiogenesis and reinforced random walk. By transforming the chemotaxis system, via a Hopf-Cole transformation, into a system of conservation laws, the authors studied the traveling wave solutions of the transformed system in previous papers. One of the purposes of this paper is to transfer the results of the transformed system to the original Keller-Segel chemotaxis model. It turns out that only partial results of the transformed system have physical meaning when they are passed back to the original system. Thus the transformed system is not entirely equivalent to the original system. Particularly the chemical growth rate parameter appeared in the original system vanishes in the transformed system. Hence to understand the role of this parameter, one has to go back to the original system. Moreover, we establish some new results on zero chemical diffusion limits of traveling wave solutions. Numerical simulations of steadily propagating waves are shown. PMID- 22841925 TI - Molecular origin of female meiotic aneuploidies. AB - Chromosome aneuploidy is a major cause of pregnancy loss, abnormal pregnancy and live births following both natural conception and in vitro fertilisation (IVF) and increases exponentially with maternal age in the decade preceding the menopause. Molecular genetic analysis has shown that these are predominantly maternal in origin and trisomies most frequently occur through errors in the first meiotic division. Analysis of chromosome copy number in the three products of female meiosis, the first and second polar bodies and the corresponding zygote by microarray comparative genomic hybridisation (array CGH), in women of advanced maternal age undergoing IVF, has recently revealed a pattern of frequent multiple meiotic errors, caused by premature predivision of sister chromatids in meiosis I and a high incidence of errors in meiosis II. This pattern is similar to those observed in various mouse models which implicate the gradual depletion of cohesins, which are essential for cohesion of sister chromatids, as the primary cause of age related aneuploidy in female meiosis. However, defects in other aspects of meiosis including the formation and stabilisation of chiasmata and the spindle assembly checkpoint (SAC) may also contribute. The challenge remains to explain the molecular basis of 'physiological' rather than 'chronological' female ageing and the contribution of multifactorial causes from the fetal to adult ovary. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. PMID- 22841926 TI - Autosomal mutations and human spermatogenic failure. AB - Infertility, defined as the inability to conceive after 1 year of unprotected intercourse, is a healthcare problem that has a worldwide impact. Male factors are involved in at least half of these cases of infertility. Despite 3 years of assisted reproductive activities, a considerable number of cases (25-30%) remain idiopathic. This situation can be explained by a poor understanding of the basic mechanisms driving male and female gametogenesis. Compared to multi-organ pathologies, only a few non-syndromic genetic causes of human infertility have been described so far, despite the fact that it is estimated that some infertility cases could be explained by genetic causes and that over 200 infertile or subfertile genetic mouse models have been described. So far, very little has been discovered in the field of human male reproductive genetics. Consequently, genetic tests proposed to infertile couples are limited, although worldwide efforts devoted to the field of human genetics of infertility are expected to provide new genetic tests in the near future. We present the requirements for performing informative genetics studies in the field of infertility, the techniques used and the results obtained so far. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. PMID- 22841927 TI - Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer. AB - This study is aimed at investigating whether or not human leukocyte antigen-G (HLA-G) expression is associated with breast cancer molecular subtypes. HLA-G expression was immunohistochemically investigated in 104 patients with invasive ductal breast carcinoma, in which 56 were luminal A, 17 were luminal B, 19 were HER-2, and 12 were basal-like/normal breast-like subtype classified according to immunohistochemical staining results of ER, HER-2, CK5/6, and EGFR. Host immune response status was assessed by estimating the density of tumor infiltrating lymphocytes (TIL). For comparison, other biomarkers such as Ki67, p53 and VEGF were also investigated. Associations of these biomarkers and TIL with molecular subtypes were statistically analyzed. We found that there were more cases with high expressions of HLA-G in non-luminal than in luminal subtypes (P=0.035). In contrast, more cases with high density of TIL was found in luminal than in non luminal subtypes (P=0.023). Compared to all the biomarkers studied, only HLA-G expression was found to be inversely associated with the density of TIL (P=0.004). Furthermore, patients with HLA-G(high)/TIL(low) status had a higher risk of recurrence than those with HLA-G(low)/TIL(high) status, regardless of the molecular subtypes. Therefore, a combination of the status of HLA-G and TIL could improve the prognostic prediction for patients with various molecular subtypes of breast cancer. PMID- 22841928 TI - Cancer mode of action, weight of evidence, and proposed cancer reference value for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX, CAS No. 121-82-4) is a component of munitions formulations, and has been detected in groundwater samples collected at various US military sites. Clean up target levels for RDX may be derived based on consideration of acceptable cumulative human exposure as expressed in toxicity reference values. Evaluations of the cancer weight of evidence and possible modes of action (MOA) for RDX-induced cancer were conducted. It was concluded that the available data provide suggestive evidence of human carcinogenic potential for RDX. While a mutagenic/genotoxic MOA for RDX is unlikely, no alterative MOA is strongly supported by the available data. A nonlinear (threshold) approach to the assessment of human cancer risk was recommended, and a recommended chronic cancer reference dose of 0.08mg/kg/day was derived. For comparison only, computations using a linear approach were also conducted, yielding a cancer risk specific dose of 0.000235mg/kg/day for 1 in 10(5) risk; this value is 2.6-fold higher the current US EPA risk specific dose for 1 in 10(5) risk. Thus, cleanup standards based on human health risk from RDX exposure could potentially depend on the willingness of risk managers to accept a nonlinear MOA and nonlinear toxicity risk value derivation. PMID- 22841929 TI - Recruitment of Hispanics into an observational study of chronic kidney disease: the Hispanic Chronic Renal Insufficiency Cohort Study experience. AB - Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21-74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD. PMID- 22841931 TI - p62/SQSTM1/A170: physiology and pathology. AB - p62/SQSTM1/A170 (hereafter referred to as p62) is a stress-inducible intracellular protein known to regulate various signal transduction pathways involved in cell survival and cell death. Comprehensive analysis of LC3 (an autophagosome localizing protein)-binding proteins resulted in the recognition of autophagy and p62. While autophagy modulates the level of p62 protein, p62 can suppress autophagy via activation of mTORC1. Moreover, growing lines of evidence point to the important role of p62 in directing ubiquitinated cargos toward autophagy as well as compaction of those cargos. Furthermore, this protein functions as a signaling hub for various signal transduction pathways, such as NF kappaB signaling, apoptosis, and Nrf2 activation, whose dysregulation is associated with Paget disease of bone and tumorigenesis. In this review, we discuss the pathophysiological significance of p62 and its role in autophagy. PMID- 22841930 TI - Informing the dosing of interventions in randomized trials. AB - Dosing is potentially the most important decision that must be made when building or refining behavioral interventions. In this paper, we propose standardized terminology and reporting of dosing information, which would inform intervention development, refinement for dissemination, and systematic reviews of dose response relationships. Dosing of interventions may be characterized by duration, frequency, and amount. To illustrate the value of operationalizing these three parameters to evaluate dose-response relationships, 31 published reports of behavioral interventions to increase adherence to antiretroviral therapy (ART) were reviewed. The ART literature was characterized by under-reporting of dosing parameters, heterogeneity in dosing schedules, and heterogeneity in type of control group, which complicate analysis of dose-response relationships in systematic review and determination of the optimal dose for intervention dissemination. Improved reporting of the three dosing parameters and comparison of intended to actual delivery can inform the identification of the most effective intervention doses and the efficient implementation of efficacious interventions in clinical practice. PMID- 22841932 TI - Sequential imaging of asymptomatic carotid atheroma using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging: a feasibility study. AB - BACKGROUND: Inflammation within atheromatous plaques is a known risk factor for plaque vulnerability. This can be detected in vivo on high-resolution magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxide (USPIO) contrast medium. The purpose of this study was to assess the feasibility of performing sequential USPIO studies over a 1-year period. METHODS: Ten patients with moderate asymptomatic carotid stenosis underwent carotid MRI imaging both before and 36 hours after USPIO infusion at 0, 6, and 12 months. Images were manually segmented into quadrants, and the signal change per quadrant was calculated at these time points. A mixed repeated measures statistical model was used to determine signal change attributable to USPIO uptake over time. RESULTS: All patients remained asymptomatic during the study. The mixed model revealed no statistical difference in USPIO uptake between the 3 time points. Intraclass correlation coefficients revealed a good agreement of quadrant signal pre-USPIO infusion between 0 and 6 months (0.70) and 0 and 12 months (0.70). Good agreement of quadrant signal after USPIO infusion was shown between 0 and 6 months (0.68) and moderate agreement was shown between 0 and 12 months (0.33). CONCLUSIONS: USPIO-enhanced sequential MRI of atheromatous carotid plaques is clinically feasible. This may have important implications for future longitudinal studies involving pharmacologic intervention in large patient cohorts. PMID- 22841933 TI - Protein kinase C (PKC) isozyme-specific substrates and their design. AB - Protein kinase C (PKC), a phospholipid-dependent serine/threonine kinase, appears to be involved in the signal transduction response to many hormones and growth factors; there are 11 different PKC isozymes. Because PKC isozymes directly and/or indirectly participate in signal transduction pathways of normal and transformed cells through phosphorylation of target proteins, it is critical to understand the diversity of the intracellular signaling pathways regulated by each PKC isozyme. Thus, PKC isozyme-specific substrates are useful to understand the characterization of the intracellular signaling pathways for each PKC isozyme. Consensus sequences and sequence information obtained from PKC target proteins are very important to design PKC isozyme-specific peptide substrates. Moreover, computational prediction programs of phosphorylation sites using a library of peptide substrates aid in the fast design of PKC isozyme-specific peptide substrates. Although a large number of target proteins and synthetic peptides for PKCs are known, only two peptide substrates (peptide 422-426 of murine elongation factor-1alpha and Alphatomega peptide) have been reported as PKC isozyme-specific peptide substrates. This discussion will review the literature concerning these native and synthetic PKC isozyme-specific peptide substrates and their design. PMID- 22841934 TI - Wetlands shrinkage, fragmentation and their links to agriculture in the Muleng Xingkai Plain, China. AB - In the past five decades, the wetlands in the Muleng-Xingkai Plain, Northeast China, have experienced rapid shrinkage and fragmentation. In this study, wetlands cover change and agricultural cultivation were investigated through a time series of thematic maps from 1954, and Landsat satellite images representing the last five decades (1976, 1986, 1995, 2000, and 2005). Wetlands shrinkage and fragmentation were studied based on landscape metrics and the land use changes transition matrix. Furthermore, the driving forces were explored according to socioeconomic development and major natural environmental factors. The results indicate a significant decrease in the wetlands area in the past five decades, with an average annual decrease rate of 9004 ha/yr. Of the 625,268 ha of native wetlands in 1954, approximately 64% has been converted to other land use types by 2005, of which conversion to cropland accounts for the largest share (83%). The number of patches decreased from 1272 (1954) to 197 (1986) and subsequently increased to 326 (2005). The mean patch size changed from 480 ha (1954) to 1521 ha (1976), and then steadily decreased to 574 ha (2005). The largest patch index (total core area index) indicates wetlands shrinkage with decreased values from 31.73 (177,935 ha) to 3.45 (39,421 ha) respectively. Climatic changes occurred over the study period, providing a potentially favorable environment for agricultural development. At the same time population, groundwater harvesting, and fertilizer application increased significantly, resulting in wetlands degradation. According to the results, the shrinkage and fragmentation of wetlands could be explained by socioeconomic development and secondarily aided by changing climatic conditions. PMID- 22841935 TI - Utilization of ground waste seashells in cement mortars for masonry and plastering. AB - In this research, four types of waste seashells, including short-necked clam, green mussel, oyster, and cockle, were investigated experimentally to develop a cement product for masonry and plastering. The parameters studied included water demand, setting time, compressive strength, drying shrinkage and thermal conductivity of the mortars. These properties were compared with those of a control mortar that was made of a conventional Portland cement. The main parameter of this study was the proportion of ground seashells used as cement replacement (5%, 10%, 15%, or 20% by weight). Incorporation of ground seashells resulted in reduced water demand and extended setting times of the mortars, which are advantages for rendering and plastering in hot climates. All mortars containing ground seashells yielded adequate strength, less shrinkage with drying and lower thermal conductivity compared to the conventional cement. The results indicate that ground seashells can be applied as a cement replacement in mortar mixes and may improve the workability of rendering and plastering mortar. PMID- 22841936 TI - Cognitive interventions in healthy older adults and people with mild cognitive impairment: a systematic review. AB - Given that the research area of cognitive intervention studies in the aging population is growing rapidly, it is important to review and gauge more recent intervention studies, in order to determine the evidence for the effectiveness of cognitive interventions. The purpose of the present review was to update the recent systematic reviews of Papp et al. (2009) and Martin et al. (2011), to evaluate the effectiveness of cognitive interventions in healthy older adults and people with MCI, by taking into account the methodological quality of the interventions studies. A systematic review of randomized controlled trials (RCT) and clinical studies published between August 2007 and February 2012 in Pubmed and PsychINFO was performed. The quality of the included RCTs was assessed according to the CONSORT criteria for RCTs. A total of thirty-five studies were included; twenty-seven RTCs and eight clinical studies. The content of the intervention studies differed widely, as did the methodological quality of the included RCTs, but was considerably low with an average of 44% of the Consort items included. The results show evidence that cognitive training can be effective in improving various aspects of objective cognitive functioning; memory performance, executive functioning, processing speed, attention, fluid intelligence, and subjective cognitive performance. However, the issue whether the effects of cognitive interventions generalize to improvement in everyday life activities is still unresolved and needs to be addressed more explicitly in future research. PMID- 22841938 TI - Pathologic basis of improving the screening utility of 2-dimensional placental morphology ultrasound. AB - OBJECTIVE: To determine the utility of measuring maximum placental length in the second trimester to predict a small for gestational age placenta by weight at delivery in clinically high-risk women. STUDY DESIGN: Placental dimensions determined by 2-dimensional (2-D) real-time ultrasound at 19-23 weeks' gestation were compared to post-natal placental weights and pathology in 95 high-risk patients with singleton pregnancies. RESULTS: Maximum placental length <10.0 cm performed poorly (false positive rate 25.5%) for the detection of a small placenta by weight at delivery. Placental pathology examination revealed eccentric cord insertion to be an important explanation for poor screening test result, since this finding was significantly more common in the false negative group (length >= 10.0 cm, weight <10th percentile) compared with the true negative group (length >= 10.0 cm, weight >= 10 th percentile) (15/28 vs. 9/38, Fisher's exact test, p = 0.005). CONCLUSIONS: Prediction of reduced placental weight by 2-D ultrasound determination of maximum placental length in clinically high-risk pregnancies confounded by the phenomenon of asymmetric chorion regression. Refinement of 2-D ultrasound methods to include orthogonal plane measurements, or replacement by 3-D techniques is predicted to significantly improve the effectiveness of diagnosing small placentas in-utero. PMID- 22841937 TI - Volumetric-modulated arc therapy (RapidArc) vs. conventional fixed-field intensity-modulated radiotherapy for 18F-FDG-PET-guided dose escalation in oropharyngeal cancer: a planning study. AB - Fluorine-18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity modulated radiotherapy (IMRT) focal dose escalation plans. MATERIALS AND METHODS: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to 18F-FDG-PET-positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gy in 30 fractions). Fixed-field IMRT and double arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI(Paddick)) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI(Paddick) scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 +/- 0.03 [RapidArc] vs. 0.77 +/- 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 +/- 1 Gy for spinal cord and 1.9 +/- 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8-49.2% with RapidArc (largest difference at DL3, 641 +/- 94 vs. 1261 +/- 118, p < 0.01). 18F-FDG-PET guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU. PMID- 22841939 TI - Vascular endothelial growth factor A (VEGFA) modulates bovine placenta steroidogenesis in vitro. AB - Our objectives were to investigate the possible role of VEGFA in bovine placenta steroid synthesis and to determine whether cloned derived placental cells present similar responses as non-cloned ones. Placental cells from cloned (term) and non cloned (days 90, 150, 210 and term) pregnancies were isolated and treated with VEGFA (50 ng/ml) for 24, 48 or 96 h. Progesterone (P(4)) and estrone sulfate (E(1)S) were assessed by RIA, while aromatase P450-positive cells were quantified using the point counting test. The percentages of steroidogenic and non steroidogenic populations were determined by flow cytometry. VEGFA augmented or decreased P(4) and E(1)S concentrations as well as aromatase P450-positive cell density, depending on gestational age and time in culture. The percentage of steroidogenic cells was lower than that of non-steroidogenic ones for each culture time (P < 0.05). VEGFA treatment did not change the proportion of steroidogenic and non-steroidogenic cells. Placental cells derived from cloned pregnancies presented higher concentrations of E(1)S and P4 than the non-cloned group. However, aromatase P450-positive cells were similar between groups (P > 0.05). VEGFA treatment altered P(4) and E(1)S levels in placental cells depending on type of gestation. These results suggest that VEGFA acts locally in the bovine placenta to modulate steroidogenesis during gestation, but in a different pattern between cloned and non-cloned derived placental cells at term. Therefore, this factor can be considered an important regulator of placental development and function. PMID- 22841940 TI - The M-Sorter: an automatic and robust spike detection and classification system. AB - Neural spike detection and classification, or spike sorting, is the first and a critical step prior to any single unit based neuroscientific studies and applications. A good spike sorter is usually characterized by high detection and classification accuracy, robust to changes in signal-to-noise ratio, objectivity in detection results or less user dependency, and real-time applicability. Here we present an automatic and robust spike detection and classification system, the M-Sorter, based on the multiple correlation of wavelet coefficients (MCWC) detection algorithm in conjunction with template matching for classification. Unlike many existing spike sorters that make use of a series of complex spike classifiers to deal with the challenges resulted from a low performance spike detector, the M-Sorter relies on a high performance yet computationally efficient detection algorithm and thus a simple classifier suffices to generate high quality spike sorting results. In this paper we provide step by step implementation procedures of the M-Sorter, and compare its performance with other popular sorters. PMID- 22841941 TI - Research priorities for suicide by self-immolation: beyond quantitative approaches. PMID- 22841942 TI - Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections. AB - MALDI MS imaging has been extensively used to produce qualitative distribution maps of proteins, peptides, lipids, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. There is growing demand to quantify the amount of target compounds in the tissue sections of different organs. We present a novel MS imaging software including protocol for the quantitation of drugs, and for the first time, an endogenous neuropeptide directly in tissue sections. After selecting regions of interest on the tissue section, data is read and processed by the software using several available methods for baseline corrections, subtractions, denoising, smoothing, recalibration and normalization. The concentrations of in vivo administered drugs or endogenous compounds are then determined semi-automatically using either external standard curves, or by using labeled compounds, i.e., isotope labeled analogs as standards. As model systems, we have quantified the distribution of imipramine and tiotropium in the brain and lung of dosed rats. Substance P was quantified in different mouse brain structures, which correlated well with previously reported peptide levels. Our approach facilitates quantitative data processing and labeled standards provide better reproducibility and may be considered as an efficient tool to quantify drugs and endogenous compounds in tissue regions of interest. PMID- 22841943 TI - Proteomic footprints of a member of Glossinavirus (Hytrosaviridae): an expeditious approach to virus control strategies in tsetse factories. AB - The Glossinavirus (Glossina pallidipes salivary gland hypertrophy virus (GpSGHV)) is a rod-shaped enveloped insect virus containing a 190,032 bp-long, circular dsDNA genome. The virus is pathogenic for the tsetse fly Glossina pallidipes and has been associated with the collapse of selected mass-reared colonies. Maintenance of productive fly colonies is critical to tsetse and trypanosomiasis eradication in sub-Saharan Africa using the Sterile Insect Technique. Proteomics, an approach to define the expressed protein complement of a genome, was used to further our understanding of the protein composition, morphology, morphogenesis and pathology of GpSGHV. Additionally, this approach provides potential targets for novel and sustainable molecular-based antiviral strategies to control viral infections in tsetse colonies. To achieve this goal, identification of key protein partners involved in virus transmission is required. In this review, we integrate the available data on GpSGHV proteomics to assess the impact of viral infections on host metabolism and to understand the contributions of such perturbations to viral pathogenesis. The relevance of the proteome findings to tsetse and trypanosomiasis management in sub-Sahara Africa is also considered. PMID- 22841944 TI - Eugregarines reduce susceptibility of the hide beetle, Dermestes maculatus, to apicomplexan pathogens and retard larval development. AB - Eugregarines are abundant in a great diversity of invertebrates, and yet their relationships with their hosts are subject to controversy and confusion. We tested the effect of the eugregarine, Pyxinia crystalligera, on growth, development, and susceptibility to two Apicomplexa pathogens of the hide beetle, D. maculatus. Heavy infection with eugregarines provided partial protection from two pathogenic members of Apicomplexa, M. trogodermae and A. tribolii. Infection with P. crystalligera caused lower weight in beetle larvae, but did not significantly retard pupation or adult emergence. A. tribolii infection of Lepidoptera and M. trogodermae infection of D. maculatus are reported for the first time. PMID- 22841945 TI - Wide interguild relationships among entomopathogenic and free-living nematodes in soil as measured by real time qPCR. AB - Entomopathogenic nematodes (EPNs) are promising biological control agents of soil dwelling insect pests of many crops. These nematodes are ubiquitous in both natural and agricultural areas. Their efficacy against arthropods is affected directly and indirectly by food webs and edaphic conditions. It has long been suggested that a greater understanding of EPN ecology is needed to achieve consistent biological control by these nematodes and the development of molecular tools is helping to overcome obstacles to the study of cryptic organisms and complex interactions. Here we extend the repertoire of molecular tools to characterize soil food webs by describing primers/probe set to quantify certain free-living, bactivorous nematodes (FLBNs) that interact with EPNs in soil. Three FLBN isolates were recovered from soil baited with insect larvae. Morphological and molecular characterization confirmed their identities as Acrobeloides maximum (RT-1-R15C and RT-2-R25A) and Rhabditis rainai (PT-R14B). Laboratory experiments demonstrated the ability of these FLBNs to interfere with the development of Steinernema diaprepesi, Steinernema riobrave and Heterorhabditis indica parasitizing the weevil Diaprepes abbreviatus (P<0.001), perhaps due to resource competition. A molecular probe was developed for the strongest competitor, A. maximum. We selected the highly conserved SSU rDNA sequence to design the primers/probe, because these sequences are more abundantly available for free living nematodes than ITS sequences that can likely provide better taxonomic resolution. Our molecular probe can identify organisms that share ?98% similarity at this locus. The use of this molecular probe to characterize soil communities from samples of nematode DNA collected within a citrus orchard revealed positive correlations (P<0.01) between Acrobeloides-group nematodes and total numbers of EPNs (S. diaprepesi, H. indica and Heterorhabditis zealandica) as well as a complex of nematophagous fungi comprising Catenaria sp. and Monachrosporium gephyropagum that are natural enemies of EPNs. These relationships can be broadly interpreted as supporting Linford's hypothesis, i.e., decomposition of organic matter (here, insect cadavers) greatly increases bactivorous nematodes and their natural enemies. PMID- 22841946 TI - Muscavirus (MdSGHV) disease dynamics in house fly populations--how is this virus transmitted and has it potential as a biological control agent? AB - The newly classified family Hytrosaviridae comprises several double-stranded DNA viruses that have been isolated from various dipteran species. These viruses cause characteristic salivary gland hypertrophy and suppress gonad development in their hosts. One member, Muscavirus or MdSGHV, exclusively infects adult house flies (Musca domestica) and, owing to its massive reproduction in and release from the salivary glands, is believed to be transmitted orally among feeding flies. However, results from recent experiments suggest that additional transmission routes likely are involved in the maintenance of MdSGHV in field populations of its host. Firstly, several hours before newly emerged feral flies begin feeding activities, the fully formed peritrophic matrix (PM) constitutes an effective barrier against oral infection. Secondly, flies are highly susceptible to topical virus treatments and intrahemocoelic injections. Thirdly, disease transmission is higher when flies are maintained in groups with infected conspecifics than when flies have access to virus-contaminated food. We hypothesize that interactions between flies may lead to cuticular damage, thereby providing an avenue to viral particles for direct access to the hemocoel. Based on our current knowledge, two options seem plausible for developing Muscavirus as a sterilizing agent to control house fly populations: The virus may either be formulated with PM-disrupting materials to facilitate oral infection from a feeding bait system, or amended with abrasive materials to enhance infection through a damaged cuticle after topical aerosol applications. PMID- 22841947 TI - The use of entomopathogenic fungi in the control of tsetse flies. AB - Tsetse flies harbor a number of pathogens in nature; but their potential as biological control agents has not been fully exploited, especially due to the difficulty of their application in the field. Since entomopathogenic fungi infect their target organisms through the cuticle, it has been possible to develop a device that deliver and autodisseminate inoculum among tsetse in the field, resulting in population reduction, comparable to mass-trapping technology. However, the success of this technology depends on the effective horizontal transmission of the inoculum between insects. We present an overview of the prospects of entomopathogenic fungi for the control of tsetse flies and highlight the challenges. PMID- 22841948 TI - The bacterial flora of tsetse fly midgut and its effect on trypanosome transmission. AB - The tsetse fly, Glossina palpalis is a vector of the trypanosome that causes sleeping sickness in humans and nagana in cattle along with associated human health problems and massive economic losses. The insect is also known to carry a number of symbionts such as Sodalis, Wigglesworthia, Wolbachia whose effects on the physiology of the insect have been studied in depth. However, effects of other bacterial flora on the physiology of the host and vector competence have received little attention. Epidemiological studies on tsetse fly populations from different geographic sites revealed the presence of a variety of bacteria in the midgut. The most common of the flora belong to the genera Entrobacter (most common), Enterococcus, and Acinetobacter. It was a little surprising to find such diversity in the tsetse midgut since the insect is monophagous consuming vertebrate blood only. Diversity of bacteria is normally associated with polyphagous insects. In contrast to the symbionts, the role of resident midgut bacterial flora on the physiology of the fly and vector competence remains to be elucidated. With regard, Sodalis glossinidius, our data showed that flies harbouring this symbiont have three times greater probability of being infected by trypanosomes than flies without the symbiont. The data delineated in these studies under score the need to carry out detailed investigations on the role of resident bacteria on the physiology of the fly and vector competence. PMID- 22841949 TI - Prevalence of SGHV among tsetse species of economic importance in Tanzania and their implication for SIT application. AB - Sterile Insect technique is an important component in area-wide integrated tsetse control. The presence of the salivary glands hypertrophy virus (SGHV) in the wild tsetse, which are the seeds for colony adaptations in the laboratory has become a stumbling block in establishing and maintaining colonies in the laboratory. The virus is transmitted both vertically (in the wild) and horizontally (in the laboratory). However, its prevalence is magnified in the laboratory as a result of the use of in vitro membrane feeding regimen. Fly species of Glossina fuscipes fuscipes, G. pallidipes, G. morsitans and G. swynnertoni were collected from the coastal and inland areas of Tanzania and virus infection rates were assessed microscopically and by PCR. The data showed that in a period of 4years, the virus was present in all species tested irrespective of their ages, sex, and season of the year. However, infection levels differed among species and from one location to another. Symptomatic infection determined by dissection was 1.2% (25/2164) from the coast as compared to 0.4% (6/1725) for inland collected flies. PCR analysis indicated a higher infection rate of 19.81% (104/525) of asymptomatic flies. From these observations, we conclude that care should be taken when planning to initiate tsetse laboratory colonies for use in SIT eradication program. All efforts should be made to select non-infected flies when initiating laboratory colonies and to try to minimize the infection with SGHV. Also management of SGHV infection in the established colony should be applied. PMID- 22841950 TI - Enhancing tsetse fly refractoriness to trypanosome infection--a new IAEA coordinated research project. AB - To date, IAEA-supported Sterile Insect Technique (SIT) projects for tsetse and trypanosomiasis control have been in areas without human sleeping sickness, but future projects could include areas of actual or potential human disease transmission. In this context it would be imperative that released sterile tsetse flies are incompetent to transmit the disease-causing trypanosome parasite. Therefore, development of tsetse fly strains refractory to trypanosome infection is highly desirable as a simple and effective method of ensuring vector incompetence of the released flies. This new IAEA Coordinated Research Project (CRP) focuses on gaining a deeper knowledge of the tripartite interactions between the tsetse fly vectors, their symbionts and trypanosome parasites. The objective of this CRP is to acquire a better understanding of mechanisms that limit the development of trypanosome infections in tsetse and how these may be enhanced. PMID- 22841951 TI - Tse tse fly symposium. Foreword. PMID- 22841952 TI - New insights into gill chemoreception: receptor distribution and roles in water and air breathing fish. AB - The location (gills, oro-branchial cavity or elsewhere) and orientation (external (water) or internal (blood) sensing) of the receptors involved in reflex changes in each of the different components of the cardiorespiratory response (breathing frequency, breath amplitude, heart rate, systemic vascular resistance) to hypoxia and hypercarbia are highly variable between species of water and air breathing fish. Although not universal, the receptors involved in eliciting changes in heart rate and breathing frequency in response to hypoxia and hypercarbia tend to be restricted exclusively to the gills while those producing increases in breath amplitude are more wide spread, frequently also being found at extrabranchial sites. The distribution of the chemoreceptors sensitive to CO(2) in the gills involved in producing ventilatory responses tend to be more restricted than that of the O(2)-sensitive chemoreceptors and the specific location of the receptors involved in the various components of the cardiorespiratory response can vary from those of the O(2)-sensitive chemoreceptors. PMID- 22841953 TI - Effects of long term exposure to the mycotoxin fumonisin B1 in p53 heterozygous and p53 homozygous transgenic mice. AB - The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis. PMID- 22841954 TI - Water spinach (Ipomoea aquatic Forsk.) reduced the absorption of heavy metals in an in vitro bio-mimicking model system. AB - This study was conducted to investigate the effect of water spinach on bioaccessibility and intestinal uptake of heavy metals (Arsenic (As), Cadmium (Cd), and Lead (Pb)) using an in vitro digestion model with Caco-2 cells. Aliquots of each heavy metal were co-digested with each part of water spinach (stem and leaf) and then cultured with Caco-2 intestinal cells for 1h at 37 degrees C. Each heavy metal of As, Cd, and Pb was quantified using an ICP-OES. As the amount of stem and leaf (10, 50, 100, and 500 mg) of water spinach increased, bioaccessibility of As, Cd, and Pb decreased to 42.63%, 12.04%, and 26.17% by leaf and 30.37%, 43.27%, 40.07% by stem, respectively. Intestinal uptake of As, Cd, and Pb reduced to 65.8%, 25.7%, and 44.8% for leaf (500 mg) and 48.4%, 51.3%, and 64.3% for stem (500mg), respectively, compared with the control without leaf and stem. The leaf from water spinach was the most effective for decreasing both bioaccessibility and cellular uptake of Cd. PMID- 22841955 TI - A high oxfendazole dose to control porcine cysticercosis: pharmacokinetics and tissue residue profiles. AB - Oxfendazole (OFZ) is efficacious for porcine cysticercosis at 30 mg/kg. OFZ is not registered to be used at this dose. The assessment of the OFZ and metabolites [(fenbendazole sulphone (FBZSO2), fenbendazole (FBZ)] plasma pharmacokinetic and tissue residue profiles after its oral administration to pigs and the withdrawal period for human consumption were reported. Forty-eight pigs allocated into two groups received OFZ (30 mg/kg) orally as a commercial (CF) or as experimental formulation (SMF). Samples (blood, muscle, liver, kidney and fat) were collected over 30 days post-treatment and analyzed by HPLC. OFZ was the main compound recovered in plasma, followed by FBZSO2 and low FBZ concentrations. OFZ AUC0-LOQ (209.9+/-33.9 MUg.h/ml) and Cmax (5.40+/-0.65 MUg/ml) parameters for the CF tended to be higher than those for the SMF (AUC0-LOQ: 159.4+/-18.3 MUg h/ml, Cmax: 3.80+/-0.35 MUg/ml). The highest total residue (OFZ+FBZSO2+FBZ) concentrations were quantified in liver, followed by kidney, muscle and fat tissue. FBZSO2 residue levels were the highest found in muscle (0.68+/-0.39 MUg/g) and fat (0.69+/-0.39 MUg/g). In liver and kidney the highest residues corresponded to FBZ (5.29+/-4.36 MUg/g) and OFZ (2.86+/-0.75 MUg/g), respectively. A withdrawal time of 17 days post-treatment was established before tissues are delivered for human consumption. PMID- 22841956 TI - Rgs19 regulates mouse palatal fusion by modulating cell proliferation and apoptosis in the MEE. AB - Palatal development is one of the critical events in craniofacial morphogenesis. During fusion of the palatal shelves, removal of the midline epithelial seam (MES) is a fundamental process for achieving proper morphogenesis of the palate. The reported mechanisms for removing the MES are the processes of apoptosis, migration or general epithelial-to-mesenchymal transition (EMT) through modulations of various signaling molecules including Wnt signaling. RGS19, a regulator of the G protein signaling (RGS) family, interacts selectively with the specific alpha subunits of the G proteins (Galphai, Galphaq) and enhances their GTPase activity. Rgs19 was reported to be a modulator of the Wnt signaling pathway. In mouse palatogenesis, the restricted epithelial expression pattern of Rgs19 was examined in the palatal shelves, where expression of Wnt11 was observed. Based on these specific expression patterns of Rgs19 in the palatal shelves, the present study examined the detailed developmental function of Rgs19 using AS-ODN treatments during in vitro palate organ cultivations as a loss-of function study. After the knockdown of Rgs19, the morphological changes in the palatal shelves was examined carefully using a computer-aided three dimensional reconstruction method and the altered expression patterns of related signaling molecules were evaluated using genome wide screening methods. RT-qPCR and in situ hybridization methods were also used to confirm these array results. These morphological and molecular examinations suggested that Rgs19 plays important roles in palatal fusion through the degradation of MES via activation of the palatal fusion related and apoptotic related genes. Overall, inhibition of the proliferation related and Wnt responsive genes by Rgs19 are required for proper palatal fusion. PMID- 22841957 TI - Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3beta/beta catenin pathway. AB - Autism is a spectrum of neurodevelopmental disorders characterized by social isolation and lack of interaction. Anatomically, autism patients often show macrocephaly and high neuronal density. To investigate the mechanism underlying the higher neuronal populations seen in ASD, we subcutaneously injected VPA (400 mg/kg) into pregnant Sprague-Dawley rats on E12, an animal model often used in ASD study. Alternatively, cultured rat neural progenitor cells were treated with VPA. Until E18, VPA induced NPC proliferation and delayed neurogenesis in fetal brain, but the subsequent differentiation of NPCs to neurons increased brain neuronal density afterward. Similar findings were observed with NPCs treated with VPA in vitro. At a molecular level, VPA enhanced Wnt1 expression and activated the GSK-3beta/beta-catenin pathway. Furthermore, inhibition of this pathway attenuated the effects of VPA. The findings of this study suggest that an altered developmental process underlies the macrocephaly and abnormal brain structure observed in the autistic brain. PMID- 22841958 TI - Induction of lucid dreams: a systematic review of evidence. AB - In lucid dreams the dreamer is aware of dreaming and often able to influence the ongoing dream content. Lucid dreaming is a learnable skill and a variety of techniques is suggested for lucid dreaming induction. This systematic review evaluated the evidence for the effectiveness of induction techniques. A comprehensive literature search was carried out in biomedical databases and specific resources. Thirty-five studies were included in the analysis (11 sleep laboratory and 24 field studies), of which 26 employed cognitive techniques, 11 external stimulation and one drug application. The methodological quality of the included studies was relatively low. None of the induction techniques were verified to induce lucid dreams reliably and consistently, although some of them look promising. On the basis of the reviewed studies, a taxonomy of lucid dream induction methods is presented. Several methodological issues are discussed and further directions for future studies are proposed. PMID- 22841959 TI - Obsessive-compulsive tendencies may be associated with attenuated access to internal states: evidence from a biofeedback-aided muscle tensing task. AB - The present study was motivated by the hypothesis that inputs from internal states in obsessive-compulsive (OC) individuals are attenuated, which could be one source of the pervasive doubting and checking in OCD. Participants who were high or low in OC tendencies were asked to produce specific levels of muscle tension with and without biofeedback, and their accuracy in producing the required muscle tension levels was assessed. As predicted, high OC participants performed more poorly than low OC participants on this task when biofeedback was not available. When biofeedback was provided, the difference between the groups was eliminated, and withdrawing the monitor again reversed this effect. Finally, when given the opportunity, high OC participants were more likely than low OC participants to request biofeedback. These results suggest that doubt in OCD may be grounded in a real and general deficiency in accessing internal states. PMID- 22841960 TI - Selection and maturation of antibodies by phage display through fusion to pIX. AB - Antibody discovery and optimization by M13 phage display have evolved significantly over the past twenty years. Multiple methods of antibody display and selection have been developed - direct display on pIII or indirect display through a Cysteine disulfide linkage or a coiled-coil adapter protein. Here we describe display of Fab libraries on the smaller pIX protein at the opposite end of the virion and its application to discovery of novel antibodies from naive libraries. Antibody selection based on pIX-mediated display produces results comparable to other in vitro methods and uses an efficient direct infection of antigen-bound phages, eliminating any chemical dissociation step(s). Additionally, some evidence suggests that pIX-mediated display can be more efficient than pIII-mediated display in affinity selections. Functional assessment of phage-derived antibodies can be hindered by insufficient affinities or lack of epitopic diversity. Here we describe an approach to managing primary hits from our Fab phage libraries into epitope bins and subsequent high throughput maturation of clones to isolate epitope- and sequence-diverse panels of high affinity binders. Use of the Octet biosensor was done to examine Fab binding in a facile label-free method and determine epitope competition groups. A receptor extracellular domain and chemokine were subjected to this method of binning and affinity maturation. Parental clones demonstrated improvement in affinity from 1-100nM to 10-500pM. PMID- 22841962 TI - Two paradoxes and a surprise on the road to an understanding of systemic lupus erythematosus. AB - Whereas systemic lupus erythematosus (SLE) as normally encountered results from the coming together of a complex mix of genetic and environmental factors, SLE also develops in virtually all those rare people who lack a functional gene for the first component of complement (C1q). The pathogenic IgG antibodies against double-stranded DNA characteristic of the disease are made in response to nucleosomes - the package of DNA and histone molecules forming the unit structure of chromatin - which are present in apoptotic cells. Analysis of the C1q phenomenon illuminates the arrangements that are normally in place to ensure tolerance is maintained to nucleosomal antigens. Surprisingly in view of the high level of apoptosis occurring in the thymus, it appears that anti-histone helper T cells, which are likely to be required for IgG anti-DNA production, are not deleted in the thymus. It seems rather that tolerance is maintained by non availability of antigen brought about by the highly efficient C1q-dependent phagocytosis of apoptotic cells. This 'immunological ignorance' may be backed up by mechanisms of peripheral tolerance if antigen does become available. Idiopathic SLE may arise when apoptotic cell clearance is sub-optimal, making clearance a promising target for therapy. PMID- 22841961 TI - Amino acid substitutions in LcrV at putative sites of interaction with Toll-like receptor 2 do not affect the virulence of Yersinia pestis. AB - LcrV, a component of the type III secretion system (T3SS) translocon in Yersinia pestis, has been concerned in suppressing inflammation through Toll-like receptor 2 (TLR2) by inducing expression of the anti-inflammatory cytokine interleukin-10 (IL-10). Previous studies have reported that LcrV aa E33, E34, K42 and/or E204 and E205 were important for interactions with TLR2 in vitro. While, recently there have been conflicting reports doubting this interaction and its importance in vivo. To further investigate the role of these residues, we replaced the wild type lcrV gene on the pCD1Ap virulence plasmid of Y. pestis with lcrV2345 gene, which encodes a mutant protein by substituting all five of the amino acid residues with glutamine. The characteristics of the wild-type LcrV and mutant LcrV2345 were evaluated in tissue culture and mice. When purified protein was incubated with HEK293 cells synthesizing human TLR2 with or without CD14, LcrV2345 induced higher levels of IL-8 than wild-type LcrV, indicating that the LcrV2345 was not impaired in its ability to interact with TLR2. LcrV2345 stimulated higher levels of tumor necrosis factor-alpha (TNF-alpha) production than LcrV in J774A.1 cells, while neither protein elicited significant levels of IL-10. We also found there was no statistically significant difference in virulence between strains with wild-type LcrV and with mutated LcrV2345 administered by either subcutaneous or intranasal route in mice. Additionally, there were no discernible differences in survival kinetics. Serum levels of cytokines, such as IL-10 and TNF-alpha, bacterial burden, and the extent of organ inflammation were also indistinguishable in both strains. Our data confirm that immunomodulation mediated by LcrV/TLR2 interactions does not play a significant role in the pathogenicity of Y. pestis. PMID- 22841964 TI - Retinal attenuates inflammatory arthritis by reciprocal regulation of IL-17 producing T cells and Foxp3(+) regulatory T cells and the inhibition of osteoclastogenesis. AB - Retinoids (e.g., vitamin A and its derivatives) can regulate immune responses. The aim of this study was to determine whether all-trans retinaldehyde (retinal), a vitamin A derivative, can inhibit inflammatory responses and joint destruction in DBA/1J mice with collagen-induced arthritis (CIA). The arthritis score and incidence of arthritis were lower in mice treated with retinal compared to those treated with cottonseed oil. Histopathologic evidence of joint damage was lower in mice treated with retinal, corresponding with a reduction in the infiltration of immune cells in mice treated with retinal type II collagen (CII)-stimulated spleen cells. In addition, the expression of proinflammatory cytokines, oxidative stress proteins, and osteoclast markers were significantly reduced in mice treated with retinal. In vitro, retinal induced increased Foxp3 expression and inhibited Th17 development. The proportion of Foxp3(+) Treg cells was increased in the spleens of mice treated with retinal, whereas the proportion of Th17 cells was reduced. In both mice and a human culture system, tartrate-resistant acid phosphatase (TRAP) positive mononuclear cells and multinucleated cells were significantly reduced after treatment with retinal. The expression of osteoclast differentiation markers was dramatically decreased upon addition of retinal. This is the first study to demonstrate the therapeutic effect of retinal on an autoimmune arthritis model in mice through reciprocal regulation of Th17 and regulatory T cells and protection of differentiation and activation of osteoclasts. Taken together, our findings indicate that retinal has profound immunoregulatory functions and potential value for the treatment of autoimmune inflammatory disorders. PMID- 22841965 TI - Identifying emerging trends in recreational drug use; outcomes from the Psychonaut Web Mapping Project. AB - BACKGROUND: This paper presents the outcomes of the 2-year European Union funded Psychonaut Web Mapping Project which aimed at developing and implementing an integrated web mapping system to promptly identify and learn about novel psychoactive substances (NPS; "legal highs") through the regular monitoring of the Internet. METHODS: More than 200 discussion forums, social media, online shops, websites and other Internet resources (e.g. YouTube, eBay, Google, Google Insight) have been extensively and regularly monitored in 7 European countries (UK, Finland, Norway, Belgium, Germany, Italy and Spain) for emerging trends of NPS throughout the period of the study. RESULTS: Key online resources have been identified as "leading edge" which have provided accurate and timely information on novel emerging compounds. In total more than 400 substances/products have been recorded. NPS have been noted online before reaching wider audiences. DISCUSSION: Although a high number of novel psychoactive substances have been identified in the 2-year duration of the project, not all have become trends that needed public health response. Conversely, new recreational drug phenomena such as "spice drugs," mephedrone and naphyrone were all identified as emerging trends in forums and websites. In addition, it has been possible for the first time to collate detailed information on these and several more compounds even though no or limited scientific publications were available. It is therefore recommended that these monitoring activities are to be continued, that more countries, researchers and health professionals are involved, and that the findings are widely shared with all the relevant agencies, health professionals and future research projects. Implications, advantages and limitations of using the Internet as primary source for identifying emerging trends are also discussed. PMID- 22841963 TI - Interferon-inducible Ifi200-family genes as modifiers of lupus susceptibility. AB - Both genetic and environmental factors contribute to the development and progression of systemic lupus erythematosus (SLE), a complex autoimmune disease. The disease exhibits a strong gender bias and develops predominantly in females. Additionally, most SLE patients exhibit increased serum levels of interferon alpha (IFN-alpha) and the "IFN signature". Studies using the mouse models of lupus have identified several lupus susceptibility loci, including the New Zealand Black (NZB)-derived autoimmunity 2 (Nba2) interval on the chromosome 1. The interval, which is syntenic to the human chromosome 1q region, harbors the FcgammaR family, SLAM/CD2-family, and the IFN-inducible Ifi200-family genes (encoding for the p200-family proteins). Studies involving the B6.Nba2 congenic mice revealed that the development of antinuclear autoantibodies (ANAs) depends on the age, gender, and activation of type I IFN-signaling. Interestingly, recent studies involving the generation of Nba2 subcongenic mouse lines and generation of mice deficient for the Fcgr2b or Aim2 gene within the interval have provided evidence that epistatic interactions among the Nba2 genes contribute to increased lupus susceptibility. Given that the expression of some of the p200-family proteins is differentially regulated by sex hormones and these proteins differentially regulate cytosolic DNA-induced production of type I IFN and proinflammatory cytokines (IL-1beta and IL-18), the major known contributors of SLE-associated inflammation, we discuss the recent advancements in our understanding of the role of p200-family proteins in lupus susceptibility modification. An improved understanding of the role of p200-family proteins in the development of autoimmunity is likely to identify new approaches to treat SLE patients. PMID- 22841966 TI - Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. AB - Numerous evidence and proofs suggest that the oxidative stress contributes to the pathogenesis of schizophrenia (SZ) and bipolar disorder (BD). The aim of this study is to determine the glutathione levels and the antioxidant enzyme activities in blood samples of patients suffering from SZ and patients with bipolar disorder in comparison with the healthy controlled subjects. It was a case-controlled study carried on upon three groups: forty-six SZ patients (41 men and 5 women, mean age=33.2+/-7years), thirty BD patients (25 men and 5 women, mean age=31.3+/-8years) and forty healthy controls (33 men and 7 women, mean age=32.3+/-7years). The glutathione levels are the total glutathione (GSHt), the reduced glutathione (GSHr), and the oxidized glutathione (GSSG) and the antioxidant enzyme activities that are the superoxide dismutase (SOD), the glutathione peroxidase (GPx), and the catalase (CAT) are determined by the spectrophotometer. We noticed that the GSHt and the GSHr levels significantly decreased in both SZ and BD patients in comparison with the healthy control subjects. As for SOD and CAT activities they remained lower for the patients with SZ when compared both with the controls or the BD patients. We noticed as well that the CAT activity was significantly lower in the BD group than that in the control group, whereas, GPx activity showed no significant change in each group. Hence, this report of the decreased plasma levels of GSHt and GSHr, and the impaired antioxidant enzyme activities in SZ and BD patients aims at highlighting the GSH deficit that seems to be contributing to these disorders, and showing that it may be an important indirect biomarker of the oxidative stress for the SZ and BD. PMID- 22841967 TI - Calcaneal quantitative ultrasound compared with hip and femoral neck dual-energy x-ray absorptiometry in people with a spinal cord injury. AB - OBJECTIVE: To evaluate the sensitivity and specificity of calcaneal quantitative ultrasound (QUS) measurements for identifying osteoporosis determined by dual energy x-ray absorptiometry (DXA) at the hip in a spinal cord injury (SCI) population. DESIGN: Cross-sectional retrospective review of data collected in the bone health registry of persons with a disability. SETTING: Inpatients and outpatients at a single acute rehabilitation hospital. PARTICIPANTS: A convenience sample of 66 participants, both inpatients and outpatients, with a spinal cord injury. METHODS: Calcaneal T scores were determined by ultrasound, and bone density of the lumbar spine, total hip, and femoral neck were determined by DXA. MAIN OUTCOME MEASUREMENTS: Right and left calcaneal QUS T scores and right and left hip and femoral neck DXA T scores. RESULTS: Right and left hip DXA T scores were strongly associated with corresponding right and left calcaneal QUS T scores (right: r = .72, P < .001; left: r = .70, P < .001). Similar associations were found when we evaluated femoral neck T scores and calcaneal QUS T scores. Receiver operating characteristic analysis for evaluating QUS to identify DXA-defined osteoporosis demonstrated an area under the curve of 0.81 for all participants (acute and chronic injury) and 0.68 for those with a chronic SCI. CONCLUSIONS: A strong association exists between calcaneal QUS T scores and bone density T scores at the hip measured by DXA. QUS may have a place in the screening of people with SCI 1 year or more after their injury to evaluate their bone status. PMID- 22841968 TI - A novel technique for conduction studies of the infrapatellar nerve. AB - OBJECTIVE: To introduce a noninvasive method for electrodiagnostic evaluation of the infrapatellar nerve (IPN). DESIGN: A prospective cohort study. SETTING: Electrodiagnostic laboratory, rehabilitation department, Hadassah University Hospital. PARTICIPANTS: A total of 38 healthy adults; 57 asymptomatic limbs were studied. METHODS: Sensory nerve action potential of the IPN was recorded with surface electrodes placed 2.5 cm below the distal pole of the patella and 2 cm medially from the medial border of the patellar tendon. Transcutaneous antidromic electrical stimulation of IPN was applied above the medial femoral condyle and 8 10 cm proximally from the active surface electrode. RESULTS: The sensory nerve action potential mean (n = 38) onset latency was 1.69 +/- 0.32 ms. Peak latency was 2.36 +/- 0.47 ms, and amplitude was 6.96 +/- 3.68 MUV. CONCLUSIONS: This article describes a novel and simple technique for IPN conduction electrodiagnostic examination. The method used provides a new tool to evaluate IPN injury in reference to anterior or inferior knee pain with associated sensory deficit. PMID- 22841969 TI - Treating pain with the lidocaine patch 5% after total knee arthroplasty. AB - OBJECTIVE: To investigate the potential benefits of the lidocaine patch 5% for pain control during the postoperative period after a total knee arthroplasty (TKA). DESIGN/SETTING: A prospective cohort study in which we analyzed patients admitted to an inpatient rehabilitation unit after a TKA. PARTICIPANTS: Fifty three consecutive patients who underwent a TKA and were admitted to an orthopedic rehabilitation unit. METHODS: Thirty-one patients received the lidocaine patch 5%, and 22 patients served as the control group. On the day of admission, the 24 item Western Ontario and McMaster Universities Arthritis Index (WOMAC) was used to evaluate each patient's pain and functional capacity before surgery. The Visual Analog Scale (VAS) was used to assess pain ratings every other day starting on rehabilitation day 1. The average end point of the study was rehabilitation day 11. MAIN OUTCOME MEASURES: The primary outcome measure was the change in VAS from day of admission. Secondary outcomes in the lidocaine patch 5% group consisted of length of use and a patient satisfaction survey. RESULTS: The lidocaine patch 5% and control group were demographically well matched. The average admission WOMAC score was 49.3 and 57.1 for the lidocaine patch 5% and control groups, respectively. The average length of stay was 13.2 +/- 5.1 days for the lidocaine patch 5% group and 12.4 +/- 3.7 days for the control group. A statistically significant difference in VAS was found on day 3 (P = .05) between the 2 groups, with the control group demonstrating better pain relief. However, both groups reported similar pain improvements by the end of their hospital stay. Of the 31 patients receiving lidocaine patch 5%, 94% of the patients reported satisfaction and attributed pain relief to its use. CONCLUSIONS: Overall, the concurrent use of lidocaine patch 5% in treating the postoperative pain of patients after TKA does not provide significant additional pain relief compared with control subjects. PMID- 22841970 TI - Process of care for hepatitis C infection is linked to treatment outcome and virologic response. AB - BACKGROUND & AIMS: Process of care-based measures are used commonly to assess the quality of medical care provided to patients with chronic hepatitis C virus (HCV) infection. However, the links between these processes and patient outcomes are not clear. METHODS: We conducted a large retrospective cohort study of 34,749 patients with HCV infection identified from the national Veterans Administration HCV Clinical Case Registry between 2003 and 2006. We examined the relationship between meeting process-based measures of HCV care (categorized into pretreatment, preventive or comorbid care, and treatment monitoring domains) and antiviral treatment-related outcomes. For each domain, we defined optimum care as receipt of all indicated care processes in that domain. Study end points were rates of antiviral treatment, treatment completion, and sustained virologic response (SVR), adjusted for patient demographics, comorbidities, use of health services, and intrafacility clustering. RESULTS: Patients who received optimum pretreatment care were significantly more likely to receive antiviral treatment (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.9-3.5), complete treatment (OR, 1.26; 95% CI, 1.13-1.43), and achieve an SVR (OR, 1.29; 95% CI, 1.01-1.65), than those with suboptimum pretreatment care. Optimum preventive or comorbidity care also independently was associated with receipt of antiviral treatment (OR, 1.36; 95% CI, 1.23-1.51), but not with completion of treatment or SVR. Optimum treatment monitoring was associated with a nonsignificant trend toward achieving an SVR (OR, 1.22; 95% CI, 0.95-1.56). CONCLUSIONS: Optimum care for HCV infection particularly the care delivered before treatment-is associated with increased rates of treatment and SVR. These data could be used to guide clinical policy as newer, more-effective treatments become available. PMID- 22841971 TI - Familial pain abdomen syndrome: a rare entity. PMID- 22841972 TI - Measles outbreak in Europe: susceptibility of infants too young to be immunized. AB - As women vaccinated against measles transfer low amounts of antibodies, an increasing number of infants lack early protection through maternal antibodies until being immunised themselves. This paper reviews the literature on disease burden of measles in the population too young to be immunized according to the respective national recommendations during recent outbreaks in EU and EEA/EFTA countries. In addition, specific control strategies adopted to protect this young population are reviewed. Pubmed, Unbound Medline, Web of Knowledge and the Eurosurveillance database were searched using MESH terms: measles and epidemiology, measles and infants, prevalence of measles, measles and outbreaks and measles and epidemic. Additionally, data from Euvac.net and ECDC were consulted. Databases were searched from January 2001 to September 2011. Fifty three papers were included in the analysis. The percentage of all measles cases during outbreaks affecting young infants ranged from 0.25% to 83.0%. Specific control strategies were adopted: e.g. administration of the first or second vaccine dose earlier than recommended. Infants younger than 12 months are often involved in measles outbreaks, and advancing the first vaccine dose could reduce the burden of disease. However, immunization before 9 months of age is not systematically recommended because of dysmature humoral immune responses of infants. High coverage and timely administration of the recommended series of vaccines are the most important measures to decrease measles incidence and measles circulation and protect vulnerable infants from infection. PMID- 22841973 TI - Do correlates of HPV vaccine initiation differ between adolescent boys and girls? AB - BACKGROUND: Guidelines now recommend that adolescents routinely receive human papillomavirus (HPV) vaccine. Because little is known about uptake among boys, we assessed HPV vaccine initiation in a population-based sample of adolescent boys and girls. METHODS: We analyzed weighted data from 751 parents who reported on an 11- to 17-year-old son or daughter for the 2010 North Carolina Child Health Assessment and Monitoring Program survey. Stratified multivariate logistic regression analyses identified correlates of HPV vaccine initiation separately for boys and girls. RESULTS: Only 14% of sons had received one or more doses of HPV vaccine compared to 44% of daughters (p<0.01). For both sons and daughters, vaccine initiation correlated with age and having received meningococcal vaccine. Among sons, initiation of HPV vaccine was lower for those living in high income households (odds ratio [OR]=0.22, 95% CI, 0.09-0.53) and higher for those whose race was neither white nor black (OR=3.26, 95% CI, 1.06-10.04). When asked to give the main reason for not vaccinating their child against HPV, parents of unvaccinated sons were more likely than those of daughters to report not getting a provider's recommendation or not being aware that the vaccine was available for their child, but less likely to report concern about safety (p<0.01). At least 86% of unvaccinated children had missed an opportunity to receive HPV vaccine. CONCLUSIONS: HPV vaccine correlates and concerns varied for parents of boys and girls. To improve very low levels of uptake among boys, providers should recommend HPV vaccine concomitant with other adolescent vaccines. PMID- 22841974 TI - Effect of viral membrane fusion activity on antibody induction by influenza H5N1 whole inactivated virus vaccine. AB - Whole inactivated virus (WIV) influenza vaccines are more immunogenic in unprimed individuals than split-virus or subunit vaccines. In mice, this superior immunogenicity has been linked to the recognition of the viral ssRNA by endosomal TLR7 receptors in immune cells, leading to IFNalpha production and Th1-type antibody responses. Recent data suggest that viral membrane fusion in target cell endosomes is necessary for TLR7-mediated IFNalpha induction. If so, virus inactivation procedures that compromise the fusion activity of WIV vaccines, like formaldehyde (FA) treatment, could potentially harm vaccine efficacy. Therefore, we measured the effect of fusion inactivation of H5N1 WIV on TLR7 activation in vitro, and on antibody isotype responses in vivo. Fusion inactivation of WIV reduced, but did not block, TLR7-dependent IFNalpha induction in murine dendritic cells in vitro. In vivo, fusion-inactive WIV was as potent as fusion-active WIV in inducing total H5N1-specific serum IgG and IgG2c subtype antibodies in unprimed mice. Both vaccines induced only small amounts of IgG1. However, FA treatment of WIV did reduce the capacity of the vaccine to induce hemagglutination-inhibiting (HI) antibodies. This possibly relates to modification of epitopes that are targets for HI antibodies rather than to loss of fusion activity. Antibody affinity maturation was not negatively affected by fusion inactivation. In conclusion, fusion activity of H5N1 WIV does not play a major role in Th1-type antibody induction. Yet, to preserve the full immunogenicity of WIV, or possibly also other inactivated influenza vaccines, harsh treatment with formaldehyde should be avoided. PMID- 22841975 TI - Prevention and synergistic control of Ph(+) ALL by a DNA vaccine and 6 mercaptopurine. AB - Although the outcome of patients with acute lymphoblastic leukemia (ALL) has been improved continuously by chemotherapy and tyrosine kinase inhibitors, prognosis of patients with Philadelphia chromosome positive (Ph(+)) ALL still remains poor. Since further intensification of chemotherapy is limited by toxic side effects and patients with high risk of transplant-related mortality are not eligible for allogeneic stem cell transplantation new treatment strategies are urgently needed for the prevention of Ph(+) ALL relapse. There is increasing evidence that the immune system plays an essential role for the eradication or immunologic control of remaining leukemia cells. We developed several DNA-based vaccines encoding a BCR-ABL(p185) specific peptide and GM-CSF, and CD40-L, IL-27 or IL-12 and evaluated the preventive and therapeutic efficacy against a lethal challenge of syngeneic Ph(+) ALL in Balb/c mice. In vivo cell depletion assays and cytokine expression studies were performed and the efficacy of the DNA vaccine was compared with 6-mercaptopurine (6-MP) alone and the combination of the DNA vaccine and 6-MP. Preventive immunization with the vaccine BCR-ABL/GM-CSF/IL-12 and the TLR-9 agonist dSLIM induced an innate and adaptive immune response mediated by NK-cells, CD4(+) T-cells and CD8(+) T-cells leading to a survival rate of 80%. Therapeutic vaccination resulted in a significantly longer leukemia free survival (40.7 days vs. 20.4 days) and a higher survival rate (56% vs. 10%) compared to chemotherapy with 6-MP. Remarkably, in combination with the vaccine 6 MP acted synergistically and led to 100% survival. These results demonstrate that minimal residual disease of Ph(+) ALL can be significantly better controlled by a combined treatment approach of immunotherapy and chemotherapy. This provides a rationale for improving maintenance therapy in order to reduce the relapse rate in patients with Ph(+) ALL. PMID- 22841976 TI - Significance of the concentration of chelating ligands on Fe3+-solubility, bioavailability, and uptake in rice plant. AB - Present study investigated the significance of the concentration of chelating ligand on Fe(3+)-solubility in growth medium and its influence on Fe bioavailability and uptake in rice plant. Rice seedlings were grown in modified Murashige and Skoog (MS) hydroponic growth medium with moderate (250 MUM) and high (500 MUM) concentrations of ethylenediaminetetraacetate (EDTA) and hydroxyiminodisuccinate (HIDS) under sterile and non-sterile conditions. Concentrations of soluble Fe in the growth medium increased with increasing ligand concentrations, and the growth of rice seedlings was higher at moderate ligand concentration than at control (without chelant) and high ligand concentration. This explains the relationship between Fe solubility and bioavailability in the growth medium, and its effect on Fe uptake in rice plant. Fe exists in the growth medium predominantly as particulate (insoluble) forms at low ligand concentration, and as soluble [Fe(OH)(2+), Fe(OH)(2)(+), Fe-L complex] and apparently soluble (colloidal) forms at moderate ligand concentration. At high ligand concentration, most of the Fe(3+) in the growth medium forms soluble Fe-L complex, however, the bioavailability of Fe from Fe-L complex decreased due to lopsided complex formation equilibrium reaction (CFER) between Fe and the ligands. Also, Fe is solubilized forming stable and soluble Fe-L complex, which is then detached as less stable, but soluble and bioavailable substance(s) after (time-dependent) biodegradation. Therefore- i) ligand concentration and stability constant of Fe-L complex (K(Fe-L)) influence Fe bioavailability and uptake in rice plant, and ii) the biodegradable ligands (e.g., HIDS) would be more effective Fe fertilizer than the environmentally persistent and less biodegradable ligands (e.g., EDTA). PMID- 22841977 TI - Calcium regulates the cell-to-cell water flow pathway in maize roots during variable water conditions. AB - Soil water shortages can decrease root hydraulic conductivity and affect Ca uptake and movement through the plant. In this study, the effects of extra Ca(2+) applied in nutrient solution on the hydraulic properties of the whole roots (Lp(r)) and cortical cells (Lp(cell)) of maize (Zea mays L.) subjected to variable water conditions were investigated. Under well-watered conditions, extra Ca(2+) significantly increased the root Ca content, total root length, and lateral root number; however, it reduced the root cortical cell volume, Lp(r), and Lp(cell). Hg(2+) inhibition experiments suggested that extra Ca(2+) could reduce the contribution of the cell-to-cell water flow pathway. Osmotic stress (10% PEG6000) significantly decreased the cortical cell volume, Lp(r), and Lp(cell) in the control plants, but smaller decreases were observed in the extra Ca(2+) plants. The Hg(2+) treatment reduced the Lp(r) larger in the extra Ca(2+) plants (74.6%) than in the control plants (53.2%), suggesting a higher contribution of the cell-to-cell pathway. The larger Hg(2+) inhibition of the Lp(cell) in the extra Ca(2+) roots (67.2%) when compared to the controls (56.4%) indicated that extra Ca(2+) can mitigate the inhibition of aquaporin expression and/or activity levels via osmotic stress. After 2 d of rehydration, the extra Ca(2+) helped the Lp(r) and Lp(cell) to recover almost completely, but these properties only partially recovered in the control plants. In conclusion, extra Ca(2+) may adjust the contribution of cell-to-cell pathway by regulating the expression and/or activity levels of AQPs according to water availability; this regulation may weaken negative effects and optimize water use. PMID- 22841978 TI - Myriocin, an inhibitor of serine palmitoyl transferase, impairs the uptake of transferrin and low-density lipoprotein in mammalian cells. AB - The role of sphingolipids in clathrin-mediated endocytosis is only poorly understood in mammalian cells. Thus the relationship between sphingolipid de novo synthesis and clathrin-mediated endocytosis of transferrin were studied in L929 fibroblasts and two other cell lines. Endocytosis was measured using live cell imaging with fluorescent transferrin or (125)I-transferrin. Lipids were primarily measured using electrospray ionization tandem mass spectrometry. At physiological temperature, transferrin uptake was significantly decreased by the inhibitor of serine palmitoyl transferase myriocin. Myriocin inhibited also the uptake of low density lipoproteins. The endocytosis inhibition by myriocin could be released by the addition of sphingoid base and by the protein phosphorylation effectors phorbol-12-myristate, 13-acetate (PMA) and okadaic acid. Myriocin influenced not only sphingolipids but also the glycerophospholipid profile. The study of phosphatidylcholine species shows adaptations to more saturated, alkylated and longer fatty acid moieties. The reported results imply that in mammalian cells, at 37 degrees C, sphingolipid de novo synthesis is required for clathrin-mediated endocytosis. PMID- 22841980 TI - A PagP fusion protein system for the expression of intrinsically disordered proteins in Escherichia coli. AB - PagP, a beta-barrel membrane protein found in Gram-negative bacteria, expresses robustly in inclusion bodies when its signal sequence is removed. We have developed a new fusion protein expression system based on PagP and demonstrated its utility in the expression of the unstructured N-terminal region of human cardiac troponin I (residues 1-71). A yield of 100mg fusion protein per liter M9 minimal media was obtained. The troponin I fragment was removed from PagP using cyanogen bromide cleavage at methionine residues followed by nickel affinity chromatography. We further demonstrate that optimal cleavage requires complete reduction of methionine residues prior to cyanogen bromide treatment, and this is effectively accomplished using potassium iodide under acidic conditions. The PagP based fusion protein system is more effective at targeting proteins into inclusion bodies than a commercially available system that uses ketosteroid isomerase; it thus represents an important advance for producing large quantities of unfolded peptides or proteins in Escherichia coli. PMID- 22841981 TI - Evaluation of upper extremity nerve conduction velocities and the relationship between fibromyalgia and carpal tunnel syndrome. AB - BACKGROUND AND AIMS: We undertook this study to evaluate upper extremity nerve conduction velocities (NCVs) in fibromyalgia syndrome (FS) and the relationship of the electrophysiological findings between carpal tunnel syndrome (CTS) and FS. METHODS: Sixty three right-handed female patients diagnosed with FS and 52 right handed age- and gender-matched healthy controls were enrolled in the study. Conduction studies of the median and ulnar nerves and median nerve F-wave latencies were assessed in both upper extremities using standard methods. CTS was diagnosed electrophysiologically if the median nerve sensory NCV was decreased and/or motor distal latency (DL) was prolonged. RESULTS: CTS was detected electrophysiologically in 26 (20.63%) of 126 extremities of 63 patients and in three (2.82%) of 104 extremities of 52 individuals of the control group. Statistically significant differences were detected between groups with respect to rate of carpal tunnel syndrome (p <0.05). There were no differences between results of NCVs of patients in FS group and healthy controls except the prolongation of the right median nerve motor DL (p = 0.019), decrease of the sensory NCV (p = 0.003) in the right median nerve, in the left median nerve (p = 0.011) and in the left ulnar nerve (p = 0.015). CONCLUSIONS: We determined an increased rate of CTS and decreased NCVs in the upper extremities in patients with FS. We should consider that complaints of paresthesia and pain in hands, increasing especially at nights, observed in FS may mask that CTS can be an associated illness. PMID- 22841979 TI - The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. AB - Type II topoisomerases are required for the management of DNA superhelicity and chromosome segregation, and serve as frontline targets for a variety of small molecule therapeutics. To better understand how these enzymes act in both contexts, we determined the 2.9-A-resolution structure of the DNA cleavage core of human topoisomerase IIalpha (TOP2A) bound to a doubly nicked, 30-bp duplex oligonucleotide. In accord with prior biochemical and structural studies, TOP2A significantly bends its DNA substrate using a bipartite, nucleolytic center formed at an N-terminal dimerization interface of the cleavage core. However, the protein also adopts a global conformation in which the second of its two inter protomer contact points, one at the C-terminus, has separated. This finding, together with comparative structural analyses, reveals that the principal site of DNA engagement undergoes highly quantized conformational transitions between distinct binding, cleavage, and drug-inhibited states that correlate with the control of subunit-subunit interactions. Additional consideration of our TOP2A model in light of an etoposide-inhibited complex of human topoisomerase IIbeta (TOP2B) suggests possible modification points for developing paralog-specific inhibitors to overcome the tendency of topoisomerase II-targeting chemotherapeutics to generate secondary malignancies. PMID- 22841983 TI - Potential roles for CD8(+) T cells in rheumatoid arthritis. AB - CD8(+) T cells have long been suggested to play a role in rheumatoid arthritis (RA). The current paradigm on the pathogenesis and maintenance of the disease would endorse these cells with predominantly protective and minor influences. However, several animal studies suggest that these cells may have a predominantly proinflammatory (cytotoxic) effect in the disease. Other studies claim otherwise, that they have a mainly regulatory role in inflammatory joints. The evidence in human disease is remarkably scarce. Studies in human samples indicate that CD8(+) T cells play an important role in the establishment of germinal centers observed in nearly 50% of RA patients, which may have a decisive role in the initiation and maintenance of the disease process. The conflicting results of experimental studies, the scarcity of data and the complexity of research needed to unravel these complex interactions may explain the relative oblivion of CD8 cells in the field of arthritis over recent decades. Is this a wise decision or may we run the risk of not finding the key to RA because we search for it where there is light as opposed to its probable location? The present review brings together available data on the potential role of CD8(+) T cells in inflammation, with emphasis on rheumatoid arthritis, hoping to foster interest and fresh research in this area. PMID- 22841984 TI - Pulmonary hypertension in systemic lupus erythematosus: prevalence, predictors and diagnostic strategy. AB - OBJECTIVES: To investigate the prevalence and predictors of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) and to validate a diagnostic strategy. METHODS: 245 patients with SLE entered a screening program. Possible PH was defined as two consecutive systolic pulmonary arterial pressure (PAP) values >= 40mmHg by echocardiography. The subsequent diagnostic procedure, including right heart catheterization if needed, confirmed or excluded the diagnosis of PH secondary to cardiopulmonary disease or SLE related pulmonary arterial hypertension (PAH). Independent predictors of PH were identified by multivariant multiple linear or logistic regression models. The sensitivity (S), specificity (SP), positive (PPV) and negative predictive values (NPV) were calculated for different screening cutoff values. RESULTS: 88% patients were women. The mean (SD) age at the time of enrolment was 45 (16) years. 12 cases of PH were detected, all secondary, with a resulting prevalence of 5%. Two consecutive echocardiographic PAP measurements >= 40mmHg performed best as the cutoff point for screening (S 100%, SP 97%, PPV 70, NPV 100), as compared with single PAP measurements >= 30mmHg or >= 40mmHg The age at the time of enrolment was the only variable independently associated with PAP values (p=0.0001), with the SLICC damage index score showing a borderline association (p=0.08). Only the age at the time of enrolment showed an independent association with PH (OR 1.10, 95% CI 1.06-1.17). CONCLUSION: We found a low prevalence of PH. Screening echocardiograms in asymptomatic lupus patients are thus not recommended. Two consecutive PAP values >= 40mmHg by echocardiogram is the best screening cutoff for starting investigations in SLE patients with suspected PH. PMID- 22841985 TI - Drug induced autoimmune hepatitis and TNF-alpha blocking agents: is there a real relationship? AB - Hepatotoxicity is an expected side effect of tumour necrosis factor-alpha (anti TNF-alpha) blocking agents including, infliximab, etanercept and adalimumab. Although mild to moderate elevations of liver enzymes have been recognised after the use of these agents, severe hepatitis is rarely reported. Reactivation of viral hepatitis and drug induced liver injury is two main causes of liver dysfunction in these patients. A broad spectrum, ranging from minor immunological alterations to systemic autoimmune disease, has been reported during treatment with anti-TNF-alpha. Therefore, in recent studies TNF-alpha blocking agents have been considered a potential cause of drug induced autoimmune hepatitis. Taking into account the advances in the field of hepatology, this review summarizes the general characteristics of anti-TNF-alpha induced liver injury and autoimmune hepatitis. PMID- 22841986 TI - H2S induces catecholamine secretion in rat adrenal chromaffin cells. AB - Hydrogen sulfide (H(2)S) is recognized as an important gaseous signaling molecule in mammalian tissues and exerts its modulating functions of different systems via targeting different ion channels and receptors. H(2)S can be synthesized from l cysteine by cystathionine beta-synthetase (CBS) or cystathionine gamma-lyase (CSE). It has been reported recently that H(2)S can be synthesized and released in rat adrenal medulla chromaffin cells (AMCs) which play a critical role in the regulation of stress response by releasing catecholamine (CA). In the present study, we combined amperometry and whole-cell patch-clamp recording to explore the direct effect of exogenous H(2)S on CA release in AMCs and the underlying ionic mechanism. Amperometry showed that local application of NaHS, the H(2)S donor, evoked CA release from AMCs. Furthermore, the CA secretory response to NaHS was totally blocked by removing extracellular Ca(2+). Whole-cell patch-clamp experiments showed that H(2)S-induced CA release is produced by membrane depolarization generated by an inhibition of Ca(2+)-activated K(+) current [I(K(Ca)) current]. We conclude that H(2)S is capable of directly inducing CA release by inhibiting the I(K(Ca)) current. This conclusion indicates that H(2)S may involve in the response of adrenal medulla to stress by modulating I(K(Ca)) current and CA release in mammalian animals. PMID- 22841987 TI - A multicenter analysis of the ophthalmic knowledge assessment program and American Board of Ophthalmology written qualifying examination performance. AB - OBJECTIVE: To compare the performance on the American Board of Ophthalmology Written Qualifying Examination (WQE) with the performance on step 1 of the United States Medical Licensing Examination (USMLE) and the Ophthalmic Knowledge Assessment Program (OKAP) examination for residents in multiple residency programs. DESIGN: Comparative case series. PARTICIPANTS: Fifteen residency programs with 339 total residents participated in this study. The data were extracted from the 5-year American Board of Ophthalmology report to each participating program in 2009 and included residency graduating classes from 2003 through 2007. Residents were included if data were available for the USMLE, OKAP examination in ophthalmology years 1 through 3, and the WQE score. Residents were excluded if one or more of the test scores were not available. METHODS: Two sample t tests, logistic regression analysis, and receiver operating characteristic (ROC) curves were used to examine the association of the various tests (USMLE, OKAP examination year 1, OKAP examination year 2, OKAP examination year 3, and maximum OKAP examination score) as a predictor for a passing or failing grade on the WQE. MAIN OUTCOME MEASURES: The primary outcome measure of this study was first time pass rate for the WQE. RESULTS: Using ROC analysis, the OKAP examination taken at the third year of ophthalmology residency best predicted performance on the WQE. For the OKAP examination taken during the third year of residency, the probability of passing the WQE was at least 80% for a score of 35 or higher and at least 95% for a score of 72 or higher. CONCLUSIONS: The OKAP examination, especially in the third year of residency, can be useful to residents to predict the likelihood of success on the high-stakes WQE examination. PMID- 22841989 TI - Assessing language dominance with functional MRI: the role of control tasks and statistical analysis. AB - There is a discrepancy between the brain regions revealed by functional neuroimaging techniques and those brain regions where a loss of function, either by lesion or by electrocortical stimulation, induces language disorders. To differentiate between essential and non-essential language-related processes, we investigated the effects of linguistic control tasks and different analysis methods for functional MRI data. Twelve subjects solved two linguistic generation tasks: (1) a verb generation task and (2) an antonym generation task (each with a linguistic control task on the phonological level) as well as two decision tasks of semantic congruency (each with a cognitive high-level control task). Differential contrasts and conjunction analyses were carried out on the single subject level and an individual lateralization index (LI) was computed. On the group level we determined the percent signal change in the left inferior frontal gyrus (IFG: BA 44 and BA 45). The conjunction analysis of multiple language tasks led to significantly greater absolute LIs than the LIs based on the single task versus fixation contrasts. A further significant increase of the magnitude of the LIs could be achieved by using the phonological control conditions. Although the decision tasks appear to be more robust to changes in the statistical threshold, the combined generation tasks had an advantage over the decision tasks both for assessing language dominance and locating Broca's area. These results underline the need for conjunction analysis based on several language tasks to suppress highly task-specific processes. They also point to the need for high-level cognitive control tasks to partial out general, language supporting but not language critical processes. Higher absolute LIs, which reflect unambiguously hemispheric language dominance, can be thus obtained. PMID- 22841988 TI - Modelling normal and impaired letter recognition: implications for understanding pure alexic reading. AB - Letter recognition is the foundation of the human reading system. Despite this, it tends to receive little attention in computational modelling of single word reading. Here we present a model that can be trained to recognise letters in various spatial transformations. When presented with degraded stimuli the model makes letter confusion errors that correlate with human confusability data. Analyses of the internal representations of the model suggest that a small set of learned visual feature detectors support the recognition of both upper case and lower case letters in various fonts and transformations. We postulated that a damaged version of the model might be expected to act in a similar manner to patients suffering from pure alexia. Summed error score generated from the model was found to be a very good predictor of the reading times of pure alexic patients, outperforming simple word length, and accounting for 47% of the variance. These findings are consistent with a hypothesis suggesting that impaired visual processing is a key to understanding the strong word-length effects found in pure alexic patients. PMID- 22841991 TI - Hearing feelings: a quantitative meta-analysis on the neuroimaging literature of emotional prosody perception. AB - With the advent of neuroimaging considerable progress has been made in uncovering the neural network involved in the perception of emotional prosody. However, the exact neuroanatomical underpinnings of the emotional prosody perception process remain unclear. Furthermore, it is unclear what the intrahemispheric basis might be of the relative right-hemispheric specialization for emotional prosody perception that has been found previously in the lesion literature. In an attempt to shed light on these issues, quantitative meta-analyses of the neuroimaging literature were performed to investigate which brain areas are robustly associated with stimulus-driven and task-dependent perception of emotional prosody. Also, lateralization analyses were performed to investigate whether statistically reliable hemispheric specialization across studies can be found in these networks. A bilateral temporofrontal network was found to be implicated in emotional prosody perception, generally supporting previously proposed models of emotional prosody perception. Right-lateralized convergence across studies was found in (early) auditory processing areas, suggesting that the right hemispheric specialization for emotional prosody perception reported previously in the lesion literature might be driven by hemispheric specialization for non-prosody-specific fundamental acoustic dimensions of the speech signal. PMID- 22841992 TI - Deja vu in unilateral temporal-lobe epilepsy is associated with selective familiarity impairments on experimental tasks of recognition memory. AB - In deja vu, a phenomenological impression of familiarity for the current visual environment is experienced with a sense that it should in fact not feel familiar. The fleeting nature of this phenomenon in daily life, and the difficulty in developing experimental paradigms to elicit it, has hindered progress in understanding deja vu. Some neurological patients with temporal-lobe epilepsy (TLE) consistently experience deja vu at the onset of their seizures. An investigation of such patients offers a unique opportunity to shed light on its possible underlying mechanisms. In the present study, we sought to determine whether unilateral TLE patients with deja vu (TLE+) show a unique pattern of interictal memory deficits that selectively affect familiarity assessment. In Experiment 1, we employed a Remember-Know paradigm for categorized visual scenes and found evidence for impairments that were limited to familiarity-based responses. In Experiment 2, we administered an exclusion task for highly similar categorized visual scenes that placed both recognition processes in opposition. TLE+ patients again displayed recognition impairments, and these impairments spared their ability to engage recollective processes so as to counteract familiarity. The selective deficits we observed in TLE+ patients contrasted with the broader pattern of recognition-memory impairments that was present in a control group of unilateral patients without deja vu (TLE-). MRI volumetry revealed that ipsilateral medial temporal structures were less broadly affected in TLE+ than in TLE- patients, with a trend for more focal volume reductions in the rhinal cortices of the TLE+ group. The current findings establish a first empirical link between deja vu in TLE and processes of familiarity assessment, as defined and measured in current cognitive models. They also reveal a pattern of selectivity in recognition impairments that is rarely observed and, thus, of significant theoretical interest to the memory literature at large. PMID- 22841994 TI - Age-related differences in the neural correlates of remembering time-based intentions. AB - The present study used event-related potentials (ERPs) to explore the effect of age on the neural correlates of monitoring processes involved in time-based prospective memory. In both younger and older adults, the addition of a time based prospective memory task to an ongoing task led to a sustained ERP activity broadly distributed over the scalp. Older adults, however, did not exhibit the slow wave activity observed in younger adults over prefrontal regions, which is considered to be associated with retrieval mode. This finding indicates that age related decline in intention maintenance might be one source of the impaired prospective memory performance displayed by older adults. An 'anterior shift' in scalp distribution of the P3 was observed in older adults, and was related to lower levels of accuracy in prospective memory performance. This relationship suggests that possible factors responsible for age-related decline in prospective memory performance include the decreased efficiency of executive/frontal functions as well as the reduced amount of resources available for the prospective memory task. PMID- 22841993 TI - Epilepsy-related long-term amnesia: anatomical perspectives. AB - There are few clues as to the neural basis of selective long-term amnesia. We report group and single-case data to shed light on this issue. In a group study of patients with transient epileptic amnesia, there were no significant correlations between volumetric measures of the hippocampus and indices of accelerated long-term forgetting or longer-term autobiographical memory loss. Post-mortem investigations in a patient with temporal lobe epilepsy who showed accelerated long-term forgetting, together with a degree of autobiographical memory loss, yielded evidence of neuronal loss and gliosis in regions of both the right and the left hippocampus. Neuronal loss and gliosis were more evident in anterior than posterior hippocampus. These results indicate that the unusual forms of long-term forgetting seen in some patients with temporal lobe epilepsy have no gross anatomical correlate. The findings leave open the possibilities that subtle structural damage or subtle functional disturbance, perhaps in the form of subclinical epileptiform activity, underly epilepsy-related long-term amnesia. PMID- 22841990 TI - What pharmacological interventions indicate concerning the role of the perirhinal cortex in recognition memory. AB - Findings of pharmacological studies that have investigated the involvement of specific regions of the brain in recognition memory are reviewed. The particular emphasis of the review concerns what such studies indicate concerning the role of the perirhinal cortex in recognition memory. Most of the studies involve rats and most have investigated recognition memory for objects. Pharmacological studies provide a large body of evidence supporting the essential role of the perirhinal cortex in the acquisition, consolidation and retrieval of object recognition memory. Such studies provide increasingly detailed evidence concerning both the neurotransmitter systems and the underlying intracellular mechanisms involved in recognition memory processes. They have provided evidence in support of synaptic weakening as a major synaptic plastic process within perirhinal cortex underlying object recognition memory. They have also supplied confirmatory evidence that that there is more than one synaptic plastic process involved. The demonstrated necessity to long-term recognition memory of intracellular signalling mechanisms related to synaptic modification within perirhinal cortex establishes a central role for the region in the information storage underlying such memory. Perirhinal cortex is thereby established as an information storage site rather than solely a processing station. Pharmacological studies have also supplied new evidence concerning the detailed roles of other regions, including the hippocampus and the medial prefrontal cortex in different types of recognition memory tasks that include a spatial or temporal component. In so doing, they have also further defined the contribution of perirhinal cortex to such tasks. To date it appears that the contribution of perirhinal cortex to associative and temporal order memory reflects that in simple object recognition memory, namely that perirhinal cortex provides information concerning objects and their prior occurrence (novelty/familiarity). PMID- 22841995 TI - Studies on Shigella boydii infection in Caenorhabditis elegans and bioinformatics analysis of immune regulatory protein interactions. AB - Shigella boydii causes bacillary dysentery or shigellosis and generates a significant burden in the developing nations. S. boydii-mediated infection assays were performed at both physiological and molecular levels using Caenorhabditis elegans as a host. Continuous exposure of worms to S. boydii showed a reduced life span indicating the pathogenicity of Shigella. Quantitative Real-Time PCR analysis was performed to analyze the expression and regulation of host specific candidate-antimicrobial genes (clec-60, clec-87, lys-7), which were expressed significantly during early infection, but weakened during the latter hours. Increased mortality of mutant RB1285 by S. boydii and Shigella flexneri indicated the role of lys-7 during Shigella infection. Protein-protein interactions (PPIs) database was used to analyze the interaction of immune proteins in both C. elegans and humans. In addition, the expression and regulation were revealed about immune genes (clec-61, clec-62, clec-63, F54D5.3 and ZK1320.2), which encode several intermediate immune protein partners (CLEC-61, CLEC-62, CLEC-63, F54D5.3, ZK1320.2, W03D2.6 and THN-2) that interact with LYS-7 and CLEC-60 and were found to play a role in C. elegans immune defense against S. boydii infections. Similarly, the immune genes that are specific to the human defense system, which encode IGHV4-39, A2M, LTF, and CD79A, were predicted to be expressed with LYZ and MBL2, thus indicating their regulation during Shigella infections. Our results using the lowest eukaryotic model system and human database indicated that the major players involved in immunity-related processes appear to be common in cases of Shigella sp. mediated immune responses. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction. PMID- 22841996 TI - Compatible solutes contribute to heat resistance and ribosome stability in Escherichia coli AW1.7. AB - This study investigated the mechanisms of heat resistance in Escherichia coli AW1.7 by quantification of cytoplasmic solutes, determination of ribosome denaturation, and by determination of protein denaturation. To assess the contribution of heat shock proteins and compatible solutes, experiments were conducted after exposure to sublethal heat shock, and with cultures grown at NaCl concentrations ranging from 0 to 6%. Heat resistance of E. coli AW1.7 was compared to the heat sensitive E. coli GGG10 and a plasmid-cured, heat sensitive derivative of E. coli AW1.7 named E. coli AW1.7DeltapHR1. Sublethal heat shock improved survival at 60 degrees C of E. coli GGG10 and AW1.7DeltapHR1 but not of E. coli AW1.7. Addition of NaCl increased the heat resistance of all three strains, but only E. coli AW1.7 exhibited high heat resistance when grown in NaCl concentrations ranging from 2 to 6%. E. coli AW1.7 and GGG10 accumulated 16.1 +/- 0.8 and 8.8 +/- 0.8mmolL-1 amino acids when grown at 0% NaCl, and 1.47 +/- 0.07 and 0.78 +/- 0.06mmolL-1 carbohydrates when grown at 6% NaCl, respectively. Ribosome denaturation was determined by differential scanning calorimetry. After growth in the presence of 0% NaCl, the 30S subunit denatured at 63.7 +/- 0.8 degrees C and 60.7 +/- 0.3 degrees C in E. coli AW1.7 and GGG10, respectively. Fourier-transformed-infrared-spectroscopy did not indicate differences in protein denaturation between the strains during heating. In conclusion, heat resistance in E. coli AW1.7 correlates to ribosome stability at 60 degrees C and is dependent on accumulation of cytoplasmic solutes. PMID- 22841998 TI - Evaluation of cytotoxicity of surfactants used in self-micro emulsifying drug delivery systems and their effects on paracellular transport in Caco-2 cell monolayer. AB - The objective of this study was to examine the cellular effects of the members of two non-ionic amphiphilic tenside groups and their mixtures on human Caco-2 cell monolayers as dependent upon their chemical structures and physicochemical properties. The first group of polyethylene glycol esters is represented by Polysorbates and Labrasol alone and in blends, while the members of the second group. Capryol 90, Capryol PGMC, Lauroglycol 90 and Lauroglycol FCC were used as propylene glycol esters. They are increasingly used in SMEDDS as recent tensides or co-tensides to increase hydrophobic bioavailability of a drug. Critical micelle concentration was measured by determination of surface tension. CMC refers to the ability of solubilization of surfactants. Cytotoxicity tests were performed on Caco-2 cell monolayers by MTT and LDH methods. Paracellular permeability as a marker of the integrity of cell monolayers, was examined with Lucifer yellow assays combined with TransEpithelial Electrical Resistance (TEER) measurements. The effect of these surfactants on tight junctions as evidence for paracellular pathway was also characterized. The results of cytotoxicity assays were in agreement, and showed significant differences among the cytotoxic properties of surfactants in a concentration-dependent manner. Polysorbates 20, 60, 80 are the most toxic compounds. In the case of Labrasol, the degree of esterification and lack of sorbit component decreased cytotoxicity. If the hydrophyl head was changed from polyethylene glycol to propylene glycol the main determined factor of cytotoxicity was the monoester content and the length of carbon chain. In our CMC experiments, we found that only Labrasol showed expressed cytotoxicity above the CMC. It refers to good ability of micelle solubilization of Labrasol. In our paracellular transport experiments each of polyethylene glycol surfactants (Polysorbates and Labrasol) altered TEER values, but propylene glycol esters did not modify the monolayer integrity. Polyethylene glycol esters alone and in blends (0.05% Labrasol--0.001% Polysorbates 20, 60, 80) were able to increase Lucifer yellow permeability significantly below the IC50 concentration. On the other hand Labrasol and Polysorbates 20 have expressed effect on tight junctions of Caco-2 monolayer. It could be concluded that polyethylene glycol ester-type tensides were able to enhance the paracellular permeability by the redistribution of junctional proteins. Our results might ensure useful data for selection of suitable tensides, co-tensides and tenside mixtures for SMEDDS formulations. PMID- 22841997 TI - Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress. AB - During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of beta-adrenergic receptors (betaARs) mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. The impact of the SNS on the immune modulation of social defeat has not been examined. The following studies were designed to determine whether SNS activation during social disruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, and glucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or six cycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. After six cycles of SDR the open field test was used to measure behaviors characteristic of anxiety and indicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatment with the beta-adrenergic antagonist propranolol. Pre-treatment with the beta adrenergic antagonist propranolol did not significantly alter corticosterone levels indicating no difference in activation of the hypothalamic-pituitary adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegaly and increase in plasma IL-6, TNFalpha, and MCP-1 were each reversed by pre treatment with propranolol. Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-induced increase in the percentage of CD11b(+) splenic macrophages and significantly decreased the expression of TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18h LPS-stimulated ex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewise propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b(+) cells ex vivo when compared to splenocytes from SDR vehicle-treated mice. Together, this study demonstrates that the immune activation and priming effects of SDR result, in part, as a consequence of SNS activation. PMID- 22842000 TI - Modulation of P2X3 receptors by spider toxins. AB - Recently, the novel peptide named purotoxin-1 (PT1) has been identified in the venom of the spider Geolycosa sp. and shown to exert marked modulatory effects on P2X3 receptors in rat sensory neurons. Here we studied another polypeptide from the same spider venom, purotoxin-2 (PT2), and demonstrated that it also affected activity of mammalian P2X3 receptors. The murine and human P2X3 receptors were heterologously expressed in cells of the CHO line, and nucleotide-gated currents were stimulated by CTP and ATP, respectively. Both PT1 and PT2 negligibly affected P2X3-mediated currents elicited by brief pulses of the particular nucleotide. When subthreshold CTP or ATP was added to the bath to exert the high affinity desensitization of P2X3 receptors, both spider toxins strongly enhanced the desensitizing action of the ambient nucleotides. At the concentration of 50nM, PT1 and PT2 elicited 3-4-fold decrease in the IC(50) dose of ambient CTP or ATP. In contrast, 100nM PT1 and PT2 negligibly affected nucleotide-gated currents mediated by mP2X2 receptors or mP2X2/mP2X3 heteromers. Altogether, our data point out that the PT1 and PT2 toxins specifically target the fast-desensitizing P2X3 receptor, thus representing a unique tool to manipulate its activity. PMID- 22842002 TI - Common pathologic pathways: a single prescription dream? PMID- 22842001 TI - Interaction of local anesthetics with lipid bilayers investigated by 1H MAS NMR spectroscopy. AB - The membrane location of the local anesthetics (LA) lidocaine, dibucaine, tetracaine, and procaine hydrochloride as well as their influence on phospholipid bilayers were studied by 31P and 1H magic-angle spinning (MAS) NMR spectroscopy. The 31P NMR spectra of the LA/lipid preparations confirmed that the overall bilayer structure of the membrane remained preserved. The relation between the molecular structure of the LAs and their membrane localization and orientation was investigated quantitatively using induced chemical shifts, nuclear Overhauser enhancement spectroscopy, and paramagnetic relaxation rates. All three methods revealed an average location of the aromatic rings of all LAs in the lipid-water interface of the membrane, with small differences between the individual LAs depending on their molecular properties. While lidocaine is placed in the upper chain/glycerol region of the membrane, for dibucaine and procaine the maximum of the distribution are slightly shifted into the glycerol region. Finally for tetracaine the aromatic ring is placed closest to the aqueous phase in the glycerol/headgroup region of the membrane. The hydrophobic side chains of the LA molecules dibucaine and tetracaine were located deeper in the membrane and showed an orientation towards the hydrocarbon core. In contrast the side chains of lidocaine and procaine are oriented towards the aqueous phase. PMID- 22842003 TI - Anti-retroviral drugs do not facilitate hepatitis C virus (HCV) infection in vitro. AB - An estimated 4 to 5 million people are co-infected with HIV/HCV worldwide. Recently observed outbreaks of acute HCV infection among HIV-positive men who have sex with men (MSM) have been linked to behavioral factors such as high risk sexual practices and recreational drug use. However, at the molecular level, many drugs such as glucocorticoids or cyclosporine A have been found to modulate viral replication. Thus, it is conceivable that drugs used in highly active antiretroviral therapy (HAART) may heighten susceptibility to HCV infection and contribute to the recent outbreaks. We therefore performed a comprehensive screen of antiretroviral drugs covering all available drug classes both individually and in typical combinations used during HAART to probe for direct effects on HCV cell entry, replication, new particle assembly and release. Importantly, no significant enhancement or inhibition of HCV cell entry, replication or new particle production was detected. While raltegravir and ritonavir boosted atazanavir reduce HCV replication, a tenfold reduction of HCVcc entry by the CCR5 antagonist maraviroc was observed. In conclusion, commonly used HAART agents do not specifically enhance HCV replication. Thus recent epidemic outbreaks of acute HCV in HIV-infected MSM are unlikely to be related to enhancing effects of HAART drugs. PMID- 22842004 TI - Inhibition of rotavirus infection in cultured cells by N-acetyl-cysteine, PPARgamma agonists and NSAIDs. AB - Although the current rotavirus vaccines have shown good tolerance and significant efficacy, it would be useful to develop alternative or complementary strategies aimed at preventing or treating acute diarrhoeal disease caused by this viral agent. A variety of antiviral strategies other than vaccines have been assayed for rotavirus infection management. The recently demonstrated sensitivity of rotavirus infectivity to thiol/disulfide reagents prompted assays for screening drugs that potentially affect cellular redox reactions. MA104 or Caco-2 cells were inoculated with the rotavirus strains RRV, Wa, Wi or M69 and then incubated with different concentrations of drugs belonging to a selected group of 60 drugs that are currently used in humans for purposes other than rotavirus infection treatment. Eighteen of these drugs were able to inhibit rotavirus infectivity to different extents. A more systematic evaluation was performed with drugs that could be used in children such as N-acetylcysteine and ascorbic acid, in addition to ibuprofen, pioglitazone and rosiglitazone, all of which affecting cellular pathways potentially needed by the rotavirus infection process. Evidence is provided here that rotavirus infectivity is significantly inhibited by NAC in different cell-culture systems. These findings suggest that NAC has the potential to be used as a therapeutic tool for treatment and prevention of rotavirus disease in children. PMID- 22842005 TI - Purinergic transmission in the rostral but not caudal medullary raphe contributes to the hypercapnia-induced ventilatory response in unanesthetized rats. AB - The medullary raphe (MR) is a putative central chemoreceptor site, contributing to hypercapnic respiratory responses elicited by changes in brain PCO2/pH. Purinergic mechanisms in the central nervous system appear to contribute to central chemosensitivity. To further explore the role of P2 receptors within the rostral and caudal MR in relation to respiratory control in room air and hypercapnic conditions, we performed microinjections of PPADS, a non-selective P2X antagonist, in conscious rats. Microinjections of PPADS into the rostral or caudal MR produced no changes in the respiratory frequency, tidal volume and ventilation in room air condition. The ventilatory response to hypercapnia was attenuated after microinjection of PPADS into the rostral but not in the caudal MR when compared to the control group (vehicle microinjection). These data suggest that P2X receptors in the rostral MR contribute to the ventilatory response to CO2, but do not participate in the tonic maintenance of ventilation under room air condition in conscious rats. PMID- 22842006 TI - Role of neurotransmitter gases in the control of the carotid body in heart failure. AB - The peripheral arterial chemoreflex, arising primarily from the carotid body in most species, plays an important role in the control of breathing and in autonomic control of cardiovascular function. The peripheral chemoreflex is enhanced in heart failure patients and animal models of heart failure and contributes to the sympathetic hyperactivity and breathing instability that exacerbates the progression of the disease. Studies in animal models have shown that carotid body chemoreceptor activity is enhanced under both normoxic and hypoxic conditions in heart failure due to disruption of local mediators that control carotid body function. This brief review highlights evidence that the alterations in the gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide in the carotid body contribute to the exaggerated carotid body function observed in heart failure. PMID- 22842007 TI - Contribution of beta-adrenergic receptors to exercise-induced bronchodilatation in healthy humans. AB - Exercise in healthy subjects is usually associated with progressive bronchodilatation. Though the decrease in vagal tone is deemed to be the main underlying mechanism, activation of bronchial beta(2)-receptors may constitute an additional cause. To examine the contribution of beta(2)-adrenergic receptors to bronchodilatation during exercise in healthy humans, we studied 15 healthy male volunteers during maximum exercise test at control conditions and after a non selective beta-adrenergic blocker (carvedilol 12.5mg twice a day until heart rate decreased at least by 10beats/min) and inhaled beta(2)-agonist (albuterol 400MUg). Airway caliber was estimated from the partial flow at 40% of control forced vital capacity (V(part40)) and its changes during exercise from the slope of linear regression analysis of V(part40) values against the corresponding minute ventilation during maximal exercise until exhaustion. At control, V(part40) increased progressively and significantly with exercise. After albuterol, resting V(part40) was significantly larger than at control increased but did not further increase during exercise. After carvedilol, V(part40) was similar to control but its increase with exercise was significantly attenuated. These findings suggest that beta(2)-adrenergic system plays a major role in exercise-induced bronchodilation in healthy subjects. PMID- 22842008 TI - Carotid chemoreceptor development and neonatal apnea. AB - The premature transition from fetal to neonatal life is accompanied by an immature respiratory neural control system. Most preterm infants exhibit recurrent apnea, resulting in repetitive oscillations in O(2) saturation (intermittent hypoxia, IH). Numerous factors are likely to play a role in the etiology of apnea including inputs from the carotid chemoreceptors. Despite major advances in our understanding of carotid chemoreceptor function in the early neonatal period, however, their contribution to the initiation of an apneic event and its eventual termination are still largely speculative. Recent findings have provided a detailed account of the postnatal changes in the incidence of hypoxemic events associated with apnea, and there is anecdotal evidence for a positive correlation with carotid chemoreceptor maturation. Furthermore, studies on non-human animal models have shown that chronic IH sensitizes the carotid chemoreceptors, which has been proposed to perpetuate the occurrence of apnea. An alternative hypothesis is that sensitization of the carotid chemoreceptors could represent an important protective mechanism to defend against severe hypoxemia. The purpose of this review, therefore, is to discuss how the carotid chemoreceptors may contribute to the initiation and termination of an apneic event in the neonate and the use of xanthine therapy in the prevention of apnea. PMID- 22842009 TI - Preschoolers' daytime respiratory sinus arrhythmia and nighttime sleep. AB - We examined the association between preschoolers' (N=29; 20 boys; M age = 3.99 years, SD=.69) daytime parasympathetic nervous system (PNS) activity indexed by respiratory sinus arrhythmia (RSA) and their nighttime sleep. Children's baseline RSA was assessed in the laboratory. Sleep was monitored for seven consecutive nights at the child's home via actigraphy and the following sleep parameters were derived: sleep minutes, sleep activity index and sleep efficiency. Regression analyses showed that after controlling for potential confounds, higher RSA was a predictor of lower sleep activity and higher sleep efficiency. Results highlight the importance of physiological regulation for the sleep of healthy preschool children. PMID- 22842010 TI - Stocking methods and parasite-induced reductions in capture: modelling Argulus foliaceus in trout fisheries. AB - Argulus foliaceus is a macroparasite which can have a significant impact on yield in recreational trout fisheries, partly by increasing fish mortalities but also by reducing the appetite of infected fish, making them less likely to respond to bait. The aim of this paper is to determine the impact of four commonly used fish stocking methods both on the parasite dynamics, and on fisheries' yields. The wider consequences of the resultant reduction in host feeding are also of interest. To this end four different stocking methods were incorporated into Anderson and May's macroparasite model, which comprises three differential equations representing the host, attached parasite and free-living parasite populations. To each of these a reduction in the fish capture rate, inversely linked to the mean parasite burden, is added and the effects interpreted. Results show that (1) the common practise of increasing the stocking rate as catches drop may be counterproductive; (2) in the absence of any wild population of reservoir hosts, the parasite will be unable to survive if the stocking rate does not exceed the rate of capture; (3) compensatory stocking to account for fish mortalities can have disastrous consequences on yield; and (4) the parasite can, under certain circumstances, maintain the host population by preventing their capture. PMID- 22842011 TI - Natural selection for costly nutrient recycling in simulated microbial metacommunities. AB - Recycling of essential nutrients occurs at scales from microbial communities to global biogeochemical cycles, often in association with ecological interactions in which two or more species utilise each others' metabolic by-products. However, recycling loops may be unstable; sequences of reactions leading to net recycling may be parasitised by side-reactions causing nutrient loss, while some reactions in any closed recycling loop are likely to be costly to participants. Here we examine the stability of nutrient recycling loops in an individual-based ecosystem model based on microbial functional types that differ in their metabolism. A supplied nutrient is utilised by a "source" functional type, generating a secondary nutrient that is subsequently used by two other types-a "mutualist" that regenerates the initial nutrient at a growth rate cost, and a "parasite" that produces a refractory waste product but does not incur any additional cost. The three functional types are distributed across a metacommunity in which separate patches are linked by a stochastic diffusive migration process. Regions of high mutualist abundance feature high levels of nutrient recycling and increased local population density leading to greater export of individuals, allowing the source-mutualist recycling loop to spread across the system. Individual-level selection favouring parasites is balanced by patch-level selection for high productivity, indirectly favouring mutualists due to the synergistic productivity benefits of the recycling loop they support. This suggests that multi-level selection may promote nutrient cycling and thereby help to explain the apparent ubiquity and stability of nutrient recycling in nature. PMID- 22842012 TI - Development and validation of a multiple choice examination assessing cognitive and behavioural knowledge of pediatric resuscitation: a report from the EXPRESS pediatric research collaborative. AB - INTRODUCTION: Assessing the knowledge of Pediatric Advanced Life Support (PALS) based learning objectives of medical trainees is an important evaluation component for both residency programs and for research studies. In this study, a multiple-choice question (MCQ) examination was developed and validated for use in a larger pediatric simulation resuscitation study (EXPRESS study). METHODS: Experts in pediatric resuscitation developed two MCQ exams using a set of pre determined learning objectives. After a single center pilot, the exam was used as an assessment of cognitive skills in the EXPRESS study, a multicenter trial examining the use of scripted debriefing and high-fidelity simulation in pediatric resuscitation education. Results from the MCQ in the pre-intervention phase of the EXPRESS study were used to assess the reliability and validity of the MCQ examination. In addition, an Exploratory Factor Analysis (EFA) was carried to assess the underlying structure of the PALS-based learning objectives. RESULTS: 435 health care professionals completed the MCQ examination with an average score of 69.3%. Significantly higher examination results were seen in physicians vs. non-physicians, senior vs. junior physicians and participants with up-to-date PALS certification. The EFA results indicated four distinct categories of items were assessed. CONCLUSION: This short MCQ examination demonstrated reasonable reliability and construct validity. It may be useful to assess pediatric resuscitation knowledge in future studies or courses. PMID- 22842013 TI - Quercetin 3-O-methyl ether protects FL83B cells from copper induced oxidative stress through the PI3K/Akt and MAPK/Erk pathway. AB - Quercetin is a bioflavonoid that exhibits several biological functions in vitro and in vivo. Quercetin 3-O-methyl ether (Q3) is a natural product reported to have pharmaceutical activities, including antioxidative and anticancer activities. However, little is known about the mechanism by which it protects cells from oxidative stress. This study was designed to investigate the mechanisms by which Q3 protects against Cu(2+)-induced cytotoxicity. Exposure to Cu(2+) resulted in the death of mouse liver FL83B cells, characterized by apparent apoptotic features, including DNA fragmentation and increased nuclear condensation. Q3 markedly suppressed Cu(2+)-induced apoptosis and mitochondrial dysfunction, characterized by reduced mitochondrial membrane potential, caspase-3 activation, and PARP cleavage, in Cu(2+)-exposed cells. The involvement of PI3K, Akt, Erk, FOXO3A, and Mn-superoxide dismutase (MnSOD) was shown to be critical to the survival of Q3-treated FL83B cells. The liver of both larval and adult zebrafish showed severe damage after exposure to Cu(2+) at a concentration of 5MUM. Hepatic damage induced by Cu(2+) was reduced by cotreatment with Q3. Survival of Cu(2+)-exposed larval zebrafish was significantly increased by cotreatment with 15MUM Q3. Our results indicated that Cu(2+)-induced apoptosis in FL83B cells occurred via the generation of ROS, upregulation and phosphorylation of Erk, overexpression of 14-3-3, inactivation of Akt, and the downregulation of FOXO3A and MnSOD. Hence, these results also demonstrated that Q3 plays a protective role against oxidative damage in zebrafish liver and remarked the potential of Q3 to be used as an antioxidant for hepatocytes. PMID- 22842014 TI - Effects of subtoxic concentrations of TiO2 and ZnO nanoparticles on human lymphocytes, dendritic cells and exosome production. AB - Metal oxide nanoparticles are widely used in the paint and coating industry as well as in cosmetics, but the knowledge of their possible interactions with the immune system is very limited. Our aims were to investigate if commercially available TiO(2) and ZnO nanoparticles may affect different human immune cells and their production of exosomes, nano-sized vesicles that have a role in cell to cell communication. We found that the TiO(2) or ZnO nanoparticles at concentrations from 1 to 100MUg/mL did not affect the viability of primary human peripheral blood mononuclear cells (PBMC). In contrast, monocyte-derived dendritic cells (MDDC) reacted with a dose dependent increase in cell death and caspase activity to ZnO but not to TiO(2) nanoparticles. Non-toxic exposure, 10MUg/mL, to TiO(2) and ZnO nanoparticles did not significantly alter the phenotype of MDDC. Interestingly, ZnO but not TiO(2) nanoparticles induced a down regulation of FcgammaRIII (CD16) expression on NK-cells in the PBMC population, suggesting that subtoxic concentrations of ZnO nanoparticles might have an effect on FcgammaR-mediated immune responses. The phenotype and size of exosomes produced by PBMC or MDDC exposed to the nanoparticles were similar to that of exosomes harvested from control cultures. TiO(2) or ZnO nanoparticles could not be detected within or associated to exosomes as analyzed with TEM. We conclude that TiO(2) and ZnO nanoparticles differently affect immune cells and that evaluations of nanoparticles should be performed even at subtoxic concentrations on different primary human immune cells when investigating potential effects on immune functions. PMID- 22842015 TI - The pilosebaceous unit--a phthalate-induced pathway to skin sensitization. AB - Allergic contact dermatitis (ACD) is caused by low-molecular weight compounds called haptens. It has been shown that the potency of haptens can depend on the formulation in which they are applied on the skin. Specifically the sensitization potency of isothiocyanates, a group of haptens which can be released from e.g. adhesive tapes and neoprene materials, increases with the presence of phthalates; however, the underlying mechanisms are not clear. A better understanding of the mechanisms governing the potency of haptens is important, e.g. to improve the risk assessment and the formulation of chemicals in consumer products. In this study we have explored phthalate-induced effects on the sensitization potency, skin distribution, and reactivity of fluorescent model isothiocyanate haptens using non-invasive two-photon microscopy to provide new insights regarding vehicle effects in ACD. The data presented in this paper indicate that the sensitization potency of isothiocyanates increases when applied in combination with dibutylphthalate due to a specific uptake via the pilosebaceous units. The results highlight the importance of shunt pathways when evaluating the bioavailability of skin sensitizers. The findings also indicate that vehicle dependent hapten reactivity towards stratum corneum proteins regulates the bioavailability, and thus the potency, of skin sensitizers. PMID- 22842016 TI - Neuroprotective and memory enhancing properties of a dual agonist of the FGF receptor and NCAM. AB - The fibroblast growth factor receptor (FGFR) plays a vital role in the development of the nervous system regulating a multitude of cellular processes. One of the interaction partners of the FGFR is the neural cell adhesion molecule (NCAM), which is known to play an important role in neuronal development, regeneration and synaptic plasticity. Thus, simultaneous activation of FGFR- and NCAM-mediated signaling pathways may be expected to affect processes underlying neurodegenerative diseases. We here report the identification of a peptide compound, Enreptin, capable of interacting with both FGFR and NCAM. We demonstrate that this dual specificity agonist induces phosphorylation of FGFR and differentiation and survival of primary neurons in vitro, and that these effects are inhibited by abrogation of both NCAM and FGFR signaling pathways. Furthermore, Enreptin crosses the blood-brain barrier after subcutaneous administration, enhances long-term memory in normal mice and ameliorates memory deficit in mice with induced brain inflammation. Moreover, Enreptin reduces cognitive impairment and neuronal death induced by Abeta25-35 in a rat model of Alzheimer's disease, and reduces the mortality rate and clinical signs of experimental autoimmune encephalomyelitis in rats. Thus, Enreptin is an attractive candidate for the treatment of neurological diseases. PMID- 22842017 TI - "Ectopic" theta oscillations and interictal activity during slow-wave state in the R6/1 mouse model of Huntington's disease. AB - The pathophysiology of Huntington's disease (HD) is primarily associated with striatal degeneration and a number of behavioral symptoms such as involuntary movements, cognitive decline, psychiatric disorders, and in the most juvenile onset cases with epilepsy. In addition to several changes in cellular and synaptic properties previously reported in HD, attention was recently driven towards the potential relationships between cognitive deficits and sleep disturbances in patients and animal models of Huntington's disease. In the present study, we have investigated whether the population-activity patterns normally expressed by the hippocampal and neocortical circuits during active and slow-wave states are affected in R6/1 mice, a model of Huntington's disease. By performing electrophysiological recordings from the hippocampus and neocortex of R6/1 mice that were either freely moving, head restrained or anesthetized, we observed an altered segregation of active and slow wave brain states, in relation with an epileptic phenotype. Slow-wave state (SWS) in R6/1 was characterized by the intrusion of active-state features (increased 6-10 Hz theta power and depressed 2-3 Hz delta power) and transient, temporally misplaced ("ectopic") theta oscillations. The epileptic phenotype, in addition to previously reported occasional ictal seizures, was characterized by the systematic presence of interictal activity, confined to SWS. Ectopic theta episodes, which could be reversed by the cholinergic antagonist atropine, concentrated interictal spikes and phase-locked hippocampal sharp-wave-ripples. These results point to major alterations of neuronal activity during rest in R6/1 mice, potentially involving anomalous activation of the cholinergic system, which may contribute to the cognitive deficits observed in Huntington's disease. PMID- 22842018 TI - Dopaminergic imaging of nonmotor manifestations in a rat model of Parkinson's disease by fMRI. AB - Nonmotor manifestations determine the life quality of patients with Parkinson's disease (PD). Identification of the nonmotor symptoms in PD as definite changes will represent a milestone in its diagnosis. Outcome measures that characterize nonmotor manifestations with specificity for dopaminergic deficiency are essential to that goal. Pain is a prevalent sensory disturbance in PD patients. The prevalence was reported to be up to 83%. Nociceptive stimuli under normal conditions elicit decreases in cerebral blood volume (CBV) in the striatum via dopaminergic neurotransmission. This nociception-induced CBV response is potentially to be defined as a characteristic of the pain symptom of PD. To validate this concept, steady-state CBV-weighted functional magnetic resonance imaging with iron oxide nanoparticles was employed to measure CBV changes in parkinsonian rats. Tyrosine hydroxylase immunohistology was used to identify the dopaminergic integrity to corroborate the imaging findings. Additional experiments that tested pain responses in parkinsonism were also carried out. The results revealed that the lesioned striatum exhibited a weakened CBV decrease in response to the nociceptive stimulus. This weakened CBV response occurred mainly in areas with dopaminergic denervation. A strong correspondence was observed between the distributions of the nociception-induced CBV responses and dopaminergic innervation. The persisting CBV signals in the striatum were abolished by the D2/D3 antagonist eticlopride. The findings of these behavioral, neuroimaging, immunohistological, and pharmacological experiments demonstrate that pain in a rat model of PD can be characterized by nociception induced striatal CBV signal changes with specificity for dopaminergic dysfunction. PMID- 22842019 TI - Function of the chloroplastic NAD(P)H dehydrogenase Nda2 for H2 photoproduction in sulphur-deprived Chlamydomonas reinhardtii. AB - The relative contributions of the PSII-dependent and Nda2-dependent pathways for H2 photoproduction were investigated in the green microalga Chlamydomonas reinhardtii after suphur-deprivation. For this purpose, H2 gas production was compared for wild-type and Nda2-deficient cells with or without DCMU (a PSII inhibitor) in the same experimental conditions. Nda2-deficiency caused a 30% decrease of the maximal H2 photoevolution rate observed shortly after the establishment of anoxia, and an acceleration of the decline of H2 photoevolution rate with time. DCMU addition to Nda2-deficient cells completely inhibited H2 photoproduction, showing that the PSII-independent H2 photoproduction relies on the presence of Nda2, which feeds the photosynthetic electron transport chain with electrons derived from oxidative catabolism. Nda2-protein abundance increased as a result of sulphur deprivation and further during the H2 photoproduction process, resulting in high rates of non-photochemical plastoquinone reduction in control cells. Nda2-deficiency had no significant effect on photosynthetic and respiratory capacities in sulphur-deprived cells, but caused changes in the cell energetic status (ATP and NADPH/NADP+ ratio). The rapid decline of H2 photoevolution rate with time in Nda2-deficient cells revealed a more pronounced inhibition of H2 photoproduction by accumulated H2 in the absence of non-photochemical plastoquinone reduction. Nda2 is therefore important for linking H2 photoproduction with catabolism of storage carbon compounds, and seems also involved in regulating the redox poise of the photosynthetic electron transport chain during H2 photoproduction. PMID- 22842020 TI - Onset of Depression Inventory (ODI)--assessment of the speed of onset of depressive episodes. AB - BACKGROUND: The development of a full blown depressive episode may be very rapid, taking less than one hour, or be very slow, taking up to months. In a previous study with outpatients it was found that the majority (58%) of depressive episodes within bipolar affective disorders (BD) develop within one week whereas this is rarely the case (7.4%) in unipolar depression (UD). Apart from a replication of these findings, the present study aimed to investigate the speed of onset in patients with BD compared to UD patients with either a depressive episode (DE) or recurrent depressive disorder (RD). METHODS: Speed of onset of depression was assessed using the structured patient interview "Onset of Depression Inventory" (ODI). In total, 24 BD patients, 42 patients with a DE and 80 patients with a RD within unipolar affective disorders were included. RESULTS: The speed of onset of depressive episodes differed significantly between the three patient groups (Kruskal-Wallis-test: Chi2=12.493, p=0.002): 50% of the BD patients developed a depressive episode within a week, compared with only 16.7% of DE patients and 25.0% of RD patients. LIMITATIONS: The ODI has not yet been validated. CONCLUSIONS: The earlier finding of a faster onset of depressive episodes in BD compared to UD patients is replicated. Clinicians should consider the possibility of a hidden bipolarity in patients who develop a depressive episode within a few days. PMID- 22842021 TI - Predictors of later bipolar disorder in patients with subthreshold symptoms. AB - INTRODUCTION: The clinical significance of subthreshold bipolar disorder (SBD), which is characterized by an insufficient number or severity of hypomanic symptoms to qualify for a formal bipolar disorder diagnosis, remains to be determined. METHODS: We examined the outcomes three years later (2004-2005; Wave 2) of 40,512 civilian, non-institutionalized subjects who endorsed elation and/or irritability but did not meet full criteria for lifetime mania or hypomania in 2001-2002 (Wave 1). RESULTS: The likelihood of developing a clear episode of mania or hypomania by Wave 2 was significantly increased in subjects with elation or only irritability at Wave 1 compared with subjects who did not endorse either (OR 2.8, p<0.01 for each). Endorsement of both symptoms at Wave 1 increased the likelihood of a new episode of mania or hypomania 4.6 times, which was significantly higher than for those with only elation or irritability (p<.05 for each). LIMITATIONS: SBD was not limited to depression, reducing comparability to previous studies. Despite the large sample size, there were not enough subjects to determine the impact of different numbers and types of additional symptoms on bipolar outcome. Although the majority of subjects were followed between the two Waves, the total duration of follow-up was probably too short to determine the long-term conversion rate to mania or hypomania. CONCLUSIONS: Elation and/or irritability, especially if accompanied by trouble concentrating, racing thoughts or hyperactivity, may represent a prodrome of formal bipolar disorder that indicate close follow-up and cautious use of antidepressants. PMID- 22842022 TI - Coping strategies for antidepressant side effects: an Internet survey. AB - BACKGROUND: Patients' coping methods to palliate side effects of antidepressants have not been reported in the literature. METHODS: Through an Internet survey, 856 participants who were diagnosed with depression and receiving antidepressants were recruited to report on the methods of coping with side effects. They were asked which side effect(s) they experienced and to write freely about the way they tried to counteract these effects. We classified active coping methods into the following sub-types: adjustment of prescriptions, additional medication, complementary therapy, consultation with physicians, and daily relief. RESULTS: The prevalence of active coping differed across side effects (from 26.7%, sexual dysfunction, to 89.5%, dry mouth). Events with a lower percentage of active coping were more likely to be managed with "adjustment of prescriptions": (sexual dysfunction, 41.9%; fatigue, 36.8%; sweating, 20.0%; tremor, 42.5%; and somnolence, 31.8%). Further, a strong negative correlation was found between the percentage of participants reporting an adjustment of prescription and that reporting an active coping (r=-0.907, p<0.001). The "daily relief" sub-type contained a variety of strategies, including negative methods such as vomiting for nausea and weight gain and drinking alcohol for insomnia. LIMITATIONS: Sampling of subjects were biased due to an Internet survey and diagnosis of depression and experience of side effects were self-reported. CONCLUSION: Patients with depression use various ways in alleviating antidepressants side effects. Some effects such as sexual dysfunction and fatigue may not be amenable to subjective coping efforts and others are sometimes managed inappropriately, which warrants a prudent attention. PMID- 22842023 TI - Latitude effect on bipolar temperaments. AB - BACKGROUND: Growing evidence points to an association of daily light exposure and both mood and mood disorders. In recent studies, we demonstrated that higher illuminance of daytime may be positively associated with hyperthymic temperament while lower illuminance of daytime may be positively associated with cyclothymic temperament. However, it is not possible to determine whether hyperthymic or cyclothymic temperament induces higher or lower illuminance via heliotropism or non-heliotropism or whether higher or lower illuminance induces hyperthymic or cyclothymic temperament via light effects. METHODS: In order to elucidate these questions, we sought to compare bipolar temperaments between residents who live in regions with varying levels of sunshine. Japan has 4 large islands -Hokkaido, Honshu, Shikoku, and Kyushu. Sapporo in Hokkaido and Oita in Kyushu located at 43 degrees and 33 degrees of latitude differ significantly in mean yearly sunshine. We investigated the data of 189 subjects (94 from Sapporo and 95 from Oita) including their data of Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A). RESULTS: Multiple regression analyses revealed that latitude (Sapporo or Oita) effect predicted significant variance of hyperthymic temperament, but not of the other temperaments. LIMITATIONS: The limitation of the present study was that there was a small but significant difference in age between the subjects of Sapporo and those of Oita. Therefore, we included age in the multiple regression analysis. Second, there were several climate factors other than sunshine which were significantly different between Sapporo and Oita. We cannot exclude these effects completely. Finally, we did not consider other factors such as psychosocial factors which might have affected bipolar temperaments. CONCLUSIONS: The present findings suggest that relatively lower latitude (potentially via more sunshine) may induce hyperthymic temperament. PMID- 22842024 TI - Does unstable mood increase risk of suicide? Theory, research and practice. AB - BACKGROUND: Suicide represents a substantial problem, with significant societal and personal impact. The identification of factors influencing suicide risk is an important step in preventing self-harming behaviour. In this article the authors explore whether emotional instability increases risk of suicide, beyond that of mood intensity. METHOD: This article provides a summary of existing theory and indirect evidence in support of an association between emotional instability and suicidality. A systematic literature search (Embase, Medline, PsychInfo) was carried out on literature conducted up to October, 2011. Meta-analysis was used to assess the strength of the proposed association. RESULTS: The systematic search identified 20 journal articles meeting the inclusion criteria, including retrospective questionnaire design studies and research conducted across several time-points. Meta-analysis revealed a moderate association, which remained statistically significant even when only including studies conducted over multiple time-points. This effect was attenuated, but remained significant, when controlling for study selection bias. LIMITATIONS: Retrospective questionnaire studies failed to adequately control for mood level. Little is still currently understood about the types of emotional instability (e.g., dysoria, anxiety) most associated with suicidality. CONCLUSIONS: Future avenues of investigation include micro- to macro-longitudinal research and the differentiation of emotion subtypes and instability metrics. Momentary assessment techniques may help to detect subtle fluctuations in mood leading to more effective and immediate intervention. Psychosocial intervention strategies for treating unstable emotions are discussed. PMID- 22842025 TI - Do antidepressants change personality?--a five-year observational study. AB - BACKGROUND: Whether antidepressants influence personality is a major clinical and societal issue due to their widespread use. In an observational study, we investigated whether depressive patients' neuroticism and extraversion scores covary with antidepressant pharmacotherapy, and if so, whether this remains significant after accounting for depressive or anxiety symptoms. METHODS: Major depressive disorder patients (N=237) were interviewed at up to four time-points in a five-year prospective longitudinal study. Changes in neuroticism plus extraversion scores were compared with changes in antidepressant pharmacotherapies and depressive plus anxiety symptoms to uncover any covariation between them. Autoregressive path models were used to examine this covariation at the sample level. Within-subject change was estimated using a random-effects latent change model. RESULTS: Significant covariation is present in the change trajectories between personality scores and depressive symptoms; declining depression scores were associated with rising extraversion and declining neuroticism. Although the personality scores of many patients changed significantly over the five-year study, none of these changes were associated with changes in antidepressant pharmacotherapy. LIMITATIONS: The study covered only two dimensions of personality. Single drug-specific analysis could not be done. Antidepressant blood levels were not measured. CONCLUSION: No evidence emerged for significant covariation of antidepressant pharmacotherapy with neuroticism or extraversion scores. By contrast, changes in both personality dimensions were associated with changes in depressive symptoms, those in neuroticism also in anxiety symptoms. If antidepressants influence these personality dimensions, the effect size is likely markedly smaller than that of the disorders for which they are prescribed. PMID- 22842026 TI - Clinical factors leading to lamotrigine prescription in bipolar outpatients: subanalysis of the SIN-DEPRES study. AB - BACKGROUND: The use of lamotrigine is a point of discrepancy among the diverse guidelines published on the management of bipolar disorder (BD). Evidence supporting the long-term efficacy is reasonably robust. Nonetheless, the effectiveness of lamotrigine in acute treatment is vigorously debated and it is unclear how this drug is used in routine clinical practice. This subanalysis of the SIN-DEPRES study was designed to understand the clinical profile of bipolar patients receiving lamotrigine. METHODS: In this prospective national multicenter study, 652 patients with clinically stable bipolar I and II disorder were recruited. Clinical assessments included sociodemographic and clinical data, the Modified Clinical Global Impression scale for BD (CGI-BP-M), the Hamilton Depression Rating Scale (HDRS), and prescriptions of psychotropic medications and their doses. RESULTS: By means of a logistic regression model, an association between receiving treatment with lamotrigine and the following clinical variables was found: number of past depressive episodes (O.R.=2.875, 95% CI: 1.203-6.869, p=0.018), depressive polarity of the most recent episode (O.R.=1.945, 95% CI: 1.267-2.985, p=0.002), severity in CGI-BD-M depression (O.R.=1.850, 95% CI: 1.215 2.817, p=0.004), bipolar II disorder diagnosis (O.R.=1.635, 95% CI: 1.078-2.482, p=0.021) and number of episodes per year (O.R.=1.310, 95% CI: 1.069-1.605, p=0.009). LIMITATIONS: Subanalysis of the SIN-DEPRES study with a cross-sectional design. CONCLUSIONS: The use of lamotrigine in clinical practice is in accordance with most of the guidelines, which support its use in patients with depressive predominant polarity and bipolar II disorder. PMID- 22842027 TI - Suicidal phenotypes associated with family history of suicidal behavior and early traumatic experiences. AB - BACKGROUND: Family history of suicidal behavior and personal history of childhood trauma are risk factors for suicidal behaviors. We hypothesize that subjects with any of these risk factors will show differential features and that subjects with both of them will display more severe phenotypes. METHODS: This study compares three groups of suicide attempters (n=878): subjects with a family history of suicidal behavior and a personal history of early traumatic experiences, subjects with a family history of suicidal behavior or a personal history of early traumatic experiences, and subjects with neither of these two risk factors, with regards to psychopathology, personality traits and suicidal behavior. RESULTS: Subjects with a family history of suicidal behavior and childhood trauma were younger at their first suicide attempt and made more frequent, severe and violent attempts when compared with the other groups. Differences in number and precocity of attempts remained after adjustments in a multinomial regression model. Finally, personality profiles were also substantially different in the group with higher impulsiveness, novelty seeking, affective lability and hopelessness. LIMITATIONS: The information provided by subjects regarding childhood abuse and family history of suicidal behavior was not confirmed by other sources. CONCLUSIONS: Suicide attempters with a family history of suicidal behavior and childhood trauma show specific characteristics that might be used to prevent future suicidal behaviors in this population. Both risk factors should be routinely investigated when assessing the suicidal risk of a patient. PMID- 22842028 TI - The Twelfth International Conference on Endothelin (ET-12), Cambridge 2011. AB - The Twelfth International Conference on Endothelin (ET-12) was held at Clare College, University of Cambridge, United Kingdom, from September 11-14, 2011, with researchers from basic and clinical science from nearly 20 countries attending. The conference featured a number of invited lectures, presentation of new research in several oral and poster sessions. It also featured newly introduced and well-received interactive panel discussion reviewing results and challenges of clinical trials using endothelin receptor antagonists conducted in the past 20 years. Evidence for new roles of endothelin in physiology and disease was presented, as well as new data from clinical trials in cancer and renal disease suggesting therapeutic efficacy of pharmacological modulation of the endothelin system. PMID- 22842029 TI - Endothelin XII. AB - Following the initial description of endothelium-dependent vasoconstriction in the early 1980s, it has been exactly 25 years since efforts to identify the sequence of the endothelin gene and peptide began in May 1987, work which resulted in a landmark paper submitted to Nature in December 1987 and published on March 31, 1988. The paper opened an entirely new field of research, followed by the inception of the International Conferences of Endothelin, the first of which was organized by Sir John Vane as Chair and held as the "First William Harvey Workshop on Endothelin" in London, UK, in December of 1988. Endothelin receptor antagonism has now been firmly established for more than a decade as a new, orally active drug treatment for patients with pulmonary arterial hypertension. Since the discovery of endothelin, on average 1,000 papers per year have been published with more than 25,000 papers available today, many of them published in the conferences' Proceedings. The present issue of Life Sciences, Endothelin XII, represents a collection of papers of original research and invited lectures presented at the Twelfth International Conference on Endothelin held in Cambridge, UK, in September 2011. PMID- 22842030 TI - In vivo biomechanical stability of osseointegrating mesoporous TiO(2) implants. AB - Mesoporous materials are of high interest as implant coatings to receive an enhanced osseointegration. In this study, titanium implants coated with mesoporous TiO(2) thin films have been evaluated both in vitro and in vivo. Material characterization showed that, with partly crystalline TiO(2) (anatase), long-range-ordered hydrophilic mesoporous thin films with a pore size of 6nm were obtained. Evaluation of the mechanical resistance showed that the films were robust enough to withstand the standard implantation procedure. In vitro apatite formation was studied using simulated body fluids, showing that the pores are accessible for ions and that formation of apatite was increased due to the presence of the mesopores. An in vivo study using a rabbit model was executed in which the removal torque and histomorphometry were evaluated. The results show that the biomechanical stability of the TiO(2) coating was unaffected by the presence of mesopores and that osseointegration was achieved without any signs of inflammation. PMID- 22842031 TI - Repairing a critical-sized bone defect with highly porous modified and unmodified baghdadite scaffolds. AB - This is the first reported study to prepare highly porous baghdadite (Ca3ZrSi2O9) scaffolds with and without surface modification and investigate their ability to repair critical-sized bone defects in a rabbit radius under normal load. The modification was carried out to improve the mechanical properties of the baghdadite scaffolds (particularly to address their brittleness) by coating their surfaces with a thin layer (~400 nm) of polycaprolactone (PCL)/bioactive glass nanoparticles (nBGs). The beta-tricalcium phosphate/hydroxyapatite (TCP/HA) scaffolds with and without modification were used as the control groups. All of the tested scaffolds had an open and interconnected porous structure with a porosity of ~85% and average pore size of 500 MUm. The scaffolds (six per scaffold type and size of 4 mm * 4 mm * 15 mm) were implanted (press-fit) into the rabbit radial segmental defects for 12 weeks. Micro-computed tomography and histological evaluations were used to determine bone ingrowth, bone quality, and implant integration after 12 weeks of healing. Extensive new bone formation with complete bridging of the radial defect was evident with the baghdadite scaffolds (modified/unmodified) at the periphery and in close proximity to the ceramics within the pores, in contrast to TCP/HA scaffolds (modified/unmodified), where bone tended to grow between the ulna adjacent to the implant edge. Although the modification of the baghdadite scaffolds significantly improved their mechanical properties, it did not show any significant effect on in vivo bone formation. Our findings suggest that baghdadite scaffolds with and without modification can serve as a potential material to repair critical sized bone defects. PMID- 22842032 TI - Nanoporous silica microparticle interaction with toll-like receptor agonists in macrophages. AB - Nanoporous silica microparticles (NSiO(2)-MP) are considered to be potential drug delivery systems and scaffolding platforms in tissue engineering. However, few biocompatibility studies regarding NSiO(2)-MP interaction with the immune system have been reported. Toll-like receptors (TLR) are involved in host defence as well as autoimmune and inflammatory diseases. The results show that NSiO(2)-MP up to 100MUgml(-1) do not affect macrophage cell viability after 24h cell culture. Moreover, NSiO(2)-MP do not compromise the cell viability of TLR-activated Raw 264.7 cells, for either cell surface TLR (TLR1/TLR2/TLR4/TLR6) or endocytic compartment TLR (TLR3/TLR7/TLR9). Furthermore, Raw 264.7 cells do not respond to NSiO(2)-MP exposure in terms of IL-6 or IL-10 secretion. NSiO(2)-MP co-treatment in the presence of TLR ligands does not impair or enhance the secretion of the pro-inflammatory cytokine IL-6 or the regulatory cytokine IL-10. Thus, NSiO(2)-MP do not affect macrophage polarization towards a pro-inflammatory or immunosuppressive status, representing added value in terms of biocompatibility compared with other SiO(2)-based micro- and nanoparticles. PMID- 22842033 TI - PDMS(star)-PEG hydrogels prepared via solvent-induced phase separation (SIPS) and their potential utility as tissue engineering scaffolds. AB - Inorganic-organic hydrogels based on methacrylated star polydimethylsiloxane (PDMS(star)-MA) and diacrylated poly(ethylene glycol) (PEG-DA) macromers were prepared via solvent-induced phase separation (SIPS). The macromers were combined in a dichloromethane precursor solution and sequentially photopolymerized, dried and hydrated. The chemical and physical properties of the hydrogels were further tailored by varying the number average molecular weight (M(n)) of PEG-DA (M(n)=3.4k and 6k gmol(-1)) as well as the weight percent ratio of PDMS(star)-MA (M(n)=7k gmol(-1)) to PEG-DA from 0:100 to 20:80. Compared to analogous hydrogels fabricated from aqueous precursor solutions, SIPS produced hydrogels with a macroporous morphology, a more even distribution of PDMS(star)-MA, increased modulus and enhanced degradation rates. The morphology, swelling ratio, mechanical properties, bioactivity, non-specific protein adhesion, controlled introduction of cell adhesion, and cytocompatibility of the hydrogels were characterized. As a result of their tunable properties, this library of hydrogels is useful to study material-guided cell behavior and ultimate tissue regeneration. PMID- 22842034 TI - Characterization of chemoselective surface attachment of the cationic peptide melimine and its effects on antimicrobial activity. AB - Antimicrobial peptides (AMPs) are promising alternatives to current treatments for bacterial infections. However, our understanding of the structural-functional relationship of tethered AMPs still requires further investigation to establish a general approach for obtaining consistent antimicrobial surfaces. In this study, we have systematically examined the effects of surface orientation of a broad spectrum synthetic cationic peptide, melimine, on its antibacterial activity against Gram-positive and Gram-negative bacteria. The attachment of melimine to maleimide-functionalized glass was facilitated by addition of a single cysteine amino acid into the peptide sequence at the N-terminus (CysN) or C-terminus (CysC), or at position 13 (Cys13, approximately central). The successful attachment of the modified melimine was monitored using X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry (ToF-SIMS) with principle component analysis. The ToF-SIMS analysis clearly demonstrated structural difference between the three orientations. The peptide density for the modified surfaces was found to be between 3.5-4.0*10(-9)molcm(-2) using a modified Bradford assay. The ability of the surfaces to resist Pseudomonas aeruginosa and Staphylococcus aureus colonization was compared using fluorescence confocal microscopy. Reductions in total P. aeruginosa and S. aureus adhesion of 70% (p<0.001) and 83% (p<0.001), respectively, after 48h were observed for the melimine samples when compared to the blank control. We found that melimine attached via the N-terminus was the most effective in reducing total bacterial adhesion and bacterial viability with two- and four times (p<0.001) more activity than melimine attached via the C-terminus for P. aeruginosa and S. aureus, respectively. Furthermore, for Cys13, despite having the highest measured peptide density of the three surfaces, the higher concentration did not confer the greatest antibacterial effect. This highlights the importance of orientation of the peptides on the surface to efficacy. Our results suggest that the optimal orientation of the cationic residues is essential for maximum surface activity, whereby the optimal activity is obtained when the cationic portion is more available to interact with colonizing bacteria. PMID- 22842036 TI - Influence of the fiber diameter and surface roughness of electrospun vascular grafts on blood activation. AB - Electrospun grafts have been widely investigated for vascular graft replacement due to their ease and compatibility with many natural and synthetic polymers. Here, the effect of the processing parameters on the scaffold's architecture and subsequent reactions of partially heparinized blood triggered by contacting these topographies were studied. Degrapol(r) (DP) and poly(lactic-co-glycolic acid) (PLGA) electrospun fibrous scaffolds were characterized with regard to fiber diameter, pore area and scaffold roughness. The study showed that electrospinning parameters greatly affect fiber diameter together with pore dimension and overall scaffold roughness. Coagulation cascade activation, early platelet adhesion and activation were analyzed after 2h of exposure of blood to the biomaterials. While no differences were found between DP and PLGA with similar topographies, the blood reactions were observed to be dependent on the fiber diameter and scaffold roughness. Scaffolds composed of thin fibers (diameter <1MUm) triggered very low coagulation and almost no platelets adhered. On the other hand, scaffolds with a bigger fiber diameter (2-3MUm) triggered higher thrombin formation and more platelets adhered. The highest platelet adhesion and activations rates as well as coagulation cascade activation were found in blood incubated in contact with the scaffolds produced with the biggest fiber diameter (5MUm). These findings indicate that electrospun grafts with small fiber diameter (<1MUm) could perform better with reduced early thrombogenicity due to lower platelet adhesion and lower activation of platelets and coagulation cascade. PMID- 22842037 TI - Mathematical model of mechanical behavior of micro/nanofibrous materials designed for extracellular matrix substitutes. AB - Electrospun micro/nanofibrous biomaterials are widely used as extracellular matrix substitutes in tissue engineering applications because of their structural and mechanical properties. To explore the influence of microstructure on the mechanical behavior of fibrous material, a mathematical model of the fiber system was developed. The model describes the microstructural properties of a fibrous matrix using a probability density function, and enables study of their mechanical properties. The results from the mathematical model were validated by qualitative comparison with the experimental results of mechanical testing of polystyrene electrospun nanofibrous materials. The analyses show a trend of three phase load-displacement behavior. Initially, as an increasing number of fibers are recruited for load bearing, the load-displacement curve has a 'J'-shaped toe region, which is followed by a nearly linear load-displacement curve, in which the number of load-bearing fibers remains nearly steady. Finally, there is a phase when the load-displacement curve descends, indicating failure of the material. The increase in flexibility of the fibrous material makes it stronger, but the randomness of fiber orientation makes the fibrous structure more flexible at the cost of lower strength. The measured mechanical properties of a fibrous matrix were also observed to be dependent on sample size. Therefore, the analyses establish a clear link between the structure and strength of fibrous materials for optimized design and fabrication of fibrous biomaterials with targeted use in tissue engineering, regenerative medicine and drug delivery. The model also establishes a need for standardization of experimental protocols for mechanical characterization of fibrous materials for consistency. PMID- 22842035 TI - A naturally derived cardiac extracellular matrix enhances cardiac progenitor cell behavior in vitro. AB - Myocardial infarction (MI) produces a collagen scar, altering the local microenvironment and impeding cardiac function. Cell therapy is a promising therapeutic option to replace the billions of myocytes lost following MI. Despite early successes, chronic function remains impaired and is likely a result of poor cellular retention, proliferation, and differentiation/maturation. While some efforts to deliver cells with scaffolds have attempted to address these shortcomings, they lack the natural cues required for optimal cell function. The goal of this study was to determine whether a naturally derived cardiac extracellular matrix (cECM) could enhance cardiac progenitor cell (CPC) function in vitro. CPCs were isolated via magnetic sorting of c-kit(+) cells and were grown on plates coated with either cECM or collagen I (Col). Our results show an increase in early cardiomyocyte markers on cECM compared with Col, as well as corresponding protein expression at a later time. CPCs show stronger serum induced proliferation on cECM compared with Col, as well as increased resistance to apoptosis following serum starvation. Finally, a microfluidic adhesion assay demonstrated stronger adhesion of CPCs to cECM compared with Col. These data suggest that cECM may be optimal for CPC therapeutic delivery, as well as providing potential mechanisms to overcome the shortcomings of naked cell therapy. PMID- 22842038 TI - Biphenyl liquid crystalline epoxy resin as a low-shrinkage resin-based dental restorative nanocomposite. AB - Low-shrinkage resin-based photocurable liquid crystalline epoxy nanocomposite has been investigated with regard to its application as a dental restoration material. The nanocomposite consists of an organic matrix and an inorganic reinforcing filler. The organic matrix is made of liquid crystalline biphenyl epoxy resin (BP), an epoxy resin consisting of cyclohexylmethyl-3,4 epoxycyclohexanecarboxylate (ECH), the photoinitiator 4-octylphenyl phenyliodonium hexafluoroantimonate and the photosensitizer champhorquinone. The inorganic filler is silica nanoparticles (~70-100 nm). The nanoparticles were modified by an epoxy silane of gamma-glycidoxypropyltrimethoxysilane to be compatible with the organic matrix and to chemically bond with the organic matrix after photo curing. By incorporating the BP liquid crystalline (LC) epoxy resin into conventional ECH epoxy resin, the nanocomposite has improved hardness, flexural modulus, water absorption and coefficient of thermal expansion. Although the incorporation of silica filler may dilute the reinforcing effect of crystalline BP, a high silica filler content (~42 vol.%) was found to increase the physical and chemical properties of the nanocomposite due to the formation of unique microstructures. The microstructure of nanoparticle embedded layers was observed in the nanocomposite using scanning and transmission electron microscopy. This unique microstructure indicates that the crystalline BP and nanoparticles support each other and result in outstanding mechanical properties. The crystalline BP in the LC epoxy resin-based nanocomposite was partially melted during exothermic photopolymerization, and the resin expanded via an order-to disorder transition. Thus, the post-gelation shrinkage of the LC epoxy resin based nanocomposite is greatly reduced, ~50.6% less than in commercialized methacrylate resin-based composites. This LC epoxy nanocomposite demonstrates good physical and chemical properties and good biocompatibility, comparable to commercialized composites. The results indicate that this novel LC nanocomposite is worthy of development and has potential for further applications in clinical dentistry. PMID- 22842039 TI - Reducing cytotoxicity while improving anti-cancer drug loading capacity of polypropylenimine dendrimers by surface acetylation. AB - Polypropylenimine (PPI) dendrimers have been widely used as effective delivery vehicles for drugs and nucleic acids during the past decade. However, biomedical applications of PPI dendrimers were limited because of their serious cytotoxicity and low drug loading capacity. In the present study, acetylated PPI dendrimers with different degrees of acetylation ranging from 14.2% to 94.3% were synthesized and used to encapsulate drugs, including methotrexate sodium, sodium deoxycholate and doxorubicin. Acetylated PPI dendrimers with a degree of acetylation >80% showed a significantly decreased cytotoxicity (>90% cell viability) on MCF-7 and A549 cells. The drug loading capacity of acetylated PPI dendrimers increased proportionally with the degree of acetylation on the dendrimer surface. In addition, 94.3% acetylated PPI dendrimers exhibited a pH responsive release profile of anticancer drugs loaded within the nanoparticles. The cytotoxicities of methotrexate sodium and doxorubicin on MCF-7 and A549 cells were significantly reduced when they were complexed with acetylated PPI dendrimers with high degrees of acetylation (>80%), owing to sustained drug release from the dendrimers. The results suggest that surface acetylation can reduce the cytotoxicity and improve the anticancer drug loading capacity of cationic dendrimers, and that acetylated PPI dendrimers are promising vehicles for anticancer drugs in clinical trials. PMID- 22842040 TI - Block copolymer of poly(ester amide) and polyesters: synthesis, characterization, and in vitro cellular response. AB - In order to expand the properties and applications of aliphatic absorbable polyesters, a new biodegradable block copolymer family, poly(ester amide)-b poly(epsilon-caprolactone) (PEA-b-PCL), was synthesized and characterized. These copolymers were synthesized by first preparing l-phenylalanine-based poly(ester amide) macroinitiators (Phe-PEAs) with free amine end groups via a solution polycondensation. The amine-terminated Phe-PEA macroinitiators were then used to initiate the ring-opening polymerization of epsilon-caprolactone monomer to prepare the PEA-b-PCL copolymers. The molecular weight (MW) of PEA-b-PCLs can be well controlled by adjusting the Phe-PEA MW and weight ratio of epsilon caprolactone to Phe-PEA, and ranged from 7 to 50kgmol(-1). The copolymers' structure and properties were characterized by various physicochemical methods, such as nuclear magnetic resonance, gel permeation chromatography and solubility testing. The in vitro enzymatic biodegradation tests were performed to evaluate the biodegradation rate of the copolymers. The results showed that the introduction of Phe-PEA to PCL did not significantly change the degradation rate of PCL. Biological studies were conducted to assess the polymer's biological properties, like supporting the cell attachment and proliferation, and inflammation response. The results showed that the bovine aortic endothelial cells had very good attachment and proliferation performance on PEA-b-PCL coating surface. TNF-alpha release profiles showed that PEA-b-PCL exhibited a muted J774 macrophage inflammatory response. PMID- 22842041 TI - Spatial arrangement of rhodopsin in retinal rod outer segment membranes studied by spin-labeling and pulsed electron double resonance. AB - We have determined the spatial arrangement of rhodopsin in the retinal rod outer segment (ROS) membrane by measuring the distances between rhodopsin molecules in which native cysteines were spin-labeled at ~1.0 mol/mol rhodopsin. The echo modulation decay of pulsed electron double resonance (PELDOR) from spin-labeled ROS curved slightly with strong background decay. This indicated that the rhodopsin was densely packed in the retina and that the rhodopsin molecules were not aligned well. The curve was simulated by a model in which rhodopsin is distributed randomly as monomers in a planar membrane. PMID- 22842042 TI - Contribution of myofibrillar and connective tissue components to the Warner Bratzler shear force of cooked beef. AB - Myofibrillar (MF-SF) and connective tissue (CT-SF) peak shear forces were interpolated from Warner-Bratzler shear force (SF) deformation curves of cooked bovine M. gluteus medius (GM) and M. semitendinosus (ST) from 112 crossbred steers in a 2*2*2 factorial experiment examining the interactions between slaughter age, growth promotants and breed cross (British versus Continental). Mixed model analyses, Pearson correlations and stepwise multiple regression identified relationships between shear forces, meat quality measurements and production treatments. Connective tissue contribution to SF increased with slaughter age and implantation in the ST and with slaughter age only in the GM. Myofibrillar contribution to SF increased with slaughter age for the ST and with Continental genetics for the GM. Variation in ST SF and MF-SF was best described by muscle weight, which increased with animal age, while GM SF and MF-SF variation was best described by cooking loss, indicating that ST and GM SF were most affected by connective and myofibrillar proteins, respectively. PMID- 22842044 TI - Interactions of monocyte subpopulations generated from cord blood CD34(+) hematopoietic progenitors with tumor cells: assessment of antitumor potential. AB - Monocytes and their subsets (CD14(++)CD16(+) and CD14(+)CD16(-)) generated from cord blood CD34(+) progenitor cells were used for determination of their capacity to interact with tumor cells in vitro and in vivo. The studies in vitro included adhesion to human umbilical vein endothelial cells, cytotoxicity, production of toxic mediators: reactive oxygen and nitrogen intermediates (ROI and RNI, respectively), and finally their effect on transplantable human tumor growth in nonobese diabetic severe combined immunodeficient mice. The CD14(++)CD16(+) subset exhibited an increased adherence to human umbilical vein endothelial cells and cytotoxicity toward tumor cells in vitro. CD14(+)CD16(-) monocytes showed a higher production of reactive oxygen and nitrogen intermediates after stimulation with tumor cells, and more pronounced inhibition of tumor growth in vivo. The results revealed significant differences in the behavior of CD14(++)CD16(+) and CD14(+)CD16(-) monocyte subsets toward tumor cells, thus providing further evidence that CD34(+) cell-derived monocytes differ in this respect from blood monocytes. The protocol for generation of monocytes with antitumor reactivity described here may be useful to obtain monocytes from CD34(+) progenitor cells of cancer patients. This might offer a basis for a novel approach for various forms of cellular immunotherapy of cancer. PMID- 22842043 TI - Hydroxyapatite nanoparticle reinforced peptide amphiphile nanomatrix enhances the osteogenic differentiation of mesenchymal stem cells by compositional ratios. AB - In the field of bone tissue engineering, there is a need for materials that mimic the native bone extracellular matrix (ECM). This need is met through the creation of biphasic composites intended to mimic both the organic and inorganic facets of the native bone ECM. However, few studies have created composites with organic ECM analogous components capable of directing cellular behaviors and many are not fabricated in the nanoscale. Furthermore, few attempts have been made at investigating how variations of organic and inorganic components affect the osteogenic differentiation of human mesenchymal stem cells (hMSCs). To address these issues, biphasic nanomatrix composites consisting of hydroxyapatite nanoparticles (HANPs) embedded within peptide amphiphile (PA) nanofibers tailored with the RGDS cellular adhesion motif (PA-RGDS) were created at various HANP to PA-RGDS ratios. Fabrication of these biphasic nanomatrix composites was confirmed via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The long-term cellularity and osteogenic differentiation of hMSCs in response to the different compositional ratios were then assessed by quantifying the timed expression of genes indicative of osteogenic differentiation, alkaline phosphatase activity, and DNA content over time. Decreased cellularity and the expression of genes over time correlated with increasing compositional ratios between HANP and PA-RGDS. The highest HANP to PA-RGDS ratio (66% HANP) exhibited the greatest improvement to the osteogenic differentiation of hMSCs. Overall, these results demonstrate that the compositional ratio of biphasic nanomatrix composites plays an important role in influencing the osteogenic differentiation of hMSCs. Based on the observations presented within this study, these biphasic nanomatrix composites show promise for future usage in bone tissue engineering applications. PMID- 22842045 TI - Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia. AB - Tyrosine kinase inhibitors have greatly improved the prognosis of chronic myeloid leukemia (CML). In addition to direct kinase inhibition, their effects can also be mediated through immune modulation, such as expansion of cytotoxic T and natural-killer cells observed during dasatinib therapy. As natural-killer cell and partially CD8(+) T-cell function are regulated by killer immunoglobulin-like receptors (KIRs), we studied whether the KIR gene profile is associated with clinical therapy response in dasatinib-treated CML patients (n = 191). In first line patients, the absence of the inhibitory KIR2DL5A (p = 0.0489), 2DL5B (p = 0.030), and 2DL5all (p = 0.0272) genes were associated with improved molecular response at the 12-month time point. In addition, the same trend was seen with two activating KIR genes, 2DS1 (p = 0.061) and 2DS2 (p = 0.071). Furthermore, when patients were clustered into two groups by their KIR gene profile, the BCR ABL1 transcript levels differed significantly between the groups (p = 0.047), showing that patients who lacked several KIR genes had better response. The comparison of first-line and second-line patients did not show any significant differences in either KIR or human leukocyte antigen genotypes. Our results show that immunogenetic factors, such as the KIR gene profile, can play a role in tyrosine kinase inhibitor therapy response. Additional studies are warranted to elucidate the functional significance of KIR genes associated with treatment outcomes. PMID- 22842046 TI - Flavonoid interactions with human transthyretin: combined structural and thermodynamic analysis. AB - Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities. PMID- 22842047 TI - Automatic magnification determination of electron cryomicroscopy images using apoferritin as a standard. AB - Interpretation of the structural information in cryomicroscopy images recorded on film or CCD camera requires a precise knowledge of the electron microscope parameters that affect image features such as magnification and defocus. Magnification must be determined in order to combine data from different images in a three-dimensional reconstruction and to accurately scale reconstructions for fitting with atomic resolution models. A method is described for estimating the absolute magnification of an electron micrograph of a frozen-hydrated specimen using horse spleen apoferritin as a standard. Apoferritin is a widely available protein complex of known structure that may be included with the specimen of interest and imaged under conditions identical to those used for imaging other biological specimens by cryomicroscopy. The sum of the structure factor intensities of images of randomly-oriented apoferritin particles shows three low resolution peaks to 25A that arise from the hollow ball structure of apoferritin. Comparison of peak positions of the experimental intensities with structure factor intensities of an atomic model of apoferritin determined by X-ray crystallography provides a scale factor for estimating the absolute magnification of the micrograph. We compare the magnification estimate using apoferritin to that obtained with tobacco mosaic virus, another common magnification standard for cryomicroscopy. We verify the precision of the method by acquiring images with a systematic variation of magnification. PMID- 22842048 TI - Structural characterization of CHCHD5 and CHCHD7: two atypical human twin CX9C proteins. AB - Twin CX(9)C proteins constitute a large protein family among all eukaryotes; are putative substrates of the mitochondrial Mia40-dependent import machinery; contain a coiled coil-helix-coiled coil-helix (CHCH) fold stabilized by two disulfide bonds as exemplified by three structures available for this family. However, they considerably differ at the primary sequence level and this prevents an accurate prediction of their structural models. With the aim of expanding structural information on CHCH proteins, here we structurally characterized human CHCHD5 and CHCHD7. While CHCHD5 has two weakly interacting CHCH domains which sample a range of limited conformations as a consequence of hydrophobic interactions, CHCHD7 has a third helix hydrophobically interacting with an extension of helix alpha2, which is part of the CHCH domain. Upon reduction of the disulfide bonds both proteins become unstructured exposing hydrophobic patches, with the result of protein aggregation/precipitation. These results suggest a model where the molecular interactions guiding the protein recognition between Mia40 and the disulfide-reduced CHCHD5 and CHCHD7 substrates occurs in vivo when the latter proteins are partially embedded in the protein import pore of the outer membrane of mitochondria. PMID- 22842049 TI - Creating an infrastructure for high-throughput high-resolution cryogenic electron microscopy. AB - New instrumentation for three-dimensional electron microscopy is facilitating an increase in the throughput of data collection and reconstruction. The increase in throughput creates bottlenecks in the workflow for storing and processing the image data. Here we describe the creation and quantify the throughput of a high throughput infrastructure supporting collection of three-dimensional data collection. PMID- 22842050 TI - Resuscitation with supplementary oxygen induces oxidative injury in the cerebral cortex. AB - Isoprostanes, neuroprostanes, isofurans, and neurofurans have all become attractive biomarkers of oxidative damage and lipid peroxidation in brain tissue. Asphyxia and subsequent reoxygenation cause a burst of oxygen free radicals. Isoprostanes and isofurans are generated by free radical attacks of esterified arachidonic acid. Neuroprostanes and neurofurans are derived from the peroxidation of docosahexanoic acid, which is abundant in neurons and could therefore more selectively represent oxidative brain injury. Newborn piglets (age 12-36 h) underwent hypoxia until the base excess reached -20 mmol/L or the mean arterial blood pressure dropped below 15 mm Hg. They were randomly assigned to receive resuscitation with 21, 40, or 100% oxygen for 30 min and then ventilation with air. The levels of isoprostanes, isofurans, neuroprostanes, and neurofurans were determined in brain tissue (ng/g) isolated from the prefrontal cortex using gas chromatography-mass spectrometry (GC/MS) with negative ion chemical ionization (NICI) techniques. A control group underwent the same procedures and observations but was not submitted to hypoxia or hyperoxia. Hypoxia and reoxygenation significantly increased the levels of isoprostanes, isofurans, neuroprostanes, and neurofurans in the cerebral cortex. Nine hours after resuscitation with 100% oxygen for 30 min, there was nearly a 4-fold increase in the levels of isoprostanes and isofurans compared to the control group (P=0.007 and P=0.001) and more than a 2-fold increase in neuroprostane levels (P=0.002). The levels of neuroprostanes and neurofurans were significantly higher in the piglets that were resuscitated with supplementary oxygen (40 and 100%) compared to the group treated with air (21%). The significance levels of the observed differences in neuroprostanes for the 21% vs 40% comparison and the 21% vs 100% comparison were P<0.001 and P=0.001, respectively. For neurofurans, the P values of the 21% vs 40% comparison and the 21% vs 100% comparison were P=0.036 and P=0.025, respectively. Supplementary oxygen used for the resuscitation of newborns increases lipid peroxidation in brain cortical neurons, a result that is indicative of oxidative brain damage. These novel findings provide new knowledge regarding the relationships between oxidative brain injury and resuscitation with oxygen. PMID- 22842051 TI - Sulfur-aided phytoextraction of Cd and Zn by Salix smithiana combined with in situ metal immobilization by gravel sludge and red mud. AB - As phytoextraction implementation may be limited by metal toxicity and leaching, we investigated the idea of in situ metal immobilization in bulk soil, while increasing metal bioavailability in the rhizosphere. Salix smithiana was grown in a pot experiment on two Cd/Zn polluted soils. Treatments with or without willows included: no additives; gravel sludge + red mud kg(-1); acidification with S to pH 3.5; and metal immobilization combined with soil acidification. Salix smithiana removed up to 0.78 +/- 0.06% total Cd and 0.34% (+/-0.02) total Zn from the non-treated soils. The phytoextraction efficiency in the S treatments was enhanced by up to ~50% in response to metal solubility that was magnified by reductive co-dissolution from Mn (IV) and Fe(III) (oxy)hydroxides during microbial S oxidation in the willow rhizosphere. The proposed technique proved to enhance phytoextraction efficiency while controlling the risk of metal leaching from the root zone and phytotoxicity. PMID- 22842052 TI - Bottom trawling resuspends sediment and releases bioavailable contaminants in a polluted fjord. AB - Sediments are sinks for contaminants in the world's oceans. At the same time, commercial bottom trawling is estimated to affect around 15 million km(2) of the world's seafloor every year. However, few studies have investigated whether this disturbance remobilises sediment-associated contaminants and, if so, whether these are bioavailable to aquatic organisms. This field study in a trawled contaminated Norwegian fjord showed that a single 1.8 km long trawl pass created a 3-5 million m(3) sediment plume containing around 9 t contaminated sediment; ie. 200 g dw m(-2) trawled, equivalent to c. 10% of the annual gross sedimentation rate. Substantial amounts of PCDD/Fs and non-ortho PCBs were released from the sediments, likely causing a semi-permanent contaminated sediment suspension in the bottom waters. PCDD/Fs from the sediments were also taken up by mussels which, during one month, accumulated them to levels above the EU maximum advised concentration for human consumption. PMID- 22842053 TI - Exploratory study using proton induced X-ray emission analysis and histopathological techniques to determine the toxic burden of environmental pollutants. AB - The aim of this novel research was to determine the toxic burden of increased elements in water resources on the inhabitant wild animals (squirrels, turtles, bats), using particle induced x-ray emission (PIXE) and histopathological approaches. PIXE analysis of skin, muscle, lung, liver and kidney revealed significant increase in Al, Cl, Fe, Mg, Mn, Si and V. Moreover, data clearly reflect a significant (P < 0.001) deposition of toxic elements (Al, Cl, Fe and K) in the lung producing interstitial/proliferative pneumonitis, intra-alveolar hemorrhages, and thickening of alveolar capillary walls. The results obtained from the liver samples emphasized that majority of the animals were intoxicated with Cl, Mg, S, Si and V, which have produced profound deterioration and swelling of the hepatocytes. Likewise, histopathology of the kidney sections spotlighted severe nephritis and degenerative changes, which could be associated with the elevated amount of Al, Cl and Mg. This data undoubtedly provide relevant information on the heavy burden of toxic elements and their pathological outcomes in wild animals and highlight their potential risks for human exposure. Thus, the information provided is critical for developing effective strategies in dealing with health hazards associated with elemental exposures. PMID- 22842054 TI - Bees, honey and pollen as sentinels for lead environmental contamination. AB - Three beehive matrices, sampled in eighteen apiaries from West France, were analysed for the presence of lead (Pb). Samples were collected during four different periods in both 2008 and 2009. Honey was the matrix the least contaminated by Pb (min = 0.004 MUg g(-1); max = 0.378 MUg g(-1); mean = 0.047 MUg g(-1); sd = 0.057). The contamination of bees (min = 0.001 MUg g(-1); max = 1.869 MUg g(-1); mean = 0.223 MUg g(-1); sd = 0.217) and pollen (min = 0.004 MUg g(-1); max = 0.798 MUg g(-1); mean = 0.240 MUg g(-1); sd = 0.200) showed similar levels and temporal variations but bees seemed to be more sensitive bringing out the peaks of Pb contamination. Apiaries in urban and hedgerow landscapes appeared more contaminated than apiaries in cultivated and island landscapes. Sampling period had a significant effect on Pb contamination with higher Pb concentrations determined in dry seasons. PMID- 22842055 TI - Changing redox potential by controlling soil moisture and addition of inorganic oxidants to dissipate pentachlorophenol in different soils. AB - The potential for dissipation of pentachlorophenol (PCP) was investigated in soils from four different sites in China. These were an umbraqualf (Soil 1), a Plinthudult (Soil 2), a Haplustalf (Soil 3) and an Argiustoll (Soil 4) which were either flooded, to produce anaerobic conditions, or incubated aerobically at 60% water-holding capacity (WHC). The dissipation of PCP in Soil 1 at 60% WHC was higher than under flooded condition, while the opposite occurred in the other three soils. Under flooded conditions, the redox potential decreased significantly in Soil 1 and Soil 4, where sulphate reduction was occurred and the dissipation of PCP was statistically significant (about 96% and 98%, respectively) at the end of incubation. After addition of inorganic oxidants, dissipation of PCP was significantly inhibited by FeCl(3), while Na(2)SO(4) and NaNO(3) had different effects, depending upon the soil type. PMID- 22842056 TI - Improved reproductive success in otters (Lutra lutra), grey seals (Halichoerus grypus) and sea eagles (Haliaeetus albicilla) from Sweden in relation to concentrations of organochlorine contaminants. AB - We studied indices of reproductive outcome in three aquatic species in relation to organochlorine concentrations during four decades. In female otters, the frequency of signs of reproduction increased after 1990. In grey seals, pregnancy rate increased 1990-2010 and uterine obstructions ceased after 1993. The frequency of uterine tumours was highest 1980-2000. The number of sea eagle nestlings per checked nest increased 1985-2000, while the frequency of desiccated eggs decreased. Organochlorine concentrations decreased at annual rates between 3.5 and 10.2%. The estimated mean concentration (mg/kg lw) for total-PCB decreased from 70 to 8 (otters), from 110 to 15 (seals) and from 955 to 275 (eagles). The corresponding concentrations for SigmaDDT decreased from 3.4 to 0.2 (otters), from 192 to 2.8 (seals) and from 865 to 65 (eagles). This study adds evidence to support the hypothesis that PCBs and DDTs have had strong negative effects on the reproduction and population levels of these species. PMID- 22842057 TI - Can topical application of tranexamic acid reduce blood loss in thoracic surgery? A prospective randomised double blind investigation. AB - OBJECTIVE: The systemic or topical use of antifibrinolytic agents is effective in reducing postoperative bleeding and blood product transfusion in cardiac surgery. We sought to study the effect of the topical application of tranexamic acid into the pleural space to reduce postoperative bleeding after lung surgery. METHODS: This was a prospective randomised double blind placebo controlled investigation. From May-2010 to February-2012, 89-patients, scheduled for pulmonary resection, were randomly allocated to one of the two study groups. Group-A received 5 g of tranexamic-acid in 100 ml of saline solution. Group-B received 100 ml of saline solution as placebo. RESULTS: The blood loss in the first 12-h was significantly less in group-A. The same trend was observed in the first 24-h but without reaching a true statistical significance. The mean volume of blood transfusion was statistically lower in group-A. The analysis between post-operative haemoglobin concentration, haematocrit, platelet-count, international-normalised ratio, fibrinogen and partial-thromboplastin-time of both groups was not statistically significant. CONCLUSION: In our experience, the topical use of tranexamic-acid after lung surgery reduces postoperative bleeding and blood transfusion volume. The topical administration of tranexamic-acid is safe without increasing the risk of post-operative complications related to pharmacological side-effects. PMID- 22842058 TI - Cultural adaptation of the Latin American version of the World Health Organization Composite International Diagnostic Interview (WHO-CIDI) (v 3.0) for use in Spain. AB - OBJECTIVE: To develop a Spanish version of the WHO-Composite International Diagnostic Interview (WHO-CIDI) applicable to Spain, through cultural adaptation of its most recent Latin American (LA v 20.0) version. METHODS: A 1-week training course on the WHO-CIDI was provided by certified trainers. An expert panel reviewed the LA version, identified words or expressions that needed to be adapted to the cultural or linguistic norms for Spain, and proposed alternative expressions that were agreed on through consensus. The entire process was supervised and approved by a member of the WHO-CIDI Editorial Committee. The changes were incorporated into a Computer Assisted Personal Interview (CAPI) format and the feasibility and administration time were pilot tested in a convenience sample of 32 volunteers. RESULTS: A total of 372 questions were slightly modified (almost 7% of approximately 5000 questions in the survey) and incorporated into the CAPI version of the WHO-CIDI. Most of the changes were minor - but important - linguistic adaptations, and others were related to specific Spanish institutions and currency. In the pilot study, the instrument's mean completion administration time was 2h and 10min, with an interquartile range from 1.5 to nearly 3h. All the changes made were tested and officially approved. CONCLUSIONS: The Latin American version of the WHO-CIDI was successfully adapted and pilot-tested in its computerized format and is now ready for use in Spain. PMID- 22842059 TI - Tissue-engineered cell sheets for stricture prevention: a new connection between endoscopy and regenerative medicine. PMID- 22842060 TI - Th17 cells regulate liver fibrosis by targeting multiple cell types: many birds with one stone. PMID- 22842061 TI - Mechanical effects of obesity related to gastroesophageal reflux. PMID- 22842062 TI - New imaging standards for evaluation of inflammatory bowel disease? PMID- 22842063 TI - An uncommon cause of right pain in the hypochondrium. PMID- 22842064 TI - Difference in the localization of tetrodotoxin between the female and male pufferfish Takifugu niphobles, during spawning. AB - In order to understand the sexual differences in TTX-usage in the pufferfish, Takifugu niphobles, localization of TTX and toxin amount in tissues of mature male and female specimens were investigated by immunohistochemical methods using anti-TTX antibody and LC/MS analysis. Subsequently, differences in the immunohistochemical signals were compared with the amount of TTX. The paraffin embedded sections of the skin, muscle, liver, gonad and intestinal tract were subjected to anti-TTX monoclonal antibody based on the fluorescent immunohistochemical techniques. Immuno-positive reaction was observed in the skin and liver in males, and the skin and ovary in females. In the skin, TTX was localized at the epidermis, the basal cell layer, the mucous cells and the sacciform cells, and with intense immunoreaction at the flat epithelial cell layer and the sacciform cells. The signal from the liver cells was stronger in males than in females. The intensity of the signal from the tissues correlated with the toxin amounts therein. These results suggest that tissue distributions of TTX and toxin amount in the pufferfish were sex-dependent. PMID- 22842065 TI - Studies on the fractionation of equine antivenom IgG by combinations of ammonium sulfate and caprylic acid. AB - This study involved the use of combined stepwise ammonium sulfate (AS) and caprylic acid (CA) fractionation of equine antivenom IgG without intermediate separation of precipitate. Using a microplate and checker board titration format, plasma was treated under 66 conditions with varying concentrations of AS (0-25% saturation) and CA (0-5% v/v). The filtrate of each well was assayed for protein and antibody activity. At about 1.5-4.0% CA without AS, the precipitated plasma gave high specific antibody activity. Twelve precipitation conditions selected from the microplate experiment were studied in detail in tubes. The highest turbidity was with 5% CA alone. The highest antibody recovery of 95.45% was observed at 15% AS with 3.0% CA. The highest specific activity with 3.28 folds purification was observed with 4.0% CA. Thus, AS could reduce the turbidity induced by CA and increase the yield but not the purity of antibody. Size exclusion HPLC showed the antibody to be one single peak with 1.5% of soluble protein aggregate. When all parameters were considered, the optimum fractionation condition appeared to be 3.5% CA alone which gave high specific antibody activity (3.26 folds purification), antibody recovery (93.93%) and low turbidity (0.56% solid). Furthermore, better overall results were observed with one hour than overnight precipitation. PMID- 22842066 TI - Hydrogen sulfide modulates the release of nitric oxide and VEGF in human keratinocytes. AB - Hydrogen sulfide (H(2)S) is a novel signaling molecule with both pro- or anti inflammatory effect. The present study aimed to: (i) characterize the in vitro effects of H(2)S on human keratinocyte's proliferation and death; (ii) investigate the ability of H(2)S to modulate VEGF and NO production; (iii) examine the intracellular signaling pathways involved in VEGF and NO modulatory effect. We found that exogenous application of H(2)S (NaHS and GYY4137 as H(2)S donors) significantly enhances NO through increase of iNOS, in a manner Akt dependent. The increment in NO down-regulates ERK1/2 activation thereby resulting in the decrease of VEGF release. We suggest that H(2)S-releasing agents may be promising therapeutics for chronic inflammatory disorders of the skin, i.e. psoriasis, in which NO increases as well as anti-VEGF treatments have been suggested to be novel effective approaches. PMID- 22842067 TI - Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat. AB - Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis. PMID- 22842070 TI - Lesions of the lateral habenula dissociate the reward-enhancing and locomotor stimulant effects of amphetamine. AB - Midbrain dopamine neurons play a key role in goal-directed behaviour as well as in some psychiatric disorders. Recent studies have provided electrophysiological, anatomical and biochemical evidence that the lateral habenula (LHb) exerts strong inhibitory control over midbrain dopamine neurons. However, the behavioural relevance of this inhibitory input is poorly understood. Our aim was to examine the contribution of the LHb to dopamine-sensitive behaviour. Here, we characterized the locomotor-stimulant and reward-enhancing properties of amphetamine in rats with and without neurotoxic lesions of the LHb. Amphetamine induced forward locomotion and reward were respectively measured in automated activity cages and with intracranial self-stimulation. Adult, male Sprague-Dawley rats were bilaterally infused with ibotenic acid in the LHb and allowed 7-10 days post-operative recovery. The locomotor-stimulant and reward-enhancing properties of amphetamine (0, 0.5 and 1.0 mg/kg, ip) were then tested in different groups of lesioned and sham-lesioned rats. Neurotoxic lesions of the LHb caused a significant enhancement of the locomotor-stimulant effect of amphetamine, an effect not seen following lesions of the medial habenula. Conversely, the reward enhancing properties of amphetamine did not differ between lesioned and sham lesioned rats responding for rewarding electrical stimulation of the posterior mesencephalon or the medial forebrain bundle. The dissociation between the locomotor-stimulant and reward-enhancing effects of amphetamine following LHb lesions suggests the contribution of two distinct substrates that are functionally dissociable and differentially sensitive to LHb modulation. PMID- 22842068 TI - Nanomolar ouabain increases NCX1 expression and enhances Ca2+ signaling in human arterial myocytes: a mechanism that links salt to increased vascular resistance? AB - The mechanisms by which NaCl raises blood pressure (BP) in hypertension are unresolved, but much evidence indicates that endogenous ouabain is involved. In rodents, arterial smooth muscle cell (ASMC) Na(+) pumps with an alpha(2) catalytic subunit (ouabain EC(50) <=1.0 nM) are crucial for some hypertension models, even though ~80% of ASMC Na(+) pumps have an alpha(1)-subunit (ouabain EC(50) ~ 5 MUM). Human alpha(1)-Na(+) pumps, however, have high ouabain affinity (EC(50) ~ 10-20 nM). We used immunoblotting, immunocytochemistry, and Ca(2+) imaging (fura-2) to examine the expression, distribution, and function of Na(+) pump alpha-subunit isoforms in human arteries and primary cultured human ASMCs (hASMCs). hASMCs express alpha(1)- and alpha(2)-Na(+) pumps. Further, alpha(2)-, but not alpha(1)-, pumps are confined to plasma membrane microdomains adjacent to sarcoplasmic reticulum (SR), where they colocalize with Na/Ca exchanger-1 (NCX1) and C-type transient receptor potential-6 (receptor-operated channels, ROCs). Prolonged inhibition (72 h) with 100 nM ouabain (blocks nearly all alpha(1)- and alpha(2)-pumps) was toxic to most cultured hASMCs. Treatment with 10 nM ouabain (72 h), however, increased NCX1 and sarco(endo)plasmic reticulum Ca(2+)-ATPase expression and augmented ATP (10 MUM)-induced SR Ca(2+) release in 0 Ca(2+), ouabain-free media, and Ca(2+) influx after external Ca(2+) restoration. The latter was likely mediated primarily by ROCs and store-operated Ca(2+) channels. These hASMC protein expression and Ca(2+) signaling changes are comparable with previous observations on myocytes isolated from arteries of many rat hypertension models. We conclude that the same structurally and functionally coupled mechanisms (alpha(2)-Na(+) pumps, NCX1, ROCs, and the SR) regulate Ca(2+) homeostasis and signaling in hASMCs and rodent ASMCs. These ouabain/endogenous ouabain-modulated mechanisms underlie the whole body autoregulation associated with increased vascular resistance and elevation of BP in human, salt-sensitive hypertension. PMID- 22842069 TI - TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. AB - Toll-like receptor (TLR)4 regulates inflammation and metabolism and has been linked to the pathogenesis of heart disease. TLR4 is upregulated in diabetic cardiomyocytes, and we examined the role of TLR4 in modulating cardiac fatty acid (FA) metabolism and the pathogenesis of diabetic heart disease in nonobese diabetic (NOD) mice. Both wild-type (WT) NOD and TLR4-deficient NOD animals had increased plasma triglyceride levels after the onset of diabetes. However, by comparison, TLR4-deficient NOD mouse hearts had lower triglyceride accumulation in the early stages of diabetes, which was associated with a reduction in myeloid differentiation primary response gene (88) (MyD88), phosphorylation of p38 MAPK (phospho-p38), lipoprotein lipase (LPL), and JNK levels but increased phospho-AMP activated protein kinase (AMPK). Oleic acid treatment in H9C2 cardiomyocytes also led to cellular lipid accumulation, which was attenuated by TLR4 small interfering RNA. TLR4 deficiency in the cells decreased FA-induced augmentation of MyD88, phospho-p38, and LPL, suggesting that TLR4 may modulate FA-induced lipid metabolism in cardiomyocytes. In addition, although cardiac function was impaired in both diabetic WT NOD and TLR4-deficient NOD animals compared with control nondiabetic mice, this deficit was less in the diabetic TLR4-deficient NOD mice, which had greater ejection fraction, greater fractional shortening, and increased left ventricular developed pressure in the early stages after the development of diabetes compared with their diabetic WT NOD counterparts. Thus, we conclude that TLR4 plays a role in regulating lipid accumulation in cardiac muscle after the onset of type 1 diabetes, which may contribute to cardiac dysfunction. PMID- 22842071 TI - Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats. AB - In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported. PMID- 22842072 TI - Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity. AB - Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4 degrees C, 6 h/day, 14 days) followed on day 15 by a single 1-h session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further, CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD. PMID- 22842073 TI - MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus. AB - The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10 mg/kg, i.p. at 2 h intervals) resulted in a 2-3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100 MUM) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus. PMID- 22842074 TI - A novel de novo 1.8 Mb microdeletion of 17q21.33 associated with intellectual disability and dysmorphic features. AB - We report on a de novo 17q21.33 microdeletion, 1.8 Mb in size, detected in a patient with mild intellectual disability, growth retardation, poor weight gain, microcephaly, long face, large beaked nose, thick lower lip, micrognathia and other dysmorphic features. The deletion was detected by whole-genome genotyping BeadChip assay and involves the genomic region between 45,682,246 and 47,544,816 bp on chromosome 17. Among the 24 RefSeq genes included in this deletion are the CA10 and CACNA1G genes that are involved in brain development and neurological processes. A possible candidate gene for the prenatal and postnatal growth retardation is the CHAD gene, which product chondroadherin is a cartilage protein with cell binding properties. These three genes may be responsible for the patient's phenotype. PMID- 22842075 TI - A 725 kb deletion at 22q13.1 chromosomal region including SOX10 gene in a boy with a neurologic variant of Waardenburg syndrome type 2. AB - Waardenburg syndrome (WS) is a rare (1/40,000) autosomal dominant disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four clinical subtypes (WS1-S4). Six genes have been identified to be associated with the different subtypes of WS, among which SOX10, which is localized within the region 22q13.1. Lately it has been suggested that whole SOX10 gene deletions can be encountered when testing for WS. In this study we report a case of a 13-year-old boy with a unique de novo 725 kb deletion within the 22q13.1 chromosomal region, including the SOX10 gene and presenting clinical features of a neurologic variant of WS2. PMID- 22842076 TI - A de novo 4.4-Mb microdeletion in 2p24.3 -> p24.2 in a girl with bilateral hearing impairment, microcephaly, digit abnormalities and Feingold syndrome. AB - We report a 26-month-old girl with profound hearing impairment, microcephaly, psychomotor retardation, short palpebral fissures, hypertelorism, epicanthic folds, a broad nasal bridge, anteverted nostrils, large low-set ears, micrognathia, brachymesophalangy of the second and the fifth fingers, clinodactyly of bilateral fifth fingers and a wide interdigital space between the first and the second toes, carrying a 4.4-Mb de novo microdeletion of chromosome 2p24.3 -> p24.2. This region contains the genes of FAM84A, NBAS, DDX1, MYCNOS and MYCN, of which haploinsufficiency or mutations of the MYCN gene is associated with Feingold syndrome. Brain magnetic resonance imaging revealed cochlear nerve hypoplasia and internal auditory canal stenosis. Temporal bone computed tomography showed abnormal dilation of bilateral vestibular and lateral semicircular canals. The present case provides evidence that haploinsufficiency of MYCN in 2p24.3 deletion in humans can cause structural and functional abnormalities of the inner ear. PMID- 22842077 TI - Elevated CpxR~P levels repress the Ysc-Yop type III secretion system of Yersinia pseudotuberculosis. AB - One way that Gram-negative bacteria respond to extracytoplasmic stress is through the CpxA-CpxR system. An activated CpxA sensor kinase phosphorylates the CpxR response regulator to instigate positive auto-amplification of Cpx pathway activation, as well as synthesis of various bacterial survival factors. In the absence of CpxA, human enteropathogenic Yersinia pseudotuberculosis accumulates high CpxR~P levels aided by the action of low molecular weight phosphodonors such as acetyl~P. Critically, these bacteria are also defective for plasmid-encoded Ysc-Yop-dependent type III synthesis and secretion, an essential determinant of virulence. Herein, we investigated whether elevated CpxR~P levels account for lost Ysc-Yop function. Decisively, reducing CpxR~P in Yersinia defective for CpxA phosphatase activity - through incorporating second-site suppressor mutations in ackA-pta or cpxR - dramatically restored Ysc-Yop T3S function. Moreover, the repressive effect of accumulated CpxR~P is a direct consequence of binding to the promoter regions of the T3S genes. Thus, Cpx pathway activation has two consequences in Yersinia; one, to maintain quality control in the bacterial envelope, and the second, to restrict ysc-yop gene expression to those occasions where it will have maximal effect. PMID- 22842078 TI - Characterization of the theta replication plasmid pGR7 from Acetobacter aceti CCM 3610. AB - A cryptic plasmid of Acetobacter aceti CCM 3610, designated pGR7, was sequenced and characterized. It is a 2446-bp circular molecule with a G + C content of 30%, which is unusual when compared to the already known plasmids isolated from Acetobacter genera. Sequence analysis of pGR7 revealed three putative open reading frames (ORFs). ORF1 displays low similarity with other Acetobacter plasmid replication proteins. The other two ORFs show similarities only to hypothetical proteins and do not encode any important protein. The replication module comprises a DnaA box-like sequence, indirect repeats, a potential prokaryotic promoter and the rep gene. The rep module organization is similar to that found in other theta-replicating plasmids from acetic acid bacteria that stably maintain in both Acetobacter and Escherichia coli, with two repeated sequences containing modules. Nevertheless, the pGR7 plasmid could replicate and be stably maintained only in Acetobacter strains and not in E. coli, another uncommon feature of this plasmid. The Rep protein was cloned into the pET30a + expression vector and purified by high-performance liquid chromatography. The helicase activity was determined and the ability of the protein to bind to the plasmid regulation region was confirmed by an electrophoretic mobility shift assay. The plasmid was stable in the Acetobacter cells after cultivation under nonselective conditions. By real-time polymerase chain reaction, the relative copy number of pGR7 was estimated to be seven copies per host chromosome equivalent. PMID- 22842080 TI - Selective cognitive impairments are related to selective hippocampus and prefrontal cortex deficits after prenatal chlorpyrifos exposure. AB - Prenatal exposure to chlorpyrifos (CPF) leads to cognitive impairments in adulthood. The cytoarchitectural basis is unclear. In the present study, we assessed the effects of prenatal CPF exposure on T-maze delayed alternation task and the win-shift/lose-shift responses associated with the morphology of the dorsal hippocampus (dHPC) and the medial prefrontal cortex (mPFC) in adult animals. Gestational ICR female mice were exposed to 0, 1 or 5mg/kg/d of CPF through gestational days 13-17. Behavioral experiments were performed on postnatal days (PD) 45-60 of the male and female offsprings; morphological samples were collected on PD 60. Our behavioral study results showed a gradual increase in the number of lose-shift errors on increased memory loads in the 5mg/kg/d CPF-treated males. A weak initial increase in the number of lose-shift errors was observed in the females. In all of the groups, no significant differences were observed in the number of win-shift errors and correct of the first choice. The morphological studies showed extensive condensed nucleus and enlarged intercellular spaces in the CA1 and DG sub-regions in the dHPC of the CPF-treated males and the DG sub-region of the CPF-treated females. The cell count was significantly reduced in these sub-regions. The morphological studies showed no obvious abnormalities at PrL and IL of mPFC in the CPF-treated males and females, but the cell count was reduced. Our findings suggest that prenatal CPF exposure at 5mg/kg/d induces selective cognitive impairments, which based on the morphological deficits in the dHPC and the mPFC. PMID- 22842081 TI - Caloric restriction improves basal redox parameters in hippocampus and cerebral cortex of Wistar rats. AB - Caloric restriction (CR) has been shown to either decrease or prevent the progression of several age-related pathologies. In previous work, we demonstrated that CR modulates astrocyte functions, suggesting that CR may exert neuroglial modulation. Here, we investigated the effects of CR on hippocampal (Hc) and cortical (Cx) oxidative stress parameters of male Wistar rats. Our results showed that CR-fed rats had 17% less body weight gain after 12 weeks of treatment. CR improved locomotion performance, increased glutathione levels and decreased glutathione peroxidase activity and the production of reactive oxygen species. However, no changes were observed in lipid peroxidation, nitric oxide content and catalase activity. Single cell gel electrophoresis assay (comet assay) revealed a reduction in the extent of basal DNA damage upon CR. Our data suggest that dietary CR could induce both hippocampal and cortical modulation resulting in metabolic changes and as a consequence, significant improvement of cellular defense-associated parameters. PMID- 22842079 TI - Sympathetic reinnervation of peripheral targets following bilateral axotomy of the adult superior cervical ganglion. AB - The ability of adult injured postganglionic axons to reinnervate cerebrovascular targets is unknown, yet these axons can influence cerebral blood flow, particularly during REM sleep. The objective of the present study was to assess quantitatively the sympathetic reinnervation of vascular as well as non-vascular targets following bilateral axotomy of the superior cervical ganglion (SCG) at short term (1 day, 7 day) and long term (8 weeks, 12 weeks) survival time points. The sympathetic innervation of representative extracerebral blood vessels [internal carotid artery (ICA), basilar artery (BA), middle cerebral artery (MCA)], the submandibular gland (SMG), and pineal gland was quantified following injury using an antibody to tyrosine hydroxylase (TH). Changes in TH innervation were related to TH protein content in the SCG. At 7 day following bilateral SCG axotomy, all targets were significantly depleted of TH innervation, and the exact site on the BA where SCG input was lost could be discerned. Complete sympathetic reinnervation of the ICA was observed at long term survival times, yet TH innervation of other vascular targets showed significant decreases even at 12 weeks following axotomy. The SMG was fully reinnervated by 12 weeks, yet TH innervation of the pineal gland remained significantly decreased. TH protein in the SCG was significantly decreased at both short term and long term time points and showed little evidence of recovery. Our data demonstrate a slow reinnervation of most vascular targets following axotomy of the SCG with only minimal recovery of TH protein in the SCG at 12 weeks following injury. PMID- 22842082 TI - Fetal mouse mesencephalic NPCs generate dopaminergic neurons from post-mitotic precursors and maintain long-term neural but not dopaminergic potential in vitro. AB - Stem cells have one major advantage over primary cells for regenerative therapies in neurodegenerative diseases. They are able to self-renew making sufficient quantities of cells available for transplantation. Embryonic stem cells and fetal neural progenitor cells (NPCs) have been transplanted into models for PD with functional recovery of motor deficits. However, their precise characteristics are still unknown and ideal conditions for their long-term expansion and differentiation into dopamine neurons remain to be explored. Mouse fetal NPCs are commonly grown as characteristic neurospheres, but they also proliferate under monolayer culture conditions. We investigated the proliferative behavior and dopaminergic differentiation capacity of fetal mouse midbrain NPCs derived from E10 to E14 embryos expanded either as neurosphere or monolayer culture. We found similar proliferation capacities in NPCs of all embryonic stages. Neuronal differentiation capacity is higher in neurosphere cultures compared to monolayer NPCs and persists in long-term cultures. We did not find dopaminergic differentiation in long-term expanded mouse NPC types, which is in contrast to rat and human fetal midbrain NPCs. Mouse NPCs generate dopaminergic neurons until up to three weeks in vitro but they do not incorporate BrdU. Quantitative analysis showed that they were not just primary neurons from the isolation process but formed to a great extent in vitro during differentiation suggesting that they are formed by promotion of post-mitotic neuroblasts. A detailed transcription profile reveals de-specification processes during in vitro cultivation, which matches their NPC behavior. We provide the constitutive work for studies using fetal midbrain NPCs of mouse including transplantation studies and transgenic models. PMID- 22842083 TI - Novel neuroprotective effect of cisternal and intra-cerebral magnesium sulfate solution infusion on delayed cerebral death in rat hippocampal neurons after transient global ischemia. AB - Several neuroprotective strategies such as barbiturate coma and hypothermic therapies have been promising in experimental studies but had limited efficacies in clinical trials. Magnesium ion has vasodilator and neuroprotective properties as a natural calcium blocker. The neuroprotective effects of cisternal and intra cerebral infusion of magnesium sulfate (MgSO(4)) solution were evaluated against delayed neuronal death (DND) of CA1 hippocampal pyramidal neurons, and the involvement of changes in cerebral blood flow (CBF) and metabolism were investigated. Osmotic pumps with various MgSO(4) solutions were embedded in the Sprague Dawley rat backs on day 1 and either cisternal or intra-cerebral (left CA1) infusion started. Global ischemic insult for 10 min was induced on day 3, and the numbers of surviving neurons and dead neurons in the CA1 region were evaluated by hematoxylin-eosin and Fluoro-Jade B staining, respectively, on day 7. The regional CBF and glucose utilization rate (CMRglc) were determined by autoradiographic methods using [(14)C]iodoantipyrine and [(14)C]deoxyglucose, respectively, on day 5 after the start of either cisternal or intra-cerebral infusion. In the cisternal infusion experiment, 100 mmol/lMgSO(4) solution significantly increased the number of surviving neurons and decreased the number of dead neurons. In the intra-cerebral infusion experiment, 1 mmol/l MgSO(4) and 10 mmol/lMgSO(4) solution significantly increased the number of surviving neurons and decreased the number of dead neurons in the infusion side in dose-dependent manner. Neither regional CBF or CMRglc changed significantly in the CA1 of the hippocampus. Pretreatment with either cisternal or intra-cerebral infusion with MgSO(4) solution can provide neuroprotection against DND without changing the CBF and metabolism. PMID- 22842084 TI - Apelin inhibits adipogenesis and lipolysis through distinct molecular pathways. AB - Apelin is an adipokine secreted by adipocytes. Co-expression of apelin and apelin receptor (APJ) in adipocytes implies the autocrine regulations of apelin on adipocyte functions through yet unknown molecular mechanisms. In the present study, we provide evidence that apelin, through its interaction with APJ receptor, inhibits adipogenesis of pre-adipocytes and lipolysis in mature adipocytes. The detailed molecular pathways underlying apelin signaling is proposed based on our experimental observations. Specifically, we show that apelin suppresses adipogenesis through MAPK kinase/ERK dependent pathways. And by preventing lipid droplet fragmentation, apelin inhibits basal lipolysis through AMP kinase dependent enhancement of perilipin expression and inhibits hormone stimulated acute lipolysis through decreasing perilipin phosphorylation. Apelin induced decrease of free fatty acid release can be attributed to its dual inhibition on adipogenesis and lipolysis. This study suggests that the autocrine signaling of apelin may serve as a novel therapeutic target for obesity and other metabolic disorders. PMID- 22842087 TI - The degradation of alkylphenols by Sphingomonas sp. strain TTNP3 - a review on seven years of research. AB - Over the past seven years, we have been working with Sphingomonas sp. strain TTNP3, a bacterium capable of growing on numerous alkylphenolic compounds as a source of carbon and energy. We succeeded in elucidating an unusual pathway involving an attack at the quaternary alpha-carbon atom of the substrate, a position previously thought to be highly resistant to biodegradation. Combining analytical and bioanalytical methods, a good understanding of the reaction mechanisms, the enzymes catalysing them and the organization of the genes encoding them could be gained. First studies on the use of Sphingomonas sp. strain TTNP3 in wastewater treatment have been performed revealing promising results. PMID- 22842086 TI - Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells. AB - Notch signalling occurs via direct cell-cell interactions and plays an important role in linking the fates of neighbouring cells. There are four different mammalian Notch receptors that can be activated by five cell surface ligands. The ability to inhibit specific Notch receptors would help identify the roles of individual family members and potentially provide a means to study and control cell differentiation. Anti-Notch antibodies in the form of single chain Fvs were generated from an antibody phage display library by selection on either the ligand binding domain or the negative regulatory region (NRR) of Notch1 and Notch2. Six antibodies targeting the NRR of Notch1 and four antibodies recognising the NRR of Notch2 were found to prevent receptor activation in cell based luciferase reporter assays. These antibodies were potent, highly specific inhibitors of individual Notch receptors and interfered with endogenous signalling in stem cell systems of both human and mouse origin. Antibody-mediated inhibition of Notch efficiently down-regulated transcription of the immediate Notch target gene hairy and enhancer of split 5 (Hes5) in both mouse and human neural stem cells and revealed a redundant regulation of Hes5 in these cells as complete down-regulation was seen only after simultaneous blocking of Notch1 and Notch2. In addition, these antibodies promoted differentiation of neural stem cells towards a neuronal fate. In contrast to the widely used small molecule gamma-secretase inhibitors, which block all 4 Notch receptors (and a multitude of other signalling pathways), antibodies allow blockade of individual Notch family members in a highly specific way. Specific inhibition will allow examination of the effect of individual Notch receptors in complex differentiation schemes regulated by the co-ordinated action of multiple signalling pathways. PMID- 22842088 TI - Measuring and reporting hemoglobin A1c. PMID- 22842090 TI - Phylogenetic relationships within anuran clade Terrarana, with emphasis on the placement of Brazilian Atlantic rainforest frogs genus Ischnocnema (Anura: Brachycephalidae). AB - We present a phylogenetic hypothesis of the anuran clade Terrarana based on partial sequences of nuclear (Tyr and RAG1) and mitochondrial (12S, tRNA-Val, and 16S) genes, testing the monophyly of Ischnocnema and its species series. We performed maximum parsimony, maximum likelihood, and Bayesian inference analyses on 364 terminals: 11 outgroup terminals and 353 ingroup Terrarana terminals, including 139 Ischnocnema terminals (accounting for 29 of the 35 named Ischnocnema species) and 214 other Terrarana terminals within the families Brachycephalidae, Ceuthomantidae, Craugastoridae, and Eleutherodactylidae. Different optimality criteria produced similar results and mostly recovered the currently accepted families and genera. According to these topologies, Ischnocnema is not a monophyletic group. We propose new combinations for three species, relocating them to Pristimantis, and render Eleutherodactylus bilineatus Bokermann, 1975 incertae sedis status within Holoadeninae. The rearrangements in Ischnocnema place it outside the northernmost Brazilian Atlantic rainforest, where the fauna of Terrarana comprises typical Amazonian genera. PMID- 22842089 TI - Ionotropic glutamate receptors mediate OFF responses in light-adapted ON bipolar cells. AB - Previous studies have suggested that photoreceptor synaptic inputs to depolarizing bipolar cells (DBCs or ON bipolar cells) are mediated by mGluR6 receptors and those to hyperpolarizing bipolar cells (HBCs or OFF bipolar cells) are mediated by AMPA/kainate receptors. Here we show that in addition to mGluR6 receptors which mediate the sign-inverting, depolarizing light responses, subpopulations of cone-dominated and rod/cone mixed DBCs use GluR4 AMPA receptors to generate a transient sign-preserving OFF response under light adapted conditions. These AMPA receptors are located at the basal junctions postsynaptic to rods and they are silent under dark-adapted conditions, as tonic glutamate release in darkness desensitizes these receptors. Light adaptation enhances rod cone coupling and thus allows cone photocurrents with an abrupt OFF depolarization to enter the rods. The abrupt rod depolarization triggers glutamate activation of unoccupied AMPA receptors, resulting in a transient OFF response in DBCs. It has been widely accepted that the DNQX-sensitive, OFF transient responses in retinal amacrine cells and ganglion cells are mediated exclusively by HBCs. Our results suggests that this view needs revision as AMPA receptors in subpopulations of DBCs are likely to significantly contribute to the DNQX-sensitive OFF transient responses in light-adapted third- and higher-order visual neurons. PMID- 22842091 TI - Phylogenetically diverse groups of Bradyrhizobium isolated from nodules of Crotalaria spp., Indigofera spp., Erythrina brucei and Glycine max growing in Ethiopia. AB - Ethiopian Bradyrhizobium strains isolated from root nodules of Crotalaria spp., Indigofera spp., Erythina brucei and soybean (Glycine max) represented genetically diverse phylogenetic groups of the genus Bradyrhizobium. Strains were characterized using the amplified fragment length polymorphism fingerprinting technique (AFLP) and multilocus sequence analysis (MLSA) of core and symbiotic genes. Based on phylogenetic analyses of concatenated recA-glnII-rpoB-16S rRNA genes sequences, Bradyrhizobium strains were distributed into fifteen phylogenetic groups under B. japonicum and B. elkanii super clades. Some of the isolates belonged to the species B. yuanmingense, B. elkanii and B. japonicum type I. However, the majority of the isolates represented unnamed Bradyrhizobium genospecies and of these, two unique lineages that most likely represent novel Bradyrhizobium species were identified among Ethiopian strains. The nodulation nodA gene sequence analysis revealed that all Ethiopian Bradyrhizobium isolates belonged to nodA sub-clade III.3. Strains were further classified into 14 groups together with strains from Africa, as well as some originating from the other tropical and subtropics regions. Strains were also clustered into 14 groups in nodY/K phylogeny similarly to the nodA tree. The nifH phylogenies of the Ethiopian Bradyrhizobium were generally also congruent with the nodA gene phylogeny, supporting the monophyletic origin of the symbiotic genes in Bradyrhizobium. The phylogenies of nodA and nifH genes were also partially congruent with that inferred from the concatenated core genes sequences, reflecting that the strains obtained their symbiotic genes vertically from their ancestor as well as horizontally from more distantly related Bradyrhizobium species. PMID- 22842092 TI - Tramps, narrow endemics and morphologically cryptic species in the epiphyllous liverwort Diplasiolejeunea. AB - Diplasiolejeunea is a pantropical, epiphytic genus of leafy liverworts that occurs from the lowlands to more than 4000m altitude. Phylogenetic analyses of a molecular dataset consisting of three markers (nuclear ribosomal ITS region, plastidic trnL-F region and rbcL gene) and 122 accessions (plus two outgroups, Colura and Cololejeunea) indicate that the evolutionary diversity of Diplasiolejeunea is underestimated by current morphology-based classification. Four morphologically semi-cryptic species have been recovered. The molecular phylogenies support a deep split into a Neotropical and a Paleotropical clade, the latter structured into Australasian, Asian and Afromadacascan lineages. Presented results confirm the ranges of two pantropical species (D. cavifolia, D. rudolphiana), provide evidence for dispersal from the Neotropics into the Paleotropics, indicate speciation along altitudinal gradients and demonstrate extensive morphological homoplasy. We propose a revised supraspecific classification of Diplasiolejeunea into a predominantly Paleotropical subgenus Physolejeunea and predominantly Neotropical subgenera Austrolejeuneopsis and Diplasiolejeunea, the former containing mainly epiphytic species, the latter mainly epiphylls. Several clades are supported by combinations of morphological character states, and could be assigned to sections at some later point. This is the first comprehensive phylogeny of a largely epiphyllous genus of liverworts. PMID- 22842093 TI - Using nuclear gene data for plant phylogenetics: progress and prospects. AB - The paper reviews the current state of low and single copy nuclear markers that have been applied successfully in plant phylogenetics to date, and discusses case studies highlighting the potential of massively parallel high throughput or next generation sequencing (NGS) approaches for molecular phylogenetic and evolutionary investigations. The current state, prospects and challenges of specific single- or low-copy plant nuclear markers as well as phylogenomic case studies are presented and evaluated. PMID- 22842094 TI - From Amazonia to the Atlantic forest: molecular phylogeny of Phyzelaphryninae frogs reveals unexpected diversity and a striking biogeographic pattern emphasizing conservation challenges. AB - Documenting the Neotropical amphibian diversity has become a major challenge facing the threat of global climate change and the pace of environmental alteration. Recent molecular phylogenetic studies have revealed that the actual number of species in South American tropical forests is largely underestimated, but also that many lineages are millions of years old. The genera Phyzelaphryne (1 sp.) and Adelophryne (6 spp.), which compose the subfamily Phyzelaphryninae, include poorly documented, secretive, and minute frogs with an unusual distribution pattern that encompasses the biotic disjunction between Amazonia and the Atlantic forest. We generated >5.8 kb sequence data from six markers for all seven nominal species of the subfamily as well as for newly discovered populations in order to (1) test the monophyly of Phyzelaphryninae, Adelophryne and Phyzelaphryne, (2) estimate species diversity within the subfamily, and (3) investigate their historical biogeography and diversification. Phylogenetic reconstruction confirmed the monophyly of each group and revealed deep subdivisions within Adelophryne and Phyzelaphryne, with three major clades in Adelophryne located in northern Amazonia, northern Atlantic forest and southern Atlantic forest. Our results suggest that the actual number of species in Phyzelaphryninae is, at least, twice the currently recognized species diversity, with almost every geographically isolated population representing an anciently divergent candidate species. Such results highlight the challenges for conservation, especially in the northern Atlantic forest where it is still degraded at a fast pace. Molecular dating revealed that Phyzelaphryninae originated in Amazonia and dispersed during early Miocene to the Atlantic forest. The two Atlantic forest clades of Adelophryne started to diversify some 7 Ma minimum, while the northern Amazonian Adelophryne diversified much earlier, some 13 Ma minimum. This striking biogeographic pattern coincides with major events that have shaped the face of the South American continent, as we know it today. PMID- 22842095 TI - Perivascular stem cell niche in head and neck cancer. AB - Cancers may contain a small sub-population of uniquely tumorigenic cells that exhibit self-renewal and multipotency, i.e. cancer stem cells (CSCs). These cells reside in invasive fronts in close proximity to blood vessels in many tumors, including head and neck squamous cell carcinomas (HNSCCs). Recent evidence suggests that CSC resist chemotherapy and "drive" local recurrence and metastatic spread. Notably, endothelial cell-initiated signaling is critical for the survival and self-renewal of CSC and may play a role in resistance to therapy. Therefore, patients with head and neck cancer might benefit from therapies that target the CSC directly or their supportive perivascular niche. PMID- 22842097 TI - Capturing circulating tumor cells of hepatocellular carcinoma. AB - Early metastases of hepatocellular carcinoma (HCC) may be detected by the isolation of circulating tumor cells (CTCs) in the bloodstream. During the course of therapeutic attempts, monitoring CTC changes in patients with HCC is helpful for the efficacy assessment. Nevertheless, the markers used for the detection, such as alpha-feto protein, asialoglycoprotein receptor or epithelial cell adhesion molecule, CD133 or CD90, are not specific for HCC CTCs. In spite of these limitations, a timely determination of the existence of CTCs will be beneficial for the monitoring of distant metastases, the evaluation of therapeutic attempts, and the prediction of prognosis. PMID- 22842096 TI - Biomodulatory approaches to photodynamic therapy for solid tumors. AB - Photodynamic Therapy (PDT) uses a photosensitizing drug in combination with visible light to kill cancer cells. PDT has an advantage over surgery or ionizing radiation because PDT can eliminate tumors without causing fibrosis or scarring. Disadvantages include the dual need for drug and light, and a generally lower efficacy for PDT vs. surgery. This minireview describes basic principles of PDT, photosensitizers available, and aspects of tumor biology that may provide further opportunities for treatment optimization. An emerging biomodulatory approach, using methotrexate or Vitamin D in combination with aminolevulinate-based PDT, is described. Finally, current clinical uses of PDT for solid malignancies are reviewed. PMID- 22842098 TI - Transcriptional control of early vein expression of CYCA2; 1 and CYCA2;4 in Arabidopsis leaves. AB - Unlike most animal tissue networks, the patterns of vein networks in plant leaves are variable and plastic, suggesting distinct control mechanisms. Thus, knowledge of the gene regulatory circuits that pattern leaf vein networks could suggest new control mechanisms of tissue network formation. However, the cis-regulatory elements required for expression at early stages of vein development are largely unknown. Here we show that the Arabidopsis genes CYCLIN A2;1 (CYCA2;1) and CYCLIN A2;4 (CYCA2;4), previously shown to act redundantly in vein cell proliferation, are expressed at early stages of vein development. We show that stage-specific expression of CYCA2;1 and CYCA2;4 in vein development depends on regulatory elements containing, respectively, one and three evolutionarily conserved transcription-factor binding sites. Our data suggest that early vein expression is encoded in regulatory elements of different structures. PMID- 22842099 TI - Visualization and exploration of Tcf/Lef function using a highly responsive Wnt/beta-catenin signaling-reporter transgenic zebrafish. AB - Evolutionarily conserved Tcf/Lef transcription factors (Lef1, Tcf7, Tcf7l1, and Tcf7l2) mediate gene expression regulated by Wnt/beta-catenin signaling, which has multiple roles in early embryogenesis, organogenesis, adult tissue homeostasis, and tissue regeneration. However, the spatiotemporal dynamics of Tcf/Lef activity during these events remain poorly understood. We generated stable transgenic zebrafish lines carrying a new Wnt/beta-catenin signaling reporter, Tcf/Lef-miniP:dGFP. The reporter revealed the transcriptional activities of four Tcf/Lef members controlled by Wnt/beta-catenin signaling, which were expressed in known Wnt/beta-catenin signaling-active sites during embryogenesis, organ development and growth, and tissue regeneration. We used the transgenic lines to demonstrate the contribution of Tcf/Lef-mediated Wnt/beta catenin signaling to the development of the anterior lateral line, dorsal and secondary posterior lateral lines, and gill filaments. Thus, these reporter lines are highly useful tools for studying Tcf/Lef-mediated Wnt/beta-catenin signaling dependent processes. PMID- 22842100 TI - Gcm proteins function in the developing nervous system. AB - A fundamental issue during nervous system development is how individual cells are formed from the undefined precursors. Differentiated neurons and glia, two major cell types mediating neuronal function, are acquired from immature precursors via a series of explicit controls exerted by transcription factors such as proteins in the family of Glial cells missing (Gcm). In mammals, Gcm proteins are involved in placenta and parathyroid gland development, whereas in the invertebrate organism Drosophila, Gcm proteins act as fate determinants for glial cell fate, regulate neural stem cell (NSC) induction and conversion, and promote glial proliferation. In particular, Gcm protein levels are carefully tuned for Drosophila gliogenesis and their stability is under precise control via the ubiquitin-proteasome system (UPS). Here we summarize recent advances on Gcm proteins function. In addition to describe various features of Gcm protein family, the significance of their functions in the developing nervous system is also discussed. PMID- 22842101 TI - Farnesyl pyrophosphate synthase: a key enzyme in isoprenoid biosynthetic pathway and potential molecular target for drug development. AB - As isoprenoid biosynthetic pathway has gained importance since last few years, key enzymes of this pathway have been characterized and their functional roles in the cell metabolism have been explored using molecular biology approaches. A key enzyme in this pathway is farnesyl pyrophosphate (EC 2.5.1.10) synthase (FPPS) which supplies precursors for the biosynthesis of essential isoprenoids like carotenoids, withanolides, ubiquinones, dolichols, sterols, among others and also helps in farnesylation and geranylation of proteins. It is a chain elongation enzyme which catalyzes head to tail condensation of two molecules of isopentenyl diphosphate with dimethylallyl diphosphate to form farnesyl pyrophosphate (FPP). Recent studies have validated FPPS as a molecular target of bisphosphonates for drug development against tumors as well as human pathogens. The present paper synthesizes the information on characterization, structural and functional relationships, evolution, localization as well as advances on FPPS enzyme as a target for drug development. PMID- 22842102 TI - Addition of maize stalks and soybean oil to a historically PCB-contaminated soil: effect on degradation performance and indigenous microbiota. AB - Objective of this study was to assess the single or combined effect of a plant oil and a lignocellulosic waste, namely soybean oil (SO) and maize stalks (MS), respectively, on resident microbiota and bioremediation performances of a soil historically contaminated by medium to highly chlorinated PCBs. Higher concentrations of both biphenyl- and chlorobenzoate-degrading cultivable bacteria were found in the MS-amended microcosms (MSM) than the non amended or SO-amended ones after 30 d incubation at 28 degrees C. Fungal growth, instead, was strikingly stimulated in the microcosms that had undergone concomitant MS and SO supplementation (MS-SOM). Denaturing gradient gel electrophoresis analyses of 16S and 18S rRNA genes showed that both amendments promoted a remarkable increase in both bacterial and fungal biodiversity. The abundances of biphenyl-2,3 dioxygenase (bph) and that of catechol-2,3-dioxygenase (C230) genes in the non amended contaminated soil were constant over time. Conversely, after 60 d incubation, bph and C230 abundances increased 2.8- and 61-fold in the MSM, respectively, and, in the MS-SOM, 1.4- and 46-fold, respectively, with respect to the zero time point. Although the overall PCB removal was not positively affected by the amendments, the concomitant presence of both MS and SO led to significantly higher depletions of hexa-, hepta-, octa- and nona-chlorinated congeners than in the non-amended microcosms (i.e. 24.6, 22, 20.5 and 9.5%, versus 19.4, 16.4, 14.7 and 6.1%, respectively). In all microcosms, PCB degradation was negatively correlated with hydrophobicity, organic matter/water partition coefficient, molecular weight and extent of chlorination of the pollutants with the notable exception of the MS-SOM ones where such a relationship was less stringent. PMID- 22842103 TI - Spectroscopic characterization and quantitative determination of atorvastatin calcium impurities by novel HPLC method. AB - Seven process related impurities were identified by LC-MS in the atorvastatin calcium drug substance. These impurities were identified by LC-MS. The structure of impurities was confirmed by modern spectroscopic techniques like (1)H NMR and IR and physicochemical studies conducted by using synthesized authentic reference compounds. The synthesized reference samples of the impurity compounds were used for the quantitative HPLC determination. These impurities were detected by newly developed gradient, reverse phase high performance liquid chromatographic (HPLC) method. The system suitability of HPLC analysis established the validity of the separation. The analytical method was validated according to International Conference of Harmonization (ICH) with respect to specificity, precision, accuracy, linearity, robustness and stability of analytical solutions to demonstrate the power of newly developed HPLC method. PMID- 22842104 TI - Synthesis and investigation on photophysical and photochemical properties of 7 oxy-3-methyl-4-phenylcoumarin bearing zinc phthalocyanines. AB - The synthesis of peripherally and non-peripherally tetrakis-(7-oxy-3-methyl-4 phenylcoumarin) and peripherally octakis-[tetrachlorotetra-(7-oxy-3-methyl-4 phenyl coumarin)] substituted zinc(II) phthalocyanines are performed and characterized for the first time in this study. The new compounds show excellent solubility in organic solvents, which makes them candidates for use in different applications. Photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen generation and photodegradation under light irradiation) properties of these novel coumarino phthalocyanines are investigated in dimethylformamide (DMF). The effects of the positions (peripheral or nonperipheral) of the substituents on the photophysical and photochemical parameters of the coumarino zinc(II) phthalocyanines are reported. The fluorescence quenching behavior of the studied zinc(II) phthalocyanines by addition of 1,4-benzoquinone (BQ) are also described. PMID- 22842105 TI - Looking forward: an impaired ability in patients with schizophrenia? AB - When two visual stimuli occur within 8 to 17 ms of one another, subjects cannot tell they are asynchronous, yet recent results show they are not processed as simultaneous. Two spatially separate squares were presented at an interval ranging from 0 to 92 ms and remained on the screen until subjects responded. Subjects pressed a right or left response key according to the judged simultaneity/asynchrony of the stimuli. We evaluated the Simon effect, i.e., the tendency to press the key on the same side as the stimulus. We found an effect even when the squares were displayed on opposite sides of the screen, with their onsets separated by less than 20 ms. Controls were biased towards the last stimulus, whereas patients with schizophrenia were biased towards the first. We investigate here whether the results are related to spatial or temporal processing. Using the same paradigm, we explored the impact of spatial grouping by comparing connected vs. unconnected stimuli and manipulating the predictability of the second stimulus location. We tested different groups of mildly symptomatic patients and matched controls in two studies. Under 20 ms, when stimuli were connected and the 2nd square location was predictable, patients tended to press the key to the side of the 1st square, whereas controls displayed the opposite tendency. The results suggest that controls put more emphasis on the last occurring event, but not patients with schizophrenia. This impairment is observed when spatial difficulties are removed, suggesting it is related to time rather than space. PMID- 22842106 TI - Cognitive control influences the use of meaning relations during spoken sentence comprehension. AB - The aim of this study was to investigate individual differences in the influence of lexical association on word recognition during auditory sentence processing. Lexical associations among individual words (e.g. salt and pepper) represent one type of semantic information that is available during the processing of words in context. We predicted that individuals would vary in their sensitivity to this type of local context as a function of suppression ability and working-memory capacity. Lexical association was manipulated in auditory sentence contexts, and multiple regression analyses were employed to examine the relation between individuals' brain responses to meaning relations in sentences and measures of working-memory capacity, cognitive control and vocabulary. Lexical association influenced the processing of words that were embedded in sentences and also showed a great deal of individual variability. Specifically, suppression ability emerged as a significant predictor of sensitivity to lexical association, such that individuals who performed poorly on our measure of suppression ability (the Stroop task), compared to those who performed well, showed larger N400 effects of lexical association. PMID- 22842107 TI - CD34+ cell content in unrelated allogeneic peripheral blood stem cell grafts transported internationally. Does the inter-laboratory variability affect comparability of graft quality data? AB - BACKGROUND: Increasing numbers of unrelated hematopoietic stem cell grafts are transported internationally and evaluated concurrently in different laboratories. The graft quality assessment using the CD34(+) enumeration could be influenced by inter-laboratory variability. METHODS: We retrospectively analyzed the content of CD34(+) cells in 154 consecutive collections being performed in different transplant centers during two periods (2003-2004, 2007-2010). All samples were tested twice in our own and partner laboratories. CD34(+) percentage and absolute number were compared. RESULTS: The percentage and the total CD34(+) content correlated well in both observed periods (CD34(+)%: r=0.899 and r=0.922; CD34(+)*10(8)/kg: r=0.966 and r=0.880; p<0.0001). Median CD34(+) percentages obtained in our centre in comparison with other laboratories were 0.54% vs. 0.46% in 2003-2004 and 0.69% vs. 0.70% in 2007-2010 period. The degree of laboratory compliance was affected by the laboratory identity. CD34(+) percentage reported by one laboratory and CD34(+)*10(8)/kg reported by three from twelve laboratories lacked statistically significant correlation with our own data. CONCLUSIONS: The study documented that results of CD34(+) cell dose assessment of the same grafts reported by different transplant centers are comparable. The graft quality data and the CD34(+) enumeration possess a limited level of inter-laboratory variability. PMID- 22842108 TI - Significance of serological monitoring in a Bombay Rh (D) negative phenotype pregnant woman: a case report. AB - A 32 year old Indian female was referred to our hospital at 32 weeks of gestation because of difficulty in blood group determination and further antenatal care. The results of cell and serum grouping of her blood sample were suggestive of Bombay (O(h)) Rh (D) negative phenotype. An indirect antiglobulin test (IAT) using a pool of red cells from two Bombay Rh (D) positive blood donors gave negative result using the tube as well as the gel technique (LISS-Coombs Card, BioRad, Switzerland), thus ruling out anti-D antibody in her serum. The anti-H titer was 16 (tube technique) and with dithiothreitol (DTT) treated patient's serum the antibody screening was negative suggestive of IgM type of anti-H antibodies. Within the patient's family, only one member (younger sister) was of O(h) phenotype and also was Rh (D) negative. The baby was born vaginally at 38+6 weeks of gestation and was non-hydropic with a packed cell volume (PCV) of 55%. The baby's blood group was AB Rh (D) negative and the cord blood direct antiglobulin test (DAT) was negative. Thus, a careful serological testing of O(h) phenotype antenatal women especially with Rh (D) negative phenotype is of utmost importance in determining the isoimmunization status. PMID- 22842109 TI - Bacteriological analysis of platelets and cases of septic reactions associated with transfusion of contaminated samples. AB - INTRODUCTION: For years, platelet transfusion therapy has been playing an important role in controlling patients with hematological and oncological diseases. However, platelet transfusion represents a serious risk for bacterial sepsis. This study aimed to verify the bacterial contamination index in platelet concentrates (PCs) obtained from the Blood Center of the State of Rio Grande do Sul (HEMORGS). METHODS: All 612 samples of PCs from HEMORGS were analyzed in August 2009 and January 2010. We used a qualitative methodology which was modified manually in order to detect bacterial contamination. The patients who received the platelet units with confirmed positive cultures had their medical records analyzed. After the prospective study, a retrospective analysis of the samples of PCs checked by the bacteriological control from HEMORGS since its foundation (2008) until 2010 was made. RESULTS: Four hundred and eighty samples (10 monthly samples of plateletpheresis and 10 of whole blood-derived platelets) were analyzed in order to compare the contamination index for both studies. Of 1092 samples, 15 were found to be contaminated (6 of retrospective analysis and 9 of prospective). In prospective study, isolated microorganisms were nine Staphylococcus epidermidis, but in retrospective two Staphylococcus sp., two glucose non-fermenting gram negative bacilli, one Streptococcus sp. and one Proteus mirabilis. We report 3 feasible cases of bacterial sepsis associated with the transfusion of CPs analyzed by prospective study. CONCLUSION: Bacterial sepsis associated with platelet transfusion is today the most frequent infectious complication of transfusion medicine. Although complex, it is important to recognize transfusion sepsis in patients to reduce morbidity and mortality. PMID- 22842110 TI - Thrombotic risk in patients undergoing peripheral stem cell apheresis and low molecular weight heparin prophylaxis pre-apheresis. AB - Patients undergoing peripheral blood stem cell (PBSC) collection for autologous transplantation may have a greater incidence of thrombosis due to a number of risk factors (RFs). These factors may be related to the patient himself (history of thromboembolism, tumour type and stage, treatment), to the procedure and/or to the mobilizing agents used. In our study of 97 patients, 32 were considered high risk (HR) patients and were therefore treated with a low prophylactic dose of enoxaparin the evening before stem cell apheresis. Neither thrombotic nor hemorrhagic complications were observed, even though pre-apheresis platelet levels were below 50*10(9)l(-1) in 19 procedures. PMID- 22842111 TI - A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange. AB - A 70 year old Caucasian woman with IgG lamda multiple myeloma presented with uncontrollable bleeding from a bone marrow biopsy site which started days after the procedure. The patient was hyperviscous, and coagulation tests showed elevated activated partial thromboplastin time (aPTT) which was not corrected with a mixing study, elevated thrombin time and reptilase time, and possible inhibitors to Factors VIII and IX. Therapeutic plasma exchange was performed using plasma with corrections of plasma viscosity (1.6 to 1.1 centipoise) and aPTT (50 to 42.1s) observed. The bleeding was controlled, and purified IgG demonstrated dysfibrinogenemic effects of the patient's paraprotein. PMID- 22842113 TI - Selected-area diffraction and spectroscopy in LEEM and PEEM. AB - This paper addresses the effects of spherical and chromatic aberration of the objective lens, as well as chromatic dispersion of magnetic prism arrays, on the ability to perform selected area Low Energy Electron Diffraction, as well as (Angle Resolved) Photo Electron Spectroscopy experiments in today's advanced cathode lens microscopy instruments. PMID- 22842112 TI - A graph theory method for determination of cryo-EM image focuses. AB - Accurate determination of micrograph focuses is essential for averaging multiple images to reach high-resolution 3-D reconstructions in electron cryo-microscopy (cryo-EM). Current methods use iterative fitting of focus-dependent simulated power spectra to the power spectra of experimental images, with the fitting performed independently for different images. Here we have developed a novel graph theory based method in which the rotational average focus and individual angular sector focuses of all images are determined simultaneously in closed form using the least square solution of overdetermined linear equations. The new method was shown to be fast, accurate, and robust in tests with large datasets of experimental low dose cryo-EM images. Its integration with three classic power spectra fitting methods also allows cross validation of the results by these vastly different methods. The new integrated focus determination method will improve reliability of automated focus determination for large-scale data processing that is increasingly common in the cryo-EM field. PMID- 22842114 TI - Characterisation of ferromagnetic rings for Zernike phase plates using the Aharonov-Bohm effect. AB - Holographic measurements on magnetised thin-film cobalt rings have demonstrated both onion and vortex states of magnetisation. For a ring in the vortex state, the difference between phases of electron paths that pass through the ring and those that travel outside it was found to agree very well with Aharonov-Bohm theory within measurement error. Thus the magnetic flux in thin-film rings of ferromagnetic material can provide the phase shift required for phase plates in transmission electron microscopy. When a ring of this type is used as a phase plate, scattered electrons will be intercepted over a radial range similar to the ring width. A cobalt ring of thickness 20 nm can produce a phase difference of pi/2 from a width of just under 30 nm, suggesting that the range of radial interception for this type of phase plate can be correspondingly small. PMID- 22842115 TI - Linear ablation for atrial fibrillation guided by acoustic imaging: "how does it sound?". PMID- 22842116 TI - Silent steam pop detected by intracardiac echocardiography. PMID- 22842117 TI - J waves and early repolarization: do not confuse me with the facts! PMID- 22842118 TI - Coex-Rank: An approach incorporating co-expression information for combined analysis of microarray data. AB - Microarrays have been widely used to study differential gene expression at the genomic level. They can also provide genome-wide co-expression information. Biologically related datasets from independent studies are publicly available, which requires robust combined approaches for integration and validation. Previously, meta-analysis has been adopted to solve this problem. As an alternative to meta-analysis, for microarray data with high similarity in biological experimental design, a more direct combined approach is possible. Gene level normalization across datasets is motivated by the different scale and distribution of data due to separate origins. However, there has been limited discussion about this point in the past. Here we describe a combined approach for microarray analysis, including gene-level normalization and Coex-Rank approach. After normalization, a linear modeling process is used to identify lists of differentially expressed genes. The Coex-Rank approach incorporates co-expression information into a rank-aggregation procedure. We applied this computational approach to our data, which illustrated an improvement in statistical power and a complementary advantage of the Coex-Rank approach from a biological perspective. Our combined approach for microarray data analysis (Coex-rank) is based on normalization, which is naturally driven. The Coex-rank process not only takes advantage of merging the power of multiple methods regarding normalization but also assists in the discovery of functional clusters of genes. PMID- 22842119 TI - Ameliorative effect of Withania coagulans on dyslipidemia and oxidative stress in nicotinamide-streptozotocin induced diabetes mellitus. AB - Present study aims to evaluate the effect of Withania coagulans fruit (aqWC) on diabetic-dyslipidemia and antioxidant/oxidant status in DM. Diabetic animals were treated with aqWC at a dose of 250 mg/kg bw for 30 days. Lipid profile, MDA, GSH, SOD, FRAP, HMG CoA reductase and acetyl CoA carboxylase activities were estimated in blood and tissues. Total cholesterol, TAG and LDL were significantly elevated whereas HDL was decreased in diabetic animals (p<0.05), simultaneously the lipid content and HMG CoA reductase activities were also increased, whereas acetyl CoA carboxylase activity decreased significantly in tissues of diabetic animals. MDA was increased and antioxidants such as SOD, GSH and FRAP decreased significantly in DM (p<0.05). Oral administration of aqWC to diabetic animals produced significant improvement in serum lipid profile and tissue lipid content. Activity of HMG CoA reductase decreased, whereas acetyl CoA carboxylase activity increased significantly in tissues after aqWC treatment. Administration of aqWC to diabetic animals also showed significant increase in antioxidant levels i.e., GSH, SOD, FRAP and reduced level of MDA in blood and tissue homogenates as compared to diabetic controls (p<0.05). These results suggest that aqWC treatment improved lipid profile and decreased oxidative stress in diabetes mellitus. PMID- 22842120 TI - Amurensin G inhibits angiogenesis and tumor growth of tamoxifen-resistant breast cancer via Pin1 inhibition. AB - Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem among estrogen-receptor-positive breast cancer patients. We have previously reported that TAM-resistant MCF-7 (TAMR-MCF-7) cells have elevated angiogenic potential via Pin1-dependent vascular endothelial growth factor (VEGF) production. Vitis amurensis grape consumed as wine and fruit contains several resveratrol-like stilbenes or oligostilbenes. In this study, we screened for the most active compound to inhibit VEGF production from V. amurensis. Among the tested compounds, amurensin G most potently suppressed VEGF production in TAMR-MCF-7 cells. The enhanced VEGF gene transcription in TAMR-MCF-7 cells was suppressed by amurensin G. Molecular analyses using reporter genes with hypoxia response elements and activator protein-1 (AP-1) elements, and western blots revealed that the activities and the nuclear levels of hypoxia inducible factor-1 (HIF-1)alpha and AP-1 in TAMR-MCF-7 cells were decreased by amurensin G. Moreover, amurensin G concentration-dependently inhibited protein expression and gene transcription of Pin1 in TAMR-MCF-7 cells, which was dependent on E2F1 inhibition. Chick chorioallantoic membrane assays confirmed that amurensin G had significant antiangiogenic and antitumor growth effects in TMAR-MCF-7 cells. These results demonstrate for the first time that amurensin G may have therapeutic potential for TAM-resistant breast cancer through blocking of Pin1-mediated VEGF gene transcription. PMID- 22842121 TI - Antioxidant activity of propolis extracts from Serbia: a polarographic approach. AB - Antioxidant activity (AO) of commercial propolis extracts (PEs), available on Serbian market, was determined by direct current (DC) polarography. Polarographic anodic current of 5.0 mmol L(-1) alkaline solution of H2O2 was recorded at potentials of mercury dissolution. Decrease of the current was plotted against the volume of gradually added PEs. The volume of PE causing 20% current decrease was determined from the linear part of the plot. Antioxidant activity was expressed in H2O2 equivalent (HPEq), representing the volume of PE that corresponds to 1.0 mmol L(-1) H2O2 decrease. Resulting HPEq ranged between 1.71+/ 0.11 and 8.00+/-0.18 MUL. Range of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity was from 0.093+/-0.004% to 0.346+/-0.006%. Total phenolic content (TCP) of PE with superior AO activity was 5.31+/-0.05% g GAE, while the extract with the lowest activity contained 1.45+/-0.02% g GAE. Antioxidant activity, determined by polarographic method, was correlated with DPPH scavenging activity (R2=0.991) and TCP (R2=0.985). Validity of obtained results was further confirmed using ANOVA and post hoc Tukey HSD test. PMID- 22842122 TI - Evaluation of cytotoxic, genotoxic and antigenotoxic potential of Solanum lycocarpum fruits glicoalkaloid extract in V79 cells. AB - Solanum lycocarpum St.-Hil (Solanaceae) is a hairy shrub or small much-branched tree of the Brazilian Cerrado, popularly known as "fruit-of-wolf". Considering that the induction of chromosomal mutations is involved in the process of carcinogenesis, and that S. lycocarpum is often used in folk medicine, it becomes relevant to study its effect on genetic material. In this sense, the aim of present study was to determine the possible cytotoxic, genotoxic and antigenotoxic potentials of S. lycocarpum fruits glycoalkaloid extract (SL) in Chinese hamster lung fibroblasts (V79 cells). The cytotoxicity was evaluated by the colony forming assay, apoptosis and necrosis assay, Trypan blue exclusion dye method and mitotic index. Genotoxic and antigenotoxic potential were evaluated by comet and chromosomal aberrations assays. Four concentrations of SL (4, 8, 16 and 32 MUg/mL) were used for the evaluation of its genotoxic potential. The DNA damage-inducing agent methyl methanesulfonate (MMS, 22 MUg/mL) was utilized in combination with extract to evaluate a possible protective effect. The results showed that SL was cytotoxic at concentrations above 32 MUg/mL by the colony forming assay. For apoptosis and necrosis assay, the concentration of 64 MUg/mL of SL showed statistically significant increase in cell death by apoptosis and necrosis, while the concentrations of 128 and 256 MUg/mL of SL demonstrated statistically significant increase in cell death by necrosis, compared with the control group. Analysis of cell viability by Trypan blue exclusion indicated >96% viability for treatments with concentrations up to 32 MUg/mL of SL. No significant differences in MI were observed between cultures treated with different concentrations of SL (4, 8, 16 and 32 MUg/mL) alone or in combination with MMS and the negative control, indicating that these treatments were not cytotoxic. The comet and chromosomal aberrations assays revealed that SL does not display genotoxic activity. Moreover, the different concentrations of SL showed protective effect against both genomic and chromosomal damages induced by MMS. PMID- 22842123 TI - Effect of thermal processing and gamma-irradiation on allergenicity of legume proteins. AB - Legumes are implicated in IgE mediated food allergy in different countries. The present study aimed to investigate the effect of different processing methods on allergenicity of legume proteins. The extracts were processed by boiling, gamma irradiation or by combination of both. The changes in soluble protein content, specific IgE binding and allergenic potential of legume proteins were assessed. Thermal processing resulted in a 3- to 4-fold reduction in soluble protein. Specific IgE binding was reduced 74+/-6.5%, 83+/-11.6% and 62+/-7.2% in the soluble protein of kidney bean, black gram and peanut, respectively, after boiling (p<0.01) whereas there was 34+/-5.2%, 74+/-15.6% and 44+/-11.1% IgE binding reduction in the insoluble protein fraction of respective legumes. Boiling followed by gamma-irradiation reduced IgE binding significantly (p<0.05). Biopotency of soluble protein of kidney bean, black gram and peanut was reduced 7 , 3- and 26-folds (p<0.001), respectively, and that of insoluble protein decreased 6-, 4- and 8-folds (p<0.001), respectively, after boiling. Combination treatment was effective in reducing the potency of both soluble and insoluble protein significantly as compared to boiling alone (p<0.001). However, gamma irradiation alone did not bring any change in allergenicity. In conclusion, boiling followed by gamma-irradiation is effective in attenuating allergenicity of legume proteins. PMID- 22842124 TI - Nitroderivatives of olive oil phenols protect HepG2 cells against oxidative stress. AB - A series of nitroderivatives has been synthetized from natural and synthetic olive oil phenols to increase the assortment of compounds with a putative effect against Parkinson disease. Before considering the potential therapeutical and nutraceutical applications of the new compounds it was critical to assess any cytotoxic effects in the liver. The precursor compounds of the nitroderivatives have shown oxidative stress protective effects, therefore we also assessed if the new compounds counteracted oxidative stress. The antioxidant activity of nitrohydroxytyrosol (NO-HTy), nitrohydroxytyrosyl-acetate (NO-HTy-A) and ethyl nitrohydroxytyrosyl-ether (NO-HTy-E) at 5-20 MUM for 20 h, as well as the protective effects of the nitroderivatives after 20 h against oxidative stress induced by tert-butylhydroperoxide (t-BOOH), were assessed in HepG2 cells. Direct treatment with the three nitroderivatives decreased ROS generation compared to the control and NO-HTy at 20MUM also increased glutathione peroxidase (GPx) activity (p<0.001). Pretreatment with the three nitroderivatives at 5-20 MUM counteracted t-BOOH cell damage by decreasing ROS generation (p<0.001) and malondialdehyde (MDA) levels (p<0.001), increasing reduced glutathione (p<0.001) and disminishing GPx (p<0.05) activity. NO-HTy, NO-HTy-A and NO-HTy-E decreased glutathione reductase activity (p<0.05). CONCLUSION: the nitroderivatives do not present cytotoxic effects in the liver and in addition may protect against the oxidative stress involved in degenerative diseases. PMID- 22842125 TI - Identification of FRAS1 as a human endometrial carcinoma-derived protein in serum of xenograft model. AB - OBJECTIVE: The value of clinical specimens in identification of tumor biomarker is limited to the great individual variations among patients, the high complexity and dynamic range of protein components, and the possibility that the identified proteins are not produced by cancer cells but are due to secondary body defense mechanisms. Herein we developed a xenograft model system, in which human endometrial carcinoma cells formed a tumor in an immune-deficient nude mouse, to instantly detect proteins derived from cancer cells. METHODS: Using one dimensional electrophoresis, liquid chromatography, and Q-TOF-MS/MS and FT-ICR MS/MS analyses, the human-specific proteins in the serum of xenograft mouse could be identified and monitored without the great variations observed in a patient based approach. RESULTS: We successfully identified 224 proteins, in which 175 (78.1%) were of mouse origin, and 45 (20.1%) were unable to be assigned as human or mouse origin. FRAS1 was identified as a uniquely human-originated protein. Its expression profile was then confirmed by Western blotting in serum samples from xenograft mice, and patients bearing endometrial carcinoma and healthy controls. CONCLUSIONS: Although the mechanism of FRAS1 derivation by cancer cells remains to be illustrated, our results suggest that the xenograft model presented here should be a promising tool in the discovery of tumor biomarkers. PMID- 22842126 TI - Utility of conization with frozen section for intraoperative triage prior to definitive hysterectomy. AB - OBJECTIVE: To review our experience with conization with intraoperative frozen section analysis and to compare results from our tertiary cancer center with those from 2 community hospitals. METHODS: The records of all women who underwent conization with intraoperative frozen section analysis from January 1, 1997, through April 30, 2011, at The University of Texas MD Anderson Cancer Center and 2 community hospitals-The Woman's Hospital of Texas and St. Luke's Episcopal Hospital-were reviewed. Findings on pathologic analysis of frozen sections, permanent loop electrosurgical excisional procedure/conization specimens, and hysterectomy specimens were compared for each patient, and the results from the cancer center were compared to those from the community hospitals. RESULTS: One hundred fifty-three patients met the inclusion criteria. Rates of accuracy of conization with frozen section analysis in predicting definitive pathologic findings were as follows: cervix with no residual disease after prior extirpative procedure, 96.5% (95% CI 86.9-100%); cervical squamous carcinoma in situ, 95.4% (95% CI 84.5-100%); cervical adenocarcinoma in situ, 98.7% (95% CI 92.7-100%); microinvasive carcinoma, 97.4% (95% CI 90.1-100%); and invasive carcinoma>=3 mm, 100%. Most importantly, conization with frozen section analysis was 100% accurate for triaging patients to simple or radical hysterectomy. Finally, this approach performed equally well in the cancer center with subspecialized pathologists and the 2 community hospitals with general pathologists. CONCLUSION: Conization with frozen section analysis is an effective technique for intraoperative triage of patients to immediate simple or radical hysterectomy and can be accurately performed in both academic and community hospitals. PMID- 22842127 TI - Impact of resident participation in surgical operations on postoperative outcomes: National Surgical Quality Improvement Program. AB - OBJECTIVE: To evaluate whether resident participation in operations influences postoperative outcomes. BACKGROUND: : Identification of potential differences in outcome associated with resident participation in operations may facilitate planning from educational and health resource perspectives. METHODS: From the National Surgical Quality Improvement Program database (2005-2007), postoperative outcomes were compared for patients with and without resident participation (RES vs no-RES). Groups were matched in a 2:1 ratio, based on age, sex, specialty, surgical procedure, morbidity probability, and important comorbidities and risk factors. RESULTS: RES (40,474; 66.7%) and no-RES (20,237; 33.3%) groups were comparable for matched characteristics. Mortality was similar (0.18% vs 0.20%, P = 0.55). Thirty-day complications classified as "mild" (4.4% vs 3.5%, P < 0.001) and "surgical" (7% vs 6.2%, P < 0.001) were higher in RES group. Individual complications were largely similar, except superficial surgical site infection (3.0% vs 2.2%, P < 0.001). Operative time was longer in the RES group [mean (SD) 122 (80) vs 97 (67) minutes, P < 0.001]. Overall complications were lower for postgraduate year 1-2 residents than for other years. These differences persisted on multivariate analysis adjusting for confounders. CONCLUSIONS: Resident involvement in surgical procedures is safe. The small overall increase in mild surgical complications is mostly caused by superficial wound infections. Reasons for this are likely multifactorial but may be related to prolonged operative time. PMID- 22842128 TI - Appendectomy timing: waiting until the next morning increases the risk of surgical site infections. AB - OBJECTIVE: To investigate the association between time from admission to appendectomy (TTA) and the incidence of perforation and infectious complications. BACKGROUND: Immediate appendectomy to prevent perforation has been challenged by recent studies supporting a semielective approach to acute appendicitis. METHODS: Patients admitted with appendicitis from July 2003 to June 2011 were reviewed. Age, sex, admission white blood cell count, surgical approach (open vs laparoscopic), TTA, and pathology report were abstracted. Primary outcomes included perforation and surgical site infection (SSI). Logistic regression was performed both to identify independent predictors of perforation and to investigate the association between TTA and SSI. RESULTS: Over 8 years, 4529 patients were admitted with appendicitis and 4108 (91%) patients underwent appendectomy. Perforation occurred in 23% (n = 942) of these patients. Logistic regression identified 3 independent predictors of perforation: age 55 years or older [odds ratio (95% confidence interval) OR (95% CI), 1.66 (1.21-2.29); P = 0.002], white blood cell count more than 16,000 [OR (95% CI), 1.38 (1.15-1.64); P < 0.001], and female sex [OR (95% CI), 1.20 (1.02-1.41); P = 0.02]. Delay to appendectomy was not associated with higher perforation rate. However, after controlling for age, leukocytosis, sex, laparoscopic approach, and perforation, TTA of more than 6 hours was independently associated with an increase in SSI [OR (95% CI), 1.54 (1.01-2.34); P = 0.04]. Delay of more than 6 hours resulted in a significant increase in SSI from 1.9% to 3.3% among patients with nonperforated appendicitis [OR (95% CI), 2.16 (1.03-4.52); P = 0.03], raising the incidence of SSI in nonperforated appendicitis to levels similar to those with perforation (3.3% vs 3.9%, P = 0.47). CONCLUSIONS: In this series, appendectomy delay did not increase the risk of perforation but was associated with a significantly increased risk of SSI in patients with nonperforated appendicitis. Prompt surgical intervention is warranted to avoid additional morbidity in this population. PMID- 22842129 TI - Long-term results with associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). PMID- 22842130 TI - Totally laparoscopic ALPPS is feasible and may be worthwhile. PMID- 22842131 TI - Sensor activity and logic behaviour of PET based dihydroimidazonaphthalimide diester. AB - An ester terminated dihydroimidazonaphthalimide as multi-functional logic device is presented. Due to the optical changes as a function of pH this simple molecule is able to act as a molecular pH metre, a digital comparator and a half-adder. It was demonstrated that the dihydroimidazonaphthalimide comparator could be used as a fundamental element of an optical device for control of pH windows. Also, the ability of the device to detect metal ions in DMF and in water/DMF (3:1, v/v) at different pHs has been evaluated by monitoring the changes of its fluorescence intensity. Among the tested metal ions (Cd(2+), Co(2+), Cu(2+), Fe(3+), Ni(2+), Pb(2+), Zn(2+), Bi(3+), Hg(2+) and Ag(+)) only Fe(3+) and Bi(3+) were efficiently detected. In water/DMF (3:1, v/v) XOR and XNOR logic gates are presented using pH and Fe(3+) as chemical inputs based on encoding binary digits of logical conventions. PMID- 22842132 TI - Investigation on the interaction between luteolin and calf thymus DNA by spectroscopic techniques. AB - The interaction of luteolin with calf thymus deoxyribonucleic acid (ctDNA) under physiological conditions (Tris-HCl buffer solutions, pH 7.4) was studied by UV Vis spectroscopy, fluorescence spectroscopy and viscosity measurement method, respectively. The results indicated that a complex of luteolin with ctDNA can be formed. Spectroscopic techniques together with viscosity determination provided evidences of intercalation mode of binding for the interaction between luteolin and ctDNA. The binding constant of luteolin to DNA calculated based on UV-Vis spectroscopy data was found to be 4.52*10(4)L mol(-1) at 310 K. The thermodynamic parameters of the complex were calculated by a double reciprocal method: Delta(r)H(m)(s)=-8.9*10(3)J mol(-1),Delta(r)S(m)(s)=60.5 JK(-1)mol(-1) and Delta(r)G(m)(s)=-2.76*10(4)J mol(-1) (310 K). The interacting forces between luteolin and DNA mainly included hydrophobic interactions and hydrogen bonds. The acridine orange displacement studies revealed that luteolin had significant effect for acridine orange bounded on DNA, which was indicative of intercalation binding. PMID- 22842133 TI - Interactions of L-Arg with calf thymus DNA using neutral red dye as a fluorescence probe. AB - The interaction between l-Arg and calf thymus DNA (ctDNA) in sodium acetate acetic acid buffer (pH=4) was investigated with the use of neutral red (NR) dye as a spectral probe coupled with UV-vis absorption, fluorescence, and circular dichroism (CD) spectroscopy technique. The UV absorption spectroscopy indicated that l-Arg interacted with ctDNA via electrostatic force and the fluorescence enhancing of the DNA-NR system verified the electrostatic interaction. In addition, detectable changes in the CD spectrum of ctDNA in the presence of l-Arg indicated conformational changes in the DNA double helix after interaction with the drug. Docking studies were found to corroborate the experimental results. All these results prove that this drug interacts with ctDNA via an electrostatic binding mode. PMID- 22842134 TI - The distance education special interest group of NONPF. PMID- 22842135 TI - Preventing ventilator-related injury in the ICU. PMID- 22842136 TI - GGT and alcohol consumption. PMID- 22842140 TI - Living with chronic kidney disease: related issues and treatment. AB - Chronic kidney disease is becoming a major health concern in patients with diabetes and hypertension. Patients often present with no symptoms, and practitioners must understand and utilize the proper treatment and health promotion activities to identify, prevent, and reverse the serious implications of this disease. PMID- 22842141 TI - Testosterone replacement therapy to improve health in older males. AB - This article provides an overview of current research and updated clinical guidelines regarding testosterone replacement therapy in older males positive for late-onset hypogonadism. PMID- 22842142 TI - NPs in the ICU: the Vanderbilt initiative. AB - Before integrating nurse practitioners into a critical care environment, it is important to understand the infrastructure and support necessary to guide clinical practice and utilization. NP practice teams should be structured with a cohesive strategy to provide 24/7 patient coverage and consistency in evidence based care. PMID- 22842145 TI - Direct gating and mechanical integrity of Drosophila auditory transducers require TRPN1. AB - The elusive transduction channels for hearing are directly gated mechanically by the pull of gating springs. We found that the transient receptor potential (TRP) channel TRPN1 (NOMPC) is essential for this direct gating of Drosophila auditory transduction channels and that the channel-spring complex was disrupted if TRPN1 was lost. Our results identify TRPN1 as a mechanical constituent of the fly's auditory transduction complex that may act as the channel and/or gating spring. PMID- 22842144 TI - DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis. AB - Neurogenesis in the developing neocortex relies on the ability of radial glial progenitor cells (RGCs) to switch from proliferative to differentiative neuron generating divisions, but the molecular mechanisms that control this switch in a correct temporal manner are not well understood. Here, we show that DOCK7, a member of the DOCK180 family of proteins, regulates RGC proliferation versus differentiation. Silencing of DOCK7 in RGCs of developing mouse embryos impedes neuronal differentiation and maintains cells as cycling progenitors. In contrast, DOCK7 overexpression promotes RGC differentiation to basal progenitors and neurons. We further present evidence that DOCK7 influences neurogenesis by controlling apically directed interkinetic nuclear migration of RGCs. DOCK7 exerts its effects by antagonizing the microtubule growth-promoting function of the centrosome-associated protein TACC3. Thus, DOCK7 interaction with TACC3 controls interkinetic nuclear migration and the genesis of neurons from RGCs during cortical development. PMID- 22842146 TI - The neuroimaging signal is a linear sum of neurally distinct stimulus- and task related components. AB - Neuroimaging (for example, functional magnetic resonance imaging) signals are taken as a uniform proxy for local neural activity. By simultaneously recording electrode and neuroimaging (intrinsic optical imaging) signals in alert, task engaged macaque visual cortex, we recently observed a large anticipatory trial related neuroimaging signal that was poorly related to local spiking or field potentials. We used these same techniques to study the interactions of this trial related signal with stimulus-evoked responses over the full range of stimulus intensities, including total darkness. We found that the two signals could be separated, and added linearly over this full range. The stimulus-evoked component was related linearly to local spiking and, consequently, could be used to obtain precise and reliable estimates of local neural activity. The trial-related signal likely has a distinct neural mechanism, however, and failure to account for it properly could lead to substantial errors when estimating local neural spiking from the neuroimaging signal. PMID- 22842147 TI - Paradoxical contribution of SK3 and GIRK channels to the activation of mouse vomeronasal organ. AB - The vomeronasal organ (VNO) is essential for intraspecies communication in many terrestrial vertebrates. The ionic mechanisms of VNO activation remain unclear. We found that the calcium-activated potassium channel SK3 and the G protein activated potassium channel GIRK are part of an independent pathway for VNO activation. In slice preparations, the potassium channels attenuated inward currents carried by TRPC2 and calcium-activated chloride channels (CACCs). In intact tissue preparations, paradoxically, the potassium channels enhanced urine evoked inward currents. This discrepancy resulted from the loss of a high concentration of lumenal potassium, which enabled the influx of potassium ions to depolarize the VNO neurons in vivo. Both Sk3 (also known as Kcnn3) and Girk1 (also known as Kcnj3) homozygous null mice showed deficits in mating and aggressive behaviors, and the deficiencies in Sk3(-/-) mice were exacerbated by Trpc2 knockout. Our results suggest that VNO activation is mediated by TRPC2, CACCs and two potassium channels, all of which contributed to the in vivo depolarization of VNO neurons. PMID- 22842148 TI - Coactivation of multiple tightly coupled calcium channels triggers spontaneous release of GABA. AB - Voltage-activated Ca(2+) channels (VACCs) mediate Ca(2+) influx to trigger action potential-evoked neurotransmitter release, but the mechanism by which Ca(2+) regulates spontaneous transmission is unclear. We found that VACCs are the major physiological triggers for spontaneous release at mouse neocortical inhibitory synapses. Moreover, despite the absence of a synchronizing action potential, we found that spontaneous fusion of a GABA-containing vesicle required the activation of multiple tightly coupled VACCs of variable type. PMID- 22842149 TI - Flow cytometry studies on the Macrobrachium rosenbergii hemocytes sub-populations and immune responses to novel pathogen spiroplasma MR-1008. AB - Flow cytometry provides rapid and reproducible methods for analyzing crustacean cellular immune responses to pathogens. We used this method to investigate the hemocytes sub-populations of freshwater prawn Macrobrachium rosenbergii and their immune responses to a novel pathogen spiroplasma MR-1008. M. rosenbergii inoculated with 100 MUl spiroplasma strain MR-1008 in logarithmic phase (10(8) spiroplasmas ml(-1)) were examined for total hemocytes count (THC) and changes in differential involvement of hemocytes sub-populations during 1-28 d after inoculation. The results showed that THC was dramatically lowered 1 d after inoculation, and it obviously increased at the 5 d after inoculation; thereafter, a high level of THC was maintained to 15 d. Three morphologically distinct hemocytes sub-populations including granular cells (GC), semigranular cells (SGC) and hyaline cells (HC) could be identified by flow cytometry, and the proportions of the 3 kinds of cell categories varied obviously during the infection of spiroplasma suggesting differential involvement according to the pathogen. The flow cytometry used in this study confirmed that the semigranular cells were the main hemocytes involved in the cellular defense against spiroplasma in the M. rosenbergii. PMID- 22842150 TI - Cryptocaryon irritans infection induces the acute phase response in Lates calcarifer: a transcriptomic perspective. AB - Cryptocaryoniasis (also known as marine white spot disease) is mediated by Cryptocaryon irritans. This obligate ectoparasitic protozoan infects virtually all marine teleosts, which includes Lates calcarifer, a highly valuable aquaculture species. Little is known about L. calcarifer-C. irritans interactions. This study was undertaken to gain an informative snapshot of the L. calcarifer transcriptomic response over the course of C. irritans infection. An in-house fabricated cDNA microarray slides containing 3872 probes from L. calcarifer liver and spleen cDNA libraries were used as a tool to investigate the response of L. calcarifer to C. irritans infection. Juvenile fish were infected with parasites for four days, and total RNA was extracted from liver tissue, which was harvested daily. We compared the transcriptomes of C. irritans-infected liver to uninfected liver over an infection period of four days; the comparison was used to identify the genes with altered expression levels in response to C. irritans infection. The greatest number of infection-modulated genes was recorded at 2 and 3 days post-infection. These genes were mainly associated with the immune response and were associated in particular with the acute phase response. Acute phase proteins such as hepcidin, C-type lectin and serum amyloid A are among the highly modulated genes. Our results indicate that an induced acute phase response in L. calcarifer toward C. irritans infection is similar to the responses observed in bacterial infections of teleosts. This response demonstrates the importance of first line defenses in teleost innate immune responses against ectoparasite infection. PMID- 22842151 TI - imzML--a common data format for the flexible exchange and processing of mass spectrometry imaging data. AB - The application of mass spectrometry imaging (MS imaging) is rapidly growing with a constantly increasing number of different instrumental systems and software tools. The data format imzML was developed to allow the flexible and efficient exchange of MS imaging data between different instruments and data analysis software. imzML data is divided in two files which are linked by a universally unique identifier (UUID). Experimental details are stored in an XML file which is based on the HUPO-PSI format mzML. Information is provided in the form of a 'controlled vocabulary' (CV) in order to unequivocally describe the parameters and to avoid redundancy in nomenclature. Mass spectral data are stored in a binary file in order to allow efficient storage. imzML is supported by a growing number of software tools. Users will be no longer limited to proprietary software, but are able to use the processing software best suited for a specific question or application. MS imaging data from different instruments can be converted to imzML and displayed with identical parameters in one software package for easier comparison. All technical details necessary to implement imzML and additional background information is available at www.imzml.org. PMID- 22842152 TI - Exploring the pan-surfome of Streptococcus suis: looking for common protein antigens. AB - Streptococcus suis is a swine and human pathogen for which no commercial vaccine is still available. Conserved and broadly distributed surface proteins have become the chosen targets for the development of efficacious vaccines that could overcome the problems of non-heterologous protection of bacterins or capsule polysaccharide-based vaccines. In this work, we have analyzed by proteomics a collection of 39 strains obtained from infected pigs. The isolates belonged to 19 of the most prevalent serotypes during the last years. We have applied the "shaving" approach to define the "pan-surfome" or the set of both common and unique surface proteins identified in such strains. This set was constituted by 113 proteins. We have categorized them for their potential for further vaccination studies, based on their distribution among strains and their a priori accessibility to antibodies. According to these criteria, the cell-wall protein SsnA appears to be the best candidate from this list, as it was that with the widest distribution among the analyzed pathogen types, it showed to be highly immunogenic and highly accessible to antibodies, as demonstrated by flow cytometry. PMID- 22842153 TI - A comparative 'bottom up' proteomics strategy for the site-specific identification and quantification of protein modifications by electrophilic lipids. AB - We report a mass spectrometry-based comparative "bottom up" proteomics approach that combines d(0)/d(4)-succinic anhydride labeling with commercially available hydrazine (Hz)-functionalized beads (Affi-gel Hz beads) for detection, identification and relative quantification of site-specific oxylipid modifications in biological matrices. We evaluated and applied this robust and simple method for the quantitative analysis of oxylipid protein conjugates in cardiac mitochondrial proteome samples isolated from 3- and 24-month-old rat hearts. The use of d(0)/d(4)-succinic anhydride labeling, Hz-bead based affinity enrichment, nanoLC fractionation and MALDI-ToF/ToF tandem mass spectrometry yielded relative quantification of oxylipid conjugates with residue-specific modification information. Conjugation of acrolein (ACR), 4-hydroxy-2-hexenal (HHE), 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-noneal (ONE) to cysteine, histidine and lysine residues were identified. HHE conjugates were the predominant subset of Michael-type adducts detected in this study. The HHE conjugates showed higher levels in mitochondrial preparations from young heart congruent with previous findings by others that the n-3/n-6 PUFA ratio is higher in young heart mitochondrial membranes. Although this study focuses on protein adducts of reactive oxylipids, the method might be equally applicable to protein carbonyl modifications caused by metal catalyzed oxidation reactions. PMID- 22842154 TI - Leukocyte p53 protein biosignature through standard-aligned two-dimensional immunoblotting. AB - Peripheral leukocytes may reflect systemic disease and stress states through their gene expression profile. Subsequent protein analyses of leukocytes are hypothesized to provide essential information regarding systemic diseases. We have developed a protein biosignature analysis of the tumour suppressor and cell stress sensor p53 based on two-dimensional gel electrophoresis and immunoblotting, and utilize fluorescently labelled reference standards to significantly improve the alignment and comparison of biosignatures, including full-length p53 and isoforms p53beta and p53gamma. Analysis of the p53 biosignatures of peripheral blood mononuclear cells from 526 healthy individuals and 65 acute myeloid leukaemia patients indicated a novel putative p53 protein variant in a subset of individuals (227 of 526 healthy tested). The p53 variant was more distinct in the reference standard aligned biosignatures of healthy individuals, compared to the non-standard aligned leukaemia biosignatures. This approximately 2 kDa heavier variant of p53 appeared with similar frequency in leukemic and healthy test persons, without coinciding with known splice forms or post-translational modifications of p53. We propose that a standardized leukocyte protein biosignature of p53 provides a powerful research tool and indicate how p53 protein biosignatures may be used in future diagnostics. This article is part of a Special Issue entitled: Integrated omics. PMID- 22842155 TI - Quantitative mass spectrometry imaging of propranolol and olanzapine using tissue extinction calculation as normalization factor. AB - In order to quantify small molecules at the early stage of drug discovery, we developed a quantitation approach based on mass spectrometry imaging (MSI) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) without the use of a labeled compound. We describe a method intended to respond to the main challenges encountered in quantification through MALDI imaging dedicated to whole-body or single heterogeneous organ samples (brain, eye, liver). These include the high dependence of the detected signal on the matrix deposition, the MALDI ionization yield of specific target molecules, and lastly, the ion suppression effect on the tissue. To address these challenges, we based our approach on the use of a normalization factor called the TEC (Tissue Extinction Coefficient). This factor takes into account the ion suppression effect that is both tissue- and drug-specific. Through this protocol, the amount of drug per gram of tissue was determined, which in turn, was compared with other analytical techniques such as Liquid Chromatography-Mass spectrometry (LC-MS/MS). PMID- 22842156 TI - The current status of cancer biomarker research using tumour-associated antigens for minimal invasive and early cancer diagnostics. AB - Tumour-associated antigens (TAA) can be detected prior to clinical diagnosis and thus would be ideal biomarkers for early detection of cancer using only a few microliters of a patient's serum. In this article we provide a summary of TAA screening and serum-profiling conducted for breast, prostate, lung and colon cancers. Different methodological approaches, including SEREX, SERPA, and phage display for TAA identification and TAA panels are summarised, and a revision of array based techniques is provided. The most promising studies performed on these cancers (performed with 80-400 serum samples, including controls) obtained sensitivities in a range of 44-95% and specificities of 80-100%. From the various studies reviewed, only one performed cross validation (AUC=0.71) in a prostate cancer study. Thus, albeit receiver operation characteristics are very promising, cross validation of most studies is still missing. Additionally, the concerted action of research groups for standardization of serum-TAA testing and cross validation is required. Along with today's technological options, the chances of establishing TAA biomarkers are now higher than ever before. This may also be true for confirmation and validation of already existing data, which is a prerequisite for implementation of TAA biomarkers into clinical diagnostics. This article is part of a Special Issue entitled: Integrated omics. PMID- 22842157 TI - Standardized and automated solid-phase extraction procedures for high-throughput proteomics of body fluids. AB - In order to balance the speed of analytical sample preparation procedures with mass spectrometry (MS)-based clinical proteomics the application of high throughput robotic systems for body fluid workup is essential. In this paper we describe the implementation of various solid-phase extraction (SPE) sample preparation protocols on two different platforms, namely: 1) Magnetic bead-based SPE of peptides and proteins from body fluids on a Hamilton liquid handling workstation; 2) Cartridge-based SPE on a SPARK Symbiosis system. All SPE protocols were optimized for MS-based proteomics and compared with respect to obtained peptide- and protein profiles. Throughput numbers that were achieved in a 24 hour time frame for the sample workup procedures were more than 700 samples for the magnetic bead-based method and over 1000 samples for the cartridge-based method. PMID- 22842158 TI - A comparison between MALDI-MS and CE-MS data for biomarker assessment in chronic kidney diseases. AB - Non-invasive detection of diseases, based on urinary proteomics, is becoming an increasingly important area of research, especially in the area of chronic kidney disease (CKD). Different platforms have been used in independent studies, mostly capillary-electrophoresis coupled ESI-MS (CE-MS), liquid chromatography coupled mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). We have compared the performance of CE-MS with MALDI-MS in detecting CKD, based on a cohort of 137 urine samples (62 cases and 75 controls). Data cross-talk between the two platforms was established for the comparison of detected biomarkers. The results demonstrate superior performance of the CE-MS approach in terms of peptide resolution and obtained disease prediction accuracy rates. However, the data also demonstrate the ability of the MALDI-MS approach to separate CKD patients from controls, at slightly reduced accuracy, but expected reduced cost and time. As a consequence, a practical approach can be foreseen where MALDI-MS is employed as an inexpensive, fast, and robust screening tool to detect probable CKD. In a second step, high resolution CE-MS could be used in those patients only that scored negative for CKD in the MALDI-MS analysis, reducing costs and time of such a program. PMID- 22842159 TI - Rabbit zona pellucida composition: a molecular, proteomic and phylogenetic approach. AB - The zona pellucida (ZP) participates in sperm-egg interactions during the first steps of fertilization. Recent studies have shown that the ZP matrix of oocytes in several species is composed of four glycoproteins, designated as ZP1, ZP2, ZP3 and ZP4, rather than the three described in mouse, pig and cow. In this study, investigations were carried out to unveil a fourth glycoprotein in the rabbit (Oryctolagus cuniculus) ZP. Using total RNA isolated from rabbit ovaries, the complementary deoxyribonucleic acid (cDNA) encoding rabbit ZP1 was amplified by reverse transcribed polymerase chain reaction (RT-PCR). The ZP1 cDNA contains an open reading frame of 1825 nucleotides encoding a polypeptide of 608 amino acid residues. The deduced amino acid sequence of rabbit ZP1 showed high identity with other species: 70% identity with human and horse ZP1, and 67% identity with mouse and rat ZP1. At the proteomic level, peptides corresponding to the four proteins were detected by mass spectrometry. In addition, a molecular phylogenetic analysis of ZP1 showed that pseudogenization of this gene has occurred at least four times during the evolution of mammals. The data presented in this manuscript provide evidence, for the first time, that the rabbit ZP is composed of four glycoproteins. PMID- 22842160 TI - Palliative weekly chemotherapy along with cetuximab in recurrent and metastatic head and neck cancers: a retrospective analysis. AB - BACKGROUND: This study was undertaken to report the results of weekly combination chemotherapy with cetuximab in recurrent/metastatic head and neck squamous cell carcinoma (R/M SCCHN). MATERIALS AND METHODS: Retrospective analysis of 35 R/M SCCHN patients who received cetuximab with weekly paclitaxel and platin (cisplatin/carboplatin) from SCCHN August 2006 to October 2008 at our Institute was performed. RESULTS: Thirty-five patients (33 [94.3%] males and 2 [5.7%] females) received the planned weekly chemotherapy protocol. Median age of these patients was 52 years. Of the SCCHN 32 evaluable patients, 25 patients showed symptomatic improvement and 7 showed no improvement. Radiological responses using RECIST criteria reported CR in 1 patient (3.1%), PR in 17 patients (53.1%), and SD in 6 patients (18.8%). The remaining six patients demonstrated disease progression while two could not be assessed. Median overall survival (OS) was 8.016 months (95% CI; 6.572--9.461) and median PFS was 5.782 months (95% CI; 4.521--7.044). The major chemotherapy-related grades 2 and 3 toxicity recorded was cetuximab-induced rash reported in 24 patients. No treatment-related death within 30 days was observed. CONCLUSION: Cetuximab with weekly combination chemotherapy (Paclitaxel + Platinum compound) has shown promise, demonstrating comparable response and outcomes with acceptable toxicity in R/M SCCHN patients. PMID- 22842161 TI - Head and neck cancer in India: need to formulate uniform national treatment guideline? AB - BACKGROUND: In a large and diverse country like India, there is a wide variation in the availability of infrastructure and expertise to treat head-neck cancer patients. Lack of consistent adherence to evidence-based management is the biggest problem. AIMS: There is an unmet need to evaluate the existing treatment practices to form the basis for development of effective and uniform treatment policies. SETTINGS AND DESIGNS: Prospective case series. MATERIALS AND METHODS: A group of previously treated, potentially curable patients presenting to our institution (from April 2009 to March 2011) were evaluated for appropriateness of initial treatment based on National Comprehensive Cancer Network or Tata Memorial Hospital guidelines. Data regarding treatment center, protocol and accuracy of delivered treatment and their eventual outcome were analyzed. STATISTICAL ANALYSIS: Descriptive. RESULTS: Amongst 450 newly registered patients, 77(17%) were previously treated with curative intent and 69(89%) of them were inappropriately treated. Seventeen (25%) patients were treated in clinics while 12(17%) in cancer centers and 34(50%) in corporate hospitals. Fourteen (20%) patients received chemotherapy, 22(32%) received radiotherapy and 14(20%) underwent surgery while 19(28%) patients received multimodality treatment. Disease stage changed to more advanced stage in 40(58%) patients and curative intent treatment could be offered only to 33(48%) patients. Amongst 56 patients available for outcome review, 18(32%) patients were alive disease-free, 20(36%) had died and 18(32%) were alive with disease. CONCLUSION: Large numbers of potentially curable patients are inappropriately treated and their outcome is significantly affected. Many initiatives have been taken in the existing National Cancer Control Program but formulation of a uniform national treatment guideline should be prioritized. PMID- 22842162 TI - Suspension of the tongue to the digastric tendon following resection of the anterior mandibular arch for oral cancer prevents postoperative tongue fall and avoids the need for tracheostomy. AB - BACKGROUND: Resection of the anterior arch of the mandible leads to tongue fall and postoperative stridor because of the detachment of tongue musculature from the mandible. In this article, a simple method of tongue suspension is described which would prevent such complications and the need for tracheostomy. SETTINGS AND DESIGN: This study was carried out on patients with oral cancer requiring resection of the anterior arch of the mandible as a part of the surgical resection at a tertiary centre. MATERIALS AND METHODS: This study was performed on 32 patients with oral cancer requiring resection of the anterior arch of the mandible as a part of the surgical resection. Following an appropriate resection of the oral cancer (including the anterior mandibular arch) and neck dissection, a silk suture is used to loop the tongue musculature on either side to the intermediate tendon of the digastric muscle. RESULT: This technique of tongue suspension was used in 32 patients who required resection of the anterior mandibular arch for oral cancer. Prophylactic tracheostomy was not performed. One patient developed stridor at extubation and required temporary tracheostomy. All other patients could be successfully extubated within 12 h of surgery and none experienced postoperative stridor or sleep apnea. One other patient required temporary tracheostomy for pulmonary toilet as he developed aspiration pneumonitis related to nasogastric feed. CONCLUSION: This simple method of tongue suspension to the digastric tendon prevents postoperative tongue fall and obviates the need for tracheostomy in most instances. PMID- 22842163 TI - Feasibility of organ-preservation strategies in head and neck cancer in developing countries. AB - BACKGROUND: Chemoradiotherapy is an established strategy for organ preservation in head-neck cancer. These protocols are associated with added toxicity and need support infrastructure. Practice setup and availability of resources vary at the community level in developing countries. AIM: To evaluate the feasibility of organ-preservation strategies in different settings in developing countries. SETTINGS AND DESIGN: Survey. MATERIALS AND METHODS: In a questionnaire-based study, questions were directed to clinicians with varied practice setups to gather information regarding infrastructure, finance, and feasibility of organ preservation protocols and their current practice trends. STATISTICAL ANALYSIS: Descriptive. RESULTS: Responses from 100 clinicians with focused practice in head neck oncology were analyzed. Sixty-one percent clinicians were practicing organ preservation for advanced head-neck cancers in their practice. However, 65% centers lacked sufficient infrastructure to support organ-preservation protocols. Forty percent patients were treated on cobalt-radiotherapy machine. Fifty-nine percent of clinicians suggested that less than third of their patients were fit to undergo chemoradiation and 67% believed that adherence to treatment protocol was observed in less than two-thirds of cases. Based on their experience 82% clinicians felt that only one-third patients requiring salvage would actually undergo treatment. The majority of the patients (68%) used personal funds for treatment and less than one-third of the patients could afford complete treatment. CONCLUSIONS: The infrastructure needed to support organ-preservation protocols varies significantly between centers in developing countries. It may not be feasible to perform organ-preservation strategies in certain centers and feasibility guidelines should be made for their judicious use in developing countries. PMID- 22842164 TI - Demographic and clinical profile of oral squamous cell carcinoma patients: a retrospective study. AB - BACKGROUND: Oral cancers are one of the ten leading cancers in the world. However, in India, it is one of the most common cancer and constitutes a major public health problem. AIM: The purpose of this study was to evaluate, retrospectively, the epidemiologic profile of patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: OSCC cases were retrospectively analyzed from January 2008 to September 2010 for age, gender, occupation, duration of the symptoms, habits (tobacco and alcohol consumption), site of primary tumor, and TNM staging, and the findings were formulated to chart the trends in central India population. RESULTS: Male to female ratio was 4.18:1. Mean age was 49.73 years. The most common site of presentation of tumor was in mandibular alveolus region. Tobacco chewing was the major cause for the development of OSCC. Maximum number of patients, i.e., 201 (68.14%) were presented within 6 months of onset of symptoms. Majority of patients were presented in Stage III (82.37%). Correlation between the two variables, i.e., site to habits, staging to site involved, staging to duration of the disease, staging to habits, and staging to age of the patient, were found to be statistically nonsignificant (P>0.05). CONCLUSIONS: The aim of the study was the demographic description of oral squamous cell carcinoma. Most of the cases report at advanced stages of the disease which often leads to delay in the management coupled with the fact that health care centers are burdened with long waiting lists. Strategies to overcome the present situation must be undertaken by oral health programs for the early diagnosis and prevention and management and follow up of oral cancer. PMID- 22842165 TI - p53 immunoprofiling of potentially malignant oral disorders: a case series analysis. AB - CONTEXT: p53 tumor suppressor gene which is a frequent target for mutations in a high percentage of oral cancer is regarded as an early event in carcinogenesis. AIM: The role of p53 was assessed in potentially malignant oral disorders (PMOD) to ascertain its prognostic significance. SETTINGS AND DESIGN: Retrospective case series analysis was carried out on 30 paraffin-embedded tissue blocks of confirmed oral leukoplakia with dysplasia. MATERIALS AND METHODS: 10 cases of each of mild, moderate, and severe dysplasia were immunohistochemically analyzed for p53 expression. The intensity of staining, intracellular localization, and basal and/or suprabasal distribution were assessed. STATISTICS: The intensity of p53 staining and its distribution were analyzed by the Chi-square test. The intracellular localization of p53 in different grades of dysplasia was subjected to one way ANOVA. P<0.05 was considered significant. RESULTS: 21/30 cases of epithelial dysplasia were positive for p53 immunopositivity. Intensity of p53 expression was strong in 12 cases and weak in 9 cases (P<0.05). p53 positivity was confined to basal cells in mild dysplasia, while severe dysplasia showed both basal and suprabasal staining (P<0.05). Nuclear and cytoplasmic staining between and within the groups were F=9.027 and F=6.465 respectively with high significance noted between mild dysplasia and severe dysplasia. CONCLUSIONS: Increased p53 expressivity and greater cellular localization with increase in the severity of dysplasia indicated a direct association between the degree of epithelial dysplasia and p53 accretion, which occurs as an early event in oral carcinogenesis. PMID- 22842166 TI - Knowledge, attitude and screening practices of general dentists concerning oral cancer in Bangalore city. AB - CONTEXT: Oral cancer presents with high mortality rates, and the likelihood of survival is remarkably better when detected early. The dental profession shares an important responsibility toward early screening, prompt referral and treatment. AIMS: The aim of the present study was to assess the oral cancer knowledge, attitude and screening practices among dental practitioners in Bangalore city. MATERIALS AND METHODS: This descriptive cross-sectional study was conducted using a 24-item self-administered questionnaire involving private dental practitioners of Bangalore city. A total of 1556 private dental practitioners of Bangalore made up the sampling frame of the study, and a sample of 250 dentists was found to be sufficient. Two hundred and fifty dentists were selected by cluster random sampling. The institutional review committee approved the study. Data were entered using SPSS 13.01. RESULTS: A total of 250 practicing dentists were approached, of which 240 participated in the study. Among the various risk factors for causing oral cancer, the use of alcohol was identified as a major risk factor by 238 (99%) dentists. The high-risk age group for oral cancer was identified as the fourth and fifth decades by 143 (59%) dentists. Adequate training for providing oral cancer examinations was acquired by 164 (68%) of the dentists. Two hundred and thirty-seven (98%) dentists strongly agreed that patients should be referred to specialists if they suspected oral cancer in any lesion. No more than 37% of the dentists routinely practiced complete oral cavity examination on all patients who attended their practice. A mere 31% of the dentists educated their patients on the adverse effects of these habits and assisted them in cessation programmes. CONCLUSIONS: These findings concerning dentists' knowledge and opinions related to oral and pharyngeal cancer suggest strongly that educational interventions for practitioners and dental students are necessary. We contend that an offering of continuing dental education programs would go a long way to enhance the prevention and early diagnosis of oral cancer. PMID- 22842167 TI - Scope of prosthodontic services for patients with head and neck cancer. AB - Patients with head and neck cancer face high morbidity due to the disease and its treatment and are affected on a variety of personal and physical levels. Maxillofacial prosthetics offer support for other disciplines in a multidisciplinary setting; can help to prevent / minimize the sequelae from disease and treatment, and offers the patient help in the rehabilitation process. Maxillofacial prosthodontics focuses on optimizing the disrupted rudimentary function of individuals whose rehabilitation will be a lifelong proposition. Normal function may not be achieved but optimal function should always be achieved and the patients can lead a near to normal life. PMID- 22842168 TI - Optimizing second-line therapy for chronic myeloid leukemia. AB - Treatment of chronic myeloid leukemia has evolved from symptom control to long term disease-free survival with cure potentially round the corner. This required faster, deeper, and longer response. Optimizing treatment decisions therefore requires clear understanding of and strict implementation of guidelines for shift from imatinib. In patients who are resistant to or intolerant of imatinib, second line TKIs have to be selected carefully. Currently available data show comparable efficacy between nilotinib and dasatinib. With a better safety profile (especially with respect to grade 3 or 4 hematologic toxicity and clinically relevant non-hematologic toxicities), nilotinib becomes the preferred choice in most instances. PMID- 22842169 TI - Locally advanced breast cancer: prevention is better than cure! PMID- 22842170 TI - Myoepithelial expression of Fas and strong nuclear expression of FasL in epithelial cells: a marker for risk stratification of breast cancer. AB - AIM: The clinical significance of Fas and FasL in hormone-sensitive carcinomas has been reported. Our objective was to evaluate the expression of apoptosis regulating genes Fas and FasL in Indian breast cancer and fibroadenoma patients in relation to hormone receptor status. STUDY DESIGN: Retrospective. MATERIALS AND METHODS: Paraffin-embedded tissue samples from 63 untreated female patients with invasive ductal carcinoma (IDC) and 32 female patients with fibroadenoma were studied. Expression of Fas and FasL was evaluated using immunohistochemical staining method. STATISTICAL ANALYSIS: Fisher's exact test and nonparametric correlation test (Spearman rank correlation test) were performed. RESULT: Fas was detected in 97% of the fibroadenomas and there was a slight decrease in levels of expression with histological grades of IDC. The expression of FasL was detected in 75% fibroadenomas and its expression increased in IDC. There was no correlation between Fas, FasL expression and hormone receptor status. Strong expression of Fas in myoepithelial cells was noted in 12 out of 32 fibroadenoma cases. CONCLUSION: Expression of Fas and FasL alone is unlikely to be important as a predictive factor as they express in both normal and malignant breast epithelium. But strong expression of Fas in myoepithelial cells along with strong nuclear expression of FasL in epithelial cells of fibroadenoma could be useful as an early predictive factor for onset of malignancy. PMID- 22842171 TI - Role of axillary sampling in the era of sentinel lymph node biopsy: a critical review. AB - Axillary lymph node dissection is the standard of care for treating and staging axilla in breast cancer. Sentinel lymph node biopsy and axillary sampling have been advocated as an alternative to axillary lymph node dissection with an added benefit of lesser morbidity. Herein, we are reviewing the role of axillary sampling in the present era of sentinel lymph node biopsy in the background of standard axillary dissection. PMID- 22842172 TI - Epidemiology of lung cancer in India: focus on the differences between non smokers and smokers: a single-centre experience. AB - CONTEXT: Lung cancer has varied epidemiology depending on the geographic region. Globally, there have been important changes in incidence trends amongst men and women, histology, and incidence in non-smokers. Indian epidemiological data on lung cancer is scarce. AIMS: We set out to study the epidemiological patterns and clinical profile of lung cancer in India. MATERIALS AND METHODS: We interviewed patients discussed in the thoracic oncology multidisciplinary meetings between 2008 and 2009. Demographic data, smoking history, place of residence, histology, stage at presentation, and treatment details were collected. Data was entered and analyzed in SPSS. RESULTS: There were 489 patients, with a median age of 56 years, of which 255 (52%) were non-smokers and 234 (48%) were smokers. One hundred and thirty-three patients had consumed smokeless tobacco. The male-to female ratio was 3.5:1. Sixty-nine patients (14.1%) were incorrectly diagnosed and treated with anti-tuberculosis treatment, which delayed the diagnosis of lung cancer by four months. Eight percent of patients had small-cell carcinoma; of the 92% patients with non-small-cell carcinoma (NSCLC), the most common histology was adenocarcinoma (43.8%), followed by squamous cell (26.2%), large cell (2.1%) and other (8.3%). Eighteen percent of patients were diagnosed by cytology, therefore were diagnosed as NSCLC, without further histologic subtyping. Most patients (43%) were in Stage III at presentation. Lung followed by bone were the common sites of metastases. The majority of the patients (49%) received palliative chemotherapy. Among definitive therapy, concurrent chemo-radiation (13%) was offered more frequently than surgery (6%). CONCLUSION: Considerably higher numbers of Indian patients with lung cancer are non-smokers, compared to the West. The global trend of rise in adenocarcinoma is paralleled in India. Non tobacco-related risk factors need further investigation. PMID- 22842173 TI - The relevance of "Nonsmoking-associated lung cancer" in India: a single-centre experience. AB - BACKGROUND: Lung cancer remains a major cause of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. AIM: The aim of this study was to analyze the clinical profile and the epidemiological trends in lung cancer patients from a single centre with an emphasis on the smoking practices. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of 258 consecutive hospital in-patients with a proven diagnosis of lung cancer at a tertiary care oncology centre between 2003 and 2007. RESULTS: The median age of patients in our study was 56 years; the male to female ratio was approximately 3.5:1. Non-small-cell lung cancer (NSCLC) was the predominant histology in 224 patients; the histology in the remaining 34 patients was small-cell carcinoma. Within NSCLC, the most common histology was adenocarcinoma followed by squamous cell carcinoma. One hundred and two patients were never-smokers as compared to 156 patients who were ever-smokers. Among the smokers, the majority of them were found to be cigarette smokers compared to 28.2% bidi smokers. There was a very significant correlation found with adenocarcinoma among nonsmokers, and with squamous cell carcinoma among the smokers compared to non-smokers. CONCLUSIONS: Our study suggests that the epidemiology of lung cancer in India is possibly changing, with close to 40% of our lung cancer patients being nonsmokers. More importantly, our study reflects the global trend of rise in adenocarcinoma histology. These observations need to be substantiated in similar studies of larger magnitude, preferably population based. PMID- 22842174 TI - Comparison study of clinicoradiological profile of primary lung cancer cases: an Eastern India experience. AB - CONTEXT: According to the first population-based cancer registry from eastern part of India, Kolkata and its surrounding areas have the highest prevalence of lung cancer in India. However, there is very limited data from this part of the country. AIMS: The aim of this study is to find out the demographic and clinicoradiological profile of primary bronchogenic carcinoma. SETTINGS AND DESIGN: This is a retrospective review of lung cancer cases diagnosed in two tertiary institutes of Kolkata over a period of 4 years. MATERIALS AND METHODS: We have reviewed the cases with proven histological or cytological diagnosis of primary bronchogenic carcinoma and chi-square test is done to calculate statistical significance. RESULTS: Out of 607 patients, male 489 and female 118, 67.7% are from rural area, 67.2% are smoker and only 9.4% are <=40 years of age. Smoking is the major risk factor for primary lung cancer (P = 0.000) but no significance could be established with the different histological subtypes (P = 0.207). Though squamous cell carcinoma (SCC) is the most predominant variety (35.1%), adenocarcinoma and undifferentiated type are overrepresented in <=40 years. SCC occurs at a significantly higher age group (60.84 +/- 12.16 years) than other subtypes (P = 0.000). At least 55.2% cases of nonsmall cell lung cancer and 54% of small cell lung cancer presented in very advanced stage. CONCLUSIONS: SCC is the most common histological subtype of primary bronchogenic carcinoma. The relatively increased frequency of adenocarcinoma in our study as compared to other studies from India is probably due to higher proportion of nonsmokers. PMID- 22842175 TI - Analysis of the perioperative and five-year oncological outcome of two hundred cases of open radical cystectomy: a single center experience. AB - OBJECTIVES: We prospectively evaluated our perioperative and five-year oncological results of 200 cases of open radical cystectomy with urinary diversion, for formulating contemporary benchmarks, for future comparison of minimally invasive techniques. This is one of the largest prospective series reported from India of open radical cystectomy. MATERIALS AND METHODS: Between 2004 and 2009, patients undergoing open radical cystectomy with urinary diversion, at our institution, were prospectively enrolled in the study. Data were recorded and analyzed statistically. RESULTS: Two hundred patients were enrolled in the study. The mean age was 65.1 years. The patients undergoing ileal conduit and orthotopic neobladder were 159 (79.5%) and 41 (20.5%), respectively. The mean operating time was 275 minutes. The mean operating time for ileal conduit and orthotopic neobladder were 262 minutes and 288 minutes, respectively. The mean estimated blood loss was 690 ml. Blood transfusion was required in 37 (18.5%) patients. The mean hospital stay was 6.1 days. Major and minor complications were recorded in 16 (8%) and 31 (15.5%) patients, respectively. Perioperative mortality was recorded in only two (1.5%) patients. The pathologically organ-confined and non-organ-confined cases were 135 (67.5%) and 65 (32.5%), respectively. Thirty-three (16.5%) patients had pathologically confirmed lymph nodes. Median follow-up was 60.1 months. Local recurrence and distant metastases were recorded in 16 (8%) and nine (4.5%) patients, respectively. A five-year disease-free survival, cancer-specific survival, and overall survival were 75.5, 71.5, and 63.5%, respectively. CONCLUSIONS: Open radical cystectomy has an acceptable perioperative morbidity and mortality, along with a favorable five-year oncological efficacy. Minimally invasive techniques need a long-term prospective comparison with this approach, before being accepted as a standard treatment for urinary bladder malignancy. PMID- 22842176 TI - Port site metastasis after laparoscopic radical nephrectomy: a single-center experience. AB - OBJECTIVE: To assess the incidence and review the probable etiologies of port site recurrence in patients undergoing laparoscopic radical nephrectomy. MATERIALS AND METHODS: One hundred thirty-six patients undergoing laparoscopic surgeries for renal malignancy, including 133 radical nephrectomies and 3 partial nephrectomies, from December 1999 to December 2008 at our institution were followed up for a median period of 59 months (12-120 months). Of the procedures, 121 were performed by transperitoneal, 5 by retroperitoneal and 10 by combined approach (retroperitoneal renal artery clipping followed by transperitoneal nephrectomy). Formal lymphadenectomy was not performed. Postoperative surveillance after radical nephrectomy included history and physical examination with blood tests 3-6 monthly, chest X-ray yearly and abdominal contrast-enhanced computed tomography (CECT) 1-2 yearly. The development of port site recurrence was diagnosed by physical examination, CECT and pathological findings. RESULTS: Conversion to open surgery was done in 33 patients. Two (1.47% overall) port site recurrences were observed, both after radical nephrectomies done for renal masses with clinical stages T2N0M0 and TIN0M0. The pathological staging in the two were T2N1M0 Fuhrman's Grade III and T3aN1M0 Grade III, respectively. CONCLUSION: Our results report that laparoscopic approach does not necessarily increase the risk of port site recurrence, provided the cases are carefully chosen, principles of oncologic surgery are followed, and conditions that increase the risk of port site metastasis are avoided. PMID- 22842177 TI - A randomized comparative trial evaluating the safety and efficacy of liposomal amphotericin B (Fungisome) versus conventional amphotericin B in the empirical treatment of febrile neutropenia in India. AB - BACKGROUND: In patients with persistent fever and netropenia, amphotericin B is administered empirically for early treatment and prevention of systemic fungal infections. Despite this treatment, there are chances of breakthrough fungal infections and drug is also toxic. MATERIALS AND METHODS: A multicentric, randomized, controlled clinical trial was conducted to compare liposomal amphotericin B two doses with conventional amphotericin B as empirical antifungal therapy. RESULTS: The average body weight of patients was 26.4 +/- 14.8 (n=22), 32.9 +/- 19.4 (n=23) and 37.9 +/- 20.0 (n=20) kg in 1 mg, 3 mg Fungisome (liposomal amphotericin B) and 1 mg/kg/day conventional amphotericin B group, respectively. The mean age was 16.2 +/- 13.4, 16.0 +/- 10.9 and 22.7 +/- 16.2 yrs in 1 and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional AMP B group, respectively. The average duration of treatment with 1 mg and 3 mg/kg/day Fungisome and 1 mg/kg/day conventional amphotericin B was 17 +/- 9.8, 16.2 +/- 8.3, and 14.7 +/- 10.7 days, respectively. The time to resolve fever was 13.3 +/- 10.2, 10.9 +/- 7.1, 10.1 +/- 6.7 days, and for absolute neutrophil count (ANC) to be above 500 cells per microliter, it took 13.4 +/- 9.6, 10.6 +/- 7.6 and 7.3 +/- 3.4 days, respectively. Liposomal formulations were well-tolerated compared to conventional amphotericin B. CONCLUSIONS: This small randomized study showed that the indigenous liposomal formulation Fungisome appears to be equally efficacious and safer than conventional amphotericin B. Also, the lower dose Fungisome (1 mg/kg/day) appears to be equally efficacious and was well-tolerated as compared to higher dose Fungisome (3 mg/kg/day). Treatment cost would be a major factor for limiting use of higher dose of Fungisome. PMID- 22842178 TI - Totally implantable venous access ports: retrospective review of long-term complications in 81 patients. AB - AIM OF THE STUDY: A totally implantable venous access port (TIVAP) has become an essential prerequisite for many chemotherapy protocols. It is serving its purpose very well, but its use is not without complications. We are presenting our experience with these devices (TIVAPs). SUBJECTS AND METHODS: We retrospectively reviewed the totally implantable venous access ports in 81 patients at our hospital between January 2009 and March 2011 for long-term problems which include postoperative and follow-up problems, excluding the immediate complications which occur at the time of insertion. RESULTS: Catheter malfunction was the most common complication (9.87%, 0.40/1000 device-days of use/observation). Catheter-related bloodstream infections were present in 5 (6.17%) patients (0.25/1000 device-days of use/observation). The mean life of the catheter was 246 days. Only 11.1% ports required removal during the treatment period. Overall, patients either completed treatment (82.8%) or died (6.1%) while receiving treatment. CONCLUSION: TIVAPs provide safe and reliable vascular access for patients on chemotherapy but require utmost care by a dedicated team of trained medical professionals and paramedics experienced with the use of such ports, in order to minimize the complications and their continued use while administering treatment. PMID- 22842179 TI - Pulmonary embolism in cancer patients. AB - AIMS AND OBJECTIVES: Pulmonary embolism (PE) is rare in the Indian population and is under-reported in patients with malignancy. We studied the clinical profile and outcome of patients with PE and cancer in the Indian population. MATERIALS AND METHODS: Data of cancer patients with PE, admitted in a tertiary cancer centre, was analyzed. The prevalence of PE was calculated as the number of patients with PE per 10,000 hospital admissions. The demographic data, details of cancer, co-morbidities, details of PE, and treatment given for PE and their outcomes were recorded and analyzed. RESULTS: There were 56,425 hospital admissions in the study period. The prevalence of PE was 6.4 per 10,000 hospital admissions .Thirty-six cancer patients were diagnosed to have PE. In females, gynecological malignancies (36.84%) and in males gastrointestinal, head and neck cancers, and hematological malignancies were the most common sites (17.7% each). PE was associated with DVT in 41.7%. Dyspnea was the most common presenting symptom. Five patients (13.88%) were asymptomatic and were incidentally detected to have PE . The most common echocardiographic finding was right ventricular dysfunction (55.55%). Mortality among the treated patients was 22% (7 / 31) and in untreated patients it was 80% (4 / 5). The factors that had an impact on a three-month survival were, the presence of massive PE (P = 0.019) and the presence of RV dysfunction at presentation (P = 0.005). CONCLUSION: The prevalence of PE and mortality due to PE is high in cancer patients. Risk stratification for venous thromboembolism (VTE) should be done in all cancer patients and thromboprophylaxis should be optimally used. PMID- 22842180 TI - The liver function test enzymes and glucose level are positively correlated in gallbladder cancer: a cancer registry data analysis from north central India. AB - AIM OF STUDY: To investigate the trend of expression of liver function test enzymes and other biochemical changes during gallbladder carcinogenesis. MATERIALS AND METHODS: Eight hundred and seventy-eight gallbladder disease patients were selected to study the liver function test enzymes and routine blood biochemical changes in the last five years (2004-08). Statistical analysis was performed using Graph Pad prism 5.02 software. RESULTS: The liver function test enzymes showed significant correlations among themselves, and with glucose in gallbladder cancer and gallstone disease patients (N = 878). Out of 878 gallbladder cases, 46 (5.24%) showed significantly higher glucose level of 216.66 mg/dL (P < 0.0001). All the three pathological conditions of gallbladder, gallbladder cancer with stones (GBCS), gallbladder cancer without stones (GBC) and calculus cholecystitis (CC), showed highly significant positive correlation (Pearson) between Serum Glutamic Oxaloactetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT) [P < 0.0001, (GBCS); P < 0.0001, (GBC), and P < 0.0001, (CC)]. SGOT and SGPT also showed positive correlation with higher glucose level independently, in both GBCS and CC (P < 0.0001 and P < 0.0001), respectively. CONCLUSION: Simultaneous elevation of glucose and liver function test enzymes in GBC makes the diagnosis complex. Any patient of gallbladder diseases with higher level of glucose may have the possibility of developing gallbladder cancer. PMID- 22842181 TI - Recent advances in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) was largely considered to be a disease of slow progression, standard treatment with Chlorambucil and having almost similar prognosis. With the introduction of molecular methods for understanding the disease pathophysiology in CLL there has been a remarkable change in the approach towards the disease. The variation in B-cell receptor response and immunoglobulin heavy chain variable region (IGHV) mutation, genetic aberration and defect in apoptosis and proliferation has had an impact on therapy initiation and prognosis. Early diagnosis of molecular variant is therefore necessary in CLL. PMID- 22842182 TI - Indian studies on genetic polymorphisms and cancer risk. AB - Genetic influences on cancer development have been extensively investigated during the last decade following publication of human genome sequence. The present review summarizes case-control studies on genetic polymorphisms and cancer risk in Indians. It is observed that the most commonly studied genes in the Indian population included members of phase I and phase II metabolic enzymes. Other than these genes, genetic polymorphisms for cell cycle and apoptosis related factors, DNA repair enzymes, immune response elements, growth factors, folate metabolizing enzymes, vitamin/hormone receptors, etc., were investigated. Several studies also evidenced a stronger risk for combined genotypes rather than a single polymorphism. Gene-environment interaction was also found to be a determining factor for cancer development in some experiments. Data for single polymorphism and single cancer type, however, was insufficient to validate an association. It appears that much more experiments involving larger sample size, cross-tabulating genetic polymorphisms and environmental factors are required in order to identify genetic markers for different cancers in Indian populations. PMID- 22842183 TI - The frequency and spectrum of K-ras mutations among Iraqi patients with sporadic colorectal carcinoma. AB - BACKGROUND: The epidemiology of colorectal cancers (CRC) is well known to differ in different geographical regions. K-ras mutations have been implicated in CRC carcinogenesis and they were extensively studied in developed countries; however, such studies are scarce from developing countries, like Iraq. AIM: To determine the frequency and spectrum of K-ras mutations among CRC Iraqi patients, and their clinico-pathological associations, if any. MATERIALS AND METHODS: Fifty consecutive surgically resected sporadic CRC were evaluated. The evaluation included screening for ten K-ras mutations in codon 12 and 13 by mutant enriched polymerase chain reaction followed by reverse hybridization to oligospecific probes. RESULTS: Out of the 50 enrolled patients, 24 (48%) had K-ras mutations. A total of 29 mutations were identified in the tumors of the latter 24 patients (20/24 tumors had single mutations, 3/24 had double mutations and 1/24 had triple mutations). The most frequently encountered mutations were the G>T transversions and G>A transitions (41.4% each). Codon 12 mutations constituted 89.7%, while codon 13 the remaining 10.3%. The most frequent mutation was GGT>GTT (Gly>Val) of codon 12 documented in 31%. No significant clinico-pathological correlations with K-ras mutational status were identified. CONCLUSION: The K-ras mutations are frequently encountered among Iraqi sporadic CRC patients, with relative higher frequencies of G>T transversions and Gly>Val codon 12 substitutions than encountered in their counterparts in developed countries. The latter is most likely to be related to differences in local carcinogens exposure, an aspect which requires further scrutiny. PMID- 22842184 TI - Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: a Phase II study. AB - AIM: The aim of this Phase II study was to evaluate the activity and safety of biweekly pegylated liposomal doxorubicin (PLD) and oxaliplatin (L-OHP) in patients with platinum-taxane resistant ovarian cancer. MATERIALS AND METHODS: Treatment consisted of PLD (20 mg/m2) on Day 1; and L-OHP (50 mg/m2) administered on Days 1 and 2, every two weeks. Response to therapy was assessed using the Response Evaluation Criteria in Solid Tumors RECIST ; toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria. RESULTS: Forty patients pretreated with platinum/taxane chemotherapy, with a median age of 61 years, were recruited for the study. Thirty-eight patients were available for response evaluation: three complete responses and nine partial responses were registered; resulting in an overall response rate of 31.5%. Twenty-eight patients gained clinical benefit (73.7%) from this chemotherapy regimen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 10 months respectively. The hematological and non-hematological toxicity profile was favorable. No Grade 4 toxicity was observed. Major toxicities included Grade 3 neutropenia (13.2%), Grade 2 palmar-plantar erythrodysesthesia (7.9%), and Grade 1-2 neuropathy in 15.8% of patients. CONCLUSION: Biweekly PLD and L-OHP combination has high activity, with less than anticipated adverse toxicity, for treatment of platinum resistant ovarian cancer. A comparison of the doublet PLD/L-OHP with single-agent treatment is warranted. PMID- 22842185 TI - Spectrum of malignancies among HIV-infected patients in South India. AB - INTRODUCTION: The current study examines the spectrum of malignancies among HIV infected South Indians enrolled in a clinical care program. MATERIALS AND METHODS: We conducted a nested matched case-control study among 42 HIV-infected cases who developed cancer and 82 HIV-infected controls between 1998 and 2008 at a tertiary care HIV care program in South India. RESULTS: The most common types of cancer included non-Hodgkin's lymphoma (38.1%), Hodgkin's lymphoma (16.7%), squamous cell carcinoma (14.3%), and adenocarcinoma (14.3%). The median duration of time from HIV infection to cancer diagnosis was 549 days [interquartile range (IQR): 58-2013]. The nadir CD4 cell count was significantly lower in cases compared to controls (134 cells/MUl vs. 169 cells/MUl; P = 0.015). Cancer patients were more likely to have a more advanced HIV disease stage at the time of cancer diagnosis compared to control patients (Stage C: 90.5% vs. 49.4%; P<0.0001). Significantly more cancer patients were receiving antiretroviral treatment relative to control patients at the time of cancer diagnosis (92.9% vs. 66.3%; P=0.001). CONCLUSIONS: HIV-infected patients who developed cancer had more advanced immunodeficiency at the time of cancer diagnosis and a lower nadir CD4 cell count. It is possible that with the continued roll-out of highly active antiretroviral therapy in India, the incidence of HIV-associated malignancies will decrease. PMID- 22842186 TI - In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines. AB - BACKGROUND: Actin cytoskeleton is involved in actin-based cell adhesion, cell motility, and matrix metalloproteinases(MMPs) MMP2, MMP9, MMP11 and MMP14 are responsible for cell invasion in breast cancer metastasis. The dietary intake of lignan from flax seed gets converted to enterolactone (EL) and enterodiol in the human system. Here we show that the enterolactone has a very significant anti metastatic activity as demonstrated by its ability to inhibit adhesion and invasion and migration in MCF-7 and MDA MB231 cell lines. MATERIALS AND METHODS: Migration inhibition assay, actin-based cell motility assay along with reverse transcriptase polymerase chain reaction (RT-PCR) for MMP2, MMP9, MMP11 and MMP14 genes were performed in MCF-7 and MDA MB 231 cell lines. RESULTS: Enterolactone seems to inhibit actin-based cell motility as evidenced by confocal imaging and photo documentation of cell migration assay. The results are supported by the observation that the enterolactone in vitro significantly down-regulates the metastasis-related metalloproteinases MMP2, MMP9 and MMP14 gene expressions. No significant alteration in the MMP11 gene expression was found. CONCLUSIONS: Therefore we suggest that the anti-metastatic activity of EL is attributed to its ability to inhibit cell adhesion, cell invasion and cell motility. EL affects normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby inhibits actin-based cell adhesion and cell motility. The process involves multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction. By down regulating the metastasis-related MMP2, MMP9 and MMP14 gene expressions, EL may be responsible for cell invasion step of metastasis. PMID- 22842187 TI - Pheochromocytoma in Indian patients: a retrospective study. AB - AIM: To review the clinical experience on pheochromocytoma in Indian subset of patients. MATERIALS AND METHODS: Ten patients diagnosed with pheochromocytoma between 2001 and 2010 at our institute were retrospectively studied for clinical, laboratory, radiological and surgical data. RESULTS: A total of 10 patients (5 females and 5 males) aged between 23 and 64 years diagnosed as pheochromocytoma were managed at our institute. The most frequent symptoms were abdominal pain (90%) and hypertension (50%). The tumor was intra-adrenal in 70% and extra adrenal in 30%. 20% were on right side and 50% on left side. CT scan of abdomen was the most widely used method for tumor localization. Among laboratory assays, 24-h urinary vanillylmandelic acid (VMA) was the most widely used. None of our patients were found to be associated with hereditary pheochromocytoma syndrome. All hypertensive patients were preoperatively treated with phenoxybenzamine and propranolol. All underwent explorative laparotomy and adrenelectomy. Malignancy was reported in 40% of cases and these received adjuvant radiotherapy. Among hypertensive patients, surgery caused remission of hypertension in 60%. All patients were followed up with 24-h urinary VMA levels and CT scan of abdomen regularly. Survival ranged from 1 to 9 years. CONCLUSIONS: The present study confirms that the clinical presentation of pheochromocytoma is variable and non specific. Often the tumor is discovered incidentally. Though pheochromocytoma is a rare tumor, proper evaluation, preoperative preparation and complete surgical excision are important for its management. PMID- 22842188 TI - Metastasis in the choroid due to parotid malignancy. PMID- 22842189 TI - Interaction between Tbx1 and Hoxd10 and connection with TGFbeta-BMP signal pathway during kidney development. AB - Renal malformations are commonly found among patients carrying a 22q11 deletion which renders loss of Tbx1 gene, an important transcriptional factor implicated in a number of developmental processes. Smad1 is known to interact with Tbx1, but the exact mechanism remains unknown. In this study, we have measured the expression of Tbx1 in both murine and human tissues using RT-PCR, and analyzed its protein product and protein-protein interactions with Western blotting and immunoprecipitation assays. Precipitated proteins were verified with mass spectrometry. As discovered, Tbx1 binds with Hoxd10. Tbx1 and Hoxd10 genes also have similar expression profiles during murine kidney development. Based on homology between mouse and human, we hypothesized that such interaction also exists in human. Through a RNA interference experiment using a human embryonic kidney HEK293 cell line, we demonstrated that TBX1 can alter TGF-beta/BMP, an important signaling pathway, through interacting with HOXD10. Above findings may shed light on the mechanism of TBX1 mutations leading to renal malformations found in patients carrying a 22q11 deletion. PMID- 22842190 TI - Interleukin-28B polymorphisms on the SVR in the treatment of naive chronic hepatitis C with pegylated interferon-alpha plus ribavirin: a meta-analysis. AB - There are accurate but inconclusive data on the association between single nucleotide polymorphisms (SNPs) of interleukin (IL)-28B and sustained virological response (SVR) in chronic hepatitis C (CHC). This meta-analysis aimed to derive a more precise estimation of the effects of IL-28B SNPs locus (rs12979860 and rs8099917) on SVR in naive CHC patients receiving pegylated interferon alpha (PEG IFN-alpha) plus ribavirin. Literature search was conducted up to June, 2011, in PubMed, EMBASE and Cochrane Database of Systematic Reviews. A total of 36 studies involving 10912 cases with CHC receiving PEG-IFN-alpha plus ribavirin met the inclusion criteria. Analyses were stratified either by ethnicity or genotype of hepatitis C virus. In genotype 1/4 patients, rs12979860 CC was associated with high SVR in CHC patients (Caucasian: odds ratio (OR), 4.567; 95% confidence interval (CI), 3.826-5.452; Asian: OR, 4.033; 95%CI, 3.050-5.333; African American: OR, 4.297; 95%CI, 2.168-8.515; Hispanics: OR, 4.350; 95%CI, 2.817 6.717) but had no effect in genotype 2/3. In Caucasian (genotype 1/4: OR, 2.542; 95%CI, 2.108-3.065; genotype 2/3: OR, 1.363; 95%CI, 1.020-1.820) and Asian (genotype 1/4: OR, 5.214; 95%CI, 3.694-7.360; genotype 2/3: OR, 1.785; 95%CI, 1.095-2.910), rs8099917 TT was associated with high SVR in both genotype 1/4 and 2/3. Meta-regression showed that in Caucasians with CHC genotype 1/4, gender male might contribute to the effect of rs12979860 on SVR but advanced fibrosis might weaken this effect. Furthermore, in Asians with CHC genotype 1/4, high baseline viral load and advanced fibrosis might also undermine the effect of rs8099917 on SVR. This meta-analysis suggested that IL-28B rs12979860 CC and rs8099917 TT were associated with high SVR rate in CHC genotype 1/4. In CHC genotype 2/3, rs8099917 TT carriers also had higher SVR. PMID- 22842191 TI - 15q11.2 microdeletion and FMR1 premutation in a family with intellectual disabilities and autism. AB - Genomic rearrangements of chromosome 15q11-q13 are responsible for diverse phenotypes including intellectual disabilities and autism. 15q11.2 deletion, implicating common PWS/AS breakpoints BP1-BP2, has been described in patients with delayed motor and speech development and behavioural problems. Here we report the clinical and molecular characterisation of a maternally inherited BP1 BP2 deletion in two siblings with intellectual, motor and speech delay, autistic syndrome disorder and several dysmorphic features. One of the patients was also a carrier of an FMR1 allele in the low premutation range. The four genes within the deletion were under-expressed in all deletion carriers but FMR1 mRNA levels remained normal. Our results suggest that BP1-BP2 deletion could be considered as a risk factor for neuropsychological phenotypes and that it presents with variable clinical expressivity. PMID- 22842192 TI - The modifying effects of fish oil on fasting ghrelin mRNA expression in weaned rats. AB - Ghrelin expression and secretion seem to be influenced by the fat content of the diet. However, data on the probable adverse effect of high fat diet (HFD) with different dietary fats and saturation level of fatty acids is inconclusive. This study aimed at investigating the effects of HFDs on fasting total and acyl ghrelin plasma levels, gastric fundus and duodenum ghrelin mRNA expressions. Weaned Wistar rats (n=50) were randomly divided to five groups of HFDs with fish oil (HF-F), olive oil (HF-O), soy oil (HF-S), butter (HF-B) and the controls. After 8 weeks, blood samples were collected. While the animals were fasting for 24h, their blood and tissue samples were obtained. Plasma parameters of total and acyl ghrelin and ghrelin mRNA expression level in stomach and duodenum were measured. The HF-B fed group had lower fasting plasma acyl ghrelin level than the control, HF-F and HF-O groups (P<0.05); furthermore, the HF-F group had significantly higher acyl ghrelin level than the HF-S one (P<0.05). After feeding, all the groups, except for the HF-B one, had a significantly lower plasma acyl ghrelin levels (P<0.05), compared with the fasting state. Ghrelin mRNA expression levels in the gastric fundus and duodenum were significantly lower in the HF-B as compared to the control group. Furthermore, the HF-F group had significantly higher mRNA level in the duodenum, in comparison with the HF-B and HF-S groups. As HF-F and HF-O diets had the highest stimulatory effect on fasting ghrelin expression and plasma level, consumption of these dietary oils can play an important role in ghrelin regulation, which might affect feeding behavior and energy intake. PMID- 22842193 TI - High expression of miR-210 predicts poor survival in patients with breast cancer: a meta-analysis. AB - BACKGROUND: Many microRNAs (miRNAs) exhibit altered expression levels in cancers, and they may be considered as valuable prognostic biomarkers for cancers. Here we aimed to summarize the recent advances in miR-210 involvement in human breast cancer and analyze the predicting role of miR-210 for survival. METHODS: A meta analysis was performed by searching PubMed, Cochrane Library, and Science Direct databases. Data were extracted from studies comparing survival in patients with breast cancer having higher expression of miR-210 with those having lower expression. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. RESULTS: A total of 511 cases of breast cancer were involved for this global meta-analysis. For post-operational survival, the HR of higher miR-210 expression in breast cancer tissue was 3.39 (95% CI: 2.04-5.63, P<0.05), which could significantly predict poorer survival. CONCLUSIONS: High expression of miR 210 might predict poor survival in patients with breast cancer. PMID- 22842194 TI - Understanding the importance of the aromatic amino-acid residues as hot-spots. AB - Protein-protein interactions (PPI) are crucial for the establishment of life. However, its basic principles are still elusive and the recognition process is yet to be understood. It is important to look at the biomolecular structural space as a whole, in order to understand the principles behind conformation function relationships. Since the application of an alanine scanning mutagenesis (ASM) study to the growth hormone it was demonstrated that only a small subset of residues at a protein-protein interface is essential for binding - the hot-spots (HS). Aromatic residues are some of the most typical HS at a protein-protein interface. To investigate the structural role of the interfacial aromatic residues in protein-protein interactions, we performed Molecular Dynamic (MD) simulations of protein-protein complexes in a water environment and calculated a variety of physical-chemical characteristics. ASM studies of single residues and of dimers or high-order clusters were performed to check for cooperativity within aromatic residues. Major differences were found between the behavior of non-HS aromatic residues and HS aromatic residues that can be used to design drugs to block the critical interactions or to predict major interactions at protein protein complexes. PMID- 22842195 TI - Isolation, functional characterization and crystallization of Aq_1259, an outer membrane protein with porin features, from Aquifex aeolicus. AB - The "hypothetical protein" Aq_1259 was identified by mass spectrometry and purified from native membranes of Aquifex aeolicus. It is a 49.4kDa protein, highly homologous (>52% identity) to several conserved hypothetical proteins from other bacteria. However, none of these proteins has been characterized using biochemical or electrophysiological techniques. Based on the sequence and circular dichroism spectroscopy, the structure of Aq_1259 is predicted to be a beta-barrel with 16 beta-strands. The strands with loops and turns are distributed evenly through the entire sequence. The function of Aq_1259 was analyzed after incorporation into a lipid bilayer. Electrophysiological measurements revealed a pore that has a basic stationary conductance of 0.48 +/- 0.038nS in a buffer with 0.5M NaH2PO4 at pH 6.5 and 0.2 +/- 0.015nS in a buffer with 0.5M NaCl at pH 6.5. Superimposed on this is a fluctuating conductance of similar amplitude. Aq_1259 could be crystallized. The crystals diffract to a resolution of 3.4A and belong to space group I222 with cell dimensions of a=138.3A, b=144.6A, c=151.8A. PMID- 22842197 TI - Learning in fully recurrent neural networks by approaching tangent planes to constraint surfaces. AB - In this paper we present a new variant of the online real time recurrent learning algorithm proposed by Williams and Zipser (1989). Whilst the original algorithm utilises gradient information to guide the search towards the minimum training error, it is very slow in most applications and often gets stuck in local minima of the search space. It is also sensitive to the choice of learning rate and requires careful tuning. The new variant adjusts weights by moving to the tangent planes to constraint surfaces. It is simple to implement and requires no parameters to be set manually. Experimental results show that this new algorithm gives significantly faster convergence whilst avoiding problems like local minima. PMID- 22842196 TI - Vaccination against encapsulated bacteria in hereditary C2 deficiency results in antibody response and opsonization due to antibody-dependent complement activation. AB - Hereditary C2 deficiency (C2D) is an important susceptibility factor for invasive infections caused by encapsulated bacteria such as pneumococci and Haemophilus influenzae type b. The infections are mostly seen in childhood indicating that antibody-mediated acquired immunity is affected. C2D persons and healthy controls were vaccinated with ActHIB(r) and Pneumo23(r). Analysis of specific antibodies to pneumococci serotype 6B, 7F, and 23F, and Hib was performed. Post-vaccination IgG antibodies against pneumococci serotype 6B and 23F at a concentration >=1.0mg/L was found in similar frequency in C2D persons and controls. Post vaccination sera from C2D persons showed poor complement-mediated opsonization and phagocytosis of pneumococci by granulocytes when depending on classical and lectin pathway activation only, but increased (p=0.007) and equaled that of the normal controls when also alternative pathway activation was allowed due to antibody-dependent C2 bypass activation. In conclusion, the C2D persons benefited from the vaccination and achieve an increased phagocytic capacity. PMID- 22842198 TI - Relationship between growth of the preovulatory follicle and its steroidogenic activity on the onset and expression of estrus behavior in CIDR-treated Bos indicus cows: an observational study. AB - Estrus synchronization induces cows to gather in sexually active groups (SAGs) composed of females displaying mounting activity. Although this technique promotes the enhancement of sexual behavior, there are cows in estrus (CE) that delay estrus expression and also cows not displaying estrus (CNDE) even in the presence of a preovulatory follicle (PF). To elucidate the physiological mechanisms of the delay in the onset of estrus or absence of estrus behavior, an observational study was undertaken in 17 Bos indicus cows treated with exogenous progesterone (CIDR) to synchronize estrus and to monitor follicular growth and its steroidogenic activity. After SAGs formation, cows were ovariectomized at 24, 48, and 72 h post-CIDR. Among ovariectomized groups there were only 9 CE which: 1) showed differences in the onset of estrus; 2) displayed distinctive follicular growth patterns; and 3) at 72 h produced the highest intrafollicular estradiol concentration, and showed a linear trend to increase expression of P450scc and P450arom. Comparison of CE vs. CNDE showed that: 1) both groups had progesterone levels indicative of cyclic activity, and a PF which grew at a similar rate and size; 2) CE showed a stronger association between time and growth; and 3) CE produced more intrafollicular estradiol and progesterone, together with the expression of higher levels of P450arom. Results suggest that pending on the pattern of growth of the PF and its steroidogenic potential to produce estradiol, the onset and expression of estrus behavior may be delayed probably until the establishment of the appropriate conditions to ensure ovulation. PMID- 22842199 TI - Does the characteristic value of the discontinuity of the isotropic-mesophase transition in n-cyanobiphenyls exist? AB - Results of the extended Landau-de Gennes model analysis and experimental studies of the isotropic-nematic (I-N) and isotropic-smectic-A (I-SmA) phase transitions in rod-like liquid crystalline n-alkylcyanobiphenyls are presented. Experiments were carried out as a function of temperature and pressure using the static dielectric permittivity and its 'nonlinear' (strong electric field related) counterpart-the low-frequency nonlinear dielectric effect. Precise estimations of the values of the discontinuity of the isotropic-mesophase transitions (DeltaT) for nCB from n = 3-14 have been obtained. It is suggested that for each nCB a unique, characteristic minimal value of DeltaT, associated with the I-N-SmA triple point, exists. For 'shorter' nCBs it can be hidden in the negative pressures domain. The possibility of the extension of the 'melting curve' into the negative pressures region as well as the appearance of the 'melting inversion' at high enough pressures is indicated. PMID- 22842200 TI - Osteoarthritis year 2012 in review: biomarkers. AB - PURPOSE: Biomarkers provide useful diagnostic information by detecting cartilage degradation in osteoarthritis (OA), reflecting disease-relevant biological activity and predicting the course of disease progression. They also serve as surrogate endpoints in the drug discovery process. The aim of this narrative review was to focus on OA biomarker-related papers published between the osteoarthritis research society international (OARSI) 2011 meeting in San Diego and the OARSI 2012 meeting in Barcelona. METHODS: The PubMed/MEDLINE and SciVerse Scopus bibliographic databases were searched using the keywords: 'biomarker' and 'osteoarthritis' and/or 'biomarker' and 'proteomics'. RESULTS: Ninety-eight papers were found with the keywords 'biomarker' and 'osteoarthritis'. Fifteen papers were found with the keywords 'biomarker' and 'proteomics'. Review articles were also included. The most relevant published studies focused on extracellular matrix (ECM) molecules in body fluids. Enrichment of the deamidated epitope of cartilage oligomeric matrix protein (D-COMP) suggests that OA disease progression is associated with post-translational modifications that may show specificity for particular joint sites. Fibulin-3 peptides (Fib3-1 and Fib3-2) have been proposed as potential biomarkers of OA along with follistatin-like protein 1 (FSTL1), a new serum biomarker with the capacity to reflect the severity of joint damage. The 'membrane attack complex' (MAC) component of complement has also been implicated in OA. CONCLUSION: Novel OA biomarkers are needed for sub-clinical disease diagnosis. Proteomic techniques are beginning to yield useful data and deliver new OA biomarkers in serum and urine. Combining biochemical markers with tissue and cell imaging techniques and bioinformatics (i.e., machine learning, clustering, data visualization) may facilitate the development of biomarker combinations enabling earlier detection of OA. PMID- 22842201 TI - The effect of staining solutions on the color stability of provisional prosthodontic materials. AB - OBJECTIVES: The aim of this study was to evaluate the effects of staining solutions on the color stability of self-cure provisional resin materials. METHODS: The specimens were prepared for each of three auto-polymerized bis-acryl resin and auto-polymerized methyl methacrylate provisional resin material. The baseline color values were measured with a colorimeter according to the CIE L(*)a(*)b(*) color scale. After the first measurement (T(0)), specimens were placed in staining solutions (coffee, coca-cola, burn and distilled water for control group) and the other measurements were taken after 24h (T(1)), 1 week (T(2)) and 4 weeks (T(3)). RESULTS: Data were analyze statistically by (a) repeated measures (ANOVA), (b) one and two way ANOVA, and (c) Tukey HSD multiple comparison tests. At the 24h immersion period, the post hoc analysis indicated that AccessCrown-coffee revealed the highest DeltaE(*) values (4.4). At the second immersion period (1 week), Structur2 SC-coffee had the highest DeltaE(*) values compared with other materials (5.4). CONCLUSIONS: The degrees of discoloration were increased with immersion time. The methylmethacrylate resin was more resistant to discoloration than bis-acryl resins. After immersion for 30 days, the coffee solution resulted in unacceptable discoloration for all the tested materials. PMID- 22842202 TI - Parental influence and the development of dental caries in children aged 0-6 years: a systematic review of the literature. AB - OBJECTIVE: A well established body of research documents the role of individual factors, such as biology and diet, in the aetiology of early childhood caries (ECC). Recently empirical attention has shifted to the relationships between broader ecological influences (e.g., education, ethnicity and income) and ECC; however, how such determinants interplay in the aetiology of ECC remains unclear. An intermediary mechanism that warrants greater empirical attention is parental influences. This oversight is interesting given the primacy of the parent in governing the child's proximate environment and the likelihood of the child endorsing adaptive or maladaptive health attitudes, beliefs and behaviours. The objective of this paper was to conduct a systematic review of the evidence for parental influences on the development of caries in children aged 0-6 years. DATA: All studies testing associations between dental caries and socio demographic factors, feeding practices, parent attributes, behaviours, oral health, attitudes, knowledge and beliefs in children aged 0-6 years, published between 2006 and 2011. SOURCE: Medline, ISI, Cochrane, Scopus, Global Health and CINAHL databases. STUDY SELECTION: Fifty-five studies were included from an initial identification of 1805 studies. CONCLUSIONS: To date, most research has focused on the association between caries and socio-demographic and feeding factors with few studies exploring parents' attributes, attitudes, knowledge and beliefs, and none exploring possible pathways between the multiple layers of influences potentially accounting for how determinants of ECC operate and traverse individual, familial, community, and socio-cultural contexts. Collaboration between Psychologists and Dentists may accelerate the identification and understanding of mechanisms that underlie risk associated with ECC. PMID- 22842204 TI - Neurological picture. Acquired ocular motor apraxia due to bifrontal haemorrhages. PMID- 22842203 TI - Population based study on patients with traumatic brain injury suggests increased risk of dementia. AB - OBJECTIVE: The relationship between traumatic brain injury (TBI) and the risk of dementia remains controversial. This population based study was designed to estimate and compare the risk of dementia in TBI and non-TBI individuals during the 5 year period after TBI. METHODS: This study was a retrospective cohort study. Data were obtained from the Longitudinal Health Insurance Database 2000. We included 44,925 patients receiving ambulatory or hospital care and 224,625 non TBI patients; patients were matched for sex, age and year of index use of healthcare. Patients <15 years of age and those admitted to the intensive care unit were excluded. Each individual was studied for 5 years to identify the subsequent development of dementia. Data were analysed by Cox proportional hazard regression. RESULTS: During the 5 year follow-up period, 1196 TBI (2.66%) and 224,625 non-TBI patients (1.53%) patients developed dementia. During the 5 year follow-up period, TBI was independently associated with a 1.68 (range 1.57-1.80) times greater risk of dementia after adjusting for sociodemographic characteristics and selected comorbidities. CONCLUSIONS: The findings of this study suggest an increased risk of dementia among individuals with TBI. We suggest the need for more intensive medical monitoring and health education in individuals with TBI. PMID- 22842205 TI - Neurological picture. Isolated cerebellar hemiatrophy related with focal dystonia. PMID- 22842206 TI - Logopenic aphasia in Alzheimer's disease: clinical variant or clinical feature? AB - BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterised by progressive decline in components of the language system. Recent evidence suggests that the logopenic/phonological (LPA) variant is a reliable in vivo marker of Alzheimer related pathology. The aim of this study was to determine if patients with clinically typical early stage Alzheimer's disease (AD) display a characteristic language disorder that resembles LPA, or if LPA is a clinical manifestation of an atypical form of AD. METHODS: Spoken language samples were obtained using the Cookie Theft picture description task from 18 post mortem confirmed cases of AD, where speech samples were taken at the first point of clinical diagnosis, and 18 post mortem confirmed healthy controls. Spoken samples were transcribed from tape recordings and analysed using the scoring system described by Wilson et al. RESULTS: Group comparisons between normal controls and AD patients showed no significant overall differences. Individual review of the linguistic variables compared with the PPA variants showed that a third of patients had normal language (n=6). The remainder showed varied patterns of linguistic impairment. In the majority of the affected group, the most salient feature was a reduction in one or more measures of syntactic complexity. One patient's deficit was comparable to that found in LPA. CONCLUSIONS: The impairment found in clinically typical early stage AD did not correspond consistently to the linguistic profiles described in any of the sub syndromes of PPA. The only reliably distinguishing feature was a reduction across a range of syntactic complexity measures. The findings suggest that LPA represents an atypical clinical presentation of AD rather than a common clinical feature of typical AD. PMID- 22842207 TI - Cloning, expression and characterization of CCL21 and CCL25 chemokines in zebrafish. AB - Chemokines are a large group of proteins implicated in migration, activation, and differentiation of leukocytes. They are well-surveyed in mammals, but less is known in lower vertebrates about their spatiotemporal expressions and functions. From an evolutionary point of view, comparative analyses may provide some fundamental insights into these molecules. In mammals, CCL21 and CCL25 are crucial for thymocyte homing. Herein, we identified and cloned the zebrafish orthologues of CCL21 and CCL25, and analyzed their expression in embryos and adult fish by in situ hybridization. We found that CCL21 was expressed in the craniofacial region, pharynx, and blood vessels in embryos. In adult fish, CCL21 transcripts were located in the kidney, spinal cord, and blood cells. In contrast, expression of CCL25 was only detected in the thymus primordia in embryos. In adult fish, transcripts of CCL25 were maintained in the thymus, and they were also found in the brain and oocytes. Furthermore, we performed an antisense oligonucleotide experiment to evaluate the biological function of CCL25. Results showed that the recruitment of thymocytes was impeded by morpholino-mediated knockdown of CCL25, suggesting that CCL25 is essential for colonization of T-cells in the thymus in early development. Together, our results demonstrate the basic profiles of two CCL chemokines in zebrafish. The tissue specific expression patterns may pave the way for further genetic dissection in this model organism. PMID- 22842208 TI - Pipeline embolization device and subsequent vessel sacrifice for treatment of a bleeding carotid pseudoaneurysm at the skull base: a case report. AB - An attempt at parent vessel reconstruction with Pipeline embolization devices to treat a mycotic pseudoaneurysm of the internal carotid artery at the skull base is presented. A 50-year-old woman with malignant otitis externa and bilateral temporal bone osteomyelitis presented with brisk bleeding from her left ear. She had bony dehiscence of the left carotid canal at CT and extravasation from a pseudoaneurysm of the carotid petrous segment at angiography. Carotid tortuosity proximally precluded placing a covered stent. After the lesion stopped bleeding spontaneously and given the presence of bilateral osteomyelitis putting the contralateral carotid at risk, the decision was made to attempt preservation of the parent vessel with flow diversion. However, bleeding recurred after 12 days, necessitating carotid sacrifice. This first reported experience in treating a carotid pseudoaneurysm at the skull base with the Pipeline device shows that transient cessation of bleeding is insufficient for flow diversion to be effective. PMID- 22842209 TI - Stroke outcome measures: a tale of two trials. PMID- 22842210 TI - Endovascular therapy yields significantly superior outcomes for large vessel occlusions compared with intravenous thrombolysis: is it time to randomize? AB - BACKGROUND AND PURPOSE: We compared outcomes between endovascular (EV) therapy and intravenous (IV) thrombolysis in large vessel strokes. METHODS: 223 patients who had received either IV (n=100) or EV (n=123) therapy were analyzed. Only patients with strokes involving the internal carotid artery terminus (ICA-T, n=45), the middle cerebral artery (M1, n=107) or the bifurcation branches (M2, n=71) were included. The primary endpoint was 3 month outcome based on the modified Rankin Scale (mRS) score, good-outcome defined as mRS <=2. RESULTS: The good outcome was 44.7% in the EV group and 26% in the IV group (p=0.003, OR 2.3, 95% CI 1.3 to 4.1). There was no difference in mortality or hemorrhage. For ICA-T occlusions, the good outcome was 27.6% in the EV and 0% in the IV group (p=0.004); for M1 occlusions, 40.6% in the EV versus 10.5% in the IV group (p=0.0006, OR 5.8, 95% CI 1.9 to 18.2); and for M2 occlusions, 76% in the EV versus 47.8% in the IV group (p=0.01, OR 3.5, 95% CI 1.2 to 10.2). For M1 occlusions, the death rate was 27.5% for the EV compared with 57.9% for the IV group (p=0.002, OR 3.6, 95% CI 1.6 to 8.3) with no difference observed in mortality for ICA-T or M2 occlusions. In the univariate analysis, age, National Institutes of Health Stroke Scale score and occlusion site were significant predictors of outcome and mortality (p<0.0001 for all). In the multivariable analysis, EV therapy (p=0.0004, OR 3.9, 95% CI 1.8 to 9) and younger age (p<0.0001, OR 0.96, 95% CI 0.9 to 0.98) were significant independent predictors of good outcome. CONCLUSIONS: There are significantly higher odds of a favorable outcome with EV compared with IV therapy for large vessel strokes. The data support the rationale of a randomized trial for large vessel occlusions. PMID- 22842211 TI - Report of two cases of a rare cause of subarachnoid hemorrhage including unusual presentation and an emerging and effective treatment option. AB - PURPOSE: To report two cases of a rare cause of subarachnoid hemorrhage (SAH), including unusual presentation and an emerging and effective treatment option. CASE REPORTS: Ruptured basilar perforator artery aneurysm is a rare cause of SAH. Catheter angiography in the immediate post hemorrhage period may be unrevealing. We report two cases of ruptured basilar pontine perforator aneurysms. In one of these cases the perforator aneurysm was not apparent on the initial or the 1 week follow-up angiograms. Both patients returned for follow-up angiography 2 months later by which time aneurysmal filling and conspicuity had increased. Both patients were treated solely with two overlapping Neuroform stents. Follow-up angiograms demonstrated complete resolution of the aneurysms in both patients. CONCLUSIONS: Rupture of aneurysms arising from basilar artery perforators is a rare cause of SAH and attention to this area should be part of an interventionist's search pattern. Aneurysms in this area may not be apparent in the immediate post rupture setting and delayed post hemorrhage angiography has a role in detecting this entity. Stent monotherapy may be effective in treating these lesions. PMID- 22842212 TI - Feasibility of ASL-based phMRI with a single dose of oral citalopram for repeated assessment of serotonin function. AB - Assessment of cerebral serotonin (5-HT) function with arterial spin labeling (ASL)-based pharmacological magnetic resonance imaging (phMRI) could be a highly useful tool in clinical psychiatric research. The goal of this study was to verify the reliability of ASL-based phMRI after an oral challenge of a selective serotonin reuptake inhibitor (SSRI) in repeated assessment of cerebral 5-HT function. In a placebo-controlled, within-subject crossover study we investigated the effect of a single oral dose of citalopram on brain cerebral blood flow (CBF) using a pulsed ASL sequence (PASL) in twelve female healthy volunteers. The within-session repeatability of the PASL signal was good for all regions tested (wsCV<15%). Both ROI- and voxel-based analyses revealed small but significant effects of a citalopram challenge on CBF values in 5-HT rich brain regions, among which the frontal gyrus and thalamus. These effects could however not be replicated between sessions, most probably due to the small effect size of the oral citalopram challenge on cerebral blood flow. We therefore conclude that the test-retest reliability of PASL phMRI with an oral citalopram challenge is low, limiting the technique's sensitivity to time-dependent changes and consequently its use as a (clinical) research tool. PMID- 22842213 TI - Short- and long-term quantitation reproducibility of brain metabolites in the medial wall using proton echo planar spectroscopic imaging. AB - Proton echo planar spectroscopic imaging (PEPSI) is a fast magnetic resonance spectroscopic imaging (MRSI) technique that allows mapping spatial metabolite distributions in the brain. Although the medial wall of the cortex is involved in a wide range of pathological conditions, previous MRSI studies have not focused on this region. To decide the magnitude of metabolic changes to be considered significant in this region, the reproducibility of the method needs to be established. The study aims were to establish the short- and long-term reproducibility of metabolites in the right medial wall and to compare regional differences using a constant short-echo time (TE30) and TE averaging (TEavg) optimized to yield glutamatergic information. 2D sagittal PEPSI was implemented at 3T using a 32 channel head coil. Acquisitions were repeated immediately and after approximately 2 weeks to assess the coefficients of variation (COV). COVs were obtained from eight regions-of-interest (ROIs) of varying size and location. TE30 resulted in better spectral quality and similar or lower quantitation uncertainty for all metabolites except glutamate (Glu). When Glu and glutamine (Gln) were quantified together (Glx) reduced quantitation uncertainty and increased reproducibility was observed for TE30. TEavg resulted in lowered quantitation uncertainty for Glu but in less reliable quantification of several other metabolites. TEavg did not result in a systematically improved short- or long-term reproducibility for Glu. The ROI volume was a major factor influencing reproducibility. For both short- and long-term repetitions, the Glu COVs obtained with TEavg were 5-8% for the large ROIs, 12-17% for the medium sized ROIs and 16 26% for the smaller cingulate ROIs. COVs obtained with TE30 for the less specific Glx were 3-5%, 8-10% and 10-15%. COVs for N-acetyl aspartate, creatine and choline using TE30 with long-term repetition were between 2-10%. Our results show that the cost of more specific glutamatergic information (Glu versus Glx) is the requirement of an increased effect size especially with increasing anatomical specificity. This comes in addition to the loss of sensitivity for other metabolites. Encouraging results were obtained with TE30 compared to other previously reported MRSI studies. The protocols implemented here are reliable and may be used to study disease progression and intervention mechanisms. PMID- 22842214 TI - Paradoxical results of adaptive false discovery rate procedures in neuroimaging studies. AB - Adaptive false discovery rate (FDR) procedures, which offer greater power than the original FDR procedure of Benjamini and Hochberg, are often applied to statistical maps of the brain. When a large proportion of the null hypotheses are false, as in the case of widespread effects such as cortical thinning throughout much of the brain, adaptive FDR methods can surprisingly reject more null hypotheses than not accounting for multiple testing at all-i.e., using uncorrected p-values. A straightforward mathematical argument is presented to explain why this can occur with the q-value method of Storey and colleagues, and a simulation study shows that it can also occur, to a lesser extent, with a two stage FDR procedure due to Benjamini and colleagues. We demonstrate the phenomenon with reference to a published data set documenting cortical thinning in attention deficit/hyperactivity disorder. The paper concludes with recommendations for how to proceed when adaptive FDR results of this kind are encountered in practice. PMID- 22842215 TI - Tissue hemostasis and chronic inflammation in colon biopsies of patients with inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is characterized by a chronic inflammation accompanied by procoagulation settings. However, tissue hemostasis in IBD patients was only incidentally reported. Accordingly, the current study characterizes changes in tissue hemostasis components in a colon inflammatory setting. Serial cryostat sections of endoscopic mucosal biopsy specimens taken from 26 consecutive IBD patients diagnosed de novo and normal colon resection specimens taken from 6 patients were immunohistochemically stained with monoclonal anti-human tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), as well as CD3 and CD68 positive cells. The hemostatic components studied differed significantly from the control subjects. Up regulation predominated in the case of TF while down-regulation was mainly found in TM and TFPI in IBD. In the control sections, TF was observed in a few fibroblast-shaped cells in the lamina propria, while in the majority of IBD sections, TF positively stained small microvessels, infiltrating mononuclear cells and fibroblast-shaped cells tightly surrounding the colon crypts. Thrombomodulin intensively stained the endothelium of the small capillary vessels in the control, whereas such staining mainly accompanied infiltrating mononuclear cells of the IBD subjects. Tissue factor pathway inhibitor positively stained the endothelium of the small capillary vessels in the control group, whereas in the IBD group endothelial cells presented only weak TFPI staining. The mean number of CD3-positive lymphocytes in IBD was 23.3 +/- 14.3, but the mean number of CD68 positive cells was 114.5 +/- 55.8. In the control sections, it was 4.1 +/- 2.4 and 39.6 +/- 17.9, respectively. There was no relationship between CD3 and CD68 (+) cells and the hemostasis markers studied. The results of the current study indicate a shift of tissue hemostasis toward the procoagulant state irrespective of the severity of inflammatory infiltration. In addition, TF distribution in the colon sections of IBD patients may indicate a role in the restoration of the barrier function in injured intestinal mucosa. PMID- 22842216 TI - Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle. AB - Cigarette smoke (CS) is a well-established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting, remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance, a mouse model of CS exposure was used. The 129/SvJ mice were exposed to CS for 6 mo, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared with controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1), and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading toward impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area, and decreased exercise tolerance. PMID- 22842219 TI - New insights into NPP1 function: lessons from clinical and animal studies. AB - The recent elucidation of rare human genetic disorders resulting from mutations in ectonucleotide pyrophosphotase/phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), has highlighted the vital importance of this molecule in human health and disease. Generalised arterial calcification in infants (GACI), a frequently lethal disease, has been reported in recessive inactivating mutations in ENPP1. Recent findings have also linked hypophosphataemia to a lack of NPP1 function. A number of human genetic studies have indicated that NPP1 is a vital regulator that influences a wide range of tissues through various signalling pathways and when disrupted can lead to significant pathology. The function of Enpp1 has been widely studied in rodent models, where both the mutant tiptoe walking (ttw/ttw) mouse and genetically engineered Enpp1(-/-) mice show significant alterations in skeletal and soft tissue mineralisation, calcium/phosphate balance and glucose homeostasis. These models therefore provide important tools with which to study the potential mechanisms underpinning the human diseases associated with altered NPP1. This review will focus on the recent advances in our current knowledge of the actions of NPP1 in relation to bone disease, cardiovascular pathologies and diabetes. A fuller understanding of the mechanisms through which NPP1 exerts its pathological effects may stimulate the development of novel therapeutic strategies for patients at risk from the devastating clinical outcomes associated with disrupted NPP1 function. PMID- 22842220 TI - Association between beta-blockers and fracture risk: a Bayesian meta-analysis. AB - BACKGROUND: The association between beta-blockers (BB) and fracture risk is controversial, due largely to conflicting findings from previous studies. The present study sought to evaluate the effect of BB on fracture risk by using a Bayesian meta-analysis approach. METHODS AND RESULTS: We systematically retrieved 13 observational studies on the association between BB use and fracture risk. This meta-analysis involved more than 907,000 men and women with mean/median age of individual studies ranging from 43 to 81 years. We used a hierarchical Bayesian random effects model to synthesize the results. BB use was associated with an average 17% reduction in the risk of any fracture (risk ratio [RR] 0.83; 95% credible interval [CrI]: 0.71-0.93), hip fracture (RR 0.83; 95% CrI: 0.70 0.92) and vertebral fracture (RR 0.81; 95% CrI: 0.61-0.99). The probability that BB use reduces fracture risk by at least 10% was 0.91. CONCLUSIONS: Beta-blockers are associated with reduced risk of fracture in older adults, but the effect size is likely to be modest. PMID- 22842217 TI - Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD. AB - Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress. PMID- 22842221 TI - Early growth response 2 negatively modulates osteoclast differentiation through upregulation of Id helix-loop-helix proteins. AB - Early growth response 2 (Egr2) is a zinc finger transcription factor that acts as an important modulator of various physiological processes. In this study, we show that Egr2 negatively regulates receptor activator of NF-kappaB ligand (RANKL) induced osteoclast differentiation. The overexpression of Egr2 in bone marrow derived macrophages (BMMs) suppresses the formation of multinuclear osteoclasts and the expression of osteoclastogenic markers, including nuclear factor of activated T cells c1 (NFATc1). On the other hand, Egr2 overexpression does not impact the phagocytic activity of osteoclast precursors or the expression of macrophage-specific markers in the presence of the osteoclastogenic stimuli, RANKL and M-CSF. We further demonstrate that Egr2 induces the expression of the inhibitors of differentiation/DNA binding (Ids) helix-loop-helix (HLH) transcription factors, which are important repressors in RANKL-mediated osteoclastogenesis. Egr2 transactivates the Id2 promoter and increases its recruitment to the Id2 promoter region. In addition, Egr2-dependent induction of Id2 promoter activity, and its binding to the Id2 promoter is abrogated by the overexpression of the Egr2 repressor, NGFI-A binding protein 2 (Nab2). Accordingly, coexpression with Nab2 restores Egr2-mediated suppression of osteoclast differentiation. Furthermore, knockdown of Egr2 using shRNA enhances osteoclastogenesis and decreases Id2 gene expression. Ectopic expression of Id2 reverses the phenotype mediated by Egr2 silencing. Taken together, our results identify Egr2 as an important modulator of RANKL-induced osteoclast differentiation and provide the link between RANKL, Egr2 and Id proteins in osteoclast-lineage cells. PMID- 22842218 TI - Inhibition of allergic inflammation by supplementation with 5-hydroxytryptophan. AB - Clinical reports indicate that patients with allergy/asthma commonly have associated symptoms of anxiety/depression. Anxiety/depression can be reduced by 5 hydroxytryptophan (5-HTP) supplementation. However, it is not known whether 5-HTP reduces allergic inflammation. Therefore, we determined whether 5-HTP supplementation reduces allergic inflammation. We also determined whether 5-HTP decreases passage of leukocytes through the endothelial barrier by regulating endothelial cell function. For these studies, C57BL/6 mice were supplemented with 5-HTP, treated with ovalbumin fraction V (OVA), house dust mite (HDM) extract, or IL-4, and examined for allergic lung inflammation and OVA-induced airway responsiveness. To determine whether 5-HTP reduces leukocyte or eosinophil transendothelial migration, endothelial cells were pretreated with 5-HTP, washed and then used in an in vitro transendothelial migration assay under laminar flow. Interestingly, 5-HTP reduced allergic lung inflammation by 70-90% and reduced antigen-induced airway responsiveness without affecting body weight, blood eosinophils, cytokines, or chemokines. 5-HTP reduced allergen-induced transglutaminase 2 (TG2) expression and serotonylation (serotonin conjugation to proteins) in lung endothelial cells. Consistent with the regulation of endothelial serotonylation in vivo, in vitro pretreatment of endothelial cells with 5-HTP reduced TNF-alpha-induced endothelial cell serotonylation and reduced leukocyte transendothelial migration. Furthermore, eosinophil and leukocyte transendothelial migration was reduced by inhibitors of transglutaminase and by inhibition of endothelial cell serotonin synthesis, suggesting that endothelial cell serotonylation is key for leukocyte transendothelial migration. In summary, 5-HTP supplementation inhibits endothelial serotonylation, leukocyte recruitment, and allergic inflammation. These data identify novel potential targets for intervention in allergy/asthma. PMID- 22842222 TI - Neonatal xenoestrogen exposure alters growth hormone-dependent liver proteins and genes in adult female rats. AB - The hypothalamic-growth hormone (GH)-liver axis represents a new concept in endocrine regulation of drug toxicity. Preponderant sex differences are found in liver gene expression, mostly dependent on the sexually dimorphic pattern of GH secretion which is set during the neonatal period by gonadal steroids. We tested if GH-dependent sexually dimorphic liver enzymes and proteins was perturbed by neonatal Bisphenol A (BPA) treatment in female rats. Female rats were sc injected with BPA (50 or 500 MUg/50 MUl) or castor oil vehicle from postnatal day 1 to 10. At five months serum prolactin, pituitary GH, and serum and liver insulin growth factor-I (IGF-I) were measured by RIA. Major urinary proteins (MUPs) were determined by electrophoresis. Liver Cyp2c11, Cyp2c12, Adh1, Hnf6, and Prlr mRNA levels were determined by real time PCR. Pituitary GH content and liver IGF-I concentration were increased by neonatal BPA treatment, indicating partial masculinization of the GH axis in treated females. GH-dependent female predominant liver enzyme genes (Cyp2c12 and Adh1) and a transcription factor (Hnf6) were downregulated or defeminized, while there were no changes in a male predominant gene (Cyp2c11) or protein (MUP). Our findings indicate that perinatal exposure to BPA may compromise the sexually dimorphic capacity of the liver to metabolize drugs and steroids. PMID- 22842224 TI - The optimal timing for imaging brain tumours and other brain lesions with 18F labelled fluoromethylcholine: a dynamic positron emission tomography study. AB - PURPOSE: To determine the optimal timing for imaging brain tumours and other brain lesions with 18F-labelled fluoromethylcholine (18F-FCho) PET. MATERIALS AND METHODS: Dynamic PET imaging with 18F-FCho (acquisition time of 28 min) was performed in 24 patients with space-occupying lesions in the brain. On the coregistered PET and MRI, lesion-to-normal tissue uptake ratios (LNRs) were calculated. Time-activity curves (TACs) were generated on the basis of the LNRs. Changes in LNR over time were calculated on the basis of the linear part of the TAC (last 22 min of the acquisition). RESULTS: TACs for 18F-FCho in gliomas of different grading showed that, after a rapid uptake phase, the mean increase in LNR was 1.07 +/- 0.93 for glioblastomas, -0.52 +/- 1.56 for anaplastic astrocytomas, 0.04 +/- 0.13 for grade 2 oligoastrocytomas and 0.37 in a case of a pilocytic astrocytoma. The average increase in LNR was 0.46 for a brain metastasis, 0.41 +/- 0.69 for radiation-induced mass lesions and 1.07 for a tumefactive demyelinating lesion. In contrast, TACs for 18F-FCho in meningiomas showed that, after a rapid uptake phase, the average change in LNR was -5.25 +/- 4.19 for typical meningiomas and -3.04 in a case of a mixed angiomatous and clear cell meningioma. CONCLUSION: On the basis of the TACs, PET imaging with 18F-FCho starting within minutes after the administration of the tracer is preferred for the detection of brain tumours and other brain lesions. If discrimination between meningioma and other brain tumours is of concern, both 'early' and 'late' PET imaging could be helpful. PMID- 22842223 TI - Nitrate reductase activity of bacteria in saliva of term and preterm infants. AB - The salivary glands of adults concentrate nitrate from plasma into saliva where it is converted to nitrite by bacterial nitrate reductases. Nitrite can play a beneficial role in adult gastrointestinal and cardiovascular physiology. When nitrite is swallowed, some of it is converted to nitric oxide (NO) in the stomach and may then exert protective effects in the gastrointestinal tract and throughout the body. It has yet to be determined either when newborn infants acquire oral nitrate reducing bacteria or what the effects of antimicrobial therapy or premature birth may be on the bacterial processing of nitrate to nitrite. We measured nitrate and nitrite levels in the saliva of adults and both preterm and term human infants in the early weeks of life. We also measured oral bacterial reductase activity in the saliva of both infants and adults, and characterized the species of nitrate reducing bacteria present. Oral bacterial conversion of nitrate to nitrite in infants was either undetectable or markedly lower than the conversion rates of adults. No measurable reductase activity was found in infants within the first two weeks of life, despite the presence of oral nitrate reducing bacteria such as Actinomyces odontolyticus, Veillonella atypica, and Rothia mucilaginosa. We conclude that relatively little nitrite reaches the infant gastrointestinal tract due to the lack of oral bacterial nitrate reductase activity. Given the importance of the nitrate-nitrite-NO axis in adults, the lack of oral nitrate-reducing bacteria in infants may be relevant to the vulnerability of newborns to hypoxic stress and gastrointestinal tract pathologies. PMID- 22842225 TI - Serum carcinoembryonic antigen measurement, abdominal contrast-enhanced computed tomography, and fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of colorectal cancer recurrence: a correlative study. AB - INTRODUCTION: The aim of this study was to evaluate the correlative role of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in carcinoembryonic antigen (CEA) measurement and contrast enhanced abdominal computed tomography (ceCT) in the detection of colorectal cancer (CRC) recurrence. MATERIALS AND METHODS: A total of 96 patients (40 female, 56 male; mean age, 60.6 +/- 12 years) with a previous diagnosis of CRC underwent 18F-FDG PET/CT on suspicion of recurrence and were evaluated retrospectively. Inclusion criteria were accepted as the presence of increased serum CEA levels or positive findings on abdominal ceCT or both. 18F-FDG PET/CT findings were compared with histopathological findings and/or clinical follow-up data as the gold standard. Patients were divided into three groups: group 1, with increased CEA levels and normal abdominal ceCT; group 2, with normal CEA levels and positive ceCT; and group 3, with increased CEA levels and positive ceCT. RESULTS: Whereas sensitivities of CEA, ceCT, and 18F-FDG PET/CT in the three patient groups were calculated as 91, 67, and 96%, specificities were 13, 51, and 62%, respectively. There were 35, 14, and 46 patients in groups 1, 2, and 3, respectively. In separate analyses conducted on the groups, sensitivity of 18F FDG PET/CT was computed as 100 and 100% and specificity as 88 and 80% for groups 1 and 2. In group 3, which comprised four patients with secondary malignancies, sensitivity and specificity of 18F-FDG PET/CT were 94 and 16%, respectively. CONCLUSION: 18F-FDG PET/CT has an additional role in the detection of CRC recurrence with a higher sensitivity compared with CEA and ceCT alone, and 18F FDG PET/CT is especially more successful in patients with isolated elevated CEA levels or positive ceCT findings without accompanying CEA elevation. PMID- 22842227 TI - NMNAT1 mutations cause Leber congenital amaurosis. AB - Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA. PMID- 22842229 TI - Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. AB - In addition to its activity in nicotinamide adenine dinucleotide (NAD(+)) synthesis, the nuclear nicotinamide mononucleotide adenyltransferase NMNAT1 acts as a chaperone that protects against neuronal activity-induced degeneration. Here we report that compound heterozygous and homozygous NMNAT1 mutations cause severe neonatal neurodegeneration of the central retina and early-onset optic atrophy in 22 unrelated individuals. Their clinical presentation is consistent with Leber congenital amaurosis and suggests that the mutations affect neuroprotection of photoreceptor cells. PMID- 22842228 TI - Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. AB - We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit. PMID- 22842230 TI - Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. AB - Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. PMID- 22842231 TI - Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. AB - Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant. PMID- 22842233 TI - Novel approach to determining the absolute configurations at the C3-positions of various types of sterols based on an induced circular dichroism. AB - Circular dichroism (CD) spectra of the 2,2'-binaphthyl ester derived from Delta(5)-sterols showed not bisignate CD but diagnostic CD bands at around 210 and 240 nm. These bands might be attributable to an interaction between an olefinic chromophore and a binaphthyl one. Various types of unsaturated sterols were thus derivatized followed by complete hydrogenation, to give saturated sterols. As a result, CD spectra of the binaphthyl derivatives of the saturated sterols showed bisignate curves centered at 240 nm (3S(beta): positive chirality; 3R(alpha): negative one). This suggested a straightforward and practical method for discriminating the absolute stereogenic center at the C-3 positions of sterols based on an induced CD. This finding should contribute significantly to the analysis of metabolites of various types of sterols. PMID- 22842234 TI - Neuroactive steroids with perfluorobenzoyl group. AB - During an initial study in searching for the alternative derivatives suitable for photolabeling of neuroactive steroids, perfluorobenzoates and perfluorobenzamides in position 17 of 5beta-androstan-3alpha-ol were synthesized from the corresponding 17-hydroxy and 17-amino derivatives. After transformation into glutamates or sulfates, 17alpha-epimers had comparable inhibitory activity at NMDA receptors to the natural neurosteroid (20-oxo-5beta-pregnan-3beta-yl sulfate), however, were more potent (2- to 36-fold) than their 17beta-substituted analogs. In one case, fluorine in position 4' of perfluorobenzoate group was substituted with azide and activity of the final glutamate was retained comparing with the corresponding perfluorobenzoate. The series was expanded with perfluorobenzoyl derivatives of pregnanolone: Perfluorobenzamide of glutamate and perfluorobenzoate of 11alpha-hydroxy pregnanolone were prepared and tested. From nine tested compounds, four of them exhibit very good inhibition activity and can serve as promising leads for photolabeling experiments. PMID- 22842235 TI - Health risk for athletes at moderate altitude and normobaric hypoxia. AB - Altitudes at which athletes compete or train do usually not exceed 2000-2500 m. At these moderate altitudes acute mountain sickness (AMS) is mild, transient and affects at the most 25% of a tourist population at risk. Unpublished data included in this review paper demonstrate that more intense physical activity associated with high-altitude training or mountaineering does not increase prevalence or severity of AMS at these altitudes. These conclusions can also be extended to the use of normobaric hypoxia, as data in this paper suggest that the severity of AMS is not significantly different between hypobaric and normobaric hypoxia at the same ambient pO(2). Furthermore, high-altitude cerebral or pulmonary oedema do not occur at these altitudes and intermittent exposure to considerably higher altitudes (4000-6000 m) used by athletes for hypoxic training are too short to cause acute high-altitude illnesses. Even moderate altitude between 2000 and 3000 m can, however, exacerbate cardiovascular or pulmonary disease or lead to a first manifestation of undiagnosed illness in older people that may belong to the accompanying staff of athletes. Moderate altitudes may also lead to splenic infarctions in healthy athletes with sickle cell trait. PMID- 22842232 TI - De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. AB - Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3. PMID- 22842236 TI - Torsional injuries of the lower limb: an analysis of the frictional torque between different types of football turf and the shoe outsole. AB - BACKGROUND: Football turf is increasingly used in European soccer competition. Little is known on the rotational torque that players experience on these fields. High rotational torques between the shoe outsole and the sports surface has been correlated with torsional injuries of the lower limb and knee. PURPOSE: To evaluate the effect of six parameters that could influence the rotational torque between the shoe outsole and the latest generation football turf. STUDY DESIGN: Controlled laboratory study. METHODS: A testing apparatus was constructed to measure the peak torque generated during a controlled rotation of the foot. Six parameters that could potentially influence the frictional forces, were considered: (1) the sports surface, (2) the shoe outsole cleat design, (3) the weather conditions, (4) the weight, (5) the presence of an impact and (6) the direction of rotation. RESULTS: The football turf without infill showed significantly lower frictional torques than natural grass whereas a football turf with sand/rubber infill had significantly higher torques. Blades were associated with significantly higher torques than studs on natural grass and on one football turf with sand/rubber infill. Dry weather was associated with higher torques only for the football turf without infill. The torque increased linearly and significantly with an increasing vertical load. The rotational torque increased significantly following an impact. Torques on external rotational movements were significantly higher with blades. CONCLUSIONS: Important differences in rotational torques are found and could be seen as potential risk factors for torsional injuries of the lower limb. PMID- 22842237 TI - The effectiveness of a preconditioning programme on preventing running-related injuries in novice runners: a randomised controlled trial. AB - OBJECTIVES: There is no consensus on the aetiology and prevention of running related injuries in runners. Preconditioning studies among different athlete populations show positive effects on the incidence of sports injuries. HYPOTHESIS: A 4-week preconditioning programme in novice runners will reduce the incidence of running-related injuries. STUDY DESIGN: Randomised controlled clinical trial; level of evidence, 1. METHODS: Novice runners (N=432) prepared for a four-mile recreational running event. Participants were allocated to the 4 week preconditioning (PRECON) group (N=211) or the control group (N=221). The PRECON group started a 4-week training programme, prior to the running programme, with walking and hopping exercises. After the 4-week period both groups started a 9-week running programme. In both groups information was registered on running exposure and running-related injuries (RRIs) using an internet-based running log. Primary outcome measure was RRIs per 100 runners. An RRI was defined as any musculoskeletal complaint of the lower extremity or lower back causing restriction of running for at least a week. RESULTS: The incidence of RRIs was 15.2% in the PRECON group and 16.8% in the control group. The difference in RRIs between the groups was not significant (chi(2)=0.161, df=1, p=0.69). CONCLUSION: This prospective study demonstrated that a 4-week PRECON programme with walking and hopping exercises had no influence on the incidence of RRIs in novice runners. PMID- 22842238 TI - Hip pads reduce the overall risk of injuries in recreational snowboarders. AB - OBJECTIVE: The purpose is to determine common injuries in recreational snowboarding as targets of preventive strategy and protective gear that reduces the overall risk of these injuries. METHODS: The subjects comprised 5561 injured recreational snowboarders. On the basis of patients' self-reporting form, 'the common snowboarding injuries' (cut-off point >2.0% in prevalence) were decided, and all injured snowboarders were categorised into two groups: common injuries and the other injuries (control). Several factors such as age, gender, self reported skill level, experienced seasons, experienced days, previous snowboarding school attendance and the use of protective gears (helmet, elbow pads, wrist guards, backbone guard, hip pads and knee pads) were recorded. Multiple logistic regression analysis was conducted to investigate which type of protective gear reduced the overall risk of the common injuries. RESULTS: The common snowboarding injuries consisted of eight types, in which distal radial fracture was the most common (17.7%), followed by head injury (9.4%) and clavicle fracture (6.5%). In univariate regression analysis, skill level, experienced seasons, experienced days and the use of hip pads and knee pads were manifested potential risk factors on the common injuries. In subsequent multivariate regression analysis, the use of hip pads was related with a lower overall risk of these common injuries (OR, 0.84; 95% CI, 0.75 to 0.95), specifically that of distal radial fracture and glenohumeral dislocation. CONCLUSIONS: The use of hip pads is recommended for snowboarders as it reduces the overall risk of common snowboarding injuries. PMID- 22842240 TI - Single step approach to make diagnostic impressions of both the arches and face bow transfer: a novel technique. AB - CONTEXT: Mounting the maxillary and mandibular dentulous casts for Diagnostic purpose requires many steps (including making maxillary and mandibular impressions, face-bow transfer, and bite registration) or many appointments. A simple new technique of doing all of this together without compromising on the accuracy can save time over the conventional mounting procedure. AIM: To compare the accuracy of a new technique of a single-step diagnostic mounting procedure with that of the conventional diagnostic mounting procedure. MATERIALS AND METHODS: Ten dentulous patients with the full complement of teeth and without any history of temporomandibular disorder and orthodontic treatment were selected for this study. A detachable metal triple tray to replace the fork part of the face bow fork that further could be attached to face bow was fabricated. Dual-arch impressions and face-bow transfer were made in these subjects using this modified triple tray. These mountings were compared with the ones done with the conventional mounting procedure. Five linear measurements (using stable reference points on the articulator and the cast) were made and the values obtained by both the methods were compared. STATISTICAL ANALYSIS: The Student's 't' test for statistical analysis was used in this study. RESULTS: The measurement values obtained by the single-step method were almost similar to the ones obtained by the conventional method. The various mean measurements for the single step and conventional methods were 37.7 +/- 6.8 and 38.5 +/- 6.5 mm; 70.0 +/- 4.4 and 70.1 +/- 4.2 mm; 57.0 +/- 4.9 and 57.3 +/- 4.2 mm; 71.3 +/- 4.5 and 71.0 +/- 4.6 mm; and 58.7 +/- 2.5 and 58.3 +/- 2.3 mm; respectively. The differences between the values obtained by the conventional and single-step methods were not statistically significant. CONCLUSION: The single-step procedure of diagnostic mounting can be used as an alternative to the conventional method, without compromising the quality of mounting. PMID- 22842241 TI - Relationship between ABO blood groups and oral cancer. AB - BACKGROUND: Cancer is a unique disease characterized by abnormal growth of cells which have the ability to invade the adjacent tissues and sometimes even distant organs. Oral cancer has multifactorial etiology and is significantly associated with risk factors of the individual's lifestyle, particularly, chronic use of tobacco, spicy food, alcohol and smoking. Many studies have indicated that genetic factors also have an influence on the etiology of cancer. AIM: To evaluate if any of the ABO blood groups are associated with an increased risk for oral cancer. MATERIALS AND METHODS: The present study was conducted at Kidwai Memorial Institute of Oncology (KMIO), Bangalore, after obtaining permission from the Director of the institute. The study sample comprised 235 oral cancer patients and 812 controls. For statistical analysis, Chi-square test and odds ratio were used to assess the relationship between ABO blood groups and oral cancer. Probability level was fixed at <=0.05. RESULTS: It was found that people with blood group A had 1.46 times higher risk of developing oral cancer compared to people of other blood groups. CONCLUSION: By employing a simple blood grouping test during community field programs, people with blood group A in the age group of 40-59 years having tobacco chewing habits can be apprised that they are more at risk to develop oral cancer than people with other blood groups. PMID- 22842242 TI - Evaluation of flexural bond strength of porcelain to used nickel-chromium alloy in various percentages. AB - AIM: The aim of this in vitro study was to evaluate the flexural bond strength of porcelain to combinations of used and new nickel-chromium alloy in various proportions. MATERIALS AND METHODS: Used and new nickel-chromium bonding alloys were combined in various proportions (groups I to V; 10 samples per group) and their flexural bond strengths with porcelain were compared. A three-point loading system was used for the application of load. Load was applied at a constant speed of 0.5 mm/minute and the load required to fracture the porcelain was recorded for each specimen. STATISTICAL ANALYSIS USED: (a) Analysis of variance (ANOVA) and (b) Duncan's multiple range tests. RESULTS: The best bond strength values were seen when 100% new alloy was used. According to the findings of this study, there was no adverse effects noted with up to 75% recast metal, but serious changes were found in the bond strength values when 100% old metal was used. CONCLUSIONS: The following conclusions were drawn from the study Fresh nickel-chromium alloy shows the greatest porcelain adherence.There is no significant change in bond strength of ceramic to alloy with up to 75% of used nickel-chromium alloy.At least 25%- of new alloy should be added when recycled nickel-chromium alloy is being used for metal ceramic restorations. PMID- 22842243 TI - Comparative evaluation of expression of proliferating cell nuclear antigen in variants of ameloblastoma and ameloblastic carcinoma. AB - AIM: To evaluate the use of proliferating cell nuclear antigen index in the different histopathological variants of ameloblastoma, such as the follicular, plexiform, and unicystic types, and in ameloblastic carcinoma by immunohistochemical staining. The proliferating cell nuclear antigen index values of the variants of ameloblastomas and ameloblastic carcinomas are compared in order to determine the biological behavior of these tumors. MATERIALS AND METHODS: For the present study, archival tissues that had been diagnosed as ameloblastoma and ameloblastic carcinoma were collected from the department of oral pathology. Specimens were embedded in paraffin wax and were sectioned at a thickness of 5 MUm and stained with hematoxylin-eosin for reconfirming the histologic pattern. It was also stained immunohistochemically for anti proliferating cell nuclear antigen antibody. RESULTS: Positive proliferating cell nuclear antigen expression is seen as a light brown, granular stain. The proliferating cell nuclear antigen values of ameloblastic carcinoma were almost five times the value of ameloblastoma. Analysis of variance test, Fischer's exact test/variance ratio test, and Student's t-test were performed and the probability values were determined. SUMMARY AND CONCLUSION: This study showed that ameloblastic carcinoma had the maximum proliferative capacity. Among the variants of ameloblastoma, the plexiform variety had the maximum proliferative capacity, followed by the follicular and unicystic varieties. Altogether, these data indicate that proliferating cell nuclear antigen is related to the biological behavior and proliferation of tumor cells in the variants of ameloblastoma and ameloblastic carcinoma. PMID- 22842244 TI - An evaluation of retention and marginal seating of Ni-Cr alloy cast restorations using three different luting cements: an in vitro study. AB - CONTEXT: Clinical and laboratory studies regarding performance of recently introduced luting cements: Adhesive resin cement and resin-modified glass ionomer cement (GIC), are limited. AIMS: To compare the retention and marginal seating of Ni-Cr alloy restorations using newer luting cements: Resin-modified GIC and adhesive resin cement with those of the oldest cement, zinc phosphate. MATERIALS AND METHODS: Thirty maxillary premolars of similar sizes were prepared to receive cast metal copings. Copings were placed on the prepared teeth and the marginal opening was examined using a Nikon Measuroscope. The specimens were randomly assigned to three groups. Group I castings were luted with zinc phosphate, Group II castings luted with resin-modified GIC, and Group III castings luted with adhesive resin cement. After cementation marginal seating was measured. Tensile loads required to dislodge the crowns were obtained using MTS machine. STATISTICAL ANALYSIS USED: Tukey's test, Analysis of Variance (ANOVA). RESULTS: For zinc phosphate cement, mean marginal seating was 31 microns. Mean retentive strength was 287 Newtons. For resin-modified GIC, mean marginal seating was 29.6 microns. Mean retentive strength was 610 Newtons. For adhesive resin cement, mean marginal seating was 49 microns. Mean retentive strength was 613 Newtons. CONCLUSIONS: Marginal seating of adhesive resin cement was significantly greater than that of zinc phosphate and resin-modified GIC. Retentive strength of adhesive resin cement and resin-modified GIC was significantly greater than that of zinc phosphate There was no significant difference of retentive strength between adhesive resin cement and resin-modified GIC. PMID- 22842245 TI - A preliminary study on the screening of emerging drug resistance among the caries pathogens isolated from carious dentine. AB - BACKGROUND: Dental caries being the commonest unmet public health problem indicates its need to urge the dentists to overcome this problem globally. Caries exhibit in different types and is found to be associated with co-aggregation property of microbial flora with other oral hygienic factors. In spite of the surgical removals, excavations and administration of antimicrobials for carious dentine, there seems to be repeated infection and chronic prevalence of caries. A complete understanding of microbial etiology and prevention of emerging drug resistant strains will aid in the eradication of this chronic dentine problem condition from the oral cavity. AIM: This study is aimed to isolate the predominant bacterial pathogens associated with caries and to screen for the emergence of drug resistance among the isolated caries pathogens. MATERIALS AND METHODS: Carious dentine specimens were collected from 75 endodontic patients and the samples were processed microbiologically to isolate the caries pathogens. Identification of the strains was done by standard biochemical characterization studies. Statistical analysis of the isolates was done by Pearson Chi-square test and Fisher's exact test. The predominant isolates were subjected to antimicrobial sensitivity test using Kirby Bauer's method. The results were recorded and analyzed for drug resistance. RESULTS: Carious dentine samples yielded a high percentage of Lactobacillus sp., and Candida albicans from different type of caries. Among the study population, dentinal caries was the most predominant type affecting most males with other associated risk factors. Nearly 47.3% of the isolated Lactobacillus sp. and 55.5% of the yeast C. albicans were screened to show resistance against the antimicrobials used for the study. CONCLUSION: This study concludes by stating that Lactobacillus sp., and C. albicans are mostly involved in the caries etiology and show resistance to the commonest antimicrobial agent. This implicates the need for periodical antimicrobial susceptibility examination of the caries pathogens that will aid to prevent the emergence of resistance property among the dentinal pathogenic organisms. PMID- 22842246 TI - Prevalence and correlates of tobacco use among urban adult men in India: a comparison of slum dwellers vs non-slum dwellers. AB - BACKGROUND: Tobacco use is reported to be rampant in urban slums in developing countries. Demographical variations in tobacco use between males living in urban slums vs those living in non-slum areas in India has not been reported, and this study was undertaken to address this issue. MATERIALS AND METHODS: Secondary data analysis of National Family Health Survey-3 (NFHS-3) was undertaken to study demographical variations in tobacco use between urban slum dwellers and non-slum dwellers in eight Indian cities. Demographic determinants for use of smoking and chewing forms of tobacco in the two groups were analyzed. SPSS version 16.0 (SPSS Inc., IL, USA) was used for statistical analysis. RESULT: The study population comprised 6887 (41.8%) males from slum areas and 9588 (58.2%) from non-slum areas of eight urban cities. Cigarette/beedi smoking was the commonest form of tobacco use among the study population. Pan masala use was the least common form of smokeless tobacco use, next only to snuff. There was a high statistical significance observed within the various demographic parameter studied in both the slum and non-slum dwelling males in study population. However, on studying the differences between the two groups, it was observed that statistical significance of P<=.001 was observed with age (15-49), secondary education, religion, household structure and marital status. The difference between the two groups in the mean number of cigarettes/beedis smoked was not statistically significant (P=.598). DISCUSSION AND CONCLUSION: Male slum dwellers are a distinct urban population, whose health needs assessment requires a different approach than that for non-slum dwellers who often can afford the services that an urban Indian city can offer. PMID- 22842247 TI - Efficacy of commercial and household denture cleansers against Candida albicans adherent to acrylic denture base resin: an in vitro study. AB - AIM: To evaluate and compare the efficacy of two commercial and two household denture cleansers against Candida albicans adherent to acrylic denture base resin. MATERIALS AND METHODS: Fifty specimens of acrylic denture base resin (10 * 10 * 2 mm) were fabricated and processed according to the manufacturer's instructions. Sterile acrylic resin specimens were inoculated by immersing in Sabouraud broth containing C albicans for 16 hours at 37 degrees C in an incubator. Then the specimens were washed and immersed in denture cleansers (four groups) - Clinsodent (powder form), Fittydent (tablet form), vinegar (4% acetic acid), diluted vinegar (50% diluted with water), and water (control group) for 8 hours at room temperature. After 8 hours the acrylic resin specimens were washed, fixed with methanol, and stained with crystal violet. Candida cells adherent to the acrylic resin specimens were counted under microscope. The number of cells adherent to the test samples were compared with that adherent to the control. STATISTICAL ANALYSIS: The data were analyzed using the independent-samples 't ' tests, analysis of variance (ANOVA), and Tukey's HSD test. RESULTS: All the denture cleansers were highly effective against C albicans. The effectiveness of commercial denture cleansers was significant better than that of household denture cleansers. Fittydent fared better than Clinsodent, but the difference between the two was not statistically significant (P=.765). Vinegar was more effective than diluted vinegar (P<.05). CONCLUSION: Within the limitations of this in vitro study, denture cleansers were found to be effective in reducing C albicans cells adhering to dentures. The commercial denture cleansers (Fittydent and Clinsodent) were more effective than household denture cleansers (vinegar and diluted vinegar). PMID- 22842248 TI - Effect of different types of tea on Streptococcus mutans: an in vitro study. AB - CONTEXT: If tea can be shown to have an inhibitory effect on the growth of Streptococcus mutans there can be a basis for using it as an agent for reducing caries. AIMS: The aim of the study was to determine the effect of aqueous and organic extracts of three types of tea (green, oolong, and black tea) on the growth of S. mutans. SETTINGS AND DESIGN: In vitro study. MATERIAL AND METHODS: Qualitative and quantitative phytochemical analysis of the three types of tea was done. Organic extracts of methanol and ethanol and aqueous extracts (50% and 100%) of tea were prepared. Fifty microliters of these extracts were inoculated into wells prepared on Mueller-Hinton agar plates that had been previously smeared with S. mutans. The agar plates were incubated at 37?C for 24 hours. A similar procedure was followed using 0.2% chlorhexidine, which served as the positive control. STATISTICAL ANALYSIS USED: Analysis of variance (ANOVA), post hoc Tukey test, Student's 't ' test (two-tailed, dependent), and Student's 't' test (two-tailed, independent) were used for analysis of the data. RESULTS: All the phytochemicals were found to be higher in oolong tea. Both aqueous and organic extracts of oolong tea showed greatest zones of inhibition, followed by green tea and black tea. Aqueous extracts of oolong and green tea showed greater zone of inhibition than chlorhexidine. All the three types of tea inhibited growth of S. mutans. The greatest inhibition was observed with aqueous extract of oolong tea. CONCLUSIONS: Oolong tea extracts (aqueous and organic) showed a greater inhibitory effect on the growth of S. mutans than the other tea extracts . PMID- 22842249 TI - Quantitative assessment of palatal bone thickness in an ethnic Indian population: a computed tomography study. AB - CONTEXT: Variations in palatal bone thickness (PBT) at various locations have caused considerable problems when using these sites for anchorage purposes. AIMS: To find the comparative thickness of the palatal bone at different locations and to validate its morphology for anchorage purposes using mini-implants (MI). SETTINGS AND DESIGN: This investigation was undertaken to compare the mean PBT and level of significance of differences between male and female subjects and between two different age-groups. MATERIALS AND METHODS: The computed tomography (CT) data for 60 patients (30 males and 30 females) in two different age-groups (group A: 15-24 years; group B: 25-35 years) were imported into CAD-based medical software, (MIMICS; Materialise, Belgium) for multiplanar reconstruction. The measurements were made in two planes- transverse and sagittal-and at different positions in each of the planes. STATISTICAL ANALYSIS: The mean and standard deviations of the PBT at different points were calculated. The Student's t-test and Mann-Whitney U test were used for comparisons between the groups. RESULTS: Significant variations were observed in the thickness of the palatal bone for both groups tested, with the anterior region at 4 mm behind the incisive papilla showing the maximum thickness. CONCLUSIONS: Despite the palatal bone being thickest in the mid-palatal suture (MPS) region, this is not the ideal site for anchorage purposes due to inadequate calcification and interposition of connective tissue, especially in young growing children. So, the alternate optimum position is the paramedian region, 3 mm lateral to the MPS and 4 mm from the incisive foramen (IF). PMID- 22842250 TI - The crown angulations and inclinations in Dravidian population with normal occlusion. AB - BACKGROUND: There has always been a constant search for the definition of idealistic and realistic orthodontic treatment goals for different ethnic groups around the world. This study was hence devised to study the mesio-distal angulations and labio-lingual inclinations of the clinical crowns in Dravidian population with pleasing profiles and non-orthodontic normal occlusion. MATERIALS AND METHODS: Forty dental casts from a Dravidian sample (21.5 years) with Class I canine and molar relation; normal maxillo-mandibular relationship; well-aligned arches; with no dental anomaly, restorations or attrition; no history of previous orthodontic treatment, and exhibiting normal growth were studied. A custom-made tip-torque device was used to measure the crown angulations and inclinations. The arithmetic mean and standard deviations for each tooth type were compared with those of Andrew's Caucasian norms using Student's 't' test. RESULTS: The study group exhibited statistically significant decrease in crown angulation (mesial tip) and increased labial crown torque in both upper and lower anteriors. The lower anteriors exhibited distal crown tip while the posteriors were significantly tipped more mesially. All the posteriors demonstrated increased lingual crown torque. CONCLUSION: Tip and torque modifications are suggested for the fine finishing and easy retention of occlusion in Dravidians while using straight wire appliance. PMID- 22842251 TI - Immediate natural tooth pontic: a viable yet temporary prosthetic solution: a patient reported outcome. AB - INTRODUCTION: In patients with hopeless prognosis of the anterior teeth there is still a strong desire to save them for the sake of esthetics. If not grossly carious, broken down or discolored the extracted tooth after suitable modifications can be placed back in its original site by splinting it to the adjacent stable teeth. MATERIALS AND METHODS: Fifteen patients (10 males, 5 females) in the age range of 40-65 years with pathologically migrated, unsalvageable teeth were treated by splinting the extracted teeth immediately with the stable adjacent teeth. After 12 weeks, all the patients were explained various treatment options available for replacement of the lost teeth. The patients were asked to fill out a simple closed ended questionnaire citing the various difficulties encountered during this transitional period, selection of further treatment modalities and the reasons for their choice. The feedback obtained was then analyzed statistically. RESULTS: Hundred percent of patients were happy with the esthetics; however, 60% of them were dissatisfied with the function that it provided. The primary problem being apprehension of splint fracture and difficulty while incising and the data was found to be statistically significant (P=0.01**). All patients demanded a permanent treatment option following this with a fixed prosthesis. None of the patients were interested in the implant supported prosthesis due to cost, treatment time involved, and need for surgery. CONCLUSION: The concept of immediate pontic placement is surely a viable treatment option and promises an excellent transient esthetic solution for a lost tooth as well as enables good preparation of the extraction site for future prosthetic replacement. PMID- 22842252 TI - Evaluation of tensile bond strength of heat cure and autopolymerizing silicone based resilient denture liners before and after thermocycling. AB - AIM: To assess the effect of simulated mouth conditions reproduced with thermocycling on the tensile bond strength of two silicone based resilient denture liners with acrylic resin bases. MATERIALS AND METHODS: Two silicone based soft denture liners (Mollosil - Chairside autopolymerization and Molloplast B - Heat polymerization) were tested. For each liner, 30 specimens with a cross sectional area of 10 Chi 10 mm and thickness 3 mm were processed between two acrylic blocks (Trevalon). Specimens were divided into a control group that was stored for 24 hours in water at 37 degrees C and a test group that was thermocycled (2500 cycles) between baths of 5 degrees and 55 degrees C. Tensile bond strength (kg/cm2) was determined in a universal testing machine using crosshead speed of 5 mm/min. STATISTICAL ANALYSIS USED: The student t-test was used to determine the significance of the difference in bond strength between the two liners. RESULTS: The mean tensile bond strength for control and thermocycled specimens of the two liners were: Mollosil (6.82 kg/cm2 and 8.41 kg/cm2) and Molloplast-B (16.30 kg/cm2 and 13.67 kg/cm2), respectively. Comparison of bond strength of control specimens with thermocycled specimens of the liners indicated a significant difference for both Mollosil (P=0.045) and Molloplast-B (P=0.027). Comparison between control specimens of both liners and thermocycled specimens of both liners indicated a highly significant difference (P<0.001). CONCLUSIONS: Heat polymerized resilient denture liner Molloplast-B had higher tensile bond strength than autopolymerizing liner Mollosil regardless of thermocycling. The bond strength of Mollosil increased after thermocycling while that of Molloplast B decreased after thermocycling. CLINICAL IMPLICATIONS: Although heat-polymerized denture liners require more processing time than autopolymerizing liners, but they display much better adhesion properties to denture base resin and should thus be preferred when soft liner has to be used for a longer duration of time. PMID- 22842253 TI - Impaired neutrophil and monocyte chemotaxis in chronic and aggressive periodontitis and effects of periodontal therapy. AB - BACKGROUND AND OBJECTIVES: Depressed chemotactic activity of polymorphoneutrophil (PMN) and monocyte (MN) appears to be one of the significant risk factors in the development of periodontal disease. Although bacteria are the primary etiologic factor in periodontal disease, the patient's host response is a determinant of disease susceptibility. Depressed chemotaxis of PMN and MN could lead to periodontal destruction by altering the host response i.e. impairment of the normal host response in neutralizing infection and alterations that result in destruction of the surrounding periodontal tissues. MATERIALS AND METHODS: Thirty patients (10 healthy subjects, 10 chronic periodontitis, and 10 with aggressive periodontitis) participated in this study. Clinical parameters like plaque index, gingival index, probing pocket depth, and radiographic assessment were done. The peripheral blood PMNs and MNs were isolated from the patient and the chemotactic response was studied. Statistical analysis was performed using post-hoc Newman Keul range test. RESULTS: PMN and MN chemotaxis was found to be statistically significant (P<0.05) at baseline and three months after periodontal therapy in chronic and aggressive periodontitis group compared to healthy subjects. However on comparison between chronic and aggressive periodontitis group statistical significance was not found (P>0.05).Comparision between chronic periodontitis, aggressive periodontitis with healthy subjects, PMN and MN chemotaxis showed statistical significance (P<0.05) at baseline and three months after periodontal therapy, Whereas statistically there was no difference when chronic periodontitis was compared with aggressive periodontitis. INTERPRETATION AND CONCLUSION: Depressed chemotaxis of PMN and MN results in increased periodontal destruction. In this study, depressed PMN and MN chemotaxis is seen in both aggressive periodontitis group and chronic periodontitis group and the response was altered although to a lesser degree after periodontal therapy in both groups indicating that effect of treatment does exist. PMID- 22842254 TI - The effect of urea on the corrosion behavior of different dental alloys. AB - OBJECTIVE: Intraoral corrosion of dental alloys has biological, functional, and esthetic consequences. Since it is well known that the salivary urea concentrations undergo changes with various diseases, the present study was undertaken to determine the effect of salivary urea concentrations on the corrosion behavior of commonly used dental casting alloys. MATERIALS AND METHODS: Three casting alloys were subjected to polarization scans in synthetic saliva with three different urea concentrations. RESULTS: Cyclic polarization clearly showed that urea levels above 20 mg/100 ml decreased corrosion current densities, increased the corrosion potentials and, at much higher urea levels, the breakdown potentials. CONCLUSION: The data indicate that elevated urea levels reduced the corrosion susceptibility of all alloys, possibly through adsorption of organics onto the metal surface. This study indicates that corrosion testing performed in sterile saline or synthetic saliva without organic components could be misleading. PMID- 22842255 TI - Retrospective study of prevalence of face fractures in southern Brazil. AB - CONTEXT: Trauma has been an important public health problem worldwide. Facial injuries are among the most common types of trauma treated at emergency departments, associated or not with injuries in other anatomic sites. The patterns of facial fractures are usually affected by geography and socioeconomic conditions. AIM: To investigate the prevalence of facial fractures in Lages, state of Santa Catarina, southern Brazil, from September 2003 to August 2008. SETTINGS AND DESIGN: Cross-sectional, retrospective, epidemiological study. MATERIALS AND METHODS: Data on patients' gender, age, etiological agent, and facial region affected by fracture were collected from the charts of patients treated with facial fractures. STATISTICAL ANALYSIS USED: Qualitative variables were expressed as absolute and relative frequencies, and quantitative variables as means and standard deviation. The Chi-square test was used to evaluate the association between gender, traffic accidents and facial region affected. The association between etiological agents and facial region affected was assessed using the chi-square test and the adjusted residuals analysis. RESULTS: 492 patients presented with oral and maxillofacial trauma, with 988 facial fractures; 80.9% of the patients were men, and the most frequent age group was 21-30 years (29.5%). The most frequent causes of fractures were: Traffic accidents in 27.9%, physical assault in 14.9%, and bicycle falls in 10.5%; several other causes scored below 10%. CONCLUSION: Regular publication of epidemiological data is extremely important for the implementation of prevention campaigns and for an increased awareness of the etiology of fractures affecting the face and other anatomic sites. PMID- 22842256 TI - Avenues for rehabilitation of auricular defects. AB - Irrespective of the cause, abnormalities in shape, size, and position of body organs are often perceived as looking wrong. This perception can subject the individual to significant peer ridicule and social ostracism. Rehabilitation of patients with auricular defects can either be done by reconstructive surgery or by prosthetic means. The article draws a comparison between the implant-supported prosthesis and reconstructive surgery, listing the benefits, limitations, indications and contraindications of both the techniques. As both the available techniques give excellent results in appropriately selected situations, the restorative team must present all the alternatives to the patient and choose judiciously the better of the two. PMID- 22842257 TI - Qualitative research and dental public health. AB - The use of Qualitative Research (QR) methods are now getting common in various aspects of health and healthcare research and they can be used to interpret, explore, or obtain a deeper understanding of certain aspects of human beliefs, attitudes, or behavior through personal experiences and perspectives. The potential scope of QR in the field of dental public health is immense, but unfortunately, it has remained underutilized. However, there are a number of studies which have used this type of research to probe into some unanswered questions in the field of public health dentistry ranging from workforce issues to attitudes of patients. In recent health research, evidence gathered through QR methods provide understanding to the social, cultural, and economic factors affecting the health status and healthcare of an individual and the population as a whole. This study will provide an overview of what QR is and discuss its contributions to dental public health research. PMID- 22842258 TI - Flexible resins in the rehabilitation of maxillectomy patient. AB - Surgical resection is an established and common method for treatment of maxillofacial tumors. Such intervening surgery in this region may involve the destruction of antral, nasal, or orbital contents and jaws. Normally, the end result is a defect which may affect speech, swallowing, mastication and facial appearance. Prosthodontic restoration of functions and facial form is an excellent method in the replacement of missing parts and restoration of contour. Pertinent research in materials, designs and methods have resulted in whole array of possible prosthess that can be provided to meet specific patient needs. This case report describes the fabrication of definitive obturator prosthesis made of flexible acrylic resin on a chrome cobalt base. PMID- 22842259 TI - Plasma cell granuloma of lip. AB - Plasma cells are medium-sized round-to-oval cells with eccentrically placed nuclei, usually found in the red pulp of the spleen, tonsils, medulla of the lymph nodes, nasal mucosa, upper airway, lamina propria of the gastrointestinal tract, and sites of inflammation. Plasma cell granuloma is a rare reactive tumor like proliferation composed chiefly of plasmacytic infiltrate. Here, we present a case of plasma cell granuloma of lip in a female patient. PMID- 22842260 TI - Single-rooted primary first molars. AB - Knowledge regarding the morphological variations in roots and root canals aids in successful dental treatment. However, literature regarding dysmorphology of roots in primary dentition is sparse. The purpose of this article is to present a case of bilateral primary mandibular first molars with an unusual morphology of single root. Review of literature regarding variations in root number in primary dentition has been discussed in this article. The etiology for occurrence of such variations has also been briefly reviewed. PMID- 22842261 TI - Bisphosphonate-associated osteonecrosis of the jaws. AB - Bisphosphonates constitute a group of drugs capable of modulating bone turnover and reduce its remodeling when an excessive resorption occurs. This is why they are indicated in a large group of bone diseases like postmenopausal osteoporosis or osteolysis associated with breast cancer or multiple myeloma. Over the last few years and due to their extensive use, many cases of complications associated with their use have been published. Among the most important possible adverse effects are the oral ones, with the appearance of ulcerations and, especially, osteonecrosis of the jaws associated with this therapy. In this paper, we have analyzed the general characteristics of these drugs and their mechanisms of action as well as the described adverse effects, especially oral and maxillofacial, have been made special reference, regarding the prevention of osteonecrosis of the jaws, heightened by cases described in the medical and odontological literature. The preventive protocol backs up the fundamental role of the odontologist in the effective prevention of this process before, during and after the treatment. PMID- 22842262 TI - A CAD-CAM prosthodontic option and gingival zenith position for a rotated maxillary right central incisor: An evaluation. AB - OBJECTIVE: Even with beautifully done restorations, an unattractive gingival zenith position, can negatively affect the smile of a person. In this short communication we describe the treatment of a rotated maxillary right central incisor using a digital photographic approach instead of the conventional approach. BACKGROUND: The conjecture literature on prosthodontic considerations and gingival zenith position in cases of rotated maxillary central incisors is sparse. The gingival zenith level (GZL) in an apical-coronal direction of lateral incisors, relative to the gingival tangential zenith line joining the adjacent central incisor and canine, is approximately 1 mm under healthy conditions. MATERIALS AND METHODS: For our patient, the treatment plan was decided by CAD-CAM technique as Zirconia, jacket crown. Clinical procedures included enameloplasty on the left central and right lateral maxillary incisors. Reduction of the rotated and crooked incisor was performed in the normal manner; periodontal plastic surgery was also done. RESULTS: The patient expressed satisfaction with the intermediary (preliminary) two-dimensional photographs that were provided by the CAD-CAM system. The technique distinguished among the different treatment modalities for aesthetics and to relieve the emotional problems which were faced by female patient. The gingival zenith level of the rotated incisor was also improved. CONCLUSION: Digital imaging provides an immediate treatment option for the patients. Software also provides an interim aid, for the clinician as well as technician, in the form of two-dimensional photographs. CAD-CAM is entirely a helping instrument against the conservative prosthetic options and gingival zenith position for a rotated central incisor. It helps in patient education and in motivation. PMID- 22842263 TI - A nodular growth on maxillary gingiva. AB - A case of angiosarcoma of maxilla is presented. The occurrence of angiosarcoma in the oral cavity is a rare incidence and maxilla is one of the rarest sites to be involved. The purpose of this article is also to emphasize the fact that sometimes small, innocent-looking masses in the oral cavity might actually turn out to be a highly destructive malignant tumor. Hence, a complete radiographic and histopathologic examination is mandatory. PMID- 22842264 TI - Association between gingival crevicular fluid prostaglandin E 2 level and preterm low birth weight. AB - BACKGROUND: Periodontal infections, which serve as a reservoir of inflammatory mediators such prostaglandin E 2 (PGE 2), may pose a threat to the fetal placental unit and cause preterm delivery. AIM: This study was conducted to estimate the PGE 2 levels in gingival crevicular fluid (GCF) and to explore the association between GCF-PGE 2 levels and preterm low birth weight (PLBW). MATERIALS AND METHODS: Twenty-two pregnant patients were selected for the study. GCF samples were collected from these patients before delivery and again at 1 month after delivery. PGE 2 level was estimated using a commercially available ELISA kit (Neogen). RESULTS: The mean GCF-PGE 2 level was 5.8 ng/ml before parturition and 5.5 ng/ml after parturition, but the difference was not statistically significant. There was negative correlation between PGE 2 levels and gestational age at birth. CONCLUSION: The study provides weak evidence that there is correlation between GCF-PGE 2 levels and birth outcome. Further clinical trials with large samples are required to confirm the association between GCF-PGE 2 levels and PLBW. PMID- 22842265 TI - Carisolv as an endodontic irrigant in deciduous teeth: an SEM study. AB - AIM: Root canal irrigation plays an important role in the debridement and disinfection of the root canal system. "The purpose of this study was to evaluate the efficacy of Carisolv , 1% sodium hypochlorite (NaOCl) gel, and 1% NaOCl solution as root canal irrigants in deciduous anterior teeth." MATERIALS AND METHODS: THIRTY-six extracted deciduous anterior teeth were used. Root canals were flooded with NaOCl solution in Group A, NaOCl gel in Group B and Carisolv in Group C and incubated for 30 min. Scanning electron microscope photomicrographs of canal wall debris in the apical, middle and coronal thirds were scored. RESULTS: The results showed that regardless of irrigation regime, canals were consistently cleaner in the coronal and middle thirds than in the apical thirds. NaOCl solution, NaOCl gel, and Carisolv had comparable activity at coronal third and middle third of root canals. At the apical third, NaOCl solution cleaned canals better than NaOCl gel and Carisolv. Carisolv cleaned debris better than NaOCl gel at the apical third. CONCLUSION: Carisolv can be used as an adjunct to root canal preparation. PMID- 22842266 TI - Access to public dental care facilities in Chandigarh. AB - OBJECTIVES: The objective of the study was to determine the level of dental health care access and associated factors, at various public health facilities in the Union Territory (UT) of Chandigarh. MATERIALS AND METHODS: A study was done using a multistage random sampling technique, to interview adult respondents at their homes and to interview the dentists in the public dental clinics and hospitals. RESULTS: The mean composite access score was 59.2 (SD 18.9) in urban areas and 60.5 (SD 20.9) in rural areas (P=0.64) on a scale of 100. The mean score for the self-perceived condition of their oral health was 6.47 (95% CI 6.17 - 6.76). Thirty-four percent of the respondents did not contact a dentist despite having a problem in the last year, primarily because dental problems were not important for them (45%), they lacked time (22%), and took self-medication (16%). Overall 58% of the respondents suggested government clinics and 44% liked private dentists for treatment of dental cavities. The government setup was preferred because the facilities were cheaper and affordable. CONCLUSIONS: Dental health care access and only limited dental facilities were available in most of the dental clinics in Chandigarh. Self-reported dental problem was low, and people ignored their dental problems. PMID- 22842267 TI - Immunomorphological assessment of regional lymph nodes for predicting metastases in oral squamous cell carcinoma. AB - BACKGROUND: Oral squamous cell carcinoma is the most common neoplasm and comprises of approximately 80% of the cancers occurring in the oral cavity. The role of the host response to this neoplasm has been recognized, and for many years the regional lymph node in tumor-bearing hosts has been considered as an anatomic barrier to the systematic dissemination of tumor cells. Morphological evaluation of the regional nodes has aided in understanding the immune response. AIM: The current study was carried out to observe the morphological changes occurring in the regional lymph nodes and to evaluate whether these features could be helpful in assessing the immunological status of the patient, and thereby, the prognosis of the patient. MATERIALS AND METHODS: The study was based on lymph nodes from 63 patients with oral squamous cell carcinoma, who underwent radical neck dissection or modified neck dissection. In the lymph node, four morphological patterns were observed that included lymphocyte predominance, germinal center predominance, mixed pattern (sinus Histiocytosis), and an unstimulated pattern. The cases were then divided into four groups according to the predominant immunoreactivity pattern based on the World Health Organization (WHO) standardized system for reporting human lymph node morphology. RESULTS: Revealed that risk of metastases to cervical lymph nodes in patients with lymphocyte predominance was less (28.6%) when compared to the high risk of metastases with germinal center predominance (68%), and these results were statistically significant (P < 0.05). Patients with a mixed pattern showed less risk of metastases (45.4%), while those with an unstimulated pattern had increased risk of metastases (66.6%), but the results were not statistically significant. It was also found that in the positive nodes, germinal center hyperplasia (50.2%) was the predominant pattern. CONCLUSION: The present study revealed that patients with lymphocyte predominance had less risk of metastases and patients with germinal center predominance had a high risk of metastases to the lymph node. PMID- 22842268 TI - Comparative evaluation of condylar position in symptomatic (TMJ dysfunction) and asymptomatic individuals. AB - CONTEXT: The etiopathogenesis of temporomandibular joint (TMJ) disorders has been attributed to multiple factors and, while the importance of centric relation (CR) has been acknowledged in dental literature, the role of condylar position and CR CO (CO-centric occlusion) discrepancy in TMJ dysfunction (TMD) has been a source of controversy. AIM: To establish the relationship between condyle position and TMD. SETTING AND DESIGN: This was a case-control study to evaluate condylar displacement and interarch CR-CO discrepancy in symptomatic subjects (with TMD) and compare them with asymptomatic subjects. MATERIALS AND METHODS: Forty subjects were screened for TMD based on Helkimo index and grouped into asymptomatic and symptomatic groups. CR was registered using the modified Roth power centric bite registration after neuromuscular deprogramming. Models thus mounted on an Advanced Dental Design (AD2) articulator were evaluated for interarch CR-CO discrepancy. The condylar position discrepancy was recorded on a device MCD (measured condylar deviation). STATISTICAL ANALYSIS: The Student's t test was used to test statistical significance. The paired t test and the unpaired t test were used for comparing results within and between the groups. Pearson correlation coefficient was used to find out the correlation between MCD measurements and dental three-dimensional (3D) model analysis measurements. The Chi-square test was used to evaluate the qualitative data. RESULTS: The average vertical and horizontal condylar displacements were significantly greater in the symptomatic group than in the asymptomatic group. There were significant deviations at the level of the occlusion in both groups. CONCLUSION: Condyle position may play a significant role in the etiopathogenesis of TMJ disorders. PMID- 22842269 TI - Tobacco cessation in India: a contemporary issue in public health dentistry. AB - In India, tobacco use is incredibly linked to poverty and accounts for the high public health costs of treating tobacco-related diseases. Dental public health programs aid in detecting the tobacco-related periodontal diseases, oral cancers, etc., where the majority belongs to the submerged portion of iceberg, which otherwise leads to substantial morbidity and mortality. Moreover, public health dentists plays a key role in identifying both clinical and subclinical cases and aid in tobacco use cessation through various modes of health education and counseling. Therefore, the community-based measures are deemed to be the most cost-effective tool for tobacco cessation. PMID- 22842270 TI - A biochemical and histopathological evaluation of generalized pulp calcification in young permanent teeth. AB - Pulp calcifications are a frequent finding on bitewing and periapical radiographs in older age-groups but their occurrence in the entire dentition in young subjects is unusual. We report such an unusual occurrence of generalized pulp calcification in a 13-year-old Indian female. Radiographic examination of the dentition revealed pulp calcifications in all permanent teeth, located mostly in the pulp chamber but with some in the root canals. The patient's dental, medical, and family history was noncontributory. Biochemical analysis of the removed pulp calcification from one of the teeth during endodontic treatment showed large amounts of calcium, phosphorus, and carbonate. However, metabolic evaluation of patient through liver and kidney function tests and other blood investigations did not reveal any metabolic disorder. The patient was also evaluated for any systemic, syndromic, or genetic involvement but this was also noncontributory. Therefore, we propose that this unusual case of generalized pulp calcification is of idiopathic origin. In this work, histopathological and biochemical evaluations of the pulp calcification was done to try and understand the initiation and progress of calcifications in pulpal tissue. PMID- 22842271 TI - Orodental findings in Hallermann-Streiff syndrome. AB - Hallermann-Streiff syndrome-also called occulomandibulofacial syndrome, Francois syndrome, oculomandibulodyscephaly with hypotrichosis, Aubry syndrome I, and Ullrich-Fremery-Dohna syndrome-is a rare genetic disorder, which comprisesmultiple congenital abnormalities affecting chiefly the head and face. It is characterized by bird-like facies, dental abnormalities, hypotrichosis, atrophy of skin, congenital cataracts, bilateral microphthalmia, and proportionate nanism. An interesting case of Hallermann-Streiff syndrome in a 23 year-old female patient is reported here, with the emphasis on the orodental findings. PMID- 22842272 TI - Effect of material, process parameters, and simulated body fluids on mechanical properties of 13-93 bioactive glass porous constructs made by selective laser sintering. AB - The effect of particle size distribution, binder content, processing parameters, and sintering schedule on the microstructure and mechanical properties of porous constructs was investigated. The porous constructs were produced by indirect selective laser sintering (SLS) of 13-93 bioactive glass using stearic acid as a polymeric binder. The binder content and d(50) particle size in the feedstock powders were simultaneously reduced from 22 to 12 wt% and from 20 to 11 MUm, respectively, to identify the minimum binder content required for the SLS fabrication. An average particle size of ~16 MUm with a binder content of 15 wt% significantly reduced post-processing time and improved mechanical properties. Increasing the laser power and scan speed at the energy density of 1 cal/cm2 maintained the feature sharpness of the parts during the fabrication of green parts and could almost double the mechanical properties of the sintered parts. Changes in the heating rates, ranging from 0.1 to 2 degrees C/min, during the post-processing of the fabricated "green" scaffolds showed that the heating rate significantly affects the densification and mechanical properties of the sintered scaffolds. The compressive strength of the scaffolds manufactured with the optimized parameters varied from 41 MPa, for a scaffold with a porosity of ~50%, to 157 MPa, for a dense part. The bioactive scaffolds soaked in simulated body fluids for durations up to 6 weeks were used to evaluate the change in mechanical properties in vitro. PMID- 22842274 TI - Influence of ageing treatment on microstructure, mechanical and bio-corrosion properties of Mg-Dy alloys. AB - Mg-Dy alloys have shown to be promising for medical applications. In order to investigate the influence of ageing treatment on their mechanical and corrosion properties, three Mg-xDy alloys (x=10, 15, 20 wt%) were prepared. Their microstructure, mechanical and corrosion behavior were investigated. The results indicate that ageing at 250 degrees C has little influence on the mechanical and corrosion properties. In contrast, ageing at 200 degrees C significantly increases the yield strength, and reduces the ductility. After ageing at 200 degrees C, the corrosion rate of Mg-20Dy alloy increases largely in 0.9 wt% NaCl solution, but remains unchanged in cell culture medium. PMID- 22842273 TI - Mechanics and kinematics of soft tissue under indentation are determined by the degree of initial collagen fiber alignment. AB - While several studies have evaluated how the degree of collagen alignment affects the response of soft tissues to tensile loading, the role of fibrillar organization in indentation is less understood. Collagen-based tissue-equivalents (TEs) provide a convenient model system to explore structure-function relationships since their microstructural properties can be easily controlled during fabrication. The purpose of this study was to evaluate the role of initial collagen alignment on the mechanical and structural behavior of soft tissues subjected to indentation using TEs as a model system. Cell-compacted TEs with either isotropic or highly anisotropic fiber alignment were subjected to four step incremental stress-relaxation indentation tests. The mechanical properties, collagen reorganization and 2D strain patterns were quantified at each indentation step and compared between groups. While no differences were seen in the peak force response, significant differences were seen in relaxation behavior, fiber kinematics and tissue strain. Specifically, highly aligned samples exhibited a slower relaxation rate, smaller changes in collagen fiber orientation, larger changes in strength of alignment, and larger strain magnitudes compared to isotropic samples. Results demonstrate the significant role that microstructural organization plays in mediating the response of soft tissues to a non-tensile (i.e., indentation) mechanical stimulus. PMID- 22842275 TI - Determination of the translational and rotational stiffnesses of an L4-L5 functional spinal unit using a specimen-specific finite element model. AB - The knowledge of spinal kinematics is of paramount importance for many aspects of clinical application (i.e. diagnosis, treatment and surgical intervention) and for the development of new spinal implants. The aim of this study was to determine the translational and rotational stiffnesses of a functional spinal unit (FSU) L4-L5 using a specimen-specific finite element model. The results are needed as input data for three-dimensional (3D) multi-body musculoskeletal models in order to simulate vertebral motions and loading in the lumbar spine during daily activities. Within the modelling process, a technique to partition the constitutive members and to calibrate their mechanical properties for the complex model is presented. The material and geometrical non-linearities originating from the disc, the ligaments and the load transfer through the zygapophysial joints were considered. The FSU was subjected to pure moments and forces in the three anatomical planes. For each of the loading scenarios, with and without vertical and follower preload, the presented technique provides results in fair agreement with the literature. The novel representation of the nonlinear behaviour of the translational and rotational stiffness of the disc as a function of the displacement can be used directly as input data for multi-body models. PMID- 22842276 TI - Compression fatigue behavior of laser processed porous NiTi alloy. AB - Porous metals are being widely used in load bearing implant applications with an aim to increase osseointegration and also to reduce stress shielding. However, fatigue performance of porous metals is extremely important to ensure long-term implant stability, because porous metals are sensitive to crack propagation even at low stresses especially under cyclic loading conditions. Herein we report high cycle compression-compression fatigue behavior of laser processed NiTi alloy with varying porosities between ~1% and 20%. The results show that compression fatigue of porous NiTi alloy samples is in part similar to metal foams. The applied stress amplitude is found to have strong influence on the accumulated strain and cyclic stability. The critical stress amplitudes associated with rapid strain accumulation in porous NiTi alloy samples, with varying relative densities, were found to correspond to 140% of respective 0.2% proof strength indicating that these samples can sustain cyclic compression fatigue stresses up to 1.4 times their yield strength without failure. PMID- 22842277 TI - Time-dependent failure of amorphous poly-D,L-lactide: influence of molecular weight. AB - The specific time-dependent deformation response of amorphous poly(lactic acid) (PLA) is known to lead to rapid failure of these materials in load-bearing situations. We have investigated this phenomenon in uniaxial compression on P(L)DLLA samples with various molecular weights. The experiments revealed a strong dependence of the yield stress on the applied strain rate. Lower molecular weights showed identical deformation kinetics as higher molecular weights, albeit at lower stress values. This dependence on molecular weight was incorporated into an Eyring-equation by introducing mobility through a virtual temperature that is shifted by the deviation of the T(g) from T(g,infinity). Stress-dependent lifetime of polymer constructs was described by the use of this modified Eyring equation, combined with a critical plastic strain. This model proves useful in predicting the molecular weight dependence of the time to failure, although it slightly overestimates life time at low stress levels for a material with very low molecular weight. The versatility of the model is demonstrated on e-beam sterilized PLDLLA, where the resulting reduction in molecular weight induces a substantial decrease in lifetime. A single T(g) measurement provides sufficient information to predict the decrease in lifetime. PMID- 22842278 TI - Flexural mechanical properties of porcine aortic heart valve leaflets. AB - Freshly excised porcine aortic heart valve cusps were subjected to a uni-axial flexural indentation test, from which the rupture characteristics and a functional stiffness parameter were determined. It was found that the flexural mechanical properties of aortic valve cusps (i) are unaffected by their coronary position and (ii) are sensitive to the effect of mechanical preconditioning. The resulting values of the cusp's flexural mechanical properties are intended as a set of reference properties which scaffolds, meant for the tissue engineering of heart valves, must approximate in order to be considered as a functional replacement. PMID- 22842279 TI - Micromechanical characterisation of failure in acrylic bone cement: the effect of barium sulphate agglomerates. AB - Acrylic bone cement has been established as a method of fixation of load-bearing orthopaedic implants for nearly five decades, and has produced excellent long term clinical results. However, increasing patient BMI values and longer life expectancies are placing ever greater demands on joint replacements, so there is a need to further improve the performance of cemented fixation. Damage accumulation in the in vivo cement mantle due to initiation and coalescence of fatigue micro-cracks has been implicated in the aseptic loosening and failure of implants. While the effect of porosity on crack initiation processes has been widely reported, the relative influence of different radiopacifying agents is less well studied. In particular, barium sulphate radiopacifier particles have been reported to form large agglomerates within the cement that have been linked to initiation of fatigue cracks in vitro. However, there appears to be little understanding of the micromechanical aspects of cement failure due to barium sulphate agglomeration. The present study utilised micro-computed tomography (MUCT) and field emission gun scanning electron microscopy (FEG-SEM), alongside mechanical testing, to provide a systematic, quantitative assessment of the effect of barium sulphate agglomeration on crack initiation processes in a conventional, vacuum-mixed acrylic cement. Three-dimensional characterisation of defect populations was performed, with agglomerates of barium sulphate particles found to be large (up to 0.37 mm equivalent spherical diameter), present at spatial densities up to 22 per mm3, and evenly distributed through each cement specimen. Fatigue cracks consistently initiated at the largest agglomerates; furthermore, fatigue life was found to scale consistently with largest defect size. As such, the tendency of barium sulphate particles to agglomerate is clearly evidenced to be detrimental to the fatigue performance of this cement in vitro. Optimisation of mixing techniques and/or cement formulations containing barium sulphate may therefore be advantageous to reduce the formation of agglomerates and their potential effects in vivo. PMID- 22842280 TI - Mechanical properties of Indonesian-made narrow dynamic compression plate. AB - Osteosynthesis plates are clinically used to fixate and position a fractured bone. They should have the ability to withstand cyclic loads produced by muscle contractions and total body weight. The very high demand for osteosynthesis plates in developing countries in general and in Indonesia in particular necessitates the utilisation of local products. In this paper, we investigated the mechanical properties, i.e. proportional limit and fatigue strength of Indonesian-made Narrow Dynamic Compression Plates (Narrow DCP) as one of the most frequently used osteosynthesis plates, in comparison to the European AO standard plate, and its relationship to geometry, micro structural features and surface defects of the plates. All Indonesian-made plates appeared to be weaker than the standard Narrow DCP because they consistently failed at lower stresses. Surface defects did not play a major role in this, although the polishing of the Indonesian Narrow DCP was found to be poor. The standard plate showed indications of cold deformation from the production process in contrast to the Indonesian plates, which might be the first reason for the differences in strength. This is confirmed by hardness measurements. A second reason could be the use of an inferior version of stainless steel. The Indonesian plates showed lower mechanical behaviour compared to the AO-plates. These findings could initiate the development of improved Indonesian manufactured DCP-plates with properties comparable to commonly used plates, such as the standard European AO-plates. PMID- 22842281 TI - Assessment of lamellar level properties in mouse bone utilizing a novel spherical nanoindentation data analysis method. AB - In this work, we demonstrate the viability of using our recently developed data analysis procedures for spherical nanoindentation in conjunction with Raman spectroscopy for studying lamellar-level correlations between the local composition and local mechanical properties in mouse bone. Our methodologies allow us to convert the raw load-displacement datasets to much more meaningful indentation stress-strain curves that accurately capture the loading and unloading elastic moduli, the indentation yield points, as well as the post-yield characteristics in the tested samples. Using samples of two different inbred mouse strains, A/J and C57BL/6J (B6), we successfully demonstrate the correlations between the mechanical information obtained from spherical nanoindentation measurements to the local composition measured using Raman spectroscopy. In particular, we observe that a higher mineral-to-matrix ratio correlated well with a higher local modulus and yield strength in all samples. Thus, new bone regions exhibited lower moduli and yield strengths compared to more mature bone. The B6 mice were also found to exhibit lower modulus and yield strength values compared to the more mineralized A/J strain. PMID- 22842282 TI - Retrieval analysis of three generations of Biolox(r) femoral heads: spectroscopic and SEM characterisation. AB - Wear and osteolysis continue to be the major reasons for revision surgery in Total Hip Arthroplasty. The introduction of the ceramic-on-ceramic bearings eliminates the problem of polyethylene wear debris. During the last 40 years, three generations of Biolox(r) ceramics were developed (Biolox(r), Biolox(r) forte, and Biolox(r) delta), each better than the previous from the density, grain size and purity point of view. We conducted a retrieval study on 15 Biolox(r) femoral heads (Biolox(r), Biolox(r) forte, and Biolox(r) delta) articulating against liners of the same type. Surface properties and residual stress were assessed using SEM, fluorescence and Raman spectroscopy. At SEM examination, the Biolox(r) delta retrievals showed a lower wear than the previous generations. The fluorescence measurements suggested different wear mechanisms in the three sets of retrievals. Micro-cracking was predominant in Biolox(r), while in Biolox(r) forte and Biolox(r) delta a wider range of residual stress values was observed upon wear. Surface polishing was observed only in Biolox(r) and Biolox(r) forte. Raman spectroscopy of Biolox(r) delta femoral heads showed a progressive improvement in material composition. Wear induced a tetragonal to monoclinic transformation. The Raman results on the retrievals, here reported for the first time, allowed to validate the in vitro ageing protocols proposed in the literature to simulate the effects of the in vivo wear. PMID- 22842283 TI - Auditing resuscitation performance: innovating to improve practice. PMID- 22842284 TI - Decreases in basic life support chest compression fraction after advanced life support arrival. PMID- 22842285 TI - A comparison of rectilinear and truncated exponential biphasic waveforms in elective cardioversion of atrial fibrillation: a prospective randomized controlled trial. AB - BACKGROUND: Several different biphasic waveforms are used clinically, but few studies have compared their efficacy. The two main waveforms are the biphasic rectilinear (BR) and biphasic truncated exponential (BTE) waveforms, both of which have important differences, particularly at the extremes of transthoracic impedance. OBJECTIVE: To compare the efficacy of two commonly used defibrillation waveforms in the elective cardioversion of atrial fibrillation. METHODS: In a prospective randomized controlled study, sequential adult patients undergoing elective cardioversion for AF were recruited. Patients were randomized to receive synchronized defibrillation using either a BR or BTE waveform, both using a 50J, 100J, 150J, 200J, 200J selected energy escalating protocol. Failure to cardiovert after the fifth shock was classed as failed defibrillation. The power of this study was 80% with 5% significance level to detect a difference of 20% or greater between groups. Survival analysis was used to compare the total energy delivered to achieve successful cardioversion between groups. RESULTS: A total of 202 patients were recruited, of which data are complete for 199 (100 BR; 99 BTE). Median number of shocks to achieve cardioversion was 2 for the BR waveform and 3 for the BTE waveform (P = 0.059). In the BR waveform group, 95/100 (95.0%) achieved sinus rhythm. In the BTE waveform group, 90/99 (90.9%) achieved sinus rhythm and this group required on average 117.1J more energy to achieve the outcome compared to the BR waveform group (P = 0.838). CONCLUSIONS: BR and BTE waveforms show similar high efficacy in the elective cardioversion of atrial fibrillation. PMID- 22842287 TI - Inverse correlation between cohesive energy and thermal expansion coefficient in liquid transition metal alloys. AB - The volume expansion coefficients (alpha) of twenty-five glass-forming transition metal alloy liquids, measured using the electrostatic levitation technique, are reported. An inverse correlation between alpha and the cohesive energy is found. The predicted values of alpha from this relationship agree reasonably well with the published data for thirty other transition metal and alloy liquids; some disagreement was found for a few alloys containing significant amounts of group III and IV elements. A theoretical argument for this empirical relationship is presented. PMID- 22842286 TI - Development and validation of quantitative real-time polymerase chain reaction assays to detect elephant endotheliotropic herpesviruses-2, 3, 4, 5, and 6. AB - Elephant endotheliotropic herpesviruses (EEHVs) can cause lethal hemorrhagic disease in both African and Asian elephants. At least seven EEHV types have been described, and sensitive real-time PCR tests have been developed for EEHV1A and 1B, which are associated with the majority of characterized Asian elephant deaths. Despite growing knowledge of the different EEHV types, the prevalence of each type within African and Asian elephants remains to be determined and there is considerable need for diagnostic tests to detect and discriminate between each EEHV species for clinical management of African and Asian elephants that develop illness from one or more of these viruses. To begin to address these issues, we developed real-time PCR assays for EEHV2, 3, 4, 5, and 6. Overall, each assay had robust PCR efficiency, a dynamic linear range over 5log(10) concentrations, a limit of detection of 10 copies/test reaction with 100% sensitivity, and low intra- and inter-assay variability. Each assay proved to be specific for the EEHV targets for which it was designed, with the exception of EEHV3 and EEHV4, which was expected because of greater DNA sequence similarity between these two EEHV species than the others. These new tools will be useful for conducting surveys of EEHV prevalence within captive and range country elephants, for diagnostic testing of elephants with suspected EEHV-associated disease, and for managing the treatment of elephants with EEHV-induced illness. PMID- 22842288 TI - Correlation between the crystal structure and the Curie temperature in RCu3(Mn3Fe)O12 (R = rare-earth) complex perovskites. AB - New members of the family of complex-perovskite oxides with the formula RCu(3)(Mn(3)Fe)O(12) (R = Ce, Pr, Tb, Dy, Ho, Er, Tm, Yb, Lu and Y) have been synthesized and characterized. Polycrystalline samples have been prepared from citrate precursors treated under moderate pressure conditions (2-3.5 GPa) and 1000 degrees C in the presence of KClO(4) as an oxidizing agent. All the samples have been studied by neutron powder diffraction (NPD) at 300 K and 2 K. These oxides crystallize in the cubic space group Im3 (no. 204). Mn(4+)/Mn(3+) and Fe(3+) occupy at random the octahedral B positions of the perovskite structure. These materials have also been characterized by magnetic and magnetotransport measurements. The observed enhancement of T(C) along the RCu(3)(Mn(3)Fe)O(12) series is understood as an effect of the chemical pressure on the (Mn,Fe)-O bonds as R(3+) size decreases. The semiconducting behaviour observed in all of the samples is related with the introduction of Fe at B position. Despite the drastic change of the transport properties, significant negative magnetoresistance values are observed in the Fe-containing compounds both at 10 K and 300 K. PMID- 22842289 TI - Membrane proteins of human fetal primitive nucleated red blood cells. AB - In humans, primitive fetal nucleated red blood cells (FNRBCs) are thought to be as vital for embryonic life as their counterpart, adult red blood cells (adult RBCs) are in later-gestation fetuses and adults. Unlike adult RBCs, the identity and functions of FNRBC proteins are poorly understood owing to a scarcity of FNRBCs for proteomic investigations. The study aimed to investigate membrane proteins of this unique cell type. We present here, the first report on the membrane proteome of human primitive FNRBCs investigated by two-dimensional liquid chromatography coupled with mass-spectrometry (2D-LCMS/MS) and bioinformatics analysis. A total of 273 proteins were identified, of which 133 (48.7%) were membrane proteins. We compared our data with membrane proteins of adult RBCs to identify common, and unique, surface membrane proteins. Twelve plasma membrane proteins with transmembrane domains and eight proteins with transmembrane domains but without known sub-cellular location were identified as unique-to-FNRBCs. Except for the transferrin receptor, all other 19 unique-to FNRBC membrane proteins have never been described in RBCs. Reverse-transcriptase PCR (RT-PCR) and immunocytochemistry validated the 2D-LCMS/MS data. Our findings provide potential surface antigens for separation of primitive FNRBCs from maternal blood for noninvasive prenatal diagnosis, and to understand the biology of these rare cells. PMID- 22842290 TI - Mass spectrometry imaging for drug distribution studies. AB - Since its introduction mass spectrometry imaging (MSI) has proven to be a powerful tool for the localization of molecules in biological tissues. In drug discovery and development, understanding the distribution of both drug and its metabolites is of critical importance. Traditional methods suffer from a lack of spatial information (tissue extraction followed by LCMS) or lack of specificity resulting in the inability to resolve parent drug from its metabolites (whole body autoradiography). MSI is a sensitive and label-free approach for imaging drugs and metabolites in tissues. In this article we review the different MSI technologies that have been applied to the imaging of pharmaceuticals. Recent technical advances, applications and current analytical limitations are discussed. PMID- 22842291 TI - Eight independent nuclear genes support monophyly of the plovers: the role of mutational variance in gene trees. AB - Molecular phylogenies of Charadriiformes based on mtDNA genes and one to three nuclear loci do not support the traditional placement of Pluvialis in the plovers (Charadriidae), assigning it instead to oystercatchers, stilts, and avocets (Haematopodidae and Recurvirostridae). To investigate this hypothesis of plover paraphyly, the relationships among Pluvialis and closely related families were revisited by sequencing two individuals of all taxa except Peltohyas for eight independent single copy nuclear protein-coding loci selected for their informativeness at this phylogenetic depth. The species tree estimated jointly with the gene trees in the coalescent programme (*)BEAST strongly supported plover monophyly, as did Bayesian analysis of the concatenated matrix. The data sets that supported plover paraphyly in Baker et al. (2007) and Fain and Houde (2007) reflect two to four independent gene histories, and thus discordance with the plover monophyly species tree might have arisen by chance through stochastic mutational variance. For the plovers we conclude there is no conclusive evidence of coalescent variance from ancient incomplete lineage sorting across the interior branch leading to Pluvialis in the species tree. Rather, earlier studies seem have been misled by faster evolving mtDNA genes with high mutational variance, and a few nuclear genes that had low resolving power at the Pluvialis sister group level. These findings are of general relevance in avian phylogenetics, as they show that careful attention needs to be paid to the number and the phylogenetic informativeness of genes required to obtain accurate estimates of the species tree, especially where there is mutational heterogeneity in gene trees. PMID- 22842292 TI - Comparative phylogeography of two widespread magpies: importance of habitat preference and breeding behavior on genetic structure in China. AB - Historical geological events and climatic changes are believed to have played important roles in shaping the current distribution of species. However, sympatric species may have responded in different ways to such climatic fluctuations. Here we compared genetic structures of two corvid species, the Azure-winged Magpie Cyanopica cyanus and the Eurasian Magpie Pica pica, both widespread but with different habitat dependence and some aspects of breeding behavior. Three mitochondrial genes and two nuclear introns were used to examine their co-distributed populations in East China and the Iberian Peninsula. Both species showed deep divergences between these two regions that were dated to the late Pliocene/early Pleistocene. In the East Chinese clade of C. cyanus, populations were subdivided between Northeast China and Central China, probably since the early to mid-Pleistocene, and the Central subclade showed a significant pattern of isolation by distance. In contrast, no genetic structure was found in the East China populations of P. pica. We suggest that the different patterns in the two species are at least partly explained by ecological differences between them, especially in habitat preference and perhaps also breeding behavior. These dissimilarities in life history traits might have affected the dispersal and survival abilities of these two species differently during environmental fluctuations. PMID- 22842293 TI - Evolution in the deep sea: biological traits, ecology and phylogenetics of pelagic copepods. AB - Deep-sea biodiversity has received increasing interest in the last decade, mainly focusing on benthic communities. In contrast, studies of zooplankton in the meso- to bathypelagic zones are relatively scarce. In order to explore evolutionary processes in the pelagic deep sea, the present study focuses on copepods of two clausocalanoid families, Euchaetidae and Aetideidae, which are abundant and species-rich in the deep-sea pelagic realm. Molecular phylogenies based on concatenated-portioned data on 18S, 28S and internal transcribed spacer 2 (ITS2), as well as mitochondrial cytochrome c oxidase subunit I (COI), were examined on 13 species, mainly from Arctic and Antarctic regions, together with species specific biological traits (i.e. vertical occurrence, feeding behaviour, dietary preferences, energy storage, and reproductive strategy). Relationships were resolved on genus, species and even sub-species levels, the latter two established by COI with maximum average genetic distances ranging from <=5.3% at the intra-specific, and 20.6% at the inter-specific level. There is no resolution at a family level, emphasising the state of Euchaetidae and Aetideidae as sister families and suggesting a fast radiation of these lineages, a hypothesis which is further supported by biological parameters. Euchaetidae were similar in lipid specific energy storage, reproductive strategy, as well as feeding behaviour and dietary preference. In contrast, Aetideidae were more diverse, comprising a variety of characteristics ranging from similar adaptations within Paraeuchaeta, to genera consisting of species with completely different reproductive and feeding ecologies. Reproductive strategies were generally similar within each aetideid genus, but differed between genera. Closely related species (congeners), which were similar in the aforementioned biological and ecological traits, generally occurred in different depth layers, suggesting that vertical partitioning of the water column represents an important mechanism in the speciation processes for these deep-sea copepods. High COI divergence between Arctic and Antarctic specimens of the mesopelagic cosmopolitan Gaetanus tenuispinus and the bipolar Aetideopsis minor suggest different geographic forms, potentially cryptic species or sibling species. On the contrary, Arctic and Antarctic individuals of the bathypelagic cosmopolitans Gaetanus brevispinus and Paraeuchaeta barbata were very similar in COI sequence, suggesting more gene flow at depth and/or that driving forces for speciation were less pronounced in bathypelagic than at mesopelagic depths. PMID- 22842294 TI - The diagnosis of calcium pyrophosphate dihydrate crystal deposition disease: the good, the bad and... ultrasonography! PMID- 22842295 TI - The pathogenesis of the anaemia of chronic disorders. AB - Anemia of chronic disorders is a typical condition of infective, immunological and neoplastic diseases. Hepcidin and proinflammatory cytokines play a leading role in its pathogenesis. Hepcidin is a hormone produced by the liver that controls iron metabolism. It ensures that iron is retained by enterocytes (where the metal is absorbed) and by macrophages (that store the iron that results from the physiological breakdown of erythrocytes). Cytokines play a role in hepcidin synthesis, and in the proliferation and the maturation of the erythroid components within bone marrow. This paper discusses the pathogenetic mechanisms of anemia in chronic disorders. PMID- 22842296 TI - Neuropeptide levels in Dercum's disease (adiposis dolorosa). AB - Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), beta-endorphin-like immunoreactivity (beta-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), gamma2-melanocyte-stimulating hormone-like immunoreactivity (gamma2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease. PMID- 22842297 TI - The role of illness perception and emotions on quality of life in fibromyalgia compared with other chronic pain conditions. AB - OBJECTIVE: Fibromyalgia syndrome (FMs) is a chronic widespread pain condition that can negatively impact on all aspects of patient's life. The purpose of this study was: first, to evaluate illness perception (IP), quality of life (QoL) and affective-emotive variables (EAV) of patients with FM; and second, to compare these variables to different pain conditions. METHODS: Consecutive 34 women (mean age 47.4+/-8.3 years) affected by FM were enrolled for the study from December 2009 to May 2011. IP was evaluated by means of the Revised Illness Perception Questionnaire, QoL through Nottigham Health Profile and EAV through the Beck Depression Inventory. Scores were compared with rheumatoid arthritis (RA) (n=20; mean age 53+/-12.8 years) and low back pain (LBP) (n=20; 51.3+/-7.8 years) groups. RESULTS: FM patients scored higher than RA and LBP groups on IP (Identity scale mean: FM=8.8+/-2.3, AR=5.5+/-3.3, LBP=4.1+/-2.9; Kruskal-Wallis=24.42). Moreover FM patients show higher EAV (mean FM=21+/-9.6, AR=8.9+/-5.6, LBP=14.9+/ 6.5; Kolmogorov-Smirnov Z=2.17) and QoL (Pain scale mean: FM=74.2+/-24.1; AR=35.7+/-19.9; LBP=56.5+/-20.4; Kolmogorov-Smirnov Z=2.27; Energy scale mean: FM=86.2+/-28.5; AR=46.8+/-35.4; LBP=61.6 +/-63.7; Kolmogorov-Smirnov Z=1.98) than RA group. CONCLUSIONS: Our study highlighted dysfunctional IP, low QoL, high EAV scores in FM patients and the significant relations between these variables. Research results provided support for relevance of a multidisciplinary approach to the management of FM, including psychological interventions, according to a biopsychosocial perspective. PMID- 22842298 TI - Effectiveness of cognitive behavioral therapy in the treatment of fibromyalgia syndrome: a meta-analytic literature review. AB - Fibromyalgia (FM) is a chronic disorder caused by a dysfunction of central nervous system sensitization. This syndrome is characterized by widespread pain and diffuse tenderness, but often also presents fatigue, sleep disturbances, and a whole range of symptoms such as morning stiffness, decreased physical function and dyscognition. FM is usually treated with pharmacological and non pharmacological treatments. The non-pharmacological interventions include cognitive behavioral therapy (CBT), physiotherapy, acupuncture and patient education programs. In order to evaluate the efficacy of CBT and compare it with other non-pharmacological treatments, we performed a review of the meta-analytic literature. We evaluated the methodological quality of publications found by following the recommendations of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data showed that CBT does not provide better results than other non-pharmacological treatments on outcomes of pain, fatigue, sleep disturbance and quality of life, at either a short or long term evaluation. On the contrary, CBT seems to be more effective on symptoms of depression for a short period, whereas it considerably improves the pain self management and reduces the number of visits to the doctor. The data currently available indicate that cost-effectiveness studies could help us to understand whether the reduction in the number of visits to the doctor could balance the cost of CBT to the health public system. PMID- 22842299 TI - Long-term cyclic intravenous iloprost in systemic sclerosis: clinical experience from a single center. AB - The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12+/-41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxon's signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allen's test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94 4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed. PMID- 22842300 TI - Hypovitaminosis D in an hospitalized old population of Western Friuli. AB - OBJECTIVES: Hypovitaminosis D is very common in the elderly in Italy and generally in the world, contributing to bone fractures and muscle weakness. The aim of the study was to evaluate bone metabolism in an old population of patients hospitalized not for musculo-skeletal complaints. METHODS: The clinical records of 175 patients, 98 female and 77 male, aged >65 years, hospitalized in a Department of Internal Medicine (Sacile, Western Friuli) were retrospectively reviewed. Serum levels of calcium, phosphorous, alkaline phosphatase, parathyroid hormone (PTH) and 25-OH vitamin D were evaluated. Correlations between these parameters were investigate. RESULTS: Abnormalities of bone metabolism parameters were frequently founded, particularly hypocalcemia, increased PTH and reduced 25 OH vitamin D. Hypovitaminosis D were detected in 88% of patients, low levels in 30.28% and very low levels in 57.72%. Hypovitaminosis D was related to female sex, old age of patients and high levels of PTH. CONCLUSIONS: Our data confirm that hypovitaminosis D is very common in elderly population. The study has been performed in an Italian Region where the supplementation of vitamin D in the elderly is not performed, suggesting that a awareness campaign of the doctors could be very useful to prevent bone metabolism abnormalities. PMID- 22842301 TI - Familial Mediterranean fever without cardinal symptoms and role of genetic screening. AB - Familial Mediterranean fever is an autosomal recessive disorder characterized by paroxysmal episodes of fever and serosal inflammation. The classical presentation is fever and severe recurrent abdominal pain due to serositis that lasts for one to three days and the resolves spontaneously. Between the episodes patients are asymptomatic. Ninety-five percent of patients with familial mediterranean fever have painful episodes localized to the abdomen, which is usually the dominant manifestation of the disease. Herein, we present a case of 34-year-old man with incomplete abdominal pain episode of familial mediterranean fever limited to the epigastrum and had no cardinals symptoms of this disease. The diagnosis was made by genetic screening. Successful treatment response was achieved by colchicine. PMID- 22842302 TI - Elbow monoarthritis: an atypical onset of juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood and an important cause of short and long term disability. Oligoarthritis is defined as an arthritis that affects four o fewer joints during the first 6 months of disease. The large majority of patients within this category belongs to a quite well defined disease which is not observed in adults. It is characterized by an early onset (before 6 years of age), an asymmetric arthritis involving mainly large joints, a female predilection, a high frequency of positive antinuclear antibodies (ANA), a high risk for developing chronic iridocyclitis and consistent HLA associations. We describe 3 clinical cases who presented monoarthritis of the elbow as early sign of oligoarticular JIA. All patients showed inflammatory markers elevation and 2/3 were ANA positive. MRI showed the presence of synovial inflammation without bone involvement. Intraarticular triamcinolone hexacetonide, led to remission in one case, while in the other two there was a re-activation of the disease treated with NSAIDs and/or MTX. The reported cases represent 0.6% of 490 patients with JIA followed by our unit in the last 10 years. Cases of exclusive involvement of the elbow at onset of JIA in literature are rare. Therefore, we report 3 cases of monoarthritis of the elbow as initial sign of oligoarticular JIA, a very atypical onset of this disease. PMID- 22842303 TI - On the history of biological drugs: the true discovery of the IL-1 receptor antagonist. PMID- 22842304 TI - Schistosoma mansoni schistosomula tegument (Smteg) immunization in absence of adjuvant induce IL-10 production by CD4+ cells and failed to protect mice against challenge infection. AB - The Schistosoma mansoni tegument interaction with the immune system plays a key role in disease establishment or elimination. We have recently demonstrated that S. mansoni schistosomula tegument (Smteg) is able to activate innate immune response and to induce protective immunity in a vaccine formulation with Freunds adjuvant. In this work, we evaluated the ability of Smteg to elicit protection in the absence of adjuvant. Smteg mice immunization resulted in significant antibody production, increased percentage of CD4+IFN-g+ and CD4+IL-10+ cells in spleen and increased production of IFN-g and IL-10 by spleen cells, but failed to reduce parasite burden, female fecundity and morbidity. We also demonstrated that BMDC stimulation with Smteg resulted in significant IL-10 production. Our results demonstrate that Smteg has immune modulatory proprieties. PMID- 22842305 TI - Text accessibility by people with reduced contrast sensitivity. AB - PURPOSE: Contrast sensitivity is reduced in people with eye disease, and also in older adults without eye disease. In this article, we compare contrast of text presented in print and digital formats with contrast sensitivity values for a large cohort of subjects in a population-based study of older adults (the Salisbury Eye Evaluation). METHODS: Contrast sensitivity values were recorded for 2520 adults aged 65 to 84 years living in Salisbury, Maryland. The proportion of the sample likely to be unable to read text of different formats (electronic books, newsprint, paperback books, laser print, and LED computer monitors) was calculated using published contrast reserve levels required to perform spot reading, to read with fluency, high fluency, and under optimal conditions. RESULTS: One percent of this sample had contrast sensitivity less than that required to read newsprint fluently. Text presented on an LED computer monitor had the highest contrast. Ninety-eight percent of the sample had contrast sensitivity sufficient for high fluent reading of text (at least 160 words/min) on a monitor. However, 29.6% were still unlikely to be able to read this text with optimal fluency. CONCLUSIONS: Reduced contrast of print limits text accessibility for many people in the developed world. Presenting text in a high contrast format, such as black laser print on a white page, would increase the number of people able to access such information. Additionally, making text available in a format that can be presented on an LED computer monitor will increase access to written documents. PMID- 22842306 TI - Benefit of adaptive optics aberration correction at preferred retinal locus. AB - PURPOSE: To investigate the effect of eccentric refractive correction and full aberration correction on both high- and low-contrast grating resolution at the preferred retinal locus (PRL) of a single low-vision subject with a long-standing central scotoma. METHODS: The subject was a 68-year-old women with bilateral absolute central scotoma due to Stargardt disease. She developed a single PRL located 25 degrees nasally of the damaged macula in her left eye, this being the better of the two eyes. High- (100%) and low-contrast (25 and 10%) grating resolution acuity was evaluated using four different correction conditions. The first two corrections were solely refractive error corrections, namely, habitual spectacle correction and full spherocylindrical correction. The latter two corrections were two versions of adaptive optics corrections of all aberrations, namely, habitual spectacle correction with aberration correction and full spherocylindrical refractive correction with aberration correction. RESULTS: The mean high-contrast (100%) resolution acuity with her habitual correction was 1.06 logMAR, which improved to 1.00 logMAR with full spherocylindrical correction. Under the same conditions, low-contrast (25%) acuity improved from 1.30 to 1.14 logMAR. With adaptive optics aberration correction, the high-contrast resolution acuities improved to 0.89/0.92 logMAR and the low-contrast acuities improved to 1.04/1.06 logMAR under both correction modalities. The low-contrast (10%) resolution acuity was 1.34 logMAR with adaptive optics aberration correction; however, with purely refractive error corrections, she was unable to identify the orientation of the gratings. CONCLUSIONS: Correction of all aberrations using adaptive optics improves both high- and low-contrast resolution acuity at the PRL of a single low-vision subject with long-standing absolute central scotoma. PMID- 22842307 TI - The Berkeley Rudimentary Vision Test. AB - PURPOSE: Very poor visual acuity often cannot be measured with letter charts even at close viewing distances. The Berkeley Rudimentary Vision Test (BRVT) was developed as a simple test to extend the range of visual acuity measurement beyond the limits of letter charts by systematically simplifying the visual task and using close viewing distances to achieve large angular sizes. The test has three pairs of hinged cards, 25 cm square. One card-pair has four single tumbling E (STE) optotypes at sizes 100 M, 63 M, 40 M, and 25 M. Another card-pair has four grating acuity (GA) targets at sizes 200 M, 125 M, 80 M, and 50 M. The third card-pair has a test of white field projection (WFP) and a test of black white discrimination (BWD). As a demonstration of feasibility, a population of subjects with severe visual impairment was tested with the BRVT. METHODS: Adults with severe visual impairments from a wide variety of causes were recruited from three different rehabilitation programs. Vision measurements were made on 54 eyes from 37 subjects; test administration times were measured. RESULTS: For this population, letter chart visual acuity could be measured on 24 eyes. Measurements of visual acuity for STE targets were made for 18 eyes and with GA targets, for two eyes. Five eyes had WFP, and one had BWD. Four had light perception only. The median testing time with the BRVT was 2.5 min. DISCUSSION: The BRVT extends the range of visual acuity up to logMAR = 2.60 (20/8000) for STEs, to logMAR = 2.90 (20/16,000) for gratings and includes the WFP and BWD tests. CONCLUSIONS: The BRVT is a simple and efficient test of spatial vision that, with 13 increments, extends the range of measurement from the limits of the letter chart up to light perception. PMID- 22842308 TI - Do reading additions improve reading in pre-presbyopes with low vision? AB - PURPOSE: This study compared three different methods of determining a reading addition and the possible improvement on reading performance in children and young adults with low vision. METHODS: Twenty-eight participants with low vision, aged 8 to 32 years, took part in the study. Reading additions were determined with (a) a modified Nott dynamic retinoscopy, (b) a subjective method, and (c) an age-based formula. Reading performance was assessed with MNREAD-style reading charts at 12.5 cm, with and without each reading addition in random order. Outcome measures were reading speed, critical print size, MNREAD threshold, and the area under the reading speed curve. RESULTS: For the whole group, there was no significant improvement in reading performance with any of the additions. When participants with normal accommodation at 12.5 cm were excluded, the area under the reading speed curve was significantly greater with all reading additions compared with no addition (p = 0.031, 0.028, and 0.028, respectively). Also, the reading acuity threshold was significantly better with all reading additions compared with no addition (p = 0.014, 0.030, and 0.036, respectively). Distance and near visual acuity, age, and contrast sensitivity did not predict improvement with a reading addition. All, but one, of the participants who showed a significant improvement in reading with an addition had reduced accommodation. CONCLUSIONS: A reading addition may improve reading performance for young people with low vision and should be considered as part of a low vision assessment, particularly when accommodation is reduced. PMID- 22842310 TI - Investigation of surfactants suitable for stabilizing of latanoprost. AB - The content of latanoprost, a therapeutic drug for glaucoma, is likely to decrease in solution. In a previous study, we confirmed that this was associated with latanoprost adsorption to the container and hydrolysis of latanoprost, and established a formulation of latanoprost eye drop solution that can be stored at room temperature. In addition, we clarified that a surfactant added to the formulation stabilized latanoprost by forming complex micelle. In this study, we investigated the influence of structure of surfactants in the stabilization of latanoprost. Non-ionic surfactants involving the polyoxyethylene chain (additive mol number: 20 or more) and the straight-chain alkyl group, with an HLB of 15.0 or more, markedly inhibited a decrease in the latanoprost content and its degradation. These surfactants are soluble in the formulation of eye drop solution, leading to micelle formation even at a low concentration, and they are not influenced by the temperature. Therefore, they may exhibit marked stabilization effects. In addition, there was no influence on the stability of latanoprost when adding benzalkonium chloride, as a preservative, to a formulation involving these surfactants. PMID- 22842309 TI - Dependence of reading speed on letter spacing in central vision loss. AB - PURPOSE: Crowding, the difficulty in recognizing a letter in close proximity with other letters, has been suggested as an explanation for slow reading in people with central vision loss. The goals of this study were (1) to examine whether increased letter spacing in words, which presumably reduces crowding among letters, would benefit reading for people with central vision loss and (2) to relate our finding to the current account of faulty feature integration of crowding. METHODS: Fourteen observers with central vision loss read aloud single sentences, one word at a time, using rapid serial visual presentation. Reading speeds were calculated based on the rapid serial visual presentation exposure durations yielding 80% accuracy. Letters were rendered in Courier, a fixed-width font. Observers were tested at 1.4* the critical print size (CPS), three were also tested at 0.8* CPS. Reading speed was measured for five center-to-center letter spacings (range: 0.5-2* the standard spacing). The preferred retinal locus for fixation was determined for nine of the observers, from which we calculated the horizontal dimension of the integration field for crowding. RESULTS: All observers showed increased reading speed with letter spacing for small spacings, until an optimal spacing, beyond which reading speed either showed a plateau, or dropped as letter spacing further increased. The optimal spacing averaged 0.95 +/ 0.06* [+/-95% confidence interval] the standard spacing for 1.4* CPS (similar for 0.8* CPS), which was not different from the standard. When converted to angular size, the measured values of the optimal letter spacing for reading show a good relationship with the calculated horizontal dimension of the integration field. CONCLUSIONS: Increased letter spacing beyond the standard size, which presumably reduces crowding among letters in text, does not improve reading speed for people with central vision loss. The optimal letter spacing for reading can be predicted based on the preferred retinal locus. PMID- 22842317 TI - The effects of viscoelastic fluid on kinesin transport. AB - Kinesins are molecular motors which transport various cargoes in the cytoplasm of cells and are involved in cell division. Previous models for kinesins have only targeted their in vitro motion. Thus, their applicability is limited to kinesin moving in a fluid with low viscosity. However, highly viscoelastic fluids have considerable effects on the movement of kinesin. For example, the high viscosity modifies the relation between the load and the speed of kinesin. While the velocity of kinesin has a nonlinear dependence with respect to the load in environments with low viscosity, highly viscous forces change that behavior. Also, the elastic nature of the fluid changes the velocity of kinesin. The new mechanistic model described in this paper considers the viscoelasticity of the fluid using subdiffusion. The approach is based on a generalized Langevin equation and fractional Brownian motion. Results show that a single kinesin has a maximum velocity when the ratio between the viscosity and elasticity is about 0.5. Additionally, the new model is able to capture the transient dynamics, which allows the prediction of the motion of kinesin under time varying loads. PMID- 22842318 TI - Analysis of patients with post-chemotherapy arthralgia and arthritis in breast cancer. AB - OBJECTIVE: Evaluate the characteristics of arthropathy and musculoskeletal pain after chemotherapy in patients with breast cancer. MATERIALS AND METHODS: In this study, we evaluate the characteristics of 15 patients with joint symptoms after receiving chemotherapy for breast cancer. Demographic information including sex, age, time of rheumatologic findings after starting of chemotherapy, and time of improvement after starting of medication, and laboratory findings detected for each patient. RESULTS: Patients comprised 15 women with mean age 43.4 +/- 10.6 years that received classic chemotherapy for breast cancer according to stage of disease including cyclophosphamide, and tamoxifen. Joint symptoms usually began about 6 months after the first session of chemotherapy. Patients had an average of 2 tender joints and 1 hour of morning stiffness. None of patients were positive for anti-nuclear antibody, and just 1 patient was positive for rheumatoid factor. Non-steroidal anti-inflammatory drugs, disease modifying anti rheumatic drugs (DMARD), corticosteroids, and venlafaxine were prescribed. 5 patients did not show an improvement and were also given low dose oral corticosteroids. Follow-up was available for all patients. 13 patients showed favorable responses, characterized by a significant decrease (more than 50%) in morning stiffness, pain, and tender joint counts after a mean of 3 months' treatment. 9 patients had complete resolution of symptoms and stopped all medications. CONCLUSION: Chemotherapy-related arthropathy is not rare, and the prognosis is fairly good with early treatment using NSAID, DMARD, and corticosteroids. PMID- 22842319 TI - Clinical profile of abdominal tuberculosis in children. AB - AIM: A retrospective study was conducted in children, suffering from abdominal TB, attending Pediatric TB clinic from 2007 to 2009. MATERIALS AND METHODS: Age wise distribution and type of abdominal TB were analyzed with clinical features. RESULTS: Out of 285 children with TB, 32 (11.2%) had abdominal tuberculosis. Male: Female ratio was 2.1:1. 7 (21.9%) children were < 5 years of age, 15 (46.9%) children were 5 - 10 years of age, and 10 (31.2%) children were > 10 years of age. The most common clinical features were fever in 24 (75%), pain in abdomen in 17 (53.1%), loss of weight in 15 (46.9%), raised ESR in 14 (43.8%), and loss of appetite in 13 (40.6%) children. TB contact was present in 10 (31.2%), and 7 (21.9%) children had tuberculosis in the past. 28 (87.5%) children had received BCG vaccine, and 17 (53.1%) had a positive Mantoux test. Extra abdominal tuberculosis was found in 17 patients (53.1%). Duration of fever was more in children less than 5 years of age (127 +/- 66 days) than that in children between 5 -10 years (37 +/- 30 days) and in > 10 years of age (73 +/- 66 days), which is statistically significant (P = 0.0228). Lymph node TB (17 patients, 53.1%) was found to be the commonest, followed by intestinal (10 patients, 31.2%) and peritoneal TB (4 patients, 12.5%). 18 (56.2%) of the total patients had recovered, 7 (21.9%) of all patients failed first line therapy and had to be started on second line drugs, of which 4 (12.5%) were proven to have drug resistant TB. CONCLUSION: Abdominal TB is seen in 11.2% of children affected with TB, of which over 53% will have extra-abdominal manifestations. Common clinical and laboratory features include fever, pain in abdomen, loss of weight, loss of appetite, and raised ESR. The duration of fever is more in children of younger age group. Lymph node TB is the most common type of abdominal TB. Drug-resistant TB is seen in at least 12.5% of the patients. PMID- 22842320 TI - Characteristics of rotavirus gastroenteritis in hospitalized children in Pune. AB - BACKGROUND: Diarrheal diseases affect millions of people around the world and have the greatest impact on children, especially those in developing countries. Rotavirus is now known to contribute significantly to the etiology of diarrheal diseases in both developing and developed countries. OBJECTIVE: To study demographic, clinical, and laboratory characteristics of rotavirus infection in cases of acute diarrhea admitted in the hospital who were below the age 5 years. MATERIALS AND METHODS: It was a prospective study conducted from June 2009 to June 2011 to determine characteristics, clinical profile, and antigenemia of rotavirus. The study group included patients up to 5 years of age hospitalized with a diagnosis of acute gastroenteritis. Statistical analysis was done using the chi-square test. Data were analyzed using SPSS (Statistical Package for Social Sciences) version 17.0. RESULTS: From the 246 cases studied in the hospitalized patients of acute gastroenteritis, 88 cases (35.77%) were found to be positive for rotavirus infection. The occurrence of infection was found to be most common in the age group of 11-20 months (38.63%) followed by the age group of 0-10 months (23.86%). There was no association with the sex of the child. In rotavirus-positive patients, associated features were fever in 48.86%, vomiting in 29.54%, and pain in abdomen in 53.4% of cases. Seasonal variation of rotavirus infection was observed in the present study with peak in the winter season. It was found that 5.68% cases which were positive for rotavirus in their stool samples were positive for rotavirus present in their urine sample, suggesting extraintestinal manifestation of rotavirus. CONCLUSION: It is concluded that in spite of clean hygienic condition and vaccination rotavirus is still an important cause of infantile diarrhea in urban area like Pune. There is association between the occurrence of rotavirus and degree of dehydration, fever, vomiting, and pain in abdomen. Peak incidence was found in the months of December and January. There is association between the occurrence of rotavirus in stool and rotavirus in blood. PMID- 22842321 TI - Methylenetetrahydrofolate reductase polymorphism (c677t) in Muslim population of eastern Uttar Pradesh, India. AB - OBJECTIVE: The aim of the present study was to investigate the distribution of methylenetetrahydrofolate reductase (C677T) polymorphism in the Muslim population of eastern Uttar Pradesh. MATERIALS AND METHODS: Total 56 subjects were analysed for MTHFR C677T polymorphism. C677T mutation analysis was done according to the PCR-RFLP (Polymerase chain reaction-Restriction fragment length polymorphism) method. RESULTS: The frequencies of three genotypes CC, CT, and TT were 0.857, 0.125, and 0.07, respectively, and the frequency of mutated T allele was found to be 0.080. CONCLUSION: Genotypes and allele frequencies revealed the low prevalence of MTHFR C677T polymorphism in Indin Muslims. C677T mutation has been suggested to be positively associated with the risk of several congenital and multifactorial disorders. The low frequency of T/T genotype in the Muslim population may be due to malnutrition in pregnant women, because of insufficient intake of folate is considered to be a survival disadvantage for foetuses with T/T genotype. PMID- 22842322 TI - Quality of life in post-traumatic orthopedically handicapped patients. AB - OBJECTIVES: The study was planned to assess quality of life (QOL) and factors affecting it in post-traumatic orthopedically handicapped patients. MATERIALS AND METHODS: This is hospital-based cross-sectional study which involves 68 patients with traumatic orthopedic handicapped injury in the Department of Orthopaedeics, Rehabilitation center and Psychiatry, Government Medical College, Patiala between May 07 and Aug 08. Details of injury were taken on semistructured proforma. All patients underwent detailed psychiatric assessment using International Classification of Disease-10 (ICD-10) and divided into two groups. Group A contains handicapped patients with psychiatric morbidity and remaining patients without psychiatric morbidity were included in Group B. Further, both groups were subjected to Quality Of Life Scale (QOLS) to assess QOL. RESULTS: QOL was poor in handicapped patients and was affected by severity of injury. Temporal association was seen between psychiatric morbidity and QOL in handicapped patients. CONCLUSION: The QOL must be assessed at every stage of treatment for better adjustment of handicapped patients. PMID- 22842323 TI - Acute buried bumper syndrome: an endoscopic peg tube salvage approach. AB - Acute buried bumper syndrome is an uncommon complication of percutaneous endoscopic gastrostomy (PEG) tube placement. If not recognized and treated appropriately, it can lead to serious complications including death. We report a case of an acute buried bumper syndrome, successfully managed with PEG tube repositioning through the original tract, without the need of replacement. PMID- 22842324 TI - Gestational choriocarcinoma presenting as hemothorax. AB - Choriocarcinoma include a spectrum of chorionic neoplasms that may be gestational or non-gestational. By virtue of their high vascularity and affinity of trophoblast for blood vessels, metastases often occur early, and the most common site of such metastases is the lung. Metastatic pleural effusions from choriocarcinoma are infrequent. Pleural seeding usually results from extension of a sub-pleural peripheral nodule. We describe a case of gestational choriocarcinoma whose clinical presentation was medical like hemothorax as in our case rather than gynecologic. PMID- 22842325 TI - Donor deferral guidelines for skin infections: is there need to re- evaluate? PMID- 22842326 TI - Prevalence of histone family E1 (HFE) mutant alleles in a Tamilian cohort from Vellore, South India. PMID- 22842327 TI - Significant association between body composition phenotypes and the osteocalcin genomic region in normative human population. AB - Osteocalcin, a major inorganic component of bone matrix and marker of bone formation, is also involved in regulation of glucose and fat mass metabolism. However, much uncertainty remains about whether the above effect on fat mass has a genetic component. Our main aim was to test whether a variation of body composition phenotypes is associated with BGLAP genomic region variants. To achieve this aim, we used an ethnically homogeneous discovery sample of 230 families consisting of 1112 apparently healthy individuals (561 males and 551 females) of European origin. We conducted association analysis between six SNPs and five obesity-related phenotypes: plasma levels of leptin, anthropometrical fat mass (FM), principal component scores of eight skinfold (SK_PC) and nine circumference (CR_PC) measurements, and body mass index (BMI). Two powerful and robust tools were applied: the pedigree disequilibrium test and variance component models, taking into account both familial and genetic effects. Significant association results were observed for all phenotypes. The most significant results were observed between the haplotype composed of three SNPs (rs2758605-rs1543294-rs2241106) and BMI (p=8.07(-7)), and CR_PC (p=5.29(-5)). The association with BMI was tested and confirmed in our replication study, including 2244 unrelated adult US Caucasians, who were previously assessed for whole genome SNP data. In addition, we obtained an evidence of potential non-additive interactions between the above three SNPs concerning their association with BMI. Bioinformatics sources suggest that the aforementioned interaction could originate from different genetic loci in this region; however, ascertaining the exact circumstances requires a detailed molecular-genetic study. PMID- 22842329 TI - The comparative gastrointestinal tolerability of proprietary versus generic alendronate in patients treated for primary osteoporosis. AB - OBJECTIVE: The objective of this study was to analyze the comparative gastrointestinal tolerability of proprietary versus generic alendronate in patients treated for primary osteoporosis. METHODS: The study was based on all patients starting therapy with alendronate in Sweden between 2005 and 2009. The primary outcome measure was the start of treatment with a gastroprotective agent and the secondary outcome was hospitalization for gastrointestinal adverse event (GIAE). The incidence of both outcomes was measured within the first six months after the initiation of the alendronate treatment. RESULTS: The crude incidence of gastroprotective treatment during the first six months following the start of the alendronate therapy was 5.45% (bootstrapped CI(95) 4.09%-7.19%) and 5.04% (bootstrapped CI(95) 4.74%-5.38%) for patients prescribed proprietary and generic alendronate, respectively. The crude six-month incidence of hospitalization for GIAE was 0.43% (bootstrapped CI(95) 0.14%-1.29%) and 0.71% (bootstrapped CI(95) 0.55%-0.91%) for proprietary and generic alendronate, respectively. Controlling for age, sex, and other available covariates, there was no significant difference in the risk of GIAEs between proprietary and generic alendronate. CONCLUSIONS: No significant difference in the incidence of GIAEs was identified between patients prescribed proprietary and generic alendronate between 2005 and 2009 in Sweden. More research is needed to provide conclusive evidence of the gastrointestinal tolerability profiles of proprietary and generic alendronate. PMID- 22842328 TI - 17beta-Hydroxyestra-4,9,11-trien-3-one (Trenbolone) preserves bone mineral density in skeletally mature orchiectomized rats without prostate enlargement. AB - Testosterone enanthate (TE) administration attenuates bone loss in orchiectomized (ORX) rats. However, testosterone administration may increase risk for prostate/lower urinary tract related adverse events and polycythemia in humans. Trenbolone enanthate (TREN) is a synthetic testosterone analogue that preserves bone mineral density (BMD) and results in less prostate enlargement than testosterone in young ORX rodents. The purpose of this experiment was to determine if intramuscular TREN administration attenuates bone loss and maintains bone strength, without increasing prostate mass or hemoglobin concentrations in skeletally mature ORX rodents. Forty, 10 month old male F344/Brown Norway rats were randomized into SHAM, ORX, ORX+TE (7.0mg/week), and ORX+TREN (1.0mg/week) groups. Following surgery, animals recovered for 1 week and then received weekly: vehicle, TE, or TREN intramuscularly for 5 weeks. ORX reduced total and trabecular (t) BMD at the distal femoral metaphysis compared with SHAMs, while both TREN and TE completely prevented these reductions. TREN treatment also increased femoral neck strength by 28% compared with ORX animals (p<0.05), while TE did not alter femoral neck strength. In addition, TE nearly doubled prostate mass, compared with SHAMs (p<0.05). Conversely, TREN induced a non-significant 20% reduction in prostate mass compared with SHAMs, ultimately producing a prostate mass that was 64% below that found in ORX+TE animals (p<0.01). Hemoglobin concentrations and levator ani/bulbocavernosus (LABC) muscle mass were elevated in ORX+TE and ORX+TREN animals to a similar degree above both SHAM and ORX conditions (p<0.01). In skeletally mature rodents, both high-dose TE and low dose TREN completely prevented the ORX-induced loss of tBMD at the distal femoral metaphysis and increased LABC mass. TREN also augmented femoral neck strength and maintained prostate mass at SHAM levels. These findings indicate that TREN may be an advantageous agent for future clinical trials evaluating agents capable of preventing bone loss resulting from androgen deficiency. PMID- 22842330 TI - Fludarabine, busulfan, antithymocyte globulin, and total body irradiation for pretransplantation conditioning in acute lymphoblastic leukemia: excellent outcomes in all but older patients with comorbidities. AB - Hematopoietic stem cell transplantation (SCT) is routinely offered to suitable candidates with high-risk or advanced acute lymphoblastic leukemia (ALL). In this report, we update our experience with SCT in patients with ALL with a novel conditioning regimen. A total of 44 patients with high-risk or advanced (greater than first complete remission) ALL in remission underwent SCT after myeloablative conditioning with fludarabine + busulfan + total body irradiation. The median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years). The cohort consists of 32 patients with high-risk disease (median age, 40 years; range, 19 64 years) and 12 patients with advanced disease (median age, 25 years; range, 19 65 years) who underwent SCT: 25 with a related donor (21 fully matched) and 19 with an unrelated donor (16 fully matched). The cumulative incidence of grade II IV acute graft-versus-host disease (GVHD) was 53.2%, and that of grade III-IV acute GVHD was 20.6%. The incidence of chronic GVHD was 55%. The 100-day nonrelapse mortality was 13.6%. Five-year progression-free survival was 56.7%, and 5-year overall survival was 66.0%. Nine patients (20%) died in remission, 6 (14%) died after relapse, and 2 survived after a second SCT for relapsed disease. Outcomes were inferior in older patients with comorbidities compared with other patients. PMID- 22842331 TI - Impact of donor characteristics and HLA matching on survival of chinese patients with hematologic malignancies undergoing unrelated hematopoietic stem cell transplantation. AB - We retrospectively analyzed the impact of donor characteristics and HLA matching on outcomes in Chinese patients undergoing unrelated hematopoietic stem cell transplantation (HSCT). A total of 693 patients with hematologic malignancies who underwent HSCT between 2005 and 2010 had available survival data at 100 days or 1 year posttransplantation in the Buddhist Tzu-Chi Stem Cell Center database. The overall survival rates at 100 days and 1 year were 83.3% and 65.2%, respectively. Mismatches of HLA-A, -B, and -DRB1 at the antigen or allele level, along with inadequate cell dose, were associated with a significant risk of mortality (hazard ratio [HR] = 2.36, P < .001; HR = 1.44, P = .005; and HR = 2.20, P = .009, respectively). In 107 donors with matched HLA-A, -B and -DRB1 and known HLA C match status, 22.4% had an HLA-C antigen mismatch, resulting in an HR of 2.87 for mortality relative to complete 8/8 matches (P = .005). Recipients with unknown HLA-C match status also had a significantly worse outcome (HR = 1.73; P = .039). Multivariate analysis revealed that cell dose and HLA-A, -B, -C, and -DRB1 antigen match status significantly affected the final outcome of survival (P = .012 and <.001, respectively). Our data indicate that HLA-C match status should be confirmed before HSCT from an unrelated donor. Inadequate cell dose remains an important determinant of poor transplantation survival. Further studies to elucidate the importance of matching of specific HLA loci are needed to better understand the risk of HSCT and improve patient outcomes. PMID- 22842332 TI - Amyloid deposits in the bone marrow of patients with immunoglobulin light chain amyloidosis do not impact stem cell mobilization or engraftment. AB - Amyloid deposits are often found in the bone marrow in patients with Immunoglobulin light chain (AL) amyloidosis. We sought to determine whether this affects stem cell collection or engraftment after high-dose melphalan and autologous stem cell transplantation (HDM-SCT). We reviewed data on 361 patients with AL amyloidosis who had Congo red staining of pretreatment bone marrow biopsy specimens and underwent HDM-SCT between July 1994 and December 2011. We analyzed data on stem cell yield, days of stem cell collection, and days to neutrophil and platelet engraftment posttransplantation. Bone marrow amyloid deposits were found in 65% of patients (n = 233). There were no significant differences in median number of stem cells collected and days to neutrophil or platelet engraftment between patients with bone marrow amyloid deposits and those without these deposits. Thus, our data indicate that although amyloid involvement of the bone marrow is common, it does not negatively affect stem cell mobilization or neutrophil and platelet engraftment after HDM-SCT. PMID- 22842333 TI - Effects of conditioning regimens and T cell depletion in hematopoietic cell transplantation for primary immune deficiency. AB - This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy related toxicity, and demonstrate promising results for the early establishment of donor immune competency. PMID- 22842334 TI - Novel bis-(-)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property. AB - The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(-)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC(50) values of 9.63MUM (for ZLA) and 8.64MUM (for ZLB), and prevent AChE-induced amyloid-beta (Abeta) aggregation with IC(50) values of 49.1MUM (for ZLA) and 55.3MUM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Abeta aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD. PMID- 22842335 TI - Anti-inflammatory activity of methyl palmitate and ethyl palmitate in different experimental rat models. AB - Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). MP and EP decreased NF-kappaB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models. PMID- 22842336 TI - Embryo exposure to elevated cortisol level leads to cardiac performance dysfunction in zebrafish. AB - In zebrafish (Danio rerio), de novo cortisol synthesis commences only after hatching, providing an interesting model to study the effects of maternal stress and abnormal cortisol deposition on embryo development and performance. We hypothesized that elevated cortisol levels during pre-hatch embryogenesis compromise cardiac performance in developing zebrafish. Cortisol was microinjected into one-cell embryos to elevate basal cortisol levels during embryogenesis. Elevated embryo cortisol content increased heart deformities, including pericardial edema and malformed chambers, and lowered resting heartbeat post-hatch. This phenotype coincided with suppression of key cardiac genes, including nkx2.5, cardiac myosin light chain 1, cardiac troponin type T2A, and calcium transporting ATPase, underpinning a mechanistic link to heart malformation. The attenuation of the heartbeat response to a secondary stressor post-hatch also confirms a functional reduction in cardiac performance. Altogether, high cortisol content during embryogenesis, mimicking increased deposition due to maternal stress, decreases cardiac performance and may reduce zebrafish offspring survival. PMID- 22842337 TI - Terphenyl-phenanthroline conjugate as a Zn2+ sensor: H2PO4(-) induced tuning of emission wavelength. AB - A new terphenyl-based macrocycle 5 incorporating phenanthroline as a fluorophore has been designed, synthesized and examined for its recognition ability toward various cations (Pb(2+), Hg(2+), Ba(2+), Cd(2+), Ag(+), Zn(2+), Cu(2+), Ni(2+), Co(2+), K(+), Mg(2+), Na(+) and Li(+)) by UV-vis, fluorescence and NMR spectroscopy. The receptor 5 showed highly selective 'Off-On' fluorescence signaling behavior for Zn(2+) ions in THF. Interestingly, the addition of H(2)PO(4)(-) ions to the [5-Zn] complex regulates the binding site for additional Zn(2+) ions and hence leads to a blue-shifted emission band. PMID- 22842338 TI - Recombinant expression of a unique chloromuconolactone dehalogenase ClcF from Rhodococcus opacus 1CP and identification of catalytically relevant residues by mutational analysis. AB - Chloromuconolactone dehalogenase ClcF plays a unique role in 3-chlorocatechol degradation by Rhodococcus opacus 1CP by compensating the inability of its chloromuconate cycloisomerase ClcB2 to dechlorinate the chemically stable cycloisomerization product (4R,5S)-5-chloromuconolactone (5CML). High sequence similarities showed relatedness of ClcF to muconolactone isomerases (MLIs, EC 5.3.3.4) of the 3-oxoadipate pathway. Although both enzyme types share the ability to dechlorinate 5CML, comparison of kcat/Km indicated a significant extent of specialization of ClcF for dechlorination. This assumption was substantiated by an almost complete inability of ClcF to convert (4S) muconolactone and the exclusive formation of cis-dienelactone from 5CML. Mutational analysis of ClcF by means of variants E27D, E27Q, Y50A, N52A, and A89S indicated relevance of some highly conserved residues for substrate binding and catalysis. Based on the putative isomerization mechanism of MLI, evidence was provided for a role of E27 in initial proton abstraction as well as of Y50 and N52 in substrate binding. In case of N52 substrate binding is likely to occur to the carboxylic group of 5CML as indicated by a significant change of product specificity. Expression in Escherichia coli BL21-CP(DE)-RIL followed by a three step purification procedure with heat treatment is a convenient strategy to obtain recombinant ClcF and variants thereof. PMID- 22842339 TI - Relief of methacholine-induced bronchospasm with extrafine beclomethasone dipropionate/formoterol in comparison with salbutamol in asthma. AB - BACKGROUND: Short-acting beta2-agonists like salbutamol and terbutaline are used as rescue medications for acute bronchoconstriction and relief of symptoms due to their rapid onset of action. The aim of this study was to assess whether inhaled beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in extrafine formulation is non-inferior to salbutamol in the speed of reverting methacholine-induced bronchoconstriction and symptoms. METHODS: Fifty-six asthmatic patients were examined in a multicentre, randomised, double blind, double dummy, active treatment and placebo controlled three period cross-over study. On three different days, a single dose of BDP/FF 100/6 MUg in pressurised metered-dose inhaler (pMDI) extrafine formulation or salbutamol 200 MUg pMDI or placebo was inhaled after FEV(1) had dropped by 30-45% with methacholine challenge. RESULTS: The median time to recovery of FEV(1) to 85% of baseline was similar for BDP/FF and salbutamol (3.66 and 2.15 min, respectively), but significantly longer for placebo (21.1 min). The planned analysis on adjusted mean time to recovery showed that the difference from methacholine-induced bronchoconstriction between BDP/FF and salbutamol was 3.82 min (95% confidence interval: -0.85 to 8.5), therefore greater than 3 min supposed in the study design. The difference between BDP/FF and salbutamol was not clinically significant. The two active treatments were also comparable in terms of the relief of symptoms (as assessed by the Borg dyspnoea scale). CONCLUSIONS: BDP/FF combination has a fast onset of action, similar to that of salbutamol, and may represent a good alternative as rescue medication in asthmatic patients. PMID- 22842340 TI - Muscarinic receptors on airway mesenchymal cells: novel findings for an ancient target. AB - Since ancient times, anticholinergics have been used as a bronchodilator therapy for obstructive lung diseases. Targets of these drugs are G-protein-coupled muscarinic M(1), M(2) and M(3) receptors in the airways, which have long been recognized to regulate vagally-induced airway smooth muscle contraction and mucus secretion. However, recent studies have revealed that acetylcholine also exerts pro-inflammatory, pro-proliferative and pro-fibrotic actions in the airways, which may involve muscarinic receptor stimulation on mesenchymal, epithelial and inflammatory cells. Moreover, acetylcholine in the airways may not only be derived from vagal nerves, but also from non-neuronal cells, including epithelial and inflammatory cells. Airway smooth muscle cells seem to play a major role in the effects of acetylcholine on airway function. It has become apparent that these cells are multipotent cells that may reversibly adopt (hyper)contractile, proliferative and synthetic phenotypes, which are all under control of muscarinic receptors and differentially involved in bronchoconstriction, airway remodeling and inflammation. Cholinergic contractile tone is increased by airway inflammation associated with asthma and COPD, resulting from exaggerated acetylcholine release as well as increased expression of contraction related proteins in airway smooth muscle. Moreover, muscarinic receptor stimulation promotes proliferation of airway smooth muscle cells as well as fibroblasts, and regulates cytokine, chemokine and extracellular matrix production by these cells, which may contribute to airway smooth muscle growth, airway fibrosis and inflammation. In line, animal models of chronic allergic asthma and COPD have recently demonstrated that tiotropium may potently inhibit airway inflammation and remodeling. These observations indicate that muscarinic receptors have a much larger role in the pathophysiology of obstructive airway diseases than previously thought, which may have important therapeutic implications. PMID- 22842341 TI - Cell "vision": complementary factor of protein corona in nanotoxicology. AB - Engineered nanoparticles are increasingly being considered for use as biosensors, imaging agents and drug delivery vehicles. Their versatility in design and applications make them an attractive proposition for new biological and biomedical approaches. Despite the remarkable speed of development in nanoscience, relatively little is known about the interaction of nanoscale objects with living systems. In a biological fluid, proteins associate with nanoparticles, and the amount and the presentation of the proteins on their surface could lead to a different in vivo response than an uncoated particle. Here, in addition to protein adsorption, we are going to introduce concept of cell "vision", which would be recognized as another crucial factor that should be considered for the safe design of any type of nanoparticles that will be used in specific biomedical applications. The impact of exactly the same nanoparticles on various cells is significantly different and could not be assumed for other cells; the possible mechanisms that justify this cellular response relate to the numerous detoxification strategies that any particular cell can utilize in response to nanoparticles. The uptake and defence mechanism could be considerably different according to the cell type. Thus, what the cell "sees", when it is faced with nanoparticles, is most likely dependent on the cell type. PMID- 22842342 TI - Reductive amination of glutaraldehyde 2,4-dinitrophenylhydrazone using 2-picoline borane and high-performance liquid chromatographic analysis. AB - A typical method for the measurement of glutaraldehyde (GLA) employs 2,4 dinitrophenylhydrazine (DNPH) to form GLA-DNPhydrazone derivatives. However, this method is subject to analytical errors because GLA-DNPhydrazone is a quaternary bis-derivative and forms three geometric isomers (E-E, E-Z and Z-Z) as a result of the two C[double bond, length as m-dash]N double bonds. To overcome this issue, a method for transforming the C[double bond, length as m-dash]N double bond into a C-N single bond, using reductive amination of DNPhydrazone derivatives, has been applied. The amination reaction of GLA-DNPhydrazones with 2 picoline borane is accelerated with catalytic amounts of acid and is completed within 10 minutes in the presence of 100 mmol L(-1) phosphoric acid. Reduction of GLA-DNPhydrazone by 2-picoline borane is unique and results in the formation of N (2,4-dinitrophenyl)-1-piperidinamine (DNPPA). NMR and LC-APCI-MS data confirmed the product identification. DNPPA is very stable and did not change when stored for at least four weeks at room temperature. DNPPA has excellent solubility of 14.6 g L(-1) at 20 degrees C in acetonitrile. The absorption maximum wavelength and the molar absorptivity of DNPPA were 351 nm and 4.2 * 10(4) L mol(-1) cm(-1) respectively. Complete separation between the reduced forms of C1-C10 aldehyde DNPhydrazones, including DNPPA, can be achieved by operating the reversed-phase high-performance liquid chromatograph at 351 nm in gradient mode using a C18 amide column. The reductive amination method for GLA overcomes analytical errors caused by E-E, E-Z and Z-Z geometrical isomers. PMID- 22842343 TI - Ultrafine nanofibers fabricated from an arylene-ethynylene macrocyclic molecule using surface assisted self-assembly. AB - Large area uniform nanofibers have been fabricated from a hexameric arylene ethynylene macrocycle (1) through in situ self-assembly on a glass substrate during solvent evaporation. The fibril morphology is controlled by the solvophilic core of 1, in conjunction with the interfacial interactions between the side chains of 1 and the substrate. PMID- 22842344 TI - OX40 signaling favors the induction of T(H)9 cells and airway inflammation. AB - The mechanisms that regulate the T(H)9 subset of helper T cells and diseases mediated by T(H)9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer of T(H)9 cells in vitro and T(H)9 cell-dependent airway inflammation in vivo. In polarizing conditions based on transforming growth factor-beta (TGF-beta), ligation of OX40 inhibited the production of induced regulatory T cells and the T(H)17 subset of helper T cells and diverted CD4(+)Foxp3(-) T cells to a T(H)9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered induction of the kinase NIK in CD4(+) T cells and the noncanonical transcription factor NF-kappaB pathway; this subsequently led to the generation of T(H)9 cells. Thus, our study identifies a previously unknown mechanism for the induction of T(H)9 cells and may have important clinical implications in allergic inflammation. PMID- 22842345 TI - A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells. AB - The sustained entry of Ca(2+) into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na(+) channel (VGSC) that was essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca(2+) influx induced by positively selecting ligands and the in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory beta-subunit of a VGSC specifically inhibited the positive selection of CD4(+) T cells. Ectopic expression of VGSC in peripheral AND CD4(+) T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca(2+) signals required for CD4(+) T cell development. PMID- 22842347 TI - Study of high-pressure Raman intensity behavior of aromatic hydrocarbons: benzene, biphenyl and naphthalene. AB - Raman spectra of benzene, naphthalene and biphenyl have been taken up to a pressure of 13 GPa. The results for benzene and naphthalene indicate that the perturbation of inter-molecular pi-pi stacking effect on the Raman intensity is neglectable. For biphenyl, all the Raman peaks show intensity enhancement during the compression process, which indicates the planar intra-molecular aromatic conformation play an important role in the intensity increments of Raman bands. For three aromatic compounds, C-H stretching vibration bands located at about 3000 cm(-1) show intriguing intensity changes during compression account for the inter-molecular C-H?pi interaction. PMID- 22842346 TI - Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. AB - The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids. PMID- 22842348 TI - MRCI study on electronic spectrum of 13 electronic states of SiP molecule. AB - The potential energy curves (PECs) of the X(2)Pi, A(2)Sigma(+), a(4)Sigma(+), B(2)Pi, c(4)Delta, C(2)Sigma(+), d(4)Sigma(-), D(2)Phi, E(2)Sigma(-), G(2)Delta, H(2)Pi, I(2)Sigma(+) and f(4)Delta electronic states of the SiP molecule are calculated employing an ab initio quantum chemical method. The PEC calculations are performed for internuclear separations from 0.10 to 1.10nm using the complete active space self-consistent field (CASSCF) method, which is followed by the internally contracted multireference configuration interaction (MRCI) approach in combination with a correlation-consistent aug-cc-pV6Z basis set. To improve the quality of the PECs, core-valence correlation and scalar relativistic corrections are included. Scalar relativistic correction calculations are carried out using the third-order Douglas-Kroll Hamiltonian approximation at the level of a cc-pV5Z basis set. Core-valence correlation corrections are included using a cc-pCVQZ basis set. The PECs obtained by the MRCI calculations are corrected for size extensivity errors by means of the Davidson modification. The PECs are extrapolated to the complete basis set limit. The spectroscopic parameters are obtained by fitting the vibrational levels, which are calculated by solving the ro-vibrational Schrodinger equation. The spectroscopic results are compared in detail with those reported in previous literature. Excellent agreement is found between the present spectroscopic results and the experimental ones. Using the Breit-Pauli operator, the spin-orbit (SO) coupling effect on the spectroscopic parameters is included in the X(2)Pi, D(2)Phi and H(2)Pi electronic states at the level of a cc-pCVTZ basis set. The energy separation of the X(2)Pi and A(2)Sigma(+) electronic states is accurately determined by including the Davidson modification, SO coupling and core-valence correlation and scalar relativistic corrections. Using the PECs determined by the MRCI+Q/CV+DK+56 calculations, the G(upsilon), B(upsilon) and D(upsilon) are calculated for each vibrational state of each electronic state, and those of the first 20 vibrational states are reported for each electronic state of the non-rotation (29)Si(31)P molecule. Comparison with the measurements demonstrates that the present results are accurate. The spectroscopic parameters of the a(4)Sigma(+), B(2)Pi, c(4)Delta, d(4)Sigma(-), D(2)Phi, E(2)Sigma(-), G(2)Delta, H(2)Pi, I(2)Sigma(+) and f(4)Delta electronic states and the G(upsilon), B(upsilon) and D(upsilon) of all the electronic states obtained here are expected to be reliable predicted results. PMID- 22842349 TI - Synthesis, materials characterization and opto(electrical) properties of unsymmetrical azomethines with benzothiazole core. AB - Optical (UV-vis and photoluminescence) properties of two soluble organic molecules based on azomethines with benzothiazole core (BTA1 and BTA2) were reported. The structures of both compounds are characterized by means FTIR, (1)H NMR, and (13)C NMR spectroscopy and elemental analysis; the results show an agreement with the proposed structure. The investigated compounds emitted blue light. Influence of excitation wavelength and concentration on maximum and intensity of emission of BTA1 and BTA2 was found. Electrochemical properties of the compounds were studied by differential pulse voltammetry. Introduction of fluorine moieties (BTA1) resulted in lower energy band gap (E(g)) of approximately ~0.5 eV, whereas BTA2 showed E(g) of ~2.8 eV. The devices comprised of BTA1 with P3HT:PCBM (1:1:1) showed an open circuit voltage (V(OC)) of 0.40 V, a short circuit current (J(SC)) of 1.19 mA/cm(2), and a fill factor (FF) of 0.23, giving a power-conversion efficiency (PCE) of 0.10% under AM1.5 G irradiation (100 mW/cm(2)). PMID- 22842350 TI - Synthesis, analysis of spectroscopic and nonlinear optical properties of the novel compound: (S)-N-benzyl-1-phenyl-5-(thiophen-3-yl)-4-pentyn-2-amine. AB - In this study, a novel compound (S)-N-benzyl-1-phenyl-5-(thiophen-3-yl)-4-pentyn 2-amine (abbreviated as BPTPA) was synthesized and structurally characterized by FT-IR, NMR and UV spectroscopy. The molecular geometry and vibrational frequencies of BPTPA in the ground state have been calculated by using the density functional method (B3LYP) invoking 6-311++G(d,p) basis set. The geometry of the molecule was fully optimized, vibrational spectra were calculated. The fundamental vibrations were assigned on the basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method and PQS program. Total and partial density of state (TDOS and PDOS) and also overlap population density of state (OPDOS) diagrams analysis were given. The energy and oscillator strength of each excitation were calculated by time-dependent density functional theory (TD-DFT) results complements with the experimental findings. The NMR chemical shifts ((1)H and (13)C) were recorded and calculated using the gauge invariant atomic orbital (GIAO) method. The dipole moment, linear polarizability and first hyperpolarizability values were also computed. The linear polarizability and first hyper polarizability of the studied molecule indicate that the compound is a good candidate of nonlinear optical materials. Finally, vibrational wavenumbers, absorption wavelengths and chemical shifts were compared with calculated values, and found to be in good agreement with experimental results. PMID- 22842351 TI - The synthesis, crystal structure and enhanced blue fluorescence emission of novel antipyrine derivatives. AB - Four new antipyrine derivatives were synthesized and characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR spectroscopy, and a representative compound 1b was confirmed based on the X-ray crystallographic analysis. The antipyrine phenylboronic acid 1b crystallizes in the monoclinic space group P2(1)/c, and displays an E configuration about the CN double bond. The absorption and fluorescence spectra of these compounds were investigated. Replacement of a six membered phenyl group with a five-membered thienyl unit in the antipyrine derivatives resulted in a bathochromic shift approximately 21 nm, while the bithienyl system caused a strong bathochromic effect of 53 nm relative to the substituted phenyl groups. The bithienyl-antipyrine hybrid 1c displayed a turn-on fluorescence response to water, acetic acid (HOAc) and sulfuric acid (H(2)SO(4)) in ethanol solution, but no fluorescence response toward alkali. Whereas the free compound was very weakly fluorescent in ethanol, the addition of water, HOAc and H(2)SO(4) leads to an appearance of strong blue fluorescence and a dramatic increase of emission intensity. PMID- 22842352 TI - Synthesis and spectral studies on Pb(II) dithiocarbamate complexes containing benzyl and furfuryl groups and their use as precursors for PbS nanoparticles. AB - Nine lead bis(dithiocarbamate) complexes based on benzyl and furfuryl groups have been prepared. The complexes were characterized using IR and NMR spectroscopy. All the complexes showed the expected signals in (1)H and (13)C NMR spectra associated with the dithiocarbamate ligands. IR and (13)C NMR spectral studies indicate that the S(2)CN double bond character increases with increase in length of alkyl chain bonded to nitrogen atom. Bis(N-benzyl-N-(2 phenylethyl)dithiocarbamato-S,S')lead(II) (3) and bis(N-furfuryl-N-(2 phenylethyl)dithiocarbamato-S,S')lead(II) (4) have been used as single source precursors for the synthesis of ethylenediamine capped PbS nanoparticles. Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), FTIR, UV-vis and fluorescence spectroscopy have been used to characterize the as-prepared lead sulfide nanoparticles. The PXRD measurements suggest that PbS nanoparticles are single phase with face-centered-cubic structure. PMID- 22842353 TI - Characterization, physiochemical and computational studies of the newly synthesized novel imidazole derivative. AB - The photophysical properties of imidazole derivative were studied in several solvents. The observed fluorescence quantum yield is attributed to a loss of planarity in the excited state provided by the non co-planarity of the aryl rings attached to C(2) and N(1) atoms of the imidazole ring. The solvent effect on the absorption and fluorescence bands was analyzed by a multi-component linear regression in which several solvent parameters were analyzed simultaneously. DFT calculations were carried out in order to find out the NBO analysis, HOMO-LUMO energies, MEP studies and hyperpolarisability behaviour. This chromophore possess more appropriate ratio of off-diagonal versus diagonal beta tensorial component (r=beta(xyy)/beta(xxx)=0.12) which reflects the in plane non-linearity anisotropy. Since they have largest MUbeta(0) value, the reported imidazole can be used as potential NLO material. Within this context, reasonable conclusions concerning the steric hindrance in the chromospheres, push-pull character, hyperpolarisability of the imidazole and their application as NLO materials will be drawn. PMID- 22842354 TI - Effectiveness of provider incentives for anaemia reduction in rural China: a cluster randomised trial. AB - OBJECTIVES: To test the impact of provider performance pay for anaemia reduction in rural China. DESIGN: A cluster randomised trial of information, subsidies, and incentives for school principals to reduce anaemia among their students. Enumerators and study participants were not informed of study arm assignment. SETTING: 72 randomly selected rural primary schools across northwest China. PARTICIPANTS: 3553 fourth and fifth grade students aged 9-11 years. All fourth and fifth grade students in sample schools participated in the study. INTERVENTIONS: Sample schools were randomly assigned to a control group, with no intervention, or one of three treatment arms: (a) an information arm, in which principals received information about anaemia; (b) a subsidy arm, in which principals received information and unconditional subsidies; and (c) an incentive arm, in which principals received information, subsidies, and financial incentives for reducing anaemia among students. Twenty seven schools were assigned to the control arm (1816 students at baseline, 1623 at end point), 15 were assigned to the information arm (659 students at baseline, 596 at end point), 15 to the subsidy arm (726 students at baseline, 667 at end point), and 15 to the incentive arm (743 students at baseline, 667 at end point). MAIN OUTCOME MEASURES: Student haemoglobin concentrations. RESULTS: Mean student haemoglobin concentration rose by 1.5 g/L (95% CI -1.1 to 4.1) in information schools, 0.8 g/L (-1.8 to 3.3) in subsidy schools, and 2.4 g/L (0 to 4.9) in incentive schools compared with the control group. This increase in haemoglobin corresponded to a reduction in prevalence of anaemia (Hb <115 g/L) of 24% in incentive schools. Interactions with pre-existing incentives for principals to achieve good academic performance led to substantially larger gains in the information and incentive arms: when combined with incentives for good academic performance, associated effects on student haemoglobin concentration were 9.8 g/L (4.1 to 15.5) larger in information schools and 8.6 g/L (2.1 to 15.1) larger in incentive schools. CONCLUSIONS: Financial incentives for health improvement were modestly effective. Understanding interactions with other motives and pre existing incentives is critical. TRIAL REGISTRATION NUMBER: ISRCTN76158086. PMID- 22842355 TI - We must give children a voice in advance care planning. PMID- 22842356 TI - Single-photon emission from electrically driven InP quantum dots epitaxially grown on CMOS-compatible Si(001). AB - The heteroepitaxy of III-V semiconductors on silicon is a promising approach for making silicon a photonic platform. Mismatches in material properties, however, present a major challenge, leading to high defect densities in the epitaxial layers and adversely affecting radiative recombination processes. However, nanostructures, such as quantum dots, have been found to grow defect-free even in a suboptimal environment. Here we present the first realization of indium phosphide quantum dots on exactly oriented Si(001), grown by metal-organic vapour phase epitaxy. We report electrically driven single-photon emission in the red spectral region, meeting the wavelength range of silicon avalanche photodiodes' highest detection efficiency. PMID- 22842357 TI - Hormesis: a peep in to the human nature. PMID- 22842358 TI - The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl CoA reductase inhibitors in malignancies: a comprehensive review. AB - The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes via actions known as pleiotropic effects. Our paper serves as a focused review of pre-clinical investigations and published clinical data regarding the pleiotropic effects of statins in malignancies and emphasizes the importance of randomized, placebo-controlled trials to further elucidate this interesting phenomenon. PMID- 22842359 TI - Micronuclei assay of exfoliated oral buccal cells: means to assess the nuclear abnormalities in different diseases. AB - The micronuclei assay (MA) in exfoliated buccal cells is an innovative genotoxicity technique, which holds promise for the study of epithelial carcinogens. Micronuclei are suitable internal dosimeters for revealing tissue specific genotoxic damage in individuals exposed to carcinogenic mixtures. This article reviews the MN assay with respect to oral buccal mucosa, which has been used since the 1980s to demonstrate cytogenetic effects of environmental and occupational exposures, lifestyle factors, dietary deficiencies, and different diseases along with the characteristics of micronuclei and other nuclear abnormalities. PMID- 22842360 TI - Oral biopsy: oral pathologist's perspective. AB - Many oral lesions may need to be diagnosed by removing a sample of tissue from the oral cavity. Biopsy is widely used in the medical field, but the practice is not quite widespread in dental practice. As oral pathologists, we have found many artifacts in the tissue specimen because of poor biopsy technique or handling, which has led to diagnostic pitfalls and misery to both the patient and the clinician. This article aims at alerting the clinicians about the clinical faults arising preoperatively, intraoperatively and postoperatively while dealing with oral biopsy that may affect the histological assessment of the tissue and, therefore, the diagnosis. It also reviews the different techniques, precautions and special considerations necessary for specific lesions. PMID- 22842361 TI - Pathogenesis of oral submucous fibrosis. AB - Data from recent epidemiological studies provide overwhelming evidence that areca nut is the main etiological factor for oral submucous fibrosis (OSF). It is logical to hypothesize that the increased collagen synthesis or reduced collagen degradation is the possible mechanism in the development of the disease. There are numerous biological pathways involved in the above processes and it is likely that the normal regulatory mechanisms are either down regulated or up regulated at different stages of the disease. The copper content of areca nut is high and the possible role of copper as a mediator of fibrosis is supported by the demonstration of the up regulation of lysyl oxidase in OSMF biopsies. The aim of this article is to emphasize that the incorporation of copper into the areca nut is through the Bordeaux mixture, which is sprayed as a fungicide on areca plantations in regions with scheduled monsoons and of which copper sulfate is an important constituent. PMID- 22842362 TI - Evaluation of radiogallium-labeled, folate-embedded superparamagnetic nanoparticles in fibrosarcoma-bearing mice. AB - CONTEXT: Elevated expression of the folate receptor (FR) occurs in many human malignancies. Thus, folate targeting is widely utilized in drug delivery purposes specially using nano-radioactive agents. AIMS: In this work, we report production and biological evaluation of gallium-67 labeled superparamagnetic iron oxide nanoparticles, embedded by folic acid ( 67 Ga-SPION-folate) complex especially in tumor-bearing mice for tumor imaging studies. SETTINGS AND DESIGN: The structure of SPION-folate was confirmed by X-ray diffraction (XRD), transmission electron microscopy (TEM) and foureir transform infrared spectroscopy (FT-IR) analyses. The radiolabeled SPION-folate formation was confirmed by instant thin layer chromatography (ITLC). Tumor induction was performed by the use of poly-aromatic hydrocarbon injection in rodents as reported previously. MATERIALS AND METHODS: [ 67 Ga]-SPION-folate was shown to possess a particle size of ~ 5-10 nm using instrumental methods followed by ITLC test. Biocompatibility of the compound was investigated using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay followed by stability tests and tumor accumulation studies in fibrosarcoma-bearing mice after subcutaneous (s.c.) application. STATISTICAL ANALYSIS USED: All values were expressed as mean +/- standard deviation (mean +/- SD) and the data were compared using Student t-test. Statistical significance was defined as P<0.05. RESULTS: [ 67 Ga]-SPION-folate was prepared by a modified co precipitation method possessing a particle size of ~ 5-10 nm using instrumental methods (>95% radiochemical purity). Biodistribution studies demonstrated tumor:blood, tumor:bone and tumor:muscle ratios of 4.23, 4.98 and 11.54 respectively after 24 h. CONCLUSIONS: Due to the nano-scale size and high penetrative property of the developed folate-containing nano-complex, this system can be an interesting drug delivery modality with therapeutic applications and folate receptor-targeting behavior, while possessing paramagnetic properties for thermotherapy. PMID- 22842363 TI - Neo adjuvant chemo-radiotherapy and rectal cancer: can India follow the West? AB - AIMS: The management of locally advanced rectal cancer has changed over the years with an emphasis on neoadjuvant chemo radiation therapy (CT-RT) followed by surgery. This study is undertaken to evaluate the efficacy of this treatment in our set of patients with a special focus on the outcome in large circumferential tumors. MATERIALS AND METHODS: The study included patients who underwent neo adjuvant CT-RT between Jan 2006 and Oct 2009 in our institution. They received radical radiotherapy with conventional fractionation to a dose of 45-50 Gy along with continuous two cycles of 5-FU infusion. All patients were assessed at four weeks clinically and by CT scan and underwent surgery if the tumor was resectable followed by adjuvant chemotherapy. RESULTS: A total of 52 patients received the neoadjuvant treatment in form of CT-RT out of which 13 patients had undergone defunctioning colostomy before commencing treatment for severe obstructive symptoms. Only 73% patients underwent surgery in form of AR (anterior resection) or APR (abdominoperineal resection) and adjuvant chemotherapy was delivered in 28 (53.8%) patients only. The patients who underwent diversion colostomy had worse disease-free survival (DFS) as compared to those who received definitive treatment (33% vs. 74.9%, P<0.009). CONCLUSIONS: This study represents Indian experience with standard neoadjuvant chemo radiotherapy followed by surgery in rectal cancer. Large circumferential tumors in our set of patients lead to poor outcome leading to more APR. Also this study supported the need for an abbreviated protocol which can be economically suited and organ preservation protocols have a long way to go. PMID- 22842364 TI - Linear accelerator based stereotactic radiosurgery for melanoma brain metastases. AB - PURPOSE: Melanoma is one of the most common malignancies to metastasize to the brain. Many patients with this disease will succumb to central nervous system (CNS) disease, highlighting the importance of effective local treatment of brain metastases for both palliation and survival of the disease. Our objective was to evaluate the outcomes associated with stereotactic radiosurgery (SRS) in the treatment of melanoma brain metastases. MATERIALS AND METHODS: We retrospectively reviewed 54 patients with a total of 103 tumors treated with SRS. Twenty patients had prior surgical resection and nine patients underwent prior whole brain radiation therapy (WBRT). 71% of patients had active extracranial disease at the time of SRS. Median number of tumors treated with SRS was 1(range: 1-6) with median radiosurgery tumor volume 2.1 cm 3 (range: 0.05-59.7 cm 3 ). The median dose delivered to the 80% isodose line was 24 Gy in a single fraction. RESULTS: The median follow-up from SRS was five months (range:1-30 months). Sixty-five percent of patients had a follow-up MRI available for review. Actuarial local control at six months and 12 months was 87 and 68%, respectively. Eighty-one percent of patients developed new distant brain metastases at a median time of two months. The six-month and 12-month actuarial overall survival rates were 50 and 25%, respectively. The only significant predictor of overall survival was surgical resection prior to SRS. Post-SRS bleeding occurred in 18% of patients and at a median interval of 1.5 months. There was only one episode of radiation necrosis with no other treatment-related toxicity. CONCLUSION: SRS for brain metastases from melanoma is safe and achieves acceptable local control. PMID- 22842365 TI - Participation in decision making regarding type of surgery and treatment-related satisfaction in North Indian women with early breast cancer. AB - INTRODUCTION: Breast conserving surgery followed by radiotherapy is an established modality of treatment in early breast cancer patients since three decades, but yet it has not been adopted worldwide. PURPOSE: The aim of this study is to investigate the factors affecting decision making regarding type of surgery and satisfaction with type of surgery in North Indian women with early breast cancer. MATERIALS AND METHODS: A questionnaire was prepared to assess the factors responsible for decision making regarding type of surgery (breast conserving surgery (BCS) versus modified radical mastectomy (MRM) and to evaluate involvement of patient in decision making regarding the type of surgery. 47 women with early breast cancer on radiotherapy or on follow-up were interviewed by the resident doctors. RESULTS: Out of 47 patients, 28 underwent BCS and 19 MRM. Women undergoing BCS were younger, more literate than in those undergoing MRM. In the two arms (BCS versus MRM), decision for surgery was made by surgeon alone in 53% versus 73%, along with patient in 42% versus 6%, and only 10% women participated in decision making in each arm. Only 50% versus 30% patients had a clear understanding of the risks and benefits of both procedures in the two arms. CONCLUSION: North Indian women do not independently take decision regarding any type of surgery. The reason for opting for either kind of surgery was based on surgeon's recommendation or concern about recurrence. Body image was not an issue amongst majority. PMID- 22842366 TI - Downregulation of gene MDR1 by shRNA to reverse multidrug-resistance of ovarian cancer A2780 cells. AB - BACKGROUND: To explore the effects of downregulated multidrug-resistance P glycoprotein (MDR1/ABCB1) and reversed multidrug-resistance in human A2780 ovarian cancer cells. MATERIALS AND METHODS: Three shRNAs targeting the MDR1 gene were synthesized, and cloned into plasmid pSUPER-enhanced green fluorescent protein 1 (EGFP1). The formed pSUPER-EGFP1-MDR1-shRNAs were transfected into the A2780 cells, respectively, and the quantitative reverse transcription polymerase chain reaction and western blot were used respectively to determine the MDR1 expression. The multidrug-resistance (MDR) of the MDR1-shRNAs transfected A2780 cells to chemotherapy drugs in vitro and in tumor-bearing nude mice were respectively evaluated. RESULTS: The MDR1 shRNA expression resulted in decreased P-glycoprotein expression in the transfected A2780 cells. The MDR1-shRNA2 transfected cells showed that the sensitivities to chemotherapy drugs were higher than other shRNAs transfected A2780 cells, and that the formed tumor in mice grew slower than those of other mice after paclitaxel was injected into tumor-bearing nude mice. CONCLUSIONS: Our data demonstrates that the RNA interference could knock down gene MDR1 and reduce the P-glycoprotein expression, and partly reverse the MDR of A2780 cells in vitro and in vivo. These results suggest that MDR-1 is an effective therapeutic target for human ovarian caner treatment. PMID- 22842367 TI - Overexpression of MDM2 protein in ameloblastomas as compared to adenomatoid odontogenic tumor. AB - BACKGROUND: Recent studies on odontogenic tumors have identified various molecular alterations responsible for their development, and determination of epithelial proliferation is a useful means of investigating the differences in biologic behavior of these tumors. One such specific marker to identify proliferative activity and tumor aggressiveness by immunohistochemistry (IHC) is MDM2, 90-95 kDa protein. OBJECTIVE: This immunohistochemical study using MDM2 expression was undertaken to understand better the diverse biological activity of two groups of odontogenic tumors namely ameloblastoma and adenomatoid odontogenic tumor (AOT) based on their cell proliferation activity. MATERIALS AND METHODS: A total of 50 cases, comprising of 36 ameloblastoma samples and 14 AOT samples, were subjected to heat-induced antigen retrieval method using citrate buffer in a pressure cooker. Consequently, the sections were stained with MDM2 monoclonal antibody and visualized using an LSAB+ kit. RESULTS: In ameloblastomas, statistically significant association was seen between plexiform ameloblastomas, follicular ameloblastomas with granular cell changes, desmoplastic and unicystic variants. The predominant nuclear staining by MDM2 revealed overexpression in ameloblastomas as compared to AOT. CONCLUSION: The MDM2 overexpression noticed in plexiform ameloblastoma, follicular ameloblastoma with granular cell changes and acanthomatous ameloblastoma when compared to simple unicystic and desmoplastic ameloblastoma suggest a relatively enhanced proliferative phenotype of these solid multicystic variants of ameloblastomas. On overall comparison, higher expression was noted in ameloblastomas when compared to AOT. This indicates differences in the aggressive nature between these two groups of odontogenic tumors favoring the perception of a greater aggressive nature of ameloblastomas. PMID- 22842368 TI - Effect of combination exercise training on metabolic syndrome parameters in postmenopausal women with breast cancer. AB - CONTEXT: Studies have shown that physical activity or exercise training may decrease the metabolic syndrome. AIM: The aim of the present study is to clarify the effect of combination exercise training on metabolic syndrome parameters in postmenopausal women with breast cancer. SETTING AND DESIGN: Twenty nine postmenopausal women (58.27 +/- 6.31 years) with breast cancer were divided into two groups randomly as experimental group (n=14) and control group (n=15). MATERIALS AND METHODS: Subjects of experimental group were performed 15 weeks combination exercise training including walking (2 sessions per week) and resistance training (2 sessions per week that was different from walking days). Before and after 15 weeks, fasting insulin and glucose, insulin resistance, high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were calculated. Also, Vo2peak, rest heart rate (RHR), systolic blood pressure (SBP), body weight (BW), body mass index (BMI) and waist to hip ratio (WHR) were measured in two groups. STATISTICAL ANALYSIS USED: Mean values of two groups in pre and post test were compared by independent and paired t-test for all measurements (P <= 0.05). RESULTS: Significant differences were observed for VO2peak, RHR, BW, BMI, WHR, SBP, fasting insulin and glucose, HDL-C and TG between experimental and control groups after 15 weeks (P< 0.05). CONCLUSIONS: Combination exercise training can improve metabolic syndrome parameters in postmenopausal women with breast cancer. PMID- 22842369 TI - Cancer in Kashmir, India: burden and pattern of disease. AB - BACKGROUND: Incidence and prevalence of cancers differ in different regions of the world. To study the profile of different cancers in a particular cancer belt helps to know the exact incidence of different cancers in that region and their likely etiology. The aim of this study was to analyze the incidence of different cancers in Kashmir valley. MATERIALS AND METHODS: Retrospective study of patients registered at our Regional Cancer Centre (RCC) from Jan. 2009 to Dec. 2011 was carried out. All patients were histologically proven malignancies and were referred to the RCC for proper staging and treatment. All patients were properly evaluated and treated. RESULTS: A total of 8648 patients were registered during this period. Esophageal cancer was the most common cancer followed by cancers of Lung, Stomach, Colorectal, Breast, Non-Hodgkin's Lymphoma, Gastro esophageal junction, Ovary, Skin, Gallbladder, Multiple Myeloma, Acute Lymphoid Leukemia, Urinary Bladder, Prostate and Hodgkin's lymphoma. CONCLUSION: Pattern of malignancies in valley is different from rest of the India. Gastrointestinal malignancies are the commonest malignancies in Kashmir valley followed by lung cancer in males and breast cancer in females. PMID- 22842370 TI - CT findings in non-small-cell lung cancer patients treated with gefitinib or erlotinib. AB - PURPOSE: We performed this study to explore the association of computed tomography (CT) findings with outcomes of patients with non-small-cell lung cancer (NSCLC) treated with tyrosin kinase inhibitor (TKI) such as gefitinib or erlotinib. MATERIALS AND METHODS: We analyzed outcomes for 240 patients according to primary tumor (T), regional nodal (N) staging and diffuse small pulmonary metastases (DSPM) at the initial presentation. Tests for epidermal growth factor receptor (EGFR) mutation were performed in 92 patients. RESULTS: On multivariate analysis for tumor response, the N3 stage was predictive of a poor response (P < 0.001), whereas DSPM was a favorable factor (P = 0.007). Multivariate analysis for progression-free survival showed that the T3-4 stage (hazard ratio [HR]: 2.5, P < 0.001), in addition to the N3 stage (HR: 2.1, P < 0.001), was predictive of a poor outcome, whereas DSPM (HR: 0.6, P = 0.006) was a favorable factor. Notably, the multivariate model that included the EGFR mutational status revealed that the T3-4 stage predicted poor progression-free survival (HR: 2.2, P = 0.017) and poor overall survival (HR: 4.1, P < 0.001). CONCLUSION: Our data suggest that, in addition to EGFR mutational status, T-stage based on CT is predictive of outcomes of TKI-treated NSCLC patients. PMID- 22842371 TI - Assessment of the redox profile and oxidative DNA damage (8-OHdG) in squamous cell carcinoma of head and neck. AB - BACKGROUND: In developing countries especially in south Asia, there are growing habits of consumption of tobacco and its products in various forms. These are known to generate a strong free radical environment and when the free radicals overwhelm the antioxidant system, they may lead to degeneration of cellular components and mutations. AIM: The aim of this study is to assess the levels of oxidative stress determinants, which may be one of the critical factors in head and neck cancer development. MATERIALS AND METHODS: This study included 100 consenting SCCHN patients and 90 matched healthy controls and we assessed the total antioxidant capacity (TAC), glutathione (GSH), free radicals (RNS, ROS) and oxidative DNA adduct (8-OHdG). RESULTS: We observed a substantial rise in reactive oxygen species (ROS, ~3.0-fold) and reactive nitrogen species (RNS, ~1.7 fold), together with significant lowering in TAC (~1.2-fold) and GSH (~1.7-fold) was observed. The 8-OHdG levels were also found to be significantly (P < 0.05) higher in patients in comparison to controls. Pearson's correlation between blood ROS and GSH were found to be negatively correlated -0.38 (P < 0.01) and RNS and DNA damage positively correlated 0.44 (P < 0.01). CONCLUSION: Our present results demonstrate significant Redox imbalance in cancer patients suggesting their paramount importance in the development of SCCHN. The 8-OHdG could be the potential biomarker for evaluating risk of SCCHN. To develop new approaches of SCCHN prevention, there is a need of detailed study and better understanding of the molecular mechanisms underlying oxidative stress and DNA damage. PMID- 22842372 TI - The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity. AB - BACKGROUND: The aim of the study was to compare the protective efficacy of l carnitine (LC) to amifostine on radiation-induced acute small intestine damage. MATERIALS AND METHODS: Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia. RESULTS: Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group. CONCLUSIONS: Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure. PMID- 22842373 TI - Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy. AB - BACKGROUND: While more elderly patients are being diagnosed with lung cancer every year, no anti-lung cancer therapy designed specifically for the elderly has been established yet. This is the first retrospective study to examine the efficacy and safety of amurubicin (AMR) for elderly patients with refractory relapsed small cell lung cancer (SCLC) as second or third-line chemotherapy. MATERIALS AND METHODS: Thirty-six patients were eligible for analyzing the frequency of hematologic and non-hematologic toxicities and effectiveness of AMR for refractory relapsed SCLC in both elderly (>= 70 years) and non-elderly (<70 years) groups. RESULTS: Among these patients as third-line chemotherapy, the response rate and the disease control rate of refractory relapsed cases were 44.4 and 55.6%, respectively. The median of progression-free survival time was 3.0 months and the median of overall survival time was 5.1 months. There were no significant differences in the frequency of the grade 3-5 hematologic or non hematologic toxicity between the elderly (>= 70 years) and non-elderly (<70 years) patients or second and third-line chemotherapies. CONCLUSIONS: AMR could be one of the effective tools in the treatment of elderly patients with refractory relapsed SCLC as third-line chemotherapy, and the recommended dose is 30 mg/m 2 for three consecutive days. PMID- 22842375 TI - In search of malignant transformation: a pilot study. AB - CONTEXT: The role of oxygen free radicals in the initiation, promotion and progression of carcinogenesis and the protective role of antioxidant defenses has been the subject of much speculation in the recent past, with conflicting reports in the literature. AIMS: The aim of this study was to measure the concentration of serum total proteins and albumin and advanced oxidation protein products (AOPP) in the sera of patients diagnosed with speckled leukoplakia and well differentiated oral squamous cell carcinoma. MATERIALS AND METHODS: The study consisted of sera analysis of 30 new cases of histologically proven well differentiated, oral squamous cell carcinoma and 10 patients with speckled leukoplakia aged between 40 and 60 years in addition to 25 healthy controls. STATISTICAL ANALYSIS USED: One-way analysis of variance (ANOVA) was used to test the difference between groups. To find out which of the two groups' mean was significantly different, post hoc test of Scheffe was used. RESULTS: The study revealed variations in sera levels of albumin and advanced oxidation protein products to be statistically significant. CONCLUSIONS: The results obtained emphasize the need for more studies with larger sample sizes to be conducted before a conclusive role for sera levels of total protein, albumin and AOPP could be drawn as markers of transition of the various oral precancerous lesions and conditions to frank oral squamous cell carcinoma. PMID- 22842374 TI - Quality of life assessment in survivors of breast cancer. AB - AIM: The aim was to assess the health-related quality of life (HRQOL) and its temporal variation at first visit and subsequent visits among breast cancer patients. DESIGN AND SETTING: The prospective study was carried out in Outpatient Department of Radiation Oncology, University Teaching and Tertiary Referral Hospital. MATERIAL AND METHODS: After clearance from the ethical committee and EORTC group, 81 surgically treated female breast cancer patients referred to the Outpatient Department of Radiation Oncology for chemoradiation and hormonal therapy were included in the study after informed written consent, irrespective of the age and stage of disease. The patients were interviewed as per the EORTC QLQ-C30 Questionnaire module at four levels at the first visit and at subsequent follow-up visits at 6, 12, and 24 months, respectively, and are still on follow up. STATISTICAL ANALYSIS: The data collected were expressed as mean/raw score (RS), standard deviation (SD), and percent mean/scale score expressed on the linear transformation scale, derived as per the calculations and equations of the EORTC QLQ-C30 Scoring Manual. Intragroup comparison (IGC) was done at four levels/visits, a, b, c and d. A P-value of <0.05 was considered significant. RESULTS: The mean age at presentation was 46.6 +/- 10.2 years. The study showed that the physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning, global health status, and symptomatology showed statistically significant improvement over time (P < 0.001). CONCLUSION: The survivors of female breast cancer over the long-term follow-up showed significant improvement and coping mechanisms involved in a majority of HRQOL parameters. PMID- 22842376 TI - Pediatric oral leiomyosarcoma: rare case report. AB - Soft tissue sarcomas comprise a group of histologically diverse malignant neoplasms arising from mesenchymal cell lines. Among these, leiomyosarcomas are sarcomas exhibiting smooth muscle differentiation. Occurrence of this neoplasm in the oral cavity is exceedingly rare and its presentation is unusual in children. We present a case report of leiomyosarcoma of the oral cavity in an eight-year old child. Primary oral leiomyosarcoma, being a rare entity in children, this case report emphasizes the prompt recognition of this tumor to institute appropriate multimodality treatment. PMID- 22842377 TI - Langerhans cell histiocytosis of long bones: MR imaging and complete follow up study. AB - Langerhans cell histiocytosis (LCH) is a relatively rare disease affecting the reticuloendothelial system in the pediatric age group. It can affect bones, lung, liver, spleen, lymph nodes and skin. MR imaging is particularly informative in diagnosis and management of bone LCH. In this report, we present the initial and 23 months post-treatment MR images of a femoral LCH lesion in a 12-year-old child to describe the role of MRI in bone LCH. PMID- 22842378 TI - Incidental cystic endocrine tumor of the pancreas: a case report with immunohistochemical study. AB - A large cystic lesion in the pancreatic tail was found incidentally in a 20-year old female during laparoscopic cholecystectomy. Pre-operative work up had revealed calculi in gall bladder and in addition, a cystic lesion in pancreas suggesting the possibility of a pseudocyst. A laparoscopic enucleation of the cyst was performed along with the removal of gallbladder. Microscopic examination of the resected specimen revealed a pancreatic cystic endocrine tumor; however, this tumor had produced no symptoms. Immunohistochemical studies of the tumor cells showed positivity for neuron-specific enolase, chromogranin A, and synaptophysin indicating their neuroendocrine nature. Prognostic markers (CK19, CD10 and Ki67) indicated good prognosis. Although endocrine tumors of the pancreas are usually solid, cystic change occurs only rarely and such tumors should be considered in the differential diagnosis of patients who have a cystic lesion in the pancreas in view of their rare transformation into a malignant tumor. PMID- 22842379 TI - Methotrexate-induced acute toxic leukoencephalopathy. AB - Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year period. PMID- 22842380 TI - Primary amyloidosis with high grade transitional cell carcinoma of bladder: a rare case report. AB - Primary amyloidosis of bladder is a rare disease that closely resembles bladder cancer on clinical presentation with painless gross hematuria. Pathologically this is a totally benign non-neoplastic lesion and its association with urothelial carcinoma of the bladder is rare. We herein report a 64-year-old diabetic male who has been treated for primary amyloidosis of bladder for the last 26 years presented recently with high-grade solid urothelial cancer with osseous metaplasia and sarcomatoid change of bladder with area of amyloid deposition. PMID- 22842381 TI - Multiple cutaneous squamous cell carcinomas: primary carcinomas versus cutaneous metastasis. AB - Multiple squamous cell carcinoma (SCC) of the skin is an exceedingly rare entity. It has been reported in a few patients of psoriasis treated with oral psoralen therapy and UV radiation, immunodeficiency states, local intramuscular metastasis and cutaneous metastasis from vulvar SCC. We report the case of a 55-year-old man who reported with a painless non-healing warty growth on the lower back persisting for the last 2 years which was excised. Its histopathology proved it to be SCC with HPV changes. On examination, 4 similar lesions were found on the upper back; out of which 1 lesion exhibited marked dysplastic changes on histopathology, but without HPV changes. This case could be either multicentrically developed SCC due to HPV infection or cutaneous metastasis as carcinoma of unknown primary site i.e. metastasis occurring before primary tumor diagnosis. PMID- 22842382 TI - Severe perirenal hematoma in a patient with a single kidney treated with sunitinib for metastatic pancreatic neuroendocrine tumor. AB - A better understanding of the angiogenic process has markedly expanded the use of antiangiogenic therapy in many solid tumors. It is known that there is a close relationship between cancer disease, vascular homeostasis, angiogenesis and coagulation cascade. In this setting, antiangiogenic therapy could interfere and potentially increase the risk of bleeding or thromboembolic events. Sunitinib is an orally available small molecule multikinase inhibitor recently approved for the treatment of unresectable or metastatic, well-differenciated pancreatic neuroendocrine tumors with disease progression in adults. Here we present the first case of a severe perirenal hematoma in a patient treated with sunitinib for metastatic pancreatic neuroendocrine tumor. PMID- 22842383 TI - Follicular dendritic cell sarcoma: a diagnostic challenge ! AB - Follicular dendritic cell sarcoma (FDCS) is a spindle cell neoplasm of histiocytic-dendritic cells origin. It is known to occur in lymph nodes and rarely has been reported in extranodal tissues like head and neck, mediastinum and gastrointestinal tract. We herein report the first FDCS arising from anal canal in a 56-year-old man. The tumor was composed of bland short spindle cells in focal whorl formation with interspersed few lymphocytes. The tumor cells were classically positive for CD21, CD23, CD35 and vimentin. Despite its misleading morphology, immunohistochemistry helped us to reach a conclusive diagnosis for relevant therapy. PMID- 22842384 TI - A rare case of metastatic ductal type prostate adenocarcinoma presenting with syndrome of inappropriate secretion of antidiuretic hormone: a case report and review. AB - Ductal adenocarcinoma of the prostate is a rare malignancy and it accounts for less than 1% of prostatic adenocarcinomas as a predominant pattern. In general, the prognosis for these patients is worse than those with typical adenocarcinoma of the prostate. SIADH is a rare paraneoplastic syndrome associated with classic and poorly differentiated acinar prostate adenocarcinoma. To our knowledge, this is the first case of paraneoplastic SIADH associated with ductal type prostate adenocarcinoma. The case highlights once again that the patients with metastatic prostate cancer who present with hyponatremia should get a diagnostic workup for SIADH done due to the potential fatal consequences of this paraneoplastic syndrome. PMID- 22842385 TI - Systemic juvenile xanthogranuloma with multiple central nervous system lesions. AB - Juvenile xanthogranulomatosis (JXG) is an uncommon histiocytic disorder that is usually benign and limited to the skin. The systemic form of JXG is rare and may be associated with severe morbidity and mortality especially in central nervous system (CNS) involvement. Here, we describe a six-year-old boy with disseminated skin lesions and neurological signs and symptoms. Diagnostic work up revealed multiple brain lesions. A skin biopsy and a stereotactic brain biopsy considered suggestive of systemic JXG. Treatment with prednisolone, vinblastine and methotrexate was successful with regression of skin and CNS lesions. The patient has been in remission for almost three years. PMID- 22842386 TI - Extremely rare giant retroperitoneal fibrolipoma: a case report. AB - Lipomas are common benign adipose tumors generally located at superficial locations. Mostly they measure a few centimeters in size; however, giant lipomas measuring more than 10 cm in size or weighing 1000 g are also seen. Deep seated lipomas are rather infrequent out of which retroperitoneal location of giant lipoma is rare. Fibrolipoma is one of the uncommon variant of lipomas. A giant retroperitoneal fibrolipoma is extremely rare and only five case reports of such tumors are there in the literature. We herein present one such case in a 36-years old female. PMID- 22842387 TI - Inflammatory myofibroblastic tumor appendix with concomitant mucosal dysplasia, simulating pseudomyxoma on preoperative aspiration cytology. AB - Inflammatory myofibroblastic tumor (IMT) has been described as a pseudosarcomatous proliferation of spindled myofibroblasts admixed with lymphoplasmacytic cells. The various terminologies like inflammatory pseudotumor, plasma cell granuloma, and inflammatory myofibrohistiocytic proliferation, used to describe this entity, highlight the controversial etiopathogenesis of this relatively indolent neoplasm. IMT has now been described in different anatomic locations. However, cases occurring in the gastrointestinal tract are rare with very few cases described in the appendix. We present a case of inflammatory myofibroblastic tumor appendix with mucosal dysplasia in a 41-year-old male, presenting with abdominal pain and lump in the right iliac fossa. Aspiration cytology yielded few atypical epithelial cells and spindle cells in a mucinous background, suggesting the possibility of pseudomyxoma peritonei. Awareness of IMT appendix with rare presence of mucosal dysplasia may help in preventing overzealous resection, especially in situations that on preoperative evaluation may suggest malignancy. PMID- 22842388 TI - Pleomorphic variant of lobular carcinoma breast: a rare case report with review of the literature. AB - Pleomorphic carcinoma is a poorly described entity whose phenotype is not well recognized as within the morphological spectrum of breast carcinoma. The purpose of this report is to describe the clinicopathological features of this tumour with review of the literature. We report a case of invasive pleomorphic lobular carcinoma with coexisting classic lobular carcinoma in situ. PMID- 22842389 TI - Primary squamous cell carcinoma of the breast: case report and management decisions. AB - Though breast carcinoma is one of the most common malignancies worldwide, adequate knowledge of this disease is still very poor. Pure primary squamous cell carcinoma of breast is one such mystery, which is encountered very rarely. Its clinical behavior should not be correlated with the standard infiltrating duct carcinoma of breast. It follows an atypical presentation in terms of tumor size, lymph node and systemic spread. It is generally a triple negative tumor with an aggressive behavior and resistance to standard chemotherapeutic regimens. Management decisions need to be individualized with emphasis toward platinum based chemotherapy and targeted therapy. PMID- 22842390 TI - Psychostimulants for chemotherapy induced cognitive changes in cancer, Ockham's razor, anyone? PMID- 22842391 TI - Resurrecting brachytherapy from brink of oblivion. PMID- 22842392 TI - Physiological characterization of juvenile Chinook salmon utilizing different habitats during migration through the Columbia River Estuary. AB - Although off-channel habitats in the estuaries of large rivers impart many benefits to fish that rear within them, it is less clear how these habitats benefit migrating anadromous species that utilize these habitats for short periods of time. We evaluated the physiological correlates (nutritional condition, growth, and smoltification) of habitat utilization (main-channel vs. off-channel) by juvenile Chinook salmon Oncorhynchus tshawytscha during emigration. Fish from the off-channel had higher condition factor scores and relative weights than fish from the main-channel throughout the study period. Plasma triglyceride and protein concentrations were significantly different between habitat types and across the sampling period, suggesting that fish utilizing the off-channel habitats were compensating for energy losses associated with emigration as compared to main-channel fish. Growth potential (RNA to DNA ratio) did not vary by habitat or sampling period, presumably due to short residency time. There were no differences in osmoregulatory capacity (gill Na(+), K(+)-ATPase activity) based on habitat type. Our results indicate that short-term off-channel habitat use may mitigate for energy declines incurred during migration, but likely does not impart significant gains in energy stores or growth. PMID- 22842393 TI - Lateral hypothalamic area mediated the protective effects of microinjection of glutamate into interpositus nucleus on gastric ischemia-reperfusion injury in rats. AB - We investigated the protective effects of chemical stimulation of cerebellar interpositus nucleus (IN) on gastric ischemia-reperfusion injury (GI-RI) and its possible regulatory mechanisms in rats. Gastric mucosal damage index (GMDI) indicated the severity of gastric mucosal injuries. Transferase dUTP nick end labeling (TUNEL) staining and proliferating cell nuclear antigen (PCNA) were performed to assess gastric mucosal cell apoptosis and proliferation. Microinjection of glutamate into IN markedly attenuated GI-RI. Either chemical lesion of IN or electrical ablation of the decussation of superior cerebellar peduncle (DSCP) obviously aggravated GI-RI. The protective effects of IN were reversed with the pretreatments of microinjection of 3-mercaptopropionic acid into IN or Bicuculline into lateral hypothalamic area (LHA), individually. The discharge frequency and intensity of greater splanchnic nerve (GSN) decreased and gastric mucosal blood flow increased after chemical stimulation of IN. The apoptosis of positive cells of gastric mucosa was decreased by chemical stimulation of IN, whereas proliferation increased. The gastric juice volume, acidity, and total acid output were all decreased after the chemical stimulation of IN. These results indicated that IN participates in regulation of GI-RI and is a specific area in central nervous system for exerting protective effects on GI RI. DSCP, LHA and GSN may involve in this process. Apoptosis and proliferation may mediate this protective process in rats too. PMID- 22842394 TI - Alkalosis leads to the over-activity of cortical principal neurons. AB - Alkalosis patients manifest anxiety, manic and convulsion. The elevation of mood and behavior is hypothetically a scenario that alkalosis resets the functional status of neuronal networks to overexcitation. In addition to the downregulation of inhibitory neurons, we examined whether alkalosis upregulates the functions of cortical principal neurons by electrophysiological approach. High extracellular pH condition downgrades inhibitory postsynaptic current frequency, as well as upregulates excitatory synaptic events and spike production in cortical principal neurons. Their functional upregulation is associated with the decreases of spike refractory period and threshold potential. Alkalosis downregulates GABA release from inhibitory neurons and upregulates the functions of principal neurons, which lead to imbalance between inhibitory and excitatory networks for the elevated mood and behaviors. PMID- 22842395 TI - Vitamin D receptor gene polymorphism and its association with Parkinson's disease in Chinese Han population. AB - Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator, and accumulating data have provided evidence for that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). In this study, we performed a case-control study to demonstrate whether the risk for the development of onset of sporadic PD might be influenced by VDR gene polymorphisms in a Chinese cohort. Two hundred and sixty PD patients and 282 matched-healthy controls were genotyped for two representative single nucleotide polymorphisms (SNPs) in VDR gene (FokI C/T and BsmI G/A) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis in. Results from our study revealed that FokI C allele carriers were likely to associate with an increased risk of PD (P=0.004) as well as early-onset PD (EOPD) (P=0.010). Moreover, the frequency of FokI C allele was significantly increased in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P=0.023 and P=0.033, respectively). For BsmI polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls, as well as gender- and age-related differences between PD patients and the controls subgroup. This study demonstrated a possible association between the VDR FokI T/C polymorphism and PD, indicating that VDR polymorphisms may well change genetic susceptibility to sporadic PD in a Han Chinese population. PMID- 22842396 TI - Characterizing emotional response to music in the prefrontal cortex using near infrared spectroscopy. AB - Known to be involved in emotional processing the human prefrontal cortex (PFC), can be non-invasively monitored using near-infrared spectroscopy (NIRS). As such, PFC NIRS can serve as a means for studying emotional processing by the PFC. Identifying patterns associated with emotions in PFC using NIRS may provide a means of bedside emotion identification for nonverbal children and youth with severe physical disabilities. In this study, NIRS was used to characterize the PFC hemodynamic response to emotional arousal and valence in a music-based emotion induction paradigm in 9 individuals without disabilities or known health conditions. In particular, a novel technique based on wavelet-based peak detection was used to characterize chromophore concentration patterns. The maximum wavelet coefficients extracted from oxygenated hemoglobin concentration waveforms from all nine recording locations on the PFC were significantly associated with emotional valence and arousal. Specifically, high arousal and negative emotions were associated with larger maximum wavelet coefficients. PMID- 22842398 TI - Direct determination of phospholipase D activity by infrared spectroscopy. AB - To determine phospholipase D (PLD) activity, an infrared spectroscopy assay was developed, based on the phosphate vibrational mode of phospholipids such as dimyristoylphophatidylcholine (DMPC), lysophosphatidylglycerol (lysoPG), dipalmitoylphosphatidylethanolamine (DPPE), and lysophosphatidylserine (lysoPS). The phosphate bands served to monitor the hydrolysis rates of phospholipids with PLD. The measurements could be performed within less than 20min with 10MUl of buffer containing 2 to 40mM DMPC and 10 to 200ng of Streptomyces chromofuscus PLD (corresponding to 350-7000pmol of DMPC hydrolyzed per minute). The limit of sensitivity was approximately 10ng of PLD at 100mM Tris-HCl (pH 8.0) with 10mM Ca(2+) and 2.5mgml(-1) Triton X-100. Reproducible specific activity of PLD (35+/ 5nmol of hydrolyzed DMPCmin(-1)MUg(-1) PLD) measured by the infrared assay remained stable over 50 to 200ng of PLD and over 5 to 40mM DMPC. The feasibility of this assay to determine the hydrolysis rate of other phospholipids such as lysoPG, DPPE, and lysoPS was confirmed. The IC(50) of cobalt (800+/-200MUM), a known S. chromofuscus PLD inhibitor, was measured by means of the infrared assay, demonstrating that this assay can be used to screen PLD activity and/or the specificity of its inhibitors. PMID- 22842397 TI - Propranolol elicits cutaneous analgesia against skin nociceptive stimuli in rats. AB - The purpose of this study was to investigate the cutaneous analgesic effect of propranolol and compare with a local anesthetic lidocaine. The potencies and equipotent doses were determined for infiltrative cutaneous analgesia on the rat back by determination of dose-response curves for propranolol and lidocaine. Propranolol as well as lidocaine elicited dose-dependent cutaneous analgesia. On a 50% effective dose (ED(50)) basis, the relative potency was propranolol (10.3 [8.9-11.9]MUmolkg(-1))>lidocaine (25.8 [24.3-27.8]MUmolkg(-1)) (P<0.01). On equianalgesic doses (ED(25), ED(50), ED(75)), propranolol produced longer action of infiltrative cutaneous analgesia than lidocaine (P<0.01). Coadministration of lidocaine (25.8MUmolkg(-1)) and propranolol (1.7MUmolkg(-1)) exhibited greater blockade and duration than lidocaine (25.8MUmolkg(-1)) or propranolol (1.7MUmolkg(-1)) alone. Propranolol displayed more potent and longer duration of action than lidocaine at producing cutaneous analgesia. Furthermore, propranolol may prove useful as an adjuvant for lidocaine in producing cutaneous analgesia. PMID- 22842399 TI - Functions of MgH2 in hydrogen storage reactions of the 6LiBH4-CaH2 reactive hydride composite. AB - A significant improvement of hydrogen storage properties was achieved by introducing MgH(2) into the 6LiBH(4)-CaH(2) system. It was found that ~8.0 wt% of hydrogen could be reversibly stored in a 6LiBH(4)-CaH(2)-3MgH(2) composite below 400 degrees C and 100 bar of hydrogen pressure with a stepwise reaction, which is superior to the pristine 6LiBH(4)-CaH(2) and LiBH(4) samples. Upon dehydriding, MgH(2) first decomposed to convert to Mg and liberate hydrogen with an on-set temperature of ~290 degrees C. Subsequently, LiBH(4) reacted with CaH(2) to form CaB(6) and LiH in addition to further hydrogen release. Hydrogen desorption from the 6LiBH(4)-CaH(2)-3MgH(2) composite finished at ~430 degrees C in non-isothermal model, a 160 degrees C reduction relative to the 6LiBH(4) CaH(2) sample. JMA analyses revealed that hydrogen desorption was a diffusion controlled reaction rather than an interface reaction-controlled process. The newly produced Mg of the first-step dehydrogenation possibly acts as the heterogeneous nucleation center of the resultant products of the second-step dehydrogenation, which diminishes the energy barrier and facilitates nucleation and growth, consequently reducing the operating temperature and improving the kinetics of hydrogen storage. PMID- 22842400 TI - New supramolecular interactions for electrochemical sensors development: different cucurbit[8]uril sensing platform designs. AB - Three different strategies for cucurbit[8]uril immobilization on a glassy carbon electrode have been assayed. The electrochemical properties of the resulting modified electrodes in solutions containing neutral, positively and negatively charged potential cucurbit[8]uril guests were investigated by cyclic voltammetry and electrochemical impedance spectroscopy. The comparison of the electrochemical behaviour exhibited by the unmodified electrodes against various probes, with respect to that of each modified electrode, resulted in an appropriate method to choose among different strategies for the development of electrochemical sensors. These sensors are based on the incorporation of the cucurbit[8]uril molecular selection properties that depend on the chemical characteristics of the potential analytes. Furthermore, atomic force microscopy was employed for the characterization of the different surfaces developed. PMID- 22842401 TI - Repetitive TMS over V5/MT shortens the duration of spatially localized motion aftereffect: the effects of pulse intensity and stimulation hemisphere. AB - Causal relevance of the cortical area V5/MT for motion (aftereffect) perception has been shown when rTMS pulses have been applied onto this area, leading to disruption of the percept. Typically, the inducing and test stimuli have consisted in a spatially contiguous area from where stimulation is presented. Observers have had no need to divide attention between spatially remote areas including motion-related signals with different vectors. Here we present experimental results showing that an adverse effect of rTMS on motion aftereffect can be obtained when contralateral V5/MT is stimulated and subjects have to report which one of the two simultaneous aftereffect percepts separated into two hemifields decays before the other. The effect appears stronger following right hemisphere V5/MT stimulation and is clearly evident even with weak rTMS pulses. PMID- 22842402 TI - Combination of retinitis pigmentosa and hearing loss caused by a novel mutation in PRPH2 and a known mutation in GJB2: importance for differential diagnosis of Usher syndrome. AB - Purpose of this study was to molecularly characterize a family in which two brothers (46 and 36 years) presented with a combination of retinitis pigmentosa (RP) and severe sensorineural hearing loss while father and sister (71 and 41 years) presented with isolated RP. Retinal phenotype was compared with phenotype of 17 patients with Usher syndrome type 1. Ophthalmological examination included assessment of Snellen visual acuity, color vision with Ishihara tables, Goldmann perimetry (targets II/1-4) and microperimetry. Fundus autofluorescence imaging and optical coherence tomography were performed. Direct sequencing of all coding exons and flanking intronic sequences of GJB2 (gap junction protein, beta 2) and PRPH2 (peripherin 2) genes was performed in younger brother. Other family members were analyzed with sequencing (GJB2), high resolution melt analysis (GJB2) or restriction enzymes (PRPH2). Brothers with hearing loss were found to carry a homozygous c.35 delG mutation in GJB2, the most common mutation associated with recessive hearing loss. All patients were found to carry a novel heterozygous mutation c.389T>C (p.Leu130Pro) on PRPH2. Age of onset was higher in PRPH2 than USH1 patients, however with some overlap. Differentiation from retinal phenotype of USH1 could only be made in the oldest patient, who retained good central visual function after more than three decades of disease. PMID- 22842405 TI - A prospective study of short- and long-term cosmetic outcome after reduction mammaplasty from three different perspectives: the patient, a department surgeon, and an independent private practitioner in plastic surgery. AB - BACKGROUND: Numerous studies have examined the outcome of reduction mammaplasty. This study evaluates the cosmetic outcome after reduction mammaplasty from the perspective of the patient, a ward surgeon, and a private practitioner in plastic surgery, and analyzes which factors influence it. METHODS: The material stems from a Danish quality assurance program in the public health care system. Nonparametric statistics and logistic regression were used to compare cosmetic outcomes and possible confounding. RESULTS: Over 80 percent of the patients evaluated the short- and long-term cosmetic outcome as good or very good. The surgeons and especially the private practitioner were more critical. The evaluation of breast features also differs between patients and surgeons. The main issue for patients is symmetry. With time, patients and the private practitioner become more critical about the scars. Surgeons are most concerned about nipple bottoming out. Predictive factors for surgeons were the patient's age, body mass index, and postoperative complications. Evaluation by patients was, in addition to complications, influenced by the preoperative information given, confidence in the treatment, and the overall course on the ward. CONCLUSIONS: Patients evaluate cosmetic outcome significantly more favorably than surgeons and especially the private practitioner. They are also concerned about different breast features. Decreased nipple sensation does not influence the patient's evaluation. Evaluation by the surgeons depends on more objective measures than does evaluation by the patients. One must not underestimate the importance of factors such as preoperative information about the surgery and complications, together with proper and qualified care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 22842403 TI - Modulation of saccadic inhibition by distractor size and location. AB - Distractors presented contralateral to a visual target inhibit the generation of saccades within a precise temporal window (Buonocore & McIntosh, 2008; Reingold & Stampe, 2002; Walker, Kentridge, & Findlay, 1995). The greatest 'dip' of saccadic inhibition typically occurs at about 90 ms after distractor onset, with a subsequent recovery period showing an elevated frequency of saccades. It is not yet known how the spatial properties of the distractor stimulus influence the saccadic inhibition signature. To study this, we manipulated the size and the field of presentation of the distractor in four experiments. Experiment 1 demonstrated that the size of a distractor in the contralateral field is logarithmically related to the magnitude of the saccadic inhibition dip. This implies that the probability of a planned saccade being inhibited increases logarithmically with the size of the distractor. Experiment 2 showed a qualitatively similar but more pronounced effect of size for distractors in the ipsilateral field. Experiment 3 compared the effects of contralateral and ipsilateral distractors directly using a within-subjects design, confirming the more pronounced impact of ipsilateral distractors. Experiment 4 replicated the more pronounced effect of ipsilateral distractors in a task in which target side was unpredictable, confirming that the effect does not result merely from participants preparing in advance to ignore events on one side. We suggest that participants are more able to resist contralateral distraction during target selection, as they can more effectively withdraw attention from locations remote from the target than from locations close to it. PMID- 22842404 TI - First human study in treatment of unresectable liver metastases from colorectal cancer with irinotecan-loaded beads (DEBIRI). AB - The objective of this pilot clinical study was to assess the safety, technical feasibility, pharmacokinetic (PK) profile and tumour response of DC BeadTM with irinotecan (DEBIRITM) delivered by intra-arterial embolisation for the treatment of metastatic colorectal cancer. Eleven patients with unresectable liver metastases from CRC, tumour burden <30% of liver volume, adequate haematological, liver and renal function, performance status of <2 were included in this study. Patients received up to 4 sessions of TACE with DEBIRI at 3-week intervals. Feasibility of the procedure, safety and tumour response were assessed after each cycle. PK was measured after the first cycle. Patients were followed up to 24 weeks. Only mild to moderate adverse events were observed. DEBIRI is a technically feasibile procedure; no technical complications were observed. Average Cmax for irinotecan and SN-38 was 194 ng/ml and 16.7 ng/ml, respectively, with average t1/2 of 4.6 h and 12.4 h following administration of DEBIRI. Best overall response during the study showed disease control in 9 patients (2 patients with partial response and 7 with stable disease, overall response rate of 18%). Our study shows that transarterial chemoembolisation with irinotecan loaded DC beads (DEBIRI) is safe, technically feasible and effective with a good PK profile. PMID- 22842406 TI - Current status of autologous tissue-based breast reconstruction in patients receiving postmastectomy radiation therapy. AB - BACKGROUND: The threshold for patients with breast cancer to receive radiation therapy continues to be lowered. The author reviewed the literature to determine the clinical impact that the increasing use of radiation therapy has had on the management of patients with breast cancer who desire autologous tissue-based breast reconstruction. METHODS: The MEDLINE database was searched for articles on breast reconstruction and radiation therapy published between January of 2008 and June of 2011. Abstracts of those articles were reviewed to identify articles that addressed the most pressing radiation-related issues facing reconstructive breast surgeons performing autologous tissue-based reconstruction. This subgroup of articles was reviewed in detail. RESULTS: Two-hundred eighty-five articles were identified. Seventeen articles were reviewed in detail. Nine articles provided level III evidence, mostly from retrospective comparative studies. Five articles provided level I (n=2) or II (n=3) evidence from high-quality, multicenter or single-center, randomized, controlled trials or prospective cohort studies. Three articles provided level IV evidence from case series and were included in the review because they offered a novel approach or perspective. Since the author's last review of the literature in 2009, there have been changes in the practice patterns in the approach to autologous breast reconstruction in patients who undergo radiation therapy. CONCLUSION: With the increasing use of radiation therapy in patients with breast cancer, future studies should seek to provide more meaningful data (level I and II evidence) to help guide clinical decision making. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 22842407 TI - A novel in vivo technique for observations of choke vessels in a rat skin flap model. AB - BACKGROUND: Choke vessels are reduced-caliber vessels that link adjacent vascular territories throughout the body. The behavior of choke vessels determines flap survival. Therefore, it is important to develop a reliable technique with which to study these vessels. The purpose of this report is to document a novel in vivo technique for the study of choke anastomotic vessels in a rat skin flap model. METHODS: This study was divided into two parts. In part I, 30 adult Sprague Dawley rats underwent whole-body lead oxide/gelatin injection and the skin was removed for radiography to analyze the skin vasculature. In part II, a dorsal skin flap was elevated in 12 rats, and a skinfold chamber was installed to observe the choke vessels between the iliolumbar artery perforator and the posterior intercostal artery perforator for 8 days. Evans blue dye was injected through the lateral tail vein. Blood flow velocity was calculated. RESULTS: In part I, three distinct patterns of dorsal cutaneous vasculature were found. A three-territory, 3.5*10-cm flap can be elevated on the dorsum of the rat. In part II, an increase in diameter of the choke arteries and the choke veins was observed, particularly in the fine venules. Blood flow velocity across the arterial segment of the choke zone was found to be 2.5 mm/second. CONCLUSIONS: The observation chamber technique for in vivo study of the choke anastomotic region of the rat dorsal skin flap model is a promising novel method for studying skin microcirculation. The time sequence of microvascular events in the choke anastomotic zone of this rat model was documented. PMID- 22842408 TI - Facial reanimation by one-stage microneurovascular free abductor hallucis muscle transplantation: personal experience and long-term outcomes. AB - BACKGROUND: In 1990, Jiang Hua introduced a new method using one-stage reconstruction with free abductor hallucis muscle transfer for dynamic reanimation of established unilateral facial paralysis. The authors present their experience with this procedure and analyze the postoperative complications and long-term functional and aesthetic outcomes. METHODS: From March of 1990 to March of 2010, 45 patients underwent the free abductor hallucis muscle transfer procedure in the authors' department. Forty-one were followed up for 54.6 months (range, 28 months to 17 years). The Toronto Facial Grading System and Facial Nerve Function Index were used to evaluate facial nerve function at 2 years after surgery and last follow-up. Complications and function of the donor foot were analyzed. RESULTS: No postoperative mortality was found. Complications occurred in four of 41 patients, including muscle loss, infection, hematoma, and hypertrophic scar. The others obtained satisfactory symmetric faces in the static state and in voluntary contraction of the transferred muscles. Mean values for the Toronto Facial Grading System (50.6+/-7.8) and the Facial Nerve Function Index (65.7+/-11.4 percent) were significantly higher at 2 years postoperatively in comparison with preoperative status (21.2+/-5.3 and 19.5+/-3.6 percent, respectively) (p<0.05). Long-term outcomes (Toronto Facial Grading System, 54.8+/ 6.9; Facial Nerve Function Index, 79.4+/-9.6 percent) were awarded higher values than early outcomes shown at 2 years postoperatively (p<0.05). CONCLUSIONS: Free abductor hallucis muscle transfer is safe and effective in dynamic reanimation of longstanding unilateral facial paralysis. Favorable long-term results demonstrate that the authors' technique is an alternative method for facial reanimation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22842409 TI - The auriculotemporal nerve in etiology of migraine headaches: compression points and anatomical variations. AB - BACKGROUND: The auriculotemporal nerve has been identified as one of the peripheral trigger sites for migraine headaches. However, its distal course is poorly mapped following emergence from the parotid gland. In addition, a reliable anatomical landmark for locating the potential compression points along the course of the nerve during surgery has not been sufficiently described. METHODS: Twenty hemifaces on 10 fresh cadavers were dissected to trace the course of the auriculotemporal nerve from the inferior border of the zygomatic arch to its termination in the temporal scalp. The compression points were mapped and the distances were measured from the most anterosuperior point of the external auditory meatus, which was used as a fixed anatomical landmark. RESULTS: Three potential compression points along the course of the auriculotemporal nerve were identified. Compression points 1 and 2 corresponded to preauricular fascial bands. Compression point 1 was centered 13.1+/-5.9 mm anterior and 5.0+/-7.0 mm superior to the most anterosuperior point of the external auditory meatus, whereas compression point 2 was centered at 11.9+/-6.0 mm anterior and 17.2+/ 10.4 mm superior to the most anterosuperior point of the external auditory meatus. A significant relationship was found between the auriculotemporal nerve and superficial temporal artery (compression point 3) in 80 percent of hemifaces, with three patterns of interaction: a single site of artery crossing over the nerve (62.5 percent), a helical intertwining relationship (18.8 percent), and nerve crossing over the artery (18.8 percent). CONCLUSION: Findings from this cadaver study provide information relevant to the operative localization of potential compression points along the auriculotemporal nerve. PMID- 22842410 TI - Long-term effect on donor sites after components separation: a radiographic analysis. AB - BACKGROUND: The long-term implications of components separation for the lateral oblique and rectus muscles remain unknown. The authors hypothesized that recreation of the tendinous insertion of the linea alba through components separation results in expansion of the rectus muscle with potential atrophy of the external obliques. METHODS: The authors conducted a retrospective study analyzing preoperative and long-term postoperative computed tomographic scans for consecutive patients undergoing bilateral components separation at a single institution over a 5-year period. Standardized measurements (area, width, and thickness) were recorded for the rectus abdominis, external oblique, internal oblique, and transversus abdominis at the L3-L4 level on axial imaging. RESULTS: Twenty-eight patients with a mean time to follow-up computed tomographic scan of 17.4+/-1.6 months were reviewed. After reconstruction of the linea alba, the right and left rectus muscles significantly increased in area (right, 38.8+/-6.3 percent; left, 35.7+/-6.6 percent; p<0.0001) and width (right, 51.8+/-9.9 percent; left, 39.9+/-7.4 percent; p<0.0001) while decreasing in thickness (right, -17.8+/-7.8 percent; left, -12.8+/-5.0 percent; p<=0.02). The right and left external oblique muscles significantly decreased in area (right, -10.7+/-4.7 percent; left, -8.92+/-4.01 percent; p<=0.03). In contrast, the internal oblique (right, 21.6+/-4.9 percent; left, 16.4+/-4.5 percent; p<=0.001) and transversus abdominis (right, 23.0+/-4.7 percent; left, 24.2+/-6.2 percent; p<0.0001) muscles increased significantly in area following surgery. CONCLUSIONS: Reestablishing the midline with components separation results in expansion of the rectus muscle, atrophy of the external oblique muscle, and presumed compensatory hypertrophy of the internal oblique and transversus abdominis muscles. Future studies are needed to determine the functional implications of these changes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22842412 TI - Cleft lip and palate: an objective measure outcome study. AB - BACKGROUND: Cleft lip and/or palate is a debilitating condition if left unrepaired, resulting in significant speech, hearing, swallowing, feeding, and psychosocial impairments. The authors' objective was to determine the potential impact of being born with cleft lip and/or palate by using previously validated health state utility assessment measures. METHODS: A utility assessment using the visual analogue scale, time trade-off, and standard gamble was used to obtain utilities for cleft lip and/or palate, monocular blindness, and binocular blindness from a prospective sample of the general population and medical students. Average utility scores were compared using paired t test. Linear regression was performed using age, race, and education as independent predictors of each of the utility scores. RESULTS: Over a 1-year prospective enrollment period, 110 participants were included in our utility analysis. The utility outcome scores for cleft lip and/or palate (visual analogue scale, time trade off, and standard gamble, 0.69+/-0.18, 0.85+/-016, and 0.84+/-0.18, respectively) were statistically different from those of binocular blindness (visual analogue scale, time trade-off, and standard gamble: 0.38+/-0.17, 0.70+/-0.24, and 0.66+/ 0.25, respectively; p<0.001) but not statistically different from those of monocular blindness (visual analogue scale, time trade-off, and standard gamble, 0.67+/-0.15, 0.86+/-0.15, and 0.84+/-0.18, respectively). There was no statistically significant difference in utility scores between male and female participants. CONCLUSION: The results of the study demonstrate objectively via health state utility scores that the perceived burden of being born with cleft lip and/or palate is comparable to living with monocular blindness. PMID- 22842411 TI - Relationship between timing of emergency procedures and limb amputation in patients with open tibia fracture in the United States, 2003 to 2009. AB - BACKGROUND: The authors aimed to characterize patterns in the timing of initial emergency procedures for patients with open tibia fracture and examine the relationship between initial procedure timing and in-hospital amputation. METHODS: Data were analyzed from the Nationwide Inpatient Sample, 2003 to 2009. Adult patients were included if they had a primary diagnosis code of open tibia fracture. Patients were excluded for the following reasons: they were transferred from or to another hospital, an immediate amputation was performed, more than one amputation was performed, no emergency procedure was documented, or they were treated at a facility that did not perform any amputations. The authors evaluated the association between timing of the first procedure and the outcome of amputation using multiple logistic regression, controlled for patient risk factors and hospital characteristics. RESULTS: Of 7560 patients included in the analysis, 1.3 percent (n=99 patients) underwent amputation on hospital day 2 or later. The majority (52.6 percent) underwent the first operative procedure on day 0 or 1. In adjusted analyses, timing of the first operative procedure beyond the day of admission was associated with more than three times greater odds of amputation (day 1, odds ratio, 3.81; 95 percent CI, 1.80 to 8.07). CONCLUSIONS: Delay of the first operative procedure beyond the day of admission appears to be associated with a significantly increased probability of amputation in patients with open tibia fracture. All practitioners involved in the management of these patients should seek a solution for any barrier, other than medical stability of the patient, to achieving early operative intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 22842413 TI - Soft-tissue refinements in the treatment of unicoronal craniosynostosis: the rotational forehead flap. AB - Unicoronal craniosynostosis is characterized by ipsilateral superior and posterior displacement of the supraorbital rim and frontal bone, ipsilateral widening of the palpebral fissure, ipsilateral superior displacement of the brow, and contralateral brow depression. In the literature, surgical treatment has focused on bony anatomy, with little written about soft-tissue correction. Over the last 25 years, the senior author (L.A.W.) has incorporated soft-tissue refinements, including a rotational flap of the forehead, elevating the contralateral brow, depressing the ipsilateral brow, and equilibrating the supratarsal sulci in unicoronal craniosynostosis. This rotational forehead repositioning is a simple innovation that has provided for improved orbital and brow symmetry on long-term follow-up. PMID- 22842414 TI - Extending the Cordeiro maxillofacial defect classification system for use in the era of vascularized composite transplantation. AB - There is a growing interest in the use of vascularized composite transplantation to reconstruct major facial and craniofacial deformities. This phenomenon is driven both by the success of recent transplantations to functionally and aesthetically restore patients and by an increase in the number of centers entering this challenging field. The authors' new classification system, based on a well-established schema, allows proper documentation of the needs of these patients and enhancement of interinstitutional communication for outcomes reporting. PMID- 22842415 TI - Discussion: late seromas and breast implants: theory and practice. PMID- 22842416 TI - Discussion: late seromas after breast implants: theory and practice. PMID- 22842417 TI - Hypothermia and complications in postbariatric body contouring. AB - BACKGROUND: Postbariatric body contouring represents a rapidly growing field. With long operative times and high rates of minor complications, evidence-based guidelines for operative management are needed. Data analyzing the impact of perioperative factors on patient outcomes are currently limited. METHODS: Patients who lost 50 pounds or more and underwent body contouring were enrolled in an institutional review board-approved prospective registry over 4 years. All cases were performed by the senior author at two community hospitals and two academic hospitals. Hypothermia was defined as a minimum temperature of 35 degrees C or lower. RESULTS: Three hundred eight patients (272 women and 36 men) were analyzed. The average operative time was 4.7 hours, and 71.4 percent of cases were performed in an academic hospital. The average minimum operative temperature was 35.6+/-0.63 degrees C (range, 34.0 to 38.0 degrees C), and the average maximum operative temperature was 36.5+/-0.75 degrees C (range, 34.8 to 39.0 degrees C). On multivariate analysis, a lower minimum temperature was associated with both seroma (p=0.003; odds ratio, 3.1 per 1 degrees C decrease) and transfusion (p=0.005; odds ratio, 2.4 per 1 degrees C decrease). CONCLUSIONS: Operative hypothermia was present in one-fifth of cases. Lower intraoperative temperature was associated with an increased risk of seroma formation, blood loss, and the need for transfusion. Despite this, there were few major complications in lengthy cases involving substantial blood loss. Maintaining normothermia is a critical component of perioperative management. The authors have adopted a protocol involving patient prewarming, a higher operating room temperature, and the routine use of warmed fluids. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 22842418 TI - Development of a three-microneedle device for hypodermic drug delivery and clinical application. AB - There is a potential use for intradermic or hypodermic drug delivery in skin surgery or aesthetic surgery. Hypodermic delivery with the use of a noninvasive device can be a more useful, reliable, and effective administration route to obtain higher compliance. The authors developed a microneedle device composed of three fine needles (three-microneedle device). The tip of each needle was fabricated with a bevel angle to release a drug broadly into the tissue in a horizontal fashion. In this study, the authors investigated the usefulness of this newly developed three-microneedle device for hypodermic liquid injection, focusing on the optimum insertion depth and the diffusion of injected materials to the tissue. The authors also assessed the efficacy of and patient satisfaction with three-microneedle device injections of botulinum toxin type A for wrinkle reduction in patients with glabellar rhytides. The three-microneedle device yielded consistent results in hypodermal diffusion. On India ink diffusion test and ultrasonographic imaging, three-microneedle device injection showed a broad diffusion in horizontal extension, as compared with usual 31-gauge needle injection. The efficiency and satisfaction of the patients receiving botulinum toxin type A with the three-microneedle device were highly rated. Three microneedle device delivery enables accurate and broad diffusion of injected substances, thus reducing the total dose and/or injection number of drugs. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22842419 TI - So you want to get paid for what you do? The saga continues. PMID- 22842422 TI - A prospective randomized study comparing two different expander approaches in implant-based breast reconstruction: one stage versus two stages. AB - BACKGROUND: Implant-based reconstruction is performed in the majority of women offered primary reconstruction for breast cancer. METHODS: Two different expander implants were compared prospectively. The primary endpoint was the number of operations needed in each group to obtain patient satisfaction. Secondary endpoints were evaluation of breast volume and shape and aspects of quality of life. Seventy consecutive breast cancer patients were randomized to either a one stage reconstruction with a round permanent expander implant (Becker 25; n=35) or a two-stage reconstruction with a crescent-shaped expander (LV 133; n=35), later replaced by a form-stable anatomical implant. Thirty patients had to be excluded and 40 patients, 20 in each group, were evaluated. The median follow-up for both groups was 3.5 years (range, 1.5 to 5 years). Plastic cups, plastic casts, and two -and three-dimensional scanning techniques were used for objective assessment of breast volume and shape. The aesthetic outcome was evaluated by a panel of experts and lay people, and by the patients. Quality of life was evaluated with a validated questionnaire (36-Item Short Form Health Survey). RESULTS: Of the patients in the one-stage group, 70 percent had revision surgery, mostly because of upper pole fullness and poor ptosis. These findings agreed with the data from the two-dimensional scanning and from the expert panel and the patients' subjective judgment. Quality of life was similar in the two groups. CONCLUSIONS: The permanent expander method failed significantly as a one-stage procedure. The crescent two-stage method gave the most acceptable results both objectively and subjectively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 22842423 TI - Immunohistochemical evaluation after ex vivo perfusion of rectus abdominis muscle flaps in a porcine model. AB - BACKGROUND: The purpose of this study was to investigate whether and how the extracorporal perfusion of muscle flaps with a miniaturized perfusion system could change the expression of the proapoptotic protein caspase 3 and of the ischemia-sensitive protein hypoxia-inducible factor (HIF)-1alpha as a first step toward the development of a clinically reliable tool for circumventing ischemia problems in free muscle flap transfer. METHODS: In this study, 25 porcine rectus abdominis muscles were used and assigned to five different groups. In the baseline group (group I), the muscle flap remained in situ; in groups II and III, the muscle flap was harvested and remained ex vivo without or with subsequent single-shot heparinized flush; and in groups IV and V, the flaps were perfused with either heparinized autologous whole blood or crystalloid fluid (Jonosteril), using a miniaturized perfusion system without Exogen oxygenation. Muscle samples were taken for immunohistochemical evaluation. The proportion of positive cells for HIF-1alpha and caspase 3 was compared for each group (groups II through V) to the baseline group (group I). RESULTS: The expression of HIF-1alpha and caspase 3 was increased in both groups without perfusion and was low during in vivo perfusion and extracorporal perfusion with crystalloid fluid. Heparinized autologous whole blood perfusion shows no protective effect, in contrast to the crystalloid fluid. CONCLUSIONS: The data of this study indicate that the extracorporal perfusion of muscle flaps with crystalloid fluid is a possible protective strategy against ischemia. Autologous heparinized whole blood seems to have no additional protective effect in a pure perfusion setting without oxygenation. PMID- 22842424 TI - Effectiveness of cerium nitrate-silver sulfadiazine in the treatment of facial burns: a multicenter, randomized, controlled trial. AB - BACKGROUND: The face is a very frequent site of burn injuries. This multicenter, randomized, controlled trial thus investigates the effectiveness of cerium nitrate-silver sulfadiazine in the treatment of facial burns compared with silver sulfadiazine. METHODS: Adult patients with acute facial burns admitted to Dutch burn centers were randomized to treatment with either cerium nitrate-silver sulfadiazine or silver sulfadiazine. Primary outcome was need for surgery and time to wound healing. Aesthetic and functional outcome was assessed at 3, 6, and 12 months after burn. RESULTS: From March of 2006 until January of 2009, 179 patients were randomized and 154 could be included. The two groups of patients (cerium nitrate-silver sulfadiazine group, n=78; silver sulfadiazine group, n=76), were comparable regarding sex, age, percentage total body surface area burned, and cause. During admission, four patients died, leaving 77 and 73 patients for primary analyses, respectively. Surgery was required in 13 (16.9 percent) compared with 15 patients (20.5 percent) (p=0.57; odds ratio, 0.8; 95 percent CI, 0.3 to 1.8), respectively. Median time to wound healing was 11.0 days in the cerium nitrate-silver sulfadiazine group (interquartile range, 7.0 to 15.0) and 9.0 days for silver sulfadiazine group (interquartile range, 5.0 to 15.75) (p=0.17). There were no significant differences in functional and aesthetic outcome. CONCLUSIONS: No differences were found in effectiveness of both treatments. The vast majority of facial burns do not require surgery, and treatment with cerium nitrate-silver sulfadiazine and silver sulfadiazine leads to satisfactory outcome, both aesthetically and functionally. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 22842426 TI - Giant nevus sebaceus: definition, surgical techniques, and rationale for treatment. AB - BACKGROUND: A reduction in the reported incidence of malignant degeneration within nevus sebaceus has led many physicians to recommend serial clinical evaluation and biopsy of suspicious areas rather than prophylactic surgical excision. Unfortunately, no well-defined inclusion criteria, including lesion size and location, have been described for the management of nevus sebaceus. METHODS: To assess whether the incidence or timing of malignant degeneration contraindicates surgical excision, the authors performed a PubMed literature search for any studies, excluding case reports, related to malignant change within nevus sebaceus since 1990. They then defined giant nevus sebaceus to consist of lesions greater than 20 cm or greater than 1 percent of the total body surface area and retrospectively examined their experience and outcomes treating giant nevus sebaceus. RESULTS: Data were pooled from six large retrospective institutional studies (2520 patients). The cumulative incidence of benign and malignant tumors was 6.1 and 0.5 percent, respectively. Of the authors' 195 patients with giant congenital nevi, only six (3.0 percent) met the definition of giant nevus sebaceus. All patients required tissue expansion for reconstruction, and two patients required concomitant skin grafting. Two complications required operative intervention. CONCLUSIONS: Early malignant degeneration within nevus sebaceus is rare. Management, however, must account for complex monitoring, particularly for lesions within the scalp, associated alopecia, involvement of multiple facial aesthetic subunits, and postpubertal transformation affecting both appearance and monitoring of the lesions. The latter considerations, rather than the reported incidence of malignant transformation, should form the bases for surgical intervention in giant nevus sebaceus. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 22842425 TI - Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps. AB - Early vascularized soft-tissue closure has long been recognized to be essential in achieving eventual infection-free union. The question of whether muscle or fasciocutaneous tissue is superior in terms of promoting fracture healing remains unresolved. In this article, the authors review the experimental and clinical evidence for the different tissue types and advocate that the biological role of flaps should be included as a key consideration during flap selection. PMID- 22842427 TI - Safety of preoperative erythropoietin in surgical calvarial remodeling: an 8 year retrospective review and analysis. AB - BACKGROUND: Calvarial remodeling is typically associated with significant blood loss. Although preoperative erythropoiesis-stimulating agents have proven to significantly decrease the need for blood transfusions, recent data in adults have raised concerns that elevating hemoglobin levels greater than 12.5 g/dl may increase the risk of thrombotic events. This study was designed to assess the risks of erythropoietin in the pediatric population. METHODS: Records were retrospectively reviewed from 2000 to 2008 at three major metropolitan children's hospitals of all children undergoing calvarial remodeling after receiving preoperative erythropoietin. Demographic and perioperative outcome data were reviewed, including transfusion reactions, pressure ulcer secondary to prolonged positioning, pneumonia, infection, deep vein thrombosis, cerebrovascular accident, pulmonary embolism, sagittal sinus thrombosis, pure red cell aplasia, and myocardial infarction. RESULTS: A total of 369 patients met the inclusion criteria (mean age, 0.86+/-1.1 years). On average, three preoperative doses of erythropoietin were administered (600 U/kg). Iron was also supplemented. No complications associated with dosing were noted, there were no thrombotic events identified, and no other major complications were seen (i.e., death or blindness). Thirty-one patients (8.40 percent) experienced one or more postoperative complications. There was no significant correlation between hemoglobin levels greater than 12.5 g/dl and the occurrence of any noted complication. CONCLUSIONS: With zero thrombotic postoperative complications, the authors estimate the risk of a thrombotic event in the pediatric population to be less than 0.81 percent (95 percent confidence). These data suggest that preoperative administration of erythropoietin in children undergoing calvarial remodeling does not appear to increase the incidence of thrombotic events or other significant complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22842428 TI - Photographic measurements in 301 cases of liposuction and abdominoplasty reveal fat reduction without redistribution. AB - BACKGROUND: There are no published studies of liposuction or abdominoplasty in a large number of patients using measurements of body dimensions. In the absence of rigorous data, some investigators have proposed that fat returns after liposuction. METHODS: A prospective study was undertaken among predominantly nonobese consecutive patients undergoing 301 liposuction and abdominoplasty procedures meeting the study criteria (inclusion rate, 70.7 percent). Lower body dimensions were measured using standardized photographs taken before and at least 3 months after surgery. Upper body measurements were compared between women who underwent simultaneous cosmetic breast surgery (n=67) and a group of women who had breast surgery alone (n=78) to investigate the possibility of fat redistribution. RESULTS: The average weight change was a loss of 2.2 lbs after lower body liposuction (p<0.01) and 4.6 lbs when combined with abdominoplasty (p<0.001). Liposuction significantly reduced abdominal, thigh, knee, and arm width (p<0.001). Midabdominal and hip width were more effectively reduced by lipoabdominoplasty than liposuction alone (p<0.001). There was no difference in upper body measurements when comparing patients who had simultaneous liposuction and/or abdominoplasty with patients who had cosmetic breast surgery alone. Measurements in patients with at least 1 year of follow-up (n=46) showed no evidence of fat reaccumulation. CONCLUSIONS: Both liposuction and abdominoplasty are valid techniques for long-term fat reduction and improvement of body proportions. There is no evidence of fat regrowth. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 22842429 TI - Discussion: photographic measurements in 301 cases of liposuction and abdominoplasty reveal fat reduction without redistribution. PMID- 22842430 TI - Complications after polyacrylamide hydrogel injection for facial soft-tissue augmentation in China: twenty-four cases and their surgical management. AB - BACKGROUND: Polyacrylamide hydrogel has been used for soft-tissue augmentation for more than 10 years. Although it is considered a nontoxic, nonimmunogenic material, complications after polyacrylamide hydrogel injections during facial soft-tissue augmentation have been reported. METHODS: Between 2003 and 2009, 24 patients underwent surgical management of complications after facial soft-tissue augmentation. Histories, preoperative imaging, and photographs of operations were recorded. RESULTS: Complications included hematomas, infection, nodule formation, and migration. Ultimately, 23 of 24 cases underwent surgery to remove the gel; the remaining case underwent surgical drainage to remove it. CONCLUSIONS: As more complications have been reported, especially ones that are difficult to treat, the safety of polyacrylamide hydrogel needs to be reconsidered. The authors' experiences provide methods to remove polyacrylamide hydrogel if complications occur. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 22842431 TI - Acute burn care. AB - LEARNING OBJECTIVES: After studying this article and accompanying Supplemental Digital Content, the participant should be able to: 1. Explain current burn prevention strategies and criteria for referral to a burn center. 2. Summarize the current advances made in the critical care of acute burn patients. 3. Outline the recent developments in burn depth assessment and burn wound dressing technology. 4. Describe the common psychosocial aspects of postburn rehabilitation. SUMMARY: Burn patients require interdisciplinary care in which the plastic surgeon plays a prominent role. Appropriate referral, assessment, treatment, and posttreatment supports are essential to achieving favorable outcomes following burn injury. The authors reviewed the current literature on epidemiology, prevention, referral criteria, critical care, wound assessment, wound dressings, and psychosocial aspects of burn injury. Recent advances in burn care are highlighted and have been made possible through ongoing collaborative epidemiologic, clinical, and basic biomedical research. A systematic interdisciplinary approach to the evaluation and treatment of acute burn injuries is pivotal to providing patients with the greatest chance of functional recovery. Plastic surgeons treating burn patients must remain current in a wide variety of areas, ranging from critical care to psychosocial rehabilitation. PMID- 22842432 TI - Industry influence on evidence-based surgery. PMID- 22842434 TI - Z-plasty on levator veli palatini: a modification of Sommerlad palatoplasty. PMID- 22842436 TI - Fat grafting and breast reconstruction with implant: another option for irradiated breast cancer patients. PMID- 22842438 TI - To sever or not the thoracodorsal nerve in latissimus dorsi flap breast reconstruction. PMID- 22842440 TI - Ethics and the limits of science. PMID- 22842442 TI - Complications of craniofacial midface distraction: 10-year review. PMID- 22842443 TI - Endoscopic technique and liposuction-assisted facial composite rhytidectomy. PMID- 22842444 TI - Employment of needles: a different technique for fat placement. PMID- 22842445 TI - Use of lipofilling for the treatment of severe burn outcomes. PMID- 22842446 TI - Three-dimensional stereophotogrammetric method of quantifying the effect of botulinum toxin type A injections on masseter hypertrophy. PMID- 22842447 TI - Alar cartilage grafts for repair of complex tip defects: cosmetic surgery in aid of reconstructive surgery. PMID- 22842448 TI - Stereolithographic modeling of the deep circumflex iliac artery and its vascular branching: a further advance in computed tomography-guided flap planning. PMID- 22842449 TI - J torsoplasty: a novel approach to avoid circumferential scars of the upper body lift. PMID- 22842450 TI - Quantification of negative pressures generated by syringes of different calibers used for liposuction. PMID- 22842451 TI - Novel approach to surgical repair of enterovaginal fistula in the irradiated pelvis. PMID- 22842452 TI - Structural fat grafting to improve aesthetic outcomes in congenital hand surgery. PMID- 22842453 TI - Pediatric digital replantations: regenerative dermis in a salvage procedure. PMID- 22842454 TI - High resolution melting analysis for detection of variable number of tandem repeats polymorphism of XRCC5. AB - Several polymorphisms in the XRCC5 (X-ray repair cross-complementing 5; OMIM: 194364) were reported. Polymorphism of variable number of tandem repeats (VNTR) in the promoter region of XRCC5 (rs6147172) was reported. The main aim of the present study is to introduce the high resolution melting analysis (HRMA) method for genotyping of the polymorphism of XRCC5 VNTR. Genotypes of XRCC5 VNTR were determined by HRMA and conventional PCR method, and confirmed by DNA sequencing. The results for genotyping using HRMA and conventional PCR showed 100% concordance. All genotypes of the XRCC5 VNTR polymorphism could be accurately detected by HRMA. PMID- 22842455 TI - Sepantronium bromide (YM155) induces disruption of the ILF3/p54(nrb) complex, which is required for survivin expression. AB - YM155, a small-molecule survivin suppressant, specifically binds to the transcription factor ILF3, which regulates the expression of survivin[1]. In this experiment we have demonstrated that p54(nrb) binds to the survivin promoter and regulates survivin expression. p54(nrb) forms a complex with ILF3, which directly binds to YM155. YM155 induces disruption of the ILF3/p54(nrb) complex, which results in a different subcellular localization between ILF3 and p54(nrb). Thus, identification of molecular targets of YM155 in suppression of the survivin pathway, might lead to development of its use as a novel potential target in cancers. PMID- 22842456 TI - Myc induced miR-144/451 contributes to the acquired imatinib resistance in chronic myelogenous leukemia cell K562. AB - Imatinib resistance remains the big hurdle for CML therapy. Previous study reveals that c-myc is important for bcr-abl CML cell proliferation, while its role in imatinib resistance is largely unknown. In this study, we first found that c-myc expression is upregulated in imatinib resistant K562R cells, which in turn enhances the expression of miR-144/451. Knockdown of c-myc or restoration of miR-144/451 in the K562R cells sensitizes K562R cells to imatinib therapy. Our study here reveals an regulatory pathway between myc and miR-144/451 and highlights that targeting either myc or miR-144/451 might be valuable for eliminating the imatinib resistant CML cells. PMID- 22842457 TI - Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation. AB - Kallmann syndrome (KS) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia. KS is commonly associated with mutations in the extracellular D2 domain of the fibroblast growth factor receptor (FGFR). In this study, for the first time, the molecular basis for the FGFR associated KS mutation (A168S) is elucidated using a variety of biophysical experiments, including multidimensional NMR spectroscopy. Secondary and tertiary structural analysis using far UV circular dichroism, fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D2 domain of FGFR. Results of isothermal titration calorimetry experiments show the KS mutation causes a 10-fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1) binding. (1)H-(15)N chemical perturbation data suggest that complete loss in the ligand (FGF) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D2 domain of FGFR. The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR. PMID- 22842459 TI - Nephronectin expression is regulated by SMAD signaling in osteoblast-like MC3T3 E1 cells. AB - Nephronectin (Npnt) is an extracellular matrix protein known to be a ligand for the integrin alpha8beta1. We previously demonstrated that Npnt expression was suppressed by TGF-beta through ERK1/2 and JNK in osteoblasts. In this study, we found that inhibition of a TGF-beta type I receptor (TGF-beta R1, Alk5) by a specific inhibitor {2-[3-(6-Methylpyridin-2-yl)-1H-pyrazol-4-yl]-1,5 naphthyridine} strongly induced Npnt expression in osteoblast-like MC3T3-E1 cells. The Alk5 inhibitor-induced increase of Npnt expression occurred in both time- and dose-dependent manners, while that expression was also induced by introduction of an siRNA for Smad2, a central intracellular mediator of TGF-beta signaling. These results suggest that the expression of Npnt is regulated by the Alk5-SMAD signaling pathway in osteoblasts. PMID- 22842460 TI - Pyrite footprinting of RNA. AB - In RNA, function follows form. Mapping the surface of RNA molecules with chemical and enzymatic probes has revealed invaluable information about structure and folding. Hydroxyl radicals ((.)OH) map the surface of nucleic acids by cutting the backbone where it is accessible to solvent. Recent studies showed that a microfluidic chip containing pyrite (FeS(2)) can produce sufficient (.)OH to footprint DNA. The 49-nt Diels-Alder RNA enzyme catalyzes the C-C bond formation between a diene and a dienophile. A crystal structure, molecular dynamics simulation and atomic mutagenesis studies suggest that nucleotides of an asymmetric bulge participate in the dynamic architecture of the ribozyme's active center. Of note is that residue U42 directly interacts with the product in the crystallized RNA/product complex. Here, we use powdered pyrite held in a commercially available cartridge to footprint the Diels-Alderase ribozyme with single nucleotide resolution. Residues C39 to U42 are more reactive to (.)OH than predicted by the solvent accessibility calculated from the crystal structure suggesting that this loop is dynamic in solution. The loop's flexibility may contribute to substrate recruitment and product release. Our implementation of pyrite-mediated (.)OH footprinting is a readily accessible approach to gleaning information about the architecture of small RNA molecules. PMID- 22842458 TI - Tyrosine phosphatase inhibition induces an ASC-dependent pyroptosis. AB - Pyroptosis is a type of cell death in which danger associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs) induce mononuclear phagocytes to activate caspase-1 and release mature IL-1beta. Because the tyrosine kinase inhibitor AG126 can prevent DAMP/PAMP induced activation of caspase-1, we hypothesized that tipping the tyrosine kinase/phosphatase balance toward phosphorylation would promote caspase-1 activation and cell death. THP-1 derived macrophages were therefore treated with the potent specific tyrosine phosphatase inhibitor, sodium orthovanadate (OVN) and analyzed for caspase-1 activation and cell death. OVN induced generalized increase in phosphorylated proteins, IL-1beta release and cell death in a time and dose dependent pattern. This OVN induced pyroptosis correlated with speck formations that contained the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Culturing the cells in the presence of extracellular K(+) (known to inhibit ATP dependent pyroptosis), a caspase inhibitor (ZVAD) or down regulating the expression of ASC with stable expression of siASC prevented the OVN induced pyroptosis. These data demonstrate that pyroptotic death is linked to tyrosine phosphatase activity providing novel targets for future pharmacologic interventions. PMID- 22842461 TI - Superparamagnetic iron oxide nanoparticles as radiosensitizer via enhanced reactive oxygen species formation. AB - Internalization of citrate-coated and uncoated superparamagnetic iron oxide nanoparticles by human breast cancer (MCF-7) cells was verified by transmission electron microscopy imaging. Cytotoxicity studies employing metabolic and trypan blue assays manifested their excellent biocompatibility. The production of reactive oxygen species in iron oxide nanoparticle loaded MCF-7 cells was explained to originate from both, the release of iron ions and their catalytically active surfaces. Both initiate the Fenton and Haber-Weiss reaction. Additional oxidative stress caused by X-ray irradiation of MCF-7 cells was attributed to the increase of catalytically active iron oxide nanoparticle surfaces. PMID- 22842462 TI - Dermatopontin, a shell matrix protein gene from pearl oyster Pinctada martensii, participates in nacre formation. AB - Dermatopontin (DPT) is identified as a major component of the shell matrix protein. However, its exact function in the shell formation remains obscure. In this study, we described the characteristic and function of DPT gene from Pinctada martensii. DPT cDNA was 797 bp long, containing an open reading fragment (ORF) of 537 bp encoding a polypeptide of 178 amino acids with an estimated molecular mass of 21.4 kDa and theoretical isoelectric point of 5.97. The 5' untranslated region (UTR) was 11 bp and the 3'UTR was 249 with 18 bp poly (A) tail. In the peptide, there was a signal sequence, six potential phosphorylation sites, one glycosylation site and eight cysteine residues. Moreover, a sequence motif (D-R-X-W/F/Y-X-F/Y/I/L/M-X(1-2)-C) was contained and repeated itself three times in the entire sequence. DPT mRNA was constitutively expressed in all studied tissues with the most abundant mRNA in the mantle, which was nacre formation-related tissue. After decreasing DPT expression using RNA interference (RNAi) technology in the mantle, the nacreous layer showed a disordered growth; whereas the prismatic layer of the shells has no significant changes. These results suggested that DPT obtained in this study was a constitutive matrix protein and participated in nacre formation in P. martensii. PMID- 22842463 TI - Silibinin attenuates allergic airway inflammation in mice. AB - Allergic asthma is a chronic inflammatory disease regulated by coordination of T helper2 (Th2) type cytokines and inflammatory signal molecules. Silibinin is one of the main flavonoids produced by milk thistle, which is reported to inhibit the inflammatory response by suppressing the nuclear factor-kappa B (NF-kappaB) pathway. Because NF-kappaB activation plays a pivotal role in the pathogenesis of allergic inflammation, we have investigated the effect of silibinin on a mouse ovalbumin (OVA)-induced asthma model. Airway hyperresponsiveness, cytokines levels, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. Pretreatment of silibinin significantly inhibited airway inflammatory cell recruitment and peribronchiolar inflammation and reduced the production of various cytokines in bronchoalveolar fluid. In addition, silibinin prevented the development of airway hyperresponsiveness and attenuated the OVA challenge-induced NF-kappaB activation. These findings indicate that silibinin protects against OVA-induced airway inflammation, at least in part via downregulation of NF-kappaB activity. Our data support the utility of silibinin as a potential medicine for the treatment of asthma. PMID- 22842464 TI - Validation of whole genome amplification for analysis of the p53 tumor suppressor gene in limited amounts of tumor samples. AB - Personalized cancer treatment requires molecular characterization of individual tumor biopsies. These samples are frequently only available in limited quantities hampering genomic analysis. Several whole genome amplification (WGA) protocols have been developed with reported varying representation of genomic regions post amplification. In this study we investigate region dropout using a phi29 polymerase based WGA approach. DNA from 123 lung cancers specimens and corresponding normal tissue were used and evaluated by Sanger sequencing of the p53 exons 5-8. To enable comparative analysis of this scarce material, WGA samples were compared with unamplified material using a pooling strategy of the 123 samples. In addition, a more detailed analysis of exon 7 amplicons were performed followed by extensive cloning and Sanger sequencing. Interestingly, by comparing data from the pooled samples to the individually sequenced exon 7, we demonstrate that mutations are more easily recovered from WGA pools and this was also supported by simulations of different sequencing coverage. Overall this data indicate a limited random loss of genomic regions supporting the use of whole genome amplification for genomic analysis. PMID- 22842465 TI - Omentin inhibits TNF-alpha-induced expression of adhesion molecules in endothelial cells via ERK/NF-kappaB pathway. AB - In the present study, we investigated whether omentin affected the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-alpha (TNF-alpha) induced human umbilical vein endothelial cells (HUVECs). Our data showed that omentin decreased TNF-alpha induced expression of ICAM-1 and VCAM-1 in HUVECs. In addition, omentin inhibited TNF-alpha-induced adhesion of THP-1 cells to HUVECs. Further, we found that omentin inhibited TNF-alpha-activated signal pathway of nuclear factor-kappaB (NF kappaB) by preventing NF-kappaB inhibitory protein (IkappaBalpha) degradation and NF-kappaB/DNA binding activity. Omentin pretreatment significantly inhibited TNF alpha-induced ERK activity and ERK phosphorylation in HUVECs. Pretreatment with PD98059 suppressed TNF-alpha-induced NF-kappaB activity. Omentin, NF-kB inhibitor (BAY11-7082) and ERK inhibitor (PD98059) reduced the up-regulation of ICAM-1 and VCAM-1 induced by TNF-alpha. These results suggest that omentin may inhibit TNF alpha-induced expression of adhesion molecules in endothelial cells via blocking ERK/NF-kappaB pathway. PMID- 22842466 TI - Formation of spherulitic amyloid beta aggregate by anionic liposomes. AB - Alzheimer's disease is the most common form of senile dementia. This neurodegenerative disorder is characterized by an amyloid deposition in senile plaques, composed primarily of fibrils of an aggregated peptide, amyloid beta (Abeta). The modeling of a senile plaque formation on a model neuronal membrane under the physiological condition is an attractive issue. In this study, we used anionic liposomes to model the senile plaque formation by Abeta. The growth behavior of amyloid Abeta fibrils was directly observed, revealing that the induction of the spherulitic Abeta aggregates could result from the growth of seeds in the presence of anionic liposomes. The seeds of Abeta fibrils strongly interacted with negatively charged liposome and the subsequent association of the seeds were induced to form the seed cluster with many growth ends, which is advantageous for the formation of spherulitic Abeta aggregates. Therefore, anionic liposomes mediated not only fibril growth but also the aggregation process. These results imply that anionic liposome membranes would affect the aggregate form of Abeta fibrils. The modeling of senile plaque reported here is considered to have great potential for study on the amyloidosis. PMID- 22842468 TI - Bi- to tetravalent glycoclusters: synthesis, structure-activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity. AB - The emerging functional versatility of cellular glycans makes research on the design of synthetic inhibitors a timely topic. In detail, the combination of ligand (or headgroup or contact site) structure with spatial parameters that depend on topological and geometrical factors underlies the physiological selectivity of glycan-protein (lectin) recognition. We herein tested a panel of bi-, tri- and tetravalent compounds against two plant agglutinins and adhesion/growth-regulatory lectins (galectins). In addition, we examined the impact of headgroup tailoring (converting lactose to 2'-fucosyllactose) in combination with valency increase in two assay types of increasing biorelevance (from solid-phase binding to cell binding). Compounds were prepared using copper catalysed azide alkyne cycloaddition from peracetylated lactosyl or 2' fucosyllactosyl azides. Significant inhibition was achieved for the plant toxin with a tetravalent compound. Different levels of sensitivity were noted for the three groups of the galectin family. The headgroup extension to 2'-fucosyllactose led to a selectivity gain, especially for the chimera-type galectin-3. Valency increase established discrimination against the homodimeric proteins, whereas the combination of valency with the headgroup extension led to discrimination against the tandem-repeat-type galectin-8 for chicken galectins but not human galectins-3 and -4. Thus, detailed structure-activity profiling of glycoclusters combined with suitably modifying the contact site for the targeted lectin will help minimize cross-reactivity among this class of closely related proteins. PMID- 22842467 TI - MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes. AB - We tested the hypothesis that miR-133a regulates DNA methylation by inhibiting Dnmt-1 (maintenance) and Dnmt-3a and -3b (de novo) methyl transferases in diabetic hearts by using Ins2(+/-) Akita (diabetic) and C57BL/6J (WT), mice and HL1 cardiomyocytes. The specific role of miR-133a in DNA methylation in diabetes was assessed by two treatment groups (1) scrambled, miR-133a mimic, anti-miR 133a, and (2) 5mM glucose (CT), 25 mM glucose (HG) and HG+miR-133a mimic. The levels of miR-133a, Dnmt-1, -3a and -3b were measured by multiplex RT-PCR, qPCR and Western blotting. The results revealed that miR-133a is inhibited but Dnmt-1 and -3b are induced in Akita suggesting that attenuation of miR-133a induces both maintenance (Dnmt-1) - and de novo - methylation (Dnmt-3b) in diabetes. The up regulation of Dnmt-3a in Akita hearts elicits intricate and antagonizing interaction between Dnmt-3a and -3b. In cardiomyocytes, over expression of miR 133a inhibits but silencing of miR-133a induces Dnmt-1, -3a and -3b elucidating the involvement of miR-133a in regulation of DNA methylation. The HG treatment up regulates only Dnmt-1 and not Dnmt-3a and -3b suggesting that acute hyperglycemia triggers only maintenance methylation. The over expression of miR-133a mitigates glucose mediated induction of Dnmt-1 illustrating the role of miR-133a in regulation of DNA methylation in diabetes. PMID- 22842469 TI - Mesoporous graphitic carbon nanodisks fabricated via catalytic carbonization of coordination polymers. AB - Mesoporous graphitic carbon nanodisks with hierarchical porous structure, facilely fabricated by catalytic carbonization of iron-based coordination polymer nanodisks, exhibit high capacitance even at high scan rates as electrode materials for electrochemical double layer capacitors. PMID- 22842470 TI - Improvement of carrier mobility of top-gated SiC epitaxial graphene transistors using a PVA dielectric buffer layer. AB - The effects of treatment with polyvinyl alcohol (PVA) and a dielectric film of HfO(2) on the properties of SiC based epitaxial graphene have been explored and analyzed. We have characterized the carrier mobility of graphene on Si-face and C face SiC with a layer of HfO(2), with or without an initial PVA treatment on the device active layer. Epitaxial graphene grown on the C-face displays a higher mobility than a film grown on the silicon face. Also, the mobility in the presence of the PVA treatment with HfO(2) dielectric layer has been improved, compared with the mobility after deposition of only gate dielectric: ~20% in C face graphene and ~90% in Si-face graphene. This is a major improvement over the degradation normally observed with dielectric/graphene systems. PMID- 22842471 TI - Enhancement from targets and suppression from cues in fast task-irrelevant perceptual learning. AB - Task-irrelevant perceptual learning (TIPL) refers to the phenomenon where the stimulus features of a subject's task are learned when they are consistently presented at times when behaviorally relevant events occur. In this article, we addressed two points concerning TIPL. First, we address the question, are all behaviorally relevant events equal in their impact on encoding processes? Second, we address the hypothesis that TIPL involves mechanisms of the alerting attentional system. Two experiments of fast-TIPL were conducted in which the attentional state of participants was manipulated by using an alerting cue (visual or auditory) that informed participants of the arrival of an upcoming target. Images were presented with task-related stimuli (cues, targets and distractors) and subjects were tested on their memory of those images. Results indicate that memory for target-paired images was enhanced and cue-paired images were suppressed relative to that of distractor-paired images. The alerting cue increased the ability to recall target-paired images presented after this cue, although this result depended on the proportion of cued trials in a session. These results demonstrate a complex interplay between task-elements and the encoding of stimuli paired with them where both enhancement and suppression of task-paired stimuli can be found depending whether those stimuli are paired with task-targets or cues. PMID- 22842472 TI - Harnessing recombination to speed adaptive evolution in Escherichia coli. AB - Evolutionary engineering typically involves asexual propagation of a strain to improve a desired phenotype. However, asexual populations suffer from extensive clonal interference, a phenomenon where distinct lineages of beneficial clones compete and are often lost from the population given sufficient time. Improved adaptive mutants can likely be generated by genetic exchange between lineages, thereby reducing clonal interference. We present a system that allows continuous in situ recombination by using an Esherichia coli F-based conjugation system lacking surface exclusion. Evolution experiments revealed that Hfr-mediated recombination significantly speeds adaptation in certain circumstances. These results show that our system is stable, effective, and suitable for use in evolutionary engineering applications. PMID- 22842473 TI - Enhanced co-production of hydrogen and poly-(R)-3-hydroxybutyrate by recombinant PHB producing E. coli over-expressing hydrogenase 3 and acetyl-CoA synthetase. AB - Recombinant Escherichia coli was constructed for co-production of hydrogen and polyhydroxybutyrate (PHB) due to its rapid growth and convenience of genetic manipulation. In particular, anaerobic metabolic pathways dedicated to co production of hydrogen and PHB were established due to the advantages of directing fluxes away from toxic compounds such as formate and acetate to useful products. Here, recombinant E. coli expressing hydrogenase 3 and/or acetyl-CoA synthetase showed improved PHB and hydrogen production when grown with or without acetate as a carbon source. When hydrogenase 3 was over-expressed, hydrogen yield was increased from 14 to 153 mmol H(2)/mol glucose in a mineral salt (MS) medium with glucose as carbon source, accompanied by an increased PHB yield from 0.55 to 5.34 mg PHB/g glucose in MS medium with glucose and acetate as carbon source. PMID- 22842474 TI - Can car air filters be useful as a sampling medium for air pollution monitoring purposes? AB - Urban air quality and real human exposure to chemical environmental stressors is an issue of high scientific and political interest. In an effort to find innovative and inexpensive means for air quality monitoring, the ability of car engine air filters (CAFs) to act as efficient samplers collecting street level air, to which people are exposed to, was tested. In particular, in the case of taxis, air filters are replaced after regular distances, the itineraries are almost exclusively urban, cruising mode is similar and, thus, knowledge of the air flow can provide with an integrated city air sample. The present pilot study focused on polycyclic aromatic hydrocarbons (PAHs), the most important category of organic pollutants associated with traffic emissions. Concentrations of SigmaPAHs in CAFs ranged between 650 and 2900 MUg CAF(-1), with benzo[b]fluoranthene, benzo[k]fluoranthene and indeno[123-cd]pyrene being the most abundant PAHs. Benzo[a]pyrene (BaP) ranged between 110 and 250 MUg CAF(-1), accounting regularly for 5-15% of the total carcinogenic PAHs. The CAF PAH loads were used to derive road-level atmospheric PAH concentrations from a standard formula relating to the CAF air flow. Important parameters/assumptions for these estimates are the cruising speed and the exposure duration of each CAF. Based on information obtained from the garage experts, an average 'sampled air volume' of 48,750 m(3) per CAF was estimated, with uncertainty in this calculation estimated to be about a factor of 4 between the two extreme scenarios. Based on this air volume, SigmaPAHs ranged between 13 and 56 ng m(-3) and BaP between 2.1 and 5.0 ng m(-3), suggesting that in-traffic BaP concentrations can be many times higher than the limit values set by the UK (0.25 ng m(-3)) and the European Union (1.0 ng m(-3)), or from active sampling stations normally cited on building roof tops or far from city centres. Notwithstanding the limitations of this approach, the very low cost, the continuous availability of very high amounts of "sample", and the "retroactivity" render it very useful and complementary to existing passive sampling techniques. This approach yields estimated air concentrations that reflect the pollutant concentrations to which taxi drivers, pedestrians, cyclists and road-related professionals are exposed. PMID- 22842475 TI - Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers. AB - Pressure-induced vasodilation (PIV) delays the decrease in cutaneous blood flow produced by local application of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor function. Individuals without a normal PIV response have a high risk of ulceration. Here we demonstrate that acid sensing ion channel 3 (Asic3) is an essential neuronal sensor for the vasodilation response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice. PMID- 22842476 TI - Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. AB - Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-alpha-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring. PMID- 22842477 TI - Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. AB - Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance. However, current evidence suggests that FFAs do not directly bind to TLR4, but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes. PMID- 22842479 TI - Visible light-harvesting cyclometalated Ir(III) complexes as triplet photosensitizers for triplet-triplet annihilation based upconversion. AB - Visible light-harvesting cyclometalated Ir(III) complexes with 3-(2 benzothiazoly)-7-diethylaminocoumarin as the C^N cyclometalation ligands were prepared. The ancillary N^N ligand is either 6-piperidine naphthalimide phenanthroline (Ir-1) or 9-aminophenanthroline (Ir-3). Ir(ppy)(2)(Phen) was prepared as model complex (Ir-2). Ir-1 and Ir-3 show strong absorption of visible light (epsilon = 109,000 M(-1) cm(-1) or 112,000 M(-1) cm(-1) at 486 or 484 nm, respectively). All the complexes show room temperature phosphorescence with drastically different phosphorescence quantum yields (Phi(P) = 4.3%, 44.3% and 46.0% for Ir-1, Ir-2 and Ir-3, respectively). With steady state and time-resolved spectra, as well as DFT calculations, the T(1) excited states of Ir-1 and Ir-3 were proposed to be the (3)IL state, whereas the (3)MLCT state was proposed for Ir-2. Long-lived emissive triplet excited states (7.6 MUs and 54.5 MUs) were observed for Ir-1 and Ir-3, compared to the short T(1) excited state lifetime of Ir-2 (1.2 MUs). The complexes were used as triplet photosensitizers for triplet triplet annihilation upconversion and upconversion quantum yields (Phi(UC)) of 19.3% and 12.7% were observed for Ir-1 and Ir-3, respectively. No upconversion was observed for Ir-2 under the same experimental conditions. PMID- 22842480 TI - Amplified electrochemiluminescence detection of nucleic acids by hairpin probe based isothermal amplification. AB - Here, we present a straightforward method for isothermal amplified detection of nucleic acids. In this proof-of-concept study, a specific DNA sequence is amplified through hairpin probe-based isothermal strand-displacement polymerization reaction and then detected via a sensitive and commercially available ECL detection platform. Results show that the DNA sequence derived from the Listeria monocytogenes hly gene can be detected down to 10 pM in solution, together with correlation of the detected signal with the initial concentration of target DNA. Moreover, the designed stem-loop structured hairpin probe shows single-base variation differentiating ability. Considering the superior sensitivity and specificity, as well as the simple-to-implement features, the developed assay demonstrates a great potential of becoming a first-line tool for quantitative analysis of nucleic acids for biomedical research. PMID- 22842478 TI - Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. AB - IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing. PMID- 22842481 TI - The PepT1-transportable soy tripeptide VPY reduces intestinal inflammation. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract. The peptide transporter PepT1 is responsible for the intestinal uptake of dietary peptides, and its expression in the gastrointestinal tract is up-regulated during intestinal inflammation, indicating that PepT1 may be a promising target for IBD therapeutics. METHODS: The transport of soy-derived di- and tripeptides across Caco-2 intestinal epithelial cells was examined, and the anti-inflammatory effects of the transported peptide VPY were evaluated in vitro in Caco-2 and THP-1 macrophages, and in vivo in a mouse model of DSS induced colitis. RESULTS: VPY inhibited the secretion of IL-8 and TNF-alpha, respectively, from Caco-2 and THP-1 cells. VPY transport and anti-inflammatory activity in Caco-2 cells was reduced in the presence of Gly-Sar, indicating this activity was mediated by PepT1. In mice, VPY treatment reduced DSS-induced colitis symptoms and weight loss, improved colon histology, reduced MPO activity, and decreased gene expression of the pro-inflammatory cytokines TNF-alpha, IL-6, IL-1beta, IFN-gamma and IL-17 in the colon. CONCLUSIONS AND GENERAL SIGNIFICANCE: VPY is a novel PepT1 substrate that can inhibit the production of pro inflammatory mediators in vitro in intestinal epithelial and immune cells, and reduce the severity of colitis in mice by down-regulating the expression of pro inflammatory cytokines in the colon, suggesting that VPY may be promising for the treatment of IBD. PMID- 22842482 TI - Decline of functional capacity in healthy aging workers. AB - OBJECTIVES: (1) To study the natural decline in functional capacity (FC) of healthy aging workers; (2) to compare FC to categories of workload; and (3) to study the differences in decline between men and women. DESIGN: Cross-sectional design. SETTING: A rehabilitation center at a university medical center. PARTICIPANTS: Volunteer sample of healthy workers (N=701) between 20 and 60 years of age, working at least 20 hours per week in the year prior to the study. Subjects were recruited via local press and personal networks. INTERVENTIONS: FC was measured with a 14-item Functional Capacity Evaluation. Demographics and health status were measured with a general demographic questionnaire and the RAND 36 questionnaire. MAIN OUTCOME MEASURES: Workload was expressed by the workload categories, as described by the Dictionary of Occupational Titles. Descriptive statistics were used to present FC of workers. Change in FC by age was tested with segmented regression analyses with a cutoff point at 45 years of age. RESULTS: Significant but small declines of FC under age 45 years were present in repetitive reaching, hand dexterity, and energetic capacity. Up to 45 years of age, hand and finger strength increased on average. Over 45 years of age, lifting, carrying, hand and finger strength, and coordinative tests declined more compared with the group aged less than 45 years. Work capacity of men and women working in sedentary and light work was sufficient in all age categories. There are no differences in decline between men and women. CONCLUSIONS: FC of healthy workers declines with age. This study demonstrates substantial variation in the type of FC decline among healthy workers between 20 and 60 years of age. Material handling, hand and finger strength, and hand coordination appear to decline the most in workers over age 45 years. The objective of rehabilitation is to maximize an individual's FC, particularly with respect to environmental demand. Thus, return to work programs must appreciate both FC and workplace demands in an effort to restore/enhance equilibrium between the 2. PMID- 22842483 TI - Test-retest reliability and minimal detectable change of the SmartWheel clinical protocol. AB - OBJECTIVES: (1) To quantify the intra- and intersession reliability and minimal detectable change (MDC) of the SmartWheel clinical protocol (SCP) and (2) to compare the reliability of the SCP between experienced and naive wheelchair users. DESIGN: Test-retest study. SETTING: Biomechanics laboratory. PARTICIPANTS: Manual wheelchair users (WCUs) (n=10) with 1 to 32 years of wheeling experience and able-bodied (AB) naive users (n=15). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Wheelchair propulsion parameters including average peak force, push frequency, push length, and velocity were measured according to the SCP but with 5 trials per session, for 2 sessions. WCUs and AB users were analyzed separately. Intraclass correlation coefficients ([ICC](2,1) and ICC(2,5)) were calculated to assess intrasession reliability. ICC(2,1) and MDC (with 95% confidence) were calculated for each SCP parameter using a single trial from each session and with the mean of 5 repeated measures to evaluate intersession reliability. RESULTS: Intra- and intersession reliability for WCU parameters ranged from high to very high correlation (ICC range, .70-.99). For AB parameters, intrasession ICC(2,1) ranged from moderate to very high (ICC range, .50-.92), while intersession ICC(2,1) indicated low to very high correlation (ICC range, .25-.90). Estimates of standard error of measurement and MDC were provided for each parameter. For both WCUs and AB users, using the means from 5 trials increased intra- and intersession ICC and decreased MDC values. All MDC values were lower for WCUs compared with AB users. CONCLUSIONS: The SCP is a reliable method for assessing propulsion parameters in WCUs, even if just 1 trial is taken per session. AB users showed lower intra- and intersession reliability compared with WCUs. Therefore, for AB users or individuals with minimal wheeling experience, averaging multiple trials is recommended for the SCP. PMID- 22842484 TI - Room for improvement: patient, parent, and practitioners' perceptions of foot problems and foot care in juvenile idiopathic arthritis. AB - OBJECTIVE: To explore the perceived impact of disease-related foot problems and foot care in juvenile idiopathic arthritis (JIA) from the perspectives of patients, parents, pediatric rheumatologists, and health professionals. DESIGN: A qualitative study using an interpretative phenomenological approach. SETTING: Outpatients department, public health service children's hospital. PARTICIPANTS: Patients (N=15; 4 adult patients, 2 parents of children with JIA, 3 pediatric rheumatologists, and 6 health professionals) from 2 National Health Service rheumatology centers (1 pediatric and 1 adult). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Qualitative outcomes were participants' perceptions elicited using semistructured interviews (telephone or face-to-face) and focus groups using an interpretative phenomenological approach. A data-driven inductive approach to coding and theme development was adopted for transcript analysis. RESULTS: Participants volunteered to take part in a total of 7 interviews and 2 focus groups. The analysis revealed 6 key themes related to the impact of foot problems and perceptions of foot care from respective groups. These were the following: (1) pain, (2) mobility impairment, (3) reduced ability to perform activities of daily living, (4) footwear difficulties, (5) poor referral pathways/delayed access to care, and (6) lack of evidence in support of conservative foot care. CONCLUSIONS: Several areas for development of foot care services were identified including a need for improved referral pathways, shorter waiting times for initial consultations, greater attention to patient compliance, and a need for better evidence in support of customized foot orthoses. Several key foot health-related outcomes were identified, which may be of importance for measuring therapeutic response to foot-related interventions. PMID- 22842485 TI - Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. AB - The aim of this study was to evaluate the safety and efficacy of vaccination with human leukocyte antigen (HLA)-A24-restricted human vascular endothelial growth factor receptor 1 (VEGFR1)-1084 and VEGFR2-169 combined with chemotherapy in patients with advanced gastric cancer. HLA-A 2402-positive patients with advanced or recurrent adenocarcinoma of the stomach were vaccinated with VEGFR1-1084 and VEGFR2-169 combined with S-1 and cisplatin. The study included 22 patients (median age 60.5 years) who received at least one cycle of the combination therapy. No severe adverse effects caused by the vaccine therapy were observed except for an inflammatory reaction at the site of injection in 6 patients. Twelve patients (55%) showed partial response and 10 had stable disease after two cycles of the combination therapy. The disease control rate (partial response and stable disease) was 100% after two cycles. The median time to progression was 9.6 months and median overall survival was 14.2 months. VEGFR1-1084-specific cytotoxic T lymphocyte (CTL) response was induced in 18 (82%) of the 22 patients and VEGFR2-169-specific CTL response was induced in 18 (82%) of the 22 patients. Patients showing CTL response to VEGFR2-169 peptide had significantly better prognosis than those without, as demonstrated by the overall survival (OS) and time to progression (TTP) (OS, p=0.028, TTP, p=0.006). The combination therapy was well tolerated and highly effective in advanced or recurrent gastric cancer. Substantial specific CTL for both peptides was frequently induced even under chemotherapy. Thus, cancer vaccination combined with standard chemotherapy warrants further analysis as a promising strategy for the treatment of advanced cancer. PMID- 22842486 TI - MAGEA4 induces growth in normal oral keratinocytes by inhibiting growth arrest and apoptosis. AB - Cancer testis antigens (CTAs) are proteins that are normally expressed only in male germ cells and are aberrantly upregulated in a variety of cancers such as melanomas and lung cancer. MAGEA proteins belong to Class I CTAs and are being utilized as targets for cancer immunotherapy. Despite the discovery of the first CTA (MAGEA1) 20 years ago, the functions of these proteins remain poorly understood and evidence suggests both oncogenic as well as tumor suppressive roles for these proteins. Herein, we investigated the role of MAGEA4 in promoting cell growth. When overexpressed, MAGEA4 promotes growth of spontaneously transformed normal oral keratinocytes (NOK-SI). To understand the mechanism of growth stimulation by MAGEA4, we explored the effect of overexpressing MAGEA4 on cell cycle and apoptosis. MAGEA4 inhibits growth arrest of cells in the G1 phase of the cell cycle. We also found that overexpression of MAGEA4 inhibits G418 induced apoptosis of NOK-SI cells. Interestingly, this inhibition was accompanied by repression of two p53 downstream genes, BAX and CDKN1A. Our results indicate that MAGEA4 promotes growth by preventing cell cycle arrest and by inhibiting apoptosis mediated by the p53 transcriptional targets. PMID- 22842487 TI - Fluoride-responsive gelator and colorimetric sensor based on simple and easy-to prepare cyano-substituted amide. AB - A new and easy-to-prepare gelator based on cyano-substituted amide (BPNIA) was designed and synthesized. BPNIA could form thermoreversible gel in DMSO-H(2)O (v/v, 9 : 1) and ultrasound-stimulated gel in DMSO. FT-IR, UV-vis and XRD spectra indicated that the gelator molecules self-assemble into a fibrous network resulting from the cooperation of intermolecular hydrogen bonding, pi-pi stacking and cyano interactions. BPNIA can act as a highly selective colorimetric sensor for fluoride in DMSO, overcoming the interference of H(2)PO(4)(-), AcO(-) and other halide anions. The deprotonation of the NH groups is responsible for the dramatic color change from colorless to yellow. Interestingly, the organogel of BPNIA could allow a two channel fluoride response by proton controlled reversible sol-gel transition and color changes. PMID- 22842488 TI - Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx. AB - STIM1 is a Ca(2+) sensing molecule. Once the Ca(2+) stores are depleted, STIM1 moves towards the plasma membrane (PM) (translocation), forms puncta (clustering), and triggers store-operated Ca(2+) entry (SOCE). Although this process has been regarded as a main mechanism for store-operated Ca(2+) channel activation, the STIM1 clustering is still unclear. Here we discovered a new phenomenon of STIM1 clustering, which is not triggered by endoplasmic reticulum (ER) Ca(2+) depletion. STIM1 subplasmalemmal translocation and clustering can be induced by ER Ca(2+) store depletion with thapsigargin (TG), G-protein-coupled receptor activator trypsin and ryanodine receptor (RyR) agonists caffeine and 4 chloro-3-ethylphenol (4-CEP) in the HEK293 cells stably transfected with STIM1 EYFP. The STIM1 clustering induced by TG was more sustained than that induced by trypsin and RyR agonists. Interestingly, 4-CEP-induced STIM1 clustering also happened in the cytosol without ER Ca(2+) store depletion. Application of some pharmacological regulators including flufenamic acid, 2-APB, and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) at concentrations without affecting ER Ca(2+) store also evoked cytosolic STIM1 clustering. However, the direct store operated ORAI channel blockers (SKF-96365, Gd(3+) and diethylstilbestrol) or the signaling pathway inhibitors (genistein, wortmannin, Y-27632, forskolin and GF109203X) did not change the STIM1 movement. Disruption of cytoskeleton by colchicine and cytochalasin D also showed no effect on STIM1 movement. We concluded that STIM1 clustering and translocation are two dynamic processes that can be pharmacologically dissociated. The ER Ca(2+) store-independent mechanism for STIM1 clustering is a new alternative mechanism for regulating store-operated channel activity, which could act as a new pharmacological target. PMID- 22842489 TI - Key cell signaling pathways modulated by zerumbone: role in the prevention and treatment of cancer. AB - Phytochemicals and their synthetic derivatives are making a significant contribution in modern drug discovery programs by targeting several human diseases, including cancer. Most of these natural compounds are often multitargeted in nature, which is generally a very desirable property for cancer therapy, as carcinomas typically involve dysregulation of multiple genes and associated cell-signaling pathways at various stages of initiation, progression and metastasis. Additionally, these natural agents generally have lower side effects, are readily available and hence are cost effective. One such natural compound is zerumbone, a cyclic eleven-membered sesquiterpene, isolated from the tropical plant Zingiber zerumbet Smith that has attracted great attention recently for its potent anticancer activities in several tumor models. This review summarizes the data based on various in vitro and in vivo studies related to the effects of zerumbone on numerous pivotal molecular targets in cancer and its reported chemopreventive/therapeutic effects in different models of cancer. PMID- 22842490 TI - Retinal surface en face optical coherence tomography: a new imaging approach in epiretinal membrane surgery. AB - PURPOSE: To describe the clinical effectiveness of a new imaging approach: en face spectral domain optical coherence tomography of the retinal surface before and after epiretinal membrane (ERM) and internal limiting membrane peeling. METHODS: Retrospective analysis of preoperative and postoperative en face spectral domain optical coherence tomography images of the inner face of the macula obtained from 20 eyes of 20 patients undergoing vitrectomy with internal limiting membrane peeling for ERM. RESULTS: Preoperatively, en face spectral domain optical coherence tomography imaging of the retinal surface clearly showed plaques surrounded by radiating folds because of ERM. It could also disclose areas possibly devoid of internal limiting membrane secondary to ERM contraction. A rough retinal surface was visible in the peeled area during the first postoperative month. At 3 months, various amounts of dimples were progressively observed in 13 of 15 eyes (87%). In all these cases, they lasted or increased in size and number at the last follow-up examination. Some residual epiretinal tissue was also detected by this technique. CONCLUSION: En face spectral domain optical coherence tomography of the retinal surface is an interesting complement to standard retinal optical coherence tomography section that provides an easy-to understand global overview of the retinal surface. It can detect and classify tiny progressive morphologic changes in the texture of the retinal surface occurring after internal limiting membrane peeling. PMID- 22842491 TI - A micromachined carbon nanotube film cantilever-based energy cell. AB - This paper reports a new type of energy cell based on micromachined carbon nanotube film (CNF)-lead zirconate titanate cantilevers that is fabricated on silicon substrates. Measurements found that this type of micro-energy cell generates both AC voltages due to the self-reciprocation of the microcantilevers and DC voltages due to the thermoelectric effect upon exposure to light and thermal radiation, resulting from the unique optical and thermal properties of the CNF. Typically the measured power density of the micro-energy cell can be from 4 to 300 MUW cm(-2) when it is exposed to sunlight under different operational conditions. It is anticipated that hundreds of integrated micro energy cells can generate power in the range of milliwatts, paving the way for the construction of self-powered micro- or nanosystems. PMID- 22842492 TI - Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production. AB - Increased pulmonary artery endothelial cell (PAEC) endothelium-dependent nitric oxide synthase (eNOS) activity mediates perinatal pulmonary vasodilation. Compromised eNOS activity is central to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Voltage-derived anion channel (VDAC)-1 was recently demonstrated to bind eNOS in the systemic circulation. We hypothesized that VDAC isoforms modulate eNOS activity in the pulmonary circulation, and that decreased VDAC expression contributes to PPHN. In PAECs derived from an ovine model of PPHN: (1) there is eNOS activity, but not expression; and (2) VDAC1 and 2 proteins are decreased. Immunocytochemistry, coimmunoprecipitation, and in situ proximity ligation assays in human PAECs (hPAECs) demonstrate binding between eNOS and both VDAC1 and -2, which increased upon stimulation with NO agonists. The ability of agonists to increase the eNOS/VDAC interaction was significantly blunted in hypertensive, compared with normotensive, ovine PAECs. Depletion of VDAC2, but not VDAC1, blocked the agonist-induced increase in eNOS activity in hPAECs. Overexpression of VDAC2 in hypertensive PAECs increased eNOS activity. Binding of VDAC2 enhances eNOS activity in the pulmonary circulation, and diminished VDAC2 constrains eNOS in PAECs derived from fetal lambs with chronic intrauterine pulmonary hypertension. We speculate that decreases in VDAC2 may contribute to the limited eNOS activity that characterizes pulmonary hypertension. PMID- 22842493 TI - Regulation of Rela/p65 and endothelial cell inflammation by proline-rich tyrosine kinase 2. AB - We investigated the role of proline-rich tyrosine kinase 2 (Pyk2) in the mechanism of NF-kappaB activation and endothelial cell (EC) inflammation induced by thrombin, a procoagulant serine protease released in high amounts during sepsis and other inflammatory conditions. Stimulation of ECs with thrombin resulted in a time-dependent activation of Pyk2. RNA interference knockdown of Pyk2 attenuated thrombin-induced activity of NF-kappaB and expression of its target genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Pyk2 knockdown impaired thrombin-induced activation of IkappaB kinase (IKK) and phosphorylation (Ser32 and Ser36) of IkappaBalpha, but, surprisingly, failed to prevent IkappaBalpha degradation. However, depletion of IKKalpha or IKKbeta was effective in inhibiting IkappaBalpha phosphorylation/degradation, as expected. Intriguingly, Pyk2 knockdown impaired nuclear translocation and DNA binding of RelA/p65, despite the inability to prevent IkappaBalpha degradation. In addition, Pyk2 knockdown was associated with inhibition of RelA/p65 phosphorylation at Ser536, which is important for transcriptional activity of RelA/p65. Depletion of IKKalpha or IKKbeta each impaired RelA/p65 phosphorylation. Taken together, these data identify Pyk2 as a critical regulator of EC inflammation by virtue of engaging IKK to promote the release and the transcriptional capacity of RelA/p65, and, additionally, by its ability to facilitate the nuclear translocation of the released RelA/p65. Thus, specific targeting of Pyk2 may be an effective anti-inflammatory strategy in vascular diseases associated with EC inflammation and intravascular coagulation. PMID- 22842494 TI - Bortezomib alleviates experimental pulmonary arterial hypertension. AB - Vascular remodeling and endothelial dysfunction are important pathogenic features of pulmonary arterial hypertension (PAH). There is a growing body of evidence that proteasome inhibitors may be beneficial in vascular diseases by inhibiting proliferation of vascular smooth muscle cells (VSMCs) and ameliorating endothelial dysfunction. Here, we evaluated whether bortezomib (BTZ) could alleviate hypoxia- and monocrotaline (MCT)-induced PAH. BTZ (at doses from 1 to 100 MUg/kg, or a dose of 100 MUg/kg) was administered to mice every other day for the last 2 weeks of a 5-week hypoxia (10% O(2)) period, or to rats once daily from Day 22 to Day 34 after MCT challenge, respectively. BTZ treatment substantially suppressed elevation of right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling in hypoxia-exposed mice. Similarly, BTZ treatment inhibited RV hypertrophy and vascular remodeling in MCT injected rats. Strikingly, BTZ rescued 70% of MCT-injected rats up to Day 60, along with a considerable reduction in RV systolic pressure and suppression of vascular remodeling, whereas, among MCT-injected rats not administered BTZ, there were no survivors by Day 41. BTZ significantly suppressed proliferation of pulmonary VSMCs in vivo and in vitro. Furthermore, BTZ increased not only endothelial nitric oxide (NO) synthase (eNOS), phosphorylated eNOS, and NO production in vitro, but also eNOS and p-eNOS in hypoxia-exposed mice and MCT injected rats, respectively. In contrast to the beneficial effects, BTZ increased active caspase-3 in cardiac ventricles of MCT-injected rats. Taken together, with caution for cardiotoxicity, BTZ could be a potential therapeutic strategy in PAH, possibly acting by inhibition of VSMC proliferation and amelioration of endothelial dysfunction. PMID- 22842497 TI - BODIPY dyes with beta-conjugation and their applications for high-efficiency inverted small molecule solar cells. AB - Small molecule BODIPY dyes incorporating conjugated substituents at the beta sites have been synthesized. Solution processed inverted bulk heterojunction cells were fabricated from the blends of the dyes and PC(71)BM. The cells exhibited very high open-circuit voltages (>0.9 V) and a high conversion efficiency of 3.22% has been achieved. PMID- 22842495 TI - Oxidative stress contributes to lung injury and barrier dysfunction via microtubule destabilization. AB - Oxidative stress is an important part of host innate immune response to foreign pathogens, such as bacterial LPS, but excessive activation of redox signaling may lead to pathologic endothelial cell (EC) activation and barrier dysfunction. Microtubules (MTs) play an important role in agonist-induced regulation of vascular endothelial permeability, but their impact in modulation of inflammation and EC barrier has not been yet investigated. This study examined the effects of LPS-induced oxidative stress on MT dynamics and the involvement of MTs in the LPS induced mechanisms of Rho activation, EC permeability, and lung injury. LPS treatment of pulmonary vascular EC induced elevation of reactive oxygen species (ROS) and caused oxidative stress associated with EC hyperpermeability, cytoskeletal remodeling, and formation of paracellular gaps, as well as activation of Rho, p38 stress kinase, and NF-kappaB signaling, the hallmarks of endothelial barrier dysfunction. LPS also triggered ROS-dependent disassembly of the MT network, leading to activation of MT-dependent signaling. Stabilization of MTs with epothilone B, or inhibition of MT-associated guanine nucleotide exchange factor (GEF)-H1 activity by silencing RNA-mediated knockdown, suppressed LPS induced EC barrier dysfunction in vitro, and attenuated vascular leak and lung inflammation in vivo. LPS disruptive effects were linked to activation of Rho signaling caused by LPS-induced MT disassembly and release of Rho-specific GEF-H1 from MTs. These studies demonstrate, for the first time, the mechanism of ROS induced Rho activation via destabilization of MTs and GEF-H1-dependent activation of Rho signaling, leading to pulmonary EC barrier dysfunction and exacerbation of LPS-induced inflammation. PMID- 22842498 TI - How to plan workflow changes: a practical quality improvement tool used in an outpatient hospital pharmacy. AB - OBJECTIVE: A quality improvement tool is provided to improve pharmacy workflow with the goal of minimizing errors caused by workflow issues. This study involved workflow evaluation and reorganization, and staff opinions of these proposed changes. PRACTICE DESCRIPTION: The study pharmacy was an outpatient pharmacy in the Tucson area. However, the quality improvement tool may be applied in all pharmacy settings, including but not limited to community, hospital, and independent pharmacies. PRACTICE INNOVATION: This tool can help the user to identify potential workflow problem spots, such as high-traffic areas through the creation of current and proposed workflow diagrams. Creating a visual representation can help the user to identify problem spots and to propose changes to optimize workflow. It may also be helpful to assess employees' opinions of these changes. CONCLUSION: The workflow improvement tool can be used to assess where improvements are needed in a pharmacy's floor plan and workflow. Suggestions for improvements in the study pharmacy included increasing the number of verification points and decreasing high traffic areas in the workflow. The employees of the study pharmacy felt that the proposed changes displayed greater continuity, sufficiency, accessibility, and space within the pharmacy. PMID- 22842496 TI - Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization. AB - The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade-induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit(+) and Sca-1(+) cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor 1alpha and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1alpha and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH. PMID- 22842499 TI - Evaluation of pharmacist utilization of a poison center as a resource for patient care. AB - The objective of this study was to evaluate pharmacist use of a Regional Poison Information Center (RPIC), identify potential barriers to utilization, and provide strategies to overcome these barriers. All calls placed to a RPIC by a pharmacist, physician, or nurse over a 5-year period were retrieved. These data were analyzed to assess the pharmacist utilization of the RPIC and the variation of call types. Additionally, a survey, designed to assess the past and future use of the RPIC by pharmacists, was distributed to pharmacists in the region. Of the 37,799 calls made to the RPIC, 26,367 (69.8%) were from nurses, 8096 (21.4%) were from physicians, and 3336 (8.8%) were from pharmacists. Among calls initiated by pharmacists, the majority involved medication identification (n = 2391, 71.7%). The survey had a 38.9% response rate (n = 715) and revealed a trend toward less RPIC utilization by pharmacists with more formal training but less practice experience. The utilization of the RPIC was lowest among pharmacists as compared to other health care professionals. This may be due to pharmacists' unfamiliarity with the poison center's scope of services and resources. Therefore, it is important that pharmacists are educated on the benefit of utilizing poison centers in clinical situations. PMID- 22842500 TI - Eosinophilic meningitis secondary to intravenous vancomycin. AB - Eosinophilic meningitis may be due to infectious or noninfectious etiologies. Parasitic infections cause this entity most frequently and of the noninfectious causes, medications play an important role. We describe a 32-year-old male who developed eosinophilic meningitis while receiving intravenous vancomycin. No other apparent cause of the eosinophilic meningitis was appreciated. This case represents the first description of eosinophilic meningitis due to systemic vancomycin. PMID- 22842501 TI - The development of a patient care center in a supermarket chain pharmacy. AB - PURPOSE: The objective of this manuscript is to describe the development and implementation of a patient care center in a grocery store supermarket chain pharmacy. METHODS: A clinical pharmacist and shared faculty member between Wayne State University and Kroger Pharmacy developed a patient care center and rotation site for P4 PharmD advanced pharmacy practice experiences (APPEs). The site was developed to provide advanced pharmacy services to patients and as a practice site for students to learn how to deliver care. Preliminary outcomes observed include the number and types of patients that utilized the patient care center and the educational experiences provided for student pharmacists practicing in this setting. RESULTS: Since implementation, 160 patients visited the patient care center. The pharmacists involved in the clinic performed 30 biometric screenings and 47 comprehensive medication reviews. CONCLUSIONS: Establishing a patient care center in a supermarket pharmacy provides important care for patients and valuable learning experiences for student pharmacists. The collaborative efforts of both Wayne State University and Kroger Pharmacy demonstrate commitment to providing clinical care to patients and strong clinical community practice experiences for students. Future goals include creating more clinical services in the community and practice experiences for students. PMID- 22842502 TI - Cryptogenic organizing pneumonia during adjuvant chemotherapy with oxaliplatin, 5 fluorouracil, and leucovorin (FOLFOX) for colon cancer. AB - Lung disease associated with FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) chemotherapy is uncommon. We describe a case of cryptogenic organizing pneumonia (COP) occurring in a 78-year-old woman after receiving 2 cycles of modified FOLFOX6 as adjuvant chemotherapy for treatment of resected nonmetastatic colon cancer. This patient presented with respiratory symptoms including cough with scant clear sputum and wheezing on day 10 of the second cycle of mFOLFOX6. Despite therapy with systemic antibiotics and supplemental oxygen, she had a steady and relentless progression of her respiratory symptoms and status, with chest radiographs revealing progressive bilateral pulmonary infiltrates. Further chest radiograph evaluation demonstrated findings consistent with COP. Antibiotics were discontinued and methylprednisolone sodium succinate initiated as the mainstay of management for COP. The patient required a higher dose of methylprednisolone sodium succinate than typical for initial response with doses up to 3 mg/kg per d leading to prompt improvement in her respiratory symptoms and function and declining need for supplemental oxygen therapy. Chest radiographs also showed improvement. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's COP and the FOLFOX chemotherapy. Clinicians should be aware of the potential for this uncommon, yet severe adverse reaction associated with the FOLFOX chemotherapy. PMID- 22842503 TI - Professional reading habits of pharmacists attending 2 educational seminars in New York City. AB - PURPOSE: Data regarding the professional reading habits of pharmacists in the United States are lacking. The purpose of this pilot study was to investigate whether pharmacists read professional publications and assess other aspects of their professional reading habits. METHODS: In December 2010, surveys were distributed to pharmacists participating in 2 educational seminars in New York City. The main outcome measures were percentages of pharmacists who read regularly (at least monthly), specific publications read, and the perceived value and impact of reading. RESULTS: A total of 184 pharmacists were surveyed. Of the 122 (66%) respondents, 112 (92%) reported reading professional publications regularly. Of these, 97 (87%) indicated the titles read, with the 4 publications reported most frequently being Drug Topics (n = 73; 75%), Pharmacy Times (n = 67; 69%), US Pharmacist (n = 60; 62%), and Pharmacist's Letter (n = 48; 49%). All 122 respondents indicated that reading positively impacted their practice, and 121 (99%) reported that reading was important. CONCLUSIONS: The value of reading professional publications was recognized by surveyed pharmacists; this likely contributed to the high reading rate reported in this study. PMID- 22842504 TI - Graves' hyperthyroidism-induced psychosis treated with aripiprazole--a case report. AB - Graves' disease is an autoimmune syndrome with symptoms such as tachycardia, atrial fibrillation, and psychiatric symptoms. Limited evidence exists for the treatment of Graves' hyperthyroidism-induced psychosis with atypical antipsychotics. A 47-year-old female with a psychiatric history of bipolar disorder presented for the first time to the psychiatric hospital. She was agitated and grossly psychotic with delusions. Electrocardiogram showed atrial fibrillation and tachycardia. Drug screen urinalysis was negative. Endocrine workup resulted in a diagnosis of Graves' disease (thyroid-stimulating hormone [TSH]: 0.005 MUIU/mL, triiodothyronine [T3]: 537 ng/dL, thyroxine [T4]: 24 mcg/dL, free T4: 4.5 ng/dL, positive antithyroid peroxidase antibody, and antinuclear antibody). Aripiprazole 10 mg daily was initiated and titrated to 15 mg daily on day 4. On day 16, her suspicious behavior, judgment, and insight improved. Other medications given included aspirin 325 mg daily, metoprolol 25 mg twice daily, titrated to 12.5 mg twice daily, and methimazole 30 mg daily, titrated to 20 mg twice daily, and discontinued on day 29. The patient received radioiodine I-131 treatment 1 week later. We report the first known case on the use of aripriprazole to treat Graves' hyperthyroidism-induced psychosis. Further studies examining the long-term effects and appropriate dose and duration of aripiprazole in this patient population are needed. PMID- 22842505 TI - Safety implications of standardized continuous quality improvement programs in community pharmacy. AB - Standardized continuous quality improvement (CQI) programs combine Web-based technologies and standardized improvement processes, tools, and expectations to enable quality-related events (QREs) occurring in individual pharmacies to be shared with pharmacies in other jurisdictions. Because standardized CQI programs are still new to community pharmacy, little is known about how they impact medication safety. This research identifies key aspects of medication safety that change as a result of implementing a standardized CQI program. Fifty-three community pharmacies in Nova Scotia, Canada, adopted the SafetyNET-Rx standardized CQI program in April 2010. The Institute for Safe Medication Practices (ISMP) Canada's Medication Safety Self-Assessment (MSSA) survey was administered to these pharmacies before and 1 year into their use of the SafetyNET-Rx program. The nonparametric Wilcoxon signed-rank test was used to explore where changes in patient safety occurred as a result of SafetyNETRx use. Significant improvements occurred with quality processes and risk management, staff competence, and education, and communication of drug orders and other information. Patient education, environmental factors, and the use of devices did not show statistically significant changes. As CQI programs are designed to share learning from QREs, it is reassuring to see that the largest improvements are related to quality processes, risk management, staff competence, and education. PMID- 22842506 TI - Current approaches to anticoagulation for reducing risk of atrial fibrillation related stroke. AB - Stroke is a major cause of death and disability and, as such, is associated with a heavy socioeconomic burden. Atrial fibrillation (AF) is an independent risk factor for ischemic stroke, and AF-related stroke tends to be more severe and poses a higher risk of recurrence than non-AF-related stroke. Anticoagulant prophylaxis with warfarin is effective in preventing stroke in eligible patients with AF, but in real-world practice this agent, though inexpensive, is underutilized. Moreover, warfarin has notable drawbacks that result in suboptimal anticoagulation and, as a result, greater disease burden and higher costs. Newer oral antithrombotic drugs with a wide therapeutic window and no requirement for routine coagulation monitoring may be as efficacious as warfarin and, given the costs associated with managing warfarin therapy, they may also prove to be more cost effective. PMID- 22842507 TI - The pharmacists' role in patient-provider pain management treatment agreements. AB - With the increased focus on improving patients' pain control and upward trends in opioid overdose and deaths, health care professionals have become increasingly interested in reducing their professional risks and improving the safety of their patients receiving chronic opioids. These fears can often be further exacerbated by media attention of deaths from opioid misuse or unintentional overdose and physician prosecution for 'overprescribing' of controlled substances, including opioids. This article discusses the role pharmacists can play in patient-provider agreements, and highlights the potential risks associated with chronic opioid therapy. In addition, it describes the important differences between abuse, addiction, physical dependence, and tolerance. Sample informed consent for chronic opioid therapy and patient-provider agreements are included. PMID- 22842508 TI - Dermatophyte-host relationship of a murine model of experimental invasive dermatophytosis. AB - Recognizing the invasive potential of the dermatophytes and understanding the mechanisms involved in this process will help with disease diagnosis and with developing an appropriate treatment plan. In this report, we present the histopathological, microbiological and immunological features of a model of invasive dermatophytosis that is induced by subcutaneous infection of Trichophyton mentagrophytes in healthy adult Swiss mice. Using this model, we observed that the fungus rapidly spreads to the popliteal lymph nodes, spleen, liver and kidneys. Similar to the human disease, the lymph nodes were the most severely affected sites. The fungal infection evoked acute inflammation followed by a granulomatous reaction in the mice, which is similar to what is observed in patients. The mice were able to mount a Th1-polarized immune response and displayed IL-10-mediated immune regulation. We believe that the model described here will provide valuable information regarding the dermatophyte-host relationship and will yield new perspective for a better understanding of the immunological and pathological aspects of invasive dermatophytosis. PMID- 22842509 TI - 2D-1D structural phase transformation of Co(II) 3,5-pyridinedicarboxylate frameworks with chromotropism. AB - Two new metal-organic frameworks [Co(pydc)(H(2)O)(2)](n) (1) and [Co(pydc)(H(2)O)(4)](n)(H(2)O)(n) (2), (pydc = 3,5-pyridinedicarboxylate) have been synthesized by a diffusion method and characterized by single-crystal X-ray diffraction. The structure of 1 reveals an infinite 2D layer with honeycomb-like cavities in which each pydc ligand bridges three Co(II) ions. The adjacent 2D layers are orderly packed in an ABAB-type array via intermolecular interactions of the combined pi-pi stacking and hydrogen bonds to form a 3D supramolecular architecture. Interestingly, compound 1 exhibits a water induced crystal-to amorphous transformation with chromotropism confirmed by spectroscopic techniques, elemental analysis, TGA and XRPD. When this amorphous phase (1A) was exposed to water vapor, it was readily converted into the second crystalline phase 1B with a color change. Moreover, a reversible process between 1A and 1B was performed. In the case of compound 2, pydc acts as didentate bridging ligand connecting two Co(II) ions, leading to a 1D zig-zag chain. Guest water molecules fill the gaps in between chains and form hydrogen bonds with the host chains stabilizing the 3D network of 2. Additionally, compound 2 also exhibits a water induced crystal-to-amorphous transformation with chromotropism and the reversible process was also performed between the dehydrated (2A) and rehydrated (2') forms. Surprisingly, the IR and UV-vis spectra, elemental analysis, TGA curve and XRPD pattern of the rehydrated second phase 1B are found to be identical to that of 2 and 2', these results confirm that 2, 2' and 1B are the same compound. PMID- 22842510 TI - Unification of trap-limited electron transport in semiconducting polymers. AB - Electron transport in semiconducting polymers is usually inferior to hole transport, which is ascribed to charge trapping on isolated defect sites situated within the energy bandgap. However, a general understanding of the origin of these omnipresent charge traps, as well as their energetic position, distribution and concentration, is lacking. Here we investigate electron transport in a wide range of semiconducting polymers by current-voltage measurements of single carrier devices. We observe for this materials class that electron transport is limited by traps that exhibit a gaussian energy distribution in the bandgap. Remarkably, the electron-trap distribution is identical for all polymers considered: the number of traps amounts to 3 * 10(23) traps per m(3) centred at an energy of ~3.6 eV below the vacuum level, with a typical distribution width of ~0.1 eV. This indicates that the electron traps have a common origin that, we suggest, is most likely related to hydrated oxygen complexes. A consequence of this finding is that the trap-limited electron current can be predicted for any polymer. PMID- 22842511 TI - A flexible and highly sensitive strain-gauge sensor using reversible interlocking of nanofibres. AB - Flexible skin-attachable strain-gauge sensors are an essential component in the development of artificial systems that can mimic the complex characteristics of the human skin. In general, such sensors contain a number of circuits or complex layered matrix arrays. Here, we present a simple architecture for a flexible and highly sensitive strain sensor that enables the detection of pressure, shear and torsion. The device is based on two interlocked arrays of high-aspect-ratio Pt coated polymeric nanofibres that are supported on thin polydimethylsiloxane layers. When different sensing stimuli are applied, the degree of interconnection and the electrical resistance of the sensor changes in a reversible, directional manner with specific, discernible strain-gauge factors. The sensor response is highly repeatable and reproducible up to 10,000 cycles with excellent on/off switching behaviour. We show that the sensor can be used to monitor signals ranging from human heartbeats to the impact of a bouncing water droplet on a superhydrophobic surface. PMID- 22842512 TI - Cross-sectional imaging of individual layers and buried interfaces of graphene based heterostructures and superlattices. AB - By stacking various two-dimensional (2D) atomic crystals on top of each other, it is possible to create multilayer heterostructures and devices with designed electronic properties. However, various adsorbates become trapped between layers during their assembly, and this not only affects the resulting quality but also prevents the formation of a true artificial layered crystal upheld by van der Waals interaction, creating instead a laminate glued together by contamination. Transmission electron microscopy (TEM) has shown that graphene and boron nitride monolayers, the two best characterized 2D crystals, are densely covered with hydrocarbons (even after thermal annealing in high vacuum) and exhibit only small clean patches suitable for atomic resolution imaging. This observation seems detrimental for any realistic prospect of creating van der Waals materials and heterostructures with atomically sharp interfaces. Here we employ cross sectional TEM to take a side view of several graphene-boron nitride heterostructures. We find that the trapped hydrocarbons segregate into isolated pockets, leaving the interfaces atomically clean. Moreover, we observe a clear correlation between interface roughness and the electronic quality of encapsulated graphene. This work proves the concept of heterostructures assembled with atomic layer precision and provides their first TEM images. PMID- 22842513 TI - Scanning positional variations in single-nucleotide polymorphism of DNA: an electrochemical study. AB - While there are a number of electrochemical methods reported that enable the detection of single nucleotide mismatches, the determination of mismatch position in a double stranded DNA remains an unsolved challenge. Using a model system, we systematically explored the electrochemical response of all possible positions of single nucleotide mismatches in a set of 25-mer DNA films. These ds-DNA sequences each with a single mismatch at one of the twenty-five positions were bound to gold surfaces through a Au-S linkage and analyzed by electrochemical impedance spectroscopy (EIS) and scanning electrochemical microscopy (SECM) in the absence and presence of Zn(2+). We expected a unique response from each mismatched sequence in order to discriminate the mismatch positions. A pattern emerges between the electrochemical signals and mismatch positions. The positions can be grouped broadly into positions that exhibit large differences between matched and mismatched DNA (around positions 5 and 9) and those that exhibit smaller differences (around positions 1, 13 and 23) in the charge transfer resistance DeltaR(ct), evaluated by EIS, and the apparent rate constant k(0), evaluated by SECM. To the best of our knowledge, this is the first study evaluating the electrochemical response of a single nucleotide mismatch as a function of mismatch positions along an oligonucleotide sequence. PMID- 22842514 TI - Expression of melanocortin receptors in human prostate cancer cell lines: MC2R activation by ACTH increases prostate cancer cell proliferation. AB - The melanocortin receptors (MCRs 1-5) are G protein coupled-receptors (GPCRs) that regulate food intake, inflammation, skin pigmentation, sexual function and steroidogenesis. Their peptide ligands, the melanocortins, are alpha-, beta- and gamma-melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH) all of which are secreted from the anterior pituitary gland under hypothalamic control. MC2R binds ACTH but has no affinity for the other melanocortins and is, thereby, pharmacologically different from MCRs that bind those ligands. Evidence suggests that elevated GPCRs transactivate the androgen receptor (AR), the critical mediator of prostate cell growth, and consequently promote prostate cancer cell proliferation. It may be that reduced central melanocortin signaling is coincidental with reversal of prostate cancer cachexia, but no data are available on the expression of, or the role for, MCRs in prostate cancer. Here, we show that MCR (1-5) mRNAs are expressed in androgen-dependent LNCaP and androgen-independent PC3 and DU-145 human prostate cancer cell lines. Further, MC2R, the specific target of ACTH, is expressed in LNCaP, PC3 and DU-145 cells. Among the several synthetic MCR peptide ligands that we used, only ACTH promoted concentration-dependent cell proliferation in the three cell lines as shown by MTT cell proliferation assay. In LNCaP cells, the effect was additive with testosterone stimulation and was partially blunted with SHU9119, a non-selective MCR antagonist. In the same cells, ACTH induced cAMP production and increased AR nuclear labeling in immunocytochemical assays. Our observations suggest that MC2R is involved in prostate carcinogenesis and that targeting MC2R signaling may provide a novel avenue in prostate carcinoma treatment. PMID- 22842516 TI - Putative depolarisation-induced retrograde signalling accelerates the repeated hypoxic depression of excitatory synaptic transmission in area CA1 of rat hippocampus via group I metabotropic glutamate receptors. AB - Excitatory synaptic transmission in area CA1 of the mammalian hippocampus is rapidly depressed during hypoxia. The depression is largely attributable to an increase in extracellular adenosine and activation of inhibitory adenosine A(1) receptors on presynaptic glutamatergic terminals. However, sequential exposure to hypoxia results in a slower subsequent hypoxic depression of excitatory synaptic transmission, a phenomenon we have previously ascribed to a reduction in the release of extracellular adenosine. In the present study we show that this delayed depression of excitatory postsynaptic currents (EPSCs) to repeated hypoxia can be reversed by a period of postsynaptic depolarisation delivered to an individual CA1 neuron, under whole-cell voltage clamp, between two periods of hypoxia. The depolarisation-induced acceleration of the hypoxic depression of the EPSC is dependent upon postsynaptic Ca(2+) influx, the activation of PKC and is blocked by intracellular application of GDP-beta-S and N-ethylmaleimide (NEM), inhibitors of membrane fusion events. In addition, the acceleration of the hypoxic depression of the EPSC was prevented by the GI mGluR antagonist AIDA, but not by the CB1 cannabinoid receptor antagonist AM251. Our results suggest a process initiated in the postsynaptic cell that can influence glutamate release during subsequent metabolic stress. This may reflect a novel neuroprotective strategy potentially involving retrograde release of adenosine and/or glutamate. PMID- 22842515 TI - Temporal dependence of cysteine protease activation following excitotoxic hippocampal injury. AB - Excitotoxic insults can lead to intracellular signaling cascades that contribute to cell death, in part by activation of proteases, phospholipases, and endonucleases. Cysteine proteases, such as calpains, are calcium (Ca(2+)) activated enzymes which degrade cytoskeletal proteins, including microtubule associated proteins, tubulin, and spectrin, among others. The current study used the organotypic hippocampal slice culture model to examine whether pharmacologic inhibition of cysteine protease activity inhibits N-methyl-D-aspartate- (NMDA-) induced excitotoxic (20 MUM NMDA) cell death and changes in synaptophysin immunoreactivity. Significant NMDA-induced cytotoxicity (as measured by propidium iodide [PI] uptake) was found in the CA1 region of the hippocampus at all timepoints examined (24, 72, 120 h), an effect significantly attenuated by co exposure to the selective NMDA receptor antagonist DL-2-Amino-5 phosphonopentanoic acid (APV), but not MDL-28170, a potent cysteine protease inhibitor. Results indicated sparing of NMDA-induced loss of the synaptic vesicular protein synaptophysin in all regions of the hippocampus by MDL-28170, though only at early timepoints after injury. These results suggest Ca(2+) dependent recruitment of cysteine proteases within 24h of excitotoxic insult, but activation of alternative cellular degrading mechanisms after 24h. Further, these data suggest that synaptophysin may be a substrate for calpains and related proteases. PMID- 22842517 TI - Suppression of heat shock protein 27 expression promotes 5-fluorouracil sensitivity in colon cancer cells in a xenograft model. AB - The present study investigates whether the expression levels of heat shock protein 27 (HSP27) in colon cancer cells are associated with 5-fluorouracil (5 FU) sensitivity in a xenograft model, as well as the mechanism responsible for regulating 5-FU sensitivity. HCT116 cells which have a high expression of HSP27 were stably transfected with specific short hairpin RNA (shRNA) in order to suppress HSP27 expression. The association between HSP27 protein expression levels and 5-FU sensitivity was evaluated in a mouse xenograft model. The mRNA expression of 5-FU metabolic enzymes and cell apoptosis were also analyzed in the transfected cells. The suppression of HSP27 protein expression led to enhanced 5 FU sensitivity. The mRNA expression levels of dihydropyrimidine dehydrogenase and orotate phosphoribosyltransferase, but not those of thymidylate synthase, and the number of apoptotic cells increased in the transfected cells after 5-FU exposure. In conclusion, the suppression of HSP27 expression in colon cancer cells may promote 5-FU sensitivity by inducing apoptosis, despite the acceleration in 5-FU metabolism. PMID- 22842518 TI - NHS must monitor time from presentation to treatment for all child patients, report says. PMID- 22842519 TI - Drug taking and drinking among 11-15 year olds in England have fallen over past 10 years. PMID- 22842520 TI - Mobile phone app from NHS "hack day" is set to transform handovers and task lists. PMID- 22842521 TI - Diversity and evolution of bioenergetic systems involved in microbial nitrogen compound transformations. AB - Nitrogen is an essential element of life that needs to be assimilated in its most reduced form, ammonium. On the other hand, nitrogen exists in a multitude of oxidation states and, consequently, nitrogen compounds (NCs) serve as electron donor and/or acceptors in many catabolic pathways including various forms of microbial respiration that contribute to the global biogeochemical nitrogen cycle. Some of these NCs are also known as reactive nitrogen species able to cause nitrosative stress because of their high redox reactivity. The best understood processes of the nitrogen cycle are denitrification and ammonification (both beginning with nitrate reduction to nitrite), nitrification (aerobic oxidation of ammonium and nitrite) and anaerobic ammonium oxidation (anammox). This review presents examples of the diverse architecture, either elucidated or anticipated, and the high degree of modularity of the corresponding respiratory electron transport processes found in Bacteria and Archaea, and relates these to their respective bioenergetic mechanisms of proton motive force generation. In contrast to the multiplicity of enzymes that catalyze NC transformations, the number of proteins or protein modules involved in connecting electron transport to and from these enzymes with the quinone/quinol pool is comparatively small. These quinone/quinol-reactive protein modules consist of cytochromes b and c and iron-sulfur proteins. Conclusions are drawn towards the evolutionary relationships of bioenergetic systems involved in NC transformation and deduced aspects of the evolution of the biogeochemical nitrogen cycle are presented. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems. PMID- 22842522 TI - Oncosecretomics coupled to bioenergetics identifies alpha-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes. AB - Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed. Meanwhile, methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors. Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable. This profile changes with microenvironmental conditions (eg. substrate availability), the oncogenes activated (and the tumor suppressors inactivated) and the interaction with the stroma (i.e. reverse Warburg effect). Here, we assessed the power of metabolic footprinting (MFP) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes, c-Myc, KLF4 and Oct1. The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells. We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion. To investigate the potential oncogene-mediated alterations in mitochondrial metabolism, we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release. Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration. KLF4 deficiency also stimulated glycolysis, albeit without cellular respiration impairment. In contrast, Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency. MFP revealed that c-Myc, KLF4 and Oct1 altered amino acid metabolism with specific patterns. We identified isoleucine, alpha-aminoadipic acid and GABA (gamma-aminoisobutyric acid) as biomarkers related. Our findings establish the impact of Oct1, KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile. PMID- 22842524 TI - Stromal cell-derived factor-1 alpha (SDF-1alpha) improves neural recovery after spinal cord contusion in rats. AB - Stromal cell-derived factor-1 alpha (SDF-1alpha) is an important cytokine, implicated in the control of stem cell trafficking and bone marrow-derived stem cell mobilization. Generally, SDF-1alpha regulates multiple physiological processes such as embryonic development and organ homeostasis. There is also good evidence that SDF-1alpha and its receptor CXCR4(1) are key regulators of neurorepair processes after brain ischemia and spinal cord injury. In this study, we investigated the influence of chronic intrathecal delivery of SDF-1alpha after spinal cord contusion. After contusion T9, male Wistar rats at the age of 12 weeks were intrathecally treated with SDF-1alpha in different doses (100, 500 and 1000 ng/ml) via an osmotic pump for 28 days. Thereafter, animals were subjected to an open field locomotor test. Behavioral scores were significantly higher in SDF-1alpha treated animals compared to placebo-treated groups. In addition, we evaluated histopathological changes in the spinal cord in the presence or absence of SDF-1alpha. Chronic delivery of SDF-1alpha decreased numbers of apoptotic cells, boosted astroglia and microglia response, induced angiogenesis, and potentiated the number of proliferating cells in a dose-dependent manner. These results clearly indicate an improved functional CNS long-term recovery after spinal cord injury. This behavioral restoration was paralleled by a reduction of apoptosis and changes in neuroinflammatory cells. PMID- 22842523 TI - GABA and glutamate are not colocalized in mossy fiber terminals of developing rodent hippocampus. AB - It has been hypothesized that, in the developing rodent hippocampus, mossy fiber terminals release GABA together with glutamate. Here, we used transgenic glutamic acid decarboxylase-67 (GAD67)-GFP expressing mice and multi-label immunohistochemistry to address whether glutamatergic and GABAergic markers are colocalized. We demonstrate that in the dentate gyrus, interneurons positive for GABA/GAD are sparsely distributed along the edge of the hilus, in a different pattern from that of the densely packed granule cells. Co-staining for synaptophysin and vesicular glutamate transporter1 (VGLUT1) in postnatal day 14 brain sections from both mice and rats showed mossy fiber terminals as a group of large (2-5 MUm in diameter) VGLUT1-positive excitatory presynaptic terminals in the stratum lucidum of area CA3a/b. Furthermore, co-staining for synaptophysin and vesicular GABA transporter (VGAT) revealed a group of small-sized (~0.5 MUm in diameter) inhibitory presynaptic terminals in the same area where identified mossy fiber terminals were present. The two types of terminals appeared to be mutually exclusive, and showed no colocalization. Thus, our results do not support the hypothesis that GABA is released as a neurotransmitter from mossy fiber terminals during development. PMID- 22842525 TI - Alteration of glucose metabolism in cultured astrocytes after AQP9-small interference RNA application. AB - Aquaglyceroporin-9 (AQP9) facilitates diffusion of water and energy substrates such as glycerol and monocarboxylates. AQP9 is present in plasma membrane and mitochondria of astrocytes and catecholaminergic neurons, suggesting that it plays a role in the energetic status of these cells. Using specific small interference RNA directed against AQP9 in astrocyte cultures, we showed that glycerol uptake is decreased which is associated with an increase in glucose uptake and oxidative metabolism. Our results not only confirm the presence of AQP9 in astrocytes but also suggest that changes in AQP9 expression alter glial energy metabolism. PMID- 22842526 TI - Leonurine protects brain injury by increased activities of UCP4, SOD, CAT and Bcl 2, decreased levels of MDA and Bax, and ameliorated ultrastructure of mitochondria in experimental stroke. AB - BACKGROUND: It has been proved that pre-treatment with leonurine could protect brain tissue against ischemic injury by exerting antioxidant effects and regulating mitochondrial function. Whether this protective effect applies to acute phase after cerebral ischemia, we therefore investigate the potential neuroprotective role of leonurine and the underlying mechanisms in cerebral ischemia. METHODS: Focal cerebral ischemia was induced in adult male Sprague Dawley rats by permanent middle cerebral artery occlusion (MCAO). Leonurine was administered intraperitoneally at 7.5 or 15 mg/kg/d at 2h after surgery, then once daily thereafter. Neurological deficit, brain water content, and infarct volume were measured at 24h, 72 h, and 7d after stroke. Superoxide dismutase (SOD), catalase (CAT) activities, and malondialdehyde (MDA) content were also measured by spectrophotometer to evaluate oxidative reactions, and the expression of uncoupling protein 4 (UCP4), Bcl-2, and Bax were detected by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemical staining (IHC), and western blot, while the ultrastructure of the mitochondria were observed under transmission electron microscope. RESULTS: Leonurine significantly alleviated neurological deficit, decreased brain water content and infarct volume after ischemic stroke, which was accompanied by decreased levels of MDA and Bax, increased activities of SOD, CAT, UCP4, and Bcl-2, and restored ultrastructure of mitochondria. CONCLUSIONS: The results showed that leonurine protected brain injury by increased activities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA and Bax, and ameliorated ultrastructure of mitochondria in experimental stroke. PMID- 22842527 TI - Functions of connexins and large pore channels on microglial cells: the gates to environment. AB - Microglial cells are not only sensitive indicators for pathology of the central nervous system (CNS), they are a key factor for neurotoxicity and degeneration in many diseases. Neuronal damage leads to reactive gliosis and to activation of microglia including cytoarchitectonic changes accompanied by alterations in surface receptor and channel expression. In this context, the release of neuroactive soluble factors like pro-inflammatory cytokines can result in increased cellular motility and a higher grade of phagocytotic activity. Ligands including glutamate, tumor necrosis factor alpha (TNF-alpha), cytokines, superoxide radicals and neurotrophins released by microglia have in turn effects on neuronal function and cell death. The current review focuses on large pore and hemichannel function in microglial cells under different conditions of activation and elucidates the role of these channels in cytokine release, as well as putative targets for clinical intervention in case of inflammatory processes. This article is part of a Special Issue entitled Electrical Synapses. PMID- 22842528 TI - Confirmatory factor analysis of the Dutch Intolerance of Uncertainty Scale: Comparison of the full and short version. AB - BACKGROUND AND OBJECTIVES: The Intolerance of Uncertainty Scale (IUS) was developed for assessing reactions to ambiguous situations, uncertainty, and future events. The IUS has been validated in different languages, but equivocal factor structures, in combination with highly interrelated items and factors, resulted in a redundancy of the items of the English version. In the current study, the psychometric properties of the Dutch version of the IUS were examined, and compared with the shortened 12-item version (IUS-12). METHODS: Confirmatory factor analyses were used to investigate different factor structures of both the full and short version of the IUS. RESULTS: Results indicated that the IUS-12 model with two factors (Prospective Anxiety and Inhibitory Anxiety) provides the best fit. The reduced measure has equally good internal consistency, and is highly correlated with the full version. LIMITATIONS: Future research could investigate whether the current findings generalize to clinical populations. CONCLUSION: To summarize, the usage of the short 12-item version of the IUS should be encouraged in future research concerning intolerance of uncertainty. PMID- 22842529 TI - [Brand-new fitness test in magnetic resonance imaging]. PMID- 22842530 TI - Permeability of anodic alumina membranes with branched channels. AB - Mass-transport properties of anodic alumina membranes exploited in a number of technological areas are strongly affected by the real pore structure and arrangement of channels that can split or terminate during the anodization process. This paper focuses on the investigation of pore branching and rearrangement caused by voltage variation in the course of the anodic oxidation of aluminum. Gas-transport measurements were utilized for the quantitative determination of an effective through porosity of multilayer anodic alumina membranes with branched channels obtained by variation of anodization voltage. It was shown that on decrease of anodization voltage a branching of pores occurs, while an increase of anodization voltage leads to the termination of some of the pores with an increase in the diameter of others. Gas permeance measurements combined with electron microscopy unambiguously prove dead-end pore formation on voltage increase, while no pore merging appears. This generally affects any mass transport properties and applications of anodic alumina membranes as the delivery of any species (e.g. ions, gas molecules, etc) through the blocked channels is impossible. PMID- 22842531 TI - Schiff base formation and recognition of amino sugars, aminoglycosides and biological polyamines by 2-formyl phenylboronic acid in aqueous solution. AB - Interactions of 2-, 3- and 4-formyl phenylboronic acids (FPBAs) with sugars, amino sugars, aminoglycosides and various poly- and monoamines have been studied by UV-vis, (1)H and (11)B NMR titrations in water at variable pH. Behavior of 2 FPBA was anomalous in several aspects. Transformation of the acid into its conjugate base was slow in NMR time scale and was accompanied by intramolecular cyclization affording the respective benzoboroxole. The equilibrium constants for imine formation (K(imine)) between 2-FPBA and simple monoamines including amino sugars were ca. 2 orders of magnitude larger than those with other isomers. Still one order of magnitude larger K(imine) values were observed for 2-FPBA with aminoglycosides (kanamycin, amikacin, gentamicin, neomycin) and polyamines (spermine, spermidine). The examination of UV-vis and (11)B NMR spectra of imines formed with 2-FPBA showed that formally neutral Schiff bases in fact were zwitterionic species containing a protonated imine group and an anionic B(OH)(3)( ) group. The enhanced stability of imines with monoamines can therefore be attributed to the electrostatic stabilization provided by the zwitterionic structure and further increased stability of imines with antibiotics and polyamines is explicable by additional stabilization of the borate anionic group by ion paring with ammonium groups not involved in Schiff base formation. Thanks to high molar absorptivity of protonated imines interaction of 2-FPBA with aminoglycosides allows detecting them spectrophotometrically in a MUM concentration range in neutral aqueous solutions in the presence of sugars, amino sugars and amino acids. PMID- 22842532 TI - Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c. AB - Anthocynanins, found in fruits and vegetables, have a variety of protective properties, which have generally been attributed to their antioxidant capacity. However, antioxidants are generally strong reductants, and some reductants have been found to block apoptosis by reducing cytosolic cytochrome c, which prevents caspase activation. We tested the ability of various anthocyanins: to reduce cytochrome c, to support cytochrome c-induced mitochondrial respiration and to inhibit apoptosis induced by heart ischemia. Anthocyanins such as delphinidin-3 glucoside (Dp3G) and cyanidin-3-glucoside (Cy3G) were able to reduce cytochrome c directly and rapidly, whereas pelargonidin-3-glucoside (Pg3G), malvinidin-3 glucoside (Mv3G) and peonidin-3-glucoside (Pn3G) had relatively low cytochrome c reducing activities. Dp3G and Cy3G but not Pg3G supported mitochondrial state 4 respiration in the presence of exogenous cytochrome c. Pre-perfusion of hearts with 20 MUM Cy3G but not Pg3G prevented ischemia-induced caspase activation. This suggests that the ability of anthocyanins to block caspase activation may be due to their ability to reduce cytosolic cytochrome c. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 22842533 TI - Zebrafish: a model animal for analyzing the impact of environmental pollutants on muscle and brain mitochondrial bioenergetics. AB - Mercury, anthropogenic release of uranium (U), and nanoparticles constitute hazardous environmental pollutants able to accumulate along the aquatic food chain with severe risk for animal and human health. The impact of such pollutants on living organisms has been up to now approached by classical toxicology in which huge doses of toxic compounds, environmentally irrelevant, are displayed through routes that never occur in the lifespan of organisms (for instance injecting a bolus of mercury to an animal although the main route is through prey and fish eating). We wanted to address the effect of such pollutants on the muscle and brain mitochondrial bioenergetics under realistic conditions, at unprecedented low doses, using an aquatic model animal, the zebrafish Danio rerio. We developed an original method to measure brain mitochondrial respiration: a single brain was put in 1.5 mL conical tube containing a respiratory buffer. Brains were gently homogenized by 13 strokes with a conical plastic pestle, and the homogenates were immediately used for respiration measurements. Skinned muscle fibers were prepared by saponin permeabilization. Zebrafish were contaminated with food containing 13 MUg of methylmercury (MeHg)/g, an environmentally relevant dose. In permeabilized muscle fibers, we observed a strong inhibition of both state 3 mitochondrial respiration and cytochrome c oxidase activity after 49 days of MeHg exposure. We measured a dramatic decrease in the rate of ATP release by skinned muscle fibers. Contrarily to muscles, brain mitochondrial respiration was not modified by MeHg exposure although brain accumulated twice as much MeHg than muscles. When zebrafish were exposed to 30 MUg/L of waterborne U, the basal mitochondrial respiratory control ratio was decreased in muscles after 28 days of exposure. This was due to an increase of the inner mitochondrial membrane permeability. The impact of a daily ration of food containing gold nanoparticles of two sizes (12 and 50 nm) was investigated at a very low dose for 60 days (40 ng gold/fish/day). Mitochondrial dysfunctions appeared in brain and muscle for both tested sizes. In conclusion, at low environmental doses, dietary or waterborne heavy metals impinged on zebrafish tissue mitochondrial respiration. Due to its incredible simplicity avoiding tedious and time-consuming mitochondria isolation, our one-pot method allowing brain respiratory analysis should give colleagues the incentive to use zebrafish brain as a model in bioenergetics. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 22842534 TI - Presenilins: role in calcium homeostasis. AB - Mutations in presenilins are responsible for the vast majority of early-onset familial Alzheimer's disease cases. Full-length presenilin structure is composed of nine transmembrane domains which are localized on the endoplasmic reticulum membrane. Upon endoproteolytic cleavage, presenilins assemble into the gamma secretase multiprotein complex and subsequently get transported to the cell surface. There is a wealth of knowledge around the role of presenilins as the catalytic component of gamma-secretase, their involvement in amyloid precursor protein processing and generation of neurotoxic beta-amyloid species. However recent findings have revealed a wide range of gamma-secretase-independent presenilin functions, including involvement in calcium homeostasis. Particularly, familial Alzheimer's disease presenilin mutations have been shown to interfere with the function of several molecular elements involved in endoplasmic reticulum calcium homeostasis. Presenilins modulate the activity of IP(3) and Ryanodine receptor channels, regulate SERCA pump function, affect capacitative calcium entry and function per se as endoplasmic reticulum calcium leak conductance pores. PMID- 22842535 TI - Endocannabinoids and the renal proximal tubule: an emerging role in diabetic nephropathy. AB - Diabetic nephropathy is a leading cause for the development of end-stage renal disease. In diabetes mellitus, a number of structural changes occur within the kidney which leads to a decline in renal function. Damage to the renal proximal tubule cells (PTCs) in diabetic nephropathy includes thickening of the basement membrane, tubular fibrosis, tubular lesions and hypertrophy. A clearer understanding of the molecular mechanisms involved in the development of diabetic kidney disease is essential for the understanding of the role cellular pathways play in its pathophysiology. The endocannabinoid system is an endogenous lipid signalling system which is involved in lipogenesis, adipogenesis, inflammation and glucose metabolism. Recent studies have demonstrated that in diabetic nephropathy, there is altered expression of the endocannabinoid system. Future investigations should clarify the role of the endocannabinoid system in the development of diabetic nephropathy and within this system, identify potential therapeutics to reduce the burden of this disease. PMID- 22842536 TI - Arbuzov chemistry with chlorofullerene C60Cl6: a powerful method for selective synthesis of highly functionalized [60]fullerene derivatives. AB - We report Arbuzov-type reactions of chlorofullerene C(60)Cl(6) with trialkyl phosphites producing highly functionalized fullerene derivatives C(60)[P(O)(OR)(2)](5)H with high yields. The designed family of [60]fullerene phosphonic acids and their esters showed unusual properties which might find valuable material science applications. PMID- 22842537 TI - SnO2 nanowall-arrays coated with rutile-TiO2 nanoneedles for high performance dye sensitized solar cells. AB - A novel architecture of SnO(2) nanowall-arrays coated with rutile-TiO(2) nanoneedles is fabricated for the first time and envisaged in dye-sensitized solar cells. Devices constructed using these architectures showed a power conversion efficiency of 4.12%, which is the highest among the SnO(2) nanostructures grown on conducting substrates by wet chemical methods. PMID- 22842538 TI - Effectiveness of 3 surgical decompression strategies for treatment of multilevel cervical myelopathy in 3 spinal centers in China: a retrospective study. AB - STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: To compare clinical outcomes and surgical-related adverse events in patients with multilevel cervical myelopathy (MCM) undergoing simple anterior, simple posterior, or 1-stage posterior-anterior surgical decompression strategies. SUMMARY OF BACKGROUND DATA: Simple anterior, simple posterior, and 1-stage posterior-anterior surgical decompression strategies have been advocated for MCM treatment in both Western and Chinese populations. However, there is limited evidence on whether 1-stage posterior-anterior strategy may offer equal or more advantages than the other 2 strategies for patients with MCM. METHODS: A retrospective review of medical records was conducted for 255 patients with MCM who had undergone surgical decompression in 3 Chinese spinal centers from 1999 to 2010. Neurological status, perioperative variables, and surgical complications were assessed. Multiple linear regression was used to evaluate factors associated with the outcomes of each strategy. RESULTS: Analyses were conducted on a total of 229 patients with MCM undergoing surgical decompression via 1-stage posterior-anterior (68 patients), simple anterior (102 patients), and simple posterior approaches (59 patients). One-stage posterior-anterior approach had the highest Japanese Orthopaedic Association recovery rate after adjusted for age and sex (adjusted mean +/- SD: 50.0 +/- 3.2, P < 0.001) and additionally adjusted for smoking, duration from onset of symptoms to surgery, comorbidities, preoperative Japanese Orthopaedic Association score, Ishihara's curvature index and Pavlov ratio, operative blood loss, operating time, anterior operated disc levels, and posterior operated levels (adjusted mean +/- SD: 51.6 +/- 11.6, P < 0.01). Anterior approach had the largest difference between the pre- and postoperative Ishihara's curvature indexes after adjusted for age and sex (adjusted mean +/- SD: 5.3 +/- 1.0, P < 0.01) and after multivariable adjustment (adjusted mean +/- SD: 6.5 +/- 2.8, P = 0.003). CONCLUSION: One-stage posterior-anterior strategy can be a reliable and effective treatment strategy for MCM in a subgroup of patients with anterior and posterior compression on spinal cord simultaneously. PMID- 22842539 TI - The effect of race on outcomes of surgical or nonsurgical treatment of patients in the Spine Patient Outcomes Research Trial (SPORT). AB - STUDY DESIGN: Retrospective review of the data collected prospectively through the Spine Patient Outcomes Research Trial (SPORT). OBJECTIVE: To determine the effect that race or ethnicity had on outcomes after spine surgery in the 3 arms of SPORT. SUMMARY OF BACKGROUND DATA: There is a dearth of research regarding the effect of race or ethnicity on outcome after treatment of spinal disorders. METHODS: All participants from the 3 arms of the SPORT were evaluated in an as treated analysis, with patients categorized as white, black, or other. Baseline and operative characteristics of the groups were compared using the chi test and analysis of variance. Differences in the changes between baseline and 1-, 2-, 3-, and 4-year time points in the operative and nonoperative treatments were evaluated with a mixed effects longitudinal regression model, and differences between racial groups were compared with a multiple degrees of freedom Wald test. RESULTS: A total of 2427 patients (85% white, 8% black, and 7% other) were included. Surgery was performed on 67% of white patients, 54% of blacks, and 68% of others. Whites and others were significantly more likely to undergo surgery than blacks (67% and 68% vs. 54%, P = 0.003). Complications and the risk of additional surgeries were not significantly different between racial groups. Regardless of race, all patients improved more with surgical management than with nonoperative treatment for all outcome measures at all time points. The average 4 year area-under-the-curve results revealed surgical and nonoperative treatment resulted in statistically significant improvement in whites relative to blacks for SF-36 bodily pain (P < 0.001), physical function (P < 0.001), and Oswestry Disability Index (P < 0.001). No significant differences were noted in treatment effect for primary outcome measures or self-rated progress across racial groups. CONCLUSION: These results illustrate important differences between racial groups in terms of response to spine care. Although there were quantitative differences between groups, these findings are not necessarily indications of health care disparities. PMID- 22842541 TI - Surface enhanced Raman spectroscopy (SERS) for the discrimination of Arthrobacter strains based on variations in cell surface composition. AB - Surface enhanced Raman spectroscopy (SERS) is a rapid and highly sensitive spectroscopic technique that has the potential to measure chemical changes in bacterial cell surface in response to environmental changes. The objective of this study was to determine whether SERS had sufficient resolution to differentiate closely related bacteria within a genus grown on solid and liquid medium, and a single Arthrobacter strain grown in multiple chromate concentrations. Fourteen closely related Arthrobacter strains, based on their 16S rRNA gene sequences, were used in this study. After performing principal component analysis in conjunction with Linear Discriminant Analysis, we used a novel, adapted cross-validation method, which more faithfully models the classification of spectra. All fourteen strains could be classified with up to 97% accuracy. The hierarchical trees comparing SERS spectra from the liquid and solid media datasets were different. Additionally, hierarchical trees created from the Raman data were different from those obtained using 16S rRNA gene sequences (a phylogenetic measure). A single bacterial strain grown on solid media culture with three different chromate levels also showed significant spectral distinction at discrete points identified by the new Elastic Net regularized regression method demonstrating the ability of SERS to detect environmentally induced changes in cell surface composition. This study demonstrates that SERS is effective in distinguishing between a large number of very closely related Arthrobacter strains and could be a valuable tool for rapid monitoring and characterization of phenotypic variations in a single population in response to environmental conditions. PMID- 22842542 TI - Prevention of overfitting in cryo-EM structure determination. PMID- 22842543 TI - Effect of body mass index on the location of the right adrenal vein in patients with primary aldosteronism. AB - BACKGROUND: Variable location of the orifice of the right adrenal vein appears to be associated with a poor success rate of sampling, especially in less experienced hands. We described the spectrum of the location of the right adrenal vein, and identified the relation of its location to body mass index in patients with primary aldosteronism. METHODS: and results: The study population consisted of 95 patients with primary aldosteronism who underwent adrenal venous sampling. On the basis of the anterior view of the right adrenal venogram, the cranio caudal level of the orifice of right adrenal vein was determined relative to vertebral bodies and disks. In 93 (98%) of the 95 patients, the orifice was located at a level ranging from the upper segment of T11 to the upper segment of L1. In the remaining two patients, it was located at the level of the lower segment of T10. High body mass index was associated with the higher level of the orifice of right adrenal vein. CONCLUSION: Our data suggested that the location of the orifice of right adrenal vein was largely related to body mass index in patients with primary aldosteronism. PMID- 22842544 TI - Antimycin A sensitizes cells to TRAIL-induced apoptosis through upregulation of DR5 and downregulation of c-FLIP and Bcl-2. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been the focus as a potential anticancer drug, because it induces apoptosis in a wide variety of cancer cells but not in most normal human cell types. In this study, we showed that combination treatment with sub-toxic doses of antimycin A (AMA), an inhibitor of electron transport, plus TRAIL induced apoptosis in human renal cancer cells, but not in normal tubular kidney cells. Treatment of Caki cells with AMA upregulated the death receptor 5 (DR5) protein and downregulated c-FLIP and Bcl-2 proteins in a dose-dependent manner. AMA-induced decrease of c-FLIPL and c-FLIPs protein levels which were caused by increased protein instability, which was confirmed by the result showing that treatment with a protein biosynthesis inhibitor, CHX, accelerated degradation of c-FLIPL and c-FLIPs proteins caused by AMA treatment. We also found that AMA induced upregulation of DR5 and downregulation of Bcl-2 at the transcriptional level. Pretreatment with N acetyl-l-cysteine (NAC) partly recovered the expression levels of c-FLIPL and c FLIPs proteins were downregulated by the AMA treatment, suggesting that AMA appears to be partially dependent on the generation of ROS for downregulation of c-FLIPL and c-FLIPs. Collectively, this study demonstrates that AMA enhances TRAIL-induced apoptosis in human renal cancer cells by upregulation of DR5 as well as downregulation of c-FLIP and Bcl-2. Furthermore, this study shows that AMA markedly increases sensitivity to cisplatin in Caki human renal cancer cells. PMID- 22842545 TI - Lipid organization regulates annexin A2 Ca(2+)-sensitivity for membrane bridging and its modulator effects on membrane fluidity. AB - Annexin A2 (AnxA2) is a phospholipid binding protein that has been implicated in many membrane-related cellular functions. AnxA2 is able to bind different acidic phospholipids such as phosphatidylserine (PS) and phosphatidylinositol-4,5 bisphosphate (PI2P). This binding is mediated by Ca(2+)-dependent and Ca(2+) independent mechanisms. The specific functions of annexin A2 related to these two phospholipids and the molecular mechanisms involved in their interaction remain obscure. Herein we studied the influence of lipid composition on the Ca(2+) dependency of AnxA2-mediated membrane bridging and on membrane fluidity. Membrane models of ten different lipid compositions and detergent-resistant membranes from two cellular sources were investigated. The results show that the AnxA2-mediated membrane bridging requires 3 to 50 times less calcium for PS-membranes than for PI2P-membranes. Membrane fluidity was measured by the ratiometric fluorescence parameter generalized polarization method with two fluorescent probes. Compared to controls containing low phospholipid ligand, AnxA2 was found to reduce the membrane fluidity of PI2P-membranes twice as much as the PS-membranes in the presence of calcium. On the contrary, at mild acidic pH in the absence of calcium AnxA2 reduces the fluidity of the PS-membranes more than the PI2P-membranes. The presence of cholesterol on the bilayer reduced the AnxA2 capacity to reduce membrane fluidity. The presented data shed light on the specific roles of PI2P, PS and cholesterol present on membranes related to the action of annexin A2 as a membrane bridging molecule during exocytosis and endocytosis events and as a plasma membrane domain phospholipid packing regulator. PMID- 22842546 TI - The lipopeptide toxins anabaenolysin A and B target biological membranes in a cholesterol-dependent manner. AB - The two novel cyanobacterial cyclic lipopeptides, anabaenolysin (Abl) A and B permeabilised mammalian cells, leading to necrotic death. Abl A was a more potent haemolysin than other known biodetergents, including digitonin, and induced discocyte-echinocyte transformation in erythrocytes. The mitochondria of the dead cells appeared intact with regard to both ultrastructure and membrane potential. Also isolated rat liver mitochondria were resistant to Abl, judged by their ultrastructure and lack of cytochrome c release. The sparing of the mitochondria could be related to the low cholesterol content of their outer membrane. In fact, a supplement of cholesterol in liposomes sensitised them to Abl. In contrast, the prokaryote-directed cyclic lipopeptide surfactin lysed preferentially non cholesterol-containing membranes. In silico comparison of the positions of relevant functional chemical structures revealed that Abl A matched poorly with surfactin in spite of the common cyclic lipopeptide structure. Abl A and the plant-derived glycolipid digitonin had, however, predicted overlaps of functional groups, particularly in the cholesterol-binding tail of digitonin. This may suggest independent evolution of Abl and digitonin to target eukaryotic cholesterol-containing membranes. Sub-lytic concentrations of Abl A or B allowed influx of propidium iodide into cells without interfering with their long-term cell viability. The transient permeability increase allowed the influx of enough of the cyanobacterial cyclic peptide toxin nodularin to induce apoptosis. The anabaenolysins might therefore not only act solely as lysins, but also as cofactors for the internalisation of other toxins. They represent a potent alternative to digitonin to selectively disrupt cholesterol-containing biological membranes. PMID- 22842547 TI - In response to: Method of electronic health record documentation and quality of primary care. PMID- 22842548 TI - 1.5Mb deletion of chromosome 4p16.3 associated with postnatal growth delay, psychomotor impairment, epilepsy, impulsive behavior and asynchronous skeletal development. AB - Several Wolf-Hirschhorn syndrome patients have been studied, mouse models for a few candidate genes have been constructed and two WHS critical regions have been postulated, but the molecular basis of the syndrome remains poorly understood. Single gene contributions to phenotypes of microdeletion syndromes have often been based on the study of patients carrying small, atypical deletions. We report a 5-year-old girl harboring an atypical 1.5Mb del4p16.3 and review seven previously published patients carrying a similar deletion. They show a variable clinical presentation and the only consistent feature is post-natal growth delay. However, four of eight patients carry a ring (4), and ring chromosomes in general are associated with growth deficiency. The Greek helmet profile is absent, although a trend towards common dysmorphic features exists. Variable expressivity and incomplete penetrance might play a role in WHS, resulting in difficult clinical diagnosis and challenge in understanding of the genotype/phenotype correlation. PMID- 22842549 TI - Detection and characterization of focal hepatic lesions with diffusion-weighted MR imaging: a pictorial review. AB - The purpose of this pictorial review is to discuss the usefulness and limitations of diffusion-weighted (DW) MR imaging of the liver, demonstrating DW images of a variety of focal hepatic diseases. We include hepatocellular carcinoma, borderline-lesions in cirrhosis, metastasis, cavernous hemangioma, cyst, focal nodular hyperplasia, hepatic adenoma, abscess, and hematoma. DW imaging is an important supplementary sequence of routine MR imaging protocols of the liver. Radiologists need to understand its usefulness and limitations in the detection and characterization of benign and malignant focal hepatic diseases. PMID- 22842550 TI - Interaction of tumor cells with the immune system: implications for dendritic cell therapy and cancer progression. AB - There is a continuous demand for preclinical modeling of the interaction of dendritic cells with the immune system and cancer cells. Recent progress in gene expression profiling with nucleic acid microarrays, in silico modeling and in vivo cell and animal approaches for non-clinical proof of safety and efficacy of these immunotherapies is summarized. Immunoinformatic approaches look promising to unfold this potential, although still unstable and difficult to interpret. Animal models have progressed a great deal in recent years, finally narrowing the gap from bench to bedside. However, translation to the clinic should be done with precaution. The most significant results concerning clinical benefit might come from detailed immunologic investigations made during well designed clinical trials of dendritic-cell-based therapies, which in general prove safe. PMID- 22842551 TI - BreastDefendTM prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. AB - We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers. PMID- 22842553 TI - Selective encapsulation of volatile and reactive methyl iodide. AB - A simple organic molecular container can selectively encapsulate the volatile and highly reactive MeI through hydrogen-bonding interactions in solution. The remarkable encapsulation of MeI without self-methylation of the container appears to be determined by the complementary binding sites and the rigidity of the hydrogen-bonding array constrained by the molecular framework. PMID- 22842552 TI - Hybrid passivated colloidal quantum dot solids. AB - Colloidal quantum dot (CQD) films allow large-area solution processing and bandgap tuning through the quantum size effect. However, the high ratio of surface area to volume makes CQD films prone to high trap state densities if surfaces are imperfectly passivated, promoting recombination of charge carriers that is detrimental to device performance. Recent advances have replaced the long insulating ligands that enable colloidal stability following synthesis with shorter organic linkers or halide anions, leading to improved passivation and higher packing densities. Although this substitution has been performed using solid-state ligand exchange, a solution-based approach is preferable because it enables increased control over the balance of charges on the surface of the quantum dot, which is essential for eliminating midgap trap states. Furthermore, the solution-based approach leverages recent progress in metal:chalcogen chemistry in the liquid phase. Here, we quantify the density of midgap trap states in CQD solids and show that the performance of CQD-based photovoltaics is now limited by electron-hole recombination due to these states. Next, using density functional theory and optoelectronic device modelling, we show that to improve this performance it is essential to bind a suitable ligand to each potential trap site on the surface of the quantum dot. We then develop a robust hybrid passivation scheme that involves introducing halide anions during the end stages of the synthesis process, which can passivate trap sites that are inaccessible to much larger organic ligands. An organic crosslinking strategy is then used to form the film. Finally, we use our hybrid passivated CQD solid to fabricate a solar cell with a certified efficiency of 7.0%, which is a record for a CQD photovoltaic device. PMID- 22842554 TI - Label-free molecular analysis of live Neospora caninum tachyzoites in host cells by selective scanning Raman micro-spectroscopy. AB - A selective scanning method was used to measure spatially resolved Raman spectra of live Neospora caninum tachyzoites colonizing human brain microvascular endothelial cells. The technique allowed the detection of nucleic acids, lipids and proteins linked to the parasites and their cellular micro-environment at ~10* shorter acquisition time compared to raster scanning. PMID- 22842555 TI - Electrospun photosensitive nanofibers: potential for photocurrent therapy in skin regeneration. AB - Poly(3-hexylthiophene) (P3HT) is one of the most promising photovoltaic (PV) polymers in photocurrent therapy. A novel photosensitive scaffold for skin tissue engineering was fabricated by blending P3HT with polycaprolactone (PCL) and electrospun to obtain composite PCL/P3HT nanofibers with three different weight ratios of PCL : P3HT (w/w) of 150 : 2 [PCL/P3HT(2)], 150 : 10 [PCL/P3HT(10)] and 150 : 20 [PCL/P3HT(20)]. The photosensitive properties of the blend solutions and the composite nanofibers of PCL/P3HT were investigated. The incident photon-to electron conversion efficiencies of the PCL/P3HT(2), PCL/P3HT(10), PCL/P3HT(20) were identified as 2.0 * 10(-6), 1.6 * 10(-5) and 2.9 * 10(-5), respectively, which confirm the photosensitive ability of the P3HT-containing scaffolds. The biocompatibility of the scaffold was evaluated by culturing human dermal fibroblasts and the results showed that the proliferation of HDFs under light stimulation on PCL/P3HT(10) was 12.8%, 11.9%, and 11.6% (p <= 0.05) higher than the cell growth on PCL, PCL/P3HT(2) and PCL/P3HT(20), respectively. Human dermal fibroblasts cultured under light stimulation on PCL/P3HT(10) not only showed better cell proliferation but also retained cell morphology similar to the phenotype observed on tissue culture plates (control). Our experimental results suggest novel and potential application of an optimized amount of P3HT-containing scaffold, especially PCL/P3HT(10) nanofibrous scaffold in photocurrent therapy for skin regeneration. PMID- 22842556 TI - Au nanocrystals grown on a better-defined one-dimensional tobacco mosaic virus coated protein template genetically modified by a hexahistidine tag. AB - In this paper, tobacco mosaic virus (TMV) coated protein (CP) was genetically modified by introducing a hexahistidine tag into it for a well-defined one dimensional template, on which Au nanocrystals (NCs) were grown. The results showed that genetic modification could not only ameliorate the one-dimensional structure of the template, but also improve the growth density of Au NCs on the template. This indicated that genetic modification could be an effective method to modulate the structure of the TMVCP template-based nanocomposites allowing for a broader application of them. PMID- 22842558 TI - The da Vinci robotic surgical assisted anterior lumbar interbody fusion: technical development and case report. AB - STUDY DESIGN: Technique development to use the da Vince Robotic Surgical System for anterior lumbar interbody fusion at L5-S1 is detailed. A case report is also presented. OBJECTIVE: To evaluate and develop the da Vinci robotic assisted laparoscopic anterior lumbar stand-alone interbody fusion procedure. SUMMARY OF BACKGROUND DATA: Anterior lumbar interbody fusion is a common procedure associated with potential morbidity related to the surgical approach. The da Vinci robot provides intra-abdominal dissection and visualization advantages compared with the traditional open and laparoscopic approach. METHODS: The surgical techniques for approach to the anterior lumbar spine using the da Vinci robot were developed and modified progressively beginning with operative models followed by placement of an interbody fusion cage in the living porcine model. Development continued to progress with placement of fusion cage in a human cadaver, completed first in the laboratory setting and then in the operating room. Finally, the first patient with fusion completed using the da Vinci robot assisted approach is presented. RESULTS: The anterior transperitoneal approach to the lumbar spine is accomplished with enhanced visualization and dissection capability, with maintenance of pneumoperitoneum using the da Vinci robot. Blood loss is minimal. The visualization inside the disc space and surrounding structures was considered better than current open and laparoscopic techniques. CONCLUSION: The da Vinci robot Surgical System technique continues to develop and is now described for the transperitoneal approach to the anterior lumbar spine. LEVEL OF EVIDENCE: 4. PMID- 22842559 TI - The mechanical performance of cervical total disc replacements in vivo: prospective retrieval analysis of prodisc-C devices. AB - STUDY DESIGN: Prospective retrieval analysis of Prodisc-C cervical total disc replacements (CTDRs) from 24 explanting surgeons during a 6-year period. OBJECTIVE: To determine the in vivo mechanical performance and fixation to bone of explanted Prodisc-C CTDRs. SUMMARY OF BACKGROUND DATA: The nature and quantity of damage sustained by an implanted device has proven to be important in the prediction of clinical longevity. We hypothesized that retrieval analysis of the Prodisc-C will display characteristic modes of wear consistent with increased posterior angulation and translation of the functional spinal unit after resection of the discoligamentous anatomy. METHODS: Thirty CTDRs from 29 patients (mean age, 45.1 +/- 1.9; range, 31-57 yr) after a mean length of implantation of 1.0 +/- 0.2 years (range, 2 d-3.5 yr) were studied. Operative level was C4-C5 in 20% (6 of 30), C5-C6 in 47% (14 of 30), C6-C7 in 20% (6 of 30), and unknown in 13% (4 of 30). Polyethylene and metallic (cobalt chrome molybdenum [CoCrMo]) components were examined using light stereo-microscopy (6X-31X), scanning electron microscopy, and energy dispersive x-ray analysis. RESULTS: CTDRs were explanted for indications of axial pain (n = 9), radicular symptoms (n = 6), atraumatic loosening (n = 6), trauma (n = 5), metal allergy (n = 1), myelopathy (n = 1), hypermobility (n = 1), and unknown (n = 1). Surface area of ongrowth (mean = 7.2 +/- 1.4%) was not associated with operative level (P = 0.37), surgeon reported axial pain (P = 0.56), or atraumatic loosening (P = 0.93). Burnishing consistent with metallic endplate impingement was present in 80% (24 of 30) of retrieved CTDRs, most commonly in the posterior quadrant (P < 0.001). There was no association between implant height (P = 0.19) or depth (P = 0.17) and posterior impingement. Backside wear was not observed on any of the disassembled implants (0 of 16). Third-body wear occurred in 23% (7 of 30) and the donor site was confirmed by scanning electron microscope/energy dispersive x-ray analysis to be the porous-coated surface of the CTDR. CONCLUSION: Early clinical failures of Prodisc-C CTDRs display surface damage evidence of metal endplate-endplate impingement, most commonly posteriorly. Backside wear was not evident; however, third-body wear was found. Future studies will determine the clinical impact of these predominant modes of wear on long-term metal-on-polyethylene semiconstrained CTDR performance. PMID- 22842560 TI - Assessment of pumped mercury vapour adsorption tubes as passive samplers using a micro-exposure chamber. AB - Mercury vapour adsorption tubes manufactured for pumped sampling and analysis have been evaluated for their performance as passive samplers. This has been done by exposing these tubes in a novel micro-exposure chamber. The uptake rates of these tubes have been found to be low (approximately 0.215 ml min(-1)) as compared to bespoke passive samplers for mercury vapour (typically in excess of 50 ml min(-1)). The measured uptake rates were shown to vary significantly between tubes and this was attributed to the variability in the air-sorbent interface and the proportion of the cross sectional area removed by the crimp in the quartz tubes used to secure the sorbent material. As a result of this variability the uptake rate of each tube must be determined using the micro exposure chamber prior to deployment. Results have shown that the uptake rate determined in the micro-exposure chamber is invariant of concentration, and therefore these uptakes rates may be determined at a high mercury vapour concentration for many tubes at once in less than one hour. The uptake rate of the adsorption tubes under these conditions may be determined with a precision of 5%. Measurements made on a limited field trial in indoor and outdoor ambient air have shown that these tubes give results in acceptable agreement with more traditional pumped sampling methods, although longer sampling periods are required in order to reduce the uncertainty of the measurement, which is currently approximately 30%. PMID- 22842561 TI - Observational follow-up study following two cohorts of children with severe pneumonia after discharge from day care clinic/hospital in Dhaka, Bangladesh. AB - OBJECTIVES: To compare the features of relapse, morbidity, mortality and re hospitalisation following successful discharge after severe pneumonia in children between a day care group and a hospital group and to explore the predictors of failures during 3 months of follow-up. DESIGN: An observational study following two cohorts of children with severe pneumonia for 3 months after discharge from hospital/clinic. SETTING: Day care was provided at the Radda Clinic and hospital care at a hospital in Dhaka, Bangladesh. PARTICIPANTS: Children aged 2-59 months with severe pneumonia attending the clinic/hospital who survived to discharge. INTERVENTION: No intervention was done except providing some medications for minor illnesses, if indicated. PRIMARY OUTCOME MEASURES: The primary outcome measures were the proportion of successes and failures of day care at follow-up visits as determined by estimating the OR with 95% CI in comparison to hospital care. RESULTS: The authors enrolled 360 children with a mean (SD) age of 8 (7) months, 81% were infants and 61% were men. The follow-up compliance dropped from 95% at first to 85% at sixth visit. The common morbidities during the follow-up period included cough (28%), fever (17%), diarrhoea (9%) and rapid breathing (7%). During the follow-up period, significantly more day care children (n=22 (OR 12.2 (95% CI 8.2-17.8))) required re-hospitalisation after completion of initial day care compared with initial hospital care group (n=11 (OR 6.1 (95% CI 3.4 10.6))). The predictors for failure were associated with tachycardia, tachypnoea and hypoxaemia on admission and prolonged duration of stay. CONCLUSIONS: There are considerable morbidities in children discharged following treatment of severe pneumonia like cough, fever, rapid breathing and diarrhoea during 3-month period. The findings indicate the importance of follow-up for early detection of medical problems and their management to reduce the risk of death. Establishment of an effective community follow-up would be ideal to address the problem of 'non compliance with follow-up'. TRIAL REGISTRATION: The original randomised control trial comparing day care with hospital care was registered at http://www.clinicaltrials.gov (identifier NCT00455468). PMID- 22842562 TI - MiR-30c: a novel regulator of salt tolerance in tilapia. AB - miRNAs comprise a class of ~22 nt noncoding RNAs that modulate the stability and/or translational potential of their mRNA targets. Emerging data suggest that stress conditions can alter the biogenesis of miRNAs, thereby changing the expression of mRNA targets. Here, we reveal that miR-30c, a kidney-enriched miRNA, emerges as a crucial osmoregulator in Nile tilapia. miR-30c loss of function leads to an inability to respond to osmotic stress. We identify HSP70 as one of the direct regulatory targets of miR-30c. miR-30c directly regulates HSP70 by targeting its 3'-UTR, and inhibition of miR-30c substantially increases HSP70 mRNA level in vivo. Taken together, our experiments suggest that miRNAs participate in a regulatory circuit that allows rapid gene program transitions in response to osmotic stress. miR-30c may be developed as a molecular marker to assist to breed or genetically engineer salt tolerant species. PMID- 22842563 TI - Eicosapentaenoic acid facilitates the folding of an outer membrane protein of the psychrotrophic bacterium, Shewanella livingstonensis Ac10. AB - Polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), are found in various cold-adapted microorganisms. We previously demonstrated that EPA containing phospholipids (EPA-PLs) synthesized by the psychrotrophic bacterium Shewanella livingstonensis Ac10 support cell division, membrane biogenesis, and the production of membrane proteins at low temperatures. In this article, we demonstrate the effects of EPA-PLs on the folding and conformational transition of Omp74, a major outer membrane cold-inducible protein in this bacterium. Omp74 from an EPA-less mutant migrated differently from that of the parent strain on SDS-polyacrylamide gel, suggesting that EPA-PLs affect the conformation of Omp74 in vivo. To examine the effects of EPA-PLs on Omp74 protein folding, in vitro refolding of recombinant Omp74 was carried out with liposomes composed of 1,2 dipalmitoleoyl-sn-glycero-3-phosphoglycerol and 1,2-dipalmitoleoyl-sn-glycero-3 phosphoethanolamine (1:1 molar ratio) with or without EPA-PLs as guest lipids. SDS-PAGE analysis of liposome-reconstituted Omp74 revealed more rapid folding in the presence of EPA-PLs. CD spectroscopy of Omp74 folding kinetics at 4 degrees C showed that EPA-PLs accelerated beta-sheet formation. These results suggest that EPA-PLs act as chemical chaperones, accelerating membrane insertion and secondary structure formation of Omp74 at low temperatures. PMID- 22842564 TI - Bmi-1 confers adaptive radioresistance to KYSE-150R esophageal carcinoma cells. AB - Radiotherapy (RT) is a major modality of cancer treatment. However, tumors often acquire radioresistance, which causes RT to fail. The exact mechanisms by which tumor cells subjected to fractionated irradiation (FIR) develop an adaptive radioresistance are largely unknown. Using the radioresistant KYSE-150R esophageal squamous cell carcinoma (ESCC) model, which was derived from KYSE-150 parental cells using FIR, the role of Bmi-1 in mediating the radioadaptive response of ESCC cells to RT was investigated. The results showed that the level of Bmi-1 expression was significantly higher in KYSE-150R cells than in the KYSE 150 parental cells. Bmi-1 depletion sensitized the KYSE-150R cells to RT mainly through the induction of apoptosis, partly through the induction of senescence. A clonogenic cell survival assay showed that Bmi-1 depletion significantly decreased the radiation survival fraction in KYSE-150R cells. Furthermore, Bmi-1 depletion increased the generation of reactive oxygen species (ROS) and the expression of oxidase genes (Lpo, Noxo1 and Alox15) in KYSE-150R cells exposed to irradiation. DNA repair capacities assessed by gamma-H2AX foci formation were also impaired in the Bmi-1 down-regulated KYSE-150R cells. These results suggest that Bmi-1 plays an important role in tumor radioadaptive resistance under FIR and may be a potent molecular target for enhancing the efficacy of fractionated RT. PMID- 22842565 TI - Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. AB - It is known that glucagon-like peptide-1 (GLP-1) is a hormone secreted postprandially from the L-cells of the small intestine and regulates glucose homeostasis. GLP-1 is now used for the treatment of diabetes because of its beneficial role against insulin resistance. The GLP-1 receptor (GLP-1R) is expressed on many cell types, including macrophages, and GLP-1 suppresses the development of atherosclerosis by inhibiting macrophage function. However, there have so far been few studies that have investigated the significance of GLP-1/GLP 1R signaling in macrophage activation. In the present study, we examined the effect of GLP-1 and exenatide, a GLP-1R agonist, on human monocyte-derived macrophage (HMDM) activation. We found that GLP-1 induced signal transducer and activator of transcription 3 (STAT3) activation. Silencing of GLP-1R suppressed the GLP-1-induced STAT3 activation. In addition, alternatively activated (M2) macrophage-related molecules, such as IL-10, CD163, and CD204 in HMDM, were significantly upregulated by GLP-1. Furthermore, the co-culture of 3T3-L1 adipocytes with GLP-1-treated RAW 264.7 macrophages increased the secretion of adiponectin compared to co-culture of the 3T3-L1 adipocytes with untreated RAW 264.7 macrophages. Our results demonstrate that GLP-1 induces macrophage polarization toward the M2 phenotype, which may contribute to the protective effects of GLP-1 against diabetes and cardiovascular diseases. PMID- 22842566 TI - Clustered DNA methylation changes in polycomb target genes in early-stage liver cancer. AB - Polycomb-group proteins mark specific chromatin conformations in embryonic and somatic stem cells that are critical for maintenance of their "stemness". These proteins also mark altered chromatin modifications identified in various cancers. In normal differentiated cells or advanced cancerous cells, these polycomb associated loci are frequently associated with increased DNA methylation. It has thus been hypothesized that changes in DNA methylation status within polycomb associated loci may dictate cell fate and that abnormal methylation within these loci may be associated with tumor development. To assess this, we examined the methylation states of four polycomb target loci -Trip10, Casp8AP2, ENSA, and ZNF484 - in liver cancer. These four targets were selected because their methylation levels are increased during mesenchymal stem cell-to-liver differentiation. We found that these four loci were hypomethylated in most early stage liver cancer specimens. For comparison, two non-polycomb tumor suppressor genes, HIC1 and RassF1A, were also examined. Whereas the methylation level of HIC1 did not differ significantly between normal and tumor samples, RassF1A was significantly hypermethylated in liver tumor samples. Unsupervised clustering analysis classified the methylation changes within polycomb and non-polycomb targets to be independent, indicating independent epigenetic evolution. Thus, pre deposited polycomb marks within somatic stem cells may contribute to the determination of methylation changes during hepatic tumorigenesis. PMID- 22842567 TI - Biosynthetic mode can determine the mechanism of protein quality control. AB - Proteins trafficking through the endoplasmic reticulum (ER) are topologically diverse. As such, multiple pathways collectively termed ER-associated degradation (ERAD) ensure that protein domains located in the lumen, membrane, and cytosol, are properly folded. The continuous nucleoplasm and cytosol also maintain a network of quality control mechanisms. These center on the Doa10, San1, and Ubr1 ubiquitin ligases. Unlike in the ER, the necessity for multiple pathways here is unclear. With all three factors localized in the nucleus, at least in part, how substrates are individually recognized is unknown. In this study, we show that the mode of biosynthesis can determine the system used for quality control. Targeting and integrating a misfolded protein to the ER membrane makes it an exclusive substrate of Doa10 whereas the soluble form of the same protein makes it a substrate of the San1/Ubr1 E3 system. PMID- 22842568 TI - NMR study of xenotropic murine leukemia virus-related virus protease in a complex with amprenavir. AB - Xenotropic murine leukemia virus-related virus (XMRV) is a virus created through recombination of two murine leukemia proviruses under artificial conditions during the passage of human prostate cancer cells in athymic nude mice. The homodimeric protease (PR) of XMRV plays a critical role in the production of functional viral proteins and is a prerequisite for viral replication. We synthesized XMRV PR using the wheat germ cell-free expression system and carried out structural analysis of XMRV PR in a complex with an inhibitor, amprenavir (APV), by means of NMR. Five different combinatorially (15)N-labeled samples were prepared and backbone resonance assignments were made by applying Otting's method, with which the amino acid types of the [(1)H, (15)N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) [14]. A titration experiment involving APV revealed that one APV molecule binds to one XMRV PR dimer. For many residues, two distinct resonances were observed, which is thought to be due to the structural heterogeneity between the two protomers in the APV:XMRV PR=1:2 complex. PR residues at the interface with APV have been identified on the basis of chemical shift perturbation and identification of the intermolecular NOEs by means of filtered NOE experiments. Interestingly, chemical shift heterogeneity between the two protomers of XMRV PR has been observed not only at the interface with APV but also in regions apart from the interface. This indicates that the structural heterogeneity induced by the asymmetry of the binding of APV to the XMRV PR dimer is transmitted to distant regions. This is in contrast to the case of the APV:HIV-1 PR complex, in which the structural heterogeneity is only localized at the interface. Long-range transmission of the structural change identified for the XMRV PR complex might be utilized for the discovery of a new type of drug. PMID- 22842569 TI - Comparison of gene-trapping efficiency between retroviral and lentiviral vectors in mouse embryonic stem cells. AB - Gene trapping is a method of inserting DNA into the genome at random, generating insertional mutations throughout the genome. The efficiency of retroviral gene trapping is not sufficient in part because of a strong preference for retroviral integration near transcription start sites. In contrast, lentiviral vectors strongly favor integration in the entire region of highly active genes, suggesting that lentiviral vectors would improve the efficiency of gene trapping. In this study, we constructed both lentiviral and retroviral gene-trap vectors and analyzed integration sites in mouse embryonic stem (ES) cells. The frequency of false-positive gene-trap events was about 12-fold higher for the retroviral vector compared to the lentiviral vector. Within intragenic regions, most of the retroviral vector integration sites were found in the 5' untranslated region, while the lentiviral vector integrated uniformly throughout transcriptional units. The trapping efficiency of unique genes was significantly higher for the lentiviral vector (~83%) than for the retroviral vector (~51%). Our data demonstrate that the lentiviral vector can trap the active genes more efficiently than the retroviral vector and will facilitate efficient generation of gene-trap libraries not only in ES cells but also in a wide variety of cell lines and primary cells. PMID- 22842570 TI - Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia. AB - Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p=0.009), whilst high expression of HOXA9 (p<0.0001), Meis1 (p=0.005) and DNMT3A (p=0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples. PMID- 22842571 TI - A rapid and efficient newly established method to detect COL1A1-PDGFB gene fusion in dermatofibrosarcoma protuberans. AB - The detection of fusion transcripts of the collagen type 1alpha1 (COL1A1) and platelet-derived growth factor-BB (PDGFB) genes by genetic analysis has recognized as a reliable and valuable molecular tool for the diagnosis of dermatofibrosarcoma protuberans (DFSP). To detect the COL1A1-PDGFB fusion, almost previous reports performed reverse transcription polymerase chain reaction (RT PCR) using multiplex forward primers from COL1A1. However, it has possible technical difficulties with respect to the handling of multiple primers and reagents in the procedure. The objective of this study is to establish a rapid, easy, and efficient one-step method of PCR using only a single primer pair to detect the fusion transcripts of the COL1A1 and PDGFB in DFSP. To validate new method, we compared the results of RT-PCR in five patients of DFSP between the previous method using multiplex primers and our established one-step RT-PCR using a single primer pair. In all cases of DFSP, the COL1A1-PDGFB fusion was detected by both previous method and newly established one-step PCR. Importantly, we detected a novel COL1A1 breakpoint in exon 5. The newly developed method is valuable to rapidly identify COL1A1-PDGFB fusion transcripts in DFSP. PMID- 22842572 TI - Creation of human cardiac cell sheets using pluripotent stem cells. AB - Although we previously reported the development of cell-dense thickened cardiac tissue by repeated transplantation-based vascularization of neonatal rat cardiac cell sheets, the cell sources for human cardiac cells sheets and their functions have not been fully elucidated. In this study, we developed a bioreactor to expand and induce cardiac differentiation of human induced pluripotent stem cells (hiPSCs). Bioreactor culture for 14 days produced around 8*10(7) cells/100 ml vessel and about 80% of cells were positive for cardiac troponin T. After cardiac differentiation, cardiomyocytes were cultured on temperature-responsive culture dishes and showed spontaneous and synchronous beating, even after cell sheets were detached from culture dishes. Furthermore, extracellular action potential propagation was observed between cell sheets when two cardiac cell sheets were partially overlaid. These findings suggest that cardiac cell sheets formed by hiPSC-derived cardiomyocytes might have sufficient properties for the creation of thickened cardiac tissue. PMID- 22842573 TI - BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition. AB - The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy. PMID- 22842574 TI - Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice. AB - TATA-box binding protein associated factor 1 (TAF1) protein is the largest and the essential component of the TFIID complex in the pathway of RNA polymerase II mediated gene transcription, and it regulates transcription of a large number of genes related to cell division. The neuron-specific isoform of the TAF1 gene (N TAF1), which we reported previously, may have an essential role in neurons through transcriptional regulation of many neuron-specific genes. In the present study, we cloned the full-length cDNA that encodes the mouse homologue of N-TAF1 (N-Taf1) protein. By carrying out of real time RT-PCR, we investigated the expression analysis of the N-Taf1 mRNA in mouse tissues and cell lines. As well as the human N-TAF1, the N-Taf1 showed limited expression in the brain and neuroblastoma, whereas Taf1 expressed elsewhere. Furthermore, in mouse embryo head or mouse brain, mRNA expression of TAF1 changes dramatically during development but N-Taf1 showed sustained expression. Our result suggests that the N-Taf1 gene has an important role in non-dividing neuronal cell rather than in cell division and proliferation during neurogenesis. PMID- 22842575 TI - Stress-induced interaction between p38 MAPK and HSP70. AB - p38 MAPK, one of the four MAPK subfamilies in mammalian cells, is activated by environmental stresses and pro-inflammatory cytokines, playing fundamental roles in many biological processes. Despite all that is known on the structure and functions of p38, many questions still exist. The coupling of activation and nuclear translocation represents an important aspect of p38 signaling. In our effort in exploring the potential chaperone for p38 translocation, we performed an endogenous pull-down assay and identified HSP70 as a potential interacting protein of p38. We confirmed the interaction between p38 and HSP70 in vitro and in vivo, and identified their interaction domains. We also showed stress-induced nuclear co-localization of these two proteins. Our preliminary result indicated that HSP70 was related to the phosphorylation of MK2, a specific nuclear downstream target of p38, suggesting HSP70 is a potential chaperone for the nuclear translocation of p38. PMID- 22842576 TI - Cryptotanshinone and tanshinone IIA enhance IL-15-induced natural killer cell differentiation. AB - Natural killer (NK) cells are a subset of lymphocytes crucial for innate and adaptive immune responses. Here we show a stimulatory effect of cryptotanshinone (CTS) and tanshinone IIA (TS), isolated from Salvia miltiorrhiza Bunge, on the differentiation of NK cells. In the presence of IL-15, tanshinones increased NK cell maturation, NK cell differentiation and the expression of several transcription factors, including Id2, GATA3, T-bet, and Ets-1. Additionally, tanshinones increased p38 MAPK phosphorylation during NK cell differentiation. Furthermore, the p38 inhibitor SB203580 blocked the developmental effects of the tanshinones and suppressed Id2, T-bet, and Ets-1 expression during NK cell differentiation. These results suggest that tanshinones significantly increased IL-15-induced NK cell differentiation via enhancing the p38 phosphorylation and the expression of transcription factors. PMID- 22842577 TI - Tumor cells can evade dependence on autophagy through adaptation. AB - The autophagy-lysosome and the proteasome constitute the two major intracellular degradation systems. Suppression of the proteasome promotes autophagy for compensation and simultaneous inhibition of autophagy can selectively increase apoptosis in transformed cells, but not in untransformed or normal cells. Transformed cells are thus more dependent on autophagy for survival. However, it is unclear whether long-term autophagy inhibition/insufficiency would affect such dependency. To address this question, we transformed wild-type and autophagy deficient cells lacking a key autophagy-related gene Atg5 with activated Ras. We found that such transformation did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumor cells, although the transformed cells were in general more sensitive to proteasome inhibition. We then compared the effect of acute versus constitutive knock-down of a key autophagy initiating molecule, Beclin 1, in an already transformed cancer cell line. In a wild-type U251 glioblastoma cell line (autophagy intact), increased sensitivity to proteasome inhibition was induced immediately after the knock-down of Beclin 1 expression with a specific siRNA (acute autophagy deficiency). On the other hand, when the tumor cell line was selected over a long period to achieve constitutive knock-down of Beclin 1, its sensitivity to proteasome inhibitors was no higher than that of the wild-type tumor cells. These results suggest that long-term autophagy deficiency either before or after oncogenic transformation can render the tumor cell survival independent of the autophagic activity, and the response to chemotherapy is no longer affected by the manipulation of the autophagy status. PMID- 22842578 TI - Increased secretion of insulin and proliferation of islet beta-cells in rats with mesenteric lymph duct ligation. AB - BACKGROUND & AIMS: It has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet beta-cells in rats. METHODS: Male Sprague-Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of beta-cells was assessed immunohistochemically using antibodies against insulin and Ki-67. RESULTS: During the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p<0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p<0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p<0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p<0.05) and 120 min (2.5-fold; p<0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2 min (more than 1.4-fold; p<0.05). Immunohistochemistry showed that the ratios of beta-cell area/acinar cell area and beta-cell area/islet area, and also beta-cell proliferation, were significantly higher in the ligation group than in the sham group (p<0.05, p<0.01 and p<0.01, respectively). The insulin content per unit wet weight of pancreas was also significantly increased in the ligation group (p<0.05). CONCLUSIONS: In rats with ligation of the mesenteric lymph duct, insulin secretion during the OGTT or IVGTT was higher, and the insulin content and beta-cell proliferation in the pancreas were also increased. Our data show that mesenteric lymph duct flow has a role in glucose metabolism. PMID- 22842579 TI - The anti-carcinogenic effect of statins in a rat model correlates with levels and synthesis of ubiquinone. AB - Ubiquinone (Q) is a product in the cholesterol synthesis pathway and is an essential component of the respiratory chain in the mitochondrial membrane. In addition, extra-mitochondrial Q has anti-oxidative properties and this fraction is increased during carcinogenesis. The aim of the present study was to investigate if extra-mitochondrial level of Q is affected by statin treatment in a rat model for liver cancer, and if this change correlates with inhibited carcinogenesis. To do this we isolated sub-cellular fractions of rat livers from a previous experiment where we have shown anti-carcinogenic effects of statins. The levels of Q(8), Q(9) and Q(10) were analysed with liquid chromatography-mass spectrometry. The Q(9)-levels, constituting the major part of Q in rats, were not significantly affected in any of the sub-cellular compartments. The levels of Q(10), constituting a minor part of Q in rats but the major part of Q in humans, were significantly decreased by about 60% in the statin treated rats. The decrease was present in all sub-cellular compartments, but was most pronounced in the cytosol. There was a significant correlation between extra-mitochondrial Q(10) levels and inhibited carcinogenesis. No such correlation was observed with extra-mitochondrial Q(9). The reduced Q(10)-levels might be explained by the reduced availability of isoprene units during statin treatment, shifting the synthesis towards isoforms with shorter side-chains. In line with this hypothesis there were increased levels of Q(8)-levels during statin treatment. The results support our previous suggestion that at least part of the anti-carcinogenic effect of statins in our rat model is mediated by effects on synthesis of Q. We also demonstrate a shift in the Q-synthesis pathway towards isoforms with shorter side-chains during statin treatment. The ratio between the different Q-isoforms might be used as a more sensitive marker of statin-induced inhibition of Q than measuring total Q levels. PMID- 22842580 TI - Effects of high fat diet on GPR109A and GPR81 gene expression. AB - GPR109A (PUMA-G, NIACR1, HCA(2)) and GPR81 (HCA(1)) are G protein-coupled receptors located predominantly on adipocytes that mediate anti-lipolytic effects. These cell surface receptors give the adipocyte the ability to "sense" metabolic changes in the environment and respond through lipolytic regulation and release of products including free fatty acids and pro- or anti-inflammatory adipokines. The endogenous ligands for GPR109A and GPR81 are beta-hydroxybutyrate and lactate, respectively, both of which are hydroxycarboxylic acids and intermediates of energy metabolism. Circulating beta-hydroxybutyrate levels are increased during a 2-3 day fast and prolonged starvation, while lactate levels are elevated during times of intense exercise. Therefore, regulation of expression of these receptors is crucial for the metabolic sensing ability of the adipocyte and ultimately whole body energy homeostasis. We investigated the effects of high fat diet-induced obesity on expression of GPR109A and GPR81. Sixteen male C57BL/6 mice were placed on a control (10% kcal fat; n=8) or a high fat (60% kcal fat; n=8) diet for 11 weeks. Diet-induced obesity significantly reduced GPR109A and GPR81 gene expression in epididymal fat pads. This decrease in GPR109A and GPR81 gene expression was positively correlated with a decrease in adipose tissue PPARgamma gene expression. In contrast, acute treatment of both 3T3-L1 adipocytes and RAW 264.7 macrophages with lipopolysaccharide significantly increased GPR109A gene expression, but had no effect on GPR81 expression in 3T3 L1 adipocytes. In conclusion, chronic obesity reduces GPR109A and GPR81 expression in the adipose tissue, while acute in vitro LPS treatment increases expression of GPR109A in adipocytes and macrophages. PMID- 22842581 TI - Differential susceptibility of human primary aortic and coronary artery vascular cells to RNA interference. AB - BACKGROUND: RNAi technology is a promising tool for gene therapy of vascular disease. However, the biological heterogeneity between endothelial (EC) and vascular smooth muscle cells (SMC) and within different vascular beds make them differentially susceptible to siRNA. This is further complicated by the task of choosing the right transfection reagent that leads to consistent gene silencing across all cell types with minimal toxicity. The goal of this study was to investigate the intrinsic RNAi susceptibility of primary human aortic and coronary artery endothelial and vascular smooth muscle cells (AoEC, CoEC, AoSMC and CoSMC) using adherent cell cytometry. METHODS: Cells were seeded at a density of 5000cells/well of a 96well plate. Twenty four hours later cells were transfected with either non-targeting unlabeled control siRNA (50nM), or non targeting red fluorescence labeled siRNA (siGLO Red, 5 or 50nM) using no transfection reagent, HiPerFect or Lipofectamine RNAiMAX. Hoechst nuclei stain was used to label cells for counting. For data analysis an adherent cell cytometer, Celigo was used. RESULTS: Red fluorescence counts were normalized to the cell count. EC displayed a higher susceptibility towards siRNA delivery than SMC from the corresponding artery. CoSMC were more susceptible than AoSMC. In all cell types RNAiMAX was more potent compared to HiPerFect or no transfection reagent. However, after 24h, RNAiMAX led to a significant cell loss in both AoEC and CoEC. None of the other transfection conditions led to a significant cell loss. CONCLUSION: This study confirms our prior observation that EC are more susceptible to siRNA than SMC based on intracellular siRNA delivery. RNAiMax treatment led to significant cell loss in AoEC and CoEC, but not in the SMC populations. Additionally, this study is the first to demonstrate that coronary SMC are more susceptible to siRNA than aortic SMC. PMID- 22842583 TI - Understanding the gap in primary care access and use between teens and younger children. AB - Primary health care use among teenagers falls short of clinical recommendations and consistently lags behind that of younger children. Using the Medical Expenditure Panel Survey, the authors explore three explanations for this age related gap: family composition, parental awareness of children's health care needs, and the relative role of predisposing, enabling, and need-based factors for teens and younger children. Teenagers are 64% more likely to have no usual source of care and 25% more likely to have had no health care visit in the prior year relative to younger children. The gap narrows in families with children from both age-groups and among children with special health care needs. The largest disparity in primary care access exists between teens in families with no younger sibling(s) and younger children in families with no teen(s). A resolution to the age-related access gap will likely require understanding of, and intervention into, family-level determinants of poor access. PMID- 22842582 TI - Akt expression and compartmentalization in prediction of clinical outcome in HER2 positive metastatic breast cancer patients treated with trastuzumab. AB - Trastuzumab is effective in about half of HER2-positive breast cancer patients. The PI3K/Akt signalling pathway plays an important role in the process of primary and secondary resistance to anti-HER2 targeted therapy. We evaluated the relationship between expression, activation and subcellular localization of selected Akt isoforms and response to trastuzumab-based anti-HER2 targeted therapy in patients with HER2-positive metastatic breast cancer. Seventy-four women with verified HER2-positive breast cancer were treated with trastuzumab for metastatic disease. Immunohistochemistry was used to evaluate Akt1, Akt2, pAkt Thr308 and pAkt Ser473 expression. For pAkt, cytoplasmic and nuclear fractions were assessed separately. Even though Akt isoforms were expressed in the majority of tumours, activated Akt (pAkt) was present in the cytoplasm only and not in the nucleus in >20% of tumours, and there was no pAkt at all in another 7-13% of tumours. Patients whose tumours showed strong Akt2 expression and had pAkt (pAkt Thr308 and/or pAkt-Ser473) detectable in the cytoplasm as well as nucleus (n+c), exhibited improved time to progression (TTP) and overall survival from the initiation of trastuzumab therapy (OSt). Patients with tumours with strong Akt2 and pAkt Thr308 (n+c) had superior TTP (17.0 vs. 7.6 months, P=0.024; HR 0.52) and OSt (51.8 vs. 16.8 months, P=0.0009; HR 0.34) compared to other tumours. Similar results were found for strong Akt2 and pAkt Ser473 (n+c): TTP 13.1 vs. 7.2 months (P=0.085, HR 0.62) and OSt 50.8 vs. 17.0 months (P=0.009; HR 0.45). This study is the first to prove the significance of Akt kinase isoform, activity and compartmentalization for the prediction of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer. PMID- 22842584 TI - In vitro inhibition of mitochondrial respiratory rate by antidepressants. AB - Mitochondria represent a possible drug target with unexplored therapeutic and toxicological potential. The possibility was suggested that antidepressants, mood stabilizers and other drugs may show some therapeutic and/or toxic effects through their action on mitochondrial functions. There are no sufficient data about the effect of these drugs on mitochondrial respiration in the brain. We investigated the in vitro effects of amitriptyline, fluoxetine, tianeptine, ketamine, lithium, valproate, olanzapine, chlorpromazine and propranolol on mitochondrial respiration in crude mitochondrial fractions of pig brains. Respiration was energized using substrates of complex I or complex II and dose dependent drug-induced changes in mitochondrial respiratory rate were measured by high-resolution respirometry. Antidepressants, but not mood stabilizers, ketamine and propranolol were found to inhibit mitochondrial respiratory rate. The effective dose of antidepressants reaching half the maximal respiratory rate was in the range of 0.07-0.46 mmol/L. Partial inhibition was found for all inhibitors. Differences between individual drugs with similar physicochemical properties indicate selectivity of drug-induced changes in mitochondrial respiratory rate. Our findings suggest that mood stabilizers do not interfere with brain mitochondrial respiration, whereas direct mitochondrial targeting is involved in mechanisms of action of pharmacologically different antidepressants. PMID- 22842585 TI - Rosiglitazone, a PPAR-gamma agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. AB - Rosiglitazone is a commonly prescribed insulin-sensitizing drug with selective agonistic activity at the peroxisome proliferator-activated receptor-gamma (PPARgamma). Previously, rosiglitazone was shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), an effect attributed to its anti-inflammatory properties. To elucidate the neuroprotective mechanisms of rosiglitazone, we investigated the effects of rosiglitazone on the expressions of striatal tyrosine hydroxylase (TH), cyclooxygenase-2 (COX-2) and glial fibrillary acidic protein (GFAP) in a 6-OHDA-lesioned rat PD model. Rosiglitazone (3 mg/kg) was administered intraperitoneally at 24 h and 30 min prior to the creation of an intranigral 6-OHDA lesion. A reduction in TH protein expression began at 3 days and a prominent decrease was observed at 7 days post-lesion, and decreases of dopamine (DA) levels began at 1 day post-lesion. In contrast, GFAP expression was significantly increased at 3 days and preserved for up to 7 days post-lesion and the patterns of GFAP expression was inversely correlated to changes in TH expression. Furthermore, COX-2 expression in the rostral striatum showed a significant increase at 6h post-lesion while that of the caudal striatum was increased at 12 h. In the 6-OHDA-lesioned model, the activation of PPARgamma by rosiglitazone significantly prevented TH protein expression reductions, and inhibited 6-OHDA-induced microglia activation in striatum. In addition, rosiglitazone attenuated in production of both COX-2 and TNF-alpha expression. In contrast, rosiglitazone pretreatment led to greater increases in striatal GFAP expression than 6-OHDA alone and changes in the expression of this protein preceded the changes that were seen with TH expression. These results suggest that the neuroprotection observed with rosiglitazone treatment may be partially due to the attenuation of COX-2 production and the strengthening of astrocyte function. Our results provide insight into the neuroprotective mechanisms of rosiglitazone against 6-OHDA-induced neuronal damages. PMID- 22842586 TI - Role of regulatory T cells in the induction of atopic dermatitis by immunosuppressive chemicals. AB - Immunosuppressive environmental chemicals may exacerbate allergic diseases, including atopic dermatitis (AD). We examined the effects of the immunosuppressive environmental chemicals methoxychlor, parathion, piperonyl butoxide, dexamethasone, and cyclophosphamide on picryl-chloride-induced AD in NC/Nga mice. Mice were orally exposed (age, 5 weeks) to these chemicals; during their sensitization and challenge (age, 8-12 weeks) with picryl chloride, we measured ear thickness and scored skin dryness, erythema, edema, and wounding. After the challenge, we analyzed dermatitis severity and cytokine gene expression in the pinna, serum levels of IgE and IgG2a, T- and B-cell numbers and cytokine production in auricular lymph nodes, and counted splenic regulatory T cells. Exposure to environmental immunosuppressive chemicals markedly increased dermatitis severity and gene expression in the pinna; serum IgE and IgG2a levels; and numbers of helper T cells and IgE-positive B cells, production of Th1 and Th2 cytokines, and production of IgE in auricular lymph-node cells and markedly decreased the numbers of splenic regulatory T cells. Prior exposure to immunosuppressive environmental chemicals aggravates AD; a decrease in the numbers of regulatory T cells may influence this process. PMID- 22842588 TI - Cholesteryl ester accumulation and accelerated cholesterol absorption in intestine-specific hormone sensitive lipase-null mice. AB - Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. The physiological role of this enzyme in enterocytes, however, stayed elusive. In the present study we generated mice lacking HSL exclusively in the small intestine (HSLiKO) to investigate the impact of HSL deficiency on intestinal lipid metabolism and the consequences on whole body lipid homeostasis. Chow diet-fed HSLiKO mice showed unchanged plasma lipid concentrations. In addition, feeding with high fat/high cholesterol (HF/HC) diet led to unaltered triglyceride but increased plasma cholesterol concentrations and CE accumulation in the small intestine. The same effect was observed after an acute cholesterol load. Gavaging of radioactively labeled cholesterol resulted in increased abundance of radioactivity in plasma, liver and small intestine of HSLiKO mice 4h post-gavaging. However, cholesterol absorption determined by the fecal dual isotope ratio method revealed no significant difference, suggesting that HSLiKO mice take up the same amount of cholesterol but in an accelerated manner. mRNA expression levels of genes involved in intestinal cholesterol transport and esterification were unchanged but we observed downregulation of HMG-CoA reductase and synthase and consequently less intestinal cholesterol biosynthesis. Taken together our study demonstrates that the lack of intestinal HSL leads to CE accumulation in the small intestine, accelerated cholesterol absorption and decreased cholesterol biosynthesis, indicating that HSL plays an important role in intestinal cholesterol homeostasis. PMID- 22842589 TI - The membrane binding kinetics of full-length PKCalpha is determined by membrane lipid composition. AB - Protein kinase Calpha (PKCalpha) is activated by its translocation to the membrane. Activity assays show the importance of PIP(2) in determining the specific activity of this enzyme. A FRET stopped flow fluorescence study was carried out to monitor the rapid kinetics of protein binding to model membranes containing POPC/POPS/DOG and eventually PIP(2). The results best fitted a binding mechanism in which protein bound to the membrane following a two-phase mechanism with a first bimolecular reaction followed by a slow unimolecular reaction. In the absence of PIP(2), the rapid protein binding rate was especially dependent on POPS concentration. Formation of the slow high affinity complex during the second phase seems to involve specific interactions with POPS and DOG since it is only sensitive to changes within relatively low concentration ranges of these lipids. Both the association and dissociation rate constants fell in the presence of PIP(2). We propose a model in which PKCalpha binds to the membranes via a two step mechanism consisting of the rapid membrane initial recruitment of PKCalpha driven by interactions with POPS and/or PIP(2) although interactions with DOG are involved too. PKCalpha searches on the lipid bilayer in two dimensions to establish interactions with its specific ligands. PMID- 22842590 TI - Cannabinoids inhibit peptidoglycan-induced phosphorylation of NF-kappaB and cell growth in U87MG human malignant glioma cells. AB - Nuclear factor (NF)-kappaB is the key transcription factor involved in the inflammatory responses, and its activation aggravates tumors. Peptidoglycan (PGN), a main cell wall component of Gram-positive bacteria, stimulates Toll-like receptor 2 (TLR-2) and activates a number of inflammatory pathways, including NF kappaB. Cannabinoids have been reported to exert anti-inflammatory and antitumor effects. The mechanisms underlying these actions, however, are largely unknown. The purpose of this study was to investigate whether cannabinoids can suppress the PGN-induced activation of NF-kappaB and cell growth via cannabinoid receptors in U87MG human malignant glioma cells. PGN treatment induced the phosphorylation of NF-kappaB and cell proliferation in a concentration-dependent manner. The main endocannabinoid, 2-arachidonoylglycerol, prevented the PGN-induced phosphorylation of NF-kappaB, which was reversed by the CB1 cannabinoid receptor antagonist, AM281. The synthetic cannabinoid, WIN55,212-2, abolished the PGN activated cell growth, and this effect was reversed by AM281. The preferential expression of CB1 rather than CB2 receptors in these cells was confirmed by reverse transcription-mediated polymerase chain reaction experiments and the observation that the WIN55,212-2-induced morphological changes were completely reversed by AM281 but not by the CB2 antagonist, AM630. Our finding that cannabinoids suppress the NF-kappaB inflammatory pathway and cell growth via CB1 receptors in glioma cells provides evidence for the therapeutic potential of targeting cannabinoid receptors for the treatment of inflammation-dependent tumor progression. PMID- 22842591 TI - Assessing PAH removal from clayey soil by means of electro-osmosis and electrodialysis. AB - Polycyclic aromatic hydrocarbons (PAH) are persistent and toxic contaminants which are difficult to remove from fine porous material like clayey soils. The present work aims at studying two electroremediation techniques for the removal of PAHs from a spiked natural silt soil from Saudi Arabia and a silty loam soil from The Netherlands which has been exposed to tar contamination for over 100 years. The two techniques at focus are electro-osmosis and electrodialysis. The latter is applied for the first time for the removal of PAH. The efficiency of the techniques is studied using these two soils, having been subjected to different PAH contact times. Two surfactants were used: the non-ionic surfactant Tween 80 and anionic surfactant sodium dodecyl sulphate (SDS) to aid desorption of PAHs from the soil. Results show a large discrepancy in the removal rates between spiked soil and long-term field contaminated soil, as expected. In spiked soil, electro-osmosis achieves up to 85% while electrodialysis accomplishes 68% PAH removal. In field contaminated soil, electro-osmosis results in 35% PAH removal whereas electrodialysis results in 79%. Short recommendations are derived for the up-scale of the two techniques. PMID- 22842592 TI - Analytical approach and occurrence for the determination of mass concentration of PCDD/PCDF and dl-PCB in flue gas emissions using long-term sampling devices. AB - In this work, a reliable methodology for the simultaneous analysis of PCDD/PCDF and dioxin-like PCB (dl-PCB) in flue gas emissions collected using continuous sampling devices is proposed. The analytical scheme followed the minimum requirements described in the EU standard EN-1948:1,2,3,4 according to samples containing large amounts of dioxins and dl-PCBs or samples collected over a long period of time of about 4 weeks. Parameters, such as reproducibility, precision, limits of detection (LOD), limits of quantification (LOQ), extract aliquot size, analytical blanks, extraction efficiency, as well as the amount of internal standards required for an accurate determination, were assessed. The findings demonstrate the suitability of the proposed analytical scheme for the analysis of PCDD/PCDF and PCB in samples collected using long-term sampling devices. The analysis of five different 5% v/v sample aliquots reported %RSD values lower than 10% for all of the 29 congeners at both low and high levels. Similarly, %RSD values were 3.2 and 2.0 for the low level samples and 0.9 and 1.1%RSD for the high level extracts for PCDD/PCDF and dl-PCB, respectively expressed in total TEQ units. Re-extraction provided values less than 3%, expressed in TEQ. Based on blank analyses, LOD values of 100 pg I-TEQ for PCDD/PCDF and 10 pg WHO-TEQ for dl PCB were achieved when 5% v/v aliquots were analyzed. Finally, the proposed analytical approach was tested with samples from a wide range of combustion processes such as hazardous and municipal waste incinerators, as well as cement kilns (with and without waste co-incineration). PMID- 22842593 TI - Anthropogenic and geogenic impacts on arsenic bioaccessibility in UK topsoils. AB - Predictive linear regression (LR) modelling between bioaccessible arsenic (B-As) and a range of total elemental compositions and soil properties was executed in order to assess the potential for developing a national B-As dataset for the UK. LR indicates that total arsenic (As) is the only highly significant independent variable for estimating B-As in urban areas where it explains 75-92% of the variance. The broad compatibility of the London, Glasgow and Swansea regression models suggests that application of these models to estimate bioaccessible As in UK soils impacted by diffuse anthropogenic urban contamination and non-ferrous metal processing should be relatively accurate. In areas dominated by Jurassic ironstones and associated clays and limestones, total As, P and pH are significant, accounting for 53, 14 and 5%, respectively, of the B-As variance. Models based on total As as the sole predictor in the combined Jurassic and Cretaceous sedimentary ironstones datasets explain about 40% of the B-As variance. The median As bioaccessible fraction (%As-BAF) is 19 to 28% in the anthropogenic contamination impacted urban domains, but much lower (5-9%) in geogenic terrains dominated by ironstones. Results of this study can be used as part of a lines of evidence approach to localised risk assessment but should not be used to replace bioaccessibility testing at individual sites where local conditions may vary considerably from the broad overview presented in this study. PMID- 22842594 TI - Comparative assessments of VOC emission rates and associated health risks from wastewater treatment processes. AB - With the growing concern regarding emission of volatile organic compounds (VOCs) from wastewater treatment plants (WWTPs), the relationship between the VOC emission rates and the associated public health risks has been rarely discussed. The objective of this study was to examine and compare the VOC emission rates and cancer and non-cancer risks by inhalation intake, using a municipal WWTP in China as an example, with respect to the effects of treatment technologies, VOC species, and seasonal variation. Given the treatment technology considered, the emission rates of VOCs in this study were estimated by means of mass balance or calculated on the molecular level. From the viewpoints of both emission rates and cancer and non-cancer risks, sedimentation was the treatment technology with the highest health risks to the workers. Slightly lower VOC emission rates and health risks than those for sedimentation were observed in anaerobic treatment. Although the aeration significantly enhanced the VOC emission rates in the aerobic treatment process, the associated health risks were limited due to the low VOC concentrations in the gas phase, which were likely attributed to the strong mixing and dilution with fresh air by aeration. Amongst the VOCs investigated, benzene was the VOC with both a relatively high emission rate and health risk, while trichloroethylene possessed a high emission rate but the lowest health risk. Without strong interfacial aeration and turbulence between the water and atmosphere, the effects of treatment technology and seasonal variation on the health risks might be connected to the VOC emission rates, while the effect of VOC species depended considerably on the respective cancer slope factors and reference concentrations; the employment of aeration provided a different conclusion in which the emission rates were enhanced without a significant increase in the related cancer risks. These findings can provide insight into future health risk management and reduction strategies for workers in WWTPs. PMID- 22842595 TI - Cross-talk between virus and host innate immunity in pediatric HIV-1 infection and disease progression. AB - Variability in the susceptibility to HIV-1 infection and disease progression depends on both virus and host determinants. Some exposed individuals remain HIV 1-uninfected and HIV-1-infected subjects develop disease at varying intervals with a small percentage remaining long-term non-progressors. As innate immunity is the earliest response to microbial entry and injury, host factors that impact innate immunity may play a role in viral infectivity and pathogenesis. In the pediatric population the interactions between the virus and the host may be of particular relevance due to the still developing adaptive immune system. Data indicate that genetic variants of defensins and Toll-Like Receptors (TLRs), key elements of innate immunity, play a role in mother-to-child transmission (MTCT) of HIV-1, and in the outcome of pediatric HIV-1 disease. Although the mechanisms by which these genetic variants influence HIV-1 interactions with the host are still largely unknown, defensins and TLRs, along with their link with regulatory T cells (Tregs), may play a critical role in the onset and persistence of immune activation, a hallmark of HIV-1 disease. PMID- 22842597 TI - Human cytomegalovirus end-organ disease is associated with high or low systemic viral load in preemptively treated solid-organ transplant recipients. AB - Human cytomegalovirus (HCMV) end-organ disease in solid-organ transplant recipients (SOTR) may be associated with either high or low HCMV load in blood. In transplantation Centers where the preemptive therapy approach is adopted, antiviral therapy of systemic HCMV infections is initiated upon reaching pre determined cut-off levels of viral DNA in blood, whereas no guidelines are provided for local end-organ infection/disease. In the latter case, clinicians often start antiviral treatment without defining the etiology of local symptoms. Here, we describe 14 cases of SOTR, in which a documented HCMV end-organ disease was observed. Nine patients had a systemic viral load lower than the cut-off for preemptive therapy and were treated based on viral load of local HCMV disease. The remaining five patients had a systemic viral load greater than the preemptive therapy cut-off and were efficiently treated for both the systemic and the local HCMV disease. Thus, HCMV infection in the post-transplant period must be monitored virologically both in blood and locally. End-organ disease in preemptively treated patients, seems to be associated with lack of development (primary HCMV infection) or reconstitution (reactivated infection) of HCMV specific CD4+ and CD8+ T-cell immunity or with its functional impairment. PMID- 22842598 TI - A phage display vector optimized for the generation of human antibody combinatorial libraries and the molecular cloning of monoclonal antibody fragments. AB - A novel phagemid vector, named pCM, was optimized for the cloning and display of antibody fragment (Fab) libraries on the surface of filamentous phage. This vector contains two long DNA "stuffer" fragments for easier differentiation of the correctly cut forms of the vector. Moreover, in pCM the fragment at the heavy chain cloning site contains an acid phosphatase-encoding gene allowing an easy distinction of the Escherichia coli cells containing the unmodified form of the phagemid versus the heavy-chain fragment coding cDNA. In pCM transcription of heavy-chain Fd/gene III and light chain is driven by a single lacZ promoter. The light chain is directed to the periplasm by the ompA signal peptide, whereas the heavy-chain Fd/coat protein III is trafficked by the pelB signal peptide. The phagemid pCM was used to generate a human combinatorial phage display antibody library that allowed the selection of a monoclonal Fab fragment antibody directed against the nucleoprotein (NP) of Influenza A virus. PMID- 22842596 TI - The Less Drugs Regimens (LDRs) therapy approach in HIV-1: an Italian expert panel perspective for the long-term management of HIV-1 infection. PMID- 22842599 TI - Different mutations in mucA gene of Pseudomonas aeruginosa mucoid strains in cystic fibrosis patients and their effect on algU gene expression. AB - Alginate biosynthesis in Pseudomonas aeruginosa is a highly regulated process in which algU and mucA genes are key elements. Mutations in mucA gene determine alginate operon overexpression and exopolysaccharide overproduction. In our study, 119 strains of P. aeruginosa were isolated from sputa of 96 cystic fibrosis patients and 84/119 showed nonmucoid phenotype, while 35/119 showed mucoid phenotypes. mucA gene was amplified and sequenced in all strains revealing mutations in 29/35 mucoid strains (82%) and in one non-mucoid strain. 4/29 strains showed mutations never described that generated premature stop and much shorter MucA proteins. In all mutated strains, algU gene expression was analyzed to determine if mutations in mucA, resulting in a strong loss of its protein, could significantly influence its function and subsequently the biosynthetic pathways under algU control. Analysis of algU expression disclosed that the length significantly affects the expression of genes involved in the production of alginate and in the motility and hence survival of P. aeruginosa strains in cystic fibrosis lungs. PMID- 22842600 TI - Laboratory diagnosis of Clostridium difficile associated diarrhoea and molecular characterization of clinical isolates. AB - We evaluated a three-step algorithm for laboratory diagnosis of Clostridium difficile-associated diarrhoea (CDAD). First, stool specimens were screened using an EIA test for glutamate dehydrogenase detection. Screen-positive specimens were tested by a rapid cytotoxintoxin A/B assay and subjected to stool culture. All cultures positive for C. difficile underwent toxigenic culture. The results showed that toxigenic culture allowed us to recover 37/156 (24.4%) stool samples harbouring toxigenic C. difficile that would have been missed by using faecal cytotoxin assay alone. This determined an increase in infection prevalence of 4.2% (from 11.4% to 15.6 %). Furthermore, to characterize the clinical Clostridium difficile isolates and the distribution of PCR ribotypes circulating in the San Carlo Borromeo hospital, molecular typing using semi-automated repetitive-sequence-based PCR (rep- PCR) and PCR ribotyping, and an evaluation of the antibiotic resistance were also performed. Among them, 71 indistinguishable strains were detected by rep-PCR and 83 by PCR-ribotyping revealing C. difficile outbreaks in our hospital. A total of 6 different ribotypes were obtained by PCR ribotyping. The most frequent ribotype was 018 (88.2%) that also showed resistance to moxifloxacin. In one case, uncommon PCR ribotype 186 was also identified. PMID- 22842601 TI - Distribution of blaOXA genes among carbapenem-resistant Acinetobacter baumannii nosocomial strains in Poland. AB - Acinetobacter baumannii is an important nosocomial pathogen occurring particularly in intensive care (ICU) as well as burn therapy units (BTU). A. baumannii strains have emerged as resistant to almost all antimicrobial agents, including carbapenems. b-lactamase-mediated resistance is the most common mechanism for carbapenem resistance in this species. Carbapenem-hydrolysing class D b-lactamases - OXA are widespread among A. baumannii strains. It is suggested that ISAba1 plays an important role in drug resistance. The aims of the study were detection of OXA encoding genes and presence of ISAba1. The study included the total of 104 isolates of carbapenem-resistant A. baumannii, obtained from patients hospitalized in ICU and BTU of Specialized Hospital in Krakow. Multiplex PCR was applied for detection of selected OXA carbapenemases encoding genes. PCR analysis showed the presence of bla OXA-51-like gene and ISAba1 in all isolates. 46 strains carried bla OXA-51-like and bla OXA-23-like genes while 48 bla OXA-51 like and bla OXA-40-like genes. 3 isolates carried: bla OXA-51-like , bla OXA-23 like and bla OXA-40-like genes. 7 strains encoded an OXA-51-like carbapenemase but were negative for enzymes belonging to the other families tested. Comparative analysis of ICU and BTU isolates revealed the dominance of: bla OXA-51-like and bla OXA-40-like among ICU while bla OXA-51-like and bla OXA-23-like in BTU. PMID- 22842602 TI - Species level identification and antifungal susceptibility of yeasts isolated from various clinical specimens and evaluation of Integral System Yeasts Plus. AB - It is essential to use easy, standard, cost-effective and accurate methods for identification and susceptibility testing of yeasts in routine practice. This study aimed to establish the species distribution and antifungal susceptibility of yeast isolates and also to evaluate the performance of the colorimetric and commercially available Integral System Yeasts Plus (ISYP). Yeast isolates (n=116) were identified by conventional methods and ISYP. Antifungal susceptibility testing was performed by the microdilution method according to the standards of CLSI M27-A3 and ISYP. Candida albicans (50%) was the most common species isolated, followed by C. parapsilosis (25%) (mostly in blood samples). According to the CLSI M27-S3 criteria, resistance rates for amphotericin B, flucytosine, fluconazole, itraconazole, and voriconazole were 0%, 0%, 4.6%, 4.5% and 1.8%, respectively. Resistance for miconazole (MIC >1 mg/L) was found as 17.9%. Sixty two (53.4%) of the isolates which were analyzed by ISYP showed disagreement with those identified by the conventional methods and API ID 32C identification kit or a specific identification code could not be assigned by ISYP. The performance of ISYP could be indicated as low for all antifungal drugs tested according to the ROC analysis (AUC: 0.28-0.56). As the current version of ISYP displays a poor performance, it is recommended to use the other commercial systems whose results are approved as reliable and in agreement with those of the reference methods in identification and susceptibility testing of yeasts. PMID- 22842603 TI - Factors modulating the outcome of treatment for the eradication of Helicobacter pylori infection. AB - A group of 180 H. pylori culture positive dyspeptic patients (64 patients with peptic ulcer, PU) completed a 2-week treatment with omeprazole, amoxicillin and metronidazole and underwent endoscopy again 6-8 weeks after the end of therapy. One hundred and twenty-four patients (68.8%) were successfully treated. Factors increasing the rates of eradication were the presence of PU (p=0.007) and anti CagA serum antibodies (p=0.003). Factors negatively modulating eradication were the presence of coccoid forms (p=0.0008) and metronidazole-resistant strains (p=0.001); degrees of histological gastritis had no significant effect on eradication rates. Microscopic examination of smeared biopsies for the detection of the coccoid morphoytpe of H. pylori may help avoiding therapeutic failures. PMID- 22842604 TI - Xenotropic and polytropic murine leukemia virus-related sequences are not detected in the majority of patients with chronic fatigue syndrome. AB - XMRV and polytropic MLV-related virus have been controversially associated with chronic fatigue syndrome (CFS). Subsequent reports failed to detect XMRV and MLV related virus in CFS patients, and the previous results have been interpreted as a massive laboratory contamination by mouse DNA sequences. Among 12 sequential CFS patients, two were positive for XMRV/MLV sequences. In contrast, 40 selected control subjects were negative. CSF patients and controls were negative for mitochondrial mouse-specific DNA sequences. These findings do not confirm the high frequency of MLV-related viruses infection in CFS patients, but also contrast the widespread laboratory contamination previously suggested. PMID- 22842605 TI - Pseudomonas aeruginosa septic arthritis of knee after intra-articular ozone injection. AB - We describe a case of septic arthritis caused by Pseudomonas aeruginosa in an immunocompetent patient following intra-articular ozone injection into the knee. To the best of our knowledge, and after considering the current literature,we believe this case is unique as no other reports of septic arthritis caused by P. aeruginosa following intra-articular ozone injection has been made. PMID- 22842606 TI - Two at one blow: reemergence of tularemia in Upper Austria. AB - After field dressing a rabbit in the state of Upper Austria, Austria two members of a family were infected with tularemia in November 2010. The patients were a man in his forties and his father-in-law in his sixties. Tularemia is a rare disease in Austria. In the last 10 years between 2 and 8 cases have been reported annually. Of the total of 40 cases none was reported in the state of Upper Austria. Thus, this case report documents the reemergence of tularemia in Upper Austria. PMID- 22842607 TI - Mycobacterium tuberculosis pneumonia and bacteremia after allogeneic hematopoietic stem cell transplant: report of an instructive pediatric case. AB - Pulmonary infections often complicate hematopoietic stem cell transplantation (HSCT) outcome. Uncommon aetiologies, like Mycobacterium tuberculosis, should be considered when the clinical conditions do not fully improve with standard antimicrobial therapy and microbiological evaluations are repeatedly negative for bacteria and fungi. We describe an interesting pediatric case of miliary lung tuberculosis after HSCT, which was successfully treated after administering the appropriate therapy. PMID- 22842608 TI - Controlled synthesis of transition metal/conducting polymer nanocomposites. AB - A novel displacement reaction has been observed to occur between conducting polymers (CP) and metal salts which can be used to fabricate nanostructured CP metal composites in a one-pot manner. Vanadium pentoxide (V(2)O(5)) nanofiber is used during the synthesis as the reactive seeds to induce the nanofibril CP-metal network formation. The CP-metal nanocomposites exhibit excellent sensory properties for hydrogen peroxide (H(2)O(2)) detection, where both high sensitivity and a low detection limit can be obtained. The sensory performance of the CP-metal composite can be further enhanced by a facile microwave treatment. It is believed that the CP-metal nanofibril network can be converted to a carbon metal network by a microwave-induced carbonization process and result in the sensory enhancement. PMID- 22842610 TI - The promise of electrochemical impedance spectroscopy as novel technology for the management of patients with diabetes mellitus. AB - Self-monitoring of blood glucose is the standard of care in management of hyperglycemia among patients with diabetes mellitus. To increase the sensitivity and specificity of current devices, a novel method of detecting glucose using electrochemical impedance spectroscopy (EIS) technology is explored. The enzyme glucose oxidase (GOx) was fixed to gold electrodes and a sine wave of sweeping frequencies was induced using a wide range of concentrations of glucose. Each frequency in the impedance sweep was analyzed for the highest response and R squared value. The frequency with both factors optimized is specific for the glucose-GOx binding interaction and was determined to be 1.17 kHz in purified solutions in both higher and lower ranges of glucose. The correlation between the impedance response and concentration at the low range of detection (0-100 mg dL( 1) of glucose) was determined to be 3.53 ohm/ln (mg dL(-1)) with an R-squared value of 0.90 with a 39 mg dL(-1) lower limit of detection. The same frequency of 1.17 kHz was verified in whole blood under the same glucose range. The above data confirm that EIS offers a new method of glucose detection as an alternative to current technology in use by patients. Additionally, the unique frequency response of individual markers allows for modulation of signals so that several other markers important in the management of diabetes could be measured with a single sensor. PMID- 22842609 TI - Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer. AB - Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis. The anticancer efficacy of topical and oral P-S was further evaluated in mice bearing A431 intradermal xenografts. Compared to the controls, topical P-S hydrogel inhibited the A431 xenografts by 70.5% (p<0.01), while oral P-S inhibited it by 43.4% (p<0.05), being significantly less effective than topical P-S (p=0.017). Topical P-S hydrogel generated significant levels (>500 nmol/g tumor tissue) of intact P-S in the tumors, accounting for 92.5% of the total metabolites in the A431 xenografts. This local delivery of high levels of intact P-S to the A431 xenografts is an important contributor to the potent activity of topical P-S and no local or systemic side effects were noted in the treatment group. Thus, topical P-S is a promising treatment modality against non-melanoma skin cancer and merits further evaluation. PMID- 22842611 TI - CXCL12 is a costimulator for CD4+ T cell activation and proliferation in chronic lymphocytic leukemia patients. AB - Activated T cells from patients with chronic lymphocytic leukemia (CLL) provide survival and proliferative signals to the leukemic clone within lymphoid tissues. Recruitment of both, CLL cells and T lymphocytes, to this supportive microenvironment greatly depends on CXCL12 production by stromal and myeloid cells. CXCL12 also supplies survival stimuli to leukemic B cells, but whether it exerts stimulatory effects on T lymphocytes from CLL patients is unknown. In order to evaluate the capacity of CXCL12 to increase CD4(+) T cell activation and proliferation in CLL patients, peripheral blood mononuclear cells were cultured with or without recombinant human CXCL12 or autologous nurse-like cells, and then T cell activation was induced by anti-CD3 mAb. CXCL12 increases the proliferation and the expression of CD25, CD69, CD154, and IFNgamma on CD3-stimulated CD4(+) T cells from CLL patients, similarly in T cells from ZAP-70(+) to ZAP-70(-) patients. Autologous nurse-like cells establish a close contact with CD4(+) T cells and increase their activation and proliferation partially through a CXCR4 dependent mechanism. In addition, we found that activated T cells in the presence of CXCL12 enhance the activation and proliferation of the leukemic clone. In conclusion, CXCL12 production by lymphoid tissue microenvironment in CLL patients might play a key dual role on T cell physiology, functioning not only as a chemoattractant but also as a costimulatory factor for activated T cells. PMID- 22842612 TI - Spot urine protein measurements: are these accurate in kidney transplant recipients? AB - BACKGROUND: Proteinuria and albuminuria are important markers of allograft pathology and are associated with graft loss and cardiovascular disease. Traditionally, these have been quantified using a 24-hr urine collection, but spot urine measurements (albumin-creatinine and protein-creatinine ratios) have become popular because of convenience. Aside from tests of correlation, there has been little evaluation of these measurements in kidney transplantation. METHODS: To further assess the value of albumin-creatinine and protein-creatinine ratios, we measured protein-creatinine ratio and 24-hr urine protein excretion (n=192) and albumin-creatinine ratio and 24-hr urine albumin excretion (n=189) in stable renal transplant patients. Bias (measured minus estimated value), precision, and accuracy was calculated. RESULTS: For the protein-creatinine ratio, percent bias ranged from 12% to 21%, and the accuracy (within 30% of 24-hr collection) was only 47% to 56% depending on the degree of proteinuria. For the albumin creatinine ratio, percent bias ranged from 9% to 21%, and the accuracy (within 30%) ranged from 38% to 80% depending on the degree of albuminuria. There was no statistical difference between accuracy of protein-creatinine and albumin creatinine ratios. CONCLUSIONS: The ability of the albumin-creatinine and protein creatinine ratios to accurately predict 24-hr albumin and protein excretion is modest. Given the similar accuracy of both measurements, either protein creatinine ratio or albumin-creatinine ratio can be used for monitoring protein excretion. However, given the limitations of both the albumin-creatinine ratio and protein-creatinine ratio in this population, a 24-hr urine collection should be considered before making major clinical decisions (e.g., biopsy) based on the presence of proteinuria. PMID- 22842613 TI - Targeting adipose tissue angiogenesis to enhance insulin sensitivity. PMID- 22842614 TI - Palladium metal nanoparticle size control through ion paired structures of [PdCl4]2- with protonated PDMAEMA. AB - The mean diameter of palladium metal particles produced by citrate reduction of the (H(+))(n) PDMAEMA/[PdCl(4)](2-) aqueous system increases from 1.4 nm to 5.0 nm as the pH decreases from 6.3 to 3.3 and the (H(+))(n) PDMAEMA/[PdCl(4)](2-) species undergo conversion from a cross linked polymer network to a single chain structure. PMID- 22842615 TI - Serological markers predict inflammatory bowel disease years before the diagnosis. AB - OBJECTIVE: Anti-neutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) have been detected in the serum of patients with ulcerative colitis (UC) and Crohn's disease (CD) and their unaffected family members. The aim of this study was to establish the value of serological markers as predictors of UC and CD. DESIGN: Individuals who developed CD or UC were identified from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. At recruitment, none of the participants had a diagnosis of CD or UC. For each incident case, two controls were randomly selected matched for centre, date of birth, sex, date of recruitment and time of follow-up. Serum of cases and controls obtained at recruitment were analysed for ASCA IgG, ASCA IgA, perinuclear anti-neutrophil cytoplasmic antibody (pANCA), antibodies against Escherichia coli outer membrane porin C (OmpC) and flagellin CBir1. Conditional logistic regression was used to determine risk of CD and UC. Receiver operating characteristic curves were constructed to test accuracy. RESULTS: A total of 77 individuals were diagnosed with CD and 167 with UC after a mean follow-up of 4.5 (SD 3.2) and 4.4 (SD 3.1) years following blood collection, respectively. Combinations of pANCA, ASCA, anti-CBir1 and anti-OmpC were most accurate in predicting incident CD and UC (area under curve 0.679 and 0.657, respectively). The predictive value of the combination of markers increased when time to diagnosis of CD or UC decreased. CONCLUSION: A panel of serological markers is able to predict development of CD and UC in individuals from a low-risk population. PMID- 22842616 TI - Acute variceal bleeding in a man with coeliac disease. PMID- 22842617 TI - The impact of preoperative biological therapy on complications after abdominal surgery for inflammatory bowel disease. PMID- 22842618 TI - Mucosal healing in inflammatory bowel diseases: a systematic review. AB - Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted. PMID- 22842619 TI - Consensus guidelines for the safe prescription and administration of oral bowel cleansing agents. AB - Oral bowel-cleansing preparations are used before colonic surgery and endoscopic and radiological assessment of the intestine to minimise faecal contamination. In February 2009, the UK National Patient Safety Agency issued a Rapid Response Report highlighting the potential risk of harm associated with the use of these preparations and instructing local NHS Trusts to implement safeguards to reduce this risk. This guidance has been prepared to help NHS Trusts to respond to these concerns, as the risk of complications is influenced by both individual patient risk factors and the choice of bowel preparation, for which definitive guidance was not previously available. This document provides an outline of the different available oral bowel-cleansing agents and the complications that may arise. This is followed by recommendations for their use in different patient groups and circumstances. The recommendations are based on consensus between the authors, each of whom circulated drafts to members of their specialist society. The evidence for these recommendations has been assessed using the modified GRADE system. The recommendations cover the choice, administration and complications (relative and absolute) of the different oral bowel-cleansing agents, with specific guidance provided for different patient groups. PMID- 22842620 TI - A somatic TSHR mutation in a patient with lung adenocarcinoma with bronchioloalveolar carcinoma, coronary artery disease and severe chronic obstructive pulmonary disease. AB - In a screen for thoracic malignancy-associated markers, thyroid stimulating hormone receptor (TSHR) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1. We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples. We found one patient with a somatic mutation at codon 458 (exon 10), which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases. This patient had lung adenocarcinoma with BAC (bronchioloalveolar carcinoma) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease (COPD). In order to characterize the genetic features of TSHR in lung cancer, we checked for TSHR expression and copy number in the 96 lung cancer tissues. TSHR protein expression was generally overexpressed in multiple thoracic malignancies (adenocarcinoma, squamous cell carcinoma and malignant pleural mesothelioma) by immunohistochemistry. Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes. PMID- 22842621 TI - A patient with chronic diarrhea of unknown cause. PMID- 22842622 TI - Use of (alternative) coreceptors for HIV entry. AB - PURPOSE OF REVIEW: Although CCR5 and CXCR4 are the predominant coreceptors associated with HIV-1 entry, many more coreceptors can support either infection or viral capture and have been associated with transmission and disease progression. Here, we describe the most recent findings pertinent to which receptors are involved with HIV-1 infection and the proposed consequences. RECENT FINDINGS: CCR5 or CXCR4 using HIV-1 can differentially utilize their respective coreceptors and influence which cell types are infected. Many alternate coreceptors have been described which expands the pool of cells within which HIV 1 can replicate or reside. A large number of C-type lectins have been described which capture HIV-1 and present the virus to CD4 T cells which can also be considered as receptors involved with transmission or disease course. The molecular mechanism through which gp120 binds host lectins, such as altered N linked glycosylation profiling, provides further mechanisms influencing HIV-1 capture and transfer. Genetic polymorphisms within the alternative coreceptors have now been shown to associate with disease, implying they can play a significant role in HIV-1 disease. SUMMARY: We have summarized the recent findings concerning the multitude of receptors and coreceptors which can interact with HIV-1 and have discussed the consequences for either HIV-1 transmission or disease progression. PMID- 22842623 TI - Amphotericin B lipid nanoemulsion aerosols for targeting peripheral respiratory airways via nebulization. AB - Amphotericin B (AmB) lipid nanoemulsions were prepared and characterized and their suitability for pulmonary delivery via nebulization was evaluated. AmB nanoemulsions were prepared by sonicating and vortexing the drug with two commercially available lipid nanoemulsions: the Intralipid((r)) or Clinoleic((r)). Loading the nanoemulsions with the drug slightly increased the size of the lipid droplets and did not affect the zeta potential of the nanoemulsions. The loading efficiency of AmB was found to be 87.46+/-2.21% in the Intralipid((r)) nanoemulsions and 80.7+/-0.70% in the Clinoleic((r)) formulation. This respectively corresponded to 21.86 mg and 20.19 mg of AmB being successfully loaded in the nanoemulsions. On aerosolization using a Pari Sprint jet nebulizer, both nanoemulsions produced very high drug output which was approximately 90% for both formulations. Using the two-stage impinger, the Clinoleic((r)) emulsion had higher fine particle fraction (FPF) than the Intralipid((r)), since the Clinoleic((r)) displayed higher deposition of AmB in the lower impinger stage (exceeding 80%), compared to 57% for the Intralipid((r)). Overall, the ease of preparation of the AmB lipid nanoemulsions, along with their in vitro nebulization performance suggest that lipid nanoemulsions could be successful nanocarriers for delivery of AmB to the peripheral respiratory airways. PMID- 22842624 TI - Novel lipid based oral formulation of curcumin: development and optimization by design of experiments approach. AB - The clinical utility of curcumin (CRM) is limited due to its poor oral bioavailability. Lipid based oral formulations (LBOFs) are emerging as useful oral drug delivery systems for 'difficult to deliver' molecules like CRM. In present study, we report novel Type IV LBOF for CRM using Gelucire 44/14, Labrasol, Vit. E TPGS and PEG 400 with superior CRM loading and enhanced oral bioavailability. The optimization of LBOF for CRM loading and post dilution droplet size was carried out by design of experiments (DoE) approach with Box Behnken design. Oral bioavailability of optimized LBOF (O-LBOF) was evaluated in male Sprague-Dawley (SD) rats at a dose of 250 mg/kg. Raw CRM (control) showed C(max) and AUC(0-infinity) of 32.29 ng/ml and 38.07 ng h/ml, respectively. O-LBOF improved C(max) and AUC(0-infinity) by 11.6 and 35.8 folds respectively over control. PMID- 22842625 TI - Novel lyophilized hydrogel patches for convenient and effective administration of microneedle-mediated insulin delivery. AB - A lyophilized hydrogel patch system was developed for microneedle-mediated insulin delivery. The matrix of Cross-linked poly(acrylamide-co-acrylic acid) were synthesized by precipitation polymerization. Recombinant human Insulin was loaded into the lyophilized polymer matrix, which can be rehydrated by water. After the hydrated patch was applied to the abdominal skin of diabetic rats after microneedle pretreatment, pharmacodynamics and pharmacokinetics evaluation was performed. The blood samples were collected to monitor blood glucose and serum insulin levels for 12 h. Blood glucose was lowered in proportion to the concentration of insulin loaded in lyophilized hydrogel patches (R(2)=0.99), with a longer duration of action compared to subcutaneous injection. Stability study confirmed more than 90% of insulin activity was retained in lyophilized hydrogel after 6 months of storage at 4 degrees C. In conclusion, hydrogel patches were demonstrated to be appropriate drug reservoir for sustained release of insulin with microneedle mediated transdermal delivery. PMID- 22842626 TI - Solubilisation capacity of Brij surfactants. AB - The aim of this study was to investigate the potential of selected Brij non-ionic surfactants for enhancing the solubility of poorly water-soluble drugs. Griseofulvin was selected as a model drug candidate enabling comparisons to be made with the solubilisation capacities of other poly(ethylene oxide)-based copolymers. UV/Vis and (1)H NMR spectroscopies were used to quantify the enhancement of solubility of griseofulvin in 1 wt% aqueous micellar solutions of Brij 78 (C(18)H(37)E(20)), Brij 98 (C(18)H(35)E(20)) and Brij 700 (C(18)H(37)E(100)) (where E represents the OCH(2)CH(2) unit of the poly(ethylene oxide) chain) at 25, 37 and 40 degrees C. Solubilisation capacities (S(cp) expressed as mg griseofulvin per g Brij) were similar for Brij 78 and 98 (range 6 11 mg g(-1)) but lower for Brij 700 (3-4 mg g(-1)) as would be expected for the surfactant with the higher ethylene oxide content. The drug loading capacity of micelles of Brij 78 was higher than many di- and triblock copolymers with hydrophilic E-blocks specifically designed for enhancement of drug solubility. PMID- 22842627 TI - Chitosan-based mucoadhesive tablets for oral delivery of ibuprofen. AB - Chitosan and its half-acetylated derivative have been compared as excipients in mucoadhesive tablets containing ibuprofen. Initially the powder formulations containing the polymers and the drug were prepared by either co-spray drying or physical co-grinding. Polymer-drug interactions and the degree of drug crystallinity in these formulations were assessed by infrared spectroscopy and differential scanning calorimetry. Tablets were prepared and their swelling and dissolution properties were studied in media of various pHs. Mucoadhesive properties of ibuprofen-loaded and drug-free tablets were evaluated by analysing their detachment from pig gastric mucosa over a range of pHs. Greater polymer drug interactions were seen for spray-dried particles compared to co-ground samples and drug loading into chitosan-based microparticles (41%) was greater than the corresponding half-acetylated samples (32%). Swelling and drug release was greater with the half-acetylated chitosan tablets than tablets containing the parent polymer and both tablets were mucoadhesive, the extent of which was dependent on substrate pH. The results illustrate the potential sustained drug delivery benefits of both chitosan and its half-acetylated derivative as mucoadhesive tablet excipients. PMID- 22842628 TI - Copper influx transporter 1 is required for FGF, PDGF and EGF-induced MAPK signaling. AB - Copper transporter 1 (CTR1) is the major copper (Cu) influx transporter in mammalian cells. We report here that CTR1 is required for the activation of signaling to the MAPK pathway by the ligands of three major receptor tyrosine kinases (RTK) including FGF, PDGF and EGF. Induction of Erk1/2 phosphorylation was compared in isogenic wild type CTR1(+/+) and CTR1(-/-) cells. Whereas all three ligands increased pErk1/2 in the CTR1(+/+) cells, they failed to do this in CTR1(-/-) cells. While FGF did not enhance the phosphorylation of AKT in the CTR1(+/+) cells, both PDGF and EGF increased pAKT in the CTR1(+/+) but not CTR1( /-) cells. The deficit in Erk1/2 phosphorylation in the CTR1(-/-) cells was rescued by adding Cu to the medium, and it was induced in CTR1(+/+) cells by treatment with a Cu chelator. Intracellular Cu availability was reduced in the CTR1(-/-) cells as reflected by increased expression of the Cu chaperone CCS. The failure of RTK-induced signaling to both Erk1/2 and AKT suggested the presence of a Cu-dependent step upstream of Ras. The Cu-dependent enzyme SOD1 is responsible for generating the hydrogen peroxide in response to RTK activation that serves to inhibit phosphatases that normally limit RTK signaling. SOD1 activity was reduced by a factor of 17-fold in the CTR1(-/-) cells, and addition of hydrogen peroxide restored signaling. We conclude that Cu acquired from CTR1 is required for signaling in pathways regulated by RTKs that play major roles in development and cancer. PMID- 22842630 TI - Berberine: new perspectives for old remedies. AB - Chemical compounds derived from plants have been used since the origin of human beings to counteract a number of diseases. Among them, the natural isoquinoline alkaloid berberine has been employed in Ayurvedic and Chinese Medicine for hundreds of years with a wide range of pharmacological and biochemical effects. More recently, a growing body of reports supports the evidence that berberine has anticancer effects, being able to block the proliferation of and to kill cancer cells. This review addresses the properties and therapeutic use of berberine and focuses on the recent advances as promising anticancer drug lead. PMID- 22842629 TI - Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. AB - Epidemiologic and case control population based studies over the past few decades have identified diet as an important determinant of cancer risk. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds has been fisetin (3,7,3',4' tetrahydroxyflavone), a flavonol and a member of the flavonoid polyphenols that also include quercetin, myricetin and kaempferol. Fisetin is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. We evaluated the effects of fisetin against melanoma and cancers of the prostate, pancreas and the lungs. Using prostate and lung adenocarcinoma cells, we demonstrated that fisetin acts as a dual inhibitor of the PI3K/Akt and the mTOR pathways. This is a significant finding considering the fact that mTOR is phosphorylated and its activation is more frequent in tumors with overexpression of PI3K/Akt. Dual inhibitors of PI3K/Akt and mTOR signaling have been suggested as valuable agents for treating such cancers. Here, we summarize our findings on the dietary flavonoid fisetin and its effects on cancer with particular focus on prostate cancer. Our observations and findings from other laboratories suggest that fisetin could be a useful chemotherapeutic agent that could be used either alone or as an adjuvant with conventional chemotherapeutic drugs for the management of prostate and other cancers. PMID- 22842631 TI - Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction. AB - Hepatocellular apoptosis is an essential pathological feature of alcoholic liver disease. Adiponectin, an adipokine predominantly secreted from adipose tissue, has been shown to play beneficial roles in alcoholic liver disease against various inflammatory and pro-apoptotic molecules. However, the effects of adiponectin on ethanol-induced apoptosis in liver cells are largely unknown. Herein, we investigated the role of globular adiponectin (gAcrp) in the prevention of ethanol-induced apoptosis and further tried to decipher the potential mechanisms involved. In the present study, we demonstrated that gAcrp significantly inhibits both ethanol-induced increase in Fas ligand expression and activation of caspase-3 in human hepatoma cell lines (HepG2 cells), suggesting that gAcrp plays a protective role against ethanol-induced apoptosis in liver cells. This protective effect of gAcrp was mediated through adiponectin receptor R1 (adipoR1). Further, globular adiponectin treatment caused induction of heme oxygenase-1 (HO-1) through, at least in part, nuclear factor (erythroid-derived 2)-like 2, (Nrf2) signaling. Treatment with SnPP, a pharmacological inhibitor of HO-1, and knockdown of HO-1 with small interfering RNA (siRNA) restored caspase-3 activity suppressed by gAcrp, indicating a critical role of HO-1 in mediating the protective role of gAcrp in ethanol-induced apoptosis in liver cells. In addition, carbon monoxide, a byproduct obtained from the catabolism of free heme was found to contribute to the anti-apoptotic effect of adiponectin. In conclusion, these data demonstrated that globular adiponectin prevents ethanol induced apoptosis in HepG2 cells via HO-1 induction and revealed a novel biological response of globular adiponectin in the protection of liver injury from alcohol consumption. PMID- 22842632 TI - Intracranial physiological calcifications evaluated with cone beam CT. AB - OBJECTIVES: The purpose of this study was to evaluate cone beam CT (CBCT) scans for the presence of physiological and pathological intracranial calcifications. METHODS: CBCT scans from male and female patients that met our ascertainment criteria were evaluated retrospectively (n=500) for the presence of either physiological or pathological intracranial calcifications. RESULTS: Out of the 500 patients evaluated, 176 had evidence of intracranial physiological calcification (35.2% prevalence), and none had evidence of pathological calcification. There was a 3:2 male-to-female ratio and no ethnic predilection; the ages of affected patients ranged from 13 years to 82 years with a mean age of 52 years. The majority of calcifications appeared in the pineal/habenular region (80%), with some also appearing in the choroid plexus region bilaterally (12%), and a smaller subset appearing in the petroclinoid ligament region bilaterally (8%). CONCLUSIONS: Intracranial physiological calcifications can be a common finding on CBCT scans, whereas pathological intracranial calcifications are rare. PMID- 22842633 TI - MRI characteristics of rheumatoid arthritis in the temporomandibular joint. AB - OBJECTIVES: The aim of this study was to investigate characteristic MRI findings of rheumatoid arthritis (RA) in the temporomandibular joints (TMJs). METHODS: 61 patients (122 TMJs) with RA in the TMJ and 50 patients (100 TMJs) with temporomandibular disorder (TMD) were included in this study. MR images of these patients were assessed by two oral radiologists for the presence or absence of osseous changes, disc displacement, joint effusion and synovial proliferation. These findings were compared between the two patient groups. RESULTS: Osseous changes in the condyle and articular eminence/fossa in the RA patient group were significantly more frequent than in the TMD patient group, and were often very severe. Joint effusion was also significantly more frequent in the RA patient group. Synovial proliferation was found in all TMJs in the RA patient group, whereas it was very uncommon in the TMD patient group. CONCLUSIONS: Severe osseous changes in the condyle and synovial proliferation were considered characteristic MRI findings of RA in the TMJs. PMID- 22842634 TI - A comparison of the thresholding strategies of micro-CT for periodontal bone loss: a pilot study. AB - OBJECTIVES: Micro-CT provides three-dimensional details and has been widely used for biomedical assessments. This study aimed to determine the most appropriate threshold method for quantitatively assessing the dynamics of periodontal destruction. METHODS: Inflammation was induced by submerging a silk ligature in the sulcus of the maxillary second molars of rats, and the animals were killed prior to ligature placement and after 7 and 21 days. The maxillae were examined for the bone resorptive activities by micro-CT, histology and tartrate-resistant acid phosphatase staining. The imaging threshold was determined by CT phantom, global and local algorithms. A bone fraction measurement from each threshold determining technique was compared with histomorphometry. The reliability and reproducibility were examined by the intraclass correlation coefficient (ICC) and the coefficient of variation. RESULTS: Significant reduction of inflammatory infiltration (p < 0.01) and active osteoclastic resorption (p < 0.05) from Day 7 to Day 21 were noted. High inter- and intraexaminer agreement were demonstrated in both histomorphometric and micro-CT assessments (ICC > 0.98). The algorithm based technique demonstrated stronger correlation to histomorphometry than phantom-based thresholds, and the highest agreement was presented by the local algorithm (ICC > 0.96). This, however, was considerably computationally expensive. CONCLUSIONS: The local threshold-determining algorithm is suggested for examining inflammation-induced bone loss. Further investigation will be aimed at enhancing computational efficiency. PMID- 22842635 TI - Visual perception of multilocular radiolucent mandibular lesions quantified by morphometric analysis. AB - OBJECTIVE: The aim of this study was to analyse the visual perceptions of different experts with respect to multilocular radiolucent lesions in circumstances when the diagnosis is either known or unknown. METHODS: 6 radiographs of ameloblastomas (AMELs), keratocystic odontogenic tumours (KOTs), central giant cell lesions (CGCLs) and myxomas (MIXs) were analysed by 16 dental experts [stomatologists/oral surgeons (SS) and dental radiologists (R)]. They delimited the lesions prior to having knowledge of the diagnosis (T1) and after 30 days, when they were aware of the histopathological results (T2). For each image, the following morphometric parameters were calculated: area (A), perimeter (P) and shape factor (SF); after image subtraction procedures (T1 - T2), the exclusive area (EA) of the non-overlapping delimited region was also calculated. RESULTS: For both groups, the T2 area was larger than the T1, although the EA of the SS group was higher than that of the R group independently of the type of lesion. The SF from the SS group was greater than that from the R group, and at T2 the SF values were higher for both groups. AMELs and MIXs showed larger SF and A values; the SS group tended to have the greatest changes in the delimitations of the lesions at T2. CONCLUSIONS: The methodology allowed us to quantify differences in the spatial perceptions of professionals. The knowledge of the diagnosis and the expertise of examiners influenced the examiner's perception of the limits of the lesions independently of the actual biological behaviour of the lesion. PMID- 22842636 TI - Multimodal registration of three-dimensional maxillodental cone beam CT and photogrammetry data over time. AB - OBJECTIVES: In recent years, one of the foci of orthodontics has been on systems for the evaluation of treatment results and the tracking of tissue variations over time. This can be accomplished through analysing three-dimensional orthodontic images obtained before and after the treatments. Since complementary information is achieved by integrating multiple imaging modalities, cone beam CT (CBCT) and stereophotogrammetry technologies are used in this study to develop a method for tracking bone, teeth and facial soft-tissue variations over time. METHODS: We propose a two-phase procedure of multimodal (Phase 1) and multitemporal (Phase 2) registration which aligns images taken from the same patient by different imaging modalities and at different times. Extrinsic (for Phase 1) and intrinsic (for Phase 2) landmark-based registration methods are employed as an initiation for a robust iterative closest points algorithm. Since the mandible moves independently of the upper skull, the registration procedure is applied separately on the mandible and the upper skull. RESULTS: The results show that the signed error distributions of both mandible and skull registrations follow a mixture of two Gaussian distributions, corresponding to alignment errors (due to our method) and temporal change over time. CONCLUSIONS: We suggest that the large values among the total registration errors correspond to the temporal change resulting from (1) the effect of treatment (i.e. the orthodontic changes of teeth positions); (2) the biological changes such as teeth growth over time, especially for teenagers; and (3) the segmentation procedure and CBCT precision change over time. PMID- 22842637 TI - A method for measuring three-dimensional mandibular kinematics in vivo using single-plane fluoroscopy. AB - OBJECTIVES: Accurate measurement of the three-dimensional (3D) motion of the mandible in vivo is essential for relevant clinical applications. Existing techniques are either of limited accuracy or require the use of transoral devices that interfere with jaw movements. This study aimed to develop further an existing method for measuring 3D, in vivo mandibular kinematics using single plane fluoroscopy; to determine the accuracy of the method; and to demonstrate its clinical applicability via measurements on a healthy subject during opening/closing and chewing movements. METHODS: The proposed method was based on the registration of single-plane fluoroscopy images and 3D low-radiation cone beam CT data. It was validated using roentgen single-plane photogrammetric analysis at static positions and during opening/closing and chewing movements. RESULTS: The method was found to have measurement errors of 0.1 +/- 0.9 mm for all translations and 0.2 degrees +/- 0.6 degrees for all rotations in static conditions, and of 1.0 +/- 1.4 mm for all translations and 0.2 degrees +/- 0.7 degrees for all rotations in dynamic conditions. CONCLUSIONS: The proposed method is considered an accurate method for quantifying the 3D mandibular motion in vivo. Without relying on transoral devices, the method has advantages over existing methods, especially in the assessment of patients with missing or unstable teeth, making it useful for the research and clinical assessment of the temporomandibular joint and chewing function. PMID- 22842638 TI - Detection of cavitated approximal surfaces using cone beam CT and intraoral receptors. AB - OBJECTIVES: The aim of this study was to compare cone beam CT (CBCT) in a small field of view (FOV) with a solid-state sensor and a photostimulable phosphor plate system for detection of cavitated approximal surfaces. METHODS: 257 non filled approximal surfaces from human permanent premolars and molars were recorded by two intraoral digital receptors, a storage phosphor plate (Digora Optime, Soredex) and a solid-state CMOS sensor (Digora Toto, Soredex), and scanned in a cone beam CT unit (3D Accuitomo FPD80, Morita) with a FOV of 4 cm and a voxel size of 0.08 mm. Image sections were carried out in the axial and mesiodistal tooth planes. Six observers recorded surface cavitation in all images. Validation of the true absence or presence of surface cavitation was performed by inspecting the surfaces under strong light with the naked eye. Differences in sensitivity, specificity and agreement were estimated by analysing the binary data in a generalized linear model using an identity link function. RESULTS: A significantly higher sensitivity was obtained by all observers with CBCT (p < 0.001), which was not compromised by a lower specificity. Therefore, a significantly higher overall agreement was obtained with CBCT (p < 0.001). There were no significant differences between the Digora Optime phosphor plate system and the Digora Toto CMOS sensor for any parameter. CONCLUSIONS: CBCT was much more accurate in the detection of surface cavitation in approximal surfaces than intraoral receptors. The differences are interpreted as clinically significant. A CBCT examination performed for other reasons should also be assessed for approximal surface cavities in teeth without restorations. PMID- 22842639 TI - A mathematical model relating changes of grey values to changes of thicknesses of a stepwedge. AB - The purpose of this report is to present a mathematical model relating changes in grey values to changes of thicknesses of a stepwedge. Radiographs of a stepwedge were obtained through a limited exposure range on a single Kodak 6100 charge coupled device detector at 63 kVp and 70 kVp. Grey values from each step were evaluated relative to the corresponding step thickness. All possible regression fits were evaluated based on their coefficient of determination (R(2)) value and their mean squared errors (MSEs) relative to the original thickness. For all exposure settings, the fifth-degree polynomial was the best possible fit, with the highest R(2) value and the lowest MSE. PMID- 22842640 TI - A new method for determining the optimal CT threshold for extracting the upper airway. AB - OBJECTIVES: The purpose of this study was to evaluate the optimal upper threshold levels of a number of individuals and determine the most suitable upper threshold. METHODS: A phantom model and ten patients were used in this study. The phantom was made of acrylic resin and urethane resin and had nine pillar-shaped air spaces. The subjects were ten female patients with jaw deformities who were not affected by respiratory disease. The optimal threshold levels were determined using the "calculation of CT value disparities" (CCTD) technique, which we devised. In other words, the mean CT values along two lines (air space and soft tissue) were calculated and the optimal threshold level was determined as the level that produced the maximum difference between the CT values measured inside and outside of the air-space border. RESULTS: The optimal upper threshold levels of the nine phantom holes calculated using the CCTD technique in the front-on standing position and side-on standing position were -434 HU and -456 HU, respectively. The optimal upper threshold level of the ten patients calculated using the CCTD technique was -472 HU. The true threshold level of each patient was defined as the optimal threshold level calculated using the CCTD technique. The mean threshold level was defined as -472 HU. The absolute differences between the volume measurements obtained with these two measures were considered. Therefore, the no error values were -460 HU and -470 HU. CONCLUSIONS: We consider that the most suitable upper threshold level for extracting the airway is from 460 HU to -470 HU. PMID- 22842641 TI - Cone beam CT image artefacts related to head motion simulated by a robot skull: visual characteristics and impact on image quality. AB - OBJECTIVES: The aim of this study was to assess artefacts and their impact on cone beam CT (CBCT) image quality (IQ) after head motion simulated by a robot skull. METHODS: A fully dentate human skull incorporated into a robot simulated pre-determined patient movements. Ten head motion patterns were selected based on the movement of the C-arm of the CBCT units (no motion as reference). Three CBCT units were used [a three-dimensional eXam (K) (KaVo Dental GmbH, Biberach, Germany), a Promax 3D MAX (P) (Planmeca Oy, Helsinki, Finland) and a Scanora((r)) 3D (S) (Soredex Oy, Tuusula, Finland)]. Axial images were qualitatively assessed at three levels: mental foramen (MF), infraorbital foramen and supraorbital foramen, and artefacts characterized as stripe-like, double contours, unsharpness or ring-like. A 100 mm visual analogue scale (VAS) was used to quantitatively assess IQ. Cross-sectional images of the lower third molar and MF bilaterally were also evaluated by VAS. Four blinded examiners assessed the images. RESULTS: For all units and motion patterns, stripe-like artefacts were the most common. The four observers agreed on the presence of at least one artefact type in 90% of the images. Axial images showed lower overall IQ after motion (VAS = 72.4 +/- 24.0 mm) than reference images (VAS = 97.3 +/- 2.6 mm). The most severe artefacts were seen at the MF level. For cross-sectional images, IQ was lowest after tremor. The mean IQ range was 74-89 and 57-90 for isolated (tilting, rotation and nodding) and combined (nodding + tilting and rotation + tilting) movements, respectively. IQ for MF was lower than for third molar for any movement except tremor. CONCLUSIONS: Head motion of any type resulted in artefacts in CBCT images. The impact on IQ depended on the region and level in the skull. PMID- 22842642 TI - Evaluation of polyphenolic profile and nutritional value of non-traditional fruit species in the Czech Republic--a comparative study. AB - Dry matter, organic acids, ascorbic acid, minerals (nitrogen, phosphorus, potassium, calcium, magnesium, sodium) and polyphenolic profile of a number of non-traditional fruit species and their genotypes, namely blue honeysuckle (Lonicera spp.), Saskatoon berry (Amelanchier alnifolia), black mulberry (Morus nigra), Tomentosa cherry (Prunus tomentosa Thunb.) and jostaberry (Ribes nigrum x Grossularia uva-crispa) were investigated. The results showed that Lonicera genotypes displayed high levels of ascorbic acid and they were rich in minerals, with the cultivar 'Amfora' achieving the leading position in nitrogen, phosphorus and potassium content among all lesser known fruit species. Amelanchier cultivars represented a valuable source of ascorbic acid and calcium, 'Tisnovsky' and 'Smoky' together with Morus nigra 'Jugoslavska' accumulated the highest level of examined polyphenolic compounds. Regular consumption of studied less common fruit species can bring health benefits so they can represent a high potential value for fruit growers and in addition they can be utilised as functional foods. PMID- 22842643 TI - Prediction of acute mammalian toxicity using QSAR methods: a case study of sulfur mustard and its breakdown products. AB - Predicting toxicity quantitatively, using Quantitative Structure Activity Relationships (QSAR), has matured over recent years to the point that the predictions can be used to help identify missing comparison values in a substance's database. In this manuscript we investigate using the lethal dose that kills fifty percent of a test population (LD50) for determining relative toxicity of a number of substances. In general, the smaller the LD50 value, the more toxic the chemical, and the larger the LD50 value, the lower the toxicity. When systemic toxicity and other specific toxicity data are unavailable for the chemical(s) of interest, during emergency responses, LD50 values may be employed to determine the relative toxicity of a series of chemicals. In the present study, a group of chemical warfare agents and their breakdown products have been evaluated using four available rat oral QSAR LD50 models. The QSAR analysis shows that the breakdown products of Sulfur Mustard (HD) are predicted to be less toxic than the parent compound as well as other known breakdown products that have known toxicities. The QSAR estimated break down products LD50 values ranged from 299 mg/kg to 5,764 mg/kg. This evaluation allows for the ranking and toxicity estimation of compounds for which little toxicity information existed; thus leading to better risk decision making in the field. PMID- 22842644 TI - Preparative isolation and purification of three sesquiterpenoid lactones from Eupatorium lindleyanum DC. by high-speed counter-current chromatography. AB - A high-speed counter-current chromatography (HSCCC) method was established for the preparative separation of three sesquiterpenoid lactones from Eupatorium lindleyanum DC. The two-phase solvent system composed of n-hexane-ethyl acetate methanol-water (1:4:2:3, v/v/v/v) was selected. From 540 mg of the n-butanol fraction of Eupatorium lindleyanum DC., 10.8 mg of 3beta-hydroxy-8beta-[4' hydroxytigloyloxy]-costunolide, 17.9 mg of eupalinolide A and 19.3 mg of eupalinolide B were obtained in a one-step HSCCC separation, with purities of 91.8%, 97.9% and 97.1%, respectively, as determined by HPLC. Their structures were further identified by ESI-MS and 1H-NMR. PMID- 22842645 TI - Ultrasensitive aptamer biosensor for arsenic(III) detection in aqueous solution based on surfactant-induced aggregation of gold nanoparticles. AB - This paper reports the colorimetric and resonance scattering (RS)-based biosensor for the ultrasensitive detection of As(III) in aqueous solution via aggregating gold nanoparticles (AuNPs) by the special interactions between arsenic-binding aptamer, target and cationic surfactant. Aptamers and the cationic surfactant could assemble to form a supramolecule, which prevented AuNPs from aggregating due to the exhaustion of cationic surfactant. The introduction of As(III) specifically interacted with the arsenic-binding aptamer to form the aptamer As(III) complex, so that the following cationic surfactant could aggregate AuNPs and cause the remarkable change in color and RS intensity. The results of circular dichroism (CD) and scanning probe microscope (SPM) testified to the formation of the supramolecule and aptamer-As(III) complex, and the observation of transmission electron microscope (TEM) further confirmed that the aggregation of AuNPs could be controlled by the interactions among the aptamer, As(III) and cationic surfactant. The variations of absorbance and RS intensity were exponentially related to the concentration of As(III) in the range from 1 to 1500 ppb, with the detection limit of 40 ppb for the naked eye, 0.6 ppb for colorimetric assay and 0.77 ppb for RS assay. Additionally, the speed of the present biosensor was rapid, and it also exhibited high selectivity over other metal ions with an excellent recovery for detection in real water samples, suggesting that the proposed biosensor will play an important role in environmental detection. PMID- 22842646 TI - In situ Raman scattering study on a controllable plasmon-driven surface catalysis reaction on Ag nanoparticle arrays. AB - Control of the plasmon-driven chemical reaction for the transformation of 4 nitrobenzenethiol to p,p'-dimercaptoazobenzene by Ag nanoparticle arrays was studied. The Ag nanoparticle arrays were fabricated by means of nanosphere lithography. By changing the PS particle size, the localized surface plasmon resonance (LSPR) peaks of the Ag nanoparticle arrays can be tailored from 460 to 560 nm. The controlled reaction process was monitored by in situ surface-enhanced Raman scattering. The reaction can be dramatically influenced by varying the duration of laser exposure, Ag nanoparticle size, laser power and laser excitation wavelength. The maximum reaction speed was achieved when the LSPR wavelength of the Ag nanoparticle arrays matched the laser excitation wavelength. The experimental results reveal that the strong LSPR can effectively drive the transfer of the 'hot' electrons that decay from the plasmon to the reactants. The experimental results were confirmed by theoretical calculations. PMID- 22842647 TI - Sedimentary record of polycyclic aromatic hydrocarbons in a sediment core from a maar lake, Northeast China: evidence in historical atmospheric deposition. AB - A maar lake is an excellent ecosystem to study the atmospheric deposition of pollutants, as its contaminants are primarily by atmospheric deposition. In this study, a sediment core from Sihailongwan Maar Lake, Northeast China, was collected and the historical atmospherically deposited polycyclic aromatic hydrocarbons (PAHs) were analyzed. The concentrations of TPAHs (the sum of the US EPA proposed 16 priority PAHs, excluding naphthalene and pyrene) ranged from 473.9 to 2289 ng g(-1) with a slow increasing stage in the deeper sediments and a sharp increasing stage in the upper sediments. The input rate of TPAHs, especially that of PAH(9) (the sum of fluoranthene, benzo(a)anthracene, chrysene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(a)pyrene, indeno(1,2,3 cd)pyrene, dibenzo(ah)anthrathene, and benzo(ghi)perylene), correlated well to the Chinese historical socioeconomic data. This indicates that sediment PAHs were mainly derived from human activities and PAH(9) can be regarded as a better indicator of the local socioeconomic development. Source identification suggested that PAHs were originated primarily from mixed sources (e.g., coal and biomass burning and petroleum combustion), except for perylene which was mostly of diagenetic origin. In addition, the down-core PAHs profile clearly illustrated that PAHs sources in Northeast China experienced a transformation from low- and moderate temperature to high-temperature combustion processes, especially after the late 1980s. Additionally, an ecological risk assessment using two redefined biological thresholds (TEQ(ERL) and TEQ(ERM)) indicated that most of the PAHs measured in the present sediment core would not cause an immediate toxic effect; only FLU and PHEN are a potential source of concern for biological impairment. PMID- 22842648 TI - Total colonic aganglionosis: a systematic review and meta-analysis of long-term clinical outcome. AB - PURPOSE: Total colonic aganglionosis (TCA) is a severe form of Hirschsprung's disease (HD), occurring in less than 10 % of the cases. It is a challenging surgical condition and outcomes of pull-through (PT) surgery are reported to be inferior to those in patients with recto-sigmoid HD. As even large centres only see a few patients with TCA, there is little information on the long-term outcome of patients after PT operation for TCA. The aim of this meta-analysis was to investigate the long-term clinical outcome in patients with TCA. METHODS: MEDLINE((r)) and EMBASE((r)) databases were searched for relevant articles that reported the outcomes of patients with TCA published between 1980 and 2011. The search terms were "Hirschsprung's disease", "Total colonic aganglionosis" AND "Outcome". All published studies containing adequate clinical data for a mean follow-up period of not less than 4 years were included. Reference lists of retrieved articles were reviewed for additional cases. Detailed records of morbidity and mortality were extracted and analysed. RESULTS: This search yielded 225 articles reporting on outcomes in TCA. Of these, 189 were excluded for having too short a follow-up period, small or single case series, inadequate clinical data and duplicated patient groups. Ultimately, 36 articles from 37 centres containing useful clinical information on the outcomes of TCA in 969 patients were identified. There were 152 early deaths prior to PT (15.7 %). Of 817 survivors, 739 underwent PT. The mortality rate for TCA post-PT was 5.7 %. The most frequently reported post-operative complication was enterocolitis in 42 % of the cases. 17.5 % of patients underwent subsequent major surgery including redo PT, stoma reformation or other laparotomy. Long-term follow-up data were available in 396 patients. Satisfactory or normal bowel control was reported in 60 % of the patients. Soiling, faecal incontinence or other poor outcome was reported in 33.5 % of the cases and 6.5 % of the patients had undergone conversion to a permanent ileostomy for post-operative complications. CONCLUSION: This meta-analysis reveals that a large number of patients with TCA have long term problems with bowel control. PMID- 22842649 TI - Investigation of myoepithelial cell differentiation into Schwann-like cells in salivary adenoid cystic carcinoma associated with perineural invasion. AB - Perineural invasion (PNI) is common in salivary adenoid cystic carcinoma (SACC). The aim of the present study was to explore the association of the Schwann-like cell differentiation with PNI in SACC. Twenty-eight cases of SACC and 10 cases of acinic cell carcinoma (ACA) were examined for the expression of the Schwann cell markers Leu-7 by immunohistochemical staining. The correlation between Leu-7 expression and PNI was analyzed using kappa analysis. Immunofluorescence double staining and pre-embedding immunogold-silver cytochemistry were used to detect the co-expression and the location of Leu-7 and the myoepithelial cell marker alpha-smooth muscle actin (alpha-SMA). PNI was identified in 16 SACCs (57.1%) and 1 ACA (10%) and the overexpression of Leu-7 was detected in 22 SACCs (78.6%) and in none of the ACAs (0%). The differences between PNI and Leu-7 expression in SACC and ACA were significant (P<0.05). A correlation was identified between the expression of Leu-7 and PNI in SACC (kappa=0.533, P=0.01). In SACC, Leu-7 and alpha-SMA were co-expressed in the cytoplasm in the same myoepithelial cells. We suggest that Schwann-like cell differentiation correlates with PNI in SACC and that the differentiation of myoepithelial into Schwann-like cells may be one of the mechanisms through which PNI occurs in SACC. PMID- 22842650 TI - A copper(I)-catalyzed reaction of 2-(2-ethynylphenyl)oxirane, sulfonyl azide, with 2-isocyanoacetate. AB - A novel and straightforward synthetic protocol for the efficient construction of 3',5'-dihydro-1H-spiro[benzo[d]oxepine-2,4'-imidazoles] through a copper(I) catalyzed reaction between 2-(2-ethynylphenyl)oxirane, sulfonyl azide, and 2 isocyanoacetate is described. PMID- 22842651 TI - Antidiabetic and antioxidant activities of Toddalia asiatica (L.) Lam. leaves in streptozotocin induced diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Toddalia asiatica (L.) Lam. have been utilized traditionally for the cure of diabetes. AIM OF THE STUDY: The present study was aimed to assess the antidiabetic and antioxidant effects of T. asiatica leaves in Streptozotocin (STZ) induced diabetic rats. MATERIALS AND METHODS: The phytochemical screening, total phenolic content, HPLC analysis, acute toxicity study and oral glucose tolerance test were carried out. Glucose lowering effect of the hexane, ethyl acetate and methanol extracts of T. asiatica leaves was studied in STZ-induced diabetic rats. The antidiabetic and antioxidant activities were studied for the ethyl acetate extract. The effects of extracts on blood glucose, body weight, plasma insulin, total protein, liver glycogen, plasma enzymes (SGOT, SGPT and ALP) and activities of SOD, CAT and GPx were analyzed. RESULTS: T. asiatica leaves ethyl acetate extract (TALEe) showed highly significant blood glucose lowering effect. Phytochemical evaluation of TALEe showed the presence of alkaloids, terpenoids, cumarins, flavonoids and phenolic compounds. The total phenolic content of TALEe was 126 mg of gallic acid equivalents/g extract. HPLC analysis revealed the presence of flindersine and ulopterol. Acute toxicity study of TALEe revealed no death or toxicity. The oral glucose tolerance test showed lowered area under curve (AUC(glucose)) values in TALEe treated rats. After treatment with TALEe (250 and 500 mg/kg) for 28 days there was a significant decrease in blood glucose, plasma enzymes (SGOT, SGPT and ALP) and significant increase in body weight, total protein, serum insulin and liver glycogen levels in treated diabetic rats. The activities of antioxidant enzymes SOD, CAT and GPx were reversed to near normal in treated diabetic rats. Histopathology of pancreas in TALEe treated groups showed regeneration of beta cells. CONCLUSION: The results of the experiments showed that TALEe exerted significant antidiabetic and antioxidant effects in STZ-induced diabetic rats justifying its traditional use. PMID- 22842652 TI - Modified autologous matrix-induced chondrogenesis (AMIC) for the treatment of a large osteochondral defect in a varus knee: a case report. AB - This paper presents a case report of a 27-year-old male patient affected by a large osteochondral defect of the medial femoral condyle (6 cm(2)) in a varus knee. He was treated with a combined approach consisting of high tibial osteotomy and autologous matrix-induced chondrogenesis technique enhanced by a bone marrow enriched bone graft. Twelve months after surgery, the patient reported considerable reduction in pain and significant increase in his quality of life. A hyaline-like cartilage completely covered the defect and was congruent with the surrounding condyle cartilage as revealed by MRI and by a second-look arthroscopy. Level of evidence IV. PMID- 22842653 TI - Predictors for moderate to severe acute postoperative pain after total hip and knee replacement. AB - PURPOSE: The ability to identify and focus care to patients at higher risk of moderate to severe postoperative pain should improve analgesia and patient satisfaction, and may affect reimbursement. We undertook this multi-centre cross sectional study to identify preoperative risk factors for moderate to severe pain after total hip (THR) and knee (TKR) replacement. METHODS: A total of 897 patients were identified from electronic medical records. Preoperative information and anaesthetic technique was gained by retrospective chart review. The primary outcomes were moderate to severe pain (pain score >= 4/10) at rest and with activity on postoperative day one. Logistic regression was performed to identify predictors for moderate to severe pain. RESULTS: Moderate to severe pain was reported by 20 % at rest and 33 % with activity. Predictors for pain at rest were female gender (OR 1.10 with 95 % CI 1.01-1.20), younger age (0.96, 0.94 0.99), increased BMI (1.02, 1.01-1.03), TKR vs. THR (3.21, 2.73-3.78), increased severity of preoperative pain at the surgical site (1.15, 1.03-1.30), preoperative use of opioids (1.63, 1.32-2.01), and general anaesthesia (8.51, 2.13-33.98). Predictors for pain with activity were TKR vs. THR (1.42, 1.28 1.57), increased severity of preoperative pain at the surgical site (1.11, 1.04 1.19), general anaesthesia (9.02, 3.68-22.07), preoperative use of anti convulsants (1.78, 1.32-2.40) and anti-depressants (1.50, 1.08-2.80), and prior surgery at the surgical site (1.28, 1.05-1.57). CONCLUSIONS: Our findings provide clinical guidance for preoperative stratification of patients for more intensive management potentially including education, nursing staffing, and referral to specialised pain management. PMID- 22842654 TI - Role of trefoil factor 1 in gastric cancer and relationship between trefoil factor 1 and gastrokine 1. AB - Trefoil factor 1 (TFF1) is a small cysteine-rich secreted protein which is principally expressed in the superficial cells of gastric mucosa. In gastric cancer, TFF1 is downregulated and plays an important role. Gastrokine 1 (GKN1) is a secreted protein with similar expression and biological functions to TFF1. This study aimed to determine the expression and biological functions of TFF1 and the relationships between TFF1 and GKN1 in gastric cancer. RT-PCR and immunohistochemistry were performed to detect TFF1 expression in gastric cancer cell lines and tissues. The transfected and co-transfected AGS cells which stably expressed TFF1 or both TFF1 and GKN1 were generated. Phenotypic changes such as cell viability, apoptosis and cell cycle modulation were assayed in the transfected cells. We found that TFF1 expression was significantly downregulated or lost in gastric cancer cell lines, gastric dysplasia and cancer. Restoration of TFF1 expression in AGS cells suppressed tumor cell viability and arrested AGS cells in the G1-S transition phase after olomoucine treatment. However, TFF1 was unable to induce cell apoptosis. In co-transfected cells, we found that TFF1 and GKN1 did not directly interact at the protein level. GKN1 was unable to cooperate with TFF1 on cell viability suppression, cell apoptosis and differentiation. Together, these results indicate that TFF1 expression is significantly downregulated in gastric cancer. TFF1 inhibited cell proliferation by delaying G1 S phase transition but not by inducing apoptosis. TFF1 may not interact or cooperate with GKN1 at the protein and functional level. PMID- 22842655 TI - The sharp slowdown in growth of medical imaging: an early analysis suggests combination of policies was the cause. AB - The growth in the use of advanced imaging for Medicare beneficiaries decelerated in 2006 and 2007, ending a decade of growth that had exceeded 6 percent annually. The slowdown raises three questions. Did the slowdown in growth of imaging under Medicare persist and extend to the non-Medicare insured? What factors caused the slowdown? Was the slowdown good or bad for patients? Using claims file data and interviews with health care professionals, we found that the growth of imaging use among both Medicare beneficiaries and the non-Medicare insured slowed to 1-3 percent per year through 2009. One by-product of this deceleration in imaging growth was a weaker market for radiologists, who until recently could demand top salaries. The expansion of prior authorization, increased cost sharing, and other policies appear to have contributed to the slowdown. A meaningful fraction of the reduction in use involved imaging studies previously identified as having unproven medical value. What has occurred in the imaging field suggests incentive based cost control measures can be a useful complement to comparative effectiveness research when a procedure's ultimate clinical benefit is uncertain. PMID- 22842656 TI - Virtual evaluation of stent graft deployment: a validated modeling and simulation study. AB - The presented study details the virtual deployment of a bifurcated stent graft (Medtronic Talent) in an Abdominal Aortic Aneurysm model, using the finite element method. The entire deployment procedure is modeled, with the stent graft being crimped and bent according to the vessel geometry, and subsequently released. The finite element results are validated in vitro with placement of the device in a silicone mock aneurysm, using high resolution CT scans to evaluate the result. The presented work confirms the capability of finite element computer simulations to predict the deformed configuration after endovascular aneurysm repair (EVAR). These simulations can be used to quantify mechanical parameters, such as neck dilations, radial forces and stresses in the device, that are difficult or impossible to obtain from medical imaging. PMID- 22842657 TI - Effect of Sn addition on the microstructure and superelasticity in Ti-Nb-Mo-Sn alloys. AB - Ti-7.5Nb-4Mo-xSn (x=0-4at%) alloys were developed as the biomedical materials. The effect of the Sn content on the microstructure and superelasticity of the alloys was investigated. It is found that Sn is a strong stabilizer of the beta phase, which is effective in suppressing the formation of alpha" and omega phases in the alloys. Moreover, the Sn addition has a significant impact on the mechanical properties of the alloys. With the increase of Sn addition, the yield stress of the alloys increase, but their elastic modulus, the fracture strength and the ductility decrease, and the deformation mode of the alloys changes from (322) twining to alpha" transformation and then to slip. The Ti-7.5Nb-4Mo-1Sn and Ti-7.5Nb-4Mo-3Sn alloys exhibit a good superelasticity with a high sigma(SIM) due to the relatively high athermal omega phases containing or the solution hardening at room temperature. Under the maximum strain of 5%, Ti-7.5Nb-4Mo-3Sn (at%) alloy exhibits higher super elastic stability than that of Ti-7.5Nb-4Mo-1Sn alloy. PMID- 22842658 TI - The mental health needs of children and adolescents with learning disabilities. AB - PURPOSE OF REVIEW: To provide an update on the mental health needs of children and adolescents with learning disabilities, by examining salient studies published predominantly in the last 12-18 months. RECENT FINDINGS: There have been further articles published supporting the findings of earlier landmark studies demonstrating an increased prevalence of mental health disorders in young people with learning disabilities. These articles suggest higher rates of comorbidity than were previously recognized. There are few published studies pertaining to the effectiveness of psychological and pharmacological treatments, although there is a recognition that the latter are more routinely and perhaps inappropriately administered. Antipsychotics are the most commonly prescribed group of medications and, despite a lack of evidence, continue to be prescribed more to address challenging behaviours rather than in the treatment of an identified psychiatric disorder. Reviews examining services and policies in other countries further highlight that the health and social care needs of individuals with learning disabilities are receiving more attention, with a shared vision that services should be inclusive and preferably community based. SUMMARY: Although there is improved knowledge of the rates of mental health disorders in young people with learning disabilities, in clinical practice these mental health needs continue to be underrecognized and untreated. PMID- 22842659 TI - Genetic correlates of medical comorbidity associated with schizophrenia and treatment with antipsychotics. AB - PURPOSE OF REVIEW: High comorbidity rates for various medical conditions have been documented in schizophrenia, being explained by factors either inherent to the disease or associated with antipsychotic treatment. The aim of this study is to review the genetic factors contributing to medical comorbidity in schizophrenia. RECENT FINDINGS: Based on clinical genetic studies in schizophrenia, comorbid impaired glucose tolerance/type 2 diabetes mellitus, most autoimmune disorders and cardiac autonomic dysregulation have the strongest evidence for familial predisposition. Similarly, of antipsychotic-induced adverse drug reactions, tardive dyskinesia, neuroleptic malignant syndrome, and antipsychotic-induced weight gain have some evidence for familial clustering. On the molecular genetic level, schizophrenia seems to share specific genes with type 2 diabetes mellitus and with autoimmune disorders. Various genes have been proposed to account for the reduced incidence of rheumatoid arthritis and cancer in schizophrenic patients and their relatives. Many pharmacogenetic association studies have pinpointed numerous, though often contradictory or poorly replicated, genes of modest effect size for tardive dyskinesia, neuroleptic malignant syndrome, clozapine-induced agranulocytosis, hyperprolactinaemia, antipsychotic-induced weight gain, and antipsychotic-induced QT prolongation. SUMMARY: Unravelling the genetic underpinnings of medical comorbidity associated with schizophrenia and its treatment is expected to highlight new pathogenetic pathways in both schizophrenia and comorbid medical conditions, and introduce personalized treatment strategies for schizophrenia patients. PMID- 22842660 TI - Biofilms: Watching bacteria build their homes. PMID- 22842661 TI - Genomic insights into the marine sponge microbiome. AB - Marine sponges (phylum Porifera) often contain dense and diverse microbial communities, which can constitute up to 35% of the sponge biomass. The genome of one sponge, Amphimedon queenslandica, was recently sequenced, and this has provided new insights into the origins of animal evolution. Complementary efforts to sequence the genomes of uncultivated sponge symbionts have yielded the first glimpse of how these intimate partnerships are formed. The remarkable microbial and chemical diversity of the sponge-microorganism association, coupled with its postulated antiquity, makes sponges important model systems for the study of metazoan host-microorganism interactions, and their evolution, as well as for enabling access to biotechnologically important symbiont-derived natural products. In this Review, we discuss our current understanding of the interactions between marine sponges and their microbial symbiotic consortia, and highlight recent insights into these relationships from genomic studies. PMID- 22842662 TI - Prediction of radiation pneumonitis in lung cancer patients: a systematic review. AB - PURPOSE: Factors prediction in the development of radiation pneumonitis (RP) remains unclear. A meta-analysis about this was performed. MATERIALS: Articles were searched in February 2012 from PubMed, EMBASE, Cochrane Library and CNKI (Chinese Journal Full-text Database) using the keywords "lung cancer," "radiation pneumonitis" or "radiation lung injury." The outcome was the RP incidence. We pooled the data using RevMan 5.1 software and tested the statistical heterogeneity. RESULTS: We included the following factors: age, gender, weight loss, smoking history, complications, performance status, pre-radiation therapy (RT) pulmonary function, TNM, histological type, tumor location, pre-RT surgery, RT combined with chemotherapy (RCT), RT/RCT combined with amifostine, plasma end/pre-RT TGF-beta1 ratio and irradiation volume. The significant risk factors for RP >= grade 2 were patients with chronic lung disease, tumor located in the middle or lower lobe, without pre-RT surgery, RCT, plasma end/pre-RT TGF-beta1 ratio >=1 and gross tumor volume (GTV). Following factors were identified significant for RP, including tumor located not in the upper lobe, smokers, combined with chronic lung diseases or diabetes mellitus, low pre-RT pulmonary function, RCT, RT/RCT without amifostine and plasma end/pre-RT TGF-beta1 ratio >=1. Dose-volume parameters included the average of mean lung dose (MLD) of disease lung, GTV and V (5), V (10) (>=34 %), V (20) (>=25 %), V (30) (>=18 %) of bilateral lung. CONCLUSIONS: More attention should be paid to the levels of patients' pulmonary function, plasma TGF-beta1 and dose-volume histogram (DVH). Rigorous studies are needed to identify the relationship between the above mentioned factors and RP >=grade 1 or 3. PMID- 22842663 TI - Preoperative exercise capacity in adult inflammatory bowel disease sufferers, determined by cardiopulmonary exercise testing. AB - BACKGROUND AND AIMS: Aerobic exercise capacity appears impaired in children with inflammatory bowel disease (IBD). Whether this holds true in adults with IBD is not known. Using cardiopulmonary exercise testing (CPET), we assessed anaerobic threshold (AT) in such patients comparing data with reference values and other elective surgical patients. We also sought to confirm whether the presence of a fistula further reduced AT. METHODS: CPET was performed between November 2007 and December 2010 on patients awaiting abdominopelvic surgery. Gender-specific normal reference values were used for comparison. Unadjusted comparison between two groups was made using Mann-Whitney U test and by unpaired t test. Data were adjusted by analysis of covariance, using age and sex as covariates. Differences between patients' observed values and reference values were tested using paired t tests. RESULTS: Four hundred and fourteen patients (234 male) were studied (mean +/- SD age, 56.6 +/- 16.4 years; weight, 74.2 +/- 15.6 kg). Adjusted AT values in Crohn's disease (CD) were lower than colorectal cancer (11.4 +/- 3.4 vs 13.2 +/- 3.5 ml.kg(-1).min(-1), p = 0.03) and for all other colorectal disease groups combined (12.6 +/- 3.5 ml.kg(-1).min(-1), p = 0.03). AT of Ulcerative colitis (UC) and CD patients together were reduced compared to population reference values (p < 0.05). CONCLUSION: After adjusting for age and sex, CD patients had a reduced AT compared to patients with colorectal cancer and other colorectal disease groups combined. The pathogenesis of this low AT remains to be defined and warrants further investigation. PMID- 22842664 TI - The association of hospital volume with rectal cancer surgery outcomes. AB - PURPOSE: An association between hospital volume and postoperative mortality has been identified for several oncologic surgical procedures. Our objective was to analyze differences in surgical outcomes for patients with rectal cancer according to hospital volume in the state of California. METHODS: A cross sectional study from 2000 to 2005 was performed using the state of California Office of Statewide Health Planning and Development database. Hospitals were categorized into low (<=30)-, medium (31-60)-, and high (>60)-volume groups based on the total number of rectal cancer operations performed during the study period. RESULTS: Overall, 7,187 rectal cancer operations were performed. Of the 321 hospitals in the study cohort, 72 % (n = 232), 20 % (n = 65), and 8 % (n = 24) were low-, medium-, and high-volume hospitals, respectively. Postoperative mortality was significantly lower- in high-volume hospitals (0.9 %) when compared to medium- (1.1 %) and low-volume hospitals (2.1 %; p < 0.001). High-volume hospitals also performed more sphincter-preserving procedures (64 %) when compared to medium- (55 %) and low-volume hospitals (51 %; p < 0.001). CONCLUSIONS: These data indicate that hospital volume correlates with improved outcomes in rectal cancer surgery. Rectal cancer patients may benefit from lower mortality and increased sphincter preservation in higher-volume centers. PMID- 22842665 TI - Colorectal lateral spreading tumor subtypes: clinicopathology and outcome of endoscopic submucosal dissection. AB - PURPOSE: This study aims to investigate the clinicopathological features of specific subtypes of laterally spreading tumor (LST) and assessed the outcome of endoscopic submucosal dissection (ESD) based upon subdifferentiation status. METHODS: A total of 137 LSTs were present in 135 patients; 96 were granular and 41 exhibited a nongranular pattern. Granular LSTs, subdivided into homogeneous and nodular mixed, and nongranular LSTs, subdivided into flat-elevated and pseudodepressed, were retrospectively evaluated with respect to clinicopathological features and results of ESD (en bloc R0 curative resection, procedure time, complication, and recurrence rate) according to specific subtype. RESULTS: The distribution of high-grade intraepithelial neoplasia and submucosal carcinomas was more prominent among granular nodular mixed tumors than among granular homogeneous tumors (P = 0.007), whereas there was no significant difference between nongranular pseudodepressed tumors and flat-elevated tumors. The frequency of en bloc R0 curative resection did not differ significantly among specific subtypes. For nodular mixed and pseudodepressed lesions, the median tumor size was significantly larger (P < 0.001 for each) and mean procedure time was also longer (P < 0.05 for each) than for the other two subtypes. All complications, which included three perforations, five episodes of postoperative bleeding, and one recurrence, occurred in granular nodular mixed and nongranular pseudodepressed tumors. CONCLUSION: The risk of cancer varies with the subtypes of LSTs. ESD is an effective treatment for LSTs, however ESD is more technically demanding and carries more complications in pseudodepressed and granular mixed subtypes. PMID- 22842666 TI - Pterostilbene, a natural analogue of resveratrol, potently inhibits 7,12 dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin carcinogenesis. AB - We reported previously that pterostilbene, a natural analogue of resveratrol from blueberries, strongly suppressed lipopolysaccharide-induced up-expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in murine macrophages. In this study, we further investigated pterostilbene's molecular mechanism of action and its anti-tumor properties. Pretreatment with pterostilbene has resulted in the reduction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunits. Pterostilbene also reduced TPA-induced phosphorylation of IkappaBalpha and p65 and caused subsequent degradation of IkappaBalpha. Moreover, pterostilbene markedly suppressed TPA-induced activation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)1/2, phosphatidylinositol 3-kinase (PI3K) and Akt, which are upstream of NFkappaB and activator protein 1 (AP-1). Furthermore, pterostilbene significantly inhibited 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced skin tumor formation measured by the tumor multiplicity of papillomas at 20 weeks. The presented data has, for the first time, revealed that pterostilbene is an effective anti-tumor agent that functions by downregulating inflammatory iNOS and COX-2 gene expression in mouse skin. It is suggested that pterostilbene is a novel functional agent capable of preventing inflammation-associated tumorigenesis. PMID- 22842667 TI - Serum sclerostin levels decline in post-menopausal women with osteoporosis following treatment with intermittent parathyroid hormone. AB - OBJECTIVE: This study was carried out in order to evaluate the effect of 18-month treatment with PTH (1-34) or PTH (1-84) on serum sclerostin levels in humans. SUBJECTS AND METHODS: We investigated 10 women with severe osteoporosis, previously treated with alendronate and 20 untreated osteoporotic women. Subjects with severe osteoporosis were randomly divided into 2 groups of 5 patients each; the first group was treated with 20 MUg of PTH (1-34) and the second one with 100 MUg of PTH (1-84) according to an open-label design. Fasting blood samples were collected at baseline and at 2, 4, and 24 h after hormone administration. The same protocol was followed at month 1, 6, 12, 18. Serum sclerostin levels were measured at each time point by a sandwich-type enzyme-linked immunosorbent assay. RESULTS: Basal serum sclerostin levels were not significantly different between patients previously treated with alendronate and those never treated. No significant acute change of serum sclerostin levels was observed after PTH administration. Fitting a mixed effect regression model, we found a significant time effect (p=0.0012) using the sclerostin level as the response variable and the month of drug administration as a single covariate. Treatment with both PTH molecules induced a monthly mean reduction of sclerostin levels of 0.1956 pmol/l. CONCLUSIONS: Our results indicate that long-term therapy with PTH (1-34) or PTH (1-84) in women with osteoporosis previously treated with alendronate is associated with a reduction in circulating sclerostin levels. This is a putative mechanism through which PTH performs its anabolic action. PMID- 22842668 TI - Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis. AB - Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation. PMID- 22842669 TI - Hypoferraemia during the early inflammatory response is dependent on tumour necrosis factor activity in a murine model of protracted peritonitis. AB - On the grounds of clinical, in vitro and in vivo studies, tumour necrosis factor (TNF) is considered to be one of the inflammatory cytokines that contributes to to the generation of hypoferraemia and anaemia of inflammation (AI). We used a recently described murine model for AI and hypoferraemia, based on sublethal caecal ligation and puncture (CLP) with ensuing protracted peritonitis, to investigate the contribution of TNF to the generation of hypoferraemia. During the early inflammatory response to CLP, a marked decrease in serum iron concentration occurs within 8 h. To determine whether TNF contributes to the generation of hypoferraemia at this time point, we studied TNF-deficient mice and wild-type mice that underwent CLP. The serum iron concentration was decreased in wild-type mice whereas TNF-deficient mice maintained normal serum iron levels following CLP. Hypoferraemia in wild-type mice was accompanied by the downregulation of ferroportin 1 (Fp1) in macrophages. In the macrophages of TNF deficient mice, Fp1 was not downregulated following CLP. The initial expression of hepcidin was detectable at the mRNA level but not at the protein level by immunohisto-chemistry in wild-type and TNF-deficient mice. Therefore, hepcidin does not appear to be involved in the regulation of early hypoferraemia. TNF appears to regulate the expression of Fp1 by transcriptional control. Our results demonstrate that TNF mediates hypoferraemia during the early inflammatory response by regulating the expression of Fp1 in macrophages. PMID- 22842671 TI - The role of thermodynamics and kinetics in ligand binding to G-quadruplex DNA. AB - Molecular dynamics simulations were used to investigate the binding of four different 2,4,6-triarylpyridines to G-quadruplex DNA. Both the binding free energies, and the kinetics of binding are required to explain the measured degree of ligand induced stabilisation of the compounds, with bulky substituents having the potential to prevent the ligand from reaching the lowest energy binding site. PMID- 22842670 TI - PhiC31 integrase-mediated cassette exchange in silkworm embryos. AB - To construct an effective site-specific integration system in the silkworm, we examined if phiC31 integrase works in silkworm embryos. As an assay system, we constructed an extrachromosomal cassette exchange reaction system between two attP sites of an acceptor plasmid and two attB sites of a donor plasmid. To evaluate the activity, integrase mRNAs synthesized from three different plasmids were used. We injected a mixture of the acceptor and donor plasmids with the mRNA synthesized in vitro from one of the three plasmids into silkworm embryos at 4-6 h after oviposition and recovered plasmid DNAs from the embryos 3 days after injection. The resultant plasmids were transformed into Escherichia coli and spread on selection medium plates containing the appropriate antibiotics. A colony-forming assay and restriction enzyme digestion of the plasmids purified from the colonies showed that the phiC31 integrase worked very efficiently in the silkworm embryos. Notably, a phiC31 integrase mRNA synthesized from two of the plasmids produced cassette exchange plasmids at a high frequency, suggesting that the mRNA can be used to construct a targeted integration system in silkworms. PMID- 22842672 TI - Prevalence and severity of atopic dermatitis in Jeju Island: a cross-sectional study of 4,028 Korean elementary schoolchildren by physical examination utilizing the three-item severity score. AB - The objective of this study was to evaluate the precise prevalence of atopic dermatitis (AD) in schoolchildren in Jeju Island in South Korea examined in 2009. Nine elementary schools were randomly selected from Jeju Island and a total of 4,028 schoolchildren were examined by a dermatologist. AD was diagnosed based on the Korean Atopic Dermatitis Research Group criteria for the disease. The severity of AD was measured with the three-item severity score (TIS). The point prevalence of AD was 9.5% overall. The prevalence among higher graders (age 9-12 years) was significantly lower than that in lower graders (age 6-9 years) (7.5% vs. 11.9%, < 0.00001). AD prevalence in girls (11.1%) was higher than that in boys (8.1%) (<0.005). In each grade, more than 50% of those affected had the mild form (TIS score 1 or 2). There were no apparent differences in severity of AD between grades or genders. This is the first Asian study of prevalence in schoolchildren using TIS score for evaluating AD severity. PMID- 22842673 TI - The use of a versatile o-vanilloyl hydrazone ligand to prepare SMM-like Dy3 molecular cluster pair. AB - A novel lanthanide molecular cluster pair (MCP), displaying single molecule magnet behaviour, was assembled using the novel o-vanilloyl hydrazone ligand, versatile in terms of denticity, tautomerism and the rotatable C-C bond. PMID- 22842674 TI - Association and CpG SNP analysis of HTR4 polymorphisms with suicidal behavior in subjects with schizophrenia. AB - Suicide is a major contributor to the morbidity and mortality rates in schizophrenia. Genetic and epigenetic factors have been reported to modulate the risk for suicide although the precise mechanism and magnitude of these contributions is unknown. Previous research indicates that suicide attempters present abnormalities in the serotonergic system. The present study aimed to identify genetic and epigenetic risk variants of the serotonin 5-HT4 receptor gene (HTR4) for suicidal behavior. We included 234 subjects diagnosed with schizophrenia. For this purpose, we analyzed 11 markers across HTR4 and performed genotype, haplotype and potential methylation analyses, correcting for clinical covariates and ethnic stratification. Three blocks were revealed from the LD analysis. Haplotypes in Block 3 were significantly associated with suicide attempt. The potential methylation analysis was not significant. Our results suggest that HTR4 polymorphisms may not play a major role in the susceptibility for suicidal behavior in subjects with schizophrenia. Moreover, although not significant, the CpG SNP potential methylation analysis would be informative for future methylation analysis on this gene. PMID- 22842675 TI - Comparative evaluation of the potency and antigenicity of two distinct BoNT/A derived formulations. AB - IncobotulinumtoxinA (Xeomin(r)) and onabotulinumtoxinA (BOTOX(r)) are unique botulinum neurotoxin type A (BoNT/A)-derived drugs. IncobotulinumtoxinA utilizes the naked 150 kDa holotoxin portion of BoNT/A, whereas onabotulinumtoxinA uses the complete native 900 kDa complex as drug substance. On the basis of purportedly similar pharmacological characteristics, these formulations were evaluated for potency by LD50 and mouse Digit Abduction Score (DAS) bioassays. DAS was also used to assess antigenicity. Full-range DAS dose-response profiles were achieved with four lots of each product, with similar observations between lots for a given product. Between products, however, the mean DAS potency of incobotulinumtoxinA (ED50 range 7.0-10.2 U/kg) was significantly lower than that of onabotulinumtoxinA (ED50 range 4.4-6.4 U/kg), consistent with lower measured potencies in the LD50 assay for incobotulinumtoxinA (potency range 62-82 U). In assessments of DAS duration of effect at similar unit doses, the observed lower potency of incobotulinumtoxinA translated into decreased peak efficacy and dose effect over time (i.e. shorter duration). In contrast, at equi-efficacious doses yielding near-maximal DAS responses, both toxin formulations were uniformly inhibited in a statistically significant manner when preincubated with rabbit derived, onabotulinumtoxinA-neutralizing antibodies, supporting the position that inhibition of 150 kDa holotoxin serves as the common basis for neutralization and, therefore, incobotulinumtoxinA would not be expected to be effective in onabotulinumtoxinA-immunoresistant subjects (and vice versa). Further, with lower lot-to-lot relative potency, incobotulinumtoxinA is not dose-equivalent or interchangeable with onabotulinumtoxinA, suggesting that various aspects of drug product formulation may influence observed pharmacology. PMID- 22842676 TI - 70th Birthday symposium of Prof. Dr. Riederer: autologous adult stem cells in ischemic and traumatic CNS disorders. AB - Ischemic and traumatic insults of the central nervous system both result in definite chronic disability, only to some extent responsive to rehabilitation. Recently, the application of autologous stem cells (fresh bone marrow-derived mononuclear cells including mesenchymal and hematopoietic stem cells) was suggested to provide a strategy to further improve neurological recovery in these disorders. During the acute phase, stem cells act mainly by neuroprotection with prevention of apoptosis, whereas during the chronic situation they provide neurorestoration by transdifferentiation and/or the secretion of neurotrophic factors. To reach these goals, in the acute phase, stem cells (10 million mononuclear cells per kg body weight) might be best applied intravenously, as during the first 7 days after the lesion, the blood-brain barrier permits passage of cells from the blood into the brain or the spinal cord. In the more chronic situation, though, those cells might be applied best intrathecally by lumbar puncture. Based on the reported results so far, it seems justified to develop well-designed clinical double-blind trials in chronic spinal cord injury and ischemic stroke patients, as efficacy and safety concerns might not be answered by preclinical studies. PMID- 22842678 TI - Monte Carlo modelling of diode detectors for small field MV photon dosimetry: detector model simplification and the sensitivity of correction factors to source parameterization. AB - The goal of this work was to examine the use of simplified diode detector models within a recently proposed Monte Carlo (MC) based small field dosimetry formalism and to investigate the influence of electron source parameterization has on MC calculated correction factors. BEAMnrc was used to model Varian 6 MV jaw collimated square field sizes down to 0.5 cm. The IBA stereotactic field diode (SFD), PTW T60016 (shielded) and PTW T60017 (un-shielded) diodes were modelled in DOSRZnrc and isocentric output ratios (OR(fclin)(detMC)) calculated at depths of d = 1.5, 5.0 and 10.0 cm. Simplified detector models were then tested by evaluating the percent difference in (OR(fclin)(detMC)) between the simplified and complete detector models. The influence of active volume dimension on simulated output ratio and response factor was also investigated. The sensitivity of each MC calculated replacement correction factor (k(fclin,fmsr)(Qclin,Qmsr)), as a function of electron FWHM between 0.100 and 0.150 cm and energy between 5.5 and 6.5 MeV, was investigated for the same set of small field sizes using the simplified detector models. The SFD diode can be approximated simply as a silicon chip in water, the T60016 shielded diode can be modelled as a chip in water plus the entire shielding geometry and the T60017 unshielded diode as a chip in water plus the filter plate located upstream. The detector-specific (k(fclin,fmsr)(Qclin,Qmsr)), required to correct measured output ratios using the SFD, T60016 and T60017 diode detectors are insensitive to incident electron energy between 5.5 and 6.5 MeV and spot size variation between FWHM = 0.100 and 0.150 cm. Three general conclusions come out of this work: (1) detector models can be simplified to produce OR(fclin)(detMC) to within 1.0% of those calculated using the complete geometry, where typically not only the silicon chip, but also any high density components close to the chip, such as scattering plates or shielding material is necessary to be included in the model, (2) diode detectors of smaller active radius require less of a correction and (3) (k(fclin,fmsr)(Qclin,Qmsr)) is insensitive to the incident the electron energy and spot size variations investigated. Therefore, simplified detector models can be used with acceptable accuracy within the recently proposed small field dosimetry formalism. PMID- 22842677 TI - The science of rotator cuff tears: translating animal models to clinical recommendations using simulation analysis. AB - PURPOSE: The purpose of this article is to review basic science studies using various animal models for rotator cuff research and to describe structural, biomechanical, and functional changes to muscle following rotator cuff tears. The use of computational simulations to translate the findings from animal models to human scale is further detailed. METHODS: A comprehensive review was performed of the basic science literature describing the use of animal models and simulation analysis to examine muscle function following rotator cuff injury and repair in the ageing population. RESULTS: The findings from various studies of rotator cuff pathology emphasize the importance of preventing permanent muscular changes with detrimental results. In vivo muscle function, electromyography, and passive muscle-tendon unit properties were studied before and after supraspinatus tenotomy in a rodent rotator cuff injury model (acute vs chronic). Then, a series of simulation experiments were conducted using a validated computational human musculoskeletal shoulder model to assess both passive and active tension of rotator cuff repairs based on surgical positioning. CONCLUSION: Outcomes of rotator cuff repair may be improved by earlier surgical intervention, with lower surgical repair tensions and fewer electromyographic neuromuscular changes. An integrated approach of animal experiments, computer simulation analyses, and clinical studies may allow us to gain a fundamental understanding of the underlying pathology and interpret the results for clinical translation. PMID- 22842680 TI - Strategies to prevent progression of high-risk bladder cancer at initial diagnosis. AB - PURPOSE OF REVIEW: As high-risk nonmuscle invasive bladder cancer (NMIBC) has a high propensity to recur and progress, the primary therapeutic goal in patients with high-risk NMIBC is the prevention or delay of disease recurrence and progression. RECENT FINDINGS: For improving transurethral resection quality, new optical enhancement technology such as optical coherence tomography, photodynamic diagnosis and narrow band imaging might be considered because these emerging optical techniques may contribute to resection completeness and reduce the recurrence risk. Recent studies have confirmed that a second resection is associated with a lower risk of progression and cancer-related death. Although maintenance bacillus Calmette-Guerin (BCG) for at least 1 year has been recommended, some studies have shown no significant advantage to maintenance BCG. Although other options may be considered in early BCG failure, there are no large trials that have shown a long-term benefit in BCG-failure patients. SUMMARY: Current literature suggests that the best treatment for patients with high-risk NMIBC involves complete transurethral resection with intravesical BCG therapy. New approaches or therapeutic agents for preventing recurrence and progression are needed in this field. PMID- 22842679 TI - GH responses to two consecutive bouts of respiratory muscle endurance training in healthy adults. AB - Repetition of voluntary exercise bouts and of different pharmacological GH releasing stimuli at 2-h intervals is associated with a complete abolishment of GH responsiveness. By contrast, a different pattern is observed after repeated neuromuscular electrostimulation, which is characterized by preservation of GH responsiveness. Aim of the study was to evaluate GH responses to repeated bouts of respiratory muscle endurance training (RMET) by mean of a specific commercially available device (Spiro Tiger(r)). Eight healthy men underwent an incremental progressive RMET protocol of 11 daily sessions. Blood samplings for GH, cortisol and lactate (LA) determinations were collected during the 12th session, which was composed of two consecutive bouts of RMET (of identical intensity and duration: 1 min at a respiration rate of 28 acts/min, 5 min at 32 acts/min, 5 min at 34 acts/min, 4 min at 36 acts/min) at a 2 h interval. Baseline GH levels (mean: 0.9+/-0.4 ng/ml) significantly (p<0.01) increased after the first bout of RMET (peak: 15.7+/-4.0 ng/ml). The administration of the second bout of RMET resulted in a significantly lower (p<0.05) GH increase (peak: 3.9+/ 0.8 ng/ml) in comparison with the first one. Baseline LA levels (mean: 1.2+/-0.1 mmol/l) significantly increased (p<0.001) after the first bout of RMET (peak: 2.3+/-0.2 mmol/l). The administration of the second RMET bout resulted in a comparable LA increase (from a basal value of 1.2+/-0.1 mmol/l up to a peak of 2.0+/-0.1 mmol/l, p<0.001). The first bout of RMET caused a significant increase of cortisol levels (p<0.01), starting from a basal mean value of 142.9+/-9.4 ng/ml up to a peak of 188.8+/-10.3 ng/ml. By contrast, the second bout of RMET did not induce any significant change of cortisol levels (basal: 149.1+/-9.0 ng/ml, peak: 168.5+/-5.1 ng/ml). In conclusion, a single bout of RMET is capable of stimulating GH and cortisol secretions and LA production. When a second bout is repeated after 2 h, there is a blunting of GH and cortisol responses with a preservation of LA release. Further studies are needed to schedule long-term RMET protocols capable of persistently stimulating GH-IGF-I release and to maximally enhance the ergogenic and metabolic benefits of this intervention either in normal subjects (e.g. athletes) or patients with an impairment of motor capabilities requested to perform normal daily activities (i.e. severely obese and elderly people). PMID- 22842681 TI - High-risk nonmuscle invasive bladder cancer: definition and epidemiology. AB - PURPOSE OF REVIEW: Nonmuscle invasive bladder cancer represents a large majority of patients diagnosed with this disease. Precise definition and risk stratification are paramount in this group as high-risk patients have higher rates of progression and mortality and may benefit from early identification and aggressive treatment. RECENT FINDINGS: The mainstay definitions of high-risk nonmuscle invasive bladder cancer are based on grade and stage. Recently, efforts have been made to incorporate other clinical variables into multivariate risk assessment tools and nomograms to predict disease behavior and guide management. Variant histology and molecular biomarkers are being explored as tools to refine risk stratification; however, results are still preliminary and need validation. SUMMARY: Future research should concentrate on ways to better risk-stratify patients and identify early those that are most likely to recur and progress quickly. Topics of focus should be on better multivariate risk assessment tools and nomograms providing continuous scales and incorporating molecular markers with validation in large multi-institutional cohorts. PMID- 22842682 TI - What's the price of a tan? PMID- 22842683 TI - In the shadows: parents of seriously ill adult children. AB - Life-threatening diseases are being diagnosed at younger ages and successfully managed for longer periods of time. Adult patients increasingly will have parents who want to be present and help during treatment. Little is known about how best to include parents of adult children in the nursing plan of care. Healthcare professionals must balance the independence and privacy needs of adult patients with parents' desire to help and provide care. PMID- 22842684 TI - The development of evidence-based supportive therapy guidelines for symptom management. AB - Systematic incorporation of toxicity assessment and grading during cancer treatment and subsequent provision of evidence-based patient interventions according to national standards for excellence are daunting tasks. To accomplish those goals, the authors' institution developed evidence-based supportive therapy guidelines for symptom management. This article describes how the guidelines provided concise, user-friendly standardization of toxicity grading and immediate clinical application of evidence-based care. PMID- 22842685 TI - Informed consent and patients with cancer: role of the nurse as advocate. AB - Informed consent is an ongoing process, and oncology nurses are important advocates to identify information gaps and patient concerns during this process. This article discusses the rights of research participants from a regulatory perspective. Two case scenarios are presented and discussed to describe how nurses can ensure that patients are truly informed and understand the clinical trial process. PMID- 22842686 TI - An innovative off-campus infusion suite designed to improve experiences of patients with cancer. AB - The Brooklyn Infusion Center of Memorial Sloan-Kettering Cancer Center was established in 2010 to better meet the needs of patients with cancer living in the Brooklyn neighborhood and surrounding areas. A multidisciplinary team comprising clinical, administrative, planning, and other representatives were charged to identify and develop a location that would provide oncology care for patients closer to home and improve the patients' experience. The primary objectives were to provide patient-centered care that accommodates the patients' preference to receive treatment closer to home and to take advantage of technology to establish processes that will provide safe, efficient, convenient, and high-quality care in a cost-effective manner. To achieve these objectives, no laboratory processing or pharmacy services were included in the plan for the Brooklyn location. This allowed the elimination of most of the challenges involved with same-day blood draws and chemotherapy orders. In addition, computer technology is used for teledermatology and other medical visits to maintain the continuity of the patients' care with their multidisciplinary teams at the Manhattan, NY, location. The data presented will illustrate how these processes have improved patients' experiences by reducing wait times for treatment, providing treatment closer to home, and implementing a truly patient-centered nursing care model. PMID- 22842687 TI - Post-thoracotomy pain syndrome: assessment and intervention. AB - Surgery is a cornerstone of treatment in early-stage non-small cell lung cancer. Chronic postoperative thoracotomy pain, post-thoracotomy pain syndrome (PTPS), is a condition occurring in 50% of postsurgical patients with lung cancer and is largely unrecognized. This article examines the diagnosis and treatment of PTPS to assist oncology nurses in providing better care to this patient population. Post-thoracotomy pain in patients with lung cancer may be under-reported and undertreated. Causes from the thoracotomy can be trauma and compression to the intercoastal nerves, fractured and compressed ribs, inflammation of the chest muscles, atrophy of chest muscles, or scar tissue rubbing. This article examines the diagnosis and treatment of PTPS to assist oncology nurses in providing better care to this patient population. If left untreated, chronic pain can have a deleterious effect on patients' recovery and overall well-being. Oncology nurses should be aware of the signs and symptoms of PTPS so that more patients are diagnosed and choose to seek treatment. PMID- 22842688 TI - Cancer support and resource needs among African American older adults. AB - Older African Americans face substantial barriers to state-of-the-art cancer care. Implementing culturally appropriate support throughout cancer therapy is critical to improving cancer outcomes and quality of life for this vulnerable population. The purpose of this study was to obtain experiential data regarding cancer diagnosis and treatment, and analyze survivors' recommendations regarding treatment-related needs, psychosocial support, and strategies and resources. Four main issues emerged from the study: (a) the need for more health-related and cancer-specific education, (b) the importance of faith and spirituality, (c) the availability of support, and (d) participants' difficulty identifying and articulating financial needs. Few participants reported requesting or receiving assistance (financial or otherwise) outside of the family during their cancer experience. However, treatment-related medication costs posed a significant hardship for many. PMID- 22842689 TI - Perceptions of roles, practice patterns, and professional growth opportunities: broadening the scope of advanced practice in oncology. AB - Broadening the scope of advanced practice providers (APPs) has been offered as a solution to increasing healthcare costs, workforce shortage, and increased demand. To understand present scope and barriers to broadening it, the authors describe the perceptions and practice patterns of APPs. This cross-sectional study used a computerized self-report survey of 32 targeted nurse practitioners and physician assistants employed in the cancer center of an urban teaching hospital; 31 were included in the quantitative analyses. Survey items covered education and training background, expertise, professional resources and support, duties, certification, and professional development. Respondents practiced in a variety of oncology specialty areas, but all had advanced degrees, most held specialty certifications, and 39% had attended a professional or educational meeting within the last year. They spent a majority of their time on essential patient-care activities, but clerical duties impeded these; however, 64% reported being satisfied with the time they spent with patients and communicating with collaborating physicians. A model of advanced oncology practice needs to be developed that will empower APPs to provide high-quality patient care at the fullest extent of their knowledge and competence. PMID- 22842690 TI - Bowel obstruction and delirium: managing difficult symptoms at the end of life. AB - Palliative care has become an essential component of oncology care, with a focus on maximizing quality of life and optimizing function, as well as promoting pain and symptom management. This article focuses on the care of a patient experiencing bowel obstruction and delirium, two common issues in patients with advanced cancer, and demonstrates the integration of palliative care and oncology care to achieve an individualized care plan. Management focuses on identifying and treating reversible causes and improving quality of life while respecting the patient's values and goals. Sometimes the causes are not easily identified or treatment of the cause may impair quality of life, at least temporarily. At other times, the causes may be irreversible and the focus is exclusively on quality of life. Determination of best care for individual patients requires synthesis of data from holistic assessment, including the patient's goals of care and values, as well as knowledge of the patient's disease state with evidence-based approaches to management. PMID- 22842691 TI - Evaluation of a cancer survivorship protocol: transitioning patients to survivors. AB - This article describes the implementation and evaluation of a survivorship protocol for cancer survivors to improve knowledge about their disease and decrease anxiety. The study included a convenience sample of 30 cancer survivors at an outpatient community cancer center in the southeastern United States following completion of acute oncology treatment. One month after the survivorship protocol was delivered, knowledge about diagnosis, treatments, recommended follow-up, signs of recurrence, and late side effects increased. Anxiety scores were lower one month after the intervention, and satisfaction with the protocol was high. The results demonstrated that the survivorship protocol is a feasible method of educating cancer survivors, supporting the Institute of Medicine's recommendation that strategies for delivering education to cancer survivors are important. Survivors have additional needs that must be addressed following treatment, and a survivorship protocol can provide the knowledge survivors need to participate in their own health care. PMID- 22842692 TI - The use of metaphor in discourse about cancer: a review of the literature. AB - Imagery and metaphors are used throughout health communication and can be particularly powerful in discourse about cancer. Providers, patients, and the media may use descriptive language to convey the impact and experience of the disease. This article reviews the literature on metaphor in discourse about cancer and its effects. Also, the positive and negative effects of popular cancer related imagery, such as military and journey metaphors, are explored. Metaphor can be used in nursing, through thoughtful use of imagery, to improve patient centered care. By noting the imagery used by patients to describe their experiences with cancer, nurses can find a common language for connecting with patients and can advocate for greater awareness and more sensitive communication by other healthcare providers. PMID- 22842693 TI - Treatment-related diarrhea in patients with cancer. AB - Diarrhea caused by chemotherapy or radiation in patients with cancer can cause dehydration, electrolyte imbalance, malnutrition, fluid depletion, and hospitalization. In severe cases, uncontrolled diarrhea can lead to therapy dose reductions or even death. Oncology professionals may simply assess for the absence or presence of diarrhea, rather than using a standard assessment tool; they also may lack awareness regarding availability of established assessment and treatment guidelines. However, use of treatment guidelines can lead to optimal prevention and management of treatment-induced diarrhea in patients with cancer. Oncology nurses play a key role in the identification and treatment of chemotherapy- and radiation therapy-induced diarrhea. PMID- 22842694 TI - Dermatologic assessment from a distance: the use of teledermatology in an outpatient chemotherapy infusion center. AB - Treatment-related dermatologic toxicities are common for patients with cancer. Rashes associated with dermatologic toxicities are best treated by a physician who specializes in dermatologic conditions resulting from cancer treatment, but scheduling and travel may present challenges for patients. This article describes a pilot project in which nurses used telemedicine technology to facilitate patient visits with an off-site dermatologist. PMID- 22842695 TI - Oncology nursing in Cuba: report of the delegation. AB - In December 2011, the first delegation of oncology nurses from the United States visited Havana, Cuba. The delegation included oncology nurses, educators, and leaders from across America and provided opportunities to learn about the healthcare system, cancer, and oncology nursing in Cuba. Delegation members attended lectures, toured facilities, and enjoyed Cuban culture. This exchange highlighted the similarities in cancer care and oncology nursing between countries and opened doors for future collaborations. PMID- 22842696 TI - Making a lasting impression. PMID- 22842697 TI - Chemotherapy and biotherapeutic agents for autoimmune diseases. AB - New trends have emerged in treating patients with autoimmune diseases with medications traditionally used in oncology. This article will summarize a comprehensive literature review performed to identify effective chemotherapy and biotherapeutic agents for treating each of the main autoimmune subtypes (nervous, gastrointestinal, blood and blood vessel, skin, endocrine, and musculoskeletal systems). In addition to agents currently used, some of the newer therapeutic options show great promise to radically improve treatment choices when considering individualized plans. Improved outcomes and symptom management using newer nontraditional therapies provide a great impetus for oncology and nononcology healthcare professionals to remain abreast of the advancements made to current treatment options. All nurses (oncology and nononcology) need to be aware of these new trends and strengthen their understanding of certain oncology medications and their side effects, as well as establish the safe-handling practices necessary to administer these agents. The Oncology Nursing Society's Treatment Basics Course is one option that can provide nononcology nurses with the knowledge needed to fulfill new practice gaps. In addition, oncology nurses need to be aware of the many autoimmune diseases that may be treated with chemotherapy or biotherapy. PMID- 22842698 TI - Efficacy and cost: avoiding undertreatment of chemotherapy-induced nausea and vomiting. AB - Although nausea and vomiting occur in patients with cancer for various reasons, chemotherapy-induced nausea and vomiting (CINV) remains one of the most distressing symptoms associated with cancer therapy. Despite advances in the management of that side effect, patients with cancer receiving chemotherapy continue to report CINV. Oncology nurses should be aware of advances in the management of CINV. Healthcare provider perceptions of CINV may not accurately represent actual occurrence of the symptom, and CINV may affect patients' quality of life or even treatment adherence for selected patients. Although evidence based guidelines are available, not all healthcare providers, including oncology nurses, follow recommendations for prevention of CINV. Inadequately treated CINV can lead to increased resource costs, as well as patient suffering. This article will review the evidence for the cost of inadequately treated CINV, as well as current clinical guidelines for management of this symptom. Oncology nurses are critical in the assessment and management of CINV, as well as in making recommendations for practice improvement. PMID- 22842700 TI - Assessment and implementation of spirituality and religiosity in cancer care: effects on patient outcomes. AB - Spirituality and religiosity have been defined by several governing bodies to mean everything from purpose in life, beliefs, faith, and hope, to transcendence with a higher being. The absence of uniformity regarding the components of spirituality and religiosity has created a barrier for professional caregivers in identifying, assessing, and providing spiritual needs. The diagnosis of cancer often leads patients to contemplate their own mortality and frequently presents unique challenges to their belief system. Spirituality is a unique component of holistic care. When appropriately addressed, it may strongly influence positive patient outcomes during the cancer journey. Consequently, nurses should actively participate in and incorporate the provision of spiritual care into the treatment plan for each patient with cancer or at least be able to assess those needs and make sure they are being addressed. PMID- 22842699 TI - Discharge needs of allogeneic transplantation recipients. AB - Hematopoietic cell transplantation (HCT) recipients are one of the most complex patient populations to teach at the time of discharge. The purpose of this article is to discuss the qualitative themes that emerged at the time of discharge for 141 transplantation recipients who were enrolled in an advanced practice nurse (APN) intervention study. The APN intervention consisted of six teaching sessions, and the qualitative data for this article involved the first session at the time of discharge. Content analysis was conducted on the patient initiated narrative content and structured into three groups: content scheduled to be covered at Session 1, content scheduled to be covered at a later session, and content that was not part of the scripted intervention. All topics were organized into the quality-of-life framework (physical, psychological, social, and spiritual or survivorship). Most of the patient-initiated topics, which were not part of the scripted intervention, were psychosocial in nature. Nurses need to be aware of the complex teaching needs that encompass not only physical issues but also psychosocial issues at discharge. That teaching awareness needs to be coupled with flexibility, competence, and comfort with challenging psychosocial issues. PMID- 22842701 TI - Induction of apoptosis and reduction of MMP gene expression in the U373 cell line by polyphenolics in Aronia melanocarpa and by curcumin. AB - Malignant brain tumours are rare but are the most challenging types of cancers to treat. Despite conventional multimodality approaches available for their management, the outlook for most patients remains dismal due to the ability of the tumour cells to invade the normal brain. Attention has now focused on novel therapeutic interventions such as as the use of micronutrients. Both chokeberry extract (Aronia melanocarpa), which is rich in natural pigments such as anthocyanins and curcumin (diferuloylmethane) found in turmeric (Curcuma longa) have been reported to possess anticancer properties in other cancers. The aim of this study was to extend our previous research to evaluate the therapeutic potential of these two agents by testing their ability to induce apoptosis in an established glioblastoma cell line (U373). This was accomplished by treating the cells for 48 h with either chokeberry extract or curcumin, and using the Annexin V assay. Gene profiles of 8 MMPs (2, 9, 14, 15, 16, 17, 24 and 25) and 4 TIMPs (1, 2, 3 and 4) were analysed for effects of mediators of invasion by quantitative real-time polymerase chain reaction (RT-PCR). The IC50 values determined for curcumin and chokeberry extract were 15 and 200 ug/ml, respectively. Our results also suggest that curcumin induces apoptosis but chokeberry extract is necrotic to this cell line. It is possible that chokeberry extract kills the cells by other non-apoptotic pathways. In addition, the RT-PCR results show downregulation of the gene expression of MMP-2, -14, -16 and -17 for both micronutrients. Taken together, the comparative data suggest that both curcumin and chokeberry extract may exhibit their anticancer potential by inducing apoptosis and inhibiting invasion by reducing MMP gene expression. PMID- 22842702 TI - The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens. AB - Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia, and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have also been frequently identified in patients with CBAVD. However, the distribution of the CFTR polymorphisms M470V, poly-T, TG-repeats and F508del mutation in the Chinese CBAVD population with presumed low cystic fibrosis (CF) frequency remains to be evaluated. Samples obtained from 109 Chinese infertile males with CBAVD and 104 normal controls were analyzed for the presence of CFTR (TG)m(T)n, M470V and F508del by PCR amplification followed by direct sequencing. Our study showed that the F508del mutation was not found in our patients. The 5T mutation was present with high frequency in Chinese CBAVD patients and IVS8-5T linked to either 12 or 13 TG repeats was highly prevalent among CBAVD patients (97.22% of 72 cases and 96.91% of 97 alleles with IVS8-5T). Moreover, a statistically significant relationship between TG12-5T-V470 haplotype and CBAVD was detected. This study indicated that the CFTR polymorphisms poly-T, TG-repeats and M470V might affect the process of CBAVD in the Chinese population. PMID- 22842703 TI - Sperm counts and sperm sex ratio in male infertility patients. AB - In recent years, investigators have noted a trend toward a declining proportion of male births in many industrialized nations. While men bear the sex-determining chromosome, the role of the female partner as it pertains to fertilization or miscarriage may also alter the gender ratio. We attempted to determine a man's secondary sex ratio (F1 generation) by directly examining the sex chromosomes of his sperm. We examined our male infertility clinic database for all men who had undergone a semen fluorescence in situ hybridization (FISH). Patient demographic and semen parameters were recorded. Chi-squared analysis was used to compare gender ratios (Y chromosomes/total chromosomes). Multivariable logistic regression was used to predict the odds of possessing a Y-bearing sperm after accounting for demographic and semen parameters. A total of 185 men underwent sperm FISH. For the entire cohort, the proportion of Y chromosome-bearing sperm was 51.5%. Men with less than five million motile sperm had a significantly lower proportion of Y chromosome-bearing sperm (50.8%) compared to men with higher sperm counts (51.6%; P=0.02). After multivariable adjustment, a higher sperm concentration, total motile sperm count and semen volume significantly increased the odds of having a Y chromosome-bearing sperm (P<0.01). As a man's sperm production declines, so does the proportion of Y chromosome-bearing sperm. Thus, a man's reproductive potential may predict his ability to sire male offspring. PMID- 22842704 TI - Study clarifies associations between hypogonadism and health in aging men. AB - Tajar and colleagues present the associations between moderate and severe hypogonadism, symptoms of androgen deficiency and the prevelence of end-organ evidence of androgen deficency in 2966 older men in the European Male Aging Study. They find lower muscle mass, reduced bone mineral density, anemia, insulin resistence, metabolic syndrome and cardiovascular disease, with greater risks of these signs of androgen deficiency at lower serum testosterone concentrations. PMID- 22842705 TI - A picture with more details is painted for prostate cancer. PMID- 22842706 TI - Mapping mutations in prostate cancer exomes. AB - Comprehensive identification of driver mutations in prostate cancer can serve to enhance our understanding of the disease and expand the use of available treatment options. Two recent and complementary studies from Barbieri et al.1 and Grasso et al.2 have reported the results of exome sequencing analysis in large cohorts of primary, treatment-naive and lethal castration-resistant prostate cancer (CRPC) cases, respectively. Together, these analyses revealed a number of novel genetic mutations representing uncharacterized drivers as well as combinations of mutations that may define important prostate cancer subtypes. PMID- 22842707 TI - Expression of hBD-2 induced by 23-valent pneumococcal polysaccharide vaccine, Haemophilus influenzae type b vaccine and split influenza virus vaccine. AB - Human beta-defensin-2 (hBD-2) is an antimicrobial peptide with high activity and broad spectrum activity. hBD-2 expression may be highly elevated by microorganisms and inflammation. We reported that the majority of common vaccines used, including 23-valent pneumococcal polysaccharide vaccine, Haemophilus influenzae type b vaccine and split influenza virus vaccine, could induce the expression of hBD-2 in epithelial cells. Among them, the 23-valent pneumococcal polysaccharide vaccine was effective at a lower concentration (0.5 ug/ml), while Haemophilus influenzae type b vaccine and split influenza virus vaccine were effective at the concentration of 1 ug/ml. However, bacteriostatic experiments revealed that the split influenza virus vaccine was capable of inducing the highest antimicrobial activity. The medium of the 23-valent pneumococcal polysaccharide vaccine treatment group had a higher antimicrobial activity than the medium of the Haemophilus influenzae type b vaccine treatment group. The transcriptional regulator of hBD-2, that is, the NF-kappaB subunit, had a high level of activity, while the normal epithelial cells showed barely detectable activity, indicating that these vaccines have potential for clinical application. PMID- 22842708 TI - Biological network modeling identifies IPCS in Leishmania as a therapeutic target. AB - Systems biology aims to develop mathematical models of biological systems by integrating experimental and theoretical techniques by leveraging on the genome wide data to unravel the complexity of gene regulation. Despite the availability of effective chemotherapy, leishmaniasis continues to be one of the major parasitic infections that affect the human population worldwide. Currently, little is known of the structural biology of the parasites that are responsible for the disease and few attempts have been made to develop second generation drugs, which may become essential if multi-drug resistance arises. These facts make the discovery of novel drug targets a priority. Multiscale modeling and simulation techniques permit us to study the spatial and temporal properties of large systems to be simulated using atomic-detail structures. The estimation of kinetic parameters for the mathematical modeling provides a basis for iterative manipulation of biochemical pathways. In this paper, emphasis is laid on the discrete regulation of gene or protein expression as modeling can be done based on pure qualitative knowledge about interaction between genes or proteins that is widely available from the existing experimental methodologies. IPC synthase is one of them, believed to play a pivotal role in the pathogenesis of Leishmania sp. and resides in an acidic macrophage phagolysosome, defining a new class of eukaryotic sphingolipid synthases. This work will facilitate the rational development of inhibitors against a protozoan enzyme with no mammalian equivalent, leading to the prospect of anti-protozoal compounds with minimal toxic side effects. Henceforth, it can be said that exploiting the interactome for novel human drug targets could provide new therapeutic avenues towards the treatment of infectious diseases, which could ameliorate the growing clinical challenge of drug-resistant infections. PMID- 22842709 TI - Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles. AB - The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst. PMID- 22842710 TI - Farm crops depredation by European bison (Bison bonasus) in the vicinity of forest habitats in northeastern Poland. AB - European bison, the largest mammal in Europe, after being exterminated in the wild and then restored during the 20th century is still listed by the International Union for Conservation of Nature (IUCN Red List of Threatened Species) as a species vulnerable to extinction. However, the increasing number of European bison, through creation of new and expansion of existing populations strongly increases the risk of human-bison conflict in the near future. We analyzed the depredation of farm crops by bison and the factors influencing the level of damage in the vicinity of two forest areas inhabited by bison in northeastern Poland. Between 2000 and 2010, the total cost of compensation was 196,200. The level of damage and amount of compensation was increasing from year to year in both forests and correlated with the number of bison. The majority of damage (57 % of cases) was recorded in winter (December-March). Snow depth and temperature did not influence the frequency of damage. The incidences of damage increased with decreasing distance from the woodland patches, therefore, 69 % of cases in Bialowieza Forest, and 80 % in Knyszyn Forest were recorded closer than 0.5 km from nearest woodland patch. The majority of the crops damaged by bison were cereals (61 %) but also hay (20 %) and rape (13 %). When compared to the availability of crops, bison strongly selected rape and rye in both regions. This study is the first addressing the increasing problem of human-bison conflict in re-introduced populations and analyzing long-term data on crop depredation. Such situations probably occur in the majority of growing and expanding bison populations, however, it has not yet to be monitored and is rather neglected in post-Soviet countries. PMID- 22842711 TI - DYT16: the original cases. AB - OBJECTIVE: DYT16 is an autosomal recessive dystonia-parkinsonism due to putative mutations at PRKRA gene. The aim of this study was to describe clinical features providing video documentation of patients with DYT16 dystonia. METHODS: We examined and videotaped all homozygous carriers of the DYT16 gene. RESULTS: We identified two phenotypes, generalised dystonia and dystonia-parkinsonism non responsive to levo-dopa, with three patients belonging to each of the groups. There was inter-individual and intra-family phenotypic heterogeneity. CONCLUSIONS: DYT16 is a rare autosomal recessive dystonia characterised by generalised dystonia or dystonia-parkinsonism. Patients are refractory to pharmacological therapy. PMID- 22842712 TI - Neurological picture. Vein of Labbe thrombosis by CT and MRI. PMID- 22842713 TI - Are premonitory urges a prerequisite of tic inhibition in Gilles de la Tourette syndrome? AB - BACKGROUND: Despite the common notion that premonitory urges facilitate tic inhibition, no studies have investigated this question systematically. We examined the relation of the trait of premonitory urges with tics and tic suppression. We hypothesised that patients with more urges would be more efficient at inhibiting tics. METHODS: 15 adult (14 men, mean age 32.2+/-7.9 years) pure Gilles de la Tourette syndrome patients participated. Tic severity was evaluated using the modified Rush Video Scale and by employing the Yale Global Tic Severity Scale. Tic suppressibility was assessed from videos of additional periods where patients were instructed to maximally suppress their tics. Rush score based inhibition potency was synthesised by combining the scores in the two conditions. A measure of pure motor tic inhibition potency was also generated based on the number of motor tics alone. Premonitory urges were assessed by the Premonitory Urge for Tics Scale. RESULTS: All participants reported urges preceding their tics and were able to voluntarily suppress their tics. However, there was no correlation between urge scores and the Rush score based inhibition potency or the pure motor tic inhibition potency. Scores of the Premonitory Urge for Tics Scale correlated with the interference subscale item of the Yale Global Tic Severity Scale. CONCLUSIONS: Urges and tic inhibition are not directly related. There seem to exist at least two distinct neurophysiological systems of urge/tic generation and tic control in adult Gilles de la Tourette syndrome patients. PMID- 22842714 TI - Recognition of psychogenic non-epileptic seizures: a curable neurophobia? AB - BACKGROUND: Diagnosing psychogenic non-epileptic seizures (PNES) remains challenging. The majority of 'PNES status' cases are likely to be seen in the emergency department or similar non-specialised units, where patients are initially assessed and managed by physicians of varying expertise in neurology. METHODS: 216 participants including medical students and doctors of all grades from a wide range of medical disciplines were shown video recordings of six patients with PNES and six other patients with convulsive epileptic seizures (ES). Participants were asked to choose between PNES and ES as a diagnosis and to rate their confidence in each diagnosis, both before and after a 15-minute teaching presentation on PNES and ES. RESULTS: Pre-teaching sensitivity for diagnosing PNES was 0.77, specificity 0.55. The positive predictive value (PPV) of diagnosing PNES was 0.63, and was 0.7 for ES. Diagnostic accuracy increased with increasing clinical grades (p=0.022), as did clinical confidence (p<0.0005). Clinical accuracy and clinical confidence increased post-teaching (p<0.0005). Sensitivity for diagnosing PNES post-teaching improved to 0.88, specificity to 0.67. The PPV of diagnosing PNES increased to 0.72, and to 0.84 for ES. CONCLUSIONS: Diagnosing PNES can be improved by clinical experience in neurology and focussed teaching interventions. PMID- 22842715 TI - Electroacupuncture at the Quchi and Zusanli acupoints exerts neuroprotective role in cerebral ischemia-reperfusion injured rats via activation of the PI3K/Akt pathway. AB - The PI3K/Akt pathway, a critical mediator of cell survival, is suppressed in cerebral ischemia/reperfusion (I/R) injury; therefore, it is a major focus in treatment of ischemic stroke. Acupuncture has long been used in China to clinically treat stroke. However, the precise mechanism of its neuroprotective activities remains largely unknown. Using a focal cerebral I/R injured rat model, in the present study we evaluated the in vivo therapeutic efficacy of electroacupuncture and investigated the underlying molecular mechanisms. We found that electroacupuncture at Quchi (LI11) and Zusanli (ST36) acupoints on the contralateral paralyzed limb significantly improved neurological deficits and cerebral infarction. In addition, electroacupuncture profoundly activated PI3K/Akt signaling in ischemic cerebral tissues. Consequently, the upregulatory effect of electroacupuncture on PI3K/Akt activation resulted in the inhibition of cerebral cell apoptosis. Moreover, electroacupuncture increased the serum secretion levels of the PI3K activators BDNF and GDNF, as well as upregulated the anti-apoptotic Bcl-2/Bax ratio in ischemic cerebrum. Our data suggest that electroacupuncture at Quchi and Zusanli acupoints exerts neuroprotective function in ischemic stroke via activation of the PI3K/Akt pathway. PMID- 22842716 TI - Mild biliary pancreatitis: interval (delayed) cholecystectomy is associated with readmission for recurrent biliary events. PMID- 22842717 TI - Application of 4% chlorhexidine solution for cord cleansing after birth reduces neonatal mortality and omphalitis. PMID- 22842718 TI - Invited commentary: assessing mechanistic interaction between coinfecting pathogens for diarrheal disease. AB - The interaction estimates from Bhavnani et al. (Am J Epidemiol. 2012;176(5):387 395) are used to evaluate evidence for mechanistic interaction between coinfecting pathogens for diarrheal disease. Mechanistic interaction is said to be present if there are individuals for whom the outcome would occur if both of 2 exposures are present but would not occur if 1 or the other of the exposures is absent. In the epidemiologic literature, mechanistic interaction is often conceived of as synergism within Rothman's sufficient-cause framework. Tests for additive interaction are sometimes used to assess such synergism or mechanistic interaction, but testing for positive additive interaction only allows for the conclusion of mechanistic interaction under fairly strong "monotonicity" assumptions. Alternative tests for mechanistic interaction, which do not require monotonicity assumptions, have been developed more recently but require more substantial additive interaction to draw the conclusion of the presence of mechanistic interaction. The additive interaction reported by Bhavnani et al. is of sufficient magnitude to provide strong evidence of mechanistic interaction between rotavirus and Giardia and between rotavirus and Escherichia. coli/Shigellae, even without any assumptions about monotonicity. PMID- 22842719 TI - Does traffic-related air pollution explain associations of aircraft and road traffic noise exposure on children's health and cognition? A secondary analysis of the United Kingdom sample from the RANCH project. AB - The authors examined whether air pollution at school (nitrogen dioxide) is associated with poorer child cognition and health and whether adjustment for air pollution explains or moderates previously observed associations between aircraft and road traffic noise at school and children's cognition in the 2001-2003 Road Traffic and Aircraft Noise Exposure and Children's Cognition and Health (RANCH) project. This secondary analysis of a subsample of the United Kingdom RANCH sample examined 719 children who were 9-10 years of age from 22 schools around London's Heathrow airport for whom air pollution data were available. Data were analyzed using multilevel modeling. Air pollution exposure levels at school were moderate, were not associated with a range of cognitive and health outcomes, and did not account for or moderate associations between noise exposure and cognition. Aircraft noise exposure at school was significantly associated with poorer recognition memory and conceptual recall memory after adjustment for nitrogen dioxide levels. Aircraft noise exposure was also associated with poorer reading comprehension and information recall memory after adjustment for nitrogen dioxide levels. Road traffic noise was not associated with cognition or health before or after adjustment for air pollution. Moderate levels of air pollution do not appear to confound associations of noise on cognition and health, but further studies of higher air pollution levels are needed. PMID- 22842720 TI - Bhavnani et Al. respond to "assessing mechanistic interaction". PMID- 22842721 TI - Use of imputed population-based cancer registry data as a method of accounting for missing information: application to estrogen receptor status for breast cancer. AB - The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program provides a rich source of data stratified according to tumor biomarkers that play an important role in cancer surveillance research. These data are useful for analyzing trends in cancer incidence and survival. These tumor markers, however, are often prone to missing observations. To address the problem of missing data, the authors employed sequential regression multivariate imputation for breast cancer variables, with a particular focus on estrogen receptor status, using data from 13 SEER registries covering the period 1992 2007. In this paper, they present an approach to accounting for missing information through the creation of imputed data sets that can be analyzed using existing software (e.g., SEER*Stat) developed for analyzing cancer registry data. Bias in age-adjusted trends in female breast cancer incidence is shown graphically before and after imputation of estrogen receptor status, stratified by age and race. The imputed data set will be made available in SEER*Stat (http://seer.cancer.gov/analysis/index.html) to facilitate accurate estimation of breast cancer incidence trends. To ensure that the imputed data set is used correctly, the authors provide detailed, step-by-step instructions for conducting analyses. This is the first time that a nationally representative, population based cancer registry data set has been imputed and made available to researchers for conducting a variety of analyses of breast cancer incidence trends. PMID- 22842722 TI - Synergistic effects between rotavirus and coinfecting pathogens on diarrheal disease: evidence from a community-based study in northwestern Ecuador. AB - In developing countries where diarrheal disease is a leading cause of morbidity and mortality in children under 5 years of age, enteric coinfection is common. There is little understanding, however, of the biologic interaction between coinfecting pathogens. The authors investigated the potential for synergistic interaction between coinfecting pathogens on diarrhea pathogenesis using an epidemiologic framework. They conducted community-based, case-control studies in 22 communities in northwestern Ecuador between 2003 and 2008. Risk ratios of diarrhea associated with single infections and coinfections were estimated. Interaction between coinfecting pathogens was assessed through departure from risk ratio additivity and multiplicativity after adjustment for age. On the additive scale, the authors found departure from the null value of 0 for rotavirus-Giardia coinfections (interaction contrast ratio = 8.0, 95% confidence interval: 3.1, 18.9) and for rotavirus-Escherichia coli coinfections (interaction contrast ratio = 9.9, 95% confidence interval: 2.6, 28.4). On the multiplicative scale, they found departure from the value of 1 for rotavirus-Giardia coinfections (multiplicative interaction = 3.6, 95% confidence interval: 1.3, 8.7). This research provides epidemiologic evidence for synergism between rotavirus and other enteric pathogens. During coinfection, the pathogenic potential of each organism appears to be enhanced. The potential for pathogenesis to be more severe in the presence of a rotavirus coinfection amplifies the need for rotavirus vaccination. PMID- 22842723 TI - Breast MALT lymphomas: a clinicopathological and cytogenetic study of 9 cases. AB - Primary breast mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon and restricted diagnostic criteria should be used to exclude breast involvement by systemic lymphomas. The molecular pathogenesis of primary breast MALT lymphomas is not clear because of the rarity of the disease. Generally the molecular studies of MALT lymphoma in extranodal sites have shown the presence of different chromosomal aberrations, mutually exclusive with substantial differences in their frequency relatively to topographic localization. Few cases of breast MALT lymphomas in the literature have been assessed for MALT lymphoma associated translocations and BCL10 expression, underlying their rarity in primary breast MALT lymphomas. In our study, we analyzed a series of nine cases of primary breast MALT lymphomas. FISH results showed evidence of MALT1 gene rearrangements in four primary breast lymphomas, in particular three cases with t(11;18)(q21;q21) and one case with t(14;18)(q32;q21). In addition, BCL10 gene rearrangement was not observed. There was no evidence of BCL10 gene translocation in any of the neoplasms assessed. Our data indicate that MALT1 gene rearrangements are not rare in primary breast MALT lymphoma in contrast with results of previous series. Finally, t(11;18) has been observed to be significantly associated with high intensity cytoplasmic BCL10 expression underlying cross-talk between MALT1 and BCL10 pathways in the pathogenesis of MALT lymphomas. PMID- 22842724 TI - Evaluation of antibodies directed against human protease-activated receptor-2. AB - Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by intramolecular docking of a tethered ligand that is released by the actions of proteases, mainly of the serine protease family. Here, we evaluate four commercially available anti-PAR2 antibodies, SAM11, C17, N19 and H99, demonstrating marked differences in the ability of these reagents to detect the target receptor in Western blot, immunocytochemical and flow cytometry applications. In Western blot analysis, we evaluated antibody reactivity against both ectopic and endogenous receptors. Against material from transfected cells, we show that SAM11 and N19, and to a lesser extent C17, but not H99, are able to detect ectopic PAR2. Interestingly, these Western blot analyses indicate that N19 and C17 detect conformations of ectopic PAR2 distinct to those recognised by SAM11. Significantly, our data also indicate that Western blot signal detected by SAM11 and C17, and much of the signal detected by N19, against cells endogenously expressing PAR2 is non-specific. Despite confounding non-specific signals, we were able to discern N19 reactivity against endogenous PAR2 as a broad smear that we also observed in ectopically expressing human and mouse cells and that is sensitive to loss of N-glycosylation. In immunocytochemistry analysis, each antibody is able to detect ectopic PAR2 although it appears that H99 detects only a subset of the ectopically expressed receptor. In addition, SAM11 and N19 are able to detect both ectopic and endogenous cell surface PAR2 by flow cytometry. In summary: (1) each antibody can detect ectopic PAR2 by immunocytochemical analysis with SAM11 and N19 suitable for cell surface detection of both ectopic and endogenous receptor by flow cytometry; (2) in Western blot analysis, N19, SAM11 and C17 can detect ectopically expressed PAR2, with only N19 able to detect the endogenous receptor by this technique and (3) in each of these approaches, appropriate controls are essential to ensure that non-specific reactivity is identified. PMID- 22842726 TI - microrna expression signature of gastric cancer cells relative to normal gastric mucosa. AB - micrornas (miRNAs) play an important role in a wide range of physiological and developmental processes by negatively regulating the expression of target genes at the post-transcriptional level. In this study, we investigated the differential miRNA expression signature between gastric cancer cells and normal gastric mucosa to determine changes in miRNA expression during gastric cancer development. We analyzed the global miRNA expression profiles of 9 gastric cancer cell lines and 6 normal gastric mucosa lines using miRNA microarrays. In addition, we performed quantitative real-time PCR (Q-PCR) to validate the results. Correlations between the miRNA expression profile and tumor clinicopathological parameters were analyzed. We found that 17 miRNAs were upregulated in gastric cancer cell lines and 146 miRNAs were downregulated compared to normal gastric mucosa. Using microarray data and Q-PCR validation, 15 miRNAs were finally selected. These candidate miRNAs were associated with gastric cancer clinicopathology to various degrees. High expression levels of hsa-miR-93 were found to predict poor survival (median, 16 vs. 40 months; log-rank test p<0.05). These findings suggest that miRNAs play vital roles in human gastric cancer. The findings may also provide clues toward understanding the molecular functions of miRNAs in various biological processes. PMID- 22842725 TI - Mili and Miwi target RNA repertoire reveals piRNA biogenesis and function of Miwi in spermiogenesis. AB - Germ cells implement elaborate mechanisms to protect their genetic material and to regulate gene expression during differentiation. Piwi proteins bind Piwi interacting RNAs (piRNAs), small germline RNAs whose biogenesis and functions are still largely elusive. We used high-throughput sequencing after cross-linking and immunoprecipitation (HITS-CLIP) coupled with RNA-sequencing (RNA-seq) to characterize the genome-wide target RNA repertoire of Mili (Piwil2) and Miwi (Piwil1), two Piwi proteins expressed in mouse postnatal testis. We report the in vivo pathway of primary piRNA biogenesis and implicate distinct nucleolytic activities that process Piwi-bound precursor transcripts. Our studies indicate that pachytene piRNAs are the end products of RNA processing. HITS-CLIP demonstrated that Miwi binds spermiogenic mRNAs directly, without using piRNAs as guides, and independent biochemical analyses of testis mRNA ribonucleoproteins (mRNPs) established that Miwi functions in the formation of mRNP complexes that stabilize mRNAs essential for spermiogenesis. PMID- 22842727 TI - Effect of compression paddle tilt correction on volumetric breast density estimation. AB - For the acquisition of a mammogram, a breast is compressed between a compression paddle and a support table. When compression is applied with a flexible compression paddle, the upper plate may be tilted, which results in variation in breast thickness from the chest wall to the breast margin. Paddle tilt has been recognized as a major problem in volumetric breast density estimation methods. In previous work, we developed a fully automatic method to correct the image for the effect of compression paddle tilt. In this study, we investigated in three experiments the effect of paddle tilt and its correction on volumetric breast density estimation. Results showed that paddle tilt considerably affected accuracy of volumetric breast density estimation, but that effect could be reduced by tilt correction. By applying tilt correction, a significant increase in correspondence between mammographic density estimates and measurements on MRI was established. We argue that in volumetric breast density estimation, tilt correction is both feasible and essential when mammographic images are acquired with a flexible compression paddle. PMID- 22842728 TI - Fabricating electrodes for amperometric detection in hybrid paper/polymer lab-on a-chip devices. AB - We present a novel, low-resource fabrication and assembly method for creating disposable amperometric detectors in hybrid paper-polymer devices. Currently, mere paper-based microfluidics is far from being able to achieve the same level of process control and integration as state-of-the-art microfluidic devices made of polymers. To overcome this limitation, in this work both substrate types are synergistically combined through a hybrid, multi-component/multi-material system assembly. Using established inkjet wax printing, we transform the paper into a profoundly hydrophobic substrate in order to create carbon electrodes which are simply patterned from carbon inks via custom made adhesive stencils. By virtue of the compressibility of the paper substrate, the resulting electrode-on-paper hybrids can be directly embedded in conventional, 3D polymeric devices by bonding through an adhesive layer. This manufacturing scheme can be easily recreated with readily available off-the-shelf equipment, and is extremely cost-efficient and rapid with turn-around times of only a few hours. PMID- 22842729 TI - Enhanced antitumor effects of BPD-MA-mediated photodynamic therapy combined with adriamycin on breast cancer in mice. AB - AIM: Photodynamic therapy (PDT) is an emerging treatment used to eradicate premalignant and early-stage cancers and to reduce tumor size in end-stage cancers. In this study, we investigated the effects of a combination of benzoporphyrin derivative monoacid ring A (BPD-MA)-mediated PDT with adriamycin (ADM) on 4T1 breast carcinoma cells in vivo and the mechanisms underlying this effect. METHODS: Normal BALA/c female mice bearing 4T1 breast carcinoma xenografts were tested. The animals were treated with PDT (BPD-MA 1 mg/kg, iv, plus single-dose laser irradiation) or ADM (5 mg/kg, iv) alone, or a combination of PDT with ADM. The tumor growth rate was determined by measuring the tumor weight. Cell apoptosis was measured with flow cytometry, and the expression of apoptosis-related molecules was assessed using Western blot. Microvessel density (MVD) was determined with immunohistochemical staining. RESULTS: Compared to PDT or ADM alone, PDT plus ADM produced a combined inhibition on the tumor growth, prolonged life span, and enhanced apoptosis in the mice bearing 4T1 subcutaneously xenografted tumors. The combination of PDT and ADM exerted additive effects on the upregulation of Bax and the downregulation of Bcl-2, and on the reduction of MVD in 4T1 xenografted tumors. CONCLUSION: Our results demonstrate that PDT plus ADM exerts enhanced in vivo antitumor effect on breast cancer, which is closely associated with the cooperative regulation of extrinsic apoptotic pathways and the inhibition of tumor angiogenesis. Thus, PDT plus ADM is a promising combined treatment strategy for breast carcinoma. PMID- 22842731 TI - The natural stilbenoid pinosylvin and activated neutrophils: effects on oxidative burst, protein kinase C, apoptosis and efficiency in adjuvant arthritis. AB - AIM: To investigate the effects of the naturally occurring stilbenoid pinosylvin on neutrophil activity in vitro and in experimental arthritis, and to examine whether protein kinase C (PKC) activation served as an assumed target of pinosylvin action. METHODS: Fresh human blood neutrophils were isolated. The oxidative burst of neutrophils was evaluated on the basis of enhanced chemiluminescence. Neutrophil viability was evaluated with flow cytometry, and PKC phosphorylation was assessed by Western blotting analysis. Adjuvant arthritis was induced in Lewis rats with heat-killed Mycobacterium butyricum, and the animals were administered with pinosylvin (30 mg/kg, po) daily for 21 d after arthritis induction. RESULTS: In isolated human neutrophils, pinosylvin (10 and 100 MUmol/L) significantly decreased the formation of oxidants, both extra- and intracellularly, and effectively inhibited PKC activation stimulated by phorbol myristate acetate (0.05 MUmol/L). The inhibition was not due to neutrophil damage or increased apoptosis. In arthritic rats, the number of neutrophils in blood was dramatically increased, and whole blood chemiluminescence (spontaneous and PMA stimulated) was markedly enhanced. Pinosylvin administration decreased the number of neutrophils (from 69 671 +/- 5588/MUL to 51 293 +/- 3947/MUL, P=0.0198) and significantly reduced the amount of reactive oxygen species in blood. CONCLUSION: Pinosylvin is an effective inhibitor of neutrophil activity, and is potentially useful as a complementary medicine in states associated with persistent inflammation. PMID- 22842732 TI - A pharmacodynamic analysis of factors affecting recovery from anesthesia with propofol-remifentanil target controlled infusion. AB - AIM: To examine individual patient's demographic parameters and clinical variables related to return of consciousness (ROC) and the pharmacodynamic relationship between propofol effect-site concentration (C(e)) and ROC from propofol-remifentanil anesthesia. METHODS: Ninety-four patients received propofol remifentanil anesthesia using the effect-site target-controlled infusion (TCI) system. All clinical events were noted, and variables possibly related to propofol C(e) at ROC were examined using linear correlation analyses. Pharmacodynamic modeling incorporating covariates was performed using NONMEM (Nonlinear Mixed Effects Modeling) VII software. RESULTS: The C(e) values of propofol at loss of consciousness (LOC) and ROC were 4.4+/-1.1 MUg/mL and 1.1+/ 0.3 MUg/mL, respectively. Age was negatively correlated with propofol C(e) at ROC (r=-0.48, P<0.01). Including age as a covariate in C(e50) (the effect-site concentration associated with 50% probability of return of consciousness) and lambda (the steepness of the concentration-versus-response relationship) significantly improved the performance of the basic model based on the likelihood ratio test, with a significant decrease in the minimum value of the objective function. The C(e50) in 25-, 50-, and 75-year-old patients was predicted to be 1.38, 1.06, and 0.74 MUg/mL, respectively. The lambda in 25-, 50-, and 75-year old patients was predicted to be 12.23, 8.70, and 5.18, respectively. CONCLUSION: Age significantly affects the relationship between propofol C(e) and ROC, and pharmacodynamic modeling including age could lead to better predictions of ROC during emergence from propofol-remifentanil anesthesia. PMID- 22842730 TI - L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta amyloid peptide production in HEK293-APPswe cells. AB - AIM: To identify a small molecule L655,240 as a novel beta-secretase (BACE1) inhibitor and to investigate its effects on beta-amyloid (Abeta) generation in vitro. METHODS: Fluorescence resonance energy transfer (FRET) was used to characterize the inhibitory effect of L655,240 on BACE1. Surface plasmon resonance (SPR) technology-based assay was performed to study the binding affinity of L655,240 for BACE1. The selectivity of L655,240 toward BACE1 over other aspartic proteases was determined with enzymatic assay. The effects of L655,240 on Abeta40, Abeta42, and sAPPbeta production were studied in HEK293 cells stably expressing APP695 Swedish mutant(K595N/M596L) (HEK293-APPswe cells). The activities of BACE1, gamma-secretase and alpha-secretase were assayed, and both the mRNA and protein levels of APP and BACE1 were evaluated using real-time PCR (RT-PCR) and Western blot analysis. RESULTS: L655,240 was determined to be a competitive, selective BACE1 inhibitor (IC(50)=4.47+/-1.37 MUmol/L), which bound to BACE1 directly (K(D)=17.9+/-0.72 MUmol/L). L655,240 effectively reduced Abeta40, Abeta42, and sAPPbeta production by inhibiting BACE1 without affecting the activities of gamma-secretase and alpha-secretase in HEK293-APPswe cells. L655,240 has no effect on APP and BACE1 mRNA or protein levels in HEK293-APPswe cells. CONCLUSION: The small molecule L655,240 is a novel BACE1 inhibitor that can effectively decreases Abeta production in vitro, thereby highlighting its therapeutic potential for the treatment of Alzheimer's disease. PMID- 22842733 TI - Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor, improves metabolic control in diabetic rodent models. AB - AIM: Dipeptidyl deptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents. The purpose of this study was to assess the acute and chronic effects of SHR117887, a novel DPP-4 inhibitor, on metabolic control and pancreatic beta-cell function in normal or diabetic rodent models. METHODS: In the acute experiments, ICR mice, diet-induced obese (DIO) rats and ob/ob mice were subjected to an oral glucose tolerance test (OGTT) following a single oral administration of SHR117887 (0.1, 0.3, 1 or 3 mg/kg). Blood samples were collected to measure glucose, insulin, DPP-4 activity and active GLP-1 level. In the chronic experiments, ob/ob mice was administered SHR117887 (3, 10 or 30 mg/kg) twice daily for 33 d to assess the effects on metabolic control and pancreatic beta-cell function. Vildagliptin (LAF237) was used as a positive control in all the experiments. RESULTS: Acute oral administration of SHR117887 dose-dependently decreased the serum DPP-4 activity and improved glucose tolerance in ICR mice, DIO rats and ob/ob mice. This was accompanied by significant increases in the serum active GLP 1 and insulin levels. Chronic administration of SHR117887 significantly decreased fasting blood glucose level and improved the lipid profiles in ob/ob mice by reducing the serum triglyceride and free fatty acid levels, and its efficacy was comparable with that of vildagliptin at the same molarity. Moreover, chronic administration of SHR117887 increased the insulin staining of islet cells, which is suggestive of improved beta-cell function. CONCLUSION: SHR117887 is a potent DPP-4 inhibitor that improves metabolic control and beta-cell function in diabetic rodent models, suggesting that it could be a new therapeutic agent for the treatment of type 2 diabetes. PMID- 22842735 TI - Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway. AB - AIM: To investigate the role of nitric oxide (NO) in oridonin-induced apoptosis and autophagy in murine fibrosarcoma L929 cells and the underlying molecular mechanisms. METHODS: Cell viability was measured using MTT assay. Intracellular NO level, SubG(1) cell ratio and autophagy cell ratios were analyzed with flow cytometry after diaminofluorescein-2 diacetate (DAF-2DA), propidium iodide (PI) and monodansylcadaverine (MDC) staining, respectively. Protein expression was examined using Western blot analysis. RESULTS: Exposure of L929 cells to oridonin (50 MUmol/L) for 24 h led to intracellular NO production. Pretreatment with NOS inhibitor 1400w or L-NAME inhibited oridonin-induced apoptosis and autophagy in L929 cells. The pretreatment decreased the apoptosis-related protein Bax translocation and cytochrome c release, increased Bcl-2 level, reversed the autophagy-associated protein Beclin 1 increase and conversion of LC3 I to LC3 II. Furthermore, pretreatment with NO scavenger DTT completely inhibited oridonin induced apoptosis and autophagy in L929 cells. In addition, oridonin (50 MUmol/L) activated ERK and p53 in L929 cells, and the interruption of ERK and p53 activation by PD 98059, pifithrin-alpha, or ERK siRNA decreased oridonin-induced apoptosis and autophagy. The inhibition of NO production reduced oridonin-induced ERK and p53 activation, and NO production was down-regulated by blocking ERK and p53 activation. CONCLUSION: NO played a pivotal role in oridonin-induced apoptosis and autophagy in L929 cells. Taken together with our previous finding that ERK contributes to p53 activation, it appears that NO, ERK, and p53 form a positive feedback loop. Consequently, we suggest that oridonin-induced apoptosis and autophagy are modulated by the NO-ERK-p53 molecular signaling mechanism in L929 cells. PMID- 22842734 TI - Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury. AB - Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury. PMID- 22842736 TI - Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats. AB - AIM: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E(2) (PGE(2)) as a biomarker. METHODS: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE(2) level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE(2) production in blood cells was investigated in vitro. RESULTS: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE(2) in both normal and arthritic rats. The inhibitory effect on PGE(2) levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I(max) model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production in vivo. The I(max) model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE(2) production in blood cells in vitro. CONCLUSION: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I(max) can be used to fit the relationship between the plasma PGE(2) and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID- 22842738 TI - Higher apoptosis index and proliferation index in colonocytes of patients with ulcerative colitis in remission. AB - Ulcerative colitis (UC) is a inflammatory disease of large bowel. The amount of people suffering from UC increases from year to year. Pathogenesis of this affection is still not entirely clear. Mechanisms of proliferation and apoptosis in colonocytes in the course of the disease are defected. THE AIM OF THE STUDY: was to assess the rate of proliferation and intensity of apoptosis in colonocytes in patients with diagnose UC. MATERIAL AND METHODS: Colon pathological samples taken from patients with diagnosed ulceraive colitis were examined. Patients were in both clinical and endoscopic remission and were treated with mesalazin. They were patient of Department of General and Colorectal Surgery. To estimate proliferation index dye with monoclonal antibody against Ki67. To determine apoptosis level immunohistochemistry with antybody against Bax was used. RESULTS: Average Ki-67 in the test group was 42,13%, the largest value amounted to 57% and the lowest of 33%. Average value of Bax was 1.47 and ranged between 0-3. High index of bax appear not only in the bottom of the crypt, but also at their outlet. CONCLUSIONS: In ulecerative colitis genetic and immunological disturbances occur despite treatment. Mesalazine acting only on certain routes associated with the UC holds the remission, without, however "the molecular remission". Thus, it appears that the results of our research are another proof of the necessary caution in weaning support treatment. PMID- 22842737 TI - Influences of FTO gene on onset age of adult overweight. AB - FTO affects changes in BMI during both childhood and adulthood. However, its effect on onset age of overweight in adulthood is not known. To address this question, we conducted a study to examine effects of FTO tag SNPs on censored age of overweight in the longitudinal Bogalusa Heart Study (BHS) cohort, which began in 1973-1974. Of participating subjects, 658 whites (308 males and 350 females) with genotype data were selected for the study. The FTO gene was examined by a survival analysis of 30 tag SNPs regarding their association with left, interval and right-censored adult overweight. After adjustment for birth weight and sex, SNP rs9939609 has a small nominal p value of 0.004 for the association with onset age, which has an expected proportion of false positives of 9.6 % after adjusting for multiple tests. It was estimated that genotypes AA, AT and TT have onset age (standard error) of 22.82 (1.07), 28.96 (1.04) and 27.76 (1.04) years, respectively, for a 50 % cumulative proportion of overweight in the population. Genotypes AA, AT and TT, respectively, have estimated survival probability of 65.8, 78.7 and 76.8 % at the age of 18; and survival probability of 6.5, 11.8 and 10.7 % at the age of 60. The odds ratios of survival beyond age >=18 years are 0.52 for AA versus AT and 0.58 for AA versus TT. We thus concluded that risk genetic variants at FTO gene can accelerate the onset age and influence the survival odds of overweight in younger adults. PMID- 22842739 TI - The use of duplex ultrasound arterial mapping (DUAM) and preoperative diagnostics in patients with atherosclerotic ischaemia of lower extremities. AB - In spite of the fact duplex Doppler ultrasonography is recognized as an scanning technique equivalent to other imaging methods for preoperative diagnostics of the lower extremity arteries, in many centres its use is limited to screening. THE AIM OF THE STUDY: was to the determine usefulness of arterial duplex mapping for preoperative diagnostics in patients with peripheral artery occlusive disease (PAOD). MATERIAL AND METHODS: In 2008-2009, 103 patients with PAOD symptoms (129 limbs) were examined in a prospective, non-randomized study. DUAM was performed in all limbs, DSA in 90, CT-angio in 29, and revascularisation procedures in 116 limbs. RESULTS: Problems with completing DUAM occurred in 10,1% of cases, including 1.5% of examinations of no diagnostic value. Consistency of DUAM and DSA results was found in 94.6% of cases, and consistency of DUAM results and the range of actually performed ranges was found in 97.8% of cases. Consistency of DUAM and CT-angio results was recorded in 68.0% of cases. The comparison between individual examinations and the actually performed procedures showed consistency of 96.5% for DUAM and 72.4% for CT-angio. CONCLUSIONS: DUAM usefulness for detecting and defining lesions in lower extremity arteries is similar to that of DSA and CT-angio. This examination may be successfully used in preoperative diagnostics, particularly for intravascular procedures, which makes possible to reduce exposition to radiation and minimalize diagnostics costs. PMID- 22842740 TI - Abdominal ultrasonography in detecting and surgical treatment of pancreatic carcinoma. AB - THE AIM OF THE STUDY: was to asses the clinical value of percutaneous abdominal ultrasonography in diagnosis, staging and surgical treatment of patients with pancreatic carcinoma. MATERIAL AND METHODS: Prospective clinical trial on diagnostic accuracy of percutaneous abdominal ultrasonography was conducted in 409 consecutive patients with pancreatic cancer which were operated on at the I Dept. of General Surgery in Cracow between 2000 and 2010. RESULTS: Diagnostic accuracy of percutaneous abdominal ultrasonography in pancreatic cancer was 91,1%. The accuracy in detecting different stages of local advancement according to TNM classification was assessed respectively 92.3%-T1, 91.3%-T2, 89.4%-T3, 92.1%-T4, a whole T1-T4 on 91.3%. Diagnostic accuracy of percutaneous abdominal ultrasonography in diagnosis of metastasis to lymph nodes, vascular infiltration, and resectability was respectively 80.7%, 86%, 91.4%. CONCLUSIONS: Percutaneous abdominal ultrasonography has high diagnostic accuracy in diagnosis, staging and predicting surgical treatment of patients with pancreatic carcinoma. PMID- 22842742 TI - Distal Pancreatectomy--own experience. AB - THE AIM OF THE STUDY: was the retrospective analysis of early results after distal pancreatectomy (DP). MATERIAL AND METHODS: During the period between January, 2000 and December, 2010 distal pancreatectomy was performed in 73 patients, including 32 (43.83%) male, and 41 (56.16%) female patients. Average patient age amounted to 53.92 +/- 14.37 years. Surgery was performed by means of laparoscopy or the classical method. RESULTS: The mean duration of the procedure amounted to 179.79 +/- 59.90 minutes. Fifty-nine (80.82%) patients were subject to splenectomy. After the resection the pancreatic stump was hand-sewn in 69 patients. Pancreatoenterostomy was performed in 4 (5.47%) patients. Early postoperative complications occurred in 11 (15%) patients. Reoperation was required in two (2.7 %) patients. The postoperative mortality rate amounted to 2.7%. The average hospitalization period after surgery amounted to 12.72 +/- 9.8 (1- 66) days. CONCLUSIONS: Distal pancreatectomy performed in a center experienced in pancreatic surgery is a safe procedure characterized by a low rate of complications and mortality. PMID- 22842741 TI - Laparoscopic adrenalectomy--assessing the learning curve. AB - Laparoscopic adrenalectomy (LA) has become the "gold standard" for treatment of most of adrenal tumors in last few years. It has many benefits comparing to open surgery, but still is considered as complicated procedure requiring experienced surgical team. THE AIM OF THE STUDY: was to assess the learning curve of laparoscopic adrenalectomy and the outcome of the first consecutive 154 LA. MATERIAL AND METHODS: 154 consecutive patients undergoing LA between 2007 and 2010 were reviewed. Collected data included: patients demographics, clinical and histological diagnosis, side and length of operation, conversions to open surgery, complications and hospitalization time. Learning curve was evaluated by dividing all patients into three groups (group I - first 50 patients, group II - second 50 patients and group III last 54 patients). Differences between the groups were analyzed. RESULTS: There were 154 LAs performed. Indications for LA were hormonally inactive adrenal adenoma(n=57), Conn's syndrome (n=30), Cushing's syndrome (n=28), pheochromocytoma (n=27), adrenal cyst (n=8), and others (n=4). Mean tumor size was 45.28 mm. There were 79 left-sided and 75 right-sided procedures and the average time of hospitalization was 4.64 days. Mean operative time was statistically different between the groups (216.2 min. - 164.6 min. - 131.9 min.; p<0.01) as well as the number of conversions to open surgery (18% - 4% - 3.7%; p=0.013). There was not any significant difference in the number of complications between analyzed groups (2% - 2% -3.7%). CONCLUSION: To improve the outcome of LA it is necessary to perform approximately 40 to 50 procedures. PMID- 22842744 TI - Renal carcinoma metachronous metastases to the gall-bladder and pancreas--case report. AB - Renal carcinoma metastases to the gastrointestinal tract are seldom reported in medical literature. The study presented a case of a 76-year old female patient who underwent nephrectomy, due to T2N0M0 clear cell renal carcinoma and was additionally diagnosed with two metachronous metastases to the gall-bladder and pancreas. Abdominal ultrasound performed 32 months after nephrectomy demonstrated the presence of cholelithiasis and gall-bladder polyp. Laparoscopic cholecystectomy was performed. Clear cell renal carcinoma metastasis restricted to the gall-bladder mucosa was diagnosed on the basis of the histopathological examination. After surgery the patient remained under follow-up. In December, 2009 (47 months after nephrectomy) abdominal computer tomography (CT) revealed the presence of a tumor located in the tail of the pancreas. Distal pancreatic resection and splenectomy was performed. The histopathological examination confirmed the presence of clear cell renal carcinoma metastasis. The patient is in good general condition, under follow-up at the Oncological Outpatient Clinic. PMID- 22842743 TI - 1000 liver transplantations at the Department of General, Transplant and Liver Surgery, Medical University of Warsaw--analysis of indications and results. AB - THE AIM OF THE STUDY: was to analyze indications and results of the first one thousand liver transplantations at Chair and Clinic of General, Transplantation and Liver Surgery, Medical University of Warsaw. MATERIAL AND METHODS: Data from 1000 transplantations (944 patients) performed at Chair and Clinic of General, Transplantation and Liver Surgery between 1994 and 2011 were analyzed retrospectively. These included 943 first transplantations and 55 retransplantations and 2 re-retransplantations. Frequency of particular indications for first transplantation and retransplantations was established. Perioperative mortality was defined as death within 30 days after the transplantation. Kaplan-Meier survival analysis was used to estimate 5-year patient and graft survival. RESULTS: The most common indications for first transplantation included: liver failure caused by hepatitis C infection (27.8%) and hepatitis B infection (18%) and alcoholic liver disease (17.7%). Early (< 6 months) and late (> 6 months) retransplantations were dominated by hepatic artery thrombosis (54.3%) and recurrence of the underlying disease (45%). Perioperative mortality rate was 8.9% for first transplantations and 34.5% for retransplantations. Five-year patient and graft survival rate was 74.3% and 71%, respectively, after first transplantations and 54.7% and 52.9%, respectively, after retransplantations. CONCLUSIONS: Development of liver transplantation program provided more than 1000 transplantations and excellent long-term results. Liver failure caused by hepatitis C and B infections remains the most common cause of liver transplantation and structure of other indications is consistent with European data. PMID- 22842745 TI - Young patient age as the cause of delayed diagnosis of gastrointestinal carcinoma. AB - Most patients diagnosed with gastrointestinal carcinomas are older people. The above-mentioned fact may lead to an erroneous finding that the problem does not concern patients aged between 20 and 30 years. Unfortunately, this assumption is often the reason for late diagnosis and delayed treatment of these malignancies. The study presented an example of three patients subject to surgical management of gastrointestinal carcinomas at the II Department of General and Gastroenterological Surgery, Medical University in Bialystok. PMID- 22842747 TI - A DFT+U study of the lattice oxygen reactivity toward direct CO oxidation on the CeO2(111) and (110) surfaces. AB - Density functional theory calculations corrected by on-site Coulomb interaction have been carried out to track down the lattice oxygen reactivity of CeO(2)(111) and (110) surfaces in direct oxidation of a single CO. The possible elementary steps in CO adsorption and subsequent reactions with lattice oxygen were systematically studied. From calculated energetics, we determined that the lattice oxygen of the (110) surface is more reactive than that of the (111) surface. By calculating the reaction pathways leading to different final products, we found that the formation of carbonate species is competitive to CO(2) formation and desorption, and such an effect could be more significant at CeO(2)(110) compared to CeO(2)(111). More importantly, it has also been found that electron localization at the characteristic 4f orbital of Ce, directly determined by subtle structural relaxation, can give rise to a unique scenario of the overall reaction coordinates. These results may bring us one step ahead toward the comprehensive understanding of catalytic performance of CeO(2)-based materials. PMID- 22842746 TI - Erythrophobia--problems of diagnostics and treatment. PMID- 22842748 TI - Dump stability and soil fertility of a coal mine spoil in Indian dry tropical environment: a long-term study. AB - Plant available nitrogen, belowground (root) biomass, soil nitrogen (N) mineralization and microbial biomass N (MBN) were studied for 12 years at the interval of 2 years (0, 2, 4, 6, 8, 10 and 12 years) and mine dump stability at the intervals of 6 years (0, 6 and 12 years) after re-vegetation on coal mine spoil site. Plant available nitrogen in revegetated mine spoil ranged from 4.51 to 6.59 MUg g(-1), net N-mineralization from 1.87 to 13.85 MUg g(-1) month(-1), MBN from 10 to 22.63 MUg g(-1), and root biomass from 28 to 566 g(-2). Mining activity has caused a change in soil characteristics including plant available nutrients like nitrate-N, ammonium-N and phosphate-P by 70, 67, and 76 %, respectively, N-mineralization by 93 %, root biomass values by 97 % and MBN values by 91 % compared to forest ecosystems. Revegetation of mine spoil produced increase in root biomass values by 1.3, 7.6 and 17.2 times, mineral N values by 1.22, 1.43 and 1.79 times, N-mineralization values by 1.8, 5.2 and 12.6 times and MBN values by 1.6, 2.0, and 3.4 times in 2, 6 and 12 years, respectively. Below ground biomass was highly co-related with microbial biomass and plant available nutrients. N-mineralization, plant available nutrients and the clay content were positively correlated with age of revegetation (P < 0.01). From the numerical modelling it was analyzed that revegetation increased the dump slope stability with a factor of safety of 1.7 and 2.1 after 6 and 12 years of plantation on dump slope, respectively, while it was 1.2 before revegetation. Thus, long term revegetation was found to have direct impact on dump stability and indirect impact on soil fertility status in mine spoil, where plant biomass and microbial biomass provide major contributions in ecological redevelopment of the mine spoil. PMID- 22842749 TI - Biodiversity monitoring at the Tonle Sap Lake of Cambodia: a comparative assessment of local methods. AB - This paper assesses local biodiversity monitoring methods practiced in the Tonle Sap Lake of Cambodia. For the assessment we used the following criteria: methodological rigor, perceived cost, ease of use (user friendliness), compatibility with existing activities, and effectiveness of intervention. Constraints and opportunities for execution of the methods were also considered. Information was collected by use of: (1) key informant interview, (2) focus group discussion, and (3) researcher's observation. The monitoring methods for fish, birds, reptiles, mammals and vegetation practiced in the research area have their unique characteristics of generating data on biodiversity and biological resources. Most of the methods, however, serve the purpose of monitoring biological resources rather than biodiversity. There is potential that the information gained through local monitoring methods can provide input for long term management and strategic planning. In order to realize this potential, the local monitoring methods should be better integrated with each other, adjusted to existing norms and regulations, and institutionalized within community-based organization structures. PMID- 22842750 TI - Advances in the study of protein-DNA interaction. AB - Protein-DNA interaction plays an important role in many biological processes. The classical methods and the novel technologies advanced have been developed for the interaction of protein-DNA. Recent developments of these methods and research achievements have been reviewed in this paper. PMID- 22842752 TI - Distinctive sorption mechanisms of 4-chlorophenol with black carbons as elucidated by different pH. AB - Black carbon (BC) has been considered as an important sorbent in the environment in recent years due to its high sorption capacity and unique sorption behavior. Sorption characteristics of black carbons from two main sources were investigated to get a better understanding of organic chemical fate in the environment. The present study showed sorption mechanisms of 4-chlorophenol, a common organic contaminant in the surroundings, in two kinds of black carbons, soot surrogate (BC1) and environmental char (BC2) derived from rice straw. Sorption capacity of 4-chlorophenol was much higher in BC1 than on BC2 due to the larger surface area of BC1. However, the surface-area normalized sorption coefficients (sorption capacity per surface area) of BC2 were higher than those of BC1, indicating electrostatic attraction and actions of polar foundational groups on BC2 can react with 4-chlorophenol. With increasing temperature, sorption of BC1 decreased but the sorption of BC2 significantly increased at pH 10 and only slightly increased at pH 4. An exothermic sorption reaction was found for BC1; however, an endothermic reaction of chemical sorption occurred on BC2 at pH 10 due to the electrostatic attraction. At pH4, sorption capacity of BC2 decreased and the small positive sorption enthalpy indicated that less electrostatic attractions occurred because of the neutral form of 4-chlorophenol and the domination of mainly hydrophobic interactions. PMID- 22842751 TI - The heterogeneity of the cigarette price effect on body mass index. AB - Previous studies estimate the average effect of cigarette price on body mass index (BMI), with recent research showing that their different methodologies all point to a negative effect after several years. This literature, however, ignores the possibility that the effect could vary throughout the BMI distribution or across socioeconomic and demographic groups due to differences in underlying obesity risks or preferences for health. We evaluate heterogeneity in the long run impact of cigarette price on BMI by performing quantile regressions and stratifying the sample by race, education, age, and sex. Cigarette price has a highly heterogeneous negative effect that is more than three times as strong at high BMI levels--where weight loss is most beneficial for health--than at low levels. The effects are also strongest for blacks, college graduates, middle-aged adults, and women. We also assess the implications for disparities, conduct robustness checks, and evaluate potential mechanisms. PMID- 22842753 TI - Comparison of sensitivity analysis methods for pollutant degradation modelling: a case study from drinking water treatment. AB - Five sensitivity analysis methods based on derivatives, screening, regression, variance decomposition and entropy are introduced, applied and compared for a model predicting micropollutant degradation in drinking water treatment. The sensitivity analysis objectives considered are factors prioritisation (detecting important factors), factors fixing (detecting non-influential factors) and factors mapping (detecting which factors are responsible for causing pollutant limit exceedances). It is shown how the applicability of methods changes in view of increasing interactions between model factors and increasing non-linearity between the model output and the model factors. A high correlation is observed between the indices obtained for the objectives factors prioritisation and factors mapping due to the positive skewness of the probability distributions of the predicted residual pollutant concentrations. The entropy-based method which uses the Kullback-Leibler divergence is found to be particularly suited when assessing pollutant limit exceedances. PMID- 22842754 TI - Control--or be controlled. PMID- 22842755 TI - Diagnosing and improving functioning in interdisciplinary health care teams. AB - Interdisciplinary teams play a key role in the delivery of health care. Team functioning can positively or negatively impact the effective and efficient delivery of health care services as well as the personal well-being of group members. Additionally, teams must be able and willing to work together to achieve team goals within a climate that reflects commitment to team goals, accountability, respect, and trust. Not surprisingly, dysfunctional team functioning can limit the success of interdisciplinary health care teams. The first step in improving dysfunctional team function is to conduct an analysis based on criteria necessary for team success, and this article provides meaningful criteria for doing such an analysis. These are the following: a common team goal, the ability and willingness to work together to achieve team goals, decision making, communication, and team member relationships. High-functioning interdisciplinary teams must exhibit features of good team function in all key domains. If a team functions well in some domains and needs to improve in others, targeted strategies are described that can be used to improve team functioning. PMID- 22842756 TI - Staff expectations on implementing new electronic applications in a changing organization. AB - This study was undertaken to describe staff expectations prior to implementation of new electronic applications in a changing organization. Changes are a part of human existence; changes based on implementation of technology and information and communication technology are taking place in the health care sector globally. The Swedish public health care and social care sector is taking a similar path. A qualitative approach with group interviews of 23 staff divided in 5 groups was performed. Latent content analysis was used to analyze the transcribed interviews. The theme, taking standpoint today in relation to the past, emerged from 3 areas of discussion: "distance holding," "ruled by the organization," and "health care development in the future." New restraints on staff affect the caregiving process. Managers should consider whether a particular change is revolutionary or evolutionary and act in the change process according to the possible psychological impact of the change. PMID- 22842757 TI - Guidelines for conducting bulletproof workplace investigations: Part II- searches, surveillance, and other legal issues. AB - A proper and thorough investigation can help avoid or successfully defend lawsuits. When conducting workplace investigations, employers must take care to conduct reasonable searches and not violate employees' rights to privacy. This article addresses privacy and other legal issues surrounding the use of various types of electronic surveillance including wiretapping, video/photography, and monitoring of e-mail. While conducting such searches, employers must be vigilant in their efforts to avoid liability for defamation and to properly document the investigation. Guidance is provided on these issues along with advice on the recommendation and/or remedial action that may result from the investigation and a checklist of additional considerations when conducting investigations resulting from harassment. PMID- 22842759 TI - The effects of national health care reform on local businesses--Part III: secondary research questions--discoveries and implications. AB - This is the third part of a 3-part examination of what may potentially be expected from the 2010 national health care reform legislation. Political researchers and pundits have speculated endlessly on the many changes mandated by the 2010 national health care reform legislation, styled the Patient Protection and Affordable Care Act. A review and assessment of this legislation at several levels (federal, state, state agency, local region, and individual business leaders) were undertaken. The results of this expanded analysis suggest strongly that nationally members of the business community and their employees will benefit from the legislation early on (years 1 through 3) and then likely will be impacted adversely as the payment mechanisms driving the legislation are tightened by new federal regulations (years 4 onward). As a result of this research, it is surmised that businesses will be immediately impacted by the legislation, with small business owners being the prime beneficiaries of the new legislation, owing to the availability of coverage to approximately 32 million individuals who previously had no access to coverage. In that regard, the soon-to be newly insured population also will be a prime beneficiary of the legislation as the limitations on chronic illnesses and other preexisting conditions will be reduced or eliminated by the legislation. PMID- 22842760 TI - How nursing managers respond to intraprofessional aggression: novel strategies to an ongoing challenge. AB - Nursing managers are identified as playing a central role in workplace aggression management. In effect, employees' decisions to report unacceptable behavior is said to be directly influenced by how a manager will respond to their claims. Using principles from critical nursing ethnography, data were collected from interviews, organizational documents, and observation of physical environment. Twenty-three semistructured interviews were conducted in both a university affiliated psychiatric hospital and a community hospital located in a large metropolitan city in Ontario. The study aimed at broadening the understanding of how nurse managers respond to intraprofessional and interprofessional workplace aggression. Several strategies were described by managers including coaching individuals so they feel capable of addressing the issue themselves, acting as mediator to allow both sides to openly and respectfully talk about the issue, and disciplining employees whose actions warrant harsh consequences. As part of the study, managers reported that dealing with workplace aggression could be difficult and time consuming and admitted that they sometimes came to doubt their abilities to be able to positively resolve such a widespread problem. Conclusions drawn from the study suggest that aggression management is not solely the responsibility of managers but must involve several actors including the aggressive individual, peers, human resources department, and unions. PMID- 22842761 TI - Electronic health records: postadoption physician satisfaction and continued use. AB - One goal of public-policy makers in general and health care managers in particular is the adoption and efficient utilization of electronic health record (EHR) systems throughout the health care industry. Consequently, this investigation focused on the effects of known antecedents of technology adoption on physician satisfaction with EHR technology and the continued use of such systems. The American Academy of Family Physicians provided support in the survey of 453 physicians regarding their satisfaction with their EHR use experience. A conceptual model merging technology adoption and computer user satisfaction models was tested using structural equation modeling. Results indicate that effort expectancy (ease of use) has the most substantive effect on physician satisfaction and the continued use of EHR systems. As such, health care managers should be especially sensitive to the user and computer interface of prospective EHR systems to avoid costly and disruptive system selection mistakes. PMID- 22842762 TI - A nurse-led interdisciplinary leadership approach targeting pressure ulcer prevention in long-term care. AB - Mounting evidence suggests that the quality of outcomes in long-term care can be improved by strengthening the leadership behaviors of nurses. Consequently, a reduction in the prevalence and incidence of pressure ulcers (PUs) is thought to be possible through a nurse-led, team-based approach. The purposes of this article were to (1) advocate for greater nurse-led interdisciplinary teamwork focusing on PU prevention and (2) describe how a transformational and practice based framework can be used to guide the long-term care team to improve PU quality care outcomes. Application of nurse-led, team-conceptualized strategies enables interdisciplinary workers to partner and more effectively participate in PU prevention programs, thus deepening engagement in the organization's overall approach to achieving quality outcomes. PMID- 22842763 TI - Validation of the French and English versions of the Worklife Pulse Survey. AB - A clear and rapid understanding of a health care organization's Quality Work Life is highly important as it can inform decision makers of issues that could impact their workers' psychological and physical health. Research has shown there is a relationship between workers' psychosocial work environment and their health and well-being. The Worklife Pulse Survey is a 21-item questionnaire providing a snapshot of health care organizations' Quality Work Life. This tool is deployed as part of Accreditation Canada's Qmentum accreditation program and is available both in English and in French. The present research sought to validate the 2 versions of the survey as well as the comparability of the generated data. The results obtained from 9578 French-speaking and 16 398 English-speaking respondents support the validity of both versions of the Worklife Pulse Survey as well as the comparability of the responses for all participants, for each gender separately, and for each age group separately. PMID- 22842764 TI - Effect of financial incentives on ethnic disparities in smoking cessation interventions in primary care: cross-sectional study. AB - BACKGROUND: Smoking cessation interventions are underprovided in primary care. Financial incentives may help address this. However, few studies in the UK have examined their impact on disparities in the delivery of smoking cessation interventions. METHODS: Cross-sectional study using 2007 data from 29 general practices in Wandsworth, London, UK. We used logistic regression to examine associations between disease group [cardiovascular disease (CVD), respiratory disease, depression or none of these diseases], ethnicity and smoking outcomes following the introduction of the Quality and Outcomes Framework in 2004. RESULTS: Significantly, more CVD patients had smoking status ascertained compared with those with respiratory disease (89 versus 72%), but both groups received similar levels of cessation advice (93 and 89%). Patients with depression or none of the diseases were less likely to have smoking status ascertained (60% for both groups) or to receive advice (80 and 75%). Smoking prevalence was high, especially for patients with depression (44%). White British patients had higher rates of smoking than most ethnic groups, but black Caribbean men with depression had the highest smoking prevalence (62%). CONCLUSIONS: Smoking rates remain high, particularly for white British and black Caribbean patients. Extending financial incentives to include recording of ethnicity and rewarding quit rates may further improve smoking cessation outcomes in primary care. PMID- 22842766 TI - Corticosteroid administration reduces the concentration of hyaluronan in bronchoalveolar lavage in a murine model of eosinophilic airway inflammation. AB - OBJECTIVE: To analyze the effect of corticosteroid administration on the concentration of hyaluronan (HA) in bronchoalveolar lavage (BAL) in a murine model of eosinophilic airway inflammation and to study the mechanisms involved. MATERIALS AND METHODS: Untreated-mice or mice treated with 1 MUg/g/day betamethasone (Bm) or 0.25 MUg/g/day(-1) budesonide (Bd) were sensitized and challenged with Dermatophagoides pteronyssinus (Dp) or saline (control group). The concentration of HA in BAL was determined by ELISA. In vitro migration assays were performed using a Boyden chamber and the expression of HA synthases (HAS) was analyzed by RT-PCR. RESULTS: We found a significant increase (P < 0.01) in the levels of HA in BAL from Dp-treated mice that was prevented by Bm or Bd. Corticosteroids also inhibited the increase in HAS expression, and the phosphorylation of Akt and ERK in the lungs of challenged mice. Finally, we found that low molecular weight HA induces the chemotaxis of BAL cells in vitro through a mechanism mediated by CD44. CONCLUSION: We conclude that corticosteroids prevent the increase in HA in BAL from Dp-challenged mice. This effect is associated with reduced expression of HAS and reduced phosphorylation of Akt and ERK in the lungs of challenged mice. PMID- 22842767 TI - Characterization of lipopolysaccharide-stimulated cytokine expression in macrophages and monocytes. AB - OBJECTIVE: In vitro cell culture models are widely used in inflammation research; however, information regarding the time- and dose-dependency of inflammatory responses toward LPS in these cell lines is scattered in the literature. MATERIAL: J774A.1 mouse macrophage and THP-1 human monocyte cell lines. TREATMENT: J774A.1 and THP-1 cells were treated with 0-500 ng/mL lipopolysaccharide for 0-24 h. METHODS: SRB and BCA tests were used to measure total protein. Real-time PCR was used to determine gene expression levels, and ELISA was used to assess the protein levels. One-way ANOVA and Tukey's Honestly Significant Difference test were used to test the significance levels. RESULTS: In J774A.1 and THP-1 cells, cytokines responded in distinct patterns upon LPS stimulation in a time- and dose-dependent manner, and the differential regulation of the response to LPS between J774A.1 and THP-1 cells appeared to correlate with the differential regulation of TLR4 at the mRNA level. CONCLUSION: In summary, this study indicated that temporal and dose-dependent responses to LPS need to be controlled for and that extrapolation of data on mechanisms may differ between cell lines of different origin. PMID- 22842768 TI - The impact of modeling nuclear fragmentation on delivered dose and radiobiology in ion therapy. AB - The importance of nuclear interactions for ion therapy arises from the influence of the particle spectrum on, first, radiobiology and therefore also on treatment planning, second, the accuracy of measuring dose and, third, the delivered dose distribution. This study tries to determine the qualitative as well as the quantitative influence of the modeling of inelastic nuclear interactions on ion therapy. Thereby, three key disciplines are investigated, namely dose delivery, dose assessment and radiobiology. In order to perform a quantitative analysis, a relative comparison between six different descriptions of nuclear interactions is carried out for carbon ions. The particle transport is simulated with the Monte Carlo code SHIELD-HIT10A while dose planning and radiobiology are covered by the analytic treatment planning program for particles TRiP, which determines the relative biological effectiveness (RBE) with the local effect model. The obtained results show that the physical dose distribution can in principle be significantly influenced by the modeling of fragmentation (about 10% for a 20% change in all inelastic nuclear cross sections for a target volume ranging from 15 to 25 cm). While the impact of nuclear fragmentation on stopping power ratios can be neglected, the fluence correction factor may be influenced by the applied nuclear models. In contrast to the results for the physical dose, the variation of the RBE is only small (about 1% for a 20% change in all inelastic nuclear cross sections) suggesting a relatively weak dependence of radiobiology on the detailed composition of the particle energy spectrum of the mixed radiation field. Also, no significant change (about 0.2 mm) of the lateral penumbra of the RBE-weighted dose is observed. PMID- 22842765 TI - Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. AB - RATIONALE: In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. OBJECTIVE: This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. METHOD: Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr 2, which are LSD-like specific, were assayed. RESULTS: Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). CONCLUSION: Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects. PMID- 22842770 TI - Highly efficient three-component coupling reaction catalyzed by gold nanoparticles supported on periodic mesoporous organosilica with ionic liquid framework. AB - A novel gold nanoparticle supported periodic mesoporous organosilica with alkylimidazolium framework, Au@PMO-IL, was shown to be a highly active and recyclable catalyst for three-component coupling reaction of aldehyde, alkyne and amine to give the corresponding propargylamine. PMID- 22842769 TI - Role of transcription factor Sp1 in the quercetin-mediated inhibitory effect on human malignant pleural mesothelioma. AB - Quercetin (Qu) is found in plants, including red onions and in the skins of red apples, and induces the apoptosis of certain malignant cells. However, no report has been issued on the apoptotic effect of Qu on human malignant pleural mesothelioma. In the present study, it was found that MSTO-211H mesothelioma cell viability was reduced and apoptotic cell death was increased by Qu (20-80 uM), which was found to have an IC50 of 58 uM. In addition, Qu increased the sub-G1 cell population, and was found to interact with specificity protein 1 (Sp1) and significantly suppressed its expression at the protein and mRNA levels. Furthermore, Qu modulated the levels of Sp1 regulatory genes, such as cyclin D1, myeloid cell leukemia (Mcl)-1 and survivin in MSTO-211H cells. Apoptotic signaling cascades were activated by the cleavage of Bid, caspase-3 and PARP, and by the downregulation of Bcl-xL and the upregulation of Bax in MSTO-211H cells. Our results strongly suggest that Sp1 be considered as a novel molecular target of Qu in human malignant pleural mesothelioma. PMID- 22842771 TI - From in vitro culture to in vivo models to study testis development and spermatogenesis. AB - The testis is a complex organ playing host to one of the most intricate mass cell divisions occurring in postnatal life. Since the beginning of the 20th century, great efforts have been made to recapitulate spermatogenesis and elucidate spermatogonial stem cell function. These efforts have resulted in the development of a variety of model systems that provide invaluable knowledge regarding testis organogenesis, key cell types and their interactions, and signaling pathways controlling testis function. The goal of this review is to elaborate on the evolution of the techniques available from in vitro culture systems to in vivo bioassays by providing up to date information and weighing their particular strengths and weaknesses. Each technique offers a different approach to the elucidation of male reproduction, the enhancement of germ-lineage genetic manipulation, the preservation of gametes, the restoration of fertility, and the improvement in our understanding of stem cell biology. PMID- 22842772 TI - Characterization and importance of microRNAs in mammalian gonadal functions. AB - Recent progress in high throughput sequencing and bioinformatic analysis and other biochemical methods have fuelled our appreciation for the important role of microRNAs (miRNAs) in disease, fertility and development. These tiny RNAs were found to be potentially involved in various aspects of cellular processes of reproductive tissues by posttranscriptional regulation of protein coding genes. Mammalian gonads which exhibit strictly regulated spatiotemporal gene expression patterns are also known to express unique sets of miRNAs and genes involved in the miRNA biogenetic pathway. Studies on miRNAs and their associated processing enzymes have evidenced the contribution of these small regulatory RNAs to germ cell differentiation, post-meiotic male germ cell function and growth, and development and maturation of oocytes through pertaining tightly regulated gene expression. The existence, preferential and temporal expression of miRNAs and their processing machinery genes in different stages of testicular and ovarian cellular development have evidenced the potential role of miRNAs in testicular and ovarian physiology. MiRNAs are also found to be associated with functional regulation of gonadal somatic cells, namely Leydig cells and Sertoli cells in testis and granulosa cells/cumulus cells in the ovary in steroid synthesis. Here, we review the recent works on the involvement and diverse roles of miRNAs in the development and physiology of gonadal cells in mammalian reproduction. PMID- 22842773 TI - Integrated electrofluidic circuits: pressure sensing with analog and digital operation functionalities for microfluidics. AB - Microfluidic technology plays an essential role in various lab on a chip devices due to its desired advantages. An automated microfluidic system integrated with actuators and sensors can further achieve better controllability. A number of microfluidic actuation schemes have been well developed. In contrast, most of the existing sensing methods still heavily rely on optical observations and external transducers, which have drawbacks including: costly instrumentation, professional operation, tedious interfacing, and difficulties of scaling up and further signal processing. This paper reports the concept of electrofluidic circuits - electrical circuits which are constructed using ionic liquid (IL)-filled fluidic channels. The developed electrofluidic circuits can be fabricated using a well developed multi-layer soft lithography (MSL) process with polydimethylsiloxane (PDMS) microfluidic channels. Electrofluidic circuits allow seamless integration of pressure sensors with analog and digital operation functions into microfluidic systems and provide electrical readouts for further signal processing. In the experiments, the analog operation device is constructed based on electrofluidic Wheatstone bridge circuits with electrical outputs of the addition and subtraction results of the applied pressures. The digital operation (AND, OR, and XOR) devices are constructed using the electrofluidic pressure controlled switches, and output electrical signals of digital operations of the applied pressures. The experimental results demonstrate the designed functions for analog and digital operations of applied pressures are successfully achieved using the developed electrofluidic circuits, making them promising to develop integrated microfluidic systems with capabilities of precise pressure monitoring and further feedback control for advanced lab on a chip applications. PMID- 22842774 TI - Protective effects of glutamine in a rat model of endotoxemia. AB - The aim of this study was to characterize the protective effects of glutamine (Gln) on brain cells undergoing experimental endotoxemia induced by lipopolysaccharide (LPS) injection. Young rats were injected with LPS or control, and a subset of LPS-injected rats were pretreated with Gln. Electron microscopy and immunohistochemistry were used to visualize apoptosis and to determine distribution and expression of nuclear factor-kappaB (NF-kappaB), heat shock protein 70 (HSP70), platelet-derived growth factor-B (PDGF-B) and PDGF receptor beta (PDGFR-beta). The levels of HSP70, PDGF-B and PDGFR-beta in the rat brain were comparatively analyzed by western blotting. In a rat brain model of endotoxemia, Gln decreases the magnitude of apoptosis, upregulates the expression of HSP70 and inhibits the translocation of NF-kappaB from the cytoplasm to the nucleus. Gln upregulates PDGF-B and PDGFR-beta expression in early and advanced sepsis. PDGF-B and PDGFR-beta upregulation in the cerebral cortex are likely neuroprotective effects of Gln. We found that Gln is capable of regulating the immunological defense of local brain tissue, which provides a theoretical basis for using Gln to prevent and treat encephalopathy. PMID- 22842776 TI - CO oxidation on Pt nanoclusters, size and coverage effects: a density functional theory study. AB - CO oxidation on Pt nanoclusters of approximately 1 nm in size was studied using density functional theory (DFT). Reaction barriers on various sites of a cuboctahedral 55-atom cluster and of several two-layer plane clusters representing (111) and (100) facets of the 147-atom cluster have been calculated at various coverage. The effect of atomic structure of various clusters was discussed. It was concluded that the 147-atom cuboctahedral cluster reveals properties of the Pt single crystal surfaces, while a 55-atom cluster cannot be fully described in terms of Pt single crystal surfaces. It was found that CO oxidation may occur faster at higher coverage and that for cluster sizes up to a few nanometers in size, larger platinum clusters can be more efficient in CO oxidation than the smaller clusters. The size effect was found to depend upon coverage. PMID- 22842775 TI - Use of email and telephone prompts to increase self-monitoring in a Web-based intervention: randomized controlled trial. AB - BACKGROUND: Self-monitoring is a key behavior change mechanism associated with sustained health behavior change. Although Web-based interventions can offer user friendly approaches for self-monitoring, engagement with these tools is suboptimal. Increased use could encourage, promote, and sustain behavior change. OBJECTIVE: To determine whether email prompts or email plus telephone prompts increase self-monitoring of behaviors on a website created for a multiple cancer risk reduction program. METHODS: We recruited and enrolled participants (N = 100) in a Web-based intervention during a primary care well visit at an urban primary care health center. The frequency of daily self-monitoring was tracked on the study website. Participants who tracked at least one behavior 3 or more times during week 1 were classified as meeting the tracking threshold and were assigned to the observation-only group (OO, n = 14). This group was followed but did not receive prompts. Participants who did not meet the threshold during week 1 were randomly assigned to one of 2 prompting conditions: automated assistance (AA, n = 36) or automated assistance + calls (AAC, n = 50). During prompting periods (weeks 2-3), participants in the AA and AAC conditions received daily automated emails that encouraged tracking and two tailored self-monitoring reports (end of week 2, end of week 3) that provided feedback on tracking frequency. Individuals in the AAC condition also received two technical assistance calls from trained study staff. Frequency of self-monitoring was tracked from week 2 through week 17. RESULTS: Self-monitoring rates increased in both intervention conditions during prompting and declined when prompting ceased. Over the 16 weeks of observation, there was a significant between-group difference in the percentage who met the self-monitoring threshold each week, with better maintenance in the AAC than in the AA condition (P < .001). Self-monitoring rates were greater in the OO group than in either the AA or AAC condition (P < .001). CONCLUSIONS: Prompting can increase self-monitoring rates. The decrease in self-monitoring after the promoting period suggests that additional reminder prompts would be useful. The use of technical assistance calls appeared to have a greater effect in promoting self-monitoring at a therapeutic threshold than email reminders and the tailored self-monitoring reports alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01415492; http://clinicaltrials.gov/ct2/show/NCT01415492 (Archived by WebCite at http://www.webcitation.org/68LOXOMe2). PMID- 22842777 TI - Effectiveness of supervised implementation of an oral health care guideline in care homes; a single-blinded cluster randomized controlled trial. AB - OBJECTIVES: The objective of this study was to assess the effectiveness of a supervised implementation of the "Oral health care Guideline for Older people in Long-term care Institutions" (OGOLI) in The Netherlands. MATERIALS AND METHODS: A sample of 12 care homes in the Netherlands was allocated randomly to an intervention or control group. While the residents in the control group received oral health care as before, the intervention consisted of a supervised implementation of the OGOLI. RESULTS: At baseline, the overall random sample comprised 342 residents, 52 % in the intervention group and 48 % in the control group. At 6 months, significant differences were observed between the intervention and the control group for mean dental as well as denture plaque, with a beneficial effect for the intervention group. The multilevel mixed-model analyses conducted with the plaque scores at 6 months as outcome variables showed that the reduction by the intervention was only significant for denture plaque. CONCLUSIONS: Supervised implementation of the OGOLI was more effective than non supervised implementation in terms of reducing mean plaque scores at 6 months. However, the multilevel mixed-model analysis could not exclusively explain the reduction of mean dental plaque scores by the intervention. CLINICAL RELEVANCE: A supervised implementation of an oral health care guideline improves oral health of care home residents. PMID- 22842778 TI - LI-cadherin cis-dimerizes in the plasma membrane Ca(2+) independently and forms highly dynamic trans-contacts. AB - LI-cadherin belongs to the family of 7D-cadherins that is characterized by a low sequence similarity to classical cadherins, seven extracellular cadherin repeats (ECs), and a short cytoplasmic domain. Nevertheless, LI-cadherins mediates Ca(2+) dependent cell-cell adhesion and induces an epitheloid cellular phenotype in non polarized CHO cells. Whereas several studies suggest that classical cadherins cis dimerize in a Ca(2+)-dependent manner and interact in trans by strand-swapping tryptophan 2 of EC1, little is known about the molecular interactions of LI cadherin, which lacks tryptophan 2. We thus expressed fluorescent LI-cadherin fusion proteins in HEK293 and CHO cells, analyzed their cell-cell adhesive properties and studied their cellular distribution, cis-interaction, and lateral diffusion in the presence and absence of Ca(2+). LI-cadherin highly concentrates in cell contact areas but rapidly leaves those sites upon Ca(2+) depletion and redistributes evenly on the cell surface, indicating that it is only kept in the contact areas by trans-interactions. Fluorescence resonance energy transfer analysis of LI-cadherin-CFP and -YFP revealed that LI-cadherin forms cis-dimers that resist Ca(2+) depletion. As determined by fluorescence redistribution after photobleaching, LI-cadherin freely diffuses in the plasma membrane as a cis-dimer (D = 0.42 +/- 0.03 MUm(2)/s). When trapped by trans-binding in cell contact areas, its diffusion coefficient decreases only threefold to D = 0.12 +/- 0.01 MUm(2)/s, revealing that, in contrast to classical and desmosomal cadherins, trans-contacts formed by LI-cadherin are highly dynamic. PMID- 22842780 TI - The efficacy of a perceptive rehabilitation on postural control in patients with chronic nonspecific low back pain. AB - Patients with chronic low back pain have a worse posture, probably related to poor control of the back muscles and altered perception of the trunk midline. The aim of this study was to evaluate the efficacy of a perceptive rehabilitation in terms of stability and pain relief in patients with chronic nonspecific low back pain. Thirty patients were enrolled and randomized into two groups: 15 patients received rehabilitation, on the basis of a specific tool to perform perceptive exercises [perceptive group (PG)], and 15 patients received a back school programme [back school group (BG)]. Both groups were assessed using stabilometry and the McGill Pain Questionnaire before and at the end of treatment. For the reference values of stabilometric parameters, 15 healthy individuals were enrolled. Significant reductions in sway length (P=0.019) and laterolateral sway velocity (P=0.038) were observed in the PG. The anteroposterior sway velocity was reduced in both the groups, but significantly only for BG (P=0.048). The percentage of sway length reduction was inversely and significantly correlated with the initial sway length value for PG (R=-0.708, P=0.003), but not for BG (R= 0.321, P=0.243). In the PG, the sagittal arrows and bi-acromial and bi-spinoiliac lines' angles were all significantly reduced. General pain relief was reported after treatment, without a significant difference (P=0.436). Our results suggest that a perceptive rehabilitation can improve the postural stability for the realignment of the trunk, controlling the back pain. The use of cognitive exercises may strengthen the usual rehabilitation of low back pain, avoiding the recurrence of symptoms. PMID- 22842781 TI - Shared agency and collaboration between the family and professionals in medical rehabilitation of children with severe disabilities. AB - Implementation of medical rehabilitation for children with severe disabilities, arranged by the Social Insurance Institution of Finland, is based on collaboration of the family with several professionals and organizations providing the necessary services. Therefore, it sets special challenges for service provision. Parents' experiences of shared agency and participation during children's rehabilitation process were analyzed in relation to the following research questions: what factors, describing the planning and implementation of rehabilitation, were associated with (a) the parents' satisfaction with planning, (b) the correspondence between the plans and the needs of the child, and (c) the correspondence between the received rehabilitation and the needs and wishes of the child and the parents. A questionnaire survey for the children's parents (n=496) included items on rehabilitation planning and implementation of services. The results were analyzed using cross-tabulations and logistic regression analyses. Taking into account of the parents' and children's preferences in rehabilitation and active participation of the rehabilitation counselor and the therapist were positively associated with parents' satisfaction with planning and the correspondence between the plan and the needs. The rehabilitation process was considered as more successful if the information received was sufficient, the parents were heard in all phases of the process, and the child was motivated to participate. Several stakeholders have responsibilities in medical rehabilitation for individuals with severe disabilities. Parents' experience of good rehabilitation planning in healthcare requires shared agency; that is, rehabilitation professionals listening to the family's preferences in decision making. Parents' experience with a successful rehabilitation process is dependent on information sharing, becoming heard, and collaboration in all phases of the process. PMID- 22842779 TI - ROS homeostasis during development: an evolutionary conserved strategy. AB - The balance between cellular proliferation and differentiation is a key aspect of development in multicellular organisms. Recent studies on Arabidopsis roots revealed distinct roles for different reactive oxygen species (ROS) in these processes. Modulation of the balance between ROS in proliferating cells and elongating cells is controlled at least in part at the transcriptional level. The effect of ROS on proliferation and differentiation is not specific for plants but appears to be conserved between prokaryotic and eukaryotic life forms. The ways in which ROS is received and how it affects cellular functioning is discussed from an evolutionary point of view. The different redox-sensing mechanisms that evolved ultimately result in the activation of gene regulatory networks that control cellular fate and decision-making. This review highlights the potential common origin of ROS sensing, indicating that organisms evolved similar strategies for utilizing ROS during development, and discusses ROS as an ancient universal developmental regulator. PMID- 22842782 TI - Gonadal development and fertility of triploid grass puffer Takifugu niphobles induced by cold shock treatment. AB - Tiger puffer Takifugu rubripes is one of the most valuable fish species in Japan; however, there has not been much progress in their selective breeding until recently despite their potential in aquaculture. Their long generation time and the large body size of their broodstock make breeding difficult. Recently, we made a surrogate broodstock, which produced gametes of different species in salmonids. Therefore, by using closely related recipients, which have small body sizes and short generation times, it is possible to accelerate breeding of the tiger puffer. Thus, we considered the grass puffer Takifugu niphobles, which has a short generation time and a small maturation size, as a potential recipient for gamete production of the tiger puffer. Furthermore, if sterile triploid individuals are used as recipients, the resulting surrogate broodstock would produce only donor-derived gametes. Therefore, we examined conditions for inducing triploidy by suppressing meiosis II to retain the second polar body in grass puffer. We found that cold shock treatment, which is 5 degrees C for 30 min starting from 5 min after fertilization, is optimal to obtain high triploidization and hatching rates. Although the resulting triploid grass puffers produced small amounts of gametes in both sexes, the offspring derived from the gametes could not live for over 3 days. Furthermore, we found that triploid grass puffer showed normal plasma sex steroid levels compared with diploids. These are important characteristics of triploid grass puffer as surrogate recipients used for germ cell transplantation. PMID- 22842783 TI - Polyvalent DP1 keeps the Wnt pathway neat and tidy. PMID- 22842784 TI - ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres. AB - Shelterin component TRF2 prevents ATM activation, while POT1 represses ATR signalling at telomeres. Here, we investigate the mechanism of G2/M arrest triggered by telomeres uncapped through TRF2 or POT1 inhibition in human cells. We find that telomere damage-activated ATR and ATM phosphorylate p53, as well as CHK1 and CHK2, thus activating two independent pathways to prevent progression into mitosis with uncapped telomeres. Surprisingly, telomere damage targets the CDC25C phosphatase for proteasome degradation in G2/M. CHK1/CHK2-dependent phosphorylation of CDC25C at Ser 216 is required for CDC25C nuclear export and destruction, which in turn acts to sustain the G2/M arrest elicited by TRF2- or POT1-depleted telomeres. In addition, CDC25C is transcriptionally downregulated by p53 in response to telomere damage. These mechanisms are distinct from the canonical DNA damage response to ionizing radiation, which triggers cell-cycle arrest through CDC25A destruction. Thus, dysfunctional telomeres promote ATM/ATR dependent degradation of CDC25C phosphatase to block mitotic entry, thereby preventing telomere dysfunction-driven genomic instability. PMID- 22842786 TI - A POTluck of peptide transporters. PMID- 22842785 TI - Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P2 and PI(5)P. AB - Normal steady-state levels of the signalling lipids PI(3,5)P(2) and PI(5)P require the lipid kinase FAB1/PIKfyve and its regulators, VAC14 and FIG4. Mutations in the PIKfyve/VAC14/FIG4 pathway are associated with Charcot-Marie Tooth syndrome and amyotrophic lateral sclerosis in humans, and profound neurodegeneration in mice. Hence, tight regulation of this pathway is critical for neural function. Here, we examine the localization and physiological role of VAC14 in neurons. We report that endogenous VAC14 localizes to endocytic organelles in fibroblasts and neurons. Unexpectedly, VAC14 exhibits a pronounced synaptic localization in hippocampal neurons, suggesting a role in regulating synaptic function. Indeed, the amplitude of miniature excitatory postsynaptic currents is enhanced in both Vac14(-/-) and Fig4(-/-) neurons. Re-introduction of VAC14 in postsynaptic Vac14(-/-) cells reverses this effect. These changes in synaptic strength in Vac14(-/-) neurons are associated with enhanced surface levels of the AMPA-type glutamate receptor subunit GluA2, an effect that is due to diminished regulated endocytosis of AMPA receptors. Thus, VAC14, PI(3,5)P(2) and/or PI(5)P play a role in controlling postsynaptic function via regulation of endocytic cycling of AMPA receptors. PMID- 22842787 TI - Chromosome ends teach unexpected lessons on DNA damage signalling. PMID- 22842788 TI - Multiscale registration of medical images based on edge preserving scale space with application in image-guided radiation therapy. AB - Mutual information (MI) is a well-accepted similarity measure for image registration in medical systems. However, MI-based registration faces the challenges of high computational complexity and a high likelihood of being trapped into local optima due to an absence of spatial information. In order to solve these problems, multi-scale frameworks can be used to accelerate registration and improve robustness. Traditional Gaussian pyramid representation is one such technique but it suffers from contour diffusion at coarse levels which may lead to unsatisfactory registration results. In this work, a new multi scale registration framework called edge preserving multiscale registration (EPMR) was proposed based upon an edge preserving total variation L1 norm (TV-L1) scale space representation. TV-L1 scale space is constructed by selecting edges and contours of images according to their size rather than the intensity values of the image features. This ensures more meaningful spatial information with an EPMR framework for MI-based registration. Furthermore, we design an optimal estimation of the TV-L1 parameter in the EPMR framework by training and minimizing the transformation offset between the registered pairs for automated registration in medical systems. We validated our EPMR method on both simulated mono- and multi-modal medical datasets with ground truth and clinical studies from a combined positron emission tomography/computed tomography (PET/CT) scanner. We compared our registration framework with other traditional registration approaches. Our experimental results demonstrated that our method outperformed other methods in terms of the accuracy and robustness for medical images. EPMR can always achieve a small offset value, which is closer to the ground truth both for mono-modality and multi-modality, and the speed can be increased 5-8% for mono-modality and 10-14% for multi-modality registration under the same condition. Furthermore, clinical application by adaptive gross tumor volume re-contouring for clinical PET/CT image-guided radiation therapy throughout the course of radiotherapy is also studied, and the overlap between the automatically generated contours for the CT image and the contours delineated by the oncologist used for the planning system are on average 90%. PMID- 22842789 TI - Skull base CT: normative values for size and symmetry of the facial nerve canal, foramen ovale, pterygoid canal, and foramen rotundum. AB - PURPOSE: Contrast-enhanced MRI is the mainstay for detecting pathology in the skull base foramina and nerve canals, through demonstration of abnormal enhancement. When MRI is contraindicated, or unable to differentiate tumor from non-neoplastic pathology, high-resolution skull base CT is indicated to assess for nerve canal or foramen widening, which is currently determined subjectively. The purpose of this study is to provide objective CT criteria that may help distinguish between normal asymmetry and pathologic nerve canal or foramen widening. METHODS: Temporal bone CTs of 50 consecutive adults without facial or trigeminal nerve pathology were retrospectively reviewed. Short axis measurements were obtained in the axial plane for three segments of the facial nerve canal (labyrinthine, tympanic, and mastoid), foramen ovale, pterygoid canal and foramen rotundum on both sides in each subject. Descriptive statistics were obtained, and left-right asymmetry was calculated. RESULTS: Nerve canal/foramen size was normally distributed across subjects, with a minimal amount of left-right asymmetry. The upper limits of the 95 % confidence interval for absolute left right asymmetry were: 0.25, 0.21, and 0.15 mm for the labyrinthine, tympanic, and mastoid segments of the facial nerve canal, respectively; 0.62 mm for foramen ovale; 0.36 mm for pterygoid canal; 0.38 mm for foramen rotundum. CONCLUSION: Relative asymmetry is more important than absolute size for determining nerve canal/foramen abnormality. These normative data may be useful adjuncts to subjective assessments of nerve canal/foramen size when using skull base CT to identify tumor. PMID- 22842790 TI - Anatomy and surgical landmarks for the ansa pectoralis: application to pectoralis major nerve selective neurotomy. AB - BACKGROUND: Ansa pectoralis neurotomy is a surgical approach in the treatment of the pectoralis major muscle spasticity causing an attitude in adduction and internal rotation of the shoulder. OBJECTIVE: To establish the anatomical landmarks allowing an easier localisation of the ansa pectoralis during neurotomy. MATERIAL AND METHODS: Fifteen adult human cadavers (10 embalmed and 5 fresh) were dissected in order to determine anatomical landmarks allowing an easier localization of the ansa pectoralis during neurotomy. RESULTS: In all the cadavers, the lateral pectoral nerve arose from the lateral cord of the brachial plexus, 0.2 cm above to 1.5 cm below the inferior border of the clavicle with a mean distance of 0.76 cm for left and right side, whereas the medial pectoral nerve arose from the medial cord of the brachial plexus, 0.7-2.3 cm below the inferior border of the clavicle with a mean distance of 0.61 cm for the left side and 0.68 cm for the right side. We systematically found both the origin of pectoral nerves and the ansa pectoralis at the level of the middle third of the distance between the sternoclavicular and the acromioclavicular joints. Moreover, ansa pectoralis was constantly localized lateral to the thoracoacromial artery. In four cases, the division of the lateral pectoral nerve was not found. In one case, medial pectoral nerve did not exist. CONCLUSION: Ansa pectoralis can be found by a curved incision made at the mid-third of the distance between the sternoclavicular and the acromioclavicular joints, the medial point being located just below the lower edge of the clavicle and the lateral point 2 cm below the inferior edge of the clavicle. PMID- 22842792 TI - Driving on ice: impaired driving skills in current methamphetamine users. AB - RATIONALE: Previous research indicates a complex link between methamphetamine (METH) and driving performance. Acute dosing with amphetamines has improved driving-related performance in some laboratory studies, while epidemiological studies suggest an association between METH use, impaired driving, and accident culpability. METHODS: Current METH users were compared to a control group of nonusers on driving simulator performance. Groups were matched for age, gender, and driving experience. Subjects were assessed for current drug use, drug dependence, and drug levels in saliva/blood as well as personality variables, sleepiness, and driving performance. RESULTS: METH users, most of whom met the criteria for METH dependence, were significantly more likely to speed and to weave from side to side when driving. They also left less distance between their vehicle and oncoming vehicles when making a right-hand turn. This risky driving was not associated with current blood levels of METH or its principal metabolite, amphetamine, which varied widely within the METH group. Other drugs were detected (principally low levels of THC or MDMA) in some METH users, but at levels that were unlikely to impair driving performance. There were higher levels of impulsivity and antisocial personality disorder in the METH-using cohort. CONCLUSIONS: These findings confirm indications from epidemiological studies of an association between METH use and impaired driving ability and provide a platform for future research to further explore the factors contributing to increased accident risk in this population. PMID- 22842791 TI - Behavioral, neurochemical and pharmaco-EEG profiles of the psychedelic drug 4 bromo-2,5-dimethoxyphenethylamine (2C-B) in rats. AB - RATIONALE AND OBJECTIVES: Behavioral, neurochemical and pharmaco-EEG profiles of a new synthetic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats were examined. MATERIALS AND METHODS: Locomotor effects, prepulse inhibition (PPI) of acoustic startle reaction (ASR), dopamine and its metabolite levels in nucleus accumbens (NAc), EEG power spectra and coherence in freely moving rats were analysed. Amphetamine was used as a reference compound. RESULTS: 2C-B had a biphasic effect on locomotion with initial inhibitory followed by excitatory effect; amphetamine induced only hyperlocomotion. Both drugs induced deficits in the PPI; however they had opposite effects on ASR. 2C-B increased dopamine but decreased 3,4-dihydroxyphenylacetic acid (DOPAC) in the NAc. Low doses of 2C-B induced a decrease in EEG power spectra and coherence. On the contrary, high dose of 2C-B 50 mg/kg had a temporally biphasic effect with an initial decrease followed by an increase in EEG power; decrease as well as increase in EEG coherence was observed. Amphetamine mainly induced an increase in EEG power and coherence in theta and alpha bands. Increases in the theta and alpha power and coherence in 2C-B and amphetamine were temporally linked to an increase in locomotor activity and DA levels in NAc. CONCLUSIONS: 2C-B is a centrally active compound similar to other hallucinogens, entactogens and stimulants. Increased dopamine and decreased DOPAC in the NAc may reflect its psychotomimetic and addictive potential and monoaminoxidase inhibition. Alterations in brain functional connectivity reflected the behavioral and neurochemical changes produced by the drug; a correlation between EEG changes and locomotor behavior was observed. PMID- 22842793 TI - Noninvasive detection of thin-liquid aspiration using dual-axis swallowing accelerometry. AB - Aspiration (the entry of foreign contents into the upper airway) is a serious concern for individuals with dysphagia and can lead to pneumonia. However, overt signs of aspiration, such as cough, are not always present, making noninstrumental diagnosis challenging. Valid, reliable tools for detecting aspiration during clinical screening and assessment are needed. In this study we investigated the validity of a noninvasive accelerometry signal-processing classifier for detecting aspiration. Dual-axis cervical accelerometry signals were collected from 40 adults on thin-liquid swallowing tasks during videofluoroscopic swallowing examinations. Signal-processing algorithms were used to remove known sources of artifact and a classifier was trained to identify signals associated with penetration-aspiration. Validity was measured in comparison to blinded ratings of penetration-aspiration from the concurrently recorded videofluoroscopies. On a bolus-by-bolus basis, the accelerometry classifier had a 10 % false-negative rate (90 % sensitivity) and a 23 % false positive rate (77 % specificity) for detecting penetration-aspiration. We conclude that accelerometry can be used to support valid, reliable, and efficient detection of aspiration risk in patients with suspected dysphagia. PMID- 22842794 TI - MicroRNA-203 enhances coxsackievirus B3 replication through targeting zinc finger protein-148. AB - Coxsackievirus B3 (CVB3) is the primary causal agent of viral myocarditis. During infection, it hijacks host genes to favour its own replication. However, the underlying mechanism is still unclear. Although the viral receptor is an important factor for viral infectivity, other factors such as microRNAs (miRNA) may also play an essential role in its replication after host cell entry. miRNAs are post-transcriptional gene regulators involved in various fundamental biological processes as well as in diseases. To identify miRNAs involved in CVB3 pathogenesis, we performed microarray analysis of miRNAs using CVB3-infected murine hearts and identified miR-203 as one of the most upregulated candidates. We found that miR-203 upregulation is through the activation of protein kinase C/transcription factor AP-1 pathway. We further identified zinc finger protein 148 (ZFP-148), a transcription factor, as a novel target of miR-203. Ectopic expression of miR-203 downregulated ZFP-148 translation, increased cell viability and subsequently enhanced CVB3 replication. Silencing of ZFP-148 by siRNA showed similar effects on CVB3 replication. Finally, analyses of the signalling cascade downstream of ZFP-148 revealed that miR-203-induced suppression of ZFP-148 differentially regulated the expression of prosurvival and proapoptotic genes of the Bcl-2 family proteins as well as the cell cycle regulators. This altered gene expression promoted cell survival and growth, which provided a favourable environment for CVB3 replication, contributing to the further damage of the infected cells. Taken together, this study identified a novel target of miR-203 and revealed, for the first time, the molecular link between miR-203/ZFP-148 and the pathogenesis of CVB3. PMID- 22842795 TI - Adverse childhood experiences and suicidal behavior of adolescent psychiatric inpatients. AB - The present study examines the association of adverse childhood experiences (ACEs) to suicidal behavior and mortality in 508 Finnish adolescents (aged 12-17 years) who required acute psychiatric hospitalization between April 2001 and March 2006. The Schedule for Affective Disorder and Schizophrenia for School-Age Children Present and Lifetime (K-SADS-PL) and the European Addiction Severity Index (EuropASI) were used to obtain information about ACEs, adolescents' suicidal behavior and psychiatric diagnoses. The cases of death were obtained from Statistics Finland. The results of our study indicated that, among girls, exposure to sexual abuse statistically significantly increased the risk of non suicidal self-injury (NSSI) (OR, 1.8; 95 % CI, 1.0-3.2) and suicide attempts (OR, 2.3; 95 % CI, 1.0-4.5). The cumulative number of ACEs was also associated with an increased risk of NSSI (OR, 1.2; 95 % CI, 1.0- 1.4) and suicide attempts (OR, 1.2; 95 % CI, 1.0-1.4) in girls. Among all deceased adolescents, ACEs were most notable among those who had died due to accidents and injuries. Gender differences in the types of ACEs were noted and discussed. PMID- 22842796 TI - Correlation between LRRK2 gene G2385R polymorphisms and Parkinson's disease. AB - The aim of the current study was to determine the correlation between the G2385R polymorphism of the LRRK2 gene and Parkinson's disease (PD) and the differences in genotypic and allelic frequencies between the Uyghur and Han Chinese populations. A case-control study was performed in which the genotypic and allelic frequencies of the LRRK2 gene G2385R polymorphism were analyzed using a polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. Results showed the frequency of the GG genotype to be the highest, whereas that of the GA-type heterozygote was the lowest. No AA genotype was identified. The frequency of the GA genotype among Han patients was higher compared with that of the control group. Han individuals who carry the A allele have a higher risk of PD than non-carriers. In the present study, the frequencies of the GA genotype and A allele among Han patients were found to be higher compared with those in the Uyghur group. Moreover, Han individuals who carry the A allele exhibited a higher risk of PD than the Uyghur individuals. No statistically significant differences in genotypic and allelic frequencies were observed between the control and PD groups who were >50 years of age. The risk of PD was higher among individuals carrying the A allele than among non-carriers. The PD (<=50 years of age), the male and the female groups were compared with the control group, but no statistically significant differences were identified in allelic or genotypic frequencies. The genotypic and allelic frequencies of the LRRK2 gene G2385R polymorphism between the Uyghur and Han populations were significantly different. The A allele of the LRRK2 gene G2385R polymorphism is correlated with an increased risk of PD, particularly at an age of >=50 years. PMID- 22842797 TI - Microfluidic sensing devices employing in situ-formed liquid crystal thin film for detection of biochemical interactions. AB - Although biochemical sensing using liquid crystals (LC) has been demonstrated, relatively little attention has been paid towards the fabrication of in situ formed LC sensing devices. Herein, we demonstrate a highly reproducible method to create uniform LC thin film on treated substrates, as needed, for LC sensing. We use shear forces generated by the laminar flow of aqueous liquid within a microfluidic channel to create LC thin films stabilized within microfabricated structures. The orientational response of the LC thin films to targeted analytes in aqueous phases was transduced and amplified by the optical birefringence of the LC thin films. The biochemical sensing capability of our sensing devices was demonstrated through experiments employing two chemical systems: dodecyl trimethylammonium bromide (DTAB) dissolved in an aqueous solution, and the hydrolysis of phospholipids by the enzyme phospholipase A(2) (PLA(2)). PMID- 22842798 TI - The effects of simvastatin on hippocampal caspase-3 and Bcl-2 expression following kainate-induced seizures in rats. AB - Status epilepticus (SE) causes neuronal loss and apoptosis by inducing several apoptosis-regulatory genes. Two such genes, cysteinyl aspartate-specific protease 3 (caspase-3), an apoptosis activator, and B-cell leukemia-2 (Bcl-2), an apoptosis suppressor, are tightly regulated for their expression and activation. Statins, inhibitors of HMG-CoA reductase, have been recently recognized as neuroprotective drugs. However, their underlying mechanisms are still unclear. In this study, we examined the neuroprotective effects of simvastatin in a rat model of SE induced by kainic acid (KA). Feeding of simvastatin for 3 days after kainate injection rescued SE-induced neuronal apoptosis, as determined by histological examination of brain sections at the level of the dorsal hippocampus. Semi-quantitative RT-PCR showed that SE treatment markedly increased caspase-3 mRNA expression and reduced Bcl-2 mRNA expression in the hippocampus. Similarly, western blot analysis and immunohistochemical analysis of the rat hippocampus demonstrated that under SE treatment, caspase-3 protein levels significantly increased and peaked at 72 h, whereas Bcl-2 protein levels decreased from 6-24 h following SE. Interestingly, simvastatin could reverse the aforementioned SE-induced changes, suggesting that the neuroprotective effects of simvastatin against neuronal apoptosis may be achieved by inhibiting caspase-3 expression and increasing Bcl-2 expression. PMID- 22842799 TI - Treatment patterns in inpatients with bipolar disorder at a psychiatric university hospital over a 9-year period: focus on mood stabilizers. AB - The increasing number of pharmacological treatment options for bipolar disorder seems to be paralleled by the number of evidence-based guidelines published previously. The aim of this study was to systematically examine the adherence to published guidelines and any change in prescription habits over time in a psychiatric hospital setting. This is a retrospective study of 531 bipolar in patients who were consecutively admitted to the Department for Psychiatry and Psychotherapy in Innsbruck. Their complete medical histories were evaluated for psychotropic medications, with a special focus on mood stabilizers (MSs). To compare the use of individual MSs or combinations with other psychotropic medications in two preselected observation periods (1999-2003 and 2004-2007), we used Fisher's exact test. Overall, the proportion of patients receiving at least one MS increased significantly from 1999-2003 to 2004-2007 (74.1 vs. 83.1%, P=0.011). Among the individual MSs, valproate was used most frequently in both time periods, showing a significant increase (P<0.001). Prescriptions of quetiapine (P<0.001) and lamotrigine (P=0.033) increased significantly, carbamazepine showed a significant decrease (P<0.001). Prescriptions of lithium and olanzapine decreased without reaching significance. The significant increase in the prescription of MS reflects the increasing awareness and implementation of recent evidence-based medicine guidelines into clinical practice. Clinical decision making, usually made on the basis of individual clinical experience, should always be reevaluated using periodically updated evidence-based medicine guidelines. PMID- 22842801 TI - You can't get there from here: misplaced incentives can undermine the goals of health care reform in the NICU setting. PMID- 22842800 TI - Ru-catalyzed hydrogenation of 3,5-diketo amides: simultaneous control of chemo- and enantioselectivity. AB - By modulating the chelating priorities of the different directing groups in 3,5 diketo amides with the assistance from coordinating solvent, highly chemo- and enantioselective hydrogenation of the C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-SunPhos]Cl in THF. PMID- 22842802 TI - Monozygotic twins discordant for trisomy 13: counselling and management issues. AB - The diagnosis and management of a heterokaryotypic monochorionic pregnancy, in which one of twins had trisomy 13, is presented. Monozygosity and discordant karyotypes were confirmed by amniocentesis of both the sacs. Radiofrequency ablation of the trisomic twin was successfully performed at 18-weeks gestation and the pregnancy ended at term with the birth of a healthy girl who remains well on follow-up at 12 months of age. We reiterate the importance of early amniocentesis of both the sacs in the presence of discordant fetal abnormalities and consideration of selective fetal termination to optimise the outcome of heterokaryotypic monochorionic twin pregnancies. PMID- 22842803 TI - Term neonate with intracranial hemorrhage and hereditary hemorrhagic telangiectasia: a case report and review of the literature. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs). The disease rarely presents in the neonatal period, primarily manifesting with epistaxis and gastrointestinal bleeding in adulthood. Occasionally, HHT can also present with symptoms related to AVMs in the cerebral, pulmonary or gastrointestinal vasculature. In prior reports, intracranial hemorrhage (ICH) secondary to cerebral AVM in neonates with HHT has been catastrophic and uniformly fatal. Here we report a case of a newborn with HHT and ICH from a suspected AVM who survived with aggressive medical management and surgical intervention, and provide a comprehensive review of the literature on ICH in neonates with HHT. PMID- 22842804 TI - Successful sulfonylurea treatment of a neonate with neonatal diabetes mellitus due to a novel missense mutation, p.P1199L, in the ABCC8 gene. AB - Neonatal/infancy-onset diabetes mellitus is a monogenic form of diabetes with onset within 6 months of age. Two distinct types of neonatal diabetes mellitus have been recognized: permanent and transient. Mutations within the K(+)ATP channel and insulin genes are found in most patients with permanent diabetes mellitus. There have been several reports of the successful transition from insulin to sulfonylurea agents in patients with permanent diabetes mellitus caused by mutations in the KCNJ11 gene. We report on a term female neonate with a novel missense mutation, p.P1199L, in the ABCC8 gene that encodes the sulfonylurea receptor 1 whose treatment was successfully converted from insulin to sulfonylurea. PMID- 22842806 TI - The Golden Rule. Application for fun and profit in electron transfer, energy transfer, and excited-state decay. AB - Time-dependent perturbation theory and application of the Golden Rule have been shown to be quantitatively applicable to electron transfer in the inverted region, energy transfer, and excited-state decay based on spectroscopic measurements on dpi(6) polypyridyl complexes of Ru(II), Os(II), and Re(I). PMID- 22842807 TI - Helicobacter pylori infection and gastroduodenal lesions in children with chronic kidney disease stage V. AB - BACKGROUND: This study aimed to investigate the dyspeptic symptoms, endoscopic findings, and frequency of Helicobacter pylori (Hp) infection in children with chronic kidney disease (CKD) stage V, and to compare findings in peritoneal dialysis (PD) and hemodialysis (HD) patients. METHODS: Sixty-five patients on PD (n = 36) or HD (n = 29) were included. Age, gender, duration and type of dialysis, and dyspeptic complaints were recorded. All patients underwent endoscopy. Rapid urease tests were performed in all patients and antral biopsy examinations done in suitable patients to investigate presence of Hp infection. RESULTS: The mean age of patients (55 % male) was 13.9 +/- 3.6 years. Frequency of dyspepsia was 43 % and was similar in HD and PD groups. The most frequent dyspeptic symptoms were early satiety (21.5 %) and bloating (17 %). Abnormal endoscopic findings were present in 81.5 % of patients (similar in both groups), and the most common lesion was gastritis (35.5 %). Hp positivity was determined in 37 % of the patients, which was similar in both groups. No significant relationship was found between dyspeptic symptoms and Hp infection. Hp infection was found to be significantly higher in 41.5 % of the patients with gastroduodenal lesions. Abnormal endoscopic findings were significantly higher in severely dyspeptic patients (88.9 %). CONCLUSIONS: We think performing an upper gastrointestinal tract examination and Hp screening may be helpful in renal transplant candidates with severe dyspeptic symptoms. PMID- 22842809 TI - Familial Takayasu arteritis in a mother and daughter. A report of two cases. AB - Takayasu arteritis (TA) is a chronic granulomatous panarteritis, predominantly affecting the aorta and its main branches. Infections, genetic factors as suggested by familial clustering, and autoimmunity may play a role in its pathogenesis. In this report, we describe familial TA in a mother and daughter with diverse clinical manifestations. In addition to being a familial form of vasculitis, both of our cases demonstrated amyloidosis, chronic renal disease thought to be due to ischemic nephropathy, and hypertensive nephrosclerosis. PMID- 22842810 TI - Extravasation of contrast into the myocardium and coronary vein during left ventricular cineangiography. PMID- 22842811 TI - Association of ELMO1 gene polymorphisms with diabetic nephropathy in Chinese population. AB - BACKGROUND: Genetic variations in the engulfment and cell motility 1 (ELMO1) gene have recently been identified to be associated with nephropathy attributed to Type 2 diabetes mellitus (T2DM). Since T2DM-associated complications are proved to be more common among Asians than Western individuals, and Chinese people have a high incidence of diabetic nephropathy (DN), this study sought to analyze the association of ELMO1 gene polymorphisms with DN to probe into the effects of ELMO1 gene on susceptibility of DN in Chinese population. METHODS: We genotyped 6 polymorphism sites of ELMO1 gene in 200 unrelated Chinese subjects (123 T2DM with DN case subjects and 77 T2DM without DN control subjects). Genotyping was detected by a Sequenom MassARRAY genotyping system. RESULTS: The strongest associations in ELMO1 gene with DN occurred at rs741301 [odds ratio (OR) 1.89; p=0.004] and rs10951509 (OR 1.76; p=0.02). Unconditional logistic regression analysis identified that the rs741301 polymorphism (presence of A allele, adjusted OR 3.27; p=0.03) and duration of T2DM (adjusted OR 1.15; p=0.04) were independent predictors for DN. The marker rs741301 located in intron 18 of ELMO1 gene was in strong linkage disequilibrium (LD) with rs11769038 (D'=0.91). Furthermore, haplotype analysis identified that haplotype 1 [CAAAGA] (OR 1.95; p=0.01), haplotype 2 [CAAAGG] (OR 0.50; p=0.01), and haplotype 9 [TGCGGG] (OR 0.17; p=0.007) of ELMO1 were significantly associated with DN. CONCLUSIONS: This study first investigated the association of ELMO1 gene polymorphisms with DN in a Chinese population, supporting its key role as a candidate gene in the susceptibility of DN. PMID- 22842812 TI - Reconstruction of multiple gastric electrical wave fronts using potential-based inverse methods. AB - One approach for non-invasively characterizing gastric electrical activity, commonly used in the field of electrocardiography, involves solving an inverse problem whereby electrical potentials on the stomach surface are directly reconstructed from dense potential measurements on the skin surface. To investigate this problem, an anatomically realistic torso model and an electrical stomach model were used to simulate potentials on stomach and skin surfaces arising from normal gastric electrical activity. The effectiveness of the Greensite-Tikhonov or the Tikhonov inverse methods were compared under the presence of 10% Gaussian noise with either 84 or 204 body surface electrodes. The stability and accuracy of the Greensite-Tikhonov method were further investigated by introducing varying levels of Gaussian signal noise or by increasing or decreasing the size of the stomach by 10%. Results showed that the reconstructed solutions were able to represent the presence of propagating multiple wave fronts and the Greensite-Tikhonov method with 204 electrodes performed best (correlation coefficients of activation time: 90%; pacemaker localization error: 3 cm). The Greensite-Tikhonov method was stable with Gaussian noise levels up to 20% and 10% change in stomach size. The use of 204 rather than 84 body surface electrodes improved the performance; however, for all investigated cases, the Greensite Tikhonov method outperformed the Tikhonov method. PMID- 22842813 TI - The neural correlates of positive self-evaluation and self-related memory. AB - Humans tend to have a positive self-evaluation (PSE). To what extent positive self-perception is interacting with valenced self-related memories is debated. The underlying neural substrates are not adequately explained yet. To explore the cerebral correlates of PSE and its influence on memory, 24 healthy subjects were asked during fMRI to decide in two conditions whether presented positive and negative personality traits characterized their own selves (self-evaluation) or an intimate other (other-evaluation). A lexical condition served as control task. In a subsequent unannounced recognition task, trait adjectives had to be classified as old or new. Activation during positive self- vs positive other evaluation was found in the medial ventral and dorsolateral prefrontal gyri, the parahippocampus and the supplementary motor area. Memory increased for positive personality traits and traits that had been referred to oneself or the other. In contrast to adjectives of the other-evaluation or lexical condition, recollection of negative vs positive traits of the self-evaluation condition specifically induced increased activation in the hippocampus and several prefrontal and temporal areas. Our data imply a specific network for PSE (although intimate others are perceived similarly). Moreover, memory for traits contradicting PSE resulted in activation increases indicating greater cognitive effort and emotional involvement. PMID- 22842814 TI - Interactions between perceived emotions and executive attention in an interpersonal game. AB - The emotions displayed by others can be cues to predict their behavior. Happy expressions are usually linked to positive consequences, whereas angry faces are associated with probable negative outcomes. However, there are situations in which the expectations we generate do not hold. Here, control mechanisms must be put in place. We designed an interpersonal game in which participants received good or bad economic offers from several partners. A cue indicated whether the emotion of their partner could be trusted or not. Trustworthy partners with happy facial expressions were cooperative, and angry partners did not cooperate. Untrustworthy partners cooperated when their expression was angry and did not cooperate when they displayed a happy emotion. Event-Related Potential (ERP) results showed that executive attention already influenced the frontal N1. The brain initially processed emotional expressions regardless of their contextual meaning but by the N300, associated to affective evaluation, emotion was modulated by control mechanisms. Our results suggest a cascade of processing that starts with the instantiation of executive attention, continues by a default processing of emotional features and is then followed by an interaction between executive attention and emotional factors before decision-making and motor stages. PMID- 22842815 TI - Self-regulatory depletion increases emotional reactivity in the amygdala. AB - The ability to self-regulate can become impaired when people are required to engage in successive acts of effortful self-control, even when self-control occurs in different domains. Here, we used functional neuroimaging to test whether engaging in effortful inhibition in the cognitive domain would lead to putative dysfunction in the emotional domain. Forty-eight participants viewed images of emotional scenes during functional magnetic resonance imaging in two sessions that were separated by a challenging attention control task that required effortful inhibition (depletion group) or not (control group). Compared to the control group, depleted participants showed increased activity in the left amygdala to negative but not to positive or neutral scenes. Moreover, whereas the control group showed reduced amygdala activity to all scene types (i.e. habituation), the depletion group showed increased amygdala activity relative to their pre-depletion baseline; however this was only significant for negative scenes. Finally, depleted participants showed reduced functional connectivity between the left amygdala and ventromedial prefrontal cortex during negative scene processing. These findings demonstrate that consuming self-regulatory resources leads to an exaggerated neural response to emotional material that appears specific to negatively valenced stimuli and further suggests a failure to recruit top-down prefrontal regions involved in emotion regulation. PMID- 22842816 TI - Damage to the ventromedial prefrontal cortex reduces interpersonal disgust. AB - Disgust for contaminating objects (core disgust), immoral behaviors (moral disgust) and unsavory others (interpersonal disgust), have been assumed to be closely related. It is not clear, however, whether different forms of disgust are mediated by overlapping or specific neural substrates. We report that 10 patients with damage to the ventromedial prefrontal cortex (vmPFC) avoided behaviors that normally elicit interpersonal disgust (e.g. using the scarf of a busker) less frequently than healthy and brain-damaged controls, whereas they avoided core and moral disgust elicitors at normal rates. These results indicate that different forms of disgust are dissociated neurally. We propose that the vmPFC is causally (and selectively) involved in mediating interpersonal disgust, shaping patterns of social avoidance and approach. PMID- 22842818 TI - Guided-wave liquid-crystal photonics. AB - In this paper we review the state of the art in the field of liquid-crystal tunable guided-wave photonic devices, a unique type of fill-once, molecular-level actuated, optofluidic systems. These have recently attracted significant research interest as potential candidates for low-cost, highly functional photonic elements. We cover a full range of structures, which span from micromachined liquid-crystal on silicon devices to periodic structures and liquid-crystal infiltrated photonic crystal fibers, with focus on key-applications for photonics. Various approaches on the control of the LC molecular orientation are assessed, including electro-, thermo- and all-optical switching. Special attention is paid to practical issues regarding liquid-crystal infiltration, molecular alignment and actuation, low-power operation, as well as their integrability in chip-scale or fiber-based devices. PMID- 22842817 TI - Repetition and brain potentials when recognizing natural scenes: task and emotion differences. AB - Repetition has long been known to facilitate memory performance, but its effects on event-related potentials (ERPs), measured as an index of recognition memory, are less well characterized. In Experiment 1, effects of both massed and distributed repetition on old-new ERPs were assessed during an immediate recognition test that followed incidental encoding of natural scenes that also varied in emotionality. Distributed repetition at encoding enhanced both memory performance and the amplitude of an old-new ERP difference over centro-parietal sensors. To assess whether these repetition effects reflect encoding or retrieval differences, the recognition task was replaced with passive viewing of old and new pictures in Experiment 2. In the absence of an explicit recognition task, ERPs were completely unaffected by repetition at encoding, and only emotional pictures prompted a modestly enhanced old-new difference. Taken together, the data suggest that repetition facilitates retrieval processes and that, in the absence of an explicit recognition task, differences in old-new ERPs are only apparent for affective cues. PMID- 22842819 TI - Dependence of the optical absorption and Na+ binding energies of coumarin-crown ethers on the size and attachment position of ether ring: density functional investigation. AB - The crowned coumarin complexes are well known compounds for their ion recognition abilities. They undergo photophysical changes upon cation binding. On the basis of density functional theory calculations, we examined the sodium cation (Na+) binding energies of coumarin-crown ethers based on 15-Crown-5 (15 C5) and 18 Crown-6 (18 C6) as well as the optical absorptions of coumarin-crown ethers based on 12-Crown-4 (12 C4), 15 C5 and 18 C6. We explored why the attachment of crown ether ring to coumarin affects the Na+ binding energies of coumarin-crown ethers and also why the optical absorption of coumarin is modified by the crown ethers. Our study reveals that the Na+ ion binding energies of coumarin-crown ethers depend strongly on the size of the crown ether ring and also on the attachment position of the ether ring on coumarin. These factors affect the intramolecular charge transfer and overall stability of the complexes. The absorptions of the coumarin and ether ring parts of coumarin-crown ether are red shifted from those of isolated coumarin and crown ether, respectively. The red-shift of the coumarin ester group absorption is much stronger depending on the attachment position of the ether ring to coumarin. The absorption intensity of the coumarin part in coumarin-crown ethers is reduced for the benzene group absorption, but is enhanced for the ester group absorption. PMID- 22842820 TI - Correlations between cognitive impairment and brain-derived neurotrophic factor expression in the hippocampus of post-stroke depression rats. AB - The aim of this study was to investigate the correlation between brain-derived neurotrophic factor (BDNF) expression and cognitive impairment in post-stroke depression (PSD) rats and to explore the mechanism(s) involved in the process of cognitive impairment. A rat model of focal cerebral ischemia was established by occluding the middle cerebral artery (MCA). Rats were subjected to isolation housing combined with chronic unexpected mild stress (CUMS) to establish a PSD rat model. The learning and memory abilities of the PSD rat model were evaluated by passive avoidance tests. Real-time PCR and immunohistochemical methods were used to detect changes in BDNF mRNA and protein expression in the hippocampus. Passive avoidance defects were revealed in the PSD and depression groups. Passive avoidance defects were more evident in the PSD group compared with the depression group and the difference was statistically significant (P<0.05). BDNF expression in the hippocampus was significantly lower in the PSD and depression groups compared with that in the normal control group (P<0.01). No significant difference in BDNF expression was identified between the normal control and stroke groups (P>0.05) or between the PSD and the depression groups (P>0.05). The decrease in BDNF expression in the hippocampus of PSD rats may aggravate cognitive impairment, however, the degree of cognitive impairment cannot be reflected by the expression levels of BDNF in the hippocampus. PMID- 22842821 TI - Interferon-beta-armed oncolytic adenovirus induces both apoptosis and necroptosis in cancer cells. AB - Interferon-beta (IFN-beta) has been widely used in cancer therapy, but the clinical trial results are generally disappointing. Our previous studies have shown that an oncolytic adenovirus carrying IFN-beta (ZD55-IFN-beta) exhibits significant anti-tumor activities. However, the underlying mechanisms are not clear. Here we showed that ZD55-IFN-beta infection-induced S-phase cell cycle arrest in a p53-dependent manner by activating the ataxia telangiectasia mutated dependent DNA damage pathway. In addition, ZD55-IFN-beta infection could initiate both caspase-dependent apoptosis and necroptosis in cancer cells. More importantly, ZD55-IFN-beta showed a synergistic effect on cancer cells when combined with doxorubicin. These results suggest that the combination of ZD55-IFN beta with doxorubicin may represent a promising clinical strategy in cancer therapy. PMID- 22842822 TI - Epidural anterior petrosectomy with subdural visualization of sphenobasal vein via the anterior transpetrosal approach--technical case report. AB - The drainage of the superficial middle cerebral vein (SMCV) is classified into four subtypes. The sphenobasal vein (SBV) drains from the SMCV to the pterygoid venous plexus at the temporal skull base. Epidural procedures in the standard anterior transpetrosal approach (ATPA) may damage the route of the SBV. We report a case in which modified surgical procedures via the ATPA were used to preserve the SBV. A 45-year-old man complained of right facial pain. Magnetic resonance images revealed a right cerebellopontine tumor suggestive of an epidermoid cyst. Right carotid angiography revealed that the SMCV drained into the pterygoid venous plexus via the SBV. The convexity dura mater of the temporal lobe was cut and the anterior part of the temporal lobe was retracted subdurally. The SBV was visualized from the subdural side. The basal dura mater of the temporal lobe posterior to the SBV was cut and the posterior part of the temporal lobe was retracted epidurally. After dissecting the dura mater medial to the greater petrosal nerve and to the edge of the petrous apex, the petrous apex was exposed and drilled out without injuring the SBV. The superior petrous sinus and the tentorium were cut. The tumor compressed the root exit zone of the trigeminal nerve. The tumor was grossly totally removed. The modified ATPA (epidural anterior petrosectomy with subdural visualization of the SBV) is effective in preserving the SBV. PMID- 22842823 TI - Therapeutic efficacy of an hTERT promoter-driven oncolytic adenovirus that expresses apoptin in gastric carcinoma. AB - The efficacy and specificity of treatment are the major challenges for cancer gene therapy. Oncolytic virotherapy is an attractive drug delivery platform of cancer gene therapy. Previous studies have determined that apoptin is a p53 independent, Bcl-2-insensitive apoptotic protein that has the ability to induce apoptosis specifically in tumor cells. In this study, we show that the administration of a dual cancer-specific oncolytic adenovirus construct, Ad-hTERT E1a-apoptin [in which the adenovirus early region 1a (E1a) gene is driven by the cancer-specific promoter of human telomerase reverse transcriptase (hTERT) and that expresses apoptin simultaneously], suppresses tumor growth in gastric carcinoma cells in vitro and reduces the tumor burden in vivo in xenografted nude mice. The observation that infection with the Ad-hTERT-E1a-apoptin construct significantly inhibited the growth of gastric cancer cells and protected normal human gastric epithelium from growth inhibition confirmed the induction of cancer cell-selective adenovirus replication, growth inhibition and apoptosis by this therapeutic approach. In vivo assays were performed using BALB/c nude mice that had established primary tumors. Subcutaneous primary tumor volume was reduced not only in the intratumoral injection group but also in the systemic delivery mice following treatment with Ad-hTERT-E1a-apoptin. Furthermore, treatment of primary models with Ad-hTERT-E1a-apoptin increased the mouse survival time. These data reinforce previous research and highlight the potential therapeutic application of Ad-hTERT-E1a-apoptin for the treatment of neoplastic diseases in clinical trials. PMID- 22842825 TI - Controllable growth of dendritic ZnO nanowire arrays on a stainless steel mesh towards the fabrication of large area, flexible dye-sensitized solar cells. AB - Well-defined ZnO nanowire (NW) arrays with controlled dendritic structures were successfully built on a stainless steel mesh and utilized as photoanodes for the fabrication of large-area, flexible dye-sensitized solar cells (DSSCs). The dendritic nanostructure proves favorable for the improvement of the overall light conversion efficiency of the DSSC. An optimized etching time for the affixion of ZnO seeds on the ZnO backbone of the dendritic "tree" and the controlled growth conditions of the branch NW are critical to achieve high conversion efficiency solar cells. PMID- 22842824 TI - Discrimination of colon cancer stem cells using noncanonical amino acid. AB - Cancer stem cells (CSCs) may be responsible for tumor recurrence. Metabolic labelling of newly synthesized proteins with non-canonical amino acids allows us to discriminate CSCs in mixed populations due to the quiescent nature of these cells. PMID- 22842827 TI - Simultaneous determination of sixteen underivatized biogenic amines in human urine by HPLC-MS/MS. AB - The broad group of biogenic amines includes polyamines and catecholamines, whose presence in human tissues and biological fluids can give important diagnostic information and act as marker of many pathologies. In particular, polyamines are involved in cancer cell growth while catecholamines act as neurotransmitters and hormones. Their simultaneous determination in biological tissues and fluids is therefore an important task. A high-performance liquid chromatography tandem mass spectrometry method is presented here for the simultaneous determination in urine of 16 biogenic amines: adrenaline (epinephrine), agmatine, cadaverine, dopamine, histamine, 3-methoxytyramine, noradrenaline (norepinephrine), norephedrine, octopamine, 2-phenylethylamine, putrescine, serotonin, spermidine, spermine, tryptamine, and tyramine. The method does not require any derivatization step. To guarantee the maximum of sensitivity, the mass spectrometer works in selected reaction monitoring mode, monitoring for each analyte the two most intensive transitions. Method validation includes the evaluation of limits of detection (that range from 0.3 to 6.6 MUg L(-1)), limits of quantitation (that range from 1.0 to 21.9 MUg L(-1)), linearity range (three orders of magnitude), recovery, intra- and inter-day precision on both concentration, and retention time. Recovery (R) is shown not to depend on the analyte concentration: the average R percent ranges from 72.9 to 100.0 %. Particular attention is devoted to the matrix effect and the correlated phenomena of ion enhancement or suppression in mass spectrometry detection. PMID- 22842828 TI - Anidulafungin--challenges in development and validation of an LC-MS/MS bioanalytical method validated for regulated clinical studies. AB - Anidulafungin is a semi-synthetic echinocandin with antifungal activity, usually administered as an intravenous infusion. In order to determine the pharmacokinetics (PK) of anidulafungin in pediatric patients, a sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) bioanalytical method (M1) was developed and validated for quantification of anidulafungin in plasma. During analysis of incurred samples (samples collected from patients enrolled in a clinical study) an isobaric chromatographic interference was observed. The source of interference was identified as an anidulafungin open-ring form (D1) and its impact on the quantification of anidulafungin was investigated. It was found that accurately quantifying anidulafungin in incurred samples required chromatographic separation of the open ring form from anidulafungin. The method was redeveloped to achieve the appropriate baseline separation and to avoid experimental conditions that favored opening the anidulafungin ring. The extraction of anidulafungin from plasma by protein precipitation remained unchanged, but the changes in chromatography warranted validation of a new method, M2, 2 years after M1 was validated. Incurred samples from three studies that were previously analyzed by M1 and were within confirmed long-term frozen stability were then reanalyzed by M2. Although the incurred sample reproducibility tests on those samples passed for each of the two methods, comparison of concentrations from the same samples obtained by M1 and M2 revealed that an overestimation of anidulafungin following the M1 method exceeded acceptance criteria. The new HPLC-MS/MS method (M2) is applicable for quantification of anidulafungin within a nominal range 50-20,000 ng/mL and requires a 50 MUL human plasma aliquot. A linear, 1/concentration squared weighted, least-squares regression algorithm was used to generate the calibration curve and its parameters were used to quantitate the incurred samples. The inter assay accuracy in heparin human plasma validation ranged from -4.33 to 0.0386 % and precision was <=7.32 %. The method M2 was validated for use in regulated bioanalysis and is presently used to quantitate anidulafungin in plasma samples from clinical studies. PMID- 22842830 TI - An overview of standard statistical methods for assessing exposure-outcome link in survival analysis (Part I): basic concepts. AB - The occurrence of a given disease in a population is measured by prevalence and incidence. Prevalence reflects the burden of a given disease in a specific population and is calculated as point prevalence or period prevalence. Incidence denotes the number of new cases of a given disease which occur in a cohort of individuals followed up for a given period of time, and may be expressed in terms of cumulative risk or incidence rate. The relationship between disease frequency (e.g., myocardial infarction) and specific exposure (e.g., smoking) is assessed by calculating relative (relative risk and odds ratio) and absolute (risk difference) measures of effect. PMID- 22842831 TI - Vascular mild cognitive impairment: concept, definition, and directions for future studies. AB - Vascular mild cognitive impairment (vascular MCI) describes an abnormal condition which is caused by vascular diseases and in which the patient presents with cognitive deficits not severe enough to fit the criteria for dementia (i.e., basic functional autonomy is not lost). As in neurodegenerative MCI, the clinical, neuroimaging, and natural history features of vascular MCI are currently under definition. It is particularly important to identify cognitive impairment of vascular origin during the early stages, as its progression may be slowed or halted by intervening with aggressive treatment of vascular risk factors and diseases. Longitudinal studies on the natural history of vascular MCI, with investigation of the factors responsible for the transition to dementia, are worthy of being planned and carried out. PMID- 22842832 TI - Serum dehydroepiandrosterone-sulfate reflects age better than health status, and may increase with cigarette smoking and alcohol drinking in middle-aged men. AB - BACKGROUND AND AIMS: Serum dehydroepiandrosterone- sulfate (DHEAS), the most abundant adrenal steroid hormone, may predict aging status and longevity in humans. The aims of this study are to clarify the fundamental properties of serum DHEAS as a biomarker for health in middle-aged men. METHODS: We investigated correlations of serum DHEAS with age or conventional health indices (body mass index, blood pressure, and 12 serum/blood tests) and associations of serum DHEAS with lifestyle factors (smoking, drinking, exercise, sleep) in 384 healthy men aged 30-49 years, randomly selected from voluntary attendees at a checkup. RESULTS: Serum DHEAS had an inverse and stronger correlation with age (Spearman's r=-0.320, p<0.001) than with any conventional health indices used here. Regardless of age and BMI adjustments, serum DHEAS had a weak correlation with serum uric acid (crude Spearman's r=0.198, p<0.001), and its correlations with other conventional health indices were weaker or non-significant. Serum DHEAS rose in parallel with increased smoking and alcohol intake (p for trend <0.001 in both), but had no significant relationships with exercise or sleep. CONCLUSIONS: Serum DHEAS reflects age better than health status evaluated by conventional health indices, and may increase with cigarette smoking and alcohol drinking in middle-aged healthy men. PMID- 22842833 TI - Introduction of angiotensin-converting enzyme inhibitors induces a fall in hemoglobin levels in elderly patients hospitalized with heart failure: a cohort study. AB - BACKGROUND AND AIMS: Although the use of angiotensin-converting enzyme-inhibitors (ACE-I) is a cornerstone of treatment for heart failure (HF), these agents have been associated with decreasing hemoglobin levels in several settings. The aim of this study was to assess whether ACE-I are associated with decreasing hemoglobin in older subjects, and whether this effect is enhanced among patients with HF. METHODS: The association between starting use of ACE-I and variations in hemoglobin levels was investigated in 10,354 hospitalized elderly, 1217 of whom had a verified diagnosis of HF, enrolled in a multicenter pharmacoepidemiology survey. RESULTS: According to Cox regression analysis, the relative risk of a decrease in hemoglobin levels >0.5 g/dL associated with starting treatment with ACE-I was 1.12 (95% CI 0.98-1.26, p=0.081) among participants without HF, and 1.98 (95% CI 1.54-2.53, p<0.0001) among patients with HF, after adjusting for potential confounders. Analysis of the interaction term in Cox regression confirmed that the association between use of ACE-I and hemoglobin decrease varied according to diagnosis of HF (p=0.003) and older age (p=0.029). CONCLUSIONS: Starting treatment with ACE-I is independently associated with increased risk of hemoglobin decrease among older hospitalized patients with HF. Hemoglobin levels should be monitored in older subjects who start ACE-I. PMID- 22842834 TI - Effect of dual-tasking on the center of pressure trajectory at gait initiation in elderly fallers and non-fallers. AB - BACKGROUND AND AIMS: The purpose of this study was to examine the center of pressure (COP) trajectory at gait initiation in single- and dualtask conditions between elderly Fallers and Non-fallers. METHODS: Seventy-one community-dwelling elderly people (mean age 80.5 +/- 7.6 years) voluntarily participated in this study. Participants were categorized as Fallers or Non-fallers on the basis of previous fall experience. In single- and dual-task conditions, participants performed gait initiation trials from a starting position on a force platform while COP data were collected. Steady-state walking time on a 10-m straight walkway in single- and dual-task conditions was also measured. In the dual-task condition, participants performed individual tests with simultaneous backward counting. Maximum COP displacements and velocities were calculated in the anteroposterior and mediolateral directions. RESULTS: In the dual-task condition, Fallers had significantly smaller backward displacements and slower backward velocities of COP than Non-fallers, although there was no significant difference in these values in the single-task condition between groups. Steadystate walking time was also not significantly different in both single- and dual-task conditions between groups. CONCLUSIONS: Gait-initiation performance in dual-task conditions may be a good discriminator between Fallers and Non-fallers. PMID- 22842835 TI - Effects of progressive resistance training on physical disability among older community-dwelling people with history of hip fracture. AB - BACKGROUND AND AIMS: Hip fracture is a common trauma in older people, and often leads to decreased muscle strength and increased physical disability. This randomized controlled trial examined whether three months of progressive resistance training (PRT) can reduce physical disability among older people with a history of hip fracture. METHODS: A population-based sample of 60-85-year-old community- dwelling persons, with hip fractures sustained on average three years earlier, were enrolled in the study. Of 78 people participating in laboratory assessments, those without contraindications for participation in resistance training were randomly assigned to a training group (TG, n=22) or a control group (CG, n=21). TG took part in resistance training for three months twice a week. Training focused on lower limb muscles. Disability was assessed by a validated questionnaire containing six questions on activities of daily living (ADL) and nine on instrumental activities of daily living (IADL). A sum score was calculated separately for both items. High scores indicated more difficulties. Group differences were analysed with the Mann-Whitney and Chi-square tests. The effects of PRT on disability were tested with the McNemar test and by covariance analysis (ANCOVA). RESULTS: TG and CG were comparable with respect to gender, age, chronic diseases, BMI, time since fracture, self-reported health, and level of physical activity at baseline. The ADL sum score in TG was 1.8 (2.0) at baseline and 1.1 (1.3) after follow-up; in CG values were 1.7 (1.8) and 1.5 (1.8) (ANCOVA p=0.034). IADL sum scores in TG were 3.9 (4.6) at baseline and 2.2 (3.8) after follow-up, and in CG 3.4 (3.6) and 2.4 (2.3) (ANCOVA p=0.529). CONCLUSIONS: Progressive resistance training reduced self-reported difficulties in ADL, even several years after fracture. More research is still needed on how to prevent physical disability among community-dwelling older people, especially after hip fracture. PMID- 22842836 TI - Risk of mortality and predisposing factors after osteoporotic hip fracture: a one year follow-up study. AB - BACKGROUND AND AIMS: To determine mortality and predisposing factors in patients with fracture of the proximal femur, one year after the initial fracture, in a tertiary hospital in Castile and Leon (Spain). METHODS: Observational case control study. Patients aged >=65 years admitted to the orthopedic surgery department of the Rio Hortega Hospital, a tertiary care hospital with approximately 560 beds, due to non-traumatic hip fracture between September 2005 and November 2006, were included. An age-matched control group of 81 institutionalized patients with similar characteristics was recruited. A protocolized telephone interview and a review of hospital medical records was made at 12 months followup. RESULTS: Of the 170 patients recruited, the final analysis was made in 139: 121 (87.1%) women and 18 (12.9%) men. The control group was formed of 81 patients: 64 (79%) women and 17 (21%) men. Mortality was 41.7% in the study group and 2.5% in controls (p; 0.001). Mortality was 31% in month 1, 24.1% between months 2 and 6 and 29.3% between months 6 and 12 (in 15.6% the date of death was unknown). Factors associated with mortality were: age >86 years (p; 0.024); prior cognitive deterioration (p; 0.011); prior locomotor disorder (p; 0.047); male gender (p; 0.017); heart disease (p; 0.042). CONCLUSIONS: Patients with hip fracture, had substantially higher mortality than comparable healthy people, and mortality was highest in the first six months after fracture. Age and prior comorbidities were associated with excess mortality. PMID- 22842837 TI - Memantine in Alzheimer's disease: experience in an Alzheimer's disease assessment unit. AB - BACKGROUND AND AIMS: Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist. Clinical and observational studies have demonstrated its efficacy on both cognitive and behavioral symptoms of moderate-to-severe Alzheimer's disease (AD) and described its good safety and tolerability profile. We report here our experience with memantine in patients with AD during a two-year follow-up. METHODS: From June 2005 to May 2010, memantine was given to 201 outpatients with moderate-to-severe AD: 93 patients were concomitantly receiving treatment with acetyl cholinesterase inhibitors (AChEIs) (Group 1) and the other 108 were prescribed memantine as monotherapy (Group 2). All patients were administered the following scales: Mini Mental State Examination, Activities of Daily Living, Instrumental Activities of Daily Living, Neuropsychiatric Inventory. We report the results of followup assessments conducted at six months and 1, 2 and 3 years. RESULTS: Sixteen patients (8%) stopped treatment within the first month because of side-effects. In each group, about 20% of subjects showed no deterioration at six months and 1 year, and this proportion decreased only slightly at 2 years. Higher NPI scores at baseline and psychotropic drug use emerged as factors significantly related to reduced response to treatment (p<0.01). CONCLUSIONS: Results confirmed the short-term effect of memantine, both in monotherapy and in combination with AchEIs in moderate-to-severe AD. This efficacy, albeit slight, was found to persist in the longer term. PMID- 22842838 TI - A case of very rapid progressive ataxia in rehabilitation setting. AB - AIM: To describe the unusual course of a patient with cerebellar ataxia who underwent rehabilitation. METHOD: At admission, the patient underwent motor rehabilitation and assessment by Tinetti Assessment, Klockgether Score, National Institute of Health Stroke Scale, Trunk Control Test, Fugl-Meyer Scale, Barthel Index, and Mini Mental State Examination. RESULTS: The patient showed very rapid and severe decline of motor and functional tests during the first month of hospitalization and complete dependence in <2 months, despite rehabilitation. He died 10 months after onset, with a neuro-pathological diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). CONCLUSION: Our case report suggests that sporadic CJD must be hypothesized when ataxia worsens rapidly and severely despite rehabilitation. PMID- 22842839 TI - Probable dementia associated with Lewy body pathology as a cause of prolonged acute confusional state in a 79-year-old patient. AB - Differentiation of "dementia with Lewy body pathology" (DLB) and delirium may be problematic in some cases, due to some of their common clinical characteristics such as fluctuations and hallucinations. Longer duration of cognitive changes usually aids in DLB diagnosis. However, presentation of DLB with an abrupt onset as a prolonged confusional state and hallucinations is also, even if rarely, described. We report the case of an elderly patient with probable dementia with Lewy body pathology, presenting with a prolonged acute confusional state, in order to draw attention to its diagnostic difficulty and the importance of careful target-oriented anamnesis in such cases. This type of dementia should be included in the differential diagnosis of elderly patients presenting with otherwise unexplained prolonged acute confusional states. PMID- 22842840 TI - [Sport and cardiac arrythmia: new aspects are exciting!]. PMID- 22842841 TI - Droplet microfluidics for amplification-free genetic detection of single cells. AB - In this article we present a novel droplet microfluidic chip enabling amplification-free detection of single pathogenic cells. The device streamlines multiple functionalities to carry out sample digitization, cell lysis, probe target hybridization for subsequent fluorescent detection. A peptide nucleic acid fluorescence resonance energy transfer probe (PNA beacon) is used to detect 16S rRNA present in pathogenic cells. Initially the sensitivity and quantification abilities of the platform are tested using a synthetic target mimicking the actual expression level of 16S rRNA in single cells. The capability of the device to perform "sample-to-answer" pathogen detection of single cells is demonstrated using E. coli as a model pathogen. PMID- 22842842 TI - Improved survival and antiretroviral treatment outcomes in adults receiving community-based adherence support: 5-year results from a multicentre cohort study in South Africa. AB - INTRODUCTION: A large increase in lay health care workers has occurred in response to shortages of professional health care staff in sub-Saharan African antiretroviral treatment (ART) programs. However, little effectiveness data of the large-scale implementation of these programs is available. We evaluated the effect of a community-based adherence-support (CBAS) program on ART outcomes across 57 South African sites. METHODS: CBAS workers provide adherence and psychosocial support for patients and undertake home visits to address household challenges affecting adherence. An observational multicohort study of adults enrolling for ART between 2004 and 2010 was performed. Mortality, loss to follow up, and virological suppression were compared by intention to treat between patients who received and did not receive CBAS until 5 years of ART, using multiple imputation of missing covariate values. RESULTS: Of the 66,953 patients who were included, 19,668 (29.4%) patients received CBAS and 47,285 (70.6%) patients did not. Complete-case covariate data were available for 54.3% patients. After 5 years, patient retention was 79.1% [95% confidence interval (CI): 77.7% to 80.4%] in CBAS patients versus 73.6% (95% CI: 72.6% to 74.5%) in non-CBAS patients; crude hazard ratio (HR) for attrition was 0.68 (95% CI: 0.65 to 0.72). Mortality and loss to follow-up were independently lower in CBAS patients, adjusted HR (aHR) was 0.65 (95% CI: 0.59 to 0.72) and 0.63 (95% CI: 0.59 to 0.68), respectively. After 6 months of ART, virological suppression was 76.6% (95% CI: 75.8% to 77.5%) in CBAS patients versus 72% (95% CI: 71.3% to 72.5%) in non-CBAS patients (P < 0.0001), adjusted odds ratio was 1.22 (95% CI: 1.14 to 1.30). Improvement in virological suppression occurred progressively for longer durations of ART [adjusted odds ratio was 2.66 (95% CI: 1.61 to 4.40) by 5 years]. CONCLUSIONS: Patients receiving CBAS had considerably better ART outcomes. Further scale-up of these programs should be considered in low-income settings. PMID- 22842843 TI - Receptor activator of nuclear factor-kappaB ligand (RANKL) and its relationship to coronary atherosclerosis in HIV patients. AB - HIV-infected individuals have an increased prevalence of coronary artery disease. Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin have been postulated as mediators of vascular calcification. 78 HIV-infected men and 32 healthy controls without history of coronary artery disease were prospectively recruited to undergo cardiac computed tomography and computed tomography angiography to assess coronary artery calcium and plaque burden. Soluble receptor activator of nuclear factor-kappaB ligand was lower in HIV infected individuals than controls [2.52 (1.08-3.98) vs. 3.33 (2.44-4.64) pg/mL, P = 0.01, median (IQR) respectively]. Soluble receptor activator of nuclear factor-kappaB ligand was negatively associated with the number of coronary segments with plaque (Spearman rho = -0.41, P < 0.001) and Agatston calcium score (rho = -0.30, P < 0.01) in HIV-infected individuals even after adjusting for traditional cardiovascular risk factors. PMID- 22842846 TI - Consideration of postpartum management in HIV-positive Haitian women: an analysis of CD4 decline, mortality, and follow-up after delivery. AB - BACKGROUND: A previous study at the GHESKIO HIV clinic confirmed that highly active antiretroviral therapy (HAART) prophylaxis reduced mother-to-child transmission (MTCT) and infant mortality in Haiti. This analysis looks at maternal outcomes in this cohort after delivery. METHODS: Records of 508 HIV positive Haitian women who delivered between 1999 and 2005 were analyzed. We examined mortality, loss to follow-up, time to death or HAART initiation, and time of decline of CD4 count to 350 cells/MUL. RESULTS: One hundred seventy women reached a CD4 <=200 or developed clinical AIDS and were started on long-term HAART. The median CD4 count at HAART initiation was 178 (interquartile range, 106 227). CD4 decline was stratified by CD4 at delivery to project the mean months to a CD4 of 350. With an initial CD4 of 350-499 cells/MUL, it was 19 months (95% confidence interval: 14 to 28) while with a CD4 >500 cells/MUL, it was 71 months (95% confidence interval: 59 to 88). At study close, 257 women remained in follow up, with loss to follow-up 3 times less in those on HAART (3.2/100 person-years) than those not on HAART (9.8/100 person-years). CONCLUSIONS: The threshold for starting treatment was often missed in HIV-infected women after delivery. Success of follow-up of women after delivery was favorably influenced by being on HAART. Women with high (>500) initial CD4 counts had a protracted time (5-7 years) before they reach a threshold CD4 count, in contrast to those with CD4 <500 cells/MUL. Strategies for postpartum treatment of women should be informed by the speed with which they are likely to progress. PMID- 22842847 TI - Association of HIV-Infection and antiretroviral therapy with levels of endothelial progenitor cells and subclinical atherosclerosis. AB - BACKGROUND: Although in the general population circulating vascular progenitor cell levels have been implicated in the homeostasis of the vascular wall through differentiation into endothelium and/or smooth muscle cells, it has not yet been assessed in HIV-infected patients. We herein investigated the number of progenitor cell subpopulations in HIV-infected patients and its relationship to carotid intima-media thickness (c-IMT). METHODS: Blood samples were collected from 200 HIV-infected patients and CD34/KDR, CD34/VE-cadherin, and CD14/Endoglin progenitor cells were identified by flow cytometry. c-IMT was determined by ultrasonography. A group of 27 healthy subjects was used as control group. RESULTS: In our population (20 ART-naive patients and 180 treated patients), traditional cardiovascular risk factors were not found predictive of vascular progenitor cell levels. However, antiretroviral therapy (ART)-treatment was identified as the main predictive value for low CD34/KDR cells and high CD14/Endoglin cells after adjustment by cardiovascular risk factors (age, sex, hypertension, diabetes, and hyperlipidaemia) and HIV-related characteristics (HIV duration and ART treatment). Low levels of circulating CD34/KDR or CD34/VE cadherin endothelial progenitor cells tended to be associated with increased c IMT. However, a positive association was found between CD14/Endoglin cells and c IMT. Low number of CD34/KDR cells was also associated with the longest exposure to nucleoside reverse transcriptase inhibitors and/or protease inhibitors. CONCLUSIONS: ART exposure is the main predictor of circulating vascular progenitor cell levels. However, their levels are only partially associated with high c-IMT in HIV-infected patients. ART has already been found to have proatherogenic effect, but our data first describe its relationship with vascular progenitor cells and c-IMT. PMID- 22842848 TI - A case of Epstein-Barr virus-related lymphadenopathy mimicking the clinical features of IgG4-related disease. AB - We report an intriguing case of Epstein-Barr virus (EBV)-related multiple lymphadenopathy that clinically mimics immunoglobulin G4-related disease (IgG4 RD). A 72-year-old woman presented with a history of asthma attacks, systemic lymphadenopathy, hypergammaglobulinemia, proteinuria, and an elevated level of serum IgG4, leading to a possible diagnosis of IgG4-RD based on current comprehensive diagnostic criteria. However, a percutaneous kidney biopsy specimen showed mild mesangial proliferative glomerulonephritis with focal membranous transformation, and there was no interstitial lesion or lymphocyte infiltration. Cervical lymph node biopsy demonstrated follicular hyperplasia associated with prominent lymphoplasmacytic infiltration in the interfollicular area. However, only a few IgG4-positive plasma cells were present. An in situ hybridization study demonstrated many EBV-infected lymphocytes in the germinal center as well as in the interfollicular area. This case illustrates the diversity of conditions associated with elevated levels of serum IgG4 and the necessity for tissue biopsy when diagnosing IgG4-RD. PMID- 22842844 TI - Performance of creatinine and cystatin C GFR estimating equations in an HIV positive population on antiretrovirals. AB - OBJECTIVE: To evaluate the performance of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C, and creatinine-cystatin C estimating equations in HIV-positive patients. METHODS: We evaluated the performance of the Modification of Diet in Renal Disease (MDRD) Study and CKD-EPI creatinine 2009, CKD-EPI cystatin C 2012, and CKD-EPI creatinine-cystatin C 2012 glomerular filtration rate (GFR) estimating equations compared with GFR measured using plasma clearance of iohexol in 200 HIV-positive patients on stable antiretroviral therapy. Creatinine and cystatin C assays were standardized to certified reference materials. RESULTS: Of the 200 participants, median (IQR) CD4 count was 536 (421) and 61% had an undetectable HIV viral load. Mean (SD) measured GFR (mGFR) was 87 (26) mL/min per 1.73 m. All CKD-EPI equations performed better than the MDRD Study equation. All 3 CKD-EPI equations had similar bias and precision. The cystatin C equation was not more accurate than the creatinine equation. The creatinine-cystatin C equation was significantly more accurate than the cystatin C equation, and there was a trend toward greater accuracy than the creatinine equation. Accuracy was equal or better in most subgroups with the combined equation compared to either alone. CONCLUSIONS: The CKD-EPI cystatin C equation does not seem to be more accurate than the CKD-EPI creatinine equation in patients who are HIV-positive, supporting the use of the CKD-EPI creatinine equation for routine clinical care for use in North American populations with HIV. The use of both filtration markers together as a confirmatory test for decreased estimated GFR based on creatinine in individuals who are HIV-positive requires further study. PMID- 22842849 TI - Tailoring the interface using thiophene small molecules in TiO2/P3HT hybrid solar cells. AB - In this paper we focus on the effect of carboxylated thiophene small molecules as interface modifiers in TiO(2)/P3HT hybrid solar cells. Our results show that small differences in the chemical structure of these molecules, for example, the presence of the -CH(2)- group in the 2-thiopheneacetic acid (TAA), can greatly increase the TiO(2) surface wettability, improving the TiO(2)/polymer contact. This effect is important to enhance exciton splitting and charge separation. PMID- 22842850 TI - Lipopolysaccharide regulates MMP-9 expression through TLR4/NF-kappaB signaling in human arterial smooth muscle cells. AB - Matrix metalloproteinases (MMPs) are critical to vascular smooth muscle cell migration in vivo. The dysregulation of MMPs is involved in the pathogenesis of abnormal arterial remodeling, aneurysm formation and atherosclerotic plaque instability. It has been confirmed that lipopolysaccharides (LPS) constitute a strong risk factor for the development of atherosclerosis. In this study, we aimed to determine a potential mechanism of LPS on MMP-9 expression in human arterial smooth muscle cells (HASMCs). RT-PCR analysis was used to detect MMP-9 mRNA expression and western blot analysis was performed to examine MMP-9 protein expression. An electrophoretic mobility shift assay was also employed to determine NF-kappaB binding activity. Results showed that LPS induced MMP-9 mRNA and protein expression in HASMCs in a TLR4-dependent manner. Notably, upon blocking the NF-kappaB binding with pyrrolidine dithiocarbamate, it was demonstrated that the expression of MMP-9 by LPS occurs through TLR4/NF-kappaB pathways. It was concluded that LPS induced MMP-9 expression through the TLR4/NF kappaB pathway. Thus, the TLR4/NF-kappaB pathway may be involved in the pathogenesis of atherosclerosis. PMID- 22842851 TI - [Diagnostics and therapy of heart failure]. AB - Heart failure represents one of the most common diseases in the western world with an estimated prevalence of 0.4-2% in Europe. The frequency and incidence is very age-dependant and chronic cardiac insufficiency has a high stage-dependant mortality. Aging of the population and prolongation of the lives of cardiac patients has led to an increasing prevalence of heart failure. However, average survival remains poor after hospitalization for a first episode of heart failure. Diagnostics and therapy of heart failure are subject to constant change due to ongoing progress in research and new randomized controlled trials. This review will focus on new developments and current guidelines for diagnosis and treatment of heart failure. Findings on natriuretic peptides and echocardiography in patients with preserved ejection fraction will be presented and innovative therapeutic measures, such as ivabradine will be discussed. Besides new drug developments insight into device therapy, such as MitraClip(r) and operative approaches for heart failure will be presented. PMID- 22842852 TI - Open versus closed reduction: diacapitular fractures of the mandibular condyle. AB - PURPOSE: The purpose of the study was to review the literature regarding the evolution of current thoughts on management of diacapitular fractures (DFs) of the mandibular condyle. METHODS: An electronic search in PubMed was undertaken in March 2012. The titles and abstracts from these results were read to identify studies within the selection criteria. Eligibility criteria included studies reporting clinical series of DFs, including both animal and human studies, without date or language restrictions. RESULTS: The search strategy initially yielded 108 references. Twenty-eight studies were identified without repetition within the selection criteria. Additional hand-searching of the reference lists of selected studies yielded three additional papers. CONCLUSIONS: The current indications for open reduction and internal fixation (ORIF) of DFs described in the literature are: (a) fractures affecting the lateral condyle with reduction of mandibular height; (b) fractures in which the proximal fragment dislocates laterally out of the glenoid fossa, which cannot be reduced by closed or open treatment of another part of the mandibular fracture. The indications for conservative treatment are: (a) fractures that do not shorten the condylar height (a fracture with displacement of the medial parts of the condyle); (b) undisplaced fractures; (c) comminution of the condylar head, when the bony fragments are too small for stable fixation; and (d) fractures in children. As the temporomandibular joint disk plays an important role as a barrier preventing ankylosis, it is important to reposition the disk (if displaced/dislocated) during the surgical treatment of DFs. The lateral pterygoid muscle should never be stripped from the medially displaced fragment because its desinsertion disrupts circulation to the medial bony fragment, and also because this muscle helps to restore the muscle function after surgery. ORIF of selected DFs improves prognosis by anatomical bone and soft tissue recovery when combined with physical therapy. If conducted properly, surgical treatment of DFs is a safe and predictable procedure and yields good results. PMID- 22842854 TI - Trimetazidine improves right ventricular function by increasing miR-21 expression. AB - Trimetazidine (TMZ) improves left ventricular (LV) function and alleviates angina. TMZ is a metabolism-related drug, but its molecular actions and non metabolic effects have not yet been elucidated. In this study, we investigated whether TMZ improves right ventricular (RV) function and decreases apoptosis in RV myocardial cells (RVMCs) by regulating miRNA-21 (miR-21) expression in vitro and in vivo. We used cultivated RVMCs and LV myocardial cells (LVMCs) and provided hypoxic stimulation for 24 h to induce MC apoptosis. RVMCs showed more severe apoptosis as indicated by terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) staining and caspase-3 protein and activity assays. The decrease in miR-21 expression was more dramatic in RVMCs. Subsequently, TMZ (10 uM) was added to the RVMCs prior to hypoxic stimulation. The TMZ-treated RVMCs showed less apoptosis and an increased expression of miR 21. The transfection of RVMCs with a miR-21-specific inhibitor weakened the protective effects of TMZ. To evaluate TMZ effectiveness in right heart failure, we used a combination treatment of hypoxia and the vascular endothelial growth factor receptor blocker, Su5416, to construct a stable model, and administered TMZ. TMZ improved RV function (as indicated by an increase in tricuspid annular plane systolic excursion), and inhibited fibrosis. TMZ also protects RVMCs againts apoptosis and increases miR-21 expression. PMID- 22842855 TI - Acoustofluidics 17: theory and applications of surface acoustic wave devices for particle manipulation. AB - In this paper, number 17 of the thematic tutorial series "Acoustofluidics exploiting ultrasonic standing waves, forces and acoustic streaming in microfluidic systems for cell and particle manipulation", we present the theory of surface acoustic waves (SAWs) and some related microfluidic applications. The equations describing SAWs are derived for a solid-vacuum interface before generalisations are made about solid-solid and solid-fluid interfaces. Techniques for SAW generation are discussed before an overview of applications is presented. PMID- 22842853 TI - Open versus closed reduction: mandibular condylar fractures in children. AB - PURPOSE: The purpose of the study was to review the literature regarding the evolution of current thoughts on management of mandibular condylar fractures (MCFs) in children. METHODS: An electronic search in PubMed was undertaken in May 2012. The titles and abstracts from these results were read to identify studies within the selection criteria. Eligibility criteria included studies published in English or German from the last 20 years (from 1992 onwards) reporting clinical series of MCFs in children and adolescents until the age of 18. RESULTS: The search strategy initially identified 542 studies. The references from 1992 onwards totaled 339 articles. Twenty-seven studies were identified without repetition within the selection criteria. Additional hand-searching yielded two additional papers. CONCLUSIONS: Pediatric MCFs require thoughtful consideration in management to avoid significant growth disturbance. Early treatment is indicated in order to improve the chances for favorable development. Long-term follow-up is required, in order to properly treat late complications that may appear. Coronal computed tomography is helpful in substantiating the correct final diagnosis. Many studies show that conservative treatment (CTR) has satisfactory long-term outcome of jaw function, occlusion, and facial esthetics, despite a high frequency of radiological aberrations. Surgery before puberty should be reserved for exceptional cases such as missile injuries, in cases with extensive dislocation and lack of contact between the fragments, in cases with multiple midfacial fractures, in which the mandible has to serve as a guide to reposition the midfacial bones, and in cases which the dislocation of the fractured stump creates a functional impediment that cannot be resolved by CTR. As the craniofacial skeleton becomes more adult-like in its form at about 12 years of age, the decreased remodeling capacity in the adolescents may occasionally result in abnormally shaped condylar heads or shortened ramus heights that may lead to persistent malocclusion. Thus, the indication of open reduction and internal fixation increases with age. PMID- 22842856 TI - Microbial community and treatment ability investigation in AOAO process for the optoelectronic wastewater treatment using PCR-DGGE biotechnology. AB - This study aimed to explore the microbial community variation and treatment ability of a full-scale anoxic-aerobic-anoxic-aerobic (AOAO) process used for optoelectronic wastewater treatment. The sludge samples in the biological treatment units were collected and subsequently subjected to polymerase chain reaction (PCR) amplification and denaturing gradient gel electrophoresis identification and the wastewater components such as BOD5 and NH3-N were evaluated during the processes. The group specific primers selected were targeting at the kingdom Bacteria, the Acidobacterium, the alpha-proteobacteria, the beta-proteobacteria ammonia oxidizers, Actinobacteria and methyllotrophs, and the 16S rDNA clone libraries were established. Ten different clones were obtained using the Bacteria primers and eight different clones were obtained using the beta-proteobacteria ammonia oxidizer primers. Over 95 % of BOD5 and 90 % of NH3-N were removed from the system. The microbial community analysis showed that the Janthinobacterium sp. An8 and Nitrosospira sp. were the dominant species throughout the AOAO process. Across the whole clone library, six clones showed closely related to Janthinobacterium sp. and these species seemed to be the dominant species with more than 50 % occupancy of the total population. Nitrosospira sp. was the predominant species within the beta-proteobacteria and occupied more than 30 % of the total population in the system. These two strains were the novel species specific to the AOAO process for optoelectronic treatment, and they were found strongly related to the system capability of removing aquatic contaminants by inspecting the wastewater concentration variation across the system. PMID- 22842857 TI - Effect of the metals iron, copper and silver on fluorobenzene biodegradation by Labrys portucalensis. AB - Organic and metallic pollutants are ubiquitous in the environment. Many metals are reported to be toxic to microorganisms and to inhibit biodegradation. The effect of the metals iron, copper and silver on the metabolism of Labrys portucalensis F11 and on fluorobenzene (FB) biodegradation was examined. The results indicate that the addition of 1 mM of Fe(2+) to the culture medium has a positive effect on bacterial growth and has no impact in the biodegradation of 1 and 2 mM of FB. The presence of 1 mM of Cu(2+) was found to strongly inhibit the growth of F11 cultures and to reduce the biodegradation of 1 and 2 mM of FB to ca. 50 %, with 80 % of stoichiometrically expected fluoride released. In the experiments with resting cells, the FB degraded (from 2 mM supplied) was reduced ca. 20 % whereas the fluoride released was reduced to 45 % of that stoichiometrically expected. Ag(+) was the most potent inhibitor of FB degradation. In experiments with growing cells, the addition of 1 mM of Ag(+) to the culture medium containing 1 and 2 mM of FB resulted in no fluoride release, whereas FB degradation was only one third of that observed in control cultures. In the experiments with resting cells, the addition of Ag(+) resulted in 25 % reduction in substrate degradation and fluoride release was only 20 % of that stoichiometrically expected. The accumulation of catechol and 4-fluorocatechol in cultures supplemented with Cu(2+) or Ag(+) suggest inhibition of the key enzyme of FB metabolism-catechol 1,2-dioxygenase. PMID- 22842858 TI - Open versus closed reduction: comminuted mandibular fractures. AB - PURPOSE: The purpose of the study was to review the literature regarding the evolution of current thoughts on management of comminuted mandibular fractures (CMFs). METHODS: An electronic search in PubMed was undertaken in May 2012. The titles and abstracts from these results were read to identify studies within the selection criteria. Eligibility criteria included studies published in English or German reporting clinical series of CMFs. RESULTS: The search strategy initially identified 409 studies. Fifteen studies were identified without repetition within the selection criteria. One case report article showing significance in the development of treatment techniques was included. Additional hand-searching yielded five additional papers. Thus, a total of 21 studies were included. CONCLUSIONS: Open reduction and internal fixation (ORIF) in cases of CMFs are indicated in (a) severe injuries with significant displacement to allow restoration of pretraumatic anatomic relationships, (b) in the edentulous and semi-dentate patient, who may benefit from ORIF of CMFs when stable occlusal relationships are absent, and (c) in cases with multiple fractures of the midface, in which the mandible has to serve as a guide to reposition the midfacial bones. However, there is still a place for closed reduction/conservative treatment (CTR). ORIF in CMFs is not indicated in cases of minimally displaced comminuted fractures that could easily and adequately be treated with CTR. If the surgical team is not well versed in the nuances of rigid internal fixation, or the necessary equipment is not available, it is far better to do simple CTR. However, it would be more reasonable to refer the patient to a hospital that can provide means of ORIF in cases of clear indication of its use in CMFs. In cases where ORIF is indicated, stabilization by compression or any other form of load-sharing osteosynthesis is obviously contraindicated because small fragments cannot be compressed and are not capable of sharing loads. Thus, the ORIF of CMFs is best performed using load-bearing osteosynthesis; most experience has been gained with 2.7-mm reconstruction plates. External pin fixation could be used in cases when there is so much comminution, soft tissue disruption (mostly gunshot wounds), and there are inadequate teeth on either side of the comminuted fracture to control the spatial relationship of the remaining mandibular fragments with maxillomandibular fixation (MMF). PMID- 22842860 TI - Role of the EU Framework in Regulation of Stem Cell-Based Products. AB - The use of stem cells for therapeutic purposes is regulated by two overlapping sets of rules. If used for transplantation, stem cells are covered by the collection, traceability and technical aspects of three European directives. When the stem cells are used as part of a medicinal product, they are covered by the legislation on pharmaceutical production and marketing authorization-in particular, by Regulation 1394/2007/EC. PMID- 22842861 TI - N-Heterocyclic carbene transition metal complexes for catalysis in aqueous media. AB - The last decade has seen an increasing number of reports on the use of NHC-metal complexes for catalysis in water, therefore this review is aimed to introduce the whole research on this area, in which the use of water or aqueous/organic media is to be applied. Since the first discovery of the NHC carbenes by Arduengo, work on the synthesis of NHC-metal organometallic compounds has revolutionized the field of catalysis, gradually displacing the typical phosphine and amine-type ligands in view of their higher stability and reactivity. Aqueous catalysis has become a hot topic in Green Chemistry due to the positive implications for the use of water as reaction media. PMID- 22842859 TI - Salivary gland carcinomas. AB - INTRODUCTION: Salivary gland carcinomas are rare tumours of heterogeneous morphology that require distinctive surgical and adjuvant therapy. METHODS: Relevant studies were electronically searched in PubMed and reviewed for innovative and important information. RESULTS: Recent insights in genetic alterations like chromosomal aberrations, expression of receptor tyrosine kinases, malfunction of tumour suppressor genes or DNA promoter methylations increased the knowledge about aetiology and pathogenesis. New histological subtypes are recognised, and a three-tiered grading system seems reasonable. Ultrasound remains the basic diagnostic imaging procedure. New developments comprise the diffusion-weighed magnetic resonance imaging, while fluorodeoxyglucose positron emission tomography/computed tomography shows good diagnostic accuracy in detecting distant metastases and local recurrence. Fine needle aspiration cytology helps in differentiating a neoplasia from a non neoplastic lesion while being unreliable in recognising malignancy. In contrast, additional core needle biopsy and/or intraoperative frozen section diagnosis increase the accuracy in diagnosing a malignant lesion. Conservative parotid surgery with nerve monitoring remains state-of-the-art. Free flaps or musculoaponeurotic flaps are proposed for prevention of Frey's syndrome. As parotid cancer often shows skip metastases, complete ipsilateral neck dissection (level I-V) is indicated particularly in high-grade lesions. Adjuvant radio(chemo)therapy increases local tumour control, whereas overall survival is not necessarily improved. Current results of systemic chemotherapy or targeted therapy in advanced tumour stages are disappointing. CONCLUSION: Despite several developments, salivary gland carcinomas remain a heterogeneous group of tumours challenging both pathologists and clinicians. PMID- 22842862 TI - Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice. AB - Prion diseases are caused by a conformational modification of the cellular prion protein (PrP (C)) into disease-specific forms, termed PrP (Sc), that have the ability to interact with PrP (C) promoting its conversion to PrP (Sc). In vitro studies demonstrated that anti-PrP antibodies inhibit this process. In particular, the single chain variable fragment D18 antibody (scFvD18) showed high efficiency in curing chronically prion-infected cells. This molecule binds the PrP (C) region involved in the interaction with PrP (Sc) thus halting further prion formation. These findings prompted us to test the efficiency of scFvD18 in vivo. A recombinant Adeno-Associated Viral vector serotype 9 was used to deliver scFvD18 to the brain of mice that were subsequently infected by intraperitoneal route with the mouse-adapted scrapie strain RML. We found that the treatment was safe, prolonged the incubation time of scrapie-infected animals and decreased the burden of total proteinase-resistant PrP (Sc) in the brain, suggesting that scFvD18 interferes with prion replication in vivo. This approach is relevant for designing new therapeutic strategies for prion diseases and other disorders characterized by protein misfolding. PMID- 22842864 TI - Formation of nanostructured porous Cu-Au surfaces: the influence of cationic sites on (electro)-catalysis. AB - The fabrication of nanostructured bimetallic materials through electrochemical routes offers the ability to control the composition and shape of the final material that can then be effectively applied as (electro)-catalysts. In this work a clean and transitory hydrogen bubble templating method is employed to generate porous Cu-Au materials with a highly anisotropic nanostructured interior. Significantly, the co-electrodeposition of copper and gold promotes the formation of a mixed bimetallic oxide surface which does not occur at the individually electrodeposited materials. Interestingly, the surface is dominated by Au(I) oxide species incorporated within a Cu(2)O matrix which is extremely effective for the industrially important (electro)-catalytic reduction of 4 nitrophenol. It is proposed that an aurophilic type of interaction takes place between both oxidized gold and copper species which stabilizes the surface against further oxidation and facilitates the binding of 4-nitrophenol to the surface and increases the rate of reaction. An added benefit is that very low gold loadings are required typically less than 2 wt% for a significant enhancement in performance to be observed. Therefore the ability to create a partially oxidized Cu-Au surface through a facile electrochemical route that uses a clean template consisting of only hydrogen bubbles should be of benefit for many more important reactions. PMID- 22842865 TI - Interpretation of gypsy moth frontal advance using meteorology in a conditional algorithm. AB - The gypsy moth, Lymantria dispar, is a non-native species that continues to invade areas in North America. It spreads generally through stratified dispersal where local growth and diffusive spread are coupled with long-distance jumps ahead of the leading edge. Long-distance jumps due to anthropogenic movement of life stages is a well-documented spread mechanism. Another mechanism is the atmospheric transport of early instars and adult males, believed to occur over short distances. However, empirical gypsy moth population data continue to support the possibility of alternative methods of long-range dispersal. Such dispersal events seemed to have occurred in the mid- to late-1990s with spread across Lake Michigan to Wisconsin. Such dispersal would be against the prevailing wind flow for the area and would have crossed a significant physical barrier (Lake Michigan). The climatology of the region shows that vigorous cyclones can result in strong easterly winds in the area at the time when early instars are present. It is hypothesized that these storms would enable individuals to be blown across the Lake and explain the appearance of new population centers observed at several locations on the western shore of Lake Michigan nearly simultaneously. A synoptic climatology model coupled with population dynamics data from the area was parameterized to show an association between transport events and population spread from 1996 to 2007. This work highlights the importance of atmospheric transport events relative to the invasion dynamics of the gypsy moth, and serves as a model for understanding this mechanism of spread in other related biological invasions. PMID- 22842863 TI - Eosinophilic gastrointestinal diseases--clinically diverse and histopathologically confounding. AB - Eosinophilic gastrointestinal diseases are a group of chronic diseases characterized by a range of symptoms caused by eosinophilic inflammation of various parts of the gastrointestinal tract. Other causes for eosinophilia need to be ruled out prior to making the diagnosis of EGIDs. The most common form of EGID is eosinophilic esophagitis (EoE), an antigen-driven disease that afflicts children and adults and has been identified across the world. Histological features include dense eosinophilia of the esophageal mucosa, eosinophil degranulation, eosinophil microabscess formation, and other features of epithelial inflammation including basal zone hyperplasia and rete pege elongation. Treatments include dietary exclusions and topical corticosteroids. PMID- 22842867 TI - Midlife vascular risk factors and Alzheimer's disease: evidence from epidemiological studies. AB - The shared risk factor profile between cardiovascular diseases and Alzheimer's disease (AD), observations on vascular pathology in AD, and altered cerebral blood flow in AD brains have led to the suggestion that AD might be a vascular disorder with neurodegenerative consequences. Targeting vascular and metabolic risk factors could be an effective way to prevent AD. Higher body mass index, elevated blood pressure, serum cholesterol concentrations, and impaired glucose regulation have been associated with increased risk of AD. Interestingly, the associations between these factors measured at mid-life are stronger, or even opposite, than with the risk factors measured at late-life. This may reflect true differences in the association (i.e., mid-life risk factors being a better measure of vascular load during adulthood), reverse causality, or bias. The vascular risk factors can directly increase the susceptibility to AD, or the effect can be mediated via cardio- and cerebrovascular diseases. PMID- 22842866 TI - The default mode network and related right hemisphere structures may be the key substrates of dementia. AB - We have employed structural equation models to explicitly distinguish dementia relevant variance in cognitive task performance (i.e., delta) from the variance that is unrelated to a dementing process (i.e., g'). Together g' and d comprise Spearman's "g". Although d represents only a minor fraction of the total variance in cognitive task performance, it is more strongly associated with dementia severity than is g'. In this analysis, we replicate delta in a new dataspace, the University of Kansas Brain Aging Project, and associate it specifically with regional grey matter atrophy by voxel-based morphometry of magnetic resonance imaging data. The latent variable d localizes to elements of the default mode network and related structures in the R hemisphere. PMID- 22842868 TI - Effects of altered cerebral hemodynamics on cognitive function. AB - Cerebral hemodynamic impairment has come under examination over the years as an independent cause for cognitive dysfunction, but only recently has the advance of imaging and ultrasound technology permitted a fuller investigation of physiopathology. Beyond the impact of fixed structural lesions such as infarction and white matter hyperintensities, hemodynamic dysfunction, which includes hypoperfusion and altered cerebral autoregulation, may be independently associated with cognitive decline. More importantly, whereas vascular-related structural pathology may produce so-called vascular dementia, disorders of blood flow and blood flow regulation may also present clinically as mild cognitive impairment or even frank dementia, but may in fact be reversible. Hemodynamic effects may occur at the level of the cerebral hemisphere due to restricted flow through a large vessel of the neck or head, at a global level in the setting of cardiac failure, or intrinsically due to dysfunction of the endothelium in the microvasculature. This review surveys clinical, imaging, and physiological evidence for the association between hemodynamic abnormalities at these different levels and cognitive impairment. PMID- 22842869 TI - Microvascular burden and Alzheimer-type lesions across the age spectrum. AB - The occurrence of microvascular and small macrovascular lesions and Alzheimer's disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still a matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden. PMID- 22842871 TI - Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer's disease. AB - Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille's Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille's model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD. PMID- 22842870 TI - Preventing Alzheimer's disease by targeting vascular risk factors: hope and gap. AB - Alzheimer's disease (AD) is a major cause of functional dependence, poor quality of life, institutionalization, and mortality among elderly people. As a multifactorial disorder, AD has been frequently linked to vascular risk factors (e.g., smoking, hypertension, obesity, diabetes, hyperlipidemia, and inflammation) in numerous prospective cohort studies of the general population. Systematic reviews and meta-analyses of prospective studies have from the life course perspective revealed an age-dependent association with the risk of AD for several vascular risk factors such as high blood pressure, obesity, and high total cholesterol, such that possessing these factors in mid-life, but not necessarily in late-life, is associated with an increased risk of AD. The biological plausibility for vascular risk factors to be involved in the pathogenesis and clinical manifestation of Alzheimer syndrome is partly supported by population-based neuroimaging and neuropathological studies. However, randomized controlled trials that target those major cardiovascular risk factors (e.g., antihypertensive, cholesterol-lowering, and anti-inflammatory therapies) have generally failed to prove as efficacious preventative approaches for AD. To bridge the gap, the multifactorial nature of AD and the proper time-window for intervention should be taken into account in the future when designing preventative interventions against this devastating disorder. PMID- 22842872 TI - Angiotensinogen gene M235T polymorphism and risk of coronary artery disease: a meta-analysis. AB - The angiotensinogen (AGT) gene M235T polymorphism has been suggested to be linked with susceptibility to coronary artery disease (CAD). In the present study, a meta-analysis was performed to assess the correlation between the M235T polymorphism and CAD. Nine studies with a total of 2281 subjects were selected for inclusion in the analysis. The references were retrieved via PubMed, China National Knowledge Infrastructure, Wanfang and VIP database (1995.1-2012.1). The analyses were performed using STATA 10.0 software. Odds ratios (OR) with 95% confidence intervals (CIs) were assessed after the collected data were pooled for analysis. A significant association was detected between M235T gene polymorphism and CAD in the population studied. The estimates (OR) of CAD risk were calculated in a homozygote comparison (OR=1.54; 95% CI, 1.09-2.16), a heterozygote comparison (OR=1.30; 95% CI, 1.07-1.58), a dominant model (OR=0.72; 95% CI, 0.55 0.94) and a recessive model (OR=1.37; 95% CI, 0.98-1.91). The current meta analysis suggests that the M235T polymorphism is associated to an increased risk of CAD. PMID- 22842873 TI - An electronic diary on a palm device for headache monitoring: a preliminary experience. AB - Patients suffering from headache are usually asked to use charts to allow monitoring of their disease. These diaries, providing they are regularly filled in, become crucial in the diagnosis and management of headache disorders because they provide further information on attack frequency and temporal pattern, drug intake, trigger factors, and short-/long-term responses to treatment. Electronic tools could facilitate diary monitoring and thus the management of headaches. Medication overuse headache (MOH) is a chronic and disabling condition that can be treated by withdrawing the overused drug(s) and adopting specific approaches that focus on the development of a close doctor-patient relationship in the post withdrawal phase. Although the headache diary is, in this context, an essential tool for the constant, reliable monitoring of these patients to prevent relapses, very little is known about the applicability of electronic diaries in MOH patients. The purpose of this study was to evaluate the acceptability of and patient compliance with an electronic headache diary (palm device) as compared with a traditional diary chart in a group of headache inpatients with MOH. A palm diary device, developed in accordance with the ICHD-II criteria, was given to 85 MOH inpatients during the detoxification phase. On the first day of hospitalization, the patients were instructed in the use of the diary and were then required to fill it in daily for the following 7 days. Data on the patients' opinions on the electronic diary and the instructions given, its screen and layout, as well as its convenience and ease of use, in comparison with the traditional paper version, were collected using a numerical rating scale. A total of 504 days with headache were recorded in both the electronic and the traditional headache diaries simultaneously. The level of patient compliance was good. The patients appreciated the electronic headache diary, deeming it easy to understand and to use (fill in); most of the patients rated the palm device handier than the traditional paper version. PMID- 22842874 TI - Vulvar varicosities mimicking a hernia: case report. AB - OBJECTIVE: Vulvar varicosities are not uncommon in pregnancy, but there are only a few published reports of symptomatic vulvar varicosities in nonpregnant women. CASE: We report 2 cases of women presenting with symptomatic vulvar masses that were more prominent after exercise or with elevated intra-abdominal pressure. Symptoms included an intermittent vulvar bulge or mass and moderate pain when the masses were present. Imaging studies did not reveal the nature of these masses. On surgical exploration, they were found to be large vulvar varicosities. CONCLUSIONS: Vulvar masses can be caused by hernias, tumors, cysts, or other unusual entities. Differentiating among these etiologies can be a diagnostic challenge. Although most often a positional vulvar mass is a sign of hernia, it is important to be aware that masses that come and go can be caused by other entities, including large varicose veins. PMID- 22842875 TI - Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations. AB - Accumulation of the DNA/RNA binding protein fused in sarcoma (FUS) as inclusions in neurons and glia is the pathological hallmark of amyotrophic lateral sclerosis patients with mutations in FUS (ALS-FUS) as well as in several subtypes of frontotemporal lobar degeneration (FTLD-FUS), which are not associated with FUS mutations. Despite some overlap in the phenotype and neuropathology of FTLD-FUS and ALS-FUS, significant differences of potential pathomechanistic relevance were recently identified in the protein composition of inclusions in these conditions. While ALS-FUS showed only accumulation of FUS, inclusions in FTLD-FUS revealed co accumulation of all members of the FET protein family, that include FUS, Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 15 (TAF15) suggesting a more complex disturbance of transportin-mediated nuclear import of proteins in FTLD-FUS compared to ALS-FUS. To gain more insight into the mechanisms of inclusion body formation, we investigated the role of Transportin 1 (Trn1) as well as 13 additional cargo proteins of Transportin in the spectrum of FUS opathies by immunohistochemistry and biochemically. FUS-positive inclusions in six ALS-FUS cases including four different mutations did not label for Trn1. In sharp contrast, the FET-positive pathology in all FTLD-FUS subtypes was also strongly labeled for Trn1 and often associated with a reduction in the normal nuclear staining of Trn1 in inclusion bearing cells, while no biochemical changes of Trn1 were detectable in FTLD-FUS. Notably, despite the dramatic changes in the subcellular distribution of Trn1 in FTLD-FUS, alterations of its cargo proteins were restricted to FET proteins and no changes in the normal physiological staining of 13 additional Trn1 targets, such as hnRNPA1, PAPBN1 and Sam68, were observed in FTLD-FUS. These data imply a specific dysfunction in the interaction between Trn1 and FET proteins in the inclusion body formation in FTLD-FUS. Moreover, the absence of Trn1 in ALS-FUS provides further evidence that ALS-FUS and FTLD-FUS have different underlying pathomechanisms. PMID- 22842876 TI - Tertiary lymphoid organ development coincides with determinant spreading of the myelin-specific T cell response. AB - While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the meninges of a subset of MS patients and were suggested to be correlates of late-stage and more aggressive disease in this patient population. However, whether these aggregates actually exist has subsequently been questioned and their functional significance has remained unclear. Here, we studied myelin basic protein (MBP) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which is one of the few animal models for MS that is dependent on B cells. We provide evidence that B cell aggregation is reflective of lymphoid neogenesis in the central nervous system (CNS) in MBP-PLP-elicited EAE. B cell aggregation was present already few days after disease onset. With disease progression CNS B cell aggregates increasingly displayed the phenotype of tertiary lymphoid organs (TLOs). Our results further imply that these TLOs were not merely epiphenomena of the disease, but functionally active, supporting intrathecal determinant spreading of the myelin-specific T cell response. Our data suggest that the CNS is not a passive "immune-privileged" target organ, but rather a compartment, in which highly active immune responses can perpetuate and amplify the autoimmune pathology and thereby autonomously contribute to disease progression. PMID- 22842877 TI - Icariin promotes bone formation via the BMP-2/Smad4 signal transduction pathway in the hFOB 1.19 human osteoblastic cell line. AB - Icariin, the main active compound of the traditional Chinese medicine, Epimedium, is commonly used for the clinical treatment of osteoporosis. However, the precise molecular mechanism of the therapeutic effect of icariin has not been elucidated. The aim of this study was to examine the effect of icariin on cell viability, alkaline phosphatase (ALP) activity, the amount of calcified nodules, and to delineate the molecular mechanism of icariin-enhanced bone formation by investigating the expression of bone morphogenic protein-2 (BMP-2), Smad4, Cbfa1/Runx2, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL) and the OPG/RANKL ratio in the hFOB 1.19 human osteoblastic cell line. We found that icariin significantly increased the cell viability, the activity of ALP and the amount of calcified nodules in the hFOB 1.19 cells. Furthermore, we observed that icariin upregulated the expression of BMP-2, Smad4, Cbfa1/Runx2, OPG, RANKL and the OPG/RANKL ratio. Our results indicate that icariin can modulate the process of bone formation via the BMP-2/Smad4 signal transduction pathway in hFOB 1.19 cells. PMID- 22842878 TI - Symptomatic suprasellar endodermal cyst, possibly originating from the Seessel's pouch, containing fluid with a high carcinoembryonic antigen level. AB - A 32-year-old man presented with a rapidly progressive decrease in visual acuity and diplopia. Magnetic resonance imaging (MRI) revealed a suprasellar cystic mass extending to the upper part of the clivus. The content of this cyst showed a slightly higher signal intensity than that of his cerebrospinal fluid (CSF) on T1 weighted images. The cyst stretched the pituitary stalk, but a normal pituitary signal was observed. The cyst wall was maximally resected under neuroendoscopy, which yielded fluid contents that were white and mucous like, with a carcinoembryonic antigen (CEA) level 1,400 ng/ml or higher. On light microscopy, one to two layers of epithelial cells with cylindrical nuclei on loose connective tissue lined the cyst cavity. These cells were positive for periodic acid-Schiff, CEA, and cytokeratin 7 and negative for cytokeratin 20. On electron microscopy, epithelial cells showed many short microvilli with coating material. The cytoplasm was rich in electron-dense material, and dense intercellular adhesion was observed, but neither goblet cells nor cilia were present. On the basis of MRI features, cytokeratin expression patterns and electron microscopic findings, the patient was considered to have a suprasellar endodermal cyst derived from Seessel's pouch. PMID- 22842879 TI - The effect of sodium thiosulfate on the metabolism of cis-platin in human plasma in vitro. AB - The anticancer drug cis-platin (CP) is widely used to treat patients, but it is also associated with significant side effects, including nephrotoxicity. Given that this metallodrug is intravenously (iv) administered, its biotransformations in the bloodstream are likely to be involved in mediating these side-effects. Previous studies have revealed that the iv administration of patients/mammalian model organisms with sodium thiosulfate (STS) can ameliorate the side effects of CP, but the underlying molecular basis remains elusive. We have studied the effect of STS on the metabolism of CP in human plasma in vitro by determining the platinum (Pt) distribution using size exclusion chromatography (SEC) coupled on line to an inductively coupled plasma atomic emission spectrometer (ICP-AES). The addition of STS to plasma 10 min before CP was added accelerated the hydrolysis of CP and resulted in the formation of a Pt-STS complex. Conversely, when plasma was incubated with CP for up to 3 h and STS was added thereafter the analysis of the obtained mixture revealed that the formation of the same Pt-STS complex which in turn greatly diminished the plasma protein binding of CP-derived hydrolysis products. Thus, the observed amelioration of the side effects of CP by STS can be rationalized in terms of the rapid formation of a biologically inactive Pt-STS complex in the bloodstream. This is the first mechanism that can explain the amelioration of the side effects of CP by STS. Based on the fact that cis-platin remained in plasma for a considerable amount of time, the optimization of the administration sequence, the molar ratio and the time delay between the administration of both drugs emerges as a viable strategy to achieve a careful balance between ameliorating the side effects while leaving the antitumour activity intact. Our results demonstrate that in vitro studies can be useful to develop feasible strategies to mitigate the side-effects of Pt-based anticancer drugs in patients. PMID- 22842881 TI - Structural modulation of internal charge transfer in small molecular donors for organic solar cells. AB - Donor-acceptor molecules with small chain extension have been synthesized and used as active material in organic solar cells. The effect of fusion of a phenyl group on the end dicyanovinylene acceptor is discussed. PMID- 22842882 TI - [Blood - surely but safely!]. PMID- 22842883 TI - [HIV, HCV, HBV and syphilis surveillance among blood donors in Germany 2008 2010]. AB - The Robert Koch Institute collects and evaluates data on the prevalence and incidence of HIV, hepatitis C (HCV), hepatitis B (HBV) and syphilis infections among blood and plasma donors in Germany according to article 22 of the Transfusion Act. This report includes data from all blood donation services in Germany for 2008-2010. The prevalence for HIV ranged from 6.6-7.0/100,000, for HCV from 68.9-81.6/100,000, for HBV from 116.2-136.6/100,000 and for syphilis from 31.0-42.1/100,000 donations. The proportion of incident infections per 100,000 donations ranged from 0.8-0.9 for HIV, 0.8-1.0 for HCV, 0.3-0.5 for HBV and 1.4-1.6 for syphilis. Since 2001 the prevalence and incidence of HBV and HCV among blood has declined whereas incident HIV infections reached a peak in 2008 and 2010 and show an increasing trend. Also, the proportion of syphilis infections among first time donors was highest in 2010. Significant differences in infection prevalence and incidence were found between the sexes, different age groups and different donation types. In order to optimise donor selection a validated donor questionnaire should be used and confidentiality in all steps of donation should be assured. The possibility of a confidential self-exclusion should be explicitly pointed out to donors. PMID- 22842884 TI - [Demography and donation frequencies of blood and plasma donor populations in Germany. Update 2010 and 5-year comparison]. AB - The Robert Koch Institute collects and evaluates nationwide data on the incidence and prevalence of transfusion-relevant infections among blood and plasma donors in Germany. Since 2006 data not only on the number of donations tested but also on the number of the respective donors have become available. The demographic profile and donation frequencies of German whole blood, plasma and platelet donors in 2010 and the percentages among the general population are described and compared to data from 2006. Although the general population eligible to donate blood is on the decline since 2003, with a loss of 2% between 2006 and 2010, this has not led to a decrease in the number of blood donors and donations. Instead, the number of new and repeat whole blood donors increased by 8% and 7%, respectively. At the same time, the number of new plasma donors grew by 23%, that of repeat plasma donors by 41%. In 2010 more than 4.3% of the population aged 18 68 years was active as repeat whole blood donors; 0.4% repeatedly donated plasma or platelets. Since 2006 the percentage of donors among the general population increased significantly, especially among the youngest age group (18-24 years). Donation frequency varied depending on donor age and sex, with an average of 1.9 per year for whole blood donations, 12.5 for plasmapheresis and 5.0 for plateletpheresis. While the donation frequency for whole blood remained unchanged since 2006, the frequency of apheresis donations increased, especially among older donors. By recruiting more new donors and retaining and reactivating existing ones more effectively, the number of whole blood and apheresis donations was augmented. PMID- 22842880 TI - 5-Hydroxymethylcytosine--the elusive epigenetic mark in mammalian DNA. AB - Over the past decade, epigenetic phenomena claimed a central role in cell regulatory processes and proved to be important factors for understanding complex human diseases. One of the best understood epigenetic mechanisms is DNA methylation. In the mammalian genome, cytosines (C) were long known to exist in two functional states: unmethylated or methylated at the 5-position of the pyrimidine ring (5mC). Recent studies of genomic DNA from the human and mouse brain, neurons and from mouse embryonic stem cells found that a substantial fraction of 5mC in CpG dinucleotides is converted to 5-hydroxymethyl-cytosine (hmC) by the action of 2-oxoglutarate- and Fe(ii)-dependent oxygenases of the TET family. These findings provided important clues in a long elusive mechanism of active DNA demethylation and bolstered a fresh wave of studies in the area of epigenetic regulation in mammals. This review is dedicated to critical assessment of the most popular techniques with respect to their suitability for analysis of hmC in mammalian genomes. It also discusses the most recent data on biochemical and chemical aspects of the formation and further conversion of this nucleobase in DNA and its possible biological roles in cell differentiation, embryogenesis and brain function. PMID- 22842885 TI - [Seroprevalence of antibodies against infectious pathogens relevant to pregnancy among healthcare workers]. AB - Healthcare workers (HCWs) are exposed to infectious diseases throughout the course of their work. The concerns of pregnant HCWs are considerable because certain otherwise mild infections may affect fetal development. We studied 424 pregnant HCWs at the University Hospital Frankfurt between March 2007 and July 2011. Serological tests were carried out for varicella zoster virus (VZV), measles, mumps, rubella (MMR), cytomegalovirus (CMV) and parvovirus B19. Our overall seroprevalence data with regard to VZV, MMR, CMV and parvovirus B 19 corresponded to the general population. However, physicians demonstrated lower seroprevalence towards the two non-vaccine-preventable diseases (CMV: 37.5% [KI 27.4-48.5]; parvovirus B19: 69.3% [KI 58.6-78.7]) compared with nurses (CMV: 53.4% [KI 46.1-60.6], parvovirus B19: 75.1% [68.4-81.1]). It was striking that, only one in five of the study population showed IgG antibodies against all of the six pregnant-relevant viral diseases tested, of the physicians as few as one in six. A routine exclusion from the workplace due to non-immunity would mean that it would not be possible to employ the majority of pregnant staff in healthcare and childcare. PMID- 22842886 TI - [Influenza vaccination rates in Hessian hospitals]. AB - Influenza infections have been shown to spread in hospitals rapidly; nosocomial transmissions occur frequently. Influenza vaccination of health care personnel (HCP) is an effective strategy for preventing influenza infections among personnel and patients. In summer 2011 we conducted an anonymous questionnaire among Hessian hospitals assessing influenza vaccination rates, kind and concept of vaccination programmes. Overall, 95.8% (68/71) of hospitals surveyed offered influenza vaccinations for HCP free of charge. Influenza vaccination rates have been recorded only by 70.4% (50/71). Over 80% (season 2009/2010: 41/50- season 2010/2011: 44/50) of hospitals questioned, mentioned influenza vaccination rates under 20%. Our findings confirm that the influenza vaccination rates might be less than the generally assumed and communicated influenza vaccination rates of 20-25%. Thirty years since the German Standing Committee on Vaccination (STIKO) recommended that all HCP get vaccinated against influenza, vaccination rates still remain below 30%. Measures to improve influenza vaccination rates among HCP are required. Monitoring of vaccination rates is a precondition to assess the acceptance of a vaccination programme. PMID- 22842887 TI - [Prevention of nosocomial transmission of human immunodeficiency virus (HIV) from HIV-positive healthcare workers. Recommendations of the German Association for the Control of Viral Diseases (DVV) e.V. and the Society for Virology (GfV) e.V]. AB - To the best of our knowledge, the German Association for the Control of Viral Diseases (DVV) e.V. and the Society for Virology (GfV) e.V. are the first in Europe to provide precise recommendations for the management of health care workers (HCWs) who are infected with human immunodeficiency virus (HIV). Requirements for HIV-infected HCWs need to be clearly defined. With a permanent viral burden of less than or equal to 50 copies/mL, HIV-positive HCWs are allowed to perform any surgery and any invasive procedure, as long as the infected HCW uses double-gloving, undergoes follow-up routinely by occupational medicine professionals, undergoes a quarterly examination of viral burden, and has a regular medical examination by a physician who has expertise in the management of HIV. Unrestricted professional activity is only possible with a strict compliance to take antiretroviral therapy and if the HIV-infected HCW strictly adheres to the recommended infection control procedures. Complete compliance with the recommendation almost certainly leads to no HIV transmission risk in patient care. PMID- 22842888 TI - [Barriers in the attendance of health care interventions by immigrants]. AB - AIM: Analysis of barriers regarding attendance at the health care system under consideration of cultural and migration-related factors. METHOD: Cross-sectional survey with immigrants from Turkey (n = 77), Spain (n = 67), Italy (n = 95) and German resettlers from the former Soviet Union (n = 196), recruited on migration and addiction services of the German Caritasverband, the Arbeiterwohlfahrt and migrant organizations. RESULTS: Spanish and Italian immigrants mainly search for help within their families and social environment. Immigrants from the former Soviet Union use home remedies and experience more linguistic difficulties as barriers for the use of health services, just like Turkish immigrants. Turkish immigrants reported feeling misunderstood regarding their cultural peculiarities by the expert staff as another main barrier. Other major influencing factors were German language proficiency and the subjective wellbeing in Germany. CONCLUSION: The consideration of cultural-related as well as linguistic factors in health care services is an essential contribution for improving health care of immigrants. PMID- 22842889 TI - [Use of family resources in future need of care. Care preferences and expected willingness of providing care among relatives: a population-based study]. AB - The family is an important resource in elderly care. It is of great interest if persons who might be in need of care in the future would use this resource. Our study assessed wishes and expectations regarding family care in a representative sample of the general population (>= 45 years, N = 1,445) using questionnaires. Logistic regressions were performed to analyze the potential impact on the willingness to use or provide family care. One quarter of the participants reported experience in family care. In case of own need 62.9% of participants would prefer care provided by relatives and 56.7% would prefer professional care. Participants are more likely to use family care if they report having relatives, are experienced in care of relatives or do not associate old age with being a burden, e.g. report low values in the image of age "being a burden/demanding". Perceived willingness of the relatives to provide care is more likely if there is little regional distance to the relatives, in male participants and if participants talked about future care with their relatives. Besides structural factors, negative images of old age might have a negative influence on the willingness to use family care. Talking about care in old age seems to have a positive impact. PMID- 22842890 TI - [Cleaning and disinfection in nursing homes. Data on quality of structure, process and outcome in nursing homes in Frankfurt am Main, Germany, 2011]. AB - Due to the Infectious Disease Prevention Act, public health services in Germany are obliged to check the infection prevention in hospitals and other medical facilities as well as in nursing homes. In Frankfurt/Main, Germany, standardized control visits have been performed for many years. In 2011 focus was laid on cleaning and disinfection of surfaces. All 41 nursing homes were checked according to a standardized checklist covering quality of structure (i.e. staffing, hygiene concept), quality of process (observation of the cleaning processes in the homes) and quality of output, which was monitored by checking the cleaning of fluorescent marks which had been applied some days before and should have been removed via cleaning in the following days before the final check. In more than two thirds of the homes, cleaning personnel were salaried, in one third external personnel were hired. Of the homes 85% provided service clothing and all of them offered protective clothing. All homes had established hygiene and cleaning concepts, however, in 15% of the homes concepts for the handling of Norovirus and in 30% concepts for the handling of Clostridium difficile were missing. Regarding process quality only half of the processes observed, i.e. cleaning of hand contact surfaces, such as handrails, washing areas and bins, were correct. Only 44% of the cleaning controls were correct with enormous differences between the homes (0-100%). The correlation between quality of process and quality of output was significant. There was good quality of structure in the homes but regarding quality of process and outcome there was great need for improvement. This was especially due to faults in communication and coordination between cleaning personnel and nursing personnel. Quality outcome was neither associated with the number of the places for residents nor with staffing. Thus, not only quality of structure but also quality of process and outcome should be checked by the public health services. PMID- 22842891 TI - [Old, sick, unemployed, without a chance? Results of a randomised controlled trial of the effects of a combined health and employment promotion program for the older long-term unemployed (AmigA-M)]. AB - Illness can be the cause and consequence of unemployment. These relationships are well documented but only few data on the effectiveness of interventions are available. The study examines the effectiveness of a combined health and employment promotion intervention (AmigA - currently projected in several sites in Germany) for the older long-term unemployed with the main goals of an improvement of health and integrability as well as sustainable reintegration into the labour market. The evaluation design is a randomised controlled trial with a multi-method approach. A total of 71 participants could be included in the evaluation. Initial results confirm earlier findings on health and unemployment and show a psychologically and physically highly burdened sample. The intervention tended to improve depression, self-efficacy and quality of life. No effects were found for physical health, integrability and sustainable reintegration. It is discussed whether a longer duration and a higher intensity of the intervention might produce better results. The necessity of help and interventions for this highly burdened group of persons is evident but further studies are necessary to decide if the evaluated intervention is adequate to reach the goals of health and employment promotion as a standard measure. PMID- 22842893 TI - [National health target "healthy ageing". Medical, psychosocial and nursing care for elderly people]. AB - What kind of health targets should be pursued concerning the health care of elderly people? What kind of activities should be implemented to ensure good health care with regard to future challenges? The Association for the Continuous Development of the National Health Target Process, health-targets.de, deals with these issues under the new national health target "Healthy Ageing". We develop concrete objectives and proposals for practical implementation in the areas of "outpatient and inpatient care", "nursing" and "rehabilitation in old age". health-targets.de supports a common health target process and initiates interventions in the field of health care for elderly people. PMID- 22842894 TI - [Guideline for public health evaluation of elastomers in contact with drinking water (elastomer guideline)]. PMID- 22842895 TI - [West Nile virus]. PMID- 22842896 TI - [Arbonematodes - arthropod transmissible nematode infections]. PMID- 22842897 TI - [XMRV is not pathogenic in human and has no significance for the safety of blood and blood products]. PMID- 22842898 TI - [Indoor air guide values for cresols]. AB - AbstractThe Ad-hoc Working Group on Indoor Guidelines of the Indoor Air Hygiene Committee and of the Supreme State Health Authorities in Germany is issuing indoor air guide values to protect public health. For health evaluation of cresols in indoor air upper airway irritation was seen as critical effect. Unfortunately, valid inhalation studies were not available. Therefore, results of a recent oral long term study with a mixture of cresols in male rats were used. The Working Group selected a BMDL10 of 13.9 mg cresols per kg body weight and day assessed by US-ATSDR as a point of departure. A path-to-path-extrapolation involved a breathing rate of 20 m3 per day, a body weight of 70 kg and an oral resorption rate of 50%. A factor of 10 each for interspecies and intraspecies variability, respectively, and a modifying factor of 2 regarding physiological differences in children were applied. Since data from inhalation studies indicated more pronounced airway irritation than data from oral studies an additional factor of 2 was introduced. A health hazard value (RW II) of 0.05 mg cresols/m3 and a precautionary value (RW I) of 0.005 mg cresols/m3 are recommended. PMID- 22842899 TI - [Guideline of the Genetic Diagnosis Committee (GEKO) for requirements regarding the content of patient information in genetic studies for medical purposes in accordance with 23 Abs. 2 no. 3 GenDG]. PMID- 22842900 TI - Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes. AB - Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non selective and Na(+)-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a-psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 A, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents. PMID- 22842901 TI - A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. AB - The jumonji (JMJ) family of histone demethylases are Fe2+- and alpha ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3 specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family. PMID- 22842902 TI - Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. AB - Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter gamma-aminobutyric acid (GABA) by means of gamma2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of gamma2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell-signal-receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience. PMID- 22842903 TI - Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. AB - Dendritic arborizations of many neurons are patterned by a process called self avoidance, in which branches arising from a single neuron repel each other. By minimizing gaps and overlaps within the arborization, self-avoidance facilitates complete coverage of a neuron's territory by its neurites. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self avoidance and self/non-self discrimination. The Pcdh locus encodes 58 related cadherin-like transmembrane proteins, at least some of which exhibit isoform specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons. Deletion of all 22 Pcdh genes in the mouse gamma-subcluster (Pcdhg genes) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhg proteins act cell autonomously during development, and that replacement of the 22 Pcdhg proteins with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighbouring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhg proteins unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 (Down syndrome cell adhesion molecule) in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination. Thus, although insect Dscam and vertebrate Pcdh proteins share no sequence homology, they seem to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arborizations. PMID- 22842905 TI - Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict. AB - Unhappy couple relationships are associated with impaired individual health, an effect thought to be mediated through ongoing couple conflicts. Little is known, however, about the underlying mechanisms regulating psychobiological stress, and particularly autonomic nervous system (ANS) reactivity, during negative couple interaction. In this study, we tested the effects of the neuropeptide oxytocin on ANS reactivity during couple conflict in a standardized laboratory paradigm. In a double-blind, placebo-controlled design, 47 heterosexual couples (total n = 94) received oxytocin or placebo intranasally prior to instructed couple conflict. Participants' behavior was videotaped and salivary alpha-amylase (sAA), a measure of sympathetic activity, and emotional arousal were repeatedly measured during the experiment. Oxytocin significantly reduced sAA during couple conflict in women, whereas men showed increases in sAA levels (sex * group interaction: B = 49.36, t = -2.68, P = 0.009). In men, these increases were related to augmented emotional arousal (r = 0.286, P = 0.028) and more positive behavior (r = 0.291, P = 0.026), whereas there was no such association in women. Our results imply sex specific effects of oxytocin on sympathetic activity, to negative couple interaction, with the neuropeptide reducing sAA responses and emotional arousal in women while increasing them in men. PMID- 22842904 TI - Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. AB - Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate. PMID- 22842907 TI - Methanogenic octadecene degradation by syntrophic enrichment culture from brackish sediments. AB - A microbial enrichment culture from brackish sediments was able to grow on octadec-1-ene (an unsaturated aliphatic hydrocarbon) as sole source of carbon and energy, under methanogenic conditions. Octadecene degradation is stopped either when bromoethanesulfonic acid, a selective inhibitor of methanogenesis is introduced, or when hydrogen is introduced. In the presence of bromoethanesulfonic acid, the degradation is restored by the addition of a hydrogenotrophic sulfate-reducing microorganism with sulfate. Results of molecular biodiversity, which revealed the presence of bacteria as well as of acetoclastic and hydrogenotrophic methanogens, are consistent with a syntrophic degradation involving Bacteria and Archaea. This is the first demonstration of syntrophic alkene degradation by microbial communities, showing that syntrophy is more widespread than we could have thought so far. These results highlight the need for a better understanding of microbial interactions and their role in the organic-matter degradation in polluted environments. PMID- 22842906 TI - DAT by perceived MC interaction on human prefrontal activity and connectivity during emotion processing. AB - BACKGROUND: Maternal care (MC) and dopamine modulate brain activity during emotion processing in inferior frontal gyrus (IFG), striatum and amygdala. Reuptake of dopamine from the synapse is performed by the dopamine transporter (DAT), whose abundance is predicted by variation in its gene (DAT 3'VNTR; 10 > 9 repeat alleles). Here, we investigated the interaction between perceived MC and DAT 3'VNTR genotype on brain activity during processing of aversive facial emotional stimuli. METHODS: Sixty-one healthy subjects were genotyped for DAT 3'VNTR and categorized in low and high MC individuals. They underwent functional magnetic resonance imaging while performing a task requiring gender discrimination of facial stimuli with angry, fearful or neutral expressions. RESULTS: An interaction between facial expression, DAT genotype and MC was found in left IFG, such that low MC and homozygosity for the 10-repeat allele are associated with greater activity during processing of fearful faces. This greater activity was also inversely correlated with a measure of emotion control as scored with the Big Five Questionnaire. Moreover, MC and DAT genotype described a double dissociation on functional connectivity between IFG and amygdala. CONCLUSION: These findings suggest that perceived early parental bonding may interact with DAT 3'VNTR genotype in modulating brain activity during emotionally relevant inputs. PMID- 22842908 TI - Effect of 17beta-estradiol on zinc content of hippocampal mossy fibers in ovariectomized adult rats. AB - Sex hormones such as estrogen (17beta-estradiol) may modulate the zinc content of the hippocampus during the female estrous cycle. The mossy fiber system is highly plastic in the adult brain and is influenced by multiple factors including learning, memory, and stress. However, whether 17beta-estradiol is able to modulate the morphological plasticity of the mossy fibers throughout the estrous cycle remains unknown. Ovariectomized (Ovx) female 70- to 90-day-old Sprague Dawley rats without or with estrogen supplement (OvxE) were compared with control rats in three stages of the estrous cycle: diestrus, proestrus, and estrus. The brain tissue from each of the five groups was processed with Timm's silver sulfide technique using the Image J program to measure the mossy fiber area in the stratum lucidum of CA3. Total zinc in the hippocampus was measured using Graphite Furnace Atomic Absorption Spectrophotometry. Two additional (Ovx and OvxE) groups were examined in spatial learning and memory tasks using the Morris water maze. Similar increases in total zinc content and mossy fiber area were observed. The mossy fiber area decreased by 26 +/- 2 % (difference +/- SEM percentages) in Ovx and 23 +/- 4 % in estrus as compared to the proestrus group and by 18 +/- 2 % in Ovx compared to OvxE. Additionally, only the OvxE group learned and remembered the task. These results suggest that estradiol has a significant effect on zinc content in hippocampal CA3 during the proestrus stage of the estrous cycle and is associated with correct performance in learning and memory. PMID- 22842910 TI - The influence of the indicator arm on end point distribution in proprioceptive localization with multi-joint arms. AB - The present study attempted to demonstrate that the indicator arm influences end point distribution in contralateral multi-joint proprioceptive tasks and also that intrinsic physical characteristics of multi-joint arms (arm stiffness) may predict the error pattern. For this purpose, we carried out two types of contralateral localization tasks with multi-jointed arm movements. In the concurrent localization task, the end point distribution was significantly more elongated in the direction of the lower stiffness at each target position when based on the indicator stiffness, while in the remembered localization task, there was no significant difference between the axes. The best-fit ellipse for the end point distribution also confirmed those results. These findings may support the idea that a large part of the configuration of end point distribution could be determined by the characteristics of arm stiffness of the indicator arm in the condition without memory decay of position representation. Further, error bias of proprioceptive localization may be influenced by the combined effect between movement direction and orientation of the lower stiffness. In conclusion, this study suggests that error patterns largely reflect indicator factors such as the elastic property of the arm in multi-joint proprioceptive tasks, which have been assumed to assess the proprioceptive sense of the reference arm. PMID- 22842911 TI - Prevalence of adenoma of gallbladder, ultrasonographic and histological assessment in a retrospective series of 450 cholecystectomy. AB - BACKGROUND: Adenomyomas of the gallbladder are difficult to examine during standard ultrasound examination of the abdomen. They sometimes undergo malignant transformation and their optimal management still remains a problem. The authors have aimed to investigate the ultrasonographic and histopathological prevalence of gallbladder adenomyomas focusing on the diagnostic performance of ultrasound examination. MATERIALS AND METHODS: A retrospective series of 450 consecutive patients who underwent cholecystectomy is reported. Data regarding characteristics of the patients, US and histology examination of the gallbladder were collected. Sensitivity, specificity, positive and negative predictive values of ultrasound scan were calculated with respect to histological examination of the gallbladder. RESULTS: The study group consisted of 261 female and 189 male. Ultrasound scan detected adenomyomas in 22 patients, confirmed by histopathology in 13 and found to be not present in 9. Incidental adenomyomas were found in 16 patients of 428 who underwent cholecystectomy for gallstones. Prevalence was 4.9% and 6.4% for ultrasound scan and histopathology respectively. Ultrasound scan showed sensitivity of 43.3% (c.i.:25.4%-62.5%), specificity of 97.8% (c.i.:95.9% 99%) with a positive predictive value of 59% (c.i.:36.3%-79.2%) and with a negative predictive value of 96.2% (c.i.:93.7%- 97.6%). On histopathology, adenomyomas localized in the fundus were predominant. Two female patients with adenomyomas of the fundus (diameter 5 mm) and single stone showed intestinal metaplasia with high-grade dysplasia. CONCLUSIONS: The diagnosis of gallbladder adenomyomas by ultrasound scan still remains a problem because of its low sensitivity, which is mainly due to the association with gallstones. Histopathological findings in the perilesional mucosa confirm the hypothesis of a metaplasia-dysplasia-carcinoma sequence already shown in the colon-rectum. At present, the selection of patients requiring cholecystectomy is still controversial. PMID- 22842912 TI - Overexpression of the structural maintenance of chromosome 4 protein is associated with tumor de-differentiation, advanced stage and vascular invasion of primary liver cancer. AB - Structural maintenance of chromosome 4 (SMC4) is associated with tumorigenesis. The present study aimed at detecting SMC4 expression in primary liver cancer and its association with clinicopathological patient data. A total of 72 primary liver cancer tissues and 6 liver cell lines were assessed for expression of SMC4 mRNA and protein with qRT-PCR, western blotting and immunohistochemistry, respectively. SMC4 siRNAs were constructed to knockdown SMC4 expression, and phenotypic changes of hepatocellular carcinoma (HCC) cells were analyzed using flow cytometry and cell viability assays. The data showed that SMC4 mRNA and protein were highly expressed in HCC tissues compared to the normal tissues. Immunohistochemical analysis revealed that 52 of 72 (72.2%) paraffin-embedded primary liver cancer tissues displayed strong cytoplasmic staining of SMC4 protein, whereas only 6 (8.3%) normal liver tissues showed immunostaining of SMC4. Statistical analysis showed that SMC4 expression was significantly associated with tumor size, de-differentiation, advanced stages and vascular invasion of the primary liver cancers. Moreover, knockdown of SMC4 expression reduced HCC cell proliferation. These data demonstrated that expression of SMC4 protein may be useful for the early detection and prediction of primary liver cancer progression. PMID- 22842913 TI - Trafficking of PrPc to mitochondrial raft-like microdomains during cell apoptosis. AB - The cellular form of prion protein (PrP (c)) is a highly conserved cell surface GPI-anchored glycoprotein that was identified in cholesterol-enriched, detergent resistant microdomains, named "rafts." The association with these specialized portions of the cell plasma membrane is required for conversion of PrP (c) to the transmissible spongiform encephalopathy-associated protease-resistant isoform. Usually, PrP (c) is reported to be a plasma membrane protein, however several studies have revealed PrP (c) as an interacting protein mainly with the membrane/organelles, as well as with cytoskeleton network. Recent lines of evidence indicated its association with ER lipid raft-like microdomains for a correct folding of PrP (c), as well as for the export of the protein to the Golgi and proper glycosylation. During cell apoptosis, PrP (c) can undergo intracellular re-localization, via ER-mitochondria associated membranes (MAM) and microtubular network, to mitochondrial raft-like microdomains, where it induced the loss of mitochondrial membrane potential and citochrome c release, after a contained raise of calcium concentration. We suggest that PrP (c) may play a role in the multimolecular signaling complex associated with cell apoptosis Lipid rafts and their components may, thus, be investigated as pharmacological targets of interest, introducing a novel and innovative task in modern pharmacology, i.e., the development of glycosphingolipid targeted drugs. PMID- 22842914 TI - Longitudinal assessment of lipid and hepatic clinical parameters in workers involved with the demolition of perfluoroalkyl manufacturing facilities. AB - OBJECTIVE: To examine in a longitudinal occupational assessment whether changes in serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are associated with changes in non-high-density lipoprotein (HDL) cholesterol. METHODS: Baseline and end-of-project PFOA, PFOS, lipid, and hepatic clinical chemistries were measured in 204 workers involved with the demolition of former perfluoroalkyl manufacturing facilities. Analyses were restricted to the 179 workers who did not take lipid-lowering medications. Two thirds had baseline PFOA and PFOS levels similar to the general population. RESULTS: The change in non-HDL cholesterol was not associated with the changes in PFOA or PFOS. An increase in HDL was associated with an increase in PFOA, although the magnitude was small. This increase in HDL resulted in a decrease in the total cholesterol/HDL ratio. CONCLUSION: Adverse associations were not observed between changes in PFOA, PFOS, non-HDL cholesterol, HDL, and hepatic clinical chemistries. PMID- 22842915 TI - Comparison of chronic occupational upper extremity versus lumbar disorders for differential disability-related outcomes and predictor variables. AB - OBJECTIVE: To systematically evaluate if an interdisciplinary functional restoration program (FRP), shown to be a viable treatment option for patients with chronic disabling occupational lumbar disorders, is as effective in treating chronic disabling occupational upper extremity disorders. METHODS: Participants were 2484 consecutive patients with either arm or lumbar disorders admitted to an FRP. Analyses compared demographic, psychosocial, and work-related factors, and 1 year post-rehabilitation socioeconomic outcomes. RESULTS: Socioeconomic outcomes showed that work-return and work-retention rates after successful completion of the FRP did not differ between the two groups, or among the upper extremity subgroups. CONCLUSIONS: FRP is equally effective for patients with chronic upper extremity or lumbar spine disorders, regardless of the injury type, site in the upper extremity, or the disparity in injury-specific and psychosocial factors identified before treatment. PMID- 22842916 TI - Intervessel connectivity and relationship with patterns of lateral water exchange within and between xylem sectors in seven xeric shrubs from the great Sahara desert. AB - The main objective of this study was to evaluate the role of intervessel contacts in determining the patterns of hydraulic integration both within and between xylem sectors. The degree of intervessel contacts and the lateral exchange capability within and between sectors were examined and correlated in different xeric shrubs. A dye injection method was used to detect the connections between vessels; an apoplastic dye was sucked through a known number of vessels and its distribution in the xylem network was followed. Hydraulic techniques were used to measure axial and tangential conductivity both within and between xylem sectors. The intra- and inter-sector integration indexes were then determined as the ratio of tangential to axial conductance. Species differed significantly in the degree of intervessel contacts, intra- and inter-sector integration index. In all cases, hydraulic integration was observed to be higher within sector than between sectors. From the correlation analyses, the intervessel contacts showed a very weak relationship with inter-sector integration index and a strong positive relationship with intra-sector integration index. Results suggested that (1) the factors affecting patterns of lateral flow within xylem sectors might be relatively different from those between sectors. (2) The degree of intervessel contacts was a major determinant of hydraulic integration within the same xylem sector. (3) Intervessel connectivity alone was a poor predictor of hydraulic integration between different sectors, implying a significant contribution of other anatomical, physiological and environmental factors in determining the patterns of integrated-sectored transport within woody stems. PMID- 22842917 TI - Health-related quality of life after total knee or hip replacement for osteoarthritis: a 7-year prospective study. AB - OBJECTIVE: To assess health-related quality of life (HRQOL) in a prospective study with 7 years of follow-up in 49 consecutive patients who underwent a total joint replacement because of osteoarthritis. METHODS: Generic HRQOL was assessed with the short-form 36 (SF-36) and specific HRQOL with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Out of the 39 subjects who have completed the 7 years of follow-up of this study, 22 (56.4 %) underwent a hip replacement surgery and the other 17 (43.6 %) a knee replacement. Six months after surgery, a significant improvement, compared to preoperative scores, was observed in two of the eight dimensions of the SF-36 (i.e. physical function and pain). The same dimensions, pain and physical function, at the same time, 6 months after surgery, measured by the WOMAC, showed a significant improvement as well, but there was no significant change in the stiffness score. From 6 months to the end of follow-up, changes in SF-36 scores showed a significant improvement in physical function (p = 0.008), role-physical (p = 0.004) and role-emotional (p = 0.01) while all scores of the WOMAC improved (p < 0.001 for pain, p < 0.001 for stiffness and p < 0.01 for physical function). CONCLUSION: The improvements observed in HRQOL at short term after surgery, are at least maintained over a 7-year follow-up period. PMID- 22842918 TI - Comparison of mesh-plug and Lichtenstein for inguinal hernia repair: a meta analysis of randomized controlled trials. AB - BACKGROUND AND PURPOSE: Mesh-plug and Lichtenstein techniques are among the most common used inguinal hernia repair procedures. The aim of this meta-analysis was to compare the recurrence and other postoperative complications between mesh-plug technique and Lichtenstein operation in inguinal hernia repair. METHODS: The electronic databases Embase, Pubmed, Springer and Cochrane Library were used to search for randomized controlled trials about mesh-plug and Lichtenstein repair techniques till Oct 2011. Two independent reviewers assessed the trials for eligibility and quality. And all related data matching our standards were abstracted for meta-analysis by RevMan 5.0.1. The evaluation criteria included recurrence, pain, hematoma, seroma, infection, paresthesia, testicular problem, urinary retention, operating time and recovery to daily activity. RESULTS: A total of 2,912 patients enrolled into 8 randomized controlled trials were included in this meta-analysis. All these RCTs compared mesh-plug and Lichtenstein procedures, and our pooled data showed similar results according to all the compared postoperative complications and return to daily activity. CONCLUSION: Mesh-plug versus Lichtenstein procedures for inguinal hernia repair was comparable in most of the analyzed outcomes. PMID- 22842919 TI - Inhibition of angiotensin II-induced contraction of human airway smooth muscle cells by angiotensin-(1-7) via downregulation of the RhoA/ROCK2 signaling pathway. AB - Sustained renin-angiotensin system (RAS) activation in asthmatic patients plays a crucial role in airway hyperresponsiveness and airflow limitation. Angiotensin II (Ang II), as a key peptide of RAS, contributes to the contraction of human airway smooth muscle by activating the RhoA/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway. Angiotensin-(1-7) [Ang-(1-7)], is a component of the angiotensin I converting enzyme 2 (ACE2)-Ang-(1-7)-Mas axis which counteracts the detrimental effects of the ACE- Ang II-angiotensin type 1 receptor (AT1R) axis in vivo; however, whether Ang-(1-7) can inhibit the effect of Ang II in the contraction of human airway smooth muscle cells (HASMCs) is unknown. In our study, collagen gel lattices and immunofluorescence were used to evaluate the contraction of HASMCs induced by Ang II. Real-time PCR and western blot analysis were performed to confirm the regulatory mechanism and the participating signaling pathway. Ang II caused the contraction of HASMCs; this effect was reversed by Ang-(1-7). In addition, irbesartan and A779, which are inhibitors of AT1R and Mas, respectively, attenuated the effect of Ang II and Ang (1-7). Furthermore, Y-27632, an inhibitor of ROCK2, attenuated the Ang II-induced contraction of HASMCs by blocking the RhoA/ROCK2 signaling pathway which is involved in this contraction, and thus may be a major regulator involved in the basal maintenance of contractility in HASMCs. These data demonstrate that Ang II induces the contraction of HASMCs and that this effect can be reversed by Ang-(1 7), partially through the downregulation of of the RhoA/ROCK2 signaling pathway. PMID- 22842920 TI - [Is there life after trauma surgery?]. PMID- 22842924 TI - Conducting metallophthalocyanine 2D covalent organic frameworks: the role of central metals in controlling pi-electronic functions. AB - Phthalocyanine covalent organic frameworks with different central metals are synthesized, and the AA-stacking structure of the 2D polymer sheets results in periodic phthalocyanine pi-columns. The central metals control the pi-electronic functions, including the improvement of light absorbance, the ease of carrier transport, and the photocurrent gain. PMID- 22842923 TI - Turning strategies in patients with cerebellar ataxia. AB - Turning while walking is a common but demanding task requiring modification of the motor program from linear walking to lateral turning and it is associated with a high risk of falls. Patients with cerebellar ataxia have unstable gait and report a high incidence of falls. In the present study, we investigated the motor strategies adopted by ataxic patients when performing turns of different degrees and directions of rotation. Ten ataxic patients and 10 controls were analyzed while performing 30 degrees /90 degrees turns to the right/left. We recorded the number of completed turn tasks, the number of steps needed, and the time taken to complete the task, time-distance parameters and the onset of head, trunk and pelvis reorientation. The ataxic patients were less able to complete 90 degrees turns, displayed a greater stride width, shorter step length, and greater number of steps when turning, and were unable to flexibly adjust their stride width across the turning task. The duration of the turning task and of the segmental reorientation did not differ from control values. Our findings indicate that ataxic patients have more difficulties in performing large turns and adopt a series of compensatory strategy aimed at reducing the instability associated with turning, such as enlarge the base of support, shorten the step length, increase the number of steps, and use the "multi-step" rather than the "spin-turn" strategy. Given the high risk of falls related to this task, it would be useful to include turning training in the rehabilitation protocol of ataxic patients. PMID- 22842922 TI - Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. AB - Relocalization of proteins is a hallmark of the DNA damage response. We use high throughput microscopic screening of the yeast GFP fusion collection to develop a systems-level view of protein reorganization following drug-induced DNA replication stress. Changes in protein localization and abundance reveal drug specific patterns of functional enrichments. Classification of proteins by subcellular destination enables the identification of pathways that respond to replication stress. We analysed pairwise combinations of GFP fusions and gene deletion mutants to define and order two previously unknown DNA damage responses. In the first, Cmr1 forms subnuclear foci that are regulated by the histone deacetylase Hos2 and are distinct from the typical Rad52 repair foci. In a second example, we find that the checkpoint kinases Mec1/Tel1 and the translation regulator Asc1 regulate P-body formation. This method identifies response pathways that were not detected in genetic and protein interaction screens, and can be readily applied to any form of chemical or genetic stress to reveal cellular response pathways. PMID- 22842925 TI - Cooperative bimetallic catalysis in asymmetric transformations. AB - The efficient synthesis of enantioenriched compounds is becoming increasingly important in modern organic, pharmaceutical, and materials chemistry. Recently, chiral cooperative bimetallic catalysts have emerged as a powerful tool to achieve high efficiency and selectivity in asymmetric transformations. This tutorial review highlights strategies and recent advances in cooperative bimetallic catalysts which have been developed for a variety of asymmetric transformations. PMID- 22842921 TI - Overall survival and self-reported fatigue in patients with esophageal cancer. AB - PURPOSE: A prospective cohort study was conducted to analyze whether self reported fatigue predicts overall survival in patients with esophageal cancer. METHODS: Patients enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry between September 2001 and January 2009 who completed a baseline quality of life instrument were eligible for evaluation. The fatigue component was scored on a 0-10 scale, with 0 as extreme fatigue. Patients were categorized as having a decreased energy level if they reported a score of <= 5. Fatigue scores >= 6 reflect normal levels of energy. RESULTS: Data from a total of 659 enrolled patients were analyzed. A total of 392 (59 %) and 267 (41 %) patients reported decreased and normal energy, respectively. Univariate analysis indicates patients with normal energy had improved 5-year survival compared to patients with decreased energy (37 vs 28 %, hazard ratio (HR) 0.74, p = 0.006). Among the patients with locally advanced disease, the same relationship was seen (28 vs 17 %, HR = 0.67, p = 0.003); this remained significant on multivariate analysis (HR = 0.71, p = 0.015). CONCLUSIONS: A decreased energy level is associated with poor survival in patients with esophageal cancer. Thus, patients with high levels of fatigue should be referred for psychological support and be considered for therapy aimed at amelioration of fatigue symptoms. PMID- 22842926 TI - Primary care is the beating heart of healthcare systems the world over. PMID- 22842927 TI - Framework for advancing improvement in primary care. AB - A consistent feature of effective healthcare delivery systems is a strong and well-integrated primary care sector. This paper presents a framework that describes the key elements of high-performing primary care and the supports required to attain it. The framework was developed by the Quality Improvement and Innovation Partnership in Ontario (now part of Health Quality Ontario) to guide the process of primary care transformation. The first section of this paper presents and describes the framework, the second proposes implementation strategies and the third identifies system-level structures and policies needed to support primary care transformation. The framework has three components: (1) the major constituencies that primary care serves - patients, families and their local communities; (2) the desired outcomes of primary care (better health, better care, better value); and (3) the attributes that will enable primary care organizations to attain these outcomes. These attributes are a population focus, patient engagement, partnerships with health and community services, innovation, performance measurement and quality improvement and team-based care.Proposed transformation strategies include building system capacity and capability, ensuring access to resources, providing support from coaches and employing effective spread and sustainability strategies. Broader system-level structures and policies necessary to support and sustain a high-performing and continually improving primary care sector include clear goals; a comprehensive approach to performance measurement; systematic evaluation of innovation; funding incentives aligned with quality outcomes; a system of local primary care organizations; support for inter-professional teams; funding for research to inform primary care policy, management and practice; patient enrolment with primary care providers; and mechanisms to support coordination and integration. PMID- 22842928 TI - The challenge of advancing quality in Canadian primary healthcare. AB - Understanding the issues in advancing quality in Canadian primary healthcare requires some comprehension of systems theory as it applies to healthcare, as well as an understanding of the context of Canadian primary healthcare, particularly the roles of family physicians. With that background, one is then prepared to appreciate the current challenge in advancing the quality agenda, where provider learning of the content and skills of quality improvement and leading change, models of community or regional governance, and infrastructure such as information technology and its necessary supports for interoperability with other healthcare systems, are all primitive. For primary care providers, driven in large part by their desire to improve the health of the individuals and populations they serve, "Framework for Advancing Improvement in Primary Care" is a welcome guide for direction in how to begin their quality journey. The framework provides the map with the destination (the Institute for Healthcare Improvement's Triple Aim) and roads to get there (six characteristics of high performing primary healthcare systems). Finally, our ability to improve the system builds from partnerships with our practice citizens - we need to move beyond the patient care construct. PMID- 22842929 TI - Frameworks and primary healthcare policy. AB - Healthcare reform in Canada needs to start with primary care reform, putting patients and their caregivers at the centre of the health system. Although the directions are well accepted, primary care reform requires changes to organizational structures (moving toward multidisciplinary practice) and to physician remuneration to be effective. Without action on these system-level enablers, little real action will be able to occur in repositioning the healthcare system. PMID- 22842930 TI - Of honey and health policy: the limits of sweet, sticky substances in reforming primary care. AB - It is a well-known axiom that one attracts more flies with honey than vinegar. Nowhere has this approach been taken more to heart than in the past decade of primary care policy in Canada. Governments, physician and nursing organizations and regional health authorities have invested in a lot of "honey" to draw healthcare providers onto a path from single-physician offices to team-based care with flexible hours and a population-based approach. In the lead essay for this edition of Healthcare Papers, Kates and colleagues have outlined a framework that embraces this paradigm. Their articulation of a framework is a place to start, but it can only be a start. To make that framework come alive, a wider variety of policy tools will be needed than have been used thus far, and by a wider variety of actors. Within the healthcare workforce itself, leadership, vision and the courage to hold ourselves to account for changes to primary care are needed. PMID- 22842931 TI - A framework for community-oriented primary healthcare. AB - To build on the very valuable contribution of Kates et al., this commentary takes a population health perspective and provides a complementary framework and means of accelerating transformative change in community-oriented primary healthcare (COPHC). The six basic requirements that make up this framework are (1) a geographical population focus, (2) patient and community engagement - a governance mechanism, (3) comprehensive COPHC services, (4) collaborative inter professional teams and partnerships, (5) performance measurement and quality improvement and (6) innovation in financing. Transformative change in COPHC can be accelerated by the following: an increase funding for the primary prevention of chronic disease; the facilitation of inter-professional collaboration with resources and data; the development of indicators and databases for the above six basic requirements; and annual public reports by the Health Council of Canada based on these indicators to track progress in the transformation of COPHC, with the co-operation of the Canadian Institute for Health Information. The 6% annual uplift in the Canada Health Transfer is a potential source to fund these initiatives. PMID- 22842932 TI - Primary healthcare transformation: moving from common sense to common practice. AB - There is no disputing that the key to any high-performing healthcare system is a high-performing primary healthcare system. As health systems around the globe grapple with aging, sicker populations, variable quality of care and unsustainable growth in health expenditures, the overhauling of primary healthcare cannot be put off any longer. Patient centred. Community designed. Team delivered. These are the tenets behind Saskatchewan's recently released framework for achieving a high-performing primary healthcare system. It has much in common with the primary healthcare framework offered by Kates and colleagues; and given its promising genesis, perhaps (finally) what has eluded many health systems so far can be achieved in the province that 50 years ago led the country in healthcare innovation. PMID- 22842933 TI - Canada's future healthcare: can it be better? Will it be better? AB - Thought leaders envisage high-performing partnerships of engaged community practitioners, informed patients and non-professional caregivers collaborating continuously, and efficiently, to improve care and outcomes for whole patient populations. These primary care health social networks would be facilitated by needs-based training, meaningful measurements, sustained funding, effective leadership and integration with available resources and processes. Broadly voiced opinion supports such integrated, community-focused partnership and data-driven healthcare models, and a province-wide implementation of the model for acute and chronic cardiac diseases in Nova Scotia has conclusively demonstrated sustained improvements in clinical and economic outcomes. A reasonable hypothesis, then, is that such strategies will be rapidly adopted to effectively manage the primary care of our increasingly aged populations, with their large and recalcitrant gaps between usual and best care. However, there are impediments to widespread adoption in the short term, not the least being disparities in various key stakeholders' level of preference, commitment, resolve and clout in making the necessary decisions to adopt and sustain the strategies. Thus, while we know things can be better in Canadian healthcare, the answers to, will they? and, when? remain less certain. PMID- 22842934 TI - Now we need a framework for action. AB - Over the past decade, there has been growing policy interest in the role of primary care within the Canadian health system, with the recognition that it has not been fully integrated and that its full potential has not been developed. The framework of Kates et al. starts to address some key organizational issues, by placing the patient, family and community at the centre of the healthcare system and by combining the Institute for Healthcare Improvement's Triple Aim approach with the Institute of Medicine's six improvement aims. What this framework does not do is provide a model of how to organize or deliver primary care or demonstrate how policy makers and those responsible for designing the healthcare system should structure organizational models, payment systems or accountability structures. Kates et al. have provided a useful first step. We now require a commitment to act. PMID- 22842936 TI - Repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex improves probabilistic category learning. AB - Traditionally, it has been thought that probabilistic category learning, one of the implicit memory functions, is dependent on the basal ganglia. However, there is growing evidence indicating the involvement of the dorsolateral prefrontal cortex (DLPFC) in probabilistic category learning. In order to identify the causal role of DLPFC in probabilistic category learning, we investigated whether repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC influences the learning ability in healthy subjects using the weather prediction task (WPT). Application of 10 Hz rTMS over the left DLPFC induced significant improvement in the total hit rate during the total trials of the WPT, compared with sham stimulation. Specifically, the improvement was significant in the early and late learning blocks of the WPT, but not in the intermediate block of learning. These results indicate that the left DLPFC may play an important role in probabilistic category learning, possibly by influencing not only on embodied information application in late stage of the learning but also on memory encoding for working memory demands in early stage of the learning via frontostriatal and frontohippocampal circuits, respectively. They also may lend support to the possibility that rTMS can improve implicit learning ability in patients with basal ganglia disorders. PMID- 22842937 TI - Adenovirus-mediated ING4/IL-24 double tumor suppressor gene co-transfer enhances antitumor activity in human breast cancer cells. AB - Cancer gene therapy represents a new and promising therapeutic modality for various types of cancer. Two or more anti-oncogenes carried by a single vector could theoretically improve treatment efficacy, reduce side-effects from vectors, and have a satisfactory clinical application prospect; however, this has seldom been studied in breast cancer. The inhibitor of growth 4 (ING4), as a member of the inhibitor of growth tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24) has also shown broad spectrum and tumor-specific antitumor activities. In this study, we aimed to prove the enhanced antitumor activity of adenovirus-mediated ING4/IL-24 double tumor suppressor gene co-transfer in human breast cancer cells. We assessed the combined effect of the ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) in vitro and in vivo on MDA-MB-231 human breast cancer cells by detecting and comparing the apoptotic status in the bicistronic anti-oncogene group (Ad-ING4-IL-24) and in the ING4 or IL-24 single anti-oncogene groups, and also investigated the possible underlying mechanism. Our results showed that the bicistronic adenovirus mediated ING4 and IL-24 co-expression induced additive growth suppression and apoptosis as well as an overlapping effect on the upregulation of p21, p27 and Bax, and the downregulation of Bcl-2 and survivin in MDA-MB-231 human breast cancer cells in vitro or in vivo. Moreover, Ad-ING4-IL-24 treatment additively reduced CD34 expression and the microvessel density in MDA-MB-231 xenografted tumors in athymic nude mice, which correlated with the decreased expression of the vascular endothelial growth factor. The enhanced antitumor activity on breast cancer elicited by Ad-ING4-IL-24 was closely associated with the activation of the apoptotic pathways and the additive inhibition of tumor angiogenesis. PMID- 22842939 TI - The impact of JIDC. PMID- 22842938 TI - Procurement of exogenous ammonia by the swallowtail butterfly, Papilio polytes, for protein biosynthesis and sperm production. AB - How to acquire sufficient quantity of nitrogen is a pivotal issue for herbivores, particularly for lepidopterans (butterflies and moths) of which diet quality greatly differs among their life stages. Male Lepidoptera often feed from mud puddles, dung, and carrion, a behavior known as puddling, which is thought to be supplementary feeding targeted chiefly at sodium. During copulation, males transfer a spermatophore to females that contains, besides sperm, nutrients (nuptial gifts) rich in sodium, proteins, and amino acids. However, it is still poorly understood how adults, mostly nectarivores, extract nitrogen from the environment. We examined the availability of two ubiquitous inorganic nitrogenous ions in nature, viz. ammonium (or ammonia) and nitrate ions, as nutrients in a butterfly, and show that exogenous ammonia ingested by adult males of the swallowtail, Papilio polytes, can serve as a resource for protein biosynthesis. Feeding experiments with (15)N-labeled ammonium chloride revealed that nitrogen was incorporated into eupyrene spermatozoa, seminal protein, and thoracic muscle. Ammonia uptake by males significantly increased the number of eupyrene sperms in the reproductive tract tissues. The females also had the capacity to assimilate ammonia into egg protein. Consequently, it is evident that acquired ammonia is utilized for the replenishment of proteins allocable for reproduction and somatic maintenance. The active exploitation of exogenous ammonia as a nutrient by a butterfly would foster better understanding of the foraging and reproductive strategies in insects. PMID- 22842940 TI - Correlates of HPV: a cross-sectional study in women with normal cytology in north central Morocco. AB - INTRODUCTION: Epidemiological studies have shown the association between risk of developing cervical cancer and the persistence of high-risk papillomavirus types in addition to some co-factors. However, little is known about co-factors associated with human papillomavirus (HPV) infection, especially in developing countries. This study aims to determine HPV status and associated risk factors in women with normal cytology living in the north-central area of Morocco. METHODOLOGY: From February 2007 to December 2008, a total of 925 women consulting in the gynaecological department of Fez University Hospital were asked about sociodemographic characteristics and reproductive and sexual health. Cervical samples were collected for cytological examination and HPV DNA detection. Data collected from 751 women with normal cytology were used in this study to assess the correlation between HPV infection and potential risk factors. RESULTS: High prevalence of HPV infection was detected (42.5%). The highest infection rate was observed in women aged > 45 years and in those with history of abortion (OR:3.76; 95%CI[1.77-7.98]) fibroma, polyp or cysts (OR:1.68; 95%CI[1.07-2.65]). No significant association was detected with other reproductive health and risk factors including oral contraception. CONCLUSION: In spite of the insignificant association of HPV infection with age, health authorities should seriously consider and implement strategies to increase and maintain a cervical cancer screening programme in women aged 45 and above. More attention must be given to women with gynaecological history (abortion, fibroma, polyp or cysts) since these events may be predictors of HPV infection. Investigations on partner sexual behaviour and some specific hygienic habits, especially public Turkish bath use, are needed to clarify the HPV incidence in this region. PMID- 22842941 TI - Clinical profile of dengue infection at a teaching hospital in North India. AB - INTRODUCTION: Dengue viral infections are among the most important mosquito-borne diseases of the Indian subcontinent and have become a major global public health concern. Spread of disease has led to increased recognition of atypical manifestations apart from the classical clinical features of dengue infection. METHODOLOGY: A cross-sectional study of admitted patients suspected to have dengue infection was conducted during the monsoon and post-monsoon seasons in the year 2010. Patients who had serological confirmation of dengue infection were classified according to World Health Organization definitions of dengue fever and dengue hemorrhagic fever. Clinical and biochemical parameters were compared between the two groups. RESULTS: Out of 356 patients with suspected dengue fever enrolled in the study, 138 (39%) had serologically confirmed dengue infection. Eighty (58%) patients were males and 58 (42%) were females. Ninety-six (70%) patients had classical dengue fever while 42 (30%) had dengue hemorrhagic fever. The most common symptoms were headache (105, 76%), abdominal pain (87, 63%), vomiting (80, 58%), rash (36, 26%), and cutaneous hypersensitivity (22, 16%). Hemorrhagic manifestations were present in 55 (40%) patients. Atypical manifestations were recorded. Notably, 14% of patients had neurological involvement and 4% had acute hepatic failure. Overall mortality was 6% and all fatal cases were due to multi-organ failure. CONCLUSION: Dengue infection poses a huge burden to the health-care system; its spectrum ranges from mild self limiting illness to severe fatal disease. It can have varied and multi-systemic manifestations which can go unrecognized. Clinicians should have a high index of suspicion for atypical manifestations. PMID- 22842942 TI - Biomarkers in sepsis at time zero: intensive care unit scores, plasma measurements and polymorphisms in Argentina. AB - INTRODUCTION: A patient's response to sepsis is influenced by their genetic background. Our objective was to use plasma markers, such as protein C (PC), D dimer, Plasminogen Activator Inhibitor-1 (PAI-1) levels, and the PAI-1 rs1799889 4G/5G and Tumor Necrosis Factor-alpha rs1800629 G/A polymorphisms to improve classical intensive care unit (ICU) scores. METHODOLOGY: We studied 380 subjects, 166 with sepsis. We performed coagulation tests: plasma PAI-1 and PC levels were evaluated by chromogenic methods; and D-dimer was evaluated by immunoturbidimetric assay. Polymorphisms were performed using for polymerase chain reactions followed by digest with specific restriction enzyme. We acquired the APACHE and SOFA scores (time zero), sex, age, body mass index, associated co morbidities, length of ICU stay (days), the severity of sepsis (sepsis, severe sepsis or septic shock), the HIV status and the ICU outcome (survival or death). RESULTS: We found significant differences between patients who died (n=80) and those who survived (n=86) in terms of the ICU length of stay (6 vs. 10 days), septic shock (64 versus 24%), age (51 versus 38 years old), HIV+ condition (34 versus 16%), SOFA (7 versus 4), APACHE (19 versus 13), D-dimer (4.32 versus 2.88 mg/ml), PC (46.0 versus 63.5 %) and PAI-1 (33.0 versus 16.5 UA/l). When we used a regression analysis with dichotomized variables, only the SOFA4, PAI-116, HIV status and the PAI-1 4G allele proved to be predictors of death at time zero. CONCLUSIONS: In the future, ICU scores may be further improved by adding certain genomic or plasma data. PMID- 22842943 TI - Northward movement of East Central South African genotype of Chikungunya virus causing an epidemic between 2006-2010 in India. AB - INTRODUCTION: Re-emergence of chikungunya virus in South India after a gap of 32 years in 2006 affected over a million people in the Indian subcontinent. We kept a close vigil over the emerging trend of this virus between 2006-2010 with a view to establish the identity of the circulating genotype(s) and to determine the route of virus transmission in different parts of India. METHODOLOGY: Nucleotide sequencing of the E1 gene region from 36 strains of chikungunya virus from three states in northern India was performed for this present study. Forty-four previously reported E1 sequences, retrieved from the global genome data base were used for making a phylogenetic tree. RESULTS: BLAST search revealed 99% homology of the northern Indian strains of the 2006-2010 outbreak with the Reunion Island isolates of 2006. Northern Indian strains of this study clustered with the East Central South African (ECSA) genotype. CONCLUSIONS: Findings indicate that the currently circulating strain of chikungunya virus in northern India had its origin from the 2006 epidemic strain of South India that moved toward northern India via the western central India between 2006-2010 in a phased manner with dominance of the ECSA genotype and not the Asian genotype. PMID- 22842944 TI - Prevalence and antibiotic resistance of bacterial pathogens isolated from childhood diarrhoea in four provinces of Kenya. AB - INTRODUCTION: Diarrhoea is one of the main causes of morbidity and mortality among children in sub-Saharan Africa, and one of the main causes of hospital admissions in rural areas of Kenya. In Kenya, antimicrobial resistance surveillance has been conducted only at the institutional levels, with limited sharing of information and analysis of data. As a result, the actual scale of regional or national antimicrobial drug resistance is not well defined. METHODOLOGY: Stool samples were collected between 1 October 2007 and 30 September 2008 from a total of 651 outpatients with diarrhoea who were under five years of age in four provinces of Kenya. Conventional, biochemical methods, multiplex PCR and antimicrobial susceptibility were conducted to identify the bacterial causes and virulence factors in the isolates, respectively. RESULTS: Of the 651 patients screened, we identified the causes of 115 cases (17.7%) as follows: Pathogenic E. coli (11.2%) [enteroaggregative (8.9%), enterotoxigenic (1.2%), enteroinvasive (0.6%), shigatoxigenic (0.5%)], Salmonella (3.5%), Shigella (2%) and Vibrio cholera O1 (0.7%). The highest levels of resistance among the E. coli isolates were observed in ampicillin and trimethoprim/sulphamethoxazole each at 95% followed by tetracycline at 81%. Shigella isolate levels of resistance ranged from 80% to 100% for ampicillin, tetracycline and trimethoprim/sulphamethoxazole. CONCLUSION: The highest prevalence of antimicrobial resistance was to ampicillin followed by trimethoprim/sulphamethoxazole and tetracycline. Though still at low levels, the major concern from our findings is the emerging resistance of enteric pathogens that was observed to quinolones (ciprofloxacin, nalidixic acid, norfloxacin) and gentamycin. PMID- 22842945 TI - Left ventricle hydatid cyst mimicking acute coronary syndrome. AB - Cardiac echinococcosis rarely mimics acute coronary syndrome. The diagnosis of cardiac hydatid cyst might be difficult on account of varying clinical presentations and nonspesific symptoms. A 75-year-old female was admitted to our hospital with typical chest pain. The patient had no history of previous cardiac symptoms or any illness leading to heart disease. Her ECG revealed ischemic changes. However, her coronary angiography revealed noncritical plaques in the left anterior descending artery. The diagnosis of cardiac echinococcosis was identified using echocardiography, computed tomography and magnetic resonance imaging. The patient was referred to cardiac surgery for resection of the cyst; however, she refused surgery. Albendezol 800 mg/day was prescribed. PMID- 22842946 TI - Pasteurella (Mannheimia) haemolytica septicemia in an infant: a case report. AB - Septicemia due to Pasteurella (Mannheimia) haemolytica is a rare occurrence. We report a fatal case of M. haemolytica septicemia in a seven-month-old infant who presented with prolonged fever, sepsis, and pneumonitis without discernable preceding history of animal bites or contact. Rare cases of systemic Mannheimia infections are reviewed and summarized. PMID- 22842947 TI - Spontaneous bacterial peritonitis and pneumonia caused by Bordetella bronchiseptica. AB - Bordetella bronchiseptica is a rare cause of invasive human infection. The most common infection in humans is the respiratory tract infection and it is usually associated with immunosuppression, particularly acquired immunodeficiency syndrome (AIDS). We report a case of a pneumonia and peritonitis in a 42-year-old female with alcoholic liver disease. The patient died despite treatment with antibiotics. This case illustrates the potential virulence of B. bronchiseptica in susceptible patients and to our knowledge it is the first case of primary peritonitis due to this organism. PMID- 22842948 TI - Globicatella sanguinis meningitis in a post head trauma patient: first case report from Asia. AB - Globicatella sanguinis is a rare isolate in clinical samples. We present a case of meningitis in a 70-year-old male patient after a head injury operation. Three consecutive cerebrospinal fluid samples obtained from the patient identified Globicatella sanguinis based on morphology, biochemical profile, and Vitek-2 identification. The patient recovered after antibiotic treatment with vancomycin. This is the first case report of Globicatella sanguinis from Asia from a case of meningitis. PMID- 22842949 TI - Antimicrobial resistance of Vibrio cholerae O1 isolated during a cholera epidemic in 2011 in dry season in Cote d'Ivoire. PMID- 22842950 TI - Immunohistochemical study of Toll-like receptors 1 and 2 expression in cutaneous lichen planus lesions. AB - Lichen planus (LP) is a chronic inflammatory, T cell-mediated autoimmune skin disease. Innate immunity could explain the interplay between environmental triggers and the autoimmune cascade leading to disease development. Toll-like receptors (TLRs) are important components of the innate immune system, with no previous evaluation of TLRs 1 and 2 in cutaneous LP. This work aims to investigate TLRs 1 and 2 expression in cutaneous LP. This case-control study included 30 patients with LP and 15 healthy controls. Biopsies from the patients' lesional skin and from the controls' normal skin were examined immunohistochemically for TLR 1 and 2 expression. A significant re-localization was found in TLR1 expression with a higher percentage of basal and a significantly lower percentage of homogenous epidermal expression in patients (73.3 and 0 %, respectively) compared with controls (13.3 and 73.3 %, respectively) (P < 0.001). TLR2 showed a significantly higher percentage of epidermal expression (more in the upper spinous layer) and significantly lower percentage of epidermal but more basal expression in patients (66.6 and 10 %, respectively) compared with controls (0 and 73.3 %, respectively) (P < 0.001). The median (IQR) of TLR1 [1 (0.75-1)] and TLR2 [1 (1-1)] staining score in patients was significantly lower than that of the controls [2 (1-2) and 1 (1-2), respectively] (P < 0.05). This work thus shows a re-localization of TLR 1 and 2 expression sites with decreased grade of expression in LP lesions. Targeting TLR signaling is expected to be a novel treatment strategy for cutaneous LP. PMID- 22842951 TI - Axially coordinated chiral salen Mn(III) anchored onto azole onium modified ZnPS PVPA as effective catalysts for asymmetric epoxidation of unfunctionalized olefins. AB - A series of chiral salen Mn(III) immobilized onto azole onium modified zinc poly(styrene-phenylvinyl phosphonate)-phosphate (ZnPS-PVPA) were prepared. The catalysts were characterized by FT-IR, diffusion reflection UV-vis, AAS, N(2) volumetric adsorption, SEM, TEM, XPS, XRD, TG and elemental analysis. The results showed that the chiral salen Mn(III) complex was successfully immobilized onto ZnPS-PVPA. These prepared catalysts were evaluated in the asymmetric epoxidation of unfunctionalized olefins with m-CPBA and NaIO(4) as oxidants and demonstrated higher catalytic activities than those of the corresponding homogeneous chiral salen Mn(III) catalyst under the same conditions. Moreover, these heterogeneous catalysts were stable and could be recycled nine times without significant loss of activity. Furthermore, this novel type of catalyst could also be validly used in large-scale reactions with superior catalytic disposition being maintained at the same level, which indicated the potential for applications in industry. PMID- 22842952 TI - Comparison of the proportion of patients potentially treated with an anti osteoporotic drug using the current criteria of the Belgian national social security and the new suggested FRAX criteria. AB - To assess the number of anti-osteoporosis treatments that would be reimbursed by the Belgian social security if either FRAX or the current criteria were used to determine access to reimbursement. This is a retrospective study based on data from 1,000 women randomly selected from an outpatient hospital specialized in bone metabolism in Belgium. Proportions of potentially refunded treatments between FRAX and current criteria were compared. Out of the 1,000 women files, 890 have sufficient information to assess FRAX. In Belgium, current criteria include a bone mineral density (BMD) T score below -2.5 at the lumbar spine, the femoral neck or the total hip and/or at least a prevalent vertebral fracture. Using these criteria, 167 women (18.8 %) would have access to reimbursement. Using the criteria based on the validated Belgian FRAX tool, only 116 women (13.0 %) would have access to reimbursement, meaning that access to reimbursement based on FRAX criteria would reduce by 30 % the anti-osteoporosis drug expenses covered by the national social security. Interestingly, only 65 women out of the 116 (56.0 %) selected with the FRAX criteria were also selected with the current criteria of the national social security. A substantial proportion of individuals that would potentially receive a reimbursement for their treatment using the FRAX criteria do not have access to any refund for their treatment with the current criteria. Since patients identified with the FRAX tool are those with the highest risk profile for future fractures, reappraisals of treatment reimbursement guidelines are expected in Belgium. PMID- 22842953 TI - Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients. AB - The purpose of this study was to evaluate the short-term efficacy of topical capsaicin treatment in patients severely affected by fibromyalgia. One hundred and thirty fibromyalgia patients were randomly divided into two groups. The control group, 56 women and 4 men who continued their medical treatment, and the capsaicin group, 70 women who apart from continuing their medical treatment, also underwent topical capsaicin 0.075 % 3 times daily for 6 weeks. At the beginning of the program, there were no significant differences between the two groups in any of the analyzed parameters. At the end of the treatment, there were significant improvements in the capsaicin group in the myalgic score (5.21 vs 3.8, p = 0.02) and global subjective improvement (22.8 vs 5 %, p = 0.001). Six weeks after the end of the treatment, the experimental group showed significant differences in Visual Analogue Scale of depression (5.63 vs 7.35, p = 0.02), Fibromyalgia Impact Questionnaire (67.89 vs 77.7, p = 0.02), role limitations due to emotional problems (36.17 vs 17.2, p = 0.05), Fatigue Severity Scale (6.2 vs 6.6, p = 0.04), myalgic score (3.94 vs 2.66, p = 0.02) and pressure pain threshold (79.25 vs 56.71, p = 0.004). In conclusion, patients severely affected by fibromyalgia can obtain short-term improvements following topical capsaicin 0.075 % treatment three times daily for 6 weeks. PMID- 22842954 TI - Does anterior shoulder balance in adolescent idiopathic scoliosis correlate with posterior shoulder balance clinically and radiographically? AB - PURPOSE: Patients with adolescent idiopathic scoliosis (AIS) often present with a disfiguring shoulder imbalance. Shoulder balance (Sh.B) is of significant importance to the patient's self-perception. Previous studies have correlated Sh.B with respect to only the clinical posterior view correlated with radiographs. It is important, however, to address Sh.B with respect to anterior view of the patients' shoulders as if patients were viewing in a mirror. In this study, we evaluated the anterior Sh.B and correlated it with posterior Sh.B clinically and radiographically in Lenke type 1 and 2 curves. METHOD: An online scoliosis database was queried to identify 74 AIS patients with Lenke 1 (n = 55, age 15.28 +/- 3.35) and 2 (n = 19, age 15.66 +/- 3.72) curves with a complete set of PA radiographs and anterior and posterior photos. Radiographic measures for Sh.B included Cobb angles, T1 tilt, first rib angle, and clavicle-rib intersection angle. Clinical measures for Sh.B included inner shoulder angle, outer shoulder angle, and axillary fold angle. Regression analysis with Pearson's correlation and ANOVA for statistical significance was used for analysis. RESULTS: For Lenke 1 curves, there was moderate statistically significant correlation between anterior and posterior clinical Sh.B (R = 0.35-0.41). There was only weak to moderate correlation between radiographic and clinical measures. For Lenke 2 curves, there was a weak to moderate correlation between anterior and posterior clinical Sh.B (R = 0.25-0.45), though not statistically significant. There was no statistically significant correlation between any radiographic measures and posterior Sh.B. There was, however, moderate and significant correlation between radiographic measures and anterior Sh.B. CONCLUSION: There is no strong correlation between anterior and posterior clinical Sh.B, and surgeons should evaluate both sides in planning deformity correction, especially in Lenke 2 curves. None of the radiographic measures showed strong correlation (R > 0.8) with anterior or posterior clinical Sh.B. A stronger correlation existed between radiographic measures and anterior Sh.B measurements compared with posterior clinical Sh.B measurements in Lenke 2 curves further necessitating anterior evaluation in this group. PMID- 22842955 TI - Intervertebral disc cell- and hydrogel-supported and spontaneous intervertebral disc repair in nucleotomized sheep. AB - PURPOSE: Regenerative repair is a promising new approach in treating damaged intervertebral discs. An experimental scheme was established for autologous and/or allogenic repair after massive disc injury. METHODS: Disc healing was promoted in 11 animals by injecting in vitro expanded autologous/homologous disc cells 2 weeks after stab injury of lumbar discs L1-2. The following control discs were used in our sheep injury model: L2-3, vehicle only; L3-4, injury only; L4-5, undamaged; and lumbar discs from four non-experimental animals. Disc cells were suspended in a biologically supportive albumin/hyaluronan two-component hydrogel solution that polymerizes when inserted in order to anchor cells at the injection site. The parameters studied were MRI, DNA, glycosaminoglycan, collagen content, histology, immunohistology for collagens type I, II and aggrecan, and mRNA expression of GAPDH, beta-actin, collagen type I, II, X, aggrecan, lubricin, and IL-1beta. RESULTS: All parameters demonstrated almost complete healing of the injured discs after 6 months, when compared with data from both the endogenous non-injured controls as well as from the healthy animals. CONCLUSION: Sheep experience spontaneous recovery from disc injury. The process of endogenous repair can be enhanced by means of hydrogel-supported cells. PMID- 22842956 TI - Three- and four-level anterior cervical discectomy and fusion with a PEEK cage and plate construct. AB - INTRODUCTION: Three- or four-level anterior cervical discectomy and fusion with autograft and plate fixation have demonstrated relatively good fusion rates and outcomes, but donor site morbidity and the limitations of autograft harvest remain problematic. The purpose of this study is to assess the radiographic and clinical outcomes of three- or four-level anterior cervical discectomy and fusion with a PEEK cage and plate construct. METHODS: This retrospective review included 43 consecutive patients who underwent three- or four-level anterior cervical discectomy and fusion with a PEEK cage and plate construct (three level: 39 cases, four level: 4 cases). The fusion rate, time to fusion, Cobb angle and disc height were assessed radiographically. Clinical outcomes were evaluated with the VAS, NDI, and SF36 scores. Complications were also recorded. RESULTS: Solid fusion was achieved in all the patients, and mean time to fusion was 13.7 +/- 5.1 weeks. The postoperative Cobb angle, lordotic angle, and disc height (5.6 degrees , 10.5 degrees and 3.15 mm, respectively) increased significantly compared to preoperative values (p = 0.038, p = 0.032, and p = 0.0004, respectively), and these improvements were maintained through final follow-up. The postoperative NDI (17.2), VAS (2.8), and SF36 (13.1) scores increased significantly compared to the preoperative scores (p = 0.026, p = 0.0007 and p = 0.041, respectively). Complications included three cases of respiratory difficulty, four cases of dysphagia and one case of hoarseness. There were no cases of donor site morbidity. CONCLUSIONS: Three- or four-level anterior cervical discectomy and fusion with a PEEK cage, and plate construct provide good clinical and radiographic outcomes including high fusion rates, low complication rates, low donor site morbidity, and good maintenance of the lordotic angle and disc height in the treatment of multilevel cervical spondylosis. PMID- 22842957 TI - Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers. AB - PURPOSE: Nateglinide is commonly used in the treatment of patients with type 2 diabetes mellitus. Our objective was to assess the association between CYP2C9 and SLCO1B1 polymorphisms and the metabolism of nateglinide in healthy Chinese male volunteers. METHODS: A total of 35 healthy Chinese male volunteers with different CYP2C9 and SLCO1B1 genotypes were given a single oral dose of 120 mg nateglinide. Plasma concentrations of nateglinide and blood glucose level were measured up to 8 h. RESULTS: In subjects with the CYP2C9*1/*3 & 521TT, CYP2C9*1/*1 & 521TC/CC and CYP2C9*1/*3 & 521TC genotype, AUC(0-infinity) of nateglinide was 56 %, 34 % and 56 % higher (P = 0.002, P = 0.041 and P = 0.013, respectively), and the CL/F of nateglinide was 35 %, 11 % and 36 % lower (P = 0.000, P = 0.003 and P = 0.002, respectively) than that in the reference group. When only considering 521 T>C polymorphism, it had no significant association with the pharmacokinetics of nateglinide. CYP2C9*3 and 521 T>C polymorphisms were the significant predictors of the AUC(0-infinity) and CL/F of nateglinide (adjusted multiple R(2) = 34 % and 43 %, respectively) according to multiple linear regression analyses, but they have no significant association with changes in the blood glucose-lowering effect of nateglinide. CONCLUSIONS: Both SLCO1B1 521 T>C and the CYP2C9*3 polymorphisms can significantly affect the pharmacokinetics of nateglinide, but they could only partially explain the interindividual variability of plasma concentration of nateglinide. Moreover, 521 T>C and the CYP2C9*3 polymorphisms have no effect on pharmacodynamics of nateglinide in healthy Chinese male subjects. PMID- 22842958 TI - Functional expression of trypsin from Streptomyces griseus by Pichia pastoris. AB - In the present study, the genes encoding trypsinogen and active trypsin from Streptomyces griseus were both cloned and expressed in the methylotrophic yeast Pichia pastoris with the alpha-factor secretion signal under the control of the alcohol oxidase promoter. The mature trypsin was successfully accumulated extracellularly in soluble form with a maximum amidase activity of 6.6 U ml(-1) (batch cultivation with flask cultivation) or 14.4 U ml(-1) (fed-batch cultivation with a 3-l fermentor). In contrast, the recombinant trypsinogen formed inclusion bodies and no activity was detected. Replacement of the trypsin propeptide Ala-Pro-Asn-Pro confirmed that its physiological function was as a repressor of activity. More importantly, our results proved that the propeptide inhibited the activity of trypsinogen after its successful folding. PMID- 22842959 TI - Red Liriope platyphylla contains a large amount of polyphenolic compounds which stimulate insulin secretion and suppress fatty liver formation through the regulation of fatty acid oxidation in OLETF rats. AB - Red Liriope platyphylla (RLP) manufactured by two repeated steps (steaming and drying) stimulates the insulin secretion ability and glucose receptor signaling pathway in an animal model for type I diabetes. This study examined the levels of glucose and lipid metabolism-related factors in a useful animal model for type II diabetes with obesity following RLP treatment for 3 weeks to determine if RLP treatment affects the glucose concentration, insulin secretion and fatty acid oxidation. The following results were obtained: i) RLP contained a large amount of polyphenolic compounds; ii) insulin secretion was induced in RLP-treated OLETF rats, although there were no significant differences in body weight, glucose tolerance test and glucose concentration; iii) the RLP-treated OLETF rats showed a significant increase in adiponectin concentration but the concentration of triglyceride and LDL decreased compared to the vehicle-treated rats; iv) although the abdominal fat mass and adipocyte size did not change with RLP treatment, expression of the adipocyte marker genes and beta-oxidation genes in fat tissue was recovered to the level of the LETO rats; v) fatty liver formation was reduced dramatically in the liver of the RLP-treated group compared to the vehicle treated group; vi) the expression of adipocyte marker genes and the beta oxidation gene in the liver tissue were generally similar to those of the abdominal fat but PPAR-gamma showed a reverse pattern in the RLP- and vehicle treated OLETF rats. These results suggest that RLP may stimulate insulin secretion and a decrease in lipid in serum, and may also suppress fatty liver formation through the regulation of fatty acid oxidation. The data presented here highlight the possibility that RLP can be considered a candidate for the prevention or alleviation of obesity-related diseases. PMID- 22842960 TI - What's in a name? PMID- 22842961 TI - Enhancing care of older adults in the emergency department. AB - The findings from a recent comprehensive systematic review, in combination with a case study, are used to illustrate the importance of translational research to inform advanced practice nursing. The review article discussed in this column is a comprehensive systematic review of age-friendly nursing interventions in the management of older persons in the emergency department (ED). Two themes were synthesized from the research and texts: (1) the ED can be a foreign and challenging environment for older patients, and (2) older ED patients need specialized care to meet their complex physical and psychosocial needs. At the same time, these authors acknowledged that much more high-quality research is needed in this field. Comments by a certified geriatric nurse practitioner elaborate on these findings and provide practical suggestions for the ED advanced practice registered nurse. PMID- 22842962 TI - A case of postablation tubal sterilization syndrome. AB - Postablation tubal sterilization syndrome (PATSS) is a cause of severe, cyclic lower abdominal pain in women. There is scant literature available on PATSS for the emergency provider. Most of the evidence that exists on PATSS is presented in case report formats. A patient with PATSS is presented in this article. The purpose of this article is to increase awareness of PATSS as a diagnosis after acute abdominal processes have been excluded and to prevent recurrent emergency department visits. Early diagnosis of PATSS will prompt the emergency department provider to initiate gynecological referral necessary for definitive treatment. PMID- 22842963 TI - Management of diabetic ketoacidosis. AB - Diabetes, a chronic medical condition, continues to increase in prevalence. One of the most severe complications of diabetes, diabetic ketoacidosis (DKA), results from insulin deficiency and is a medical emergency that is frequently encountered in the emergency department. Prompt diagnosis, assessment of key laboratory values, appropriate treatment, and close monitoring are important to the successful treatment of this complex metabolic disorder. Fluid repletion and insulin administration are mainstays of DKA treatment and serve to restore normal hemodynamic status while decreasing the metabolic acidosis. Careful monitoring of glucose concentrations, vital signs, and electrolytes is essential to prevent complications arising from the treatment of DKA. This article provides an overview of the pathophysiology, presentation, diagnosis, treatment, monitoring, and complications of DKA. PMID- 22842964 TI - Acute aortic emergencies--part 1: aortic aneurysms. AB - This article is a 2-part series about patients with aortic emergencies. Patients with acute aortic disease who present to the emergency department represent some of the highest acuity patients that emergency clinicians will ever encounter in acute care settings. Part 1 focuses on aortic aneurysms in the thorax or abdomen. An aortic aneurysm involves transverse dilatation, leading to rupture and hemorrhage. Diagnosis is largely based on clinical presentation and carefully selected imaging studies. Emergency interventions are guided by whether or not the patient is hypertensive or in shock. For patients in shock, attention should focus on restoring intravascular volume while not generating excessive blood pressure. Open surgical intervention or endovascularly placed stent grafting should then be expedited. Both options are not without complications, most commonly being stroke, paraplegia, and death. Part 2 will explore aortic dissection. PMID- 22842966 TI - Rural teletrauma: applications, opportunities, and challenges. AB - Conditions favoring telemedicine in rural acute trauma care are increasingly outnumbering barriers against it. This article is a review of current considerations in teletrauma, with examples from an established rural system. PMID- 22842967 TI - Development of a bariatric patient readiness assessment tool for the emergency department. AB - Morbidly obese patients present safe patient handling challenges to emergency department (ED) personnel. Emergency departments are often ill-equipped to safely manage the patient of this size. The purpose of this study was to develop an assessment tool to determine ED readiness to safely manage the morbidly obese patient. Published guidelines by the Facility Guidelines Institute and the National Association of Bariatric Nurses were used for tool development. The tool assesses policy, equipment, space/structural requirements, and patient handling and -moving tasks. A 2-phase, nonexperimental, exploratory study in a convenience sample of 5 EDs was conducted, applying a usability testing model to determine the usability and utility of the tool. Four of 5 hospital EDs agreed that the tool was easy to use and helpful in determining their readiness to safely manage the morbidly obese patient. The tool was found to be usable on a limited basis. Additional application of the tool on a larger scale is recommended. PMID- 22842968 TI - The element of naturalness when evaluating image quality of digital photo documentation after sexual assault. AB - Digital photography is a valuable adjunct to document physical injuries after sexual assault. In order for a digital photograph to have high image quality, there must exist a high level of naturalness. Digital photo documentation has varying degrees of naturalness; however, for a photograph to be natural, specific technical elements for the viewer must be satisfied. No tool was available to rate the naturalness of digital photo documentation of female genital injuries after sexual assault. The Photo Documentation Image Quality Scoring System (PDIQSS) tool was developed to rate technical elements for naturalness. Using this tool, experts evaluated randomly selected digital photographs of female genital injuries captured following sexual assault. Naturalness of female genital injuries following sexual assault was demonstrated when measured in all dimensions. PMID- 22842969 TI - The role of procalcitonin in community-acquired pneumonia: a literature review. AB - Community-acquired pneumonia (CAP) is a significant clinical and public health problem. Recently, attention has been paid to the potential for procalcitonin (PCT) both to differentiate the diagnosis and to indicate the prognosis of pneumonia. The purpose of this literature review was to evaluate the eligibility of PCT for defining typical bacterial infections and for predicting severity and mortality in trials for CAP. The literature review suggests that PCT has the ability to supplement clinical information to determine whether or not the cause of the infection is likely to be bacterial. In addition, PCT seems to be superior to the most prevalent inflammatory biomarker C-reactive protein and also demonstrates a significant correlation between the current clinical scoring systems and actual mortality. PMID- 22842970 TI - Relationship between musculoskeletal disorders, job demands, and burnout among emergency nurses. AB - Musculoskeletal disorders (MSDs) represent one of the most common occupational problems in nursing. MSDs can negatively impact one's quality of life. The aim of the study was to investigate the relationship between MSDs, job demands, and burnout among emergency nurses. The researchers hypothesized that increased job demands were associated with more MSDs and consequently higher levels of burnout. The study was conducted on a convenience sample of 58 nurses working in the emergency departments of Zagazig University Hospital and Al-Ahrar, Hospital Egypt from October to December 2010, using a cross-sectional analytic design. Data were collected using a self-administered questionnaire that included the Standardized Nordic Questionnaire, the Job Content Questionnaire, and the Maslach Burnout Inventory. The results revealed that 32.8% of the nurses were overweight and 17.2% were obese. The most common sites of pain were the neck (67.2%), shoulder (65.5%), and lower back (63.8%). Lower back pain was the most common site affected (72.4%) with a mean 5.1 on a scale ranging from 0 to 13. A positive correlation existed between the scores of job demand and burnout (r = 0.340, p < 0.01), and the number of reported MSDs with the score of job demand (r = 0.33, p < 0.05). Multiple linear stepwise regression analysis identified the score of job demand and the severity of lower back pain as positive independent predictors of the burnout whereas the job demand score was the independent predictor of the number of MSDs. This study documents an increased prevalence of MSDs among emergency nurses, as predicted by increased job demand and associated with a higher level of burnout. Hence, it is important for hospital and nursing administrators to address the factors contributing to job stress and burnout, with emphasis on job satisfaction and work organization to alleviate the burden of psychosocial factors in this setting. PMID- 22842971 TI - Porous vanadium-doped titania with active hydrogen: a renewable reductant for chemoselective hydrogenation of nitroarenes under ambient conditions. AB - A vanadium-doped porous titania rich in active hydrogen (V-TiO(2)(H*)) has been successfully prepared and demonstrated to be an efficient and green reductant with renewable capacity. This V-TiO(2)(H*) material can instantly (<10 s) and selectively reduce nitroarenes to aminoarenes under ambient conditions without catalysts. PMID- 22842972 TI - Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion. AB - Tumor metastasis is the main cause of cancer-related deaths of patients. Breast cancer is highly malignant with considerable metastatic potential, which urges the necessity for developing novel potential drug candidate to prevent tumor metastasis. Here, we report our finding with Cucurbitacin E (CuE, alpha elaterin), a tetracyclic triterpenes compound isolated from Cucurbitaceae. The potency of CuE on breast cancer metastasis inhibition was assessed in vivo and in vitro. In our animal experiments, intraperitoneal administrations of CuE significantly inhibited breast tumor metastasis to the lung without affecting apoptosis or proliferation of inoculated 4T1 and MDA-MB-231 breast cancer cells. Treatment of metastatic breast tumor cells with CuE markedly blocked tumor cell migration and invasion in vitro. Subsequent studies showed that CuE impaired Arp2/3-dependent actin polymerization and suppressed Src/FAK/Rac1/MMP involved pathway. Overall, our data demonstrate that CuE blocks breast cancer metastasis by suppressing tumor cell migration and invasion. We provide first evidence of a novel role for CuE as a potential candidate for treating breast cancer metastasis. PMID- 22842974 TI - Differences in clinical profile of individuals with severe and markedly elevated coronary artery calcification detected by electron beam computed tomography. AB - Although several studies have demonstrated the association between coronary artery calcification (CAC) and coronary artery disease events, the underlying mechanism has not been fully elucidated. Furthermore, extensive CAC still remains a poorly understood phenomenon. The objective of this study is to determine the clinical characteristics and differences between 831 asymptomatic individuals with very high CAC scores (CACS >= 1000) and 497 asymptomatic individuals with CAC scores of 400 to 999. Individuals with CACS >= 1000 were more likely to have hypertension ([HTN]; P = .0004), hypercholesterolemia (P = .0001), diabetes mellitus ([DM] P = .005), and high body mass index ([BMI]; P = .03) compared with individuals with CACS = 400-999. On multivariable analysis, age (P < .0001) and BMI (P = .01) were found to be significant risk factors for the presence of very high CAC. While for males, age (P < .0001), hypercholesterolemia (P = .001), DM (P = .002), and obesity (P = .003) were independent risk factors; in females only HTN (P = .04) was independent risk factor. PMID- 22842973 TI - Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis. AB - Collagen IV comprises the predominant protein network of basement membranes, a specialized extracellular matrix, which underlie epithelia and endothelia. These networks assemble through oligomerization and covalent crosslinking to endow mechanical strength and shape cell behavior through interactions with cell surface receptors. A recently discovered sulfilimine (S=N) bond between a methionine sulfur and hydroxylysine nitrogen reinforces the collagen IV network. We demonstrate that peroxidasin, an enzyme found in basement membranes, catalyzes formation of the sulfilimine bond. Drosophila peroxidasin mutants have disorganized collagen IV networks and torn visceral muscle basement membranes, pointing to a critical role for the enzyme in tissue biogenesis. Peroxidasin generates hypohalous acids as reaction intermediates, suggesting a paradoxically anabolic role for these usually destructive oxidants. This work highlights sulfilimine bond formation as what is to our knowledge the first known physiologic function for peroxidasin, a role for hypohalous oxidants in tissue biogenesis, and a possible role for peroxidasin in inflammatory diseases. PMID- 22842977 TI - Lanthanide-ion-tuned magnetic properties in a series of three-dimensional cyano bridged Ln(III)W(V) assemblies. AB - The reaction of [W(CN)(8)](3-) with Ln(3+) and pyrazine in acetonitrile yielded a series of isostructural compounds formulated as Ln(H(2)O)(4)(pyrazine)(0.5)W(CN)(8) (Ln = La(1), Ce(2), Pr(3), Nd(4), Sm(5), Eu(6), Gd(7)). The Ln(III) and W(V) centers in the structure are linked through cyanide groups to form two-dimensional (2D) layers, which are further pillared by pyrazine, generating 3D frameworks. The magnetic behavior for compounds 1-7 were driven by the lanthanide ions involved. The Ln(III) and W(V) ions in compounds 2 and 5 are ferromagnetically coupled with magnetic ordering occurring at 2.8 K, comparable with magnetic ordering with the critical temperature of 1.9 K for compound 4. In addition, the antiferromagnetic interactions were observed in compounds 3 and 7, while no significant magnetic couplings were found in compounds 1 and 6. PMID- 22842978 TI - Modic type I changes and recovery of back pain after lumbar microdiscectomy. AB - PURPOSE: To investigate whether the presence of Modic changes type I (MC I) found on preoperative MRI scans represent a risk factor for persistent back pain 12 months after surgery amongst patients operated for lumbar disc herniation. METHODS: Cohort study of 178 consecutive patients operated with lumbar microdiscectomy. Preoperative MRI scans were evaluated by two independent neuroradiologists. Primary outcome measure was the visual analogue scale (VAS) for back pain. Secondary outcome measures were; VAS for leg pain, physical function (Oswestry disability index), and health-related quality of life (EQ-5D), self-reported benefit of the operation and employment status. The presence of MC I was used as exposition variable and adjusted for other risk factors in multivariate analyses. RESULTS: The Modic classification showed a high inter observer reproducibility. Patients with MC I had less improvement of back pain 12 months after surgery, compared to those who had no or other types of MC, but this negative association no longer showed statistical significance when adjusted for smoking, which remained the only independent risk factor for persistent back pain. CONCLUSIONS: Patients with preoperative MC I can expect less but still significant improvement of back pain 1 year after microdiscectomy, but not if they smoke cigarettes. PMID- 22842979 TI - Targeting alphaV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model. AB - Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-alpha(V) integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into four groups: (1) control; (2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; (3) intetumumab intravenously 4 h before and weekly after cell infusion; (4) intetumumab intravenously weekly starting 7 days after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett's test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median = 14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median = 2, p = 0.0055), including 30 % of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ vs. 52 days, p = 0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment. PMID- 22842980 TI - Perception, knowledge, and use by general practitioners of Belgium of a new WHO tool (FRAX) to assess the 10-year probability of fracture. AB - The FRAX tool that calculates the 10-year probability of having a fracture has recently been validated for Belgium. Little is known about the perception and knowledge that GPs have about this tool in their daily practice. A survey has been conducted as part of a screening campaign for various diseases. The primary objective of the present study was to assess the perception and the knowledge of the FRAX tool by GPs. The secondary objective was to assess the impact of an information brochure about the FRAX tool on these outcomes. The survey was sent to a sample of 700 GPs after only half of them had received the information brochure. The survey results show that, out of the 193 doctors who responded to the survey, one-third know the FRAX tool but less than 20 % use it in their daily clinical practice. Among those who use it, the FRAX tool is largely seen as a complementary but not as an essential tool in the diagnosis or in the management of osteoporosis. It appears that the brochure could improve the knowledge of the FRAX tool but it would not be more efficient on its use in daily practice than the other sources of information. At present, the use of the FRAX tool in Belgium is limited but an information brochure could have a positive impact on the knowledge of the FRAX tool. PMID- 22842981 TI - Brucellar spondylodiscitis: comparison of patients with and without abscesses. AB - Brucellosis is an important cause of spondylodiscitis in endemic areas. Brucellar spondylodiscitis is a serious complication because of its association with abscess formation. Prospective studies comparing patients with and without abscesses are lacking. The objective of this study was to determine the frequency and demographic, clinical, laboratory, and radiological features of brucellar spondylodiscitis and to compare patients with and without abscesses regarding treatment and outcome. Out of 135 consecutive patients with brucellosis, 31 patients with spondylodiscitis were recruited for the study. Patients were grouped according to magnetic resonance imaging findings. The frequency of spondylodiscitis was 23.0 %. Sites of involvement were lumbar (58.1 %), lumbosacral (22.6 %), cervical (9.7 %), thoracolumbar (6.5 %), and thoracic (3.2 %). Abscesses occurred in 19 (61.3 %) patients and were associated with low hemoglobin levels. Medical treatment included a combination of streptomycin (for the first 3 weeks), doxycycline, and rifampin. The total duration of treatment was 12-39 (mean 17.0 +/- 8.5 SD) weeks. By 12 weeks of treatment, evidence of clinical improvement (67 vs. 28 %) and radiological regression (92 vs. 50 %) was significantly greater in patients without abscesses. The duration of treatment was longer if an abscess was present. Two female patients with abscesses required surgical intervention. Both patients presented with high fever, neurologic deficit, and high Brucella standard tube agglutination test titers. Each patient should be evaluated individually, based on clinical findings, laboratory data, and radiological results, when undergoing treatment for brucellar spondylodiscitis. If abscesses are found, a longer course of treatment and even surgical intervention may be needed. PMID- 22842982 TI - Peritumoral FOXP3+ regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3+ regulatory T cell is prognostic predictor of breast cancer patients. AB - It has been reported that the prognostic significances of tumor-infiltrating FOXP3(+) regulatory T cells (Tregs) in breast carcinoma depend on their relative density and tissue locations. We here assessed the changes of Tregs before and after neoadjuvant chemotherapy (NC) and their relationships with tumor response and patient survival. Intratumoral and peritumoral infiltration of FOXP3(+) Tregs were evaluated by immunohistochemistry in 132 cases of invasive breast carcinomas before and after NC. After NC, the density of infiltrated Tregs within tumor bed remained stable, whereas it decreased significantly (P = 0.015) in the tissue surrounding tumor. The changes were significant in those tumors that usually response to NC, including the HER2-enriched and basal-like subtypes (P = 0.035; P = 0.004). Univariate and multivariate analyses identified the decreased peritumoral Tregs were an independent predictor for pathologic complete response (pCR), while the intratumoral Tregs after chemotherapy was proved to be associated with overall survival and progression-free survival of the patients. The findings of the study indicated that peritumoral Treg was sensitive to chemotherapy and associated with pCR, while intratumoral Treg was an independent prognostic predictor of breast cancer patients. PMID- 22842984 TI - Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A. AB - The randomized phase III trial TARGIT A showed non-inferiority regarding local control after intraoperative radiotherapy (IORT 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only) in comparison to standard WBRT (50-56 Gy) after breast-conserving surgery in selected patients. This is the first analysis of long-term toxicities in the setting of TARGIT. Between 02/2002 and 12/2008, 305 patients were treated within TARGIT A (Arm A: n = 34 IORT, n = 20 IORT + WBRT for risk factors; Arm B WBRT: n = 55) or received IORT as a planned boost (control group: n = 196) at a single center. Toxicity was assessed according to the LENT SOMA scales. No significant differences were seen between Arm A and Arm B regarding fibrosis, breast edema, retraction, ulceration, lymphedema, hyperpigmentation, and pain. Arm A had significantly less telangiectases compared to Arm B (p = 0.049). In the subanalysis (Arm A IORT vs. Arm A IORT + WBRT vs. Arm B), fibrosis had a cumulative rate of 5.9 versus 37.5 versus 18.4 %, respectively (38.2 % IORT boost control group), at 3 years. No telangiectases were seen after IORT alone (0 % Arm A IORT vs. 17.5 % Arm A IORT + WBRT vs. 17.7 % Arm B). The hazard ratio of higher grade toxicity as first event was 0.46 (95 % CI, 0.26-0.83) for Arm A IORT as compared to Arm B (p = 0.010). No recurrences were seen after a median follow-up of 40 months (Arm A) and 42 months (Arm B). With its very low chronic skin toxicity rates and outstanding long-term results regarding toxicity and local control, IORT with 50 kV X-rays is a safe and effective method for treatment of selected breast cancer patients. PMID- 22842983 TI - Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression. AB - Mammalian target of rapamycin (mTOR) is an attractive target for cancer treatment. While rapamycin and its derivatives (e.g., everolimus) have been shown to inhibit mTOR signaling and cell proliferation in preclinical models of breast cancer, mTOR inhibition has demonstrated variable clinical efficacy with a trend toward better responses in estrogen receptor alpha positive (ERalpha+) compared to ERalpha negative (ERalpha-) tumors. Recently, serum- and glucocorticoid regulated kinase 1 (SGK1) was identified as a substrate of mTOR kinase activity. Previous studies have alternatively suggested that either mTORC1 or mTORC2 is exclusively required for SGK1's Ser422 phosphorylation and activation in breast cancer cells. We investigated the effect of rapamycin on the growth of several ERalpha+ and ERalpha- breast cancer cell lines and examined differences in the phosphorylation of mTOR substrates (SGK1, p70S6K, and Akt) that might account for the differing sensitivity of these cell lines to rapamycin. We also examined which mTOR complex contributes to SGK1-Ser422 phosphorylation in ERalpha+ versus ERalpha- breast cell lines. We then assessed whether inhibiting SGK1 activity added to rapamycin-mediated cell growth inhibition by either using the SGK1 inhibitor GSK650394A or expressing an SGK1 shRNA. We observed sensitivity to rapamycin-mediated growth inhibition and inactivation of insulin-mediated SGK1 Ser422 phosphorylation in ERalpha+ MCF-7 and T47D cells, but not in ERalpha- MDA MB-231 or MCF10A-Myc cells. In addition, either depleting SGK1 with shRNA or inhibiting SGK1 with GSK650394A preferentially sensitized MDA-MB-231 cells to rapamycin. Finally, we found that rapamycin-sensitive SGK1-Ser422 phosphorylation required ERalpha expression in MCF-7 derived cell lines. Therefore, targeting SGK1 activity may improve the efficacy of rapamycin and its analogs in the treatment of ERalpha- breast cancer. PMID- 22842986 TI - The consequences of Lactobacillus vini and Dekkera bruxellensis as contaminants of the sugarcane-based ethanol fermentation. AB - This work describes the effects of the presence of the yeast Dekkera bruxellensis and the bacterium Lactobacillus vini on the industrial production of ethanol from sugarcane fermentation. Both contaminants were quantified in industrial samples, and their presence was correlated to a decrease in ethanol concentration and accumulation of sugar. Then, laboratory mixed-cell fermentations were carried out to evaluate the effects of these presumed contaminants on the viability of Saccharomyces cerevisiae and the overall ethanol yield. The results showed that high residual sugar seemed the most significant factor arising from the presence of D. bruxellensis in the industrial process when compared to pure S. cerevisiae cultures. Moreover, when L. vini was added to S. cerevisiae cultures it did not appear to affect the yeast cells by any kind of antagonistic effect under stable fermentations. In addition, when L. vini was added to D. bruxellensis cultures, it showed signs of being able to stimulate the fermentative activity of the yeast cells in a way that led to an increase in the ethanol yield. PMID- 22842985 TI - Molecular characteristics and prognostic features of breast cancer in Nigerian compared with UK women. AB - Although breast cancer (BC) incidence is lower in African-American women compared with White-American, in African countries such as Nigeria, BC is a common disease. Nigerian women have a higher risk for early-onset, with a high mortality rate from BC, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours are different to those of western women. In this study, 308 BC samples from Nigerian women with complete clinical history and tumour characteristics were included and compared with a large series of BC from the UK as a control group. Immunoprofile of these tumours was characterised using a panel of 11 biomarkers of known relevance to BC. The immunoprofile and patients' outcome were compared with tumour grade-matched UK control group. Nigerian women presenting with BC were more frequently premenopausal, and their tumours were characterised by large primary tumour size, high tumour grade, advanced lymph node stage, and a higher rate of vascular invasion compared with UK women. In the grade-matched groups, Nigerian BC showed over representation of triple-negative and basal phenotypes and BRCA1 deficiency BC compared with UK women, but no difference was found regarding HER2 expression between the two series. Nigerian women showed significantly poorer outcome after development of BC compared with UK women. This study demonstrates that there are possible genetic and molecular differences between an indigenous Black population and a UK based series. The basal-like, triple negative and BRCA1 dysfunction groups of tumours identified in this study may have implications in the development of screening programs and therapies for African patients and families that are likely to have a BRCA1 dysfunction, basal like and triple negative. PMID- 22842987 TI - Effect of growth media on cell envelope composition and nitrile hydratase stability in Rhodococcus rhodochrous strain DAP 96253. AB - Rhodococcus is an important industrial microorganism that possesses diverse metabolic capabilities; it also has a cell envelope, composed of an outer layer of mycolic acids and glycolipids. Selected Rhodococcus species when induced are capable of transforming nitriles to the corresponding amide by the enzyme nitrile hydratase (NHase), and subsequently to the corresponding acid via an amidase. This nitrile biochemistry has generated interest in using the rhodococci as biocatalysts. It was hypothesized that altering sugars in the growth medium might impact cell envelope components and have effects on NHase. When the primary carbon source in growth media was changed from glucose to fructose, maltose, or maltodextrin, the NHase activity increased. Cells grown in the presence of maltose and maltodextrin showed the highest activities against propionitrile, 197 and 202 units/mg cdw, respectively. Stability of NHase was also affected as cells grown in the presence of maltose and maltodextrin retained more NHase activity at 55 degrees C (45 and 23 %, respectively) than cells grown in the presence of glucose or fructose (19 and 10 %, respectively). Supplementation of trehalose in the growth media resulted in increased NHase stability at 55 degrees C, as cells grown in the presence of glucose retained 40 % NHase activity as opposed to 19 % without the presence of trehalose. Changes in cell envelope components, such mycolic acids and glycolipids, were evaluated by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC), respectively. Changing sugars and the addition of inducing components for NHase, such as cobalt and urea in growth media, resulted in changes in mycolic acid profiles. Mycolic acid content increased 5 times when cobalt and urea were added to media with glucose. Glycolipids levels were also affected by the changes in sugars and addition of inducing components. This research demonstrates that carbohydrate selection impacts NHase activity and stability. Cell envelope components such as mycolic acids are also influenced by sugars and inducers such as cobalt and urea. This is information that can be useful when implementing rhodococcal catalysts in industrial applications. PMID- 22842989 TI - Paramagnetic aluminium beta-diketiminate. AB - The beta-diketiminate ligand framework is shown to undergo reduction to form a neutral main group radical stabilized by spiroconjugation of the unpaired electron over the group 13 element centre. The synthesized paramagnetic complex was characterized by EPR spectroscopy and computational chemistry. PMID- 22842988 TI - Production of a hybrid 16-membered macrolide antibiotic by genetic engineering of Micromonospora sp. TPMA0041. AB - Some polyketide-derived bioactive compounds contain sugars attached to the aglycone core, and these sugars often enhance or impart specific biological activity to the molecule. Mycinamicin II, a 16-member macrolide antibiotic produced by Micromonospora griseorubida A11725, contains a branched lactone and two different deoxyhexose sugars, D-desosamine and D-mycinose, at the C-5 and C 21 positions, respectively. We previously engineered an expression plasmid pSETmycinose containing the D-mycinose biosynthesis genes from M. griseorubida A11725. This plasmid was introduced into Micromonospora sp. FERM BP-1076 cells, which produce the 16-membered macrolide antibiotic izenamicin. The resulting engineered strain TPMA0041 produced 23-O-mycinosyl-20-deoxy-izenamicin B(1) and 22-O-mycinosyl-izenamicin B(2). 23-O-mycinosyl-20-deoxy-izenamicin B(1) has been produced by the engineered strain M. rosaria TPMA0001 containing pSETmycinose as 23-O-mycinosyl-20-deoxo-20-dihydro-12,13-deepoxyrosamicin (=IZI) in our recent study, and 22-O-mycinosyl-izenamicin B(2) has previously been synthesized as a macrolide antibiotic TMC-016 with strong antibacterial activity. The production of 22-O-mycinosyl-izenamicin B(2) (=TMC-016) was increased when propionate, a precursor of methylmalonyl-CoA, was added to the culture broth. PMID- 22842990 TI - Methods for assessing cardiovascular disease risk in a UK black population. AB - OBJECTIVE: To assess differences between cardiovascular disease (CVD) risk estimation methods when applied to a black UK population. DESIGN: Cross-sectional study. SETTING: 51 GP practices in Lambeth, south-east London. PATIENTS: 26,370 black and 52,288 white registered patients aged 40-74 years. MAIN OUTCOME MEASURES: 10-year CVD risk score estimates derived using Framingham, QRISK2, ASSIGN and ETHRISK algorithms. kappa measures of agreement between risk scores and age-adjusted black/white mean risk ratios (RR) derived for each score. RESULTS: There was a moderate agreement between the various risk scores for the black population (pooled kappa 0.59 (95% CI 0.57 to 0.61) for men and 0.42 (95% CI 0.39 to 0.46) for women). For the white population, agreement was significantly improved (pooled kappa 0.74 (95% CI 0.73 to 0.76) for men and 0.51 (95% CI 0.49 to 0.54) for women). Except for QRISK2, each method consistently overpredicted the CVD risk for the black population in comparison with national (Health Survey for England) prevalence figures. QRISK2 estimates were the least divergent from national data, giving a black/white mean RR of 0.73 (95% CI 0.71 to 0.74) for men and 0.85 (95% CI 0.83 to 0.87) for women. CONCLUSIONS: The choice of risk estimation method does make a difference to estimates of CVD risk for black patients. The QRISK2 method, which incorporates ethnicity as a risk factor, appears to have the best fit with national data for this population. PMID- 22842991 TI - Scientific letter: Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: implications for pathogenesis and prevention of pericardial constriction. PMID- 22842992 TI - STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (review). AB - Signal transducer and activator of transcription 3 (STAT3) regulates many critical functions in human normal and malignant tissues, such as differentiation, proliferation, survival, angiogenesis and immune function. Constitutive activation of STAT3 is implicated in a wide range of human cancers. As such, STAT3 has been studied as a tumour therapeutic target. This review aimed principally to summarise the updated research on STAT3 inhibition studies and their therapeutic potential in solid tumours. Recent literature associated with STAT3 inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis. Constitutive activation of STAT3 has been identified as abnormal and oncogenic. The pathway of STAT3 activation and signal transduction identifies 3 approaches for inhibition: modulating upstream positive or negative regulators, regulating RNA (DN-STAT3, anti-sense RNA, siRNA and microRNA) or targeting STAT3 protein at different domains. The last approach using small molecule STAT3 inhibitors has been the most examined so far with both preclinical and clinical studies. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact. PMID- 22842993 TI - Underestimation of HIV prevalence in surveys when some people already know their status, and ways to reduce the bias. AB - OBJECTIVE: To quantify refusal bias due to prior HIV testing, and its effect on HIV prevalence estimates, in general-population surveys. DESIGN: Four annual, cross-sectional, house-to-house HIV serosurveys conducted during 2006-2010 within a demographic surveillance population of 33 000 in northern Malawi. METHODS: The effect of prior knowledge of HIV status on test acceptance in subsequent surveys was analysed. HIV prevalence was then estimated using ten adjustment methods, including age-standardization; multiple imputation of missing data; a conditional probability equations approach incorporating refusal bias; using longitudinal data on previous and subsequent HIV results; including self-reported HIV status; and including linked antiretroviral therapy clinic data. RESULTS: HIV test acceptance was 55-65% in each serosurvey. By 2009/2010 79% of men and 85% of women had tested at least once. Known HIV-positive individuals were more likely to be absent, and refuse interviewing and testing. Using longitudinal data, and adjusting for refusal bias, the best estimate of HIV prevalence was 7% in men and 9% in women in 2008/2009. Estimates using multiple imputations were 4.8 and 6.4%, respectively. Using the conditional probability approach gave good estimates using the refusal risk ratio of HIV-positive to HIV-negative individuals observed in this study, but not when using the only previously published estimate of this ratio, even though this was also from Malawi. CONCLUSION: As the proportion of the population who know their HIV-status increases, survey-based prevalence estimates become increasingly biased. As an adjustment method for cross-sectional data remains elusive, sources of data with high coverage, such as antenatal clinics surveillance, remain important. PMID- 22842996 TI - Heterogeneous data fusion for brain tumor classification. AB - Current research in biomedical informatics involves analysis of multiple heterogeneous data sets. This includes patient demographics, clinical and pathology data, treatment history, patient outcomes as well as gene expression, DNA sequences and other information sources such as gene ontology. Analysis of these data sets could lead to better disease diagnosis, prognosis, treatment and drug discovery. In this report, we present a novel machine learning framework for brain tumor classification based on heterogeneous data fusion of metabolic and molecular datasets, including state-of-the-art high-resolution magic angle spinning (HRMAS) proton (1H) magnetic resonance spectroscopy and gene transcriptome profiling, obtained from intact brain tumor biopsies. Our experimental results show that our novel framework outperforms any analysis using individual dataset. PMID- 22842997 TI - Systematic and integrative reviews of the literature: how are they changing our thoughts about practice? PMID- 22842995 TI - Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies. AB - OBJECTIVE: Rilpivirine (RPV) is the latest approved nonnucleoside reverse transcriptase inhibitor (NNRTI). It displays in-vitro activity extending over other NNRTI-resistant HIV strains. There is scarce information about the rate of RPV resistance-associated mutations (RAMs) in patients failing other NNRTIs. METHODS: RPV RAMs were examined in plasma samples collected from HIV patients that had recently failed NNRTI-based regimens at 22 clinics in Spain. RESULTS: Resistance tests from a total of 1064 patients failing efavirenz (EFV) (54.5%), nevirapine (NVP) (40%) or etravirine (ETR) (5.5%) were examined. The prevalence of RPV RAMs was K101E (9.1%), K101P (1.4%), E138A (3.9%), E138G (0.3%), E138K (0.3%), E138Q (0.8%), V179L (0.2%), Y181C (21.8%), Y181I (0.5%), Y181V (0.2%), H221Y (8.3%), F227C (0.1%) and M230L (1.5%). K101E/M184I was seen in 1%. E138K/M184I were absent. Mutations L100I and V108I were significantly more frequent in patients failing EFV than NVP (7.9 vs. 0.2 and 12.2 vs. 7.3%, respectively). Conversely, Y181C, Y181I, V106A, H221Y and F227L were more prevalent following NVP than EFV failures. Using the Spanish resistance interpretation algorithm, 206 genotypes (19.3%) from patients failing NNRTI (NVP 52%, EFV 40.8% and ETR 7.8%) were considered as RPV resistant. In patients with ETR failure, cross-resistance to RPV was seen in 27.6%, mainly as result of Y181C (81.3%), V179I (43.8%), V90I (31.3%) and V108I (18.8%). CONCLUSION: RPV resistance is overall recognized in nearly 20% of patients failing other NNRTIs. It is more common following ETR (27.6%) or NVP (25%) failures than EFV (14.5%). E138 mutants are rarely seen in this context. PMID- 22842998 TI - Change is the challenge. PMID- 22842994 TI - Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AB - OBJECTIVES: The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). DESIGN AND METHODS: Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. RESULTS: Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4 T-cell counts and CD4 T/CD8 T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4 T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. CONCLUSION: When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation. PMID- 22842999 TI - Elective induction of labor prior to 39 weeks: initiating a change in culture. PMID- 22843000 TI - Elective induction: is it worth the risk? Part 2 of a 3-part series. PMID- 22843001 TI - Internet resources. PMID- 22843002 TI - Rethinking placental transfusion and cord clamping issues. AB - A brief delay in clamping the umbilical cord results in a placental transfusion that supplies the infant with a major source of iron during the first few months of life. Cord circulation continues for several minutes after birth and placental transfusion results in approximately 30% more blood volume. Gravity influences the amount of placental transfusion that an infant receives. Placing the infant skin-to-skin requires a longer delay of cord clamping (DCC) than current recommendations. Uterotonics are not contraindicated with DCC. Cord milking is a safe alternative to DCC when one must cut the cord prematurely. Recent randomized controlled trials demonstrate benefits for term and preterm infants from DCC. The belief that DCC causes hyperbilirubinemia or symptomatic polycythemia is unsupported by the available research. Delay of cord clamping substantively increases iron stores in early infancy. Inadequate iron stores in infancy may have an irreversible impact on the developing brain despite oral iron supplementation. Iron deficiency in infancy can lead to neurologic issues in older children including poor school performance, decreased cognitive abilities, and behavioral problems. The management of the umbilical cord in complex situations is inconsistent between birth settings. A change in practice requires collaboration between all types of providers who attend births. PMID- 22843004 TI - Reducing recurrent preterm births: best evidence for transitioning to predictive and preventative strategies. AB - Women who have delivered an infant between 16 and 36 weeks' gestation have an increased risk of preterm birth (PTB) in a subsequent pregnancy. The high incidence of recurrent PTB remains relatively unchanged despite intensive research efforts and advances in perinatal care. Attempts to decrease the incidence of recurrent PTB have not always been successful, with research efforts being focused on clinical, pharmacotherapy and biochemical, and ultrasound strategies. Fortunately, there is adequate evidence in the literature to justify clinical management guidelines that may impact the PTB rate: smoking cessation, treatment of asymptomatic bacteriuria, transvaginal ultrasonography of the cervix, administration of vaginal progesterone or 17alpha-hydroxyprogesterone caproate, cerclage, and fetal fibronectin. This article is intended to give brief highlights of these strategies and the current science that supports their conclusions. PMID- 22843005 TI - Discussing vaccination with concerned patients: an evidence-based resource for healthcare providers. AB - Data regarding rates of vaccination among children and pregnant women show that there has been a decrease in the number of vaccinations being administered in these vulnerable populations. Surveys of parents elicit a wide variety of concerns and fears driving vaccine refusal, many of which have been refuted by research. It has been demonstrated that healthcare providers are a major source of information for patients who have questions about vaccinations. Given the established vital role of vaccinations in preventing the spread of diseases with serious morbidity and mortality profiles, it is important that healthcare providers understand and feel comfortable discussing the principles of vaccination, the recommended vaccine schedules, and the effects of vaccinations. This article provides an overview of vaccination principles, reviews the potential health and financial costs of nonvaccination, and addresses a number of common concerns cited by parents and pregnant women who are considering vaccine abstention or alternate vaccination scheduling. The information in this article will enable healthcare providers to accurately counsel patients about vaccination choices. PMID- 22843007 TI - Integrative literature review defining evidence-based neurodevelopmental supportive care of the preterm infant. AB - Neurodevelopmental supportive care (NDSC) is a well-researched topic and extensive evidence is available on its benefits in terms of the outcome for preterm infants. The programs, strategies, and individual elements of NDSC have been evaluated; however, knowledge and implementation of the developmental care approach is fragmented and the evidence base for elements of NDSC that make up the holistic model is not explicitly documented. The aim of this study was to identify and critically appraise the methodologic quality of relevant research studies and synthesize the current best available evidence of NDSC. A comprehensive investigation of NDSC including studies using research methods other than clinical trials may provide a combination of results from several primary studies, therefore an integrative literature review was utilized as the method of choice. Sixteen research articles were found to be of good methodologic quality and level and strength of evidence after critical appraisal. They described or defined the elements of NDSC explicitly. Extraction of data from these articles contributed to the formulation of 25 conclusion statements. Each of these statements could be grouped under 9 categories that resulted from a process of synthesis, and each of these categories could be substantiated from its literature support, clinical impact, and supporting evidence, including the specific literature references and volume and level of evidence associated with that element of NDSC, providing the evidence base for defining NDSC. PMID- 22843006 TI - Factors that influence the practice of elective induction of labor: what does the evidence tell us? AB - Elective induction of labor has been linked to increased rates of prematurity and rising rates of cesarean birth. The purpose of this investigation was to evaluate current trends in induction of labor scholarship focusing on evidence-based factors that influence the practice of elective induction. A key word search was conducted to identify studies on the practice of elective induction of labor. Analysis of the findings included clustering and identification of recurrent themes among the articles with 3 categories being identified. Under each category, the words/phrases were further clustered until a construct could be named. A total of 49 articles met inclusion criteria: 7 patient, 6 maternity care provider, and 4 organization factors emerged. Only 4 of the articles identified were evidence based. Patient factors were divided into preferences/convenience, communication, fear, pressure/influence, trust, external influences, and technology. Provider factors were then divided into practice preferences/convenience, lack of information, financial incentives, fear, patient desire/demand, and technology. Organization factors were divided into lack of enforcement/accountability, hospital culture, scheduling of staff, and market share issues. Currently, there is limited data-based information focused on factors that influence elective induction of labor. Despite patient and provider convenience/preferences being cited in the literature, the evidence does not support this practice. PMID- 22843008 TI - Impact of the design of neonatal intensive care units on neonates, staff, and families: a systematic literature review. AB - Newborn intensive care is for critically ill newborns requiring constant and continuous care and supervision. The survival rates of critically ill infants and hospitalization in neonatal intensive care units (NICUs) have improved over the past 2 decades because of technological advances in neonatology. The design of NICUs may also have implications for the health of babies, parents, and staff. It is important therefore to articulate the design features of NICU that are associated with improved outcomes. The aim of this study was to explore the main features of the NICU design and to determine the advantages and limitations of the designs in terms of outcomes for babies, parents, and staff, predominately nurses. A systematic review of English-language, peer-reviewed articles was conducted for a period of 10 years, up to January 2011. Four online library databases and a number of relevant professional Web sites were searched using key words. There were 2 main designs of NICUs: open bay and single-family room. The open-bay environment develops communication and interaction with medical staff and nurses and has the ability to monitor multiple infants simultaneously. The single-family rooms were deemed superior for patient care and parent satisfaction. Key factors associated with improved outcomes included increased privacy, increased parental involvement in patient care, assistance with infection control, noise control, improved sleep, decreased length of hospital stay, and reduced rehospitalization. The design of NICUs has implications for babies, parents, and staff. An understanding of the positive design features needs to be considered by health service planners, managers, and those who design such specialized units. PMID- 22843010 TI - Comparative effects of using alcohol, natural drying, and salicylic sugar powder on umbilical stump detachment of neonates. AB - This study compares the effectiveness of alcohol, natural drying, and salicylic sugar powder on umbilical separation time of the neonate in our high-humidity region. From September 2007 to May 2008, a total of 143 neonates in a community hospital were divided into 3 groups according to their birth month in sequence. Each umbilical care regimen was randomly assigned to a 3-month period. Data on occurrence of omphalitis and cord separation time were collected by telephone follow-up until stump separation. The salicylic sugar powder group had the lowest rates of colonization and shortest cord separation time compared with the natural drying and alcohol groups. No omphalitis developed in any of the 3 groups. Natural drying and salicylic sugar powder are safe and effective ways to care for the umbilical cord stump in high-humidity regions. Nursing professionals should consider choosing a more effective umbilical care regimen and provide mothers with thorough instruction. PMID- 22843011 TI - Will nursing ever be evidence-based? PMID- 22843012 TI - Prediction of novel genes associated with negative regulators of toll-like receptors-induced inflammation based on endotoxin tolerance. AB - Prior exposure of innate immune cells to lipopolysaccharide (LPS) has caused them to be refractory to further endotoxin stimulation, also termed endotoxin tolerance (ET). Bacterial LPS signals through Toll-like receptor (TLR) 4, which was thought to enable the innate immune system to deal with invasive pathogens and to restrain systemic inflammation efficiently. We established a robust model of ET and determined the level of TNF-alpha and IL-6 in cultured human monocytes. Then, microarray assay was applied to assess gene expression in this model. The results showed that 356 non-tolerizable genes were differentially expressed at a high level in tolerant monocytes. The genes selected were classified into several categories based on gene ontology (GO) and KEGG pathway database. And then literature annotations, protein-protein interaction (PPI) network, and functional consistency were applied to analyze the non-tolerizable genes. Finally, the microarray results were verified by quantitative real-time PCR of seven representative genes, including the two candidate genes, Spry2 and Smurf2, which were supposed to play a critical role in TLRs-induced inflammation based on literature retrieval. Our results would provide useful information for further analysis of regulating TLRs-induced inflammation, and would facilitate the study of associated mechanisms. PMID- 22843013 TI - Opposite effects of quercetin, luteolin, and epigallocatechin gallate on insulin sensitivity under normal and inflammatory conditions in mice. AB - Flavonoids are polyphenolic compounds ubiquitous in plants. Quercetin, luteolin, and epigallocatechin gallate (EGCG) are flavonoids with a number of biochemical and cellular actions relevant to glucose homeostasis, but their regulation of insulin action is still uncertain. This study aims to evaluate the regulation of insulin action by quercetin, luteolin, and EGCG under normal and inflammatory conditions in mice. Oral administration of quercetin, luteolin, and EGCG impaired glucose tolerance and blunted the effect of insulin to low blood glucose. Luteolin and EGCG, but not quercetin, inhibited glucose load-induced insulin receptor substrate-1(IRS-1) tyrosine and Akt phosphorylation in adipose tissue. Meanwhile, insulin-stimulated glucose uptake was also inhibited by these flavonoids. We induced insulin resistance in mice by treatment with activated macrophages-derived conditioned medium (Mac-CM) and observed that quercetin, luteolin, and EGCG reversed glucose intolerance with improving insulin sensitivity. Quercetin, luteolin, and EGCG inhibited inflammation-evoked IKKbeta activation and IRS-1 serine phosphorylation in adipose tissue, and thereby effectively restored glucose load-stimulated IRS-1 tyrosine and Akt phosphorylation, leading to an increase in insulin-mediated glucose uptake in adipocytes. The aforementioned results showed opposite effects of quercetin, luteolin, and EGCG on insulin sensitivity in mice. The different modulation of IRS-1 function by phosphorylating modification under normal and inflammatory conditions should be a key controlling for their action in regulation of insulin sensitivity. PMID- 22843014 TI - How do urodynamics findings influence the treatment of the typical patient with overactive bladder? AB - Overactive bladder (OAB) is a clinical symptom complex whose hallmark is the symptom of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence. Historically, urodynamics (UDS) evaluation has not been recommended in the initial evaluation of OAB, since it is defined primarily by clinical symptoms. As the pathophysiology of the OAB complex has become more clearly elucidated from recent studies, the role of UDS has again become a topic of discussion as a tool that can provide objective data to reflect these new findings. The utility of UDS in the diagnosis and treatment of OAB is still evolving, but in certain clinical scenarios, especially when empiric treatment has failed, it can provide definitive information that can identify associated pathologies and/or alter the treatment course. Herein, we will discuss the current literature regarding use of UDS in OAB patients and offer our own opinions as to its use. PMID- 22843015 TI - A pan-European registration system for volunteer participation is within sight. PMID- 22843016 TI - Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. AB - PURPOSE: The aim of this overview of systematic reviews is to summarise and critically evaluate the evidence from systematic reviews of the adulteration and contamination of herbal medicinal products (HMPs). METHODS: Five electronic databases were searched to identify all relevant systematic reviews. RESULTS: Twenty-six systematic reviews met our inclusion criteria. The most commonly HMPs were adulterated or contaminated with dust, pollens, insects, rodents, parasites, microbes, fungi, mould, toxins, pesticides, toxic heavy metals and/or prescription drugs. The most severe adverse effects caused by these adulterations were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis, renal or liver failure, cerebral edema, coma, intracerebral haemorrhage, and death. Adulteration and contamination of HMPs were most commonly noted for traditional Indian and Chinese remedies, respectively. CONCLUSIONS: Collectively these data suggest that there are reasons for concerns with regards to the quality of HMPs. Adulteration and contamination of HMPs can cause serious adverse effects. More stringent quality control and its enforcement seem to be necessary to avoid health risks. PMID- 22843018 TI - Nonlinear dynamics of the movement of the venus flytrap. AB - The Venus flytrap has long been regarded as one of the most amazing examples of movement in the plant kingdom. The trapping ability of the flytrap consists of three unique features. First, trap closure represents one of the fastest movements in the plant kingdom. Second, a decision-making stage allows the plant to "decide" whether to completely close or open the trap, based on stimuli provided from the trapped object. Finally, the Venus flytrap contains a "memory function" that requires two mechanical stimuli within about 30 seconds to initiate trap closure. The movement involved in trap closure consists of nonlinear dynamics that have not been well understood. By understanding the movement, through nonlinear dynamics analysis, it will be possible to better understand this biological process. A mathematical model describing the movement of the Venus flytrap was first proposed by the authors in Yang et al., Plant Signal. Behav. 5(8), 968-978 (2010). In the current work, the earlier research has been advanced and an in-depth nonlinear and control analysis of the dynamic process has been provided. PMID- 22843019 TI - Isolation and molecular structures of novel organotellurium(IV) halides, oxyhalide and mixed halide. AB - The formation of chiral (R)-[2-(4-ethyl-2-oxazolinyl)phenyl]tellurium(IV) trihalides (trichloride (5), tribromide (6) and triiodide (7)) and (R)-[2-(4 ethyl-2-oxazolinyl)phenyl]tellurium(II) bromide (8) is described. The molecular structure of the first chiral organotellurium(IV) triiodide (7) is discussed. The most interesting feature of the structure of 5 is the observation of the shortest intramolecular TeN distance for any organotellurium(IV) trichloride. Compounds 5 and 6 do not undergo electrophilic addition reaction with olefins. Attempted addition reaction of 6 with olefin in methanol leads to the isolation of the rare partially hydrolysed tellurium(IV) halide, methyl-2-(dibromooxotellurium)benzoate (9). Novel stable mixed halide 12 was isolated from the bromination of 11. DFT calculations indicate that both the isomers 12a and 12b have similar stability. PMID- 22843017 TI - First reported case in the UK of acute prolonged neuropsychiatric toxicity associated with analytically confirmed recreational use of phenazepam. AB - PURPOSE: There is increasing evidence from around Europe of the availability and misuse of long-acting benzodiazepines such as phenazepam. There is little information on the acute toxicity of these compounds; we describe here a case of analytically confirmed phenazepam-related acute toxicity. CASE REPORT: A 42-year old man with no previous medical or psychiatric history was brought to the Emergency Department by his friends because he had developed prolonged ongoing confusion and disorientation following use of up to three different "legal high" powders. There was no obvious medical cause for this acute confusion and disorientation. His symptoms continued for approximately 60 h after suspected use. Subsequent toxicological analysis of a serum sample confirmed use of phenazepam (concentration 0.49 mg/L); no other drugs were detected during an extensive analytical screening. CONCLUSION: This is the second case of analytically confirmed acute toxicity related to phenazepam in Europe. This adds to the scant published information on the acute toxicity of this drug, and will provide healthcare and legislative authorities with further information on which to base advice and consideration of the need for its control. PMID- 22843020 TI - Angiographically documented cerebral vasospasm following transsphenoidal surgery for pituitary tumors. AB - Symptomatic cerebral vasospasm (CVS) after transsphenoidal surgery (TSS) is very rare compared with vasospasm resulting from aneurysmal subarachnoid hemorrhage (SAH). Fewer than six cases documented by cerebral angiography have been reported. We evaluated the records of 15 patients in whom SAH developed after TSS. Their clinical symptoms, radiological and laboratory findings were analyzed. Among 15 patients with postoperative SAH, 11 did not show CVS during their postoperative course. However, four patients presented with various clinical symptoms suggestive of CVS on postoperative days 7-9. They showed an abrupt drop of serum sodium level 1 or 2 days before the onset of CVS symptoms. Patients with TSS-related SAH should be managed with proactive and aggressive treatment. Hyponatremia, which usually occurs around the first week after TSS, should not be ignored as a matter of metabolic or hormonal disequilibrium commonly encountered after pituitary surgery. PMID- 22843021 TI - Perinatal characteristics and retinoblastoma. AB - PURPOSE: The etiology of retinoblastoma remains poorly understood. In the present study, we examined associations between perinatal factors and retinoblastoma risk in California children. METHODS: We identified 609 retinoblastoma cases (420 unilateral, 187 bilateral, and 2 with laterality unknown) from California Cancer Registry records of diagnoses 1988-2007 among children < 6 years of age. We randomly selected 209,051 controls from California birth rolls. The source of most study data was birth certificates. Multivariable logistic regression was used to examine associations between retinoblastoma and perinatal characteristics. RESULTS: Bilateral retinoblastoma was associated with greater paternal age [for fathers over 35, crude odds ratio (OR) = 1.73, 95 % confidence interval (CI) 1.20, 2.47] and with twin births (OR = 1.93, 95 % CI 0.99, 3.79). Among unilateral cases, we observed an increased risk among children of US-born Hispanic mothers (OR = 1.34, 95 % CI 1.01, 1.77) while a decreased risk was observed for infants born to mothers with less than 9 years of education (OR = 0.70, 95 % CI 0.49, 1.00), a group that consisted primarily of mothers born in Mexico. We observed that maternal infection in pregnancy with any STD (OR = 3.59, 95 % CI 1.58, 8.15) was associated with bilateral retinoblastoma. CONCLUSIONS: This study supports the findings of previous investigations reporting associations between parental age, HPV infection, and retinoblastoma. PMID- 22843022 TI - Cigarette smoking, alcohol intake, and thyroid cancer risk: a pooled analysis of five prospective studies in the United States. AB - OBJECTIVE: We examined the associations between cigarette smoking, alcohol intake, and thyroid cancer risk in a pooled analysis of five prospective studies. METHODS: Data from five prospective U.S. studies were standardized and then combined into one aggregate dataset (384,433 men and 361,664 women). Pooled hazard ratios (HR) and 95 % confidence intervals (CI) for thyroid cancer were estimated from mutually adjusted models of cigarette smoking and alcohol intake, which were additionally adjusted for age, sex, education, race, marital status, body mass index, and cohort. RESULTS: Over follow-up, 1,003 incident thyroid cancer cases (335 men and 668 women) were identified. Compared to never smokers, current smoking was associated with reduced risk of thyroid cancer (HR = 0.68, 95 % CI 0.55-0.85); this association was slightly stronger among non-drinkers (HR = 0.46, 95 % CI 0.29-0.74). No reduction in risk was observed for former, compared to never, smokers. Greater smoking intensity, duration, and pack-years were associated with further reductions in risk among former and current smokers. Alcohol intake was also inversely associated with thyroid cancer risk (>=7 drinks/week versus 0, HR = 0.72, 95 % CI 0.58-0.90, p trend = 0.002). Inverse associations with smoking and alcohol were more pronounced for papillary versus follicular tumors. CONCLUSION: The results of this pooled analysis suggest that both cigarette smoking and alcohol consumption are associated with reduced risks of papillary thyroid cancer and, possibly, follicular thyroid cancer. PMID- 22843023 TI - TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy. AB - Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy. PMID- 22843024 TI - Placebo response in relation to clinical trial design: a systematic review and meta-analysis of randomized controlled trials for determining biologic efficacy in psoriasis treatment. AB - There is a need to better define how the efficacy of investigational drugs is affected by study design, implementation, and placebo responses in randomized controlled trials. The improvements observed in placebo groups within trials examining psoriasis treatments may be partially due to study design and implementation. We conducted a systematic review of randomized placebo-controlled trials assessing the efficacy of biologics in the treatment of psoriasis and psoriatic arthritis to evaluate rates of placebo and active drug responders to determine specific factors within study design that may contribute to placebo responses. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, ustekinumab, alefacept, and efalizumab that utilized Psoriasis Area Severity Index as an outcomes measure. We compared the rates of the placebo treatment arm versus the active drug arm achieving 75 % improvement of Psoriasis Area Severity Index. 31 trials involving 8285 active treatment and 3999 placebo patients were included. Rates of placebo responders (4.14 %) were significantly lower than active drug responders (48.4 %). The overall odds ratio calculated was 23.94 (p < 0.0001, 95 % CI 16.02-35.76). Binomial regression models showed that treatment indication, randomization fraction, a PASI inclusion requirement, and the time period of outcomes measure documentation affect placebo responses. Placebo responses seen in randomized controlled trials evaluating biologics in the treatment of psoriasis are not likely due to a physiologic mechanism, but may be secondary to chronic disease course and factors of clinical trial design and implementation. PMID- 22843025 TI - Effects of cryopreservation of Phaseolus vulgaris L. seeds on early stages of germination. AB - In this work, we studied the effects of cryopreservation on various parameters of early stages of germination of Phaseolus vulgaris seeds (0, 7 and 14 days). Percentages of germination, fresh mass of different plant parts, levels of chlorophyll pigments (a, b, total), malondialdehyde, other aldehydes, phenolics (cell wall-linked, free, and total) and protein were determined. No phenotypic changes were observed visually in seedlings recovered from cryopreserved seeds. However, several significant effects of seed liquid nitrogen exposure were recorded at the biochemical level. There was a significant negative effect of cryopreservation on shoot protein content, which decreased from 3.11 mg g(-1) fresh weight for non-cryopreserved controls to 0.44 mg g(-1) fresh shoot weight for cryopreserved seeds. On the other hand, cryopreservation significantly increased levels of other aldehydes than malondialdehyde in shoots at day 7, from 56.47 MUmol g(-1) for non-cryopreserved controls to 253.19 MUmol g(-1) fresh shoot weight for cryopreserved samples. Liquid nitrogen exposure significantly reduced phenolics contents (free, cell-wall linked, total) in roots at day 7 after onset of germination. In general, roots were more affected by cryostorage compared with other plant parts, while leaves were the least affected. The effects of seed cryopreservation seem to decline progressively along with seedling growth. PMID- 22843026 TI - Agrobacterium-mediated co-transformation of rice using two selectable marker genes derived from rice genome components. AB - A method for Agrobacterium-mediated co-transformation of rice (Oryza sativa L.) was developed using rice-derived selection markers. Two T-DNAs were efficiently introduced into separate loci using selectable marker gene cassettes consisting of the mutated acetolactate synthase gene (mALS) under the control of the callus specific promoter (CSP) (CSP:mALS) and the ferredoxin nitrite reductase gene (NiR) under the control of its own promoter (NiR P:NiR). The CSP:mALS gene cassette confers sulfonylurea herbicide resistance to transgenic rice callus. The NiR P:NiR construct complements NiR-deficient mutant cultivars such as 'Koshihikari', which are defective in the regulation of nitrogen metabolism. In the present study, the CaMV35S:GUS and CaMV35S:GFP gene cassettes were co introduced into the 'Koshihikari' genome using our system. Approximately 5-10 independent transgenic lines expressing both the GUS and GFP reporters were obtained from 100 Agrobacterium co-inoculated calli. Furthermore, transgenic 'Koshihikari' rice lines with reduced content of two major seed allergen proteins, the 33 and 14-16 kDa allergens, were generated by this co transformation system. The present results indicate that the generation of selectable antibiotic resistance marker gene-free transgenic rice is possible using our rice-derived selection marker co-transformation system. Key message An improved rice transformation method was developed based on Agrobacterium-mediated co-transformation using two rice genome-derived selectable marker gene cassettes. PMID- 22843027 TI - [Transcranial and invasive brain stimulation for depression]. AB - Considering the substantial proportion of depressed patients which does not sufficiently benefit from antidepressant pharmacotherapy or psychotherapy, there is increasing interest in non-pharmacological antidepressant strategies. Thus, a whole array of stimulation approaches has been developed as potential new antidepressant interventions. These methods include transcranial convulsive and non-convulsive approaches, e.g. electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as well as invasive techniques, e.g. deep brain stimulation (DBS), vagus nerve stimulation (VNS) and epidural cortical stimulation (ECS). Each method represents a specific therapeutic approach with distinct targets within neural networks involved in the pathophysiology of depression. The ECT procedure is an established treatment with the highest efficacy of all antidepressant interventions and TMS reaches the highest level of evidence among the novel neurostimulation approaches and may be clinically used. However, the field yields a promising rapid development which may substantially enrich the armamentarium of antidepressant interventions in the near future. PMID- 22843028 TI - [Crowned dens syndrome: a rare differential diagnosis of acute neck pain]. PMID- 22843029 TI - Cell viability of microencapsulated Bifidobacterium animalis subsp. lactis under freeze-drying, storage and gastrointestinal tract simulation conditions. AB - The purpose of this study was to improve the survival of Bifidobacterium animalis subsp. lactis 10140 during freeze-drying process by microencapsulation, using a special pediatric prebiotics mixture (galactooligosaccharides and fructooligosaccharides). Probiotic microorganisms were encapsulated with a coat combination of prebiotics-calcium-alginate prior to freeze-drying. Both encapsulated and free cells were then freeze-dried in their optimized combinations of skim milk and prebiotics. Response surface methodology (RSM) was used to produce a coating combination as well as drying medium with the highest cell viability during freeze-drying. The optimum encapsulation composition was found to be 2.1 % Na-alginate, 2.9 % prebiotic, and 21.7 % glycerol. Maximum survival predicted by the model was 81.2 %. No significant (p > 0.05) difference between the predicted and experimental values verified the adequacy of final reduced models. The protection ability of encapsulation was then examined over 120 days of storage at 4 and 25 degrees C and exposure to a sequential model of infantile GIT conditions including both gastric conditions (pH 3.0 and 4.0, 90 min, 37 degrees C) and intestinal conditions (pH 7.5, 5 h, 37 degrees C). Significantly improved cell viability showed that microencapsulation of B. lactis 10140 with the prebiotics was successful in producing a stable symbiotic powdery nutraceutical. PMID- 22843030 TI - "That must be so hard"--examining the impact of children's palliative care services on the psychological well-being of parents. AB - In 2003 the New Opportunities Fund (NOF, now known as The Big Lottery) awarded L48 million to 70 home-based care teams to enable them to provide a range of services to allow children with non-malignant life-limiting conditions to be cared for at home. Four grants were made available in Bristol, North Somerset, South Gloucestershire and Bath and North East Somerset to enhance existing children's palliative care services. As there is limited evidence about the impact of palliative care services on psychological well-being, this study measured parental stress and the psychological wellbeing of parents of newly referred children with life-limiting and life-threatening conditions. Measures were administered at the point of referral and at 12 months follow-up. Statistical analysis indicated that there was no significant change at 12 month follow-up. The lack of deterioration in levels of parental stress and psychological wellbeing is viewed positively within this context. It is hypothesised that multi-agency and partnership working was a significant contributory factor in not increasing levels of parental stress and psychological wellbeing through social support. PMID- 22843031 TI - Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair. AB - Metformin, one of the most widely used antidiabetic drugs, has recently been associated with potential antitumorigenic effects. In this study, we evaluated the possible cytotoxic impact of combined low doses of metformin and ionizing radiation (IR) on 2 human hepatoma cell lines. The cytotoxic effect of metformin combined with IR was subsequently determined by clonogenic survival and cell cycle assays, assessment of mitochondrial complex I and lactate dehydrogenase (LDH) activity, measurement of cellular adenosine triphosphate (ATP) levels, comet assay and analyses of the formation and disappearance of phosphorylated histone H2AX (gamma-H2AX) protein. The combination of metformin and IR caused a much stronger cytotoxicity than the treatment with metformin or IR alone, leading to an ~80% decrease in cell viability and ~35% increase in the accumulation of cells in the G2/M phase of the cell cycle in the 2 hepatoma cell lines. In addition, a reduction in mitochondrial complex I activity (~70%) and a significant increase in LDH activity, as well as lactate production were observed in the cells exposed to metformin. Interestingly, a severe depletion in ATP, increased olive tail moment and the delayed disappearance of gamma-H2AX expression were detected in the hepatoma cells treated by metformin plus IR. These findings show that the combination of a low concentration of metformin and IR results in the considerable enhancement of cytotoxic effects in human hepatoma cell lines, leading to decreased DNA repair by reducing ATP production. The data provided in this study may elucidate the remarkable efficiency of this combination treatment and suggest that metformin may be used as a potential adjunct to the radiotherapy of hepatocellular carcinoma. PMID- 22843032 TI - The storytelling brain. Commentary on "On social attribution: implications of recent cognitive neuroscience research for race, law, and politics". AB - The well-established techniques of the professional storyteller not only have the potential to model complex "truth" but also to dig deeply into that complexity, thereby perhaps getting closer to that truth. This applies not only to fiction, but also to medicine and even science. Compelling storytelling ability may have conferred an evolutionary survival advantage and, if so, is likely represented in the neural circuitry of the human brain. Functional imaging will likely point to a neuroanatomical basis for compelling storytelling ability; this will presumably reflect underlying cellular and molecular mechanisms. PMID- 22843033 TI - Knowledge, attitudes and behavioral intentions of agricultural professionals toward genetically modified (GM) foods: a case study in Southwest Iran. AB - While there has been a number of consumers' studies looking at factors that influence individuals' attitudes and behavior toward GM foods, few studies have considered agricultural professionals' intentions in this regard. This study illuminates agricultural professionals' insights toward GM foods in Southwest Iran. A random sample of 262 respondents was studied. The results indicated that the majority of the respondents had little knowledge about GM foods. They perceived few benefits or risks of GM foods. Their perceived benefits and trust in individuals and institutions had positive impacts on the behavioral intentions of the agricultural professionals. The results also revealed that the low knowledge level of the respondents had a negative impact on the behavioral intentions toward GM foods. This state of affairs is problematic, either GM foods have serious problems or the knowledge conveyed to the Iranian agricultural experts is inappropriate. We recommend a well defined communication strategy to provide information in such a way that allows individuals to feel adequately informed about GM foods. Furthermore, the development of trust and knowledge regarding GM foods can be greater when risk analysis frameworks are transparent, risk assessment methodologies are objective, all stakeholders are engaged in the risk management process, and risk communication focuses on consumers. PMID- 22843034 TI - A panoramic view to relationships between reproductive failure and immunological factors. AB - PURPOSE: To examine the possible roles of various immunological factors in recurrent miscarriage and unexplained infertility. METHODS: The synthesis and review of the relevant current literature in English language. RESULTS: Substantial evidence suggests that antiphospholipid antibodies, lupus anticoagulant, antisperm antibodies, antithyroid antibodies, anti-endometrial antibodies, antiovarian antibodies, anti-C trachomatis antibodies, cytokines, and immunological events in endometriosis and premature ovarian failure due to immunologic factors may contribute to reproductive failure including unexplained infertility and/or non-chromosomal recurrent miscarriage. CONCLUSIONS: Elimination or suppression of the immunological factors related with reproductive failure might occupy an important place in the treatment of unexplained infertility and non-chromosomal recurrent miscarriage. PMID- 22843035 TI - Ovarian cancer in elderly patients: a difference in treatment based on age? AB - PURPOSE: The aim of this study was to examine if treatment strategies differ by age in the elderly population with ovarian cancer in daily clinical practice. METHODS: A retrospective analysis of elderly patients with ovarian cancer who were referred to our institution between January 2007 and August 2010 was done. A univariate analysis for overall survival was estimated according to the Kaplan Meier method, censoring surviving patients at the time of last follow-up. RESULTS: We evaluated 32 elderly patients: 17 "young-old" patients (65-74 years old), 14 "old-old" patients (75-84 years old) and 1 "oldest-old" patient (>=85 years old). At last follow-up, 20 patients (62.5%) were alive and 12 patients (37.5%) were deceased. Median time follow-up was 18.52 months. Median overall survival was 19.05 months. Median age was 73.50 years. In the subgroup of "young old" patients, there were less "high malignant potential" (64.3 vs. 70.0%) and grade 3 ovarian cancers (84.6 vs. 90.0%), less advanced stages (III-IV: 64.7 vs. 86.7%), higher number of optimal surgical procedures (50.0 vs. 30.0%) and more frequent use of chemotherapy (82.4 vs. 66.7%). Single agent carboplatin was administered in 81.8 vs. 77.8% of "young-old" and "old-oldest old" patients, and average number of lines was 2 vs. 1. Other characteristics were similar in the two subgroups ("young-old" vs. "old-oldest old" patients). By the univariate analysis, there was no statistical significance difference in overall survival (p=0.393) between the two subgroups, with only a positive trend for young-old patients. CONCLUSIONS: In old- and oldest-old patients, the characteristics of disease are worse and optimal treatment strategy is less frequently applied. The management of patients by multidisciplinary team is needed and it could better individualize and apply the optimal treatment approach. PMID- 22843036 TI - Reading comprehension in autism spectrum disorders: the role of oral language and social functioning. AB - Reading comprehension is an area of difficulty for many individuals with autism spectrum disorders (ASD). According to the Simple View of Reading, word recognition and oral language are both important determinants of reading comprehension ability. We provide a novel test of this model in 100 adolescents with ASD of varying intellectual ability. Further, we explore whether reading comprehension is additionally influenced by individual differences in social behaviour and social cognition in ASD. Adolescents with ASD aged 14-16 years completed assessments indexing word recognition, oral language, reading comprehension, social behaviour and social cognition. Regression analyses show that both word recognition and oral language explain unique variance in reading comprehension. Further, measures of social behaviour and social cognition predict reading comprehension after controlling for the variance explained by word recognition and oral language. This indicates that word recognition, oral language and social impairments may constrain reading comprehension in ASD. PMID- 22843038 TI - Radiofrequency currents exert cytotoxic effects in NB69 human neuroblastoma cells but not in peripheral blood mononuclear cells. AB - Recently, a number of electric and electrothermal therapies have been applied to the treatment of specific cancer types. However, the cellular and molecular mechanisms involved in the response to such therapies have not been well characterized yet. Capacitive-resistive electric transfer (CRET) therapy uses electric currents at frequencies within the 0.45-0.6 MHz range to induce hyperthermia in target tissues. Preliminary trials in cancer patients have shown consistent signs that CRET could slow down growth of tumor tissues in brain gliomas, without inducing detectable damage in the surrounding healthy tissue. Previous studies by our group have shown that subthermal treatment with 0.57-MHz electric currents can induce a cytostatic, not cytotoxic response in HepG2 human hepatocarcinoma cells; such effect being mediated by cell cycle alterations. In contrast, the study of the response of NB69 human neuroblastoma cells to the same electric treatment revealed consistent indications of cytotoxic effects. The present study extends the knowledge on the response of NB69 cells to the subthermal stimulus, comparing it to that of primary cultures of human peripheral blood mononuclear cells (PBMC) exposed to the same treatment. The results showed no sensitivity of PBMC to the 0.57 MHz subthermal currents and confirmed that the treatment exerts a cytotoxic action in NB69 cells. The data also revealed a previously undetected cytostatic response of the neuroblastoma cell line. CRET currents affected NB69 cell proliferation by significantly reducing the fraction of cells in the phase G2/M of the cell cycle at 12 h of exposure. These data provide new information on the mechanisms of response to CRET therapy, and are consistent with a cytotoxic and/or cytostatic action of the electric treatment, which would affect human cells of tumor origin but not normal cells with a low proliferation rate. PMID- 22843039 TI - A one-step solid phase extraction method for bioanalysis of a phosphorothioate oligonucleotide and its 3' n-1 metabolite from rat plasma by uHPLC-MS/MS. AB - Oligonucleotide therapeutics have emerged as a promising class of drugs to treat a wide range of diseases caused by genetic abnormalities. Replacement of the phosphodiester linkage with a phosphorothioate is one of the most successful modifications made to oligonucleotides to enhance their in vivo stability. The longer elimination phase of phosphorothioates and other modified oligonucleotides requires sensitive and selective methods to quantify the parent drug and their metabolites simultaneously. Liquid chromatography tandem mass spectrometry has excellent selectivity between the parent drug and its metabolites and a wide dynamic range. However, the biological sample extraction remains a formidable challenge in developing quantitative LC-MS methods for oligonucleotides. Protein precipitation, protein digestion, liquid-liquid extraction, reversed phase solid phase extraction (SPE), strong anion exchange SPE, and combinations of them have been reported to extract oligonucleotides from biological matrices. Unfortunately, these methods either have low recoveries or present potential problems for applications with chromatography due to the large amount of matrix substances in the resulting solutions. In this study, a weak anion exchange SPE method was optimized. The recovery ranged from 60% to 80% depending on the concentration. This is the first report of a one-step SPE method with recoveries greater than 60% across the method dynamic range. This sample extraction procedure was used in combination with ultrahigh-performance liquid chromatography-tandem mass spectrometry. The lower limit of quantitation was 10 ng/mL (1.3 nM), and the dynamic range was 10-1,000 ng/mL. The intra- and inter day precision and accuracy were within 8.4% and 10.5%, respectively. PMID- 22843040 TI - Into the night: camera traps reveal nocturnal activity in a presumptive diurnal primate, Rhinopithecus brelichi. AB - Most living primates exhibit a daytime or nighttime activity pattern. Strict diurnality is thought to be the rule among anthropoids except for owl monkeys. Here we report the diel activity pattern of an Asian colobine, the Guizhou snub nosed monkey Rhinopithecus brelichi, based on a methodology that relied on using 24-h continuously operating camera traps. We conducted the study in Fanjingshan National Nature Reserve in Guizhou, China from March 22 to May 19 and from June 17 to October 14, 2011. After standardizing all time elements to a meridian-based time according to the geographic coordinates of the study site, we showed unequivocally that the monkeys, though predominantly diurnal, exhibited activity beyond daylight hours throughout the study. Specifically, their activity at night and during twilight periods suggests a complex interplay of behavioral adaptations, among others, to living in a temperate environment where day length and food resources fluctuate substantially across seasons. We contend that, under prevailing ecological conditions, so-called strictly diurnal primates may adjust their activity schedule opportunistically in order to increase energy intake. We also discuss the advantages of using camera traps in primate studies, and how the standardized use of meridian-based time by researchers would benefit comparisons of diel activity patterns among primates. PMID- 22843041 TI - Part 2: effect of training surface on acute physiological responses after sport specific training. AB - This study compared the effect of sand and grass training surfaces during a sport specific conditioning session in well-trained team sport athletes (n = 10). The participants initially completed a preliminary testing session to gather baseline (BASE) performance data for vertical jump, repeated sprint ability, and 3-km running time trial. Three days subsequent to BASE, all the athletes completed the first sport-specific conditioning session, which was followed by a repeat of the BASE performance tests the following day (24 hours postexercise). Seven days later, the same training session was completed on the opposing surface and was again followed 24 hours later by the BASE performance tests. During each session, blood lactate, ratings of perceived exertion (RPE), and heart rate (HR) were recorded, with player movement patterns also monitored via global positioning system units. Additionally, venous blood was collected preexercise, postexercise, and 24 hours postexercise, and analyzed for serum concentrations of Myoglobin, Haptoglobin, and C-Reactive Protein. Results showed significantly higher HR and RPE responses on SAND (p > 0.05), despite significantly lower distance and velocity outputs for the training session (p > 0.05). There were no differences in 24 hours postexercise performance (p > 0.05), and blood markers of muscle damage, inflammation and hemolysis were also similar between the surfaces (p > 0.05). These results suggest that performing a sport-specific conditioning session on a sand (vs. grass) surface can result in a greater physiological response, without any additional decrement to next-day performance. PMID- 22843042 TI - Acute and chronic effects of hyperbaric oxygen therapy on blood circulation of human muscle and tendon in vivo. AB - This study aimed to investigate the acute and chronic effects of hyperbaric oxygen therapy on blood circulation of human muscle and tendon in vivo. Using near-infrared spectroscopy and red laser lights, we determined acute changes in blood volume (THb) and oxygen saturation (StO2) of the medial gastrocnemius muscle and Achilles tendon during 60 minutes of hyperbaric oxygen therapy (1.3 atm absolute and 50% O2, experiment 1). In addition, we determined the chronic effects of hyperbaric oxygen therapy (60 minutes, 2 times per week, 6 weeks) on THb and StO2 of muscle and tendon (experiment 2). In experiment 1, THb of the muscle increased gradually from resting level, but StO2 did not change. On the other hand, THb and StO2 of the tendon increased during hyperbaric oxygen therapy. In experiment 2, the pattern of changes in the measured variables during 60 minutes of therapy was similar for both the muscle and tendon between the first and last therapies. During resting, THb and StO2 of the tendon were significantly lower after 6 weeks of therapy, although those of the muscle were not. In conclusion, oxygen saturation of the tendon increased during hyperbaric oxygen therapy, whereas that of the muscle did not. This result would be related to the difference in the treated effects between muscle and tendon. However, oxygen saturation of the tendon, but not the muscle, during resting decreased after 6 weeks of therapy. PMID- 22843043 TI - Within- and between-session reliability of power, force, and rate of force development during the power clean. AB - Although there has been extensive research regarding the power clean, its application to sports performance, and use as a measure of assessing changes in performance, no research has determined the reliability assessing the kinetics of the power clean across testing session. The aim of this study was to determine the within- and between-session reliability of kinetic variables during the power clean. Twelve professional rugby league players (age 24.5 +/- 2.1 years; height 182.86 +/- 6.97 cm; body mass 92.85 +/- 5.67 kg; 1 repetition maximum [1RM] power clean 102.50 +/- 10.35 kg) performed 3 sets of 3 repetitions of power cleans at 70% of their 1RM, while standing on a force plate, to determine within-session reliability and repeated on 3 separate occasions to determine reliability between sessions. Intraclass correlation coefficients revealed a high reliability within- (r >= 0.969) and between-sessions (r >= 0.988). Repeated-measures analysis of variance showed no significant difference (p > 0.05) in peak vertical ground reaction force, rate of force development, and peak power between sessions, with small standard error of the measurements and smallest detectable differences for each kinetic variable (3.13 and 8.68 N; 84.39 and 233.93 N.s; 24.54 and 68.01 W, respectively). Therefore, to identify a meaningful change in performance, the strength and conditioning coach should look for a change in peak force >=8.68 N, rate of force development >=24.54 N.s, and a change in peak power >=68.01 W to signify an adaptive response to training, which is greater than the variance between sessions, in trained athletes proficient at performing the power clean. PMID- 22843044 TI - Effects of kettlebell training on postural coordination and jump performance: a randomized controlled trial. AB - The aim of this study was to investigate the effectiveness of a worksite intervention using kettlebell training to improve postural reactions to perturbation and jump performance. This single-blind randomized controlled trial involved 40 adults (n = 40) from occupations with a high prevalence of musculoskeletal pain and discomfort (mean age 44 years, body mass index 23 kg.m, 85% women). A blinded examiner took measures at baseline and follow-up. Participants were randomly assigned to a training group-doing kettlebell swings 3 times a week for 8 weeks-or to a control group. The outcome measures were postural reactions to sudden perturbation and maximal countermovement jump height. Compared with the control group, the training group had a significant decreased stopping time after perturbation (-109 ms, 95% confidence interval [ 196 to -21]). Jump height increased significantly in the training group (1.5 cm, 95% confidence interval [0.5 to 2.5]), but this was nonsignificantly different from control. Kettlebell training improves postural reactions to sudden perturbation. Future studies should investigate whether kettlebell training can reduce the risk of low back injury in occupations with manual material handling or patient handling where sudden perturbations often occur. PMID- 22843045 TI - The validity of the SmartJump contact mat. AB - The aim of this study was to establish the criterion validity of the SmartJump contact mat in assessing vertical jump height (VJH) and peak power (PP). Twenty three participants (15 men, age = 26 +/- 6 years; 8 women, age = 26 +/- 9 years) completed a maximal effort vertical jump using 3 different jump types (countermovement jump [CMJ], countermovement with arms [CMJA], and squat jump [SJ]). Data were simultaneously collected on both the contact mat and force platform. Vertical jump height was calculated using the time in air (TIA) method with both force platform (TIA(platform)) and contact mat (TIA(mat)) data and the takeoff velocity (TOV) method using the force platform (TOV(platform)) data. Peak power was calculated using a validated equation. The results showed that VJH and PP calculated using the TIA(mat) method were significantly greater than that calculated from the TIA(platform) and TOV(platform) methods for all jump types (VJH: p < 0.001, PP: p < 0.001). The results from this study show clear discrepancies between apparatus and calculation methods that may have implications for practitioners and should be considered when assessing VJH and PP in the field. PMID- 22843046 TI - Meta-analysis demonstrates association between Arg72Pro polymorphism in the P53 gene and susceptibility to keloids in the Chinese population. AB - Although there is evidence suggesting genetic susceptibility for keloids, studies investigating the association between Arg72Pro polymorphism in the P53 gene and tendency to form keloids have given variable results. We made a meta analysis of the effects of P53 Arg72Pro polymorphism on keloid risk in the Chinese population by conducting searches of the published literature in Pubmed, Embase, CBMdisc, and CNKI databases up to June 2011. Six studies were included in the meta-analysis, with a total of 359 keloid cases and 493 healthy controls. Meta-analysis results, respectively in the PCR-reverse dot blot and PCR-RFLP subgroups, showed significant associations between P53 Arg72Pro polymorphism and susceptibility to keloid in the comparisons of Pro allele vs Arg allele (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.45-3.60; OR = 0.74, 95%CI = 0.56-0.98); Pro/Pro vs Pro/Arg + Arg/Arg (OR = 2.91, 95%CI = 1.88-4.53; OR = 0.54, 95%CI = 0.32-0.92); Pro/Pro vs Arg/Arg (OR = 2.79, 95%CI = 1.54-5.06; OR = 0.51, 95%CI = 0.28-0.92); Pro/Pro vs Pro/Arg (OR = 2.85, 95%CI = 1.75-4.63; OR = 0.57, 95%CI = 0.32-0.99). We conclude that the Pro allele of P53 Arg72Pro polymorphism is a risk factor for keloids in the Chinese population. PMID- 22843047 TI - Inhibitory effect of alternatively spliced RAGEv1 on the expression of NF-kB and TNF-alpha in hepatocellular carcinoma cells. AB - Binding of specific ligands to the receptor for advanced glycation end-products (RAGE) can trigger a series of signal transductions, which leads to pathogenesis in many chronic degenerative diseases, including cancer. Alternative splicing of RAGE mRNA has resulted in many variants, including RAGE variant 1 (RAGEv1). This particular splice variant of RAGE can provide a major soluble form of RAGE in blood circulation, which can neutralize deleterious ligands, thus diminishing signaling that can lead to inflammation and pathogenesis in cancer cells. However, the molecular mechanisms involved in suppressing signaling cascades in the cells are unknown. We investigated the molecular role of the RAGEv1 isoform in modulating NF-kB and TNF-alpha gene expression in human hepatocellular carcinoma HepG2 cells. Transient transfection using an engineered plasmid containing the RAGEv1 gene resulted in a significant increase in normalized RAGEv1 mRNA transcripts in HepG2 cells. This finding was supported by the detection of the RAGEv1 protein, which was found in the whole-cell extracts and the cell culture media. This high degree of RAGEv1 expression significantly reduced the expression of normalized mRNA transcripts of NF-kB and TNF-alpha in HepG2 cells. We suggest that RAGEv1 could reduce activity of the NF-kB signaling pathway in liver cancer cells, thus providing a potential alternative therapy for the treatment of liver cancer. PMID- 22843048 TI - Luteinizing hormone receptor splicing variants in bovine Leydig cells. AB - The luteinizing hormone receptor (LHR) plays a key role in testosterone production through its interaction with the gonadotropins, LH and chorionic gonadotropin. We examined the LHR splicing pattern in bovine Leydig cells; LH induced expression of eight cloned splicing variants was detected by real-time PCR. Luteinizing hormone applied to cultured Leydig cells resulted in expression of full-length LHR and the A and B isoforms, as well as secretion of testosterone, which first increased, then declined, and then increased further, with increased LH levels. The secretion of testosterone progressively increased with increasing LH, but the expression levels of LHR (FL, A, and B) did not increase correspondingly. We conclude that the LHR splicing pattern is complex in bovine Leydig cells, and that expression of full-length LHR and isoforms A and B changes when induced with LH. PMID- 22843049 TI - A novel mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. AB - Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant cutaneous disorder, characterized by a mixture of hyperpigmented and hypopigmented macules mostly on the dorsal portions of the extremities. Pathogenic mutations have been identified in the double-stranded RNA-specific adenosine deaminase (DSRAD) gene. We studied a Chinese family that included four affected individuals with DSH phenotypes. PCR and direct sequencing were carried out to detect the entire coding region and exon-intron boundaries of the DSRAD gene. A novel nucleotide c.3002G>T missense mutation in the exon 11 of the DSRAD gene was detected in the proband and his father. This information expands the database on DSRAD gene mutations associated with DSH. PMID- 22843050 TI - Relative h-index to compare the scientific performance of researchers. AB - I propose the Relative h-index of a scientist, which is based on his or her Hirsch's h-index divided by the total number of published papers recorded in the database. The Relative index h allows for a comparison of the scientific output among researchers and can be very useful for research support institutions, universities, and institutes to rank researchers for the purposes of recruitment, promotions, awards, and grant funding for projects. PMID- 22843051 TI - RAPD and ISSR-assisted identification and development of three new SCAR markers specific for the Thinopyrum elongatum E (Poaceae) genome. AB - Diploid Thinopyrum elongatum, a wild relative of wheat, contains many agronomically desirable traits and has potential for increasing genetic variability and introducing desirable characters in this crop. Few molecular markers are available for rapid screening of T. elongatum genome segments in the wheat genetic background. We used 36 RAPD primers and 33 ISSR primers to screen for polymorphisms in the common wheat variety Chinese Spring and in T. elongatum. Two RAPD markers and one ISSR marker, designated OPF03(1407), LW10(1487) and UBC841(701), were identified and were specific for the T. elongatum E genome. Three pairs of primers flanking these specific sequences were designed to produce SCAR markers. All three SCAR markers were T. elongatum E genome-specific. Two of these SCAR markers, SCAR(807) and SCAR(577), were present in all seven T. elongatum chromosomes, while SCAR(839) was specific for T. elongatum chromosomes 2E and 3E. These newly developed SCAR markers should be useful for detecting alien genome chromatin or chromosome segments in the genetic background of common wheat. PMID- 22843052 TI - Human papillomavirus infection in Brazilian women with normal cervical cytology. AB - We examined the prevalence of human papillomavirus (HPV) infection in a sample of Brazilian women presenting normal cervical cytology. Possible interactions between patient characteristics and HPV infection were analyzed in order to provide background data to improve cervical cancer screening and prophylaxis. Cervical samples of 399 women, received for routine evaluation in the Health Department of Ouro Preto, MG, Brazil, were subjected to HPV-DNA testing by PCR with MY09/11 primers. HPV-positive specimens were typed by RFLP. A structured epidemiological questionnaire was administered to each woman. HPV prevalence among these cytologically normal women was 11%. Twelve viral types were detected, the most common being HPV-16, -6, -61, -83, and -66. HPV was more prevalent in younger women; high-risk viral types were detected in 61% of the infected women and 27% of the infected women had multiple HPV infections. Significant associations of HPV infection were found with age, literacy, residence, marital status, lifetime number of sexual partners, and parity. We detected a great diversity of HPV types in women with normal cytology. This kind of information about local populations is useful for HPV prevention and vaccination strategies. PMID- 22843053 TI - Development of swine-specific DNA markers for biosensor-based halal authentication. AB - The pig (Sus scrofa) mitochondrial genome was targeted to design short (15-30 nucleotides) DNA markers that would be suitable for biosensor-based hybridization detection of target DNA. Short DNA markers are reported to survive harsh conditions in which longer ones are degraded into smaller fragments. The whole swine mitochondrial-genome was in silico digested with AluI restriction enzyme. Among 66 AluI fragments, five were selected as potential markers because of their convenient lengths, high degree of interspecies polymorphism and intraspecies conservatism. These were confirmed by NCBI blast analysis and ClustalW alignment analysis with 11 different meat-providing animal and fish species. Finally, we integrated a tetramethyl rhodamine-labeled 18-nucleotide AluI fragment into a 3-nm diameter citrate-tannate coated gold nanoparticle to develop a swine-specific hybrid nanobioprobe for the determination of pork adulteration in 2.5-h autoclaved pork-beef binary mixtures. This hybrid probe detected as low as 1% pork in deliberately contaminated autoclaved pork-beef binary mixtures and no cross-species detection was recorded, demonstrating the feasibility of this type of probe for biosensor-based detection of pork adulteration of halal and kosher foods. PMID- 22843054 TI - An alternative cetyltrimethylammonium bromide-based protocol for RNA isolation from blackberry (Rubus L.). AB - Isolation of high-quality RNA free of contaminants, such as polyphenols, proteins, plant secondary metabolites, and genomic DNA from plant tissues, is usually a challenging but crucial step for molecular analysis. We developed a novel protocol based on the cetyltrimethylammonium bromide method to isolate high-quality RNA from blackberry plant tissues, especially fruits. Most DNA was removed when acetic acid was utilized, before RNA precipitation. Thus, lithium chloride, a reagent widely used for RNA purification, was not needed. The isolation time was shortened to less than 3 h. The RNA was quite pure, with little DNA contamination. The quality of the RNA was assessed by spectrophotometric readings and electrophoresis on agarose gels. It was good enough for downstream enzymatic reactions, such as reverse transcription-PCR, cloning and real-time PCR assay. The method yielded an amount of total RNA comparable to previously described protocols. PMID- 22843055 TI - Synergistic and threshold effects of GH1 and GHR promoter size variation on body growth and fat accrual in young Nelore (Bos indicus) bulls. AB - A synergistic effect in the somatotropic axis (GH1-GHR-IGF1) was observed in 736 young Nelore (Bos indicus) bulls under ad libitum grass feeding conditions on irrigated pasture in central Brazil. Stepwise substitution of shorter alleles of the promoter region of the growth hormone gene (GH1) and the P1 promoter of the GH1 receptor gene (GHR) with longer alleles was associated with significantly increased body weight gain (W550, weight at age 550 days; ADG, average daily gain) and fat accrual (FAT, rib eye fat thickness). A threshold effect on ADG was associated with allele size variation at the GH1. A best fit model indicated a 3- to 6-fold effect of GH1 variation on ADG, when compared to the variation at the GHR and a known microsatellite at the somatomedin gene (IGF1, insulin-like growth factor 1). A threshold effect on FAT was associated with substitution of the short GHR allele by the longer GHR alleles; the effect of the GHR variation on FAT was 10-fold that of the variation at the GH1 and IGF1 loci. Among the 10 GH1-GHR-IGF1 multi-genotypes identified, the predominant genotype was homozygous for the large GH1 promoter (long/long, G2/G2 or domestic type), short GHR promoter (short/short or wild type), and short IGF1 microsatellite (short/short or wild type). This predominant multi-genotype suggests that selection pressure in the Nelore breed has been directed towards high ADG and W550, and low FAT. Our results mirror previous findings in the oMtla-oGH transgenic mouse model, in which the level of somatotropic gene expression acts through a threshold mechanism, and low expression results in adipogenesis, while high expression increases body growth. PMID- 22843056 TI - A developmentally regulated lipocalin-like gene is overexpressed in Tomato yellow leaf curl virus-resistant tomato plants upon virus inoculation, and its silencing abolishes resistance. AB - To discover genes involved in tomato resistance to Tomato yellow leaf curl virus (TYLCV), we previously compared cDNA libraries from susceptible (S) and resistant (R) tomato lines. Among the genes preferentially expressed in R plants and upregulated by TYLCV infection was a gene encoding a lipocalin-like protein. This gene was termed Solanum lycopersicum virus resistant/susceptible lipocalin (SlVRSLip). The SlVRSLip structural gene sequence of R and S plants was identical. SlVRSLip was expressed in leaves during a 15-day window starting about 40 days after sowing (20 days after planting). SlVRSLip was upregulated by Bemisia tabaci (the TYLCV vector) feeding on R plant leaves, and even more strongly upregulated following whitefly-mediated TYLCV inoculation. Silencing of SlVRSLip in R plants led to the collapse of resistance upon TYLCV inoculation and to a necrotic response along the stem and petioles accompanied by ROS production. Contrary to previously identified tomato lipocalin gene DQ222981, SlVRSLip was not regulated by cold, nor was it regulated by heat or salt. The expression of SlVRSLip was inhibited in R plants in which the hexose transporter gene LeHT1 was silenced. In contrast, the expression of LeHT1 was not inhibited in SlVRSLip silenced R plants. Hence, in the hierarchy of the gene network conferring TYLCV resistance, SlVRSLip is downstream of LeHT1. Silencing of another gene involved in resistance, a Permease-I like protein, did not affect the expression of SlVRSLip and LeHT1; expression of the Permease was not affected by silencing SlVRSLip or LeHT1, suggesting that it does not belong to the same network. The triple co-silencing of SlVRSLip, LeHT1 and Permease provoked an immediate cessation of growth of R plants upon infection and the accumulation of large amounts of virus. SlVRSLip is the first lipocalin-like gene shown to be involved in resistance to a plant virus. PMID- 22843057 TI - Magnetic resonance imaging findings in patients with systemic scleroderma and musculoskeletal symptoms. AB - OBJECTIVE: To explore the role of whole-body magnetic resonance imaging (MRI) in detecting musculoskeletal involvement in patients with systemic scleroderma and musculoskeletal symptoms. METHODS: Eighteen consecutive patients (8 men, 10 women) with systemic scleroderma (median age 46 years) presenting with musculoskeletal complaints underwent whole-body MRI at 1.5 T. Images were evaluated for abnormal signal intensity and/or thickening of subcutaneous fatty tissue septa, muscular fasciae, intramuscular perifascial septa, muscle signal intensity and articular or tendon sheath synovial abnormalities on STIR and post gadolinium scans. Additionally, C-reactive protein, creatinine kinase and the modified Rodnan skin score were determined. RESULTS: MRI indicated evidence of fasciitis, articular synovial inflammation, and subcutaneous thickening in 16 (89 %) patients. MRI findings were compatible with myopathy or myositis in 14 (78 %) patients, tenosynovitis in 11 (61 %) patients and enthesitis in 10 (56 %) patients. Typically, these manifestations were distributed symmetrically and mostly generalised. We only found few correlations with modified Rodnan skin score, C-reactive protein and creatinine kinase. CONCLUSION: In patients with systemic scleroderma experiencing musculoskeletal symptoms, whole-body MRI is able to detect involvement of muscles, fasciae, joints and entheses more confidently compared with clinical and laboratory parameters. PMID- 22843058 TI - Comparative diagnostic performance of 18F-FDG PET/CT versus whole-body MRI for determination of remission status in multiple myeloma after stem cell transplantation. AB - OBJECTIVES: To compare the diagnostic performance of whole-body magnetic resonance imaging (WBMRI) versus (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) for determination of remission status in patients with multiple myeloma (MM) after stem cell transplantation (SCT). METHODS: Thirty-one patients were examined by both WBMRI and PET/CT after SCT. Imaging results and clinical remission status as determined by the clinical gold standard (Uniform Response Criteria) were compared. RESULTS: One hundred four lesions were detected in 21 patients. PET/CT had a sensitivity of 50.0 %, a specificity of 85.7 %, a positive predictive value of 62.5 %, a negative predictive value of 78.3 %, and an overall accuracy of 74.2 % for determination of remission status. MRI had a sensitivity of 80.0 %, a specificity of 38.1 %, a positive predictive value of 38.1 %, a negative predictive value of 80 %, and an overall accuracy of 51.6 %. Concordant results were observed in only 12 (11.5 %) of the 104 lesions. CONCLUSIONS: In the post-treatment setting, both FDG PET/CT and WBMRI provide information about the extent of disease, allowing for a more comprehensive evaluation of persisting or recurrent myeloma. MRI may often be false positive because of persistent non-viable lesions. Therefore, PET/CT might be more suitable than MRI for determination of remission status. PMID- 22843060 TI - Expression of miRNA-146a in nasopharyngeal carcinoma is upregulated by Epstein Barr virus latent membrane protein 1. AB - We aimed to investigate the relationship between miRNA-146a and latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC). The expression levels of LMP1 in 40 cases of NPC, 28 cases of chronic nasopharyngitis and NPC cell lines CNE1 and CNE1-GL (in which LMP1 was stably transfected) were detected by immunohistochemical staining. The expression of miRNA-146a in 16 cases of NPC, 13 cases of chronic nasopharyngitis and cell lines was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. A plasmid containing the luciferase gene under the control of miRNA-146a promoter (pri-miRNA-146a) was constructed and transfected into NPC cells, and the luciferase activity was detected. LMP1 was positive in 17.9% (5/28) of chronic nasopharyngitis cases and 62.5% (25/40) of NPC cases (p<0.01). The miRNA-146a levels in NPC were significantly higher than that in chronic nasopharyngitis (p<0.01), and were higher in CNE1-GL cells than those in CNE1 cells (p<0.01). The expression of miRNA-146a in human NPC was elevated by EBV associated antigen LMP1, probably through the activation of the miRNA-146a promoter. PMID- 22843061 TI - Production of triterpenoid anti-cancer compound taraxerol in Agrobacterium transformed root cultures of butterfly pea (Clitoria ternatea L.). AB - Independent transformed root somaclones (rhizoclones) of butterfly pea (Clitoria ternatea L.) were established using explant co-cultivation with Agrobacterium rhizogenes. Rhizoclones capable of sustained growth were maintained under low illumination in auxin-free agar-solidified MS medium through subcultures at periodic intervals. Integration of T(L)-DNA rolB gene in the transformed rhizoclone genome was verified by Southern blot hybridization, and the transcript expression of T(R)-DNA ags and man2 genes was ascertained by reverse transcription polymerase chain reaction analysis. The major compound isolated and purified from the transformed root extracts was identified as the pentacyclic triterpenoid compound taraxerol using IR, (1)H-NMR, and (13)C-NMR spectroscopy. The taraxerol yield in cultured hairy roots, as quantified by HPTLC analysis, was up to 4-fold on dry weight basis compared to that in natural roots. Scanning of bands from cultured transformed roots and natural roots gave super-imposable spectra with standard taraxerol, suggesting a remarkable homology in composition. To date, this is the first report claiming production of the cancer therapeutic phytochemical taraxerol in genetically transformed root cultures as a viable alternative to in vivo roots of naturally occurring plant species. PMID- 22843062 TI - Experimental investigation and optimization of process variables affecting the production of extracellular lipase by Kluyveromyces marxianus IFO 0288. AB - In this study, the production and optimization of extracellular lipase from Kluyveromyces marxianus IFO 0288 was investigated by using optimized nutritional and cultural conditions in a yeast medium containing glucose as the carbon source in fully aerobic batch fermentation (150 rpm). The influence of four fermentation parameters (type of lipidic source, initial culture pH, temperature, and length of fermentation) on growth and lipase production was investigated and evaluated using the conventional "one variable at a time" approach and response surface methodology. An 18-fold increase in lipase production during 65 h of fermentation was obtained with optimized nutritional (0.5 % olive oil) and cultivation (pH 6.5, 35 degrees C) conditions by employing the conventional optimization method. By applying the response surface methodology technique the initial pH value of 6.4 and temperature of 32.5 degrees C were identified as optimal and led to further improvements (up to 18-fold) of extracellular lipase production. The results provide, for the first time, evidence that K. marxianus has the potential to be used as an efficient producer of extracellular lipase with prospective application in a variety of industrial and biotechnological areas. PMID- 22843063 TI - Optimization of elicitation conditions with methyl jasmonate and salicylic acid to improve the productivity of withanolides in the adventitious root culture of Withania somnifera (L.) Dunal. AB - Adventitious root cultures derived from leaf derived callus of Withania somnifera (L.) Dunal were treated with methyl jasmonate and salicylic acid independently. Biomass accumulation, culture age, elicitation period, and culture duration were optimized for higher withanolides production in the two best-responding varieties collected from Kolli hills (Eastern Ghats) and Cumbum (Western Ghats) of Tamil Nadu, India. Between the two elicitors, salicylic acid (SA) improved the production of major withanolides (withanolide A, withanolide B, withaferin A, and withanone) as well as minor constituents (12-deoxy withastramonolide, withanoside V, and withanoside IV) in the Kolli hills variety. Treatment of root biomass (11.70 g FW) on 30-day-old adventitious root cultures with 150 MUM SA for 4 h elicitor exposure period resulted in the production of 64.65 mg g(-l) dry weight (DW) withanolide A (48-fold), 33.74 mg g(-l) DW withanolide B (29-fold), 17.47 mg g(-l) DW withaferin A (20-fold), 42.88 mg g(-l) DW withanone (37-fold), 5.34 mg g(-l) DW 12-deoxy withastramonolide (nine fold), 7.23 mg g(-l) DW withanoside V (seven fold), and 9.45 mg g(-l) DW withanoside IV (nine fold) after 10 days of elicitation (40th day of culture) when compared to untreated cultures. This is the first report on the use of elicitation strategy on the significant improvement in withanolides production in the adventitious root cultures of W. somnifera. PMID- 22843064 TI - Joseph Gensoul and the earliest illustrated operations for maxillary sinus carcinoma. AB - Surgery has evolved along with anatomical illustrations through the ages. Joseph Gensoul (1797-1858), an important figure of the great Lyonnaise medical tradition of the 19th century, was occupied with many different surgical diseases, mostly diseases of the face. Apart from his many contributions stand various techniques on ophthalmological, otorhinolaryngological and oral and maxillofacial surgery. In this context, two rare illustrations depicting an innovative facial surgical operation performed by the great surgeon Joseph Gensoul are thoroughly analyzed. The two illustrations represent the "before" and "after" phases of Gensoul's most eminent operation, most probably practiced for a maxillary sinus carcinoma. This surgical operation is probably the earliest recorded of its kind in the history of surgery, even though the development of maxillary surgery is connected with the practice of Irwin Moure, who also practiced a type of lateral rhinotomy about a century later than Gensoul. Surgical illustrations are closely related to the history of surgery in every corner of the world. PMID- 22843065 TI - Sudden sensorineural hearing loss: systemic steroid therapy and the risk of glucocorticoid-induced hyperglycemia. AB - Sudden sensorineural hearing loss is usually treated with systemic glucocorticoids. Intratympanic injections of glucocorticoids offer a possibly equivalent treatment alternative, avoiding adverse systemic effects on blood glucose. We, therefore, investigated the extent to which different doses of systemic glucocorticoid therapy affects blood glucose levels. We conducted a retrospective analysis of treatment courses in 179 patients from the Departments of Otorhinolaryngology, Ophthalmology and Dermatology who underwent short-course systemic glucocorticoid therapy. Patients were subdivided into three groups on the basis of their cumulative prednisolone dose from days 1 to 3 (Group 1: <750 mg; Group 2: 750-1,499 mg; Group 3: >1,499 mg); in addition, a distinction was made between diabetic and non-diabetic patients. Among the non-diabetic patients on days 2-4, diabetic levels of fasting blood glucose were detected significantly more often (P < 0.01) in Group 3 (67 %) than in Group 1 (28 %) and Group 2 (21 %). Furthermore, there was a highly significant mean Pearson correlation (r = 0.329; P < 0.01) between blood glucose levels and glucocorticoid dose. This correlation was even more pronounced in the diabetic patients (r = 0.51; P = 0.02). In this category, hyperglycemia was detected in 40 % of patients in Group 1, 63 % in Group 2 and 100 % in Group 3. The prevalence of glucocorticoid-induced hyperglycemia during systemic therapy is high and rises as the dose increases. This should be kept in mind when choosing the dosage. Besides, it should also be considered that even short-term hyperglycemia presents possible health risks and the risk of inducing diabetes. This is especially of interest as intratympanic therapy offers a possible alternative to the systemic application. PMID- 22843066 TI - Role of metallothionein 1E in the migration and invasion of human glioma cell lines. AB - Metallothionein 1E (MT1E) has been found to be highly expressed in motile cell lines. We investigated whether MT1E actually modulates the migration and invasion of human glioma cell lines and the types of factors that have an effect on MT1E. RNA differential display was performed using GenefishingTM technology in the human glioma cell lines U343MG-A, U87MG and U87MG-10'; the results were validated by RT-PCR and northern blot analysis, in order to detect possible genetic changes as the determining factors for migration ability in malignant glioma. MT1E was identified in U87MG, a highly motile cell line. The migration and invasion abilities of human glioma cell lines, and MT1E transfectants were investigated using simple scratch testing and Matrigel invasion assays. Morphological and cytoskeletal (actin, vimentin) changes were documented by light and confocal microscopy. The expression of MT1E in four glioma cell lines was assessed by RT PCR and western blotting. In addition, the effects of MT1E on the activity of the NF-kappaB p50/p65 transcription factor, MMP-2 and -9 were examined by western blotting and zymography. The endogenous MT1E expression in the human glioma cell lines was statistically correlated with their migratory abilities and invasion. The U87-MT-AS cells became more round and had decreased stress fibers, compared with the U87MG cells. Endogenous MT1E expression in the four human glioma cell lines was directly correlated with migration. Two antisense MT1E-transfected cell lines showed decreased NF-kappaB p50 translocation into the nucleus, which led to decreased activity of MMP-9 in conditioned media. It may be postulated that MT1E can enhance the migration and invasion of human glioma cells by inducing MMP-9 inactivation via the upregulation of NF-kappaB p50. PMID- 22843067 TI - Housing characteristics of older Asian Americans. AB - This study described the housing tenure and residential density of elders from the six largest Asian American ethnic groups in the US: Chinese, Filipino, Japanese, Korean, Asian Indian, and Vietnamese. These groups were compared to non Hispanic White elders. Based on data from the 2000 US Census of Population, multilevel regression analyses showed that Japanese elders were most like the non Hispanic White comparison group across the two housing dimensions. Older Vietnamese persons were least likely to own their homes compared to the other Asian American groups, and with the exception of the Japanese elders, all Asian groups were more likely than non-Hispanic Whites to live in crowded residences. In general, considerable heterogeneity in housing characteristics was observed across the six older Asian American ethnic groups, even after controlling for assimilation and housing discrimination indicators. PMID- 22843068 TI - Chromosome number variation and evolution in Neotropical Leguminoseae (Mimosoideae) from northeastern Brazil. AB - Most members of the subfamily Mimosoideae have pantropical distributions, variable habits, and a basic chromosome number x = 13. We examined karyotypic evolution of 27 species of this subfamily occurring principally in northeastern Brazil by examining chromosomes stained with Giemsa. All of the species had semi reticulated interphase nuclei and early condensing segments in the proximal region of both chromosome arms. The basic number x = 13 was the most frequent, with 2n = 2x = 26 in 19 of the species, followed by 2n = 4x = 52 and 2n = 6x = 78. However, the three species of the genus Calliandra had the basic number x = 8, with 2n = 2x = 16, while Mimosa cordistipula had 2n = 4x = 32. The karyotypes were relatively symmetrical, although bimodality was accentuated in some species, some with one or two acrocentric pairs. As a whole, our data support earlier hypotheses that the Mimosoideae subfamily has a basic number of x = 13 and underwent karyotypic evolution by polyploidy. However, x = 13 seems to be a secondary basic number that originated from an ancestral stock with x1 = 7, in which polyploidy followed by descending disploidy gave rise to the current lineages with x = 13. Another lineage, including current representatives of Calliandra with x = 8, may have arisen by ascending disploidy directly from an ancestral monoploid stock with x1 = 7. PMID- 22843069 TI - Detection limits of the strip test and PCR for genetically modified corn in Brazil. AB - Brazilian legislation establishes a labeling limit for products that contain more than 1% material from genetically modified organisms (GMOs). We assessed the sensitivity of the lateral flow strip test in detection of the GMO corn varieties Bt11 and MON810 and the specificity and sensitivity of PCR techniques for their detection. For the strip test, the GMO seeds were mixed with conventional seeds at levels of 0.2, 0.4 and 0.8% for Bt11, and 0.4, 0.8 and 1.6% for MON810. Three different methodologies were assessed and whole seeds, their endosperm and embryonic axis were used. For the PCR technique, the GMO seeds of each of the two varieties were mixed with conventional seeds at levels of 20, 10, 5, 2, 1, and 0.5%. The seeds were ground and the DNA extracted. For detection of the GMO material, specific primers were used for MON810 and Bt11 and maize zein as an endogenous control. The sensitivity of the strip test varied for both maize varieties and methodologies. The test was positive for Bt11 only at 0.8%, in contrast with the detection limit of 0.4% indicated by the manufacturer. In the multiplex PCR, the primers proved to be specific for the different varieties. These varieties were detected in samples with one GMO seed in 100. Thus, this technique proved to be efficient in detecting contaminations equal to or greater than 1%. PMID- 22843070 TI - Pyrroloquinoline quinone rescues hippocampal neurons from glutamate-induced cell death through activation of Nrf2 and up-regulation of antioxidant genes. AB - Pyrroloquinoline quinone (PQQ) has been shown to protect primary cultured hippocampal neurons from glutamate-induced cell apoptosis by scavenging reactive oxygen species (ROS) and activating phosphatidylinositol-3-kinase (PI3K)/Akt signaling. We investigated the downstream pathways of PI3K/Akt involved in PQQ protection of glutamate-injured hippocampal neurons. Western blot analysis indicated that PQQ treatment following glutamate stimulation triggers phosphorylation of glycogen synthase kinase 3beta, accompanied by maintenance of Akt activation. Immunostaining and quantitative RT-PCR revealed that PQQ treatment promotes nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), and up-regulates mRNA expression of Nrf2 and the antioxidant enzyme genes, heme oxygenase-1 and glutamate cysteine ligase catalytic in glutamate-injured hippocampal neurons; this is a process dependent on the PI3K/Akt pathway, as evidenced by blocking experiments with PI3K inhibitors. In addition, increased ROS production and decreased glutathione levels in glutamate injured hippocampal neurons were found to be reduced by PQQ treatment. Collectively, our findings suggest that PQQ exerts neuroprotective activity, possibly through PI3K/Akt-dependent activation of Nrf2 and up-regulation of antioxidant genes. However, the ability of PQQ to scavenge ROS was not totally regulated by PI3K/Akt signaling; possibly it is governed by other mechanisms. PMID- 22843071 TI - Changes in protein profile detected in seedlings of Caesalpinia peltophoroides (Fabaceae) after exposure to high concentration of cadmium. AB - Sibipiruna (Caesalpinia peltophoroides Benth) is a tree of the Brazilian Atlantic Forest. It is a flowering ornamental tree widely planted throughout Brazil and indicated for restoration of degraded areas. We examined protein profile changes in leaves of seedlings of C. peltophoroides grown in nutrient solution under greenhouse conditions, after exposure to cadmium (Cd; 32 mg/L). A two-dimensional gel was used to analyze proteins expressed in response to stress 24 and 72 h after initiation of treatment with Cd. Various protein bands were identified that were related to stress response and/or metabolic adjustments, including proteins involved with resistance to stress, including detoxification, degradation, antioxidant, transport, signal transduction, photosynthesis, electron transport, biosynthesis reactions, and transcription regulation. After 24 h of Cd exposure, the genes of most of these proteins were upregulated. These putative proteins were associated with resistance to stress, including heat shock proteins, heat stress transcriptional factor and other transcriptional factors, aquaporins, glutathione transferase and choline monooxygenase. Most of the putative proteins observed after 72 h of exposure to Cd were downregulated. They were mainly photosynthetic process proteins, such as NAD(P)H-quinone oxidoreductase, photosystem I assembly, and photosystem II CP47 chlorophyll apoprotein. There were also proteins involved with degradation, biosynthesis and antioxidant activity, such as ATP-dependent Clp protease, methylthioribose-1 phosphate and glutathione peroxidase 2. Based on preliminary proteomic analysis, we conclude that proteins related to photosynthetic activity are inhibited, decreasing plant performance under stress conditions and that several proteins related to defense mechanisms are activated, inducing the plant defense response. PMID- 22843072 TI - RAPD analysis of genetic diversity and population structure of Elymus sibiricus (Poaceae) native to the southeastern Qinghai-Tibet Plateau, China. AB - Genetic diversity of Elymus sibiricus (Poaceae) was examined in eight populations from the southeast Qinghai-Tibet Plateau. We detected 291 RAPD polymorphic loci in 93 samples. The percentage of polymorphic bands (PPB) was 79%. Genetic diversity (H(E)) was 0.264, effective number of alleles (N(E)) was 1.444, Shannon's information index (H(O)) was 0.398, and expected Bayesian heterozygosity (H(B)) was 0.371. At the population level, PPB = 51%, N(E) = 1.306, H(E) = 0.176, I = 0.263, and H(B) = 0.247. A high level of genetic differentiation was detected based on Nei's genetic diversity analysis (G(ST) = 32.0%), Shannon's index analysis (33.7%), and the Bayesian method (theta(B) = 33.5%). The partitioning of molecular variance by AMOVA demonstrated significant genetic differentiation within populations (60%) and among populations (40%). The average number of individuals exchanged between populations per generation (N(m)) was 1.06. The populations were found to share high levels of genetic identity. No significant correlation was found between geographic distance and pairwise genetic distance (r = 0.7539, P = 0.9996). Correlation analysis revealed a significant correlation (r = 0.762) between RAPD H(E) found in this study and ISSR H(E) values from a previous study. PMID- 22843073 TI - MLH1 and XRCC1 polymorphisms in Mexican patients with colorectal cancer. AB - DNA repair proteins maintain DNA integrity; polymorphisms in genes coding for these proteins can increase susceptibility to colorectal cancer (CRC) development. We analyzed a possible association of MLH1 -93G>A and 655A>G and XRCC1 Arg194Trp and Arg399Gln polymorphisms with CRC in Mexican patients. Genomic DNA samples were obtained from peripheral blood of 108 individuals with CRC (study group) at diagnosis and 120 blood donors (control group) from Western Mexico; both groups were mestizos. The polymorphisms were detected by PCR-RFLP. Association was estimated by calculating the odds ratio (OR). We found that the MLH1 and XRCC1 polymorphisms were in Hardy- Weinberg equilibrium. The MLH1 655A>G polymorphism in the 655G allele was associated with a 2-fold increase risk for CRC (OR = 2.04 and 95% confidence interval (95%CI) = 1.12-3.69; P < 0.01), while the MLH1 -93G>A polymorphism allele was associated with a protective effect (OR = 0.60, 95%CI = 0.40-0.89; P = 0.01 in the -93A allele and OR = 0.32, 95%CI = 0.13-0.79; P = 0.01 in the AA genotype). The XRCC1 Arg194Trp and Arg399Gln polymorphisms did not show any significant associations. In conclusion, we found that MLH1 -93G>A and 655A>G polymorphisms are associated with CRC in Mexican patients. PMID- 22843074 TI - Novel single nucleotide polymorphisms of the bovine methyltransferase 3b gene and their association with meat quality traits in beef cattle. AB - DNA methylation is essential for adipose deposition in mammals. We screened SNPs of the bovine DNA methyltransferase 3b (DNMT3b) gene in Snow Dragon beef, a commercial beef cattle population in China. Nine SNPs were found in the population and three of six novel SNPs were chosen for genotyping and analyzing a possible association with 16 meat quality traits. The frequencies of the alleles and genotypes of the three SNPs in Snow Dragon beef were similar to those in their terminal-paternal breed, Wagyu. Association analysis disclosed that SNP1 was not associated with any of the traits; SNP2 was significantly associated with lean meat color score and chuck short rib score, and SNP3 had a significant effect on dressing percentage and back-fat thickness in the beef population. The individuals with genotype GG for SNP2 had a 25.7% increase in lean meat color score and a 146% increase in chuck short rib score, compared with genotype AA. The cattle with genotype AG for SNP3 had 35.7 and 24% increases in dressing percentage and 28.8 and 29.2% increases in back-fat thickness, compared with genotypes GG and AA, respectively. Genotypic combination analysis revealed significant interactions between SNP1 and SNP2 and between SNP2 and SNP3 for the traits rib-eye area and live weight. We conclude that there is considerable evidence that DNMT3b is a determiner of beef quality traits. PMID- 22843076 TI - Aneugenic effects of the genistein glycosidic derivative substituted at C7 with the unsaturated disaccharide. AB - Genistein, due to its recognized chemopreventive and antitumour potential, is a molecule of interest as a lead compound in drug design. Recently, we found that the novel genistein derivative, [7-O-(2,3,4,6-tetra-O-acetyl-beta-D galactopyranosyl)-(1 -> 4)-(6-O-acetyl-hex-2-ene-alpha-D-erythro pyranosyl)genistein, named G21, induced aberrations in mitotic spindle formation. In the presented study, we investigated the properties of G21 relevant to its genotoxic activity. The inhibition of topoisomerase IIalpha activity was evaluated in decatenation assay and immunoband depletion assay, the covalent DNA topoisomerase IIalpha complexes and histone gammaH2AX were detected immunofluorescently. Genotoxic effects of the tested compounds were assessed in micronucleation assay. The presence of centromeres in the micronuclei and the multiplication of centrosomes were evaluated in fluorescence immunolabelled specimens. The inhibition of tubulin polymerization was measured spectrophotometrically. We found that both tested drugs were able to inhibit topoisomerase II activity; however, G21, in contrast to genistein, blocked this enzyme at the concentration far exceeding cytotoxic IC(50). We also found that both compounds caused micronucleation in DU 145 prostate cancer cells, but in contrast to genistein, G21 exhibited aneugenic activity, manifested by the presence of centromeres in micronuclei formed in cells treated with the drug. Aneugenic properties of G21 resulted from the inhibition of tubulin polymerization and centrosome disruption, not observed in the presence of genistein. The study supports and extends our previous observations that the mechanisms of cytotoxicity of genistein and its new glycosidic derivative-G21 are significantly different. PMID- 22843075 TI - The method of bladder cuff excision during laparoscopic radical nephroureterectomy does not affect oncologic outcomes in upper tract urothelial carcinoma. AB - PURPOSE: To determine whether the method of bladder cuff excision (BCE) during laparoscopic radical nephroureterectomy for upper urinary tract urothelial carcinoma is associated with rates of disease recurrence or metastases. METHODS: We performed a retrospective review of all laparoscopic radical nephroureterectomies performed at our institution over 10 years. Three methods of BCE were used: transurethral incision (TUI) with Collins knife and a single intravesical port, open extravesical, and open intravesical via cystotomy. Logistic regression analyses were performed to determine whether BCE method was associated with recurrence or metastases. RESULTS: Laparoscopic radical nephroureterectomy was performed in 110 patients. BCE was performed via TUI in 61 patients, open extravesical in 29, and open intravesical in 20. After a median follow-up of 22 months, 36 patients (32.7 %) developed recurrences. Metastases were observed in 18 patients (16.4 %). Recurrence rates were 32.8, 27.6, and 40.0 % in the TUI, extravesical, and intravesical groups, respectively (p = 0.69). Positive surgical margins occurred in nine patients with no significant difference between groups. Factors associated with recurrence or metastases in a multivariate regression analysis were stage, positive surgical margins and carcinoma in situ (CIS). The method of BCE was not associated with oncologic outcomes. CONCLUSIONS: The three methods of bladder cuff excision (TUI, extravesical, and intravesical) are oncologically valid with similar recurrence and metastases rates when performed during laparoscopic radical nephroureterectomy. Stage, positive margin status and CIS are predictive of adverse oncologic outcomes and can facilitate postoperative prognostication. PMID- 22843077 TI - Primary candidiasis and squamous cell carcinoma of the larynx: report of a case. AB - Primary candidiasis is rare and often confused with a pre-cancerous lesion, squamous cell carcinoma, or verrucous carcinoma. We report an extremely rare case of squamous cell carcinoma of the vocal cord following primary candidiasis. A 62 year-old man presented to our department reporting a 1-month history of hoarseness. He underwent laryngeal microscopic surgery for a presumptive diagnosis of glottic carcinoma. Histopathologic examination revealed candidiasis and scattered moderate dysplasia. He was treated with itraconazole for 4 weeks, and followed up without any recurrence of candidiasis. However, the 42-month follow-up examination revealed a focal whitish lesion on the right true vocal cord, and a repeat biopsy of this area revealed squamous cell carcinoma without evidence of candidiasis. The patient was treated with radiotherapy and remains well with no signs of tumor recurrence or candidiasis. PMID- 22843078 TI - Improvement of dissolution and hypoglycemic efficacy of glimepiride by different carriers. AB - Effects of tromethamine (Tris), polyvinylpyrrolidone (PVP-K25), and low molecular weight chitosan (LM-CH) on dissolution and therapeutic efficacy of glimepiride (Gmp) were investigated using physical mixtures (PMs), coground mixtures, coprecipitates (Coppts) or kneaded mixtures (KMs), and compared with drug alone. Fourier transform infrared spectroscopy, differential scanning colorimetry, and X ray diffractometry were performed to identify any physicochemical interaction with Gmp. Surface morphology was examined via scanning electron microscopy. The results of Gmp in vitro dissolution revealed that it was greatly enhanced by Coppt with Tris or PVP-K25 and KM with LM-CH at a drug to carrier ratio of 1:8. Gmp amorphization by PVP-K25 and LM-CH was a major factor in increasing Gmp dissolution. Being basic, Tris might increase the pH of the microdiffusion layer around Gmp particles improving its dissolution. Formation of water-soluble complexes suggested by solubility study may also explain the enhanced dissolution. Capsules were prepared from Coppts and KM 1:8 drug to carrier binary systems and also with Tris PMs. In vivo, the hypoglycemic efficacy of Gmp capsules in rabbits increased by 1.63-, 1.50-, and 1.46-fold for 1:8 Coppts with Tris or PVP-K25 and KM with LM-CH respectively, compared with Gmp alone. Surprisingly, the response to Tris PM 1:20 capsules was 1.52-fold revealing statistically insignificant difference to that of Tris Coppt 1:8 (1.63 fold). As a conclusion, dissolution enhancement and hypoglycemic potentiation by 1:20 PM of Gmp/Tris, being simple and easy to prepare, may enable development of a reduced dose and fast-release oral dosage form of Gmp. PMID- 22843079 TI - Comparison of plasticizer effect on thermo-responsive properties of Eudragit RS films. AB - Preparation of an intelligent drug delivery system which releases the drug in response to the environmental stimuli in a controlled manner is one of the interesting subjects and it is the purpose of this study. Films composed of Eudragit RS and different percentages of plasticizers (0%, 5%, 10%, or 20% w/w based on polymer weight), poly ethylene glycol 400 or triethyl citrate (TEC), were prepared by solvent casting method. Glass transition temperatures of the films were determined by differential scanning colorimetery. Water uptake and drug permeation through membranes with the glass transition temperature (Tg) close to the body temperature were investigated. Propranolol hydrochloride and acetaminophen were used as model drugs in permeation studies. The results showed that Eudragit RS films with 20% of either plasticizer showed thermo-responsivity around body temperature. The water uptake of the films and the permeation rates of both drugs increased at temperatures above the Tg of the films. The films containing TEC was found to be more appropriate thermo-responsive membrane due to a higher sensitivity to temperature and more ability to control drug release. PMID- 22843080 TI - Efficiency and stability enhancement of cis-epoxysuccinic acid hydrolase by fusion with a carbohydrate binding module and immobilization onto cellulose. AB - Cis-epoxysuccinic acid hydrolase (CESH) is an enzyme that catalyzes cis epoxysuccinic acid to produce enantiomeric L(+)-tartaric acid. The production of tartaric acid by using CESH would be valuable in the chemical industry because of its high yield and selectivity, but the low stability of CESH hampers its application. To improve the stability of CESH, we fused five different carbohydrate-binding modules (CBMs) to CESH and immobilized the chimeric enzymes on cellulose. The effects of the fusion and immobilization on the activity, kinetics, and stability of CESH were compared. Activity measurements demonstrated that the fusion with CBMs and the immobilization on cellulose increased the pH and temperature adaptability of CESH. The chimeric enzymes showed significantly different enzyme kinetics parameters, among which the immobilized CBM30-CESH exhibited twofold catalytic efficiency compared with the native CESH. The half life measurements indicated that the stability of the enzyme in its free form was slightly increased by the fusion with CBMs, whereas the immobilization on cellulose significantly increased the stability of the enzyme. The immobilized CBM30-CESH showed the longest half-life, which is more than five times the free native CESH half-life at 30 degrees C. Therefore, most CBMs can improve enzymatic properties, and CBM30 is the best fusion partner for CESH to improve both its enzymatic efficiency and its stability. PMID- 22843081 TI - Combined laparoscopic and open extraperitoneal approach to scrotal hernias. AB - BACKGROUND: Laparoscopic repair of scrotal hernias is often a difficult endeavor to successfully complete. The longstanding nature of these hernias often results in significant adhesions and anatomic distortion of the inguinal floor. These two issues make reduction of the hernia arduous and subsequent reinforcement of the parietal sac difficult. We have previously described techniques to increase the chances of success when attempting laparoscopic repair of scrotal hernias. Here, we describe some of those techniques as well as a combined laparoscopic and open approach to achieve a robust preperitoneal repair of incarcerated scrotal hernias when the usual totally extraperitoneal approach does not work. PATIENTS AND METHODS: We performed a retrospective review of 1890 TEP hernia repairs we performed from 1990 to 2010. Rate of conversion to an open approach or a combined laparoscopic and open approach was examined. Incidence of complications or recurrences was assessed over a 12-month follow-up period. RESULTS: Among the 1890 TEP repairs, 94 large scrotal hernias were identified. Of these, nine cases (9.5 %) required conversion to an open procedure due to an incarcerated and indurated omentum. Three were completed with a conventional open preperitoneal whereas six patients (6.4 %) underwent repair with the combined approach. In this group, no recurrences or complications were found over a 12-month period. CONCLUSION: In cases where a large scrotal hernia may be difficult or dangerous to reduce laparoscopically, immediate conversion to an open repair may not be necessary. A combined laparoscopic and open approach can greatly assist in the visualization and dissection of the preperitoneal space, thereby facilitating reduction of the hernia and placement of the mesh. PMID- 22843082 TI - Prevalence and resolution of anemia with paraesophageal hernia repair. AB - BACKGROUND: Paraesophageal hernias may produce a variety of clinical sequelae including anemia and esophagogastric ulcerations or erosions. We examined the prevalence of anemia in patients with paraesophageal hernias and frequency of anemia resolution with hernia repair. METHODS: Patients undergoing paraesophageal hernia repairs from July 1996 to September 2010 were included. Data gathered included age, gender, type of hernia, presence of symptomatic anemia, presence of esophagogastric ulcer/erosion, type of repair, and anemia resolution. RESULTS: One hundred eighty-three patients underwent paraesophageal hernia repair; of these, 68 (37%) were anemic. Of these anemic patients, 39 (57%) were symptomatic from their anemia or specifically referred for anemia, and 20 (29%) had esophagogastric ulceration/erosion. Fifty-eight had documented follow-up. Overall, of these, 35 (60%) had resolution of their anemia. Seventy percent of symptomatic patients had resolution of their anemia, compared to 48% of asymptomatic patients (p = 0.1). Of patients with esophagogastric ulceration/erosion, 85% were symptomatic and 88% had resolution of anemia, compared to 50% of patients without ulceration/erosion (p = 0.015). CONCLUSIONS: Anemia was a common finding in patients with paraesophageal hernia and most patients were symptomatic because of their anemia. Those patients with esophageal or gastric ulceration/erosion were very likely to have symptomatic anemia, and, interestingly, these patients were more likely to have their anemia resolve with paraesophageal hernia repair. PMID- 22843083 TI - Damage control surgery with abdominal vacuum and delayed bowel reconstruction in patients with perforated diverticulitis Hinchey III/IV. AB - OBJECTIVE: With the use of abdominal vacuum therapy, we have developed a damage control concept for patients with perforated diverticulitis and generalized peritonitis. The primary aim of this concept was to enhance recovery and allow bowel reconstruction in a second-look operation. METHODS: A total of 51 patients (28 female, 55%) with a median (range) age of 69 (28-87) years, with perforated diverticulitis Hinchey III (n = 40, 78%) or Hinchey IV (n = 11, 22%) and a median (range) Mannheim peritonitis index of 26 (12-39), admitted between October 2006 and September 2011, were prospectively enrolled in the study. At initial operation, limited resection of the diseased segment, lavage, and application of abdominal vacuum-assisted closure dressing was performed. After patient resuscitation, a second look was performed in an elective setting. RESULTS: Hospital mortality rate was 9.8%; 35 (76%) of patients were discharged with reconstructed colon, and 93% of patients live without a stoma at follow-up. Risk factors for mortality were American Society of Anesthesiologist score (p = 0.01), organ failure at initial presentation (p = 0.03), cardiac comorbidity (p = 0.05), and a Hartmann procedure at second look (p = 0.00). CONCLUSION: With this abdominal vacuum-based damage control concept, an acceptable hospital mortality rate and a high rate of bowel reconstruction at second look were achieved in patients with perforated diverticulitis and generalized peritonitis. PMID- 22843084 TI - Systematic review and meta-analysis of the influence of HER2 expression and amplification in operable oesophageal cancer. AB - INTRODUCTION: The prognostic significance of human epidermal growth factor 2 (HER2) overexpression in patients diagnosed with oesophageal cancer is controversial. We performed a systematic review and meta-analysis to determine the influence of HER2 overexpression and amplification on outcomes in operable oesophageal cancer. METHODS: MEDLINE and Embase (January 1990 to November 2011) was searched for translational studies that correlated HER2 expression with survival in operable oesophageal cancer. RESULTS: Fourteen studies involving 1,464 patients who had undergone potentially curative oesophagectomy for oesophageal cancer [322 (22%) HER2-positive] were included. Five-year mortality was significantly higher in HER2-positive patients [odds ratio (OR) 1.43, 95% confidence interval (CI) 1.04 to 1.95, p = 0.03]. Analysis related to histological cell type demonstrated significantly higher 5-year mortality in HER2 positive squamous cell carcinoma [OR 2.88, 95% CI 1.34 to 6.17, p = 0.006] and adenocarcinoma [OR 1.91, 95% CI 1.15 to 3.17, p = 0.01] on sensitivity analysis of higher-quality studies. CONCLUSION: HER2 overexpression and gene amplification in operable oesophageal cancer was an indicator of poor prognosis. PMID- 22843085 TI - Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma. AB - OBJECTIVE: Tumor-stroma ratio (TSR) has been identified as a new and practicable prognostic histological characteristic of solid tumors. The aim of this study was to evaluate the prognostic value of TSR in resected esophageal squamous cell carcinoma (ESCC). METHODS: A total of 95 patients who underwent esophagectomy for ESCC were included in this study. TSR was assessed visually on the hematoxylin eosin-stained tissue sections of surgical specimens by two independent observers. Patients with more than 50% intratumor stroma were quantified as the stroma-rich group and those with less than 50% as the stroma-poor group. RESULTS: No significant differences were observed in patient, tumor, and treatment characteristics between the stroma-rich and stroma-poor groups. The 3-year overall survival and disease-free survival rates were 64% and 57%, respectively, in the stroma-poor group, and 23% and 23%, respectively, in the stroma-rich group. Both 3-year overall and disease-free survival rates in the stroma-poor group were significantly better than those in the stroma-rich group (p < 0.01). In a multivariate analysis, TSR was identified as a highly significant prognostic factor for 3-year overall survival (hazard ratio 3.450; p = 0.001) and 3-year disease-free survival (hazard ratio 2.995; p = 0.001), independent of pTNM stage and radicality of the primary tumor. CONCLUSION: Stroma-rich tumors were associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic histological characteristic in ESCC. TSR is simple and quick to determine, is reproducible, and could be easily incorporated in routine histological evaluation. PMID- 22843086 TI - A collaborative analysis of stereotactic lung radiotherapy outcomes for early stage non-small-cell lung cancer using daily online cone-beam computed tomography image-guided radiotherapy. AB - INTRODUCTION: We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. METHODS: Five hundred and five stage I-IIB (T1-3N0M0) non-small-cell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42-92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/mmHg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9-8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20-64 Gy) in three fractions (range, 1-15) over 8 days (range, 1-27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60-180). RESULTS: With a median follow-up of 1.6 years (range, 0.1-7.3), the 2-year Kaplan-Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size (>= 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. CONCLUSIONS: In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival was encouraging in operable patients. PMID- 22843088 TI - Stereotactic body radiotherapy for central lung tumors. AB - INTRODUCTION: Patients with centrally located lung tumors have been reported to have a higher risk of toxicity when treated with stereotactic body radiotherapy (SBRT) compared with patients with peripheral tumors. The optimal SBRT fractionation schedule for treatment of central tumors is unknown. The primary purpose of this study was to assess toxicity in patients with central lesions treated with SBRT at our institution, the majority of whom were treated with four fractions. METHODS: Forty-seven patients with 51 central lesions, either primary lung cancer or lung metastases, were treated with SBRT at the Department of Therapeutic Radiology, Yale University School of Medicine/Yale Cancer Center from 2007 to 2011. The patients were treated with three to five fractions with the majority of patients receiving 50 Gy in four fractions of 12.5 Gy. Forty of the lesions were located within 2 cm of the proximal tracheobronchial tree whereas 11 were located within 2 cm of other mediastinal structures. Toxicity data were collected and analyzed according to pretreatment and tumor characteristics and dosimetric parameters. Lobar control data were compiled. RESULTS: With a median follow-up of 11.3 months (range, 4.8-40.8), four patients experienced grade 3 dyspnea and one patient developed hemoptysis that contributed to respiratory failure and subsequent death. Grade 2 toxicity included fatigue (n = 3), dyspnea (n = 3), chest-wall pain (n = 1), and cough (n = 1). Patients with grade 3+ toxicity had larger maximum tumor diameters compared with those patients without grade 3+ toxicity (median diameter 4.3 cm versus 2.9 cm, p = 0.02). There were no detectable significant differences between the two groups with respect to baseline pulmonary function tests, distance to tracheobronchial tree, maximum point dose to the tracheobronchial tree, maximum dose to 5 cc of the tracheobronchial tree, mean lung dose, and volume of lung receiving 5 Gy, 10 Gy, and 20 Gy. There were two patients who experienced local recurrences. The median biological equivalent dose (linear quadratic formula, alpha/beta = 10) for patients with local recurrence was 76 Gy compared with 112.5 Gy for patients without local recurrence (2-tailed t test, p = 0.04). The 2-year actuarial lobar local control for the entire cohort was 94%. The 2-year lobar local-control rate for patients receiving a biological equivalent dose of 100 Gy or more was 100% and for those receiving less than 100 Gy was 80% (log rank, p = 0.02). CONCLUSION: SBRT for central lung tumors seems to be safe, although treatment of larger tumors does carry an increased risk of high-grade toxicity. Efforts to decrease the toxicity risk by decreasing the biologically equivalent dose resulted in increased local failure. PMID- 22843087 TI - Prognostic models to predict survival in non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin with or without bevacizumab. AB - BACKGROUND: To determine prognostic factors and build a model to predict 1-year overall survival (OS) and 6-month progression-free survival (PFS) in advanced non small-cell lung cancer (NSCLC) patients treated with first-line paclitaxel and carboplatin with or without bevacizumab. MATERIALS AND METHODS: We analyzed 26 pretreatment clinical variables in 850 NSCLC patients treated in the randomized Eastern Cooperative Oncology Group 4599 study. Univariate and multivariate analyses were performed to identify prognostic factors. Cox regression with 50% randomly sampled data was used to build nomograms with a prognostic score assigned to each factor. The model was validated with the remaining 50% of data. RESULTS: Eleven poor factors for OS (hazard ratio) were as follows: skin metastasis (4.49), body mass index less than 18.5 (2.09), increased serum lactate dehydrogenase (1.74), adrenal metastasis (1.52), performance status greater than 0 (1.45), low serum albumin (1.45), men (1.39), bone metastasis (1.39), large cell/not otherwise specified histology (1.29), mediastinal nodal metastasis (1.23), and treatment without bevacizumab (1.18). Seven poor factors for PFS were as follows: skin metastasis (3.13), treatment without bevacizumab (1.52), bone metastasis (1.41), liver metastasis (1.40), low serum albumin (1.39), performance status greater than 0 (1.21), and mediastinal nodal metastasis (1.14). Based on these factors, we built and validated two nomograms predicting 1-year OS and 6 month PFS. CONCLUSION: Using our proposed models, the probability of survival with first-line paclitaxel and carboplatin with or without bevacizumab in nonsquamous NSCLC patients can be estimated. These prognostic models provide a tool for research design and clinical decision making, such as patient stratification and therapy selection. PMID- 22843089 TI - Embodied inference and spatial cognition. AB - How much about our interactions with--and experience of--our world can be deduced from basic principles? This paper reviews recent attempts to understand the self organised behaviour of embodied agents, like ourselves, as satisfying basic imperatives for sustained exchanges with the environment. In brief, one simple driving force appears to explain many aspects of perception, action and the perception of action. This driving force is the minimisation of surprise or prediction error, which--in the context of perception--corresponds to Bayes optimal predictive coding (that suppresses exteroceptive prediction errors) and- in the context of action--reduces to classical motor reflexes (that suppress proprioceptive prediction errors). In what follows, we look at some of the phenomena that emerge from this single principle, such as the perceptual encoding of spatial trajectories that can both generate movement (of self) and recognise the movements (of others). These emergent behaviours rest upon prior beliefs about itinerant (wandering) states of the world--but where do these beliefs come from? In this paper, we focus on the nature of prior beliefs and how they underwrite the active sampling of a spatially extended sensorium. Put simply, to avoid surprising states of the world, it is necessary to minimise uncertainty about those states. When this minimisation is implemented via prior beliefs- about how we sample the world--the resulting behaviour is remarkably reminiscent of searches seen in foraging or visual searches with saccadic eye movements. PMID- 22843090 TI - The spatial intersection of minds. AB - Spatial formats of information are ubiquitous in the cognitive and neural sciences. There are neural uses of space in the topographic maps found throughout cortex. There are metaphorical uses of space in cognitive linguistics, physical uses of space in ecological psychology, and mathematical uses of space in dynamical systems theory. These varied informational uses of space each provide a single contiguous medium through which cognitive processes can be shared across subsystems. As we further develop our understanding of how the human mind processes information in real time, the continuous sharing and cascading of information patterns between brain areas can be extended to a sharing and cascading of information between multiple brains and bodies to produce coordinated behavior. Essentially, the way you and the people around you negotiate your shared space affects the way you think, because space is a fundamental part of how you think. It is via space that the mental processes of one mind can form an intersection with the mental processes of another mind. PMID- 22843091 TI - Inhibitory effect of PPARgamma on NR0B1 in tumorigenesis of lung adenocarcinoma. AB - NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor gamma (PPARgamma) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARgamma was examined. The transactivation ability of PPARgamma was inhibited by NR0B1 in lung adenocarcinoma, and the N terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARgamma. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARgamma overexpression. ALDH activity increased by treatment with PPARgamma inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARgamma expression was a negative prognostic factor in Pathological Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARgamma on the malignant grade of lung adenocarcinoma. PMID- 22843092 TI - Sudden cardiac arrest in adolescence: the case of ventricular fibrillation 11 years after presenting with Kawasaki's disease. PMID- 22843093 TI - Relationship between depression and subclinical left ventricular changes in the general population. AB - OBJECTIVE: Individuals with depression are at risk of heart failure. This study was designed to elucidate the relationship between depression and subclinical left ventricular (LV) changes in the general Korean population. DESIGN: Cross sectional cohort study. SETTING: University hospital. PATIENTS: A total of 2420 participants, aged 40-79 years, without known cardiovascular disease, were recruited from the Korean Genome Epidemiology Study. METHODS: All individuals underwent conventional two-dimensional echocardiography and tissue Doppler imaging (TDI) to measure LV changes. In addition, subjects answered the Beck depression inventory I (BDI-I) questionnaire to assess depression levels. Participants were assigned to one of three groups based on the BDI-I score: no depression (0<= BDI-I <10), mild depression (10<= BDI-I <20), and moderate to severe depression (BDI-I >=20). RESULTS: LV diastolic function parameters, such as the transmitral A wave velocity and E/A ratio, TDI early diastolic velocity (E(a)), and E/E(a) ratio, were progressively altered across the levels of depression (all p<0.01). After multivariate adjustment, subjects with moderate to severe depression showed a significantly higher LV mass index (p=0.019) and lower TDI E(a) velocity (p=0.006) compared with those without depression. In linear regression models, the presence of depression (BDI-I >=10) was independently associated with a lower TDI E(a) velocity (p=0.004). CONCLUSIONS: Individuals with moderate to severe depression showed subclinical alterations in LV structure and function. These findings support the hypothesis that clinical depression may be an independent risk factor for the development of cardiovascular disease. PMID- 22843094 TI - Posterior laryngitis: a study of persisting symptoms and health-related quality of life. AB - Posterior laryngitis is a common cause of chronic cough, hoarseness, voice fatigue and throat pain. The aim of the present study was to examine how patients with posterior laryngitis have been examined, treated and followed up, and to assess their present health-related quality of life (HRQOL). Patients treated for posterior laryngitis at consultation at the ear-, nose- and throat clinic during 2000-2008 were contacted by mail. The letter contained questionnaires addressing the current symptoms and medication, and the HRQOL 36-item short-form questionnaire (SF-36). Medical records were scrutinized. One hundred and twenty two patients with verified signs and symptoms of posterior laryngitis were included. Forty percent of the patients had been treated for acid-related symptoms prior to consultation. The most common symptoms at the time of consultation were the sensation of hoarseness (women 40 %, men 37 %), globus (women 35 %, men 33 %) and cough (women 33 %, men 26 %). The most frequent diagnosis was gastro-oesophageal reflux disease. Ninety percent of the women and 92 % of the men were treated with proton pump inhibitors (PPIs). At the time of study, 63 % of the patients still had symptoms. The results of the SF-36 questionnaire showed significantly lower HRQOL for women. Patients with posterior laryngitis present varying symptoms, and are often not adequately treated or followed up. When PPI treatment fails, other aetiologies of their complaints, such as visceral hypersensitivity, weakly gaseous acid reflux or non-acid reflux are not considered. Symptoms from posterior laryngitis have a negative impact on the HRQOL for women. PMID- 22843096 TI - Does cooling the tonsillar fossae during thermal welding tonsillectomy have an effect on postoperative pain and healing? AB - The objective of this study was to evaluate the effect of cooling the tonsillar fossa during thermal welding tonsillectomy on pain and wound healing. Prospective, blinded, clinical study was conducted. 30 patients who underwent tonsillectomy by thermal welding were evaluated. When one of the tonsillar fossa was cooled by isotonic fluid, the other has left untreated. Postoperative pain and mucosal healing pattern were assessed. Data were recorded and statistically analyzed. Healing process of the cooled down tonsillar fossae were significantly better on the 7th and 14th postoperative day (p < 0.01). Control tonsillar fossae had significantly higher pain scores on the 3rd, 7th and 14th postoperative day (p < 0.05). Administration of isotonic fluid, during thermal welding tonsillectomy for cooling tonsillar fossae, accelerates wound-healing process significantly and decreases tonsillectomy related pain complaints post operatively. PMID- 22843095 TI - Perspectives of pharmacological treatment in otosclerosis. AB - To review our current knowledge of the pathologic bone metabolism in otosclerosis and to discuss the possibilities of non-surgical, pharmacological intervention. Otosclerosis has been suspected to be associated with defective measles virus infection, local inflammation and consecutive bone deterioration in the human otic capsule. In the early stages of otosclerosis, different pharmacological agents may delay the progression or prevent further deterioration of the disease and consecutive hearing loss. Although effective anti-osteoporotic drugs have become available, the use of sodium fluoride and bisphosphonates in otosclerosis has not yet been successful. Bioflavonoids may relieve tinnitus due to otosclerosis, but there is no data available on long-term application and effects on sensorineural hearing loss. In the initial inflammatory phase, corticosteroids or non-steroidal anti-inflammatory drugs may be effective; however, extended systemic application may lead to serious side effects. Vitamin D administration may have effects on the pathological bone loss, as well as on inflammation. No information has been reported on the use of immunosuppressive drugs. Anti cytokine targeted biological therapy, however, may be feasible. Indeed, one study on the local administration of infliximab has been reported. Potential targets of future therapy may include osteoprotegerin, RANK ligand, cathepsins and also the Wnt-beta-catenin pathway. Finally, anti-measles vaccination may delay the progression of the disease and potentially decrease the number of new cases. In conclusion, stapes surgery remains to be widely accepted treatment of conductive hearing loss due to otosclerosis. Due to lack of solid evidence, the place of pharmacological treatment targeting inflammation and bone metabolism needs to be determined by future studies. PMID- 22843097 TI - Mathematical modeling of therapeutic strategies for myeloid malignancies. AB - The existence of malignant stem cells has been proven for hematopoietic disorder as well as some solid tumors. Although significant improvements in cancer therapy have been made, tumor recurrence is frequent and can partly be due to the absence of therapeutic target which tumor stem cells are regarded as. In this paper we shall explore different therapeutic scenarios for successful tumor treatment by using a predictive mathematical model based on the cell compartment method. In particular, we shall study the effects of the chemotherapeutic target rate and of the interval of G-CSF administration on therapy for myeloid malignancies through simulating chemotherapy with G-CSF (granulocyte colony-stimulating factor) support. The results indicate that if target rate is raised to an enough high value, the efficiency of chemotherapy increases so greatly that the tumor mature cells perish completely and normal mature cells are maintained at a normal level. Furthermore, the administration of G-CSF can increase the amount of the normal mature cells to a normal level. However, too long interval of G-CSF administration is demonstrated not propitious to patients' healing. These results indicate that the simulations may be an effective approach to help designing therapeutic scenarios for successful tumor treatment by chemotherapy. PMID- 22843098 TI - Mitotic failures in cancer: Aurora B kinase and its potential role in the development of aneuploidy. AB - One of the basic requirements during the process of cell division is to maintain genetic integrity and ensure normal ploidy. The family of Aurora kinases, composed of Aurora A, B and C, takes a major role in the control of centrosome cycle, mitotic entry, chromosome condensation and coordination of chromosomal movements. Deregulation of kinase expression was described in a series of different malignancies which was also associated with aneuploidy. Recently, Aurora kinases gained significant interest as potential therapeutic targets in oncology. While there is increasing evidence about the activities of Aurora A kinase during cancer progression, data are controversial regarding the role of Aurora B. In this review the biology of Aurora kinases and its potential relation to cancer progression is discussed with special focus on functional changes and determination of Aurora B kinase. PMID- 22843099 TI - Six commercially available angiotensin II AT1 receptor antibodies are non specific. AB - Commercially available Angiotensin II AT1 receptor antibodies are widely employed for receptor localization and quantification, but they have not been adequately validated. In this study, six commercially available AT1 receptor antibodies were characterized by established criteria: sc-1173 and sc-579 from Santa Cruz Biotechnology, Inc., AAR-011 from Alomone Labs, Ltd., AB15552 from Millipore, and ab18801 and ab9391 from Abcam. The immunostaining patterns observed were different for every antibody tested, and were unrelated to the presence or absence of AT1 receptors. The antibodies detected a 43 kDa band in western blots, corresponding to the predicted size of the native AT1 receptor. However, identical bands were observed in wild-type mice and in AT1A knock-out mice not expressing the target protein. Moreover, immunoreactivity detected in rat hypothalamic 4B cells not expressing AT1 receptors or transfected with AT1A receptor construct was identical, as revealed by western blotting and immunocytochemistry in cultured 4B cells. Additional prominent immunoreactive bands above and below 43 kDa were observed by western blotting in extracts from tissues of AT1A knock-out and wild-type mice and in 4B cells with or without AT1 receptor expression. In all cases, the patterns of immunoreactivity were independent of the AT1 receptor expression and different for each antibody studied. We conclude that, in our experimental setup, none of the commercially available AT1 receptor antibodies tested met the criteria for specificity and that competitive radioligand binding remains the only reliable approach to study AT1 receptor physiology in the absence of full antibody characterization. PMID- 22843100 TI - Ecophysiology of photosynthesis in macroalgae. AB - Macroalgae occur in the marine benthos from the upper intertidal to depths of more than 200 m, contributing up to 1 Pg C per year to global primary productivity. Freshwater macroalgae are mainly green (Chlorophyta) with some red (Rhodophyta) and a small contribution of brown (Phaeophyceae) algae, while in the ocean all three higher taxa are important. Attempts to relate the depth distribution of three higher taxa of marine macroalgae to their photosynthetic light use through their pigmentation in relation to variations in spectral quality of photosynthetically active radiation (PAR) with depth (complementary chromatic adaptation) and optical thickness (package effect) have been relatively unsuccessful. The presence (Chlorophyta, Phaeophyceae) or absence (Rhodophyta) of a xanthophyll cycle is also not well correlated with depth distribution of marine algae. The relative absence of freshwater brown algae does not seem to be related to their photosynthetic light use. Photosynthetic inorganic carbon acquisition in some red and a few green macroalgae involves entry of CO(2) by diffusion. Other red and green macroalgae, and brown macroalgae, have CO(2) concentrating mechanisms; these frequently involve acid and alkaline zones on the surface of the alga with CO(2) (produced from HCO(3) (-)) entering in the acid zones, while some macroalgae have CCMs based on active influx of HCO(3) (-). These various mechanisms of carbon acquisition have different responses to the thickness of the diffusion boundary layer, which is determined by macroalgal morphology and water velocity. Energetic predictions that macroalgae growing at or near the lower limit of PAR for growth should rely on diffusive CO(2) entry without acid and alkaline zones, and on NH(4) (+) rather than NO(3) (-) as nitrogen source, are only partially borne out by observation. The impact of global environmental change on marine macroalgae mainly relates to ocean acidification and warming with shoaling of the thermocline and decreased nutrient flux to the upper mixed layer. Predictions of the impact on macroalgae requires further experiments on interactions among increased inorganic carbon, increased temperature and decreased nitrogen and phosphorus supply, and, when possible, studies of genetic adaptation to environmental change. PMID- 22843102 TI - Neural correlates of emotional regulation while viewing films. AB - Negative and arousal-inducing film clips were used to assess the neural correlates of emotional expression and suppression. Compared to viewing neutral clips, both negative (disgusting) and arousal (action) clips activated primarily posterior regions in the parietal and occipital cortex when participants were instructed to express their emotions. When instructed to suppress their emotions while viewing negative clips, a broad frontoparietal network was activated that included lateral, medial, and orbital regions in the prefrontal cortex as well as lateral and medial regions of the posterior parietal cortex. The suppression of arousal clips also activated prefrontal and parietal regions, though not to the same extent as the suppression of negative clips. The findings demonstrate the potency of using movies to engage emotional processes and highlight a broad frontoparietal network that is engaged during the suppression of negative film clips. PMID- 22843101 TI - Implications of alternative electron sinks in increased resistance of PSII and PSI photochemistry to high light stress in cold-acclimated Arabidopsis thaliana. AB - Exposure of control (non-hardened) Arabidopsis leaves to high light stress at 5 degrees C resulted in a decrease of both photosystem II (PSII) (45 %) and Photosystem I (PSI) (35 %) photochemical efficiencies compared to non-treated plants. In contrast, cold-acclimated (CA) leaves exhibited only 35 and 22 % decrease of PSII and PSI photochemistry, respectively, under the same conditions. This was accompanied by an accelerated rate of P700(+) re-reduction, indicating an up-regulation of PSI-dependent cyclic electron transport (CET). Interestingly, the expression of the NDH-H gene and the relative abundance of the Ndh-H polypeptide, representing the NDH-complex, decreased as a result of exposure to low temperatures. This indicates that the NDH-dependent CET pathway cannot be involved and the overall stimulation of CET in CA plants is due to up-regulation of the ferredoxin-plastoquinone reductase, antimycin A-sensitive CET pathway. The lower abundance of NDH complex also implies lower activity of the chlororespiratory pathway in CA plants, although the expression level and overall abundance of the other well-characterized component involved in chlororespiration, the plastid terminal oxidase (PTOX), was up-regulated at low temperatures. This suggests increased PTOX-mediated alternative electron flow to oxygen in plants exposed to low temperatures. Indeed, the estimated proportion of O(2)-dependent linear electron transport not utilized in carbon assimilation and not directed to photorespiration was twofold higher in CA Arabidopsis. The possible involvement of alternative electron transport pathways in inducing greater resistance of both PSII and PSI to high light stress in CA plants is discussed. PMID- 22843103 TI - Are mechanics different between male and female runners with patellofemoral pain? AB - INTRODUCTION: Patellofemoral pain (PFP) has often been attributed to abnormal hip and knee mechanics in females. To date, there have been few investigations of the hip and knee mechanics of males with PFP. The purpose of this study was to compare the lower extremity mechanics and alignment of male runners with PFP with healthy male runners and female runners with PFP. We hypothesized that males with PFP would move with greater varus knee mechanics compared with male controls and compared with females with PFP. Furthermore, it was hypothesized that males with PFP would demonstrate greater varus alignment. METHODS: A gait and single-leg squat analysis was conducted on each group (18 runners per group). Measurement of each runner's tibial mechanical axis was also recorded. Motion data were processed using Visual 3D (C-Motion, Bethesda, MD). ANOVAs were used to analyze the data. RESULTS: Males with PFP ran and squatted in greater peak knee adduction and demonstrated greater peak knee external adduction moment compared with healthy male controls. In addition, males with PFP ran and squatted with less peak hip adduction and greater peak knee adduction compared with females with PFP. The static measure of mechanical axis of the tibial was not different between groups. However, a post hoc analysis revealed that males with PFP ran with greater peak tibial segmental adduction. CONCLUSION: Males with PFP demonstrated different mechanics during running and during a single-leg squat compared with females with PFP and with healthy males. Based upon the results of this study, therapies for PFP may need to be sex specific. PMID- 22843104 TI - High volumes of resistance exercise are not required for greater bone mineral density during growth. AB - PURPOSE: The purpose of this study was to determine the minimum amount of resistance exercise that would stimulate bone formation, via an elevation in bone mineral density (BMD), during the growth period in male rats. METHODS: Forty male rats were randomly divided into control group (Con, n = 8), one ladder climb resistance-trained group (1LC, n = 8), two ladder climb resistance-trained group (2LC, n = 8), three ladder climb resistance-trained group (3LC, n = 8), and four ladder climb resistance-trained group (4LC, n = 8). All exercised groups were conditioned to climb a vertical ladder with weights appended to their tail 3 d.wk(-1) for a total of 6 wk. RESULTS: After 6 wk, left tibia BMD (mean +/- SE) was significantly greater for 2LC, 3LC, and 4LC (0.233 +/- 0.003 g.cm(-2)) when compared with Con (0.218 +/- 0.003 g.cm). Left femur BMD was significantly greater for 2LC, 3LC, and 4LC (0.318 +/- 0.003 g.cm(-2)) when compared with 1LC (0.299 +/- 0.008 g.cm(-2)) and Con (0.289 +/- 0.010 g.cm(-2)).There were no significant differences in BMD between 2LC, 3LC, and 4LC groups. CONCLUSION: The results suggest that during growth, a low amount of resistance exercise was just as effective as high volumes of strength training for stimulating bone modeling. PMID- 22843105 TI - Musculoskeletal and estrogen changes during the adolescent growth spurt in girls. AB - INTRODUCTION: The adolescent growth spurt is associated with rapid growth and hormonal changes, thought to contribute to the increased anterior cruciate ligament injury risk in girls. However, relatively little is known about these musculoskeletal and estrogen changes during the growth spurt in girls. PURPOSE: To investigate the longitudinal changes in estrogen as well as anterior knee laxity and lower limb strength and flexibility throughout the adolescent growth spurt in girls. METHODS: Thirty-three healthy girls, age 10-13 yr, in Tanner stage II and 4-6 months from their peak height velocity were recruited. Participants were tested up to four times during the 12 months of their growth spurt, according to the timing of their maturity offset (test 1: maturity offset = -6 to -4 months; test 2: maturity offset = 0 months; test 3: maturity offset = +4 months; test 4: maturity offset = +8 months). During each testing session, anterior knee laxity, lower limb flexibility, and isokinetic strength as well as saliva measures of estradiol concentration were measured. RESULTS: A significant (P = 0.002) effect of time on anterior knee laxity was found from the time of peak height velocity, although no changes in estradiol concentration were displayed over time (P = 0.811). Participants displayed a significant increase (P < 0.05) in isokinetic quadriceps strength over time, with no apparent increase in isokinetic hamstring strength. CONCLUSIONS: We speculate that increased quadriceps strength, combined with increased knee laxity and no accompanying hamstring strength development during the adolescent growth spurt in girls, might contribute to a decrease in their knee joint stability during landing tasks. These musculoskeletal changes could potentially increase anterior cruciate ligament injury risk at a time of rapid height and lower limb growth. PMID- 22843106 TI - CANPLAY pedometer normative reference data for 21,271 children and 12,956 adolescents. AB - PURPOSE: The mean expected values of pedometer-determined steps per day for children and adolescents have been derived primarily from isolated studies on small or specific populations. The purpose of this study is to provide sex- and age-specific normative values so that researchers, clinicians/practitioners, other childcare workers, and families can compare children's and adolescents' pedometer-determined data to that of their peers. METHODS: Data were collected between 2005 and 2011 on 21,271 children 5-12 yr and 12,956 adolescents 13-19 yr. Participants were recruited by telephone, logged their pedometer-determined steps per day for 7 d, and mailed back their logs. Normative data were provided in three formats: 1) mean steps per day by single-year age by sex; 2) increments of 5 percentile values for each single-year age by sex, smoothed within and across years; and 3) quintiles (in ascending order: lowest, lower than average, average, higher than average, and highest) for four combined age groups (5-7, 8-10, 11-14, and 15-19 yr) stratified by sex. RESULTS: Mean steps per day increased from 11,602 steps per day among 5-yr-olds to a sample peak mean value of 12,348 steps per day among 10-yr-olds, and then declined to 9778-10,073 among 15- to 19-yr olds. Although not significantly different among 19-yr-olds, mean steps per day were higher among boys than girls at every age. CONCLUSIONS: CANPLAY data represent the largest and most comprehensive set of sex- and age-specific normative reference data for children's and adolescents' pedometer-determined physical activity to date. A clear assemblage of such values is fundamental for surveillance, screening, comparison purposes, planning strategies, prioritizing efforts and distributing resources, evaluating intervention effects, and tracking change. PMID- 22843107 TI - Girls' physical activity levels during organized sports in Australia. AB - PURPOSE: The primary aim of this study was to objectively examine the physical activity (PA) levels of girls during organized sports (OS) and to compare the levels between games and practices for the same participants. The secondary aims of this study were to document lesson context and coach behavior during practices and games. METHODS: Participants were 94 girls recruited from 10 teams in three OS (netball, basketball, and soccer) from the western suburbs of Sydney. Each participant wore an ActiGraph GT3X monitor for the duration of one practice and one game. The System for Observing Fitness Instruction Time was concurrently used to document lesson context and coach behavior. RESULTS: Girls spent a significantly higher percentage of time in moderate-to-vigorous PA (MVPA) during practices compared with games (33.8% vs 30.6%; t = 2.94, P < 0.05). Girls spent approximately 20 min.h(-1) in MVPA during practices and approximately 18 min.h( 1) in MVPA during games. An average of 2957 and 2702 steps per hour were accumulated during practices and games, respectively. However, girls spent roughly two-thirds of their OS time in light PA or sedentary. On the basis of the System for Observing Fitness Instruction Time findings, coaches spent a large proportion of practice time in management (15.0%) and knowledge delivery (18.5%). An average of 13.0 and 15.8 occurrences per hour were observed during games and practices where coaches promoted PA. CONCLUSIONS: For every hour of game play or practice time, girls accumulated approximately one third of the recommended 60 min of MVPA time and approximately one quarter of the 12,000 steps that girls are recommended to accumulate daily. For this population, OS seems to make a substantial contribution to the recommended amounts of MVPA and steps for participating girls. OS alone, however, does not provide amounts of PA sufficient to meet daily recommendations for adolescent girls. PMID- 22843108 TI - Formoterol concentrations in blood and urine: the World Anti-Doping Agency 2012 regulations. AB - INTRODUCTION: We examined urinary and serum concentrations of formoterol in asthmatic and healthy individuals after a single dose of 18 MUg inhaled formoterol and after repeated inhaled doses in healthy individuals. Results were evaluated using the World Anti-Doping Agency (WADA) 2012 threshold for formoterol. METHODS: On the day of this open-label, crossover study, 10 asthmatic subjects who regularly used beta2-agonists and 10 healthy participants with no previous use of beta2-agonists received a single dose of 18 MUg formoterol. Further, 10 nonasthmatic participants inhaled 18 MUg formoterol every second hour until obtaining a total of 72 MUg, which is twice the maximum daily dose (36 MUg formoterol) permitted by the WADA. Blood samples were collected at baseline, 30 min, 1, 2, 3, 4, and 6 h after the first inhalation. Urine samples were collected at baseline, 0-4, 4-8, and 8-12 h after the first inhalation. RESULTS: Median urine concentration, corrected for specific gravity, after the single-dose administration peaked during 0-4 h after inhalation at a maximum of 7.4 ng.mL(-1) in asthmatic subjects and 7.9 ng.mL(-1) in healthy subjects. Median urine concentration after repeated doses peaked during 4-8 h after inhalation of a total of 72 MUg formoterol at a maximum of 16.8 ng.mL(-1) in healthy participants. The maximum individual concentration of 25.6 ng.mL(-1) was found after inhalation of a total of 72 MUg formoterol. CONCLUSIONS: We found no significant differences in urinary and serum concentrations of formoterol between asthmatic and healthy subjects. We found high interindividual variability in the concentrations in all groups. Our data support the WADA 2012 urinary threshold of 30 ng.mL(-1) formoterol as being an adverse analytical finding. PMID- 22843109 TI - Neuromuscular dysfunction in diabetes: role of nerve impairment and training status. AB - PURPOSE: The purpose of this study was to investigate the effect of diabetes, motor nerve impairment, and training status on neuromuscular function by concurrent assessment of the torque-velocity relationship and muscle fiber conduction velocity (MFCV). METHODS: Four groups were studied (n = 12 each): sedentary patients with diabetes in the first (lower) and fourth (higher) quartile of motor nerve conduction velocity (D1 and D4, respectively), trained diabetic (TD) patients, and nondiabetic sedentary control (C) subjects. Maximal isometric and isokinetic contractions were assessed over a wide range of angular velocities for the elbow flexors and knee extensors to evaluate the torque velocity relationship. Simultaneously, MFCV was estimated from surface electromyography of the vastus lateralis and biceps brachii. RESULTS: Isometric strength was similar among groups. The dynamic strength of elbow flexors was reduced in patients with diabetes at the higher contraction speeds. The strength of knee extensors was lower in sedentary patients with diabetes at all velocities considered, with significantly lower values in D1 than that in D4 at 60 degrees , 90 degrees , and 120 degrees .s(-1), whereas it was similar between TD and C subjects, especially at low contraction velocities. At the vastus lateralis, but not the biceps brachii, MFCV was lower in D1 and D4 as compared with TD and C subjects, showing similar values. CONCLUSIONS: Muscle weakness in diabetes affects also the upper limb, although to a lower extent than the lower limb, is only partly related to motor nerve impairment, and is dependent on contraction velocity. Exercise training might counteract diabetes-induced alterations in muscle fiber contractile properties and MFCV. PMID- 22843110 TI - Development of a novel eccentric arm cycle ergometer for training the upper body. AB - Several investigators have demonstrated that chronic eccentric leg cycling is an effective method for improving lower body neuromuscular function (e.g., quadriceps muscle size, strength, and mobility) in a variety of patient and athletic populations. To date, there are no reports of using eccentric arm cycling (EC(arm)) as an exercise modality, probably in large part because of the lack of commercially available EC(arm) ergometers. PURPOSE: Our purposes for conducting this study were to 1) describe the design and construction of an EC(arm) ergometer and 2) compare EC(arm) to traditional concentric arm cycling (CC(arm)). METHODS: All of the parts of a Monark 891E cycle ergometer (Monark Exercise AB, Vansbro, Sweden) were removed, leaving the frame and flywheel. An electric motor (2.2 kW) was connected to the flywheel via a pulley and a belt. Motor speed and pedaling rate were controlled by a variable frequency drive. A power meter quantified power and pedaling rate, and provided feedback to the individual. Eight individuals performed 3-min EC(arm) and CC(arm) trials at 40, 80, and 120 W (60 rpm) while VO(2) was measured. RESULTS: The EC(arm) ergometer was simple to use, was adjustable, provided feedback on power output to the user, and allowed for a range of eccentric powers. VO(2) during EC(arm) was substantially lower compared with CC(arm) (P < 0.001). At similar VO(2) (0.97 +/- 0.18 vs 0.91 +/- 0.09 L.min(-1), for EC(arm) and CC(arm), respectively, P = 0.26), power absorbed during EC(arm) was approximately threefold greater than that produced during CC(arm) (118 +/- 1 vs 40 +/- 1 W, P < 0.001). CONCLUSION: This novel EC(arm) ergometer can be used to perform repetitive, high-force, multijoint, eccentric actions with the upper body at a low level of metabolic demand and may allow researchers and clinicians to use EC(arm) as a training and rehabilitation modality. PMID- 22843111 TI - Why isn't flow-mediated dilation enhanced in athletes? AB - PURPOSE: Studies performed in animals and humans strongly suggest that exercise training and physical activity enhance arterial endothelial function. Studies of athletes have, however, been less definitive. METHODS: We recruited a range of Olympic and world class athletes who participate in upper or lower limb predominant activities and examined brachial and superficial femoral artery diameter responses to 5-min ischemia (flow-mediated dilation [FMD]) and glyceryl trinitrate, wall thickness (WT) and wall-to-lumen ratio using Doppler and two dimensional ultrasound. Subjects were elite male canoe paddlers (n = 12), squash players (n = 13), lower limb dominant athletes (i.e., runners/cyclists/triathletes, n = 13), or age- and sex-matched control subjects (n = 16). RESULTS: Athletes demonstrated lower superficial femoral artery FMD than controls (P < 0.05), whereas in the brachial artery, a lower FMD was found in squash players (P < 0.05). Both arteries showed a significant inverse correlation between diameter and FMD (P < 0.05), and a significant inverse relationship was apparent between wall-to-lumen ratio and FMD in the superficial femoral artery (P < 0.05). CONCLUSIONS: Although artery FMD was lower in athletes, artery size was larger and WT smaller than controls. The apparent reduction in artery FMD may relate to the profound structural remodeling in the diameter and WT of the conduit arteries of athletes. These findings have implications for the interpretation of FMD data, particularly as it pertains to the effect of athletic endeavor on cardiovascular health. PMID- 22843112 TI - Sex differences in marathon running with advanced age: physiology or participation? AB - The sex difference in marathon performance increases with age and place of the finisher, even at the elite level. Sociological factors may explain the increased sex gap, but there is limited empirical evidence for specific factors. PURPOSE: The purposes of this study were to determine the sex difference in velocity for the marathon across the place of finisher (1st-10th place) with advanced age and (2) to determine the association between the sex difference in participation (ratio of men-to-women finishers) and the sex difference in running velocity. METHODS: Running times of the first 10 placed men and women in the 5-yr age brackets between 20 and 79 yr and the number of men and women who finished the New York City marathon were analyzed for a 31-yr period (1980-2010). RESULTS: The sex difference in running velocity increased between the 1st and the 10th place because of a greater relative drop in velocity of women than men (P < 0.001). The sex difference increased with advanced age and decreased across the 31 yr, but more for the older age groups (P < 0.001). The number of women finishers also increased relative to men for the 31 yr, but more in the older age groups (P < 0.001). Importantly, approximately 34% of the sex difference in velocity among the first-place finishers was associated with the ratio of men-to-women finishers (r = 0.58, r2 = 0.34, P < 0.001). CONCLUSIONS: The greater sex difference in velocity that occurs with age and with increased place was primarily explained by the lower number of women finishers than men. These data provide evidence that lower participation rates and less depth among women competitors can amplify the sex difference in running velocity above that due to physiological sex differences alone. PMID- 22843113 TI - Objectively measured physical activity in the 1993 Pelotas (Brazil) birth cohort. AB - INTRODUCTION: Data on physical activity levels of adolescents are mostly derived from self-reported instruments, and the vast majority of studies using objective measures are from high-income countries. The aim of this study was to describe the patterns of objectively measured physical activity in Brazilian adolescents. METHODS: In 2004-2005 (mean age of 13.3 yr), a subsample of the 1993 Pelotas (Brazil) Birth Cohort with data on all previous visits was approached. Physical activity was measured using the ActiGraph GT1M accelerometer (ActiGraph Corporation, Pensacola, FL). Demographic and other variables were assessed by self-report. RESULTS: A total of 486 individuals (51% boys) provided valid data on objectively measured physical activity (response rate = 95.1%). The mean registered time of accelerometer data was 1191 min.d (SD = 112). The mean times (in minutes) spent in sedentary, light, moderate, and vigorous activities were 962 (SD = 114), 176 (SD = 46), 36 (SD = 16), and 17 (SD = 10) min.d, respectively. More than 30% of the adolescents accumulated >=60 min.d of moderate to-vigorous physical activity (MVPA). Physical activity intensity (counts per minute) and the prevalence of accumulation >=60 min.d of MVPA were higher among boys and in those who walked or cycled to school. The prevalence of accumulation >60 min.d of MVPA was 125% higher in those from lower economic levels compared with higher economic levels (P < 0.001). CONCLUSION: A large proportion of Brazilian adolescents of the 1993 Pelotas Birth Cohort do not achieve the current recommendation for health-related physical activity, and active commuting to school may be a target for interventions aimed at increasing physical activity. Physical activity levels are higher in lower socioeconomic groups than that in higher groups. PMID- 22843114 TI - Exercise in pregnancy: effect on fitness and obstetric outcomes-a randomized trial. AB - OBJECTIVE: A prospective randomized controlled trial was designed to assess the benefits and possible risks of aerobic exercise during pregnancy, using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy. METHODS: Inactive women were randomized at 12-14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45-60 min, 4 d.wk, through 36 wk gestation. Thirty-one subjects in each group completed the study. RESULTS: Compared with women who remained sedentary, active women improved aerobic fitness (P < 0.05) and muscular strength (P < 0.01), delivered comparable size infants with significantly fewer cesarean deliveries (P < 0.01), and recovered faster postpartum (P < 0.05), at least related to the lower incidence of cesarean section. Active women developed no gestational hypertension (P = 0.16 compared with controls) and reported no injuries related to the exercise regimen. In the active group, there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk. There were no differences between groups in the incidence of gestational diabetes, musculoskeletal pains during pregnancy, flexibility on sit-and-reach test, mean length of pregnancy, neonatal Apgar scores, placenta weights, overall length of labor, weight gain during pregnancy, or weight retention postpartum. CONCLUSION: Previously sedentary women who began exercising at 12-14 wk improved fitness and delivery outcomes. PMID- 22843115 TI - Effect of ischemic preconditioning on lactate accumulation and running performance. AB - PURPOSE: Repeated bouts of ischemia followed by reperfusion (i.e., ischemic preconditioning (IPC)) protect against damage after a myocardial infarction. Recent observational data indicate that IPC improves exercise performance. However, no previous study has examined potential underlying mechanisms for this effect of IPC. Therefore, we examined the potential of IPC to improve 5-km running time trial performance and reduce lactate accumulation during an incremental exercise test. METHODS: In a randomized, crossover study, 13 healthy men performed running exercise, which was preceded by IPC (4 * 5-min 220 mm Hg bilateral leg occlusion) or a control intervention (C) (4 * 5-min 20 mm Hg bilateral leg occlusion). Participants performed a graded maximal treadmill running test, starting with five 3-min submaximal stages (10-14 km.h), followed by increments of 1 km.h every 2 min to 16 km.h, followed by an incline of the treadmill of 2% every 2 min. Blood lactate was examined at each 3-min stage. After 45 min of rest in the supine position, subjects then performed a 5-km running time trial. RESULTS: We found similar submaximal gas parameters during running exercise with both interventions. The overall increase in blood lactate during the submaximal stages was 1.07 +/- 0.11 mmol.L lower when exercise was preceded with IPC versus C (P = 0.023). The 5-km running time trial was completed in a time that was 34 s faster after IPC versus C (95% confidence interval, 5-64 s; P = 0.027). CONCLUSION: IPC improves 5-km time trial performance in healthy male individuals. Moreover, we found that IPC is associated with an attenuated rise in blood lactate concentration at submaximal level during an incremental running test. This could indicate that IPC allows for higher work rates and thus improves time trial performance. PMID- 22843117 TI - Impact of magnetic resonance in the preoperative staging and the surgical planning for treating small bowel neoplasms. AB - PURPOSE: The role of MR enteroclysis/enterography (MRE) in the diagnosis of small bowel (SB) tumor has not been fully evaluated. The aims of this study were to assess the capability of MRE correctly identifying the site, stage and histology of such neoplasms. METHODS: MR enteroclysis/enterography was employed in consecutive patients suspected of having an SB tumor following negative upper and lower endoscopies. The SB was subdivided into proximal jejunum, middle SB and distal ileum. The histological examination (HE) of the surgical specimen was the reference standard. RESULTS: One hundred and fifty-eight patients were examined. Thirty-one out of 32 (96.9 %) SB detected by HE were correctly identified by MRE. The concordance rate between MRE and HE was 100 % for localization, and 87.1, 80.6 and 96.8 % for T, N and M stages, respectively. The concordance rate was 62.2 % for histological diagnosis. CONCLUSIONS: The high concordance rates between MRE and HE for the localization of SB tumors and for their staging have a significant impact upon surgical planning, particularly if laparoscopy is being considered. A preoperative histological diagnosis is not sufficiently reliable. PMID- 22843116 TI - Mass spectrometry-based proteomics as a tool to identify biological matrices in forensic science. AB - In forensic casework analysis, identification of the biological matrix and the species of a forensic trace, preferably without loss of DNA, is of major importance. The biological matrices that can be encountered in a forensic context are blood (human or non-human), saliva, semen, vaginal fluid, and to a lesser extent nasal secretions, feces, and urine. All these matrices were applied on swabs and digested with trypsin in order to obtain peptides. These peptides were injected on a mass spectrometer (ESI Q-TOF) resulting in the detection of several biomarkers that were used to build a decision tree for matrix identification. Saliva and blood were characterized by the presence of alpha-amylase 1 and hemoglobin, respectively. In vaginal fluid, cornulin, cornifin, and/or involucrin were found as biomarkers while semenogelin, prostate-specific antigen, and/or acid phosphatase were characteristic proteins for semen. Uromodulin or AMBP protein imply the presence of urine, while plunc protein is present in nasal secretions. Feces could be determined by the presence of immunoglobulins without hemoglobin. The biomarkers for the most frequently encountered biological matrices (saliva, blood, vaginal fluid, and semen) were validated in blind experiments and on real forensic samples. Additionally, by means of this proteomic approach, species identification was possible. This approach has the advantage that the analysis is performed on the first "washing" step of the chelex DNA extraction, a solution which is normally discarded, and that one single test is sufficient to determine the identity and the species of the biological matrix, while the conventional methods require cascade testing. This technique can be considered as a useful additional tool for biological matrix identification in forensic science and holds the promise of further automation. PMID- 22843118 TI - Spatiotemporal expression and functional implication of CXCL14 in the developing mice cerebellum. AB - Cerebellar granule neurons migrate from the external granule cell layer (EGL) to the internal granule cell layer (IGL) during postnatal morphogenesis. This migration process through 4 different layers is a complex mechanism which is highly regulated by many secreted proteins. Although chemokines are well-known peptides that trigger cell migration, but with the exception of CXCL12, which is responsible for prenatal EGL formation, their functions have not been thoroughly studied in granule cell migration. In the present study, we examined cerebellar CXCL14 expression in neonatal and adult mice. CXCL14 mRNA was expressed at high levels in adult mouse cerebellum, but the protein was not detected. Nevertheless, Western blotting analysis revealed transient expression of CXCL14 in the cerebellum in early postnatal days (P1, P8), prior to the completion of granule cell migration. Looking at the distribution of CXCL14 by immunohistochemistry revealed a strong immune reactivity at the level of the Purkinje cell layer and molecular layer which was absent in the adult cerebellum. In functional assays, CXCL14 stimulated transwell migration of cultured granule cells and enhanced the spreading rate of neurons from EGL microexplants. Taken together, these results revealed the transient expression of CXCL14 by Purkinje cells in the developing cerebellum and demonstrate the ability of the chemokine to stimulate granule cell migration, suggesting that it must be involved in the postnatal maturation of the cerebellum. PMID- 22843119 TI - MYC and PIM2 co-expression in mouse bone marrow cells readily establishes permanent myeloid cell lines that can induce lethal myeloid sarcoma in vivo. AB - The hematopoietic cell malignancy is one of the most prevalent type of cancer and the disease has multiple pathologic molecular signatures. Research on the origin of hematopoietic cancer stem cells and the mode of subsequent maintenance and differentiation needs robust animal models that can reproduce the transformation and differentiation event in vivo. Here, we show that co-transduction of MYC and PIM2 proto-oncogenes into mouse bone marrow cells readily establishes permanent cell lines that can induce lethal myeloid sarcoma in vivo. Unlike the previous doubly transgenic mouse model in which coexpression of MYC and PIM2 transgenes exclusively induced B cell lymphoma, we were able to show that the same combination of genes can also transform primary bone marrow myeloid cells in vitro resulting in permanent cell lines which induce myeloid sarcoma upon in vivo transplantation. By inducing cancerous transformation of fresh bone marrow cells in a controlled environment, the model we established will be useful for detailed study of the molecular events involved in initial transformation process of primary myeloid bone marrow cells and provides a model that can give insight to the molecular pathologic characteristics of human myeloid sarcoma, a rare presentation of solid tumors of undifferentiated myeloid blast cells associated with various types of myeloid leukemia. PMID- 22843121 TI - Retraction note: Graft fixation alternatives in anterior cruciate ligament reconstruction. PMID- 22843120 TI - Changes in diet, body mass and fatty acid composition during pre-hibernation in a subtropical bat in relation to NPY and AgRP expression. AB - Prior to hibernation, mammals accumulate large amounts of fat in their bodies. In temperate mammalian species, hibernation is improved by increasing the levels of poly-unsaturated fatty acids (PUFA) in the body. The saturation of fatty acids (FA) in both white adipose tissue (WAT) and membrane phospholipids of mammals often reflects their diet composition. We found that the greater mouse-tailed bat (Rhinopoma microphyllum) accumulates large amounts of fat at the end of summer by gradually shifting to a fat-rich diet (queen carpenter ants, Camponotus felah). PUFA are almost absent in this diet (<1 % of total FA), which contains a high fraction of saturated (SFA) and mono-unsaturated (MUFA) fatty acids. We found similar low levels of PUFA in mouse-tailed bat WAT, but not in their heart total lipids. The expression of two appetite-stimulating (orexigenic) hypothalamic neuropeptides, AgRP and NPY, increased in parallel to the shift in diet and with fat gain in these bats. To the best of our knowledge, this is the only documented example of specific pre-hibernation diet in bats, and one which reveals the most saturated FA composition ever documented in a mammal. We suggest that the increase in expression levels of NPY and AgRP may contribute to the observed diet shift and mass gain, and that the FA composition of the bat's specialized diet is adaptive in the relatively high temperatures we recorded in both their winter and summer roosts. PMID- 22843122 TI - Gastric estrogen increases pituitary estrogen receptor alpha and prolactin mRNAs during the different pathological conditions of the liver. AB - Mammalian liver is an estrogen-responsive tissue mediated by hepatic estrogen receptors. Although Ueyama et al. (Endocrinology 143:3162-3170, 2002) have reported the presence of aromatase and active production of gastric 17beta estradiol in parietal cells, there are a few studies on gastric 17beta-estradiol exploring the relationship between gastro-hepato function and the gastro pituitary-gonadal axis. The alteration of gastric 17beta-estradiol flow into the systemic circulation by portal vein ligation (PVL) or partial hepatectomy (PH), and the effect of gastric 17beta-estradiol on the pituitary function was investigated. In the PVL rats, arterial 17beta-estradiol increased 9.5 times that of controls on day 3, and gradually decreased near to control levels in the portal vein by 4 weeks, which was still 5 times higher than those in the arteries of the control rats. In the PH rats, arterial 17beta-estradiol increased 2 times that of controls on day 3, and gradually decreased to the control levels. Regeneration and growth of the liver remnants were observed about 2 weeks after PH. In the PVL and PH animals, pituitary ERalpha and prolactin mRNAs levels increased, positively correlating with an increase of arterial 17beta-estradiol levels. Both reduced LHbeta mRNA. It is apparent that hepatic dysfunction causes changes in gastric 17beta-estradiol levels in the systemic circulation; and that elevated gastric 17beta-estradiol affects pituitary function(s). This data suggest that gastric 17beta-estradiol has a pivotal role in the regulation of the gastro-hepato-pituitary axis. PMID- 22843123 TI - Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. AB - We aim to investigate the preventive and therapeutic effects of ghrelin on a rat NAFLD model and possible underlying mechanism. Sprague-Dawley rats were fed with high-fat diet for 8 weeks to induce NAFLD. A group of rats were also treated with ghrelin throughout the NAFLD induction. After 8 weeks, rats were sacrificed for liver injury measurements. Rats with NAFLD showed obvious histological changes including necrosis and inflammation foci, elevated serum enzyme (ALT and AST) levels, dysregulated hepatic lipid metabolism, increased formation of oxidative stress, and lipid peroxidation markers, up-regulated levels of pro-inflammatory cytokines and apoptotic cells in the liver. Treatment of ghrelin improved liver injury through counter-acting those events. The improvement of ghrelin was accompanied with a restoration of LKB1/AMPK and PI3 K/Akt pathways. Ghrelin treatment alone did not influence the healthy rat liver. In addition, "therapeutic" ghrelin administration (2 weeks) after the establishment of early NAFLD symptoms (4 weeks) in rats further proved the beneficial effects of ghrelin. In conclusion, administration of ghrelin could attenuate NAFLD-induced liver injury, oxidative stress, inflammation, and apoptosis partly through the action of LKB1/AMPK and PI3 K/Akt pathways. PMID- 22843125 TI - Characteristics of Northern Plains American Indians seeking substance abuse treatment in an urban, non-tribal clinic: a descriptive study. AB - Because few data exist on substance abuse rates in American Indian (AI) communities, the Methamphetamine and Other Drug project was developed and implemented by five nodes within the National Institute on Drug Abuse Clinical Trials Network (NIDA CTN). This article presents findings from AI clients in a Northern Plains urban non-Native substance abuse treatment setting. Alcohol and marijuana were used earlier, longer, and by more clients, followed by stimulants and prescription opioids. Most regularly smoked tobacco. Differences in substance use patterns were associated with age of onset and victimization. Age of onset was correlated with victimization, gender, cognitive impairment, and suicidal behavior. Despite considerable health and economic disparities, most clients found support for recovery in relationships and elements of Native culture. PMID- 22843126 TI - Life satisfaction and health-related quality of life in immigrants and native born Germans: the role of immigration-related factors. AB - PURPOSE: There is a lack of population-based studies on health-related quality of life (HRQoL) and satisfaction with life (SWL) of immigrants compared to the native populations. Findings of previous research are inconclusive. Our study compares HRQoL and SWL in immigrants and native-born Germans, investigating immigration-related factors as suspected determinants of HRQoL and SWL in immigrants. METHODS: In the German Socio-economic panel from 2006, HRQoL (measured with the SF-12v2) and SWL as well as immigration-related factors were assessed in 21,079 subjects (including 2,971 immigrants). Analyses of variance were applied as statistical tests in our study. RESULTS: Native-born Germans report a higher amount of SWL and of HRQoL on the physical health component compared to the immigrants. With effect sizes ranging from E2 = 0.001 to 0.111, these findings are of minimal practical relevance. In immigrants, the physical health component of HRQoL is significantly associated with younger age at migration and with country of origin. As the effect sizes are extremely low, these findings have limited practical relevance. CONCLUSION: There are small differences in SWL and HRQoL of immigrants and native-born Germans. Some immigration-related factors are related to HRQoL, but not to SWL. As immigrants are a quite heterogeneous group, it seems useful to focus on immigration-related factors, not simply comparing immigrants and the native-born. Our findings suggest that research on the association of immigration-related factors with quality of life in immigrants seems a promising approach to better identify subgroups of immigrants with lower levels of quality of life. PMID- 22843127 TI - Standard chest radiograph predicts left ventricular lead location in chronic resynchronization therapy patients more accurately than intraoperative fluoroscopy. AB - INTRODUCTION: Targeting the proper left ventricular lead site is important in cardiac resynchronization therapy (CRT) procedures, as suboptimal lead locations may result in a lack of clinical response. Left ventricular lead locations are typically confirmed using fluoroscopy (fluoro) with AP, RAO, and LAO orientations. However, standard fluoro may inadequately delineate true left ventricular lead locations, due to insufficient angulation or extreme cardiac rotation. Posteroanterior and lateral chest radiograph (CXRPAL), performed routinely to verify lead stability and freedom from complication, may better confirm left ventricular lead location due to utilization of a straight lateral view. HYPOTHESIS: Compared to fluoro, lead localization using CXRPAL will be more predictive of true left ventricular lead location in CRT patients. METHODS: Of 252 medically optimized CHF patients who underwent CRT implantation by multiple operators from October 2001 to August 2011, 46 (mean age, 58.9 +/- 13.2 years; 10 female; 19 ICM; 19 LBBB; mean ejection fraction, 26.6 +/- 8.9 %; mean QRS width, 144.4 ms) had CT scanning performed as part of routine medical care and comprise this study. Operative reports of left ventricular lead location by fluoro were reviewed. Left ventricular lead location was identified on CXRPAL by three independent observers blinded to operative results. Left ventricular lead locations according to fluoro and CXRPAL were correlated with CT scan at a mean follow-up of 57.6 +/- 28.8 months (Tables 1 and 2). RESULTS: Compared to standard fluoro, CXRPAL agreed better with CT scan (kappa = 0.413 fluoro vs. kappa = 0.864 CXRPAL on the vertical axis, and kappa = 0.086 fluoro vs. kappa = 0.864 CXRPAL on the horizontal axis) for identification of left ventricular lead location. CONCLUSIONS: In this small study of 46 CRT patients, interpretation of left ventricular lead location using CXRPAL correlated better with true lead location identified on CT scan, compared to standard fluoroscopy. Use of a steep lateral view during CRT implantation may be necessary to accurately identify left ventricular lead locations. PMID- 22843128 TI - Cross-cultural development of the EORTC QLQ-SWB36: a stand-alone measure of spiritual wellbeing for palliative care patients with cancer. AB - BACKGROUND: No existing stand-alone measures of spiritual wellbeing have been developed in cross-cultural and multiple linguistic contexts. AIM: Cross-cultural development of a stand-alone European Organisation for Research and Treatment of Cancer (EORTC) measure of spiritual wellbeing for palliative care patients with cancer. DESIGN: Broadly following EORTC Quality of Life Group (QLG) guidelines for developing questionnaires, the study comprised three phases. Phase I identified relevant issues and obtained the views of palliative care patients and professionals about those issues. Phase II operationalised issues into items. Phase III pilot-tested those items with palliative care patients. Amendments to the guidelines included an intermediate Phase IIIa, and debriefing questions specific to the measure. SETTING/PARTICIPANTS: Phase III pilot-testing recruited 113 people with incurable cancer from hospitals and hospices in six European countries and Japan. RESULTS: A provisional 36-item measure ready for Phase IV field-testing, the EORTC QLQ-SWB36, has been developed. Careful attention to translation and simultaneous development in multiple languages means items are acceptable and consistent between different countries and languages. Phase III data from 113 patients in seven countries show that the items are comprehensible across languages and cultures. Phase III patient participants in several countries used the measure as a starting point for discussing the issues it addresses. CONCLUSION: The EORTC QLG's rigorous cross-cultural development process ensures that the EORTC QLQ-SWB36 identifies key issues for spiritual wellbeing in multiple cultural contexts, and that items are comprehensible and consistent across languages. Some cross-cultural differences were observed, but data were insufficient to enable generalisation. Phase IV field-testing will investigate these differences further. PMID- 22843129 TI - Comparison of indocyanine green angiography and laser speckle contrast imaging for the assessment of vasculature perfusion. AB - BACKGROUND: Assessment of the vasculature is critical for overall success in cranial vascular neurological surgery procedures. Although several methods of monitoring cortical perfusion intraoperatively are available, not all are appropriate or convenient in a surgical environment. Recently, 2 optical methods of care have emerged that are able to obtain high spatial resolution images with easily implemented instrumentation: indocyanine green (ICG) angiography and laser speckle contrast imaging (LSCI). OBJECTIVE: To evaluate the usefulness of ICG and LSCI in measuring vessel perfusion. METHODS: An experimental setup was developed that simultaneously collects measurements of ICG fluorescence and LSCI in a rodent model. A 785-nm laser diode was used for both excitation of the ICG dye and the LSCI illumination. A photothrombotic clot model was used to occlude specific vessels within the field of view to enable comparison of the 2 methods for monitoring vessel perfusion. RESULTS: The induced blood flow change demonstrated that ICG is an excellent method for visualizing the volume and type of vessel at a single point in time; however, it is not always an accurate representation of blood flow. In contrast, LSCI provides a continuous and accurate measurement of blood flow changes without the need of an external contrast agent. CONCLUSION: These 2 methods should be used together to obtain a complete understanding of tissue perfusion. PMID- 22843130 TI - Meningiomas in pregnancy: a clinicopathologic study of 17 cases. AB - BACKGROUND: Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause. OBJECTIVE: We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy. METHODS: Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed. RESULTS: Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra- and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis. CONCLUSION: Our series suggests that pregnancy associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation. PMID- 22843131 TI - Increased frameless stereotactic accuracy with high-field intraoperative magnetic resonance imaging. AB - BACKGROUND: Frameless stereotaxy commonly registers preoperative magnetic resonance imaging (MRI) to patients by using surface scalp anatomy or adhesive fiducial scalp markers. Patients' scalps may shift slightly between preoperative imaging and final surgical positioning with pinion placement, introducing error. This might be reduced when frameless stereotaxy is performed in a high-field intraoperative MRI (iMRI), as patients are positioned before imaging. This could potentially improve accuracy. OBJECTIVE: To compare frameless stereotactic accuracy using a high-field iMRI with that using standard preoperative MRI. METHODS: Data were obtained in 32 adult patients undergoing frameless stereotactic-guided brain tumor surgery. Stereotactic images were obtained with 1.5T MRI scanner either preoperatively (14 patients) or intraoperative (18 patients). System-generated accuracy measurements and distances from the actual center of each fiducial marker to that represented by neuronavigation were recorded. Finally, accuracy at multiple deep targets was assessed by using a life sized human head stereotactic phantom in which fiducials were placed on deformable foam to mimic scalp. RESULTS: : System-generated accuracy measurements were significantly better for the iMRI group (mean +/- SEM = 1.04 +/- 0.05 mm) than for the standard group (1.82 +/- 0.09 mm; P < .001). Measured distances from the actual center of scalp fiducial markers to that represented by neuronavigation were also significantly smaller for iMRI (1.72 +/- 0.10 mm) in comparison with the standard group (3.17 +/- 0.22 mm; P < .001). Deep accuracy in the phantom model was significantly better with iMRI (1.67 +/- 0.12 mm) than standard imaging (2.28 +/- 0.14 mm; P = .003). CONCLUSION: Frameless stereotactic accuracy is increased by using high-field iMRI compared with standard preoperative imaging. PMID- 22843133 TI - Simple and reliable determination of the modified rankin scale score in neurosurgical and neurological patients: the mRS-9Q. AB - BACKGROUND: The modified Rankin Scale (mRS) is a 6-level outcome scale used to assess level of function in neurological disease. OBJECTIVE: We examined the interobserver reliability and intraobserver reliability of the mRS-9Q, a 9 question "yes/no" survey that measures the mRS score in neurosurgical and neurological patients. METHODS: The mRS-9Q was administered in person or by telephone, and a Web-based tool was used to calculate the mRS score and to perform error checking. Part 1 compared the mRS-9Q with an mRS structured interview (n = 80). Part 2 compared mRS-9Q administration by telephone and by hard copy (n = 80). Part 3 compared mRS-9Q administration by an expert interviewer with administration by a nonexpert (n = 83). Part 4 examined reproducibility of the mRS-9Q over a 2-week period (n = 84). RESULTS: Agreement was very good in all study parts. In Part 1 (mRS-9Q vs mRS with structured interview), kappa = 0.80 and kappaw = 0.96. In Part 2 (mRS-9Q telephone vs hard copy), kappa = 0.83 and kappaw = 0.95. In Part 3 (mRS-9Q expert vs nonexpert), kappa = 0.73 and kappaw = 0.93. In Part 4 (mRS-9Q reproducibility), kappa = 0.76 and kappaw = 0.93. CONCLUSION: The mRS-9Q is a simple, easy-to-administer survey with a custom Web-based mRS calculation and error-checking tool. The mRS-9Q can reliably determine the mRS by hard copy survey or by telephone and can be administered by experts or nonmedical study personnel. The mRS-9Q can be used to measure functional outcome in a broad population of patients with neurosurgical and neurological diseases. PMID- 22843132 TI - Comparison of superior-level facet joint violations during open and percutaneous pedicle screw placement. AB - BACKGROUND: Superior-level facet joint violation by pedicle screws may result in increased stress to the level above the instrumentation and may contribute to adjacent segment disease. Previous studies have evaluated facet joint violations in open or percutaneous screw cases, but there are no reports describing a direct institutional comparison. OBJECTIVE: To compare the incidence of superior-level facet violation for open vs percutaneous pedicle screws and to evaluate patient and surgical factors that affect this outcome. METHODS: We reviewed 279 consecutive patients who underwent an index instrumented lumbar fusion from 2007 to 2011 for degenerative spine disease with stenosis with or without spondylolisthesis. We used a computed tomography grading system that represents progressively increasing grades of facet joint violation. Patient and surgical factors were evaluated to determine their impact on facet violation. RESULTS: Our cohort consisted of 126 open and 153 percutaneous cases. Percutaneous procedures had a higher overall violation grade (P = .02) and a greater incidence of high grade violations (P = .006) compared with open procedures. Bivariate analysis showed significantly greater violations in percutaneous cases for age < 65 years, obesity, pedicle screws at L4, and 1- and 2-level surgeries. Multivariate analysis showed the percutaneous approach and depth of the spine to be independent risk factors for high-grade violations. CONCLUSION: This study demonstrates greater facet violations for percutaneously placed pedicle screws compared with open screws. PMID- 22843134 TI - Brain tumor surgery with 3-dimensional surface navigation. AB - BACKGROUND: Precise lesion localization is necessary for neurosurgical procedures not only during the operative approach, but also during the preoperative planning phase. OBJECTIVE: To evaluate the advantages of 3-dimensional (3-D) brain surface visualization over conventional 2-dimensional (2-D) magnetic resonance images for surgical planning and intraoperative guidance in brain tumor surgery. METHODS: Preoperative 3-D brain surface visualization was performed with neurosurgical planning software in 77 cases (58 gliomas, 7 cavernomas, 6 meningiomas, and 6 metastasis). Direct intraoperative navigation on the 3-D brain surface was additionally performed in the last 20 cases with a neurosurgical navigation system. For brain surface reconstruction, patient-specific anatomy was obtained from MR imaging and brain volume was extracted with skull stripping or watershed algorithms, respectively. Three-dimensional visualization was performed by direct volume rendering in both systems. To assess the value of 3-D brain surface visualization for topographic lesion localization, a multiple-choice test was developed. To assess accuracy and reliability of 3-D brain surface visualization for intraoperative orientation, we topographically correlated superficial vessels and gyral anatomy on 3-D brain models with intraoperative images. RESULTS: The rate of correct lesion localization with 3-D was significantly higher (P = .001, chi), while being significantly less time consuming (P < .001, chi) compared with 2-D images. Intraoperatively, visual correlation was found between the 3-D images, superficial vessels, and gyral anatomy. CONCLUSION: The proposed method of 3-D brain surface visualization is fast, clinically reliable for preoperative anatomic lesion localization and patient-specific planning, and, together with navigation, improves intraoperative orientation in brain tumor surgery and is relatively independent of brain shift. PMID- 22843135 TI - Contrast-enhanced ultrasound ventriculography. AB - BACKGROUND: During external ventricular drainage (EVD) weaning, cranial computed tomography (cCT) is necessary to evaluate ventricle width. Because intrahospital transfer of critically ill patients is associated with higher mortality, bedside techniques are necessary to evaluate ventricle width. Transcranial sonography is able to show the ventricles in patients with sufficient temporal acoustic window. Contrast-enhanced ultrasound (CEUS) is able to overcome the limitations of insufficient insonation. OBJECTIVE: We demonstrate the feasibility of bedside transcranial CEUS ventriculography to measure ventricles and verify the passage of cerebrospinal fluid (CSF) through the foramen of Magendie into the subarachnoid space during EVD weaning in critically ill patients. METHODS: Six patients were examined by transcranial and transnuchal CEUS. Harmonic imaging with low mechanical index was used. One milliliter of an ultrasound contrast agent was administered via EVD line. Comparison with the cCT scans at the time of discharge was used to confirm CEUS-ventriculography results. RESULTS: Ventricles were visualized in all patients. CSF transmission via the foramen of Magendie was demonstrated in 5 patients. Mean ventricle width (centimeters) was 0.67 (CEUS) vs 0.73 (cCT) (standard deviation 0.43, 0.45, P = .116) [third ventricle], 0.88 vs 1.02 (0.28, 0.22, P = .055) [fourth ventricle], 1.40 vs 1.37 (0.56, 0.54, P = .620) [left lateral ventricle], 1.37 vs 1.37 (0.55, 0.54, P = .952) [right lateral ventricle], 2.33 vs 2.23 (0.51, 0.58, P = .169) [left anterior horn], and 2.25 vs 2.07 (0.56, 0.64, P = .204) [right anterior horn]. Mean duration for CEUS ventriculography was 3:15 minutes. CONCLUSION: CEUS ventriculography is an effective bedside procedure in critically ill patients with EVD. CEUS allows measurement of ventricle width, ventricle communication, and CSF transfer to the subarachnoidal space through the cisternal foramina. PMID- 22843136 TI - Augmented autologous pericranium duraplasty in 100 posterior fossa surgeries--a retrospective case series. AB - BACKGROUND: Primary closure of the dura in posterior fossa (p-fossa) surgeries is technically difficult and usually requires the use of a dural substitute. A variety of substitutes are currently available and data suggest that autologous materials are preferred in comparison with nonautologous substitutes. OBJECTIVE: To report our experience using locally harvested autologous pericranium as a dural substitute in patients who underwent p-fossa surgeries. METHODS: Retrospective analysis of patients who had undergone p-fossa craniotomies between 2005 and 2011. All patients received locally harvested autologous pericranium for duraplasty augmented with a dural sealant. Data were reviewed for complications including: surgical site infection, meningitis, cerebrospinal fluid leak, the radiographic formation of a pseudomeningocele, and any new neurological symptoms related to the incision or repair. RESULTS: One hundred patients were identified. Indications for surgery included tumor, vascular lesions, or hemorrhage requiring surgical intervention, symptomatic Chiari I malformation, microvascular decompression for trigeminal neuralgia, and trauma requiring surgical decompression. The complication rate was 1% with 1 patient developing an nonsteroidal anti-inflammatory drug-induced aseptic meningitis and graft dehiscence requiring surgical revision. CONCLUSION: Autologous pericranium with dural sealant augmentation is an effective way to repair the durotomy in p-fossa surgeries. To the best of our knowledge, this is currently the largest study using this technique in the adult neurosurgical literature. Our results report a much lower rate of complications in comparison with other duraplasty studies. PMID- 22843137 TI - Hyoid-related internal carotid artery dissection. PMID- 22843138 TI - Adjunctive effect of intravitreal bevacizumab prior to lens-sparing vitrectomy in aggressive posterior retinopathy of prematurity: a case report. AB - BACKGROUND: Intravitreal injection of bevacizumab in retinopathy of prematurity has shown satisfactory results without any systemic complications. However, increased fibrosis and tissue contraction are reported as adverse effects in some cases. CASE: A premature girl, born at 29 weeks + 4 days of gestation, had bilateral aggressive posterior retinopathy of prematurity (APROP) on her first screening at 3 weeks of age. She received extensive, near confluent, laser ablation of the avascular retina and off-label intravitreal bevacizumab (0.75 mg) injection OU. The right eye showed a slight regression, but a localized tractional membrane was noted OS. After another intravitreal bevacizumab injection in each eye, the left eye underwent lens-sparing vitrectomy (LSV) because of contraction of the proliferative membrane leading to a dome-shaped tractional retinal detachment (TRD). OBSERVATIONS: At 6-week follow-up, the left eye showed complete retinal reattachment. Both eyes showed prompt resolution of vascular engorgement with anterior progression of the peripheral retinal vasculature. CONCLUSIONS: Intravitreal bevacizumab is safe and effective as a treatment of APROP. In some cases tissue contraction may occur, but because TRD is localized to the posterior pole, effective LSV can be performed. PMID- 22843139 TI - Effect of central and peripheral leucine on energy metabolism in the Djungarian hamster (Phodopus sungorus). AB - Branched-chain amino acids, particularly leucine, are thought to activate nutrient sensing pathways in the hypothalamus that regulate food intake and energy homeostasis. In the light of recent controversial findings of leucine's effect on energy homeostasis further clarification of the metabolic impact of dietary leucine supplementation is required. We examined the pharmacological and dietary effects of leucine on energy metabolism in the Djungarian hamster (Phodopus sungorus), a well-established model for studies of alterations in leptin sensitivity and energy metabolism. We acutely administered leucine into the lateral ventricle (1.1 MUg) of hamsters to characterize whether leucine exhibits anorexigenic properties in this species as has been described in other rodents. Next the catabolic effect of dietary administered leucine via supplemented rodent diet (15 % leucine), drinking water (17 g/L leucine) and oral gavages (10 mg/day); as well as the effect of subcutaneously (0.1 and 3 mg/day) and intraperitoneally (0.1, 3 and 6 mg/day) injected leucine which avoids the gastrointestinal-track was analyzed. Centrally administered leucine reduced 24 h food intake (by 32 %) and body weight. Both parameters were also reduced in hamsters with leucine supplemented diet, but this catabolic response was based on a pronounced taste aversion to the leucine-diet. In all other experiments, dietary leucine and peripheral injections of leucine had no effect on food intake, body weight and basal blood glucose levels. Our data suggest that in the Djungarian hamster dietary leucine fails to exhibit catabolic effects that would override the evolutionary conserved adaptations of the species which is critical for its survival. PMID- 22843141 TI - [Management of a national society of nephrology: looking back on two years' experience as its president]. AB - Achieving results when leading a scientific society is a slow process and efforts sometimes remain ineffective, while in other cases a desired effect materializes later than expected. The major aim of a two-year program (2010-2012) of the Italian Society of Nephrology (SIN) was to highlight the work of the nephrologist within the healthcare system as well as to the public. An important achievement was the inclusion by the WHO of chronic kidney disease (CKD) among the chronic illnesses that will be the focus of the healthcare system in the next decade. SIN has launched a series of activities to establish a close collaboration with the healthcare system for the prevention and timely treatment of CKD. This will include the compilation of national guidelines for CKD shared with 12 other scientific societies and open to general practitioners, and will pave the way for common protocols with general practitioners. Several large epidemiological surveys have been set up to obtain not only an updated map of CKD in Italy, but also to evaluate the different rates of disease progression in patients followed in specialized centers or general outpatient clinics. The collaboration of SIN with the European Society (ERA-EDTA) has been a major achievement, favoring the subscription of young nephrologists and their contact with young colleagues abroad. In spite of economic difficulties, SIN has given significant support to national research and to fellowships for young researchers. The educational task has included web symposia and long-distance learning facilities. SIN has focused on three projects: early detection of CKD, kidney transplant program improvement, and analysis with healthcare economists of new management models for the distribution of nephrological services. PMID- 22843140 TI - Evidence for a role of tight junctions in regulating sodium permeability in zebrafish (Danio rerio) acclimated to ion-poor water. AB - Freshwater teleosts are challenged by diffusive ion loss across permeable epithelia including gills and skin. Although the mechanisms regulating ion loss are poorly understood, a significant component is thought to involve paracellular efflux through pathways formed via tight junction proteins. The mammalian orthologue (claudin-4) of zebrafish (Danio rerio) tight junction protein, claudin b, has been proposed to form a cation-selective barrier regulating the paracellular loss of Na(+). The present study investigated the cellular localization and regulation of claudin-b, as well as its potential contribution to Na(+) homeostasis in adult zebrafish acclimated to ion-poor water. Using a green fluorescent protein-expressing line of transgenic zebrafish, we found that claudin-b was expressed along the lamellar epithelium as well as on the filament in the inter-lamellar regions. Co-localization of claudin-b and Na(+)/K(+)-ATPase was observed, suggesting its interaction with mitochondrion-rich cells. Claudin-b also appeared to be associated with other cell types, including the pavement cells. In the kidney, claudin-b was expressed predominantly in the collecting tubules. In addition, exposure to ion-poor water caused a significant increase in claudin-b abundance as well as a decrease in Na(+) efflux, suggesting a possible role for claudin-b in regulating paracellular Na(+) loss. Interestingly, the whole-body uptake of a paracellular permeability marker, polyethylene glycol-400, increased significantly after prolonged exposure to ion-poor water, indicating that an increase in epithelial permeability is not necessarily coupled with an increase in passive Na(+) loss. Overall, our study suggests that in ion-poor conditions, claudin-b may contribute to a selective reduction in passive Na(+) loss in zebrafish. PMID- 22843142 TI - [GIN on line, a dream come true]. PMID- 22843143 TI - [Glomerular hyperfiltration, prediabetes and prehypertension: bad company early on?]. PMID- 22843144 TI - [Eculizumab: a shift for the treatment of glomerulonephritis with C3 deposits?]. PMID- 22843145 TI - [Last but not least: quality of terminal care in patients with advanced CKD]. PMID- 22843146 TI - [Autologous mesenchymal stem cells for induction therapy: transplant on the up and up!]. PMID- 22843147 TI - [Cystinosis: a chronic disease (also) in adulthood]. PMID- 22843148 TI - [The admirable podocyte, nuncio of preeclampsia]. PMID- 22843149 TI - [Incremental peritoneal dialysis - yes]. AB - The incremental modality at the start of peritoneal dialysis (Incr-DP) is implicit in the definition of adequacy, which is expressed as the sum of dialysis clearance and renal clearance.Theoretically, it is possible to demonstrate that with a glomerular filtration rate at the start of dialysis of 6 mL/min, the minimum Kt/V target of 1.70 indicated by the current guidelines is easily exceeded with both 2-exchange of CAPD (incremental CAPD) and APD of 3 or 4 weekly sessions (Incr-APD), with a daytime icodextrin dwell. The GSDP (Peritoneal Dialysis Study Group) census data suggest that Incr-DP favors the choice of peritoneal dialysis. Although limited to a few studies with a relatively small number of patients, data show that Incr- CAPD is associated with a better quality of life, the achievement of Kt/V targets, and satisfactory ultrafiltration. The clearance of medium molecules is equivalent in Incr-DP and full-dose PD as it depends on the duration of the dwell and not on the number of exchanges. The maintenance of body weight, protein intake and peritoneal permeability may be explained by the lower glucose load with Incr-DP. The preservation of residual renal function is similar to that recorded with full-dose PD, while the peritonitis rate seems to be lower. The favorable results reported in the literature and the indications of the most recent guidelines about the importance of reducing the exposure to glucose to a minimum and safeguarding the patient's quality of life in our opinion further justify the use of Incr-DP. PMID- 22843150 TI - [Incremental peritoneal dialysis - no]. AB - The incremental approach to peritoneal dialysis provides reduced dialytic purification by an intermittent schedule maintaining the total solute clearance above the minimal targets, even if they have not been validated as adequacy targets for intermittent treatments. The early initiation of peritoneal dialysis (GFR >8 mL/min 1.73 m2) has been demonstrated not to be useful to improve patient survival. Standard initiation of dialysis (GFR 5-7 mL/min 1.73 m2) using the incremental modality implies a loss of dialysis clearance that is likely to have an effect on-often asymptomatic-cardiovascular disease. There is no scientific evidence that incremental peritoneal dialysis helps to preserve residual renal function or the peritoneal membrane nor that it reduces the peritonitis rate or complications due to uremia. The central role of the extent of residual renal function regarding the prescription of incremental peritoneal dialysis and the usual procedures for its assessment set the stage for possible underdialysis, even for short periods. PMID- 22843151 TI - [Incremental peritoneal dialysis - conclusions]. AB - Peritoneal dialysis (PD) adequacy, defined as the sum of renal clearance and peritoneal clearance with a minimum Kt/V target of 1.70, can be achieved with incremental dialysis (Incr-PD), which should therefore not be confused with early dialysis. The Peritoneal Dialysis Study Group census data show that the use of Incr-PD is widespread in Italy and has increased over the years. In 2010 Incr-PD was used in 50% of the centers performing peritoneal dialysis (PD), against 38.5% in 2008 and 29.2% in 2005. The use of PD is also significantly higher in these centers than in those not using Incr-PD (27.5% vs 21.4%; p<0.001). Despite the widespread use of Incr-PD, there is no evidence in the literature showing significantly different clinical results between starting PD incrementally or on full-dose. However, some data suggest a benefit of Incr-PD in that it favors the choice of PD and is associated with a better quality of life. This method allows for the dialysis adequacy and ultrafiltration targets indicated by the current guidelines to be achieved easily without the risk of underdialysis. In view of the frequent errors in the collection of diuresis and of the progressive reduction over time of residual renal function (RRF), frequent RRF monitoring is necessary so that the dialysis dose can be adjusted. Furthermore, dialysis adequacy should always be measured by collection of the dialysate. PMID- 22843152 TI - [Membranous glomerulonephritis secondary to allogeneic stem cell transplant: review of the literature]. AB - Renal injury associated with hematopoietic stem cell transplant (HSCT) may be related to a combination of factors. Chronic graft-versus-host disease (cGVHD) is the most common complication of allogeneic HSCT. Although the kidneys are not considered the primary target organs for GVHD, chronic impairment of renal function may occur in 20% to 60% of HSCT patients. Membranous glomerulonephritis (MG) is the most frequent renal complication observed in patients who develop nephrotic syndrome after allogeneic HSCT. In this setting, the pathogenesis of MG is not clearly understood and the most appropriate treatment approach has not been established. In order to summarize the current knowledge on this issue, a review of the pertinent literature has been performed. The available data on MG diagnosed in patients submitted to allogeneic HSCT were identified using the MEDLINE database (last accessed: Jan 30, 2012). Fifty-nine patients with allogeneic HSCT-related MG with a median age of 43 years were identified. MG occurred at a median time of 17 months after allogeneic HSCT. A history of acute or concomitant clinically apparent cGVHD was present in 69% and 31% of cases, respectively. cGVHD, nonmyeloablative conditioning regimens, immunosuppression withdrawal, and the use of peripheral blood stem cell grafts were identified as risk factors. Among the 53 patients with available outcome data, complete remission, partial response, and inefficacy of treatment were recorded in 65%, 22% and 13% of cases, respectively. MG after allogeneic HSCT seems to be etiologically related to subclinical or overt cGVHD, which flares up after discontinuation of immunosuppression. The available measures can induce sustained long-term remission in about two-thirds of affected patients. PMID- 22843153 TI - [Kidney transplant in patients with HIV infection]. AB - Until recently, human immunodeficiency virus (HIV) infection was an absolute contraindication to solid organ transplantation because it was feared that the anti-rejection therapy could result in accelerated HIV disease. At the end of the 1990s it became clear that HIV infection, once deemed a fatal disease, could be effectively turned into a chronic condition by the use of highly active antiretroviral therapy. Since then, the mortality rate from opportunistic infections has decreased dramatically, while liver and renal insufficiency have become the major causes of morbidity and mortality in these patients in the long term. A growing number of HIV patients develop end-stage renal disease secondary to immune-mediated glomerulonephritis, HIV-associated nephropathy, nephrotoxic effects induced by antiretroviral medication, or diabetic and vascular nephropathy, and therefore need maintenance dialysis. For this reason we have to reconsider kidney transplant as a possible treatment option. During the last decade, the results of many studies have shown that transplantation can be safe and effective as long as the HIV infection is effectively controlled by antiretroviral therapy. The short- and medium-term patient and graft survival rates in HIV-positive transplant recipients are comparable with those of the overall transplant population, but the incidence of acute rejection episodes is higher. The main clinical problem in the management of HIV-positive transplant recipients originates from the interference between immunosuppressive regimens and antiretroviral drugs. Thus, a close collaboration between infectious disease specialists and nephrologists is mandatory in order to optimize transplantation programs in these patients. PMID- 22843154 TI - [Limitations of blood pressure target in non-dialysis chronic kidney disease: a question of method?]. AB - International guidelines recommend to reduce blood pressure (BP) levels below 130/80 mmHg in non-dialysis chronic kidney disease (CKD) patients. However, this BP target has not been validated by randomized controlled trials and is mainly driven by data obtained in observational and post-hoc analyses suggesting that it improves the renal and, to some extent, cardiovascular prognosis. The inconclusive results on the prognostic role of the BP target in patients with CKD might also relate to the limited ability of office BP readings to adequately stratify the global risk of this population. In fact, alterations of the pressure profile (such as white-coat hypertension) and nighttime hypertension are common in CKD patients. Recent studies have demonstrated that ambulatory blood pressure monitoring (ABPM) is superior to clinic BP measurements in predicting renal death and cardiovascular events. Therefore, while waiting for the results from the ongoing randomized Systolic Blood Pressure Intervention Trial (SPRINT) comparing the effect on cardiorenal prognosis of two BP target levels, the more widespread use of ABPM is desirable in CKD patients. PMID- 22843155 TI - [Pharmacokinetics of antibiotics in continuous renal replacement therapies (CRRT)]. AB - In the critically ill patient, acute kidney injury (AKI) is frequently associated with infective complications requiring appropriate antimicrobial treatment. AKI and multiple organ dysfunction syndrome can affect the pharmacokinetic parameters of many drugs. Furthermore, the start of renal replacement therapy (RRT) is an additional variable to be taken into consideration to avoid inappropriate antimicrobial therapy. Continuous renal replacement therapies (CRRT) are widely adopted in the intensive care unit (ICU) and antibiotics that are significantly eliminated by the kidney are likely to be removed during RRT. Generally, drug dosing adjustments are required if the extracorporeal clearance accounts for more than 25-30% of the total body clearance. The molecular weight cutoffs of the more widely used membranes are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the antibiotics most commonly used in ICU patients. However, CRRTs are still not standardized and the impact of RRT on plasma drug concentrations can be substantially different depending on the CRRT modality (diffusive, convective or both), membrane characteristics and delivered dialysis dose. In any case, drug-dosing adjustments should be based on the knowledge of the pharmacokinetic and pharmacodynamic properties of the different classes of antimicrobials, taking into account that high extracorporeal clearances could lead to drug underexposure in clinical conditions where appropriate antibiotic treatment is essential. PMID- 22843156 TI - [Chronic kidney disease prevalence and trends (1998-2008) in an area of southern Italy. The data of the VIP project]. AB - Chronic kidney disease (CKD) is a common disorder whose prevalence is increasing worldwide. In Italy the prevalence of CKD, especially the early stages, is still not exactly known. Our study examines the prevalence and trends in ten years (1200 subjects in 1998-1999 and 1200 subjects in 2008-2009) of the estimated glomerular filtration rate (eGFR) in a population of southern Italy. We analyzed, within the VIP project, the prevalence of CKD (eGFR <60) in our area and its relationship to diabetes and hypertension as well as the trend between the years 1998-1999 and 2008-2009. The estimate of the GFR was obtained with the Cockcroft Gault formula corrected for body surface area. The prevalence of CKD, stratified by the population of Campania, was about 5.9% in males and 3.9% in females in the years 1998-1999; ten years later (2008-2009) it had increased to 6.2% in males and 4.5% in females. The differences between males and females and between the two decades are not statistically significant although the trend shows a clear increase in subjects affected by CKD among both sexes. Among the male population the prevalence of CKD in persons with hypertension or diabetes, in those with both diseases, and in those free from these diseases was 11.2%, 12%, 13.8% and 6.3% (p=0.018), respectively. The same groups among females showed a CKD prevalence of 8%, 9.2%, 9.7% and 4.4%, respectively (p=0.042). Our work provides a picture of the prevalence of CKD in an area of southern Italy. It highlights the increase in CKD and calls upon a greater use of renal function tests in clinical practice, so that individuals at increased risk of developing cardiovascular complications may be detected as early as possible. PMID- 22843157 TI - [Ultrasound and color Doppler imaging for kidney and urinary tract tumors]. AB - When a renal mass is suspected, conventional ultrasound and color Doppler imaging are often used for initial assessment. Ultrasound screening has many advantages over contrast-enhanced CT and MRI, such as accessibility, low costs, and no need for intravenous iodine contrast administration or ionizing radiation. Sonography is very helpful to distinguish cystic from solid lesions and to monitor the growth and structural pattern of cysts. Detection of small renal carcinoma of less than 3 cm in diameter is limited, however, and small tumors are detected by conventional ultrasound only in 67-79% of cases. In fact, small renal malignancies may have an echogenicity similar to the normal renal parenchyma. In these cases it is very hard to distinguish the tumor, particularly when there is no evident disarrangement of the normal renal contours and no extension into the central renal complex. Renal cell carcinoma can also be hypo- or hyperechoic and indistinguishable from renal adenoma/oncocytoma or angiomyolipomas, which are commonly described as hyperechoic masses. In other words, the pattern and ultrasound characteristics of renal masses often overlap between benign and malignant tumors. A diagnosis of a malignant cystic lesion requires evidence of multiple, thickened internal septa, calcifications, vascularity, and parietal nodularity. When a solid lesion does not show the typical appearance of a simple cyst (a round anechoic lesion with a smooth well-defined wall, without internal debris, and showing increased through-transmission), further evaluation with contrast-enhanced CT or MRI is necessary. Contrast-enhanced ultrasound (CEUS) improves the sensitivity for detection of small renal masses. Compared to CT, CEUS is able to better visualize the number of septa, the septum and wall thickness, the presence of a solid component, and enhancement in some cases, resulting in upgrading of the Bosniak classification and affecting treatment planning. PMID- 22843158 TI - [Acute heart failure secondary to takotsubo cardiomyopathy in a patient on peritoneal dialysis with residual renal function loss]. AB - Takotsubo cardiomyopathy (TTC) is characterized by clinical and electrocardio graphic signs that mimic myocardial ischemia, typical left ventricular kinesis abnormalities, and no evidence of obstructive coronary disease. It is associated with emotional or physical stress usually in postmenopausal women. A major pathogenetic role is played by excessive sympathetic stimulation of the left ventricle. Only two cases of TTC have been described in patients on hemodialysis and one case has been described in a patient on peritoneal dialysis associated with peritonitis. We observed a case of TTC in a patient on nocturnal intermittent peritoneal dialysis with a transplanted kidney and loss of residual renal function. We found that she had suffered significant emotional stress immediately before the symptoms arose. The clinical features were typical ischemic chest pain and acute heart failure. Beta-blockers were the principal pharmacological treatment. The necessary ultrafiltration was obtained with peritoneal dialysis in automated modality, reducing the abdominal filling volumes according to the patient's compliance and modifying the glucose concentration according to her hemodynamic condition. The obtained ultrafiltration was appropriate and in accordance with the few experiences reported in the literature. The symptoms resolved within a week and the left ventricular kinesis and ejection fraction normalized in almost three weeks. This clinical case suggests that peritoneal dialysis, also in automated mode, can be as effective as extracorporeal ultrafiltration in the treatment of acute heart failure. PMID- 22843159 TI - [Restrospective analysis of the renal biopsy activity in Piedmont]. AB - The Piedmont Group of Clinical Nephrology has compared the activity of 18 nephrology centers in the region Piedmont/Valle d'Aosta with regard to renal biopsy (RB). Data on the RBs performed in every nephrology unit, taking into account their entire experience (in some cases spanning more than 30 years), were analyzed. 3396 RBs were performed between 1996 and 2011. Thirty to forty percent were done in patients aged >-65 years (1568 in patients >-65 years, 29 in patients >-85 years). 598 BRs were performed in children over the last 20 years. The following contraindications to RB were considered: chronic renal failure by 8 centers (44.4%), serum creatinine (SCr >3 mg/dL) by 3 centers, longitudinal renal size <8 cm by 3 centers, and renal cortex thickness <1 cm by 2 centers. 1798 RBs were performed in patients with SCr >2 mg/dL and 275 in patients on dialysis. The percentage of RBs performed in patients with SCr >2 mg/dL ranged from 27% to 55% between centers. As regards RB in the course of acute renal failure in an ANCA positive context, 4 centers allowed administration of corticosteroids and 8 centers administration of immunosuppressive treatment as well, even in the absence of histological data. In drug-related nephropathies, RB was considered indicated to confirm the farhypothesis of immunoallergic interstitial nephropathy either if the responsible drug was not among the traditional ones known to induce tubulo-interstitial renal disease or if the pharmacological hypothesis seemed no longer sufficient to justify the renal presentation. All centers but one were against performing RB in case of atheroembolic disease. Three centers performed RB in the intensive care unit. As regards RB in patients undergoing treatment with anticoagulants, aspirin was discontinued 5-14 days before the procedure (mean 8 days) and given again 7-15 days afterwards (mean 11.4 days). Ten centers replaced the anticoagulants with low-dose heparin, which was discontinued the day before the procedure; 11 centers asked advice from cardiologists. RB was repeated in 113 cases after a delay of 1 month to 8 years from the first RB. Our analysis shows uniformity in the approach to RB in this Italian region, with some differences compared with the literature: particular attention was paid to severely critical patients, elderly patients, and patients treated with anticoagulant drugs. PMID- 22843160 TI - [Interview with Prof. Quirino Maggiore: a nephrologist with a fitting name. Interview by Mario Timio]. PMID- 22843161 TI - The systematic study of the electroporation and electrofusion of B16-F1 and CHO cells in isotonic and hypotonic buffer. AB - The fusogenic state of the cell membrane can be induced by external electric field. When two fusogenic membranes are in close contact, cell fusion takes place. An appropriate hypotonic treatment of cells before the application of electric pulses significantly improves electrofusion efficiency. How hypotonic treatment improves electrofusion is still not known in detail. Our results indicate that at given induced transmembrane potential electroporation was not affected by buffer osmolarity. In contrast to electroporation, cells' response to hypotonic treatment significantly affects their electrofusion. High fusion yield was observed when B16-F1 cells were used; this cell line in hypotonic buffer resulted in 41 +/- 9 % yield, while in isotonic buffer 32 +/- 11 % yield was observed. Based on our knowledge, these fusion yields determined in situ by dual color fluorescence microscopy are among the highest in electrofusion research field. The use of hypotonic buffer was more crucial for electrofusion of CHO cells; the fusion yield increased from below 1 % in isotonic buffer to 10 +/- 4 % in hypotonic buffer. Since the same degree of cell permeabilization was achieved in both buffers, these results indicate that hypotonic treatment significantly improves fusion yield. The effect could be attributed to improved physical contact of cell membranes or to enhanced fusogenic state of the cell membrane itself. PMID- 22843162 TI - Analysis of the influences of short-term levosimendan exposure on oxidant/antioxidant status and trace-element levels in the physiological status of the thoracic aorta of rats. AB - The objective of this study was to evaluate the effect of levosimendan (chemical formula C14H12N6O) exposure on oxidant/antioxidant status and trace-element levels in the thoracic aorta of rats. Eighteen male Wistar albino rats were randomly divided into two groups of eight animals each. Group 1 was not exposed to levosimendan and served as a control. Levosimendan (12 MUg/kg) diluted in 10 ml 0.5 % dextrose was administered intraperitoneally to group 2. Animals of both groups were killed after 3 days, and their thoracic aortae were harvested for determination of changes in tissue oxidant/antioxidant status and trace-element levels. The animals in both groups were killed 72 h after levosimendan exposure, and thoracic aortae were harvested for determination of the lipid peroxidation product MDA and antioxidant GSH levels and the activities of antioxidant enzymes such as SOD, GSH-Px and CAT. It was found that MDA, GSH and CAT enzyme levels increased in thoracic aortae of rats after levosimendan administration. SOD and CA enzyme activities and the level of antioxidant GSH decreased in thoracic aortae of rats after levosimendan treatment. Pb, Cd and Fe levels of thoracic aortae were significantly higher (P < 0.001) and Mg, Mn, Zn and Cu were significantly lower (P < 0.001) in the levosimendan group compared to the control group. These results suggest that short-term levosimendan treatment caused an increase in free radical production and a decrease in antioxidant enzyme activity in thoracic aortae of levosimendan-treated rats. It also causes a decrease or increase in many mineral levels of the thoracic aorta, which is an undesirable condition for normal pharmacological function. PMID- 22843163 TI - Anthropological analysis of extensive rodent gnaw marks on a human skull using post-mortem multislice computed tomography (pmMSCT). PMID- 22843164 TI - Molecular mechanisms elucidating why old stomach is more vulnerable to indomethacin-induced damage than young stomach. AB - BACKGROUND/AIMS: Detailed underlying changes have never been explored to explain how old stomach is more susceptible to non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage than young stomach, although presumptively speculated as weakened mucosal defense system as well as attenuated regenerating capacity in old stomach. METHODS: In order to investigate molecular mechanisms relevant to NSAID-induced gastric damage, we administered indomethacin to 6-week old and 60-week-old rats. RESULTS: In spite of the same oral administration of indomethacin (0.1 mg indomethacin dissolved in 1 ml carboxyl methylcellulose) irrespective of body weights of rat, gastric mucosal damages were significantly increased in the older rats compared to the younger rats (p < 0.05). Before indomethacin administration, inflammatory mediators including cytokines, chemokines, proteases, and adhesion molecules were significantly increased in old stomach and these differences were further increased after indomethacin administration (p < 0.05). Furthermore, the levels of total oxidants and apoptotic executors were significantly increased in old stomach, whereas lipoxin A4 and anti-apoptotic proteins such as survivin and Bcl-2 were significantly decreased. Increased NF-kappaB-DNA binding activity as well as the activation of JNK and p38 was responsible for the increased expressions of inflammatory mediators as well as oxidants. CONCLUSIONS: A preventive strategy to reduce either redox activation or pro-inflammatory mediators should be considered in older patients taking long-standing NSAID administration. PMID- 22843165 TI - Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): raising the bar for diagnosis. PMID- 22843166 TI - 5-Fluorouracil encapsulated HA/PLGA composite microspheres for cancer therapy. AB - 5-Fluorouracil (5FU) was successfully entrapped within poly(lactide-co-glycolide) (PLGA) and hydroyapatite (HA) composite microspheres using the emulsification/solvent extraction technique. The effects of HA to PLGA ratio, solvent ratio as well as polymer inherent viscosity (IV) on encapsulation efficiency were investigated. The degradation and drug release rates of the microspheres were studied for 5 weeks in vitro in phosphate buffered solution of pH 7.4 at 37 degrees C. The drug release profile followed a biphasic pattern with a small initial burst followed by a zero-order release for up to 35 days. The initial burst release decreased with increasing HA content. The potential of HA in limiting the initial burst release makes the incorporation of HA into PLGA microspheres advantageous since it reduces the risk of drug overdose from high initial bursts. The linear sustained drug release profile over the course of 5 weeks makes these 5-FU-loaded HA/PLGA composite microparticles a promising delivery system for the controlled release of chemotherapy drugs in the treatment of cancer. PMID- 22843167 TI - Overcoming hypoxia in 3D culture systems for tissue engineering of bone in vitro using an automated, oxygen-triggered feedback loop. AB - Tissue engineering is an attractive approach to heal bony defects. However, three dimensional cell-scaffold constructs display uneven oxygen supply resulting in inhomogeneous tissue quality. We assessed different strategies to improve oxygen supply in vitro. Scaffolds with differing inner surface were seeded with preosteoblastic cells and cultivated either statically or in perfusion bioreactors. Oxygen concentration and pH were measured in the center of the scaffolds. An inductive feedback mechanism was build to increase bioreactor pump speed according to the oxygen concentrations measured within the scaffolds. While pH remained stable, oxygen concentration decreased significantly under static conditions within the cell-seeded scaffolds. Reducing the scaffolds' inner surface as well as increasing perfusion speeds in bioreactors resulted in improved oxygen supply. We conclude that improving oxygen supply to three dimensional culture systems for bone tissue engineering is feasible in an automated manner. Culture conditions have to be adapted to each cell-scaffold system individually. PMID- 22843168 TI - The untold story of Dabigatran etexilate: alveolar hemorrhage in an elderly patient with interstitial pulmonary fibrosis. AB - We report an 85-year-old male, with history of interstitial pulmonary fibrosis (IPF), who was presented with progressive dyspnea, hypoxia, and anemia of 2 months duration. Six months before presentation, the patient was placed on Dabigatran etexilate (Dabigatran) (110 mg BID) for atrial fibrillation. His prior anemia workup included a negative upper endoscopy and colonoscopy. Bronchoscopy revealed copious amounts of bloody secretions. The bronchial tree was washed and Dabigatran was discontinued. The patient's medical condition improved and was subsequently discharged home. Our case illustrates the failure of current literature to predict the isolated bronchoalveolar bleed secondary to Dabigatran therapy. PMID- 22843169 TI - Antithrombotic therapy in heparin-induced thrombocytopenia: guidelines translated for the clinician. AB - Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome initiated by heparin exposure and characterized by thrombocytopenia and paradoxical thrombophilia. HIT is mediated by the formation of antibodies against the platelet factor 4/heparin complex, which leads to platelet activation, thrombin generation, and potentially fatal thrombotic sequelae. The clinical presentation of HIT is variable and can be easily overlooked. Although a number of functional and antigen-based immunoassays have been developed to detect the presence of HIT antibodies, initial diagnosis is often based on recognition of thrombocytopenia in the appropriate clinical context and later confirmed with immunologic testing. Given the serious clinical consequences of HIT, immediate cessation of heparin products and administration of non-heparin anticoagulants are crucial components of treatment. We provide a review of the clinical syndrome and practical summary of treatment recommendations from the most recent 2012 American College of Chest Physicians evidence-based guidelines for the treatment and prevention of HIT. PMID- 22843170 TI - The effect of sulphurous water in patients with osteoarthritis of hand. Double blind, randomized, controlled follow-up study. AB - The aim of the study was to demonstrate the effectiveness of sulphurous water in patients with osteoarthritis of the hand. Forty-seven patients with osteoarthritis of the hand were enrolled into the double-blind, randomized, controlled study, satisfying ACR criteria. One group of the patients (n = 24) received balneotherapy, bathing in sulphurous thermal water for 20 min per occasion, 15 times in all during a period of 3 weeks. The control group (n = 21) had a bath exclusively in warm tap water. Assessments were carried out in both groups on four occasions: at the beginning and at the end of the treatment, and 3 and 6 months after the beginning of the treatment. The parameters studied were the following: pain in the hand, morning stiffness in the joints, grip strength of both hands, and Health Assessment Questionnaire Disability Index (HAQ) and AUSCAN Hand Osteoarthritis Index and EuroQol quality of life questionnaire. At the end of treatment, the improvement was more pronounced in the patient group treated with the sulphurous water. After 3 months, significant improvement could be detected in all parameters, except the morning stiffness and EQ5D. After 6 months, the values of pain, HAQ and AUSCAN continued to be significantly better in comparison with the baseline values. The improvement in quality of life was significant only at the end of the treatment, 6 months later not any longer. The difference between the two groups was significant after 3 months in point of pain and EQVAS. Balneotherapy and within this the sulphurous spa water alone may be effective for the attenuation of pain in patients with hand osteoarthrosis. PMID- 22843172 TI - MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells. AB - Restoring p53 activity by inhibiting the interaction between p53 and the mouse double minutes clone 2 (MDM2) offers an attractive approach to cancer therapy. Nutlin-3a is a small-molecule inhibitor that inhibits MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. In this study, we determined the efficacy of Nutlin-3a in inducing p53-mediated cell death in osteosarcoma (OS) cell lines both in vivo and in vitro. Targeted disruption of the p53-MDM2 interaction by Nutlin-3a stabilizes p53 and selectively activates the p53 pathway only in OS cells with wild-type p53, resulting in a pronounced anti-proliferative and cytotoxic effect due to G1 cell cycle arrest and apoptosis both in vitro and in vivo. p53 dependence of these alternative outcomes of Nutlin-3a treatment was shown by the abrogation of these effects when p53 was knocked-down by small interfering RNA. These data suggest that the disruption of p53-MDM2 interaction by Nutlin-3a might be beneficial for OS patients with MDM2 amplification and wt p53 status. PMID- 22843171 TI - The promising role of lung ultrasound in systemic sclerosis. AB - Ultrasound (US) has an emergent and relevant role in the assessment of systemic sclerosis (SSc) even if there are many fields and applications that still have not been sufficiently explored. In this review, we will report an update of the available data regarding the use of US in lung involvement that might cause disability and mortality in SSc patients. Lung US does not employ ionizing radiation and is more rapid and less expensive than traditional high-resolution tomography (HRCT). Furthermore, recent initial studies have demonstrated that US scores correlated to HRCT and functional respiratory test results in SSc interstitial lung disease. The research agenda for the future should include a more profound investigation of its specificity (comparison with healthy subjects and other diseases) and sensitivity to change at follow-up, to adequately disseminate its use in daily practice and clinical trials. PMID- 22843173 TI - Delayed recurrence of hemifacial spasm after successful microvascular decompression: follow-up results at least 5 years after surgery. AB - BACKGROUND: Microvascular decompression (MVD) for hemifacial spasm (HFS) is regarded as the gold-standard treatment due to its efficacy and durability. However, some patients still suffer from delayed recurrence after initially successful MVD.In this study, we describe our clinical experience in a single institute following up initially successful MVD for HFS 5 or more years after surgery. We analyzed the probability of, risk/predisposing factors for, and timing of delayed recurrence. METHODS: We retrospectively reviewed data from 587 patients meeting our inclusion criteria who underwent MVD for HFS from March, 1999, to June, 2006. We evaluated the time-dependent probability of recurrence and factors affecting delayed recurrence and time of recurrence. RESULTS: The probability of delayed recurrence was 1.0, 1.7, and 2.9 % at 1 year, 2 years, and 5 years after surgery, respectively. Mean time to recurrence was 153.1 months (95 % confidence interval [151.4-154.9]). The probability of late recurrence was increased in patients with co-morbid arterial hypertension (p = 0.036). However, there was a trend towards an association of delayed recurrence with co-existence of young age, male gender, vein or VA offender, and experience of transient facial weakness. CONCLUSIONS: Delayed recurrence of HFS after initially successful MVD is rare; however, there are patients who experience delayed recurrence more than 2 years after MVD, even until 5 years after MVD. Our results suggest that arterial hypertension contributes to late recurrence. We did not find a statistically significant relationship between recurrence and other putative risk/predisposing factors. PMID- 22843174 TI - Posttraumatic seizures in children with severe traumatic brain injury. AB - PURPOSE: Traumatic brain injury (TBI) remains a leading cause of childhood death and disability worldwide. Seizures are a common complication of TBI and they are particularly common in pediatric populations. The proper management of children sustaining severe TBI is still controversial. Our study aims to share our experience contributing to build evidence for better care. METHODS: Retrospective chart review was performed on individuals ages 0 to <18 who presented to a level 1 trauma center during a 10-year period with the diagnosis of severe TBI. Data analyzed included patient's demographics, event information, clinical and radiological presentation, management, and midterm follow-up. Presence of seizures was tracked through EEG monitoring, staff witnessing, or guardian referral. RESULTS: The incidence of early posttraumatic seizures (EPTS) observed in our population (19 %) exceeds those previously reported. Such findings likely reflect the importance of close monitoring including EEG. An association between the presence of EPTS and the development of late posttraumatic seizures (LPTS) was evidenced (p=0.001; 95 % CI 2.2, 16.5), while this association should not be assumed as a measure of causality, it should be considered for the management of patients presenting EPTS. Non-accidental trauma and young age were identified as independent predictors for the development of seizures. CONCLUSIONS: Seizures are a common complication of severe TBI among children aged 0-3 years. Given the detrimental effects that seizures produce on the injured brain, close observation and appropriate monitoring with EEG are essential for the management of children sustaining severe TBI. PMID- 22843175 TI - Symptomatic epileptic spasms in clusters without hypsarrhythmia: surgical management of two cases. PMID- 22843176 TI - Influences motivating smokers in a radon-affected area to quit smoking. AB - AIMS: Domestic radon gas concentrations in parts of the UK are sufficiently high to increase lung cancer risk among residents, and recent studies have confirmed that the risk of smokers developing lung cancer is significantly enhanced by the presence of radon. Despite campaigns encouraging residents of radon-affected areas (RAEs) to test and remediate their homes, public response to the risks posed by radon remains relatively modest, particularly among smokers and young families, limiting the health benefits and cost-effectiveness achievable by remediation. The observation that smokers, who are most at risk from radon, are not explicitly targeted by current radon remediation campaigns prompted an assessment of the value of smoking-cessation initiatives in reducing radon induced lung cancers by reaching at-risk subgroups of the population hitherto uninfluenced by radon-awareness programmes. This study addresses the motivation of current quitters in a designated RAE using a postal questionnaire administered around one year after the cessation attempt. METHODS: Residents of the Northamptonshire RAE who had joined the smoking-cessation programme between July and September 2006 and who remained verifiably tobacco free at four weeks, were subsequently invited to participate in a questionnaire-based investigation into factors affecting their decision to cease smoking. From an initial population of 445 eligible individuals, 205 of those contacted by telephone after 12 months agreed to complete postal questionnaires, and unsolicited questionnaires were sent to a further 112 participants for whom telephone contact had proved impossible. One hundred and three completed questionnaires were returned and analysed, the principal tools being chi(2) , Mann-Whitney and Kruskal-Wallis tests. RESULTS: Individuals decide to quit smoking from self-interest, principally on health grounds, and regard the effects of their smoke on others, particularly children and unborn babies, as less significant. The risk of developing respiratory, coronary/cardiac or cancerous conditions provides the greatest motivation to the decision to quit, with knowledge of radon among the lowest-ranked influences. CONCLUSIONS: This study confirms that quitters place risks to their personal health as the highest factors influencing their decision to quit, and health professionals should be aware of this when designing smoking cessation initiatives. As radon risk is ranked very low by quitters, there would appear to be the potential to raise radon awareness through smoking-cessation programmes, with the objective of increasing the uptake and success rate of such programmes and encouraging participation in radon-remediation programmes. PMID- 22843177 TI - Progress and challenges in the cardiovascular field. PMID- 22843178 TI - Current status of percutaneous coronary intervention of chronic total occlusion. AB - This paper describes the current status of percutaneous coronary intervention (PCI) for totally occluded coronary arteries. Chronic total occlusion is associated with 10%-20% of all PCI procedures. Results show that opening an occluded vessel, especially one supplying a considerable area of myocardium, may be beneficial for a patient's angina relief and heart function. We describe the devices used currently in re-canalization such as new wires, microcatheters (including Tonus and Cosair) and intravascular ultrasound guidance. Different techniques to improve the success rate and reduce complications are discussed in detail. PMID- 22843179 TI - Global impact of RNA splicing on transcriptome remodeling in the heart. AB - In the eukaryotic transcriptome, both the numbers of genes and different RNA species produced by each gene contribute to the overall complexity. These RNA species are generated by the utilization of different transcriptional initiation or termination sites, or more commonly, from different messenger RNA (mRNA) splicing events. Among the 30,000+ genes in human genome, it is estimated that more than 95% of them can generate more than one gene product via alternative RNA splicing. The protein products generated from different RNA splicing variants can have different intracellular localization, activity, or tissue-distribution. Therefore, alternative RNA splicing is an important molecular process that contributes to the overall complexity of the genome and the functional specificity and diversity among different cell types. In this review, we will discuss current efforts to unravel the full complexity of the cardiac transcriptome using a deep-sequencing approach, and highlight the potential of this technology to uncover the global impact of RNA splicing on the transcriptome during development and diseases of the heart. PMID- 22843180 TI - Clinical considerations of anticoagulation therapy for patients with atrial fibrillation. AB - Atrial fibrillation (AF) increases the risk of stroke. New anticoagulation agents have recently provided alternative and promising approaches. This paper reviews the current state of anticoagulation therapy in AF patients, focusing on various clinical scenarios and on comparisons, where possible, between western and eastern populations. PMID- 22843181 TI - Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation. AB - OBJECTIVE: Mesenchymal stem cell (MSC) transplantation is a promising therapy for ischemic heart diseases. However, poor cell survival after transplantation greatly limits the therapeutic efficacy of MSCs. The purpose of this study was to investigate the protective effect of angiopoietin-1 (Ang1) preconditioning on MSC survival and subsequent heart function improvement after transplantation. METHODS: MSCs were cultured with or without 50 ng/ml Ang1 in complete medium for 24 h prior to experiments on cell survival and transplantation. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Hoechst staining were applied to evaluate MSC survival after serum deprivation in vitro, while cell survival in vivo was detected by terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling (TUNEL) assay 24 and 72 h after transplantation. Heart function and infarct size were measured four weeks later by small animal echocardiography and Masson's trichrome staining, respectively. RESULTS: Ang1 preconditioning induced Akt phosphorylation and increased expression of Bcl-2 and the ratio of Bcl-2/Bax. In comparison with non-preconditioned MSCs, Ang1 preconditioned cell survival was significantly increased while the apoptotic rate decreased in vitro. However, the PI3K/Akt pathway inhibitor, LY294002, abrogated the protective effect of Ang1 preconditioning. After transplantation, the Ang1 preconditioned-MSC group showed a lower death rate, smaller infarct size, and better heart functional recovery compared to the non-preconditioned-MSC group. CONCLUSIONS: Ang1 preconditioning enhances MSC survival, contributing to further improvement of heart function. PMID- 22843182 TI - Value of a new post-procedural intravascular ultrasound score in predicting target vessel revascularization after coronary drug-eluting stents implantation. AB - OBJECTIVE: There is no simple or feasible post-procedural intravascular ultrasound (IVUS) score to predict major adverse cardiac events (MACE) in patients undergoing drug-eluting stents (DES) implantation. The aim of this study is to validate a new IVUS score for predicting MACE. METHODS: A total of 295 patients (with 322 lesions) were enrolled. IVUS score was calculated in each lesion based on five IVUS morphological characteristics: inflow/outflow disease, malapposition, underexpansion, tissue protrusion, and edge dissection (iMUTE score). We assigned two points to an underexpansion and one point for each presence of other factors. Patients were divided into low score (iMUTE score<2, n=137) and high score (iMUTE score>=2, n=158) groups. RESULTS: At one year follow up, a trend was seen in favor of the low iMUTE score group in MACE (3.65% vs. 10.10%; P=0.052), and there was more target vessel revascularization (TVR) in the high iMUTE score group compared with low score group (6.96% vs. 1.46%; P=0.044). Low iMUTE score was an independent predictor of freedom from TVR at one year (adjusted hazard ratio (HR) 0.5, 95% confidence interval (CI) 0.1-0.8; P=0.02). CONCLUSIONS: Post-procedural IVUS iMUTE scoring was simple and feasible in clinical practice, and can provide independent prognostic value for TVR in patients undergoing DES implantation. PMID- 22843183 TI - Screening for significant atherosclerotic renal artery stenosis with a regression model in patients undergoing transradial coronary angiography/intervention. AB - OBJECTIVE: Early detection of atherosclerotic renal artery stenosis (ARAS) is clinically important with respect to blood pressure control, prevention of renal insufficiency, and even improving survival. We investigated whether the presence of significant ARAS (luminal diameter narrowing >=70%) could be predicted using a logistic regression model before coronary angiography/intervention. METHODS: Initially, we developed a logistic regression model for detecting significant ARAS based upon clinical and angiographic features and biochemical measurements in a cohort of 1813 patients undergoing transfemoral coronary and renal angiography. This model was then prospectively applied to an additional 495 patients who received transradial renal angiography to ascertain its predictive accuracy for the presence of significant ARAS. RESULTS: Multivariate regression analysis revealed that older age (>=65 years), resistant hypertension, type 2 diabetes, creatinine clearance (Ccr) <=60 ml/min, and multivessel coronary disease were independent predictors for significant ARAS. A logistic regression model for detecting ARAS by incorporating conventional risk factors and multivessel coronary disease was generated as: P/(1-P)=exp(-2.618+1.112[age>=65 years]+1.891[resistant hypertension]+0.453[type 2 diabetes]+0.587[Ccr<=60 ml/min]+2.254[multivessel coronary disease]). When this regression model was prospectively applied to the additional 495 patients undergoing transradial coronary and renal angiography, significant ARAS could be detected with a sensitivity of 81.2%, specificity of 88.9%, and positive and negative predictive accuracies of 53.8% and 96.7%, respectively. CONCLUSIONS: The logistic regression model generated in this study may be useful for screening for significant ARAS in patients undergoing transradial coronary angiography/intervention. PMID- 22843184 TI - Renal insufficiency is an independent predictor of in-hospital mortality for patients with acute myocardial infarction receiving primary percutaneous coronary intervention. AB - OBJECTIVE: To investigate the relationship between renal function and clinical outcomes among patients with acute ST-segment elevation myocardial infarction (ASTEMI), who were treated with emergency percutaneous coronary intervention (PCI). METHODS: 420 patients hospitalized in Peking University First Hospital, diagnosed with ASTEMI treated with emergency (PCI) from January 2001 to June 2011 were enrolled in this study. Estimated glomerular filtration rate (eGFR) was used as a measure of renal function. We compared the clinical parameters and outcomes between ASTEMI patients combined renal insufficiency and the patients with normal renal function. RESULTS: There was a significant increase in the concentrations of fibrinogen and D-Dimer (P<0.05) and a much higher morbidity of diabetes mellitus in the group of patients with chronic kidney disease (CKD; eGFR<60 ml/(min.1.73 m(2))) (P<0.01). CKD (eGFR<60 ml/(min.1.73 m(2))) was an independent predictor of in-hospital mortality for patients hospitalized with ASTEMI receiving PCI therapy rapidly (P=0.032, odds ratio (OR) 4.159, 95% confidence interval (CI) 1.127-15.346). CONCLUSIONS: Renal insufficiency is an independent predictor of in-hospital mortality for patients hospitalized with ASTEMI treated with primary PCI. PMID- 22843185 TI - Complex coronary lesions and rotational atherectomy: one hospital's experience. AB - OBJECTIVE: To evaluate the safety and effectiveness of rotational atherectomy followed by drug eluting stent (DES) implantation in patients with complex coronary lesions. METHODS: From August 2006 to August 2012, 253 consecutive patients with 289 lesions and who underwent rotational atherectomy in our center were enrolled in this study. RESULTS: The overall procedure success rate was 98% with the cost of two (0.8%) coronary perforations, three (1.2%) dissections, five (2.0%) slow flows or no flows, three (1.2%) peri-procedure myocardial infarctions, and two (0.8%) in hospital deaths. During follow-up (mean three years), one (0.4%) patient died, two (0.8%) patients had acute myocardial infarction, 14 (5.5%) had restenosis, and target lesion revascularization occurred in eight patients (3.2%). CONCLUSIONS: Rotational atherectomy followed by DES implantation is a safe and effective technique for patients with complex coronary lesions, especially calcified and non-dilatable lesions. PMID- 22843186 TI - Tea consumption and risk of stroke: a dose-response meta-analysis of prospective studies. AB - OBJECTIVE: To determine the association between tea consumption and the risk of stroke. METHODS: We searched the PubMed database from January 1966 to March 2012 and reviewed reference lists of retrieved articles to identify relevant studies. Studies were included if they reported relative risks (RRs) and corresponding 95% confidence intervals (CIs) of stroke with respect to three or more categories of tea consumption. A random-effects model was used to combine the study-specific risk estimates. RESULTS: Fourteen studies, consisting of 513,804 participants with a median follow-up of 11.5 years, were included in this meta-analysis. We observed a modest but statistically significant inverse association between tea consumption and risk of stroke. An increase of three cups/d in tea consumption was associated with a 13% decreased risk of stroke (RR 0.87; 95% CI, 0.81-0.94). The decreased risk of stroke with tea consumption was consistent among most subgroups. Based on the three studies that provided results for stroke subtypes, tea consumption was also inversely associated with the risk of ischemic stroke (RR 0.76; 95% CI, 0.69-0.84), but not cerebral hemorrhage (RR 0.96; 95% CI, 0.82 1.11) or subarachnoid hemorrhage (RR 0.81; 95% CI, 0.57-1.16). CONCLUSIONS: Tea consumption is associated with a decreased risk of stroke, particularly ischemic stroke. More well-designed, rigorously conducted studies are needed in order to make confident conclusions about the association between tea consumption and stroke subtypes. PMID- 22843187 TI - Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. AB - BACKGROUND: The influence of a positive surgical margin (PSM) on survival outcome of post radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UUT-UC) is unclear. The objectives of this study were to determine the significance of PSM on cancer-specific survival (CSS), recurrence-free survival (RFS), and metastasis-free survival (MFS) post RNU. METHODS: From a multicenter collaborative database, data on SM status, stage, grade, lymph node status, lymphovascular invasion (LVI), tumor location, follow-up, and survival was retrieved for 472 patients. Patients underwent open RNU with bladder cuff excision. Clinicopathological features were compared using chi(2) or Fisher exact test and unpaired t test for categorical and continuous variables, respectively. Survival was estimated using the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regression models were calculated. RESULTS: Median follow-up was 27.5 months (12.1-49.3 months). PSM was identified in 44 patients (9.3%) and correlated with pT stage (p = 0.002), grade (p < 0.001), LVI (p < 0.001), and location (p < 0.001). Univariate analyses revealed that PSM was a poor prognostic factor for CSS, RFS, and MFS (p = 0.003, 0.04, and <0.001, respectively). The 5-yr CSS and MFS for PSM was 59.1 and 51.6%, respectively, compared with 83.3 and 79.3% for patients with negative SM. Multivariate analyses revealed that SM status was an independent predictor of MFS [hazard ratio 2.7; p = 0.001). CONCLUSIONS: PSM after RNU is an important prognostic factor for developing UUT-UC metastases. The status of the surgical margin should be systematically reported on the pathological report and may be a useful variable to include in nomogram risk prediction tools. PMID- 22843188 TI - Clinical, pathological and surgical characteristics of duodenal gastrointestinal stromal tumor and their influence on survival: a multi-center study. AB - BACKGROUND: The duodenum is a rare site of primary gastrointestinal stromal tumor (GIST). Overall (OS) and disease-free survival (DFS) after limited resection (LR) versus pancreaticoduodenectomy (PD) were studied. METHODS: All patients who underwent surgery for primary, localized duodenal GIST between 2000 and 2011 were identified from four prospective institutional databases. OS and DFS were calculated by Kaplan-Meier method. Univariate analysis was performed. RESULTS: Eighty-four patients (median follow-up 42 months) underwent LR (n = 56, 67%) or PD (n = 28, 33%). Patients in the PD group had a larger median tumor size (7 cm vs. 5 cm, p = 0.024) and higher mitotic count (39% vs. 19% >5/50 high-power fields, p = 0.05). Complications were observed in five patients (9%) in the LR group and ten patients (36%) in the PD group. OS and DFS for the entire cohort were 89% and 64% at 5 years, respectively. No difference in outcome between LR and PD were observed. Eleven patients were treated with preoperative IM. A major RECIST response was obtained in nine (80%), whereas two had stable disease. Twenty-three patients received postoperative Imatinib (IM). A trend toward a better OS in IM-treated patients could be detected only in the high-risk group. CONCLUSIONS: Type of duodenal resection does not impact outcome. The choice should be determined by duodenal site of origin and tumor size. IM may be considered in cases at high risk of recurrence; in neoadjuvant setting, IM might facilitate resection and possibly increase the chance of preserving normal biliary and pancreatic anatomy. PMID- 22843189 TI - Knotted ureteral stent: a rare complication of ureteral stent usage. AB - The use of ureteral stents has become a routine urological practice. There are many different complications with ureteral stent use. One rare complication is knotting, which can be a very difficult condition to treat. We report a case in which a complete knot was found in the proximal part of an indwelling ureteral stent with a proximal ureteral stone. PMID- 22843190 TI - The effect of transfer and hospital volume in subarachnoid hemorrhage patients. AB - INTRODUCTION: Prompt management of aneurysmal subarachnoid hemorrhage (SAH) is critical. Literature is inconclusive regarding outcomes for patients directly admitted to specialized centers versus transferred from lower-volume hospitals. Providers are often unclear about the safety of transferring critical patients. This study evaluated the "transfer effect" in a large sample of aneurysmal SAH patients undergoing treatment. METHODS: Using Nationwide Inpatient Sample 2002 2007 data, we analyzed outcomes of SAH patients treated with coil or clip procedures. Analyses studied the effect of direct-admit versus transfer admission on mortality, discharge disposition, complications, length of stay (LOS), and total charges. RESULTS: Of 47,114 patients, 31,711 (67.3 %) were direct-admits and 15,403 (32.7 %) were transfers. More transfer patients were coiled than direct-admits (45.3 vs. 33.7 %, p < 0.0001) and fewer underwent ventriculostomy (26.6 vs. 31.5 %, p = 0.003). Older age (OR 1.2, p < 0.0001), higher disease severity (OR 1.4, p < 0.0001), lower volume (OR 1.5, p < 0.0001), and ventriculostomy (OR 2.1, p < 0.0001) increased mortality and predicted non routine discharge, complications, LOS, and charges. Transfer patients had similar mortality (OR 0.9, p = 0.13) and complications (OR 0.9, p = 0.22) as direct admits, but incurred higher non-routine discharge (OR 1.3, p = 0.002). Analysis of grade V patients demonstrated similar outcomes between direct-admits and transfers; however, charges for treating transfer patients were notably higher ($401,386 vs. $242,774, p = 0.03). CONCLUSION: Patients treated in the lowest volume hospitals were 1.6 times more likely to die than those treated at the highest quintile hospitals. Among the critically ill grade V patients, transfer to higher-volume specialized centers did not increase the likelihood of a poor prognosis. PMID- 22843191 TI - Emergency Neurological Life Support (ENLS): what to do in the first hour of a neurological emergency. AB - Emergency Neurological Life Support (ENLS) is a series of protocols, generated by experienced neurocritical care and emergency physicians that describe key steps when managing a patient within the first hours of a neurological emergency. The protocols are designed to help standardize these important early steps for several reasons: (1) patients will likely experience better outcomes, (2) they provide the essential elements to communicate to receiving physicians a patient's diagnosis and emergency treatment, (3) this approach forms the foundation for eventual consensus on neurological emergency decisions, and (4) this consensus can inform researchers about the important clinical questions that need resolution to enhance patient care. ENLS is online and free to use. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS, reviews the history of its creation, and enumerates future goals as ENLS becomes adopted more widely. PMID- 22843192 TI - A family with spinocerebellar ataxia type 5 found to have a novel missense mutation within a SPTBN2 spectrin repeat. AB - A family with late-onset autosomal dominant pure cerebellar ataxia, consistent with spinocerebellar ataxia type 5 (SCA5) but lacking previously reported SPTBN2 mutations, was identified. DNA was collected from seven individuals across two generations and the SPTBN2 gene on chromosome 11 was sequenced. A nonsynonymous heterozygous substitution in exon 12 was detected in individuals diagnosed with SCA5 while unaffected family members did not possess this variant. The identified c.1415C>T variant results in a p.T472M substitution in the second SPEC domain of the beta-III spectrin protein. The threonine at position 472 is not in close proximity to the characteristic residues that define the SPEC domain and is variable across diverse SPEC domains, yet is highly conserved in SPTBN2. Consistent with these observations, bioinformatic analysis of the p.T472M variant suggests it to be pathological. Two deletions within the SPTBN2 SPEC domains (E532_M544del and L629_R634delinsW) have been previously reported to cause SCA5, but this is the first missense mutation in this region of the protein shown to likely be pathogenic. PMID- 22843193 TI - Biomedical signal acquisition with streaming wireless communication for recording evoked potentials. AB - BACKGROUND: Commercial electrophysiology systems for recording evoked potentials always connect patients to the acquisition unit via long wires. Wires guarantee timely transfer of signals for synchronization with the stimuli, but they are susceptible to electromagnetic and electrostatic interferences. Though wireless solutions are readily available (e.g. Bluetooth), they introduce high delay variability that will distort the evoked potential traces. We developed a complete wireless acquisition system with a fixed delay. METHODS: The system supports up to 4 bipolar channels; each is amplified by 20,000* and digitized to 24 bits. The system incorporates the "driven-right-leg" circuit to lower the common noise. Data are continuously streamed using radio-frequency transmission operating at 915 MHz and then tagged with the stimulus SYNC signal at the receiver. The delay, noise level and transmission error rate were measured. Flash visual evoked potentials were recorded monocularly from both eyes of six adults with normal vision. The signals were acquired via wireless and wired transmissions simultaneously. The recording was repeated on some participants within 2 weeks. RESULTS: The delay was constant at 20 ms. The system noise was white and Gaussian (2 microvolts RMS). The transmission error rate was about one per million packets. The VEPs recorded with wireless transmission were consistent with those with wired transmission. The VEP amplitudes and shapes showed good intra-session and inter-session reproducibility and were consistent across eyes. CONCLUSIONS: The wireless acquisition system can reliably record visual evoked potentials. It has a constant delay of 20 ms and very low error rate. PMID- 22843194 TI - An unknown cause of aortic valve stenosis: polycythemia vera. AB - Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an abnormal increase in red blood cells. The involvement of the heart during the course of the illness represents a common cause of morbidity and it is linked to an increased thrombogenic risk subsequent to higher blood viscosity. In our study we evaluated by echocardiography a PV patient population. Our study enrolled 44 patients affected by PV. 17 of them were women and 27 were men. Mean patient age was 66.7. The average follow-up period was 5 years and the average duration of the illness was 5.7 years, since the time of diagnosis. All patients were evaluated quarterly by a cardiovascular objective examination and an ultrasound of the heart, with regard to platelet count and hematocrit (Ht) variations during the follow-up period, according to the therapy administered. Patients were treated with hydrossiurea and pipobroman and they underwent an eritrocitoapheresis in emergency conditions in which Ht levels rose too much, in spite of the myelosuppressive therapy. The echocardiographic assessment of the heart structure and function by the B mode technique revealed the presence of a sclerocalcific degeneration of the aortic valve in 58% of patients, involving the aortic root more then the valve. An average trans-aortic flow velocity of 1.92 m/s was detected by Doppler technique; a stenosis was demonstrated in 11 patients (25.5% of the entire population). After diagnosing the presence of a stenosis, we researched a possible cause of it. PV is a systemic disease well-known causing coronary thrombosis in a more or less high percentage of patients according to the record of cases taken into account. In our experience, more then thrombotic disease, found only in 13.4% of patients, we detected a high prevalence and incidence of mild to severe aortic stenosis, found in 25.5% of the sample studied. About all possible causes of stenosis, nowadays this results dependent of Ht values at moment of diagnosis, in the light of these results, it is reasonable to infer that aortic valve stenosis could depend by high haemodynamic stress on valve that is characteristic of polycythemic patients without chemotherapy. PMID- 22843195 TI - Three-month cumulative incidence of thromboembolism and bleeding after periprocedural anticoagulation management of arterial vascular bypass patients. AB - The objective of this study was to determine 3-month cumulative incidence of peri procedural thromboembolism (TE) including graft occlusion, and peri-procedural bleeding for chronically anticoagulated vascular bypass graft (BG) patients requiring temporary warfarin interruption for an invasive procedure. Appropriate peri-procedural management of patients receiving chronic warfarin therapy to preserve lower extremity arterial BG patency is unknown. In a protocol driven, cohort study design, all BG patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation (1997-2007) were followed forward in time to estimate the 3-month cumulative incidence of TE and bleeding. Decisions to provide "bridging" low molecular weight heparin (LMWH) were individualized based on estimated risk of TE and bleeding. There were 78 BG patients (69 +/- 10 years; 38% women), of whom 73% had a distal autogenous and 53% had prosthetic BG; 45% received antiplatelet therapy. Peri-procedural LMWH was prescribed for 77% of patients and did not vary by BG distal anastomosis location or type. The 3-month cumulative incidence of TE was 5.1% (95% CI 1.4-12.6), including two BG occlusions, one DVT, and one myocardial infarction. Major bleeding occurred in 1 patient (1.28%, 95% CI 0.0-6.94). One patient died due to heart failure. TE and bleeding did not differ by bridging status. The 3-month cumulative incidence of TE among BG patients in whom warfarin is temporarily interrupted for an invasive procedure may be higher than in other "bridging" populations (atrial fibrillation, prosthetic heart valve, venous thromboembolism). This finding underscores the often tenuous nature of distal bypass grafts necessitating an aggressive approach to peri-procedural anticoagulation management. PMID- 22843196 TI - In vitro studies using a global hemostasis assay to examine the anticoagulation effects in plasma by the direct thrombin inhibitors: dabigatran and argatroban. AB - This study aimed to assess whether a global hemostatic assay we developed can measure the anticoagulant effects of the direct thrombin inhibitors (DTIs)- dabigatran and argatroban. A normal plasma pool (NPP) spiked with one of the DTIs and five plasma samples from patients with coronary heart disease spiked with dabigatran were examined. Fibrin formation and fibrin degradation were initiated by adding recombinant tissue factor (together with washed-frozen-thawed platelets and CaCl(2)) and recombinant tissue plasminogen activator. Fibrin optical density (OD) was recorded, based on which coagulation activation profile (Cp) and fibrinolysis activation profile (Fp) were determined. Moreover, the sum of OD values registered over time (fibrin OD-sum) was calculated to reflect the capacity of fibrin formation under the general effect by Cp and Fp. The endogenous thrombin potential (ETP) and the standard clotting markers i.e., activated partial thromboplastin time (APTT) and prothrombin time expressed as International Normalized Ratio (INR) were also analyzed. Results demonstrated that APTT, INR and ETP could detect the effects of the DTIs except for INR in NPP containing dabigatran. In our global assay, the DTIs depressed the fibrin formation (shown as decreased fibrin OD-sum value) by leading to decrease of Cp and increase of Fp. Thus, our global assay which examines both fibrin formation and degradation seems more advantageous than the other methods mentioned above, as regards the possibility of being a laboratory tool to monitor the antithrombotic therapy with DTIs. PMID- 22843198 TI - Time preferences in long-tailed macaques (Macaca fascicularis) and humans (Homo sapiens). AB - Rosati et al. (Curr Biol 17(19):1663-1668, 2007) found in a self-control test in which choice was between a smaller, immediately delivered food and a larger, delayed food, that chimpanzees preferred the larger reward (self-control); humans, however, preferred the smaller reward (impulsivity). They attributed their results to a species difference in self-control. In Experiment 1, monkeys (long-tailed macaques) were exposed to a self-control task in two conditions: where the food was hidden under differently colored bowls and where it was visible. When these two conditions were compared, choice shifted from greater preference for the impulsive alternative in the hidden condition to greater preference for the self-control alternative in the visible condition. Additionally, in both conditions, preference shifted from self-control to impulsivity over sessions. These results were explained in terms of the reversed contingency effect (a propensity to reach for more over less when rewards are visible) and not to a capacity for self-control. In Experiment 2, humans that demonstrated preference for more over less in choice preferred the impulsive alternative when choice to either alternative was followed by the same intertrial interval-a preference that accelerates trial rates relative to preference of the self-control alternative. When trial rates were equated so that neither choice accelerated session's end, humans demonstrated self-control. These results suggest that Rosati et al.'s demonstration of impulsivity in humans was due to participants' desire to minimize session time. PMID- 22843197 TI - Cataract-associated D3Y mutation of human connexin46 (hCx46) increases the dye coupling of gap junction channels and suppresses the voltage sensitivity of hemichannels. AB - Connexin46 (Cx46), together with Cx50, forms gap junction channels between lens fibers and participates in the lens pump-leak system, which is essential for the homeostasis of this avascular organ. Mutations in Cx50 and Cx46 correlate with cataracts, but the functional relationship between the mutations and cataract formation is not always clear. Recently, it was found that a mutation at the third position of hCx46 that substituted an aspartic acid residue with a tyrosine residue (hCx46D3Y) caused an autosomal dominant zonular pulverulent cataract. We expressed EGFP-labeled hCx46wt and hCx46D3Y in HeLa cells and found that the mutation did not affect the formation of gap junction plaques. Dye transfer experiments using Lucifer Yellow (LY) and ethidium bromide (EthBr) showed an increased degree of dye coupling between the cell pairs expressing hCx46D3Y in comparison to the cell pairs expressing hCx46wt. In Xenopus oocytes, two electrode voltage-clamp experiments revealed that hCx46wt formed voltage sensitive hemichannels. This was not observed in the oocytes expressing hCx46D3Y. The replacement of the aspartic acid residue at the third position by another negatively charged residue, glutamic acid, to generate the mutant hCx46D3E, restored the voltage sensitivity of the resultant hemichannels. Moreover, HeLa cell pairs expressing hCx46D3E and hCx46wt showed a similar degree of dye coupling. These results indicate that the negatively charged aspartic acid residue at the third position of the N-terminus of hCx46 could be involved in the determination of the degree of metabolite cell-to-cell coupling and is essential for the voltage sensitivity of the hCx46 hemichannels. PMID- 22843199 TI - Primary dediffentiated liposarcoma of the dura mater: case report. PMID- 22843201 TI - Regression of pulmonary vascular disease after therapy of Abernethy malformation in visceral heterotaxy. AB - A 1-year-old boy who had left isomerism and corrected transposition of the great arteries (c-TGA) with moderate-sized ventricular septal defect, severe pulmonary artery hypertension (PAH), and pulmonary vascular disease with significant right to-left shunting received a diagnosis of type 2 Abernethy malformation, which was partly responsible for disproportionate PAH in the child. The malformation was treated by plugging of the portosystemic shunt. Follow-up cardiac catheterization on sildenafil demonstrated significant left-to-right shunting (2.16:1) and a fall in pulmonary vascular resistance, making surgical correction possible. This case highlights the importance of searching for additional rare causes of PAH in patients with congenital heart diseases when the degree of pulmonary hypertension is disproportional to the defect size. PMID- 22843200 TI - Contrasting effects of sunitinib within in vivo models of metastasis. AB - Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients. PMID- 22843203 TI - Medium and long-term outcomes after bilateral pulmonary artery stenting in children and adults with congenital heart disease. AB - Percutaneous stenting of branch pulmonary arteries (PAs) has become an important interventional therapy in the complete management of congenital heart disease. Few data exist on long-term outcomes for patients requiring placement of bilateral stents. This study aimed to determine the medium- to long-term outcomes after bilateral stenting of branch PAs in patients with congenital heart disease. A retrospective study analyzed all procedural and follow-up data on patients undergoing bilateral PA stenting during a single procedure. From October 2001 to May 2012, 26 patients underwent bilateral PA stenting (total of 62 stents). The mean age of these patients was 9.5 +/- 12 years, and their mean weight was 27 +/- 19 kg. The mean procedural time was 191 +/- 67 min, and the mean fluoroscopy time was 50 +/- 29 min. The mean gradient across the right pulmonary artery decreased from 35 +/- 22 to 11 +/- 12 mmHg (p < 0.001). The left pulmonary artery gradient decreased from 32 +/- 17 to 10 +/- 12 mmHg (p < 0.001), and the right ventricle to descending aorta pressure ratio decreased from 71 +/- 18 % to 46 +/- 13 % (p < 0.001). Intraprocedural adverse events were encountered in four patients (1 small PA dissection, 2 intraprocedural arrhythmias, and 1 first-degree burn on the thigh). The mean follow-up period was 41 +/- 23 months. Two deaths occurred. Further interventions were required for 12 patients. Bilateral PA stenting is effective and safe, with an instantaneous significant decrease in pressure gradients. The need for reintervention is common, so continued follow-up assessment is warranted. PMID- 22843202 TI - Thromboembolic complications in Fontan patients: population-based prevalence and exploration of the etiology. AB - After the Fontan procedure, patients face an increased risk for thromboembolic events (TE). The etiology for this increased thrombogenecity is incompletely understood. This study aimed to determine the prevalence of TE in Danish Fontan patients and to bring new insights into the etiology of TE. Using a population based design, we retrospectively identified all TEs in 210 Fontan patients. Whole blood assays (thromboelastography, thromboelastography functional fibrinogen and Multiplate) reflecting global hemostasis, clot strength and platelet aggregation were analyzed prospectively in 112 patients and plasma was analyzed in 76 patients for biomarkers reflecting endothelial-, glycocalyx-, platelet-, and fibrinolysis function (histone-complexed DNA fragments, Protein C, soluble CD40 ligand, soluble thrombomodulin, syndecan-1, tissue-type plasminogen activator). The results were compared in groups stratified according to age, antithrombotic therapy, TE, and glycocalyx degradation (syndecan-1 < or >= median). Correlation between biomarkers and demographic-, anatomical-, clinical- and biochemical parameters was investigated. The prevalence of TE was 8.1 % after a mean follow up of 8.4 years. None of the stratified groups demonstrated evidence of hypercoagulability in the whole blood assays and no unexpected significant differences were found between the groups. All biomarkers, except protein C, correlated with one another and after stratification of glycocalyx degradation only syndecan-1 levels >= median correlated with other biomarkers. The prevalence of TEs was 8.1 % after mean follow-up of 8.4 years. Overall, the hemostatic profile appeared normal, however, in a subset of patients, evidence of some endothelial activation/damage including glycocalyx degradation and fibrinolysis was found, identifying a potentially more thrombogenic group. PMID- 22843204 TI - Aortic aneurysms remain a significant source of morbidity and mortality after use of Dacron((r)) patch aortoplasty to repair coarctation of the aorta: results from a single center. AB - Aortic aneurysm formation after coarctation repair is a serious and life threatening complication. Repairs using synthetic materials such as Dacron((r)) may carry the highest risk of aneurysm formation and rupture. The authors sought to determine the prevalence of aneurysm formation in patients who previously underwent coarctation repair using Dacron((r)) patch aortoplasty at their institution. Between 1977 and 1994, 63 patients underwent isolated coarctation repair using Dacron((r)) patch aortoplasty. Aneurysms were defined as an aortic dimension 1.5 times that of the aorta at the level of the diaphragm as shown by angiography, computed tomography (CT) scan, or magnetic resonance imaging (MRI). Of 61 early survivors, 29 (47 %) experienced an aneurysm in the area of previous repair. Nine patients (31 %) had spontaneous rupture of the aneurysm, which caused death in seven cases. Elective or emergent aneurysm repair was performed for 20 patients without complication, and 2 patients are being monitored at this writing. The mean interval from patch placement to aneurysm repair was 15 years (range, 4-27 years). Overall freedom from the development of an aortic aneurysm was 97 % at 5 years, 90 % at 10 years, 69 % at 20 years, and 42 % at 25 years. After repair of coarctation using Dacron((r)) patch aortoplasty, the risk for aneurysm formation in the area of repair and death from rupture is extremely high. Therefore, in accordance with the 2008 American Heart Association/American College of Cardiology (AHA/ACC) guidelines, all patients with repaired aortic coarctation should undergo either CT or MRI imaging at least every 5 years to assess for aortic aneurysm formation. More frequent imaging should be obtained for patients previously repaired with Dacron((r)) patch aortoplasty. PMID- 22843205 TI - Evaluating treatment effect within a multivariate stochastic ordering framework: Nonparametric combination methodology applied to a study on multiple sclerosis. AB - Multiple sclerosis is an autoimmune complex disease that affects the central nervous system. It has a multitude of symptoms that are observed in different people in many different ways. At this time, there is no definite cure for multiple sclerosis. However, therapies that slow the progression of disability, controlling symptoms and helping patients to maintain a normal quality of life, are available. We will focus on relapsing-remitting multiple sclerosis patients treated with interferons or glatiramer acetate. These treatments have been shown to be effective, but their relative effectiveness has not been well established yet. To assess the superiority of a treatment, instead of classical parametric methods, we propose a statistical approach within the permutation setting and the nonparametric combination of dependent permutation tests. In this framework, we may easily handle with hypothesis testing problems for multivariate monotonic stochastic ordering. This approach has been motivated by the analysis of a large observational Italian multicentre study on multiple sclerosis, with several continuous and categorical outcomes measured at multiple time points. PMID- 22843206 TI - Diquafosol ophthalmic solution for dry eye treatment. AB - INTRODUCTION: There has been rapid progress in our understanding of dry eye pathogenesis, as well as the development of improved diagnostic clinical tests. Various types of dry eye treatment drugs have been developed. This review summarizes the basic and clinical research carried out in the development of diquafosol for ophthalmic use. RESULTS: Diquafosol is a dinucleotide, purinoreceptor P2Y(2) receptor agonist. Basic pharmacological studies have shown that it acts on P2Y(2) receptors at the ocular surface, to promote tear and mucin secretion via elevated intracellular Ca(2+) concentrations. Diquafosol also improves tear and mucin secretion in experimental dry eye models. Based on the results of laboratory experiments, the authors conducted a series of clinical studies in patients with dry eye disease. Diquafosol was effective in the treatment of dry eye disease at an optimal dose of 3% six times a day. In comparison to commercially available 0.1% sodium hyaluronate ophthalmic solution, 3% diquafosol ophthalmic solution showed non-inferiority in improving corneal fluorescein staining scores and superiority in improving keratoconjunctival Rose Bengal staining scores. CONCLUSIONS: Diquafosol ophthalmic solution has a novel mechanism of action that is characterized by its stimulatory effects on tear and mucin secretion. This drug has the potential to be effective in patients with tear film instability and short break-up time type of dry eye, which are essential factors in dry eye pathogenesis. PMID- 22843207 TI - Evolution of insulin development: focus on key parameters. AB - INTRODUCTION: Although insulin products and treatment strategies have improved significantly, clinical challenges still exist. Meeting glycemic goals while minimizing glucose variability and hypoglycemia is of utmost importance when considering existing insulin therapies and designing investigational insulin treatments. METHODS: A PubMed search identified relevant, peer-reviewed articles related to the evolution of insulin development for this nonsystematic review. Search terms included "animal insulin," "synthetic insulin," "regular human insulin," "insulin lispro," "insulin aspart," "insulin glulisine," "insulin glargine," "insulin detemir," "insulin degludec," "biphasic human insulin," "insulin premixes," "ultra-long acting," "oral insulin," and "inhaled insulin." RESULTS: While the discovery of animal insulin significantly decreased mortality rates from diabetes, issues with availability and large variability between batches led to difficulty in determining proper doses and, subsequently, challenges in achieving glycemic control and avoiding hypoglycemia. The development of synthetic insulin created a more readily available supply, but hypoglycemia still persisted. Recombinant DNA technology solved insulin production problems and allowed for the development of better retarding agents, but pharmacokinetic/pharmacodynamic profiles still did not mimic natural insulin. Insulin premixes offered improved glycemic control, decreased intrapatient variability versus self-mixing, and required fewer injections per day; however, patient adherence remained a problem due to the need to inject 30-60 minutes before a meal for optimal control. This prompted the development of rapid-acting insulin analogs that could be injected right before a meal and long-acting insulin analogs with flatter time-action profiles. CONCLUSION: Despite advances in insulin development, a need to provide more physiologic basal insulin coverage and reduce hypoglycemic risk in patients with diabetes remains. Newer insulin analogs and more convenient routes of insulin delivery have shown promising safety and efficacy results. Many patients with diabetes have not reached glycemic goals on currently available insulins. Additional studies are necessary to tailor optimal insulin delivery strategies to specific subsets of diabetes patients. PMID- 22843208 TI - Cost per responder associated with biologic therapies for Crohn's disease, psoriasis, and rheumatoid arthritis. AB - INTRODUCTION: Biologic therapies have demonstrated efficacy and safety in several chronic systemic disorders. The authors indirectly compared response rates and costs per responder associated with biologic treatments for moderate-to-severe Crohn's disease (CD), psoriasis (Ps), and/or rheumatoid arthritis (RA). METHODS: A systematic literature search was performed to identify phase 3 randomized controlled trials of biologics for CD (adalimumab, infliximab), Ps (adalimumab, etanercept, infliximab, ustekinumab 45 mg, ustekinumab 90 mg), or methotrexate refractory RA (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab). Food and Drug Administration-approved dosing schedules were evaluated. Published response rates were extracted, with response defined in CD, Ps, and RA as: >=70-point reduction in CD Activity Index at 12 months; >=75% improvement in Psoriasis Area and Severity Index at 3 months; and >=50% improvement in American College of Rheumatology component scores at 6 months. Within each indication, mixed-treatment comparison meta-analyses were conducted to derive pooled estimates and 95% CIs of response rate difference versus placebo for each biologic, adjusting for cross-trial variation in control arm response rates. Cost per responder was estimated for each biologic as projected per patient drug costs (2011 US$) divided by response rate difference. RESULTS: Altogether, 23 publications were selected. In CD, 12-month cost per responder was estimated at $116,291 (95% CI $71,637-208,348) for adalimumab and $125,169 (95% CI $60,532-267,101) for infliximab. Among biologics approved in Ps, 3-month cost per responder was lowest for adalimumab ($9,756; 95% CI $8,668 11,131), infliximab ($12,828; 95% CI $11,772-13,922), and ustekinumab 45 mg ($13,821; 95% CI $12,599-15,167). In RA, biologics with the lowest 6-month cost per responder were adalimumab ($27,853; 95% CI $19,284-40,270), etanercept ($29,140; 95% CI $14,170-61,030), and tocilizumab ($31,363; 95% CI $14,713 64,232). CONCLUSION: Meta-analyses of clinical trials found considerable variation in cost-effectiveness of biologic therapies for CD, Ps, and RA. These results may help determine biologic utilization in these chronic diseases. PMID- 22843209 TI - Postoperative radiotherapy in periampullary cancers: a brief review. AB - BACKGROUND: The treatment of periampullary cancers is complex and challenging. Adjuvant therapy for resected periampullary and pancreatic cancers has been the subject of intense clinical investigations for several decades. Periampullary cancer management has often been clubbed with pancreatic cancers. DISCUSSION: Following surgery, adjuvant chemoradiotherapy has been widely accepted as standard of care in the USA, although different prospective and retrospective studies have shown conflicting results. Controversy regarding the effectiveness of chemoradiotherapy exists in the literature, both in terms of survival as well as toxicity. However, conventional postoperative radiotherapy practice needs to be reviewed in view of changes and developments in radiation techniques in the last decade. In this article, we review the management of periampullary cancers with special emphasis on the adjuvant postoperative radiotherapy. PMID- 22843210 TI - Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel. AB - PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib. PMID- 22843211 TI - Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study. AB - BACKGROUND: This is the first phase I, dose-finding study of AZD8055, a first-in class dual mTORC1/2 inhibitor, in Japanese patients with advanced solid tumors. PATIENTS AND METHODS: Patients received a single oral dose of AZD8055, followed by twice-daily (BID) dosing. The starting dose was 10 mg with dose escalations in subsequent cohorts to a maximum of 90 mg BID or a non-tolerated dose. RESULTS: Seventeen patients were dosed: 10 mg (n=3), 40 mg (n=4), 60 mg (n=3), 90 mg (n=7). In the 90 mg cohort, one dose limiting toxicity (n=1) of increased aspartate aminotransferase and increased alanine aminotransferase was observed in the 90 mg BID cohort (n=1). Four patients, all in the 90 mg BID cohort, experienced a serious adverse event considered to be related to AZD8055: increased alanine aminotransferase (n=3), increased aspartate aminotransferase (n=3), increased gamma-glutamyltransferase (n=2). The 90 mg BID dose was considered as tolerated in Japanese patients but higher doses were not investigated as this dose was also the maximum tolerated dose in Western patients. AZD8055 was rapidly absorbed with greater-than-proportional increases in exposure with increasing dose. No responses were reported, but two patients had stable disease. Mean pAKT and p4EBP1 levels decreased in most cohorts. Conclusion The tolerability and pharmacokinetic profiles of AZD8055 in Japanese patients were similar to those reported in Western patients. PMID- 22843212 TI - Productive and reproductive performance and egg quality of laying hens fed diets containing different levels of date pits with enzyme supplementations. AB - Two experiments were conducted to investigate the effect of phytase and/or multienzymes (protease, amyloglucoidase, xylanase, B-glucanase, cellulose, and hemicellulase) on improving the utilization of date pit (DP) in laying hens. In the first one, DP completely replaced corn in four isocaloric and isonitrogenous diets: (1) DP50 without additives, (2) DP50 + 500 FTU phytase/kg, (3) DP50 + 0.1 % multienzymes, and (4) DP50 + 500 FTU phytase/kg + 0.1 % multienzymes, in addition to the diet without DP. In the second experiment, DP was included at 0 %, 15 %, and 30 % in isocaloric and isonitrogenous diets. Meanwhile, diets containing 15 % and 30 % DP (DP15 and DP30) were fed without or with 500 FTU phytase/kg diet and/or 0.1 % multienzymes. In both experiments, each diet was fed to six groups of five hens housed individually (520 cm(2) per hen) during 30-42 and 28-42 weeks in the first and second experiment, respectively. In the first experiment, productive performance and shell quality of laying hens significantly decreased due to complete substitution of corn, but fertility and hatchability were not affected. Phytase, multienzymes supplementation did not restore laying performance to the control level. The results of experiment 2 indicated that DP could be included in laying hens diets up to 30 % when supplemented with multienzymes. PMID- 22843213 TI - Challenges of controlling contagious bovine pleuropneumonia in sub-Saharan Africa: a Zambian perspective. AB - Contagious bovine pleuropneumonia (CBPP) is a disease of economic importance that is widely distributed in sub-Saharan African and contributes significantly to cattle morbidity and mortality. Control of CBPP offers a number of challenges as a result many developing countries in Africa are still struggling with this disease. In this study, we look at the challenges encountered in CBPP control in sub-Saharan Africa from the Zambian perspective. In conducting this study, we reviewed scientific literature and reports from the Ministry of Agriculture and Livestock and related animal institutions, and also made interviews with experts and key government officials involved in CBPP control in Zambia. Among the challenges identified for the successful control of CBPP were as follows: failure in the delivery of veterinary services, lack of a cattle identification system, natural phenomenon, livestock husbandry systems in the traditional sector, human movements, traditional practices among cattle farmers and cattle marketing systems. It was seen that the epidemiology of CBPP in Zambia is influenced by both ecological and anthological factors. Therefore, design and implementation of any control or eradication programme should be area/regional-dependent taking into account the different factors influencing disease transmission and maintenance. PMID- 22843214 TI - Effect of carbohydrate source and cottonseed meal level in the concentrate: IV. Feed intake, rumen fermentation and milk production in milking cows. AB - Four early-lactation crossbred cows (82.5 % Holstein) were selected to investigate the effect of carbohydrate source and cottonseed meal level in the concentrate on rumen fermentation and milk production. Cows were randomly assigned to receive four dietary treatments according to a 2 * 2 factorial arrangement in a 4 * 4 Latin Square design. Factor A was carbohydrate source: cassava chip (CC) and CC + rice bran at a ratio 3:1 (CR3:1), and factor B was variation in the level of cottonseed meal (CM): low (LCM) and high (HCM) in isonitrogenous diets (180 g CP/kg DM). It was found that carbohydrate source did not affect feed intake, dry matter digestibility, rumen fermentation, microbial population, milk yield and composition, or economic return (P > 0.05). However, cows fed with CC had a higher population of amylolytic bacteria than cows fed with CR3:1 (P < 0.05). Cows fed with HCM had a higher total feed intake, milk yield and composition, and milk income when compared with cows fed on LCM although the concentrate and roughage intakes, dry matter digestibility, rumen fermentation, and microbial populations were similar between treatments (P > 0.05). In addition, the carbohydrate source and cottonseed meal level interactions were not significant for any parameter. It could be concluded that cassava chip and high level of cottonseed meal could usefully be incorporated into concentrates for dairy cows without impacting on rumen fermentation or milk production. PMID- 22843215 TI - Willingness to pay for cattle and buffalo insurance: an analysis of dairy farmers in central India. AB - In India, insurance market especially in agricultural sector is usually underdeveloped. The idea of livestock insurance emerged in India before three decades, yet, it has not operated in a significant way till date. It is well noted that livestock insurance scheme is the relevant strategy in managing different risks related to livestock farming but very little attention has been paid to address the livestock insurance needs of the dairy farmers. This study, therefore, addresses the basic question that how many people and to what extent they are willing to pay for livestock insurance and determine the main factors which influence insurance participation of dairy farmers. The data was collected from Gorakhpur district of Uttar Pradesh in India with a sample survey of 120 cattle and buffalo farmers. For eliciting willingness to pay, a contingent valuation scenario was presented to dairy animal owners in the group of five to six. A logit discrete binary regression model was used to know the factors influencing adoption of livestock insurance. The results suggest that most of the farmers were willing to participate in cattle and buffalo insurance. The amount of premium varies across different breeds of dairy animals. The low level of education of many dairy farmers have negatively influenced the decision to purchase livestock insurance. Farmers having more experience in rearing dairy animals are more likely to be willing to pay for cattle and buffalo insurance. PMID- 22843216 TI - Bovine tuberculosis in South Darfur State, Sudan: an abattoir study based on microscopy and molecular detection methods. AB - Bovine tuberculosis (BTB) is a widespread zoonosis in developing countries but has received little attention in many sub-Saharan African countries including Sudan and particularly in some parts such as Darfur states. This study aimed to detect bovine tuberculosis among caseous materials of cattle slaughtered in abattoirs in South Darfur State, Sudan by using microscopic and PCR-based methods. The study was a cross-sectional abattoir-based study which examined a total of 6,680 bovine carcasses for caseous lesions in South Darfur State between 2007 and 2009. Collected specimens were examined for the presence of acid-fast bacilli (AFB) by using microscopic and culture techniques. Isolated mycobacteria were identified by selected conventional cultural and biochemical tests in comparison to a single tube multiplex PCR (m-PCR) assay which detect Mycobacterium bovis-specific 168-bp amplicons. Of the total 6,680 slaughtered cattle examined in South Darfur, 400 (6 %) showed caseations restricted to lymph nodes (86.8 %) or generalized (13.2 %). Bovine tuberculosis was diagnosed in 12 (0.18 %), bovine farcy in 59 (0.88 %), unidentified mycobacteria in 6 (0.09 %), and missed or contaminated cultures in 7 (0.1 %). Out of 18 cultures with nonbranching acid-fast rods, 12 amplified unique 168-bp sequence specific for M. bovis and subsequently confirmed as M. bovis. With the exception of the reference M. tuberculosis strains, none of the remaining AFB amplified the 337-bp amplicon specific for M. tuberculosis. It could be concluded that bovine tuberculosis is prevalent among cattle in South Darfur representing 4.5 % from all slaughtered cattle with caseous lesions. The study sustains microscopy as a useful and accessible technique for detecting AFB. m-PCR assay proved to be valuable for confirmation of BTB and its differentiation from other related mycobacteriosis, notably bovine farcy. PMID- 22843217 TI - Successful approach to treatment of Helicobacter bilis infection in X-linked agammaglobulinemia. AB - Helicobacter bilis, an unusual cause of chronic infections in patients with X linked agammaglobulinemia (XLA), is notoriously difficult to diagnose and eradicate. Based on the limited number of cases reported worldwide, we highlight the typical features of H. bilis infection in XLA and provide a rational and successful approach to diagnosis and treatment of this challenging infection. PMID- 22843219 TI - Hemicrania continua: disease or syndrome? PMID- 22843218 TI - Variability of three-dimensional forces increase during experimental knee pain. AB - Knee pain is a common symptom of different knee pathologies, affecting muscle strength and force generation. Although the control of precise three-dimensional forces is essential for the performance of functional tasks, current evidence of pain effects in force variability is limited to single-directional assessments of contractions at moderate force levels. This study assessed the effects of experimental knee joint pain in the three-dimensional force variability during isometric knee extensions at a wide range of target forces (2.5-80 % of maximal voluntary contraction, MVC). Fifteen healthy subjects performed contractions before, immediately following, and after injections of hypertonic (painful) or isotonic (control) saline into the infrapatellar fat pad. Pain intensity was measured on a 10-cm visual analogue scale. Force magnitude, direction, and variability were assessed using a six-axis force sensor while activity of quadriceps and hamstring muscles was recorded by surface electromyography. Significant correlation was found between tangential force displacements and variability of quadriceps muscle activity. Experimental knee pain increased the variability of the task-related force component at all force levels, while variability of tangential force components increased at low forces (<=5 % of MVC). The mean quadriceps activity decreased during painful contractions only at 80 % of MVC. Pain adaptations underlying increased force variability at low contraction levels probably involve heterogeneous reorganization of muscle activity, which could not be detected by surface electrodes. These findings indicate a less efficient motor strategy during knee joint pain, suggesting that pain relief may enhance training for the control of smooth forces by knee pain patients. PMID- 22843220 TI - Comment on the editorial by Goadsby and Akerman 'The trigeminovascular system does not require a peripheral sensory input to be activated--migraine is a central disorder', in Cephalalgia January 2012. PMID- 22843221 TI - Different trigemino-vascular responsiveness between adolescent and adult rats in a migraine model. AB - BACKGROUND: Pediatric migraine displays different clinical features from adult migraine. Because the trigemino-vascular system (TGVS) plays a pivotal role in migraine pathophysiology, this study compared TGVS responses in a migraine model induced by intracisternal (i.c.) instillation of capsaicin in adolescent and adult rats. METHODS: TGVS responses measured included c-Fos-protein-expressing neurons in the trigeminal cervical complex (TCC), calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglia (TG) and dura mater, and dural protein extravasation. The formulas for estimating total numbers of activated TCC neurons were established based on the c-Fos-positive neuronal numbers in three sample sections, +0.6, -1.2 and -9 mm and +0.6, -0.6 and -6 mm, from the obex in adult and adolescent rats, respectively. RESULTS: After capsaicin instillation, adolescent rats had comparable TCC neurons activated as adult rats, but less TGVS peripheral responsiveness than adults, including CGRP immunoreactivity in the TG, and protein extravasation and CGRP depletion (inversely reflected by CGRP immunoreactivity) in the dura mater. CONCLUSIONS: Age-dependent differences in TGVS responsiveness in the i.c. capsaicin-induced migraine model of rats are reminiscent of less severe migraine in pediatric patients. This finding may provide new insight into the pathophysiology of migraine and guide the development of new anti-migraine drugs for children. PMID- 22843222 TI - Comment on: "Headaches during war: analysis of presentation, treatment, and factors associated with outcome". PMID- 22843223 TI - On the relationship between beta-blockers, migraines and post-traumatic stress disorder: response to Peterlin et al. PMID- 22843224 TI - Bilateral paroxysmal cephalalgia: a novel indomethacin-responsive primary headache syndrome? AB - INTRODUCTION: Paroxysmal hemicrania (PH) is a primary headache disorder characterised by frequent, short-lasting, very severe, strictly unilateral attacks occurring in association with cranial autonomic features. A striking feature of this disorder is its clear response to indomethacin. CASE REPORT: In contrast to this stereotypic presentation, we describe a man with indomethacin responsive headaches that have a temporal profile similar to that of PH but whose attacks have a bilateral distribution without associated cranial autonomic features. DISCUSSION: There have been several case reports of patients presenting with short-lasting, frequent, bilateral headaches responding to indomethacin, without cranial autonomic features. These cases have been described as representing bilateral PH although strict unilaterality of pain and cranial autonomic phenomena are cardinal features of PH. These cases may represent a novel indomethacin-responsive syndrome and therefore, for now, should be studied separately from PH until their pathophysiological basis is better understood. PMID- 22843225 TI - Post-dural (post-lumbar) puncture headache: risk factors and clinical features. AB - OBJECTIVE: This is an analytic, interventional, cross sectional study to evaluate the risk factors of post-dural (post-lumbar) puncture headache (PDPH) and the validity of the diagnostic criteria for PDPH from the ICHD II. METHODS: Six hundred-and-forty patients (332 non-pregnant women and 308 men) aged 8-65 years underwent spinal anesthesia with Quincke 25G or 27G needles in elective surgery. RESULTS: Forty-eight (7.5%) of the patients developed PDPH. The binary logistic regression analysis identified as risk factors: gender [11.1% female vs. 3.6% male, OR 2.25 (1.07-4.73); p = 0.03], age [11.0% 31-50 years of age vs. 4.2% others, OR 2.21 (1.12-4.36); p = 0.02], previous history of PDPH [26.4% positive vs. 6.2% negative, OR 4.30 (1.99-9.31); p < 0.01] and bevel orientation [16.1% perpendicular vs. 5.7% parallel, OR 2.16 (1.07-4.35); p = 0.03]. The period of latency between lumbar puncture and headache onset range from 6 to 72 hours and the duration from 3 to 15 days. In 34/48 (71%) patients with PDPH, at least one of the following was present: neck stiffness, tinnitus, hypoacusia, photophobia, or nausea. CONCLUSION: In conclusion, 14/48 patients (29%) suffered none of the above-mentioned symptoms, indicating that a significant number of patients may suffer from PDPH in the absence of any symptoms apart from the headache itself. This suggests that a further analyses of existing studies should be made to determine if a criteria change may need consideration. PMID- 22843226 TI - How general practitioners treat migraine patients: evaluation of a headache guideline. AB - AIM: The aim of the study was to evaluate the pharmacological treatment of migraine patients by general practitioners before referral to a neurologist. First, was the pharmacological treatment in accordance with the Dutch College of General Practitioners headache guideline? Second, which migraine characteristics were associated with receiving migraine-specific medication? METHODS: Migraine patients (age >= 18 years) who visited the neurology outpatient clinic for the first time were included. Migraine characteristics and pharmacological status were collected retrospectively for each patient from the general practitioner's referral letter, hospital record and a headache characteristics questionnaire. RESULTS: A total of 420 migraine patients were included. Only 18.3% of the patients with two or more migraine attacks per month were using prophylactic medication. Furthermore, only 11.7% of patients with symptoms of nausea and/or vomiting were using anti-emetic medication. More than half of patients (51.7%) were using triptans and were likely to have typical migraine symptoms and a long history of migraine. CONCLUSIONS: Migraine prophylactic medication and anti emetics are underutilized in the primary care setting for migraine patients in the Netherlands, when compared to the general practitioners guideline. It is important to enhance the knowledge of general practitioners regarding the diagnosis of migraine, and to increase awareness of the headache guideline. PMID- 22843227 TI - Comparison study of olfactory function and substantia nigra hyperechogenicity in idiopathic REM sleep behavior disorder, Parkinson's disease and normal control. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is a preclinical feature of synucleinopathies, such as Parkinson's disease (PD).This study aimed to investigate the presence of potential early manifestations of parkinsonism, such as olfactory dysfunction and substantia nigra (SN) hyperechogenicity, in idiopathic RBD (iRBD) patients, PD patients and normal controls. We performed an olfactory function test using the cross-cultural smell identification test (CC SIT) and midbrain transcranial sonography (TCS) in 15 patients with iRBD as confirmed by polysomnography, 30 patients with PD, and 30 normal controls. The CC SIT scores of the iRBD patients and PD patients were significantly lower than those of the normal controls and similar between iRBD and PD (mean +/- SD, 7.1 +/ 2.2 and 7.6 +/- 2.4 vs. 10.4 +/- 1.2, respectively, p < 0.01). The sum of bilateral SN echosignals in the iRBD patients was greater than that of the normal controls but lower than that of the PD patients (0.29 +/- 0.47, 0.11 +/- 0.17 and 0.72 +/- 0.41 cm(2), respectively, p < 0.01). In conclusion, we found that the concomitant abnormality of olfaction and increased SN echogenicity was more frequent in iRBD compared with normal control. Olfactory dysfunction and SN hyperechogenicity could be preclinical manifestations of parkinsonism in iRBD patients. PMID- 22843228 TI - Folic acid inhibits endothelial cell proliferation through activating the cSrc/ERK 2/NF-kappaB/p53 pathway mediated by folic acid receptor. AB - Folate is important for normal cell division. Folate deficiency has been implicated in various diseases, including atherosclerosis, neural tube defects, and cancer. However, the effect of folate on angiogenesis was unclear. The aim of this study was to investigate the anti-angiogenic action of folic acid (FA). FA (0-10 MUmol/L) concentration-dependently decreased DNA synthesis and proliferation in cultured human umbilical venous endothelial cells (HUVEC). Western blot analyses demonstrated that the levels of p21, p27 and p53 protein in HUVEC were increased by FA. The FA-inhibited [3H]thymidine incorporation was completely blocked when the expressions of p21 and p27 were knocked-down together. Knock-down of p53 prevented the FA-induced increases in p21 and p27 protein level. The levels of phosphorylated Src (p-Src) and p-Src-FA receptor (FR) complex in HUVEC were increased by FA. Knock-down of FR reduced the FA induced increases of p-Src and p53. The FA-induced increases of p21, p27 and p53 protein levels were abolished when cSrc was knocked-down. FA also increased NF kappaB nuclear translocation and binding onto the p53 promoter. The FA-induced up regulation of the p53 promoter activity was prevented by knocked-down of ERK. Matrigel angiogenesis assay in mice demonstrate the anti-angiogenic effect of FA in vivo. In conclusion, our data indicate that FA bound to FR in HUVEC, subsequently activated the cSrc/ERK 2/NF-kappaB/p53 signaling pathway, which in turn up-regulated the expression of p21 and p27, and finally resulted in cell cycle arrest at the G0/G1 phase. In the present study, we uncover a completely novel role of FA for anti-angiogenesis. PMID- 22843229 TI - The clinical and genetic distinction between familial supravalvular aortic stenosis (Eisenberg syndrome) and Williams-Beuren syndrome. PMID- 22843230 TI - CYP-nsSNP: a specialized database focused on effect of non-synonymous SNPs on function of CYPs. AB - The cytochrome P450 (CYP) enzymes play the central role in synthesis of endogenous substances and metabolism of xenobiotics. The substitution of single amino acid caused by non-synonymous single nucleotide polymorphism (nsSNP) will lead to the change in enzymatic activity of CYP isozymes, especially the drugmetabolizing ability. CYP-nsSNP is a specialized database focused on the effect of nsSNPs on enzymatic activity of CYPs. Its unique feature lies in providing the qualitative and quantitative description of the CYP variants in terms of enzymatic activity. In addition, the database also offers the general information about nsSNP and compounds that are involved in corresponding enzymatic reaction. The current CYP-nsSNP can be accessible at http://cypdatabase.sjtu.edu.cn/ and includes more than 300 genetic variants of 12 CYP isozymes together with about 100 compounds. In order to keep the accuracy of information within database, all experimental data were collected from the scientific literatures, and the users who conducted research to identify the novel CYP variants are encouraged to contribute their data. Therefore, CYP-nsSNP can be considered as a valuable source for experimental and computational studies of impact of genetic polymorphism on the function of CYPs. PMID- 22843231 TI - A distance-based cluster algorithm for genomic analysis in genetic disease. AB - Both environmental and genetic factors play roles in the development of some diseases. Complex diseases, such as Crohn's disease or Type II diabetes, are caused by a combination of environmental factors and mutations in multiple genes. Patients who have been diagnosed with such diseases cannot easily be treated. However, many diseases can be avoided if people at high risk change their living style, one example being their diet. But how can we tell their susceptibility to diseases before symptoms are found and help them make informed decisions about their health? The susceptibility to complex diseases can be predicted through the analysis of the genetic data. With the development of DNA microarray technique, it is possible to access the human genetic information related to specific diseases. This paper used a combinatorial method to analyze the genetic casecontrol data for Crohn's disease. A distance based cluster method has been applied to publicly available genotype data on Crohn's disease for epidemiological study and achieved a highly accurate result. PMID- 22843232 TI - Electrostatic potential studies as a consequence of cation-pi interaction in cytochrome c fold of alpha proteins. AB - Interactions between cationic and aromatic side chains of amino acid residues, the so-called cation-pi interactions, are thought to contribute to the overall stability of the folded structure of peptides and proteins. We have analyzed the electrostatic behavior of residues involved in cation-pi interactions for understanding the consequences of these non-covalent interactions. The average value of electrostatic potential for Arg and Lys were found to be positive which signifies their donor nature whereas Phe, Tyr and Trp showed negative values as they are acceptors. Similar trends were observed at the alpha carbon atom. We also observed that there is an opposite behavior of Lys as compared to Arg, Phe, Tyr and Trp towards electrostatic potential development on the last heavy atom. Furthermore the structural parameters like hydrophobicity and conservation score of interacting residues show that Lys to be acting totally different as compared to other residues and hence was found to be most influenced. PMID- 22843233 TI - Predicting the impact of deleterious single point mutations in SMAD gene family using structural bioinformatics approach. AB - Functional alteration in SMAD proteins leads to dis-regulation of its mechanism results in possibilities of high risk diseases like fibrosis, cancer, juvenile polyposis etc. Studying single nucleotide polymorphism (SNP) in SMAD genes helps understand the malfunction of these proteins. In this study, we focused on deleterious effects of nsSNPs in both structural and functional level using publically available bioinformatics tools. We have mainly focused on identifying deleterious nsSNPs in both structural and functional level in SMAD genes by using SIFT, PolyPhen, SNPs&GO, I-Mutant 3.0, MUpro and PANTHER. Structure analysis was carried out with the major mutation that occurred in the native protein coded by SMAD genes and its amino acid positions (R358W, K306S, R310G, S433R and R361C). SRide was used to check the stability of the native and mutant modelled proteins. In addition, we used MAPPER to identify SNPs present in transcription factor binding sites. These findings demonstrate that the in silico approaches can be used efficiently to identify potential candidate SNPs in large scale analysis. PMID- 22843234 TI - SAGPAR: structural grammar-based automated pathway reconstruction. AB - In-silico metabolic engineering is a very useful branch of systems biology for modeling, analysis and prediction of various outcomes of metabolic pathways. It can also be used for detecting interactions and dynamics within a network. Various protocols have been proposed for modeling a pathway. But most of these protocols have various disadvantages and shortcomings with respect to automated pathway modeling and analysis. In the present article, we have proposed a novel algorithm for automated pathway reconstruction. We have also made a comparative study of our algorithm with other standard protocols and discussed its advantages over others. We present StructurAl Grammar-based automated PAthway Reconstruction (SAGPAR), a fast and robust algorithm that generates any metabolic pathway using some given structural representations of metabolites. Users can model any pathway based on some pre-required features that are asked as an input by the algorithm. The algorithm also takes into considerations various thermodynamic thresholds and structural properties while modeling a pathway. The given algorithm has been tested on the standard pathway datasets of 25 pathways of Mycoplasma pneumoniae M129 and 24 pathways of Homo sapiens. The dataset is taken from KEGG and PubChem Compound data repositories. SAGPAR performs much better than some already present metabolic pathway analysis tools like Copasi, PHT, Gepasi, Jarnac and Path-A. PMID- 22843235 TI - DNA sequence evolution through Integral Value Transformations. AB - In deciphering the DNA structures, evolutions and functions, Cellular Automata (CA) plays a significant role. DNA can be thought as a one-dimensional multi state CA, more precisely four states of CA namely A, T, C, and G which can be taken as numerals 0, 1, 2 and 3. Earlier, Sirakoulis et al. (2003) reported the DNA structure, evolution and function through quaternary logic one dimensional CA and the authors have found the simulation results of the DNA evolutions with the help of only four linear CA rules. The DNA sequences which are produced through the CA evolutions, however, are seen by us not to exist in the established databases of various genomes although the initial seed (initial global state of CA) was taken from the database. This problem motivated us to study the DNA evolutions from more fundamental point of view. Parallel to CA paradigm we have devised an enriched set of discrete transformations which have been named as Integral Value Transformations (IVT). Interestingly, on applying the IVT systematically, we have been able to show that each of the DNA sequence at various discrete time instances in IVT evolutions can be directly mapped to a specific DNA sequence existing in the database. This has been possible through our efforts of getting quantitative mathematical parameters of the DNA sequences involving fractals. Thus we have at our disposal some transformational mechanism between one DNA to another. PMID- 22843236 TI - In silico targeted genome mining and comparative modelling reveals a putative protein similar to an Arabidopsis drought tolerance DNA binding transcription factor in Chromosome 6 of Sorghum bicolor genome. AB - Arabidopsis Thaliana HARDY (AtHRD) is a gene with an APETELA 2 / Ethylene Responsive Factor (AP2/ERF) domain linked to improved performance under drought in rice. We hypothesized that the sorghum genome could possess a similar gene product and were motivated to conduct a computational genome scale mining for the protein and analyse its structural and functional properties. AtHRD sequence was used as a query to BLAST against the sorghum genome dataset followed by multiple alignment analysis. A homology model of the target was built using a template detected based on the pair-wise comparison of hidden Markov models for alignments. DNA docking with a matrix of homologous interface contacts was done. Functional and structural analysis of the query and target was conducted using various online servers. A High-scoring segment pair from Chromosome 6 of the sorghum genome in the region between 54948120 and 54948668 had 68 amino acid similarities out of the 184 residues and was 1.4% above twilight zone threshold. The homology model showed 86.8% residues in most favoured regions. The target protein which had an AP2/ERF domain when docked with GCC box DNA motif had conserved residues involved in binding; it had a long unstructured region beyond the AP2 domain with several motifs for the recognition of serine/threonine protein kinase group. The protein model showed that it could bind to a GCC box which is present in several drought responsive genes. The presence of possible signalling domains and intrinsic disorder in the target protein suggest that this could play a role in drought tolerance which is an inherent character of sorghum. These results offer a jumpstart for validation experiments which could pave the way for cis/trans genic improvement of a range of crops. PMID- 22843237 TI - Molecular characterization of Mtb-OMP decarboxylase by modeling, docking and dynamic studies. AB - Tuberculosis (TB), the second most deadly disease in the world is caused by Mycobacterium tuberculosis (Mtb). In the present work a unique enzyme of Mtb orotidine 5' monophosphate decarboxylase (Mtb-OMP Decase) is selected as drug target due to its indispensible role in biosynthesis of pyrimidines. The present work is focused on understanding the structural and functional aspects of Mtb-OMP Decase at molecular level. Due to absence of crystal structure, the 3D structure of Mtb-OMP Decase was predicted by MODELLER9V7 using a known structural template 3L52. Energy minimization and refinement of the developed 3D model was carried out with Gromacs 3.2.1 and the optimized homology model was validated by PROCHECK,WHAT-IF and PROSA2003. Further, the surface active site amino acids were quantified by WHAT-IF pocket. The exact binding interactions of the ligands, 6 idiouridine 5' monophosphate and its designed analogues with the receptor Mtb-OMP Decase were predicted by docking analysis with AUTODOCK 4.0. This would be helpful in understanding the blockade mechanism of OMP Decase and provide a candidate lead for the discovery of Mtb-OMP Decase inhibitors, which may bring insights into outcome new therapy to treat drug resistant Mtb. PMID- 22843238 TI - In silico study of Alzheimer's disease in relation to FYN gene. AB - To understand the role of FYN (Fibroblast Yes related novel) gene products in relation to neurodegeneration and Alzheimer's disease we have analyzed the SNPs (single nucleotide polymorphism) associated with this gene. This can help us to understand the genetic variations that can alter the function of the gene products. A total of 3463 SNPs are investigated for FYN. To determine whether a non-synonymous SNP (nsSNP) in this gene affects its protein product, we used certain computational tools which predicted two nsSNPs (rs1801109, rs1801121) to have significant damaging effects. The amino acid change for rs1801109 is from alanine to aspartate, i.e. from a neutral, non-polar amino acid to a polar, acidic amino acid (electrically charged) and for rs1801121 it is from isoleucine to phenylalanine, i.e. from an aliphatic, hydrophobic molecule to an aromatic, highly hydrophobic residue. Hence, due to the complete change in charges and side chains of the amino acid residues brought about by these nsSNPs, respectively, might affect the structure and function of the protein. The results presented from this in silico study will open up new prospect for genetic analysis of FYN gene and their correlation with clinical data will be very useful in understanding the genetics of Alzheimer's disease. PMID- 22843239 TI - Primary non-Hodgkin's lymphoma of the colon: a case report and literature review. PMID- 22843240 TI - Generic and patient-specific models of the arterial tree. AB - Recent advance in imaging modalities used frequently in clinical routine can provide description of the geometrical and hemodynamical properties of the arterial tree in great detail. The combination of such information with models of blood flow of the arterial tree can provide further information, such as details in pressure and flow waves or details in the local flow field. Such knowledge maybe be critical in understanding the development or state of arterial disease and can help clinicians perform better diagnosis or plan better treatments. In the present review, the state of the art of arterial tree models is presented, ranging from 0-D lumped models, 1-D wave propagation model to more complex 3-D fluid-structure interaction models. Our development of a generic and patient specific model of the human arterial tree permitting to study pressure and flow waves propagation in patients is presented. The predicted pressure and flow waveforms are in good agreement with the in vivo measurements. We discuss the utility of these models in different clinical application and future development of interest. PMID- 22843241 TI - Juvenile food limitation in standardized tests: a warning to ecotoxicologists. AB - Standard ecotoxicological tests are as simple as possible and food sources are mainly chosen for practical reasons. Since some organisms change their food preferences during the life-cycle, they might be food limited at some stage if we do not account for such a switch. As organisms tend to respond more sensitively to toxicant exposure under food limitation, the interpretation of test results may then be biased. Using a reformulation of the von Bertalanffy model to analyze growth data of the pond snail Lymnaea stagnalis, we detected food limitation in the early juvenile phase. The snails were held under conditions proposed for a standardized test protocol, which prescribes lettuce as food source. Additional experiments showed that juveniles grow considerably faster when fed with fish flakes. The model is based on Dynamic Energy Budget (DEB) theory, which allows for mechanistic interpretation of toxic effects in terms of changes in energy allocation. In a simulation study with the DEB model, we compared the effects of three hypothetical toxicants in different feeding situations. The initial food limitation when fed with lettuce always intensified the effect of the toxicants. When fed with fish flakes, the predicted effect of the toxicants was less pronounced. From this study, we conclude that (i) the proposed test conditions for L. stagnalis are not optimal, and require further investigation, (ii) fish flakes are a better food source for juvenile pond snails than lettuce, (iii) analyzing data with a mechanistic modeling approach such as DEB allows identifying deviations from constant conditions, (iv) being unaware of food limitation in the laboratory can lead to an overestimation of toxicity in ecotoxicological tests. PMID- 22843242 TI - Several enteropathogens are circulating in suckling and newly weaned piglets suffering from diarrhea in the province of Villa Clara, Cuba. AB - Intestinal contents of suckling (n = 45) and newly weaned (n = 45) piglets, suffering from diarrhea in the province of Villa Clara in Cuba, were tested for viral, bacterial, and parasitic enteropathogens from May to June 2008. At least one enteropathogen was identified in 53.3 % of piglets and enterotoxigenic Escherichia coli (ETEC; 25.6 %) was the major pathogen; mostly STa(+)/STb(+) or F4(+)/STa(+)/STb(+) ETEC were isolated. The overall occurrence of the rest of pathogens was 10 % for transmissible gastroenteritis virus (TGEV) and Cryptosporidium parvum, 6.7 % for rotavirus A and Isospora suis, 5.6 % for alpha toxigenic Clostridium perfringens, 3.3 % for verotoxigenic E. coli (VTEC), and 2.2 % for Salmonella enterica subspecies enterica serovar Newport. TGEV and alpha toxigenic C. perfringens were only identified in suckling piglets, while Salmonella Newport and VTEC were only detected in weaned pigs. Porcine epidemic diarrhea virus (PEDV), beta-toxigenic C. perfringens, Eimeria spp., and helminths were not identified. Eight kinds of mixed infections were detected in 25 % of enteropathogen positive piglets. ETEC was present in 10 of 12 mixed infections, and TGEV infections were never combined. This survey demonstrates that several enteropathogens are circulating in piggeries located in the province of Villa Clara in Cuba, and that is necessary to improve surveillance, prevention, and control of enteric infections in order to increase production efficiency. PMID- 22843243 TI - Proteomics analysis of date palm leaves affected at three characteristic stages of brittle leaf disease. AB - Proteomics analysis has been performed in leaf tissue from field date palm trees showing the brittle leaf disease (BLD) or maladie des feuilles cassantes, the main causal agent of the date palm decline in south Tunisia. To study the evolution of the disease, proteins from healthy and affected leaves taken at three disease stages (S1, S2 and S3) were trichloroacetic acid acetone extracted and subjected to two-dimensional gel electrophoresis (5-8 pH range). Statistical analysis showed that the protein abundance profile is different enough to differentiate the affected leaves from the healthy ones. Fifty-eight variable spots were successfully identified by matrix-assisted laser desorption ionization time of flight, 60 % of which corresponded to chloroplastic ones being involved in the photosynthesis electronic chain and ATP synthesis, metabolic pathways implicated in the balance of the energy, and proteases. Changes in the proteome start at early disease stage (S1), and are greatest at S2. In addition to the degradation of the ribulose-1.5-bisphosphate carboxylase oxygenase in affected leaflets, proteins belonging to the photosynthesis electronic chain and ATP synthesis decreased following the disease, reinforcing the relationship between BLD and manganese deficiency. The manganese-stabilizing proteins 33 kDa, identified in the present work, can be considered as protein biomarkers of the disease, especially at early disease step. PMID- 22843244 TI - Isolation and functional characterisation of banana phytoene synthase genes as potential cisgenes. AB - Carotenoids occur in all photosynthetic organisms where they protect photosystems from auto-oxidation, participate in photosynthetic energy transfer and are secondary metabolites. Of the more than 600 known plant carotenoids, few can be converted into vitamin A by humans and so these pro-vitamin A carotenoids (pVAC) are important in human nutrition. Phytoene synthase (PSY) is a key enzyme in the biosynthetic pathway of pVACs and plays a central role in regulating pVAC accumulation in the edible portion of crop plants. Banana is a major commercial crop and serves as a staple crop for more than 30 million people. There is natural variation in fruit pVAC content across different banana cultivars, but this is not well understood. Therefore, we isolated PSY genes from banana cultivars with relatively high (cv. Asupina) and low (cv. Cavendish) pVAC content. We provide evidence that PSY in banana is encoded by two paralogs (PSY1 and PSY2), each with a similar gene structure to homologous genes in other monocots. Further, we demonstrate that PSY2 is more highly expressed in fruit pulp compared to leaf. Functional analysis of PSY1 and PSY2 in rice callus and E. coli demonstrates that both genes encode functional enzymes, and that Asupina PSYs have approximately twice the enzymatic activity of the corresponding Cavendish PSYs. These results suggest that differences in PSY enzyme activity contribute significantly to the differences in Asupina and Cavendish fruit pVAC content. Importantly, Asupina PSY genes could potentially be used to generate new cisgenic or intragenic banana cultivars with enhanced pVAC content. PMID- 22843246 TI - Transient Charles Bonnet syndrome in a patient with reversible cerebral vasoconstriction syndrome. PMID- 22843245 TI - The control of chlorophyll levels in maturing kiwifruit. AB - Chlorophyll is present in many plant organs, including immature fruit where it is usually degraded during ripening. Mature green kiwifruit (Actinidia deliciosa) are an exception, with high concentrations of chlorophyll remaining in the fruit flesh. In gold-fleshed kiwifruit (A. chinensis), chlorophyll is degraded to colourless catabolites upon fruit ripening, leaving yellow carotenoids visible. We have identified candidate genes for the control of chlorophyll degradation in kiwifruit and examined the transcript levels of these genes in maturing kiwifruit using quantitative real-time PCR. Results indicate that the biosynthesis and degradation, or turnover, of chlorophyll is transcriptionally regulated in green- and gold-fleshed kiwifruit. Both species of kiwifruit were found to have two homologues of the stay-green gene (SGR), a small protein that is postulated to aid in the dismantling of the light-harvesting complex, allowing free chlorophyll to enter the degradation pathway. However, with the exception of very mature green fruit, where degreening was observed, SGR2 was more highly expressed in gold fruit, indicating a potential regulatory step of chlorophyll degradation. When the SGR genes were over-expressed in tobacco leaves, degreening was observed. Our results show that chlorophyll degradation is differentially regulated in kiwifruit, and suggest that gold kiwifruit transcribe more degradation genes, leading to earlier and more sustained chlorophyll degradation in this fruit than in green kiwifruit. PMID- 22843247 TI - Mobilizing culture as an asset: a transdisciplinary effort to rethink gender violence. AB - The contested relationship between gender violence and the "culture concept" can be found in the cultural defense of gender violence, gender violence linked to postcolonial retraditionalizations of family life, the underpolicing of gender violence associated with communities labeled as culturally backward, and the overpolicing of activities categorized by human rights advocates as harmful traditional practices. Culture has been used to defend, explain, or excuse gender violence, and seen as a barrier to the elimination of gender violence. Here, however, the authors analyze how culture has been mobilized strategically as a resource in the struggle against gender violence. PMID- 22843248 TI - Acupuncture for postoperative pain in day surgery patients undergoing arthroscopic shoulder surgery. AB - The purpose of this quasi-experimental study was to examine the effect of acupuncture on postoperative pain in day surgery patients undergoing arthroscopic shoulder surgery. Twenty-two participants scheduled to undergo arthroscopic shoulder surgery were included. The results showed that on postoperative day one pain decreased (-1.1) in patients receiving acupuncture compared to the control group in which pain increased (2.0), p=.014. Sleep quality was also significantly higher in the acupuncture group compared to the control group, p=.042. In conclusions, acupuncture seems to have a reducing effect on postoperative pain as well as increase sleep quality in day surgery patients undergoing arthroscopic shoulder surgery. In regards to application, nurses should be encouraged to use additional nonpharmacologic approaches like acupuncture in postoperative pain management, as this can be a part of the multimodal analgesic regimes to improve patients care. PMID- 22843250 TI - Measurement model exploring a syndemic in emerging adult gay and bisexual men. AB - The current study was designed to develop a better understanding of the nature of the relationships between mental health burden, drug use, and unprotected sexual behavior within a sample of emerging adult gay and bisexual men, ages 18-19 (N = 598) and to test a theory of syndemics using structural equation modeling. Participants were actively recruited from community-based settings and the Internet for participation in a seven-wave cohort study. Data for participant characteristics and mental health were collected via computer-assisted survey, while drug use and unprotected sex behaviors for the month prior to assessment were collected via a calendar-based technique. Using the baseline data, we developed and tested structural equation models for mental health burden, drug use, and unprotected sex and also tested a second-order model for a single syndemic. First-order measurement models for each of the three epidemics were successfully identified using observed data. Tests of a second-order model seeking to explain the three epidemics as a single syndemic fit poorly. However, a second-order construct comprised of mental health burden and drug use fit the data well and was highly associated with the first-order construct of unprotected sex. The findings advance a theory of syndemics and suggest that in order to be maximally effective both HIV prevention and HIV care must be delivered holistically such that sexual risk behaviors are addressed in relation to, and in sync with, the drug use and mental health of the individual. PMID- 22843249 TI - Immunogenetics of the NKG2D ligand gene family. AB - NKG2D ligands (NKG2DLs) are a group of major histocompatibility complex (MHC) class I-like molecules, the expression of which is induced by cellular stresses such as infection, tumorigenesis, heat shock, tissue damage, and DNA damage. They act as a molecular danger signal alerting the immune system for infected or neoplastic cells. Mammals have two families of NKG2DL genes: the MHC-encoded MIC gene family and the ULBP gene family encoded outside the MHC region in most mammals. Rodents such as mice and rats lack the MIC family of ligands. Interestingly, some mammals have NKG2DL-like molecules named MILL that are phylogenetically related to MIC, but do not function as NKG2DLs. In this paper, we review our current knowledge of the MIC, ULBP, and MILL gene families in representative mammalian species and discuss the origin and evolution of the NKG2DL gene family. PMID- 22843251 TI - Improvement of diabetic or obese patients' erythrocyte deformability by the program of the brain-oriented obesity control system (BOOCS). AB - Diabetes is characterized by absolute or relative insulin deficiency complicated with microangiopathy, whereas obesity stems from insulin resistance. A psychosomatic approach to obesity and diabetes has been highlighted, including the brain-oriented obesity control system (BOOCS). Impaired deformability of erythrocytes in obese or diabetic patients is closely linked to disturbed microcirculation, and improvement of abnormal erythrocyte rheology is a prerequisite for the prevention and treatment of microangiopathy. Therefore, erythrocyte filterability, whole cell deformability defined as flow rate of erythrocyte suspension relative to that of saline, was assessed by the nickel mesh-filtration technique. Subjects included healthy controls (group A, n = 14), diabetic, non-obese participants (group B, n = 29), and non-diabetic, obese participants (group C, n = 32) in the 6-month BOOCS program, and most patients in groups B and C (86.9 %) completed this program. Baseline mean erythrocyte filterabilities were 89.4 +/- 1.7 % in group A, 82.8 +/- 5.2 % in group B, and 84.1 +/- 5.6 % in group C, showing significant intergroup differences (p < 0.001). This program significantly improved (p < 0.001) the impaired erythrocyte filterability in groups B (87.9 +/- 4.4 %) and C (88.5 +/- 3.7 %). Declines in HbA1c (p = 0.387) and body mass index (p = 0.479) were not correlated to this improvement. These findings indicate that the mechanisms of BOOCS-induced improvement of diabetic or obese patients' erythrocyte deformability are multifactorial, and that the BOOCS program for these patients is a holistic, cost effective, and highly compliant approach possibly ameliorating microcirculation. PMID- 22843252 TI - Serotonin 5-HT(7) receptor blockade reverses behavioral abnormalities in PACAP deficient mice and receptor activation promotes neurite extension in primary embryonic hippocampal neurons: therapeutic implications for psychiatric disorders. AB - The serotonin 5-HT(7) receptor has been linked to various psychiatric disorders, including schizophrenia, anxiety and depression, and is antagonized by antipsychotics such as risperidone, clozapine and lurasidone. In this study, we examined whether inhibiting the 5-HT(7) receptor could reverse behavioral abnormalities in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental mouse model for psychiatric disorders such as schizophrenia. The selective 5-HT(7) antagonist SB-269970 effectively suppressed abnormal jumping behavior in PACAP-deficient mice. SB-269970 tended to alleviate the higher immobility in the forced swim test in PACAP-deficient mice, although SB-269970 reduced the immobility also in wild-type mice. In addition, we found that mutant mice had impaired performance in the Y-maze test, which was reversed by SB-269970. In the mutant mouse brain, 5-HT(7) protein expression did not differ from wild-type mice. In primary embryonic hippocampal neurons, the 5-HT(7) agonist AS19 increased neurite length and number. Furthermore, SB-269970 significantly inhibited the increase in neurite extension mediated by the 5 HT(1A/7) agonist 8-OH-DPAT. These results indicate that 5-HT(7) receptor blockade ameliorates psychomotor and cognitive deficits in PACAP-deficient mice, providing additional evidence that the 5-HT(7) receptor is a rational target for the treatment of psychiatric disorders. PMID- 22843253 TI - Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity. AB - ACS6, a novel hydrogen sulfide (H2S)-releasing sildenafil, has been demonstrated to inhibit superoxide formation through donating H2S. We have previously found that ACS6 antagonizes homocysteine-induced apoptosis and cytotoxicity. The aim of the present study is to explore the molecular mechanisms underlying ACS6-exerted protective action against the neurotoxicity of homocysteine. In the present work, we used PC12 cells to explore whether paraoxonase-1 (PON-1) is implicated in ACS6 induced neuroprotection against homocysteine neurotoxicity. We show that ACS6 treatment results in prevention of homocysteine-caused neurotoxicity and overproduction of reactive oxygen species (ROS). Homocysteine downregulates the expression and activity of PON-1; however, this effect is significantly blocked by co-treatment with ACS6. The specific inhibitor of PON-1 2-hydroxyquinoline reverses the inhibitory effect of ACS6 on homocysteine-induced neurotoxicity and intracellular ROS accumulation. These results indicate that ACS6 protects PC12 cells against homocysteine-induced neurotoxicity by upregulating PON-1 and suggest a promising role of PON-1 as a novel therapeutic strategy for homocysteine-induced toxicity. PMID- 22843254 TI - Singlet oxygen generation enhanced by silver-pectin nanoparticles. AB - We demonstrate the potential application of silver-pectin nanoparticles on photodynamic therapy, on a solution-base platform. Photodynamic therapy is a medical technique which uses a combination of photosensitizing drugs and light to induce selective damage on the target tissue, by electronically excited and highly reactive singlet state of oxygen. Metal enhanced singlet oxygen generation in riboflavin water solution with silver-pectin nanoparticles was observed and quantified. Here 13 nm silver nanospheres enclosed by a pectin layer were synthesized and it interaction with riboflavin molecule was analyzed. Pectin, a complex carbohydrate found in plants primary cell walls, was used to increase the biocompatibility of the silver nanoparticles and to improve metal enhanced singlet oxygen generation (28.5 %) and metal-enhanced fluorescence (30.7 %) processes at room temperature. The singlet oxygen sensor fluorescent green reagent was used to quantify the enhancement of the riboflavin singlet oxygen production induced by the silver colloid. We report a 1.7-fold increase of riboflavin emission and a 1.8-fold enhancement of singlet oxygen production. PMID- 22843255 TI - Brain tumor-associated seizures: glutamate, transporters, and an old drug. PMID- 22843256 TI - Feasibility of antiepileptic drug withdrawal following extratemporal resective epilepsy surgery. AB - OBJECTIVE: To identify the rate of successful antiepileptic drug (AED) withdrawal after resective surgery and the predictors of postwithdrawal seizure recurrence in patients with extratemporal epilepsy. METHODS: We retrospectively analyzed the postoperative AED profile of 106 consecutive patients who had completed 2 or more years after resections involving frontal, parietal, and occipital lobes for AED resistant epilepsy. To identify the potential predictors of seizure recurrence, we compared the attributes of recurred and nonrecurred groups by univariate and multivariate analyses. RESULTS: We attempted AED withdrawal in 94 (88.7%) patients. Forty-four (41.5%) patients had seizure recurrence while reducing AED, of which 14 (31.8%) did not become seizure-free subsequently. On multivariate analysis, an abnormal postoperative EEG and longer preoperative duration of epilepsy predicted seizure recurrence, while early postoperative seizures and presence of gliosis or dysplasia were additional predictors on univariate analysis. At mean follow-up duration of 4.6 years, 63 (59.4%) patients were seizure-free. The cumulative probability of achieving complete AED-free status was 20% at fourth year, 34% at sixth year, 40% at eighth year, and 52% at 10th year after surgery. CONCLUSIONS: Following resective extratemporal epilepsy surgery, AED can be successfully discontinued in only in a minority of patients. One-third of patients who recur fail to regain seizure control upon AED reintroduction. Longer duration of epilepsy prior to surgery, abnormal postoperative EEG, early postoperative seizures, and focal gliosis or dysplasia as substrate predispose to seizure recurrence. This information will be helpful in making rational decisions on AED withdrawal following extratemporal resective epilepsy surgery. PMID- 22843257 TI - A comparison of tau and 14-3-3 protein in the diagnosis of Creutzfeldt-Jakob disease. AB - OBJECTIVE: To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. METHODS: We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy). RESULTS: We found tau and 14-3-3 proteins to be closely correlated, but tau had a significantly better ability to predict disease status than 14-3-3 protein. Also, tau distinguished disease status at least as well as when both assays' results are combined in a variety of ways. Importantly, the area under the receiver operating characteristic curve for tau (0.82) was significantly larger than that for 14-3-3 protein (0.68) (p < 0.001). Diagnostic test statistics are provided for the study subjects with 58.3% prevalence, and for a more typical, nonselected, 7.5% prevalence as received by our center. CONCLUSION: In this study, tau is superior to 14-3-3 protein as a marker in the diagnosis of Creutzfeldt-Jakob disease, and is as efficient singly compared to a variety of combinations with 14-3-3 protein. This is the first study of this magnitude to examine prion disease diagnostic tests in a carefully characterized patient population with detailed statistical evaluation. PMID- 22843258 TI - Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies. AB - OBJECTIVE: To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria. METHODS: We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval. RESULTS: Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test). CONCLUSION: Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei. PMID- 22843259 TI - MRI characteristics and scoring in HDLS due to CSF1R gene mutations. AB - OBJECTIVE: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony stimulating factor 1 receptor gene (CSF1R) on chromosome 5. METHODS: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. RESULTS: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. CONCLUSION: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion. PMID- 22843260 TI - The expansions of ALS. PMID- 22843261 TI - Imaging markers of incipient dementia: the white matter matters. PMID- 22843263 TI - Comment: Tau vs 14-3-3 protein--adjuncts for the diagnosis of CJD. PMID- 22843262 TI - Trajectory of white matter hyperintensity burden preceding mild cognitive impairment. AB - OBJECTIVE: To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly. METHODS: A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up. RESULTS: During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present. CONCLUSIONS: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset. PMID- 22843264 TI - MRI-leukoaraiosis thresholds and the phenotypic expression of dementia. AB - OBJECTIVE: To examine the concept of leukoaraiosis thresholds on working memory, visuoconstruction, memory, and language in dementia. METHODS: A consecutive series of 83 individuals with insidious onset/progressive dementia clinically diagnosed with Alzheimer disease (AD) or small vessel vascular dementia (VaD) completed neuropsychological measures assessing working memory, visuoconstruction, episodic memory, and language. A clinical MRI scan was used to quantify leukoaraiosis, total white matter, hippocampus, lacune, and intracranial volume. We performed analyses to detect the lowest level of leukoaraiosis associated with impairment on the neuropsychological measures. RESULTS: Leukoaraiosis ranged from 0.63% to 23.74% of participants' white matter. Leukoaraiosis explained a significant amount of variance in working memory performance when it involved 3% or more of the white matter with curve estimations showing the relationship to be nonlinear in nature. Greater leukoaraiosis (13%) was implicated for impairment in visuoconstruction. Relationships between leukoaraiosis, episodic memory, and language measures were linear or flat. CONCLUSIONS: Leukoaraiosis involves specific threshold points for working memory and visuoconstructional tests in AD/VaD spectrum dementia. These data underscore the need to better understand the threshold at which leukoaraiosis affects and alters the phenotypic expression in insidious onset dementia syndromes. PMID- 22843265 TI - Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases. AB - OBJECTIVE: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS). METHODS: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion. RESULTS: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 * 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 * 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 * 10(-4)). CONCLUSIONS: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS. PMID- 22843266 TI - Compensatory role of the cortico-rubro-spinal tract in motor recovery after stroke. AB - OBJECTIVES: Studies on nonhuman primates have demonstrated that the cortico-rubro spinal system can compensate for damage to the pyramidal tract (PT). In humans, so-called alternate motor fibers (aMF), which may comprise the cortico-rubro spinal tract, have been suggested to play a similar role in motor recovery after stroke. Using diffusion tensor imaging, we examined PT and aMF in the context of human motor recovery by relating their microstructural properties to functional outcome in chronic stroke patients. METHODS: PT and aMF were reconstructed based on their origins in primary motor, dorsal premotor, and supplementary motor cortices in 18 patients and 10 healthy controls. The patients' degree of motor recovery was assessed using the Wolf Motor Function Test (WMFT). RESULTS: Compared to controls, fractional anisotropy (FA) was lower along ipsilesional PT and aMF in chronic stroke patients, but clusters of higher FA were found bilaterally in aMF within the vicinity of the red nuclei. FA along ipsilesional PT and aMF and within the red nuclei correlated significantly with WMFT scores. Probabilistic connectivity of aMF originating from ipsilesional primary motor cortex was higher in patients, whereas the ipsilesional PT exhibited lower connectivity compared to controls. CONCLUSIONS: The strong correlations observed between microstructural properties of bilateral red nuclei and the level of motor function in chronic stroke patients indicate possible remodeling during recovery. Our results shed light on the role of different corticofugal motor tracts, and highlight a compensatory function of the cortico-rubro-spinal system which may be used as a target in future restorative treatments. PMID- 22843267 TI - Relapsing course of immunoglobulin G4-related pachymeningitis. PMID- 22843268 TI - Glutamate is associated with a higher risk of seizures in patients with gliomas. AB - OBJECTIVE: To investigate the relationship of glutamate and glutamate transporter expression in human gliomas and surrounding peritumoral brain to the presence of tumor-associated seizures (TAS). METHODS: We studied a retrospective (group 1: 190 patients) and then a prospective (group 2: 98 patients) cohort of patients who underwent a craniotomy for a supratentorial glioma. Tumor and peritumor tissue specimens were assayed for glutamate concentration and expression of glial glutamate transporters. Differences between the seizure (TAS) and seizure-free (non-TAS) groups were compared. RESULTS: A total of 42% of patients had TAS, with 95% of seizures first occurring preoperatively. Clinical factors independently associated with risk of TAS were younger age, temporal lobe location, and tumors with oligodendroglial components. Molecular features in tumor specimens associated with TAS were higher glutamate concentrations, reduced EAAT2 expression, and increased system X(c)(-) expression. In group 2, these results were also replicated in the peritumor tissue. Logistic regression analysis identified raised glutamate concentrations in tumor and peritumor tissue, increased expression of peritumor system X(c)(-), younger age, temporal lobe location, and tumors with oligodendroglial components as independently predictive of preoperative seizures. CONCLUSION: Relative increased glutamate concentration in gliomas, and altered glutamate transporter expression, are associated with the presence of TAS and may play a mechanistic role in their pathogenesis. PMID- 22843269 TI - Frontal lobe abnormalities on MRS correlate with poor letter fluency in ALS. AB - OBJECTIVE: To examine whether frontal lobe abnormalities on magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) correlate with poor letter fluency (LF). METHODS: Twenty-five patients with ALS (20 with definite, probable, or possible ALS and 5 with progressive muscular atrophy) performed an LF task, involving F word generation in 1 minute, and underwent MRS. Comparisons were made between patients with ALS with impaired LF and unimpaired LF based on an empirically derived cutoff score. A Spearman correlation was performed between the patient's N-acetyl acetate/creatinine-phosphocreatinine ratio (NAA/Cr) and the number of F words generated. RESULTS: LF was impaired in 50% of patients with ALS. Patients with impaired LF had reduced NAA/Cr in the DLPFC compared with those with unimpaired LF (p = 0.007). There was a significant correlation between LF and NAA/Cr in the DLPFC (r = 0.51, p = 0.0009). The ALS Functional Rating Scale score, clinical region of motor onset, and disease category had no effect on LF or NAA/Cr in the DLPFC. CONCLUSIONS: A reduced NAA/Cr in the DLPFC of patients with ALS is a marker of neuronal dysfunction and correlates with impaired performance on a clinical measure of executive function. PMID- 22843270 TI - Microstructural white matter changes in cognitively normal individuals at risk of amnestic MCI. AB - OBJECTIVE: Since Alzheimer disease (AD) is a slowly progressive disorder and its pathologic features are likely to be present for many years before symptoms become manifest, we investigated whether microstructural white matter changes similar to those identified in patients with AD can be detected in cognitively normal individuals without dementia destined to develop amnestic mild cognitive impairment (aMCI). METHODS: We studied 193 cognitively normal individuals, of whom 173 remained cognitively stable (CN-stable) and 20 were diagnosed with aMCI (CN-aMCI converter) 2 years later. Structural MRI and diffusion tensor imaging were acquired at baseline to assess gray matter atrophy and microstructural white matter changes, respectively. RESULTS: At baseline, compared with CN-stable, CN aMCI converters had substantial reductions in white matter integrity in the precuneus, parahippocampal cingulum, parahippocampal gyrus white matter, and fornix. Other diffuse white matter changes were observed in the frontal, parietal, and subcortical regions, whereas gray matter structures were relatively intact. The fractional anisotropy (FA) values of the precuneus were found to be a predictor of conversion from cognitively normal to aMCI. In addition, the FA values of the left parahippocampal gyrus white matter were predictive of subsequent episodic memory decline. CONCLUSIONS: Microstructural white matter changes are present in cognitively normal individuals in the pre-aMCI stage, and may serve as a potential imaging marker of early AD-related brain changes. PMID- 22843271 TI - New ischemic lesions coexisting with acute intracerebral hemorrhage. AB - OBJECTIVES: Acute cerebral infarction may coexist with hypertensive intracerebral hemorrhage (ICH) because lacunae and hypertensive ICH share common risk factors and small-vessel pathology. We sought to determine the frequency and predictors of new ischemic lesions (NIL) on diffusion-weighted imaging (DWI), in patients with acute hypertensive ICH, and to investigate whether NIL predicts subsequent clinical cerebrovascular events. METHODS: This prospective study enrolled 97 patients with acute hypertensive ICH diagnosed within 3 days after onset. DWI and gradient echo T2*-weighted imaging were performed 5 days after onset. NIL was defined as hyperintense DWI lesions accompanying low intensity on apparent diffusion coefficient maps. Patients were regularly followed up for subsequent clinical cerebrovascular events or vascular deaths. RESULTS: Forty-nine asymptomatic NILs were observed in 26 (26.8%) patients, with 37 of the 49 NILs (75.5%) located in subcortical white matter or brainstem. Multiple logistic regression analysis showed that baseline microbleeds >2 and moderate to severe white matter leukoaraiosis were independently associated with NIL. During a median follow-up of 42 months (interquartile range, 38-47 months), 9 patients experienced clinical cerebrovascular events or vascular deaths. Cox proportional hazards models showed that NILs were independently associated with the composite of clinical cerebrovascular events or vascular death and marginally associated with clinical ischemic stroke. CONCLUSIONS: NILs frequently occur during the acute phase of ICH and are mainly associated with small-vessel pathogenesis. NILs occurring together with ICH may be a useful marker to identify patients at high risk of future clinical cerebrovascular events or vascular death. PMID- 22843272 TI - A mental lexicon without semantics. PMID- 22843273 TI - Childhood febrile status epilepticus: chicken or egg? Does it matter? PMID- 22843274 TI - Medication management after epilepsy surgery: are we closer to an answer? PMID- 22843275 TI - Statins do not cause intracerebral hemorrhage. PMID- 22843276 TI - Small ischemic lesions following intracerebral hemorrhage: silent but deadly. PMID- 22843277 TI - A designer drug for amyloid polyneuropathy. PMID- 22843278 TI - MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study. AB - OBJECTIVE: The FEBSTAT study is a prospective study that seeks to determine the acute and long-term consequences of febrile status epilepticus (FSE) in childhood. METHODS: From 2003 to 2010, 199 children age 1 month to 5 years presenting with FSE (>30 minutes) were enrolled in FEBSTAT within 72 hours of the FSE episode. Of these, 191 had imaging with emphasis on the hippocampus. All MRIs were reviewed by 2 neuroradiologists blinded to clinical details. A group of 96 children with first simple FS who were imaged using a similar protocol served as controls. RESULTS: A total of 22 (11.5%) children had definitely abnormal (n = 17) or equivocal (n = 5) increased T2 signal in the hippocampus following FSE compared with none in the control group (p < 0.0001). Developmental abnormalities of the hippocampus were more common in the FSE group (n = 20, 10.5%) than in controls (n = 2, 2.1%) (p = 0.0097) with hippocampal malrotation being the most common (15 cases and 2 controls). Extrahippocampal imaging abnormalities were present in 15.7% of the FSE group and 15.6% of the controls. However, extrahippocampal imaging abnormalities of the temporal lobe were more common in the FSE group (7.9%) than in controls (1.0%) (p = 0.015). CONCLUSIONS: This prospective study demonstrates that children with FSE are at risk for acute hippocampal injury and that a substantial number also have abnormalities in hippocampal development. Follow-up studies are in progress to determine the long term outcomes in these children. PMID- 22843279 TI - Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome. AB - OBJECTIVE: To systematically study abnormalities in cytokine profiles in polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, which has been increasingly recognized as a cause of demyelinating neuropathy associated with plasma cell dyscrasia and elevated serum level of vascular endothelial growth factor (VEGF). METHODS: In this case-control study, we measured serum levels of 27 cytokines in patients with POEMS syndrome using a multiplex suspension array system, and compared them with those of controls. In 10 patients, serial changes after treatment were analyzed. RESULTS: Interleukin (IL)-12 as well as VEGF levels were markedly increased (p < 0.0001) in all the patients (n = 23). Ten kinds of other proinflammatory cytokines such as IL-6 and tumor necrosis factor-alpha were also significantly increased in the POEMS syndrome group, but in some patients the serum levels of such cytokines remained within the normal ranges. After treatments, the IL-12 as well as VEGF levels significantly decreased with clinical improvements (p > 0.01 and p > 0.05, respectively). CONCLUSIONS: Our findings suggest that serum IL-12 is a biomarker of the disease activity in POEMS syndrome. The overproduction of IL-12, as well as VEGF, is likely to play an important role in the pathogenesis of the disorder, and could contribute to the peripheral nerve demyelination in POEMS syndrome. PMID- 22843280 TI - Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. AB - OBJECTIVE: To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures. METHODS: This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (>=12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6 week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration. RESULTS: Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia. CONCLUSIONS: This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures. PMID- 22843281 TI - Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia. AB - OBJECTIVE: To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis. METHODS: Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2). RESULTS: Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [(adj)OR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; (adj)OR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels ((adj)OR 0.549, 95% CI 0.341-0.883 in model 1; (adj)OR 0.560, 95% CI 0.353 0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 ((adj)OR 1.390, 95% CI 1.040-1.860). CONCLUSION: Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke. PMID- 22843282 TI - Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. AB - OBJECTIVES: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. RESULTS: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. CONCLUSIONS: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. PMID- 22843283 TI - Prosopis farcta beans increase HDL cholesterol and decrease LDL cholesterol in ostriches (Struthio camelus). AB - Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase (gamma-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and gamma-GT activity decreased significantly. PMID- 22843284 TI - Detection of Legionella pneumophila on clinical samples and susceptibility assessment by flow cytometry. AB - Culture in selective media represents the standard diagnostic method to confirm Legionella pneumophila infection, despite requiring a prolonged incubation period; antigen detection by immunofluorescence (IFS) and molecular techniques are also available, but they do not allow antimicrobial susceptibility evaluation. Our objective was to optimise flow cytometry (FC) protocols for the detection of L. pneumophila in respiratory samples and for susceptibility evaluation to first-line drugs. In order to optimise the FC protocol, a specific monoclonal antibody, conjugated with fluorescein isothiocyanate (FITC), was incubated with type strain L. pneumophila ATCC 33152. The limit of detection was established by analysing serial dilutions of bacterial suspension; specificity was assayed using mixtures of prokaryotic and eukaryotic microorganisms. The optimised FC protocol was used to assess 50 respiratory samples and compared with IFS evaluation. The susceptibility profile to erythromycin, ciprofloxacin and levofloxacin was evaluated by FC using propidium iodide and SYBR Green fluorescent dyes; the results were compared with the Etest afterwards. The optimal specific antibody concentration was 20 MUg/ml; 10(2)/ml Legionella organisms were detected by this protocol and no cross-reactions with other microorganisms were detected. The five positive respiratory samples (10 %) determined by IFS were also detected by FC, showing 100 % correlation. After 1 h of incubation at 37 degrees C with different antimicrobials, SYBR Green staining could discriminate between treated and non-treated cells. A novel flow cytometric approach for the detection of L. pneumophila from clinical samples and susceptibility evaluation is now available, representing an important step forward for the diagnosis of this very relevant agent. PMID- 22843286 TI - Regional distribution of calretinin and calbindin-D28k expression in the brain of the urodele amphibian Pleurodeles waltl during embryonic and larval development. AB - The sequence of appearance of calretinin and calbindin-D28k immunoreactive (CRir and CBir, respectively) cells and fibers has been studied in the brain of the urodele amphibian Pleurodeles waltl. Embryonic, larval and juvenile stages were studied. The early expression and the dynamics of the distribution of CBir and CRir structures have been used as markers for developmental aspects of distinct neuronal populations, highlighting the accurate extent of many regions in the developing brain, not observed on the basis of cytoarchitecture alone. CR and, to a lesser extent, CB are expressed early in the central nervous system and show a progressively increasing expression from the embryonic stages throughout the larval life and, in general, the labeled structures in the developing brain retain their ability to express these proteins in the adult brain. The onset of CRir cells primarily served to follow the development of the olfactory bulbs, subpallium, thalamus, alar hypothalamus, mesencephalic tegmentum, and distinct cell populations in the rhombencephalic reticular formation. CBir cells highlighted the development of, among others, the pallidum, hypothalamus, dorsal habenula, midbrain tegmentum, cerebellum, and central gray of the rostral rhombencephalon. However, it was the relative and mostly segregated distribution of both proteins in distinct cell populations which evidenced the developing regionalization of the brain. The results have shown the usefulness in neuroanatomy of the analysis during development of the onset of CBir and CRir structures, but the comparison with previous data has shown extensive variability across vertebrate classes. Therefore, one should be cautious when comparing possible homologue structures across species only on the basis of the expression of these proteins, due to the variation of the content of calcium-binding proteins observed in well-established homologous regions in the brain of different vertebrates. PMID- 22843285 TI - Aspergillus thyroiditis: a review of the literature to highlight clinical challenges. AB - Aspergillus involvement of the thyroid is the most commonly reported fungal thyroiditis. Aspergillus thyroiditis (AT) has primarily been a postmortem diagnosis in immunocompromised patients with diagnosed disseminated invasive Aspergillus or high suspicion of fungal infection during life. With better treatment modalities for the comorbidities that place patients at high risk for fungal infections, as well as better antifungal therapies for Aspergillus infections specifically, the spectrum of disease and presentation of AT may be shifting from what was primarily a postmortem finding to an antemortem diagnosis, necessitating a high index of clinical suspicion and timely intervention. We present a review of the literature to better clarify clinical features, diagnostic modalities, and management considerations pertaining to this disease. PMID- 22843288 TI - The Royal College diploma program: credential creep or value added? PMID- 22843290 TI - Prone insertion of a size 0.5 intubating laryngeal airway overcomes severe upper airway obstruction in an awake neonate with Pierre Robin syndrome. PMID- 22843287 TI - Diversity of prokaryotes associated with soils around coal-fire gas vents in MaNasi county of Xinjiang, China. AB - Bacterial and archaeal diversity in surface soils of three coal-fire vents was investigated by T-RFLP analysis and clone libraries of 16S rRNA genes. Soil analysis showed that underground coal fires significantly influenced soil pH, moisture and NO(3) (-) content but had little effect on other elements, organic matter and available nutrients. Hierarchical cluster analysis showed that bacterial community patterns in the soils were very similar, but abundance varied with geographic distance. A clone library from one soil showed that the bacterial community was mainly composed of Firmicutes, Proteobacteria, Acidobacteria, Bacteroidetes, Planctomycetes, Actinobacteria, and unidentified groups. Of these, Firmicutes was the most abundant, accounting for 71.4 % of the clones, and was mainly represented by the genera Bacillus and Paenibacillus. Archaeal phylotypes were closely related to uncultivated species of the phyla Crenarchaeota (97.9 % of clones) and Thaumarchaeota (2.1 %). About 28 % of archaeal phylotypes were associated with ammonia oxidization, especially phylotypes that were highly related to a novel, ammonia-oxidizing isolate from the phylum Thaumarchaeota. These results suggested that microbial communities in the soils were diverse and might contain a large number of novel cultivable species with the potential to assimilate materials by heterotrophic metabolism at high temperature. PMID- 22843289 TI - Epidemiology of acute kidney injury in Canadian critical care units: a prospective cohort study. AB - PURPOSE: We undertook this study to characterize the epidemiology of acute kidney injury (AKI) in Canadian critical care units. We aimed to identify predictors of mortality for patients diagnosed with AKI. METHODS: We conducted a prospective cohort study of consecutive patients admitted to critical care units at five Canadian hospitals over a 30-day period. Each patient was followed until hospital discharge or for a maximum of 30 days. The serum creatinine criteria for the Acute Kidney Injury Network (AKIN-SCr) system were used to identify, classify, and characterize patients who developed AKI. We used multivariable logistic regression to predict 30-day mortality among patients with AKI. RESULTS: We identified 603 patients, 161 (26.7%) of whom developed AKI. Compared to patients without AKI, those with AKI were more likely to die (29.2% vs 8.6%, P < 0.001). The risk of death increased with increasing AKIN-SCr stage (P < 0.001). In all, 19 patients (11.8% of those with AKI) commenced dialysis a median of one day (interquartile range, one to two days) after AKI diagnosis. At AKI diagnosis, the blood urea nitrogen (BUN) level (adjusted odds ratio [OR] 1.68, 95% confidence interval [CI] 1.01 to 2.79/10 mmol.L(-1)) and serum bicarbonate (adjusted OR 0.88, 95% CI 0.81 to 0.95/1 mmol.L(-1)) were associated with 30-day mortality and predicted death with an area under the receiver-operating characteristic curve of 0.79 (95% CI 0.71 to 0.86). CONCLUSIONS: Acute kidney injury is a common complication of critical illness in Canada. The development of even the mildest stage of AKI is associated with a substantially higher risk of death. At AKI diagnosis, routine clinical data may be helpful for predicting adverse outcomes. PMID- 22843291 TI - Surgery of primary tumors in stage IV breast cancer: an updated meta-analysis of published studies with meta-regression. AB - Systemic therapy is the mainstream treatment of stage IV breast cancer. Surgical excision of the primary breast cancer tumor in the presence of synchronous metastatic disease is debated, but a shared indication is not proposed by current guidelines. The purpose of this analysis is to aggregate the published survival data of surgery of an intact primary tumor in stage IV disease. The authors searched PubMed for publications reporting data about the survival benefit of surgery of the primary tumor in patients with metastatic breast cancer. Hazard ratios for survival when reported after multivariate analysis (with 95 % confidence intervals) were obtained from publications and pooled in a meta analysis. A meta-regression weighted for the extent of disease, ER/HER2 status, age, visceral or bone disease, rate of radiotherapy, and systemic therapies offered was performed. A total of 15 publications were included in this meta analysis. Surgery of the primary tumor appeared to be an independent factor for an improved survival in the multivariate analyses from the individual studies, with an HR of 0.69 (p < 0.00001). According to meta-regression, the survival benefit was independent of age, extent, site of the metastatic disease, and HER2 status, but was directly proportional to the rate of patients exposed to systemic therapies and radiotherapy and inversely correlated with the ER+ status of the population included. Surgery of the primary tumor in stage IV breast cancer seems to offer a survival benefit in metastatic patients, in particular when it is offered in a multimodality treatment program. PMID- 22843292 TI - Allogeneic mRNA-based electrotransfection of autologous dendritic cells and specific antitumor effects against osteosarcoma in rats. AB - Vaccination with dendritic cells (DCs) transfected with tumor-derived mRNA antigen has emerged as a promising strategy for generating protective immunity in mammals. However, the integration of allogeneic osteosarcoma mRNA and autologous DCs has not been fully examined. This study was designed to investigate the antitumor effects of tumor vaccine produced by autologous DCs transfected of allogeneic osteosarcoma mRNA through electroporation in tumor-bearing rats model. In the present study, extraction of Wistar rat tumor mRNA was performed as a two step procedure. First, total RNA was extracted by use of Trizol; then, mRNA purification was performed by use of polyT-coated magnetic beads. Then, we transfected the allogeneic-derived tumor mRNA to Sprague-Dawley (SD) rat bone marrow-derived DCs through electroporation. The tumor vaccine was applied to tumor-bearing rats model, and the specific antitumor effects of the tumor vaccine were observed. The immunization using autologous DCs electrotransfected with allogeneic osteosarcoma total RNA induced specific CTL responses, which were statistically significant (P < 0.05), and the cytotoxic activity was confirmed in cold target inhibition assays and using mAbs blocking MHC class I molecules. In in vivo experiments, 70 % of the rats immunized with allogeneic osteosarcoma RNA transfected to DCs were typically able to reject tumor challenge and remained tumor-free. Vaccinated survivors developed long immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. In the present study, we demonstrated that allogeneic tumor mRNA isolated from rat osteosarcoma cell line could be applied to produce tumor vaccine inducing specific antitumor effects, especially in DC based immunotherapy strategy. This study also provides the foundations for an effective and broadly applicable treatment to a wide range of cancer indications for which tumor-associated antigens have not been identified. PMID- 22843293 TI - Use of angiotensin-converting enzyme inhibitors and cardiovascular outcomes following primary vascular surgery: a nationwide propensity score matched follow up study. AB - OBJECTIVE: To examine the association between angiotensin-converting enzyme (ACE) inhibitor use and clinical outcome after primary vascular reconstruction in a population-based follow-up study. METHODS: All Danish patients undergoing primary vascular surgical reconstruction between 1996 and 2007 were included. For each ACE user up to 5 nonuser was identified using propensity score matching followed by Cox regression. All drugs were included as time-dependent variables. RESULTS: Totally 17 495 matched patients with a median follow-up period of 582 days were included. All-cause mortality was 20.4% for ACE users and 24.9% for nonusers (adjusted hazard ratio [adj HR] 0.88, 95% confidence interval [CI] 0.81-0.96). The cumulative risk of myocardial infarction was 6.2% for ACE users and 4.7% for nonusers (adj HR 1.20, 95%CI 1.03-1.39). Cumulative risk of new vascular surgery was 24.0% for ACE users and 23.1% for nonusers (adj HR 1.21, 95% CI 1.13-1.30). No differences were seen concerning stroke and major amputation. CONCLUSION: The ACE use was associated with lower all-cause mortality but also an increased long term risk of recurrent vascular reconstruction. PMID- 22843294 TI - What are parents worried about? Health problems and health concerns for children. AB - Patient-centered care requires pediatricians to address parents' health concerns, but their willingness to solicit parental concerns may be limited by uncertainty about which topics will be raised. The authors conducted surveys of parents to identify current health-related issues of concern. METHODS: Participants rated 30 items as health problems for children in their community (large, medium, small, or no problem) and volunteered concerns for their own children. RESULTS: A total of 1119 parents completed the survey. Allergies (69%), lack of exercise (68%), asthma (65%), attention deficit hyperactivity disorder (65%), Internet safety (63%), obesity (59%), smoking (58%), and bullying (57%) were identified as important problems (large or medium) with variation among demographic subgroups. Concerns for their own children included healthy nutrition; obesity; lack of exercise, healthy growth and development; safety and injury prevention; and mental health issues. CONCLUSION: Parents' health concerns for children are varied and may differ from those routinely addressed during well-child care. PMID- 22843295 TI - Comparison of three typing methods for Pseudomonas aeruginosa isolates from patients with cystic fibrosis. AB - The aim of this study was to compare two traditional pattern matching techniques, pulsed-field gel electrophoresis (PFGE) and random amplified polymorphic DNA (RAPD), with the more reproducible technique of multilocus sequence typing (MLST) to genotype a blinded sample of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. A blinded sample of 48 well-characterized CF P. aeruginosa isolates was genotyped by PFGE, RAPD, and MLST, each performed in a different laboratory. The discriminatory power and congruence between the methods were compared using the Simpson's index, Rand index, and Wallace coefficient. PFGE and MLST had the greatest congruence with the highest Rand index (0.697). The discriminatory power of PFGE, RAPD, and MLST were comparable, with high Simpson's indices (range 0.973-0.980). MLST identified the most clonal relationships. When clonality was defined as agreement between two or more methods, MLST had the greatest predictive value (100 %) in labeling strains as unique, while PFGE had the greatest predictive value (96 %) in labeling strains as clonal. This study demonstrated the highest level of agreement between PFGE and MLST in genotyping P. aeruginosa isolates from CF patients. MLST had the greatest predictive value in identifying strains as unique and, thus, has the potential to be a cost-efficient, high-throughput, first-pass typing method. PMID- 22843297 TI - Measuring and modeling ammonium adsorption by calcareous soils. AB - The aim of this study was assessment of ammonium (NH 4(+) ) adsorption isotherms in some agricultural calcareous soils and modeling of that by using the mechanistic exchange model. Ten surface soils (0-30 cm) were collected from areas covered with different land uses in Hamedan, western Iran. Isotherm experiments were carried out by concentrations of NH 4(+) prepared from NH4Cl salt (0, 10, 20, 30, 40, 50, 100, and 150 mg NH 4(+) l(-1)) in presence of 0.01 M CaCl2 solution. The empirical models including simple adsorption isotherm and Freundlich equations were fitted well to the experimental data. The average amounts of adsorbed NH 4(+) in studied soils varied from 8.95 to 35.23 %. Adsorption percentage indicated positive correlation with pH, cation-exchange capacity (CEC), equivalent calcium carbonate, and clay content and had negative correlation with sand content. In order to predict and model NH 4(+) adsorption, cation-exchange model in PHREEQC program was used. The model could simulate the NH 4(+) adsorption very well in all studied soils. The values of CEC played the major role in modeling of NH 4(+) adsorption in this study indicating that cation exchange process was the major mechanism controlling NH 4(+) adsorption in studied soils. PMID- 22843299 TI - Comment to Lira-Dale et al.: Effect of intraprostatic epinephrine on intraoperative blood loss reduction during transurethral resection of the prostate. PMID- 22843296 TI - Phosphorous speciation in surface sediments of the Cochin estuary. AB - Sequential chemical extraction using chelating agents were used to study the P dynamics and its bioavailability along the surface sediments of the Cochin estuary (southwest coast of India). Sediments were analyzed for major P species (iron bound P, calcium bound P, acid soluble organic P, alkali soluble organic P and residual organic P), Fe, Ca, total carbon, organic carbon, total nitrogen and total sulfur contents. An abrupt increase in the concentration of dissolved inorganic P with increasing salinity was observed in the study region. Iron-bound P exhibited a distinct seasonal pattern with maximum values in the monsoon season when fresh water condition was prevailed in the estuary. As salinity increased, the percentage of iron-bound P decreased, while that of calcium-bound P and total sedimentary sulfur increased. C/P and N/P ratios were low which indicate that large amounts of organic matter enriched with P tend to accumulate in surface sediments. The high organic P contribution in the sedimentary P pool may indicate high organic matter load with incomplete mineralization, as well as comparatively greater percentage of humic substance and resistant organic compounds. Principal component analysis is employed to find the possible processes influencing the speciation of P in the study region and indicate the following processes: (1) the spatial and seasonal variations of calcium bound P and acid soluble organic P was mainly controlled by sediment texture and organic carbon content, (2) sediment redox conditions control the distribution of iron bound P and (3) the terrigenous input of organic P is a significant processes controlling total P content in surface sediments. The bioavailable P was very high in the surface sediments which on an average accounts for 59 % in the pre-monsoon, 65 % in the monsoon and 53 % in the post-monsoon seasons. The surface sediments act as a potential internal source of P in the Cochin estuary. PMID- 22843300 TI - Two year follow-up study of stressors and occupational stress in submariners. AB - BACKGROUND: Submariners are an occupational group within the Royal Navy (RN) who work in isolated and extreme conditions. This preliminary study forms part of a longitudinal study of occupational stress in the RN. AIMS: To compare stress prevalence in submariners with matched controls and to identify predictors of occupational stress in submariners over a 2 year follow-up period. METHODS: Participants completed a Work and Well-Being Questionnaire to measure occupational stressors and the General Health Questionnaire-12 (GHQ-12) to measure stress at time point 1, and a follow-up GHQ-12 2 years later. Demographically matched controls from the surface fleet of the RN were identified for each submariner. Regression models were developed for submariners and their controls to predict future stress at time point 2 using psychosocial predictors from time point 1. RESULTS: Participants comprised 144 submariners and 144 general service controls. There were no differences between submariners and their surface fleet counterparts in the prevalence of occupational stress. Nevertheless, different predictors for the development of stress were found between the two groups. For submariners, over-commitment and rank were the main predictors; whereas for controls, the predictors were length of service, body mass index and physical work. CONCLUSIONS: Submariners were not more likely to suffer from occupational stress than surface fleet controls in the RN. However, the psychosocial predictors of stress were significantly different for this RN specialist group, demonstrating the importance of developing individual models of stress for different occupational groups. PMID- 22843301 TI - Congenital glucose-galactose malabsorption: a novel deletion within the SLC5A1 gene. AB - Glucose-galactose malabsorption (GGM) is an autosomal recessive disease caused by mutations in the Na(+)/glucose cotransporter gene SLC5A1 (OMIM 182380, phenotype number 606824). Patients with GGM present with neonatal onset of severe life threatening diarrhoea and dehydration. We describe a 5-day-old girl with the typical clinical course of GGM. Our clinical diagnosis was confirmed by an abnormal chromatography of the stool and normal small bowel biopsies. Mutation analysis revealed a novel, homozygous deletion within exon 10 of the SLC5A1 gene, i.e. c.1107_1109 del AGT. PMID- 22843302 TI - Use of benzodiazepines in adults with schizophrenia is associated with increased mortality. PMID- 22843303 TI - Not just a walk in the park: efficacy to effectiveness for after school programs in communities of concentrated urban poverty. AB - This study examined a model for mental health consultation, training and support designed to enhance the benefits of publicly-funded recreational after-school programs in communities of concentrated urban poverty for children's academic, social, and behavioral functioning. We assessed children's mental health needs and examined the feasibility and impact of intervention on program quality and children's psychosocial outcomes in three after-school sites (n = 15 staff, 89 children), compared to three demographically-matched sites that received no intervention (n = 12 staff, 38 children). Findings revealed high staff satisfaction and feasibility of intervention, and modest improvements in observed program quality and staff-reported children's outcomes. Data are considered with a public health lens of mental health promotion for children in urban poverty. PMID- 22843304 TI - Diagnostic criteria of latent autoimmune diabetes in adults (LADA): a review and reflection. AB - Diabetes has become a major public health problem in China nowadays. There are almost 97 million diabetic patients nationwide. Latent autoimmune diabetes in adults (LADA) is a subtype of autoimmune diabetes. Although it has been reported for about 20 years, the diagnostic criteria of this disease remain controversial. The discussion mainly focused on serum autoantibodies, period of insulin need and age of diagnosis. Besides, beta cell function, metabolic parameters, genetic factors and cell immunity may also contribute to the formulation of the criteria. Here, we aim to review and discuss the diagnostic criteria of latent autoimmune diabetes in adults. PMID- 22843305 TI - Obesity and overweight prevalence and its association with undiagnosed hypertension in Shanghai population, China: a cross-sectional population-based survey. AB - The aim of this study was to determine the prevalence of overweight and obese subjects in the Shanghai population of China and its association with undiagnosed hypertension, by taking age, gender and place of residence (urban or suburban) into account. A cross-sectional population-based survey was conducted in 2007. The sample included 13,359 participants aged 15-69 years.Weight, height, and blood pressure were recorded, and information about gender, age and place of residence was obtained. Overweight and obesity prevalence were calculated by the body mass index (BMI) definition recommended by Working Group on Obesity in China (normal weight, 18.5-23.9 kg/m(2); overweight, 24-27.9 kg/m(2); obesity, >= 28 kg/m(2)). Undiagnosed hypertension was defined by China criteria in accord with that of WHO-ISH (subjects with systolic pressure >= 140 mmHg, and/or diastolic pressure >= 90 mmHg). Multiple logistic regression analyses were used to assess the association of overweight or obesity with undiagnosed hypertension by adjusting for age, gender and place of residence. The overall overweight, obesity, and undiagnosed hypertension prevalence were 27.6% (95% CI: 26.8-28.4), 6.6% (95% CI: 6.2-7.0), and 15.5% (95% CI: 14.9-16.1), respectively. Compared to normal weight subjects, the odds ratios (OR) for subjects who were overweight and had hypertension was 2.33 (95% CI: 2.10-2.59); that for obesity and hypertension was 4.27 (95% CI: 3.66-4.99). These data suggest that overweight and obesity prevalence and their association with undiagnosed hypertension are high in our study population. PMID- 22843307 TI - Endoscopically drained abdominal abscess compressing the sigmoid. AB - Intra-abdominal abscesses (IAA) complicate numerous medical and surgical pathologic conditions. Accurate radiological diagnosis combined with percutaneous or surgical drainage and antibiotics is the current standard of care for IAA. We herein report a case of a 52-year-old woman with a 10-day history of fever and abdominal pain. An intra-abdominal abscess externally compressing the sigmoid was revealed and successfully drained during colonoscopy. PMID- 22843308 TI - A coincidence of renal cell carcinoma and hematological malignancies. AB - Hematological malignancies with renal cell carcinoma (RCC) are rarely seen. We reported here two cases of coincidence of RCC with multiple myeloma (MM) and Hodgkin's disease (HD). A 69-year-old male patient with tumor that was located at the upper pole of left kidney was admitted to our clinic. Partial tumoral resection was performed and stage-I RCC was diagnosed after the histopathological examination of tumor. Moreover, he was diagnosed with IgG kappa stage-IIA MM as a result of bone marrow examination and serum immunofixation electrophoresis. Radiotherapy, combination chemotherapy, and autologous stem cell transplantation (ASCT) were performed. The patient is still alive who achieve a complete remission. A 53-year-old male patient suffered from cervical lymphadenopathy. He has a story of right radical nefrectomy that has been performed 4 years ago. Stage II-B lymphocyte-predominant HD was diagnosed. Combination chemotherapy was started, but relapse occurred 25 months later. ASCT was not planned due to cardiovascular problems and the patient died. Clinicians should keep in mind the coincidence of RCC with MM and HD. PMID- 22843306 TI - Comparative cost analysis of three different anesthesia methods in gynecological laparoscopic surgery. AB - In the current study, we assessed and evaluated the costs and benefits of three popular methods of general anesthesia practiced in our department for gynecological laparoscopic surgery in recent years. Sixty adult female patients who underwent elective gynecological laparoscopic surgery under general anesthesia were randomly divided into three groups: group V, group I and group C. In group V, anesthesia was induced intravenously with midazolam, remifentanil, propofol and vecuronium, and maintained with continuous infusion of propofol and remifentanil. In group I, anesthesia was intravenously induced with midazolam, fentanyl, propofol and vecuronium, and maintained with inhaled isoflurane and intravenous bonus of fentanyl. In group C, anesthesia was induced as in group I, but maintained with isoflurane inhalation combined with propofolremifentanil infusion. All patients received vecuronium for muscle relaxation. Perioperative incidences of complications and total anesthesia costs for patients in all groups were recorded. In addition, postoperative satisfaction of the patients was also noted, and similar outcomes of the satisfaction were reported in all 60 patients. Although there was no statistical significance among groups, the incidence of postoperative nausea and vomiting were higher in group C, and the rates of shivering and the needs for analgesics were higher in group V. Anesthesia costs in group I were the lowest. Therefore, it is concluded that the costs of anesthesia induced with midazolam, fentanyl, propofol, vecuronium, and maintained with isoflurane, fentanyl and vecuronium are cheapest, and there is no significant difference in patients' satisfaction and safety among the three above mentioned methods of anesthesia in our department. PMID- 22843309 TI - Reliability evaluation of alumina-blasted/acid-etched versus laser-sintered dental implants. AB - Step-stress accelerated life testing (SSALT) and fractographic analysis were performed to evaluate the reliability and failure modes of dental implant fabricated by machining (surface treated with alumina blasting/acid etching) or laser sintering for anterior single-unit replacements. Forty-two dental implants (3.75 * 10 mm) were divided in two groups (n=21 each): laser sintered (LS) and alumina blasting/acid etching (AB/AE). The abutments were screwed to the implants and standardized maxillary central incisor metallic crowns were cemented and subjected to SSALT in water. Use-level probability Weibull curves and reliability for a mission of 50,000 cycles at 200 N were calculated. Polarized light and scanning electron microscopes were used for failure analyses. The Beta (beta) value derived from use-level probability Weibull calculation of 1.48 for group AB/AE indicated that damage accumulation likely was an accelerating factor, whereas the beta of 0.78 for group LS indicated that load alone likely dictated the failure mechanism for this group, and that fatigue damage did not appear to accumulate. The reliability was not significantly different (p>0.9) between AB/AE (61 %) and LS (62 %). Fracture of the abutment and fixation screw was the chief failure mode. No implant fractures were observed. No differences in reliability and fracture mode were observed between LS and AB/AE implants used for anterior single-unit crowns. PMID- 22843311 TI - Low level laser effect after micro-marsupialization technique in treating ranulas and mucoceles: a case series report. AB - The aim of this preliminary study was to investigate the influence of low level laser therapy (LLLT) in alleviating pain caused by micro-marsupialization and the healing of oral ranulas and selected mucoceles. Eleven patients underwent micro marsupialization treatment associated with LLLT. The patients were irradiated with a 660-nm continuous wave from an indium-gallium-arsenide-phosphorous (InGaAsP) diode laser, at 100 mW, with a spot size on the tissue surface of 0.0283 cm(2) (irradiance = 3.53 W/cm(2)). Irradiation was carried out immediately following micro-marsupialization treatment, as well as at 24, 48, and 72 h post micro-marsupialization. All treated oral ranulas and selected mucoceles presented clinical healing. No evidence of recurrence could be identified during a mean of 11.0-month follow-up period. The use of InGaAsP diode lasers, within the parameters tested, appears to present a good alternative treatment to reduce pain and heal oral ranulas and selected mucoceles associated with micro marsupialization. PMID- 22843310 TI - Effect of low-level laser therapy after extraction of impacted lower third molars. AB - The aim of this study is to evaluate the effectiveness of the low-level laser therapy (LLLT) in the control of pain, swelling, and trismus associated with surgical removal of impacted lower third molars. Thirty patients were randomized into two treatment groups, each with 15 patients-group test (LLLT) and a group control (no-LLLT)-and were told to avoid any analgesics 12 h before the procedure. In group test, the 980-nm diode-laser (G-Laser 25 Galbiati, Italy) was applied, using a 600-MUm handpiece, intraorally (lingual and vestibular) at 1 cm from the involved area and extraoral at the insertion point of the masseter muscle immediately after surgery and at 24 h. The group control received only routine management. Parameters used for LLLT were: continuous mode, at 300 mW (0.3 W) for a total of 180 s (60 s * 3) (0.3 W * 180 s=54 J). Group test showed improvement in the interincisal opening and remarkable reduction of trismus, swelling and intensity of pain on the first and the seventh postoperative days. Although LLLT has been reported to prevent swelling and trismus following the removal of impacted third molars, some of these studies reported a positive laser effect while others did not. All references to the use of laser therapy in the postoperative management of third molar surgery employ different methodologies and, in some, explanations as to selection of their respective radiation parameters are not given. This study has demonstrated that LLLT, with these parameters, is useful for the reduction of postoperative discomfort after third molar surgery. PMID- 22843312 TI - Characterization of genes encoding prolactin and prolactin receptors in starry flounder Platichthys stellatus and their expression upon acclimation to freshwater. AB - This study aims to investigate the genes encoding prolactin (PRL) and prolactin receptors (PRLR) and their tissue-specific expression in starry flounder Platichthys stellatus. Starry flounder PRL gene consisting of five exons encodes an ORF of 212 amino acid residue comprised of a putative signal peptide of 24 amino acids and a mature protein of 188 amino acids. It showed amino acid identities of 73 % with tuna Thunnus thynnus, 71 % with black porgy Acanthopagrus schlegelii, 69 % with Nile tilapia Oreochromis niloticus, 64 % with pufferfish Takifugu rubripes, 63 % with rainbow trout Oncorhynchus mykiss, and 60 % with mangrove rivulus Kryptolebias marmoratus. Phylogenetic analysis of piscine PRLs also demonstrated a similarity between starry flounder and other teleosts but with a broad distinction from non-teleost PRLs. PRLR gene consists of eight exons encoding a protein of 528 amino acid residues. It showed a similarity to the PRLR2 subtype as reflected by amino acid identities of 54 % with A. schlegelii, 48.1 % with K. marmoratus, 46.3 % with tilapia O. mossambicus, and 46.1 % with O. niloticus PRLR2 as compared to PRLR1 isoform having less than 30 % identities. While mRNA transcript corresponding to PRL was detected only from the pituitary, most of PRLR mRNA was detected in the gill, kidney, and intestine, with a small amount in the ovary. The level of PRL transcript progressively increased during 6 days of acclimation to freshwater and then decreased but stayed higher than that of seawater at 60 days of acclimation. An opposite pattern of changes including a decrease at the beginning of the acclimation but a slight increase in the level osmolality was found as adaptation continued. The results support the osmoregulatory role of PRL signaling in starry flounder. PMID- 22843313 TI - Cloning and expression analysis of follicle-stimulating hormone and luteinizing hormone receptor during the reproductive cycle in Korean rockfish (Sebastes schlegeli). AB - Full-length cDNA sequences encoding the receptors for follicle-stimulating hormone (FSHR) and luteinizing hormone (LHR) were isolated from ovary of Korean rockfish (Sebastes schlegeli) using reverse transcription-polymerase chain reaction (PCR) and rapid amplification of cDNA ends procedures. The cDNA of the KrFSHR encodes a predicted protein of 703 amino acids that showed the greatest homology with European seabass (Dicentrarchus labrax) (78 %) and gilthead seabream (Sparus aurata) (73 %). The cDNA of the KrLHR encodes a predicted protein of 703 amino acids and exhibited the highest homology with European seabass (Dicentrarchus labrax) (79 %) and gilthead seabream (Sparus aurata) (76 %). Besides the gonads, expressions of GTHRs mRNA were also obtained in extra gonadal tissues. Seasonal changes in the gonads expression profiles of KrGTHRs mRNA were examined by quantitative real-time PCR, and the present results suggest that levels for KrFSHR mRNA increase during gonadal growth, whereas KrLHR shows high levels during the late gamete generation period. Our study provides molecular characterization of the GTHRs and expressions profile during reproductive cycles, reinforcing previous knowledge of GTHRs important role in the reproductive endocrine regulation of Korean rockfish. PMID- 22843314 TI - Evaluation of a DNA vaccine candidate co-expressing GP3 and GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) with interferon alpha/gamma in immediate and long-lasting protection against HP-PRRSV challenge. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has become one of the most economically important diseases to the global pork industry. Current vaccination strategies only provide a limited protective efficacy. In this study, a DNA vaccine, pVAX1((c))-alpha-gamma-GP35, co-expressing GP3 and GP5 of PRRSV with interferon alpha/gamma was constructed, and its immediate and long-lasting protection against highly pathogenic PRRSV (HP-PRRSV) challenge were examined in pigs. For immediate protection, the results showed that pVAX1((c))-alpha-gamma GP35 could provide partially protective efficacy, which was similar to the pVAX1((c))-alpha-gamma (expressing interferon alpha/gamma). For long-lasting protection, pigs inoculated with pVAX1((c))-alpha-gamma-GP35 developed significantly higher PRRSV-specific antibody response, T cell proliferation, IFN gamma, and IL-4, than those vaccinated with pVAX1((c))-GP35 (expressing GP3 and GP5 of PRRSV). Following homologous challenge with HP-PRRSV strain SD-JN, pigs inoculated with pVAX1((c))-alpha-gamma-GP35 showed almost no clinical signs, no lung lesions, and significantly lower viremia, as compared to those in pVAX1((c)) GP35 group. It indicated that pVAX1((c))-alpha-gamma-GP35 could induce enhanced immune responses and provide both immediate and long-lasting protection against HP-PRRSV challenge in pigs. The DNA vaccine pVAX1((c))-alpha-gamma-GP35 might be an attractive candidate vaccine for the prevention and control of HP-PRRSV infections. PMID- 22843318 TI - Impending megacolon: small bowel distension as a predictor of toxic megacolon in ulcerative colitis. PMID- 22843315 TI - Caring for the country: fatigue, sleep and mental health in Australian rural paramedic shiftworkers. AB - This study investigated sleep quality, fatigue, mental health and physical activity in rural paramedic shiftworkers. Although limited, previous studies have associated high fatigue levels and poorer health in this sector with shiftwork rostering and occupational demands. A modified version of the Standard Shiftwork Index was completed by 150 paramedics (117 male and 31 females) from rural Victoria. Single sample t tests found significantly higher levels of fatigue, depression, anxiety, and stress, and significantly poorer sleep quality than reference samples. Paramedics also reported less physical activity than community samples. By regression analysis, sleep quality explained the greatest amount of variance in fatigue scores, followed by depression and age. No gender differences in levels of depression or fatigue were found. Consistent with an earlier study of metropolitan paramedics based on the same methodology, findings suggest rural ambulance paramedic shiftworkers are at particular risk for increased levels of fatigue and depression (regardless of age or gender) and poor quality sleep. Organisational intervention was suggested. PMID- 22843316 TI - Association of environmental traits with the geographic ranges of ticks (Acari: Ixodidae) of medical and veterinary importance in the western Palearctic. A digital data set. AB - We compiled information on the distribution of ticks in the western Palearctic (11 degrees W, 45 degrees E; 29 degrees N, 71 degrees N), published during 1970 2010. The literature search was filtered by the tick's species name and an unambiguous reference to the point of capture. Records from some curated collections were included. We focused on tick species of importance to human and animal health, in particular: Ixodes ricinus, Dermacentor marginatus, D. reticulatus, Haemaphysalis punctata, H. sulcata, Hyalomma marginatum, Hy. lusitanicum, Rhipicephalus annulatus, R. bursa, and the R. sanguineus group. A few records of other species (I. canisuga, I. hexagonus, Hy. impeltatum, Hy. anatolicum, Hy. excavatum, Hy. scupense) were also included. A total of 10,280 records was included in the data set. Almost 42 % of published references are not adequately referenced (and not included in the data set), host is reported for only 61 % of records and a reference to time of collection is missed for 84 % of published records. Ixodes ricinus accounted for 44.3 % of total records, with H. marginatum and D. marginatus accounting for 7.1 and 8.1 % of records, respectively. The lack of homogeneity of the references and potential pitfalls in the compilation were addressed to create a digital data set of the records of the ticks. We attached to every record a coherent set of quantitative descriptors for the site of reporting, namely gridded interpolated monthly climate and remotely sensed data on vegetation (NDVI). We also attached categorical descriptors of the habitat: a standard classification of land biomes and an ad hoc classification of the target territory from remotely sensed temperature and NDVI data. A descriptive analysis of the data revealed that a principal components reduction of the environmental (temperature and NDVI) variables described the distribution of the species in the target territory. However, categorical descriptors of the habitat were less effective. We stressed the importance of building reliable collections of ticks with specific references as to collection point, host and date of capture. The data set is freely downloadable. PMID- 22843317 TI - EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. AB - Epidermal growth factor receptor (EGFR) mutations play a predictive role in advanced stages of non-small-cell lung cancer (NSCLC) patients. We conducted this study in order to assess EGFR status in a Portuguese population and its role in NSCLC patients' outcomes. Patients were submitted to EGFR assessment by high resolution melting and/or direct sequencing. Kaplan-Meier curve was used to assess overall survival and progression-free survival (PFS). Two hundred forty eight out of 322 participants were assessed for EGFR status. Forty-two patients (16.9 %) presented EGFR-mutated status: one patient (2.4 %) presented exon 18; 21 patients (50 %), exon 19; one patient (2.4 %), exon 20; and 18 patients (45.2 %), exon 21 mutations, p < 0.001. PFS was not assessed (n.a.) for patient with exon 18 mutation, and for the other patients with mutations, it was 7 months (3.96 10.03) (exon 19), <1 month (exon 20), and 7 months (0-14.2) (exon 21) (p = 0.027). Overall survival (OS) was 11 months (exon 18), 11 months (1-18) (exon 19), 1 month (exon 20), and 7.5 months (2-70) (exon 21) (p = n.a). This study suggests that the EGFR mutation is herein observed in a higher proportion than expected for a Caucasian population, and OS is a little less than that published in the literature. PMID- 22843321 TI - "Every disease...man can get can start in this cab": focus groups to identify south Asian taxi drivers' knowledge, attitudes and beliefs about cardiovascular disease and its risks. AB - South Asian (SA) taxi drivers potentially possess a double epidemiologic risk for cardiovascular disease (CVD) due to their ethnicity and occupation. This study investigates SA taxi drivers' knowledge, attitudes, beliefs about general health, CVD and approaches to reduce CVD risk. Five focus groups were conducted with 31 SA taxi drivers in the participants' primary language (Bengali, Hindi, Urdu or Punjabi). Audio-recordings of the sessions were transcribed, translated and entered into ATLAS.ti 6.2 for coding and analysis. SA drivers in an urban setting perceive themselves to be at high risk for CVD because of high work-related stress, physical inactivity, poor diet and poor health care access. Participants attributed their occupation to increasing risk for heart disease; none believed that being SA increased their risk. Interventions to lower CVD risk among SA taxi drivers should be multi-level and involve the individual drivers and the taxi industry. PMID- 22843319 TI - Role of platelets in NOX2 activation mediated by TNFalpha in heart failure. AB - Tumor necrosis factor (TNF) alpha may contribute to the deterioration of cardiovascular function in heart failure (HF) through various mechanisms, including the generation of reactive oxygen species (ROS). NADPH oxidase is the major source of ROS in the vascular system, but the interplay between TNFalpha and NADPH oxidase activation is elusive. As platelets possess NADPH oxidase enzyme, they represent an important tool to investigate the interplay between NADPH oxidase and TNFalpha in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNFalpha were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNFalpha with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNFalpha in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNFalpha, at concentrations commonly found in HF patients' peripheral circulation, activates platelet NOX2. Thus, TNFalpha increases ROS production and the extracellular levels of NOX2. These phenomena are inhibited by the NOX2-specific blocking peptide gp91ds-tat. The study provides evidence that circulating NOX2, as well as the activation of NOX2 on platelets, is increased in HF likely as a consequence of the underlying inflammatory process. PMID- 22843322 TI - Age and glycemic control among low-income Latinos. AB - Younger adult patients with diabetes often have poorer glycemic control (HbA1c) than older patients. It is not known if this relationship holds true in the Latino population. Objective was to explore the relationship between age and HbA1c in a Mexican American population and what plausible factors might mediate this relationship. We analyzed data from 387 patients with diabetes self identified as Mexican American recruited as a part of a cross-sectional study of safety net patients in two cities. Patients completed questionnaires and their last HbA1c was extracted from the medical record. We conducted multivariate regression analyses and Baron and Kenny tests of mediation. Participants were young with mean age of 53 +/- 12 years. Younger age was associated with a higher HbA1c and having a higher fat diet. High fat diet partially mediated the relationship between age and HbA1c (p < 0.001 to p < 0.01). Age's indirect effect on HbA1c through diet was significant (Sobel = -2.44, p = 0.01). Younger Mexican American patients had higher HbA1c compared to older patients. Having a diet high in fat partially explained this relationship. Future epidemiological studies are needed to understand the multifaceted relationship between age and glycemic control. PMID- 22843320 TI - Glycosylation potential of human prostate cancer cell lines. AB - Altered glycosylation is a universal feature of cancer cells and altered glycans can help cancer cells escape immune surveillance, facilitate tumor invasion, and increase malignancy. The goal of this study was to identify specific glycoenzymes, which could distinguish prostate cancer cells from normal prostatic cells. We investigated enzymatic activities and gene expression levels of key glycosyl- and sulfotransferases responsible for the assembly of O- and N-glycans in several prostatic cells. These cells included immortalized RWPE-1 cells derived from normal prostatic tissues, and prostate cancer cells derived from metastasis in bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP). We found that all cells were capable of synthesizing complex N-glycans and O-glycans with the core 1 structure, and each cell line had characteristic biosynthetic pathways to modify these structures. The in vitro measured activities corresponded well to the mRNA levels of glycosyltransferases and sulfotransferases. Lectin and antibody binding to whole cells supported these results, which form the basis for the development of tumor cell-specific targeting strategies. PMID- 22843327 TI - Do different styles of antismoking ads influence the types of smokers who call quitlines? AB - This study examined the relationship between television antismoking advertisements and the proportion of smokers who call a smokers' quitline who are ready to quit or have high confidence in quitting. The primary data of interest came from completed intake interviews of smokers. Using a generalized linear model, we modeled the proportion of Quitline callers who are ready to quit and/or have high confidence in quitting. The primary explanatory variable was monthly target audience rating points (TARPs) for antismoking advertisements, a measure of broadcast media exposure, obtained from the state's media buyer. The proportions of callers ready to quit and with high confidence in quitting were negatively associated with total TARPs. This result, over all ad types, was driven by why to quit-graphic ads. These results suggest that why to quit-graphic ads influence smokers who are less ready to quit or have lower confidence they can quit, likely new quitters, to call the Quitline. PMID- 22843328 TI - 'I'm not doing this for me': mothers' accounts of creating smoke-free homes. AB - This article explores mothers' narratives of changing home smoking behaviours after participating in an intervention (Reducing Families' Exposure to Smoking in the Home [REFRESH]) aimed at reducing families' exposure to secondhand smoke (SHS) in homes in Scotland. An analysis of qualitative findings illuminates quantitative changes in levels of SHS exposure. Prospective quantitative and qualitative data were drawn from 21 smoking mothers with at least one child under 6 years. Quantitative change was measured by home air quality, i.e. fine particulate matter <2.5MUg (PM(2.5)). These measurements guided the organization of mothers into categories of change (smoke-free home at baseline [SFB], smoke free home at final, some change and no change [NC]). Qualitative data from 17 mothers with non-SFB were analysed thematically within and across these categories. Three comparative case studies illustrate the varying changes made, barriers to change and how mothers valued such changes. The outcomes varied post intervention, with homes smoke-free, partially smoke-free or making NC. The changes in home smoking behaviour were incremental, yet beneficial to reducing SHS exposure, and related to the nature of the restrictions and personal circumstances in the home pre-intervention. Across all change categories, mothers valued the changes they had made and expressed an intention to increase the changes. PMID- 22843326 TI - A quantitative real-time PCR method using an X-linked gene for sex typing in pigs. AB - At present, a wide range of molecular sex-typing protocols in wild and domestic animals are available. In pigs, most of these methods are based on PCR amplification of X-Y homologous genes followed by gel electrophoresis which is time-consuming and in some cases expensive. In this paper, we describe, for the first time, a SYBR green-based quantitative real-time PCR (qPCR) assay using an X linked gene, the glycoprotein M6B, for genetic sexing of pigs. Taking into account the differences in the glycoprotein M6B gene copy number between genders, we determine the correct sex of 54 pig samples from either diaphragm or hair follicle from different breeds using the 2(-DeltaDeltaCT) method for relative quantification. Our qPCR assay represents a quick, inexpensive, and reliable tool for sex determination in pigs. This new protocol could be easily adapted to other species in which the sex determination was required. PMID- 22843324 TI - Molecular characterization and phylogenetic analysis of porcine epidemic diarrhea virus (PEDV) samples from field cases in Fujian, China. AB - The outbreak of porcine epidemic diarrhea virus (PEDV) has been a big problem of swine industry in China in recent years. In this study, we investigated molecular diversity, phylogenetic relationships, and protein characterization of Fujian field samples with other PEDV reference strains. Sequence analysis of the S1 and sM genes showed that each sample had unique characteristics, and the sample P55 may be differentiated from the others by the unique deletions and insertions of sM gene. Phylogenetic analysis based on S1 or sM gene, which have high levels of variations, indicated that each sample was related to the specific reference strain, and this finding was consistent with the protein characterization prediction analysis. The study is useful to better understand the prevalence of PEDV and its prevention and control in Fujian. PMID- 22843323 TI - Genetic variation and phylogenetic analysis of porcine circovirus type 2 infections in central China. AB - Porcine circovirus type 2 (PCV2) infection causes postweaning multisystemic wasting syndrome and porcine circovirus-associated diseases in many regions. A total of 77 sequences, including 31 sampled from Henan province of China, were retrieved from GenBank and subjected to amino acid variation and phylogenetic analyses. The two PCV genotypes prevailing in Henan were PCV-2a and PCV-2b with PCV-2b accounting for 93.5 % (29/31) of the Henan isolates. The 31 Henan isolates all shared between 92.7 and 100 % sequence similarity. Amino acid variation analysis of the capsid protein revealed that Henan PCV2 strains tended to accumulate more substitutions within epitopic regions-a substitution pattern consistent with host immune system-mediated selection of virus immune escape variants. The analysed PCV sequences carry evidence of at least six unique recombination events. Selective pressure analysis of the relative recombination free ORF2 sequences of these viruses revealed evidence of sites that are likely evolving in response to host-driven immune pressures-a finding that coupled with information on the prevalent diversity in Henan PCV2 isolates of known immunoreactive genomic loci will aid in future studies aiming to assess the evolutionary responses of PCV2 in China to the widespread deployment of anti-PCV vaccines in the country. PMID- 22843329 TI - Caught in a dilemma: why do non-smoking women in China support the smoking behaviors of men in their families? AB - Intimate relationships influence family members' health practices. Although cigarette smoking in China is predominantly a male behavior, (non-smoking) women's roles should be taken into account for the development of home-smoking interventions. Drawing on ethnographic interviews with 22 families in a rural area of China, this article explores non-smoking women's attitudes towards male smoking. The findings suggest that women's ability to influence male behavior is largely determined by culturally defined gender roles, underpinned by ideologies of familism and collectivism. Despite concerns about the adverse results of smoking to their family members and households, non-smoking women ultimately maintain the (male) smokers' argument that smoking plays an important role in construction and maintenance of intra- and extra-family relationships. By accepting male smoking and men's engagement in the social practice of smoking and cigarette exchanges, women maintain their identities as supportive wives, filial daughters/in-law and responsible family members who pursue family collective interests at the expense of their own personal beliefs. Future smoking control initiatives that target non-smoking women to influence male smoking should take into account the women's overarching need to maintain the status and harmony of their families. PMID- 22843325 TI - Strategies of bacterial over expression of membrane transporters relevant in human health: the successful case of the three members of OCTN subfamily. AB - The OCTN subfamily includes OCTN1, 2, and 3 which are structurally and functionally related. These transporters are involved in maintenance of the carnitine homeostasis, which is essential in mammals for fatty acid beta oxidation, VLDL assembly, post-translational modifications, and other essential functions. Indeed, defects of these transporters lead to severe pathologies. OCTN1 and OCTN2 are expressed in many human tissues, while OCTN3 gene has been identified only in mouse and rat. The transporters mediate transport of carnitine and other substrates with different efficiencies and mechanisms. In order to over express the three proteins, a screening of many combinations of E. coli strains with plasmid constructs has been conducted. Only Rosetta(DE3) or Rosettagami2(DE3) gave significant expression. Higher protein amounts were firstly obtained with pET-41a(+) or pGEX-4T1 carrying fusion protein tags which required additional purification passages. Vectors carrying only a 6His tag, suitable for single passage purification, were preferred even though they lead to lower initial expression levels. Expressions were then increased optimizing several critical parameters. hOCTN1 was obtained with pH6EX3 in RosettaGami2(DE3)pLysS. hOCTN2 and mOCTN3 were obtained using pET-21a(+) in Rosetta(DE3). In particular, hOCTN2 was expressed only after codon bias, substituting the second triplet CGG with AAA (R2K mutant). The best growth conditions for hOCTN1 and mOCTN3 were 28 degrees C and 6 h of induction, while 4 h of induction for hOCTN2R2K. The proteins collected in the insoluble fraction of cell lysates, solubilized with sarkosyl, were purified by Ni-chelating chromatography. Final yield was 2.0, 3.0, or 3.5 mg/l of cell culture for mOCTN3, hOCTN1, or hOCTN2R2K. The data indicated that, in spite of the close evolutionary relations, several factors play different critical roles in bacterial expression of the three proteins, thus general criteria cannot be underlined. However, the strategy of dealing with related proteins revealed to be finally successful for over expressing all the three subfamily members. PMID- 22843333 TI - Lung ultrasound imaging in haemodialysis. PMID- 22843334 TI - The emergency physician and the prompt management of severe hyperkalemia. PMID- 22843332 TI - Differential routes of carboplatin administration influence lymphocyte apoptosis in retroperitoneal lymph nodes. AB - We aimed to investigate carboplatin distribution in retroperitoneal lymph nodes and its effect on lymphocyte apoptosis following intravenous (IV), intra-arterial (IA), and retroperitoneal (RP) administration. Sixty-three healthy female canines were randomly assigned as IV, IA, or RP administration of carboplatin. At 0.5, 1, 2, 4, 8, 24, and 72 h after carboplatin treatment, retroperitoneal lymph nodes (n = 6 at each time point) were collected and high-performance liquid chromatography was employed to measure the carboplatin content. The differences in carboplatin pharmacokinetics of the three administration routes were compared. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) was carried out to measure the lymphocyte apoptosis of the retroperitoneal lymphocytes. The peak concentration of carboplatin in plasma following IV administration was the highest among all approaches; as to the peak time, RP administration was longer than the other two administrations. Concentration for carboplatin in the retroperitoneal lymph node was highest following IA administration at early time points, but at higher time points, concentration was significantly higher following RP administration. Penetration of carboplatin into the retroperitoneal space was higher following RP administration. Following RP administration, the level of apoptotic lymphocytes in the retroperitoneal lymph nodes was significantly greater than either IV or IA. Following RP administration of carboplatin, the concentration, area under the curve of carboplatin and the number of apoptotic lymphocytes were significantly higher than those following IV and IA administration. This suggests that RP administration of carboplatin is beneficial for the treatment of retroperitoneal lymph node metastasis. PMID- 22843331 TI - Vaccination with the repeat beta-hCG C-terminal peptide carried by heat shock protein-65 (HSP65) for inducing antitumor effects. AB - The beta-subunit of human chorionic gonadotropin (beta-hCG) is ectopically expressed in various types of cancer and has been utilized as an antigenic target in anti-cancer vaccines. In view of the low immunogenicity of this self-peptide, we designed a method based on the isocaudamer technique to generate 14 tandem repeats of the 10-residue sequence X of beta-hCG (109-118). These tandemly repeated copies were then combined with beta-hCG C-terminal 37 peptides (CTP37) and finally fused to mycobacterial heat-shock protein 65 (HSP65) to construct a fusion protein HSP65-X14-betahCGCTP37 as an immunogen. In this study, BALB/c female mice were immunized via subcutaneous injection of the designed protein. Humoral immune and cellular immune responses were effectively elicited. A high titer of anti-beta-hCG antibody was detected in immunized mice sera by enzyme linked immunosorbent assay and verified by Western blot analysis. The fusion protein, HSP65-X14-beta-hCGCTP37, effectively inhibited the growth of Ehrlich ascites carcinoma in mice. These results suggest that HSP65-X14-betahCGCTP37 may be an effective tumor vaccine, and the use of multiple tandem repeats of a certain epitope is an effective method to overcome the low immunogenicity of self peptide antigens. PMID- 22843330 TI - D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. AB - D-Penicillamine (3,3-dimethyl-D-cysteine; DP) is an FDA-approved redox-active D cysteine-derivative with antioxidant, disulfide-reducing, and metal chelating properties used therapeutically for the control of copper-related pathology in Wilson's disease and reductive cystine-solubilization in cystinuria. Based on the established sensitivity of metastatic melanoma cells to pharmacological modulation of cellular oxidative stress, we tested feasibility of using DP for chemotherapeutic intervention targeting human A375 melanoma cells in vitro and in vivo. DP treatment induced caspase-dependent cell death in cultured human metastatic melanoma cells (A375, G361) without compromising viability of primary epidermal melanocytes, an effect not observed with the thiol-antioxidants N acetyl-L-cysteine (NAC) and dithiothreitol. Focused gene expression array analysis followed by immunoblot detection revealed that DP rapidly activates the cytotoxic unfolded protein response (UPR; involving phospho-PERK, phospho eIF2alpha, Grp78, CHOP, and Hsp70) and the mitochondrial pathway of apoptosis with p53 upregulation and modulation of Bcl-2 family members (involving Noxa, Mcl 1, and Bcl-2). DP (but not NAC) induced oxidative stress with early impairment of glutathione homeostasis and mitochondrial transmembrane potential. SiRNA-based antagonism of PMAIP1 expression blocked DP-induced upregulation of the proapoptotic BH3-only effector Noxa and prevented downregulation of the Noxa antagonist Mcl-1, rescuing melanoma cells from DP-induced apoptosis. Intraperitoneal administration of DP displayed significant antimelanoma activity in a murine A375 xenograft model. It remains to be seen if melanoma cell-directed induction of UPR and apoptosis using DP or improved DP-derivatives can be harnessed for future chemotherapeutic intervention. PMID- 22843335 TI - Midline mystery. PMID- 22843337 TI - Symbolic loss in American adolescents: mourning in teenage cinema. AB - I argue that the changing economic conditions in the contemporary world have caused a shift in religious and cultural values among American youth. This shift in cultural and religious values and practices is interpreted in this essay as an experience of symbolic loss, or a loss of socially shared historic ideals and symbols (Homans in Childhood and selfhood: essays on tradition, religion, and modernity in the psychology of Erik H. Erikson. Bucknell University Press, Lewisburg, pp 189-228, 2008). I argue that the symbolic loss among American youth can most clearly be seen in the contemporary horror film genre in America. I assess the popularity of this genre, its value structure and the psychosocial consequences of the symbolic losses experienced by American youth as witnessed in this film genre. I suggest two ways in which adolescents and adults can work to re-create cultural and religious meanings that both foster courage and serenity in the face of the profound despair that accompanies the rage and paranoia in the contemporary horror film genre. PMID- 22843338 TI - Not in isolation: how history can inform the debate on professionalization. AB - As ethics services have become more integrated into healthcare organizations, the controversy regarding the possible professionalization of healthcare ethics practices has re-emerged. Some of the debate focuses on whether healthcare ethics practice possesses the attributes of a 'true profession.' This study examines the history of the professions and the relevance of this historical material, as well as sociological insights, for contemporary concerns. It explores whether the mismatch between traditional models of professional knowledge and the knowledge foundation for healthcare ethics is at the core of these concerns. It also takes the position that given the role healthcare ethics plays in assisting patients, families, healthcare providers, and others with complex moral decisions it is important to work towards developing standards that can be used to guide and evaluate the work. PMID- 22843342 TI - Testing for evidence of an X-linked genetic basis for a greater proportion of males with high cognitive ability. AB - X-linked genetic differences between male and females have been posited to cause greater variance in cognitive ability in males. Males with only one X chromosome tend to express the genes on the X chromosome more fully than females, who express an "average" of their two X chromosomes due to X-inactivation. Greater variability in expression of genes on the X chromosome could account for greater variability in male cognitive ability. This would affect both the high and low ends of the cognitive ability distribution, but the possibility of high-end impact has drawn the most attention and controversy. The objective of this paper was to outline a method to test for empirical evidence that greater X-chromosomal variation in males is associated with greater variation in cognitive ability in males at the high end of the distribution. The method utilizes exogenous variation in the maternal X chromosome of twins to test the effect of sex on within-pair variation. We applied this method to g composite test scores at age 10 using data from the Twins Early Development Study. Twin-pair zygosity was used as an instrument reflecting whether twins had different maternal X chromosomes. We estimated differences in the association between variation in the maternal X chromosome in males and females and within-pair variation in test scores using a difference in differences specification of a linear regression model. We found no evidence supporting the proposition that the "averaging" effect of X-inactivation in females resulted in greater variation in male cognitive ability. There was evidence of differential selection for cognitive ability in the sample, however, indicating that the value of our study was primarily to introduce a novel method of addressing the question. PMID- 22843339 TI - Development of a new polyclonal antibody for the determination of polychlorinated biphenyls in indoor air by ic-ELISA. AB - A new polyclonal antibody (pAb) was prepared and used for the determination of polychlorinated biphenyls (PCBs) in air samples to promote the application of immunoassay technology in the determination of PCBs. Three PCB congeners immunogen mixture was used to stimulate immune responses in rabbits. The specific pAb to PCBs was obtained and used to develop an indirect competitive enzyme linked immunosorbent assay (ic-ELISA). A standard curve for Aroclor 1248 was prepared using concentrations ranging from 0.1 to 100 MUg L(-1). The average IC50 value was 16.21 MUg L(-1) and the limit of detection at 10% inhibition (IC90) was 0.069 MUg L(-1). The entire procedure was then evaluated using spiked air samples. The recoveries of Aroclor 1248 at various spiking levels in the air samples ranged from 84 to 113%, with relative standard deviations of 3 to 6%. Under optimum conditions, the cross-reactivity profiles of the assays were obtained using three selected congeners, four Aroclor products, and other structurally related compounds of PCBs. The assays were found to be highly specific for PCB congeners and Aroclors 1248 and 1242. The air samples were then analyzed using gas chromatography coupled with high-resolution mass spectrometry to confirm the ic-ELISA results. The attained results demonstrated that the proposed method was an effective and inexpensive technique for the PCBs determination in air samples. PMID- 22843340 TI - A rapid decrease in temperature induces latewood formation in artificially reactivated cambium of conifer stems. AB - BACKGROUND AND AIMS: Latewood formation in conifers occurs during the later part of the growing season, when the cell division activity of the cambium declines. Changes in temperature might be important for wood formation in trees. Therefore, the effects of a rapid decrease in temperature on cellular morphology of tracheids were investigated in localized heating-induced cambial reactivation in Cryptomeria japonica trees and in Abies firma seedlings. METHODS: Electric heating tape and heating ribbon were wrapped on the stems of C. japonica trees and A. firma seedlings. Heating was discontinued when 11 or 12 and eight or nine radial files of differentiating and differentiated tracheids had been produced in C. japonica and A. firma stems, respectively. Tracheid diameter, cell wall thickness, percentage of cell wall area and percentage of lumen area were determined by image analysis of transverse sections and scanning electron microscopy. KEY RESULTS: Localized heating induced earlier cambial reactivation and xylem differentiation in stems of C. japonica and A. firma as compared with non-heated stems. One week after cessation of heating, there were no obvious changes in the dimensions of the differentiating tracheids in the samples from adult C. japonica. In contrast, tracheids with a smaller diameter were observed in A. firma seedlings after 1 week of cessation of heating. Two or three weeks after cessation of heating, tracheids with reduced diameters and thickened cell walls were found. The results showed that the rapid decrease in temperature produced slender tracheids with obvious thickening of cell walls that resembled latewood cells. CONCLUSIONS: The results suggest that a localized decrease in temperature of stems induces changes in the diameter and cell wall thickness of differentiating tracheids, indicating that cambium and its derivatives can respond directly to changes in temperature. PMID- 22843341 TI - Gibberellin is required for the formation of tension wood and stem gravitropism in Acacia mangium seedlings. AB - BACKGROUND AND AIMS: Angiosperm trees generally form tension wood on the upper sides of leaning stems. The formation of tension wood is an important response to gravitational stimulus. Gibberellin appears to be involved in the differentiation of secondary xylem, but it remains unclear whether gibberellin plays a key role in the formation of tension wood and plant gravitropism. Therefore, a study was designed to investigate the effects of gibberellin and of inhibitors of the synthesis of gibberellin, namely paclobutrazole and uniconazole-P, on the formation of tension wood and negative stem gravitropism in Acacia mangium seedlings. METHODS: Gibberellic acid (GA(3)), paclobutrazole and uniconazole-P were applied to seedlings via the soil in which they were growing. Distilled water was applied similarly as a control. Three days after such treatment, seedlings were tilted at an angle of 45 degrees from the vertical, and samples of stems were collected for analysis 2 weeks, 2 months and 6 months after tilting. The effects of treatments on the stem recovery degree (Ro) were analysed as an index of the negative gravitropism of seedlings, together the width of the region of tension wood in the upper part of inclined stems. KEY RESULTS: It was found that GA(3) stimulated the negative gravitropism of tilted seedling stems of A. mangium, while paclobutrazole and uniconazole-P inhibited recovery to vertical growth. Moreover, GA(3) stimulated the formation of tension wood in tilted A. mangium seedlings, while paclobutrazole and uniconazole-P strongly suppressed the formation of tension wood, as assessed 2 weeks after tilting. CONCLUSIONS: The results suggest that gibberellin plays an important role at the initial stages of formation of tension wood and in stem gravitropism in A. mangium seedlings in response to a gravitational stimulus. PMID- 22843343 TI - Pulmonary hypertension in an infant treated with ibuprofen. AB - Presence of symptomatic patent ductus arteriosus is common in small preterm infants and ibuprofen is commonly used for its medical closure. While efficacy is comparable to indomethacin, there are few case reports of severe hypoxemia and pulmonary hypertension following prophylactic ibuprofen administration. Cumulative dose effects and chemical composition may be important considerations. Possible mechanisms of occurrence of this complication in a preterm infant are discussed. PMID- 22843346 TI - The roles of categorical and coordinate spatial relations in recognizing buildings. AB - Categorical spatial information is considered more useful for recognizing objects, and coordinate spatial information for guiding actions--for example, during navigation or grasping. In contrast with this assumption, we hypothesized that buildings, unlike other categories of objects, require both categorical and coordinate spatial information in order to be recognized. This hypothesis arose from evidence that right-brain-damaged patients have deficits in both coordinate judgments and recognition of buildings and from the fact that buildings are very useful for guiding navigation in urban environments. To test this hypothesis, we assessed 210 healthy college students while they performed four different tasks that required categorical and coordinate judgments and the recognition of common objects and buildings. Our results showed that both categorical and coordinate spatial representations are necessary to recognize a building, whereas only categorical representations are necessary to recognize an object. We discuss our data in view of a recent neural framework for visuospatial processing, suggesting that recognizing buildings may specifically activate the parieto-medial-temporal pathway. PMID- 22843344 TI - Three structural representatives of the PF06855 protein domain family from Staphyloccocus aureus and Bacillus subtilis have SAM domain-like folds and different functions. AB - Protein domain family PF06855 (DUF1250) is a family of small domains of unknown function found only in bacteria, and mostly in the order Bacillales and Lactobacillales. Here we describe the solution NMR or X-ray crystal structures of three representatives of this domain family, MW0776 and MW1311 from Staphyloccocus aureus and yozE from Bacillus subtilis. All three proteins adopt a four-helix motif similar to sterile alpha motif (SAM) domains. Phylogenetic analysis classifies MW1311 and yozE as functionally equivalent proteins of the UPF0346 family of unknown function, but excludes MW0776, which likely has a different biological function. Our structural characterization of the three domains supports this separation of function. The structures of MW0776, MW1311, and yozE constitute the first structural representatives from this protein domain family. PMID- 22843345 TI - Crystal structure of a catalytically active GG(D/E)EF diguanylate cyclase domain from Marinobacter aquaeolei with bound c-di-GMP product. AB - Recent studies of signal transduction in bacteria have revealed a unique second messenger, bis-(3'-5')-cyclic dimeric GMP (c-di-GMP), which regulates transitions between motile states and sessile states, such as biofilms. C-di-GMP is synthesized from two GTP molecules by diguanylate cyclases (DGC). The catalytic activity of DGCs depends on a conserved GG(D/E)EF domain, usually part of a larger multi-domain protein organization. The domains other than the GG(D/E)EF domain often control DGC activation. This paper presents the 1.83 A crystal structure of an isolated catalytically competent GG(D/E)EF domain from the A1U3W3_MARAV protein from Marinobacter aquaeolei. Co-crystallization with GTP resulted in enzymatic synthesis of c-di-GMP. Comparison with previously solved DGC structures shows a similar orientation of c-di-GMP bound to an allosteric regulatory site mediating feedback inhibition of the enzyme. Biosynthesis of c-di GMP in the crystallization reaction establishes that the enzymatic activity of this DGC domain does not require interaction with regulatory domains. PMID- 22843348 TI - Strategies to enhance waste minimization and energy conservation within organizations: a case study from the UK construction sector. AB - Strategies for enhancing environmental management are a key focus for the government in the UK. Using a manufacturing company from the construction sector as a case study, this paper evaluates selected interventionist techniques, including environmental teams, awareness raising and staff training to improve environmental performance. The study employed a range of methods including questionnaire surveys and audits of energy consumption and generation of waste to examine the outcomes of the selected techniques. The results suggest that initially environmental management was not a focus for either the employees or the company. However, as a result of employing the techniques, the company was able to reduce energy consumption, increase recycling rates and achieve costs savings in excess of L132,000. PMID- 22843347 TI - Treatment adherence in a lay health adviser intervention to treat tobacco dependence. AB - Lay health advisers (LHAs) are increasingly used to deliver tobacco dependence treatment, especially with low-socioeconomic status (SES) populations. More information is needed about treatment adherence to help interpret mixed evidence of LHA intervention effectiveness. This study examined adherence to behavioral counseling and nicotine patches in an LHA intervention with 147 Ohio Appalachian female daily smokers. Participants were randomly selected from clinics and randomized to the intervention condition of a randomized controlled trial. Overall, 75.5% of participants received all seven planned LHA visits, 29.3% used patches for >7 weeks and approximately half received high average ratings on participant responsiveness. Depressive symptoms and low nicotine dependence were associated with lower patch adherence while high poverty-to-income ratio was associated with high responsiveness. Compared with those with fewer visits, participants who received all visits were more likely to be abstinent (22.5 versus 2.8%, P=0.026) or have attempted quitting (85.0 versus 47.4%, P=0.009) at 3 months. High participant responsiveness was associated with 12-month abstinence. LHA interventions should focus on improving adherence to nicotine patches and managing depression because it is an independent risk factor for low adherence. PMID- 22843349 TI - Urban governance and spatial inequality in service delivery: a case study of solid waste management in Abuja, Nigeria. AB - Spatial inequality in service delivery is a common feature in African cities. Several factors account for the phenomenon but there is growing attention towards urban governance and the role of the state. Urban governance policies such as privatization serve as key strategies through which the state regulates and (re)produces spatial inequality in service delivery. This study examined how governance practices related to privatization and the regulatory role of the state reinforce spatial inequalities in the delivery of solid waste services in Abuja, Nigeria. It focused primarily on the issue of cost recovery. Privatization became a major focus in Abuja in 2003 when the government launched a pilot scheme. Although it has brought improvements in service delivery, privatization has also increased the gap in the quality of services delivered in different parts of the city. Drawing on empirical data, the study revealed that little sensitivity to income and affordability, and to income differentials between neighbourhoods in the fixing of user charges and in the choice of the billing method is contributing to spatial inequalities in service delivery. Furthermore, the study suggests that these practices are linked to a broader issue, a failure of the government to see the people as partners. It therefore calls for more inclusive governance especially in decision-making processes. The study also emphasizes the need for a policy document on solid waste management, as this would encourage a critical assessment of vital issues including how privatization is to be funded, especially in low-income areas. PMID- 22843350 TI - Application of GIS/AHP in siting sanitary landfill: a case study in Northern Cyprus. AB - The present study utilized a multi-criteria evaluation (MCE) method in a geographical information systems (GIS) environment to evaluate the suitability of potential landfill sites in Northern Cyprus. To determine the most suitable landfill site, one of the MCE techniques, called analytical hierarchy process (AHP), was combined with a GIS to examine 12 criteria: distance from waste generation centres; distance from roads; slope; distance from surface waters; distance from groundwater areas; distance from environmentally sensitive areas; vegetation types; soil productivity; soil permeability; distance from settlements; distance from cultural sites; distance from stone quarries. The relative importance weights of these criteria were estimated using AHP and criteria maps were developed by using GIS spatial analysis. At the final stage two different suitability maps were produced using two different groups of weights. The first group suitability map had 11 052 (ha) with high suitability class, whereas the high suitability areas decreased to 5982 (ha) in the second group. Moreover, the seven potential sites identified within the first group decreased to four in the second suitability map. However, potential sites such as Gungor, Degirmenlik, Kirklar and Cayonu had similarities with higher suitability values and these same locations were regarded as suitable according to the both first and second suitability map results. PMID- 22843351 TI - Management status of end-of-life vehicles and development strategies of used automotive electronic control components recycling industry in China. AB - Recycling companies play a leading role in the system of end-of-life vehicles (ELVs) in China. Automotive manufacturers in China are rarely involved in recycling ELVs, and they seldom provide dismantling information for recycling companies. In addition, no professional shredding plant is available. The used automotive electronic control components recycling industry in China has yet to take shape because of the lack of supporting technology and profitable models. Given the rapid growth of the vehicle population and electronic control units in automotives in China, the used automotive electronic control components recycling industry requires immediate development. This paper analyses the current recycling system of ELVs in China and introduces the automotive product recycling technology roadmap as well as the recycling industry development goals. The strengths, weaknesses, opportunities and challenges of the current used automotive electronic control components recycling industry in China are analysed comprehensively based on the 'strengths, weaknesses, opportunities and threats' (SWOT) method. The results of the analysis indicate that this recycling industry responds well to all the factors and has good opportunities for development. Based on the analysis, new development strategies for the used automotive electronic control components recycling industry in accordance with the actual conditions of China are presented. PMID- 22843352 TI - Trace element concentrations in soils along urbanization gradients in the city of Wien, Austria. AB - Urban soil is an important component of urban ecosystems. This study focuses on heavy metal contamination in soils of Wien (Austria) and results are compared to those for a few large European cities. We analysed the elemental contents of 96 samples of topsoil from urban, suburban and rural areas in Wien along a dynamic (floodplain forest) and a stable (oak-hornbeam forest) urbanization gradient. The following elements were quantified using ICP-OES technique: Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Pb, P, S and Zn. For heavy metals PI (pollution index) values were used to assess the level of pollution. The PI values indicated high level of pollution by Pb in the suburban and rural area of stable gradient and in the urban area of dynamic gradient; moderate level of pollution was indicated for Cd in the urban area of stable gradient. The level of pollution was moderate for Co in the suburban and rural area of the stable gradient, and for Cu in suburban area of stable gradient, and urban area of dynamic gradient. The pollution level of Zn was moderate in all areas. Urban soils, especially in urban parks and green areas may have a direct influence on human health. Thus, the elemental analysis of soil samples is one of the best ways to study the effects of urbanization. Our results indicated that the heavy metal contamination was higher in Wien than in a few large European cities. PMID- 22843353 TI - Progressive muscle relaxation in persons with schizophrenia: a systematic review of randomized controlled trials. AB - OBJECTIVE: The aim of this systematic review was to assess the effectiveness of progressive muscle relaxation on psychological distress and anxiety symptoms and on response/remission for people with schizophrenia. METHODS: Randomized controlled trials were considered if they investigated progressive muscle relaxation in patients with schizophrenia. EMBASE, PsycINFO, PubMed, ISI Web of Science, CINAHL, PEDro and Cochrane Library were searched. The selection of studies, data extraction and quality assessment were performed independently by two reviewers. RESULTS: Three randomized controlled trials involving 146 patients met the inclusion criteria. Progressive muscle relaxation can acutely reduce state anxiety and psychological distress and improve subjective well-being. No studies investigated the evidence for progressive muscle relaxation as an add-on treatment for general psychopathology and for positive or negative symptoms. Also, no studies assessed the value of progressive muscle relaxation in longer term treatment and for relapse prevention. There were no data to draw any conclusions about progressive muscle relaxation in comparison with other treatment modalities. None of the studies encountered adverse events. Dose response relationships could not be determined. CONCLUSION: Progressive muscle relaxation might be a useful add-on treatment to reduce state anxiety and psychological distress and improve subjective well-being in persons with schizophrenia. PMID- 22843354 TI - Determinants of pain and functioning in hip osteoarthritis - a two-year prospective study. AB - OBJECTIVE: To identify predictors of pain and disability in hip osteoarthritis. DESIGN: A prospective analysis of determinants of pain and functioning in hip osteoarthritis. STUDY SETTING: Rehabilitation clinic in a central hospital. PATIENTS: A total of 118 men and women aged 55-80 years who had radiologically diagnosed hip osteoarthritis and associated clinical symptoms and participated in a randomized controlled trial. MAIN MEASURES: The self-reported disease-specific pain and physical function were assessed using the pain and functioning subscales of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis index. The self-reported generic physical and mental functioning were assessed by using the Finnish-validated SF-36-item Health Survey RAND-36 subscales for function and physical and mental component summary scores. Outcome measures were recorded at 0, 3, 6, 12, 18 and 24 months. RESULTS: Multivariate linear mixed model analyses revealed that lower disease-specific pain score and better functioning (WOMAC) were predicted by higher educational level (9.61 (3.15 to 16.07); 9.07 (2.05 to 16.09)), supervised exercise training (-10.13 (-17.87 to -2.39); -11.58 (-19.40 to -3.77)), habitual conditioning physical activity (-0.48 (-0.96 to -0.01); 0.39 (-0.84 to 0.05)), absence of comorbidities (-6.30 (-12.35 to -0.24); -7.87 ( 14.45 to -1.30)) and absence of additional knee osteoarthritis (-7.62 (-13.87 to 1.36); -8.02 (-14.81 to -1.23)), respectively. The same factors, except for the comorbidities, also predicted general physical functioning score (RAND-36). CONCLUSIONS: Higher education, absence of knee osteoarthritis and comorbidities, supervised exercise training and habitual conditioning physical activity predicted a lower presence of pain and better functional status in patients with hip osteoarthritis. PMID- 22843355 TI - Can falls be predicted with gait analytical and posturographic measurement systems? A prospective follow-up study in a nursing home population. AB - OBJECTIVE: To validate previously proposed findings and to develop an objective, feasible and efficient bifactorial (risk factors: gait impairment and balance disorders) fall risk assessment. DESIGN: Prospective follow-up study Setting: Nursing homes (Halle/Saale, Germany). SUBJECTS: One hundred and forty-six nursing home residents (aged 62-101 years) were recruited. METHODS: Gait data were collected using a mobile inertial sensor-based system (RehaWatch). Postural regulation data were measured with the Interactive Balance System. Falls were recorded in standardized protocols over a follow-up period of 12 months. MAIN MEASURES: Gait parameters (e.g. spatial-temporal parameters), posturographic parameters (e.g. postural subsystems), number of falls. RESULTS: Seventeen (12%) of the participants had more than two falls per year. The predictive validity of the previously selected posturographic parameters was inadequate (sensitivity: 47%). The new measurement tool defined 67 participants showing an increased risk of falls. In reality, only 8 participants actually fell more than twice during the follow-up period (positive predictive value (PPV): 12%). The negative predictive value (NPV) was 88%. The posturographic frequency range F2-4 (peripheral-vestibular system), stride time and standard deviation of landing phase were the most powerful parameters for fall prediction. Gait and postural variability were larger in the high-risk group (e.g. gait speed; confidence interval (CI)(high): 0.57-0.79 vs. CI(low): 0.72-0.81 m/s). CONCLUSION: RehaWatch and the Interactive Balance System are able to measure two of the most important fall risk factors, but their current predictive ability is not satisfactory yet. The correlation with physiological mechanisms is only shown by the Interactive Balance System. PMID- 22843356 TI - Fall and fracture rates following a change from carpet to vinyl floor coverings in a geriatric rehabilitation hospital. A longitudinal, observational study. AB - OBJECTIVE: To investigate whether changing from 5 mm thick carpet tiles to vinyl on a concrete subfloor would alter fall or fracture rates. DESIGN: Longitudinal, observational study. SETTING: Six wards (129 beds) of a geriatric rehabilitation hospital. SUBJECTS: All inpatients during this time. INTERVENTIONS: The floor covering was changed from 5 mm carpet tiles to vinyl on these wards when they were closed for other maintenance. This occurred in stages from November 2007 to December 2009. MEASURES: Falls are routinely reported using a quality improvement event reporting form. Fall and fracture rates were calculated in the 12 months prior to and following the change in floor covering on each ward. RESULTS: There were 854 falls on the carpet tiles in the 12 months prior to the flooring change and 878 falls on the vinyl in the 12 months after (19.5 and 19.6 falls/1000 bed days, respectively, [P = 0.95] NS. Fifteen fractures occurred on carpet and 11 fractures on vinyl, [P = 0.39] NS. Using run charts there were no detectable trends in either the fall or fracture rates following the change in flooring surface. CONCLUSION: There may be no difference in fall rates or fractures on carpet or vinyl floor covering of similar thickness and subfloor type. PMID- 22843357 TI - Automated estimation of number of implanted iodine-125 seeds for prostate brachytherapy based on two-view analysis of pelvic radiographs. AB - Digital pelvic radiographs are used to identify the locations of implanted iodine 125 seeds and their numbers after insertion. However, it is difficult and laborious to visually identify and count all implanted seeds on the pelvic radiographs within a short time. Therefore, our purpose in this research was to develop an automated method for estimation of the number of implanted seeds based on two-view analysis of pelvic radiographs. First, the images of the seed candidates on the pelvic image were enhanced using a difference of Gaussian filter, and were identified by binarizing the enhanced image with a threshold value determined by multiple-gray level thresholding. Second, a simple rule-base method using ten image features was applied for false positive removal. Third, the candidates for the likely number of a multiply overlapping seed region, which may include one or more seeds, were estimated by a seed area histogram analysis and calculation of the probability of the likely number of overlapping seeds. As a result, the proposed method detected 99.9% of implanted seeds with 0.71 false positives per image on average in a test for training cases, and 99.2% with 0.32 false positives in a validation test. Moreover, the number of implanted seeds was estimated correctly at an overall recognition rate of 100% in the validation test using the proposed method. Therefore, the verification time for the number of implanted seeds could be reduced by the provision of several candidates for the likely number of seeds. PMID- 22843359 TI - Predicting pubic arch interference in prostate brachytherapy on transrectal ultrasonography-computed tomography fusion images. AB - We investigated the usefulness of the fusion image created by transrectal ultrasonography (TRUS) and large-bore computed tomography (CT) for predicting pubic arch interference (PAI) during prostate seed brachytherapy. The TRUS volume study was performed in 21 patients, followed by large-bore computed tomography of patients in the lithotomy position. Then, we created TRUS-CT fusion images using a radiation planning treatment system. TRUS images in which the prostate outline was the largest were overlaid on CT images with the narrowest pubic arch. PAI was estimated in the right and left arch separately and classified to three grades: no PAI, PAI positive within 5 mm and PAI of >5 mm. If the estimated PAI was more than 5 mm on at least one side of the arch, we judged there to be a significant PAI. Brachytherapy was performed in 18 patients who were evaluated as not having significant PAI on TRUS. Intra-operative PAI was observed in one case, which was also detected with a fusion image. On the other hand, intra-operative PAI was not observed in one case that had been evaluated as having significant PAI with a fusion image. In the remaining three patients, TRUS suggested the presence of significant PAI, which was also confirmed by a fusion image. Intra-operative PAI could be predicted by TRUS-CT fusion imaging, even when it was undetectable by TRUS. Although improvement of the reproducibility of the patients' position to avoid false-positive cases is warranted, TRUS-CT fusion imaging has the possibility that the uncertainty of TRUS can be supplemented. PMID- 22843358 TI - Oxidative stress due to radiation in CD34(+) hematopoietic progenitor cells: protection by IGF-1. AB - Radiation exerts direct as well as indirect effects on DNA through the generation of reactive oxygen species (ROS). Irradiated hematopoietic progenitor cells (HPCs) experience DNA strand breaks, favoring genetic instability, due to ROS generation. Our aim was to study the effect of a range of radiation doses in HPCs and the possible protective mechanisms activated by insulin-like growth factor-1 (IGF-1). ROS generation was evaluated, in the presence or absence of IGF-1 in liquid cultures of human HPCs-CD34(+) irradiated with 1-, 2- and 5-Gy X-rays, using a flow cytometry assay. Manganese superoxide dismutase (MnSOD) expression was studied by western blot analysis and visualized by an immunofluorescence assay. Apoptosis was estimated using the following assays: Annexin-V assay, DNA degradation assay, BCL-2/BAX mRNA and protein levels and caspase-9 protein immunofluorescence visualization. Viability and clonogenic potential were studied in irradiated HPCs. The generation of superoxide anion radicals at an early and a late time point was increased, while the hydrogen peroxide generation at a late time point was stable. IGF-1 presence further enhanced the radiation-induced increase of MnSOD at 24 h post irradiation. IGF-1 inhibited the mitochondria mediated pathway of apoptosis by regulating the m-RNA and protein expression of BAX, BCL-2 and the BCL-2/BAX ratio and by decreasing caspase-9 protein expression. IGF-1 presence in culture media of irradiated cells restored the clonogenic capacity and the viability of HPCs as well. In conclusion, IGF-1 protects HPCs-CD34(+) from radiation effects, by eliminating the oxidative microenvironment through the enhancement of MnSOD activation and by regulating the mitochondria-mediated pathway of apoptosis. PMID- 22843361 TI - Four-dimensional CT-based evaluation of volumetric modulated arc therapy for abdominal lymph node metastasis from hepatocellular carcinoma. AB - This study aimed to identify the potential benefits and limitations of a new volumetric modulated arc therapy (VMAT) planning system in Monaco, compared with conventional intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). Four-dimensional CT scans of 13 patients with abdominal lymph node metastasis from hepatocellular carcinoma were selected. Internal target volume was defined as the combined volume of clinical target volumes (CTVs) in the multiple 4DCT phases. Dose prescription was set to 45 Gy for the planning target volume (PTV) in daily 3.0-Gy fractions. The PTV dose coverage, organs at risk (OAR) doses, delivery parameters and treatment accuracy were assessed. Compared with 3DCRT, both VMAT and IMRT provided a systematic improvement in PTV coverage and homogeneity. Planning objectives were not fulfilled for the right kidney, in which the 3DCRT plans exceeded the dose constraints in two patients. Equivalent target coverage and sparing of OARs were achieved with VMAT compared with IMRT. The number of MU/fraction was 462 +/- 68 (3DCRT), 564 +/- 105 (IMRT) and 601 +/- 134 (VMAT), respectively. Effective treatment times were as follows: 1.8 +/- 0.2 min (3DCRT), 6.1 +/- 1.5 min (IMRT) and 4.8 +/- 1.0 min (VMAT). This study suggests that the VMAT plans generated in Monaco improved delivery efficiency for equivalent dosimetric quality to IMRT, and were superior to 3DCRT in target coverage and sparing of most OARs. However, the superiority of VMAT over IMRT in delivery efficiency is limited. PMID- 22843360 TI - Impact of early radiological response evaluation on radiotherapeutic outcomes in the patients with nasal cavity and paranasal sinus malignancies. AB - We analyzed the correlation between primary tumor response within 6 months after radiation therapy (RT) including proton beam therapy (PBT) and progression free survival rate (PFS) in patients with nasal cavity and paranasal sinus malignancies to clarify the impact of early radiological evaluation of treatment response on prognosis. Sixty-five patients treated between January 1998 and December 2008, and whose follow-up duration was more than 2 years were included. The Response Evaluation Criteria in Solid Tumors (version 1.1) was used for the evaluation of treatment. Median age was 59 years (range 21-83 years). Olfactory neuroblastoma (n = 20, 30%) and squamous cell carcinoma (n = 15, 23%) were the major pathological tumor types. The median follow-up duration was 51.6 months. Radiological response evaluation within 6 months after treatment demonstrated that 15% of the patients achieved complete response (CR), and 3-year progression free survival rates of all patients was 49.2%. The 3-year PFS rates according to response for the treatment were 55.6% in the patients with CR and 46.4% in those with non-CR, respectively (P = 0.643). However, the 3-year PFS rates were 80.% in the patients with CR and 10.% in those with non-CR (P = 0.051) in the patients with squamous cell carcinoma (SCC) histology. Radiological response evaluation within 6 months did not have a significant impact on prognosis when analysis included all histology, although early radiological response within 6 months after RT had a borderline significant impact on treatment outcomes for the patients with nasal and paranasal SCC. PMID- 22843362 TI - Cell division cycle 25 homolog c effects on low-dose hyper-radiosensitivity and induced radioresistance at elevated dosage in A549 cells. AB - The underlying mechanisms behind both low-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR), generally occurring at elevated radiation levels, remain unclear; however, elucidation of the relationship between cell cycle division 25 homolog c (Cdc25c) phosphatase and HRS/IRR may provide important insights into this process. Two cell lines with disparate HRS status, A549 and SiHa cells, were selected as cell models for comparison of dose-dependent Cdc25c phosphatase expression subsequent to low-dose irradiation. Knockdown of Cdc25c in A549 cells was mediated by transfection with a pGCsi-RAN-U6neo vector containing hairpin siRNA sequences. S216-phosphorylated Cdc25c protein [p-Cdc25c (Ser216)], cell survival and mitotic ratio were measured by western blot, colony-forming assay and histone H3 phosphorylation analysis. Variant p-Cdc25c (Ser216) expression was observed in the two cell lines after irradiation. The p-Cdc25c (Ser216) expression noted in SiHa cells after administration of 0-1 Gy radiation was similar to the radioresistance model; however, in A549 cells, the dose response for the phosphorylation of the Cdc25c Ser216 residue overlapped the level required to overcome the HRS response. Furthermore, Cdc25c repression prior to low-dose radiation induced more distinct HRS and prevented the development of IRR. The dose required to overcome the HRS response coincided with the effect of early G2-phase checkpoint arrest in A549 cells (approximately 0.3 Gy), and Cdc25c knockdown in A549 cells (approximately 0.5 Gy) corresponded to the phosphorylation of the Cdc25c Ser216 residue. Resultant data confirmed that dose dependent Cdc25c phosphatase does effectively act as an early G2-phase checkpoint, thus indicating mechanistic importance in the HRS to IRR transition in A549 cells. PMID- 22843364 TI - Dosimetric evaluation of the impacts of different heterogeneity correction algorithms on target doses in stereotactic body radiation therapy for lung tumors. AB - Heterogeneity correction algorithms can have a large impact on the dose distributions of stereotactic body radiation therapy (SBRT) for lung tumors. Treatment plans of 20 patients who underwent SBRT for lung tumors with the prescribed dose of 48 Gy in four fractions at the isocenter were reviewed retrospectively and recalculated with different heterogeneity correction algorithms: the pencil beam convolution algorithm with a Batho power-law correction (BPL) in Eclipse, the radiological path length algorithm (RPL), and the X-ray Voxel Monte Carlo algorithm (XVMC) in iPlan. The doses at the periphery (minimum dose and D95) of the planning target volume (PTV) were compared using the same monitor units among the three heterogeneity correction algorithms, and the monitor units were compared between two methods of dose prescription, that is, an isocenter dose prescription (IC prescription) and dose-volume based prescription (D95 prescription). Mean values of the dose at the periphery of the PTV were significantly lower with XVMC than with BPL using the same monitor units (P < 0.001). In addition, under IC prescription using BPL, RPL and XVMC, the ratios of mean values of monitor units were 1, 0.959 and 0.986, respectively. Under D95 prescription, they were 1, 0.937 and 1.088, respectively. These observations indicated that the application of XVMC under D95 prescription results in an increase in the actually delivered dose by 8.8% on average compared with the application of BPL. The appropriateness of switching heterogeneity correction algorithms and dose prescription methods should be carefully validated from a clinical viewpoint. PMID- 22843363 TI - Coenzyme Q10 protects retinal cells from apoptosis induced by radiation in vitro and in vivo. AB - The key pathogenetic event of many retinopathies is apoptosis of retinal cells. Our previous studies have demonstrated that Coenzyme Q10 (CoQ10) prevents apoptosis of corneal keratocytes both in vitro and in vivo, by virtue of its ability to inhibit mitochondrial depolarization, independently of its free radical scavenger role. The aim of this study was to evaluate whether CoQ10 can protect cultured retinal cells and the retinas of rats from radiation-induced apoptosis, if instilled as eye drops in the cornea. In vitro experiments were carried out on cultured ARPE-19 or RGC-5 cells pretreated with CoQ10 before eliciting apoptosis by UV- and gamma-radiation, chemical hypoxia (Antimycin A) and serum starvation. Cell viability was evaluated by light microscopy and fluorescence activated cell sorting analysis. Apoptotic events were scored by time-lapse videomicroscopy. Mitochondrial permeability transition was evaluated by JC-1. The anti-apoptotic effectiveness of CoQ10 in retina was also evaluated by an in situ end-labeling assay in Wistar albino rats treated with CoQ10 eye drops prior to UV irradiation of the eye. CoQ10 substantially increased cell viability and lowered retinal cell apoptosis in response both to UV- and gamma radiation and to chemical hypoxia or serum starvation by inhibiting mitochondrion depolarization. In the rat, CoQ10, even when applied as eye drops on the cornea, protected all retina layers from UVR-induced apoptosis. The ability of CoQ10 to protect retinal cells from radiation-induced apoptosis following its instillation on the cornea suggests the possibility for CoQ10 eye drops to become a future therapeutic countermeasure for radiation-induced retinal lesions. PMID- 22843367 TI - Dosimetric and delivery characterizations of full-arc and half-arc volumetric modulated arc therapy for maxillary cancer. AB - We compared the efficiency and accuracy of full-arc and half-arc volumetric modulated arc therapy (VMAT) delivery for maxillary cancer. Plans for gantry rotation angles of 360 degrees and 180 degrees (full-arc and half-arc VMAT) were created for six maxillary cancer cases with the Monaco treatment planning system, and delivered using an Elekta Synergy linear accelerator. Full-arc and half-arc VMAT were compared with regard to homogeneity index (HI), conformity index (CI), mean dose to normal brain, total monitor units (MU), delivery times, root mean square (r.m.s.) gantry accelerations ( degrees /s(2)), and r.m.s. gantry angle errors ( degrees ). The half-arc VMAT plans achieved comparable HI and CI to the full-arc plans. Mean doses to the normal brain and brainstem with the half-arc VMAT plans were on average 16% and 17% lower than those with the full-arc VMAT plans. For other organs at risk (OARs), no significant DVH differences were observed between plans. Half-arc VMAT resulted in 11% less total MU and 20% shorter delivery time than the full-arc VMAT, while r.m.s. gantry acceleration and r.m.s. gantry angle error during half-arc VMAT delivery were 30% and 23% less than those during full-arc VMAT delivery, respectively. Furthermore, the half-arc VMAT plans were comparable with the full-arc plans regarding dose homogeneity and conformity in maxillary cancer, and provided a statistical decrease in mean dose to OAR, total MU, delivery time and gantry angle error. Half-arc VMAT plans may be a suitable treatment option in radiotherapy for maxillary cancer. PMID- 22843368 TI - Safety regulations of food and water implemented in the first year following the Fukushima nuclear accident. AB - An earthquake and tsunami of historic proportions caused massive damage across the northeastern coast of Japan on the afternoon of 11 March 2011, and the release of radionuclides from the stricken reactors of the Fukushima nuclear power plant 1 was detected early on the next morning. High levels of radioiodines and radiocesiums were detected in the topsoil and plants on 15 March 2011, so sampling of food and water for monitoring surveys began on 16 March 2011. On 17 March 2011, provisional regulation values for radioiodine, radiocesiums, uranium, plutonium and other transuranic alpha emitters were set to regulate the safety of radioactively contaminated food and water. On 21 March 2011, the first restrictions on distribution and consumption of contaminated items were ordered. So far, tap water, raw milk, vegetables, mushrooms, fruit, nut, seaweeds, marine invertebrates, coastal fish, freshwater fish, beef, wild animal meat, brown rice, wheat, tea leaves and other foodstuffs had been contaminated above the provisional regulation values. The provisional regulation values for radioiodine were exceeded in samples taken from 16 March 2011 to 21 May 2011, and those for radiocesiums from 18 March 2011 to date. All restrictions were imposed within 318 days after the provisional regulation values were first exceeded for each item. This paper summarizes the policy for the execution of monitoring surveys and restrictions, and the outlines of the monitoring results of 220 411 samples and the enforced restrictions predicated on the information available as of 31 March 2012. PMID- 22843365 TI - Dose reduction trial from 60 Gy in 10 fractions to 54 Gy in 9 fractions schedule in high-dose-rate interstitial brachytherapy for early oral tongue cancer. AB - To compare the effects of 60 Gy/10 fractions (twice a day) with those of 54 Gy/9 fractions in high-dose-rate interstitial brachytherapy (HDR-ISBT) for early tongue cancer, we performed a matched-pair analysis of patients with early tongue cancer (T1-2N0M0), who were treated with 60 or 54 Gy of radiation between 1996 and 2004. Seventeen patients treated with 54 Gy and 34 matched-pair patients treated with 60 Gy were extracted and analyzed. Local recurrence occurred in two patients in the 54-Gy arm and five patients in the 60-Gy arm. The 2-year local control rates were 88% for both the 54-Gy arm and 60-Gy arm (not significant). The 2-year overall survival rates were 88% in the 60-Gy arm and 82% in the 54-Gy arm. Two-year actuarial complication-free rates were 91% in the 60-Gy arm and 83% in the 54-Gy arm (not significant), respectively. There was no significant association between the total dose and local control rate and late complications. The outcome of 54 Gy/ 9 fractions was similar to that of 60 Gy/ 10 fractions in patients with early tongue cancer. PMID- 22843366 TI - Japanese structure survey of radiation oncology in 2009 based on institutional stratification of the Patterns of Care Study. AB - The ongoing structure of radiation oncology in Japan in terms of equipment, personnel, patient load and geographic distribution was evaluated in order to radiation identify and improve any deficiencies. A questionnaire-based national structure survey was conducted from March 2010 to January 2011 by the Japanese Society for Therapeutic Radiology and Oncology (JASTRO). These data were analyzed in terms of the institutional stratification of the Patterns of Care Study (PCS). The total numbers of new cancer patients and total of cancer patients (new and repeat) treated with radiation in 2009 were estimated at 201,000 and 240,000, respectively. The type and numbers of systems in actual use consisted of Linac (816), telecobalt (9), Gamma Knife (46), (60)Co remote afterloading system (RALS) (29) and (192)Ir RALS systems (130). The Linac systems used dual energy function for 586 (71.8%), 3DCRT for 663 (81.3%) and IMRT for 337 units (41.3%). There were 529 JASTRO-certified radiation oncologists (ROs), 939.4 full-time equivalent (FTE) ROs, 113.1 FTE medical physicists and 1836 FTE radiation therapists. The frequency of interstitial radiation therapy use for prostate and of intensity modulated radiotherapy increased significantly. PCS stratification can clearly identify the maturity of structures based on their academic nature and caseload. Geographically, the more JASTRO-certified physicians there were in a given area, the more radiation therapy tended to be used for cancer patients. In conclusion, the Japanese structure has clearly improved during the past 19 years in terms of equipment and its use, although a shortage of manpower and variations in maturity disclosed by PCS stratification remained problematic in 2009. PMID- 22843369 TI - Comparison of dose-volume analysis between standard Manchester plan and magnetic resonance image-based plan of intracavitary brachytherapy for uterine cervical cancer. AB - To investigate the feasibility of image-based intracavitary brachytherapy (IBICBT) for uterine cervical cancer, we evaluated the dose-volume histograms (DVHs) for the tumor and organs at risk (OARs) and compared results from the IBICBT plan and the standard Manchester system (Manchester plan) in eight patients as a simulation experiment. We performed magnetic resonance imaging (MRI) and computed tomography (CT) following MRI-adapted applicator insertion, then superimposed MR images on the planning CT images to describe the contours of high-risk clinical target volume (HR CTV) and OARs. The median volume of HR CTV was 29 cm(3) (range, 21-61 cm(3)). Median D90 (HR CTV) and V100 (HR CTV) were 116.1% prescribed doses (PD) (90.0-150.8%) and 96.7% (84.2-100%), respectively, for the Manchester plan. In comparison, we confirmed that the median D90 (HR CTV) was 100% PD in the IBICBT plan for all patients. Mean D(2cc) (bladder) was 101.8% PD for the Manchester plan and 83.2% PD for the IBICBT plan. Mean D(2cc) (rectum) was 80.1% PD for the Manchester plan and 64.2% PD for the IBICBT plan. Mean D(2cc) (sigmoid) was 75% PD for the Manchester plan and 57.5% PD for the IBICBT plan. One patient with a large tumor (HR CTV, 61 cm(3)) showed lower D90 (HR CTV) with the Manchester plan than with the IBICBT plan. The Manchester plan may represent overtreatment for small tumors but insufficient dose distribution for larger tumors. The IBICBT plan could reduce OAR dosage while maintaining adequate tumor coverage. PMID- 22843370 TI - Salvage radiotherapy after radical prostatectomy: outcomes and prognostic factors especially focusing on pathological findings. AB - External beam radiotherapy is a potential salvage or adjuvant therapy after radical prostatectomy (RP). The purpose of this study was to investigate the treatment outcome of salvage radiotherapy (RT) following RP for clinically localized prostate cancer and to identify factors that may predict the outcome of salvage RT. Between 2000 and 2006, 41 patients received salvage RT because of increasing prostate-specific antigen (PSA) levels following an RP for clinically localized prostate cancer. All the patients received conformal radiotherapy to the prostate bed. The prescribed radiation dose was 60-70 Gy in 26-35 fractions. The overall 5-year biochemical disease-free survival rate was 38%. A multivariate analysis showed that the following pathological findings of the surgical specimen were significantly associated with biochemical failure following salvage RT: a high Gleason score, a negative surgical margin, seminal vesicle invasion, lymphatic vessel invasion and negative vascular invasion. Among these factors, lymphatic vessel invasion was the strongest predictor. In conclusion, the pathological features affected the outcome of salvage RT following RP. Lymphatic vessel invasion was strongly associated with the risk of biochemical failure despite salvage RT. Meanwhile, vascular invasion was not a significant hazardous factor. PMID- 22843372 TI - Quality assurance of MLC leaf position accuracy and relative dose effect at the MLC abutment region using an electronic portal imaging device. AB - We investigated an electronic portal image device (EPID)-based method to see whether it provides effective and accurate relative dose measurement at abutment leaves in terms of positional errors of the multi-leaf collimator (MLC) leaf position. A Siemens ONCOR machine was used. For the garden fence test, a rectangular field (0.2 20 cm) was sequentially irradiated 11 times at 2-cm intervals. Deviations from planned leaf positions were calculated. For the nongap test, relative doses at the MLC abutment region were evaluated by sequential irradiation of a rectangular field (2 20 cm) 10 times with a MLC separation of 2 cm without a leaf gap. The integral signal in a region of interest was set to position A (between leaves) and B (neighbor of A). A pixel value at position B was used as background and the pixel ratio (A/B 100) was calculated. Both tests were performed at four gantry angles (0, 90, 180 and 270 degrees ) four times over 1 month. For the nongap test the difference in pixel ratio between the first and last period was calculated. Regarding results, average deviations from planned positions with the garden fence test were within 0.5 mm at all gantry angles, and at gantry angles of 90 and 270 degrees tended to decrease gradually over the month. For the nongap test, pixel ratio tended to increase gradually in all leaves, leading to a decrease in relative doses at abutment regions. This phenomenon was affected by both gravity arising from the gantry angle, and the hardware-associated contraction of field size with this type of machine. PMID- 22843373 TI - Interfractional and intrafractional errors assessed by daily cone-beam computed tomography in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: a prospective study. AB - This prospective study was to assess interfractional and intrafractional errors and to estimate appropriate margins for planning target volume (PTV) by using daily cone-beam computed tomography (CBCT) guidance in nasopharyngeal carcinoma (NPC). Daily pretreatment and post-treatment CBCT scans were acquired separately after initial patient setup and after the completion of each treatment fraction in 10 patients treated with IMRT. Online corrections were made before treatment if any translational setup error was found. Interfractional and intrafractional errors were recorded in the right-left (RL), superior-inferior (SI) and anterior posterior (AP) directions. For the translational shifts, interfractional errors >2 mm occurred in 21.7% of measurements in the RL direction, 12.7% in the SI direction and 34.1% in the AP direction, respectively. Online correction resulted in 100% of residual errors <=2 mm in the RL and SI directions, and 95.5% of residual errors <=2 mm in the AP direction. No residual errors >3 mm occurred in the three directions. For the rotational shifts, a significant reduction was found in the magnitudes of residual errors compared with those of interfractional errors. A margin of 4.9 mm, 4.0 mm and 6.3 mm was required in the RL, SI and AP directions, respectively, when daily CBCT scans were not performed. With daily CBCT, the margins were reduced to 1.2 mm in all directions. In conclusion, daily CBCT guidance is an effective modality to improve the accuracy of IMRT for NPC. The online correction could result in a 70-81% reduction in margin size. PMID- 22843371 TI - The usefulness of an independent patient-specific treatment planning verification method using a benchmark plan in high-dose-rate intracavitary brachytherapy for carcinoma of the uterine cervix. AB - To develop an easy independent patient-specific quality assurance (QA) method using a benchmark plan for high-dose-rate intracavitary brachytherapy for cervix cancer, we conducted benchmark treatment planning with various sizes and combinations of tandem-ovoid and tandem-cylinder applications with 'ideal' geometry outside the patient. Two-dimensional-based treatment planning was conducted based on the Manchester method. We predicted the total dwell time of individual treatment plans from the air kerma strength, total dwell time and prescription dose of the benchmark plan. In addition, we recorded the height (dh), width (dw) and thickness (dt) covered with 100% isodose line. These parameters were compared with 169 and 29 clinical cases for tandem-ovoid or tandem-cylinder cases, respectively. With regard to tandem-ovoid cases, differences in total dwell time, dh, dt and dw between benchmark and individual plans were on average -0.2% +/- 3.8%, -1.0 mm +/- 2.6 mm, 0.8 mm +/- 1.3 mm and 0.1 mm +/- 1.5 mm, respectively. With regard to tandem-cylinder cases, differences in total dwell time, dh(front) (the distance from tandem tip to tandem ring), dt and dw between benchmark and individual plans were on average 1.5% +/- 3.1%, -1.5 mm +/- 4.9 mm, 0.1 mm +/- 1.0 mm and 0.2 mm +/- 0.8 mm, respectively. Of two cases, more than 13% differences in total dwell time were observed between benchmark plans and the clinical cases, which turned out to be due to the use of the wrong source position setting. These results suggest that our method is easy and useful for independent verification of patient-specific treatment planning QA. PMID- 22843374 TI - Cancer of the pelvis: definitive three-dimensional conformal radiotherapy for patients with isolated recurrence in the para-aortic lymph nodes. AB - The purpose of this study was to evaluate the outcome of definitive three dimensional conformal radiotherapy (RT) for isolated para-aortic lymph node (LN) recurrence in patients with controlled primary cancer of the pelvis. Twenty-four consecutive patients with isolated para-aortic LN recurrence were retrospectively analyzed. The patients were included in this study if they were eligible to receive definitive RT for abdominal para-aortic LN recurrence with controlled primary cancer of the pelvis without other distant/recurrent diseases. The median time between the front-line therapy and RT for isolated para-aortic LN metastases was 21 months. Nineteen (79%) patients had an objective tumor response. In-field failure occurred in four patients (17%), while failure outside of the irradiated field was recognized in 12 patients (50%). The overall survival, progression-free survival and local control rates at 5 years were 56%, 29% and 72%, respectively. Statistically significant prognostic factors of the overall survival rate in the univariate analyses were an objective tumor response (P = 0.0098) and the time between front-line therapy and RT (P = 0.033). The maximum tumor size was a significant prognostic factor of the overall survival rates in the multivariate analyses (P = 0.046). The toxicities were mild; leukopenia of Grade 3 was detected in one patient, and no Grade 3 or higher non-hematological toxicity was observed. In conclusion, definitive three-dimensional RT for isolated abdominal para-aortic LN recurrence in patients with controlled primary cancer of the pelvis may be feasible, and can provide a relatively longer-term survival. The results justify further investigation of higher dose RT using modern RT planning techniques. PMID- 22843375 TI - Computerized estimation of patient setup errors in portal images based on localized pelvic templates for prostate cancer radiotherapy. AB - We have developed a computerized method for estimating patient setup errors in portal images based on localized pelvic templates for prostate cancer radiotherapy. The patient setup errors were estimated based on a template matching technique that compared the portal image and a localized pelvic template image with a clinical target volume produced from a digitally reconstructed radiography (DRR) image of each patient. We evaluated the proposed method by calculating the residual error between the patient setup error obtained by the proposed method and the gold standard setup error determined by consensus between two radiation oncologists. Eleven training cases with prostate cancer were used for development of the proposed method, and then we applied the method to 10 test cases as a validation test. As a result, the residual errors in the anterior posterior, superior-inferior and left-right directions were smaller than 2 mm for the validation test. The mean residual error was 2.65 +/- 1.21 mm in the Euclidean distance for training cases, and 3.10 +/- 1.49 mm for the validation test. There was no statistically significant difference in the residual error between the test for training cases and the validation test (P = 0.438). The proposed method appears to be robust for detecting patient setup error in the treatment of prostate cancer radiotherapy. PMID- 22843376 TI - Percutaneous interstitial brachytherapy for adrenal metastasis: technical report. AB - We developed and evaluated the feasibility of a brachytherapy technique as a safe and effective treatment for adrenal metastasis. Adapting a paravertebral insertion technique in radiofrequency ablation of adrenal tumors, we developed an interstitial brachytherapy for adrenal metastasis achievable on an outpatient basis. Under local anesthesia and under X-ray CT guidance, brachytherapy applicator needles were percutaneously inserted into the target. A treatment plan was created to eradicate the tumor while preserving normal organs including the spinal cord and kidney. We applied this interstitial brachytherapy technique to two patients: one who developed adrenal metastasis as the third recurrence of uterine cervical cancer after reirradiation, and one who developed metachronous multiple metastases from malignant melanoma. The whole procedure was completed in 2.5 hours. There were no procedure-related or radiation-related early/late complications. FDG PET-CT images at two and three months after treatment showed absence of FDG uptake, and no recurrence of the adrenal tumor was observed for over seven months until expiration, and for six months until the present, respectively. This interventional interstitial brachytherapy procedure may be useful as a safe and eradicative treatment for adrenal metastasis. PMID- 22843377 TI - Treatment outcomes of definitive chemoradiotherapy for patients with hypopharyngeal cancer. AB - We analyzed the efficacy of definitive chemoradiotherapy (CRT) for patients with hypopharyngeal cancer (HPC). Subjects comprised 97 patients who were treated with definitive CRT from 1990 to 2006. Sixty-one patients (62.9%) with resectable disease who aimed to preserve the larynx received induction chemotherapy (ICT), whereas 36 patients (37.1%) with resectable disease who refused an operation or who had unresectable disease received primary alternating CRT or concurrent CRT (non-ICT). The median dose to the primary lesion was 66 Gy. The median follow-up time was 77 months. The 5-year rates of overall survival (OS), progression-free survival (PFS), local control (LC), and laryngeal preservation were 68.7%, 57.5%, 79.1%, and 70.3%, respectively. The T-stage was a significant prognostic factor in terms of OS, PFS and LC in both univariate and multivariate analyses. The 5 year rates of PFS were 45.4% for the ICT group and 81.9% for the non-ICT group. The difference between these groups was significant with univariate analysis (P = 0.006). Acute toxicity of Grade 3 to 4 was observed in 34 patients (35.1%). Grade 3 dysphagia occurred in 20 patients (20.6%). Twenty-nine (29.8%) of 44 patients with second primary cancer had esophageal cancer. Seventeen of 29 patients had manageable superficial esophageal cancer. The clinical efficacy of definitive CRT for HPC is thought to be promising in terms of not only organ preservation but also disease control. Second primary cancer may have a clinical impact on the outcome for HPC patients, and special care should be taken when screening at follow-up. PMID- 22843378 TI - Usefulness of double dose contrast-enhanced magnetic resonance imaging for clear delineation of gross tumor volume in stereotactic radiotherapy treatment planning of metastatic brain tumors: a dose comparison study. AB - The purpose of this study was to compare the size and clearness of gross tumor volumes (GTVs) of metastatic brain tumors on T1-weighted magnetic resonance images between a single dose contrast administration protocol and a double dose contrast administration protocol to determine the optimum dose of contrast enhancement for clear delineation of GTV in stereotactic radiotherapy (SRT). A total of 28 small metastatic brain tumors were evaluated in 13 patients by intra individual comparison of GTV measurements using single dose and double dose contrast-enhanced thin-slice (1-mm) magnetic resonance imaging (MRI). All patients had confirmed histological types of primary tumors and had undergone hypo-fractionated SRT for metastatic brain tumors. The mean tumor diameter with single dose and double dose contrast-enhancement was 12.0 +/- 1.1 mm and 13.2 +/- 1.1 mm respectively (P < 0.001). The mean incremental ratio (MIR) obtained by comparing mean tumor diameters was 11.2 +/- 0.02 %. The mean volume of GTV-1 (single dose contrast-enhancement) and GTV-2 (double dose contrast-enhancement) was 1.38 +/- 0.41 ml and 1.59 +/- 0.45 ml respectively (P < 0.01). The MIR by comparing mean tumor volumes was 32.3 +/- 0.4 %. The MIR of GTV-1 with < 1 ml volume and GTV-1 with > 1 ml volume was 41.8 +/- 0.05 % and 12.4 +/- 0.03 % respectively (P < 0.001). We conclude that double dose contrast-enhanced thin slice MRI is a more useful technique than single dose contrast-enhanced thin slice MRI, especially for clear delineation of GTVs of small metastatic brain tumors in treatment planning of highly precise SRT. PMID- 22843379 TI - Simulation approach for the evaluation of tracking accuracy in radiotherapy: a preliminary study. AB - Real-time tumor tracking in external radiotherapy can be achieved by diagnostic (kV) X-ray imaging with a dynamic flat-panel detector (FPD). It is important to keep the patient dose as low as possible while maintaining tracking accuracy. A simulation approach would be helpful to optimize the imaging conditions. This study was performed to develop a computer simulation platform based on a noise property of the imaging system for the evaluation of tracking accuracy at any noise level. Flat-field images were obtained using a direct-type dynamic FPD, and noise power spectrum (NPS) analysis was performed. The relationship between incident quantum number and pixel value was addressed, and a conversion function was created. The pixel values were converted into a map of quantum number using the conversion function, and the map was then input into the random number generator to simulate image noise. Simulation images were provided at different noise levels by changing the incident quantum numbers. Subsequently, an implanted marker was tracked automatically and the maximum tracking errors were calculated at different noise levels. The results indicated that the maximum tracking error increased with decreasing incident quantum number in flat-field images with an implanted marker. In addition, the range of errors increased with decreasing incident quantum number. The present method could be used to determine the relationship between image noise and tracking accuracy. The results indicated that the simulation approach would aid in determining exposure dose conditions according to the necessary tracking accuracy. PMID- 22843380 TI - 4D registration and 4D verification of lung tumor position for stereotactic volumetric modulated arc therapy using respiratory-correlated cone-beam CT. AB - We propose a clinical workflow of stereotactic volumetric modulated arc therapy (VMAT) for a lung tumor from planning to tumor position verification using 4D planning computed tomography (CT) and 4D cone-beam CT (CBCT). A 4D CT scanner, an Anzai belt and a BodyFix were employed to obtain 10-phase respiratory-correlated CT data for a lung patient under constrained breathing conditions. A planning target volume (PTV) was defined by adding a 5-mm margin to an internal target volume created from 10 clinical target volumes, each of which was delineated on each of the 10-phase planning CT data. A single-arc VMAT plan was created with a D(95) prescription dose of 50 Gy in four fractions on the maximum exhalation phase CT images. The PTV contours were exported to a kilovoltage CBCT X-ray Volume Imaging (XVI) equipped with a linear accelerator (linac). Immediately before treatment, 10-phase 4D CBCT images were reconstructed leading to animated lung tumor imaging. Initial bone matching was performed between frame-averaged 4D planning CT and frame-averaged 4D CBCT datasets. Subsequently, the imported PTV contours and the animated moving tumor were simultaneously displayed on the XVI monitor, and a manual 4D registration was interactively performed on the monitor until the moving tumor was symmetrically positioned inside the PTV. A VMAT beam was delivered to the patient and during the delivery further 4D CBCT projection data were acquired to verify the tumor position. The entire process was repeated for each fraction. It was confirmed that the moving tumor was positioned inside the PTV during the VMAT delivery. PMID- 22843381 TI - 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis. AB - The steroid androst-5-ene-3beta,17beta-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-kappaB (NFkappaB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body gamma- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID- 22843382 TI - 1H, 13C and 15N assignments of the holo-acyl carrier protein of Pseudomonas aeruginosa. AB - Acyl carrier proteins (ACPs) are a group of highly conserved and abundant proteins in bacteria. ACPs play a central role as the acyl group carriers in bacterial fatty acid biosynthesis, providing building blocks for membrane biogenesis and the production of secondary metabolites. In the versatile human pathogen Pseudomonas aeruginosa, three ACP homologs have been identified. One homolog, AcpP, exhibits the strongest sequence homology to the canonical Escherichia coli ACP. Here we report the (1)H, (13)C and (15)N assignments of the holo-AcpP of P. aeruginosa. PMID- 22843384 TI - Challenges for assessing the performance of biomass degrading biocatalysts. AB - Common analytical challenges impact current work to estimate the cost of converting plant biomass to fermentable sugars. The most noteworthy are measuring cellulase and hemicellulase activities, cellulase and hemicellulase protein, biomass compositions (before and after pretreatment), and the products formed. The use of high-throughput (HTP) methods has shown considerable promise for improving both analytical precision and technician efficiency, but can also present pitfalls regarding experimental accuracy and relevance. Recent work demonstrates that HTP systems which include biomass composition analysis, thermal chemical pretreatment, and biomass saccharification can be realized. PMID- 22843385 TI - Overview of computer modeling of cellulose. AB - Although it has a deceptively simple primary structure, the collective organization of bulk cellulose, particularly as it exists in cellulose fibers in the cell walls of living plants and other organisms, is quite diverse and complex. While some experimental techniques, such as vibrational spectroscopy and diffraction from partially crystalline samples, are able to provide insights into the organization of bulk cellulose, its intrinsic complexity has left many questions still unanswered. For this reason, additional probes of cellulose structure would be highly desirable. With the continuing advances in computer power through massive parallelization, and the steady progress in computer codes and force fields for modeling carbohydrate systems, molecular mechanics simulations have become an attractive means of studying cellulosic systems at the atomic and molecular level. The coming decade will almost certainly see remarkable advances in the understanding of cellulose using such simulations. PMID- 22843383 TI - Piperphentonamine (PPTA) attenuated cerebral ischemia-induced memory deficits via neuroprotection associated with anti-apoptotic activity. AB - The calcium sensitizers levosimendan and piperphentonamine hydrochloride (PPTA) are used as cardiovascular drugs for treatment of heart failure. Given that levosimendan has been reported to exhibit a neuroprotective profile in a model of traumatic brain injury, it was interesting to know whether PPTA, a new calcium sensitizer recently developed in China, exerts a similar effect. The objective of this study was to determine whether PPTA exhibited neuroprotective effects and whether these properties were associated with memory. Four-vessel occlusion (4 VO) was used to induce global cerebral ischemia/reperfusion injury in rats treated with or without PPTA (5, 10 mg/kg, i.p., 2 h after the onset of reperfusion and then once a day for 15 consecutive days). Memory was measured using the step-through passive avoidance test. Neurochemical changes were examined in rat PC12 cells treated with oxygen-glucose deprivation (OGD) for 4 h followed by reoxygenation (OGD-R) for 24 h, in the absence or presence of PPTA. In vehicle-treated animals, 4-VO for 10 min produced memory deficits, as demonstrated by decreased retention in step-through passive avoidance, and massive neuron loss in the hippocampal CA1 subregion. These effects were attenuated by PPTA. The results were consistent with those observed in PC12 cells. PPTA treatment increased cell viability, as indicated by MTT assay, inhibited apoptosis, and decreased extracellular lactate dehydrogenase levels in Na(2)S(2)O(4)-treated PC12 cells. These results provide novel demonstration for the ability of PPTA to attenuate cerebral ischemia-induced memory deficits via neuroprotection in the hippocampus. The neuroprotective effect of PPTA appears to be associated with its anti-apoptotic activity. PPTA has the therapeutic potential for ischemic stroke. PMID- 22843386 TI - Imaging cellulose using atomic force microscopy. AB - Cellulose is an important biopolymer primarily stored as plant cell wall material. Plant-synthesized cellulose forms elementary fibrils that are micrometers in length and 3-5 nm in dimensions. Cellulose is a dynamic structure, and its size and property vary in different cellulose-containing materials. Atomic force microscopy offers the capability of imaging surface structure at the subnanometer resolution and under nearly physiological conditions, therefore providing an ideal tool for cellulose characterization. PMID- 22843387 TI - Preservation and preparation of lignocellulosic biomass samples for multi-scale microscopy analysis. AB - Biomass exhibits structural and chemical complexity over multiple size scales, presenting many challenges to the effective characterization of these materials. The macroscopic nature of plants requires that some form of size reduction, such as dissection and microtomy, be performed to prepare samples and reveal features of interest for any microscopic and nanoscopic analyses. These size reduction techniques, particularly sectioning and microtomy, are complicated by the inherent porosity of plant tissue that often necessitates fixation and embedding in a supporting matrix to preserve structural integrity. The chemical structure of plant cell walls is vastly different from that of the membrane bound organelles and protein macromolecular complexes within the cytosol, which are the focus of many traditional transmission electron microscopy (TEM) investigations in structural biology; thus, staining procedures developed for the latter are not optimized for biomass. While the moisture content of biomass is dramatically reduced compared to the living plant tissue, the residual water is still problematic for microscopic techniques conducted under vacuum such as scanning electron microscopy (SEM). This requires that samples must be carefully dehydrated or that the instrument must be operated in an environmental mode to accommodate the presence of water. In this chapter we highlight tools and techniques that have been successfully used to address these challenges and present procedural details regarding the preparation of biomass samples that enable effective and accurate multi-scale microscopic analysis. PMID- 22843388 TI - Coherent Raman microscopy analysis of plant cell walls. AB - Coherent Raman scattering (CRS) microscopy is a label-free method for chemical imaging, as it offers chemical specificity with orders of magnitude better sensitivity than the state-of-the-art confocal Raman scattering microscopy. Currently CRS technique includes coherent anti-Stokes Raman scattering (CARS), and stimulated Raman scattering (SRS). This chapter describes the methods of using CRS microscopy to image major polymers in plant cell wall (i.e., lignin and cellulose). This method can also be used to real-time monitor the chemical processes involved in biomass pretreatment. These together demonstrate CRS as an effective method for imaging complex chemistry in biological systems. PMID- 22843389 TI - Immunological approaches to plant cell wall and biomass characterization: Glycome Profiling. AB - The native complexity of plant cell walls makes research on them challenging. Hence, it is advantageous to have a diversity of tools that can be used to analyze and characterize plant cell walls. In this chapter, we describe one of two immunological approaches that can be employed for screening of plant cell wall/biomass materials from diverse plants and tissues. This approach, Glycome Profiling, lends itself well to moderate to high-throughput screening of plant cell wall/biomass samples. Glycome Profiling is being further optimized to reduce the amount of sample required for the analysis, and to improve the sensitivity and throughput of the assay. We are optimistic that Glycome Profiling will prove to be a broadly applicable experimental approach that will find increasing application to a wide variety of studies on plant cell wall/biomass samples. PMID- 22843391 TI - A method to evaluate biomass accessibility in wet state based on thermoporometry. AB - The substrate accessibility to enzyme has been considered as one of the most important factors for biomass conversion. To avoid the irreversible collapse of pore structure during the drying of sample, the measurement needs to be performed in a wet state. In this report, a thermoporometry method based on DSC isothermal step procedure is explained in details. This detects the amount of nonfreezing bound water in a wet sample and the value is expressed into pore size distribution with the Gibbs-Thomson equation. Information on pore size distribution and pore volume can be used to evaluate biomass accessibility. PMID- 22843390 TI - Immunological approaches to plant cell wall and biomass characterization: immunolocalization of glycan epitopes. AB - Plant cell walls are dynamic structures that show changes in composition and configuration depending on the developmental stage, biotic, and abiotic factors. Therefore, it is necessary to have tools for visualizing the components of the cell wall in situ at any stage. Here, we describe how specific monoclonal antibodies can be used to examine the distribution of plant cell wall glycan epitopes at the whole plant, tissue, cell, and subcellular levels. Understanding the basic cell wall structure is essential for devising efficient strategies to convert cell walls to fermentable sugars for ethanol production. PMID- 22843392 TI - Cellulase processivity. AB - There are two types of processive cellulases, exocellulases and processive endoglucanases. There are also two classes of exocellulases, ones that attack the reducing ends of cellulose chains and ones that attack the nonreducing ends. There are a number of ways of assaying processivity but none of them are ideal. It appears that exocellulases, all of which have their active sites in a tunnel, couple movement along a cellulose chain with cleavage of cellobiose from the end of the cellulose molecule. There are two sets of structures that suggest how an exocellulase might move along a cellulose chain. For family 48 exocellulases there are two different ways that a chain can be bound in the active site while for family 6 exocellulases there are several different ligand-bound structures. Site-directed mutagenesis of Thermobifida fusca exocellulases Cel48A and Cel6B and the processive endoglucanase Cel9A have identified some mutations that increase processivity and some that decrease processivity. In addition a mutation in Cel6B was identified that appears to allow the mutant enzyme to move along a cellulose chain in the absence of cleavage. PMID- 22843393 TI - A simple method for determining specificity of carbohydrate-binding modules for purified and crude insoluble polysaccharide substrates. AB - Experimental identification of carbohydrate-binding modules (CBM) and determination of ligand specificity of each CBM are complementary and compulsory steps for their characterization. Some CBMs are very specific for their primary substrate (e.g., cellulose), whereas others are relatively promiscuous or nonspecific in their substrate preference. Here we describe a simple procedure based on in-tube adsorption of a CBM to various insoluble polysaccharides, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) for determining the distribution of the CBM between the bound and unbound fractions. This technique enables qualitative assessment of the binding strength and ligand specificity for each CBM. PMID- 22843394 TI - Bacterial cadherin domains as carbohydrate binding modules: determination of affinity constants to insoluble complex polysaccharides. AB - Cadherin (CA) and cadherin-like (CADG) doublet domains from the complex polysaccharide-degrading marine bacterium, Saccharophagus degradans 2-40, demonstrated reversible calcium-dependent binding to different complex polysaccharides, which serve as growth substrates for the bacterium. Here we describe a procedure based on adsorption of CA and CADG doublet domains to different insoluble complex polysaccharides, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) for visualizing and quantifying the distribution of cadherins between the bound and unbound fractions. Scatchard plots were employed to determine the kinetics of interactions of CA and CADG with several complex carbohydrates. On the basis of these binding studies, the CA and CADG doublet domains are proposed to form a new family of carbohydrate-binding module (CBM). PMID- 22843395 TI - Affinity electrophoresis as a method for determining substrate-binding specificity of carbohydrate-active enzymes for soluble polysaccharides. AB - Affinity electrophoresis is a simple and rapid tool for the analysis of protein binding affinities to soluble polysaccharides. This approach is particularly suitable for the characterization of the carbohydrate-active enzymes that contain a carbohydrate-binding module and for their mutants and chimeras. Knowledge of the binding characteristics of these enzymes can be the first step to elucidate the enzymatic activity of a putative enzyme; moreover in some cases, enzymes are able to bind polysaccharides targets other than their specified substrate, and this knowledge can be essential to understand the basics of the intrinsic mechanism of these enzymes in their natural environment. PMID- 22843396 TI - Single-molecule tracking of carbohydrate-binding modules on cellulose using fluorescence microscopy. AB - Single-molecule fluorescence detection is an invaluable technique for the study of molecular behavior in biological systems, both in vitro and in vivo. In this chapter, we focus on detailed protocols that utilize Total Internal Reflection Fluorescence Microscopy (TIRF-M) to visualize single molecules of carbohydrate binding module (CBM) labeled with green fluorescent protein (GFP). The content describes step-by-step sample preparation and data acquisition, processing, and analysis. These methods can also be further used to study interactions between domains of cellulase molecules and between cellulases and cellulose. PMID- 22843397 TI - Bioprospecting metagenomics for new glycoside hydrolases. AB - To efficiently deconstruct recalcitrant plant biomass to fermentable sugars in industrial processes, biocatalysts of higher performance and lower cost are required. The genetic diversity found in the metagenomes of natural microbial biomass decay communities may harbor such enzymes. The aim of this chapter is to describe strategies, based on metagenomic approaches, for the discovery of glycoside hydrolases (GHases) from microbial biomass decay communities, especially those from unknown or never-been-cultivated microorganisms. PMID- 22843398 TI - Anaerobic high-throughput cultivation method for isolation of thermophiles using biomass-derived substrates. AB - Flow cytometry (FCM) techniques have been developed for sorting mesophilic organisms, but the difficulty increases if the target microbes are thermophilic anaerobes. We demonstrate a reliable, high-throughput method of screening thermophilic anaerobic organisms using FCM and 96-well plates for growth on biomass-relevant substrates. The method was tested using the cellulolytic thermophiles Clostridium thermocellum (T(opt) = 55 degrees C), Caldicellulosiruptor obsidiansis (T(opt) = 78 degrees C) and the fermentative hyperthermophiles, Pyrococcus furiosus (T(opt) = 100 degrees C) and Thermotoga maritima (T(opt) = 80 degrees C). Multi-well plates were incubated at various temperatures for approximately 72-120 h and then tested for growth. Positive growth resulting from single cells sorted into individual wells containing an anaerobic medium was verified by OD(600). Depending on the growth substrate, up to 80 % of the wells contained viable cultures, which could be transferred to fresh media. This method was used to isolate thermophilic microbes from Rabbit Creek, Yellowstone National Park (YNP), Wyoming. Substrates for enrichment cultures including crystalline cellulose (Avicel), xylan (from Birchwood), pretreated switchgrass and Populus were used to cultivate organisms that may be of interest to lignocellulosic biofuel production. PMID- 22843399 TI - Assessing the protein concentration in commercial enzyme preparations. AB - Although a poor indicator of how a cellulase preparation will perform on biomass, the filter paper unit (FPU) still finds wide use in the literature as an apparent measure of performance efficacy. In actuality, the assessment of commercial enzyme preparation performance in terms of biomass conversion or solubilization of insoluble polysaccharides is largely dependent on the substrate composition, which cannot be easily standardized. Commercial cellulase preparations are evaluated based upon their performance or specific activity. The ability to compare commercial enzyme preparation efficacy across a wide variety of different preparations requires defining the amount of enzyme protein required in milligrams per gram of cellulose to achieve a targeted level of cellulose hydrolysis in a specified timeframe. Since biomass substrates are highly variable, reproducible and accurate protein determination is as important as performance testing to be able to rank order the effectiveness of diverse preparations. This chapter describes a protocol that overcomes many of the difficulties encountered with determining the protein concentration in commercial cellulase preparations. PMID- 22843400 TI - Reducing the effect of variable starch levels in biomass recalcitrance screening. AB - Cell wall recalcitrance is the largest contributor to the high expense of lignocellulose conversion to biofuels (Himmel ME et al., Science 315:804-807, 2007). In response to this problem, researchers at the BioEnergy Science Center (BESC) are working to determine the contributing factors of biomass recalcitrance. The primary approach to this is screening large sample sets of genetic and environmental variants of model and feedstock plant species for differences in recalcitrance to combined hydrothermal pretreatment and enzymatic hydrolysis (Decker S et al., BioEnergy Res 2:179-192, 2009). To handle these large sample sets (up to several thousand samples per set), the BESC has developed high throughput screening systems to evaluate both cell wall composition and recalcitrance (Selig MJ et al., Biotechnol Lett 33:961-967, 2011; Selig MJ et al., Ind Biotechnol 6, 104-111, 2010). Molecular beam mass spectroscopy and high throughput, 2-stage acid hydrolysis are used to determine amounts and ratios of cell wall components such as lignin, cellulose, and xylan. Recalcitrance is measured by glucose and xylose release after high throughput hydrothermal pretreatment and enzymatic saccharification, screening large numbers (up to 1,000 s per week) of biomass samples (Selig MJ et al., Ind Biotechnol 6, 104-111, 2010; Sykes R et al., Methods Mol Biol 581, 169-183, 2009). Implementation of these high throughput techniques revealed additional concerns when screening biomass samples for recalcitrance, principal among these was the contribution of starch to glucose release quantitation in both compositional analysis and recalcitrance screening. PMID- 22843401 TI - Analysis of transgenic glycoside hydrolases expressed in plants: T. reesei CBH I and A. cellulolyticus EI. AB - Plant cell walls are composed of three basic structural biomolecules: cellulose, hemicellulose, and lignin with cellulose being the most abundant biopolymer on earth. Cellulose is composed of cellodextrins, which are linear polymers of glucose, and considered to be microcrystalline in structure. The conversion of cellulose to free glucose is one of the primary steps in the fermentative conversion of biomass to fuels and chemicals. However, the crystalline nature of this complex, noncovalent structure is highly resistant to enzymatic hydrolysis. Thus, the substantial cost currently associated with biomass saccharification primarily represents the cost of biomass degrading enzymes. Despite the fact that the microbial cellulose hydrolytic "machinery" for the recycling of carbon from plant biomass already exists in nature, the natural enzymatic degradation of plant material is typically a slow and complex process. Thus, if commercial biofuels production is to become a reality, it must be more cost-effective. One method proposed for achieving this objective is to express all or some of the requisite cellulolytic enzymes in planta, thus reducing both enzyme and thermochemical pretreatment costs. PMID- 22843402 TI - Structural characterization of the heteroxylans from poplar and switchgrass. AB - Heteroxylans are polysaccharides with a backbone composed of 1,4-linked beta-D xylosyl residues. In hardwoods some of these xylosyl residues are substituted at O-2 with 4-O-methyl alpha-D-glucuronic and occasionally with alpha-D-glucuronic acid. In grasses, the xylan backbone is predominantly substituted with alpha-L arabinofuranosyl residues (most often at O-3, but sometimes at O-2). Grass heteroxylan backbone residues may also have small amounts of alpha-D-glucuronic acid and/or 4-O-methyl alpha-D-glucuronic acid at O-2. Heteroxylans have a role in maintaining the structural integrity of the cell walls that comprise the bulk of lignocellulosic biomass. Moreover, differences in the molecular features of these hemicellulosic polysaccharides, including their degree of polymerization, degree of branching and spatial arrangement of side chains along the xylan backbone, have been correlated to altered cell wall properties (Izydorczyk MS, Biliaderis CG, Carbohydr Polym 28:33-48, 1995) and the ease with which biomass can be enzymatically converted to fermentable sugars. Thus, understanding the relationship between heteroxylan structure and biomass properties is required to engineer bioenergy crops with improved processing characteristics. In this chapter we describe some of the analytical methods we routinely use to perform in depth structural analysis of heteroxylans from poplar and switchgrass biomass. PMID- 22843403 TI - Laser microdissection and genetic manipulation technologies to probe lignin heterogeneity and configuration in plant cell walls. AB - Single and multiple T-DNA knockouts of genes encoding arogenate dehydratases (ADTs) in Arabidopsis were obtained in homozygous form. These were analyzed for potential differences in lignin contents and compositions, as well as for distinct phenotypes over growth and development. Of these different lines, distinct reductions in lignin contents were obtained, with those having different G:S ratios depending upon the combination of ADT genes being knocked out. Results from pyrolysis GC/MS analyses indicated that differential carbon flux occurred into the vascular bundles (vb) and interfascicular fibers (if). These results provide additional new insight into factors controlling lignin heterogeneity and configuration. PMID- 22843404 TI - Lignin-degrading enzyme activities. AB - Over the past three decades, the activities of four kinds of enzyme have been purported to furnish the mechanistic foundations for macromolecular lignin depolymerization in decaying plant cell walls. The pertinent fungal enzymes comprise lignin peroxidase (with a relatively high redox potential), manganese peroxidase, an alkyl aryl etherase, and laccase. The peroxidases and laccase, but not the etherase, are expressed extracellularly by white-rot fungi. A number of these microorganisms exhibit a marked preference toward lignin in their degradation of lignocellulose. Interestingly, some white-rot fungi secrete both kinds of peroxidase but no laccase, while others that are equally effective express extracellular laccase activity but no peroxidases. Actually, none of these enzymes has been reported to possess significant depolymerase activity toward macromolecular lignin substrates that are derived with little chemical modification from the native biopolymer. Here, the assays commonly employed for monitoring the traditional fungal peroxidases, alkyl aryl etherase, and laccase are described in their respective contexts. A soluble native polymeric substrate that can be isolated directly from a conventional milled-wood lignin preparation is characterized in relation to its utility in next-generation lignin depolymerase assays. PMID- 22843405 TI - Abstracts of the RAMI Section of Interns Study Day of the Royal Academy of Medicine in Ireland. April 21, 2012. PMID- 22843407 TI - Brain. Editorial. PMID- 22843406 TI - Experiences from occupational exposure limits set on aerosols containing allergenic proteins. AB - Occupational exposure limits (OELs) together with determined airborne exposures are used in risk assessment based managements of occupational exposures to prevent occupational diseases. In most countries, OELs have only been set for few protein-containing aerosols causing IgE-mediated allergies. They comprise aerosols of flour dust, grain dust, wood dust, natural rubber latex, and the subtilisins, which are proteolytic enzymes. These aerosols show dose-dependent effects and levels have been established, where nearly all workers may be exposed without adverse health effects, which are required for setting OELs. Our aim is to analyse prerequisites for setting OELs for the allergenic protein-containing aerosols. Opposite to the key effect of toxicological reactions, two thresholds, one for the sensitization phase and one for elicitation of IgE-mediated symptoms in sensitized individuals, are used in the OEL settings. For example, this was the case for flour dust, where OELs were based on dust levels due to linearity between flour dust and its allergen levels. The critical effects for flour and grain dust OELs were different, which indicates that conclusion by analogy (read across) must be scientifically well founded. Except for subtilisins, no OEL have been set for other industrial enzymes, where many of which are high volume chemicals. For several of these, OELs have been proposed in the scientific literature during the last two decades. It is apparent that the scientific methodology is available for setting OELs for proteins and protein-containing aerosols where the critical effect is IgE sensitization and IgE-mediated airway diseases. PMID- 22843408 TI - How Dravet syndrome became a model for studying childhood genetic epilepsies. PMID- 22843409 TI - Is the migrainous female brain different? Some new evidence. PMID- 22843410 TI - Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy. AB - Learning and memory dysfunction is the most common neuropsychological effect of mesial temporal lobe epilepsy, and because the underlying neurobiology is poorly understood, there are no pharmacological strategies to help restore memory function in these patients. We have demonstrated impairments in the acquisition of an allocentric spatial task, in patients with unilateral hippocampal sclerosis. We also show that patients have accelerated forgetting of the learned spatial task and that this is associated with damage to the non-dominant hippocampal formation. We go on to show a very similar pattern of chronic allocentric learning and accelerated forgetting in a status epilepticus model of mesial temporal lobe epilepsy in rats, which is associated with reduced and abnormal hippocampal neurogenesis. Finally, we show that reversal of the neurogenic deficit using fluoxetine is associated with reversal of the learning deficit but not the accelerated forgetting, pointing to a possible dissociation in the underlying mechanisms, as well as a potential therapeutic strategy for improving hippocampal-dependent learning in patients with mesial temporal lobe epilepsy. PMID- 22843411 TI - Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado Joseph disease. AB - Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease. PMID- 22843412 TI - The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow. AB - Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 +/- 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 +/- 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 +/- 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 +/- 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H(2)(15)O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA associated parkinsonism. PMID- 22843413 TI - The catechol-O-methyltransferase Val(158)Met polymorphism modulates fronto cortical dopamine turnover in early Parkinson's disease: a PET study. AB - Cognitive deficits occur in up to 30% of patients with early Parkinson's disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinson's disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinson's disease as a function of the catechol-O methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinson's disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinson's disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4 dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinson's disease. PMID- 22843414 TI - Her versus his migraine: multiple sex differences in brain function and structure. AB - Migraine is twice as common in females as in males, but the mechanisms behind this difference are still poorly understood. We used high-field magnetic resonance imaging in male and female age-matched interictal (migraine free) migraineurs and matched healthy controls to determine alterations in brain structure. Female migraineurs had thicker posterior insula and precuneus cortices compared with male migraineurs and healthy controls of both sexes. Furthermore, evaluation of functional responses to heat within the migraine groups indicated concurrent functional differences in male and female migraineurs and a sex specific pattern of functional connectivity of these two regions with the rest of the brain. The results support the notion of a 'sex phenotype' in migraine and indicate that brains are differentially affected by migraine in females compared with males. Furthermore, the results also support the notion that sex differences involve both brain structure as well as functional circuits, in that emotional circuitry compared with sensory processing appears involved to a greater degree in female than male migraineurs. PMID- 22843415 TI - Impaired autophagic function in rat islets with aging. AB - Type 2 diabetes is characterized by a deficit in beta-cell function and mass, and its incidence increases with age. Autophagy is a highly regulated intracellular process for degrading cytoplasmic components, particularly protein aggregates and damaged organelles. Impaired or deficient autophagy is believed to cause or contribute to aging and age-related disease. Autophagy may be necessary to maintain structure, mass, and function of pancreatic beta-cells. In this study, we investigated the effects of age on beta-cell function and autophagy in pancreatic islets of 4-month-old (young), 14-month-old (adult), and 24-month-old (old) male Wistar rats. We found that islet beta-cell function decreased gradually with age. Protein expression of the autophagy markers LC3/Atg8 and Atg7 exhibited a marked decline in aged islets. The expression of Lamp-2, a good indicator of autophagic degradation rate, was significantly reduced in the islets of old rats, suggesting that autophagic degradation is decreased in the islets of aged rats. However, protein expression of beclin-1/Atg6, which plays an important role in the induction and formation of the pre-autophagosome structure by associating with a multimeric complex of autophagy regulatory proteins (Atg14, Vps34/class 3 PI3 kinase, and Vps15), was most prominent in the islets of adult rats, and was higher in 24-month-old islets than in 4-month-old islets. The levels of p62/SQSTM1 and polyubiquitin aggregates, representing the functions of autophagy and proteasomal degradation, were increased in aging islets. 8 Hydroxydeoxyguanosine, a marker of mitochondrial and nuclear DNA oxidative damage, exhibited strong immunostaining in old islets. Analysis by electron microscopy demonstrated swelling and disintegration of cristae in the mitochondria of aged islets. These results suggest that beta-cell and autophagic function in islets decline simultaneously with increasing age in Wistar rats, and that impaired autophagy in the islets of older rats may cause accumulation of misfolded and aggregated proteins and reduce the removal of abnormal mitochondria in beta-cells, leading to reduced beta-cell function. Dysfunctional autophagy in islets during the aging process may be an important mechanism leading to the development of type 2 diabetes. PMID- 22843416 TI - Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes. AB - Human pluripotent stem cells (hPSCs) have arisen as a source of cells for biomedical research due to their developmental potential. Stem cells possess the promise of providing clinicians with novel treatments for disease as well as allowing researchers to generate human-specific cellular metabolism models. Aging is a natural process of living organisms, yet aging in human heart cells is difficult to study due to the ethical considerations regarding human experimentation as well as a current lack of alternative experimental models. hPSC-derived cardiomyocytes (CMs) bear a resemblance to human cardiac cells and thus hPSC-derived CMs are considered to be a viable alternative model to study human heart cell aging. In this study, we used hPSC-derived CMs as an in vitro aging model. We generated cardiomyocytes from hPSCs and demonstrated the process of aging in both human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived CMs. Aging in hESC-derived CMs correlated with reduced membrane potential in mitochondria, the accumulation of lipofuscin, a slower beating pattern, and the downregulation of human telomerase RNA (hTR) and cell cycle regulating genes. Interestingly, the expression of hTR in hiPSC-derived CMs was not significantly downregulated, unlike in hESC-derived CMs. In order to delay aging, vitamin C was added to the cultured CMs. When cells were treated with 100 MUM of vitamin C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging cells, were observed. Taken together, these results suggest that hPSC-derived CMs can be used as a unique human cardiomyocyte aging model in vitro and that vitamin C shows anti-aging effects in this model. PMID- 22843417 TI - The effect of behavioural risk factors on osteoporosis in Irish women. AB - BACKGROUND: Osteoporosis constitutes a major public health concern and its underlying pathogenesis is complex and multifactorial. Although hereditary factors strongly contribute to bone health, behavioural factors can modulate the genetically determined pattern of skeletal modelling and remodelling. AIM: The aim of this study was to investigate the effect(s) of behavioural risk factors on osteoporosis in Irish women. METHODS: Pre- and post-menopausal adult women (n = 189; 44 +/- 15 years) participated in this cross-sectional study. Demographic, anthropometric and lifestyle data were collected during a single clinic visit. Dietary calcium intake and lifetime physical activity (PA) were assessed for each subject. Lumbar and femoral bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA). Multivariate analysis was used to determine the independent predictors of low BMD. RESULTS: Low BMD was present in 59% of subjects (42% pre- and 77% post-menopausal). Smoking was the strongest behavioural predictor of lumbar and femoral BMD. Age, height, family history, smoking, metabolic (MET) and mechanical (MECH) PA (lifetime) and weight (body mass) accounted for 39% of the variance in lumbar BMD. Age, height, family history, alcohol consumption, MET and MECH PA (lifetime) and weight accounted for 41% of the variance in femoral BMD. CONCLUSIONS: Prevalence of osteopenia and osteoporosis is high in Irish women and is associated with modifiable risk factors. A clearer focus should be paid to educate Irish women on preventative health behaviours for osteoporosis to curb the prevalence of this disease and the human and fiscal costs associated with it. PMID- 22843418 TI - Comparative studies of saponins in 1-3-year-old main roots, fibrous roots, and rhizomes of Panax notoginseng, and identification of different parts and growth year samples. AB - Notoginsenosides R1, R4, Fa, and K (N-R1, N-R4, N-Fa, and N-K), as well as ginsenosides Rg1, Rb1, Rd, Re, Rf, Rg2 and Rh1 (G-Rg1, G-Rb1, G-Rd, G-Re, G-Rf, G Rg2 and G-Rh1) in 47 Notoginseng samples including 1-, 2- and 3-year-old main roots, rhizomes and fibrous roots of Panax notoginseng were determined by high performance liquid chromatography-diode array detection method. Total contents (%) of the 11 saponins were 9.82-14.57 for 2-year old and 14.20-16.00 for 3-year old rhizomes; 2.72-4.50 for 2-year-old and 1.98-4.92 for 3-year-old fibrous roots; 1.75-3.05 for 1-year-old whole roots; and 3.71-8.98 for 2-year-old and 7.03-11.23 for 3-year-old main roots. Contents of most saponins and total content of 11 saponins were in the order 3- >2- >1-year-old main root samples. G-Rf content, sum of G-Rf and G-Rh1 were, respectively, 0.08-0.18 and 0.14-0.32 for 2- or 3-year-old rhizomes, and 0.01-0.07 and 0.03-0.10 for 2- or 3-year-old main roots. Combined contents of N-R1, G-Rg1 and G-Rb1 were 5.78-9.37 in 3-year-old main roots, and 2.99-7.13 in 2-year-old main roots, of which nearly one-third of samples were lower than the limit (5 %) in the Chinese Pharmacopoeia. Those of 2- or 3-year-old fibrous roots (1.47-3.83) and 1-year-old whole roots (1.41-2.44) were much lower than the limit, and were considered not suitable for use as Notoginseng. Two-year-old main roots are not appropriate for collection as Notoginseng. Different parts and growth years of P. notoginseng can be identified from each another according to differences in saponin content. PMID- 22843419 TI - Subdural hematoma caused by epithelioid angiosarcoma originating from the skull. AB - Cancers metastatic to the skull or dura may cause subdural hematoma (SDH). However, the frequency is low, and the presence of underlying cancers has almost always been known in such situations. We report a case of skull angiosarcoma manifesting as SDH, posing a diagnostic challenge to physicians. A 75-year-old man visited our clinic with sensorimotor disturbance of gradual onset approximately 1 month after a minor head trauma. He was diagnosed with SDH after imaging studies, and underwent surgery to evacuate the hematoma. Because the hematoma was organized, surgery was switched from burr-hole drainage to craniotomy. The bone flap as well as the dura over the hematoma had grossly normal appearance, and only the hematoma itself was submitted for histological examination. Although postoperative recovery was uneventful, the patient experienced recurrence of the SDH 2 months after surgery. At the second surgery, the bone flap and dura were intermingled with tumor tissue, and histological examination revealed that an epithelioid angiosarcoma originating from the skull was responsible for the SDH. Timely diagnosis of angiosarcoma manifesting as SDH is difficult because of its rarity. In retrospect, however, the diagnosis might have been established earlier if the bone flap and/or the dura had been biopsied at the time of the first surgery. The present case gives us a lesson that SDH may be an unusual manifestation of malignant tumors of skull or dural origin, and histological examination of not only hematoma capsule but also of the surrounding tissues may provide important diagnostic clues. PMID- 22843420 TI - International models of investigator-initiated trials: implications for Japan. AB - BACKGROUND: Academic/institutional investigator-initiated clinical trials benefit individuals and society by supplementing gaps in industry-sponsored clinical trials. MATERIALS: In May 2010, experts from Japan, the Republic of Korea, the UK, and the United States, met at a symposium in Tokyo, Japan, to discuss how policies related to the conduct of clinical trials, which have been shown to be effective, may be applied to other regions of the world. RESULTS: In order to increase the availability of anticancer drugs world-wide, nations including Japan should examine the benefits of increasing the number of investigator-initiated clinical trials. These trials represent one of the most effective ways to translate basic scientific knowledge into clinical practice. These trials should be conducted under GCP guidelines and include Investigational New Drug application submissions with the ultimate goal of future drug approval. CONCLUSIONS: To maximize the effectiveness of these trials, a policy to educate health care professionals, cancer patients and their families, and the public in general on the benefits of clinical trials should be strengthened. Finally, policies that expedite the clinical development of novel cancer drugs which have already been shown to be effective in other countries are needed in many nations including Japan to accelerate drug approval. PMID- 22843422 TI - Using personal qualities assessment to measure the moral orientation and personal qualities of medical students in a non-Western culture. AB - How to select candidates with appropriate personal qualities for medical school is an important issue. This study examined the psychometric properties and group differences of the Personal Qualities Assessment (PQA) to test the feasibility of using it as a tool to assess the medical school applicants in a non-Western culture. Seven hundred forty-six medical students in Taiwan completed two psychometric measures: Mojac to assess moral orientation and NACE to assess four aspects of interpersonal relationships. Thirty-one students completed the tests twice to establish test-retest reliability. A subsample of 127 students also completed a measure of the "Big Five" personality traits to examine the construct validity of these scales. Both Mojac and NACE had acceptable internal consistency and test-retest reliability. Conceptually, coherent and significant relationships were observed between test components and between the NACE and Big Five. NACE but not Mojac varied significantly between different sociodemographic groups. Both tests demonstrated acceptable psychometric properties. However, the predictive validity of PQA requires future studies. PMID- 22843421 TI - Mechanisms of BRCA1 tumor suppression. AB - The p220 BRCA1 tumor suppressor protein has been implicated in multiple biochemical and biologic functions since its molecular cloning 18 years ago. Here, we discuss those functions most relevant for its tumor-suppressing activities with an emphasis on new findings. In particular, this review focuses on what is known of the activities of those BRCA1-binding partners that have tumor suppressor functions, on the reversion of mutant BRCA1 alleles concomitant with therapy resistance, on insights gained from studies of BRCA1 structure function relationships, recent findings from animal models, and the potential role of BRCA1 in some nonhereditary tumors. From this information, a more detailed and refined picture of BRCA1 tumor suppression is beginning to emerge. Although key mysteries remain--such as why BRCA1 tumor suppression is focused on carcinomas of the breast and ovary--the pace of discovery is increasing. SIGNIFICANCE: BRCA1 functions as a clinically important classical tumor suppressor in hereditary breast and ovarian cancer; here, we review progress in understanding how BRCA1 operates to suppress tumor formation. PMID- 22843423 TI - The cultural competence of health care professionals: conceptual analysis using the results from a national pilot study of training and assessment. AB - The cultural competence of health professionals affects the satisfaction with, and outcomes of, patient care. Patient-centered cultural training was implemented with 76 trainees. Four months later, they were assessed using standardized patient scenarios and their performance compared to a control group. A questionnaire was used to evaluate the training. Assessment scores were analyzed using t tests to compare groups. Interrater reliability was calculated for individual scenarios. The cultural training received positive evaluations with many trainees indicating their intention to change future practice. Those who received cultural training gained higher scores upon assessment than those who had not. This difference was significant for three scenarios with nonclinical evaluators. Interrater reliability ranged from .913 to .427. The significant difference in performance between the groups supports the validity and educational impact of this approach. However, variable reliability highlights the difficulties with developing robust assessments in this area that are feasible within resource constraints. PMID- 22843424 TI - Analysis of redox responses during TNT transformation by Clostridium acetobutylicum ATCC 824 and mutants exhibiting altered metabolism. AB - The transformation of trinitrotoluene (TNT) by several mutant strains of Clostridium acetobutylicum has been examined to analyze the maximal rate of initial transformation, determine the effects of metabolic mutations of the host on transformation rate, and to assess the cell metabolic changes brought about during TNT transformation. Little difference in the maximal rate of TNT degradation in early acid phase cultures was found between the parental ATCC 824 strain and strains altered in the acid forming pathways (phosphotransacetylase, or butyrate kinase) or in a high-solvent-producing strain (mutant B). This result is in agreement with the previous findings of a similar degradation rate in a degenerate strain (M5) that had lost the ability to produce solvent. A series of antisense constructs were made that reduced the expression of hydA, encoding the Fe-hydrogenase, or hydE and hydF, genes encoding hydrogenase maturating proteins. While the antisense hydA strain had only ~30 % of the activity of wild type, the antisense hydE strain exhibited a TNT degradation rate around 70 % that of the parent. Overexpression of hydA modestly increased the TNT degradation rate in acid phase cells, suggesting the amount of reductant flowing into hydrogenase rather than the hydrogenase level itself was a limiting factor in many situations. The redox potential, hydrogen evolution, and organic acid metabolites produced during rapid TNT transformation in early log phase cultures were measured. The redox potential of the acid-producing culture decreased from -370 to -200 mV immediately after addition of TNT and the hydrogen evolution rate decreased, lowering the hydrogen to carbon dioxide ratio from 1.4 to around 1.1 for 15 min. During the time of TNT transformation, the treated acidogenic cells produced less acetate and more butyrate. The results show that during TNT transformation, the cells shift metabolism away from hydrogen formation to reduction of TNT and the resulting effects on cell redox cofactors generate a higher proportion of butyrate. PMID- 22843425 TI - Biotechnological production of arbutins (alpha- and beta-arbutins), skin lightening agents, and their derivatives. AB - Arbutins (alpha- and beta-arbutins) are glycosylated hydroquinones that are commercially used in the cosmetic industry. These compounds have an inhibitory function against tyrosinase, a critical enzyme for generating pigments, which leads to the prevention of melanin formation, resulting in a whitening effect on the skin. Although beta-arbutin is found in various plants including bearberry, wheat, and pear, alpha-arbutin and other arbutin derivatives are synthesized by chemical and enzymatic methods. This article presents a mini-review of recent studies on the production of alpha-arbutin and other alpha- and beta-arbutin derivatives via enzymatic bioconversion methods. In addition, the structures of alpha- and beta-arbutin derivatives and their biological activities are discussed. The catalytic characteristics of various enzymes used in the biosynthesis of arbutin derivatives are also reviewed. PMID- 22843426 TI - The inverse problem of bioelectricity: an evaluation. AB - This invited paper presents a personal view on the current status of the solution to the inverse problem of bioelectricity. Its focus lies on applications in the field of electrocardiography. The topic discussed is also relevant in other medical domains, such as electroencephalography, electroneurography and electromyography. In such domains the methodology involved rests on the same basic principles of physics and electrophysiology as well as on the applied techniques of signal analysis and numerical analysis. PMID- 22843427 TI - Pharmacological management of co-morbid conditions at the end of life: is less more? AB - BACKGROUND: Co-morbid conditions (CMCs) are present in over half of patients with cancer over 50 years of age. As life-limiting illnesses progress, the benefits and burdens of treatments for CMCs become unclear. Relevant issues include physiological changes in advanced illness, time-to-benefit of medications, burden of medications, and psychological impact of discontinuing medications. Optimal prescribing is unclear due to lack of evidence. OBJECTIVES: The objectives are to determine prescribing practice, for CMCs, in a single SPC service. METHODS: Patients referred to a single specialist palliative care (SPC) service, who died between 1/8/2010 and 30/9/2012, were identified. Medical notes were reviewed, and data collected on prescribing at 3 months, 1 month, and 1 week prior to death. RESULTS: Fifty-two patients with a median age of 74.5 years were identified; 41 patients (79%) had a malignant condition. 50% died in hospital. Patients had a mean of three CMCs. A mean of 4.6 medications for CMCs were prescribed to patients over 65. A mean of 10 medications in total were prescribed at 1 week before death. One week before death, one-third of patients continued to be prescribed aspirin, and over one-quarter a statin. CONCLUSIONS: Total medication burden increases as time to death shortens, due to continuation of medications for CMCs, and addition of medications for symptom control. There is a need for research to demonstrate the impact of polypharmacy at the end of life, in order to formulate a framework to guide practice. PMID- 22843428 TI - [Solid salivary gland tumors]. PMID- 22843429 TI - Representations from the past: social relations and the devolution of social representations. AB - Psychological life is subject to the influence of a constructed and potentially reconstituted past, as well as to future anticipated outcomes and expectations. Human behaviour occurs along a temporal trajectory that marks the projects individuals adopt in their quests of human action. Explanations of social behaviour are limited insofar as they exclude a historical concern with human purpose. In this paper, we draw on Bartlett's notion of collective remembering to argue that manifest social relations are rooted in past events that give present behaviours meaning and justification. We further propose an epidemiological time series framework for social representations, that are conceptualised as evolving over time and that are subject to a 'ratchet effect' that perpetuates meaning in a collective. We argue that understanding forms of social behaviour that draw on lay explanations of social relations requires a deconstructive effort that maps the evolutionary trajectory of a representational project in terms of its adaptation over time. We go on to illustrate our proposal visiting data that emerged in an inquiry investigating Maltese immigrants' perspectives towards their countries of settlement and origin. This data reveals an assimilationist acculturation preference amongst the Maltese in Britain that seems incongruous with the current climate of European integration and Maltese communities in other countries around the world. We demonstrate that a historical concern with regard to this apparent behaviour helps explain how Maltese immigrants to Britain opt for certain forms of intercultural relations than others that are normally preferable. We demonstrate that these preferences rely on an evolved justification of the Maltese getting by with foreign rulers that other scholars have traced back to the medieval practice of chivalry. PMID- 22843430 TI - Neural oscillators triggered by loading and hip orientation can generate activation patterns at the ankle during walking in humans. AB - Spinal pattern generators (SPGs), which are neural networks without a central input from the brain may be responsible for controlling locomotion. In this study, we used neural oscillators to examine the rhythmic patterns generated at the ankle during walking. Seven healthy male subjects were requested to walk at their normal self-selected speed on a treadmill. Force measurements acquired from pressure insoles, electromyography and kinematic data were captured simultaneously. The SPG model consisted of a simple oscillator made up of two neurons; one neuron will activate an ankle extensor and the other will activate an ankle flexor. The outputs of the oscillator represented the muscle activation of each muscle. A nonlinear least squares algorithm was used to determine a set of parameters that would optimise the differences between model output and experimental data. Insole forces and hip angles of six consecutive strides were used as inputs to the model, which generated outputs that closely fitted experimental data. Our results showed that it is possible to reproduce muscle activations using neural oscillators. A close correlation between simulated and measured muscle activations indicated that spinal control should not be underestimated in models of human locomotion. PMID- 22843431 TI - Validation of an instrument for assessing teacher knowledge of basic language constructs of literacy. AB - Recent national reports have stressed the importance of teacher knowledge in teaching reading. However, in the past, teachers' knowledge of language and literacy constructs has typically been assessed with instruments that are not fully tested for validity. In the present study, an instrument was developed; and its reliability, item difficulty, and item discrimination were computed and examined to identify model fit by applying exploratory factor analysis. Such analyses showed that the instrument demonstrated adequate estimates of reliability in assessing teachers' knowledge of language constructs. The implications for professional development of in-service teachers as well as preservice teacher education are also discussed. PMID- 22843432 TI - MicroRNA-125b-1 accelerates a C-terminal mutant of C/EBPalpha (C/EBPalpha-C(m)) induced myeloid leukemia. AB - MicroRNA-125b-1 (miR-125b-1) is a target of the chromosomal translocations t(11;14)(q24;q32) and t(2;11)(p21;q23), which are found in human B-lymphoid and myeloid malignancies, respectively. These translocations result in overexpression of mature miR-125b, consisting of 22 nucleotides. To analyze the role of miR-125b 1 in leukemogenesis, we created a bone marrow transplantation model using a retrovirus vector containing GFP expression elements. Sole transduction of miR 125b-1 into bone marrow cells resulted in expansion of hematopoietic cells expressing GFP. Compared with cells lacking GFP expression, we observed that GFP(+)/CD11b(+) or GFP(+)/Gr(-)1(+) cells were increased in the bone marrow and spleen. Although previous studies reported sole induction of miR-125b-induced leukemia, we did not find leukemic transformation in our model. Transduction of miR-125b-1 did accelerate myeloid tumors induced by a C-terminal mutant of CAAT enhancer binding protein (C/EBPalpha-C(m)), a class II-like mutation. As miR-125b has been shown to hasten the development of leukemia in a BCR/ABL-transduced animal model, our present results support the conclusion that overexpression of miR-125b cooperates with other genetic alterations in the pathogenesis of myeloid malignancies. PMID- 22843433 TI - An EFSUMB introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for quantification of tumour perfusion. AB - Dynamic Contrast Enhanced Ultrasound (DCE-US) is an imaging technique that utilizes microbubble contrast agents in diagnostic ultrasound. The EFSUMB guidelines published in 2004, updated in 2008 and 2011 focused on the use of DCE US, including essential technical requirements, training, investigational procedures and steps, guidance on image interpretation, established and recommended clinical indications and safety considerations. However the quantification of images acquired with ultrasound contrast agents (UCAs) is not discussed in the guidelines. The purpose of this EFSUMB document is to provide some recommendations and descriptions of the quantification of ultrasound images, technical requirements for analysis of time-intensity curves (TICs), methodology for data analysis, and interpretation of the results. PMID- 22843434 TI - Occupational exposure to diesel engine emissions and risk of lung cancer: evidence from two case-control studies in Montreal, Canada. AB - OBJECTIVE: To examine the risk of lung cancer among men associated with exposure to diesel engine emissions incurred in a wide range of occupations and industries. METHODOLOGY: 2 population-based lung cancer case-control studies were conducted in Montreal. Study I (1979-1986) comprised 857 cases and 533 population controls; study II (1996-2001) comprised 736 cases and 894 population controls. A detailed job history was obtained, from which we inferred lifetime occupational exposure to 294 agents, including diesel engine emissions. ORs were estimated for each study and in the pooled data set, adjusting for socio-demographic factors, smoking history and selected occupational carcinogens. While it proved impossible to retrospectively estimate absolute exposure concentrations, there were estimates and analyses by relative measures of cumulative exposure. RESULTS: Increased risks of lung cancer were found in both studies. The pooled analysis showed an OR of lung cancer associated with substantial exposure to diesel exhaust of 1.80 (95% CI 1.3 to 2.6). The risk associated with substantial exposure was higher for squamous cell carcinomas (OR 2.09; 95% CI 1.3 to 3.2) than other histological types. Joint effects between diesel exhaust exposure and tobacco smoking are compatible with a multiplicative synergistic effect. DISCUSSION: Our findings provide further evidence supporting a causal link between diesel engine emissions and risk of lung cancer. The risk is stronger for the development of squamous cell carcinomas than for small cell tumours or adenocarcinomas. PMID- 22843436 TI - Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts. PMID- 22843435 TI - Associations of multiple metals with kidney outcomes in lead workers. AB - OBJECTIVES: Environmental exposure to multiple metals is common. A number of metals cause nephrotoxicity with acute and/or chronic exposure. However, few epidemiologic studies have examined the impact of metal coexposure on kidney function. Therefore, the authors evaluated associations of antimony and thallium with kidney outcomes and assessed the impact of cadmium exposure on those associations in lead workers. METHODS: Multiple linear regression was used to examine associations between ln-urine thallium, antimony and cadmium levels with serum creatinine- and cystatin-C-based glomerular filtration measures and ln urine N-acetyl-beta-D-glucosaminidase (NAG). RESULTS: In 684 participants, median urine thallium and antimony were 0.39 and 0.36 MUg/g creatinine, respectively. After adjustment for lead dose, urine creatinine and kidney risk factors, higher ln-urine thallium was associated with higher serum creatinine- and cystatin-C based estimates of glomerular filtration rate; associations remained significant after adjustment for antimony and cadmium (regression coefficient for serum creatinine-based estimates of glomerular filtration rate =5.2 ml/min/1.73 m2; 95% CI =2.4 to 8.0). Antimony associations with kidney outcomes were attenuated by thallium and cadmium adjustment; thallium and antimony associations with NAG were attenuated by cadmium. CONCLUSIONS: Urine thallium levels were significantly associated with both serum creatinine- and cystatin-C-based glomerular filtration measures in a direction opposite that expected with nephrotoxicity. Given similarities to associations recently observed with cadmium, these results suggest that interpretation of urine metal values, at exposure levels currently present in the environment, may be more complex than previously appreciated. These results also support multiple metal analysis approaches to decrease the potential for inaccurate risk conclusions. PMID- 22843437 TI - Environmental tobacco smoke and the risk of pancreatic cancer among non-smokers: a meta-analysis. AB - BACKGROUND: Experimental studies have linked exposure to tobacco-specific nitrosamines with pancreatic carcinogenesis. A number of epidemiological studies have examined the association between environmental tobacco smoke (ETS) and risk of pancreatic cancer but they have not yet been jointly summarised. OBJECTIVES: To investigate the association between exposure to ETS and risk of pancreatic cancer by systematically reviewing and synthesising the available evidence. METHODS: We conducted a comprehensive literature search using MEDLINE and EMBASE and manual searching of the reference lists of the relevant research reports and review articles to identify full texts and abstracts published through October 2011. We used the random-effects model to pool summary relative risks (RR) comparing the highest category of exposure to ETS to people who had never been exposed. RESULTS: Exposure to ETS during childhood was not associated with risk of pancreatic cancer (three prospective and two retrospective studies; summary RR 1.12; 95% CI 0.89 to 1.43). In addition, no association was found with exposure to ETS during adulthood at home (five prospective and three retrospective studies; summary RR 1.23; 95% CI 0.86 to 1.77) or at work (one prospective and two retrospective studies; summary RR 0.94; 95% CI 0.67 to 1.33). CONCLUSIONS: This meta-analysis does not provide evidence for an association between exposure to ETS and risk of pancreatic cancer. PMID- 22843438 TI - The study of the relation between maternal occupational exposure to solvents and birth defects should include oxygenated solvents. PMID- 22843439 TI - Changes in lymphocyte subsets in workers exposed to 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD). AB - OBJECTIVES: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to have toxic effects on the haematopoietic system in animals but epidemiological studies in humans have shown inconsistent results. In this cross-sectional study we investigated changes in peripheral blood cell counts and lymphocyte subsets among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: Forty-seven workers who had been exposed to high levels of TCDD in the past and 38 low-exposed workers were included in the current investigation. Complete blood counts and differential and major lymphocyte subsets were analysed. Current plasma levels of TCDD (TCDD(current)) were determined by high-resolution gas chromatography/isotope dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDD(max)) were estimated using a one-compartment first order kinetic model. RESULTS: Cell counts and lymphocyte subsets were similar between high- and low-exposed workers, except for a non-dose dependent increase in CD4/CD8 ratio among high-exposed workers. Interestingly, most lymphocyte subsets, in particular the B cell compartment, showed a decrease with increasing levels of both TCDD(current) and TCDD(max). CONCLUSIONS: Overall, our study showed that plasma TCDD levels had no effect on white blood cell counts and major subsets. However, a non-significant decrease in most lymphocyte subsets was noted, with the strongest effect for B cells. The latter finding may suggest that dioxin exposure might have an adverse impact on the haematopoietic system and lends some support to B cell lymphoma induction by dioxin. PMID- 22843440 TI - Comparison of two expert-based assessments of diesel exhaust exposure in a case control study: programmable decision rules versus expert review of individual jobs. AB - OBJECTIVES: Professional judgment is necessary to assess occupational exposure in population-based case-control studies; however, the assessments lack transparency and are time-consuming to perform. To improve transparency and efficiency, we systematically applied decision rules to questionnaire responses to assess diesel exhaust exposure in the population-based case-control New England Bladder Cancer Study. METHODS: 2631 participants reported 14 983 jobs; 2749 jobs were administered questionnaires ('modules') with diesel-relevant questions. We applied decision rules to assign exposure metrics based either on the occupational history (OH) responses (OH estimates) or on the module responses (module estimates); we then combined the separate OH and module estimates (OH/module estimates). Each job was also reviewed individually to assign exposure (one-by-one review estimates). We evaluated the agreement between the OH, OH/module and one-by-one review estimates. RESULTS: The proportion of exposed jobs was 20-25% for all jobs, depending on approach, and 54-60% for jobs with diesel-relevant modules. The OH/module and one-by-one review estimates had moderately high agreement for all jobs (kappa(w)=0.68-0.81) and for jobs with diesel-relevant modules (kappa(w)=0.62-0.78) for the probability, intensity and frequency metrics. For exposed subjects, the Spearman correlation statistic was 0.72 between the cumulative OH/module and one-by-one review estimates. CONCLUSIONS: The agreement seen here may represent an upper level of agreement because the algorithm and one-by-one review estimates were not fully independent. This study shows that applying decision-based rules can reproduce a one-by-one review, increase transparency and efficiency, and provide a mechanism to replicate exposure decisions in other studies. PMID- 22843442 TI - Ulnar neuropathy and ulnar neuropathy-like symptoms in relation to biomechanical exposures assessed by a job exposure matrix: a triple case-referent study. AB - OBJECTIVES: We aimed to evaluate relations between occupational biomechanical exposures and (1) ulnar neuropathy confirmed by electroneurography (ENG) and (2) ulnar neuropathy-like symptoms with normal ENG. METHODS: In this triple case referent study, we identified all patients aged 18-65 years, examined with ENG at a neurophysiological department on suspicion of ulnar neuropathy, 2001-2007. We mailed a questionnaire to 546 patients with ulnar neuropathy, 633 patients with ulnar neuropathy-like symptoms and two separate groups of community referents, matched on sex, age and primary care centre (risk set sampling). The two patient groups were also compared to each other directly. We constructed a Job Exposure Matrix to provide estimates of exposure to non-neutral postures, repetitive movements, hand-arm vibrations and forceful work. Conditional and unconditional logistic regressions were used. RESULTS: The proportion who responded was 59%. Ulnar neuropathy was related to forceful work with an exposure-response pattern reaching an OR of 3.85 (95% CI 2.04 to 7.24); non-neutral postures strengthened effects of forceful work. No relation was observed with repetitive movements. Ulnar neuropathy-like symptoms were related to repetitive movements with an OR of 1.89 (95% CI 1.01 to 3.52) in the highest-exposure category (>=2.5 h/day); forceful work was unrelated to the outcome. CONCLUSIONS: Ulnar neuropathy and ulnar neuropathy-like symptoms differed with respect to associations with occupational biomechanical exposures. Findings suggested specific effects of forceful work on the ulnar nerve. Thus, results corroborated the importance of an electrophysiological diagnosis when evaluating risk factors for ulnar neuropathy. Preventive effects may be achieved by reducing biomechanical exposures at work. PMID- 22843441 TI - Prenatal exposure to traffic-related air pollution and fetal growth in a cohort of pregnant women. AB - OBJECTIVES: Scant evidence is available on effects of air pollution on longitudinally measured fetal biometry, and thus it remains unclear as to whether there are critical windows of exposure or specificity of effects. Our objective was to examine the association between exposure to nitrogen dioxide (NO2) during pregnancy and fetal and neonatal anthropometry in a cohort of Spanish women. METHODS: Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses. Biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) were evaluated in each trimester by ultrasound. As neonatal outcomes, weight, length and head circumference were analysed. SD scores adjusted by gestational age, mother characteristics and fetus sex were calculated at 12, 20 and 32 weeks of gestation as well as at birth. The association between fetal growth and average exposure to NO2 in the relevant windows was investigated using regression models, adjusted for socio-demographic and lifestyle-related variables. RESULTS: Exposure to NO2 was inversely associated with BPD, AC and EFW at week 32 and with growth in these parameters in weeks 20-32. BPD and FL were also affected earlier, at week 20. NO2 levels above the median (38 MUg/m3) reduced size at week 32 by around 9% in all parameters except for FL (6%). The critical windows of exposure were in early pregnancy, before 20 weeks. Exposure in this period was also inversely associated with neonatal length and head circumference. CONCLUSIONS: Maternal exposure to NO2 is associated with impaired fetal growth from mid-gestation onwards. PMID- 22843443 TI - Activation of intestinal peroxisome proliferator-activated receptor-alpha increases high-density lipoprotein production. AB - AIMS: Peroxisome proliferator-activated receptor (PPAR)-alpha is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-alpha activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-alpha, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-alpha ligands. Therefore, we examined the effects of PPAR-alpha activation on intestinal lipid and lipoprotein metabolism. METHODS AND RESULTS: The impact of PPAR-alpha activation was evaluated in term of HDL-related gene expression in mice, ex vivo in human jejunal biopsies and in Caco-2/TC7 cells. Apolipoprotein-AI/HDL secretion, cholesterol esterification, and trafficking were also studied in vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes, treatment with the dual PPAR-alpha/delta ligand GFT505 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL production genes such as apolipoprotein-AI and ATP-binding cassette A1 transporter in murine intestines. A similar increase was observed upon PPAR-alpha activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-alpha activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein B secretion. CONCLUSION: Peroxisome proliferator-activated receptor-alpha activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-alpha ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia. PMID- 22843444 TI - Positive association of serum prolactin concentrations with all-cause and cardiovascular mortality. AB - AIMS: Increased serum prolactin (PRL) concentrations have been associated with adverse cardiovascular risk profiles, but the relation between PRL and mortality risk is unknown. METHODS AND RESULTS: We evaluated 3929 individuals (1946 men and 1983 women) aged 20-81 (mean 50.3 years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (sex-specific tertiles) serum PRL concentrations with all-cause and cause-specific mortality were analysed separately for men and women by age- and multivariable-adjusted Cox regression models. During a median follow-up period of 10.1 years (38 231 person-years), 419 deaths (10.7%), 132 cardiovascular deaths (3.4%), and 152 cancer deaths (3.9%) were observed. After multivariable adjustment, we observed a positive association of PRL with all cause mortality in men and women [hazard ratio (HR) per SD increase: 1.17, 95% confidence interval (CI): 1.07-1.29 and HR: 1.22, 95% CI: 1.03-1.46, respectively]. Similarly, individuals with PRL concentrations in the highest tertile (when compared with lowest PRL tertile) experienced the highest mortality risk (men: HR, 1.75; 95% CI, 1.32-2.32; women: HR, 1.66; 95% CI, 1.08-2.56), with a significant trend across PRL tertiles (P- for trend <0.05). Cause-specific mortality analyses yielded similar associations for cardiovascular death in both sexes, but for cancer death only in men. CONCLUSION: This is the first study to report an independent positive association of PRL concentrations with all-cause and cardiovascular mortality. Further studies are required to confirm our findings and to elucidate the potential role of PRL as a useful biomarker of cardiovascular risk and mortality assessment. PMID- 22843445 TI - Transforming growth factor-beta: transforming plaque to stability. PMID- 22843446 TI - Cost-effectiveness of optimizing prevention in patients with coronary heart disease: the EUROASPIRE III health economics project. AB - AIMS: The EUROASPIRE III survey indicated that the guidelines on cardiovascular disease prevention are poorly implemented in patients with established coronary heart disease (CHD). The purpose of this health economic project was to assess the potential clinical effectiveness and cost-effectiveness of optimizing cardiovascular prevention in eight EUROASPIRE III countries (Belgium, Bulgaria, Croatia, Finland, France, Italy, Poland, and the U.K.). METHODS AND RESULTS The individual risk for subsequent cardiovascular events was estimated, based on published Framingham equations. Based on the EUROASPIRE III data, the type of suboptimal prevention, if any, was identified for each individual, and the effects of optimized tailored prevention (smoking cessation, diet and exercise, better management of elevated blood pressure and/or LDL-cholesterol) were estimated. Costs of prevention and savings of avoided events were based on country-specific data. A willingness to pay threshold of ?30,000/quality-adjusted life year (QALY) was used. The robustness of the results was validated by sensitivity analyses. Overall, the cost-effectiveness analyses for the eight countries showed mainly favourable results with an average incremental cost effectiveness ratio (ICER) of ?12,484 per QALY. Only in the minority of patients at the lowest risk for recurrent events, intensifying preventive therapy seems not cost-effective. Also, the single impact of intensified cholesterol control seems less cost-effective, possibly because their initial 2-year risk was already fairly low, hence the room for improvement is rather limited. CONCLUSION: These results underscore the societal value of optimizing prevention in most patients with established CHD, but also highlight the need for setting priorities towards patients more at risk and the need for more studies comparing intensified prevention with usual care in these patients. PMID- 22843447 TI - Coronary artery calcium for the prediction of mortality in young adults <45 years old and elderly adults >75 years old. AB - AIMS: To determine if coronary artery calcium (CAC) scoring is independently predictive of mortality in young adults and in the elderly population and if a young person with high CAC has a higher mortality risk than an older person with less CAC. METHODS AND RESULTS: We studied a cohort of 44 052 asymptomatic patients referred for CAC scans for cardiovascular risk stratification. All-cause mortality rates (MRs) were calculated after stratifying by age groups (<45, 45 54, 55-64, 65-74, and >=75) and CAC score (0, 1-100, 100-400, and >400). Multivariable Cox regression models were constructed to assess the independent value of CAC for predicting all-cause mortality in the <45- and >=75-year-old age groups. The MR increased in both the <45- and >=75-year-old age groups with an increasing CAC group. After multivariable adjustment, increasing CAC remained independently predictive of increased mortality compared with CAC = 0 [<45 age group, hazard ratio (95% confidence interval): CAC = 1-100, 2.3 (1.2-4.2); CAC = 100-400, 7.4 (3.3-16.6); CAC > 400, 34.6 (15.5-77.4); >=75 age group: CAC = 1 100, 7.0 (2.4-20.8); CAC = 100-400, 9.2 (3.2-26.5); CAC > 400, 16.1 (5.8-45.1)]. Persons <45 years old with CAC = 100-400 and CAC > 400 had 2- and 10-fold increased MRs, respectively, compared with persons >=75 with no CAC. Individuals >=75 years old with CAC = 0 had a 5.6-year survival rate of 98%, similar to those in other age groups with CAC = 0 (5.6-year survival, 99%). CONCLUSION: The value of CAC for predicting mortality extends to both elderly patients and those <45 years old. Elderly persons with no CAC have a lower MR than younger persons with high CAC. PMID- 22843449 TI - Expanding indications for resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is one of the major advances in the treatment of patients with chronic heart failure due to impaired left ventricular ejection fraction. Current guidelines recommend with the highest levels of recommendation and evidence CRT in patients with low ejection fraction wide QRS, LBBB, and mild to severe heart failure (New York Heart Association class II to IV). However, other patients might benefit from CRT. This is the case for patients with permanent atrial fibrillation, patients conventional pacemaker indication, patients with mildly impaired left ventricular function (>35 %), or asymptomatic patients (NYHA I). We will discuss in this manuscript each new potential indication for CRT. PMID- 22843448 TI - Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy. AB - BACKGROUND: Although the pathophysiology and treatment of adult heart failure (HF) are well studied, HF in children remains poorly understood. In adults, adrenergic receptor (AR)-mediated adaptation plays a central role in cardiac abnormalities in HF, and these patients respond well to beta-blocker (BB) therapy. However, in children with HF, there is a growing body of literature suggesting a lack of efficacy of adult HF therapies. Due to these unanticipated differences in response to therapy and the paucity of data regarding the molecular adaptation of the paediatric heart, we investigated the molecular characteristics of HF in children. METHODS AND RESULTS: Explanted hearts from adults and children with idiopathic dilated cardiomyopathy and non-failing controls were used in the study. Our results show that the molecular characteristics of paediatric HF are strikingly different from their adult counterparts. These differences include: (i) down-regulation of beta1- and beta2 AR in children, whereas beta2-AR expression is maintained in adults; (ii) up regulation of connexin43 in children, whereas down-regulation is observed in adults; (iii) no differences in phosphatase expression, whereas up-regulation is observed in adults; (iv) no decrease in the phosphorylation of phospholamban at the Ser16 or Thr17 sites in children, which are known characteristics of adult HF. CONCLUSION: There is a different adaptation of beta-AR and adrenergic signalling pathways in children with HF compared with adults. Our results begin to address the disparities in cardiovascular research specific to children and suggest that age-related differences in adaptation could influence the response to therapy. These findings could lead to a paradigm shift in the contemporary management of children with HF. PMID- 22843450 TI - Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. AB - To study the clinical characteristics, treatment approach and outcome of pleomorphic xanthoastrocytoma (PXA), patients were identified using the National Cancer Intitute's Surveillance, Epidemiology, and End Results (SEER) database. A total of 214 patients were identified with PXA using the November 2010 submission. Patient demographics, tumor characteristics, extent of surgical resection, the use of radiotherapy, and overall survival were evaluated. Overall survival for PXA was then compared to that of pilocytic astrocytoma, oligodendroglioma, ependymom and glioblastoma also using the SEER database. Kaplan-Meier, univariate and multivariate analyses were performed. The majority of patients were found to be young adults with the most common tumor location being temporal lobe. Surgery was performed on most (95 %) patients, while 25 % of patients received radiation therapy. Five and 10 year overall survival rates were 75 and 67 %, respectively. Grade was only available for a limited number of patients but appeared to affect prognosis. Patients with grade IV tumors had a median overall survival of 45 months, whereas median survival was not reached for grade I-III patients. On multivariate analysis, male gender and increasing age were associated with worse overall survival (p values 0.05 and <0.006, respectively). Extent of resection trended towards significance in favor of gross total resection. PXA is a rare diagnosis that affects young adults. Surgical resection is the primary modality of treatment with an overall good prognosis. Elderly patients, those with higher grade disease and patients with incomplete resections may have a worse prognosis. The role of radiation therapy for PXA remains unclear but is more often used for patients with high grade tumors. Compared to other common brain tumors, PXA's appear to fare worse than pilocytic astrocytoma and oligodendroglioma, especially in younger patients. However, even high grade PXA patients have significantly better overall survival compared to glioblastoma. PMID- 22843451 TI - Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research. AB - Low grade gliomas affecting the visual pathway, commonly referred to as optic pathway gliomas (OPGs), have a relatively high survival rate but can cause significant vision loss. While previous treatment outcomes for tumors of the central nervous system have focused primarily on changes in tumor size or patient survival, more recently preservation of vision has also become a primary objective when treating these tumors. Visual acuity (VA) is the most testable and reliable visual parameter in young children with OPGs. Unfortunately, standardized VA assessments have neither been employed to make treatment decisions nor used as primary outcomes in clinical trials. The lack of a standardized VA assessment has also hindered the ability to interpret and compare results between studies. It is essential that all members of the multidisciplinary care team (i.e., pediatric neuro-oncologist, neurologist, neurosurgeon, and ophthalmologist) can accurately interpret VA results and properly use them to guide management decisions. Specifically, determining what constitutes a significant change in VA and the factors that may influence these results should be incorporated into collective team recommendations. This review describes the VA assessment in children with OPGs and proposes a standardized VA testing protocol for future pediatric OPG clinical treatment trials. PMID- 22843453 TI - Persistent primitive trigeminal artery: a review. AB - The trigeminal artery is the largest of the fetal carotid-basilar anastomotic arteries, and it persists for the longest embryonic period. The artery usually involutes after the development of the posterior communicating artery. The exact causes of persistence of this primitive vessel into adulthood are not completely clear. Angiographic and anatomical descriptions of the various persistent trigeminal artery (PTA) configurations and their relation to the remainder of the cerebrovascular tree and the other surrounding structures have been reported. Persistent trigeminal artery can be associated with many other vascular anomalies and disorders including aneurysms, arteriovenous malformations and carotid cavernous fistulae. A thorough understanding of the anatomical and angiographic features of this persistent embryonic arterial channel is of utmost importance when making therapeutic decisions and embarking on surgical or endovascular intervention for any pertinent pathological condition. We review the embryology, angiographic features, microsurgical anatomy and associated vascular anomalies and disorders of the persistent trigeminal artery. PMID- 22843454 TI - Armored brain in patients with hydrocephalus after shunt surgery: review of the literatures. AB - Armored brain or chronic calcified subdural hematoma is a rare complication of cerebrospinal fluid diversion with few cases reported in the literature. Seventeen patients with this pathology have been published. A complete review of the literatures regarding this topic has been collected and discussed. The author also presents a 12- year old boy with triventricular hydrocephalus who had undergone ventriculoperitoneal medium pressure shunt system since birth. The patient presented to our clinic with a 2-year history of seizures. The patient was conscious and without neurological deficits on examination. Computed tomography of the brain showed bilateral high density mass with surface calcification. X ray skull and MRI confirmed the calcified subdural hematoma bilaterally. We preferred conservative treatment and the patient continued his antiepileptic treatment. At one year follow up, the patient had the same neurological state. The case highlights the importance of frequent follow up CT brain after shunt surgery. PMID- 22843452 TI - Changes in anti-heat shock protein 27 antibody and C-reactive protein levels following cardiac surgery and their association with cardiac function in patients with cardiovascular disease. AB - The relationship between serum anti-heat shock protein (Hsp)27 antibody and high sensitive C-reactive protein (hs-CRP) levels and indices of cardiac function were investigated in patients undergoing coronary artery bypass grafting (CABG) or heart valve replacement. The changes in anti-Hsp27 antibody titers and hs-CRP levels were compared among patients undergoing off-pump and on-pump CABG or valvular heart replacement. Fifty-three patients underwent off-pump, on-pump CABG, and heart valvular replacement in each group. Serum anti-Hsp27 titers and hs-CRP values were measured 24 h before and after the operation and at discharge. Echocardiography was performed before surgery and before discharge. The results were compared with values from 83 healthy controls. hs-CRP levels increased and anti-Hsp27 antibody decreased following surgery (P < 0.001 and P < 0.05, respectively), although these changes were independent of operative procedure (P = 0.361 and P = 0.120, respectively). Anti-Hsp27 antibody levels were higher at the time of discharge (P = 0.016). Only in coronary patients were anti-Hsp27 antibody levels negatively associated with E/E' (r = -0.268, P = 0.022), a marker of pulmonary capillary wedge pressure. In conclusions, anti-Hsp27 antibody levels are associated with indices of cardiac function in coronary patients. Cardiopulmonary bypass had no significant effect on the induction of changes in anti-Hsp27 levels. Moreover, anti-Hsp27 antibody levels fell in all groups postoperatively; this may be due to the formation of immune complexes of antigen antibody, and antibody levels were higher at the time of discharge. PMID- 22843455 TI - Noninvasive estimation of cerebral perfusion pressure with transcranial Doppler ultrasonography in traumatic brain injury. AB - AIM: In traumatic brain injury (TBI) patients, to overcome the secondary insults, cerebral perfusion pressure (CPP) oriented therapy is recommended. The study is assigned to estimate CPP values with middle cerebral artery (MCA) flow velocities measured noninvasively using transcranial Doppler ultrasonography (TCD). MATERIAL AND METHODS: Forty-seven TBI patients were studied. Intracranial pressure (ICP), mean arterial pressure (MAP) and MCA flow velocities of the patients were monitored. Invasive CPP was calculated as the difference between MAP and ICP. The formula : 'MAP x FVd/FVm +14' was used to estimate CPP noninvasively. Correlation of the noninvasive and invasive values were analysed. RESULTS: The mean values of noninvasive CPP and invasive CPP were 66.10 +/- 10.55 mmHg and 65.40 +/- 10.03 mmHg respectively. The correlation between noninvasive and invasive CPP measurements was strongly significant (p < 0.001) with a correlation coefficient of r = 0.920. CONCLUSION: With ICP monitoring systems, CPP is calculated and the therapy is guided according to these values. As it is recognized that brain perfusion can be assessed with TCD waveforms, noninvasive CPP estimation with MCA flow velocities may help to observe the trends in CPP values. PMID- 22843456 TI - Morphological analysis and morphometry of the foramen magnum: an anatomical investigation. AB - AIM: The objectives were to study the morphology of the foramen magnum in dry skulls and to evaluate its antero-posterior diameter, transverse diameter and the foramen magnum index. MATERIAL AND METHODS: The foramen magna of 53 dry human cadaver skulls that were obtained from the neuroanatomy laboratory were examined. Different shapes of the foramen magnum were macroscopically noted and classified. The antero-posterior and transverse diameters were measured and the average foraminal index was calculated. RESULTS: The foramen magnum shapes were determined as a round shape in 22.6% of cases, egg shape in 18.9%, tetragonal in 18.9%, oval in 15.1%, irregular in 15.1%, hexagonal in 5.6% and pentagonal in 3.8% of the cases. In 20.7% of skulls, the occipital condyle was observed to protrude into the foramen. The mean antero-posterior and transverse diameter of the foramen magnum was determined as 31 +/- 2.4 mm and 25.2 +/- 2.4 mm respectively. The average foramen magnum index was 1.2 +/- 0.1. CONCLUSION: The present study has determined the various shapes of foramen magnum and its morphometry. The data obtained may be of useful to the neurosurgeon in analyzing the morphological anatomy of craniovertebral junction. The findings are also enlightening for the anthropologists, morphologists and clinical anatomists. PMID- 22843457 TI - Predictable morphometric parameters for rupture of intracranial aneurysms - a series of 142 operated aneurysms. AB - AIM: Intracranial aneurysm rupture is followed by high mortality and morbidity. In order to understand the aneurysm's natural course, it is necessary to recognize the predisposing factors for the rupture. MATERIAL AND METHODS: Analysis included 142 operated aneurysms (94 hemorrhaging and 48 unruptured) in the period from 2008 to 2010. RESULTS: The ratio between the width of the aneurysm neck and diameter of the carrying blood vessel - artery in ruptured aneurysms (OR) was 1.58 +/- 0.61, and in unruptured aneurysms 1.14 +/- 0.52 (p < 0.01). Aspect ratio of ruptured aneurysm was 1.89 +/- 0.59, and in unruptured 1:33 +/- 0.17. The angle of inclination of ruptured aneurysms was 139.22 +/- 21.53, while in unruptured aneurysms it was 101.73 +/- 21.26. CONCLUSION: Based on the results of our research, a predictive model of morphometric characteristics of the vessel bearing the aneurysm to rupture can be identified: an irregular shape of the aneurysm, AR > 1.6, OR > 1.5 and inclination angle > 135 deg. PMID- 22843458 TI - Micro-surgical decompression for greater occipital neuralgia. AB - AIM: To evaluate the clinical effect of micro-surgical decompression of greater occipital nerve for greater occipital neuralgia (GON). MATERIAL AND METHODS: 76 patients underwent surgical decompression of the great occipital nerve. A nerve block was tested before operation. The headache rapidly resolved after infiltration of 1% Lidocaine near the tender area of the nerve trunk. RESULTS: 89 procedures were performed for 76 patients. The mean follow up duration was 20 months (range 7-52 months). The headache symptoms of 68 (89.5%) patients were completely resolved, and another 5 (6.6%) patients were significantly relieved without the need for any further medical treatment. Three (3.9%) patients experienced recurrence of the disorder. All patients experienced hypoesthesia of the innervated area of the great occipital nerve. They recovered gradually within 1 to 6 months after surgery. CONCLUSION: Micro-surgical decompression of the greater occipital nerve is a safe and effective method for greater occipital neuralgia. We believe our findings support the notion that the technique should also be considered as the first-line procedure for GON. PMID- 22843459 TI - Effectiveness of single posterior decompressive laminectomy in symptomatic lumbar spinal stenosis: a retrospective study. AB - AIM: The best method for surgical intervention in symptomatic lumbar stenosis is not clear. The present study aims to assess first year outcomes and complication rates of patients treated with single posterior decompressive laminectomy. MATERIAL AND METHODS: Patients requiring surgery for severe, symptomatic, lumbar spinal stenosis were evaluated retrospectively. Oswestry disability index scores as well as the complications attributable to surgery were recorded before, at the sixth month and at the twelfth month of the surgery. RESULTS: Eighty patients were enrolled to the study. The mean age of the population was 63,14 +/- 11,57. Neurogenic claudication was the most common finding (65%). Of the patients, 67.5% had severe spinal stenosis. The mean ODI score at the baseline was relatively high than in the literature and was measured as 74.30 +/- 5.38. At the end of the 6 months follow-up period, all patients' ODI scores significantly improved. Moreover, this improvement continued till the end of the 12 month. The mean change in ODI at the end of the first year was 41.80% +/- 12.73. CONCLUSION: In selected cases of symptomatic lumbar spinal stenosis, single posterior decompression using laminectomy is safe and effective. PMID- 22843460 TI - Haemodynamic augmentation in the treatment of vasospasm in aneurysmal subarachnoid hemorrhage. AB - AIM: Hypertension, hypervolemia and hemodilution therapy is a common approach to cerebral vasospasm after subarachnoid haemorrhage. This study is designed to see the difference of moderate or aggressive hypervolemia supported with induced hypertension in symptomatic vasospasm detected with transcranial Doppler ultrasonography (TCD) measurements. MATERIAL AND METHODS: Fifty eight patients who had aneurysm clipping and were admitted to the neurointensive care unit were treated with normovolemia and induced hypertension (n=35) or hypervolemia supported with induced hypertension (n=23) targeting a mean arterial pressure of 110-130 mm Hg and central venous pressure of 8-12 mm Hg. Daily TCD, fluid intake, fluid balance and haemodynamic values were recorded for 14 days. RESULTS: There were no differences detected in mean arterial pressure, central venous pressure, hematocrit values, fluid balance and middle cerebral artery flow velocities between the two groups through 14 days (p > 0.05). Hyponatremia, pulmonary edema and cerebral ischemia were observed as complications. CONCLUSION: Hypervolemia adds no benefit compared to normovolemia in the treatment of vasospasm occurred as a result of subarachnoid hemorrhage. Induced hypertension establishes the haemodynamic augmentation to prevent and treat vasospasm. PMID- 22843461 TI - Cluster analysis of mRNA expression levels identifies multiple sequential patterns following focal cerebral ischemia. AB - AIM: The purpose of this study is to detect gene expression patterns following focal cerebral ischemia. MATERIAL AND METHODS: 25 male Wistar rats were divided into control (n = 8) and ischemic (n = 17) groups. In the ischemic group, slowly progressing focal ischemia was simulated by two-vein occlusion with spreading depression (SD) a cortical microinjection of KCl induced. Ischemic tissue was removed at 2, 8, 24, or 72 h postischemia. Using semiquantitative reverse transcription polymerase chain reaction, we investigated mRNA expression levels of 13 representative genes related to cerebral ischemia. Cluster analysis of the gene expression levels was done. RESULTS: In the ischemic group, the expression levels of c-fos, cyclin D1, and COX-2 were significantly higher at 2 h postischemia, and those of bcl-2, bcl-xL, and HO 1 at 72 h. Based on the cluster analysis, we statistically divided examined genes into three groups: group A, early expression (COX-2, c-fos, and bcl-2); group B, s expression (c-jun, SOD-1, bad, p53, SOD-2, bcl-xL, and bax); and group C, late expression (cyclin D1, c-myc, and HO-1). CONCLUSION: We statistically classified the genes into three groups after focal ischemia. The genes of the early- and late-expression groups can be possible therapeutic targets for the treatment of cerebral ischemia. PMID- 22843462 TI - Echinococcus alveolaris: presenting as a cerebral metastasis. AB - Echinococcus multilocularis (EM) is caused by the larval stage of the tapeworm. The main endemic regions for human alveolar echinococcosis are Central Europe, Russia, Turkey, Japan, China, Eastern France, North America. EM is an endemic disease in Turkey and especially common in the eastern Anatolia Region as seen in our case. The liver is the primary focus of the disease, cerebral localization is rare. Cerebral hydatid disease is approximately 5% of alveolar hydatid cases and generally considered to be fatal. Surgical treatment should be considered whenever possible. We present a case of cerebral alveolar hydatid disease that was thought to be cerebral metastasis. PMID- 22843463 TI - Giant intramedullary epidermoid extending from the brain stem to the upper thoracic spinal cord. AB - Epidermoid cysts are benign tumors originating from ectoderm remnants. Most epidermoid cyst cases are intracranial. Spinal epidermoid cysts are uncommon and most of the reported cases are in the thoracic and lumbar spine. Occurrence of intramedullary epidermoid cysts in the cervical spine is extremely rare. An 18-year-old male with a giant intramedullary tumor extending from the brain stem to the upper thoracic spinal cord presented at our outpatient department. The patient underwent total excision of a silvery white lesion through a midline myelotomy. Histopathological examination was suggestive of an epidermoid cyst. We present a brief report of the case and discuss the relevant literature. PMID- 22843464 TI - Solitary fibrous tumor of the tentorium: a case report. AB - The authors describe the clinical and pathological features of a solitary fibrous tumor of the tentorium, a rare location for the tumor in the CNS. A 52-year-old lady presented to the neurosurgical services with headache of four months and vertigo of one and a half months duration. On examination, she had left-sided cerebellar signs and bilateral papilloedema. Cranial MR imaging showed an enhancing tumor based on the left tentorium. Clinical impression was a meningioma. The patient underwent left suboccipital craniectomy. The tumor was firm and vascular, extending above the tent through a defect. Total excision was achieved. The correct diagnosis of solitary fibrous tumor could be made only by histopathology. Solitary fibrous tumors of the tentorium, though rare, should be included in the differential diagnosis of dural based masses. PMID- 22843465 TI - Sutural diastasis caused by pseudotumor cerebri. AB - The diagnosis of pseudotumor cerebri is based on the triad of: (1) papilloedema, (2) elevated intracranial pressure with a normal cerebrospinal constituency and (3) normal central nervous system imaging studies. However, the diagnosis of pseudotumor cerebri is not always straightforward. We report a 19-year-old morbidly obese girl who developed pseudotumor cerebri associated with sutural diastasis of the cranium based on the direct radiographies. Following a ventriculo-peritoneal shunt operation, we demonstrated the closing and perisuturally sclerosis on all major cranial sutures. A careful examination of direct radiographies might be critical for diagnosis of pseudotumor cerebri. Prompt recognition, evaluation, and treatment are needed to prevent permanent visual loss. PMID- 22843466 TI - Infratentorial oligodendroglioma in a child: a case report and review of the literature. AB - Oligodendrogliomas are the tumors of normal glial cells of brain called oligodendrocytes. They represent a small proportion of childhood brain tumors and are infrequently encountered in the posterior fossa. CT scan and MRI are very helpful for the preoperative management of oligodendrogliomas. However, due to the rarity and non-specific imaging features, it may be difficult to differentiate oligodendroglioma from astrocytoma especially in an infratentorial location. The short- and long-term outcome and the exact treatment protocol of posterior fossa oligodendroglioma is yet to be established. We report a rare case of an oligodendroglioma of the vermis in an 8-year-old female with a brief review of the literature. PMID- 22843467 TI - Should we resect all multiple intraspinal extradural arachnoid cysts? A case report. AB - Multiple spinal extradural arachnoid cysts (SEACs) are relatively rare lesions, which may cause symptoms due to spinal cord compression. Radical resection of multiple SEACs during one-stage surgery is the primary treatment for the rare lesion, because of its effective and safe operation. Here, we present a 13-year old female, who presented with a 3-month history of progressive weakness in the right leg. For the first time, we reported partial resection of multiple SEACs without treating the other parts, can also lead to a favorable outcome. No change in the cysts and spinal deformity were observed during a follow-up period of 5 years. PMID- 22843468 TI - Primary cerebellopontine angle melanoma: a case report and review. AB - Primary melanomas at the cerebellopontine (CP) angle are extremely rare and considered a diagnostic dilemma. With only 16 prior cases reported so far, there is not enough material in world literature. We report a 29-year-old male who presented with vertigo, headache and features of lower cranial nerve involvement with MRI revealing a melanotic lesion at CP angle. The patient underwent right suboccipital craniectomy and only subtotal excision of the tumor was possible. Histopathologically it turned out to be malignant melanoma. Since a thorough search for any possible primary was futile, it was considered a primary melanoma. Patient was given adjuvant radiotherapy. Ten months later, he presented with weakness and multiple spinal metastases and two months later he succumbed to his disease. We did a comprehensive review of literature about various melanocytic tumors at the CP angle. Pathologically, melanocytic tumors range from benign melanocytomas to malignant melanoma with variable prognosis. The clinical presentation depends upon whether the lesions are diffuse or discrete. Surgery is the primary modality of treatment and the amount of tumor excised is related to the prognosis. We conclude the discussion with a novel classification for melanotic tumors of CNS and the current diagnostic pathway for a melanotic lesion at the CP angle. PMID- 22843470 TI - Intramedullary neurenteric cyst of the conus medullaris without associated spinal malformation: a case report and review of the literature. AB - Spinal neurenteric (NE) cysts are rare congenital anomalies that may occur either alone or in the context of a complex malformative disorder. They are usually intradural-extramedullary lesions. Intramedullary NE cysts not associated with other congenital anomalies are very rare and only a few cases have been reported in the conus medullaris region. Intramedullary neurenteric cysts not associated with other spinal anomalies are very rare especially in the conus medullaris region. MRI is useful to define the cyst and the osseous anomalies associated with this lesion. The goal of treatment of an intramedullary neurenteric cyst is total excision at the first operation, if possible. Life-long follow-up with annual MRI is recommended due to the risk of cyst recurrence. We report an intramedullary NE cyst of the conus medullaris without associated malformation and the relevant literature is briefly reviewed. PMID- 22843469 TI - Primary intracerebral malignant fibrous histiocytoma mimicking a meningioma. AB - We describe herein a patient with primary intracerebral malignant fibrous histiocytoma (MFH) to demonstrate this very rare central nervous system tumor. A 42-year-old male was admitted to our institute with the complaints of headache and speech impairment. Magnetic resonance imaging (MRI) revealed a tumor consistent with meningioma and we decided the surgery. The tumor was excised totally during the initial surgery. Histopathological examination revealed a mesenchymal tumor with an invasion of the adjacent brain and underlying dura mater. On the postoperative 4th month, the follow up MRI showed tumor recurrence at the same location and of similar size. Reoperation was performed and the tumor was again removed gross totally. However, the patient demonstrated a rapidly progressive course leading to death within the first year after the surgery. Two significant points of this case of primary central nervous system MFH are the rarity of its occurrence and its mimicking a meningioma. PMID- 22843471 TI - Endovascular coil embolization of parent artery for giant intracranial basilar artery dissection: a case report. AB - Isolated dissection of the basilar artery (BA) is rare and still a big challenge regarding treatment. The suitable therapeutic strategies for dissection of the BA remain controversial. We report the case of a young patient with a giant unruptured dissection of the BA successfully treated by endovascular coil embolization. A 14-year-old male who underwent computed tomography (CT) scan following a minor head trauma was incidentally found to have a lesion located anterior to brain stem. Further imaging with magnetic resonance imaging (MRI), computed tomography angiography (CTA) and digital subtraction angiography (DSA) were consistent with a diagnosis of giant unruptured dissection of the BA. The patient was initially observed conservatively. The follow-up DSA obtained 3 months later revealed extension of the dissection inferiorly to involve the left VA. The dissection expanded at the conjunction of VAs in the shape of ball. Therefore, coil embolization to occlude BA at the bottom of aneurysm was performed as a further treatment. Follow-up DSA 6 months later demonstrated complete obliteration of the dissection and good compensative perfusion from extensively collateral circulation. For young patients with isolated dissection of the BA, coil embolization to occlude BA at the bottom of aneurysm might be tolerable and effective. PMID- 22843472 TI - Long-term benefit of bilateral subthalamic deep brain stimulation on camptocormia in Parkinson's disease. AB - We report the case of a 63-year-old female with a long history of severe Parkinson's disease (PD) and subsequent onset of debilitating camptocormia who underwent successful bilateral subthalamic nucleus deep brain stimulation surgery (STN DBS). The literature and previous reports are reviewed. The patient history and details of the surgical procedure are reported including the implantable pulse generator (IPG) settings and response to stimulation. The results of her PD symptom and camptocormia improvements are discussed. Five year postoperatively, the patient has enjoyed good results for both her PD symptoms as well as significant and sustained improvement in her thoracolumbar flexion deformity. She remains on minimal medications and no longer requires any assistive devices for ambulation. Comparison and contrast of the current world literature on DBS for camptocormia is reviewed. We discuss the current targets used for DBS in the setting of camptocormia in the cases reported, both PD associated and not associated. The optimal target has yet to be defined and further work on appropriate patient selection is needed. PMID- 22843473 TI - Central nervous system B-cell lymphoma in multiple sclerosis. AB - The differential diagnosis of multiple sclerosis is extensive and it can be challenging to diagnose initially in the absence of pathognomonic clinical features. Furthermore, these patients can also develop other diseases during their course of treatment, which usually lasts for many years. Some conditions, such as primary central nervous system lymphoma, can mimic clinically some of the symptoms prominent in multiple sclerosis. Early treatment with corticosteroids can also dramatically improve patient symptoms in both conditions. We report a case of a man diagnosed with histologically confirmed relapsing remitting multiple sclerosis who subsequently developed histologically confirmed primary central nervous system lymphoma. The course of his disease and treatment are presented and the current literature reviewed. PMID- 22843474 TI - Intramedullary spinal cord involvement from metastatic gastric carcinoma: a case report. AB - Intramedullary spinal cord metastasis (ISCM) is a rarely seen complication of cancer. We report a case of ISCM from gastric cancer. A 42-year-old male presented with a rare intramedullary spinal cord metastasis from gastric carcinoma manifesting as rapidly worsening motor and sphincter disturbances. The primary tumor had been treated 2 years previously. Magnetic resonance imaging (MRI) revealed the tumor localized in the thoracic spinal cord. The tumor was totally removed. The histological diagnosis was gastric adenocarcinoma. He has been stable postoperatively. Surgical treatment may be considered for cases with even rapid-growing tumors such as gastric carcinoma with no evidence of multi organ dissemination, especially when presenting with progressive neurological deterioration. PMID- 22843475 TI - Primary amenorrhea due to empty sella: an underestimated entity. AB - We report a 16-year-old girl who had stunted growth and primary amenorrhea presenting with headache and vomiting. MRI of brain showed posterior fossa dermoid cyst with hydrocephalus and empty sella. Growth hormone (GH), Leutinizing hormone (LH) and Follicular stimulating hormone (FSH) were grossly reduced on endocrinological work-up. She underwent suboccipital midline craniectomy and complete excision of dermoid cyst .She had no additional deficit after the surgery. She had menarche six months after the surgery and developed adequate secondary sexual characters, however her height remains subnormal at follow-up after 2 years as compared to age matched controls. We briefly review the radiological features, pathogenesis and outcome of this underestimated entity. PMID- 22843476 TI - Fat graft migration causing recurrent cervical cord compression. AB - AIM: Fat graft migration following spinal cord surgery is an uncommon problem. Only few cases of fat graft migration causing cauda equine syndrome, recurrent sciatica, and root compression following lumbar spine surgery have been reported. We report a case of fat graft migration causing symptomatic cervical cord compression. MATERIAL AND METHODS: A 45-years-old male with cervical spondylosis underwent anterior C4-5 discectomy and excision of hypertrophied ligament. A dural tear that occurred during the procedure was repaired with fat graft harvested from thigh. Significant improvement in stiffness was noted postoperatively. After 15 days, the patient presented again with worsening lower limbs stiffness. Magnetic resonance imaging of spine was done which revealed displacement of the fat graft causing cervical cord compression. RESULTS: Re exploration was done and the migrated fat graft was removed. Post operatively patient noticed significant improvement in stiffness in both lower limbs. CONCLUSION: Autologous fat graft is one of the best materials used in sealing the dural cerebrospinal fluid leak during spinal surgery. However sometimes it may migrate and cause compression of cord and roots with relative symptoms. This complication should be kept in mind as removal of migrated fat graft will relieve these symptoms. PMID- 22843477 TI - A new variant nummular headache: large diameter accompanied with bitrigeminal hyperalgesia and successful treatment with carbamazepine. AB - Nummular headache (NH) is defined as a focal head pain that is exclusively felt in a small area, which is typically 1-6 cm in diameter. Neurological examinations are normal in all patients, but this report describes a new variant. A patient was identified who presented with focal head pain that was approximately 8 cm in diameter and bitrigeminal hyperalgesia on neurological examination. Treatment with carbamazepine provided significant analgesic relief in terms of both the frequency and intensity of pain. The findings enlarge the clinical diversity of this headache disorder. The pathogenic mechanisms of NH may be similar to trigeminal neuralgia in particular patients. PMID- 22843478 TI - Coexistence of spinal teratoma of the conus medullaris and arteriovenous malformation in an adult: a case report. AB - The coexistence of spinal teratoma of the conus medullaris and arteriovenous malformation (AVM) is exceptional, which has not been reported previously in the literature. The precise mechanism of the coexistence of these conditions is not known, however, the dysembryonic origin of spinal cord teratoma and AVM seems to play a part in this process. A 34-year-old male patient was admitted with lower back pain, bilateral lower extremity numbness and weakness, and sexual disturbance. Magnetic resonance imaging (MRI) showed an AVM extended cranially from the top of a heterogeneous expansile lesion of the conus medullaris. Surgical exploration and histopathological examination revealed a mature teratoma associated with the AVM. A literature review supported the dysembryonic origin of spinal cord teratomas and AVMs. This unique case may provide insight into the etiopathogenesis of the coexistence of spinal teratoma of the conus medullaris and AVM. PMID- 22843479 TI - Adeloye-Odeku disease: an African disease in the Indian child? AB - The "Adeloye-Odeku disease" or congenital dermoid cysts over the anterior fontanelle, is a rare congenital disorder of children initially described in Nigeria. It has been rarely reported in the Indian population (3 cases in 2 reports). These rare lesions are operated on by neurosurgeons in view of their location and differential diagnoses. We present two infants with the condition and a comprehensive review of the literature on pubmed using six common phrases used to describe this condition. The review was undertaken to analyze the reasons for the paucity of cases from the Indian sub-continent. The ethnicity, differential diagnosis, radiological features and management is discussed. PMID- 22843480 TI - Retropharyngeal hematoma secondary to whiplash injury in childhood: a case report. AB - Whiplash Associated Disorders (WAD) has been reported as an adult phenomenon. Whiplash injury has classically been described as a cervical soft tissue hyperextension- flexion injury after a trauma such as a rear end impact car crash, contact sport injuries, blows to the head from a falling object or a punch and shaken baby syndrome and is mostly seen in adults . It is important as it may cause severe disability due to spinal cord injury, decrease work productivity and even retropharyngeal hematoma resulting airway obstruction and mortality due to bleeding amongst deep cervical fascias. We describe a case of retropharyngeal hematoma after whiplash injury in a childhood. PMID- 22843481 TI - Systematic Reviews in neurosurgery - the ongoing quest for quality. PMID- 22843482 TI - Role of transcranial Doppler in traumatic brain injury. PMID- 22843483 TI - Re: pure peroneal intraneural ganglion cyst. Hindsight is 20/20. PMID- 22843484 TI - Advances in ablation of ventricular tachycardia in nonischemic cardiomyopathy. AB - Management of patients with nonischemic cardiomyopathy (NICM) and ventricular tachycardia (VT) remains challenging. The role of catheter ablation for VT continues to evolve for these patients. Prior reports have described the location of the arrhythmogenic substrate for patients with NICM to be frequently located along the basal left ventricle, with an epicardial predilection. Furthermore, predictors for identifying whether mapping the endocardium or epicardial surface of the heart have been identified for improved success of VT ablation in this patient population. This chapter will review the latest advances in catheter ablation of ventricular tachycardia in patients with NICM. PMID- 22843487 TI - Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: comparison with a UK Caucasian cohort. PMID- 22843488 TI - Anti-TNF therapy in women with rheumatoid arthritis with a history of carcinoma in situ of the cervix. PMID- 22843485 TI - Arabidopsis phytochrome a is modularly structured to integrate the multiple features that are required for a highly sensitized phytochrome. AB - Phytochrome is a red (R)/far-red (FR) light-sensing photoreceptor that regulates various aspects of plant development. Among the members of the phytochrome family, phytochrome A (phyA) exclusively mediates atypical phytochrome responses, such as the FR high irradiance response (FR-HIR), which is elicited under prolonged FR. A proteasome-based degradation pathway rapidly eliminates active Pfr (the FR-absorbing form of phyA) under R. To elucidate the structural basis for the phyA-specific properties, we systematically constructed 16 chimeric phytochromes in which each of four parts of the phytochrome molecule, namely, the N-terminal extension plus the Per/Arnt/Sim domain (N-PAS), the cGMP phosphodiesterase/adenyl cyclase/FhlA domain (GAF), the phytochrome domain (PHY), and the entire C-terminal half, was occupied by either the phyA or phytochrome B sequence. These phytochromes were expressed in transgenic Arabidopsis thaliana to examine their physiological activities. Consequently, the phyA N-PAS sequence was shown to be necessary and sufficient to promote nuclear accumulation under FR, whereas the phyA sequence in PHY was additionally required to exhibit FR-HIR. Furthermore, the phyA sequence in PHY alone substantially increased the light sensitivity to R. In addition, the GAF phyA sequence was important for rapid Pfr degradation. In summary, distinct structural modules, each of which confers different properties to phyA, are assembled on the phyA molecule. PMID- 22843486 TI - Targeted delivery of cytokine therapy to rheumatoid tissue by a synovial targeting peptide. AB - OBJECTIVES: The synovial endothelium targeting peptide (SyETP) CKSTHDRLC has been identified previously and was shown to preferentially localise to synovial xenografts in the human/severe combined immunodeficient (SCID) mouse chimera model of rheumatoid arthritis (RA). The objective of the current work was to generate SyETP-anti-inflammatory-cytokine fusion proteins that would deliver bioactive cytokines specifically to human synovial tissue. METHODS: Fusion proteins consisting of human interleukin (IL)-4 linked via a matrix metalloproteinase (MMP)-cleavable sequence to multiple copies of either SyETP or scrambled control peptide were expressed in insect cells, purified by Ni-chelate chromatography and bioactivity tested in vitro. The ability of SyETP to retain bioactive cytokine in synovial but not control skin xenografts in SCID mice was determined by in vivo imaging using nano-single-photon emission computed tomography-computed tomography (nano-SPECT-CT) and measuring signal transducer and activator of transcription 6 (STAT6) phosphorylation in synovial grafts following intravenous administration of the fusion protein. RESULTS: In vitro assays confirmed that IL-4 and the MMP-cleavable sequence were functional. IL-4 SyETP augmented production of IL-1 receptor antagonist (IL-1ra) by fibroblast like synoviocytes (FLS) stimulated with IL-1beta in a dose-dependent manner. In vivo imaging showed that IL-4-SyETP was retained in synovial but not in skin tissue grafts and the period of retention was significantly enhanced through increasing the number of SyETP copies from one to three. Finally, retention correlated with increased bioactivity of the cytokine as quantified by STAT6 phosphorylation in synovial grafts. CONCLUSIONS: The present work demonstrates that SyETP specifically delivers fused IL-4 to human rheumatoid synovium transplanted into SCID mice, thus providing a proof of concept for peptide targeted tissue-specific immunotherapy in RA. This technology is potentially applicable to other biological treatments providing enhanced potency to inflammatory sites and reducing systemic toxicity. PMID- 22843489 TI - Recognition of citrullinated and carbamylated proteins by human antibodies: specificity, cross-reactivity and the 'AMC-Senshu' method. PMID- 22843492 TI - Independent validation of the antiphospholipid score for the diagnosis of antiphospholipid syndrome. PMID- 22843491 TI - Autologous regulatory T cells for the treatment of type 1 diabetes. AB - The immune system is tasked with defending the host from a wide array of pathogens and environmental insults. When uncontrolled, this endeavor may lead to off-target reactivity to self-tissues resulting in multiple autoimmune diseases including type 1 diabetes (T1D). This multifactorial disease process involves over 40 susceptibility genes and is influenced by poorly characterized environmental factors. While many questions regarding the pathogenesis of the disease process remain, it has become increasingly clear that the progression to disease results from a breakdown in the processes that maintain peripheral immune tolerance. The end result of this process is localized tissue inflammation, islet dysfunction, and ultimately the destruction of pancreatic beta cells due to concomitant defects in innate and adaptive immune responses. A number of immunomodulatory intervention trials have now been conducted in patients at risk for or with recent onset T1D, often with the goal of restoring immune tolerance by inducing regulatory T cells (Tregs). Unfortunately, many of these trials have fallen short of inducing persistent immune regulation. This shortfall has led to additional efforts to more directly shift the balance from destructive effector T cell (Teff) responses to favor Tregs, including the use of autologous Treg cell therapy. In this review we will discuss key concepts related to the use of autologous Treg cell therapy for the treatment of T1D. Among these topics, we will discuss the notions of genetic control of Treg activity, Treg cellular plasticity, and requirements for antigen-specificity. PMID- 22843493 TI - Characteristics of hypertension in the Chinese population. AB - In China, the prevalence of hypertension is currently 18.8 %, and a major risk factor for hypertension is unbalanced dietary sodium and potassium intakes. High dietary sodium intake may change the circadian rhythm of 24-h blood pressure, which is characterized by a higher nighttime blood pressure. The prevalence of isolated nighttime hypertension, defined as a nighttime blood pressure of at least 120 mm Hg systolic or 70 mm Hg diastolic and a daytime systolic/diastolic blood pressure less than 135/85 mm Hg, is higher in Chinese than in Europeans. The complications of hypertension are also different across ethnicities, being mainly stroke instead of myocardial infarction in Chinese. Lowering of blood pressure provides more protection against stroke than against myocardial infarction, and calcium channel blockers provide more protection against stroke than do other classes of antihypertensive drugs. Current Chinese hypertension guidelines recommend calcium channel blockers as the most suitable class of drugs of the five classes of antihypertensive drugs. PMID- 22843494 TI - The ubiquitous mineralocorticoid receptor: clinical implications. AB - Mineralocorticoid receptors (MR) exist in many tissues, in which they mediate diverse functions crucial to normal physiology, including tissue repair and electrolyte and fluid homeostasis. However, inappropriate activation of MR within these tissues, and especially in the brain, causes hypertension and pathological vascular, cardiac, and renal remodeling. MR binds aldosterone, cortisol and corticosterone with equal affinity. In aldosterone-target cells, co-expression with the 11beta-hydroxysteroid dehydrogenase 2 (HSD2) allows aldosterone specifically to activate MR. Aldosterone levels are excessive in primary aldosteronism, but in conditions with increased oxidative stress, like CHF, obesity and diabetes, MR may also be inappropriately activated by glucocorticoids. Unlike thiazide diuretics, MR antagonists are diuretics that do not cause insulin resistance. Addition of MR antagonists to standard treatment for hypertension and cardiac or renal disease decreases end-organ pathology and sympathetic nerve activation (SNA), and increases quality of life indices. PMID- 22843495 TI - Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells. AB - Pancreas cancer cells escape most treatment options. Heat shock protein (Hsp)90 is frequently over-expressed in pancreas carcinomas and protects a number of cell cycle regulators such as the proto-oncogene Cdc25A. We show that inhibition of Hsp90 with geldanamycin (GD) destabilizes Cdc25A independent of Chk1/2, whereas the standard drug for pancreas carcinoma treatment, gemcitabine (GEM), causes Cdc25A degradation through the activation of Chk2. Both agents applied together additively inhibit the expression of Cdc25A and the proliferation of pancreas carcinoma cells thereby demonstrating that both Cdc25A-destabilizing/degrading pathways are separated. The role of Hsp90 as stabilizer of Cdc25A in pancreas carcinoma cells is further supported by two novel synthetic inhibitors 4 tosylcyclonovobiocic acid and 7-tosylcyclonovobiocic acid and specific Hsp90AB1 (Hsp90beta) shRNA. Our data show that targeting Hsp90 reduced the resistance of pancreas carcinoma cells to treatment with GEM. PMID- 22843496 TI - Mitochondrial metabolism in Parkinson's disease impairs quality control autophagy by hampering microtubule-dependent traffic. AB - Abnormal presence of autophagic vacuoles is evident in brains of patients with Parkinson's disease (PD), in contrast to the rare detection of autophagosomes in a normal brain. However, the actual cause and pathological significance of these observations remain unknown. Here, we demonstrate a role for mitochondrial metabolism in the regulation of the autophagy-lysosomal pathway in ex vivo and in vitro models of PD. We show that transferring mitochondria from PD patients into cells previously depleted of mitochondrial DNA is sufficient to reproduce the alterations in the autophagic system observed in PD patient brains. Although the initial steps of this pathway are not compromised, there is an increased accumulation of autophagosomes associated with a defective autophagic activity. We prove that this functional decline was originated from a deficient mobilization of autophagosomes from their site of formation toward lysosomes due to disruption in microtubule-dependent trafficking. This contributed directly to a decreased proteolytic flux of alpha-synuclein and other autophagic substrates. Our results lend strong support for a direct impact of mitochondria in autophagy as defective autophagic clearance ability secondary to impaired microtubule trafficking is driven by dysfunctional mitochondria. We uncover mitochondria and mitochondria-dependent intracellular traffic as main players in the regulation of autophagy in PD. PMID- 22843497 TI - Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer. AB - Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ~40% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with >=6% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4%) patients with constitutive BRCA1 and three (0.5%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen. PMID- 22843500 TI - Drosophila FMRP participates in the DNA damage response by regulating G2/M cell cycle checkpoint and apoptosis. AB - Fragile X syndrome, the most common form of inherited mental retardation, is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a ubiquitously expressed, multi-domain RNA-binding protein, but its in vivo function remains poorly understood. Recent studies have shown that FMRP participates in cell cycle control during development. Here, we used Drosophila mutants to test if FMRP plays a role in DNA damage response under genotoxic stress. We found significantly fewer dfmr1 mutants survived to adulthood than wild-types following irradiation or exposure to chemical mutagens, demonstrating that the loss of drosophila FMRP (dFMRP) results in hypersensitivity to genotoxic stress. Genotoxic stress significantly reduced mitotic cells in wild-type brains, indicating the activation of a DNA damage-induced G2/M checkpoint, while mitosis was only moderately suppressed in dfmr1 mutants. Elevated expression of cyclin B, a protein critical for the G2 to M transition, was observed in the larval brains of dfmr1 mutants. CycB mRNA transcripts were enriched in the dFMRP-containing complex, suggesting that dFMRP regulates DNA damage-induced G2/M checkpoint by repressing CycB mRNA translation. Reducing CycB dose by half in dfmr1 mutants rescued the defective G2/M checkpoint and reversed hypersensitivity to genotoxic stress. In addition, dfmr1 mutants exhibited more DNA breaks and elevated p53 dependent apoptosis following irradiation. Moreover, a loss-of-heterozygosity assay showed decreased irradiation-induced genome stability in dfmr1 mutants. Thus, dFMRP maintains genome stability under genotoxic stress and regulates the G2/M DNA damage checkpoint by suppressing CycB expression. PMID- 22843501 TI - Non-syndromic retinal ciliopathies: translating gene discovery into therapy. AB - Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies. PMID- 22843498 TI - Enhanced beta-secretase processing alters APP axonal transport and leads to axonal defects. AB - Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by amyloid plaques and neurofibrillary tangles in the brain. Before these hallmark features appear, signs of axonal transport defects develop, though the initiating events are not clear. Enhanced amyloidogenic processing of amyloid precursor protein (APP) plays an integral role in AD pathogenesis, and previous work suggests that both the Abeta region and the C-terminal fragments (CTFs) of APP can cause transport defects. However, it remains unknown if APP processing affects the axonal transport of APP itself, and whether increased APP processing is sufficient to promote axonal dystrophy. We tested the hypothesis that beta secretase cleavage site mutations of APP alter APP axonal transport directly. We found that the enhanced beta-secretase cleavage reduces the anterograde axonal transport of APP, while inhibited beta-cleavage stimulates APP anterograde axonal transport. Transport behavior of APP after treatment with beta- or gamma secretase inhibitors suggests that the amount of beta-secretase cleaved CTFs (betaCTFs) of APP underlies these transport differences. Consistent with these findings, betaCTFs have reduced anterograde axonal transport compared with full length, wild-type APP. Finally, a gene-targeted mouse with familial AD (FAD) Swedish mutations to APP, which enhance the beta-cleavage of APP, develops axonal dystrophy in the absence of mutant protein overexpression, amyloid plaque deposition and synaptic degradation. These results suggest that the enhanced beta secretase processing of APP can directly impair the anterograde axonal transport of APP and are sufficient to lead to axonal defects in vivo. PMID- 22843502 TI - Disruption of a Sox9-beta-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. AB - Mutations in fibroblast growth factor (FGF) receptors are responsible for a variety of skeletal birth defects, but the underlying mechanisms responsible remain unclear. Using a mouse model of thanatophoric dysplasia type II in which FGFR3(K650E) expression was directed to the appendicular skeleton, we show that the mutant receptor caused a block in chondrocyte differentiation specifically at the prehypertrophic stage. The differentiation block led to a severe reduction in hypertrophic chondrocytes that normally produce vascular endothelial growth factor, which in turn was associated with poor vascularization of primary ossification centers and disrupted endochondral ossification. We show that the differentiation block and defects in joint formation are associated with persistent expression of the chondrogenic factor Sox9 and down-regulation of beta catenin levels and activity in growth plate chondrocytes. Consistent with these in vivo results, FGFR3(K650E) expression was found to increase Sox9 and decrease beta-catenin levels and transcriptional activity in cultured mesenchymal cells. Coexpression of Fgfr3(K650E) and Sox9 in cells resulted in very high levels of Sox9 and cooperative suppression of beta-catenin-dependent transcription. Fgfr3(K650E) had opposing effects on Sox9 and beta-catenin protein stability with it promoting Sox9 stabilization and beta-catenin degradation. Since both Sox9 overexpression and beta-catenin deletion independently blocks hypertrophic differentiation of chondrocytes and cause chondrodysplasias similar to those caused by mutations in FGFR3, our results suggest that dysregulation of Sox9 and beta-catenin levels and activity in growth plate chondrocytes is an important underlying mechanism in skeletal diseases caused by mutations in FGFR3. PMID- 22843499 TI - Genome-wide meta-analysis of common variant differences between men and women. AB - The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 * 10(-8)) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ~115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits. PMID- 22843503 TI - Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels. AB - Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 * 10(-12)) and SNP rs13144478 (P = 6.19 * 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 * 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin related disease. PMID- 22843505 TI - H-ferritin overexpression promotes radiation-induced leukemia/lymphoma in mice. AB - H-ferritin (HF) is a core subunit of the iron storage protein ferritin and is related to the pathogenesis of malignant diseases. HF overexpression is present in human hematologic malignancies, suggesting that HF overexpression may contribute to the development of hematologic cancers. However, in vivo evidence that HF is directly linked to hematologic tumorigenesis has not yet been shown. In this study, we show that transgenic (tg) mice overexpressing the human HF gene (hHF-tg) developed aggressive radiation-induced thymic lymphoma/leukemia (TL) compared with wild-type (WT) mice, providing evidence that HF overexpression promotes leukemia/lymphomagenesis. Fractionated X-irradiation of hHF-tg mice caused a higher incidence and earlier onset of TL compared with WT mice. Immunological and pathological features of TLs were similar in both groups. However, proliferative activity of hHF-tg lymphoma cells was higher than that of WT lymphoma cells, and microarray analyses revealed that some leukemia/lymphoma related genes were differentially expressed in hHF-tg TLs compared with WT TLs. To investigate whether cell damage induced by irradiation is related to leukemia/lymphomagenesis, we evaluated apoptotic levels in the thymus and bone marrow (BM) of hHF-tg and WT groups after fractionated X-irradiation. Apoptosis was augmented in the hHF-tg BM, but not in the thymus, compared with the WT BM, suggesting a possible linkage between increased BM apoptosis by HF overexpression and accelerated radiation-induced TL development. Our findings indicate that HF overexpression is closely related to the development of leukemia/lymphoma, which could have implications for the prevention of malignant hematologic diseases. PMID- 22843506 TI - Differential role of Sloan-Kettering Institute (Ski) protein in Nodal and transforming growth factor-beta (TGF-beta)-induced Smad signaling in prostate cancer cells. AB - Transforming growth factor-beta (TGF-beta) signaling pathways contain both tumor suppressor and tumor promoting activities. We have demonstrated that Nodal, another member of the TGF-beta superfamily, and its receptors are expressed in prostate cancer cells. Nodal and TGF-beta exerted similar biological effects on prostate cells; both inhibited proliferation in WPE, RWPE1 and DU145 cells, whereas neither had any effect on the proliferation of LNCaP or PC3 cells. Interestingly, Nodal and TGF-beta induced migration in PC3 cells, but not in DU145 cells. TGF-beta induced predominantly phosphorylation of Smad3, whereas Nodal induced phosphorylation of only Smad2. We also determined the expression and differential role of Ski, a corepressor of Smad2/3, in Nodal and TGF-beta signaling in prostate cancer cells. Similar levels of Ski mRNA were found in several established prostate cell lines; however, high levels of Ski protein were only detected in prostate cancer cells and prostate cancer tissue samples. Exogenous Nodal and TGF-beta had no effects on Ski mRNA levels. On the other hand, TGF-beta induced a rapid degradation of Ski protein mediated by the proteasomal pathway, whereas Nodal had no effect on Ski protein. Reduced Ski levels correlated with increased basal and TGF-beta-induced Smad2/3 phosphorylation. Knockdown of endogenous Ski reduced proliferation in DU145 cells and enhanced migration of PC3 cells. We conclude that high levels of Ski expression in prostate cancer cells may be responsible for repression of TGF-beta and Smad3 signaling, but Ski protein levels do not influence Nodal and Smad2 signaling. PMID- 22843504 TI - Individual common variants exert weak effects on the risk for autism spectrum disorders. AB - While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest. PMID- 22843509 TI - 'What a waste...' the World Bank's call for action. PMID- 22843507 TI - HMG-CoA Reductase Inhibitors for Prevention and Treatment of Severe Sepsis. AB - HMG-CoA reductase inhibitors, or statins, are among the most commonly prescribed pharmaceuticals in the world, especially among the elderly. The remarkable conjuncture of this fact with the rising incidence of severe sepsis among people over age 65 could prove to be of serendipitous benefit, because numerous actions of the statins make them of potential use in the prevention and treatment of severe sepsis. Severe sepsis continues to be a highly lethal condition, for which there are, as yet, no effective pharmacological treatments, save antibiotics. We explore the biological plausibility of statins as prophylaxis agents and as treatment for severe sepsis and thoroughly review the preclinical and clinical studies that have explored the effects of statins in infected and septic patients. Statins remain only promising treatments for severe sepsis, without convincing evidence that they reduce patient mortality. Ongoing randomized trials may provide conclusive evidence, whether positive or negative. PMID- 22843508 TI - Chronic osteomyelitis. AB - Chronic osteomyelitis is a multifaceted bacterial infection with common features. It absolutely requires surgery for remission. The duration and form of concomitant administration of antibiotic agents for adult patients is still based on expert opinion. The traditional recommendation of 6-12 weeks of antibiotic therapy, where, for at least the first 2-6 weeks, antibiotics should be administered intravenously, is more and more challenged in favor of an oral antibiotic treatment with selected agents from the start. There is no evidence that the total duration of antibiotic therapy for more than 4-6 weeks improves outcome, when compared with shorter regimens. Hopefully, the future will show randomized trials in the adult population, allowing optimal timing of surgical and medical therapy and sparing of unnecessary prescription, with concomitant development of antibiotic resistance. External advice from an expert team with combined surgeons and infectious disease physicians may help to reduce antibiotic consumption in a cost-effective way. PMID- 22843510 TI - Bilateral internal mammary arteries: a new trick for coronary artery bypass grafting. PMID- 22843511 TI - Retrospective institutional study of 31 patients treated for pulmonary artery sarcoma. AB - OBJECTIVES: The study aimed to determine the optimal surgical procedure to treat pulmonary artery sarcomas responsible for pulmonary hypertension. METHODS: Between 1997 and 2010, 31 patients were treated surgically for pulmonary artery sarcomas. Sixteen patients were male; the mean age was 56 years (range, 26-78 years). Common symptoms were characteristic of acute or chronic pulmonary thromboembolic disease. Also, 21 patients experienced mild to severe pulmonary hypertension, with a mean total peripheral resistance of 473 dyn s cm(-5). Clinical presentation and preoperative work-up confirmed the suspicion of pulmonary artery sarcoma in 18 patients. The required surgical procedures included the following: pulmonary endarterectomy in 25 patients (combined with a right pneumonectomy in five and with a replacement of the main pulmonary artery by a homograft reconstruction in one), pneumonectomy only in five (three right and two left), with the use of cardiopulmonary bypass in three cases. In one patient, the right pulmonary artery only was replaced on cardiopulmonary bypass. RESULTS: Final pathology showed 26 high-grade and five intermediate-grade sarcomas. The 30-day mortality was 13% (four patients). Repeat pulmonary resection was required in two patients due to recurrent disease. Moreover, 18 patients received adjuvant therapy. Mean follow-up was 19 months (range, 1-99 months); of the 11 patients alive at follow-up, four were noted to have recurrent disease. The 1-, 3- and 5- year survival was 63, 29 and 22%, respectively. CONCLUSIONS: The prognosis of this very infrequent disease remains poor. Bilateral pulmonary endarterectomy may yield significant survival rates because it provides completeness of resection without sacrificing the pulmonary vascular bed. PMID- 22843512 TI - How to achieve an aortic root remodelling by performing an aortic root reimplantation. AB - The aortic root remodelling procedure, introduced by Yacoub in the early 1980s, is the valve-sparing aortic root replacement procedure that better reproduces the anatomical and functional properties of the native aortic root. Long-term durability of the repair, in terms of freedom from recurrent aortic regurgitation, has been questioned and can probably be improved by appropriate patient selection. Reproducibility of the operation, however, depends on subjective evaluations and surgical skill. We report a simplification of the technique designed to possibly increase the reproducibility of the aortic root remodelling operation while retaining its functional advantages. PMID- 22843513 TI - Selective cerebral perfusion using moderate flow in complex cardiac surgery provides sufficient neuroprotection. Are children young adults? AB - OBJECTIVE: Selective cerebral perfusion (SCP) is commonly applied during the correction of complex congenital cardiac defects. In this study, we assessed the impact of different flow levels of SCP on potential brain ischaemia. METHODS: Fifteen piglets (7-10 kg, age 3-4 weeks) received SCP via the right common carotid artery during cardiopulmonary bypass at 25 degrees C for 90 min. Regular brain perfusion (1 ml/g brain weight/min), moderate hypoperfusion (0.5 ml/g/min) and extensive hypoperfusion (0.25 ml/g/min) were evaluated. Clinical parameters and tissue oxygenation index (TOI) were registered online until 3 h of reperfusion. Hematoxylin and eosin (HE) staining and immunohistological analyses for apoptosis inducing factor (AIF) and nitrotyrosine (NO-Tyr) were performed on sections of the hippocampus. RESULTS: Intracerebral pressure remained stable throughout the study. Haemodynamic parameters, blood gas and lactate measurements were stable until the end of the study. Extensive hypoperfusion led to a moderate reduction of TOI. NO-Tyr immuno-positive cells were 15.7% at regular cerebral perfusion, 23.9% at moderate hypoperfusion (P = n.s.) and 46.1% at extensive hypoperfusion (P < 0.05). AIF immuno-positive nuclei were present in 8.3% of the hippocampus cells after regular perfusion, in 10.8% after moderate hypoperfusion (P = n.s.) and in 17.9% after extensive hypoperfusion (P < 0.05). CONCLUSIONS: SCP using a moderate SCP flow regime demonstrates comparable results to normal brain perfusion while after extensive hypoperfusion significant morphological brain injury could be found. Thus moderate, but not extensive, hypoperfusion might have the potential to prevent perfusion-related cerebral oedema and an increasing risk of brain injury. PMID- 22843514 TI - Recent advances in our understanding of lung cancer visceral pleural invasion and other forms of minimal invasion: implications for the next TNM classification. PMID- 22843515 TI - Active immunotherapy: current state of the art in vaccine approaches for NHL. AB - Immune therapy of cancer is a rapidly evolving field, with long-deserved successes now finally achieved. As new pathways triggered by the immune synapsis are elucidated, and new molecules responsible for immune checkpoints are being discovered, it is becoming clear that vaccination against a single antigen aided by non-specific immune stimulation is not sufficient for an efficient, long term, immune response. Though lymphoma is a highly curable malignancy, there is still a subset of patients that is at very high risk of disease relapse even after successfully completing chemotherapy or a stem cell transplant. Patients with minimal residual disease are particularly suitable for vaccination. Over the past 3 decades, the classic model of lymphoma-specific idiotype vaccine has evolved and recent data on vaccination with nonspecific oligodeoxynucleotides has provided very encouraging results. Furthermore, the introduction of checkpoint blockade via agonist or antagonist monoclonal antibodies holds the promise of significant improvement in the efficacy of future vaccines. What follows is a brief summary of the historical highlights in lymphoma immunotherapy as well as an update on the most recently published clinical trials and a look at future developments. PMID- 22843516 TI - Geothrix fermentans secretes two different redox-active compounds to utilize electron acceptors across a wide range of redox potentials. AB - The current understanding of dissimilatory metal reduction is based primarily on isolates from the proteobacterial genera Geobacter and Shewanella. However, environments undergoing active Fe(III) reduction often harbor less-well-studied phyla that are equally abundant. In this work, electrochemical techniques were used to analyze respiratory electron transfer by the only known Fe(III)-reducing representative of the Acidobacteria, Geothrix fermentans. In contrast to previously characterized metal-reducing bacteria, which typically reach maximal rates of respiration at electron acceptor potentials of 0 V versus standard hydrogen electrode (SHE), G. fermentans required potentials as high as 0.55 V to respire at its maximum rate. In addition, G. fermentans secreted two different soluble redox-active electron shuttles with separate redox potentials (-0.2 V and 0.3 V). The compound with the lower midpoint potential, responsible for 20 to 30% of electron transfer activity, was riboflavin. The behavior of the higher potential compound was consistent with hydrophilic UV-fluorescent molecules previously found in G. fermentans supernatants. Both electron shuttles were also produced when cultures were grown with Fe(III), but not when fumarate was the electron acceptor. This study reveals that Geothrix is able to take advantage of higher-redox-potential environments, demonstrates that secretion of flavin-based shuttles is not confined to Shewanella, and points to the existence of high potential-redox-active compounds involved in extracellular electron transfer. Based on differences between the respiratory strategies of Geothrix and Geobacter, these two groups of bacteria could exist in distinctive environmental niches defined by redox potential. PMID- 22843517 TI - Characterization of the twin-arginine transport secretome in Sinorhizobium meliloti and evidence for host-dependent phenotypes. AB - The twin-arginine transport (Tat) system is essential for cell viability in Sinorhizobium meliloti and may play a role during the development of root nodules. Utilizing an in vivo recombination strategy, we have constructed 28 strains that contain deletions in predicted Tat substrates. Testing of these mutations for symbiotic proficiency on the plant hosts alfalfa and sweet clover shows that some of these mutations affect associations with these hosts differentially. PMID- 22843518 TI - Antiviral protection and the importance of Wolbachia density and tissue tropism in Drosophila simulans. AB - Wolbachia, a maternally transmitted endosymbiont of insects, is increasingly being seen as an effective biological control agent that can interfere with transmission of pathogens, including dengue virus. However, the mechanism of antiviral protection is not well understood. The density and distribution of Wolbachia in host tissues have been implicated as contributing factors by previous studies with both mosquitoes and flies. Drosophila flies infected with five diverse strains of Wolbachia were screened for the ability to mediate antiviral protection. The three protective Wolbachia strains were more closely related and occurred at a higher density within whole flies than the two nonprotective Wolbachia strains. In this study, to further investigate the relationship between whole-fly Wolbachia density and the ability to mediate antiviral protection, tetracycline was used to decrease the abundance of the high density, protective Wolbachia strain wAu prior to viral challenge. Antiviral protection was lost when the density of the protective Wolbachia strain was decreased to an abundance similar to that of nonprotective Wolbachia strains. We determined the Wolbachia density and distribution in tissues of the same five fly Wolbachia combinations as used previously. The Wolbachia density within the head, gut, and Malpighian tubules correlated with the ability to mediate antiviral protection. These findings may facilitate the development of Wolbachia biological control strategies and help to predict host-Wolbachia pairings that may interfere with virus-induced pathology. PMID- 22843519 TI - Stability of a Pseudomonas putida KT2440 bacteriophage-carried genomic island and its impact on rhizosphere fitness. AB - The stability of seven genomic islands of Pseudomonas putida KT2440 with predicted potential for mobilization was studied in bacterial populations associated with the rhizosphere of corn plants by multiplex PCR. DNA rearrangements were detected for only one of them (GI28), which was lost at high frequency. This genomic island of 39.4 kb, with 53 open reading frames, shows the characteristic organization of genes belonging to tailed phages. We present evidence indicating that it corresponds to the lysogenic state of a functional bacteriophage that we have designated Pspu28. Integrated and rarely excised forms of Pspu28 coexist in KT2440 populations. Pspu28 is self-transmissible, and an excisionase is essential for its removal from the bacterial chromosome. The excised Pspu28 forms a circular element that can integrate into the chromosome at a specific location, att sites containing a 17-bp direct repeat sequence. Excision/insertion of Pspu28 alters the promoter sequence and changes the expression level of PP_1531, which encodes a predicted arsenate reductase. Finally, we show that the presence of Pspu28 in the lysogenic state has a negative effect on bacterial fitness in the rhizosphere under conditions of intraspecific competition, thus explaining why clones having lost this mobile element are recovered from that environment. PMID- 22843521 TI - Specific gene responses of Rhodococcus jostii RHA1 during growth in soil. AB - Transcriptome analysis of Rhodococcus jostii RHA1 during growth in sterilized soil was performed. A total of 165 soil-specific genes were identified by subtracting genes upregulated in late growth phases and on solid medium from 264 genes commonly upregulated during growth on biphenyl or pyruvate in sterilized soil. Classification of the 165 genes into functional categories indicated that this soil-specific group is rich in genes for the metabolism of fatty acids, amino acids, carbohydrates, and nitrogen and relatively poor in those for cellular processes and signaling. The ro06365-ro06369 gene cluster, in which ro06365 to ro06368 were highly upregulated in transcriptome analysis, was characterized further. ro06365 and ro06366 show similarity to a nitrite/nitrate transporter and a nitrite reductase, respectively, suggesting their involvement in nitrogen metabolism. A strain with an ro06366 deletion, D6366, showed growth retardation when we used nitrate as the sole nitrogen source and no growth when we used nitrite. A strain with a deletion of ro06365 to ro06368, DNop, utilized neither nitrite nor nitrate and recovered growth using nitrite and nitrate by introduction of the deleted genes. Both of the mutants showed growth retardation in sterilized soil, and the growth retardation of DNop was more significant than that of D6366. When these mutants were cultivated in medium containing the same proportions of ammonium, nitrate, and nitrite ions as those in the sterilized soil, they showed growth retardation similar to that in the soil. These results suggest that the ro06365-ro06369 gene cluster has a significant role in nitrogen utilization in sterilized soil. PMID- 22843520 TI - Intercity spread of echovirus 6 in Shandong Province, China: application of environmental surveillance in tracing circulating enteroviruses. AB - Environmental surveillance is an effective approach in investigating circulating enteroviruses and had been conducted in the cities of Jinan and Linyi since February 2008 and April 2010, respectively. This study analyzed 46 sewage samples collected in the two cities in 2011 and found that echovirus 6 (E6) was the predominant serotype, with 134 isolates (65 in Jinan and 69 in Linyi) from 23 (50%) samples. This differs from the 2010 data that found 29 E6 isolates in Jinan and only 3 in Linyi. Phylogenetic analysis of the VP1 coding region showed that all environmental E6 samples from 2008 to 2011 (n = 167) segregated into two lineages and revealed an increase in VP1 gene diversity in 2011, suggesting that the increased number of E6 detections reflects a real epidemic in the two cities. Most Linyi isolates (n = 61, or 88%) in 2011 segregated into sublineage 1a, together with 18 Jinan isolates in 2011. Interestingly, the ancestral VP1 sequence of sublineage 1a inferred using the maximum-likelihood method had 100% identity with the sequence of one environmental isolate from Jinan in August 2010, suggesting an intercity spread from Jinan to Linyi. By Bayesian phylodynamic methods, the most recent common ancestor of Linyi isolates in sublineage 1a dated back to 24 December 2010, revealing that this sublineage was likely imported into Linyi from August to December in 2010. This study demonstrates that environmental surveillance is a sensitive method in tracing transmission pathways of circulating enteroviruses among different regions and reveals that E6-associated aseptic meningitis is an emerging concern in China. PMID- 22843522 TI - Construction and application of a luxABCDE reporter system for real-time monitoring of Enterococcus faecalis gene expression and growth. AB - The present work describes the construction of a novel molecular tool for luciferase-based bioluminescence (BL) tagging of Enterococcus faecalis. To this end, a vector (pSL101) and its derivatives conferring a genetically encoded bioluminescent phenotype on all tested strains of E. faecalis were constructed. pSL101 harbors the luxABCDE operon from pPL2lux and the pREG696 broad-host-range replicon and axe-txe toxin-antitoxin cassette, providing segregational stability for long-term plasmid persistence in the absence of antibiotic selection. The bioluminescent signals obtained from three highly expressed promoters correlated linearly (R(2) > 0.98) with the viable-cell count. We employed lux-tagged E. faecalis strains to monitor growth in real time in milk and urine in vitro. Furthermore, bioluminescence imaging (BLI) was used to visualize the magnitude of the bacterial burden during infection in the Galleria mellonella model system. To our knowledge, pSL101 is the first substrate addition-independent reporter system developed for BLI of E. faecalis and an efficient tool for spatiotemporal tracking of bacterial growth and quantitative determination of promoter activity in real time, noninvasively, in infection model systems. PMID- 22843523 TI - Dominance of Lactobacillus acidophilus in the facultative jejunal Lactobacillus microbiota of fistulated beagles. AB - Lactobacilli were isolated from jejunal chyme from five fistulated beagles. Cultivable lactobacilli varied from 10(4) to 10(8) CFU/ml. Seventy-four isolates were identified by partial 16S rRNA gene sequencing and differentiated by repetitive element PCR (Rep-PCR), Lactobacillus acidophilus was dominant, and nearly 80% of 54 isolates shared the same DNA fingerprint pattern. PMID- 22843524 TI - Inactivation of the ybdD gene in Lactococcus lactis increases the amounts of exported proteins. AB - Random insertional mutagenesis performed on a Lactococcus lactis reporter strain led us to identify L. lactis ybdD as a protein-overproducing mutant. In different expression contexts, the ybdD mutant shows increased levels of exported proteins and therefore constitutes a new and attractive heterologous protein production host. This study also highlights the importance of unknown regulatory processes that play a role during protein secretion. PMID- 22843525 TI - Identification of a gene involved in the synthesis of a dipeptidyl peptidase IV inhibitor in Aspergillus oryzae. AB - WYK-1 is a dipeptidyl peptidase IV inhibitor produced by Aspergillus oryzae strain AO-1. Because WYK-1 is an isoquinoline derivative consisting of three l amino acids, we hypothesized that a nonribosomal peptide synthetase was involved in its biosynthesis. We identified 28 nonribosomal peptide synthetase genes in the sequenced genome of A. oryzae RIB40. These genes were also identified in AO 1. Among them, AO090001000009 (wykN) was specifically expressed under WYK-1 producing conditions in AO-1. Therefore, we constructed wykN gene disruptants of AO-1 after nonhomologous recombination was suppressed by RNA interference to promote homologous recombination. Our results demonstrated that the disruptants did not produce WYK-1. Furthermore, the expression patterns of 10 genes downstream of wykN were similar to the expression pattern of wykN under several conditions. Additionally, homology searches revealed that some of these genes were predicted to be involved in WYK-1 biosynthesis. Therefore, we propose that wykN and the 10 genes identified in this study constitute the WYK-1 biosynthetic gene cluster. PMID- 22843526 TI - Heavy metal and disinfectant resistance of Listeria monocytogenes from foods and food processing plants. AB - The persistence of Listeria monocytogenes in food processing plants and other ecosystems reflects its ability to adapt to numerous stresses. In this study, we investigated 138 isolates from foods and food processing plants for resistance to the quaternary ammonium disinfectant benzalkonium chloride (BC) and to heavy metals (cadmium and arsenic). We also determined the prevalence of distinct cadmium resistance determinants (cadA1, cadA2, and cadA3) among cadmium-resistant isolates. Most BC-resistant isolates were resistant to cadmium as well. Arsenic resistance was encountered primarily in serotype 4b and was an attribute of most isolates of the serotype 4b epidemic clonal group ECIa. Prevalence of the known cadmium resistance determinants was serotype associated: cadA1 was more common in isolates of serotypes 1/2a and 1/2b than 4b, while cadA2 was more common in those of serotype 4b. A subset (15/77 [19%]) of the cadmium-resistant isolates lacked the known cadmium resistance determinants. Most of these isolates were of serotype 4b and were also resistant to arsenic, suggesting novel determinants that may confer resistance to both cadmium and arsenic in these serotype 4b strains. The findings may reflect previously unrecognized components of the ecological history of different serotypes and clonal groups of L. monocytogenes, including exposures to heavy metals and disinfectants. PMID- 22843527 TI - Mutational analysis of the pentose phosphate and Entner-Doudoroff pathways in Gluconobacter oxydans reveals improved growth of a Deltaedd Deltaeda mutant on mannitol. AB - The obligatory aerobic acetic acid bacterium Gluconobacter oxydans 621H oxidizes sugars and sugar alcohols primarily in the periplasm, and only a small fraction is metabolized in the cytoplasm. The latter can occur either via the Entner Doudoroff pathway (EDP) or via the pentose phosphate pathway (PPP). The Embden Meyerhof pathway is nonfunctional, and a cyclic operation of the tricarboxylic acid cycle is prevented by the absence of succinate dehydrogenase. In this work, the cytoplasmic catabolism of fructose formed by oxidation of mannitol was analyzed with a Deltagnd mutant lacking the oxidative PPP and a Deltaedd Deltaeda mutant devoid of the EDP. The growth characteristics of the two mutants under controlled conditions with mannitol as the carbon source and enzyme activities showed that the PPP is the main route for cytoplasmic fructose catabolism, whereas the EDP is dispensable and even unfavorable. The Deltaedd Deltaeda mutant (lacking 6-phosphogluconate dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase) formed 24% more cell mass than the reference strain. In contrast, deletion of gnd (6-phosphogluconate dehydrogenase) severely inhibited growth and caused a strong selection pressure for secondary mutations inactivating glucose-6 phosphate dehydrogenase, thus preventing fructose catabolism via the EDP also. These Deltagnd zwf* mutants (with a mutation in the zwf gene causing inactivation of the glucose-6-phosphate dehydrogenase) were almost totally disabled in fructose catabolism but still produced about 14% of the carbon dioxide of the reference strain, possibly by catabolizing substrates from the yeast extract. Overexpression of gnd in the reference strain improved biomass formation in a similar manner as deletion of edd and eda, further confirming the importance of the PPP for cytoplasmic fructose catabolism. PMID- 22843528 TI - A novel biosensor selective for organoarsenicals. AB - Organoarsenicals used as herbicides and growth promoters for farm animals are degraded to inorganic arsenic. Available bacterial whole-cell biosensors detect only inorganic arsenic. We report a biosensor selective for the trivalent organoarsenicals methylarsenite and phenylarsenite over inorganic arsenite. This sensor may be useful for detecting degradation of arsenic-containing herbicides and growth promoters. PMID- 22843529 TI - Uncoupling of substrate-level phosphorylation in Escherichia coli during glucose limited growth. AB - The respiratory chain of Escherichia coli contains three different cytochrome oxidases. Whereas the cytochrome bo oxidase and the cytochrome bd-I oxidase are well characterized and have been shown to contribute to proton translocation, physiological data suggested a nonelectrogenic functioning of the cytochrome bd II oxidase. Recently, however, this view was challenged by an in vitro biochemical analysis that showed that the activity of cytochrome bd-II oxidase does contribute to proton translocation with an H(+)/e(-) stoichiometry of 1. Here, we propose that this apparent discrepancy is due to the activities of two alternative catabolic pathways: the pyruvate oxidase pathway for acetate production and a pathway with methylglyoxal as an intermediate for the production of lactate. The ATP yields of these pathways are lower than those of the pathways that have so far always been assumed to catalyze the main catabolic flux under energy-limited growth conditions (i.e., pyruvate dehydrogenase and lactate dehydrogenase). Inclusion of these alternative pathways in the flux analysis of growing E. coli strains for the calculation of the catabolic ATP synthesis rate indicates an electrogenic function of the cytochrome bd-II oxidase, compatible with an H(+)/e(-) ratio of 1. This analysis shows for the first time the extent of bypassing of substrate-level phosphorylation in E. coli under energy-limited growth conditions. PMID- 22843530 TI - A two-component regulatory system controls autoregulated serpin expression in Bifidobacterium breve UCC2003. AB - This work reports on the identification and molecular characterization of a two component regulatory system (2CRS), encoded by serRK, which is believed to control the expression of the ser(2003) locus in Bifidobacterium breve UCC2003. The ser(2003) locus consists of two genes, Bbr_1319 (sagA) and Bbr_1320 (serU), which are predicted to encode a hypothetical membrane-associated protein and a serpin-like protein, respectively. The response regulator SerR was shown to bind to the promoter region of ser(2003), and the probable recognition sequence of SerR was determined by a combinatorial approach of in vitro site-directed mutagenesis coupled to transcriptional fusion and electrophoretic mobility shift assays (EMSAs). The importance of the serRK 2CRS in the response of B. breve to protease-mediated induction was confirmed by generating a B. breve serR insertion mutant, which was shown to exhibit altered ser(2003) transcriptional induction patterns compared to the parent strain, UCC2003. Interestingly, the analysis of a B. breve serU mutant revealed that the SerRK signaling pathway appears to include a SerU-dependent autoregulatory loop. PMID- 22843531 TI - Pyrosequencing analysis of bacterial diversity in 14 wastewater treatment systems in China. AB - To determine if there is a core microbial community in the microbial populations of different wastewater treatment plants (WWTPs) and to investigate the effects of wastewater characteristics, operational parameters, and geographic locations on microbial communities, activated sludge samples were collected from 14 wastewater treatment systems located in 4 cities in China. High-throughput pyrosequencing was used to examine the 16S rRNA genes of bacteria in the wastewater treatment systems. Our results showed that there were 60 genera of bacterial populations commonly shared by all 14 samples, including Ferruginibacter, Prosthecobacter, Zoogloea, Subdivision 3 genera incertae sedis, Gp4, Gp6, etc., indicating that there is a core microbial community in the microbial populations of WWTPs at different geographic locations. The canonical correspondence analysis (CCA) results showed that the bacterial community variance correlated most strongly with water temperature, conductivity, pH, and dissolved oxygen (DO) content. Variance partitioning analyses suggested that wastewater characteristics had the greatest contribution to the bacterial community variance, explaining 25.7% of the variance of bacterial communities independently, followed by operational parameters (23.9%) and geographic location (14.7%). Results of this study provided insights into the bacterial community structure and diversity in geographically distributed WWTPs and discerned the relationships between bacterial community and environmental variables in WWTPs. PMID- 22843532 TI - High-throughput amplicon sequencing reveals distinct communities within a corroding concrete sewer system. AB - Microbially induced concrete corrosion (MICC) is an important problem in sewers. Here, small-subunit (SSU) rRNA gene amplicon pyrosequencing was used to characterize MICC communities. Microbial community composition differed between wall- and ceiling-associated MICC layers. Acidithiobacillus spp. were present at low abundances, and the communities were dominated by other sulfur-oxidizing associated lineages. PMID- 22843533 TI - Predicting the presence of non-O157 Shiga toxin-producing Escherichia coli in ground beef by using molecular tests for Shiga toxins, intimin, and O serogroups. AB - When 3,972 ground beef enrichments with 6 confirmed to contain a non-O157 Shiga toxin-producing intimin-positive Escherichia coli isolate were tested for Shiga toxin, intimin, and O group (O26, O45, O103, O111, O121, and O145) genes, 183 potential positives and only 2 of the 6 confirmed positives were identified. PMID- 22843535 TI - Role of calcium alginate and mannitol in protecting Bifidobacterium. AB - Fourier transform infrared (FTIR) spectroscopy was carried out to ascertain the mechanism of Ca-alginate and mannitol protection of cell envelope components and secondary proteins of Bifidobacterium animalis subsp. lactis Bb12 after freeze drying and after 10 weeks of storage at room temperature (25 degrees C) at low water activities (a(w)) of 0.07, 0.1, and 0.2. Preparation of Ca-alginate and Ca alginate-mannitol as microencapsulants was carried out by dropping an alginate or alginate-mannitol emulsion containing bacteria using a burette into CaCl(2) solution to obtain Ca-alginate beads and Ca-alginate-mannitol beads, respectively. The wet beads were then freeze-dried. The a(w) of freeze-dried beads was then adjusted to 0.07, 0.1, and 0.2 using saturated salt solutions; controls were prepared by keeping Ca-alginate and Ca-alginate-mannitol in aluminum foil without a(w) adjustment. Mannitol in the Ca-alginate system interacted with cell envelopes during freeze-drying and during storage at low a(w)s. In contrast, Ca-alginate protected cell envelopes after freeze-drying but not during 10-week storage. Unlike Ca-alginate, Ca-alginate-mannitol was effective in retarding the changes in secondary proteins during freeze-drying and during 10 weeks of storage at low a(w)s. It appears that Ca-alginate-mannitol is more effective than Ca-alginate in preserving cell envelopes and proteins after freeze-drying and after 10 weeks of storage at room temperature (25 degrees C). PMID- 22843534 TI - Obacunone represses Salmonella pathogenicity islands 1 and 2 in an envZ-dependent fashion. AB - Obacunone belongs to a class of unique triterpenoids called limonoids, present in Citrus species. Previous studies from our laboratory suggested that obacunone possesses antivirulence activity and demonstrates inhibition of cell-cell signaling in Vibrio harveyi and Escherichia coli O157:H7. The present work sought to determine the effect of obacunone on the food-borne pathogen Salmonella enterica serovar Typhimurium LT2 by using a cDNA microarray. Transcriptomic studies indicated that obacunone represses Salmonella pathogenicity island 1 (SPI1), the maltose transporter, and the hydrogenase operon. Furthermore, phenotypic data for the Caco-2 infection assay and maltose utilization were in agreement with microarray data suggesting repression of SPI1 and maltose transport. Further studies demonstrated that repression of SPI1 was plausibly mediated through hilA. Additionally, obacunone seems to repress SPI2 under SPI2 inducing conditions as well as in Caco-2 infection models. Furthermore, obacunone seems to repress hilA in an EnvZ-dependent fashion. Altogether, the results of the study seems to suggest that obacunone exerts an antivirulence effect on S. Typhimurium and may serve as a lead compound for development of antivirulence strategies for S. Typhimurium. PMID- 22843536 TI - Production of an extracellular matrix as an isotropic growth phase of Penicillium rubens on gypsum. AB - Indoor mold represents an important environmental concern, but a fundamental knowledge of fungal growth stages is needed to limit indoor fungal proliferation on finishing materials used in buildings. The present study focused on the succession of germination stages of the common indoor fungus Penicillium rubens on a gypsum substrate. This substrate is used as a model system representing porous materials that are widely used in indoor environments. Imaging with cryo scanning electron microscopy showed that the formation of an extracellular matrix (ECM) is a phase of the isotropic growth of P. rubens that is uniquely related to germinating conidia. Furthermore, the ECM is observed only when a dry-state inoculation of the surface is applied, i.e., applying conidia directly from a 7 day-old colony, mimicking airborne contamination of the surface. When inoculation is done by spraying an aqueous conidial suspension, no ECM is observed. Moreover, it is concluded that the formation of an ECM requires active processes in the fungal cell. The porosity of the substrate proved that the ECM substance has high viscosity characteristics. The present results stress that studies of indoor fungal growth should consider the method of inoculation, knowing that the common aqueous suspension may obscure specific stages in the initial phases of germination. PMID- 22843537 TI - Molecular and biochemical analyses of the GH44 module of CbMan5B/Cel44A, a bifunctional enzyme from the hyperthermophilic bacterium Caldicellulosiruptor bescii. AB - A large polypeptide encoded in the genome of the thermophilic bacterium Caldicellulosiruptor bescii was determined to consist of two glycoside hydrolase (GH) modules separated by two carbohydrate-binding modules (CBMs). Based on the detection of mannanase and endoglucanase activities in the N-terminal GH5 and the C-terminal GH44 module, respectively, the protein was designated CbMan5B/Cel44A. A GH5 module with >99% identity from the same organism was characterized previously (X. Su, R. I. Mackie, and I. K. Cann, Appl. Environ. Microbiol. 78:2230-2240, 2012); therefore, attention was focused on CbMan5A/Cel44A-TM2 (or TM2), which harbors the GH44 module and the two CBMs. On cellulosic substrates, TM2 had an optimal temperature and pH of 85 degrees C and 5.0, respectively. Although the amino acid sequence of the GH44 module of TM2 was similar to those of other GH44 modules that hydrolyzed cello-oligosaccharides, cellulose, lichenan, and xyloglucan, it was unique that TM2 also displayed modest activity on mannose-configured substrates and xylan. The TM2 protein also degraded Avicel with higher specific activity than activities reported for its homologs. The GH44 catalytic module is composed of a TIM-like domain and a beta-sandwich domain, which consists of one beta-sheet at the N terminus and nine beta-sheets at the C terminus. Deletion of one or more beta-sheets from the beta-sandwich domain resulted in insoluble proteins, suggesting that the beta-sandwich domain is essential for proper folding of the polypeptide. Combining TM2 with three other endoglucanases from C. bescii led to modest synergistic activities during degradation of cellulose, and based on our results, we propose a model for cellulose hydrolysis and utilization by C. bescii. PMID- 22843538 TI - Microbial community structure and activity linked to contrasting biogeochemical gradients in bog and fen environments of the Glacial Lake Agassiz Peatland. AB - The abundances, compositions, and activities of microbial communities were investigated at bog and fen sites in the Glacial Lake Agassiz Peatland of northwestern Minnesota. These sites contrast in the reactivity of dissolved organic matter (DOM) and the presence or absence of groundwater inputs. Microbial community composition was characterized using pyrosequencing and clone library construction of phylogenetic marker genes. Microbial distribution patterns were linked to pH, concentrations of dissolved organic carbon and nitrogen, C/N ratios, optical properties of DOM, and activities of laccase and peroxidase enzymes. Both bacterial and archaeal richness and rRNA gene abundance were >2 times higher on average in the fen than in the bog, in agreement with a higher pH, labile DOM content, and enhanced enzyme activities in the fen. Fungi were equivalent to an average of 1.4% of total prokaryotes in gene abundance assayed by quantitative PCR. Results revealed statistically distinct spatial patterns between bacterial and fungal communities. Fungal distribution did not covary with pH and DOM optical properties and was vertically stratified, with a prevalence of Ascomycota and Basidiomycota near the surface and much higher representation of Zygomycota in the subsurface. In contrast, bacterial community composition largely varied between environments, with the bog dominated by Acidobacteria (61% of total sequences), while the Firmicutes (52%) dominated in the fen. Acetoclastic Methanosarcinales showed a much higher relative abundance in the bog, in contrast to the dominance of diverse hydrogenotrophic methanogens in the fen. This is the first quantitative and compositional analysis of three microbial domains in peatlands and demonstrates that the microbial abundance, diversity, and activity parallel with the pronounced differences in environmental variables between bog and fen sites. PMID- 22843539 TI - Management of pain with comorbid substance abuse. AB - Substance use disorders are a large public health problem in the United States. Over the past decade, there has been a trend of increased prescription drug misuse, morbidity, and mortality related to prescription opioids. For providers who treat pain, this has led to clinical dilemmas as the newly appreciated risks must be balanced with the benefits of treatment, particularly in patients with known substance use disorders. Acute, chronic, and palliative each present distinct issues in pain treatment. A best practices model of pain treatment, including risk stratification and integrative treatment, may provide the best prospect for safe and effective treatment. PMID- 22843541 TI - Quantification of myocardial blood flow by adenosine-stress CT perfusion imaging in pigs during various degrees of stenosis correlates well with coronary artery blood flow and fractional flow reserve. AB - AIMS: Only few preliminary experimental studies demonstrated the feasibility of adenosine stress CT myocardial perfusion imaging to calculate the absolute myocardial blood flow (MBF), thereby providing information whether a coronary stenosis is flow limiting. Therefore, the aim of our study was to determine whether adenosine stress myocardial perfusion imaging by Dual Source CT (DSCT) enables non-invasive quantification of regional MBF in an animal model with various degrees of coronary flow reduction. METHODS AND RESULTS: In seven pigs, a coronary flow probe and an adjustable hydraulic occluder were placed around the left anterior descending coronary artery to monitor the distal coronary artery blood flow (CBF) while several degrees of coronary flow reduction were induced. CT perfusion (CT-MBF) was acquired during adenosine stress with no CBF reduction, an intermediate (15-39%) and a severe (40-95%) CBF reduction. Reference standards were CBF and fractional flow reserve measurements (FFR). FFR was simultaneously derived from distal coronary artery pressure and aortic pressure measurements. CT MBF decreased progressively with increasing CBF reduction severity from 2.68 (2.31-2.81)mL/g/min (normal CBF) to 1.96 (1.83-2.33) mL/g/min (intermediate CBF reduction) and to 1.55 (1.14-2.06)mL/g/min (severe CBF-reduction) (both P < 0.001). We observed very good correlations between CT-MBF and CBF (r = 0.85, P < 0.001) and CT-MBF and FFR (r = 0.85, P < 0.001). CONCLUSION: Adenosine stress DSCT myocardial perfusion imaging allows quantification of regional MBF under various degrees of CBF reduction. PMID- 22843543 TI - Pain Management in patients with diabetic nephropathy: the emerging role of alpha lipoic acid. PMID- 22843540 TI - Emerging association between addictive gaming and attention-deficit/hyperactivity disorder. AB - Children's and adolescent's use of computer games and videogames is becoming highly popular and has increased dramatically over the last decade. There is growing evidence of high prevalence of addiction to computer games and videogames among children, which is causing concern because of its harmful consequences. There is also emerging evidence of an association between computer game and videogame addiction and attention deficit/hyperactivity disorder (ADHD). This is indicated by the occurrence of gaming addiction as a co-morbid disorder of ADHD, common physiological and pharmacological mechanisms, and potential genetic association between the two disorders. A proper understanding of the psychological and neurotransmitter mechanisms underlying both disorders is important for appropriate diagnostic classification of both disorders. Furthermore, it is important for development of potential pharmacological treatment of both disorders. Relatively few studies have investigated the common mechanisms for both disorders. This paper reviews new findings, trends, and developments in the field. The paper is based on a literature search, in Medline and PUBMED, using the keywords addictive gaming and ADHD, of articles published between 2000 and 2012. PMID- 22843544 TI - Technique tip: use of anterior cruciate ligament jig for hindfoot fusion by calcanio-talo-tibial nail. AB - BACKGROUND: The use of intramedullary nail fixation for tibio-talo-calcaneal fusion is gaining popularity. There is chance of failure of procedure following faulty operative technique specially alignment. METHODS: The article describes a useful application of tibial tunnel jig in inserting the calcanio-talo-tibial guide wire. RESULTS: There is precision of few millimeters in the exit point of guide wire on talus. CONCLUSIONS: The authors believe that this helps in better positioning of nail and hence better alignment and better operative outcome. PMID- 22843545 TI - Charcot arthropathy. PMID- 22843547 TI - Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma. AB - Human clear cell renal cell carcinoma (CCC) remains resistant to treatments despite the progress in targeted therapies. Several signaling pathways acting during renal development are reactivated during kidney tumorigenesis; this is the case of the sonic hedgehog (SHH)-Gli. Interestingly, the precursor of active vitamin D3 (VD3), cholecalciferol, has been demonstrated to be a strong inhibitor of SHH-Gli signaling. Here, we show the preclinical efficacy of cholecalciferol in CCC both in vitro and in vivo. A panel of CCC cell lines, tumors and normal corresponding tissues from CCC patients were used to evaluate the expression of the VD3 receptor and metabolizing enzymes and the effects of cholecalciferol treatment. Subsequently, xenografted mice were treated with cholecalciferol in a prophylactic or therapeutic manner; their response and the adverse effects were evaluated on the basis of weekly monitoring, followed by blood collection procedures and X-ray micro-computed tomography. VD3 receptor and metabolizing enzymes are dramatically decreased in human cell lines and tumors. Cholecalciferol decreases cell proliferation and increases cell death by inhibition of the SHH-Gli pathway. Xenografted mice treated with cholecalciferol exhibit absence of tumor development or substantial growth inhibition. The treatment was shown to be safe; it did not induce calcification or calcium reabsorption. These findings establish that, although VD3 receptors and metabolizing enzymes are absent in CCC, cholecalciferol supplementation is a strong tool to block the reactivation of SHH-Gli pathway in this pathology, leading ultimately to tumor regression. Cholecalciferol may have highly therapeutic potential in CCC. PMID- 22843546 TI - Attention-deficit/hyperactivity disorder genomics: update for clinicians. AB - Attention deficit, hyperactivity disorder (ADHD) is familial and highly heritable. Several candidate genes involved in neurotransmission have been identified, however these confer minimal risk, suggesting that for the most part, ADHD is not caused by single common genetic variants. Advances in genotyping enabling investigation at the level of the genome have led to the discovery of rare structural variants suggesting that ADHD is a genomic disorder, with potentially thousands of variants, and common neuronal pathways disrupted by numerous rare variants resulting in similar ADHD phenotypes. Heritability studies in humans also indicate the importance of epigenetic factors, and animal studies are deciphering some of the processes that confer risk during gestation and throughout the post-natal period. These and future discoveries will lead to improved diagnosis, individualized treatment, cures, and prevention. These advances also highlight ethical and legal issues requiring management and interpretation of genetic data and ensuring privacy and protection from misuse. PMID- 22843548 TI - Independent genetic control of early and late stages of chemically induced skin tumors in a cross of a Japanese wild-derived inbred mouse strain, MSM/Ms. AB - MSM/Ms is an inbred mouse strain derived from a Japanese wild mouse, Mus musculus molossinus. In this study, we showed that MSM/Ms mice exhibit dominant resistance when crossed with susceptible FVB/N mice and subjected to the two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA)/ 12-O tetradecanoylphorbol-13-acetate (TPA). A series of F1 backcross mice were generated by crossing p53(+/+) or p53(+/-) F1 (FVB/N * MSM/Ms) males with FVB/N female mice. These generated 228 backcross animals, approximately half of which were p53(+/-), enabling us to search for p53-dependent skin tumor modifier genes. Highly significant linkage for papilloma multiplicity was found on chromosomes 6 and 7 and suggestive linkage was found on chromosomes 3, 5 and 12. Furthermore, in order to identify stage-dependent linkage loci we classified tumors into three categories (<2mm, 2-6mm and >6mm), and did linkage analysis. The same locus on chromosome 7 showed strong linkage in groups with <2mm or 2-6mm papillomas. No linkage was detected on chromosome 7 to papillomas >6mm, but a different locus on chromosome 4 showed strong linkage both to papillomas >6mm and to carcinomas. This locus, which maps near the Cdkn2a/p19(Arf) gene, was entirely p53-dependent, and was not seen in p53 (+/-) backcross animals. Suggestive linkage conferring susceptibility to carcinoma was also found on chromosome 5. These results clearly suggest distinct loci regulate each stage of tumorigenesis, some of which are p53 dependent. PMID- 22843549 TI - A reanalysis of the evidence for increased efficiency in benzene metabolism at airborne exposure levels below 3 p.p.m. AB - An analysis of monitoring data on workers in Tianjin, China, reported a 9-fold increase in the production of benzene metabolites per unit exposure as air concentrations declined from 88.9 to 0.03 p.p.m. The increase is attributed to an enhanced efficiency of benzene metabolism at lower air concentrations. This finding, however, is not consistent with other studies demonstrating that adsorbed benzene is almost completely metabolized at airborne levels ranging from <1 to 70 p.p.m. In this article (i) the modeling performed in Kim et al. is repeated and the model predictions are reproduced; (ii) the impacts of technical issues in the corrections for background levels of metabolites, accounting for biases in the regression modeling, and the uncertainties introduced by the use of a calibration model to estimate benzene air levels for certain workers are evaluated and (iii) alternative methods of correcting for background levels of metabolites are examined. The new analysis indicates that findings of increased production are probably smaller and are highly uncertain, 4.8 fold [0.1-18] (mean and [95% confidence limits]). Defining background levels as either the levels in all workers with no occupational exposures or in workers with predicted air levels of <0.03 p.p.m. results in estimates of 2.4 fold [<0.1-15] and 3.3 fold [<0.1-19] increases, respectively. Based on this reanalysis, the Tianjin data appear to be too uncertain to support any conclusions of a change in the efficiency of benzene metabolism with variations in exposure. PMID- 22843550 TI - Genetic variation and alterations of genes involved in NFkappaB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer. AB - Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor kappa B (NFkappaB) is a major regulator of inflammation and variation in NFkappaB associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFkappaB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFkappaB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFkappaB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC. PMID- 22843551 TI - A review of Ghana's 2009-2013 integrated strategic response plan for pandemic influenza: illustrative study of the perceived adequacy of preparedness for the pandemic influenza of sub-Sahara Africa. AB - OBJECTIVES: To review the National Integrated Strategic Plan for Pandemic Influenza for 2009-2013 and assess whether it is in congruence with the nation's emergency preparedness status. METHOD: The authors examined the National Plan 'as is' and evaluated it against the 'State and Local Pandemic Influenza Planning Checklist' of the Department of Health and Human Services and the Centers for Disease Control and Prevention. The authors matched the activities in the National Plan apropos the national emergency response capabilities. From the legal framework, published studies and other grey literature on the thematic areas of the Plan, the authors developed key items found in response programmes and drew a 5-point Likert-type scale for assessment. The authors analysed the results in relation to WHO's framework for hospital emergency preparedness, and conducted two-sample non-parametric Wilcoxon rank sum (Mann-Whitney) tests. RESULTS/DISCUSSION: The result showed that Ghana's health emergency preparedness is in disarray. About 75% of the health facilities lack emergency preparedness plans, surge capacity planning, triage for mass event and mutual aid agreements. CONCLUSIONS: The authors concluded that the Plan is incongruent with Ghana's public health emergency preparedness. The evaluation is important for Ghana and the subregion. PMID- 22843552 TI - Emergency cricothyroidotomy performed by inexperienced clinicians--surgical technique versus indicator-guided puncture technique. AB - BACKGROUND: To improve the ease and safety of cricothyroidotomy especially in the hand of the inexperienced, new instruments have been developed. In this study, we compared a new indicator-guided puncture technique (PCK) with standard surgical technique (ST) regarding success rate, performance time and complications. METHODS: Cricothyroidotomy in 30 human cadavers performed by 30 first year anaesthesia residents. The set chosen for use was randomised: PCK-technique (n=15) and ST (n=15). Success rates, insertion times and complications were compared. Traumatic lesions were anatomically confirmed after dissection. RESULTS: The ST-group had a higher success rate (100% vs 67%; p=0.04). There was no difference in time taken to complete the procedure (PCK 82 s. vs ST 95 s.; p=0.89). There was a higher complication rate in the PCK-group (67% vs 13%; p=0.04). Most frequent complication in the PCK-group was injury to the posterior tracheal wall (n=8), penetration to the oesophageal lumen (n=4) and injury to the thyroid and/or cricoid cartilage (n=5). In the ST-group in only 2 cases minor complications were observed (small vessel injury). CONCLUSIONS: In this human cadaver study the PCK technique produced more major complications and more failures than the ST. In the hand of the inexperienced operator the standard surgical approach seems to be a safe procedure, which can successfully be performed within an adequate time. The PCK technique cannot be recommended for inexperienced operators. PMID- 22843554 TI - Association between CASP8 and CASP10 polymorphisms and toxicity outcomes with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer. AB - Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens. PMID- 22843553 TI - Targeting angiogenesis in metastatic breast cancer. AB - Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC. PMID- 22843555 TI - Interceptive orthodontic treatment in bullied adolescents and its impact on self esteem and oral-health-related quality of life. AB - The aim of this follow-up study was to measure the self-reported frequency and severity of bullying in orthodontic patients previously identified as being bullied, who have commenced interceptive orthodontic treatment, and to investigate the effect on an individual's self-esteem and oral-health-related quality of life (OHRQoL). Forty-three adolescents previously identified as being bullied due to the presence of a malocclusion were invited to take part in a follow-up study following commencement of orthodontic treatment at three UK Hospitals. Validated questionnaires were used to assess the self-reported frequency and severity of bullying, self-esteem and OHRQoL. The participation rate at follow-up was 63 per cent. Following commencement of orthodontic treatment, 21 (78 per cent) participants reported they were currently no longer being bullied due to the presence of their malocclusion. In comparison to their pre-treatment scores, participants reported fewer functional limitations (P = 0.013), decreased emotional (P < 0.001) and social impact (P < 0.001), and improved overall oral health (P = 0.03) and OHRQoL (P = 0.002). In addition, an improvement in functional limitations (P = 0.021), emotional (P = 0.008), social impact (P = 0.008) and OHRQoL (P = 0.02) was reported by participants who were no longer being bullied in comparison to those who continued to report bullying. There appears to be no effect on an individual's self-esteem. Orthodontic treatment may have a positive effect on adolescents experiencing bullying related to their malocclusion and their OHRQoL. PMID- 22843556 TI - Diabetes and pancreatic cancer. AB - Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage. PMID- 22843557 TI - "Tree in bud" attributable to organising pneumonia. PMID- 22843558 TI - Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility. AB - RATIONALE: The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. OBJECTIVE: To compare EMP numbers in stable COPD patients with those during and after exacerbation. METHODS: We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41- MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. RESULTS: VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. CONCLUSIONS: Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation. PMID- 22843559 TI - The role of facemask spirometry in motor neuron disease. PMID- 22843561 TI - The mitochondrial Dnm1-like fission component is required for lgA2-induced mitophagy but dispensable for starvation-induced mitophagy in Ustilago maydis. AB - Selective elimination of mitochondria by autophagy (mitophagy) is a crucial developmental process to dispose of disintegrated or superflous organelles. However, little is known about underlying regulatory mechanisms. We have investigated mitophagy in response to conditional overexpression of the a2 mating type locus gene lga2, which encodes a small mitochondrial protein critically involved in uniparental mitochondrial DNA inheritance during sexual development of Ustilago maydis. In this study, we show that conditional overexpression of lga2 efficiently triggers mitophagy that is dependent on atg8 and atg11, consistent with selective autophagy. lga2-triggered mitophagy is preceded by mitochondrial dysfunction, including depletion of mitochondrial RNA transcripts, and is mechanistically distinct from starvation-induced mitophagy despite a common requirement for atg11. In particular, lga2-triggered mitophagy strongly depends on the mitochondrial fission factor Dnm1, but it is only slightly affected by N-acetylcysteine, which is an inhibitor of starvation-induced mitophagy. To further delineate the role of mitochondrial fission, we analyzed lga2 effects in Deltafis1 mutants. This revealed that mitochondrial fragmentation was only attenuated and mitophagy was largely unaffected. In further support of a Fis1-independent role for Dnm1, mitochondrial association of green fluorescent protein-tagged Dnm1 as well as Dnm1-opposed mitochondrial fusion during sexual development were fis1 independent. In conclusion, our results specify the role of the mitochondrial fission factor Dnm1 in mitophagy and uncover differences between mitophagy pathways in the same cellular system. PMID- 22843562 TI - Analysis of promoter function in Aspergillus fumigatus. AB - The filamentous fungus Aspergillus fumigatus is an important opportunistic pathogen that can cause high mortality levels in susceptible patient populations. The increasing dependence on antifungal drugs to control A. fumigatus has led to the inevitable acquisition of drug-resistant forms of this pathogen. In other fungal pathogens, drug resistance is often associated with an increase in transcription of genes such as ATP-binding cassette (ABC) transporters that directly lead to tolerance to commonly employed antifungal drugs. In A. fumigatus, tolerance to azole drugs (the major class of antifungal) is often associated with changes in the sequence of the azole target enzyme as well as changes in the transcription level of this gene. The target gene for azole drugs in A. fumigatus is referred to as cyp51A. In order to dissect transcription of cyp51A transcription and other genes of interest, we constructed a set of firefly luciferase reporter genes designed for use in A. fumigatus. These reporter genes can either replicate autonomously or be targeted to the pyrG locus, generating an easily assayable uracil auxotrophy. We fused eight different A. fumigatus promoters to luciferase. Faithful behaviors of these reporter gene fusions compared to their chromosomal equivalents were evaluated by 5' rapid amplification of cDNA ends (RACE) and quantitative reverse transcription-PCR (qRT PCR) analysis. We used this reporter gene system to study stress-regulated transcription of a Hsp70-encoding gene, map an important promoter element in the cyp51A gene, and correct an annotation error in the actin gene. We anticipate that this luciferase reporter gene system will be broadly applicable in analyses of gene expression in A. fumigatus. PMID- 22843563 TI - Growth-differentiation factor-15 improves reclassification for the diagnosis of heart failure with normal ejection fraction in morbid obesity. AB - AIMS: This study aimed to examine the incremental value of growth-differentiation factor-15 (GDF-15) to N-terminal pro brain natriuretic hormone (NT-proBNP) levels for the diagnosis of left ventricular diastolic dysfunction (LVDD) and possible heart failure (HF) in morbidly obese patients. Method and results We analysed data from 207 obese subjects [body mass index (BMI) 41 +/- 8 kg/m(2)] with normal ejection fraction, LVDD, and symptoms and/or signs of HF (referred to as 'LVDD with possible HF', n = 88) and with normal left ventricular function (n = 119) before participating in a medical weight loss programme, in addition to the study of healthy lean subjects (n = 51). Median NT-proBNP (interquartile range) for obese subjects with 'LVDD and possibe HF' and with normal LV function was 52 (29 96) and 42 (25-66) pg/mL, respectively (P = 0.12). There was no correlation of NT proBNP with parameters of left ventricular filling pressure, i.e. E/E' (r(2) = 0.002, P = 0.63) or E' velocity (r(2) = 0.02, P = 0.24). In contrast, GDF-15 was 665 (496-926) with 'LVDD and possible HF' and 451 (392- 679) pg/mL without (P < 0.0001). GDF-15 was significantly correlated to E/E', E' velocity, E/A ratio, isovolumetric relaxation time, duration of reversed pulmonary vein atrial systolic flow, and left atrial size. The area under the receiver operating characteristic curve that defines LVDD with possible HF was 0.56 for NT-proBNP and 0.74 for GDF-15 (P < 0.0001). The addition of GDF-15 to a multivariate predicition model increased the net reclassification improvement (NRI) by 9% (P= 0.022). CONCLUSION: In morbidly obese individuals, GDF-15 levels seem to better correlate with diastolic dysfunction than NT-proBNP levels. GDF-15 significantly improves reclassification for the diagnosis of 'LVDD with possible HF' and, thus, adds incremental value to NT-proBNP. PMID- 22843564 TI - Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support. AB - AIMS: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine and is emerging as a biomarker of cardiac remodelling. Left ventricular assist devices (LVADs) provide unloading of the left ventricle, resulting in partial reverse remodelling. Our aim was to study GDF-15 in patients with a non-ischaemic dilated cardiomyopathy (DCM) during LVAD support. METHODS AND RESULTS: We analysed circulating GDF-15 in 30 patients before and 1, 3, and 6 months after LVAD implantation and before heart transplantation or explantation. In addition, mRNA and protein expression of GDF-15 were evaluated in myocardial tissue obtained prior to and after LVAD support. Circulating GDF-15 was significantly higher before LVAD implantation as compared with healthy controls (P < 0.001). After 1 month of mechanical support, GDF-15 levels were significantly decreased compared with pre-implantation levels (P < 0.001) and remained stable thereafter. Circulating GDF-15 was significantly correlated with kidney function and the severity of myocardial fibrosis. Interestingly, GDF-15 mRNA and protein expression in the myocardium were hardly detectable. CONCLUSIONS: High circulating levels of GDF-15 in patients with end-stage non-ischaemic DCM correlate with myocardial fibrosis and kidney function and decline strongly after 1 month of mechanical unloading, remaining stable thereafter. However, cardiac mRNA and protein expression of GDF-15 are very low, suggesting that the heart is not an important source of GDF-15 production in these patients. PMID- 22843565 TI - Raising the bar for research to lower the weight of the population. PMID- 22843566 TI - Multiple morphology ventricular tachycardia in non-compaction cardiomyopathy: multi-modal imaging. PMID- 22843567 TI - Metabolomics-on-a-chip of hepatotoxicity induced by anticancer drug flutamide and Its active metabolite hydroxyflutamide using HepG2/C3a microfluidic biochips. AB - We used the recently introduced "metabolomics-on-a-chip" approach to test secondary drug toxicity in bioartificial organs. Bioartificial organs cultivated in microfluidic culture conditions provide a beneficial environment, in which the cellular cytoprotective mechanisms are enhanced, compared with Petri dish culture conditions. We investigated the metabolic response of HepG2/C3a cells exposed to flutamide, an anticancer prodrug, and hydroxyflutamide (HF), its active metabolite, in a microfluidic biochip. The cellular response was analyzed by (1)H nuclear magnetic resonance spectroscopy to identify cell-specific molecule response markers. The metabolic response to flutamide results in a disruption of glucose homeostasis and in mitochondrial dysfunctions. This flutamide-specific metabolic response was illustrated by a reduction of the extracellular glucose and fructose consumptions and a general reduction of the tricarboxylic acid cycle activity leading to the reduction of the consumption of several amino acids. We also found a higher production of 3-hydroxybutyrate and lactate, and the reduction of the albumin production compared with controls. The toxic metabolic signature associated with the active metabolite HF was illustrated by a high energy demand and an increase in several amino acid metabolism. Finally, for both molecules, the hepatotoxicity was correlated to the glutathione (GSH) metabolism illustrated by the levels of the 2-hydroxybutyrate and pyroglutamate productions and the increase of the glutamate and glycine productions. Thus, the entire set of results contributed to extract specific mechanistic toxic signatures and their relation to hepatotoxicity, which appeared consistent with literature reports. As new finding of HepG2/C3a cells hepatotoxicity, we propose a metabolic network with a related list of metabolite variations to describe the GSH depletion when followed by a cell death for the HepG2/C3a cells cultivated in our polydimethylsiloxane microfluidic biochips. Our findings illustrate the potential of metabolomics-on-a-chip as an in vitro alternative method for predictive toxicology. PMID- 22843568 TI - Characterization of human-induced pluripotent stem cell-derived cardiomyocytes: bioenergetics and utilization in safety screening. AB - Cardiotoxicity remains the number one reason for drug withdrawal from the market, and Food and Drug Administration issued black box warnings, thus demonstrating the need for more predictive preclinical safety screening, especially early in the drug discovery process when much chemical substrate is available. Whereas human-ether-a-go-go related gene screening has become routine to mitigate proarrhythmic risk, the development of in vitro assays predicting additional on- and off-target biochemical toxicities will benefit from cellular models exhibiting true cardiomyocyte characteristics such as native tissue-like mitochondrial activity. Human stem cell-derived tissue cells may provide such a model. This hypothesis was tested using a combination of flux analysis, gene and protein expression, and toxicity-profiling techniques to characterize mitochondrial function in induced pluripotent stem cell (iPSC) derived human cardiomyocytes in the presence of differing carbon sources over extended periods in cell culture. Functional analyses demonstrate that iPSC-derived cardiomyocytes are (1) capable of utilizing anaerobic or aerobic respiration depending upon the available carbon substrate and (2) bioenergetically closest to adult heart tissue cells when cultured in galactose or galactose supplemented with fatty acids. We utilized this model to test a variety of kinase inhibitors with known clinical cardiac liabilities for their potential toxicity toward these cells. We found that the kinase inhibitors showed a dose-dependent toxicity to iPSC cardiomyocytes grown in galactose and that oxygen consumption rates were significantly more affected than adenosine triphosphate production. Sorafenib was found to have the most effect, followed by sunitinib, dasatinib, imatinib, lapatinib, and nioltinib. PMID- 22843569 TI - Three-dimensional HepaRG model as an attractive tool for toxicity testing. AB - The culture of HepaRG cells as three dimensional (3D) structures in the spinner bioreactor may represent added value as a hepatic system for toxicological purposes. The use of a cost-effective commercially available bioreactor, which is compatible with high-throughput cell analysis, constitutes an attractive approach for routine use in the drug testing industry. In order to assess specific aspects of the biotransformation capacity of the bioreactor-based HepaRG system, the induction of CYP450 enzymes (i.e., CYP1A2, 2B6, 2C9, and 3A4) and the activity of the phase II enzyme, uridine diphosphate glucuronoltransferase (UGT), were tested. The long-term functionality of the system was demonstrated by 7-week stable profiles of albumin secretion, CYP3A4 induction, and UGT activities. Immunofluorescence-based staining showed formation of tissue-like arrangements including bile canaliculi-like structures and polar distribution of transporters. The use of in silico models to analyze the in vitro data related to hepatotoxic activity of acetaminophen (APAP) demonstrated the advantage of the integration of kinetic and dynamic aspects for a better understanding of the in vitro cell behavior. The bioactivation of APAP and its related cytotoxicity was assessed in a system compatible to high-throughput screening. The approach also proved to be a good strategy to reduce the time necessary to obtain fully differentiated cell cultures. In conclusion, HepaRG cells cultured in 3D spinner-bioreactors are an attractive tool for toxicological studies, showing a liver-like performance and demonstrating a practical applicability for toxicodynamic approaches. PMID- 22843570 TI - Effects of morphine on the differentiation and survival of developing pyramidal neurons during the brain growth spurt. AB - Although morphine is frequently administered to treat procedural pain in neonates and young children, little is known about the effects of this drug on developing neural circuitry during the brain growth spurt. Here we systematically explored the impact of morphine on neuronal survival and differentiation during the peak synaptogenic period. By focusing on the rat medial prefrontal cortex, we show that single bolus ip injections of morphine, although it induces deep sedation and analgesia, do not entrain apoptosis in this cortical region either at postnatal day 7 or at postnatal day 15. Iontophoretic single cell injections of Lucifer Yellow followed by semiautomatic neuronal arbor tracing revealed that repeated daily administration of this drug between postnatal days 7 and 15 or 15 and 20 did not interfere with dendritic development of layer 5 pyramidal neurons. Confocal microscopic analysis of dendritic spines at the aforementioned distinct stages of the brain growth spurt demonstrated that neither single bolus nor repeated administration of morphine affected the density of these postsynaptic structures. Altogether, these preclinical rodent experimental observations argue against overt neurotoxic effects of morphine exposure during the brain growth spurt. PMID- 22843571 TI - Genome sequence of the polychlorinated-biphenyl degrader Pseudomonas pseudoalcaligenes KF707. AB - Pseudomonas pseudoalcaligenes KF707 is a soil polychlorinated biphenyl (PCB) degrader, able to grow both planktonically and as a biofilm in the presence of various toxic metals and metalloids. Here we report the genome sequence (5,957,359 bp) of P. pseudoalcaligenes KF707, which provides insights into metabolic degradation pathways, flagellar motility, and chemotaxis. PMID- 22843572 TI - Complete genome sequence of Streptococcus thermophilus strain MN-ZLW-002. AB - Streptococcus thermophilus MN-ZLW-002 was originally isolated from traditionally fermented Chinese dairy products. One of the strain-dependent characteristics of this bacterium is its ability to produce exopolysaccharides (EPSs). This study determined and analyzed the genome sequence of MN-ZLW-002. Its complete genome comprised 2,046 genes and 1,848,520 nucleotides with an average GC content of 39%. The EPS cluster of MN-ZLW-002 includes 25 open reading frames (ORFs), and some results indicate a horizontal gene transfer between MN-ZLW-002 and other lactic acid bacteria (LAB). PMID- 22843573 TI - Whole-genome sequences of two clinical isolates of Mycobacterium tuberculosis from Kerala, South India. AB - We report the annotated genome sequence of two clinical isolates of Mycobacterium tuberculosis isolated from Kerala, India. PMID- 22843574 TI - Draft genome sequence of Ureibacillus thermosphaericus strain thermo-BF, isolated from Ramsar hot springs in Iran. AB - Ureibacillus thermosphaericus strain Thermo-BF is an aerobic, thermophilic bacillus which has been characterized to biosynthesize gold nanoparticles. Here we present the draft genome sequence of Ureibacillus thermosphaericus strain Thermo-BF which consists of a 2,864,162-bp chromosome. This is the first report of a shotgun sequenced draft genome of a species in the Ureibacillus genus. PMID- 22843575 TI - Complete genome sequence of the endophytic bacterium Burkholderia sp. strain KJ006. AB - Endophytes live inside plant tissues without causing any harm and may even benefit plants. Here, we provide the high-quality genome sequence of Burkholderia sp. strain KJ006, an endophytic bacterium of rice with antifungal activity. The 6.6-Mb genome, consisting of three chromosomes and a single plasmid, contains genes related to plant growth promotion or degradation of aromatic compounds. PMID- 22843576 TI - Complete genome sequence of the hyperthermophilic archaeon Pyrococcus sp. strain ST04, isolated from a deep-sea hydrothermal sulfide chimney on the Juan de Fuca Ridge. AB - Pyrococcus sp. strain ST04 is a hyperthermophilic, anaerobic, and heterotrophic archaeon isolated from a deep-sea hydrothermal sulfide chimney on the Endeavour Segment of the Juan de Fuca Ridge in the northeastern Pacific Ocean. To further understand the distinct characteristics of this archaeon at the genome level (polysaccharide utilization at high temperature and ATP generation by a Na(+) gradient), the genome of strain ST04 was completely sequenced and analyzed. Here, we present the complete genome sequence analysis results of Pyrococcus sp. ST04 and report the major findings from the genome annotation, with a focus on its saccharolytic and metabolite production potential. PMID- 22843577 TI - Complete genome sequence of the B12-producing Shimwellia blattae strain DSM 4481, isolated from a cockroach. AB - Here we announce the complete genome sequence of the coenzyme B(12)-producing enteric bacterium Shimwellia blattae (formerly Escherichia blattae). The genome consists of a single chromosome (4,158,636 bp). The genome size is smaller than that of most other enteric bacteria. Genome comparison revealed significant differences from the Escherichia coli genome. PMID- 22843578 TI - Draft genome sequence of Corynebacterium bovis DSM 20582, which causes clinical mastitis in dairy cows. AB - Bovine mastitis represents the most economically important disease in dairy cows and can be caused by Corynebacterium bovis, a commensal in the bovine udder. The draft genome sequence provides insights into the adaptation of this bacterium to the bovine habitat and its lipolytic capabilities to utilize components of cow's milk. PMID- 22843579 TI - Complete genome sequence of the opportunistic food-borne pathogen Cronobacter sakazakii ES15. AB - Cronobacter sakazakii is an emerging pathogen associated with several outbreaks of food-borne illness in premature infants. To characterize its physiology and pathogenicity at the molecular level, C. sakazakii ES15 was isolated and its genome was completely sequenced and analyzed. Here, the results are announced and major findings from its annotation data are reported. PMID- 22843580 TI - Draft genome sequence and comparative analysis of the superb aromatic-hydrocarbon degrader Rhodococcus sp. strain DK17. AB - Rhodococcus sp. strain DK17 is capable of utilizing various derivatives of benzene and bicyclics containing both aromatic and alicyclic moieties as sole carbon and energy sources. Here, we present the 9,107,362-bp draft genome sequence of DK17 and its genomic analysis in comparison with other members of the genus Rhodococcus. PMID- 22843581 TI - Draft genome sequence of Staphylococcus saprophyticus subsp. saprophyticus M1-1, isolated from the gills of a Korean rockfish, Sebastes schlegeli Hilgendorf, after high hydrostatic pressure processing. AB - A bacterium designated M1-1 was isolated from the gills of a Korean rockfish, Sebastes schlegeli Hilgendorf, after high hydrostatic pressure processing. Studies of 16S rRNA phylogeny and comparative genomics demonstrated that the isolate belongs to Staphylococcus saprophyticus subsp. saprophyticus. Here, we report the draft genome sequence of S. saprophyticus subsp. saprophyticus M1-1 (KACC 16562). PMID- 22843582 TI - Draft genome sequence of Escherichia coli LCT-EC106. AB - Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the intestine of warm-blooded organisms. Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans. Here, we present the complete genome sequence of Escherichia coli LCT-EC106, which was isolated from CGMCC 1.2385. PMID- 22843583 TI - Genome sequence of the filamentous bacterium Fibrisoma limi BUZ 3T. AB - Fibrisoma limi strain BUZ 3(T), a Gram-negative bacterium, was isolated from coastal mud from the North Sea (Fedderwardersiel, Germany) and characterized using a polyphasic approach in 2011. The genome consists of a chromosome of about 7.5 Mb and three plasmids. PMID- 22843584 TI - Complete genome sequence of the hyperthermophilic cellulolytic crenarchaeon "Thermogladius cellulolyticus" 1633. AB - Strain 1633, a novel member of the genus Thermogladius, isolated from a freshwater hot spring, is an anaerobic hyperthermophilic crenarchaeon capable of fermenting proteinaceous and cellulose substrates. The complete genome sequence reveals genes for protein and carbohydrate-active enzymes, the Embden-Meyerhof pathway for glucose metabolism, cytoplasmic NADP-dependent hydrogenase, and several energy-coupling membrane-bound oxidoreductases. PMID- 22843585 TI - Complete genome sequences of Mycoplasma leachii strain PG50T and the pathogenic Mycoplasma mycoides subsp. mycoides small colony biotype strain Gladysdale. AB - Mycoplasma mycoides subsp. mycoides small colony biotype (SC) is the high consequence animal pathogen causing contagious bovine pleuropneumonia. We report the complete genome sequences of the pathogenic strain M. mycoides subsp. mycoides SC Gladysdale and a close phylogenetic relative, Mycoplasma leachii PG50(T), another bovine pathogen of the M. mycoides phylogenetic clade. PMID- 22843586 TI - Genome sequence of Blattabacterium sp. strain BGIGA, endosymbiont of the Blaberus giganteus cockroach. AB - Cockroaches harbor the obligate flavobacterial endosymbiont Blattabacterium sp., which resides within the host's bacteriocytes and can recycle ammonia and urea nitrogenous wastes into amino acids for the host. We report the complete genome sequence of the Blattabacterium sp. associated with the giant roach Blaberus giganteus. PMID- 22843587 TI - Genome sequence of the rice pathogen Dickeya zeae strain ZJU1202. AB - Dickeya zeae is a phytopathogenic bacterium causing soft rot diseases in a wide range of economically important crops. Here we present the draft genome sequence of strain ZJU1202, which is the causal agent of rice foot rot in China. The draft genome will contribute to epidemiological and comparative genomic studies and the quarantine of this devastating phytopathogen. PMID- 22843588 TI - Draft genome sequence of the sponge-associated strain Bacillus atrophaeus C89, a potential producer of marine drugs. AB - Bacillus atrophaeus C89, isolated from the marine sponge Dysidea avara, is a potential producer of bioactive compounds, such as neobacillamide A and bacillamide C. Here, we present a 4.2-Mb assembly of its genome. The nonribosomal peptide synthetases (NRPSs) make it possible to produce the bioactive compounds. PMID- 22843589 TI - Draft genome sequence of Gluconobacter oxydans WSH-003, a strain that is extremely tolerant of saccharides and alditols. AB - Gluconobacter oxydans is known for its incomplete oxidation of a wide range of alcohols, sugars, and acids in a bioprocess. The corresponding oxidation products are secreted almost completely into the medium. Here, we present the high-quality draft genome sequence of G. oxydans WSH-003, an industrial strain with both high l-sorbose productivity and extreme tolerance to saccharides and alditols. PMID- 22843590 TI - Genome sequence of Klebsiella pneumoniae LZ, a potential platform strain for 1,3 propanediol production. AB - Klebsiella pneumoniae LZ is a bacterium isolated from soil which can produce 1,3 propanediol from glycerol. Here we present a 5,431,750-bp assembly of its genome sequence. We annotated 9 coding sequences (CDSs) responsible for glycerol fermentation to 1,3-propanediol, 19 CDSs encoding glycerol utilization, and 134 CDSs related to its virulence and defense. PMID- 22843591 TI - Genome sequence of a novel indigo-producing strain, Pseudomonas monteilii QM. AB - Pseudomonas monteilii is a versatile bacterium found in various niches. A newly isolated strain, P. monteilii QM, can effectively produce indigoids from indoles. Here we present a 5.76-Mb assembly of the P. monteilii genome for the first time. It may provide abundant molecular information for the transformation of aromatics. PMID- 22843593 TI - Complete genome sequence of the metabolically versatile halophilic archaeon Haloferax mediterranei, a poly(3-hydroxybutyrate-co-3-hydroxyvalerate) producer. AB - Haloferax mediterranei, an extremely halophilic archaeon, has shown promise for production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) from unrelated cheap carbon sources. Here we report the complete genome (3,904,707 bp) of H. mediterranei CGMCC 1.2087, consisting of one chromosome and three megaplasmids. PMID- 22843592 TI - Genome sequences for six Rhodanobacter strains, isolated from soils and the terrestrial subsurface, with variable denitrification capabilities. AB - We report the first genome sequences for six strains of Rhodanobacter species isolated from a variety of soil and subsurface environments. Three of these strains are capable of complete denitrification and three others are not. However, all six strains contain most of the genes required for the respiration of nitrate to gaseous nitrogen. The nondenitrifying members of the genus lack only the gene for nitrate reduction, the first step in the full denitrification pathway. The data suggest that the environmental role of bacteria from the genus Rhodanobacter should be reevaluated. PMID- 22843594 TI - Genome sequence of the Antarctic psychrophile bacterium Planococcus antarcticus DSM 14505. AB - Planococcus antarcticus DSM 14505 is a psychrophile bacterium that was isolated from cyanobacterial mat samples, originally collected from ponds in McMurdo, Antarctica. This orange-pigmented bacterium grows at 4 degrees C and may possess interesting enzymatic activities at low temperatures. Here we report the first genomic sequence of P. antarcticus DSM 14505. PMID- 22843595 TI - Complete genome sequence of Streptococcus salivarius PS4, a strain isolated from human milk. AB - Streptococcus salivarius is a commensal species commonly found in the human oropharyngeal tract. Some strains of this species have been developed for use as oral probiotics, while others have been associated with a variety of opportunistic human infections. Here, we report the complete sequence of strain PS4, which was isolated from breast milk of a healthy woman. PMID- 22843596 TI - Genome sequence of Pediococcus pentosaceus strain IE-3. AB - We report the 1.8-Mb genome sequence of Pediococcus pentosaceus strain IE-3, isolated from a dairy effluent sample. The whole-genome sequence of this strain will aid in comparative genomics of Pediococcus pentosaceus strains of diverse ecological origins and their biotechnological applications. PMID- 22843597 TI - Genome sequence of Staphylococcus capitis QN1, which causes infective endocarditis. AB - Staphylococcus capitis is a subtype of coagulase-negative staphylococci (CoNS) which could emerge as a significant pathogen causing infective endocarditis, prosthetic valve endocarditis, and late-onset sepsis. We isolated S. capitis strain QN1 from the skin swab sample of a female. Here we prepared a genome sequence for this strain consisting of 30 contigs totaling 2,430,101 bases and a GC content of 32.76%. PMID- 22843598 TI - Genome sequence of Sphingobium indicum B90A, a hexachlorocyclohexane-degrading bacterium. AB - Sphingobium indicum B90A, an efficient degrader of hexachlorocyclohexane (HCH) isomers, was isolated in 1990 from sugarcane rhizosphere soil in Cuttack, India. Here we report the draft genome sequence of this bacterium, which has now become a model system for understanding the genetics, biochemistry, and physiology of HCH degradation. PMID- 22843599 TI - Genome sequence of the moderately halotolerant, arsenite-oxidizing bacterium Pseudomonas stutzeri TS44. AB - We present the draft genome sequence of Pseudomonas stutzeri TS44, a moderately halotolerant, arsenite-oxidizing bacterium isolated from arsenic-contaminated soil. The genome contains genes for arsenite oxidation, arsenic resistance, and ectoine/hydroxyectoine biosynthesis. The genome information will be useful for exploring adaptation of P. stutzeri TS44 to an arsenic-contaminated environment. PMID- 22843600 TI - Draft genome sequence of Mycobacterium bolletii strain M24, a rapidly growing mycobacterium of contentious taxonomic status. AB - The whole-genome sequence of Mycobacterium bolletii M24, isolated from the bronchoalveolar lavage fluid of a Malaysian patient, is reported here. The circular chromosome of 5,507,730 bp helped to clarify the taxonomic position of this organism within the M. abscessus complex and revealed the presence of proteins potentially important for pathogenicity in a human host. PMID- 22843601 TI - Complete genome sequence of Corynebacterium pseudotuberculosis strain 1/06-A, isolated from a horse in North America. AB - Corynebacterium pseudotuberculosis causes disease in several animal species, although distinct biovars exist that appear to be restricted to specific hosts. In order to facilitate a better understanding of the differences between biovars, we report here the complete genome sequence of the equine pathogen Corynebacterium pseudotuberculosis strain 1/06-A. PMID- 22843602 TI - Draft genome sequence of Serratia marcescens strain LCT-SM213. AB - Serratia marcescens is a species of Gram-negative, rod-shaped bacterium of the family Enterobacteriaceae. S. marcescens can cause nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections, and wound infections. Here, we present the draft genome sequence of Serratia marcescens strain LCT-SM213, which was isolated from CGMCC 1.1857. PMID- 22843603 TI - Genome sequence of the plant growth-promoting bacterium Enterobacter cloacae GS1. AB - Here, we present the genome sequence of Enterobacter cloacae GS1. This strain proficiently colonizes rice roots and promotes plant growth by improving plant nutrition. Analyses of the E. cloacae GS1 genome will throw light on the genetic factors involved in root colonization, growth promotion, and ecological success of this rhizobacterium. PMID- 22843604 TI - Draft genome sequence of the soil bacterium Burkholderia terrae strain BS001, which interacts with fungal surface structures. AB - Burkholderia terrae BS001 is a soil bacterium which was originally isolated from the mycosphere of the ectomycorrhizal fungus Laccaria proxima. It exhibits a range of fungus-interacting traits which reveal its propensity to actively interact at fungal interfaces. Here, we present the approximately 11.5-Mb (G+C content, 61.52%) draft genome sequence of B. terrae BS001 with the aim of providing insight into the genomic basis of its ecological success in fungus affected soil settings. PMID- 22843605 TI - Draft genome sequence of the marine actinomycete Streptomyces sulphureus L180, isolated from marine sediment. AB - Marine-derived actinobacteria are rich sources of valuable natural products and industrial enzymes for biotechnology applications. The marine-derived Streptomyces sulphureus strain L180 was isolated from the marine sediment in a sea cucumber farm at a depth of about 10 m in Dalian, China, and its 16S rRNA gene sequence was determined to have the highest identity to that of Streptomyces sulphureus NRRL B-1627(T) (99.65%). Here, we report the draft genome sequence of this strain. PMID- 22843606 TI - Complete genome sequence of the broad-host-range strain Sinorhizobium fredii USDA257. AB - Here we announce the complete genome sequence of the symbiotic and nitrogen fixing bacterium Sinorhizobium fredii USDA257. The genome shares a high degree of sequence similarity with the closely related broad-host-range strains S. fredii NGR234 and HH103. Most strikingly, the USDA257 genome encodes a wealth of secretory systems. PMID- 22843607 TI - Dogs are more sensitive to antagonists of inhibitor of apoptosis proteins than rats and humans: a translational toxicokinetic/toxicodynamic analysis. AB - Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-alpha) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFkappaB signaling, at lower exposures compared with rat. In addition, downstream increases in systemic levels of cytokines and chemokines, such as monocyte chemotactic protein-1 (MCP-1), were observed. A semimechanistic population toxicokinetic/toxicodynamic (TK/TD) model incorporating transit compartments was used to fit MCP-1 plasma concentrations from rats or dogs given iv GDC-0152 doses. Estimated TD parameters inferred that lower GDC-0152 plasma concentrations triggered more severe increases in plasma MCP-1 in dogs compared with rats. Human simulations performed using dog TD parameters and human pharmacokinetics predicted 300-2400% increases of MCP-1 in humans at iv doses from 0.76 to 1.48mg/kg. Similar simulations using rat TD parameters suggest little or no change. Patients given iv doses of GDC-0152 up to 1.48mg/kg iv showed no substantial increases in systemic MCP-1 or signs of a severe TNF-alpha driven systemic inflammatory response. Emerging clinical data reported for other IAP antagonists are consistent with our observations. Taken together, the data suggest dogs are more sensitive to IAP antagonists compared with humans and rats. This study illustrates how TK/TD analysis can be utilized to quantitatively translate and context an identified preclinical safety risk in dogs to humans. PMID- 22843608 TI - Coxiella burnetii in bulk tank milk of dairy cattle in south-west England. PMID- 22843609 TI - Feeling the impact. PMID- 22843610 TI - Need for mental health care in adolescents and its determinants: the TRAILS Study. AB - BACKGROUND: Although a great deal of evidence is available on the patterns and determinants of unmet health care needs among adolescents with mental health problems, little is known about the factors that influence the need for care. The aim of this study is to assess the occurrence of need for care for mental problems in adolescents and the determinants of this need. METHODS: Data were obtained from three assessment waves of TRAILS (TRacking Adolescents' Individual Lives Survey) (N = 1406). Need for care was assessed at age 16/17 (parent report). Determinants concerned previous health care utilization, emotional and behavioral problems (child behavior checklist and youth self-report) and child and family characteristics. RESULTS: Of the 1406 parents, 409 parents (29%) reported that their child needed help for mental problems. Of these adolescents, only 29% received specialized mental health treatment. The determinants of need for mental health care at age 16/17 were family break-up and parental internalizing problems (age 10/11), parent-reported internalizing and externalizing (age 10/11 and 13/14) and receiving specialized help (age 13/14). CONCLUSION: A substantial proportion of all adolescents need care for their mental problems, according to their parent. There is also a large group of adolescents with mental health problems according to their parents, but for whom no parental reported need for care is expressed. The findings stress the importance of early interventions focusing on raising parental and child awareness of mental health problems. PMID- 22843611 TI - Relative validity of a short qualitative food frequency questionnaire for use in food consumption surveys. AB - BACKGROUND: The aim of the present study was to assess the relative validity of a self-administered qualitative food frequency questionnaire (FFQ) applied in the Belgian food consumption survey. METHODS: Comparison of food consumption data from an FFQ with 7-day estimated diet records (EDR) was made in a sample of 100 participants (aged 15-90 years). The FFQ comprised a total of 50 foods. Both FFQ and EDR foods were categorized into 15 conventional food groups. RESULTS: De attenuated Spearman rank correlation coefficients between the FFQ and the EDR ranged from -0.16 for potatoes and grains to 0.83 for alcoholic beverages, with a median of 0.40 for all 15 food groups. The proportion of participants classified in the same tertile of intake by the FFQ and EDR ranged from 32% for potatoes and grains to 76% for alcoholic beverages. Extreme classification into opposite tertiles was <10% for milk and soy products, alcoholic beverages, fried restgroup foods and fats. CONCLUSION: Notwithstanding the short nature and the absence of portion size questions, the FFQ appears to be reasonably valid in both genders and across different age categories for most food groups. However, for the food groups bread and cereals, potatoes and grains, and sauces, estimates should be interpreted with caution because of poor ranking agreement. PMID- 22843612 TI - Drug-specific quality indicators assessing outpatient antibiotic use among French general practitioners. AB - Quality indicators assessing the use of antibiotics among general practitioners (GPs) would be useful to target antibiotic stewardship interventions. We adapted to an individual GP level a set of 12 drug-specific quality indicators of outpatient antibiotic use in Europe developed by the European surveillance of antimicrobial consumption project. We performed a cross-sectional study analysing reimbursement data on outpatient antibiotic prescriptions in adults in south eastern France in 2009. Substantial heterogeneity in antibiotic prescribing among French GPs was observed, and opportunity to improve antibiotic prescribing can be identified. PMID- 22843613 TI - Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves. AB - The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates. PMID- 22843614 TI - Publication of JRR transfers to Oxford University Press (OUP). PMID- 22843615 TI - Aerosol delivery of beclin1 enhanced the anti-tumor effect of radiation in the lungs of K-rasLA1 mice. AB - Radiotherapy alone has several limitations for treating lung cancer. Inhalation, a non-invasive approach for direct delivery of therapeutic agents to the lung, may help to enhance the therapeutic efficacy of radiation. Up-regulating beclin1, known as a tumor suppressor gene that plays a major role in autophagy, may sensitize tumors and lead to tumor regression in lungs of K-ras(LA1) lung cancer model mice. To minimize the side-effects of radiotherapy, fractionated exposures (five times, 24-h interval) with low dose (2 Gy) of radiation to the restricted area (thorax, 2 cm) were conducted. After sensitizing the lungs with radiation, beclin1, complexed with a nano-sized biodegradable poly(ester amine), was prepared and delivered into the murine lung via aerosol three times/week for four weeks. In a histopathological analysis, animals treated with beclin1 and radiation showed highly significant tumor regression and low progression to adenocarcinoma. An increase in the number of autophagic vacuoles and secondary lysosomes was detected. Dissociation of beclin1-bcl2 stimulated autophagy activation and showed a synergistic anti-tumor effect by inhibiting the Akt-mTOR pathway, cell proliferation and angiogenesis. The combination of radiation with non-invasive aerosol delivery of beclin1 may provide a prospect for developing novel therapy regimens applicable in clinics. PMID- 22843616 TI - MicroRNA-148b enhances the radiosensitivity of non-Hodgkin's Lymphoma cells by promoting radiation-induced apoptosis. AB - Growing evidence has demonstrated that microRNAs (miRNAs) play an important role in regulating cellular radiosensitivity. This study aimed to explore the role of miRNAs in non-Hodgkin's lymphoma (NHL) radiosensitivity. Microarray was employed to compare the miRNA expression profiles in B cell lymphoma cell line Raji before and after a 2-Gy dose of radiation. A total of 20 differentially expressed miRNAs were identified including 10 up-regulated and 10 down-regulated (defined as P < 0.05). Among the differentially expressed miRNAs, miR-148b was up-regulated 1.53 fold in response to radiation treatment. A quantitative real-time polymerase chain reaction (PCR) assay confirmed the up-regulation of miR-148b after radiation. Transient transfection experiments showed that miR-148b was up regulated by miR-148b mimic and down-regulated by miR-148b inhibitor in the Raji cells. A proliferation assay showed that miR-148b could inhibit the proliferation of Raji cells before and after radiation. A clonogenic assay demonstrated that miR-148b sensitized Raji cells to radiotherapy. MiR-148b did not affect the cell cycle profile of post-radiation Raji cells compared with controls. An apoptosis assay showed that miR-148b enhanced apoptosis of Raji cells after irradiation. Taken together, these results demonstrate that miR-148b increased the radiosensitivity of NHL cells probably by promoting radiation-induced apoptosis, which suggests that miR-148b plays an important role in the response of NHL to ionizing radiation. PMID- 22843617 TI - Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex RAD(R) in mice. AB - The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD((r)), also known as ON01210.Na (4-carboxystyryl 4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury. PMID- 22843618 TI - The diagnostic value of 18F-FDG-PET/CT in hematopoietic radiation toxicity: a Tibet minipig model. AB - This study was undertaken to assess the diagnostic value of 2-[(18)F]-fluoro-2 deoxy-D-glucose positron emission tomography with computed tomography ([(18)F] FDG-PET/CT) in the detection of radiation toxicity in normal bone marrow using Tibet minipigs as a model. Eighteen Tibet minipigs were caged in aseptic rooms and randomly divided into six groups. Five groups (n = 3/group) were irradiated with single doses of 2, 5, 8, 11 and 14 Gy of total body irradiation (TBI) using an 8-MV X-ray linear accelerator. These pigs were evaluated with [(18)F]-FDG PET/CT, and their marrow nucleated cells were counted. The data were initially collected at 6, 24 and 72 h after treatment and were then collected on Days 5-60 post-TBI at 5-day intervals. At 24 and 72 h post-TBI, marrow standardized uptake value (SUV) data showed a dose-dependent decrease in the radiation dose range from 2-8 Gy. Upon long-term observation, SUV and marrow nucleated cell number in the 11-Gy and 14-Gy groups showed a continuous and marked reduction throughout the entire time course, while Kaplan-Meier curves of survival showed low survival. In contrast, the SUVs in the 2-, 5- and 8-Gy groups showed early transient increases followed by a decline from approximately 72 h through Days 5 15 and then normalized or maintained low levels through the endpoint; marrow nucleated cell number and survival curves showed approximately the same trend and higher survival, respectively. Our findings suggest that [(18)F]-FDG-PET/CT may be helpful in quickly assessing the absorbed doses and predicting the prognosis in patients. PMID- 22843619 TI - Synergistic effect of heat shock protein 90 inhibitor, 17-allylamino-17 demethoxygeldanamycin and X-rays, but not carbon-ion beams, on lethality in human oral squamous cell carcinoma cells. AB - The purpose of this study is to clarify the effect of a heat shock protein 90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in combination with X rays or carbon-ion beams on cell killing in human oral squamous cell carcinoma LMF4 cells. Cell survival was measured by colony formation assay. Cell-cycle distribution was analyzed by flow cytometry. Expression of DNA repair-related proteins was investigated by western blotting. The results showed 17-AAG to have synergistic effects on cell lethality with X-rays, but not with carbon-ion beams. The 17-AAG decreased G(2)/M arrest induced by X-rays, but not by carbon-ion beams. Both X-ray and carbon-ion irradiation up-regulated expression of non homologous end-joining-associated proteins, Ku70 and Ku80, but 17-AAG inhibited only X-ray-induced up-regulation of these proteins. These results show that 17 AAG with X-rays releases G(2)/M phase arrest; cells carrying misrepaired DNA damage then move on to the G(1) phase. We demonstrate, for the first time, that the radiosensitization effect of 17-AAG is not seen with carbon-ion beams because 17-AAG does not affect these changes. PMID- 22843620 TI - Involvement of connexin43 hemichannel in ATP release after gamma-irradiation. AB - Ionizing radiation induces biological effects not only in irradiated cells but also in non-irradiated cells, which is called the bystander effect. Recently, in vivo and in vitro experiments have suggested that both gap junction hemichannel connexin43 (Cx43) and extracellular adenosine triphosphate (ATP) released from cells play a role in the bystander effect. We have reported that gamma irradiation induces ATP release from B16 melanoma cells, which is dependent on the P2X(7) receptor. However, the mechanism of ATP release caused by irradiation remains unclear. We here show the involvement of Cx43 in P2X(7) receptor dependent ATP release after 0.5 Gy gamma-irradiation. Inhibitors of gap junction hemichannels and an inhibitory peptide for Cx43 (gap26), but not an inhibitory peptide for pannexin1 (Panx1), significantly blocked gamma-irradiation-induced ATP release from B16 melanoma cells. We confirmed high expression of Cx43 mRNA in B16 melanoma cells. These results suggest involvement of Cx43 in radiation induced ATP release. We found that after 0.5 Gy gamma-irradiation tyrosine phosphorylation was significantly blocked by P2X(7) receptor antagonist, but not gap26, suggesting that tyrosine phosphorylation is a downstream event from the P2X(7) receptor. Since tyrosine kinase inhibitor significantly suppressed radiation-induced ATP release, tyrosine phosphorylation appears to play an important role in the Cx43-mediated ATP release downstream of the P2X(7) receptor. In conclusion, the Cx43 hemichannel, which lies downstream of the P2X(7) receptor, is involved in ATP release in response to radiation. Our results suggest a novel mechanism for radiation-induced biological effects mediated by both ATP and Cx43. PMID- 22843621 TI - Gene expression profiles in promoted-growth rice seedlings that germinated from the seeds implanted by low-energy N+ beam. AB - The stimulation effect that some beneficial agronomic qualities have exhibited in present-generation plants have also been observed due to ion implantation on plants. However, there is relatively little knowledge regarding the molecular mechanism of the stimulation effects of ion-beam implantation. In order to extend our current knowledge about the functional genes related to this stimulation effect, we have reported a comprehensive microarray analysis of the transcriptome features of the promoted-growth rice seedlings germinating from seeds implanted by a low-energy N(+) beam. The results showed that 351 up-regulated transcripts and 470 down-regulated transcripts, including signaling proteins, kinases, plant hormones, transposable elements, transcription factors, non-coding protein RNA (including miRNA), secondary metabolites, resistance proteins, peroxidase and chromatin modification, are all involved in the stimulating effects of ion-beam implantation. The divergences of the functional catalog between the vacuum and ion implantation suggest that ion implantation is the principle cause of the ion beam implantation biological effects, and revealed the complex molecular networks required to adapt to ion-beam implantation stress in plants, including enhanced transposition of transposable elements, promoted ABA biosynthesis and changes in chromatin modification. Our data will extend the current understanding of the molecular mechanisms and gene regulation of stimulation effects. Further research on the candidates reported in this study should provide new insights into the molecular mechanisms of biological effects induced by ion-beam implantation. PMID- 22843623 TI - Subcutaneous administration of rhIGF-I post irradiation exposure enhances hematopoietic recovery and survival in BALB/c mice. AB - It is unclear how to effectively mitigate against irradiation injury. In this study, we studied the capacity of recombinant human insulin-like growth factor-I (rhIGF-I) on hematologic recovery in irradiated BALB/c mice and its possible mechanism. BALB/c mice were injected with rhIGF-I subcutaneously at a dose of 100 MUg/kg twice daily for 7 days after total body irradiation. Compared with a saline control group, treatment with rhIGF-I significantly improved the survival of mice after lethal irradiation (7.5 Gy). It was found that treatment with rhIGF I not only could increase the frequency of Sca-1(+) cells in bone marrow harvested at Day 14 after irradiation, but also it could decrease the apoptosis of mononuclear cells induced by irradiation as measured by flow cytometry, suggesting that rhIGF-I may mediate its effects primarily through promoting hematopoietic stem cell/progenitor survival and protecting mononuclear cells from apoptosis after irradiation exposure. Moreover, we have found that rhIGF-I might facilitate thrombopoiesis in an indirect way. Our data demonstrated that rhIGF-I could promote overall hematopoietic recovery after ionizing radiation and reduce the mortality when administered immediately post lethal irradiation exposure. PMID- 22843622 TI - Radio-sensitivities and angiogenic signaling pathways of irradiated normal endothelial cells derived from diverse human organs. AB - The purpose of the present investigation was to study the effects of ionizing radiation on endothelial cells derived from diverse normal tissues. We first compared the effects of radiation on clonogenic survival and tube formation of endothelial cells, and then investigated the molecular signaling pathways involved in endothelial cell survival and angiogenesis. Among the different endothelial cells studied, human hepatic sinusoidal endothelial cells (HHSECs) were the most radio-resistant and human dermal microvascular endothelial cells were the most radio-sensitive. The radio-resistance of HHSECs was related to adenosine monophosphate-activated protein kinase and p38 mitogen-activated protein kinase-mediated expression of MMP-2 and VEGFR-2, whereas the increased radio-sensitivity of HDMECs was related to extracellular signal-regulated kinase mediated generation of angiostatin. These observations demonstrate that there are distinct differences in the radiation responses of normal endothelial cells obtained from diverse organs, which may provide important clues for protection of normal tissue from radiation exposure. PMID- 22843624 TI - Impact of concurrent chemotherapy on definitive radiotherapy for women with FIGO IIIb cervical cancer. AB - The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40-60 Gy in 20-30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m(2)/week). After a median follow-up period of 44.0 months (range 4.2-114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44-4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39-4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64-3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer. PMID- 22843625 TI - The clinical application of 4D 18F-FDG PET/CT on gross tumor volume delineation for radiotherapy planning in esophageal squamous cell cancer. AB - A combination of four-dimensional computed tomography with (18)F fluorodeoxyglucose positron emission tomography (4D CT-FDG PET) was used to delineate gross tumor volume (GTV) in esophageal cancer (EC). Eighteen patients with EC were prospectively enrolled. Using 4D images taken during the respiratory cycle, the average CT image phase was fused with the average FDG PET phase in order to analyze the optimal standardized uptake values (SUV) or threshold. PET based GTV (GTV(PET)) was determined with eight different threshold methods using the auto-contouring function on the PET workstation. The difference in volume ratio (VR) and conformality index (CI) between GTV(PET) and CT-based GTV (GTV(CT)) was investigated. The image sets via automatic co-registrations of 4D CT-FDG PET were available for 12 patients with 13 GTV(CT) values. The decision coefficient (R(2)) of tumor length difference at the threshold levels of SUV 2.5, SUV 20% and SUV 25% were 0.79, 0.65 and 0.54, respectively. The mean volume of GTV(CT) was 29.41 +/- 19.14 ml. The mean VR ranged from 0.30 to 1.48. The optimal VR of 0.98, close to 1, was at SUV 20% or SUV 2.5. The mean CI ranged from 0.28 to 0.58. The best CI was at SUV 20% (0.58) or SUV 2.5 (0.57). The auto-contouring function of the SUV threshold has the potential to assist in contouring the GTV. The SUV threshold setting of SUV 20% or SUV 2.5 achieves the optimal correlation of tumor length, VR, and CI using 4D-PET/CT images. PMID- 22843626 TI - Eradicative brachytherapy with hyaluronate gel injection into pararectal space in treatment of bulky vaginal stump recurrence of uterine cancer. AB - The purpose of this study is to develop a procedure for eradicative brachytherapy that can deliver a curative boost dose to bulky (>4 cm) vaginal stump recurrence of uterine cancer without risk of damaging surrounding organs. We separated risk organs (the rectum and sigmoid) from the target during brachytherapy, with a hyaluronate gel injection into the pararectal space via the percutaneous paraperineal approach under local anesthesia. The rectum anchored to the sacrum by native ligament was expected to shift posteriorly. We encountered a patient with bulky stump recurrence of uterine cancer, approximately 8 cm in maximum diameter. She was complaining of abdominal pain and constipation due to bowel encasement. Following 50 Gy of external beam radiotherapy, we applied a single fraction of brachytherapy under gel separation and delivered 14.5 Gy (50.8 GyE: equivalent dose in 2-Gy fraction calculated with linear quadratic model at alpha/beta = 3) to the target. The gel injection procedure was completed in 30 min without complications. A total irradiation dose of 100.8 GyE was delivered to the target and the cumulative minimum dose to the most irradiated rectosigmoidal volume of 2 cc (cumulative D(2cc)) was calculated as 58.5 GyE with gel injection, and was estimated to be 96 GyE without. Over three years, the local stump tumor has completely disappeared, with no complications. Brachytherapy with a pararectal gel injection can be a safe and effective eradicative option for bulky vaginal stump recurrence. PMID- 22843627 TI - Surveillance on interfacility differences in dose-prescription policy of intensity-modulated radiation therapy plans for prostate cancer. AB - Intensity-modulated radiation therapy (IMRT) has recently become popular in Japan. Prostate cancer is indisputably one of the main targets of IMRT. However, the current status and interfacility differences in dose-prescription policies for prostate IMRT are unknown. Therefore, a nationwide survey of 43 institutions that had implemented prostate IMRT was conducted by sending a questionnaire regarding the above-mentioned issues. Thirty-three institutions (77%) had responded to the questionnaire by the end of October 2010. A total of 5245 patients with localized prostate cancer had been treated with IMRT by the end of 2009. Regular multileaf collimator-based techniques were the most common beam delivery method. Dose-prescription policies were divided into four major categories: isocenter-based (@isocenter), dose delivered to 95% of the planning target volume (PTV) (D95)-based (D95@PTV), mean dose to the PTV-based (Mean@PTV), and mean dose to the clinical target volume (CTV)-based (@CTV). The mean doses of the CTV and PTV, and the volume of the PTV receiving 95% of the dose (V95) were significantly higher with the D95@PTV policy than with the other prescription policies. Low-dose areas and hot spots were observed within the PTV in plans with @isocenter and @CTV policies. In conclusion, there are currently considerable differences among institutions in Japan regarding target doses for prostate IMRT. The D95@PTV prescription policy resulted in significant dose escalation compared with the other policies. These differences should be taken into consideration when interpreting treatment outcomes and creating multi-institutional protocols in the future. PMID- 22843628 TI - Uncertainty in patient set-up margin analysis in radiation therapy. AB - We investigated the uncertainty in patient set-up margin analysis with a small dataset consisting of a limited number of clinical cases over a short time period, and propose a method for determining the optimum set-up margin. Patient set-up errors from 555 registration images of 15 patients with prostate cancer were tested for normality using a quantile-quantile (Q-Q) plot and a Kolmogorov Smirnov test with the hypothesis that the data were not normally distributed. The ranges of set-up errors include the set-up errors within the 95% interval of the entire patient data histogram, and their equivalent normal distributions were compared. The patient set-up error was not normally distributed. When the patient set-up error distribution was assumed to have a normal distribution, an underestimate of the actual set-up error occurred in some patients but an overestimate occurred in others. When using a limited dataset for patient set-up errors, which consists of only a small number of the cases over a short period of time in a clinical practice, the 2.5% and 97.5% intervals of the actual patient data histogram from the percentile method should be used for estimating the set up margin. Since set-up error data is usually not normally distributed, these intervals should provide a more accurate estimate of set-up margin. In this way, the uncertainty in patient set-up margin analysis in radiation therapy can be reduced. PMID- 22843629 TI - Biophysical characterization of a relativistic proton beam for image-guided radiosurgery. AB - We measured the physical and radiobiological characteristics of 1 GeV protons for possible applications in stereotactic radiosurgery (image-guided plateau-proton radiosurgery). A proton beam was accelerated at 1 GeV at the Brookhaven National Laboratory (Upton, NY) and a target in polymethyl methacrylate (PMMA) was used. Clonogenic survival was measured after exposures to 1-10 Gy in three mammalian cell lines. Measurements and simulations demonstrate that the lateral scattering of the beam is very small. The lateral dose profile was measured with or without the 20-cm plastic target, showing no significant differences up to 2 cm from the axis A large number of secondary swift protons are produced in the target and this leads to an increase of approximately 40% in the measured dose on the beam axis at 20 cm depth. The relative biological effectiveness at 10% survival level ranged between 1.0 and 1.2 on the beam axis, and was slightly higher off-axis. The very low lateral scattering of relativistic protons and the possibility of using online proton radiography during the treatment make them attractive for image-guided plateau (non-Bragg peak) stereotactic radiosurgery. PMID- 22843630 TI - 4D digitally reconstructed radiography for verifying a lung tumor position during volumetric modulated arc therapy. AB - We have proposed four dimensional (4D) digitally reconstructed radiography (DRR) for verifying a lung tumor position during volumetric modulated arc therapy (VMAT). An internal target volume (ITV) was defined based on two clinical target volumes (CTVs) delineated on maximum exhalation and maximum inhalation images acquired by 4D planning computed tomography (CT). A planning target volume (PTV) was defined by adding a margin of 5 mm to the ITV on the maximum exhalation 3D CT images. A single-arc VMAT plan was created on the same CT data using Pinnacle SmartArc with a maximum multi-leaf collimator leaf speed of 1 mm/degree, thereby resulting in quasi-conformal field shapes while optimizing each beam intensity for each gantry angle. During VMAT delivery, cone-beam CT (CBCT) projection data were acquired by an on-board kilovoltage X-ray unit and a flat panel 2D detector. Four CBCT image sets with different respiratory phases were reconstructed using in-house software, where respiratory phases were extracted from the projection data. Subsequently a CTV was delineated on each of the 4D CBCT images by an oncologist. Using the resulting 4D CBCT data including the CTV contours, 4D DRRs during the VMAT delivery were calculated as a function of gantry angle. It was confirmed that the contoured CTV was within the radiation field during the four fraction lung VMAT delivery. The proposed 4D DRR may facilitate the verification of the position of a respiratory moving lung tumor during VMAT delivery on each treatment day. PMID- 22843631 TI - Dose-modifying factor for captopril for mitigation of radiation injury to normal lung. AB - Our goal is to develop countermeasures for pulmonary injury following unpredictable events such as radiological terrorism or nuclear accidents. We have previously demonstrated that captopril, an angiotensin converting enzyme (ACE) inhibitor, is more effective than losartan, an angiotensin type-1 receptor blocker, in mitigating radiation-pneumopathy in a relevant rodent model. In the current study we determined the dose modifying factors (DMFs) of captopril for mitigation of parameters of radiation pneumonitis. We used a whole animal model, irradiating 9-10-week-old female rats derived from a Wistar strain (WAG/RijCmcr) with a single dose of irradiation to the thorax of 11, 12, 13, 14 or 15 Gy. Our study develops methodology to measure DMFs for morbidity (survival) as well as physiological endpoints such as lung function, taking into account attrition due to lethal radiation-induced pneumonitis. Captopril delivered in drinking water (140-180 mg/m(2)/day, comparable with that given clinically) and started one week after irradiation has a DMF of 1.07-1.17 for morbidity up to 80 days (survival) and 1.21-1.35 for tachypnea at 42 days (at the peak of pneumonitis) after a single dose of ionizing radiation (X-rays). These encouraging results advance our goals, since DMF measurements are essential for drug labeling and comparison with other mitigators. PMID- 22843633 TI - Understanding the relationship between weight loss, emotional well-being and health-related quality of life in patients attending a specialist obesity weight management service. AB - This study explored predictors of clinically meaningful improvement in health related quality of life (HRQOL) among obese patients completing a specialist weight management programme. One hundred and ninety-nine adults aged from 20-88 with a BMI >30 with comorbidities or BMI>35 with/without comorbidities were sampled. The results suggested that both weight loss and changes in depression were significant predictors of HRQOL improvement. However, predictors differed between weight loss groups. Clinically meaningful improvement in HRQOL was found to be due to weight loss when participants had lost 5 kg or more in weight. In contrast, among individuals who lost 0.1-4.9 kg, improvement in HRQOL was accounted for by positive changes in depression scores. PMID- 22843632 TI - Process and outcomes of a skin protection intervention for young adults. AB - Efforts to reduce skin cancer risk behaviors using appearance-oriented interventions (e.g. ultraviolet (UV) light photos showing skin damage) or motivational interviewing (MI) have shown promise in recent trials. In the study a randomized 2 (UV photo versus no UV photo) x 2 (MI versus no MI) factorial design with longitudinal follow up was used. Results showed that progression in stage of change (SOC) was significantly more likely in the photo than the education condition. Treatment credibility as rated by participants and counselor perceived positive therapeutic alliance predicted SOC progression. There was also preliminary evidence for differential intervention effectiveness by baseline SOC. The implications are discussed. PMID- 22843634 TI - Judging risk for multiple diseases: the role of disease worry. AB - Risk perceptions and disease worry of 1,959 healthy adults were measured in a telephone-based survey. In the model for each of eight health conditions, people's perceived risk was related to their worry for that condition (p < .0001) and their worry for the other seven conditions (p < .001). There was also an interaction indicating that the less people were worried about a certain condition, the more their worry about the other seven conditions increased their risk perception for that condition (p < .0001). The results are important for preventing biased risk perceptions in multiple-disease contexts. PMID- 22843635 TI - Combination of negative pressure wound therapy and hyalomatrix application for soft tissue defect of the great toe. AB - Soft tissue defect of the hallux can be particularly difficult to manage because of the absence of local muscle tissue for coverage. The author presents his experience of a combination therapy for severe posttraumatic soft tissue defect of the hallux in a young patient. PMID- 22843636 TI - Leg ulcer as a complication of a posttraumatic tibial arteriovenous fistula treated by endovascular approach with stent-graft placement. AB - Endovascular treatment of posttraumatic arteriovenous fistulae (AVFs) in the lower extremities by means of covered stent-grafts is widely accepted, and many cases have been reported in the iliac-femoral region. However, few reports exist on the treatment of infrapopliteal AVFs, with or without a pseudoaneurysm, using this method. The authors present this case report dealing with a patient who had undergone a tibial and peroneal open fracture in his left limb 34 years ago. He developed a leg ulcer as a consequence of AVF between the tibialis posterior artery and vein, which resulted in venous insufficiency, which was treated by the endovascular approach with the placement of a stent-graft. Total healing was achieved over a period of 3 months. Angio-CT was performed, showing stent-graft patency 6 months after the endovascular procedure. PMID- 22843637 TI - Increasing older adults' walking through primary care: results of a pilot randomized controlled trial. AB - BACKGROUND: Physical activity can positively influence health for older adults. Primary care is a good setting for physical activity promotion. OBJECTIVE: To assess the feasibility of a pedometer-based walking programme in combination with physical activity consultations. METHODS: DESIGN: Two-arm (intervention/control) 12-week randomized controlled trial with a 12-week follow-up for the intervention group. SETTING: One general practice in Glasgow, UK. PARTICIPANTS: PARTICIPANTS were aged >=65 years. The intervention group received two 30-minute physical activity consultations from a trained practice nurse, a pedometer and a walking programme. The control group continued as normal for 12 weeks and then received the intervention. Both groups were followed up at 12 and 24 weeks. OUTCOME MEASURES: Step counts were measured by sealed pedometers and an activPALTM monitor. Psychosocial variables were assessed and focus groups conducted. RESULTS: The response rate was 66% (187/284), and 90% of those randomized (37/41) completed the study. Qualitative data suggested that the pedometer and nurse were helpful to the intervention. Step counts (activPAL) showed a significant increase from baseline to week 12 for the intervention group, while the control group showed no change. Between weeks 12 and 24, step counts were maintained in the intervention group, and increased for the control group after receiving the intervention. The intervention was associated with improved quality of life and reduced sedentary time. CONCLUSIONS: It is feasible to recruit and retain older adults from primary care and help them increase walking. A larger trial is necessary to confirm findings and consider cost-effectiveness. PMID- 22843638 TI - Proposed new diagnoses of anxious depression and bodily stress syndrome in ICD-11 PHC: an international focus group study. AB - BACKGROUND: The World Health Organization is revising the primary care classification of mental and behavioural disorders for the International Classification of Diseases (ICD-11-Primary Health Care (PHC)) aiming to reduce the disease burden associated with mental disorders among member countries. OBJECTIVE: To explore the opinions of primary care professionals on proposed new diagnostic entities in draft ICD-11-PHC, namely anxious depression and bodily stress syndrome (BSS). METHODS: Qualitative study with focus groups of primary health-care workers, using standard interview schedule after draft ICD-11-PHC criteria for each proposed entity was introduced to the participants. RESULTS: Nine focus groups with 4-15 participants each were held at seven locations: Austria, Brazil, Hong Kong, New Zealand, Pakistan, Tanzania and United Kingdom. There was overwhelming support for the inclusion of anxious depression, which was considered to be very common in primary care settings. However, there were concerns about the 2-week duration of symptoms being too short to make a reliable diagnosis. BSS was considered to be a better term than medically unexplained symptoms but there were disagreements about the diagnostic criteria in the number of symptoms required. CONCLUSION: Anxious depression is well received by primary care professionals, but BSS requires further modification. International field trials will be held to further test these new diagnoses in draft ICD-11-PHC. PMID- 22843639 TI - Family planning and inflammatory bowel disease: the patient and the practitioner. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are commonly in their child-bearing years. Maintainance medication, as recommended by international guidelines, is an emotive topic and an anxiety source. This study measures the awareness of patients and primary practitioners of the issues involved. METHODS: A prospective questionnaire was sent to female patients (18-50 years) with an IBD diagnosis in Kerry General Hospital, Ireland, who were identified from radiology and pathology databases. A seperate questionnaire was sent to General Practitioners (GPs) in the region. RESULTS: About 31 female patients (42%) and 49 GPs (43%) returned completed questionnaires. About 29% had Crohn's disease and 71% ulcerative colitis. A total of 42% of patients would allow having IBD or its treatment to influence decisions about family planning. Most patients were on maintainance medications. Despite this, 68% had not discussed family planning with a doctor. One-third believed all medications should be stopped during pregnancy and 68% reported significant anxiety about future pregnancies. A total of 68% GPs report regular contact with IBD patients, but consultations with pregnant IBD patients are less frequent. About 41% of GPs have not opportunistically raised family planning with this patient group and 67% would refer to a tertiary specialist for advice. About 2% of GP's had need to research the topic in the last 12 months. CONCLUSIONS: There is a significant patient knowledge deficit about pregnancy and IBD resulting in unwarranted fears and anxiety. Further evidence based education for GP's with increased gastroenterologist/IBD nurse specialist support should maximize exploitation of health promotion opportunities to electively address this issue. PMID- 22843640 TI - Unicystic mucoepidermoid carcinoma presenting as a salivary duct cyst. AB - A cystic swelling in the parotid gland should lead to a differential diagnosis that includes benign cystic lesion of the gland, benign tumors that are frequently associated with cystic degeneration or entirely cystic de novo, or even a malignant neoplasm. The case presented is that of a cystic parotid swelling of 2 years' duration in a 52-year-old female patient. The clinical differentials in the present case were reviewed and were entirely different from the final histological diagnosis of low-grade mucoepidermoid carcinoma. The uniqueness of this case is the very rare unicystic presentation of the lesion. The authors also discuss why the clinical and radiological investigations were not suggestive of the final diagnosis. PMID- 22843642 TI - The drugs industry: a bad product well marketed. PMID- 22843641 TI - Ultrastructurally confirmed myofibrosarcoma: a series of 10 new cases, with a discussion on diagnostic criteria. AB - Some view ultrastructure as key to myofibrosarcoma diagnosis, whereas others argue that electron microscopy is too little used in contemporary practice to be considered an important diagnostic tool. These views are discussed in the context of 10 ultrastructurally confirmed cases of myofibrosarcoma, some occurring at rare sites such as skin and penis. Patient age ranged from 21 to 83 years, with a 6:4 male to female ratio. Size ranged from 2 to 7.5 cm and all had infiltrative margins. Histologically, all consisted of variably cellular fascicles of spindle cells with mild to moderately pleomorphic nuclei, small punctate nucleoli, and eosinophilic cytoplasm. All cases showed alpha-smooth muscle actin positivity and 2 showed very focal weak positivity for desmin. Ultrastructurally, the tumor cells contained rough endoplasmic reticulum, mainly peripheral smooth-muscle myofilaments, and fibronectin fibrils or fibronexus junctions at the cell surface. The most confident diagnosis of myofibrosarcoma is provided by ultrastructural examination. However, given the right histological appearance, use of a panel of antibodies that includes alpha-smooth muscle actin, desmin, and h-caldesmon, serves as an acceptable practical way of diagnosing myofibrosarcoma. PMID- 22843643 TI - The Olympic Games and the limits of human endeavour. PMID- 22843644 TI - The first descriptions of syringomyelia. PMID- 22843645 TI - What sort of DNAR order is that? PMID- 22843646 TI - Life in the slow lane: making hospitals safer, slowly but surely. AB - Recognition that serious deficiencies in mutual respect and team work were hampering safe and effective patient care led to the creation of the cultural change initiative described here. We feel this has widespread applicability to other healthcare settings. The After Action Review (AAR) concept was adapted for use in the NHS for the first time as it provides a deceptively simple vehicle to structure healthy blame free team interactions with the aim of improving practice and team behaviours. The organizational and psychological barriers to being able to do this in multi-professional teams are accentuated by the hierarchical nature of the clinical context, but this project has begun to make lasting change so that AAR is an approach that is now widely understood and frequently used. PMID- 22843647 TI - Dead in the water--are we killing the hospital autopsy with poor consent practices? AB - It is now a recognized fact that the practice of conducting a consent (or hospital) post-mortem examination is in decline. There have been many reasons put forth to explain this demise, but the quality of the consenting process is frequently cited as having a high impact. This article focuses on consent practices for post-mortem examinations in England and Wales, and considers if our consent techniques are adversely affecting post-mortem examination uptake. We examine the regulatory compliance of trusts with their statutory obligations by analyzing the Human Tissue Authority's compliance and inspection reports. We further analyze 21 publicly available NHS Trust policies on post-mortem examination consent procedures, and consider whether these are fit for the purpose of meeting the dual needs of clinicians and the bereaved. Despite more Human Tissue Authority inspections, there is a disproportionate rise in enforcement actions, with up to 48% of sampled Trusts exhibiting shortcomings in their legal duties. Additionally, only 52.4% of sampled trusts follow the Human Tissue Authority best-practice model, with 23.8% having no documented procedures. Despite the well founded evidence base for best-practice models, consent practices for post-mortem examinations remains poor and is likely to have a gross adverse effect on the rate of post-mortem examinations. We recommend that NHS Trusts rigorously review their protocols and introduce a team-approach between clinicians and trained bereavement staff in core-consent teams, as the Human Tissue Authority suggests, whilst at the same time placing a strong emphasis on education for junior and senior colleagues alike. PMID- 22843648 TI - Injuries, envenomations and stings from exotic pets. AB - A variety of exotic vertebrate and invertebrate species are kept as 'pets' including fishes, amphibians (for example, frogs and toads), reptiles (turtles, crocodiles, lizards and snakes), birds, mammals (for example, primates, civets, and lions), and invertebrates (for example spiders, scorpions, and centipedes), and ownership of some of these animals is rising. Data for 2009-2011 suggest that the number of homes with reptiles rose by approximately 12.5%. Recent surveys, including only some of these animals, indicated that they might be present in around 18.6% of homes (equal to approximately 42 million animals of which around 40 million are indoor or outdoor fish). Many exotic 'pets' are capable of causing injury or poisoning to their keepers and some contacts prove fatal. We examined NHS Health Episode Statistics for England using selected formal categories for hospital admissions and bed days for 2004-2010 using the following categories of injury, envenomation or sting; bitten or struck by crocodile or alligator; bitten or crushed by other reptiles: contact with venomous snakes and lizards; contact with scorpions. Between 2004 and 2010 these data conservatively show a total of 760 full consultation episodes, 709 admissions and 2,121 hospital bed days were associated with injuries probably from exotic pets. Injuries, envenomations and stings from exotic pets constitute a small but important component of emerging medical problems. Greater awareness of relevant injuries and medical sequelae from exotic pet keeping may help medics formulate their clinical assessment and advice to patients. PMID- 22843649 TI - The origins of inoculation. PMID- 22843650 TI - Swine flu myocarditis presenting with life threatening ventricular tachycardia. PMID- 22843651 TI - 'Overdiagnosis' and mortality in breast cancer screening. PMID- 22843654 TI - C-reactive protein/interleukin-6 ratio as marker of the size of the uncomplicated thoracic aortic aneurysms. AB - OBJECTIVES: The role of C-reactive protein (CRP) and interleukin-6 (IL-6) as markers in the prognosis of asymptomatic thoracic aortic aneurysm (TAA) patients has not been well established. As such, we evaluated a group of patients for a possible association between serum CRP and IL-6 and aneurysm dimension. METHODS: Serum CRP and IL-6 were determined and aneurysmal size was measured in 26 patients with TAA. RESULTS: The mean (SD) CRP and IL-6 were 0.58 (1.07) and 7.47 (17.78) pg/ml, respectively. Serum CRP, IL-6 and the ratio CRP/IL-6 correlated with the descending aortic aneurysmal dimension (r = 0.426, r = 0.743 and r = 0.328, respectively). A significant correlation was also found between values of the ratio above 0.8 and aneurysmal dimension (both ascending and descending aneurysms) (r = 0.785). Additionally, a significant association between smoking, age group above 69 years and dyslipidemia and aneurysm dimension was established (P = 0.002, P = 0.061 and P = 0.070, respectively). CONCLUSIONS: This report shows that serum CRP, IL-6 levels and the ratio CRP/IL-6 are associated with descending aortic aneurysmal dimensions. Also values of the ratio CRP/IL-6 above 0.8 are associated with aneurysmal dimensions for both ascending and descending aortic aneurysms. It is still early to establish the clinical significance of those findings, and further studies with larger groups of patients with longer follow-up are required in order to truly assess the usefulness of the serum CRP and IL-6 as markers in relation to the progression of the disease. PMID- 22843655 TI - Congenital pericardial defect with ruptured acute type A aortic dissection. AB - We report 2 cases of congenital pericardial defect with ruptured acute type A aortic dissection. Case 1: An 83-year old man presented with sudden chest and back pain, and computed tomography (CT) showed acute aortic dissection with left pleural massive effusion. Because of his unstable haemodynamic condition with low blood pressure, an emergency operation was performed. We observed small amounts of bloody pericardial effusion, massive left-sided bloody pleural effusion and a partial left-sided pericardial defect of the pulmonary artery. The ascending aorta was replaced. The postoperative course was uneventful. Case 2: A 79-year old man presented with fainting followed by cardiac arrest and was resuscitated. Chest CT showed acute aortic dissection and massive haemothorax. Emergency operation was attempted, but was given up. We observed partial left-sided pericardial defect of the pulmonary artery. Further, we reviewed 6 cases of congenital pericardial defect with ruptured acute aortic dissection, including our 2 cases. In all the cases, the patients did not develop cardiac tamponade but had massive haemothorax due to congenital pericardial defects leading to confusion in diagnoses and surgical strategies. Therefore, it may be necessary to consider congenital pericardial defects before performing an operation in case of acute type A aortic dissection with massive haemothorax. PMID- 22843656 TI - Surgical management of superior vena cava syndrome after failed endovascular stenting. AB - The superior vena cava syndrome encompasses a constellation of symptoms and signs resulting from obstruction of the superior vena cava. We report a successful surgical management after failed endovascular stenting for superior vena cava syndrome, caused by a postradiation fibrosis after conventional radiotherapy for breast cancer. We emphasize the rarity of this uncommon surgical procedure and the bailout procedure for failed angioplasty and intravascular stenting. Key points of superior vena cava syndrome and its management are discussed. PMID- 22843664 TI - A synthetic approach reveals extensive tunability of auxin signaling. AB - Explaining how the small molecule auxin triggers diverse yet specific responses is a long-standing challenge in plant biology. An essential step in auxin response is the degradation of Auxin/Indole-3-Acetic Acid (Aux/IAA, referred to hereafter as IAA) repressor proteins through interaction with auxin receptors. To systematically characterize diversity in degradation behaviors among IAA|receptor pairs, we engineered auxin-induced degradation of plant IAA proteins in yeast (Saccharomyces cerevisiae). We found that IAA degradation dynamics vary widely, depending on which receptor is present, and are not encoded solely by the degron containing domain II. To facilitate this and future studies, we identified a mathematical model able to quantitatively describe IAA degradation behavior in a single parameter. Together, our results demonstrate the remarkable tunability conferred by specific configurations of the auxin response pathway. PMID- 22843666 TI - RNA silencing induced by an artificial sequence that prevents proper transcription termination in rice. AB - Posttranscriptional gene silencing (PTGS) is a sequence-specific mRNA degradation caused by small RNA, such as microRNA (miRNA) and small interfering RNA (siRNA). miRNAs are generated from MIRNA loci, whereas siRNAs originate from various sources of double-stranded RNA. In this study, an artificial RNA silencing inducible sequence (RSIS) was identified in rice (Oryza sativa). This sequence causes PTGS of 5' or 3' flanking-sequence-containing genes. Interestingly, two target genes can be simultaneously suppressed by linking a unique target sequence to either the 5' or 3' end of RSIS. Multiple gene suppression can be also achieved though a single transformation event by incorporating the multisite gateway system. Moreover, RSIS-mediated PTGS occurs in nuclei. Deep sequencing of small RNAs reveals that siRNAs are produced from RSIS-expressing cassettes and transitive siRNAs are produced from endogenous target genes. Furthermore, siRNAs are typically generated from untranscribed transgene terminator regions. The read through transcripts from the RSIS-expression cassette were consistently observed, and most of these sequences were not polyadenylated. Collectively, this data indicates that RSIS inhibits proper transcription termination. The resulting transcripts are not polyadenylated. These transcripts containing RSIS become templates for double-stranded RNA synthesis in nuclei. This is followed by siRNA production and target degradation of target genes. PMID- 22843665 TI - Gibberellin signaling: a theme and variations on DELLA repression. PMID- 22843667 TI - PIN auxin efflux carriers are necessary for pulse-induced but not continuous light-induced phototropism in Arabidopsis. AB - Auxin efflux carrier PIN-FORMED (PIN) proteins are thought to have central roles in regulating asymmetrical auxin translocation during tropic responses, including gravitropism and phototropism, in plants. Although PIN3 is known to be involved in phototropism in Arabidopsis (Arabidopsis thaliana), no severe defects of phototropism in any of the pin mutants have been reported. We show here that the pulse-induced, first positive phototropism is impaired partially in pin1, pin3, and pin7 single mutants, and severely in triple mutants. In contrast, such impairment was not observed in continuous-light-induced second positive phototropism. Analysis with an auxin-reporter gene demonstrated that PIN3 mediated auxin gradients participate in pulse-induced phototropism but not in continuous-light-induced phototropism. Similar functional separation was also applicable to PINOID, a regulator of PIN localization. Our results strongly suggest the existence of functionally distinct mechanisms i.e. a PIN-dependent mechanism in which transient stimulation is sufficient to induce phototropism, and a PIN-independent mechanism that requires continuous stimulation and does not operate in the former phototropism process. Although a previous study has proposed that blue-light photoreceptors, the phototropins, control PIN localization through the transcriptional down-regulation of PINOID, we could not detect this blue-light-dependent down-regulation event, suggesting that other as yet unknown mechanisms are involved in phototropin-mediated phototropic responses. PMID- 22843668 TI - Moderate intensity, but not high intensity, treadmill exercise training alters power output properties in myocardium from aged rats. AB - Aging is characterized by a progressive decline in cardiac function, but endurance exercise training has been shown to retard a number of deleterious effects of aging. However, underlying mechanisms by which exercise training improves age-related decrements in myocardial contractile function are not well understood. The purpose of this study was to determine the effects of exercise training on power output properties in permeablized (skinned) myocytes of old rats. Thirty-month-old rats were divided into sedentary control (C) and groups undergoing 11 weeks of treadmill exercise training at moderate intensity (MI) and at high intensity (HI). Peak power output normalized to maximal force was significantly increased in MI but not in HI compared to C with significant increases in atrial myosin light chain 1 in ventricle. These results suggest that MI exercise training is beneficial as a significant increase was seen in the ability of the myocardium to do work, but this effect was not seen with HI training. PMID- 22843669 TI - D-chiro-inositol and pinitol extend the life span of Drosophila melanogaster. AB - D-chiro-inositol, a member of the inositol family, and pinitol, a 3-methoxy analogue of D-chiro-inositol, have been proposed to have antidiabetic, antiinflammatory, anticancer and stamina enhancing effects. We found that supplementing the diet of Drosophila with D-chiro-inositol and pinitol extended adult longevity in both male and female flies. Life span extension was accompanied by protection against oxidative and starvation stresses, improvement in health span, and no reduction in fecundity. Pinitol increased the fly life span, both in dietary restriction and in ad libitum conditions, suggesting that pinitol increased life span in a manner that was independent of the dietary restriction pathway. Nuclear localization of dFOXO increased in D-chiro-inositol and pinitol-fed flies when compared with controls. Pinitol treatment significantly activated JNK and S6K, but not AKT, indicating that the activation of dFOXO by pinitol is acquired by the activation of S6K and JNK signaling. Hence, our study indicated that D-chiro-inositol and pinitol could be novel food derived antiaging compounds. PMID- 22843670 TI - Aging in the glomerulus. AB - Kidney function declines with age in the majority of the population. Although very few older people progress to end stage, the consequences of doing so are burdensome for the patient and very expensive for the society. Although some of the observed decline is likely due to changes in the vasculature, much is associated with the development of age-associated glomerulosclerosis. This article will review the well-established structural and functional changes in the glomerulus with age. The role of calorie restriction in modifying age-related pathology will be discussed. The importance of the podocyte as a critical cell in the aging process is considered using animal models and human biopsy material. Newer data on changes in gene expression driven by nuclear factor kappa beta (NFkB) and possible changes in biology in the glomerulus are discussed. The relationship between pathways involved in aging and the decline in kidney function is reviewed. There is speculation on the significance of these changes in relation to normal and pathological aging. PMID- 22843671 TI - Prediction of adverse health outcomes in older people using a frailty index based on routine primary care data. AB - BACKGROUND: A general frailty indicator could guide general practitioners (GPs) in directing their care efforts to the patients at highest risk. We investigated if a Frailty Index (FI) based on the routine health care data of GPs can predict the risk of adverse health outcomes in community-dwelling older people. METHODS: This was a retrospective cohort study with a 2-year follow-up period among all patients in an urban primary care center aged 60 and older: 1,679 patients (987 women [59%], median age, 73 years [interquartile range, 65-81]). For each patient, a baseline FI score was computed as the number of health deficits present divided by the total number of 36 deficits on the FI. Adverse health outcomes were defined as the first registered event of an emergency department (ED) or after-hours GP visit, nursing home admission, or death. RESULTS: In total, 508 outcome events occurred within the sample population. Kaplan-Meier survival curves were constructed according to FI tertiles. The tertiles were able to discriminate between patients with low, intermediate, and high risk for adverse health outcomes (p value < .001). With adjustments for age, consultation gap, and sex, a one deficit increase in the FI score was associated with an increased hazard for adverse health outcomes (hazard ratio, 1.166; 95% confidence interval [CI], 1.129-1.210) and a moderate predictive ability for adverse health outcomes (c-statistic, 0.702; 95% CI, 0.680-0.724). CONCLUSIONS: An FI based on International Classification of Primary Care (ICPC)-encoded routine health care data does predict the risk of adverse health outcomes in elderly population. PMID- 22843672 TI - Gender differences in the relationship between smoking and frailty: results from the Beijing Longitudinal Study of Aging. AB - BACKGROUND: Smoking is common in China, where the population is aging rapidly. This study evaluated the relationship between smoking and frailty and their joint association with health and survival in older Chinese men and women. METHODS: Data came from the Beijing Longitudinal Study of Aging, a representative cohort study with a 15-year follow-up. Community-dwelling people (n = 3257) aged more than 55 years at baseline were followed between 1992 and 2007, during which time 51% died. A frailty index (FI) was constructed from 28 self-reported health deficits. RESULTS: Almost half (1,485 people; 45.6%) of the participants reported smoking at baseline (66.8% men, 25.3% women). On average, male smokers were frailer (FI = 0.17+/-0.13) than male nonsmokers (FI = 0.13+/-0.10; p = .038). No such differences were seen in women. Men who smoked had the lowest survival probability; female nonsmokers had the highest. Compared with female nonsmokers, the risk of death for male smokers was 1.58 (95% CI = 1.41-1.95; p < .001), adjusted for age and education. Across all FI values, female smokers and male nonsmokers had comparable survival rates. CONCLUSION: Smoking was associated with an increased rate of both worsening health and mortality. At all levels of health status, as defined by deficit accumulation, women who smoked lost the survival advantage conferred by their sex. PMID- 22843673 TI - Novel antibodies reacting with two neighboring gangliosides are induced in rabbits immunized with bovine brain gangliosides. AB - Immunization of rabbits with bovine brain gangliosides induced an experimental neuropathy, with clinical signs resembling Guillain-Barre syndrome. All the immunized animals developed immunoglobulin G immunoreactivity to GM1 ganglioside. In a few (4 of 27) animals, an additional anti-ganglioside antibody population showing an unusual binding behavior was detected. Enzyme-linked immunosorbent assay and thin-layer chromatography immunostaining analyses showed that the binding of these unusual antibodies required the presence of two co-localized gangliosides. Maximal interaction was observed to a mixture of GM1 and GD1b, but the antibodies also showed "density-dependent" binding to GD1b. The antibodies were purified by affinity chromatography and displayed the ability to target antigens in biological membranes (rat synaptosomes). PMID- 22843674 TI - The urgency of the development of CO2 capture from ambient air. AB - CO(2) capture and storage (CCS) has the potential to develop into an important tool to address climate change. Given society's present reliance on fossil fuels, widespread adoption of CCS appears indispensable for meeting stringent climate targets. We argue that for conventional CCS to become a successful climate mitigation technology--which by necessity has to operate on a large scale--it may need to be complemented with air capture, removing CO(2) directly from the atmosphere. Air capture of CO(2) could act as insurance against CO(2) leaking from storage and furthermore may provide an option for dealing with emissions from mobile dispersed sources such as automobiles and airplanes. PMID- 22843675 TI - Conditional cooperation can hinder network reciprocity. PMID- 22843676 TI - Structural and functional analysis of phosphorylation-specific binders of the kinase ERK from designed ankyrin repeat protein libraries. AB - We have selected designed ankyrin repeat proteins (DARPins) from a synthetic library by using ribosome display that selectively bind to the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase 2) in either its nonphosphorylated (inactive) or doubly phosphorylated (active) form. They do not bind to other kinases tested. Crystal structures of complexes with two DARPins, each specific for one of the kinase forms, were obtained. The two DARPins bind to essentially the same region of the kinase, but recognize the conformational change within the activation loop and an adjacent area, which is the key structural difference that occurs upon activation. Whereas the rigid phosphorylated activation loop remains in the same form when bound by the DARPin, the more mobile unphosphorylated loop is pushed to a new position. The DARPins can be used to selectively precipitate the cognate form of the kinases from cell lysates. They can also specifically recognize the modification status of the kinase inside the cell. By fusing the kinase with Renilla luciferase and the DARPin to GFP, an energy transfer from luciferase to GFP can be observed in COS-7 cells upon intracellular complex formation. Phosphorylated ERK2 is seen to increase by incubation of the COS-7 cells with FBS and to decrease upon adding the ERK pathway inhibitor PD98509. Furthermore, the anti-ERK2 DARPin is seen to inhibit ERK phosphorylation as it blocks the target inside the cell. This strategy of creating activation-state-specific sensors and kinase-specific inhibitors may add to the repertoire to investigate intracellular signaling in real time. PMID- 22843677 TI - Utility of gadolinium enhanced cardiovascular MRI to differentiate Fabry's disease from other causes of hypertrophic cardiomyopathy. PMID- 22843678 TI - Aggregation-resistant domain antibodies engineered with charged mutations near the edges of the complementarity-determining regions. AB - Antibodies commonly contain hydrophobic residues within their complementarity determining regions (CDRs) that mediate binding to target antigens. Unfortunately, hydrophobic CDRs can also promote antibody aggregation, which is especially concerning for therapeutic antibodies due to the immunogenicity of antibody aggregates. Here we investigate how the sequences of CDRs within single domain (V(H)) antibodies specific for the Alzheimer's amyloid beta peptide can be engineered to resist aggregation without reducing binding affinity. We find that domain antibodies containing clusters of hydrophobic residues within their third CDR (CDR3) are prone to aggregate within days at 25 degrees C and minutes above 70 degrees C. However, inserting two or more negatively charged residues at each edge of CDR3 potently suppresses antibody aggregation without altering binding affinity. We also find that inserting charged mutations at one edge of CDR3 (N- or C-terminal) prevents aggregation, but only if such mutations are located at the edge closest to most hydrophobic portion of CDR3. In contrast, charged mutations outside of CDR3 fail to suppress aggregation. Our findings demonstrate that the sequence of CDR loops can be engineered in a systematic manner to improve antibody solubility without altering binding affinity or specificity. PMID- 22843679 TI - Migfilin protein promotes migration and invasion in human glioma through epidermal growth factor receptor-mediated phospholipase C-gamma and STAT3 protein signaling pathways. AB - Migfilin is critical for cell shape and motile regulation. However, its pathological role in glioma is unknown. Using an immunohistochemical staining assay, we demonstrate that there is a significant correlation between expression of Migfilin and pathological tumor grade in 217 clinical glioma samples. High Migfilin expression is associated with poor prognosis for patients with glioma. Investigation of the molecular mechanism shows that Migfilin promotes migration and invasion in glioma cells. Moreover, Migfilin positively modulates the expression and activity of epidermal growth factor receptor, and Migfilin mediated migration and invasion depend on epidermal growth factor receptor induced PLC-gamma and STAT3-signaling pathways. Our results may provide significant clinical application, including use of Migfilin as a molecular marker in glioma for early diagnosis and as an indicator of prognosis. PMID- 22843680 TI - Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 protein and plays a role in dopamine receptor internalization. AB - Calcyon, once known for interacting directly with the dopamine D(1) receptor (D(1)DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Although its direct interaction with D(1)DR has been shown to be misinterpreted, it still plays important roles in D(1)DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D(1)DR through PSD-95. Calcyon is phosphorylated on Ser-169 by the PKC activator phorbol 12-myristate 13-acetate or by the D(1)DR agonist SKF-81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D(1)DR at the cell surface was enhanced by phorbol 12-myristate 13-acetate and SKF-81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of calcyon and the internalization of the surface D(1)DR are tightly correlated. Our results suggest that calcyon regulates D(1)DR trafficking by forming a ternary complex with D(1)DR through PSD-95 and thus possibly linking glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders. PMID- 22843681 TI - Regulation of the subcellular localization of the G-protein subunit regulator GPSM3 through direct association with 14-3-3 protein. AB - G-protein signaling modulator-3 (GPSM3), also known as G18 or AGS4, is a member of the Galpha(i/o)-Loco (GoLoco) motif containing proteins. GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits; recently revealed is the existence of an additional regulatory site within GPSM3 directed toward monomeric Gbeta subunits during their biosynthesis. Here, using in silico and proteomic approaches, we have found that GPSM3 also interacts directly with numerous members of the 14-3-3 protein family. This interaction is dependent on GPSM3 phosphorylation, creating a mode II consensus 14-3-3 binding site. 14-3-3 binding to the N-terminal disordered region of GPSM3 confers stabilization from protein degradation. The complex of GPSM3 and 14-3-3 is exclusively cytoplasmic, and both moieties mutually control their exclusion from the nucleus. Phosphorylation of GPSM3 by a proline-directed serine/threonine kinase and the resultant association of 14-3-3 is the first description of post translational regulation of GPSM3 subcellular localization, a process that likely regulates important spatio-temporal aspects of G-protein-coupled receptor signaling modulation by GPSM3. PMID- 22843682 TI - Identification of protein interfaces between alpha-synuclein, the principal component of Lewy bodies in Parkinson disease, and the molecular chaperones human Hsc70 and the yeast Ssa1p. AB - Fibrillar alpha-synuclein (alpha-Syn) is the principal component of Lewy bodies, which are evident in individuals affected by Parkinson disease (PD). This neuropathologic form of alpha-Syn plays a central role in PD progression as it has been shown to propagate between neurons. Tools that interfere with alpha-Syn assembly or change the physicochemical properties of the fibrils have potential therapeutic properties as they may be sufficient to interfere with and/or halt cell-to-cell transmission and the systematic spread of alpha-Syn assemblies within the central nervous system. Vertebrate molecular chaperones from the constitutive/heat-inducible heat shock protein 70 (Hsc/p70) family have been shown to hinder the assembly of soluble alpha-Syn into fibrils and to bind to the fibrils and very significantly reduce their toxicity. To understand how Hsc70 family members sequester soluble alpha-Syn, we set up experiments to identify the molecular chaperone-alpha-Syn surface interfaces. We cross-linked human Hsc70 and its yeast homologue Ssa1p and alpha-Syn using a chemical cross-linker and mapped the Hsc70- and Ssa1p-alpha-Syn interface. We show that the client binding domain of Hsc70 and Ssa1p binds two regions within alpha-Syn similar to a tweezer, with the first spanning residues 10-45 and the second spanning residues 97-102. Our findings define what is necessary and sufficient for engineering Hsc70- and Ssa1p derived polypeptide with minichaperone properties with a potential as therapeutic agents in Parkinson disease through their ability to affect alpha-Syn assembly and/or toxicity. PMID- 22843683 TI - Relative movements of transmembrane regions at the outer mouth of the cystic fibrosis transmembrane conductance regulator channel pore during channel gating. AB - Multiple transmembrane (TM) segments line the pore of the cystic fibrosis transmembrane conductance regulator Cl(-) channel; however, the relative alignment of these TMs and their relative movements during channel gating are unknown. To gain three-dimensional structural information on the outer pore, we have used patch clamp recording to study the proximity of pairs of cysteine side chains introduced into TMs 6 and 11, using both disulfide cross-linking and Cd(2+) coordination. Following channel activation, disulfide bonds could apparently be formed between three cysteine pairs (of 15 studied): R334C/T1122C, R334C/G1127C, and T338C/S1118C. To examine the state dependence of cross-linking, we combined these cysteine mutations with a nucleotide-binding domain mutation (E1371Q) that stabilizes the channel open state. Investigation of the effects of the E1371Q mutation on disulfide bond formation and Cd(2+) coordination suggests that although R334C/T1122C and T338C/S1118C are closer together in the channel open state, R334C/G1127C are close together and can form disulfide bonds only when the channel is closed. These results provide important new information on the three-dimensional structure of the outer mouth of the cystic fibrosis transmembrane conductance regulator channel pore: TMs 6 and 11 are close enough together to form disulfide bonds in both open and closed channels. Moreover, the altered relative locations of residues in open and in closed channels that we infer allow us to propose that channel opening and closing may be associated with a relative translational movement of TMs 6 and 11, with TM6 moving "down" (toward the cytoplasm) during channel opening. PMID- 22843684 TI - The arginine of the DRY motif in transmembrane segment III functions as a balancing micro-switch in the activation of the beta2-adrenergic receptor. AB - Recent high resolution x-ray structures of the beta2-adrenergic receptor confirmed a close salt-bridge interaction between the suspected micro-switch residue ArgIII:26 (Arg3.50) and the neighboring AspIII:25 (Asp3.49). However, neither the expected "ionic lock" interactions between ArgIII:26 and GluVI:-06 (Glu6.30) in the inactive conformation nor the interaction with TyrV:24 (Tyr5.58) in the active conformation were observed in the x-ray structures. Here we find through molecular dynamics simulations, after removal of the stabilizing T4 lysozyme, that the expected salt bridge between ArgIII:26 and GluVI:-06 does form relatively easily in the inactive receptor conformation. Moreover, mutational analysis of GluVI:-06 in TM-VI and the neighboring AspIII:25 in TM-III demonstrated that these two residues do function as locks for the inactive receptor conformation as we observed increased G(s) signaling, arrestin mobilization, and internalization upon alanine substitutions. Conversely, TyrV:24 appears to play a role in stabilizing the active receptor conformation as loss of function of G(s) signaling, arrestin mobilization, and receptor internalization was observed upon alanine substitution of TyrV:24. The loss of function of the TyrV:24 mutant could partly be rescued by alanine substitution of either AspIII:25 or GluVI:-06 in the double mutants. Surprisingly, removal of the side chain of the ArgIII:26 micro-switch itself had no effect on G(s) signaling and internalization and only reduced arrestin mobilization slightly. It is suggested that ArgIII:26 is equally important for stabilizing the inactive and the active conformation through interaction with key residues in TM-III, -V, and -VI, but that the ArgIII:26 micro-switch residue itself apparently is not essential for the actual G protein activation. PMID- 22843685 TI - Insights into Duffy binding-like domains through the crystal structure and function of the merozoite surface protein MSPDBL2 from Plasmodium falciparum. AB - Invasion of human red blood cells by Plasmodium falciparum involves interaction of the merozoite form through proteins on the surface coat. The erythrocyte binding-like protein family functions after initial merozoite interaction by binding via the Duffy binding-like (DBL) domain to receptors on the host red blood cell. The merozoite surface proteins DBL1 and -2 (PfMSPDBL1 and PfMSPDBL2) (PF10_0348 and PF10_0355) are extrinsically associated with the merozoite, and both have a DBL domain in each protein. We expressed and refolded recombinant DBL domains for PfMSPDBL1 and -2 and show they are functional. The red cell binding characteristics of these domains were shown to be similar to full-length forms of these proteins isolated from parasite cultures. Futhermore, metal cofactors were found to enhance the binding of both the DBL domains and the parasite-derived full-length proteins to erythrocytes, which has implications for receptor binding of other DBL-containing proteins in Plasmodium spp. We solved the structure of the erythrocyte-binding DBL domain of PfMSPDBL2 to 2.09 A resolution and modeled that of PfMSPDBL1, revealing a canonical DBL fold consisting of a boomerang shaped alpha-helical core formed from three subdomains. PfMSPDBL2 is highly polymorphic, and mapping of these mutations shows they are on the surface, predominantly in the first two domains. For both PfMSPDBL proteins, polymorphic variation spares the cleft separating domains 1 and 2 from domain 3, and the groove between the two major helices of domain 3 extends beyond the cleft, indicating these regions are functionally important and are likely to be associated with the binding of a receptor on the red blood cell. PMID- 22843686 TI - Exploring the role of a conserved class A residue in the Omega-Loop of KPC-2 beta lactamase: a mechanism for ceftazidime hydrolysis. AB - Gram-negative bacteria harboring KPC-2, a class A beta-lactamase, are resistant to all beta-lactam antibiotics and pose a major public health threat. Arg-164 is a conserved residue in all class A beta-lactamases and is located in the solvent exposed Omega-loop of KPC-2. To probe the role of this amino acid in KPC-2, we performed site-saturation mutagenesis. When compared with wild type, 11 of 19 variants at position Arg-164 in KPC-2 conferred increased resistance to the oxyimino-cephalosporin, ceftazidime (minimum inhibitory concentration; 32->128 mg/liter) when expressed in Escherichia coli. Using the R164S variant of KPC-2 as a representative beta-lactamase for more detailed analysis, we observed only a modest 25% increase in k(cat)/K(m) for ceftazidime (0.015->0.019 MUm(-1) s(-1)). Employing pre-steady-state kinetics and mass spectrometry, we determined that acylation is rate-limiting for ceftazidime hydrolysis by KPC-2, whereas deacylation is rate-limiting in the R164S variant, leading to accumulation of acyl-enzyme at steady-state. CD spectroscopy revealed that a conformational change occurred in the turnover of ceftazidime by KPC-2, but not the R164S variant, providing evidence for a different form of the enzyme at steady state. Molecular models constructed to explain these findings suggest that ceftazidime adopts a unique conformation, despite preservation of Omega-loop structure. We propose that the R164S substitution in KPC-2 enhances ceftazidime resistance by proceeding through "covalent trapping" of the substrate by a deacylation impaired enzyme with a lower K(m). Future antibiotic design must consider the distinctive behavior of the Omega-loop of KPC-2. PMID- 22843687 TI - The histone chaperone Spt6 is required for activation-induced cytidine deaminase target determination through H3K4me3 regulation. AB - H3K4me3 plays a critical role in the activation-induced cytidine deaminase (AID) induced DNA cleavage of switch (S) regions in the immunoglobulin heavy chain (IgH) locus during class-switch recombination (CSR). The histone chaperone complex facilitates chromatin transcription (FACT) is responsible for forming H3K4me3 at AID target loci. Here we show that the histone chaperone suppressor of Ty6 (Spt6) also participates in regulating H3K4me3 for CSR and for somatic hypermutation in AID target loci. We found that H3K4me3 loss was correlated with defects in AID-induced DNA breakage and reduced mutation frequencies in IgH loci in both S and variable regions and in non-IgH loci such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and small nucleolar RNA host gene 3 (SNHG3). Global gene expression analysis revealed that Spt6 can act as both a positive and negative transcriptional regulator in B cells, affecting ~5% of the genes that includes suppressor of Ty4 (Spt4) and AID. Interestingly, Spt6 regulates CSR and AID expression through two distinct histone modification pathways, H3K4me3 and H3K36me3, respectively. Tandem SH2 domain of Spt6 plays a critical role in CSR and H3K4me3 regulation involving Set1 histone methyltransferase. We conclude that Spt6 is a unique histone chaperone capable of regulating the histone epigenetic state of both AID targets and the AID locus. PMID- 22843688 TI - Effects of a mitochondrial mutator mutation in yeast POS5 NADH kinase on mitochondrial nucleotides. AB - Saccharomyces cerevisiae contains three NADH/NAD(+) kinases, one of which is localized in mitochondria and phosphorylates NADH in preference to NAD(+). Strand et al. reported that a yeast mutation in POS5, which encodes the mitochondrial NADH kinase, is a mutator, specific for mitochondrial genes (Strand, M. K., Stuart, G. R., Longley, M. J., Graziewicz, M. A., Dominick, O. C., and Copeland, W. C. (2003) Eukaryot. Cell 2, 809-820). Because of the involvement of NADPH in deoxyribonucleotide biosynthesis, we asked whether mitochondria in a pos5 deletion mutant contain abnormal deoxyribonucleoside triphosphate (dNTP) pools. We found the pools of the four dNTPs to be more than doubled in mutant mitochondrial extracts relative to wild-type mitochondrial extracts. This might partly explain the mitochondrial mutator phenotype. However, the loss of antioxidant protection is also likely to be significant. To this end, we measured pyridine nucleotide pools in mutant and wild-type mitochondrial extracts and found NADPH levels to be diminished by ~4-fold in Deltapos5 mitochondrial extracts, with NADP(+) diminished to a lesser degree. Our data suggest that both dNTP abnormalities and lack of antioxidant protection contribute to elevated mitochondrial gene mutagenesis in cells lacking the mitochondrial NADH kinase. The data also confirm previous reports of the specific function of Pos5p in mitochondrial NADP(+) and NADPH biosynthesis. PMID- 22843689 TI - Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis. AB - The interleukin (IL)-1beta-processing inflammasome has recently been identified as a target for pathogenic evasion of the inflammatory response by a number of bacteria and viruses. We postulated that the periodontal pathogen, Porphyromonas gingivalis may suppress the inflammasome as a mechanism for its low immunogenicity and pathogenic synergy with other, more highly immunogenic periodontal bacteria. Our results show that P. gingivalis lacks signaling capability for the activation of the inflammasome in mouse macrophages. Furthermore, P. gingivalis can suppress inflammasome activation by another periodontal bacterium, Fusobacterium nucleatum. This repression affects IL-1beta processing, as well as other inflammasome-mediated processes, including IL-18 processing and cell death, in both human and mouse macrophages. F. nucleatum activates IL-1beta processing through the Nlrp3 inflammasome; however, P. gingivalis repression is not mediated through reduced levels of inflammasome components. P. gingivalis can repress Nlrp3 inflammasome activation by Escherichia coli, and by danger-associated molecular patterns and pattern associated molecular patterns that mediate activation through endocytosis. However, P. gingivalis does not suppress Nlrp3 inflammasome activation by ATP or nigericin. This suggests that P. gingivalis may preferentially suppress endocytic pathways toward inflammasome activation. To directly test whether P. gingivalis infection affects endocytosis, we assessed the uptake of fluorescent particles in the presence or absence of P. gingivalis. Our results show that P. gingivalis limits both the number of cells taking up beads and the number of beads taken up for bead-positive cells. These results provide a novel mechanism of pathogen mediated inflammasome inhibition through the suppression of endocytosis. PMID- 22843690 TI - Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules. AB - The cytoprotective enzyme heme oxygenase-1 (HO-1) is often overexpressed in different types of cancers and promotes cancer progression. We have recently shown that the Ras-Raf-ERK pathway induces HO-1 to promote survival of renal cancer cells. Here, we examined the possible mechanisms underlying HO-1-mediated cell survival. Considering the growing evidence about the significance of apoptosis and autophagy in cancer, we tried to investigate how HO-1 controls these events to regulate survival of cancer cells. Rapamycin (RAPA) and sorafenib, two commonly used drugs for renal cancer treatment, were found to induce HO-1 expression in renal cancer cells Caki-1 and 786-O; and the apoptotic effect of these drugs was markedly enhanced upon HO-1 knockdown. Overexpression of HO-1 protected the cells from RAPA- and sorafenib-induced apoptosis and also averted drug-mediated inhibition of cell proliferation. HO-1 induced the expression of anti-apoptotic Bcl-xL and decreased the expression of autophagic proteins Beclin-1 and LC3B-II; while knockdown of HO-1 down-regulated Bcl-xL and markedly increased LC3B-II. Moreover, HO-1 promoted the association of Beclin-1 with Bcl-xL and Rubicon, a novel negative regulator of autophagy. Drug-induced dissociation of Beclin-1 from Rubicon and the induction of autophagy were also inhibited by HO-1. Together, our data signify that HO-1 is up-regulated in renal cancer cells as a survival strategy against chemotherapeutic drugs and promotes growth of tumor cells by inhibiting both apoptosis and autophagy. Thus, application of chemotherapeutic drugs along with HO-1 inhibitor may elevate therapeutic efficiency by reducing the cytoprotective effects of HO-1 and by simultaneous induction of both apoptosis and autophagy. PMID- 22843691 TI - Hypoxia-inducible factor-1alpha (HIF1alpha) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element like motif to modulate cytokine release. AB - Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca(2+))- and zinc (Zn(2+))-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-alpha and interleukin-1alpha) induced TRPA1 gene expression via nuclear factor-kappaB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1alpha (HIF1alpha). HIF1alpha unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn(2+), suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1alpha mechanism that links inflammatory mediators to ion channel expression. PMID- 22843692 TI - Prenyltransferases regulate CD20 protein levels and influence anti-CD20 monoclonal antibody-mediated activation of complement-dependent cytotoxicity. AB - Anti-CD20 monoclonal antibodies (mAbs) are successfully used in the management of non-Hodgkin lymphomas and chronic lymphocytic leukemia. We have reported previously that statins induce conformational changes in CD20 molecules and impair rituximab-mediated complement-dependent cytotoxicity. Here we investigated in more detail the influence of farnesyltransferase inhibitors (FTIs) on CD20 expression and antitumor activity of anti-CD20 mAbs. Among all FTIs studied, L 744,832 had the most significant influence on CD20 levels. It significantly increased rituximab-mediated complement-dependent cytotoxicity against primary tumor cells isolated from patients with non-Hodgkin lymphomas or chronic lymphocytic leukemia and increased CD20 expression in the majority of primary lymphoma/leukemia cells. Incubation of Raji cells with L-744,832 led to up regulation of CD20 at mRNA and protein levels. Chromatin immunoprecipitation assay revealed that inhibition of farnesyltransferase activity was associated with increased binding of PU.1 and Oct-2 to the CD20 promoter sequences. These studies indicate that CD20 expression can be modulated by FTIs. The combination of FTIs with anti-CD20 mAbs is a promising therapeutic approach, and its efficacy should be examined in patients with B-cell tumors. PMID- 22843693 TI - Tetraspanin CD151 stimulates adhesion-dependent activation of Ras, Rac, and Cdc42 by facilitating molecular association between beta1 integrins and small GTPases. AB - Tetraspanin CD151 associates with laminin-binding alpha(3)beta(1)/alpha(6)beta(1) integrins in epithelial cells and regulates adhesion-dependent signaling events. We found here that CD151 plays a role in recruiting Ras, Rac1, and Cdc42, but not Rho, to the cell membrane region, leading to the formation of alpha(3)beta(1)/alpha(6)beta(1) integrin-CD151-GTPases complexes. Furthermore, cell adhesion to laminin enhanced CD151 association with beta(1) integrin and, thereby, increased complex formation between the beta(1) family of integrins and small GTPases, Ras, Rac1, and Cdc42. Adhesion receptor complex-associated small GTPases were activated by CD151-beta(1) integrin complex-stimulating adhesion events, such as alpha(3)beta(1)/alpha(6)beta(1) integrin-activating cell-to laminin adhesion and homophilic CD151 interaction-generating cell-to-cell adhesion. Additionally, FAK and Src appeared to participate in this adhesion dependent activation of small GTPases. However, engagement of laminin-binding integrins in CD151-deficient cells or CD151-specific siRNA-transfected cells did not activate these GTPases to the level of cells expressing CD151. Small GTPases activated by engagement of CD151-beta(1) integrin complexes contributed to CD151 induced cell motility and MMP-9 expression in human melanoma cells. Importantly, among the four tetraspanin proteins that associate with beta(1) integrin, only CD151 exhibited the ability to facilitate complex formation between the beta(1) family of integrins and small GTPases and stimulate beta(1) integrin-dependent activation of small GTPases. These results suggest that CD151 links alpha(3)beta(1)/alpha(6)beta(1) integrins to Ras, Rac1, and Cdc42 by promoting the formation of multimolecular complexes in the membrane, which leads to the up regulation of adhesion-dependent small GTPase activation. PMID- 22843694 TI - Color-tuned channelrhodopsins for multiwavelength optogenetics. AB - Channelrhodopsin-2 is a light-gated ion channel and a major tool of optogenetics. It is used to control neuronal activity via blue light. Here we describe the construction of color-tuned high efficiency channelrhodopsins (ChRs), based on chimeras of Chlamydomonas channelrhodopsin-1 and Volvox channelrhodopsin-1. These variants show superb expression and plasma membrane integration, resulting in 3 fold larger photocurrents in HEK cells compared with channelrhodopsin-2. Further molecular engineering gave rise to chimeric variants with absorption maxima ranging from 526 to 545 nm, dovetailing well with maxima of channelrhodopsin-2 derivatives ranging from 461 to 492 nm. Additional kinetic fine-tuning led to derivatives in which the lifetimes of the open state range from 19 ms to 5 s. Finally, combining green- with blue-absorbing variants allowed independent activation of two distinct neural cell populations at 560 and 405 nm. This novel panel of channelrhodopsin variants may serve as an important toolkit element for dual-color cell stimulation in neural circuits. PMID- 22843695 TI - Novel one-step immunoassays to quantify alpha-synuclein: applications for biomarker development and high-throughput screening. AB - Familial Parkinson disease (PD) can result from alpha-synuclein gene multiplication, implicating the reduction of neuronal alpha-synuclein as a therapeutic target. Moreover, alpha-synuclein content in human cerebrospinal fluid (CSF) represents a PD biomarker candidate. However, capture-based assays for alpha-synuclein quantification in CSF (such as by ELISA) have shown discrepancies and have limited suitability for high-throughput screening. Here, we describe two sensitive, in-solution, time-resolved Forster's resonance energy transfer (TR-FRET)-based immunoassays for total and oligomeric alpha-synuclein quantification. CSF analysis showed strong concordance for total alpha-synuclein content between two TR-FRET assays and, in agreement with a previously characterized 36 h protocol-based ELISA, demonstrated lower alpha-synuclein levels in PD donors. Critically, the assay suitability for high-throughput screening of siRNA constructs and small molecules aimed at reducing endogenous alpha-synuclein levels was established and validated. In a small-scale proof of concept compound screen using 384 well plates, signals ranged from <30 to >120% of the mean of vehicle-treated cells for molecules known to lower and increase cellular alpha-synuclein, respectively. Furthermore, a reverse genetic screen of a kinase-directed siRNA library identified seven genes that modulated alpha synuclein protein levels (five whose knockdown increased and two that decreased cellular alpha-synuclein protein). This provides critical new biological insight into cellular pathways regulating alpha-synuclein steady-state expression that may help guide further drug discovery efforts. Moreover, we describe an inherent limitation in current alpha-synuclein oligomer detection methodology, a finding that will direct improvement of future assay design. Our one-step TR-FRET-based platform for alpha-synuclein quantification provides a novel platform with superior performance parameters for the rapid screening of large biomarker cohorts and of compound and genetic libraries, both of which are essential to the development of PD therapies. PMID- 22843696 TI - Opposite orientations of a transcription factor heterodimer bind DNA cooperatively with interaction partners but have different effects on interferon beta gene transcription. AB - ATF2-Jun, IRF3, and HMGI recognize a composite regulatory element within the interferon-beta enhancer (IFNb). Cooperative ATF2-Jun-IRF3 complex formation at IFNb has been proposed to require a fixed orientation of ATF2-Jun binding. Our results show that ATF2-Jun heterodimers bound IFNb in both orientations alone and in association with IRF3 and HMGI. Two sets of symmetrically located amino acid residues in ATF2 and Jun facilitated the interactions between heterodimers bound in opposite orientations and IRF3 at IFNb. IRF3 and HMGI bound IFNb in association with both orientations of ATF2-Jun heterodimers with the same cooperativity. ATF2-Jun heterodimers that bound IFNb in opposite orientations in vitro had different effects on interferon-beta gene transcription when they were co-expressed with IRF3 in cultured cells. These heterodimers had different transcriptional activities at different endogenous genes. Different regions of ATF2 and Jun mediated their orientation-dependent transcriptional activities at different genes. These studies revealed that cooperative DNA binding does not require a unique nucleoprotein complex configuration, and that transcription factor complexes that bind the same enhancer in different configurations can have different transcriptional activities. PMID- 22843698 TI - Leptospirosis and Weil's disease in the UK. AB - The recent high-profile death of a British Olympic rower from leptospirosis has raised awareness to this uncommon but potentially fatal disease. The re-emergence of the disease abroad is well documented in the literature, but less is known about cases in the UK. The increase in participation in water sports, foreign travel and often a combination of the two, has increased the exposure of tourists subsequently returning to the UK from areas of high prevalence. Leptospirosis is a zoonotic infection. The bacteria are shed in the urine of animals to the environment from where humans are infected by incidental hosts. There is a wide spectrum of severity of symptoms, from a self-limiting febrile illness to fatal pulmonary haemorrhage, renal or liver failure. It is thought that cases remain unrecognized every year in the UK, largely due to the mild nature of symptoms and the wide differential for febrile illness and partly due to lack of awareness among clinicians. This review examines the epidemiology of leptospirosis in the UK, over the period 2006-10, the clinical features, diagnostic techniques and treatment. PMID- 22843697 TI - The mitosis and neurodevelopment proteins NDE1 and NDEL1 form dimers, tetramers, and polymers with a folded back structure in solution. AB - Paralogs NDE1 (nuclear distribution element 1) and NDEL1 (NDE-like 1) are essential for mitosis and neurodevelopment. Both proteins are predicted to have similar structures, based upon high sequence similarity, and they co-complex in mammalian cells. X-ray diffraction studies and homology modeling suggest that their N-terminal regions (residues 8-167) adopt continuous, extended alpha helical coiled-coil structures, but no experimentally derived information on the structure of their C-terminal regions or the architecture of the full-length proteins is available. In the case of NDE1, no biophysical data exists. Here we characterize the structural architecture of both full-length proteins utilizing negative stain electron microscopy along with our established paradigm of chemical cross-linking followed by tryptic digestion, mass spectrometry, and database searching, which we enhance using isotope labeling for mixed NDE1-NDEL1. We determined that full-length NDE1 forms needle-like dimers and tetramers in solution, similar to crystal structures of NDEL1, as well as chain-like end-to end polymers. The C-terminal domain of each protein, required for interaction with key protein partners dynein and DISC1 (disrupted-in-schizophrenia 1), includes a predicted disordered region that allows a bent back structure. This facilitates interaction of the C-terminal region with the N-terminal coiled-coil domain and is in agreement with previous results showing N- and C-terminal regions of NDEL1 and NDE1 cooperating in dynein interaction. It sheds light on recently identified mutations in the NDE1 gene that cause truncation of the encoded protein. Additionally, analysis of mixed NDE1-NDEL1 complexes demonstrates that NDE1 and NDEL1 can interact directly. PMID- 22843699 TI - Hypertension impairs myocardin function: a novel mechanism facilitating arterial remodelling. AB - AIMS: Hypertension evokes detrimental changes in the arterial vessel wall that facilitate stiffening and thus lead to a further rise in mean blood pressure, eventually causing heart failure. The underlying pathophysiological remodelling process is elicited by an increase in wall stress (WS) and is strictly dependent on the activation of vascular smooth muscle cells (SMC). However, it remains unclear as to why these cells fail to maintain their contractile and quiescent phenotype in a hypertensive environment. METHODS AND RESULTS: In this context, we reveal that the knockdown of myocardin--a pivotal transcriptional determinant of the contractile SMC phenotype--is sufficient to induce SMC proliferation. In line with this observation, immunofluorescence analysis of the media of remodelling arteries from hypertensive mice demonstrated a significant decrease in the abundance of myocardin and an increase in SMC proliferation. Subsequent analyses of isolated perfused mouse arteries and human cultured SMCs exposed to cyclic stretch (i.e. mimicking one component of WS) suggested that this biomechanical force facilitates serine phosphorylation of myocardin. Furthermore, this biomechanical stimulus promotes rapid translocation of myocardin from the nucleus to the cytoplasm, inhibits its mRNA expression, and causes proteasomal degradation of the cytoplasmic protein. CONCLUSIONS: Collectively, these findings suggest that hypertension negates the activity of myocardin in SMCs on multiple levels, hence eliminating a crucial determinant of SMC quiescence. This mechanism may control the initial switch from the contractile towards the synthetic SMC phenotype during hypertension and may offer an interesting novel approach to prevent cardiovascular disease. PMID- 22843700 TI - Calpains in the cardiovascular system. PMID- 22843701 TI - Sonic boon: ultrasound enhances angiogenic cell therapy. PMID- 22843702 TI - Cooperation between proteolytic systems in cardiomyocyte recycling. AB - Cardiomyocytes are terminally differentiated cells and thus do not have the ability to dilute damaged proteins and organelles by cell division. Thus, proteolytic and recycling systems within the cardiomyocyte are essential to maintain cardiac function. The major proteolytic systems in the cell are: the ubiquitin-proteasome system, autophagy, and calpain. The ubiquitin-proteasome system degrades specific proteins by labelling them with ubiquitin. Autophagy degrades cytosolic proteins and organelles; this is generally believed to be a non-specific type of degradation. Calpain is a Ca(2+)-sensitive cysteine protease that degrades intracellular substrates including cytoskeletal proteins, and participates in Ca(2+)-mediated intracellular processes. All three systems exist in the cardiomyocyte and play pivotal roles in maintaining cardiac function. However, there is still controversy regarding the role of each protein degradation system in the heart. Our recent reports using cardiac-specific knockout mice have revealed the cardioprotective roles of autophagy and calpain in the development of heart failure. While these proteolytic systems exhibit distinct molecular mechanisms, they work cooperatively (one process can regulate another). PMID- 22843704 TI - beta-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gbetagamma/Erk-dependent pathway. AB - AIMS: Activation of the beta(1)-adrenergic receptor and its G protein, G(s), induces cardiac hypertrophy. However, activation of classic Galpha(s) effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by G(s). Recently, we discovered that betagamma subunits of G(q) induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether beta adrenergic receptors might also induce cardiac hypertrophy via Erk(Thr188) phosphorylation. METHODS AND RESULTS: beta-Adrenergic receptor activation induced Erk(Thr188) phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of Erk(Thr188) phosphorylation-deficient mutants (Erk2(T188A) and Erk2(T188S)) significantly attenuated beta-adrenergic cardiomyocyte hypertrophy in vitro. Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced Erk(Thr188) phosphorylation. Erk(Thr188) phosphorylation required Gbetagamma released from G(s) and was prevented by Gbetagamma inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2(T188S) transgenic mice, supporting the physiological relevance of Erk(Thr188) phosphorylation. CONCLUSIONS: Activation of G(s) by beta-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gbetagamma, which then associates with activated Erk1/2 and induces Erk(Thr188) phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in beta adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling. PMID- 22843705 TI - Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition. AB - AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties. METHODS AND RESULTS: Linagliptin (83 mg/kg chow for 7 days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxidase subunits and proinflammatory markers, and white blood cell infiltration in the vasculature were determined. Oxidative burst and adhesion of isolated human neutrophils to endothelial cells were measured in the presence of different DPP-4 inhibitors, and their direct vasodilatory effects (isometric tension in isolated aortic rings) were compared. In vivo linagliptin treatment ameliorated LPS-induced endothelial dysfunction and was associated with reduced formation of vascular, cardiac, and blood ROS, aortic expression of inflammatory genes and NADPH oxidase subunits in addition to reduced aortic infiltration with inflammatory cells. Linagliptin was the most potent inhibitor of oxidative burst in isolated activated human neutrophils and it suppressed their adhesion to activated endothelial cells. Of the inhibitors tested, linagliptin and alogliptin had the most pronounced direct vasodilatory potency. CONCLUSION: Linagliptin demonstrated pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties independent of its glucose-lowering properties. These pleiotropic properties are generally not shared by other DPP-4 inhibitors and might translate into cardiovascular benefits in diabetic patients. PMID- 22843703 TI - Developmental basis for filamin-A-associated myxomatous mitral valve disease. AB - AIMS: We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development. METHODS AND RESULTS: Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype. CONCLUSIONS: These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease. PMID- 22843707 TI - Role of adenosine A(2B) receptor stimulation in ischaemic postconditioning: dawn of a new paradigm in cardioprotection. PMID- 22843708 TI - Oiling vascular growth: adipokines can induce (pathological) angiogenesis by using the VEGF/VEGFR system. PMID- 22843711 TI - Posaconazole as successful treatment for fungemia due to Cryptococcus albidus in a liver transplant recipient. PMID- 22843710 TI - Polycomb (PcG) proteins, BMI1 and SUZ12, regulate arsenic-induced cell transformation. AB - Inorganic arsenic is a well-documented human carcinogen associated with cancers of the skin, lung, liver, and bladder. However, the underlying mechanisms explaining the tumorigenic role of arsenic are not well understood. The present study explored a potential mechanism of cell transformation induced by arsenic exposure. Exposure to a low dose (0.5 MUm) of arsenic trioxide (As(2)O(3)) caused transformation of BALB/c 3T3 cells. In addition, in a xenograft mouse model, tumor growth of the arsenic-induced transformed cells was dramatically increased. In arsenic-induced transformed cells, polycomb group (PcG) proteins, including BMI1 and SUZ12, were activated resulting in enhanced histone H3K27 tri methylation levels. On the other hand, tumor suppressor p16(INK4a) and p19(ARF) mRNA and protein expression were dramatically suppressed. Introduction of small hairpin (sh) RNA-BMI1 or -SUZ12 into BALB/c 3T3 cells resulted in suppression of arsenic-induced transformation. Histone H3K27 tri-methylation returned to normal in BMI1- or SUZ12-knockdown BALB/c 3T3 cells compared with BMI1- or SUZ12 wildtype cells after arsenic exposure. As a consequence, the expression of p16(INK4a) and p19(ARF) was recovered in arsenic-treated BMI1- or SUZ12-knockdown cells. Thus, arsenic-induced cell transformation was blocked by inhibition of PcG function. Taken together, these results strongly suggest that the polycomb proteins, BMI1 and SUZ12 are required for cell transformation induced by organic arsenic exposure. PMID- 22843712 TI - Diddensiella caesifluorescens gen. nov., sp. nov., a riboflavin-producing yeast species of the family Trichomonascaceae. AB - Four strains of a novel heterothallic yeast species were isolated from rotten wood collected in or near the Pilis Mountains in Hungary. The strains produced riboflavin in liquid culture. Analysis of gene sequences for the D1/D2 domains of the LSU nuclear rRNA, as well as analysis of concatenated gene sequences for the D1/D2 nuclear LSU rRNA, mitochondrial SSU rRNA and cytochrome oxidase II placed the novel species in a small clade including only two recognized species, Candida santjacobensis and Candida transvaalensis, in the family Trichomonascaceae. DNA sequence analyses demonstrated that the novel species was distinct from all currently recognized teleomorphic yeast genera. The name Diddensiella caesifluorescens gen nov., sp. nov. is proposed to accommodate the novel genus and species. The new genus proposed here can be recognized only from gene sequence analysis, because the characters of its asexual reproduction and ascospore formation are shared by several members of the genera Trichomonascus, Sugiyamaella and Spencermartinsiella. The type and isotype strains of D. caesifluorescens are NCAIM Y.01949(T) ( = NRRL Y-48781(T) = CBS 12613(T)) and NCAIM Y.01956(I) ( = NRRL Y-48782(I) = CBS 12614(I)), respectively. In view of their close relatedness to D. caesifluorescens, C. santjacobensis and C. transvaalensis are transferred to the genus Diddensiella as new combinations in accordance with changes in the International Code of Nomenclature for algae, fungi and plants. PMID- 22843713 TI - Mycobacterium iranicum sp. nov., a rapidly growing scotochromogenic species isolated from clinical specimens on three different continents. AB - The isolation and characterization of a novel, rapidly growing, scotochromogenic mycobacterial species is reported. Eight independent strains were isolated from clinical specimens from six different countries of the world, two in Iran, two in Italy and one in each of following countries: Greece, The Netherlands, Sweden and the USA. Interestingly, two of the strains were isolated from cerebrospinal fluid. The strains were characterized by rapid growth and presented orange pigmented scotochromogenic colonies. DNA-based analysis revealed unique sequences in the four regions investigated: the 16S rRNA gene, the rRNA gene internal transcribed spacer 1 and the genes encoding the 65 kDa heat-shock protein and the beta-subunit of RNA polymerase. The phylogenetic analysis placed the strains among the rapidly growing mycobacteria, being most closely related to Mycobacterium gilvum. The genotypic and phenotypic data both strongly supported the inclusion of the strains investigated here as members of a novel species within the genus Mycobacterium; the name Mycobacterium iranicum sp. nov. is proposed to indicate the isolation in Iran of the first recognized strains. The type strain is M05(T) ( = DSM 45541(T) = CCUG 62053(T) = JCM 17461(T)). PMID- 22843714 TI - Loktanella cinnabarina sp. nov., isolated from a deep subseafloor sediment, and emended description of the genus Loktanella. AB - A Gram-stain-negative, aerobic, heterotrophic and salt-tolerant bacterium, designated strain LL-001(T), was isolated from a deep subseafloor sediment in Japanese waters. Cells were non-motile rods and colonies were smooth, convex, circular and vermilion. The conditions for growth were 15-35 degrees C, pH 5.5 7.5 and 1-8 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain LL-001(T) belonged to the genus Loktanella within the family Rhodobacteraceae of the class Alphaproteobacteria. 16S rRNA gene sequence similarity between strain LL-001(T) and members of the genus Loktanella was 94.5 98.5 %; the highest sequence similarity was with Loktanella hongkongensis UST950701-009P(T). DNA-DNA relatedness between strain LL-001(T) and L. hongkongensis UST950701-009P(T) was 41.5-43.6 %. The DNA G+C content of strain LL 001(T) was 69.3 mol%. On the basis of biochemical features and 16S rRNA gene sequence comparison, strain LL-001(T) is considered to represent a novel species of the genus Loktanella, for which the name Loktanella cinnabarina sp. nov. is proposed. The type strain is LL-001(T) ( = JCM 18161(T) = CECT 8072(T)). The description of the genus Loktanella is also emended. PMID- 22843715 TI - Weissella oryzae sp. nov., isolated from fermented rice grains. AB - A taxonomic study was conducted on two Gram-reaction-positive, catalase-negative, irregular short-rod-shaped or coccoid lactic acid bacteria, designated strains SG25(T) and SG23, that were isolated from grains of fermented Japanese rice (Oryza sativa L. subsp. japonica). A phylogenetic analysis based on 16S rRNA gene sequence data clearly showed that the strains belonged to the genus Weissella and were most closely related to Weissella soli LMG 20113(T) (with a sequence similarity of 96.9 % for each novel strain). The peptidoglycan of each strain contained the amino acids glutamic acid, lysine, serine and alanine in a molar ratio of 1.0 : 1.2 : 0.5 : 3.0, respectively. On the basis of the unusual phenotypic characteristics of the novel strains and the low levels of DNA-DNA relatedness recorded between each novel strain and Weissella soli JCM 12536(T), strains SG25(T) and SG23 represent a single novel species in the genus Weissella, for which the name Weissella oryzae sp. nov. is proposed. The type strain is SG25(T) ( = JCM 18191(T) = DSM 25784(T)). PMID- 22843716 TI - Erythrobacter jejuensis sp. nov., isolated from seawater. AB - A Gram-staining-negative, yellow-pigmented, non-motile, strictly aerobic, rod shaped bacterium, designated strain CNU001(T), was isolated from seawater collected on the coast of Jeju Island, South Korea, and subjected to a polyphasic taxonomic study. The temperature, pH and NaCl ranges for growth were 10-30 degrees C, pH 6.0-10.0 and 2.0-5.0 %, respectively. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain CNU001(T) belonged to the genus Erythrobacter in the family Erythrobacteraceae, with Erythrobacter longus DSM 6997(T) (96.6 % sequence similarity), Erythrobacter gaetbuli SW-161(T) (96.3 %), Erythrobacter vulgaris 022 2-10(T) (96.2 %), Erythrobacter nanhaisediminis T30(T) (96.1 %) and other members of the genus Erythrobacter (<96.0 %) identified as the novel strain's closest relatives. The major cellular fatty acids were C18 : 1omega7c and C17 : 1omega6c. The polar lipids were found to be diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, one sphingoglycolipid, one unidentified aminolipid and six other unidentified lipids. The major respiratory quinone was ubiquinone-10 (UQ 10) and the genomic DNA G+C content of the novel strain was 58.9 mol%. On the basis of phenotypic, phylogenetic and genotypic data, strain CNU001(T) represents a novel species within the genus Erythrobacter, for which the name Erythrobacter jejuensis sp. nov. is proposed. The type strain is CNU001(T) ( = KCTC 23090(T) = JCM 16677(T)). PMID- 22843717 TI - Galbibacter marinus sp. nov., isolated from deep-sea sediment. AB - A taxonomic study was carried out on a novel bacterium, designated strain ck-I2 15(T), which was isolated from deep-sea sediment collected from the South-west Indian Ocean Ridge. Cells of strain ck-I2-15(T) were Gram-reaction-negative, rod shaped, non-motile, moderately halophilic and capable of denitrification. Growth was observed with 0-9 % (w/v) NaCl and at temperatures of 10-37 degrees C. The novel strain was unable to degrade gelatin. The dominant cellular fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 9 (iso-C17 : 1omega9c and/or 10-methyl C16 : 0). The major respiratory quinone was MK6 and the polar lipid profile comprised phosphatidylethanolamine, one unidentified phospholipid, two unidentified aminolipids, one unidentified glycolipid and four other unidentified lipids. The G+C content of the genomic DNA was 38 mol%. 16S rRNA gene sequence comparison indicated that strain ck-I2-15(T) was most closely related to Galbibacter mesophilus Mok-17(T) (92.9 % sequence similarity), followed by 'Joostella atrarenae' M1-2 (92.8 %), Joostella marina En5(T) (92.7 %) and Zhouia amylolytica HN-171(T) (91.6 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ck-I2-15(T) formed a clade with the genus Galbibacter, within the family Flavobacteriaceae. Several phenotypic properties allowed strain ck-I2-15(T) to be distinguished from its closest phylogenetic relatives. On the basis of the phenotypic and phylogenetic data, strain ck-I2 15(T) represents a novel species of the genus Galbibacter, for which the name Galbibacter marinus is proposed. The type strain is ck-I2-15(T) ( = CCTCC AB 209062(T) = LMG 25228(T) = MCCC 1A03044(T)). PMID- 22843718 TI - Phylogenetic analysis identifies a 'Candidatus Phytoplasma oryzae'-related strain associated with yellow leaf disease of areca palm (Areca catechu L.) in India. AB - Yellow leaf disease (YLD) with phytoplasmal aetiology is a serious disease of arecanut palm in India. The present study was undertaken to characterize the 16S rRNA and secA gene sequences of the Indian arecanut YLD phytoplasma for 'Candidatus Phytoplasma' species assignment and 16Sr group/subgroup classification. Phytoplasma 16S rRNA genes were amplified using three sets of semi-nested/nested primers, 1F7/7R3-1F7/7R2, 4Fwd/3Rev-4Fwd/5Rev and P1/P7 R16F2n/R16R2, producing amplicons of 491, 1150 and 1250 bp, respectively, from diseased samples. The amplicons were cloned and sequenced. A blast search showed that the sequences had 99 % similarity with sugar cane white leaf phytoplasma (16SrXI) and Napier grass stunt phytoplasma (16SrXI). Phylogenetic analysis based on the 16S rRNA gene revealed the clustering of YLD phytoplasma with the rice yellow dwarf and Bermuda grass white leaf groups. The YLD phytoplasma F2nR2 sequence shared 97.5 % identity with that of 'Candidatus Phytoplasma oryzae' and 97.8 % identity with that of 'Candidatus Phytoplasma cynodontis'. Hence, for finer differentiation, we examined the secA gene-based phylogeny, where the YLD phytoplasma clustered with Napier grass stunt and sugar cane grassy shoot phytoplasmas, both belonging to the rice yellow dwarf group. Hence, we are assigning the Indian arecanut YLD phytoplasma as a 'Candidatus Phytoplasma oryzae'-related strain. Virtual RFLP analysis of a 1.2 kb fragment of the 16S rRNA gene (F2nR2 region) identified the Indian arecanut YLD phytoplasma as a member of 16SrXI-B subgroup. We name the phytoplasma Indian yellow leaf disease phytoplasma, to differentiate it from the Hainan YLD phytoplasma, which belongs to group 16SrI. PMID- 22843719 TI - Caloramator quimbayensis sp. nov., an anaerobic, moderately thermophilic bacterium isolated from a terrestrial hot spring. AB - An anaerobic, moderately thermophilic, terminal-spore-forming bacterium, designated strain USBA A(T), was isolated from a terrestrial hot spring located at an altitude of 2683 m in the Andean region of Colombia (04 degrees 50' 14.0" N 75 degrees 32' 53.4" W). Cells of strain USBA A(T) were Gram-stain-positive, straight to slightly curved rods (0.9*2.5 um), that were arranged singly or in pairs, and were motile by means of flagella. Growth occurred at 37-55 degrees C and pH 6.0-8.0, with a doubling time of 2 h under the optimal conditions (50 degrees C and pH 7.0). Glucose fermentation in strain USBA A(T) required yeast extract or peptone (each at 0.2 %, w/v). The novel strain fermented sugars, amino acids, Casamino acids, propanol, propionate, starch and dextrin, but no growth was observed on galactose, lactose, xylose, histidine, serine, threonine, benzoate, butyrate, lactate, pyruvate, succinate, methanol, ethanol, glycerol, casein, gelatin or xylan. The end products of glucose fermentation were formate, acetate, ethanol and lactate. Strain USBA A(T) did not grow autotrophically (with CO2 as carbon source and H2 as electron donor) and did not reduce thiosulfate, sulfate, elemental sulfur, sulfite, vanadium (V) or Fe (III) citrate. Growth of strain USBA A(T) was inhibited by ampicillin, chloramphenicol, kanamycin, penicillin and streptomycin (each at 10 ug ml(-1)). The predominant fatty acids were iso-C15 : 0, C16 : 0 and iso-C17 : 0 and the genomic DNA G+C content was 32.6 mol%. 16S rRNA gene sequence analysis indicated that strain USBA A(T) belonged in the phylum Firmicutes and that its closest relative was Caloramator viterbiensis JW/MS-VS5(T) (95.0 % sequence similarity). A DNA-DNA relatedness value of only 30 % was recorded in hybridization experiments between strain USBA A(T) and Caloramator viterbiensis DSM 13723(T). Based on the phenotypic, chemotaxonomic and phylogenetic evidence and the results of the DNA-DNA hybridization experiments, strain USBA A(T) represents a novel species of the genus Caloramator, for which the name Caloramator quimbayensis sp. nov. is proposed. The type strain is USBA A(T) ( = CMPUJ U833(T) = DSM 22093(T)). PMID- 22843720 TI - Cecembia calidifontis sp. nov., isolated from a hot spring runoff, and emended description of the genus Cecembia. AB - Two red-pigmented isolates, designated RQ-33(T) and TU-13, were recovered from hot spring runoffs on the Island of Sao Miguel in the Azores, Portugal. These organisms have an optimum growth temperature of approximately 45 degrees C and an optimum pH for growth between 7.5 and 8.5. Based on 16S rRNA gene sequence analysis, the novel isolates were most closely related to the type strain of Cecembia lonarensis at 96.4 % pairwise similarity. Cells of the two isolates were non-motile, rod-shaped, Gram-stain-negative, strictly aerobic, and oxidase- and catalase-positive. The major fatty acids were iso-C15 : 0 and C15 : 0, phosphatidylethanolamine was the major polar lipid, and menaquinone 7 was the major respiratory quinone. Based on phylogenetic analyses, and physiological and biochemical characteristics, these isolates from the Azores represent a novel species of the genus Cecembia for which the name Cecembia calidifontis is proposed with strain RQ-33(T) ( = DSM 21411(T) = LMG 24596(T)) as the type strain. The description of the genus Cecembia is also emended. PMID- 22843722 TI - Oceanobacillus indicireducens sp. nov., a facultative alkaliphile that reduces an indigo dye. AB - An indigo-reducing facultatively alkaliphilic and halophilic strain, designated strain A21(T), was isolated from a fermented Polygonum indigo (Polygonum tinctorium Lour.) liquor sample aged for 4 days prepared in a laboratory. 16S rRNA gene sequence phylogeny suggested that strain A21(T) was a member of the genus Oceanobacillus with the closest relative being the type strain of Oceanobacillus chironomi (similarity: 96.0 %). The cells of the isolate stained Gram-positive and were facultatively anaerobic straight rods that were motile by peritrichous flagella. The strain grew between 18 and 48 degrees C with optimum growth at 39 degrees C. It grew in the pH range of 7-12. It hydrolysed casein, gelatin and Tween 20 but not Tweens 40, 60 and 80, starch or DNA. No isoprenoid quinone was detected and the DNA G+C content was 39.7 mol%. The whole-cell fatty acid profile mainly consisted of iso-C15 : 0, anteiso-C15 : 0 and C16 : 0. DNA DNA hybridization experiments with O. chironomi revealed 13 % relatedness. Owing to the differences in phenotypic and chemotaxonomic characteristics, and phylogenetic analyses based on 16S rRNA gene sequences and DNA-DNA relatedness data from reported Oceanobacillus species, the isolate merits classification as a representative of a novel species, for which the name Oceanobacillus indicireducens sp. nov. is proposed. The type strain is A21(T) ( = JCM 17251(T) = NCIMB 14685(T)). The description of the genus Oceanobacillus is also emended. PMID- 22843721 TI - Stomatobaculum longum gen. nov., sp. nov., an obligately anaerobic bacterium from the human oral cavity. AB - A strictly anaerobic Gram-stain-variable but positive by structure, non-spore forming bacterium designated Lachnospiraceae bacterium ACC2 strain DSM 24645(T) was isolated from human subgingival dental plaque. Bacterial cells were 4-40 um long non-motile rods, often swollen and forming curved filaments up to 200 um. Cells contained intracellular, poorly crystalline, nanometre-sized iron- and sulfur-rich particles. The micro-organism was able to grow on yeast extract, trypticase peptone, milk, some sugars and organic acids. The major metabolic end products of glucose fermentation were butyrate, lactate, isovalerate and acetate. The growth temperature and pH ranges were 30-42 degrees C and 4.9-7.5, respectively. Major fatty acids were C14 : 0, C14 : 0 DMA (dimethyl aldehyde), C16 : 0, C16 : 1omega7c DMA. The whole-cell hydrolysate contained meso diaminopimelic acid, indicating peptidoglycan type A1gamma. The DNA G+C content was calculated to be 55.05 mol% from the whole-genome sequence and 55.3 mol% as determined by HPLC. There were no predicted genes responsible for biosynthesis of respiratory lipoquinones, mycolic acids and lipopolysaccharides. Genes associated with synthesis of teichoic and lipoteichoic acids, diaminopimelic acid, polar lipids and polyamines were present. According to the 16S rRNA gene sequence phylogeny, strain DSM 24645(T) formed, together with several uncultured oral clones, a separate branch within the family Lachnospiraceae, with the highest sequence similarity to the type strain of Moryella indoligenes at 94.2 %. Based on distinct phenotypic and genotypic characteristics, we suggest that strain DSM 24645(T) represents a novel species in a new genus, for which the name Stomatobaculum longum gen. nov., sp. nov. is proposed. The type strain of Stomatobaculum longum is DSM 24645(T) ( = HM-480(T); deposited in BEI Resources, an NIH collection managed by the ATCC). PMID- 22843723 TI - Veillonella tobetsuensis sp. nov., an anaerobic, gram-negative coccus isolated from human tongue biofilms. AB - Four previously unknown, gram-negative, anaerobic coccal strains were isolated from the tongue biofilm of healthy human adults (ages 22-29 years). The isolates displayed all phenotypic characteristics of the genus Veillonella. Comparative analysis of the 16S rRNA, dnaK and rpoB gene sequences indicated that the four strains were phylogenetically homogeneous and comprised a distinct novel lineage within the genus Veillonella. The production of major cellular fatty acids (C13 : 0 and C17 : 1omega8) was consistent with that of other members of the genus Veillonella. Based on these observations, strains B16(T), A16, B4 and Y6 represent a novel species, for which the name Veillonella tobetsuensis sp. nov. is proposed, with the type strain B16(T) ( = JCM 17976(T) = ATCC BAA-2400(T)). PMID- 22843724 TI - Rheinheimera tilapiae sp. nov., isolated from a freshwater culture pond. AB - A bacterial strain designated Ruye-90(T) was isolated from a freshwater tilapiine cichlid fish culture pond in Taiwan and characterized using a polyphasic taxonomic approach. Strain Ruye-90(T) was gram-negative, aerobic, yellow coloured, rod-shaped, and motile by means of a single polar flagellum. Growth occurred at 4-30 degrees C (optimum, 20-30 degrees C), at pH 7.0-9.0 (optimum, pH 8.0-9.0) and with 0-2 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Ruye-90(T) belonged to the genus Rheinheimera and its most closely related neighbour was Rheinheimera tangshanensis JA3-B52(T) with sequence similarity of 97.5 %. The major fatty acids were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c, 41.3 %), C16 : 0 (19.3 %), C18 : 1omega7c (8.4 %) and C12 : 0 3-OH (7.0 %). The major respiratory quinone was Q-8. The DNA G+C content of the genomic DNA was 49.0 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, aminolipid and two uncharacterized phospholipids. The DNA-DNA relatedness of strain Ruye 90(T) with respect to recognized members of the genus Rheinheimera was less than 70 %. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain Ruye-90(T) represents a novel species in the genus Rheinheimera, for which the name Rheinheimera tilapiae sp. nov. is proposed. The type strain is Ruye-90(T) ( = LMG 26339(T) = BCRC 80263(T) = KCTC 23315(T)). PMID- 22843725 TI - Alkalibacterium gilvum sp. nov., slightly halophilic and alkaliphilic lactic acid bacterium isolated from soft and semi-hard cheeses. AB - Nine novel strains of halophilic and alkaliphilic lactic acid bacteria isolated from European soft and semi-hard cheeses by using a saline, alkaline medium (7 % NaCl, pH 9.5) were taxonomically characterized. The isolates were Gram-stain positive, non-sporulating and non-motile. They lacked catalase and quinones. Under anaerobic cultivation conditions, lactate was produced from D-glucose with the production of formate, acetate and ethanol with a molar ratio of approximately 2 : 1 : 1. Under aerobic cultivation conditions, acetate and lactate were produced from D-glucose. The isolates were slightly halophilic, highly halotolerant and alkaliphilic. The optimum NaCl concentration for growth ranged between 2.0 % and 5.0 % (w/v), with a growth range of 0-1 % to 15-17.5 %. The optimum pH for growth ranged between 8.5 and 9.5, with a growth range of 7.0 7.5 to 9.5-10.0. Comparative sequence analysis of the 16S rRNA genes revealed that the isolates occupied a phylogenetic position within the genus Alkalibacterium, showing the highest sequence similarity (98.2 %) to Alkalibacterium kapii T22-1-2(T). The isolates constituted a single genomic species with DNA-DNA hybridization values of 79-100 % among the isolates and <29 % between the isolates and other members of the genus Alkalibacterium, from which the isolates were different in motility and flagellation, growth responses to NaCl concentrations and pH, and profiles of sugar fermentation. The DNA G+C contents were between 36.0 and 37.6 mol%. The cell-wall peptidoglycan was type A4beta, Orn-D-Asp. The major components of cellular fatty acids were C14 : 0, C16 : 0 and C16 : 1omega9c. Based on the phenotypic characteristics and genetic distinctness, the isolates are classified as a novel species within the genus Alkalibacterium, for which the name Alkalibacterium gilvum sp. nov. is proposed. The type strain is 3AD-1(T) ( = DSM 25751(T) = JCM 18271(T)). PMID- 22843726 TI - Pseudorhodobacter wandonensis sp. nov., isolated from wood falls, and emended description of the genus Pseudorhodobacter. AB - A Gram-stain-negative, aerobic, non-motile and rod-shaped bacterial strain, designated WT-MW11(T), was isolated from wood falls on the coast of Wando, an island of South Korea, and its taxonomic position was investigated by using a polyphasic approach. Strain WT-MW11(T) grew optimally at pH 7.0-8.0, at 25 degrees C and in the presence of 2.0-3.0 % (w/v) NaCl. Bacteriochlorophyll a was not produced. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain WT-MW11(T) clustered with Pseudorhodobacter ferrugineus IAM 12616(T) and Pseudorhodobacter aquimaris HDW-19(T), with which it exhibited 16S rRNA gene sequence similarity values of 97.9 and 95.5 %, respectively. Strain WT-MW11(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The polar lipid profile of strain WT-MW11(T) was similar to those of P. ferrugineus JCM 20687(T) and P. aquimaris HDW-19(T). The DNA G+C content of strain WT-MW11(T) was 61.6 mol% and its mean DNA-DNA relatedness value with P. ferrugineus JCM 20687(T) was 12.3 %. The phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain WT-MW11(T) was distinguishable from the two recognized species of the genus Pseudorhodobacter. On the basis of the data presented, strain WT-MW11(T) is considered to represent a novel species of the genus Pseudorhodobacter, for which the name Pseudorhodobacter wandonensis sp. nov. is proposed. The type strain is WT-MW11(T) ( = KCTC 23672(T) = CCUG 61506(T)). The description of the genus Pseudorhodobacter is emended. PMID- 22843727 TI - Specific chaperones for the type VII protein secretion pathway. AB - Mycobacteria use the dedicated type VII protein secretion systems ESX-1 and ESX-5 to secrete virulence factors across their highly hydrophobic cell envelope. The substrates of these systems include the large mycobacterial PE and PPE protein families, which are named after their characteristic Pro-Glu and Pro-Pro-Glu motifs. Pathogenic mycobacteria secrete large numbers of PE/PPE proteins via the major export pathway, ESX-5. In addition, a few PE/PPE proteins have been shown to be exported by ESX-1. It is not known how ESX-1 and ESX-5 recognize their cognate PE/PPE substrates. In this work, we investigated the function of the cytosolic protein EspG(5), which is essential for ESX-5-mediated secretion in Mycobacterium marinum, but for which the role in secretion is not known. By performing protein co-purifications, we show that EspG(5) interacts with several PPE proteins and a PE/PPE complex that is secreted by ESX-5, but not with the unrelated ESX-5 substrate EsxN or with PE/PPE proteins secreted by ESX-1. Conversely, the ESX-1 paralogue EspG(1) interacted with a PE/PPE couple secreted by ESX-1, but not with PE/PPE substrates of ESX-5. Furthermore, structural analysis of the complex formed by EspG(5) and PE/PPE indicates that these proteins interact in a 1:1:1 ratio. In conclusion, our study shows that EspG(5) and EspG(1) interact specifically with PE/PPE proteins that are secreted via their own ESX systems and suggests that EspG proteins are specific chaperones for the type VII pathway. PMID- 22843728 TI - A conformational switch in a partially unwound helix selectively determines the pathway for substrate release from the carnitine/gamma-butyrobetaine antiporter CaiT. AB - CaiT is a homotrimeric antiporter that exchanges l-carnitine (CRN) with gamma butyrobetaine (GBB) across the bacterial membrane. Three structures have been resolved to date for CaiT, all in the inward-facing state: CRN-bound (with four CRNs per subunit), GBB-bound (two GBBs per subunit), and apo. One of the reported binding sites is the counterpart of the primary site observed in structurally similar transporters. However, the mechanism and pathway(s) of CRN/GBB unbinding and translocation, or even the ability of the substrates to dislodge from the reported binding sites, are yet to be determined. To shed light on these issues, we performed a total of 1.3 MUs of molecular dynamics simulations and examined the dynamics of substrate-bound CaiT structures under different conditions. We find that both CRN and GBB are able to dissociate completely from their primary site into the cytoplasm. Substrate molecules initially located at the secondary sites dissociate even faster (within tens of nanoseconds) into the extra- or intracellular regions. Interestingly, the unbinding pathway from the primary site appears to be dictated by the geometry of the unwound part of the transmembrane (TM) helix 3, mostly around Thr(100) therein. Arg(262) on TM7, which apparently mimics the role of Na(+) in CaiT structural homologues, plays a key role in triggering the dissociation of the substrate away from the primary site and guiding its release to the cytoplasm provided that the unwound part of TM3 switches from a shielding to a yielding pose. PMID- 22843729 TI - Palmitoylation and membrane association of the stress axis regulated insert (STREX) controls BK channel regulation by protein kinase C. AB - Large-conductance, calcium- and voltage-gated potassium (BK) channels play an important role in cellular excitability by controlling membrane potential and calcium influx. The stress axis regulated exon (STREX) at splice site 2 inverts BK channel regulation by protein kinase A (PKA) from stimulatory to inhibitory. Here we show that palmitoylation of STREX controls BK channel regulation also by protein kinase C (PKC). In contrast to the 50% decrease of maximal channel activity by PKC in the insertless (ZERO) splice variant, STREX channels were completely resistant to PKC. STREX channel mutants in which Ser(700), located between the two regulatory domains of K(+) conductance (RCK) immediately downstream of the STREX insert, was replaced by the phosphomimetic amino acid glutamate (S700E) showed a ~50% decrease in maximal channel activity, whereas the S700A mutant retained its normal activity. BK channel inhibition by PKC, however, was effectively established when the palmitoylation-mediated membrane-anchor of the STREX insert was removed by either pharmacological inhibition of palmitoyl transferases or site-directed mutagenesis. These findings suggest that STREX confers a conformation on BK channels where PKC fails to phosphorylate and to inhibit channel activity. Importantly, PKA which inhibits channel activity by disassembling the STREX insert from the plasma membrane, allows PKC to further suppress the channel gating independent from voltage and calcium. Our results present an important example for the cross-talk between ion channel palmitoylation and phosphorylation in regulation of cellular excitability. PMID- 22843730 TI - Calcitonin gene-related peptide enhances experimental autoimmune encephalomyelitis by promoting Th17-cell functions. AB - T(h)17 cells, an inflammatory T helper cell subset, are involved in the pathogenesis of various inflammatory, autoimmune and allergic diseases. Recent evidence supports the idea that immune cell functions and the inflammatory response are finely regulated by various physiological substances. Calcitonin gene-related peptide (CGRP), a neuropeptide released from the sensory nerve endings, is one of these mediators. By binding to its receptor composed of receptor activity-modifying protein 1 (RAMP1) and calcitonin receptor-like receptor, CGRP modulates various immune cell functions, but the function of CGRP in T(h)17 cells is largely unknown. Here, we investigated the effect of CGRP signaling on T(h)17 cells and T(h)17 cell-mediated inflammation and observed that CGRP activates nuclear factor of activated T cells c2 through cAMP/PKA to increase IL-17 production in vitro. In vivo, IL-17 production is suppressed in RAMP1-deficient mice in the experimental autoimmune encephalomyelitis (EAE) model and RAMP1-deficient mice are completely resistant to EAE. Furthermore, T(h)17 cell function and EAE induction are also suppressed in T cell-specific RAMP1 deficient mice. Taken together, our findings indicate that CGRP promotes T(h)17 cell-mediated autoimmune inflammation through the regulation of IL-17 expression. PMID- 22843731 TI - Wales plans new legislation on dangerous dogs. PMID- 22843732 TI - Select committee presses for code of conduct on milk contracts. PMID- 22843734 TI - Welsh Government and National Trust to collaborate on badger vaccination. PMID- 22843736 TI - Collaboration key to improving livestock productivity in Africa. PMID- 22843737 TI - FAO and OIE urge laboratories to destroy their stocks of rinderpest virus. PMID- 22843739 TI - Sharing best practice in veterinary education. PMID- 22843740 TI - Award recognises contributions to advances in humane slaughter. PMID- 22843742 TI - Reducing methane production by cows. PMID- 22843743 TI - Animal athletes: a performance review. PMID- 22843744 TI - Validating topical skin therapies in randomised controlled studies. PMID- 22843745 TI - PCR detection of leptospiral carriers among seronegative horses. PMID- 22843746 TI - Intramuscular mast cell tumour in a dog. PMID- 22843747 TI - TAK1 contributes to the enhanced responsiveness of LTB(4)-treated neutrophils to Toll-like receptor ligands. AB - Pattern-recognition receptors such as Toll-like receptors (TLRs) are essential sensors implicated in the early and efficient innate immune response against pathogens. We have previously demonstrated that leukotriene B(4)(LTB(4)) has the capacity to enhance leukocyte responses to TLR9 ligands and to control viral infection. In this report, we provide evidence that LTB(4) treatment of human neutrophils leads to a potentiation in proinflammatory cytokine secretion induced by various myeloid differentiation factor 88-dependent TLR agonists. LTB(4) failed to enhance TLR mRNA levels as well as expression of TLR2 and TLR4 receptors, suggesting that LTB(4) acts through intracellular mechanism(s) to potentiate neutrophil responses to TLR ligands. We found that while IRAK can be activated by LTB(4), this process is dispensable to LTB(4) to potentiate neutrophil responses to TLR ligands since pretreatment of neutrophils with IRAK1/4 inhibitor did not affect its potentiating effects. However, our data clearly show that LTB(4) treatment of neutrophils led to the phosphorylation of downstream signaling molecules, TAK1 and p38, a process found essential to observe an increased secretion of cytokines by neutrophils activated with TLR ligands. Pretreatment of neutrophils with TAK1 or p38 kinase inhibitors strongly repressed the effect of LTB(4) on cytokine synthesis by neutrophils stimulated with LTA, LPS or CpG. The same pattern was observed in agonist-treated human embryonic kidney 293 cells transfected with TAK1-targeting siRNA where secretion of IL-8 was significantly reduced to basal levels. These results indicate that TAK1 and p38 kinases appear to be central in the 'priming effect' of LTB(4) on neutrophils to enhance response to TLR ligands. PMID- 22843748 TI - Unusual presentation of a spinal epidural abscess. AB - A 59-year-old female patient presented with a 3-day history of abdominal pain and confusion. She had no significant medical history. On admission her Glasgow Coma Scale was 14/15; she was septic and examination revealed right upper quadrant tenderness. She deteriorated quickly, becoming acidotic and hypoxic, and was sedated, intubated and transferred to the intensive care unit. Blood tests revealed raised inflammatory markers and blood cultures grew Staphylococcus aureus. Initial CT head revealed raised intracranial pressure and she was treated for meningoencephalitis. Repeat CT head 12 days later showed resolving oedema, and a lumbar puncture was attempted. This drew only frank pus and an abscess was suspected. CT spine confirmed a possible paravertebral abscess. Once extubated, MRI spine was possible which confirmed spinal epidural abscesses 1 month postadmission. These were rapidly drained by the neurosurgical team and the patient is currently receiving rehabilitation in a specialist centre. PMID- 22843749 TI - A rare but severe pulmonary side effect of cetuximab in two patients. AB - Cetuximab is a monoclonal antibody that treats malignant disease by inhibiting epidermal growth factor receptor. Many common adverse events have been reported and include skin rashes, infusion reactions, gastrointestinal complaints and headache. Up to now, cetuximab-associated pulmonary toxicity has been rarely reported in the literature. The present report describes two cases with probable interstitial pneumonitis 5-6 weeks after commencing treatment with chemotherapy combined with cetuximab. One patient recovered and the second patient died due to gastrointestinal bleeding 3 weeks after an initial response to steroids. PMID- 22843750 TI - Unusual presentation of midgut malrotation with incidental nutcracker syndrome in adulthood: case report and literature review. AB - Malrotation of the midgut is generally regarded as paediatric pathology with the majority of patients presenting in childhood. The diagnosis is rare in adults, which sometimes results in delayed diagnosis and treatment. We present the case of a 28-year-old woman who presented with vomiting and mild acute pain in the abdomen. CT scan showed abnormal location of the midgut and abnormal relation of the superior mesenteric artery (SMA) and superior mesenteric vein (SMV) and duodenal jejunal flexure, confirming midgut malrotation. Peroperative findings showed the duodenum, small bowel loops located on the right side of the abdomen. The caecum and appendix were located at the midline in the epigastrium with the presence of Ladd's bands. SMA right and anterior to SMV whirled around SMA. Incidentally, the intraoperatively dilated left renal vein was compressed between the SMA and the aorta, which was confirmed retrospectively on CT scan with no symptoms related to the condition. PMID- 22843751 TI - 'Milk of calcium' in the breast. PMID- 22843752 TI - Ischaemic colitis associated with oral contraceptive and bisacodyl use. AB - A woman with a history of hip replacement presented 3 days prior to revision of the hip with abdominal pain, diarrhoea and haematochezia. These symptoms began 6 h after she began taking bisacodyl in preparation for her upcoming surgery. She was on low-dose estradiol for hormone replacement therapy (HRT). Subsequent colonoscopy and biopsies were consistent with acute colonic ischaemia (CI). She was treated with intravenous fluids and antibiotics and discharged and told to stop HRT and bisacodyl. Follow-up colonoscopy 1 month after discharge was normal. This case adds to the three other previously reported cases of bisacodyl associated CI. PMID- 22843753 TI - Bilateral ptosis: an atypical presentation of neurocysticercosis. AB - Isolated ptosis is a rare presentation of neurocysticercosis (NCC). Here we report the case of a 45-year-old woman who presented with acute onset bilateral symmetrical ptosis with no other neurological deficit. Her imaging revealed a single cystic ring-enhancing lesion with perilesional oedema in the midbrain suggestive of NCC. She responded well to prednisolone. PMID- 22843754 TI - Cerebral cavernous malformation: a diagnostic challenge in a young patient with intracerebral haemorrhage. AB - An 18-year-old Caucasian man presented with a sudden onset right hemiparesis. On examination, he had objective evidence of an upper motor neuron lesion affecting the right side of his body. CT scan showed a left thalamic haemorrhage. MRI, gradient echo and cerebral angiogram showed no structural lesion and the cause of the bleeding was ultimately attributed to the use of cocaine. During the subsequent 2 years the patient had two further similar episodes, with an MRI eventually demonstrating a cerebral cavernous malformation. This was excised using frameless stereotactic surgery, following which the patient made an uneventful recovery. PMID- 22843755 TI - Eagle's syndrome, a rare cause of neck pain. AB - Eagle's syndrome (ES) sometimes called styloid or stylohyoid syndrome is defined as the symptomatic elongation of the styloid process or mineralisation of the stylohyoid ligament. The symptoms related to this condition can be confused with those attributed to a wide variety of facial neuralgias. We report a 34-year-old male patient who presented with a recurrent neck pain and dysphagia. He was diagnosed to have an elongated styloid process. An intraoral transtonsillar shortening of the styloid process was done. We discuss the clinical presentation, diagnosis and treatment of ES as well as a review of the literature. PMID- 22843756 TI - Occipital meningoencephalocele in a preterm neonate. PMID- 22843757 TI - Ocular snow storm: an unusual presentation of phacolytic glaucoma. PMID- 22843758 TI - Small cell carcinoma of gastro-oesophageal junction with remarkable response to chemo-radiotherapy. AB - Small cell carcinoma of the gastrointestinal tract is rare, and no effective strategy has yet been established. On the basis of regimens reportedly effective for small cell lung cancer, we performed chemotherapy with cisplatin plus etoposide in combination with radiotherapy to relieve obstruction, in a patient with small cell carcinoma of the gastro-oesophageal junction. Chemotherapy was switched to carboplatin plus etoposide due to renal toxicity. No distant metastases were detected and lesion spread was limited. A complete response, with no evidence of recurrence to date, was achieved. Curative resection was suggested but refused by the patient. He has been closely followed up in our outpatient clinic for more than a year and has shown no evidence of recurrence since the completion of treatment. Although cisplatin plus etoposide is a standard chemotherapy regimen for small cell carcinoma, carboplatin plus etoposide may be effective in cases in which cisplatin is contraindicated due to renal toxicity. PMID- 22843759 TI - Plummer-Vinson syndrome. PMID- 22843760 TI - The stone man disease: fibrodysplasia ossificans progressiva: imaging revisited. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling connective tissue disorder of unknown aetiology. Its occurrence is usually sporadic but may be an inherited autosomal-dominant condition with wide range of expression. FOP is characterised by congenital malformations of the great toes and abnormal progressive heterotopic ossification of striated muscles, tendons, ligaments, fascia and aponeuroses of the trunk and extremities leading to painful swellings. The ossifications typically appear within the first decade of life, resulting in progressive morbidity and severe disability. So far, there has been no effective treatment or prevention. In the early localised phase of disease it may be misdiagnosed, hence the role of correct diagnosis through imaging is essential. Herein, we report a case of a 10-year-old female who was evaluated radiologically and diagnosed as a case of FOP. The findings of plain radiography are described and the role of CT is highlighted. PMID- 22843761 TI - Examining the role of carbonation and temperature on water swallowing performance: a swallowing reaction-time study. AB - Various therapeutic approaches for dysphagia management are based on modifications of bolus properties to change swallowing biomechanics and increase swallowing safety. Limited evidence exists for the effects of carbonation and bolus temperature on swallowing behavior. Here, we investigated the effects of carbonation and temperature on swallowing behavior using a novel automated and complex swallowing reaction time task via pressure signal recordings in the hypopharynx. Healthy participants (n = 39, 27.7+/-5 years old) were randomized in two different experiments and asked to perform 10 normal-paced swallows, 10 fast paced swallows, and 10 challenged swallows within a predetermined time-window of carbonated versus still water (experiment 1) and of cold (4 degrees C) versus hot (45 degrees C) versus room temperature (21 degrees C) water (experiment 2). Quantitative measurements of latencies and percentage of successful challenged swallows were collected and analyzed nonparametrically. An increase in successfully performed challenged swallowing task was observed with carbonated water versus still water (P = 0.021), whereas only cold water shortened the latencies of normally paced swallows compared with room (P = 0.001) and hot (P = 0.004) temperatures. Therefore, it appears that chemothermal stimulation with carbonation and cold are most effective at modulating water swallowing, which in part is likely to be driven by central swallowing afferent activity. PMID- 22843762 TI - Odor recognition memory: two encoding trials are better than one. AB - The primary purpose of this study was to determine the effect of one versus two encoding trials in the classical yes/no recognition memory paradigm using olfactory stimuli. A group of 24 young adults rated 18 standard microencapsulated odorant targets for familiarity (first encoding block) or pleasantness (second encoding block). Once-encoded targets were in only one block and twice-encoded targets were in both, with items counterbalanced across participants. Participants performed a 20-min nonverbal distractor task followed by a yes/no recognition test incorporating 18 additional odors as foils. Memory performance for twice-encoded targets was superior to that for once-encoded targets. For once encoded targets, performance did not differ between those rated for familiarity versus those rated for pleasantness. Less pleasant odors produced overall better recognition, with a tendency for less familiar odors to produce overall better recognition. There was a tendency for the second encoding trial to have a larger effect for less pleasant or familiar odors than for more pleasant or familiar odors. The main conclusion is that recognition memory for odors is better for items encoded two times than for items encoded only once. Implications of these findings and suggestions for future research are discussed. PMID- 22843763 TI - Stability-indicating TLC-densitometric method for simultaneous determination of paracetamol and chlorzoxazone and their toxic impurities. AB - A highly sensitive, selective and accurate thin-layer chromatographic (TLC) densitometric method has been developed and validated for the simultaneous determination of paracetamol (PAR) and chlorzoxazone (CZ) and their toxic impurities, 4-amino phenol (4AP) and 2-amino-4-chlorophenol (2ACP), respectively, which are also considered to be the hydrolytic degradation products and related substances of the studied drugs. A developing system consisting of chloroform methanol-glacial acetic acid (9.5:0.5:0.25, by volume) was found to be sufficient for chromatographic separation among the four studied components using pre activated silica gel 60 F254 TLC plates with ultraviolet detection at 225 nm. Calibration curves were constructed in the ranges of 0.3-3, 1-10, 0.06-3 and 0.04 3 ug/band for PAR, CZ, 4AP and 2ACP, respectively, using polynomial equations. The developed method was validated according to International Conference on Harmonization guidelines and demonstrated good accuracy and precision. Moreover, the method was successfully applied for the determination of PAR and CZ in different marketed samples and the results were statistically compared to those obtained by the reported reversed-phase high-performance liquid chromatography method using F-test and Student's-t test. The low detection and quantitation limits of the developed method make it suitable for quality control and stability studies of PAR and CZ in different pharmaceutical formulations. PMID- 22843764 TI - Augmented reality visualization with use of image overlay technology for MR imaging-guided interventions: assessment of performance in cadaveric shoulder and hip arthrography at 1.5 T. AB - PURPOSE: To prospectively assess overlay technology in providing accurate and efficient targeting for magnetic resonance (MR) imaging-guided shoulder and hip joint arthrography. MATERIALS AND METHODS: A prototype augmented reality image overlay system was used in conjunction with a clinical 1.5-T MR imager. A total of 24 shoulder joint and 24 hip joint injections were planned in 12 human cadavers. Two operators (A and B) participated, each performing procedures on different cadavers using image overlay guidance. MR imaging was used to confirm needle positions, monitor injections, and perform MR arthrography. Accuracy was assessed according to the rate of needle adjustment, target error, and whether the injection was intraarticular. Efficiency was assessed according to arthrography procedural time. Operator differences were assessed with comparison of accuracy and procedure times between the operators. Mann-Whitney U test and Fisher exact test were used to assess group differences. RESULTS: Forty-five arthrography procedures (23 shoulders, 22 hips) were performed. Three joints had prostheses and were excluded. Operator A performed 12 shoulder and 12 hip injections. Operator B performed 11 shoulder and 10 hip injections. Needle adjustment rate was 13% (six of 45; one for operator A and five for operator B). Target error was 3.1 mm+/-1.2 (standard deviation) (operator A, 2.9 mm+/-1.4; operator B, 3.5 mm+/-0.9). Intraarticular injection rate was 100% (45 of 45). The average arthrography time was 14 minutes (range, 6-27 minutes; 12 minutes [range, 6-25 minutes] for operator A and 16 minutes [range, 6-27 min] for operator B). Operator differences were not significant with regard to needle adjustment rate (P=.08), target error (P=.07), intraarticular injection rate (P>.99), and arthrography time (P=.22). CONCLUSION: Image overlay technology provides accurate and efficient MR guidance for successful shoulder and hip arthrography in human cadavers. PMID- 22843765 TI - US assessment of medial arterial calcification: a sensitive marker of diabetes related microvascular and macrovascular complications. AB - PURPOSE: To examine the sensitivity of ultrasonography (US) compared with conventional radiography in detection of lower limb (thigh) medial arterial calcification (MAC) in type 2 diabetic patients and evaluate its association with diabetes-related complications. MATERIALS AND METHODS: The study was approved by the local research ethics committee, and informed written consent was obtained. US was performed in 289 patients with type 2 diabetes mellitus, and MAC severity was assigned a score from 0 to 8. Among the patients, 263 underwent radiographic examinations. All subjects underwent clinical evaluation to detect the presence of diabetes-related complications. RESULTS: US helped detect MAC in more subjects compared with radiography (65.8% vs 12.2%). US helped detect MAC from mild (scores 1-4) to severe (scores 5-8) degrees, while mild degree of MAC was poorly demonstrated with radiography. The incidence of nephropathy, retinopathy, sensory neuropathy, and macrovascular complications increased with the severity of MAC (based on US scoring). With univariate analysis, the presence of MAC was associated with nephropathy (P<.001), retinopathy (P<.001), sensory neuropathy (P=.004), and macrovascular complications (P<.001). After adjustment for potential confounders, the presence of severe MAC was associated with nephropathy, retinopathy, and macrovascular complications, with the odds ratios of 3.4 (95% confidence interval [CI]: 1.53, 7.43; P=.003), 2.6 (95% CI: 1.22, 5.32; P=.013), and 3.8 (95% CI: 1.37, 10.6; P=.01), respectively. CONCLUSION: In type 2 diabetic Chinese patients, US was more sensitive than conventional radiography in the detection of MAC, particularly when the MAC was mild. The presence of severe MAC was associated with diabetic nephropathy, retinopathy, and macrovascular complications. US detection of MAC was a potential early marker to identify diabetes-related complications. PMID- 22843766 TI - Pattern of cardiac sympathetic denervation in idiopathic Parkinson disease studied with 11C hydroxyephedrine PET. AB - PURPOSE: To determine whether cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) affects the left ventricle in a distinct regional pattern versus a more global pattern with use of carbon 11 (11C) meta-hydroxyephedrine (HED) positron emission tomography (PET). MATERIALS AND METHODS: This prospective study was approved by the institutional review board and was compliant with HIPAA. Informed consent was obtained from all subjects. Cardiac PET was performed with 11C HED in 27 patients with IPD (20 men and seven women aged 50-74 years; mean age, 62 years+/-6 [standard deviation]). 11C HED retention indexes (RIs), which reflect nerve density and integrity, were determined. RIs for 33 healthy control subjects (15 men and 18 women aged 20-78 years; mean age, 47 years+/-17) were used as a control database. Patients with IPD were compared with control subjects by using z score analysis. Global and segmental measurements of sympathetic denervation were expressed as percentage extent, z score severity, and severity-extent product (SEP). Group comparisons were performed with the Student t test. RESULTS: The mean 11C HED RI was 0.086 mL of blood per minute per milliliter tissue+/-0.015 for control subjects and 0.043 mL of blood per minute per milliliter tissue+/-0.016 for patients with IPD (P<0001). When compared with normative data from the control database, profound cardiac denervation (global extent>50%) was seen in most patients (19 of 27 patients, 70%). Four patients had normal 11C HED studies and four had mild denervation (global extent<25%). The mean global denervation extent was 62%+/-38, the mean severity z score was -2.7+/ 1.2, and the mean SEP was -202+/-131 (range, -358 to 0). Segmental analysis revealed relative sparing of anterior and proximal septal segments (mean extent, 48%-51%; mean severity z score, -2.47 to -2.0; mean SEP, -167 to -139), with lateral and proximal inferior segments more severely affected (mean extent, 68% 73%; mean severity z score, -2.8 to -2.62; mean SEP, -271 to -230). Patients with normal findings or preserved denervation did not significantly differ in mean age (t=1.09) or disease duration (t=0.44) compared to patients with severe sympathetic denervation. CONCLUSION: Cardiac sympathetic denervation in IPD is extensive, with a segmental pattern that involves the proximal lateral left ventricular wall most severely, with relative sparing of the anterior and proximal septal walls. PMID- 22843767 TI - Prostate cancer aggressiveness: in vivo assessment of MR spectroscopy and diffusion-weighted imaging at 3 T. AB - PURPOSE: To determine the individual and combined performance of magnetic resonance (MR) spectroscopic imaging and diffusion-weighted (DW) imaging at 3 T in the in vivo assessment of prostate cancer aggressiveness by using histopathologically defined regions of interest on radical prostatectomy specimens to define the prostate cancer regions to be investigated. MATERIALS AND METHODS: The local institutional ethics review board approved this retrospective study and waived the informed consent requirement. Fifty-four patients with biopsy-proved prostate cancer underwent clinical MR spectroscopic imaging followed by prostatectomy. Guided by the histopathologic map, all spectroscopy voxels that contained tumor tissue were selected, and metabolite ratios (choline [Cho] plus creatine [Cr]-to-citrate [Cit] and Cho/Cr ratios) were derived. For each spectroscopic voxel, 25th percentile apparent diffusion coefficient (ADC) of the region corresponding to that voxel was determined, representing the most aberrant tumor part on the ADC map, which was often smaller than spectroscopic imaging voxels. Maximum metabolic ratios and minimum 25th percentile ADC of each tumor were related to tumor aggressiveness and were used to differentiate aggressiveness classes. A logistic regression model (LRM) was used to combine data from both modalities. RESULTS: Significant correlation was found between aggressiveness classes and maximum Cho+Cr/Cit ratio (rho=0.36), maximum Cho/Cr ratio (rho=0.35), and minimum 25th percentile ADC (rho=-0.63) in the peripheral zone (PZ). In the transition zone (TZ), the correlation was significant for only Cho+Cr/Cit and Cho/Cr ratios (rho=0.58 and rho=0.60, respectively). For differentiation between aggressiveness classes, LRM use did not result in significantly improved differentiation over any individual variables. CONCLUSION: These findings enabled confirmation that MR spectroscopic imaging and DW imaging offer potential for in vivo noninvasive assessment of prostate cancer aggressiveness, and both modalities have comparable performance. The combination did not result in better performance. Nonetheless, the better performances of metabolite ratios in the TZ and of ADCs in the PZ suggest that they have complementary value. PMID- 22843768 TI - Intravoxel incoherent motion diffusion-weighted imaging in nonalcoholic fatty liver disease: a 3.0-T MR study. AB - PURPOSE: To compare pure molecular diffusion, D, perfusion-related diffusion, D*, and perfusion fraction, f, determined from diffusion-weighted (DW) magnetic resonance (MR) imaging on the basis of the intravoxel incoherent motion (IVIM) theory in patients with type 2 diabetes with and without liver steatosis. MATERIALS AND METHODS: This prospective study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. Between December 2009 and September 2011, 108 patients with type 2 diabetes (51 men, 57 women; mean age, 50 years) underwent 3.0-T single-voxel point-resolved proton MR spectroscopy of the liver (segment VII) to calculate the liver fat fraction from water (4.76 ppm) and methylene (1.33 ppm) peaks, corrected for T1 and T2 decay. Steatosis was defined as a liver fat fraction of at least 5.56%. DW imaging was performed by using a single-shot echo-planar sequence with 11 b values (0, 5, 15, 25, 35, 50, 100, 200, 400, 600, 800 sec/mm2). Liver D, D*, and f were measured and compared in patients with and patients without steatosis (Mann-Whitney test). RESULTS: The mean liver fat fraction was 7.8% (standard deviation, 9%; range, 0.99%-45%). Forty patients had liver steatosis. D was significantly lower in steatotic compared with nonsteatotic livers (mean, 1.03*10(-3) mm2/sec+/-0.23 [standard deviation] vs 1.24*10(-3) mm2/sec+/-0.15, respectively; P<.0001), as was D* (mean, 72.2*10(-3) mm2/sec+/-61.4 vs 110.6*10( 3) mm2/sec+/-79; P=.0025). However, f was significantly higher in steatotic compared with nonsteatotic livers (mean, 33.8%+/-9.4 vs 26.9%+/-8.8; P=.0003). CONCLUSION: D is significantly decreased in steatosis. The reduction in D* reflects decreased liver parenchymal perfusion in steatosis. Therefore, steatosis can affect diffusion parameters obtained with IVIM. PMID- 22843769 TI - Small hepatocellular carcinomas: improved sensitivity by combining gadoxetic acid enhanced and diffusion-weighted MR imaging patterns. AB - PURPOSE: To determine if the combination of gadoxetic acid-enhanced magnetic resonance (MR) imaging and diffusion-weighted (DW) imaging helps to increase accuracy and sensitivity in the diagnosis of small hepatocellular carcinomas (HCCs) compared with those achieved by using each MR imaging technique alone. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed consent. The study included 130 patients (95 men, 35 women) with 179 surgically confirmed small HCCs (<=2.0 cm) and 130 patients with cirrhosis (90 men, 40 women) without HCC who underwent gadoxetic acid-enhanced MR imaging and DW imaging at 3.0 T between May 2009 and July 2010. Three sets of images were analyzed independently by three observers to detect HCC: a gadoxetic acid set (unenhanced, early dynamic, and hepatobiliary phases), a DW imaging set, and a combined set. Data were analyzed by using alternative-free response receiver operating characteristic analysis. Diagnostic accuracy (area under the receiver operating characteristic curve [A(z)]), sensitivity, specificity, and positive predictive value were calculated. RESULTS: The mean A(z) values for the combined set (0.952) were significantly higher than those for the gadoxetic acid set (A(z) = 0.902) or the DW imaging set alone (A(z) = 0.871) (P <= .008). On a per-lesion basis, observers showed higher sensitivity in their analyses of the combined set (range, 91.1%-93.3% [163-167 of 179]) than in those of the gadoxetic acid set (range, 80.5%-82.1% [144-147 of 179]) or the DW imaging set alone (range, 77.7%-79.9% [139-143 of 179]) (P <= .003). Positive predictive values and specificity for all observers were equivalent for the three imaging sets. CONCLUSION: The combination of gadoxetic acid-enhanced MR imaging and DW imaging yielded better diagnostic accuracy and sensitivity in the detection of small HCCs than each MR imaging technique alone. PMID- 22843771 TI - Lipopolysaccharide-induced murine embryonic resorption involves nitric oxide mediated inhibition of the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. AB - The initial inactivation of prostaglandins (PGs) is mediated by 15 hydroxyprostaglandin dehydrogenase (15-PGDH). PGs are potent mediators of several biological processes, including inflammation and reproduction. In uterus, PGs play a key role in infection-induced pregnancy loss, in which concentration of this mediator increased. This process is accompanied with the induction of nitric oxide synthase expression and a marked increase in uterine levels of nitric oxide. There is no information concerning nitric oxide contribution to potential changes in PG catabolism, but experimental evidence suggests that nitric oxide modulates PG pathways. The specific objectives of the study were to evaluate the protein expression of HPGD (15-PGDH) and to characterize the nitric oxide dependent regulation of this enzyme in a model of lipopolysaccharide (LPS) induced embryonic resorption. Results show that LPS decreased HPGD protein expression and augmented PGE synthase activity; therefore, PGE2 levels increased in uterus in this inflammatory condition. Just as LPS, the treatment with a nitric oxide donor diminished HPGD protein expression in uterine tissue. In contrast, the inhibition of nitric oxide synthesis both in control and in LPS treated mice increased 15-PGDH levels. Also, we have found that this enzyme and PGE2 levels are not modulated by peroxynitrite, an oxidant agent derived from nitric oxide. This study suggests that LPS and nitric oxide promote a decrease in the ability of the uterus for PG catabolism during bacterially triggered pregnancy loss in mice. PMID- 22843772 TI - Calcium-calmodulin and pH regulate protein tyrosine phosphorylation in stallion sperm. AB - The mechanisms leading to capacitation in stallion sperm are poorly understood. The objective of our study was to define factors associated with regulation of protein tyrosine phosphorylation in stallion sperm. Stallion sperm were incubated for 4 h in modified Whitten's media with or without bicarbonate, calcium, or BSA. When sperm were incubated in air at 30*106/ml at initial pH 7.25, protein tyrosine phosphorylation was detected only in medium containing 25 mM bicarbonate alone; calcium and BSA inhibited phosphorylation. Surprisingly, this inhibition did not occur when sperm were incubated at 10*106/ml. The final pH values after incubation at 30*106 and 10*106 sperm/ml were 7.43 +/- 0.04 and 7.83 +/- 0.07 (mean +/- s.e.m.) respectively. Sperm were then incubated at initial pH values of 7.25, 7.90, or 8.50 in either air or 5% CO2. Protein tyrosine phosphorylation increased with increasing final medium pH, regardless of the addition of bicarbonate or BSA. An increase in environmental pH was observed when raw semen was instilled into the uteri of estrous mares and retrieved after 30 min (from 7.47 +/- 0.10 to 7.85 +/- 0.08), demonstrating a potential physiological role for pH regulation of capacitation. Sperm incubated in the presence of the calmodulin (CaM) inhibitor W-7 exhibited a dose-dependent increase in protein tyrosine phosphorylation, suggesting that the inhibitory effect of calcium was CaM mediated. These results show for the first time a major regulatory role of external pH, calcium, and CaM in stallion sperm protein tyrosine phosphorylation. PMID- 22843773 TI - Is the halo always holy? Glucocorticoid impact on detecting cranial large-vessel arteritis. PMID- 22843774 TI - The interobserver reliability of ultrasound in knee osteoarthritis. AB - OBJECTIVE: To assess the interobserver reliability between sonographers with different levels of experience in detecting inflammatory and structural damage abnormalities in patients with knee OA. METHODS: After achieving consensus on definitions and scanning protocols, three ultrasonographers with different levels of experience in musculoskeletal US examined the knees of nine patients with OA. US examinations were conducted with independent blinded evaluations of inflammatory (joint effusion, synovial hypertrophy, power Doppler signal, Baker's cysts) and structural (osteophytes, cortical bone irregularities, femoral hyaline cartilage abnormalities, protrusion of the medial meniscus) lesions. All abnormalities were scored by applying a dichotomous scale (0-1). In addition, at each knee joint site global scores for joint inflammation, cortical bone abnormalities and cartilage damage were calculated by summing the single-lesion scores. Reliability was assessed using kappa (kappa) coefficients. RESULTS: Seventeen knees were examined. Inflammatory abnormalities were observed with moderate to very good agreement (kappa = 0.55-0.88) between the observers. From fair to very good agreement (kappa = 0.31-0.82) was registered between sonographers for structural damage lesions. The overall kappa was 0.716 for junior and 0.571 for beginner sonographers comparing their findings with those of senior sonographers. CONCLUSION: This represents the first ultrasonographic study focusing on the analysis of interobserver reliability between sonographers with different levels of experience in demonstrating inflammatory and structural abnormalities in knee OA. Globally, even considering some variable results that were mainly obtained by the evaluation of single components of bone involvement, US offered a reliable assessment of a wide set of abnormalities in knee OA. PMID- 22843775 TI - Dynamism of immune reactions and regulation. PMID- 22843780 TI - Editorial commentary. "Late" treatment with neuraminidase inhibitors for severely ill patients with influenza: better late than never? PMID- 22843781 TI - Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. AB - BACKGROUND: Neuraminidase inhibitor (NAI) antiviral drugs can shorten the duration of uncomplicated influenza when administered early (<48 hours after illness onset) to otherwise healthy outpatients, but the optimal timing of effective therapy for critically ill patients is not well established. METHODS: We analyzed California surveillance data to characterize the outcomes of patients in intensive care units (ICUs) treated with NAIs for influenza A(H1N1)pdm09 (pH1N1). Demographic and clinical data were abstracted from medical records, using standardized case report forms. RESULTS: From 3 April 2009 through 10 August 2010, 1950 pH1N1 cases hospitalized in ICUs were reported. Of 1859 (95%) with information available, 1676 (90%) received NAI treatment, and 183 (10%) did not. The median age was 37 years (range, 1 week-93 years), 1473 (79%) had >=1 comorbidity, and 492 (26%) died. The median time from symptom onset to starting NAI treatment was 4 days (range, 0-52 days). NAI treatment was associated with survival: 107 of 183 untreated case patients (58%) survived, compared with 1260 of 1676 treated case patients (75%; P <= .0001). There was a trend toward improved survival for those treated earliest (P < .0001). Treatment initiated within 5 days after symptom onset was associated with improved survival compared to those never treated (P < .05). CONCLUSIONS: NAI treatment of critically ill pH1N1 patients improves survival. While earlier treatment conveyed the most benefit, patients who started treatment up to 5 days after symptom onset also were more likely to survive. Further research is needed about whether starting NAI treatment >5 days after symptom onset may also convey benefit. PMID- 22843782 TI - Therapeutic approach to the treatment-naive patient with hepatitis C virus genotype 1 infection: a step-by-step approach. AB - Recent advances in the treatment of hepatitis C virus infection (HCV) have led to high rates of viral cure. However, the use of newly approved protease inhibitors with activity against HCV still requires careful patient selection, counseling, and decision making before initiation of treatment. Laboratory work-up, staging of liver disease, and careful review of comorbid conditions is mandatory. Patients with cirrhosis may require treatment regimens that differ from those without cirrhosis. Because pegylated interferon alfa and ribavirin remain a key part of the treatment regimen, absolute and relative contraindications to their use must be considered. Management of common adverse events including anemia and rash must be embraced by the healthcare provider. PMID- 22843784 TI - Clostridium difficile carriage in healthy infants in the community: a potential reservoir for pathogenic strains. AB - BACKGROUND: Clostridium difficile has long been considered to be a nosocomial pathogen but has emerged in the community in recent years. During infancy, asymptomatic C. difficile colonization is common. However, knowledge of colonization determinants and strain characteristics is limited. We studied the dynamics of C. difficile colonization in healthy infants from the community. Determinants of colonization and strain genotypes were also determined in a cohort of infants attending day nurseries. METHODS: A 1-year follow-up study involving 10 healthy infants was performed to determine the incidence and kinetics of intestinal C. difficile colonization. In addition, a 1-point study involving 85 healthy infants (age, 0-3 years) from 2 day nurseries was performed. C. difficile isolates were typed by polymerase chain reaction-ribotyping and analyzed for the presence of toxin genes. RESULTS: During the follow-up study, all infants acquired C. difficile and were colonized for several months. An early (neonatal) and a late (4-6 months of age) acquisition period were identified. In day nurseries, 38 infants (45%) carried C. difficile, with 11 (13%) carrying a toxigenic isolate. Age and several environmental factors were associated with the C. difficile carrier state. Strains causing disease in adults were identified in infants. Interestingly, no infant carried the common epidemic 027 or 078 strains. CONCLUSIONS: This study provides information on the dynamics of colonization in infants in the community and on the genotype of involved strains. C. difficile colonization appears mainly as an age-dependent process. Pathogenic strains circulate in asymptomatic infants from the community, who represent a potential reservoir of pathogenic strains. PMID- 22843783 TI - Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. AB - BACKGROUND: Influenza vaccines may be reformulated annually because of antigenic drift in influenza viruses. However, the relationship between antigenic characteristics of circulating viruses and vaccine effectiveness (VE) is not well understood. We conducted an assessment of the effectiveness of US influenza vaccines during the 2010-2011 season. METHODS: We performed a case-control study comparing vaccination histories between subjects with acute respiratory illness with positive real-time reverse transcription polymerase chain reaction for influenza and influenza test-negative controls. Subjects with acute respiratory illness of <=7 days duration were enrolled in hospitals, emergency departments, or outpatient clinics in communities in 4 states. History of immunization with the 2010-2011 vaccine was ascertained from vaccine registries or medical records. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, age, race, insurance status, enrollment site, and presence of a high-risk medical condition. RESULTS: A total of 1040 influenza-positive cases and 3717 influenza-negative controls were included from the influenza season, including 373 cases of influenza A(H1N1), 334 cases of influenza A(H3N2), and 333 cases of influenza B. Overall adjusted VE was 60% (95% confidence interval [CI], 53%-66%). Age-specific VE estimates ranged from 69% (95% CI, 56%-77%) in children aged 6 months-8 years to 38% (95% CI, -16% to 67%) in adults aged >=65 years. CONCLUSIONS: The US 2010-2011 influenza vaccines were moderately effective in preventing medically attended influenza during a season when all 3 vaccine strains were antigenically similar to circulating viruses. Continued monitoring of influenza vaccines in all age groups is important, particularly as new vaccines are introduced. PMID- 22843785 TI - Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5. AB - RATIONALE: Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I(Kur) current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress. OBJECTIVE: To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5. METHODS AND RESULTS: Labeling studies with the sulfenic acid specific probe DAz and horseradish peroxidase-streptavidin Western blotting demonstrated a global increase in sulfenic acid-modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress. CONCLUSIONS: Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases. PMID- 22843786 TI - RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium. AB - RATIONALE: Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in endothelial cell function by regulating angiogenesis; however, the mechanism underlying the role of RTEF-1 in the endothelium in vivo is not well defined. OBJECTIVE: We investigated the biological functions of RTEF-1 by disrupting the gene that encodes it in mice endothelium -specific RTEF-1 deficient transgenic mice (RTEF-1(-/-)). METHODS AND RESULTS: RTEF-1(-/-) mice showed significantly increased blood glucose levels and insulin resistance, accompanied by decreased levels of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA in the endothelium and decreased serum IGFBP-1 levels. Additionally, the RTEF-1(-/-) phenotype was exacerbated when the mice were fed a high-fat diet, which correlated with decreased IGFBP-1 levels. In contrast, vascular endothelial cadherin/RTEF-1-overexpressing(1) transgenic mice (VE Cad/RTEF1) demonstrated improved glucose clearance and insulin sensitivity in response to a high-fat diet. Furthermore, we demonstrated that RTEF-1 upregulates IGFBP-1 through selective binding and promotion of transcription from the insulin response element site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion. CONCLUSIONS: To the best of our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an insulin response element and also mediates the effects of insulin on gene expression. These results show that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to our understanding of the role of vascular endothelial cells in metabolism. PMID- 22843787 TI - Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: a report from the Pediatric Cardiomyopathy Registry. AB - BACKGROUND: Restrictive cardiomyopathy (RCM) has been associated with poor prognosis in childhood. The goal of the present analysis was to use the Pediatric Cardiomyopathy Registry to analyze outcomes of childhood RCM, with a focus on the impact of phenotype comparing pure RCM with cases that have additional features of hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: We analyzed the Pediatric Cardiomyopathy Registry database (1990-2008; N=3375) for cases of RCM. Cases were defined as pure when RCM was the only assigned diagnosis. Additional documentation of HCM at any time was used as the criterion for RCM/HCM phenotype. RCM accounted for 4.5% of cases of cardiomyopathy. In 101 (66%), pure RCM was diagnosed; in 51 (34%), there was a mixed phenotype. Age at diagnosis was not different between groups, but 10% of the pure RCM group was diagnosed in infancy versus 24% of the RCM/HCM group. Freedom from death was comparable between groups with 1-, 2-, and 5-year survival of RCM 82%, 80%, and 68% versus RCM/HCM 77%, 74%, and 68%. Transplant-free survival was 48%, 34%, and 22% and 65%, 53%, and 43%, respectively (P=0.011). Independent risk factors at diagnosis for lower transplant-free survival were heart failure (hazard ratio 2.20, P=0.005), lower fractional shortening z score (hazard ratio 1.12 per 1 SD decrease in z score, P=0.014), and higher posterior wall thickness in the RCM/HCM group only (hazard ratio 1.32, P<0.001). Overall, outcomes were worse than for all other forms of cardiomyopathy. CONCLUSIONS: Transplant-free survival is poor for RCM in childhood. Survival is independent of phenotype; however, the RCM/HCM phenotype has significantly better transplant-free survival. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00005391. PMID- 22843788 TI - Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer. AB - PURPOSE: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. EXPERIMENTAL DESIGN: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. RESULTS: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. CONCLUSIONS: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. PMID- 22843790 TI - Epigallocatechin-3-gallate diminishes cytokine-stimulated Cyr61 expression in human osteoblastic cells: a therapeutic potential for arthritis. AB - OBJECTIVE: To assess the effects of epigallocatechin-3-gallate (EGCG) on cytokine induced Cyr61 synthesis in human osteoblastic cells and the associated signalling pathways. The therapeutic effect of EGCG on CIA in rats was also studied. METHODS: The expression of Cyr61 and NF-kappaB pathway molecules was examined by western blotting. CCL2 expression was assessed by northern blotting and ELISA. Interaction between NF-kappaB and Cyr61 promoter was evaluated by electrophoretic mobility shift assay. In rat CIA, osteoblastic expression of Cyr61 was examined by immunohistochemistry and disease progression was assessed by clinical, radiographic and histological examinations. RESULTS: EGCG inhibited Cyr61 expression stimulated by cytokines in primary human osteoblasts and human osteoblastic cell line U2OS. In U2OS, oncostatin M (OSM) induced IkappaB-alpha degradation through the mTOR/rictor/Akt pathway, and EGCG attenuated the action. Electrophoretic mobility shift assay revealed that the OSM-enhanced NF-kappaB/DNA binding was reduced by EGCG, possibly through abrogating nucleus localization of p65 and p50. Cyr61 enhanced OSM-induced expression of CCL2. Moreover, EGCG diminished OSM-stimulated CCL2 expression at least partially via suppressing Cyr61 induction. Co-distribution of CD68(+) macrophages and Cyr61(+) osteoblasts in osteolytic areas was obvious in the CIA model. Clinical, radiographic and immunohistochemical analyses revealed that administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the number of Cyr61 synthesizing osteoblasts. CONCLUSION: By modulating the mTOR/rictor/Akt/NF-kappaB pathway, EGCG attenuated Cyr61 production in osteoblastic cells and in turn diminished macrophage chemotaxis. Our data support the therapeutic potential of EGCG on arthritis. PMID- 22843789 TI - A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. AB - PURPOSE: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity. EXPERIMENTAL DESIGN: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. RESULTS: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 * 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 * 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. CONCLUSIONS: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity. PMID- 22843792 TI - Total knee replacement: pursuit of the paramount result. PMID- 22843791 TI - Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis. AB - OBJECTIVES: Adalimumab, etanercept and infliximab are effective TNF inhibitors (TNFis) in the treatment of RA, but no randomized clinical trials have compared the three agents. Prior observational data are not consistent. We compared their effectiveness over 1 year in a prospective cohort. METHODS: Analyses were performed on subjects' first episode of TNFi use in the Rheumatic Diseases Portuguese Register, Reuma.pt. The primary outcome was the proportion of patients with European League Against Rheumatism good response sustained at two consecutive observations separated by 3 months during the first year of TNFi use. Comparisons were performed using conventional adjusted logistic regression, as well as matching subjects across the three agents using a propensity score. In addition, baseline predictors of treatment response to TNFi were identified. RESULTS: The study cohort included 617 RA patients, 250 starting etanercept, 206 infliximab and 161 adalimumab. Good response was achieved by 59.6% for adalimumab, 59.2% for etanercept and 51.9% for infliximab (P = 0.21). The modelled probability of good response did not significantly differ across agents (etanercept vs adalimumab OR = 0.97, 95% CI 0.55, 1.71; etanercept vs infliximab OR = 1.25, 95% CI 0.74, 2.12; infliximab vs adalimumab OR = 0.80, 95% CI 0.47, 1.36). Matched propensity score analyses also showed no significant treatment response differences. Greater educational attainment was a predictor of better response, while smoking, presence of ACPA, glucocorticoid use and worse physician assessment of disease activity at baseline each predicted a reduced likelihood of treatment response. CONCLUSION: Over 1 year, we found no difference in effectiveness between adalimumab, etanercept and infliximab. PMID- 22843793 TI - Secular trends in lung function and its relation to survival in Swedish 75 year olds 1976-2006. AB - BACKGROUND: several studies have found that lung function correlates with survival in older people. We examined secular trends in lung function and its relation to survival in Swedish 75 year olds. METHOD: representative samples from the general population in Gothenburg, Sweden, were examined at the age of 75 in 1976-77 (n = 743) and 2005-06 (n = 765) with comprehensive somatic and psychiatric examinations. Lung function was measured as peak expiratory flow (PEF). RESULTS: the mean PEF was higher in 75 year olds examined 2005-06 compared with those examined 1976-77 both among women (339 versus 307 l/min; P < 0.001) and men (490 versus 400 l/min, P < 0.001). The birth cohort effect was still significant after adjusting for a number of confounders. PEF correlated with survival between age 75 and 78 years among those examined in 1976-77 both in women (OR per 10 l/min increase in PEF = 1.112, 95% CI: 1.047-1.182) and in men (OR = 1.040, 95% CI: 1.015-1.066), but not in those examined 2005-06 (women: OR = 1.071, 95% CI: 0.965-1.188; men: OR = 1.000, 95% CI: 0.957-1.046). CONCLUSION: we found better lung function in the later-born cohort of 75 year olds, which was only partially explained by changes in smoking, height and weight, physical activity, socio-economic/educational factors and pulmonary/cardiovascular morbidity. The association between better lung function and short-term survival was strong in 1976-77, but had disappeared in 2005-06. More studies are needed to elucidate the role of lung function for long-term survival and identify other factors that explain the secular trends in lung function. PMID- 22843794 TI - Structure and activity of the acid-sensing ion channels. AB - The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviors including fear, anxiety, pain, depression, learning, and memory. ASICs have also been implicated in neuronal degeneration accompanying ischemia and multiple sclerosis. As a whole, ASICs represent novel therapeutic targets for several clinically important disorders. An understanding of the correlation between ASIC structure and function will help to elucidate their mechanism of action and identify potential therapeutics that specifically target these ion channels. Despite the seemingly simple nature of proton binding, multiple studies have shown that proton-dependent gating of ASICs is quite complex, leading to activation and desensitization through distinct structural components. This review will focus on the structural aspects of ASIC gating in response to both protons and the newly discovered activators GMQ and MitTx. ASIC modulatory compounds and their action on proton-dependent gating will also be discussed. This review is dedicated to the memory of Dale Benos, who made a substantial contribution to our understanding of ASIC activity. PMID- 22843796 TI - Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption. AB - The proton-coupled folate transporter (PCFT-SLC46A1) mediates intestinal folate absorption and folate transport across the choroid plexus, processes defective in hereditary folate malabsorption (HFM). This paper characterizes the functional defect, and the roles of two mutated PCFT residues, associated with HFM (G338R and A335D). The A335D-PCFT and other mutations at this residue result in an unstable protein; when expression of a mutant protein was preserved, function was always retained. The G338R and other charged mutants resulted in an unstable protein; substitutions with small neutral and polar amino acids preserved protein but with impaired function. Pemetrexed and methotrexate (MTX) influx kinetics mediated by the G338C mutant PCFT revealed marked (15- to 20-fold) decreases in K(t) and V(max) compared with wild-type PCFT. In contrast, there was only a small (~2-fold) decrease in the MTX influx K(i) and an increase (~3-fold) in the pemetrexed influx K(i) for the G338C-PCFT mutant. Neither a decrease in pH to 4.5, nor an increase to 7.4, restored function of the G338C mutant relative to wild-type PCFT excluding a role for this residue in proton binding or proton coupling. Homology modeling localized the A335 and G338 residues embedded in the 9th transmembrane, consistent with the inaccessibility of the A335C and G338C proteins to MTS reagents. Hence, the loss of intrinsic G338C-PCFT function was due solely to impaired oscillation of the carrier between its conformational states. The data illustrate how alterations in carrier cycling can impact influx K(t) without comparable alterations in substrate binding to the carrier. PMID- 22843795 TI - A network-oriented perspective on cardiac calcium signaling. AB - The normal contractile, electrical, and energetic function of the heart depends on the synchronization of biological oscillators and signal integrators that make up cellular signaling networks. In this review we interpret experimental data from molecular, cellular, and transgenic models of cardiac signaling behavior in the context of established concepts in cell network architecture and organization. Focusing on the cellular Ca(2+) handling machinery, we describe how the plasticity and adaptability of normal Ca(2+) signaling is dependent on dynamic network configurations that operate across a wide range of functional states. We consider how (mal)adaptive changes in signaling pathways restrict the dynamic range of the network such that it cannot respond appropriately to physiologic stimuli or perturbation. Based on these concepts, a model is proposed in which pathologic abnormalities in cardiac rhythm and contractility (e.g., arrhythmias and heart failure) arise as a consequence of progressive desynchronization and reduction in the dynamic range of the Ca(2+) signaling network. We discuss how a systems-level understanding of the network organization, cellular noise, and chaotic behavior may inform the design of new therapeutic modalities that prevent or reverse the disease-linked unraveling of the Ca(2+) signaling network. PMID- 22843798 TI - WHO/UNICEF's Baby-Friendly Initiative: the big picture. PMID- 22843799 TI - The importance of hands. PMID- 22843797 TI - Activation of Toll-like receptor 3 amplifies mesenchymal stem cell trophic factors and enhances therapeutic potency. AB - Clinical trials of bone marrow mesenchymal stem cell (MSC) therapy have thus far demonstrated moderate and inconsistent benefits, indicating an urgent need to improve therapeutic efficacy. Although administration of sufficient cells is necessary to achieve maximal therapeutic benefits, documented MSC clinical trials have largely relied on injections of ~1 * 10(6) cells/kg, which appears too low to elicit a robust therapeutic response according to published preclinical studies. However, repeated cell passaging necessary for large-scale expansion of MSC causes cellular senescence and reduces stem cell potency. Using the RNA mimetic polyinosinic-polycytidylic acid [poly(I:C)] to engage MSC Toll-like receptor 3 (TLR3), we found that poly(I:C), signaling through multiple mitogen activated protein kinase pathways, induced therapeutically relevant trophic factors such as interleukin-6-type cytokines, stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor while slightly inhibiting the proliferation and migration potentials of MSC. At the suboptimal injection dose of 1 * 10(6) cells/kg, poly(I:C)-treated MSC, but not untreated MSC, effectively stimulated regeneration of the failing hamster heart 1 mo after cell administration. The regenerating heart exhibited increased CD34(+)/Ki67(+) and CD34(+)/GATA4(+) progenitor cells in the presence of decreased inflammatory cells and cytokines. Cardiac functional improvement was associated with a ~50% reduction in fibrosis, a ~40% reduction in apoptosis, and a ~55% increase in angiogenesis, culminating in prominent cardiomyogenesis evidenced by abundant distribution of small myocytes and a ~90% increase in wall thickening. These functional, histological, and molecular characterizations thus establish the utility of TLR3 engagement for enabling the low-dose MSC therapy that may be translated to more efficacious clinical applications. PMID- 22843800 TI - Stealth formula marketing--coming soon to a city near you? PMID- 22843801 TI - International perspectives on the Baby-Friendly Initiative. PMID- 22843802 TI - Health professionals' insights regarding the Baby-Friendly Hospital Initiative. PMID- 22843803 TI - Compliance with Baby-Friendly policies and practices in hospitals and community health centers in Quebec. AB - BACKGROUND: Since 2001, Quebec's ministry of health and social services has prioritized implementation of the Baby-Friendly Initiative (BFI), which includes the original hospital initiative and its expansion to community services. OBJECTIVE: The objective was to document across the province compliance with the BFI's Ten Steps to Successful Breastfeeding in hospitals, Seven Point Plan in community health centers (CHCs), and International Code of Marketing of Breast Milk Substitutes (Code). METHODS: Using managers/staff, mothers, and observers, the author measured the extent of implementation of indicators formulated for each step/point and the Code, based on the revised WHO/UNICEF recommendations. RESULTS: Mean compliance scores in Quebec were 3.13 for 140 CHCs (range, 0 to 7) and 4.54 for 60 hospitals/birthing centers (range, 0 to 10). The mean compliance score for the Code was 0.69 for both CHCs and hospitals/birthing centers. The evaluation documented marked variations in implementation level for each of the steps/points and the Code. Also, managers/staff, mothers, and observers differed in their report of BFI compliance for most steps/points and the Code. Facilities that had applied for or obtained BFI designation demonstrated higher compliance with the BFI than those that had not. CONCLUSIONS: Results disseminated to participating organizations allowed comparisons on a regional/provincial perspective and in relation to BFI-designated facilities. Furthermore, this first portrait of BFI compliance in Quebec provided provincial, regional, and local health authorities with valuable information that can be used to bring about policy and organizational changes to achieve the international standards required for Baby-Friendly certification. PMID- 22843804 TI - Response to the article "Breastfeeding duration in relation to child care arrangement and participation in the special supplemental nutrition program for women, infants and children". PMID- 22843806 TI - What is happening with exclusive breastfeeding in Peru? PMID- 22843808 TI - What is a "baby-friendly hospital" and what does it mean to me? PMID- 22843810 TI - Changing day services: do you agree? AB - Models of day services for people with intellectual disabilities in Scotland are changing, with the purpose, content and availability being reviewed. There has been concern that a move to more flexible 'alternative day opportunities' is driven more by reduced budgets than a policy of modernising day services in response to individual needs. During a day services review, a questionnaire was used to rate and to collect views on existing services from 60 carers, service users and staff. This included evaluating day activities available, care plans, opening times, transport and the most valued aspects of existing day services. Respondents indicated general satisfaction with existing day services, although half believed that day services should be reviewed. The most valued parts of day services were forming and building friendships, and a safe place to go. Day services are highly valued by families and service users. Recommendations are made for a robust and transparent review process. PMID- 22843811 TI - Butch tops and femme bottoms? Sexual positioning, sexual decision making, and gender roles among young gay men. AB - Gender and power are theoretical constructs linked to discussions of sexual transmission of HIV/AIDS among heterosexual couples. Despite the fact that HIV rates are rising among young men who have sex with men in the United States, work examining the role of gender in sexual decision making of young men who have sex with men remains in its infancy. Through qualitative interviews with 34 young gay men (YGM), the authors seek to contribute to the literature in this area by focusing on the ways that YGM understand and enact sexual positions during anal sex. The authors' results highlight the diversity of YGM's sexual preferences, as well as the high degree of sexual fluidity. Ideas of gender appear to inform part of this process; however, YGM critiqued conventional gender norms and emphasized the centrality of relationships (i.e., casual vs. romantic) in their sexual decision making. The authors discuss the importance of considering gender and interpersonal factors when designing HIV/AIDS prevention messages for YGM. PMID- 22843812 TI - A man with abdominal pain: enough evidence for surgery? PMID- 22843813 TI - Commentary. PMID- 22843814 TI - Commentary. PMID- 22843816 TI - Colloquium on rethinking the future of scientific communication. PMID- 22843815 TI - A not so crystal-clear case. PMID- 22843817 TI - English translation of the dutch blood transfusion guideline 2011. PMID- 22843820 TI - Languages of art and languages of science. PMID- 22843822 TI - Clinical course of acute canine polyradiculoneuritis following treatment with human IV immunoglobulin. AB - Treatment of dogs with acute canine polyradiculoneuritis (ACP) is restricted to physical rehabilitation and supportive care. In humans with Guillain-Barre syndrome, the counterpart of ACP, randomized trials show that IV immunoglobulin (IVIg) speeds recovery. The authors of the current study hypothesized that dogs with ACP would tolerate IVIg well and recover faster than dogs managed with supportive treatment only. Sixteen client-owned dogs with ACP were treated with IVIg, and 14 client-owned dogs served as a retrospective control group. Diagnosis was confirmed using clinical features, electrodiagnostics, cerebrospinal fluid analysis, and muscle/nerve biopsies. The duration of the initial progressive phase, the time from IVIg administration until the dogs were ambulating without assistance, and the duration of the complete episode were evaluated. Adverse reactions (anaphylaxis, mild hematuria) were observed in two dogs. Dogs treated with IVIg were ambulating without assistance after a median of 27.5 days (range, 15-127 days) from onset of clinical signs. The control group was ambulatory without assistance at a median of 75.5 days (range, 5-220 days). Even though this result is not statistically significant, there is a clear trend toward faster recovery in dogs treated with IVIg. PMID- 22843821 TI - Studying signal transduction in single dendritic spines. AB - Many forms of synaptic plasticity are triggered by biochemical signaling that occurs in small postsynaptic compartments called dendritic spines, each of which typically houses the postsynaptic terminal associated with a single glutamatergic synapse. Recent advances in optical techniques allow investigators to monitor biochemical signaling in single dendritic spines and thus reveal the signaling mechanisms that link synaptic activity and the induction of synaptic plasticity. This is mostly in the study of Ca2+-dependent forms of synaptic plasticity for which many of the steps between Ca2+ influx and changes to the synapse are now known. This article introduces the new techniques used to investigate signaling in single dendritic spines and the neurobiological insights that they have produced. PMID- 22843823 TI - 49-month survival following caval venectomy without nephrectomy in a dog with a pheochromocytoma. AB - An 11 yr old spayed female Labrador retriever was diagnosed with a right adrenal tumor. At surgery, adhesions to the right kidney were dissected, allowing the right kidney to be preserved. The tumor showed extensive invasion into the suprarenal vena cava. It was felt that thrombus removal via venotomy could not be performed. Instead, the vena cava was ligated caudal to the liver and cranial to the right renal vein. The neoplastic gland was then excised en bloc together with the portion of the invaded caudal vena cava. Hind limb edema had developed preoperatively and increased transiently in the first days postoperatively. The animal was discharged 6 days postoperatively with no other clinical disorders, and hind limb edema resolved over time. Histopathology identified a pheochromocytoma. The dog died 49 mo later. A neoplastic thrombus of the vena cava may require venotomy to allow thrombus removal. Occasionally, removal of the thrombus by venotomy may prove impossible. In such a situation, en bloc removal of the concerned portion of the vena cava may be performed with a good long-term outcome provided that gradual occlusion of the vena cava by the thrombus has allowed time for collateral circulation to develop. PMID- 22843824 TI - L-2-hydroxyglutaric aciduria in two female Yorkshire terriers. AB - Two female Yorkshire terrier puppies were presented with generalized tonic-clonic seizures and ataxia. MRI revealed bilaterally symmetrical, diffuse regions of gray matter hyperintensity on T2-weighted and fluid-attenuated inversion recovery sequences. Urinary organic acids were quantified by gas chromatography-mass spectroscopy and were consistent with a diagnosis of L-2-hydroxyglutaric aciduria (L2HGA). The L2HGDH gene encodes for the enzyme L-2-hydroxyglutarate dehydrogenase, which helps break down L-2-hydroxyglutaric acid. In both puppies described in this report, a homozygous mutation at the translation initiation codon of the homolog canine L2HGDH gene was detected (c.1A>G; p.Met1?), confirming the diagnosis of L2HGA at the DNA level. Canine L2HGA is caused by more than one mutation of L2HGDH, as reported in humans. PMID- 22843825 TI - Bilateral segmental aplasia with unilateral uterine horn torsion in a Pomeranian bitch. AB - Bilateral segmental aplasia of the uterine horns with unilateral pyometra and uterine horn torsion were diagnosed in a Pomeranian bitch that presented with chronic abdominal distension and an acute onset of anorexia and lethargy. Because radiographic and ultrasonographic findings revealed the presence of markedly enlarged bilateral uterine horns filled with fluid in the caudal abdomen, a tentative diagnosis of either pyometra or hydrometra with uterine horn torsion was made. Exploratory laparotomy showed bilateral, segmentally distended uterine horns with unilateral uterine horn torsion. Ovariohysterectomy was performed, and bilateral segmental aplasia of the uterine horns with the development of unilateral uterine horn torsion was diagnosed histopathologically. To the authors' knowledge, this is the first report of uterine horn torsion in conjunction with segmental aplasia of the uterine horn in a bitch. PMID- 22843826 TI - MRI findings of a middle ear cholesteatoma in a dog. AB - This article describes the MRI features of a middle ear cholesteatoma in an 8 yr old flat-coated retriever. Physical examination revealed pain on opening the jaw, and otoscopic examination showed tympanic membrane rupture associated with hyperplastic tissue at the entrance of the middle ear. Standard MRI sequences allowed for the identification of a severely expanded bulla containing material that was isointense to brain tissue on T1-weighted images and of mixed intensity on T2-weighted and fluid-attenuated inversion recovery sequences. No postcontrast enhancement of the content was present, but the lining of the bulla was partially enhanced. The images allowed evaluation of the surgical margins and the secondary changes due to the expansion of the mass. Surgery was performed and histopathology confirmed the presumptive diagnosis of cholesteatoma. In the present case, MRI appeared to serve as a good alternative to computed tomography for the diagnosis of cholesteatoma. PMID- 22843827 TI - Comparison of epidural and systemic tramadol for analgesia following ovariohysterectomy. AB - The objective of the study was to compare epidural and systemic tramadol for postoperative analgesia in bitches undergoing ovariohysterectomy. Twenty animals, randomly divided into two groups, received either epidural (EPI) or intramuscular (IM) tramadol (2 mg/kg) 30 min before anesthetic induction. Analgesia, sedation, cardiorespiratory parameters, end-tidal isoflurane, blood catecholamines and cortisol, and arterial blood gases were measured at different time points up to 24 hr after agent administration. There were no differences between the two groups regarding cardiorespiratory parameters, end-tidal isoflurane, and pain scores. Two dogs in the IM and one in the EPI group required supplemental analgesia. Cortisol was increased (P<0.05) at 120 min (3.59 MUg/dL and 3.27 MUg/dL in the IM and EPI groups, respectively) and 240 min (2.45 MUg/dL and 2.54 MUg/dL in the IM and EPI groups, respectively) compared to baseline. Norepinephrine was also increased (P<0.05) at 120 min in both groups compared to baseline values. Epinephrine values were higher (P<0.05) in the IM group compared with the EPI group at 50 min, 120 min, and 1,440 min after tramadol administration. Epidural tramadol is a safe analgesic, but does not appear to have improved analgesic effects compared with IM administration. PMID- 22843828 TI - Clinical and MRI findings in three dogs with polycystic meningiomas. AB - One spayed female Labrador retriever and two castrated male golden retrievers were evaluated for chronic (i.e., ranging from 3 wk to 24 wk) neurologic signs localizable to the prosencephalon. Signs included seizures, circling, and behavior changes. MRI demonstrated extra-axial, contrast-enhancing, multiloculated, fluid-filled, cyst-like lesions with a mass effect, causing compression and displacement of brain parenchyma. Differential diagnoses included cystic neoplasm, abscess or other infectious cyst (e.g., alveolar hydatid cyst), or fluid-filled anomaly (e.g., arachnoid cyst). The cyst-like lesions were attached to the rostral falx cerebri in all cases. In addition, case 2 had a second polycystic mass at the caudal diencephalon. Surgical biopsy (case 3 with a single, rostral tumor via transfrontal craniectomy) and postmortem histology (in cases 1 and 2) confirmed polycystic meningiomas. Tumor types were transitional (cases 1 and 3) and fibrous (case 2), with positive immunohistochemical staining for vimentin. Case 3 was also positive for E-cadherin, s100, and CD34. In all cases, staining was predominantly negative for glial fibrillary acid protein and pancytokeratins, supporting a diagnosis of meningioma. This report describes the first cases of polycystic meningiomas in dogs. Polycystic meningiomas are a rare, but important, addition to the differential diagnoses for intracranial cyst-like lesions, significantly affecting planning for surgical resection and other therapeutic interventions. PMID- 22843829 TI - Understanding and evaluating veterinary clinical research. AB - Results from investigations conducted in clinical settings contribute greatly to determining how veterinarians practice medicine. It is important for the practitioner to understand how clinical information is collected, analyzed, and communicated in journals and presentations at conferences. Clinical research is either retrospective in observational studies, looking at historical medical records as the source of data, or prospective in both experimental and observational studies, where the study is designed before any patients are included. Prospective, experimental studies provide the more reliable results, although they form a minority of published reports. Randomized, controlled trials are the most reliable format, and attempts should be made to use this design more often in veterinary medicine. Care must be taken in the conduct of clinical research to reduce sources of bias that can yield false findings, particularly in small, retrospective studies. Statistical analysis is the key to data interpretation, but must be applied appropriately to avoid either wrong assumptions or misconception. Regardless of how studies are conducted, it is important for the practitioner to be an astute reader of the clinical literature. An understanding of clinical research methods will result in better medical standard of care recommendations and practice. PMID- 22843830 TI - MRI of a split cord malformation in a German shepherd dog. AB - A 9 yr old spayed female German shepherd dog was referred for MRI of the thoracic and lumbar spine because she had clinical signs of chronic neurogenic bladder dysfunction of an unknown cause. Transverse T2-weighted images identified a type II split cord malformation (i.e., diastematomyelia) in the thoracic spine. Split cord malformations are forms of spinal dysraphism where the abnormal development of spinal cord results in sagittal splitting of a portion of the cord into two hemicords. The location of the lesion in the thoracic spine was consistent with the dog's clinical signs of an upper motor neuron bladder. Split cord malformations that occur in humans have similar MRI characteristics and can result in similar clinical signs as those identified in the dog described in this report. PMID- 22843831 TI - Gliomatosis cerebri in two dogs. AB - A 3.5 yr old Saint Bernard was evaluated for nonambulatory tetraparesis and cranial nerve dysfunction, and a 7 yr old rottweiler was evaluated for progressive paraparesis. Clinical signs of left-sided vestibular and general proprioceptive ataxia and cranial nerve VII dysfunction in the Saint Bernard suggested a lesion affecting the brain stem. Signs in the rottweiler consisted of general proprioceptive/upper motor neuron paraparesis, suggesting a lesion involving the third thoracic (T3) to third lumbar (L3) spinal cord segments. MRI was normal in the Saint Bernard, but an intra-axial lesion involving the T13-L2 spinal cord segments was observed in the rottweiler. In both dogs, the central nervous system (CNS) contained neoplastic cells with features consistent with gliomatosis cerebri (GC). In the Saint Bernard, neoplastic cells were present in the medulla oblongata and cranial cervical spinal cord. In the rottweiler, neoplastic cells were only present in the spinal cord. Immunohistochemistry disclosed two distinct patterns of CD18, nestin, and vimentin staining. GC is a rarely reported tumor of the CNS. Although GC typically involves the cerebrum, clinical signs in these two dogs reflected caudal brainstem and spinal cord involvement. PMID- 22843832 TI - Corynebacterium spp. in dogs and cats with otitis externa and/or media: a retrospective study. AB - The role of Corynebacterium spp. in the pathogenesis of canine and feline otitis externa/media and their appropriate antimicrobial therapy are unclear. The objectives of this study were to (1) better establish the pathogenicity of Corynebacterium spp. in otitis utilizing reported criteria and by assessing clinical response to antibiotic therapy and (2) to determine the antimicrobial susceptibility patterns of Corynebacterium spp. associated with otitis. The study was retrospective, targeting cultures positive for Corynebacterium spp. Corynebacterium spp. were part of mixed microbial populations in 79/81 cultures. Corynebacterium spp. pathogenicity was highly questionable because of their almost invariable presence with other microbes and the observation that Corynebacterium spp. usually disappear from the ear with resolution of other infections, even when the Corynebacterium spp. are resistant to the prescribed antibiotic(s). However, 2/81 cultures came from two canine ears wherein Corynebacterium spp. may have been pathogenic. Antimicrobial sensitivities for Corynebacterium spp. were available for 54 isolates. Most isolates were susceptible to chloramphenicol (53/54), amikacin (50/54), tetracycline (50/54), gentamicin (46/54), and enrofloxacin (32/54). Among those antibiotics available in otic products, gentamicin and enrofloxacin would be rational choices for the empirical, topical therapy of Corynebacterium spp. PMID- 22843833 TI - Emergence and spread of B2-ST131-O25b, B2-ST131-O16 and D-ST405 clonal groups among extended-spectrum-beta-lactamase-producing Escherichia coli in Japan. AB - OBJECTIVES: The increasing prevalence of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli has been associated with the emergence of the CTX-M producing sequence type 131 (ST131) pandemic clonal group, a member of the O25b serogroup and the B2 phylogenetic group. To assess the clonal spread of ESBL producing E. coli in Japan, a regional surveillance programme was conducted. METHODS: A total of 581 ESBL-producing clinical specimen E. coli isolates were collected between 2001 and 2010. Clonal groups, including ST131, D-ST405, D-ST393 and D-ST69, were determined using the PCR O type, phylogenetic grouping by triplex PCR, allele-specific PCR and multilocus sequence typing (MLST). A subset of clonal groups underwent PFGE. RESULTS: Among clonal strains, 215 isolates (37%) were identified as belonging to the ST131 group, 185 as B2-ST131-O25b (32%), 26 as B2-ST131-O16 (4%), 3 as B1-ST131-O25b (0.5%) and 1 as B2-ST131-O-non typeable (0.1%). Forty-one isolates (7%) were identified as belonging to the D ST405 clonal group, seven (1%) as D-ST69 and two (0.3%) as D-ST393. The B2-ST131 O16 clonal group was characterized by CTX-M-14 and a significantly lower ciprofloxacin resistance rate than the B2-ST131-O25b clonal group. The B2-ST131 O16 and B2-ST131-O25b clonal groups each made up a single PFGE cluster, with 65% similarity. The rate of ESBL-producing E. coli increased over the years (0.2% in 2001 to 9.7% in 2010) and corresponded to increases in the numbers of the B2 ST131-O25b, B2-ST131-O16 and D-ST405 clonal groups. CONCLUSIONS: The B2-ST131 O25b, B2-ST131-O16 and D-ST405 clonal groups have contributed to the spread of ESBL-producing E. coli in Japan. PMID- 22843834 TI - In vitro evaluation of tobramycin and aztreonam versus Pseudomonas aeruginosa biofilms on cystic fibrosis-derived human airway epithelial cells. AB - OBJECTIVES: Aztreonam for inhalation solution (AZLI) was recently approved by the FDA for treating cystic fibrosis (CF) patients infected with Pseudomonas aeruginosa. Here we investigated the effect of aztreonam alone or in combination with tobramycin on P. aeruginosa biofilms grown on CF airway epithelial cells. METHODS: P. aeruginosa biofilms, produced by laboratory strains or clinical isolates, were formed on confluent CF airway cells before treatment overnight with aztreonam or tobramycin alone or in combination. Alternatively, antibiotics were added 1 h after bacterial inoculation to assess their ability to impair biofilm formation at 5 h. Bacterial cfu remaining after treatment were then determined by plate counting. RESULTS: In the absence of antibiotics, all strains developed biofilms that disrupted CF airway epithelial monolayers overnight. Tobramycin reduced the cfu of all strains grown as biofilms. Aztreonam reduced the cfu of some strains by ~1 log unit without preserving the integrity of cystic fibrosis airway cell monolayers, while decreasing the biofilms of other clinical isolates by ~4 log units and protecting the monolayers from being compromised. The combination of aztreonam and tobramycin reduced the cfu of two strains by an additional 0.5 and 2 log units, respectively. Of all the mechanisms explored, Psl exopolysaccharide production might explain the variations in biofilm tolerance to aztreonam in some of the strains. CONCLUSIONS: Effects of aztreonam on P. aeruginosa biofilms in the in vitro co-culture model are strain-dependent. The simultaneous application of aztreonam and tobramycin may be beneficial for a subset of CF patients by eliminating susceptible P. aeruginosa strains. PMID- 22843835 TI - The Lourdes medical cures revisited. AB - This article examines the cures recorded in Lourdes, France, between 1858, the year of the Visions, and 1976, the date of the last certified cure of the twentieth century. Initially, the records of cures were crude or nonexistent, and allegations of cures were accepted without question. A Medical Bureau was established in 1883 to examine and certify the cures, and the medical methodology improved steadily in the subsequent years. We discuss the clinical criteria of the cures and the reliability of medical records. Some 1,200 cures were said to have been observed between 1858 and 1889, and about one hundred more each year during the "Golden Age" of Lourdes, 1890-1914. We studied 411 patients cured in 1909-14 and thoroughly reviewed the twenty-five cures acknowledged between 1947 and 1976. No cure has been certified from 1976 through 2006. The Lourdes phenomenon, extraordinary in many respects, still awaits scientific explanation. Lourdes concerns science as well as religion. PMID- 22843836 TI - Contrast-enhanced peripheral MRA: technique and contrast agents. AB - In the last decade contrast-enhanced magnetic resonance angiography (CE-MRA) has gained wide acceptance as a valuable tool in the diagnostic work-up of patients with peripheral arterial disease. This review presents current concepts in peripheral CE-MRA with emphasis on MRI technique and contrast agents. Peripheral CE-MRA is defined as an MR angiogram of the arteries from the aortic bifurcation to the feet. Advantages of CE-MRA include minimal invasiveness and lack of ionizing radiation. The basic technique employed for peripheral CE-MRA is the bolus-chase method. With this method a paramagnetic MRI contrast agent is injected intravenously and T1-weighted images are acquired in the subsequent arterial first-pass phase. In order to achieve high quality MR angiograms without interfering venous contamination or artifacts, a number of factors need to be taken into account. This includes magnetic field strength of the MRI system, receiver coil configuration, use of parallel imaging, contrast bolus timing technique, and k-space filling strategies. Furthermore, it is possible to optimize peripheral CE-MRA using venous compression techniques, hybrid scan protocols, time-resolved imaging, and steady-state MRA. Gadolinium(Gd)-based contrast agents are used for CE-MRA of the peripheral arteries. Extracellular Gd agents have a pharmacokinetic profile similar to iodinated contrast media. Accordingly, these agents are employed for first-pass MRA. Blood-pool Gd-based agents are characterized by prolonged intravascular stay, due to macromolecular structure or protein binding. These agents can be used for first-pass, as well as steady-state MRA. Some Gd-based contrast agents with low thermodynamic stability have been linked to development of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Using optimized technique and a stable MRI contrast agent, peripheral CE-MRA is a safe procedure with diagnostic accuracy close to that of conventional catheter X-ray angiography. PMID- 22843837 TI - Accuracy of MR findings in characterizing peroneal tendons disorders in comparison with surgery. AB - BACKGROUND: Previous studies have shown that magnetic resonance imaging (MRI) has a high sensitivity for peroneal tendon pathology but more studies with surgery as a reference standard are needed. PURPOSE: To evaluate the accuracy of MRI compared to surgery for characterizing chronic peroneal tendon pathology. MATERIAL AND METHODS: Ninety-seven patients (57 men, 40 women; mean age, 39 years; range, 15-64 years) with chronic lateral ankle instability underwent MRI followed by surgery, with a mean MR to surgery interval of 30 days. Sagittal, coronal, and axial T1-weighted spin-echo and fat-suppressed T2-weighted fast spin echo images were obtained for all patients. Two blinded observers evaluated the MR images without clinical information, and the results were compared to surgical findings. The following peroneal injuries were observed: tendon split, interstitial tear, swelling of the tendon, fluid collection, superior peroneal retinaculum injury, and tendon dislocation. RESULTS: Swelling of the peroneus longus tendon was the most common finding on MR imaging, followed by fluid collection and a split of the peroneus brevis tendon. Surgical findings showed that nine cases (9%) of interstitial tears were in the peroneus brevis and two cases (2%) were in the peroneus longus, with eight cases (8%) of splits in the peroneus brevis tendon. The sensitivity and specificity for detecting interstitial tears in the peroneus brevis were 44% and 99%, respectively. The sensitivity and specificity for detecting swelling in the peroneus brevis were 50% and 99%, respectively. The sensitivity and specificity for detecting interstitial tears for peroneus longus injuries were 50% and 96%, respectively. The sensitivity and specificity for detecting swelling in these injuries were and 100% and 96%, respectively. CONCLUSION: MRI findings of chronic peroneal tendon pathology are diagnostically specific but not sensitive. MRI showed high sensitivity for diagnosing tendon swelling in the peroneus longus, but not in the peroneus brevis. MRI is sensitive but not specific for detecting negative findings. PMID- 22843838 TI - Sclerosing angiomatoid nodular transformation of the spleen: clinical and radiologic characteristics. AB - BACKGROUND: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign primary vascular lesion of the spleen. Although there have been many reports about the pathology of SANTs of the spleen, there have been no comprehensive descriptions of the imaging findings of SANTs of the spleen. PURPOSE: To determine the clinical characteristics and imaging findings of SANTs of the spleen. MATERIAL AND METHODS: We retrospectively evaluated seven patients with pathologically confirmed SANT, who underwent CT (n = 7), MRI (n = 4), ultrasonography (n = 4), and PET/CT (n = 3). Follow-up CT examinations were obtained in five patients. Clinical characteristics such as symptoms and concurrent disease were assessed. CT and MRI findings were evaluated by two radiologists, including the number, border, signal intensity, enhancement pattern, hemorrhage, and cystic change or necrosis. The longest diameter of each tumor was measured on CT. Echogenicity on ultrasonography and standardized uptake value on PET/CT were also evaluated. RESULTS: No specific symptom was associated with SANT. Two patients had a history of malignancy, one with cervical cancer and the other with early gastric cancer. Tumor growth was observed in four of five patients. On CT, all seven SANTs appeared as single, well-demarcated masses. CT showed a heterogeneous enhancement in seven patients. MRI showed centripetal progressive enhancement and absence of cystic change or necrosis in four patients, with three of these patients showing evidence of old hemorrhage. Ultrasonography showed heterogeneous hypoechoic mass in four patients. PET/CT showed increased standardized uptake value, ranging from 2.0 to 2.8, in three patients. CONCLUSION: SANT of the spleen is a single, well-demarcated solid mass without cystic change or necrosis. Increased FDG activity and tumor growth on follow-up imaging are common. PMID- 22843839 TI - Pulmonary artery and right ventricle assessment in pulmonary hypertension: correlation between functional parameters of ECG-gated CT and right-side heart catheterization. AB - BACKGROUND: Right ventricular function predicts outcome in patients with pulmonary hypertension (PH). Therefore accurate assessment of right ventricular function is essential to graduate severity, assess follow-up, and response to therapy. PURPOSE: To evaluate whether PH severity could be assessed using electrocardiography-gated CT (ECG-gated CT) functional parameters. A further objective was to evaluate cardiac output (CO) using two ECG-gated CT methods: the reference Simpson technique and the fully automatic technique generated by commercially available cardiac software. MATERIAL AND METHODS: Our institutional review board approved this study; patient consent was not required. Twenty-seven patients who had undergone ECG-gated CT and right heart catheterization (RHC) were included. Two independent observers measured pulmonary artery (PA) diameter, PA distensibility, aorta diameter, right ventricular cardiac output (CT-RVCO) and right ventricular ejection fraction (CT-RVEF) with automatic and Simpson techniques on ECG-gated CT. RHC-CO and mean pulmonary arterial pressure (mPAP) were measured on RHC. Relationship between ECG-gated CT and RHC measurements was tested with linear regression analysis. RESULTS: Inter-observer agreement was good for all measurements (r > 0.7) except for CT-RVCO calculated with Simpson's technique (r = 0.63). Pulmonary artery (PA) distensibility was significantly correlated to mPAP (r = -0.426, P = 0.027). CT-RVEF was correlated with mPAP only when issued from Simpson technique (r = -0.417, P = 0.034). CT-RVEF was not significantly correlated to RHC-CO (P > 0.2). CT-RVCO measured with Simpson technique (r = 0.487, P = 0.010) and automatic segmentation (r = 0.549, P = 0.005) correlated equally with RHC-CO. CONCLUSION: CT-RVEF and CT-RVCO measured on ECG-gated CT are significantly correlated, respectively, to mPAP and RHC-CO in this population with severe reduction of the right ventricular ejection fraction and could be useful for evaluating and following patients with PH. PMID- 22843840 TI - Membrane disruption by antimicrobial fatty acids releases low-molecular-weight proteins from Staphylococcus aureus. AB - The skin represents an important barrier for pathogens and is known to produce fatty acids that are toxic toward gram-positive bacteria. A screen of fatty acids as growth inhibitors of Staphylococcus aureus revealed structure-specific antibacterial activity. Fatty acids like oleate (18:1Delta9) were nontoxic, whereas palmitoleate (16:1Delta9) was a potent growth inhibitor. Cells treated with 16:1Delta9 exhibited rapid membrane depolarization, the disruption of all major branches of macromolecular synthesis, and the release of solutes and low molecular-weight proteins into the medium. Other cytotoxic lipids, such as glycerol ethers, sphingosine, and acyl-amines blocked growth by the same mechanisms. Nontoxic 18:1Delta9 was used for phospholipid synthesis, whereas toxic 16:1Delta9 was not and required elongation to 18:1Delta11 prior to incorporation. However, blocking fatty acid metabolism using inhibitors to prevent acyl-acyl carrier protein formation or glycerol-phosphate acyltransferase activity did not increase the toxicity of 18:1Delta9, indicating that inefficient metabolism did not play a determinant role in fatty acid toxicity. Nontoxic 18:1Delta9 was as toxic as 16:1Delta9 in a strain lacking wall teichoic acids and led to growth arrest and enhanced release of intracellular contents. Thus, wall teichoic acids contribute to the structure-specific antimicrobial effects of unsaturated fatty acids. The ability of poorly metabolized 16:1 isomers to penetrate the cell wall defenses is a weakness that has been exploited by the innate immune system to combat S. aureus. PMID- 22843841 TI - Fatty acids regulate stress resistance and virulence factor production for Listeria monocytogenes. AB - Fatty acids (FAs) are the major structural component of cellular membranes, which provide a physical and chemical barrier that insulates intracellular reactions from environmental fluctuations. The native composition of membrane FAs establishes the topological and chemical parameters for membrane-associated functions and is therefore modulated diligently by microorganisms especially in response to environmental stresses. However, the consequences of altered FA composition during host-pathogen interactions are poorly understood. The food borne pathogen Listeria monocytogenes contains mostly saturated branched-chain FAs (BCFAs), which support growth at low pH and low temperature. In this study, we show that anteiso-BCFAs enhance bacterial resistance against phagosomal killing in macrophages. Specifically, BCFAs protect against antimicrobial peptides and peptidoglycan hydrolases, two classes of phagosome antimicrobial defense mechanisms. In addition, the production of the critical virulence factor, listeriolysin O, was compromised by FA modulation, suggesting that FAs play a key role in virulence regulation. In summary, our results emphasize the significance of FA metabolism, not only in bacterial virulence regulation but also in membrane barrier function by providing resistance against host antimicrobial stress. PMID- 22843842 TI - Involvement of the global regulator H-NS in the survival of Escherichia coli in stationary phase. AB - Long-term batch cultures of Escherichia coli grown in nutrient-rich medium accumulate mutations that provide a growth advantage in the stationary phase (GASP). We have examined the survivors of prolonged stationary phase to identify loci involved in conferring a growth advantage and show that a mutation in the hns gene causing reduced activity of the global regulator H-NS confers a GASP phenotype under specific conditions. The hns-66 allele bears a point mutation within the termination codon of the H-NS open reading frame, resulting in a longer protein that is partially functional. Although isolated from a long-term stationary-phase culture of the parent carrying the rpoS819 allele that results in reduced RpoS activity, the hns-66 survivor showed a growth disadvantage in the early stationary phase (24 to 48 h) when competed against the parent. The hns-66 mutant is also unstable and reverts at a high frequency in the early stationary phase by accumulating second-site suppressor mutations within the ssrA gene involved in targeting aberrant proteins for proteolysis. The mutant was more stable and showed a moderate growth advantage in combination with the rpoS819 allele when competed against a 21-day-old parent. These studies show that H-NS is a target for mutations conferring fitness gain that depends on the genetic background as well as on the stage of the stationary phase. PMID- 22843843 TI - The histidine kinase PdhS controls cell cycle progression of the pathogenic alphaproteobacterium Brucella abortus. AB - Bacterial differentiation is often associated with the asymmetric localization of regulatory proteins, such as histidine kinases. PdhS is an essential and polarly localized histidine kinase in the pathogenic alphaproteobacterium Brucella abortus. After cell division, PdhS is asymmetrically segregated between the two sibling cells, highlighting a differentiation event. However, the function(s) of PdhS in the B. abortus cell cycle remains unknown. We used an original approach, the pentapeptide scanning mutagenesis method, to generate a thermosensitive allele of pdhS. We report that a B. abortus strain carrying this pdhS allele displays growth arrest and an altered DivK-yellow fluorescent protein (YFP) polar localization at the restrictive temperature. Moreover, the production of a nonphosphorylatable PdhS protein or truncated PdhS proteins leads to dominant negative effects by generating morphological defects consistent with the inhibition of cell division. In addition, we have used a domain mapping approach combined with yeast two-hybrid and fluorescence microscopy methods to better characterize the unusual PdhS sensory domain. We have identified a fragment of the PdhS sensory domain required for protein-protein interaction (amino acids [aa] 210 to 434), a fragment sufficient for polar localization (aa 1 to 434), and a fragment (aa 527 to 661) whose production in B. abortus correlates with the generation of cell shape alterations. The data support a model in which PdhS acts as an essential regulator of cell cycle progression in B. abortus and contribute to a better understanding of the differentiation program inherited by the two sibling cells. PMID- 22843844 TI - Epoxide-mediated CifR repression of cif gene expression utilizes two binding sites in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR). This virulence factor, named CFTR inhibitory factor (Cif), is regulated by a TetR-family, epoxide-responsive repressor known as CifR via direct binding and repression. We identified two sites of CifR binding in the intergenic space between cifR and morB, the first gene in the operon containing the cif gene. We have mapped these binding sites and found they are 27 bp in length, and they overlap the -10 and +1 sites of both the cifR and morB regulatory region and the start of transcription, respectively. In addition, we found that CifR binds to each repression site with differing affinity. Mutagenesis of these binding sites resulted in a loss of DNA binding in vitro, and mutation of one of these sites in vivo resulted in an increase in transcription of both the cif and cifR genes. We characterized cif and cifR gene expression in sputum and found that, whereas cif gene expression varied relative to an in vitro coculture control, cifR gene expression was consistently higher. Analysis of a longitudinal sample of CF isolates from nine patients revealed that Cif protein was expressed over time, although variably, and these changes could not be linked to mutations in the cifR gene or the promoters of these genes. Finally, we tested CifR responsiveness to other epoxides and showed that CifR can respond to multiple epoxides to various degrees. PMID- 22843845 TI - Novel rapidly diversifiable antimicrobial RNA polymerase switch region inhibitors with confirmed mode of action in Haemophilus influenzae. AB - A series of inhibitors with a squaramide core was synthesized following its discovery in a high-throughput screen for novel inhibitors of a transcription coupled translation assay using Escherichia coli S30 extracts. The inhibitors were inactive when the plasmid substrate was replaced with mRNA, suggesting they interfered with transcription. This was confirmed by their inhibition of purified E. coli RNA polymerase. The series had antimicrobial activity against efflux negative strains of E. coli and Haemophilus influenzae. Like rifampin, the squaramides preferentially inhibited synthesis of RNA and protein over fatty acids, peptidoglycan, and DNA. However, squaramide-resistant mutants were not cross-resistant to rifampin. Nine different mutations were found in parts of rpoB or rpoC that together encode the so-called switch region of RNA polymerase. This is the binding site of the natural antibiotics myxopyronin, corallopyronin, and ripostatin and the drug fidaxomicin. Computational modeling using the X-ray crystal structure of the myxopyronin-bound RNA polymerase of Thermus thermophilus suggests a binding mode of these inhibitors that is consistent with the resistance mutations. The squaramides are the first reported non-natural-product related, rapidly diversifiable antibacterial inhibitors acting via the switch region of RNA polymerase. PMID- 22843846 TI - Activity of the osmotically regulated yqiHIK promoter from Bacillus subtilis is controlled at a distance. AB - The yqiHIK gene cluster from Bacillus subtilis is predicted to encode an extracellular lipoprotein (YqiH), a secreted N-acetylmuramoyl-L-alanine amidase (YqiI), and a cytoplasmic glycerophosphodiester phosphodiesterase (YqiK). Reverse transcriptase PCR (RT-PCR) analysis showed that the yqiHIK genes are transcribed as an operon. Consistent with the in silico prediction, we found that the purified YqiI protein exhibited hydrolytic activity toward peptidoglycan sacculi. Transcription studies with yqiH-treA reporter fusion strains revealed that the expression of yqiHIK is subjected to finely tuned osmotic control, but enhanced expression occurs only in severely osmotically stressed cells. Primer extension analysis pinpointed the osmotically responsive yqiHIK promoter, and site-directed mutagenesis was employed to assess functionally important sequences required for promoter activity and osmotic control. Promoter variants with constitutive activity were isolated. A deletion analysis of the yqiHIK regulatory region showed that a 53-bp AT-rich DNA segment positioned 180 bp upstream of the -35 sequence is critical for the activity and osmotic regulation of the yqiHIK promoter. Hence, the expression of yqiHIK is subjected to genetic control at a distance. Upon the onset of growth of cells of the B. subtilis wild-type strain in high-salinity medium (1.2 M NaCl), we observed gross morphological deformations of cells that were then reversed to a rod-shaped morphology again when the cells had adjusted to the high-salinity environment. The products of the yqiHIK gene cluster were not critical for reestablishing rod-shaped morphology, but the deletion of this operon yielded a B. subtilis mutant impaired in growth in a defined minimal medium and at high salinity. PMID- 22843847 TI - Functional characterization of the role of the chromosome I partitioning system in genome segregation in Deinococcus radiodurans. AB - Deinococcus radiodurans, a radiation-resistant bacterium, harbors a multipartite genome. Chromosome I contains three putative centromeres (segS1, segS2, and segS3), and ParA (ParA1) and ParB (ParB1) homologues. The ParB1 interaction with segS was sequence specific, and ParA1 was shown to be a DNA binding ATPase. The ATPase activity of ParA1 was stimulated when segS elements were coincubated with ParB1, but the greatest increase was observed with segS3. ParA1 incubated with the segS-ParB1 complex showed increased light scattering in the absence of ATP. In the presence of ATP, this increase was continued with segS1-ParA1B1 and segS2 ParA1B1 complexes, while it decreased rapidly after an initial increase for 30 min in the case of segS3. D. radiodurans cells expressing green fluorescent protein (GFP)-ParB1 produced foci on nucleoids, and the DeltaparB1 mutant showed growth retardation and ~13%-higher anucleation than the wild type. Unstable mini F plasmids carrying segS1 and segS2 showed inheritance in Escherichia coli without ParA1B1, while segS3-mediated plasmid stability required the in trans expression of ParA1B1. Unlike untransformed E. coli cells, cells harboring pDAGS3, a plasmid carrying segS3 and also expressing ParB1-GFP, produced discrete GFP foci on nucleoids. These findings suggested that both segS elements and the ParA1B1 proteins of D. radiodurans are functionally active and have a role in genome segregation. PMID- 22843848 TI - Factors limiting SOS expression in log-phase cells of Escherichia coli. AB - In Escherichia coli, RecA-single-stranded DNA (RecA-ssDNA) filaments catalyze DNA repair, recombination, and induction of the SOS response. It has been shown that, while many (15 to 25%) log-phase cells have RecA filaments, few (about 1%) are induced for SOS. It is hypothesized that RecA's ability to induce SOS expression in log-phase cells is repressed because of the potentially detrimental effects of SOS mutagenesis. To test this, mutations were sought to produce a population where the number of cells with SOS expression more closely equaled the number of RecA filaments. Here, it is shown that deleting radA (important for resolution of recombination structures) and increasing recA transcription 2- to 3-fold with a recAo1403 operator mutation act independently to minimally satisfy this condition. This allows 24% of mutant cells to have elevated levels of SOS expression, a percentage similar to that of cells with RecA-green fluorescent protein (RecA-GFP) foci. In an xthA (exonuclease III gene) mutant where there are 3-fold more RecA loading events, recX (a destabilizer of RecA filaments) must be additionally deleted to achieve a population of cells where the percentage having elevated SOS expression (91%) nearly equals the percentage with at least one RecA GFP focus (83%). It is proposed that, in the xthA mutant, there are three independent mechanisms that repress SOS expression in log-phase cells. These are the rapid processing of RecA filaments by RadA, maintaining the concentration of RecA below a critical level, and the destabilizing of RecA filaments by RecX. Only the first two mechanisms operate independently in a wild-type cell. PMID- 22843849 TI - Novel repressor of Escherichia coli O157:H7 motility encoded in the putative fimbrial cluster OI-1. AB - Escherichia coli O157:H7 is a gastrointestinal pathogen that has become a serious public health concern, as it is associated with outbreaks and severe diseases such as hemolytic-uremic syndrome. The molecular basis of its greater virulence than that of other serotypes is not completely known. OI-1 is a putative fimbria encoding genomic island that is found almost exclusively in O157:H7 Shiga toxin producing E. coli strains and may be associated with the enhanced pathogenesis of these strains. In this study, we identified and characterized a novel repressor of flagellar synthesis encoded by OI-1. We showed that deletion of Z0021 increased the motility of E. coli O157:H7, which correlated with an increase in flagellin production and enhanced assembly of flagella on the cell surface. In contrast, overexpression of Z0021 inhibited motility. We demonstrated that Z0021 exerted its regulatory effects downstream of the transcription and translation of flhDC but prior to the activation of class II/III promoters. Furthermore, the master regulator of flagellar synthesis, FlhD(4)C(2), was shown to be a high-copy suppressor of the nonmotile phenotype associated with elevated levels of Z0021--a finding consistent with Z0021-FlhD(4)C(2) being a potential regulatory complex. This work provides insight into the mechanism by which Z0021, which we have named fmrA, represses flagellar synthesis and is the first report of a fimbrial-operon encoded inhibitor of motility in E. coli O157:H7. PMID- 22843852 TI - Residues in the N-terminal domain of MutL required for mismatch repair in Bacillus subtilis. AB - Mismatch repair is a highly conserved pathway responsible for correcting DNA polymerase errors incorporated during genome replication. MutL is a mismatch repair protein known to coordinate several steps in repair that ultimately results in strand removal following mismatch identification by MutS. MutL homologs from bacteria to humans contain well-conserved N-terminal and C-terminal domains. To understand the contribution of the MutL N-terminal domain to mismatch repair, we analyzed 14 different missense mutations in Bacillus subtilis MutL that were conserved with missense mutations identified in the human MutL homolog MLH1 from patients with hereditary nonpolyposis colorectal cancer (HNPCC). We characterized missense mutations in or near motifs important for ATP binding, ATPase activity, and DNA binding. We found that 13 of the 14 missense mutations conferred a substantial defect to mismatch repair in vivo, while three mutant alleles showed a dominant negative increase in mutation frequency to wild-type mutL. We performed immunoblot analysis to determine the relative stability of each mutant protein in vivo and found that, although most accumulated, several mutant proteins failed to maintain wild-type levels, suggesting defects in protein stability. The remaining missense mutations located in areas of the protein important for DNA binding, ATP binding, and ATPase activities of MutL compromised repair in vivo. Our results define functional residues in the N terminal domain of B. subtilis MutL that are critical for mismatch repair in vivo. PMID- 22843853 TI - Shedding of kidney injury molecule-1 by membrane-type 1 matrix metalloproteinase. AB - Co-expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) with kidney injury molecule-1 (KIM-1) in HEK293T cells resulted in cleavage and shedding of KIM-1 ectodomain. Analysis of cleavage products using KIM-1 mutants localized cleavage site at the juxtamembrane region. HT1080 cells were stably transfected with expression plasmid for KIM-1 or its mutant with deletion of the juxtamembrane region (Asp(261)-Gly(295)) to establish HT/KIM-1 or HT/DeltaKIM-1 cells, respectively. KIM-1 protein appeared on cell surface at low level in HT/KIM-1 cells, and accumulated by the treatment with MMP inhibitor BB-94 or small interfering RNA (siRNA) to MT1-MMP, indicating that MT1-MMP is involved in cleavage and shedding of KIM-1. In contrast, HT/DeltaKIM-1 cells expressed KIM-1 protein at high level regardless of BB-94 or siRNA treatment. Cells expressing high level KIM-1 protein exhibited phagocytosis of Escherichia coli and reduced cell adhesion and spreading on collagen-coated plate compared with KIM-1 negative cells. Control HT1080 and HT/KIM-1 cells showed significantly higher invasive growth in collagen gel, cell migration on collagen-coated plate and liver metastasis in chick embryo than HT/DeltaKIM-1 cells. These results suggest that KIM-1 negatively regulates cellular function mediated through interaction with collagen, and MT1-MMP abrogates it through the cleavage and shedding of KIM-1. PMID- 22843850 TI - ZipA is required for FtsZ-dependent preseptal peptidoglycan synthesis prior to invagination during cell division. AB - Rod-shaped bacteria grow by a repetitive cycle of elongation followed by division, and the mechanisms responsible for these two processes have been studied for decades. However, little is known about what happens during the transition between the two activities. At least one event occurs after elongation ends and before division commences, that being the insertion of new cell wall peptidoglycan into a narrowly circumscribed ribbon around midcell where septation is destined to take place. This insertion does not depend on the presence of the septation-specific protein PBP3 and is therefore known as PBP3-independent peptidoglycan synthesis (PIPS). Here we report that only FtsZ and ZipA are required to generate PIPS in wild-type Escherichia coli. PIPS does not require the participation of other members of the divisome, the MreB-directed cell wall elongation complex, alternate peptidoglycan synthases, the major peptidoglycan amidases, or any of the low-molecular-weight penicillin binding proteins. ZipA directed PIPS may represent an intermediate stage that connects cell wall elongation to septal invagination and may be the reason ZipA is essential in the gammaproteobacteria. PMID- 22843851 TI - Interaction of the extreme N-terminal region of FliH with FlhA is required for efficient bacterial flagellar protein export. AB - The flagellar type III protein export apparatus plays an essential role in the formation of the bacterial flagellum. FliH forms a complex along with FliI ATPase and is postulated to provide a link between FliI ring formation and flagellar protein export. Two tryptophan residues of FliH, Trp7 and Trp10, are required for the effective docking of the FliH-FliI complex to the export gate made of six membrane proteins. However, it remains unknown which export gate component interacts with these two tryptophan residues. Here, we performed targeted photo cross-linking of the extreme N-terminal region of FliH (FliH(EN)) with its binding partners. We replaced Trp7 and Trp10 of FliH with p-benzoyl-phenylalanine (pBPA), a photo-cross-linkable unnatural amino acid, to produce FliH(W7pBPA) and FliH(W10pBPA). They were both functional and were photo-cross-linked with one of the export gate proteins, FlhA, but not with the other gate proteins, indicating that these two tryptophan residues are in close proximity to FlhA. Mutant FlhA proteins that are functional in the presence of FliH and FliI but not in their absence showed a significantly reduced function also by N-terminal FliH mutations even in the presence of FliI. We suggest that the interaction of FliH(EN) with FlhA is required for anchoring the FliI hexamer ring to the export gate for efficient flagellar protein export. PMID- 22843854 TI - Complete genome sequence of an H5N2 avian influenza virus isolated from a parrot in southern China. AB - We report the complete genome sequence of an H5N2 avian influenza virus (AIV) that was first isolated from a parrot in Guangdong in southern China in 2004. Genomic sequence and phylogenetic analyses showed that it was highly homologous with the North American H5N2 viruses and all eight genes of this virus belonged to the North American gene lineage. These data will help in the investigation of the epidemiology and host range of AIVs in southern China. PMID- 22843855 TI - Complete genome sequence of a novel type of human parechovirus strain reveals natural recombination events. AB - Human parechoviruses (HPeVs) are a species in the Parechovirus genus of the Picornaviridae family. We report a complete genome sequence of a novel HPeV strain, CH-ZJ1, that was found in an infant with gastroenteritis in Zhenjiang City, China. The complete genome consists of 7,298 nucleotides (nt), excluding the 3' poly(A) tail; the open reading frame is mapped between nucleotide positions 654 and 7211 and encodes a 2,185-amino acid (aa) polyprotein. The phylogenetic tree obtained for the complete genome of this HPeV strain and the other HpeV strains available in GenBank indicated that CH-ZJ1 is intervenient between HpeV type 4 (HpeV4) and HpeV5. Phylogenetic analysis based on the 3D and VP1 genes reveals two incongruent trees. Recombination detection indicated that CH-ZJ1 might be a recombinant which was produced by more than one genomic recombination event that occurred among HPeV1, HPeV4, and HPeV3 strains. PMID- 22843856 TI - Complete genomic sequence of an H5N1 influenza virus from a parrot in southern China. AB - An H5N1 avian influenza virus (AIV) designated A/Parrot/Guangdong/C99/2005 (H5N1) was first isolated from a sick parrot in Guangdong in southern China in 2005. The complete genome of this strain was analyzed. Genome sequence analysis showed that all 8 gene segments of the virus nucleotide had 99.0% homology to A/chicken/Henan/12/2004 (H5N1). Phylogenetic analysis demonstrated that all 8 gene segments of the virus were derived from the Eurasian lineage. The availability of genome sequences is useful to investigate the host range and genetic evolution of the H5N1 avian influenza virus in Southern China. PMID- 22843857 TI - The complete genome sequence of bacteriophage CP21 reveals modular shuffling in Campylobacter group II phages. AB - Campylobacter group II phages described so far share a high degree of sequence similarity. We report the 182,833-bp genomic sequence of the closely related group II phage CP21 and show that it has a completely different genomic organization. As in other group II phages, the CP21 genome is composed of large modules separated by long DNA repeat regions which obviously trigger recombination and modular shuffling. PMID- 22843858 TI - Iteravirus-like genome organization of a densovirus from Sibine fusca Stoll. AB - The complete genome of Sibine fusca densovirus was cloned and sequenced. The genome contained 5,012 nucleotides (nt), including inverted terminal repeats (ITRs) of 230 nt with terminal hairpins of 161 nt. Its DNA sequence and monosense organization with 3 open reading frames (ORFs) is typical of the genus Iteravirus in the subfamily Densovirinae of the Parvoviridae. PMID- 22843859 TI - Complete genome sequence of phytopathogenic Pectobacterium carotovorum subsp. carotovorum bacteriophage PP1. AB - Pectobacterium carotovorum subsp. carotovorum is a phytopathogen causing soft rot disease on diverse plant species. To control this plant pathogen, P. carotovorum subsp. carotovorum-targeting bacteriophage PP1 was isolated and its genome was completely sequenced to develop a novel biocontrol agent. Interestingly, the 44,400-bp genome sequence does not encode any gene involved in the formation of lysogen, suggesting that this phage may be very useful as a biocontrol agent because it does not make lysogen after host infection. This is the first report on the complete genome sequence of the P. carotovorum subsp. carotovorum targeting bacteriophage, and it will enhance our understanding of the interaction between phytopathogens and their targeting bacteriophages. PMID- 22843860 TI - Genome sequences of SAT 2 foot-and-mouth disease viruses from Egypt and Palestinian Autonomous Territories (Gaza Strip). AB - Two foot-and-mouth disease virus (FMDV) genome sequences have been determined for isolates collected from recent field outbreaks in North Africa (Egypt) and the Middle East (Palestinian Autonomous Territories). These data represent the first examples of complete genomic sequences for the FMDV SAT 2 topotype VII, which is thought to be endemic in countries immediately to the south of the Sahara desert. Further studies are now urgently required to provide insights into the epidemiological links between these outbreaks and to define the pathogenicity of this emerging lineage. PMID- 22843861 TI - Complete genome sequence of a polyomavirus isolated from horses. AB - A polyomavirus was isolated from the eyes of horses, and the sequence was determined. A nearly identical VP1 sequence was amplified from the kidney of another animal. We report the complete genome sequence of the first polyomavirus to be isolated from a horse. Analysis shows it to be most closely related overall to human and nonhuman primate polyomaviruses. PMID- 22843862 TI - Complete genome sequence of a chikungunya virus isolated in Guangdong, China. AB - Chikungunya virus belongs to the genus Alphavirus in the family Togaviridae. Here we report the complete genome sequence of a chikungunya virus strain, GD05/2010, isolated in 2010 from a patient with chikungunya fever in Guangdong, China. The sequence information is important for surveillance of this emerging arboviral infection in China. PMID- 22843863 TI - Complete genome sequence of a highly pathogenic porcine reproductive and respiratory syndrome virus variant. AB - Following the 2006 outbreaks of the highly pathogenic porcine reproductive and respiratory syndrome, the causative agent was identified as the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV). To investigate whether the HP-PRRSV variant continues circulating and accelerating evolution, we sequenced and analyzed the complete genome of the identified HP-PRRSV field strain SD16. The sequence data indicate that the HP-PRRSV variant continues to prevail and accelerate evolution, especially in the nonstructural protein. PMID- 22843864 TI - Complete genome sequences of two Persicivirga bacteriophages, P12024S and P12024L. AB - The phylum Bacteroidetes is one of the major bacterial phyla in marine environments, where bacteriophages are highly abundant. Bacteriophages infecting members of the phylum Bacteroidetes, however, have not been well represented in public genome databases. Here we announce the genome sequences of two bacteriophages, P12024S and P12024L, that were isolated from coastal seawater and lytically infect Persicivirga sp. IMCC12024, a marine Bacteroidetes bacterium. PMID- 22843865 TI - Complete genome sequence of Marinomonas bacteriophage P12026. AB - Members of the genus Marinomonas in the Gammaproteobacteria are broadly distributed in marine environments where they could be infected by bacteriophages. Here we report the genome sequence of bacteriophage P12026 that can lytically infect bacterial strain IMCC12026, a member of the genus Marinomonas. To our knowledge, this is the first genome sequence of a lytic bacteriophage infecting the genus Marinomonas. PMID- 22843866 TI - In vitro intragenomic rearrangement of porcine circovirus type 2. AB - We report here for the first time the genome sequence of a rearranged porcine circovirus type 2 (PCV2) strain, CH-IVT1, isolated from PCV2-infected PK-15 cells. The complete circular genome of the CH-IVT1 is 605 nucleotides (nt) in length. The finding will help us to understand the molecular evolution of PCV2 and the relationship between PCV2 and PCV-associated diseases. PMID- 22843867 TI - Complete genome sequence of Croceibacter bacteriophage P2559S. AB - Croceibacter atlanticus HTCC2559(T), a marine bacterium isolated from the Sargasso Sea, is a phylogenetically unique member of the family Flavobacteriaceae. Strain HTCC2559(T) possesses genes related to interaction with primary producers, which makes studies on bacteriophages infecting the strain interesting. Here we report the genome sequence of bacteriophage P2559S, which was isolated off the coast of the Republic of Korea and lytically infects HTCC2559(T). Many genes predicted in the P2559S genome had their homologs in Bacteroides phages. PMID- 22843868 TI - Complete genome sequence of Staphylococcus aureus bacteriophage GH15. AB - GH15 is a polyvalent phage that shows activity against a wide range of Staphylococcus aureus strains. In this work, the complete genome sequence of GH15 was determined. With a genome size of 139,806 bp (double-stranded DNA), GH15 is the largest staphylococcal phage sequenced to date. The complete genome encodes 214 open reading frames (ORFs) and 4 tRNAs. The closest relatives are the class III staphylococcal myobacteriophages, including K, A5W, ISP, Sb-1, and G1. Interestingly, although corresponding gene sequences demonstrate very high similarity, all the introns and inteins present in the phages listed above are absent in GH15. As such, GH15 can be considered phylogenetically unique among the staphylococcal myobacteriophages, indicating the diversity of this family. PMID- 22843869 TI - Targeting PI3KC2beta impairs proliferation and survival in acute leukemia, brain tumours and neuroendocrine tumours. AB - BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2beta isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2beta was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2beta or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2beta also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2beta contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies. PMID- 22843870 TI - The impact of timing of EGFR and IGF-1R inhibition for sensitizing head and neck cancer to radiation. AB - BACKGROUND: Targeting the epidermal growth factor receptor (EGFR) improved radiotherapy outcome by 10-15% in head and neck tumors (HNSCC). We tested the therapeutic benefits of co-targeting EGFR and insulin-like growth factor-1 receptor (IGF-1R) to further enhance tumor response to radiation. MATERIALS AND METHODS: Mice bearing FaDu tumor xenografts were treated with ganitumab (previously known as AMG479, an anti-IGF-1R antibody), panitumumab (an anti-EGFR antibody), or both in combination with fractionated doses of radiation. Tumor growth delay and tumor cure/recurrence served as end-points. RESULTS: The best tumor growth delay was achieved when ganitumab and panitumumab were given concurrently with radiation. Tumor cure/recurrence studies showed that combining ganitumab, panitumumab and radiation resulted in significantly higher radiocurability rates than use of either of the agents given with radiation. CONCLUSION: These findings provide the rationale for clinical testing of the combination of ganitumab and panitumumab for the treatment of HNSCC. PMID- 22843871 TI - Down-regulation of 8-hydroxydeoxyguanosine and peroxiredoxin II in the pathogenesis of endometriosis-associated ovarian cancer. AB - AIM: To evaluate the roles of oxidative stress marker 8-hydroxydeoxyguanosine (8 OHdG) and peroxiredoxin (PRX) antioxidants in the development of endometriosis and endometriosis-associated ovarian cancer (EAC). MATERIALS AND METHODS: Tissue expressions of 8-OHdG, PRX II and PRX IV were determined immunohistochemically in tissue from 22 women with benign endometriosis (BE) and 33 women with EAC, among whom endometriosis and cancer tissues were analyzed separately. RESULTS: When all three groups were compared simultaneously, EAC tumor cells had significantly weaker nuclear 8-OHdG and PRX II expression (p<0.05 and p<0.01, respectively) and significantly weaker cytoplasmic 8-OHdG expression (p<0.01) than EAC endometriosis and BE epithelial cells. This same trend was also observed when groups were compared pair-wise. CONCLUSION: Nuclear PRX II and 8-OHdG were down regulated in EAC tumorous tissue compared with BE and EAC endometriotic tissue, suggesting a role of oxidative stress in the pathogenesis of EAC. PMID- 22843872 TI - Sex steroids and cervical cancer. AB - During the 19th century, studies indicated that reproductive events were involved in cervical cancer. Human papillomavirus (HPV) infection is a prerequisite for development of cancer, but co-factors, among them the action of sexual steroid hormones, are necessary. Childbirth has been an important risk factor but now probably plays a minor role in the industrialized world, where parity is low. Long-term oral contraceptive use has been thoroughly studied epidemiologically, and correlates to cervical cancer in most studies. In vitro studies on cervical cell lines transfected with HPV and animal studies indicate that sex steroid hormones are capable to induce cancer. In in vivo cervical cancer tissue studies there have been observations that endogenous progesterone in serum correlates to a negative pattern of expression of cellular and extracellular proteins, tumor markers. Immune response could be another mechanism. Estradiol might be associated with a positive pattern and high estradiol and low progesterone levels increase duration of survival in cervical cancer. Studies where treatment of compounds that influence sex steroid hormones have been given are rare and have been disappointing. PMID- 22843873 TI - Increased gene expression of the ABCC5 transporter without distinct changes in the expression of PDE5 in human cervical cancer cells during growth. AB - Carcinoma of the uterine cervix represents the second most frequent female malignancy worldwide, but few biochemical tumour markers have been implemented into clinical practice. Elevated extracellular guanosine 3', 5'-cyclic monophosphate (cGMP) levels have been reported to be a sensitive, early and reliable marker for screening relapse in carcinoma of the uterine cervix. The mechanism behind this observation remains unknown. The possibility exists that the cancer cells develop resistance to the antiproliferative effect of high intracellular cGMP levels. The enhanced cGMP expression may originate from either an increase in cellular export capacity by increased expression of member 5 in subfamily C of ATP-Binding-Cassette transporters (ABCC5), or increased substrate (cGMP) levels for this pump. The latter situation occurs with increased expression of inducible nitric oxide synthase (iNOS) and/or soluble guanylyl cyclase (sGC) and/or reduced expression of member 5 of the cyclic nucleotide phosphodiesterases (PDE5). Four transformed human cell lines derived from carcinomas of the uterine cervix (C-4 I, C-33 A, SiHa and ME-180 cells) and one non-transformed human cell line (WI-38) were included in the study in order to unveil which biokinetic components are involved. The expressions of iNOS, sGC, PDE5 and ABCC5 in the initial and final phase of the exponential growth curve were compared. Assuming that the WI-38 control cells mimic the situation in a normal tissue, iNOS remains un-expressed during proliferation, and the expression of sGC is low but shows a clear increase during exponential growth. PDE5 is highly expressed and increases (~130%) during growth whereas ABCC5 exhibited low to moderate expression, with a moderate increase (~40%) during growth. The malignant cells exhibited moderate ABCC5 expression with a distinct increase during exponential growth, whereas PDE5 expression remained virtually unchanged. Dysregulation of the cGMP biokinetics in growing malignant cells may account for the elevation of extracellular cGMP observed in patients with carcinoma of the uterine cervix. PMID- 22843874 TI - Non-invasive fluorescent-protein imaging of orthotopic pancreatic-cancer-patient tumorgraft progression in nude mice. AB - In order to individualize and therefore have more effective treatment for pancreatic cancer, we have developed a multicolor, imageable, orthotopic mouse model for individual patients with pancreatic cancer by passaging their tumors through transgenic nude mice expressing green fluorescent protein (GFP) and red fluorescent protein (RFP). The tumors acquired brightly fluorescent stroma from the transgenic host mice, which was stably associated with the tumors through multiple passages. In the present study, pancreatic cancer patient tumor specimens were initially established in NOD.CB17-Prkdc(scid)/NcrCrl (NOD/SCID) mice. The tumors were then passaged orthotopically into transgenic nude mice ubiquitously expressing GFP and subsequently to nude mice ubiquitously expressing RFP. The tumors, with very bright GFP and RFP stroma, were then orthotopically passaged to non-transgenic nude mice. It was possible to image the brightly fluorescent tumors non-invasively longitudinally as they progressed in the non transgenic nude mice. This non-invasive imageable tumorgraft model will be valuable to screen for effective treatment options for individual patients with pancreatic cancer, as well as for the discovery of improved agents for this treatment-resistant disease. PMID- 22843875 TI - Aromatase in colon carcinoma. AB - Aromatase is one of the key estrogen-producing enzymes and is regarded as one of the therapeutic targets in estrogen receptor-positive breast cancer patients. Human colon carcinoma has also been recently proposed as being an estrogen responsive malignancy, but the detailed status of aromatase has not yet been reported. Therefore, in this study, we evaluated the aromatase expression in colon carcinoma using immunohistochemistry and real-time polymerase chain reaction. Aromatase mRNA was significantly higher (p=0.03) in colon carcinoma than in the corresponding non-neoplastic mucosa (n=31). Aromatase immunoreactivity tended to be positively associated with the intratumoral concentration of estrogens (n=53), and in particular, the concentration of estradiol was significantly higher (p=0.02) in aromatase-positive cases in men. Aromatase immunoreactivity was detected in the cytoplasm of the carcinoma cells in 217/328 (65%) examined colon carcinoma cases. Aromatase immunoreactivity was significantly positively correlated with tubular differentiation, and inversely correlated with Ki-67 labeling index, although not necessarily correlated with the clinical outcome of the patients. All these results demonstrate that colon carcinoma expresses functional aromatase, and that estrogens are locally synthesized in the tumor tissues. The findings reported here could contribute to a better understanding of the actions of estrogen in colon carcinoma. PMID- 22843876 TI - Tumor progression and metastasis: role of translational deregulation. AB - Translation deregulation is implicated in cellular transformation. Aberrant flux through signalling pathways that impinge on the translation process and perturbations in the relative levels of key regulatory translation initiation factors has been documented in a variety of human cancer types. Recently, studies have demonstrated that translation deregulation also contributes to the metastatic phenotype through selective effects on the translation of mRNAs whose products are involved in various steps of metastasis including migration, invasion, angiogenesis, homing, and activation of survival loops at distal sites. Herein, we present the latest findings implicating perturbed translational control in the metastatic process. PMID- 22843877 TI - Human papillomavirus DNA and p16 gene in squamous cell lung carcinoma. AB - AIM: To investigate the presence of human papillomavirus (HPV) DNA in squamous cell carcinoma (SCC) of the lung, and to examine the protein expression and genomic status of p16 and their correlation. MATERIALS AND METHODS: Fifty cases of surgically removed primary lung SCC were analyzed. HPV detection was performed by Polymerase Chain Reaction (PCR) of L1 region and E6/E7 region of high-risk viral genotype. p16 protein and gene analysis were carried out by immunohistochemistry and Fluorescence In Situ Hybridization (FISH), respectively. RESULTS: HPV DNA was found in two out of 50 cases (4%, p>0.05). In five cases, p16 protein expression was positive. The data showed that in 45/50 cases (90%, p<0.05) HPV DNA and p16 were both negative, in 2/50 cases (4%) both were positive, and in 3/50 (6%) cases, HPV DNA was negative and p16 positive. FISH analysis for p16 gene showed aneusomia of chromosome 9 with or without loss of p16 gene in all cases (100%, p<0.05). CONCLUSION: Our study shows that in pulmonary SCC, there is no association between the presence of HPV DNA and the expression of p16 protein. Furthermore, the loss of the p16 gene and the instability of chromosome 9 were frequently found in HPV DNA-negative cases. PMID- 22843878 TI - Gene amplification of ZNF217 located at chr20q13.2 is associated with lymph node metastasis in ovarian clear cell carcinoma. AB - BACKGROUND: Recently we reported that amplification of the Zinc Finger Protein 217 (ZNF217) gene adversely affects survival of patients with ovarian clear cell carcinoma. This study sought to determine the mechanism by which ZNF217 amplification affects patient survival. MATERIALS AND METHODS: Fluorescence in situ hybridization (FISH) was used to detect ZNF217 gene amplification status and ZNF217-specific siRNA was used to inactivate ZNF217 for in vitro biological analyses. RESULTS: We found ZNF217 gene amplification to be significantly correlated with lymph node metastasis (p<0.05) in ovarian clear cell carcinoma. Profound inhibition of cell migration and invasion was observed in siRNA-treated cells with ZNF217 amplification, compared to cells without amplification. CONCLUSION: These findings provide new insight into the biological role of ZNF217 gene amplification in ovarian clear cell carcinoma. Additionally, our observations have an important therapeutic implication for patients with ovarian clear cell carcinomas with ZNF217 amplification, as these patients may potentially benefit from ZNF217 targeted-therapy. PMID- 22843879 TI - PKCalpha suppresses 7,12-dimethylbenz[a]anthracene-induced skin tumor formation. AB - BACKGROUND: Protein kinase C (PKC)alpha is distributed in almost all tissues and participates in various signaling pathways. However, the role of PKCalpha in carcinogenesis remains unclear. In this study, we performed complete skin carcinogenesis in PKCalpha knockout mice by repeated administration of 7,12 dimethylbenz[a]anthracene (DMBA). MATERIALS AND METHODS: Complete skin carcinogenesis was performed by repeated DMBA treatment using PKCalpha knockout mice. The number of tumors was determined weekly. Tumor types were determined by Hematoxylin and eosin (H & E) analysis. Tumor growth was assayed by proliferating cell nuclear antigen (PCNA) staining. RESULTS: In the knockout mice, the average number of tumors was 16.6/mouse at 20 weeks. In contrast, in the wild-type (WT) mice, the tumor number was 6.9/mouse. Growth and malignant grade of tumors in PKCalpha knockout mice did not differ from those in WT mice. CONCLUSION: PKCalpha suppresses tumor formation, but not tumor growth and progression in skin carcinogenesis. PMID- 22843880 TI - beta-elemene effectively suppresses the growth and survival of both platinum sensitive and -resistant ovarian tumor cells. AB - The development of cisplatin drug resistance remains a chief concern in ovarian cancer chemotherapy. beta-Elemene is a natural plant product with broad-spectrum antitumor activity towards many types of carcinomas. This study aimed to define the biological and therapeutic significance of beta-elemene in chemoresistant ovarian cancer. In the present study, beta-elemene significantly inhibited cell growth and proliferation of both the cisplatin-sensitive human ovarian cancer cell line A2780 and its cisplatin-resistant counterpart A2780/CP. beta-Elemene also suppressed the growth of several other chemosensitive and chemoresistant ovarian cancer cell lines, including ES-2, MCAS, OVCAR-3, and SKOV-3, with the half maximal inhibitory concentration (IC(50)) values ranging from 54 to 78 MUg/ml. In contrast, the IC(50) values of beta-elemene for the human ovarian epithelial cell lines IOSE-386 and IOSE-397 were 110 and 114 MUg/ml, respectively, which are almost two-fold those for the ovarian cancer cell lines. Cell cycle analysis demonstrated that beta-elemene induced a persistent block of cell cycle progression at the G(2)/M phase in A2780 and A2780/CP cells. This was mediated by alterations in cyclin and cyclin-dependent kinase expression, including the down-regulation of CDC2, cyclin A, and cyclin B1, and the up regulation of p21(WAF1/CIP1) and p53 proteins. Moreover, beta-elemene triggered apoptosis and irreversible cell death in both sensitive and resistant ovarian cancer cells via the activation of caspase-3, -8 and 9; the loss of mitochondrial membrane potential (deltaPsim); the release of cytochrome c into the cytosol; and changes in the expression of BCL-2 family proteins. All of these molecular changes were associated with beta-elemene-induced growth inhibition and cell death of ovarian cancer cells. Our results demonstrate that beta-elemene has antitumor activity against both platinum-sensitive and resistant ovarian cancer cells, and thus has the potential for development as a chemotherapeutic agent for cisplatin-resistant ovarian cancer. PMID- 22843881 TI - The length of the Barrett's mucosa in baboons, revisited. AB - BACKGROUND: Chewing of regurgitated food with rumination elicits, gastroesophageal reflux (GER) in baboons. Protracted reflux transforms the distal multilayered squamous cell-lined epithelium into columnar-lined mucosa, with mucus-producing glands having interspersed oxyntic glands. In humans, this histological constellation is called Barrett's mucosa type 2 (BMT2). MATERIALS AND METHODS: The distal esophagus together with the proximal stomach was removed en bloc, at autopsy, from 35 adult baboons. Longitudinal sections were stained with toluidine blue, a stain that permits easy discrimination between parietal and chief gastric glands. Using a calibrated ocular scale, the length of the BMT2 was assessed in all 35 baboons. RESULTS: The mean length of the BMT2 was 9.80 mm (range 1.0 mm-40.2 mm). CONCLUSION: BMT2 in baboons is an integrated part of the natural phenomenon of mucosal adaptation to daily regurgitation of gastric acid into the distal esophagus (natural GER), whereas BMT2 in humans might reflect an evolutionary atavism in the esophagus, triggered by a non-physiological disorder (pathological GER). The baboon offers a suitable model to monitor the series of histological events that take place in the distal esophagus under the influence of protracted GER. PMID- 22843882 TI - Cell-free serum DNA in patients with bladder cancer: results of a prospective multicenter study. AB - BACKGROUND/AIM: Cell-free DNA may serve as a biomarker for patients with cancer; we designed our study to determine its potential in patients with bladder cancer (BCA). MATERIALS AND METHODS: Short beta-actin (ACTB)-106 and large ACTB-384 fragments were quantified using real time PCR (RT-PCR); the ratio of ACTB 384/ACTB-106 was defined as DNA integrity. We analyzed the serum from 95 patients with and from 132 without BCA. RESULTS: Patients with BCA had increased ACTB-106 levels and lower DNA integrity compared to patients without cancer. However, patients undergoing transurethral bladder resection (TURB) with histological exclusion of BCA had a similar ACTB-106 level and DNA integrity, as patients with BCA. Cell-free DNA was not correlated with smoker status, pT stage, grade or lymph node metastasis, or DNA integrity. There was a weak inverse correlation of age with DNA integrity in patients with BCA. CONCLUSION: Analysis of serum cell free DNA levels and fragmentation patterns are of limited value regarding the identification of patients with BCA. PMID- 22843883 TI - Screening for cytotoxic compounds in poor-prognostic chronic lymphocytic leukemia. AB - BACKGROUND/AIM: For chronic lymphocytic leukemia (CLL) patients with poor prognostic genomic aberrations the therapeutic options are limited. We used the Spectrum Collection library to identify compounds with anti-leukemia activity in high-risk CLL. MATERIALS AND METHODS: We identified substances with equal high cytotoxic activity in vitro in samples from poor-prognostic CLL (11q-/17p-, n=3) as compared to those from favourable-prognostic CLL (13q-, n=3). Cell survival was measured by fluorometric microculture cytotoxicity assay. RESULTS: Out of 2,000 compounds, 65 had a similar effect in both prognostic groups. Fifteen compounds were selected for dose-response experiments in 16 additional CLL samples. Of these compounds, 12 continued to have similar cytotoxicity between prognostic subgroups. Additional experiments demonstrated that in CLL cells with 11q or 17p deletion, 5-azacytidine induced apoptosis in a dose-dependent manner and lipoprotein lipase expression was reduced following orlistat treatment. CONCLUSION: Using primary cultures of cells from high-risk CLL patients for compound screening is a feasible approach and that 5-azacytidine and orlistat exemplify substances that exhibit cytotoxicity in poor-risk CLL. PMID- 22843885 TI - PI3K/mTOR signaling pathways in medulloblastoma. AB - Medulloblastoma is the most common malignant brain tumor in children. Recent studies have implicated sonic hedgehog (SHH) and insulin growth factor (IGF) as important mediators in deregulated pathways, which directly inactivate tuberous sclerosis complex, leading to activation of the serine/threonine kinase, mammalian target of rapamycin (mTOR). mTOR consists of two catalytic subunits of biochemically distinct complexes called mTORC1 and mTORC2. This study aims to further elucidate the role of the mTOR pathway, in the development of medulloblastoma, and assess the use of mTOR inhibitors as novel therapeutic agents. Medulloblastoma cells treated with mTORC1 inhibitor, rapamycin, down regulated pERK expression initially; however ERK activation was evident upon prolonged treatment. Phosphorylation of mTORC1 substrate, p70S6K at thr389 was reduced by rapamycin and pretreatment with rapamycin abrogated platelet-derived growth factor (PDGF)-induced activation of S6K, as well as that of mTORC2 substrate pAKT(Ser473). Activation of AKT was decreased at 1, 3, and 6 h of treatment, but extended treatment with rapamycin increased expression of pAKT(Ser473). Expression of cyclic dependent kinase inhibitor, P27, decreased following PDGF and increased following rapamycin treatment, suggesting their respective impact on cell proliferation via cell cycle control. Cell proliferation was increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of medulloblastoma cells, while it was suppressed following treatment with rapamycin or U0126 (MEK1/2 inhibitor). pp242, a novel combined mTORC1/2 inhibitor, and rapamycin limited proliferation by reducing the S-Phase entry as assessed by EdU incorporation, while PDGF increased EdU incorporation. pp242 reduced the number of cells entering the S-phase to a greater extent than did rapamycin. Migration of medulloblastoma cells towards fibronectin was suppressed in a time-dependent manner after rapamycin treatment. These results indicate that the mTOR pathway is involved in the pathogenesis of medulloblastoma, and that targeting this pathway may provide a strategy for therapy of medulloblastoma. PMID- 22843884 TI - Improved gene transfer into bladder cancer cells using adenovirus vector containing RGD motif. AB - BACKGROUND: The transduction efficacy of adenovirus serotype 5 (Ad5) vector in high-grade human bladder cancer cells is generally extremely low due to the non expression of coxsackie and adenoviral receptor (CAR). We investigated whether fiber-modified adenovirus vector containing an RGD motif in the HI loop of the adenovirus fiber knob could increase the transduction efficiency of Ad5 into human bladder cancer cells in vitro. MATERIALS AND METHODS: We examined the expressions of CAR, and of alpha(v), beta(3) and beta(5) integrin, and the transduction efficacy of fiber-modified adenovirus vector in four human bladder cancer cell lines (TCC-SUP, 253J, T24 and KK47). RESULTS: The expression of CAR was lower and those of alpha(v) and beta(3) integrin were higher in four human cancer cell lines compared with the control cell line, KK47. The transduction efficacy of fiber-modified adenovirus vector increased by 20- to 470-fold compared with Ad5. CONCLUSION: Fiber-modified adenovirus vector may be useful in order to establish new effective gene therapy strategies for the treatment of high-grade human bladder cancer. PMID- 22843886 TI - The expression of FHIT in salivary carcinoma ex pleomorphic adenoma. AB - BACKGROUND: Carcinoma ex-pleomorphic adenoma (Ca-ex-PA) is considered to be a malignant transformation product of pre-existing pleomorphic salivary adenoma (PSA). AIM: Our study aimed to characterise alterations in the immunohistochemical expression of the Fragile Histidine Traid (FHIT) and Cyclin dependent Kinase Inhibitor 2A (CDKN2A) (p16(INK4a)) genes during tumour progression model from PSA to Ca-ex-PA in a cross sectional study. MATERIALS AND METHODS: Paraffin blocks of 29 cases of PSA which were surrounded by normal parotid gland, and 26 cases of Ca-ex-PA were retrieved and validated. In all cases of Ca-ex-PA, a PSA 'ghost' was identified and the malignant element was either undifferentiated carcinoma or adenocarcinoma. Immunohistochemical staining and evaluation for CDKN2A and FHIT in 55 specimens were undertaken. RESULTS: The results showed positive nuclear expression of p16 and FHIT in normal parotid gland. None (0%) of the PSA cases demonstrated loss of expression of nuclear FHIT, while 6/26 (23.1%) showed loss of FHIT express. Loss of CDKN2A expression was found in 12/29 (41.4%) of PSAs and 8/26 (30.8%) of Ca-ex-PAs. The nuclear expression pattern for FHIT was significantly more frequent in Ca-ex-PAs compared to PSAs (p=0.014). CONCLUSION: Our data suggest that inactivation of tumour suppressor genes plays an important role in the evolution of Ca-ex-PA. Furthermore, alteration of CDKN2A expression was found to be an early event in the malignant transformation of pleomorphic adenoma and could be considered as a target for gene therapy. More interestingly, we found that nuclear FHIT expression could be used as a good marker to distinguish PSA from Ca-ex-PA. PMID- 22843887 TI - Preservation of HUGL-1 expression as a favourable prognostic factor in pancreatic carcinoma. AB - AIM: The expression of the human homologue of Drosophila tumour suppressor gene lgl (HUGL-1) in pancreatic cancer was retrospectively assessed in 97 patients with surgically treated pancreatic cancer in order to correlate the HUGL-1 profile with patients' survival. MATERIALS AND METHODS: Immunohistochemistry was performed on 4-MUm-thick paraffin sections from representative tumour blocks using a standard protocol. The expression of HUGL-1 was evaluated semiquantitatively as negative (0), weak (1), medium (2) or strong (3). The results were correlated with clinicopathological parameters and with patients' survival, considering an observation period of 17 (mean) +/- 16 (SD) months. RESULTS: In normal and inflammatory tissue, a uniform and relatively strong staining was observed in ductal epithelium, ganglion cells and some acinar epithelia. The endocrine islets exhibited a weak positivity. Human pancreatic cancer revealed variable intensities of HUGL-1 expression. A total of 69 tumour specimens were classified as negative and 28 as positive. The HUGL-1 expression was not correlated with clinical variables (age, gender), staging or tumour grading. HUGL-1 positivity proved to be prognostically favourable (p=0.0241) conferring a higher survival rate, especially for patients who had survived more than 12 months. The presence of distant metastases (M1) at diagnosis had a weak significant influence on survival (p=0.0474). The other staging parameters (T, N, UICC stage), tumour grading and clinical variables (age, gender) gave no significant prognostic information. In a multivariate Cox model, only HUGL-1 expression passed the entry limits. CONCLUSION: Preservation of HUGL-1 expression in pancreatic adenocarcinoma is a good prognostic factor that contributes to a better overall survival. PMID- 22843888 TI - HDAC inhibitors synergize antiproliferative effect of sorafenib in renal cell carcinoma cells. AB - AIM: To investigate the anticancer effect of histone deacetylase inhibitors (HDACIs) in combination with sorafenib in wild-type and mutant von Hippel-Lindau (VHL)-expressing renal cell carcinomas (RCCs). MATERIALS AND METHODS: We exposed clear cell RCC cells to HDACIs (vorinostat or belinostat) or sorafenib. We performed 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays, western blotting, flow cytometry and enzyme-linked immunosorbent assays (ELISA) to evaluate mechanisms of cell death, and used CalcuSyn to analyze the potential synergism. RESULTS: HDACIs alone inhibited the growth of clear cell RCC cell lines, increased acetylation of histone 3 and of tubulin, activated caspases-8, -9, and -3, and augmented the sub-G(1) population, independently of VHL and permeability glycoprotein (P-gp). Moreover, pre-treatment of Caki-1 (wild-type VHL) and 786-O (mutant VHL) with HDACIs followed by sorafenib reduced cell viability synergistically via activation of caspases and downregulation of the levels of myeloid leukemia cell differentiation protein (MCL1), phospho-extracellular signal-regulated kinase (ERK), and secreted vascular endothelial growth factor (VEGF). CONCLUSION: Sorafenib is more effective in combination with HDACIs even for clear cell RCCs harboring mutant VHL. PMID- 22843889 TI - Prognostic significance of glutathione peroxidase 1 (GPX1) down-regulation and correlation with aberrant promoter methylation in human gastric cancer. AB - BACKGROUND: This study aimed at examining the association of gene silencing and promoter methylation of glutathione peroxidase 1 (GPX1) and glutathione peroxidase 3 (GPX3) in gastric cancer cells and determined the clinical significance of GPX1 and GPX3 expression loss in gastric cancer tissue. MATERIALS AND METHODS: Analysis of mRNA expression was carried out by reverse transcription polymerase chain reaction (RT-PCR). Methylation of the GPX1 promoter region was analyzed by bisulfite sequencing, and that of the GPX3 promoter region was analyzed by methylation-specific PCR (MSP). Tissue microarray-based immunohistochemistry of GPX1 and GPX3 in 1,163 resected gastric cancer specimens was performed to assess the associations with clinicopathological parameters. RESULTS: Reduced GPX1 and GPX3 mRNA expression was associated with promoter methylation in gastric cancer cell lines. A correlation between DNA promoter methylation and loss of GPX1 expression was noted in 16 gastric cancer tissue samples (p=0.005). Loss of GPX1 and GPX3 proteins was found in 24.4% and 30.8% of gastric cancer tissues. Loss of GPX1 expression was significantly associated with advanced gastric cancer (p=0.039) and lymphatic invasion (p=0.010); loss of GPX3 expression was associated with advanced gastric cancer (p<0.001) and lymph node metastasis (p<0.001). Kaplan-Meier analysis showed that low expression of GPX1 was associated with poor cancer-specific survival (p=0.010). CONCLUSION: Data from this study implicate aberrant hypermethylation of promoter regions of GPX1 and GPX3 as a mechanism for down-regulation of GPX1 and GPX3 mRNA expression in gastric cancer cells. Loss of GPX1 expression was associated with aggressiveness and poor survival in patients with gastric cancer. PMID- 22843890 TI - Elevated nuclear YB1 expression is associated with poor survival of patients with early breast cancer. AB - BACKGROUND: Y-Box-Binding (YB1) protein represents a multifunctional protein, which plays a significant role in processes of proliferation, apoptosis and control of tumour cell response to toxic agents, including chemotherapy. The present study aimed at evaluating the prognostic significance of YB1 expression in breast cancer. MATERIALS AND METHODS: We analyzed nuclear and cytoplasmic expression of YB1 in 101 patients with stage II breast cancer, with 17 years of follow-up. Immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against YB1. Results were tested for their correlation with clinical and pathological data. RESULTS: Patients with a pronounced expression of the nuclear form the YB1 protein demonstrated a highly significant shortening of disease-free survival, disease-specific survival and overall survival. The prognostic value of YB1 was also corroborated by multivariate analysis. CONCLUSION: We demonstrated that high nuclear expression of YB1 is associated with poor survival of patients with early-stage breast cancer. PMID- 22843891 TI - Reduction of DNA damage by curcumin and celecoxib in epithelial cell cultures of the oropharynx after incubation with tobacco smoke condensate. AB - BACKGROUND: Tobacco smoke, as the major risk factor for the development of squamous cell cancer of the head and neck (HNSCC), contains various xenobiotics, such as polycyclic aromatic hydrocarbons, nitrosamines, aromatic amines and phenols. Chemoprevention either by artificial agents such as celecoxib, or natural compounds such as curcumin, might offer a chance to reduce the risk of developing malignant transformation. MATERIALS AND METHODS: In order to evaluate the DNA-damaging effects of smoke condensate towards human mucosa cells of the oropharynx, mini organ cultures (MOC) of macroscopically healthy pharyngeal tissue of 40 patients with oropharyngeal SCC were used. After incubation with smoke condensate DNA damage was evaluated with the alkaline single-cell microgel electrophoresis (comet assay). The chemoprotective potential of curcumin and celecoxib was analyzed after their incubation with the condensate-treated MOCs. As DNA-damaging and chemopreventive effects might not be equally distributed over the whole DNA, fragmentation of the epithelial growth factor receptor (EGFR) gene was additionally examined by Comet fluorescence in situ hybridization (FISH). RESULTS: As expected, tobacco smoke condensate caused significant DNA fragmentation compared to the negative control. No enhanced damage was observed on the EGFR gene. DNA fragmentation was significantly reduced when MOCs were incubated with celecoxib (p <= 0.001) and with curcumin (p <= 0.001). CONCLUSION: Both celecoxib and curcumin showed considerable chemoprotective effects towards the impact of smoke condensate. No evidence was found for higher susceptibility to damage in the EGFR gene. PMID- 22843892 TI - Combined effects of lapatinib and cisplatin on colony formation of head and neck squamous cell carcinoma. AB - BACKGROUND: Lapatinib targets human epidermal growth factor-receptor (EGFR) and Her2/neu receptor tyrosine-kinases and hence is under investigation in multimodal therapy concepts of advanced head and neck squamous cell carcinoma (HNSCC). We studied combined effects of lapatinib and cisplatin on colony formation (CF) of epithelial cells of individual HNSCC in short term ex vivo assays. MATERIALS AND METHODS: Biopsies of HNSCC were minced, collagenase-digested and exposed to serial lapatinib dilutions or solvent control (DMSO). The same lapatinib concentrations were tested in mixture with 1.67 MUM, 3.33 or 6.67 MUM cisplatin. After alpha 72-h incubation, adherent cells were ethanol-fixed and epithelial cells were stained using a Cy2TM-labeled pan-cytokeratin antibody; then fluorescent colonies were counted. RESULTS: 33 of 51 ex vivo growing HNSCC (64.7%) exhibited epithelial CF allowing for cut-off detection. Lowest cut-off (complete chemotherapeutical suppressed CF) was noted at 6.25 MUM lapatinib in three HNSCC (9.1%). The percentage of HNSCC achieving cut-off by 6.67 MUM cisplatin (21.2%) was raised by addition of lapatinib at 6.25, 12.5, and 25 MUM up to 33%, 45.5%, and 60.6%, respectively. However, we observed significant inter individual different dose-response curves of HNSCC in response to lapatinib, e.g. variation in concentrations inhibiting CF to 50% (IC(50)) was 60-fold. At the individual level, antagonism, additivity, and synergism were detected as appropriate models describing the mode of action of cisplatin and lapatinib mixtures. CONCLUSION: Lapatinib suppresses CF of epithelial HNSCC cells, and in combination with cisplatin its efficacy is increased. However, caution is advisable due to significant heterogeneity in the response of HNSCC to lapatinib alone and when combined with cisplatin. PMID- 22843893 TI - Overexpression of Epstein-Barr virus-encoded microRNA-BART7 in undifferentiated nasopharyngeal carcinoma. AB - AIM: To validate Epstein-Barr virus BamHI-A rightward transcript 7 microRNA (ebv miR-BART7) expression in plasma from patients with nasopharyngeal carcinoma (NPC) and explore the oncogenic role of ebv-miR-BART7 in NPC cells. PATIENTS AND METHODS: Plasma ebv-miR-BART7 levels were measured using real-time quantitative RT-PCR. Effects on cell proliferation, invasion, migration, and resistance to cisplatin were studied on NPC cells using real-time cell analyzer. RESULTS: The plasma ebv-miR-BART7 level was significantly higher in patients with NPC in comparison with that from healthy individuals. The ebv-miR-BART7 was detectable in all the patient plasma samples and was independent of the EBV DNA level. In vitro expression of ebv-miR-BART7 enhanced proliferation, migration, and invasion of NPC cells. Furthermore, NPC cells expressing ebv-miR-BART7 were more resistant to cisplatin. High-throughput gene expression analysis suggested that ebv-miR BART7 affects multiple cancer-related pathways. CONCLUSION: Our results indicate that plasma ebv-miR-BART7 could be used in NPC screening, especially in cases where EBV DNA is not detectable. The association of ebv-miR-BART7 with common oncogenic pathways suggests that ebv-miR-BART7 is a potential biomarker for undifferentiated NPC. PMID- 22843894 TI - Establishment and characterization of a new human gallbladder carcinoma cell line. AB - BACKGROUND: Prognosis for patients with gallbladder carcinoma (GBC) is poor and the standard treatment for GBC has not yet been established. MATERIALS AND METHODS: We established the human GBC cell line TYGBK-1, from a patient with papillary, tubular adenocarcinoma. RESULTS: The doubling time was 48 hours. This cell line has a missense mutation of p53 and no mutation of the K-RAS gene. This cell line was transplantable to nude mice. We characterized the sensitivity of TYGBK-1 to gemcitabine. We also examined the association of two gemcitabine related genes (deoxycytidine kinase, dCK, and Hu antigen R, HuR). Among four GBC cell lines (TYGBK-1, NOZ, G-415, TGBC2TKB), TYGBK-1 and NOZ exhibited sensitivity to gemcitabine. Furthermore, these cells expressed both dCK and HuR mRNA, rather than gemcitabine-resistant cells. CONCLUSION: The newly established GBC cell line TYGBK-1, may represent an effective tool for development of chemotherapeutic treatment for GBC. PMID- 22843895 TI - Glyoxalase I (GLO1) is up-regulated in pancreatic cancerous tissues compared with related non-cancerous tissues. AB - BACKGROUND: Glyoxalase I (GLO1), an enzyme involved in the detoxification of methylglyoxal in the glycolysis pathway, has been found to be frequently overexpressed in various types of cancer. Recent studies showed that GLO1 is related to proliferation and apoptosis in human cancer cells. However, expression of GLO1 in pancreatic cancer (PC) has not been precisely defined. Since PC is one of the most malignant types of cancer, we investigated the levels of GLO1 in tissues from patients with PC. MATERIALS AND METHODS: We examined the expression of GLO1 in tumors from patients with PC and adjacent normal tissues by western blotting. RESULTS: Western blotting demonstrated that GLO1 was significantly overexpressed in pancreatic cancerous tissues compared with adjacent non cancerous tissues (n=20, p<0.05). CONCLUSION: GLO1 could be a clinically useful target in the therapy of PC. PMID- 22843896 TI - Role of androgen excess in the development of estrogen receptor-positive and estrogen receptor-negative breast cancer. AB - The androgen-excess theory posits a central role of androgens in promoting breast cancer development. At first glance, this appears to contradict the currently accepted central role of estrogens in this process, but as we will show, the apparent contradiction is not a real one. In the present article, we review the mechanisms by which androgen excess may stimulate cancer growth in different subsets of estrogen receptor-positive and estrogen receptor-negative tumors. We also propose an endocrine classification of postmenopausal breast cancer based on the simultaneous evaluation of a patient's serum testosterone levels and the estrogen receptor status of the tumor. This classification identifies several different subsets of tumors and may have important clinical implications. PMID- 22843897 TI - Gentle strength training in rehabilitation of breast cancer patients compared to conventional therapy. AB - Movement therapy during the rehabilitation of breast cancer has become more important over the last years. PATIENTS AND METHODS: In a randomized controlled study the feasibility of gentle strenght training was compared to conventional gymnastic exercises during rehabilitation of breast cancer patients. The aim oft this study was to identify alternative sports intervention in the treatment of breast cancer patients. The intervention group (IG) was lifting standardized weights weekly (50 % of h1RM), while the control group (CG) received conventional gymnastic exercises. A bicycle ergometry adjusted to the WHO system was performed with all participants at study entry (T0), after three (T1) and six months (T2). The quality of life was measured by standardized report forms (EORTC QLQ C30 Version 3 and BR23). RESULTS: Both methods showed a slight improvement in submaximal endurance performance, a significant improvement in the subjective feeling of effort (IG: 75 W: <0.01, CG: 75 W <0.01), in psychosocial and psychological parameters like quality of life (IG: <0.01, CG <0.01) and in fatigue (IG: <0,01, CG: <0.01). CONCLUSION: This study shows positive effects for gentle strength lifting in the rehabilitation of breast cancer patients and turned out to be a probate alternative to gymnastic exercises. PMID- 22843898 TI - Detection of human papillomavirus in lung cancer: systematic review and meta analysis. AB - BACKGROUND: Since the first reports (in 1979) suggesting an etiological role for human papillomavirus (HPV) in bronchial squamous cell carcinoma, literature reporting HPV detection in lung cancer has expanded rapidly, but a comprehensive meta-analysis has yet to be published. We performed a systematic review and formal meta-analysis of the literature reporting on HPV detection in lung cancer. MATERIALS AND METHODS: MEDLINE and Current Contents were searched through April 2012. The effect size was calculated as event rates and their 95% Confidence intervals (CI), with homogeneity testing using Cochran's Q and I(2) statistics. Meta-regression was used to test the impact of study-level co-variates (HPV detection method, geographical origin of study, cancer histology) on effect size, and potential publication bias was estimated using funnel plot symmetry (Begg and Mazumdar rank correlation, Egger's regression, and Duval and Tweedie's trim and fill method). RESULTS: One hundred studies were eligible, covering 7,381 lung cancer cases from different geographical regions. Altogether, 1,653 (22.4%) samples tested HPV-positive; effect size was 0.348 (95% CI=0.333-0.363; fixed effects model), and 0.220 (95% CI=0.18-0.259; random effects model). There was significant heterogeneity between the studies stratified by HPV detection technique, but the random effects in between-strata comparison was not significant (p=0.193). When stratified by i) different geographical regions, and ii) different histological types, the between-strata comparison was significant (p=0.0001). However, in meta-regression, HPV detection method (p=0.473), geographical origin (p=0.298) and histological type (p=0.589) were not significant study-level co-variates. No evidence for significant publication bias was found in funnel plot symmetry testing. In sensitivity analysis, all meta analytic results seemed robust to all one-by-one study removals. CONCLUSION: These meta-analytic results imply that the reported variability in HPV detection rates in lung cancer is better explained by geographical study origin and histological types of cancer than by the HPV detection method itself. In formal meta-regression, however, none of these three factors were significant study level co-variates accounting for the heterogeneity of the summary effect size estimates, i.e. HPV prevalence in lung cancer. PMID- 22843900 TI - Neoadjuvant epirubicin/docetaxel (ET) concomitant chemotherapy for primary breast cancer with tumor diameter >=3.1 cm: results of the Kyushu ET therapy phase II trial. AB - AIM: Neoadjuvant epirubicin/docetaxel (ET) combination chemotherapy was administered to breast cancer patients in order to investigate their clinical and pathological response. Moreover, the breast-conserving surgery (BCS) rate, disease-free (DFS) and overall survival (OS), safety profile and the correlation of biological markers were investigated. PATIENTS AND METHODS: Out of the 46 enrolled patients, 45 patients were analyzed for clinical response, and 40 patients were examined for pathological response. Estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor type2 (HER2) expression were examined immunohistologically. RESULTS: The median tumor size was 4.5 cm in diameter. Complete (CR) and partial responses were seen in 3 and 30 patients, respectively. A pathological CR was achieved in 4 patients and correlated with ER and PgR negativity. Moreover, BCS was performed on 16 patients. The 5-year cumulative DFS was 60.7% and OS was 91.8%. CONCLUSION: ET therapy is clinically effective with a pathological CR rate of 10% for patients with a large tumor, and should be considered as a neoadjuvant treatment option. PMID- 22843899 TI - Serum hepatocyte growth factor and interleukin-6 are effective prognostic markers for non-small cell lung cancer. AB - AIM: We surveyed prognostic biomarkers for resectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We obtained preoperative serum from 109 patients, and measured the levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and nicotinamide N-methytransferase (NNMT) in the sera. RESULTS: The median HGF and IL-6 contents were 860 pg/ml and 2.7 pg/ml, respectively. Analysis of survival curves indicated that an HGF or IL-6 level higher than the median was associated with poor overall survival (HGF, p=0.019; IL-6, p=0.002). In addition, we analyzed stage III lung cancer alone. Higher HGF and IL-6 levels were associated with poor overall survival (HGF, p=0.016; IL-6, p=0.013). Disease-free survival was not statistically significantly affected by these cytokine contents. The tumor status (pT factor) and nodal status (pN factor) were not associated with the survival of stage III patients. CONCLUSION: The levels of HGF and IL-6 in serum could be useful prognostic indicators of the survival of patients with stage III NSCLC undergoing surgery and chemotherapy. PMID- 22843901 TI - Biochemical failure after carbon ion radiotherapy for prostate cancer. AB - BACKGROUND/AIM: Biochemical failure after radiotherapy for prostate cancer occurs infrequently, but some cases progress to a poor outcome. The aim of this study was to examine prognosis after biochemical failure. PATIENTS AND METHODS: A total of 728 patients were treated with carbon ion radiotherapy, and biochemical failure occurred in 90 (12.4%). Their outcomes were examined according to risk factors, histological findings, and androgen deprivation therapy (ADT). RESULTS: Biochemical failure rates were 12%, 6%, and 15% in low-, intermediate- and high risk patients. Most patients responded favorably to salvage therapy. Some high risk patients (25%) progressed to poor outcome; half experienced failure after ADT, while the rest during ADT, indicating that ADT had a slight influence. Patients who died from their disease had approximately two years of biochemical failure-free time and three years of survival after failure. Their tumor showed the presence and the increased proportion of histologically high-grade growth patterns. CONCLUSION: Histological growth patterns and short biochemical failure free time are prognostic factors for poor outcome regardless of ADT. PMID- 22843902 TI - Clinical significance of chemoradiotherapy and surgical resection for cT4 esophageal cancer. AB - AIM: To clarify the clinical significance of definitive chemoradiotherapy (CRT) and CRT followed by esophagectomy for cT4 esophageal cancer. PATIENTS AND METHODS: The treatment results for cT4 esophageal cancer were examined in 81 patients who received definitive CRT [radiation 50-70 Gy, cisplatin and 5 fluorouracil; group I] and 19 patients who underwent esophagectomy after preoperative CRT [40Gy, Group II]. RESULTS: Among the 81 patients in group I, toxicities (grade 3 or 4) were observed in 32 patients, while partial response and complete response were recognized in 8 and 47 patients, respectively. Of the 19 group II patients, an R0 resection was performed in 16 patients, and the mortality rate was 5%. The 5-year survival rates were 19% and 42% in groups I and II, respectively. CONCLUSION: Long-term survival can be expected after multimodal therapy, even for patients with cT4 esophageal cancer. Esophagectomy is therefore a valid treatment option when down-staging can be achieved. PMID- 22843903 TI - Dexamethasone plus somatostatin-analog manipulation as bone metastasis microenvironment-targeting therapy for the treatment of castration-resistant prostate cancer: a meta-analysis of uncontrolled studies. AB - BACKGROUND: Antisurvival factor therapy for prostate cancer cells (ASF) in castration-resistant prostate cancer, is a hormonal manipulation consisting of a somatostatin analog, which reduces the growth hormone-dependent, systemic IGF-1 production and of oral dexamethasone, which supresses the urokinase type plasminogen activator -mediated "local" increase of IGF-1 bioavailability in the bone metastases, while the patients continue on a luteinizing hormone-releasing hormone analog therapy. AIM: To revisit relevant evidence and provide a quantitative summary estimate of ASF efficacy. MATERIALS AND METHODS: A structured review of relevant literature and a meta-analysis of uncontrolled studies and cohorts within trials was carried out at tertiary academic centers. A computerized literature search was conducted in the electronic database Medline from inception to January 2012. To be eligible for inclusion, a study had to report data on the efficacy of ASF in the treatment of castration-resistant prostate cancer, independently of study design or duration. Data synthesis was performed using restricted maximum-likelihood random effects model. RESULTS: Four studies fulfilled the inclusion criteria and were used for the evidence synthesis. The probability of a partial response within six months (defined as at least a 50% decrease from baseline prostate-specific antigen concentrations) was 59.5% (95% confidence interval, 49.3% to 69.3%). No evidence of heterogeneity was noted (I(2) 0%). The response noted did not persist over time (median progression free survival of seven months and median overall survival of 16 months). The uncontrolled nature of the evidence and the paucity of other outcomes of interest need to be taken into account in the interpretation of the results. CONCLUSION: ASF manipulation is a safe alternative to standard therapy and induces partial remission lasting for at least six months. This partial response is consistently accompanied with an improvement in bone pain, performance status and quality of life. PMID- 22843904 TI - Clinical significance of tumor pathology for postoperative survival of patients undergoing surgery for stage IV colorectal cancer. AB - Uni- and multivariate analyses were performed in order to assess the most valuable clinical features that were associated with the overall survival of 169 patients who underwent surgery for stage IV colorectal cancer (CRC). Univariate analyses demonstrated that tumor pathology (other/tub1, 2), the proportion of neutrophils and lymphocytes, serum level of C-reactive protein and albumin, neutrophil to lymphocyte ratio, and intraoperative bleeding volume were associated with overall survival. Multivariate analysis using these seven selected features disclosed that only tumor pathology was associated with the overall survival (p<0.001). In addition, tumor pathology was able to divide not only the patients as a whole (p<0.001), but also both patients with stage IVa (p=0.007) and IVb (p=0.007), into two groups for overall survival, respectively. Tumor pathology is not only associated with the overall survival but is also able to divide both patients as a whole and those sub-classified by stage, into two independent groups before surgery. PMID- 22843905 TI - Main effects and interactions of carbonic anhydrase IX, hypoxia-inducible factor 1alpha, ezrin and glucose transporter-1 in multivariate analysis for disease outcome in rectal cancer. AB - Strong expression of carbonic anhydrase IX (CA IX), hypoxia-inducible factor 1alpha (HIF-1alpha), ezrin and glucose transporter-1 (GLUT-1) were previously shown to be interrelated and to affect clinicopathological prognostic factors. In the current study, operative samples from 178 rectal cancer patients, 77 treated with short-course, 47 with long-course preoperative radiotherapy (RT), and 54 with no preoperative treatment, as well as 80 preoperative biopsies from the RT group were analysed using multivariate modelling in order to assess the role of these markers as predictors of disease outcome. Multivariate survival analysis revealed several sets of panels with the potential ability to identify patients at increased or decreased risk of dying from their disease or disease recurrence. The most remarkable panel, consisting of moderate/strong expression of CA IX, positive HIF-1alpha expression and negative/weak GLUT-1 expression in operative samples and negative/weak ezrin expression in preoperative biopsies was associated with 47.5-fold risk of death from this disease. These results should, however, be interpreted with caution due to the heterogeneity of the patient population in this retrospective study. PMID- 22843906 TI - No additional benefit of adding ifosfamide to docetaxel in castration-resistant metastatic prostate cancer. AB - BACKGROUND: In the treatment of many types of cancer, combination chemotherapy has been shown to be better than single-agent chemotherapy. The aim of our phase I-II clinical trial was to assess the efficacy and toxicity of docetaxel ifosfamide combination chemotherapy in patients with castration-resistant metastatic prostate cancer (CRPC). PATIENTS AND METHODS: A total of 31 patients were enrolled to receive first-line chemotherapy consisting of 40-60 mg/m(2) docetaxel followed by 3.0 g/m(2) ifosfamide with mesna. All drugs were administered intravenously. The maximum duration of the chemotherapy was six cycles. The median age of the patients was 70 (range 58-82) years. Prostate specific antigen (PSA) responses were determined according to the PSA working group guidelines and all toxicities, time-to-progression and overall survival were determined according to the WHO criteria. RESULTS: The objective PSA response rate was 32% in 11/31 patients. The mean PSA value at baseline was 300 (range 2.5-1577) MUg/l. The overall median survival was 14.1 months; 15 patients were alive at a median follow-up time of 18 months. The observed side-effects were as expected, with grade 3-4 neutropenia developing in 38% of the cycles, whereas febrile neutropenia occurred in only 12% of the patients. The median number of administered cycles was 4.8. No acute hypersensitivity reactions were observed. Transient renal insufficiency developed in two patients, thus necessitating dose reductions. CONCLUSION: The combination of docetaxel and ifosfamide seems to be well-tolerated and has some activity in patients with CRPC. However, newer docetaxel-based combination chemotherapy regimens need to be further developed in other to provide more efficacious and well-tolerated treatment options for earlier phases of CRPC. PMID- 22843907 TI - A case of paraneoplastic autoimmune pancreatitis: mini-review of paraneoplastic syndromes in breast cancer. AB - Breast cancer (BC), the most common type of cancer in women of the Western world, is often associated with paraneoplastic syndromes (PNS). Autoimmune pancreatitis is a recently recognized entity belonging to the spectrum of IgG4-related systemic diseases, which are characterized by target-organ plasmacytic infiltration and fibrosis. In this report we review PNS associated with BC and we present the first case of BC-associated autoimmune pancreatitis as well as its successful management with steroids and immunosuppressive BC-tailored chemotherapy. PMID- 22843908 TI - Definitive radiation therapy for extramammary Paget's disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is frequently inoperable because of old age and/or coexisting disease. We therefore reviewed the efficacy and toxicity of radiation therapy for EMPD. PATIENTS AND METHODS: Fourteen patients with EMPD underwent definitive radiation therapy. Three patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 52-80.2 Gy (median=60.6 Gy) were delivered to tumor sites in 26-43 fractions (median=33 fractions). RESULTS: Four patients had developed recurrence at a median follow-up period of 47 months. The 5-year local control and disease free rates were 71% and 63%, respectively. Two patients died of old age and renal failure at 6 and 51 months, respectively, after irradiation. The 5-year disease free, cause-specific and overall survival rates were 46%, 100% and 79%, respectively. No therapy-related toxicities of grade 3 or greater were observed. CONCLUSION: Radiation therapy is effective and safe, and appears to offer a curative treatment option for patients with EMPD. PMID- 22843909 TI - Yes-associated protein is not an independent prognostic marker in breast cancer. AB - BACKGROUND: The development of tissue microarray (TMA) technology has provided the opportunity to perform analyses of tissue samples on a large scale in an uniform fashion. This study was designed with the use of TMA to explore the Yes associated protein (YAP) status in breast cancer. PATIENTS AND METHODS: YAP expression in tumor and tumor-free samples from 94 patients with primary breast cancer was analyzed by TMA. The clinicopathological data for age, estrogen receptor status, histological grading and TNM staging were also collected. RESULTS: There were 29 patients (30.8%) with 1(+) expression, in YAP, 59 patients (62.8%) with 2(+) expression and 6 (6.4%) with 3(+) expression. There was no significant relationship between YAP expression and the other clinicopathological variables. By multivariate analysis, YAP expression failed to produce any significant relationship with the overall survival rate. CONCLUSION: YAP expression is not an independent prognostic factor in patients with breast cancer. PMID- 22843910 TI - Oral cancer in Swedish snuff dippers. AB - Over recent decades there has been debate over whether or not Swedish snuff is carcinogenic in humans. Animal studies and molecular biological and experimental studies have shown the carcinogenic potential of Swedish snuff, but this has not been proved in prospective randomized studies. We present a case series of patients with oral squamous cell carcinomas diagnosed at the sites where the patients had used Swedish snuff for several years. Sixteen male patients were referred to and treated at Oral and Maxillofacial Surgery Departments and Ear, Nose and Throat clinics at seven different hospitals in Sweden. The mean age of the patients at the time of diagnosis was 72.9 years and the mean time of snuff use prior to cancer diagnosis was 42.9 years. This case series shows that Swedish snuff may not be a harmless alternative to smoking. PMID- 22843911 TI - Tumor angiogenesis in 75 cases of pleomorphic carcinoma of the lung. AB - BACKGROUND: Pleomorphic carcinoma (PC) of the lung is a rare tumor that usually has an aggressive clinical course and a poor prognosis. In this study, 75 cases of PC were reviewed to identify its clinical features, and we examined the expression of angiogenic factors. PATIENTS AND METHODS: We immunohistochemically examined the expression of angiogenic factors in tissue specimens of PC. RESULTS: 66 males and 9 females were examined. The median survival time was 16.5 months. The stage and symptomatical diagnosis were significantly associated with the survival. In the immunohistochemical analyses, vascular endothelial growth factor (VEGF) was expressed in many cases of PC. A high score for angiogenesis was significantly related to a poorer prognosis. CONCLUSION: We conclude that PC should be considered an aggressive disease, and that the stage and symptomatical diagnosis are strong prognostic factors. Furthermore, tumor angiogenesis provides significant prognostic information about the clinical outcome in PC. PMID- 22843912 TI - Clinical significance of circulating tumor cells and free DNA in non-small cell lung cancer. AB - AIM: This pilot study assessed correlations between circulating tumor cells (CTCs) and circulating free DNA (cfDNA) of metastatic non-small cell lung cancer (NSCLC) after acquisition of resistance to epidermal growth factor receptor tyrosine kinase inhibitors. PATIENTS AND METHODS: CTCs were counted using the CellSearch system (Veridex). cfDNA was analyzed for EGFR mutation status by the Cycleave real-time PCR assay. RESULTS: Twenty-four patients participated in this study. CTCs were detected in 8 of 24 cases (33.3%), at a mean of 2.6 CTCs per 7.5 ml blood (range: 1-24). EGFR mutations in cfDNA were detected in 6 out of 24 cases (25%). The EGFR mutation detection rates in cfDNA were significantly higher in patients with >= 2 CTCs per 7.5 ml (100%) than in those with <2 CTCs per 7.5 ml (10%) (p=0.0001). CONCLUSION: The presence of CTCs was correlated with the positivity of EGFR mutation in cfDNA. PMID- 22843913 TI - Extraskeletal myxoid chondrosarcoma of the left buccal mucosa. AB - Extraskeletal chondrosarcoma (ECS) is a rare malignant neoplasm of bone or soft tissue origin, characterized by the presence of spindle cells admixed with well differentiated cartilage or chondroid stroma. A case of ECS is reported in a 102 year-old woman who presented with a painful swelling of 2 cm in the left buccal vestibular area. Orthopantomography was insignificant. Biopsy and histopathological examination revealed a tumor composed of an undifferentiated small round cell component that surrounded a myxoid matrix of malignant cartilage. Immunohistochemical studies showed the tumor cells to be positive for nuclear S-100 protein immunostaining, focally positive for vimentin and synaptophysin, and negative for epithelial membrane antigen, desmin, chromogranin, Leu-7, glial fibrillary acid protein, actin muscle-specific, cytokeratin, carcinoembryonic antigen, and CD99 (MIC2). The proliferative index (MIB-1) was 20%. The tumor was treated by surgery with wide margins. There was no evidence of disease at one-year follow-up. This report presents a very rare case of ECS of the left buccal mucosa of the maxilla, and describes the histological characteristics and the immunoprofile. PMID- 22843914 TI - Successful resection of esophageal carcinoma associated with double aortic arch: a case report. AB - Double aortic arch (DAA) is an extremely rare vascular malformation which causes tracheal and esophageal compression, resulting in respiratory symptoms such as stridor and wheezing, or feeding problems such as dysphagia, usually during the first few months of life. In contrast, this disorder is rarely diagnosed in adults. We herein present an elderly case with thoracic esophageal carcinoma with DAA. To the best of our knowledge, this is only the second report of a successfully resected case of esophageal cancer associated with DAA in the English literature. Moreover, this is the first reported case of symptomatic DAA with esophageal carcinoma. Spiral computed tomography and three-dimensional reconstruction was very useful for preoperative assessment of the abnormal vessels. PMID- 22843915 TI - Splenomegaly during oxaliplatin-based chemotherapy for colorectal carcinoma. AB - AIM: The aim of this study was to evaluate changes in splenic size and platelet counts, in patients with colorectal cancer during oxaliplatin based chemotherapy, and to determine their clinical significance. PATIENTS AND METHODS: The prospectively archived records of 50 patients with colorectal cancer that received oxaliplatin-based chemotherapy were reviewed. RESULTS: Thirty-eight men and 12 women, of median age 58 (range 35-77) years, were enrolled. Median spleen volume ratios were 1.3-fold after 6 cycles and 1.9-fold after 12 cycles. The incidence of splenomegaly was 30% after 6 cycles and 67% after 12 cycles, and of thrombocytopenia was 70% after 6 cycles, 82% after 9 cycles, and 80% after 12 cycles. Thrombocytopenia was found to be related to splenomegaly, and this pattern was notable after 6 cycles of chemotherapy. CONCLUSION: Splenic enlargement and reduction in platelet counts were common during chemotherapy. Furthermore, these changes were found to occur rapidly after 6 cycles of chemotherapy. PMID- 22843916 TI - Mesenchymal characterization: alternative to simple CTC detection in two clinical trials. AB - BACKGROUND: Breast cancer is one of the most common malignancies in women. Approximately 25% of patients with early-stage disease will develop metastatic recurrence. Two clinical trials were undertaken in order to detect circulating tumor cells (CTCs) in primary breast cancer. PATIENTS AND METHODS: Four-hundred patients with early breast cancer were enrolled in the trial. After enrichment from their peripheral blood, their CTCs were characterized by gene expression of cancer cell markers. RESULTS: CTCs had a predominant epithelial phenotype in 8.75% of patients and de-differentiated characteristics (mesenchymal, stem phenotypes alone or both) in 37.6%. CONCLUSION: Tumor epithelial cells undergoing epithelial-mesenchymal transition give rise to cells with mesenchymal aggressive phenotype. Detection of mesenchymal and cancer stem cells, which are tumor initiating cells, is more relevant than simple counting of CTCs to assess their presence in the blood of patients with breast cancer. This study will be the basis for future evaluation of the outcome of the disease and the prognostic value of early-detected CTCs. PMID- 22843917 TI - Radical radiotherapy for superficial esophageal cancer: impact of clinical N stage on survival. AB - AIM: To retrospectively analyze the results of radical radiotherapy for patients with superficial esophageal cancer (SEC). PATIENTS AND METHODS: Forty-eight patients with SEC were reviewed. The median dose of external beam radiotherapy was 66 Gy (range, 30 to 70 Gy). Intraluminal brachytherapy was used in 10 patients, and 15 patients (31%) underwent chemotherapy. The median follow-up period was 28 months (range, 4 to 116 months). RESULTS: Sixteen patients had recurrence (11 patients: in-field local recurrence; 3 patients: regional lymph node recurrence; 2 patients: distant metastasis), and the 5-year local control (LC) rate was 74.2%. The 5-year overall survival and disease-free survival (DFS) rates were 44.5% and 48.6%, respectively. Patients with clinical N1 disease (5 year DFS: 0%) had significantly poorer DFS than patients with clinical N0 disease (5-year DFS: 51%, p=0.019). CONCLUSION: Radical radiotherapy yielded relatively favorable LC rates in patients with SEC, and clinical N stage was a significant prognostic factor for DFS. PMID- 22843918 TI - hGH and GHR expression in large cell neuroendocrine carcinoma of the colon and rectum. AB - Large cell neuroendocrine carcinoma (LCNEC) is an aggressive neoplasm with a low frequency of occurrence in the digestive tract. We present a series of eight patients diagnosed with LCNEC of the colon and rectum. Grossly, tumors were presented as endophytic/ulcerative, annular and polypoid masses, with a gray white color and necrosis in most cases. Histologically, they were high-grade tumors composed of large cells of organoid, nesting, trabecular, rosette-like and palisading patterns, with a high mitotic rate. Tumors were immunoreactive for neuroendocrine markers, including chromogranin A (2/8), synaptophysin (7/8), and neuron-specific enolase (8/8). Moreover, we analyzed the expression of growth hormone (hGH) and growth hormone receptor (GHR) in colorectal LCNECs and six tumors were immunoreactive for hGH, while five tumors were immunoreactive for GHR. To our knowledge hGH and GHR expression has not been previously analyzed in colorectal LCNEC. Their overexpression suggests a role of hGH and GHR in the development of colorectal LCNEC. PMID- 22843919 TI - MRI and ultrasound-guided prostate biopsy using soft image fusion. AB - OBJECTIVES: Transrectal ultrasound (TRUS)-guided random biopsies is the gold standard when diagnosing prostate cancer. A new 3D system with organ tracking, allows accurate targeted biopsies using magnetic resonance imaging (MRI) and TRUS soft image fusion. The aim of the study was to evaluate the accuracy of targeted biopsies. MATERIALS AND METHODS: Retrospective study of 90 consecutive patients with suspected prostate cancer underwent MRI prior to biopsy using 3D T2w and diffusion weighted imaging (12 min protocol). Suspicious tumours (MRI targets) were highlighted on axial T2w images and classified as high, moderate or low degree of cancer suspicion. Navigation system: Urostation(Koelis(r), Grenoble, France). Primary endpoint: Rate of successful targeted biopsies. Positive biopsies with Gleason score. RESULTS: MRI was positive in 80/90 (89%) patients, in which 115 MRI targets were identified and biopsied. There were 112/115 (97%) successful biopsies inside target, and 60/115 (52%) targets were positive for cancer. Positive biopsies according to degree of cancer suspicion were: high 50/55 (91%), medium 6/22 (27%) and low 4/38 (10%). All MRI-negative patients had negative random biopsies. CONCLUSION: The high rate (97%) of successful biopsies in this study indicates that targeted biopsies using MRI and TRUS soft image fusion technique might be an accurate method. PMID- 22843920 TI - Relapse of endometrial carcinoma: follow-up of 272 patients with relapse. AB - A total of 2090 patients with endometrial carcinoma were followed-up for at least five years. The treatment modalities, as well as the results of treatment, regarding 272 patients with disease relapse are presented. The results are not encouraging. We found no statistically significant difference regarding overall survival, when the patients were divided according to initial stage or ploidy status. There was also no significant difference between overall survival and the mode of treatment. 108 out of 272 patients with relapse died of their disease. Regarding patients in stage I-II we present the survival for every studied year, where we compared those with more than one site of metastasis (n=108), more than one metastasis (n=59), or no relapse at all (n=1289) with an age-corrected Swedish female population. We found that the vast majority of patients did not die from their cancer-related illnesses, and also found an increased death-rate among those with cancer without relapse, compared to those without cancer (20% compared to 14%, 5 year follow-up). We conclude that the majority of patients would benefit from an increased effort to cure other illnesses rather than concentrating on cancer treatment alone. PMID- 22843922 TI - Impact of immunohistochemical analysis of sentinel lymph node biopsy on breast cancer management. AB - BACKGROUND: Little evidence of the impact of immunohistochemical analysis (IHC) on the indications for adjuvant therapies is available. This study determined the modification rate of adjuvant chemotherapy and lymph node area radiotherapy using IHC and its impact on survival. PATIENTS AND METHODS: Between 2001 and 2005, 416 patients underwent surgery for invasive breast cancer with sentinel lymph node (SLN) biopsy. RESULTS: A total of 112 patients had positive SLNs: 12.5% isolated tumor cells, 35.7% micrometastasis and 51.8% macrometastasis. Only 4% of patients (14 out of 342 patients) had modified indications for chemotherapy and 7% of patients (25 out of 342) for lymph node area radiotherapy due to IHC findings. CONCLUSION: IHC analysis led to modifications in adjuvant chemotherapy and lymph node area radiotherapy in 4% and 7% of patients, respectively. The prognosis of patients with nodal metastasis discovered by ultrastaging was similar to that for conventional Haematoxylin-Eosin-Safran (HES) staining. Our data support the use of SLN ultrastaging. PMID- 22843921 TI - Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with metastatic gastric cancer. AB - BACKGROUND: The current standard treatment for patients with metastatic gastric cancer (MGC) is systemic chemotherapy. For gastric cancer patients with ovarian metastases, i.e. Krukenberg tumors, it is not known whether metastasectomy is associated with additional benefits. PATIENTS AND METHODS: All patients who were diagnosed with gastric cancer and ovarian metastases between March 2000 and July 2010 in a medical center were included in the current study. The clinicopathological features and the treatment records were reviewed in detail and their association with overall survival (OS) was analyzed. RESULTS: A total of 85 patients were identified. Thirty five (41.2%) and 50 (58.8%) patients did and did not undergo metastasectomy of Krukenberg tumors, respectively. The performance status and the proportion of patients receiving subsequent systemic therapy were well-matched between the two groups. Regarding disease status, patients who underwent metastasectomy had significantly larger Krukenberg tumors, pronounced bilateral disease and less extensive metastases outside the ovaries than patients who did not undergo metastasectomy. Patients who underwent metastasectomy had a better OS [median=14.1 months; 95% confidence interval (CI)=8.6-19.6 months] than patients who did not undergo metastasectomy (median OS=8 months; 95% CI=5.6-10.4 months, p=0.001). There was no aberrant postoperative morbiditie rate observed, and the median length of hospital stay after metastasectomy alone was 6 days. Based on multivariate analysis, metastasectomy remained an independent predictor of better OS (hazard ratio=0.36, p=0.002). The administration of subsequent systemic therapy, the use of platinum based chemotherapy, and a better performance status also predict a better OS. CONCLUSION: Metastasectomy of Krukenberg tumors may be associated with survival benefits in patients with MGC. Further prospective studies are warranted. PMID- 22843923 TI - Chaperon normal goblet cells intercalated with dysplastic cells in duodenal adenomas express synaptophysin. AB - BACKGROUND: Several authors demonstrated that normal goblet cells intermingle with dysplastic cells in duodenal adenomas. Goblet cells in the normal duodenum were found to cross-react with the neurotransmitter synaptophysin, a synaptic glycoprotein present in neuroendocrine cells and in virtually all neurons of the central nervous system. In this work, we investigated whether goblet cells in duodenal adenomas express synaptophysin. MATERIALS AND METHODS: Sections from 29 duodenal adenomas were immunostained for synaptophysin. RESULTS: All intercalated normal goblet cells in duodenal adenomas expressed synaptophysin. The mean percentage of synaptophysin-expressing goblet cells in the basal third of the adenomas was 49%, in the middle third 38% and in the superficial third 5% (basal and middle thirds vs. superficial third, p<0.05). Synaptophysin-positive goblet cells were also stained with alcian blue (pH 2.5) and MUC2, that stain sialomucins. In the normal ileum, only occasional goblet cells were stained (faintly) with synaptophysin. On the other hand, all goblet cells in the normal cecum were synaptophysin negative. CONCLUSION: Normal goblet cells found in duodenal adenomas express synaptophysin. Consequently, duodenal adenomas with synaptophysin-expressing goblet cells should also be stained with alcian blue (pH 2.5) or with MUC2 to confirm that these are native normal goblet cells, thereby rejecting the possibility of a composite adenoma-microcarcinoid in the duodenum. PMID- 22843924 TI - Thalidomide for the treatment of myelodysplastic syndrome in Taiwan: results of a phase II trial. AB - BACKGROUND: Thalidomide inhibits angiogenesis and exerts complex immunomodulatory activities. This phase II study aimed to examine the efficacy of thalidomide in Taiwanese patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Sixty patients [intention to treat group (ITT)] with MDS were treated with thalidomide (100 mg/day, increased by 100 mg/day weekly to a maximum of 400 mg/day) for 12 weeks. Forty-two patients of the ITT group were considered as comprising the evaluable population (EP). RESULTS: Thalidomide resulted in hematological improvement (HI) in 28% of ITT analysis and in HI in 40% of the EP. Thalidomide was more effective for MDS patients with low to intermediate-1 International Prognostic Score System scores. The response rates were 7% for ITT and 10% for EP patients. Only two patients exhibited a cytogenetic response. Net reduced levels of vascular endothelial growth factor and basic fibroblast growth factor cytokines were observed in the peripheral blood and the bone marrow of thalidomide-treated patients. CONCLUSION: Low-dose thalidomide is an effective and safe treatment for patients with low-risk MDS. PMID- 22843925 TI - Association of location of lymph node metastases with postoperative recurrence of esophageal squamous cell carcinoma. AB - Lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (ESCC) has important prognostic implications. In this study, we examined the association between postoperative recurrence and the location of LN metastases in patients with clinical stage II/III ESCC. Of 90 patients who underwent curative esophagectomy with systemic lymphadenectomy at our Department between 2000 and 2007, we identified 49 recurrences and 37 deaths during follow-up. UICC pathological stage, pathological intramural metastasis, total number of LN metastases, and number of involved LNs in upper paraesophageal, subcarinal, lower paraesophageal, post mediastinal, perigastric, and celiac locations were significantly associated with recurrence-free survival (RFS) in univariate analysis. In multivariate analysis, the number of involved subcarinal and lower paraesophageal LNs were independent factors predictive of postoperative recurrence. Our findings suggest that patients with LN metastases at these locations are at risk of recurrence and should be considered for more aggressive adjuvant therapies. PMID- 22843926 TI - Impact of adjuvant immunochemotherapy using protein-bound polysaccharide-K on overall survival of patients with gastric cancer. AB - Protein-bound polysaccharide K (PSK) is an anticancer agent used for adjuvant therapy against gastric cancer. The aim of this study was to evaluate the effect of PSK on the overall survival of patients with gastric cancer. A total of 254 patients who underwent surgical curative resection were included in this retrospective study. We identified 138 patients who received antimetabolites alone (control group) and 115 patients who received antimetabolites plus PSK (PSK group). In patients with early tumor recurrence, overall survival was significantly better in the PSK group (p=0.023). In patients with pN3 lymph node metastasis, median overall survival was better in the PSK group compared with the control group (p=0.032). Our results suggest that adjuvant immunochemotherapy with PSK increased the overall survival for patients with pN3 and early tumor recurrence. Thus, the combination of PSK with oral chemotherapeutic agents might be suitable for postoperative adjuvant therapy against gastric cancer in patients with lymph node metastases. PMID- 22843927 TI - The mTOR inhibitor everolimus in combination with carboplatin in metastatic breast cancer--a phase I trial. AB - AIM: Despite advances in the the first- and second-line treatment of metastatic breast cancer, there remains a large unmet need for additional treatment options. As preclinical studies have suggested that combining everolimus with carboplatin may produce higher activity than each drug by itself, we initiated a phase I study of this combination. PATIENTS AND METHODS: Patients with pre-treated metastatic breast cancer received weekly carboplatin at AUC2 and daily oral everolimus at different dose-levels (level I: 2.5 mg; II: 5 mg; III: 7.5 mg; IV: 10 mg). Three patients were assigned to dose-levels I to III, and six to dose level IV. The primary end-point was to determine the maximum tolerated dose (MTD). RESULTS: Fifteen patients were recruited to the study. The median number of previous chemotherapies was four (range: 1-11). No dose-limiting toxicity occurred at levels I-III during the first cycle. Based on the pre-determined definition, the maximum planned dose-level IV was selected as the MTD. Patients received a median of four cycles of treatment (range 1-13). Most frequent grade 3 and 4 toxicities included leukopenia, thrombocytopenia and infection. Response rates were as follows: 21% partial response, 43% stable disease, and 36% progressive disease. CONCLUSION: Carboplatin and everolimus is a well-tolerated combination for heavily pre-treated metastatic breast cancer. Everolimus (10 mg/d) and carboplatin (AUC2 weekly) were defined as the MTD. This dose is currently being employed in an ongoing phase II trial. PMID- 22843928 TI - Brain metastasis in a patient with a sarcomatoid variant RCC with well-controlled extracerebral metastases by temsirolimus. AB - BACKGROUND: The sarcomatoid variant of metastatic renal cell carcinoma (RCC) has often an aggressive course and a poor prognosis, particularly when accompanied with brain metastasis. CASE REPORT: We describe the case of a patient with sarcomatoid variant RCC in whom brain metastasis was observed as a new lesion during treatment with temsirolimus, despite other extracerebral metastatic lesions being well-controlled and progression-free. RESULTS: This discrepancy between the effectiveness of temsirolimus for extracerebral metastases and the simultaneous progression of brain metastases of RCC raises a concern that while vascular endothelial growth factor (VEGF)-targeted therapy may have clinical efficacy, it may also carry a risk for new brain metastases due to weakening of the structure of the blood brain barrier. CONCLUSION: This case indicates that computed tomography monitoring of the brain should be regularly performed during VEGF-targeted therapy in patients with sarcomatoid variant RCC, even if brain metastases are absent and extracerebral metastatic lesions are well controlled. PMID- 22843929 TI - Acute liver failure, rupture and hemorrhagic shock as primary manifestation of advanced metastatic disease. AB - BACKGROUND: Malignancies rarely cause of acute liver failure, the presence of which have to be ruled-out during transplant evaluation. Tumor-related liver ruptures sporadically occur and might further complicate patient management. CASE REPORT: We report the case of a previously healthy 56-year-old male with complaints of abdominal pain. Initially, levels of liver enzymes were elevated, however, comprehensive imaging examinations revealed no gross abnormalities. As acute liver failure developed, transplantation was evaluated. Sudden liver rupture and hemorrhage forced the performance of an emergency laparotomy. Hepatectomy was planned, until a donor organ was allocated. Intraoperatively, the liver unexpectedly revealed diffuse tumor infiltration. Without further therapeutical options, the patient died. Immunohistochemistry showed metastatic infiltration of a carcinoma of unknown primary. CONCLUSION: Even in previously healthy patients suffering from acute liver failure, exclusion of malignancies is mandatory before transplantation. As imaging might be misleading, a biopsy should be considered early in unresolved cases. PMID- 22843930 TI - Decreased immunoexpression of standard form of CD44 is an independent favourable predictor of nodal metastasis in colorectal carcinoma. AB - BACKGROUND: CD44 is a transmembrane glycoprotein and is associated with cell matrix and cell-cell interactions. CD44 expression was shown to be relevant to tumour progression in various types of human cancer. The objective of this study was to investigate the relationship between the expression levels of the standard form of CD44 (CD44s), and clinicopathological characteristics in a subset of colorectal carcinomas (CRC). PATIENTS AND METHODS: A total of 96 cases of CRC were retrieved from the archives at the Department of Pathology at King Abdulaziz University, Jeddah, KSA. Immunohistochemistry was performed using antibodies to CD44s. A cut-off of <10% of positive neoplastic cells was used to define low expression, 10-50% to define moderate expression and >50% to define extensive expression. Statistical tests were used to determine the association of CD44s with clinicopathological characteristics in a subset of colorectal carcinomas and survival. RESULTS: Immunostaining results showed that there was no association between C44 immunoexpression and age of patients, tumour grade, depth of invasion, vascular invasion, recurrence and survival. CD44s immunolabelling was found to have an association with nodal metastasis and to be an independent predictor of nodal metastasis. CONCLUSION: Loss of CD44s immunolabelling in CRC is an independent favourable predictor of regional lymph node metastasis. On the other hand, CD44s loss has no significant association with disease recurrence or survival. Extensive in vivo and in vitro molecular studies are required to elucidate the possible mechanistic association of CD44s with tumour initiation, progression, invasion and metastasis in primary CRC, and in nodal and distant metastases. PMID- 22843931 TI - Combination of core biopsy and fine-needle aspiration increases diagnostic rate for small solid renal tumors. AB - AIM: Our aim was to evaluate the performance of combination of fine-needle aspiration (FNA) and core biopsy (CB) as a method for the diagnosis of small solid renal tumors. PATIENTS AND METHODS: Ninety patients with a radiologically detected small solid renal tumor (<= 4 cm) underwent a biopsy. Patient underwent FNA (FNA group, n=32) or CB (CB group, n=30) or combination of both FNA and CB (combination group, n=28). The diagnostic rate and accuracy of both techniques were assessed. RESULTS: The diagnostic rate of the combination group (92.9%) was superior to that of the FNA group (62.5%) and CB group (76.7%) (p=0.006, and p=0.147, respectively). In the combination group, 11 CBs were diagnostic with 13 nondiagnostic FNAs, while 4 FNAs were diagnostic with 6 nondiagnostic CBs. For tumors <= 2 cm, the combination of FNA and CB significantly increased the diagnostic rate, compared with FNA alone (p=0.033) and CB alone (p=0.044). The accuracy for FNA, CB and the combination of FNA and CB was 88%, 100% and 100%, respectively. CONCLUSION: The combination of FNA and CB increased the diagnostic rate of renal biopsy for the small solid renal tumors. PMID- 22843932 TI - Cell-free DNA level as a prognostic biomarker for epithelial ovarian cancer. AB - BACKGROUND: The use of cell-free DNA (cfDNA) as a non-invasive biomarker has been evaluated in many types of cancer. This study investigated the prognostic significance of cfDNA level for ovarian cancer. MATERIALS AND METHODS: Preoperative sera of 36 patients with ovarian cancer and of 16 with benign tumors were analyzed using commercially available copy number assay kits to measure the cfDNA level of genes including beta-2-microglobulin (B2M), member RAS oncogene family (RAB25), claudin 4 (CLDN4) and ATP-binding cassette subfamily F member 2 (ABCF2). Cox regression analysis was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: cfDNA level of these genes had no association with other prognostic factors of ovarian cancer. In particular, in patients with advanced stage disease, a low RAB25 level was an independent prognostic factor for disease-free survival (HR=18.2, 95% CI=2.0-170.0) and overall survival (HR=33.6, 95% CI=1.8-634.8). CONCLUSION: Our findings suggest that the preoperative serum cfDNA level of RAB25 could be a useful biomarker predicting survival outcomes in patients with advanced ovarian cancer. PMID- 22843933 TI - The functional polymorphism of erythropoietin gene rs1617640 G>T is not associated with susceptibility and clinical outcome of early-stage breast cancer. AB - Recent data suggest that erythropoietin (EPO) plays a substantial role in cancer development and clinical outcome by stimulating cell proliferation, invasion and angiogenesis. A functional polymorphism (rs1617640 G>T) in the promoter region of the EPO gene increases EPO protein expression. In the present study, we investigated the association of EPO rs1617640 G>T with susceptibility and clinical outcome of early-stage breast cancer. Genomic DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 controls was genotyped for EPO rs1617640 G>T. No association was found between EPO rs1617640 G>T and early-stage breast cancer susceptibility and clinical outcome (hazard ratio=1.24, 95% confidence interval=1.82-1.90, p=0.31). In conclusion, our findings suggest a lack of influence of EPO rs1617640 G>T on early-stage breast carcinogenesis and clinical outcome. PMID- 22843934 TI - Enhanced expression of peroxisome proliferate-activated receptor gamma (PPAR gamma) in advanced prostate cancer. AB - BACKGROUND: Recent studies have underlined the role of nuclear receptors in the involvement of prostate cancer signalling pathways. PATIENTS AND METHODS: A total of 84 benign prostate hyperplasia (BPH), 84 low risk prostate cancer (LPC) and 64 advanced disease (APC) cases were sampled on a tissue microarray (TMA) and stained for retinoic acid receptor (RAR)-alpha, retionoid X receptor (RXR)-alpha, liver X receptor (LXR)-alpha, farnesoid X receptor (FXR) and proliferate activated receptor gamma (PPAR)-gamma and the (pro)-inflammatory molecules cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-alpha and inducible Nitric oxide synthase (iNOS) immunohistochemically. RESULTS: PPAR-gamma expression in APC tissues was found to be significantly higher than that in LPC and BPH specimens (p<0.001). In contrast, RXR-a expression was significantly lower (p<0.001). COX2 staining demonstrated a trend towards overexpression in APC (p=0.025). No significant differences were found for RAR-alpha, iNOS and TNF alpha expression. Staining of FXR and LXR was seen diffusely in the cytoplasm as well as in the nucleus, preventing sufficient evaluation by definition. CONCLUSION: This study provides the basis for applying PPAR-gamma ligands clinically in treatment of APC. PMID- 22843935 TI - Estrogen receptor, progesterone receptor, and nuclear size features in female breast cancer in Libya: correlation with clinical features and survival. AB - BACKGROUND: The features of Libyan patients with breast cancer have not been fully investigated. The aim of this study was to evaluate the expression patterns of estrogen (ER) and progesterone receptor (PR), as well as nuclear morphometric features, in patients with breast cancer, and to correlate them with clinicopathological features and prognosis. PATIENTS AND METHODS: Data for a total of 62 female Libyan patients with breast cancer, diagnosed between 2000 and 2006, were retrospectively studied. Their clinical and pathological data were collected and analysed. Immunohistochemical evaluation of ER and PR expression was also performed. Further more nuclear morphometry was carried out. RESULTS: Of the 62 patients, disease in 10 was of the lobular type, 43 had invasive ductal and 9 had other carcinoma types; 47 out of 62 had lymph node involvement. Positive hormonal receptor expression was more common among those with lymph node negative than lymph node-positive tumours. ER- and PR-positive patients appeared to have a better survival than ER- and PR-negative patients. The most significant difference, with respect to survival, was found between those bearing tumors with completely negative hormonal staining (J score 0) and those with positive staining (J score 1, 2 and 3). Larger nuclear size was associated with lymph node involvement and high-grade tumours (p<0.01 and p<0.0001, respectively), with shorter survival, larger tumour size and higher stage. CONCLUSION: The cut-off points for defining the groups with good or worse prognosis might be set, between score 0 and 1 (corresponding to 1% or fewer positive cells). Patients with ER- and PR-positive cancer had better overall survival than patients with hormonal receptor-negative cancer. In our hospital setting, ER and PR expressions and mean nuclear area (MNA) in breast carcinoma may be prognostically useful markers in guiding future treatment in prospective studies. PMID- 22843937 TI - Subtotal colectomy for malignant left-sided colon obstruction is associated with a lower anastomotic leak rate than segmental colectomy. AB - AIM: To compare subtotal colectomy to segmental colectomy for malignant left sided colonic obstruction. PATIENTS AND METHODS: Obstruction was defined by failure to trespass a colonic stenosis during endoscopy, by truncation of the contrast column during contrast enema, by severe colonic dilatation (cecum >10 cm, transverse colon >8 cm, descending colon >6 cm) or by serosal tears. From 53 consecutive patients treated for malignant left-sided colon obstruction at our surgical department from July 2002 to July 2010, 19 patients had subtotal colectomy and 30 patients had segmental colectomy. Four patients were excluded: two of them had non-colorectal primary cancer and the other two had a two-stage procedure. RESULTS: The rate of severe colonic dilatation and serosal tears, the physiological severity score and the expected morbidity were higher in the group with subtotal colectomy than in the group of segmental colectomy (p<0.05). However, the anastomotic leak rate was lower in the group with subtotal colectomy (0/19) than in the group with segmental colectomy (6/30) (p=0.042). Overall, there were no statistically significant differences regarding mortality or morbidity between the two groups. CONCLUSION: Despite worse preoperative conditions, patients who underwent subtotal colectomy for left-sided obstructing colonic cancer had a significantly lower anastomotic leak rate than those who underwent segmental colectomy. This fact supports the concept of subtotal colectomy for this entity. However, perioperative mortality seems to be independent of the presence or absence of an anastomotic leak. PMID- 22843936 TI - Effects of intermittent 5-fluorouracil and low-dose cisplatin therapy on advanced and recurrent gastric cancer. AB - BACKGROUND: Although combination therapy consisting of 5-fluorouracil (5-FU) and cisplatin for the treatment of gastric cancer has been reported, no consistent regimen has been established. Our aim was to determine the optimal treatment schedule of this therapy, for patients with advanced or recurrent gastric cancer. PATIENTS AND METHODS: We conducted a phase II study to evaluate the efficacy and safety of combination therapy consisting of intermittent 5-FU and low-dose cisplatin in 26 patients with advanced or recurrent gastric cancer. The treatment cycle consisted of intravenous cisplatin at 3.3 mg/m(2)/day for 5 consecutive days. 5-FU was administered as a continuous intravenous infusion at 300-500 mg/body every other day (days 1, 3, 5) for 4 weeks. RESULTS: The partial response rate was 34.6%. The median survival duration was 12.8 months and the one-year survival was 53.1%. There were a few adverse effects. CONCLUSION: Our results suggest that this mode of combination therapy led to a fairly favorable outcome for patients with advanced or recurrent gastric cancer. PMID- 22843938 TI - Preliminary experience on the use of the Adnatest(r) system for detection of circulating tumor cells in prostate cancer patients. AB - BACKGROUND: The Adnatest(r) system combines immunomagnetic enrichment of epithelial cells with polymerase chain reaction for prostate cancer (PC)-specific transcripts for the detection circulating tumor cells (CTCs). We evaluated the Adnatest(r) in patients with castration-resistant PC receiving docetaxel chemotherapy. PATIENTS AND METHODS: CTCs were assessed in 16 patients with castration-resistant PC before cycles one and three of chemotherapy. Furthermore, markers of stem cells and epithelial-mesenchymal transition were assessed. Treatment response was assessed by imaging and prostate-specific antigen measurements. RESULTS: Before chemotherapy, 11 patients were Adnatest(r)-positive whereas five patients were Adnatest(r)-positive before cycle three. A positive Adnatest(r) correlated with radiological progression (p=0.02). Rates of disease progression in epidermal growth factor receptor (EGFR)-positive and -negative patients were 100% and 7.7% (p=0.03). CONCLUSION: In this preliminary study, the Adnatest(r) detected CTCs in a considerable proportion of patients with castration-resistant PC. First data on certain markers (EGFR and aldehyd dehydrogenase 1) encourage future studies investigating transcripts predicting treatment response. PMID- 22843939 TI - Phase II study of cisplatin with irinotecan as induction chemotherapy followed by chemoradiotherapy for unresectable stage III non-small cell lung cancer. AB - BACKGROUND/AIM: We evaluated the anti-tumor activity and safety of cisplatin with irinotecan (IP) induction chemotherapy followed by chemoradiotherapy with etoposide/cisplatin (EP). PATIENTS AND METHODS: Induction chemotherapy consisted of irinotecan i.v. and cisplatin i.v. and was administered on day 1 and day 8 of each cycle. Patients underwent two cycles of chemotherapy with a 3-week interval. In the absence of progressive disease, 66 Gy radiation was administered concurrently with etoposide on days 1 to 5 and 29 to 33, as well as with cisplatin on day 1, 8, 29, and 36. RESULTS: Twenty patients were enrolled between July 2007 and December 2009. This study was closed prematurely due to lack of efficacy in induction chemotherapy. The overall response rate was 45% [95% confidence interval (CI), 25 to 65%], which did not meet the upper limit for first stage rejection of the treatment. The rates of 3-year progression-free survival and overall survival were 17.1% (95% CI, 0 to 36.8%) and 25% (95% CI, 0.2 to 49.8%), respectively. The primary toxicities included neutropenia, diarrhea and fatigue. CONCLUSION: This study failed to demonstrate a benefit for induction chemotherapy which was characterized by suboptimal antitumor activity and was poorly tolerated, with excess treatment-related toxicity. PMID- 22843940 TI - Touch imprint cytology and frozen-section analysis for intraoperative evaluation of sentinel nodes in early breast cancer. AB - Sentinel lymph node biopsy (SLNB) is currently the suggested axillary staging procedure in patients with early-stage breast cancer (BC) and usually requires intraoperative frozen-section (FS) examination of the removed nodes. However, other techniques, such as touch imprint cytology (IC), real-time reverse transcriptase-polymerase chain reaction and rapid cytokeratin immunostaining on FS may be used. The aim of this preliminary study was to assess the usefulness of intraoperative IC and FS section analysis together in improving the accuracy of sentinel lymph node evaluation in patients with early BC, who underwent SLNB. A series of 126 consecutive women (median age 52, range 34-71 years) with T1 (<=20 mm) BC, were prospectively enrolled in the study. A total of 221 axillary nodes were processed for both IC and FS intraoperative evaluation. Final pathology revealed 74 out of 221 (33.5%) nodes with metastasis, out of which 51 (68.9%) had macrometastases. Overall, 31 out of 126 (24.6%) patients were staged as having pN1mi or pN1a. The sensitivity, specificity, and accuracy in detecting metastases were 75.7%, 100% and 91.9% for FS, 70.3%, 98.6% and 89.1% for IC, and 89.2%, 100% and 96.0% for IC+FS together, respectively. The sensitivity of FS and IC did not differ significantly (p=0.46), while the combination of FS+IC showed a higher sensitivity (p=0.03), and similar accuracy. Our preliminary data confirm that IC is a simple and rapid technique with good sensitivity, suggesting that the combination of FS and IC may be useful in all patients requiring intraoperative SLNB evaluation. PMID- 22843941 TI - Quality of life in breast cancer patients with bisphosphonate-related osteonecrosis of the jaws and patients with head and neck cancer: a comparative study using the EORTC QLQ-C30 and QLQ-HN35 questionnaires. AB - BACKGROUND/AIM: This exploratory study aimed at examining the diagnostic utility, validity and reliability of already established quality of life (QoL) measures in cancer patients with osteonecrosis of the jaws (ONJ). PATIENTS AND METHODS: This was a prospective, observational, controlled clinical study. Female patients diagnosed with metastatic breast cancer and stage 2 or 3 ONJ (group I), metastatic breast cancer alone (group II), or cancer of the oral cavity (group III) were questioned. The EORTC QLQ-C30 version 3.0 and the QLQ-HN35 head and neck-specific questionnaires were used. RESULTS: Completed questionnaires were obtained from 64 patients. Overall internal consistency was acceptable to excellent with a Cronbach's alpha of 0.728 to 0.892. The Spearman-Brown coefficient was 0.888 and 0.872 for QLQ-C30 and HN35, respectively. Several scales of the questionnaire were sensitive to patient group: Global health status/Qol, HN Social eating, HN Pain, HN Swallowing, HN Senses, Role Function. Symptom intensity correlated with ONJ stage (2 vs. 3). CONCLUSION: EORTC QLQ-HN35 in conjunction with QLQ-C30 is a valid and informative tool in assessing QoL in patients with metastatic breast cancer and ONJ. Administration of the instrument to patients with ONJ of various nationalities is feasible and such efforts would greatly assist in recording the additional health burden created by this complication of bisphosphonate therapy. The use of HN35 module may be feasible in patients with any type of metastatic cancer who develop ONJ. PMID- 22843942 TI - Elevated preoperative inflammatory markers based on neutrophil-to-lymphocyte ratio and C-reactive protein predict poor survival in resected non-small cell lung cancer. AB - BACKGROUND: Previous studies showed the prognostic impact of inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP), in resected non-small cell lung cancer (NSCLC). However, there are no studies that examined both of these markers simultaneously. PATIENTS AND METHODS: Three hundred and one consecutive cases of resected NSCLC with a follow-up period of more than 5 years were reviewed retrospectively. RESULTS: A significant association was only observed between NLR and patients' survival (p<0.0001). High CRP also led to a higher 5-year survival rate than low CRP (38.71% vs. 70.71%, p<0.0001). We evaluated the prognostic significance of the use of NLR and CRP combined. The 5-year survival of patients with both low NLR and low CRP was 74.18%. On the other hand, that of patients with both of these at a low level was significantly poor (20.00%, p<0.0001). Univariate and multivariate analyses of the clinicopathological factors affecting survival revealed that the combined use of preoperative NLR and CRP was an independent prognostic determinant. CONCLUSION: The combined use of preoperative NLR and CRP might be useful to predict the prognosis of patients with NSCLC. PMID- 22843943 TI - Dose-dense intensified sequential versus conventionally-dosed anthracycline and taxane-containing neoadjuvant therapy in patients with inflammatory breast cancer. AB - BACKGROUND: This post-hoc analysis aimed to compare an intense dose-dense sequential chemotherapy (DD-CT) and a conventionally-dosed chemotherapy (CD-CT) in the neoadjuvant AGO-1 study, focusing on the subgroup with inflammatory breast cancer (IBC). PATIENTS AND METHODS: Out of 668 randomised patients, 101 patients presented with IBC. Patients received epirubicin followed by paclitaxel every 2 weeks (DD-CT) or simultaneously every 3 weeks (CD-CT). RESULTS: No differences in pathological complete response rates were observed [odds ratio (OR)=1.27, p=0.33]. Most patients were scheduled for mastectomy before starting therapy; however, in 21.7% breast-conserving surgery was performed. Disease-free survival rates [Hazard Ratio (HR)=0.65; p=0.597] and overall survival rates (HR=1.40; p=0.327) were similar for both treatment arms. Patients with breast-conserving surgery had a significantly better outcome than patients treated with mastectomy (disease-free survival: HR=0.41; p=0.034 and overall survival: HR=0.09; p=0.003). CONCLUSION: Patients with IBC benefited not from DD-CT but from breast-conserving surgery after neoadjuvant chemotherapy. PMID- 22843944 TI - First-line bevacizumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimisation analysis. AB - AIM: To carry out a cost minimisation analysis including a comparison of the costs arising from first-line treatment by bevacizumab plus docetaxel (BD) versus bevacizumab plus paclitaxel (BP) of patients with metastatic breast cancer (mBC). PATIENT AND METHODS: All consecutive patients with human epidermal growth receptor 2-negative mBC and treated at Besancon University hospital between 2006 and 2010 by a first-line therapy containing bevacizumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization and healthcare travel. RESULTS: Progression-free survival difference between the two treatments was insignificant (p-value=0.31). BP treatment was associated with a higher mean total cost than that of BD treatment, ?53,093 +/- 34,395 versus ?60,196 +/- 48,766, respectively. CONCLUSION: Whereas bevacizumab is recommended for first-line treatment of mBC with paclitaxel-based chemotherapy, our study has shown that BD treatment is the most cost-efficient regimen. It could be an attractive option in France, with a potential cost saving of ?24,000,000 per year. PMID- 22843945 TI - Efficacy of carboplatin and paclitaxel with bevacizumab as salvage chemotherapy for non-small cell lung cancer after failure of platinum-doublet chemotherapy. AB - BACKGROUND: Salvage chemotherapy using carboplatin (C), paclitaxel (P), and bevacizumab (BEV) for patients with pre-treated, advanced non-squamous non-small cell lung cancer (NSCLC) has not yet been reported. PATIENT AND METHODS: Medical records of patients with non-squamous NSCLC who received CP plus BEV between November 2009 and September 2011 and experienced progression after at least one platinum-based-chemotherapy regimen, were examined in this retrospective study. RESULTS: Twenty-one patients were eligible for this study. The median number of prior chemotherapy regimens was 3 (range, 2 to 9). The median number of cycles of CP with BEV was 4 (range, 1 to 6). Seven patients underwent BEV maintenance therapy, and the median number of cycles of BEV maintenance was 8 (range, 2 to 13). Toxicity levels were acceptable. The overall median survival time was not reached and one-year survival rate was 54.95%. The overall progression-free survival was 6.1 months (95% confidence interval, 4.4-9.3 months). CONCLUSION: CP with BEV was effective and feasible as a salvage chemotherapy after failure of platinum-based chemotherapy for patients with non-squamous NSCLC. PMID- 22843946 TI - Association between COX-2 expression and effectiveness of COX-2 inhibitors in a phase II trial in patients with metastatic colorectal adenocarcinoma. AB - AIM: The role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis has been suggested in pre-clinical models. In a previously reported phase II trial, the addition of COX-2 inhibitor celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy in patients with metastatic colorectal carcinoma (mCRC). We evaluated the COX-2 expression in the available tumors from enrolled patients by immunohistochemistry, as well as its correlation with clinical outcome. PATIENTS AND METHODS: Fifty-one patients with mCRC were enrolled in the phase II study between June 2002 and November 2005. Patients received a combination of irinotecan 70 mg/m(2) over 30 min i.v. on days 1 and 8, capecitabine 1,000 mg/m(2) twice per day orally on days 1-14 and the COX-2 inhibitor celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days. Formalin fixed paraffin-embedded tumor tissue samples were available for 17 patients enrolled on this study. COX-2 expression was evaluated by immunohistochemistry and was correlated with clinical outcome. RESULTS: In the phase II study, the objective response rate was 41%. The median time to progression was 7.7 months and median survival time was 21.2 months. Tumor COX-2 expression, by immunohistochemistry, was assessed for 17 patients enrolled in the same phase II study. While not statistically significant, the response rate was better for patients in the low COX-2 expression group, while time to progression and overall survival was longer in patients in the high COX-2 expression group. This discrepancy can be partially attributed to the small sample size. CONCLUSION: In the previously published phase II study, the addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy. COX-2 expression by immunohistochemistry was neither prognostic nor predictive for response. PMID- 22843947 TI - Circulating vascular endothelial growth factor in childhood solid tumors: plasma and serum measurements. AB - BACKGROUND: Serum and plasma vascular endothelial growth factor (VEGF) were measured in children with a solid tumor to investigate which provides better prognostic information. PATIENTS AND METHODS: Seventeen patients under treatment were divided into two groups: without (n 8) and with (n 9) detectable disease at radiological assessment (groups I and II). The control group consisted of 26 healthy children. VEGF was tested by enzyme-linked ELISA kit. RESULTS: Serum VEGF concentrations in group II were statistically higher than those in group I (p<0.05) and those in controls (p=0.001), whereas the difference between group I and controls was not statistically significant (p=0.067). Plasma VEGF concentrations in group II were also statistically higher than those in group I (p<0.01) and those in controls (p=0.0001); the difference between group I and controls was also statistically significant (p=0.004). CONCLUSION: Plasma would be the more useful specimen for measurement of circulating VEGF in cancer childhood. PMID- 22843948 TI - Predictive factors for breast cancer in patients diagnosed with ductal intraepithelial neoplasia, grade 1B. AB - BACKGROUND: For ductal intraepithelial neoplasia, grade 1B, studies that predict breast cancer risk after an 11-gauge vacuum-assisted breast biopsy have yielded contradictory results. In order to identify a predictive model of breast cancer risk, we assessed the underestimation rate according to radiological and clinical findings. PATIENTS AND METHODS: Our study involved 212 patients. We compared the area under the receiver operating characteristic curves and the clinical utility of a logistic regression and partitioning model. RESULTS: Overall upgrade to malignancy occurred in 42 (19.8%) out of the 212 cases. The area under the curve for the logistic regression and partitioning model were 0.65 (95% confidence interval=0.61-0.70) and 0.58 (95% confidence interval=0.54-0.62), respectively. The lowest predicted underestimation rate obtained with the logistic regression model was 9.5%. CONCLUSION: From this large series, we were unable to define any accurate safety model for breast cancer. Surgery should be thus recommended. PMID- 22843949 TI - Applicability of histoculture drug response assays in colorectal cancer chemotherapy. AB - AIM: The present study, using the histoculture drug response assay (HDRA) compared chemosensitivity with the clinical response of a treatment regime in patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: A total of 324 patients with primary CRC were prospectively enrolled. HDRAs were performed using seven combinations of anticancer drugs, including 5-fluorouracil with leucovorin (FL), FL with oxaliplatin (FOLFOX), irinotecan (FOLFIRI), and their combinations with bevacizumab and cetuximab. RESULTS: Among 324 HDRA results, tumor inhibition rates of regimes using FOLFOX (34.2-39.2%) were higher than those using FOLFIRI (24.2-32.7%, p<0.001). Out of 86 evaluated chemotherapeutic regimes, the correlation rate of HDRA to the clinical effect of chemotherapy was calculated to be 66.3% (57/86), with a 72.7% (40/55) sensitivity and a 54.7% (17/31) specificity. CONCLUSION: HDRA might be a feasible and useful technique for predicting therapy efficacy and selecting the appropriate anticancer regime for individual patients, notwithstanding its low accuracy. PMID- 22843950 TI - Effect of serum selenium levels on radiotherapy-related toxicity in patients undergoing radiotherapy for head and neck cancer. AB - AIM: To investigate whether there is a difference in selenium levels before and after radiotherapy (RT) and to study the effects of serum selenium levels on RT related toxicity in patients undergoing RT for head and neck cancer. PATIENTS AND METHODS: A population of 47 consecutive patients was enrolled in the study. RT was given by conventional fractionation. RT-related acute toxicity was evaluated once a week. Blood samples were obtained before and after RT to evaluate selenium levels. RESULTS: There was no significant difference between the levels of selenium before and after RT (58.09 +/- 1.36 MUg/l and 56.34 +/- 1.11 MUg/l, p value=0.747, respectively). Grade III-IV mucositis, dysphagia, radiodermatitis, and nausea were seen in 6 (12.7%), 32 (68.2%), 24 (51.1%), and 3 (6.4%) patients, respectively. It was found that there was no statistically significant difference in the levels of selenium before and after RT, and no observed differences in regard to RT-related toxicities. CONCLUSION: The serum selenium levels do not affect RT-related toxicities. PMID- 22843954 TI - Retraction. PMID- 22843979 TI - Genome-wide approaches to understanding behaviour in Drosophila melanogaster. AB - Understanding how an organism exhibits specific behaviours remains a major and important biological question. Studying behaviour in a simple model organism like the fruit fly Drosophila melanogaster has the advantages of advanced molecular genetics approaches along with well-defined anatomy and physiology. With advancements in functional genomic technologies, researchers are now attempting to uncover genes and pathways involved in complex behaviours on a genome-wide scale. A systems-level network approach, which will include genomic approaches, to study behaviour will be key to understanding the regulation and modulation of behaviours and the importance of context in regulating them. PMID- 22843980 TI - Automated glycopeptide analysis--review of current state and future directions. AB - Glycosylation of proteins is involved in immune defense, cell-cell adhesion, cellular recognition and pathogen binding and is one of the most common and complex post-translational modifications. Science is still struggling to assign detailed mechanisms and functions to this form of conjugation. Even the structural analysis of glycoproteins-glycoproteomics-remains in its infancy due to the scarcity of high-throughput analytical platforms capable of determining glycopeptide composition and structure, especially platforms for complex biological mixtures. Glycopeptide composition and structure can be determined with high mass-accuracy mass spectrometry, particularly when combined with chromatographic separation, but the sheer volume of generated data necessitates computational software for interpretation. This review discusses the current state of glycopeptide assignment software-advances made to date and issues that remain to be addressed. The various software and algorithms developed so far provide important insights into glycoproteomics. However, there is currently no freely available software that can analyze spectral data in batch and unambiguously determine glycopeptide compositions for N- and O-linked glycopeptides from relevant biological sources such as human milk and serum. Few programs are capable of aiding in structural determination of the glycan component. To significantly advance the field of glycoproteomics, analytical software and algorithms are required that: (i) solve for both N- and O-linked glycopeptide compositions, structures and glycosites in biological mixtures; (ii) are high-throughput and process data in batches; (iii) can interpret mass spectral data from a variety of sources and (iv) are open source and freely available. PMID- 22843981 TI - Bayesian ontology querying for accurate and noise-tolerant semantic searches. AB - MOTIVATION: Ontologies provide a structured representation of the concepts of a domain of knowledge as well as the relations between them. Attribute ontologies are used to describe the characteristics of the items of a domain, such as the functions of proteins or the signs and symptoms of disease, which opens the possibility of searching a database of items for the best match to a list of observed or desired attributes. However, naive search methods do not perform well on realistic data because of noise in the data, imprecision in typical queries and because individual items may not display all attributes of the category they belong to. RESULTS: We present a method for combining ontological analysis with Bayesian networks to deal with noise, imprecision and attribute frequencies and demonstrate an application of our method as a differential diagnostic support system for human genetics. AVAILABILITY: We provide an implementation for the algorithm and the benchmark at http://compbio.charite.de/boqa/. CONTACT: Sebastian.Bauer@charite.de or Peter.Robinson@charite.de SUPPLEMENTARY INFORMATION: Supplementary Material for this article is available at Bioinformatics online. PMID- 22843982 TI - Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. AB - SUMMARY: Genetic correlations are the genome-wide aggregate effects of causal variants affecting multiple traits. Traditionally, genetic correlations between complex traits are estimated from pedigree studies, but such estimates can be confounded by shared environmental factors. Moreover, for diseases, low prevalence rates imply that even if the true genetic correlation between disorders was high, co-aggregation of disorders in families might not occur or could not be distinguished from chance. We have developed and implemented statistical methods based on linear mixed models to obtain unbiased estimates of the genetic correlation between pairs of quantitative traits or pairs of binary traits of complex diseases using population-based case-control studies with genome-wide single-nucleotide polymorphism data. The method is validated in a simulation study and applied to estimate genetic correlation between various diseases from Wellcome Trust Case Control Consortium data in a series of bivariate analyses. We estimate a significant positive genetic correlation between risk of Type 2 diabetes and hypertension of ~0.31 (SE 0.14, P = 0.024). AVAILABILITY: Our methods, appropriate for both quantitative and binary traits, are implemented in the freely available software GCTA (http://www.complextraitgenomics.com/software/gcta/reml_bivar.html). CONTACT: hong.lee@uq.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22843983 TI - Meta-Storms: efficient search for similar microbial communities based on a novel indexing scheme and similarity score for metagenomic data. AB - BACKGROUND: It has long been intriguing scientists to effectively compare different microbial communities (also referred as 'metagenomic samples' here) in a large scale: given a set of unknown samples, find similar metagenomic samples from a large repository and examine how similar these samples are. With the current metagenomic samples accumulated, it is possible to build a database of metagenomic samples of interests. Any metagenomic samples could then be searched against this database to find the most similar metagenomic sample(s). However, on one hand, current databases with a large number of metagenomic samples mostly serve as data repositories that offer few functionalities for analysis; and on the other hand, methods to measure the similarity of metagenomic data work well only for small set of samples by pairwise comparison. It is not yet clear, how to efficiently search for metagenomic samples against a large metagenomic database. RESULTS: In this study, we have proposed a novel method, Meta-Storms, that could systematically and efficiently organize and search metagenomic data. It includes the following components: (i) creating a database of metagenomic samples based on their taxonomical annotations, (ii) efficient indexing of samples in the database based on a hierarchical taxonomy indexing strategy, (iii) searching for a metagenomic sample against the database by a fast scoring function based on quantitative phylogeny and (iv) managing database by index export, index import, data insertion, data deletion and database merging. We have collected more than 1300 metagenomic data from the public domain and in-house facilities, and tested the Meta-Storms method on these datasets. Our experimental results show that Meta Storms is capable of database creation and effective searching for a large number of metagenomic samples, and it could achieve similar accuracies compared with the current popular significance testing-based methods. CONCLUSION: Meta-Storms method would serve as a suitable database management and search system to quickly identify similar metagenomic samples from a large pool of samples. CONTACT: ningkang@qibebt.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22843985 TI - TMBB-DB: a transmembrane beta-barrel proteome database. AB - MOTIVATION: We previously reported the development of a highly accurate statistical algorithm for identifying beta-barrel outer membrane proteins or transmembrane beta-barrels (TMBBs), from genomic sequence data of Gram-negative bacteria (Freeman,T.C. and Wimley,W.C. (2010) Bioinformatics, 26, 1965-1974). We have now applied this identification algorithm to all available Gram-negative bacterial genomes (over 600 chromosomes) and have constructed a publicly available, searchable, up-to-date, database of all proteins in these genomes. RESULTS: For each protein in the database, there is information on (i) beta barrel membrane protein probability for identification of beta-barrels, (ii) beta strand and beta-hairpin propensity for structure and topology prediction, (iii) signal sequence score because most TMBBs are secreted through the inner membrane translocon and, thus, have a signal sequence, and (iv) transmembrane alpha-helix predictions, for reducing false positive predictions. This information is sufficient for the accurate identification of most beta-barrel membrane proteins in these genomes. In the database there are nearly 50 000 predicted TMBBs (out of 1.9 million total putative proteins). Of those, more than 15 000 are 'hypothetical' or 'putative' proteins, not previously identified as TMBBs. This wealth of genomic information is not available anywhere else. AVAILABILITY: The TMBB genomic database is available at http://beta-barrel.tulane.edu/. CONTACT: wwimley@tulane.edu. PMID- 22843986 TI - zCall: a rare variant caller for array-based genotyping: genetics and population analysis. AB - SUMMARY: zCall is a variant caller specifically designed for calling rare single nucleotide polymorphisms from array-based technology. This caller is implemented as a post-processing step after a default calling algorithm has been applied. The algorithm uses the intensity profile of the common allele homozygote cluster to define the location of the other two genotype clusters. We demonstrate improved detection of rare alleles when applying zCall to samples that have both Illumina Infinium HumanExome BeadChip and exome sequencing data available. AVAILABILITY: http://atguweb.mgh.harvard.edu/apps/zcall. CONTACT: bneale@broadinstitute.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22843987 TI - Recombinant oncolytic adenovirus H101 combined with siBCL2: cytotoxic effect on uveal melanoma cell lines. AB - BACKGROUND: Deregulation of Bcl2 pathway is implicated in the pathogenesis of uveal melanoma (UM). Oncolytic adenovirus H101 is the world's first oncolytic viral therapy for cancer approved for clinical use. We aimed to explore a potential synergy of downregulating Bcl2 pathway using a small interfering RNA (siBCL2) combined with H101 therapy on UM cell lines. METHODS: The sensitivity to adenovirus infection was analysed by flow cytometry. PCR, real-time-PCR and western blot were used to detect Bcl2, p53, Bax and fibre expression. Appropriate multiplicity of H101 infection and cell survival rate were measured by a cell counting kit-8 assay. UM cells were stained with Annexin-V and propidium iodide for apoptosis assay and cell cycle distribution. RESULTS: VUP cells (without elevation of Bcl2) exhibited greater sensitivity to adenovirus infection than OM431 cells (Bcl2 elevated cell line). Bcl2 expression was markedly reduced by siBCL2 or siBCL2 plus H101. Combined treatment with siBCL2 and H101 produced substantial growth inhibition of OM431 cells by enhancing apoptosis and cell cycle arrest through Bax-p53-induced apoptotic pathway. CONCLUSIONS: SiBCL2 and H101 exhibited synergistic cytotoxic effect in Bcl2 elevated UM cell lines and could potentially serve as a novel targeted molecular therapy for UM. PMID- 22843988 TI - Rice kinesin O12 is identical to kinesin OsKCH1. PMID- 22843989 TI - Proteomic and transcriptomic profiling of Staphylococcus aureus surface LPXTG proteins: correlation with agr genotypes and adherence phenotypes. AB - Staphylococcus aureus infections involve numerous adhesins and toxins, which expression depends on complex regulatory networks. Adhesins include a family of surface proteins covalently attached to the peptidoglycan via a conserved LPXTG motif. Here we determined the protein and mRNA expression of LPXTG-proteins of S. aureus Newman in time-course experiments, and their relation to fibrinogen adherence in vitro. Experiments were performed with mutants in the global accessory-gene regulator (agr), surface protein A (Spa), and fibrinogen-binding protein A (ClfA), as well as during growth in iron-rich or iron-poor media. Surface proteins were recovered by trypsin-shaving of live bacteria. Released peptides were analyzed by liquid chromatography coupled to tandem mass spectrometry. To unambiguously identify peptides unique to LPXTG-proteins, the analytical conditions were refined using a reference library of S. aureus LPXTG proteins heterogeneously expressed in surrogate Lactococcus lactis. Transcriptomes were determined by microarrays. Sixteen of the 18 LPXTG-proteins present in S. aureus Newman were detected by proteomics. Nine LPXTG-proteins showed a bell-shape agr-like expression that was abrogated in agr-negative mutants including Spa, fibronectin-binding protein A (FnBPA), ClfA, iron-binding IsdA, and IsdB, immunomodulator SasH, functionally uncharacterized SasD, biofilm related SasG and methicillin resistance-related FmtB. However, only Spa and SasH modified their proteomic and mRNA profiles in parallel in the parent and its agr- mutant, whereas all other LPXTG-proteins modified their proteomic profiles independently of their mRNA. Moreover, ClfA became highly transcribed and active in fibrinogen-adherence tests during late growth (24 h), whereas it remained poorly detected by proteomics. On the other hand, iron-regulated IsdA-B-C increased their protein expression by >10-times in iron-poor conditions. Thus, proteomic, transcriptomic, and adherence-phenotype demonstrated differential profiles in S. aureus. Moreover, trypsin peptide signatures suggested differential protein domain exposures in various environments, which might be relevant for anti-adhesin vaccines. A comprehensive understanding of the S. aureus physiology should integrate all three approaches. PMID- 22843990 TI - Quantitative phosphoproteomic analysis of soybean root hairs inoculated with Bradyrhizobium japonicum. AB - Root hairs are single hair-forming cells on roots that function to increase root surface area, enhancing water and nutrient uptake. In leguminous plants, root hairs also play a critical role as the site of infection by symbiotic nitrogen fixing rhizobia, leading to the formation of a novel organ, the nodule. The initial steps in the rhizobia-root hair infection process are known to involve specific receptor kinases and subsequent kinase cascades. Here, we characterize the phosphoproteome of the root hairs and the corresponding stripped roots (i.e. roots from which root hairs were removed) during rhizobial colonization and infection to gain insight into the molecular mechanism of root hair cell biology. We chose soybean (Glycine max L.), one of the most important crop plants in the legume family, for this study because of its larger root size, which permits isolation of sufficient root hair material for phosphoproteomic analysis. Phosphopeptides derived from root hairs and stripped roots, mock inoculated or inoculated with the soybean-specific rhizobium Bradyrhizobium japonicum, were labeled with the isobaric tag eight-plex iTRAQ, enriched using Ni-NTA magnetic beads and subjected to nanoRPLC-MS/MS1 analysis using HCD and decision tree guided CID/ETD strategy. A total of 1625 unique phosphopeptides, spanning 1659 nonredundant phosphorylation sites, were detected from 1126 soybean phosphoproteins. Among them, 273 phosphopeptides corresponding to 240 phosphoproteins were found to be significantly regulated (>1.5-fold abundance change) in response to inoculation with B. japonicum. The data reveal unique features of the soybean root hair phosphoproteome, including root hair and stripped root-specific phosphorylation suggesting a complex network of kinase substrate and phosphatase-substrate interactions in response to rhizobial inoculation. PMID- 22843991 TI - Complementary proteome and transcriptome profiling in phosphate-deficient Arabidopsis roots reveals multiple levels of gene regulation. AB - Phosphate (Pi) deficiency impairs plant growth and productivity in many agricultural ecosystems, causing severe reductions in crop yield. To uncover novel aspects in acclimation to Pi starvation, we investigated the correlation between Pi deficiency-induced changes in transcriptome and proteome profiles in Arabidopsis roots. Using exhaustive tandem mass spectrometry-based shotgun proteomics and whole-genome RNA sequencing to generate a nearly complete catalog of expressed mRNAs and proteins, we reliably identified 13,298 proteins and 24,591 transcripts, subsets of 356 proteins and 3106 mRNAs were differentially expressed during Pi deficiency. Most dramatic changes were noticed for genes involved in Pi acquisition and in processes that either liberate Pi or bypass Pi/ATP-consuming metabolic steps, for example during membrane lipid remodeling and glycolytic carbon flux. The concordance between the abundance of mRNA and its encoded protein was generally high for highly up-regulated genes, but the analysis also revealed numerous discordant changes in mRNA/protein pairs, indicative of divergent regulation of transcription and post-transcriptional processes. In particular, a decreased abundance of proteins upon Pi deficiency was not closely correlated with changes in the corresponding mRNAs. In several cases, up-regulation of gene activity was observed solely at the protein level, adding novel aspects to key processes in the adaptation to Pi deficiency. We conclude that integrated measurement and interpretation of changes in protein and transcript abundance are mandatory for generating a complete inventory of the components that are critical in the response to environmental stimuli. PMID- 22843992 TI - Quantitative proteomics reveals regulation of karyopherin subunit alpha-2 (KPNA2) and its potential novel cargo proteins in nonsmall cell lung cancer. AB - The process of nucleocytoplasmic shuttling is mediated by karyopherins. Dysregulated expression of karyopherins may trigger oncogenesis through aberrant distribution of cargo proteins. Karyopherin subunit alpha-2 (KPNA2) was previously identified as a potential biomarker for nonsmall cell lung cancer by integration of the cancer cell secretome and tissue transcriptome data sets. Knockdown of KPNA2 suppressed the proliferation and migration abilities of lung cancer cells. However, the precise molecular mechanisms underlying KPNA2 activity in cancer remain to be established. In the current study, we applied gene knockdown, subcellular fractionation, and stable isotope labeling by amino acids in cell culture-based quantitative proteomic strategies to systematically analyze the KPNA2-regulating protein profiles in an adenocarcinoma cell line. Interaction network analysis revealed that several KPNA2-regulating proteins are involved in the cell cycle, DNA metabolic process, cellular component movements and cell migration. Importantly, E2F1 was identified as a potential novel cargo of KPNA2 in the nuclear proteome. The mRNA levels of potential effectors of E2F1 measured using quantitative PCR indicated that E2F1 is one of the "master molecule" responses to KPNA2 knockdown. Immunofluorescence staining and immunoprecipitation assays disclosed co-localization and association between E2F1 and KPNA2. An in vitro protein binding assay further demonstrated that E2F1 interacts directly with KPNA2. Moreover, knockdown of KPNA2 led to subcellular redistribution of E2F1 in lung cancer cells. Our results collectively demonstrate the utility of quantitative proteomic approaches and provide a fundamental platform to further explore the biological roles of KPNA2 in nonsmall cell lung cancer. PMID- 22843993 TI - Integrative proteomic profiling of protein activity and interactions using protein arrays. AB - Proteomic studies based on abundance, activity, or interactions have been used to investigate protein functions in normal and pathological processes, but their combinatory approach has not been attempted. We present an integrative proteomic profiling method to measure protein activity and interaction using fluorescence based protein arrays. We used an on-chip assay to simultaneously monitor the transamidating activity and binding affinity of transglutaminase 2 (TG2) for 16 TG2-related proteins. The results of this assay were compared with confidential scores provided by the STRING database to analyze the functional interactions of TG2 with these proteins. We further created a quantitative activity-interaction map of TG2 with these 16 proteins, categorizing them into seven groups based upon TG2 activity and interaction. This integrative proteomic profiling method can be applied to quantitative validation of previously known protein interactions, and in understanding the functions and regulation of target proteins in biological processes of interest. PMID- 22843994 TI - A novel method for the simultaneous enrichment, identification, and quantification of phosphopeptides and sialylated glycopeptides applied to a temporal profile of mouse brain development. AB - We describe a method that combines an optimized titanium dioxide protocol and hydrophilic interaction liquid chromatography to simultaneously enrich, identify and quantify phosphopeptides and formerly N-linked sialylated glycopeptides to monitor changes associated with cell signaling during mouse brain development. We initially applied the method to enriched membrane fractions from HeLa cells, which allowed the identification of 4468 unique phosphopeptides and 1809 formerly N-linked sialylated glycopeptides. We subsequently combined the method with isobaric tagging for relative quantification to compare changes in phosphopeptide and formerly N-linked sialylated glycopeptide abundance in the developing mouse brain. A total of 7682 unique phosphopeptide sequences and 3246 unique formerly sialylated glycopeptides were identified. Moreover 669 phosphopeptides and 300 formerly N-sialylated glycopeptides differentially regulated during mouse brain development were detected. This strategy allowed us to reveal extensive changes in post-translational modifications from postnatal mice from day 0 until maturity at day 80. The results of this study confirm the role of sialylation in organ development and provide the first extensive global view of dynamic changes between N-linked sialylation and phosphorylation. PMID- 22843996 TI - Pelvic inflammatory disease in adolescents between the time of testing and treatment and after treatment for gonorrhoeal and chlamydial infection. AB - In incarcerated adolescents, 13% developed pelvic inflammatory disease (PID) between the time of testing and treatment for chlamydial and gonorrhoeal infection, and 13% developed PID in the 30 days following single-dose treatment for one or both of these infections. PMID- 22843995 TI - Profiling lipid-protein interactions using nonquenched fluorescent liposomal nanovesicles and proteome microarrays. AB - Fluorescent liposomal nanovesicles (liposomes) are commonly used for lipid research and/or signal enhancement. However, the problem of self-quenching with conventional fluorescent liposomes limits their applications because these liposomes must be lysed to detect the fluorescent signals. Here, we developed a nonquenched fluorescent (NQF)1 liposome by optimizing the proportion of sulforhodamine B (SRB) encapsulant and lissamine rhodamine B-dipalmitoyl phosphatidylethanol (LRB-DPPE) on a liposomal surface for signal amplification. Our study showed that 0.3% of LRB-DPPE with 200 MUm of SRB provided the maximal fluorescent signal without the need to lyse the liposomes. We also observed that the NQF liposomes largely eliminated self-quenching effects and produced greatly enhanced signals than SRB-only liposomes by 5.3-fold. To show their application in proteomics research, we constructed NQF liposomes that contained phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and profiled its protein interactome using a yeast proteome microarray. Our profiling led to the identification of 162 PI(3,5)P2-specific binding proteins (PI(3,5)P2-BPs). We not only recovered many proteins that possessed known PI(3,5)P2-binding domains, but we also found two unknown Pfam domains (Pfam-B_8509 and Pfam-B_10446) that were enriched in our dataset. The validation of many newly discovered PI(3,5)P2-BPs was performed using a bead-based affinity assay. Further bioinformatics analyses revealed that the functional roles of 22 PI(3,5)P2-BPs were similar to those associated with PI(3,5)P2, including vesicle-mediated transport, GTPase, cytoskeleton, and kinase. Among the 162 PI(3,5)P2-BPs, we found a novel motif, HRDIKP[ES]NJLL that showed statistical significance. A docking simulation showed that PI(3,5)P2 interacted primarily with lysine or arginine side chains of the newly identified PI(3,5)P2-binding kinases. Our study showed that this new tool would greatly benefit profiling lipid-protein interactions in high-throughput studies. PMID- 22843998 TI - Immune response to hepatitis A vaccination in HIV-infected men in Greece. AB - HIV-infected patients are at increased risk for acquiring hepatitis A virus (HAV) infection. We evaluated the seroconversion rate (anti-HAV antibodies >= 20 mIU/ml) and the geometric mean antibody titres (GMTs) in a group of 351 HIV infected men, who had received two doses of a hepatitis A vaccine. We analysed blood samples collected at one, six, 12 and 18 months following the administration of the second dose of the vaccine. The seroconversion rate one month after the second dose of the vaccine was 74.4% (260/351). At month 18 after the end of vaccination, 56.1% of the subjects remained seropositive. GMTs were 315, 203, 153 and 126 mIU/ml at months 1, 6, 12, and 18, respectively. Logistic regression revealed that the CD4 count is the only factor affecting response to vaccination (P = 0.019). A higher response rate and higher GMTs were observed in patients with CD4 counts >= 500 cells/mm(3) (76.6%) than in patients with CD4 counts 200-499 cells/mm(3). In conclusion, even in patients with near-normal CD4 counts, the response to the hepatitis A vaccine is impaired. PMID- 22843997 TI - Virological failure at one year in triple-class experienced patients switching to raltegravir-based regimens is not predicted by baseline factors. AB - We evaluated rates and determinants of virological failure in triple-class experienced patients receiving raltegravir-based regimens from a national observational study over 48 weeks, defined by any one of the following: (1) no HIV-RNA suppression to undetectable levels (<50 copies/mL) during follow-up; (2) detectable viral load after obtaining undetectable levels; and (3) leaving the study before 48 weeks. Among 101 eligible patients, 26 (25.7%; 95% CI 17.2-34.2) had virological failure. No significant differences between patients with and without virological failure were observed for gender, age, route of transmission, baseline CD4/HIV-RNA, CDC group, hepatitis B or C co-infections, resistance (based on the last genotype available), type and number of concomitant drug classes, concomitant use of darunavir, atazanavir, etravirine, enfuvirtide or maraviroc, and health-related quality-of-life measures. A high rate of treatment response was observed. The analyses did not identify any baseline factor associated with failure, including resistance status. Even if we cannot exclude the presence of pre-existing minority resistant variants not captured by genotypic tests, the lack of baseline predictors of failure suggests the need to monitor patients closely during follow up for other factors, such as potential drug interactions and reduced levels of adherence, which may favour virological failure. PMID- 22843999 TI - HIV infection and sexual partnerships and behaviour among adolescent girls in Nairobi, Kenya. AB - Early sexual partnerships place young women in sub-Saharan Africa at high risk for HIV. Few studies have examined both individual- and partnership-level characteristics of sexual relationships among adolescent girls. A cross-sectional survey of sexual history and partnerships was conducted among 761 adolescent girls aged 15-19 years in Nairobi, Kenya. Rapid HIV testing was conducted and correlates of HIV infection were determined using multivariate logistic regression. The HIV prevalence was 7% and seropositive adolescents had a younger age at sexual debut (P < 0.01), more sexual partners in 12 months (P = 0.03), and were more likely to report transactional or non-consensual sex (P < 0.01). Girls who reported not knowing their partner's HIV status were 14 times as likely to be HIV-seropositive than girls who knew their partner's status (adjusted odds ratio: 14.2 [1.8, 109.3]). Public health messages to promote HIV testing and disclosure within partnerships could reduce sexual risk behaviours and HIV transmission among adolescents. PMID- 22844000 TI - Factors associated with late presentation of HIV infection in Catalonia, Spain. AB - We sought to describe the prevalence, trends and factors associated with late diagnosis of HIV infection between 2001 and 2008 in Catalonia, Spain. Adults over 13 years of age with available CD4 cell counts, who were notified to the Catalonia Voluntary HIV Surveillance System between January 2001 and December 2008, were included in the study. Late presentation for HIV infection was defined as a CD4 cell count <350 cells/MUL or with an AIDS-defining condition at presentation. Multivariable logistic regression was used to identify factors independently associated with late diagnosis of HIV. Of the 4651 newly diagnosed HIV-infected individuals with available CD4 counts, 2598 (55.9%) were diagnosed late. The proportion of people with a late diagnosis decreased from 60.4% in 2001 to 50% in 2008, a significant trend (P < 0.001). Older age, male gender, foreign birth, heterosexuality and injecting drug use were independent risk factors for late diagnosis. Strategies to actively promote HIV testing to populations at risk of late diagnosis of HIV or those never attending health systems should be implemented. PMID- 22844001 TI - Social support mediates the relationship between HIV stigma and depression/quality of life among people living with HIV in Beijing, China. AB - Stigma towards people living with HIV is pervasive in China and related to poor service utilization, psychosocial distress and diminished quality of life (QOL). In an effort to identify mechanisms to reduce HIV stigma and its negative consequences, we examined whether social support mediates the relation between enacted stigma and both depressive symptoms and QOL among 120 HIV outpatients in Beijing, China. Generally, perceived social support was associated with less stigma, less depressive symptomatology and better QOL. Using multivariable regression models, we found that social support was a full mediator of the impact of stigma on both depressive symptomatology and QOL. The findings suggest social support may be an important target of interventions to reduce the impact of stigma on poor psychosocial health outcomes. PMID- 22844002 TI - Colposcopy referral rate can be reduced by high-risk human papillomavirus triage in the management of recurrent atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology in Finland. AB - The aim of this study was to establish whether a combination of high-risk human papillomavirus (hrHPV) testing and cervical cytology could reduce colposcopy referral among women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion cytology. We randomized 598 women in the Helsinki area, Finland into three study groups. Different strategies of hrHPV testing, cytology and colposcopy with biopsy were used; subsequent hrHPV test results and cytological findings were compared with histology. The rates of hrHPV positivity and CIN2+ were compared. In total, 62.5% of all samples were hrHPV-positive. Altogether 45 (12.7%) CIN2 or worse (CIN2+) lesions were found in study groups A and B. Among hrHPV-positive women the rate of CIN2+ was 19.0% (n = 43), in contrast with 1.6% (n = 2) among hrHPV-negative women (relative risk = 12.2, 95% confidence interval [CI] 3.6-81.1, P < 0.001). Among all hrHPV-negative women whose cytological findings were normal or ASCUS, dysplastic lesions were uncommon (n = 4/119, 3.4%), and all were CIN1. If these women had not been referred to colposcopy, the number of colposcopies would have been reduced by 33.6%. We conclude that hrHPV testing combined with repeat cervical cytology had a high negative predictive value in patients with recurrent low-grade cervical cytology. This could reduce the referral rate to colposcopy without jeopardizing patient safety. PMID- 22844004 TI - Lipodystrophy and reversal of facial lipoatrophy in perinatally HIV-infected children and adolescents after discontinuation of stavudine. AB - Lipodystrophy (LD) was evaluated in 205 children receiving antiretroviral therapy by a single investigator: 51 (24.9%) had LD; 46 peripheral lipoatrophy, three central lipohypertrophy and two combined type. All cases of peripheral and combined LD also had facial lipoatrophy. Serial photographs were provided by the families to confirm the severity of facial lipoatrophy. Forty-six (95.8%) children with peripheral or combined LD, and 75 (48.7%) without LD were exposed to stavudine (d4T) for a median duration of 45.9 versus 26.4 months (P = 0.005). In multivariate analysis, exposure to d4T for more than three months was the only factor associated with peripheral or combined LD (P < 0.001). Noticeable improvement of facial lipoatrophy was found in 11/48 (22.9%) children after a mean duration of 45.6 months following d4T discontinuation, mostly occurring during early adolescence. PMID- 22844003 TI - HIV prevalence and sexual behaviour at older ages in rural Malawi. AB - Research on HIV infection and sexual behaviour in sub-Saharan Africa typically focuses on individuals aged 15-49 years under the assumption that both become less relevant for older individuals. We test this assumption using data from rural Malawi to compare sexual behaviour and HIV infection for individuals aged 15-49 with individuals aged 50-64 and 65 and over years. Although general declines with age were observed, levels of sexual activity and HIV remained considerable: 26.7% and 73.8% of women and men aged 65+ reported having sex in the last year, respectively; men's average number of sexual partners remained above one; and HIV prevalence is significantly higher for men aged 50-64 (8.9%) than men aged 15-49 (4.1%). We conclude that older populations are relevant to studies of sexual behaviour and HIV risk. Their importance is likely to increase as access to antiretrovirals in Africa increases. We recommend inclusion of adults aged over 49 years in African HIV/AIDS research and prevention efforts. PMID- 22844005 TI - HIV-1 discordant couples in Karnataka, South India: is the sex ratio of index cases changing? AB - India has an estimated 2.5 million HIV infections, most of which are heterosexually transmitted. Women comprise 40% of infected adults. In India, 90% of women between the ages of 15 and 45 years are married. Previous literature has suggested that sexual intercourse with an HIV-infected husband represents a married woman's greatest risk for being infected. However, a recent meta-analysis of discordant couples from sub-Saharan Africa reported that women were the index case in half of all couples. Similar data are not available from India. This cross-sectional study describes the epidemiology of 925 discordant couples from five districts in Karnataka province, one of the high HIV prevalence provinces in India. Men were the index case in 74% of couples. However, in young couples (where the index case was aged <30 years), women were more likely to be the infected partner (64% of couples). Condom use was reported by 46% of these discordant couples. These results suggest an emerging predominance of female index case infections among younger discordant couples in India, and point to the need for focusing HIV preventive messages on youth and couples before marriage. PMID- 22844006 TI - Skin and soft tissue infections among HIV-infected persons in the late combination antiretroviral therapy era. AB - Skin and soft tissue infections (SSTIs) occur at higher rates among HIV-infected persons, but current trends and risk factors are largely undefined. We evaluated SSTIs among a prospective cohort of HIV-infected persons during the late combination antiretroviral therapy (cART) era (2006-2010). Of the 1918 HIV infected persons evaluated, 379 (20%) developed an SSTI during a median of 3.7 years of follow-up; of these, 118 (31%) developed at least one recurrent SSTI. The incidence rate of SSTIs was 101 (95% confidence interval [CI] 93-109) cases per 1000 person-years, and rates did not significantly change during the study period. Compared with not receiving cART and having an HIV RNA level >1000 copies/mL, patients receiving cART with an HIV RNA level <1000 copies/mL had a reduced risk of an SSTI (hazard ratio 0.64, 95% CI 0.48-0.86, P < 0.01). In summary, initial and recurrent SSTIs are common among HIV-infected persons, and HIV control is associated with a lower risk of SSTIs. PMID- 22844007 TI - Anogenital warts and human papillomavirus: knowledge, perceived nuisance and risk perception in Dutch soldiers. AB - Genital warts are one of the most prevalent sexually transmitted infections in the Netherlands and cause both frustration and misinterpretation in young adults. Poor knowledge may be associated with shame and depression. We used questionnaires to study knowledge, perceived nuisance and risk perception in 100 predominantly heterosexual men with clinically-confirmed condylomata acuminata. Our data show that the majority of patients considered having warts as (very) bothersome. Results confirmed the Internet as a widely used information source. Incorrect information on the relationship between warts and both anogenital cancers and infertility was widespread. Results from knowledge questionnaires showed that higher knowledge scores were associated with higher perceived nuisance. We hypothesize that high levels of nuisance related to genital warts may stimulate the need to seek information and therefore increase knowledge. It does not seem likely that an increase of human papillomavirus-related knowledge would increase experiences of nuisance. PMID- 22844008 TI - The use of an electronic checklist in the electronic patient record to achieve annually recommended outcomes based on British HIV Association guidelines. AB - An electronic search was performed of the electronic patient record (EPR) system to identify whether each of 13 key interventions recommended by the British HIV Association (BHIVA) had been performed for all eligible patients attending in 2009 and 2010 at one of our HIV clinics: 345 and 358 eligible HIV-positive patients were identified in 2009 and 2010, respectively. The success rates for having completed each intervention in 2009 and 2010, respectively, were all better for 2010 and none was <94%. These improved results in 2010 over those of 2009 could be attributed to the clinicians' improved experience in using the checklist and the facility of EPR to provide flagged reminders. PMID- 22844009 TI - Outcome of partner notification in patients diagnosed with genital warts attending a provincial clinic in East Anglia, England. AB - We retrospectively reviewed partner notification of patients diagnosed with first episode genital warts seen in the genitourinary (GU) medicine clinic, Great Yarmouth, UK, from January 2005 to December 2008. Of 947 patients diagnosed with genital warts, 486 (51.3%) were men, median age 25 years; 461 (48.7%) were women, median age 21 years and the partner notification index was 32.9%. In our cohort, 310 patients 33.2% reported having had a casual partner that could not be traced. The median relationship duration of partners whose contact attended was nine months and those whose contact did not attend was two months, (chi(2) = 49.72, P < 0.0001). The odds ratio (OR) of a contact attending after seeing a health adviser was 2.94 (95% confidence interval [CI] = 1.79-4.86). In our cohort 35.6% of contacts whose partners saw a health adviser attended compared with 15.7% of contacts whose partner did not see a health adviser (chi(2) = 19.7, P < 0.0001). Among the contacts 26% had genital warts, 28% had another sexually transmitted infection (STI) and 12% had both genital warts and another STI. The low partner notification index was associated with the reported casual partnerships seen in the cohort. Partner notification was enhanced when patients saw a health adviser. PMID- 22844010 TI - Cushing's syndrome with adrenal suppression induced by inhaled budesonide due to a ritonavir drug interaction in a woman with HIV infection. AB - A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide. Diagnosis of iatrogenic Cushing's syndrome in HIV-positive patients who are on ritonavir-boosted protease inhibitors (PIs) presents a clinical challenge due to similar clinical features of lipohypertrophy related to ritonavir-boosted PIs. Although this complication has been widely described with the use of inhaled fluticasone, the interaction with inhaled budesonide at therapeutic dose is not widely recognized. PMID- 22844011 TI - A case of oral ulceration and disseminated histoplasmosis in HIV infection. AB - A 51-year-old Malawian woman presented with persistent mouth ulceration and an eight-month history of non-specific respiratory symptoms. Histoplasma capsulatum was diagnosed on gum, gastric and lymph node biopsies. Identification of H. capsulatum prompted HIV testing and the patient tested positive with a CD4 count of 40 cells/mm(3). The diagnosis of histoplasmosis was delayed due to its unusual presentation. PMID- 22844012 TI - Methicillin-resistant Staphylococcus aureus as a cause of genital ulcer adenopathy syndrome. AB - The differential diagnosis in anogenital ulcer-adenopathy syndrome in men who have sex with men (MSM) is becoming more complex, particularly with lymphogranuloma venereum and syphilis re-establishing endemicity among MSM. Sexual contact has been shown to transmit methicillin-resistant Staphylococcus aureus (MRSA), probably through intimate skin-to-skin contact. We present a case of MRSA genital ulceration and local lymphadenopathy in a man whose sexual partners are men, reporting high-risk sexual behaviour, highlighting the importance of also considering MRSA infection in these cases, and the potential for spread of MRSA infection in the MSM community. PMID- 22844013 TI - Dermatitis artefacta manifesting as genital scars: a result of an unusual behaviour pattern. AB - A 25-year-old man, diagnosed previously with borderline personality disorder, presented with curvilinear genital scars. A meticulous history and examination led to a diagnosis of dermatitis artefacta with an atypical behaviour pattern. PMID- 22844014 TI - A case of hepatitis A vaccination failure in an HIV-positive man who had sex with men in Israel. AB - Hepatitis A virus (HAV) vaccination is recommended for men who have sex with men (MSM) and other susceptible populations, who are at increased risk for HAV infection, such as HIV-positive persons. Vaccines failures are uncommon, and in HIV-positive individuals whose CD4 count is >= 500 cells/mm(2), seroconversion is achieved in 73-94% of vaccinees following the second dose. Data were retrieved from the patient's file at the sexually transmitted disease clinic and the AIDS clinic describing this rare case of vaccine failure. A 35-year-old, HIV-positive MSM was vaccinated against HAV on 2007, while his CD4 count was 551 cells/mm(2). Two years later, he was hospitalized due to acute HAV. The patient's serum drawn two months prior to the onset of acute HAV was retrospectively tested and showed no response to the vaccine. The source of the HAV infection was not identified. The patient's partner who was HIV-negative and had been vaccinated simultaneously with the same batch developed protective antibodies. In conclusion, HIV-positive patients and their providers should be informed about HAV vaccine failure, and post-immunization serologies to hepatitis should be considered to evaluate immunization response. Alternative approaches to develop immunity are needed for non-responders. PMID- 22844015 TI - An unexpected undetectable viral load in a vulnerable woman. AB - We present a case of a vulnerable HIV-positive African woman who on initial visits to the clinic had an undetectable HIV viral load without giving a history of being on antiretroviral therapy (ART) who then had an abrupt and significant rise in viral load and fall in CD4 count to below the recommended treatment level of 350 cells/MUL. She gave a history of having been given a 'white tablet' from the man who had trafficked her. As genuine 'elite controllers' are rare and do not usually follow this pattern, we suspect that this woman was unknowingly on ART. PMID- 22844016 TI - Gonorrhoea: diagnosis by appointment? PMID- 22844017 TI - Bacille Calmette-Guerin disease following Bacille Calmette-Guerin vaccination of an HIV-infected health-care worker. AB - We present a case of Bacille Calmette-Guerin (BCG) lymphadenitis following immunization of a health-care worker with risk factors for HIV but undiagnosed infection. This case highlights the potential risks of BCG and clearly demonstrates the need to consider HIV testing in all patients prior to BCG vaccination. PMID- 22844018 TI - Two cases of giant cell hepatitis in HIV-infected patients. AB - Giant cell hepatitis (GCH) has been rarely described in adult HIV patients, and its outcome remain unknown. We report two cases of GCH among 81 HIV patients co infected with the hepatitis C virus (HCV). Both patients had a sustained virological response, suppression of HCV viral load and HIV viral suppression after highly active antiretroviral therapy. Our findings would suggest that the presence of giant cells does not influence the clinical course of hepatitis. PMID- 22844019 TI - Clinical care versus ethical obligations: HIV-1 and -2 co-infection with hepatitis B in a pregnant Jehovah's Witness. AB - Co-infection with HIV-1 and -2 is rare, even in west Africa. We present the case of a 38-year-old pregnant Jehovah's Witness presenting late in pregnancy with triple infection with HIV-1, HIV-2 and hepatitis B virus. There was a successful outcome in averting vertical transmission despite objections to management based on religious and cultural beliefs. PMID- 22844020 TI - Giant cell carcinoma causing rapidly progressive respiratory failure as the presenting feature of AIDS. AB - The incidence of lung cancer has been increasing among HIV-positive patients. The majority of these cases were in patients previously diagnosed as HIV-positive and treated with highly active antiretroviral therapy (HAART). Here, we report a 56 year-old male patient with lung cancer, who was diagnosed as HIV-positive after the onset of neck pain and lumbago and thus, was not treated with anti-AIDS therapy. The patient developed rapidly progressive and fatal respiratory failure. Autopsy demonstrated giant cell carcinoma of the lung responsible for carcinomatous lymphangitis. This case highlighted the possibility that pulmonary carcinogenesis in HIV-positive patients is not necessarily associated with HAART therapy. PMID- 22844022 TI - Role of current perceived needs in explaining the association between past trauma exposure and distress in humanitarian settings in Jordan and Nepal. AB - BACKGROUND: Attention is increasingly shifting towards the role of daily stressors in explaining mental health outcomes in humanitarian emergencies. AIMS: To assess the role of current perceived needs in explaining the association between past traumatic exposure and distress in humanitarian settings. METHOD: A series of mediator analyses were conducted, using data from Jordan (displaced Iraqi people) and Nepal (Bhutanese refugees). The General Health Questionnaire (GHQ-12), the newly developed Humanitarian Emergency Settings Perceived Needs Scale (HESPER) and the traumatic events list of the Composite International Diagnostic Interview (CIDI) were used as measures of distress, current perceived needs and past traumatic events respectively. RESULTS: Current perceived needs were found to mediate the association between past traumatic exposure and distress in Jordan and, less strongly, in Nepal. CONCLUSIONS: An integrated approach that includes a focus on daily stressors should be adopted to mitigate the impact of traumatic exposure in humanitarian settings. PMID- 22844021 TI - Ethnic density as a buffer for psychotic experiences: findings from a national survey (EMPIRIC). AB - BACKGROUND: Aetiological mechanisms underlying ethnic density associations with psychosis remain unclear. AIMS: To assess potential mechanisms underlying the observation that minority ethnic groups experience an increased risk of psychosis when living in neighbourhoods of lower own-group density. METHOD: Multilevel analysis of nationally representative community-level data (from the Ethnic Minorities Psychiatric Illness Rates in the Community survey), which included the main minority ethnic groups living in England, and a White British group. Structured instruments assessed discrimination, chronic strains and social support. The Psychosis Screening Questionnaire ascertained psychotic experiences. RESULTS: For every ten percentage point reduction in own-group density, the relative odds of reporting psychotic experiences increased 1.07 times (95% CI 1.01-1.14, P = 0.03 (trend)) for the total minority ethnic sample. In general, people living in areas of lower own-group density experienced greater social adversity that was in turn associated with reporting psychotic experiences. CONCLUSIONS: People resident in neighbourhoods of higher own-group density experience 'buffering' effects from the social risk factors for psychosis. PMID- 22844023 TI - Cigarette smoking as a risk factor for other substance misuse: 10-year study of individuals with and without attention-deficit hyperactivity disorder. AB - BACKGROUND: We previously documented that cigarette smoking is a risk factor for subsequent alcohol and drug misuse and dependence in adolescent girls with attention-deficit hyperactivity disorder (ADHD). AIMS: To revisit this hypothesis with a large longitudinal sample of both genders followed up for 10 years into young adulthood. METHOD: We used data from two identically designed, longitudinal, case-control family studies of boys and girls with and without ADHD ascertained from psychiatric and paediatric sources. We studied 165 individuals with ADHD and 374 controls followed up longitudinally and masked for 10 years. We assessed ADHD, smoking and substance use status using structured diagnostic interviews. We tested the association between cigarette smoking and subsequent substance use outcomes using Cox proportional hazard regression models. RESULTS: Youth with ADHD who smoked cigarettes (n = 27) were significantly more likely to subsequently develop drug misuse and dependence compared with youth with ADHD who did not smoke (n = 138, P<0.05). CONCLUSIONS: These results confirm that cigarette smoking increases the risk for subsequent drug and alcohol use disorders among individuals with ADHD. These findings have important public health implications, and underscore the already pressing need to prevent smoking in children with ADHD. PMID- 22844024 TI - Interaction between the BDNF gene Val/66/Met polymorphism and morning cortisol levels as a predictor of depression in adult women. AB - BACKGROUND: Common genetic variants, such as the brain-derived neurotrophic factor (BDNF) Val/66/Met polymorphism (rs6265), are known to interact with environmental factors such as early adversity to increase the risk of subsequent major depression. Much less is known about how they interact with individual differences in cortisol, although these also represent a risk for major depression. AIMS: To determine whether this BDNF variant moderated the risk represented by higher levels of morning salivary cortisol in adult women. METHOD: We recruited 279 premenopausal women who were at high risk of major depressive disorder because of either negative self-evaluation, unsupportive core relationship or chronic subclinical symptoms of depression or anxiety. Morning salivary cortisol was measured daily for up to 10 days at entry. Participants were followed up for about 12 months by telephone calls at 3-4 monthly intervals. Major depression and severe life events were assessed through interviews at baseline and follow-up; DNA was obtained from the saliva. RESULTS: There were 53 onsets (19%) of depressive episodes during follow-up. There was a significant U shaped relationship between adjusted morning cortisol levels at baseline and the probability of depression onset during follow-up. In total, 51% experienced at least one severe life event/difficulty, and this strongly predicted subsequent onsets of depressive episodes. The BDNF Val/66/Met genotype was not directly associated with onsets of depression or with cortisol levels, but there was significant interaction between Val/66/Met and cortisol: the association between baseline cortisol and depression was limited to those with the Val/66/Val variant. There was no interaction between life events and either this BDNF polymorphism or cortisol levels. CONCLUSIONS: Morning salivary cortisol interacts with the BDNF Val/66/Met polymorphism in predicting new depressive episodes. This paper adds to the evidence that single gene polymorphisms interact with endogenous factors to predict depression. PMID- 22844025 TI - Depressive symptoms and pragmatic rehabilitation for chronic fatigue syndrome. AB - BACKGROUND: Previous research has suggested that depressed mood may predict outcome and moderate response to treatment in chronic fatigue syndrome, although findings have differed between studies. AIMS: To examine potential moderators of response to pragmatic rehabilitation v. general practitioner treatment as usual in a recent randomised trial for patients with chronic fatigue syndrome in primary care (IRCTN74156610). METHOD: Simple regressions, with weighting adjustments to allow for missing data, were calculated. Demographic, medical and psychological variables, and treatment arm, were entered separately and as an interaction term. The outcome variable in each case was change in Chalder Fatigue Scale scores, from baseline to 1-year follow-up, our primary outcome point. RESULTS: Longer illness durations predicted poorer outcome across the two treatment arms. For patients allocated to pragmatic rehabilitation compared with those allocated to treatment as usual, higher levels of depressive symptoms at baseline were associated with smaller improvements in fatigue (P = 0.022). CONCLUSIONS: For patients in primary care with higher levels of depressive symptoms, either more intensive or longer pragmatic rehabilitation, or cognitive behavioural therapy, may be required in order to show a significant improvement in fatigue. PMID- 22844026 TI - Three arguments against prescription requirements. AB - In this essay, I argue that prescription drug laws violate patients' rights to self-medication. Patients have rights to self-medication for the same reasons they have rights to refuse medical treatment according to the doctrine of informed consent (DIC). Since we should accept the DIC, we ought to reject paternalistic prohibitions of prescription drugs and respect the right of self medication. In section 1, I frame the puzzle of self-medication; why don't the same considerations that tell in favour of informed consent also justify a right of self-medication? In section 2, I show that the prescription drug system was historically motivated by paternalism. In section 3, I outline the justifications for the DIC in more detail. I show that consequentialist, epistemic, and deontic considerations justify the DIC. In sections 4-6, I argue that these considerations also justify rights of self-medication. I then propose that rights of self-medication require non-prohibitive prescription policies in section 7. I consider two objections in sections 8 and 9: that patients ought not to make medically risky or deadly decisions, and that unrestricted access to prescription grade pharmaceuticals would result in widespread misuse and abuse. Section 10 concludes. PMID- 22844027 TI - The value of autonomy and the right to self-medication. AB - In 'Three Arguments Against Prescription Requirements', Jessica Flanigan argues that 'prescription drug laws violate patients' rights to self-medication' and that patients 'have rights to self-medication for the same reasons they have rights to refuse medical treatment according to the doctrine of informed consent (DIC), claiming that the strongest of these reasons is grounded on the value of autonomy. However, close examination of the moral value of autonomy shows that rather than being the strongest justification for the DIC, respect for the value of autonomy is actually the weakest, and it is dependent upon the first two well being-based justifications for the DIC. Recognising this has important implications for Flanigan's argument against prescription requirements. PMID- 22844028 TI - Commentary on 'Three arguments against prescription requirements'. PMID- 22844029 TI - Intellectual property rights and detached human body parts. AB - This paper responds to an invitation by the editors to consider whether the intellectual property (IP) regime suggests an appropriate model for protecting interests in detached human body parts. It begins by outlining the extent of existing IP protection for body parts in Europe, and the relevant strengths and weaknesses of the patent system in that regard. It then considers two further species of IP right of less obvious relevance. The first are the statutory rights of ownership conferred by domestic UK law in respect of employee inventions, and the second are the economic and moral rights recognised by European and international law in respect of authorial works. In the argument made, both of these species of IP right may suggest more appropriate models of sui generis protection for detached human body parts than patent rights because of their capacity better to accommodate the relevant public and private interests in respect of the same. PMID- 22844030 TI - Training healthcare professionals as moral case deliberation facilitators: evaluation of a Dutch training programme. AB - Until recently, moral case deliberation (MCD) sessions have mostly been facilitated by external experts, mainly professional ethicists. We have developed a train the facilitator programme for healthcare professionals aimed at providing them with the competences needed for being an MCD facilitator. In this paper, we present the first results of a study in which we evaluated the programme. We used a mixed methods design. One hundred and twenty trained healthcare professionals and five trainers from 16 training groups working in different healthcare organisations throughout the Netherlands were included. After completion of the programme, participants feel sufficiently confident and equipped to facilitate an MCD session. Feeling competent does not mean that participants have no doubts or questions left. Rather, they are aware of their limitations and see the need for continuous learning. According to the respondents, the actual exercise of facilitating MCD during and in between the training sessions contributed most to the development of competences necessary for being an MCD facilitator. Respondents without prior experience of participating in MCD sessions felt less competent after the training than those who had participated in MCD sessions before. Self-attributed competence varied between participants with different professional backgrounds. PMID- 22844031 TI - Applications of transrectal ultrasound in prostate cancer. AB - Transrectal ultrasound (TRUS) was first developed in the 1970s. TRUS-guided biopsy, under local anaesthetic and prophylactic antibiotics, is now the most widely accepted method to diagnose prostate cancer. However, the sensitivity and specificity of greyscale TRUS in the detection of prostate cancer is low. Prostate cancer most commonly appears as a hypoechoic focal lesion in the peripheral zone on TRUS but the appearances are variable with considerable overlap with benign lesions. Because of the low accuracy of greyscale TRUS, TRUS guided biopsies have become established in the acquisition of systematic biopsies from standard locations. The number of systematic biopsies has increased over the years, with 10-12 cores currently accepted as the minimum standard. This article describes the technique of TRUS and biopsy and its complications. Novel modalities including contrast-enhanced modes and elastography as well as fusion techniques for increasing the sensitivity of TRUS-guided prostate-targeted biopsies are discussed along with their role in the diagnosis and management of prostate cancer. PMID- 22844032 TI - Comparison of visual grading and free-response ROC analyses for assessment of image-processing algorithms in digital mammography. AB - OBJECTIVE: To compare two methods for assessment of image-processing algorithms in digital mammography: free-response receiver operating characteristic (FROC) for the specific task of microcalcification detection and visual grading analysis (VGA). METHODS: The FROC study was conducted prior to the VGA study reported here. 200 raw data files of low breast density (Breast Imaging-Reporting and Data System I-II) mammograms (Novation DR, Siemens, Germany)-100 of which abnormal were processed by four image-processing algorithms: Raffaello (IMS, Bologna, Italy), Sigmoid (Sectra, Linkoping, Sweden), and OpView v. 2 and v. 1 (Siemens, Erlangen, Germany). Four radiologists assessed the mammograms for the detection of microcalcifications. 8 months after the FROC study, a subset (200) of the 800 images was reinterpreted by the same radiologists, using the VGA methodology in a side-by-side approach. The VGA grading was based on noise, saturation, contrast, sharpness and confidence with the image in terms of normal structures. Ordinal logistic regression was applied; OpView v. 1 was the reference processing algorithm. RESULTS: In the FROC study all algorithms performed better than OpView v. 1. From the current VGA study and for confidence with the image, Sigmoid and Raffaello were significantly worse (p<0.001) than OpView v. 1; OpView v. 2 was significantly better (p=0.01). For the image quality criteria, results were mixed; Raffaello and Sigmoid for example were better than OpView v. 1 for sharpness and contrast (although not always significantly). CONCLUSION: VGA and FROC discordant results should be attributed to the different clinical task addressed. ADVANCES IN KNOWLEDGE: The method to use for image-processing assessment depends on the clinical task tested. PMID- 22844033 TI - Assessment of paediatric CT dose indicators for the purpose of optimisation. AB - OBJECTIVES: To establish local diagnostic reference levels (LDRLs) at the Royal Children's Hospital (RCH) Melbourne, Parkville, Australia, for typical paediatric CT examinations and compare these with international diagnostic reference levels (DRLs) to benchmark local practice. In addition, the aim was to develop a method of analysing local scan parameters to enable identification of areas for optimisation. METHODS: A retrospective audit of patient records for paediatric CT brain, chest and abdomen/pelvis examinations was undertaken. Demographic information, examination parameters and dose indicators--volumetric CT dose index (CTDI(vol)) and dose-length product (DLP)--were collected for 220 patients. LDRLs were derived from mean survey values and the effective dose was estimated from DLP values. The normalised CTDI(vol) values, mAs values and scan length were analysed to better identify parameters that could be optimised. RESULTS: The LDRLs across all age categories were 18-45 mGy (CTDI(vol)) and 250-700 mGy cm (DLP) for brain examinations; 3-23 mGy (CTDI(vol)) and 100-800 mGy cm (DLP) for chest examinations; and 4-15 mGy (CTDI(vol)) and 150-750 mGy cm (DLP) for abdomen/pelvis examinations. Effective dose estimates were 1.0-1.6 mSv, 1.8-13.0 mSv and 2.5-10.0 mSv for brain, chest and abdomen/pelvis examinations, respectively. CONCLUSION: The RCH mean CTDI(vol) and DLP values are similar to or lower than international DRLs. Use of low-kilovoltage protocols for body imaging in younger patients reduced the dose considerably. There exists potential for optimisation in reducing body scan lengths and justifying the selection of reference mAs values. The assessment method used here proved useful for identifying specific parameters for optimisation. Advances in knowledge Assessment of individual CT parameters in addition to comparison with DRLs enables identification of specific areas for CT optimisation. PMID- 22844034 TI - Thin-section CT findings in Pseudomonas aeruginosa pulmonary infection. AB - OBJECTIVE: The aim of this study was to assess clinical and pulmonary thin section CT findings in patients with acute Pseudomonas aeruginosa (PA) pulmonary infection. METHODS: We retrospectively identified 44 patients with acute PA pneumonia who had undergone chest thin-section CT examinations between January 2004 and December 2010. We excluded nine patients with concurrent infections. The final study group comprised 35 patients (21 males, 14 females; age range 30-89 years, mean age 66.9 years) with PA pneumonia. The patients' clinical findings were assessed. Parenchymal abnormalities, enlarged lymph nodes and pleural effusion were evaluated on thin-section CT. RESULTS: Underlying diseases included malignancy (n=13), a smoking habit (n=11) and cardiac disease (n=8). CT scans of all patients revealed abnormal findings, including ground-glass opacity (n=34), bronchial wall thickening (n=31), consolidation (n=23) and cavities (n=5). Pleural effusion was found in 15 patients. CONCLUSION: PA pulmonary infection was observed in patients with underlying diseases such as malignancy or a smoking habit. The CT findings in patients with PA consisted mainly of ground-glass attenuation and bronchial wall thickening. ADVANCES IN KNOWLEDGE: The CT findings consisted mainly of ground-glass attenuation, bronchial wall thickening and cavities. These findings in patients with an underlying disease such as malignancy or a smoking habit may be suggestive of pneumonia caused by PA infection. PMID- 22844035 TI - Effectiveness of soft tissue massage and exercise for the treatment of non specific shoulder pain: a systematic review with meta-analysis. AB - OBJECTIVE: To determine the effectiveness of exercise and soft tissue massage either in isolation or in combination for the treatment of non-specific shoulder problems. METHODS: Database searches for articles from 1966 to December 2011 were performed. Studies were eligible if they investigated 'hands on' soft tissue massage performed locally to the shoulder or exercises aimed at improving strength, range of motion or coordination; non-surgical painful shoulder disorders; included participants aged 18-80 years and outcomes measured included pain, disability, range of motion, quality of life, work status, global perceived effect, adverse events or recurrence. RESULTS: Twenty-three papers met the selection criteria representing 20 individual trials. We found low-quality evidence that soft tissue massage was effective for producing moderate improvements in active flexion and abduction range of motion, pain and functional scores compared with no treatment, immediately after the cessation of treatment. Exercise was shown by meta-analysis to produce greater improvements than placebo, minimal or no treatment in reported pain (weighted mean=9.8 of 100, 95% CI 0.6 to 19.0) but these changes were of a magnitude that was less than that considered clinically worthwhile. Exercise did not produce greater improvements in shoulder function than placebo, minimal or no treatment (weighted mean=5.7 of 100, 95% CI 3.3 to 14.7). CONCLUSION: There is low-quality evidence that soft tissue massage is effective for improving pain, function and range of motion in patients with shoulder pain in the short term. Exercise therapy is effective for producing small improvements in pain but not in function or range of motion. PMID- 22844036 TI - Pistorious at the Olympics: the saga continues. PMID- 22844037 TI - Treatment of acute ankle sprains: evidence on the use of an ankle brace is unclear. PMID- 22844038 TI - Impact of ethnicity upon cardiovascular adaptation in competitive athletes: relevance to preparticipation screening. AB - Regular participation in intensive physical exercise is associated with several structural and electrophysiological cardiac adaptations that enhance diastolic filling and facilitate a sustained increase in the cardiac output that is fundamental to athletic excellence. Such cardiac adaptations are collectively referred to as the 'Athlete's Heart' and are frequently reflected on the 12-lead ECG and imaging studies. Thorough knowledge relating to exercise-associated cardiovascular adaptation is imperative for the purposes of differentiating physiological adaptation from cardiac pathology, since an erroneous diagnosis of cardiac disease has potentially serious consequences for the athlete's physical, psychological, social and financial well-being. The majority of studies investigating the cardiovascular adaptation to exercise are based on cohorts of Caucasian athletes. However, there is mounting evidence that ethnicity is an important determinant of the objective manifestations of cardiovascular adaptation to exercise. The most pronounced paradigm of ethnically distinct cardiovascular adaptation to exercise stems from athletes of African/Afro Caribbean descent, who exhibit a significantly higher prevalence of repolarisation anomalies and left ventricular hypertrophy, compared to Caucasian athletes; the differentiation between athlete's heart and hypertrophic cardiomyopathy is particularly challenging in this ethnic group. The extrapolation of ECG and echocardiographic criteria used to diagnose potentially serious cardiac disorders in Caucasian athletes to the African/Afro-Caribbean athlete population would result in an unacceptable number of unnecessary investigations and increased risk of false disqualification from competitive sport. Accurate interpretation of the athlete's ECG and echocardiogram is crucial, particularly when one considers the continuous expansion of preparticipation screening programmes. This review attempts to highlight ethnically determined differences in cardiovascular adaptation to exercise and provides a practical guide for the interpretation of baseline investigations in athletes of diverse ethnic backgrounds. PMID- 22844039 TI - The role of the design of tibial components and stems in knee replacement. AB - Stems improve the mechanical stability of tibial components in total knee replacement (TKR), but come at a cost of stress shielding along their length. Their advantages include resistance to shear, reduced tibial lift-off and increased stability by reducing micromotion. Longer stems may have disadvantages including stress shielding along the length of the stem with associated reduction in bone density and a theoretical risk of subsidence and loosening, peri prosthetic fracture and end-of-stem pain. These features make long stems unattractive in the primary TKR setting, but often desirable in revision surgery with bone loss and instability. In the revision scenario, stems are beneficial in order to convey structural stability to the construct and protect the reconstruction of bony defects. Cemented and uncemented long stemmed implants have different roles depending on the nature of the bone loss involved. This review discusses the biomechanics of the design of tibial components and stems to inform the selection of the component and the technique of implantation. PMID- 22844040 TI - A reappraisal of functional reconstruction of extension of the knee following quadriceps resection or loss. AB - The current indications for functional restoration of extension of the knee following quadriceps resection or loss require reappraisal. The contribution of pedicled and free functional muscle transfer is likely to be over-emphasised in many studies, with good functional outcomes predominantly reported only in the context of cases with residual quadriceps function. In cases with total quadriceps resection or loss, all forms of reconstruction perform poorly. Furthermore, in smaller resections with loss of two or fewer components of the quadriceps, minimal impairment of function occurs in the absence of functional reconstruction, suggesting that functional restoration may not be warranted. Thus there is a paradox in the current approach to quadriceps reconstruction, in that small resections are likely to be over-treated and large resections remain under treated. This review suggests a shift is required in the approach and rationale for reconstructing functional extension of the knee after quadriceps resection or loss. A classification based on current evidence is suggested that emphasises more clearly the indications and rationale for functional transfers. PMID- 22844041 TI - Diffusion tensor imaging of the spinal cord and its clinical applications. AB - The identification of the extent of neural damage in patients with acute or chronic spinal cord injury is imperative for the accurate prediction of neurological recovery. The changes in signal intensity shown on routine MRI sequences are of limited value for predicting functional outcome. Diffusion tensor imaging (DTI) is a novel radiological imaging technique which has the potential to identify intact nerve fibre tracts, and has been used to image the brain for a variety of conditions. DTI imaging of the spinal cord is currently only a research tool, but preliminary studies have shown that it holds considerable promise in predicting the severity of spinal cord injury. This paper briefly reviews our current knowledge of this technique. PMID- 22844042 TI - Cost savings of using a cemented total hip replacement: an analysis of the National Joint Registry data. AB - The debate whether to use cemented or uncemented components in primary total hip replacement (THR) has not yet been considered with reference to the cost implications to the National Health Service. We obtained the number of cemented and uncemented components implanted in 2009 from the National Joint Registry for England and Wales. The cost of each component was established. The initial financial saving if all were cemented was then calculated. Subsequently the five year rates of revision for each type of component were reviewed and the predicted number of revisions at five years for the actual components used was compared with the predicted number of revisions for a cemented THR. This was then multiplied by the mean cost of revision surgery to provide an indication of the savings over the first five years if all primary THRs were cemented. The saving at primary THR was calculated to be L10 million with an additional saving during the first five years of between L5 million and L8.5 million. The use of cemented components in routine primary THR in the NHS as a whole can be justified on a financial level but we recognise individual patient factors must be considered when deciding which components to use. PMID- 22844043 TI - Changes in bone mineral density of the acetabulum, femoral neck and femoral shaft, after hip resurfacing and total hip replacement: two-year results from a randomised study. AB - It is accepted that resurfacing hip replacement preserves the bone mineral density (BMD) of the femur better than total hip replacement (THR). However, no studies have investigated any possible difference on the acetabular side. Between April 2007 and March 2009, 39 patients were randomised into two groups to receive either a resurfacing or a THR and were followed for two years. One patient's resurfacing subsequently failed, leaving 19 patients in each group. Resurfaced replacements maintained proximal femoral BMD and, compared with THR, had an increased bone mineral density in Gruen zones 2, 3, 6, and particularly zone 7, with a gain of 7.5% (95% confidence interval (CI) 2.6 to 12.5) compared with a loss of 14.6% (95% CI 7.6 to 21.6). Resurfacing replacements maintained the BMD of the medial femoral neck and increased that in the lateral zones between 12.8% (95% CI 4.3 to 21.4) and 25.9% (95% CI 7.1 to 44.6). On the acetabular side, BMD was similar in every zone at each point in time. The mean BMD of all acetabular regions in the resurfaced group was reduced to 96.2% (95% CI 93.7 to 98.6) and for the total hip replacement group to 97.6% (95% CI 93.7 to 101.5) (p = 0.4863). A mean total loss of 3.7% (95% CI 1.0 to 6.5) and 4.9% (95% CI 0.8 to 9.0) of BMD was found above the acetabular component in W1 and 10.2% (95% CI 0.9 to 19.4) and 9.1% (95% CI 3.8 to 14.4) medial to the implant in W2 for resurfaced replacements and THRs respectively. Resurfacing resulted in a mean loss of BMD of 6.7% (95% CI 0.7 to 12.7) in W3 but the BMD inferior to the acetabular component was maintained in both groups. These results suggest that the ability of a resurfacing hip replacement to preserve BMD only applies to the femoral side. PMID- 22844044 TI - The sensitivity, specificity and predictive values of raised plasma metal ion levels in the diagnosis of adverse reaction to metal debris in symptomatic patients with a metal-on-metal arthroplasty of the hip. AB - Plasma levels of cobalt and chromium ions and Metal Artefact Reduction Sequence (MARS)-MRI scans were performed on patients with 209 consecutive, unilateral, symptomatic metal-on-metal (MoM) hip arthroplasties. There was wide variation in plasma cobalt and chromium levels, and MARS-MRI scans were positive for adverse reaction to metal debris (ARMD) in 84 hips (40%). There was a significant difference in the median plasma cobalt and chromium levels between those with positive and negative MARS-MRI scans (p < 0.001). Compared with MARS-MRI as the potential reference standard for the diagnosis of ARMD, the sensitivity of metal ion analysis for cobalt or chromium with a cut-off of > 7 ug/l was 57%. The specificity was 65%, positive predictive value was 52% and the negative predictive value was 69% in symptomatic patients. A lowered threshold of > 3.5 ug/l for cobalt and chromium ion levels improved the sensitivity and negative predictive value to 86% and 74% but at the expense of specificity (27%) and positive predictive value (44%). Metal ion analysis is not recommended as a sole indirect screening test in the surveillance of symptomatic patients with a MoM arthroplasty. The investigating clinicians should have a low threshold for obtaining cross-sectional imaging in these patients, even in the presence of low plasma metal ion levels. PMID- 22844045 TI - Does a mobile-bearing, high-flexion design increase knee flexion after total knee replacement? AB - This prospective randomised controlled double-blind trial compared two types of PFC Sigma total knee replacement (TKR), differing in three design features aimed at improving flexion. The outcome of a standard fixed-bearing posterior cruciate ligament-preserving design (FB-S) was compared with that of a high-flexion rotating-platform posterior-stabilised design (RP-F) at one year after TKR. The study group of 77 patients with osteoarthritis of the knee comprised 37 men and 40 women, with a mean age of 69 years (44.9 to 84.9). The patients were randomly allocated either to the FB-S or the RP-F group and assessed pre-operatively and at one year post-operatively. The mean post-operative non-weight-bearing flexion was 107 degrees (95% confidence interval (CI) 104 degrees to 110 degrees )) for the FB-S group and 113 degrees (95% CI 109 degrees to 117 degrees ) for the RP F group, and this difference was statistically significant (p = 0.032). However, weight-bearing range of movement during both level walking and ascending a slope as measured during flexible electrogoniometry was a mean of 4 degrees lower in the RP-F group than in the FB-S group, with 58 degrees (95% CI 56 degrees to 60 degrees ) versus 54 degrees (95% CI 51 degrees to 57 degrees ) for level walking (p = 0.019) and 56 degrees (95% CI 54 degrees to 58 degrees ) versus 52 degrees (95% CI 48 degrees to 56 degrees ) for ascending a slope (p = 0.044). Further, the mean post-operative pain score of the Western Ontario and McMaster Universities Osteoarthritis Index was significantly higher in the RP-F group (2.5 (95% CI 1.5 to 3.5) versus 4.2 (95% CI 2.9 to 5.5), p = 0.043). Although the RP-F group achieved higher non-weight-bearing knee flexion, patients in this group did not use this during activities of daily living and reported more pain one year after surgery. PMID- 22844046 TI - The effect of surgical factors on early patient-reported outcome measures (PROMS) following total knee replacement. AB - Patient-reported outcome measures (PROMs) are increasingly being used to assess functional outcome and patient satisfaction. They provide a framework for comparisons between surgical units, and individual surgeons for benchmarking and financial remuneration. Better performance may bring the reward of more customers as patients and commissioners seek out high performers for their elective procedures. Using National Joint Registry (NJR) data linked to PROMs we identified 22,691 primary total knee replacements (TKRs) undertaken for osteoarthritis in England and Wales between August 2008 and February 2011, and identified the surgical factors that influenced the improvements in the Oxford knee score (OKS) and EuroQol-5D (EQ-5D) assessment using multiple regression analysis. After correction for patient factors the only surgical factors that influenced PROMs were implant brand and hospital type (both p < 0.001). However, the effects of surgical factors upon the PROMs were modest compared with patient factors. For both the OKS and the EQ-5D the most important factors influencing the improvement in PROMs were the corresponding pre-operative score and the patient's general health status. Despite having only a small effect on PROMs, this study has shown that both implant brand and hospital type do influence reported subjective functional scores following TKR. In the current climate of financial austerity, proposed performance-based remuneration and wider patient choice, it would seem unwise to ignore these effects and the influence of a range of additional patient factors. PMID- 22844047 TI - Long-term outcome in an uncemented, hydroxyapatite-coated total knee replacement: a 15- to 18-year survivorship analysis. AB - A consecutive series of patients with a hydroxyapatite-coated uncemented total knee replacement (TKR) performed by a single surgeon between 1992 and 1995 was analysed. All patients were invited for clinical review and radiological assessment. Revision for aseptic loosening was the primary outcome. Assessment was based on the Knee Society clinical score (KSS) and an independent radiological analysis. Of 471 TKRs performed in 356 patients, 432 TKRs in 325 patients were followed for a mean of 16.4 years (15 to 18). The 39 TKRs in 31 patients lost to follow-up had a mean KSS of 176 (148 to 198) at a mean of ten years. There were revisions in 26 TKRs (5.5%), of which 11 (2.3%) were for aseptic loosening. Other further surgery was carried out on 49 TKRs (10.4%) including patellar resurfacing in 20, arthrolysis in 19, manipulation under anaesthetic in nine and extensor mechanism reconstruction in one. Survivorship at up to 18 years without aseptic loosening was 96% (95% confidence interval 91.9 to 98.1), at which point the mean KSS was 176 (134 to 200). Of 110 knees that underwent radiological evaluation, osteolysis was observed in five (4.5%), one of which was revised. These data indicate that uncemented hydroxyapatite-coated TKR can achieve favourable long-term survivorship, at least as good as that of cemented designs. PMID- 22844049 TI - Diagnostic accuracy of imaging modalities for suspected scaphoid fractures: meta analysis combined with latent class analysis. AB - Follow-up radiographs are usually used as the reference standard for the diagnosis of suspected scaphoid fractures. However, these are prone to errors in interpretation. We performed a meta-analysis of 30 clinical studies on the diagnosis of suspected scaphoid fractures, in which agreement data between any of follow-up radiographs, bone scintigraphy, magnetic resonance (MR) imaging, or CT could be obtained, and combined this with latent class analysis to infer the accuracy of these tests on the diagnosis of suspected scaphoid fractures in the absence of an established standard. The estimated sensitivity and specificity were respectively 91.1% and 99.8% for follow-up radiographs, 97.8% and 93.5% for bone scintigraphy, 97.7% and 99.8% for MRI, and 85.2% and 99.5% for CT. The results were generally robust in multiple sensitivity analyses. There was large between-study heterogeneity for the sensitivity of follow-up radiographs and CT, and imprecision about their sensitivity estimates. If we acknowledge the lack of a reference standard for diagnosing suspected scaphoid fractures, MRI is the most accurate test; follow-up radiographs and CT may be less sensitive, and bone scintigraphy less specific. PMID- 22844048 TI - Oxford phase 3 unicompartmental knee replacement in Korean patients. AB - Medium-term survivorship of the Oxford phase 3 unicompartmental knee replacement (UKR) has not yet been established in an Asian population. We prospectively evaluated the outcome of 400 phase 3 Oxford UKRs in 320 Korean patients with a mean age at the time of operation of 69 years (48 to 82). The mean follow-up was 5.2 years (1 to 10). Clinical and radiological assessment was carried out pre- and post-operatively. At five years, the mean Knee Society knee and functional scores had increased significantly from 56.2 (30 to 91) pre-operatively to 87.2 (59 to 98) (p = 0.034) and from 59.2 (30 to 93) to 88.3 (50 to 100) (p = 0.021), respectively. The Oxford knee score increased from a mean of 25.8 (12 to 39) pre operatively to 39.8 (25 to 58) at five years (p = 0.038). The ten-year survival rate was 94% (95% confidence interval 90.1 to 98.0). A total of 14 UKRs (3.5%) required revision. The most common reason for revision was dislocation of the bearing in 12 (3%). Conversion to a total knee replacement was required in two patients who developed osteoarthritis of the lateral compartment. This is the largest published series of UKR in Korean patients. It shows that the mid-term results after a minimally invasive Oxford phase 3 UKR can yield satisfactory clinical and functional results in this group of patients. PMID- 22844050 TI - Arthroscopic subacromial decompression is effective in selected patients with shoulder impingement syndrome. AB - A total of 92 patients with symptoms for over six months due to subacromial impingement of the shoulder, who were being treated with physiotherapy, were included in this study. While continuing with physiotherapy they waited a further six months for surgery. They were divided into three groups based on the following four clinical and radiological criteria: temporary benefit following steroid injection, pain in the mid-arc of abduction, a consistently positive Hawkins test and radiological evidence of impingement. Group A fulfilled all four criteria, group B three criteria and group C two criteria. A total of nine patients improved while waiting for surgery and were excluded, leaving 83 who underwent arthroscopic subacromial decompression (SAD). The new Oxford shoulder score was recorded pre-operatively and at three and 12 months post-operatively. A total of 51 patients (group A) had a significant improvement in the mean shoulder score from 18 (13 to 22) pre-operatively to 38 (35 to 42) at three months (p < 0.001). The mean score in this group was significantly better than in group B (21 patients) and C (11 patients) at this time. At one year patients in all groups showed improvement in scores, but patients in group A had a higher mean score (p = 0.01). At one year patients in groups A and B did better than those in group C (p = 0.01). Arthroscopic SAD is a beneficial intervention in selected patients. The four criteria could help identify patients in whom it is likely to be most effective. PMID- 22844051 TI - Correction of dorsally-malunited extra-articular distal radial fractures using volar locked plates without bone grafting. AB - Malunion is the most common complication of the distal radius with many modalities of treatment available for such a problem. The use of bone grafting after an osteotomy is still recommended by most authors. We hypothesised that bone grafting is not required; fixing the corrected construct with a volar locked plate helps maintain the alignment, while metaphyseal defect fills by itself. Prospectively, we performed the procedure on 30 malunited dorsally-angulated radii using fixed angle volar locked plates without bone grafting. At the final follow-up, 22 wrists were available. Radiological evidence of union, correction of the deformity, clinical and functional improvement was achieved in all cases. Without the use of bone grafting, corrective open wedge osteotomy fixed by a volar locked plate provides a high rate of union and satisfactory functional outcomes. PMID- 22844052 TI - CT scanning reduces the risk of missing a fracture of the thoracolumbar spine. AB - The aim of this study was first, to determine whether CT scans undertaken to identify serious injury to the viscera were of use in detecting clinically unrecognised fractures of the thoracolumbar vertebrae, and second, to identify patients at risk of 'missed injury'. We retrospectively analysed CT scans of the chest and abdomen performed for blunt injury to the torso in 303 patients. These proved to be positive for thoracic and intra-abdominal injuries in only 2% and 1.3% of cases, respectively. However, 51 (16.8%) showed a fracture of the thoracolumbar vertebrae and these constituted our subset for study. There were eight women and 43 men with mean age of 45.2 years (15 to 94). There were 29 (57%) stable and 22 (43%) unstable fractures. Only 17 fractures (33.3%) had been anticipated after clinical examination. Of the 22 unstable fractures, 11 (50%) were anticipated. Thus, within the whole group of 303 patients, an unstable spinal injury was missed in 11 patients (3.6%); no harm resulted as they were all protected until the spine had been cleared. A subset analysis revealed that patients with a high Injury Severity Score, a low Glasgow Coma Scale and haemodynamic instability were most likely to have a significant fracture in the absence of positive clinical findings. This is the group at greatest risk. Clinical examination alone cannot detect significant fractures of the thoracolumbar spine. It should be combined with CT imaging to reduce the risk of missed injury. PMID- 22844053 TI - The role of fusion in the management of burst fractures of the thoracolumbar spine treated by short segment pedicle screw fixation: a prospective randomised trial. AB - The purpose of this study was to determine whether patients with a burst fracture of the thoracolumbar spine treated by short segment pedicle screw fixation fared better clinically and radiologically if the affected segment was fused at the same time. A total of 50 patients were enrolled in a prospective study and assigned to one of two groups. After the exclusion of three patients, there were 23 patients in the fusion group and 24 in the non-fusion group. Follow-up was at a mean of 23.9 months (18 to 30). Functional outcome was evaluated using the Greenough Low Back Outcome Score. Neurological function was graded using the American Spinal Injury Association Impairment Scale. Radiological outcome was assessed on the basis of the angle of kyphosis. Peri-operative blood transfusion requirements and duration of surgery were significantly higher in the fusion group (p = 0.029 and p < 0.001, respectively). There were no clinical or radiological differences in outcome between the groups (all outcomes p > 0.05). The results of this study suggest that adjunctive fusion is unnecessary when managing patients with a burst fracture of the thoracolumbar spine with short segment pedicle screw fixation. PMID- 22844054 TI - The treatment of unstable fractures of the ankle using the Acumed fibular nail: development of a technique. AB - Techniques for fixation of fractures of the lateral malleolus have remained essentially unchanged since the 1960s, but are associated with complication rates of up to 30%. The fibular nail is an alternative method of fixation requiring a minimal incision and tissue dissection, and has the potential to reduce the incidence of complications. We reviewed the results of 105 patients with unstable fractures of the ankle that were fixed between 2002 and 2010 using the Acumed fibular nail. The mean age of the patients was 64.8 years (22 to 95), and 80 (76%) had significant systemic medical comorbidities. Various different configurations of locking screw were assessed over the study period as experience was gained with the device. Nailing without the use of locking screws gave satisfactory stability in only 66% of cases (4 of 6). Initial locking screw constructs rendered between 91% (10 of 11) and 96% (23 of 24) of ankles stable. Overall, seven patients had loss of fixation of the fracture and there were five post-operative wound infections related to the distal fibula. This lead to the development of the current technique with a screw across the syndesmosis in addition to a distal locking screw. In 21 patients treated with this technique there have been no significant complications and only one superficial wound infection. Good fracture reduction was achieved in all of these patients. The mean physical component Short-Form 12, Olerud and Molander score, and American Academy of Orthopaedic Surgeons Foot and Ankle outcome scores at a mean of six years post-injury were 46 (28 to 61), 65 (35 to 100) and 83 (52 to 99), respectively. There have been no cases of fibular nonunion. Nailing of the fibula using our current technique gives good radiological and functional outcomes with minimal complications, and should be considered in the management of patients with an unstable ankle fracture. PMID- 22844055 TI - More re-operations after uncemented than cemented hemiarthroplasty used in the treatment of displaced fractures of the femoral neck: an observational study of 11,116 hemiarthroplasties from a national register. AB - Using data from the Norwegian Hip Fracture Register, 8639 cemented and 2477 uncemented primary hemiarthroplasties for displaced fractures of the femoral neck in patients aged > 70 years were included in a prospective observational study. A total of 218 re-operations were performed after cemented and 128 after uncemented procedures. Survival of the hemiarthroplasties was calculated using the Kaplan Meier method and hazard rate ratios (HRR) for revision were calculated using Cox regression analyses. At five years the implant survival was 97% (95% confidence interval (CI) 97 to 97) for cemented and 91% (95% CI 87 to 94) for uncemented hemiarthroplasties. Uncemented hemiarthroplasties had a 2.1 times increased risk of revision compared with cemented prostheses (95% confidence interval 1.7 to 2.6, p < 0.001). The increased risk was mainly caused by revisions for peri prosthetic fracture (HRR = 17), aseptic loosening (HRR = 17), haematoma formation (HRR = 5.3), superficial infection (HRR = 4.6) and dislocation (HRR = 1.8). More intra-operative complications, including intra-operative death, were reported for the cemented hemiarthroplasties. However, in a time-dependent analysis, the HRR for re-operation in both groups increased as follow-up increased. This study showed that the risk for revision was higher for uncemented than for cemented hemiarthroplasties. PMID- 22844056 TI - Patient-reported complications after elective joint replacement surgery: are they correct? AB - Using general practitioner records and hospital notes and through direct telephone conversation with patients, we investigated the accuracy of nine patient-reported complications gathered from a self-completed questionnaire after elective joint replacement surgery of the hip and knee. A total of 402 post discharge complications were reported after 8546 elective operations that were undertaken within a three-year period. These were reported by 136 men and 240 women with a mean age of 71.8 years (34 to 93). A total of 319 reported complications (79.4%; 95% confidence interval 75.4 to 83.3) were confirmed to be correct. High rates of correct reporting were demonstrated for infection (94.5%) and the need for further surgery (100%), whereas the rates of reporting deep-vein thrombosis (DVT), pulmonary embolism, myocardial infarction and stroke were lower (75% to 84.2%). Dislocation, peri-prosthetic fractures and nerve palsy had modest rates of correct reporting (36% to 57.1%). More patients who had knee surgery delivered incorrect reports of dislocation (p = 0.001) and DVT (p = 0.013). Despite these variations, it appears that post-operative complications may form part of a larger patient-reported outcome programme after elective joint replacement surgery. PMID- 22844057 TI - Metal hypersensitivity testing in patients undergoing joint replacement: a systematic review. AB - We report a systematic review and meta-analysis of the peer-reviewed literature focusing on metal sensitivity testing in patients undergoing total joint replacement (TJR). Our purpose was to assess the risk of developing metal hypersensitivity post-operatively and its relationship with outcome and to investigate the advantages of performing hypersensitivity testing. We undertook a comprehensive search of the citations quoted in PubMed and EMBASE: 22 articles (comprising 3634 patients) met the inclusion criteria. The frequency of positive tests increased after TJR, especially in patients with implant failure or a metal on-metal coupling. The probability of developing a metal allergy was higher post operatively (odds ratio (OR) 1.52 (95% confidence interval (CI) 1.06 to 2.31)), and the risk was further increased when failed implants were compared with stable TJRs (OR 2.76 (95% CI 1.14 to 6.70)). Hypersensitivity testing was not able to discriminate between stable and failed TJRs, as its predictive value was not statistically proven. However, it is generally thought that hypersensitivity testing should be performed in patients with a history of metal allergy and in failed TJRs, especially with metal-on-metal implants and when the cause of the loosening is doubtful. PMID- 22844058 TI - The assessment of the risk of fracture in femora with metastatic lesions: comparing case-specific finite element analyses with predictions by clinical experts. AB - Previously, we showed that case-specific non-linear finite element (FE) models are better at predicting the load to failure of metastatic femora than experienced clinicians. In this study we improved our FE modelling and increased the number of femora and characteristics of the lesions. We retested the robustness of the FE predictions and assessed why clinicians have difficulty in estimating the load to failure of metastatic femora. A total of 20 femora with and without artificial metastases were mechanically loaded until failure. These experiments were simulated using case-specific FE models. Six clinicians ranked the femora on load to failure and reported their ranking strategies. The experimental load to failure for intact and metastatic femora was well predicted by the FE models (R(2) = 0.90 and R(2) = 0.93, respectively). Ranking metastatic femora on load to failure was well performed by the FE models (tau = 0.87), but not by the clinicians (0.11 < tau < 0.42). Both the FE models and the clinicians allowed for the characteristics of the lesions, but only the FE models incorporated the initial bone strength, which is essential for accurately predicting the risk of fracture. Accurate prediction of the risk of fracture should be made possible for clinicians by further developing FE models. PMID- 22844059 TI - The Baumann procedure to correct equinus gait in children with diplegic cerebral palsy: long-term results. AB - Although equinus gait is the most common abnormality in children with spastic cerebral palsy (CP) there is no consistency in recommendations for treatment, and evidence for best practice is lacking. The Baumann procedure allows selective fractional lengthening of the gastrocnemii and soleus muscles but the long-term outcome is not known. We followed a group of 18 children (21 limbs) with diplegic CP for ten years using three-dimensional instrumented gait analysis. The kinematic parameters of the ankle joint improved significantly following this procedure and were maintained until the end of follow-up. We observed a normalisation of the timing of the key kinematic and kinetic parameters, and an increase in the maximum generation of power of the ankle. There was a low rate of overcorrection (9.5%, n = 2), and a rate of recurrent equinus similar to that found with other techniques (23.8%, n = 5). As the procedure does not impair the muscle architecture, and allows for selective correction of the contracted gastrocnemii and soleus, it may be recommended as the preferred method for correction of a mild fixed equinus deformity. PMID- 22844060 TI - Arthroscopic partial limbectomy for labral injury of the hip: a case with a 16 year follow-up. AB - Although good to excellent short-term results of arthroscopic partial limbectomy of the hip have been reported, there is little information on the long-term outcome of the procedure. We report a case with a 16-year follow-up. A 34-year old woman presented with a three-month history of severe pain and limitation of movement of the hip. Plain radiographs and arthrography showed no abnormality. MRI showed an effusion and a deformity of the anterosuperior part of the labrum. This was confirmed as an inverted labral tear that was debrided arthroscopically. At 16 years post-operatively, she remained symptom-free. Plain radiographs showed no abnormality and MRI suggested that the sealing effect of the scar tissue prevented articular damage and degeneration. PMID- 22844062 TI - Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment. AB - CONTEXT: Increased bone fragility is a frequent complication of hypercortisolism due predominantly to suppression of bone formation. Sclerostin is an osteocyte produced negative regulator of bone formation, which is up-regulated by glucocorticoids in mice. OBJECTIVE: Our objective was to assess the effect of endogenous hypercortisolism on circulating sclerostin and bone turnover in humans. DESIGN: We measured sclerostin, beta-C-terminal telopeptide, amino terminal propeptide of type 1 procollagen, and fibroblast growth factor 23 in blood samples of 21 patients with endogenous hypercortisolism and 21 age- and gender-matched controls. In 12 patients, measurements were repeated at various time intervals after successful surgical treatment (transsphenoidal surgery or adrenalectomy). RESULTS: Plasma sclerostin levels were significantly decreased in patients compared with controls (112+/-49 vs. 207+/-48 pg/ml, P<0.001). In the 12 patients who were evaluated after surgical treatment, sclerostin levels increased from 121.4+/-46.5 to 175.8+/-78.5 pg/ml (P=0.003). These changes in plasma sclerostin levels were accompanied by significant increases in levels of fibroblast growth factor 23 (from 44.2+/-12.2 to 84.0+/-58.8 pg/ml, P=0.017) and of the bone turnover markers amino-terminal propeptide of type 1 procollagen (from 31.7+/-18.2 to 94.2+/-92.2 ng/ml, P=0.037) and beta-C-terminal telopeptide (from 134.2+/-44 to 409.2+/-285 pg/ml, P=0.005). CONCLUSIONS: Contrary to the findings in mice, circulating sclerostin is decreased in patients with chronic endogenous hypercortisolism and increases after treatment. These findings suggest that in humans, chronic exposure to glucocorticoids affects the number or function of osteocytes rather than the production of sclerostin. PMID- 22844064 TI - Editorial: Molecular Endocrinology articles in the spotlight for August 2012. PMID- 22844063 TI - A novel tool in the diagnosis and follow-up of (cyclic) Cushing's syndrome: measurement of long-term cortisol in scalp hair. AB - BACKGROUND: Measurement of cortisol in 24-h urine collections and midnight saliva are standard screening tests for Cushing's syndrome (CS). These tests reflect cortisol levels during a maximum of 24 h and do not provide historical information. Therefore, they can yield normal results in case of cyclic CS, which is a rare disorder that is characterized by alternating episodes of endogenous cortisol excess and normal cortisol secretion. The measurement of cortisol in scalp hair is a novel tool that might be helpful to establish the diagnosis of (cyclic) CS. Our aim was to study whether hair cortisol timelines correspond with clinical course in patients with CS and whether we could create retrospective timelines of cortisol exposure that correspond with symptomatic periods in patients suspected of cyclic CS. METHODS: Scalp hair was collected in 14 patients with confirmed CS and six patients suspected of cyclic CS. Cortisol was extracted from the hair samples with methanol, and an ELISA was used to measure cortisol levels in hair extracts. A group of 96 nonobese individuals were used as a control group. RESULTS: Hair cortisol levels were significantly elevated in CS patients (P<0.0001). Sensitivity and specificity of hair cortisol measurements for CS were 86 and 98%, respectively. Hair cortisol timelines of patients with CS and cyclic CS corresponded with clinical course. CONCLUSION: Hair samples can provide a historical timeline that corresponds with clinical course in patients with (cyclic) CS. This new diagnostic tool can contribute significantly to early recognition of patients suffering from cyclic CS. PMID- 22844066 TI - Does preoperative steroid treatment affect the histology in giant cell (cranial) arteritis? AB - INTRODUCTION: Giant cell arteritis (GCA) has been successfully treated with steroids for many years and temporal artery biopsy (TAB) is regarded as the gold standard diagnostic test. The primary aim of this study was to determine whether steroid pretreatment abrogates histological features of GCA reducing diagnostic return, as suspected on the basis of anecdotal evidence. This impacts upon patients suspected of having GCA and the need for prompt treatment balanced with the diagnostic need for TAB. METHODS: A 6-year single-centre retrospective study of biopsies (2005-2011) was performed with interrogation of the medical notes for information regarding steroid use. The null hypothesis considered there was no association between steroid use and biopsy outcome. RESULTS: No significant difference was found between steroid use and biopsy outcome, with biopsies still producing positive results after weeks of steroid treatment. CONCLUSIONS: TAB is still useful in the diagnosis of GCA, even after commencing steroid treatment. PMID- 22844067 TI - Post-mortem analysis of bone marrow osteoclasts using tartrate-resistant acid phosphatase staining: does histochemistry work and correlate with time since death? AB - AIMS: In bone marrow (BM) biopsies, tartrate-resistant acid phosphatase (TRAP) staining represents the gold standard for the characterisation of osteoclasts. TRAP is one of the few enzymes that is histochemically detectable on formalin fixed paraffin-embedded tissue. This study investigated whether TRAP is also able to visualise BM osteoclasts in autopsy tissue. It was hypothesised that, due to a progressive loss of enzymatic activity in osteoclasts post-mortem, TRAP staining could allow the time of death of a patient to be determined. METHODS: TRAP stained BM slides of 96 cases including 51 pathology and 23 forensic autopsies and 22 biopsies were histologically evaluated and their staining intensity (SI) semi-quantitatively graded. In the autopsy cases, the results were correlated with the post-mortem interval (PMI, time span in days between death and autopsy). RESULTS: TRAP staining intensities (TRAP-SIs) did not differ between men and women and showed a steady decrease with age. TRAP-SIs were significantly stronger in biopsies than in autopsy cases. Among the autopsies, TRAP-SIs were highly variable and not dependent on PMI, except for three forensic cases with PMI >=7 days which showed a complete loss of TRAP stainability. On the whole, the TRAP SIs of pathology and forensic cases did not differ significantly. CONCLUSIONS: This study clearly shows that BM osteoclasts stay TRAP-positive for 7 days post mortem, although with markedly reduced TRAP-SIs compared with biopsies. Since TRAP-SIs were not correlated with the duration of PMI, TRAP staining of BM osteoclasts cannot serve as a tool to determine the time of death of a patient. PMID- 22844068 TI - Roles of fibroblasts from the interface zone in invasion, migration, proliferation and apoptosis of gastric adenocarcinoma. AB - AIMS: Interface zone fibroblasts (INFs) are very important in the progression and metastasis of tumours but their effect on the invasion and migration of gastric cancer cells is still unclear. METHODS: Primary fibroblasts were isolated from the distal normal zone (normal zone fibroblasts, NFs), interface zone (INFs) and tumour zone (cancer-associated fibroblasts, CAFs) of 60 human gastric carcinoma tissue samples. The crosstalk between these fibroblasts and human gastric cancer MGC-803 cells was evaluated using an indirect co-culture model in vitro. RESULTS: A high level of fibroblast activation protein (FAP) in the invasion front of gastric cancer was found in the gastric cancer tissue samples and no FAP expression was found in 20 normal gastric tissue samples by immunohistochemistry. High FAP expression was associated with Lauren classification, degree of differentiation, tumour node metastasis stage and depth of tumour invasion (p<0.05 or p<0.01). INFs promoted invasion and migration of MGC-803 cells. The number of invasions in INFs, CAFs and NFs were 120.10+/-27.53 (95% CI 102.12 to 138.10), 63.00+/-14.80 (95% CI 53.33 to 72.67) and 14.22+/-6.20 (95% CI 10.17 to 18.27), respectively; the number of invasions in INFs were 8.45-fold and 1.89 fold higher than those in NFs and CAFs, respectively (p<0.05). The number of migrations in INFs, CAFs and NFs were 118.00+/-16.83 (95% CI 107.00 to 129.00), 61.00+/-16.36 (95% CI 50.31 to 71.69) and 24.00+/-11.52 (95% CI 16.47 to 31.53), respectively; the number of migration in INFs were 4.91-fold and 1.92-fold higher than those in NFs and CAFs, respectively (p<0.05). INFs also significantly promoted cell proliferation and inhibited apoptosis in MGC-803 cells compared with NFs and CAFs (p<0.05). CONCLUSIONS: These findings indicate that INFs exhibit a more robust biological modulatory activity than CAFs and NFs. INFs may be a key factor leading to tumour progression and metastasis and may be of use as a tool for post-treatment surveillance. PMID- 22844069 TI - The rapid evolution of X-linked male-biased gene expression and the large-X effect in Drosophila yakuba, D. santomea, and their hybrids. AB - The X chromosome has a large effect on hybrid dysfunction, particularly on hybrid male sterility. Although the evidence for this so-called large-X effect is clear, its molecular causes are not yet fully understood. One possibility is that, under certain conditions, evolution proceeds faster in X-linked than in autosomal loci (i.e., faster-X effect) due to both natural selection and their hemizygosity in males, an effect that is expected to be greatest in genes with male-biased expression. Here, I study genome-wide variation in transcript abundance between Drosophila yakuba and D. santomea, within these species and in their hybrid males to evaluate both the faster-X and large-X effects at the level of expression. I find that in X-linked male-biased genes (MBGs) expression evolves faster than in their autosomal counterparts, an effect that is accompanied by a unique reduction in expression polymorphism. This suggests that Darwinian selection is driving expression differences between species, likely enhanced by the hemizygosity of the X chromosome in males. Despite the recent split of the two sister species under study, abundant changes in both cis- and trans-regulatory elements underlie expression divergence in the majority of the genes analyzed, with significant differences in allelic ratios of transcript abundance between the two reciprocal F(1) hybrid males. Cis-trans coevolution at molecular level, evolved shortly after populations become isolated, may therefore contribute to explain the breakdown of the regulation of gene expression in hybrid males. Additionally, the X chromosome plays a large role in this hybrid male misexpression, which affects not only MBG but also, to a lesser degree, nonsex-biased genes. Interestingly, hybrid male misexpression is concentrated mostly in autosomal genes, likely facilitated by the rapid evolution of sex-linked trans-acting factors. I suggest that the faster evolution of X-linked MBGs, at both protein and expression levels, contributes to explain the large effect of the X chromosome on hybrid male sterility, likely mediating widespread autosomal misexpression through the preferential recognition of cis-regulatory elements by conspecific trans-acting factors (i.e., cis-trans conspecific recognition). PMID- 22844070 TI - Extreme conservation and non-neutral evolution of the cpmA Circadian locus in a globally distributed Chroococcidiopsis sp. from naturally stressful habitats. AB - Cyanobacteria are among the most ancient organisms known to have circadian rhythms. The cpmA gene is involved in controlling the circadian output signal. We studied polymorphism and divergence of this gene in six populations of a stress tolerant cyanobacterium, Chroococcidiopsis sp., sampled in extreme habitats across the globe. Despite high haplotype diversity (0.774), nucleotide diversity of cpmA is very low (pi = 0.0034): the gene appears to be even more conserved than housekeeping genes. Even though the populations were sampled thousands kilometers apart, they manifested virtually no genetic differentiation at this locus (F(ST) = 0.0228). Using various tests for neutrality, we determined that evolution of cpmA significantly departures from the neutral model and is governed by episodic positive selection. PMID- 22844071 TI - Ancient DNA reveals genetic stability despite demographic decline: 3,000 years of population history in the endemic Hawaiian petrel. AB - In the Hawaiian Islands, human colonization, which began approximately 1,200 to 800 years ago, marks the beginning of a period in which nearly 75% of the endemic avifauna became extinct and the population size and range of many additional species declined. It remains unclear why some species persisted whereas others did not. The endemic Hawaiian petrel (Pterodroma sandwichensis) has escaped extinction, but colonies on two islands have been extirpated and populations on remaining islands have contracted. We obtained mitochondrial DNA sequences from 100 subfossil bones, 28 museum specimens, and 289 modern samples to investigate patterns of gene flow and temporal changes in the genetic diversity of this endangered species over the last 3,000 years, as Polynesians and then Europeans colonized the Hawaiian Islands. Genetic differentiation was found to be high between both modern and ancient petrel populations. However, gene flow was substantial between the extirpated colonies on Oahu and Molokai and modern birds from the island of Lanai. No significant reductions in genetic diversity occurred over this period, despite fears in the mid-1900s that this species may have been extinct. Simulations show that even a decline to a stable effective population size of 100 individuals would result in the loss of only 5% of the expected heterozygosity. Simulations also show that high levels of genetic diversity may be retained due to the long generation time of this species. Such decoupling between population size and genetic diversity in long-lived species can have important conservation implications. It appears that a pattern of dispersal from declining colonies, in addition to long generation time, may have allowed the Hawaiian petrel to escape a severe genetic bottleneck, and the associated extinction vortex, and persist despite a large population decline after human colonization. PMID- 22844073 TI - Very low rate of gene conversion in the yeast genome. AB - Gene duplication is a major driver of organismal adaptation and evolution and plays an important role in multiple human diseases. Whole-genome analyses have shown similar and high rates of gene duplication across a variety of eukaryotic species. Most of these studies, however, did not address the possible impact of interlocus gene conversion (IGC) on the evolution of gene duplicates. Because IGC homogenizes pairs of duplicates, widespread conversion would cause gene duplication events that happened long ago to appear more recent, resulting in artificially high estimates of duplication rates. Although the majority of genome wide studies (including in the budding yeast Saccharomyces cerevisiae [Scer]) point to levels of IGC between paralogs ranging from 2% to 18%, Gao and Innan (Gao LZ, Innan H. 2004. Very low gene duplication rate in the yeast genome. Science 306:1367-1370.) found that gene conversion in yeast affected >80% of paralog pairs. If conversion rates really are this high, it would imply that the rate of gene duplication in eukaryotes is much lower than previously reported. In this work, we apply four different methodologies-including one approach that closely mirrors Gao and Innan's method-to estimate the level of IGC in Scer. Our analyses point to a maximum conversion level of 13% between paralogs in this species, in close agreement with most estimates of IGC in eukaryotes. We also show that the exceedingly high levels of conversion found previously derive from application of an accurate method to an inappropriate data set. In conclusion, our work provides the most striking evidence to date supporting the reduced incidence of IGC among Scer paralogs and sets up a framework for future analyses in other eukaryotes. PMID- 22844072 TI - Fish lateral line innovation: insights into the evolutionary genomic dynamics of a unique mechanosensory organ. AB - The mechanosensory lateral line, found only in fishes and amphibians, is an important sense organ associated with aquatic life. Lateral line patterns differ among teleost, the most diverse vertebrate taxa, hypothetically in response to selective pressures from different aquatic habitats. In this article, we conduct evolutionary genomic analyses of 34 genes associated with lateral line system development in teleosts to elucidate the significance of contrasting evolutionary rates and changes in the protein coding sequences. We find that duplicated copies of these genes are preferentially retained in the teleost genomes and that episodic events of positive selection have occurred in 22 of the 30 postduplication branches. In general, teleost genes evolved at a faster rate relative to their tetrapod counterparts, and the mutation rates of 26 of the 34 genes differed among teleosts and tetrapods. We conclude that following whole genome duplication, evolutionary rates and episodic events of positive selection on the lateral line system development genes might have been one of the factors favoring the subsequent adaptive radiation of teleosts into diverse habitats. These results provide the foundation for further detailed explorations into lateral line system genes and the evolution of diverse phenotypes and adaptations. PMID- 22844074 TI - DNA damage repair pathways in cancer stem cells. AB - The discovery of tumor-initiating cells endowed with stem-like features has added a further level of complexity to the pathobiology of neoplastic diseases. In the attempt of dissecting the functional properties of this uncommon cellular subpopulation, investigators are taking full advantage of a body of knowledge about adult stem cells, as the "cancer stem cell model" implies that tissue resident stem cells are the target of the oncogenic process. It is emerging that a plethora of molecular mechanisms protect cancer stem cells (CSC) against chemotherapy- and radiotherapy-induced death stimuli. The ability of CSCs to survive stressful conditions is correlated, among others, with a multifaceted protection of genome integrity by a prompt activation of the DNA damage sensor and repair machinery. Nevertheless, many molecular-targeted agents directed against DNA repair effectors are in late preclinical or clinical development while the identification of predictive biomarkers of response coupled with the validation of robust assays for assessing biomarkers is paving the way for biology-driven clinical trials. PMID- 22844076 TI - Skin tumours induced by narrowband UVB have higher frequency of p53 mutations than tumours induced by broadband UVB independent of Ogg1 genotype. AB - Different wavelengths of ultraviolet (UV) light have different promoting effects on skin carcinogenesis. Narrowband UVB (NB-UVB) has a single-peak wavelength of 311 nm and is widely used for treating skin diseases. Our previous work showed that, in comparison with conventional broadband UVB (BB-UVB), long-term exposure to NB-UVB induces higher frequency of skin cancer in mice, and it suggested that this is mediated through the formation of cyclobutane pyrimidine dimers (CPDs). To explore whether the frequency of p53 mutations in skin tumours correlates with CPD-induced mutations, we compared the frequency and types of p53 mutations between NB-UVB-induced and BB-UVB-induced malignant skin tumours produced in wild type and Ogg1 knockout mice, which are deficient in repair of oxidative 8 oxoguanine (8-oxoG), a DNA damage mediated by reactive oxygen species (ROS). The frequency of p53 mutation was significantly higher in NB-UVB-induced than in BB UVB-induced tumours in both wild-type and Ogg1 knockout mice. Most of the p53 mutations found were G:C -> A:T transitions at dipyrimidine sites in both the NB UVB- and BB-UVB-exposed groups. However, G:C -> T:A mutations caused by 8-oxoG did not increase in Ogg1 knockout mice exposed to either NB-UVB or BB-UVB. Our results strongly suggest that NB-UVB induces highly malignant tumours caused by p53 dipyrimidine mutations through the formation of CPDs. PMID- 22844075 TI - Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. AB - Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC 9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. PMID- 22844077 TI - In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling. AB - Estragole is a naturally occurring food-borne genotoxic compound found in a variety of food sources, including spices and herbs. This results in human exposure to estragole via the regular diet. The objective of this study was to quantify the dose-dependent estragole-DNA adduct formation in rat liver and the urinary excretion of 1'-hydroxyestragole glucuronide in order to validate our recently developed physiologically based biodynamic (PBBD) model. Groups of male outbred Sprague Dawley rats (n = 10, per group) were administered estragole once by oral gavage at dose levels of 0 (vehicle control), 5, 30, 75, 150, and 300mg estragole/kg bw and sacrificed after 48h. Liver, kidney and lungs were analysed for DNA adducts by LC-MS/MS. Results obtained revealed a dose-dependent increase in DNA adduct formation in the liver. In lungs and kidneys DNA adducts were detected at lower levels than in the liver confirming the occurrence of DNA adducts preferably in the target organ, the liver. The results obtained showed that the PBBD model predictions for both urinary excretion of 1'-hydroxyestragole glucuronide and the guanosine adduct formation in the liver were comparable within less than an order of magnitude to the values actually observed in vivo. The PBBD model was refined using liver zonation to investigate whether its predictive potential could be further improved. The results obtained provide the first data set available on estragole-DNA adduct formation in rats and confirm their occurrence in metabolically active tissues, i.e. liver, lung and kidney, while the significantly higher levels found in liver are in accordance with the liver as the target organ for carcinogenicity. This opens the way towards future modelling of dose-dependent estragole liver DNA adduct formation in human. PMID- 22844079 TI - Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4. AB - Epidemiological studies revealed increased renal cancer incidences and higher cancer mortalities in hypertensive individuals. Activation of the renin angiotensin-aldosterone system leads to the formation of reactive oxygen species (ROS). In vitro, in renal cells, and ex vivo, in the isolated perfused mouse kidney, we could show DNA-damaging potential of angiotensin II (Ang II). Here, the pathway involved in the genotoxicity of Ang II was investigated. In kidney cell lines with properties of proximal tubulus cells, an activation of NADPH oxidase and the production of ROS, resulting in the formation of DNA strand breaks and micronuclei induction, was observed. This DNA damage was mediated by the Ang II type 1 receptor (AT1R), together with the G protein G ( alpha-q/11 ) . Subsequently, phospholipase C (PLC) was activated and intracellular calcium increased. Both calcium stores of the endoplasmic reticulum and extracellular calcium were involved in the genotoxicity of Ang II. Downstream, a role for protein kinase C (PKC) could be detected, because its inhibition hindered Ang II from damaging the cells. Although PKC was activated, no involvement of its known target, the NADPH oxidase isoform containing the Nox2 subunit, could be found, as tested by small-interfering RNA down-regulation. Responsible for the DNA-damaging activity of Ang II was the NADPH oxidase isoform containing the Nox4 subunit. In summary, in kidney cells the DNA-damaging activity of Ang II depends on an AT1R-mediated activation of NADPH oxidase via PLC, PKC and calcium signalling, with the NADPH subunit Nox4 playing a crucial role. PMID- 22844078 TI - Inter-laboratory variation in DNA damage using a standard comet assay protocol. AB - There are substantial inter-laboratory variations in the levels of DNA damage measured by the comet assay. The aim of this study was to investigate whether adherence to a standard comet assay protocol would reduce inter-laboratory variation in reported values of DNA damage. Fourteen laboratories determined the baseline level of DNA strand breaks (SBs)/alkaline labile sites and formamidopyrimidine DNA glycosylase (FPG)-sensitive sites in coded samples of mononuclear blood cells (MNBCs) from healthy volunteers. There were technical problems in seven laboratories in adopting the standard protocol, which were not related to the level of experience. Therefore, the inter-laboratory variation in DNA damage was only analysed using the results from laboratories that had obtained complete data with the standard comet assay protocol. This analysis showed that the differences between reported levels of DNA SBs/alkaline labile sites in MNBCs were not reduced by applying the standard assay protocol as compared with the laboratory's own protocol. There was large inter-laboratory variation in FPG-sensitive sites by the laboratory-specific protocol and the variation was reduced when the samples were analysed by the standard protocol. The SBs and FPG-sensitive sites were measured in the same experiment, indicating that the large spread in the latter lesions was the main reason for the reduced inter-laboratory variation. However, it remains worrying that half of the participating laboratories obtained poor results using the standard procedure. This study indicates that future comet assay validation trials should take steps to evaluate the implementation of standard procedures in participating laboratories. PMID- 22844080 TI - Genotoxicity assessment and detoxification induction in Dreissena polymorpha exposed to benzo[a]pyrene. AB - The use of DNA adduct analysis has previously focused on the use of marine organisms for biomonitoring, whereas similar investigations in freshwater organisms are sparse. In that context, we have investigated the relevance of DNA adducts as biomarkers of genotoxicity in the freshwater mussels Dreissena polymorpha. The objective of the present study is to determine the stability of DNA adducts induced by benzo[a]pyrene (B[a]P) in zebra mussels. Mussels were exposed to dissolved B[a]P (10-100 ug/l) for 4 days. Afterwards, mussels were kept in clean water for 28 days and DNA adduct levels were subsequently measured in two different organs, the digestive glands and the gills, using the (32)P postlabelling technique. In parallel, the expression of genes involved in the detoxification system was assessed by qPCR (catalase, superoxide dismutase, glutathione S transferase, HSP70, aryl hydrocarbon receptor, P glycoprotein). We observed a higher level of DNA adducts in the digestive glands compared to the gills. Moreover, in gills, the level of DNA adduct was dependent on the B[a]P concentration. The levels of adducts tended to decrease in both organs after 28 days in clean water. In addition, an early induction of HSP70, PgP, AHR and SOD mRNA levels was noticed in the gills compared to the digestive glands. CAT and GST gene expression increased from 12h exposure in both organs. A higher gene expression level of those genes was observed in the gills, except for AHR and CAT genes. Data converge towards the fact that DNA adducts hence represent a very promising biomarker of B[a]P contamination and potentially of exposure to polycyclic aromatic hydrocarbons. In addition, for the first time in this study, B[a]P detoxification system was characterised in D. polymorpha. PMID- 22844081 TI - A co-culture system of human intestinal Caco-2 cells and lymphoblastoid TK6 cells for investigating the genotoxicity of oral compounds. AB - Here, we assessed a co-culture system of intestinal Caco-2 cells and lymphoblastoid TK6 cells for modelling the role of intestinal first-pass effects, i.e. absorption and metabolism, in the genotoxicity of oral drugs and food contaminants. Caco-2 cells were seeded onto semipermeable culture inserts for 21 days until differentiation, and then TK6 cells were added to the basal compartment. After apical loading with mutagenic compounds [methylmethanesulfonate (MMS), benzo[a]-pyrene (BaP) and aflatoxin B1 (AFB1)], comet and micronucleus assays were performed on both cell lines. MMS (10 ug/ml) showed positive results in the micronucleus assays in both cell lines, even though DNA damage was only detected in the Caco-2 cells with the comet assay. At concentrations of 0.5-50 uM, BaP induced dose-dependent comet and micronucleus formation at 24h in Caco-2 cells, but no DNA damage was observed in TK6 cells. Although AFB1 failed to induce comet formation, it resulted in a high level of micronuclei in both cell lines. Treatment of Caco-2 cells with the CYP3A4 inhibitor, ketoconazole, inhibited the AFB1-induced cytotoxicity and micronucleus formation in TK6 cells, suggesting that intestinal metabolism is involved in the AFB1 genotoxic response in TK6 cells. Our results suggest that the Caco-2/TK6 co culture model is suitable for modelling the role of intestinal biotransformation and transport processes in the genotoxic potential of oral drugs and food contaminants in target blood cells. PMID- 22844082 TI - What predicts persistent early conduct problems? Evidence from the Growing Up in Scotland cohort. AB - BACKGROUND: There is a strong case for early identification of factors predicting life-course-persistent conduct disorder. The authors aimed to identify factors associated with repeated parental reports of preschool conduct problems. METHOD: Nested case-control study of Scottish children who had behavioural data reported by parents at 3, 4 and 5 years. RESULTS: 79 children had abnormal conduct scores at all three time points ('persistent conduct problems') and 434 at one or two points ('inconsistent conduct problems'). 1557 children never had abnormal scores. Compared with children with no conduct problems, children with reported problems were significantly more likely to have mothers who smoked during pregnancy. They were less likely to be living with both parents and more likely to be in poor general health, to have difficulty being understood, to have a parent who agrees that smacking is sometimes necessary and to be taken to visit other people with children rarely. The results for children with persistent and inconsistent conduct problems were similar, but associations with poverty and maternal smoking were significantly less strong in the inconsistent group. CONCLUSION: These factors may be valuable in early identification of risk of major social difficulties. PMID- 22844084 TI - Estimating EQ-5D utility values for major health behavioural risk factors in England. AB - BACKGROUND: Major behavioural risk factors, namely obesity, alcohol consumption, smoking, lack of fruit and vegetable intake and physical inactivity negatively impact on self-reported quality of life. However, little is known about their impact on preference-based measures of health-related quality of life commonly used to inform economic evaluations. METHODS: Preference-based health-related quality of life outcomes associated with major behavioural risk factors were estimated using the EuroQol EQ-5D responses of 14 117 participants, aged >=16 years, in the 2008 Health Survey for England. Multivariable linear regression was used to model the relationship between the five risk factors and EQ-5D utility scores. In addition, logistic regression was used to model their relationship to dichotomous reports of problems for each of the five EQ-5D dimensions. RESULTS: Only one-third of participants had a body mass index within normal range, never drank alcohol, consumed at least five portions of fruit or vegetable/day or exercised regularly, while nearly half of participants were smokers or ex smokers. In the fully adjusted multivariable analyses, reductions in EQ-5D utility scores (95% CI) of 0.105 (0.072 to 0.137), 0.062 (0.042 to 0.082) and 0.142 (0.129 to 0.155) were estimated for a body mass index >=40 kg/m(2), heavy smoking (>=20 cigarettes/day) and physical inactivity, respectively. Hazardous alcohol consumption (men >4 and <=8 units/day; women >3 and <=6 units/day) and daily fruit and vegetable intake between three and less than five portions were associated with small positive effects on EQ-5D utility scores (p<0.05). CONCLUSIONS: The high prevalence and substantial utility loss associated with obesity, smoking and physical inactivity highlight the potential impact that interventions aimed at their prevention or alleviation may have on population health. PMID- 22844083 TI - Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-aged Japanese and Korean men. AB - BACKGROUND: Cigarette smoking is a risk factor of coronary heart disease. Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with coronary heart disease. The authors hypothesised that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence. METHODS: Random samples from populations of 313 Japanese and 302 Korean men aged 40-49 years were examined for calcification of the coronary artery and aorta using electron beam CT. CAC and AC were quantified using the Agatston score. The authors examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorised into two groups using median pack-years as a cut-off point in each of Japanese and Koreans. The never-smoker group was used as a reference for the multiple logistic regression analyses. RESULTS: The ORs of CAC (score >=10) for smokers with higher pack-years were 2.9 in Japanese (p<0.05) and 1.3 in Koreans (non-significant) compared with never-smokers. The ORs of AC (score >=100) for smokers with higher pack-years were 10.4 in Japanese (p<0.05) and 3.6 in Koreans (p<0.05). CONCLUSION: Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men. PMID- 22844085 TI - The PCBs elimination network: the information exchange platform created for the risk reduction of polychlorinated biphenyls (PCBs). PMID- 22844086 TI - microRNAs associated with the different human Argonaute proteins. AB - MicroRNAs (miRNAs) are small noncoding RNAs that function in literally all cellular processes. miRNAs interact with Argonaute (Ago) proteins and guide them to specific target sites located in the 3'-untranslated region (3'-UTR) of target mRNAs leading to translational repression and deadenylation-induced mRNA degradation. Most miRNAs are processed from hairpin-structured precursors by the consecutive action of the RNase III enzymes Drosha and Dicer. However, processing of miR-451 is Dicer independent and cleavage is mediated by the endonuclease Ago2. Here we have characterized miR-451 sequence and structure requirements for processing as well as sorting of miRNAs into different Ago proteins. Pre-miR-451 appears to be optimized for Ago2 cleavage and changes result in reduced processing. In addition, we show that the mature miR-451 only associates with Ago2 suggesting that mature miRNAs are not exchanged between different members of the Ago protein family. Based on cloning and deep sequencing of endogenous miRNAs associated with Ago1-3, we do not find evidence for miRNA sorting in human cells. However, Ago identity appears to influence the length of some miRNAs, while others remain unaffected. PMID- 22844087 TI - Expression of endogenous retroviruses is negatively regulated by the pluripotency marker Rex1/Zfp42. AB - Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription. PMID- 22844088 TI - Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing. AB - Approximately 15% of human genetic diseases are estimated to involve dysregulation of alternative pre-mRNA splicing. Antisense molecules designed to alter these and other splicing events typically target continuous linear sequences of the message. Here, we show that a structural feature in a pre-mRNA can be targeted by bipartite antisense molecules designed to hybridize with the discontinuous elements that flank the structure and thereby alter splicing. We targeted a hairpin structure at the boundary between exon 10 and intron 10 of the pre-mRNA of tau. Mutations in this region that are associated with certain forms of frontotemporal dementia, destabilize the hairpin to cause increased inclusion of exon 10. Via electrophoretic mobility shift and RNase protection assays, we demonstrate that bipartite antisense molecules designed to simultaneously interact with the available sequences that immediately flank the tau pre-mRNA hairpin do indeed bind to this structured region. Moreover, these agents inhibit exon 10 splicing and reverse the effect of destabilizing disease-causing mutations, in both in vitro splicing assays and cell culture. This general bipartite antisense strategy could be employed to modulate other splicing events that are regulated by RNA secondary structure. PMID- 22844089 TI - One Hand Clapping: detection of condition-specific transcription factor interactions from genome-wide gene activity data. AB - We present One Hand Clapping (OHC), a method for the detection of condition specific interactions between transcription factors (TFs) from genome-wide gene activity measurements. OHC is based on a mapping between transcription factors and their target genes. Given a single case-control experiment, it uses a linear regression model to assess whether the common targets of two arbitrary TFs behave differently than expected from the genes targeted by only one of the TFs. When applied to osmotic stress data in S. cerevisiae, OHC produces consistent results across three types of expression measurements: gene expression microarray data, RNA Polymerase II ChIP-chip binding data and messenger RNA synthesis rates. Among the eight novel, condition-specific TF pairs, we validate the interaction between Gcn4p and Arr1p experimentally. We apply OHC to a large gene activity dataset in S. cerevisiae and provide a compendium of condition-specific TF interactions. PMID- 22844090 TI - A benchmark for chromatin binding measurements in live cells. AB - Live-cell measurement of protein binding to chromatin allows probing cellular biochemistry in physiological conditions, which are difficult to mimic in vitro. However, different studies have yielded widely discrepant predictions, and so it remains uncertain how to make the measurements accurately. To establish a benchmark we measured binding of the transcription factor p53 to chromatin by three approaches: fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS) and single-molecule tracking (SMT). Using new procedures to analyze the SMT data and to guide the FRAP and FCS analysis, we show how all three approaches yield similar estimates for both the fraction of p53 molecules bound to chromatin (only about 20%) and the residence time of these bound molecules (~1.8 s). We also apply these procedures to mutants in p53 chromatin binding. Our results support the model that p53 locates specific sites by first binding at sequence-independent sites. PMID- 22844091 TI - DNA stabilization at the Bacillus subtilis PolX core--a binding model to coordinate polymerase, AP-endonuclease and 3'-5' exonuclease activities. AB - Family X DNA polymerases (PolXs) are involved in DNA repair. Their binding to gapped DNAs relies on two conserved helix-hairpin-helix motifs, one located at the 8-kDa domain and the other at the fingers subdomain. Bacterial/archaeal PolXs have a specifically conserved third helix-hairpin-helix motif (GFGxK) at the fingers subdomain whose putative role in DNA binding had not been established. Here, mutagenesis at the corresponding residues of Bacillus subtilis PolX (PolXBs), Gly130, Gly132 and Lys134 produced enzymes with altered DNA binding properties affecting the three enzymatic activities of the protein: polymerization, located at the PolX core, 3'-5' exonucleolysis and apurinic/apyrimidinic (AP)-endonucleolysis, placed at the so-called polymerase and histidinol phosphatase domain. Furthermore, we have changed Lys192 of PolXBs, a residue moderately conserved in the palm subdomain of bacterial PolXs and immediately preceding two catalytic aspartates of the polymerization reaction. The results point to a function of residue Lys192 in guaranteeing the right orientation of the DNA substrates at the polymerization and histidinol phosphatase active sites. The results presented here and the recently solved structures of other bacterial PolX ternary complexes lead us to propose a structural model to account for the appropriate coordination of the different catalytic activities of bacterial PolXs. PMID- 22844092 TI - Sequence signatures of direct complementarity between mRNAs and cognate proteins on multiple levels. AB - A potential connection between physico-chemical properties of mRNAs and cognate proteins, with implications concerning both the origin of the genetic code and mRNA-protein interactions, is unexplored. We compare pyrimidine content of naturally occurring mRNA coding sequences with the propensity of cognate protein sequences to interact with pyrimidines. The latter is captured by polar requirement, a measure of solubility of amino acids in aqueous solutions of pyridines, heterocycles closely related to pyrimidines. We find that the higher the pyrimidine content of an mRNA, the stronger the average propensity of its cognate protein's amino acids to interact with pyridines. Moreover, window averaged pyrimidine profiles of individual mRNAs strongly mirror polar requirement profiles of cognate protein sequences. For example, 4953 human proteins exhibit a correlation between the two with |R| > 0.8. In other words, pyrimidine-rich mRNA regions quantitatively correspond to regions in cognate proteins containing residues soluble in pyrimidine mimetics and vice versa. Finally, by studying randomized genetic code variants we show that the universal genetic code is highly optimized to preserve these correlations. Overall, our findings redefine the stereo-chemical hypothesis concerning code's origin and provide evidence of direct complementary interactions between mRNAs and cognate proteins before development of ribosomal decoding, but also presently, especially if both are unstructured. PMID- 22844093 TI - Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de-repress VEGF-signalling genes and promote cell survival. AB - Protein kinase CK2 promotes cell survival and the activity of this kinase is elevated in several cancers including chronic myeloid leukaemia. We have shown previously that phosphorylation of the Proline-Rich Homeodomain protein (PRH/Hhex) by CK2 inhibits the DNA-binding activity of this transcription factor. Furthermore, PRH represses the transcription of multiple genes encoding components of the VEGF-signalling pathway and thereby influences cell survival. Here we show that the inhibitory effects of PRH on cell proliferation are abrogated by CK2 and that CK2 inhibits the binding of PRH at the Vegfr-1 promoter. Phosphorylation of PRH by CK2 also decreases the nuclear association of PRH and induces its cleavage by the proteasome. Moreover, cleavage of phosphorylated PRH produces a stable truncated cleavage product which we have termed PRHDeltaC (HhexDeltaC). PRHDeltaC acts as a transdominant negative regulator of full-length PRH by sequestering TLE proteins that function as PRH co repressors. We show that this novel regulatory mechanism results in the alleviation of PRH-mediated repression of Vegfr-1. We suggest that the re establishment of PRH function through inhibition of CK2 could be of value in treatment of myeloid leukaemias, as well as other tumour types in which PRH is inactivated by phosphorylation. PMID- 22844094 TI - Revealing the importance of meristems and roots for the development of hypersensitive responses and full foliar resistance to Phytophthora infestans in the resistant potato cultivar Sarpo Mira. AB - The defence responses of potato against Phytophthora infestans were studied using the highly resistant Sarpo Mira cultivar. The effects of plant integrity, meristems, and roots on the hypersensitive response (HR), plant resistance, and the regulation of PR genes were analysed. Sarpo Mira shoots and roots grafted with the susceptible Bintje cultivar as well as non-grafted different parts of Sarpo Mira plants were inoculated with P. infestans. The progress of the infection and the number of HR lesions were monitored, and the regulation of PR genes was compared in detached and attached leaves. Additionally, the antimicrobial activity of plant extracts was assessed. The presented data show that roots are needed to achieve full pathogen resistance, that the removal of meristems in detached leaves inhibits the formation of HR lesions, that PR genes are differentially regulated in detached leaves compared with leaves of whole plants, and that antimicrobial compounds accumulate in leaves and roots of Sarpo Mira plants challenged with P. infestans. While meristems are necessary for the formation of HR lesions, the roots of Sarpo Mira plants participate in the production of defence-associated compounds that increase systemic resistance. Based on the literature and on the presented results, a model is proposed for mechanisms involved in Sarpo Mira resistance that may apply to other resistant potato cultivars. PMID- 22844095 TI - Down-regulation of a single auxin efflux transport protein in tomato induces precocious fruit development. AB - The PIN-FORMED (PIN) auxin efflux transport protein family has been well characterized in the model plant Arabidopsis thaliana, where these proteins are crucial for auxin regulation of various aspects of plant development. Recent evidence indicates that PIN proteins may play a role in fruit set and early fruit development in tomato (Solanum lycopersicum), but functional analyses of PIN silenced plants failed to corroborate this hypothesis. Here it is demonstrated that silencing specifically the tomato SlPIN4 gene, which is predominantly expressed in tomato flower bud and young developing fruit, leads to parthenocarpic fruits due to precocious fruit development before fertilization. This phenotype was associated with only slight modifications of auxin homeostasis at early stages of flower bud development and with minor alterations of ARF and Aux/IAA gene expression. However, microarray transcriptome analysis and large scale quantitative RT-PCR profiling of transcription factors in developing flower bud and fruit highlighted differentially expressed regulatory genes, which are potential targets for auxin control of fruit set and development in tomato. In conclusion, this work provides clear evidence that the tomato PIN protein SlPIN4 plays a major role in auxin regulation of tomato fruit set, possibly by preventing precocious fruit development in the absence of pollination, and further gives new insights into the target genes involved in fruit set. PMID- 22844096 TI - Hydroponics versus field lysimeter studies of urea, ammonium and nitrate uptake by oilseed rape (Brassica napus L.). AB - N-fertilizer use efficiencies are affected by their chemical composition and suffer from potential N-losses by volatilization. In a field lysimeter experiment, (15)N-labelled fertilizers were used to follow N uptake by Brassica napus L. and assess N-losses by volatilization. Use of urea with NBPT (urease inhibitor) showed the best efficiency with the lowest N losses (8% of N applied compared with 25% with urea alone). Plants receiving ammonium sulphate, had similar yield achieved through a better N mobilization from vegetative tissues to the seeds, despite a lower N uptake resulting from a higher volatilization (43% of applied N). Amounts of (15)N in the plant were also higher when plants were fertilized with ammonium nitrate but N-losses reached 23% of applied N. In parallel, hydroponic experiments showed a deleterious effect of ammonium and urea on the growth of oilseed rape. This was alleviated by the nitrate supply, which was preferentially taken up. B. napus was also characterized by a very low potential for urea uptake. BnDUR3 and BnAMT1, encoding urea and ammonium transporters, were up-regulated by urea, suggesting that urea-grown plants suffered from nitrogen deficiency. The results also suggested a role for nitrate as a signal for the expression of BnDUR3, in addition to its role as a major nutrient. Overall, the results of the hydroponic study showed that urea itself does not contribute significantly to the N nutrition of oilseed rape. Moreover, it may contribute indirectly since a better use efficiency for urea fertilizer, which was further increased by the application of a urease inhibitor, was observed in the lysimeter study. PMID- 22844097 TI - The role of Ca2+ in the activity of Mycobacterium tuberculosis DNA gyrase. AB - DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis and needs to catalyse DNA supercoiling, relaxation and decatenation reactions in order to fulfil the functions normally carried out by gyrase and DNA topoisomerase IV in other bacteria. We have obtained evidence for the existence of a Ca(2+)-binding site in the GyrA subunit of M. tuberculosis gyrase. Ca(2+) cannot support topoisomerase reactions in the absence of Mg(2+), but partial removal of Ca(2+) from GyrA by dialysis against EGTA leads to a modest loss in relaxation activity that can be restored by adding back Ca(2+). More extensive removal of Ca(2+) by denaturation of GyrA and dialysis against EGTA results in an enzyme with greatly reduced enzyme activities. Mutation of the proposed Ca(2+) binding residues also leads to loss of activity. We propose that Ca(2+) has a regulatory role in M. tuberculosis gyrase and suggest a model for the modulation of gyrase activity by Ca(2+) binding. PMID- 22844098 TI - Discovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments. AB - Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network. PMID- 22844099 TI - Towards the classification of DYT6 dystonia mutants in the DNA-binding domain of THAP1. AB - The transcription factor THAP1 (THanatos Associated Protein 1) has emerged recently as the cause of DYT6 primary dystonia, a type of rare, familial and mostly early-onset syndrome that leads to involuntary muscle contractions. Many of the mutations described in the DYT6 patients fall within the sequence-specific DNA-binding domain (THAP domain) of THAP1 and are believed to negatively affect DNA binding. Here, we have used an integrated approach combining spectroscopic (NMR, fluorescence, DSF) and calorimetric (ITC) methods to evaluate the effect of missense mutations, within the THAP domain, on the structure, stability and DNA binding. Our study demonstrates that none of the mutations investigated failed to bind DNA and some of them even bind DNA stronger than the wild-type protein. However, some mutations could alter DNA-binding specificity. Furthermore, the most striking effect is the decrease of stability observed for mutations at positions affecting the zinc coordination, the hydrophobic core or the C-terminal AVPTIF motif, with unfolding temperatures ranging from 46 degrees C for the wild type to below 37 degrees C for two mutations. These findings suggest that reduction in population of folded protein under physiological conditions could also account for the disease. PMID- 22844100 TI - HapZipper: sharing HapMap populations just got easier. AB - The rapidly growing amount of genomic sequence data being generated and made publicly available necessitate the development of new data storage and archiving methods. The vast amount of data being shared and manipulated also create new challenges for network resources. Thus, developing advanced data compression techniques is becoming an integral part of data production and analysis. The HapMap project is one of the largest public resources of human single-nucleotide polymorphisms (SNPs), characterizing over 3 million SNPs genotyped in over 1000 individuals. The standard format and biological properties of HapMap data suggest that a dedicated genetic compression method can outperform generic compression tools. We propose a compression methodology for genetic data by introducing HapZipper, a lossless compression tool tailored to compress HapMap data beyond benchmarks defined by generic tools such as gzip, bzip2 and lzma. We demonstrate the usefulness of HapZipper by compressing HapMap 3 populations to <5% of their original sizes. HapZipper is freely downloadable from https://bitbucket.org/pchanda/hapzipper/downloads/HapZipper.tar.bz2. PMID- 22844101 TI - The ATPase activity of Fml1 is essential for its roles in homologous recombination and DNA repair. AB - In fission yeast, the DNA helicase Fml1, which is an orthologue of human FANCM, is a key component of the machinery that drives and governs homologous recombination (HR). During the repair of DNA double-strand breaks by HR, it limits the occurrence of potentially deleterious crossover recombinants, whereas at stalled replication forks, it promotes HR to aid their recovery. Here, we have mutated conserved residues in Fml1's Walker A (K99R) and Walker B (D196N) motifs to determine whether its activities are dependent on its ability to hydrolyse ATP. Both Fml1(K99R) and Fml1(D196N) are proficient for DNA binding but totally deficient in DNA unwinding and ATP hydrolysis. In vivo both mutants exhibit a similar reduction in recombination at blocked replication forks as a fml1Delta mutant indicating that Fml1's motor activity, fuelled by ATP hydrolysis, is essential for its pro-recombinogenic role. Intriguingly, both fml1(K99R) and fml1(D196N) mutants exhibit greater sensitivity to genotoxins and higher levels of crossing over during DSB repair than a fml1Delta strain. These data suggest that without its motor activity, the binding of Fml1 to its DNA substrate can impede alternative mechanisms of repair and crossover avoidance. PMID- 22844102 TI - Mixture models and wavelet transforms reveal high confidence RNA-protein interaction sites in MOV10 PAR-CLIP data. AB - The Photo-Activatable Ribonucleoside-enhanced CrossLinking and ImmunoPrecipitation (PAR-CLIP) method was recently developed for global identification of RNAs interacting with proteins. The strength of this versatile method results from induction of specific T to C transitions at sites of interaction. However, current analytical tools do not distinguish between non experimentally and experimentally induced transitions. Furthermore, geometric properties at potential binding sites are not taken into account. To surmount these shortcomings, we developed a two-step algorithm consisting of a non parametric two-component mixture model and a wavelet-based peak calling procedure. Our algorithm can reduce the number of false positives up to 24% thereby identifying high confidence interaction sites. We successfully employed this approach in conjunction with a modified PAR-CLIP protocol to study the functional role of nuclear Moloney leukemia virus 10, a putative RNA helicase interacting with Argonaute2 and Polycomb. Our method, available as the R package wavClusteR, is generally applicable to any substitution-based inference problem in genomics. PMID- 22844103 TI - Machine perfusion versus cold storage for the preservation of kidneys from donors >= 65 years allocated in the Eurotransplant Senior Programme. AB - BACKGROUND: In the Eurotransplant Senior Programme (ESP), kidneys from donors aged >= 65 years are preferentially allocated locally and transplanted into patients aged >= 65 years on dialysis. The purpose of this study was to analyse whether the results of transplantation in the ESP can be improved by preservation of organs by hypothermic machine perfusion (MP) compared with simple cold storage (CS). METHODS: Overall, 85 deceased heart-beating donors >= 65 years of age were included in this analysis with follow-up until 1 year post-transplant. For each donor, one kidney was randomly assigned to preservation by CS and the contralateral kidney to MP from organ procurement until transplantation. Delayed graft function (DGF), primary non-function (PNF) and 1-year patient and graft survival rates were evaluated as primary and secondary endpoints. RESULTS: The median recipient age was 66 years in both groups and the median cold ischaemia time was 11 h for MP and 10.5 h for CS (P = 0.69). The DGF rate was 29.4% for MP and 34.1% for CS (P = 0.58). Only extended duration of cold ischaemia time was an independent risk factor for the development of DGF (odds ratio 1.2, P < 0.0001). PNF was significantly reduced (3.5% MP versus 12.9% CS, P = 0.02). The 1-year patient and graft survival rates were similar for MP and CS (94% versus 95% and 89 versus 81%, P > 0.05). The 1-year graft survival rate was significantly improved after MP in recipients who developed DGF (84% MP versus 48% CS, P = 0.01). CONCLUSIONS: Continuous pulsatile hypothermic MP for kidneys from donors aged >= 65 years can reduce the rate of never-functioning kidneys and improve the 1-year graft survival rate of kidneys with DGF. In this small cohort, the known advantage of MP for the reduction of DGF could not be confirmed, possibly due to relatively short cold ischaemia times. PMID- 22844104 TI - Spatial analysis to locate new clinics for diabetic kidney patients in the underserved communities in Alberta. AB - BACKGROUND: Canadians with chronic diseases often live far away from healthcare facilities, which may compromise their level of care. We used a new method for selecting optimal locations for new healthcare facilities in remote regions. METHODS: We used a provincial laboratory database linked to data from the provincial health ministry. From all patients with serum creatinine measured at least once between 2002 and 2008 in Alberta, Canada, we selected those with diabetes and an estimated glomerular filtration rate (eGFR) of 15-60 mL/min/1.73 m(2). We then used two methods to select potential locations for new clinics that would serve the greatest number of remote-dwelling patients: plots showing the unadjusted density of such patients per 100 km(2) and SatScan analysis presenting the prevalent clusters of patients on the basis of chronic kidney disease (CKD) rates (adjusted for population size). RESULTS: We studied 32,278 patients with concomitant diabetes and CKD. A substantial number of patients (8%) resided >200 km from existing nephrologists' clinics. Density plots mapped with ArcGIS were useful for localizing a large cluster of underserved patients. However, objective assessment with SatScan technique and ArcGIS permitted us to detect additional clusters of patients in the northwest and southeast regions of Alberta--and suggested potential locations for new clinics in these areas. CONCLUSIONS: Objective techniques such as SatScan can identify clusters of underserved patients with CKD and identify potential new facility locations for consideration by decision-makers. Our findings may also be applicable to patients with other chronic diseases. PMID- 22844105 TI - Targeting B-cells in lupus nephritis: should cautious optimism remain? PMID- 22844106 TI - Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. AB - BACKGROUND: Primary hyperoxaluria Type 1, an inherited disorder with increased endogenous oxalate production, leads to the development of urolithiasis, nephrocalcinosis and end-stage renal disease (ESRD). Contrary to the general belief that patients diagnosed during adulthood experience a relatively mild course of disease, we were confronted with several cases of ESRD caused by previously undiagnosed primary hyperoxaluria. METHODS: To study renal and patient survival in relation with genotype, age at onset of disease and therapeutic delay, we performed a nationwide search among all Dutch nephrologists and paediatric nephrologists. RESULTS: Of the 79 included patients, 38% was diagnosed at an adult age. ESRD was present at the time of diagnosis in 26% of paediatric diagnosed patients versus 52% of adult-diagnosed patients (P = 0.021). Homozygosity for the pyridoxine-responsive p.Gly170Arg or p.Phe152Ile genotype was found in 26% of paediatric diagnosed patients versus 68% of adult-diagnosed patients (P < 0.001). Of homozygous p.Gly170Arg or p.Phe152Ile patients, 48% developed ESRD at a median age of 37 years, compared with 48% in those with other mutations at a median age of 0.5 years (P < 0.001). Of the 16 patients found through family screening, 81% had a preserved renal function. CONCLUSIONS: The high prevalence of pyridoxine-responsive genotypes and favourably prognosis of timely treatment warrant early diagnostic screening for primary hyperoxaluria Type 1 in patients with recurrent urolithiasis. This will preserve kidney function and prevent diagnosis of adult diagnosed patients in ESRD. PMID- 22844107 TI - Dialysis water and fluid purity: more than endotoxin. AB - The evolution of extracorporeal treatment of end-stage renal failure has enforced focus on the purity of dialysis fluid. A major challenge of high-flux haemodialysis (HD) and haemodiafiltration relates to the necessity for ultrapure dialysis fluid and for sterile non-pyrogenic substitution fluid. The present review focuses especially on the possible microbial contamination including, next to intact micro-organisms, a variety of microbial derivatives. It is pointed out that there are conditions (e.g. contamination by non-culturable micro-organisms or bacterial derivatives other than lipopolysaccharides) where the detection of biologically relevant contaminants can be missed when applying the recommended standard detection methods such as bacterial culture and limulus amoebocyte lysate test. Possible approaches for action upon positive sampling results, exceeding the levels recommended in the latest ISO 11663:2009, are described in detail and illustrated with flow charts. The issue of purity of dialysis fluids is highly relevant, since the chronic exposure of HD patients to low levels of cytokine-inducing microbial components can significantly contribute to the micro inflammatory status of these patients. PMID- 22844109 TI - Associations between microRNA expression and mesenchymal marker gene expression in glioblastoma. AB - The subclassification of glioblastoma (GBM) into clinically relevant subtypes using microRNA (miRNA)- and messenger RNA (mRNA)-based integrated analysis has been attempted. Because miRNAs regulate multiple gene-signaling pathways, understanding miRNA-mRNA interactions is a prerequisite for understanding glioma biology. However, such associations have not been thoroughly examined using high throughput integrated analysis. To identify significant miRNA-mRNA correlations, we selected and quantified signature miRNAs and mRNAs in 82 gliomas (grade II: 14, III: 16, IV: 52) using real-time reverse-transcriptase polymerase chain reaction. Quantitative expression data were integrated into a single analysis platform that evaluated the expression relationship between miRNAs and mRNAs. The 21 miRNAs include miR-15b, -21, -34a, -105, -124a, -128a, -135b, -184, -196a-b, 200a-c, -203, -302a-d, -363, -367, and -504. In addition, we examined 23 genes, including proneural markers (DLL3, BCAN, and OLIG2), mesenchymal markers (YKL-40, CD44, and Vimentin), cancer stem cell-related markers, and receptor tyrosine kinase genes. Primary GBM was characterized exclusively by upregulation of mesenchymal markers, whereas secondary GBM was characterized by significant downregulation of mesenchymal markers, miR-21, and -34a, and by upregulation of proneural markers and miR-504. Statistical analysis showed that expression of miR 128a, -504, -124a, and -184 each negatively correlated with the expression of mesenchymal markers in GBM. Our functional analysis of miR-128a and -504 as inhibitors demonstrated that suppression of miR-128a and -504 increased the expression of mesenchymal markers in glioblastoma cell lines. Mesenchymal signaling in GBM may be negatively regulated by miR-128a and -504. PMID- 22844108 TI - Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. AB - This single-institution phase II study was performed to estimate the response rate to lapatinib in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Twenty-one eligible patients were enrolled. Brain and spine MRIs, including 3-dimensional volumetric tumor analysis, and audiograms were performed once at baseline and again every 12 weeks. The primary response end point was evaluable in 17 patients and defined as >=15% decrease in VS volume. Hearing was evaluable as a secondary end point in 13 patients, with responses defined as an improvement in the pure tone average of at least 10 dB or a statistically significant increase in word recognition scores. Four of 17 evaluable patients experienced an objective volumetric response (23.5%; 95% confidence interval [CI], 10%-47%), with median time to response of 4.5 months (range, 3-12). In responders, reduction in VS volumes ranged from -15.7% to 23.9%. Four of 13 patients evaluable for hearing met hearing criteria for response (30.8%; 95% CI, 13%-58%). One sustained response exceeded 9 months in duration. Median time to overall progression (ie, volumetric progression or hearing loss) was 14 months. The estimated overall progression-free survival and volumetric progression-free survival at 12 months were 64.2% (95% CI, 36.9% 82.1%) and 70.6% (95% CI, 43.1%-86.6%), respectively. Toxicity was generally minor, and no permanent dose modifications were required. Lapatinib carries minor toxicity and has objective activity in NF2 patients with progressive VS, including volumetric and hearing responses. Future studies could explore combination therapy with other molecular targeted agents such as bevacizumab. PMID- 22844110 TI - Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses. AB - Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10-/- T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-gamma/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10-/- T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-gamma and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-gamma/IL-17 T cell response also is significant. PMID- 22844111 TI - Glioma big potassium channel expression in human cancers and possible T cell epitopes for their immunotherapy. AB - Big potassium (BK) ion channels have several spliced variants. One spliced variant initially described within human glioma cells is the glioma BK (gBK) channel. This isoform consists of 34 aa inserted into the intracellular region of the basic BK ion channel. PCR primers specific for this inserted region confirmed that human glioma cell lines and freshly resected surgical tissues from glioblastoma multiforme patients strongly expressed gBK mRNA. Normal human brain tissue very weakly expressed this transcript. An Ab specific for this gBK isoform confirmed that human glioma cells displayed this protein in the cell membrane, mitochondria, Golgi, and endoplasmic reticulum. Within the gBK region, two putative epitopes (gBK1 and gBK2) are predicted to bind to the HLA-A*0201 molecule. HLA-A*0201-restricted human CTLs were generated in vitro using gBK peptide-pulsed dendritic cells. Both gBK1 and gBK2 peptide-specific CTLs killed HLA-A2+/gBK+ gliomas, but they failed to kill non-HLA-A2-expressing but gBK+ target cells in cytolytic assays. T2 cells loaded with exogenous gBK peptides, but not with the influenza M1 control peptide, were only killed by their respective CTLs. The gBK-specific CTLs also killed a variety of other HLA-A*0201+ cancer cells that possess gBK, as well as HLA-A2+ HEK cells transfected with the gBK gene. Of clinical relevance, we found that T cells derived from glioblastoma multiforme patients that were sensitized to the gBK peptide could also kill target cells expressing gBK. This study shows that peptides derived from cancer associated ion channels maybe useful targets for T cell-mediated immunotherapy. PMID- 22844112 TI - Proteinase 3, the autoantigen in granulomatosis with polyangiitis, associates with calreticulin on apoptotic neutrophils, impairs macrophage phagocytosis, and promotes inflammation. AB - Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3 CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory "reprogramming" of macrophages. PMID- 22844113 TI - Resolvin D1 and resolvin D2 govern local inflammatory tone in obese fat. AB - The unprecedented increase in the prevalence of obesity and obesity-related disorders is causally linked to a chronic state of low-grade inflammation in adipose tissue. Timely resolution of inflammation and return of this tissue to homeostasis are key to reducing obesity-induced metabolic dysfunctions. In this study, with inflamed adipose, we investigated the biosynthesis, conversion, and actions of Resolvins D1 (RvD1, 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z docosahexaenoic acid) and D2 (RvD2, 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z docosahexaenoic acid), potent anti-inflammatory and proresolving lipid mediators (LMs), and their ability to regulate monocyte interactions with adipocytes. Lipid mediator-metabololipidomics identified RvD1 and RvD2 from endogenous sources in human and mouse adipose tissues. We also identified proresolving receptors (i.e., ALX/FPR2, ChemR23, and GPR32) in these tissues. Compared with lean tissue, obese adipose showed a deficit of these endogenous anti-inflammatory signals. With inflamed obese adipose tissue, RvD1 and RvD2 each rescued impaired expression and secretion of adiponectin in a time- and concentration-dependent manner as well as decreasing proinflammatory adipokine production including leptin, TNF-alpha, IL 6, and IL-1beta. RvD1 and RvD2 each reduced MCP-1 and leukotriene B4-stimulated monocyte adhesion to adipocytes and their transadipose migration. Adipose tissue rapidly converted both resolvins (Rvs) to novel oxo-Rvs. RvD2 was enzymatically converted to 7-oxo-RvD2 as its major metabolic route that retained adipose directed RvD2 actions. These results indicate, in adipose, D-series Rvs (RvD1 and RvD2) are potent proresolving mediators that counteract both local adipokine production and monocyte accumulation in obesity-induced adipose inflammation. PMID- 22844114 TI - GB virus C envelope protein E2 inhibits TCR-induced IL-2 production and alters IL 2-signaling pathways. AB - GB virus type C (GBV-C) viremia is associated with reduced CD4+ T cell expansion following IL-2 therapy and with a reduction in T cell activation in HIV-infected individuals. The mechanism(s) by which GBV-C might alter T cell activation or IL 2 signaling have not been studied. In this study, we assess IL-2 release, IL-2R expression, IL-2 signaling, and cell proliferation in tet-off Jurkat cells expressing the GBV-C envelope glycoprotein (E2) following activation through the TCR. TCR activation was induced by incubation in anti-CD3/CD28 Abs. IL-2 release was measured by ELISA, STAT5 phosphorylation was assessed by immunoblot, and IL 2Ralpha (CD25) expression and cell proliferation were determined by flow cytometry. IL-2 and IL-2Ralpha steady-state mRNA levels were measured by real time PCR. GBV-C E2 expression significantly inhibited IL-2 release, CD25 expression, STAT5 phosphorylation, and cellular proliferation in Jurkat cells following activation through the TCR compared with control cell lines. Reducing E2 expression by doxycycline reversed the inhibitory effects observed in the E2 expressing cells. The N-terminal 219 aa of E2 was sufficient to inhibit IL-2 signaling. Addition of purified recombinant GBV-C E2 protein to primary human CD4+ and CD8+ T cells inhibited TCR activation-induced IL-2 release and upregulation of IL-2Ralpha expression. These data provide evidence that the GBV-C E2 protein may contribute to the block in CD4+ T cell expansion following IL-2 therapy in HIV-infected individuals. Furthermore, the effects of GBV-C on IL-2 and IL-2-signaling pathways may contribute to the reduction in chronic immune activation observed in GBV-C/HIV-coinfected individuals. PMID- 22844115 TI - Olfactomedin 4 inhibits cathepsin C-mediated protease activities, thereby modulating neutrophil killing of Staphylococcus aureus and Escherichia coli in mice. AB - Neutrophils kill bacteria generally through oxidative and nonoxidative mechanisms. Whereas much research has focused on the enzymes essential for neutrophil killing, little is known about the regulatory molecules responsible for such killing. In this study, we investigated the role of olfactomedin 4 (OLFM4), an olfactomedin-related glycoprotein, in neutrophil bactericidal capability and host innate immunity. Neutrophils from OLFM4-/- mice have increased intracellular killing of Staphylococcus aureus and Escherichia coli in vitro. The OLFM4-/- mice have enhanced in vivo bacterial clearance and are more resistant to sepsis when challenged with S. aureus or E. coli by i.p. injection. OLFM4 was found to interact with cathepsin C, a cysteine protease that plays an important role in bacterial killing and immune regulation. We demonstrated that OLFM4 inhibited cathepsin C activity in vitro and in vivo. The cathepsin C activity in neutrophils from OLFM4-/- mice was significantly higher than that in neutrophils from wild-type littermate mice. The activities of three serine proteases (neutrophil elastase, cathepsin G, and proteinase 3), which require cathepsin C activity for processing and maturity, were also significantly higher in OLFM4-/- neutrophils. The bacterial killing and clearance capabilities observed in OLFM4-/- mice that were enhanced relative to wild-type mice were significantly compromised by the additional loss of cathepsin C in mice with OLFM4 and cathepsin C double deficiency. These results indicate that OLFM4 is an important negative regulator of neutrophil bactericidal activity by restricting cathepsin C activity and its downstream granule-associated serine proteases. PMID- 22844116 TI - Integrin alphaXbeta2 is a leukocyte receptor for Candida albicans and is essential for protection against fungal infections. AB - The opportunistic fungus Candida albicans is one of the leading causes of infections in immunocompromised patients, and innate immunity provides a principal mechanism for protection from the pathogen. In the present work, the role of integrin alpha(X)beta2 in the pathogenesis of fungal infection was assessed. Both purified alpha(X)beta2 and alpha(X)beta2-expressing human epithelial kidney 293 cells recognized and bound to the fungal hyphae of SC5314 strain of C. albicans but not to the yeast form or to hyphae of a strain deficient in the fungal mannoprotein, Pra1. The binding of the integrin to the fungus was inhibited by beta-glucans but not by mannans, implicating a lectin like activity in recognition but distinct in specificity from that of alpha(M)beta2. Mice deficient in alpha(X)beta2 were more prone to systemic infection with the LD50 fungal inoculum decreasing 3-fold in alpha(X)beta2 deficient mice compared with wild-type mice. After challenging i.v. with 1.5 * 104 cell/g, 60% of control C57BL/6 mice died within 14 d compared with 100% mortality of alpha(X)beta2-deficient mice within 9 d. Organs taken from alpha(X)beta2-deficient mice 16 h postinfection revealed a 10-fold increase in fungal invasion into the brain and a 2-fold increase into the liver. These data indicate that alpha(X)beta2 is important for protection against systemic C. albicans infections and macrophage subsets in the liver, Kupffer cells, and in the brain, microglial cells use alpha(X)beta2 to control fungal invasion. PMID- 22844117 TI - Resolution of experimental lung injury by monocyte-derived inducible nitric oxide synthase. AB - Although early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about the mechanisms mediating resolution. To search for determinants of resolution, we exposed wild type (WT) mice to intratracheal LPS and assessed the response at intervals to day 10, when injury had resolved. Inducible NO synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS-/- mice were exposed to intratracheal LPS, early lung injury was attenuated; however, recovery was markedly impaired compared with WT mice. iNOS-/- mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS-/- mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid derived iNOS but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of cosignaling molecule CD86 in iNOS-/- mice compared with WT mice. Ab mediated blockade of CD86 in iNOS-/- mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair. PMID- 22844118 TI - Nanotopography-guided migration of T cells. AB - T cells navigate a wide variety of tissues and organs for immune surveillance and effector functions. Although nanoscale topographical structures of extracellular matrices and stromal/endothelial cell surfaces in local tissues may guide the migration of T cells, there has been little opportunity to study how nanoscale topographical features affect T cell migration. In this study, we systematically investigated mechanisms of nanotopography-guided migration of T cells using nanoscale ridge/groove surfaces. The velocity and directionality of T cells on these nanostructured surfaces were quantitatively assessed with and without confinement, which is a key property of three-dimensional interstitial tissue spaces for leukocyte motility. Depending on the confinement, T cells exhibited different mechanisms for nanotopography-guided migration. Without confinement, actin polymerization-driven leading edge protrusion was guided toward the direction of nanogrooves via integrin-mediated adhesion. In contrast, T cells under confinement appeared to migrate along the direction of nanogrooves purely by mechanical effects, and integrin-mediated adhesion was dispensable. Therefore, surface nanotopography may play a prominent role in generating migratory patterns for T cells. Because the majority of cells in periphery migrate along the topography of extracellular matrices with much lower motility than T cells, nanotopography-guided migration of T cells would be an important strategy to efficiently perform cell-mediated immune responses by increasing chances of encountering other cells within a given amount of time. PMID- 22844119 TI - Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage. AB - Lymphatic vessels transport interstitial fluid, soluble Ag, and immune cells from peripheral tissues to lymph nodes (LNs), yet the contribution of peripheral lymphatic drainage to adaptive immunity remains poorly understood. We examined immune responses to dermal vaccination and contact hypersensitivity (CHS) challenge in K14-VEGFR-3-Ig mice, which lack dermal lymphatic capillaries and experience markedly depressed transport of solutes and dendritic cells from the skin to draining LNs. In response to dermal immunization, K14-VEGFR-3-Ig mice produced lower Ab titers. In contrast, although delayed, T cell responses were robust after 21 d, including high levels of Ag-specific CD8+ T cells and production of IFN-gamma, IL-4, and IL-10 upon restimulation. T cell-mediated CHS responses were strong in K14-VEGFR-3-Ig mice, but importantly, their ability to induce CHS tolerance in the skin was impaired. In addition, 1-y-old mice displayed multiple signs of autoimmunity. These data suggest that lymphatic drainage plays more important roles in regulating humoral immunity and peripheral tolerance than in effector T cell immunity. PMID- 22844120 TI - A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination. AB - Diverse Ag-specific memory TCR repertoires are essential for protection against pathogens. Subunit vaccines that combine peptide or protein Ags with TLR agonists are very potent at inducing T cell immune responses, but their capacity to elicit stable and diverse memory CD4 T cell repertoires has not been evaluated. In this study, we examined the evolution of a complex Ag-specific population during the transition from primary effectors to memory T cells after peptide or protein vaccination. Both vaccination regimens induced equally diverse effector CD4 TCR repertoires, but peptide vaccines skewed the memory CD4 TCR repertoire toward high-affinity clonotypes whereas protein vaccines maintained low-affinity clonotypes in the memory compartment. CD27-mediated signaling was essential for the maintenance of low-affinity clonotypes after protein vaccination but was not sufficient to promote their survival following peptide vaccination. The rapid culling of the TCR repertoire in peptide-immunized mice coincided with a prolonged proliferation phase during which low-affinity clonotypes disappeared despite exhibiting no sign of enhanced apoptosis. Our study reveals a novel affinity threshold for memory CD4 T cell differentiation following vaccination and suggests a role for nonapoptotic cell death in the regulation of CD4 T cell clonal selection. PMID- 22844121 TI - Type I alveolar epithelial cells mount innate immune responses during pneumococcal pneumonia. AB - Pneumonia results from bacteria in the alveoli. The alveolar epithelium consists of type II cells, which secrete surfactant and associated proteins, and type I cells, which constitute 95% of the surface area and meet anatomic and structural needs. Other than constitutively expressed surfactant proteins, it is unknown whether alveolar epithelial cells have distinct roles in innate immunity. Because innate immunity gene induction depends on NF-kappaB RelA (also known as p65) during pneumonia, we generated a murine model of RelA mutated throughout the alveolar epithelium. In response to LPS, only 2 of 84 cytokine transcripts (CCL20 and CXCL5) were blunted in lungs of mutants, suggesting that a very limited subset of immune mediators is selectively elaborated by the alveolar epithelium. Lung CCL20 induction required epithelial RelA regardless of stimulus, whereas lung CXCL5 expression depended on RelA after instillation of LPS but not pneumococcus. RelA knockdown in vitro suggested that CXCL5 induction required RelA in type II cells but not type I cells. Sorted cell populations from mouse lungs revealed that CXCL5 was induced during pneumonia in type I cells, which did not require RelA. TLR2 and STING were also induced in type I cells, with RelA essential for TLR2 but not STING. To our knowledge, these data are the first direct demonstration that type I cells, which constitute the majority of the alveolar surface, mount innate immune responses during bacterial infection. These are also, to our knowledge, the first evidence for entirely RelA-independent pathways of innate immunity gene induction in any cell during pneumonia. PMID- 22844122 TI - Stability and function of secondary Th1 memory cells are dependent on the nature of the secondary stimulus. AB - Following acute infection in some mouse models, CD4+ memory T cells steadily decline over time. Conversely, in humans, CD4+ memory T cells can be maintained for many years at levels similar to CD8+ T cells. Because we previously observed that the longevity of Th1 memory cell survival corresponded to their functional avidity, we hypothesized that secondary challenge, which enriches for high functional avidity Th1 responders, would result in more stable Th1 memory populations. We found that following a heterologous secondary challenge, Th1 memory cells were maintained at stable levels compared with primary Th1 memory cells, showing little to no decline after day 75 postinfection. The improved stability of secondary Th1 memory T cells corresponded to enhanced homeostatic turnover; enhanced trafficking of effector memory Th1 cells to tissue sites of infection, such as the liver; and acquisition or maintenance of high functional avidity following secondary challenge. Conversely, a weaker homologous rechallenge failed to induce a stable secondary Th1 memory population. Additionally, homologous secondary challenge resulted in a transient loss of functional avidity by Th1 memory cells recruited into the secondary response. Our findings suggest that the longevity of Th1 memory T cells is dependent, at least in part, on the combined effects of primary and secondary Ag-driven differentiation. Furthermore, they demonstrate that the quality of the secondary challenge can have profound effects on the longevity and function of the ensuing secondary Th1 memory population. PMID- 22844124 TI - A GpC-rich oligonucleotide acts on plasmacytoid dendritic cells to promote immune suppression. AB - Short synthetic oligodeoxynucleotides (ODNs) rich in CpG or GpG motifs have been considered as potential modulators of immunity in clinical settings. In this study, we show that a synthetic GpC-ODN conferred highly suppressive activity on mouse splenic plasmacytoid dendritic cells, demonstrable in vivo in a skin test assay. The underlying mechanism involved signaling by noncanonical NF-kappaB family members and TGF-beta-dependent expression of the immunoregulatory enzyme IDO. Unlike CpG-ODNs, the effects of GpC-ODN required TLR7/TRIF-mediated but not TLR9/MyD88-mediated events, as do sensing of viral ssRNA and the drug imiquimod. Induction of IDO by a GpC-containing ODN could also be demonstrated in human dendritic cells, allowing those cells to assist FOXP3+ T cell generation in vitro. Among potentially therapeutic ODNs, this study identifies GpC-rich sequences as novel activators of TLR7-mediated, IDO-dependent regulatory responses. PMID- 22844123 TI - Prostaglandin E2 induces oncostatin M expression in human chronic wound macrophages through Axl receptor tyrosine kinase pathway. AB - Monocytes and macrophages (m) are plastic cells whose functions are governed by microenvironmental cues. Wound fluid bathing the wound tissue reflects the wound microenvironment. Current literature on wound inflammation is primarily based on the study of blood monocyte-derived macrophages, cells that have never been exposed to the wound microenvironment. We sought to compare pair-matched monocyte derived macrophages with m isolated from chronic wounds of patients. Oncostatin M (OSM) was differentially overexpressed in pair-matched wound m. Both PGE2 and its metabolite 13,14-dihydro-15-keto-PGE2 (PGE-M) were abundant in wound fluid and induced OSM in wound-site m. Consistently, induction of OSM mRNA was observed in m isolated from PGE2-enriched polyvinyl alcohol sponges implanted in murine wounds. Treatment of human THP-1 cell-derived m with PGE2 or PGE-M caused dose dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human m, PGE2 phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analogue demonstrating interplay between the cAMP and RTK pathways. PGE2-dependent Axl phosphorylation led to AP-1 transactivation, which is directly implicated in inducible expression of OSM. Treatment of human m or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNF-alpha and IL-1beta. OSM treatment also improved wound closure during the early inflammatory phase of healing. In summary, this work recognizes PGE2 in the wound fluid as a potent inducer of m OSM, a cytokine with an anti-inflammatory role in cutaneous wound healing. PMID- 22844125 TI - Intratumoral hu14.18-IL-2 (IC) induces local and systemic antitumor effects that involve both activated T and NK cells as well as enhanced IC retention. AB - hu14.18-IL-2 (IC) is an immunocytokine consisting of human IL-2 linked to hu14.18 mAb, which recognizes the GD2 disialoganglioside. Phase 2 clinical trials of i.v. hu14.18-IL-2 (i.v.-IC) in neuroblastoma and melanoma are underway and have already demonstrated activity in neuroblastoma. We showed previously that intratumoral hu14.18-IL-2 (IT-IC) results in enhanced antitumor activity in mouse models compared with i.v.-IC. The studies presented in this article were designed to determine the mechanisms involved in this enhanced activity and to support the future clinical testing of intratumoral administration of immunocytokines. Improved survival and inhibition of growth of both local and distant tumors were observed in A/J mice bearing s.c. NXS2 neuroblastomas treated with IT-IC compared with those treated with i.v.-IC or control mice. The local and systemic antitumor effects of IT-IC were inhibited by depletion of NK cells or T cells. IT-IC resulted in increased NKG2D receptors on intratumoral NKG2A/C/E+ NKp46+ NK cells and NKG2A/C/E+ CD8+ T cells compared with control mice or mice treated with i.v. IC. NKG2D levels were augmented more in tumor-infiltrating lymphocytes compared with splenocytes, supporting the localized nature of the intratumoral changes induced by IT-IC treatment. Prolonged retention of IC at the tumor site was seen with IT-IC compared with i.v.-IC. Overall, IT-IC resulted in increased numbers of activated T and NK cells within tumors, better IC retention in the tumor, enhanced inhibition of tumor growth, and improved survival compared with i.v.-IC. PMID- 22844126 TI - Phase II study of the safety and efficacy of temsirolimus in East Asian patients with advanced renal cell carcinoma. AB - OBJECTIVE: Temsirolimus, an inhibitor of the mammalian target of rapamycin, is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe. Temsirolimus was not yet evaluated in East Asian patients. METHODS: This non-randomized Phase II study enrolled 82 patients with advanced renal cell carcinoma [20 (24%) Japanese, 30 (37%) Korean and 32 (39%) Chinese patients; median age (range): 55 (26-83) years]. Most (71%) received prior systemic therapy for metastatic disease; two-thirds were intermediate risk. Six Japanese patients received intravenous temsirolimus 20 mg/m(2) weekly for tolerability assessment (Group A); the remaining 76 received a 25 mg flat dose weekly (Group B). Temsirolimus was dosed once weekly. Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent to-treat population. RESULTS: In the entire population, regardless of treatment group, the clinical benefit rate was 48% (95% confidence interval: 36, 59). Objective response rate was 11% (95% confidence interval: 5, 20), median progression-free survival was 7.3 months (95% confidence interval: 4.0, 9.2) and median time to treatment failure was 5.4 months (95% confidence interval: 3.5, 7.4). No patient in Group A demonstrated dose-limiting toxicity. The most frequent Grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, hypophosphatemia and stomatitis (5% each). Serious adverse events reported in >= 5% of patients were pneumonia (9%) and interstitial lung disease (7%). Temsirolimus and its major metabolite, sirolimus, were long-lived throughout the dosage interval, with no evidence of accumulation. CONCLUSION: Temsirolimus was well tolerated and showed promising activity in Japanese, Korean and Chinese patients with advanced renal cell carcinoma. PMID- 22844127 TI - Utility of inflammation-based prognostic scoring in patients given systemic chemotherapy first-line for advanced inoperable bladder cancer. AB - OBJECTIVE: Our intent was to investigate the impact of specific parameters clinical status, performance status (Eastern Cooperative Oncology Group (ECOG)), C-reactive protein, serum albumin, and inflammation (Glasgow Prognostic Score)-on progression-free survival and overall survival in patients given systemic chemotherapy as the first-line treatment of advanced bladder cancer. METHODS: A total of 67 patients treated for advanced bladder cancer in a 7-year period (2004 10) were reviewed. Prior to administration of first-line chemotherapy (gemcitabine plus cisplatin), baseline ECOG performance status, C-reactive protein, albumin, Glasgow Prognostic Score and clinical status were assessed. Patients with both elevated C-reactive protein (>1.0 mg/dl) and low albumin (<3.5 mg/dl) were assigned a Glasgow Prognostic Score of 2, while lesser scores were set when one (Glasgow Prognostic Score 1) or both levels (Glasgow Prognostic Score 0) were within the normal range. To evaluate relationships to progression free survival and overall survival, univariate and multivariate analyses were conducted. RESULTS: By multivariate analysis, ECOG performance status (hazard ratio = 3.48, 95% confidence interval 1.87-6.45, P = 0.001) and hypoalbuminemia (hazard ratio = 2.04, 95% confidence interval 1.10-3.78, P = 0.023) were found to be factors independently associated with reduced progression-free survival. Factors independently associated with shortened overall survival were ECOG performance status (hazard ratio = 5.32, 95% confidence interval 2.22-12.71, P = 0.001) and Glasgow Prognostic Score 2 (hazard ratio = 7.00, 95% confidence interval 2.53-19.36, P = 0.001). CONCLUSIONS: These outcomes indicate that a systemic inflammatory response coupled with hypoalbuminemia (Glasgow Prognostic Score 2) correlates significantly with shortened overall survival and may thus be useful as a prognostic index in this setting. PMID- 22844128 TI - Evaluation of three definitions of progression-free survival in preoperative cancer therapy (JCOG0801-A). AB - OBJECTIVE: Progression-free survival is an often-used endpoint in clinical trials comparing preoperative therapy and surgery-first therapy. Because the surgery date is always later in the preoperative arm than in the surgery-first arm, it is difficult to define progression-free survival optimally. We evaluated three progression-free survival definitions that used different methods to handle incomplete resection. METHODS: The three definitions specify the event date of incomplete resection (IR) as follows: 'IR = event' method, date of surgery; 'IR not event' method, date of radiological or clinical progression after incomplete resection; landmark method, landmark time. According to these definitions, the theoretical strengths and weaknesses of the three definitions are investigated. Three patterns of progression-free survival and overall survival were estimated using the data of the Japan Clinical Oncology Group studies. RESULTS: Theoretically, 'IR = event' inflates alpha error while 'IR not event' method and landmark method reduce the statistical power under the alternative hypothesis. In JCOG9907, hazard ratios for the three definitions were: 'IR = event', 0.80 (95% confidence interval, 0.59-1.07; P = 0.13); 'IR not event', 0.81 (95% confidence interval, 0.60-1.09; P = 0.16); landmark, 0.80 (95% confidence interval, 0.59 1.07; P = 0.15). No P value of any methods corresponded with the positive result for overall survival (P = 0.03). In the preoperative arms of the four studies, maximum differences in median and percentage of 1 year progression-free survival among the three definitions were 0-6.4 months and 1.2-5.2%. CONCLUSIONS: Progression-free survival sometimes fails as a surrogate of overall survival, and differences among results obtained with various progression-free survival definitions can be large. Overall survival should be used as primary endpoint in studies evaluating preoperative therapy. PMID- 22844129 TI - Phase II study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. AB - OBJECTIVE: This single-arm, open-label, Phase II study evaluated the efficacy and safety of single-agent bevacizumab, a monoclonal antibody against vascular endothelial growth factor, in Japanese patients with recurrent malignant glioma. METHODS: Patients with histologically confirmed, measurable glioblastoma or World Health Organization Grade III glioma, previously treated with temozolomide plus radiotherapy, received 10 mg/kg bevacizumab intravenous infusion every 2 weeks. The primary endpoint was 6-month progression-free survival in the patients with recurrent glioblastoma. RESULTS: Of the 31 patients enrolled, 29 (93.5%) had glioblastoma and 2 (6.5%) had Grade III glioma. Eleven (35.5%) patients were receiving corticosteroids at baseline; 17 (54.8%) and 14 (45.2%) patients had experienced one or two relapses, respectively. The 6-month progression-free survival rate in the 29 patients with recurrent glioblastoma was 33.9% (90% confidence interval, 19.2-48.5) and the median progression-free survival was 3.3 months. The 1-year survival rate was 34.5% with a median overall survival of 10.5 months. There were eight responders (all partial responses) giving an objective response rate of 27.6%. The disease control rate was 79.3%. Eight of the 11 patients taking corticosteroids at baseline reduced their dose or discontinued corticosteroids during the study. Bevacizumab was well-tolerated and Grade >=3 adverse events of special interest to bevacizumab were as follows: hypertension [3 (9.7%) patients], congestive heart failure [1 (3.2%) patient] and venous thromboembolism [1 (3.2%) patient]. One asymptomatic Grade 1 cerebral hemorrhage was observed, which resolved without treatment. CONCLUSION: Single-agent bevacizumab provides clinical benefit for Japanese patients with recurrent glioblastoma. PMID- 22844130 TI - A case of composite hemangioendothelioma arising from the spleen. PMID- 22844131 TI - Cancer mortality attributable to tobacco by region based on the WHO Global Report. PMID- 22844132 TI - Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature. AB - Among the clusters of imprinted genes in humans, one of the most relevant regions involved in human growth is localised in 11p15. Opposite epigenetic and genomic disturbances in this chromosomal region contribute to two distinct imprinting disorders associated with disturbed growth, Silver-Russell and Beckwith-Wiedemann syndromes. Due to the complexity of the 11p15 imprinting regions and their interactions, the interpretation of the copy number variations in that region is complicated. The clinical outcome in case of microduplications or microdeletions is therefore influenced by the size, the breakpoint positions and the parental inheritance of the imbalance as well as by the imprinting status of the affected genes. Based on their own new cases and those from the literature, the authors give an overview on the genotype-phenotype correlation in chromosomal rearrangements in 11p15 as the basis for a directed genetic counselling. The detailed characterisation of patients and families helps to further delineate risk figures for syndromes associated with 11p15 disturbances. Furthermore, these cases provide us with profound insights in the complex regulation of the (imprinted) factors localised in 11p15. PMID- 22844133 TI - Life table assay of field-caught Mediterranean fruit flies, Ceratitis capitata, reveals age bias. AB - Though traps are used widely to sample phytophagous insects for research or management purposes, and recently in aging research, possible bias stemming from differential response of individuals of various ages to traps has never been examined. In this paper, we tested the response of Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) males and females of four ages (spanning from 1 to 40 days) to McPhail-type traps baited with a synthetic food attractant in field cages and found that the probability of trapping was significantly influenced by age. The type of food on which flies were maintained before testing (sugar or protein) also had a strong effect and interacted with age. In another experiment, we collected wild C. capitata adults of unknown age using 1-3 methods and then reared them in the laboratory until death. The survival schedules of these flies were subsequently used in a life table assay to infer their age at the time of capture. Results showed that on a single sampling date, males captured in traps baited with a food attractant were younger compared with males aspirated from fruiting host trees, or males captured in traps baited with a sex attractant. Likewise, females captured in food-baited traps were younger compared with aspirated females. In addition to providing the first evidence of age-dependent sampling bias for a phytophagous insect species, this paper also provides a novel approach to estimate the differences in the age composition of samples collected with different techniques. These findings are of utmost importance for several categories of insects, medically important groups notwithstanding. PMID- 22844134 TI - Elimination of position-biased responding in individuals with autism and intellectual disabilities. AB - Five individuals with autism or other developmental disabilities participated in paired-stimulus preference assessments during repeated baseline probes. All subjects initially showed a pronounced bias by typically selecting the stimulus placed in either the left or right position. Biased responding for 3 subjects was eliminated when training trials were conducted in which a stimulus of known lesser quality was presented as one of the choices. Reinforcer-quality training was unsuccessful for 2 subjects, as was a condition in which reinforcer magnitude was modified to favor unbiased responding. These subjects' biased responding was eliminated only when a correction procedure (repetition of error trials) was implemented. PMID- 22844135 TI - Comparing the effects of differential reinforcement of other behavior and response-cost contingencies on tics in youth with Tourette syndrome. AB - Tics are rapid, repetitive, stereotyped movements or vocalizations that arise from neurobiological dysfunction and are influenced by environmental factors. Although persons with tic disorders often experience aversive social reactions in response to tics, little is known about the behavioral effects of such consequences. Along several dimensions, the present study compared the effects of two treatments on tics: response cost (RC) and differential reinforcement of other behavior (DRO). Four children with Tourette syndrome were exposed to free to-tic baseline, DRO, RC, and quasibaseline rebound evaluation conditions using an alternating treatments design. Both DRO and RC produced substantial decreases in tics from baseline levels. No differential effects of DRO and RC contingencies were seen on self-reported stress or in the strength of the reflexive motivating operation (i.e., premonitory urge) believed to trigger tics, and neither condition produced tic-rebound effects. Implications of these findings and directions for future research are discussed. PMID- 22844136 TI - The emergence of untrained mands and tacts in children with autism. AB - Despite Skinner's (1957) assertion that verbal operants are initially functionally independent, recent studies have suggested that in some cases the acquisition of one verbal operant (e.g., mand) gives rise to the other (e.g., tact) without explicit training. The present study aimed to evaluate the functional independence of mands and tacts during instruction with children with autism. Four boys with autism (3 to 6 years old) were taught to construct two 4 piece structures. Two participants were taught directly to mand, whereas the other 2 were taught to tact the names of the pieces. The effects of training were evaluated in a multiple probe design across verbal operants and tasks. Three of the 4 participants demonstrated an immediate transfer of control from 1 verbal operant to the other. These results were consistent with previous research with typically developing young children. PMID- 22844137 TI - Comparing the teaching interaction procedure to social stories for people with autism. AB - This study compared social stories and the teaching interaction procedure to teach social skills to 6 children and adolescents with an autism spectrum disorder. Researchers taught 18 social skills with social stories and 18 social skills with the teaching interaction procedure within a parallel treatment design. The teaching interaction procedure resulted in mastery of all 18 skills across the 6 participants. Social stories, in the same amount of teaching sessions, resulted in mastery of 4 of the 18 social skills across the 6 participants. Participants also displayed more generalization of social skills taught with the teaching interaction procedure to known adults and peers. PMID- 22844138 TI - Further analysis of variables that affect self-control with aversive events. AB - The purpose of this study was to examine variables that affect self-control in the context of academic task completion by elementary school children with autism. In the baseline assessment of Study 1, mathematics problem completion was shown to be an aversive event, and sensitivity to task magnitude, task difficulty, and delay to task completion were measured. The effects of manipulating values of those parameters on self-control then were assessed. For all participants, self-control increased as a function of one or more changes in task parameter values. In study 2, the effects of a commitment response on self control was assessed. Results indicated that for all participants, levels of self control were higher when the opportunity to commit to the immediate aversive event was available. PMID- 22844139 TI - A computer-based program to teach braille reading to sighted individuals. AB - Instructors of the visually impaired need efficient braille-training methods. This study conducted a preliminary evaluation of a computer-based program intended to teach the relation between braille characters and English letters using a matching-to-sample format with 4 sighted college students. Each participant mastered matching visual depictions of the braille alphabet to their printed-word counterparts. Further, each participant increased the number of words they read in a braille passage following this training. These gains were maintained at variable levels on a maintenance probe conducted 2 to 4 weeks after training. PMID- 22844140 TI - An evaluation of the stimulus equivalence paradigm to teach single-subject design to distance education students via Blackboard. AB - The purpose of the current study was to examine the degree to which instruction based on stimulus equivalence procedures could be used to teach single-subject design methodology to graduate-level professionals through a Web-based course management system known as Blackboard (see http://www.blackboard.com). Specifically, we used the stimulus equivalence paradigm to teach relations among the names, definitions, graphical representations of the designs, and two practical scenarios of when it would be appropriate to implement each design. Most participants demonstrated the emergence of untaught relations, and some participants showed generalization to novel vignettes and graphs. Relations largely were not maintained at follow-up but were retaught. PMID- 22844141 TI - Increasing accurate preference assessment implementation through pyramidal training. AB - Preference assessments directly evaluate items that may serve as reinforcers, and their implementation is an important skill for individuals who work with children. This study examined the effectiveness of pyramidal training on teachers' implementation of preference assessments. During experiment 1, 3 special education teachers taught 6 trainees to conduct paired-choice, multiple stimulus without replacement, and free-operant preference assessments. All trainees acquired skills necessary to implement preference assessments with 90% or greater accuracy during the training sessions and demonstrated generalization of skills to their classrooms or clinic. During experiment 2, 5 teachers who served as trainees in experiment 1 trained 18 preschool teachers. All preschool teachers met the mastery criterion following training. Training teachers to implement preference assessments may increase teachers' acceptance and use of behavior-analytic procedures in school settings. PMID- 22844142 TI - Progressing from identification and functional analysis of precursor behavior to treatment of self-injurious behavior. AB - This multiple-study experiment evaluated the utility of assessing and treating severe self-injurious behavior SIB based on the outcomes of a functional analysis of precursor behavior. In Study 1, a precursor to SIB was identified using descriptive assessment and conditional probability analyses. In Study 2, a functional analysis of precursor behavior was conducted. Finally, study 3 evaluated the effects of a treatment in which precursor behavior produced the maintaining variable identified in the precursor functional analysis. Studies 1 and 3 were conducted in two settings in the participants natural environment, where data collection was ongoing throughout the course of the study. Results showed that it was possible to identify a precursor to infrequent but severe SIB, that a functional analysis of precursor behavior suggested a clear operant function, and that treatment based on the results of the precursor functional analysis reduced SIB in the natural environment. PMID- 22844144 TI - Script fading to promote unscripted bids for joint attention in children with autism. AB - We used a script-fading procedure to teach 3 children with autism to initiate bids for joint attention. We examined the effects of (a) scripts, (b) varied adult scripted responses, and (c) multiple-exemplar script training on promoting unscripted language during bids for joint attention. All 3 participants learned to initiate bids for joint attention, and the response generalized to untrained stimuli, conversation partners, and the classroom environment. PMID- 22844143 TI - A tutorial on the use of Excel 2010 and Excel for Mac 2011 for conducting delay discounting analyses. AB - In recent years, researchers and practitioners in the behavioral sciences have profited from a growing literature on delay discounting. The purpose of this article is to provide readers with a brief tutorial on how to use Microsoft Office Excel 2010 and Excel for Mac 2011 to analyze discounting data to yield parameters for both the hyperbolic discounting model and area under the curve. This tutorial is intended to encourage the quantitative analysis of behavior in both research and applied settings by readers with relatively little formal training in nonlinear regression. PMID- 22844145 TI - Effects of access to a stimulating object on infant behavior during tummy time. AB - Placing infants in a prone position for "tummy time" often is recommended to ensure appropriate infant development and to combat the effects associated with infants spending extended periods of time in a supine position. However, tummy time may be associated with inappropriate infant behavior such as crying and noncompliance. We provided continuous access to a preferred stimulus to decrease negative vocalizations and to increase the duration of an infant's head being elevated during tummy time. PMID- 22844146 TI - The effect of outdoor activity context on physical activity in preschool children. AB - The purpose of the current study was to develop and test a method for assessing the effect of outdoor activity context on level of physical activity in preschool children. The observational system for recording physical activity in children was used to define the test conditions and various levels of physical activity within a multielement design. In general, all participants were fairly sedentary during the analysis. The fixed playground equipment condition produced the most moderate-to-vigorous physical activity, a finding that does not correspond to the descriptive assessment literature on childhood physical activity. PMID- 22844147 TI - Differential effects of seating arrangements on disruptive behavior of fifth grade students during independent seatwork. AB - We investigated teacher versus student seat selection in the context of group and individual seating arrangements. Disruptive behavior during group seating occurred at twice the rate when students chose their seats than when the teacher chose. During individual seating, disruptive behavior occurred more than three times as often when the students chose their seats. The results are discussed in relation to choice and the matching law. PMID- 22844148 TI - Preliminary investigation of a video-based stimulus preference assessment. AB - Video clips may be an effective format for presenting complex stimuli in preference assessments. In this preliminary study, we evaluated the correspondence between preference hierarchies generated from preference assessments that included either toys or videos of the toys. The top-ranked item corresponded in both assessments for 5 of the 6 participants, and the top- and bottom-ranked items corresponded for 4 participants. The implications of these results for future research on video preference assessments are discussed. PMID- 22844149 TI - The effects of video modeling with voiceover instruction on accurate implementation of discrete-trial instruction. AB - The present study replicates and extends previous research on the use of video modeling (VM) with voiceover instruction to train staff to implement discrete trial instruction (DTI). After staff trainees reached the mastery criterion when teaching an adult confederate with VM, they taught a child with a developmental disability using DTI. The results showed that the staff trainees' accurate implementation of DTI remained high, and both child participants acquired new skills. These findings provide additional support that VM may be an effective method to train staff members to conduct DTI. PMID- 22844151 TI - Comparing the effects of echoic prompts and echoic prompts plus modeled prompts on intraverbal behavior. AB - We compared strategies to teach vocal intraverbal responses to an adolescent diagnosed with autism and Down syndrome. One strategy involved echoic prompts only. The second strategy involved an echoic prompt paired with a modeled prompt in the form of sign language. Presenting the modeled prompt with the echoic prompt resulted in faster acquisition of correct responding. Results are discussed in terms of using functional stimulus classes to facilitate vocal intraverbal acquisition with learners who have a history of sign language training. PMID- 22844150 TI - Teaching children with autism to engage in peer-directed mands using a picture exchange communication system. AB - We evaluated differential reinforcement of alternative behavior (DRA) plus prompting to increase peer-directed mands for preferred items using a picture exchange communication system (PECS). Two nonvocal individuals with autism participated. Independent mands with a peer increased with the implementation of DRA plus prompting for both participants. In addition, peers engaged in brief social interactions following the majority of mands for leisure items. These results suggest that teaching children to use PECS with peers may be one way to increase manding and social interactions in individuals with limited or no vocal repertoire. PMID- 22844152 TI - Using a taped intervention to improve kindergarten students' number identification. AB - A multiple baseline design across students was used to evaluate the effects of a taped numbers (TN) intervention on the number-identification accuracy of 4 kindergarten students. During TN, students attempted to name the numbers 0 through 9 on randomized lists before each number was provided via a tape player 2 s later. All 4 students showed immediate increases and reached 100% in number identification accuracy. One student reached 100% accuracy after TN was supplemented with performance feedback, reinforcement, and overcorrection. PMID- 22844154 TI - Effects of a motivating operation manipulation on the maintenance of mands. AB - We assessed the maintenance of newly acquired mands under presession reinforcer access (reinforcer efficacy abolished) and no presession reinforcer access (reinforcer efficacy established) conditions with 3 children with autism spectrum disorder. Results suggested that the no presession access condition established the value of the reinforcer and evoked responding relative to the presession access condition. Results are discussed in the context of implications for assessing maintenance of previously acquired skills. PMID- 22844155 TI - Impact of treatment integrity on intervention effectiveness. AB - Treatment integrity has cogent implications for intervention effectiveness. Understanding these implications is an important, but often neglected, undertaking in behavior analysis. This paper reviews current research on treatment integrity in applied behavior analysis. Specifically, we review research evaluating the relation between integrity failures and the efficacy of behavioral interventions. Avenues for future research are provided. PMID- 22844157 TI - Working at the Weekend: Fathers' Time with Family in the United Kingdom. AB - Whereas most resident fathers are able to spend more time with their children on weekends than on weekdays, many fathers work on the weekends spending less time with their children on these days. There are conflicting findings about whether fathers are able to make up for lost weekend time on weekdays. Using unique features of the United Kingdom's National Survey of Time Use 2000 (UKTUS) I examine the impact of fathers' weekend work on the time fathers spend with their children, family, and partners (N = 595 fathers). I find that weekend work is common among fathers and is associated with less time with children, families, and partners. Fathers do not recover lost time with children on weekdays, largely because weekend work is a symptom of overwork. Findings also reveal that even if fathers had compensatory time, they are unlikely to recover lost time spent as a family or couple. PMID- 22844158 TI - The Geographic Concentration of Enterprise in Developing Countries. AB - A nation's economic geography can have an enormous impact on its development. In Thailand, we show that a high concentration of enterprise in an area predicts high subsequent growth in and around that area. We also find spatially contiguous convergence of enterprise with stagnant areas left behind. Exogenous physiographic conditions are correlated with enterprise location and growth. We fit a structural, micro-founded model of occupation transitions with fine-tuned geographic capabilities to village data and replicate these salient facts. Key elements of the model include costs, credit constraints on occupation choice, and spatially varying expansion of financial service providers. PMID- 22844159 TI - Laboring Underground: The Employment Patterns of Hispanic Immigrant Men in Durham, NC. AB - The dramatic increase in Hispanic immigration to the United States in recent decades has been coterminous with fundamental shifts in the labor market towards heightened flexibility, instability, and informality. As a result, the low-wage labor market is increasingly occupied by Hispanic immigrants, many of whom are undocumented. While numerous studies examine the implications for natives' employment prospects, our understanding of low-wage immigrants themselves remains underdeveloped. Drawing on original data collected in Durham, North Carolina, this article provides a more holistic account of immigrant Hispanic's labor market experiences, examining not only wages but also employment instability and benefit coverage. The analysis evaluates the role of human capital and immigration characteristics, including legal status, in shaping compensation outcomes, as well as the influence of other employment characteristics. Findings highlight the salience of nonstandard work arrangements such as subcontracting and informal employment to the labor market experiences of immigrant Hispanic men, and describe the constellation of risk factors that powerfully bound immigrant employment outcomes. Keywords: Hispanic; immigration; wages; low-wage labor market; employment relations. PMID- 22844160 TI - A One-Pot Selective Synthesis of N-Boc Protected Secondary Amines: Tandem Direct Reductive Amination/N-Boc Protection. AB - A one-pot tandem direct reductive amination of aldehydes with primary amines resulting in N-Boc secondary amines using a (Boc)(2)O/sodium triacetoxyborohydride (STAB) system is reported. The tandem procedure is efficient, selective, and versatile, giving excellent yields of N-Boc protected secondary amines even in those cases where the products are prone to intramolecular lactamization. PMID- 22844161 TI - Lithiation and Electrophilic Substitution of Dimethyl Triazones. AB - The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin-lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted to the corresponding imidazolone heterocycles. PMID- 22844162 TI - Secondary metabolites produced by fungi derived from a microbial mat encountered in an iron-rich natural spring. AB - A collection of fungal isolates was obtained from a complex microbial mat, which occupied an iron-rich freshwater spring that feeds into Clear Creek, Golden, Colorado, USA. Two of the fungal isolates, a Glomeromycete (possible Entrophospora sp.) and a Dothideomycete (possible Phaeosphaeria sp.), were investigated for bioactive secondary metabolites. In total, six new compounds consisting of clearanols A-E (5, 6, 10-12) and disulochrin (7) were purified and their structures were determined. Disulochrin exhibited modest antibacterial activity against methicillin-resistant Staphylococcus aureus, whereas clearanol C showed weak inhibitory activity against Candida albicans biofilm formation. PMID- 22844163 TI - Two ways to listen: Do L2-dominant bilinguals perceive stop voicing according to language mode? AB - How listeners categorize two phones predicts the success with which they will discriminate the given phonetic distinction. In the case of bilinguals, such perceptual patterns could reveal whether the listener's two phonological systems are integrated or separate. This is of particular interest when a given contrast is realized differently in each language, as is the case with Greek and English stop-voicing distinctions. We had Greek-English early sequential bilinguals and Greek and English monolinguals (baselines) categorize, rate, and discriminate stop-voicing contrasts in each language. All communication with each group of bilinguals occurred solely in one language mode, Greek or English. The monolingual groups showed the expected native-language constraints, each perceiving their native contrast more accurately than the opposing nonnative contrast. Bilinguals' category-goodness ratings for the same physical stimuli differed, consistent with their language mode, yet their discrimination performance was unaffected by language mode and biased toward their dominant language (English). We conclude that bilinguals integrate both languages in a common phonetic space that is swayed by their long-term dominant language environment for discrimination, but that they selectively attend to language specific phonetic information for phonologically motivated judgments (category goodness ratings). PMID- 22844164 TI - Counting Child Domestic Servants in Latin America. AB - This paper summarizes trends in the use of child domestic servants in six Latin American countries using IPUMS-International census samples for 1960 to 2000. Child domestics are among the most vulnerable of child workers, and the most invisible. They may be treated kindly and allowed to attend school, or they may be secluded in their employers' home, overworked, verbally abused, beaten, and unable to leave or report their difficulties to kin. Estimates and imputations are based on labor force and relationship-to-head variables. We find that domestic service makes up a substantial fraction of girls' employment in some countries. We also analyze trends in live-in versus live-out status and school enrollment of child domestic servants. While all child workers are disadvantaged in enrollment relative to non-workers, domestics are sometimes better off than non-domestic workers. In some samples, live-ins are more likely to go to school than live-out child domestics. In others, they are substantially worse off. PMID- 22844165 TI - Alternatives to the journal impact factor: I3 and the top-10% (or top-25%?) of the most-highly cited papers. AB - Journal impact factors (IFs) can be considered historically as the first attempt to normalize citation distributions by using averages over 2 years. However, it has been recognized that citation distributions vary among fields of science and that one needs to normalize for this. Furthermore, the mean-or any central tendency statistics-is not a good representation of the citation distribution because these distributions are skewed. Important steps have been taken to solve these two problems during the last few years. First, one can normalize at the article level using the citing audience as the reference set. Second, one can use non-parametric statistics for testing the significance of differences among ratings. A proportion of most-highly cited papers (the top-10% or top-quartile) on the basis of fractional counting of the citations may provide an alternative to the current IF. This indicator is intuitively simple, allows for statistical testing, and accords with the state of the art. PMID- 22844166 TI - Discussing some basic critique on Journal Impact Factors: revision of earlier comments. AB - In this study the issue of the validity of the argument against the applied length of citation windows in Journal Impact Factors calculations is critically re-analyzed. While previous studies argued against the relatively short citation window of 1-2 years, this study shows that the relative short term citation impact measured in the window underlying the Journal Impact Factor is a good predictor of the citation impact of the journals in the next years to come. Possible exceptions to this observation relate to journals with relatively low numbers of publications, and the citation impact related to publications in the year of publication. The study focuses on five Journal Subject Categories from the science and social sciences, on normal articles published in these journals, in the 2 years 2000 and 2004. PMID- 22844167 TI - Properties of journal impact in relation to bibliometric research group performance indicators. AB - In this paper we present a compilation of journal impact properties in relation to other bibliometric indicators as found in our earlier studies together with new results. We argue that journal impact, even calculated in a sufficiently advanced way, becomes important in evaluation practices based on bibliometric analysis only at an aggregate level. In the relation between average journal impact and actual citation impact of groups, the influence of research performance is substantial. Top-performance as well as lower performance groups publish in more or less the same range of journal impact values, but top performance groups are, on average, more successful in the entire range of journal impact. We find that for the high field citation-density groups a larger size implies a lower average journal impact. For groups in the low field citation density regions however a larger size implies a considerably higher average journal impact. Finally, we found that top-performance groups have relatively less self-citations than the lower performance groups and this fraction is decreasing with journal impact. PMID- 22844168 TI - Global Partial Likelihood for Nonparametric Proportional Hazards Models. AB - As an alternative to the local partial likelihood method of Tibshirani and Hastie and Fan, Gijbels, and King, a global partial likelihood method is proposed to estimate the covariate effect in a nonparametric proportional hazards model, lambda(t|x) = exp{psi(x)}lambda(0)(t). The estimator, psi(x), reduces to the Cox partial likelihood estimator if the covariate is discrete. The estimator is shown to be consistent and semiparametrically efficient for linear functionals of psi(x). Moreover, Breslow-type estimation of the cumulative baseline hazard function, using the proposed estimator psi(x), is proved to be efficient. The asymptotic bias and variance are derived under regularity conditions. Computation of the estimator involves an iterative but simple algorithm. Extensive simulation studies provide evidence supporting the theory. The method is illustrated with the Stanford heart transplant data set. The proposed global approach is also extended to a partially linear proportional hazards model and found to provide efficient estimation of the slope parameter. This article has the supplementary materials online. PMID- 22844169 TI - Non-parametric Evaluation of Biomarker Accuracy under Nested Case-control Studies. AB - To evaluate the clinical utility of new risk markers, a crucial step is to measure their predictive accuracy with prospective studies. However, it is often infeasible to obtain marker values for all study participants. The nested case control (NCC) design is a useful cost-effective strategy for such settings. Under the NCC design, markers are only ascertained for cases and a fraction of controls sampled randomly from the risk sets. The outcome dependent sampling generates a complex data structure and therefore a challenge for analysis. Existing methods for analyzing NCC studies focus primarily on association measures. Here, we propose a class of non-parametric estimators for commonly used accuracy measures. We derived asymptotic expansions for accuracy estimators based on both finite population and Bernoulli sampling and established asymptotic equivalence between the two. Simulation results suggest that the proposed procedures perform well in finite samples. The new procedures were illustrated with data from the Framingham Offspring study. PMID- 22844170 TI - Instability, Sensitivity, and Degeneracy of Discrete Exponential Families. AB - In applications to dependent data, first and foremost relational data, a number of discrete exponential family models has turned out to be near-degenerate and problematic in terms of Markov chain Monte Carlo simulation and statistical inference. We introduce the notion of instability with an eye to characterize, detect, and penalize discrete exponential family models that are near-degenerate and problematic in terms of Markov chain Monte Carlo simulation and statistical inference. We show that unstable discrete exponential family models are characterized by excessive sensitivity and near-degeneracy. In special cases, the subset of the natural parameter space corresponding to non-degenerate distributions and mean-value parameters far from the boundary of the mean-value parameter space turns out to be a lower-dimensional subspace of the natural parameter space. These characteristics of unstable discrete exponential family models tend to obstruct Markov chain Monte Carlo simulation and statistical inference. In applications to relational data, we show that discrete exponential family models with Markov dependence tend to be unstable and that the parameter space of some curved exponential families contains unstable subsets. PMID- 22844171 TI - A Perturbation Method for Inference on Regularized Regression Estimates. AB - Analysis of high dimensional data often seeks to identify a subset of important features and assess their effects on the outcome. Traditional statistical inference procedures based on standard regression methods often fail in the presence of high-dimensional features. In recent years, regularization methods have emerged as promising tools for analyzing high dimensional data. These methods simultaneously select important features and provide stable estimation of their effects. Adaptive LASSO and SCAD for instance, give consistent and asymptotically normal estimates with oracle properties. However, in finite samples, it remains difficult to obtain interval estimators for the regression parameters. In this paper, we propose perturbation resampling based procedures to approximate the distribution of a general class of penalized parameter estimates. Our proposal, justified by asymptotic theory, provides a simple way to estimate the covariance matrix and confidence regions. Through finite sample simulations, we verify the ability of this method to give accurate inference and compare it to other widely used standard deviation and confidence interval estimates. We also illustrate our proposals with a data set used to study the association of HIV drug resistance and a large number of genetic mutations. PMID- 22844172 TI - Invasive ants alter foraging and parental behaviors of a native bird. AB - Introduced species can exert outsized impacts on native biota through both direct (predation) and indirect (competition) effects. Ants frequently become established in new areas after being transported by humans across traditional biological or geographical barriers, and a prime example of such establishment is the red imported fire ant (Solenopsis invicta). Introduced to North America in the 1930's, red imported fire ants are now firmly established throughout the southeastern United States. Although these invasive predators can dramatically impact native arthropods, their effect on vertebrates through resource competition is essentially unknown. Using a paired experimental design, we compared patterns of foraging and rates of provisioning for breeding eastern bluebirds (Sialia sialis) in unmanipulated (control) territories to those in adjacent (treated) territories where fire ants were experimentally reduced. Bluebirds inhabiting treated territories foraged nearer their nests and provisioned offspring more frequently than bluebirds inhabiting control territories with unmanipulated fire ant levels. Additionally, nestlings from treated territories were in better condition than those from control territories, though these differences were largely confined to early development. The elimination of significant differences in body condition towards the end of the nestling period suggests that bluebird parents in control territories were able to make up the food deficit caused by fire ants, potentially by working harder to adequately provision their offspring. The relationship between fire ant abundance and bluebird behavior hints at the complexity of ecological communities and suggests negative effects of invasive species are not limited to taxa with which they have direct contact. PMID- 22844173 TI - The Evolution, Contributions, and Prospects of the Youth Development Study: An Investigation in Life Course Social Psychology. AB - Grounded in social structure and personality, life course, and status attainment perspectives of social psychology, the Youth Development Study has followed a cohort of teenagers from the beginning of high school through their mid-thirties. Evidence for the effective exercise of agency derives from diverse adolescent work patterns leading to outcomes that are consistent with youth's earlier goals, motivations, and resources. Thus, the socioeconomic career begins well before the completion of formal education. The YDS has revealed multiple pathways of contemporary transition to adulthood, the circumstances surrounding parental residential and financial support to their transitioning children, and the cessation of deviant behavior as adult roles are acquired. Agentic pathways during this period are significant precursors of success during subsequent economic downturn. The new YDS Second Generation Study is well poised to address the impacts of parental trajectories on the adjustment and well-being of children. PMID- 22844174 TI - Financial Arrangements and Relationship Quality in Low-Income Couples. AB - This study explored the association between household financial arrangements and relationship quality using a representative sample of low-income couples with children. We detailed the banking arrangements couples utilize, assessed which factors relate to holding a joint account versus joint and separate, only separate, or no account, and analyzed the association between fiscal practices and men's and women's relationship quality. The majority of couples held joint accounts, though over one-quarter also have separate accounts; nearly one-tenth have no account. Joint bank accounts were associated with higher levels of relationship quality on numerous dimensions, though more consistently for women than men. Individualistic arrangements appeared to undermine women's relationship satisfaction and reduce feelings of intimacy, sexual compatibility, and satisfaction with conflict resolution. PMID- 22844175 TI - Subtyping Children With Speech Sound Disorders by Endophenotypes. AB - PURPOSE: The present study examined associations of 5 endophenotypes (i.e., measurable skills that are closely associated with speech sound disorders and are useful in detecting genetic influences on speech sound production), oral motor skills, phonological memory, phonological awareness, vocabulary, and speeded naming, with 3 clinical criteria for classifying speech sound disorders: severity of speech sound disorders, our previously reported clinical subtypes (speech sound disorders alone, speech sound disorders with language impairment, and childhood apraxia of speech), and the comorbid condition of reading disorders. PARTICIPANTS AND METHOD: Children with speech sound disorders and their siblings were assessed at early childhood (ages 4-7 years) on measures of the 5 endophenotypes. Severity of speech sound disorders was determined using the z score for Percent Consonants Correct-Revised (developed by Shriberg, Austin, Lewis, McSweeny, & Wilson, 1997). Analyses of variance were employed to determine how these endophenotypes differed among the clinical subtypes of speech sound disorders. RESULTS AND CONCLUSIONS: Phonological memory was related to all 3 clinical classifications of speech sound disorders. Our previous subtypes of speech sound disorders and comorbid conditions of language impairment and reading disorder were associated with phonological awareness, while severity of speech sound disorders was weakly associated with this endophenotype. Vocabulary was associated with mild versus moderate speech sound disorders, as well as comorbid conditions of language impairment and reading disorder. These 3 endophenotypes proved useful in differentiating subtypes of speech sound disorders and in validating current clinical classifications of speech sound disorders. PMID- 22844176 TI - Individual and Instructional Determinants of Student Engagement in Physical Education. AB - This study was conducted to identify student characteristics and instructional factors that impact student engagement in physical education (PE). Data were derived from the systematic observation of 124 sessions taught by 31 physical educators and the administration of health and PE engagement questionnaires to 2,018 students in grades 5-8. Physical activity was directly affected by student engagement and perceived competence in PE and indirectly affected by students' body image through its association with PE engagement. Multilevel analyses revealed that the proportion of class time devoted to game play was negatively associated with student engagement in PE. Although less frequently used during PE sessions, skill practice was positively associated with student engagement and inactive instruction was negatively associated with student engagement. These effects were particularly pronounced among students with poor competence beliefs. Implications for PE instructional practice and future research are presented. PMID- 22844178 TI - Wages, Welfare Benefits and Migration. AB - Differences in economic opportunities give rise to strong migration incentives, across regions within countries, and across countries. In this paper we focus on responses to differences in welfare benefits across States. We apply the model developed in Kennan and Walker (2008), which emphasizes that migration decisions are often reversed, and that many alternative locations must be considered. We model individual decisions to migrate as a job search problem. A worker starts the life-cycle in some home location and must determine the optimal sequence of moves before settling down. The model is sparsely parameterized. We estimate the model using data from the National Longitudinal Survey of Youth (1979). Our main finding is that income differences do help explain the migration decisions of young welfare-eligible women, but large differences in benefit levels provide surprisingly weak migration incentives. PMID- 22844177 TI - A peptide's perspective of water dynamics. AB - This Perspective is focused on amide groups of peptides interacting with water. The 2D IR spectroscopy has already enabled structural aspects of the peptide backbone to be determined through its ability to measure the coupling between different amide-I modes. Here we describe why nonlinear IR is emerging as the method of choice to examine the fast components of the water dynamics near peptides and how isotopically edited peptide links can be used to probe the local water at a residue level in proteins. This type of research necessarily involves an intimate mix of theory and experiment. The description of the results is underpinned by relatively well established quantum-statistical theories that describe the important manifestations of peptide vibrational frequency fluctuations. PMID- 22844180 TI - Unraveling the Enigma of Bangungut: Is Sudden Unexplained Nocturnal Death Syndrome (SUNDS) in the Philippines a Disease Allelic to the Brugada Syndrome? AB - BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) has been reported worldwide. SUNDS is endemic in Southeast Asia and is colloquially known as Bangungut in the Philippines, Lai Tai in Thailand, and Pokkuri in Japan. Although SUNDS in Thailand and Japan have been determined to be phenotypically, genetically and functionally identical to the Brugada syndrome, the relationship between Bangungut/SUNDS in the Philippines and the Brugada syndrome has not been clarified. This paper explores the concordance between Bangungut/SUNDS and the Brugada syndrome. METHODS: We summarized autopsy studies on Bangungut retrieved from PubMed since 1917 and current epidemiological data on Philippine SUNDS to clarify its diagnostic features. We also reviewed current hypotheses of the pathophysiological mechanism of the Brugada syndrome to explore its applicability to Bangungut/SUNDS. RESULTS: The use of the term Bangungut is confusing as it includes many diseases that may cause SUNDS. However, our review reveals a notable subset of Bangungut, identified as Bangungut/SUNDS with no gross cardiac pathology that conforms to the clinical picture of the folk-belief of Bangungut and of the Brugada syndrome, namely: predominance among male in the 20-40 age range; sudden death during sleep or at rest, usually following ingestion of a large meal at night; and victims were in apparent good health prior to their demise. Current pathophysiological mechanisms of Brugada syndrome seemed plausible explanations for a majority of this subset of Bangungut/SUNDS. CONCLUSION: Bangungut/SUNDS and the Brugada syndrome appear closely related. Pathophysiological mechanisms of the Brugada syndrome may explain the enigma of Bangungut/SUND. Whether Bangungut/SUNDS is phenotypically, genetically and functionally an allele of the Brugada syndrome remains inconclusive due to lack of research data. We therefore proposed a research agenda including genetic testing and pharmacological challenge of probands and their family members suspected of SUNDS to conclusively establish the relationship between these two syndromes. PMID- 22844181 TI - Construct Validity of a Measure of Affective Communication in Psychotherapy. AB - The present study evaluates the psychometric properties of a therapist measure for evaluating the affective communication created between the patient and therapist during the initial stages of treatment. The Affective Communication Questionnaire (ACQ) was administered to a sample of 81 therapists, each rating a single patient, and principal component analysis indicated the measure has coherent dimensions with strong internal consistency. The construct validity of the ACQ was then established in a sample of 16 therapists rating 73 patients diagnosed with Borderline Personality Disorder (BPD). The measure was found to have a strong relationship to the related constructs of transference, countertransference, and affect experience in predicted directions. The measure also was found to have a modest relationship to independent assessments of patient functioning; most notably more negative affect was significantly related to more odd/eccentric (cluster A) and less anxious/fearful (cluster C) personality disorder symptoms, and greater narrative coherence. Differences in affective communication as a function of treatment type were also evaluated. The clinical and research implications of the findings are discussed. PMID- 22844182 TI - FUTURE LIFE GOALS OF HIV-POSITIVE GAY AND BISEXUAL MALE EMERGING ADULTS. PMID- 22844183 TI - Implementation Quality: Lessons Learned in the Context of the Head Start REDI Trial. AB - This study uses data collected in the intervention classrooms (N = 22) of Head Start REDI (Research-based, Developmentally Informed), a randomized clinical trial testing the efficacy of a comprehensive preschool curriculum targeting children's social-emotional competence, language, and emergent literacy skills delivered by teachers who received weekly coaching support. Multiple dimensions of implementation (Dosage, Fidelity, Generalization, and Child Engagement) were assessed across curriculum components. Results indicated that REDI Trainers perceived significant growth in teacher implementation quality over time but that patterns differed by implementation dimension. Dosage and Fidelity of all intervention components were high at the beginning of the year and remained so over time while Generalization was low at baseline but increased significantly across the year. Variation in implementation was associated with variation on several child outcome measures in the social-emotional domain but not in the language and literacy domains. PMID- 22844184 TI - Direct Synthesis of Anatase Films with ~100% (001) Facets and [001] Preferred Orientation. AB - Anatase films exhibiting ~100% (001) reactive facets at the surface were grown hydrothermally on gold substrate from a homogeneous solution of TiF(4) and NaF. In addition to NaF, it was found that TiO(2) films with very similar properties could be prepared with the fluoride salts LiF, CsF, HF, NH(4)F, and N(CH(2)CH(3))(4)F. The polycrystalline anatase films are continuous, approximately 1 MUm thick, and evenly coat the substrate. The surface grain size is ~400 nm. Grazing angle XRD measurements show that the films exhibit a high degree of preferred orientation with the c-axis normal to the substrate surface. SEM images reveal that the grains span the thickness of the films. Annealing the films at 500 degrees C removes fluorine and causes crystallites within the grains to restructure as shown by SEM, XRD, and Raman spectroscopy. Supported anatase films grown from this one-pot method may serve as oxidative photocatalysts and electrodes for photoelectrochemical applications such as solar cells and hydrogen evolution. PMID- 22844185 TI - Sharing and Integration of Cognitive Neuroscience Data: Metric and Pattern Matching across Heterogeneous ERP Datasets. AB - In the present paper, we use data mining methods to address two challenges in the sharing and integration of data from electrophysiological (ERP) studies of human brain function. The first challenge, ERP metric matching, is to identify correspondences among distinct summary features ("metrics") in ERP datasets from different research labs. The second challenge, ERP pattern matching, is to align the ERP patterns or "components" in these datasets. We address both challenges within a unified framework. The utility of this framework is illustrated in a series of experiments using ERP datasets that are designed to simulate heterogeneities from three sources: (a) different groups of subjects with distinct simulated patterns of brain activity, (b) different measurement methods, i.e, alternative spatial and temporal metrics, and (c) different patterns, reflecting the use of alternative pattern analysis techniques. Unlike real ERP data, the simulated data are derived from known source patterns, providing a gold standard for evaluation of the proposed matching methods. Using this approach, we demonstrate that the proposed method outperforms well-known existing methods, because it utilizes cluster-based structure and thus achieves finer-grained representation of the multidimensional (spatial and temporal) attributes of ERP data. PMID- 22844186 TI - Recollections of Childhood Religious Identity and Behavior as a Function of Adult Religiousness. AB - People have a strong motivation to maintain a self-concept that is coherent and consistent over time. Religion is an central source of social identity for many people, but its importance is prone to dramatic change across the life course. To maintain a consistent perception of self, recollections of one's own past religiousness may shift to better fit with the present. This study examined changes between early and middle adulthood in retrospective perceptions of religious behavior and identity in childhood. Data from a population-based birth cohort sample were matched with data from individuals who participated in at least two of three adult follow-up studies, at intervals of approximately 10 years. Logistic regression was used to analyze the association of final recollections of childhood behavior and identity with previous recollections and current religious characteristics. Consistent with the predictions of temporal self-appraisal theory, participants' perception of their religious identity as children tended to change over time to match their adult religious identity. Recollections of childhood religious behavior were more stable than recollections of religious identity, and change was unrelated to adult behavior. These results have implications for studying religious characteristics using retrospective measures, regarding their accuracy and their independence from contemporary measures. PMID- 22844187 TI - Longitudinal Associations between Parental and Children's Depressive Symptoms in the Context of Interparental Relationship Functioning. AB - Using longitudinal, multi-informant data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, the present study tested associations between trajectories of parental and child depressive symptoms from ages 11 to 15 years. Consistent with predictions, changes in mothers' and fathers' depressive symptoms were positively associated with change in children's depressive symptoms over time. In addition, youth characteristics of sex and pubertal development moderated the trajectories, with children more advanced on pubertal development showing higher initial levels of depressive symptoms, and girls demonstrating steeper slopes of depressive symptoms over time. The context of interparental relationship functioning (i.e., marital conflict, marital conflict resolution) moderated both the trajectories of child depressive symptoms and the interplay between parental and child depressive symptoms in ways largely consistent with hypotheses. Implications of the findings are discussed in terms of treating youth depressive symptoms with a consideration of the broader family context, including parental and interparental functioning. PMID- 22844188 TI - Therapist Focus on Parent Involvement in Community-Based Youth Psychotherapy. AB - Parent involvement in the treatment of childhood disruptive behavior problems is a critical component of effective care. Yet little is known about the amount of time therapists are involving parents in treatment and factors that predict therapists' efforts to involve parents in routine care. The purpose of this study is to examine therapists' within-session involvement of parents in community based outpatient mental health treatment. The data are from a larger longitudinal observational study of psychotherapy for children ages 4-13 with disruptive behavior problems and include videotaped psychotherapy sessions coded for the therapeutic strategies delivered as well as measures of child, parent/family, and therapist characteristics at baseline. Parent involvement is defined as the proportion of time in the session that therapists direct treatment strategies towards parents. Results indicated that therapists directed treatment strategies towards parents an average of 44% of the time within a session. Multilevel modeling was used to examine client-level (child, parent, and family functioning) and provider-level (therapist experience and background) predictors of parent involvement. Therapists involved parents more when the child had higher levels of behavior problems, when the parent reported higher levels of internalized caregiver strain, and when the therapist was more experienced. The results highlight potential areas to target in efforts to increase parent involvement, including training less experienced therapists to increase their focus on directing strategies towards parents. PMID- 22844189 TI - Fertility intentions and interest in integrated family planning services among women living with HIV in Nyanza Province, Kenya: a qualitative study. AB - Despite increasing efforts to address the reproductive health needs of people living with HIV, a high unmet need for contraception exists among HIV+ women in sub-Saharan Africa. This study explores the fertility intentions and family planning (FP) preferences of Kenyan women accessing HIV treatment. We conducted 30 semistructured interviews and qualitatively analyzed the data with a grounded theory approach. Fears of premature death, financial hardship, and perinatal HIV transmission emerged as reasons for participants' desire to delay/cease childbearing. Participants strongly identified FP needs, yet two-thirds were using male condoms alone or no modern method of contraception. Women preferred the HIV clinic as the site of FP access for reasons of convenience, provider expertise, and a sense of belonging, though some had privacy concerns. Our findings support the acceptability of integrated FP and HIV services. Efforts to empower women living with HIV to prevent unintended pregnancies must expand access to contraceptive methods, provide confidential services, and take into account women's varied reproductive intentions. PMID- 22844190 TI - Taking Effective Treatments to Scale: Organizational Effects on Outcomes of Multisystemic Therapy for Youth with Co-occurring Substance Use. AB - A prospective multi-site study examined organizational climate and structure effects on the behavior and functioning of delinquent youth with and without co occurring substance treated with an evidence-based treatment for serious antisocial behavior (i.e., Multisystemic Therapy). Participants were 1979 youth treated by 429 therapists across 45 provider organizations in North America. Results of Mixed Effects Regression Models showed some aspects of climate and structure had no effects, some had similar effects, and some had slightly differential and sometimes counter-intuitive effects on the outcomes of these youth. Implications are considered for research to increase the array and availability of effective treatments for youth with co-occurring substance use across service sectors. PMID- 22844191 TI - Successful treatment of early-stage jejunum adenocarcinoma by endoscopic mucosal resection using double-balloon endoscopy: a case report. AB - Small bowel adenocarcinoma (SBA) has generally been considered to have a poor prognosis because of nonspecific presentations and difficulties in detection of the disease. The advent of capsule endoscopy (CE) and double-balloon endoscopy (DBE) makes it possible to access to the small intestine for endoscopic interventions. We describe a successful case of early jejunum adenocarcinoma completely resected by endoscopic mucosal resection (EMR) using double-balloon endoscopy (DBE). Early diagnosis and EMR using new technologies such as CE and DBE may improve the recognition of this disease that, at present, has a poor prognosis. PMID- 22844192 TI - Preventive role of wire-guided cannulation to reduce hyperamylasemia and pancreatitis following endoscopic retrograde cholangiopancreatography. AB - Background and Study Aims. The usefulness of wire-guided cannulation for avoiding hyperamylasemia and pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) is conflicting, and therefore we designed this study to determine whether wire-guided cannulation reduces the rate of post-ERCP hyperamylasemia and pancreatitis and compare its efficacy to conventional method. Patients and Methods. Seven hundred and forty-eight patients with hepatobiliary diseases consecutively underwent diagnostic or therapeutic ERCP at the unit of Taleghani referral hospital in Tehran. Among them, 546 patients were eligible for wire-guided cannulation and underwent this procedure and others underwent sphincterotome biliary cannulation using contrast injection as the conventional method. Results. Patients in the two groups were comparable in terms of gender and age. Successful biliary cannulation was achieved similary in the guidewire and conventional group (89.2% versus 86.4%) that in 5.4% and 14.1% of them it was difficultly performed, respectively (P = 0.003). The main pancreatic duct was more visualized in 99.0% of patients in conventional group in comparison with 79.0% in another group (P < 0.001). Multivariate regression analysis showed that wire-guided cannulation had a protective role for post-ERCP hyperamylasemia (OR: 0.336, 95% CI: 0.181-0.623, P < 0.001). However, there were no significant differences between the two groups in rates of other procedure-related complications, such as, pancreatitis, bleeding, and perforation. Conclusion. The use of guidewire cannulation in comparison with conventional method can be accompanied with lower post-ERCP hyperamylasemia, and therefore selection of this cannulation technique especially in high-risk group is recommended. PMID- 22844193 TI - Phylogenomic and domain analysis of iterative polyketide synthases in Aspergillus species. AB - Aspergillus species are industrially and agriculturally important as fermentors and as producers of various secondary metabolites. Among them, fungal polyketides such as lovastatin and melanin are considered a gold mine for bioactive compounds. We used a phylogenomic approach to investigate the distribution of iterative polyketide synthases (PKS) in eight sequenced Aspergilli and classified over 250 fungal genes. Their genealogy by the conserved ketosynthase (KS) domain revealed three large groups of nonreducing PKS, one group inside bacterial PKS, and more than 9 small groups of reducing PKS. Polyphyly of nonribosomal peptide synthase (NRPS)-PKS genes raised questions regarding the recruitment of the elegant conjugation machinery. High rates of gene duplication and divergence were frequent. All data are accessible through our web database at http://metabolomics.jp/wiki/Category:PK. PMID- 22844195 TI - Reliable Phylogenetic Trees Building: A New Web Interface for FIGENIX. AB - The community needed a reliable and user friendly tool to quickly produce robust phylogenetic trees which are crucial in evolutionary studies and genomes' functional annotation. FIGENIX is software dedicated to this and was published in 2005. Several laboratories around the world use it in their research, but it was difficult to use for non-expert users, thus we developed a new graphical user interface for the benefit of all biologists. PMID- 22844194 TI - Determinants of exon-level evolutionary rates in Arabidopsis species. AB - What causes the variations in evolutionary rates is fundamental to molecular evolution. However, in plants, the causes of within-gene evolutionary rate variations remain underexplored. Here we use the principal component regression to examine the contributions of eleven exon features to the within-gene variations in nonsynonymous substitution rate (d(N)), synonymous substitution rate (d(S)), and the d(N)/d(S) ratio in Arabidopsis species. We demonstrate that exon features related to protein structural-functional constraints and mRNA splicing account for the largest proportions of within-gene variations in d(N)/d(S) and d(N). Meanwhile, for d(S), a combination of expression level, exon length, and structural-functional features explains the largest proportion of within-gene variances. Our results suggest that the determinants of within-gene variations differ from those of between-gene variations in evolutionary rates. Furthermore, the relative importance of different exon features also differs between plants and animals. Our study thus may shed a new light on the evolution of plant genes. PMID- 22844196 TI - Safety and efficacy of apixaban in the treatment of atrial fibrillation. AB - Atrial fibrillation is a common arrhythmia that increases the risk of stroke and systemic embolism. Warfarin is a highly effective treatment in reducing this risk, but a narrow therapeutic range, drug and food interactions, required monitoring, and bleeding limit its use. We review Apixaban, an oral inhibitor of Factor Xa, which has been shown in large randomized trials to have superior efficacy in stroke reduction without an excess in bleeding events when compared with aspirin in those deemed unsuitable to receive warfarin, and demonstrates superior efficacy in reducing stroke and systemic embolism in addition to a reduction in bleeding events when compared to warfarin. PMID- 22844197 TI - An unusual cause of biliary obstruction. AB - Portal biliary ductopathy (PBD) is a condition in which biliary and pancreatic ducts are extrinsically compressed by collateral branches of the portal venous system, which in turn have become dilated and varicosed due to portal hypertension. While the majority of patients with PBD are asymptomatic, a minority can present with symptoms of biliary obstruction and cholangitis with the potential of developing secondary chronic liver disease. This paper reports the case of a 29 year old male presenting with acute cholangitis, in whom PBD was diagnosed radiologically. A brief review of current literature regarding the diagnosis and management of this condition will also be presented. PMID- 22844198 TI - Transfundal uterine incision performed with prophylactic common iliac artery balloon occlusion for patient with placenta previa totalis. AB - A 37-year-old primigravida at 35 weeks of gestation presented with known anterior wall dominant placenta previa totalis and suspected placenta accreta was successfully treated with transfundal uterine (transverse) incision performed with prophylactic common iliac artery balloon occlusion. This new surgical approach could be an alternative procedure for avoiding excessive blood loss during caesarean delivery. PMID- 22844199 TI - Typical Spike-and-Wave Activity in Hypoxic-Ischemic Brain Injury and its Implications for Classifying Nonconvulsive Status Epilepticus. AB - INTRODUCTION: Typical spike-and-wave activity (TSWA) in the electroencephalogram (EEG) indicates idiopathic generalized epilepsy (IGE). IGE-related nonconvulsive status epilepticus (NCSE) is typically an absence status epilepticus (ASE). ASE and TSWA respond dramatically to benzodiazepines. Patients with no history of seizure/epilepsy may develop ASE "de novo" in the context of an acute brain disorder. However, we are aware of only one previous case of de novo ASE with TSWA in hypoxic-ischemic brain injury. CASE PRESENTATION: A 65-year-old man, with congestive heart failure and history of substance abuse, survived cardiorespiratory arrest after 18 minutes of cardiopulmonary resuscitation. Post resuscitation, the patient was in coma with intact brainstem function. Toxicology was positive for cocaine and marijuana. Eyelid myoclonus suggested NCSE, which was initially treated with lorazepam and fosphenytoin. EEG monitoring showed sustained TSWA confirming NCSE and demonstrating de novo ASE (the patient and his family never had seizure/epilepsy). The TSWA was resistant to lorazepam, levetiracetam, and low-dose midazolam; it was eliminated only with midazolam at a dose that resulted in burst-suppression (>=1.2 mg/kg/hour). CONCLUSION: This is an unusual case of TSWA and hypoxic-ischemic brain injury in a patient with no history of seizure/epilepsy. The TSWA was relatively resistant to benzodiazepines suggesting that cerebral hypoxia-ischemia spared the thalamocortical apparatus generating TSWA but impaired the cortical/thalamic inhibitory circuits where benzodiazepines act to suppress TSWA. Albeit rare, 'post-hypoxic' TSWA offers us some valuable insights for classifying and managing nonconvulsive status epilepticus. PMID- 22844200 TI - Dislodgment of VDD Lead Connected to DR Pacer and Managed by Mode Switch. AB - An 80-year-old patient having a dual chamber DR pacer connected to a VDD lead presented with chronic lead dislodgment with the atrial ring displaced into the right ventricle. There was no ventricular capture at maximal ventricular output, and given the clinical settings, the condition was managed with a conservative approach, the mode was switched to AAI ensuring a minimal adequate ventricular pacing backup in a non dependent patient. PMID- 22844201 TI - Left atrial myxoma mimicking mitral stenosis. AB - Cardiac myxoma is a benign (non-malignant) neoplasm that represents the most common primary tumour of the heart. We present the case of a 36 year old woman with background hypertension who presented with features of left ventricular failure and seizures, and was found during transthoracic echocardiography to have left atrial myxoma protruding through the mitral valve orifice. She subsequently had excision of the atrial myxoma. The usefulness of early transthoracic echocardiography in any patient presenting with features of heart failure even when the aetiology seems obvious cannot be over-emphasised. PMID- 22844202 TI - Immunotherapy for prostate cancer enters its golden age. AB - In the United States, prostate cancer is the most frequent malignancy in men and ranks second in terms of mortality. Although recurrent or metastatic disease can be managed initially with androgen ablation, most patients eventually develop castration-resistant disease within a number of years, for which conventional treatments (eg, chemotherapy) provide only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer, and this field is evolving rapidly. Encouragingly, the US Food and Drug Administration (FDA) has recently approved two novel immunotherapy agents for patients with advanced cancer: the antigen presenting cell-based product sipuleucel-T and the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab, based on improvements in overall survival in patients with castration-resistant prostate cancer and metastatic melanoma, respectively. Currently, a number of trials are investigating the role of various immunological approaches for the treatment of prostate cancer, many of them with early indications of success. As immunotherapy for prostate cancer enters its golden age, the challenge of the future will be to design rational combinations of immunotherapy agents with each other or with other standard prostate cancer treatments in an effort to improve patient outcomes further. PMID- 22844203 TI - Eye movement prediction and variability on natural video data sets. AB - We here study the predictability of eye movements when viewing high-resolution natural videos. We use three recently published gaze data sets that contain a wide range of footage, from scenes of almost still-life character to professionally made, fast-paced advertisements and movie trailers. Inter-subject gaze variability differs significantly between data sets, with variability being lowest for the professional movies. We then evaluate three state-of-the-art saliency models on these data sets. A model that is based on the invariants of the structure tensor and that combines very generic, sparse video representations with machine learning techniques outperforms the two reference models; performance is further improved for two data sets when the model is extended to a perceptually inspired colour space. Finally, a combined analysis of gaze variability and predictability shows that eye movements on the professionally made movies are the most coherent (due to implicit gaze-guidance strategies of the movie directors), yet the least predictable (presumably due to the frequent cuts). Our results highlight the need for standardized benchmarks to comparatively evaluate eye movement prediction algorithms. PMID- 22844204 TI - The central limit theorem under random truncation. AB - Under left truncation, data (X(i), Y(i)) are observed only when Y(i) <= X(i). Usually, the distribution function F of the X(i) is the target of interest. In this paper, we study linear functionals ? phi dF(n) of the nonparametric maximum likelihood estimator (MLE) of F, the Lynden-Bell estimator F(n). A useful representation of ? phi dF(n) is derived which yields asymptotic normality under optimal moment conditions on the score function phi. No continuity assumption on F is required. As a by-product, we obtain the distributional convergence of the Lynden-Bell empirical process on the whole real line. PMID- 22844205 TI - The phylogenetic Kantorovich-Rubinstein metric for environmental sequence samples. AB - It is now common to survey microbial communities by sequencing nucleic acid material extracted in bulk from a given environment. Comparative methods are needed that indicate the extent to which two communities differ given data sets of this type. UniFrac, which gives a somewhat ad hoc phylogenetics-based distance between two communities, is one of the most commonly used tools for these analyses. We provide a foundation for such methods by establishing that, if we equate a metagenomic sample with its empirical distribution on a reference phylogenetic tree, then the weighted UniFrac distance between two samples is just the classical Kantorovich-Rubinstein, or earth mover's, distance between the corresponding empirical distributions. We demonstrate that this Kantorovich Rubinstein distance and extensions incorporating uncertainty in the sample locations can be written as a readily computable integral over the tree, we develop L(p) Zolotarev-type generalizations of the metric, and we show how the p value of the resulting natural permutation test of the null hypothesis 'no difference between two communities' can be approximated by using a Gaussian process functional. We relate the L(2)-case to an analysis-of-variance type of decomposition, finding that the distribution of its associated Gaussian functional is that of a computable linear combination of independent [Formula: see text] random variables. PMID- 22844207 TI - The problems and challenges of the aging population of malaysia. PMID- 22844206 TI - Size-controlled aerosol synthesis of silver nanoparticles for plasmonic materials. AB - Aerosol techniques were used to synthesize spherical and monodisperse silver nanoparticles for plasmonic materials. The particles were generated with an evaporation-condensation technique followed by size selection and sintering with a differential mobility analyzer and a tube furnace, respectively. Finally, the nanoparticles were collected on a glass substrate with an electrostatic precipitator. The particle size distributions were measured with a scanning mobility particle sizer and verified with a transmission electron microscope. A spectrophotometer was used to measure the optical extinction spectra of the prepared samples, which contained particles with diameters of approximately 50, 90 and 130 nm. By controlling the particle size, the dipolar peak of the localized surface plasmon resonance was tuned between wavelengths of 398 and 448 nm. In addition, quadrupolar resonances were observed at shorter wavelengths as predicted by the simplified theoretical model used to characterize the measured spectra. PMID- 22844208 TI - Gestational diabetes mellitus. AB - Gestational Diabetes Mellitus (GDM) is the most common medical complication and metabolic disorder of pregnancy. This review provides an overview into the morbidity associated with GDM as well as the current methods of screening, diagnosis and management with the aim of early recognition and prevention of complications to both the mother and foetus. PMID- 22844209 TI - Easy way to learn standardization : direct and indirect methods. AB - In direct age-adjustment, a common age-structured population is used as standard. This population may actually exist (e.g., United States population, 1999) or may be fictitious (e.g., two populations may be combined to create a standard). In indirect age-adjustment, a common set of age-specific rates is applied to the populations whose rates are to be standardized. The simplest and most useful form of indirect adjustment is the standardized mortality ratio (SMR) (5). PMID- 22844210 TI - Absence of Apo B R3500Q Mutation among Kelantanese Malays with Hyperlipidaemia. AB - Familial defective apolipoprotein B-100 (FDB) is an autosomal dominant genetic disorder associated with hypercholesterolaemia and premature coronary heart disease. FDB is caused by mutations in and around the codon 3500 of the apolipoprotein B (apo B) gene. Apo B R3500Q mutation is the first apo B mutation known to be associated with FDB and it is the most frequently reported apo B mutation in several different populations. The objective of the present study was to determine the association of apo B R3500Q mutation with elevated plasma cholesterol concentration in Kelantanese population in which both hypercholesterolaemia and coronary heart disease are common. Sixty-two Malay subjects with hyperlipidaemia, attending the lipid clinic at Hospital Universiti Sains Malaysia, Kelantan, were selected for this study. The DNA samples were analysed for the presence of apo B R3500Q mutation by polymerase chain reaction based restriction fragment analysis method using mutagenic primers. This mutation was not detected in the subjects selected for this study. Apo B R3500Q mutation does not appear to be a common cause of hypercholesterolaemia in Kelantanese Malays. PMID- 22844211 TI - Helicobacter pylori related functional dyspepsia in a defined malaysian population. AB - The objective of the study was to determine the prevalence of H. pylori in functional dyspepsia among the three main races in Malaysia. Gastric antral biopsies from 233 (98 males, 135 females; age range: 17-75 years, mean age 39.5 years) patients attending the Universiti Kebangsaan Malaysia (UKM) gastroenterology clinic were assessed for the presence of H. pylori by culture and histology. About a third of the cases (79 of 233 (34%); 34 males, 45 females; mean age 42.6 yrs) were positive for H. pylori. The presence of H. pylori was always associated with antral gastritis. Malay patients were least likely to be positive for H. pylori (10 of 88 (11.4%); 5 males, 5 females; mean age 35.7 yrs) compared to the Chinese (43 of 95 (45%); 19 males; 24 females; mean age 40.2 yrs) and Indian patients (23 of 41 (56%); 10 males, 13 females; mean age 48.1 yrs). We found that H. pylori were most common among Chinese followed by Indians. However, the relative risk for the Indians was 8.58 and 6.29 for the Chinese compared to Malays. We conclude that the prevalence of H. pylori in patients with functional dyspepsia differs considerably with respect to ethnic groups. PMID- 22844212 TI - Clinical experience of medical students at university sains malaysia. AB - Experience of acute medical, surgical conditions, and clinical procedures of undergraduate students were assessed via a questionnaire survey during the final week of the 1993/1998 programme at the School of Medical Sciences, Univestiti Sains Malaysia. Individual performances were assessed by a scoring system. One hundred and twenty four students responded, (response rate 97%). More than 90% had seen myocardial infarction, cerebrovascular accident, pneumonia, respiratory distress, gastroenteritis, coma, and snake bite. Less than 33% had witnessed acute psychosis, diabetic ketoacidosis, acute hepatic failure, status epilepticus, near drowning, hypertensive encephalopathy, acute haemolysis or child abuse.Acute surgical/obstetrics cases, seen by >90% students, included fracture of long bones, head injury, acute abdominal pain, malpresentation and foetal distress. Less than 33% had observed epistaxis, sudden loss of vision, peritonitis or burns. Among operations only herniorrhaphy, Caesarian section, internal fixation of fracture and cataract extraction were seen by >80% students. The main deficits in clinical procedures are in rectal and vaginal examinations, urine collection and microscopic examinations. The performance of individual students, assessed by a scoring system, showed 15 students had unacceptably low scores (<149/230, 50%), 37 had good scores (>181.4/230, 70%) and 5 had superior scores (197.6/230, 80%). PMID- 22844213 TI - Comparison of the pattern of nosocomial infection between the neonatal intensive care units of hospitals kuala terengganu and universiti sains malaysia, kelantan. AB - Nosocomial infection is a common problem in the Neonatal Intensive Care Unit (NICU) and a knowledge of the pattern of nosocomial infection will contribute greatly to the intensification of infection control measures and the development of antibiotic policies in the NICU. This study aims to compare the incidence and clinical characteristics of neonates with nosocomial infection in NICU of both Kuala Terengganu Hospital (HKT) and Universiti Sains Malaysia Hospital (HUSM). Neonates who had both clinical signs of sepsis and positive blood cultures, 48 hours after admission to NICU, from 1(st) January to 31(st) December 1998, in both hospitals were retrospectively studied. Among neonates admitted to NICU, 30 (5.4%) in HKT and 65 (3.6%) in HUSM had nosocomial infection (p = 0.07). The mean duration of hospitalisation was shorter (HUSM 37 days, HKT 49 days; p = 0.02), and the number of neonates with predisposing factors for infection is higher (HUSM 100%, HKT 73.3%; p < 0.001) in HUSM compared with HKT. There were no differences in gestation, mean age of onset of infection and mortality between both hospitals. The most common organism isolated from the blood in HKT was Klebsiella pneumoniae (33.3%), and in HUSM Klebsiella aerogenes (24.6%). Half of Klebsiella pneumoniae isolates were resistant to cephalosporins and aminoglycosides in HKT and a similar number of Klebsiella aerogenes isolates were resistant to piperacillin and aminoglycosides in HUSM. In conclusion nosocomial infection is a common problem in both hospitals. Except for more frequent predisposing factors for infection in HUSM, and a longer duration of hospital stay among neonates in HKT, the clinical characteristics of neonates with nosocomial infection in both hospitals were similar. PMID- 22844214 TI - Random amplified polymorphic DNA analysis to differentiate strains of Vibrio vulnificus isolated from cockles and shrimps. AB - A random amplified polymorphic DNA (RAPD) fingerprinting method has been developed to differentiate Vibrio vulnificus strains isolated. Twenty-nine strains isolated from cockles and twenty-one strains isolated from shrimps were analyzed. A total of 10 primers were screened with Vibrio vulnificus strains to identify those capable of generating DNA polymorphisms and two primers were selected. Primer GEN 1-50-01 and GEN 1-50-08 produced polymorphisms in most strains tested, with the band sizes ranging from 10.0 to 0.25 kb pair. Dendrogram analysis showed that primer GEN 1-50-01 produced 10 clusters and 24 single strains at a 40% similarity, whereas primer GEN 1-50-08 produced 11 clusters and 20 single strains at a 40% similarity. This study revealed the potential use of PCR fingerprinting in epidemiological studies. PMID- 22844215 TI - Absorbed Dose to Water Determination Using IAEA, HPA, NACP, AAPM, NCRP and ICRU Protocols for 1.25 MeV Gamma Ray 6 MV and 10 MV X-Rays: An Intercomparison of Results when IAEA was taken as a Standard Protocol. AB - Absorbed dose to water was measured with ionisation chambers NE 2561 (#267), NE 2581 (#334), NE 2571 (#1028), using the IAEA standard water phantom. The ionisation chamber was inserted in the water phantom at a reference depth dependent on the type of the radiation quality used. Three radiation qualities were used namely 1.25 MeV gamma ray, 6 MV x-rays and 10 MV x-rays. The values of the absorbed dose to water were determined by the N(K)- and N(X)- based methods, i.e with the use of IAEA, HPA, NACP, AAPM, NCRP and ICRU protocols. The aim of this study was to make an intercomparison of the results, by taking the IAEA protocol as a standard. The largest deviation contributed by any of these protocols was recorded for each quality. It was found that AAPM, NCRP and ICRU protocols contributed 0.94% for 1.25 MeV gamma ray, NACP contributed 2.12% for the 6 MV x-rays, and NACP contributed 2.35% for 10 MV x-rays. Since the acceptable limit of deviation set by the IAEA for this absorbed dose work is +/- 3%, it is clear that the overall deviations obtained were all satisfactory. PMID- 22844216 TI - Split-Course Radiotherapy in Stage IV Head & Neck Cancer. AB - Short course hypo-fractionated radiotherapy is a standard regime for the palliation of stage IV head and neck cancers. However few patients respond favorably and require further radiotherapy in curative intent. We have used split course radiotherapy technique to find out this conversion rate from palliative to curative intent. This was a prospective study conducted from November 1998 to October 1999; twenty-six (26) patients with stage IV head & neck cancers were treated with a hypofractionated regime of radiotherapy. A tumor dose of 30 Gy in 10 fractions [time dose fraction (TDF) 62] over 2 weeks was delivered using a 6 MV linear accelerator. A conventional 2 field or 3 field technique was used. Patients were assessed for the regression of tumor on fifth day, tenth day of radiotherapy and 4 weeks after the completion of radiotherapy. Patients showing complete response and good partial response were allowed to receive further radiotherapy of 30 Gy in 15 fractions [TDF 49]. There were 21 males and 5 females in the study with a median age of 44 years (range 19-77 years). All patients completed the initial regime. Complete responses were observed among 14 patients (54%); partial response in 6 patients (23%), and no response was seen among 6 patients (23%). Sixteen patients (61%) were suitable for radical radiotherapy after phase-I course of the above schedule. Seventeen patients (65%) showed an improvement in the general well being with a better quality of life. One year actuarial survival was (76%), with a median survival time of 12 months. Split course technique is a useful radiotherapy treatment in stage IV head and neck cancers to distinguish between the subset of patients who would require curative treatment and who would not. PMID- 22844218 TI - Is pre-psychotic intervention of schizophrenia realistic ? PMID- 22844220 TI - Ear infection and hearing loss amongst headphone users. AB - The use of headphone has been thought to cause infection in the ear canal and contribute to hearing loss. In this study, we examined 136 Customer Service Representative from Celcom (Malaysia) Sdn. Bhd. who use headphone throughout their working hours. The purpose of this study was to determine the prevalence of ear canal infection and other related diseases of the ear, nose and throat. Their hearing thresholds were also determined using the Amplaid 309 Clinical Audiometer. We found no incidence of infection of the external ear canal amongst the subjects. There were 4 cases of chronic middle ear infection and 4 cases of impacted wax. Hearing impairment was found in 25 subjects (21.2%). However, there was no significant association between hearing loss and the exposure to sound from headphone usage because the high frequencies were not predominantly affected. There was also no association between hearing loss and duration of service. PMID- 22844219 TI - The importance of exercise as a therapeutic agent. AB - Adaptations in the structural and/or functional properties of cells, tissues and organ systems in the human body occurs when exposed to various stimuli. While there is unanimous agreement that regular physical activity is essential for optimal function of the human body, it is evident that extrinsic factors, such as diet, smoking, exercise habits, are reflected in the morbidity and mortality statistics of the population. Ageing is obligatorily associated with reduced maximal aerobic power and reduced muscle strength, i.e. with reduced physical fitness. As a consequence of diminished exercise tolerance, a large and increasing number of the aged population will be living below, at or just above 'threshold' of physical ability, needing only a minor illness to render them completely dependent. Physical training can readily produce a profound improvement of functions essential for physical fitness in old age. Adaptation to regular physical activity causes less disruption of the cells' internal environment and minimises fatigue which enhances performances and the economy of energy output during daily physical activity. Regular physical exercise reduces the risk of premature mortality in general, and of coronary heart disease, hypertension and diabetes mellitus. Physical activity also improves mental health and is important for health and optimal function of muscles, bones and joints. The most recent recommendations advice the people of all ages to include a minimum of 30 minutes of physical activity of moderate intensity, such as brisk walking, on most, if not all, days of the week. PMID- 22844221 TI - Preliminary screening of endophytic fungi from medicinal plants in malaysia for antimicrobial and antitumor activity. AB - The screening of antimicrobial activity against Gram-positive bacteria, Gram negative bacteria, yeast and fungi was carried out on isopropanol extracts prepared from 121 isolates of endophytic fungi isolated from medicinal plants in Malaysia. Sensitivity was found to vary among the microorganisms. Bacillus subtilis, Saccharomyces cerevisiae and Alternaria sp. were susceptible to extracts from three, two and two isolates of endophytic fungi, respectively. None were found effective against Salmonella typhimurium. Sixteen endophytic fungal isolates tested were also found to exhibit antitumor activity in the yeast cell based assay. PMID- 22844222 TI - Role of vitamin e on oxidative stress in smokers. AB - Cigarette smoke contains numerous oxygen free radicals that when inhaled, overwhelm antioxidant defenses and produce a condition of oxidative stress. This study investigated whether or not supplementation with vitamin E can affect the state of oxidative stress in healthy smokers. In this randomised double blind trial, 32 smokers received 200 mg of vitamin E or placebo daily for 8 weeks. All smokers in the vitamin E group completed the trial whilst only nine in the placebo group completed the trial. Plasma vitamin E concentrations increased significantly [P<0.02] in the vitamin E group. The release of malondialdehyde [MDA] from erythrocytes was not significantly different between the two groups at baseline and was clearly reduced [P<0.01] after 8 weeks of vitamin E supplementation. Vitamin E increased erythrocyte superoxide dismutase activity [P<0.02] and decreased gluthathione peroxidase activity [P<0.02]. No changes were detected in plasma MDA. We conclude that daily supplementation with 200 mg of vitamin E for 8 weeks improved the oxidative stress state in smokers. PMID- 22844223 TI - Wernicke's Encephalopthy Associated with Hyperemesis Gravidarum - A Case Report. AB - Two cases of Wernicke's encephalopathy due to hyperemesis gravidarum are described. The first patient presented with bilateral papilloedema, altered sensorium and the second with bilateral retinal haemorrhages, ophthalmoplegia and nystagmus. Both patients were diagnosed with Wernicke's encephalopathy on clinical ground since there were no laboratory facilities to measure red cell transketolase and thiamine pyrophosphate levels. This is a rare but treatable complication of hyperemesis gravidarum (HG) and due to lack of diagnostic tools, there is often diagnostic uncertainty, delay in commencing appropriate treatment, as well as irreversible damage to the upper brain stem and death. PMID- 22844224 TI - Oral myiasis : case report. AB - Myiasis occurs when living tissues of mammals are invaded by eggs or larvae of flies, mainly from the order of Diptera. Most of the previousty reported cases are in the tropics and they were usually associated with inadequate personal hygiene, sometimes with poor manual dexterity. This report describes two cases of oral myiasis in cerebral palsy patients in Seremban General Hospital, Malaysia. This article also discusses the therapeutic property of maggots and highlights the importance of oral health care in the special needs patients. PMID- 22844225 TI - Food Service Employee Alcohol Use, Hangovers and Norms During and After Work Hours. AB - AIMS: This paper presents analyses of norms and behavior concerning drinking before, during, and after work hours among U.S. bar-restaurant chain employees, with a focus on hangovers at work and their correlates. METHODS: A mixed method approach combined qualitative analysis of 64 face-to-face interviews held with randomly chosen service, managerial and kitchen staff and quantitative analyses (including multivariable linear regression and bivariate analyses) of data drawn from 1,286 completed telephone surveys (response rate 68%) with 18-29 year old employees. RESULTS: Relatively few survey respondents reported past-year drinking in the hour prior to work (5%) or during work hours (2.7%), but extensive drinking in non- work hours (85.5%), and 36.5% of respondents reported coming to work with a hangover at least once. Correlates of hangover at work were past year intoxication and holding positive norms for hangovers. These findings were elaborated by interview data describing heavy drinking after work at nearby bars, restaurants and employee homes. CONCLUSIONS: The findings illustrated that employee drinking during work hours was not normative. However, study results portrayed widely-shared norms for heavy drinking outside of work, with hangovers and related harms appearing as the primary work time repercussions of after-work alcohol consumption. PMID- 22844226 TI - Psychometric Evaluation of the Timeline Followback for Exercise among College Students. AB - OBJECTIVES: Two separate studies assessed the psychometric properties of a retrospective behavioral measure adapted for exercise called the Timeline Followback for Exercise (TLFB-E). Study one examined criterion, convergent, and predictive validity. Study two examined test-retest reliability. METHODS: Study one participants (N = 66) were college students 20.0 +/- 1.4yr. Validity of frequency, intensity, time, and type (FITT) of exercise as assessed on the TLFB-E was examined using Pearson r correlations with accelerometers, weekly exercise contracts between participants and researchers, question four of the College Alumni Questionnaire, and a health-related physical fitness battery. Study two participants were a different sample (N = 40) of college students 18.63 +/- 1.0yr. Pearson r correlations determined reliability of the TLFB-E for exercise frequency, intensity, and time between two interviews separated by one month. Kappa statistic determined reliability of the TLFB-E for type of exercise. RESULTS: The TLFB-E displayed evidence of criterion validity when compared to accelerometers (r = .35 to .39) and evidence of convergent validity when compared to weekly exercise contracts (r = .65 to .80) and question four of the College Alumni Questionnaire (r = .06 to .75). The TLFB-E displayed evidence of modest to adequate test-retest reliability (r = .79 to .97) for exercise frequency, intensity, and time and moderate Kappa (k = .49) for exercise type. CONCLUSIONS: The TLFB-E produces evidence of reliable and valid scores among college students and improves upon other self-report, retrospective questionnaires by enabling daily collection of exercise FITT over a specified time period. PMID- 22844227 TI - Lean breed Landrace pigs harbor fecal methanogens at higher diversity and density than obese breed Erhualian pigs. AB - The diversity of fecal methanogens of Erhualian (obese type) and Landrace (lean type) pigs was examined using separate 16S rRNA gene libraries for each breed. A total of 763 clones were analyzed; 381 from the Erhualian library and 382 from the Landrace library were identified belonging to the genus Methanobrevibacter. Others were identified belonging to the genus Methanosphaera. The two libraries showed significant differences in diversity (P < 0.05) and composition (P < 0.0001). Only two operational taxonomic units (OTUs) were found in both libraries, whereas six OTUs were found only in the Erhualian library and 23 OTUs were found only in the Landrace library. Real-time PCR showed that the abundance of fecal methanogens in Landrace pigs was significantly higher than that in Erhualian pigs (P < 0.05). Results showed that the Landrace pig (lean) harbored a greater diversity and higher numbers of methanogen mcrA gene copies than the Erhualian pig (obese). These differences may be related to the fatness or leanness in these two pig breeds. The results provide new leads for further investigations on the fat storage of pigs or even humans. PMID- 22844228 TI - Change in Parenting Democracy during the Transition to Adolescence: The Roles of Young Adolescents' Noncompliance and Mothers' Perceived Influence. AB - OBJECTIVE: This study assessed the direct relation between young adolescents' regulated noncompliance and mothers' democratic childrearing practices as well as the potential mediating role of mothers' perceived influence during the transition to adolescence. DESIGN: Three years of self-reported adolescent noncompliance, perceived influence, and parenting democracy were gathered from 166 mothers and their firstborn children (55% female), ages 9 - 11 years at time 1. RESULTS: Longitudinal path analysis indicated a total effect between adolescents' regulated noncompliance and higher maternal democracy. In addition, the total effect was mediated by mothers' perceived influence, such that adolescents' regulated noncompliance at time 1 was associated with greater perceptions of influence at time 2, which, in turn, was associated with greater maternal democracy at time 3. CONCLUSIONS: Mothers with young adolescents who resist in a relatively mature, regulated manner tend to have more positive perceptions of their influence on their emerging adolescents' behavior. In turn, mothers expecting to maintain their influence despite normative adolescent resistance are more likely to use democratic parenting strategies, granting their adolescents more input in decisions. PMID- 22844230 TI - Translational Control across Eukaryotes. PMID- 22844229 TI - Approach/Avoidance Orientations Affect Self-Construal and Identification with In group. AB - Approach and avoidance are two basic motivational orientations. Their activation influences cognitive and perceptive processes: Previous work suggests that an approach orientation instigates a focus on larger units as compared to avoidance. Study 1 confirms this assumption using a paradigm that more directly taps a person's tendency to represent objects as belonging to small or large units than prior studies. It was further predicted that the self should also be represented as belonging to larger units, and hence be more interdependent under approach than under avoidance. Study 2 supports this prediction. As a consequence of this focus on belonging to larger units, it was finally predicted that approach results in a stronger identification with one's in-group than avoidance. Studies 3 and 4 support that prediction. PMID- 22844231 TI - Perceptions on Point-of-Care Tests for Sexually Transmitted Infections - Comparison between Frontline Clinicians and Professionals in Industry. AB - OBJECTIVES: To determine if a gap exists between sexually transmitted infection (STI) clinicians and industry professionals regarding perceptions of the ideal types and characteristics of STI point-of-care tests (POCTs). METHODS: Our online survey design contained sections on demographics; barriers of use for available STI POCTs; characteristics of an ideal POCT, including prioritizing pathogens for targets; and "building your own POCT". Practicing clinicians and academic experts from two venues, STI-related international conference attendees and U.S. STD clinic clinicians, were invited to participate in the clinician survey. Professionals from industry in the STI diagnostic field were invited to participate in the industry survey. Chi-square test and conditional logistical regression were used for data analysis. RESULTS: Clinician survey participants (n=218) identified "the time frame required" (39.9%), "complexity" (31.2%), and "interruption of work flow" (30.3%) as the top three barriers making it difficult to use STI POCTs, while the industry survey participants (n=107) identified "complexity" (65.4%), "unreliability" (53.3%), and "difficulty in reading results" (34.6%) as the top three barriers (all p values <0.05). Sensitivity was always the most important attribute to be considered for a new STI POCT by both participant groups. Participants of the clinician group chose cost as the second priority attribute, while those of the industry group chose specificity as the second priority. CONCLUSION: We identified differences in the perceptions regarding barriers and ideal attributes for STI POCTs between frontline clinical providers and industry personnel. Tailored training is warranted to inform scientists, biomedical engineers, and other industry experts about characteristics that clinicians desire for STI POCTs. PMID- 22844232 TI - Cognitive-Behavioral Therapy for Immigrants Presenting With Social Anxiety Disorder: Two Case Studies. AB - Cognitive-behavioral therapy (CBT) for the treatment of Social Anxiety Disorder (SAD) has demonstrated efficacy in numerous randomized trials. However, few studies specifically examine the applicability of such treatment for ethnic minority clients. Thus, the purpose of this article is to present two case studies examining the utility of individualized CBT for SAD with two clients who immigrated to the United States, one from Central America and one from China, for whom English was not their primary language. Both clients demonstrated improvement on a semi-structured interview and self-report measures. Necessary adaptations were modest, suggesting that therapy could be conducted in a culturally sensitive manner without much deviation from the treatment protocol. Results are discussed in terms of adapting treatment to enhance acceptability for and better fitting the needs of ethnic minority clients and non-native speakers of English. Implications for treating ethnic minority clients, as well as the practice of culturally sensitive treatment, are discussed. PMID- 22844233 TI - YUP: A Molecular Simulation Program for Coarse-Grained and Multi-Scaled Models. AB - Coarse-grained models can be very different from all-atom models and are highly varied. Each class of model is assembled very differently and some models need customized versions of the standard molecular mechanics methods. The most flexible way to meet these diverse needs is to provide access to internal data structures and a programming language to manipulate these structures. We have created YUP, a general-purpose program for coarse-grained and multi-scaled models. YUP extends the Python programming language by adding new data types. We have then used the extended language to implement three classes of coarse-grained models. The coarse-grained RNA model type is an unusual non-linear polymer and the assembly was easily handled with a simple program. The molecular dynamics algorithm had to be extended for a coarse-grained DNA model so that it could detect a failure that is invisible to a standard implementation. A third model type took advantage of access to the force field to simulate the packing of DNA in viral capsid. We find that objects are easy to modify, extend and redeploy. Thus, new classes of coarse-grained models can be implemented easily. PMID- 22844234 TI - Conformational Analysis of Free and Bound Retinoic Acid. AB - The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty six all-trans-RA (ATRA) and forty-eight 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacuo. Their relative conformational energies were estimated utilizing the M06, M06-2x and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the re-refined RA conformers the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug target structural information for use in structure-based drug discovery applications. PMID- 22844235 TI - Which of our modeling predictions are robust? AB - In theoretical ecology it is well known that the steady state expressions of the variables in a food chain crucially depend on the parity of the length of the chain. This poses a major problem for modeling real food webs because it is difficult to establish their true number of trophic levels, with sometimes rare predators and often rampant pathogens. Similar problems arise in the modeling of chronic viral infections. We review examples where seemingly general interpretations strongly depend on the number of levels in a model, and on its specific equations. This Perspective aims to open the discussion on this problem. PMID- 22844236 TI - A quick guide to software licensing for the scientist-programmer. PMID- 22844237 TI - An integrated regulatory network reveals pervasive cross-regulation among transcription and splicing factors. AB - Traditionally the gene expression pathway has been regarded as being comprised of independent steps, from RNA transcription to protein translation. To date there is increasing evidence of coupling between the different processes of the pathway, specifically between transcription and splicing. To study the interplay between these processes we derived a transcription-splicing integrated network. The nodes of the network included experimentally verified human proteins belonging to three groups of regulators: transcription factors, splicing factors and kinases. The nodes were wired by instances of predicted transcriptional and alternative splicing regulation. Analysis of the network indicated a pervasive cross-regulation among the nodes; specifically, splicing factors are significantly more connected by alternative splicing regulatory edges relative to the two other subgroups, while transcription factors are more extensively controlled by transcriptional regulation. Furthermore, we found that splicing factors are the most regulated of the three regulatory groups and are subject to extensive combinatorial control by alternative splicing and transcriptional regulation. Consistent with the network results, our bioinformatics analyses showed that the subgroup of kinases have the highest density of predicted phosphorylation sites. Overall, our systematic study reveals that an organizing principle in the logic of integrated networks favor the regulation of regulatory proteins by the specific regulation they conduct. Based on these results, we propose a new regulatory paradigm postulating that gene expression regulation of the master regulators in the cell is predominantly achieved by cross-regulation. PMID- 22844238 TI - Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse. AB - A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22+/-0.07 uM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(infinity)) required to produce physiological effects has been estimated to be 7.9+/-2.7 uM.min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(infinity). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse. PMID- 22844239 TI - Why SIT works: normal function despite typical myofiber pattern in Situs Inversus Totalis (SIT) hearts derived by shear-induced myofiber reorientation. AB - The left ventricle (LV) of mammals with Situs Solitus (SS, normal organ arrangement) displays hardly any interindividual variation in myofiber pattern and experimentally determined torsion. SS LV myofiber pattern has been suggested to result from adaptive myofiber reorientation, in turn leading to efficient pump and myofiber function. Limited data from the Situs Inversus Totalis (SIT, a complete mirror image of organ anatomy and position) LV demonstrated an essential different myofiber pattern, being normal at the apex but mirrored at the base. Considerable differences in torsion patterns in between human SIT LVs even suggest variation in myofiber pattern among SIT LVs themselves. We addressed whether different myofiber patterns in the SIT LV can be predicted by adaptive myofiber reorientation and whether they yield similar pump and myofiber function as in the SS LV. With a mathematical model of LV mechanics including shear induced myofiber reorientation, we predicted myofiber patterns of one SS and three different SIT LVs. Initial conditions for SIT were based on scarce information on the helix angle. The transverse angle was set to zero. During reorientation, a non-zero transverse angle developed, pump function increased, and myofiber function increased and became more homogeneous. Three continuous SIT structures emerged with a different location of transition between normal and mirrored myofiber orientation pattern. Predicted SIT torsion patterns matched experimentally determined ones. Pump and myofiber function in SIT and SS LVs are similar, despite essential differences in myocardial structure. SS and SIT LV structure and function may originate from same processes of adaptive myofiber reorientation. PMID- 22844240 TI - Genome-wide localization of protein-DNA binding and histone modification by a Bayesian change-point method with ChIP-seq data. AB - Next-generation sequencing (NGS) technologies have matured considerably since their introduction and a focus has been placed on developing sophisticated analytical tools to deal with the amassing volumes of data. Chromatin immunoprecipitation sequencing (ChIP-seq), a major application of NGS, is a widely adopted technique for examining protein-DNA interactions and is commonly used to investigate epigenetic signatures of diffuse histone marks. These datasets have notoriously high variance and subtle levels of enrichment across large expanses, making them exceedingly difficult to define. Windows-based, heuristic models and finite-state hidden Markov models (HMMs) have been used with some success in analyzing ChIP-seq data but with lingering limitations. To improve the ability to detect broad regions of enrichment, we developed a stochastic Bayesian Change-Point (BCP) method, which addresses some of these unresolved issues. BCP makes use of recent advances in infinite-state HMMs by obtaining explicit formulas for posterior means of read densities. These posterior means can be used to categorize the genome into enriched and unenriched segments, as is customarily done, or examined for more detailed relationships since the underlying subpeaks are preserved rather than simplified into a binary classification. BCP performs a near exhaustive search of all possible change points between different posterior means at high-resolution to minimize the subjectivity of window sizes and is computationally efficient, due to a speed-up algorithm and the explicit formulas it employs. In the absence of a well established "gold standard" for diffuse histone mark enrichment, we corroborated BCP's island detection accuracy and reproducibility using various forms of empirical evidence. We show that BCP is especially suited for analysis of diffuse histone ChIP-seq data but also effective in analyzing punctate transcription factor ChIP datasets, making it widely applicable for numerous experiment types. PMID- 22844241 TI - Digital epidemiology. AB - Mobile, social, real-time: the ongoing revolution in the way people communicate has given rise to a new kind of epidemiology. Digital data sources, when harnessed appropriately, can provide local and timely information about disease and health dynamics in populations around the world. The rapid, unprecedented increase in the availability of relevant data from various digital sources creates considerable technical and computational challenges. PMID- 22844242 TI - Finding a needle in a haystack: the role of electrostatics in target lipid recognition by PH domains. AB - Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3). The interaction of GRP1-PH with PI(3,4,5)P3 in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic 'decoy' lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)P3-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as 'decoys', disrupting the interaction of GRP1-PH with the PI(3,4,5)P3 molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)P3 within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)P3, forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation. PMID- 22844243 TI - Histone H2A mono-ubiquitination is a crucial step to mediate PRC1-dependent repression of developmental genes to maintain ES cell identity. AB - Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3), respectively. Compared to H3K27me3, localization and the role of H2AK119u1 are not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1 dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1 dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation. PMID- 22844244 TI - Intact p53-dependent responses in miR-34-deficient mice. AB - MicroRNAs belonging to the miR-34 family have been proposed as critical modulators of the p53 pathway and potential tumor suppressors in human cancers. To formally test these hypotheses, we have generated mice carrying targeted deletion of all three members of this microRNA family. We show that complete inactivation of miR-34 function is compatible with normal development in mice. Surprisingly, p53 function appears to be intact in miR-34-deficient cells and tissues. Although loss of miR-34 expression leads to a slight increase in cellular proliferation in vitro, it does not impair p53-induced cell cycle arrest or apoptosis. Furthermore, in contrast to p53-deficient mice, miR-34-deficient animals do not display increased susceptibility to spontaneous, irradiation induced, or c-Myc-initiated tumorigenesis. We also show that expression of members of the miR-34 family is particularly high in the testes, lungs, and brains of mice and that it is largely p53-independent in these tissues. These findings indicate that miR-34 plays a redundant function in the p53 pathway and suggest additional p53-independent functions for this family of miRNAs. PMID- 22844245 TI - The Arabidopsis HEI10 is a new ZMM protein related to Zip3. AB - In numerous species, the formation of meiotic crossovers is largely under the control of a group of proteins known as ZMM. Here, we identified a new ZMM protein, HEI10, a RING finger-containing protein that is well conserved among species. We show that HEI10 is structurally and functionally related to the yeast Zip3 ZMM and that it is absolutely required for class I crossover (CO) formation in Arabidopsis thaliana. Furthermore, we show that it is present as numerous foci on the chromosome axes and the synaptonemal complex central element until pachytene. Then, from pachytene to diakinesis, HEI10 is retained at a limited number of sites that correspond to class I COs, where it co-localises with MLH1. Assuming that HEI10 early staining represents an early selection of recombination intermediates to be channelled into the ZMM pathway, HEI10 would therefore draw a continuity between early chosen recombination intermediates and final class I COs. PMID- 22844246 TI - Large-scale introgression shapes the evolution of the mating-type chromosomes of the filamentous ascomycete Neurospora tetrasperma. AB - The significance of introgression as an evolutionary force shaping natural populations is well established, especially in animal and plant systems. However, the abundance and size of introgression tracts, and to what degree interspecific gene flow is the result of adaptive processes, are largely unknown. In this study, we present medium coverage genomic data from species of the filamentous ascomycete Neurospora, and we use comparative genomics to investigate the introgression landscape at the genomic level in this model genus. We revealed one large introgression tract in each of the three investigated phylogenetic lineages of Neurospora tetrasperma (sizes of 5.6 Mbp, 5.2 Mbp, and 4.1 Mbp, respectively). The tract is located on the chromosome containing the locus conferring sexual identity, the mating-type (mat) chromosome. The region of introgression is confined to the region of suppressed recombination and is found on one of the two mat chromosomes (mat a). We used Bayesian concordance analyses to exclude incomplete lineage sorting as the cause for the observed pattern, and multilocus genealogies from additional species of Neurospora show that the introgression likely originates from two closely related, freely recombining, heterothallic species (N. hispaniola and N. crassa/N. perkinsii). Finally, we investigated patterns of molecular evolution of the mat chromosome in Neurospora, and we show that introgression is correlated with reduced level of molecular degeneration, consistent with a shorter time of recombination suppression. The chromosome specific (mat) and allele specific (mat a) introgression reported herein comprise the largest introgression tracts reported to date from natural populations. Furthermore, our data contradicts theoretical predictions that introgression should be less likely on sex-determining chromosomes. Taken together, the data presented herein advance our general understanding of introgression as a force shaping eukaryotic genomes. PMID- 22844247 TI - Let-7b/c enhance the stability of a tissue-specific mRNA during mammalian organogenesis as part of a feedback loop involving KSRP. AB - Gene silencing mediated by either microRNAs (miRNAs) or Adenylate/uridylate-rich elements Mediated mRNA Degradation (AMD) is a powerful way to post transcriptionally modulate gene expression. We and others have reported that the RNA-binding protein KSRP favors the biogenesis of select miRNAs (including let-7 family) and activates AMD promoting the decay of inherently labile mRNAs. Different layers of interplay between miRNA- and AMD-mediated gene silencing have been proposed in cultured cells, but the relationship between the two pathways in living organisms is still elusive. We conditionally deleted Dicer in mouse pituitary from embryonic day (E) 9.5 through Cre-mediated recombination. In situ hybridization, immunohistochemistry, and quantitative reverse transcriptase-PCR revealed that Dicer is essential for pituitary morphogenesis and correct expression of hormones. Strikingly, alphaGSU (alpha glycoprotein subunit, common to three pituitary hormones) was absent in Dicer-deleted pituitaries. alphaGSU mRNA is unstable and its half-life increases during pituitary development. A transcriptome-wide analysis of microdissected E12.5 pituitaries revealed a significant increment of KSRP expression in conditional Dicer-deleted mice. We found that KSRP directly binds to alphaGSU mRNA, promoting its rapid decay; and, during pituitary development, alphaGSU expression displays an inverse temporal relationship to KSRP. Further, let-7b/c downregulated KSRP expression, promoting the degradation of its mRNA by directly binding to the 3'UTR. Therefore, we propose a model in which let-7b/c and KSRP operate within a negative feedback loop. Starting from E12.5, KSRP induces the maturation of let-7b/c that, in turn, post-transcriptionally downregulates the expression of KSRP itself. This event leads to stabilization of alphaGSU mRNA, which ultimately enhances the steady state expression levels. We have identified a post-transcriptional regulatory network active during mouse pituitary development in which the expression of the hormone alphaGSU is increased by let7b/c through downregulation of KSRP. Our study unveils a functional crosstalk between miRNA- and AMD-dependent gene regulation during mammalian organogenesis events. PMID- 22844248 TI - Lipoproteins in Drosophila melanogaster--assembly, function, and influence on tissue lipid composition. AB - Interorgan lipid transport occurs via lipoproteins, and altered lipoprotein levels correlate with metabolic disease. However, precisely how lipoproteins affect tissue lipid composition has not been comprehensively analyzed. Here, we identify the major lipoproteins of Drosophila melanogaster and use genetics and mass spectrometry to study their assembly, interorgan trafficking, and influence on tissue lipids. The apoB-family lipoprotein Lipophorin (Lpp) is the major hemolymph lipid carrier. It is produced as a phospholipid-rich particle by the fat body, and its secretion requires Microsomal Triglyceride Transfer Protein (MTP). Lpp acquires sterols and most diacylglycerol (DAG) at the gut via Lipid Transfer Particle (LTP), another fat body-derived apoB-family lipoprotein. The gut, like the fat body, is a lipogenic organ, incorporating both de novo synthesized and dietary fatty acids into DAG for export. We identify distinct requirements for LTP and Lpp-dependent lipid mobilization in contributing to the neutral and polar lipid composition of the brain and wing imaginal disc. These studies define major routes of interorgan lipid transport in Drosophila and uncover surprising tissue-specific differences in lipoprotein lipid utilization. PMID- 22844249 TI - Identification of chromatin-associated regulators of MSL complex targeting in Drosophila dosage compensation. AB - Sex chromosome dosage compensation in Drosophila provides a model for understanding how chromatin organization can modulate coordinate gene regulation. Male Drosophila increase the transcript levels of genes on the single male X approximately two-fold to equal the gene expression in females, which have two X chromosomes. Dosage compensation is mediated by the Male-Specific Lethal (MSL) histone acetyltransferase complex. Five core components of the MSL complex were identified by genetic screens for genes that are specifically required for male viability and are dispensable for females. However, because dosage compensation must interface with the general transcriptional machinery, it is likely that identifying additional regulators that are not strictly male-specific will be key to understanding the process at a mechanistic level. Such regulators would not have been recovered from previous male-specific lethal screening strategies. Therefore, we have performed a cell culture-based, genome-wide RNAi screen to search for factors required for MSL targeting or function. Here we focus on the discovery of proteins that function to promote MSL complex recruitment to "chromatin entry sites," which are proposed to be the initial sites of MSL targeting. We find that components of the NSL (Non-specific lethal) complex, and a previously unstudied zinc-finger protein, facilitate MSL targeting and display a striking enrichment at MSL entry sites. Identification of these factors provides new insight into how MSL complex establishes the specialized hyperactive chromatin required for dosage compensation in Drosophila. PMID- 22844250 TI - The three faces of riboviral spontaneous mutation: spectrum, mode of genome replication, and mutation rate. AB - Riboviruses (RNA viruses without DNA replication intermediates) are the most abundant pathogens infecting animals and plants. Only a few riboviral infections can be controlled with antiviral drugs, mainly because of the rapid appearance of resistance mutations. Little reliable information is available concerning i) kinds and relative frequencies of mutations (the mutational spectrum), ii) mode of genome replication and mutation accumulation, and iii) rates of spontaneous mutation. To illuminate these issues, we developed a model in vivo system based on phage Qbeta infecting its natural host, Escherichia coli. The Qbeta RT gene encoding the Read-Through protein was used as a mutation reporter. To reduce uncertainties in mutation frequencies due to selection, the experimental Qbeta populations were established after a single cycle of infection and selection against RT(-) mutants during phage growth was ameliorated by plasmid-based RT complementation in trans. The dynamics of Qbeta genome replication were confirmed to reflect the linear process of iterative copying (the stamping-machine mode). A total of 32 RT mutants were detected among 7,517 Qbeta isolates. Sequencing analysis of 45 RT mutations revealed a spectrum dominated by 39 transitions, plus 4 transversions and 2 indels. A clear template*primer mismatch bias was observed: A*C>C*A>U*G>G*U> transversion mismatches. The average mutation rate per base replication was ~9.1*10(-6) for base substitutions and ~2.3*10(-7) for indels. The estimated mutation rate per genome replication, MU(g), was ~0.04 (or, per phage generation, ~0.08), although secondary RT mutations arose during the growth of some RT mutants at a rate about 7-fold higher, signaling the possible impact of transitory bouts of hypermutation. These results are contrasted with those previously reported for other riboviruses to depict the current state of the art in riboviral mutagenesis. PMID- 22844251 TI - Drosophila fatty acid transport protein regulates rhodopsin-1 metabolism and is required for photoreceptor neuron survival. AB - Tight regulation of the visual response is essential for photoreceptor function and survival. Visual response dysregulation often leads to photoreceptor cell degeneration, but the causes of such cell death are not well understood. In this study, we investigated a fatty acid transport protein (fatp) null mutation that caused adult-onset and progressive photoreceptor cell death. Consistent with fatp having a role in the retina, we showed that fatp is expressed in adult photoreceptors and accessory cells and that its re-expression in photoreceptors rescued photoreceptor viability in fatp mutants. The visual response in young fatp-mutant flies was abnormal with elevated electroretinogram amplitudes associated with high levels of Rhodopsin-1 (Rh1). Reducing Rh1 levels in rh1 mutants or depriving flies of vitamin A rescued photoreceptor cell death in fatp mutant flies. Our results indicate that fatp promotes photoreceptor survival by regulating Rh1 abundance. PMID- 22844252 TI - Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue. AB - The circadian regulatory network is organized in a hierarchical fashion, with a central oscillator in the suprachiasmatic nuclei (SCN) orchestrating circadian oscillations in peripheral tissues. The nature of the relationship between central and peripheral oscillators, however, is poorly understood. We used the tetOFF expression system to specifically restore Clock function in the brains of Clock(Delta19) mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whether brain-specific rescue of circadian rhythmicity was sufficient to restore circadian transcriptional output in the liver. Compared to Clock mutants, Clock rescue mice showed significantly larger numbers of cycling transcripts with appropriate phase and period lengths, including many components of the core circadian oscillator. This indicates that the SCN oscillator overcomes local circadian defects and signals directly to the molecular clock. Interestingly, the vast majority of core clock genes in liver were responsive to Clock expression in the SCN, suggesting that core clock genes in peripheral tissues are intrinsically sensitive to SCN cues. Nevertheless, most circadian output in the liver was absent or severely low-amplitude in Clock-rescue animals, demonstrating that the majority of peripheral transcriptional rhythms depend on a fully functional local circadian oscillator. We identified several new system-driven rhythmic genes in the liver, including Alas1 and Mfsd2. Finally, we show that 12-hour transcriptional rhythms (i.e., circadian "harmonics") are disrupted by Clock loss of-function. Brain-specific rescue of Clock converted 12-hour rhythms into 24 hour rhythms, suggesting that signaling via the central circadian oscillator is required to generate one of the two daily peaks of expression. Based on these data, we conclude that 12-hour rhythms are driven by interactions between central and peripheral circadian oscillators. PMID- 22844253 TI - Recent loss of self-incompatibility by degradation of the male component in allotetraploid Arabidopsis kamchatica. AB - The evolutionary transition from outcrossing to self-fertilization (selfing) through the loss of self-incompatibility (SI) is one of the most prevalent events in flowering plants, and its genetic basis has been a major focus in evolutionary biology. In the Brassicaceae, the SI system consists of male and female specificity genes at the S-locus and of genes involved in the female downstream signaling pathway. During recent decades, much attention has been paid in particular to clarifying the genes responsible for the loss of SI. Here, we investigated the pattern of polymorphism and functionality of the female specificity gene, the S-locus receptor kinase (SRK), in allotetraploid Arabidopsis kamchatica. While its parental species, A. lyrata and A. halleri, are reported to be diploid and mainly self-incompatible, A. kamchatica is self compatible. We identified five highly diverged SRK haplogroups, found their disomic inheritance and, for the first time in a wild allotetraploid species, surveyed the geographic distribution of SRK at the two homeologous S-loci across the species range. We found intact full-length SRK sequences in many accessions. Through interspecific crosses with the self-incompatible and diploid congener A. halleri, we found that the female components of the SI system, including SRK and the female downstream signaling pathway, are still functional in these accessions. Given the tight linkage and very rare recombination of the male and female components on the S-locus, this result suggests that the degradation of male components was responsible for the loss of SI in A. kamchatica. Recent extensive studies in multiple Brassicaceae species demonstrate that the loss of SI is often derived from mutations in the male component in wild populations, in contrast to cultivated populations. This is consistent with theoretical predictions that mutations disabling male specificity are expected to be more strongly selected than mutations disabling female specificity, or the female downstream signaling pathway. PMID- 22844254 TI - Rapid turnover of long noncoding RNAs and the evolution of gene expression. AB - A large proportion of functional sequence within mammalian genomes falls outside protein-coding exons and can be transcribed into long RNAs. However, the roles in mammalian biology of long noncoding RNA (lncRNA) are not well understood. Few lncRNAs have experimentally determined roles, with some of these being lineage specific. Determining the extent by which transcription of lncRNA loci is retained or lost across multiple evolutionary lineages is essential if we are to understand their contribution to mammalian biology and to lineage-specific traits. Here, we experimentally investigated the conservation of lncRNA expression among closely related rodent species, allowing the evolution of DNA sequence to be uncoupled from evolution of transcript expression. We generated total RNA (RNAseq) and H3K4me3-bound (ChIPseq) DNA data, and combined both to construct catalogues of transcripts expressed in the adult liver of Mus musculus domesticus (C57BL/6J), Mus musculus castaneus, and Rattus norvegicus. We estimated the rate of transcriptional turnover of lncRNAs and investigated the effects of their lineage-specific birth or death. LncRNA transcription showed considerably greater gain and loss during rodent evolution, compared with protein coding genes. Nucleotide substitution rates were found to mirror the in vivo transcriptional conservation of intergenic lncRNAs between rodents: only the sequences of noncoding loci with conserved transcription were constrained. Finally, we found that lineage-specific intergenic lncRNAs appear to be associated with modestly elevated expression of genomically neighbouring protein coding genes. Our findings show that nearly half of intergenic lncRNA loci have been gained or lost since the last common ancestor of mouse and rat, and they predict that such rapid transcriptional turnover contributes to the evolution of tissue- and lineage-specific gene expression. PMID- 22844255 TI - The SCFDia2 ubiquitin E3 ligase ubiquitylates Sir4 and functions in transcriptional silencing. AB - In budding yeast, transcriptional silencing, which is important to regulate gene expression and maintain genome integrity, requires silent information regulator (Sir) proteins. In addition, Rtt106, a histone chaperone involved in nucleosome assembly, functions in transcriptional silencing. However, how transcriptional silencing is regulated during mitotic cell division is not well understood. We show that cells lacking Dia2, a component of the SCF(Dia2) E3 ubiquitin ligase involved in DNA replication, display defects in silencing at the telomere and HMR locus and that the F-box and C-terminal regions of Dia2, two regions important for Dia2's ubiquitylation activity, are required for proper transcriptional silencing at these loci. In addition, we show that Sir proteins are mislocalized in dia2Delta mutant cells. Mutations in Dia2 and Rtt106 result in a synergistic loss of silencing at the HMR locus and significant elevation of Sir4 proteins at the HMR locus, suggesting that silencing defects in dia2Delta mutant cells are due, at least in part, to the altered levels of Sir4 at silent chromatin. Supporting this idea, we show that SCF(Dia2) ubiquitylates Sir4 in vitro and in vivo. Furthermore, Sir4 binding to silent chromatin is dynamically regulated during the cell cycle, and this regulation is lost in dia2Delta mutant cells. These results demonstrate that the SCF(Dia2) complex is involved in transcriptional silencing, ubiquitylates Sir4, and regulates transcriptional silencing during the cell cycle. PMID- 22844256 TI - Oocyte family trees: old branches or new stems? PMID- 22844257 TI - F-box protein specificity for g1 cyclins is dictated by subcellular localization. AB - Levels of G1 cyclins fluctuate in response to environmental cues and couple mitotic signaling to cell cycle entry. The G1 cyclin Cln3 is a key regulator of cell size and cell cycle entry in budding yeast. Cln3 degradation is essential for proper cell cycle control; however, the mechanisms that control Cln3 degradation are largely unknown. Here we show that two SCF ubiquitin ligases, SCF(Cdc4) and SCF(Grr1), redundantly target Cln3 for degradation. While the F-box proteins (FBPs) Cdc4 and Grr1 were previously thought to target non-overlapping sets of substrates, we find that Cdc4 and Grr1 each bind to all 3 G1 cyclins in cell extracts, yet only Cln3 is redundantly targeted in vivo, due in part to its nuclear localization. The related cyclin Cln2 is cytoplasmic and exclusively targeted by Grr1. However, Cdc4 can interact with Cdk-phosphorylated Cln2 and target it for degradation when cytoplasmic Cdc4 localization is forced in vivo. These findings suggest that Cdc4 and Grr1 may share additional redundant targets and, consistent with this possibility, grr1Delta cdc4-1 cells demonstrate a CLN3 independent synergistic growth defect. Our findings demonstrate that structurally distinct FBPs are capable of interacting with some of the same substrates; however, in vivo specificity is achieved in part by subcellular localization. Additionally, the FBPs Cdc4 and Grr1 are partially redundant for proliferation and viability, likely sharing additional redundant substrates whose degradation is important for cell cycle progression. PMID- 22844258 TI - Genetic variants in REC8, RNF212, and PRDM9 influence male recombination in cattle. AB - We use >250,000 cross-over events identified in >10,000 bovine sperm cells to perform an extensive characterization of meiotic recombination in male cattle. We map Quantitative Trait Loci (QTL) influencing genome-wide recombination rate, genome-wide hotspot usage, and locus-specific recombination rate. We fine-map three QTL and present strong evidence that genetic variants in REC8 and RNF212 influence genome-wide recombination rate, while genetic variants in PRDM9 influence genome-wide hotspot usage. PMID- 22844259 TI - The yeast Rab GTPase Ypt1 modulates unfolded protein response dynamics by regulating the stability of HAC1 RNA. AB - The unfolded protein response (UPR) is a conserved mechanism that mitigates accumulation of unfolded proteins in the ER. The yeast UPR is subject to intricate post-transcriptional regulation, involving recruitment of the RNA encoding the Hac1 transcription factor to the ER and its unconventional splicing. To investigate the mechanisms underlying regulation of the UPR, we screened the yeast proteome for proteins that specifically interact with HAC1 RNA. Protein microarray experiments revealed that HAC1 interacts specifically with small ras GTPases of the Ypt family. We characterized the interaction of HAC1 RNA with one of these proteins, the yeast Rab1 homolog Ypt1. We found that Ypt1 protein specifically associated in vivo with unspliced HAC1 RNA. This association was disrupted by conditions that impaired protein folding in the ER and induced the UPR. Also, the Ypt1-HAC1 interaction depended on IRE1 and ADA5, the two genes critical for UPR activation. Decreasing expression of the Ypt1 protein resulted in a reduced rate of HAC1 RNA decay, leading to significantly increased levels of both unspliced and spliced HAC1 RNA, and delayed attenuation of the UPR, when ER stress was relieved. Our findings establish that Ypt1 contributes to regulation of UPR signaling dynamics by promoting the decay of HAC1 RNA, suggesting a potential regulatory mechanism for linking vesicle trafficking to the UPR and ER homeostasis. PMID- 22844261 TI - The Turn the Tables Technique (T(3)): A Program Activity to Provide Group Facilitators Insight into Teen Sexual Behaviors and Beliefs. AB - The Turn the Tables Technique (T(3)) is an activity designed to provide group facilitators who lead HIV/STI prevention and sexual health promotion programs with detailed and current information on teenagers' sexual behaviors and beliefs. This information can be used throughout a program to tailor content. Included is a detailed lesson plan of T(3), a description of the purpose of T(3), how it was implemented, the context in which it was used, how T(3) addressed common challenges in HIV prevention with teenagers, and future implications for its use. PMID- 22844260 TI - OSD1 promotes meiotic progression via APC/C inhibition and forms a regulatory network with TDM and CYCA1;2/TAM. AB - Cell cycle control is modified at meiosis compared to mitosis, because two divisions follow a single DNA replication event. Cyclin-dependent kinases (CDKs) promote progression through both meiosis and mitosis, and a central regulator of their activity is the APC/C (Anaphase Promoting Complex/Cyclosome) that is especially required for exit from mitosis. We have shown previously that OSD1 is involved in entry into both meiosis I and meiosis II in Arabidopsis thaliana; however, the molecular mechanism by which OSD1 controls these transitions has remained unclear. Here we show that OSD1 promotes meiotic progression through APC/C inhibition. Next, we explored the functional relationships between OSD1 and the genes known to control meiotic cell cycle transitions in Arabidopsis. Like osd1, cyca1;2/tam mutation leads to a premature exit from meiosis after the first division, while tdm mutants perform an aberrant third meiotic division after normal meiosis I and II. Remarkably, while tdm is epistatic to tam, osd1 is epistatic to tdm. We further show that the expression of a non-destructible CYCA1;2/TAM provokes, like tdm, the entry into a third meiotic division. Finally, we show that CYCA1;2/TAM forms an active complex with CDKA;1 that can phosphorylate OSD1 in vitro. We thus propose that a functional network composed of OSD1, CYCA1;2/TAM, and TDM controls three key steps of meiotic progression, in which OSD1 is a meiotic APC/C inhibitor. PMID- 22844262 TI - An industry perspective on the use of "atoxigenic" strains of Aspergillus flavus as biological control agents and the significance of cyclopiazonic acid. AB - Several nonaflatoxigenic strains of Aspergillus flavus have been registered in the United States to reduce aflatoxin accumulation in maize and other crops, but there may be unintended negative consequences if these strains produce cyclopiazonic acid (CPA). AF36, a nonaflatoxigenic, CPA-producing strain has been shown to produce CPA in treated maize and peanuts. Alternative strains, including Afla-Guard(r) brand biocontrol agent and K49, do not produce CPA and can reduce both aflatoxin and CPA in treated crops. Chronic toxicity of CPA has not been studied, and recent animal studies show significant harmful effects from short term exposure to CPA at low doses. Grower and industry confidence in this approach must be preserved through transparency. PMID- 22844264 TI - A Comparative Interaction between Copper Ions with Alzheimer's beta Amyloid Peptide and Human Serum Albumin. AB - The interaction of Cu(2+) with the first 16 residues of the Alzheimer's amyliod beta peptide, Abeta(1-16), and human serum albumin (HSA) were studied in vitro by isothermal titration calorimetry at pH 7.2 and 310 K in aqueous solution. The solvation parameters recovered from the extended solvation model indicate that HSA is involved in the transport of copper ion. Complexes between Abeta(1-16) and copper ions have been proposed to be an aberrant interaction in the development of Alzheimer's disease, where Cu(2+) is involved in Abeta(1-16) aggregation. The indexes of stability indicate that HSA removed Cu(2+) from Abeta(1-16), rapidly, decreased Cu-induced aggregation of Abeta(1-16), and reduced the toxicity of Abeta(1-16) + Cu(2+) significantly. PMID- 22844263 TI - On the discovery, biological effects, and use of Cisplatin and metallocenes in anticancer chemotherapy. AB - The purpose of this paper is to summarize mode of action of cisplatin on the tumor cells, a brief outlook on the metallocene compounds as antitumor drugs as well as the future tendencies for the use of the latter in anticancer chemotherapy. Molecular mechanisms of cisplatin interaction with DNA, DNA repair mechanisms, and cellular proteins are discussed. Molecular background of the sensitivity and resistance to cisplatin, as well as its influence on the efficacy of the antitumor immune response was evaluated. Furthermore, herein are summarized some metallocenes (titanocene, vanadocene, molybdocene, ferrocene, and zirconocene) with high antitumor activity. PMID- 22844265 TI - Clostridium difficile DNA polymerase IIIC: basis for activity of antibacterial compounds. AB - Based on the finding that aerobic Gram-positive antibacterials that inhibit DNA polymerase IIIC (pol IIIC) were potent inhibitors of the growth of anaerobic Clostridium difficile (CD) strains, we chose to clone and express the gene for pol IIIC from this organism. The properties of the recombinant enzyme are similar to those of related pol IIICs from Gram-positive aerobes, e.g. B. subtilis. Inhibitors of the CD enzyme also inhibited B. subtilis pol IIIC, and were competitive with respect to the cognate substrate 2'-deoxyguanosine 5' triphosphate (dGTP). Significantly, several of these inhibitors of the CD pol IIIC had potent activity against the growth of CD clinical isolates in culture. PMID- 22844266 TI - Multifunctionalized electrospun silk fibers promote axon regeneration in central nervous system. AB - The repair of central nerves remains a major challenge in regenerative neurobiology. Regenerative guides possessing critical features such as cell adhesion, physical guiding and topical stimulation are needed. To generate such a guide, silk protein materials are prepared using electrospinning. The silk is selected for this study due to its biocompatibility and ability to be electrospun for the formation of aligned biofunctional nanofibers. The addition of Brain Derived Neurotrophic Factor (BDNF), Ciliary Neurotrophic Factor (CNTF) or both to the electrospun fibers enable enhanced function without impact to the structure or the surface morphology. Only a small fraction of the loaded growth factors is released over time allowing the fibers to continue to provide these factors to the cells for extended periods of time. The entrapped factors remain active and available to the cells as rat retinal ganglion cells (RGCs) exhibit longer axonal growth when in contact with the biofunctionalized fibers. Compare to non functionalized fibers, the growth of neurites increased 2 fold on fibers containing BDNF, 2.5 fold with fibers containing CNTF and by almost 3-fold on fibers containing both factors. The results demonstrate the potential of aligned and functionalized electrospun silk fibers to promote nerve growth in the central nervous system, underlying the great potential of complex biomaterials in neuroregenerative strategies following axotomy and nerve crush traumas. PMID- 22844267 TI - Detecting optic disc on asians by multiscale gaussian filtering. AB - The optic disc (OD) is an important anatomical feature in retinal images, and its detection is vital for developing automated screening programs. Currently, there is no algorithm designed to automatically detect the OD in fundus images captured from Asians which are larger and have thicker vessels compared to Caucasians. In this paper, we propose such a method to complement current algorithms using two steps: OD vessel candidate detection and OD vessel candidate matching. The first step is achieved with multiscale Gaussian filtering, scale production, and double thresholding to initially extract the vessels' directional map of various thicknesses. The map is then thinned before another threshold is applied to remove pixels with low intensities. This result forms the OD vessel candidates. In the second step, a Vessels' Directional Matched Filter (VDMF) of various dimensions is applied to the candidates to be matched, and the pixel with the smallest difference designated the OD center. We tested the proposed method on a new database consisting of 402 images from a diabetic retinopathy (DR) screening programme consisting of Asians. The OD center was successfully detected with an accuracy of 99.25% (399/402). PMID- 22844268 TI - Early degenerative effects of diabetes mellitus on pancreas, liver, and kidney in rats: an immunohistochemical study. AB - Liver and kidney commonly affected by diabetes in chronic cases but pathogenetic mechanisms are not fully understood in early stages of the disease. The aim of this study was to investigate the immunohistochemical expression of caspase-3, cyclooxygenase (COX)-1 and-2, calcium sensing receptor (CSR), and hypoxia inducible factor-1alpha (HIF-1alpha) in pancreas, liver, and kidney in streptozotocin (STZ) induced DM. Study group (n = 6) were received streptozotocin (50 mg/kg) and control group (n = 6) physiologic saline. The blood glucose and ketonuria were measured, and necropsy was performed on them on third, fourth, and fifth days. Immunohistochemistry revealed that marked increase in caspase-3 reaction pancreas, liver, and kidney in the study group than control group. COX-1 slightly increased in these organs in study group compared to controls. Immunohistochemically COX-2 reaction was markedly positive in liver and kidney, but slightly increased in pancreas. The most increased reaction was observed in CRS and all organs were markedly positive. HIF-1alpha expression was also increased but the reaction was more severe in pancreas than liver and kidney. This study indicated that degeneration starts in organs in early stages of the disease and the most effective route for degeneration related to increase of calcium influx and hypoxia upon cells in DM. PMID- 22844269 TI - Inhibition of aldose reductase by Gentiana lutea extracts. AB - Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications. PMID- 22844270 TI - Pathophysiological insights into cardiovascular health in metabolic syndrome. PMID- 22844271 TI - Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high-fat diet. AB - Inflammation has been implicated in the hypothalamic leptin and insulin resistance resulting defective food intake during high fat diet period. To investigate hypothalamic inflammation in dietary induced obesity (DIO) and obesity resistant (DIO-R) rats, we established rat models of DIO and DIO-R by feeding high fat diet for 10 weeks. Then we switched half of DIO and DIO-R rats to chow food and the other half to high fat diet for the following 8 weeks to explore hypothalamic inflammation response to the low fat diet intervention. Body weight, caloric intake, HOMA-IR, as well as the mRNA expression of hypothalamic TLR4, NF-kappaB, TNF-alpha, IL-1beta, and IL-6 in DIO/HF rats were significantly increased compared to DIO-R/HF and CF rats, whereas IL-10 mRNA expression was lower in both DIO/HF and DIO-R/HF rats compared with CF rats. Switching to chow food from high fat diet reduced the body weight and improved insulin sensitivity but not affecting the expressions of studied inflammatory genes in DIO rats. Take together, upregulated hypothalamic inflammation may contribute to the overeating and development of obesity susceptibility induced by high fat diet. Switching to chow food had limited role in correcting hypothalamic inflammation in DIO rats during the intervention period. PMID- 22844272 TI - Depression and Anxiety Disorders among Patients with Psoriasis: A Hospital-Based Case-Control Study. AB - Background. Psoriasis is a common, genetically determined inflammatory and proliferative disease of the skin. Psychological stress can exacerbate the disease. This study sought to investigate the depression and anxiety disorders among patients with psoriasis and control group. Method. In this hospital-based case-control study, One hundred patients with psoriasis (case) referred to the dermatology department and 100 patients with otolaryngology problems and dermatological healthy volunteers (control) who referred to the Otolaryngology Department of Bouali Sina Hospital in Sari, Iran, in 2007 were studied. Demographic characteristics were recorded. Beck Depression Inventory and Spielberger State-Trait Anxiety Scale I-II were administered to the patients in both groups. Data were analyzed using SPSS statistical software and descriptive statistical tests. Results. From One-hundred patients in each group, 44 (45%) were men. Depression score was 67% and 12% in psoriatic patients and control, respectively. The Beck depression scores of patients with psoriasis were significantly higher than scores of the control group (P < 0.05). Based on Spielberger State-Trait Anxiety Scale, anxiety was found in 45% of patients in case group and 18% of controls. Conclusion. The results revealed that psoriatic patients reported significantly higher degrees of depression and anxiety than controls. In addition, psoriatic women were more depressed than psoriatic men. PMID- 22844273 TI - Ki-67 Antigen Overexpression Is Associated with the Metaplasia-Adenocarcinoma Sequence in Barrett's Esophagus. AB - Introduction. The objective of this study was to evaluate Ki-67 antigen expression in patients with Barrett's esophagus and esophageal adenocarcinoma and to assess its correlation with the metaplasia-esophageal adenocarcinoma progression. Methods. Using immunohistochemistry we evaluated the Ki-67 index in patients with Barrett's esophagus, esophageal adenocarcinoma, and controls. We included patients with endoscopically visible columnar mucosa of the distal esophagus (whose biopsies revealed specialized intestinal-type metaplasia), patients with esophageal and esophagogastric tumors types I and II, and patients with histologically normal gastric mucosa (control). Results. In the 57 patients studied there were no statistically significant differences between the groups with respect to age or race. Patients with cancer were predominantly men. The Ki 67 index averaged 10 +/- 4 % in patients with normal gastric mucosa (n = 17), 21 +/- 15 % in patients with Barrett's esophagus (n = 21), and 38 +/- 16 % in patients with cancer (n = 19). Ki-67 expression was significantly different between all groups (P < 0.05). There was a strong linear correlation between Ki 67 expression and the metaplasia-adenocarcinoma sequence (P < 0.01). In patients with cancer, Ki-67 was not associated with clinical or surgical staging. Conclusions. Ki-67 antigen has increased expression along the metaplasia adenocarcinoma sequence. There is a strong linear correlation between Ki-67 proliferative activity and Barrett's carcinogenesis. PMID- 22844275 TI - Pulmonary metastasis from pseudomyxoma peritonei. AB - Pseudomyxoma peritonei (PMP) is a rare clinical condition, where copious mucinous ascites accumulate in the peritoneal cavity due to dissemination of mucin producing tumor. Because of this disseminating, yet nonmetastasizing, behavior, PMP attracts much interest from surgical oncologists in that aggressive locoregional therapy can give the opportunity of long survival and even cure. Although extra-abdominal metastasis is exceptionally rare, the lung is the most likely site in such a case. In this paper, the clinical findings and treatment of eleven cases with pulmonary metastasis from PMP were reviewed, including ten cases in the literature and one case which we experienced. The clinical features of PMP cases with pulmonary metastasis were similar to cases without pulmonary metastasis. The histological type was low-grade mucinous neoplasm in most cases. Pulmonary lesions were resected in seven cases in which abdominal lesions were controlled by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy or another therapeutic modality. Disease-free state was maintained in five cases at the end of the follow-up period. However, it should be noted that rapid progression after resection was seen in two cases, suggesting that biological features may have changed by surgical intervention. PMID- 22844274 TI - Comparison of Tissue Architectural Changes between Radiofrequency Ablation and Cryospray Ablation in Barrett's Esophagus Using Endoscopic Three-Dimensional Optical Coherence Tomography. AB - Two main nonsurgical endoscopic approaches for ablating dysplastic and early cancer lesions in the esophagus have gained popularity, namely, radiofrequency ablation (RFA) and cryospray ablation (CSA). We report a uniquely suited endoscopic and near-microscopic imaging modality, three-dimensional (3D) optical coherence tomography (OCT), to assess and compare the esophagus immediately after RFA and CSA. The maximum depths of architectural changes were measured and compared between the two treatment groups. RFA was observed to induce 230~260 MUm depth of architectural changes after each set of ablations over a particular region, while CSA was observed to induce edema-like spongiform changes to ~640 MUm depth within the ablated field. The ability to obtain micron-scale depth resolved images of tissue structural changes following different ablation therapies makes 3D-OCT an ideal tool to assess treatment efficacy. Such information could be potentially used to provide real-time feedback for treatment dosing and to identify regions that need further retreatment. PMID- 22844276 TI - A real world report on intravenous high-dose and non-high-dose proton-pump inhibitors therapy in patients with endoscopically treated high-risk peptic ulcer bleeding. AB - Background and Study Aims. The optimal dose of intravenous proton-pump inhibitor (PPI) therapy for the prevention of peptic ulcer (PU) rebleeding remains controversial. This study aimed to understand the real world experiences in prescribing high-dose PPI and non-high-dose PPI for preventing rebleeding after endoscopic treatment of high-risk PU. Patients and Methods. A total of 220 subjects who received high-dose and non-high-dose pantoprazole for confirmed acute PU bleeding that were successfully treated endoscopically were enrolled. They were divided into rebleeding (n = 177) and non-rebleeding groups (n = 43). Randomized matching of the treatment-control group was performed. Patients were randomly selected for non-high-dose and high-dose PPI groups (n = 44 in each group). Results. Univariate analysis showed, significant variables related to rebleeding were female, higher creatinine levels, and higher Rockall scores (?6). Before case-control matching, the high-dose PPI group had higher creatinine level, higher percentage of shock at presentation, and higher Rockall scores. After randomized treatment-control matching, no statistical differences were observed for rebleeding rates between the high-dose and non-high-dose groups after case-control matching. Conclusion. This study suggests that intravenous high-dose pantoprazole may not be superior to non-high-dose regimen in reducing rebleeding in high-risk peptic ulcer bleeding after successful endoscopic therapy. PMID- 22844277 TI - Dexmedetomidine versus Remifentanil for Sedation during Awake Fiberoptic Intubation. AB - This study compared remifentanil and dexmedetomidine as awake fiberoptic intubation (AFOI) anesthetics. Thirty-four adult ASA I-III patients were enrolled in a double-blinded randomized pilot study to receive remifentanil (REM) or dexmedetomidine (DEX) for sedation during AFOI (nasal and oral). Thirty patients completed the study and received 2 mg midazolam IV and topical anesthesia. The REM group received a loading dose of 0.75 mcg/kg followed by an infusion of 0.075 mcg/kg/min. The DEX group received a loading dose of 0.4 mcg/kg followed by an infusion of 0.7 mcg/kg/hr. Time to sedation, number of intubation attempts, Ramsay sedation scale (RSS) score, bispectral index (BIS), and memory recall were recorded. All thirty patients were successfully intubated by AFOI (22 oral intubations/8 nasal). First attempt success rate with AFOI was higher in the REM group than the DEX group, 72% and 38% (P = 0.02), respectively. The DEX group took longer to attain RSS of >=3 and to achieve BIS <80, as compared to the REM group. Postloading dose verbal recall was poorer in the DEX group. Dexmedetomidine seems a useful adjunct for patients undergoing AFOI but is dependent on dosage and time. Further studies in the use of dexmedetomidine for AFOI are warranted. PMID- 22844278 TI - Aging and down syndrome. PMID- 22844279 TI - Factors associated with diabetic retinopathy in chinese patients with type 2 diabetes mellitus. AB - Objective. To investigate the risk factors of DR in Chinese T2DM patients. Methods. 2009 patients with T2DM were included in this cross-sectional study. All patients underwent eye examination, and the DR stage was defined by an ophthalmologist. Correlation analysis was performed to evaluate the relation between DR and clinical variables. Logistic regression models were used to assess risk for those factors associated with DR. Results. A total of 597 T2DM patients (29.7%) had DR, of which 548 (27.3%) were nonproliferative diabetic retinopathy and 49 (2.4%) were proliferative diabetic retinopathy. Positive correlations were found between DR and duration of diabetes, systolic blood pressure (SBP), diastolic blood pressure, glycated hemoglobin, glycated albumin, 24 hurinary albumin excretion, peripheral atherosclerosis (PA), diabetes nephropathy (DN), diabetic peripheral neuropathy, and anemia. Negative correlations were found between DR and C-peptide and glomerular filtration rate. Logistic regression analysis revealed that duration of diabetes, SBP, DN, anemia, PA, and C-peptide were each independent risk factors of DR. Conclusion. The duration of diabetes, SBP, DN, anemia, and PA are positively associated with DR in Chinese T2DM patients, while C-peptide is negatively associated with DR. Monitoring and evaluation of these related factors will likely contribute to the prevention and treatment of DR. PMID- 22844281 TI - Effect of a selective progesterone receptor modulator on induction of apoptosis in uterine fibroids in vivo. AB - Aim. To determine if hormonal treatment induces apoptosis in uterine fibroids. Methods. Immunohistochemical examination of fibroid tissue, using avidin-biotin complex and cleaved caspase-3 antibody for detecting apoptosis, was performed in premenopausal women who underwent 12-week treatment with oral SPRM (6 patients with 5 mg and 5 patients with 10 mg of ulipristal acetate per day) or gonadoliberin agonist (GnRHa, 17 patients) and subsequent myomectomy or hysterectomy for symptomatic uterine fibroids. Ten patients with no presurgical hormonal treatment were used as controls. Results. Apoptosis was present in a significantly higher proportion of patients treated with ulipristal acetate compared to GnRHa (P = 0.01) and to patients with no hormonal treatment (P = 0.01). In contrast to an AI of 158.9 in SPRM patients, the mean AI was 27.5 and 2.0 in GnRHa and control groups, respectively. No statistical difference in the AI was observed between the two groups of patients treated with ulipristal acetate (5 mg or 10 mg). Conclusion. Treatment with ulipristal acetate induces apoptosis in uterine fibroid cells. This effect of SPRM may contribute to their positive clinical effect on uterine fibroids. PMID- 22844282 TI - Accuracy of linear measurements of galileos cone beam computed tomography in normal and different head positions. AB - Introduction. The aim of this study was to determine the accuracy of linear measurements in dry human skulls in ideal position and different deviated positions of the skull. Methods. 6 dry human skulls were included in the study. Opaque markers were attached to alveolar bone. Buccolingual and mesiodistal distances and heights were measured in 5 different regions of either jaws using a digital caliper. Radiographic distances were measured in ideal, rotation, tilt, flexion, and extension positions of the skulls. The physical and radiographic measurements were compared to estimate linear measurement accuracy. Results. The mean difference between physical measurements and radiographic measurements was 0.05 +/- 0.45. There was a significant difference between physical measurements and radiographic measurements in ideal, rotation, tilt, and extension positions (P value < 0.05). Conclusions. The accuracy of measurements in GALILEOUS CBCT machine varies when the position of the skull deviates from ideal; however, the differences are not clinically significant. PMID- 22844280 TI - Psychological disturbances and quality of life in obese and infertile women and men. AB - Anovulatory cycles and endometriosis are the main causes of female infertility. The most frequently anovulatory cycles are related to polycystic ovary syndrome (PCOS) commonly associated with obesity and hormonal disturbances in the course of obesity. Recently published studies revealed that infertility affects about one in six couples during their lifetime and is more frequent in obese. Obesity is also associated with male infertility related to erectile dysfunction, hormonal disturbances and lower semen quality. Any of these above mentioned disorder is the important risk factor of psychological disturbances and poor quality of life among women and men in the reproductive age. On the other hand the mood disorders may exacerbate the hormonal disturbances and worsen the effectiveness of infertility management. Infertility, its therapy with accompanying psychological disturbances may also significantly affect the partners relationships. The review summarize the results described in the current literature on the association between obesity and infertility and psychological disturbances as well as their impact on quality of life and sexual functioning in women and men. Moreover, the impact of infertility and psychological disturbances on partners relationships is discussed. PMID- 22844283 TI - Current evidence on atypical odontalgia: diagnosis and clinical management. AB - Patients with atypical odontalgia (AO) complain of medically unexplained toothache. No evidence-based diagnostic criteria or treatment guidelines are yet available. The present paper addresses seven clinical questions about AO based on current knowledge in the literature and discusses diagnostic criteria and guidelines for treatment and management. The questions are (i) What is the prevalence of AO in the community? (ii) What psychological problems are experienced by patients with AO? (iii) Are there any comorbidities of AO? (iv) Is local anesthesia effective for the relief of pain in AO? (v) Are there any characteristic symptoms of AO other than spontaneous pain? (vi) Are antidepressants effective for treatment of AO? (vii) Are anticonvulsants effective for treatment of AO? Our literature search provided answers for these questions; however, there is insufficient evidence-based data to establish guidelines for the diagnosis and treatment of AO. Overall, some diagnostic criteria for neuropathic pain and persistent dentoalveolar pain disorder may be applied to AO patients. The patient's psychogenic background should always be considered in the treatment and/or management of AO. The clinicians may need to treat AO patients using Patient-Oriented Evidence that Matters approach. PMID- 22844284 TI - In vitro wound healing improvement by low-level laser therapy application in cultured gingival fibroblasts. AB - The aim of this study was to determine adequate energy doses using specific parameters of LLLT to produce biostimulatory effects on human gingival fibroblast culture. Cells (3 * 10(4) cells/cm(2)) were seeded on 24-well acrylic plates using plain DMEM supplemented with 10% fetal bovine serum. After 48-hour incubation with 5% CO(2) at 37 degrees C, cells were irradiated with a InGaAsP diode laser prototype (LASERTable; 780 +/- 3 nm; 40 mW) with energy doses of 0.5, 1.5, 3, 5, and 7 J/cm(2). Cells were irradiated every 24 h totalizing 3 applications. Twenty-four hours after the last irradiation, cell metabolism was evaluated by the MTT assay and the two most effective doses (0.5 and 3 J/cm(2)) were selected to evaluate the cell number (trypan blue assay) and the cell migration capacity (wound healing assay; transwell migration assay). Data were analyzed by the Kruskal-Wallis and Mann-Whitney nonparametric tests with statistical significance of 5%. Irradiation of the fibroblasts with 0.5 and 3 J/cm(2) resulted in significant increase in cell metabolism compared with the nonrradiated group (P < 0.05). Both energy doses promoted significant increase in the cell number as well as in cell migration (P < 0.05). These results demonstrate that, under the tested conditions, LLLT promoted biostimulation of fibroblasts in vitro. PMID- 22844285 TI - Effects of a pseudophysiological environment on the elastic and viscoelastic properties of collagen gels. AB - Vascular tissue engineering focuses on the replacement of diseased small-diameter blood vessels with a diameter less than 6 mm for which adequate substitutes still do not exist. One approach to vascular tissue engineering is to culture vascular cells on a scaffold in a bioreactor. The bioreactor establishes pseudophysiological conditions for culture (medium culture, 37 degrees C, mechanical stimulation). Collagen gels are widely used as scaffolds for tissue regeneration due to their biological properties; however, they exhibit low mechanical properties. Mechanical characterization of these scaffolds requires establishing the conditions of testing in regard to the conditions set in the bioreactor. The effects of different parameters used during mechanical testing on the collagen gels were evaluated in terms of mechanical and viscoelastic properties. Thus, a factorial experiment was adopted, and three relevant factors were considered: temperature (23 degrees C or 37 degrees C), hydration (aqueous saline solution or air), and mechanical preconditioning (with or without). Statistical analyses showed significant effects of these factors on the mechanical properties which were assessed by tensile tests as well as stress relaxation tests. The last tests provide a more consistent understanding of the gels' viscoelastic properties. Therefore, performing mechanical analyses on hydrogels requires setting an adequate environment in terms of temperature and aqueous saline solution as well as choosing the adequate test. PMID- 22844286 TI - Synthesis of Block Copolymers of Varying Architecture Through Suppression of Transesterification during Coordinated Anionic Ring Opening Polymerization. AB - Well-defined di- and triblock copolymers consisting of epsilon-caprolactone (CL), L-lactide (LA), and trimethylene carbonate (TMC) were synthesized via "PLA first route" in coordinated anionic ring opening polymerization/copolymerization (CAROP) with tin (II) octoate as catalyst. The desired block structure was preserved by use of protective additive alpha-methylstyrene by preventing the transesterification side-reactions. MALDI-TOF analysis revealed that the protection mechanism is associated with alpha-methylstyrene and tin (II) octoate complexation. Additionally, it was shown that use of alpha-methylstyrene in ring opening polymerization allowed the formation of polyesters with high molar mass. PMID- 22844287 TI - Stress Analysis of a Class II MO-Restored Tooth Using a 3D CT-Based Finite Element Model. AB - A computational method has been developed for stress analysis of a restored tooth so that experimental effort can be minimized. The objectives of this study include (i) developing a method to create a 3D FE assembly model for a restored tooth based on CT images and (ii) conducting stress analysis of the restored tooth using the 3D FE model established. To build up a solid computational model of a tooth, a method has been proposed to construct a 3D model from 2D CT-scanned images. Facilitated with CAD tools, the 3D tooth model has been virtually incorporated with a Class II MO restoration. The tooth model is triphasic, including the enamel, dentin, and pulp phases. To mimic the natural constraint on the movement of the tooth model, its corresponding mandible model has also been generated. The relative high maximum principal stress values were computed at the surface under loading and in the marginal region of the interface between the restoration and the tooth phases. PMID- 22844289 TI - The Effect of Taraxacum officinale Hydroalcoholic Extract on Blood Cells in Mice. AB - Objectives. Dandelion (Taraxacum officinale) is a herbaceous perennial plant of the family Asteraceae and has medicinal and culinary uses. Dandelion has been used as a remedy for anemia, purifing the blood, and providing immune modulation. Therefore, the aim of this study was to investigate the effect of hydro alcoholic extract on blood cells in mice. Methods. Five groups each including ten adult female (Balb/C) mice weighing 30 +/- 5 g were chosen. Normal saline was administered as placebo for group, and dandelion hydro alcoholic extract in doses of 50,100, and 200 mg/kg was injected intraperitoneally for 20 days to test groups and the last group was control group.WBC, RBC, HB, HCT, platelet, and other cells were measured with automated cell counter. Main Results. The number of RBC and the rate of HB in three doses of 100 and 200 mg/kg significantly increased (P < 0.05). As compared with control group, the number of WBC in three doses of 50, 100, and 200 mg/kg increased, but it was significantly in 200 mg/kg dandelion treated group as compared with control group(P < 0.05). The rate of platelet in three doses of 50, 100 and 200 mg/kg significantly decreased as compared with control group (P < 0.01). 3 doses of dandelion increased lymphocyte numbers significantly compared with controls. Conclusion. The study indicates efficacy of dandelion extract on RBC and HB in doses of 50, 100, and 200 mg/kg and in 200 mg/kg on WBC to achieve normal body balance. PMID- 22844288 TI - Neutrophil reverse migration becomes transparent with zebrafish. AB - The precise control of neutrophil-mediated inflammation is critical for both host defense and the prevention of immunopathology. In vivo imaging studies in zebrafish, and more recently in mice, have made the novel observation that neutrophils leave a site of inflammation through a process called neutrophil reverse migration. The application of advanced imaging techniques to the genetically tractable, optically transparent zebrafish larvae was critical for these advances. Still, the mechanisms underlying neutrophil reverse migration and its effects on the resolution or priming of immune responses remain unclear. Here, we review the current knowledge of neutrophil reverse migration, its potential roles in host immunity, and the live imaging tools that make zebrafish a valuable model for increasing our knowledge of neutrophil behavior in vivo. PMID- 22844290 TI - The effect of amifostine on submandibular gland histology after radiation. AB - Background. The purpose of this study was to assess the effects of amifostine on submandibular gland histology in patients receiving chemoradiation therapy. Methods. We conducted a retrospective submandibular gland histologic slide review of HNSCC patients receiving chemoradiation for head and neck squamous cell carcinoma with three different levels of amifostine exposure. We used six scoring parameters: fatty replacement, lobular architecture degeneration, interstitial fibrosis, ductal degeneration, acinar degeneration, and inflammatory component presence. Results. Differences in gender, tumor stage, amifostine dose, age, number of days after neck dissection, and smoking history (pack years) exposure were not significant between the three groups, although there was a difference between groups in the primary subsite (P = 0.006). The nonparametric Cuzick's test for histologic parameters with varied amifostine treatment showed no significance among the three groups. Conclusions. Although patients did not receive a full dose of amifostine due to side effects, varying doses of amifostine had no apparent evident cytoprotective effects in three groups of cancer patients treated with primary chemoradiation. PMID- 22844293 TI - Extraskeletal chondroma of the preauricular region: a case report and literature review. AB - An extraskeletal chondroma is a rare benign cartilaginous tumor that develops in soft tissue. Histologically, it is a lobulated nodule surrounded by a fibrous capsule; the inside consists of mature hyaline cartilage containing a few normal chondrocytes. We present a rare case of extraskeletal chondroma in the preauricular region. A 43-year-old man presented with a 2-cm-diameter right preauricular tumor that had been developing for 1 year. Magnetic resonance imaging showed a solid lobulated tumor in the right preauricular region, which was proximate to the capsule of the right temporomandibular joint (TMJ). This was subsequently resected under general anesthesia. The tumor was not in contact with the TMJ capsule and had not invaded the surrounding tissue, facilitating en bloc excision. Histopathologically, the tumor comprised mainly of hyaline cartilage containing chondrocytes with chondrocytic lacunae and was diagnosed as a chondroma. The postoperative period was uneventful, and there was no evidence of recurrence at the 2-year followup. We describe the clinical characteristics of our case and review the literature, emphasizing the differential diagnosis. PMID- 22844291 TI - Autoantibodies in autoimmune pancreatitis. AB - Autoimmune pancreatitis (AIP) was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-gamma globulinaemia, and antinuclear antibody (ANA) positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis. PMID- 22844294 TI - Late onset takayasu arteritis and rheumatoid arthritis. AB - We encountered the rare case of a 48-year-old Caucasian woman who developed Takayasu arteritis (TA) while suffering from seropositive rheumatoid arthritis (RA). Several studies have reported an association between TA and various autoimmune disorders, however, the concurrent presence of Takayasu arteritis and rheumatoid arthritis is described in only few cases in the literature to date. The exact nature of the relationship between TA and RA remains unknown. Perhaps the development of these two diseases represents non-specific systemic inflammatory changes in the presence of a hereditary background predisposing to both RA and TA. PMID- 22844292 TI - Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? AB - Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX. PMID- 22844295 TI - Erythromelalgia: an uncommon presentation precipitated by aspirin withdrawal. AB - Erythromelalgia is a rare disorder frequently associated with myeloproliferative disorders. We describe a case of elderly patient diagnosed with myeloproliferative disorder in remission. The patient was on aspirin for secondary prevention of stroke and was taken off aspirin and developed erythromelalgia within two weeks of withdrawal of aspirin. After restarting aspirin, patient's symptoms improved within 2 weeks. PMID- 22844296 TI - Acute pancreatitis secondary to gestational hypertriglyceridaemia. AB - Gestational hypertriglyceridaemia is a rare cause of acute pancreatitis. Its pathophysiology is incompletely understood. Severity scoring and effective management remain challenging. We report a case of acute pancreatitis secondary to gestational hypertriglyceridaemia. We describe the use of computed tomography to provide an alternative determination of severity, as well as plasmapheresis as a means of treating the condition. PMID- 22844297 TI - Cutaneous inflammatory malignant fibrous histiocytoma presenting with a leukemoid reaction: a case report and review of the literature. AB - Malignant fibrous histiocytoma (MFH) is the most common sarcoma found in adults. We discuss a case of inflammatory MFH of dermal/epidermal origin presenting with a severe leukemoid reaction (LR). A 60 years old white male presented to hematology/oncology clinic complaining of mild shortness of breath on exertion. Past medical history was remarkable for removal of a left upper extremity necrotic mass 4.4 * 3 * 3 cm. Microscopy of the specimen showed clear surgical margin, and tumor cells restricted to the dermis without lymphovascular invasion. Immunohistochemestry was positive for CD 68 and CD 99. Chest x-ray was negative for metastatic disease. White blood cell count was 109.4 k/mm(3) with 24 k/mm(3) band neutrophils, and absolute neutrophil count of 69 k/mm(3). CT scan of the thorax revealed numerous bilateral pulmonary nodules suspicious for metastasis. Based on these findings patient was diagnosed with metastatic cutaneous IMFH associated with a LR. Following review of medical literature, this appears to be the first reported case of inflammatory cutaneous MFH associated with LR. This histological variant is rare, and carries a poor prognosis. Thus, we would like to emphasize the need for investigating alternative therapies capable of improving the survival of these patients. PMID- 22844298 TI - Postdiverticular stasis-introduction of a new etiology for small intestine obstruction: a case series. AB - Introduction. Intestinal obstruction in the setting of Meckel's diverticulum in young age and with orange and meat bezoar is a rare, previously unreported condition. Since the obstruction point is located immediately after Meckel's diverticulum in our patients, we attempt to introduce "localized peristalsis insufficiency" as a new etiology for small intestine obstruction while reviewing the findings of previous studies. Conclusion. Intestinal obstruction in the setting of Meckel's diverticulum and with orange and meat bezoar is a rare, previously unreported condition. Considering the previous reports, we may present the theory of localized peristalsis insufficiency in patients with Meckel's diverticulum. PMID- 22844299 TI - A fatal case of nafcillin-induced hepatotoxicity: a case report and the literature review. AB - Background. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8 mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative. PMID- 22844301 TI - Insights into Neonatal Oral Feeding through the Salivary Transcriptome. AB - Background. The development of safe and effective oral feeding skills in the newborn is complex and may be associated with significant morbidities. Our understanding of neonatal oral feeding maturation at the molecular level is limited, providing an opportunity to utilize emerging molecular techniques to accurately assess neonatal oral feeding skills. Objective. To identify key regulatory genes in neonatal saliva involved in successful oral feeding. Methods. Previously, our laboratory identified 9,286 genes in saliva that statistically significantly altered their gene expression as premature newborns gained advanced oral feeding skills. In this report, genes previously identified underwent an updated and targeted pathway analysis with Ingenuity Pathway Analysis (IPA) to identify potential candidate genes involved in successful oral feeding. Genes were considered if they were in the five most significantly up- and down regulated physiological pathways and were associated with the keywords "feeding", "digestion" and "development". Results. There were 2,186 genes that met criteria. Pathways associated with feeding behavior, cranial nerve development, and the development of the nervous, skeletal, and muscular systems were highlighted. Discussion. These data provide important insights into the biological processes involved in oral feeding in the newborn at a molecular level and identify novel pathways associated with successful oral feeding. PMID- 22844300 TI - Oxygen Saturation and Suck-Swallow-Breathe Coordination of Term Infants during Breastfeeding and Feeding from a Teat Releasing Milk Only with Vacuum. AB - Background. Vacuum is an important factor in milk removal from the breast, yet compression is the predominant component of milk removal from bottle teats. Since bottle-feeding infants have lower oxygen saturation, vacuum levels, and different suck-swallow-breathe (SSwB) coordination to breastfeeding infants, we hypothesised that when infants fed from a teat that required a vacuum threshold of -29 mmHg for milk removal, that oxygen saturation, heart rate, and suck swallow-breathe (SSwB) patterns would be similar to those of breastfeeding. Study Design. Infants (n = 16) were monitored during one breastfeed and one feed from the experimental teat. Simultaneous recordings were made of oxygen saturation, heart rate, vacuum, tongue movement, respiration, and swallowing. Results. There were no differences in oxygen saturation and heart rate between the breast and the teat. Infants displayed fewer sucks and breaths per swallow during nutritive sucking (NS) compared to non-nutritive sucking (NNS). The number of sucks per breath was similar for NS and NNS although respiratory rates were slower during NS. These patterns did not differ between the breast and the teat. Conclusion. These results suggest that vacuum may be conducive to safe and coordinated milk removal by the infant during both breast and bottle-feeding. PMID- 22844302 TI - Highlights for the management of a child with proteinuria and hematuria. AB - The identification of hematuria or proteinuria in an otherwise healthy child can cause anxiety to both the family and the pediatrician. The etiology of hematuria and proteinuria includes a long list of conditions, and detailed workup can be exhaustive, expensive and not essential in most of the patients. As will be described in this paper, most of the children with proteinuria or hematuria have a benign etiology. The primary role of the pediatrician is to identify hematuria/proteinuria, recognize the common causes of hematuria/proteinuria, and more importantly identify children with serious conditions that need referral to the nephrologist in a timely manner. PMID- 22844303 TI - NMR findings in patients after wrist trauma with a negative plain radiographs. AB - BACKGROUND: The purpose was to assess the prevalence and location of the injuries of the carpal bones and soft tissue of the wrist on NMR in patients with negative radiographs. MATERIAL/METHODS: A total of 89 patients (9-81years) were consecutively examined after wrist trauma. Radiograms were performed in four projections: AP, PA, oblique and lateral. In 63 cases of negative radiographs and persistent clinical problem, simplified NMR (T1,T2, STIR; in coronal plane) was conducted with a 1.5 Tesla magnet. Results were evaluated by two independent observers. A positive X-ray result was stated when at least one observer suggested bone fracture. The MR images were viewed for detection of possible bone fracture, bone edema and soft tissue injuries. Cohen's kappa coefficient was calculated to assess the quality of chosen criteria by means of agreement between both observers and both methods. RESULTS: As many as 26 X-ray studies were classified as positive. Substantial agreement between independent observers was found (kappa=0.63). In 17 cases out of 63 with two negative wrist radiogram, the NMR result was positive (19%). The most frequently fractured or injured bone was scaphoid (10 cases) and distal radius (5 cases). Fair agreement was found between X-ray and NMR studies (kappa=0.37) due to different diagnostic information received in both methods. CONCLUSIONS: Simplified NMR imaging of the wrist proved to be strongly efficient in the detection of pathological changes in injured wrists. PMID- 22844304 TI - Oversampling in the computed tomography measurements applied for bone structure studies as a method of spatial resolution improvement. AB - BACKGROUND: Our purpose was to check the potential ability of oversampling as a method for computed tomography axial resolution improvement. The method of achieving isotropic and fine resolution, when the scanning system is characterized by anisotropic resolutions is proposed. In case of typical clinical system the axial resolution is much lower than the planar one. The idea relies on the scanning with a wide overlapping layers and subsequent resolution recovery on the level of scanning step. MATERIAL/METHODS: Simulated three-dimensional images, as well as the real microtomographic images of rat femoral bone were used in proposed solution tests. Original high resolution images were virtually scanned with a wide beam and a small step in order to simulate the real measurements. The low resolution image series were subsequently processed in order to back to the original fine one. Original, virtually scanned and recovered images resolutions were compared with the use of modulation transfer function (MTF). RESULTS/CONCLUSIONS: A good ability of oversampling as a method for the resolution recovery was showed. It was confirmed by comparing the resolving powers after and before resolution recovery. The MTF analysis showed resolution improvement. The resolution improvement was achieved but the image noise raised considerably, which is clearly visible on image histograms. Despite this disadvantage the proposed method can be successfully used in practice, especially in the trabecular bone studies because of high contrast between trabeculae and intertrabecular spaces. PMID- 22844305 TI - Comparative thyroid gland volume by two methods: Ultrasonography and planar scintigraphy. AB - BACKGROUND: Knowledge of thyroid gland volume plays a key role in the treatment of thyroid diseases by radioactive iodine 131I. Radioiodine therapy is a routine procedure of treatment hyperthyroidism for over 50 years. MATERIAL/METHODS: Today modern diagnostic has a number of medical diagnostics instruments whose using to estimate of thyroid volume. Undoubtedly these method we can include a ultrasonography (US) and planar scintigraphy (PS) whose characterized by noninvasive. RESULTS/CONCLUSIONS: The aims of this papers is evaluate of thyroid volume on the basis of method ultrasonography and planar scintigraphy. PMID- 22844306 TI - Evaluation of solitary pulmonary nodule detected during computed tomography examination. AB - The solitary pulmonary nodule (SPN) has always been a diagnostic challenge for the radiologists. Currently, with increased utilization of computed tomography (CT) greater number of nodules is being discovered, with numerous indeterminate lesions, which frequently cannot be immediately classified into benign or malignant category.In this article we review the imaging features of benign and malignant round opacities; we demonstrate currently used standards and also more advanced techniques that are helpful in evaluating SPNs such as contrast-enhanced CT, PET/CT imaging and also pathologic sampling with biopsy or surgical resection.We also summarize the methods of evaluating and managing SPNs based on the latest guidelines from the Fleischner Society and American College of Chest Physicians. PMID- 22844308 TI - Use of expanded polytetrafluoroethylen (ePTFE) stent graft in autogenic AV fistula with false aneurysm in lower extremity. AB - A 28-year-old German-Caucasian man arrived with deep vein thrombosis DVT, pain, oedema and rubor of right lower limb and drug abuse. The US Doppler imaging showed an autogenic AV fistula and false aneurysm of the right superficial femoral artery and femoral vein. The CT imaging showed additional closing of the left external iliac artery and common femoral artery, and of the distal and middle parts of the superficial femoral artery. The patient was treated within the angiography suite using a 8/25 mm (8 mm diameter/25 mm length) peripheral graft with expanded polytetrafluoroethylen ePTFE stent. After stent deployment, the dilatation was performed using 8/20 mm (8 mm diameter/20 mm length) balloons. After intervention, the digital subtraction angiography showed a good stent position with complete exclusion of false aneurysm and AV fistula. The outcome of US Doppler imaging also confirmed successful intervention. PMID- 22844307 TI - Focal cortical dysplasia - review. AB - Focal cortical dysplasia is a malformation of cortical development, which is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults.Both genetic and acquired factors are involved in the pathogenesis of cortical dysplasia. Numerous classifications of the complex structural abnormalities of focal cortical dysplasia have been proposed - from Taylor et al. in 1971 to the last modification of Palmini classification made by Blumcke in 2011. In general, three types of cortical dysplasia are recognized.Type I focal cortical dysplasia with mild symptomatic expression and late onset, is more often seen in adults, with changes present in the temporal lobe.Clinical symptoms are more severe in type II of cortical dysplasia usually seen in children. In this type, more extensive changes occur outside the temporal lobe with predilection for the frontal lobes.New type III is one of the above dysplasias with associated another principal lesion as hippocampal sclerosis, tumor, vascular malformation or acquired pathology during early life.Brain MRI imaging shows abnormalities in the majority of type II dysplasias and in only some of type I cortical dysplasias.THE MOST COMMON FINDINGS ON MRI IMAGING INCLUDE: focal cortical thickening or thinning, areas of focal brain atrophy, blurring of the gray-white junction, increased signal on T2- and FLAIR-weighted images in the gray and subcortical white matter often tapering toward the ventricle. On the basis of the MRI findings, it is possible to differentiate between type I and type II cortical dysplasia. A complete resection of the epileptogenic zone is required for seizure free life. MRI imaging is very helpful to identify those patients who are likely to benefit from surgical treatment in a group of patients with drug-resistant epilepsy.However, in type I cortical dysplasia, MR imaging is often normal, and also in both types the lesion seen on MRI may be smaller than the seizure generating region seen in the EEG. The abnormalities may also involve vital for life brain parts, where curative surgery will not be an option. Therefore, other diagnostic imaging techniques such as FDG PET, MEG, DTI and intra-cranial EEG are widely used to establish the diagnosis and to decide on management.With advances in both genetics and neuroimaging, we may develop a better understanding of patients with drug-resistant epilepsy, which will help us to provide more successful pharmacological and/or surgical treatment in the future. PMID- 22844309 TI - DSA volumetric 3D reconstructions of intracranial aneurysms: A pictorial essay. AB - A gold standard of cerebral vessel imaging remains the digital subtraction angiography (DSA) performed in three projections. However, in specific clinical cases, many additional projections are required, or a complete visualization of a lesion may even be impossible with 2D angiography. Three-dimensional (3D) reconstructions of rotational angiography were reported to improve the performance of DSA significantly. In this pictorial essay, specific applications of this technique are presented in the management of intracranial aneurysms, including: preoperative aneurysm evaluation, intraoperative imaging, and follow up. Volumetric reconstructions of 3D DSA are a valuable tool for cerebral vessels imaging. They play a vital role in the assessment of intracranial aneurysms, especially in evaluation of the aneurysm neck and the aneurysm recanalization. PMID- 22844310 TI - Dolichoectasia of the circle of Willis arteries and fusiform aneurysm of basilar artery - case report and review of the literature. AB - BACKGROUND: Dolichoectasia of intracranial arteries is a rare arteriopathy characterized by elongation and widening of the arteries and disturbance of the laminar blood flow. It involves mostly vertebral and basilar arteries. In advanced cases, formation of a fusiform aneurysm is possible. CASE REPORT: A sixty-four-year-old female with hypertension was admitted to the hospital with severe non-systemic vertigo and dysarthria, which had lasted for a couple of weeks. Imaging of the brain revealed dolichoectasia of arteries of the circle of Willis coexisting with a fusiform aneurysm of the basilar artery. CONCLUSIONS: Intracranial arterial dolichoectasia may be asymptomatic for a long time. However, in many cases it leads to neurological symptoms associated with haemodynamic disturbance (due to unstable wall clots) and mass effect caused by the widened vessel. PMID- 22844311 TI - Pneumatosis cystoides interstitialis: A complication of graft-versus-host disease. A report of two cases. AB - BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a rare disorder characterized by the presence of multiple gas collections in the subserosal or submucosal intestinal wall of the large or small intestine. We report two cases of PCI in the course of chronic graft-versus-host disease. CASE REPORT: A 5-year old girl was treated for acute lymphoblastic leukemia. Twenty-four months after the hematopoietic stem cell transplantation, in the course of graft-versus-host disease, she developed subcutaneous emphysema of the right inguinal and pudendal region. PCI was diagnosed based on a CT examination. A 3-year-old boy was treated for juvenile myelomonocytic leukemia. Fourteen months after the hematopoietic stem cell transplantation he presented with an increased severity of intestinal symptoms, including intermittent bleeding from large intestine. PCI was diagnosed based on a CT exam and was confirmed by a colonoscopy. CONCLUSIONS: Pneumatosis cystoides interstitialis in the course of chronic graft-versus-host disease has a heterogeneous clinical presentation that does not correlate with results of imaging. CT is a method of choice to diagnose PCI. In patients with PCI, the presence of free air in the peritoneal cavity does not confirm an intestinal perforation. PMID- 22844312 TI - A peculiar blow-out fracture of the inferior orbital wall complicated by extensive subcutaneous emphysema: A case report and review of the literature. AB - BACKGROUND: Blow-out fracture of the orbit is a common injury. However, not many cases are associated with massive subcutaneous emphysema. Even fewer cases are caused by minor trauma or are associated with barotrauma to the orbit due to sneezing, coughing, or vomiting. The authors present a case of blow-out fracture complicated by extensive subcutaneous and mediastinal emphysema that occurred without any obvious traumatic event. CASE REPORT: A 43-year-old man presented to the Emergency Department with a painful right-sided exophthalmos that he had noticed in the morning immediately after waking up. The patient also complained of diplopia. Physical examination revealed exophthalmos and crepitations suggestive of subcutaneous emphysema. The eye movements, especially upward gaze, were impaired. CT showed blow-out fracture of the inferior orbital wall with a herniation of the orbital soft tissues into the maxillary sinus. There was an extensive subcutaneous emphysema in the head and neck going down to the mediastinum. The patient did not remember any significant trauma to the head that could explain the above mentioned findings. At surgery, an inferior orbital wall fracture with a bony defect of 3*2 centimeter was found and repaired. CONCLUSIONS: Blow-out fractures of the orbit are usually a result of a direct trauma caused by an object with a diameter exceeding the bony margins of the orbit. In 50% of cases, they are complicated by orbital emphysema and in 4% of cases by herniation of orbital soft tissues into paranasal sinuses. The occurrence of orbital emphysema without trauma is unusual. In some cases it seems to be related to barotrauma due to a rapid increase in pressure in the upper airways during sneezing, coughing, or vomiting, which very rarely leads to orbital wall fracture. Computed tomography is the most accurate method in detecting and assessing the extent of orbital wall fractures. PMID- 22844313 TI - Hyper Ig E syndrome (Job syndrome, HIES) - radiological images of pulmonary complications on the basis of three cases. AB - BACKGROUND: Hyperimmunoglobulinemia E syndrome (hyper-IgE syndrome, Job syndrome, HIES) is a complex immune deficiency with multiorgan clinical manifestations and diverse genetic background. The clinical triad of symptoms observed in approximately 75% of patients with HIES includes: recurrent abscesses of staphylococcal etiology, recurrent respiratory infections and elevated immunoglobulin E in serum. CASE REPORT: The paper discusses three cases of female patients presenting typical pulmonary complications of the hyper-Ig E syndrome. In the first case, the development of aspergilloma in a postinflamatory cyst was observed, in the other one, pneumonia with pleural effusion, and as a consequence of inflammatory infiltrations - fibrotic changes, giving rise to lobectomy, while in the last of these cases, the course of lung disease was complicated by formation of staphylococcal abscess. In one of the girls, bronchiectasis appeared at follow-up. CONCLUSIONS: Complications of pulmonary infections are the most common causes of death in hyper-Ig E syndrome. Late diagnosis significantly worsens the respiratory function and reduces the chance for normal development of a child. Introduction of comprehensive treatment, including prophylaxis, decreases the recurrences. Therefore, the important role is attributed to the radiologist in the multidisciplinary care of patients with this syndrome. PMID- 22844314 TI - Atypical imaging features of adrenal gland lesions in children - report of three cases and review of literature. AB - BACKGROUND: The differential diagnosis of adrenal pathology depends on the child's age and imaging findings. CASE REPORT: Three children without clinical symptoms of neoplasm, with an adrenal lesion discovered on diagnostic ultrasound imaging. Laboratory tests for neoplasm were negative. The final diagnosis was based on histopathological examinations after surgical resection. CONCLUSIONS: 1. The value of diagnostic imaging and laboratory tests in differential diagnosis of adrenal gland lesions is limited. 2. Malignant tumors of adrenal glands should be taken into account in children. 3. Surgical resection should be considered in diagnostic algorithm of adrenal gland masses. 4. The final diagnosis is always based on histopathological examination. PMID- 22844315 TI - Umbilical cord blood transplantation. AB - Since the first umbilical cord blood transplantation (CBT) in 1998, cord blood (CB) has now become one of the most commonly used sources of hematopoietic stem cells for transplantation. CBT has advantages of easy procurement, no risk to donor, low risk of transmitting infections, immediate availability and immune tolerance allowing successful transplantation despite human leukocyte antigen disparity. Several studies have shown that the number of cells transplanted is the most important factor for engraftment in CBT, and it limits the wide use of CB in adult patients. New strategies for facilitating engraftment and reducing transplantation-related mortality are ongoing in the field of CBT and include the use of a reduced-intensity conditioning regimen, double-unit CBT, ex vivo expansion of CB, and co-transplantation of CB and mesenchymal stem cells. Recently, the results of two international studies with large sample sizes showed that CB is an acceptable alternative source of hematopoietic stem cells for adult recipients who lack human leukocyte antigen-matched adult donors. Along with the intensive researches, development in banking process of CB will amplify the use of CB and offer the chance for cure in more patients. PMID- 22844317 TI - Recent incidence of congenital heart disease in neonatal care unit of secondary medical center: a single center study. AB - PURPOSE: With feasibility in the diagnoses of congenital heart disease (CHD) in the antenatal period, we suspect changes have occurred in its incidence. No data have been reported about the current incidence of simple forms of CHD in Korea. We have attempted to assess the recent incidence and characteristics of CHD in the neonatal care unit of a secondary referral medical center. METHODS: Medical records of 497 neonatal care unit patients who underwent echocardiography in the past 5 years were reviewed. Pre-term infants with patent ductus arteriosus and other transient, minimal lesions were excluded from this study. RESULTS: Although the number of inpatients remained stable, the incidence of simple forms of CHD showed a gradual decrease over the 5-year study period; a markedly low incidence of complex forms was seen as well. CHD was observed in 3.7% full-term and 6.8% pre-term infants. CHD was observed in 152 infants weighing >2,500 g (3.5% of corresponding birth weight infants); 65 weighing 1,000 to 2,500 g (9.3%); and 6 weighing <1,000 g (8.0%). The incidence of CHD was higher in the pre-term group and the low birth weight group than in each corresponding subgroup (P<0.001); however, the incidence of complex CHD in full-term neonates was high. The number of patients with extracardiac structural anomalies has also shown a gradual decrease every year for the past 5 years. CONCLUSION: Findings from our study suggest that the recent incidence and disease pattern of CHD might have changed for both complex and simple forms of CHD in Korea. PMID- 22844316 TI - Endocrine problems in children with Prader-Willi syndrome: special review on associated genetic aspects and early growth hormone treatment. AB - Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder characterized by hypothalamic-pituitary dysfunction. The main clinical features include neonatal hypotonia, distinctive facial features, overall developmental delay, and poor growth in infancy, followed by overeating with severe obesity, short stature, and hypogonadism later in development. This paper reviews recent updates regarding the genetic aspects of this disorder. Three mechanisms (paternal deletion, maternal disomy, and deficient imprinting) are recognized. Maternal disomy can arise because of 4 possible mechanisms: trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and postfertilization mitotic nondisjunction (Mit). Recently, TR/GC caused by nondisjunction at maternal meiosis 1 has been identified increasingly, as a result of advanced maternal childbearing age in Korea. We verified that the d3 allele increases the responsiveness of the growth hormone (GH) receptor to endogenous GH. This paper also provides an overview of endocrine dysfunctions in children with PWS, including GH deficiency, obesity, sexual development, hypothyroidism, and adrenal insufficiency, as well as the effects of GH treatment. GH treatment coupled with a strictly controlled diet during early childhood may help to reduce obesity, improve neurodevelopment, and increase muscle mass. A more active approach to correct these hormone deficiencies would benefit patients with PWS. PMID- 22844319 TI - A fatal case of acute pulmonary embolism caused by right ventricular masses of acute lymphoblastic lymphoma-leukemia in a 13 year old girl. AB - We report a case of a 13-year-old girl with acute lymphoblastic lymphoma leukemia, who presented with a cardiac metastasis in the right ventricle, resulting in a pulmonary embolism. At the time of her leukemia diagnosis, a cardiac mass was incidentally found. The differential diagnosis for this unusual cardiac mass included cardiac tumor, metastasis, vegetation, and thrombus. Empirical treatment was initiated, including anticoagulation and antibiotics. She underwent plasmapheresis and was administered oral prednisolone for her leukemia. Five days later, she experienced sudden hemodynamic collapse and required extracorporeal membrane oxygenation insertion and emergency surgery. These interventions proved futile, and the patient died. Pathology revealed that the cardiac mass comprised an aggregation of small, round, necrotic cells consistent with leukemia. This is the first known case of acute lymphoblastic leukemia presenting as a right ventricular mass, with consequent fatal acute pulmonary embolism. A cardiac mass in a child with acute leukemia merits investigation to rule out every possible etiology, including vegetation, thrombus, and even a mass of leukemic cells, which could result in the fatal complication of pulmonary embolism. PMID- 22844318 TI - Neuroprotective effects of L-carnitine against oxygen-glucose deprivation in rat primary cortical neurons. AB - PURPOSE: Hypoxic-ischemic encephalopathy is an important cause of neonatal mortality, as this brain injury disrupts normal mitochondrial respiratory activity. Carnitine plays an essential role in mitochondrial fatty acid transport and modulates excess acyl coenzyme A levels. In this study, we investigated whether treatment of primary cultures of rat cortical neurons with L-carnitine was able to prevent neurotoxicity resulting from oxygen-glucose deprivation (OGD). METHODS: Cortical neurons were prepared from Sprague-Dawley rat embryos. L Carnitine was applied to cultures just prior to OGD and subsequent reoxygenation. The numbers of cells that stained with acridine orange (AO) and propidium iodide (PI) were counted, and lactate dehydrogenase (LDH) activity and reactive oxygen species (ROS) levels were measured. The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and the terminal uridine deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay were performed to evaluate the effect of L-carnitine (1 uM, 10 uM, and 100 uM) on OGD induced neurotoxicity. RESULTS: Treatment of primary cultures of rat cortical neurons with L-carnitine significantly reduced cell necrosis and prevented apoptosis after OGD. L-Carnitine application significantly reduced the number of cells that died, as assessed by the PI/AO ratio, and also reduced ROS release in the OGD groups treated with 10 uM and 100 uM of L-carnitine compared with the untreated OGD group (P<0.05). The application of L-carnitine at 100 uM significantly decreased cytotoxicity, LDH release, and inhibited apoptosis compared to the untreated OGD group (P<0.05). CONCLUSION: L-Carnitine has neuroprotective benefits against OGD in rat primary cortical neurons in vitro. PMID- 22844320 TI - Aortic valve replacement surgery for a case of infantile Takayasu arteritis. AB - Takayasu arteritis is a chronic inflammatory disease of unknown etiology primarily affecting the aorta and its major branches and usually occurring in the second or third decade of life. Here, we report a case of Takayasu arteritis in a 10-month-old patient. The infant presented with signs of congestive heart failure and severe aortic regurgitation. Echocardiography and computed tomography angiography showed an abnormally dilated thoracic and abdominal aorta. The infant was initially treated with prednisolone, followed by commissuroplasty of the aortic valve but neither approach ameliorated the heart failure. The patient was eventually treated with a mechanical aortic valve replacement surgery at the age of 12 months, and her condition stabilized. Although unusual, this case indicates that the diagnosis of Takayasu arteritis should be considered in children with unexplained systemic symptoms, aortic valve regurgitation, and heart failure. Because severe aortic regurgitation may be a fatal complication of Takayasu arteritis, early aortic valve replacement surgery should be considered, even in very young children. PMID- 22844321 TI - Interleukin-12p70 expression by dendritic cells of HIV-1-infected patients fails to stimulate gag-specific immune responses. AB - A variety of immune-based therapies has been developed in order to boost or induce protective CD8(+) T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naive T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2 gag mRNA enhances their capacity to induce HIV gag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN) gamma. Our results confirm the ability of HxB2 gag-expressing DCs to expand functional HIV-specific CD8(+) T cells. However, although most of the patients had detectable gag-specific CD8(+) T cell responses, no significant differences in the level of expansion of functional CD8(+) T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals. PMID- 22844322 TI - Hepatitis C virus infection and mixed cryoglobulinemia. AB - Hepatitis C virus (HCV) chronic infection is recognized as the major cause of mixed cryoglobulinemia (MC). Its persistence represents a continuous stimulus for host immune system with production of circulating immune complexes (ICs), one third of them with cryoprecipitate property. Several factors contribute to the biological activities of ICs, many of which are not completely known. Among them, complement factors play a crucial role in the cold-insoluble ICs-mediated vasculitis, involving primarily small blood vessels in different tissues including skin, kidney, peripheral, and central nervous system. Liver represents the major target of HCV infection with inflammatory infiltrates, resembling secondary lymphoid follicles. Cytokine like CXCL13 contribute to B-cell homing in intraportal lymphoid aggregates, in which B-cell clonal selection may arise. B cell clonal expansion starts as an antigen-driven event and expands towards indolent and malignant B-cell proliferation. Occurrence of intrahepatic B-cell clonalities correlates with extrahepatic clinical manifestations of HCV infection. In this context, cryoglobulinemic patients should be considered a peculiar HCV-infected population that needs a clinical multidisciplinary approach and more articulated therapeutic measures. PMID- 22844323 TI - Interactions of miR-34b/c and TP53 polymorphisms on the risk of intracranial aneurysm. AB - Several lines of evidence indicate that inflammatory processes play a key role in the happening and development of intracranial aneurysm (IA). Recently, polymorphisms in the TP53 gene were shown to be associated with inflammation and inflammatory disease. The aim of this study was to investigate the interactions of miR-34b/c and TP53 Arg72-Pro polymorphisms on the risk of IA in a Chinese population. A total of 590 individuals (including 164 patients with IA and 426 controls) were involved in this study. The polymorphisms (i.e., miR-34b/c rs4938723 and TP53 Arg72-Pro) were genotyped by polymerase chain reaction restriction fragment length polymorphism assay and DNA sequencing. We found that the CC genotype of miR-34b/c rs4938723 was significantly associated with a decreased risk of IA compared with the TT genotype. Moreover, a significant gene interaction of the carriers with the combined genotypes of miR-34b/c rs4938723CC and TP53 Arg72Pro CG/CC/GG had a decreased risk of IA, compared with those carrying miR-34b/c rs4938723CT/TT+TP53 Arg72Pro GG/CG/CC combined genotypes. These findings suggest that the miR-34b/c rs4938723CC and TP53 Arg72-Pro polymorphisms may be involved in the susceptibility to IA. PMID- 22844324 TI - Impact of the NK cell receptor LIR-1 (ILT-2/CD85j/LILRB1) on cytotoxicity against multiple myeloma. AB - The role of different receptors in natural-killer- (NK-) cell-mediated cytotoxicity against multiple myeloma (MM) cells is unknown. We investigated if an enhancement of NK-cell-mediated cytotoxicity against MM could be reached by blocking of the inhibitory leukocyte immunoglobulin-like receptor 1 (LIR-1). Our investigations revealed high levels of LIR-1 expression not only on the NK cell line NK-92, but also on myeloma cells (MOLP-8, RPMI8226) as well as on a lymphoblastoid cell line (LBCL; IM-9). Subsequent cytotoxicity assays were designed to show the isolated effects of LIR-1 blocking on either the effector or the tumor side to rule out receptor-receptor interactions. Although NK-92 was shown to be capable of myeloma cell lysis, inhibition of LIR-1 on NK-92 did not enhance cytotoxicity. Targeting the receptor on MM and LBCL did not also alter NK 92-mediated lysis. We come to the conclusion that LIR-1 alone does not directly influence NK-cell-mediated cytotoxicity against myeloma. To our knowledge, this work provides the first investigation of the inhibitory capability of LIR-1 in NK 92-mediated cytotoxicity against MM and the first functional evaluation of LIR-1 on MM and LBCL. PMID- 22844325 TI - Mycobacterium avium subsp. paratuberculosis in an Italian cohort of type 1 diabetes pediatric patients. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne's disease in ruminants. Recent studies have linked MAP to type 1 diabetes (T1D) in the Sardinian population. The aim of this study was to investigate the prevalence of MAP infection in a T1D cohort from continental Italy compared with healthy control subjects. 247 T1D subjects and 110 healthy controls were tested for the presence of MAP. MAP DNA was detected using IS900-specific polymerase chain reaction (PCR). The presence of antibodies towards a MAP antigen, heparin binding hemoagglutinin (HBHA), was detected by ELISA. We demonstrated a higher MAP DNA prevalence in plasma samples from T1D patients and a stronger immune response towards MAP HBHA, compared with healthy control subjects. Moreover, in the recent onset patients, we observed an association between anti-MAP antibodies and HLA DQ2 (DQA1 0201/DQB1 0202). These findings taken together support the hypothesis of MAP as an environmental risk factor for the development of T1D in genetically predisposed subjects, probably involving a mechanism of molecular mimicry between MAP antigens and pancreatic islet beta-cells. PMID- 22844327 TI - Systemic lupus erythematosus: genomics, mechanisms, and therapies. PMID- 22844326 TI - Pathogenetic mechanisms of hepatitis C virus-induced B-cell lymphomagenesis. AB - Hepatitis C virus (HCV) infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide, accounting for 3% of the global population. Although the liver is considered to be the primary target, extrahepatic manifestations are well recognized among patients with chronic HCV infection. Epidemiological studies have clearly demonstrated a correlation between chronic HCV infection and occurrence of B-cell non-Hodgkin's lymphomas (B-NHL). The clinical evidence that antiviral therapy has a significant role in the treatment at least of some HCV-associated lymphoproliferative disorders, especially indolent B-NHL, further supports the existence of an etiopathogenetic link. However, the mechanisms exploited by HCV to induce B-cell lymphoproliferation have so far not completely clarified. It is conceivable that different biological mechanisms, namely, chronic antigen stimulation, high affinity interaction between HCV-E2 protein and its cellular receptors, direct HCV infection of B-cells, and "hit and run" transforming events, may be combined themselves and cooperate in a multifactorial model of HCV-associated lymphomagenesis. PMID- 22844328 TI - Eurycoma longifolia: Medicinal Plant in the Prevention and Treatment of Male Osteoporosis due to Androgen Deficiency. AB - Osteoporosis in elderly men is now becoming an alarming health issue due to its relation with a higher mortality rate compared to osteoporosis in women. Androgen deficiency (hypogonadism) is one of the major factors of male osteoporosis and it can be treated with testosterone replacement therapy (TRT). However, one medicinal plant, Eurycoma longifolia Jack (EL), can be used as an alternative treatment to prevent and treat male osteoporosis without causing the side effects associated with TRT. EL exerts proandrogenic effects that enhance testosterone level, as well as stimulate osteoblast proliferation and osteoclast apoptosis. This will maintain bone remodelling activity and reduce bone loss. Phytochemical components of EL may also prevent osteoporosis via its antioxidative property. Hence, EL has the potential as a complementary treatment for male osteoporosis. PMID- 22844329 TI - Ferulic Acid, an Angelica sinensis-Derived Polyphenol, Slows the Progression of Membranous Nephropathy in a Mouse Model. AB - Membranous nephropathy (MN) is a leading cause of adult nephrotic syndrome but lacks adequate treatment. Different extracts of Angelica sinensis (AS) and one of its active compounds, ferulic acid (FA), were used to evaluate the therapeutic effects in a MN mouse model. The MN model was grouped into three subgroups: no treatment (N-T), treatment at induction of MN (Pre-T), and treatment after full blown MN (Post-T). The results showed that the methanol (ME) layer of AS extract exhibited a therapeutic effect on MN-induced proteinuria. The ME layer-enriched compound, FA, improved the hypoalbuminemia, hyperlipidemia, and proteinuria in both Pre-T and Post-T groups. Ferulic acid also reduced the formation of oxidative protein products and increased the synthesis of antioxidant enzymes in groups Pre-T and Post-T. Regarding angiogenesis factors, the antiangiogenic factors in renal glomeruli were increased in group N-T, but, after FA treatment, only one of the antiangiogenic factors, thrombospondin-1, showed a significant decrease. Furthermore, the expression of Th2 predominant showed significant decrease in both Pre-T and Post-T groups when compared to that of N-T group. In summary, FA retarded the progression of MN, and the mechanisms involved the regulation of oxidative stresses, angiogenic and antiangiogenic factors, and attenuation of Th2 response. PMID- 22844330 TI - Clerodendrum inerme Leaf Extract Alleviates Animal Behaviors, Hyperlocomotion, and Prepulse Inhibition Disruptions, Mimicking Tourette Syndrome and Schizophrenia. AB - Previously, we found a patient with intractable motor tic disorder, a spectrum of Tourette syndrome (TS), responsive to the ground leaf juice of Clerodendrum inerme (CI). Here, we examined the effect of the ethanol extract of CI leaves (CI extract) on animal behaviors mimicking TS, hyperlocomotion, and sensorimotor gating deficit. The latter is also observed in schizophrenic patients and can be reflected by a disruption of prepulse inhibition of acoustic startle response (PPI) in animal models induced by methamphetamine and NMDA channel blockers (ketamine or MK-801), based on hyperdopaminergic and hypoglutamatergic hypotheses, respectively. CI extract (10-300 mg/kg, i.p.) dose-dependently inhibited hyperlocomotion induced by methamphetamine (2 mg/kg, i.p.) and PPI disruptions induced by methamphetamine, ketamine (30 mg/kg, i.p.), and MK-801 (0.3 mg/kg, i.p.) but did not affect spontaneous locomotor activity, rotarod performance, and grip force. These results suggest that CI extract can relieve hyperlocomotion and improve sensorimotor gating deficit, supporting the therapeutic potential of CI for TS and schizophrenia. PMID- 22844331 TI - Absence of Genotoxic and Mutagenic Effects of Zingiber zerumbet (L.) Smith (Zingiberaceae) Extract. AB - The present study evaluated the potential genotoxicity of the ethanol extracts from the rhizome of Zingiber zerumbet (L.) Smith (EEZZR) using a standard battery of tests. Chemical analysis with liquid chromatography-tandem mass spectrometry revealed that EEZZR contained Zerumbone (200.3 +/- 0.37 MUg/g) and 6-gingerol (102.5 +/- 0.28 MUg/g). There were no increases in the number of revertant colonies with EEZZR at concentrations of 150-5000 MUg per plate, regardless of the metabolic activation system (S-9 mix) used in the histidine-dependent auxotrophic mutants of Salmonella typhimurium (strains TA97, TA98, TA100, TA102, and TA1535) compared to the vehicle control. Furthermore, EEZZR at doses of 150 5000 MUg mL(-1) did not increase the number of structural aberrations in Chinese hamster lung cells in the presence or absence of S-9 mix. An oral administration of EEZZR to ICR mice, with doses of up to 2000 mg/kg, caused no significant increases in the number of micronucleated polychromatic erythrocytes (MNPCEs) and mean ratio of polychromatic erythrocytes to total erythrocytes. Lastly, RZZEE did not increase the incidence of MNPCEs in bone marrow. Based on these findings, it may be concluded that the use of EEZZR in traditional medicine poses no risk of genotoxicity. PMID- 22844332 TI - In Vitro and In Vivo Genotoxicity Assessment of Aristolochia manshuriensis Kom. AB - Arisolochiae species plants containing aristolochic acids I and II (AA I and AA II) are well known to cause aristolochic acid nephropathy (AAN). Recently, there are various approaches to use AAs-containing herbs after the removal of their toxic factors. However, there is little information about genotoxicity of Arisolochiae manshuriensis Kom. (AMK) per se. To obtain safety information for AMK, its genotoxicity was evaluated in accordance with OECD guideline. To evaluate genotoxicity of AMK, we tested bacterial reverse mutation assay, chromosomal aberration test, and micronucleus test. Here, we also determined the amounts of AA I and II in AMK (2.85 +/- 0.08 and 0.50 +/- 0.02 mg/g extract, resp.). In bacterial reverse mutation assay, AMK dose-dependently increased revertant colony numbers in TA98, TA100 and TA1537 regardless of metabolic activation. AMK increased the incidence of chromosomal aberration in Chinese hamster ovary-K1 cells, but there was no statistically significant difference. The incidences of micronucleus in bone marrow erythrocyte were significantly increased in mice after oral administration of AMK (5000 mg/kg), comparing with those of vehicle group (P < 0.05). The results of three standard tests suggest that the genotoxicity of AMK is directly related to the AAs contents in AMK. PMID- 22844333 TI - Polyphenol-Rich Fraction of Brown Alga Ecklonia cava Collected from Gijang, Korea, Reduces Obesity and Glucose Levels in High-Fat Diet-Induced Obese Mice. AB - Ecklonia cava (E. cava) is a brown alga that has beneficial effects in models of type 1 and type 2 diabetes. However, the effects of E. cava extracts on diet induced obesity and type 2 diabetes have not been specifically examined. We investigated the effects of E. cava on body weight, fat content, and hyperglycemia in high-fat diet- (HFD) induced obese mice and sought the mechanisms involved. C57BL/6 male mice were fed a HFD (60% fat) diet or normal chow. After 3 weeks, the HFD diet group was given extracts (200 mg/kg) of E. cava harvested from Jeju (CA) or Gijang (G-CA), Korea or PBS by oral intubation for 8 weeks. Body weights were measured weekly. Blood glucose and glucose tolerance were measured at 7 weeks, and fat pad content and mRNA expression of adipogenic genes and inflammatory cytokines were measured after 8 weeks of treatment. G-CA was effective in reducing body weight gain, body fat, and hyperglycemia and improving glucose tolerance as compared with PBS-HFD mice. The mRNA expression of adipogenic genes was increased, and mRNA expression of inflammatory cytokines and macrophage marker gene was decreased in G-CA-treated obese mice. We suggest that G-CA reduces obesity and glucose levels by anti-inflammatory actions and improvement of lipid metabolism. PMID- 22844334 TI - Auricular acupressure for managing postoperative pain and knee motion in patients with total knee replacement: a randomized sham control study. AB - Background. Postoperative pain management remains a significant challenge for all healthcare providers. A randomized controlled trial was conducted to examine the adjuvant effects of auricular acupressure on relieving postoperative pain and improving the passive range of motion in patients with total knee replacement (TKR). Method. Sixty-two patients who had undergone a TKR were randomly assigned to the acupressure group and the sham control group. The intervention was delivered three times a day for 3 days. A visual analog scale (VAS) and the Short Form McGill Pain Questionnaire were used to assess pain intensity. Pain medication consumption was recorded, and the knee motion was measured using a goniometer. Results. The patients experienced a moderately severe level of pain postoperatively (VAS 58.66 +/- 20.35) while being on the routine PCA. No differences were found in pain scores between the groups at all points. However, analgesic drug usage in the acupressure group patients was significantly lower than in the sham control group (P < 0.05), controlling for BMI, age, and pain score. On the 3rd day after surgery, the passive knee motion in the acupressure group patients was significantly better than in the sham control group patients (P < 0.05), controlling for BMI. Conclusion. The application of auricular acupressure at specific therapeutic points significantly reduces the opioid analgesia requirement and improves the knee motion in patients with TKR. PMID- 22844335 TI - Brachystemma calycinum D. Don Effectively Reduces the Locomotor Disability in Dogs with Naturally Occurring Osteoarthritis: A Randomized Placebo-Controlled Trial. AB - Objective. The aim of this randomized placebo-controlled trial was to evaluate the beneficial effect of a whole plant extract of Brachystemma calycinum D. Don (BCD) in naturally occurring osteoarthritis (OA) in dogs. Methods. Dogs had stifle/hip OA and poor limb loading based on the peak of the vertically oriented ground reaction force (PVF) measured using a force platform. At baseline, PVF and case-specific outcome measure of disability (CSOM) were recorded. Dogs (16 per group) were then assigned to receive BCD (200 mg/kg/day) or a placebo. The PVF was measured at week (W) 3 and W6. Locomotor activity was recorded throughout the study duration using collar-mounted accelerometer, and CSOM was assessed biweekly by the owner. Results. BCD-treated dogs had higher PVF at W3 and W6 when compared to Baseline (P < 0.001) and at W6 when compared to placebo-treated dogs (P = 0.040). Higher daily duration (P = 0.024) and intensity (P = 0.012) of locomotor activity were observed in BCD-treated dogs compared to baseline. No significant change was observed in either group for CSOM. Conclusions. Treatment with BCD improved the limb impairment and enhanced the locomotor activity in dogs afflicted by naturally-occurring OA. Those preclinical findings provide interesting and new information about the potential of BCD as an OA therapeutic. PMID- 22844337 TI - Neuroendocrine mechanisms of acupuncture. PMID- 22844336 TI - The Yang-Tonifying Herbal Medicine Cynomorium songaricum Extends Lifespan and Delays Aging in Drosophila. AB - Aging is highly correlated with the progressive loss of physiological function, including cognitive behavior and reproductive capacity, as well as an increased susceptibility to diseases; therefore, slowing age-related degeneration could greatly contribute to human health. Cynomorium songaricum Rupr. (CS) is traditionally used to improve sexual function and treat kidney dysfunction in traditional Chinese medicine, although little is known about whether CS has effects on longevity. Here, we show that CS supplementation in the diet extends both the mean and maximum lifespan of adult female flies. The increase in lifespan with CS was correlated with higher resistance to oxidative stress and starvation and lower lipid hydroperoxides (LPO) levels. Additionally, the lifespan extension was accompanied by beneficial effects, such as improved mating readiness, increased fecundity, and suppression of age-related learning impairment in aged flies. These findings demonstrate the important antiaging effects of CS and indicate the potential applicability of dietary intervention with CS to enhance health and prevent multiple age-related diseases. PMID- 22844338 TI - Green Tea Polyphenols for the Protection against Renal Damage Caused by Oxidative Stress. AB - Green tea, prepared from the leaves of Camellia sinensis L., is a beverage that is popular worldwide. Polyphenols in green tea have been receiving much attention as potential compounds for the maintenance of human health due to their varied biological activity and low toxicity. In particular, the contribution of antioxidant activity to the prevention of diseases caused by oxidative stress has been focused upon. Therefore, in this study, we investigated the effects of (-) epigallocatechin 3-O-gallate and (-)-epigallocatechin 3-O-gallate, which account for a large fraction of the components of green tea polyphenol, on oxidative stress-related renal disease. Our observations suggest that green tea polyphenols have a beneficial effect on pathological states related to oxidative stress of the kidney. PMID- 22844339 TI - Active Hydrophilic Components of the Medicinal Herb Salvia miltiorrhiza (Danshen) Potently Inhibit Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8). AB - Many active components of herbal products are small organic anions, and organic anion transporters were previously demonstrated to be a potential site of drug drug interactions. In this study, we assessed the inhibitory effects of six hydrophilic components of the herbal medicine Danshen, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, and tanshinol, on the function of the murine organic anion transporters, mOat1 and mOat3. All of Danshen components significantly inhibited mOat1- and mOat3 mediated substrate uptake (P < 0.001) with lithospermic acid (LSA), protocatechuic acid, rosmarinic acid (RMA), and salvianolic acid A (SAA) producing virtually complete inhibition under test conditions. Kinetic analysis demonstrated that LSA, RMA, and SAA were competitive inhibitors. As such, K(i) values were estimated as 14.9 +/- 4.9 MUM for LSA, 5.5 +/- 2.2 MUM for RMA, and 4.9 +/- 2.2 MUM for SAA on mOat1-mediated transport, and as 31.1 +/- 7.0 MUM for LSA, 4.3 +/- 0.2 MUM for RMA, and 21.3 +/- 7.7 MUM for SAA on mOat3-mediated transport. These data suggest that herb-drug interactions may occur in vivo on the human orthologs of these transporters in situations of polypharmacy involving Danshen and clinical therapeutics known to be organic anion transporter substrates. PMID- 22844342 TI - Effectiveness of Mentha piperita in the Treatment of Infantile Colic: A Crossover Study. AB - Background. Infantile colic is a distressing and common condition for which there is no proven standard treatment. Objective. To compare the efficacy of Mentha piperita with simethicone in treatment for infantile colic. Methods. A double blind crossover study was performed with 30 infants attending IMIP, Recife, Brazil. They were randomized to use Mentha piperita or simethicone in the treatment of infantile colic during 7 days with each drug. Primary outcomes were mother_s opinion about responses to the treatment, number of daily episodes of colic, and time spent crying, measured by a chronometer. Mann-Whitney and chi square tests were used to compare the results. This study was previously approved by the Ethical Committee in Research at IMIP. Results. At baseline daily episodes of infantile colic was 3.9 (+/-1.1) and the mean crying time per day was 192 minutes (+/-51.6). At the end of the study daily episodes of colic fell to 1.6 (+/-0.6) and the crying duration decreased to 111 (+/-28) minutes. All mothers reported decrease of frequency and duration of the episodes of infantile colic and there were no differences between responses to Mentha piperita and simethicone. Conclusions. These findings suggest that Mentha piperita may be used to help control infantile colic. However, these results must be repeated by others studies. PMID- 22844340 TI - Emerging glycolysis targeting and drug discovery from chinese medicine in cancer therapy. AB - Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the "Warburg Effect." Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM) is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment. PMID- 22844343 TI - Supramolecular hydrogels formed by the conjugates of nucleobases, Arg-Gly-Asp (RGD) peptides, and glucosamine. AB - Here we report the generation of a novel class of supramolecular hydrogelators based on the integration of nucleobase, Arg-Gly-Asp (RGD) peptides, and glucosamine in a single molecule. These novel small molecule hydrogelators self assemble in water to form stable supramolecular nanofibers/hydrogels and exhibit useful biostability. This approach provides a new opportunity for systematic exploration of the self-assembly of small biomolecules by varying any individual segment to generate a large array of supramolecular hydrogels for biological functions and for biomedical applications. PMID- 22844341 TI - Cancer-related stress and complementary and alternative medicine: a review. AB - A cancer diagnosis elicits strong psychophysiological reactions that characterize stress. Stress is experienced by all patients but is usually not discussed during patient-healthcare professional interaction; thus underdiagnosed, very few are referred to support services. The prevalence of CAM use in patients with history of cancer is growing. The purpose of the paper is to review the aspects of cancer related stress and interventions of commonly used complementary and alternative techniques/products for amelioration of cancer-related stress. Feasibility of intervention of several CAM techniques and products commonly used by cancer patients and survivors has been established in some cancer populations. Efficacy of some CAM techniques and products in reducing stress has been documented as well as stress-related symptoms in patients with cancer such as mindfulness-based stress reduction, yoga, Tai Chi Chuan, acupuncture, energy-based techniques, and physical activity. Much of the research limitations include small study samples and variety of intervention length and content. Efficacy and safety of many CAM techniques and some herbs and vitamin B and D supplements need to be confirmed in further studies using scientific methodology. Several complementary and alternative medicine therapies could be integrated into standard cancer care to ameliorate cancer-related stress. PMID- 22844344 TI - "Group sex" parties and other risk patterns: A qualitative study about the perceptions of sexual behaviors and attitudes of adolescents in Soweto, South Africa. AB - This study explored perceptions about sexual behaviors and attitudes of adolescents living in Soweto, Johannesburg, South Africa, from the perspective of parents, counselors and adolescents. A qualitative methodology was applied. Nine focus group discussions (FGDs) were held; three with parents of adolescents, two with counselors who work with adolescents, two with female adolescents aged 16-18 years and two with male adolescents aged 16-18 years. In total, 80 participants were recruited from in and around Soweto. FGDs were guided by a semi-structured interview guide, audio-recorded, transcribed verbatim and translated into English. Data were analyzed using Maxqda, a qualitative software analysis program. There were eight key themes related to adolescent sexuality and perceived attitudes towards relationships. Five themes were common to all participant groupings (parents, counselors and adolescents): (1) dating during adolescence, (2) adolescent females dating older males, (3) condom use amongst adolescents, (4) pregnancy and (5) homosexuality. (6) Sex as a regular and important activity among adolescents and (7) group sex practices among adolescents emerged as themes from adolescent and counselor FGDs. Lastly, (8) the role of the media as an influence on adolescent sexuality was common to adolescent and parent groups. Risky sexual behaviors continue among adolescents, with group sex parties a concerning emergent phenomenon that necessitates further study. HIV, other STIs and pregnancy prevention interventions should address multiple levels of influence to address context-specific influences. PMID- 22844346 TI - Comparison of semiparametric, parametric, and nonparametric ROC analysis for continuous diagnostic tests using a simulation study and acute coronary syndrome data. AB - We aimed to compare the performance of three different individual ROC methods (one from each of the broad categories of parametric, nonparametric and semiparametric analysis) for assessing continuous diagnostic tests: the binormal method as a parametric method, an empirical approach as a nonparametric method, and a semiparametric method using generalized linear models (GLM). We performed a simulation study with various sample sizes under normal, skewed, and monotone distributions. In the simulations, we used estimates of the ROC curve parameters a and b, estimates of the area under the curve (AUC), the standard errors and root mean square errors (RMSEs) of these estimates, and the 95% AUC confidence intervals for comparison. The three methodologies were also applied to an acute coronary syndrome dataset in which serum myoglobin levels were used as a biomarker for detecting acute coronary syndrome. The simulation and application studies suggest that the semiparametric ROC analysis using GLM is a reliable method when the distributions of the diagnostic test results are skewed and that it provides a smooth ROC curve for obtaining a unique cutoff value. A sample size of 50 is sufficient for applying the semiparametric ROC method. PMID- 22844345 TI - Modulation of HIV pathogenesis and T-cell signaling by HIV-1 Nef. AB - HIV-1 Nef protein is an approximately 27-kDa myristoylated protein that is a virulence factor essential for efficient viral replication and infection in CD4(+) T cells. The functions of CD4(+) T cells are directly impeded after HIV infection. HIV-1 Nef plays a crucial role in manipulating host cellular machinery and in HIV pathogenesis by reducing the ability of infected lymphocytes to form immunological synapses by promoting virological synapses with APCs, and by affecting T-cell stimulation. This article reviews the current status of the efficient Nef-mediated spread of virus in the unreceptive environment of the immune system by altering CD4(+) T-lymphocyte signaling, intracellular trafficking, cell migration and apoptotic pathways. PMID- 22844347 TI - Risk factors for mortality among 2009 A/H1N1 influenza hospitalizations in Maricopa County, Arizona, April 2009 to March 2010. AB - We analyzed individual-level data on pandemic influenza A/H1N1pdm hospitalizations from the enhanced surveillance system of the Maricopa County Department of Public Health, AZ, USA from April 1st, 2009 to March 31st, 2010. We also assessed the the risk of death among A/H1N1 hospitalizations using multivariate logistic regression. Hospitalization rates were significantly higher among Native Americans (risk ratio (RR) = 6.2; 95% CI: 6.15, 6.21), non Hispanic Black (RR = 3.84; 95% CI: 3.8, 3.9), and Hispanics (RR = 2.0; 95% CI: 2.0, 2.01) compared to non-Hispanic Whites. Throughout the spring, 59.2% of hospitalized patients received antiviral treatment; the proportion of patients treated increased significantly during the fall to 74.4% (Chi-square test, P < 0.0001). In our best-fit logistic model, the adjusted risk of death among A/H1N1 inpatients was significantly higher during the fall wave (August 16, 2009 to March 31, 2010, OR = 3.94; 95% CI: 1.72, 9.03) compared to the spring wave (April 1, 2009 to August 15, 2009). Moreover, chronic lung disease (OR = 3.5; 95% CI: 1.7, 7.4), cancer within the last 12 months (OR = 4.3; 95%CI: 1.3, 14.8), immuno suppression (OR = 4.0; 95% CI: 1.84, 8.9), and admission delays (OR = 4.6; 95% CI: 2.2, 9.5) were significantly associated with an increased the risk of death among A/H1N1 inpatients. PMID- 22844348 TI - A perspective on the proposal for neurocognitive disorder criteria in DSM-5 as applied to HIV-associated neurocognitive disorders. AB - HIV-associated neurocognitive disorders remain common in the current era of effective antiretroviral therapy. However, the severity at presentation of these disorders has been reduced, and the typical manifestations have changed. A revision of the American Academy of Neurology (AAN) criteria has been made on this basis, and a revision of the analogous criteria by the American Psychiatric Association will be forthcoming in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5. This article compares the relevant sets of diagnostic criteria that will be employed. It is concluded that a greater degree of integration of the revised, HIV-specific AAN criteria for HIV-associated neurocognitive disorders with the criteria proposed for the DSM-5 would prove advantageous for research, clinical, educational and administrative purposes. PMID- 22844350 TI - Mitochondria are the primary source of the H(2)O(2) signal for glucocorticoid induced apoptosis of lymphoma cells. AB - Glucocorticoids are a class of steroid hormones commonly used for the treatment of hematological malignancies due to their ability to induce apoptosis in lymphoid cells. An understanding of the critical steps in glucocorticoid-induced apoptosis is required to identify sources of drug resistance. Previously, we found that an increase in hydrogen peroxide is a necessary signal for glucocorticoid-induced apoptosis. In the current study, we found that mitochondria are the source of the signal. Glucocorticoid treatment inhibited Complex I and Complex III of the electron transport chain (ETC). Mitochondrial matrix reactive oxygen species (ROS) increased concomitantly with the oxidation of the mitochondrial glutathione pool. Treatment with Tiron, a superoxide scavenger, inhibited the signal. This suggests that the hydrogen peroxide signal originates as superoxide from the mitochondria and is metabolized to hydrogen peroxide. An inability to generate mitochondrial oxidants in response to glucocorticoids could cause drug resistance. PMID- 22844352 TI - HER2 expression in renal cell carcinoma is rare and negatively correlated with that in normal renal tissue. AB - The aim of this study was to evaluate the status of HER2 protein expression in patients with renal cell carcinoma (RCC) and to determine its prognostic significance. A total of 42 paraffin-embedded tumor tissues and 42 additional corresponding adjacent normal tissues from RCC patients were randomly collected and studied using immunohistochemistry (IHC). Protein samples of 6 fresh specimens from tumor and adjacent normal tissues obtained during surgery were extracted and tested using western blotting to confirm the IHC results. Of the 42 tumor tissues and adjacent normal tissues tested, IHC showed that 7 tumors (16.67%) and 33 adjacent normal tissues (78.57%) expressed the HER2 protein. In addition, results of the western blotting revealed weak HER2 reactivity in primary tumor cells in two of 6 specimens obtained during surgery. All 6 normal tissues showed positive expression, which was in accordance with the outcome of IHC. In conclusion, HER2 is frequently expressed in normal renal tissues and rarely expressed in RCC tissues. Furthermore, the HER2 status of normal tissue is negatively correlated with that of the RCC tissues (r=-0.410, P=0.007) and the TNM stage (r=-0.246, P=0.027), suggesting that HER2 is involved in RCC oncogenesis. PMID- 22844351 TI - Tumor stem cells: A new approach for tumor therapy (Review). AB - Recent studies have demonstrated the existence of a minority of tumor cells possessing the stem cell properties of self-renewal and differentiation in leukemia and several solid tumors. However, these cells do not possess the normal regulatory mechanisms of stem cells. Following transplantation, they are capable of initiating tumorigenesis and are therefore known as 'tumor stem cells'. Cellular origin analysis of tumor stem cells has resulted in three hypotheses: Embryonal rest hypothesis, anaplasia and maturation arrest. Several signaling pathways which are involved in carcinogenesis, including Wnt/beta-catenin, Notch and Oct-4 signaling pathways are crucial in normal stem cell self-renewal decisions, suggesting that breakdown in the regulation of self-renewal may be a key event in the development of tumors. Thus, tumors can be regarded as an abnormal organ in which stem cells have escaped from the normal constraints on self-renewal, thus, leading to abnormally differentiated tumor cells that lose the ability to form tumors. This new model for maligancies has significance for clinical research and treatment. PMID- 22844353 TI - IL-23 directly enhances the proliferative and invasive activities of colorectal carcinoma. AB - Interleukin-23 (IL-23) plays an essential role in the mucosal immune system. It has been suggested that IL-23 is able to induce carcinogenesis as well as inflammation and a recent study revealed that IL-23R is expressed in colorectal carcinoma cells. However, neither the differences in the IL-23R expression among the patients nor the concrete functions of IL-23 in colorectal carcinoma cells have been revealed. The aim of the present study was to examine the characteristics of IL-23R expression in colorectal carcinoma and the direct effects of IL-23 on colorectal cancer cells. We examined the IL-23R expression in human colorectal cancer tissue samples by immunohistochemistry. Cell proliferation and invasion assays under IL-23 stimulation were performed using cultured cells derived from colorectal cancer. ELISA and real-time PCR were used to evaluate the transforming growth factor (TGF)-beta production due to IL-23 stimulation. All of the TNM stage IV patients were positive for IL-23R. IL-23R expression in the carcinoma tissue was also relatively high at the deepest point of invasion in certain cases. The proliferative and invasive activities and/or TGF-beta production of DLD-1 cells increased by IL-23 stimulation, whereas no change was observed in the activities of MIP101 and KM12c cells. IL-23 directly enhanced the malignancy of the colon carcinoma cells. An autocrine mechanism via TGF-beta production may underlie these effects. IL-23 is therefore a potential target for cancer immunotherapy. However, the homogeneity in IL-23R expression and the effects of IL-23 on colorectal carcinoma cells should be considered. PMID- 22844354 TI - Advantages of the quenching probe method over other PCR-based methods for detection of the JAK2 V617F mutation. AB - The detection of a V617F mutation (G to T exchange at nucleotide 1,849) in the JAK2 gene is crucial for the diagnosis of myeloproliferative neoplasms (MPN) such as polycythemia vera. Although sequence analysis is the standard method for detection, it is not suitable for clinical examinations due to the requirement of expensive equipment. In this study, we evaluated the efficiencies of four PCR based methods to detect JAK2 V617F: allele-specific PCR (AS-PCR), PCR-restriction fragment length polymorphism (PCR-RFLP), high-resolution melting analysis (HRM) and the quenching probe method (QP). The HEL cell line, which harbors a homozygous JAK2 V617F mutation, as well as bone marrow samples from 16 MPN patients and normal control samples, were used in this assessment. The sensitivity of the detection limit of all four methods was also examined using samples of HEL cells mixed in a variety of ratios with cells containing wild-type JAK2. The results of all four methods were found to be concordant. AS-PCR was shown to be the most sensitive; however, it produced false positive results. Although PCR-RFLP demonstrated high specificity, it was time consuming. By contrast, results were obtained using HRM and QP in only 2 h. It was easier to recognize the curves derived from the mutant allele obtained using QP. QP is also suitable for the rough estimation of allele burden. JAK2 V617F assays are mainly used for diagnosis at presentation in clinical settings. We therefore conclude that in situations where high sensitivity is not required, QP is the preferable method for the detection of JAK2 V617F. To the best of our knowledge, this is the first report to demonstrate the efficiency of the QP method for the detection of JAK2 V617F using a standard thermal cycler. PMID- 22844355 TI - A unique cytogenetic abnormality, t(2;7)(p13.1;p21.3), in a Philadelphia-positive chronic myeloid leukemia. AB - The Philadelphia (Ph) chromosome is present in more than 90% of patients suffering from chronic myeloid leukemia (CML). It is the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the transfer of the 3' portion of the proto-oncogene ABL from 9q34 to the 5' portion of the breakpoint cluster region (BCR) on 22q11. Currently, most CML cases are treated with Imatinib and variant rearrangements are thought to have no specific prognostic significance, although the events of therapy resistance have not yet been studied. In this study we report a novel case of CML exhibiting an uncommon t(2;7)(p13.1;p21.3) besides t(9;22)(q34;q11). This unusual translocation has been characterized by fluorescence in situ hybridization (FISH) and array-proven multicolor banding (aMCB), the latter being extremely significant in characterizing breakpoint regions in detail. The underlying mechanisms and prognostic implications of this cytogenetic abnormality are discussed in this study. PMID- 22844349 TI - Mammary gland development. AB - The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial-mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development-pubertal growth, pregnancy, lactation, and involution-occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease. PMID- 22844357 TI - Evaluation of the uptake function of liver in rats with obstructive jaundice before and after relief from obstruction by superparamagnetic iron oxide-enhanced magnetic resonance imaging. AB - The aim of this study was to investigate the changes in the uptake function of the liver in rats with obstructive jaundice prior to and following relief from obstructive jaundice, and to investigate whether superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) could be used to assess liver uptake function. In total, 40 male Sprague Dawley rats were randomly assigned into four groups: Obstructive jaundice, internal drainage, external drainage and sham surgery. The common bile ducts in the obstructive jaundice group were ligated. Internal drainage (ID) and external drainage (ED) groups were ligated, followed by internal drainage or external drainage, respectively. The T2 and T2* values of the liver parenchyma were measured. Liver sections were stained with Perls' Prussian blue, and hematoxylin and eosin. The number of SPIO-nanoparticle clusters was counted manually using a microscope. Total bilirubin of the blood was measured. Results showed that the T2 and T2* values and total bilirubin of the obstructive jaundice group were significantly higher compared to the other three groups. The number of SPIO-nanoparticle clusters in the obstructive jaundice group was significantly lower compared to the other three groups. In conclusion, obstructive jaundice suppresses liver uptake function in rats, which may be reversed by internal and external biliary drainage. However, no significant difference was found between the therapeutic effect of ID and ED on liver uptake function. Thus, SPIO-enhanced MRI may be used to evaluate the uptake function of the liver. PMID- 22844356 TI - Expression of K19 and K7 in dysplastic nodules and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumors characterized by a multistep process of tumor development. Nodular lesions that differ from the surrounding liver parenchyma and are characterized by cytological or structural atypia are termed dysplastic nodules (DNs). DNs are well-known precancerous HCC lesions. Expression of keratin (K) 19 and K7, molecular markers of hepatic progenitor cells and cholangiocytes, has been reported in certain HCCs. However, it remains unclear whether K19-positive HCC cells are derived from true hepatic progenitor cells or mature cells that have undergone a dedifferentiation or a transdifferentiation process. In total, 107 tissue sections (13 low-grade DNs, 15 high-grade DNs, 27 small HCCs and 52 large HCCs) from resected liver samples and 132 HCC tissue microarray (TMA) cores were subjected to immunohistochemical analysis for K19 and K7. Clinicopathological data of the HCC patients were evaluated. K19 expression was found in 0% of DNs, 19% of small HCCs (<=2 cm), 8% of large HCCs (>2 cm) and 8% of TMA samples. K7 expression was found in 14% of DNs, 41% of small HCCs, 15% of large HCCs and 6% of TMA samples. Among the five K19-positive small HCCs, four were distinctly nodular and one tumor was an infiltrative type. No vaguely nodular HCC was positive for K19. K19 expression was significantly associated with histological grade (P=0.023), serum alpha-fetoprotein level (P=0.001) and K7 expression (P=0.001) in HCC. K19 expression was an independent prognostic factor for overall survival in non-viral HCC patients (P=0.003). K19 expression is extremely rare in DNs and occurs in progressed small HCCs. Our results suggest that K19 expression may be an acquired feature of carcinoma cells during HCC progression in certain HCCs. PMID- 22844358 TI - Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness. AB - Voltage-dependent K+ channels (Kv) are involved in the proliferation and differentiation of mammalian cells, since Kv antagonists impair cell cycle progression. Although myofibers are terminally differentiated, some myoblasts may re-enter the cell cycle and proliferate. Since Kv1.3 and Kv1.5 expression is remodeled during tumorigenesis and is involved in smooth muscle proliferation, the purpose of this study was to analyze the expression of Kv1.3 and Kv1.5 in smooth muscle neoplasms. In the present study, we examined human samples of smooth muscle tumors together with healthy specimens. Thus, leiomyoma (LM) and leiomyosarcoma (LMS) tumors were analyzed. Results showed that Kv1.3 was poorly expressed in the healthy muscle and indolent LM specimens, whereas aggressive LMS showed high levels of Kv1.3 expression. Kv1.5 staining was correlated with malignancy. The findings show a remodeling of Kv1.3 and Kv1.5 in human smooth muscle sarcoma. A correlation of Kv1.3 and Kv1.5 expression with tumor aggressiveness was observed. Thus, our results indicate Kv1.5 and Kv1.3 as potential tumorigenic targets for aggressive human LMS. PMID- 22844360 TI - The importance of molecular cytogenetic analysis prior to using cell lines in research: The case of the KG-1a leukemia cell line. AB - KG-1 and its less differentiated subline KG-1a are leukemia cell lines used in research in a number of laboratories. The karyotypes of the two lines were initially identical. In the following years, further analysis revealed that the cell lines had acquired additional karyotypical abnormalities and differed in the presence of certain typical chromosomal rearrangements. To obtain cytogenetic authentication prior to the use of the two cell lines, we analyzed their karyotype by combining DAPI- and CMA-chromosome bandings and a fluorescence in situ hybridization (FISH)-based approach by using BAC clones useful for the identification of chromosome regions of interest. Sequences of the MYC, PLZF, RARA and BCR genes, that are known to play a critical role in leukemogenesis, and certain BAC clones mapped to five known common fragile sites (CFS) were used for the FISH analysis. A telomeric probe (TTAGGG)n and a set of BAC clones were used to characterize the marker chromosome der(1) that was observed in the cell line KG-1a. The existence of notable differences between the karyotype of the KG-1a cell line previously described, and that described in this study, demonstrate that the use of established cancer cell lines should be preceded by cytogenetic and/or molecular characterization. PMID- 22844359 TI - Inhibitory effects of lupeal acetate of Cortex periplocae on N nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. AB - Lupeal acetate of Cortex periplocae (CPLA), a triterpene compound extracted from a traditional Chinese herb, has been identified as an inhibitor of cancer cell growth. The objective of the present study was to evaluate the potential mechanisms through which CPLA inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. We treated F344 rats subcutaneously with the esophageal carcinogen NMBA (0.5 mg/kg body weight) and intramuscularly with CPLA (20 mg/kg), 3 times a week for 5 weeks. Rats were then sacrificed at weeks 9, 15 or 25, esophageal tissues were collected and tumor data were recorded. To investigate the mechanisms by which CPLA modulates tumorigenesis in esophagus, we evaluated the protein expression of glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin and the gene expression of c-myc. CPLA significantly (P<0.05) reduced the incidence of esophageal tumors observed at 25 weeks from 93.3% in NMBA-treated controls to 33.3% in the NMBA- and CPLA-treated rats. CPLA reduced beta-catenin and c-myc expression, but increased GSK-3beta expression, in preneoplastic lesions of the esophagus. These results suggest a novel tumor suppressive role of CPLA through the activation of GSK-3beta expression and the inhibition of beta-catenin and c-myc expression. Therefore, CPLA is a potential therapeutic candidate for esophageal squamous cell carcinoma. PMID- 22844361 TI - Patched homolog 1 gene mutation (p.G1093R) induces nevoid basal cell carcinoma syndrome and non-syndromic keratocystic odontogenic tumors: A case report. AB - Mutations in the Patched homolog 1 (PTCH1) gene lead to an autosomal dominant disorder known as nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome (GS). Several PTCH1 mutations have been observed in NBCCS associated with keratocystic odontogenic tumors (KCOTs), including non-syndromic KCOTs. The missense mutation c.3277G>C (p.G1093R) in exon 19 of the PTCH1 gene has only been reported in non-syndromic KCOTs. The present study reports for the first time a familial case (father and daughter) of NBCCS and KCOTs, carrying the same c.3277G>C (p.G1093R) germline mutation. This observation suggests that this missense mutation is involved in the pathogenesis of NBCCS as well as in a subset of non-syndromic KCOTs. The identification of a missense mutation may lead to an earlier diagnosis of NBCCS. PMID- 22844362 TI - An unusual occurrence of solitary extramedullary plasmacytoma in the conjunctiva. AB - The occurrence of a solitary plasmacytoma in the conjunctiva is unusual. This relatively uncommon neoplastic disorder occurs more frequently in other organs and is derived from B-lymphocytes. In the present study the case of a 17-year-old female, who had a lesion of the lower fornix conjunctiva in the left eye, is presented. The lesion was resected and the patient underwent amniotic membrane transplantation. Pathological examination of the specimen showed a plasmacytoma. Bone marrow aspirate showed that the cellularity and number of plasma cells were normal, and no myeloma cells were observed. A complete skeletal survey failed to show bony masses or osteolytic events. Following surgery, the patient was provided with a course of radiotherapy. During the follow-up period of 12 months the lesion did not recur. PMID- 22844363 TI - Genetic polymorphisms of XPD and CDA and lung cancer risk. AB - To determine the susceptibility genes of lung cancer, we investigated the frequency distributions of the xeroderma pigmentosum complementary group D (XPD) and cytidine deaminase (CDA) genes in patients. A case-control study was conducted involving lung cancer patients and healthy controls. The genotypic distributions of XPD exon 10 G->A (Asp312Asn) and 23 T->G (Lys751Gln), and CDA 79 A->C (Lys27Gln) and 208 G->A (Ala70Thr), were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results demonstrated that the XPD Asp312Asn genotype distribution was G/G (82.52%) and A/G (17.48%) in the lung cancer patients, and G/G (82.52%), A/G (16.50%) and A/A (10.98%) in the controls. The genotypes of Lys751Gln were T/T (83.49%) and T/G (16.50%) in the lung cancer patients, and T/T (84.47%) and T/G (15.53%) in the controls. Mutations in the XPD single nucleotide polymorphism loci did not demonstrate a significant difference between the two groups (P>0.05). The risk of lung cancer in individuals with mutations at positions 312 and 751 increased 6.13 fold (P=0.047). The CDA Lys27Gln genotype distribution was A/A (78.65%), A/C (20.39%) and C/C (0.98%) in the lung cancer patients, and A/A (79.61%), A/C (19.42%) and C/C (0.98%) in the controls (P=0.985). The CDA Ala70Thr genotype distribution was G/G (98.06%) and A/G (1.94%) in the controls, while all the genotypes were wild-type in the lung cancer patients. The difference between the lung cancer patients and the controls was not statistically significant (P=0.155). There was also no significant difference in the frequency distribution of XPD or CDA between the different pathological types (P>0.05). Our findings demonstrate that the mutation of XPD codons 312 and 751 increases the risk of lung cancer. By contrast, polymorphisms of CDA appear to have little association with lung cancer. PMID- 22844364 TI - Expression of CA125 and cisplatin susceptibility of pleural effusion-derived human lung cancer cells from a Thai patient. AB - Advances in understanding lung cancer biology and tumor markers aid clinicians in managing the disease. Cancer-associated antigen (CA)125 has garnered increasing attention in lung cancer research and may benefit the treatment and follow-up of this type of cancer. In Thai lung cancer patients, knowledge regarding ethnic differences in cancer cell biology is largely absent. We generated lung cancer cells from the pleural effusion fluids of a Thai patient and designated these as P1 cells. P1 cells were assessed for growth rate, response to chemotherapy, and the presence of tumor markers, in particular CA125 expression. Results of immunofluorescence indicated that P1 cells exhibited strong expression levels of CA125, comparable to that of established H460 lung cancer cells. Furthermore, P1 cells were analyzed for the expression of additional markers. Results revealed that H460 cells exhibited strong immunofluorescent signals from cytokeratin-19 fragments (CYFRA 21-1) and squamous cell carcinoma antigen (SCCA) while P1 presented only CYFRA 21-1 signals. We also found evidence of relative cisplatin resistance in P1 compared to the susceptibility level of established lung cancer cells. Thus, the results and methodology described in this study may aid the development of lung cancer diagnostic and therapeutic approaches and, in particular, advance understanding of ethnic differences. PMID- 22844365 TI - Reduced migration of Ishikawa cells associated with downregulation of aquaporin 5. AB - Aquaporin (AQP)-dependent cell migration has broad implications in angiogenesis, tumor metastasis, wound healing, glial scarring and other events requiring cell movement. There are 13 isoforms of AQP (0-12) that have been identified in mammals. It is unclear whether AQP5 plays a role in the development of endometrial cancer. We recently demonstrated that ovarian steroids may affect the expression of AQP5 in the female genital tract. In this study, we considered whether AQP5 may affect cell migration in Ishikawa cells, an adenocarcinoma cell line derived from the endometrium. The results showed that the downregulation of AQP5 results in reduced Ishikawa cell migration. The estrogen (E2) receptor in the promoter of AQP5 mediated the regulation of AQP5 expression in the normal endometrium and endometrial cancer. By contrast, the upregulation of AQP5 by E2 increased cell migration, invasion and adhesion through increased annexin-2, which is responsible for F-actin remodeling and rearrangement. E2 regulates Ishikawa cell migration by regulating the AQP5 expression. PMID- 22844366 TI - Bortezomib-based treatment for relapsed and refractory angioimmunoblastic T-cell lymphoma: Case report and literature review. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma (PTCL) subtype, accounting for 15-20% of PTCL and 2% of all non-Hodgkin lymphoma (NHL), with a poor prognosis. In the present study, we describe a 76 year-old patient with AITL who failed to respond to conventional chemotherapy but responded to bortezomib-based treatment and demonstrated persistent clinical improvement at the 18-month follow-up. These data suggest that bortezomib-based treatment may be a reliable, safe and effective alternative for treating relapsed/refractory AITL. PMID- 22844367 TI - A new marker, SOX11, aids the diagnosis of mantle cell lymphoma in the prostate: A case report. AB - Mantle cell lymphoma (MCL) of the prostate, either primary or secondary, is a rare entity. This case report examines an 83-year-old male who complained of not only nocturia (2-3 times), but also frequency and urgency of urination. The maximal urinary flow rate was 4.1 ml/sec. A transrectal ultrasound-guided prostate biopsy was advised after a hard enlargement of the prostate was detected; however, it was refused. Therefore, a plasma kinetic transurethral resection of the prostate was performed. Postoperative pathological examinations demonstrated MCL of the prostate. Positive immunohistochemistry for CD5 and cyclin D1 was observed. The diagnosis was confirmed by the introduction of a new diagnostic marker, SOX11. The maximal flow rate achieved was 15 ml/sec following surgery. To the best of our knowledge, this is the first study of MCL being diagnosed using SOX11 as a marker in the prostate. This case should alert clinicians and pathologists to pay close attention to the diagnosis of malignant lymphoma of the prostate. This study provides further insights into the diagnosis and therapy of MCL. PMID- 22844368 TI - Identification of a DNA methylation marker that detects the presence of lymph node metastases of gastric cancers. AB - The accurate detection of the presence of lymph node metastases (LNM) of gastric cancers (GCs) is useful for the implementation of necessary and sufficient treatment, but current methods of detection are unsatisfactory. In the present study, we focused on DNA methylation markers since they have several advantages, including biological and chemical stability and informativeness even in the presence of contaminating cells. Using three metastatic lymph nodes and three primary GCs without LNM, methylation bead array analyses were performed, which enabled the interrogation of 485,577 CpG sites. A total of 31 CpG sites that were hypermethylated in the metastatic lymph nodes, compared with the GCs without LNM, were isolated. Using primary GCs with and without LNM (28 GCs with LNM and 10 without), their methylation levels were measured using quantitative PCR following treatment with sodium bisulfite or a methylation-sensitive restriction enzyme. Of the genomic regions around the 31 CpG sites, 10 regions demonstrated higher methylation levels in the GCs with LNM compared with the GCs without LNM (P<0.05). Finally, the hypermethylation of the 10 regions was validated using another set of samples (129 GCs with LNM and 20 without). Hypermethylation of the region around the cg06436185 CpG site predicted the presence of LNM at a sensitivity of 43% and specificity of 85%. Additionally, the hypermethylation of the region was associated with a poor survival rate among GC patients with LNM. The results of the present study indicated that the methylation status of the region was a promising candidate marker to detect the presence of LNM of GCs and may reflect the malignant potential of GCs. PMID- 22844369 TI - Identification of clinicopathological factors predicting lymph node metastasis in differentiated submucosal gastric cancer: Impact on surgical strategy. AB - The aim of this study was to identify the clinicopathological factors predictive of lymph node metastasis (LNM) in differentiated submucosal gastric cancer (SGC), and to establish a simple criterion which may be useful in selecting the optimal treatment for cases with SGC. A total of 70 patients with differentiated and surgically treated SGC were retrospectively examined, and the association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated. In the univariate analysis, tumor size, lymphatic vessel involvement and the presence of intermingled components of undifferentiated cancer cells were significantly associated with a higher rate of LNM (all P<0.05). In the multivariate analysis, lymphatic vessel involvement (OR=392.269; 95% CI 1.380-1115.032; P=0.038) and presence of intermingled components of undifferentiated cancer cells (OR=98.515; 95% CI 2.687-3612.400; P=0.012) were found to be independent pathological risk factors for LNM. LNM was observed in 75.0% (3/4) of patients with the two risk factors, but in none of the 45 patients without the two risk factors. Lymphatic vessel involvement and presence of intermingled components of undifferentiated cancer cells are independently associated with the presence of LNM in differentiated SGC. Thus, these two risk factors may be used to establish a simple criterion to guide further surgical procedures in cases with SGC revealed after endoscopic mucosal resection (EMR). PMID- 22844370 TI - Effects of cyclohexanone analogues of curcumin on growth, apoptosis and NF-kappaB activity in PC-3 human prostate cancer cells. AB - Curcumin is a non-nutritive yellow pigment found in the spice turmeric, which is derived from the rhizome of the plant Curcuma longa Linn. Six cyclohexanone analogues of curcumin (A(1)-A(6)) were investigated for their effects on growth and apoptosis in PC-3 human prostate cancer cells. The ability of these compounds to inhibit NF-kappaB activity in PC-3 cells was also determined. Five out of the six curcumin analogues (A(2)-A(6)) had stronger inhibitory effects compared to curcumin on the growth of cultured PC-3 cells. Compounds A(2)-A(6) also had stronger stimulatory effects on apoptosis in PC-3 cells than curcumin, and these curcumin analogues more potently inhibited NF-kappaB activity than curcumin. The inhibitory effects of these compounds on NF-kappaB activity correlated with their effects on growth inhibition and apoptosis stimulation in PC-3 cells. The results of the present study provide a rationale for in vivo studies with A(2)-A(6) using suitable animal models of prostate cancer. PMID- 22844371 TI - Case report of concurrent primary malignancies of the breast and nasopharynx. AB - The aim of this study was to report a case of concurrent primary malignancies of the breast and nasopharynx and discuss the potential relationship between Epstein Barr virus (EBV) infection and breast cancer. A 39-year-old female presented with a palpable mass present for 1 year in her left breast. Immunohistochemical staining was performed and the results showed that the tumor cells were immunopositive for the estrogen receptor, progesterone receptor and p53 protein, and markedly positive for C-erb B2. In addition, 30% of the tumor cells were positive for the Ki-67 antigen. Blood test results revealed that EBV-CA-IgG was present and EBV-EA-IgG was reactivated. The patient was diagnosed with breast cancer (T1N0M0) and EBV infection. A mastectomy with axillary clearance was performed on the left breast. Histopathological examination provided evidence of invasive ductal adenocarcinoma. Further evaluation due to epistaxis following the breast surgery resulted in a diagnosis of nasopharyngeal carcinoma (T2N1M0). Histopathology showed a non-keratinizing undifferentiated carcinoma. The patient was treated with chemoradiotherapy for nasopharyngeal carcinoma. Twelve months following surgery and chemoradiotherapy the patient was assessed at the Cancer Hospital of Guangxi Medical University outpatient clinic and no evidence of relapse or metastasis was found. Thus, EBV infection may be involved in the pathogenesis of breast cancer, as observed in nasopharyngeal carcinoma. PMID- 22844372 TI - Ras-proximate-1 GTPase-activating protein and Rac2 may play pivotal roles in the initial development of myelodysplastic syndrome. AB - Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia. Adhesion molecules and the Wnt signaling pathway are mostly involved with the self-renewal, proliferation and differentiation of hematopoietic stem cells (HSCs) while Rho GTPases are closely correlated with the cytoskeleton and therefore cell morphology. To gain insight into the poorly understood pathophysiology of MDS, the present study focused on analyzing the gene expression profiles of these molecules with whole genomic array using CD34(+) cells from MDS patients. These profiles showed that N-cadherin, E cadherin and c-myc binding protein tended to be downregulated, whereas beta catenin, Ras-proximate-1 GTPase-activating protein (Rap1GAP), c-myc promoter binding protein, Rac1, Rac2 and CDC42 tended to be upregulated. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of beta-catenin, was observed. The array results were confirmed by real-time quantitative polymerase chain reaction (RQ-PCR) using CD34(+) cells from a cohort of patients with MDS-refractory anemia (RA) [WHO (2008) RCUD, RCMD and MDS-U] who had normal karyotypes. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA [WHO (2008) RCUD, RCMD and MDS-U] who also had normal karyotypes. We believe that the cadherin-beta-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of beta-catenin. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This study provides vital and new insights into the pathophysiology of MDS. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS. PMID- 22844374 TI - A case of carcinomatous meningitis despite prophylactic cranial irradiation in small cell lung cancer during treatment with amrubicin. AB - A 47-year-old man was diagnosed with limited-disease small cell lung cancer. Treatment was initiated with concurrent chemotherapy and radiotherapy. A partial response was achieved, and prophylactic cranial irradiation (PCI) was administered. Local recurrence was identified on follow-up and treated with amrubicin (AMR). After two courses of AMR, a state of stable disease was achieved and AMR treatment was continued. After the third course of AMR, the patient was urgently hospitalized suffering from a headache and disturbance of consciousness, and a diagnosis of carcinomatous meningitis was made. This case report concerns a case of carcinomatous meningitis despite PCI during treatment with AMR. PMID- 22844373 TI - Bisphosphonates regulate cell proliferation, apoptosis and pro-osteoclastic expression in MG-63 human osteosarcoma cells. AB - Bisphosphonates are well established in the management of cancer-induced skeletal complications. Recent studies suggest that nitrogen-containing bisphosphonates (N BPs) promote the apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To investigate whether N-BPs exhibit a direct antitumor effect on osteoclasts, the current study investigated the effects of zoledronic acid (ZOL) on MG-63 cells in vitro. MG-63 cells were treated with ZOL. The inhibitory effect of ZOL on the growth of MG-63 cells was measured by MTT assay. ZOL-induced apoptosis of the MG-63 cells was examined by Hoechst 33258 staining, electron microscopy, Annexin V-FITC and propidium iodide staining. Reverse-transcription polymerase chain reaction (RT-PCR) and western blotting analysis were employed to assess the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL). The MTT assay showed that ZOL induced a distinct dose- and time-dependent reduction of cell viability with an IC(50) value of 52.37+/-1.0 MUM for 72 h. Flow cytometric analysis further revealed that the cell apoptosis was induced by arrest of the cell cycle in the G(1) phase. RT-PCR and western blot analysis demonstrated that ZOL upregulated OPG expression. These results suggest that ZOL has direct effects on osteosarcoma cell growth and apoptosis. Increased OPG expression is an indirect effect, possibly via changes in the local microenvironment. PMID- 22844375 TI - Multidisciplinary management of very advanced stage III and IV melanoma: Proof-of principle. AB - Patients with potentially resectable advanced stage III and IV melanoma are a selected subgroup that gain maximal advantage if treated in a melanoma center. Surgery combined with chemo/chemobiotherapy may yield durable remission and long term palliation. Thirty-seven non-randomly selected patients underwent systemic therapy with the aim of consolidating treatment by surgery. Data were collected prospectively, and analyzed retrospectively. The median follow-up from diagnosis was 50 (3-307) months and 15 (1-156) months when calculated from the last intervention. Twenty-two males and 15 females, with a median age at diagnosis of 44 (20-71) years, with 13 trunk, 13 extremity, 3 head and neck and 8 unknown primary melanomas were included. There were 17 stage III and 20 stage IV patients with a median Breslow thickness of 3.7 (0.45-26) mm. Chemo/chemobiotherapy achieved 7 clinical complete responses (cCRs), 28 partial responses (PRs) and 2 instances of stable disease. Six of the 7 cCRs were operated on, securing pathological complete response in 5 and PR in one. Four of these five and the PR patient still have no evidence of disease (NED). Twenty-one of 30 PR patients were rendered NED by surgery; 14 of these 21 patients succumbed to melanoma, and one is alive with stable disease. Overall, 11 of 37 patients have not succumbed to melanoma, with a median of 72 (14-156) months survival following the last intervention. Of the eight patients with unknown primary melanomas, five have not succumbed to melanoma, with a median of 89 (30-156) months survival following the last intervention. Patients with marginally resectable stage III and IV melanoma have a significant 30% chance, according to this series, for durable remission if treated by a multidisciplinary team in a melanoma center using induction chemobiotherapy and surgery. Results are more favorable for patients with an unknown primary lesion. In view of the currently approved new effective treatments for melanoma, this study may be considered a proof-of-principle investigation, enabling long-term remissions by combining induction therapy and surgery. PMID- 22844377 TI - Serum anti-AEG-1 auto-antibody is a potential novel biomarker for malignant tumors. AB - Malignant tumors are the leading cause of mortality worldwide. The search for new biomarkers for the early diagnosis of the onset of cancer to reduce high mortality is crucial. The potential of minimal invasive testing using serum from patients renders auto-antibodies promising biomarkers for cancer diagnosis. In this study, a 181 amino acid peptide of extracellular astrocyte elevated gene-1 (AEG-1) was expressed and purified, and the peptide was used in an ELISA assay to detect anti-AEG-1 auto-antibodies (AEG-1-Abs) in 483 serum samples from different cancer patients and 230 serum samples from normal blood donors. The results showed that AEG-1-Abs at titers >=1:50 were detected in 238 of 483 (49%) cancer patients, and the positive antibody responses in different cancer patients were as follows: 44 of 98 (45%) in breast cancer patients, 48 of 96 (50%) in hepatic carcinoma patients, 43 of 88 (49%) in rectal cancer patients, 51 of 113 (45%) in lung cancer patients, and 52 of 88 (59%) in gastric cancer patients. These results were compared with 0 of 230 (0%) in normal individuals. Moreover, AEG-1 Abs at titers >=1:50 were also detected in 24 of 94 (26%) cancer patients in TNM stages I and II, and the positive rates of AEG-1-Abs decreased with age. These results suggest that the AEG-1-Ab response acts as a diagnostic biomarker for cancer patients with AEG-1-positive expression, and may also prove to be a possible inducer, with substantial immunity against AEG-1 by immunization boosting with AEG-1 vaccines. PMID- 22844376 TI - In vitro and in vivo antitumor effects of the recombinant immunotoxin IL6(T23) PE38KDEL in multiple myeloma. AB - IL6(T23)-PE38KDEL is a chimeric molecule composed of interleukin 6 (IL6), missing the N-terminal 23 amino acids, and fused to a truncated mutant form of Pseudomonas exotoxin (PE38KDEL). The aim of this study was to evaluate this recombinant immunotoxin in terms of its specific cytotoxicity to IL6R overexpressing multiple myeloma (MM) cells in vitro, as well as its antitumor effects and side effects in vivo. IL6(T23)-PE38KDEL was expressed in Escherichia coli, refolded and purified from inclusion bodies. The purified IL6(T23)-PE38KDEL was found to be selectively cytotoxic to IL6 receptor-positive tumor cells in vitro. IC(50) values of IL6(T23)-PE38KDEL were evaluated by MTS assay. Toxicity and maximum-tolerated dose of IL6(T23)-PE38KDEL were determined in mice. The antitumor activity of IL6(T23)-PE38KDEL was evaluated in mice with MM through intravenous injection and interventional therapy. Intravenous administration of IL6(T23)-PE38KDEL caused a significantly increased survival time in treated mice, and exhibited dose- and time-dependent antitumor effects against MM mice. Moreover, complete tumor regression was observed in 30 and 80% of mice treated intravenously and intraperitoneally, respectively, with 0.4 mg/kg/day for 10 days. These results demonstrated that the recombinant immunotoxin IL6(T23) PE38KDEL kills IL6R-overexpressing cancer cells, and causes significant tumor regression. PMID- 22844378 TI - The Glasgow prognostic score is valuable for colorectal cancer with both synchronous and metachronous unresectable liver metastases. AB - Systemic inflammation as evidenced by the Glasgow prognostic score (GPS) predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS in patients with both synchronous and metachronous unresectable colorectal cancer liver metastases (CRLM). The subjects were 40 patients who were diagnosed as having unresectable CRLM between March 2000 and August 2010 at Jikei University Hospital. For the assessment of systemic inflammatory response using the GPS, the patients were classified into three groups: patients with normal albumin (>=3.5 g/dl) and normal CRP (<=1.0 mg/dl) as GPS 0 (n=27), those with low albumin (<3.5 g/dl) or elevated CRP (>1.0 mg/dl) as GPS 1 (n=6), and both low albumin (<3.5 g/dl) and elevated CRP (>1.0 mg/dl) as GPS 2 (n=7). We retrospectively investigated the relationship between patient characteristics including GPS and survival using univariate and multivariate analyses. Results of the univariate analysis revealed that absence of primary tumor resection (p=0.0161), absence of systemic chemotherapy (p=0.0119), serum carcinoembroynic antigen (CEA) of >=100 ng/ml (p=0.0148), serum carbohydrate antigen (CA)19-9 of >=100 U/ml (p<0.0001) and GPS 2 (p=0.0362) were significant predictors of poor survival. Results of the multivariate analysis revealed that serum CEA of >=100 ng/ml (p=0.0015), CA19-9 of >=100 U/ml (p<0.0001) and GPS 2 (p=0.0042) were independent predictors. In conclusion, GPS at diagnosis of unresectable CRLM is an independent prognostic predictor of overall survival. PMID- 22844379 TI - Humoral and cellular immune responses to influenza vaccination in children with cancer receiving chemotherapy. AB - The immune response to influenza vaccination in children with cancer is controversial. The objective of this study was to characterize the cellular and humoral immune responses to an influenza vaccine in children with cancer who were receiving chemotherapy. In this study, children with cancer, who were not previously immunized, received an influenza vaccine via intramuscular injection. Blood samples were obtained prior to and at 4 weeks after immunization. Antibodies were measured using a hemagglutination inhibition (HI) assay. Cell mediated immunity was measured by specific lymphoproliferation with (3)H thymidine incorporation and by measuring cell frequencies following staining with monoclonal antibodies (CD8, CD4, CD19, CD45RA and CD27) using flow cytometry following incubation with the influenza antigen for 5 days. Geometric mean titers (GMT), mean counts per minute (cpm), cell frequencies prior to and following vaccination and percentage patient responses were compared using the Mann-Whitney non-parametric U and Chi-square tests; where p<0.05 was considered to indicate a statistically significant result. A total of 56 children were included. Their mean age was 6.64+/-3.61 years. Acute lymphoblastic leukemia (ALL) was diagnosed in 75, solid tumors in 23 and lymphoma in 2% of the children. Subjects with titers >=40 hemagglutination units (HU) increased from 43% prior to vaccination to 73% following vaccination (p=0.01), whereas the GMT increased from 31.35 [95% confidence interval (CI), 29-111] to 143.45 HU (95% CI, 284-640) following vaccination (p<0.001). An increase in CD45RA expression in CD8(+) T cells was observed following vaccination (p=0.01). An increase in CD27 expression was observed in the CD4/8-negative cell population stimulated with the influenza antigen following vaccination (p<0.05). No serious adverse effects were observed. An increase in the seropositivity rate and GMT values following influenza vaccination were also observed. Influenza immunization was well tolerated among these children with cancer and increased the humoral and cellular immune responses with the activation of probable lymphoid precursors. PMID- 22844380 TI - Methylation and aberrant expression of the Wnt antagonist secreted Frizzled related protein 1 in bladder cancer. AB - The aims of this study were to determine the methylation and expression status of secreted Frizzled-related protein 1 (SFRP1) in bladder cancer, to explore the mechanisms involved and to study the role of SFRP1 in the pathogenesis of bladder cancer. SFRP1 mRNA was detected by reverse transcription PCR (RT-PCR). The DNA methylation status was determined by methylation-specific PCR and protein was detected using western blotting. The results of the present study demonstrated that SFRP1 was methylated in the bladder cancer cell lines T24 and 5637, but not in SCaBER cells. After treating T24 and 5637 cells with a demethylating agent, the cells expressed SFRP1 mRNA and protein. Among the 45 patients with bladder cancer, methylation of SFRP1 was detected in 28 patients (62.2%). Of the matched cancer-adjacent tissues, 6 (13.3%) were found to have methylated SFRP1. The result is statistically significant (P<0.01). In conclusion, SFRP1 is downregulated in certain bladder cancer patients as a consequence of methylation. SFRP1 methylation may be involved in the pathogenesis of bladder cancer via excessive activation of the Wnt signaling pathway. PMID- 22844381 TI - Expression of miR-21, miR-31, miR-96 and miR-135b is correlated with the clinical parameters of colorectal cancer. AB - The aim of this study was to determine the expression of miR-21, miR-31, miR-96 and miR-135b in 52 paired colorectal cancer (CRC) tissues and to analyze the correlation between microRNAs (miRNAs) and clinicopathological features. We developed a quantification method that relies on a standard plot, constructed from known concentrations of standards, in order to measure the number of miRNAs. In addition to this, we analyzed the expression levels of miR-21, miR-31, miR-96 and miR-135b in 52 cases of primary CRC and corresponding normal mucosal tissue using real-time PCR with SYBR-Green I. An independent sample t-test was used to compare the differential expression between tumor tissues and normal mucosal tissues. The Mann-Whitney U and Kruskall-Wallis tests were used to compare the correlation between miRNA expression levels and clinicopathological features. The expression of miR-21, miR-31, miR-96 and miR-135b was upregulated in the CRC tissues compared to normal mucosal tissues (P<0.05). Furthermore, miR-21 and miR 135b were positively correlated with the clinical stage (P=0.048 and P=0.029, respectively), while miR-96 and miR-135b were correlated with liver metastasis (P=0.006 and P=0.013, respectively). Our results suggest that miR-21, miR-31, miR 96 and miR-135b may function in the process of CRC development and progression. miR-135b levels in particular may correlate with the degree of malignancy. PMID- 22844382 TI - Oncological and functional results of extraperitoneal laparoscopic radical prostatectomy. AB - The oncological and functional results of 329 cases in a population treated with extraperitoneal laparoscopic radical prostatectomy (ELRP) were evaluated retrospectively. A total of 329 inconsecutive patients with prostate cancer (PCa) who underwent ELRP were retrospectively analyzed. The median initial prostate specific antigen (PSA) level was 17.35 ng/ml. The median biopsy Gleason score was 7.77. Patients with a T2 or T3a clinical stage had received preoperative neoadjuvant hormonal therapy (NHT) for 3 to 9 months prior to ELRP. No conversion or re-intervention were observed. The median time for anastomosis, surgery time and postoperative catheterization time were 13.0 min, 90.0 min and 6 days, respectively. The median estimated blood loss was 75 ml. There were 12 temporary urinary leakages requiring prolonged catheterization to 14 days. There was 1 case of deep vein thrombosis, 1 case of alimentary tract hemorrhage and 7 cases of anterior urethral stricture. The median follow-up time was 27 months. A total of 17 patients were lost during the follow-up period. No rectal injury, lymphocele, incision hernia, postoperative persistent urinary leak or anastomotic stricture occurred. Younger patients (<=67 years of age) had a more rapid recovery of continence and a better postoperative potency. The overall positive surgical margin rate was 16.7%, which correlated with the pathological stage and Gleason score, respectively (both P<0.001). A total of 89 (28.6%) patients were diagnosed with biochemical recurrence. The initial PSA value, PSM, pathological stage and Gleason score were identified as independent prognostic factors for biochemical recurrence-free survival using multivariate analysis. Our results demonstrated that preoperative NHT had significant effects on the pathological Gleason score (P<0.001) and surgical margin (P=0.027), but no significant impact on biochemical recurrence (P=0.202). The reproducibility of ELRP has been proven as a reliable curative treatment in Western countries during the last 15 years. Due to the increase in PCa patients, the results of our study may aid surgeons who use ELRP for the first time. PMID- 22844383 TI - HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility. AB - CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-myc in human malignancies. Autoantibodies to CIP2A protein have been reported to be present in higher levels in sera from patients with hepatocellular carcinoma (HCC) than in sera of healthy individuals. The CIP2A gene has been demonstrated as a potential cancer susceptibility gene. To elucidate whether common CIP2A variants are associated with HCC susceptibility, we conducted a case-control study comprising 233 cases of HCC and 280 controls matched on age, gender and ethnicity in the Chinese Han population. Two haplotype-tagging single nucleotide polymorphisms (htSNPs) (rs2278911 and rs4855656) from the HapMap database were analyzed, which provide an almost complete coverage of the genetic variations in the CIP2A gene. We found that neither of these htSNPs and haplotypes were associated with the risk of HCC. However, an interaction was observed between hepatitis virus B and C infection (HBV and HCV) and the C carriers (TC or CC) of rs2278911 on HCC risk (OR=12.35; 95% CI, 4.93-19.87). No such association was found for rs4855656. Our study also demonstrated that two htSNPs (rs2278911 and rs4855656) in the CIP2A gene are not associated with the risk of HCC. HBV and HCV infection was found to exert a synergistic effect on the risk of HCC in individuals with the C carriers (TC or CC) of rs2278911 in the Chinese Han population. PMID- 22844384 TI - Methylenetetrahydrofolate reductase C677T gene polymorphism and colorectal cancer risk: A case-control study. AB - We designed a case-control study to determine the plasma homocysteine (Hcy) level and evaluate the potential role of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in colorectal cancer (CRC). Total Hcy was quantified using the fluorescence polarization immunoassay (FPIA) on the IMx analyzer. Genomic DNA was analyzed by the real-time polymerase chain reaction (RT PCR). The plasma levels of Hcy in the CRC group (12.63+/-3.11 MUmol/l) were significantly higher compared with those in the control group (10.87+/-2.42 MUmol/l; P<0.05). The frequency of the MTHFR 677TT genotype in CRC patients was markedly high. The MTHFR 677TT genotype was significantly correlated with an increased risk of CRC (odds ratio, 1.671; 95% confidence interval, 1.094-2.553; P=0.018). This study suggests that the MTHFR C677T polymorphism indicates susceptibility to CRC and is correlated with CRC pathogenesis, suggesting that the homozygous variant MTHFR C677T polymorphism is a candidate risk factor for CRC. PMID- 22844385 TI - Measurement of predatory behaviour in cow dung-colonising insect larvae, using compound-specific (13)C-tracing of dietary fatty acids. AB - Studies of the trophic interactions between organisms in opaque environments where direct observation can be difficult, such as soil or leaf litter, often require the use of indirect inferential approaches. Here, the use of compound specific (13)C-tracing of dietary biomarker fatty acids is evaluated as a method for studying predation by larvae of the dung-breeding fly, Mesembrina meridiana (Diptera: Muscidae); the technique was used to differentiate dung from high enrichment (13)C-labelled prey in their gut contents. Potential prey, (13)C labelled larvae of the dung-breeding fly, Neomyia cornicina (Diptera: Muscidae), were placed into unlabelled dung microcosms in the laboratory. A single 7-day-old M. meridiana larva was allowed to feed in each microcosm for 8 h. The magnitude of increases in the delta(13)C values of fatty acids (i14:0, 14:0, i15:0, a15:0, 15:0, 16:0 and 18:0) in the gut contents, relative to those of M. meridiana deprived of prey, demonstrated the predation of N. cornicina larvae which were estimated to have constituted at least 35% of the average dietary wet mass of these M. meridiana larvae. The tracing of specific labelled compounds increased confidence in dietary assessment and helped to avoid systematic errors associated with compound-dependent efficiency of assimilation in the gut. The results demonstrate the potential value of this method in helping to elucidate trophic interactions in predator-prey systems within opaque environments. The precision of the quantitative dietary estimation that arose from these isotopic data was superior to that generated using fatty acid distributional data, a widely used and evidentially independent line of evidence. PMID- 22844386 TI - Perceived Racial Discrimination as a Predictor of Health Behaviors: the Moderating Role of Gender. AB - Perceived racial discrimination (PRD) has been implicated in undermining the mental and physical health of racial/ethnic minorities. Researchers have begun to explore the indirect role of health behaviors as one factor in helping to explain this relationship. The goal of the present study was to examine the relationship between PRD and a wide range of health behaviors using a prospective, longitudinal design and to explore the role of gender in moderating these relationships. Using data from the Maryland Adolescent Development in Context Study, we examined the relationship between adolescent PRD (accumulated across ages 14-21) and health behaviors (i.e., diet, substance use, exercise) at age 30 in a sample of middle-class black men and women. Using structural equation modeling, results revealed that more cumulative PRD during adolescence was associated with less healthy eating, more substance use (among men), and more exercise (among women) in young adulthood. Implications of these findings for understanding the role of health behaviors in explaining the link between PRD and health outcomes are considered. PMID- 22844387 TI - Senescence Marker Protein 30: Functional and Structural Insights to its Unknown Physiological Function. AB - Senescence marker protein 30 (SMP30) is a multifunctional protein involved in cellular Ca(2+) homeostasis and the biosynthesis of ascorbate in non-primate mammals. The primary structure of the protein is highly conserved among vertebrates, suggesting the existence of a significant physiological function common to all mammals, including primates. Enzymatic activities of SMP30 include aldonolactone and organophosphate hydrolysis. Protective effects against apoptosis and oxidative stress have been reported. X-ray crystallography revealed that SMP30 is a six-bladed beta-propeller with structural similarity to paraoxonase 1, another protein with lactonase and organophosphate hydrolase activities. SMP30 has recently been tied to several physiological conditions including osteoporosis, liver fibrosis, diabetes, and cancer. This review aims to describe the recent advances made toward understanding the connection between molecular structure, enzymatic activity and physiological function of this highly conserved, multifaceted protein. PMID- 22844388 TI - Targeted Delivery of VEGF after a Myocardial Infarction Reduces Collagen Deposition and Improves Cardiac Function. AB - The development of adjunctive therapies which attenuate adverse remodeling and improve LV function post myocardial infarction (MI) is of significant clinical interest. Previously, we have shown that targeted delivery of therapeutic vascular endothelial growth factor (VEGF) to the infarct border zone significantly increases vascular perfusion and results in improvements in LV function. In this study, we tested the hypothesis that improvements in cardiac function observed with this novel targeted drug delivery system strongly correlate with reductions in collagen deposition in the scar tissue after an MI. Rats received anti-P-selectin conjugated immunoliposomes containing VEGF immediately post-MI. Over 4 weeks, evolutionary changes in LV geometry and function were correlated with collagen deposition and infarct size quantified by Gomori's trichrome and picrosirius red staining. Targeted VEGF treated hearts showed a 37% decrease in collagen deposition in the anterior wall, as well as significant improvements in LV filling pressures. Multi-regression analysis showed that the extent of collagen deposition post MI can be predicted by a linear combination of normalized LV mass and ejection fraction. Targeted delivery of VEGF post-MI results in significant decreases in collagen deposition and adverse remodeling. Improvements in cardiac function in this model are related to degree of collagen deposition and extent of scar formation. PMID- 22844389 TI - Identification of Emerging Self-Injurious Behavior in Young Children: A Preliminary Study. AB - Self-injurious behavior (SIB) is a chronic disorder that often begins in early childhood; however, few studies have examined the onset of SIB in young children. This preliminary study reports on the identification, assessment and observation of SIB in 32 children who had begun to engage in SIB within the previous 6 months. Participants were ages birth to 5 years and presented with or were at risk for intellectual and/or developmental disabilities. Assessment measures included parental interviews, developmental and language measures, standardized measures of problem behavior, and direct observations conducted in the home. Results indicated that for most children, SIB emerged prior to age 1 year, and multiple topographies of SIB and other problem behaviors developed in most children. Multiple measures were useful in identifying SIB and in characterizing the behavior by topography, frequency, and severity. Findings from the examination of child communication in relation to SIB were inconclusive. Results are discussed in relation to theories of SIB emergence, and previous observational studies of young children with SIB. PMID- 22844390 TI - Intersession consistency of single-trial classification of the prefrontal response to mental arithmetic and the no-control state by NIRS. AB - Near-infrared spectroscopy (NIRS) has been recently investigated for use in noninvasive brain-computer interface (BCI) technologies. Previous studies have demonstrated the ability to classify patterns of neural activation associated with different mental tasks (e.g., mental arithmetic) using NIRS signals. Though these studies represent an important step towards the realization of an NIRS-BCI, there is a paucity of literature regarding the consistency of these responses, and the ability to classify them on a single-trial basis, over multiple sessions. This is important when moving out of an experimental context toward a practical system, where performance must be maintained over longer periods. When considering response consistency across sessions, two questions arise: 1) can the hemodynamic response to the activation task be distinguished from a baseline (or other task) condition, consistently across sessions, and if so, 2) are the spatiotemporal characteristics of the response which best distinguish it from the baseline (or other task) condition consistent across sessions. The answers will have implications for the viability of an NIRS-BCI system, and the design strategies (especially in terms of classifier training protocols) adopted. In this study, we investigated the consistency of classification of a mental arithmetic task and a no-control condition over five experimental sessions. Mixed model linear regression on intrasession classification accuracies indicate that the task and baseline states remain differentiable across multiple sessions, with no significant decrease in accuracy (p = 0.67). Intersession analysis, however, revealed inconsistencies in spatiotemporal response characteristics. Based on these results, we investigated several different practical classifier training protocols, including scenarios in which the training and test data come from 1) different sessions, 2) the same session, and 3) a combination of both. Results indicate that when selecting optimal classifier training protocols for NIRS-BCI, a compromise between accuracy and convenience (e.g., in terms of duration/frequency of training data collection) must be considered. PMID- 22844391 TI - Single-item screening for agoraphobic symptoms: validation of a web-based audiovisual screening instrument. AB - The advent of web-based treatments for anxiety disorders creates a need for quick and valid online screening instruments, suitable for a range of social groups. This study validates a single-item multimedia screening instrument for agoraphobia, part of the Visual Screener for Common Mental Disorders (VS-CMD), and compares it with the text-based agoraphobia items of the PDSS-SR. The study concerned 85 subjects in an RCT of the effects of web-based therapy for panic symptoms. The VS-CMD item and items 4 and 5 of the PDSS-SR were validated by comparing scores to the outcomes of the CIDI diagnostic interview. Screening for agoraphobia was found moderately valid for both the multimedia item (sensitivity.81, specificity.66, AUC.734) and the text-based items (AUC.607 .697). Single-item multimedia screening for anxiety disorders should be further developed and tested in the general population and in patient, illiterate and immigrant samples. PMID- 22844393 TI - Genes for carbon metabolism and the ToxA virulence factor in Pseudomonas aeruginosa are regulated through molecular interactions of PtxR and PtxS. AB - Homologs of the transcriptional regulator PtxS are omnipresent in Pseudomonas, whereas PtxR homologues are exclusively found in human pathogenic Pseudomonas species. In all Pseudomonas sp., PtxS with 2-ketogluconate is the regulator of the gluconate degradation pathway and controls expression from its own promoter and also from the P(gad) and P(kgu) for the catabolic operons. There is evidence that PtxS and PtxR play a central role in the regulation of exotoxin A expression, a relevant primary virulence factor of Pseudomonas aeruginosa. We show using DNaseI-footprint analysis that in P. aeruginosa PtxR binds to the -35 region of the P(toxA) promoter in front of the exotoxin A gene, whereas PtxS does not bind to this promoter. Bioinformatic and DNaseI-footprint analysis identified a PtxR binding site in the P(kgu) and P(gad) promoters that overlaps the -35 region, while the PtxS operator site is located 50 bp downstream from the PtxR site. In vitro, PtxS recognises PtxR with nanomolar affinity, but this interaction does not occur in the presence of 2-ketogluconate, the specific effector of PtxS. DNAaseI footprint assays of P(kgu) and P(gad) promoters with PtxS and PtxR showed a strong region of hyper-reactivity between both regulator binding sites, indicative of DNA distortion when both proteins are bound; however in the presence of 2-ketogluconate no protection was observed. We conclude that PtxS modulates PtxR activity in response to 2-ketogluconate by complex formation in solution in the case of the P(toxA) promoter, or via the formation of a DNA loop as in the regulation of gluconate catabolic genes. Data suggest two different mechanisms of control exerted by the same regulator. PMID- 22844394 TI - Multi-center evaluation of post-operative morbidity and mortality after optimal cytoreductive surgery for advanced ovarian cancer. AB - PURPOSE: While optimal cytoreduction is the standard of care for advanced ovarian cancer, the related post-operative morbidity has not been clearly documented outside pioneering centers. Indeed most of the studies are monocentric with inclusions over several years inducing heterogeneity in techniques and goals of surgery. We assessed the morbidity of optimal cytoreduction surgery for advanced ovarian cancer within a short inclusion period in 6 referral centers dedicated to achieve complete cytoreduction. PATIENTS AND METHODS: The 30 last optimal debulking surgeries of 6 cancer centers were included. Inclusion criteria included: stage IIIc- IV ovarian cancer and optimal surgery performed at the site of inclusion. All post-operative complications within 30 days of surgery were recorded and graded using the Memorial secondary events grading system. Student t, Chi2 and non-parametric statistical tests were performed. RESULTS: 180 patients were included. There was no demographic differences between the centers. 63 patients underwent surgery including intestinal resections (58 recto-sigmoid resection), 24 diaphragmatic resections, 17 splenectomies. 61 patients presented complications; One patient died post-operatively. Major (grade 3-5) complications requiring subsequent surgeries occurred in 21 patients (11.5%). 76% of patients with a major complication had undergone an ultraradical surgery (P = 0.004). CONCLUSION: While ultraradical surgery may result in complete resection of peritoneal disease in advanced ovarian cancer, the associated complication rate is not negligible. Patients should be carefully evaluated and the timing of their surgery optimized in order to avoid major complications. PMID- 22844392 TI - Efficacy of Mycobacterium indicus pranii immunotherapy as an adjunct to chemotherapy for tuberculosis and underlying immune responses in the lung. AB - BACKGROUND: The 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis. METHODS: We sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol. RESULTS: MIP therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology. CONCLUSION: MIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung. PMID- 22844395 TI - Targeted delivery of human VEGF gene via complexes of magnetic nanoparticle adenoviral vectors enhanced cardiac regeneration. AB - This study assessed the concept of whether delivery of magnetic nanobeads (MNBs)/adenoviral vectors (Ad)-encoded hVEGF gene (Ad(hVEGF)) could regenerate ischaemically damaged hearts in a rat acute myocardial infarction model under the control of an external magnetic field. Adenoviral vectors were conjugated to MNBs with the Sulfo-NHS-LC-Biotin linker. In vitro transduction efficacy of MNBs/Ad encoded luciferase gene (Ad(luc)) was compared with Ad(luc) alone in human umbilical vein endothelial cells (HUVECs) under magnetic field stimulation. In vivo, in a rat acute myocardial infarction (AMI) model, MNBs/Ad(hVEGF) complexes were injected intravenously and an epicardial magnet was employed to attract the circulating MNBs/Ad(hVEGF) complexes. In vitro, compared with Ad(luc) alone, MNBs/Ad(luc) complexes had a 50-fold higher transduction efficiency under the magnetic field. In vivo, epicardial magnet effectively attracted MNBs/Ad(hVEGF) complexes and resulted in strong therapeutic gene expression in the ischemic zone of the infarcted heart. When compared to other MI-treated groups, the MI M(+)/Ad(hVEGF) group significantly improved left ventricular function (p<0.05) assessed by pressure-volume loops after 4 weeks. Also the MI-M(+)/Ad(hVEGF) group exhibited higher capillary and arteriole density and lower collagen deposition than other MI-treated groups (p<0.05). Magnetic targeting enhances transduction efficiency and improves heart function. This novel method to improve gene therapy outcomes in AMI treatment offers the potential into clinical applications. PMID- 22844396 TI - Exendin-4 protected against cognitive dysfunction in hyperglycemic mice receiving an intrahippocampal lipopolysaccharide injection. AB - BACKGROUND: Chronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer's disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study. METHODOLOGY/PRINCIPAL FINDINGS: Ten days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 ug/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-kappaB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection. CONCLUSIONS/SIGNIFICANCE: These findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-kappaB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases. PMID- 22844397 TI - Irinotecan (CPT-11) chemotherapy alters intestinal microbiota in tumour bearing rats. AB - Intestinal microbiota mediate toxicity of irinotecan (CPT-11) cancer therapies and cause systemic infection after CPT-11-induced loss of barrier function. The intestinal microbiota and their functions are thus potential targets for treatment to mitigate CPT-11 toxicity. However, microbiota changes during CPT-11 therapy remain poorly described. This study analysed changes in intestinal microbiota induced by CPT-11 chemotherapy. Qualitative and quantitative taxonomic analyses, and functional analyses were combined to characterize intestinal microbiota during CPT-11-based chemotherapy, and in presence or absence of oral glutamine, a treatment known to reduce CPT-11 toxicity. In the first set of experiments tumour-bearing rats received a dose-intensive CPT-11 regimen (125 mg kg(-1)*3 days), with or without oral glutamine bolus (0.75 g kg(-1)). In a subsequent more clinically-oriented chemotherapy regimen, rats received two cycles of CPT-11 (50 mg kg(-1)) followed by 5-flurouracil (50 mg kg(-1)). The analysis of fecal samples over time demonstrated that tumours changed the composition of intestinal microbiota, increasing the abundance of clostrridial clusters I, XI, and Enterobacteriaceae. CPT-11 chemotherapy increased cecal Clostridium cluster XI and Enterobacteriaceae, particularly after the dose intensive therapy. Glutamine treatment prevented the reduced abundance of major bacterial groups after CPT-11 administration; i.e. total bacteria, Clostridium cluster VI, and the Bacteroides-group. Virulence factor/toxin genes of pathogenic Escherichia coli and Clostridium difficile were not detected in the cecal microbiota. In conclusion, both colon cancer implantation and CPT-11-based chemotherapies disrupted the intestinal microbiota. Oral glutamine partially mitigated CPT-11 toxicity and induced temporary changes of the intestinal microbiota. PMID- 22844398 TI - Novel microRNAs differentially expressed during aging in the mouse brain. AB - MicroRNAs (miRNAs) are endogenous small RNA molecules that regulate gene expression post-transcriptionally. Work in Caenorhabditis elegans has shown that specific miRNAs function in lifespan regulation and in a variety of age associated pathways, but the roles of miRNAs in the aging of vertebrates are not well understood. We examined the expression of small RNAs in whole brains of young and old mice by deep sequencing and report here on the expression of 558 known miRNAs and identification of 41 novel miRNAs. Of these miRNAs, 75 known and 18 novel miRNAs exhibit greater than 2.0-fold expression changes. The majority of expressed miRNAs in our study decline in relative abundance in the aged brain, in agreement with trends observed in other miRNA studies in aging tissues and organisms. Target prediction analysis suggests that many of our novel aging associated miRNAs target genes in the insulin signaling pathway, a central node of aging-associated genetic networks. These novel miRNAs may thereby regulate aging-related functions in the brain. Since many mouse miRNAs are conserved in humans, the aging-affected brain miRNAs we report here may represent novel regulatory genes that also function during aging in the human brain. PMID- 22844399 TI - Topology of transcriptional regulatory networks: testing and improving. AB - With the increasing amount and complexity of data generated in biological experiments it is becoming necessary to enhance the performance and applicability of existing statistical data analysis methods. This enhancement is needed for the hidden biological information to be better resolved and better interpreted. Towards that aim, systematic incorporation of prior information in biological data analysis has been a challenging problem for systems biology. Several methods have been proposed to integrate data from different levels of information most notably from metabolomics, transcriptomics and proteomics and thus enhance biological interpretation. However, in order not to be misled by the dominance of incorrect prior information in the analysis, being able to discriminate between competing prior information is required. In this study, we show that discrimination between topological information in competing transcriptional regulatory network models is possible solely based on experimental data. We use network topology dependent decomposition of synthetic gene expression data to introduce both local and global discriminating measures. The measures indicate how well the gene expression data can be explained under the constraints of the model network topology and how much each regulatory connection in the model refuses to be constrained. Application of the method to the cell cycle regulatory network of Saccharomyces cerevisiae leads to the prediction of novel regulatory interactions, improving the information content of the hypothesized network model. PMID- 22844400 TI - Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. AB - Although tuberculosis (TB) causes more deaths than any other pathogen, most infected individuals harbor the pathogen without signs of disease. We explored the metabolome of >400 small molecules in serum of uninfected individuals, latently infected healthy individuals and patients with active TB. We identified changes in amino acid, lipid and nucleotide metabolism pathways, providing evidence for anti-inflammatory metabolomic changes in TB. Metabolic profiles indicate increased activity of indoleamine 2,3 dioxygenase 1 (IDO1), decreased phospholipase activity, increased abundance of adenosine metabolism products, as well as indicators of fibrotic lesions in active disease as compared to latent infection. Consistent with our predictions, we experimentally demonstrate TB induced IDO1 activity. Furthermore, we demonstrate a link between metabolic profiles and cytokine signaling. Finally, we show that 20 metabolites are sufficient for robust discrimination of TB patients from healthy individuals. Our results provide specific insights into the biology of TB and pave the way for the rational development of metabolic biomarkers for TB. PMID- 22844401 TI - Bone balance within a cortical BMU: local controls of bone resorption and formation. AB - Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the 'integration of information' occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors. PMID- 22844402 TI - Distinct soil bacterial communities revealed under a diversely managed agroecosystem. AB - Land-use change and management practices are normally enacted to manipulate environments to improve conditions that relate to production, remediation, and accommodation. However, their effect on the soil microbial community and their subsequent influence on soil function is still difficult to quantify. Recent applications of molecular techniques to soil biology, especially the use of 16S rRNA, are helping to bridge this gap. In this study, the influence of three land use systems within a demonstration farm were evaluated with a view to further understand how these practices may impact observed soil bacterial communities. Replicate soil samples collected from the three land-use systems (grazed pine forest, cultivated crop, and grazed pasture) on a single soil type. High throughput 16S rRNA gene pyrosequencing was used to generate sequence datasets. The different land use systems showed distinction in the structure of their bacterial communities with respect to the differences detected in cluster analysis as well as diversity indices. Specific taxa, particularly Actinobacteria, Acidobacteria, and classes of Proteobacteria, showed significant shifts across the land-use strata. Families belonging to these taxa broke with notions of copio- and oligotrphy at the class level, as many of the less abundant groups of families of Actinobacteria showed a propensity for soil environments with reduced carbon/nutrient availability. Orders Actinomycetales and Solirubrobacterales showed their highest abundance in the heavily disturbed cultivated system despite the lowest soil organic carbon (SOC) values across the site. Selected soil properties ([SOC], total nitrogen [TN], soil texture, phosphodiesterase [PD], alkaline phosphatase [APA], acid phosphatase [ACP] activity, and pH) also differed significantly across land-use regimes, with SOM, PD, and pH showing variation consistent with shifts in community structure and composition. These results suggest that use of pyrosequencing along with traditional analysis of soil physiochemical properties may provide insight into the ecology of descending taxonomic groups in bacterial communities. PMID- 22844403 TI - Dietary factors impact on the association between CTSS variants and obesity related traits. AB - BACKGROUND/AIMS: Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology--this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors--increased by high protein, glycemic index and energy diets. METHODS: Four tag SNPs (rs7511673, rs11576175, rs10888390 and rs1136774) were selected to capture all common variation in the CTSS region. Association between these four SNPs and several adiposity measurements (BMI, waist circumference, waist for given BMI and being a weight gainer-experiencing the greatest degree of unexplained annual weight gain during follow-up or not) given, where applicable, both as baseline values and gain during the study period (6-8 years) were tested in 11,091 European individuals (linear or logistic regression models). We also examined the interaction between the CTSS variants and dietary factors--energy density, protein content (in grams or in % of total energy intake) and glycemic index--on these four adiposity phenotypes. RESULTS: We found several associations between CTSS polymorphisms and anthropometric traits including baseline BMI (rs11576175 (SNP N degrees 2), p = 0.02, beta = -0.2446), and waist change over time (rs7511673 (SNP N degrees 1), p = 0.01, beta = -0.0433 and rs10888390 (SNP N degrees 3), p = 0.04, beta = -0.0342). In interaction with the percentage of proteins contained in the diet, rs11576175 (SNP N degrees 2) was also associated with the risk of being a weight gainer (p(interaction) = 0.01, OR = 1.0526)--the risk of being a weight gainer increased with the percentage of proteins contained in the diet. CONCLUSION: CTSS variants seem to be nominally associated to obesity related traits and this association may be modified by dietary protein intake. PMID- 22844405 TI - Bayesian Latent Class Models in malaria diagnosis. AB - AIMS: The main focus of this study is to illustrate the importance of the statistical analysis in the evaluation of the accuracy of malaria diagnostic tests, without admitting a reference test, exploring a dataset (n=3317) collected in Sao Tome and Principe. METHODS: Bayesian Latent Class Models (without and with constraints) are used to estimate the malaria infection prevalence, together with sensitivities, specificities, and predictive values of three diagnostic tests (RDT, Microscopy and PCR), in four subpopulations simultaneously based on a stratified analysis by age groups (< 5, >= 5 years old) and fever status (febrile, afebrile). RESULTS: In the afebrile individuals with at least five years old, the posterior mean of the malaria infection prevalence is 3.2% with a highest posterior density interval of [2.3-4.1]. The other three subpopulations (febrile >= 5 years, afebrile or febrile children less than 5 years) present a higher prevalence around 10.3% [8.8-11.7]. In afebrile children under-five years old, the sensitivity of microscopy is 50.5% [37.7-63.2]. In children under-five, the estimated sensitivities/specificities of RDT are 95.4% [90.3-99.5]/93.8% [91.6-96.0]--afebrile--and 94.1% [87.5-99.4]/97.5% [95.5-99.3]--febrile. In individuals with at least five years old are 96.0% [91.5-99.7]/98.7% [98.1-99.2]- afebrile--and 97.9% [95.3-99.8]/97.7% [96.6-98.6]--febrile. The PCR yields the most reliable results in four subpopulations. CONCLUSIONS: The utility of this RDT in the field seems to be relevant. However, in all subpopulations, data provide enough evidence to suggest caution with the positive predictive values of the RDT. Microscopy has poor sensitivity compared to the other tests, particularly, in the afebrile children less than 5 years. This type of findings reveals the danger of statistical analysis based on microscopy as a reference test. Bayesian Latent Class Models provide a powerful tool to evaluate malaria diagnostic tests, taking into account different groups of interest. PMID- 22844404 TI - Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers. AB - The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM) was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS) obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs) and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5%) and higher sleep disturbance (11.5%). Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB) predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories. PMID- 22844406 TI - ADP ribosylation by PARP-1 suppresses HOXB7 transcriptional activity. AB - Interactions with cofactors regulate transcriptional activity and also help HOX proteins to achieve the specificity required for transcriptional regulation of target genes. In this study, we describe a novel protein/protein interaction of HOXB7 with poly (ADP-ribose) polymerase-1 (PARP-1) that involves the homeodomain of HOXB7 and the first zinc finger domain of PARP-1. Upon binding to PARP-1, HOXB7 undergoes poly(ADP-ribosyl)altion resulting in a reduction of its transcriptional activity. Since aspartic acid and glutamic acid residues are acceptors of the ADP ribose moiety transferred by PARP-1, deletion of the evolutionarily conserved C-terminal Glu-rich tail of HOXB7 dramatically attenuates ADP-ribosylation of HOXB7 by PARP-1. Further, a mutant of HOXB7 without the Glu-rich tail loses the ability to be negatively regulated by PARP-1 and becomes transcriptionally more active in luciferase reporter assays. Since the homeodomain is highly conserved among HOX proteins, five other HOX proteins were tested. All six showed interaction with, and were poly(ADP-ribosyl)ated by PARP-1. However, among them, this modification altered the DNA binding activity of only HOXA7 and HOXB7. In summary, this study identifies a new interacting partner of HOX proteins. More importantly, this study reveals a novel mechanism whereby polyADP-ribosylation regulates transcriptional activities of HOX proteins such as HOXB7 and HOXA7. PMID- 22844407 TI - Excessive attractor instability accounts for semantic priming in schizophrenia. AB - One of the most pervasive findings in studies of schizophrenics with thought disorders is their peculiar pattern of semantic priming, which presumably reflects abnormal associative processes in the semantic system of these patients. Semantic priming is manifested by faster and more accurate recognition of a word target when preceded by a semantically related prime, relative to an unrelated prime condition. Compared to control, semantic priming in schizophrenics is characterized by reduced priming effects at long prime-target Stimulus Onset Asynchrony (SOA) and, sometimes, augmented priming at short SOA. In addition, unlike controls, schizophrenics consistently show indirect (mediated) priming (such as from the prime 'wedding' to the target 'finger', mediated by 'ring'). In a previous study, we developed a novel attractor neural network model with synaptic adaptation mechanisms that could account for semantic priming patterns in healthy individuals. Here, we examine the consequences of introducing attractor instability to this network, which is hypothesized to arise from dysfunctional synaptic transmission known to occur in schizophrenia. In two simulated experiments, we demonstrate how such instability speeds up the network's dynamics and, consequently, produces the full spectrum of priming effects previously reported in patients. The model also explains the inconsistency of augmented priming results at short SOAs using directly related pairs relative to the consistency of indirect priming. Further, we discuss how the same mechanism could account for other symptoms of the disease, such as derailment ('loose associations') or the commonly seen difficulty of patients in utilizing context. Finally, we show how the model can statistically implement the overly-broad wave of spreading activation previously presumed to characterize thought-disorders in schizophrenia. PMID- 22844408 TI - Identifying protein phosphorylation sites with kinase substrate specificity on human viruses. AB - Viruses infect humans and progress inside the body leading to various diseases and complications. The phosphorylation of viral proteins catalyzed by host kinases plays crucial regulatory roles in enhancing replication and inhibition of normal host-cell functions. Due to its biological importance, there is a desire to identify the protein phosphorylation sites on human viruses. However, the use of mass spectrometry-based experiments is proven to be expensive and labor intensive. Furthermore, previous studies which have identified phosphorylation sites in human viruses do not include the investigation of the responsible kinases. Thus, we are motivated to propose a new method to identify protein phosphorylation sites with its kinase substrate specificity on human viruses. The experimentally verified phosphorylation data were extracted from virPTM--a database containing 301 experimentally verified phosphorylation data on 104 human kinase-phosphorylated virus proteins. In an attempt to investigate kinase substrate specificities in viral protein phosphorylation sites, maximal dependence decomposition (MDD) is employed to cluster a large set of phosphorylation data into subgroups containing significantly conserved motifs. The experimental human phosphorylation sites are collected from Phospho.ELM, grouped according to its kinase annotation, and compared with the virus MDD clusters. This investigation identifies human kinases such as CK2, PKB, CDK, and MAPK as potential kinases for catalyzing virus protein substrates as confirmed by published literature. Profile hidden Markov model is then applied to learn a predictive model for each subgroup. A five-fold cross validation evaluation on the MDD-clustered HMMs yields an average accuracy of 84.93% for Serine, and 78.05% for Threonine. Furthermore, an independent testing data collected from UniProtKB and Phospho.ELM is used to make a comparison of predictive performance on three popular kinase-specific phosphorylation site prediction tools. In the independent testing, the high sensitivity and specificity of the proposed method demonstrate the predictive effectiveness of the identified substrate motifs and the importance of investigating potential kinases for viral protein phosphorylation sites. PMID- 22844409 TI - In silico study of rotavirus VP7 surface accessible conserved regions for antiviral drug/vaccine design. AB - BACKGROUND: Rotaviral diarrhoea kills about half a million children annually in developing countries and accounts for one third of diarrhea related hospitalizations. Drugs and vaccines against the rotavirus are handicapped, as in all viral diseases, by the rapid mutational changes that take place in the DNA and protein sequences rendering most of these ineffective. As of now only two vaccines are licensed and approved by the WHO (World Health Organization), but display reduced efficiencies in the underdeveloped countries where the disease is more prevalent. We approached this issue by trying to identify regions of surface exposed conserved segments on the surface glycoproteins of the virion, which may then be targeted by specific peptide vaccines. We had developed a bioinformatics protocol for these kinds of problems with reference to the influenza neuraminidase protein, which we have refined and expanded to analyze the rotavirus issue. RESULTS: Our analysis of 433 VP7 (Viral Protein 7 from rotavirus) surface protein sequences across 17 subtypes encompassing mammalian hosts using a 20D Graphical Representation and Numerical Characterization method, identified four possible highly conserved peptide segments. Solvent accessibility prediction servers were used to identify that these are predominantly surface situated. These regions analyzed through selected epitope prediction servers for their epitopic properties towards possible T-cell and B-cell activation showed good results as epitopic candidates (only dry lab confirmation). CONCLUSIONS: The main reasons for the development of alternative vaccine strategies for the rotavirus are the failure of current vaccines and high production costs that inhibit their application in developing countries. We expect that it would be possible to use the protein surface exposed regions identified in our study as targets for peptide vaccines and drug designs for stable immunity against divergent strains of the rotavirus. Though this study is fully dependent on computational prediction algorithms, it provides a platform for wet lab experiments. PMID- 22844410 TI - Zoledronic acid as an adjuvant therapy in patients with breast cancer: a systematic review and meta-analysis. AB - BACKGROUND: Zoledronic acid is widely used as adjuvant chemotherapy for the treatment of breast cancer. However, previous trials reported inconsistent findings regarding their clinical efficacy and safety. We carried out a comprehensive systematic review and meta-analysis to evaluate the effects of zoledronic acid on disease-free survival (DFS), overall survival (OS), and drug related toxicities. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures with a time limit of Dec. 1, 2011. Randomized controlled trials evaluated the effects of zoledronic acid on OS, DFS, and RFS compared with control were eligible for inclusion in our research. Of 175 identified studies, we collected data from 7 randomized controlled trials of zoledronic acid that had OS, DFS, and RFS reported as one of the endpoint. Overall, we noted that patients receiving zoledronic acid therapy had significant longer OS than the group with non-zoledronic acid therapy (HR, 0.85, 95%CI, 0.73 to 1.00, P = 0.047). Furthermore, zoledronic acid therapy also had a clear effect on frature events (RR, 0.66, 95%CI, 0.52 to 0.84, P<0.001). Subgroup analysis indicated that zoledronic acid therapy showed a great beneficial effect on disease recurrence in patients with early-stage breast cancer, however, it also significantly increased the harm of disease recurrence in patients with advanced breast cancer. Bone pain, neutropenic fever, pyrexia, rash were more frequent in the zoledronic acid therapy group. CONCLUSION/SIGNIFICANCE: Treatment with zoledronic acid had a clear effect on fracture events, and it might contribute an important role for overall survival. PMID- 22844411 TI - Cryopreserved reticulocytes derived from hematopoietic stem cells can be invaded by cryopreserved Plasmodium vivax isolates. AB - The development of a system for the continuous culture of Plasmodium vivax in vitro would benefit from the use of reticulocytes derived from differentiated hematopoietic stem cells (HCS). At present, the need to use both fresh reticulocytes and fresh P. vivax isolates represents a major obstacle towards this goal, particularly for laboratories located in non-endemic countries. Here, we describe a new method for the cryopreservation of HSC-derived reticulocytes to be used for both P. falciparum and P. vivax invasion tests. Cryopreserved P. falciparum and P. vivax isolates could invade both fresh and cryopreserved HSC derived reticulocytes with similar efficiency. This new technique allows the storage of HSC-derived reticulocytes which can be used for later invasion tests and represents an important step towards the establishment of a continuous P. vivax culture. PMID- 22844412 TI - Effect of short-term thyroxine administration on energy metabolism and mitochondrial efficiency in humans. AB - The physiologic effects of triiodothyronine (T3) on metabolic rate are well documented; however, the effects of thyroxine (T4) are less clear despite its wide-spread use to treat thyroid-related disorders and other non-thyroidal conditions. Here, we investigated the effects of acute (3-day) T4 supplementation on energy expenditure at rest and during incremental exercise. Furthermore, we used a combination of in situ and in vitro approaches to measure skeletal muscle metabolism before and after T4 treatment. Ten healthy, euthyroid males were given 200 ug T4 (levothyroxine) per day for 3 days. Energy expenditure was measured at rest and during exercise by indirect calorimetry, and skeletal muscle mitochondrial function was assessed by in situ ATP flux ((31)P MRS) and in vitro respiratory control ratio (RCR, state 3/state 4 rate of oxygen uptake using a Clark-type electrode) before and after acute T4 treatment. Thyroxine had a subtle effect on resting metabolic rate, increasing it by 4% (p = 0.059) without a change in resting ATP demand (i.e., ATP flux) of the vastus lateralis. Exercise efficiency did not change with T4 treatment. The maximal capacity to produce ATP (state 3 respiration) and the coupled state of the mitochondria (RCR) were reduced by approximately 30% with T4 (p = 0.057 and p = 0.04, respectively). Together, the results suggest that T4, although less metabolically active than T3, reduces skeletal muscle efficiency and modestly increases resting metabolism even after short-term supplementation. Our findings may be clinically relevant given the expanding application of T4 to treat non-thyroidal conditions such as obesity and weight loss. PMID- 22844413 TI - Direct fitness correlates and thermal consequences of facultative aggregation in a desert lizard. AB - Social aggregation is a common behavioral phenomenon thought to evolve through adaptive benefits to group living. Comparing fitness differences between aggregated and solitary individuals in nature--necessary to infer an evolutionary benefit to living in groups--has proven difficult because communally-living species tend to be obligately social and behaviorally complex. However, these differences and the mechanisms driving them are critical to understanding how solitary individuals transition to group living, as well as how and why nascent social systems change over time. Here we demonstrate that facultative aggregation in a reptile (the Desert Night Lizard, Xantusia vigilis) confers direct reproductive success and survival advantages and that thermal benefits of winter huddling disproportionately benefit small juveniles, which can favor delayed dispersal of offspring and the formation of kin groups. Using climate projection models, however, we estimate that future aggregation in night lizards could decline more than 50% due to warmer temperatures. Our results support the theory that transitions to group living arise from direct benefits to social individuals and offer a clear mechanism for the origin of kin groups through juvenile philopatry. The temperature dependence of aggregation in this and other taxa suggests that environmental variation may be a powerful but underappreciated force in the rapid transition between social and solitary behavior. PMID- 22844414 TI - Biomechanics of the chick embryonic heart outflow tract at HH18 using 4D optical coherence tomography imaging and computational modeling. AB - During developmental stages, biomechanical stimuli on cardiac cells modulate genetic programs, and deviations from normal stimuli can lead to cardiac defects. Therefore, it is important to characterize normal cardiac biomechanical stimuli during early developmental stages. Using the chicken embryo model of cardiac development, we focused on characterizing biomechanical stimuli on the Hamburger Hamilton (HH) 18 chick cardiac outflow tract (OFT), the distal portion of the heart from which a large portion of defects observed in humans originate. To characterize biomechanical stimuli in the OFT, we used a combination of in vivo optical coherence tomography (OCT) imaging, physiological measurements and computational fluid dynamics (CFD) modeling. We found that, at HH18, the proximal portion of the OFT wall undergoes larger circumferential strains than its distal portion, while the distal portion of the OFT wall undergoes larger wall stresses. Maximal wall shear stresses were generally found on the surface of endocardial cushions, which are protrusions of extracellular matrix onto the OFT lumen that later during development give rise to cardiac septa and valves. The non-uniform spatial and temporal distributions of stresses and strains in the OFT walls provide biomechanical cues to cardiac cells that likely aid in the extensive differential growth and remodeling patterns observed during normal development. PMID- 22844415 TI - The immunomodulatory activity of meningococcal lipoprotein Ag473 depends on the conformation made up of the lipid and protein moieties. AB - We have previously demonstrated that the meningococcal antigen Ag473 in the presence of Freund's adjuvant can elicit protective immune responses in mouse challenge model. In this study, we evaluated the structural requirement for the immunological activity and the possible signaling pathway of recombinant Ag473 antigen produced in E. coli. We found that lipidated Ag473 (L-Ag473) possesses an intrinsic adjuvant activity that could be attributed to its ability to activate dendritic cells and promote their maturation. In addition, we found that L-Ag473 can activate human monocytes and promote maturation of human monocyte-derived dendritic cells. These results provide an indirect support that L-Ag473 may also be immunogenic in human. Interestingly, the observed activity is dependent on the overall conformation of L-Ag473 because heating and proteinase K treatment can diminish and abolish the activity. Furthermore, our data suggest a species differential TLR recognition of L-Ag473. Overall, these data suggest a new paradigm for the ligand-TLR interaction in addition to demonstrating the self adjuvanting activity of the vaccine candidate L-Ag473. PMID- 22844416 TI - Similarities of Drosophila rab GTPases based on expression profiling: completion and analysis of the rab-Gal4 kit. AB - We recently generated rab-Gal4 lines for 25 of 29 predicted Drosophila rab GTPases. These lines provide tools for the expression of reporters, mutant rab variants or other genes, under control of the regulatory elements of individual rab loci. Here, we report the generation and characterization of the remaining four rab-Gal4 lines. Based on the completed 'rab-Gal4 kit' we performed a comparative analysis of the cellular and subcellular expression of all rab GTPases. This analysis includes the cellular expression patterns in characterized neuronal and non-neuronal cells and tissues, the subcellular localization of wild type, constitutively active and dominant negative rab GTPases and colocalization with known intracellular compartment markers. Our comparative analysis identifies all Rab GTPases that are expressed in the same cells and localize to the same intracellular compartments. Remarkably, similarities based on these criteria are typically not predicted by primary sequence homology. Hence, our findings provide an alternative basis to assess potential roles and redundancies based on expression in developing and adult cell types, compartment identity and subcellular localization. PMID- 22844417 TI - A neurotoxic phospholipase A2 impairs yeast amphiphysin activity and reduces endocytosis. AB - BACKGROUND: Presynaptically neurotoxic phospholipases A(2) inhibit synaptic vesicle recycling through endocytosis. PRINCIPAL FINDINGS: Here we provide insight into the action of a presynaptically neurotoxic phospholipase A(2) ammodytoxin A (AtxA) on clathrin-dependent endocytosis in budding yeast. AtxA caused changes in the dynamics of vesicle formation and scission from the plasma membrane in a phospholipase activity dependent manner. Our data, based on synthetic dosage lethality screen and the analysis of the dynamics of sites of endocytosis, indicate that AtxA impairs the activity of amphiphysin. CONCLUSIONS: We identified amphiphysin and endocytosis as the target of AtxA intracellular activity. We propose that AtxA reduces endocytosis following a mechanism of action which includes both a specific protein-protein interaction and enzymatic activity, and which is applicable to yeast and mammalian cells. Knowing how neurotoxic phospholipases A(2) work can open new ways to regulate endocytosis. PMID- 22844418 TI - CTX (crosslaps) rather than osteopontin is associated with disturbed glucose metabolism in gestational diabetes. AB - OBJECTIVE: Reciprocal interaction between bone and glucose metabolism might play a pivotal role in the development of type 2 diabetes. We recently demonstrated that osteocalcin is increased in women with gestational diabetes (GDM) compared to healthy pregnant women and related to enhanced insulin secretion. Here, we aimed to investigate the role of the bone resorption marker CTX and osteopontin (OPN), a key molecule in subclinical inflammation underlying insulin resistance, in gestational diabetes. METHODS: Insulin sensitivity and secretion (derived from OGTT) as well as CTX and osteopontin were investigated in 26 GDM and 52 women with normal glucose tolerance during pregnancy [CON] between 24th and 28th gestational weeks; 24 women also underwent postpartum examination. RESULTS: CTX was significantly higher in GDM compared to CON (0.44+/-0.20 vs.0.28+/-0.12 ng/ml, p<.0001) and positively correlated with osteocalcin (R = 0.64, p<.0001) and parameters of insulin secretion. Osteopontin plasma concentrations were decreased in GDM compared to CON (28.81+/-22.12 vs.37.68+/-19.63 ng/ml, p = 0.04), and did not show any relation to insulin secretion or sensitivity, but were significantly correlated with CRP (R = 0.3, p<0.007) and liver enzymes. Twelve weeks after delivery CTX and OPN were increased compared to pregnancy (both p<.0001) and did not differ between GDM and CON. CONCLUSION: Our findings support the idea of a tight regulation between bone and glucose metabolism, and suggest, that less curbed CTX during pregnancy might be involved in osteocalcin mediated amelioration of insulin secretion in GDM. On the other hand, osteopontin was unrelated to insulin resistance in GDM, but associated with inflammatory markers and liver enzymes in all women. PMID- 22844419 TI - Human tumor cells induce angiogenesis through positive feedback between CD147 and insulin-like growth factor-I. AB - Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). In this study, we made a three-dimensional (3D) tumor angiogenesis model using a co-culture system of human hepatocellular carcinoma cells SMMC-7721 and humanumbilical vein endothelial cells (HUVECs) in vitro. We found that CD147 expressing cancer cells could promote HUVECs to form net-like structures resembling the neo-vasculature, whereas the ability of proliferation, migration and tube formation of HUVECs was significantly decreased in tumor conditioned medium (TCM) of SMMC-7721 cells transfected with specific CD147-siRNA. Furthermore, by assaying the change of pro-angiogenic factors in TCM, we found that the inhibition of CD147 expression led to significant decrease of VEGF and insulin-like growth factor-I (IGF-I) secretion. Interestingly, we also found that IGF-I up-regulated the expression of CD147 in both tumor cells and HUVECs. These findings suggest that there is a positive feedback between CD147 and IGF-I at the tumor-endothelial interface and CD147 initiates the formation of an angiogenesis niche. PMID- 22844420 TI - Genome-wide association mapping and identification of candidate genes for the rumpless and ear-tufted traits of the Araucana chicken. AB - Araucana chickens are known for their rounded, tailless rumps and tufted ears. Inheritance studies have shown that the rumpless (Rp) and ear-tufted (Et) loci each act in an autosomal dominant fashion, segregate independently, and are associated with an increased rate of embryonic mortality. To find genomic regions associated with Rp and Et, we generated genome-wide SNP profiles for a diverse population of 60 Araucana chickens using the 60 K chicken SNP BeadChip. Genome wide association studies using 40 rumpless and 11 tailed birds showed a strong association with rumpless on Gga 2 (P(raw) = 2.45*10(-10), P(genome) = 0.00575), and analysis of genotypes revealed a 2.14 Mb haplotype shared by all rumpless birds. Within this haplotype, a 0.74 Mb critical interval containing two Iroquois homeobox genes, Irx1 and Irx2, was unique to rumpless Araucana chickens. Irx1 and Irx2 are central for developmental prepatterning, but neither gene is known to have a role in mechanisms leading to caudal development. A second genome-wide association analysis using 30 ear-tufted and 28 non-tufted birds revealed an association with tufted on Gga 15 (P(raw) = 6.61*10(-7), P(genome) = 0.0981). We identified a 0.58 Mb haplotype common to tufted birds and harboring 7 genes. Because homozygosity for Et is nearly 100% lethal, we employed a heterozygosity mapping approach to prioritize candidate gene selection. A 60 kb region heterozygous in all Araucana chickens contains the complete coding sequence for TBX1 and partial sequence for GNB1L. TBX1 is an important transcriptional regulator of embryonic development and a key genetic determinant of human DiGeorge syndrome. Herein, we describe localization of Rp and Et and identification of positional candidate genes. PMID- 22844421 TI - Risk of resource failure and toolkit variation in small-scale farmers and herders. AB - Recent work suggests that global variation in toolkit structure among hunter gatherers is driven by risk of resource failure such that as risk of resource failure increases, toolkits become more diverse and complex. Here we report a study in which we investigated whether the toolkits of small-scale farmers and herders are influenced by risk of resource failure in the same way. In the study, we applied simple linear and multiple regression analysis to data from 45 small scale food-producing groups to test the risk hypothesis. Our results were not consistent with the hypothesis; none of the risk variables we examined had a significant impact on toolkit diversity or on toolkit complexity. It appears, therefore, that the drivers of toolkit structure differ between hunter-gatherers and small-scale food-producers. PMID- 22844422 TI - Modulatory role of PYY in transport and metabolism of cholesterol in intestinal epithelial cells. AB - BACKGROUND: Gastrointestinal peptides are involved in modulating appetite. Other biological functions attributed to them include the regulation of lipid homeostasis. However, data concerning PYY remain fragmentary. The objectives of the study were: (i) To determine the effect of PYY on intestinal transport and synthesis of cholesterol, the biogenesis of apolipoproteins (apos) and assembly of lipoproteins and (ii) To analyze whether the effects of PYY are similar according to whether cells are exposed to PYY on apical or basolateral surface. METHODOLOGY/PRINCIPAL FINDINGS: Caco-2/15 cells were incubated with PYY (1-36) administered either to the apical or basolateral medium, at concentrations of 50 or 200 nM for 24 hours. De novo synthesis of cholesterol, cholesterol uptake, and assembly of lipoproteins were evaluated through the incorporation of [(14)C] acetate, [(14)C]-cholesterol, and [(14)C]-oleate, respectively. Biogenesis of apos (A-I, A-IV, E, B-48 and B-100) was examined by the incorporation of [(35)S] methionine. The influence of PYY on protein and mRNA levels of many key mediators of lipid metabolism was analyzed by Western blot and PCR, respectively. Our results show that PYY influenced cholesterol metabolism in Caco-2/15 cells depending on the site of PYY delivery. Apical addition of PYY significantly lowered the incorporation of [(14)C]-cholesterol likely via the reduction of NPC1L1, stimulated intracellular cholesterol synthesis probably through an increase in SREBP-2 expression, whereas it concomitantly increased apo A-I synthesis and decreased LDL secretion. In contrast, basolateral PYY reduced the production of chylomicrons (CM) as well as the biogenesis of apos B-48 and B-100, while lowering the expression of the transcription factors RXRalpha and PPAR(alpha,beta). CONCLUSIONS/SIGNIFICANCE: PYY is capable of influencing cholesterol homeostasis in intestinal Caco-2/15 cells depending on the site delivery. Apical PYY was able to decrease cholesterol uptake via NPC1L1 downregulation, whereas basolateral PYY diminished CM output through the biogenesis decline of apos B-48 and B-100. PMID- 22844423 TI - Reperfusion does not improve impaired rapid-onset cortical plasticity in patients with severe stenosis of the internal carotid artery. AB - BACKGROUND: Severe stenosis of the internal carotid artery (ICA) has been associated with impaired cognition in patients, but its effect on rapid-onset cortical plasticity is not known. Carotid endarterectomy (CEA) in patients with severe ICA stenosis reduces stroke risk, but the impact on cognition or physiology of the respective hemisphere remains controversial. METHODS/RESULTS: 16 patients with severe stenosis of the ICA and 16 age and sex matched controls were included. Rapid-onset cortical plasticity was assessed using the paired associative stimulation (PAS) protocol. PAS models long-term synaptic potentiation in human motor cortex, combining repetitive stimulation of the peripheral ulnar nerve with transcranial magnetic stimulation of the contralateral motor cortex. Cognitive status was assessed with a neuropsychological test battery. In patients, verbal learning and rapid-onset cortical plasticity were significantly reduced as compared to controls. Identical follow-up tests in 9 of the 16 patients six months after CEA revealed no improvement of cognitive parameters or cortical plasticity. CONCLUSIONS: Decreased rapid-onset cortical plasticity in patients with severe stenosis of the ICA was not improved by reperfusion. Thus, other strategies known to increase plasticity should be tested for their potential to improve cortical plasticity and subsequently cognition in these patients. PMID- 22844424 TI - Low molecular weight heparin ablates lung cancer cisplatin-resistance by inducing proteasome-mediated ABCG2 protein degradation. AB - Cancer side population (SP) cells, which are often referred to as cancer stem cells, are thought to be responsible for lung cancer chemotherapy resistance, and currently no drug can specifically target these cells. We hypothesize low molecular-weight heparin (LMWH) may affect the biological properties of SP cells and could be used to clinically target these cells. To test this, SP cells were isolated from cisplatin (DDP)-resistant lung adenocarcinoma A549/DDP cells by flow cytometric sorting. Compared to non-SP cells, SP cells formed increased numbers of colonies in vitro, and had a 1000-fold increase in tumorigenicity in vivo. Proliferation and apoptosis assays demonstrated LMWH had no significant effect on lung SP cell proliferation or apoptosis. However, LMWH reduced lung SP cell colony formation ability and protein expression of the multidrug transporter, ABCG2, by FACS and western blot analyses without affecting its mRNA levels by RT-PCR. Consistently, immunohistochemistry stainings of ABCG2 in LMWH treated tumor tissues were significantly reduced compared with those in controls. Further, we found proteasomal inhibitor MG132, but not lysosomal inhibitors leupeptin and pepstatin A, could restore ABCG2 protein levels in LMWH-treated SP cells. These suggest LMWH ablates lung SP cell chemoresistance by proteasome mediated reduction of ABCG2 protein levels without affecting its mRNA levels. We also determined LMWH combined with cisplatin could overcome cisplatin-resistance and induced lung SP cells apoptosis both in vitro and in vivo. This study provides an experimental basis for using a combination of LMWH, which targets lung SP cells, with chemotherapy to improve lung cancer survival. PMID- 22844425 TI - Investigating concordance among genetic data, subspecies circumscriptions and hostplant use in the nymphalid butterfly Polygonia faunus. AB - Subspecies are commonly used taxonomic units to formally describe intraspecific geographic variation in morphological traits. However, the concept of subspecies is not clearly defined, and there is little agreement about what they represent in terms of evolutionary units, and whether they can be used as reliably useful units in conservation, evolutionary theory and taxonomy. We here investigate whether the morphologically well-characterized subspecies in the North American butterfly Polygonia faunus are supported by genetic data from mitochondrial sequences and eight microsatellite loci. We also investigate the phylogeographic structure of P. faunus and test whether similarities in host-plant use among populations are related to genetic similarity. Neither the nuclear nor the mitochondrial data corroborated subspecies groupings. We found three well defined genetic clusters corresponding to California, Arizona and (New Mexico+Colorado). There was little structuring among the remaining populations, probably due to gene flow across populations. We found no support for the hypothesis that similarities in host use are related to genetic proximity. The results indicate that the species underwent a recent rapid expansion, probably from two glacial refugia in western North America. The mitochondrial haplotype network indicates at least two independent expansion phases into eastern North America. Our results clearly demonstrate that subspecies in P. faunus do not conform to the structuring of genetic variation. More studies on insects and other invertebrates are needed to better understand the scope of this phenomenon. The results of this study will be crucial in designing further experiments to understand the evolution of hostplant utilization in this species. PMID- 22844426 TI - Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. AB - BACKGROUND: Associations have been made between obesity and reduced intestinal numbers of members of the phylum Bacteroidetes, but there is no direct evidence of the role these bacteria play in obesity. Herein, the effects of Bacteroides uniformis CECT 7771 on obesity-related metabolic and immune alterations have been evaluated. METHODS AND FINDINGS: Adult (6-8 week) male wild-type C57BL-6 mice were fed a standard diet or a high-fat-diet HFD to induce obesity, supplemented or not with B. uniformis CECT 7771 for seven weeks. Animal weight was monitored and histologic, biochemical, immunocompetent cell functions, and features of the faecal microbiota were analysed after intervention. The oral administration of B. uniformis CECT 7771 reduced body weight gain, liver steatosis and liver cholesterol and triglyceride concentrations and increased small adipocyte numbers in HFD-fed mice. The strain also reduced serum cholesterol, triglyceride, glucose, insulin and leptin levels, and improved oral tolerance to glucose in HFD fed mice. The bacterial strain also reduced dietary fat absorption, as indicated by the reduced number of fat micelles detected in enterocytes. Moreover, B. uniformis CECT 7771 improved immune defence mechanisms, impaired in obesity. HFD induced obesity led to a decrease in TNF-alpha production by peritoneal macrophages stimulated with LPS, conversely, the administration of B. uniformis CECT 7771 increased TNF-alpha production and phagocytosis. Administering this strain also increased TNF-alpha production by dendritic cells (DCs) in response to LPS stimulation, which was significantly reduced by HFD. B. uniformis CECT 7771 also restored the capacity of DCs to induce a T-cell proliferation response, which was impaired in obese mice. HFD induced marked changes in gut microbiota composition, which were partially restored by the intervention. CONCLUSIONS: Altogether, the findings indicate that administration of B. uniformis CECT 7771 ameliorates HFD-induced metabolic and immune dysfunction associated with intestinal dysbiosis in obese mice. PMID- 22844427 TI - A novel viral SOCS from infectious spleen and kidney necrosis virus: interacts with Jak1 and inhibits IFN-alpha induced Stat1/3 activation. AB - Interferon (IFN)-induced Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway is important in controlling immune responses and is negatively response-regulated by the suppressor of cytokine signaling (SOCS) proteins. However, several viruses have developed various strategies to inhibit this pathway to circumvent the anti-viral immunity of the host. The infectious spleen and kidney necrosis virus (ISKNV) is the type species of the genus Megalocytivirus in the family Iridoviridae and a causative agent of epizootics in fish. ISKNV ORF103R encodes a predicted viral SOCS (vSOCS) with high homology to the vertebrate SOCS1, but lacks a SOCS-box domain. Interestingly, vSOCS only exists in the genus Megalocytivirus. ISKNV-vSOCS can block the IFN-alpha-induced Jak/Stat pathway in HepG2 cells. Over-expression of ISKNV-vSOCS inhibited the activities of IFN-stimulated response element (ISRE) promoter; however, the inhibitions by ISKNV-vSOCS were dose-dependent. ISKNV-vSOCS interacted with Jak1 protein and inhibited its tyrosine kinase activity in vitro. ISKNV-vSOCS also impaired the phosphorylation of Stat1 and Stat3 proteins and suppressed their activations. The point mutations (F18D, S66A, S85A, and R64K) of ISKNV-vSOCS significantly impaired the inhibition of IFN-alpha-induced ISRE-promoter activation. In conclusion, vSOCS inhibits IFN-alpha-induced Stat1/Stat3 signaling, suggesting that Megalocytivirus has developed a novel strategy to evade IFN anti-viral immunity via vSOCS protein. PMID- 22844428 TI - Mycobacterium tuberculosis complex enhances susceptibility of CD4 T cells to HIV through a TLR2-mediated pathway. AB - Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex) could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC(2)155, and stimulated CD4+ cells were infected with R5-and X4 tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01). Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4 tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition. PMID- 22844429 TI - Second-chance signal transduction explains cooperative flagellar switching. AB - The reversal of flagellar motion (switching) results from the interaction between a switch complex of the flagellar rotor and a torque-generating stationary unit, or stator (motor unit). To explain the steeply cooperative ligand-induced switching, present models propose allosteric interactions between subunits of the rotor, but do not address the possibility of a reaction that stimulates a bidirectional motor unit to reverse direction of torque. During flagellar motion, the binding of a ligand-bound switch complex at the dwell site could excite a motor unit. The probability that another switch complex of the rotor, moving according to steady-state rotation, will reach the same dwell site before that motor unit returns to ground state will be determined by the independent decay rate of the excited-state motor unit. Here, we derive an analytical expression for the energy coupling between a switch complex and a motor unit of the stator complex of a flagellum, and demonstrate that this model accounts for the cooperative switching response without the need for allosteric interactions. The analytical result can be reproduced by simulation when (1) the motion of the rotor delivers a subsequent ligand-bound switch to the excited motor unit, thereby providing the excited motor unit with a second chance to remain excited, and (2) the outputs from multiple independent motor units are constrained to a single all-or-none event. In this proposed model, a motor unit and switch complex represent the components of a mathematically defined signal transduction mechanism in which energy coupling is driven by steady-state and is regulated by stochastic ligand binding. Mathematical derivation of the model shows the analytical function to be a general form of the Hill equation (Hill AV (1910) The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol 40: iv-vii). PMID- 22844430 TI - Pharyngeal microflora disruption by antibiotics promotes airway hyperresponsiveness after respiratory syncytial virus infection. AB - BACKGROUND: Regulatory T cells (Treg cells), which are essential for regulation of immune response to respiratory syncytial virus (RSV) infection, are promoted by pharyngeal commensal pneumococcus. The effects of pharyngeal microflora disruption by antibiotics on airway responsiveness and relative immune responses after RSV infection have not been clarified. METHODS: Female BALB/c mice (aged 3 weeks) were infected with RSV and then treated with either oral antibiotics or oral double distilled water (ddH(2)O) from 1 d post infection (pi). Changes in pharyngeal microflora were analyzed after antibiotic treatment for 7 d and 14 d. At 8 d pi and 15 d pi, the inflammatory cells in bronchoalveolar lavage fluid (BALF) were investigated in combination with tests of pulmonary histopathology, airway hyperresponsiveness (AHR), pulmonary and splenic Treg cells responses. Pulmonary Foxp3 mRNA expression, IL-10 and TGF-beta1 in BALF and lung homogenate were investigated at 15 d pi. Ovalbumin (OVA) challenge was used to induce AHR after RSV infection. RESULTS: The predominant pharyngeal commensal, Streptococcus, was cleared by antibiotic treatment for 7 d. Same change also existed after antibiotic treatment for 14 d. After RSV infection, AHR was promoted by antibiotic treatment at 15 d pi. Synchronous decreases of pulmonary Treg cells, Foxp3 mRNA and TGF-beta1 were detected. Similar results were observed under OVA challenge. CONCLUSIONS: After RSV infection, antibiotic treatment cleared pharyngeal commensal bacteria such as Streptococcus, which consequently, might induce AHR and decrease pulmonary Treg cells. PMID- 22844431 TI - Immunocytochemical localization of amines and GABA in the optic lobe of the butterfly, Papilio xuthus. AB - Butterflies have sophisticated color vision. While the spectral organization of the compound eye has been well characterized in the Japanese yellow swallowtail butterfly, Papilio xuthus, neural mechanisms underlying its color vision are largely unexplored. Towards a better understanding of signal processing in the visual system of P. xuthus, we used immunocytochemical techniques to analyze the distribution of transmitter candidates, namely, histamine, serotonin, tyramine and gamma-aminobutyric acid (GABA). Photoreceptor terminals in the lamina and medulla exhibited histamine immunoreactivity as demonstrated in other insects. The anti-histamine antiserum also labeled a few large medulla neurons. Medulla intrinsic neurons and centrifugal neurons projecting to the lamina showed serotonin immunoreactivity. Tyramine immunostaining was detected in a subset of large monopolar cells (LMCs) in the lamina, transmedullary neurons projecting to the lobula plate, and cell bodies surrounding the first optic chiasma. An anti GABA antiserum labeled a subset of LMCs and populations of columnar and tangential neurons surrounding the medulla. Each of the four antisera also labeled a few centrifugal neurons that innervate the lobula complex from the central brain, suggesting that they have neuromodulatory roles. A distinctive feature we found in this study is the possibility that tyramine and GABA act as transmitters in LMCs of P. xuthus, which has not been reported in any other insects so far. PMID- 22844432 TI - Identifying regional variation in the prevalence of postpartum haemorrhage: a systematic review and meta-analysis. AB - OBJECTIVE: To provide regional estimates of the prevalence of maternal haemorrhage and explore the effect of methodological differences between studies on any observed regional variation. METHODS: We conducted a systematic review of the prevalence of maternal haemorrhage, defined as blood loss greater than or equal to 1) 500 ml or 2) 1000 ml in the antepartum, intrapartum or postpartum period. We obtained regional estimates of the prevalence of maternal and severe maternal haemorrhage by conducting meta-analyses and used meta-regression to explore potential sources of between-study heterogeneity. FINDINGS: No studies reported the prevalence of antepartum haemorrhage (APH) according to our definitions. The prevalence of postpartum haemorrhage (PPH) (blood loss >=500 ml) ranged from 7.2% in Oceania to 25.7% in Africa. The prevalence of severe PPH (blood loss >=1000 ml) was highest in Africa at 5.1% and lowest in Asia at 1.9%. There was strong evidence of between-study heterogeneity in the prevalence of PPH and severe PPH in most regions. Meta-regression analyses suggested that region and method of measurement of blood loss influenced prevalence estimates for both PPH and severe PPH. The regional patterns changed after adjusting for the other predictors of PPH indicating that, compared with European women, Asian women have a lower prevalence of PPH. CONCLUSIONS: We found evidence that Asian women have a very low prevalence of PPH compared with women in Europe. However, more reliable estimates will only be obtained with the standardisation of the measurement of PPH so that the data from different regions are comparable. PMID- 22844433 TI - The effective fragment molecular orbital method for fragments connected by covalent bonds. AB - We extend the effective fragment molecular orbital method (EFMO) into treating fragments connected by covalent bonds. The accuracy of EFMO is compared to FMO and conventional ab initio electronic structure methods for polypeptides including proteins. Errors in energy for RHF and MP2 are within 2 kcal/mol for neutral polypeptides and 6 kcal/mol for charged polypeptides similar to FMO but obtained two to five times faster. For proteins, the errors are also within a few kcal/mol of the FMO results. We developed both the RHF and MP2 gradient for EFMO. Compared to ab initio, the EFMO optimized structures had an RMSD of 0.40 and 0.44 A for RHF and MP2, respectively. PMID- 22844434 TI - Spatial and social organization in a burrow-dwelling lizard (Phrynocephalus vlangalii) from China. AB - Shared ecological resources such as burrow complexes can set the stage for social groupings and the evolution of more complex social behavior such as parental care. Paternity testing is increasingly revealing cases of kin-based groupings, and lizards may be a good system to inform on the early evolution of sociality. We examined spatial and social organization in the lizard Phrynocephalus vlangalii from China and tested genetic relatedness (based on eight microsatellite DNA loci) between offspring and parents that shared burrow complexes. Adult males and females had similar spatial patterns: they overlapped most with members of the opposite sex and least with their own sex. Males in better body condition overlapped with more females, and both sexes showed high site fidelity. Most lizards used a single burrow, but some individuals used two or three burrows. While high site fidelity is consistent with sociality in lizards, juveniles did not preferentially share burrows with parents, and we documented only a few cases of parent-offspring associations through burrow sharing. We suggest that P. vlangalii conforms to a classical polygynous mating system in which the burrow forms the core of the male's territory and may be offered as an important resource for females, but this remains to be determined. PMID- 22844435 TI - Guanidylation and tail effects in cationic antimicrobial lipopeptoids. AB - BACKGROUND: Cationic antimicrobial peptides (CAMPs) are attractive scaffolds for the next generation of antimicrobial compounds, due to their broad spectrum of activity against multi-drug resistant bacteria and the reduced fitness of CAMP insensitive mutants. Unfortunately, they are limited by poor in vivo performance, including ready cleavage by endogenous serum proteases. METHODOLOGY/PRINCIPAL FINDINGS: To explore the potential for peptoid residues to replace well studied CAMP scaffolds we have produced a series of antimicrobial lipopeptoids, with sequences similar to previously reported lipopeptides. The activity of the peptoids was assessed against a panel of clinically relevant and laboratory reference bacteria, and the potential for non-specific binding was determined through hemolytic testing and repeating the antimicrobial testing in the presence of added bovine serum albumin (BSA). The most active peptoids displayed good to moderate activity against most of the gram positive strains tested and moderate to limited activity against the gram negatives. Antimicrobial activity was positively correlated with toxicity towards eukaryotic cells, but was almost completely eliminated by adding BSA. CONCLUSION/SIGNIFICANCE: The lipopeptoids had similar activities to the previously reported lipopeptides, confirming their potential to act as replacement, proteolytically stable scaffolds for CAMPs. PMID- 22844436 TI - Oscillatory cortical network involved in auditory verbal hallucinations in schizophrenia. AB - BACKGROUND: Auditory verbal hallucinations (AVH), a prominent symptom of schizophrenia, are often highly distressing for patients. Better understanding of the pathogenesis of hallucinations could increase therapeutic options. Magnetoencephalography (MEG) provides direct measures of neuronal activity and has an excellent temporal resolution, offering a unique opportunity to study AVH pathophysiology. METHODS: Twelve patients (10 paranoid schizophrenia, 2 psychosis not otherwise specified) indicated the presence of AVH by button-press while lying in a MEG scanner. As a control condition, patients performed a self-paced button-press task. AVH-state and non-AVH state were contrasted in a region-of interest (ROI) approach. In addition, the two seconds before AVH onset were contrasted with the two seconds after AVH onset to elucidate a possible triggering mechanism. RESULTS: AVH correlated with a decrease in beta-band power in the left temporal cortex. A decrease in alpha-band power was observed in the right inferior frontal gyrus. AVH onset was related to a decrease in theta-band power in the right hippocampus. CONCLUSIONS: These results suggest that AVH are triggered by a short aberration in the theta band in a memory-related structure, followed by activity in language areas accompanying the experience of AVH itself. PMID- 22844437 TI - Essential role of RAB27A in determining constitutive human skin color. AB - Human skin color is predominantly determined by melanin produced in melanosomes within melanocytes and subsequently distributed to keratinocytes. There are many studies that have proposed mechanisms underlying ethnic skin color variations, whereas the processes involved from melanin synthesis in melanocytes to the transfer of melanosomes to keratinocytes are common among humans. Apart from the activities in the melanogenic rate-limiting enzyme, tyrosinase, in melanocytes and the amounts and distribution patterns of melanosomes in keratinocytes, the abilities of the actin-associated factors in charge of melanosome transport within melanocytes also regulate pigmentation. Mutations in genes encoding melanosome transport-related molecules, such as MYO5A, RAB27A and SLAC-2A, have been reported to cause a human pigmentary disease known as Griscelli syndrome, which is associated with diluted skin and hair color. Thus we hypothesized that process might play a role in modulating skin color variations. To address that hypothesis, the correlations of expression of RAB27A and its specific effector, SLAC2-A, to melanogenic ability were evaluated in comparison with tyrosinase, using human melanocytes derived from 19 individuals of varying skin types. Following the finding of the highest correlation in RAB27A expression to the melanogenic ability, darkly-pigmented melanocytes with significantly higher RAB27A expression were found to transfer significantly more melanosomes to keratinocytes than lightly-pigmented melanocytes in co-culture and in human skin substitutes (HSSs) in vivo, resulting in darker skin color in concert with the difference observed in African-descent and Caucasian skins. Additionally, RAB27A knockdown by a lentivirus-derived shRNA in melanocytes concomitantly demonstrated a significantly reduced number of transferred melanosomes to keratinocytes in co culture and a significantly diminished epidermal melanin content skin color intensity (DeltaL* = 4.4) in the HSSs. These data reveal the intrinsically essential role of RAB27A in human ethnic skin color determination and provide new insights for the fundamental understanding of regulatory mechanisms underlying skin pigmentation. PMID- 22844438 TI - State-transition diagrams for biologists. AB - It is clearly in the tradition of biologists to conceptualize the dynamical evolution of biological systems in terms of state-transitions of biological objects. This paper is mainly concerned with (but obviously not limited too) the immunological branch of biology and shows how the adoption of UML (Unified Modeling Language) state-transition diagrams can ease the modeling, the understanding, the coding, the manipulation or the documentation of population based immune software model generally defined as a set of ordinary differential equations (ODE), describing the evolution in time of populations of various biological objects. Moreover, that same UML adoption naturally entails a far from negligible representational economy since one graphical item of the diagram might have to be repeated in various places of the mathematical model. First, the main graphical elements of the UML state-transition diagram and how they can be mapped onto a corresponding ODE mathematical model are presented. Then, two already published immune models of thymocyte behavior and time evolution in the thymus, the first one originally conceived as an ODE population-based model whereas the second one as an agent-based one, are refactored and expressed in a state transition form so as to make them much easier to understand and their respective code easier to access, to modify and run. As an illustrative proof, for any immunologist, it should be possible to understand faithfully enough what the two software models are supposed to reproduce and how they execute with no need to plunge into the Java or Fortran lines. PMID- 22844439 TI - The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning. AB - BACKGROUND: Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX 2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. OBJECTIVE: To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. METHODS: COX-2 knockout (KO) mice (COX-2(-/-)), prostacyclin receptor KO (IP(-/-)) mice, and respective wildtype (WT, COX-2(+/+) and IP(+/+)) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. RESULTS: There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2(+/+), COX-2(-/-), IP(+/+), and IP(-/-) mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2(-/-) or IP(-/-) mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. CONCLUSIONS: This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX 2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC. PMID- 22844440 TI - Selection, phenotyping and identification of acid and hydrogen peroxide producing bacteria from vaginal samples of Canadian and East African women. AB - The common but poorly understood condition known as bacterial vaginosis (BV) increases vulnerability to HIV infection and is associated with the absence of H(2)O(2)-producing Lactobacillus. Vaginal lactic acid bacteria (LAB) produce anti HIV factors such as organic acids and hydrogen peroxide (H(2)O(2)), and may bind and inactivate HIV particles during scavenging of mannose. These factors define potential criteria for initial selection of candidate probiotics to block heterosexual transmission of HIV. Therefore, the primary goal of this study was to characterize acid production on mannose and H(2)O(2) production in vaginal isolates from Canadian adolescents (192 isolates, 16 individuals) and commercial sex workers in Nairobi, Kenya (576 isolates, 96 individuals). Selection of isolates from H(2)O(2)-detecting media suggested an idiosyncratic individual level profile and extensive phenotypic diversity, including the identification of a subset of "double-strong" acid- and H(2)O(2)-producers with phenotypes similar to well-characterized probiotic strains. Molecular fingerprinting of all isolates by capillary electrophoresis of 16S-23S rRNA interspacer amplicons was coupled with chaperonin-60 universal target (cpn60 UT) sequencing in a subset, tentatively identifying 96% of isolates although only 19% were sequenced. Most isolates belonged to Lactobacillus, Streptococcus, Bifidobacterium or Gardnerella, with a total of 37 species in 15 genera, as well as 5 potentially novel organisms, identified in this study. This sensitivity was likely enhanced by phenotype-based selection on two chromogenic media formulations. Identification of double-strong isolates may provide a rational basis for selection and further characterization of vaginal probiotics, with potential application as part of HIV prevention initiatives in western Canada and East Africa. PMID- 22844441 TI - Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. AB - BACKGROUND: Sleep restriction is associated with development of metabolic ill health, and hormonal mechanisms may underlie these effects. The aim of this study was to determine the impact of short term sleep restriction on male health, particularly glucose metabolism, by examining adrenocorticotropic hormone (ACTH), cortisol, glucose, insulin, triglycerides, leptin, testosterone, and sex hormone binding globulin (SHBG). METHODOLOGY/PRINCIPAL FINDINGS: N = 14 healthy men (aged 27.4+/-3.8, BMI 23.5+/-2.9) underwent a laboratory-based sleep restriction protocol consisting of 2 baseline nights of 10 h time in bed (TIB) (B1, B2; 22:00 08:00), followed by 5 nights of 4 h TIB (SR1-SR5; 04:00-08:00) and a recovery night of 10 h TIB (R1; 22:00-08:00). Subjects were allowed to move freely inside the laboratory; no strenuous activity was permitted during the study. Food intake was controlled, with subjects consuming an average 2000 kcal/day. Blood was sampled through an indwelling catheter on B1 and SR5, at 09:00 (fasting) and then every 2 hours from 10:00-20:00. On SR5 relative to B1, glucose (F(1,168) = 25.3, p<0.001) and insulin (F(1,168) = 12.2, p<0.001) were increased, triglycerides (F(1,168) = 7.5, p = 0.007) fell and there was no significant change in fasting homeostatic model assessment (HOMA) determined insulin resistance (F(1,168) = 1.3, p = 0.18). Also, cortisol (F(1,168) = 10.2, p = 0.002) and leptin (F(1,168) = 10.7, p = 0.001) increased, sex hormone binding globulin (F(1,167) = 12.1, p<0.001) fell and there were no significant changes in ACTH (F(1,168) = 0.3, p = 0.59) or total testosterone (F(1,168) = 2.8, p = 0.089). CONCLUSIONS/SIGNIFICANCE: Sleep restriction impaired glucose, but improved lipid metabolism. This was associated with an increase in afternoon cortisol, without significant changes in ACTH, suggesting enhanced adrenal reactivity. Increased cortisol and reduced sex hormone binding globulin (SHBG) are both consistent with development of insulin resistance, although hepatic insulin resistance calculated from fasting HOMA did not change significantly. Short term sleep curtailment leads to changes in glucose metabolism and adrenal reactivity, which when experienced repeatedly may increase the risk for type 2 diabetes. PMID- 22844442 TI - Genetic variants in CASP3, BMP5, and IRS2 genes may influence survival in prostate cancer patients receiving androgen-deprivation therapy. AB - Several genome-wide association studies (GWAS) have been conducted to identify the common single nucleotide polymorphisms (SNPs) that influence the risk of prostate cancer. It was hypothesized that some prostate cancer-associated SNPs might relate to the clinical outcomes in patients treated for prostate cancer using androgen-deprivation therapy (ADT). A cohort of 601 patients who have received ADT for prostate cancer was genotyped for 29 SNPs that have been associated with prostate cancer in Cancer Genetic Markers of Susceptibility GWAS, and within the genes that have been implicated in cancer. Prognostic significance of these SNPs on the disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model. Three SNPs, namely CASP3 rs4862396, BMP5 rs3734444 and IRS2 rs7986346, were found to be closely associated with the ACM (P<=0.042), and BMP5 rs3734444 and IRS2 rs7986346 were also noted to be significantly related to the PCSM (P<=0.032) after adjusting for the known clinicopathologic predictors. Moreover, patients carrying a greater number of unfavorable genotypes at the loci of interest had a shorter time to ACM and PCSM during ADT (P for trend <0.001). Our results suggest that CASP3 rs4862396, BMP5 rs3734444 and IRS2 rs7986346 may affect the survival in patients after ADT for prostate cancer, and the analysis of these SNPs can help identify patients at higher risk of poor outcome. PMID- 22844443 TI - Plant extract synthesized PLA nanoparticles for controlled and sustained release of quercetin: a green approach. AB - BACKGROUND: Green synthesis of metallic nanoparticles (NPs) has been extensively carried out by using plant extracts (PEs) which have property of stabilizers/emulsifiers. To our knowledge, there is no comprehensive study on applying a green approach using PEs for fabrication of biodegradable PLA NPs. Conventional methods rely on molecules like polyvinyl alcohol, polyethylene glycol, D-alpha-tocopheryl poly(ethylene glycol 1000) succinate as stabilizers/emulsifiers for the synthesis of such biodegradable NPs which are known to be toxic. So, there is urgent need to look for stabilizers which are biogenic and non-toxic. The present study investigated use of PEs as stabilizers/emulsifiers for the fabrication of stable PLA NPs. Synthesized PLA NPs through this green process were explored for controlled release of the well known antioxidant molecule quercetin. METHODOLOGY/PRINCIPAL FINDINGS: Stable PLA NPs were synthesized using leaf extracts of medicinally important plants like Syzygium cumini (1), Bauhinia variegata (2), Cedrus deodara (3), Lonicera japonica (4) and Eleaocarpus sphaericus (5). Small and uniformly distributed NPs in the size range 70+/-30 nm to 143+/-36 nm were formed with these PEs. To explore such NPs for drugs/ small molecules delivery, we have successfully encapsulated quercetin a lipophilic molecule on a most uniformly distributed PLA 4 NPs synthesized using Lonicera japonica leaf extract. Quercetin loaded PLA-4 NPs were observed for slow and sustained release of quercetin molecule. CONCLUSIONS: This green approach based on PEs mediated synthesis of stable PLA NPs pave the way for encapsulating drug/small molecules, nutraceuticals and other bioactive ingredients for safer cellular uptake, biodistribution and targeted delivery. Hence, such PEs synthesized PLA NPs would be useful to enhance the therapeutic efficacy of encapsulated small molecules/drugs. Furthermore, different types of plants can be explored for the synthesis of PLA as well as other polymeric NPs of smaller size. PMID- 22844444 TI - A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro. AB - We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5 tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC(50) values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1(LAI) from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti HIV agents by coupling additional antibodies of interest with alternative HIV inhibitors via recombinantly-produced, self-assembling, modules. PMID- 22844445 TI - Reliability of the peer-review process for adverse event rating. AB - BACKGROUND: Adverse events are poor patient outcomes caused by medical care. Their identification requires the peer-review of poor outcomes, which may be unreliable. Combining physician ratings might improve the accuracy of adverse event classification. OBJECTIVE: To evaluate the variation in peer-reviewer ratings of adverse outcomes; determine the impact of this variation on estimates of reviewer accuracy; and determine the number of reviewers who judge an adverse event occurred that is required to ensure that the true probability of an adverse event exceeded 50%, 75% or 95%. METHODS: Thirty physicians rated 319 case reports giving details of poor patient outcomes following hospital discharge. They rated whether medical management caused the outcome using a six-point ordinal scale. We conducted latent class analyses to estimate the prevalence of adverse events as well as the sensitivity and specificity of each reviewer. We used this model and Bayesian calculations to determine the probability that an adverse event truly occurred to each patient as function of their number of positive ratings. RESULTS: The overall median score on the 6-point ordinal scale was 3 (IQR 2,4) but the individual rater median score ranged from a minimum of 1 (in four reviewers) to a maximum median score of 5. The overall percentage of cases rated as an adverse event was 39.7% (3798/9570). The median kappa for all pair-wise combinations of the 30 reviewers was 0.26 (IQR 0.16, 0.42; Min = -0.07, Max = 0.62). Reviewer sensitivity and specificity for adverse event classification ranged from 0.06 to 0.93 and 0.50 to 0.98, respectively. The estimated prevalence of adverse events using a latent class model with a common sensitivity and specificity for all reviewers (0.64 and 0.83 respectively) was 47.6%. For patients to have a 95% chance of truly having an adverse event, at least 3 of 3 reviewers are required to deem the outcome an adverse event. CONCLUSION: Adverse event classification is unreliable. To be certain that a case truly represents an adverse event, there needs to be agreement among multiple reviewers. PMID- 22844446 TI - Protons sensitize epithelial cells to mesenchymal transition. AB - Proton radiotherapy has gained more favor among oncologists as a treatment option for localized and deep-seated tumors. In addition, protons are a major constituent of the space radiation astronauts receive during space flights. The potential for these exposures to lead to, or enhance cancer risk has not been well studied. Our objective is to study the biological effects of low energy protons on epithelial cells and its propensity to enhance transforming growth factor beta 1 (TGFbeta1)-mediated epithelial-mesenchymal transition (EMT), a process occurring during tumor progression and critical for invasion and metastasis. Non-transformed mink lung epithelial cells (Mv1Lu) and hTERT- immortalized human esophageal epithelial cells (EPC) were used in this study. EMT was identified by alterations in cell morphology, EMT-related gene expression changes determined using real-time PCR, and EMT changes in specific cellular markers detected by immunostaining and western blotting. Although TGFbeta1 treatment alone is able to induce EMT in both Mv1Lu and EPC cells, low energy protons (5 MeV) at doses as low as 0.1 Gy can enhance TGFbeta1 induced EMT. Protons alone can also induce a mild induction of EMT. SD208, a potent TGFbeta Receptor 1 (TGFbetaR1) kinase inhibitor, can efficiently block TGFbeta1/Smad signaling and attenuate EMT induction. We suggest a model for EMT after proton irradiation in normal and cancerous tissue based on our results that showed that low and high doses of protons can sensitize normal human epithelial cells to mesenchymal transition, more prominently in the presence of TGFbeta1, but also in the absence of TGFbeta1. PMID- 22844447 TI - Sequencing of IncX-plasmids suggests ubiquity of mobile forms of a biofilm promoting gene cassette recruited from Klebsiella pneumoniae. AB - Plasmids are a highly effective means with which genetic traits that influence human health, such as virulence and antibiotic resistance, are disseminated through bacterial populations. The IncX-family is a hitherto sparsely populated group of plasmids that are able to thrive within Enterobacteriaceae. In this study, a replicon-centric screening method was used to locate strains from wastewater sludge containing plasmids belonging to the IncX-family. A transposon aided plasmid capture method was then employed to transport IncX-plasmids from their original hosts (and co-hosted plasmids) into a laboratory strain (Escherichia coli Genehogs(r)) for further study. The nucleotide sequences of the three newly isolated IncX-plasmids (pLN126_33, pMO17_54, pMO440_54) and the hitherto un-sequenced type-plasmid R485 revealed a remarkable occurrence of whole or partial gene cassettes that promote biofilm-formation in Klebsiella pneumonia or E. coli, in all four instances. Two of the plasmids (R485 and pLN126_33) were shown to directly induce biofilm formation in a crystal violet retention assay in E. coli. Sequence comparison revealed that all plasmid-borne forms of the type 3 fimbriae encoding gene cassette mrkABCDF were variations of a composite transposon Tn6011 first described in the E. coli IncX plasmid pOLA52. In conclusion, IncX-plasmids isolated from Enterobacteriaceae over almost 40 years and on three different continents have all been shown to carry a type 3 fimbriae gene cassette mrkABCDF stemming from pathogenic K. pneumoniae. Apart from contributing general knowledge about IncX-plasmids, this study also suggests an apparent ubiquity of a mobile form of an important virulence factor and is an illuminating example of the recruitment, evolution and dissemination of genetic traits through plasmid-mediated horizontal gene transfer. PMID- 22844448 TI - Neisseria gonorrhoeae suppresses dendritic cell-induced, antigen-dependent CD4 T cell proliferation. AB - Neisseria gonorrhoeae is the second most common sexually transmitted bacterial pathogen worldwide. Diseases associated with N. gonorrhoeae cause localized inflammation of the urethra and cervix. Despite this inflammatory response, infected individuals do not develop protective adaptive immune responses to N. gonorrhoeae. N. gonorrhoeae is a highly adapted pathogen that has acquired multiple mechanisms to evade its host's immune system, including the ability to manipulate multiple immune signaling pathways. N. gonorrhoeae has previously been shown to engage immunosuppressive signaling pathways in B and T lymphocytes. We have now found that N. gonorrhoeae also suppresses adaptive immune responses through effects on antigen presenting cells. Using primary, murine bone marrow derived dendritic cells and lymphocytes, we show that N. gonorrhoeae-exposed dendritic cells fail to elicit antigen-induced CD4+ T lymphocyte proliferation. N. gonorrhoeae exposure leads to upregulation of a number of secreted and dendritic cell surface proteins with immunosuppressive properties, particularly Interleukin 10 (IL-10) and Programmed Death Ligand 1 (PD-L1). We also show that N. gonorrhoeae is able to inhibit dendritic cell- induced proliferation of human T-cells and that human dendritic cells upregulate similar immunosuppressive molecules. Our data suggest that, in addition to being able to directly influence host lymphocytes, N. gonorrhoeae also suppresses development of adaptive immune responses through interactions with host antigen presenting cells. These findings suggest that gonococcal factors involved in host immune suppression may be useful targets in developing vaccines that induce protective adaptive immune responses to this pathogen. PMID- 22844449 TI - Amino acid transporter genes are essential for FLO11-dependent and FLO11 independent biofilm formation and invasive growth in Saccharomyces cerevisiae. AB - Amino acids can induce yeast cell adhesion but how amino acids are sensed and signal the modulation of the FLO adhesion genes is not clear. We discovered that the budding yeast Saccharomyces cerevisiae CEN.PK evolved invasive growth ability under prolonged nitrogen limitation. Such invasive mutants were used to identify amino acid transporters as regulators of FLO11 and invasive growth. One invasive mutant had elevated levels of FLO11 mRNA and a Q320STOP mutation in the SFL1 gene that encodes a protein kinase A pathway regulated repressor of FLO11. Glutamine transporter genes DIP5 and GNP1 were essential for FLO11 expression, invasive growth and biofilm formation in this mutant. Invasive growth relied on known regulators of FLO11 and the Ssy1-Ptr3-Ssy5 complex that controls DIP5 and GNP1, suggesting that Dip5 and Gnp1 operates downstream of the Ssy1-Ptr3-Ssy5 complex for regulation of FLO11 expression in a protein kinase A dependent manner. The role of Dip5 and Gnp1 appears to be conserved in the S. cerevisiae strain ?1278b since the dip5 gnp1 ?1278b mutant showed no invasive phenotype. Secondly, the amino acid transporter gene GAP1 was found to influence invasive growth through FLO11 as well as other FLO genes. Cells carrying a dominant loss-of-function PTR3(647::CWNKNPLSSIN) allele had increased transcription of the adhesion genes FLO1, 5, 9, 10, 11 and the amino acid transporter gene GAP1. Deletion of GAP1 caused loss of FLO11 expression and invasive growth. However, deletions of FLO11 and genes encoding components of the mitogen-activated protein kinase pathway or the protein kinase A pathway were not sufficient to abolish invasive growth, suggesting involvement of other FLO genes and alternative pathways. Increased intracellular amino acid pools in the PTR3(647::CWNKNPLSSIN)-containing strain opens the possibility that Gap1 regulates the FLO genes through alteration of the amino acid pool sizes. PMID- 22844450 TI - Statin-associated polymyalgia rheumatica. An analysis using WHO global individual case safety database: a case/non-case approach. AB - OBJECTIVE: To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO). METHODS: We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI). RESULTS: We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89-20.85). CONCLUSION: The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism. PMID- 22844451 TI - A network-based gene expression signature informs prognosis and treatment for colorectal cancer patients. AB - BACKGROUND: Several studies have reported gene expression signatures that predict recurrence risk in stage II and III colorectal cancer (CRC) patients with minimal gene membership overlap and undefined biological relevance. The goal of this study was to investigate biological themes underlying these signatures, to infer genes of potential mechanistic importance to the CRC recurrence phenotype and to test whether accurate prognostic models can be developed using mechanistically important genes. METHODS AND FINDINGS: We investigated eight published CRC gene expression signatures and found no functional convergence in Gene Ontology enrichment analysis. Using a random walk-based approach, we integrated these signatures and publicly available somatic mutation data on a protein-protein interaction network and inferred 487 genes that were plausible candidate molecular underpinnings for the CRC recurrence phenotype. We named the list of 487 genes a NEM signature because it integrated information from Network, Expression, and Mutation. The signature showed significant enrichment in four biological processes closely related to cancer pathophysiology and provided good coverage of known oncogenes, tumor suppressors, and CRC-related signaling pathways. A NEM signature-based Survival Support Vector Machine prognostic model was trained using a microarray gene expression dataset and tested on an independent dataset. The model-based scores showed a 75.7% concordance with the real survival data and separated patients into two groups with significantly different relapse-free survival (p = 0.002). Similar results were obtained with reversed training and testing datasets (p = 0.007). Furthermore, adjuvant chemotherapy was significantly associated with prolonged survival of the high risk patients (p = 0.006), but not beneficial to the low-risk patients (p = 0.491). CONCLUSIONS: The NEM signature not only reflects CRC biology but also informs patient prognosis and treatment response. Thus, the network-based data integration method provides a convergence between biological relevance and clinical usefulness in gene signature development. PMID- 22844452 TI - Clonal analysis in recurrent astrocytic, oligoastrocytic and oligodendroglial tumors implicates IDH1- mutation as common tumor initiating event. AB - BACKGROUND: To investigate the dynamics of inter- and intratumoral molecular alterations during tumor progression in recurrent gliomas. METHODOLOGY/PRINCIPAL FINDINGS: To address intertumoral heterogeneity we investigated non microdissected tumor tissue of 106 gliomas representing 51 recurrent tumors. To address intratumoral heterogeneity a set of 16 gliomas representing 7 tumor pairs with at least one recurrence, and 4 single mixed gliomas were investigated by microdissection of distinct oligodendroglial and astrocytic tumor components. All tumors and tumor components were analyzed for allelic loss of 1p/19q (LOH 1p/19q), for TP53- mutations and for R132 mutations in the IDH1 gene. The investigation of non-microdissected tumor tissue revealed clonality in 75% (38/51). Aberrant molecular alterations upon recurrence were detected in 25% (13/51). 64% (9/14) of these were novel and associated with tumor progression. Loss of previously detected alterations was observed in 36% (5/14). One tumor pair (1/14; 7%) was significant for both. Intratumoral clonality was detected in 57% (4/7) of the microdissected tumor pairs and in 75% (3/4) of single microdissected tumors. 43% (3/7) of tumor pairs and one single tumor (25%) revealed intratumoral heterogeneity. While intratumoral heterogeneity affected both the TP53- mutational status and the LOH1p/19q status, all tumors with intratumoral heterogeneity shared the R132 IDH1- mutation as a common feature in both their microdissected components. CONCLUSIONS/SIGNIFICANCE: The majority of recurrent gliomas are of monoclonal origin. However, the detection of divertive tumor cell clones in morphological distinct tumor components sharing IDH1- mutations as early event may provide insight into the tumorigenesis of true mixed gliomas. PMID- 22844453 TI - Estrogens induce expression of membrane-associated estrogen receptor alpha isoforms in lactotropes. AB - Estrogens are key to anterior pituitary function, stimulating hormone release and controlling cell fate to achieve pituitary dynamic adaptation to changing physiological conditions. In addition to their classical mechanism of action through intracellular estrogen receptors (ERs), estrogens exert rapid actions via cell membrane-localized ERs (mERs). We previously showed that E2 exerts a rapid pro-apoptotic action in anterior pituitary cells, especially in lactotropes and somatotropes, through activation of mERs. In the present study, we examined the involvement of mERalpha in the rapid pro-apoptotic action of estradiol by TUNEL in primary cultures of anterior pituitary cells from ovariectomized rats using a cell-impermeable E2 conjugate (E2-BSA) and an ERalpha selective antagonist (MPP dihydrochloride). We studied mERalpha expression during the estrous cycle and its regulation by gonadal steroids in vivo by flow cytometry. We identified ERalpha variants in the plasma membrane of anterior pituitary cells during the estrous cycle and studied E2 regulation of these mERalpha variants in vitro by surface biotinylation and Western Blot. E2-BSA-induced apoptosis was abrogated by MPP in total anterior pituitary cells and lactotropes. In cycling rats, we detected a higher number of lactotropes and a lower number of somatotropes expressing mERalpha at proestrus than at diestrus. Acute E2 treatment increased the percentage of mERalpha-expressing lactotropes whereas it decreased the percentage of mERalpha-expressing somatotropes. We detected three mERalpha isoforms of 66, 39 and 22 kDa. Expression of mERalpha66 and mERalpha39 was higher at proestrus than at diestrus, and short-term E2 incubation increased expression of these two mERalpha variants. Our results indicate that the rapid apoptotic action exerted by E2 in lactotropes depends on mERalpha, probably full-length ERalpha and/or a 39 kDa ERalpha variant. Expression and activation of mERalpha variants in lactotropes could be one of the mechanisms through which E2 participates in anterior pituitary cell renewal during the estrous cycle. PMID- 22844454 TI - Cyproheptadine enhances the I(K) of mouse cortical neurons through sigma-1 receptor-mediated intracellular signal pathway. AB - Cyproheptadine (CPH) is a histamine- and serotonin-receptor antagonist, and its effects are observed recently in the modulation of multiple intracellular signals. In this study, we used cortical neurons and HEK-293 cells transfected with Kv2.1 alpha-subunit to address whether CPH modify neural voltage-gated K(+) channels by a mechanism independent of its serotonergic and histaminergic properties. Our results demonstrate that intracellularly delivered CPH increased the I(K) by reducing the activity of protein kinas A (PKA). Inhibition of G(i) eliminated the CPH-induced effect on both the I(K) and PKA. Blocking of 5-HT-, M , D(2)-, H(1)- or H(2)-type GPCR receptors with relevant antagonists did not eliminate the CPH-induced effect on the I(K). Antagonists of the sigma-1 receptor, however, blocked the effect of CPH. Moreover, the inhibition of sigma-1 by siRNA knockdown significantly reduced the CPH-induced effect on the I(K). On the contrary, sigma-1 receptor agonist mimicked the effects of CPH on the induction of I(K). A ligand-receptor binding assay indicated that CPH bound to the sigma-1 receptor. Similar effect of CPH were obtained from HEK-293 cells transfected with the alpha-subunit of Kv2.1. In overall, we reveal for the first time that CPH enhances the I(K) by modulating activity of PKA, and that the associated activation of the sigma-1 receptor/G(i)-protein pathway might be involved. Our findings illustrate an uncharacterized effect of CPH on neuron excitability through the I(K), which is independent of histamine H(1) and serotonin receptors. PMID- 22844455 TI - N-myc downstream regulated gene 1 (NDRG1) promotes metastasis of human scirrhous gastric cancer cells through epithelial mesenchymal transition. AB - Our recent study demonstrated that higher expression of N-myc downregulated gene 1 (NDRG1) is closely correlated with poor prognosis in gastric cancer patients. In this study, we asked whether NDRG1 has pivotal roles in malignant progression including metastasis of gastric cancer cells. By gene expression microarray analysis expression of NDRG1 showed the higher increase among a total of 3691 up regulated genes in a highly metastatic gastric cancer cell line (58As1) than their parental low metastatic counterpart (HSC-58). The highly metastatic cell lines showed decreased expression of E-cadherin, together with enhanced expression of vimentin and Snail. This decreased expression of E-cadherin was restored by Snail knockdown in highly metastatic cell lines. We next established stable NDRG1 knockdown cell lines (As1/Sic50 and As1/Sic54) from the highly metastatic cell line, and both of these cell lines showed enhanced expression of E-cadherin and decreased expression of vimentin and Snail. And also, E-cadherin promoter-driven luciferase activity was found to be increased by NDRG1 knockdown in the highly metastatic cell line. NDRG1 knockdown in gastric cancer cell showed suppressed invasion of cancer cells into surround tissues, suppressed metastasis to the peritoneum and decreased ascites accumulation in mice with significantly improved survival rates. This is the first study to demonstrate that NDRG1 plays its pivotal role in the malignant progression of gastric cancer through epithelial mesenchymal transition. PMID- 22844456 TI - Tristetraprolin inhibits poly(A)-tail synthesis in nuclear mRNA that contains AU rich elements by interacting with poly(A)-binding protein nuclear 1. AB - BACKGROUND: Tristetraprolin binds mRNA AU-rich elements and thereby facilitates the destabilization of mature mRNA in the cytosol. METHODOLOGY/PRINCIPAL FINDINGS: To understand how tristetraprolin mechanistically functions, we biopanned with a phage-display library for proteins that interact with tristetraprolin and retrieved, among others, a fragment of poly(A)-binding protein nuclear 1, which assists in the 3'-polyadenylation of mRNA by binding to immature poly(A) tails and thereby increases the activity of poly(A) polymerase, which is directly responsible for polyadenylation. The tristetraprolin/poly(A) binding protein nuclear 1 interaction was characterized using tristetraprolin and poly(A)-binding protein nuclear 1 deletion mutants in pull-down and co immunoprecipitation assays. Tristetraprolin interacted with the carboxyl-terminal region of poly(A)-binding protein nuclear 1 via its tandem zinc finger domain and another region. Although tristetraprolin and poly(A)-binding protein nuclear 1 are located in both the cytoplasm and the nucleus, they interacted in vivo in only the nucleus. In vitro, tristetraprolin bound both poly(A)-binding protein nuclear 1 and poly(A) polymerase and thereby inhibited polyadenylation of AU-rich element-containing mRNAs encoding tumor necrosis factor alpha, GM-CSF, and interleukin-10. A tandem zinc finger domain-deleted tristetraprolin mutant was a less effective inhibitor. Expression of a tristetraprolin mutant restricted to the nucleus resulted in downregulation of an AU-rich element-containing tumor necrosis factor alpha/luciferase mRNA construct. CONCLUSION/SIGNIFICANCE: In addition to its known cytosolic mRNA-degrading function, tristetraprolin inhibits poly(A) tail synthesis by interacting with poly(A)-binding protein nuclear 1 in the nucleus to regulate expression of AU-rich element-containing mRNA. PMID- 22844458 TI - In vivo site-specific transfection of naked plasmid DNA and siRNAs in mice by using a tissue suction device. AB - We have developed an in vivo transfection method for naked plasmid DNA (pDNA) and siRNA in mice by using a tissue suction device. The target tissue was suctioned by a device made of polydimethylsiloxane (PDMS) following the intravenous injection of naked pDNA or siRNA. Transfection of pDNA encoding luciferase was achieved by the suction of the kidney, liver, spleen, and heart, but not the duodenum, skeletal muscle, or stomach. Luciferase expression was specifically observed at the suctioned region of the tissue, and the highest luciferase expression was detected at the surface of the tissue (0.12+/-0.03 ng/mg protein in mice liver). Luciferase expression levels in the whole liver increased linearly with an increase in the number of times the liver was suctioned. Transfection of siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene significantly suppressed the expression of GAPDH mRNA in the liver. Histological analysis shows that severe damage was not observed in the suctioned livers. Since the suction device can be mounted onto the head of the endoscope, this method is a minimally invasive. These results indicate that the in vivo transfection method developed in this study will be a viable approach for biological research and therapies using nucleic acids. PMID- 22844457 TI - Mycobacterium tuberculosis population in northwestern Russia: an update from Russian-EU/Latvian border region. AB - This study aimed to characterize the population structure of Mycobacterium tuberculosis in Pskov oblast in northwestern Russia, to view it in the geographical context, to compare drug resistance properties across major genetic families. Ninety M. tuberculosis strains from tuberculosis (TB) patients, permanent residents in Pskov oblast were subjected to LAM-specific IS6110-PCR and spoligotyping, followed by comparison with SITVITWEB and MIRU-VNTRplus databases. The Beijing genotype (n = 40) was found the most prevalent followed by LAM (n = 18), T (n = 13), Haarlem (n = 10), Ural (n = 5), and Manu2 (n = 1); the family status remained unknown for 3 isolates. The high rate of Beijing genotype and prevalence of LAM family are similar to those in the other Russian settings. A feature specific for M. tuberculosis population in Pskov is a relatively higher rate of Haarlem and T types. Beijing strains were further typed with 12-MIRU (followed by comparison with proprietary global database) and 3 hypervariable loci QUB-3232, VNTR-3820, VNTR-4120. The 12-MIRU typing differentiated 40 Beijing strains into 14 types (HGI = 0.82) while two largest types were M2 (223325153533) prevalent throughout former USSR and M11 (223325173533) prevalent in Russia and East Asia. The use of 3 hypervariable loci increased a discrimination of the Beijing strains (18 profiles, HGI = 0.89). Both major families Beijing and LAM had similar rate of MDR strains (62.5 and 55.6%, respectively) that was significantly higher than in other strains (21.9%; P = 0.001 and 0.03, respectively). The rpoB531 mutations were more frequently found in Beijing strains while LAM drug resistant strains mainly harbored rpoB516 and inhA -15 mutations. Taken together with a high rate of multidrug resistance among Beijing strains from new TB cases (79.3% versus 44.4% in LAM), these findings suggest the critical impact of the Beijing genotype on the current situation with MDR-TB in the Pskov region in northwestern Russia. PMID- 22844459 TI - Activation of soluble adenylyl cyclase protects against secretagogue stimulated zymogen activation in rat pancreaic acinar cells. AB - An early feature of acute pancreatitis is activation of zymogens, such as trypsinogen, within the pancreatic acinar cell. Supraphysiologic concentrations of the hormone cholecystokinin (CCK; 100 nM), or its orthologue cerulein (CER), induce zymogen activation and elevate levels of cAMP in pancreatic acinar cells. The two classes of adenylyl cyclase, trans-membrane (tmAC) and soluble (sAC), are activated by distinct mechanisms, localize to specific subcellular domains, and can produce locally high concentrations of cAMP. We hypothesized that sAC activity might selectively modulate acinar cell zymogen activation. sAC was identified in acinar cells by PCR and immunoblot. It localized to the apical region of the cell under resting conditions and redistributed intracellularly after treatment with supraphysiologic concentrations of cerulein. In cerulein treated cells, pre-incubation with a trans-membrane adenylyl cyclase inhibitor did not affect zymogen activation or amylase secretion. However, treatment with a sAC inhibitor (KH7), or inhibition of a downstream target of cAMP, protein kinase A (PKA), significantly enhanced secretagogue-stimulated zymogen activation and amylase secretion. Activation of sAC with bicarbonate significantly inhibited secretagogue-stimulated zymogen activation; this response was decreased by inhibition of sAC or PKA. Bicarbonate also enhanced secretagogue-stimulated cAMP accumulation; this effect was inhibited by KH7. Bicarbonate treatment reduced secretagogue-stimulated acinar cell vacuolization, an early marker of pancreatitis. These data suggest that activation of sAC in the pancreatic acinar cell has a protective effect and reduces the pathologic activation of proteases during pancreatitis. PMID- 22844460 TI - Doxycycline regulated induction of AKT in murine prostate drives proliferation independently of p27 cyclin dependent kinase inhibitor downregulation. AB - The PI3 kinase/AKT pathway has been shown to increase degradation of the p27 cyclin dependent kinase inhibitor through phosphorylation of consensus AKT sites on p27 and SKP2, and AKT driven proliferation may be checked by feedback mechanisms that increase p27 expression and induce senescence. However, these AKT sites are not conserved in mouse, and it has not been clear whether AKT negatively regulates murine p27. Transgenic mice with a probasin promoter controlled prostate specific reverse tetracycline transactivator (ARR2Pb-rtTA) were generated and used to achieve doxycycline inducible expression of a tetracycline operon regulated constitutively active myristoylated AKT1 transgene (tetO-myrAKT). Doxycycline induction of myrAKT occurred within 1 day and rapidly induced proliferation (within 4 days) and the development of prostatic intraepithelial neoplasia (PIN) lesions in ventral prostate, which did not progress to prostate cancer. Cells in these lesions expressed high levels of p27, had increased proliferation, and there was apoptosis of centrally located cells. Doxycycline withdrawal resulted in apoptosis of cells throughout the lesions and rapid clearing of hyperplastic glands, confirming in vivo the critical antiapoptotic functions of AKT. Significantly, analyses of prostates immediately after initiating doxycycline treatment further showed that p27 expression was rapidly increased, coincident with the induction of myrAKT and prior to the development of hyperplasia and PIN. These findings establish in vivo that murine p27 is not negatively regulated by AKT and indicate that proliferation in PI3 kinase/AKT pathway driven mouse models is mediated by p27 independent mechanisms that may be distinct from those in human. Further studies using prostate specific doxycycline regulated transgene expression may be useful to assess the acute effects of inducing additional transgenes in adult murine prostate epithelium, and to assess the requirements for continued transgene expression in transgene induced tumors. PMID- 22844461 TI - Differential gene expression in tamoxifen-resistant breast cancer cells revealed by a new analytical model of RNA-Seq data. AB - Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), is a common obstacle to successful breast cancer treatment. While adjuvant therapy with Tam has been shown to significantly decrease the rate of disease recurrence and mortality, recurrent disease occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERalpha functions, cell cycle regulation, transcription/translation, and mitochondrial dysfunction. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and proliferation processes in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent. PMID- 22844462 TI - Effect of cooperation level of group on punishment for non-cooperators: a functional magnetic resonance imaging study. AB - Sometimes we punish non-cooperators in our society. Such behavior could be derived from aversive emotion for inequity (inequity aversion) to make non cooperators cooperative. Thus, punishing behavior derived from inequity is believed to be important for maintaining our society. Meanwhile, our daily experiences suggest that the degree of cooperation by the members of society (cooperation level of the group) could change the punishing behavior for non cooperators even if the inequity were equal. Such effect of the cooperation level of the group cannot be explained by simple inequity aversion. Although punishment related brain regions have been reported in previous functional magnetic resonance imaging (fMRI) study, little is known about such regions affected by the cooperation level of the group. In the present fMRI study, we investigated the effect of the cooperation level of the group on the punishing behavior for non-cooperators and its related brain activations by a paradigm in which the degree of the cooperative state varied from low to high. Punishment-related activations were observed in brain regions such as the anterior insula, dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC). The quantity of punishment in a high cooperation context was greater than in a low cooperation context, and activation in the right DLPFC and ACC in a high cooperation context showed greater activity than in a low cooperation context. This indicates that the cooperation level of the group, as well as aversive emotion for inequity, is the important factor of punishing behavior. PMID- 22844463 TI - A naturally occurring hypoallergenic variant of vespid Antigen 5 from Polybia scutellaris venom as a candidate for allergen-specific immunotherapy. AB - Stings by insects from the Hymenoptera order are known to cause life-threatening allergic reactions and impair life quality. Despite the effectiveness of conventional vespid venom immunotherapy, more standardized and safer allergy vaccines are required and recombinant hypoallergenic variants are important clinical tools. Antigen 5 is a major allergen of vespid venoms and it was previously reported that Antigen 5 from Polybia scutellaris (Poly s 5) could be a hypoallergenic variant. In this work we assess the immunological behavior and allergenic activity of Poly s 5 in order to explore its suitability for specific immunotherapy. With this aim, recombinant Poly s 5 was expressed in Pichia pastoris and the presence of cross-reactive epitopes with Pol a 5, a known allergenic Antigen 5, was investigated both at the IgG and IgE levels, by ELISA assays and a basophil-mediator release assay respectively. A molecular model was also built to better understand the relationship between immunological and structural aspects. In mice, Poly s 5 induced IgG antibodies which cross-reacted with Pol a 5. However, Poly s 5 induced only minimal amounts of IgE and was a poor inducer of basophil-mediator release, even when the cells were sensitized with Pol a 5-specific IgE. Moreover, Poly s 5-specific serum showed a specific protective activity and was able to inhibit the Pol a 5-induced basophil degranulation. Structural analysis from the molecular model revealed that a few amino acid substitutions in the N-terminal region of Poly s 5 should lead to an alteration of the surface topography and electrostatic potential of the epitopes which could be responsible for its hypoallergenic behavior. These findings, taken as a whole, show that Poly s 5 is likely a naturally occurring hypoallergenic Antigen 5 variant. PMID- 22844464 TI - The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells. AB - The T box transcription factor TBX2, a master regulator of organogenesis, is aberrantly amplified in aggressive human epithelial cancers. While it has been shown that overexpression of TBX2 can bypass senescence, a failsafe mechanism against cancer, its potential role in tumor invasion has remained obscure. Here we demonstrate that TBX2 is a strong cell-autonomous inducer of the epithelial mesenchymal transition (EMT), a latent morphogenetic program that is key to tumor progression from noninvasive to invasive malignant states. Ectopic expression of TBX2 in normal HC11 and MCF10A mammary epithelial cells was sufficient to induce morphological, molecular, and behavioral changes characteristic of EMT. These changes included loss of epithelial adhesion and polarity gene (E-cadherin, beta catenin, ZO1) expression, and abnormal gain of mesenchymal markers (N-cadherin, Vimentin), as well as increased cell motility and invasion. Conversely, abrogation of endogenous TBX2 overexpression in the malignant human breast carcinoma cell lines MDA-MB-435 and MDA-MB-157 led to a restitution of epithelial characteristics with reciprocal loss of mesenchymal markers. Importantly, TBX2 inhibition abolished tumor cell invasion and the capacity to form lung metastases in a Xenograft mouse model. Meta-analysis of gene expression in over one thousand primary human breast tumors further showed that high TBX2 expression was significantly associated with reduced metastasis-free survival in patients, and with tumor subtypes enriched in EMT gene signatures, consistent with a role of TBX2 in oncogenic EMT. ChIP analysis and cell-based reporter assays further revealed that TBX2 directly represses transcription of E-cadherin, a tumor suppressor gene, whose loss is crucial for malignant tumor progression. Collectively, our results uncover an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells. PMID- 22844465 TI - Structure of an MmyB-like regulator from C. aurantiacus, member of a new transcription factor family linked to antibiotic metabolism in actinomycetes. AB - Actinomycetes are important bacterial sources of antibiotics and other secondary metabolites. Many antibiotic gene clusters are controlled by pathway-specific activators that act in response to growth conditions. Here we present the crystal structure of an MmyB-like transcription regulator MltR (PDB code 3pxp) (Caur_2278) from Chloroflexus aurantiacus, in complex with a fatty acid (myristic acid). MltR is a distant homolog of the methylenomycin activator MmyB and consists of an Xre-type N-terminal DNA-binding domain and a C-terminal ligand binding module that is related to the Per-Arnt-Sim (PAS) domain. This structure has enabled identification of a new family of bacterial transcription factors that are distributed predominantly in actinomycetes. Bioinformatics analysis of MltR and other characterized family members suggest that they are likely associated with antibiotic and fatty acid metabolism in actinomycetes. Streptomyces coelicolor SCO4944 is a candidate as an ancestral member of the family. Its ortholog in S. griseus, SGR_6891, is induced by A-factor, a gamma butyrolactone that controls antibiotic production and development, and is adjacent to the A-factor synthase gen, afsA. The location of mltR/mmyB homologs, in particular those adjacent to less well-studied antibiotic-related genes, makes them interesting genetic markers for identifying new antibiotic genes. A model for signal-triggered DNA-binding by MltR is proposed. PMID- 22844467 TI - Feasibility and effectiveness of provider initiated HIV testing and counseling of TB suspects in Vizianagaram district, South India. AB - BACKGROUND: Though internationally recommended, provider initiated HIV testing and counseling (PITC) of persons suspected of tuberculosis (TB) is not a policy in India; HIV seroprevalence among TB suspects has never been reported. The current policy of PITC for diagnosed TB cases may limit opportunities of early HIV diagnosis and treatment. We determined HIV seroprevalence among persons suspected of TB and assessed feasibility and effectiveness of PITC implementation at this earlier stage in the TB diagnostic pathway. METHODS: All adults examined for diagnostic sputum microscopy (TB suspects) in Vizianagaram district (population 2.5 million), in November-December 2010, were offered voluntary HIV counseling and testing (VCT) and assessed for TB diagnosis. RESULTS: Of 2918 eligible TB suspects, 2465(85%) consented to VCT. Among these, 246(10%) were HIV positive. Of the 246, 84(34%) were newly diagnosed as HIV (HIV status not known previously). To detect a new case of HIV infection, the number needed to screen (NNS) was 26 among 'TB suspects', comparable to that among 'TB patients'. Among suspects aged 25-54 years, not diagnosed as TB, the NNS was 17. CONCLUSION: The seroprevalence of HIV among 'TB suspects' was as high as that among 'TB patients'. Implementation of PITC among TB suspects was feasible and effective, detecting a large number of new HIV cases with minimal additional workload on staff of HIV testing centre. HIV testing of TB suspects aged 25-54 years demonstrated higher yield for a given effort, and should be considered by policy makers at least in settings with high HIV prevalence. PMID- 22844466 TI - Identification of galectin-1 as a critical factor in function of mouse mesenchymal stromal cell-mediated tumor promotion. AB - Bone marrow derived mesenchymal stromal cells (MSCs) have recently been implicated as one source of the tumor-associated stroma, which plays essential role in regulating tumor progression. In spite of the intensive research, the individual factors in MSCs controlling tumor progression have not been adequately defined. In the present study we have examined the role of galectin-1 (Gal-1), a protein highly expressed in tumors with poor prognosis, in MSCs in the course of tumor development. Co-transplantation of wild type MSCs with 4T1 mouse breast carcinoma cells enhances the incidence of palpable tumors, growth, vascularization and metastasis. It also reduces survival compared to animals treated with tumor cells alone or in combination with Gal-1 knockout MSCs. In vitro studies show that the absence of Gal-1 in MSCs does not affect the number of migrating MSCs toward the tumor cells, which is supported by the in vivo migration of intravenously injected MSCs into the tumor. Moreover, differentiation of endothelial cells into blood vessel-like structures strongly depends on the expression of Gal-1 in MSCs. Vital role of Gal-1 in MSCs has been further verified in Gal-1 knockout mice. By administering B16F10 melanoma cells into Gal-1 deficient animals, tumor growth is highly reduced compared to wild type animals. Nevertheless, co-injection of wild type but not Gal-1 deficient MSCs results in dramatic tumor growth and development.These results confirm that galectin-1 is one of the critical factors in MSCs regulating tumor progression. PMID- 22844468 TI - The anti-tumorigenic mushroom Agaricus blazei Murill enhances IL-1beta production and activates the NLRP3 inflammasome in human macrophages. AB - Agaricus blazei Murill (AbM) has been reported to possess immune activity against tumors and infections through stimulation of mononuclear phagocytes. Recently, AbM extract was shown to induce the production of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta), in human monocytes. IL-1beta is a key pro inflammatory cytokine produced by activated macrophages and monocytes and its secretion is strictly controlled by the inflammasome. The purpose of this study is to investigate the effect of AbM water extracts on the regulation of IL-1beta production and activation of the NLRP3 inflammasome in human THP-1 macrophages. The NLRP3 inflammasome consists of an NLRP3 receptor, an adaptor protein called ASC, and the inflammatory protease, caspase-1. Typically, stimulation of immune cells with microbial products results in production of pro-IL-1beta, but a second stress-related signal activates the inflammasome and caspase-1, leading to processing and secretion of IL-1beta. Our results show that AbM enhances transcription of IL-1beta and triggers NLRP3 inflammasome-mediated IL-1beta secretion in human THP-1 macrophages. AbM-mediated IL-1beta secretion was markedly reduced in macrophages deficient in NLRP3 and ASC, demonstrating that the NLRP3 inflammasome is essential for AbM-induced IL-1beta secretion. In addition, caspase-1 was activated and involved in proteolytic cleavage and secretion of IL-1beta in AbM-treated macrophages. AbM-mediated IL-1beta secretion also decreased in cells treated with cathepsin B inhibitor, suggesting that AbM can induce the release of cathepsin B. Furthermore, our data show that AbM induced inflammasome activation requires the release of ATP, binding of extracellular ATP to the purinergic receptor P2X(7), the generation of reactive oxygen species, and efflux of potassium. Taken together, these findings reveal that AbM activates the NLRP3 inflammasome via multiple mechanisms, resulting in the secretion of IL-1beta. PMID- 22844469 TI - Perceptual auditory aftereffects on voice identity using brief vowel stimuli. AB - Humans can identify individuals from their voice, suggesting the existence of a perceptual representation of voice identity. We used perceptual aftereffects- shifts in perceived stimulus quality after brief exposure to a repeated adaptor stimulus--to further investigate the representation of voice identity in two experiments. Healthy adult listeners were familiarized with several voices until they reached a recognition criterion. They were then tested on identification tasks that used vowel stimuli generated by morphing between the different identities, presented either in isolation (baseline) or following short exposure to different types of voice adaptors (adaptation). Experiment 1 showed that adaptation to a given voice induced categorization shifts away from that adaptor's identity even when the adaptors consisted of vowels different from the probe stimuli. Moreover, original voices and caricatures resulted in comparable aftereffects, ruling out an explanation of identity aftereffects in terms of adaptation to low-level features. In Experiment 2, we show that adaptors with a disrupted configuration, i.e., altered fundamental frequency or formant frequencies, failed to produce perceptual aftereffects showing the importance of the preserved configuration of these acoustical cues in the representation of voices. These two experiments indicate a high-level, dynamic representation of voice identity based on the combination of several lower-level acoustical features into a specific voice configuration. PMID- 22844470 TI - What determines the temporal changes of species degree and strength in an oceanic island plant-disperser network? AB - Network models of frugivory and seed dispersal are usually static. To date, most studies on mutualistic networks assert that interaction properties such as species' degree (k) and strength (s) are strongly influenced by species abundances. We evaluated how species' degree and strength change as a function of temporal variation not only in species abundance, but also in species persistence (i.e., phenology length). In a two-year study, we collected community-wide data on seed dispersal by birds and examined the seasonal dynamics of the above mentioned interaction properties. Our analyses revealed that species abundance is an important predictor for plant strength within a given sub-network. However, our analyses also reveal that species' degree can often be best explained by the length of fruiting phenology (for plants degree) or by the number of fruiting species (for dispersers degree), which are factors that can be decoupled from the relative abundance of the species participating in the network. Moreover, our results suggest that generalist dispersers (when total study period is considered) act as temporal generalists, with degree constrained by the number of plant species displaying fruits in each span. Along with species identity, our findings underscore the need for a temporal perspective, given that seasonality is an inherent property of many mutualistic networks. PMID- 22844471 TI - Responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes: a randomized trial. AB - BACKGROUND: The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-over design 42 men (age 50-70 y) consumed three high-fat shakes containing saturated fat (SFA), monounsaturated fat (MUFA) or n-3 polyunsaturated (PUFA). Men were selected on BMI and health status (lean, obese or obese diabetic) and phenotyped with MRI for adipose tissue distribution. Before and 2 and 4 h after shake consumption blood was drawn for measurement of expression of metabolic and inflammation-related genes in peripheral blood mononuclear cells (PBMCs), plasma triglycerides (TAG), glucose, insulin, cytokines and ex vivo PBMC immune response capacity. The MUFA and n-3 PUFA challenge, compared to the SFA challenge, induced higher changes in expression of inflammation genes MCP1 and IL1beta in PBMCs. Obese and obese diabetic subjects had different PBMC gene expression and metabolic responses to high-fat challenges compared to lean subjects. The MUFA challenge induced the most pronounced TAG response, mainly in obese and obese diabetic subjects. CONCLUSION/SIGNIFICANCE: The PBMC gene expression response and metabolic response to high-fat challenges were affected by fat type and metabolic risk phenotype. Based on our results we suggest using a MUFA challenge to reveal differences in response capacity of subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00977262. PMID- 22844472 TI - Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure. AB - Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF). The major acute-phase mediators associated with FHF, including IL-1beta, IL-6, and TNF-alpha, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs) have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra) plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1beta, IL-6), and animal survival were assessed after cell transplantation. Our results showed that AF MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF. PMID- 22844473 TI - beta-Glucan derived from Aureobasidium pullulans is effective for the prevention of influenza in mice. AB - beta-(1->3)-D-glucans with beta-(1->6)-glycosidic linked branches produced by mushrooms, yeast and fungi are known to be an immune activation agent, and are used in anti-cancer drugs or health-promoting foods. In this report, we demonstrate that oral administration of Aureobasidium pullulans-cultured fluid (AP-CF) enriched with the beta-(1->3),(1->6)-D-glucan exhibits efficacy to protect mice infected with a lethal titer of the A/Puerto Rico/8/34 (PR8; H1N1) strain of influenza virus. The survival rate of the mice significantly increased by AP-CF administration after sublethal infection of PR8 virus. The virus titer in the mouse lung homogenates was significantly decreased by AP-CF administration. No significant difference in the mRNA expression of inflammatory cytokines, and in the population of lymphocytes was observed in the lungs of mice administered with AP-CF. Interestingly, expression level for the mRNA of virus sensors, RIG-I (retinoic acid-inducible gene-I) and MDA5 (melanoma differentiation-associated protein 5) strongly increased at 5 hours after the stimulation of A. pullulans-produced purified beta-(1->3),(1->6)-D-glucan (AP-BG) in murine macrophage-derived RAW264.7 cells. Furthermore, the replication of PR8 virus was significantly repressed by pre-treatment of AP-BG. These findings suggest the increased expression of virus sensors is effective for the prevention of influenza by the inhibition of viral replication with the administration of AP CF. PMID- 22844474 TI - The alveolin IMC1h is required for normal ookinete and sporozoite motility behaviour and host colonisation in Plasmodium berghei. AB - Alveolins, or inner membrane complex (IMC) proteins, are components of the subpellicular network that forms a structural part of the pellicle of malaria parasites. In Plasmodium berghei, deletions of three alveolins, IMC1a, b, and h, each resulted in reduced mechanical strength and gliding velocity of ookinetes or sporozoites. Using time lapse imaging, we show here that deletion of IMC1h (PBANKA_143660) also has an impact on the directionality and motility behaviour of both ookinetes and sporozoites. Despite their marked motility defects, sporozoites lacking IMC1h were able to invade mosquito salivary glands, allowing us to investigate the role of IMC1h in colonisation of the mammalian host. We show that IMC1h is essential for sporozoites to progress through the dermis in vivo but does not play a significant role in hepatoma cell transmigration and invasion in vitro. Colocalisation of IMC1h with the residual IMC in liver stages was detected up to 30 hours after infection and parasites lacking IMC1h showed developmental defects in vitro and a delayed onset of blood stage infection in vivo. Together, these results suggest that IMC1h is involved in maintaining the cellular architecture which supports normal motility behaviour, access of the sporozoites to the blood stream, and further colonisation of the mammalian host. PMID- 22844475 TI - Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. METHODOLOGY/PRINCIPAL FINDINGS: We studied the EGFR targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. CONCLUSIONS/SIGNIFICANCE: Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy. PMID- 22844477 TI - Increase in caesarean deliveries after the Australian Private Health Insurance Incentive policy reforms. AB - BACKGROUND: The Australian Private Health Insurance Incentive (PHII) policy reforms implemented in 1997-2000 increased PHI membership in Australia by 50%. Given the higher rate of obstetric interventions in privately insured patients, the reforms may have led to an increase in surgical deliveries and deliveries with longer hospital stays. We aimed to investigate the effect of the PHII policy introduction on birth characteristics in Western Australia (WA). METHODS AND FINDINGS: All 230,276 birth admissions from January 1995 to March 2004 were identified from administrative birth and hospital data-systems held by the WA Department of Health. Average quarterly birth rates after the PHII introduction were estimated and compared with expected rates had the reforms not occurred. Rate and percentage differences (including 95% confidence intervals) were estimated separately for public and private patients, by mode of delivery, and by length of stay in hospital following birth. The PHII policy introduction was associated with a 20% (-21.4 to -19.3) decrease in public birth rates, a 51% (45.1 to 56.4) increase in private birth rates, a 5% (-5.3 to -5.1) and 8% (-8.9 to -7.9) decrease in unassisted and assisted vaginal deliveries respectively, a 5% (-5.3 to -5.1) increase in caesarean sections with labour and 10% (8.0 to 11.7) increase in caesarean sections without labour. Similarly, birth rates where the infant stayed 0-3 days in hospital following birth decreased by 20% (-21.5 to -18.5), but rates of births with >3 days in hospital increased by 15% (12.2 to 17.1). CONCLUSIONS: Following the PHII policy implementation in Australia, births in privately insured patients, caesarean deliveries and births with longer infant hospital stays increased. The reforms may not have been beneficial for quality obstetric care in Australia or the burden of Australian hospitals. PMID- 22844476 TI - The transcription factor NFATp plays a key role in susceptibility to TB in mice. AB - In T cells, the transcription factor nuclear factor of activated T cells p (NFATp) is a key regulator of the cytokine genes tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma). Here, we show that NFATp-deficient (NFATp(-/-)) mice have a dramatic and highly significant increase in mortality after Mycobacterium tuberculosis (MTb) infection as compared to mortality of control animals after MTb infection. Animals deficient in NFATp have significantly impaired levels of TNF and IFN-gamma transcription and protein expression in naive or total CD4(+) T cells, but display wild-type levels of TNF mRNA or protein from MTb-stimulated dendritic cells (DC). The rapid mortality and disease severity observed in MTb-infected NFATp(-/-) mice is associated with dysregulated production of TNF and IFN-gamma in the lungs, as well as with increased levels of TNF, in their serum. Furthermore, global blocking of TNF production by injection of a TNF neutralizaing agent at 6 weeks, but not 12 weeks, post-MTb-infection further decreased the survival rate of both wild-type and NFATp(-/-) mice, indicating an early role for TNF derived from cells from the monocyte lineage in containment of infection. These results thus demonstrate that NFATp plays a critical role in immune containment of TB disease in vivo, through the NFATp dependent expression of TNF and IFN-gamma in T cells. PMID- 22844478 TI - Atrophic cardiac remodeling induced by taurine deficiency in Wistar rats. AB - INTRODUCTION: Micronutrient deficiency is observed in heart failure patients. Taurine, for example, represents 50% of total free amino acids in the heart, and in vivo studies have linked taurine deficiency with cardiomyopathy. METHODS: Thirty-four male Wistar rats (body weight = 100 g) were weighed and randomly assigned to one of two groups: Control (C) or taurine-deficient (T (-)). Beta alanine at a concentration of 3% was added to the animals' water to induce taurine deficiency in the T (-) group. On day 30, the rats were individually submitted to echocardiography; morphometrical and histopathological evaluation and metalloproteinase activity, oxidative stress and inflammation evaluation were performed. Tissue samples were collected to determine the taurine concentration in the heart. RESULTS: Taurine deficiency led to decreases in: ventricular wall thickness, left ventricle dry weight, myocyte sectional area, left ventricle posterior wall thickness and ventricular geometry. With regard to heart function, the velocity of the A wave, the ratio between the E and A wave, the ejection fraction, fractional shortening and cardiac output values were decreased in T (-) rats, suggesting abnormal diastolic and systolic function. Increased fibrosis, inflammation and increased activation of metalloproteinases were not observed. Oxidative stress was increased in deficient animals. CONCLUSIONS: These data suggest that taurine deficiency promotes structural and functional cardiac alterations with unique characteristics. PMID- 22844479 TI - Thyroid hormone enhances nitric oxide-mediated bacterial clearance and promotes survival after meningococcal infection. AB - Euthyroid sick syndrome characterized by reduced levels of thyroid hormones (THs) is observed in patients with meningococcal shock. It has been found that the level of THs reflects disease severity and is predictive for mortality. The present study was conducted to investigate the impact of THs on host defense during meningococcal infection. We found that supplementation of thyroxine to mice infected with Neisseria meningitidis enhanced bacterial clearance, attenuated the inflammatory responses and promoted survival. In vitro studies with macrophages revealed that THs enhanced bacteria-cell interaction and intracellular killing of meningococci by stimulating inducible nitric oxide synthase (iNos)-mediated NO production. TH treatment did not activate expression of TH receptors in macrophages. Instead, the observed TH-directed actions were mediated through nongenomic pathways involving the protein kinases PI3K and ERK1/2 and initiated at the membrane receptor integrin alphavbeta3. Inhibition of nongenomic TH signaling prevented iNos induction, NO production and subsequent intracellular bacterial killing by macrophages. These data demonstrate a beneficial role of THs in macrophage-mediated N. meningitidis clearance. TH replacement might be a novel option to control meningococcal septicemia. PMID- 22844480 TI - Matrix-MTM adjuvant induces local recruitment, activation and maturation of central immune cells in absence of antigen. AB - Saponin-based adjuvants are widely used to enhance humoral and cellular immune responses towards vaccine antigens, although it is not yet completely known how they mediate their stimulatory effects. The aim of this study was to elucidate the mechanism of action of adjuvant Matrix-MTM without antigen and Alum was used as reference adjuvant. Adjuvant Matrix-MTM is comprised of 40 nm nanoparticles composed of Quillaja saponins, cholesterol and phospholipid. BALB/c mice were subcutaneously injected once with, 3, 12 or 30 ug of Matrix-MTM, resulting in recruitment of leukocytes to draining lymph nodes (dLNs) and spleen 48 h post treatment. Flow cytometry analysis identified CD11b(+) Gr-1(high) granulocytes as the cell population increasing most in dLNs and spleen. Additionally, dendritic cells, F4/80(int) cells, T-, B- and NK-cells were recruited to dLNs and in spleen the number of F4/80(int) cells, and to some extent, B cells and dendritic cells, increased. Elevated levels of early activation marker CD69 were detected on T-, B and NK-cells, CD11b(+) Gr-1(high) cells, F4/80(int) cells and dendritic cells in dLNs. In spleen CD69 was mainly up-regulated on NK cells. B cells and dendritic cells in dLNs and spleen showed an increased expression of the co-stimulatory molecule CD86 and dendritic cells in dLNs expressed elevated levels of MHC class II. The high-dose (30 ug) of Matrix-MTM induced detectable serum levels of IL-6 and MIP-1beta 4 h post administration, most likely representing spillover of locally produced cytokines. A lesser increase of IL-6 in serum after administration of 12 ug Matrix-MTM was also observed. In conclusion, early immunostimulatory properties were demonstrated by Matrix-MTM alone, as therapeutic doses resulted in a local transient immune response with recruitment and activation of central immune cells to dLNs. These effects may play a role in enhancing uptake and presentation of vaccine antigens to elicit a competent immune response. PMID- 22844481 TI - Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus. AB - Elderly humans show increased susceptibility to invasive staphylococcal disease after skin and soft tissue infection. However, it is not understood how host immunity changes with aging, and how that predisposes to invasive disease. In a model of severe skin infection, we showed that aged mice (16- to 20-month-old) exhibit dramatic bacterial dissemination compared with young adult mice (2-month old). Bacterial dissemination was associated with significant reductions of CXCL1 (KC), polymorphonuclear cells (PMNs), and extracellular DNA traps (NETs) at the infection site. PMNs and primary skin fibroblasts isolated from aged mice showed decreased secretion of CXCL2 (MIP-2) and KC in response to MRSA, and in vitro analyses of mitochondrial functions revealed that the mitochondrial electron transport chain complex I plays a significant role in induction of chemokines in the cells isolated from young but not old mice. Additionally, PMNs isolated from aged mice have reduced ability to form NETs and to kill MRSA. Expression of nuclease by S. aureus led to increased bacterial systemic dissemination in young but not old mice, suggesting that defective NETs formation in elderly mice permitted nuclease and non-nuclease expressing S. aureus to disseminate equally well. Overall, these findings suggest that gross impairment of both skin barrier function and innate immunity contributes to the propensity for MRSA to disseminate in aged mice. Furthermore, the study indicates that contribution of bacterial factors to pathogenicity may vary with host age. PMID- 22844482 TI - Acute myeloid leukemia (AML) with erythroid predominance exhibits clinical and molecular characteristics that differ from other types of AML. AB - The clinical importance of erythroid predominance in bone marrow of patients with acute myeloid leukemia (AML) is controversial. These cases represent a heterogeneous group of diseases that historically have been classified into different categories. We studied 313 AML patients and specifically compared the clinical, cytogenetic, and molecular features of cases of AML with erythroid predominance, arbitrarily defined as >=50% erythroid precursors, to AML cases without erythroid predominance. We also assessed 51 patients with a high-grade myelodysplastic syndrome (MDS), refractory anemia with excess blasts (RAEB). All neoplasms were classified according to the World Health Organization classification. With the exception of therapy-related AML/MDS, the presence of erythroid predominance in variously classified categories of AML was associated with a survival advantage. In addition, AML with erythroid predominance had a lower frequency of cytogenetic abnormalities as well as a lower frequency of mutations involving NPM1, NRAS and FLT3 as compared with AML without erythroid predominance. We conclude that the clinical, cytogenetic, and molecular features of AML with erythroid predominance in the non-therapy-related setting are much closer to those of a high-grade myelodysplastic syndrome than they are to other types of AML. PMID- 22844484 TI - Effects of precipitation increase on soil respiration: a three-year field experiment in subtropical forests in China. AB - BACKGROUND: The aim of this study was to determine response patterns and mechanisms of soil respiration to precipitation increases in subtropical regions. METHODOLOGY/PRINCIPAL FINDINGS: Field plots in three typical forests [i.e. pine forest (PF), broadleaf forest (BF), and pine and broadleaf mixed forest (MF)] in subtropical China were exposed under either Double Precipitation (DP) treatment or Ambient Precipitation (AP). Soil respiration, soil temperature, soil moisture, soil microbial biomass and fine root biomass were measured over three years. We tested whether precipitation treatments influenced the relationship of soil respiration rate (R) with soil temperature (T) and soil moisture (M) using R = (a+cM)exp(bT), where a is a parameter related to basal soil respiration; b and c are parameters related to the soil temperature and moisture sensitivities of soil respiration, respectively. We found that the DP treatment only slightly increased mean annual soil respiration in the PF (15.4%) and did not significantly change soil respiration in the MF and the BF. In the BF, the increase in soil respiration was related to the enhancements of both soil fine root biomass and microbial biomass. The DP treatment did not change model parameters, but increased soil moisture, resulting in a slight increase in soil respiration. In the MF and the BF, the DP treatment decreased soil temperature sensitivity b but increased basal soil respiration a, resulting in no significant change in soil respiration. CONCLUSION/SIGNIFICANCE: Our results indicate that precipitation increasing in subtropical regions in China may have limited effects on soil respiration. PMID- 22844483 TI - Organizational and functional status of the Y-linked genes and loci in the infertile patients having normal spermiogram. AB - Male fertility is an orchestrated interplay of loci on the Y chromosome with a number of genes from across the other chromosomes. In this context, micro deletions in the Y chromosome have been correlated with spermatogenic failure often leading to infertility. However, causes of infertility in the patients with the normal spermiogram have remained unclear and therefore pose another level of challenge. In the present study, we analyzed 64 STSs, studied different Y-linked genes and loci and conducted single nucleotide variant (SNV) analyses in 31 infertile males with normal spermiogram along with 67 normal fertile males (NFMs) to gain an insight into the organization of their Y chromosome. Further, employing quantitative real-time PCR (qPCR), we studied copy number variation of DYZ1 arrays and three genes and mutational status of SRY by direct sequence analyses. STS analyses of the AZFa, b and c regions in these patients showed known and new mutations. Further, copies of DAZ and BPY2 in the patients were found to be affected (p < 0.001) compared to those in NFMs. All the patients had normal copy number of the SRY however its sequence analysis (in silico) showed mutations in eight patients. In four of these eight patients, SRY mutations resulted into truncated proteins. Similarly, DYZ1 analysis showed micro-deletions and it's much reduced copy number (p < 0.001) as compared to those in NFMs. Present study in males with unexplained infertility revealed deletions similar to those observed in oligospermic and azoospermic patients. Thus, there are some common but still unknown factors underlying infertility in these patients irrespective of their spermatogenic status. This work is envisaged to augment DNA diagnosis, proving beneficial in the context of in vitro fertilization (IVF) and genetic counselling. PMID- 22844485 TI - Conformational analysis of Clostridium difficile toxin B and its implications for substrate recognition. AB - Clostridium difficile (C. difficile) is an opportunistic pathogen that can cause potentially lethal hospital-acquired infections. The cellular damage that it causes is the result of two large clostridial cytotoxins: TcdA and TcdB which act by glucosylating cytosolic G-proteins, mis-regulation of which induces apoptosis. TcdB is a large flexible protein that appears to undergo significant structural rearrangement upon accommodation of its substrates: UDP-glucose and a Rho-family GTPase. To characterize the conformational space of TcdB, we applied normal mode and hinge-region analysis, followed by long-timescale unbiased molecular dynamics. In order to examine the TcdB and RhoA interaction, macromolecular docking and simulation of the TcdB/RhoA complex was performed. Generalized Masked Delaunay analysis of the simulations determined the extent of significant motions. This combination of methods elucidated a wide range of motions within TcdB that are reiterated in both the low-cost normal mode analysis and the extensive MD simulation. Of particular interest are the coupled motions between a peripheral 4-helix bundle and a small loop in the active site that must rearrange to allow RhoA entry to the catalytic site. These extensive coupled motions are indicative of TcdB using a conformational capture mechanism for substrate accommodation. PMID- 22844486 TI - Cortical actin nanodynamics determines nitric oxide release in vascular endothelium. AB - The release of the main vasodilator nitric oxide (NO) by the endothelial NO synthase (eNOS) is a hallmark of endothelial function. We aim at elucidating the underlying mechanism how eNOS activity depends on cortical stiffness (K(cortex)) of living endothelial cells. It is hypothesized that cortical actin dynamics determines K(cortex) and directly influences eNOS activity. By combined atomic force microscopy and fluorescence imaging we generated mechanical and optical sections of single living cells. This approach allows the discrimination between K(cortex) and bulk cell stiffness (K(bulk)) and, additionally, the simultaneous analysis of submembranous actin web dynamics. We show that K(cortex) softens when cortical F-actin depolymerizes and that this shift from a gel-like stiff cortex to a soft G-actin rich layer, triggers the stiffness-sensitive eNOS activity. The results implicate that stiffness changes in the ~100 nm phase of the submembranous actin web, without affecting K(bulk), regulate NO release and thus determines endothelial function. PMID- 22844487 TI - Identification of plant quantitative trait loci modulating a rhizobacteria-aphid indirect effect. AB - Plants simultaneously interact with a plethora of species both belowground and aboveground, which can result in indirect effects mediated by plants. Studies incorporating plant genetic variation indicate that indirect effects mediated by plants may be a significant factor influencing the ecology and evolution of species within a community. Here, we present findings of a Quantitative Trait Locus (QTL) mapping study, where we mapped a rhizobacteria-aphid indirect effect onto the barley genome. We measured the size of aphid populations on barley when the barley rhizosphere either was or was not supplemented with a rhizobacterial species. Using a QTL mapping subset, we located five regions of the barley genome associated with the rhizobacteria-aphid indirect effect. Rhizobacterial supplementation led to an increase in aphid population size (mapped to three barley QTL), or a decrease in aphid population size (mapped to two barley QTL). One QTL associated with plant resistance to aphids was affected by a significant QTL-by-environment interaction, because it was not expressed when rhizobacteria was supplemented. Our results indicated that rhizobacterial supplementation of barley roots led to either increased or reduced aphid population size depending on plant genotype at five barley QTL. This indicates that the direction of a rhizobacteria-aphid indirect effect could influence the selection pressure on plants, when considering species that affect plant fitness. Further research may build on the findings presented here, to identify genes within QTL regions that are involved in the indirect interaction. PMID- 22844488 TI - Associations between apolipoprotein E genotype, diet, body mass index, and serum lipids in Lithuanian adult population. AB - BACKGROUND: Apolipoprotein E (APOE) polymorphism is associated with lipid levels. Some studies have reported that blood lipid response to diet or obesity varies depending on APOE genotypes. The aim of this study was to assess the effect of APOE genotypes, the intake of saturated fatty acids (SFA), and obesity on serum lipid levels in Lithuanian adult population. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional health survey was carried out in five municipalities of Lithuania. The random sample was obtained from lists of 25-64 year-old inhabitants registered at primary health care centres. The data from 996 subjects (416 men and 580 women) were analysed in this study. Two single-nucleotide polymorphisms (rs429358 and rs7412) were assessed using a real-time polymerase chain reaction. 24-hour recall and food frequency questionnaire were used for evaluation of dietary habits. Serum lipids were determined using enzymatic methods. Men and women with the APOE2 genotype had the lowest level of total cholesterol (TC) (p = 0.002 for men, and p = 0.02 for women) and low-density lipoprotein cholesterol (LDL-C) (p<0.001). Multivariate linear regression analysis showed that age, genotype APOE2, SFA intake, and body mass index (BMI) were significant determinants of TC and LDL-C level (with p values ranging from 0.043 to 0.001). Our data did not reveal any statistically significant interactions between APOE genotype and SFA intake or between APOE genotype and BMI regarding TC and LDL-C level (all p>0.05). However, the predictive power of the regression model for LDL-C improved when gene-BMI interaction and gene-BMI interaction plus gene-nutrient interaction were added (p = 0.04 and p = 0.032 for R(2) change, respectively). CONCLUSIONS/SIGNIFICANCE: APOE genotypes, SFA intake, and obesity were found to be associated with blood lipid levels in Lithuanian adult population. Analysis of gene-diet and gene-obesity interactions did not confirm that the effects of diet and obesity on TC and LDL-C level significantly depended on APOE genotype. PMID- 22844489 TI - Improving community coverage of oral cholera mass vaccination campaigns: lessons learned in Zanzibar. AB - BACKGROUND: Recent research in two cholera-endemic communities of Zanzibar has shown that a majority (~94%) of the adult population was willing to receive free oral cholera vaccines (OCVs). Since OCV uptake in the 2009 campaign reached only ~50% in these communities, an evaluation of social and cultural factors and of barriers was conducted to understand this difference for future cholera control planning. METHODOLOGY/PRINCIPAL FINDINGS: A random sample of 367 adult peri-urban and rural community residents (46.6% immunized vs. 53.4% unimmunized) was studied with a semi-structured interview that inquired about social and cultural features of cholera depicted in a vignette and barriers to OCV uptake. Symptoms (rectal pain, loose skin only in rural community) and perceived causes (uncovered food, contact with contaminated water) specific for severe diarrhea were associated with uptake. Purchasing drugs from pharmacies to stop diarrhea and vomiting was negatively associated with uptake. Increasing household size, age and previous enteric illness episode were positively related to uptake, the latter only at the rural site. The most prominent barrier to uptake was competing obligations or priorities (reported by 74.5%, identified as most important barrier by 49.5%). Next most prominent barriers were lacking information about the campaign (29.6%, 12.2%), sickness (14.3%, 13.3%) and fear of possible vaccine side effects (15.3%, 5.6%). The majority of unvaccinated respondents requested repetition of the vaccination with free OCVs. CONCLUSIONS/SIGNIFICANCE: Factors associated with uptake indicated a positive impact of the vaccination campaign and of sensitization activities on vaccine acceptance behavior. Unlike communities opposed to cholera control or settings where public confidence in vaccines is lacking, identified barriers to uptake indicated a good campaign implementation and trust in the health system. Despite prospects and demand for repeating the vaccination, local decision-makers should reconsider how careful logistical arrangements may improve community coverage and thus effectiveness of vaccination campaigns. PMID- 22844490 TI - Analysing humanly generated random number sequences: a pattern-based approach. AB - In a random number generation task, participants are asked to generate a random sequence of numbers, most typically the digits 1 to 9. Such number sequences are not mathematically random, and both extent and type of bias allow one to characterize the brain's "internal random number generator". We assume that certain patterns and their variations will frequently occur in humanly generated random number sequences. Thus, we introduce a pattern-based analysis of random number sequences. Twenty healthy subjects randomly generated two sequences of 300 numbers each. Sequences were analysed to identify the patterns of numbers predominantly used by the subjects and to calculate the frequency of a specific pattern and its variations within the number sequence. This pattern analysis is based on the Damerau-Levenshtein distance, which counts the number of edit operations that are needed to convert one string into another. We built a model that predicts not only the next item in a humanly generated random number sequence based on the item's immediate history, but also the deployment of patterns in another sequence generated by the same subject. When a history of seven items was computed, the mean correct prediction rate rose up to 27% (with an individual maximum of 46%, chance performance of 11%). Furthermore, we assumed that when predicting one subject's sequence, predictions based on statistical information from the same subject should yield a higher success rate than predictions based on statistical information from a different subject. When provided with two sequences from the same subject and one from a different subject, an algorithm identifies the foreign sequence in up to 88% of the cases. In conclusion, the pattern-based analysis using the Levenshtein-Damarau distance is both able to predict humanly generated random number sequences and to identify person-specific information within a humanly generated random number sequence. PMID- 22844491 TI - Promoter DNA methylation regulates murine SUR1 (Abcc8) and SUR2 (Abcc9) expression in HL-1 cardiomyocytes. AB - Two mammalian genes encode the SURx (SUR1, Abcc8 and SUR2, Abcc9) subunits that combine with Kir6.2 (Kcnj11) subunits to form the ATP-sensitive potassium (KATP) channel in cardiac myocytes. Different isoform combinations endow the channel with distinct physiological and pharmacological properties, and we have recently reported that the molecular composition of sarcolemmal KATP channels is chamber specific in the mouse heart. KATP channel composition is determined by what subunits are expressed in a cell or tissue. In the present study, we explore the role of CpG methylation in regulating SUR1 and SUR2 expression. In HL-1 cardiomyocytes, as in atrial myocytes, SUR1 expression is markedly greater than SUR2. Consistent with CpG methylation-dependent silencing of SUR2 expression, bisulfite sequencing of genomic DNA isolated from HL-1 cells demonstrates that 57.6% of the CpGs in the promoter region of the SUR2 gene are methylated, compared with 0.14% of the the CpG residues in the SUR1 sequence. Moreover, treatment with 10 uM 5-aza-2'-deoxycytidine (Aza-dC) significantly increased both the unmethylated fraction of the SUR2 CpG island and mRNA expression. However, we cannot rule out additional mechanisms of Aza-dC action, as Aza-dC also causes a decrease in SUR1 expression and lower doses of Aza-dC do not alter the unmethylated DNA fraction but do elicit a small increase in SUR2 expression. The conclusion that DNA methylation alone is not the only regulator of SUR subunit expression is also consistent with observations in native myocytes, where the CpG islands of both SUR genes are essentially unmethylated in both atrial and ventricular myocytes. Collectively, these data demonstrate the potential for CpG methylation to regulate SURx subunit expression and raises the possibility that regulated or aberrant CpG methylation might play a role in controlling channel structure and function under different physiological conditions or different species. PMID- 22844492 TI - Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning. AB - ER-bound PTP1B is expressed in hippocampal neurons, and accumulates among neurite contacts. PTP1B dephosphorylates beta-catenin in N-cadherin complexes ensuring cell-cell adhesion. Here we show that endogenous PTP1B, as well as expressed GFP PTP1B, are present in dendritic spines of hippocampal neurons in culture. GFP PTP1B overexpression does not affect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of beta-catenin-Tyr-654 phosphorylation increased ~5-fold in the hippocampus of adult PTP1B(-/-) (KO) mice compared to wild type (WT) mice and this was accompanied by a reduction in the amount of beta-catenin associated with N cadherin. To determine whether PTP1B-deficiency alters learning and memory, we generated mice lacking PTP1B in the hippocampus and cortex (PTP1B(fl/fl)-Emx1 Cre). PTP1B(fl/fl)-Emx1-Cre mice displayed improved performance in the Barnes maze (decreased time to find and enter target hole), utilized a more efficient strategy (cued), and had better recall compared to WT controls. Our results implicate PTP1B in structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylation of beta-catenin on Tyr-654. Disruption of hippocampal PTP1B function or expression leads to elongation of dendritic filopodia and improved learning and memory, demonstrating an exciting novel role for this phosphatase. PMID- 22844493 TI - Functional inactivation of the genome-wide association study obesity gene neuronal growth regulator 1 in mice causes a body mass phenotype. AB - To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1 I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control. PMID- 22844494 TI - Absence of PTHrP nuclear localization and carboxyl terminus sequences leads to abnormal brain development and function. AB - We assessed whether the nuclear localization sequences (NLS) and C terminus of parathyroid hormone-related protein (PTHrP) play critical roles in brain development and function. We used histology, immunohistochemistry, histomorphometry, Western blots and electrophysiological recordings to compare the proliferation and differentiation of neural stem cells, neuronal hippocampal synaptic transmission, and brain phenotypes including shape and structures, in Pthrp knock-in mice, which express PTHrP (1-84), a truncated form of the protein that is missing the NLS and the C-terminal region of the protein, and their wild type littermates. Results showed that Pthrp knock-in mice display abnormal brain shape and structures; decreased neural cell proliferative capacity and increased apoptosis associated with up-regulation of cyclin dependent kinase inhibitors p16, p21, p27 and p53 and down-regulation of the Bmi-1 oncogene; delayed neural cell differentiation; and impaired hippocampal synaptic transmission and plasticity. These findings provide in vivo experimental evidence that the NLS and C-terminus of PTHrP are essential not only for the regulation of neural cell proliferation and differentiation, but also for the maintenance of normal neuronal synaptic transmission and plasticity. PMID- 22844495 TI - DIOL triterpenes block profibrotic effects of angiotensin II and protect from cardiac hypertrophy. AB - BACKGROUND: The natural triterpenes, erythrodiol and uvaol, exert anti inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. METHODOLOGY/PRINCIPAL FINDINGS: The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-gamma, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. CONCLUSIONS/SIGNIFICANCE: Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac myofibroblasts. They inhibit the angiotensin II-induced proliferation in a PPAR-gamma-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-gamma. PMID- 22844496 TI - Association of MDM2 SNP309 variation with lung cancer risk: evidence from 7196 cases and 8456 controls. AB - BACKGROUND: Evidence suggests that MDM2 T309G polymorphism may be a risk factor for several cancers. Increasing investigations have been conducted on the association of MDM2 T309G polymorphisms with lung cancer risk and have yielded conflicting results. Previous meta-analyses on this issue have reported inconclusive data. The aim of the present study was to derive a more precise estimation of the relationship. METHODS AND FINDINGS: Updated meta-analyses examining the association between MDM2 T309G polymorphism and lung cancer risk were performed. Separate analyses on ethnicity, smoking status, histological types and gender as well as source of controls were also implemented. Eligible studies were identified for the period up to Feb 2012. Lastly, ten publications including eleven case-control studies were selected for analysis. The overall data failed to indicate a significant association between MDM2 T309G polymorphism and lung cancer risk (GG vs TT OR = 1.14; 95%CI = 0.95-1.37; dominant model: OR = 1.05; 95%CI = 0.92-1.19; recessive model: OR = 1.12; 95%CI = 0.99-1.27). In a subgroup analysis by smoking status, increased lung cancer risk was shown among never-smokers (GG vs TT: OR = 1.76; 95%CI = 1.36-2.29; dominant model: OR = 1.48; 95%CI = 1.22-1.81; recessive model: OR = 1.37; 95%CI = 1.11-1.69). In subgroup analysis by gender, elevated risk was presented among women under a recessive model (OR = 1.29; 95%CI = 1.04-1.59). In the subgroup analysis by ethnicity, histological types and source of controls, no marked associations were observed. CONCLUSIONS: Compared to the previous meta-analyses, the results of this study confirmed that MDM2 T309G polymorphism might be a risk factor for lung cancer among never-smokers. However, the data failed to suggest a marked association between the G allele of MDM2 T309G and lung cancer risk among Asians. More interestingly, subgroup analysis by gender indicated that homozygous GG alleles might raise lung cancer risk among females. PMID- 22844497 TI - The Pseudomonas aeruginosa type III secretion system has an exotoxin S/T/Y independent pathogenic role during acute lung infection. AB - The type III secretion system (T3SS) is a complex nanomachine of many pathogenic gram-negative bacteria. It forms a proteinaceous channel that is inserted into the host eukaryotic cell membrane for injection of bacterial proteins that manipulate host cell signaling. However, few studies have focused on the effector independent functions of the T3SS. Using a murine model of acute lung infection with Pseudomonas aeruginosa, an important human opportunistic pathogen, we compared the pathogenicity of mutant bacteria that lack all of the known effector toxins ( DeltaSTY), with mutant bacteria that also lack the major translocator protein PopB (DeltaSTY/DeltaPopB) and so cannot form a functional T3SS channel in the host cell membrane. Mortality was higher among mice challenged with DeltaSTY compared to mice challenged with DeltaSTY/DeltaPopB mutant bacteria. In addition, mice infected with DeltaSTY showed decreased bacterial clearance from the lungs compared to those infected with DeltaSTY/DeltaPopB. Infection was in both cases associated with substantial killing of lung infiltrating macrophages. However, macrophages from DeltaSTY-infected mice died by pro-inflammatory necrosis characterized by membrane permeabilization and caspase-1 mediated IL-1beta production, whereas macrophages from DeltaSTY/DeltaPopB infected mice died by apoptosis, which is characterized by annexin V positive staining of the cell membrane and caspase-3 activation. This was confirmed in macrophages infected in vitro. These results demonstrate a T3SS effector toxin independent role for the T3SS, in particular the T3SS translocator protein PopB, in the pathogenicity of P. aeruginosa during acute lung infection. PMID- 22844498 TI - Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade. AB - PURPOSE: End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis. METHODS: End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score. MEASUREMENTS AND MAIN RESULTS: There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6+/-10.6% (p = 0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice. CONCLUSIONS: In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti platelet drugs may be protective in sepsis. PMID- 22844500 TI - Content Factor: a measure of a journal's contribution to knowledge. AB - Impact Factor, the pre-eminent performance metric for medical journals, has been criticized for failing to capture the true impact of articles; for favoring methodology papers; for being unduly influenced by statistical outliers; and for examining a period of time too short to capture an article's long-term importance. Also, in the era of search engines, where readers need not skim through journals to find information, Impact Factor's emphasis on citation efficiency may be misplaced. A better metric would consider the total number of citations to all papers published by the journal (not just the recent ones), and would not be decremented by the total number of papers published. We propose a metric embodying these principles, "Content Factor", and examine its performance among leading medical and orthopaedic surgery journals. To remedy Impact Factor's emphasis on recent citations, Content Factor considers the total number of citations, regardless of the year in which the cited paper was published. To correct for Impact Factor's emphasis on efficiency, no denominator is employed. Content Factor is thus the total number of citations in a given year to all of the papers previously published in the journal. We found that Content Factor and Impact Factor are poorly correlated. We further surveyed 75 experienced orthopaedic authors and measured their perceptions of the "importance" of various orthopaedic surgery journals. The correlation between the importance score and the Impact Factor was only 0.08; the correlation between the importance score and Content Factor was 0.56. Accordingly, Content Factor better reflects a journal's "importance". In sum, while Content Factor cannot be defended as the lone metric of merit, to the extent that performance data informs journal evaluations, Content Factor--an easily obtained and intuitively appealing metric of the journal's knowledge contribution, not subject to gaming--can be a useful adjunct. PMID- 22844499 TI - Time-resolved influences of functional DAT1 and COMT variants on visual perception and post-processing. AB - BACKGROUND: Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task. METHODS: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed. RESULTS: Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500-1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced. CONCLUSIONS: Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems. PMID- 22844501 TI - Development and characterization of a new TILLING population of common bread wheat (Triticum aestivum L.). AB - Mutagenesis is an important tool in crop improvement. However, the hexaploid genome of wheat (Triticum aestivum L.) presents problems in identifying desirable genetic changes based on phenotypic screening due to gene redundancy. TILLING (Targeting Induced Local Lesions IN Genomes), a powerful reverse genetic strategy that allows the detection of induced point mutations in individuals of the mutagenized populations, can address the major challenge of linking sequence information to the biological function of genes and can also identify novel variation for crop breeding. Wheat is especially well-suited for TILLING due to the high mutation densities tolerated by polyploids. However, only a few wheat TILLING populations are currently available in the world, which is far from satisfying the requirement of researchers and breeders in different growing environments. In addition, current TILLING screening protocols require costly fluorescence detection systems, limiting their use, especially in developing countries. We developed a new TILLING resource comprising 2610 M(2) mutants in a common wheat cultivar 'Jinmai 47'. Numerous phenotypes with altered morphological and agronomic traits were observed from the M(2) and M(3) lines in the field. To simplify the procedure and decrease costs, we use unlabeled primers and either non-denaturing polyacrylamide gels or agarose gels for mutation detection. The value of this new resource was tested using PCR with RAPD and Intron-spliced junction (ISJ) primers, and also TILLING in three selected candidate genes, in 300 and 512 mutant lines, revealing high mutation densities of 1/34 kb by RAPD/ISJ analysis and 1/47 kb by TILLING. In total, 31 novel alleles were identified in the 3 targeted genes and confirmed by sequencing. The results indicate that this mutant population represents a useful resource for the wheat research community. We hope that the use of this reverse genetics resource will provide novel allelic diversity for wheat improvement and functional genomics. PMID- 22844502 TI - Removing N-terminal sequences in pre-S1 domain enhanced antibody and B-cell responses by an HBV large surface antigen DNA vaccine. AB - Although the use of recombinant hepatitis B virus surface (HBsAg) protein vaccine has successfully reduced global hepatitis B infection, there are still a number of vaccine recipients who do not develop detectable antibody responses. Various novel vaccination approaches, including DNA vaccines, have been used to further improve the coverage of vaccine protection. Our previous studies demonstrated that HBsAg-based DNA vaccines could induce both humoral and CMI responses in experimental animal models. However, one form of the the HBsAg antigen, the large S antigen (HBs-L), expressed by DNA vaccine, was not sufficiently immunogenic in eliciting antibody responses. In the current study, we produced a modified large S antigen DNA vaccine, HBs-L(T), which has a truncated N-terminal sequence in the pre-S1 region. Compared to the original HBs-L DNA vaccine, the HBs-L(T) DNA vaccine improved secretion in cultured mammalian cells and generated significantly enhanced HBsAg-specific antibody and B cell responses. Furthermore, this improved HBsL DNA vaccine, along with other HBsAg-expressing DNA vaccines, was able to maintain predominantly Th1 type antibody responses while recombinant HBsAg protein vaccines produced in either yeast or CHO cells elicited mostly Th2 type antibody responses. Our data indicate that HBsAg DNA vaccines with improved immunogenicity offer a useful alternative choice to recombinant protein-based HBV vaccines, particularly for therapeutic purposes against chronic hepatitis infection where immune tolerance led to poor antibody responses to S antigens. PMID- 22844503 TI - Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. AB - BACKGROUND: Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. We hypothesized that components of the adenosine monophosphate-activated kinase (AMPK) pathway are targeted by miRs and alter AMPK signaling during pathological cardiac stress. METHODOLOGY/PRINCIPAL FINDINGS: Using a mouse model of hypertrophic cardiomyopathy (HCM), we demonstrated early elevation of miR-195 and miR-451 in HCM hearts, which targets MO25, a central component of the MO25/STRAD/LKB1 complex that acts as an upstream kinase for AMPK. We show functional targeting of MO25 by miR-195 and -451. Further in vitro interrogation of MO25 as a functional target validated this hypothesis where over-expression of miR-195 in C2C12 cells knocked down MO25 expression levels and downstream AMPK signaling (phosphorylation of Acetyl CoA carboxylase [ACC] and AMPK activity assay), similar to MO25 knockdown in C2C12 cells by siRNA. Parallel changes were measured in 60 day R403Q HCM male hearts that were rescued by short-term administration of AICAR, an AMPK agonist. CONCLUSIONS/SIGNIFICANCE: Elevated miR 195 targets the LKB1/AMPK signaling axis in HCM progression and implicates a functional role in HCM disease progression. MiR-195 may serve as potential therapeutics or therapeutic targets for heart disease. PMID- 22844505 TI - Bitter taste stimuli induce differential neural codes in mouse brain. AB - A growing literature suggests taste stimuli commonly classified as "bitter" induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes) was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total), including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA), presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5) were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05) to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05) from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among "bitter" stimuli, data that challenge a strict monoguesia model for the bitter quality. PMID- 22844504 TI - MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis. AB - Annexin A1 (ANXA1) inhibits NF-kappaB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-kappaB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-alpha, IFN-gamma, IL-1beta, IL-6 and IL-10 by RT-PCR; prostaglandin E(2) (PGE(2)), cytoplasmic phospholipase A(2) (cPLA(2)) and myeloperoxidase by immunoassay; and COX-2 and NF- kappaB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A(2); reduced significantly the induced levels of TNF-alpha, IFN-gamma, IL-1beta, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-kappaB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE(2) in the colon and PGE(2) metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-kappaB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-kappaB. MC-12 merits further development as an agent for the control of IBD. PMID- 22844506 TI - Molecular evolution of GII-4 Norovirus strains. AB - BACKGROUND: Human Noroviruses (NoV) are the major cause of acute nonbacterial gastroenteritis and the leading cause of outbreaks of gastroenteritis worldwide. Genotype II-4 (GII-4) NoV has been shown to spread rapidly and is the most commonly detected strain worldwide, particularly in association with outbreaks. Previously, we have shown that circulating GII-4 NoV strains exist as populations of selectively neutral variants, and that the emergence of epidemic GII-4 NoV strains correlated with mutations in at least two key sites (Sites A and B) within the P2 domain of the surface exposed major capsid protein (VP1). METHODOLOGY: We developed a rapid pyrosequencing method for screening of the two Sites A and B and a homology based modelling system was used to predict the effects of amino acid substitutions at these sites on the antigenic properties of the virus (defined as surface motif types). PRINCIPLE FINDING/CONCLUSION: Here, we describe the characterisation of amino acid diversity at Sites A and B for 1062 GII-4 NoV strains from clinical specimen associated with outbreak of gastroenteritis (2000-2011) and 250 GII-4 NoV sequences from Genbank. Our data identified a high diversity of different Site A and B site combinations at amino acid level and amino acid diversity was higher at Site B than Site A. Site A motifs could be grouped into 3 clusters based on similar surface motif types. We predict that Site A is a major epitope on the virus surface, responsible for defining the antigenic profile, and a more subtle role for Site B, maintaining minor antigenic variation within the virus population. PMID- 22844508 TI - Nuttalliella namaqua (Ixodoidea: Nuttalliellidae): first description of the male, immature stages and re-description of the female. AB - Nuttalliella namaqua is the only species of the enigmatic third tick family. Females possess features of hard and soft ticks and have been designated as the "missing link" between the main tick families. Its position at the base of the tick tree suggests that some of the features unique to hard and soft ticks were present in the ancestral tick lineage. Larvae, nymphae and males have not been described to date and questions regarding their biological affinities to the main tick families remain unclear. The current study addressed these questions via the description of larvae, nymphae and males and resolved issues pertaining to female morphology. Field collected as well as laboratory-engorged females laid eggs and viable larvae subsequently hatched. The larvae possess morphological structures not present in subsequent stages: namely, a sclerotized scutum, pores on the dorsal surface of legs and a dentate anal plate. The last two characters are not present in ixodids and argasids. N. namaqua larvae and nymphae show a similar morphology to females: a unique hypostomal structure i.e., bluntly rounded apically in nymphae and females and ball-like in the larvae. A re-description of some structures in female N. namaqua has resolved differences in the original descriptions, namely that N. namaqua have 4 palpal segments as found in ixodids and argasids and posthypostomal setae. The male was discovered for the first time and described. Characteristic male features include: a pseudoscutum over most of the dorsum, an outgrowth on the chelicerae forming a unique rod-like structure similar to a spematodactyl in mites and medial extension of palpal segment 2 forming a large ventral crib for segment 4. All life stages possess some features found in hard and soft ticks and its status as the "missing link" between the tick families remains. PMID- 22844507 TI - A role for mesenchyme dynamics in mouse lung branching morphogenesis. AB - Mammalian airways are highly ramified tree-like structures that develop by the repetitive branching of the lung epithelium into the surrounding mesenchyme through reciprocal interactions. Based on a morphometric analysis of the epithelial tree, it has been recently proposed that the complete branching scheme is specified early in each lineage by a programme using elementary patterning routines at specific sites and times in the developing lung. However, the coupled dynamics of both the epithelium and mesenchyme have been overlooked in this process. Using a qualitative and quantitative in vivo morphometric analysis of the E11.25 to E13.5 mouse whole right cranial lobe structure, we show that beyond the first generations, the branching stereotypy relaxes and both spatial and temporal variations are common. The branching pattern and branching rate are sensitive to the dynamic changes of the mesoderm shape that is in turn mainly dependent upon the volume and shape of the surrounding intrathoracic organs. Spatial and temporal variations of the tree architecture are related to local and subtle modifications of the mesoderm growth. Remarkably, buds never meet after suffering branching variations and continue to homogenously fill the opening spaces in the mesenchyme. Moreover despite inter-specimen variations, the growth of the epithelial tree and the mesenchyme remains highly correlated over time at the whole lobe level, implying a long-range regulation of the lung lobe morphogenesis. Together, these findings indicate that the lung epithelial tree is likely to adapt in real time to fill the available space in the mesenchyme, rather than being rigidly specified and predefined by a global programme. Our results strongly support the idea that a comprehensive understanding of lung branching mechanisms cannot be inferred from the branching pattern or behavior alone. Rather it needs to be elaborated upon with the reconsideration of mesenchyme-epithelium coupled growth and lung tissues mechanics. PMID- 22844509 TI - Perceptual grouping over time within and across auditory and tactile modalities. AB - In auditory scene analysis, population separation and temporal coherence have been proposed to explain how auditory features are grouped together and streamed over time. The present study investigated whether these two theories can be applied to tactile streaming and whether temporal coherence theory can be applied to crossmodal streaming. The results show that synchrony detection between two tones/taps at different frequencies/locations became difficult when one of the tones/taps was embedded in a perceptual stream. While the taps applied to the same location were streamed over time, the taps applied to different locations were not. This observation suggests that tactile stream formation can be explained by population-separation theory. On the other hand, temporally coherent auditory stimuli at different frequencies were streamed over time, but temporally coherent tactile stimuli applied to different locations were not. When there was within-modality streaming, temporally coherent auditory stimuli and tactile stimuli were not streamed over time, either. This observation suggests the limitation of temporal coherence theory when it is applied to perceptual grouping over time. PMID- 22844510 TI - Regulation of TB vaccine-induced airway luminal T cells by respiratory exposure to endotoxin. AB - Tuberculosis (TB) vaccine-induced airway luminal T cells (ALT) have recently been shown to be critical to host defense against pulmonary TB. However, the mechanisms that maintain memory ALT remain poorly understood. In particular, whether respiratory mucosal exposure to environmental agents such as endotoxin may regulate the size of vaccine-induced ALT population is still unclear. Using a murine model of respiratory genetic TB vaccination and respiratory LPS exposure, we have addressed this issue in the current study. We have found that single or repeated LPS exposure increases the number of antigen-specific ALT which are capable of robust secondary responses to pulmonary mycobacterial challenge. To investigate the potential mechanisms by which LPS exposure modulates the ALT population, we have examined the role of ALT proliferation and peripheral T cell recruitment. We have found that LPS exposure-increased ALT is not dependent on increased ALT proliferation as respiratory LPS exposure does not significantly increase the rate of proliferation of ALT. But rather, we find it to be dependent upon the recruitment of peripheral T cells into the airway lumen as blockade of peripheral T cell supplies markedly reduces the initially increased ALT. Thus, our data suggest that environmental exposure to airborne agents such as endotoxin has a profound modulatory effect on TB vaccine-elicited T cells within the respiratory tract. Our study provides a new, M.tb antigen-independent mechanism by which the respiratory mucosal anti-TB memory T cells may be maintained. PMID- 22844511 TI - Common genetic variants associated with sudden cardiac death: the FinSCDgen study. AB - BACKGROUND: Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD. METHODOLOGY/PRINCIPAL FINDINGS: We studied the association between 28 candidate SNPs and SCD in a meta analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11-1.45, P = 3.4*10(-4)) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11-1.48, P = 7.9*10( 4)). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01-1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P<0.05). CONCLUSIONS/SIGNIFICANCE: Two novel genetic variants, one in the cardiac sodium channel gene SCN5A and another at 4q25 previously associated with atrial fibrillation, are associated with SCD. PMID- 22844512 TI - Identification of novel markers of mouse fetal ovary development. AB - In contrast to the developing testis, molecular pathways driving fetal ovarian development have been difficult to characterise. To date no single master regulator of ovarian development has been identified that would be considered the female equivalent of Sry. Using a genomic approach we identified a number of novel protein-coding as well as non-coding genes that were detectable at higher levels in the ovary compared to testis during early mouse gonad development. We were able to cluster these ovarian genes into different temporal expression categories. Of note, Lrrc34 and AK015184 were detected in XX but not XY germ cells before the onset of sex-specific germ cell differentiation marked by entry into meiosis in an ovary and mitotic arrest in a testis. We also defined distinct spatial expression domains of somatic cell genes in the developing ovary. Our data expands the set of markers of early mouse ovary differentiation and identifies a classification of early ovarian genes, thus providing additional avenues with which to dissect this process. PMID- 22844513 TI - Environmental effects on compulsive tail chasing in dogs. AB - Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder observed both in humans and animals. Examples of Canine Compulsive Disorder (CD) include excessive tail chasing (TC), light/shadow chasing and flank sucking. We performed a questionnaire survey to investigate the characteristics of compulsive (TC) and its possible associations with environmental correlates and personality in a pet population of 368 dogs from four dog breeds. We observed an early onset of TC at 3-6 months of age and a large variation in TC frequency in all breeds, with an overrepresentation of milder cases. Almost half of the TC dogs showed lowered responsiveness during bouts and displayed also other types of compulsions more often than the controls. Interestingly, dogs that received dietary supplements, especially vitamins and minerals, expressed less TC compared to dogs that did not receive any supplements. Neutered females had less TC, suggesting an influence of ovarian hormones on TC. Tail chasers were shyer and had separated earlier from their mothers than the controls. Finally, our genetic study did not find an association between TC and CDH2, a locus previously associated with the canine flank sucking compulsion. In conclusion, the early-onset and the variable nature of the repetitive behaviour, which is affected by environmental factors such as micronutrients, neutering and maternal care, share several similar components between canine and human compulsions and supports canine TC as a model for human OCD. PMID- 22844514 TI - Identification of tyrosine-9 of MAVS as critical target for inducible phosphorylation that determines activation. AB - BACKGROUND: Innate immunity to viruses involves receptors such as RIG-I, which senses viral RNA and triggers an IFN-beta signaling pathway involving the outer mitochondrial membrane protein MAVS. However, the functional status of MAVS phosphorylation remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate for the first time that MAVS undergoes extensive tyrosine phosphorylation upon viral infection, indicating that MAVS phosphorylation might play an important role in MAVS function. A tyrosine-scanning mutational analysis revealed that MAVS tyrosine-9 (Y9) is a phosphorylation site that is required for IFN-beta signaling. Indeed, MAVS Y9F mutation severely impaired TRAF3/TRAF6 recruitment and displayed decreased tyrosine phosphorylation in response to VSV infection compared to wild type MAVS. Functionally, MAVS Y9 phosphorylation contributed to MAVS antiviral function without interfering with its apoptosis property. CONCLUSIONS/SIGNIFICANCE: These experiments identify a novel residue of MAVS that is crucially involved in the recruitment of TRAF3/TRAF6 and in downstream propagation of MAVS signaling. PMID- 22844515 TI - MicroRNA regulation of the synaptic plasticity-related gene Arc. AB - Expression of activity-regulated cytoskeleton associated protein (Arc) is crucial for diverse types of experience-dependent synaptic plasticity and long-term memory in mammals. However, the mechanisms governing Arc-specific translation are little understood. Here, we asked whether Arc translation is regulated by microRNAs. Bioinformatic analysis predicted numerous candidate miRNA binding sites within the Arc 3'-untranslated region (UTR). Transfection of the corresponding microRNAs in human embryonic kidney cells inhibited expression of an Arc 3'UTR luciferase reporter from between 10 to 70% across 16 microRNAs tested. Point mutation and deletion of the microRNA-binding seed-region for miR 34a, miR-326, and miR-19a partially or fully rescued reporter expression. In addition, expression of specific microRNA pairs synergistically modulated Arc reporter expression. In primary rat hippocampal neuronal cultures, ectopic expression of miR-34a, miR-193a, or miR-326, downregulated endogenous Arc protein expression in response to BDNF treatment. Conversely, treatment of neurons with cell-penetrating, peptide nucleic acid (PNA) inhibitors of miR-326 enhanced Arc mRNA expression. BDNF dramatically upregulated neuronal expression of Arc mRNA and miR-132, a known BDNF-induced miRNA, without affecting expression of Arc targeting miRNAs. Developmentally, miR-132 was upregulated at day 10 in vitro whereas Arc-targeting miRNAs were downregulated. In the adult brain, LTP induction in the dentate gyrus triggered massive upregulation of Arc and upregulation of miR-132 without affecting levels of mature Arc-targeting miRNAs. Turning to examine miRNA localization, qPCR analysis of dentate gyrus synaptoneurosome and total lysates fractions demonstrated synaptic enrichment relative to small nucleolar RNA. In conclusion, we find that Arc is regulated by multiple miRNAs and modulated by specific miRNA pairs in vitro. Furthermore, we show that, in contrast to miR-132, steady state levels of Arc-targeting miRNAs do not change in response to activity-dependent expression of Arc in hippocampal neurons in vitro or during LTP in vivo. PMID- 22844516 TI - Mg2+ in the major groove modulates B-DNA structure and dynamics. AB - This study investigates the effect of Mg(2+) bound to the DNA major groove on DNA structure and dynamics. The analysis of a comprehensive dataset of B-DNA crystallographic structures shows that divalent cations are preferentially located in the DNA major groove where they interact with successive bases of (A/G)pG and the phosphate group of 5'-CpA or TpG. Based on this knowledge, molecular dynamics simulations were carried out on a DNA oligomer without or with Mg(2+) close to an ApG step. These simulations showed that the hydrated Mg(2+) forms a stable intra-strand cross-link between the two purines in solution. ApG generates an electrostatic potential in the major groove that is particularly attractive for cations; its intrinsic conformation is well-adapted to the formation of water-mediated hydrogen bonds with Mg(2+). The binding of Mg(2+) modulates the behavior of the 5'-neighboring step by increasing the BII (epsilon zeta>0 degrees ) population of its phosphate group. Additional electrostatic interactions between the 5'-phosphate group and Mg(2+) strengthen both the DNA cation binding and the BII character of the 5'-step. Cation binding in the major groove may therefore locally influence the DNA conformational landscape, suggesting a possible avenue for better understanding how strong DNA distortions can be stabilized in protein-DNA complexes. PMID- 22844517 TI - Insulin-increased L-arginine transport requires A(2A) adenosine receptors activation in human umbilical vein endothelium. AB - Adenosine causes vasodilation of human placenta vasculature by increasing the transport of arginine via cationic amino acid transporters 1 (hCAT-1). This process involves the activation of A(2A) adenosine receptors (A(2A)AR) in human umbilical vein endothelial cells (HUVECs). Insulin increases hCAT-1 activity and expression in HUVECs, and A(2A)AR stimulation increases insulin sensitivity in subjects with insulin resistance. However, whether A(2A)AR plays a role in insulin-mediated increase in L-arginine transport in HUVECs is unknown. To determine this, we first assayed the kinetics of saturable L-arginine transport (1 minute, 37 degrees C) in the absence or presence of nitrobenzylthioinosine (NBTI, 10 umol/L, adenosine transport inhibitor) and/or adenosine receptors agonist/antagonists. We also determined hCAT-1 protein and mRNA expression levels (Western blots and quantitative PCR), and SLC7A1 (for hCAT-1) reporter promoter activity. Insulin and NBTI increased the extracellular adenosine concentration, the maximal velocity for L-arginine transport without altering the apparent K(m) for L-arginine transport, hCAT-1 protein and mRNA expression levels, and SLC7A1 transcriptional activity. An A2AAR antagonist ZM-241385 blocked these effects. ZM241385 inhibited SLC7A1 reporter transcriptional activity to the same extent in cells transfected with pGL3-hCAT-1(-1606) or pGL3-hCAT-1(-650) constructs in the presence of NBTI + insulin. However, SLC7A1 reporter activity was increased by NBTI only in cells transfected with pGL3-hCAT-1(-1606), and the ZM-241385 sensitive fraction of the NBTI response was similar in the absence or in the presence of insulin. Thus, insulin modulation of hCAT-1 expression and activity requires functional A(2A)AR in HUVECs, a mechanism that may be applicable to diseases associated with fetal insulin resistance, such as gestational diabetes. PMID- 22844518 TI - IL-6 indirectly modulates the induction of glyceroneogenic enzymes in adipose tissue during exercise. AB - BACKGROUND: Glyceroneogenesis is an important step in the control of fatty acid re-esterification with PEPCK and PDK4 being identified as key enzymes in this process. We have previously shown that glyceroneogenic enzymes such as PDK4 are rapidly induced in white adipose tissue during exercise. Recent studies have suggested that IL-6 regulates adipose tissue metabolism and gene expression during exercise. Interestingly, IL-6 has been reported to directly decrease PEPCK expression. The purpose of this investigation was to determine the role of IL-6 in modulating the effects of exercise on the expression of glyceroneogenic enzymes in mouse adipose tissue. We hypothesized that the exercise-mediated induction of PDK4 and PEPCK would be greater in adipose tissue from IL-6 deficient mice compared to wild type controls. METHODOLOGY AND PRINCIPLE FINDINGS: Treatment of cultured epididymal adipose tissue (eWAT) with IL-6 (150 ng/ml) increased the phosphorylation of AMPK, ACC and STAT3 and induced SOCS3 mRNA levels while decreasing PEPCK and PDK4 mRNA. AICAR decreased the expression of PDK4 and PEPCK. The activation of AMPK by IL-6 was independent of increases in lipolysis. An acute bout of treadmill running (15 meters/minute, 5% incline, 90 minutes) did not induce SOCS3 or increase phosphorylation of STAT3 in eWAT, indicating that IL-6 signalling was not activated. Exercise-induced increases in PEPCK and PDK4 mRNA expression were attenuated in eWAT from IL-6(-/-) mice in parallel with a greater relative increase in AMPK phosphorylation compared to exercised WT mice. These changes occurred independent of alterations in beta adrenergic signalling in adipose tissue from IL-6(-/-) mice. CONCLUSIONS AND SIGNIFICANCE: Our findings question the role of IL-6 signalling in adipose tissue during exercise and suggest an indirect effect of this cytokine in the regulation of adipose tissue gene expression during exercise. PMID- 22844519 TI - Women's greater ability to perceive happy facial emotion automatically: gender differences in affective priming. AB - There is evidence that women are better in recognizing their own and others' emotions. The female advantage in emotion recognition becomes even more apparent under conditions of rapid stimulus presentation. Affective priming paradigms have been developed to examine empirically whether facial emotion stimuli presented outside of conscious awareness color our impressions. It was observed that masked emotional facial expression has an affect congruent influence on subsequent judgments of neutral stimuli. The aim of the present study was to examine the effect of gender on affective priming based on negative and positive facial expression. In our priming experiment sad, happy, neutral, or no facial expression was briefly presented (for 33 ms) and masked by neutral faces which had to be evaluated. 81 young healthy volunteers (53 women) participated in the study. Subjects had no subjective awareness of emotional primes. Women did not differ from men with regard to age, education, intelligence, trait anxiety, or depressivity. In the whole sample, happy but not sad facial expression elicited valence congruent affective priming. Between-group analyses revealed that women manifested greater affective priming due to happy faces than men. Women seem to have a greater ability to perceive and respond to positive facial emotion at an automatic processing level compared to men. High perceptual sensitivity to minimal social-affective signals may contribute to women's advantage in understanding other persons' emotional states. PMID- 22844520 TI - The Ca2+/calcineurin-dependent signaling pathway in the gray mold Botrytis cinerea: the role of calcipressin in modulating calcineurin activity. AB - In the gray mold fungus Botrytis cinerea the Galpha subunit Bcg1 of a heterotrimeric G protein is an upstream activator of the Ca(2+)/calmodulin dependent phosphatase calcineurin. In this study we focused on the functional characterization of the catalytic subunit of calcineurin (BcCnA) and its putative regulator calcipressin (BcRcn1). We deleted the genes encoding both proteins to examine their role concerning growth, differentiation and virulence. The DeltabccnA mutant shows a severe growth defect, does not produce conidia and is avirulent, while the loss of BcRcn1 caused retardation of hyphal growth and delayed infection of host plants, but had no impact on conidiation and sclerotia formation. Expression of several calcineurin-dependent genes and bccnA itself is positively affected by BcRcn1. Complementation of the Deltabcrcn1 mutant with a GFP-BcRcn1 fusion construct revealed that BcRcn1 is localized in the cytoplasm and accumulates around the nuclei. Furthermore, we showed that BcCnA physically interacts with BcRcn1 and the regulatory subunit of calcineurin, BcCnB. We investigated the impact of several protein domains characteristic for modulation and activation of BcCnA via BcRcn1, such as the phosphorylation sites and the calcineurin-docking site, by physical interaction studies between BcCnA and wild type and mutated copies of BcRcn1. Based on the observed phenotypes we conclude that BcRcn1 acts as a positive modulator of BcCnA and the Ca(2+)/calcineurin mediated signal transduction in B. cinerea, and that both proteins regulate fungal development and virulence. PMID- 22844521 TI - A preliminary study of copy number variation in Tibetans. AB - Genetic features of Tibetans have been broadly investigated, but the properties of copy number variation (CNV) have not been well examined. To get a preliminary view of CNV in Tibetans, we scanned 29 Tibetan genomes with the Illumina Human-1 M high-resolution genotyping microarray and identified 139 putative copy number variable regions (CNVRs), consisting of 70 deletions, 61 duplications, and 8 multi-allelic loci. Thirty-four of the 139 CNVRs showed differential allele frequencies versus other East-Asian populations, with P values <0.0001. These results indicated a distinct pattern of CNVR allele frequency distribution in Tibetans. The Tibetan CNVRs are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and -DR gene clusters) and biological process categories of "response to DNA damage stimulus" and "DNA repair" (such as RAD51, RAD52, and MRE11A). These genes are related to the adaptive traits of high infant birth weight and darker skin tone of Tibetans, and may be attributed to recent local adaptation. Our results provide a different view of genetic diversity in Tibetans and new insights into their high-altitude adaptation. PMID- 22844522 TI - Dental pulp stem cells differentiation reveals new insights in Oct4A dynamics. AB - Although the role played by the core transcription factor network, which includes c-Myc, Klf4, Nanog, and Oct4, in the maintenance of embryonic stem cell (ES) pluripotency and in the reprogramming of adult cells is well established, its persistence and function in adult stem cells are still debated. To verify its persistence and clarify the role played by these molecules in adult stem cell function, we investigated the expression pattern of embryonic and adult stem cell markers in undifferentiated and fully differentiated dental pulp stem cells (DPSC). A particular attention was devoted to the expression pattern and intracellular localization of the stemness-associated isoform A of Oct4 (Oct4A). Our data demonstrate that: Oct4, Nanog, Klf4 and c-Myc are expressed in adult stem cells and, with the exception of c-Myc, they are significantly down regulated following differentiation. Cell differentiation was also associated with a significant reduction in the fraction of DPSC expressing the stem cell markers CD10, CD29 and CD117. Moreover, a nuclear to cytoplasm shuttling of Oct4A was identified in differentiated cells, which was associated with Oct4A phosphorylation. The present study would highlight the importance of the post translational modifications in DPSC stemness maintenance, by which stem cells balance self-renewal versus differentiation. Understanding and controlling these mechanisms may be of great importance for stemness maintenance and stem cells clinical use, as well as for cancer research. PMID- 22844523 TI - Efficient recombinant production in mammalian cells using a novel IR/MAR gene amplification method. AB - We previously found that plasmids bearing a mammalian replication initiation region (IR) and a nuclear matrix attachment region (MAR) efficiently initiate gene amplification and spontaneously increase their copy numbers in animal cells. In this study, this novel method was applied to the establishment of cells with high recombinant antibody production. The level of recombinant antibody expression was tightly correlated with the efficiency of plasmid amplification and the cytogenetic appearance of the amplified genes, and was strongly dependent on cell type. By using a widely used cell line for industrial protein production, CHO DG44, clones expressing very high levels of antibody were easily obtained. High-producer clones stably expressed the antibody over several months without eliciting changes in both the protein expression level and the cytogenetic appearance of the amplified genes. The integrity and reactivity of the protein produced by this method was fine. In serum-free suspension culture, the specific protein production rate in high-density cultures was 29.4 pg/cell/day. In conclusion, the IR/MAR gene amplification method is a novel and efficient platform for recombinant antibody production in mammalian cells, which rapidly and easily enables the establishment of stable high-producer cell clone. PMID- 22844524 TI - Stability of synchronization clusters and seizurability in temporal lobe epilepsy. AB - PURPOSE: Identification of critical areas in presurgical evaluations of patients with temporal lobe epilepsy is the most important step prior to resection. According to the "epileptic focus model", localization of seizure onset zones is the main task to be accomplished. Nevertheless, a significant minority of epileptic patients continue to experience seizures after surgery (even when the focus is correctly located), an observation that is difficult to explain under this approach. However, if attention is shifted from a specific cortical location toward the network properties themselves, then the epileptic network model does allow us to explain unsuccessful surgical outcomes. METHODS: The intraoperative electrocorticography records of 20 patients with temporal lobe epilepsy were analyzed in search of interictal synchronization clusters. Synchronization was analyzed, and the stability of highly synchronized areas was quantified. Surrogate data were constructed and used to statistically validate the results. Our results show the existence of highly localized and stable synchronization areas in both the lateral and the mesial areas of the temporal lobe ipsilateral to the clinical seizures. Synchronization areas seem to play a central role in the capacity of the epileptic network to generate clinical seizures. Resection of stable synchronization areas is associated with elimination of seizures; nonresection of synchronization clusters is associated with the persistence of seizures after surgery. DISCUSSION: We suggest that synchronization clusters and their stability play a central role in the epileptic network, favoring seizure onset and propagation. We further speculate that the stability distribution of these synchronization areas would differentiate normal from pathologic cases. PMID- 22844525 TI - Is telomere length socially patterned? Evidence from the West of Scotland Twenty 07 Study. AB - Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35 year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages. PMID- 22844526 TI - Are trade-offs among species' ecological interactions scale dependent? A test using pitcher-plant inquiline species. AB - Trade-offs among species' ecological interactions is a pervasive explanation for species coexistence. The traits associated with trade-offs are typically measured to mechanistically explain species coexistence at a single spatial scale. However, species potentially interact at multiple scales and this may be reflected in the traits among coexisting species. I quantified species' ecological traits associated with the trade-offs expected at both local (competitive ability and predator tolerance) and regional (competitive ability and colonization rate) community scales. The most common species (four protozoa and a rotifer) from the middle trophic level of a pitcher plant (Sarracenia purpurea) inquiline community were used to link species traits to previously observed patterns of species diversity and abundance. Traits associated with trade-offs (competitive ability, predator tolerance, and colonization rate) and other ecological traits (size, growth rate, and carrying capacity) were measured for each of the focal species. Traits were correlated with one another with a negative relationship indicative of a trade-off. Protozoan and rotifer species exhibited a negative relationship between competitive ability and predator tolerance, indicative of coexistence at the local community scale. There was no relationship between competitive ability and colonization rate. Size, growth rate, and carrying capacity were correlated with each other and the trade-off traits: Size was related to both competitive ability and predator tolerance, but growth rate and carrying capacity were correlated with predator tolerance. When partial correlations were conducted controlling for size, growth rate and carrying capacity, the trade-offs largely disappeared. These results imply that body size is the trait that provides the basis for ecological interactions and trade-offs. Altogether, this study showed that the examination of species' traits in the context of coexistence at different scales can contribute to our understanding of the mechanisms underlying community structure. PMID- 22844527 TI - Plasma cathepsin S and cystatin C levels and risk of abdominal aortic aneurysm: a randomized population-based study. AB - BACKGROUND: Human abdominal aortic aneurysm (AAA) lesions contain high levels of cathepsin S (CatS), but are deficient in its inhibitor, cystatin C. Whether plasma CatS and cystatin C levels are also altered in AAA patients remains unknown. METHODS AND RESULTS: Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatS and cystatin C levels by ELISA. Student's t test demonstrated higher plasma levels of total, active, and pro-CatS in AAA patients than in controls (P<0.001). ROC curve analysis confirmed higher plasma total, active, and pro-CatS levels in AAA patients than in controls (P<0.001). Logistic regression suggested that plasma total (odds ratio [OR] = 1.332), active (OR = 1.21), and pro-CatS (OR = 1.25) levels were independent AAA risk factors that associated positively with AAA (P<0.001). Plasma cystatin C levels associated significantly, but negatively, with AAA (OR = 0.356, P<0.001). Univariate correlation demonstrated that plasma total and active CatS levels correlated positively with body-mass index, diastolic blood pressure, and aortic diameter, but negatively with the lowest ankle-brachial index (ABI). Plasma cystatin C levels also correlated negatively with the lowest ABI. Multivariate linear regression showed that plasma total, active, and pro-CatS levels correlated positively with aortic diameter and negatively with the lowest ABI, whereas plasma cystatin C levels correlated negatively with aortic diameter and the lowest ABI, after adjusting for common AAA risk factors. CONCLUSIONS: Correlation of plasma CatS and cystatin C with aortic diameter and the lowest ABI suggest these serological parameters as biomarkers for human peripheral arterial diseases and AAA. PMID- 22844528 TI - Experimental evidence for the interplay of exogenous and endogenous factors on the movement ecology of a migrating songbird. AB - Movement patterns during songbird migration remain poorly understood despite their expected fitness consequences in terms of survival, energetic condition and timing of migration that will carry over to subsequent phases of the annual cycle. We took an experimental approach to test hypotheses regarding the influence of habitat, energetic condition, time of season and sex on the hour-by hour, local movement decisions of a songbird during spring stopover. To simulate arrival of nocturnal migrants at unfamiliar stopover sites, we translocated and continuously tracked migratory red-eyed vireos (Vireo olivaceus) throughout spring stopover with and without energetic reserves that were released in two replicates of three forested habitat types. Migrants moved the most upon release, during which time they selected habitat characterized by greater food abundance and higher foraging attack rates. Presumably under pressure to replenish fuel stores necessary to continue migration in a timely fashion, migrants released in poorer energetic condition moved faster and further than migrants in better condition and the same pattern was true for migrants released late in spring relative to those released earlier. However, a migrant's energetic condition had less influence on their behavior when they were in poor quality habitat. Movement did not differ between sexes. Our study illustrates the importance of quickly finding suitable habitat at each stopover site, especially for energetically constrained migrants later in the season. If an initial period prior to foraging were necessary at each stop along a migrant's journey, non-foraging periods would cumulatively result in a significant energetic and time cost to migration. However, we suggest behavior during stopover is not solely a function of underlying resource distributions but is a complex response to a combination of endogenous and exogenous factors. PMID- 22844529 TI - Which interventions offer best value for money in primary prevention of cardiovascular disease? AB - BACKGROUND: Despite many decades of declining mortality rates in the Western world, cardiovascular disease remains the leading cause of death worldwide. In this research we evaluate the optimal mix of lifestyle, pharmaceutical and population-wide interventions for primary prevention of cardiovascular disease. METHODS AND FINDINGS: In a discrete time Markov model we simulate the ischaemic heart disease and stroke outcomes and cost impacts of intervention over the lifetime of all Australian men and women, aged 35 to 84 years, who have never experienced a heart disease or stroke event. Best value for money is achieved by mandating moderate limits on salt in the manufacture of bread, margarine and cereal. A combination of diuretic, calcium channel blocker, ACE inhibitor and low cost statin, for everyone with at least 5% five-year risk of cardiovascular disease, is also cost-effective, but lifestyle interventions aiming to change risky dietary and exercise behaviours are extremely poor value for money and have little population health benefit. CONCLUSIONS: There is huge potential for improving efficiency in cardiovascular disease prevention in Australia. A tougher approach from Government to mandating limits on salt in processed foods and reducing excessive statin prices, and a shift away from lifestyle counselling to more efficient absolute risk-based prescription of preventive drugs, could cut health care costs while improving population health. PMID- 22844530 TI - Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration. AB - Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by alpha2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O glycosylated with alpha2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing alpha2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth. PMID- 22844531 TI - Overexpression of the DEC1 protein induces senescence in vitro and is related to better survival in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death in China and has limited effective therapeutic options except for early surgery, since the underlying molecular mechanism driving its precursor lesions towards invasive ESCC is not fully understood. Cellular senescence is the state of the permanent growth arrest of a cell, and is considered as the initial barrier of tumor development. Human differentiated embryo chondrocyte expressed gene 1 (Dec1) is an important transcription factor that related to senescence. In this study, DEC1 immunohistochemical analysis was performed on tissue microarray blocks constructed from ESCC combined with adjacent precursor tissues of 241 patients. Compared with normal epithelia, DEC1 expression was significantly increased in intraepithelial neoplasia and DEC1 expression was significantly decreased in ESCC in comparison with intraepithelial neoplasia. In vitro, DEC1 overexpression induced cellular senescence, and it inhibited cell growth and colony formation in ESCC cell line EC9706. Fresh esophagectomy tissue sections from five ESCC patients were detected by immunohistochemistry of DEC1 and senescence-associated beta-galactosidase (SA-beta-Gal) activity, and strongly positive expression of DEC1 was correlated to more senescent cells in these fresh tissue sections. Kaplan-Meier method analysis of the 241 patients revealed that DEC1 expression levels were significantly correlated with the survival of ESCC patients after surgery. The expression levels of DEC1 were also correlated with age, tumor embolus, depth of invasion of ESCC, lymph metastasis status and pTNMs. These results suggest that DEC1 overexpression in precursor lesions of ESCC is a protective mechanism by inducing cellular senescence in ESCC initiation, and DEC1 may be a potential prognostic marker of ESCC. PMID- 22844532 TI - Rabring7 degrades c-Myc through complex formation with MM-1. AB - We have reported that a novel c-Myc-binding protein, MM-1, repressed E-box dependent transcription and transforming activities of c-Myc and that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. MM-1 also binds to the ubiquitin-proteasome system, leading to degradation of c-Myc. In this study, we identified Rabring7, a Rab7-binding and RING finger-containing protein, as an MM-1-binding protein, and we found that Rabring7 mono-ubiquitinated MM-1 in the cytoplasm without degradation of MM-1. Rabring7 was also found to bind to c-Myc and to ubiquitinate c-Myc in a threonine 58-dependent manner. When c-Myc was co-transfected with MM-1 and Rabring7, c-Myc was degraded. Furthermore, it was found that c-Myc was stabilized in MM-1-knockdown cells even when Rabring7 was transfected and that Rabring7 was bound to and co-localized with MM-1 and c-Myc after MM-1 and Rabring7 had been translocated from the cytoplasm to the nucleus. These results suggest that Rabring7 stimulates c-Myc degradation via mono-ubiquitination of MM 1. PMID- 22844533 TI - Crystal structure of a monomeric thiolase-like protein type 1 (TLP1) from Mycobacterium smegmatis. AB - An analysis of the Mycobacterium smegmatis genome suggests that it codes for several thiolases and thiolase-like proteins. Thiolases are an important family of enzymes that are involved in fatty acid metabolism. They occur as either dimers or tetramers. Thiolases catalyze the Claisen condensation of two acetyl Coenzyme A molecules in the synthetic direction and the thiolytic cleavage of 3 ketoacyl-Coenzyme A molecules in the degradative direction. Some of the M. smegmatis genes have been annotated as thiolases of the poorly characterized SCP2 thiolase subfamily. The mammalian SCP2-thiolase consists of an N-terminal thiolase domain followed by an additional C-terminal domain called sterol carrier protein-2 or SCP2. The M. smegmatis protein selected in the present study, referred to here as the thiolase-like protein type 1 (MsTLP1), has been biochemically and structurally characterized. Unlike classical thiolases, MsTLP1 is a monomer in solution. Its structure has been determined at 2.7 A resolution by the single wavelength anomalous dispersion method. The structure of the protomer confirms that the N-terminal domain has the thiolase fold. An extra C terminal domain is indeed observed. Interestingly, it consists of six beta strands forming an anti-parallel beta-barrel which is completely different from the expected SCP2-fold. Detailed sequence and structural comparisons with thiolases show that the residues known to be essential for catalysis are not conserved in MsTLP1. Consistent with this observation, activity measurements show that MsTLP1 does not catalyze the thiolase reaction. This is the first structural report of a monomeric thiolase-like protein from any organism. These studies show that MsTLP1 belongs to a new group of thiolase related proteins of unknown function. PMID- 22844534 TI - Structure and binding interface of the cytosolic tails of alphaXbeta2 integrin. AB - BACKGROUND: Integrins are signal transducer proteins involved in a number of vital physiological processes including cell adhesion, proliferation and migration. Integrin molecules are hetero-dimers composed of two distinct subunits, alpha and beta. In humans, 18 alpha and 8 beta subunits are combined into 24 different integrin molecules. Each of the subunit comprises a large extracellular domain, a single pass transmembrane segment and a cytosolic tail (CT). The CTs of integrins are vital for bidirectional signal transduction and in maintaining the resting state of the receptors. A large number of intracellular proteins have been found to interact with the CTs of integrins linking integrins to the cytoskeleton. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we have investigated structure and interactions of CTs of the leukocyte specific integrin alphaXbeta2. We determined the atomic resolution structure of a myristoylated CT of alphaX in perdeuterated dodecylphosphocholine (DPC) by NMR spectroscopy. Our results reveal that the 35-residue long CT of alphaX adopts an alpha-helical conformation for residues F4-N17 at the N-terminal region. The remaining residues located at the C-terminal segment of alphaX delineate a long loop of irregular conformations. A segment of the loop maintains packing interactions with the helical structure by an extended non-polar surface of the alphaX CT. Interactions between alphaX and beta2 CTs are demonstrated by (15)N-(1)H HSQC NMR experiments. We find that residues constituting the polar face of the helical conformation of alphaX are involved in interactions with the N-terminal residues of beta2 CT. A docked structure of the CT complex indicates that a network of polar and/or salt bridge interactions may sustain the heteromeric interactions. CONCLUSIONS/SIGNIFICANCE: The current study provides important insights into the conservation of interactions and structures among different CTs of integrins. PMID- 22844536 TI - Behavioural responses of dusky dolphin groups (Lagenorhynchus obscurus) to tour vessels off Kaikoura, New Zealand. AB - BACKGROUND: Commercial viewing and swimming with dusky dolphins (Lagenorhynchus obscurus) near Kaikoura, New Zealand began in the late 1980s and researchers have previously described changes in vocalisation, aerial behaviour, and group spacing in the presence of vessels. This study was conducted to assess the current effects that tourism has on the activity budget of dusky dolphins to provide wildlife managers with information for current decision-making and facilitate development of quantitative criteria for management of this industry in the future. METHODOLOGY/PRINCIPAL FINDINGS: First-order time discrete Markov chain models were used to assess changes in the behavioural state of dusky dolphin pods targeted by tour vessels. Log-linear analysis was conducted on behavioural state transitions to determine whether the likelihood of dolphins moving from one behavioural state to another changed based on natural and anthropogenic factors. The best-fitting model determined by Akaike Information Criteria values included season, time of day, and vessel presence within 300 m. Interactions with vessels reduced the proportion of time dolphins spent resting in spring and summer and increased time spent milling in all seasons except autumn. Dolphins spent more time socialising in spring and summer, when conception occurs and calves are born, and the proportion of time spent resting was highest in summer. Resting decreased and traveling increased in the afternoon. CONCLUSIONS/SIGNIFICANCE: Responses to tour vessel traffic are similar to those described for dusky dolphins elsewhere. Disturbance linked to vessels may interrupt social interactions, carry energetic costs, or otherwise affect individual fitness. Research is needed to determine if increased milling is a result of acoustic masking of communication due to vessel noise, and to establish levels at which changes to behavioural budgets of dusky dolphins are likely to cause long-term harm. Threshold values from these studies would allow managers to set appropriate operational conditions based on quantifiable criteria. PMID- 22844535 TI - Effect of multiple parasitic infections on the tolerance to pollutant contamination. AB - The horizontally-transmitted acanthocephalan parasite Polymorphus minutus and the vertically-transmitted microsporidian parasite Dictyocoela roeselum have both been shown to influence on the antitoxic responses of mono-infected Gammarus roeseli exposed to cadmium. The present study investigates the effect of this co infection on the antitoxic defence responses of naturally infected females exposed to cadmium stress. Our results revealed that, depending on the cadmium dose, bi-infection induced only slight, significant increased cell damage in G. roeseli as compared to non-infection. In addition, the antitoxic defence pattern of cadmium-exposed bi-infected hosts was similar to the pattern of cadmium exposed D. roeselum-infected hosts. Reduced glutathione concentrations, carotenoid levels and gamma-glutamylcystein ligase activity decreased, while metallothionein concentrations increased. This similar pattern indicates that host physiology can be controlled to some extent by microsporidia under stress conditions. It supports the hypothesis of a disruption of acanthocephalan effects in the presence of microsporidia. However, the global negative effects of bi infection on host condition should be tested on more biological models, since competition between parasites depends on life history trade-off. PMID- 22844537 TI - The expression of EPOR in renal cortex during postnatal development. AB - Erythropoietin (EPO), known for its role in erythroid differentiation, has been shown to be an important growth factor for brain and heart. EPO is synthesized by fibroblast-like cells in the renal cortex. Prompted by this anatomical relationship and its significant impact on the maturation process of brain and heart, we asked whether EPO could play a role during the development of renal cortex. The relationship between the development of renal cortex and the change of EPO receptor (EPOR), through which EPO could act as a renotropic cytokine, became interesting to us. In this study, the day of birth was recorded as postnatal day 0(P0). P7, P14, P21, P28, P35, P42 and mature mice (postnatal days>56) were used as the animal model of different developmental stages. Immunohistochemistry and Western blotting were used to detect the expression of EPOR in mouse renal cortex. Results showed that expression of EPOR decreased with the development of renal cortex and became stable when kidney became mature. The expression of EPOR was detected at the renal tubule of all developmental stages and a relatively higher expression was observed at P14. However, at the renal corpuscle the expression was only observed at P7 and quickly became undetectable after that. All these suggested that a translocation of EPOR from renal corpuscle to renal tubule may take place during the developmental process of renal cortex. Also, EPO may be an essential element for the maturation of renal cortex, and the requirement for EPO was changed during postnatal development process. PMID- 22844538 TI - Rapid detection and identification of human hookworm infections through high resolution melting (HRM) analysis. AB - BACKGROUND: Hookworm infections are still endemic in low and middle income tropical countries with greater impact on the socioeconomic and public health of the bottom billion of the world's poorest people. In this study, a real-time polymerase chain reaction (PCR) coupled with high resolution melting-curve (HRM) analysis was evaluated for an accurate, rapid and sensitive tool for species identification focusing on the five human hookworm species. METHODS: Real-time PCR coupled with HRM analysis targeting the second internal transcribed spacer (ITS-2) of nuclear ribosomal DNA as the genetic marker was used to identify and distinguish hookworm species in human samples. Unique and distinct characteristics of HRM patterns were produced for each of the five hookworm species. The melting curves were characterized by peaks of 79.24+/-0.05 degrees C and 83.00+/-0.04 degrees C for Necator americanus, 79.12+/-0.10 degrees C for Ancylostoma duodenale, 79.40+/-0.10 degrees C for Ancylostoma ceylanicum, 79.63+/ 0.05 degrees C for Ancylostoma caninum and 79.70+/-0.14 degrees C for Ancylostoma braziliense. An evaluation of the method's sensitivity and specificity revealed that this assay was able to detect as low as 0.01 ng/ul hookworm DNA and amplification was only recorded for hookworm positive samples. CONCLUSION: The HRM assay developed in this study is a rapid and straightforward method for the diagnosis, identification and discrimination of five human hookworms. This assay is simple compared to other probe-based genotyping methods as it does not require multiplexing, DNA sequencing or post-PCR processing. Therefore, this method offers a new alternative for rapid detection of human hookworm species. PMID- 22844539 TI - Thioredoxin from the Indianmeal moth Plodia interpunctella: cloning and test of the allergenic potential in mice. AB - BACKGROUND/OBJECTIVE: The Indianmeal moth Plodia interpunctella is a highly prevalent food pest in human dwellings, and has been shown to contain a number of allergens. So far, only one of these, the arginine kinase (Plo i 1) has been identified. OBJECTIVE: The aim of this study was to identify further allergens and characterise these in comparison to Plo i 1. METHOD: A cDNA library from whole adult P. interpunctella was screened with the serum of a patient with indoor allergy and IgE to moths, and thioredoxin was identified as an IgE-binding protein. Recombinant thioredoxin was generated in E. coli, and tested together with Plo i 1 and whole moth extracts in IgE immunoblots against a large panel of indoor allergic patients' sera. BALB/c mice were immunised with recombinant thioredoxin and Plo i 1, and antibody production, mediator release from RBL cells, T-cell proliferation and cytokine production were measured. RESULT: For the first time a thioredoxin from an animal species was identified as allergen. About 8% of the sera from patients with IgE against moth extracts reacted with recombinant P. interpunctella thioredoxin, compared to 25% reacting with recombinant Plo i 1. In immunised BALB/c mice, the recombinant allergens both induced classical Th2-biased immune responses such as induction IgE and IgG1 antibodies, upregulation of IL-5 and IL-4 and basophil degranulation. CONCLUSION: Thioredoxin from moths like Plo i 1 acts like a classical Type I allergen as do the thioredoxins from wheat or corn. This clearly supports the pan-allergen nature of thioredoxin. The designation Plo i 2 is suggested for the new P. interpunctella allergen. PMID- 22844540 TI - Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. AB - Epithelial to mesenchymal transition (EMT) has been hypothesized as a mechanism by which cells change phenotype during carcinogenesis, as well as tumor metastasis. Whether EMT is involved in cancer metastasis has a specific, practical impact on the field of circulating tumor cells (CTCs). Since the generally accepted definition of a CTC includes the expression of epithelial surface markers, such as EpCAM, if a cancer cell loses its epithelial surface markers (which is suggested in EMT), it will not be separated and/or identified as a CTC. We have developed, and previously reported on the use of, a purely negative enrichment technology enriching for CTCs in the blood of squamous cell carcinoma of the head and neck (SCCHN). This methodology does not depend on the expression of surface epithelial markers. Using this technology, our initial data on SCCHN patient blood indicates that the presence of CTCs correlates with worse disease-free survival. Since our enrichment is not dependent on epithelial markers, we have initiated investigation of the presence of mesenchymal markers in these CTC cells to include analysis of: vimentin, epidermal growth factor receptor, N-cadherin, and CD44. With the aid of confocal microscopy, we have demonstrated not only presumed CTCs that express and/or contain: a nucleus, cytokeratins, vimentin, and either EGFR, CD44, or N-cadherin, but also cells that contain all of the aforementioned proteins except cytokeratins, suggesting that the cells have undergone the EMT process. We suggest that our negative depletion enrichment methodology provides a more objective approach in identifying and evaluating CTCs, as opposed to positive selection approaches, as it is not subjective to a selection bias and can be tailored to accommodate a variety of cytoplasmic and surface markers which can be evaluated to identify a multitude of phenotypic patterns within CTCs from individual patients, including so-called EMT as presented here. PMID- 22844541 TI - Effect of reference genome selection on the performance of computational methods for genome-wide protein-protein interaction prediction. AB - BACKGROUND: Recent progress in computational methods for predicting physical and functional protein-protein interactions has provided new insights into the complexity of biological processes. Most of these methods assume that functionally interacting proteins are likely to have a shared evolutionary history. This history can be traced out for the protein pairs of a query genome by correlating different evolutionary aspects of their homologs in multiple genomes known as the reference genomes. These methods include phylogenetic profiling, gene neighborhood and co-occurrence of the orthologous protein coding genes in the same cluster or operon. These are collectively known as genomic context methods. On the other hand a method called mirrortree is based on the similarity of phylogenetic trees between two interacting proteins. Comprehensive performance analyses of these methods have been frequently reported in literature. However, very few studies provide insight into the effect of reference genome selection on detection of meaningful protein interactions. METHODS: We analyzed the performance of four methods and their variants to understand the effect of reference genome selection on prediction efficacy. We used six sets of reference genomes, sampled in accordance with phylogenetic diversity and relationship between organisms from 565 bacteria. We used Escherichia coli as a model organism and the gold standard datasets of interacting proteins reported in DIP, EcoCyc and KEGG databases to compare the performance of the prediction methods. CONCLUSIONS: Higher performance for predicting protein-protein interactions was achievable even with 100-150 bacterial genomes out of 565 genomes. Inclusion of archaeal genomes in the reference genome set improves performance. We find that in order to obtain a good performance, it is better to sample few genomes of related genera of prokaryotes from the large number of available genomes. Moreover, such a sampling allows for selecting 50-100 genomes for comparable accuracy of predictions when computational resources are limited. PMID- 22844542 TI - Cytotoxic T-lymphocyte associated antigen 4 polymorphisms and asthma risk: a meta analysis. AB - BACKGROUND: A number of studies assessed the association of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms with asthma in different populations. However, the results were contradictory. We performed a meta-analysis to examine the association between CTLA-4 polymorphisms and asthma susceptibility. METHODS: Pubmed, EMBASE, HuGE Navigator, and Wanfang Database were searched. Data were extracted independently by two reviewers. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. RESULTS: Seventeen studies involving 6378 cases and 8674 controls were included. Significant association between +49 A/G polymorphism and asthma was observed for AA vs. AG+GG (OR = 1.18, 95% CI 1.01-1.37, P = 0.04). There were no significant associations between -318 C/T, -1147 C/T, CT60 A/G, -1722 C/T, or rs926169 polymorphisms and asthma risk. CONCLUSIONS: This meta-analysis suggested that the +49 A/G polymorphism in CTLA-4 was a risk factor for asthma. PMID- 22844543 TI - Satiating capacity and post-prandial relationships between appetite parameters and gut-peptide concentrations with solid and liquefied carbohydrate. AB - BACKGROUND: Differences in satiating capacity of liquid and solid meals are unclear. OBJECTIVE: Investigating appetite parameters, physiological measurements and within-subject relationships after consumption of a single macronutrient, subject-specific carbohydrate meal in liquefied versus solid form, controlled for energy density, weight and volume. DESIGN: In a cross-over design, ten male subjects (age = 21.1+/-3.9 y, BMI = 22.4+/-1.2 kg/m(2)) consumed a solid (CS, whole peaches +750 ml water) and liquefied carbohydrate (CL, peach blended in 500 ml water +250 ml water) lunch. Appetite profiles, insulin-, glucose- and ghrelin concentrations were measured over three hours. Post-prandial relationships between appetite and blood parameters were calculated using subject-specific regression analyses. RESULTS: Fullness ratings were higher in the CL (85+/-5 mm) compared to the CS condition (73+/-8 mm) at 20 min (p<0.03). Glucose concentrations peaked 20 to 30 min after the start of the lunch in the CL condition, and 30 to 40 min after start of the CS condition. Correspondingly, insulin concentrations were peaked at 20-30 min in the CL condition, and at 30-40 min in the CS condition. AUC or condition x time interactions were not different comparing the CL and the CS condition. Insulin was significantly higher in the CS compared to the CL condition 40 min after the start of the lunch (p<0.05). Fullness scores were significantly related to insulin concentrations but not to glucose concentrations; desire to eat scores were significantly associated with ghrelin concentrations in both, the CL and the CS condition. The relationship between fullness scores and glucose concentrations was not statistically significant. CONCLUSION: Liquefied and solid carbohydrate meals do not differ in satiating capacity, supported by appetite profile and relevant blood parameters. Postprandially, fullness and desire to eat were associated with respectively insulin and ghrelin concentrations. PMID- 22844544 TI - The complete mitochondrial genome of Galba pervia (Gastropoda: Mollusca), an intermediate host snail of Fasciola spp. AB - Complete mitochondrial (mt) genomes and the gene rearrangements are increasingly used as molecular markers for investigating phylogenetic relationships. Contributing to the complete mt genomes of Gastropoda, especially Pulmonata, we determined the mt genome of the freshwater snail Galba pervia, which is an important intermediate host for Fasciola spp. in China. The complete mt genome of G. pervia is 13,768 bp in length. Its genome is circular, and consists of 37 genes, including 13 genes for proteins, 2 genes for rRNA, 22 genes for tRNA. The mt gene order of G. pervia showed novel arrangement (tRNA-His, tRNA-Gly and tRNA Tyr change positions and directions) when compared with mt genomes of Pulmonata species sequenced to date, indicating divergence among different species within the Pulmonata. A total of 3655 amino acids were deduced to encode 13 protein genes. The most frequently used amino acid is Leu (15.05%), followed by Phe (11.24%), Ser (10.76%) and IIe (8.346%). Phylogenetic analyses using the concatenated amino acid sequences of the 13 protein-coding genes, with three different computational algorithms (maximum parsimony, maximum likelihood and bayesian analysis), all revealed that the families Lymnaeidae and Planorbidae are closely related two snail families, consistent with previous classifications based on morphological and molecular studies. The complete mt genome sequence of G. pervia showed a novel gene arrangement and it represents the first sequenced high quality mt genome of the family Lymnaeidae. These novel mtDNA data provide additional genetic markers for studying the epidemiology, population genetics and phylogeographics of freshwater snails, as well as for understanding interplay between the intermediate snail hosts and the intra-mollusca stages of Fasciola spp.. PMID- 22844546 TI - The Impact of Credit on Village Economies. AB - This paper evaluates the short-term impact of Thailand's 'Million Baht Village Fund'program, among the largest scale government microfinance iniative in the world, using pre- and post-program panel data and quasi-experimental cross village variation in credit-per-household. We find that the village funds have increased total short-term credit, consumption, agricultural investment, income growth (from business and labor), but decreased overall asset growth. We also find a positive impact on wages, an important general equilibrium effect. The findings are broadly consistent qualitatively with models of credit-constrained household behavior and models of intermediation and growth. PMID- 22844545 TI - Exercise-induced Signals for Vascular Endothelial Adaptations: Implications for Cardiovascular Disease. AB - This article reviews recent advances in our understanding of hemodynamic signals, external/compressive forces, and circulating factors that mediate exercise training-induced vascular adaptations, with particular attention to the roles of these signals in prevention and treatment of endothelial dysfunction and cardiovascular (CV) diseases. PMID- 22844548 TI - Cutaneous metastases secondary to pancreatic cancer. AB - AIM: To evaluate prognoses after cutaneous metastases, derived from pancreatic cancer. METHODS: We treated two patients with cutaneous metastases from pancreatic cancer. We reviewed 40 reported patients in addition to our cases and analyzed clinical features of cutaneous metastases from pancreatic cancer. RESULTS: The median survival time (MST) was 5 mo after diagnoses of cutaneous metastases. The cumulative 2-year survival rate was 3.5%. The most frequent site of cutaneous metastases was the umbilicus. The MST of patients who were treated with chemotherapy or chemoradiotherapy (CRT) was 6.5 mo, which was statistically longer in comparison to patients without treatment. Prognoses of cutaneous metastases are similar to other metastatic sites from pancreatic cancer. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer. CONCLUSION: The prognoses of cutaneous metastases are similar to other metastatic pancreatic cancers. Receiving chemotherapy or CRT was the only prognostic factor of cutaneous metastases from pancreatic cancer. PMID- 22844549 TI - Oxaliplatin induced disseminated intravascular coagulation: A case report and review of literature. AB - Oxaliplatin in combination with a fluoropyrimide is a treatment option for colorectal cancer patients in the adjuvant and metastatic settings. Very few hematological emergencies have been reported associated with Oxaliplatin. These include autoimmune hemolytic anemia, thrombocytopenia and pancytopenia. We present a case report of a patient who developed hematuria and disseminated intravascular coagulation while receiving the second cycle of FOLFOX and bevacizumab for metastatic colon cancer. PMID- 22844547 TI - Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. AB - Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future. PMID- 22844550 TI - Adenocarcinoma of the small bowel in a patient with occlusive Crohn's disease. AB - A 40-year-old male, diagnosed with mild Crohn's disease (CD) 11 years ago but with no prior abdominal surgeries, was diagnosed with a small bowel stricture, due to ongoing abdominal pain and intolerance of enteral diet, and referred for surgical treatment. Exploratory laparoscopy revealed a white solid mass causing a near total jejunal obstruction with significant proximal dilatation. An adjacent small node was sampled for frozen biopsy, revealing a lymph node infiltrated with adenocarcinoma. Laparoscopic assisted small bowel resection and appendectomy were carried out. Final pathological results supported the initial report of diffuse small bowel adenocarcinoma. In conclusion, once a small bowel stricture associated with CD is suspected, rapid action should be considered to avoid late diagnosis of a neoplasia. PMID- 22844551 TI - Inhibitors for Bacterial Cell-Wall Recycling. AB - Gram-negative bacteria have evolved an elaborate process for the recycling of their cell wall, which is initiated in the periplasmic space by the action of lytic transglycosylases. The product of this reaction, beta-D-N-acetylglucosamine (1->4)-1,6-anhydro-beta-D-N-acetylmuramyl-L-Ala-gamma-D-Glu-meso-DAP-D-Ala-D-Ala (compound 1), is internalized to begin the recycling events within the cytoplasm. The first step in the cytoplasmic recycling is catalyzed by the NagZ glycosylase, which cleaves in a hydrolytic reaction the N-acetylglucosamine glycosidic bond of metabolite 1. The reactions catalyzed by both the lytic glycosylases and NagZ are believed to involve oxocarbenium transition species. We describe herein the synthesis and evaluation of four iminosaccharides as possible mimetics of the oxocarbenium species, and disclose one as a potent (compound 3, K(i) = 300 +/- 15 nM) competitive inhibitor of NagZ. PMID- 22844552 TI - Small molecule suppression of carbapenem resistance in NDM-1 producing Klebsiella pneumoniae. AB - The already considerable global public health threat of multi-drug resistant Gram negative bacteria has become even more of a concern following the emergence of New-Delhi metallo-beta-lactamase (NDM-1) producing strains of Klebsiella pneumoniae and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2 aminoimidazole derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of K. pneumoniae to imipenem and meropenem, in addition to suppressing resistance of other beta lactam non-susceptible K. pneumoniae strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold while exhibiting little bactericidal activity itself. PMID- 22844553 TI - How Quantum Coherence Assists Photosynthetic Light Harvesting. AB - This perspective examines how hundreds of pigment molecules in purple bacteria cooperate through quantum coherence to achieve remarkable light harvesting efficiency. Quantum coherent sharing of excitation, which modifies excited state energy levels and combines transition dipole moments, enables rapid transfer of excitation over large distances. Purple bacteria exploit the resulting excitation transfer to engage many antenna proteins in light harvesting, thereby increasing the rate of photon absorption and energy conversion. We highlight here how quantum coherence comes about and plays a key role in the photosynthetic apparatus of purple bacteria. PMID- 22844554 TI - An objective structured biostatistics examination: a pilot study based on computer-assisted evaluation for undergraduates. AB - We designed and evaluated an objective structured biostatistics examination (OSBE) on a trial basis to determine whether it was feasible for formative or summative assessment. At Ataturk University, we have a seminar system for curriculum for every cohort of all five years undergraduate education. Each seminar consists of an integrated system for different subjects, every year three to six seminars that meet for six to eight weeks, and at the end of each seminar term we conduct an examination as a formative assessment. In 2010, 201 students took the OSBE, and in 2011, 211 students took the same examination at the end of a seminar that had biostatistics as one module. The examination was conducted in four groups and we examined two groups together. Each group had to complete 5 stations in each row therefore we had two parallel lines with different instructions to be followed, thus we simultaneously examined 10 students in these two parallel lines. The students were invited after the examination to receive feedback from the examiners and provide their reflections. There was a significant (P=0.004) difference between male and female scores in the 2010 students, but no gender difference was found in 2011. The comparison among the parallel lines and among the four groups showed that two groups, A and B, did not show a significant difference (P>0.05) in either class. Nonetheless, among the four groups, there was a significant difference in both 2010 (P=0.001) and 2011 (P=0.001). The inter-rater reliability coefficient was 0.60. Overall, the students were satisfied with the testing method; however, they felt some stress. The overall experience of the OSBE was useful in terms of learning, as well as for assessment. PMID- 22844555 TI - The current strategy for managing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1. AB - Multiple endocrine neoplasia type 1 (MEN1) is an inherited autosomal dominant disease presenting with pancreatic neuroendocrine tumors (pNETs), parathyroid tumors, or pituitary tumors. Using the PubMed database, we reviewed the literature on information regarding the proper diagnosis and treatment of MEN1 associated pNET. Many cases of MEN1-associated pNET are functioning pNETs. Gastrinomas and insulinomas tend to occur frequently in the duodenum and pancreas, respectively. In addition to diagnostic imaging, the selective arterial secretagogue injection test (SASI test) is useful for localizing functioning pNET. The standard treatment is surgical resection. However, in the case of a functioning pNET, the tumor should first be accurately located using the SASI test before an appropriate surgical method is selected. In cases of a MEN1 associated non-functioning pNET that exceeds 2 cm in diameter, the incidence of distant metastasis is significantly increased, and surgery is recommended. In cases of unresectable pNET, a somatostatin analog has been shown to demonstrate antitumor effects and is considered to be a promising treatment. In addition, molecular-targeted drugs have recently been found to be effective in phase III clinical trials. PMID- 22844556 TI - The crucial role of cholangiocytes in cholangiopathies. AB - Cholangiopathies are diseases involving the intrahepatic biliary tree. They appear to involve, chronic inflammation of the bile ducts, which can lead to the development of bile duct cholestasis, proliferation/ductopenia, biliary fibrosis, and malignant transformation. Sustained stimulatory insults to biliary epithelial cells can induce a ductular reaction, which has a key role in the initiation and progression of cholangiopathies. The epithelial-mesenchymal interaction between reactive cholangiocytes and mesenchymal cells with the inflammatory infiltrates plays a major role in this pathogenesis. Cytokines, chemokines, growth factors and morphogens mediate these interactions in an autocrine or paracrine manner. The main hepatic myofibroblasts (MFs) in cholangiopathies originate from portal fibroblasts. Hepatic stellate cells and fibrocytes also transform into MFs. Whether cholangiocytes or hepatocytes are a source of MFs via the epithelial mesenchymal transition (EMT) remains a matter of controversy. Although there have been numerous indirect findings supporting the theory of a cholangiocyte EMT in human tissues, recent studies using lineage tracing methods have demonstrated strong evidence against the EMT. Understanding the pathogenic mechanisms involved in cholangiopathies can allow for better-targeted anti-fibrotic therapies in animal models. Before anti-fibrotic therapies can translate into clinical trials, improved monitoring of the fibrotic progression of cholangiopathies and an accurate assessment regarding the effectiveness of the proposed treatments must be achieved. PMID- 22844558 TI - Clinical impact of second-look endoscopy after endoscopic submucosal dissection of gastric neoplasms. AB - BACKGROUND/AIMS: One major complication of endoscopic submucosal dissection (ESD) is delayed bleeding. Most hospitals routinely perform second-look endoscopy to reduce the chances of delayed bleeding without solid evidence supporting the practice. The aim of this study was to evaluate whether second-look endoscopy prevents delayed bleeding and to verify the clinicopathological features of delayed bleeding to determine how to identify lesions that may require second look endoscopy. METHODS: We investigated 440 lesions in 397 patients who underwent ESD for gastric neoplasm from January 2008 to June 2010. Two-thirds of the enrolled cases were adenomas, and 290 lesions were located in the lower portion of the stomach. Clinically evident bleeding from mucosal defects 24 hours after ESD was considered as delayed bleeding. We reviewed the data, including the characteristics of patients, lesions, and procedures. Furthermore, the rate of delayed bleeding before and after second-look endoscopy, performed within three days of ESD, was investigated to determine the utility of second-look endoscopy. RESULTS: Delayed bleeding was evident in 9 of 440 lesions (2.0%), all of which underwent endoscopic hemostasis. The only significant factor predicting delayed bleeding was resected specimen over 40 mm in size (p=0.003). Delayed bleeding occurred in 8 of 9 cases (89%) before the second-look endoscopy, which was performed within 72 hours after ESD. CONCLUSIONS: In this study, second-look endoscopy may be useful for preventing post-ESD bleeding, especially when resected specimens are over 40 mm in size. PMID- 22844557 TI - Cellular and molecular basis of intestinal barrier dysfunction in the irritable bowel syndrome. AB - The etiopathogenesis of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, is not well known. The most accepted hypothesis is that IBS is the result of the disturbance of the 'brain-gut axis.' Although the pathophysiological mechanisms of intestinal dysfunction are complex and not completely understood, stress, infections, gut flora, and altered immune response are thought to play a role in IBS development. The intestinal barrier, composed of a single-cell layer, forms a physical barrier that separates the intestinal lumen from the internal milieu. The loss of integrity of this barrier is related with mucosal immune activation and intestinal dysfunction in IBS. The number of mast cells and T lymphocytes is increased in the intestinal mucosa of certain IBS patients, and the mediators released by these cells could compromise the epithelial barrier function and alter nerve signaling within the enteric nervous system. The association of clinical symptoms to structural and functional abnormalities of the mucosal barrier in IBS patients highlights the importance of understanding the physiological role of the gut barrier in the pathogenesis of this disorder. This review summarizes the clinical and experimental evidences indicating the cellular and molecular mechanisms of IBS symptomatology, and its relevance for future translational research. PMID- 22844559 TI - The COX-2-1195AA Genotype Is Associated with Diffuse-Type Gastric Cancer in Korea. AB - BACKGROUND/AIMS: The potential role of the cyclooxygenase (COX)-2 polymorphism has been reported in relation to the risk of gastrointestinal tract malignancies. Therefore, we investigated whether COX-2 polymorphisms are associated with the risk of gastric cancer (GC) in Korea, one of the areas with a high prevalence of this condition. METHODS: We evaluated the genotypic frequencies of COX-2-765 and 1195 in 100 peptic ulcer patients, 100 GC patients, and 100 healthy controls. The polymorphisms of the COX-2-765 and -1195 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphisms. RESULTS: The frequencies of the COX-2-1195 GG, GA, and AA genotype were 20%, 60%, and 20% in intestinal type GC and 8%, 48%, and 44% in diffuse-type GC, respectively (p=0.021). There were no significant differences in the frequency of COX-2-765 genotypes between intestinal-type GC and diffuse-type GC (p=0.603). Age- and sex-adjusted logistic regression analysis showed that the COX-2-1195 AA genotype was the independent risk factor of diffuse-type GC compared with the COX-2-1195 GG genotype (p=0.041; odds ratio, 6.22; 95% confidence interval, 1.077 to 35.870). CONCLUSIONS: The COX 2-1195 AA genotype may render subjects more susceptible to diffuse-type GC. PMID- 22844560 TI - The learning curve for colorectal stent insertion for the treatment of malignant colorectal obstruction. AB - BACKGROUND/AIMS: We aimed to assess the effectiveness of self-expanding metal stent (SEMS) insertion by evaluating the learning curve in relation to the experience of an endoscopist. METHODS: We retrospectively analyzed the outcomes of 120 SEMS insertion procedures performed by one endoscopist in patients with malignant colorectal obstruction. We compared the technical and clinical success rates, complication rates, and duration of the procedures by quartiles. RESULTS: The mean age of the patients (76 men and 44 women) was 64.6 years. The overall technical success rate was 95.0% (114/120), and the clinical success rate was 90.0% (108/120). The median procedure duration was 16.2 minutes (range, 3.4 to 96.5 minutes). From the first to the last quartile, the technical success rates were 90.0%, 96.7%, 96.7%, and 96.7% (p=0.263), and the clinical success rates were 90.0%, 90.0%, 96.7%, and 83.3% (p=0.588), respectively. Procedure-related complications were observed in 28 patients (23.3%). The complication rates for SEMS insertion when patients were divided by quartiles were 26.7%, 23.3%, 10.0%, and 33.3% (p=0.184), respectively. Moreover, the number of stents per procedure was 1.13, 1.03, 1.00, and 1.00 (p=0.029), respectively. The median duration of SEMS insertion decreased significantly, 20.9 to 14.8 minutes after the first 30 procedures (p=0.005). CONCLUSIONS: An experienced endoscopist was able to perform the SEMS insertion procedure easily and effectively after performing 30 SEMS insertions. PMID- 22844561 TI - Predictive factors for colonic diverticular rebleeding: a retrospective analysis of the clinical and colonoscopic features of 111 patients. AB - BACKGROUND/AIMS: Colonic diverticular bleeding can stop spontaneously or be stopped by endoscopic hemostasis. We analyzed the clinical and colonoscopic features of patients with colonic diverticular bleeding to establish the predictive factors for rebleeding. METHODS: A total of 111 patients (median age, 72 years) with colonic diverticular bleeding in Aso Iizuka Hospital between April 2007 and July 2010 were enrolled. Age, sex, body mass index (BMI), comorbidity, medication, location of bleeding, colonoscopic findings and hemostatic methods were analyzed retrospectively from the hospital records. RESULTS: The most common sites of bleeding were the ascending (39.6%) and sigmoid (29.7%) colon. Overt rebleeding occurred in 30 patients (27.0%). Spontaneous hemostasis was seen in 81 patients (73.0%), and endoscopic hemostatic treatment was performed in 30 patients. The BMI in the patients with colonic diverticular rebleeding was significantly higher than in patients without rebleeding. Colonoscopic findings of actively bleeding or nonbleeding visible vessels in the responsible diverticula were more frequent in the group with rebleeding. CONCLUSIONS: A higher BMI and colonoscopic findings of actively bleeding or nonbleeding visible vessels can be used as predictive factors for colonic diverticular rebleeding. Patients with such findings should be carefully followed up after hemostasis of the initial colonic diverticular bleeding. PMID- 22844562 TI - Effects of the oral administration of mosapride citrate on capsule endoscopy completion rate. AB - BACKGROUND/AIMS: In capsule endoscopy (CE), the capsule does not always reach the cecum within its battery life, which may reduce its diagnostic yield. We evaluated the effect of mosapride citrate, a 5-hydroxytryptamine-4 agonist that increases gastrointestinal motility, on CE completion. METHODS: In a retrospective study, we performed univariate and multivariate analyses for 232 CE procedures performed at our hospital. To identify factors that affect CE completion, the following data were systematically collected: gender, age, gastric transit time (GTT), nonsteroidal anti-inflammatory drug administration, previous abdominal surgery, hospitalization, use of a polyethylene glycol solution, use of mosapride citrate (10 mg), body mass index (BMI), and total recording time. RESULTS: The univariate analysis showed that oral mosapride citrate, GTT, and BMI were associated with improved CE completion. Multivariate analyses showed that oral mosapride citrate (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.01 to 3.91) and GTT (OR, 2.34; 95% CI, 1.13 to 4.87) were significant factors for improving the CE completion. Oral mosapride citrate significantly shortened the GTT and small bowel transit time (SBTT). CONCLUSIONS: Oral mosapride citrate reduced the GTT and SBTT during CE and improved the CE completion rate. PMID- 22844563 TI - Endoscopy Nurse Participation May Increase the Polyp Detection Rate by Second Year Fellows during Screening Colonoscopies. AB - BACKGROUND/AIMS: The aim of this study was to assess the effects of endoscopy nurse participation on polyp detection rate (PDR) and adenoma detection rate (ADR) of second-year fellows during screening colonoscopies. METHODS: This was a single-center, prospective, randomized study comparing a fellow alone and a fellow plus an endoscopy nurse as an additional observer during afternoon outpatient screening colonoscopies. The primary end points were PDR and ADR. RESULTS: One hundred ninety-one colonoscopies performed by a fellow alone and 192 colonoscopies performed by a fellow plus an endoscopy nurse were analyzed. The PDR was significantly higher when the nurse was involved (53.1% vs. 41.3%, p<0.05); however, there was no significant difference in the ADR between the two groups (38.5% vs. 29.8%, p=0.073). There was no difference in the percentage of patients with >=2 polyps, advanced adenomas, polyp size, polyp location, and polyp shapes between the two groups. There was no difference in the PDR according to the level of experience of the endoscopy nurse. CONCLUSIONS: Endoscopy nurse participation as an additional observer during screening colonoscopy performed by second-year fellow increases the PDR; however, the level of experience of the nurse was not an important factor. PMID- 22844565 TI - Effect of a diet with unrestricted sodium on ascites in patients with hepatic cirrhosis. AB - BACKGROUND/AIMS: There has been debate on whether a sodium-restricted diet (SRD) should be used in cirrhotic patients with ascites in China in recent years. The purpose of this study was to compare the effect of sodium-restricted and unrestricted diets on plasma renin activity (PRA), renal blood flow (RBF) and ascites in patients with liver cirrhosis. METHODS: Two hundred cirrhotic patients with ascites were randomly divided into two groups (98 cases in the sodium unrestricted diet [SUD] group and 102 cases in the SRD group); 95 patients (96.94%) in the SUD group and 97 patients (95.1%) in the SRD group had post hepatitis B cirrhosis. RESULTS: Blood sodium and RBF were higher in SUD group than in SRD group (p<0.001), while PRA were significantly lower in SUD group than the SRD group 10 days after treatment (p<0.001). Renal impairment caused by low blood sodium was higher in SRD group than in SUD group (p<0.01). Ascites disappeared in higher proportion of patients in SUD group than in SRD group (p<0.001). CONCLUSIONS: SUD can increase the level of blood sodium and RBF, and be beneficial to diuresis and ascite reduction and disappearance. PMID- 22844564 TI - Increased incidence of endoscopic erosive esophagitis in solid organ transplant recipients. AB - BACKGROUND/AIMS: Solid organ transplant recipients frequently report gastrointestinal symptoms, especially heartburn or dyspepsia. However, the prevalence of endoscopic erosive esophagitis (EE) and associated risk factors after transplantation are unknown. The aim of this study was to determine whether there was a high incidence of endoscopic findings of EE in solid organ transplant recipients. METHODS: This retrospective case-control study included 256 of 3,152 solid organ transplant recipients who underwent sequential screening upper endoscopic examinations and an equal number of controls. RESULTS: Forty-four (17.2%) and 16 (6.2%) cases of EE were detected in the solid organ transplant and control groups, respectively (p<0.001). In the multivariate analysis, transplantation was significantly associated with EE (odds ratio [OR], 6.48; 95% confidence interval, 2.74 to 15.35). Factors such as old age (OR, 1.17), the presence of a hiatal hernia (OR, 5.84), an increased duration of immunosuppression (OR, 1.07), and the maintenance administration of mycophenolate mofetil (OR, 4.13) were independently associated with the occurrence of EE in the solid organ transplant recipients. CONCLUSIONS: A significant increase in the incidence of endoscopically detected EE was observed in solid organ transplant recipients. This increased incidence was associated with the type and duration of the immunosuppressive therapy. PMID- 22844566 TI - Comparative study of shear wave velocities using acoustic radiation force impulse technology in hepatocellular carcinoma: the extent of radiofrequency ablation. AB - BACKGROUND/AIMS: The purpose of this study was to assess the value of acoustic radiation force impulse (ARFI) for predicting the extent of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) by correlating the elasticity of HCC and peritumoral parenchyma (as measured by ARFI) with the extent of ablation determined by computed tomography (CT). METHODS: From September 2009 to June 2011, 158 patients underwent RFA ablation for HCC (single, <=3 cm). We evaluated the data of a total of 38 prospectively enrolled patients who underwent both ARFI imaging and contrast-enhanced CT after one session of 12 minutes of RFA without a change in needle position. The ARFI imaging indices, including the mean shear wave velocity (SWV) of HCC, mean SWV of the peritumoral parenchyma and tumor size, were evaluated to determine the statistical correlation with RFA extent after one session of 12 minutes of RFA. RESULTS: A stiffer liver parenchyma in patients with cirrhosis results in a smaller ablation zone. CONCLUSIONS: SWV of ARFI in liver parenchyma was well correlated with RFA extent. After evaluating the correlation between ARFI and RFA extent, we suggest that the SWV in liver parenchyma might be a non-invasive supplementary tool for predicting the extent of RFA. PMID- 22844567 TI - Effect of nonalcoholic Fatty liver disease on the development of type 2 diabetes in nonobese, nondiabetic korean men. AB - BACKGROUND/AIMS: We have a limited understanding of the effect of nonalcoholic fatty liver disease (NAFLD) on the development of type 2 diabetes. METHODS: The study subjects included male who had received biennial medical check-ups between 2005 and 2009 and who had been diagnosed with fatty liver disease. The subjects with sustained NAFLD (FL, n=107) and sustained non-NAFLD (NFL, n=1,054) were followed to determine the development of type 2 diabetes. RESULTS: In the FL group, there were more subjects with impaired fasting glucose (IFG), type 2 diabetes and high HOMA-IR than there were in the NFL group during the 5-year follow-up period (32.7 vs. 17.6%, 1.9 vs. 0.3%, 17.9 vs. 5.2% respectively, p<0.05). The FL group showed a higher risk than NFL group for abnormal glucose metabolism as determined using IFG (odds ratio [OR], 2.13; confidence interval [CI], 1.36 to 3.35), type 2 diabetes (OR, 7.63; 95% CI, 1.03 to 56.79) and high HOMA-IR (OR, 3.25; 95% CI, 1.79 to 5.91) and metabolic parameters such as body mass index (OR, 3.35; 95% CI, 1.87 to 6.02), triglyceride (OR, 3.05; 95% CI, 1.92 to 4.86) and fasting blood sugar (OR, 2.18; 95% CI, 1.39 to 3.41). CONCLUSIONS: Sustained NAFLD appears to be associated with an increased risk for the development of type 2 diabetes and deterioration of metabolic parameters in non obese, non-diabetic Korean men. PMID- 22844568 TI - Sodium iodide symporter and phosphatase and tensin homolog deleted on chromosome ten expression in cholangiocarcinoma analysis with clinicopathological parameters. AB - BACKGROUND/AIMS: This study was performed to investigate the correlation of sodium iodide symporter (NIS) expression with the functionality and loss of phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression in human cholangiocarcinoma (CCA). METHODS: Immunohistochemistry for the expression of NIS and PTEN was performed in 60 biopsy specimens of CCA. The clinicopathological parameters were retrospectively identified from medical records. The expression pattern of NIS and loss of PTEN expression were analyzed in association with the clinicopathological characteristics, including survival. RESULTS: Normal biliary trees displayed NIS expression, but hepatocytes did not. NIS expression was divided into two patterns: cytoplasmic and membranous. Fifty nine cases, all except for one case, displayed NIS expression in tumor cells. Twenty-two cases (33.3%) were mixed pattern, and 39 cases (65.05%) were cytoplasmic pattern; the pure membranous pattern was not noted. There was no association between the NIS expression pattern and clinicopathological parameters, including age, sex, differentiation grade, T stage and tumor, node, metastasis stage (p>0.05). The survival rates were similar among various NIS expression patterns. Normal hepatocytes and biliary trees exhibited PTEN expression in the nucleus and cytoplasm. CCA cells displayed nuclear staining. Thirty-six (60.0%) of 60 cases displayed a loss of PTEN expression. The loss of PTEN expression was observed in the advanced T-stage group (p=0.0036), but there was no association between the loss of PTEN expression and other clinicopathological parameters (p>0.05). No association between the loss of PTEN expression and survival was noted. CONCLUSIONS: NIS is expressed in most types of human CCA. The expression pattern suggests a role in cancer development. PTEN loss expression is common in the context of human CCA, especially in the advanced T stage. PMID- 22844569 TI - Involvement of nuclear factor kappa B in high-fat diet-related pancreatic fibrosis in rats. AB - BACKGROUND/AIMS: High-fat diets contribute to pancreatic fibrogenesis, but the pathogenesis remains unclear. This study investigated the role of nuclear factor kappa B (NF-kappaB) in high-fat diet-induced pancreatic fibrosis in rats. METHODS: Male Wistar rats were fed a high-fat diet or standard normal chow for 20 weeks. Pancreatic fibrosis was determined by Sirius red staining. Immunohistochemical staining, reverse transcription-polymerase chain reaction and Western blotting were used to identify NF-kappaB-associated genes or protein expressions. RESULTS: Inflammation, fat deposition, pancreatic stellate cell activation and fibrosis were observed in the pancreases of the high-fat diet group. NF-kappaB subunit p65 (NF-kappaB/p65) expression was localized to the nucleus, and intercellular adhesion molecule 1 (ICAM-1) was over-expressed. Pancreatic gene expression levels of NF-kappaB/p65, ICAM-1 and tumor necrosis factor alpha were all elevated significantly in rats fed a high-fat diet compared with control rats. Western blotting also revealed significantly increased levels of ICAM-1 and nuclear NF-kappaB/p65 in rats fed high-fat diets comparison with control rats. CONCLUSIONS: NF-kappaB is involved in high-fat diet-related pancreatic fibrosis. PMID- 22844570 TI - Solitary synchronous metastatic gastric cancer arising from t1b renal cell carcinoma: a case report and systematic review. AB - Metastasis to the stomach from renal cell carcinoma (RCC) is extremely rare. Usually, gastric metastasis seems to be a late event in patients with RCC and is accompanied by disseminated tumor spread to other organs. Solitary synchronous gastric metastasis from small, localized RCC has rarely been reported. We report a case of 79-year-old man with synchronous gastric metastasis presenting with a single erosive lesion from pT1 RCC. The patient underwent radical nephrectomy and endoscopic resection for metastatic gastric cancer. The resected specimen showed an ill-defined tumor, approximately 0.6 cm long, with a clear resection margin. The morphologic features of the tumor cells were consistent with those of metastatic RCC of the clear cell type. At 6 months's follow-up, the patient did not show local recurrence or additional metastasis on upper endoscopy and computed tomography scan. PMID- 22844571 TI - Carcinosarcoma in the cecum. AB - Carcinosarcoma of the colon is rare. Seventeen cases have been reported in the English literature. Most cases occurred in the left side of the colon. Indeed, there is only one reported case of cecal carcinosarcoma. Carcinosarcoma has a tendency to distantly metastasize and shows dismal prognosis. We report a case of carcinosarcoma in the cecum and review the literature describing colonic carcinosarcoma. PMID- 22844572 TI - Simultaneous Duodenal Metal Stent Placement and EUS-Guided Choledochoduodenostomy for Unresectable Pancreatic Cancer. AB - Patients with pancreatic cancer frequently suffer from both biliary and duodenal obstruction. For such patients, both biliary and duodenal self-expandable metal stent placement is necessary to palliate their symptoms, but it was difficult to cross two metal stents. Recently, endoscopic ultrasonography-guided choledochoduodenostomy (EUS-CDS) was reported to be effective for patients with an inaccessible papilla. We report two cases of pancreatic cancer with both biliary and duodenal obstructions treated successfully with simultaneous duodenal metal stent placement and EUS-CDS. The first case was a 74-year-old man with pancreatic cancer. Duodenoscopy revealed that papilla had been invaded with tumor and duodenography showed severe stenosis in the horizontal portion. After a duodenal uncovered metal stent was placed across the duodenal stricture, EUS-CDS was performed. The second case was a 63-year-old man who previously had a covered metal stent placed for malignant biliary obstruction. After removing the previously placed metal stent, EUS-CDS was performed. Then, a duodenal covered metal stent was placed across the duodenal stenosis. Both patients could tolerate a regular diet and did not suffer from stent occlusion. EUS-CDS combined with duodenal metal stent placement may be an ideal treatment strategy in patients with pancreatic cancer with both duodenal and biliary malignant obstruction. PMID- 22844573 TI - An unusual cause of acute pancreatitis: annular pancreas and papillary opening of the cystic duct. PMID- 22844574 TI - Managing and Querying Whole Slide Images. AB - High-resolution pathology images provide rich information about the morphological and functional characteristics of biological systems, and are transforming the field of pathology into a new era. To facilitate the use of digital pathology imaging for biomedical research and clinical diagnosis, it is essential to manage and query both whole slide images (WSI) and analytical results generated from images, such as annotations made by humans and computed features and classifications made by computer algorithms. There are unique requirements on modeling, managing and querying whole slide images, including compatibility with standards, scalability, support of image queries at multiple granularities, and support of integrated queries between images and derived results from the images. In this paper, we present our work on developing the Pathology Image Database System (PIDB), which is a standard oriented image database to support retrieval of images, tiles, regions and analytical results, image visualization and experiment management through a unified interface and architecture. The system is deployed for managing and querying whole slide images for In Silico brain tumor studies at Emory University. PIDB is generic and open source, and can be easily used to support other biomedical research projects. It has the potential to be integrated into a Picture Archiving and Communications System (PACS) with powerful query capabilities to support pathology imaging. PMID- 22844575 TI - A Clinical Database-Driven Approach to Decision Support: Predicting Mortality Among Patients with Acute Kidney Injury. AB - In exploring an approach to decision support based on information extracted from a clinical database, we developed mortality prediction models of intensive care unit (ICU) patients who had acute kidney injury (AKI) and compared them against the Simplified Acute Physiology Score (SAPS). We used MIMIC, a public de identified database of ICU patients admitted to Beth Israel Deaconess Medical Center, and identified 1400 patients with an ICD9 diagnosis of AKI and who had an ICU stay > 3 days. Multivariate regression models were built using the SAPS variables from the first 72 hours of ICU admission. All the models developed on the training set performed better than SAPS (AUC = 0.64, Hosmer-Lemeshow p < 0.001) on an unseen test set; the best model had an AUC = 0.74 and Hosmer Lemeshow p = 0.53. These findings suggest that local customized modeling might provide more accurate predictions. This could be the first step towards an envisioned individualized point-of-care probabilistic modeling using one's clinical database. PMID- 22844576 TI - Photoacoustic spectroscopy of beta-hematin. AB - Malaria affects over 200 million individuals annually, resulting in 800,000 fatalities. Current tests use blood smears and can only detect the disease when 0.1-1% of blood cells are infected. We are investigating the use of photoacoustic flowmetry to sense as few as one infected cell among 10 million or more normal blood cells, thus diagnosing infection before patients become symptomatic. Photoacoustic flowmetry is similar to conventional flow cytometry, except that rare cells are targeted by nanosecond laser pulses to induce ultrasonic responses. This system has been used to detect single melanoma cells in 10 ml of blood. Our objective is to apply photoacoustic flowmetry to detection of the malaria pigment hemozoin, which is a byproduct of parasite-digested hemoglobin in the blood. However, hemozoin is difficult to purify in quantities greater than a milligram, so a synthetic analog, known as beta-hematin was derived from porcine haemin. The specific purpose of this study is to establish the efficacy of using beta-hematin, rather than hemozoin, for photoacoustic measurements. We characterized beta-hematin using UV-vis spectroscopy, TEM, and FTIR, then tested the effects of laser irradiation on the synthetic product. We finally determined its absorption spectrum using photoacoustic excitation. UV-vis spectroscopy verified that beta-hematin was distinctly different from its precursor. TEM analysis confirmed its previously established nanorod shape, and comparison of the FTIR results with published spectroscopy data showed that our product had the distinctive absorbance peaks at 1661 and 1206 cm(-1). Also, our research indicated that prolonged irradiation dramatically alters the physical and optical properties of the beta-hematin, resulting in increased absorption at shorter wavelengths. Nevertheless, the photoacoustic absorption spectrum mimicked that generated by UV-vis spectroscopy, which confirms the accuracy of the photoacoustic method and strongly suggests that photoacoustic flowmetry may be used as a tool for diagnosis of malaria infection. PMID- 22844577 TI - Concise Total Synthesis of (+)-Gliocladins B and C. AB - The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel-Crafts based strategy to provide an efficient multigram-scale access to the C3-(3' indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C. PMID- 22844578 TI - Successful cryopreservation of human ovarian cortex tissues using supercooling. AB - The development of new method to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life (QOL) of female cancer patients. Here we show novel cryopreservation method of human ovarian cortex tissues by using supercooling (S.C.) procedure. Our method will be helpful in order to preserve fertility of female cancer patients. PMID- 22844579 TI - Gas-tight triblock-copolymer membranes are converted to CO2 permeable by insertion of plant aquaporins. AB - We demonstrate that membranes consisting of certain triblock-copolymers were tight for CO2. Using a novel approach, we provide evidence for aquaporin facilitated CO2 diffusion. Plant aquaporins obtained from heterologous expression were inserted into triblock copolymer membranes. These were employed to separate a chamber with a solution maintaining high CO2 concentrations from one with depleted CO2 concentrations. CO2 diffusion was detected by measuring the pH change resulting from membrane CO2 diffusion from one chamber to the other. An up to 21 fold increase in diffusion rate was determined. Besides the supply of this proof of principle, we could provide additional arguments in favour of protein facilitated CO2 diffusion to the vivid on-going debate about the principles of membrane gas diffusion in living cells. PMID- 22844581 TI - A prospective study of in-utero exposure to magnetic fields and the risk of childhood obesity. AB - We conducted a prospective study to examine whether in-utero exposure to magnetic fields (MFs) increases the risk of childhood obesity. Participating women carried a meter measuring MF levels during pregnancy and 733 of their children were followed up to 13 years to collect clinically recorded information on growth patterns with 33 weight measurements per child on average. Prenatal exposure to high MF level was associated with increased risk of being obese in offspring than those with lower MF level (odds ratio = 1.69, 95% confidence interval: 1.01 2.84). The association demonstrated a dose-response relationship and was stronger (more than 2.3 fold increased risk) among children who were followed up to the end of the study. The association existed only for persistent obesity, but not for transitory (unlikely) obesity. Maternal exposure to high MF during pregnancy may be a new and previously unknown factor contributing to the world-wide epidemic of childhood obesity/overweight. PMID- 22844580 TI - Altered death receptor signaling promotes epithelial-to-mesenchymal transition and acquired chemoresistance. AB - Altered death receptor signaling and resistance to subsequent apoptosis is an important clinical resistance mechanism. Here, we investigated the role of death receptor resistance in breast cancer progression. Resistance of the estrogen receptor alpha (ER)-positive, chemosensitive MCF7 breast cancer cell line to tumor necrosis factor (TNF) was associated with loss of ER expression and a multi drug resistant phenotype. Changes in three major pathways were involved in this transition to a multidrug resistance phenotype: ER, Death Receptor and epithelial to mesenchymal transition (EMT). Resistant cells exhibited altered ER signaling, resulting in decreased ER target gene expression. The death receptor pathway was significantly altered, blocking extrinsic apoptosis and increasing NF-kappaB survival signaling. TNF resistance promoted EMT changes, resulting in a more aggressive phenotype. This first report identifying specific mechanisms underlying acquired resistance to TNF could lead to a better understanding of the progression of breast cancer in response to chemotherapy treatment. PMID- 22844582 TI - Novel agents in Waldenstrom Macroglobulinemia. AB - Waldenstrom's Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is considered an incurable disease, with an overall median survival of only 5-6 years. The success of targeted therapy in multiple myeloma (MM) has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias WM, both in the preclinical settings and as part of clinical trials. Among therapeutical options, first-line therapies have been based on single-agent or combination regimens with alkylator agents, nucleoside analogues, and the monoclonal antibody anti-CD20. Based on the understanding of the complex interaction between tumor cells and bone marrow microenvironment and the signaling pathways that are deregulated in WM pathogenesis, a number of novel therapeutic agents are now available; and demonstrated significant efficacy in WM. The range of the ORR to these novel agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as LBH589, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. This review will mainly focus on those novel agent that entered clinical trial for the treatment of WM. PMID- 22844583 TI - Cell Trafficking in Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder characterized by both circulating peripheral disease as well as involvement of the lymph nodes and bone marrow. Increasing evidence suggests that the stromal microenvironment provides anti-apoptotic and pro-survival signals to CLL cells, and may contribute significantly to resistance to a wide variety of treatments. Our understanding of the complex interactions involved in CLL cell trafficking continues to grow. Chemokines and corresponding chemokine receptors are key factors for organizing CLL cell trafficking and homing and the complex cellular interactions between CLL and accessory cells. Important chemokines include CCL3, CCL4, and CCL22, which are released by CLL cells, and CXCL12, CXCL13, CXCL9, 10, 11, CCL 19, and CCL21, which are constitutively secreted by various stromal cells. Integrins such as VLA-4 (CD49d) as well as selectins and CD44 also likely play a role in directing CLL cell migration within the tissue microenvironments. Data are also emerging that other molecules such as MMP-9 and cytoskeletal proteins also contribute to CLL cell trafficking. Though this interplay is complex, it is critical that we improve our understanding of CLL cell trafficking to facilitate the development of novel therapies that target these pathways. Several drugs in clinical development, such as CXCR4 antagonists and PI3K, Btk, and Syk inhibitors appear to modulate CLL cell trafficking and CLL-stroma interactions. Here, we review the current understanding of the molecular interactions that underlie CLL cell trafficking and we highlight some of the promising approaches underway to target these pathways therapeutically in CLL. PMID- 22844584 TI - Effects of Telmisartan with Hydrochlorothiazide versus Valsartan with Hydrochlorothiazide in Patients with Moderate-to-Severe Hypertension. AB - Combination therapy is recommended for patients with blood pressure (BP) significantly above goal by recent consensus guidelines around the globe. The use of angiotensin II receptor blockers (ARBs) alone or in combination with a thiazide diuretic is a preferred treatment strategy due to both efficacy and safety considerations. However, there are few data known about the benefits of ARB-diuretic combination therapy in patients with moderate-to-severe hypertension. We performed a subanalysis from two large clinical trials that compared the antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg, both combined with hydrochlorothiazide (HCTZ) 25 mg in a subpopulation of 725 patients with moderate-to-severe hypertension (systolic BP SBP >= 160 mm Hg). Treatment with telmisartan-HCTZ induced significantly greater reductions in BP ( 31.1/-18.3 mm Hg) than valsartan-HCTZ (-28.4/-16.3 mm Hg; SBP P = 0.0265, diastolic BP P = 0.0041). More patients receiving the telmisartan combination achieved a BP goal < 140/90 mm Hg than those receiving valsartan-HCTZ. There were similar safety and tolerability data for the two active treatment groups. These findings support the use of longer-acting ARBs combined with higher doses of thiazide diuretic to improve BP control in patients with moderate-to-severe hypertension. PMID- 22844585 TI - Determinants of childhood obesity in representative sample of children in north East of iran. AB - Childhood obesity has become, a global public health problem, and epidemiological studies are important to identify its determinants in different populations. This study aimed to investigate factors associated with obesity in a representative sample of children in Neishabour, Iran. This study was conducted among 1500 randomly selected 6-12-year-old students from urban areas of Neishabour, northeast of Iran. Then, through a case-control study, 114 obese (BMI >= 95th percentile of Iranian reference) children were selected as the case group and were compared with 102 controls (15th <= BMI < 85th percentile). Factors suggested to be associated with weight status were investigated, for example, parental obesity, child physical activity levels, socio-economic status (SES), and so forth. The analysis was conducted using univariate and multivariate logistic regression (MLR) in SPSS version 16. In univariate logistic regression model, birth weight, birth order, family extension, TV watching, sleep duration, physical activity, parents' job, parents' education, parental obesity history, and SES were significantly associated with children's obesity. After MLR analysis, physical activity and parental obesity history remained statistically significant in the model. Our findings showed that physical activity and parental obesity history are the most important determinants for childhood obesity in our population. This finding should be considered in implementation of preventive interventions. PMID- 22844586 TI - Ultrasound applications in critical care medicine. PMID- 22844587 TI - Late-life depressive symptoms, religiousness, and mood in the last week of life. AB - Aim of the current study is to examine whether previous depressive symptoms modify possible effects of religiousness on mood in the last week of life. After death interviews with proxy respondents of deceased sample members of the Longitudinal Aging Study Amsterdam provided information on depressed mood in the last week of life, as well as on the presence of a sense of peace with the approaching end of life. Other characteristics were derived from interviews with the sample members when still alive. Significant interactions were identified between measures of religiousness and previous depressive symptoms (CES-D scores) in their associations with mood in the last week of life. Among those with previous depressive symptoms, church-membership, church-attendance and salience of religion were associated with a greater likelihood of depressed mood in the last week of life. Among those without previous depressive symptoms, church attendance and salience of religion were associated with a higher likelihood of a sense of peace. For older adults in the last phase of life, supportive effects of religiousness were more or less expected. Fore those with recent depressive symptoms, however, religiousness might involve a component of existential doubt. PMID- 22844588 TI - Temperament, character, and adolescents' depressive symptoms: focusing on affect. AB - Positive (PA) and negative affect (NA) are two separate systems markers of subjective well-being and measures of the state depression (low PA combined with high NA). The present study investigated differences in temperament, character, locus of control, and depressive symptoms (sleep quality, stress, and lack of energy) between affective profiles in an adolescent sample. Participants (N = 304) were categorized into four affective profiles: "self-fulfilling" (high PA, low NA), "high affective" (high PA, high NA), "low affective" (low PA, low NA), and "self-destructive" (low PA, high NA). Personality was measured by the Temperament and Character Inventory and affective profiles by the Positive Affect and Negative Affect Schedule. The "self-fulfilling" profile was characterized by, compared to the other affective profiles, higher levels of sleep quality, less stress and more energy and also higher levels of persistence and a mature character (i.e., high scores in self-directedness and cooperativeness). "Self destructive" adolescents reported higher levels of external locus of control, high scores in harm avoidance and reward dependence combined with less mature character. The results identify the importance of character maturity in well being and suggest that depressive state can be positively influenced by promoting positive emotions which appears to be achieved by character development. PMID- 22844589 TI - The retrograde and retroperitoneal totally laparoscopic hysterectomy for endometrial cancer. AB - Introduction. We retrospectively report our experience with the utilization of an original procedure for total laparoscopic hysterectomy based on completely retrograde and retroperitoneal technique for surgical staging and treatment of the endometrial cancer. The surgical, financial, and oncological advantages are here discussed. Methods. The technique used here has been based on a combination of a retroperitoneal approach with a retrograde and lateral dissection of the bladder and retrograde culdotomy with variable resection of parametrium. No disposable instruments and no uterine manipulator were utilized. Results. Intraoperative and postoperative complications were observed in 10% of the cases overall. Operative time length and mean haemoglobin drop value results were 129 min and 125 mL, respectively. Most patients were dismissed on days 3-5 from the hospital. Seventy-eight percent of the patients were alive with no evidence of disease at mean followup of 49 months. Conclusions. Our original laparoscopic technique is based on a retroperitoneal approach in order to rapidly control main uterine vessels coagulation, constantly check the ureter, and eventually decide type and site of lymph nodes removal. This procedure has important cost saving implications and the avoidance of uterine manipulator is of matter in case such as these of uterine malignancy. PMID- 22844590 TI - Continuing care for mentally stable psychiatric patients in primary care: patients' preferences and views. AB - Objective. To investigate the preferences of psychiatric patients regarding attendance for their continuing mental health care once stable from a primary care setting as opposed to a specialized psychiatric service setting. Methods. 150 consecutive psychiatric patients attending outpatient review in a community mental health centre in Dublin were approached and asked to complete a semistructured questionnaire designed to assess the objectives of the study. Results. 145 patients completed the questionnaire giving a response rate of 97%. Ninety-eight patients (68%) preferred attending a specialized psychiatry service even when stabilised on their treatment. The common reason given by patients in this category was fear of substandard quality of psychiatric care from their general practitioners (GPs) (67 patients, 68.4%). Twenty-nine patients (20%) preferred to attend their GP for continuing mental health care. The reasons given by these patients included confidence in GPs, providing same level of care as psychiatrist for mental illness (18 patients or 62%), and the advantage of managing both mental and physical health by GPs (13 patients, 45%). Conclusion. Most patients who attend specialised psychiatric services preferred to continue attending specialized psychiatric services even if they become mentally stable than primary care, with most reasons revolving around fears of inadequate psychiatric care from GPs. PMID- 22844591 TI - Preparation and In Vivo Evaluation of Dichloro(1,2 Diaminocyclohexane)platinum(II)-Loaded Core Cross-Linked Polymer Micelles. AB - The therapeutic performance of oxaliplatin can be improved by incorporating the central cis-dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) motif into the core cross-linked block copolymer micelles. We describe here the preparation, cellular uptake, and in vivo evaluation of core cross-linked micelles loaded with DACHPt. Stable drug-loaded micelles were prepared at high drug loading (~25 w/w%) and displayed a considerably increased in vitro cytotoxicity compared to free oxaliplatin against A2780 ovarian cancer cells. The DACHPt-loaded micelle formulation was well tolerated in mice and exhibited improved antitumor activity than oxaliplatin alone in an ovarian tumor xenograft model. PMID- 22844592 TI - Understanding the mechanisms of proteinuria: therapeutic implications. AB - A large body of evidence indicates that proteinuria is a strong predictor of morbidity, a cause of inflammation, oxidative stress and progression of chronic kidney disease, and development of cardiovascular disease. The processes that lead to proteinuria are complex and involve factors such as glomerular hemodynamic, tubular absorption, and diffusion gradients. Alterations in various different molecular pathways and interactions may lead to the identical clinical end points of proteinuria and chronic kidney disease. Glomerular diseases include a wide range of immune and nonimmune insults that may target and thus damage some components of the glomerular filtration barrier. In many of these conditions, the renal visceral epithelial cell (podocyte) responds to injury along defined pathways, which may explain the resultant clinical and histological changes. The recent discovery of the molecular components of the slit diaphragm, specialized structure of podocyte-podocyte interaction, has been a major breakthrough in understanding the crucial role of the epithelial layer of the glomerular barrier and the pathogenesis of proteinuria. This paper provides an overview and update on the structure and function of the glomerular filtration barrier and the pathogenesis of proteinuria, highlighting the role of the podocyte in this setting. In addition, current antiproteinuric therapeutic approaches are briefly commented. PMID- 22844594 TI - High mass accuracy phosphopeptide identification using tandem mass spectra. AB - Phosphoproteomics is a powerful analytical platform for identification and quantification of phosphorylated peptides and assignment of phosphorylation sites. Bioinformatics tools to identify phosphorylated peptides from their tandem mass spectra and protein sequence databases are important part of phosphoproteomics. In this work, we discuss general informatics aspects of mass spectrometry-based phosphoproteomics. Some of the specifics of phosphopeptide identifications stem from the labile nature of phosphor groups and expanded peptide search space. Allowing for modifications of Ser, Thr, and Tyr residues exponentially increases effective database size. High mass resolution and accuracy measurements of precursor mass-to-charge ratios help to restrict the search space of candidate peptide sequences. The higher-order fragmentations of neutral loss ions enhance the fragment ion mass spectra of phosphorylated peptides. We show an example of a phosphopeptide identification where accounting for fragmentation from neutral loss species improves the identification scores in a database search algorithm by 50%. PMID- 22844593 TI - An overview of molecular mechanism of nephrotic syndrome. AB - Podocytopathies (minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS)) together with membranous nephropathy are the main causes of nephrotic syndrome. Some changes on the expression of nephrin, podocin, TGF-beta, and slit diaphragm components as well as transcription factors and transmembrane proteins have been demonstrated in podocytopathies. Considering the pathogenesis of proteinuria, some elucidations have been directed towards the involvement of epithelial-mesenchymal transition. Moreover, the usefulness of some markers such as TGF-beta1, nephrin, synaptopodin, dystroglycans, and malondialdehyde have been determined in the differentiation between MCD and FSGS. Experimental models and human samples indicated an essential role of autoantibodies in membranous glomerulonephritis, kidney damage, and proteinuria events. Megalin and phospholipase-A2-receptor have been described as antigens responsible for the formation of the subepithelial immune complexes and renal disease occurrence. In addition, the complement system seems to play a key role in basal membrane damage and in the development of proteinuria in membranous nephropathy. This paper focuses on the common molecular changes involved in the development of nephrotic proteinuria. PMID- 22844595 TI - Application of iTRAQ Reagents to Relatively Quantify the Reversible Redox State of Cysteine Residues. AB - Cysteines are one of the most rarely used amino acids, but when conserved in proteins they often play critical roles in structure, function, or regulation. Reversible cysteine modifications allow for potential redox regulation of proteins. Traditional measurement of the relative absolute quantity of a protein between two samples is not always necessarily proportional to the activity of the protein. We propose application of iTRAQ reagents in combination with a previous thiol selection method to relatively quantify the redox state of cysteines both within and between samples in a single analysis. Our method allows for the identification of the proteins, identification of redox-sensitive cysteines within proteins, and quantification of the redox status of individual cysteine containing peptides. As a proof of principle, we applied this technique to yeast alcohol dehydrogenase-1 exposed in vitro to H(2)O(2) and also in vivo to the complex proteome of the Gram-negative bacterium Bacillus subtilis. PMID- 22844596 TI - Biomarker Discovery of Pancreatic and Gastrointestinal Cancer by 2DICAL: 2 Dimensional Image-Converted Analysis of Liquid Chromatography and Mass Spectrometry. AB - Biomarkers tested by blood sample are of great use to clinicians as they provide useful information to aid an early and accurate diagnosis. Comprehensive "omics" studies are expected to facilitate the identification of such new biomarkers, and much research is being performed in this area. Our proteomics analysis system of 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL) has successfully identified several new blood biomarkers from the clinical blood samples of pancreatic and colorectal cancer patients. PMID- 22844597 TI - Length and PKA Dependence of Force Generation and Loaded Shortening in Porcine Cardiac Myocytes. AB - In healthy hearts, ventricular ejection is determined by three myofibrillar properties; force, force development rate, and rate of loaded shortening (i.e., power). The sarcomere length and PKA dependence of these mechanical properties were measured in porcine cardiac myocytes. Permeabilized myocytes were prepared from left ventricular free walls and myocyte preparations were calcium activated to yield ~50% maximal force after which isometric force was measured at varied sarcomere lengths. Porcine myocyte preparations exhibited two populations of length-tension relationships, one being shallower than the other. Moreover, myocytes with shallow length-tension relationships displayed steeper relationships following PKA. Sarcomere length-K(tr) relationships also were measured and K(tr) remained nearly constant over ~2.30 MUm to ~1.90 MUm and then increased at lengths below 1.90 MUm. Loaded-shortening and peak-normalized power output was similar at ~2.30 MUm and ~1.90 MUm even during activations with the same [Ca(2+)], implicating a myofibrillar mechanism that sustains myocyte power at lower preloads. PKA increased myocyte power and yielded greater shortening induced cooperative deactivation in myocytes, which likely provides a myofibrillar mechanism to assist ventricular relaxation. Overall, the bimodal distribution of myocyte length-tension relationships and the PKA-mediated changes in myocyte length-tension and power are likely important modulators of Frank Starling relationships in mammalian hearts. PMID- 22844598 TI - Plain Radiography May Be Safely Omitted for Selected Major Trauma Patients Undergoing Whole Body CT: Database Study. AB - Introduction. Whole body CT is being used increasingly in the primary survey of major trauma patients. We evaluated whether omitting plain films of the chest and pelvis in the primary survey was safe. We compared the probability of survival of patients and time to CT who had plain X-rays to those who did not. Method. We performed a database study on major trauma patients admitted between 2008 and 2010 using data from Trauma, Audit and Research Network (TARN) and our PACS system. We included adult major trauma patients who has an ISS of greater than 15 and underwent whole body CT. Results. 245 patients were included in the study. 44 (17.9%) did not undergo plain films. The median time to whole body CT from the time of admission was longer (47 minutes) in patients having plain films, than those who did not have plain films performed (30 minutes), P < 0.005. Mortality was increased in the group who received plain films, 9.5% compared to 4.5%, but this was not statistically significant (P = 0.77). Conclusion. We conclude that plain films may be safely omitted during the primary survey of selected major trauma patients. PMID- 22844599 TI - Prehospital care. PMID- 22844600 TI - Functional Cloning and Expression of the Schizophyllum commune Glucuronoyl Esterase Gene and Characterization of the Recombinant Enzyme. AB - The gene encoding Schizophyllum commune glucuronoyl esterase was identified in the scaffold 17 of the genome, containing two introns of 50 bp and 48 bp, with a transcript sequence of 1179 bp. The gene was synthesized and cloned into Pichia pastoris expression vector pGAPZalpha to achieve constitutive expression and secretion of the recombinant enzyme in soluble active form. The purified protein was 53 kD with glycosylation and had an acidic pI of 3.7. Activity analysis on several uronic acids and their derivatives suggests that the enzyme recognized only esters of 4-O-methyl-D-glucuronic acid derivatives, even with a 4 nitrophenyl aglycon but did not hydrolyze the ester of D-galacturonic acid. The kinetic values were K(m) 0.25 mM, V(max) 16.3 MUM.min(-1), and k(cat) 9.27 s(-1) with 4-nitrophenyl 2-O-(methyl 4-O-methyl-alpha-D-glucopyranosyluronate)-beta-D xylopyranoside as the substrate. PMID- 22844601 TI - Handling of radical prostatectomy specimens: total embedding with large-format histology. AB - A problem when handling radical prostatectomy specimens (RPS) is that cancer is often not visible at gross examination, and the tumor extent is always underestimated by the naked eye. The challenge is increased further by the fact that prostate cancer is a notoriously multifocal and heterogeneous tumor. For the pathologist, the safest method to avoid undersampling of cancer is evidently that the entire prostate is submitted. Even though whole mounts of sections from RPS appear not to be superior to sections from standard blocks in detecting adverse pathological features, their use has the great advantage of displaying the architecture of the prostate and the identification and location of tumour nodules more clearly, with particular reference to the index tumour; further, it is easier to compare the pathological findings with those obtained from digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate biopsies. We are in favour of complete sampling of the RPS examined with the whole mount technique. There are reasons in favour and a few drawbacks. Its implementation does not require an additional amount of work from the technicians' side. It gives further clinical significance to our work of uropathologists. PMID- 22844603 TI - Diagnostic testing for degenerative disc disease. AB - The diagnostic of degenerative disc disease should be reached with the help of various diagnostic studies. This article briefly review the information gained by the following tests: radiographs, computed tomography, magnetic resonance, and discography. The article explains how each modality provides a piece of the diagnostic puzzle and how discography confirms the origin of the patient's pain. PMID- 22844602 TI - 2D MR Spectroscopy Combined with Prior-Knowledge Fitting Is Sensitive to HCV Associated Cerebral Metabolic Abnormalities. AB - There is an evidence of neurocognitive dysfunction even in the absence of advanced liver disease in chronic hepatitis C virus (HCV) infection. Brain metabolism has been investigated non-invasively using one-dimensional (1D) in vivo Magnetic Resonance Spectroscopy (MRS) over three decades. Even though highly concentrated cerebral metabolites (N-acetylaspartate, creatine, choline, glutamate/glutamine, myo-inositol) have been detected using MRS, other metabolites at low concentrations (~1-3 mM or less) including glutathione, aspartate and GABA are quite difficult to observe using 1D MRS. In order to resolve overlapping resonances from a number of metabolites, a remedy is to add a second spectral dimension to the existing 1D MRS. Localized two-dimensional correlated spectroscopy (L-COSY) has been developed over the last decade to enhance the spectral dispersion by using the second spectral dimension. We have evaluated this L-COSY technique in the frontal white/gray matter regions of 14 HCV+ (mean age of 56.2 years) and 14 HCV- (mean age of 46.6 years) subjects. Our preliminary results showed significantly increased myo-inositol and glutathione in the HCV+ compared to the HCV- subjects. Hence, glutathione and myo-inositol should be considered along with other metabolites as important markers of inflammation. PMID- 22844604 TI - Advances in development of countermeasures for potential biothreat agents. PMID- 22844605 TI - A Comparative Study of the Removal of Smear Layer by Two Endodontic Irrigants and Nd:YAG Laser: A Scanning Electron Microscopic Study. AB - The aim of this study was to compare the effect of 17% EDTA, 5% maleic acid, and Nd:YAG laser on smear layer removal by SEM. Eighty single-rooted teeth were divided into three groups of 25 according to the final procedure for smear layer removal: irrigation by 17% EDTA or 5% maleic acid or Nd:YAG laser irradiation. The other five teeth was used as control. Roots were sectioned into buccal and lingual parts, and smear layer presence was recorded in the coronal, middle, and apical thirds under SEM. Data were analyzed by Kruskal-Wallis, Mann-Whitney, Friedman, and Wilcoxon tests. There was no significant difference between smear layer removal of 17% EDTA and 5% maleic acid. Nd:YAG laser showed the least effect significantly. The coronal part of samples was significantly cleaner than the middle, and the middle was cleaner than the apical section. 17% EDTA and 5% maleic acid were more effective in smear layer removal compared to Nd:YAG laser. PMID- 22844606 TI - Lipid droplet binding of hepatitis C virus core protein genotype 3. AB - Background. Hepatitis C virus (HCV) genotype 3 is known to cause steatosis (fatty liver) that is more frequent and severe than other genotypes. We previously identified sequence elements within genotype 3 HCV Core domain 3 that were sufficient for lipid accumulation. Aims. We examined various genotype 3 Core domains for lipid droplet localization and compared the lipid droplet binding regions of domain 2 with a genotype 1 isolate. Methods. We generated HCV Core domain constructs fused with green fluorescent protein and performed immunofluorescence to visualize lipid droplets. Results. Constructs containing HCV Core domain 2 are appropriately localized to lipid droplets with varying degrees of efficiency. When compared to genotype 1, there are polymorphisms within domain 2 that do not appear to alter lipid droplet localization. Conclusions. In summary, the differences in a steatosis-associated HCV Core genotype 3 isolate do not appear to involve altered lipid droplet localization. PMID- 22844608 TI - A method for the in vivo measurement of zebrafish tissue neutrophil lifespan. AB - Neutrophil function is thought to be regulated, in large part, by limitation of lifespan by apoptosis. A number of studies suggest that circulating neutrophils have a half-life of approximately 6 hours, although contradictory evidence exists. Measuring tissue neutrophil lifespan, however, is more problematic. It is thought that tissue neutrophils survive longer, perhaps with a half-life in the order of 3-5 days, but this has never been directly measured. Zebrafish are an emerging model organism, with several advantages for the study of vertebrate immunity. In zebrafish, neutrophils constitutively assume tissue locations allowing their direct study in vivo. Using a transgenic approach, neutrophils were labelled with a photoconvertible pigment, Kaede. Photoconversion parameters were optimised and the stability of the Kaede confirmed. Individual neutrophils were photoconverted by scanning a confocal 405 nm laser specifically over each cell and their survival monitored for 48 hours, revealing an in vivo half-life for zebrafish tissue neutrophils of around 120 hours (117.7 hrs, 95% CI 95.67 157.8). Laser energy did not extend neutrophil lifespan, and we conclude that this represents a lower bound for the lifespan of a resting tissue neutrophil in the developing zebrafish larva. This is the first direct measurement of the lifespan of an in vivo tissue neutrophil. PMID- 22844607 TI - Current trends in the management of gastroesophageal reflux disease: a review. AB - Gastroesophageal reflux disease (GERD) is a chronic disorder of the upper gastrointestinal tract with global distribution. The incidence is on the increase in different parts of the world. In the last 30 to 40 years, research findings have given rise to a more robust understanding of its pathophysiology, clinical presentation, and management. The current definition of GERD (The Montreal definition, 2006) is not only symptom-based and patient-driven, but also encompasses esophageal and extraesophageal manifestations of the disease. The implication is that the disease can be confidently diagnosed based on symptoms alone. Nonerosive reflux disease (NERD) remains the predominant form of GERD. Current thinking is that NERD and erosive reflux disease (ERD) are distinct phenotypes of GERD rather than the old concept which regarded them as components of a disease spectrum. Non erosive reflux disease is a very heterogeneous group with significant overlap with other functional gastrointestinal disorders. There is no gold standard for the diagnosis of GERD. Esophageal pH monitoring and intraluminal impedance monitoring have thrown some light on the heterogeneity of NERD. A substantial proportion of GERD patients continue to have symptoms despite optimal PPI therapy, and this has necessitated research into the development of new drugs. Several safety concerns have been raised about chronic use of proton pump inhibitors but these are yet to be substantiated in controlled studies. The debate about efficacy of long-term medical treatment compared to surgery continues, however, recent data indicate that modern surgical techniques and long term PPI therapy have comparable efficacy. These and other issues are subjects of further research. PMID- 22844609 TI - Vaginal use of Ibuprofen isobutanolammonium (ginenorm): efficacy, tolerability, and pharmacokinetic data: a review of available data. AB - Vaginal infection and inflammation with or without vulvar involvement are very common gynecologicaly clinical conditions associated with morbidity and reduced quality of life. Vaginal infections are commonly treated with causal antimicrobial treatments. In addition to specific antimicrobial treatment, anti inflammatory therapy, both systemic or topical (vaginal douche), could be useful in the integrated treatment approach of these conditions reducing symptoms and speeding up the recovery in vulvovaginitis. Ibuprofen is a well-known effective and well-tolerated anti-COX (anti-COX1 and COX2) compound. In addition, several in vitro studies suggest that Ibuprofen shares antimicrobial and antifungal activities. Ibuprofen isobutanolammonium (Ib-isb) (Ginenorm) is a soluble salt from formulation suitable for external and intravaginal use. This salt completely dissociates in aqueous solution. Ib-isob is available in sachet and vaginal douche pharmaceutical formulations. Clinical efficacy of Ib-isob has been documented in 10 clinical studies (6 controlled and 4 open trials) which have enrolled in total 399 women with vulvovaginitis. The six controlled clinical trials were performed both versus placebo (2 studies) or versus active comparators such as benzydamine. In these studied, Ib-Isb has been used in general for 7 consecutive days with a twice application daily regimen at the dose of 1 g per application. Topical application of Ib-isob induced a marked and rapid reduction in signs (erythema, oedema) and symptoms (itching and burning sensation) of vulvovaginitis. In head-to-head studies carried out in comparison with other topical products, Ib-isob induced a more rapid reduction in both subjective and objective symptoms. In particular a remarkable significant improvement of all the symptoms has been observed in the group of patients treated with Ib-isob in comparison with women receiving benzydamine. The clinical data available for Ib-isob confirm that this salt, specifically developed for gynecological use, is effective and well tolerated in vulvovaginal inflammation conditions. Efficacy of Ib-isob was greater in comparison with commonly used products. Ibuprofen-isob may be considered a useful and effective tool for the topical treatment of nonspecific vaginal diseases. PMID- 22844610 TI - Cutaneous T-cell lymphoma in asians. AB - Cutaneous T-cell lymphoma describes a heterogeneous group of neoplasms of skin homing T cells that vary considerably in clinical presentation, histologic appearance, immunophenotype, and prognosis. This paper addresses the cutaneous T cell lymphoma in Asians with respect to clinical-epidemiologic and histopathological features. Compared with Western countries, Asia usually has higher rates of cutaneous T-cell lymphomas such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like lymphoma, subcutaneous panniculitis T-cell lymphoma, and adult T-cell leukemia/lymphoma and lower rates of cutaneous B-cell lymphomas. Among many variants of mycosis fungoides, hypopigmented lesions, pityriasis lichenoides-like lesions, and ichthyosiform lesions are more prevalent in Asia than in the West. Adult T-cell leukemia/lymphoma is endemic in southwestern Japan especially in the Kyushu island. The clinicopathologic characteristics of cutaneous lymphoma vary according to geography, and this may be ascribed to genetic and environmental etiologic factors. PMID- 22844611 TI - Serum levels of fetal antigen 1 in extreme nutritional States. AB - Objective. Recent data suggest that fetal antigen (FA1) is linked to disorders of body weight. Thus, we measured FA1 serum levels in two extreme nutritional states of morbid obesity (MO) and anorexia nervosa (AN) and monitored its response to weight changes. Design. FA1 and insulin serum concentrations were assessed in a cross-sectional study design at defined time points after gastric restrictive surgery for 25 MO patients and 15 women with AN. Results. Absolute FA1 serum levels were within the assay normal range and were not different between the groups at baseline. However, the ratio of FA1/BMI was significantly higher in AN. FA1 was inversely correlated with BMI before and after weight change in AN, but not in MO patients. In addition, MO patients displayed a significant concomitant decrease of FA1 and insulin with the first 25% of EWL, while in AN patients a significant increase of FA1 was observed in association with weight gain. Conclusion. FA1 is a sensitive indicator of metabolic adaptation during weight change. While FA1 serum levels in humans generally do not correlate with BMI, our results suggest that changes in FA1 serum levels reflect changes in adipose tissue turnover. PMID- 22844612 TI - Interaction of herbs and glibenclamide: a review. AB - Herbs and herbal products are considered to be safer and people mix it often with the oral hypoglycemic agent in diabetes therapy. But numerous reports say that every combination of herbs and drugs is not safe. Some combinations may be beneficial and some may be harmful also. So before taking any herbal remedies with oral hypoglycemic agent, patient should consult physician. In this paper we are summarizing the reports available on the interaction of herbal remedies to one of the oral hypoglycemic agents (glibenclamide) and categorizing the effect of the combination is beneficial and harmful. PMID- 22844613 TI - Military wives' transition and coping: deployment and the return home. AB - The objective of this qualitative study is to explore the experiences of wives of deployed soldiers. Semistructured interviews were used to answer the research questions. Meleis' Transitions Theory was used to guide the understanding of the wives' experiences. Phase One: news of deployment, property of awareness, themes of emotional chaos and making preparations. Phase Two: during deployment, property of engagement, themes of taking the reins and placing focus elsewhere, along with the property of change and difference, with themes of emotional and physical turmoil, staying strong, and reaching out. Phase Three: after deployment, property of time span, themes of absence makes the heart grow fonder and reestablishing roles. The study concluded that the wife often feels forgotten during deployment. Nurses can give better care by understanding how the different phases of deployment and separation affect the wife's coping ability and her physical and emotional health. PMID- 22844614 TI - Sleep telemedicine: a survey study of patient preferences. AB - Telemedicine is an increasingly recognized option for cost-effective management of chronic conditions. We surveyed Sleep Clinic patients about their experiences and preferences regarding different forms of telemedicine. Adult Sleep Clinic patients seen between 2009 and 2011 received a brief survey either by postal mail (n = 156) or, for those with an available email address, electronically (n = 282). The overall response rate was 28.1% (n = 123 responses), with email response rates being higher than postal mail responses. The most commonly reported barriers to in-person physician visits were parking cost (44%), time away from work/school (34%), and cost of gas (26%). Whereas 89% of respondents indicated using telephone and 55% of respondents indicated using email to communicate with providers, none reported experience with video telemedicine. Despite this lack of experience, over 60% reported feeling comfortable or willing to try it. Of those who were uncomfortable about video telemedicine, the two main reasons were that in-person visits feel more natural (48%) and that the doctor might need to perform an examination (24%). More than half of respondents reported willingness to pay a copay for a video visit. Video telemedicine represents a feasible option for chronic sleep disorders management. PMID- 22844615 TI - The use of nurse checklists in a bedside computer-based information system to focus on avoiding secondary insults in neurointensive care. AB - The feasibility and accuracy of using checklists after every working shift in a bedside computer-based information system for documentation of secondary insults in the neurointensive care unit were evaluated. The ultimate goal was to get maximal attention to avoid secondary insults. Feasibility was investigated by assessing if the checklists were filled in as prescribed. Accuracy was evaluated by comparing the checklists with recorded minute-by-minute monitoring data for intracranial pressure-ICP, cerebral perfusion pressure CPP, systolic blood pressure SBP, and temperature. The total number of checklist assessments was 2,184. In 85% of the shifts, the checklists were filled in. There was significantly longer duration of monitoring time at insult level when Yes was filled in regarding ICP (mean 134 versus 30 min), CPP (mean 125 versus 26 min) and temperature (mean 315 versus 120 min). When a secondary insult was defined as >5% of monitoring time spent at insult level, the sensitivity/specificity for the checklist assessments was 31%/100% for ICP, 38%/99% for CPP, and 66%/88% for temperature. Checklists were feasible and appeared relatively accurate. Checklists may elevate the alertness for avoiding secondary insults and help in the evaluation of the patients. This concept may be the next step towards tomorrow critical care. PMID- 22844616 TI - Effect of Acute Mental Stress on Heart Rate and QT Variability in Postmyocardial Infarction Patients. AB - Emotionally charged events are associated with an increased risk of sudden cardiac death (SCD). In this study we assessed RR and QT variability index (QTVI) at baseline during anger recall test (AR). We calculated QTVI from a 5-min ECG recording and from a 10-beats segment around the presumed maximum sympathetic activation in thirty post-myocardial infarction patients under beta-blocker therapy and 10 controls underwent. In all groups, the low-frequency component of RR and SBP increased during AR. In all recordings, the QTVI calculated on a 5-min ECG recording and the QTVI(10 beats) were higher in patients than in controls (P < 0.05). The QTVI during AR remained unchanged from baseline within each group. Conversely, during AR, the QTVI(10 beats) in controls diminished significantly (P < 0.05) from baseline whereas in patients remained unchanged. The inability to buffer an acute stress-induced increase in sympathetic activity could explain why events charged with acute stress are associated with an increased risk of ventricular arrhythmias in this setting of patients and support the role of cognitive behavior stress management strategies. PMID- 22844617 TI - Correlates of morbidity and mortality in severe necrotizing pancreatitis. AB - Acute severe pancreatitis is associated with a high morbidity and mortality and frequently is accompanied by underlying pancreatic parenchymal necrosis. Patients with pancreatic necrosis must be identified, because the morbidity and mortality rate in this subgroup is much higher. Our objective was to compare the clinical outcomes of these patients based on the degree of pancreatic necrosis. A total of 35 patients were noted to have pancreatic necrosis. These were divided into 2 groups based on extent of necrosis: group A had less than 50% necrosis and group B had more than 50% necrosis. The rate of mortality (5% versus 40%) was significantly higher in group B. The rate of organ dysfunction also rose along with the rates of other morbidities and variables that were related to a patient's hospital stay. Only APACHE II significantly correlated with the degree of necrosis, wherein the chances of substantial necrosis rose by 20% with each unit increase of APACHE II score. APACHE II Score could be employed and studied further prospectively to help identify patients with pancreatic necrosis. PMID- 22844618 TI - Predictors of hypocalcemia after thyroidectomy: results from the nationwide inpatient sample. AB - Hypocalcemia is a common complication following thyroidectomy. However, the incidence of postoperative hypocalcemia varies widely in the literature, and factors associated with hypocalcemia after thyroid surgery are not well established. We aimed to identify incidence trends and independent risk factors of postoperative hypocalcemia using the nationwide inpatient sample (NIS) database from 1998 to 2008. Overall, 6,605 (5.5%) of 119,567 patients who underwent thyroidectomy developed hypocalcemia. Total thyroidectomy resulted in a significantly higher increased incidence (9.0%) of hypocalcemia when compared with unilateral thyroid lobectomy (1.9%; P < .001). Thyroidectomy with bilateral neck dissection, the strongest independent risk factor of postoperative hypocalcemia (odds ratio, 9.42; P < .001), resulted in an incidence of 23.4%. Patients aged 45 years to 84 years were less likely to have postoperative hypocalcemia compared with their younger and older counterparts (P < .001). Hispanic (P = .003) and Asian (P = .027) patients were more likely, and black patients were less likely (P = .003) than white patients to develop hypocalcemia. Additional factors independently associated with postoperative hypocalcemia included female gender, nonteaching hospitals, and malignant neoplasms of thyroid gland. Hypocalcemia following thyroidectomy resulted in 1.47 days of extended hospital stay (3.33 versus 1.85 days P < .001). PMID- 22844619 TI - Oral rehabilitation in a patient with major maxillofacial trauma: a case management. AB - Traumatic injuries may cause anatomic deficiencies in soft and hard tissues. These defects often result in the loss of attached mucosa and alveolar processes, which might reduce potential prosthesis support and require bone and skin grafting. As a result of major maxillofacial trauma, complete or partial avulsion of the palate may require extensive surgical and prosthodontic rehabilitation. The appropriate treatment for the maxillary defect demands a multidisciplinary approach by a team which consists of various fields of dentistry and medicine. The planning prostheses should replace not only missing teeth but also lost soft tissues and bone, and they should include the hard palate, residual alveolar ridges, and, in some instances, the soft palate. This paper describes the treatment procedures including plastic surgery operation procedures and prosthetic rehabilitation in a 19-year-old woman after her severe bicycle accident. PMID- 22844620 TI - Management of unilateral masseter hypertrophy and hypertrophic scar-a case report. AB - Masseter muscle hypertrophy is a rare condition of idiopathic cause. It clinically presents as an enlargement of one or both masseter muscles. Most patients complain of facial asymmetry; however, symptoms such as trismus, protrusion, and bruxism may also occur. Several treatment options reported for masseter hypertrophy are present, which range from simple pharmacotherapy to more invasive surgical reduction. Keloid scar with unilateral masseter hypertrophy is a rarely seen in clinical practice. This paper reports a case of unilateral masseter hypertrophy with keloid scar in the angle of the mandible for which surgical treatment was rendered to the patient by using a single approach. PMID- 22844621 TI - First Report of Nocardia asiatica Presenting as an Anterior Mediastinal Mass in a Patient with Myasthenia Gravis: A Case Report and Review of the Literature. AB - The spectrum of infections with Nocardia spp. is heterogeneous. It has classically been associated with lung, brain, or skin involvement. We describe an unusual presentation of Nocardia asiatica (N. asiatica) in an Iraqi patient with myasthenia gravis suffering from a disseminated infection and presenting with an anterior mediastinal cystic mass. N. asiatica has only been three times described outside Japan and Thailand, and the rarity of this entity deserves this communication. PMID- 22844622 TI - A case of Brucella endocarditis in association with subclavian artery thrombosis. AB - Brucellosis is a common zoonosis, endemic in Mediterranean countries, and caused by bacteria of Brucella genus. Brucellosis is a systemic infection and the clinical presentation varies widely from asymptomatic and mild to severe disease. Cardiovascular complications are extremely rare. We present a case of arterial thrombosis in a previously healthy young patient with Brucella endocarditis. Careful attention must be paid to any sign or symptom of thrombosis in patients affected by brucellosis, regardless of the presence of endocarditis and cardiovascular risk factors. PMID- 22844623 TI - Acute schistosomiasis in brazilian traveler: the importance of tourism in the epidemiology of neglected parasitic diseases. AB - Parasitic infectious diseases acquired in tourist areas may pose a challenge to physicians and to travel medicine practitioners. Acute schistosomiasis may be seen in returning travelers and migrants after primary infection. This form of schistosomiasis is frequently misdiagnosed due to its temporal delay and its nonspecific presentation and might occur even in countries where the disease is endemic, such as in Brazil. The patient developed the acute phase of schistosomiasis with severe clinical manifestations. The quantitative analysis revealed the presence of 240 eggs per gram of stool. The treatment was administered with oxamniquine, and the control of cure of the patient was monitored and was favorable. The present paper aims to emphasize the importance of a detailed clinical history including information regarding travel history. PMID- 22844624 TI - Blocked atrial bi/trigeminy in utero evolving in supraventricular tachycardia after birth. AB - Transient episodes of fetal bradycardia (heart rate less than 110 bpm) are usually benign and typically result from increased vagal stimulation in the fetus. Causes of sustained fetal bradycardia include sinus bradycardia, blocked atrial bigeminy/trigeminy, high-degree atrioventricular block, and long QT syndrome. We present the case of a 34-year-old Caucasian patient referred to our department for "blocked atrial bigeminy with pseudobradycardia" detected elsewhere at 33 weeks of gestation. A fetal echocardiography showed during all the examination a blocked atrial trigeminy with a mean fetal heart rate of 100 bpm. After birth three subsequent ECGs until day 3 showed no evidence of atrial extrasystoles, confirming the well-known frequent regression of this kind of fetal benign arrhythmia, but on day 11 recurrence of supraventricular trigeminy and development of episodes of paroxystic supraventricular tachycardia were observed. On the basis of this observation, we recommend that fetuses with complex atrial ectopic beats should be closely monitored before and after birth for evidence of new arrhythmias. PMID- 22844625 TI - Occult spinal dysraphism in obstetrics: a case report of caesarean section with subarachnoid anaesthesia after remifentanil intravenous analgesia for labour. AB - Neuraxial techniques of anaesthesia and analgesia are the current choice in obstetrics for efficacy and general low risk of major complications. Concern exists about neuraxial anaesthesia in patients with occult neural tube defects, regarding both labour analgesia and anaesthesia for Caesarean section. Recently, remifentanil infusion has been proposed as an analgesic technique alternative to lumbar epidural, especially when epidural analgesia appears to be contraindicated. Here, we discuss the case of a pregnant woman attending at our institution with occult, symptomatic spinal dysraphism who requested labour analgesia. She was selected for remifentanil intravenous infusion for labour pain and then underwent urgent operative delivery with spinal anaesthesia with no complications. PMID- 22844626 TI - Ovarian fibroma with serous cystadenoma-an unusual combination: a case report. AB - Surface epithelial tumors account for more than 90% of ovarian tumors, of which serous tumors comprise 46%. Sex-cord stromal tumors constitute 8% of ovarian tumors, fibroma being the commonest, comprising 70% in this category. Combination of different types of tumors can occur in ovary with most common being Mucinous cystadenoma and Brenner tumour. We report a case of a very rare combination of ovarian tumour-Fibroma with Serous cystadenoma of the ovary. This combination is not mentioned in any standard textbooks or reference books of gynaecologic pathology. Extensive search of the English Literature showed only one reported case with this combination of ovarian tumors. To the best of our knowledge, this is the second case to be reported in English Literature. PMID- 22844627 TI - Pediatric multiple sclerosis-a challenging demyelinating disease: case report and brief review of the literature. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology. The peak onset is between age 20 and 40 years and usually affects more women than men. Although much knowledge has been achieved on the diagnosis and treatment of adult patients with MS, it remains a matter of debate and controversy in childhood. We present a case of MS in 9-year-old girl, review the current state of the knowledge on pediatric MS, and discuss the available tools for the diagnosis and treatment. PMID- 22844628 TI - In utero fetal ovarian torsion with imaging findings on ultrasound and MRI. AB - Early diagnosis of ovarian torsion is critical in avoiding complications and planning management. Therefore, it is important to understand and assess the imaging findings of ovarian torsion. Ultrasound is the imaging modality of choice; however, it is not always definitive and diagnosis can be challenging. MRI is a better imaging modality to evaluate for signs of complications and to arrive at a more definitive diagnosis. We present a case of in utero ovarian torsion diagnosed during routine prenatal ultrasound with imaging findings on ultrasound and MRI postnatally. PMID- 22844629 TI - Multiple Large Tumefactive MS Plaques in a Young Man: A Diagnostic Enigma and Therapeutic Challenge. AB - Tumefactive demyelinating lesion is defined as large solitary demyelinating lesion with imaging characteristics mimicking neoplasm. These atypical features include size more than 2 cm, mass effect, edema, and/or ring enhancement. Distinguishing tumefactive lesions from other etiologies of intracranial space occupying lesions is essential to avoid inadvertent surgical or toxic chemotherapeutic intervention. Symptoms are generally atypical for multiple sclerosis (MS) and usually related to the pressure of a focal mass lesion without a history of MS. The clinical presentation and MRI appearance of these lesions often lead to biopsy. Here, we present a young man with fulminating neurological symptoms and multiple large tumefactive lesions on either hemisphere. Since patient and parents were not agreed on brain biopsy, a course of steroid therapy was commenced which ended to considerable improvement and confirmed the diagnosis of tumefactive MS. Thirteen months later, he experienced another relapse when his treatment was continued by weekly intramuscular injection of interferon b1a (Avonex). Two further MRIs showed shrinkage of tumefactive plaques and resolution of edema in the periphery of lesions. PMID- 22844630 TI - A penetrating stab wound of the perianal area causing a combined rectal and bladder injury: one case report. AB - Although the management of either isolated rectal or bladder injury is no more controversial, their combined effect and their optimal management has been seldom reported in the English literature. From a case report of a 45-year-old male who was found to have a combined bladder and rectal injury secondary to a stab wound of the perianal area, the authors develop a diagnostic and therapeutic algorithm for the management of this uncommon trauma. PMID- 22844631 TI - Leiomyoma of the female urethra-a rare tumor: case report and review of the literature. AB - Leiomyoma is a benign smooth muscle tumor which is rarely found in urethra. Only a handful of cases have been reported in the literature. We hereby report a case of urethral leiomyoma in a twenty-seven-year-old female who presented with intermittent hematuria. Mass was completely excised with a rim of normal tissue. Patient remained asymptomatic with no evidence of recurrence in followup. PMID- 22844632 TI - Gouty tophi in the penis: a case report and review of the literature. AB - Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate crystals in different anatomical locations. We report the case of a 61-year-old man who received consultation for gouty tophi in the penis, which is an unusual location for this type of pathology, that was resolved with the surgical removal of the tophi. We provide a review on gout and its treatment as well as other locations where atypical gouty tophi have been described. PMID- 22844633 TI - Endothelin-B Receptors and Left Ventricular Dysfunction after Regional versus Global Ischaemia-Reperfusion in Rat Hearts. AB - Background. Endothelin-1 (ET-1) is implicated in left ventricular dysfunction after ischaemia-reperfusion. ETA and ETB receptors mediate diverse actions, but it is unknown whether these actions depend on ischaemia type and duration. We investigated the role of ETB receptors after four ischaemia-reperfusion protocols in isolated rat hearts. Methods. Left ventricular haemodynamic variables were measured in the Langendorff-perfused model after 40- and 20-minute regional or global ischaemia, followed by 30-minute reperfusion. Wild-type (n = 39) and ETB deficient (n = 41) rats were compared. Infarct size was measured using fluorescent microspheres after regional ischaemia-reperfusion. Results. Left ventricular dysfunction was more prominent in ETB-deficient rats, particularly after regional ischaemia. Infarct size was smaller (P = 0.006) in wild-type (31.5 +/- 4.4%) than ETB-deficient (45.0 +/- 7.3%) rats after 40 minutes of regional ischaemia-reperfusion. Although the recovery of left ventricular function was poorer after 40-minute ischaemia-reperfusion, end-diastolic pressure in ETB deficient rats was higher after 20 than after 40 minutes of regional ischaemia reperfusion. Conclusion. ETB receptors exert cytoprotective effects in the rat heart, mainly after regional ischaemia-reperfusion. Longer periods of ischaemia suppress the recovery of left ventricular function after reperfusion, but the role of ETB receptors may be more important during the early phases. PMID- 22844634 TI - Alzheimer's disease dementia as the diagnosis best supported by the cerebrospinal fluid biomarkers: difference in cut-off levels from thai experience. AB - Objectives. To determine how beta-amyloid 1-42 (Abeta 1-42), total tau (tTau), and phosphorylated tau (pTau) levels in CSF behave in a cohort of Thai patients from the Memory Clinic in Bangkok, Thailand. Methods. During 2009-2011, twenty eight subjects from the memory clinic at Siriraj Hospital had CSF analysis for AD biomarkers. Abeta 1-42, tTau, and pTau (at amino acid 181) were measured in CSF by ELISA technique. Results. Mean of Thai mental state examination (TMSE) of 28 Thai cohort was 16.48 (6.63). Fourteen had AD, ten had non-AD dementia, and four non-cases were those with subjective memory complaint (SMC) without dementia. Mean CSF Abeta 1-42, tTau, ptau (181), and pTau/Abeta 1-42 in the AD group were 241.36 (60.14) pg/mL, 222.79 (212.24) pg/mL, 40.79 (27.84) pg/mL, and 0.18 (0.12) accordingly. Mean CSF Abeta 1-42, tTau, pTau (181), and pTau/Abeta 1-42 in the non-AD dementia group were 430.40 (125.18) pg/mL, 349.30 (692.16) pg/mL, 36.80 (14.90) pg/mL, and 0.09 (0.04) accordingly. Mean CSF Abeta 1-42, tTau, pTau (181), and pTau/Abeta 1-42 in the non-cases with SMC without dementia were 499.75 (93.44) pg/mL, 137.25 (62.74) pg/mL, 31.75 (17.48) pg/mL, and 0.06 (0.02). There is significant difference (P < 0.05) among the 3 groups in CSF Abeta 1-42 and pTau/Abeta 1-42. We propose mean + 1.5 SD of CSF Abeta 1-42 in AD group (331.57 pg/mL) to be the cut-off point in Thai subjects. Conclusion. There are significant different in CSF Abeta 1-42 and CSF p-tau/Abeta 1-42 among those with AD, non-AD dementia and non cases with SMC without dementia in Thai cohort. Cut off point of CSF Abeta 1-42 of 331.57 pg/mL is suggested in Thai study. PMID- 22844635 TI - Apolipoprotein e: essential catalyst of the Alzheimer amyloid cascade. AB - The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Abeta, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or "pathological chaperone". Alternatively it has been posited that apoE regulates Abeta clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Abeta rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Abeta binding proteins, including ACT and apo J can inhibit or promote Abeta oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment. PMID- 22844636 TI - A changing perspective on the role of neuroinflammation in Alzheimer's disease. AB - Alzheimer's disease (AD) is a complex, neurodegenerative disorder characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. Glial cells, particularly microglial cells, react to the presence of the amyloid plaques and neurofibrillary tangles producing an inflammatory response. While once considered immunologically privileged due to the blood-brain barrier, it is now understood that the glial cells of the brain are capable of complex inflammatory responses. This paper will discuss the published literature regarding the diverse roles of neuroinflammation in the modulation of AD pathologies. These data will then be related to the well-characterized macrophage phenotypes. The conclusion is that the glial cells of the brain are capable of a host of macrophage responses, termed M1, M2a, M2b, and M2c. The relationship between these states and AD pathologies remains relatively understudied, yet published data using various inflammatory stimuli provides some insight. It appears that an M1-type response lowers amyloid load but exacerbates neurofibrillary tangle pathology. In contrast, M2a is accompanied by elevated amyloid load and appears to ameliorate, somewhat, neurofibrillary pathology. Overall, it is clear that more focused, cause-effect studies need to be performed to better establish how each inflammatory state can modulate the pathologies of AD. PMID- 22844637 TI - Why chromosome palindromes? AB - We look at sex-limited chromosome (Y or W) evolution with particular emphasis on the importance of palindromes. Y chromosome palindromes consist of inverted duplicates that allow for local recombination in an otherwise nonrecombining chromosome. Since palindromes enable intrachromosomal gene conversion that can help eliminate deleterious mutations, they are often highlighted as mechanisms to protect against Y degeneration. However, the adaptive significance of recombination resides in its ability to decouple the evolutionary fates of linked mutations, leading to both a decrease in degeneration rate and an increase in adaptation rate. Our paper emphasizes the latter, that palindromes may exist to accelerate adaptation by increasing the potential targets and fixation rates of incoming beneficial mutations. This hypothesis helps reconcile two enigmatic features of the "palindromes as protectors" view: (1) genes that are not located in palindromes have been retained under purifying selection for tens of millions of years, and (2) under models that only consider deleterious mutations, gene conversion benefits duplicate gene maintenance but not initial fixation. We conclude by looking at ways to test the hypothesis that palindromes enhance the rate of adaptive evolution of Y-linked genes and whether this effect can be extended to palindromes on other chromosomes. PMID- 22844638 TI - The role of reticulate evolution in creating innovation and complexity. AB - Reticulate evolution encompasses processes that conflict with traditional Tree of Life efforts. These processes, horizontal gene transfer (HGT), gene and whole genome duplications through allopolyploidization, are some of the main driving forces for generating innovation and complexity. HGT has a profound impact on prokaryotic and eukaryotic evolution. HGTs can lead to the invention of new metabolic pathways and the expansion and enhancement of previously existing pathways. It allows for organismal adaptation into new ecological niches and new host ranges. Although many HGTs appear to be selected for because they provide some benefit to their recipient lineage, other HGTs may be maintained by chance through random genetic drift. Moreover, some HGTs that may initially seem parasitic in nature can cause complexity to arise through pathways of neutral evolution. Another mechanism for generating innovation and complexity, occurring more frequently in eukaryotes than in prokaryotes, is gene and genome duplications, which often occur through allopolyploidizations. We discuss how these different evolutionary processes contribute to generating innovation and complexity. PMID- 22844639 TI - Repeated evolution of testis-specific new genes: the case of telomere-capping genes in Drosophila. AB - Comparative genome analysis has allowed the identification of various mechanisms involved in gene birth. However, understanding the evolutionary forces driving new gene origination still represents a major challenge. In particular, an intriguing and not yet fully understood trend has emerged from the study of new genes: many of them show a testis-specific expression pattern, which has remained poorly understood. Here we review the case of such a new gene, which involves a telomere-capping gene family in Drosophila. hiphop and its testis-specific paralog K81 are critical for the protection of chromosome ends in somatic cells and male gametes, respectively. Two independent functional studies recently proposed that these genes evolved under a reproductive-subfunctionalization regime. The 2011 release of new Drosophila genome sequences from the melanogaster group of species allowed us to deepen our phylogenetic analysis of the hiphop/K81 family. This work reveals an unsuspected dynamic of gene birth and death within the group, with recurrent duplication events through retroposition mechanisms. Finally, we discuss the plausibility of different evolutionary scenarios that could explain the diversification of this gene family. PMID- 22844640 TI - Phylogenetic position of aquificales based on the whole genome sequences of six aquificales species. AB - Species belonging to the order Aquificales are believed to be an early branching lineage within the Bacteria. However, the branching order of this group in single gene phylogenetic trees is highly variable; for example, it has also been proposed that the Aquificales should be grouped with epsilon-proteobacteria. To investigate the phylogenetic position of Aquificales at the whole-genome level, here we reconstructed the phylogenetic trees of 18 bacteria including six Aquificales species based on the concatenated data of proteins shared by these bacteria. In the phylogenetic tree based on the whole-genome information, Aquificales was more closely related to Thermotogales than to Proteobacteria, suggesting that the Aquificales is a relatively early branching lineage within the Bacteria. Moreover, we classified the phylogenetic tree of each conserved orthologous protein by its topology. As a result, in the most major type of the phylogenetic trees, Aquificales was closely related to the Thermotogales. However, Aquificales was closely related to epsilon-proteobacteria in 21.0% of all phylogenetic trees, suggesting that many proteins phylogenetically related to the epsilon-proteobacteria may be encoded in the genomes of the members of the Aquificales. This unique feature may be responsible for the high variability in the branching order of Aquificales in single-gene phylogenetic trees. PMID- 22844641 TI - Anti-inflammatory effects of interleukin-19 in vascular disease. AB - Despite aggressive dietary modification, lipid-lowering medications, and other interventional medical therapy, vascular disease continues to be a leading cause of mortality in the western world. It is a significant medical and socioeconomic problem contributing to mortality of multiple diseases including myocardial infarction, stroke, renal failure, and peripheral vascular disease. Morbidity and mortality of vascular disease are expected to worsen with the increasing number of patients with comorbid conditions such as obesity, metabolic syndrome, and diabetes mellitus type 2. Vascular diseases such as atherosclerosis, restenosis, and allograft vasculopathy are recognized to be driven by inflammation, and as such, cytokines which mediate inflammation not only represent important targets of rational therapy, but also can be considered as possible therapeutic modalities themselves. In this paper, we will examine the role of inflammatory cytokines and lymphocyte T(h)1/T(h)2 polarity in vascular inflammation, with a focus on atherosclerotic vascular disease. We will then introduce a recently described T(h)2 interleukin, interleukin-19 (IL-19), as a previously unrecognized mediator of vascular inflammatory disorders. We will review our current understanding of this interleukin in health and disease and present the possibility that IL-19 could represent a potential therapeutic to combat vascular inflammatory disease. PMID- 22844642 TI - Vascularisation pattern of chronic pancreatitis compared with pancreatic carcinoma: results from contrast-enhanced endoscopic ultrasound. AB - Discriminating between focal chronic pancreatitis and pancreatic cancer is always a challenge in clinical medicine. Contrast-enhanced endoscopic ultrasound using Doppler techniques can uniquely reveal different vascularisation patterns in pancreatic tissue alterated by chronic inflammatory processes and even allows a discrimination from pancreatic cancer. This paper will describe the basics of contrast-enhanced high mechanical index endoscopic ultrasound (CEHMI EUS) and contrast enhanced low mechanical index endoscopic ultrasound (CELMI EUS) and explain the pathophysiological differences of the vascularisation of chronic pancreatitis and pancreatic carcinoma. Furthermore it will discuss how to use these techniques in daily clinical practice. PMID- 22844643 TI - Management issues in healthcare information technology. PMID- 22844644 TI - Geographical information systems and health: current state and future directions. AB - This paper provides an introduction to Geographical Information Systems (GIS) and how they can be used. It reviews the current state of GIS use in health care before identifying the barriers to more pervasive use of GIS in health. Finally, it makes recommendations for the direction of health GIS research over the next decade and concludes with a call to action to health informatics researchers to stop ignoring a tool and methodology that has such immense potential for improving the health of our communities. PMID- 22844645 TI - Wearable sensors in healthcare and sensor-enhanced health information systems: all our tomorrows? AB - Wearable sensor systems which allow for remote or self-monitoring of health related parameters are regarded as one means to alleviate the consequences of demographic change. This paper aims to summarize current research in wearable sensors as well as in sensor-enhanced health information systems. Wearable sensor technologies are already advanced in terms of their technical capabilities and are frequently used for cardio-vascular monitoring. Epidemiologic predictions suggest that neuropsychiatric diseases will have a growing impact on our health systems and thus should be addressed more intensively. Two current project examples demonstrate the benefit of wearable sensor technologies: long-term, objective measurement under daily-life, unsupervised conditions. Finally, up-to date approaches for the implementation of sensor-enhanced health information systems are outlined. Wearable sensors are an integral part of future pervasive, ubiquitous and person-centered health care delivery. Future challenges include their integration into sensor-enhanced health information systems and sound evaluation studies involving measures of workload reduction and costs. PMID- 22844646 TI - Design of activation functions for inference of fuzzy cognitive maps: application to clinical decision making in diagnosis of pulmonary infection. AB - OBJECTIVES: Fuzzy cognitive maps (FCMs) representing causal knowledge of relationships between medical concepts have been used as prediction tools for clinical decision making. Activation functions used for inferences of FCMs are very important factors in helping physicians make correct decision. Therefore, in order to increase the visibility of inference results, we propose a method for designing certain types of activation functions by considering the characteristics of FCMs. METHODS: The activation functions, such as the sinusoidal-type function and linear function, are designed by calculating the domain range of the functions to be reached during the inference process of FCMs. Moreover, the designed activation functions were applied to the decision making process with the inference of an FCM model representing the causal knowledge of pulmonary infections. RESULTS: Even though sinusoidal-type functions oscillate and linear functions monotonously increase within the entire range of the domain, the designed activation functions make the inference stable because the proposed method notices where the function is used in the inference. And, the designed functions provide more visible numeric results than do other functions. CONCLUSIONS: Comparing inference results derived using activation functions designed with the proposed method and results derived using activation functions designed with the existing method, we confirmed that the proposed method could be more appropriately used for designing activation functions for the inference process of an FCM for clinical decision making. PMID- 22844647 TI - A three-year autoregressive cross-lagged panel analysis on nicotine dependence and average smoking. AB - OBJECTIVES: Previous studies have been limited to the use of cross sectional data to identify the relationships between nicotine dependence and smoking. Therefore, it is difficult to determine a causal direction between the two variables. The purposes of this study were to 1) test whether nicotine dependence or average smoking was a more influential factor in smoking cessation; and 2) propose effective ways to quit smoking as determined by the causal relations identified. METHODS: This study used a panel dataset from the central computerized management systems of community-based smoking cessation programs in Korea. Data were stored from July 16, 2005 to July 15, 2008. 711,862 smokers were registered and re registered for the programs during the period. 860 of those who were retained in the programs for three years were finally included in the dataset. To measure nicotine dependence, this study used a revised Fagerstrom Test for Nicotine Dependence. To examine the relationship between nicotine dependence and average smoking, an autoregressive cross-lagged model was explored in the study. RESULTS: The results indicate that 1) nicotine dependence and average smoking were stable over time; 2) the impact of nicotine dependence on average smoking was significant and vice versa; and 3) the impact of average smoking on nicotine dependence is greater than the impact of nicotine dependence on average smoking. CONCLUSIONS: These results support the existing data obtained from previous research. Collectively, reducing the amount of smoking in order to decrease nicotine dependence is important for evidence-based policy making for smoking cessation. PMID- 22844648 TI - Pitfalls and Security Measures for the Mobile EMR System in Medical Facilities. AB - OBJECTIVES: The goal of this paper is to examine the security measures that should be reviewed by medical facilities that are trying to implement mobile Electronic Medical Record (EMR) systems designed for hospitals. METHODS: The study of the security requirements for a mobile EMR system is divided into legal considerations and sectional security investigations. Legal considerations were examined with regard to remote medical services, patients' personal information and EMR, medical devices, the establishment of mobile systems, and mobile applications. For the 4 sectional security investigations, the mobile security level SL-3 from the Smartphone Security Standards of the National Intelligence Service (NIS) was used. RESULTS: From a compliance perspective, legal considerations for various laws and guidelines of mobile EMR were executed according to the model of the legal considerations. To correspond to the SL-3, separation of DMZ and wireless network is needed. Mobile access servers must be located in only the smartphone DMZ. Furthermore, security measures like 24-hour security control, WIPS, VPN, MDM, and ISMS for each section are needed to establish a secure mobile EMR system. CONCLUSIONS: This paper suggested a direction for applying regulatory measures to strengthen the security of a mobile EMR system in accordance with the standard security requirements presented by the Smartphone Security Guideline of the NIS. A future study on the materialization of these suggestions after their application at actual medical facilities can be used as an illustrative case to determine the degree to which theory and reality correspond with one another. PMID- 22844649 TI - Integration of Evidence into a Detailed Clinical Model-based Electronic Nursing Record System. AB - OBJECTIVES: The purpose of this study was to test the feasibility of an electronic nursing record system for perinatal care that is based on detailed clinical models and clinical practice guidelines in perinatal care. METHODS: THIS STUDY WAS CARRIED OUT IN FIVE PHASES: 1) generating nursing statements using detailed clinical models; 2) identifying the relevant evidence; 3) linking nursing statements with the evidence; 4) developing a prototype electronic nursing record system based on detailed clinical models and clinical practice guidelines; and 5) evaluating the prototype system. RESULTS: We first generated 799 nursing statements describing nursing assessments, diagnoses, interventions, and outcomes using entities, attributes, and value sets of detailed clinical models for perinatal care which we developed in a previous study. We then extracted 506 recommendations from nine clinical practice guidelines and created sets of nursing statements to be used for nursing documentation by grouping nursing statements according to these recommendations. Finally, we developed and evaluated a prototype electronic nursing record system that can provide nurses with recommendations for nursing practice and sets of nursing statements based on the recommendations for guiding nursing documentation. CONCLUSIONS: The prototype system was found to be sufficiently complete, relevant, useful, and applicable in terms of content, and easy to use and useful in terms of system user interface. This study has revealed the feasibility of developing such an ENR system. PMID- 22844650 TI - Seoul National University Bundang Hospital's Electronic System for Total Care. AB - OBJECTIVES: Seoul National University Bundang Hospital, which is the first Stage 7 hospital outside of North America, has adopted and utilized an innovative and emerging information technology system to improve the efficiency and quality of patient care. The objective of this paper is to briefly introduce the major components of the SNUBH information system and to describe our progress toward a next-generation hospital information system (HIS). METHODS: SNUBH opened in 2003 as a fully digital hospital by successfully launching a new HIS named BESTCare, "Bundang hospital Electronic System for Total Care". Subsequently, the system has been continuously improved with new applications, including close-loop medication administration (CLMA), clinical data warehouse (CDW), health information exchange (HIE), and disaster recovery (DR), which have resulted in the achievement of Stage 7 status. RESULTS: The BESTCare system is an integrated system for a university hospital setting. BESTCare is mainly composed of three application domains: the core applications, an information infrastructure, and channel domains. The most critical and unique applications of the system, such as the electronic medical record (EMR), computerized physician order entry (CPOE), clinical decision support system (CDSS), CLMA, CDW, HIE, and DR applications, are described in detail. CONCLUSIONS: Beyond our achievement of Stage 7 hospital status, we are currently developing a next-generation HIS with new goals of implementing infrastructure that is flexible and innovative, implementing a patient-centered system, and strengthening the IT capability to maximize the hospital value. PMID- 22844651 TI - The use of the health belief model to assess predictors of intent to receive the novel (2009) H1N1 influenza vaccine. AB - OBJECTIVES: 1) Assess participants' perceptions of severity, risk, and susceptibility to the novel H1N1 influenza virus and/or vaccine, vaccine benefits and barriers, and cues to action and 2) Identify predictors of participants' intention to receive the novel H1N1 vaccine. DESIGN: Cross-sectional, descriptive study SETTING: Local grocery store chain and university in the central Virginia area PARTICIPANTS: Convenience sample of adult college students and grocery store patrons INTERVENTION: Participants filled out an anonymous, self-administered questionnaire based upon the Health Belief Model. MAIN OUTCOME MEASURES: Participants' predictors of intention to receive the novel H1N1 vaccine RESULTS: A total of 664 participants completed a questionnaire. The majority of participants were aged 25-64 years old (66.9%). The majority were female (69.1%), Caucasian (73.7%), and felt at risk for getting sick from the virus (70.3%). Most disagreed that they would die from the virus (68.0%). Participants received novel H1N1 vaccine recommendations from their physicians (28.2%), pharmacists (20.7%), and nurses (16.1%). The majority intended to receive the H1N1 vaccine (58.1%). Participants were significantly more likely to intend to receive the H1N1 vaccine if they had lower scores on the perceived vaccine barriers domain (OR= 0.57, CI: 0.35-0.93). Physicians' recommendations (OR=0.26, CI: 0.11-0.62) and 2008 seasonal flu vaccination (OR=0.45, CI: 0.24-0.83) were significant predictors of intention to receive the H1N1 vaccine. CONCLUSIONS: Most participants felt at risk for getting the novel H1N1 virus and intended to receive the novel H1N1 vaccine. Educating patients about vaccine benefits and increasing healthcare professionals' vaccine recommendations may increase vaccination rates in future pandemics. PMID- 22844652 TI - Copper-Catalyzed Azide-Alkyne Click Chemistry for Bioconjugation. AB - The copper-catalyzed azide-alkyne cycloaddition reaction is widely used for the connection of molecular entities of all sizes. A protocol is provided here for the process with biomolecules. Ascorbate is used as reducing agent to maintain the required cuprous oxidation state. Since these convenient conditions produce reactive oxygen species, five equivalents of a copper-binding ligand is used with respect to metal. The ligand both accelerates the reaction and serves as a sacrificial reductant, protecting the biomolecules from oxidation. A procedure is also described for testing the efficiency of the reaction under desired conditions for purposes of optimization, before expensive biological reagents are used. PMID- 22844653 TI - Oxadiazole 2-oxides are toxic to the human hookworm, Ancylostoma ceylanicum, however glutathione reductase is not the primary target. AB - Hookworm disease, characterized by severe anemia and cognitive and growth delays, currently affects an estimated 740 million people worldwide. Despite the prevalence of this parasitic disease, few effective drug therapies are in use today, and the heavy reliance upon benzimidazoles highlights the need for the development of novel chemotherapies. Recent work with the trematode parasite Schistosoma mansoni has identified oxadiazole 2-oxides as effective antischistosomal compounds that function by targeting and inhibiting the antioxidant enzyme, thioredoxin glutathione reductase. In this study, a related enzyme, glutathione reductase, from the human hookworm Ancylostoma ceylanicum was identified and characterized, and its in vitro activity in the presence of the oxadiazole 2-oxides was analyzed. Ex vivo worm killing assays were also conducted to establish the relationship between a given compound's effect upon worm survival and inhibition of recombinant glutathione reductase (rAceGR). Finally, the in vivo anthelminthic efficacy of furoxan (Fx) was assessed in the hamster model of hookworm infection. The predicted amino acid sequence of AceGR contained a prototypical glutathione reductase active site sequence, but no thioredoxin reductase consensus sequences, suggesting that the glutathione and thioredoxin pathways of A. ceylanicum are distinct. Although ten of the forty-two oxadiazole 2-oxides tested inhibited rAceGR activity by at least fifty percent, and fifteen compounds were toxic to parasites ex vivo, little overlap existed between these two results. We therefore suggest that AceGR is not the primary target of the oxadiazole 2-oxides in effecting parasite death. Lastly, oral treatment of A. ceylanicuminfected hamsters with furoxan resulted in significantly improved weight gains and reduced intestinal worm burdens compared to vehicle treated controls, supporting continued development of this molecule as a novel anthelminthic. PMID- 22844654 TI - The Health Deviation of Post-Breast Cancer Lymphedema: Symptom Assessment and Impact on Self-Care Agency. AB - Breast cancer is the leading cancer among women world-wide, affecting 1 of 8 women during their lifetimes. In the US alone, some 2 million breast cancer survivors comprise 20% of all cancer survivors. Conservatively, it is estimated that some 20-40% of all breast cancer survivors will develop the health deviation of lymphedema or treatment-related limb swelling over their lifetimes. This chronic accumulation of protein-rich fluid predisposes to infection, leads to difficulties in fitting clothing and carrying out activities of daily living, and impacts self-esteem, self-concept, and quality of life. Lymphedema is associated with self-care deficits (SCD) and negatively impacts self-care agency (SCA) and physiological and psychosocial well-being. Objectives of this report are two fold: (1) to explore four approaches of assessing and diagnosing breast cancer lymphedema, including self-report of symptoms and the impact of health deviations on SCA; and (2) to propose the development of a clinical research program for lymphedema based on the concepts of Self-Care Deficit Nursing Theory (SCDNT). Anthropometric and symptom data from a National-Institutes-of-Health-funded prospective longitudinal study were examined using survival analysis to compare four definitions of lymphedema over 24 months post-breast cancer surgery among 140 of 300 participants (all who had passed the 24-month measurement). The four definitions included differences of 200 ml, 10% volume, and 2 cm circumference between pre-op baseline and/or contralateral limbs, and symptom self-report of limb heaviness and swelling. Symptoms, SCA, and SCD were assessed by interviews using a validated tool. Estimates of lymphedema occurrence varied by definition and time since surgery. The 2 cm girth change provided the highest estimation of lymphedema (82% at 24 months), followed by 200 ml volume change (57% at 24 months). The 10% limb volume change converged with symptom report of heaviness and swelling at 24 months (38-39% lymphedema occurrence), with symptom report being the earliest predictor of lymphedema occurrence than any other measurement. Findings verify the importance of subjective assessment by symptom report of limb changes and SCD following breast cancer treatment as an essential tool in early detection and treatment of lymphedema. Findings also support the importance of pre-operative baseline measurements, symptom history, and SCA for later post-op comparisons. These preliminary findings underscore the importance of strengthening SCA by educating breast cancer survivors. Self assessment, early detection, and early treatment hold the best promise for optimal management of this chronic condition, limiting detrimental effects on SCA, and improving quality of life and physiological and psychosocial well-being. These findings lay the foundation for a clinical research program in breast cancer lymphedema based on SCDNT in which education in and awareness for self-report of lymphedema associated symptoms is a first step in screening. Increasing patient knowledge through education will increase SCA by identifying ane providing information to meet self-care requisites (SCR) related to the health deviation of lymphedema. The nurse has the opportunity to assist patients in developing self-care actions as needed to meet universal and health deviation therapeutic requisites to address self-care demands following breast cancer treatment. PMID- 22844655 TI - Pegloticase for treating refractory chronic gout. AB - Gout is a metabolic disorder of excess uric acid accumulation that manifests clinically as inflammatory arthritis, chronic arthropathy and the formation of deposits of uric acid known as tophi. A primary objective of gout management is to reduce the excess urate burden by regular use of drugs that reduce serum urate levels. Conventional urate-lowering drugs available in the U.S. are allopurinol, febuxostat and probenecid. Some patients are intolerant to or unresponsive to urate-lowering therapies and, therefore, are said to have refractory gout. Recently, a polyethylene glycol-conjugated uricase, pegloticase, was approved for treating refractory gout. In recent clinical trials, pegloticase normalized plasma urate levels, reduced the size of tophi, and improved functional status and quality of life in patients with refractory disease. Immunogenicity to pegloticase is associated with loss of urate-lowering response and the risk of infusion reactions. Pegloticase is effective in treating hyperuricemia and the clinical manifestations of gout in patients who cannot be adequately managed with conventional therapy. PMID- 22844656 TI - Semuloparin for the prevention of venous thromboembolic events in cancer patients. AB - Cancer-associated venous thromboembolism increases the morbidity and mortality in patients with cancer, being the second leading cause of death among these patients. As such, it has important clinical and economical consequences and current guidelines recommend thromboprophylaxis for cancer patients who are admitted to the hospital for medical illness or for major cancer surgery but not for routine use in ambulatory patients receiving chemotherapy. Semuloparin (AVE 5026) is a hemisynthetic, ultra-low-molecular-weight heparin, with high anti factor Xa and residual antithrombin activities that was submitted for approval to the European Medicines Agency and the U.S. Food and Drug Administration in September 2011 for the prevention of venous thromboembolism in cancer patients. In a multicenter trial (SAVE-ONCO), once-daily, subcutaneous semuloparin at 20 mg administered to 1,608 patients receiving chemotherapy for locally advanced or metastatic solid tumors significantly prevented venous thromboembolism without increasing major bleeding, suggesting that semuloparin thrombo-prophylaxis can be beneficial in cancer patients receiving chemotherapy. PMID- 22844657 TI - Vismodegib in basal cell carcinoma. AB - Vismodegib is a novel, small-molecule inhibitor of smoothened, a key component of the hedgehog signaling pathway. Increased hedgehog pathway signaling is critical in the development of hereditary and spontaneous basal cell carcinomas of the skin, and has been implicated in the development of a number of other tumors. In preclinical models, vismodegib demonstrated potent antitumor activity in hedgehog dependent tumors, particularly basal cell carcinomas. Clinically, phase I and II studies showed dramatic anticancer activity in patients with advanced basal cell carcinomas. In January 2012, vismodegib was approved by the FDA for the treatment of unresectable or metastatic basal cell carcinomas of the skin. PMID- 22844658 TI - Glutamatergic approaches in major depressive disorder: focus on ketamine, memantine and riluzole. AB - The role of glutamate in modulating various mood states is being increasingly recognized and researched. Existing antidepressants have been shown to exert effects on various glutamatergic mechanisms, even if such agents are traditionally classified as working via other mechanisms, such as selective serotonin reuptake inhibitors. The NMDA receptor antagonist ketamine has been investigated in various mood disorders, especially major depressive disorder (MDD). It was found to produce a rapid, robust and persistent antidepressant effect. Although it can produce cognitive, dissociative and perceptual disturbances, these tend to be transient and do not outlast the antidepressant effect. Trials with memantine and riluzole, agents with actions broadly similar to and different from ketamine on the glutamatergic system, are also reviewed in MDD and prospects for future research in the area are discussed. Although preclinical studies are discussed, the main focus of the review is on clinical outcomes. PMID- 22844659 TI - Heart failure biomarkers: focus on interleukin-1 receptor-like 1-based blood tests. AB - Heart failure is a leading cause of morbidity and mortality in the Western world. It is often a progressive disease, and the pathophysiology behind this adverse development is not completely understood. Biomarkers are of increasing importance in heart failure research. Despite a growing number of candidate markers, only a select few have made it into clinical practice. Interleukin-1 receptor-like 1 (IL1RL1), also known as protein ST2, is the receptor for interleukin-33 (IL-33), a cytokine involved in T-cell-mediated immune responses. IL1RL1 expression is induced by cardiomyocyte stretch, and IL1RL1 may thus reflect the activity of two interacting processes in heart failure: inflammation and hemodynamic stress. In recent years, the soluble, truncated IL1RL1 isoform B has been shown to provide prognostic information in heart failure. Although ILRL1 isoform B does not seem to aid in the diagnosis of the disease, an elevated plasma/serum concentration of this marker is firmly associated with adverse outcome in patients with heart failure. This association has been established in different heart failure cohorts and is independent of age, etiology of heart failure and left ventricular function. Ultimately, the IL-33/IL1RL1 pathway may become a therapeutic target in heart failure. PMID- 22844660 TI - A report from the American Society of Hypertension's 2012 annual scientific meeting and exposition (May 19-22, 2012 - New York, New York, USA). AB - Competing with the AIDS walk held on Sunday May 20, 2012, the 2012 Annual Scientific Meeting and Exposition of the American Society of Hypertension was held in New York. Sitting through oral presentations and standing by posters was a scientifically rewarding task to get the most updated news on the management of high blood pressure and related cardiovascular risk determinants. The following report aims at summarizing clinical and preclinical findings reported during the meeting that have a direct impact on how hypertension and the cardiovascular risk is, should or could possibly be managed in the future. PMID- 22844661 TI - Guest editors' introduction: Special section on the IEEE Virtual Reality Conference (VR). PMID- 22844662 TI - [Non-agonist inhibitors of Cdk5-dependent phosphorylation of PPAR as insulin sensitizers in the future?]. PMID- 22844663 TI - [Fitness for Couch-Potatoes? ]. PMID- 22844664 TI - [Leukemia: A highly malignant disease]. PMID- 22844665 TI - [Genetic basis of leukemia: Serious consequences of chromosomal translocations]. PMID- 22844666 TI - [Translocations of the MLL gene: New insights into high-risk leukemia]. PMID- 22844667 TI - [Treatment of acute lymphoblastic leukemia in childhood: state of things and outlook for the future]. PMID- 22844668 TI - [Treatment of children and adolescents with relapsed ALL: therapy target long term healing]. PMID- 22844669 TI - [Stem cell transplantation for acute leukemias: Balancing risks and benefits of different treatment methods]. PMID- 22844670 TI - [Infectious complications in acute lymphoblastic leukemia: Individually tailored prevention and treatment]. PMID- 22844671 TI - [Sequelae after successful treatment of ALL in childhood and adolescence: follow up is precautionary]. PMID- 22844672 TI - [Immunotherapy with allogeneic NK cells after stem cell transplantation: harnessing a potent "killer" of tumor cells]. PMID- 22844673 TI - Image of the month: A uniquely shaped common bile duct stone. PMID- 22844674 TI - The efficacy of Phaseolus vulgaris as a weight-loss supplement: a systematic review and meta-analysis of randomised clinical trials. AB - A variety of dietary supplements are presently available as slimming aids, but their efficacy has not been proven. One such slimming aid is the bean extract, Phaseolus vulgaris. The aim of the present systematic review is to evaluate the evidence for or against the efficacy of P. vulgaris. Electronic and non electronic searches were conducted to identify relevant human randomised clinical trials (RCT). Hand searches of bibliographies were also conducted. No age, time or language restrictions were imposed. The eligibility of studies was determined by two reviewers independently, and the methodological quality of the included studies was assessed. We identified eleven eligible trials, and six were included. All the included RCT had serious methodological flaws. A meta-analysis revealed a statistically non-significant difference in weight loss between P. vulgaris and placebo groups (mean difference (MD) - 1.77 kg, 95 % CI - 3.33, 0.33). A further meta-analysis revealed a statistically significant reduction in body fat favouring P. vulgaris over placebo (MD - 1.86 kg, 95 % CI - 3.39, - 0.32). Heterogeneity was evident in both analyses. The poor quality of the included RCT prevents us from drawing any firm conclusions about the effects of P. vulgaris supplementation on body weight. Larger and more rigorous trials are needed to objectively assess the effects of this herbal supplement. PMID- 22844675 TI - Early high-sodium solid diet does not affect sodium intake, sodium preference, blood volume and blood pressure in adult Wistar-Kyoto rats. AB - A high-Na diet may lead to the development of hypertension in both humans and rats; however, the causes of Na intake in amounts greater than physiologically needed as well as the mechanisms whereby high-Na food elevates blood pressure are not clear. Therefore, we decided to test the hypothesis that a high-Na diet introduced after suckling affects Na intake, food preference, resting blood pressure and blood volume in adult rats. Male Wistar-Kyoto (WKY) rats, 4 weeks old, were divided into three groups and placed on either a high-Na (3.28%), a medium-Na (0.82%) or a regular diet (0.22%) with the same energy content for 8 weeks. Subsequently, food preference, resting arterial blood pressure, blood volume, plasma osmolality and Na blood level were evaluated. When offered a choice of diets, all the groups preferred the regular chow, and there was no significant difference in total Na intake between the groups. When the rats experienced the change from their initial chow to a new one with different Na content, they continued to eat the same amount of food. Body weight, resting arterial blood pressure, blood volume, plasma osmolality and Na blood level were comparable between the groups. In conclusion, the results show that a high-Na diet introduced immediately after suckling does not affect Na preference and Na intake in adult WKY rats. Furthermore, the findings provide evidence that both blood volume and arterial blood pressure are highly protected in normotensive rats on a high-Na diet. PMID- 22844676 TI - Simulating multiple character interactions with collaborative and adversarial goals. AB - This paper proposes a new methodology for synthesizing animations of multiple characters, allowing them to intelligently compete with one another in dense environments, while still satisfying requirements set by an animator. To achieve these two conflicting objectives simultaneously, our method separately evaluates the competition and collaboration of the interactions, integrating the scores to select an action that maximizes both criteria. We extend the idea of min-max search, normally used for strategic games such as chess. Using our method, animators can efficiently produce scenes of dense character interactions such as those in collective sports or martial arts. The method is especially effective for producing animations along story lines, where the characters must follow multiple objectives, while still accommodating geometric and kinematic constraints from the environment. PMID- 22844677 TI - Special section on the IEEE conference on visual analytics science and technology (VAST). PMID- 22844678 TI - Germany: Excellence revisited. PMID- 22844679 TI - [Education of physicians: necessary but not sufficient to decrease antibiotic prescription]. PMID- 22844680 TI - [Linezolide versus vancomycin in MRSA nosocomial pneumonia: probably better- but...]. PMID- 22844681 TI - Review of subcutaneous interferon beta-1a, delivered via the electronic self injection device RebiSmartTM, for the treatment of multiple sclerosis. AB - Multiple sclerosis is a chronic disease requiring lifelong treatment with disease modifying drugs that aim to prevent relapses and slow the progression of disability. The established first-line treatments for multiple sclerosis all require regular injections, and real-world observations suggest that long-term adherence to treatment is low. Indeed, poor adherence to disease-modifying drug treatment has been associated with poorer clinical outcomes. Autoinjectors have been developed to improve the success of self-injection, whilst also making injections more comfortable for patients, with the aim of minimizing obstacles to treatment adherence. RebiSmartTM is a new electronic autoinjector for subcutaneous administration of interferon beta-1a (Rebif(r)) that includes several unique features designed to further reduce barriers to adherence, including a dosing log and adjustable comfort settings. PMID- 22844682 TI - Neuroleptics: bedwetting. PMID- 22844683 TI - Romiplostim: leukaemia after myelodysplastic syndromes. PMID- 22844684 TI - Silodosin: erectile and ejaculatory disorders. PMID- 22844685 TI - Escitalopram: torsades de pointes. PMID- 22844686 TI - Tianeptine: more cases of dependence. PMID- 22844687 TI - Lenalidomide: second cancers. PMID- 22844688 TI - Classification of two steroids, prostanozol and methasterone, as Schedule III anabolic steroids under the Controlled Substance Act. Final rule. AB - With the issuance of this Final Rule, the Administrator of the DEA classifies the following two steroids as "anabolic steroids'' under the Controlled Substances Act (CSA): prostanozol (17[beta]-hydroxy-5[alpha]-androstano[3,2-c]pyrazole) and methasterone (2[alpha],17[alpha]-dimethyl-5[alpha]-androstan-17[beta]-ol-3-one). These steroids and their salts, esters, and ethers are Schedule III controlled substances subject to the regulatory control provisions of the CSA. PMID- 22844689 TI - Causes of crestal bone resorption in the dental implant patient. PMID- 22844690 TI - Challenges, transitions, and healthy aging: introduction to the special issue. PMID- 22844692 TI - A longitudinal analysis of social engagement in late-life widowhood. AB - Very little is known of the longitudinal changes that occur in contact with children and participation in social activities during late-life widowhood. Using data on social networks and activities drawn from the Australian Longitudinal Study of Ageing, trajectories of change in social engagement were modeled for 1266 participants (mean age 76.7 years) over a 16-year period. Levels of social engagement were found to remain high during older age and rose following the transition to widowhood. Frequency of phone contact with children and participation in social activities were higher for widowed than married participants. However, the very-old, males, those in lower socio-economic groups, in poorer health, or without a child living nearby were found to have lower levels of social engagement in widowhood, and may be at increased risk of social isolation. High levels of social engagement during widowhood may assist individuals in successfully overcoming the challenges of spousal bereavement. PMID- 22844691 TI - Cigarette smokers, never-smokers, and transitions: implications for successful aging. AB - One of the social identities held by people is defined by whether or not they smoke cigarettes. Although this identity can and does change for many people over the course of their lives, most research has not examined the effects of transitioning from a smoker to a non-smoker. Using a life span perspective, our analyses contrasted the extent to which successful aging is experienced by: (1) persons who ever smoked and those who never smoked; (2) former smokers and current smokers; and (3) persons who transitioned from being a smoker to being a non-smoker at different ages. Using data from a random sample of 5688 persons between the ages of 50 and 74 living in New Jersey, we found that persons who never smoked were most likely to age successfully; there were no differences in patterns of successful aging when all former smokers were compared to current smokers; and persons who quit smoking before age 30 experienced modest benefits compared with those who continued to smoke. PMID- 22844693 TI - Restorative integral support (RIS) for older adults experiencing co-occurring disorders. AB - The restorative integral support (RIS) model is a whole person response that assists people to overcome adversity. The adverse childhood experiences (ACE) Study conducted by Kaiser Permanente and the Centers for Disease Control and Prevention shows the association between stressors in childhood and multiple later-life health and social problems. Older adults experiencing co-occurring disorders are an under-served and vulnerable population where gaps in both practice models and research to inform effective service provision exist. The current empirical case study presents Senior Hope as one social service agency employing RIS to intervene on the linkage between ACEs and co-occurring disorders to assist older adults. RIS usefully articulates the way in which Senior Hope is developing ACE-informed programs that mobilize resilience and recovery to help older adults achieve positive mental health outcomes. Implementation and research on the RIS model is recommended to enhance services for groups with ACE characteristics. PMID- 22844694 TI - Factors associated with ADL and IADL dependency among Korean centenarians: reaching the 100-year-old life transition. AB - This study aims to examine the functional status of Korean centenarians, who have crossed the relatively rare but increasingly common life transition of living for a century. As functional health is one of the essential components of healthy aging, our primary objective is to identify the correlates of two aspects of functioning, activities of daily living (ADL) and instrumental activities of daily living (IADL). Using a census survey conducted by the Korean National Statistical Office (KNSO) in 2005, we documented ADL and IADL limitations and analyzed their relationship to sociodemographic factors, health behaviors, social connectedness, and presence of diseases. The study participants were 796 adults aged 100 years or older. The mean age was 101.5 +/- 1.8, and females were 89.9% of the sample. Both ADL and IADL dependences were more common among females, those who did less physical activity, those who had more diseases, and those who did not participate in social activities. Intervention programs designed to address life-stage issues such as focusing on initiating healthy behaviors from youth, managing chronic diseases in mid-life, and fostering social participation in later life are recommended ways to improve functional independence and promote healthy aging among current and future generations of Korean centenarians. PMID- 22844695 TI - Immunohistochemical evaluation of expression of heat shock proteins HSP70 and HSP90 in mammary gland neoplasms in bitches. AB - Heat shock proteins have essential roles in a number of pathophysiologic conditions including carcinogenesis and represent a group of novel molecular markers in cancer management. The aim of this study was to investigate heat shock protein expression in correlation with other neoplasm traits such as: histological type, differentiation grade, proliferative activity, estrogenic receptor expression, and cyclooxygenase-2 and p53 proteins. Material for the investigation comprised 133 tumors of the mammary gland collected from bitches. In total 14 adenomas, 66 complex carcinomas, 47 simple carcinomas and 6 solid carcinomas were collected. Evaluations were conducted with histopathological and immunohistochemical methods using suitable antibodies. Expression of heat shock protein 70 was observed in all types of evaluated neoplasms. A higher average number of cells undergoing expression of heat shock protein 70, which was statistically insignificant, was established in complex and simple cancers and in cancers with the 1st and the 2nd degree of histological malignancy. Expression of heat shock protein 90 was observed in all studied neoplasms; it was very insignificant in adenomas, compared to cancers, and the highest expression was established in the solid cancers, as well as in cancers with the 2nd degree of histological malignancy. This high expression of heat shock protein 90 was correlated with proliferative activity. The results suggest that heat shock protein 90 is involved in canine mammary gland carcinogenesis. The results also suggest that heat shock protein 90 may be a prognostic factor, but this requires detailed clinical confirmation. PMID- 22844696 TI - Effect of infection of turkeys with haemorrhagic enteritis adenovirus isolate on the selected parameters of cellular immunity and the course of colibacillosis. AB - The aim of the study was to determine the effect of a Polish low-virulence isolate of haemorrhagic enteritis adenovirus (HEV) on the immune system in turkeys and on the course of colibacillosis in birds infected under laboratory conditions. Turkeys were infected per os with HEV at the dose of 10(4.3)EID50/mL and with E. coli (APEC) (serotypes 078:K80:H9) at the dose of 4x10(9)CFU/mL by injection to the thoracic air sac. The birds infected with the HEV were infected with the APEC either simultaneously or after 5 days. Five days after HEV infection, the percentages of subpopulations of the CD3+CD4+ and CD3+CD8alpha+ T cells and the IgM+ B cells were determined in blood and spleens of the HEV infected turkeys and in the control (uninfected) birds. The course of colibacillosis was more severe in turkeys infected with the APEC 5 days after infection with the HEV than in those infected with the HEV and APEC simultaneously and than in those infected only with APEC. Five turkeys out of the 18 infected with the APEC 5 days after infection with HEV, died. Their body weights were statistically significantly lower with higher FCR values 41 days after the infection in comparison to turkeys in the other groups. A considerable decrease in the percentage of the T and B cells subpopulations in the blood were found in turkeys infected with the HEV and while the percentage of CD3+CD4+ T cells subpopulation in the spleen increased significantly, the contribution of the CD3+CD8alpha+ T cells and IgM+ B cells subpopulations were decreased. These changes in the immune system of turkeys, occurring 5 days after infection with the HEV, made them more susceptible to infection with the APEC. PMID- 22844697 TI - Influence of zearalenone on selected biochemical parameters in juvenile rainbow trout (Oncorhynchus mykiss). AB - Zearalenone (ZEA) is a mycoestrogen frequently found in food and animal feed materials all over the world. Despite its hydrophobic character, ZEA is also found in surface and ground waters which suggests an environmental risk for aquatic animals. Knowledge concerning mycotoxin-related mechanisms of toxicity is still incomplete, e.g. little is known about the influence of ZEA exposure on fish. The aim of this study was to investigate the effect of ZEA on selected biochemical parameters in juvenile rainbow trout after 24, 72, and 168 h of intraperitoneal exposure (10 mg/kg of body weight). The analysis showed a slight tendency towards prolonged blood clotting time and significant iron deficiency in the liver and ovary of exposed animals. However, no differences in aminotransferase (AlaAT, AspAT) activity or glucose levels in fish plasma was observed. The results of this study suggest that although trout exposed to ZEA did not exhibit any distinct symptoms of liver damage, the mycotoxin tested was able interfere with blood coagulation and iron-storage processes. PMID- 22844698 TI - The effect of different dietary sodium levels on blood mineral concentrations and tibia mineralization in turkeys. AB - The objective of this study was to determine the effect of different dietary levels of sodium in diets with and without sodium chloride on mineral metabolism, including blood electrolyte levels and tibia mineralization parameters, in young turkeys (to six weeks of age). The influence of diets with a low (L), medium (M) and high (H) sodium content, at 0.34, 1.34 and 2.82 g/kg respectively, was compared. The content of chloride and potassium in turkey diets (1.7 - 5.9 and 11 g/kg, respectively) was above the recommended levels. The sodium-deficient diet L decreased the serum concentrations of sodium, chloride and phosphorus, and it increased the serum levels of calcium and magnesium in turkeys, compared with groups M and H. Relative to group L, different dietary sodium levels in groups M and H contributed to a similar increase in the body weights of birds (1.06 vs. 1.46 and 1.44 kg, p < 0.001) and in the absolute (4.60 vs. 6.83 and 6.62 g, p < 0.001) and relative tibia weight (0.42 vs. 0.46 and 0.46% body weight, p = 0.031). No significant differences were found between groups with respect to the content of ash, calcium and phosphorus in tibia dry matter. Supplemental sodium increased the bone density index (from 50.6 to 68.4 and 66.3 mg/mm in groups L, M and H, respectively, p < 0.001), the maximum bending moment (from 5.27 to 7.40 and 7.33 N/mm, p = 0.002) and the minimum breaking strength of tibia (from 0.136 to 0.191 and 0.189, p = 0.002). In conclusion, our study indicates that the applied dietary treatment with a moderate sodium level (1.34 g/kg) resulted in a rate of bird growth and tibia mineralization similar to those observed with the treatment with much higher Na content (2.82 g/kg). PMID- 22844699 TI - Prevalence of antibiotic resistance genes in staphylococci isolated from ready-to eat meat products. AB - Prevalence of mecA, blaZ, tetO/K/M, ermA/B/C, aph, and vanA/B/C/D genes conferring resistance to oxacillin, penicillin, tetracycline, erythromycin, gentamicin, and vancomycin was investigated in 65 staphylococcal isolates belonging to twelve species obtained from ready-to-eat porcine, bovine, and chicken products. All coagulase negative staphylococci (CNS) and S. aureus isolates harbored at least one antibiotic resistance gene. None of the S. aureus possessed more than three genes, while 25% of the CNS isolates harbored at least four genes encoding resistance to clinically used antibiotics. In 15 CNS isolates the mecA gene was detected, while all S. aureus isolates were mecA-negative. We demonstrate that in ready-to-eat food the frequency of CNS harboring multiple antibiotic resistance genes is higher than that of multiple resistant S. aureus, meaning that food can be considered a reservoir of bacteria containing genes potentially contributing to the evolution of antibiotic resistance in staphylococci. PMID- 22844701 TI - High agreement of routine cytopathology and immunocytochemistry in canine lymphomas. AB - The aim of this study was to compare the concordance of immunophenotype established with routine cytopathology (slides stained with Giemsa solution) and immunocytochemistry according to CD3 and CD79 alpha immunoreactivity. The study was performed on cytological samples of 70 canine lymphomas subtyped on the basis of the updated Kiel classification system. Additionally, cytologic samples were examined immunocytochemically for the CD3 and CD79 alpha antigens presence and thus immunophenotype of neoplastic growth was confirmed. The cytopathological and immunocytochemical diagnoses were then compared; in order to measure the concordance between immunocytochemistry (IC) result and Giemsa stain result of the same sample the Cohen's kappa coefficient was calculated. On the basis of the results of immunocytochemistry of 70 cases of canine lymphoma examined 42 were recognized as B cell lymphoma and 28 as T cell lymphoma. Full accordance between the results of routine cytopathology and IC was obtained in 63 out of 70 examined dogs (90% of cases). It can be concluded that cytopathological examination of Giemsa stained smears is helpful in determining the lymphoma cells immunophenotype. Additionally, it seems that combination of routine cytopathology and immunocytochemistry in cases of canine lymphomas allows to obtain the precise diagnosis in 90% of cases, and allows to receive most important information that is necessary for planning of appropriate therapy and to determine prognosis. Finally, this routine procedure allowed to eliminate the need of collection of tissue samples during surgery or core-biopsy and thus time, cost and patient discomfort related to more complex and invasive medical procedures can be easily reduced. PMID- 22844700 TI - Activity of selected antioxidative enzymes in rats exposed to dimethoate and pyrantel tartrate. AB - This study presents the results of research concerning the effect of single and combined application of pyrantel tartrate and dimethoate on selected antioxidative enzymes: catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), in rat erythrocytes. Pyrantel tartrate was applied twice, at a dose of 85 mg/kg bw at a two week interval, i.e. on day 14 and 28 of the experiment, orally, in a water solution with a stomach tube. Dimethoate was administered with drinking water for 28 days at a dose of 25 mg/kg bw/day. It was found that pyrantel tartrate caused only small changes in the activity of the antioxidative enzymes under analysis. Subchronic exposure of rats to dimethoate caused a significant increase in the activity of CAT, SOD and GPx in erythrocytes, indicating the existence of strong oxidative stress. In combined intoxication, no significant effects of administering pyrantel tartrate on the activity of CAT, SOD and GPx was found in animals poisoned with dimethoate. The profile of changes was similar to that observed in rats exposed only to the organophosphorus insecticide. This may indicate a lack of interaction between the compounds used in the experiment. PMID- 22844702 TI - Infection of European eel, Anguilla anguilla (L.), with the nematode Anguillicoloides crassus (Kuwahara, Niimi et Itagaki, 1974) in Polish waters. AB - The aim of this study was to determine the degree of Anguillicoloides crassus infection in European eel inhabiting Polish waters based on selected parasitic descriptors and on anatomical pathology of the swimbladder using macroscopic methods. In all, 154 European eel specimens were sampled from eleven sites in Poland and A. crassus was present in the swimbladder of 114 fish. The intensity of A. crassus infection in all the eel specimens ranged from 1 to 62 parasites at a mean value of 7.5. High values of mean infection intensity were noted in samples from Pomeranian lakes Bukowo, Lebsko, and Jamno. The health of the swimbladder was evaluated using the swimbladder degenerative index (SDI). The mean value of the SDI for all of the eel examined was 3.3, and extensively degenerated swimbladders were observed mainly in samples in the Szczecin Lagoon and from lakes. According to the individual SDI ratings, 9.1% of the eel specimens did not exhibit pathological symptoms of the swimbladder (SDI-0) and an extremely damaged (SDI-6) swimbladder was noted in 11.7% of the fish examined. In the case of eel infected with A. crassus, higher SDI values were reflected in initially increasing shares in subsequent categories. In fish that were not infected with the nematode, only 20% (8 individuals) of the swimbladders showed no symptoms of pathology (SDI-0). PMID- 22844703 TI - Antimicrobial susceptibility of Brachyspira hyodysenteriae isolated from 21 Polish farms. AB - Swine dysentery (SD) is a common disease among pigs worldwide, which contributes to major production losses. Antimicrobial susceptibility testing of B. hyodysenteriae, the etiological agent of SD, is mainly performed by the agar dilution method. This method has certain limitations due to difficulties in interpretation of results. The aim of this study was the analysis of antimicrobial susceptibility of Brachyspira hyodysenteriae (B. hyodysenteriae) Polish field isolates by broth microdilution procedure. The study was performed on 21 isolates of B. hyodysenteriae, collected between January 2006 to December 2010 from cases of swine dysentery. VetMIC Brachyspira panels with antimicrobial agents (tiamulin, valnemulin, doxycycline, lincomycin, tylosin and ampicillin) were used for susceptibility testing of B. hyodysenteriae. The minimal inhibitory concentration (MIC) was determined by the broth dilution procedure. The lowest antimicrobial activity was demonstrated for tylosin and lincomycin, with inhibition of bacterial growth using concentrations > 128 microg/ml and 32 microg/ml, respectively. In the case of doxycycline, the MIC values were < or = 2.0 microg/ml. No decreased susceptibility to tiamulin was found among the Polish isolates and MIC values for this antibiotic did not exceed 1.0 microg/ml. The results of the present study confirmed that Polish B. hyodysenteriae isolates were susceptible to the main antibiotics (tiamulin and valnemulin) used in treatment of swine dysentery. Further studies are necessary to evaluate a possible slow decrease in susceptibility to tiamulin and valnemulin of B. hyodysenteriae strains in Poland. PMID- 22844704 TI - Application of real-time PCR for detection of Lawsonia intracellularis and Brachyspira hyodysenteriae in fecal samples from pigs. AB - The aim of the study was to develop and validate real-time PCR method for the quantification of Lawsonia intracellularis and Brachyspira hyodysenteriae in porcine feces. Before the optimization process was performed two different extraction methods were compared to select the more efficient one. Based on the results achieved at this stage the boiling procedure was rejected and a commercially available silica-membrane based method was chosen for further analysis. The primers and the Taqman probe for B. hyodysenteriae and L. intracellularis were based on the sequence of NADH oxidase gene and 16S rDNA gene, respectively. The detection limit of the real-time PCR for suspension of feces inoculated with B. hyodysenteriae and L. intracellularis was determined to be 1.5x10(3) CFU/ml and 6.5x10(1) CFU/ml, respectively. The results of this study demonstrate that our real-time PCR is able to detect low number of B. hyodysenteriae and L. intracellularis cells which is satisfying in routine diagnosis of swine dysentery and proliferative enteropathy. Therefore, it is possible to identify both subclinically infected pigs and those representing an acute form of mentioned diseases. In summary, the quantitative real-time PCR is useful for routine diagnosis of L. intracellularis and B. hyodysenteriae. Compared to conventional PCR, the new validated quantification method based on real-time PCR is fast and with reduced risk of laboratory contamination. The novel technique is specific and even more sensitive than the previously used one. Furthermore, the new real-time PCR enables quick detection and quantification of both pathogens in fecal samples, which helps to estimate the health status of a pig herd. PMID- 22844705 TI - The influence of feed phosphates on the structural, mechanical and chemical properties of bone tissue in pigs. AB - The aim of the study was to assess the influence of various feed phosphates on the structural and mechanical properties as well as on the chemical composition of femurs in adult pigs (weight approx. 110 kg). Three types of phosphates- monocalcium phosphate (MCP), dicalcium phosphate (n-DCP) and calcium-sodium phosphate (CSP)--were used alternatively in pigs fed with the standard feed mixture. The MCP and CSP phosphates were typical, imported products used traditionally in pig feeding. Dicalcium phosphate (n-DCP) was manufactured in Poland on the basis of phosphoric acid with the new pro-ecological method. The following parameters were determined: the mean physical density of the samples of the compact and spongy bone tissue, values of Young's modulus, strength and the energy of deformation, and Vickers microhardness (HV). Also the content of C, O, Na, Mg, Al, and Si, as well as Ca, P and Sr was determined. Significant differences in mean values of the mentioned parameters occurred between the studied groups. The best mechanical properties were shown by the bones from the n DCP group, and the compact bone tissue (diaphysis) contained the most Ca, P, and Sr when compared to the MCP and CSP groups. PMID- 22844706 TI - Assessment of treatment of Osteochondrosis dissecans (OCD) of shoulder joint in dogs--the results of two years of experience. AB - Osteochondrosis is a common and clinically important joint disorder that occurs in human and many species of animals such as pigs, horses and dogs. The aim of this article is to present the results of conservative and surgical treatment of Osteochondrosis dissecans (OCD) and to compare the recovery time in relation to race, age and extent of cartilage damage. The study was performed on 36 dogs of both sexes, aged from 4 to 24 months, weighing 12-70 kg, of different breeds (predisposed and non-specific for this disease). All patients underwent clinical, orthopedic and radiological examination through which the location of OCD changes in the shoulder joint and the degree of this problem were established. Based on the examinations the patients were qualified for particular treatment procedures. Control tests were performed after 14, 30 and 60 days, which allowed for a precise evaluation of the progress of therapy. Achieved results indicate that dogs age and the lesions extent in the shoulder joint have an impact on the outcome of treatment. Studies showed that the best therapeutic effects were obtained in dogs aged 6-10 months, which underwent surgery. The study proved that the early diagnosis of OCD strongly influence the recovery rate and may inhibit the development of degenerative changes in the joint (DJD). PMID- 22844707 TI - Concentration of serum amyloid A and ceruloplasmin activity in milk from cows with subclinical mastitis caused by different pathogens. AB - The aim of the present study was to determine the concentration of serum amyloid A (SAA) and the activity of ceruloplasmin (Cp) in milk from cows with subclinical mastitis caused by different pathogens. Eighty-four milk samples from cows with subclinical mastitis and fourteen milk samples from healthy cows were examined. SAA concentration was determined using the commercial ELISA kit (Tridelta Development Ltd., Greystones, Wicklow, Ireland). Cp activity was assessed spectrophotometrically, using the Rice method. The results reveal that the concentration of SAA (with exception of CNS) and activity of Cp in cow milk can be regarded as markers of subclinical mastitis, irrespective of the microorganism inducing the disease. In conclusion, measurement of SAA and Cp in milk samples could be a useful method in diagnosing subclinical mastitis in cows, but the method should be adapted for field use. PMID- 22844708 TI - The influence of steroids on noradrenaline-mediated contractile reactivity of the superficial nasal and facial veins in cycling gilts. AB - The nasal venous blood may be directed through the facial vein into the systemic circulation or through the frontal vein into the venous cavernous sinus of the perihypophyseal vascular complex, where hormones and pheromones permeate from the venous blood into the arterial blood supplying the brain and hypophysis. The present study was designed to determine the effect of noradrenaline (NA) on the tension of the nasal, frontal and facial veins of cycling gilts, and influence of ovarian steroid hormones on NA-mediated contractile reactivity. Additionally, the enzyme dopamine-beta-hydroxylase catalysing the conversion of dopamine to noradrenaline (DbetaH) was immunolocalized in these vessels. Among three studied veins, the frontal proximal vein, that fulfill a key role in the supply of the nasal venous blood into the venous cavernous sinus, reacted to NA most strongly (P < 0.001) and this reaction was weaker in the periestrous period than in luteal phase (P < 0.001). Inversely, the reaction to NA of the facial proximal vein, that carry blood to the peripheral circulation, was stronger in the periestrous period than in luteal phase (P < 0.05). P4, E2 and T significantly lowered NA mediated tension of the frontal proximal vein during the periestrous period (P < 0.001), while in the luteal phase P4 might antagonize relaxing effect of E2 to this vessel. The result suggests that supply of the nasal venous blood into the venous cavernous sinus is greater during the periestrous period than during the luteal phase. DbetaH was clearly expressed in the muscular layer of the isolated superficial nasal and facial veins of gilts in both studied stages of the estrous cycle. We suggest that the reactivity of the superficial veins of the nose and face to NA combined with the previously demonstrated reactivity of these veins to steroid ovarian hormones and male steroid pheromones may regulate the access of priming pheromone androstenol (resorebed in the nasal cavity) to the brain of gilts during periestrous period via humoral local destination transfer. PMID- 22844709 TI - Influence of betulinic acid on lymphocyte subsets and humoral immune response in mice. AB - Betulinic acid is a pentacyclic triterpene found in many plant species, among others, in the bark of white birch Betula alba. Betulinic acid was reported to display a wide range of biological effects, including antiviral, antiparasitic, antibacterial, anticancer and anti-inflammatory activities. The effects of betulinic acid (50, 5, 0.5 mg/kg) administered orally five times at 24 hours intervals to non-immunized and red blood cells (SRBC)-immunized mice were determined. The present study examined the total number of lymphocytes in the thymus, spleen and mesenteric lymph nodes, and the percentage of subsets of T cells (CD4+CD8+, CD4CD8, CD4+, CD8+) in thymus,T (CD3+, CD4+, CD8+) and B (CD19+) lymphocytes in the spleen and mesenteric lymph nodes, as well as white blood cell (WBC) and differential leukocyte counts in non-immunized mice, and humoral immune response in SRBC-immunized mice. SRBC was injected 24 hours after administration of the last dose of betulinic acid. It was found that betulinic acid administered orally five times at the dose of 0.5 mg/kg increased the total number of thymocytes, splenocytes, lymphocytes of mesenteric lymph node cells, and the weight ratio of the spleen and mesenteric lymph nodes in non-immunized mice. Betulinic acid also changed the percentage of T cell subsets in the thymus and T and B lymphocytes in peripheral lymphatic organs. The effects of betulinic acid on T and B cell subpopulations depended on the dose applied. The strongest stimulating effect of betulinic acid was observed when the drug was administered at the dose of 0.5 mg/kg. Five exposures to betulinic acid (0.5 mg/kg) decreased the percentage of immature CD4+CD8+ thymic cells with corresponding increases in the percentage and absolute count of mature, single-positive CD4+ thymocytes and decreased the percentage and total count of CD3+ splenocytes and mesenteric lymph node cells with corresponding decreases in the percentage and absolute count of CD4+ and CD8+ cells. Multiple administration of betulinic acid at the investigated doses augmented the percentage and absolute count of CD19+ cells in the peripheral lymphatic organs. Moreover, betulinic acid at the dose of 5 mg/kg administered prior to SRBC immunization increased the number of plaque forming cells (PFC) but decreased the production of anti-SRBC antibodies on day 4 after priming. Thus, betulinic acid is a potential biological response modifier and may strengthen the immune response of its host. PMID- 22844710 TI - A correlation between the canine Inflammatory Bowel Disease Activity Index score and the histopathological evaluation of the small intestinal mucosa in canine inflammatory bowel disease. AB - The aim of this study was to assess the degree of correlation between the intensity of clinical symptoms and the macroscopic and histopathological evaluation of the small intestinal mucous membrane in dogs. The results point to a statistically significant correlation between the values of the CIBDAI index and the histopathological assessment of the duodenum mucous membrane in patients with minor and moderate intensity of the disease. The lowest correlation coefficient was obtained for the indicator comparing macroscopic and histopathological evaluations. A positive correlation between the CIBDAI score and the histopathological index offers a base for applying it in the monitoring and treatment of mild, moderate and severe cases of canine inflammatory bowel disease. PMID- 22844711 TI - Avian influenza viruses in wild birds at the Jeziorsko reservoir in Poland in 2008-2010. AB - During a 3-year surveillance study for avian influenza virus (AIV) infections at the Jeziorsko reservoir in central Poland, 549 oropharyngeal or cloacal swabs from 366 birds of 14 species belonging to 3 orders (Anseriformes, Charadriiformes and Gruiformes) were tested. AIV was detected in 14 birds (3.8%): Common Teals (12x), Mallard (1x) and Garganey (1x). Three potentially dangerous H5 AIV were detected in Common Teals (2x) and Garganey (1x) but all of them revealed a low pathogenic pathotype. A unique cleavage site amino acid motif PQREIR*GLF was found in one H5 isolate from a Garganey. PMID- 22844712 TI - Limited genetic diversity of Aerococcus viridans strains isolated from clinical and subclinical cases of bovine mastitis in Slovakia. AB - The Aerococcus viridans isolates from bovine mastitis in Slovakia were isolated and characterized by classical microbiological and biochemical, and molecular techniques including IGS-PCR and rep-PCR, ARDRA and 16S rDNA gene sequencing. The substantial variability of antibiotic resistance patterns was observed. The majority of strains were resistant to beta-lactam antibiotics, the resistance to tetracycline was observed in 3 tested strains, resistance to lincomycin was found in 4 strains and practically all tested strains were sensitive to neomycin and ciprofloxacin. While variable at a phenotypic level, no significant genetic variability among A. viridans isolates was detected by molecular DNA based methods. The data obtained suggest that a few A. viridans strains spread among cow's population in Slovak farms. PMID- 22844713 TI - Simultaneous detection of astrovirus, rotavirus, reovirus and adenovirus type I in broiler chicken flocks. AB - Enteric diseases cause substantial economic losses to the poultry industry. Astroviruses, rotaviruses, reoviruses, and adenovirus type 1 have been reported as a significant cause of intestinal symptoms in poultry. In the present study, intestinal samples from 70 commercial broiler chicken flocks were examined for the presence of astroviruses, rotavirus, and reovirus by reverse transcription polymerase chain reaction, and for the presence of group I adenovirus by polymerase chain reaction. Astroviruses were identified in 38.6% of samples tested. Both avian nephritis virus and chicken astrovirus were identified in the astrovirus positive flocks, where 74.1% of these flocks were positive for only one type of astrovirus, whereas, 25.9% of these flocks were positive for both types of astrovirus. Reoviruses, rotaviruses, and adenoviruses were identified in 21.4, 18.6, and 14.3% of these flocks, respectively. Concomitant infection with two or more viruses in the same flock were also prominent, where 5.7, 5.7, 2.9, 2.9, 1.4, and 1.4% of these flocks were positive with both astrovirus and rotavirus; astrovirus and adenovirus; astrovirus and reovirus; rotavirus and adenovirus; rotavirus and reovirus; and reovirus and adenovirus respectively. Moreover, 4.3 and 2.7% of these flocks were positive for astrovirus, reovirus, and adenovirus; and astrovirus, reovirus, and rotavirus, respectively. Further studies will focus on identifying specific viral factors or subtypes/subgroups associated with disease through pathogenesis studies, economic losses caused by infections and co-infections of these pathogens, and the costs and benefits of countermeasures. PMID- 22844714 TI - Botulinum toxin type A-induced changes in the chemical coding of dorsal root ganglion neurons supplying the porcine urinary bladder. AB - Botulinum toxin type A (BTX) is a potent neurotoxin, which in recent years has been effectively applied in experimental treatments of many neurogenic disorders of the urinary bladder. BTX is a selective, presynaptically-acting blocking agent of acetylcholine release from nerve terminals what, in turn, leads to the cessation of somatic motor and/or parasympathetic transmission. However, application of this toxin in urological practice is still in the developmental stages and the full mechanism of its action remain elusive. Thus, the present study was aimed at investigating the neurochemical characterization of dorsal root ganglion (DRG) neurons supplying the porcine urinary bladder after BTX treatment. Retrograde tracer Fast Blue (FB) was injected into the urinary bladder wall in six juvenile female pigs and three weeks later, intramural bladder injections of BTX (100 IU per animal) were carried out in all the animals. After a week, DRG from L1 to Cql were harvested from the pigs and neurochemical characterization of FB+ neurons was performed using double- labeling immunofluorescence technique on 10-microm-thick cryostat sections. BTX injections led to a significant decrease in the number of FB+ neurons containing substance P (SP), calcitonin gene-related peptide (CGRP), calbindin (CB), somatostatin (SOM) and neuronal nitric oxide synthase (nNOS) when compared with that found in the healthy animals (19% vs. 45%, 18% vs. 36%, 0.6% vs. 3%, 0.4 vs. 4% and 0.1% vs. 6%, respectively) These data demonstrated that BTX changed the chemical coding of bladder sensory neurons, and therefore this drug should be taken into consideration when it planning experimental therapy of selected neurogenic bladder disorders. PMID- 22844715 TI - Tetrodotoxin induced changes in the chemical coding of dorsal root ganglion neurons supplying the porcine urinary bladder. AB - Tetrodotoxin (TTX) mode of action is based on a blocking of fast sodium channels in nerve cell membrane what, in turn, abolishes the propagation of the action potential along the nerve fibers. TTX is currently used in experimental therapies focused on neoplastic or neurogenic pain, however, as for now there is no data concerning the influence of TTX on dorsal root ganglion (DRG) sensory neurons function. Thus, the present study was aimed at characterization of neurochemical coding of porcine sensory bladder-projecting cells after bladder instillation with TTX. Retrograde tracer Fast Blue (FB) was injected into the urinary bladder wall of six juvenile female pigs and three weeks later bladder instillation with TTX (12 microg per animal) was carried out in all animals. A week later, DRGs of interest were harvested from all animals and the neurochemical characterization of FB+ neurons was performed using routine double-immunofluorescence labeling technique on 10-microm-thick cryostat sections. In TTX-treated animals the number of FB+ cells containing galanin (GAL), nitric oxide synthase (NOS), somatostatin (SOM) and calbindin (CB) was 2.5%, 2%, 0.25% and 0.2%, respectively and that of pituitary adenylate cyclase-activating polypeptide (PACAP)-immunoreactive (IR) cells was 43%. These data when compared with previous reports, demonstrated that TTX profoundly changed the chemical coding of porcine bladder-projecting sensory neurons thus implicating that it may be used in case of hypoactivity of afferent part of reflex arc responsible for transmission of sensory information from the urinary bladder. PMID- 22844716 TI - Zearalenone and deoxynivalenol mycotoxicosis in dairy cattle herds. AB - Mycotoxin contaminations pose a growing problem in animal production from the economic and toxicological point of view. Clinical symptoms of mycotoxicosis are relatively unspecific, making the disease difficult to diagnose. This study presents a clinical case of dairy cattle infected with natural mycotoxins produced by fungi of the genus Fusarium (zearalenone [ZEA] and deoxynivalenol [DON]) in eastern Poland. In dead and infected cows, the presence of ZEA and DON was determined in the blood serum, significant changes were observed in blood morphological and biochemical profiles, extravasations and bowel inflammations were also observed. The results reported testify to an acute autoimmune process in the intestines as well as immunosuppression. PMID- 22844717 TI - Inhibition of in vitro Histophilus somni biofilm production by recombinant Hsp60 antibodies. AB - Histophilus somni is an opportunistic pathogen causing respiratory, genitourinary and generalized infections in cattle. An important virulence factor is its ability to produce a biofilm. The aim of this work was to confirm that H. somni Hsp60 (Gro-EL) is a constituent of the biofilm produced by this bacterium in vitro and to check whether or not the presence of a specific antibody within the culture medium can inhibit biofilm production. Biofilm production by H. somni cultured in vitro was confirmed by crystalline violet staining. The presence of Hsp60 in the biofilm was confirmed by using specific antibodies produced in a mouse and goat hyperimmunized with H. somni recombinant Hsp60 (rHsp60). Large complexes of biofilm stained with Hsp60 antibodies were microscopically detected. This indicates that the Hsp60 protein is a common constituent of the biofilm produced by H. somni in vitro. In a second experiment, mouse serum containing anti-H. somni rHsp60 antibodies was added to an H. somni culture. It was found that the presence of anti-rHsp60 antibodies in the culture medium inhibited biofilm production in vitro. Only small biofilm particles were seen in the presence of the specific antibody, whereas in control cultures (without specific antiserum) large biofilm complexes were produced. The results indicate that antibodies specific to Hsp60 may be useful for preventing H. somni biofilm formation in vitro. If this also occurs in vivo, it may be helpful for eradicating H. somni infection in cattle through the elimination of carriers. Further in vivo studies are needed to confirm this idea. PMID- 22844718 TI - The effect of supplementing organic diets with fish meal and premix on the performance of pigs and some meat and blood characteristics. AB - The aim of this study was to determine the effect of fish meal and mineral vitamin premix, supplementing organic diets, on the performance of pigs and some meat and blood characteristics. The experiment was conducted on an organic pig fattening farm. The study involved 120 pigs with an approximate 25 kg body weight. Animals were divided into 3 groups, kept in pens, 10 animals each. Group I (control) animals were fed with plant feedstuffs of organic origin. Diets for group II and III were enriched with fish meal or fish meal and vitamin-mineral premix, respectively. The experiment was carried out till pigs reached a weight of 115 kg. Feed samples were subjected to laboratory analyses. Body weight (3 times) and feed intake were recorded. Blood samples were collected (2 times) to determine hematological and biochemical indices. Some parameters in meat samples were also determined. The fish meal addition improved (P < or = 0.05) the average daily gains as well as feed conversion ratio during fattening period and mineral vitamin premix significantly (P < or = 0.05) fortified fish meal influence. Fish meal supplement improved (P < or = 0.05) also some carcass characteristics. Supplementation of the diet with premix additionally decreased (P < or = 0.05) backfat thickness and increased share of meat in carcass. Fish meal improved (P < or = 0.05) some meat characteristics and elevated content of some polyunsaturated fatty acids. An increase in hemoglobin, red blood cell, white blood cell and cholesterol level in blood of animals from both experimental groups were also found. The results obtained proved the usefulness of fish meal and mineral vitamin premix in the fatteners nutrition based on organic diets. PMID- 22844719 TI - Modulation of specific biochemical blood parameters by helminth infection in laboratory Beagle dogs. AB - The objective of this study was to examine the independent effect of helminths infection on biochemical blood parameters in Beagles intended for laboratory use which may contribute to a change of experimental results. As a result of research, the authors confirmed the negative effect of helminth invasion on the metabolism of the liver and kidney in laboratory dogs. Stool samples from thirty Beagle puppies were examined for parasites before the puppies were moved to the animal facility, and all were dewormed with Vetminth paste on the day they were moved. Stool examination was performed three more times and animals were given Drontal Plus flavor (Bayer) and Baycox 5% (Bayer). A fourth parasitological examination revealed no intestinal parasites in the feces. Three blood biochemical tests were performed. Experimental results clearly indicate the significant impact of intestinal parasites in dogs used in experiments. PMID- 22844720 TI - Comparison of the influence of EDTA-K3 and sodium citrate on haematology analysis in healthy dogs. AB - The study was carried out on 30 clinically healthy dogs of various breeds. Haemoglobin concentration, haematocrit, platelet count and platelet haematocrit were significantly lower in citrate blood than in tripotassium ethylenediaminetetraacetic acid (EDTA-K3) blood. The study confirmed the limited usage of sodium citrate in haematology analysis, unless canine EDTA-dependent thrombocytopenia is suspected. PMID- 22844721 TI - The identification of Anaplasma spp. isolated from fallow deer (Dama dama) on a free-range farm in eastern Poland. AB - The aim of the present study was to investigate the occurrence of Anaplasma spp. in group of 50 fallow deer (Dama dama) from free-range farm in eastern Poland and determine what species of Anaplasma could infect these animals based on PCR gene sequencing. The PCR technique revealed the presence of 16S RNA Anaplasma spp. genetic material in the blood of 7 out of 50 examined animals. The sequences of the PCR products obtained showed a 100% homology with each other and 100% homology with GU 183908 sequence of A. phagocytophilum, isolated in our earlier study from a horse with clinical form of anaplasmosis. Here, we report the first molecular evidence of Anaplasma spp. among naturally infected fallow deer in eastern Poland. PMID- 22844722 TI - The effect of humic-fatty acid preparation on selected haematological and biochemical serum parameters of growing rabbits. AB - In this study, we assessed the effect of a humic-fatty acid preparation (HFA) used in rabbit feed on certain haematological and biochemical serum parameters (the lipid profile and the Ca, P and Fe contents). A higher RBC, HGB and HCT values were observed in the groups that were given HFA. An increase in Fe concentrations were also noted. The total and LDL cholesterol were lower in the groups which received HFA than in the control group. PMID- 22844723 TI - Factors affecting acetone concentration in blood of dairy cows at the first stage of lactation. AB - The aim of this paper was to determine effects of selected genetic and environmental factors on the concentration of acetone in blood of cows in the first trimester of lactation. The study included 124 Polish Holstein-Friesian primiparous cows born, reared and managed on the same farm. The samples of blood were collected on day 2, 5, 30, 60 and 90 after calving. The highest serum acetone concentration in the animals examined was observed on day 5 after calving. The level of this compound was inversely related to the contribution of the original Holstein-Friesian breed in gene pool. Significantly higher serum acetone level was observed in cows calved in January-March period when compared to other months of the year. Besides, the level of acetone determined on day 5 after calving was associated positively with body weight determined at the same day and negatively with body weight changes between days 5 and 60 after calving. PMID- 22844725 TI - [The three-dimensional structure of the ribosome]. PMID- 22844724 TI - Biological effects of conjugated linoleic acids supplementation. AB - Conjugated linoleic acids (CLA) are a group of polyunsaturated fatty acids (PUFA) with a single pair of conjugated double bonds. The major natural CLA isomer is 18:2 cis-9, trans-11 (c9, t11) linoleic acid, or rumenic acid (RA). Chemically synthesized CLA is also available, mostly as a mixture of RA and 18:2 trans-10, cis-12 (t10, c12) isomers in equal amounts (50:50). Consumption of ruminant meat (beef and lamb) and dairy products (milk and cheese) is the main source of dietary exposure to CLA. Despite numerous studies on animal and human models (tumorigenesis, obesity, immune response) it has not been established whether additional supplementation of CLA is of benefit. Moreover, some studies, conducted both in animals and in humans, reveal that CLA isomers may induce insulin resistance. Presently, balanced diet rich in CLA from natural sources is recommended. The purpose of this review was to sum up the results available in the literature. PMID- 22844726 TI - [Hepcidin and diabetic anemia: is there an association?]. AB - BACKGROUND: Anemia is common in diabetes. The role of hepcidin in diabetic anemia is unknown. OBJECTIVES: To assess the relationship between serum hepcidin and anemia in diabetic patients without renal failure. METHODS: We prospectively studied 86 consecutive type II diabetic patients--39 with anemia (cases) and 47 without anemia (controls). Patients with renal failure, iron and vitamin B12 deficiency and chronic inflammatory diseases were excluded. RESULTS: Univariate analyses showed that patients with anemia were older and had longer duration of diabetes compared to patients without anemia (P < 0.051). The median hepcidin level was 15 ng/mL (2-140 ng/ml) in patients with anemia compared to 14 ng/mL (2 128 ng/ml) in patients without anemia (P = 0.386]) Serum erythropoietin and creatinine levels were higher in patients with anemia compared to patients without anemia (P < 0.05). Patients with anemia had tower HbA1c levels (P = 0.035), and greater usage of anti-diabetic drugs; metformin 73% versus 46.8% (P = 0.016), and sulfonylurea 47.2% versus 19.1% (P = 0.006). After adjusting for age, the two groups still differed in duration of diabetes (P = 0.043), erythropoietin (P = 0.007) creatinine (P < 0.001), and usage of metformin, sulfonylurea and insulin (P < 0.05). CONCLUSIONS: Subjects with diabetic anemia have Longer diabetes duration than subjects with diabetes without anemia. Based on the results of this small study, hepcidin was not associated with diabetic anemia. PMID- 22844727 TI - [The learning curve of video-assisted thoracoscopic surgery (VATS) for lung lobectomy--a single Israeli center experience]. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) is a method of lung lobe resection that has been implemented in medical centers worldwide since 1992. This procedure utilizes video equipment to assist in performing lobectomies without the need to open the chest wall As of 2009, VATS has been performed in the generaL thoracic surgery department of Rambam HeaLthcare Campus, Haifa. Since then, more than 200 patients were successfully operated on using this method. This study analyzed the Learning curve experienced by its surgeons and departmental staff since VATS implementation. METHODS: Patient files for all cases which underwent VATS in the department from January 2009 to June 2010 were retrospectively evaluated. The patients were divided into three groups based on their operation date; each group included patients that were operated on during a half-year interval. Data was collected and compared between the groups in regard to the percentage of surgeries that used VATS versus procedures which involved opening the chest wall, procedure time, duration of hospital stay, conversion ratios for closed to open operations, and intra and post-operative complications. Subsequent results were then compared to those reported from other countries around the world. RESULTS: VATS Lobectomies comprised the smallest percentage of the total Lobectomies performed in the department during the first 6 months of analysis (January 2009 - June 2009] as compared to the following year of analysis (July 2009 - June 2010), that involved a much more extensive use of VATS. The first 6 months of VATS implementation also involved fewer intra-operative complications and shorter operation times as compared to the following year. The length of stay and the number of post-operative complications were similar in each time interval analyzed. CONCLUSIONS: VATS lobectomy requires surgeons and departmental staff to face a steep learning curve. Operators should invest 6-12 months usage of VATS and perform 30-60 operations in order to achieve constant results that are consistent with those reported from other medical centers worldwide. PMID- 22844728 TI - [Factors influencing short-term and long-term prognosis in patients hospitalized for chest pain]. AB - BACKGROUND: The differential diagnosis of chest pain in the emergency department (ED) is broad, but the ability of the physician to distinguish between life threatening and benign situations is Limited. OBJECTIVES: (1) To evaluate the in hospital major adverse cardiac events (MACE) among patients admitted to the hospital for chest pain and their five years mortality rate. (2) To find factors in the ED which influence the short- and Long-term prognosis. METHODS: This is a retrospective cohort study. All patients admitted to the hospital only for chest pain, in a five months period, were identified. In-hospital MACE and five years mortality rates were recorded and evaluated in respect to the demographic and personal history of the patients and to tests performed in the emergency department. RESULTS: The MACE rate was Less than 10%. In-hospital mortality was 0.46%. People who had in-hospital MACE were older, with typical chest pain, higher blood CPK level within the normal range, and ST depression on ECG in the ED. The five-year mortality rate was 13.6%. MortaLity was higher among women, older people with past MI, diabetics and in patients with lower hemoglobin and higher creatinine Levels at the ED. CONCLUSIONS: In this group of ED patients with chest pain the MACE rate is small, and mostly appears in older patients with typical chest pain, higher CPK Levels within the normal range and ST depression on ECG. Long term prognosis depended on age, history of diabetes meLlitus and the blood hemoglobin level at the ED. PMID- 22844729 TI - [Sarcoidosis presenting with recurrent aseptic meningitis and acute hearing loss]. AB - Neurologic complications occur in 5% of patients with sarcoidosis. Neurosarcoidosis ranges from mild neurologic deficits to a destructive, life threatening disease, and at times is the only presenting symptom of sarcoidosis, thus posing a diagnostic challenge for the doctor neurologic symptoms include cranial nerve palsies, with the vestibulocochlear nerve rarely being involved. We present a patient with neurosarcoidosis manifesting as recurrent episodes of aseptic meningitis, vertigo, and acute hearing loss. PMID- 22844730 TI - [Nitrate prescriptions in primary care--are we over-prescribing? A pilot intervention]. AB - PREFACE: Nitrates vasodilate coronary arteries that are already compensatory dilated due to ischemia and increase the coronary blood flow. In the short term, the use of nitrates, after myocardial infraction has advantages, while prolonged use can even be associated with an increase in sudden death. PURPOSE: To characterize patients treated with nitrates in a primary care clinic and examine whether a lecture concerning benefits and harms of nitrates will cause discontinuation of their use. METHODS: An interventional study performed in one primary care clinic. The clinic physician attended a Lecture on nitrates, including benefits and harms. The outcome measure was the number of patients that stopped using nitrates. The last stage included interviews with patients concerning their symptoms, six months after intervention. RESULTS: Of the 8794 patients treated in the clinic, 284 (3.2%) were treated with nitrates; 166 of the patients were using nitrates on a regular basis; 75 (26.4%) of those using nitrates did not have a clinical indication for chronic use. Nitrates were discontinued in 40 patients (53.5% of those taking nitrates with no indication). Of the patients who stopped taking nitrates, 26 (65%) remained asymptomatic after 6 months. DISCUSSION: We found that there was over-prescription of nitrates and that the family physician, based on anamnesis and data from the medical file, can stop nitrate treatment to about 10% of these patients without any significant harm. CONCLUSION: A family physician can stop nitrate treatment based on anamnesis and data from the medical file. PMID- 22844731 TI - [The cognitive deficit in schizophrenia]. AB - Schizophrenia is a chronic debilitating disorder with a wide spectrum of clinical phenomenology, of which the positive signs, delusions and haLLucinations are best known. The cognitive deficit in schizophrenia patients is one of the prominent dimensions of the disorder The deficit starts early in the course of the disease even before the other signs manifest, it is profound and pervasive and involves several skills including the working memory, attention, learning and social functioning. The current pharmacotherapy for schizophrenia does not affect the cognitive status. Moreover, it appears that the severity of the deficit is the best predictor for social functioning in the community. In recent years, the cognitive deficit is the focus of research. As a result, a battery of cognitive tests was established and validated as a consensus measure for assessing the deficit and evaluating the effectiveness of novel compounds geared to enhance cognitive function in schizophrenia. PMID- 22844732 TI - [Prevention and treatment of atherosclerosis and cardiovascular diseases]. AB - Atherosclerosis is one of the main causes of morbidity and mortality world-wide and specifically in Israel. These guidelines update the previous guidelines of the Israeli Society for Research, Prevention and Treatment of Atherosclerosis, published in 2005. The need for an update is based on new scientific data published in recent years necessitating changes in the recommendations for preventing and treating atherosclerosis. These guidelines were written in collaboration between all the societies outlined here and the content of this statement was approved by the delegates of these societies. The recommendations were written taking into consideration guidelines published by other international medical societies and also the specific needs of the Israeli medical system. Due to limitations of space, in the current paper we present: assessment of cardiovascular risk, smoking cessation and the treatment of dyslipidemia. Other sections including: recommendations to the general population, nutritional and physical activity recommendations, treatment of hypertension, prevention of ischemic stroke and the metabolic syndrome are available at http://www.ima.org.il/harefuah. PMID- 22844733 TI - [Biological markers in the diagnosis of dementia and Alzheimer's disease]. AB - Alzheimer's disease is the leading cause of dementia in advanced age with a prevalence of above 40% among persons 80 years or older. In recent years, new studies have made some important discoveries regarding the pathogenesis of the diseases and potential therapeutic measures. These developments have led to the announcement of new guidelines for the diagnosis of the disease published by the National Institute on Aging and the ALzheimer's Association. These guidelines expand the definition of ALzheimer's disease to include 2 new phases of the disease: pre-symptomatic and mildly symptomatic but pre-dementia. For the first time, the guidelines also incorporated the usage of biological markers to assist in the diagnosis of the disease, although they are still only in the research agenda. These biomarkers include atrophy of the medial temporal lobe by MRI, reduction of glucose metabolism in specific brain areas by PET-FDG and presence of beta-amyloid staining in the brain by PET-amyloid scan. In addition, there are also cerebrospinal fluid ICSF) biomarkers characteristic of Alzheimer's disease, which consist of low levels of Abeta42 and elevated levels of total and phosphorylated TAU. These biomarkers may be used to diagnose the disease in the early pre-symptomatic phase, to differentiate Alzheimer's disease from other causes of dementia and may be helpful in the follow-up of newly developed specific treatments. PMID- 22844734 TI - [An approach to non-motor symptoms of Parkinson's disease: an update on pathophysiology and treatment]. AB - The diagnosis of Parkinson's disease (PD) is based on the identification of at least two of the cardinal motor signs of the disease: rest tremor, bradykinesia, rigidity, and in progressive state the loss of postural reflexes. The disease is manifested mainly by motor signs but several non-motor features are present in patients with PD. Often, these non-motor symptoms can precede the motor features of the disease. We review part of the different non-motor symptoms that can be present in patients with PD. In many cases, the non-motor symptoms could cause important Limitations in the functionality of the patients, no less than the motor symptoms, and they are often difficult to treat. PMID- 22844735 TI - [Clozapine--the neglected potential]. AB - Clozapine has been in use since 1975. It was withdrawn due to its toxic effects on granulocytes. It was reintroduced due to its positive effect on schizophrenia in patients who did not respond to two antipsychotic drugs. These patients suffer from a chronic debilitating disease, with numerous and sometimes chronic hospitalizations. Clozapine also has antiaggression and antisuicide effects, as well as specific effects on the negative symptoms of schizophrenia. There are severe side effects that may appear. These include suppression of granulocytes, cardiotoxic effect on the myocard, as well as cardiac conduction defects. It may also cause weight gain and early appearance of diabetis mellitus. All these side effects require strict and intensive monitoring. Clozapine blood Levels are needed for ascertaining the required dose. This article describes several reasons for the low level of use of clozapine in Israel. These include its side effect profile, tendency to use new medications, the demanding monitoring for side effects and the need for long term treatment to achieve clinical improvement. PMID- 22844736 TI - [Comprehensive geriatric assessments: what are their place and how do they contribute to care for elderly patients in Israel's health care system?]. AB - INTRODUCTION AND BACKGROUND: Comprehensive geriatric assessment (CGA) is considered a good method for diagnosing frail older people, deferring disability and providing adequate care. Since it is more expensive than a regular clinic, it should be used efficiently. STUDY GOALS: To ascertain whether CGA is provided to the appropriate population and identify changes pre- and six months post-CGA in intervention and control groups. STUDY DESIGN: Two surveys--one retrospective including atd 580 older people receiving CGA in Maccabi Healthcare Services in 2007 (data from Maccabi's database), the other a prospective semi-experimental survey, with a representative sample of 211 older people, receiving CGA in 2008, and 166 matching patients who had not received CGA (both groups interviewed twice within a six-month intervaL). FINDINGS: A total of 59% of CGA people were women, average age 79 years. Geriatric symptoms: 42% with functional disability, 63% Limited in out-of-home functions (e.g., shopping), 52%--cognitive decline, 33%- suspected depression, 41%--repeated falls, 35%--urinary incontinence. Morbidity data included: 55% suffered from heart disease, 29% diabetes, 18% malignancies, taking 7.8 medications on average. There was an improvement in health-related quality-of-life and use of services by patients receiving CGA, while this remained unchanged in the control group, with no change in the geriatric symptoms of both groups. IMPLICATIONS FOR POLICY: CGA clinics receive referrals with multiple geriatric symptoms. It is important to expand them and to formulate structured criteria to identify target populations and disseminate the criteria to physicians, in order to increase referral of suitable patients. PMID- 22844737 TI - [Medical resonance imaging (MRI)--the technology, the regulation and the utilization pattern in Israel]. AB - Medical resonance imaging (MRI) is a technology for imaging and diagnosis of tissues and organs which does not use ionizing radiation. It was developed in the 1960's and 1970's and has been in clinical use since the 1980's. Over the last two decades there has been a substantial increase in utilization of MRI due to: improvements in imaging technology and image processing, the development of new indications for its use, and the increase in availability and accessibility of MRI in several medical fields. However, there is also overutilization of this technology due to: the use of imaging as a substitute for regular physical examinations, repeated examinations for the same medical reason, "defensive" medicine, and due to the public's desire for sophisticated examinations. These issues are all responsible for the increased use of MRI. MRI is an expensive technology and therefore, cost-lowering medical and economic mechanisms are employed to Limit its use. Until recently there were ten MRI scanners in Israel and this review presents their utilization patterns. The number of MRI scanners will double in the coming years. This may improve accessibility in different regions of the country, shorten waiting times, and improve medical diagnosis due to implementation for new indications. An international comparison showed that the number of MRI scanners in Israel is lower than the average number of MRI scanners in OECD countries. However, the utilization of MRI scanners in Israel is high relative to other OECD countries, indicating the high level of efficiency of the Israeli healthcare system. PMID- 22844738 TI - [310 Ninth International Course on Occupational Skin Disease Visby, Sweden, May 2011]. PMID- 22844739 TI - [Benchmarking adoption and use of information and communication technologies in the health sector Paris, France, 30th-31th January 2012]. PMID- 22844740 TI - [Dietary intake of beef]. PMID- 22844741 TI - [Nutritional value of beef]. AB - Beef has specific nutritional qualities relative to other meats. In humans, a balanced diet, based on a ten-day period, requires intake of several nutrient classes, including iron (in the form of heme, for its high bioavailability), zinc and selenium, vitamin B12, B vitamins (especially B2 (PP) and B6), and biologically useful proteins. The lipid profile of beef depends largely on the cut. It is also influenced by the fatty acid profile of the animalfeed, andby the race andage of the animal. Adequate meat intake is recommended for all individuals, and especially those most at risk of malnutrition, such as adolescents, women of childbearing age, pregnant women, the elderly, and those individuals with a high level sports activity. PMID- 22844742 TI - [Meat and human health: excess and errors]. AB - Many studies have examined the influence of meat consumption on human health. Meat eaters have a higher body mass index and more weight gain than vegetarians. The risk of type 2 diabetes has also been linked to high meat consumption. However, the statistical correlations with these metabolic disorders are weak. There is inconsistent evidence of a higher cardiovascular risk. A link between high meat consumption and cancer, particularly colorectal cancer, has been observed in nearly all epidemiological studies. Some studies have also shown a link with breast, prostate and lung cancer. The mode of cooking could be partly En 2 responsible for this effect, due for example to heterocyclic aromatic amines production euro during grilling and intensive cooking. Advice is given. PMID- 22844743 TI - [Economic dimension and environmental impact of beef production in France]. AB - Following recent publication of data on its environmental impact, beef production is being strongly challenged. However, these data concern global ruminant production, which is highly diverse and does not necessarily correspond to the European and French situations. While it is undeniable that ruminant production contributes to global warming, there are several ways of mitigating greenhouse gas emissions, and permanent pastures serve as carbon sinks. Beef production is also a vital economic sector for many regions, where it would not be possible to produce cereals or to develop intensive animal production systems. Beef production also contributes to many collective services, justifying its continued financial support. PMID- 22844744 TI - [Conclusion]. PMID- 22844745 TI - [Modeling the spine and spinal cord]. AB - 3D reconstruction of the spine may cover morphological, mechanical and functional aspects, among others. Since the computer era, rapid progress has been made in the development of practical applications, as well in the analysis of spinal pathophysiology during growth and aging. This technology is particularly usefulfor the planning, simulation and execution of corrective surgery, invention of new procedures, and therapeutic follow-up. PMID- 22844746 TI - [Chest modelling and automotive accidents]. AB - Automobile development is increasingly based on mathematical modeling. Accurate models of the human body are now available and serve to develop new means of protection. These models used to consist of rigid, articulated bodies but are now made of several million finite elements. They are now capable of predicting some risks of injury. To develop these models, sophisticated tests were conducted on human cadavers. For example, chest modeling started with material characterization and led to complete validation in the automobile environment. Model personalization, based on medical imaging, will permit studies of the behavior and tolerances of the entire population. PMID- 22844747 TI - [The personalized digital heart]. AB - Progress in medical image analysis, biomathematics and biophysics has led to the development of the first personalized digital cardiac models that reproduce the anatomy and physiology of individual patients, permitting quantitative analysis of organ function and prediction of therapeutic effects. This article describes recent research in this field by our Asclepios project team at Inria, in collaboration with other Inria teams (Macs, Reo and Sisyphe) and external academic, clinical and industrial partners. While a number of mathematical and computational issues have to be solved before such personalized digital cardiac models can be used in routine clinical practice, these first results announce a new generation of tools in digital medicine which will help to improve preventive and predictive personalized medicine. PMID- 22844748 TI - [Biomechanical modeling of pelvic organ mobility: towards personalized medicine]. AB - Female pelvic mobility is crucial for urinary, bowel and sexual function and for vaginal delivery. This mobility is ensured by a complex organ suspension system composed of ligaments, fascia and muscles. Impaired pelvic mobility affects one in three women of all ages and can be incapacitating. Surgical management has a high failure rate, largely owing to poor knowledge of the organ support system, including the barely discernible ligamentous system. We propose a 3D digital model of the pelvic cavity based on MRI images and quantitative tools, designed to locate the pelvic ligaments. We thus obtain a coherent anatomical and functional model which can be used to analyze pelvic pathophysiology. This work represents a first step towards creating a tool for localizing and characterizing the source of pelvic imbalance. We examine possible future applications of this model, in terms of personalized therapy and prevention. PMID- 22844749 TI - [Laparoscopic cholecystectomy with transgastric gallbladder extraction]. AB - OBJECTIVE: To describe and evaluate a new cholecystectomy technique combining classical dissection with currently available mini-instrumentation (3 and 5 mm) and gallbladder removal through a short gastrotomy. METHODS: After a feasibility study, we set up a protocol for this procedure using instrumentation currently available on the market. We performed 106 procedures, including 99 in a prospective study between January 2008 and July 2010. RESULTS: Cholecystectomy was performed with the described technique in 99 of 106 eligible patients (22 males and 77 females, mean age 45.8 years (range 18-77); median BMI 26.4 kg/m2 (range 22-36)). Forty-eight patients had at least one gallstone larger than 10 mm. There were no postoperative gastric complications and recovery was always rapid. CONCLUSION: This procedure is technically feasible, safe and reproducible. The results are good, with minimal abdominal wall trauma. Normal physical activity can be resumed rapidly with no risk of incisional hernia. PMID- 22844750 TI - [Videoscopic abdominal aortic aneurysm repair]. AB - Videoscopic abdominal aortic aneurysm repair is a mini-invasive technique With the current controversies surrounding the long-term results and cost of aortic stentgrafts, videoscopy offers permanent repair of aortic aneurysms while avoiding the abdominal complications of conventional open surgery. In our experience, videoscopy provides short- and mid-term outcomes similar to those of conventional open repair in terms of safety, reliability and durability. However, this is a challenging technique and we must underscore the importance of the learning curve and of previous training in laparoscopic suture. PMID- 22844751 TI - [Simulation in pediatric surgery]. AB - Simulation in paediatric surgery is essential for educational, ethical, medicolegal and economic reasons, and is particularly important for rare procedures. There are three different levels of simulation:--simulation of basic techniques in order to learn or improve surgical skills (dissection, intracorporeal knots, etc.);--preparation for surgery using virtual reality, to perfect and test various procedures on a virtual patient, and to determine the best approaches for individual cases;--behavioral simulation underlines the importance of the preoperative check-list and facilitates crisis management (complications, conversion, etc.). PMID- 22844752 TI - [Great apes: who are they? Are they able to self-medicate?]. AB - Six great ape species (chimpanzees, bonobos, Western gorillas, Eastern gorillas, Sumatran orangutans and Bornean orangutans) live in tropical forests of Africa and South-East Asia. Their habitat, severely threatened by deforestation, contains a vast chemical and biological diversity. During the last decade, we have isolated and identified novel pharmacologically active compounds from plants used by wild chimpanzees in Kibale National Park, Uganda. Our continuous observations over the last 12 years confirm that chimpanzees, when sick, may ingest plant material that are not generally eaten, supporting the existence of self-medication among great apes. Knowledge of great-ape diseases, and the medicinal resources of tropical forests, may be improved by preserving and studying our closest relatives in their natural habitat. PMID- 22844753 TI - [Malaria in hominids]. AB - Malaria parasites (Plasmodium spp) that infect great apes are very poorly documented Malaria was first described in gorillas, chimpanzees and orangutans in the early 20th century, but most studies were confined to a handful of chimpanzees in the 1930-1950s and a few orangutans in the 1970s. The three Plasmodium species described in African great apes were very similar to those infecting humans. The most extensively studied was P reichenowi, because of its close phylogenetic relation to P. falciparum, the predominant parasite in Africa and the most dangerous for humans. In the last three years, independent molecular studies of various chimpanzee and gorilla populations have revealed an unexpected diversity in the Plasmodium species they harbor, which are also phylogenetically close to P falciparum. In addition, cases of non human primate infection by human malaria parasites have been observed. These observations shed fresh light on the origin and evolutionary history of P. falciparum and provide a unique opportunity to probe the biological specificities of this major human parasite. PMID- 22844754 TI - [Nematodes of the genus Oesophagostomum: an emerging risk for humans and apes in Africa?]. AB - Nematodes of the genus Oesophagostomum are common intestinal parasites found in cattle, pigs and primates. They can cause severe illness, resulting from the formation of granulomas, caseous lesions and abscesses in the intestinal wall. Human oesophagostomosis is endemic in northern Ghana and Togo. In these regions, epidemiological investigations have been conducted to determine the biological characteristics, transmission dynamics and optimal management of clinical cases. Nodular oesophagostomosis has also been described in free-ranging chimpanzees and gorillas. Clinical signs associated with nodules have been observed in great apes raised in sanctuaries, while the health status of their wild counterparts does not seem to be significantly affected It has been suggested that some nonhuman primates may act as reservoirs for human oesophagostomosis. In Ghana, identification of genetic differences among Oesophagostomum nematodes infecting different primate hosts suggests that oesophagostomosis is a rare zoonosis. In Uganda, where the situation is diferent, cross-infection is probably more frequent. PMID- 22844755 TI - [Bleeding risk and acute coronary syndromes in the elderly]. AB - Bleeding has recently emerged as an important factor in the management and outcome of acute coronary syndromes (ACS), particularly in elderly patients undergoing percutaneous invasive revascularization. There is evidence that patients who experience major bleeding in the acute phase of ACS are at a higher risk of death or a new infarct in the following months, although the causal nature of this relationship is controversial. In this short review we present the different definitions of bleeding, recommended strategies for the treatment of non ST elevation ACS, predictors of bleeding, and therapeutic options for reducing this risk in elderly patients. PMID- 22844756 TI - [A 13-year-old girl with acute lymphocystic leukemia who caused headache and vomiting during chronic graft versus host disease]. PMID- 22844757 TI - [Advance of the research for disease-responsible genes]. AB - Over the last three decades, many disease-responsible genes have been identified due to advancement of technologies in molecular biology. Methodologies to identify disease-responsible genes have been changed according to the history. Although large subject numbers were needed previously, valuable data derived from only one rare patient have led to identify some disease-responsible genes. Recently launched next-generation sequencers have heralded the new personal genome era. We should know that we may be able to identify some disease responsible genes by the investigation of only one patient who we meet at the bed side. PMID- 22844758 TI - [The effect of noninvasive positive pressure ventilation in children with severe motor and intellectual disabilities with respiratory insufficiency]. AB - We investigated the clinical course of 20 children (persons) with severe motor and intellectual disabilities (SMID) who were treated with noninvasive positive pressure ventilation (NPPV) for respiratory insufficiency. NPPV was effective in 10 of 11 patients treated for acute respiratory failure, and in 7 of 9 patients treated for chronic respiratory failure. Twelve patients were treated with NPPV for more than one year. There were no complications associated with NPPV in any of the patients. NPPV improved ventilation impairment soon after ventilation was started, and avoided the need for the endtracheal intubation by adjusting airway management and the choice of mask in all but one of the patients with acute respiratory failure. NPPV in combination with wearing a chin strap was highly effective in patients with open state or upper airway obstruction. Five patients were successfully weaned off the ventilator soon after recovery from acute respiratory failure using NPPV, whereas 5 patients who continued NPPV during the chronic phase after recovery did not experience recurrent episodes of acute respiratory failure. We conclude that NPPV may be an effective treatment for SMID with respiratory insufficiency. PMID- 22844759 TI - [The effect of parent training program on children with attention deficit/hyperactivity disorders and/or pervasive developmental disorders]. AB - Mothers of 18 children with attention deficit/hyperactivity disorders (AD/HD) and 6 with pervasive developmental disorders (PDD) underwent a parent training (PT) program. After the program, the Beck Depression Inventory- II (BDI - II) score, which indicates parenting stress, significantly decreased from 15 to 8 (p=0.036). A total of 22 mothers had increased parenting self-esteem, and better parent child relationships were noted in these cases. An analysis of children's behavior by using Achenbach's Child Behavior Checklist showed that introversion tendency, physical failure, aggressive behavior, and extroversion score improved significantly after PT (p<0.05). After PT, out-of-control behaviors improved in 19 children and continued in 5. We conclude that PT for mothers of children with AD/HD and/or high-functioning PDD is effective in improving both the parenting skills of mothers and adaptive behaviors of children. PMID- 22844760 TI - [Nineteen cases of school-aged children with degenerative or metabolic neurological disorders initially presenting with learning difficulty and/or behavior disturbance]. AB - We reported 19 cases of school-aged children. They were initially judged to have learning difficulty or school maladaptation because of attention deficits, hyperactive behaviors or poor school performance, followed by the diagnosis such as degenerative or metabolic neurological diseases. The patients consisted of 4 cases of adrenoleukodystrophy, 5 cases of dentatorubral-pallidoluysian atrophy, 3 cases of Sanfilippo syndrome, 3 cases of subacute sclerosing panencephalitis, and each one case of juvenile Gaucher disease, juvenile Huntington disease, juvenile metachromatic leukodystrophy and Leigh disease. They had markedly poor school performance, and/or abnormal behaviors, followed by seizures, character disorders or psychomotor regression. The diagnostic clues included brain CT scan and/or MRI, peculiar facial appearance and notable family histories. When the children were indicated to have learning difficulty or maladjustment to school life, we should make deliberate differential diagnoses before concluding that they have a learning disorder and/or attention-deficit/hyperactivity disorder. Instead they should be recommended to visit child neurologists, when they present with any problems as aforesaid. PMID- 22844761 TI - [Effect of topiramate for patients with intractable epilepsy]. AB - The effects of topiramate (TPM) were evaluated in 51 patients with intractable epilepsy. Callosotomy and hemispherotomy were performed in 16 patients and one patient before the administration of TPM, respectively. The 50% responder rate (50%RR) was recorded in 39% of the total patient population and in 58% of patients with symptomatic location-related epilepsy (SLE). TPM was most effective for frontal lobe epilepsy (FLE), and the 50%RR was recorded in 88% of those patients. TPM (50%RR) was more effective in secondary generalized seizures (in 75%) and complex partial seizures (in 67%) in comparison to that of tonic-clonic seizures (in 44%) and drop attacks (in 29%). Seventy-one percent of the patients with atypical absence seizures increased seizure frequency. The 50%RR was recorded in 22% of the patients who underwent epilepsy surgery, and 29% of those patients also showed seizure aggravation due to TPM. These results suggest the efficacy of TPM for intractable epilepsy. PMID- 22844762 TI - [Clinical study of patients undergoing paperless electroencephalography in emergency room]. AB - Fifty-eight patients who visited the emergency room of our center with febrile convulsions and impaired consciousness, and underwent paperless electroencephalography soon after arrival. They consisted of 25 male and 33 female children, ranging in age from 5 months to 15 years and 4 months, with a mean age of 4 years and 10 months. The final diagnoses were poor responsiveness associated with fever and febrile delirium in 5 patients, febrile convulsions in 26, encephalitis/encephalopathy in 24, convulsions associated with mild gastroenteritis in 2, and aseptic meningitis in 1. The appearance of spindle wave within 24 hours after admission was considered to be a favorable prognostic factor, whereas generalized high-amplitude delta waves without fast-wave components and dysrhythmic flat basic waves were considered poor prognostic factors. We conclude that bed-side paperless electroencephalography is useful for the evaluation of changes in the brain function and course of treatment. PMID- 22844763 TI - [Report of study on transitional medicine for epilepsy: questionnaire survey of pediatric neurologists]. AB - We conducted a questionnaire survey to investigate the situation of transitional medicine for epilepsy. Among the epilepsy patients cared by pediatric neurologists, 27% were adult patients including some elderly epilepsy patients. Seventy-six percent of the pediatric neurologists felt some difficulties in providing care for adult epilepsy. The main issues were psychiatric/psychological co-morbidity, medical co-morbidity, and a lack of in-patient facilities in the vicinity. This survey demonstrated that the lack of the transitional medicine for epilepsy in Japan is a profound problem, and the factors that hamper transfer of epilepsy patients to adult specialties should be resolved. To solve this problem, it is imperative that the Japanese Society of Child Neurology and Japan Epilepsy Society conduct collaborative activities with three relevant societies; Societas Neurologica Japonica, the Japanese Society of Psychiatry and Neurology, and the Japan Neurosurgical Society. PMID- 22844764 TI - [Contrast-enhanced MR imaging in bacterial meningitis in children--temporal profile and correlation with the prognosis]. AB - Treatment periods for bacterial meningitis are often very long, and often this prolonged treatment is based on the judgment of its effectiveness by the degree of enhancement on brain magnetic resonance imaging (MRI). In this study, we analyzed the contrast MRI in the acute and recovery phases of bacterial meningitis in twelve patients, and graded the contrast level of the subdural space and subarachnoid space separately. While the contrast level of the subarachnoid space increased with time in 4 cases, that of the subdural space increased in 10 cases, and 9 of them revealed a good prognosis without continuation of the treatment. These findings indicate that increased contrast level of the subdural space is common in the recovery phase of bacterial meningitis, and that repetitive MRI investigation is not valuable to determine the duration of treatment. PMID- 22844765 TI - [Effectiveness of social skills training for children with developmental disorders: behavioral analysis using a two-dimensional motion capture system]. AB - The current study sought to develop a new behavioral analysis methods to evaluate the effects of social skills training (SST). SST is known to be an effective method to improve the social skills of children with behavioral problems. However, current evaluation methods involve behavioral rating scales that are heavily dependent on evaluators' particular experiences they have had. To quantitatively examine the behavioral effects of SST, we examined subjects' head movements related to social behavior, using a two-dimensional motion capture system (Kissei Comtec, Japan). Four children (three male, one female, 7-8 years of age) with pervasive developmental disorder (PDD) or attention deficit/hyperactivity disorder (AD/HD) participated in 16 sessions of SST. Before and after SST, head-coordinates on a two-dimensional plane were calculated using their behavior during a pair task, measured by four digital cameras. After SST, the number of communication behaviors was increased compared to before SST. In addition, children looked longer at another child within 30 degrees of the central visual field. Time-series analysis of the visual field during the detection of another child revealed significant auto-correlation from about -1.12 second. before to the beginning of communication behavior (p<0.05). The results suggested that our method can provide a quantitative index of characteristics related to skilled social behaviors. We conclude that a two-dimensional motion capture system would be useful for visualization of the interventional effects of SST, which would supplement assessments by the conventional observational strategies. PMID- 22844766 TI - [Studies on bone mineral status with bone quantitative ultrasonography in severely handicapped school children--correlations with gross motor function and dietary status]. AB - OBJECTIVE: Severely handicapped children and adolescents have reduced bone mineral density and high prevalence of pathological fractures. Bone quantitative ultrasonography (QUS) is a radiation-free method for assessing bone density. It is portable and easy to use in subjects with severe bodily deformities. METHODS: We evaluated 166 students (age 6-20 years) at a school for disabled children for bone mineral density using the osteo-sono-assessment index (OSI) calculated by measuring the velocity of ultrasound waves, the speed of sound (SOS) and the transmission index (TI), at the calcaneus. All examinations were performed using an AOS-100 analyzer (ALOKA Ltd., Tokyo, Japan). The Gross Motor Function Classification System (GMFCS) for cerebral palsy was also applied. We assessed OSI for dietary texture modifications and methods of feeding. RESULTS: Those with pathological fractures tended to have lower OSI than other students. Such fractures were individually unrelated to age, sex and GMFCS. OSI was significantly higher at GMFCS level I than level II. OSI in levels I to III was equally significantly higher than that in levels IV and V. As to feeding methods, the tube feeding group tended to have lower OSI than the oral ingestion group. In the oral ingestion group, those receiving a regular diet had significantly higher OSI than the mixed-minced diet group. However, students with a gastrostomy tended to have higher OSI than those receiving gastro-nasal tube feeding. CONCLUSIONS: Gross motor function (applied GMFCS) is a major factor affecting bone mineral density. Tube feeding reduces bone mineral density. However, forced oral intake may also reduce it. In the tube feeding group, a modified diet of appropriate texture delivered via gastrostomy may be the key to improving bone mineral density. PMID- 22844767 TI - [A girl case of panayiotopoulos syndrome with encephalopathy-like manifestation]. PMID- 22844768 TI - [New findings of ubiquitin-proteasome system from yeast to higher organisms]. PMID- 22844769 TI - [Proteasome structure and function: from yeast to human]. PMID- 22844771 TI - [Plant U-box E3 ubiquitin ligases]. PMID- 22844770 TI - [RING-type ubiquitin ligase and proteasome function in plants]. PMID- 22844772 TI - [F-box proteins of plants and their various roles]. PMID- 22844773 TI - [SUMO systems and SUMO E3 ligases in plant]. PMID- 22844774 TI - [Understanding of Ub-proteasome pathway using proteomic approach in plants]. PMID- 22844775 TI - [Role of ubiquitin ligase in innate immune response in mammal]. PMID- 22844776 TI - [Molecular mechanisms of axon degeneration regulated by the ubiquitin proteasome system]. PMID- 22844777 TI - [Involvement of ubiquitin system in mammalian autophagy]. PMID- 22844778 TI - [Comprehensive study of protein ubiquitylation sites by conjugation of engineered lysine-less ubiquitin]. PMID- 22844779 TI - [Study of pathophysiology of age-related macular degeneration]. PMID- 22844780 TI - [Clinical manifestations, treatment and outcome of ocular infections caused by Paecilomyces species]. AB - PURPOSE: To report the predisposing factors, patient background, treatment and outcomes of ocular infections caused by Paecilomyces spp. in Japan. METHODS: We reviewed the medical records and the published literature in Japan on ocular infections caused by microbiologically-proven Paecilomyces spp. Nineteen eyes of 18 patients; 4 eyes of 4 of our patients and 15 eyes of 14 published Japanese patients were studied. RESULTS: Ten men and 8 women (9 OD, 8 OS, 1 OU) were diagnosed with ocular infections caused by Paecilomyces spp. The mean age was 69 years (range 33 to 90 years). The initial diagnosis of ocular infection caused by Paecilomyces spp. was keratitis in 14 eyes and endophthalmitis in 5 eyes. The final diagnosis was keratitis in 2 eyes, keratitis with involvement of the anterior segment of the eye, i.e., hypopyon or corneal rupture, in 12 eyes, and endophthalmitis in 5 eyes. The predisposing factors had a history of ocular surgery, corneal trauma and soft contact lens use. Other factors were diabetes and old age. The infections developed more often in the fall and winter. The identified Paecilomyces spp. had a high sensitivity to micafungin and voriconazole, but low sensitivity to amphotericin B, flucytosine and fluconazole. The prognosis of Paecilomyces spp. ocular infections was very poor, viz., final vision was counting fingers or worse in 60%, ocular perforation in 42%, and eye enucleation in 11%. The percentage of eyes with a final visual acuity worse than counting fingers was 0% in those with keratitis, 50% in those with involvement of the anterior segment, and 100% in those with endophtalmitis (p = 0.0446). Among the antifungal agents, the percentage of cases with final vision of counting fingers or worse was 90% with fluconazole, 80% with itraconazole, 100% with miconazole, and 71% with voriconazole. CONCLUSION: The results show that if the Paecilomyces spp. infection spreads intraocularly, it is difficult to mitigate the clinical damage even with antifungal agents with high sensitivity. PMID- 22844781 TI - [Effect of topical 0.1% brimonidine tartrate and 0.5% timolol maleate on pulmonary and cardiovascular functions]. AB - OBJECTIVE: To compare the effects of topical 0.1% brimonidine tartrate and 0.5% timolol maleate on pulmonary and cardiovascular function. SUBJECTS AND METHODS: A single-masked, randomized, parallel, 4-week-long study. One hundred elderly volunteers without respiratory or cardiovascular diseases underwent a pulmonary function test, blood pressure and pulse measurements, and 12-lead electrocardiography. The patients were divided into 2 groups, the Brimonidine group and the Timolol group. RESULTS: The one-second forced expiratory volume (FEV1.0), generally used for respiratory function, showed a significantly greater reduction in the Timolol group. The decrease in systolic blood pressure in the Timolol group was significantly smaller than in the Brimonidine group. The decrease in pulse rate in the Brimonidine group was significantly smaller than in the Timolol group. There were no appreciable findings or abnormal changes in the 12-lead electrocardiograms in either group. CONCLUSION: Brimonidine is an antiglaucoma agent with lower pulmonary risk than timolol. PMID- 22844782 TI - [Detection for retinal pigment epithelial lesions in fellow eye of age-related macular degeneration by retro-mode]. AB - PURPOSE: Using the Retro-mode (RM), to detect drusen and other minute lesions of the retinal pigment epithelium (RPE) invisible in current imaging methods in the fellow eye of Japanese patients with exudative age-related macular degeneration(AMD). DESIGN: A retrospective cross-sectional study. PATIENTS AND METHODS: The fellow eyes of nineteen Japanese patients with unilateral exudative AMD were examined using RM imaging (F-10 fundus camera, Nidek), in contrast with fluorescein angiography, indocyanine green angiography, and optic coherence tomography (3D OCT-1000, Topcon Co). We were able to identify the type of drusen and minute granular lesions (MGLs) in the RPE. RESULTS: In all patients, RM imaging gave easier to identify images of all types of drusen than other current imaging methods. Moreover, MGLs of the RPE either adjacent to drusen or without drusen, invisible in other current methods, were detected by RM imaging. CONCLUSIONS: The RM provides clearer imaging of all kind of drusen, and MGLs of the RPE invisible with current methods. These MGLs are possible precursors of drusen. PMID- 22844783 TI - [Retinal and choroidal thickness changes following intravitreal ranibizumab injection for exudative age-related macular degeneration]. AB - PURPOSE: To evaluate the retinal and choroidal thickness changes following intravitreal ranibizumab injection (IVR) for exudative age-related macular degeneration (AMD). METHODS: Twenty-eight eyes of 28 patients (average age 72.2) with newly diagnosed AMD (typical AMD 24 and PCV 4) were retrospectively examined during a 1-year follow-up. All cases first received 3 consecutive monthly injections and thereafter pro re nata (PRN) retreatment. Central retinal thickness and subfoveal choroidal thickness were measured before and 1, 3, 6 and 12 months after initial treatment using optical coherence tomography. RESULTS: The average number of injections was 5.2 times. Mean central retinal thickness significantly decreased from 456 microm at baseline to 337 microm 1 month after IVR and 280 microm 1-year after initial IVR (respectively, p<0.01). Mean subfoveal choroidal thickness was 225 microm (typical AMD was 227 microm at baseline) at baseline, 225 microm 6 months after initial IVR and 220 microm 1 year after initial IVR. There was no significant difference compared to baseline (p = 0.78 and 0.45). CONCLUSIONS: Although central retinal thickness of AMD decreased even 1-year after initial IVR, subfoveal choroidal thickness remained at 6 months and 1-year after initial IVR. Subfoveal choroidal thickness of AMD is less affected by IVR in the long term. PMID- 22844784 TI - [A case of anterior segment dysgenesis showing change in anterior eye features]. AB - PURPOSE: Using an ultrasound biomicroscope (UBM) and an endoscope just after birth, We observed the morphological changes in the anterior segment in a case of anterior segment dysgenesis. CASE: The patient was a 9-day-old baby girl born with central opacity and high intraocular pressure. The central cornea was thin and the opacity was ring-shaped. Corneal vascularization was associated with the increase in the central corneal opacity, and finally progressed to fatty degeneration. Just after birth, UBM showed a double anterior chamber in one part of the cornea. The space in the cornea was filled with solid material, and the corneal thickness worsened. Surgical endoscopy showed a red membrane on the inner side of the cornea. The red color faded with time. CONCLUSION: We reasoned that an immature corneal stroma developed after birth, and that this secondary stroma filled the space between the retrocorneal membrane and the corneal stroma. We also reasoned that the red membrane of the posterior cornea might be caused by bleeding from the corneal neovascular vessels, or that the vascular membrane of the posterior cornea encouraged proliferation of collagen fibers. Later on the vessels and bleeding regressed. PMID- 22844785 TI - [Clinico-pathological study of extraocular muscles: a case of chronic progressive external ophthalmoplegia and a case of myotonic dystrophy]. AB - BACKGROUND: A small number of patients with ocular motility disorder suffer from myodystrophic disease. Clinico-pathological reports on the extraocular muscles of such patients are rare. CASE 1: A 23-year-old woman complained of a 40 prism diopter (PD) exotropia and slight ptosis palpebrae OD. Adduction was restricted bilaterally. Chronic progressive external ophthalmoplegia was suspected. The medial rectus muscle, which was resected as a part of strabismus surgery, was examined by light-microscopy. Muscle fibers were atrophic and many ragged-red fibers were present. Eye alignment was 8 PD exophoric at 14 months after surgery. CASE 2: A 34-year-old man suffering from myotonic dystrophy presented with a 60 PD exotropia and bilateral ptosis palpebrae. Adduction was restricted bilaterally. Exotropia and ptosis OS were corrected surgically. Microscopic examination of the medial rectus muscle revealed increased adipose and collagen tissues. The muscle fibers were significantly reduced in diameter and contained multiple nuclei. The levator palpebrae muscle showed moderate atrophic change. The patient was 12 PD exophoric one month after surgery and 25 PD exotropic 8 months after surgery, and was satisfied with the results. CONCLUSION: Whenever properly indicated surgical correction is useful in treating and diagnosing strabismus due to myodystrophy when combined with pathological examinations. PMID- 22844786 TI - [A review 51: Retinopathy of prematurity]. PMID- 22844787 TI - [Biological rhythms and sleep]. AB - Sleep is regulated by dual oscillatory processes, one is the hierarchical multi oscillatory circadian system and the other is the ultradian rest-activity cycle. The circadian system is composed of the central clock located in the suprachiasmatic nucleus and the peripheral clocks in a variety of tissues which express overt rhythms. The peripheral clock(s) for sleep and wakefulness in nocturnal rodents are strongly regulated by the central clock. By contract, the peripheral clock(s) in humans is more independent of and easily desynchronized from the central clock. Nocturnal sleep is characterized by REM and nonREM cycles which appear alternatively at 1.5 to 2 hour intervals. The origin of ultradian rhythm is not known. We propose an integrated model for the regulation of sleep and wakefulness by two different oscillatory systems. PMID- 22844789 TI - [Insomnia and lifestyle-related diseases]. AB - As both insomnia and lifestyle-related diseases are associated with a variety of underlying factors, they have been considered to occur as a complication of each other. Moreover, evidence has been presented in recent studies that they are closely related to each other as risks of development and exacerbation. As unhealthy lifestyle-habits have long been recognized to increase the risks of lifestyle-related diseases and their worsening, it is natural that sleep, which takes up one third of a person's life, is markedly associated with disorders such as hypertension and diabetes. It is important to provide interventions for insomnia and other sleep disorders based on the same viewpoint as for lifestyle related diseases, and understand that lifestyle advice, including sleep hygiene, and drug treatment with sleeping pills are also effective for the treatment of lifestyle-related diseases themselves. PMID- 22844788 TI - [Changes in Japanese sleep habits and its significance]. AB - The average of sleep time in Japanese is decreasing year by year. According to data of NHK's survey, it has been lowered by one hour since 1960. The reasons are different between generations. In adolescence, the increased frequency of using internet and convenience store may cause the shortage of sleep and the deterioration of circadian rhythms. In adulthood, the working environment, such as increased number of shift-workers and excessive job time, is getting worse, and it could shorten the sleep time and exacerbate sleep quality. In old age, the frequency of taking medicine becomes higher in connection with aging. We need to be careful about the interactions between hypnotics and taking drugs prescribed to treat complications. PMID- 22844790 TI - [Clock genes and clock-controlled genes in mammals]. AB - The suprachiasmatic nucleus (SCN) is considered the master circadian pacemaker that controls most of the physical circadian rhythms of mammals including behavior. Studies of clock genes have implied that oscillatory mechanisms function in peripheral organs and isolated cells, and that they are entrained to the SCN. The circadian clock is an intracellular, transcriptional-translational mechanism that shares the same molecular components in the SCN and in peripheral cells. Hundreds of tissue-specific circadian genes that regulate an impressive diversity of biological processes have been identified using DNA microarray technology. This review summarized the recent information of clock and clock controlled genes in mammals. PMID- 22844791 TI - [Molecular oscillatory machinery of circadian rhythms]. AB - Many metabolic and physiological processes display daily rhythms oscillated by the internal circadian clock system. This rhythm is generated by interlocked transcription-(post) translation feedback loops of clock genes: the core oscillatory loop, being composed of CLOCK/BMAL1 heterodimer activating the expressions of PER and CRY that directly repress CLOCK/BMAL1, is accompanied by accessory loops consisted with REV-ERB nuclear receptor repressing Bmal1 or with DBP competing with E4BP4 on D-box site. These clock proteins are regulated by phosphorylation and ubiquitination (PER/CRY), and acetylation (CLOCK/BMAL1). Recently, a deacetylating protein SIRT1 mediated metabolic pathway is discovered to be interlocked with core oscillatory loop via Nampt expression, a late limiting enzyme in NAD+ salvage pathway. Since many key-step enzymes of metabolisms are regulated by the circadian clock, circadian clock system may intimately link to cellular metabolism. PMID- 22844792 TI - [Circadian rhythm of leptin, orexin and ghrelin]. AB - Both metabolic syndrome and sleep disorder are major health problems. Leptin, orexin, ghrelin are implicated in regulation of energy homeostasis and sleep/wakefulness. The levels of these substances exhibit circadian fluctuations, and abnormalities in these rhythms were observed in those disorders. Serum leptin levels were increased during night. Cerebrospinal fluid orexin A levels were increased during active phase. Plasma ghrelin concentrations were increased before meals and during night. High concentrations of leptin during sleep might help keeping sleep by inhibition of feeding behavior and arousal through inhibition of neuropeptide Y and orexin neurons. On the contrary, high concentrations of ghrelin before meal might enhance wakefulness through activation of orexin neurons. These results suggest that the circadian rhythms of these substances are important for maintenance of normal energy homeostasis and sleep/wakefulness. PMID- 22844794 TI - [Sleep regulatory mechanisms]. AB - The fact that resting wakefulness does not satisfy the need for sleep suggests that sleep has a critical role for the brain, probably for its maintenance or repair. Neuronal oxidative stress, neuroinflammation, or energy insufficiency in the brain is now considered to be a trigger or cause for sleep induction. And the timing for sleep is controlled by circadian clock which also exists in the brain. Sleep is occurred in the brain, which is regulated by the brain itself. "Why do we sleep ?" Although everyone wants to know the answer for this issue, scientists should still question that "How do we sleep"? PMID- 22844793 TI - [Crosstalk between central and peripheral biological clocks]. AB - Mammalian circadian system is multi-oscillator system. Clock gene expression analysis revealed that central clock, suprachiasmatic nucleus, organizes and synchronizes the peripheral oscillators in the whole body cells. Similarly, human circadian system is considered to be dual oscillation system because of internal desynchronization between melatonin, body temperature rhythms(driven by oscillator I) and sleep-wake rhythm (driven by oscillator II) under temporal isolation of dim light conditions. These oscillators control their periods mutually which means there is crosstalk of oscillators. Although the effect from oscillator II to oscillator I is weak under experimental dim light conditions, sleep-wake behavior controls light input to light sensitive oscillator I and feedbacks to sleep-wake driving oscillator II under lighting condition we live. To understand these mechanisms is important for prevention of circadian rhythm related diseases. PMID- 22844795 TI - [Melatonin as a regulator of human sleep and circadian systems]. AB - Melatonin(N-acetyl-5-methoxytryptamine) is synthesized from tryptophan and is intensively secreted into the blood only in darkness (nighttime) by the pineal gland. Melatonin is not only the most reliable marker of internal circadian phase but also a potent sleep-promoting and circadian phase regulatory agent in humans. There is evidence that daytime administered melatonin is able to exhibit short acting hypnagogic effect and phase-shifting of the circadian rhythms such that sleep timing and associated various physiological functions realign at a new desired phase. Under favor of these properties, melatonin and melatonin receptor agonists have been shown to be potent therapeutic agents for the treatment of circadian rhythm sleep disorders and some type of insomnia. PMID- 22844796 TI - [Epidemiological studies of sleep disturbance in Japan]. AB - Sleep has been a great interest in modern developed countries, epidemiological studies have been carried out extensively. In 2006, average sleep duration of the Japanese men, has been reported 7 hours 49 minutes (9 minutes shorter than 20 years ago) and women has been reported 7 hours 35 minutes (7 minutes shorter than 20 years ago). Sleep habits is affected by gender, age and also social factors and lifestyle. Thus, sleep-related problems have become an important public health issue in the society in developed countries. It is important to progress the preventive health promotion activities and results that are based on the development of future epidemiological studies of sleep. PMID- 22844797 TI - [Definitions and clinical classifications of sleep disorders]. AB - Sleep disorders are defined as disorders which symptoms or pathophysiology are related with sleep regardless of comorbid physical and/or mental disorders. Sleep disorders are classified into 6 major categories: sleep related breathing disorders which exhibit abnormal breathing during sleep, sleep related movement disorders which show involuntary movements and/or abnormal sensations during sleep and/or nighttime, hypersomnia of central origin not due to other sleep disorders, circadian rhythm sleep disorders due to desynchronization between sleep-wake pattern and required social schedule, parasomnia which exhibit abnormal behavior during sleep and/or around sleep, and insomnia not due to other sleep disorders. PMID- 22844798 TI - [Diagnosis and treatment in circadian rhythm sleep disorders]. AB - Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article. PMID- 22844799 TI - [Links between circadian system and human health]. AB - There is now reason to speculate that disruption of circadian rhythms of physiology and behavior may have broader implications for human health. A long history of clinical epidemiology in humans demonstrates an increased incidence of obesity, cardiovascular disease and cancer among shift workers. Clues from studies on the molecular genetics of circadian clock genes may offer insight into the molecular mechanisms underlying the circadian variation of metabolic coordination. A better understanding of the impact of circadian gene networks on nutrient balance at the molecular, cellular, and system levels promises to shed light on the emerging association between disorders of diabetes, obesity, sleep, and circadian timing. PMID- 22844800 TI - [The impact of sleep disturbances on neuroendocrine and autonomic functions]. AB - Sleep plays a pivotal role in the regulation of autonomic functions such as heart rate, body temperature and blood pressure. It also influences endocrine functions, including the secretion of pituitary hormones, leptin and ghrelin, as well as energy homeostasis. In non-rapid eye movement (NREM) sleep, autonomic functioning is relatively stable with a parasympathetic dominance, whereas autonomic activity is considerably variable in REM sleep. Here, we review the regulatory role of sleep on autonomic functioning in REM and NREM sleep. We also review the role of endocrine hormones, i.e., the secretion patterns of hormones that are influenced by sleep-wake homeostasis and circadian rhythm variably. Additionally, we discuss the effect of sleep curtailment on the risk of developing metabolic diseases such as diabetes and obesity. PMID- 22844801 TI - [Sleep disorders in shift workers and life-style related disease]. AB - With Japanese social change toward a 24-hour society, a substantial proportion (ca. 27%) of workers is engaged in shift work schedules. It is known that shift workers may occasionally show a complaint of insomnia and/or excessive sleepiness. Thus, circadian rhythm sleep disorder, shift work type(shift work disorder), seems to be prevalent in our society. In shift work disorder, there is a complaint of insomnia or excessive sleepiness that is temporally associated with a recurring work schedule that overlaps the usual time of sleep. Complication may include gastrointestinal symptoms and life-style disease. The present paper overviews evidence on the relationship between shift work disorder and life-style related disease. PMID- 22844802 TI - [Sleep/wake cycle, circadian disruption and the development of obesity]. AB - It is increasingly recognized that obesity is an important health problem. The mechanisms that underlie obesity have not been fully elucidated, and effective therapeutic approaches are currently of general interest. Recent studies have provided evidence that circadian clock is a crucial factor in the development of obesity and related metabolic disease. Genetic disruption of clock genes in mice displayed metabolic dysfunctions of specific tissues at distinct phases of the sleep/wake cycle. In addition, circadian desynchrony, a characteristic of shift work and short sleep, are associated with obesity in human. Here, I describe the advances in understanding the interrelationship among circadian disruption, sleep deprivation and obesity. PMID- 22844804 TI - [Sleep rhythm and cardiovascular diseases]. AB - Sleep disturbance is a common problem in general adult population. Recent evidence suggests the link between the occurrence of cardiovascular events and several sleep disturbances including sleep apnea syndrome, insomnia and periodic limb movements during sleep. Sleep duration may affect the cardiovascular outcome. Shift work also may increase the risk of ischemic heart disease. Normalization of sleep rhythm has a potential to be a therapeutic target of ischemic heart diseases, although further study is required to evaluate the preventive effect on cardiovascular events. Here we describe the current understandings regarding the roles of sleep disorders during the pathogenesis of cardiovascular events. PMID- 22844803 TI - [Sleep disorder and hypertension]. AB - Sleep disorder is a common condition in developed countries. Large epidemiological studies have revealed the relationships of short sleep duration and insomnia with hypertension. This review article summarizes the literature on these relationships. Decreased melatonin secretion, change in sleep structures, or increased sympathetic nervous system activity was suggested to serve as a pathophysiology for the relationship between sleep disorder and hypertension. Adequate sleep duration may be important for preventing hypertension in modern society. PMID- 22844805 TI - [Diabetes and sleeping habits]. AB - Number of diabetic patients has continued to increase in the world, disturbance of sleep habits have been pointed out as one of the factor recently. Sleep habits are categorized into quantity and quality of sleep. Inappropriate sleep duration and decline in quality of sleep have caused the exacerbation and onset of diabetes. On the other hand, it is known that many patients with diabetes have already suffered from sleep disorders. Here, we will give an outline of the relationship between sleep habits and diabetes. PMID- 22844806 TI - [Sleep habits and its relation to depression]. AB - There have been a lot of studies on the relationship between insomnia and depression, however, only a little is elucidated about the relationship between sleep habits and depression. In modern societies, long working hours, shift-work, and late bed-time are quite prevalent. However, based on the findings of a few recent papers, it is suggested that long working hours, shift work, heavy internet use, eveningness and late bed-time are associated with short sleep duration and/or insomnia. Then, short sleep duration and/or insomnia would contribute to developing depression. So, as is in the case of metabolic syndrome or hypertension, depression would be a life-style related disease. PMID- 22844807 TI - [A sleep disordered breathing as the lifestyle-related diseases]. AB - Lifestyle related disease is a generic term for diseases such as cardiovascular diseases, diabetes mellitus and cancer caused by life style or life habit, and one of its fundamental causes is obesity. The reason why most people put on weight after their middle age is mainly because of the increase of visceral fat by the decrease in basal metabolism and the amount of momentum despite of unchanging appetite. Due to this sequence of weight gain, after middle age upper respiratory tract becomes narrower, and it worsens obstructive sleep apnea syndrome (OSAS). Since mastication is to provoke and maintain arousal, OSAS patients, who especially feel strong sleepiness, tend to encourage them to be obesity by frequent mastication that leads them to the tendency to overeat. Two main symptoms of OSAS are snoring and sleepiness; however, the essence of sleepiness is the worse quality of sleep due to apnea. In addition, a vicious circle is eventually generated because sleep deprivation and sleep disorders affects hypertension and glucose intolerance, and those worsen lifestyle disease. In order to break this off, it is necessary to review life style and habit, and improve not only on diet and exercise therapy but also on sleep. PMID- 22844808 TI - [Treatment strategy of insomnia for the patients with metabolic syndrome]. AB - Insomnia has been reported to underlie the development and aggravation of metabolic syndrome including hypertension, cardiovascular disease, and diabetes. Treatment of insomnia is important for both the management and prevention of these comorbid disorders. We introduced the treatment strategy of insomnia for the patients with metabolic syndrome. For the better management of insomnia, sleep hygiene education should be given first, and adequate drug therapy should be started thereafter. Cognitive behavioral therapy is useful not only for insomnia symptom but also for the reducing amount of drug and prevention of the recurrence of insomnia. We expect that progress in the management of insomnia would result in the better treatment outcome of metabolic syndrome in general practice. PMID- 22844809 TI - [Drug chronotherapy: the coordination of biological rhythms with medical treatment]. AB - Chronotherapy is defined as a coordination of biological rhythms with medical treatment. At present, several medications, including bronchodilating agents and H2 blockers, are administered with consideration for biological rhythms in routine clinical practice. In addition, recent studies have revealed that bedtime administration of antihypertensive medications can ameliorate the disturbed circadian rhythm of blood pressure and improve the prognosis in patients with hypertension. Because chronotherapy is a simple and inexpensive method of optimizing safe and effective pharmacotherapy, merits of this therapy should be evaluated in many medications. PMID- 22844810 TI - [Endogenous sleep-promoting substance]. AB - Prostaglandin (PG) D2 is the endogenous somnogen that accumulates in the brain during prolonged wakefulness. PGD2 is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the cerebrospinal fluid as a sleep hormone. PGD2 stimulates DP1 receptors and increases the local extracellular concentration of adenosine in the basal forebrain as a paracrine sleep-promoting molecule. Adenosine activates sleep-active neurons in the ventrolateral preoptic area (VLPO) through adenosine A2A receptors. Sleep-promoting neurons in the VLPO send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus, which contribute to arousal through histamine H1 receptors. The neural network between VLPO and TMN is considered to play a key role in the regulation of sleep. PMID- 22844811 TI - [Chronological nutrition and prevention of lifestyle-related diseases]. AB - Lifestyle controls the circadian rhythms produced by clock genes and affects telomere length that regulates healthspan. Biological clocks are classified into oscillatory (clock genes) and hourglass clocks (telomeres). Clock genes align behavioral and biochemical processes with the day/night cycle. Telomeres, the repeated series of DNA sequences that cap the ends of chromosomes, become shorter during cell division. Shortened telomeres have been documented in various pathological states in lifestyle-related diseases, such as atherosclerosis and diabetes. Human activity is driven by NADH and ATP produced from nutrients, and the resulting NAD and AMP play a predominant role in energy regulation. Caloric restriction and proper exercise increase both AMP and NAD, and extend the healthspan. SIRT1, the NAD-dependent deacetylase, attenuates telomere shortening, while PGC-1alpha, a master modulator of gene expression, is phosphorylated by AMP kinase and deacetylated by SIRT1. Prevention of lifestyle related diseases by chronological nutrition is described based on these mechanisms. PMID- 22844812 TI - [Present status and future of hypnotic drug treatment for insomnia]. AB - Pharmacological treatments of insomnia have become safer since the first benzodiazepine receptor agonist (BzRA) hypnotic was introduced in the 1960's. Though BzRAs could hardly cause a fatal condition even in cases of overdosing, they had inherited the arguments on addiction and withdrawal from the prior studies of barbiturate hypnotics that indicated they are strongly addictive. In the 2000s, it was repeatedly demonstrated that insomnia as well as sleep deprivation underlie the development and deterioration of comorbid diseases such as hypertension, cardiovascular diseases, diabetes and depression, and that the proper use of hypnotic drugs is unlikely to cause tolerance, addiction nor rebound phenomena, but likely to be associated with improvement of QOL. Thus, the 2005's consensus report on chronic insomnia by NIH has recommended general physicians to facilitate insomnia treatment to prevent the development of physical and/or mental disorders. The author reviewed in this article the efficacy and side effects of BzRA hypnotics, a hypnotic drug therapy combined with cognitive and behavioral interventions, uses of melatonin receptor agonist in general and sleep medicine practices, and future utilization of newly developed orexin antagonists for insomnia treatment. PMID- 22844813 TI - [Gastric malignant lymphoma]. AB - Primary gastric lymphoma is a rare tumor and the frequency is less than 5% of gastric neoplasms. Although the histological diagnosis is diverse, the majority is MALT lymphoma and diffuses large B-cell lymphoma. MALT lymphoma is derived from marginal B-cell of lymphoid follicle, which is induced by Helicobacter pylori infection. The 60-80% of them is regressed by the eradication treatment. A part of MALT lymphoma is characterized by chromosomal translocations, t(11;18), t(1;14) or t(14;18) that is poor response factors to the eradication. Interestingly, all chimeric proteins produced by the translocations have activated NF-kappaB in the cells. The phenotype of diffuse large B-cell lymphoma is heterogeneous. However, the combination treatment of rituximab plus CHOP is effective and it is capable to preserve the stomach. A non-surgical treatment is recommended to gastric lymphoma. PMID- 22844814 TI - [Endophenotypes in schizophrenia: a review of electrophysiological studies]. AB - Schizophrenia patients consistently show some deficiency in electrophysiological measures, such as PPI (Prepulse Inhibition), ERP (Event-Related Potential) components (mismatch negativity, P50, P300), EEG (Electroencephalography), and MEG (Magnetoencephalography). These components have been intensively studied as quantitative biological markers (i.e., endophenotypes) for psychiatric disorders. Recently brain oscillations, especially gamma (30-80 Hz) band activity (GBA), are being increasingly investigated as new candidate endophenotypes. In this review, we summarize the current status, perspective, and limitations of representative paradigms for investigating abnormal electrophysiological components of schizophrenia, along with relevant genetic polymorphism. PMID- 22844815 TI - [Adolescents with gender identity disorder: reconsideration of the age limits for endocrine treatment and surgery]. AB - The third versions of the guideline for treatment of people with gender identity disorder (GID) of the Japanese Society of Psychiatry and Neurology does not include puberty-delaying hormone therapy. It is recommended that feminizing/masculinizing hormone therapy and genital surgery should not be carried out until 18 year old and 20 year old, respectively. On the other hand, the sixth (2001) and the seventh (2011) versions of the standards of care for the health of transsexual, transgender, and gender nonconforming people of World Professional Association for Transgender Health (WPATH) recommend that transsexual adolescents (Tanner stage 2, [mainly 12-13 years of age]) are treated by the endocrinologists to suppress puberty with gonadotropin-releasing hormone (GnRH) agonists until age 16 years old, after which cross-sex hormones may be given. A questionnairing on 181 people with GID diagnosed in the Okayama University Hospital (Japan) showed that female to male (FTM) transsexuals hoped to begin masculinizing hormone therapy at age of 15.6 +/- 4.0 (mean +/- S.D.) whereas male to female (MTF) transsexuals hoped to begin feminizing hormone therapy as early as age 12.5 +/- 4.0, before presenting secondary sex characters. After confirmation of strong and persistent cross-gender identification, adolescents with GID should be treated with cross-gender hormone or puberty delaying hormone to prevent developing undesired sex characters. These treatments may prevent transsexual adolescents from attempting suicide, being depressive, and refusing to attend school. Subsequent early breast and genital surgery may help being employed in desired sexuality. PMID- 22844816 TI - [Constructing a multicenter collaboration system]. AB - Providing medical care for Gender Identity Disorder (GID) poses enormous challenges and difficulties. The one obstacle to overcome is building a pluralistic treatment system in collaboration with experts from various fields of medicine as outlined in "Guidelines for Treatment and Diagnosis of GID version 3rd" established by the Japanese Society of Psychiatry and Neurology. Another obstacle includes the multilayered decision tree in deployment of physical as well as psychiatric treatment. Offering continuous supports of the pluralistic treatment system following the multilayered decision tree poses a major obstacle. In this report, we examined these obstacles from a perspective of the actually accessible healthcare resources and came up with a proposal of constructing a multicenter collaboration system. As one of concrete example of a solution to these obstacles, we demonstrated our activity of "Kansai GID network." By sustaining these activities, many obstacles posed in the treatment of GID could be overcome. We hope substantial and comprehensive treatment systems for GID shall be promptly established in Japan. PMID- 22844817 TI - [Improvement of therapeutic environment--effort to establish the medical center for GID in a general hospital]. AB - Treatment for gender identity disorder (GID) should be done in cooperation with psychologist, gynecologist, urologist, plastic surgeon and extramural scholars as a team treatment. And if possible, it should be a comprehensive treatment with supports of a social worker, a coordinator and an expert nurse. The ethical committee for individual GID patient treatment has already dissolved according to the third edition of the guideline. We call the therapeutic team Okayama University Hospital Gender Center. It treats not only GID patients, but also gender associated diseases such as disorders of sex development (DSD). Unfortunately, there are not so many institutions which meet our conditions throughout the country. In the present circumstances we can't go along with their needs. So many GID patients go abroad and have Sex reassignment surgery (SRS). To solve this problem national insurance for SRS should be approved as soon as possible and many institutes should start GID treatment. PMID- 22844818 TI - [The history of the concept of gender identity disorder]. AB - The Metamorphoses Greek myth includes a story about a woman raised as a male falling in love with another woman, and being transformed into a man prior to a wedding ceremony and staying with her. It is therefore considered that people who desire to live as though they have the opposite gender have existed since ancient times. People who express a sense of discomfort with their anatomical sex and related roles have been reported in the medical literature since the middle of the 19th century. However, homosexual, fetishism, gender identity disorder, and associated conditions were mixed together and regarded as types of sexual perversion that were considered ethically objectionable until the 1950s. The first performance of sex-reassignment surgery in 1952 attracted considerable attention, and the sexologist Harry Benjamin reported a case of 'a woman kept in the body of a man', which was called transsexualism. John William Money studied the sexual consciousness about disorders of sex development and advocated the concept of gender in 1957. Thereafter the disparity between anatomical sex and gender identity was referred to as the psychopathological condition of gender identity disorder, and this was used for its diagnostic name when it was introduced into DSM-III in 1980. However, gender identity disorder encompasses a spectrum of conditions, and DSM-III -R categorized it into three types: transsexualism, nontranssexualism, and not otherwise specified. The first two types were subsequently combined and standardized into the official diagnostic name of 'gender identity disorder' in DSM-IV. In contrast, gender identity disorder was categorized into four groups (including transsexualism and dual-role transvestism) in ICD-10. A draft proposal of DSM-5 has been submitted, in which the diagnostic name of gender identity disorder has been changed to gender dysphoria. Also, it refers to 'assigned gender' rather than to 'sex', and includes disorders of sexual development. Moreover, the subclassifications regarding sexual orientation have been deleted. The proposed DSM-5 reflects an attempt to include only a medical designation of people who have suffered due to the gender disparity, thereby respecting the concept of transgender in accepting the diversity of the role of gender. This indicates that transgender issues are now at a turning point. PMID- 22844819 TI - [How everyone recognize about polypharmacy?]. AB - Some investigations report that dosage amount and number of antipsychotics in Japan were higher than those in the other country. This problem was discussed as quality of psychiatric medication by "the conference of the future about psychiatric health, medicine and welfare" (Japanese ministry of health, labor and welfare; 2009). The report of this conference said "In order to accelerate improvement to single dosage and loss in quantity, we should be grasped of the actual condition about the polypharmacy and extensive medication of antipsychotics for schizophrenic patients, and we should be discussed about the methods of information and evaluation". But there is no evidence about the polypharmacy is good or bad, and no one knows actual condition about the Japanese antipsychotics medications. In order to answer this question, we are undergoing "the clinical study about safety and effective correction of polypharmacy and agent extensive medication of antipsychotics". PMID- 22844820 TI - [The trend for megadose polypharmacy in antipsychotic pharmacotherapy: a prescription survey conducted by the psychiatric clinical pharmacy research group]. AB - Combination therapy is a characteristic of pharmacotherapy for patients with schizophrenia in Japan, and this can result in megadose polypharmacy. Attitudes of physicians to pharmacotherapy have been changing since the advent of second generation antipsychotics. After 2008, the prescription rate for second generation antipsychotics in Japan exceeded 80%, overtaking that of first generation antipsychotics, but the rate of monotherapy prescription remains low. The increase in the prescription rate for second generation antipsychotics has resulted in a decrease in the combination rate and dose of antiparkinsonian drugs, but no marked change has been seen for anxiolytic/hypnotic drugs, or the combination rate and dose of mood stabilizers. Furthermore, the rate of combination prescription for second generation antipsychotics has increased over the last few years, and further studies of new forms of megadose polypharmacy are now necessary. PMID- 22844821 TI - [Measures to reduce high-dose multiple antipsychotics in Japan]. AB - In Japan, multiple antipsychotic drugs are administered at a high dose to schizophrenia patients, which is rare in other countries. Many of such patients suffer from side effects, among which extrapyramidal and autonomic side effects frequently occur. Many anticholinergic agents and cathartics are concomitantly used for schizophrenia patients, and their vital prognoses are likely to be poor. With this background, we suggest a method in which antipsychotic drugs are slowly reduced as follows: for low potency drugs, the dose is decreased with 25 mg or lower of chlorpromazine equivalent dose per week, and, for high potency ones, the dose is decreased with 50 mg or lower of chlorpromazine equivalent dose per week. In February 2009, the author's patients with schizophrenia, who had been undergoing the slow reduction of antipsychotic drugs for a few years, showed an average number of antipsychotics being 1.26 (SD: 0.50), with the average dose being equivalent to 527 mg of chlorpromazine (SD: 297 mg), and the rate of achieving monotherapy was 70%. A randomized controlled trial involving the National Mental Sanatoriums and a private hospital demonstrated that antipsychotic drugs can be reduced with relative safety according to our method. Currently, prescription reform is being conducted in many hospitals, while prescription as practiced in the previous century still continues in some hospitals. It is considered that the problems regarding high-dose administration of multiple drugs can possibly be solved if many centers employ our method. PMID- 22844822 TI - [Review of 300 cases of parotidectomy for benign parotid tumors]. AB - OBJECTIVE: The objective of this study was to analyze the diagnosis and postoperative complications of benign parotid tumors for a series of 300 patients who underwent the same diagnostic methods and operation procedure in a single institute. MATERIALS & METHODS: A series of 300 patients who underwent primary parotidectomy for benign parotid tumors over a 12-year period was reviewed. RESULTS: There were 145 female and 155 male paitents. The site of the tumors was divided into three groups, superficial, deep, and lower pole tumor. The number of each type of the tumor was 152, 45, 103 cases, respectively. The most common pathology of the parotid tumor was a pleomorphic adenoma (147 cases) followed by a Warthin tumor (111 cases). Pleomorphic adenomas and Warthin tumors accounted for 86% of all benign tumors. The accuracy rate of fine needle aspiration cytology (FNAC) for all benign tumors was 66%, 80% for pleomorphic adenoma and 67% for Warthin tumor. Transient facial nerve dysfunction was observed in 63 patients (20.3%) in all benign parotid tumors, and no patients developed a permanent weakness. The incidence of transient facial nerve dysfunction was 16.4% in superficial tumors, 55.3% in deep tumors, and 10.7% in lower pole tumors. Significant risk factors for development of a transient facial palsy were the site of tumors, operation time, and bleeding volume. Transient facial nerve dysfunction recovered with 1.7 months and 2.8 months in superficial and deep tumors, respectively. CONCLUSIONS: The accuracy rate of FNAC for benign parotid benign tumors was 66%. The incidence of transient facial nerve dysfunction in deep tumors was significantly higher compared to that in superficial and lower pole tumors. According to the rate of facial palsy, operation time, and bleeding volume, benign parotid tumor should be divided into three groups, superficial, deep, and lower pole tumors. PMID- 22844823 TI - [Usefulness and indication of superselective intra-arterial chemotherapy via the radial artery for advanced head and neck cancer--aN indication for inaccessible to treatment with seldingers method]. AB - Neck metastasis is the most significant predictive indicator of head and neck cancer. Various treatments including surgery and chemoradiation have typically resulted in poor outcomes. As a result, we have applied progressive interventional radiology (IVR), Seldinger's method, in cases deemed to have poor prognostic factors. However, a recurring problem with the standard procedure has been cases in which the target artery cannot be successfully accessed. As a result of this limitation, we have initiated an approach whereby we proceed from the radial artery in order to control neck metastasis. OBJECTIVE: Evaluate the usefulness of superselective intra-arterial chemotherapy via the radial artery for advanced head and neck cancer. METHOD AND PATIENTS: From May, 1998 to December 2010, 25 patients for whom catheter insertion in the thyrocervical artery, a major branch of the subclavian artery, was impossible, were treated using superselective intra-arterial chemotherapy via the radial artery. Intra arterial chemotherapy was administered at 100-150 mg/m2 of CDDP and 10-15 mg/m2 of DOC four times per week, with 60 Gy radiation therapy being concurrently. Analysis of the success of insertion, duration of time required for insertion to the target artery, chemotherapy effective rates, and method safety were carried out retrospectively. RESULT: For the target arteries in which catheters could not be effectively inserted using Seldinger's method, insertion was successful and CDDP was safely administered. No complications in regards to intra-arterial chemotherapy were observed. The mean time to insert the catheter into the target arteries was approximately 25 minutes. In contrast, when applying Seldinger's method the mean time was over 1 hour with the result being failure to insert the catheter within the target arteries. Working with our approach, the effective rate of chemotherapy recorded was 100%. The 5-year overall survival rate was 38%. Furthermore, the patients could walk and move freely on the day of treatment. CONCLUSION: This novel method proved useful for the treatment of advanced head and neck cancer in poor prognostic cases in which the target arteries could not be accessed using Seldinger's method. PMID- 22844824 TI - [A case of propranolol therapy for infantile capillary hemangiomas of the parotis]. AB - A 4-month-old healthy female infant presented with rapid onset of subaural swelling over a three-month period. A head and neck exam demonstrated a subaural elastic hard mass with a red birthmark below the left auricle. MRI of the neck demonstrated a well-defined parotid mass consistent with a haemangioma. We treated this infant with 1 mg/kg of propranolol, which was gradually increased over two months to a dose of 2 mg/kg daily. The tumor began to reduce in size within three days after drug administration, and became less prominent in one month, and had almost totally disappeared within four months. On ten-month follow up, the patient was asymptomatic and repeated MRI demonstrated further regression of the tumor. Propranolol could be the first-line choice for treating haemangioma rather than simple PMID- 22844825 TI - Pre-liver transplantation, cardiac assessment. AB - Liver transplantation (LT) is a stressful condition for the cardiovascular system of patients with advanced hepatic disease. The underlying hemodynamic and cardiac status of patients with cirrhosis is crucial to determine which patients should became recipients. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output, a compromised ventricular response to stress, low systemic vascular resistance and bradycardia. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure and myocardial infarction. This review examines screening strategies for transplant candidates and details the prognostic value of common test used to identify ischemic heart disease, heart failure, portopulmonary hypertension. There are discused evidence-based recommendations for their evaluation and management. PMID- 22844827 TI - Simultaneous resection of the primary colorectal tumor and liver metastases--a safe and effective operation. AB - BACKGROUND: The aim of this retrospective study was to compare the results achieved by simultaneous resection (SR) vs. delayed resection (DR) in patients with synchronous colorectal liver metastases (SCRLM). METHODS: In "Dan Setlacec" Center of General Surgery and Liver Transplantation from Fundeni Clinical Institute, between 1995 and 2010, 117 patients underwent SR and 25 patients underwent DR. It was compared the outcome of the patients in the two groups. It was also assessed if certain subgroups of patients present a better outcome after DR than after SR. RESULTS: The location of the primary tumor, the number and diameter of liver metastases, and the proportion of major hepatectomies were similar in the two groups (p value > 0.05). For all patients, the morbidity, mortality, disease-free and overall surrvival rates were not statistically significant different between the two groups (p value > 0.05). In subgroups of patients with rectal tumors, with multiple liver metastases, and undergoing major hepatectomies, the morbidity, mortality and survival rates achieved by SR were similar to those achieved by DR. CONCLUSION: Simultaneous resection of SCRLM is similarly safe and efficient as the delayed resection, even in patients with rectal tumors, with multiple liver metastases, or undergoing major hepatectomies. PMID- 22844826 TI - [Trauma scores: a review of the literature]. AB - BACKGROUND: A quantitative method for measuring trauma severity has many potential applications: patient triage, a common terminology about injuries severity, prognosis assessment, trauma care audit and epidemiological. METHOD: Systematic review of the literature using computer searching of Library of Medicine and the National Institutes of Health International MEDLINE database using PubMed Entre interface. We have selected articles about the main scoring systems used in today's trauma care. RESULTS: Trauma scores were introduced more than 30 years ago, for assigning numerical values to anatomical lesions and physiological changes after an injury. Physiologic Scores describe changes due to a trauma and translated by changes in vital signs and consciousness. Anatomical Scores describe all the injuries recorded by clinical examination, imaging, surgery or autopsy. If physiological scores are used at first contact with the patient (for triage) and then repeated to monitor patient progress, anatomic scores are used after the diagnosis is complete, generally after patient discharge or postmortem. They are used to stratify trauma patients and to measure lesion severity. Scores that include both anatomical and physiological criteria (mixed scores) are useful for patient prognosis. CONCLUSIONS: Despite their imperfections, trauma scores are very important tools in trauma patients management and research. Using large national databases allow a better research, validation and development of scoring systems. PMID- 22844828 TI - Prognostic factors for the primary and secondary retroperitoneal sarcomas. Impact on the therapeutic approach. AB - BACKGROUND: There is little knowledge on retroperitoneal sarcoma, but there are many controversies. The objective of the current study was to define the common and distinctive features of primary and secondary retroperitoneal sarcomas in terms of presentation, prognostic and therapeutic approach to improve the current management of these tumors. Vascular involvement impact was assesed in the two sets of patients. PATIENTS AND METHODS: We have performed a retrospective and prospective study on a group of 34 patients diagnosed with primary and secondary retroperitoneal sarcomas. RESULTS: We have found that primary and secondary retroperitoneal sarcomas have many common features, but hold distinctive aspects in terms of manifestation, predictors of survival and treatment. CONCLUSIONS: Vascular involvement is one of the most important predictors of poor survival in primary retroperitoneal sarcoma patients, because it often limits radicality. In this group, radicality is a major prognostic factor for a higher survival. Instead, secondary retroperitoneal sarcomas appear to be less dependent on the radicality of the treatment and their survival can be increased by complementary treatments. PMID- 22844829 TI - [Right colon cancer--clinicopathological findings]. AB - BACKGROUND: The right colon cancer (RCC) has some particularities from point of view of epidemiology, clinical aspects, therapy and prognosis. MATERIAL AND METHODS: We retrospectively analyzed the patients operated in the First Surgical Unit Iasi during 2004 until 2009, for right colon cancer. The patients' data from the medical files were digitally encoded and included into a MS Access database, and statistically analyzed. RESULTS: 219 cases were included into the analysis, which represents 24.17% from all the patients with colorectal cancer. The median age was 66 years old. A palpable mass into the right abdominal quadrant was founded in 41.5% and anemia in 65.3%. Abdominal ultrasound exam has been performed in all the patients, with 71.3% sensitivity for primary tumor positive diagnosis. Resectability was 89.5% but without multivisceral resections. The intraoperative complication rate was 6.8%; postoperative morbidity was 19.4% with an incidence of anastomotic leak of 1.38%. The postoperative mortality rate was 2.77%. The mean overall survival was 40.13 +/- 1.93 months (median: 49.26). The prognosis factors for the survival rate were: histologic type of the tumor, stage and tumor grading, vascular and perineural invasion. The presence of metastasis in more than 3 lymphnodes as well as resection of fewer than 11 lymphnodes were found as negative prognosis factors for the survival rate. CONCLUSIONS: RCC has an increasing incidence and it is associated especially with elderly patients. The RCC resectability is about 90% with acceptable rates of morbidity and mortality. Perineural and vascular invasion as well as rate of positive lymphnodes and count of resected lymphnodes are prognosis factor for overall survival rate. PMID- 22844830 TI - [Benefits of mechanical suture in our experience]. AB - The evolution of mechanical suture technology experienced a continuous improvement but the implementation of these devices in current practice of Romanian surgery encountered difficulties related mostly to increased costs. PURPOSE: Review of casuistic related to the use of mechanical suture devices. METHODS: We studied the casuistic between 2008 and July 2011. More parameters were analyzed compared to cases in which manual suture was used. RESULTS: 74 patients benefited from using mechanical suture. Circular staplers EAEC type were used in 53 cases, TA staplers in 48 cases and Endo GIA in 19 cases. Operations performed were: 44 colo-rectal anastomoses (2 laparoscopic), 9 eso-jejunal anastomoses, 17 gastric resections, 2 duodenal stump closures and 2 rectal stump closures. One (2.56%) colorectal anastomotic fistula was found which led to death. There was a single anastomotic imperfection where we performed ileostomy with favorable evolution. Duration of Dixon's operation was shortened by 36 minutes average. The anastomosis could be lowered to 3 cm from the anal verge. There were 3 late local rectal cancer recurrences, 1 recto-vaginal fistula and 1 rectovesical fistula. There were no anastomotic stenoses. CONCLUSIONS: There were two main advantages of using mechanical anastomosis: (1) the opportunity of palette broadening of laparoscopic operations, (2) the possibility of making safe anastomosis in difficult to access areas (rectum, esophagus). The use of mechanical staplers offers advantages especially in patients with rectal tumors, especially in obese male patients with narrow basin, where we can save many cases from rectal amputation. Staplers bring more comfort to the surgeon offering physical and psychological feeling of a perfect anastomosis. Although staplers cost is high, in selected cases, this disadvantage is offset by reducing the duration of operations, hospitalization and subsequent cost of stomas maintenance. PMID- 22844831 TI - [Transanal endoscopic microsurgery--our initial experience]. AB - The aim of this study was to describe a single institution's experience with transanal endoscopic microsurgery (TEMS) in patients with benign and malignant rectal tumors. MATERIAL AND METHOD: This was a prospective descriptive survey. Between January 2006 and January 2010, 14 patients underwent transanal endoscopic microsurgery excision of benign (8) or malignant (6) rectal tumors, located 4 to 15 cm from the dentate line. Median age was 59.7 years and the mean follow up was 29 months. RESULTS: The average tumor size was 3.4 cm, median operating time was 40 min. Median length of hospital stay was 4.35 days. During the follow-up period, benign tumor recurrence was observed in one patient (7.14%), managed by repeated TEMS. Histologic staging of malignant tumors was T1 (2) and T2 (4). In two patients with inadequate resection margins open radical surgery was performed. One had recurrent disease, which was managed by radical surgery. No cancer-related deaths were observed during the follow-up period. There was no operative mortality. No major postoperative complications were recorded. Anal incontinence persisted for 3 weeks in one patient. CONCLUSION: Transanal endoscopic microsurgery excision is a safe and precise technique and should become a procedure of choice for benign rectal tumors and selected early malignant neoplasms. PMID- 22844832 TI - [Indications for surgery in thyroiditis]. AB - INTRODUCTION: Inflammatory processes of the thyroid represents a main proportion of the gland's pathology but the majority of them are treated by medical methods, surgery being indicated. PATIENTS AND METHODS: In 14 cases (3%) from 464 operations for different thyroid conditions we have encountered authentic inflammatory lesions in 9 cases of Hashimoto's thyroiditis (two associated with papillary thyroid carcinoma and one with malignant lymphoma), two cases of Riedel's thyroiditis and respectively de Quervain thyoiditis, tuberculous thyroiditis and actynomicosis one case each. The common lymphoplasmacytic infiltration in Basedow's disease was not considered likewise as the inflammatory nespecific lesions encountered in benign and malignant pathology of the gland. The clinical and imagistic data, biological evaluation and titer of anticorps but particularly the paraffine examination together with intraoperative estimations are decisive for the diagnosis. RESULTS AND DISCUSSIONS: Firm diagnosis of thyroiditis was rarely affirmed before operation, surgical indication being formulated on clinical criterions dominated by cancer suspicion. Among these are diffuse or (multi)nodular thyromegaly with a dominant nodule with recent appearance and rapid growing in temporal and geographic proximity of Chemobyl disaster, with hard consistence, celsian or compressive features and adenopathy. More added the imagistic signs but especially suspect aspects of the FNAB (follicular or with Hurthle cells smears) and also of the frozen sections. Certainty diagnosis was established by paraffine examination not always without hesitations or reexamination (Hashimoto's thyroiditis diagnosed in one case was finally a malignant lymphoma). Large removal decided after intraoperative findings induced for the most of patients a definitive hypothyroidism. CONCLUSION: All the diagnosis resources must be exhausted for the diagnosis of the inflammatory lesions of the thyroid to avoid unnecessary surgery. On the other side the chronic overstimulation by the TSH of the glandular tissue affected by the immune process, represent an important factor of producing neoplasia. PMID- 22844833 TI - The combined role of intravenous contrast enhanced ultrasound (CEUS) and computed tomography (CT) in liver abscess diagnosis. AB - BACKGROUND AND AIMS: Through this study, we intend to review the main aspects regarding the contrast enhanced ultrasound evaluation of liver abscesses, pursuing a comparative analysis between the medical literature and our own experience. MATERIAL AND METHODS: From June 2008 until December 2010 we have evaluated in our department a consecutive series of 11 patients with liver abscesses (7 males, 63.63%) all between the ages of 45 and 74. All the patients displayed a clinical and biological picture leading to an inflammatory process. The imaging diagnosis was made after confronting the results of the contrast enhanced ultrasound with those of the computed tomography. RESULTS: In 10 out of 11 patients that were part of the study, we have assessed 14 liver abscesses. A single patient showed spread lesions inside both liver lobes, and they were assessed as hepatic micro abscesses. Three of the patients showed multiple right lobe lesions, 7 patients showed single lesions and one patient showed disseminated lesions within both lobes. We examined six mature lesions, 4 lesions with incomplete necrosis and 4 immature lesions, with no necrosis. The particular aspect of mycotic microabscesses is mentioned at the conventional ultrasound and at the CEUS as well. CONCLUSION: Various types of hepatic abscesses have different imaging findings, and typical CT and CEUS findings can suggest the diagnosis. PMID- 22844834 TI - The role of capsule endoscopy in the detection of small bowel disease. AB - Videocapsule endoscopy (VCE) can identify lesions in the small bowel which would otherwise be hard to detect. We have selected 53 patients with digestive symptoms in which upper and lower endoscopy had provided no findings. Patients were classified into three groups, based on their main indication for VCE exploration: group one--obscure gastrointestinal bleeding (OGIB); group two--unspecific abdominal symptoms; group 3--monitoring of a prior known pathology. We found that VCE has high predictive values, sensibility and specificity in the diagnosis of OGIB. VCE was also useful in the detection and extent evaluation of lesions in Crohn's and celiac disease. VCE is also able to detect tumors of the small bowel with sufficient accuracy, and can be used to monitor patients with hereditary pre malignant diseases such as FAP. There were few light adverse effects and no major complications. We conclude that VCE is a safe and effective procedure for the detection of small bowel lesions. PMID- 22844835 TI - [Hypospadias--one-stage repair]. AB - The tubularised incised plate (TIP) is a common surgical technique used in the treatment of hypospadias. The study includes 52 urethroplasties, performed between 2007-2010. We performed Mathieu urethroplasty in 12% of the cases, Duplay urethroplasy in 88% of the cases and we used the Snoodgrass technique in 82% of the cases. The hospital stay varied between 3-8 days after surgery. We included in the study 32 patients with distal penile hypospadias, 8 with proximal hypospadias and 12 with midshaft hypospadias. To prevent fistula formation it is important to perform well sealed sutures, to interpose subcutaneous tissue between the urethroplasty and the cutaneous sutures, not to overlap the urethral and cutaneous sutures. The incidence of urethral fistula after the Duplay procedure was higher then after the Mathieu procedure, but the cases operated by the Duplay technique were manier and more difficult. The complications were more frequent in the cases with proximal hypospadias than in the cases with distal hypospadias, as well as the reintervention rate but not related to the surgical techniques. We present elements of diagnostic, embriology and etiopathogeny of hypospadias. PMID- 22844836 TI - [Surgical treatment of single brain metastases]. AB - Recent neurosurgical statistics indicate brain metastases as the most frequent intracerebral tumor. Under these circumstances, single brain metastases study and therapeutic management represent a major problem for a neurosurgeon and his efforts to prolong the patient survival rate and improve their quality of life. This study of the surgical treatment of single brain metastases has focused on a survey of the data which highlight most accurately the efficiency of a therapeutic method: general survival data or survival data function of primary neoplasm, mortality rate and causes, data regarding the connection between survival rate and death cause, tumor relapse rate, post surgery complications and post surgery neurological status. This study has surveyed a group of 320 patients presenting single brain metastases, which have been subject to surgery between 2001-2010. Median general survival rate for the patients with single brain metastases in this group was 9.64 months, regardless of the histologic type of the primary neoplasm. These data complies with other studies in the most majority of neurosurgical series which indicate a median survival of 10 months. The study clearly showed that the longest median survival rate was noticed in case of patients with a neurological death cause (12.54 months) and the shortest in case of patients deceased due to the systemic disease dissemination (5.08 months). A good neurological state prior to surgery, administering a complete surgical treatment, followed by radiotherapy and/or chemotherapy, as well as a good therapeutic control of the primary neoplasm are the decisive factors in obtaining the longest survival rate and the lowest risk in triggering systemic dissemination. PMID- 22844837 TI - Reconstructive rhinoplasty in cases with basal cell carcinoma of the nose. AB - Basal cell Carcinoma (BCC) is the most common type of skin cancer, 85% of BCC are located in the head and neck area, of which 30% on the nose. The author present a retrospective study, own experience in surgical treatment in 31 cases with basal cell carcinoma of the nose operated in the period 2005-2011. The age of patients was between 50 to 90 years old. The anatomical site of the nose the most frecvently involved was ala 58%, and followed of the nasal tip 18%, lateral nose wall 12%, dorsum 9% and 3% basalioma terebrans. In all of the cases in this study it was performed the repair of the skin tumour defects of the nose, using varied local skin flaps, septal graft and auricle cartilage free grafts a ndcomposite (skin + cartilage) of conchal and helical rim. Treatment methods were depend on the tumor localization and extension. The best treatment option in BCC of the nose was radical surgical excision whith safety margin of the tumour, followed of reconstructive rhinoplasty. PMID- 22844838 TI - [Laparoscopic Roux-en Y gastric bypass]. PMID- 22844839 TI - Dorsal pancreas agenesis and ductal adenocarcinoma: surgical implications of an extremely rare association. AB - It is presented the case of a 44-year-old woman with ductal adenocarcinoma of the pancreatic head with associated dorsal pancreas agenesis. In this case, curative intent surgery implies removal of the whole pancreas with its consequences- parental insulin requirement and exocrine pancreatic insufficiency. A review of the literature on the previously reported cases was performed. PMID- 22844840 TI - [Amyand's hernia--case presentation and a discussion about diagnosis problems and surgical treatment]. AB - We present the case of a 62 years old patient, with multiple associated tares, which was operated in emergency for an Amyand's hernia. The appendix was perforated and generated a big pussy collection (aprox. 200 ml) in the hernia sac. The impossibility of mobilization of the appendix, which was just 2/3 in the hernia sac, made us perform a median laparotomy for safety reasons. The position and fixation of the cecum made impossible the exteriorization of the appendix in the hernia sac. The postoperative evolution, under a complex supervision, was favorable. Due to the rarity of the clinical entity, of the specific issues and of the literature review, we decided to communicate the clinical observation. PMID- 22844841 TI - Complicated axillary lymphadenectomy due to a pectoralis quartus muscle. AB - During lymphadenectomy in the left axilla of a 38-year-old woman with a 1.4 cm invasive ductal breast carcinoma an accessory muscle was found. Due to the presence of the anomalous muscle the lymphadenectomy was carried out with difficulty through a limited field. Based on its anatomical characteristics, the supernumerary muscle was recognized as the pectoralis quartus. To our knowledge this is the first report of a pectoralis quartus muscle as a surgical finding. The surgeon should be aware of the possible presence of this anomaly as well as its anatomical characteristics in order to avoid any complications. PMID- 22844842 TI - [Upside-down stomach and hiatal hernia]. AB - Hiatal hernias represent a special variant of diaphragmatic hernia in which there is a transdiaphragmatic migration of the stomach through the esophageal hiatus. There are 4 types admitted--sliding (type I), paraesophageal (type II), mixt combining elements for both previous types (type III) and complex (type IV) and represents at most 5-15% from all hiatal hernias. Upside-down stomach is a special form of organoaxial volvulus of the entire stomach in a sac of mixt hiatal hernia (type III) or complex (type IV). There are asymptomatic forms, but the majority of the patients present signs of gastroesophageal reflux and up to one third may show complications such as bleeding, acute volvulus with obstruction or perforation. Surgical intervention is the only treatment option for the gastric volvulus and offers a durable resolution. The ideal surgical technique, the gold standard, consists in reduction of the stomach in the gastric lodge, resection of the sac and calibration of the hiatus adding a gastropexy or antireflux procedure. PMID- 22844844 TI - [Extended lymphadenectomy for left NSLC--case report]. AB - The paper brings up a topical issue in the surgical treatment of non small lung cancer, namely optimal lymphadenectomy for tracking left, considering the anatomical features of specific drainage. This can be achieved by various methods recently introduced in the classical arsenal left lung cancer diagnosis. It's presented in detail a case of extended lymphadenectomy for lung cancer non small left to right paratraheal approach without ligament arterial section. The method allowed a correct staging and reporting of the case more accurate prognosis. The immediate goal of the authors is to discuss on this surgical technique and for long term to achieve a lot with statistical significance in order to assess the value of this method. PMID- 22844845 TI - Sacral schwannoma found incidentally--report of a case. AB - Sacral schwannoma is a rare retrorectal tumor in adults. Postoperative sacral neurological deficit is difficult to avoid. Currently, there is no established consensus regarding best treatment options. We present a case of a 33 years old patient with atypical discomfort in lower abdomen and no neurological complaints who was diagnosed with a pelvic mass by abdominal ultrasound. CT, MRI and MSCT showed an inhomogeneous presacral mass involving right S1 sacral foramen. Although there were no neurological complaints, EMG and ENG showed a minor chronic lesion of L5 root bilaterally, more on the right side, affecting the fibers to the small muscles of the feet. We treated this patient with total extirpation of the mass without additional curretage. No radiotherapy was applied and postoperative neurological functions were preserved. PMID- 22844843 TI - [Obstructive jaundice by genodermatosis--case report]. AB - BACKGROUND: Neurofibromatosis type I, or Recklinnghausen disease, is the most frequently occurring neurofibromatosis, in 1/3000-11,5000 of children born. This disease is a genodermatosis with 1/3000-1/5000 autosomal dominant transmission. Incriminated in the pathological appearance of the disease gene is located on chromosome 17, gene product, neurofibromina, is a protein involved in controlling cell differentiation and proliferation. Skin manifestations can be associated with the same papillary tumors and the internal organ. Treatment is surgery for larger tumors. Worse prognosis in malignant developpment, with the lower quality of life in the presence of complications, as in this case: mechanical obstructive jaundice. MATERIAL AND METHOD: Patients aged 75 years, admitted for obstructive jaundice (progressive, pruritic), cutaneous papillomas (0.5-3 cm) on the trunk and several hyperpigmented brown spots (5-6 cm diameter). Cutaneous lesions (45 years old) have been previously diagnosed by histological examination. RESULTS: We did surgery under general anesthesia: cholecystectomy, intraoperative choledocoscopy of bile duct. In the last portion of bile duct we found pedicled tumors. We did partial excision of tumors and coledoco-duodenoanastomosis in healthy tissue. Histological examination showed neurofibrodermatoza type I. Discharge 12 days postoperatively. CONCLUSIONS: Preoperative diagnosis suggested the possibility of mechanical jaundice by malignancy. Etiologic diagnosis of this rare form of obstructive jaundice could not be established before surgery, only by histological examination of the excised tumors. PMID- 22844846 TI - Can the U.S. get an "A" in science? PMID- 22844847 TI - Winner takes all. PMID- 22844849 TI - The benevolence of black holes. PMID- 22844848 TI - Siri, why aren't you smarter? PMID- 22844850 TI - The joyful mind. PMID- 22844852 TI - Lakes on ice. PMID- 22844851 TI - New life for ancient DNA. PMID- 22844853 TI - Deadly rays from clouds. PMID- 22844854 TI - Building a better science teacher. PMID- 22844855 TI - Quiet little traitors. PMID- 22844856 TI - Which species will live? PMID- 22844858 TI - Free won't. PMID- 22844857 TI - Phage factor. Interview by Brendan Borrell. PMID- 22844859 TI - Olympic hurtfuls. PMID- 22844860 TI - Detecting nasopharyngeal reflux: a novel pH probe technique. AB - OBJECTIVES: We sought to ascertain the normal pH values in the aerosolized environment of the nasopharynx in healthy subjects and utilize a novel pH probe that allows measuring acidity in a nonliquid environment. METHODS: Between November 2009 and February 2011, healthy volunteers without a history of reflux or eustachian tube dysfunction were enrolled in the prospective study. A total of 20 subjects had a Dx-pH Measurement System Probe (Respiratory Technology Corp) placed near the torus tubarius. The pH probe records the pH throughout the 24 hour study. A pH below 5.5 while the subject was upright or below 5.0 while the subject was supine was used as a criterion to determine a reflux event. Recording was stopped during meals. RESULTS: For normal individuals with no history of reflux or eustachian tube dysfunction, the pH values obtained from the nasopharynx ranged from 6.10 to 7.92. The average pH was 7.03 (SD, 0.67). Eight subjects (40%) had at least 1 reflux event during the 24-hour pH study. CONCLUSIONS: By utilizing a novel self-condensing pH probe, we were able to perform a 24-hour pH study in the nasopharynx of 20 healthy individuals. In our study, the average pH for individuals without symptomatic reflux or eustachian tube dysfunction was 7.03. Interestingly, 8 control subjects had at least 1 episode of pH below 5.5 while awake or below 5.0 while asleep, which was considered to be a reflux event in our study. PMID- 22844861 TI - Potential benefits of pH 8.8 alkaline drinking water as an adjunct in the treatment of reflux disease. AB - OBJECTIVES: At the cellular level, tissue-bound pepsin is fundamental to the pathophysiologic mechanism of reflux disease, and although the thresholds for laryngeal damage in laryngopharyngeal reflux and for esophageal damage in gastroesophageal reflux disease differ, both forms of damage are due to pepsin, which requires acid for its activation. In addition, human pepsin remains stable at pH 7.4 and may be reactivated by hydrogen ions from any source. Thus, most tap and bottled waters (typically pH 6.7 to 7.4) would not be expected to affect pepsin stability. The purposes of these in vitro studies were to investigate whether artesian well water containing natural bicarbonate (pH 8.8) might irreversibly denature (inactivate) human pepsin, and to establish its potential acid-buffering capacity. METHODS: Laboratory studies were performed to determine whether human pepsin was inactivated by pH 8.8 alkaline water. In addition, the buffering capacity of the alkaline water was measured and compared to that of the two most popular commercially available bottled waters. RESULTS: The pH 8.8 alkaline water irreversibly inactivated human pepsin (in vitro), and its hydrochloric acid-buffering capacity far exceeded that of the conventional-pH waters. CONCLUSIONS: Unlike conventional drinking water, pH 8.8 alkaline water instantly denatures pepsin, rendering it permanently inactive. In addition, it has good acid-buffering capacity. Thus, the consumption of alkaline water may have therapeutic benefits for patients with reflux disease. PMID- 22844862 TI - Application of natural orifice transluminal endoscopic surgery (NOTES) instrumentation to the endolarynx. AB - OBJECTIVES: RealHand instruments are high-dexterity instruments that have been designed for natural orifice transluminal endoscopic surgery applications. They provide dexterity by offering a full range of motion to endoscopic instruments. We hypothesize that RealHand instruments will resolve some of the limitations encountered in traditional endolaryngeal surgery. They have the potential to do so in the following ways: (1) they negate the limitation of mobility of traditional laryngoscopy instrumentation, which is rigid and fixed; (2) they maintain the ability of direct visualization through a telescope while precluding the need for an operating microscope; (3) they provide the dexterity to perform tasks that are otherwise not possible with traditional instrumentation; and (4) they provide flexibility that can be advantageous in difficult foreign body retrieval from distal airways. METHODS: To test this hypothesis, we developed and optimized a cadaveric lamb larynx model for endolaryngeal microsurgery. To evaluate the feasibility of the RealHand instruments in their application to laryngeal surgery, we had 2 otolaryngology senior residents and 2 laryngology fellows-in-training perform 5 different endoscopic tasks: (1) foreign body removal; (2) arytenoidectomy; (3) microflap elevation; (4) cricopharyngeal myotomy; and (5) endoknot suture tying. RESULTS: Experience with RealHand instruments demonstrated that although they are limited in application to phonosurgery, they have the potential for more facile tissue manipulation in the supraglottic and hypopharyngeal structures. Endoscopic suturing ability is enhanced. CONCLUSIONS: RealHand high-dexterity instrumentation allows for full range-of-motion instrumentation and, with modification, has potential for wider application in endoscopic laryngeal surgery. PMID- 22844863 TI - Outcomes of balloon dilation in pediatric subglottic stenosis. AB - OBJECTIVES: We report outcomes of balloon dilation in the endoscopic management of pediatric subglottic stenosis (SGS) and discuss the role of balloon dilation in both primary and adjuvant therapy. METHODS: We performed a retrospective review of treatment with noncompliant, high-pressure balloons for SGS in the past 2 years at a tertiary pediatric hospital. Fifty-one dilations were performed in 28 children with SGS. The children's mean age was 42 months. The mean SGS grade was 2.46. RESULTS: Fifteen children had primary balloon dilation, and 13 had adjuvant balloon dilation. Overall, 16 children (57.1%) had successful balloon dilation. Of those who underwent primary dilation, 9 (60.0%) were able to avoid open reconstruction or tracheotomy and 6 had their symptoms temporarily improved (average, 36 days) until definitive open reconstruction. Of the patients who underwent adjuvant dilation, 7 (53.8%) were successfully decannulated. Nine of the 12 failed balloon dilations were in children who had concomitant airway disorders; in contrast, only 6 of 16 children in whom treatment was successful had concomitant airway disorders (p = 0.048). There was no statistical association between successful versus failed treatment and age (51.6 versus 27.9 months; p = 0.23), degree of stenosis (grade 2.3 versus grade 2.6; p = 0.41), presence of lung disease (33.3% versus 70%; p = 0.07), or soft versus firm stenosis (60.0% versus 53.1%; p = 0.71). CONCLUSIONS: Balloon dilation plays an important role in the primary and adjuvant management of pediatric SGS. The presence of concomitant airway lesions is significantly associated with failure of balloon dilation treatment. Meticulous surveillance of the dilated airway is necessary, given this failure rate. PMID- 22844864 TI - Dysphagia in severe anorexia nervosa and potential therapeutic intervention: a case series. AB - OBJECTIVES: In severe anorexia nervosa, there are a litany of medical complications that affect virtually every body system, and severe weakness is a typical characteristic. To our knowledge, aspiration risk, dysphagia recognition, and dysphagia management and intervention have not been well described in the literature in regard to severe anorexia nervosa. The purpose of this case series is to increase awareness among clinicians of possible oropharyngeal dysphagia symptoms that may present in patients with severe anorexia nervosa. METHODS: We describe the cases of 3 patients with severe anorexia nervosa who presented with symptoms of dysphagia. The speech-language pathology team administered dysphagia therapy to the 3 patients utilizing neuromuscular electrical stimulation (NMES) in conjunction with swallowing therapy tasks that included strengthening exercises and compensatory strategies. RESULTS: After the course of dysphagia treatment intervention, the 3 patients were able to tolerate an oral diet with improved swallowing function and no ongoing aspiration. CONCLUSIONS: The use of NMES in conjunction with traditional swallowing exercises in the treatment of dysphagia in patients with anorexia nervosa may reduce the need for enteral feeding and prolonged hospitalization. In regard to dysphagia intervention and management within this population and across other populations, rigorous randomized controlled studies are necessary for determining the efficacy of NMES and traditional swallowing therapy implementation. PMID- 22844865 TI - Aberrant expression levels of MTA1 and RECK in nasopharyngeal carcinoma: association with metastasis, recurrence, and prognosis. AB - OBJECTIVES: We investigated the expression and clinical value of MTA1 and RECK genes in patients with nasopharyngeal carcinoma (NPC). METHODS: We examined MTA1 and RECK expression in nasopharyngeal tissue from patients with chronic nasopharyngitis, lymph nodes with metastasis of NPC, and primary NPC tumor tissue by means of in situ hybridization and analyzed their correlation with the clinicopathologic features of NPC. RESULTS: The positive expression of MTA1 in the NPC tissues and metastatic lymph nodes was significantly higher than that in the chronic nasopharyngitis tissues (p < 0.05). The positive expression of RECK in the NPC tissues and metastatic lymph nodes was significantly lower than that in the chronic nasopharyngitis tissues (p < 0.05). The RECK expression level was inversely correlated with the MTA1 expression level in the NPC tissues (p < 0.05). The increased MTA1 and decreased RECK expressions in the NPC tissues had no association with gender, age, T-stage, or clinical stage (p > 0.05). However, they had a positive correlation with cervical lymph node metastasis, tumor recurrence, and 5-year overall survival rate of the patients with NPC (p < 0.05). Moreover, multivariate analysis showed that MTA1 and RECK expressions were independent prognostic factors for survival (p < 0.05). CONCLUSIONS: The conversely abnormal expression levels of MTA1 and RECK may be collectively involved in progression of malignancies and may serve as molecular predictors for metastasis, recurrence, and prognosis of NPC. PMID- 22844866 TI - Cross-sectional vestibular nerve analysis in vestibular neuritis. AB - OBJECTIVES: We examined the association between the size and cross-sectional area of the superior vestibular nerve as measured on constructive interference in steady-state (CISS) parasagittal magnetic resonance imaging (MRI) and the vestibular nerve function as measured by electronystagmography. METHODS: The retrospective observational cohort study took place at an academic tertiary referral center. Twenty-six patients who met established clinical and electronystagmographic criteria for vestibular neuritis and who underwent parasagittal CISS MRI were identified. Two blinded investigators measured vestibular nerve height and width bilaterally at the level of the fundus of the internal auditory canal and calculated the cross-sectional nerve areas. The inter rater reliability and agreement were analyzed. Symptom duration, age, and gender were also examined. RESULTS: A statistically significant decrease was observed in both vestibular nerve cross-sectional area and height as compared to the contralateral vestibular nerve. A non-statistically significant trend was observed for a relative decreased cross-sectional nerve area with increased age, as well as a decrease in nerve area with an increase in symptom duration. CONCLUSIONS: Decreases in both vestibular nerve cross-sectional area and height are observed in patients with unilateral vestibular neuritis as measured on parasagittal CISS MRI. PMID- 22844867 TI - Quality of life of patients with bilateral vestibulopathy. AB - OBJECTIVES: Currently, there is no evidence of an effective treatment for patients with bilateral vestibulopathy (BV). Their main complaints are oscillopsia and imbalance. Opinions about the impact of BV on their quality of life are controversial, and their handicap is not always recognized, even among otoneurologists. The aim of this study was to objectively assess the health status of BV patients in order to evaluate the need for pursuing efforts toward the development of new treatments. METHODS: The short-form health survey (SF-36), the dizziness handicap inventory (DHI), the short falls efficacy scale international (short FES-I), and an oscillopsia severity questionnaire were submitted to 39 BV patients. The SF-36 scores were compared to the scores of a general Dutch population. The DHI scores were correlated to the oscillopsia severity scores. The short FES-I scores were compared to scores in an elderly population. Residual otolithic function was correlated to all scores, and hearing to SF-36 scores. RESULTS: Compared to the general Dutch population, the BV patients scored significantly worse on the "physical functioning", "role physical", "general health", "vitality", and "social functioning" SF-36 variables (p < 0.05). The DHI scores were strongly correlated with the oscillopsia severity scores (r = 0.75; p < 0.000001). The short FES-I scores indicated a slight to moderate increase in the patients' fear of falling. No significant score differences were found between BV patients with residual otolithic function and patients with complete BV. There was no correlation between hearing status and SF 36 scores. CONCLUSIONS: The results correlate with our clinical impression that BV has a strong negative impact on physical and social functioning, leading to a quality-of-life deterioration. There is a clear need for a therapeutic solution. Efforts toward the development of a vestibular implant are justified. PMID- 22844868 TI - Predicting surgical outcomes in pediatric cervicofacial nontuberculous mycobacterial lymphadenitis. AB - OBJECTIVES: We examined surgical outcomes in children with cervicofacial nontuberculous mycobacterial lymphadenitis and attempted to identify predictors of complications. METHODS: A retrospective chart review from 2 tertiary pediatric centers was used to identify .11 presentation or operative variables (age at surgery, gender, symptom duration, pain, violaceous skin changes, skin breakdown, fluctuance, purified protein derivative positivity, operative procedure, use of nerve integrity monitoring, and use of skin flap advancement) and to compare these to 5 postoperative complications (facial nerve dysfunction [paresis or paralysis], poor scarring, recurrence, wound infection, and wound dehiscence without infection). RESULTS: The 45 patients analyzed for presentation or operative variables (28 female, 17 male; average age, 31.2 months) typically presented with painless masses averaging 8.2 weeks in duration, along with violaceous skin changes in 29 of the 45 cases (64%) and skin breakdown in 9 cases (20%). The surgical procedures included parotidectomy with or without selective lymphadenectomy in 38 of the 45 cases (84%) and lymphadenectomy alone in 7 cases (16%). Skin resection and cervicofacial advancement flap reconstruction was performed in 20 cases (44%). Nerve integrity monitoring was utilized in 32 cases (71%). In the 44 patients analyzed for postoperative complications, we found facial nerve paresis in 14 (31.8%), poor scarring in 9 (20.5%), wound infection in 6 (13.6%), recurrence in 4 (9.1%), and facial nerve paralysis in 2 (4.5%). Nine of the 14 cases (64.3%) of initial facial nerve paresis resolved. At final follow-up, facial nerve paresis persisted in 5 of the 14 children (35.7%) with initial postoperative paresis and in 1 of the 2 children (50.0%) with initial postoperative paralysis. Facial nerve paralysis persisted in the other child with initial postoperative paralysis. Overall, 6 of these 7 patients (85.7%) with persistent facial nerve dysfunction had follow-up of less than 1 month. All transient and permanent facial nerve dysfunction was in the distribution of the marginal mandibular nerve only. No statistically significant predictors of complications were identified. CONCLUSIONS: We report acceptable but not insignificant rates of marginal mandibular distribution facial nerve injury, poor scarring, wound infection, and recurrence following resection of cervicofacial nontuberculous mycobacterial lymphadenitis in children that must be discussed with patients and parents before operation. No presentation or operative variables predicted the complications. PMID- 22844869 TI - Novel device for tissue cooling during endoscopic laryngeal laser surgery: thermal damage study in an ex vivo calf model. AB - OBJECTIVES: Minimizing collateral thermal damage during endoscopic laryngeal laser surgery remains a priority, and tissue cooling is one way to achieve this goal. Cooling systems utilizing compressed air have been shown to reduce the extent of thermal trauma on the vocal folds, but these units are not ideal for endoscopic applications because cooling is inefficient at the low airflows needed. We examined whether a novel vortex cooling device that generates cooled air at low flow rates would provide a cooling benefit beyond that which could be obtained by using room-temperature air for cooling tissue or by using no cooling during simulated laryngeal laser surgery. METHODS: A continuous-wave thulium laser was used to incise glottic tissue in 12 calf vocal folds. Cooling was achieved with a prototype vortex cooler (9 degrees C air output; flow rate, 3 L/min), and tissue temperature measurements were compared to those with room-air cooling and no cooling. Thermal damage was analyzed histologically by measuring the depth of lactate dehydrogenase inactivation surrounding the mucosal incision. The cooling conditions were tested during time-constant cuts (8 seconds) and depth-constant cuts (into the thyroarytenoid muscle). RESULTS: During time constant cuts, comparison between vortex cooling and room-air cooling revealed that vortex cooling resulted in a thermal damage zone that was 14% smaller (519 versus 603 microm; p < 0.05). During depth-constant cuts, vortex cooling created a thermal damage zone that was 32% smaller than that created with no cooling (p <0.01) and 9% smaller than that created with room-air cooling (p < 0.01). CONCLUSIONS: Vortex cooling reduces thermal damage more effectively than room-air cooling or no cooling during both time-constant and depth-constant thulium laser cuts. PMID- 22844870 TI - Voice outcomes following the gray minithyrotomy. AB - OBJECTIVES: Most practitioners have limited treatment options for vocal fold scar and sulcus vocalis. The Gray minithyrotomy (GMT) is a surgical procedure for the treatment of these conditions, although limited objective data exist regarding voice outcomes. This study compares the quantified subjective and visual perceptual outcomes following GMT for the treatment of vocal fold scar and sulcus vocalis. METHODS: We performed a retrospective review of patients who underwent GMT in a single institution. Patient-reported satisfaction, Voice Handicap Index 10 scores, results of video perceptual analysis, and complications were recorded. RESULTS: Sixteen patients underwent GMT for phonotraumatic or postoperative scar (11), radiation-induced scar (3), or sulcus vocalis (2). Seven underwent bilateral operations. Follow-up data were available for 12 patients. Eight patients had 2 or more failed surgical interventions before GMT. Seven of the 13 procedures resulted in a self-reported improvement. Although the mean preoperative Voice Handicap Index-10 score (30.6) across all patients did not decrease after the operation, 6 of the 13 GMT procedures resulted in improvement (mean decrease, 7.5). Complications, encountered in 5 patients, included ecchymosis, neck abscess, tongue numbness, wound dehiscence, and aspiration pneumonia. CONCLUSIONS: The GMT is a viable treatment for severe vocal fold scar and sulcus vocalis. Our results show improvement in half of a cohort that was marked by previous failures at improving voice. These results point to the recalcitrant nature of voice difficulties in treating vocal fold scar and sulcus, and may properly guide clinicians and patients in their expectations following this infrequently used technique. PMID- 22844871 TI - Suppressing unspecific cell uptake for targeted delivery using hydroxyethyl starch nanocapsules. AB - Synthesizing nanocarriers with stealth properties and delivering a "payload" to the particular organ remains a big challenge but is the prime prerequisite for any in vivo application. As a nontoxic alternative to the modification by poly(ethylene glycol) PEG, we describe the synthesis of cross-linked hydroxyethyl starch (HES, M(w) 200,000 g/mol) nanocapsules with a size range of 170-300 nm, which do not show nonspecific uptake into cells. The specific uptake was shown by coupling a folic acid conjugate as a model targeting agent onto the surface of the nanocapsules, because folic acid has a high affinity to a variety of human carcinoma cell lines which overexpress the folate receptor on the cell surface. The covalent binding of the folic acid conjugate onto HES capsules was confirmed by FTIR and NMR spectroscopy. The coupling efficiency was determined using fluorescence spectroscopy. The specific cellular uptake of the HES nanocapsules after folic acid coupling into the folate-receptor presenting cells was studied by confocal laser scanning microscopy (CLSM) and flow cytometry. PMID- 22844872 TI - Effects of added silica nanoparticles on hectorite gels. AB - We present a study on the macroscopic, microscopic, and rheological behavior of mixtures of natural hectorite clay and different types of anionic Ludox silica spheres. Adding silica spheres to the weak hectorite gels leads the collapse of the suspensions, while the strong gels remain space-filling, though their storage modulus and the yield stress values diminish. We discuss what kind of structural rearrangements are possibly responsible for the macroscopic and rheological changes in the clay/silica mixtures. PMID- 22844873 TI - Influence of seed endophyte amounts on swainsonine concentrations in Astragalus and Oxytropis locoweeds. AB - Locoism is a toxic syndrome of livestock caused by the ingestion of a subset of legumes known as locoweeds endemic to arid and semiarid regions of the western United States. Locoweeds contain the toxic alkaloid swainsonine, which is produced by the endophytic fungi Undifilum species. Two chemotypes of plants can coexist within toxic populations of locoweeds: chemotype 1 plants are defined as individuals containing swainsonine concentrations greater than 0.01% and quantitatively greater amounts of Undifilum, while chemotype 2 plants are defined as individuals containing less than 0.01% swainsonine and quantitatively smaller amounts of Undifilum. To elucidate the mechanisms that govern chemotypes, the amount of Undifilum in seeds/embryos was manipulated, thus altering subsequent swainsonine concentrations in three locoweed species: Astragalus mollissimus, Astragalus lentiginosus, and Oxytropis sericea. Chemotype 1 seeds that were fungicide-treated or had the seed coat removed resulted in plants with swainsonine concentrations comparable to those in chemotype 2 plants. Conversely, embryos from seeds of chemotypes 1 and 2 that were inoculated with the endophyte resulted in plants with swainsonine concentrations comparable to those of chemotype 1 plants. This reproducible interconversion between the two swainsonine chemotypes suggests that the quantity of endophyte present in the seed at the time of germination is a key determinant of the eventual chemotype. Additionally, this is the first report of the inoculation of locoweeds with the endophyte Undifilum species. PMID- 22844874 TI - Ganglion dynamics and its implications to geologic carbon dioxide storage. AB - Capillary trapping of a nonwetting fluid phase in the subsurface has been considered as an important mechanism for geologic storage of carbon dioxide (CO(2)). This mechanism can potentially relax stringent requirements for the integrity of cap rocks for CO(2) storage and therefore can significantly enhance storage capacity and security. We here apply ganglion dynamics to understand the capillary trapping of supercritical CO(2) (scCO(2)) under relevant reservoir conditions. We show that, by breaking the injected scCO(2) into small disconnected ganglia, the efficiency of capillary trapping can be greatly enhanced, because the mobility of a ganglion is inversely dependent on its size. Supercritical CO(2) ganglia can be engineered by promoting CO(2)-water interface instability during immiscible displacement, and their size distribution can be controlled by injection mode (e.g., water-alternating-gas) and rate. We also show that a large mobile ganglion can potentially break into smaller ganglia due to CO(2)-brine interface instability during buoyant rise, thus becoming less mobile. The mobility of scCO(2) in the subsurface is therefore self-limited. Vertical structural heterogeneity within a reservoir can inhibit the buoyant rise of scCO(2) ganglia. The dynamics of scCO(2) ganglia described here provides a new perspective for the security and monitoring of subsurface CO(2) storage. PMID- 22844875 TI - Pd-catalyzed C-H fluorination with nucleophilic fluoride. AB - The palladium-catalyzed C-H fluorination of 8-methylquinoline derivatives with nucleophilic fluoride is reported. This transformation involves the use of AgF as the fluoride source in combination with a hypervalent iodine oxidant. Both the scope and mechanism of the reaction are discussed. PMID- 22844876 TI - The vascular architecture of the supravaginal and vaginal parts of the human uterine cervix: a study using corrosion casting and scanning electron microscopy. AB - The aim of this study was to visualize and describe the vascular architecture of the vaginal and supravaginal parts of the human uterine cervix. Uteri collected at autopsy (n = 42) were perfused via the afferent vessels with fixative followed by Mercox resin. After polymerization of the resin, corrosion was performed. The obtained vascular casts of the cervix, visualizing all vessels including capillaries, were examined using scanning electron microscopy. Both in the vaginal and supravaginal parts of the cervix, four distinct vascular zones were distinguished - the outer zone containing large arteries and veins, the arteriole and venule zone, the endocervical mucosal capillaries zone and the pericanalar zone containing small veins and capillaries. In the pericanalar zone ran small veins, responsible for draining the mucosal capillaries. Both in the muscular layer, as well as in the pericanalar zone, arterioles and venules passed close to each other, often adjoining. This study introduces the idea of two systems responsible for draining blood from the mucosal capillaries. It is also the first to suggest the possible existence of a countercurrent transport between adjoining veins and arteries. PMID- 22844964 TI - Pharmacovigilance in hospice/palliative care: rapid report of net clinical effect of metoclopramide. AB - BACKGROUND: Understanding the performance of prescribed medications in day-to-day practice is important to minimize harm, maximize clinical benefits, and, eventually, better target the people who are most likely to benefit, especially in hospice/palliative care where there may be limited time to optimize prescribing. Metoclopramide, a benzamide prokinetic antiemetic, is widely used for a number of indications including nausea, vomiting, hiccups, and reflux. It has recently had a new "black box" warning issued by the Food and Drug Administration in relation to tardive dyskinesia to limit use to 12 weeks. METHODS: A consecutive cohort of patients from 12 participating centers in two countries who were having metoclopramide initiated had data collected at three time points--baseline, 2 days (clinical benefit), and day 7 (clinical harm). Additionally, harms could be recorded at any time. RESULTS: Of the 53 people included in the cohort, 23 (43%) reported benefit at 48 hours, but only 18 (34%) of these people were still using it one week after commencing it. For the other 5, the medication was ceased due to harms. The most frequent harms were akathisia (n=4), headache (n=4), and abdominal pain (n=4). Nine people (17%) had no clinical benefit and experienced harms. CONCLUSION: Overall, one in three people gained net clinical benefit at one week. Limiting effects include side-effects that need to be sought actively in clinical care. PMID- 22844877 TI - Guided bone regeneration in long-bone defects with a structural hydroxyapatite graft and collagen membrane. AB - There are few synthetic graft alternatives to treat large long-bone defects resulting from trauma or disease that do not incorporate osteogenic or osteoinductive factors. The aim of this study was to test the additional benefit of including a permeable collagen membrane guide in conjunction with a preformed porous hydroxyapatite bone graft to serve as an improved osteoconductive scaffold for bone regeneration. A 10-mm-segmental long-bone defect model in the rabbit radius was used. The hydroxyapatite scaffolds alone or with a collagen wrap were compared as experimental treatment groups to an empty untreated defect as a negative control or a defect filled with autologous bone grafts as a positive control. All groups were evaluated after 4 and 8 weeks of in vivo implantation using microcomputed tomography, mechanical testing in flexure, and histomorphometry. It was observed that the use of the wrap resulted in an increased bone volume regenerated when compared to the scaffold-only group (59% greater at 4 weeks and 27% greater after 8 weeks). Additionally, the increase in density of the regenerated bone from 4 to 8 weeks in the wrap group was threefold than that in the scaffold group. The use of the collagen wrap showed significant benefits of increased interfacial bone in-growth (149% greater) and periosteal remodeling (49%) after 4 weeks compared to the scaffold-alone with the two groups being comparable after 8 weeks, by when the collagen membrane showed close-to complete resorption. While the autograft and wrap groups showed significantly greater flexural strength than the defect group after 8 weeks, the scaffold-alone group was not significantly different from the other three groups. It is most likely that the wrap shows improvement of function by acting like a scaffold for periosteal callus ossification, maintaining the local bone-healing environment while reducing fibrous infiltration (15% less than scaffold only at 4 weeks). This study indicates that the use of a collagen membrane with a hydroxyapatite structural graft provides benefits for bone tissue regeneration in terms of early interfacial integration. PMID- 22844965 TI - Cytological diagnosis of extranodal NK/T-cell lymphoma, nasal type, in cerebrospinal fluid. PMID- 22844966 TI - Coagulation profile of liquid-state plasma. AB - BACKGROUND: Use of liquid plasma (LP) has been reported as early as the mid 1930s. Unlike fresh-frozen plasma (FFP), LP is maintained at 1 to 6 degrees C for up to 40 days after collection and processing. Despite its approved use by the US Food and Drug Administration, the coagulation profile of LP is incompletely described. In this study we evaluate the coagulation profile of LP stored up to 30 days. STUDY DESIGN AND METHODS: LP was prepared by removing plasma from nonleukoreduced whole blood within 24 hours of collection. Three LP units from each ABO group were collected and stored at 1 to 6 degrees C. Plasma aliquots were obtained at Postcollection Days 1 to 5, 10, 15, 20, 25, and 30 and then stored at -70 degrees C. Each aliquot was tested for prothrombin time, activated partial thromboplastin time, and other coagulation and fibrinolytic factors. RESULTS: There was a significant decrease in Factor (F)V, FVII, FVIII, von Willebrand factor (VWF), protein S (PS) activity, and endogenous thrombin potential on Day 15 compared with Day 1. No significant difference was observed for PS antigen, D-dimer, or thrombin-antithrombin complex. At least 50% activity of all measured factors was noted on Day 15, compared to Day 1. Considerable heterogeneity was observed between the different blood groups for FVII, FVIII, and VWF. CONCLUSION: These data demonstrate that LP maintains at least 50% of factor activity and thrombin-generating capacity up to 15 days of refrigerated storage. It may be more appropriate to limit LP storage and supplement with FFP when used for management of massively bleeding patients. PMID- 22844967 TI - Urinary symptoms and pelvic floor muscle function during the third trimester of pregnancy in nulliparous women. AB - AIM: To evaluate pelvic floor muscle (PFM) function and its association with urinary symptoms in the third trimester of pregnancy. MATERIAL AND METHODS: A cross-sectional study was conducted among 91 nulliparous women at 30-34 weeks of pregnancy. PFM was evaluated by surface electromyography (sEMG) and manual muscle testing, while urinary symptoms were identified by interview. Chi-square and Fisher's exact tests were used to analyze proportions and Mann-Whitney test was used to analyze differences in means. RESULTS: Average sEMG values were 4.8 uV for basic tonus (BT), 19.2 uV for maximum voluntary contraction (MVC), and 12.9 uV for average sustained contraction (ASC), and 48.4% presented muscle strength grade 3. Nocturia was reported by 80.2%, followed by increased daytime frequency (59.3%), stress urinary incontinence (50.5%), and urge urinary incontinence (25.3%). No association was found between urinary symptoms and MVC or ASC or PFM manual tested strength. CONCLUSION: No association was observed between PFM function and urinary incontinence, except decreased BT among late third trimester pregnant women with irritative bladder symptoms. PMID- 22844969 TI - Osteochondroma of C1 causing vertebral artery occlusion. AB - Spinal osteochondromas constitute a small percentage of all intraspinal tumours, and are a rare cause of neurological symptoms. We describe a patient with a vertebral artery occlusion secondary to an osteochondroma of the C1 vertebra presenting with symptoms of cerebral ischaemia. This case is reported because of its extreme rarity. PMID- 22844968 TI - Treatment of Burkitt lymphoma in equatorial Africa using a simple three-drug combination followed by a salvage regimen for patients with persistent or recurrent disease. AB - Prior to the introduction of the International Network for Cancer Treatment and Research (INCTR) protocol INCTR 03-06, survival of patients with Burkitt lymphoma at four tertiary care centres in equatorial Africa was probably no more than 10 20%. The results reported here for 356 patients have demonstrated marked improvement in survival through the use of a uniform treatment protocol consisting of cyclophosphamide, methotrexate, vincristine, and intrathecal therapy, and the introduction of non-cross resistant second-line (salvage) therapy, consisting of ifosfamide, mesna, etoposide and cytarabine, when patients failed to achieve a complete response to first-line therapy or relapsed early. Overall survival rates of 67% and 62% were observed at 1 and 2 years (relapse is rare after 1 year of remission). Of interest was the small impact of cerebrospinal fluid (CSF) and bone marrow involvement on outcome. However, the presence or absence of abdominal involvement clearly defined two prognostic groups. An additional finding was the association between CSF pleocytosis and orbital tumours, suggesting that spread of tumour cells to the central nervous system may sometimes occur via direct involvement of cranial nerves in the orbit. Survival rates may be increased in patients with abdominal involvement by combining first- and second-line therapy, but verification will require a further clinical study. PMID- 22844970 TI - Increased growth rate of a WHO grade I ganglioglioma during pregnancy. AB - We report the case of a 32-year-old woman with a left frontal ganglioglioma (WHO grade I). Quantitative analysis based on three dimensional magnetic resonance images revealed a threefold increase of growth rate during pregnancy as compared to pre-pregnancy, causing neurological deterioration and leading to prompt surgical treatment 3 months after delivery. PMID- 22844971 TI - Mirror-image temporal arteriovenous malformations presenting with left cervical internal carotid aneurysm. AB - We report an unusual case of bilateral mirror-image arteriovenous malformations (AVMs) in association with a large internal carotid aneurysm. The patient, a 45 year-old man, was asymptomatic apart from a lump in his neck. Both AVMs were successfully occluded with embolisation and the patient remains clinically well. PMID- 22844972 TI - A prospective qualitative study on patients' perceptions of endoscopic endonasal transsphenoidal surgery. AB - BACKGROUND: Endoscopic transsphenoidal surgery has been shown to be a safe and effective treatment option for patients with pituitary tumours, but no study has explored patients' perceptions before and after this surgery. OBJECTIVE: The authors in this study aim to explore patients' perceptions on endoscopic transsphenoidal surgery. METHODS: Using qualitative research methodology, two semi-structured interviews were conducted with 30 participants who were adults aged > 18 undergoing endoscopic transsphenoidal surgery for the resection of a pituitary tumour between December 2008 and June 2011. The interviews were audiotaped and transcribed. The resulting data was analyzed using a modified thematic analysis. RESULTS: Seven overarching themes were identified: (1) Patients had a positive surgical experience; (2) patients were satisfied with the results of the procedure; (3) patients were initially surprised that neurosurgery could be performed endonasally; (4) patients expected a cure and to feel better after the surgery; (5) many patients feared that something might go wrong during the surgery; (6) patients were psychologically prepared for the surgery; (7) most patients reported receiving adequate pre-op and post-op information. CONCLUSIONS: This is the first qualitative study reporting on patients' perceptions before and after an endoscopic endonasal transsphenoidal pituitary surgery, which is increasingly used as a standard surgical approach for patients with pituitary tumours. Patients report a positive perception and general satisfaction with the endoscopic transsphenoidal surgical experience. However, there is still room for improvement in post-surgical care. Overall, patients' perceptions can help improve the delivery of comprehensive care to future patients undergoing pituitary tumour surgery. PMID- 22844973 TI - An integrative lens model approach to bias and accuracy in human inferences: hindsight effects and knowledge updating in personality judgments. AB - The present article integrates research on the accurate inference of personality traits with process models of hindsight bias (the tendency to exaggerate in hindsight what one had said in foresight). Specifically, the article suggests a new model that integrates assumptions of the lens model on accurate personality judgments and accounts that view hindsight effects as a by-product of knowledge updating. We suggest 3 processes that have the potential to explain the occurrence of hindsight effects in personality judgments: (a) changes in an individual's cue perceptions, (b) changes in the utilization of more valid cues, and (c) changes in the consistency with which cue knowledge is applied. In 2 studies (N1 = 91, N2 = 93), participants were presented with target pictures and were asked to judge each target's levels of the Big Five. Thereafter, they received feedback and had to recall their original judgments. Results show that there were clear hindsight effects for all 5 personality dimensions. Importantly, we found evidence that both the utilization of more valid cues and changes in cue perceptions--but not changes in the consistency with which cue knowledge is applied--account for the hindsight effects. Implications of these results for models explaining hindsight effects, the inference of personality judgments, and the accuracy of these inferences are discussed. PMID- 22844974 TI - Effectiveness of a national approach to prescribing education for multiple disciplines. AB - AIMS: To evaluate the effectiveness of a national approach to prescribing education on health professional students' prescribing and therapeutics knowledge, across multiple disciplines. METHODS: In a university examination setting, 83 medical, 40 pharmacy and 13 nurse practitioner students from three different universities completed a set of multiple choice questions (MCQs) before and after completing an online module from the National Prescribing Curriculum (NPC). To minimize overestimation of knowledge, students had to indicate the level of certainty for each answer on a three-point scale. MCQs were scored using a validated certainty-based marking scheme resulting in a composite score (maximum 30 and minimum -60). Students were asked to rate their perception of usefulness of the module. RESULTS: At the pre-module phase, there were no significant differences in the composite MCQ scores between the medical (9.0 +/- 10.3), pharmacy (10.2 +/- 10.6) and nurse practitioner (8.0 +/- 10.7) students. The scores improved significantly for all groups at the post-module phase (P < 0.01 for all groups) by similar extents (post-module results: medical, 14.5 +/- 9.6; pharmacy, 14.4 +/- 9.9; nurse practitioner, 12.1 +/- 9.6). 39.4% of the MCQs answered incorrectly with high level of certainty at the pre-module phase were still answered incorrectly with high level of certainty at the post-module phase. Almost all students (with no significant difference between the groups) found the NPC modules, post-module MCQs and feedback useful as a learning tool. CONCLUSIONS: A national online approach to prescribing education can improve therapeutics knowledge of students from multiple disciplines of health care and contribute towards streamlining interdisciplinary learning in medication management. PMID- 22844975 TI - A preterm infant with anaemia and left leg mild hemihypertrophy (case presentation). PMID- 22844976 TI - Self-declared sensitive skin in China: a community-based study in three top metropolises. AB - OBJECTIVES: To investigate the prevalence and the factors related to the sensitive skin in China. METHODS: A community-based study was undertaken in three major cities in China, Beijing, Shanghai and Guangzhou, from November 2009 to January 2010. The participants in the study were screened by cluster sampling, and were investigated by interview at their own homes. A questionnaire, including skin sensitivity, the occurrence of burning, prickling or irritating sensations correlated with the factors, history of skin diseases and skin types, was given to each participant aged over 15 years. RESULTS: Totally 9154 questionnaires were completed (3931 men and 5223 women). The mean prevalence of very sensitive and sensitive skin in three cities was 13% (17.12% in Beijing, 9.10% in Shanghai and 22.39% in Guangzhou.) The mean prevalence was 8.62% in men and 15.93% in women, with significant difference between men and women in three selected cities (P < 0.001). The total prevalence of very sensitive and sensitive skin was 16.44% in <25 years group, 14.14% in 25-49 years group and 9.73% in >=50 years group. Moreover, 18.54% of participants claimed with dry skin, 16.70% with greasy skin and 8.04% with normal skin claimed to have the symptoms of sensitive skin. CONCLUSIONS: The prevalence of sensitive skin in the three cities of China is much lower than that in Europe and the United States. There was significant difference of the prevalence of sensitive skin among three cities located in different climatic and latitude regions and between men and women. The prevalence gradually decreased with the increasing age. The skin sensitivity was associated to the positive history of atopic dermatitis. PMID- 22844977 TI - Genetic investigation of patients with undetectable peaks of growth hormone after two provocation tests. PMID- 22844978 TI - Estimating measurement error when annualizing health care costs. AB - OBJECTIVE: Health insurers routinely annualize members' health care costs for reporting, predicting high cost cases and evaluating health management programmes. Annualization is the practice of extrapolating to a yearly cost from less than a year of data. In this paper, we systematically estimate the measurement error inherent in this approach. STUDY DESIGN: The paper uses a retrospective observational study using longitudinal claims data from three types of insured populations: Medicare managed care, public employees and a self insured employer. METHODS: The unit of analysis was a block 'year' consisting of 12 consecutive months of cost data for any individual member. These blocks were constructed recursively allowing use of all available data that an individual could contribute. We tested the accuracy of the annualized costs by calculating the absolute error (AE) representing the difference, in dollars, between the actual annual costs and the predicted annual costs, and the absolute percentage error (APE) which is the absolute error divided by the actual 12-month costs. RESULTS: Under the best case scenario (when 11 months of data were used to annualize costs), the mean AE ranged from approximately $2700 for the Medicare population to about $400 for the two working-aged populations; and the mean APE ranged from 9.6% to 11.0% in the three populations. Accuracy diminished systematically with fewer months of available data. CONCLUSIONS: Due to the largely unpredictable nature of monthly costs, annualization can produce substantial measurement error. Given the importance of cost metrics for decision making, we offer several alternative approaches that insurers should consider to improve measurement accuracy. PMID- 22844979 TI - Low-dose sublingual ketamine does not modulate experimentally induced mechanical hyperalgesia in healthy subjects. AB - OBJECTIVE: Musculoskeletal pain has been associated with N-methyl-d-aspartate (NMDA) receptor-mediated mechanisms. This randomized controlled trial (RCT) investigated the effect of the NMDA receptor antagonist ketamine (25 mg sublingually) on modulating experimental muscle pain. DESIGN: Two groups (N = 11/group) of age- and sex-matched healthy subjects performed eccentric exercise using the nondominant arm wrist extensors (time 0) to induce muscle soreness 24 hours later (time 1). INTERVENTION: Immediately prior to exercise, subjects were administered either a 25 mg ketamine lozenge or a placebo. At time 1, experimental muscle pain was augmented by injection of hypertonic saline into the extensor carpi radialis brevis (ECRB) muscle of the exercised arm. OUTCOME MEASURES: Pressure pain thresholds (PPTs), muscle soreness, muscle pain intensity (electronic visual analog scale [VAS]), and maximal wrist extension force were assessed at time 0 (pre- and postexercise) and at time 1 (pre-, during, and post saline-induced pain). RESULTS: Regardless of group, PPT was reduced at ECRB (P < 0.021) and at the common extensor origin (P < 0.034) at time 1 preinjection compared with time 0 pre-exercise. At time 1, elevated levels of muscle soreness and force attenuation were similar between groups compared with time 0 pre exercise (P < 0.0001), and similar hypertonic saline-induced pain areas and pain intensity profiles were evident. CONCLUSION: In comparison with placebo, a single low-dose sublingual pharmacological intervention targeting the processes of sensitization via antagonism of NMDA receptors did not modulate the effects of acute experimentally induced mechanical hyperalgesia, suggesting a higher dose or repeat doses may be required. PMID- 22844980 TI - Immediate and short-term effects of Mulligan's mobilization with movement on knee pain and disability associated with knee osteoarthritis--a prospective case series. AB - Manual therapy has proven to be a benefit in the management of knee osteoarthritis (OA), but the effects of the method of Mulligan's mobilization with movement (MWM) have yet to be explored in knee OA. As a first step, this case series investigated MWM's immediate and short-term benefits over three occasions of treatment in 19 patients with knee OA. Patients (71.1 +/- SD 13.9 years, 14 females and 5 males) received individually prescribed MWM and performed self-MWM. Outcome measures included: 1) pain intensity (visual analog scales) during walking, ascending and descending stairs, and sit-to-stand; 2) passive flexion and extension range of motion (ROM); and 3) Activities of Daily Living Scale of the Knee Outcome Survey (KOS-ADLS). Pain and ROM were assessed at baseline, after the initial treatment, before the second treatment and at exit following the fourth consultation. The KOS-ADLS was assessed at baseline and at exit. Significant improvements from baseline were detected in flexion ROM and pain scores in all tasks following the initial treatment (P < 0.05/3). The KOS ADLS score improved significantly from baseline (67.1% +/- SD 16.6%) to exit (86.3% +/- SD 12.6%) (P < 0.001). MWM was associated with immediate pain relief and improved knee function, suggesting its potential as a component of early management of knee OA. PMID- 22844981 TI - Real medicine. AB - A substantial part of a paediatrician's work increasingly involves caring for children and young people with mental health, developmental, emotional and behavioural problems. Over time, recognition of these aspects has redefined and broadened the notion of what classically constitutes 'Paediatrics.' This paper discusses the ways in which paediatricians and psychiatrists can support each other in this work. It highlights the role of supervision and specifically advocates for the expansion of consultation/liaison psychiatry services. PMID- 22844982 TI - Malaria parasite signal peptide peptidase is an ER-resident protease required for growth but not for invasion. AB - The establishment of parasite infection within the human erythrocyte is an essential stage in the development of malaria disease. As such, significant interest has focused on the mechanics that underpin invasion and on characterization of parasite molecules involved. Previous evidence has implicated a presenilin-like signal peptide peptidase (SPP) from the most virulent human malaria parasite, Plasmodium falciparum, in the process of invasion where it has been proposed to function in the cleavage of the erythrocyte cytoskeletal protein Band 3. The role of a traditionally endoplasmic reticulum (ER) protease in the process of red blood cell invasion is unexpected. Here, using a combination of molecular, cellular and chemical approaches we provide evidence that PfSPP is, instead, a bona fide ER-resident peptidase that remains intracellular throughout the invasion process. Furthermore, SPP-specific drug inhibition has no effect on erythrocyte invasion whilst having low micromolar potency against intra erythrocytic development. Contrary to previous reports, these results show that PfSPP plays no role in erythrocyte invasion. Nonetheless, PfSPP clearly represents a potential chemotherapeutic target to block parasite growth, supporting ongoing efforts to develop antimalarial-targeting protein maturation and trafficking during intra-erythrocytic development. PMID- 22844983 TI - Towards global consensus on outcome measures for atopic eczema research: results of the HOME II meeting. AB - The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence-based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence-based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long-term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research. PMID- 22844985 TI - Patient care by VA psychologists in the 1950s and 1960s. AB - In 1946, the Veterans Administration, now the Department of Veterans Affairs (VA), underwent extensive organizational and professional changes to accommodate the health care needs of veterans returning from World War Two. In addition to an introduction and brief history of these changes, three psychologists who began their careers in the VA in the first years after that reorganization discuss their patient care experiences, both as trainees and as staff psychologists. PMID- 22844986 TI - Exciting discoveries about new p53 target genes, cancer drugs and diagnostic tools, and mechanisms of various human diseases. PMID- 22844984 TI - Separating the contributions of primary and unwanted cues in psychophysical studies. AB - A fundamental issue in the design and the interpretation of experimental studies of perception relates to the question of whether the participants in these experiments could perform the perceptual task assigned to them using another feature, or cue, than that intended by the experimenter. An approach frequently used by auditory- and visual-perception researchers to guard against this possibility involves applying random variations to the stimuli across presentations or trials so as to make the "unwanted" cue unreliable for the participants. However, the theoretical basis of this widespread practice is not well developed. In this article, we describe a 2-channel model based on general principles of psychophysical signal detection theory, which can be used to assess the respective contributions of the unwanted cue and of the primary cue to performance or thresholds measured in perceptual discrimination experiments involving stimulus randomization. Example applications of the model to the analysis of results obtained in representative studies from the auditory- and visual-perception literature are provided. In several cases, the results of the model-based analyses indicate that the effectiveness of the randomization procedure was less than originally assumed by the authors of these studies. These findings underscore the importance of quantifying the potential influence of unwanted cues on the results of psychophysical experiments, even when stimulus randomization is used. PMID- 22844987 TI - Eye movements reveal dynamics of task control. AB - With the goal to determine the cognitive architecture that underlies flexible changes of control settings, we assessed within-trial and across-trial dynamics of attentional selection by tracking of eye movements in the context of a cued task-switching paradigm. Within-trial dynamics revealed a switch-induced, discrete delay in onset of task-congruent fixations, a result that is consistent with a higher level configuration process. Next, we derived predictions about the trial-to-trial dynamic coupling of control settings from competing models, assuming that control is achieved either through task-level competition or through higher level configuration processes. Empirical coupling dynamics between trial n-1 eye movements and trial n response times--estimated through mixed linear modeling--revealed a pattern that was consistent with the higher level configuration model. The results indicate that a combination of eye movement data and mixed modeling methods can yield new constraints on models of flexible control. This general approach can be useful in any domain in which theoretical progress depends on high-resolution information about dynamic relationships within individuals. PMID- 22844988 TI - Solvent-extractable polycyclic aromatic hydrocarbons in biochar: influence of pyrolysis temperature and feedstock. AB - Despite the increasing agricultural use of biochar as a way of combining the utilization of biomass for energy production with the removal of CO(2) from the atmosphere, it is not known how variations in pyrolysis temperature and feedstock type affect concentration and composition of polycyclic aromatic hydrocarbons (PAHs) that inevitably form and associate with biochar. To close this knowledge gap, we quantified 11 unsubstituted three- to five-ring PAHs as well as alkylated forms of phenanthrene and anthracene in grass and wood chars produced in 100 degrees C increments across a temperature range (100 to 700 degrees C). Our results show that solvent-extractable PAH concentrations in biochars produced at heat treatment temperatures (HTTs) of 400 and 500 degrees C greatly exceed those observed at higher and lower temperature, supporting a low HTT solid-phase formation mechanism operable at temperatures commonly used for industrial biochar production. The maximum extractable yield of 'pyrolytic' unsubstituted PAHs for grass (22 MUg g(-1) at HTT = 500 degrees C) greatly exceeds the value for wood (5.9 MUg g(-1)). Moreover, PAH signatures (e.g., total monomethylphenanthrene to phenanthrene ratios, MP/P ~2-3) at intermediate temperatures (400 degrees C) resemble those of fossil oils rather than that commonly attributed to pyrolytic products. Further research is needed to characterize the PAH evolution in modern pyrolysis reactors and assess the fate of biochar-bound PAHs in soils and sediments. Various commonly applied PAH ratios and indicator compounds show promise as markers for specific feedstock materials and pyrolysis conditions of biochars in environmental systems. PMID- 22844989 TI - A study to investigate the walking speed of elderly adults with relation to pedestrian crossings. AB - Elderly pedestrians are particularly at risk on the roads. The objective of this study was to investigate the walking speed of elderly adults and determine if it allows the safe clearance of pedestrian crossings. The increasing elderly population and high fatality rates of this age group on Irish roads necessitate this investigation. Fifty-two community-dwelling adults over the age of 65 years completed a 10-meter walk test. Acceleration and steady-state walking speed were accounted for. Twenty traffic-light-controlled pedestrian crossings were analyzed within a 1 kilometer radius of 4 day care centers in Kilkenny, Ireland. Values were recorded for the distance of the crossings and time of the light signals. The mean acceleration of the 52 participants was 0.20 +/- 0.15 ms(-2) (mean +/- SD) and the mean steady-state walking speed was 0.82 +/- 0.27 ms(-1). In total, 30% of the pedestrian crossings investigated would not have permitted this sample of participants enough time to safely cross the road given the time of the green and amber light signals. Over 96% of participants would have been unable to cross a road of average distance on the amber signal alone. A substantial number of elderly adults walked slower than the speed required to safely cross the road. PMID- 22844990 TI - Highly stereoselective synthesis of primary, secondary, and tertiary alpha-S sialosides under Lewis acidic conditions. AB - N-acetyl 4-O,5-N-oxazolidinone protected sialyl phosphates of either anomeric configuration are excellent donors for the formation of alpha-S-sialosides at -78 degrees C in dichloromethane with primary, secondary, and tertiary thiols including galactose 3-, 4-, and 6-thiols. The reactions, which proceed under typical Lewis acid promoted glycosylation conditions, are highly alpha-selective and do not suffer from competing elimination of the phosphate. PMID- 22844991 TI - Authentication of organic feed by near-infrared spectroscopy combined with chemometrics: a feasibility study. AB - Organic products tend to retail at a higher price than their conventional counterparts, which makes them susceptible to fraud. In this study we evaluate the application of near-infrared spectroscopy (NIRS) as a rapid, cost-effective method to verify the organic identity of feed for laying hens. For this purpose a total of 36 organic and 60 conventional feed samples from The Netherlands were measured by NIRS. A binary classification model (organic vs conventional feed) was developed using partial least squares discriminant analysis. Models were developed using five different data preprocessing techniques, which were externally validated by a stratified random resampling strategy using 1000 realizations. Spectral regions related to the protein and fat content were among the most important ones for the classification model. The models based on data preprocessed using direct orthogonal signal correction (DOSC), standard normal variate (SNV), and first and second derivatives provided the most successful results in terms of median sensitivity (0.91 in external validation) and median specificity (1.00 for external validation of SNV models and 0.94 for DOSC and first and second derivative models). A previously developed model, which was based on fatty acid fingerprinting of the same set of feed samples, provided a higher sensitivity (1.00). This shows that the NIRS-based approach provides a rapid and low-cost screening tool, whereas the fatty acid fingerprinting model can be used for further confirmation of the organic identity of feed samples for laying hens. These methods provide additional assurance to the administrative controls currently conducted in the organic feed sector. PMID- 22844992 TI - Radical versus nucleophilic mechanism of formaldehyde polymerization catalyzed by (WO3)3 clusters on reduced or stoichiometric TiO2(110). AB - (WO(3))(3) clusters deposited on the (110) rutile TiO(2) surface are excellent catalysts for the formaldehyde (CH(2)O) polymerization reaction (J. Phys. Chem. C 2010, 114, 17017). The present B3LYP study unravels the possible paths of this catalyzed reaction. According to the stoichiometry of the r-TiO(2) surface, the (WO(3))(3) clusters can be neutral, singly charged, or doubly charged. We find that only neutral (WO(3))(3) and anionic (WO(3))(3)(-) clusters are reactive toward CH(2)O molecules. In both cases it is possible to determine more than one mechanism on the basis of a nucleophilic attack of the formaldehyde O atom to the W ions of the cluster. The reaction proceeds through successive attacks of other CH(2)O molecules and the formation of acetal and polyacetal intermediates, which inhibits the chain propagation. Only in the case of the anionic (WO(3))(3)(-) catalyst is a totally different reaction path possible at low temperatures. This path involves the formation of radical species where the unpaired electron is localized on the organic moiety bound to the cluster. The polymer chain propagation follows a radical mechanism with low activation barriers. Thus, a cluster's electron charging speeds up the formaldehyde polymerization at low temperatures. On the basis of these unexpected results, we conclude that electron rich supports and low working temperatures are the keys to kinetic control of the reaction favoring a fast radical chain propagation mechanism. PMID- 22844993 TI - British Journal of Neurosurgery. Editorial. PMID- 22844994 TI - Can spontaneous fusion of vertebral bodies be considered as nature's solution to the growth of ossification of posterior longitudinal ligament? PMID- 22844997 TI - Condition-dependent natal dispersal in a large herbivore: heavier animals show a greater propensity to disperse and travel further. AB - Natal dispersal is defined as the movement between the natal range and the site of first breeding and is one of the most important processes in population dynamics. The choice an individual makes between dispersal and philopatry may be condition dependent, influenced by either phenotypic attributes and/or environmental factors. Interindividual variability in dispersal tactics has profound consequences for population dynamics, particularly with respect to metapopulation maintenance. A better understanding of the mechanisms underlying this variability is thus of primary interest. We investigated the ranging behaviour of 60 juvenile European roe deer, Capreolus capreolus, monitored with GPS collars for 1 year prior to their first reproduction, from 2003 to 2010 in South-West France. Dispersal occurs across a spatial continuum so that dividing individuals into two categories (dispersers vs. philopatric) may lead to information loss. Therefore, to investigate condition-dependent dispersal more accurately, we developed an individual-based measure of dispersal distance, which took into account interindividual variation in ranging behaviour. We assessed the influence of body mass, the degree of habitat heterogeneity and sex on dispersal initiation date, dispersal propensity and distance. The overall population dispersal rate was 0.34, with a mean +/- SD linear distance between natal and post-dispersal home ranges of 12.3 +/- 10.5 km. Dispersal distances followed a classical leptokurtic distribution. We found no sex bias in either dispersal rate or distance. Forest animals dispersed less than those living in more heterogeneous habitats. Heavier individuals dispersed with a higher probability, earlier and further than lighter individuals. Our individual-based standardised dispersal distance increased linearly with body mass, with some suggestion of a body mass threshold of 14 kg under which no individual dispersed. Natal dispersal in roe deer was thus dependent on both phenotypic attributes and environmental context. Our results suggest that population connectivity can be altered by a change in average body condition and is likely higher in the rich and heterogeneous habitats typical of modern day agricultural landscapes. PMID- 22844998 TI - Endocytosis and intracellular trafficking as gateways for nanomedicine delivery: opportunities and challenges. AB - More than 40 nanomedicines are already in routine clinical use with a growing number following in preclinical and clinical development. The therapeutic objectives are often enhanced disease-specific targeting (with simultaneously reduced access to sites of toxicity) and, especially in the case of macromolecular biotech drugs, improving access to intracellular pharmacological target receptors. Successful navigation of the endocytic pathways is usually a prerequisite to achieve these goals. Thus a comprehensive understanding of endocytosis and intracellular trafficking pathways in both the target and bystander normal cell type(s) is essential to enable optimal nanomedicine design. It is becoming evident that endocytic pathways can become disregulated in disease and this, together with the potential changes induced during exposure to the nanocarrier itself, has the potential to significantly impact nanomedicine performance in terms of safety and efficacy. Here we overview the endomembrane trafficking pathways, discuss the methods used to determine and quantitate the intracellular fate of nanomedicines, and review the current status of lysosomotropic and endosomotropic delivery. Based on the lessons learned during more than 3 decades of clinical development, the need to use endocytosis-relevant clinical biomarkers to better select those patients most likely to benefit from nanomedicine therapy is also discussed. PMID- 22844999 TI - Ovarian pregnancy resulting from cryopreserved blastocyst transfer. AB - Ovarian pregnancy very rarely occurs and its exact mechanism is unclear. Here, we report a case of ovarian pregnancy resulting from cryopreserved blastocyst transfer. The patient was a 34-year-old woman who had undergone bilateral ovarian cystectomy for endometriosis. Both fallopian tubes indicated normal findings on laparoscopic surgery, and we removed the gestational product of the right ovary. Pathological analysis confirmed the diagnosis of right ovarian pregnancy. Ectopic pregnancy is one of the major complications of in vitro fertilization-embryo transfer. Although ovarian pregnancy is an extremely rare occurrence, the possibility of developing this event after cryopreserved blastocyst transfer should be recognized. PMID- 22845000 TI - Editorial: choline and brain function. PMID- 22845001 TI - Abnormal uterine bleeding following lumbar epidural corticosteroid injections and facet medial branch blocks in both pre- and postmenopausal women: a case series. AB - BACKGROUND: Epidural steroid injections (ESIs) are now increasing in popularity with regard to the management of chronic lumbar radiculopathy. While ESIs have been shown to be effective in relieving low back and radicular pain, adverse reactions have also been reported, notably abnormal vaginal bleeding. OBJECTIVE: We present a case series of four women, both pre- and postmenopausal, with chronic lumbar radiculopathy and corresponding pathology who developed abnormal vaginal bleeding after receiving either ESIs or facet medial branch blocks (MBBs) for pain management. Setting. University of California, Los Angeles. PATIENTS: Four women, both pre- and postmenopausal. CONCLUSIONS: We discuss the potential effects of corticosteroids on the hypothalamic-pituitary-ovarian axis and highlight our patients' risk factors for abnormal vaginal bleeding, both exogenous and endogenous, as well as focus on the technical approaches to corticosteroid administration utilized in our patients' procedures. We acknowledge that because this is a small case series, further prospective investigation is warranted regarding the above topics. Until then, it may be beneficial to consider whether patients, both pre- and postmenopausal, have risk factors for abnormal uterine bleeding prior to undergoing interventional pain management strategies, specifically ESI and MBB, and to inform all women upon consent that abnormal vaginal bleeding is a potential risk following procedures with corticosteroids. PMID- 22845002 TI - Electromyographic analysis of trunk and hip muscles during resisted lateral band walking. AB - The purpose of this study was to simultaneously quantify bilateral activation/recruitment levels (% maximum voluntary isometric contraction [MVIC]) for trunk and hip musculature on both moving and stance lower limbs during resisted lateral band walking. Differential electromyographic (EMG) activity was recorded in neutral, internal, and external hip rotation in 21 healthy participants. EMG signals were collected with DE-3.1 double-differential surface electrodes at a sampling frequency of 1,000 Hz during three consecutive lateral steps. Gluteus medius average EMG activation was greater (p = 0.001) for the stance limb (52 SD 18% MVIC) than moving limb (35 SD 16% MVIC). Gluteus maximus EMG activation was greater (p = 0.002) for the stance limb (19 SD 13% MVIC) than moving limb (13 SD 9% MVIC). Erector spinae activation was greater (p = 0.007) in hip internal rotation (30 SD 13% MVIC) than neutral rotation (26 SD 10% MVIC) and the moving limb (31 SD 15% MVIC) was greater (p = 0.039) than the stance limb (23 SD 11% MVIC). Gluteus medius and maximus muscle activation were greater on the stance limb than moving limb during resisted lateral band walking. Therefore, clinicians may wish to consider using the involved limb as the stance limb during resisted lateral band walking exercise. PMID- 22845003 TI - Comparative in vitro analysis of different hematopoietic cell populations from human cord blood: in search of the best option for clinically oriented ex vivo cell expansion. AB - BACKGROUND: Ex vivo expansion of hematopoietic stem and progenitor cells has become a priority in the experimental hematology arena. In this study we have obtained different hematopoietic cell populations from umbilical cord blood and simultaneously assessed their proliferation and expansion kinetics. Our main goal was to determine which one of these cell populations would be more suitable for clinical-grade ex vivo expansion. STUDY DESIGN AND METHODS: By using immunomagnetic-negative selection and cell sorting, five cell populations were obtained: unseparated mononuclear cells (MNCs; I); two lineage-negative cell populations, one enriched for CD34+ CD38+ cells (II) and the other enriched for CD34+ CD38- cells (III); and two CD34+ cell fractions purified by fluorescence activated cell sorting, one containing CD34+ CD38+ cells (IV) and the other containing CD34+ CD38- cells (V). The kinetics of such populations were analyzed in both relative and absolute terms. RESULTS: No expansion was observed in Population I; in contrast, significant increments in the numbers of both progenitor and stem cells were observed in cultures of Populations II to V. Population V (reaching 12,800-fold increase in total cells; 1280-fold increase in CD34+ cells; 490-fold increase in colony-forming cells; and 12-fold increase in long-term culture-initiating cells) showed the highest proliferation and expansion potentials. CONCLUSION: Our study suggests that the cell fraction containing greater than 98% CD34+ CD38- cells would be the ideal one for large scale ex vivo expansion; however, based on our data, it seems that, except for MNCs, all other cell populations could also be used as input cell fractions. PMID- 22845004 TI - The end-of-life experience for a cohort of patients with pulmonary arterial hypertension. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease of the pulmonary circulation. There has never been an investigation of the end-of-life symptoms in patients with PAH. In this investigation, we surveyed surrogates of recent decedents with PAH. We evaluate their responses to better understand the end-of-life experience of patients with PAH. METHODS: The survey instrument includes demographic information and the Edmonton Symptoms Assessment Scale. Accredo Therapeutics mailed the survey to surrogates of recent decedents with PAH, and responses were anonymously returned to investigators at Virginia Commonwealth University and used in our descriptive analysis. RESULTS: Of 100 surveys distributed over 24 months (February 2009 to February 2011), we obtained 36 responses (response rate 36%). We found that most patient deaths (90%) were related to PAH, that the majority of patients died in the hospital (67%), with the majority of in-hospital deaths (83%) occurring in intensive care. Palliative care was infrequently involved in patients' care, and many surrogates were unaware of palliative care and hospice services available to the decedents. Patients died with a high symptom burden, especially dyspnea. CONCLUSION: In this cohort, patients with PAH usually died from their disease, often in the hospital setting with a high symptom burden. Further study will be needed to confirm the findings from this study and to better understand the forces leading to the trends uncovered in this investigation. PMID- 22845005 TI - Co-factor-enhanced food allergy. AB - BACKGROUND: Alcohol, exercise or non-steroidal anti-inflamatory drugs (NSAID) are frequently mentioned as amplifiers of food allergic reactions but only individual cases or small series have been previously published. METHODS: Descriptive study including 74 cases of suspected co-factor enhanced food allergy, assessed by skin prick tests, specific IgE and oral challenges. RESULTS: Anaphylaxis accounted for 85.1% of reactions. In 99% of cases culprit food allergens were plant-derived, mainly vegetables and cereals. NSAID were involved in 58%, exercise in 52.7% and alcohol in 12.2%. Lipid transfer protein was the most frequently involved allergen. CONCLUSIONS: Co-factor enhanced food allergy should be considered when assessing food, alcohol, exercise and NSAID allergic reactions. PMID- 22845006 TI - Regression of a renal cell carcinoma following allogeneic peripheral blood stem cell transplant for acute myeloid leukaemia: evidence of a graft-versus-tumour effect without significant graft-versus-host disease. PMID- 22845007 TI - Are health professionals' perceptions of patient safety related to figures on safety incidents? AB - OBJECTIVE: The study aims to explore whether health care professionals' perceptions of patient safety in their practice were associated with the number of patient safety incidents identified in patient records. SETTING: Seventy primary care practices of general practice, general dental practice, midwifery practices and allied health care practices were used in the study. METHODS: A retrospective audit of 50 patient records was performed to identify patient safety incidents in each of the practices and a survey among health professionals to identify their perceptions of patient safety. RESULTS: All health professions felt that 'communication breakdowns inside the practice' as well as 'communication breakdowns outside the practice' and 'reporting of patient safety concerns' were a threat to patient safety in their work setting. We found little association between the perceptions of health professionals and the number of safety incidents. The only item with a significant relation to a higher number of safety incidents referred to the perception of 'communication problems outside the practice' as a threat to patient safety. CONCLUSIONS: This study indicates that the assessment of professionals' perceptions may be complementary to observed safety incidents, but not linked to an objective measure of patient safety. PMID- 22845008 TI - Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. AB - AIM: Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. METHODS: Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. RESULTS: Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P < 0.0001). On day 1, the geometric mean ratio of the fraction from the previous day in minimum daily HR between DT1 and non-titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P < 0.05) with significant differences noted through to day 12. Non-titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min-1; P <= 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. CONCLUSION: Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg. PMID- 22845009 TI - Oesophageal complication from button battery ingestion in an infant. AB - The substantial risks of button battery ingestion in children have been known to clinicians for some time. Modern button batteries are twice as large (20 mm rather than 10 mm) and twice as powerful (3 V rather than 1.5 V) as older batteries. Ingestion of modern batteries causes earlier and more severe tissue injury, as these larger batteries are more likely to impact at areas of physiological narrowing. A high index of suspicion for ingestion, use of appropriate imaging and early removal of batteries is necessary to prevent complications. PMID- 22845010 TI - Observed characteristics of suicidal hangings: an 11-year retrospective review. AB - Many studies have been published regarding suicidal hanging deaths, and most forensic pathologists and coroners are very familiar with such causes of death. Forensic pathologists are challenged over their rulings regarding manner of death in part because the general public has a limited scope of knowledge. One such challenge centers on the question of whether a hanging can be a suicide if the individual is not fully suspended. The authors designed a retrospective study to review suspension in hangings and to analyze other criteria used to help in deciding manner of death. We examined 229 suicidal hanging deaths over an 11-year period (1997 through early 2009) using the data from two separate jurisdictions in Ohio. In conclusion, we found that the vast majority (83.4%) of people who hanged themselves were found partially suspended. Among other criteria analyzed, only the presence of petechial hemorrhages and acute neck injury was statistically significant. PMID- 22845011 TI - Design rules for charge-transport efficient host materials for phosphorescent organic light-emitting diodes. AB - The use of blue phosphorescent emitters in organic light-emitting diodes (OLEDs) imposes demanding requirements on a host material. Among these are large triplet energies, the alignment of levels with respect to the emitter, the ability to form and sustain amorphous order, material processability, and an adequate charge carrier mobility. A possible design strategy is to choose a pi-conjugated core with a high triplet level and to fulfill the other requirements by using suitable substituents. Bulky substituents, however, induce large spatial separations between conjugated cores, can substantially reduce intermolecular electronic couplings, and decrease the charge mobility of the host. In this work we analyze charge transport in amorphous 2,8-bis(triphenylsilyl)dibenzofuran, an electron transporting material synthesized to serve as a host in deep-blue OLEDs. We show that mesomeric effects delocalize the frontier orbitals over the substituents recovering strong electronic couplings and lowering reorganization energies, especially for electrons, while keeping energetic disorder small. Admittance spectroscopy measurements reveal that the material has indeed a high electron mobility and a small Poole-Frenkel slope, supporting our conclusions. By linking electronic structure, molecular packing, and mobility, we provide a pathway to the rational design of hosts with high charge mobilities. PMID- 22845012 TI - Insight on the formation of chitosan nanoparticles through ionotropic gelation with tripolyphosphate. AB - This work reports details pertaining to the formation of chitosan nanoparticles that we prepare by the ionic gelation method. The molecular interactions of the ionic cross-linking of chitosan with tripolyphosphate have been investigated and elucidated by means of all-electron density functional theory. Solvent effects have been taken into account using implicit models. We have identified primary interaction ionic cross-linking configurations that we define as H-link, T-link, and M-link, and we have quantified the corresponding interaction energies. H links, which display high interaction energies and are also spatially broadly accessible, are the most probable cross-linking configurations. At close range, proton transfer has been identified, with maximum interaction energies ranging from 12.3 up to 68.3 kcal/mol depending on the protonation of the tripolyphosphate polyanion and the relative coordination of chitosan with tripolyphosphate. On the basis of our results for the linking types (interaction energies and torsion bias), we propose a simple mechanism for their impact on the chitosan/TPP nanoparticle formation process. We introduce the beta ratio, which is derived from the commonly used alpha ratio but is more fundamental since it additionally takes into account structural details of the oligomers. PMID- 22845013 TI - Efficient preparation of 2,4-diaminopyrimidine nucleosides: total synthesis of lysidine and agmatidine. AB - An efficient route for the synthesis of 2,4-diaminopyrimidine ribosides from cytidine is described consisting of six steps with overall yields >50% and only one chromatographic step. The key amine addition step utilizes LiCl and 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) to ensure clean conversion to a single tautomeric product. This route has been used to prepare the modified tRNA nucleosides lysidine and agmatidine in quantities suitable for structural characterization. PMID- 22845014 TI - Synthesis and structure-activity relationships of lapacho analogues. 1. Suppression of human keratinocyte hyperproliferation by 2-substituted naphtho[2,3 b]furan-4,9-diones, activation by enzymatic one- and two-electron reduction, and intracellular generation of superoxide. AB - A series of linearly anellated lapacho quinone analogues substituted at the 2 position of the tricyclic naphtho[2,3-b]furan-4,9-dione system were synthesized and evaluated for their ability to suppress keratinocyte hyperproliferation using HaCaT cells as the primary test system. While very good in vitro potency with IC(50) values in the submicromolar range was attained with electron-withdrawing substituents, some compounds were found to induce plasma membrane damage, as evidenced by the release of LDH activity from cytoplasm of the keratinocytes. The most potent analogue against keratinocyte hyperproliferation was the 1,2,4 oxadiazole 18, the potency of which was combined with comparably low cytotoxic membrane damaging effects. Structure-activity relationship studies with either metabolically stable or labile analogues revealed that the quinone moiety was required for activity. Selected compounds were studied in detail for their capability to generate superoxide radicals both in isolated enzymatic one- and two-electron reduction assays as well as in a HaCaT cell-based assay. PMID- 22845015 TI - Diagnosis and management of melanoma with regional lymph node metastases: a population-based study in France. AB - BACKGROUND: Stage III melanoma represents a borderline situation regarding the potential curability of this potentially aggressive cancer and consequently, regional lymph node metastases (RLNM) are a major challenge for melanoma management. OBJECTIVE: To describe the management of melanoma with RLNM as practised in France in 2008 and compare results with previous data from 2004, considering that new French recommendations were published in 2005. METHODS: Retrospective population-based study in five regions of France totalling 8.3 million inhabitants, targeting all incident cases of RLNM diagnosed in 2008. Questionnaires were mailed to physicians to identify cases and collect data, with verification by cancer registries for cases diagnosed concomitantly with the primary tumour using sentinel lymph node biopsies (SLNB). RESULTS: Data were collected for 101 patients in 2008, and compared to 89 cases treated in 2004. Palpation by a dermatologist was the most common circumstance of diagnosis of RLNM in 2008 (36%), followed by SLNB (29%), self-palpation by the patient (16%) and lymph node ultrasonography (6%), without significant modification from 2004. After lymphadenectomy an adjuvant therapy was proposed in 62% of cases, mainly consisting in high-dose interferon (HD-IFN) (80%). Overall, HD-IFN was proposed in 49% of cases, but effectively started in only 40% of cases after being proposed, and prematurely withdrawn in 28%, showing major changes as compared with 2004 (33%, 77% and 67%, respectively, P < 0.05). Adjuvant chemotherapy was not proposed to any patients in 2008, compared to 29% in 2004. Surveillance procedures included medical imaging less often in 2008 (76%) than in 2004 (92%) (P = 0.004), but more often included FDG-PET (23% vs. 12%, P = 0.09). CONCLUSION: Overall, actual practice was in accordance with French recommendations. The main developments from 2004 to 2008 were the disappearance of adjuvant chemotherapies and a more accurate selection of patients for adjuvant interferon. PMID- 22845016 TI - Regulating gene expression at the post-transcriptional level: spotlight on RNA binding proteins. PMID- 22845017 TI - Ion transport with charge-protected and non-charge-protected cations using the compensated Arrhenius formalism. Part 2. Relationship between ionic conductivity and diffusion. AB - Temperature-dependent ionic conductivities and cation/anion self-diffusion coefficients are measured for four electrolyte families: TbaTf-linear primary alcohols, LiTf-linear primary alcohols, TbaTf-n-alkyl acetates, and LiTf-n-alkyl acetates. The Nernst-Einstein equation does not adequately describe the data. Instead, the compensated Arrhenius formalism is applied to both conductivity and diffusion data. General trends based on temperature and alkyl chain length are observed when conductivity is plotted against cation or anion diffusion coefficient, but there is no clear pattern to the data. However, plotting conductivity exponential prefactors against those for diffusion results in four distinct curves, one each for the alcohol and acetate families described above. Furthermore, the TbaTf-alcohol and TbaTf-acetate data are "in line" with each other. The conductivity prefactors for the LiTf-alcohol data are smaller than those for the TbaTf data. The LiTf-acetate data have the lowest conductivity prefactors. This trend in prefactors mirrors the observed trend in degree of ionic association for these electrolytes. PMID- 22845018 TI - Clear cell adenocarcinoma arising from umbilical endometriosis. AB - Umbilical endometriosis is a very rare condition, and as far as we are aware, there have been no reported cases of its malignant transformation. Here, we report a case of clear cell adenocarcinoma arising from umbilical endometriosis in a 60-year-old woman who underwent hysterectomy for a uterine myoma at the age of 38, and who denied cyclic bleeding at the site of an umbilical cutaneous nodule correlating with menses until the age of 48. An umbilical tumor (3 cm diameter) was identified by magnetic resonance imaging and an abnormal accumulation was found only at the umbilical lesion by positron emission tomography examination. We observed endometriosis adjacent to the clear cell adenocarcinoma and transformation to carcinoma from endometriosis at the umbilical lesion histopathologically. Clear cell adenocarcinoma of the umbilicus was thought to have arisen from endometriosis; it expressed HER-2 protein and showed strong mesothelial characteristics immunohistochemically. PMID- 22845019 TI - Prescribing pattern of glucose lowering drugs in the United Kingdom in the last decade: a focus on the effects of safety warnings about rosiglitazone. AB - AIM: In the last decade, new glucose lowering drugs (GLDs) have been launched, and also several warnings regarding their safety. The cardiovascular safety of thiazolidinediones (TZD) has been questioned. We analyzed the prescription pattern of GLDs from 2000 to November 2009 in the United Kingdom (UK) using the THIN database with special focus on the effects of the safety warnings about rosiglitazone issued in May 2007 and January 2008. METHODS: Annual prevalence and incidence of GLD prescriptions were measured. For TZD, the monthly prevalence and incidence of prescription were calculated from May 2006 to January 2009. The switching pattern around the FDA alert and the characteristics of subjects starting treatment with TZD before and after the alerts were observed. RESULTS: The prevalence of prescriptions of GLDs increased during the 10 year period, metformin increasing more than three times. Rosiglitazone prevalence showed an increased trend until May 2007, (2.3/1000 person-years) and decreased thereafter (January 2009: 1.1/1000 person-years). The use of pioglitazone increased surpassing rosiglitazone from April 2008 onwards. The incidence of rosiglitazone use decreased sharply after May 2007 (0.8/1000 person-years). The prevalence of use of other therapies remained rather stable from 2000 to 2007 but increased afterwards. After May 2007, rosiglitazone users were increasingly switched to pioglitazone. There was an increased proportion of new users of pioglitazone with cardiovascular risk after the alerts. CONCLUSIONS: The prescription of GLDs in the UK has increased in the last decade. For TZDs, it changed after May 2007 as well as the characteristics of the subjects treated with them. PMID- 22845020 TI - Gelatin coated hybrid lipid nanoparticles for oral delivery of amphotericin B. AB - Amphotericin B (AmB) loaded polymer lipid hybrid nanoparticles (AmB-PLNs) comprised of lecithin (anionic lipid) and gelatin (Type A, cationic below its isoelectric point 7.0-9.0) were prepared by a two-step desolvation method to improve the oral bioavailability of AmB. The optimized AmB-PLNs were found to have particle size 253 +/- 8 nm, polydispersity index (PDI) 0.274 +/- 0.008, and entrapment efficiency 50.61 +/- 2.20% at 6% w/w of initial theoretical drug loading. Scanning electron microscopy (SEM) revealed spherical shaped nanoparticles whereas confocal laser scanning electron microscopy (CLSM) and fluorescent resonance energy transfer (FRET) analysis confirmed the orientation of the lecithin (located in the core) and gelatin (exterior coat) within the system. The developed formulation exhibited a sustained drug release profile with a release pattern best fitted to Higuchi kinetics. Experiments on Caco-2 cell lines revealed a 5.89-fold increase in the intestinal permeability of AmB-PLNs whereas in vivo pharmacokinetic studies exhibited a 4.69-fold increase in the oral bioavailability upon incorporation of AmB into PLNs as compared to that of free drug. The developed formulation showed significantly lesser hemolytic toxicity as compared to the free drug, Fungizone (micellar solution of AmB) and Fungisome (liposomal formulation of AmB). Furthermore, blood urea nitrogen (BUN) and plasma creatinine levels, indicative of nephrotoxicity, were also found to be significantly lesser for developed PLN formulation as compared to free drug and Fungizone while comparable to that of Fungisome. The histopathology of the kidney tissues further confirmed the absence of any changes in the morphology of the renal tubules. PMID- 22845021 TI - The new patent regime and disease priorities in India. AB - The World Trade Organization (WTO) and Trade-Related Aspects of Intellectual Property Rights (TRIPS), which made product patents compulsory for countries to follow, meant that the entire market for generic drugs was out of bounds for manufacturing till the time the products went off-patent. The TRIPS has generated widespread discussions and debates around the costs and benefits of new patent regimes on countries such as India. This article analyses whether the post-WTO system was consistent with, and conducive to, improved public health in India. It is a first-of-its-kind effort in which the data on pharmaceutical patents applications were collected, collated, cleaned and classified according to IPC codes, to enable preliminary understanding of the nature and type of the applications. The patent applications that are filed in India are not found to be consistent with the disease burden of the country. PMID- 22845022 TI - Is smoking associated with alcohol-drug dependence in patients with pain and chronic pain patients? An evidence-based structured review. AB - OBJECTIVE: The objective of this study was to determine if there is consistent evidence for smoking to be considered a red flag for development of opioid dependence during opioid exposure in patients with pain and chronic pain patients (CPPs). METHODS: Six hundred and twenty-three references were found that addressed the areas of smoking, pain, and drug-alcohol dependence. Fifteen studies remained after exclusion criteria were applied and sorted into four groupings addressing four hypotheses: patients with pain and CPPs who smoke are more likely than their nonsmoking counterparts to use opioids, require higher opioid doses, be drug-alcohol dependent, and demonstrate aberrant drug-taking behaviors (ADTBs). Each study was characterized by the type of study it represented according to the Agency for Health Care Policy and Research (AHCPR) guidelines and independently rated by two raters according to 13 quality criteria to generate a quality score. The percentage of studies in each grouping supporting/not supporting each hypothesis was calculated. The strength and consistency of the evidence in each grouping was rated by the AHCPR guidelines. RESULTS: In each grouping, 100% of the studies supported the hypothesis for that grouping. The strength and consistency of the evidence was rated as A (consistent multiple studies) for the first hypothesis and as B (generally consistent) for the other. CONCLUSIONS: There is limited consistent indirect evidence that smoking status in patients with pain and CPPs is associated with alcohol-drug and opioid dependence. Smoking status could be a red flag for opioid-dependence development on opioid exposure. PMID- 22845023 TI - Use of recombinant activated Factor VII for refractory after lung transplant bleeding as an effective strategy to restrict blood transfusion and associated complications. AB - BACKGROUND: Recombinant activated factor VIIa (rFVIIa) has been increasingly used to stop massive bleeding after cardiothoracic surgical procedures. However, the risk : benefit profile of such a potent hemostatic agent remains unclear in the postsurgical patient, and the cost benefit is even less clear. In patients after lung transplantation, volume of blood transfused is of major concern, and all attempts are made to minimize large blood transfusions in this cohort. We report our experience with rFVIIa in patients with refractory bleeding after lung transplant surgery. STUDY DESIGN AND METHODS: All lung transplant patients who underwent single- or double-lung transplantation who received rFVIIa in the 5 year period, from January 2005 to June 2011, were included. A total of 15 patients were identified from a total of 95 lung transplant cases operated during this study period. Patient demographics, intra- and postoperative records were reviewed to assess the efficacy and safety of rFVIIa treatment. RESULTS: Patients with major bleeding treated with rFVIIa showed improved hemostasis with rapid normalization of coagulation variables. rFVIIa treatment was not associated with an increase in mechanical ventilation time, length of intensive care unit stay, or hospital stay compared to other lung transplant patients. In addition, the use of rFVIIa was associated with reduction in transfusion requirements of red blood cells, fresh-frozen plasma, and platelets (all p < 0.001). No definite thromboembolic-related event was recorded in our cohort. CONCLUSIONS: These data demonstrate that rFVIIa was associated with reduced blood loss, improvement of coagulation variables, and decreased need for transfusions. This reduction in losses led to a reduced requirement for blood transfusion, which may translate to a decrease in transfusion-related complications. Further investigation is needed to determine rFVIIa's safety and its efficacy in improving postoperative morbidity and mortality specifically in the field of post-lung transplantation surgery. PMID- 22845024 TI - Radionuclide generators - a new renaissance in the development of technologies to provide diagnostic and therapeutic radioisotopes for clinical applications. PMID- 22845025 TI - Temperature efficiency for dormancy release in apricot varies when applied at different amounts of chill accumulation. AB - Our aim was to assess the possible differential effect of increasing temperatures due to global warming on dormancy progression in apricot. The effect of a range of chilling temperatures on vegetative and reproductive bud dormancy progression in excised shoots was examined during two seasons. Temperature treatments were applied in different dormant stages to evaluate the possible interaction of date * temperature for dormancy release in apricot. During sampling, chill accumulated in the field ranged from 0 to 49 chill portions (CPs), corresponding to 0-100% of the chilling requirement (CR) of the apricot selection Z505-2. Forcing conditions were applied after a 60-day chill treatment on each sampling date, and rate to budbreak (1/mean time to bud break: MTB(-1) ) was established in vegetative (terminal and lateral) and reproductive buds to determine depth of dormancy. Results showed that the stage of dormancy has a strong influence on the effect of different temperatures on dormancy progression in apricot. For the first time, a non-linear effect of different chilling temperatures during the dormancy cycle in apricot was obtained, especially in the superior range of temperatures traditionally considered to release dormancy. Thus, introduction of this differential effect could help to improve the models to estimate dormancy release in the context of climate change. PMID- 22845027 TI - A clinical guideline for intrauterine device use in adolescents. AB - PURPOSE: To present an evidence-based review of the data for and against the use of the intrauterine device (IUD) in adolescent females and to provide guidelines for selection of appropriate candidates. DATA SOURCES: Clinical research, expert opinions, and systematic reviews of IUD use in adolescents. CONCLUSIONS: The use of the IUD in adolescents has been questioned in the past as a result of concerns surrounding increased risks for pelvic inflammatory disease and infertility in adolescents. Current research reveals no contraindications to IUD use based solely on age or parity and illuminates many benefits to use, including a decrease in menorrhagia and dysmenorrhea. IMPLICATIONS FOR PRACTICE: The U.S. adolescent pregnancy rates rose from 2005 to 2007, reversing a decade-long downward trend. Adolescents need safe, effective, user-friendly contraceptive methods. IUDs are a safe and effective option for adolescents and provide an additional contraceptive option for nurse practitioners to offer their patients to prevent unintended pregnancy and enhance adolescent sexual health and well being. Proper selection of candidates for IUD use can mitigate clinical and legal risks associated with IUD use. PMID- 22845026 TI - Development and evaluation of a palliative medicine curriculum for third-year medical students. AB - OBJECTIVE: To assess the impact, retention, and magnitude of effect of a required didactic and experiential palliative care curriculum on third-year medical students' knowledge, confidence, and concerns about end-of-life care, over time and in comparison to benchmark data from a national study of internal medicine residents and faculty. DESIGN: Prospective study of third-year medical students prior to and immediately after course completion, with a follow-up assessment in the fourth year, and in comparison to benchmark data from a large national study. SETTING: Internal Medicine Clerkship in a public accredited medical school. PARTICIPANTS: Five hundred ninety-three third-year medical students, from July 2002 to December 2007. MAIN OUTCOME MEASURES: Pre- and postinstruction performance on: knowledge, confidence (self-assessed competence), and concerns (attitudes) about end-of-life care measures, validated in a national study of internal medicine residents and faculty. Medical student's reflective written comments were qualitatively assessed. INTERVENTION: Required 32-hour didactic and experiential curriculum, including home hospice visits and inpatient hospice care, with content drawn from the AMA-sponsored Education for Physicians on End of-life Care (EPEC) Project. RESULTS: Analysis of 487 paired t tests shows significant improvements, with 23% improvement in knowledge (F(1,486)=881, p<0.001), 56% improvement in self-reported competence (F(1,486)=2,804, p<0.001), and 29% decrease in self-reported concern (F(1,486)=208, p<0.001). Retesting medical students in the fourth year showed a further 5% increase in confidence (p<0.0002), 13% increase in allaying concerns (p<0.0001), but a 6% drop in knowledge. The curriculum's effect size on M3 students' knowledge (0.56) exceeded that of a national cross-sectional study comparing residents at progressive training levels (0.18) Themes identified in students' reflective comments included perceived relevance, humanism, and effectiveness of methods used to teach and assess palliative care education. CONCLUSIONS: We conclude that required structured didactic and experiential palliative care during the clinical clerkship year of medical student education shows significant and largely sustained effects indicating students are better prepared than a national sample of residents and attending physicians. PMID- 22845029 TI - Childhood obesity: Can electronic medical records customized with clinical practice guidelines improve screening and diagnosis? AB - PURPOSE: The purpose of this project was to determine if customization of the electronic medical record (EMR) using evidence-based practice guidelines developed by the National Association of Pediatric Nurse Practitioners and the Expert Panel recommendations for the prevention, screening, and treatment of childhood and adolescent overweight and obesity would improve the rate of screening and diagnosis of obesity in children, 7 to 18 years of age. DATA RESOURCES: A retrospective review of encounters before and after implementation of customized EMR was conducted in a community health center. Data collected were compared for documentation of body mass index (BMI), completion of growth charts, scoring of risk questionnaire, and diagnosis of overweight or obesity. CONCLUSIONS: There was a clear increase in the frequency of recording BMI, completing BMI growth charts, and scoring questionnaires between written and electronic medical records. The number of children diagnosed with overweight or obesity increased with customized EMR but still remains well below the rates of obesity for this community. IMPLICATIONS FOR PRACTICE: Customizing EMR with clinical practice guidelines improved adherence to recommendations for screening and identification of childhood overweight and obesity. Increased recognition and diagnosis will lead to improved interventions and improve outcomes for childhood obesity. PMID- 22845030 TI - Core competencies required for the cardiac surgical nurse practitioner. AB - PURPOSE: To propose a set of core competencies for the cardiac surgery nurse practitioner (CSNP). DATA SOURCES: Research, review articles, standards of practice, hospital practice guidelines. CONCLUSION: Although there have been preliminary studies that demonstrate the effectiveness and cost savings associated with the use of a CSNP, specific competencies have yet to be defined. The CSNP provides direct patient care and functions simultaneously as part of an interdisciplinary team. The CSNP cares for the patient from preadmission until postdischarge. The CSNP facilitates the transfer of information along the transitions of care that is vital to positive patient outcomes. IMPLICATIONS FOR PRACTICE: Changes in health care have forced providers to find ways to decrease the cost of services while maintaining high-quality, efficient care for their patients. In addition, there is a rising acuity of the patient population admitted for cardiac surgery. The continued development of the role of the CSNP and evidence that supports the cost savings and improved patient outcomes that result from the use of CSNPs will encourage more and more cardiac surgery programs to use CSNPs along the continuum of care. PMID- 22845031 TI - Viscous versus nonviscous soluble fiber supplements: mechanisms and evidence for fiber-specific health benefits. AB - PURPOSE: This review focuses on the health benefits of viscous versus nonviscous soluble fibers, why symptoms can occur with increased fiber consumption, and how to avoid symptoms to improve adherence with a high-fiber diet. DATA SOURCES: Review of scientific literature as well as evidence-based guidelines and resources. CONCLUSIONS: While it is generally known that "fiber is good for you," it is less well known that specific health benefits are associated with specific fiber characteristics. Many of the health benefits of fiber can be directly correlated with the viscosity of soluble fibers when hydrated (i.e., gel forming). A reduction in viscosity of a given fiber will attenuate these health benefits, and a nonviscous fiber does not exhibit these health benefits. IMPLICATIONS FOR PRACTICE: Increasing the viscosity of chyme with a viscous soluble fiber has been shown clinically to lower cholesterol for cardiovascular health, improve glycemic control in type 2 diabetes, normalize stool form in both constipation (softens hard stool) and diarrhea (firms loose/liquid stool), and improve the objective clinical measures of metabolic syndrome (glycemic control, lipoprotein profile, body mass index/weight loss, and blood pressure). PMID- 22845033 TI - Silent no more! The lived experiences of women with lichen sclerosis. AB - PURPOSE: Lichen Sclerosis (LS) is an often unrecognized and misdiagnosed chronic inflammatory skin condition of the anogenital area that affects quality of life, bringing severe discomfort and distress to affected men, women, and children. The purpose of this qualitative study is to explore the lived experiences of women with LS. DATA SOURCES: Content analysis was conducted of data obtained from three public online forums/blogs used by women with LS. A total of 527 postings/entries were analyzed for patterns and themes by four researchers. CONCLUSIONS: Five core themes emerged as a result of this study, revealing feelings of frustration and despair stemming from healthcare providers' lack of knowledge in relation to Lichen Sclerosis, often leading to misdiagnosis, prolonged suffering, and an altered quality of life. IMPLICATIONS FOR PRACTICE: Knowledgeable healthcare providers and additional research into the cause, treatment, and cure of Lichen Sclerosis are needed. Advance-practice nurses stand to play an important role in the areas of education, research, policy making, and clinical practice to advocate for and empower women with LS. PMID- 22845032 TI - Pilot testing of an HIV medication adherence intervention in a public clinic in the Deep South. AB - PURPOSE: Strict adherence to HIV medications is critical to ensure long-term disease control, and adherence interventions that are possible in a clinic setting with limited resources are needed. DATA SOURCES: This randomized controlled pilot study tested an adherence intervention guided by the Information Motivation-Behavioral Skills (IMB) model. The intervention included HIV education, a peer video, motivational interviewing, and attention to behavioral skills including communication with providers and adherence-enhancing devices. Dependent variables included 3-4 week adherence recall, medication refill rate, changes in IMB subscale scores, appointment attendance, and HIV-associated laboratory findings. Seventy-three individuals starting or restarting antiretroviral therapy were enrolled and 56 were randomized. CONCLUSIONS: Improvements were seen in most outcomes, with small to moderate effect sizes, but the study was not powered to show statistical significance. Threats to power included a 51% attrition rate, resulting mostly from loss to clinical care or prolonged gaps in care. IMPLICATIONS FOR PRACTICE: A telephone-based intervention to improve HIV medication adherence shows promise. Further study is needed with greater attention to retention in care. PMID- 22845034 TI - Cognitive dissonance experienced by nurse practitioner faculty. AB - PURPOSE: The purpose of this study was to explicate the concept of cognitive dissonance as experienced and reported by nurse practitioner (NP) faculty members. DATA SOURCES: Responses from NP faculty members to an online survey about their experiences with cognitive dissonance. CONCLUSIONS: The respondents detailed their experiences with cognitive dissonance, citing differences between expectations for which they are rewarded and those for which they are paid. IMPLICATIONS FOR PRACTICE: Expecting all faculty members to excel in practice, research, teaching, and service may create unrealistic workloads for NP faculty members. Examining expectations and considering creation of a clinical track for faculty who practice may be options administrators of NP programs might explore. PMID- 22845035 TI - Apoptosis of mouse mast cells is reciprocally regulated by the IgG receptors FcgammaRIIB and FcgammaRIIIA. AB - BACKGROUND: Mast cells are important effector cells in allergy. They usually have a long life span and resist cell death induction. Fcgamma receptor- and IgG immune complex-mediated apoptosis has been demonstrated in B-lineage cells, but not in mast cells. The aim of the current study was to investigate whether mast cells could respond to apoptosis induction by IgG immune complex aggregation of Fcgamma receptors. It is known that mouse mast cells express the low-affinity Fcgamma receptors FcgammaRIIB and FcgammaRIIIA, which bind IgG especially in the form of antigen-IgG immune complexes. METHODS: Mouse bone marrow-derived cultured mast cells were examined for surface expression of FcgammaRIIB and FcgammaRIIIA. Apoptosis of such cells from wild-type, FcgammaRIIB(-/-) or FcgammaRIIIA(-/-) mice was measured following receptor aggregation by IgG immune complexes. RESULTS: Our data demonstrate that aggregation of either FcgammaRIIB or FcgammaRIIIA by IgG immune complexes induced apoptosis of mouse bone marrow derived cultured mast cells. However, mast cells expressing both FcgammaRIIB and FcgammaRIIIA were able to resist cell death induction by IgG immune complexes. CONCLUSION: Our findings reveal a fine-tuning system for regulating mast cell apoptosis through aggregating Fcgamma receptors by IgG immune complexes. Such apoptosis regulation may have a substantial impact on mast cell homeostasis during allergic inflammation. PMID- 22845036 TI - CO2-induced degradation of amine-containing adsorbents: reaction products and pathways. AB - A comprehensive study was conducted to investigate the stability of a wide variety of mesoporous silica-supported amine-containing adsorbents in the presence of carbon dioxide under dry conditions. CO(2)-induced degradation of grafted primary and secondary monoamines (pMono, sMono), diamines with one primary and one secondary amines (Diamine) and triamine with one primary and two secondary amines (TRI) as well as different impregnated polyamines such as branched and linear polyethylenimine (BPEI and LPEI) and polyallylamine (PALL) was investigated using extensive CO(2) adsorption-desorption cycling as well as diffuse reflectance infrared Fourier transform (DRIFT) and (13)C CP MAS NMR measurements. Except for sMono, all other supported amines underwent significant deactivation in the presence of dry CO(2) under mild conditions. In all cases, the decrease in CO(2) uptake was associated with the formation of urea linkages at the expense of amine groups. The urea-containing species were identified, and the deactivation pathways were delineated. PMID- 22845037 TI - Converging evidence for control of color-word Stroop interference at the item level. AB - Prior studies have shown that cognitive control is implemented at the list and context levels in the color-word Stroop task. At first blush, the finding that Stroop interference is reduced for mostly incongruent items as compared with mostly congruent items (i.e., the item-specific proportion congruence [ISPC] effect) appears to provide evidence for yet a third level of control, which modulates word reading at the item level. However, evidence to date favors the view that ISPC effects reflect the rapid prediction of high-contingency responses and not item-specific control. In Experiment 1, we first show that an ISPC effect is obtained when the relevant dimension (i.e., color) signals proportion congruency, a problematic pattern for theories based on differential response contingencies. In Experiment 2, we replicate and extend this pattern by showing that item-specific control settings transfer to new stimuli, ruling out alternative frequency-based accounts. In Experiment 3, we revert to the traditional design in which the irrelevant dimension (i.e., word) signals proportion congruency. Evidence for item-specific control, including transfer of the ISPC effect to new stimuli, is apparent when 4-item sets are employed but not when 2-item sets are employed. We attribute this pattern to the absence of high contingency responses on incongruent trials in the 4-item set. These novel findings provide converging evidence for reactive control of color-word Stroop interference at the item level, reveal theoretically important factors that modulate reliance on item-specific control versus contingency learning, and suggest an update to the item-specific control account (Bugg, Jacoby, & Chanani, 2011). PMID- 22845038 TI - Detection of latent bloodstains beneath painted surfaces using reflected infrared photography. AB - Bloodstain evidence is a highly valued form of physical evidence commonly found at scenes involving violent crimes. However, painting over bloodstains will often conceal this type of evidence. There is limited research in the scientific literature that describes methods of detecting painted-over bloodstains. This project employed a modified digital single-lens reflex camera to investigate the effectiveness of infrared (IR) photography in detecting latent bloodstain evidence beneath a layer or multiple layers of paint. A qualitative evaluation was completed by comparing images taken of a series of samples using both IR and standard (visible light) photography. Further quantitative image analysis was used to verify the findings. Results from this project indicate that bloodstain evidence can be detected beneath up to six layers of paint using reflected IR; however, the results vary depending on the characteristics of the paint. This technique provides crime scene specialists with a new field method to assist in locating, visualizing, and documenting painted-over bloodstain evidence. PMID- 22845039 TI - Impact of the emulsification-diffusion method on the development of pharmaceutical nanoparticles. AB - Nanotechnology is having a profound impact in many scientific fields and it has become one of the most important and exciting discipline. Like all technological advances, nanotechnology has its own scientific basis with a broad interdisciplinary effect. Perhaps, we are witnessing an exponential growth of nanotechnology, reflection of this is the important increase in the number of patents, scientific papers and specialized "nano" meetings and journals. The impact in the pharmaceutical area is related to the use of colloidal drug delivery systems as carriers for bioactive agents, in particular, the nanoparticle technology. The term nanoparticles designates solid submicronic particles formed of acceptable materials (e.g. polymers, lipids, etc.) containing an active substance. It includes both nanospheres (matricial systems) and nanocapsules (membrane systems). The knowledge of the nanoparticle preparation methods is a key issue for the formulator involved with drug-delivery research and development. In general, the methods based on preformed polymers, in particular biodegradable polymers, are preferred due to their easy implementation and lower potential toxicity. One of the most widely used methods to prepare polymeric nanoparticles is emulsification-diffusion. This method has been discussed in some reviews that compile research works but has a small number of patents. In this review, the emulsification-diffusion method is discussed from a technological point of view in order to show the operating conditions and formulation variables from data extracted of recent patents and experimental works. The main idea is to provide the reader with a general guide for formulators to make decisions about the usefulness of this method to develop specific nanoparticulate systems. The first part of this review provides an overview of the emulsification-diffusion method to prepare polymeric nanoparticles, while the second part evaluates the influence of preparative variables on the properties of the obtained particles relating the events to the formation mechanism. Novel innovations and applications of the method have also been compiled. PMID- 22845040 TI - Spray-dried polymeric nanoparticles for pharmaceutics: a review of patents. AB - Polymeric nanoparticles have been the focus of several researches in the last three decades in diverse areas including the delivery of pharmaceutical, diagnostic and cosmetic agents. These nanocarriers are able to improve the bioavailability and intrinsic solubility of drugs, to target different agents to a specific location or to protect the agent against extrinsic factors, such as radiation and extreme pH conditions. Despite the high interest in the development of these formulations, they hold some disadvantages like the limited physicochemical stability, which hinders the scaling-up of the preparation methods. In this context, spray-drying techniques have been proposed to obtain powder compositions containing polymeric nanoparticles allowing this limited property to be circumvented. In this context, this review is focused on the latest patents related to obtaining spray-dried polymeric nanoparticles, which have been divided into three different groups, according to their approach: i) spray-drying solutions to obtain nanoparticles, ii) spray-drying emulsions/ dispersions to obtain nanoparticles, and iii) nanoparticles dried by spray drying. PMID- 22845041 TI - Nanoparticles via nanoprecipitation process. AB - Various encapsulation approaches have been explored during the last years in order to encapsulate classical active molecules and new synthesized molecules principally for the in vivo therapy as drug delivery nanocarriers and also for the in vivo biomedical diagnostic. These approaches lead to new and versatile systems exhibiting high encapsulation yields of small molecules mainly. Due to the use of biodegradable polymers, the final particles and dispersions exhibit low cytotoxicity and in some cases total biocompatibility. To enhance local targeting efficiency, nanoparticles are chemically grafted using specific antibody for a specific disease. One of the easiest processes leading to rapid particles formation is the nanoprecipitation. Such process is mainly based on polymer transfer from good solvent to poor solvent condition, leading consequently to nanoparticles formation via self-assembly of precipitated polymer chains. The article discussed some of patents associated with Nanoprecipitation Process. PMID- 22845042 TI - Impact of patents on preparation of nanoparticles from preformed polymers in the pharmaceutical field. PMID- 22845043 TI - A practical educational tool for teaching child-care hospital professionals attending evidence-based practice courses for continuing medical education to appraise internal validity in systematic reviews. AB - RATIONALE, AIMS AND OBJECTIVES: Having a quick, practical, educational tool designed for busy child-care professionals to check whether systematic reviews (SRs) contain valid information would help them regularly update their evidence based knowledge and apply it to their patients. Continuing our annual workshop courses encouraging paediatric hospital professionals to use evidence-based information, in a preliminary study, we compared the commonly used Critical Appraisal Skill Programme (CASP) questionnaire for appraising overall internal validity in SRs with a new, practical tool designed to check internal validity quickly. METHOD: During a course in 2010, two 'teacher-brokers' taught experienced paediatric hospital professionals to use and compare the CASP and the new practical tool to appraise a Cochrane SR on beclomethasone for asthma in children by assessing internal validity only from the two most weighted randomized controlled trials in the forest plot. At 15 days and 6 months, participants then answered questionnaires designed to assess qualitative data including feelings about working together, memorization and possibly provide feedback for Cochrane reviewers. RESULTS: Using the CASP, participants agreed that the Cochrane SR analysed contained overall valid results. Conversely, using the new quick tool, they found poor internal validity. Participants worked well together in a group, took less time to apply the new tool than the CASP (1 vs. 2.5 hours) and provided Cochrane feedback. CONCLUSIONS: Our quick practical tool for teaching critical appraisal encourages busy child-care hospital professionals to work together, carefully check validity in SRs, apply the findings in clinical practice and provide useful feedback for Cochrane reviewers. PMID- 22845044 TI - Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system. AB - BACKGROUND AND OBJECTIVE: Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10 MUg/hour (BTDS 10). METHODS: This single centre study enrolled 20 healthy subjects who had demonstrated ketoconazole mediated CYP3A4 inhibition via an erythromycin breath test. Subjects were randomized into a placebo-controlled, two-treatment, two-period crossover study. Subjects participated in a 7- to 14-day screening period, two baseline evaluations (day 0 [period 1] and day 16 [period 2]), two 12-day treatment periods (periods 1 and 2) separated by a 4-day washout period, and a study completion visit. Subjects received one BTDS 10 for 7 days per treatment period, administered concomitantly with either ketoconazole 200 mg twice daily or matching placebo. The main outcome measures were the ratios of geometric means for area under the plasma drug concentration versus time curve (AUC) from time zero to time of last measurable concentration (AUC(last)), AUC from time zero to infinity (AUC(infinity)), and maximum plasma drug concentration (C(max)). RESULTS: The ratio of geometric means (BTDS 10 with ketoconazole/BTDS 10 with placebo) was 99.4 (90% confidence interval [CI] 87.2, 113.3) for AUC(last) and 97.8 (90% CI 87.7, 109.1) for C(max). The ratio of geometric means for AUC(infinity) was 86.7 (90% CI 70.7, 106.2). The plasma concentrations of the metabolites norbuprenorphine and norbuprenorphine-3beta-glucuronide were slightly elevated following ketoconazole administration. BTDS 10 with ketoconazole was well tolerated and no apparent safety concerns were noted. CONCLUSION: The lack of a clinically significant CYP3A4 interaction with ketoconazole following transdermal delivery of buprenorphine is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects. Metabolism of buprenorphine during therapy with BTDS is also not expected to be affected by co-administration of other CYP3A4 inhibitors. PMID- 22845045 TI - Comparison of the antipsoriatic effect and tolerability of calcipotriol containing products in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. AB - BACKGROUND AND OBJECTIVE: In 1972, Dumas and Scholtz developed the psoriasis plaque test to evaluate the potency of local corticosteroids. Through further modification of this method, the efficacy between antipsoriatic products can be differentiated. This method allowed for the simultaneous application of several products to different test sites in the same psoriasis patient. The objective of this current study was to compare the antipsoriatic effect of six topical products using a modified version of the original psoriasis plaque test with emphasis on the predictive capacity of this model. Validation of the use of immunohistochemical and histological scoring of biopsy material, in conjunction with clinical scoring, in the prediction of antipsoriatic effects was an additional objective. METHODS: This study was a single-centre, investigator blinded, within-subject randomized, active- and vehicle-controlled, intraindividual comparison of six topical products in patients with psoriasis vulgaris. The products evaluated were calcipotriol ointment (50 MUg/g); calcipotriol cream (50 MUg/g); two-compound ointment (calcipotriol 50 MUg/g; betamethasone dipropionate 0.5 mg/g); two-compound gel (calcipotriol 50 MUg/g; betamethasone dipropionate 0.5 mg/g) [all in their marketed formulations]; an investigational ointment (calcipotriol 25 MUg/g; hydrocortisone 10 mg/g); and a vehicle control. Psoriasis patients (>=18 years of age; n = 24) received simultaneous topical application of each of the products 6 days a week for a period of 21 days, at different test sites located on psoriasis plaques. Clinical assessment of the test sites was completed twice a week. Test site biopsies were taken at the final visit for histological analysis. The primary endpoint was the absolute change in total clinical score (TCS; erythema, scaling and infiltration) from baseline. RESULTS: For all products, the change in TCS correlated well with changes in histological and immunohistochemical values. The two-compound ointment and the two-compound gel both resulted in a large and significant reduction in TCS. Calcipotriol ointment and the calcipotriol/hydrocortisone ointment were less effective, although they were still more effective than the calcipotriol cream and the ointment vehicle. CONCLUSION: This study has demonstrated that the modified psoriasis plaque test can provide a relatively quick and effective method to evaluate the antipsoriatic effect of several topical treatments in small cohorts and that, by combining clinical scoring and histological assessment, a more accurate prediction of the antipsoriatic effect can be made. The two-compound formulations (ointment and gel) had a comparable antipsoriatic effect, which was superior to the other products tested. Furthermore, these data indicate that the gel formulation could provide an alternative effective treatment option to the well established two-compound ointment for psoriasis patients. CLINICAL TRIAL REGISTRATION: Registered as EudraCT no: 2007-005463-10. PMID- 22845047 TI - TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. AB - The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases. PMID- 22845046 TI - Cost-effectiveness comparison of response strategies to a large-scale anthrax attack on the chicago metropolitan area: impact of timing and surge capacity. AB - Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality. However, there is uncertainty about the optimal cost effective response strategy based on timing of intervention, public health resources, and critical care facilities. We conducted a decision analytic study to compare response strategies to a theoretical large-scale anthrax attack on the Chicago metropolitan area beginning either Day 2 or Day 5 after the attack. These strategies correspond to the policy options set forth by the Anthrax Modeling Working Group for population-wide responses to a large-scale anthrax attack: (1) postattack antibiotic prophylaxis, (2) postattack antibiotic prophylaxis and vaccination, (3) preattack vaccination with postattack antibiotic prophylaxis, and (4) preattack vaccination with postattack antibiotic prophylaxis and vaccination. Outcomes were measured in costs, lives saved, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We estimated that postattack antibiotic prophylaxis of all 1,390,000 anthrax-exposed people beginning on Day 2 after attack would result in 205,835 infected victims, 35,049 fulminant victims, and 28,612 deaths. Only 6,437 (18.5%) of the fulminant victims could be saved with the existing critical care facilities in the Chicago metropolitan area. Mortality would increase to 69,136 if the response strategy began on Day 5. Including postattack vaccination with antibiotic prophylaxis of all exposed people reduces mortality and is cost-effective for both Day 2 (ICER=$182/QALY) and Day 5 (ICER=$1,088/QALY) response strategies. Increasing ICU bed availability significantly reduces mortality for all response strategies. We conclude that postattack antibiotic prophylaxis and vaccination of all exposed people is the optimal cost-effective response strategy for a large-scale anthrax attack. Our findings support the US government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack. Future policies should consider expanding critical care capacity to allow for the rescue of more victims. PMID- 22845048 TI - Cell sources for articular cartilage repair strategies: shifting from monocultures to cocultures. AB - The repair of articular cartilage is challenging due to the sparse native cell population combined with the avascular and aneural nature of the tissue. In recent years, cartilage tissue engineering has shown great promise. As with all tissue engineering strategies, the possible therapeutic outcome is intimately linked with the used combination of cells, growth factors, and biomaterials. However, the optimal combination has remained a controversial topic and no consensus has been reached. In consequence, much effort has been dedicated, to further design, investigate, and optimize cartilage repair strategies. Specifically, various research groups have performed intensive investigations attempting to identify the single most optimal cell source for articular cartilage repair strategies. However, recent findings indicate that not the heavily investigated monocell source, but the less studied combinations of cell sources in coculture might be more attractive for cartilage repair strategies. This review will give a comprehensive overview on the cell sources that have been investigated for articular cartilage repair strategies. In particular, the advantages and disadvantages of investigated cell sources are comprehensively discussed with emphasis on the potential of cocultures in which benefits are combined, while the disadvantages of single-cell sources for cartilage repair are mitigated. PMID- 22845049 TI - Environmental impact of minimally invasive surgery in the United States: an estimate of the carbon dioxide footprint. AB - PURPOSE: To attempt to quantitate the carbon footprint of minimally invasive surgery (MIS) through approximated scope 1 to 3 CO(2) emissions to identify its potential role in global warming. PATIENTS AND METHODS: To estimate national usage, we determined the number of inpatient and outpatient MIS procedures using International Classification of Diseases, ninth revision-clinical modification codes for all MIS procedures in a 2009 sample collected in national databases. Need for surgery was considered essential, and therefore traditional open surgery was used as the comparator. Scope 1 (direct) CO(2) emissions resulting from CO(2) gas used for insufflation were based on both escaping procedural CO(2) and metabolic CO(2) eliminated via respiration. Scopes 2 and 3 (indirect) emissions related to capture, compression, and transportation of CO(2) to hospitals and the disposal of single-use equipment not used in open surgery were calculated. RESULTS: The total CO(2) emissions were calculated to be 355,924 tonnes/year. For perspective, if MIS in the United States was considered a country, it would rank 189 th on the United Nations 2008 list of countries' carbon emissions per year. Limitations include the inability to account for uncertainty using the various models and tools for approximating CO(2) emissions. CONCLUSION: CO(2) emission of MIS in the United States may have a significant environmental impact. This is the first attempt to quantify CO(2) emissions related to MIS in the United States. Strategies for reduction, while maintaining high quality medical care, should be considered. PMID- 22845050 TI - Beneficial effects of the melanocortin analogue Nle4-D-Phe7-alpha-MSH in acne vulgaris. AB - BACKGROUND: alpha-Melanocyte-stimulating hormone (alpha-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As alpha-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent alpha-MSH analogue, afamelanotide (Nle(4)-D-Phe(7)-alpha-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. METHODS: Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. RESULTS: The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. CONCLUSIONS: Afamelanotide appears to have anti inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris. PMID- 22845051 TI - Solution-processed and air-stable n-type organic thin-film transistors based on thiophene-fused dicyanoquinonediimine (DCNQI) deriatives. AB - pi-Conjugated systems 2a and 2b containing thiophene-fused DCNQI with long alkyl and trifluoromethylphenyl groups were synthesized as potential active materials for solution-processed and air-stable n-type organic thin-film transistors (OTFTs). The electrochemical measurements revealed that the lowest unoccupied molecular orbital (LUMO) of the compounds have an energy level less than -4.0 eV, indicating air stable n-type materials. The long alkyl groups endowed the compounds good solubility and solution-processability. X-ray diffraction measurements revealed the difference of the molecular arrangement depending on the alkyl groups, which were also observed in the UV-vis absorptions of the films. A relatively good mobility up to 0.003 cm(2) V(-1) s(-1) for 2a by spin coating was obtained with good air stability. PMID- 22845052 TI - Pharmacokinetics of paracetamol and its metabolites in women at delivery and post partum. AB - AIM: A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. METHODS: Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. RESULTS: Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h-1) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h-1), to oxidative metabolites (4.95 vs. 2.77 l h-1) and of unchanged paracetamol (1.15 vs. 0.75 l h-1). In contrast, there was no difference in clearance to paracetamol sulphate. CONCLUSION: The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group. PMID- 22845054 TI - A model to identify patients at risk for prescription opioid abuse, dependence, and misuse. AB - OBJECTIVE: The objective of this study was to use administrative claims data to identify and analyze patient characteristics and behavior associated with diagnosed opioid abuse. DESIGN: Patients, aged 12-64 years, with at least one prescription opioid claim during 2007-2009 (n = 821,916) were selected from a de identified administrative claims database of privately insured members (n = 8,316,665). Patients were divided into two mutually exclusive groups: those diagnosed with opioid abuse during 1999-2009 (n = 6,380) and those without a diagnosis for opioid abuse (n = 815,536). A logistic regression model was developed to estimate the association between an opioid abuse diagnosis and patient characteristics, including patient demographics, prescription drug use and filling behavior, comorbidities, medical resource use, and family member characteristics. Sensitivity analyses were conducted on the model's predictive power. RESULTS: In addition to demographic factors associated with abuse (e.g., male gender), the following were identified as "key characteristics" (i.e., odds ratio [OR] > 2): prior opioid prescriptions (OR = 2.23 for 1-5 prior Rxs; OR = 6.85 for 6+ prior Rxs); at least one prior prescription of buprenorphine (OR = 51.75) or methadone (OR = 2.97); at least one diagnosis of non-opioid drug abuse (OR = 9.89), mental illness (OR = 2.45), or hepatitis (OR = 2.36); and having a family member diagnosed with opioid abuse (OR = 3.01). CONCLUSIONS: Using medical as well as drug claims data, it is feasible to develop models that could assist payers in identifying patients who exhibit characteristics associated with increased risk for opioid abuse. These models incorporate medical information beyond that available to prescription drug monitoring programs that are reliant on drug claims data and can be an important tool to identify potentially inappropriate opioid use. PMID- 22845053 TI - Structure-functional selectivity relationship studies of beta-arrestin-biased dopamine D2 receptor agonists. AB - Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first beta-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these beta-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered. PMID- 22845055 TI - Red blood cell transfusion compared with gelatin solution and no infusion after cardiac surgery: effect on microvascular perfusion, vascular density, hemoglobin, and oxygen saturation. AB - BACKGROUND: After cardiac surgery, red blood cell (RBC) transfusion may improve systemic hemodynamics and thereby microvascular blood flow and O2 delivery (DO2). STUDY DESIGN AND METHODS: In a nonrandomized prospective observational study on post-cardiac surgery patients, systemic hemodynamics and microvascular blood flow, vascular density (sidestream dark-field imaging), hemoglobin (Hb) content, and saturation (reflectance spectrophotometry) were measured before and 1 hour after start of transfusion of 1 to 2 units of leukoreduced RBCs (270+/-203 mL), 500 mL of gelatin solution, or control (no infusion), when patients were considered clinically hypovolemic with (RBC group, n=12) or without (gelatin group, n=14) anemia (Hb<10 g/dL) or not (n=13), respectively. RESULTS: Systemic Hb was lower and increased in the RBC transfusion but not in gelatin and control groups. There were no differences in changes in systemic DO2, O2 uptake, and extraction between groups. RBC transfusion, compared with gelatin or control, increased medium-sized vascular density, Hb content, and saturation in the microcirculation, while blood flow remained unchanged. Changes of microvascular Hb and saturation paralleled changes in systemic Hb. CONCLUSION: The data argue in favor of efficacy of RBC transfusion after cardiac surgery. RBC transfusion increases systemic Hb and this in turn increases medium-sized vascular density and DO2 in the sublingual microcirculation, independently of systemic hemodynamics and volume status. PMID- 22845056 TI - Structural water cluster as a possible proton acceptor in the adduct decay reaction of oat phototropin 1 LOV2 domain. AB - LOV domains (Light, Oxygen, Voltage) are the light-sensory modules of phototropins, the blue-light photoreceptor kinases in plants, and of a wide variety of flavoproteins found in all three domains of life. These 12 kDa modules bind a flavin chromophore (FMN or FAD) noncovalently and undergo a photochemical activation in which the sulfur atom of a conserved cysteine forms an adduct to the C(4a) carbon of the flavin. The adduct breaks spontaneously in a base catalyzed reaction involving a rate-limiting proton-transfer step, regenerating the dark state in seconds. This photocycle involves chromophore and protein structural changes that activate the C-terminal serine/threonine kinase. Previous studies (Biochemistry 2007, 46, 7016-7021) showed that decreased hydration obtained at high glycerol concentrations stabilizes the adduct state in a manner similar to that attained at low temperatures, resulting in much longer adduct decay times. This kinetic effect was attributed to an increased protein rigidity that hindered structural fluctuations necessary for the decay reaction. In this work, we studied the adduct decay kinetics of oat phototropin 1 (phot1) LOV2 at varying hydration using a specially designed chamber that allowed for measurement of UV-visible and FTIR spectra of the same samples. Therefore, we obtained LOV protein concentrations, adduct decay kinetics, and the different populations of bound water by deconvolution of the broad water absorption peak around 3500 cm( 1). A linear dependence of the adduct decay rate constant on the concentration of double and triple hydrogen-bonded waters strongly suggests that the adduct decay is a pseudo-first-order reaction in which both the adduct and the strongly bound waters are reactants. We suggest that a cluster of strongly bound water functions as the proton acceptor in the rate-limiting step of adduct decay. PMID- 22845057 TI - Criminal behavior in opioid-dependent patients before and during maintenance therapy: 6-year follow-up of a nationally representative cohort sample. AB - Lifetime prevalence of opioid dependence is about 0.4% in western countries. Opioid-dependent patients have high morbidity and mortality and a high risk of criminal behavior. Few studies have addressed the long-term impact of opioid maintenance therapy on convictions and criminal behavior. The PREMOS study is a prospective, longitudinal, naturalistic clinical study of a nationally representative sample of 2694 opioid-dependent patients to investigate convictions and criminal behavior at baseline and after 6 years of maintenance treatment. At follow-up, 2284 patients still were eligible (84.7%). A comprehensive assessment including a patient and doctor questionnaire, and the EuropASI was completed at baseline and follow-up. Data on criminality at follow up had been received for 1147 (70.6%) patients. A large number (84.5%) of them had been charged or convicted at any time before baseline assessment, most frequently with drug-related offenses (66.8%), acquisitive crime (49.1%), or acts of violence (22.0%). Reported charges and convictions had declined to 17.9% for the last 12 months before follow-up, which was also reflected by a significant decrease in the EuropASI subscore "legal problems" from 1.52 at baseline to 0.98 after 6 years. These data indicate a significant and clinically relevant reduction in criminal behavior in opioid-dependent patients in long-term maintenance treatment. Maintenance therapy is effective in the reduction in both narcotics-related and acquisition crime. PMID- 22845058 TI - Response pattern of amino compounds in phloem and xylem of trees to soil drought depends on drought intensity and root symbiosis. AB - This study aimed to identify drought-mediated differences in amino nitrogen (N) composition and content of xylem and phloem in trees having different symbiotic N(2)-fixing bacteria. Under controlled water availability, 1-year-old seedlings of Robinia pseudoacacia (nodules with Rhizobium), Hippophae rhamnoides (symbiosis with Frankia) and Buddleja alternifolia (no such root symbiosis) were exposed to control, medium drought and severe drought, corresponding soil water content of 70-75%, 45-50% and 30-35% of field capacity, respectively. Composition and content of amino compounds in xylem sap and phloem exudates were analysed as a measure of N nutrition. Drought strongly reduced biomass accumulation in all species, but amino N content in xylem and phloem remained unaffected only in R. pseudoacacia. In H. rhamnoides and B. alternifolia, amino N in phloem remained constant, but increased in xylem of both species in response to drought. There were differences in composition of amino compounds in xylem and phloem of the three species in response to drought. Proline concentrations in long-distance transport pathways of all three species were very low, below the limit of detection in phloem of H. rhamnoides and in phloem and xylem of B. alternifolia. Apparently, drought-mediated changes in N composition were much more connected with species-specific changes in C:N ratios. Irrespective of soil water content, the two species with root symbioses did not show similar features for the different types of symbiosis, neither in N composition nor in N content. There was no immediate correlation between symbiotic N fixation and drought-mediated changes in amino N in the transport pathways. PMID- 22845059 TI - A review of models of vertical, leg, and knee stiffness in adults for running, jumping or hopping tasks. AB - The 'stiffness' concept originates from Hooke's law which states that the force required to deform an object is related to a spring constant and the distance that object is deformed. Research into stiffness in the human body is undergoing unprecedented popularity; possibly because stiffness has been associated with sporting performance and some lower limb injuries. However, some inconsistencies surrounding stiffness measurement exists bringing into question the integrity of some research related to stiffness. The aim of this study was to review literature which describes how vertical, leg and knee stiffness has been measured in adult populations while running, jumping or hopping. A search of the entire MEDLINE, PubMed and SPORTDiscus databases and an iterative reference check was performed. Sixty-seven articles were retrieved; 21 measured vertical stiffness, 51 measured leg stiffness, and 22 measured knee stiffness. Thus, some studies measured several 'types' of stiffness. Vertical stiffness was typically the quotient of ground reaction force and centre of mass displacement. For leg stiffness it was and change in leg length, and for the knee it was the quotient of knee joint moments and change in joint angle. Sample size issues and measurement techniques were identified as limitations to current research. PMID- 22845060 TI - Horses for courses: a DNA-based test for race distance aptitude in thoroughbred racehorses. AB - Variation at the myostatin (MSTN) gene locus has been shown to influence racing phenotypes in Thoroughbred horses, and in particular, early skeletal muscle development and the aptitude for racing at short distances. Specifically, a single nucleotide polymorphism (SNP) in the first intron of MSTN (g.66493737C/T) is highly predictive of best race distance among Flat racing Thoroughbreds: homozygous C/C horses are best suited to short distance races, heterozygous C/T horses are best suited to middle distance races, and homozygous T/T horses are best suited to longer distance races. Patent applications for this gene marker association, and other linked markers, have been filed. The information contained within the patent applications is exclusively licensed to the commercial biotechnology company Equinome Ltd, which provides a DNA-based test to the international Thoroughbred horse racing and breeding industry. The application of this information in the industry enables informed decision making in breeding and racing and can be used to assist selection to accelerate the rate of change of genetic types among distinct populations (Case Study 1) and within individual breeding operations (Case Study 2). PMID- 22845061 TI - Die-off ratio correlates with increased TNF-alpha:IL-10 ratio and decreased IVF success rates correctable with humira. AB - BACKGROUND: Human embryos develop at varying rates in culture, with only a fraction of the eggs retrieved developing to 'transfer quality' embryos. We investigated whether the ratios between the number of eggs retrieved or the number of pro-nucleate embryos formed and the number of Day 3 embryos with >=5 cells [oocyte 'die-off ratios' (DOR)] were correlated with the chance of IVF success, independent of other factors such as embryo grade score and patient's age. We also investigated what factors may be correlated with this ratio. METHODS: 608 IVF fresh cycles in subfertile women were retrospectively evaluated. For each cycle, an oocyte DOR number was calculated as follows: Number of eggs retrieved divided by the number of Day 3 embryos with >=5 cells. This number was correlated with the subsequent success rates for the index cycles. A 'post fertilization' or 'embryo' die-off ratio (EDOR; the number of pro-nucleate embryos/the number of day 3 embryos >=5 cells) was also calculated. RESULTS: The oocyte DOR showed a reverse linear correlation with IVF live birth rate. Live birth rate = (-5.75; DOR) +71.6 (with DOR > 1; P <= 0.005; R = -0.87). In addition, the oocyte DOR continued to show an inverse correlation with success rates even when embryo quality and patient's age were held constant. The post fertilization or EDOR also continued to show a statistically significant negative correlation with live birth rate (R = -0.91; P <= 0.01). The preconception TNF alpha:IL-10 ratio, an immmunologic marker (drawn 3.3 +/- 2.6 months preconception), was more strongly correlated with high oocyte DOR than either age or number of eggs retrieved (P = 0.04, 0.14, 0.72, respectively). When anti-TNF alpha therapy (Humira) was given preconception, the oocyte DOR's negative effect on live birth rate was nearly eliminated (correlation coefficient between oocyte DOR and live birth rate: cycles using no Humira, R = -0.90, P <= 0.006; cycles using Humira, R = 0.25, P <= 0.55). CONCLUSIONS: In subfertile women undergoing IVF, the oocyte DOR may help predict IVF success rates. This factor may offer an additional tool to help improve implantation rate, clinical pregnancy rate, live birth rate, and live birth rate per embryo transferred for an upcoming IVF cycle. Although many mechanisms may contribute to the oocyte DOR's negative effect on IVF success rates, its correlation with elevated preconception TNF-alpha:IL-10 ratio and correction with Humira suggests a strong immunologic component that may be treatable. PMID- 22845062 TI - Successful management of cervico-isthmic pregnancy delivered at term. AB - A 29-year-old woman was diagnosed with a cervico-isthmic pregnancy based on ultrasound findings at 8 weeks of gestation. At 30 weeks of gestation, placenta previa was confirmed. During cesarean section at 37 weeks, the placenta did not spontaneously detach from the uterus; therefore, we decided to leave it in the uterus to avoid major hemorrhage. Blood loss was 775 mL and a healthy infant was delivered. After the operation, weekly methotrexate injection was initiated. Shortly after the eighth course of injection, massive vaginal bleeding suddenly occurred and bilateral uterine artery embolization was performed to control it. After the procedure, the retained placental tissue was removed and the patient was discharged with good general condition. Although a cervico-isthmic pregnancy constitutes a high-risk pregnancy, fertility-sparing management without a hysterectomy or blood transfusion was possible by not removing the placenta manually during the operation. PMID- 22845063 TI - The interaction between Lyn and FcepsilonRIbeta is indispensable for FcepsilonRI mediated human mast cell activation. AB - BACKGROUND: FcepsilonRIbeta reportedly functions as an amplifier of the FcepsilonRIgamma-mediated activation signal using a reconstitution system. However, the amplification mechanisms in human mast cells (MCs) are poorly understood. We previously reported the hyperexpression of FcepsilonRIbeta of MCs in giant papillae from vernal keratoconjunctivitis patients, compared with that in conjunctivae from nonallergic conjunctivitis patients. Elucidation of the molecular mechanisms of the amplification induced by FcepsilonRIbeta should provide new targets for novel therapeutic interventions. The aim is to understand in greater details the function of FcepsilonRIbeta in human MC FcepsilonRI expression and signaling. METHODS: FcepsilonRIbeta and Lyn expression was reduced using a lentiviral shRNA silencing technique. Localization of Lyn and FcepsilonRIbeta in cultured MCs was examined by confocal microscopic analysis. Mediators were measured by ELISAs. RESULTS: The diminution of FcepsilonRIbeta significantly downregulated cell surface FcepsilonRI expression and FcepsilonRI mediated mediator release/production. The downregulation of FcepsilonRI-mediated degranulation was not only due to the decrease in FcepsilonRI expression. The diminution of FcepsilonRIbeta inhibited the redistribution of Lyn within the cell membrane following IgE sensitization. The diminution of Lyn in MCs significantly downregulated FcepsilonRI-mediated degranulation. The recombinant cell penetrating forms of phosphorylated FcepsilonRIbeta immunoreceptor tyrosine-based activation motif (ITAM) for intracellular delivery disturbed the interaction between Lyn and phosphorylated endogenous FcepsilonRIbeta ITAM, resulted in inhibiting IgE-dependent histamine release from MCs in vitro and from giant papillae specimens ex vivo. CONCLUSION: The interaction between Lyn and FcepsilonRIbeta is indispensable for FcepsilonRI-mediated human MC activation, and specific inhibition of the interaction may represent a new therapeutic strategy for the treatment of human allergic diseases. PMID- 22845064 TI - What's learned together stays together: speakers' choice of referring expression reflects shared experience. AB - When referring to named objects, speakers can choose either a name (mbira) or a description (that gourd-like instrument with metal strips); whether the name provides useful information depends on whether the speaker's knowledge of the name is shared with the addressee. But, how do speakers determine what is shared? In 2 experiments a naive participant (director) learned names for novel objects, then instructed another participant (matcher), who viewed 3 objects, to click on the target object. Directors learned novel names in 2 phases. First, the director and the matcher learned (shared) names either together or alone; second, the director learned (privileged) names alone. Directors typically used a name for items with shared names and a description for items with privileged names. When the director and matcher learned the names individually but with knowledge of what the other learned, directors were much more likely to use privileged names than when director and matcher learned shared names together. Experiment 1b separated effects of collaborative learning from partner-specific effects, showing collaborative learning experience with 1 person helps a speaker distinguish shared and privileged information with a new partner who has the same knowledge. Experiment 2 showed that partner-specific effects persisted even when semantic category was a reliable cue to which names were privileged. The results are interpreted as evidence that ordinary memory processes provide access to shared knowledge in real-time production of referring expressions and that shared experience when learning shared names provides a strong memory cue to the ground status of names. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 22845065 TI - To err is human; to structurally prime from errors is also human. AB - Natural language contains disfluencies and errors. Do listeners simply discard information that was clearly produced in error, or can erroneous material persist to affect subsequent processing? Two experiments explored this question using a structural priming paradigm. Speakers described dative-eliciting pictures after hearing prime sentences that either were disfluent but with a consistent dative structure or were sentences that began as datives but were corrected to transitives (e.g., The mechanic is giving the new part... uh... is recognizing the new part). If an erroneous and corrected sentence fragment is discarded, then the original form of an ultimately transitive utterance should not influence future production. However, if the syntactic parse of an error is not discarded, then it should influence speakers' subsequent choice of syntactic structure. In both experiments, structural priming was significantly reduced when primes were corrected to a non-dative structure (relative to disfluent but ultimately dative primes). However, target descriptions did show an influence from corrected errors when the prime and target shared the same verb. Thus, a parse mapping a verb to a specific argument structure can persist despite being explicitly marked as an error, reflecting the incremental and predictive nature of comprehension. PMID- 22845066 TI - Metacognitive awareness and adaptive recognition biases. AB - Prior literature has primarily focused on the negative influences of misleading external sources on memory judgments. This study investigated whether participants can capitalize on generally reliable recommendations in order to improve their net performance; the focus was on potential roles for metacognitive monitoring (i.e., knowledge about one's own memory reliability) and performance feedback. In Experiment 1, participants received explicit external recommendations (Likely Old or Likely New) that were 75% valid during recognition tests containing deeply and shallowly encoded materials. In Experiment 2, participants received recommendations of differing validity (65% and 85%). Discrimination improved across both experiments when external recommendations were present versus absent. This improvement was influenced by metacognitive monitoring ability measured in the absence of recommendations. Thus, effective incorporation of external recommendations depended in part on how sensitive observers were to gradations of their internal evidence when recommendations were absent. Finally, corrective feedback did not improve participants' ability to use external recommendations, suggesting that metacognitive monitoring ability during recognition is not easily improved via feedback. PMID- 22845067 TI - The longer we have to forget the more we remember: The ironic effect of postcue duration in item-based directed forgetting. AB - The effects of the duration of remember and forget cues were examined to test the differential rehearsal account of item-based directed forgetting. In Experiments 1 and 2, cues were shown for 300, 600, or 900 ms, and a directed forgetting effect (better recognition of remember than forget items) was found at each duration. In addition, recognition of both remember and forget items increased with cue duration. These 2 effects did not interact. The results of Experiment 2 further showed that memory for the cue associated with the study items increased with cue duration as well. The results of Experiment 1 were replicated in Experiment 3 for cue durations of 1, 2, and 3 s. Finally, a similar pattern of results was found for cue durations of 2, 4, and 6 s for associative recognition of random word pairs. If subjects cannot immediately terminate the processing of forget items, the lingering processing of these items is as beneficial as the continued processing of remember items. Alternatively, subjects may use inefficient or counterproductive strategies that ironically improve memory for the information they wish to forget. PMID- 22845069 TI - Updating during reading comprehension: why causality matters. AB - The present set of 7 experiments systematically examined the effectiveness of adding causal explanations to simple refutations in reducing or eliminating the impact of outdated information on subsequent comprehension. The addition of a single causal-explanation sentence to a refutation was sufficient to eliminate any measurable disruption in comprehension caused by the outdated information (Experiment 1) but was not sufficient to eliminate its reactivation (Experiment 2). However, a 3 sentence causal-explanation addition to a refutation eliminated both any measurable disruption in comprehension (Experiment 3) and the reactivation of the outdated information (Experiment 4). A direct comparison between the 1 and 3 causal-explanation conditions provided converging evidence for these findings (Experiment 5). Furthermore, a comparison of the 3 sentence causal-explanation condition with a 3 sentence qualified-elaboration condition demonstrated that even though both conditions were sufficient to eliminate any measurable disruption in comprehension (Experiment 6), only the causal explanation condition was sufficient to eliminate the reactivation of the outdated information (Experiment 7). These results establish a boundary condition under which outdated information will influence comprehension; they also have broader implications for both the updating process and knowledge revision in general. PMID- 22845068 TI - The strategic retention of task-relevant objects in visual working memory. AB - The serial and spatially extended nature of many real-world visual tasks suggests the need for control over the content of visual working memory (VWM). We examined the management of VWM in a task that required participants to prioritize individual objects for retention during scene viewing. There were 5 principal findings: (a) Strategic retention of task-relevant objects was effective and was dissociable from the current locus of visual attention; (b) strategic retention was implemented by protection from interference rather than by preferential encoding; (c) this prioritization was flexibly transferred to a new object as task demands changed; (d) no-longer-relevant items were efficiently eliminated from VWM; and (e) despite this level of control, attended and fixated objects were consolidated into VWM regardless of task relevance. These results are consistent with a model of VWM control in which each fixated object is automatically encoded into VWM, replacing a portion of the content in VWM. However, task-relevant objects can be selectively protected from replacement. PMID- 22845070 TI - Development, awareness and inductive selectivity. AB - Two studies examined whether adults and children could learn to make context dependent inferences about novel stimuli and the role of awareness of context cues in such learning. Participants were trained to match probes to targets on the basis of shape or color with the relevant dimension shifting according to item context. A selective induction test then examined context-dependent responding in a more complex matching task. Awareness of the role of context was assessed using a behavioral task and explicit questions. Experiment 1 showed that after training with the procedure described by Sloutsky and Fisher (2008), only a minority of adults showed evidence of context-dependent responding in the selective induction test. Experiment 2 used a modified training protocol that promoted attention to context cues. This led to reliable selective induction in a majority of adults and a sizeable proportion of 4- to 6-year-olds. Crucially, in both age groups, selective induction was dependent on awareness of context. Hence, children as young as 4 can learn to make selective inferences about novel stimuli, but only when they are aware of the relevant context cues. These results challenge previous claims that selective induction in children is the product of implicit learning. PMID- 22845071 TI - Zooming in and out from the mental number line: evidence for a number range effect. AB - The representation of numbers is commonly viewed as an ordered continuum of magnitudes, referred to as the mental number line. Previous work has repeatedly shown that number representations evoked by a given task can be easily altered, yielding an ongoing discussion about the basic properties of the mental number line and how malleable they are. Here we studied whether the resolution of the mental number line is fixed or depends on the relative magnitudes that are being processed. In 2 experiments, participants compared the same number pairs under 2 conditions that differed in terms of the overall range of numbers present. We report a novel number range effect, such that comparisons of the same number pairs were responded to faster under the smaller versus larger number range. This finding is consistent with the idea that the resolution of the mental number line can be adjusted, as if a unit difference is perceived as larger in smaller ranges. PMID- 22845165 TI - Epidemiology, mortality rate and survival in a homogeneous population of hypopituitary patients. AB - INTRODUCTION: Hypopituitarism is associated with higher prevalence of cardiovascular risk factors and premature death. Furthermore, some clinical and therapeutic features of hypopituitarism have been associated with a worse prognosis. OBJECTIVE: We reviewed, retrospectively, a large series of adult patients with hypopituitarism using stringent epidemiological criteria. Prevalence, association with cardiovascular risk factors, mortality and survival have been analysed. DESIGN AND METHODS: Two hundred and nine adult hypopituitary patients (56.9% females) from a population of 405 218 inhabitants, followed for 10 years. RESULTS: Prevalence of hypopituitarism at the end of the study was 37.5 cases/100 000 inhabitants. Incidence of hypopituitarism was 2.07 cases/100 000 inhabitants and year. Thirty-two patients died during the period of the study. Standardized mortality rate (SMR) was 8.05, higher in males (8.92 vs 7.34) and in younger patients (84.93 vs 5.26). Diagnosis of acromegaly (P = 0.033), previous radiotherapy (P = 0.02), higher BMI (P = 0.04), diabetes mellitus (P = 0.03) and cancer (P < 0.0001) were associated with mortality. A lower survival was associated with older age at diagnosis, nontumoural causes, previous radiotherapy, diabetes mellitus with poor metabolic control and malignant disease. CONCLUSIONS: Prevalence of hypopituitarism was 37.5 cases/100 000 inhabitants, and annual incidence was 2.07 cases/100 000 inhabitants. SMR was 8 times higher in hypopituitarism than in general population and was also higher in males and younger patients. Reduced survival was significantly related to cancer, nontumoural causes of hypopituitarism, older age at diagnosis, previous radiotherapy and diabetes mellitus with poor metabolic control. PMID- 22845166 TI - The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. AB - AIM: To describe gut colonization in preterm infants using standard culture and 16S gene rRNA profiling, exploring differences in healthy infants and those who developed NEC/late onset sepsis (LOS). METHODS: Ninety-nine stools from 38 infants of median 27-week gestation were cultured; 44 stools from 27 infants had their microbial profiles determined by 16S. Ordination analyses explored effects of patient variables on gut communities. RESULTS: Standard microbiological culture identified a mean of two organisms (range 0-7), DGGE 12 (range 3-18) per patient. Enterococcus faecalis and coagulase negative staphylococci (CONS) were most common by culture (40% and 39% of specimens). Meconium was not sterile. No fungi were cultured. Bacterial community structures in infants with NEC and LOS differed from healthy infants. Infants who developed NEC carried more CONS (45% vs 30%) and less Enterococcus faecalis (31% vs 57%). 16S identified Enterobacter and Staphylococcus presence associated with NEC/LOS, respectively. CONCLUSIONS: Important differences were found in the gut microbiota of preterm infants who develop NEC/LOS. The relationship of these changes to current practices in neonatal intensive care requires further exploration. PMID- 22845167 TI - Dumbbells of five-connected silicon atoms and superconductivity in the binary silicides MSi3 (M = Ca, Y, Lu). AB - The new metastable binary silicides MSi(3) (M = Ca, Y, Lu) have been synthesized by high-pressure, high-temperature reactions at pressures between 12(2) and 15(2) GPa and temperatures from 900(100) to 1400(150) K. The atomic patterns comprise intricate silicon layers of condensed molecule-like Si(2) dimers. The alkaline earth element adopts the oxidation state +2, while the rare-earth and transition metals realize +3. All of the compounds exhibit BCS-type superconductivity with weak electron-phonon coupling below critical temperatures of up to 7 K. PMID- 22845169 TI - A review of pediatric vasculitis with a focus on juvenile polyarteritis nodosa. AB - Systemic polyarteritis nodosa (PAN) is a vasculitis characterized and defined by necrotizing inflammatory changes in medium and/or small arteries. Children and adults with vasculitis differ in the relative frequency of some clinical manifestations and concomitant diseases. The European League against Rheumatism (EULAR)/Pediatric Rheumatology European Society (PRES) working group has proposed a classification of childhood vasculitis. With support from EULAR, the Pediatric Rheumatology International Trials Organization (PRINTO), and PRES, a formal statistical validation process, which included large-scale, web-based data collection, was undertaken. I now propose a set of criteria for systemic juvenile PAN that combines a modified mix of the EULAR/PRES criteria and the EULAR/PRINTO/PRES criteria. Cutaneous juvenile PAN is characterized by the presence of cutaneous features with no systemic involvement. The common cutaneous manifestations include cutaneous nodules and livedo racemosa. Our research group previously established an algorithm for the differential diagnosis of primary cutaneous vasculitis. We have recently developed a new version of that algorithm to diagnose vasculitis with cutaneous manifestations from a dermatologic point of view. Treatment of systemic juvenile PAN is based on a combination of corticosteroids and immunosuppressant agents. The clinical course of cutaneous juvenile PAN is generally benign. PMID- 22845168 TI - Novel flame retardants in urban-feeding ring-billed gulls from the St. Lawrence River, Canada. AB - This study investigated the occurrence of a comprehensive suite of polybrominated diphenyl ethers (PBDEs) and current-use flame retardants (FRs) in ring-billed gulls breeding in a highly industrialized section of the St. Lawrence River, downstream from Montreal (QC, Canada). Despite major point-sources and diffuse contamination by FRs, nearly no FR data have been reported in birds from this area. Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (BEHTBP) was detected in 89% of ring-billed gull livers (mean: 2.16 ng/g ww; max: 17.6 ng/g ww). To our knowledge, this is the highest detection frequency and highest concentrations reported thus far in any avian species or populations. Dechlorane Plus (DP) isomers were also particularly abundant (anti-DP detected in 100% and syn-DP in 93% of livers). Other detected FR compounds (3-14% detection) included 2 ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTBB), hexachlorocyclopentenyl dibromocyclooctane (HCDBCO) and beta-1,2-dibromo-4-(1.2-dibromoethyl)-cyclohexane (beta-TBECH). Mean BDE-209 (57.2 +/- 12.2 ng/g ww) in ring-billed gull livers was unexpectedly high for this midtrophic gull species, exceeding levels reported in several apex raptors such as peregrine falcons. BDE-209's relative contribution to ?PBDEs was on average 25% (exceeding BDE-47 and BDE-99) and contrasted with profiles typically reported for fish-eating gull species. The present study highlighted preoccupying gaps in upcoming FR regulations and stressed the need for further investigation of the sources of FR exposure in highly urbanized areas. PMID- 22845170 TI - Multiple clonal MLL fusions in a patient receiving CHOP-based chemotherapy. AB - MLL rearrangements were analysed in the blood of a patient receiving chemotherapy for diffuse large B-cell lymphoma using inverse polymerase chain reaction targeting exon 12, parallel sequencing and a custom algorithm design. Of thirteen MLL rearrangements detected, five were capable of generating MLL fusion genes, including MLL-MLLT3, the most common fusion in acute myeloid leukaemia (AML). Other fusions, all previously clinically unobserved, included MLL-NKD1, a fusion to the negative regulator of Wnt/beta-catenin signaling, a pathway linked to leukaemic cell proliferation. The majority of the fusions exhibited clonal persistence from before treatment until 6 months post-chemotherapy, suggesting the fusions may confer a survival advantage to the mutant clone. MLL breakpoints were partly clustered at a specific location, indicating commonality in the process of their formation. Further, the same MLL breakpoint location exhibited a 50-100-fold increase in C to T transitions, consistent with attack by activation induced cytidine deaminase (AICDA). As is also observed in AML and acute lymphoblastic leukaemia, in this single patient setting, MLL is capable of interacting with multiple fusion partners. This finding defines a discrete site of MLL susceptibility to fragmentation, linked to possible deregulation of AICDA function. PMID- 22845171 TI - Methods for the bias adjustment of meta-analyses of published observational studies. AB - BACKGROUND: A unique challenge in meta-analysis of observational studies is bias adjustment. Two different approaches have been proposed for doing this - using summary scores versus component scores. The prevailing view on this matter is that summary quality scores are inaccurate because information from its components can cancel each other out. METHODS: A head-to-head comparison of the component score adjustment with our method using summary scores is undertaken, using data reported by the authors of the component method. RESULTS: It is demonstrated that the consideration of components or of aggregate scores does indeed lead to the same conclusions. Yet, the latter does not require imputation of the direction and magnitude of changes to effect sizes. CONCLUSIONS: The summary quality score used for bias adjustment within the context of an appropriate model may be most expedient. Implications for the bias adjustment of meta-analyses of observational studies are discussed. PMID- 22845172 TI - Comment on Lethality of H5N1 Infection in Humans. PMID- 22845173 TI - Validation, correlation, and comparison of the da Vinci trainer(TM) and the daVinci surgical skills simulator(TM) using the Mimic(TM) software for urologic robotic surgical education. AB - PURPOSE: Virtual reality simulators with self-assessment software may assist novice robotic surgeons to augment direct proctoring in robotic surgical skill acquisition. We compare and correlate the da Vinci TrainerTM (dVT) and da Vinci Surgical Skills Simulators (dVSSS) in subjects with varying robotic experience. MATERIALS AND METHODS: Students, urology residents, fellows, and practicing urologists with varying robotic experience were enrolled after local institutional review board approval. Three virtual reality tasks were preformed in sequential order (pegboard 1, pegboard 2, and tubes)-initially on the dVSSS and then on the dVT. The MimicTM software used on both systems provides raw values and percent scores that were used in statistical evaluation. Statistical analysis was performed with the two-tailed independent t-test, analysis of variance, Tukey, and the Pearson rank correlation coefficient where appropriate. RESULTS: Thirty-two participants were recruited for this study and separated into five groups based on robotic surgery experience. In regards to construct validity, both simulators were able to differentiate differences among the five robotic surgery experience groups in the tubes suturing task (p<=0.00). Sixty seven percent (4/6) robotic experts thought that surgical simulation should be implemented in residency training. The overall cohort considered both platforms easy to learn and use. CONCLUSIONS: Although performance scores were less in the dVT compared with the dVSSS, both simulators demonstrate good content and construct validity. The simulators appear to be equivalent for assessing surgeon proficiency and either can be used for robotic skills training with self assessment feedback. PMID- 22845174 TI - Lanthanum salts improve bone formation in a small animal model of post-menopausal osteoporosis. AB - Two different lanthanum salts, lanthanum carbonate (LaCO(3)) and Lancer((r)), a lanthanide citrate mixture, were tested for their effects on bone metabolism in a small animal model for post-menopausal osteoporosis. Forty female outbred Wistar Han rats, sham-operated (SHAM, positive control, n = 10) or ovariectomized (OVX, n = 30) at 4 months of age, were allotted into following groups (n = 10/group): (i) SHAM, (ii) OVX control (negative control), (iii) OVX + LaCO(3) (1.74 g/kg feed) and (iv) OVX + Lancer((r)) (8 g/kg feed). Effects on bone were investigated by bone markers [osteocalcin (Oc) in serum and excretion of pyridinoline (PYD) in urine] and by physical parameters of bone structure and bone composition (bone mass, calcium, phosphorus and magnesium content in bone crude ash). Bone micro architecture and bone mineral density were evaluated by peripheral quantitative computed tomography and micro-computed tomography (MUCT). The animal model could be validated by differences between OVX control and SHAM. Body mass and feed intake were the same among the four groups. Oc was clearly increased in the two experimental groups (p < 0.001) vs. SHAM and OVX control. Bone mass and calcium content in bone ash were significantly higher than in OVX control. The Ca/P ratio in bone ash of the two lanthanide groups did not differ from SHAM. Bone protecting effects of lanthanides were clearly demonstrated by an increased trabecular density which is the region of interest for osteoporotic bone loss. A 3D imaging of bone micro-architecture by MUCT visualized descriptively the positive effects of lanthanides on bone formation. The results of this study demonstrate an improvement of bone formation and bone-protecting effects of lanthanides in the OVX rat. Thus, lanthanum salts suggest a prevention of post menopausal bone loss and may be of benefit in experimental osteopenia following ovariectomy. PMID- 22845176 TI - Novel method for controllable fabrication of a superhydrophobic CuO surface on AZ91D magnesium alloy. AB - A novel method for controllable fabrication of a superhydrophobic CuO surface on AZ91D magnesium alloy is reported in this paper. Hierarchical structure composed of micro/nano-featherlike CuO was obtained by electrodeposition of Cu-Zn alloy coating and subsequently an electrochemical anodic treatment in alkaline solution. After modification with lauric acid, the surface became hydrophobicity/superhydrophobicity. The formation of featherlike CuO structures was controllable by varying the coating composition. By applying SEM, ICP-AES, and water contact angle analysis, the effects of coating composition on the surface morphology and hydrophobicity of the as-prepared surfaces were detailedly studied. The results indicated that at the optimal condition, the surface showed a good superhydrophobicity with a water contact angle as high as 155.5 +/- 1.3 degrees and a sliding angle as low as about 3 degrees . Possible growth mechanism of featherlike CuO hierarchical structure was discussed. Additionally, the anticorrosion effect of the superhydrophobic surface was studied by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) measurements. The interface model for anticorrosion mechanism of superhydrophobic surface in corrosive medium was proposed. Besides, the mechanical stability test indicated that the resulting superhydrophobic surfaces have good mechanical stability. PMID- 22845175 TI - Low iron availability in continuous in vitro colonic fermentations induces strong dysbiosis of the child gut microbial consortium and a decrease in main metabolites. AB - Iron (Fe) deficiency affects an estimated 2 billion people worldwide, and Fe supplements are a common corrective strategy. The impact of Fe deficiency and Fe supplementation on the complex microbial community of the child gut was studied using in vitro colonic fermentation models inoculated with immobilized fecal microbiota. Chyme media (all Fe chelated by 2,2'-dipyridyl to 26.5 mg Fe L(-1) ) mimicking Fe deficiency and supplementation were continuously fermented. Fermentation effluent samples were analyzed daily on the microbial composition and metabolites by quantitative PCR, 16S rRNA gene 454-pyrosequencing, and HPLC. Low Fe conditions (1.56 mg Fe L(-1) ) significantly decreased acetate concentrations, and subsequent Fe supplementation (26.5 mg Fe L(-1) ) restored acetate production. High Fe following normal Fe conditions had no impact on the gut microbiota composition and metabolic activity. During very low Fe conditions (0.9 mg Fe L(-1) or Fe chelated by 2,2'-dipyridyl), a decrease in Roseburia spp./Eubacterium rectale, Clostridium Cluster IV members and Bacteroides spp. was observed, while Lactobacillus spp. and Enterobacteriaceae increased consistent with a decrease in butyrate (-84%) and propionate (-55%). The strong dysbiosis of the gut microbiota together with decrease in main gut microbiota metabolites observed with very low iron conditions could weaken the barrier effect of the microbiota and negatively impact gut health. PMID- 22845177 TI - Evaluating the 4-hour and 30-minute rules: effects of room temperature exposure on red blood cell quality and bacterial growth. AB - BACKGROUND: A 30-minute rule was established to limit red blood cell (RBC) exposure to uncontrolled temperatures during storage and transportation. Also, RBC units issued for transfusion should not remain at room temperature (RT) for more than 4 hours (4-hour rule). This study was aimed at determining if single or multiple RT exposures affect RBC quality and/or promote bacterial growth. STUDY DESIGN AND METHODS: Growth and RT exposure experiments were performed in RBCs inoculated with Serratia liquefaciens and Serratia marcescens. RBCs were exposed once to RT for 5 hours (S. liquefaciens) or five times to RT for 30 minutes (S. marcescens) with periodic sampling for bacterial counts. Noncontaminated units were exposed to RT once (5 hr) or five times (30 min each) and sampled to measure in vitro quality variables. RBC core temperature was monitored using mock units with temperature loggers. Growth and RT exposure experiments were repeated three and at least six times, respectively. Statistical analysis was done using mixed model analysis. RESULTS: RBC core temperature ranged from 7.3 to 11.6 degrees C during 30-minute RT exposures and the time to reach 10 degrees C varied from 22 to 55 minutes during 5-hour RT exposures. RBC quality was preserved after single or multiple RT exposures. Increased growth of S. liquefaciens was only observed after 2 hours of continuous RT exposure. S. marcescens concentration increased significantly in multiple-exposed units compared to the controls but did not reach clinically important levels. CONCLUSION: Single or multiple RT exposures did not affect RBC quality but slightly promoted bacterial growth in contaminated units. The clinical significance of these results remains unclear and needs further investigation. PMID- 22845178 TI - Whole-body vibration training: metabolic cost of synchronous, side-alternating or no vibrations. AB - Whole-body vibration training improves strength and can increase maximal oxygen consumption ([.V]O(2max)). No study has compared the metabolic demand of synchronous and side-alternating whole-body vibration. We measured [.V]O2 and heart rate during a typical synchronous or side-alternating whole-body vibration session in 10 young female sedentary participants. The 20-min session consisted of three sets of six 45-s exercises, with 15 s recovery between exercises. Three conditions were randomly tested on separate days: synchronous at 35 Hz and 4 mm amplitude, side-alternating at 26 Hz and 7.5 mm amplitude (peak acceleration matched at 20 g in both vibration conditions), and no vibrations. Mean [.V]O2 (expressed as %[.V]O(2max)) did not differ between conditions: 29.7 +/- 4.2%, 32.4 +/- 6.5%, and 28.7 +/- 6.7% for synchronous, side-alternating, and no vibrations respectively (P = 0.103). Mean heart rate (% maximal heart rate) was 65.6 +/- 7.3%, 69.8 +/- 7.9%, and 64.7 +/- 5.6% for synchronous, side alternating, and no vibrations respectively, with the side-alternating vibrations being significantly higher (P = 0.019). When analysing changes over exercise sessions, mean [.V]O2 was higher for side-alternating (P < 0.001) than for synchronous and no vibrations. In conclusion, side-alternating whole-body vibration elicits higher heart rate responses than synchronous or no vibrations, and could elevate [.V]O2, provided the session lasts more than 20 min. PMID- 22845179 TI - Spectroscopic and computational study of melittin, cecropin A, and the hybrid peptide CM15. AB - Antimicrobial peptides (AMPs), such as cecropin A from silk moth, are key components of the innate immune system. They are effective defensive weapons against invading pathogens, yet they do not target host eukaryotic cells. In contrast, peptide toxins, such as honeybee melittin, are nondiscriminating and target both eukaryotic and prokaryotic cells. An AMP-toxin hybrid peptide that is composed of cecropin A and melittin (CM15) improves upon the antimicrobial activity of cecropin A without displaying the nonspecific, hemolytic properties of melittin. Here we report fluorescence and UV resonance Raman spectra of melittin, cecropin A, and CM15 with the goal of elucidating peptide-membrane interactions that help guide specificity. We have probed the potency for membrane disruption, local environment and structure of the single tryptophan residue, backbone conformation near the peptide hinge, and amide backbone structure of the peptides in lipid environments that mimic eukaryotic and prokaryotic membranes. These experimental results suggest that melittin inserts deeply into the bilayer, whereas cecropin A remains localized to the lipid headgroup region. A surprising finding is that CM15 is a potent membrane-disruptor despite its largely unfolded conformation. A molecular dynamics analysis complements these data and demonstrates the ability of CM15 to associate favorably with membranes as an unfolded peptide. This combined experimental-computational study suggests that new models for peptide-membrane interactions should be considered. PMID- 22845180 TI - Glaucoma in Timor-Leste: a population-based study. PMID- 22845182 TI - Mullerian cyst of the uterus treated with laparoscopy and diagnosed using immunohistology. AB - Among uterine cystic tumors, uterine cyst arising from secondary Mullerian epithelium is exceedingly rare. A 45-year-old woman presented with pelvic cystic mass, which was initially diagnosed as a paraovarian cyst by ultrasound and magnetic resonance imaging. At laparoscopy, the cyst proved to be a pedunculated uterine cyst, which was easily resected. Histologically, the cyst wall was lined by fallopian epithelium and positively stained for WT-1, estrogen receptor, and progesterone receptor. The final diagnosis was Mullerian cyst of the uterus. Preoperative diagnosis of uterine Mullerian cyst is usually impossible. Laparoscopy is useful as a minimally invasive treatment to diagnose and resect the cyst at the same time. Specific immunostaining is useful to make a definite diagnosis of Mullerian cyst of the uterus. PMID- 22845183 TI - Flow cytometry technique for analysing Leishmania promastigote phagocytosis by human polymorphonuclear leucocytes and monocytes. AB - In this study, we developed a flow cytometry technique for studying Leishmania (L.) mexicana phagocytosis by human polymorphonuclear leucocytes (PMNs) and monocytes. Leishmania promastigotes are elongated in shape and flagellated. This influences the light scatter when phagocytosis is measured by flow cytometry. Accordingly, we developed an oxidative burst method for measuring the phagocytic process. As this is an indirect marker of phagocytosis, we used confocal, light and electron microscopy to verify that promastigotes were, indeed, internalized by the phagocytes. For both PMNs and monocytes, the optimal conditions for achieving high sensitivity in flow cytometry detection were 5% pooled human serum and 15 min. incubation time. Incubations at 35, 37 and 39 degrees C were also equally efficient for both PMNs and monocytes. Optimal parasite ratios were 10 parasites per PMN and 20 parasites per monocyte. Under these conditions, Leishmania were readily phagocytosed by human PMNs and monocytes and the effects of other influences, such as treatment, would be readily detectable. This indicated that these cells may play a role in the immune response against Leishmania. PMID- 22845184 TI - Effects of written plus oral information vs. oral information alone on precolonoscopy anxiety. AB - AIMS AND OBJECTIVES: To determine the effect of written plus oral information vs. oral information alone on precolonoscopy anxiety. BACKGROUND: Information provision has been considered to reduce precolonoscopy anxiety. However, the best means to provide information before colonoscopy has not yet been determined as there is inconsistency in the outcomes of the clinical trials. DESIGN: A two group, pretest, post-test, prospective, quasi-experimental design with non-random assignment. METHODS: Participants were assigned to group 1 or 2 in the study. In the enrolment all the participants completed the questionnaires to collect personal characteristics data and assessed subjects' anxiety level by the Chinese version of the State Scale of State-Trait Anxiety Inventory as baseline data. After that, subjects in group 1 received written plus oral information before colonoscopy, while those in group 2 received oral information before colonoscopy. On the day for colonoscopy all subjects completed the Chinese version of the State Scale of State-Trait Anxiety Inventory again. RESULTS: There was no difference in state anxiety and personal characteristic between the two groups at enrolment. After the intervention, although the state anxiety scores were dropped, there were no statistical significant differences between two groups or within groups 1 and 2. CONCLUSIONS: Information provision before colonoscopy did not reduce the anxiety level in patients directly before colonoscopy. RELEVANCE TO CLINICAL PRACTICE: There was a trend that information had a positive effect on patients' state anxiety. Future information provision studies may need to add more interactive methods appropriately and take patients' gender, educational level and coping style into consideration. PMID- 22845185 TI - High diagnostic accuracy of subcutaneous Triptorelin test compared with GnRH test for diagnosing central precocious puberty in girls. AB - CONTEXT: The GnRH test is the gold standard to confirm the diagnosis of central precocious puberty (CPP); however, this compound is not always readily available. Diagnostic accuracy of subcutaneous GnRH analogues tests compared to classical GnRH test has not been reported. OBJECTIVE: To evaluate the diagnostic accuracy of Triptorelin test (index test) compared to the GnRH test (reference test) in girls with suspicion of CPP. DESIGN: A prospective, case-control, randomized clinical trial was performed. CPP or precocious thelarche (PT) was diagnosed according to maximal LH response to GnRH test and clinical characteristics during follow-up. PATIENTS AND INTERVENTIONS: Forty-six girls with premature breast development randomly underwent two tests: (i) intravenous GnRH 100 MUg, (ii) subcutaneous Triptorelin acetate (0.1 mg/m(2), to a maximum of 0.1 mg) with blood sampling at 0, 3 and 24 h for LH, FSH and estradiol ascertainment. MEASUREMENTS: Gonadotrophins and estradiol responses to Triptorelin test were measured by ultrasensitive assays. RESULTS: Clinical features were similar between CPP (n = 33) and PT (n = 13) groups. Using receiver operating characteristic curves, maximal LH response (LH-3 h) under Triptorelin test >= 7 IU/l by immunofluorometric assay (IFMA) or >= 8 IU/l by electrochemiluminescence immunoassay (ECLIA) confirmed the diagnosis of CPP with specificity of 1.00 (95% CI: 0.75-1.00) and sensitivity 0.76 (95% CI: 0.58-0.89). Considering either LH-3 h or maximal estradiol response at 24 h (cut-off value, 295 pm), maintaining the specificity at 1.00, the test sensitivity increased to 0.94 (95% CI: 0.80-0.99) and the diagnostic efficiency to 96%. CONCLUSION: The Triptorelin test had high accuracy for the differential diagnosis of CPP vs PT in girls providing a valid alternative to the classical GnRH test. This test also allowed a comprehensive evaluation of the pituitary-ovarian axis. PMID- 22845186 TI - Activin A and its regulatory molecules in placenta and fetal membranes of women with preterm premature rupture of the membranes associated with acute chorioamnionitis. AB - LABELED PROBLEM: To investigate regulation of activin A and related molecules in placenta/fetal membranes from preterm premature rupture of membranes (pPROM) associated with acute chorioamnionitis (ACA). METHOD OF STUDY: Tissues were obtained from women with spontaneous preterm deliveries (PTD), pPROM without ACA, pPROM with ACA. Activin A, follistatin, and nodal and cripto mRNA were measured by RT-PCR. RESULTS: Activin A mRNA was up-regulated in tissues from pPROM, in presence or absence of HCA, respect to PTD and in pPROM with ACA respect to pPROM without ACA. Follistatin mRNA expression did not differ between the groups. In placenta, nodal mRNA showed the same trend of activin A, while cripto was down regulated in pPROM with ACA than other groups. Nodal and cripto were not expressed by fetal membranes. CONCLUSION: The study shows the involvement of activin A pathway in pPROM with ACA. Further studies will focus on its role in placental immune functions. PMID- 22845187 TI - Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. AB - OBJECTIVE: Long-term follow-up with the use of low-dose opioids in intrathecal (IT) drug delivery system (DDS) for the treatment of intractable, severe chronic nonmalignant pain. DESIGN: This is a prospective, cohort long-term outcome study. Intervention. The intervention was the implantation of DDS. METHOD AND PATIENTS: A total of 61 consecutive patients (60% females, 40% males) with a mean age of 59.2 years and a mean duration of symptoms prior to implant of 6.2 years were referred for implant of DDS for severe intractable noncancer pain. After adequate patient evaluation, each underwent a trial with IT opioids. Three patients failed the trial and 58 patients were implanted. Follow-up was 36 months, with intervals at 6, 12, 18, 24, and 36 months. The Brief Pain Inventory was used for follow-up assessment criteria at baseline prior to implant as well as throughout the duration of the study. OUTCOME MEASURES: Outcome measures included self-reported pain scores (worst and average), functional improvement, and IT dose, and oral opioid consumption. RESULTS: We observed a statistically significant reduction in both worst and average pain from baseline (8.91 and 7.47 at baseline) throughout the duration of the study (4.02 and 3.41, respectively, at 36 months) (P = 0.012 and P < 0.001, respectively). We also documented a statistically significant improvement in physical and behavioral function. All subjects showed a significant reduction in the oral opioid consumption. The dose of IT opioids remained low and virtually unchanged for 36 months of follow-up: 1.4 morphine equivalent/day at 6 months and 1.48 at 36 months. Oral opioid averaged 128.9 mg of morphine equivalent/patient/day at baseline to 3.8 at 3 month and remained at the same level throughout the study. CONCLUSION: Low-dose IT opioid can provide sustained significant improvement in pain and function for long-term follow-up in chronic noncancer pain. PMID- 22845188 TI - Severe chronic blepharitis and scarring ectropion associated with discoid lupus erythematosus. AB - Discoid lupus erythematosus is a common form of chronic cutaneous lupus erythematosus, an autoimmune inflammatory disease that affects most of the human organs, including the skin, kidneys, joints, heart and lungs. We describe a 45 year-old Caucasian woman with a 21-year history of eyelid redness and irritation. She had been treated with antibiotics, steroids and eyelid hygiene, a therapy that resulted to brief periods of relief of symptoms. In the last 12 months, her symptoms seemed to have exacerbated, despite the administration of a local therapy. Following biopsy, a diagnosis of discoid lupus erythematosus was confirmed and the patient was placed on a systemic therapy with hydroxychloroquine. The eyelid inflammation decreased but severe scarring of the marginal eyelids persisted, resulting in cicatricial ectropion. PMID- 22845190 TI - The influence of motivation in recruitment and retention of rural and remote allied health professionals: a literature review. AB - INTRODUCTION: Recruitment and retention of allied health professionals (AHPs) to remote and rural Australia is challenging and correlates with poorer health status of remote and rural residents. While much has been written about the recruitment and retention problem, this study took a new approach by reviewing the literature describing the motivation of AHPs to work in remote and rural areas and then analyzing the findings from the perspective of motivation theory using Herzberg's extrinsic and intrinsic classification. Intrinsic motivation incentives are known to contribute to job satisfaction and come from within the individual, for example the pleasure derived from autonomy or challenge at work. In contrast, extrinsic motivation incentives are provided by the job and include such factors as salary and professional development provisions. Extrinsic incentives are important because they prevent job dissatisfaction. Job satisfaction has been shown to be linked with increased retention. METHOD: Thirty five articles, including 26 from Australia, met the inclusion criteria. The key findings related to motivation from each article are outlined and the results classified into the extrinsic-intrinsic framework. The incentives are then further analyzed as having a positive or a negative influence. RESULTS: In total, 38 different incentives were described a total of 246 times. Of the total, almost half (n=115) comprised extrinsic incentives with a negative influence, with poor access to professional development, professional isolation and insufficient supervision the most frequently reported. Rural lifestyle and diverse caseloads were the most frequently mentioned positive extrinsic incentives, while autonomy and community connectedness were the most cited positive intrinsic incentives. Negative intrinsic incentives were mentioned least frequently (n=18); however, of these, feeling overwhelmed and that your work was not valued by the community were the most commonly reported. CONCLUSIONS: The results demonstrate the significant burden of extrinsic incentives with a negative influence that are perceived by AHPs in remote and rural areas. The high turnover rate of AHPs in remote and rural areas is likely to be, in part, due to the job dissatisfaction from these disincentives. More positive intrinsic incentives were reported than negative. This suggests the potential for intrinsic incentives, known to contribute to job satisfaction, to be mediating the extrinsic disincentives. The policy implications of this work include the importance of addressing extrinsic disincentives. Simultaneously, the existing intrinsic incentives need to be nurtured and developed. Organizations that implement strategies to enhance both extrinsic and intrinsic motivation incentives are more likely to successfully address their AHP workforce shortage. PMID- 22845189 TI - Statins and risk of treated incident diabetes in a primary care population. AB - AIMS: (i) To examine the incidence of new onset treated diabetes in patients treated with different types of statins and (ii) the relationship between the duration and dose of statins and the subsequent development of new onset treated diabetes. METHODS: A retrospective cohort study was performed using the Irish Health Services Executive Primary Care Reimbursement Services national pharmacy claims database. Individuals who received any medicines were identified from January 2001 to January 2009 (n = 1 235 671). Patients newly treated with statins from 1 January 2002 to 31 December 2007 were identified (n = 239 628). Cases were identified as individuals newly treated with antidiabetic medication (n = 38 503). Adjusted hazards ratios (HR) with 95% confidence intervals (CI) were calculated to examine the association between statins (any vs. none) and time to new onset treated diabetes using Cox proportional hazard regression. The dose and duration response relationship between statins and new onset treated diabetes was examined using restricted spline functions to assess the linearity of the relationship. RESULTS: Statin use was associated with an increased risk of new onset treated diabetes (HR = 1.18, 95% CI 1.15, 1.22). Increased risk of new onset treated diabetes was found with rosuvastatin (HR = 1.41, 95% CI 1.31, 1.52), atorvastatin (HR = 1.23, 95% CI 1.19, 1.27) and simvastatin (HR = 1.15, 95% CI 1.05, 1.25). There were statistically significant overall dose and duration effects for all statins, excepting fluvastatin, which only demonstrated a duration effect. CONCLUSION: An increased risk of new onset treated diabetes was found in those treated with statins showing significant duration and dose effect. Further study is required to confirm this association. PMID- 22845191 TI - Modeling the uptake of semivolatile organic compounds by passive air samplers: importance of mass transfer processes within the porous sampling media. AB - Air sampling based on diffusion of target molecules from the atmospheric gas phase to passive sampling media (PSMs) is currently modeled using the two-film approach. Originally developed to describe chemical exchange between air and water, it assumes a uniform chemical distribution in the bulk phases on either side of the interfacial films. Although such an assumption may be satisfied when modeling uptake in PSMs in which chemicals have high mobility, its validity is questionable for PSMs such as polyurethane foam disks and XAD-resin packed mesh cylinders. Mass transfer of chemicals through the PSMs may be subject to a large resistance because of the low mass fraction of gas-phase chemicals in the pores, where diffusion occurs. Here we present a model that does not assume that chemicals distribute uniformly in the PSMs. It describes the sequential diffusion of vapors through a stagnant air-side boundary layer and the PSM pores, and the reversible sorption onto the PSM. Sensitivity analyses reveal the potential influence of the latter two processes on passive sampling rates (PSRs) unless the air-side boundary layer is assumed to be extremely thick (i.e., representative of negligible wind speeds). The model also reveals that the temperature dependence of PSRs, differences in PSRs between different compounds, and a two-stage uptake, all observed in field calibrations, can be attributed to those mass transfer processes within the PSM. The kinetics of chemical sorption to the PSM from the gas phase in the macro-pores is a knowledge gap that needs to be addressed before the model can be applied to specific compounds. PMID- 22845192 TI - Strikingly different effects of hydrogen bonding on the photodynamics of individual nucleobases in DNA: comparison of guanine and cytosine. AB - Ab initio surface hopping dynamics calculations were performed to study the photophysical behavior of cytosine and guanine embedded in DNA using a quantum mechanical/molecular mechanics (QM/MM) approach. It was found that the decay rates of photo excited cytosine and guanine were affected in a completely different way by the hydrogen bonding to the DNA environment. In case of cytosine, the geometrical restrictions exerted by the hydrogen bonds did not influence the relaxation time of cytosine significantly due to the generally small cytosine ring puckering required to access the crossing region between excited and ground state. On the contrary, the presence of hydrogen bonds significantly altered the photodynamics of guanine. The analysis of the dynamics indicates that the major contribution to the lifetime changes comes from the interstrand hydrogen bonds. These bonds considerably restricted the out-of-plane motions of the NH(2) group of guanine which are necessary for the ultrafast decay to the ground state. As a result, only a negligible amount of trajectories decayed into the ground state for guanine embedded in DNA within the simulation time of 0.5 ps, while for comparison, the isolated guanine relaxed to the ground state with a lifetime of about 0.22 ps. These examples show that, in addition to phenomena related to electronic interactions between nucleobases, there also exist relatively simple mechanisms in DNA by which the lifetime of a nucleobase is significantly enhanced as compared to the gas phase. PMID- 22845193 TI - Control beliefs are related to smoking prevention in prenatal care. AB - BACKGROUND: Smoking during pregnancy is one of the most important avoidable health risks for the unborn child. Gynaecologists and midwives play a fundamental role in the prevention of smoking during pregnancy. However, a large number of health care practitioners still do not address smoking in pregnant patients. OBJECTIVES: We examined whether gynaecologists and midwives engage in screening and counselling of pregnant women and conducting interventions to prevent smoking during pregnancy. Further, we examined the role of gynaecologists' and midwives' control beliefs. Control beliefs involve efficacy expectations--the practitioner's confidence in his capacity to conduct prevention efforts adequately--and outcome expectations--the practitioner's expectation that such prevention efforts are successful in general. METHODS: A total of 486 gynaecologists and 366 midwives completed a questionnaire on screening of smoking, counselling and other interventions they conduct to prevent smoking during pregnancy. Moreover, gynaecologists and midwives rated their control beliefs regarding their influence on pregnant patients' smoking habits. RESULTS: The majority of gynaecologists and midwives reported screening all pregnant patients regarding smoking, explaining the risks and recommending smoking cessation. By contrast, only a minority engages in more extensive prevention efforts. Strong control beliefs were predictive of a higher likelihood of screening and counselling, as well as of engaging in more extensive interventions. CONCLUSIONS: The findings point to the importance of strengthening gynaecologists' and midwives' control beliefs by professional education and training on smoking prevention. PMID- 22845310 TI - Human leukocyte antigen-haploidentical hematopoietic stem cell transplant for a patient with histiocytic sarcoma. PMID- 22845311 TI - Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2. AB - Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr-Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC(50)) compared with parental K562 cells for imatinib (IC(50)(IM); 9 uM to 19 uM, p = 0.002) and nilotinib (IC(50)(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC(50)(IM) or IC(50)(NIL) or significantly decrease IC(50) upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 uM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations. PMID- 22845312 TI - Evaluation of enniatins A, A1, B, B1 and beauvericin in Portuguese cereal-based foods. AB - Sixty-one samples of Portuguese cereal-based foods were analysed for the occurrence of emerging mycotoxins called enniatins (A, A1, B and B1) and beauvericin. Samples were extracted with a mixture of acetonitrile/water (85/15, v/v) using an Ultra-Turrax homogeniser, and mycotoxins were detected with liquid chromatography coupled to a mass spectrometer. This method was validated and adequate values of recovery (70-103%) and relative standard deviation (<15%) were obtained. Signal suppression/enhancement was studied and matrix-matched calibration used to minimise this effect, but no additional clean-up step was necessary. The mass spectrometer was operated in selected reaction monitoring (SRM) mode and with selected transitions for each compound to quantify and to qualify them. Fifty-nine per cent of samples were contaminated. The percentages of enniatins were 53%, 49%, 44% and 16% for A1, B, B1, and A, respectively, and for beauvericin it was 1.6%. For the total samples, the mean contamination was 30, 24, 15, 2.1 and 0.1 ng g-1 for enniatins A1, B, B1 and A, and beauvericin, respectively. The wheat-based samples showed higher levels and greater prevalence than any other cereals monitored. These results were used to estimate the daily intake of ENs from wheat-based cereal by the Portuguese population. At the same time, the usefulness of this method in the analysis of other important mycotoxins (aflatoxin B1, ochratoxin A, deoxynivalenol, T-2 toxin, fumonisin B1 and zearalenone) was evaluated. PMID- 22845313 TI - Early investigation of QTc liability: the role of multiple ascending dose (MAD) study. AB - The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints. We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study. Among the main advantages of this approach are the ability to study the ECG effects of a wide range of doses to the maximum tolerated doses, eliminating routine analyses at unnecessary timepoints, making early go-no-go decisions, making phase II studies more efficient and, if necessary, being able to implement rigorous ECG monitoring in populations and pivotal studies of regulatory interest. If clear evidence for the presence or absence of QTc effect is found, the data from a modified MAD study may support a request for a waiver from the requirement to conduct a TQT study. In the event that a TQT study is considered unnecessary, there are obvious significant savings without compromising collection of vital safety data. PMID- 22845314 TI - Regulation of apoptosis in HL-1 cardiomyocytes by phosphorylation of the receptor tyrosine kinase EphA2 and protection by lithocholic acid. AB - BACKGROUND AND PURPOSE: Heart failure and atrial fibrillation are associated with apoptosis of cardiomyocytes, suggesting common abnormalities in pro-apoptotic cardiac molecules. Activation of the receptor tyrosine kinase EphA2 causes apoptosis in vitro, and dysregulation of EphA2-dependent signalling is implicated in LEOPARD and Noonan syndromes associated with cardiomyopathy. Molecular pathways and regulation of EphA2 signalling in the heart are poorly understood. Here we elucidated the pathways of EphA2-dependent apoptosis and evaluated a therapeutic strategy to prevent EphA2 activation and cardiac cell death. EXPERIMENTAL APPROACH: EphA2 signalling was studied in an established model of doxazosin-induced apoptosis in HL-1 cells. Apoptosis was measured with TUNEL assays and as cell viability using a formazan method. Western blotting and siRNA for EphA2 were also used. KEY RESULTS: Apoptosis induced by doxazosin (EC(50) = 17.3 MUM) was associated with EphA2 activation through enhanced phosphorylation (2.2-fold). Activation of pro-apoptotic downstream factors, phospho-SHP-2 (3.9 fold), phospho-p38 MAPK (2.3-fold) and GADD153 (1.6-fold) resulted in cleavage of caspase 3. Furthermore, two anti-apoptotic enzymes were suppressed (focal adhesion kinase, by 41%; phospho-Akt, by 78%). Inactivation of EphA2 with appropriate siRNA mimicked pro-apoptotic effects of doxazosin. Finally, administration of lithocholic acid (LCA) protected against apoptosis by increasing EphA2 protein levels and decreasing EphA2 phosphorylation. CONCLUSIONS AND IMPLICATIONS: EphA2 phosphorylation and activation of SHP-2 are critical steps in apoptosis. Reduction of EphA2 phosphorylation by LCA may represent a novel approach for future anti-apoptotic treatment of heart failure and atrial fibrillation. PMID- 22845316 TI - The long view: 40 years of Marek's disease research and Avian Pathology. AB - Marek's disease (MD), named after the Hungarian veterinary pathologist over 100 years ago, is a major disease affecting poultry health worldwide. Research in the late 1960s that led to the identification of the causative herpesvirus and the development of a highly successful vaccine is undoubtedly one of the best success stories in veterinary medicine. As Avian Pathology is celebrating its 40th anniversary, we review the last four decades of MD research that has provided major advances in our understanding of the virus, the pathogenic mechanisms of the disease, methods of diagnosis and the control through different generations of vaccines. Particular attention has been paid to the contributions made by publications in Avian Pathology. Despite this tremendous progress, MD continues to pose major challenges particularly from increasing virulence and emergence of new pathotypes. Further research on the molecular mechanisms of the disease, genetic resistance, vaccine-induced protection and evolution of virulence will be needed to develop more sustainable control strategies in the coming years. PMID- 22845317 TI - The long view: 40 years of avian leukosis research. AB - The present review is aimed at the non-specialist reader and is one of a number being written on important diseases of poultry to celebrate the 40th anniversary of the birth of Avian Pathology, the journal of the World Veterinary Poultry Association. The diseases of the avian leukosis complex have a number of features of distinction. They were the first neoplastic diseases in any species to be shown, 100 years ago, to be transmissible and caused by viruses, and have consequently been studied extensively by biomedical scientists as models for the role of viruses in cancer. They also became, from around the 1920s, the major cause of mortality and economic loss to the developed poultry industry, and were studied by agricultural scientists searching to understand and control them. The remit of the review is to cover research carried out over the 40 years since 1971, when the journal was founded. In this review on avian leukosis, an introductory summary is given of knowledge acquired over the preceding 60 years. Subsequently a selection is provided of discoveries, both fundamental and more applied, that seem to us to be of particular importance and interest. Much of the work was carried out by biomedical scientists interested in cancer. Probably the most significant was the discovery in the avian retroviruses of oncogenes that cause leukosis and other tumours and of their origin from proto-oncogenes in normal cells. These oncogenes are involved in cancer in many species, including chickens and humans. Other work was performed by agricultural scientists interested in poultry disease. Interests of the two groups have overlapped, particularly as a result of a shift of emphasis to molecular biology research. PMID- 22845318 TI - Protection induced by commercially available live-attenuated and recombinant viral vector vaccines against infectious laryngotracheitis virus in broiler chickens. AB - Viral vector vaccines using fowl poxvirus (FPV) and herpesvirus of turkey (HVT) as vectors and carrying infectious laryngotracheitis virus (ILTV) genes are commercially available to the poultry industry in the USA. Different sectors of the broiler industry have used these vaccines in ovo or subcutaneously, achieving variable results. The objective of the present study was to determine the efficacy of protection induced by viral vector vaccines as compared with live attenuated ILTV vaccines. The HVT-LT vaccine was more effective than the FPV-LT vaccine in mitigating the disease and reducing levels of challenge virus when applied in ovo or subcutaneously, particularly when the challenge was performed at 57 days rather than 35 days of age. While the FPV-LT vaccine mitigated clinical signs more effectively when administered subcutaneously than in ovo, it did not reduce the concentration of challenge virus in the trachea by either application route. Detection of antibodies against ILTV glycoproteins expressed by the viral vectors was a useful criterion to assess the immunogenicity of the vectors. The presence of glycoprotein I antibodies detected pre-challenge and post challenge in chickens vaccinated with HVT-LT indicated that the vaccine induced a robust antibody response, which was paralleled by significant reduction of clinical signs. The chicken embryo origin vaccine provided optimal protection by significantly mitigating the disease and reducing the challenge virus in chickens vaccinated via eye drop. The viral vector vaccines, applied in ovo and subcutaneously, provided partial protection, reducing to some degree clinical signs, and challenge VIRUS replication in the trachea. PMID- 22845319 TI - Multiplex polymerase chain reaction for screening avian pathogenic Escherichia coli for virulence genes. AB - Colibacillosis is a disease in poultry caused by avian pathogenic Escherichia coli (APEC) strains which leads to great economic losses in the poultry industry. These E. coli strains contain various virulence genes which grant the bacteria the ability to proliferate in the poultry host and cause disease. Many genes which can contribute to virulence have been identified and can be used to screen E. coli strains to infer pathogenicity and aid in the identification and classification of APEC. Multiplex polymerase chain reaction methods were designed and optimized to rapidly detect 18 different virulence genes in E. coli strains that were isolated in South Africa and Zimbabwe from various sources, including from chickens showing signs of colibacillosis. Virulence gene profiles were constructed for each E. coli isolate from the multiplex data for the comparison of the colibacillosis isolates with the other isolates. The South African E. coli isolated from chickens with signs of colibacillosis showed higher virulence gene prevalence in comparison with the Zimbabwean and other samples except those isolated from chicken faeces. The multiplex polymerase chain reaction designed in the present study successfully screened E. coli isolates for various APEC-related virulence genes, including genes recently described in the literature. PMID- 22845320 TI - Investigation into the aetiology of runting and stunting syndrome in chickens. AB - Currently, the aetiology of runting and stunting syndrome (RSS) in chickens is unknown. The impact of RSS on weight gain and microscopic lesions in immunological organs and the duodenum, was investigated in 1-day-old commercial broilers at 12 days following exposure to RSS-contaminated litter. Furthermore, the presence of the viral nucleic acids of three astroviruses and one parvovirus was analysed by in situ hybridization from days 1 through 5 post exposure. A 70% decrease in weight was observed in the RSS-exposed group at the end of the experiments when compared with the unexposed controls. Lesions in the bursa of Fabricius and thymus were present in both groups but were significantly higher at the end of the study in the RSS-exposed group. In contrast, no significant difference in Harderian gland lesions was observed between the groups. Histological lesions in the duodenum were already present 24 h after exposure in the RSS-exposed group only, peaked at day 4 and declined until the end of the study. Results of the in situ hybridization studies clearly indicate replication of three astroviruses (chicken astrovirus, avian nephritis virus [ANV]-1, ANV-2) in the duodenum but not in other organs evaluated. Chicken astrovirus nucleic acids were detected on days 1 and 2 post exposure, while ANV-1 and ANV-2 nucleic acids were observed on several days during the period investigated. Surprisingly, no viral nucleic acid specific for the chicken parvovirus was observed. The results indicate that astroviruses probably play an important role during RSS due to the concurrence of viral RNA detection and lesions in the duodenum. PMID- 22845321 TI - Effect of low-pathogenicity influenza virus H3N8 infection on Mycoplasma gallisepticum infection of chickens. AB - Mycoplasma infection is still very common in chicken and turkey flocks. Several low-pathogenicity avian influenza (LPAI) viruses are circulating in wild birds that can be easily transmitted to poultry flocks. However, the effect of LPAI on mycoplasma infection is not well understood. The aim of the present study was to investigate the infection of LPAI virus H3N8 (A/mallard/Hungary/19616/07) in chickens challenged with Mycoplasma gallisepticum. Two groups of chickens were aerosol challenged with M. gallisepticum. Later one of these groups and one mycoplasma-free group were aerosol challenged with the LPAI H3N8 virus. The birds were observed for clinical signs for 8 days, then euthanized, and examined for the presence of M. gallisepticum in the trachea, lung, air sac, liver, spleen, kidney and heart, and for developing anti-mycoplasma and anti-viral antibodies. The LPAI H3N8 virus did not cause any clinical signs but M. gallisepticum infection caused clinical signs, reduction of body weight gain and colonization of the inner organs. These parameters were more severe in the birds co-infected with M. gallisepticum and LPAI H3N8 virus than in the group challenged with M. gallisepticum alone. In addition, in the birds infected with both M. gallisepticum and LPAI H3N8 virus, the anti-mycoplasma antibody response was reduced significantly when compared with the group challenged with M. gallisepticum alone. Co-infection with LPAI H3N8 virus thus enhanced pathogenesis of M. gallisepticum infection significantly. PMID- 22845322 TI - Standardization of a model to study revaccination against Marek's disease under laboratory conditions. AB - Revaccination, the practice of administering Marek's disease (MD) vaccine a second time, has been used in commercial poultry flocks for many years. The rationale is largely anecdotal as the few published reports have failed to provide support for the value of the practice. In the present work, we have standardized a model to study MD revaccination under laboratory conditions. Nine bird experiments were conducted to evaluate homologous revaccination (same vaccine administered twice) and heterologous revaccination (administration of two different vaccines) with various challenge models. Our results demonstrated that heterologous revaccination (with a second vaccine more protective than the first vaccine) but not homologous revaccination provided a beneficial increase in protection. Administration of the first vaccine at 18 days of embryonation followed by a more protective second vaccine at hatch reproduced systematically the benefits of revaccination. In addition, our results show that revaccination protocols might aid in solving major drawbacks associated with various highly protective experimental MD vaccines; that is, lymphoid organ atrophy and residual virulence. Strain RM1 is one of the most protective vaccines against early challenge with highly virulent MD virus but it induces severe lymphoid atrophy in chickens lacking maternal antibodies against MD virus. In this study, strain RM1 did not induce lymphoid organ atrophy when administered as second vaccine in a revaccination protocol. Similarly, strain 648A100/BP5 maintains residual virulence in chickens lacking maternal antibodies against MD virus but did not induce any lesions when used as a second vaccine. Until now, arbitrary revaccination protocols have been occasionally proven useful to the poultry industry. The model developed in this study will allow for a better understanding of this phenomenon and its optimization. A more rational use of this practice will be of great help to control MD outbreaks until better vaccines are available. PMID- 22845324 TI - CpG oligonucleotides and recombinant interferon-gamma in combination improve protection in chickens to Salmonella enterica serovar Enteritidis challenge as an adjuvant component, but have no effect in reducing Salmonella carriage in infected chickens. AB - Salmonella enterica serovar Enteritidis is the most common cause of human salmonellosis in many developed nations. It is frequently associated with both poultry meat and eggs. In the present study we have determined whether CpG oligonucleotides that stimulate the immune system via Toll like-receptors 15 and 21 in the chicken can be used as immunomodulatory agents to break carriage of S. Enteritidis in in vitro and in vivo infection models. We also investigated its use as a component in an adjuvant to stimulate cell mediated immunity with a killed vaccine preparation. Following infection of the chicken macrophage-like cell line HD11 with Salmonella enterica serovar Gallinarum, cells were stimulated with an oligonucleotide containing a CpG motif, or with a non-CpG oligonucleotide control at concentrations ranging from 0 to 80 uM. Addition of the CpG oligonucleotide greatly enhanced clearance of S. Enteritidis in dose-dependent manner, whilst the control oligonucleotide had no significant effect. In contrast, stimulation of cells infected with S. Gallinarum had no effect. The CpG or control oligonucleotide with recombinant chicken interferon-gamma was administered intramuscularly into chickens experimentally colonized with S. Enteritidis, although neither preparation produced any change in intestinal colonization levels to that in untreated control birds. Finally, CpG oligonucleotides were incorporated with recombinant interferon-gamma, double stranded RNA (Poly I:C) and squalene as a Th1-stimulating combined adjuvant for synergistic activation of cellular immunity (CASAC) together with whole killed Salmonella as the antigen as an experimental vaccine. Following vaccination and challenge of chickens with S. Enteritidis, CASAC gave significant protection to intestinal colonization whereas the same antigen given with a proprietary adjuvant did not. Neither adjuvant increased protection to systemic infection. The data suggest that adjuvants incorporating CpG motifs and interferon-gamma may improve protection afforded by killed-Salmonella vaccines. PMID- 22845323 TI - Influence of vaccination with CVI988/Rispens on load and replication of a very virulent Marek's disease virus strain in feathers of chickens. AB - Several highly efficacious vaccines are currently available for control of Marek's disease, a lymphoproliferative disease in chickens. However, these vaccines are unable to prevent infection with Marek's disease virus (MDV) in vaccinated birds. This leads to shedding of virulent MDV from feather follicle epithelium and skin epithelial cells of vaccinated and infected chickens. The objective of the present study was to study the interactions between a vaccine strain (CVI988/Rispens) and a very virulent strain of MDV (RB1B) in feathers. We examined genome load and replication of CVI988 and MDV-RB1B strains at various time points post infection. Moreover, we evaluated cytokine expression in feathers as indicators of immunity generated in response to vaccines against MDV. Analysis of feathers collected between 4 and 21 days post infection (d.p.i.) revealed a steady level of CVI988 genome load in the presence or absence of RB1B. Infection with MDV resulted in a significant increase in RB1B genome load peaking at 14 d.p.i. Importantly, vaccination with CVI988 resulted in a significant reduction in accumulation of MDV-RB1B in feathers. RB1B genome accumulation in feather tips was associated with increased expression of interferon-alpha at 14 d.p.i. and interferon-Sgamma at earlier time points, 4 and 7 d.p.i. compared with 10 and 14 d.p.i. Interleukin-10 and interleukin-6 were up-regulated at 14 d.p.i. in the infected groups. This study expands our understanding of the dynamics of replication of vaccine and virulent MDV strains in the feathers and illuminates mechanisms associated with immunity to Marek's disease. PMID- 22845325 TI - Ciprofloxacin resistance in E. coli isolated from turkeys in Great Britain. AB - Fluoroquinolones are a widely used group of antimicrobials in both human and animal medicine, with ciprofloxacin being a critically important fluoroquinolone for serious human infections. The present study reports on a 1-year survey for the presence of ciprofloxacin-resistant Escherichia coli in turkeys from Great Britain. Boot swabs were taken from 442 turkey flocks comprised of 125 breeding flocks and 317 meat flocks from 337 different farms over a 1-year period (2006 to 2007). CHROMagar ECC containing 1 mg/l ciprofloxacin was used to obtain ciprofloxacin-resistant isolates. Isolates were tested for sensitivity to 16 different antimicrobials. Isolates with ciprofloxacin minimum inhibitory concentrations >=8 mg/l were tested for mutations in gyrA by polymerase chain reaction and DNA sequencing. Selected isolates were tested by multiplex polymerase chain reaction for qnrA, qnrB and qnrS, qepA and aac(6')-Ib-cr genes. Conjugations were performed to assess the transferability of resistance to quinolones. Ciprofloxacin-resistant E. coli was found in 22.4% of turkey breeding flocks and 60.9% of meat flocks. Two main mutations in gyrA, as well as a range of silent mutations, were identified in resistant isolates. Flocks with transferable resistance genes qnrB, qnrS, and aac(6')-Ib-cr were found at a low flock prevalence of 4.2%, 1.6% and 1.0%, respectively; however, under laboratory conditions only transfer of qnrS genes could be demonstrated. This work has confirmed the occurrence of ciprofloxacin-resistant E. coli strains throughout turkey breeding and meat flocks, with almost one-third of E. coli isolates being resistant to ciprofloxacin. Of those, more than 87% were also resistant to three or more antimicrobial classes. PMID- 22845326 TI - Astroviruses associated with stunting and pre-hatching mortality in duck and goose embryos. AB - The first detection of avian nephritis virus (ANV) in goose embryos and of turkey astrovirus-1 (TAstV-1) in duck embryos is described. Intestinal samples from duck and goose embryos from five duck and four goose flocks in Croatia were tested by polymerase chain reaction for the presence of ANV, TAstV-1, turkey astrovirus-2, chicken astrovirus, duck astrovirus and also for the presence of avian reovirus, Derzsy's disease virus and duck enteritis virus. The kidneys from duck and goose embryos were also tested for ANV, while liver samples were tested for duck astrovirus. Duck embryos were also tested to detect duck circovirus and goose embryos for the presence of goose circovirus and goose haemorrhagic polyomavirus. All embryos were in the final stage of incubation and were characterized by moderate to markedly retarded growth. ANV was confirmed in the intestines and kidneys of embryos from two duck and two goose flocks and TAstV-1 was found in embryos from two duck flocks. One duck flock was positive for both ANV and TAstV 1. No other viruses were found in tested flocks. Phylogenetic analysis based on the ANV polymerase gene fragment of ANV sequences detected in duck and goose embryos revealed greatest similarity (88.1 to 97.2%) with ANV isolates from chickens. Further, the existence of at least two types of ANV circulating in Croatian duck and goose flocks was confirmed. Based on the phylogenetic analysis of the portion of TAstV-1 polymerase gene, two detected TAstV-1 nucleotide sequences were 99.5% similar. Compared with six TAstV-1 sequences, Croatian sequences showed one unique nucleotide change. In addition to other possible causes of stunted growth and late embryonic death, these findings suggest that ANV and/or TAstV-1 infection may be a contributing factor in the pre-hatching mortality of ducklings and goslings. PMID- 22845327 TI - Comparison of the replication and transmissibility of an infectious laryngotracheitis virus vaccine delivered via eye-drop or drinking-water. AB - Live attenuated vaccines have been extensively used to control infectious laryngotracheitis (ILT). Most vaccines are registered/recommended for use via eye drop although vaccination via drinking-water is commonly used in the field. Drinking-water vaccination has been associated with non-uniform protection. Bird to-bird passage of chick-embryo-origin (CEO) ILT vaccines has been shown to result in reversion to virulence. The purpose of the present study was to examine the replication and transmission of a commercial CEO infectious laryngotracheitis virus (ILTV) vaccine strain following drinking-water or eye-drop inoculation. Two groups of 10 specific-pathogen-free chickens were each vaccinated with Serva ILTV vaccine strain either via eye-drop or drinking-water. Groups of four or five unvaccinated birds were placed in contact with vaccinated birds at regular intervals. Tracheal swabs were collected every 4 days from vaccinated and in contact birds to assess viral replication and transmission using quantitative polymerase chain reaction. Compared with eye-drop-vaccinated birds, drinking water-vaccinated birds showed delayed viral replication but had detectable viral DNA for a longer period of time. Transmission to chickens exposed by contact on day 0 of the experiments was similar in both groups. Birds exposed to ILTV by contact with eye-drop vaccinated birds on days 4, 8, 12 and 16 of the experiment had detectable ILTV for up to 8 days post exposure. ILTV was not detected in chickens that were exposed by contact with drinking-water vaccinated birds on day 12 of the experiment or later. Results from this study provide valuable practical information for the use of ILT vaccine. PMID- 22845329 TI - Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity. AB - As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 MUM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 MUM. PMID- 22845331 TI - OXA-162, a novel variant of OXA-48 displays extended hydrolytic activity towards imipenem, meropenem and doripenem. AB - CONTEXT: Isolation and characterization of OXA-162, a novel variant of OXA-48. OBJECTIVES: Klebsiella pneumoniae isolate with decreased susceptibility to carbapenems was recovered from a Turkish patient. This study aimed at characterizing the carbapenem resistance determinants of this isolate. MATERIALS AND METHODS: Antibiotic susceptibility tests, analytic isoelectric focusing (IEF), cloning and sequencing were performed. Cloned beta-lactamase was purified by means of preparative gel electrophoresis and the kinetic constants were determined under initial rate conditions. RESULTS: The identified bla(OXA-162) gene was located on a ca. 45-kb plasmid carrying a transposon consisted of two IS1999-2 elements. OXA-162 differed from OXA-48 by a single amino acid substitution (Thr213Ala) which increased the catalytic efficiency (k(cat)/K(M)) of OXA-162 towards imipenem and meropenem. Also this substitution caused a gain of hydrolysis ability towards doripenem. Analysis of OXA-162 model implied that the amino acid change might generate an extension in the opening of the substrate entry site and might cause extended hydrolytic activity towards imipenem, meropenem and doripenem. DISCUSSION AND CONCLUSION: OXA-162, a derivative of OXA 48 has enhanced catalytic properties. PMID- 22845330 TI - Synthesis, characterization, and antimicrobial evaluation of some new hydrazinecarbothioamide, 1,2,4-triazole and 1,3,4-thiadiazole derivatives. AB - In this work, we reported the synthesis and evaluation of antibacterial and antifungal activities of three new compound series obtained from 6-(phenyl/4 chlorophenyl)imidazo[2,1-b]thiazole-3-acetic acid hydrazide: 2-{[6-(phenyl/4 chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetyl}-N alkyl/arylhydrazinecarbothioamides (2a-d), 4-alkyl/aryl-2,4-dihydro-5-{[6 (phenyl/4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]methyl}-3H-1,2,4-triazole-3 thiones (3a-n), and 2-alkyl/arylamino-5-{[6-(phenyl/4-chlorophenyl)imidazo[2,1 b]thiazol-3-yl]methyl}-1,3,4-thiadiazoles (4a-g). The newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR (APT), mass and elemental analysis. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Candida albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, Trichophyton mentagrophytes var. erinacei NCPF 375, Microsporum gypseum NCPF 580, and T. tonsurans NCPF 245. 3c, 3f, 3m, 3n, and 4e showed the highest antibacterial activity. Particularly 3c, 3f, 3g, 3k, 3n, 4a, 4e, and 4g showed the highest antifungal activity against tested fungi. PMID- 22845332 TI - Super toner and ink repellent superoleophobic surface. AB - Offset of imaging material from a fuser surface to paper during fusing is highly undesirable in printing. Here the wetting and repellent characteristics of three imaging materials (a solid wax ink, a waxy polyester toner, and a polyester toner) in their molten states have been studied on three model print surfaces: a transparency (surrogate for paper), a PTFE film, and a model superoleophobic surface, with the aim of assessing their performance in fusing. The superoleophobic surface, with water and hexadecane contact angles of ~156 degrees and sliding angles at ~10 degrees , comprises 3 MUm diameter pillar arrays on silicon wafer and was fabricated by photolithography followed by surface modification with a fluorosilane. The contact angles of the three imaging materials range from 40 to 79 degrees on the transparency and the sessile drops do not slide even at 90 degrees tilted angle, indicating that they all wet, adhere, and pin on the transparency. Although the contact angles of the three imaging materials are slightly higher (63-85 degrees ) on PTFE, the sessile drops do not slide on PTFE either. Because PTFE is widely used as a fuser surface material in combination with different waxy imaging materials commercially, we attribute the successful implementation of PTFE to the use of the wax additive. With the superoleophobic surface, there is a dramatic increase in advancing and static contact angles for all three imaging materials. The advancing and static contact angles are in the 150-168 degrees range for waxy toner, indicative of superhigh repellency. Although the advancing and static contact angles for the polyester toner decrease slightly at 147 and 130 degrees , respectively, the repellency is still very high. More importantly, the sessile drops of all three imaging materials are mobile upon tilting and they all have high receding contact angles. The overall results suggest that the adhesion between the superoleophobic surface and the ink and toner materials are very small relative to those with paper and PTFE. The important of high repellency and low adhesion to offset performance is discussed. PMID- 22845333 TI - Performance scores and standings during the 43rd Artistic Gymnastics World Championships, 2011. AB - Scores in artistic gymnastics are subject to changes in the rules that occur each Olympic cycle as outlined in the Code of Points, because rules influence the composition of routines and therefore performance. The aim of this study was to identify the most important routine apparatus for success in a World competition. The data were the official results for the 478 gymnasts (262 men, 216 women) who competed in the 43rd Artistic Gymnastic World Championships in 2011 in Tokyo, Japan. The factors least influenced by the technical standard of competitors were performance scores on uneven bars and balance beam for women, and those on pommel horse for men. For uneven bars, balance beam, and pommel horse, scores were consistently good predictors of final standing. Our results suggest that high scores on these apparatus have a greater influence on overall performance than scores on the other apparatus, regardless of the competitors' standard. PMID- 22845334 TI - Advancing risk assessment for emerging infectious diseases for blood and blood products: proceedings of a public workshop. PMID- 22845335 TI - HMGB-1 as a target for inflammation controlling. AB - In the present study, we evaluated recent patents that describe products or methods able to down-regulate the pro-inflammatory action of HMGB-1, also called as amphoterin. High Mobility Group Box-1 (HMGB-1) has been implicated in the pathogenesis of inflammatory diseases. HMGB-1 has been proposed to be a crucial mediator in the pathogenesis of many diseases including sepsis, arthritis, cancer, autoimmunity diseases and diabetes. It has been suggested that HMGB-1 itself can signal through RAGEs (receptor for advanced glycation end products) and through the Toll-Like Receptors TLR2 and TLR4. Activation of these receptors results ultimately in the activation of Nuclear Factor-kappaB (NFkappaB), inducing the up-regulation of leukocyte adhesion molecules, production of pro inflammatory cytokines and angiogenic factors in both hematopoietic and endothelial cells, thereby promoting inflammation. There are several patents proposed for controlling the production, secretion and neutralization of HMGB-1 and consequently the inflammatory process. We have divided the patents in six groups based on mechanism of action. The group 1 is associated with inhibition of HMGB-1 using anti-HMGB-1 antibodies; group 2: inhibition of HMGB-1 releases from the nucleus into the extracellular space; group 3: HMGB-A box as a competitive antagonist of HMGB-1; group 4: blockage of RAGE-HMGB-1 signaling using RAGE antagonists; group 5: blockage of TLR-HMGB-1 signaling using anti-TLR2 antibodies and group 6: other molecules that modulate HMGB-1 activity using e.g. human soluble thrombomodulin. The mechanism of HMGB-1 action, its role and efficiency of each group of patents proposed for controlling inflammation are discussed. PMID- 22845336 TI - Effect of electromagnetic field on the polymerization of microtubules extracted from rat brain. AB - Microtubules (MTs) are ubiquitous eukaryotic proteinaceous filaments showing a hollow cylindrical structure. MTs are composed of alpha-beta-tubulin heterodimers arranged in linear protofilaments. MTs have a significant electric dipolar moment along their axes, which makes them capable of being aligned parallel to the applied electromagnetic field direction. Tubulin heterodimers were purified from rat brains. MTs were obtained by polymerization in vitro. Samples of microtubules adsorbed under and without electromagnetic fields with 500 Hz frequency. Our results demonstrate the effect of electromagnetic field with 500 Hz frequency to increase the polymerization of MTs. Some relevant patents are also outlined in this article. PMID- 22845337 TI - APN telephone follow up to low-income first time mothers. AB - AIMS AND OBJECTIVES: To examine the effects of a low cost advanced practice nurse telephone intervention for 2 months postbirth in low-income first time mothers with healthy full term infants. BACKGROUND: Currently women with non-complicated, healthy full term newborn deliveries receive little to no routine postpartum support. This is problematic if mothers are first time mothers, poor, have problems accessing health care, have language barriers and sparse social support. DESIGN: A two group randomised clinical trial. This study was conducted in an inner city South Florida county hospital. METHODS: A control group (n = 69) received routine hospital discharge care. An intervention group (n = 70) received routine hospital discharge care plus APN follow up telephone calls for week 8 postdischarge. Comparison of outcomes included maternal health (stress, social support, physical health), infant health (routine medical visits, immunisations, weight gain), morbidity (urgent care visits, emergency room visits, re hospitalisations), and health care charges (urgent care visits, emergency room visits, re-hospitalisations). Data were analysed using descriptive statistics and two-sample t-tests. RESULTS: Intervention group mothers had significantly lower perceived stress, significantly greater perceived maternal health and social support; infants had healthier weight gain, fewer emergency room visits; significantly lower total health care charges ($14,333 vs. $70,834) compared to controls. CONCLUSION: Study results indicate that APN follow up telephone calls to low-income first time mothers with healthy full term infants is an effective, safe, low cost, easy to apply intervention that improved mothers' and infants' health outcomes and reduced healthcare charges. RELEVANCE TO CLINICAL PRACTICE: APNs are uniquely positioned to conduct follow up interventions aimed at providing continuity of care including APN telephone follow up. This is imperative for vulnerable populations especially during times of major budget cuts that affect health care services. PMID- 22845339 TI - How does use of a prescription monitoring program change medical practice? AB - OBJECTIVES: The objectives of this study were to test for differences in prescription monitoring program (PMP) use between two states, Connecticut (CT) and Rhode Island (RI), with a different PMP accessibility; to explore use of PMP reports in clinical practice; and to examine associations between PMP use and clinician's responses to suspected diversion or "doctor shopping" (i.e., multiple prescriptions from multiple providers). DESIGN, SETTING, SUBJECTS: From March to August 2011, anonymous surveys were emailed to providers licensed to prescribe Schedule II medications in CT (N = 16,924) and RI (N = 5,567). OUTCOME MEASURES: PMP use, use of patient reports in clinical practice, responses to suspected doctor shopping, or diversion. RESULTS: Responses from 1,385 prescribers were received: 998 in CT and 375 in RI. PMP use was greater in CT, where an electronic PMP is available (43.9% vs 16.3%, chi(2) = 85.2, P < 0.0001). PMP patient reports were used to screen for drug abuse (36.2% CT vs 10.0% RI, chi(2) = 60.9, P < 0.0001) and detect doctor shopping (43.9% CT vs 18.5% RI, chi(2) = 68.3, P < 0.0001). Adjusting for potential confounders, responses by PMP users to suspicious medication use behavior were more likely to entail clinical response (i.e., refer to another provider odds ratio, OR, 1.75 [95% confidence interval, CI, 1.10, 2.80]; screen for drug abuse OR 1.93 [1.39, 2.68]; revisit pain/treatment agreement OR 1.97 [1.45, 2.67]; conduct urine screen OR 1.82 [1.29, 2.57]; refer to substance abuse treatment OR 1.30 [0.96, 1.75]) rather than legal intervention (OR 0.45 [0.21, 0.94]) or inaction (OR 0.09 [0.01, 0.70]). CONCLUSIONS: Prescribers' use of an electronic PMP may influence medical practice, especially opioid abuse detection, and is associated with clinical responses to suspected doctor shopping or diversion. PMID- 22845338 TI - Regenerative periodontal therapy of infrabony defects using minimally invasive surgery and a collagen-enriched bovine-derived xenograft: a 1-year prospective study on clinical and aesthetic outcome. AB - AIM: To evaluate the clinical and aesthetic outcome of regenerative periodontal therapy (RPT) using minimally invasive surgery and a collagen-enriched bovine derived xenograft (1); to identify risk factors for failure (clinical attachment level (CAL) gain <= 1 mm) and advanced gingival recession (REC) increase (>1 mm) (2). MATERIAL AND METHODS: Ninety-five non-smoking patients, with <= 25% full mouth plaque and bleeding presenting >= 6 months after initial periodontal therapy with >= 1 isolated inter-dental infrabony defect were recruited. Patients were consecutively treated by the same clinician using minimally invasive surgery and a collagen-enriched bovine-derived xenograft. Clinical, radiographic and aesthetic data were collected before surgery and up to 1 year. Multivariate analyses were used to identify risk factors for failure and advanced REC increase. RESULTS: Eighty-four patients (39 men, 45 women; mean age 53) complied and demonstrated mean probing depth (PD) of 7.8 mm, CAL of 10.0 mm and defect depth of 5.2 mm before surgery. At 1 year, postsurgery mean PD reduction was 3.5 mm (range 0.0-8.0), CAL gain was 3.1 mm (range 0.0-7.0) and radiographic defect fill was 53% (range 0-100). Forty-nine percentage showed >= 4 mm CAL gain, whereas 15% were considered failures. Mean inter-dental and midfacial REC increase was 0.3 mm (range-2.0-2.0) and 0.5 mm (range-1.5-2.0) respectively. Midfacial REC increase and contour deterioration contributed most to a small, yet significant reduction in the Pink Esthetic Score from 10.06 to 9.42 (p = 0.002). Risk factors for failure included defects with a non-supportive anatomy (OR: >= 10.4), plaque (OR: 14.7) and complication(s) (OR: 12.0). Risk factors for advanced midfacial REC increase included defects with a non-supportive anatomy (OR: 58.8) and a thin-scalloped gingival biotype (OR: 76.9). CONCLUSIONS: RPT using minimally invasive surgery and a collagen-enriched bovine-derived xenograft demonstrated favourable clinical outcome after 1 year, even though soft tissue aesthetics could not be fully preserved. Defects with a non-supporting anatomy may be at risk for failure and advanced midfacial recession. PMID- 22845340 TI - A quantitative method for determining the antiwashout characteristics of cement based dental materials including mineral trioxide aggregate. AB - AIM: To introduce and assess a novel method for measuring washout resistance of cement-based dental materials, including mineral trioxide aggregate (MTA), to qualitatively verify the results with a clinical simulation and to evaluate the washout resistance of a new root-end filling material. METHODOLOGY: A method for assessment of washout resistance of root-end filling materials was developed by adapting the CRD-C 661-06 (a method for evaluating the resistance of freshly mixed concrete to washout in water), to permit testing of dental cements. White Portland cement (PC), MTA-Plus mixed with either water or a polymer-based antiwashout gel (MTA-AW), MTA-Angelus, IRM and amalgam were tested with either distilled water or HBSS as washout media. Additionally, the washout resistance was tested qualitatively by spraying the test materials at the terminus of simulated canals with a metered jet of water. RESULTS: A mass loss of 2-7% for PC, 0.4-4% for MTA-Plus, -0.9% for MTA-AW, 5-10% for MTA-Angelus and 0% for IRM and amalgam was recorded with the modified CRD-C 661-06 method. No significant difference was found between using water and HBSS as washout media for the same material. The results of the modified CRD-C 661-06 method were similar to those obtained on the simulated canals. CONCLUSIONS: The modified CRD-C 661-06 method provided repeatable results that were comparable to the simulated clinical method. The antiwashout gel used with MTA-Plus reduced the material washout and was similar to IRM and amalgam. PMID- 22845342 TI - Effect of 2,4-dichlorophenoxyacetic acid (2,4-D) on PCDD/F emissions from open burning of biomass. AB - To understand the effect of leaf-surface pesticides on emissions of PCDD/F during biomass burns, nine combustion experiments simulating the open burning of biomass were conducted. Needles and branches of Pinus taeda (Loblolly pine) were sprayed with the pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) at 1 and 10 times the manufacturer's recommended application concentration. The biomass was then dried overnight, burned in an open burn test facility, and emission samples were collected, analyzed, and compared against emission samples from burning untreated biomass. Blank tests and analysis of PCDD/F in the raw biomass were also performed. Emission results from burning a water-sprayed control show a ~20-fold increase in PCDD/F levels above that of the raw biomass alone, implicating combustive formation versus simple volatilization. Results from burns of pine branches sprayed with pesticide showed a statistically significant increase in the PCDD/F TEQ emissions when burning biomass at ten times the recommended pesticide concentration (from 0.22 to 1.14 ng TEQ/kg carbon burned (C(b)), both ND = 0). Similarly, a 150-fold increase in the total PCDD/F congener mass (tetra- to octa-chlorinated D/F) above that of the control was observed (from 52 to 7800 ng/kg C(b)), confirming combustive formation of PCDD/F from 2,4-D. More replicate testing is needed to evaluate effects at lower pesticide concentrations. PMID- 22845341 TI - Effect of raloxifene and atorvastatin in atherosclerotic process in ovariectomized rats. AB - AIM: The goal of this study was to investigate the combined effects of raloxifene and atorvastatin in aged ovariectomized rats during endothelial dysfunction and atherosclerotic process. MATERIAL AND METHODS: This study was conducted on 28 Wistar albino female rats randomly divided into four groups. All groups were ovariectomized and one group was kept as the control group (OVX). For four weeks, the remaining three groups were treated with the statin atorvastatin (OVX+AV), the selective estrogen receptor modulator raloxifene (OVX+RL), and both atorvastatin and raloxifene (OVX+RL+AV), respectively. At the end of the treatment period, all rats were sacrificed and thoracic aortas excised, and endothelial cells were immunohistochemically stained for markers in the atherosclerotic process, such as inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-alpha). RESULTS: Compared to the ovariectomized group, the iNOS level was significantly increased in the OVX+RL group (P=0.002), but contrarily decreased in the groups OVX+AV (P=0.002) and OVX+RL+AV (P=0.002). eNOS levels in the groups OVX+AV (P=0.002) and OVX+RL+AV (P=0.002) were significantly lower than that in the OVX group. When compared to the OVX group, significant reductions in ET-1 and TNF alpha levels were found in all treatment groups. A significant decrement in MCP-1 level was found in the OVX+AV group (P=0.002). CONCLUSION: In aged ovariectomized rats, the administration of both raloxifene and atorvastatin significantly decreased the levels of ET-1 and TNF-alpha on endothelial cells. Combined treatment with these drugs shortly after menopause might play a potential preventive role in the early stages of atherosclerosis development. PMID- 22845343 TI - Management of chickenpox with frozen mother's milk. AB - OBJECTIVES: If a mother has contracted chickenpox, the antibodies in her milk confer immunity against chickenpox to her breastfed babies. This passive immunization may avoid or spare the breastfed babies' symptoms of chickenpox. It is hypothesized that frozen breast milk may shorten chickenpox duration because specific antibodies against varicella zoster have been detected in human milk and they are resistant to digestion and are stable in frozen milk. DESIGN: The clinical outcomes of chickenpox in a 9-year-old boy and his father on frozen breast milk are reported. SETTINGS: The study comprised a varicella-vaccine refusing family attending a private office of pediatrics. INTERVENTIONS AND RESULTS: The boy presented with a crusted varicella rash. The medical history revealed premature cessation of the typical varicella rash on day 3. It was coincidental with a supply of frozen human milk by his mother. Next, the father (41 years old) of this patient contracted chickenpox: he was on frozen breast milk from day 2, and no new pox emerged thereafter. CONCLUSIONS: The rash spread and numbered 50 to 150 lesions on day 2. Instead, the typical rash was expected to appear in three successive crops of lesions throughout the first week. The disease usually numbers approximately 250-500 lesions in unvaccinated healthy persons. Frozen breast milk may shorten chickenpox duration. PMID- 22845344 TI - Dehalogenation of diverse halogenated substrates by a highly enriched Dehalococcoides-containing culture derived from the contaminated mega-site in Bitterfeld. AB - An enrichment culture dominated by one type of Dehalococcoides sp. (83% of clones) was characterised. This culture, originally derived from contaminated groundwater from the area of Bitterfeld-Wolfen (Saxony-Anhalt, Germany), dehalogenates chlorinated ethenes to ethene. Further, the culture also dehalogenated vinyl bromide (VB) and 1,2-dichloroethane (DCA) to ethene, 1,2,3,4- and 1,2,3,5-tetrachlorobenzene (TeCB), penta- and hexachlorobenzene (PeCB and HCB) to trichlorobenzenes (TCB), lindane to monochlorobenzene (MCB) and pentachlorophenol (PCP) to 2,3,4,6-tetrachlorophenol (TeCP). Growth was proven by quantitative PCR for all active cultures, except for those with TeCB, lindane and PCP. The growth yields obtained ranged from (2.9 +/- 0.7) * 10(7) cells MUmol(-1) Br(-) released on VB to (34.8 +/- 5.4) * 10(7) cells MUmol(-1) Cl(-) released on VC. Genes coding for nine putative reductive dehalogenases, the enzymes that mediate the respiratory process of dehalogenation, were identified. Phylogenetic analysis revealed eight reductive dehalogenases with similar sequences in other Dehalococcoides strains and one unique sequence. PMID- 22845345 TI - Thoracoscopic-assisted four-phase esophagectomy with four-field lymph node dissection for esophageal cancer: case report and description of a new technique. AB - Complete (R0) resection and extent of lymphadenectomy are important prognostic factors for survival in patients undergoing surgery for esophageal carcinoma. We describe the first case of combined open and thoracoscopic esophagectomy with extended lymphadenectomy including abdominal, cervical, right, and left mediastinal (four-field, four-phase) nodal clearance in a 37-year-old woman with squamous cell carcinoma of the esophagus. This report provides a tailored strategy to achieve a high level of tumor clearance and complete resection. The approach described challenges the limitations of standard radical nodal clearance and may encourage surgeons to consider more extensive resections. PMID- 22845394 TI - A three-dimensional finite element analysis for overdenture attachments supported by teeth and/or mini dental implants. AB - PURPOSE: The aim of this study was to establish the optimum design and attachment combination to support an overdenture with minimal stress and flexing produced in the alveolar bone surrounding any natural teeth and/or mini dental implants. MATERIALS AND METHODS: Twelve models were included in the study: the six main models (A, B, C, D, E, and F) were categorized according to the support designs of the overdenture prosthesis, and each model was further subdivided according to the attachment combinations into model 1: with Dalbo elliptic and/or O-ring attachments only and model 2: with flexible acrylic attachments. Vertical loads (35 N) and 17.5 N lateral loads under static conditions were applied to the models to simulate the occlusal forces following the concept of lingualized occlusion. All conditions were created using a finite element software program. Maximum von Mises stress at the level of the attachments and at the bone support foundation interfaces were compared in all 12 models. The flexing of the mandible and the attachments were also compared qualitatively. RESULTS: Stress on these models was analyzed after the given loading condition. The results showed that the model with three freestanding mini dental implants and flexible acrylic attachments showed the lowest von Mises stress and flexing, while the models with four freestanding mini dental implants and O-ring attachments showed the highest von Mises stress. CONCLUSION: Three freestanding mini dental implants with flexible acrylic attachment systems supporting an overdenture were better choices than four mini dental implants with O-ring attachment systems, which showed the maximum flexing and stress values in this qualitative comparison. PMID- 22845346 TI - Modulation of vaccine response by concomitant probiotic administration. AB - Evidence suggests that probiotic bacteria modulate both innate and adaptive immunity in the host, and in some situations can result in reduced severity of common illnesses, such as acute rotavirus infection and respiratory infections. Responses to vaccination are increasingly being used to provide high quality information on the immunomodulatory effects of dietary components in humans. The present review focuses on the effect of probiotic administration upon vaccination response. The majority of studies investigating the impact of probiotics on responses to vaccination have been conducted in healthy adults, and at best they show modest effects of probiotics on serum or salivary IgA titres. Studies in infants and in elderly subjects are very limited, and it is too early to draw any firm conclusions regarding the potential for probiotics to act as adjuvants in vaccination. Although some studies are comparable in terms of duration of the intervention, age and characteristics of the subjects, most differ in terms of the probiotic selected. Further well designed, randomized, placebo-controlled studies are needed to understand fully the immunomodulatory properties of probiotics, whether the effects exerted are strain-dependent and age-dependent and their clinical relevance in enhancing immune protection following vaccination. PMID- 22845397 TI - The quality of clinical practice guidelines in China: a systematic assessment. AB - BACKGROUND: Clinical guidelines are an important tool for improving service quality, the benefits of guidelines depend on their quality. In China, there has been a great increase in production of guidelines. However, little is known about their quality. METHOD: We identified Chinese guidelines published between 2006 and 2010 by searching three Chinese full-text databases, major Chinese guidelines websites and Google. Three appraisers independently evaluated each guideline by using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Subgroup analyses were performed according to source, title, version, aspect of care and developer of guidelines. RESULTS: A total of 327 guidelines were eligible and 57 were excluded for their lacking of any account of the guideline development methodology. Of the 270 guidelines, 77 (28.5%) can be recommended, 6 (2.2%) were evidence-based guidelines. Sixteen (5.9%) guidelines described the methods used to search for evidence, 61 (22.6%) appraised the quality of evidence and 53 (19.6%) graded the strength of recommendations. Two guidelines declared the involvement of methodological experts and none reported considering patients' values. 29 (10.7%) guidelines received drug company sponsorship but only two declared the views of the funding bodies did not influence the recommendations, 259 (95.9%) didn't declare the interest conflicts of guideline developers. Guidelines downloaded from Internet and with updated versions yielded higher quality than the rest. CONCLUSIONS: Although numerous guidelines were produced in China, the quality was generally low. Focusing on improving the quality of Chinese guidelines, rather than continuing to produce them in great quantity, is urgently needed. PMID- 22845398 TI - Tumor microenvironment regulates epithelial-mesenchymal transitions in metastasis. PMID- 22845399 TI - Targeted therapy: overcoming drug resistance with clinical cancer genome. PMID- 22845396 TI - The case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening. AB - The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease- and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology. PMID- 22845401 TI - Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice? AB - BACKGROUND AND AIMS: Prospective randomized trials have proven that sorafenib is a valid treatment option for patients with advanced-stage hepatocellular carcinoma (HCC). The aim of the present study is to evaluate the effectiveness and safety of sorafenib in patients encountered in routine clinical practice. METHODS: From September 2008 to March 2011, 42 cirrhotic patients (30 male; 12 female; mean age: 70.2 +/- 7.6 years; range: 56-85 years) with HCC of Barcelona Clinic Liver Cancer stage B (n = 5) or C (n = 37; mean size: 66.6 +/- 42.3 mm; mean number per patient: 3.3 +/- 2.8) were treated with sorafenib at either a standard dose of 800 mg/day (n = 29; 69.1%) or at 400 mg/day with subsequent dose escalation (ramp-up strategy; n = 13, 30.9%). Baseline clinical parameters were comparable. Clinical data and side effects, laboratory analyses (in particular, serum alpha-fetoprotein) and radiological data (tumor response according to amended RECIST criteria) were assessed every 3 months. Survival was calculated by Kaplan-Meier analysis. RESULTS: Mean follow-up was 12.2 +/- 9 months (range: 1-32 months). Median overall survival was 26.1 months with overall 6- and 12-month survival rates of 92.1 and 85%, respectively. Median time to radiological progression was 8 months. The progression-free rate was 64.3%. Fatigue, skin disorders and diarrhea were the most frequent grade 3-4 side effects. Treatment discontinuation occurred in 25 patients. The starting dose for the last 13 enrolled patients was 400 mg/day; in the absence of toxicity this dosage was gradually increased to 800 mg/day after 3 weeks ('ramp-up strategy'). No grade 3/4 adverse events were observed in the ramp-up group. CONCLUSION: Sorafenib is a valid treatment option for advanced-stage HCC. Starting at a lower dosage may allow prolonged compliance to treatment and might be considered according to patient tolerance. PMID- 22845402 TI - New frontiers in therapeutic resistance in cancer. AB - Despite advances in personalized medicine and targeted therapies, therapeutic resistance remains a persistent dilemma encountered by clinicians, scientists and patients. In this article we summarize the highlights of the third Quebec Conference on Therapeutic Resistance in Cancer. This unique meeting provided researchers and clinicians with insights into: intrinsic and acquired resistance; tumor heterogeneity; complexities of biomarker-driven trials; challenges of 'omics data analysis; and models of clinical applications of personalized medicine. Emphasized throughout the conference was the importance of collaborations - between industry and academia, and between basic researchers and clinicians - so that therapeutic resistance can be studied where it matters most, in patients. PMID- 22845403 TI - Loss of miR-126 is crucial to pancreatic cancer progression. AB - The tumor-suppressor miRNA 126 (miR-126) is downregulated in many tumors and has recently been placed at the heart of complex metastatic pathways. Hamada and colleagues have identified miR-126 as being downregulated in pancreatic ductal adenocarcinoma (PDAC) patient samples and cell lines. The protein ADAM9 has been implicated in the progression of various solid tumors including PDAC. ADAM9 is overexpressed in PDAC and also a direct target of miR-126. The miR-126/ADAM9 axis was subsequently established to control migration and invasion in PDAC, as well as reversal of epithelial-to-mesenchymal transition. miR-126 is also known to target other crucial oncogenes in PDAC such as KRAS and CRK. Replacing miR-126 in PDAC patients may be a novel strategy for preventing progression and metastasis. PMID- 22845404 TI - Hormonal therapy in gynecological sarcomas. AB - Gynecological sarcomas are rare, constituting 3-5% of uterine malignancies. Endometrial stromal sarcomas and some uterine leiomyosarcomas are characterized by estrogen receptor (ER) and progesterone receptor (PgR) expression with variable impact on their clinical behavior and potential response to systemic therapies. A variety of hormonal treatments have been tested, since they act as targeted treatment against ER and PgR and have a tolerable side effect profile, which allows them to be administered for prolonged periods. Their role has been studied more extensively in endometrial stromal sarcomas, as the majority of cases are ER/PgR positive, while recently, an emerging role for hormonal manipulation has been described in ER/PgR-positive uterine leiomyosarcomas. Owing to the rarity and heterogeneous nature of uterine sarcomas, current treatment recommendations are based on small retrospective studies and case reports. This review comprises a critical appraisal of the existing data regarding hormonal manipulation in uterine sarcomas and attempts to make recommendations for endocrine treatments in specific settings, as well as suggest targets/medications for future research. PMID- 22845405 TI - Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. AB - The outcome of ovarian cancer remains poor with conventional therapy. Intraperitoneal chemotherapy has some advantages over systemic chemotherapy, including favorable pharmacokinetics and optimal treatment timing. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) provides improved exposure of the entire seroperitoneal surface to the agent and utilizes the direct cytoxic and drug-enhancing effect of hyperthermia. While standard normothermic, nonintraoperative, intraperitoneal chemotherapy has been demonstrated to be beneficial in randomized trials and meta-analyses, there are no data from randomized HIPEC trials available yet. Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. Data from ongoing randomized HIPEC trials to adequately answer the question of whether the addition of HIPEC actually prolongs survival in patients with peritoneal dissemination of primary and recurrent ovarian cancer are awaited in the near future. PMID- 22845406 TI - Robotic-assisted radical cystectomy: current technique and outcomes. AB - Robotic-assisted radical cystectomy continues to evolve as a surgical option in the management of muscle-invasive bladder cancer. Current oncologic outcomes appear comparable in the short-term with open radical cystectomy. Long-term follow-up, however, remains lacking for this emerging technique. Modern robotic technology allows a comparable extent of pelvic lymph node dissection as open surgery, a previous criticism of the procedure. Complications compare very favorably to open surgery in comparative series, and blood loss and transfusion rates are routinely lower. Length of stay has been shortened in some series, though not uniformly. Finally, robotic assistance can increase the cost of radical cystectomy. PMID- 22845407 TI - Treating patients with metastatic renal carcinoma: an escape from Phase III. AB - The wide availability of drugs for the treatment of advanced renal cell carcinoma has recently provided many alternatives for patients historically treated with immunotherapy alone. The six drugs currently available for the treatment of metastatic renal cell carcinoma became available to physicians after the approval processes performed by regulatory agencies, based mainly on the results of Phase III studies. Owing to the stringent entry criteria of the studies, patients are not representative of the entire population. Results of Phase III studies are extrapolated to all renal cell carcinoma populations without taking into account patients with different comorbidities. The purpose of this review is to analyze and weigh the safety data available for the drugs approved for metastatic renal cell carcinoma and to suggest the best therapy in terms of both efficacy and safety based on the multiplicity of features of each patient in relation to the main characteristics of each agent. PMID- 22845408 TI - Recent advances in urinary bladder cancer detection. AB - Urinary bladder cancer (BCa) is the most common malignancy of the urinary tract. In recent decades, the overall incidence of BCa appears to be on the increase. Despite the increase in incidence, mortality rates in North America and Europe appear to have declined in the last decade, probably due to improved detection and treatment. The mainstay of diagnosis is by cystoscopy, aided with imaging and urine tests (e.g., cytology). This article reviews the recent advances made in detection of primary and recurrent bladder cancer. PMID- 22845410 TI - Current and emerging treatments in the management of castration-resistant prostate cancer. AB - Historically, patients diagnosed with castration-resistant prostate cancer (CRPC) have had poor survival rates. In recent years there have been significant advances in the treatment of CRPC. In addition to cytotoxic chemotherapy, treating physicians and their patients now have the option of several new agents that target not only androgen- and cytotoxic-mediated pathways, but also the patient's own immune system. In this review, we discuss the existing US FDA approved therapies, a wide range of experimental treatments that are currently in development, and also palliative options for patients with symptoms secondary to metastatic disease. We also discuss the progression-free survival, overall survival, PSA levels and other end points used in clinical trials in order to evaluate and compare novel therapeutic options for CRPC. Currently, docetaxel and sipuleucel-T are the first line treatment options for patients with CRPC; approved second-line treatments for first line treatment failure are limited to cabazitaxel and abiraterone acetate. Recently, a few experimental agents, MDV3100 and radium-223, have demonstrated efficacy in improving overall survival in patients who had previously failed chemotherapy. These agents, and possibly others introduced in this review, are positioned to change the treatment landscape for CRPC. PMID- 22845411 TI - Hypofractionated radiotherapy in prostate cancer. AB - In regards to prostate cancer, the classic radiotherapy dose ranges from 70-80 Gy, administered in daily 2-Gy fractions. However, when taking into account the particular radiobiological model of prostate cancer cells, one realizes that there is a potential theoretical advantage to delivering a greater biological effective dose per treatment in a lower number of fractions. Both recent and older publications have attempted to explore this treatment option. This critical review comprehensively examines the current state of knowledge concerning hypofractionated radiotherapy in prostate cancer. PMID- 22845409 TI - Contemporary management of muscle-invasive bladder cancer. AB - The current standard treatment for muscle-invasive nonmetastatic bladder cancer is neoadjuvant platinum-based chemotherapy followed by radical cystectomy. However, neoadjuvant chemotherapy is not widely accepted even with level 1 evidence. Adjuvant chemotherapy should be discussed if patients have not received neoadjuvant chemotherapy before surgery and have high-risk pathologic features. Although not considered standard of care, bladder-sparing therapy can be considered for highly selected patients and for those medically unfit for surgery. Even though there are no level 1 data, the treatment outcomes for highly select patients given bladder-sparing therapy appear promising, with many patients retaining a functional bladder. Personalized chemotherapy is currently being actively pursued to target the underlying molecular changes and tailor to individual needs. PMID- 22845412 TI - Radiotherapy following radical prostatectomy. AB - Radiotherapy following radical prostatectomy has been controversial and no consensus has developed on the most appropriate use of radiotherapy after radical prostatectomy. In the last decade the results of three randomized controlled trials examining the effects of early radiotherapy after radical prostatectomy in patients with high-risk features (positive surgical margins, extracapsular extension and seminal vesical involvement) have been published. The results of these trials indicate that early radiotherapy changes the natural history of high risk prostate cancer. Specifically, early radiotherapy reduces the risk of biochemical recurrence, improves clinical disease-free survival, decreases the utilization of salvage androgen suppression and, in the study with longest follow up, early radiotherapy improves overall survival. This article will review the evidence, provide a commentary on the existing evidence, and describe key issues going forward (timing of radiotherapy, androgen suppression and radiotherapy techniques). PMID- 22845413 TI - Dyslipidemia, statins and prostate cancer. AB - Dyslipidemia and prostate cancer are two of the most common medical conditions affecting adult males in the USA. In recent years, a large volume of research has focused on investigating the relationship between these two disease processes as well as the effect of the cholesterol-lowering medications, such as 3-hydroxyl-3 methylglutaryl-coenzyme A reductase inhibitors (better known as 'statins'), on the development and progression of prostate cancer. While there is a paucity of prospective research, encouraging results have been reported in several retrospective clinical studies. Additionally, basic science research has identified interactions between lipids and prostate cancer cells in several key areas. This article will discuss recent clinical and basic science research examining the relationship between dyslipidemia, statins and prostate cancer. PMID- 22845415 TI - Dextranomer in stabilized sodium hyaluronate (Solesta(r)): in adults with faecal incontinence. AB - Dextranomer in stabilized sodium hyaluronate, hereafter referred to as dextranomer/hyaluronic acid, is a biocompatible bulking agent administered by submucosal injection. It is hypothesized to expand the submucosal layer of the proximal anal canal, thereby augmenting bowel control. Treatment with dextranomer/hyaluronic acid was associated with symptomatic improvements in adult patients with faecal incontinence participating in a randomized, double-blind, sham-controlled, multinational study and a noncomparative, multinational study. In the double-blind study, patients in the dextranomer/hyaluronic acid group met the primary efficacy objective in that a significantly higher proportion of patients responded to treatment (>=50% reduction from baseline in the number of incontinence episodes) at the 6-month post-treatment timepoint than in the sham group (two of three primary response criteria), with the durability of the treatment response (>=25% reduction from baseline in the number of incontinence episodes) confirmed at the 12-month post-treatment timepoint (third primary response criterion). For the most part, dextranomer/hyaluronic acid did not significantly differ from the sham treatment in terms of quality of life and various other symptomatic endpoints at 6 months post-treatment in the double blind study, although there were significant improvements from baseline in various parameters, such as the mean number of incontinence-free days, the median number of incontinence episodes and mean Faecal Incontinence Quality of Life domain scores, at 12 months post-treatment. In general, dextranomer/hyaluronic acid was well tolerated for up to 18 months post-treatment, with the majority of treatment-related adverse events considered mild or moderate in intensity. PMID- 22845417 TI - Statement of Retraction. PMID- 22845416 TI - The cause(s) of myopia and the efforts that have been made to prevent it. AB - In spite of a long history of study, as well as a significant, recent increase in research attention, the cause(s) and the means of preventing or mitigating the progression of myopia in children are still elusive. The high and growing prevalence of myopia, especially in Asian populations, as well as its progressive nature in children and its effect on visual acuity, have contributed to the recent surge in interest. Animal research carried out in the 1970s also helped spark this interest by legitimising the study of environmental influences on the refractive development of the eye. Efforts that include the use of visual training or biofeedback, bifocal and progressive lenses, contact lenses and pharmaceuticals are reviewed. Current research trends that focus on the relationship between genetics and environment, as well as studies, both animal and human, that explore the effect of peripheral refractive error on the refractive development of the central retina are also reviewed. PMID- 22845418 TI - Skill qualities as risk factors for contact injury in professional rugby league players. AB - We investigated the relationship between skill qualities and contact injury risk in professional rugby league players. Sixty-six professional rugby league players aged 23 +/- 4 years (mean +/- s) participated in this three-year prospective study. Players underwent assessments of tackling proficiency, dual-task draw-and pass proficiency, reactive agility, pattern recall, and pattern prediction. The frailty model was applied to calculate the adjusted risk ratios of injury. When the players' age and playing position were adjusted in the frailty model, the risk ratios showed that reactive agility was a predictor for the risk of injury. Players with reactive agility decision times of >80 ms had a lower incidence (relative risk = 0.68, 95% CI 0.47-0.98, P = 0.04) of injuries than players with reactive agility decision times of <= 80 ms. Although there was no relationship between injury and the majority of skill qualities (P = 0.47-0.93), players with poor reactive agility performances (specifically longer decision times) had a lower risk of injury, suggesting that poor perceptual skill is protective against contact injuries in professional rugby league players. These players might inadvertently avoid the heavy collisions that result in injury, or at best result in partial contact that does not result in exposure to the full force of a tackle. PMID- 22845419 TI - Electrical isolation of the superior vena cava using upstream phrenic pacing to avoid phrenic nerve injury. AB - BACKGROUND: Phrenic nerve (PN) injury is a potential complication that can occur during superior vena cava (SVC) isolation to cure atrial fibrillation (AF). Avoiding radiofrequency (RF) energy delivery is the safer alternative but may result in failed isolation. High-output PN pacing above the ablation site (upstream PN pacing) to confirm whether the PN is intact is a promising technique to avoid PN injury. This study was conducted to elucidate the safety of delivering RF energy at the site of capture of the right PN using upstream high output pacing during electrical SVC isolation. METHODS: SVC isolation was conducted in 41 drug-resistant AF patients. When high-output pacing (25 mA) from the distal tip of the ablation catheter captured the PN at the right atrial-SVC junction, upstream PN pacing (cycle length: 1000-1500 ms) was applied during RF delivery. The application of RF energy was stopped upon the failure or weakness of diaphragmatic twitching. The feasibility of SVC isolation using upstream PN pacing was investigated. RESULTS: In all 41 patients, SVC isolation was successfully achieved. RF energy was delivered at the PN capture site in 26 patients (154 +/- 138 second, 18 +/- 5 W), and upstream PN pacing was successfully applied in all of the patients. Out of 46 SVC isolations, including five repeated sessions, PN injury occurred in one patient, who recovered spontaneously within 2 weeks. CONCLUSIONS: Upstream PN pacing may be effective for the safe completion of SVC isolation and to reduce the severity of PN injury. PMID- 22845420 TI - Diazoxide may protect endothelial glycocalyx integrity during coronary artery bypass grafting. AB - OBJECTIVES: Plasma hyaluronan and syndecan-1 levels represent shedding of the endothelium glycocalyx during ischemia and edema. Diazoxide, a K(ATP)-channel opener, has been shown to decrease myocardial edema during coronary artery bypass grafting (CABG). We evaluated whether diazoxide exerts an impact on plasma hyaluronan and syndecan-1 levels during CABG. DESIGN: Representative blood samples for hyaluronan and syndecan-1, before, during and after surgery, were obtained in 13 out of 16 patients that had a history of stable coronary artery disease undergoing CABG with or without diazoxide. Electron microscopy from biopsies procured from the right atrium in 9 patients was performed to confirm ultrastructural differences among patients before and during CABG. RESULTS: Ultrastructural differences were apparent between individual patients already before operation at base line reflecting differences in the severity of myocardial ischemia and edema. A significant decrease of hyaluronan and syndecan 1 values was observed in patients with diazoxide after surgery (p < 0.04). Significant correlation of plasma hyaluronan and syndecan-1 levels was observed in patients with diazoxide but not in controls (p < 0.005, Spearman rank rho). CONCLUSION: Diazoxide may have an impact on levels of peripheral plasma hyaluronan and syndecan-1 after CABG, suggesting decreased shedding of the endothelial glycocalyx layer. PMID- 22845421 TI - A single session of motivational interviewing as an additive means to improve adherence in periodontal infection control: a randomized controlled trial. AB - AIM: To evaluate the effect of a single session of motivational interviewing (MI) on self-performed periodontal infection control. MATERIAL AND METHODS: A randomized, examiner masked, controlled clinical trial of 6-month duration was performed involving 44 patients with chronic periodontitis, referred for periodontal treatment. At baseline, all subjects were examined concerning marginal gingival bleeding (MBI) and plaque (PI). Test subjects received a single MI-session before initiation of the periodontal treatment. Otherwise, all patients followed the same treatment protocol for conventional educational intervention and non-surgical periodontal therapy. Efficacy variables for evaluation of self-performed periodontal infection control were MBI (primary variable) and PI. RESULTS: The MI intervention resulted in a negligible decrease (3-4%) in MBI and PI that was not significantly different from the changes observed in the control group without any intervention. Neither was any additive effect of the initial MI-session found on the standard of oral hygiene subsequent to conventional treatment. A desirable MBI score of <=20% at the end of treatment was associated with being a female patient, whereas high plaque scores at baseline counteracted a corresponding desirable final PI of <=20%. CONCLUSION: A single freestanding MI session as a prelude to conventional periodontal treatment had no significant effect on the individuals' standard of self-performed periodontal infection control in a short-term perspective. PMID- 22845422 TI - The influence of adverse reactions, subjective distress, and anxiety on retention of first-time blood donors. AB - BACKGROUND: This study investigated the effects of adverse events (i.e., needle reactions, fatigue, and vasovagal reactions) and feelings of distress and anxiety on retention of first-time blood donors. All effects were explored separately for men and women. STUDY DESIGN AND METHODS: First-time blood donors (n = 2438) received a questionnaire, asking them about their experience of adverse events, subjective distress, and anxiety at their first donation. Provision of a second donation was checked approximately 18 months later. After exclusion of nonresponders and donors who did not experience an adverse event, 1278 first-time donors were included in the logistic regression analyses. RESULTS: Nine percent of donors who experienced an adverse event at their first donation did not return for a second donation. Vasovagal reactions decreased retention in both males and females (men-odds ratio [OR], 0.45; 95% CI, 0.23-0.89; women-OR, 0.71; 95% CI, 0.51-0.98). Fatigue decreased retention in males only (OR, 0.62; 95% CI, 0.42 0.91), and subjective distress decreased retention in females only (OR, 0.77; 95% CI, 0.65-0.92). CONCLUSION: In addition to decreasing vasovagal reactions, retention interventions could productively target coping with fatigue and reducing subjective distress after adverse reactions. PMID- 22845423 TI - Bilateral ovarian involvement: a rare presentation of disseminated multiple myeloma. AB - Extramedullary spread of multiple myeloma is extremely rare. This paper reports a case of bilateral ovarian involvement in plasma cell myeloma. The patient was a 48-year-old Persian woman who experienced constitutional symptoms, bone pain and flashing for one year. Her condition showed multiple myeloma with lytic lesions of the skull, plasma cell infiltration in bone marrow and positive light chain lambda type in serum. Workup showed huge bilateral ovarian masses, and ovarian metastasis from plasma cell myeloma was confirmed after pathologic assessment. Multiple myeloma spread to ovary is rare and according to our knowledge, this is the fourth reported case of bilateral ovarian involvement in extramedullary multiple myeloma. PMID- 22845424 TI - Stochasticity of TOL plasmid catabolic promoters sets a bimodal expression regime in Pseudomonas putida mt-2 exposed to m-xylene. AB - The expression dynamics of the catabolic promoters of the TOL plasmid pWW0 has been examined in single cells of Pseudomonas putida mt-2 exposed to m-xylene. To this end, we employed an a la carte bi-cistronic gfp-lacZ reporter system for generating monocopy transcriptional fusions to each of the four promoters (Pr, Ps, Pu and Pm) of the regulatory network. Whereas expression of xylR (the master regulatory gene of the TOL system) behaved in a unimodal fashion, the activation of Pu and Pm displayed a high degree of stochasticity. This event resulted in a time-dependent shift in the bacterial population between two induction states without intermediate expression levels. Bimodality of the Pm promoter for the lower TOL pathway was largely due to the propagation of the Ps output throughout the network, which caused stochastic overproduction of the second regulator of the system, XylS. Surprisingly, activation of Pm by the form of XylS that was bound to the pathway intermediate 3-methylbenzoate was relatively minor. These stochastic phenomena in response to m-xylene disappeared in the stationary phase. Taken together, the data suggests that genetically homogeneous populations of P. putida mt-2 employ a strategy of phenotypic variation (metabolic bet-hedging) when confronted with mixtures of nutrients. PMID- 22845425 TI - Pulsed radiofrequency application reduced mechanical hypersensitivity and microglial expression in neuropathic pain model. AB - OBJECTIVE: Pulsed radiofrequency (PRF) procedure has been used in clinical practice for the treatment of chronic neuropathic pain conditions without neuronal damage. The purpose of this study was to investigate the changes in pain response and glial expression after the application of PRF on a dorsal root ganglion (DRG) in a neuropathic pain model. DESIGN: A neuropathic pain model (14 female Sprague-Dawley [SD] rats; 200-250 g) was made by a unilateral L5 spinal nerve ligation (SNL) and transection on the distal side of the ligation. The development of mechanical and cold hypersensitivity on the hindpaw was established postoperative day 9 (POD 9). The rats were then randomly assigned to the PRF (+) and the PRF (-) groups. Furthermore, PRF (2 bursts/s, duration = 20 milliseconds, output voltage = 45 V) was applied on the ipsilateral DRG for 180 seconds, with a maximum temperature of 42 degrees C, at POD 10. Pain behaviors were tested throughout the 12 days after PRF. We also examined the changes of the spinal glial expression by immunohistochemistry. RESULTS: Significant reduction of mechanical hypersensitivity in the PRF (+) group was observed from day 1 after a single PRF procedure and was maintained throughout the following 12 days. Immunoreactivity for OX42 in the ipsilateral dorsal horn also decreased compared with that of the PRF (-) group. However, cold hypersensitivity and glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn was not affected by a PRF procedure. CONCLUSIONS: Our result demonstrated that the mechanical hypersensitivity, induced by L5 SNL, was attenuated by a PRF procedure on the ipsilateral DRG. This analgesic effect may be associated with an attenuation of the microglial activation in the dorsal horn. PMID- 22845426 TI - New species of insect trypanosomatids from Costa Rica and the proposal for a new subfamily within the Trypanosomatidae. AB - Several new species of trypanosomatids (Euglenozoa, Kinetoplastea, Trypanosomatidae), isolated from the intestines of Neotropical insects (Heteroptera), were genotyped on the basis of spliced leader RNA, and also defined phylogenetically using gene sequences of small subunit ribosomal RNA and glycosomal glyceraldehyde phosphate dehydrogenase. The taxonomic descriptions also included characterization using morphometry and electron microscopy. Our phylogenetic analyses placed the new species within the clade, previously designated "SE" for "Slowly Evolving" sequences of ribosomal RNA genes, a clade that also includes numerous monoxenous parasites of insects from the genera Crithidia, Leptomonas, and Wallaceina, as well as the dixenous genus Leishmania. Based on the high phylogenetic support for this clade, which is consistently recovered in all recent phylogenetic reconstructions, a proposal is put forward to recognize this natural taxon as a new subfamily, Leishmaniinae, within the family Trypanosomatidae. PMID- 22845427 TI - Use of evidence-based therapy for the secondary prevention of acute coronary syndromes in Malaysian practice. AB - RATIONALE: Despite the availability of various prevention guidelines on acute coronary syndrome (ACS), secondary prevention practice utilizing aspirin, beta blockers, angiotensin converting enzyme inhibitors and statins still can be sub optimal. AIMS AND OBJECTIVES: To review and document the utilization of pharmacotherapy for the secondary prevention of ACS in patients discharged from a Malaysian hospital. METHODS: A retrospective cross-sectional study was conducted at a tertiary hospital in Penang, Malaysia. Patients with a primary diagnosis of ACS were identified from medical records over a 4-month period. A range of clinical data was extracted from medical records, including medical history, clinical presentation and pharmacotherapy both on admission and at discharge. This audit focused on the use of four guideline-recommended therapies: aspirin +/ clopidogrel, beta-blockers, statins and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blockers (ARBs). RESULTS: Data pertaining to a total of 380 ACS patients was extracted and reviewed, the mean age of the study population was 57.49 years and 73.9% of population was males. Patients with unstable angina accounted for 56.6% of the admissions whereas 23.4% and 20% of the patients were admitted for ST-elevation myocardial infarction and non-ST segment elevation infarct respectively. 95.7% of the patients received antiplatelets comprising of at least aspirin, and 82% received aspirin plus clopidogrel. Furthermore, 80.3% of the patients received a beta-blocker at discharge, 95% a statin and 69.7% received either an ACEI or ARB. Compared with patients who presented with myocardial infarction (with or without ST-segment elevation), those presenting with unstable angina were less likely to receive the combination of aspirin plus clopidogrel or an ACEI/ARB at discharge. Patients over 65 years of age were also less likely to receive a beta-blocker at discharge, compared with younger patients. CONCLUSIONS: There is a good adherence to evidence-based guidelines for the secondary prevention of ACS in this local setting. However, there is some potential underutilization in the older population and patients presenting with unstable angina. PMID- 22845464 TI - Reactivity of rhodium(I) complexes bearing nitrogen-containing ligands toward CH3I: synthesis and full characterization of neutral cis-[RhX(CO)2(L)] and acetyl [RhI(MU-I)(COMe)(CO)(L)]2 complexes. AB - The neutral rhodium(I) square-planar complexes [RhX(CO)(2)(L)] [X = Cl (3), I (4)] bearing a nitrogen-containing ligand L [diethylamine (a), triethylamine (b), imidazole (c), 1-methylimidazole (d), pyrazole (e), 1-methylpyrazole (f), 3,5 dimethylpyrazole (g)] are straightforwardly obtained from L and [Rh(MU X)(CO)(2)](2) [X = Cl (1), I (2)] precursors. The synthesis is extended to the diethylsulfide ligand h for 3h and 4h. According to the CO stretching frequency of 3 and 4, the ranking of the electronic density on the rhodium center follows the order b > a ~ d > c > g > f ~ h > e. The X-ray molecular structures of 3a, 3d 3f, 4a, and 4d-4f were determined. Results from variable-temperature (1)H and (13)C{(1)H} NMR experiments suggest a fluxional associative ligand exchange for 4c-4h and a supplementary hydrogen-exchange process in 4e and 4g. The oxidative addition reaction of CH(3)I to complexes 4c-4g affords the neutral dimeric iodo bridged acetylrhodium(III) complexes [RhI(MU-I)(COCH(3))(CO)(L)](2) (6c-6g) in very good isolated yields, whereas 4a gives a mixture of neutral 6a and dianionic [RhI(2)(MU-I)(COCH(3))(CO)][NHMeEt(2)](2) and 4h exclusively provides the analogue dianionic complex with [SMeEt(2)](+) as the counterion. X-ray molecular structures for 6d(2) and 6e reveal that the two apical CO ligands are in mutual cis positions, as are the two apical d and e ligands, whereas isomer 6d(1) is centrosymmetric. Further reactions of 6d and 6e with CO or ligand e gave quantitatively the monomeric complexes [RhI(2)(COCH(3))(CO)(2)(d)] (7d) and [RhI(2)(COCH(3))(CO)(e)(2)] (8e), respectively, as confirmed by their X-ray structures. The initial rate of CH(3)I oxidative addition to 4 as determined by IR monitoring is dependent on the nature of the nitrogen-containing ligand. For 4a and 4h, reaction rates similar to those of the well-known rhodium anionic [RhI(2)(CO)(2)](-) species are observed and are consistent with the formation of this intermediate species through methylation of the a and h ligands. The reaction rates are reduced significantly when using imidazole and pyrazole ligands and involve the direct oxidative addition of CH(3)I to the neutral complexes 4c-4g. Complexes 4c and 4d react around 5-10 times faster than 4e-4g mainly because of electronic effects. The lowest reactivity of 4f toward CH(3)I is attributed to the steric effect of the coordinated ligand, as supported by the X-ray structure. PMID- 22845428 TI - Mokken scaling of the Caring Dimensions Inventory (CDI-25). AB - AIMS AND OBJECTIVES: To validate a Turkish version of the Caring Dimensions Inventory in a group of Turkish nursing students. BACKGROUND: There are no studies about how nurses or nursing students perceive caring in nursing in Turkey. There is also no valid and reliable instrument in Turkey for evaluating caring in nursing. DESIGN: Descriptive study design. METHODS: Using a convenience sample of nursing students (n = 266), standard forward-back translation techniques were used with the Caring Dimensions Inventory. An expert panel considered the translations and provided content validation. A final version of the Caring Dimensions Inventory was tested with 10 nursing students, and we found no difficulties with the items in the instrument. Mokken Scaling analysis of the Caring Dimensions Inventory was used. RESULTS: A range of psychosocial and professional/technical items was included in the Mokken scale with 'Providing privacy for a patient' as the most endorsed (mean = 4.66) item and 'Being with a patient during a clinical procedure' being the least endorsed (mean = 3.87). There is a tendency for the most endorsed items to be psychosocial with the professional/technical items being less endorsed, with the exception of the least endorsed item 'Being with a patient during a clinical procedure' which is a psychosocial item. CONCLUSION: The Turkish version of the Caring Dimensions Inventory is a reliable instrument for measuring nurses' perceptions about caring. RELEVANCE TO CLINICAL PRACTICE: The results using the Caring Dimensions Inventory will help to identify how caring in nursing is perceived by nursing students in Turkey. Repeating this study in different groups such as working nurses will help to determine nurses who work in clinical settings perceive caring in nursing. PMID- 22845465 TI - Minimally invasive esophagectomy in a previously pneumonectomized patient. AB - INTRODUCTION: Surgical resection represents the only therapeutic action having a radical intent for the treatment of resectable esophageal neoplasms. Minimally invasive esophagectomy for esophageal cancer is being more and more frequently performed. Few cases of esophagectomy after pneumonectomy have been described in the literature, and, to our knowledge, none of them was performed by the minimally invasive technique. SUBJECT AND METHODS: A 77-year-old woman, who had undergone left thoracotomic pneumonectomy due to squamous cell lung cancer 2 years before, underwent minimally invasive esophagectomy because of esophageal cancer at the authors' institution. The intervention was performed by right thoracoscopic esophageal mobilization with the patient in the prone position, followed by the laparoscopic and cervicotomic stages, with cervical anastomosis. RESULTS: Total operative time was 230 minutes. Intensive care unit stay was 1 day, followed by a hospital stay of 13 days. We did not observe any major postoperative complication. CONCLUSIONS: Minimally invasive esophagectomy with thoracoscopic esophageal mobilization in the prone position is a valid option in the treatment of esophageal cancer and may be feasible in previously left pneumonectomized patients. PMID- 22845466 TI - Determining the age of adult flesh flies, Boettcherisca peregrina, using pteridine fluorescence. AB - To assess the potential application of pteridine fluorescence in determining the age of adult Boettcherisca peregrina (Diptera: Sarcophagidae) Robineau-Desvoidy and further for the postmortem interval, the age-dependent changes of pteridine fluorescence were investigated for the adults maintained at five constant temperatures. From the results, significant linear relationships were found between pteridine fluorescence and the age of the adults maintained at 16, 20, 24, 28 or 32 degrees C (P < 0.001, r(2) > 0.85). In addition, the relationships between the rate of pteridine accumulation and temperature were well described using linear equations for adult females and males. Then for each cohort of the flies at the ambient temperature, a calendar was constructed and used to determine the ages of females and males, respectively, in which was recorded in reverse time order the amount of pteridine accumulated per hour by the flies and their expected pteridine level when they emerged at the specified time. A significant linear relationship between estimated ages and chronological ages was observed for female or male adults, with the mean errors of the estimated ages of +/-1.82 days for females and +/-1.58 days for males. It is suggested that pteridine fluorescence analysis has a potential value in determining the age of adult B. peregrina. PMID- 22845467 TI - Evaluation of methods to concentrate and purify ocean virus communities through comparative, replicated metagenomics. AB - Viruses have global impact through mortality, nutrient cycling and horizontal gene transfer, yet their study is limited by complex methodologies with little validation. Here, we use triplicate metagenomes to compare common aquatic viral concentration and purification methods across four combinations as follows: (i) tangential flow filtration (TFF) and DNase + CsCl, (ii) FeCl3 precipitation and DNase, (iii) FeCl3 precipitation and DNase + CsCl and (iv) FeCl3 precipitation and DNase + sucrose. Taxonomic data (30% of reads) suggested that purification methods were statistically indistinguishable at any taxonomic level while concentration methods were significantly different at family and genus levels. Specifically, TFF-concentrated viral metagenomes had significantly fewer abundant viral types (Podoviridae and Phycodnaviridae) and more variability among Myoviridae than FeCl3 -precipitated viral metagenomes. More comprehensive analyses using protein clusters (66% of reads) and k-mers (100% of reads) showed 50-53% of these data were common to all four methods, and revealed trace bacterial DNA contamination in TFF-concentrated metagenomes and one of three replicates concentrated using FeCl3 and purified by DNase alone. Shared k-mer analyses also revealed that polymerases used in amplification impact the resulting metagenomes, with TaKaRa enriching for 'rare' reads relative to PfuTurbo. Together these results provide empirical data for making experimental design decisions in culture-independent viral ecology studies. PMID- 22845468 TI - Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes. AB - Cardioactive glycosides exert positive inotropic effects on cardiomyocytes through the inhibition of Na(+)/K(+)-ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na(+)/K(+)-ATPase-independent effects. In the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 (ATP-binding cassette protein A1) transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, digoxin and ouabain simultaneously enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes. PMID- 22845469 TI - Effect of diindolylmethane on Ca2+ homeostasis and viability in PC3 human prostate cancer cells. AB - The effect of the natural product diindolylmethane on cytosolic Ca(2+) concentrations ([Ca(2+)](i)) and viability in PC3 human prostate cancer cells was explored. The Ca(2+)-sensitive fluorescent dye fura-2 was applied to measure [Ca(2+)](i). Diindolylmethane at concentrations of 20-50 uM induced [Ca(2+)](i) rise in a concentration-dependent manner. The response was reduced partly by removing Ca(2+). Diindolylmethane-evoked Ca(2+) entry was suppressed by nifedipine, econazole, SK&F96365, protein kinase C modulators and aristolochic acid. In the absence of extracellular Ca(2+), incubation with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) inhibited or abolished diindolylmethane-induced [Ca(2+)](i) rise. Incubation with diindolylmethane also inhibited thapsigargin or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C with U73122 reduced diindolylmethane-induced [Ca(2+)](i) rise. At concentrations of 50-100 uM, diindolylmethane killed cells in a concentration-dependent manner. This cytotoxic effect was not altered by chelating cytosolic Ca(2+) with 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Annexin V/PI staining data implicate that diindolylmethane (50 and 100 uM) induced apoptosis in a concentration-dependent manner. In conclusion, diindolylmethane induced a [Ca(2+)](i) rise in PC3 cells by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via phospholipase A(2)-sensitive store-operated Ca(2+) channels. Diindolylmethane caused cell death in which apoptosis may participate. PMID- 22845470 TI - Surgical repair of mitral valve prolapse through a minimal right vertical infraaxillary thoracotomy. AB - BACKGROUND: Minimally invasive mitral valve surgery has been proven a safe and cosmetic alternative to the conventional median sternotomy approach. The aim of this study is to retrospectively evaluate the clinical outcome of mitral valve repair for leaflet prolapse through a minimal right vertical infraaxillary thoracotomy (RVIAT). METHODS: From January 2003 to December 2011, 68 patients with mitral regurgitation (MR) due to leaflet prolapse underwent mitral valve repair through a RVIAT approach. There were 37 males and 31 females. The mean age of the patients was 37.8 +/- 10.5 years. Of the 68 patients, 45 had posterior leaflet prolapse and 23 had anterior leaflet prolapse. RESULTS: The mean incision length was 7.3 +/- 1.8 cm (range 5.5 to 10.0 cm). Mitral valve repair technique included quadrangular resection with or without sliding repair (40 cases), edge to edge technique (six cases), artificial chordae (18 cases), chordal transfer (four cases), and ring annuloplasty was performed in all 68 patients. There was no severe morbidity and operative mortality. Echocardiography after operation demonstrated absence or trivial mitral regurgitation in 52 patients and mild regurgitation in 16 patients. During the 3 months ~ 8 years' follow-up period, one patient (1.5%) underwent mitral valve replacement through the median sternotomy due to recurrent severe MR. Other patients were in good condition. CONCLUSION: Surgical repair of mitral valve prolapse can be successfully performed through the RVIAT approach achieving excellent cosmetic and clinical results. PMID- 22845471 TI - Could gold nanoprobes be an important tool in cancer diagnostics? PMID- 22845472 TI - Dynamics of genome 'iPOP': predicting disease or 'narciss-ome'? PMID- 22845473 TI - Challenges facing lipoarabinomannan urine antigen tests for diagnosing HIV associated tuberculosis. PMID- 22845475 TI - Recent advances in miRNA-based diagnostic applications. AB - This report highlights presentations and discussions of the 8th Cambridge Health Institute conference on miRNA in Human Disease and Development held in Cambridge (MA, USA) on 12-13 March 2012. The areas covered included development of miRNA based diagnostic and therapeutic applications, as well as mechanistic miRNA studies in cancer, cardiovascular disease and neurodegenerative conditions. There were also several industry-sponsored events showcasing miRNA technologies. PMID- 22845476 TI - Companion diagnostics: emerging strategies and issues in pharmaceutical development. AB - This article summarizes the broad messages from pharmaceutical and diagnostic companies on the collaborations required to support companion diagnostics. Since the groundbreaking herceptin HER2 diagnostic model in 1998, it has taken until 2011 for the US FDA to issue a draft guidance document, which was then immediately followed with approvals for two new drugs and their companion diagnostics. This conference summarized the current state of thinking in new projects and innovative technologies in pharmaceutical and diagnostic codevelopment. Attitudes are slowly changing and collaborations are rapidly ensuing, although the alignment between pharmaceutical and diagnostic understanding of value, timelines, outcomes and impact is difficult and remains a contentious area. The value of this conference has been to address these issues. PMID- 22845477 TI - Magnetic particle-based ultrasensitive biosensors for diagnostics. AB - The process of sensitive and accurate detection of small quantities of disease biomarkers is critical for the clinical diagnosis of disease. In this regard, magnetic particles (MPs) have been widely used because of their unique magnetic properties allowing for efficient target capture, enrichment and convenient separation. These properties, coupled with great signal amplification, have enabled MP-based biosensors to achieve ultrasensitivities. Over the past few years, several ultrasensitive MP-based biosensors suitable for early clinical diagnostics have been reported. This article highlights some of the most recent developments, with a focus on MP-based ultrasensitive assays that use an antibody or aptamer as the target-binding agent, and that utilize efficient signal amplification/readout strategies. PMID- 22845479 TI - Preimplantation genetic diagnosis: recent triumphs and remaining challenges. AB - Over the last 20 years, preimplantation genetic diagnosis (PGD) has changed from being an experimental procedure to one that is carried out in specialized diagnostic centers worldwide. Genetic awareness and the rapid identification of germline mutations or chromosomal abnormalities enable individuals to know their risk of transmitting a genetic disease before they have children. This has created a demand for PGD from couples who wish to avoid terminations of affected pregnancies. Although PGD is expensive because it requires couples to go through IVF, there is a trend for diagnosis to move towards automation, which will reduce cost and the need for specialized expertise. This will allow diagnosis to be carried out in routine molecular diagnostic laboratories. PMID- 22845478 TI - Detection of miRNAs with a nanopore single-molecule counter. AB - miRNAs are short noncoding RNA molecules that are important in regulating gene expression. Due to the correlation of their expression levels and various diseases, miRNAs are being investigated as potential biomarkers for molecular diagnostics. The fast-growing miRNA exploration demands rapid, accurate, low-cost miRNA detection technologies. This article will focus on two platforms of nanopore single-molecule approach that can quantitatively measure miRNA levels in samples from tissue and cancer patient plasma. Both nanopore methods are sensitive and specific, and do not need labeling, enzymatic reaction or amplification. In the next 5 years, the nanopore-based miRNA techniques will be improved and validated for noninvasive and early diagnosis of diseases. PMID- 22845480 TI - Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing. AB - In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4-ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR-ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARalpha for all-trans retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia. PMID- 22845481 TI - Hotspot oncomutations: implications for personalized cancer treatment. AB - Understanding the extent to which specific tumor mutations impact or mediate patient response to particular cancer therapies has become a rapidly increasing area of research. Recent research findings regarding four predominant mutational targets (KRAS, BRAF, EGFR and PIK3CA) show that these tumor mutations have predictive power for identifying which patients are likely to respond to particular therapies, and have prognostic significance irrespective of treatment. However, in this regard, the literature is frequently nuanced and sometimes contradictory. This lack of clarity may be due, at least in part, to the utilization of mutation detection methods with varying sensitivities across studies of different patient populations. Nevertheless, considerable evidence suggests minor tumor subpopulations may be contributing to inappropriate patient stratification, development of resistance to treatment, and the relapse that often follows treatment with molecularly targeted therapies. Consequently, mutant tumor subpopulations need to be considered in order to improve strategies for personalized cancer treatment. PMID- 22845483 TI - Molecular diagnostics of ocular diseases: the application of antibody microarray. AB - Proteomic analyses as applied to ocular aqueous humor provide evidence that this approach may be used to identify ocular disease with particular reference to cataract and glaucoma. Protein alterations bear pathogenic relevance for disease development. Among the different methods available, antibody microarray seems to be the most readily transferable to the clinic. However, this method still bears some limitations, such as the relatively small number of proteins analyzed and the poor specificity. Proteomic analysis is able to depict the pathogenesis of common ocular diseases and to produce data of both diagnostic and prognostic relevance. Proteome alterations detected in the aqueous humor of glaucomatous patients reflect degeneration occurring in target tissues - that is, the trabecular meshwork, retina and optic nerve head. Performed studies indicate good performances of aqueous humor analysis by antibody microarray for glaucoma diagnosis. Future development is addressed to improve antibody microarray specificity and to set up minimally invasive procedures for aqueous humor sampling. PMID- 22845484 TI - Multiplexed nucleic acid-based assays for molecular diagnostics of human disease. AB - In recent years, there has been an explosion of molecular tests developed to diagnose human disease, including tests to detect disease-causing pathogens, human genetic or protein markers indicative of disease (e.g., cancer and autoimmune disease), and genetic markers for predisposition to disease. Significant features of nucleic acid-based tests include high sensitivity and specificity, and the ability to multiplex or interrogate more than one marker simultaneously in each sample. Multiplex assays provide cost and information content advantages, and therefore allow for higher confidence results than singleplex assays. This article reviews the current state of the art in multiplexed nucleic acid-based techniques used for diagnosis of human disease and provides a glimpse of promising techniques for the future. PMID- 22845482 TI - How many molecular subtypes? Implications of the unique tumor principle in personalized medicine. AB - Cancers are complex multifactorial diseases. For centuries, conventional organ based classification system (i.e., breast cancer, lung cancer, colon cancer, colorectal cancer, prostate cancer, lymphoma, leukemia, and so on) has been utilized. Recently, molecular diagnostics has become an essential component in clinical decision-making. However, tumor evolution and behavior cannot accurately be predicted, despite numerous research studies reporting promising tumor biomarkers. To advance molecular diagnostics, a better understanding of intratumor and intertumor heterogeneity is essential. Tumor cells interact with the extracellular matrix and host non-neoplastic cells in the tumor microenvironment, which is influenced by genomic variation, hormones, and dietary, lifestyle and environmental exposures, implicated by molecular pathological epidemiology. Essentially, each tumor possesses its own unique characteristics in terms of molecular make-up, tumor microenvironment and interactomes within and between neoplastic and host cells. Starting from the unique tumor concept and paradigm, we can better classify tumors by molecular methods, and move closer toward personalized cancer medicine and prevention. PMID- 22845485 TI - A pilot study exploring the effects of a 12-week t'ai chi intervention on somatic symptoms of depression in patients with heart failure. AB - BACKGROUND: Patients with chronic heart failure (HF) and with elevated depression symptoms are at greater risk of morbidity and mortality. Somatic symptoms of depression are particularly prevalent in HF and are related to worse disease prognosis. T'ai chi practice is related to increased emotional well-being in various clinical populations; however, relatively little is known about t'ai chi's effects on somatic versus cognitive symptom dimensions of depression in HF. PURPOSE: The objective of the study was to measure whether a t'ai chi intervention effectively reduces somatic and/or cognitive symptoms of depression in patients with HF. METHODS: Patients with HF were assigned to either t'ai chi training (n=16) or a usual-care group (n=12). At baseline and after the 12-week intervention period, participants were evaluated for changes in depressive symptoms using Beck Depression Inventory (BDI) total scores (BDI-t) and subcategorized scores of BDI-somatic (BDI-s) and BDI-cognitive (BDI-c), and for symptoms of fatigue using the Multidimensional Fatigue Symptom Inventory-Short Form. RESULTS: Patients with HF in the t'ai chi group compared to the usual-care group had reduced BDI-s (p<=0.017), but not BDI-c (p=0.50) scores from pre- to postintervention. Although t'ai chi did not significantly reduce fatigue, changes in physical fatigue (p<=0.05) were independently associated with changes in BDI-t scores. CONCLUSIONS: T'ai chi practice reduced somatic symptoms of depression, which have been linked to worse prognosis in HF. Reductions in fatigue appear to explain some but not all of the reductions in somatic symptoms of depression. PMID- 22845487 TI - High levels of Mn2+ inhibit secretory pathway Ca2+/Mn2+-ATPase (SPCA) activity and cause Golgi fragmentation in neurons and glia. AB - Excess Mn(2+) in humans causes a neurological disorder known as manganism, which shares symptoms with Parkinson's disease. However, the cellular mechanisms underlying Mn(2+) -neurotoxicity and the involvement of Mn(2+) -transporters in cellular homeostasis and repair are poorly understood and require further investigation. In this work, we have analyzed the effect of Mn(2+) on neurons and glia from mice in primary cultures. Mn(2+) overload compromised survival of both cell types, specifically affecting cellular integrity and Golgi organization, where the secretory pathway Ca(2+) /Mn(2+) -ATPase is localized. This ATP-driven Mn(2+) transporter might take part in Mn(2+) accumulation/detoxification at low loads of Mn(2+) , but its ATPase activity is inhibited at high concentration of Mn(2+) . Glial cells appear to be significantly more resistant to this toxicity than neurons and their presence in cocultures provided some protection to neurons against degeneration induced by Mn(2+) . Interestingly, the Mn(2+) toxicity was partially reversed upon Mn(2+) removal by wash out or by the addition of EDTA as a chelating agent, in particular in glial cells. These studies provide data on Mn(2+) neurotoxicity and may contribute to explore new therapeutic approaches for reducing Mn(2+) poisoning. PMID- 22845488 TI - Atrial bigeminy results in decreased left ventricular function: an insight into the mechanism of PVC-induced cardiomyopathy. AB - BACKGROUND: Premature ventricular complexes have been recently recognized as a reversible cause of cardiomyopathy. The purpose of this study was to determine if premature complexes independent of "dyssynchrony" resulted in increased left ventricular (LV) dimensions and decreased LV function. METHODS: Ten mongrel dogs underwent the implantation of a pacemaker and were randomized to a control group (n = 5) or a paced group (n = 5). In the paced group, the pacemaker was connected to two endocardial atrial leads, one inserted into the atrial port and the other one into the ventricular port with an atrioventricular delay adjusted to ensure the presence of coupled pacing simulating atrial bigeminy with conducted beats in the absence of aberrancy. Echocardiographic parameters of LV size (LV end diastolic diameter [LV-EDD], LV end-systolic diameter [LV-ESD]), and LV ejection fraction (LVEF) were measured at baseline and after 4 weeks of monitoring (control group) or pacing (paced group). RESULTS: In the control group, LV size decreased with no significant changes in LVEF: 55% at baseline versus 70% at 4 weeks (P = 0.23). In the paced group, LV-EDD decreased with no significant change in LV-ESD. Unlike the control group, LVEF decreased significantly from 69 +/- 9% at baseline to 32 +/- 22% after 4 weeks of pacing (P = 0.05). CONCLUSION: We have shown that 4 weeks of coupled pacing simulating atrial bigeminy significantly reduced LV function. Our findings suggest that premature complexes independent of ventricular dyssynchrony might lead to the development of cardiomyopathy. PMID- 22845489 TI - How many check dams do we need to build on the Loess Plateau? PMID- 22845490 TI - LC-MS/MS method for the determination of the fungal pigment bikaverin in maize kernels as an indicator of ear rot. AB - Bikaverin is a polyketide-derived pigment produced by multiple species of the fungus Fusarium, some of which can cause ear and kernel rot of maize. A method was developed for the analysis of bikaverin by high-performance liquid chromatography (LC) coupled to electrospray ionisation tandem mass spectrometry (MS/MS). The quantitative nature of the LC-MS/MS method was demonstrated over a range of concentrations of bikaverin in maize. For spike-recovery experiments utilising maize spiked with bikaverin to a level 5 ug g-1 of maize, the measured recovery (%) was 70.6 +/- 10.4. Based on the utilised method, the limit of detection (based on a signal-to-noise ratio (S/N) > 3) was better than 0.5 ug g-1 from bikaverin spiked into uncontaminated ground maize. Further, the limit of quantitation (LOQ) was 3 ug g-1 (based on S/N > 10) from bikaverin spiked into ground maize. The method was applied to assess contamination of maize with bikaverin following inoculation of developing maize ears with Fusarium verticillioides under agricultural field conditions. PMID- 22845486 TI - Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. AB - The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers. PMID- 22845491 TI - Sexual function, mood and menopause symptoms in Lithuanian postmenopausal women. AB - OBJECTIVES: To assess sexual function in a clinical sample of Lithuanian postmenopausal women and identify the most important determinants of sexual function, including the use of hormone replacement therapy (HT), emotional status and menopausal symptoms. METHODS: Three hundred postmenopausal women who were referred to a gynecologist for a routine yearly check-up were enrolled for the study. Data for 246 women were appropriate for statistical analysis. Participants filled the Female Sexual Function Index for evaluation of sexual function, the Greene Climacteric Scale for the assessment of menopause symptoms and the Hospital Anxiety and Depression Scale for the evaluation of depression and anxiety symptoms. RESULTS: Sexual function was better in younger women and in HT users compared with non-users. Thus, to analyze the other variables, an adjustment for age was applied. HT significantly increased the likelihood of higher desire, lubrication, satisfaction, and lower pain when adjusting results for age. HT reduced the likelihood of psychological and depression symptoms and increased the likelihood of vasomotor symptoms of menopause when results adjusted for age were analyzed. HT did not appear to affect anxiety symptoms after the results were adjusted for age. CONCLUSIONS: HT increased chances for better sexual desire, lubrication, satisfaction, less pain and lower depression symptoms in postmenopausal women, even when the results were adjusted by age. HT did not improve sexual arousal, orgasm, menopausal and anxiety symptoms. Depression, anxiety, menopausal symptoms and age were the main risk factors for the possible development of sexual dysfunction. PMID- 22845492 TI - Human Mendelian pain disorders: a key to discovery and validation of novel analgesics. AB - We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery. PMID- 22845493 TI - The ubiquity of iron. AB - The importance of iron in living systems can be traced to the many complexes within which it is found, to its chemical mobility in undergoing oxidation reduction reactions, and to the abundance of iron in Earth's crust. Iron is the most abundant element, by mass, in the Earth, constituting about 80% of the inner and outer cores of Earth. The molten outer core is about 8000 km in diameter, and the solid inner core is about 2400 km in diameter. Iron is the fourth most abundant element in Earth's crust. It is the chemically functional component of mononuclear iron complexes, dinuclear iron complexes, [2Fe-2S] and [4Fe-4S] clusters, [Fe-Ni-S] clusters, iron protophorphyrin IX, and many other complexes in protein biochemistry. Metals such as nickel, cobalt, copper, and manganese are present in the crust and could in principle function chemically in place of iron, but they are scarce in Earth's crust. Iron is plentiful because of its nuclear stability in stellar nuclear fusion reactions. It seems likely that other solid planets, formed by the same processes as Earth, would also foster the evolution of life and that iron would be similarly important to life on those planets as it is on Earth. PMID- 22845494 TI - Pain relief and tolerability balance of immediate release tapentadol or oxycodone treatment for patients with moderate to severe osteoarthritis or low back pain. AB - PURPOSE: Opioid treatment effectiveness may be best compared using definitions of treatment response, which combine measures assessing pain reduction and the occurrence of adverse events (AEs). This analysis of data from two phase III clinical trials was conducted to examine the pain relief and tolerability (PRT) balance of immediate release (IR) tapentadol and oxycodone in patients with moderate to severe osteoarthritis (OA) or low back pain. METHODS: This was a post hoc analysis of two multicenter, randomized, double-blind studies (10-day and 90 day) that evaluated the efficacy and safety of tapentadol IR in patients with moderate-severe OA pain. PRT was defined as adequate pain reduction (30% or 50% pain intensity improvement from baseline) and no gastrointestinal AE or other type of treatment-emergent AE. The percentage of patients and mean number of days per patient meeting the PRT criteria were summarized. RESULTS: In the 10-day trial, the percentages of patients meeting PRT criteria (30% reduction) for both tapentadol groups were consistently above that for oxycodone 10 mg, although only significantly different for the 50 mg formulation. The mean number of days per patient meeting the PRT criteria was 3.7, 3.2, and 2.3 days for tapentadol 50 mg, 75 mg and oxycodone 10 mg, respectively. No significant difference between the groups was observed using the 50% pain reduction criterion. For the 90-day trial, using multiple definitions, tapentadol IR showed a significantly higher proportion of days meeting PRT criteria. CONCLUSION: Pain reduction and tolerability are both important attributes of an effective analgesic treatment. Based on data from two trials, tapentadol IR produced an improved PRT balance compared with oxycodone IR. PMID- 22845495 TI - An action research study to explore the nature of the nurse consultant role in the care of children and young people. AB - AIMS AND OBJECTIVES: An action research study was undertaken to explore the development of the nurse consultant role when caring for children and young people. BACKGROUND: Five nurse consultants in different areas of specialist care in a tertiary paediatric hospital undertook the study when implementing the new role of nurse consultant into the hospital. METHODS: Action research meetings took place over a year. The nurse consultants then collated and analysed data using thematic analysis during the second year. A research fellow facilitated meetings, carried out participant observation, and coordinated the action research project. RESULTS: Data analysis revealed 22 subthemes grouped into four overarching themes: shaping the role; shaping child-centred care through consultancy; taking responsibility for practice; and leadership. These roles and their ease and complexity within the nurse consultant role are examined in further detail in this paper. Balancing the four key components in a newly developing role was initially complex and required support. Over time the nurse consultants developed the necessary skills to perform fully in all areas. A major challenge was developing the research role, a key function of the nurse consultant role. By the end of the study, all nurse consultants were actively embarking upon their own research either in preparation for or as part of Doctoral studies. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: While there are many similarities with nurse consultants in adult practice, one major difference was the nurse consultant role in supporting families when caring for children and young people. This meant having a three-way communication style: with the family, the child/young person, and other healthcare professionals. This communication style was observed by the research fellow in participant observation of the nurse consultants undertaking clinical care and is described further in the analysis of the role. PMID- 22845496 TI - Semaphorin 7A protein variants differentially regulate T-cell activity. AB - BACKGROUND: Semaphorin 7A (Sema7A) carries the John-Milton-Hagen human blood group antigen on red blood cells and shows molecular diversity. It is known that Sema7A has immunomodulatory functions, but its regulatory effects on T-cell activation are not completely understood. In this study, the functional role of the R461C Sema7A polymorphism on T-cell responses was investigated. STUDY DESIGN AND METHODS: Soluble recombinant wild-type Sema7A (Sema7A_wt) and its R461C variant (Sema7A_R461C) were produced in human embryonic kidney cells. Specific assays were performed to determine the effects of Sema7A_wt and Sema7A_R461C on T cell activation in terms of proliferation, phenotypic alterations, granzyme B transcript levels, and secretion of proinflammatory cytokines. RESULTS: Sema7A_wt did not affect T-cell activity, but Sema7A_R461C led to marked antigen independent activation of T cells. In the presence of antigen stimulation, Sema7A_R461C had a major costimulatory effect on T-cell response. Upon Sema7A_R461C stimulation, CD4+ T cells strongly proliferated and exhibited a cytotoxic phenotype with significant up regulation of granzyme B transcripts (up to 220-fold), even in the absence of antigen stimulation. Antibody blocking studies indicated that Sema7A_R461C-mediated T-cell activation is largely beta1 integrin dependent. CONCLUSION: These data demonstrate that Sema7A_R461C, unlike wild-type Sema7A, causes differential regulation of T-cell responses. Since Sema7A has important immunomodulatory functions in inflammatory responses, it might play a key role in autoimmune diseases and other major disorders. Further studies are needed to elucidate the regulatory role of Sema7A and its variants. PMID- 22845497 TI - Regulation of archaella expression by the FHA and von Willebrand domain containing proteins ArnA and ArnB in Sulfolobus acidocaldarius. AB - The ability of microorganisms to sense and respond to sudden changes in their environment is often based on regulatory systems comprising reversible protein phosphorylation. The archaellum (former: archaeal flagellum) is used for motility in Archaea and therefore functionally analogous to the bacterial flagellum. In contrast with archaellum-mediated movement in certain members of the Euryarchaeota, this process, including its regulation, remains poorly studied in crenarchaeal organisms like Sulfolobus species. Recently, it was shown in Sulfolobus acidocaldarius that tryptone limiting conditions led to the induction of archaella expression and assembly. Here we have identified two proteins, the FHA domain-containing protein ArnA and the vWA domain-containing protein ArnB that are involved in regulating archaella expression in S. acidocaldarius. Both proteins are phosphorylated by protein kinases in vitro and interact strongly in vivo. Phenotypic analyses revealed that these two proteins are repressors of archaella expression. These results represent the first step in understanding the networks that underlie regulation of cellular motility in Crenarchaeota and emphasize the importance of protein phosphorylation in the regulation of cellular processes in the Archaea. PMID- 22845498 TI - Vitamin C in plasma and leucocytes in relation to periodontitis. AB - AIM: To test the hypothesis that vitamin C concentrations in plasma, polymorphonuclear neutrophilic leucocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are lower in periodontitis patients compared with healthy controls. METHODS: Twenty-one untreated periodontal patients and 21 healthy controls matched for age, gender, race and smoking habits were selected. Dietary vitamin C intake was assessed by a self-administered dietary record. Fasting blood samples were obtained and analysed for vitamin C concentrations in plasma, PMNs and PBMCs by means of high-pressure liquid chromatography (HPLC). RESULTS: Plasma vitamin C was lower in periodontitis patients compared with controls (8.3 and 11.3 mg/l, respectively, p = 0.03). Only in the control group a positive correlation was present between vitamin C intake and plasma values. No differences could be assessed between patients and controls regarding vitamin C dietary intake and levels in PMNs and PBMCs. In the patient group, pocket depth appeared to be negatively associated with the vitamin C concentration in PMNs. CONCLUSION: Although the relationship between low plasma vitamin C levels and periodontitis is clear, the disease cannot be explained by insufficient vitamin C storage capacity of leucocytes; the question remains through which mechanism low plasma vitamin C levels are related to periodontitis. PMID- 22845548 TI - Cerebral microcirculatory responses of insulin-resistant rats are preserved to physiological and pharmacological stimuli. AB - OBJECTIVE: Previously, we have shown that IR impairs the vascular reactivity of the major cerebral arteries of ZO rats prior to the occurrence of Type-II diabetes mellitus. However, the functional state of the microcirculation in the cerebral cortex is still being explored. METHODS: We tested the local CoBF responses of 11-13-week-old ZO (n = 31) and control ZL (n = 32) rats to several stimuli measured by LDF using a closed cranial window setup. RESULTS: The topical application of 1-100 MUm bradykinin elicited the same degree of CoBF elevation in both ZL and ZO groups. There was no significant difference in the incidence, latency, and amplitude of the NMDA-induced CSD-related hyperemia between the ZO and ZL groups. Hypercapnic CoBF response to 5% carbon-dioxide ventilation did not significantly change in the ZO compared with the ZL. Topical bicuculline-induced cortical seizure was accompanied by the same increase of CoBF in both the ZO and ZL at all bicuculline doses. CONCLUSIONS: CoBF responses of the microcirculation are preserved in the early period of the metabolic syndrome, which creates an opportunity for intervention to prevent and restore the function of the major cerebral vascular beds. PMID- 22845549 TI - The roles of GSTM1 and GSTT1 null genotypes and other predictors in anti tuberculosis drug-induced liver injury. AB - WHAT IS KNOWN AND OBJECTIVE: Anti-tuberculosis drugs (ATD), although highly effective, often cause liver injury. Glutathione S-transferases (GST) play a crucial protective role in the detoxifying mechanisms of drugs. Several studies have investigated the genetic null variants of GSTM1 and GSTT1 as possible risk factors for ATD-induced liver injury; however, those findings are inconsistent. We investigated GSTM1 and GSTT1 null genotypes in Brazilian patients with tuberculosis (TB), adjusting for other possible predictors of ATD-induced liver injury. METHODS: This was a prospective cohort study with patients who were treated for TB from 2006 to 2011. GSTM1 and GSTT1 gene deletions were analysed from genomic DNA by polymerase chain reaction (PCR). Demographic, clinical and laboratory data were extracted from medical records and possible predictors of liver injury were evaluated. RESULTS AND DISCUSSION: This study enrolled 177 patients. Anti-tuberculosis drugs-induced liver injury incidence was 33.3%. Hepatitis B infection (HBV) and increased alanine aminotransferase (ALT) baseline were significant predictors. Neither GSTM1 nor GSTT1 null genotypes were associated with ATD-induced liver injury; nevertheless, the comparison among four different liver toxicity grades showed that GSTM1 non-null genotype was significant more frequent among the higher grades of liver toxicity. WHAT IS NEW AND CONCLUSION: GSTM1 and GSTT1 null genotypes do not seem to play important roles in ATD-induced liver injury in Brazilians. However, there was evidence that GSTM1 polymorphisms were possibly related to the intensity of toxicity. Active HBV and initial high ALT could predict ATD-induced liver injury. PMID- 22845551 TI - Co-complexation of lithium gallates on the titanium molecular oxide {[Ti(eta5 C5Me5)(MU-O)}3(MU3-CH)]. AB - Amide and lithium aryloxide gallates [Li(+){RGaPh(3)}(-)] (R = NMe(2), O-2,6 Me(2)C(6)H(3)) react with the MU(3)-alkylidyne oxoderivative ligand [{Ti(eta(5) C(5)Me(5))(MU-O)}(3)(MU(3)-CH)] (1) to afford the gallium-lithium-titanium cubane complexes [{Ph(3)Ga(MU-R)Li}{Ti(eta(5)-C(5)Me(5))(MU-O)}(3)(MU(3)-CH)] [R = NMe(2) (3), O-2,6-Me(2)C(6)H(3) (4)]. The same complexes can be obtained by treatment of the [Ph(3)Ga(MU(3)-O)(3){Ti(eta(5)-C(5)Me(5))}(3)(MU(3)-CH)] (2) adduct with the corresponding lithium amide or aryloxide, respectively. Complex 3 evolves with formation of 5 as a solvent-separated ion pair constituted by the lithium dicubane cationic species [Li{(MU(3)-O)(3)Ti(3)(eta(5) C(5)Me(5))(3)(MU(3)-CH)}(2)](+) together with the anionic [(GaPh(3))(2)(MU NMe(2))](-) unit. On the other hand, the reaction of 1 with Li(p-MeC(6)H(4)) and GaPh(3) leads to the complex [Li{(MU(3)-O)(3)Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3) CH)}(2)][GaLi(p-MeC(6)H(4))(2)Ph(3)] (6). X-ray diffraction studies were performed on 1, 2, 4, and 5, while trials to obtain crystals of 6 led to characterization of [Li{(MU(3)-O)(3)Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3) CH)}(2)][PhLi(MU-C(6)H(5))(2)Ga(p-MeC(6)H(4))Ph] 6a. PMID- 22845550 TI - Analysis of Foxo1-regulated genes using Foxo1-deficient pancreatic beta cells. AB - Several reports have suggested that Foxo1, a key regulator in differentiation, growth and metabolism, is involved in pancreatic beta-cell function. However, detailed analyses have been hampered by a lack of Foxo1-deficient beta cells. To elucidate Foxo1's function in beta cells, we produced a beta-cell line with inducible Foxo1 deletion. We generated a conditional knockout mouse line, in which Cre recombinase deletes the Foxo1 gene. We then established a beta-cell line from an insulinoma induced in this knockout mouse by the beta-cell-specific expression of simian virus 40 T antigen. In this cell line, designated MIN6 Foxo1flox/flox, adenovirus-mediated Cre expression ablates the Foxo1 gene, generating MIN6-Foxo1-KO cells. Using these knockout and floxed cell lines, we found that Foxo1 ablation enhanced the glucose-stimulated insulin secretion (GSIS) at high glucose concentrations and enhanced beta-cell proliferation. We also conducted DNA microarray analyses of MIN6-Foxo1-KO cells infected with either an adenovirus vector expressing a constitutively active FOXO1 or a control vector and identified several Foxo1-regulated genes, including some known to be related to beta-cell function. These cells should be useful for further studies on Foxo1's roles in beta-cells and may lead to novel strategies for treating the impaired insulin secretion in type 2 diabetes mellitus. PMID- 22845552 TI - Feasibility and safety of retroperitoneal laparoendoscopic single-site dismembered pyeloplasty: a clinical report of 10 cases. AB - OBJECTIVE: To retrospectively review our experience with respect to evaluating the feasibility and safety of laparoendoscopic single-site (LESS) dismembered pyeloplasty for ureteropelvic junction obstruction (UPJO) through a retroperitoneal approach. PATIENTS AND METHODS: Between March 2011 and January 2012, 10 consecutive patients underwent LESS retroperitoneoscopic dismembered pyeloplasty performed by one experienced laparoscopic surgeon at our institution. A single-port access was inserted through a 2.5-cm transverse skin incision below the 12th rib along the midaxillary line. Standard steps of the multisite retroperitoneoscopic Anderson-Hynes dismembered pyeloplasty technique using conventional instruments or a combination of conventional and bent laparoscopic instruments were performed. Follow-up studies were conducted by intravenous urography (IVU), diuretic renal scan, and renal ultrasonography. RESULTS: LESS retroperitoneoscopic dismembered pyeloplasty was successful in 9 patients, whereas 1 required four-port retroperitoneoscopic conversion because of difficulties in remaining in the retroperitoneal space due to a peritoneal tear during the procedure. The mean operative time was 148.4 minutes (range, 103-210 minutes). The mean estimated blood loss was 31 mL (range, 10-70 mL), and the mean postoperative hospital stay was 5.7 days (range, 3-13 days). Intraoperative complications were limited to the one case of peritoneal tear. An aberrant crossing vessel was noted in 4 patients, and transposition was not required in these patients. Urine leakage occurred in 1 patient postoperatively and was successfully treated by conservative management. The mean follow-up period was 6.2 months (range, 5-10 months). Satisfactory drainage with decreased hydronephrosis on IVU, diuretic renal scan, and renal ultrasonography was observed in all cases at the 3-month imaging studies. CONCLUSIONS: In experienced hands, LESS retroperitoneoscopic dismembered pyeloplasty is a feasible and safe alternative for correcting UPJO, although it remains technically challenging. The long-term outcome awaits further studies. PMID- 22845553 TI - The mechanism of antibacterial activity of tetrandrine against Staphylococcus aureus. AB - Tetrandrine (TET) is a bis-benzylisoquinoline alkaloid derived from the radix of Stephania tetrandra S. Moore. TET performs a wide spectrum of biological activities. The radix of S. tetrandrae has been used traditionally in Asia, including Korea, to treat congestive circulatory disorders and inflammatory diseases. The aim of this study was to examine the mechanism of antibacterial activity of tetrandrine against Staphylococcus aureus. The mechanism was investigated by studying the effects of TET in combination with detergent or membrane potential un-couplers. In addition, the direct involvement of peptidoglycan (PGN) was assessed in titration assays. TET activity against S. aureus was 125-250 MUg/mL, and the minimum inhibitory concentration (MIC) of the two reference strains was 250 MUg/mL. The OD(600) of each suspension treated with a combination of ethylenediaminetetraacetic acid (EDTA), tris(hydroxymethyl) aminomethane (TRIS), and Triton X-100 (TX) with TET (0.25*MIC) had been reduced from 43% to 96%. Additional structure-function studies on the antibacterial activity of TET in combination with other agents may lead to the discovery of more effective antibacterial agents. PMID- 22845554 TI - Fulminant fungal infection of a biventricular assist device. PMID- 22845555 TI - Determination of phthalic acid diesters in human milk at low ppb levels. AB - Phthalic acid diesters (PAE) are omnipresent in the human environment and food is a major contributor to the overall human exposure towards these chemicals. Due to developmental effects, PAE infants' exposure via human milk has been subjected to a number of analytical studies. These previous studies, however, revealed that normal laboratory blank values are in the range of or even higher than human milk levels due to the presence of PAE in laboratory environments. In order to provide more reliable data on PAE exposure via human milk, the aim of this study was to develop and validate a robust and sensitive analytical method. This should be capable of removing matrix components efficiently and guarantee limits of quantification in the low ppb range. The method development took into account liquid-liquid extraction and selective pressurised fluid extraction (sPFE) as well as chromatography-based clean-up steps. The final method consisted of a liquid-liquid extraction followed by an automated chromatographic clean-up by an sPFE device. After volume reduction the cleaned extracts were analysed by quadrupole GC/MS. Quantification was based on internal standards. An extensive quality assurance and method test programme demonstrated conservatively determined limits of detection and quantification from 0.3 to 10 ng g-1 in human milk, with recoveries of internal standards from 50% to 101%. Thus, the method allowed the quality-assured detection of di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), di-allyl phthalate (DAP), benzylbutyl phthalate (BBP) and di-cyclohexyl phthalate (DcHP) in 30 human milk samples provided by 30 volunteers from southern Germany. DiBP, DBP and DEHP were the most commonly detected PAE, with median levels of 1.0, 0.6 and 2.3 ng g-1, respectively. PMID- 22845556 TI - Left phrenic nerve injury during cryoballoon ablation of the left superior pulmonary vein. AB - Transcatheter ablation of the pulmonary veins (PVs) has been established as a therapeutic option for patients with symptomatic atrial fibrillation. Cryothermal energy is an alternative energy source that has been developed to overcome some of the disadvantages of radiofrequency ablation. The major complication of the cryoballoon technique seems to be right-sided phrenic nerve injury (PNI) following ablation of the right superior PV. This case report describes a left sided PNI after cryoballoon ablation of the left superior PV. PMID- 22845557 TI - Promising outcomes of definitive chemoradiation and cetuximab for patients with esophageal squamous cell carcinoma. AB - This study investigated cetuximab added to definitive concurrent chemoradiation for esophageal squamous cell carcinoma (ESCC). Previously untreated patients with stage II-IVa ESCC received cetuximab (400 mg/m(2) per week in week 1, then 250 mg/m(2) per week during weeks 2-8), paclitaxel (45 mg/m(2) per week) and cisplatin (20 mg/m(2) per week) in weeks 2-8 with 59.4 Gy radiotherapy. Epidermal growth factor receptor (EGFR) status in tumor specimens was assessed. Thirty-one patients were enrolled and evaluated for toxicity. Of the 29 patients assessable for a response, 20 (69.0%) had a clinical complete response (CR). Over a median follow up of 23.6 months, disease progression was observed in seven patients. The 1- and 2-year progression-free survival (PFS) rates were 85.5% and 75.1%, respectively. The PFS was shorter for patients with lymphatic metastatic disease than for those with locally confined tumor; the 1-year PFS rates were 78.7% and 92.3%, respectively (P = 0.038). Sixteen (55.2%) patients were immunohistochemically positive for EGFR. The patients with EGFR-expressing tumor had a CR rate of 75.0% compared with 61.5% in those with negative EGFR expression (P = 0.024). The PFS for patients with EGFR-expressing tumor was longer compared with the PFS of patients with negative EGFR (P = 0.133). The patients with prominent cetuximab-induced rash (>=grade 2) had a better CR rate and PFS than those with no or grade 1 rash (P < 0.05). The rates of grades 3/4 esophagitis, hematological and dermatological toxicities were 9.7%, 29.0% and 16.1%, respectively. The regimen of definitive chemoradiation plus cetuximab achieved good clinical response and has an acceptable safety profile in Chinese ESCC patients. PMID- 22845559 TI - Liquid "laundry pods": a missed global toxicosurveillance opportunity. PMID- 22845558 TI - Elderly deaths associated with balneotherapy in Denizli, Turkey province: three autopsy cases. AB - BACKGROUND: Turkey is one of the richest countries in the world in terms of balneotherapy resources. Thermomineral water baths are preferred by the elderly because of their positive beneficial effects over regulation of musculoskeletal system functions. However, existing cardiovascular and respiratory system diseases may constitute a risk and trigger ischemic changes in the heart. METHODS: In this study, 2 cases are presented who suffered sudden cardiac death while having a thermal bath and 1 drowning case that was precipitated by chronic myocardial infarction. While 1 case was 63 years old, 2 cases were above 65 years of age. Two (2) cases had atherosclerotic coronary artery disease, whereas 1 case had heart failure. RESULTS: The success of spa treatment, which is based on stimulation/harmonization therapy, restores bodily harmony and depends on the health of organs and functions playing a role in this process. CONCLUSIONS: In the elderly, some conditions, particularly limited pulmonary and cardiovascular functionality, should be taken into consideration while applying those treatments. PMID- 22845560 TI - DNA methyltransferase inhibitor RG108 and histone deacetylase inhibitors cooperate to enhance NB4 cell differentiation and E-cadherin re-expression by chromatin remodelling. AB - Epigenetic silencing of cancer-related genes by abnormal methylation and the reversal of this process by DNA methylation inhibitors represents a promising strategy in cancer therapy. As DNA methylation affects gene expression and chromatin structure, we investigated the effects of novel DNMT (DNA methyltransferase) inhibitor, RG108, alone and in its combinations with structurally several HDAC (histone deacetylase) inhibitors [sodium PB (phenyl butyrate) or BML-210 (N-(2-aminophenyl)-N'phenyloctanol diamine), and all-trans RA (retinoic acid)] in the human PML (promyelocytic leukaemia) NB4 cells. RG108 at different doses from 20 to 100 MUM caused time-, but not a dose-dependent inhibition of NB4 cell proliferation without cytotoxicity. Temporal pretreatment with RG108 before RA resulted in a dose-dependent cell growth inhibition and remarkable acceleration of granulocytic differentiation. Prolonged treatments with RG108 and RA in the presence of HDAC inhibitors significantly increased differentiation. RG108 caused time-dependent re-expression of methylation silenced E-cadherin, with increase after temporal or continuous treatments with RG108 and RA, or RA together with PB in parallel, in cell maturation, suggesting the role of E-cadherin as a possible therapeutic marker. These processes required both PB-induced hyperacetylation of histone H4 and trimethylation of histone H3 at lysine 4, indicating the cooperative action of histone modifications and DNA methylation/demethylation in derepression of E-cadherin. This work provides novel experimental evidence of the beneficial role of the DNMT inhibitor RG108 in combinations with RA and HDACIs in the effective differentiation of human PML based on epigenetics. PMID- 22845610 TI - Endothelial Japanese encephalitis virus infection enhances migration and adhesion of leukocytes to brain microvascular endothelia via MEK-dependent expression of ICAM1 and the CINC and RANTES chemokines. AB - Currently, the underlying mechanisms and the specific cell types associated with Japanese encephalitis-associated leukocyte trafficking are not understood. Brain microvascular endothelial cells represent a functional barrier and could play key roles in leukocyte central nervous system trafficking. We found that cultured brain microvascular endothelial cells were susceptible to Japanese encephalitis virus (JEV) infection with limited amplification. This type of JEV infection had negligible effects on cell viability and barrier integrity. Instead, JEV-infected endothelial cells attracted more leukocytes adhesion onto surfaces and the supernatants promoted chemotaxis of leukocytes. Infection with JEV was found to elicit the elevated production of intercellular adhesion molecule-1, cytokine induced neutrophil chemoattractant-1, and regulated-upon-activation normal T-cell expressed and secreted, contributing to the aforementioned leukocyte adhesion and chemotaxis. We further demonstrated that extracellular signal-regulated kinase was a key upstream regulator which stimulated extensive endothelial gene induction by up-regulating cytosolic phospholipase A2, NF-kappaB, and cAMP response element-binding protein via signals involving phosphorylation. These data suggest that JEV infection could activate brain microvascular endothelial cells and modify their characteristics without compromising the barrier integrity, making them favorable for the recruitment and adhesion of circulating leukocytes, thereby together with other unidentified barrier-disrupting mechanisms contributing to Japanese encephalitis and associated neuroinflammation. PMID- 22845611 TI - Does attention-deficit-hyperactivity disorder exacerbate executive dysfunction in children with neurofibromatosis type 1? AB - AIM: Although approximately 40% of children with neurofibromatosis type 1 (NF1) meet diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD), the impact of ADHD on the executive functioning of children with NF1 is not understood. We investigated whether spatial working memory and response inhibition are impaired in children with NF1 without a diagnosis of ADHD and whether executive deficits are exacerbated in children with a comorbid diagnosis. METHOD: Forty-nine children aged 7 to 15 years with NF1 only (31 males, 18 females; mean age 11y, SD 2y 4mo) or 35 with NF1 and ADHD (18 males, 17 females; mean age 10y 8mo, SD 2y 4mo) and 30 typically developing comparison children (16 males, 14 females; mean age 10y, SD 2y 8mo) were compared on measures of spatial working memory and response inhibition. Group differences in IQ and visuospatial ability were controlled for as required. RESULTS: Compared with typically developing children, children with NF1 with or without comorbid ADHD demonstrated significant impairment of both spatial working memory (both p<0.004) and inhibitory control (both p<0.010). There were, however, no differences between the two NF1 groups in spatial working memory (p=0.91) or response inhibition (p=0.78). INTERPRETATION: Executive dysfunction occurs with the same severity in children with NF1, whether or not they have a comorbid diagnosis of ADHD, suggesting that executive impairments are not unique contributors to ADHD symptomatology in NF1. The findings are discussed within the context of recent evidence in Nf1 optic glioma (OPG) mice, in which a mechanistic connection between NF1 gene expression, executive system failure, and dopaminergic pathway integrity has been established. PMID- 22845612 TI - The current role of ultrasound use in teaching regional anesthesia: a survey of residency programs in the United States. AB - BACKGROUND AND OBJECTIVES: The purpose of this survey was to determine the current teaching practices of regional anesthesia and the prevalence of ultrasound use in guiding peripheral nerve blocks in the academic institutions across the United States. METHODS: A survey was distributed to all American Board of Anesthesiology-accredited residency programs via email and/or the U.S. postal service. The survey was designed to determine the number of peripheral nerve blocks (PNBs) performed, the role of the ultrasound guidance, the barriers to its use, and the methods by which teaching physicians acquired their ultrasound skills. RESULTS: We received 82 responses (62%) of the 132 programs surveyed. Eighty-eight percent of the responding programs performed more than 20 PNBs/week and 46% performed more than 40 PNBs/week. Three-fourths of the respondents relied on ultrasound to guide the majority of single injection and continuous PNBs. When using ultrasound, most programs (79%) used real-time ultrasound without nerve stimulator. Most teaching physicians supervising ultrasound-guided PNBs received their training via workshops and/or from other colleagues. The three main reasons for using ultrasound were to 1) achieve a higher success rate; 2) improve safety; and 3) teach anesthesia trainees. However, the three main barriers to using ultrasound were 1) lack of training; 2) perceived decreased efficiency; and 3) the lack of immediate availability of equipment. Overall, ultrasound was less utilized to guide lower extremity vs upper extremity PNBs. CONCLUSIONS: Ultrasound-guided PNBs are universally taught across residency programs in the United States. Most teaching physicians believe that ultrasound increases PNB's success and improves safety of regional anesthesia. Barriers to ultrasound use are lack of faculty training and unavailability of ultrasound equipment. PMID- 22845561 TI - Enhancing team-sport athlete performance: is altitude training relevant? AB - Field-based team sport matches are composed of short, high-intensity efforts, interspersed with intervals of rest or submaximal exercise, repeated over a period of 60-120 minutes. Matches may also be played at moderate altitude where the lower oxygen partial pressure exerts a detrimental effect on performance. To enhance run-based performance, team-sport athletes use varied training strategies focusing on different aspects of team-sport physiology, including aerobic, sprint, repeated-sprint and resistance training. Interestingly, 'altitude' training (i.e. living and/or training in O(2)-reduced environments) has only been empirically employed by athletes and coaches to improve the basic characteristics of speed and endurance necessary to excel in team sports. Hypoxia, as an additional stimulus to training, is typically used by endurance athletes to enhance performance at sea level and to prepare for competition at altitude. Several approaches have evolved in the last few decades, which are known to enhance aerobic power and, thus, endurance performance. Altitude training can also promote an increased anaerobic fitness, and may enhance sprint capacity. Therefore, altitude training may confer potentially-beneficial adaptations to team-sport athletes, which have been overlooked in contemporary sport physiology research. Here, we review the current knowledge on the established benefits of altitude training on physiological systems relevant to team-sport performance, and conclude that current evidence supports implementation of altitude training modalities to enhance match physical performances at both sea level and altitude. We hope that this will guide the practice of many athletes and stimulate future research to better refine training programmes. PMID- 22845613 TI - Synthesis and mass spectral characterization of mycobacterial phosphatidylinositol and its dimannosides. AB - A family of naturally occurring mycobacterial phosphatidylinositol (PI) and its dimannosides (PIM(2), AcPIM(2), and Ac(2)PIM(2)) that all possess the predominant natural 19:0/16:0 phosphatidyl acylation pattern were prepared to study their mass spectral fragmentations. Among these, the first synthesis of a fully lipidated PIM (i.e., (16:0,18:0)(19:0/16:0)-PIM(2)) was achieved from (+/-) 1,2:4,5-diisopropylidene-D-myo-inositol in 16 steps in 3% overall yield. A key feature of the strategy was extending the utility of the p-(3,4 dimethoxyphenyl)benzyl protecting group for its use at the O-3 position of inositol to allow installation of the stearoyl residue at a late stage in the synthesis. Mass spectral studies were performed on the synthetic PIMs and compared to those reported for natural PIMs identified from a lipid extract of M. bovis BCG. These analyses confirm that fragmentation patterns can be used to identify the structures of specific PIMs from the cell wall lipid extract. PMID- 22845614 TI - Crestal bone resorption after the application of two periodontal surgical techniques: a randomized, controlled clinical trial. AB - AIM: To radiographically assess, by means of digital subtraction radiography, crestal bone loss following two periodontal surgical techniques, over a period of 6 months. MATERIAL AND METHODS: A total of 30 chronic periodontitis patients participated in this randomized controlled clinical trial and were separated into two groups. Modified Widman flap was applied in the control group and apically positioned flap, without intervention to the bone, in the experimental group. Clinical measurements (plaque index, gingival bleeding index, probing pocket depth and clinical attachment level) were recorded at baseline, 6 weeks, 3 and 6 months after surgery. Digital radiographs were taken at baseline, 1, 3, 6 weeks, 3 and 6 months after surgical treatment and subtracted digitally in pairs. RESULTS: Both groups showed statistically significant improvement of clinical parameters. Statistically significant differences between the two groups were observed only in probing pocket depth (PPD) at 6 weeks interval, where the test group showed more reduction (smallest statistically significant differences observed, SSSDO = 0.64). Both groups showed the same rate of crestal bone resorption. CONCLUSIONS: Bone resorption of the alveolar crest is a phenomenon that is observed as a consequence of periodontal surgical treatment without significant differences between the two techniques. Furthermore, both surgical techniques lead to satisfactory clinical results, indicating that bone removal during periodontal surgical treatment is not always necessary. PMID- 22845616 TI - Evaluation of a computer-based intervention to enhance metabolic monitoring in psychiatry inpatients treated with second-generation antipsychotics. AB - WHAT IS KNOWN AND OBJECTIVE: Second-generation antipsychotics (SGAs) play an important role in the pharmacologic management of various psychiatric conditions. Use of these medications has been associated with metabolic complications. Adherence to guideline-recommended monitoring is suboptimal. We evaluated the effect of a computerized physician order entry (CPOE) pop-up alert designed to improve rates of laboratory metabolic monitoring of patients treated with SGAs on a University Hospital inpatient psychiatry unit. METHODS: A single-centre, retrospective chart review was performed in which patient demographics and SGA drug and laboratory data were extracted from the CPOE database. We assessed the number of orders for appropriate metabolic monitoring data for patients admitted within a 6-month period before or after the alert implementation. RESULTS AND DISCUSSION: Pre-alert (n = 171) and post-alert (n = 157) groups were similar with respect to age, length of stay, sex, race and comorbidities. Following alert implementation, significant increases in monitoring both random (92.4% vs. 100%) and fasting (46.8% vs. 70%) glucose levels as well as random (28.7% vs. 74.5%) and fasting (18.7% vs. 59.9%) lipid panels (all P <= 0.001) were observed. The number of patients with both a fasting glucose level and fasting lipid panel available for monitoring increased from 12.9% to 47.8% (P < 0.0001). Significantly more post-alert laboratory orders were submitted at the same time as the SGA drug order (P < 0.0001), suggesting that the alert itself had a direct influence on the ordering of metabolic monitoring labs. WHAT IS NEW AND CONCLUSIONS: Implementation and use of an electronic pop-up alert in an inpatient psychiatric unit significantly improved rates of ordering fasting blood glucose and lipid levels for inpatients treated with SGAs. Overall rates remain suboptimal, suggesting a need for additional strategies to further improve metabolic monitoring. PMID- 22845615 TI - Microfluidic study of competence regulation in Streptococcus mutans: environmental inputs modulate bimodal and unimodal expression of comX. AB - Streptococcus mutans regulates genetic competence through a complex network that receives inputs from a number of environmental stimuli, including two signalling peptides designated as CSP and XIP. The response of the downstream competence genes to these inputs shows evidence of stochasticity and bistability and has been difficult to interpret. We have used microfluidic, single-cell methods to study how combinations of extracellular signals shape the response of comX, an alternative sigma factor governing expression of the late competence genes. We find that the composition of the medium determines which extracellular signal (XIP or CSP) can elicit a response from comX and whether that response is unimodal or bimodal across a population of cells. In a chemically defined medium, exogenous CSP does not induce comX, whereas exogenous XIP elicits a comX response from all cells. In complex medium, exogenous XIP does not induce comX, whereas CSP elicits a bimodal comX response from the population. Interestingly, bimodal behaviour required an intact copy of comS, which encodes the precursor of XIP. The comS-dependent capability for both unimodal and bimodal response suggests that a constituent - most likely peptides - of complex medium interacts with a positive feedback loop in the competence regulatory network. PMID- 22845618 TI - 16 year experience with aspiration of noncomplex breast cysts: cytology results with focus on positive cases. AB - We performed a retrospective review of 5375 aspirations performed during the last 16 years of noncomplex cysts. Cytology results and outcomes following aspirations of simple and complicated cysts performed by the senior author at our institution were reviewed. Complex cysts with associated solid components which were core biopsied are excluded from this review. We present our data as the largest series to date performed by one breast radiologist at a single institution. Our data separate cysts with atypia or malignant cytology into those sampled concurrently with solid neoplasms and those which were isolated lesions. Various technical issues which have not been previously addressed in the literature are discussed. Noncomplex cysts are benign 99% of the time. Cysts with papillary cytology require no further workup. Margin-negative seromas do not require cytologic analysis of fluid. Sixteen malignancies were revealed (0.3%), eight of which were solitary cysts (0.1%). Atypical cytology predicted malignancy in 21%; therefore, atypical cytology requires further workup. Malignant cytology was associated with breast cancer in 90.9% of patients; therefore, all patients with malignant cytology require biopsy. PMID- 22845617 TI - Adequacy of early enteral nutrition in adult patients in the intensive care unit. AB - AIMS AND OBJECTIVES: To evaluate the adequacy of energy and protein intake of patients in a Korean intensive care unit in the first four days after initiation of enteral feeding and to investigate the factors that had impact on adequate intake. BACKGROUND: Underfeeding is a common problem for patients hospitalised in the intensive care unit and is associated with severe negative consequences, including increased morbidity and mortality. DESIGN: A prospective, cohort study was conducted in a medical intensive care unit of a university hospital in Korea. METHODS: A total of 34 adult patients who had a primary medical diagnosis and who had received bolus enteral nutrition for the first four days after initiation of enteral nutrition were enrolled in this study. The data on prescription and intake of energy and protein, feeding method and feeding interruption were recorded during the first four days after enteral feeding initiation. Underfeeding was defined as the intake <90% of required energy and protein. RESULTS: Most patients (62%) received insufficient energy, although some (29%) received adequate energy. More than half of patients (56%) had insufficient protein intake during the first four days after enteral feeding was initiated. Logistic regression analysis showed that the factors associated with underfeeding of energy were early initiation of enteral nutrition, under-prescription of energy and prolonged interruption of prescribed enteral nutrition. CONCLUSION: Underfeeding is frequent in Korean critically ill patients owing to early initiation, under-prescription and prolonged interruption of enteral feeding. RELEVANCE TO CLINICAL PRACTICE: Interventions need to be developed and tested that address early initiation, under-prescription and prolonged interruption of enteral nutrition. Findings from this study are important as they form the foundation for the development of evidence-based care that is badly needed to eliminate underfeeding in this large vulnerable Korean intensive care unit population. PMID- 22845619 TI - Hygiene and sanitation practices amongst residents of three long-term refugee camps in Thailand, Ethiopia and Kenya. AB - OBJECTIVE: To further the understanding of sanitation and hygiene in long-term camp populations. METHODS: Data were collected by structured observation of handwashing (126 households), a questionnaire on sanitation, hygiene and household characteristics (1089 households) and discussions with mothers. Random walk algorithms were used to select households for observation and survey. Respondents for qualitative methods were a convenience sample. RESULTS: Across all key handwash occasions [excluding events with no handwash (n=275)], soap was used for 30% of handwashes. After latrine use, both hands were washed with soap on 20% of occasions observed. Availability of soap in households differed across sites and mirrored the extent to which it was distributed free of charge. Qualitative data suggested lack of free soap as a barrier to 'safe' handwashing. Laundry was the priority for soap. In Ethiopia and Kenya, open defecation was practised by a significant minority and was more prevalent amongst households of rural origin. In Ethiopia, open defecation was significantly more prevalent amongst women. CONCLUSIONS: Despite continuing hygiene education, rates of 'safe' handwashing are sub-optimal. Soap scarcity in some households and the prioritisation of laundry are barriers to safe practice. Heterogeneity with respect to education and place of origin may need to be taken into account in the design of improved interventions. PMID- 22845620 TI - Data distribution: normal or abnormal? What to do about it. PMID- 22845621 TI - Determination of arsenic in chicken feed by hydride generation atomic absorption spectrometry after pre-concentration with polyurethane foam. AB - A pre-concentration procedure with solid-phase extraction was developed for the determination of arsenic (As) in chicken feed using hydride generation atomic absorption spectrometry (HG-AAS). The procedure was based on the sorption of As(III) ions as complexes with ammonium pyrrolidine dithiocarbamate onto a mini column packed with polyurethane foam. After pre-concentration, the As was removed from the mini-column by acid solution, and the analyte content in the eluate was measured by HG-AAS. The following main experimental conditions were established: adjustment of the As solution pH with 0.05 mol l-1 HCl, 2.88 * 10-3 mol l-1 complexing agent concentration and 6.0 mol l-1 eluting hydrochloric acid concentration. The proposed method produced an enrichment factor of 67, with 0.050 and 0.165 ug g-1 limits of detection and quantification, respectively. The procedure was applied to the determination of As content in two types of chicken feed using the proposed procedure and atomic absorption spectrometry with electrothermal atomisation (ETAAS). The t-test indicated that the results were not significantly different at a confidence level of 95%. PMID- 22845623 TI - Intermuscular hemangioma of the left ventricle. AB - Intermuscular hemangioma is a histological type of hemangioma and rarely originates from the heart. This paper reports a case of giant intermuscular hemangioma of the left ventricle in a 20-year-old male patient. PMID- 22845622 TI - Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons. AB - BACKGROUND: Intestinal glucose induces gastric relaxation via vagally mediated sensory-motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP-sensitive potassium channels, and indirectly, via the release of 5-hydroxytryptamine (5-HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5 HT, via regulation of neuronal 5-HT(3) receptors. METHODS: Whole-cell patch clamp recordings were made from acutely dissociated GI-projecting vagal afferent neurons exposed to equiosmolar Krebs' solution containing different concentrations of d-glucose (1.25-20 mmol L(-1)) and the response to picospritz application of 5-HT assessed. The distribution of 5-HT(3) receptors in neurons exposed to different glucose concentrations was also assessed immunohistochemically. KEY RESULTS: Increasing or decreasing extracellular d glucose concentration increased or decreased, respectively, the 5-HT-induced inward current and the proportion of 5-HT(3) receptors associated with the neuronal membrane. These responses were blocked by the Golgi-disrupting agent Brefeldin-A (5 MUmol L(-1)) suggesting involvement of a protein-trafficking pathway. Furthermore, l-glucose did not mimic the response of d-glucose implying that metabolic events downstream of neuronal glucose uptake are required to observe the modulation of 5-HT(3) receptor mediated responses. CONCLUSIONS & INFERENCES: These results suggest that, in addition to inducing the release of 5 HT from enterochromaffin cells, glucose may also increase the ability of GI vagal sensory neurons to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified or prolonged. PMID- 22845624 TI - Therapy of cardiac device pocket infections with vacuum-assisted wound closure long-term follow-up. AB - BACKGROUND: Cardiac device infections are serious complications that require aggressive treatment strategies, including interventional or surgical lead extraction. METHODS: Here we describe the long-time follow-up of vacuum-assisted closure (V.A.C.) treatment in five patients with local cardiac device infection (LDI). In these patients the device was removed, the electrodes were shortened, and a V.A.C. treatment was applied. The primary endpoint was defined as time to re-LDI. RESULTS: Three patients had LDI of a pacemaker pocket, whereas two presented with an infection of their ICD pocket. The V.A.C. treatment was applied for 34.4 +/- 17.9 days. The mean hospitalization time was 38.6 +/- 19.2 days. The follow-up period was assessed for 34.6 +/- 19.2 months. Only one patient developed re-LDI, 69 days after removal of the device. The other four patients did not show any signs of reinfection during the follow-up period. None of the five patients sustained serious adverse events. CONCLUSIONS: V.A.C. treatment may be an option for selected patients with LDI who refuse a laser-guided lead extraction or surgical removal of the electrodes as the primary therapy. PMID- 22845625 TI - On the suppression mechanism of the pseudo-Jahn-Teller effect in middle E6 (E = P, As, Sb) rings of triple-decker sandwich complexes. AB - Quantum chemical calculations of the CpMoE(6)MoCp (E = P, As, Sb) triple-decker sandwich complexes showed that E(6) fragments in the central decks of the complexes are planar. Analysis of molecular orbitals involved in vibrational coupling demonstrated that filling the unoccupied molecular orbitals involved in vibronic coupling with electron pairs of Mo atoms suppresses the PJT effect in the CpMoE(6)MoCp (E = P, As, Sb) sandwich, with the E(6) ring becoming planar (D(6h)) upon complex formation. The AdNDP analysis revealed that bonding between C(5)H(5)(-) units and Mo atoms has a significant ionic contribution, while bonding between Mo atoms and E(6) fragment becomes appreciably covalent through the delta-type M -> L back-donation mechanism. PMID- 22845626 TI - Phase diagram, design of monolayer binary colloidal crystals, and their fabrication based on ethanol-assisted self-assembly at the air/water interface. AB - Flexible structural design and accurate controlled fabrication with structural tunability according to need for binary or multicomponent colloidal crystals have been expected. However, it is still a challenge. In this work, the phase diagram of monolayer binary colloidal crystals (bCCs) is established on the assumption that both large and small polystyrene (PS) colloidal spheres can stay at the air/water interface, and the range diagram for the size ratio and number ratio of small to large colloidal spheres is presented. From this phase diagram, combining the range diagram, we can design and relatively accurately control fabrication of the bCCs with specific structures (or patterns) according to need, including single or mixed patterns with the given relative content. Further, a simple and facile approach is presented to fabricate large-area (more than 10 cm(2)) monolayer bCCs without any surfactants, using differently sized PS spheres, based on ethanol-assisted self-assembly at the air/water interface. bCCs with different patterns and stoichiometries are thus designed from the established phase diagram and then successfully fabricated based on the volume ratios (V(S/L)) of the small to large PS suspensions using the presented colloidal self-assembling method. Interestingly, these monolayer bCCs can be transferred to any desired substrates using water as the medium. This study allows us to design desired patterns of monolayer bCCs and to more accurately control their structures with the used V(S/L). PMID- 22845627 TI - Optimization of serum EVELISA for milk testing of Johne's disease. AB - Johne's disease (JD) or paratuberculosis, caused by Mycobacterium avium ssp. paratuberculosis (MAP), is one of the most economically important diseases of dairy cattle. Control of JD could be achieved by good herd management practices, and diagnosis; however, this approach has been hampered by the low sensitivity of currently available enzyme-linked immunosorbent assay (ELISA) tests. In our previous study, we developed a sensitive serum ELISA test, ethanol-vortex enzyme linked immunosorbent assay (EVELISA), using ethanol extract of MAP. The objective of this study is to demonstrate that the EVELISA can be used for detection of anti-MAP antibodies in milk samples. In this study, we tested and optimized concentrations of antigen, milk, and secondary antibody for better differentiation of milk samples of cattle with MAP infections from those of cattle in JD-free herds. We evaluated five environmental mycobacteria as absorbents of cross-reactive antibodies in milk and found that the mycobacteria had no significant effect on EVELISA results. Using the optimized conditions, a total of 57 milk samples from Holstein dairy cattle (37 animals found positive on the fecal polymerase chain reaction test and 20 animals from JD-free herds) were tested for anti-MAP antibody in milk by using the EVELISA method. The average of ELISA values in the JD-positive milk samples (mean+/-SD=0.355+/-0.455) was significantly higher than that in the JD-negative milk samples (mean+/-SD=0.071+/ 0.011). These results warrant further studies for evaluation and validation of the EVELISA for milk testing of cattle for JD. PMID- 22845628 TI - Cyclic sulfur ylides from alpha-amino acids. 1. Design, synthesis, and reactivity. PMID- 22845630 TI - Medication errors: perspectives of newly graduated and experienced nurses. AB - This study investigated the perspectives of newly graduated and experienced nurses concerning medication errors. This is a descriptive cross-sectional study conducted in a military education and research hospital in Turkey, which was performed between July and August 2009. Totally, 169 nurses were involved in this study: 87 were new graduates and 82 were experienced nurses. The Modified Gladstone's Scale of Medication Errors was used to collect data on rates, causes and reporting of medication errors. The two highest perceived causes of medication errors were nurse exhaustion and nurse distraction. Most medication errors were preventable errors. The reasons for error occurrence and failure to inform co-workers of medical errors were examined. IMPLICATIONS: Training nurses to understand the causes of medication errors and related prevention methods should be provided to newly graduated nurses, and continuous training should be provided. PMID- 22845631 TI - Relationships among the perceived health status, family support and life satisfaction of older Korean adults. AB - The objective of this study was to examine the perceived health status, family support and life satisfaction of older Korean adults and the relationships among them. This study was designed to be a descriptive correlation study using questionnaire. Subjects were 246 older people who were over 65 years of age in Seoul and Daegu metropolitan city, Korea. Measures were the Cornell Medical Index Simple Korean Form to measure the perceived health status, the Family Support Instrument to measure the family support and the Standard Life Satisfaction Instrument for Korean people to measure the life satisfaction. Perceived health state was worse as average 3.3, family support was good as average 3.4 and life satisfaction was low as average 3.1. There were statistically significant positive correlations among perceived health state, family support and life satisfaction and between family support and life satisfaction. The predictors of life satisfaction in elderly were family support, age, monthly allowance and perceived health state. These factors explained 37.5% of the total variance. The major influencing factor was family support. This cross-sectional study provides preliminary evidence that to develop nursing strategy to increase family support of older Korean adults is needed. PMID- 22845632 TI - Community palliative care nurse experiences and perceptions of follow-up bereavement support visits to carers. AB - Community (district) nurses (CNs) are well positioned to provide follow-up home visits to bereaved families and carers of their recently deceased palliative clients. An Australian survey of CN's (n = 58, response rate 29%) described their experiences of bereavement support visits, perceptions of their role in bereavement care and their professional support needs. Although positive experiences were commonly reported, with 95% of participants considering bereavement follow-up visits as consistent with their role, 53% found the visits difficult for reasons such as the nurse or client not understanding the purpose, the CN's excessive personal identification with the client's situation, the emotional intensity of visits, and lack of confidence or skills despite prior training. The nature and quality of the CN's prior relationship with the bereaved family was an important determinant of the visits' success. Results highlight the value of bereavement support visits, while identifying professional development needs. Managing emotionally intense episodes should receive priority in preparing CN's for this challenging role. PMID- 22845633 TI - Effects of the contact isolation application on anxiety and depression levels of the patients. AB - This study was aimed to assess the effects of contact isolation application on anxiety and depression levels of the patients, the effects of certain sociodemographics and patient characteristics on anxiety and depression levels, and the thoughts of the isolated patients about contact isolation. This non randomized quasi-experimental study was carried out with 60 isolated and 57 non isolated patients with hospital infection. The data were acquired from Hospital Anxiety and Depression Scale (HADS-A (anxiety) and HADS-D (depression)) and patient information form. There was no statistically significant difference between the anxiety and depression levels of the isolated and non-isolated patients. In the isolated patients, the depression points were higher in patients who were, women, received primary education and had lower income levels. Of the patients, 86.4% of them told that they were happy to be in the isolation room. Contact isolation application did not affect anxiety and depression levels of the patients. However, personal attributes increased the development of depression. In contact isolated patients, personal attributes should be taken into consideration in nursing care planning to prevent development of depression. PMID- 22845634 TI - Oral care practices of intensive care nurses: a descriptive study. AB - The aim of this study was to investigate intensive care unit (ICU) nurses' views and practices on oral care and to define the factors related to oral care measures. A study was carried out in eight ICUs of a teaching hospital in 2008. One hundred one nurses constituted the study sample. The data were collected using 'Oral Care Practices Survey' which included demographic characteristics (5 items) and current oral care practices (13 items). Oral care was given the highest priority by nearly 60% of the nurses. The most commonly used solution was sodium bicarbonate (79.2%), and the most frequently used equipment was foam swab (82.2%). Oral care was carried out less than every 4 h per day by 44.5% of the nurses. The oral care products and solutions were reported to be different in almost every unit. The relationship between the use of toothpaste and the place of employment was statistically significant (x(2) = 24.566, d.f. = 6, P = 0.000). There was a statistical significance between the clinics and frequency of oral care (x(2) = 81.486, d.f. = 42, P = 0.000). This study suggests that there is a wide variety of type and frequency of oral care measures among ICU nurses. Optimal oral care supported by evidence is an effective prevention method for eliminating oral complications. PMID- 22845635 TI - Nursing documentation: experience of the use of the nursing process model in selected hospitals in Ibadan, Oyo State, Nigeria. AB - The descriptive study was conducted to determine the extent of utilization of the nursing process for documentation of nursing care in three selected hospitals, Ibadan, Nigeria. One hundred fifty nurses and 115 discharged clients' records were selected from the hospitals. Questionnaires and checklists were used to collect data. Utilization of nursing process for care was 100%, 73.6% and 34.8% in the three hospitals. Nurses encountered difficulties in history taking, formulation of nursing diagnoses, objectives, nursing orders and evaluation. Most nurses disagreed or were undecided with the use of authorized abbreviations and symbols (34.3%, 40.3% and 69.5%), recording errors that occurred during care (37.1%, 56.1% and 52.2%) and inclusion of change in clients' condition (54.3%, 56.1% and 73.8%). Most nurses appreciated the significance of documentation. Lack of time, knowledge and need for extensive writing are the major barriers against documentation. Seventy-seven point four per cent of the 115 clients' records from one hospital showed evidence of documentation, no evidence from the other two. Study findings have implications for continuing professional education, practice and supervision. PMID- 22845636 TI - The effect of the one-to-one interaction process with group supportive psychotherapy on the levels of hope, anxiety and self-care practice for patients that have experienced organ loss: an alternative nursing care model. AB - This quasi-experimental research examined the effect of the one-to-one interaction process with group supportive psychotherapy on the levels of hope, anxiety and self-care practice for patients that have experienced organ loss. Eighty patients from the hospital units were selected by matched pairs and paired according to gender, interval of age, type and time length of organ loss. Simple random sampling was used to allocate each subject in the experimental and control groups, which consisted of 40 pairs. Questionnaires included hope, anxiety and self-care practice assessments. The experimental treatments consisted of the one to-one interaction process with group psychotherapy. The results showed that the patients that received treatments in the experimental group had higher mean scores regarding the differences in levels of hope, anxiety and self-care practice than those in the control group. This integrative approach is an alternative method for giving patients self-confidence in their self-care practice, in maintaining hope and in reducing anxiety. The method assisted patients in understanding their own problems and corrective actions so that they could be accepted by others by exchanging their feelings, thoughts, opinions and experiences through confrontation and self-exploration both individually and in group. PMID- 22845637 TI - Development and pilot test of pictograph-enhanced breast health-care instructions for community-residing immigrant women. AB - Current written text-based health-care instructions are not suitable for presenting lengthy, complex breast health-care instructions and are difficult for immigrant women with limited literacy skills. The aims of this study were to develop breast health-care instructions enhanced by pictographs (simple line drawings representing health-care actions) and pilot test the instructions in a sample of six immigrant women with limited literacy skills. Based on the Mayer's Cognitive Theory of Multimedia Learning, pictographs were developed in addition to low-literacy text. The text and the pictographs were then pilot tested with six immigrant women in community health centres for clarity, comprehension and acceptability through face-to-face interviews. Participants perceived that the drawings were engaging and enhanced clarity of the intended health-care messages. The black and white simple line drawings were well received by participants of varying race and ethnicity. The pictograph-based approach might be an effective tool in developing health-care instructions for immigrant women with limited literacy skills. Future research is needed to compare the effect of pictograph enhanced instructions with written text-based instructions on adherence to instructions and health outcomes. PMID- 22845638 TI - A person-centred lifestyle change intervention model: working with older people experiencing chronic illness. AB - A person-centred health promotion model of care to improve self-care and lifestyle changes for older people with chronic illnesses is conceptualized in this paper. The model supports effective interpersonal communication with nurses and health-care consumers and is developed to concept stage. Older people with chronic illnesses who experience stress, anxiety or social isolation are more likely to be admitted and re-admitted to acute hospitals. Interventions to decrease the risk factors are frequently unsuccessful in this patient group. Programmes, led by nurses, aimed at reducing stress, anxiety and social isolation while supporting older people postdischarge from hospital might be successful. The model integrates research from synthesized case studies and a critical literature review. The practices of interrelating four key elements-'construct', 'context', 'process' and 'outcome'-are proposed for nurses to assist patients advancing self-care and lifestyle change. The model is designed for implementation in outpatient, clinic or community settings. PMID- 22845639 TI - A Chinese version of the Caring Assessment Report Evaluation Q-sort scale for measuring patients' perception on nurses' caring behaviours: reliability and validity assessment. AB - A reliable and valid instrument for understanding patients' perceptions of nurses' caring behaviour as well as assessing the quality of nursing care is necessary. The purpose of this study was to assess the reliability and validity of a Chinese version of the Caring Assessment Report Evaluation Q-sort (CARE-Q) Scale for the measurement of patients' perceptions of nurses' caring behaviours. The study sample comprised 250 patients from a medical centre in central Taiwan. Content validity, construct validity, internal consistency and stability reliability were assessed. The Content Validity Index of the Chinese version of CARE-Q was 0.90. Cronbach's alpha indicated good internal consistency reliability. Stability reliabilities for the six subscales ranged from 0.83 to 0.92. The results reveal that the Chinese version of the CARE-Q scale for the measurement of patients' perceptions on nurses' caring behaviours indicates high reliability (internal consistency and stability) and good content validity. PMID- 22845640 TI - The effectiveness of therapeutic interventions on quality of life for vitiligo patients: a systematic review. AB - This paper reviews the effectiveness of therapeutic interventions on quality of life for adult patients with vitiligo. We systematically searched nine databases from 1990 to February 2010 and reviewed randomized controlled trials and quasi experimental studies of current therapeutic interventions for vitiligo, including oral, topical, combination, camouflage, cognitive-behavioural therapy and grafting. Quality of life outcomes were collected. The Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument was used for quality assessment. Nine studies were included for this review, and all treatments were found to improve quality of life for vitiligo patients. Disease-altering interventions were effective in improving quality of life. Lifestyle-altering interventions were found to be selectively effective for patients with more severe quality of life impairment. Current interventions for vitiligo are effective in improving quality of life either by enhancing physical appearance of the patient or by addressing the psychological distress directly. Less effectiveness was achieved for the functional and social dimensions, which are more dependent on social and cultural norms. This suggests that current interventions alone are inadequate to address the holistic quality of life challenges associated with vitiligo. PMID- 22845641 TI - Translating and testing the Liver Disease Symptom Index 2.0 for administration to people with liver cirrhosis in Egypt. AB - The Liver Disease Symptom Index (LDSI) 2.0 is a simple, short and specific liver disease questionnaire in English, but an Arabic version does not exist, therefore we translated the LDSI-2.0 into Arabic and tested its psychometric properties in a pilot cross-sectional study. A convenience sample of 38 patients with liver cirrhosis from one hospital in Cairo, Egypt, were interviewed for approximately 45 min. Patients completed a background data sheet, the translated LDSI-2.0 and the Short Form (SF)-36v(2). Construct convergent validity was examined by correlating LDSI-2.0 items with the SF-36v(2) eight domains. Reliability was estimated using measures of internal consistency, test-retest reliability and internal consistency reliability. Median completion time was 10 min. The correlation between the translated LDSI-2.0 items and the SF-36 domains confirmed that there was moderate to high overlapping between the two measures, suggesting convergent validity of the LDSI-2.0. The LDSI-2.0 showed good to very good retest reliability (kappa value 0.62-0.94). Chronbach's alpha coefficient for the multi item scales ranged from 0.73 to 0.96. The Arabic LDSI-2.0 therefore has satisfactory validity, retest reliability and internal consistency. PMID- 22845642 TI - Kenya and distance education: a model to advance graduate nursing. AB - Africa is faced with a myriad of challenges, such as HIV/AIDS, malaria, tuberculosis, and a variety of political and historical complications that have affected the educational system for advanced nursing practice. In Kenya, the current situation in the higher education sector does not give nurses an opportunity to pursue graduate education after they have acquired the basic diploma in nursing due to limited government support and the type of education system existing in the country today. Although distance education has been available in Kenya for professionals such as teachers, in public universities, this kind of opportunity is unreachable for nurses who are working and need to further their education. Nurses desire to have access to advanced practice education to equip them with the relevant knowledge to cope and address the complex health issues arising in the management and care of patients. A collaborative model is presented as a potential solution for this need. Four major constituents are identified including hospitals and agencies, communities of interest, Kenyan universities and international education partners. Each has a part to play including contributions to information, communication of opinion and expertise, money and support, infrastructure and in-kind resources. Distance education is cost-effective and will help in building capacity at various levels of nursing including leadership in clinical practice, teaching, administration and research. PMID- 22845643 TI - "The midwifery two-step": a study on evidence-based midwifery practice. AB - INTRODUCTION: To date, there has been little documentation of how practice-based midwifery networks in the United States might influence the transfer and development of knowledge in childbearing and women's health care. The first phase of this participatory action research project was to conduct a qualitative study with a community of midwifery practices to understand their perspectives on evidence-based practice and how an organized network could facilitate their work. METHODS: Midwives within the community of interest were invited by letter or e mail to participate in individual or small group interviews about knowledge transfer, primary concerns of evidence-based practice, and potential for a midwifery practice-based research network. Participatory action research strategies and organizational ethnographic approaches to data collection were used to guide qualitative interviews. RESULTS: Eight midwifery practices enrolled in the study with 23 midwives participating in interviews. They attended births at 2 hospitals in the community. Two broad areas of discourse about evidence based practice were identified: 1) challenges from influential persons, finances and resources, and the cultural perception of midwifery, and 2) strategies to foster best practice in the face of those challenges. The midwives believed a research network could be useful in learning collectively about their practices and in the support of their work. DISCUSSION: Evidence-based practice is a goal but also has many challenges in everyday implementation. Practice-based research networks hold promise to support clinicians to examine the evidence and form strong coalitions to foster best clinical practice. The second phase of this study will work with this community of midwives to explore collective strategies to examine and improve practice. PMID- 22845644 TI - Laparoscopic repair of incarcerated congenital diaphragmatic hernias presenting beyond the newborn period. AB - PURPOSE/BACKGROUND: Congenital diaphragmatic hernias (CDHs) diagnosed outside of the newborn period are an uncommon occurrence in developed countries. Incarceration of viscera presenting as bowel obstruction is a rare clinical scenario with only a few cases reported in the literature, all of which have been repaired via laparotomy. We have recently encountered a series of these cases that we approached laparoscopically. SUBJECTS AND METHODS: We performed a retrospective review to identify patients who underwent laparoscopic repair of CDH with incarceration after the neonatal period. Demographics, presentation characteristics, operative details, and outcomes were reviewed. results: Between 2008 and 2011, three patients underwent laparoscopic repair of left-sided incarcerated CDH presenting with bowel obstruction. The mean age was 60.8 months (range, 2-157 months) with a mean weight of 30.2 kg (range, 11-66.5 kg). All cases were completed laparoscopically using a 5-mm umbilical port with three to four additional 3-mm instruments. The mean operative time was 133 minutes (range, 117-164 minutes). There were no intraoperative or postoperative complications. Mean length of hospital stay was 4 days (range, 1-8 days). Median follow-up was 6.3 months (range, 0.8-42.3 months). One patient suffered a recurrence after a motor vehicle collision and subsequently underwent a successful second laparoscopic repair. CONCLUSIONS: The laparoscopic approach for patients presenting with an incarcerated CDH beyond the newborn period appears to be an appropriate approach and should be considered when this diagnosis is encountered. PMID- 22845645 TI - Construct validity of the Quality of Upper Extremity Skills Test for children with cerebral palsy. AB - AIM: The aim of the study was to investigate the construct validity of the Quality of Upper Extremity Skills Test (QUEST) in children with cerebral palsy (CP). METHOD: A total of 170 QUEST assessments from a convenience sample of 94 children with CP involved in clinical and research treatment programmes (54 males, 40 females; mean age 6y 10mo, SD 2y 11mo, range 2-16y; Gross Motor Function Classification System levels I-V) were reviewed. RESULTS: The QUEST was not unidimensional; many items demonstrated poor fit when total scores were analysed; goodness of fit improved when domains were considered independently and limbs separately examined. QUEST items involving elbow flexion and/or forearm in pronation were easily achieved, thus reducing test sensitivity. Postures items in the grasp domain behaved erratically, with little total score relationship. INTERPRETATION: Calculating total scores is discouraged. Reporting QUEST results separately for domains and each limb is recommended. Posture items in the grasp domain had little relationship with total scores and it is recommended that they be removed from the test. PMID- 22845646 TI - Dietary practices in glutaric aciduria type 1 over 16 years. AB - BACKGROUND: In glutaric aciduria type 1 (GA1), dietary treatment with emergency management (EM) is essential to prevent encephalopathic crisis (EC). In the present study, dietary practices were examined in a single UK centre without access to newborn screening. METHODS: Twenty GA1 patients (11 males, median age: 10.2 years, range 2.2-24.1 years) were evaluated. Nine presented without EC (median diagnosis age: 1.1 years, range 4 days to 8 years) and 11 with EC (median diagnosis age 10 months, range 6 months to 1.7 years). Dietary treatment, neurological outcome, anthropometry and biochemical/haematological markers were assessed. RESULTS: Diet treatment varied according to age of diagnosis and symptom severity. Four of six pre-encephalopathic children diagnosed before 2 years of age were treated with carnitine, protein restriction (medium l.2 g kg day(-1)) and lysine-free/low tryptophan protein substitute (PS) (medium dose: 1.6 g kg day(-1)). EM consisted of natural protein cessation and glucose polymer with PS delivered via an enteral feeding tube. Older children (>3 years) without EC were given carnitine and protein restriction, and seven of nine EC patients had PS via an enteral feeding tube. Clinical deterioration occurred in two patients without EC; one taking PS and protein restriction (with a second untreatable pathology) and one after protein restriction only. In patients presenting with EC, four died and one had some improvement in movement, with the rest remaining stable but with severe disability. Patients taking PS had better nutritional markers [serum vitamin B(12) (P < 0.001), albumin (P < 0.001), haemoglobin (P < 0.001) and essential plasma amino acids]. CONCLUSIONS: Early diagnosis of GA1 before EC is essential because PS and protein restriction with meticulous EM prevents EC. PS also improves nutritional status irrespective of clinical condition. PMID- 22845647 TI - Social networks and the spread of Salmonella in a sleepy lizard population. AB - Although theoretical models consider social networks as pathways for disease transmission, strong empirical support, particularly for indirectly transmitted parasites, is lacking for many wildlife populations. We found multiple genetic strains of the enteric bacterium Salmonella enterica within a population of Australian sleepy lizards (Tiliqua rugosa), and we found that pairs of lizards that shared bacterial genotypes were more strongly connected in the social network than were pairs of lizards that did not. In contrast, there was no significant association between spatial proximity of lizard pairs and shared bacterial genotypes. These results provide strong correlative evidence that these bacteria are transmitted from host to host around the social network, rather than that adjacent lizards are picking up the same bacterial genotype from some common source. PMID- 22845648 TI - Contraceptive use among HIV-positive women in Quang Ninh province, Vietnam. AB - OBJECTIVE: To investigate contraceptive use among HIV-positive women in Ha long city and Cam Pha town of Quang Ninh, a Northern province of Vietnam. METHODS: Cross-sectional questionnaire study among HIV-positive women identified through the district HIV/AIDS register. Information on socioeconomic characteristics and contraceptive use before and after HIV diagnosis was obtained through structured questionnaires. Chi-square testing was used to assess whether the included women differed from the target population in terms of age. Crude Odds ratios (ORs) were calculated to show the association between contraceptive use and the women's socioeconomic characteristics. Logistic regression analyses were applied to adjust for possible confounding. The women's contraceptive use before HIV testing and after HIV testing was described and compared by Chi-square testing, and the association between post-test counselling and the women's use of condom was assessed by ORs. RESULTS: Of the 351 participants, 63% stated they had used contraception before HIV diagnosis and 89% stated they had used contraception after HIV diagnosis. Forty six per cent of the women had been using either the pill or an intrauterine device (IUD) before the diagnosis whereas the same applied for only 8% of the women after diagnosis. Thirty-nine per cent stated they had been using condom before HIV diagnosis whereas 87% stated condom use after HIV diagnosis. Condom use was more common among women who had received post test counselling (OR 3.03, 95% CI 1.03-8.90). CONCLUSIONS: A change of contraceptive methods from IUD and oral contraception before HIV diagnosis to condom use after HIV diagnosis was observed. The women's use of condoms after HIV diagnosis was associated with having received post-test counselling. PMID- 22845649 TI - The number of basal rates required to achieve near-normal basal glucose control in pump-treated type 2 diabetes. AB - BACKGROUND: It has been reported that most pump-treated patients with type 2 diabetes require only two or fewer basal rates. Using daily continuous glucose monitoring (CGM)-directed titration, this premise was re-evaluated at near-normal glycemic control. PATIENTS AND METHODS: Thirty subjects who were insulin-naive (n = 10), on basal insulin (n = 10), or on basal-bolus insulin therapy (n=10) ate a fixed diet. The basal rate was started as a single rate and then adjusted to a basal glucose goal of 70-130 mg/dL. The insulin-to-carbohydrate ratio (ICR) (in g/U) was adjusted to 2-4-h postmeal CGM glucose goal of 80-120% of premeal glucose. RESULTS: The mean (SE) CGM basal glucose was 99.9 (4.9) mg/dL, and 4.5% (1.4%) of the readings were <70 mg/dL. The mean 2-4-h postmeal glucose was 113.3% (4.8%) of the premeal glucose. Only six subjects (20%) required two basal rates, while the remainder needed only one. The mean (SE) dosing relationships were as follows: total basal dose (TBD) (in U/day) = 0.226(0.018) * weight (in kg); TBD (in U/day) = 0.339(0.012) * total daily dose (TDD) (in U/day); ICR (in g/U) = 126(8)/TBD (in U/day); and ICR (in g/U) = 365(14)/TDD (in U/day). CONCLUSIONS: This study confirms that one basal rate is adequate for the majority of subjects with type 2 diabetes. The mathematical proportionality between dosing factors closely agrees with those obtained in CGM-titrated pump-treated type 1 diabetes but differs from those derived from clinical studies in which insulin titration was based on infrequent self-monitored plasma glucose testing and while on an unstructured diet. PMID- 22845650 TI - Childhood attention-deficit/hyperactivity disorder (ADHD) and growth in adolescent alcohol use: the roles of functional impairments, ADHD symptom persistence, and parental knowledge. AB - Research on the relation between childhood attention-deficit/hyperactivity disorder (ADHD) and adolescent alcohol use has found mixed results. Studies are needed that operationalize alcohol use in developmentally appropriate ways and that test theoretically plausible moderators and mediators in a longitudinal framework. The current study tested childhood ADHD as a predictor of alcohol use frequency at age 17 and age-related increases in alcohol use frequency, through adolescence for 163 adolescents with ADHD diagnosed in childhood and 120 adolescents without ADHD histories. Childhood ADHD did not predict either alcohol outcome. However, parental knowledge of the teen's friendships, activities, and whereabouts moderated the association such that childhood ADHD predicted alcohol use frequency at age 17 when parental knowledge was below median levels for the sample. Mediational pathways that explained this risk included social impairment, persistence of ADHD symptoms, grade point average, and delinquency. Social impairment was positively associated with alcohol use frequency through delinquency; it was negatively associated with alcohol use frequency as a direct effect independent of delinquency. These nuanced moderated-mediation findings help to explain previously inconsistent results for the ADHD-adolescent alcohol use association. The findings also imply that future research and intervention efforts should focus on ADHD-related social and academic impairments as well as symptom persistence and parenting efforts. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22845652 TI - Is there a general factor of prevalent psychopathology during adulthood? AB - The patterns of comorbidity among prevalent mental disorders in adults lead them to load on "externalizing," "distress," and "fears" factors. These factors are themselves robustly correlated, but little attention has been paid to this fact. As a first step in studying the implications of these interfactor correlations, we conducted confirmatory factor analyses on diagnoses of 11 prevalent Diagnostic and Statistical Manual of Mental Disorders (4th ed.) mental disorders in a nationally representative sample. A model specifying correlated externalizing, distress, and fears factors fit well, but an alternative model was tested in which a "general" bifactor was added to capture what these disorders share in common. There was a modest but significant improvement in fit for the bifactor model relative to the 3-factor oblique model, with all disorders loading strongly on the bifactor. Tests of external validity revealed that the fears, distress, and externalizing factors were differentially associated with measures of functioning and potential risk factors. Nonetheless, the general bifactor accounted for significant independent variance in future psychopathology, functioning, and other criteria over and above the fears, distress, and externalizing factors. These findings support the hypothesis that these prevalent forms of psychopathology have both important common and unique features. Future studies should determine whether this is because they share elements of their etiology and neurobiological mechanisms. If so, the existence of common features across diverse forms of prevalent psychopathology could have important implications for understanding the nature, etiology, and outcomes of psychopathology. PMID- 22845653 TI - Data distribution: normal or abnormal? PMID- 22845651 TI - Restless pillow, ruffled mind: sleep and affect coupling in interepisode bipolar disorder. AB - Disturbances in sleep and affect are prominent features of bipolar disorder, even during interepisode periods. Few longitudinal studies have prospectively examined the relationship between naturally occurring sleep and affect, and no studies to date have done so during interepisode periods of bipolar disorder and using the entire set of "gold standard" sleep parameters. Participants diagnosed with bipolar I disorder who were interepisode (n = 32) and healthy controls (n = 36) completed diagnostic and symptom severity interviews, and a daily sleep and affect diary, as well as an actigraphy sleep assessment, for eight weeks (M = 54 days, +/- 8 days). Mutual information analysis was used to assess the degree of statistical dependence, or coupling, between time series data of sleep and affect. As measured by actigraphy, longer sleep onset latency was coupled with higher negative affect more strongly in the bipolar group than in the control group. As measured by sleep diary, longer wakefulness after sleep onset and lower sleep efficiency were coupled with higher negative affect significantly more strongly in the bipolar group than in the control group. By contrast, there were no significant differences between groups in the degree of coupling between any measures of sleep and positive affect. Findings support the coupling of sleep disturbance and negative affect during interepisode bipolar disorder. Ongoing monitoring of sleep-affect coupling may provide an important target for intervention in bipolar disorder. PMID- 22845654 TI - C-H activation in pyridoxal-5'-phosphate Schiff bases: the role of the imine nitrogen. A combined experimental and computational study. AB - The origins of C-H activation in pyridoxal-5'-phosphate (PLP) Schiff bases and modulation of reaction specificity in PLP-enzymes are still not completely understood. There are no available studies that compare the reactivity of C4' carbons in ketimine Schiff bases with that of Calpha carbons in their aldimine counterparts, which is essential to unravel the mechanisms that govern the evolution of their common carbanionic intermediates. Second-order rate constants for phosphate-catalyzed proton/deuterium exchange reactions in D(2)O of C4' carbons suffer a 10(5)-fold increase due to Schiff base formation (k(B) = 5.3 * 10(1) M(-1) s(-1)) according to NMR measurements. The C4' carbon acidity is also increased to pK(a) = 9.8, which is significantly higher than that of Calpha in PLP-aldimines. DFT calculations reveal the role of each heteroatom in modulating the electrophilicity of C4' and Calpha carbons. Specifically, the protonation state of pyridine nitrogen is the main factor in determining the absolute carbon acidity in aldimines (pK(a) of Calpha varies from ~14 to ~23) and ketimines (pK(a) of C4' varies from ~12 to ~18), whereas the protonation state of both imine nitrogen and O3' phenol oxygen modulates the relative acidities of Calpha and C4' from 1.5 to 7.5 pK(a) units. Our results provide an explanation to the modulation of reaction specificity observed in different PLP-enzymes based on the differences in the protonation state of the cofactor and H-bonding patterns in the active site. PMID- 22845656 TI - Palmar pits associated with the nevoid basal cell carcinoma syndrome. PMID- 22845657 TI - A house of cards. PMID- 22845659 TI - Three novel allelic variants of the RAET1E/ULBP4 gene in humans. AB - Discovery of three novel alleles of RAET1E/ULBP4 by sequence-based typing: RAET1E*008, RAET1E*009 and RAET1E*010. PMID- 22845660 TI - Tissue Doppler imaging and 2-dimensional speckle tracking of left ventricular function in horses exposed to lasalocid. AB - BACKGROUND: Tissue Doppler imaging (TDI) and 2-dimensional speckle tracking (2DST) can quantify left ventricular (LV) function in horses. OBJECTIVES: To evaluate LV function by TDI and 2DST in horses with myocardial dysfunction after accidental ionophore intoxication. ANIMALS: Sixty-seven horses exposed to lasalocid in feed. METHODS: Prospective study. Horses were included in the study if a full cardiac examination was performed, consisting of determination of cardiac troponin I (cTnI), electrocardiography, and echocardiography. By TDI, radial systolic velocity and strain were measured. By 2DST, circumferential (SC) and radial (SR) strain at papillary muscle and chordal level and longitudinal (SL) strain were measured. RESULTS: Twenty horses showed signs of myocardial injury. Forty-nine examinations were performed on these horses between day 30 and 490 after suspected onset of exposure. Five horses had increased cTnI and ventricular tachycardia and 15 had increased cTnI without ventricular tachycardia. Horses with mild myocardial damage showed few significant differences compared with a control group. Horses with severe myocardial damage showed severely decreased TDI, 2DST and fractional shortening measurements (P < .05), indicating impaired LV function. Long-term follow-up of 2 surviving horses demonstrated full recovery in 1 horse and permanent myocardial fibrosis in the other. The lowest measurements per horse (n = 20) for all TDI measurements, SL, SR at chordal level, and FS correlated significantly with maximal cTnI (P < .05). Over all examinations (n = 49), TDI and 2DST measurements correlated well with FS (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: The TDI and 2DST measurements allowed accurate detection and quantification of LV dysfunction in horses exposed to lasalocid. PMID- 22845661 TI - The experience of working on a locked acute psychiatric ward. AB - This study's aim was to elucidate health-care staff experience of working on a locked acute psychiatric ward. In many countries changes in health care has contributed to fewer beds available in inpatient care, and a concentration of patients with severe psychiatric conditions. This implies a changing work environment in acute psychiatric care. Qualitative interviews with health-care staff (n= 10) were carried out on a ward for patients with affective disorder and eating disorder in a Swedish hospital. Qualitative content analysis was used. Four themes were identified from the data: 'undergoing changes in care delivery', 'feeling a need for security and control', 'managing the demands at work' and 'feeling a sense of responsibility'. This study adds to earlier research into how a sense of responsibility can place a significant burden on health-care staff working on a locked psychiatric ward and also contribute to increased control of patients. This study also shows that relationships and power structures among health-care staff need to be addressed when organizational changes are made in care delivery. Further research is needed to reach a comprehensive understanding of care on locked acute psychiatric wards, including a development of nursing and medicine as knowledge domains in one common context. PMID- 22845662 TI - New models for medical education: Web-based conferencing to support HIV training in Sub-Saharan Africa. AB - BACKGROUND: Healthcare workers in Africa managing human immunodeficiency virus (HIV)-infected patients often receive inadequate HIV-specific medical education. The acceptability and feasibility of Web-based distance learning tools to enhance HIV training in Africa have not been extensively evaluated. MATERIALS AND METHODS: In this prospective observational study, we assessed the feasibility of Web-conferencing to deliver HIV-specific medical training to clinicians supporting HIV care and treatment across 12 Sub-Saharan African countries over a 10-month period. Webinar attendance, technical quality, and participant satisfaction were measured for each Webinar. Demographic details about participants were recorded. RESULTS: Attendance increased from 40 participants in Month 1 to over 160 in Month 10. Thirty-six percent of participants were physicians, and 21% were in allied health professions. A mean of 95% of respondents found the content to be relevant. Participants reported that the opportunity to interact with HIV clinicians from other countries and expert teaching from leading scientists were major reasons for attendance. Audio quality was variable across countries and over time. Barriers to attendance included lack of information technology (IT) literacy and Internet connectivity. CONCLUSIONS: This analysis demonstrates that Webinars are feasible and acceptable to support HIV training. Significant impediments to scale up in use of Web-conferencing for HIV education in resource-limited settings include lack of IT hardware and limited IT literacy. Strengthening IT capacity and Internet infrastructure is necessary to support expanded use of Webinars as a tool for continuing HIV education. PMID- 22845663 TI - Risk factors for surgery and postoperative recurrence: analysis of a south China cohort with Crohn's disease. AB - BACKGROUND AND AIMS: To investigate the risk factors for primary surgery and postoperative recurrence in a cohort of Chinese Crohn's disease (CD) patients. METHODS: Medical notes of consecutive diagnosed patients from 2003 until 2010 were reviewed. Fifty-seven postoperative patients--finished regular follow-up- were recruited for postoperative recurrence analysis. RESULTS: One hundred eleven of 323 (34.4%) patients of this cohort underwent primary surgery. The cumulative frequency of resection was 16.6%, 35.4%, 53%, and 94.5% for 1, 5, 10, and 30 years, respectively, after onset of disease. Male (OR: 1.994; 95% CI: 1.291 3.078, p = 0.002), stricture (OR: 4.832; 95% CI: 3.064-7.621, p = 0.000), or penetrating (OR: 4.923; 95% CI: 3.060-7.919, p = 0.000) were associated with an increased risk for primary surgery, while early use of immunomodulators was (OR: 0.438; 95% CI: 0.218-0.880, p = 0.020) associated with a decreased risk. Fifty seven (21.1%) patients were diagnosed as postoperative clinical recurrence and the cumulative recurrence rates were 6.1%, 17.1%, and 36.8% for 1, 2, and 3 years, respectively. Perianal disease was associated with an increased risk for clinical recurrence (OR: 5.606; 95% CI: 1.59-19.766, p = 0.007). CONCLUSIONS: The operation frequency is high in CD. Male, penetrating, and stricture diseases are associated with an increased risk for primary surgery while early use of immunomodulators is associated with a decreased risk. The postoperative recurrence rate is also high. Patients with perianal disease are at higher risk for clinical recurrence. PMID- 22845664 TI - CXCR4-tropic, but not CCR5-tropic, human immunodeficiency virus infection is inhibited by the lipid raft-associated factors, acyclic retinoid analogs, and cholera toxin B subunit. AB - Development of an effective low-cost anti-acquired immunodeficiency syndrome (AIDS) drugs is needed for treatment of AIDS patients in developing countries. Host cell lipid raft microdomains, which are enriched with cholesterol, glycolipids, ceramide, and gangliosides, are important for human immunodeficiency virus type 1 (HIV-1) entry. Retinoid analogs have been shown to modulate ceramide levels in the cell membrane, while cholera toxin B subunit (CT-B) specifically binds to the ganglioside GM1. In this study, we found that the acyclic retinoid analogs geranylgeranoic acid (GGA) and NIK-333 as well as CT-B efficiently attenuate CXCR4-tropic, but not CCR5-tropic, HIV-1 vector infection. We also found that GGA and NIK-333 suppress CXCR4-tropic HIV-1 infection by attenuating CXCR4 expression. CT-B also attenuated CXCR4-tropic HIV-1 infection, but did not suppress CXCR4 expression. These results suggest a distinct role for lipid raft microdomains in CXCR4- and CCR5-tropic HIV-1 infections and illuminate novel agents for the development of AIDS therapy. PMID- 22845665 TI - Induction of P-glycoprotein and Bcrp at the rat blood-brain barrier following a subchronic morphine treatment is mediated through NMDA/COX-2 activation. AB - Subchronic morphine treatment induces P-glycoprotein (P-gp) up-regulation at the blood-brain barrier. This study investigates the rate and extent to which P-gp and breast cancer-resistance protein (Bcrp) increase at the rat blood-brain barrier following subchronic morphine treatment. Rats were given increasing doses of morphine (10-40 mg/kg) or saline i.p. twice daily for 5 days. The brain cortex large vessels and microvessels were then mechanical isolated 6, 9, 12, 24, and 36 h after the last injection. The gene and protein expression of P-gp and Bcrp in morphine-treated and control rats were compared by qRT-PCR and western blotting. The levels of Mdr1a and Bcrp mRNAs were not significantly modified 6 h post morphine, but the Mdr1a mRNA increased 1.4-fold and Bcrp mRNA 2.4-fold at 24 h. P gp and Bcrp protein expression in brain microvessels was unchanged 6 h post morphine and increased 1.5-fold at 24 h. This effect was more pronounced in large vessels than in microvessels. However, extracellular morphine concentrations of 0.01-10 MUM did not modify the expressions of the MDR1 and BCRP genes in hCMEC/D3 human endothelial brain cells in vitro. MK-801 (NMDA antagonist) and meloxicam (cyclo-oxygenase-2 inhibitor) given after morphine treatment completely blocked P gp and Bcrp up-regulation. Interestingly, misoprostol and iloprost, two well known agonists of prostaglandin E2 receptors induced both MDR1 and BCRP mRNA levels in hCMEC/D3. Thus, morphine does not directly stimulate P-gp and Bcrp expression by the brain endothelium, but glutamate released during morphine withdrawal may do so by activating the NMDA/cyclo-oxygenase-2 cascade. PMID- 22845667 TI - Bendable inorganic thin-film battery for fully flexible electronic systems. AB - High-performance flexible power sources have gained attention, as they enable the realization of next-generation bendable, implantable, and wearable electronic systems. Although the rechargeable lithium-ion battery (LIB) has been regarded as a strong candidate for a high-performance flexible energy source, compliant electrodes for bendable LIBs are restricted to only a few materials, and their performance has not been sufficient for them to be applied to flexible consumer electronics including rollable displays. In this paper, we present a flexible thin-film LIB developed using the universal transfer approach, which enables the realization of diverse flexible LIBs regardless of electrode chemistry. Moreover, it can form high-temperature (HT) annealed electrodes on polymer substrates for high-performance LIBs. The bendable LIB is then integrated with a flexible light emitting diode (LED), which makes an all-in-one flexible electronic system. The outstanding battery performance is explored and well supported by finite element analysis (FEA) simulation. PMID- 22845668 TI - Valuing lives and allocating resources: a defense of the modified youngest first principle of scarce resource distribution. AB - In this paper, I argue that the 'modified youngest first' principle provides a morally appropriate criterion for making decisions regarding the distribution of scarce medical resources, and that it is morally preferable to the simple 'youngest first' principle. Based on the complete lives system's goal of maximizing complete lives rather than individual life episodes, I argue that essential to the value we see in complete lives is the first person value attributed by the experiencer of that life. For a life to be 'complete' or 'incomplete,' the subject of that life must be able to understand the concept of a complete life, to have started goals and projects, and to know what it would be for that life to be complete. As the very young are not able to do this, it can reasonably be said that their characteristically human lives have not yet begun, giving those accepting a complete lives approach good reason to accept the modified youngest first principle over a simple 'youngest first' approach. PMID- 22845666 TI - Iron-catalyzed formation of 2-aminopyridines from diynes and cyanamides. AB - Diynes and cyanamides undergo an iron-catalyzed [2 + 2 + 2] cycloaddition to form highly substituted 2-aminopyridines in an atom-efficient manner that is both high yielding and regioselective. This system was also used to cyclize two terminal alkynes and a cyanamide to afford a 2,4,6-trisubstituted pyridine product regioselectively. PMID- 22845669 TI - Non-smoking-related chronic obstructive pulmonary disease: a neglected entity? AB - Chronic obstructive pulmonary disease (COPD) is an increasing cause of morbidity and mortality worldwide, and it has been strongly correlated to tobacco smoking. While a number of studies have concentrated on smokers only, recent published data demonstrate that at least one fourth of patients with COPD are non-smokers, and that the burden of COPD in non-smokers is also higher than previously believed. Risk factors of COPD in non-smokers may include genetic factors, long standing asthma, outdoor air pollution (from traffic and other sources), environmental smoke exposure (ETS), biomass smoke, occupational exposure, diet, recurrent respiratory infection in early childhood, tuberculosis and so on. In Asian region, indoor/outdoor air pollution and poor socioeconomic status may play important roles in the pathogenesis of non-smoking-related COPD. The prevalence of COPD among never smokers varies widely across nations. Such a variation may arise from several aspects, including study design, definition of COPD, diagnostic criteria, age and gender distribution of the studied population, local risk factors and socioeconomic status. More investigations and efforts are required to elucidate the involved factors and their shared contributions to non smoking-related COPD so as to achieve better estimation and reduction of the burden of this neglected entity worldwide. PMID- 22845672 TI - Raman enhancement on a broadband meta-surface. AB - Plasmonic metamaterials allow confinement of light to deep subwavelength dimensions, while allowing for the tailoring of dispersion and electromagnetic mode density to enhance specific photonic properties. Optical resonances of plasmonic molecules have been extensively investigated; however, benefits of strong coupling of dimers have been overlooked. Here, we construct a plasmonic meta-surface through coupling of diatomic plasmonic molecules which contain a heavy and light meta-atom. Presence and coupling of two distinct types of localized modes in the plasmonic molecule allow formation and engineering of a rich band structure in a seemingly simple and common geometry, resulting in a broadband and quasi-omni-directional meta-surface. Surface-enhanced Raman scattering benefits from the simultaneous presence of plasmonic resonances at the excitation and scattering frequencies, and by proper design of the band structure to satisfy this condition, highly repeatable and spatially uniform Raman enhancement is demonstrated. On the basis of calculations of the field enhancement distribution within a unit cell, spatial uniformity of the enhancement at the nanoscale is discussed. Raman scattering constitutes an example of nonlinear optical processes, where the wavelength conversion during scattering may be viewed as a photonic transition between the bands of the meta material. PMID- 22845673 TI - Coeliac disease, epilepsy, and cerebral calcifications: association with TG6 autoantibodies. AB - A 4-year-old boy presented with occipital seizures but normal initial neuroimaging and proved refractory to antiepileptic medications. On repeat neuroimaging after 1 year, he had developed bi-occipital calcification and was then found to have positive coeliac serology. He was diagnosed with coeliac disease, epilepsy, and cerebral calcifications (CEC) and became seizure free after starting the gluten-free diet. Positive antibody binding to neurons and glia was demonstrated on indirect immunofluorescence. High levels of immunoglobulin-A directed against transglutaminase isoenzyme 6 (TG6) were found in the patient's serum. The positive response to the diet, TG6 antibodies, and neuronal antibody binding suggest that CEC might be autoimmune in nature, as in other extra-intestinal manifestations of gluten-related diseases, such as gluten ataxia. PMID- 22845674 TI - Sudden change in R-wave amplitude. Is it a device malfunction? PMID- 22845675 TI - Quantitative electroencephalography during rapid eye movement (REM) and non-REM sleep in combat-exposed veterans with and without post-traumatic stress disorder. AB - Sleep disturbances are a hallmark feature of post-traumatic stress disorder (PTSD), and associated with poor clinical outcomes. Few studies have examined sleep quantitative electroencephalography (qEEG), a technique able to detect subtle differences that polysomnography does not capture. We hypothesized that greater high-frequency qEEG would reflect 'hyperarousal' in combat veterans with PTSD (n = 16) compared to veterans without PTSD (n = 13). EEG power in traditional EEG frequency bands was computed for artifact-free sleep epochs across an entire night. Correlations were performed between qEEG and ratings of PTSD symptoms and combat exposure. The groups did not differ significantly in whole-night qEEG measures for either rapid eye movement (REM) or non-REM (NREM) sleep. Non-significant medium effect sizes suggest less REM beta (opposite to our hypothesis), less REM and NREM sigma and more NREM gamma in combat veterans with PTSD. Positive correlations were found between combat exposure and NREM beta (PTSD group only), and REM and NREM sigma (non-PTSD group only). Results did not support global hyperarousal in PTSD as indexed by increased beta qEEG activity. The correlation of sigma activity with combat exposure in those without PTSD and the non-significant trend towards less sigma activity during both REM and NREM sleep in combat veterans with PTSD suggests that differential information processing during sleep may characterize combat-exposed military veterans with and without PTSD. PMID- 22845677 TI - Structural periodicity in the coordination chemistry of aqueous Pu(IV) sulfates. AB - Extended X-ray absorption fine structure measurements have been conducted on solutions of Pu(IV) with varying concentrations of sulfate anion in aqueous solution. Data support the periodic progression to primarily bidentate sulfate coordination about An(IV) centers when moving heavier in the actinides. This observation is attributed to the increase in Lewis acidity of the tetravalent actinides across the series, a consequence of the filling of the 5f orbitals and the actinide contraction. Though the changes in the chemical formation energies of the An(IV) complexes between Th and Pu are small, it is these small energetic differences that are critical to understanding how to effect more efficient and effective chemical separations among isovalent metal ions. PMID- 22845678 TI - Practicing medicine without borders: tele-consultations and tele-mentoring for improving paediatric care in a conflict setting in Somalia? AB - OBJECTIVES: In a district hospital in conflict-torn Somalia, we assessed (i) the impact of introducing telemedicine on the quality of paediatric care, and (ii) the added value as perceived by local clinicians. METHODS: A 'real-time' audio visual exchange of information on paediatric cases (Audiosoft Technologies, Quebec, Canada) took place between clinicians in Somalia and a paediatrician in Nairobi. The study involved a retrospective analysis of programme data, and a perception study among the local clinicians. RESULTS: Of 3920 paediatric admissions, 346 (9%) were referred for telemedicine. In 222 (64%) children, a significant change was made to initial case management, while in 88 (25%), a life threatening condition was detected that had been initially missed. There was a progressive improvement in the capacity of clinicians to manage complicated cases as demonstrated by a significant linear decrease in changes to initial case management for meningitis and convulsions (92-29%, P = 0.001), lower respiratory tract infection (75-45%, P = 0.02) and complicated malnutrition (86-40%, P = 0.002). Adverse outcomes (deaths and lost to follow-up) fell from 7.6% in 2010 (without telemedicine) to 5.4% in 2011 with telemedicine (30% reduction, odds ratio 0.70, 95% CI: 0.57-0.88, P = -0.001). The number needed to be treated through telemedicine to prevent one adverse outcome was 45. All seven clinicians involved with telemedicine rated it to be of high added value. CONCLUSION: The introduction of telemedicine significantly improved quality of paediatric care in a remote conflict setting and was of high added value to distant clinicians. PMID- 22845676 TI - MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex. AB - Evidence suggests that the acquisition of recognition memory depends upon CREB dependent long-lasting changes in synaptic plasticity in the perirhinal cortex.The CREB-responsive microRNA miR-132 has been shown to regulate synaptic transmission and we set out to investigate a role for this microRNA in recognition memory and its underlying plasticity mechanisms. To this end we mediated the specific overexpression of miR-132 selectively in the rat perirhinal cortex and demonstrated impairment in short-term recognition memory. This functional deficit was associated with a reduction in both long-term depression and long-term potentiation. These results confirm that microRNAs are key coordinators of the intracellular pathways that mediate experience-dependent changes in the brain. In addition, these results demonstrate a role for miR-132 in the neuronal mechanisms underlying the formation of short-term recognition memory. PMID- 22845679 TI - Data distribution: normal or abnormal? Why it matters. PMID- 22845680 TI - Driving of a small solvated peptide in the IR and THz range--a comparative study of energy flow. AB - We present a comparative study of energy flow from a vibrationally excited solvated dialanine molecule to the surrounding water in the IR and THz range. We employ the driven molecular dynamics (DMD) approach to investigate the energy flow from the solute molecule to water molecules. As a result, we find a more rapid and efficient energy flow from the solute to the water when exciting THz modes compared to IR modes. Our results show a strong coupling of the low frequency mode of the solute and the water dynamics in the THz regime. In contrast, when exciting the IR modes of the solute, we find much more localized motions. PMID- 22845681 TI - An update in incretin-based therapy: a focus on glucagon-like peptide-1 receptor agonists. AB - The glucagon-like peptide-1 receptor agonists, exenatide and liraglutide, offer a unique mechanism in the treatment of type 2 diabetes mellitus (T2DM) as part of the incretin system. Their mechanism of action is to increase insulin secretion, decrease glucagon release, reduce food intake, and slow gastric emptying. They target postprandial blood glucose values and have some effect on fasting levels as well. In addition, they promote weight loss and may help to preserve beta-cell function, both major problems in T2DM patients. Changes in hemoglobin A1c are similar to those produced by other T2DM agents, including thiazolidinediones, low dose metformin, and sulfonylureas, and better than those caused by alpha reductase inhibitors and dipeptidyl peptidase-4 inhibitors. These agents have been safely studied in combination with metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin therapy. Overall, data are limited for head-to head comparisons, but it appears that liraglutide may have better efficacy and tolerability compared with exenatide; however, more studies are needed. They are overall well tolerated, with the main adverse events being similar to those with metformin (gastrointestinal intolerances that are transient and dose dependent). However, patients must be monitored for pancreatitis as a rare but possible side effect. For T2DM patients willing to use an injectable agent, exenatide and liraglutide offer another therapeutic option to control hyperglycemia with the potential for weight loss and may be combined with other agents safely. PMID- 22845682 TI - Employees' behavioral reactions to supervisor aggression: an examination of individual and situational factors. AB - This research examines employees' behavioral reactions to perceived supervisor aggression. The goal is to understand what makes employees react constructively or destructively to aggression. Three types of behavioral reactions are investigated: retaliation, coworker displaced aggression, and problem solving. We suggest employee reactions are influenced by individual and situational characteristics. We test these ideas by examining the moderating effects of 1 individual factor (locus of control) and 2 situational factors (fear of retaliation and behavioral modeling) on the relationships between perceived supervisor aggression and employee behaviors. The results of an experiment and 2 field studies provide support for the predictions and some unexpected findings. Implications for understanding reactions to perceived supervisor aggression are presented. PMID- 22845683 TI - Desmoplastic melanocytic nevi with lymphocytic aggregates. AB - Desmoplastic melanocytic nevi can be difficult to distinguish from desmoplastic melanoma. The presence of lymphocytic aggregates in association with a sclerosing melanocytic proliferation is commonly regarded as a feature in support of a diagnosis of desmoplastic melanoma. However, the finding is not specific for melanoma. Herein we report six cases of sclerosing melanocytic nevi with associated lymphocytic aggregates. They occurred in five women and one man, ranging in age from 11 to 61 years. Three lesions were sclerosing Spitz nevi; one was an amelanotic sclerosing blue nevus, one an acquired intradermal sclerosing nevus, and one was a congenital compound melanocytic nevus with sclerosis of its dermal component. The lesions were interpreted as benign, i.e. melanocytic nevi, because of their histopathologic attributes (symmetric silhouette, benign cytologic features) and results from immunohistochemical studies (all lesions strongly expressed Melan-A and p16) and fluorescence in situ hybridization (FISH). Three lesions tested by FISH lacked copy number changes of 11p, 6q or 6p. None of the lesions recurred. The cases highlight that contextual information is essential for the diagnosis of desmoplastic melanoma and sclerosing nevus. The presence of lymphocytic aggregates per se does not prove that a sclerosing melanocytic proliferation is malignant. PMID- 22845684 TI - A systematic review of the evidence on service user involvement in interpersonal skills training of mental health students. AB - Service user involvement has become a common feature of education programmes for mental health students. However, little is known about the effects of this type of education on the interpersonal skills of students taking part. This paper reports findings from a systematic review that formed part of a wider investigation into service user involvement in teaching interpersonal skills. The review aimed to locate and assess the quality of the published evidence relating to the effects of service user involvement on mental health students interpersonal skills and to synthesize results, using a definition of interpersonal skill that includes attitudes, empathy and skills as its key components. Results from this study indicate that the quality of evidence in this area is poor. However, sufficient synthesis of the evidence base was possible to allow conclusions and recommendations for both research and practice. Conclusions were that the involvement of service users in this area is both acceptable and valuable for students and had specific impacts on attitudes, empathy and skills. Some difficulties and reservations about the style of involvement are discussed. Recommendations for the conduct of future research are also made. PMID- 22845685 TI - Re: Dose-titration effects of fish oil in osteoarthritis dogs. PMID- 22845686 TI - Secondary disclosure of parental HIV status among children affected by AIDS in Henan, China. AB - For children affected by AIDS, one psychological challenge is whether or how to disclose their parents' HIV status to others (secondary disclosure). The current study, utilizing data from 962 rural children affected by AIDS in central China, examines children's perceptions regarding secondary disclosure (intention of disclosure, openness, and negative feelings) and their association with children's demographic and psychosocial factors. The findings indicated that a high proportion of children preferred not to disclose parental HIV status to others, would not like to tell the truth to others in the situations of having to talk about parental HIV, and also had strong negative feelings about the disclosure. The study findings confirmed that keeping secrecy of parental HIV infection was associated with higher level of negative psychological outcomes (e.g., depression, loneliness, perceived stigma, and enacted stigma), and children's age was strongly associated with both their perceptions of secondary disclosure and psychological measures. PMID- 22845687 TI - The impact of local anesthetic distribution on block onset in ultrasound-guided interscalene block. AB - BACKGROUND: Recent investigations of local anesthetic distribution in the lower extremity have revealed that completely surrounding the sciatic nerve with local anesthetic provides the advantage of more rapid and complete anesthesia in the territory served by the nerve. We hypothesized that a pattern of distribution that entirely envelops the targeted nerve roots during interscalene block would provide similar benefits of more rapid anesthesia onset. METHODS: During interscalene block guided by ultrasound with nerve stimulator confirmation, the pattern of local anesthetic distribution was recorded and later classified as complete or incomplete envelopment of the visible nerve elements in 50 patients undergoing ambulatory shoulder arthroscopic surgery. The pattern was then compared with the extent of block setup at pre-determined intervals, as well as to post-operative pain levels and block duration. RESULTS: Twenty-two patients (44%) had complete envelopment of the nerves in the plane of injection during ultrasound imaging of the interscalene block. There was no difference in the fraction of blocks that were fully set-up at 10 min with regards to complete or incomplete envelopment of the nerves by local anesthetic. All of the patients had complete setup of the block by 20 min. In addition, the post-operative pain levels and duration of block did not vary among the two groups with complete vs. incomplete local anesthetic distribution around the nerves. CONCLUSION: The presence or absence of complete envelopment of the nerve elements in the interscalene groove by local anesthetic did not determine the likelihood of complete block effect at pre-determined time intervals after the procedure. PMID- 22845688 TI - Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. AB - The neuroprotective actions of citicoline have been documented for experimental stroke therapy. We used a systematic review and meta-analysis to assess this evidence. From 64 identified studies using citicoline in stroke animal models, only those describing ischemic occlusive stroke and reporting data on infarct volume and/or neurological outcome were included (14 studies, 522 animals). Overall, the quality of the studies was modest (5, 4-6), while the absence of studies involving animals with co-morbidities, females, old animals or strain differences indicated that studies did not fulfill the STAIR recommendations. Weighted mean difference meta-analysis showed citicoline to reduce infarct volume by 27.8% [(19.9%, 35.6%); p < 0.001]. In the stratified analysis, citicoline effect on reducing infarct volume was higher in proximal occlusive models of middle cerebral artery (MCA) compared with distal occlusion. Moreover, the efficacy was superior using multiple doses than single dose and when a co treatment was administered compared with citicoline monotherapy, the only independent factor identified in the meta-regression. Citicoline improved neurological deficit by 20.2% [(6.8%, 33.7%); p = 0.015], but only four studies including 176 animals reported these data. In conclusion, this meta-analysis provides evidence of citicoline efficacy in stroke animal models and shows the optimal neuroprotective profile and the missing experimental requirements before jumping into clinical trials. PMID- 22845689 TI - Exploring the biological activities of Echeveria leucotricha. AB - Echeveria leucotricha J. A. Purpus (Crassulaceae) was evaluated for its potential antibacterial, antifungal, antiparasitic, cytotoxic and anti-inflammatory bioactivities. Aerial parts were extracted with hexane, methanol and chloroform, and fractionated accordingly. Biological activity was assessed in vitro against five Gram-positive and four Gram-negative bacteria, four human pathogenic fungi and the protozoan Leishmania donovani. Extracts and fractions showing bioactivities were further investigated for their cytotoxic activities on macrophages. Results show that several extracts and fractions exhibited significant antibacterial, antifungal, and antiparasitic activities, but no anti inflammatory activity was recorded. Here, we report for the first time, and to the best of our knowledge, these bioactivities, which suggest that this plant can be used in the traditional Mexican medicine. PMID- 22845690 TI - Unique capsule endoscopic appearance of segmental intestinal dilatation in a child. PMID- 22845691 TI - Plasma mediated off-resonance plasmonic enhanced ultrafast laser-induced nanocavitation. AB - The generation of nanobubbles around plasmonic nanostructures is an efficient approach for imaging and therapy, especially in the field of cancer research. We show a novel method using infrared femtosecond laser that generates ~800 nm bubbles around off-resonance gold nanospheres using 200 mJ/cm(2) 45 fs pulses. We present experimental and theoretical work that demonstrate that the nanobubble formation results from the generation of a nanoscale plasma around the particle due to the enhanced near-field rather than from the heating of the particle. Energy absorbed in the nanoplasma is indeed more than 11 times the energy absorbed in the particle. When compared to the usual approach that uses nanosecond laser to induce the extreme heating of in-resonance nanoparticles to initiate bubble formation, our off-resonance femtosecond technique is shown to bring many advantages, including avoiding the particles fragmentation, working in the optical window of biological material and using the deposited energy more efficiently. PMID- 22845692 TI - Robot-assisted thoracoscopic thymectomy for treating myasthenia gravis in children. AB - INTRODUCTION: In the United States, the prevalence of myasthenia gravis (MG) is approximately 14-20 per 100,000. One treatment option involves a thymectomy, which can lead to remission of symptoms. The amount of thymic tissue removed is correlated with a better outcome for patients. Thus, it is critical that the procedure used when performing a thymectomy maximize the resection of thymic tissue. Robotic-assisted thoracoscopic thymectomy provides a minimally invasive platform that avoids the mortality and morbidity of a median sternotomy while providing better visualization and a more delicate dissection than is available in a standard thoracoscopic procedure. PATIENTS AND METHODS: Following Institutional Review Board approval, in total, 9 patients who underwent robotic thymectomy were reviewed. Intraoperative statistics such as operative time and blood loss were reviewed from operative records. Postoperative outcomes such as hospital stay, discharge medications, and complications were reviewed from hospital charts. Lastly, disease response was evaluated in consultation with a pediatric neurologist who specializes in MG. RESULTS: Age at operation ranged from 2 to 15 years of age (average, 9.4 years). A majority of patients had an MGFA classification of II or greater (n=5). All patients were on pyridostigmine preoperatively, and 7 of 9 (77%) were taking prednisone. Mean operative time was 160.1+/-6.1 minutes. Average postoperative hospital stay was 1.1+/-0.3 days. One patient had a documented persistent pneumothorax on postoperative Day 1, which was treated with nasal cannula oxygen for an additional day. There were no additional operative complications, and all patients were discharged home on acetaminophen with codeine for pain control. Eight of 9 patients had improvement in MG symptoms after the procedure. CONCLUSIONS: Robotic-assisted thoracoscopic thymectomy is a safe and effective operation for children with MG. Robotic assistance allows for articulating instruments, three-dimensional visualization, and minimal blood loss. These factors may allow for a more complete resection compared with a standard thoracoscopic thymectomy. PMID- 22845693 TI - Amnesia, anesthesia, and warranted fear. AB - Is a painful experience less bad for you if you will not remember it? Do you have less reason to fear it? These questions bear on how we think about medical procedures and surgeries that use an anesthesia regimen that leaves patients conscious - and potentially in pain - but results in complete 'drug-induced amnesia' after the fact. I argue that drug-induced amnesia does not render a painful medical procedure a less fitting object of fear, and thus the prospect of amnesia does not give patients a reason not to fear it. I expose three mistakes in reasoning that might explain our tendency to view pain or discomfort as less fearful in virtue of expected amnesia: a mistaken view of personal identity; a mistaken view of the target of anticipation; and a mistaken method of incorporating past evidence into calculations about future experiences. Ultimately my argument has implications for whether particular procedures are justified and how medical professionals should speak with anxious patients about the prospect of drug-induced amnesia. PMID- 22845694 TI - Musculoskeletal growth in the upper arm in infants after obstetric brachial plexus lesions and its relation with residual muscle function. AB - AIM: Denervation after obstetric brachial plexus lesion (OBPL) is associated with reduced musculoskeletal growth in the upper arm. The aim of this study was to investigate whether reduced growth of upper arm flexor and extensor muscles is related to active elbow function and humeral length. METHOD: In this study, 31 infants age less than 6 months (mean age 4.3mo; range 2.1-5.9mo; 17 males; 14 females;) with unilateral OBPL (Narakas class I, 19; II, 3; III, 2; and IV, 7) treated at the VU medical centre, in whom neurosurgical reconstruction was considered were prospectively studied using magnetic resonance imaging of both arms at a mean age of 4.3 months. Humeral length and the cross-sectional area (CSA) of elbow flexor and extensor muscles were measured in both upper arms. Paresis of elbow function was estimated when the infants were a mean age of 4.5 months using the Gilbert score. RESULTS: Both flexor and extensor CSAs were significantly smaller on the affected side than on the unaffected side (88% [SD 32%], p=0.020, and 88% [SD 24%], p=0.001 respectively), as was humeral length (96% [SD 7%], p=0.005) (unaffected side 100% in all cases). There was no relation between the reduction in flexor and extensor CSA and residual muscle function. In 17 out of 31 patients, hypertrophy of flexor and/or extensor muscles was observed. Humeral length was not related to muscle parameters. INTERPRETATION: Denervation has different effects on muscle growth and function as well as bone growth. In young infants with an OBPL, muscle size is not a predictor of muscle function. Flexion contractures of the elbow later in childhood may not be explained by a dominance of flexor muscle mass in infants. PMID- 22845695 TI - Randomized controlled pilot study of 2 weeks' treatment with high cutoff membrane for hemodialysis patients with elevated C-reactive protein. AB - Chronic inflammation in hemodialysis (HD) patients is associated with cardiovascular complications and mortality. Circulating immune active proteins in the molecular range 15-45 kD that cannot be efficiently cleared by high-flux (HF) dialysis may be causally involved. We intended to test the feasibility of using a high cutoff (HCO) dialyzer in chronic HD patients and its influence on inflammation and monocyte activation. The Gambro HCO1100 dialyzer was compared to a conventional HF membrane in a randomized double-blind crossover trial in 19 chronic HD patients selected for the presence of elevated serum C-reactive protein levels. Patients were treated for six consecutive dialysis sessions (2 weeks) with each membrane. Safety analysis recorded adverse events and albumin losses through the protein-leaking membranes. Efficacy analysis observed reductions in the number of proinflammatory (CD14+CD16+) monocyte subpopulations in circulating blood. Treatment with the HCO membrane was well tolerated, although the number of adverse events was slightly higher. Despite significant serum albumin loss (from 34.1 +/- 2.7 to 29.6 +/- 3.0 g/L; P < 0.01), there was no need to supplement albumin, and rising activity of cholinesterase during HCO treatment indicated compensation by enhanced hepatic synthesis. The HCO membrane cleared high amounts of proinflammatory cytokines, but did not reduce predialysis inflammatory monocytes and markers. Although the time of HD session was extended, the study was hampered by a lower Kt/V in the HCO compared to the HF period. Treatment of chronic HD patients with this HCO dialyzer for 2 weeks is tolerable in terms of albumin loss and able to clear proinflammatory cytokines; however, this was not sufficient to decrease monocyte activation. Therefore, a more selective, less albumin-leaking membrane is desirable to allow prolonged high efficient dialysis with more effective cytokine clearance. PMID- 22845696 TI - What interval between colorectal cancer resection and first surveillance colonoscopy? An audit of practice and yield. AB - AIM: Colonoscopic follow-up after colorectal cancer resection (CRC) is recommended to screen for anastomotic recurrence and metachronous neoplasia, although guidelines vary in the timings of the first investigation. We aimed to quantify current practice and yield of neoplasia at first colonoscopy in relation to time from original resection. METHOD: We conducted a retrospective case note study of all CRCs treated with curative intent within our hospital between two time periods: 2001-2003 and 2006-2007. Variables collected were the extent of preoperative luminal imaging, tumour site, procedure, timing and findings of initial colonoscopy, postoperative CT findings and mortality. The first follow-up colonoscopy findings including neoplasia formation and recurrence rates were matched with rates of complete preoperative luminal imaging. Two-year and 5-year outcomes were sought. RESULTS: A total of 863 patients underwent CRC with curative intent within these two time periods (518 vs 345). Colonoscopic follow up rates by 2 years were 32.8%vs 54.1%. Within the first cohort 63.5% of patients underwent colonoscopy by 5 years. Significant volumes of neoplasia and resectable recurrences were found before 2 years within these groups. Earlier detection of recurrent malignancy was associated with an improved patient outcome. Complete preoperative screening of the bowel was not associated with a lower incidence of neoplasia at first postoperative colonoscopy. CONCLUSION: Our study demonstrates significant colonoscopic detection rates of neoplasia within 2 years of CRC. Patient outcomes were improved with earlier detection. We would therefore suggest an interval of no more than 2 years between resection and first surveillance colonoscopy. PMID- 22845697 TI - Development of functionalized cyclotriveratrylene analogues: introduction of withdrawing and pi-conjugated groups. AB - Cyclotriveratrylene analogues (CTVs) are supramolecular bowl-shaped molecules known for their ability to complex organic and organometallic guests, to form liquid crystals, polymers, or nanostructures. In this Article, we report the synthesis of new cyclotriveratrylene analogues with fluorescence properties in which various electron-withdrawing or pi-extended conjugated groups are appended to the wide rim ortho to the methoxy-donating groups. Synthetically, these functionalized CTVs cannot be obtained as CTVs with electron-rich functions by the typical method (i.e., the trimerization of the corresponding benzyl alcohol) but are prepared from a common key intermediate, the C(3) triiodocyclotriveratrylene (CTV-I(3)), in good yields. Despite the synthetic difficulties encountered due to the presence of three reactive centers, we have demonstrated the possibility of performing Sonogashira coupling and Huisgen cycloaddition reactions directly to the CTV core for the first time. CTVs with pi extended conjugated groups reveal interesting fluorescence profiles. More broadly, this study utilizes CTV-I(3) to introduce novel functionalities into CTVs to keep exploring their potential applications. PMID- 22845698 TI - Ionically-mediated electromechanical hysteresis in transition metal oxides. AB - Nanoscale electromechanical activity, remanent polarization states, and hysteresis loops in paraelectric TiO(2) and SrTiO(3) thin films are observed using scanning probe microscopy. The coupling between the ionic dynamics and incipient ferroelectricity in these materials is analyzed using extended Landau Ginzburg-Devonshire (LGD) theory. The possible origins of electromechanical coupling including ionic dynamics, surface-charge induced electrostriction, and ionically induced ferroelectricity are identified. For the latter, the ionic contribution can change the sign of first order LGD expansion coefficient, rendering material effectively ferroelectric. The lifetime of these ionically induced ferroelectric states is then controlled by the transport time of the mobile ionic species and well above that of polarization switching. These studies provide possible explanation for ferroelectric-like behavior in centrosymmetric transition metal oxides. PMID- 22845699 TI - Stigma, public awareness about intellectual disability and attitudes to inclusion among different ethnic groups. AB - BACKGROUND: Attitudes to the inclusion of people with intellectual disabilities (IDs) have been studied extensively, yet evidence on public awareness about ID and stigma is limited. The relationship between attitudes, knowledge and stigma associated with ID is poorly understood. The present study examined these factors and the relationships between them in the context of a multicultural society. METHOD: UK residents of working age (n = 1002) were presented with a diagnostically unlabelled vignette of someone with a mild ID. They were asked to label the difficulties presented and to complete measures of social distance and attitudes to the inclusion of people with IDs. RESULTS: While attitudes to the inclusion of people with IDs were relatively positive overall, social contact was viewed with ambivalence. Inclusion attitudes and social distance were only moderately correlated. Across the whole sample 28% recognised typical symptoms of mild ID. Recognition of ID was associated with lower stigma and more positive attitudes than attribution of the difficulties presented to other causes. White Westerners showed increased knowledge, lower stigma and favoured inclusion more than participants from ethnic minorities. Among the latter group, Asians showed lower stigma and attitudes more in line with inclusion policies than participants of Black African/Caribbean backgrounds. Once a host of contextual factors were considered jointly, only contact was consistently associated with the variables measured. CONCLUSIONS: Stigma associated with ID is of concern across all ethnic groups, although it appears to be increased among the public from ethnic minorities. Given that contact and awareness are associated with reduced stigma, they should be considered as prime foci for efforts to tackle ID stigma. The current findings serve as baseline for attempts to increase public awareness and tackle stigma. PMID- 22845700 TI - Cohort monitoring of persons with hypertension: an illustrated example from a primary healthcare clinic for Palestine refugees in Jordan. AB - OBJECTIVE: Recording and reporting systems borrowed from the DOTS framework for tuberculosis control can be used to record, monitor and report on chronic disease. In a primary healthcare clinic run by UNRWA in Amman, Jordan, serving Palestine refugees with hypertension, we set out to illustrate the method of cohort reporting for persons with hypertension by presenting on quarterly and cumulative case finding, cumulative and 12-month analysis of cohort outcomes and to assess how these data may inform and improve the quality of hypertension care services. METHOD: This was a descriptive study using routine programme data collected through E-Health. RESULTS: There were 97 newly registered patients with hypertension in quarter 1, 2012, and a total of 4130 patients with hypertension ever registered since E-Health started in October 2009. By 31 March 2012, 3119 (76%) of 4130 patients were retained in care, 878 (21%) had failed to present to a healthcare worker in the last 3 months and the remainder had died, transferred out or were lost to follow-up. Cumulative and 12-month cohort outcome analysis indicated deficiencies in several components of clinical performance related to blood pressure measurements and fasting blood glucose tests to screen simultaneously for diabetes. Between 8% and 15% of patients with HT had serious complications such as cardiovascular disease and stroke. CONCLUSION: Cohort analysis is a valuable tool for the monitoring and management of non-communicable chronic diseases such as HT. PMID- 22845701 TI - Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population. AB - BACKGROUND: Postmarketing reports have linked exenatide use with acute pancreatitis and pancreatic cancer, but a definitive relationship has yet to be established. SUBJECTS AND METHODS: We conducted a retrospective cohort analysis of patients with type 2 diabetes with employer-provided health insurance from 2007 to 2009. Multivariate models estimated the association between exenatide use and acute pancreatitis and pancreatic cancer. We required at least 1 year of exenatide exposure in the pancreatic cancer analysis. Sensitivity analyses were conducted that quasirandomized exenatide use based on patient out-of-pocket costs. RESULTS: Among 268,561 patients included in the acute pancreatitis analysis, only 2.6% used exenatide. Hospitalization for acute pancreatitis was rare (0.247% of patients). In unadjusted and adjusted analyses, patients who did not use exenatide were more likely to be hospitalized for acute pancreatitis (0.249% vs. 0.196% in unadjusted analysis), but the difference was not statistically significant in either analysis (P = 0.22 and P = 0.70, respectively). Among 209,306 patients in the pancreatic cancer analysis, 0.070% were diagnosed with pancreatic cancer, and 0.88% had at least 1 year of continuous exenatide exposure prior to the diagnosis. Those with exenatide exposure had higher rates of pancreatic cancer compared with those without (0.081% vs. 0.070% in unadjusted analysis). In both unadjusted and adjusted analyses, the difference was not statistically significant (P = 0.80 and P = 0.46, respectively). In sensitivity analyses, results were similar. CONCLUSIONS: We found no association between exenatide use and either hospitalization for acute pancreatitis or pancreatic cancer in a large sample of privately insured U.S. patients. PMID- 22845702 TI - A cationic antimonite chain templated by sulfate: [Sb6O7(4+)][(SO4(2-))2]. AB - An extended metal oxide possessing a cationic charge on the host has been synthesized by hydrothermal methods. The structure consists of 1D antimony oxide [Sb(6)O(7)](4+) chains with a new structural motif of four Sb atoms wide and unprotonated sulfate anions between the chains. The material was characterized by powder and single-crystal X-ray diffraction. Thermal behavior and chemical resistance in aqueous acidic conditions (pH ~2) indicate a highly stable cationic material. The stability is attributed to the entirely inorganic composition of the structure, where 1D covalently extended chains are electrostatically bound to divalent anions. PMID- 22845703 TI - Efficient method for site-specific 18F-labeling of biomolecules using the rapid condensation reaction between 2-cyanobenzothiazole and cysteine. AB - An efficient method based on a rapid condensation reaction between 2 cyanobenzothiazole (CBT) and cysteine has been developed for (18)F-labeling of N terminal cysteine-bearing peptides and proteins. An (18)F-labeled dimeric cRGD ([(18)F]CBTRGD(2)) has been synthesized with an excellent radiochemical yield (92% based on radio-HPLC conversion, 80% decay-corrected, and isolated yield) and radiochemical purity (>99%) under mild conditions using (18)F-CBT, and shown good in vivo tumor targeting efficiency for PET imaging. The labeling strategy was also applied to the site-specific (18)F-labeling of a protein, Renilla lucifierase (RLuc8) with a cysteine residue at its N-terminus. The protein labeling was achieved with 12% of decay-corrected radiochemical yield and more than 99% radiochemical purity. This strategy should provide a general approach for efficient and site-specific (18)F-labeling of various peptides and proteins for in vivo molecular imaging applications. PMID- 22845704 TI - Behavior modification after inactivation of cerebellar dentate nuclei. AB - Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction. PMID- 22845705 TI - Transient inactivation of basolateral amygdala during selective satiation disrupts reinforcer devaluation in rats. AB - Basolateral amygdala (BLA) function is critical for flexible, goal-directed behavior, including performance on reinforcer devaluation tasks. Here we tested, in rats, the hypothesis that BLA is critical for conditioned reinforcer devaluation during the period when the primary reinforcer (food) is being devalued (by feeding it to satiety), but not thereafter for guiding behavioral choices. We used a spatially independent task that used two visual cues, each predicting one of two foods. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received BLA or sham lesions, or cannulae implanted in BLA. Under control conditions (sham lesions, saline infusions), devaluation of one food significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. BLA lesions impaired this devaluation effect. Transient inactivation of BLA by microinfusion of the gamma-aminobutyric acid receptor type A agonist muscimol resulted in an impairment only when BLA was inactivated during satiation. When muscimol was infused after satiation and therefore, BLA was inactivated only during the choice test, rats showed no impairment. Thus, BLA is necessary for registering or updating cues to reflect updated reinforcer values, but not for guiding choices once the value has been updated. Our results are the first to describe the contribution of rat BLA to specific components of reinforcer devaluation and are the first to show impairment in reinforcer devaluation following transient inactivation in the rat. PMID- 22845706 TI - Explaining neural signals in human visual cortex with an associative learning model. AB - "Predictive coding" models posit a key role for associative learning in visual cognition, viewing perceptual inference as a process of matching (learned) top down predictions (or expectations) against bottom-up sensory evidence. At the neural level, these models propose that each region along the visual processing hierarchy entails one set of processing units encoding predictions of bottom-up input, and another set computing mismatches (prediction error or surprise) between predictions and evidence. This contrasts with traditional views of visual neurons operating purely as bottom-up feature detectors. In support of the predictive coding hypothesis, a recent human neuroimaging study (Egner, Monti, & Summerfield, 2010) showed that neural population responses to expected and unexpected face and house stimuli in the "fusiform face area" (FFA) could be well described as a summation of hypothetical face-expectation and -surprise signals, but not by feature detector responses. Here, we used computer simulations to test whether these imaging data could be formally explained within the broader framework of a mathematical neural network model of associative learning (Schmajuk, Gray, & Lam, 1996). Results show that FFA responses could be fit very closely by model variables coding for conditional predictions (and their violations) of stimuli that unconditionally activate the FFA. These data document that neural population signals in the ventral visual stream that deviate from classic feature detection responses can formally be explained by associative prediction and surprise signals. PMID- 22845708 TI - Naloxone prevents the rapid reacquisition but not acquisition of alcohol seeking. AB - Opioid receptors are involved in reinstatement of alcohol seeking, yet there are no reports of their role in reacquisition of an extinguished alcohol seeking response. Here we investigated the effects of the opioid antagonist naloxone on reacquisition and compared these effects with those on acquisition. Rats were trained, extinguished, then retrained to respond for alcoholic beer. Upon retraining, a second group of rats with no prior experience with the contingency between response and reinforcer was trained under the same conditions. Reacquisition was faster than acquisition. Systemic injection of naloxone (1.25 or 5 mg/kg) reduced reacquisition but had no effect on acquisition. These results suggest that reacquisition and acquisition of alcohol seeking have dissociable neurochemical substrates. PMID- 22845707 TI - Voluntary running-wheel exercise decreases the threshold for rewarding intracranial self-stimulation. AB - Physical exercise has mood-enhancing and antidepressant properties although the mechanisms underlying these effects are not known. The present experiment investigated the effects of prolonged access to a running wheel on electrical self-stimulation of the lateral hypothalamus (LHSS), a measure of hedonic state, in rats. Rats with continuous voluntary access to a running wheel for either 2 or 5 weeks exhibited dramatic leftward shifts in the effective current 50 (ECu50; current value that supports half of maximum responding) of their LHSS current response functions compared to their baselines, indicating a decrease in reward threshold, whereas control rats current-response functions after 2 or 5 weeks were not significantly different from baseline. An inverse correlation existed between the change in ECu50 from baseline and the amount an animal had run in the day prior to LHSS testing, indicating that animals that exhibited higher levels of running showed a more robust decrease in LHSS threshold. We conclude that long term voluntary exercise increases sensitivity to rewarding stimuli, which may contribute to its antidepressant properties. PMID- 22845709 TI - Phase behavior of 1-dodecyl-3-methylimidazolium fluorohydrogenate salts (C12MIm(FH)(n)F, n = 1.0-2.3) and their anisotropic ionic conductivity as ionic liquid crystal electrolytes. AB - The effects of the HF composition, n, in 1-dodecyl-3-methylimidazolium fluorohydrogenate salts (C(12)MIm(FH)(n)F, n = 1.0-2.3) on their physicochemical and structural properties have been investigated using infrared spectroscopy, thermal analysis, polarized optical microscopy, X-ray diffraction, and anisotropic ionic conductivity measurements. The phase diagram of C(12)MIm(FH)(n)F (n vs transition temperature) suggests that C(12)MIm(FH)(n)F is a mixed crystal system that has a boundary around n = 1.9. For all compositions, a liquid crystalline mesophase with a smectic A interdigitated bilayer structure is observed. The temperature range of the mesophase decreases with increasing n value (from 61.8 degrees C for C(12)MIm(FH)(1.0)F to 37.0 degrees C for C(12)MIm(FH)(2.3)F). The layer spacing of the smectic structure decreases with increasing n value or increasing temperature. Two structural types with different layer spacings are observed in the crystalline phase (type I, 1.0 <= n <= 1.9, and type II, 1.9 <= n <= 2.3). Ionic conductivities parallel and perpendicular to the smectic layers (sigma(||) and sigma([perpendicular])) increase with increasing n value, whereas the anisotropy of the ionic conductivities (sigma(||)/sigma([perpendicular])) is independent of the n value, since the thickness of the insulating sheet formed by the dodecyl group remains nearly unchanged. PMID- 22845710 TI - Success rate, efficacy, and safety/tolerability of overnight switching from immediate- to extended-release pramipexole in advanced Parkinson's disease. AB - BACKGROUND AND PURPOSE: For Parkinson's disease (PD), an extended-release (ER) pramipexole formulation taken once daily, has shown efficacy, safety, and tolerability resembling those of immediate-release (IR) pramipexole taken three times daily. The present study assessed, in advanced PD, the success of an overnight switch from adjunctive IR to ER. METHODS: Levodopa users experiencing motor fluctuations were randomized to adjunctive double-blind (DB) placebo, IR, or ER. Amongst completers of >=18 weeks, ER recipients were kept on DB ER, whilst IR recipients were switched overnight to DB ER at unchanged daily dosage. After a DB week, switch success was assessed. During the next 5 weeks, all patients underwent ER titration to optimal open-label maintenance dosage. RESULTS: One week post-switch, 86.2% of 123 IR-to-ER and 83.8% of 105 ER-to-ER patients had <=15% (or <=3-point, for pre-switch scores <=20) increase on UPDRS Parts II + III, and 77.9% (of 122) and 70.2% (of 104) had <=1-h increase in daily OFF-time. At 32 weeks, the groups showed comparable improvements from DB baseline (pramipexole inception), including, on UPDRS II + III, adjusted mean (SE) changes of -14.8 (1.5) for IR-to-ER and -13.3 (1.6) for ER-to-ER. Rates of premature discontinuation owing to adverse events were 6.5% for IR-to-ER and 4.9% for ER-to ER. CONCLUSIONS: By OFF-time and UPDRS criteria, majorities of patients with advanced PD were successfully switched overnight from pramipexole IR to ER at unchanged daily dosage. During subsequent maintenance, pramipexole showed sustained efficacy, safety, and tolerability, regardless of formulation (IR or ER) in the preceding DB trial. PMID- 22845711 TI - Opinions of Maryland adults regarding communication practices of dentists and staff. AB - Communication practices of dental care providers are especially important to provider-patient and provider-caregiver communication because most patients report that they obtain oral health information from their dentist. The purpose of this study was to determine the perceptions of English-speaking Maryland adults who had a child 6 years and younger in the home about the communication practices of their dentists and staff. Five questions from the Consumer Assessment of Healthcare Providers and Systems survey were included in a random digit dial telephone survey administered in March and April 2010. A total of 803 surveys were completed with adults 18-65 years of age who had a child in their home 6 years of age and younger. Land and cell phones were used. The analysis included frequencies, percentages, chi-square tests, and multivariate logistic regression. The response rate was 24%. Overall, those with higher levels of education and women were more likely to respond favorably about the communication practices of their dentist and staff. Respondents whose child was insured with Medicaid/State Children's Health Insurance Program (SCHIP) were less likely to respond favorably. Medicaid/SCHIP recipients are the individuals with the greatest dental disease and in need of preventive information and regimens for themselves and for their children. Spending time with patients and providing them with accurate information in a manner that patients feel respected and listened to contributes to the patient's ability to understand and act upon this information. Thus, these communication practices are pivotal to increasing oral health literacy and decreasing dental disparities. PMID- 22845713 TI - Underestimating a serving size may lead to increased food consumption when using Canada's Food Guide. AB - It is unclear whether Canadians accurately estimate serving sizes and the number of servings in their diet as intended by Canada's Food Guide (CFG). The objective of this study was to determine if participants can accurately quantify the size of 1 serving and the number of servings consumed per day. White, Black, South Asian, and East Asian adults (n = 145) estimated the quantity of food that constituted 1 CFG serving, and used CFG to estimate the number of servings that they consumed from their 24-h dietary recall. Participants estimated 1 serving size of vegetables and fruit (+43%) and grains (+55%) to be larger than CFG serving sizes (p <= 0.05); meat alternatives (-33%) and cheese (-31%) to be smaller than a CFG serving size (p <= 0.05); and chicken, carrots, and milk servings accurately (p > 0.05). Serving size estimates were positively correlated with the amount of food participants regularly consumed at 1 meal (p < 0.001). From their food records, all ethnicities estimated that they consumed fewer servings of vegetables and fruit (-15%), grains (-28%), and meat and alternatives (-14%) than they actually consumed, and more servings of milk and alternatives (+26%, p <= 0.05) than they actually consumed. Consequently, 68% of participants believed they needed to increase consumption by greater than 200 kcal to meet CFG recommendations. In conclusion, estimating serving sizes to be larger than what is defined by CFG may inadvertently lead to estimating that fewer servings were consumed and overeating if Canadians follow CFG recommendations without guidance. Thus, revision to CFG or greater public education regarding the dietary guidelines is warranted. PMID- 22845714 TI - The legacy of Hans Selye and the origins of stress research: a retrospective 75 years after his landmark brief "letter" to the editor# of nature. AB - Hans Selye's single author short letter to Nature (1936, 138(3479):32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the "general adaptation syndrome", later renamed by Selye "stress response": the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers. Because of the major role of glucocorticoids (named by Selye), he performed extensive structure-activity studies in the 1930s-1940s, resulting in the first rational classification of steroid hormones, e.g. corticoids, testoids/androgens, and folliculoids/estrogens. During those years, he recognized the respective anti- and pro-inflammatory actions of gluco- and mineralocorticoids in animal models, several years before demonstration of anti rheumatic actions of cortisone and adrenocorticotrophic hormones in patients. Nevertheless, Selye did not receive a Nobel Prize, which was awarded in 1950 to the clinician Hench and the two chemists who isolated and synthesized some of the glucocorticoids. Nonetheless, Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered "Stress in heath and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of". PMID- 22845715 TI - Pulse transit time as a quick predictor of a successful axillary brachial plexus block. AB - BACKGROUND: It can take up to 30 min to determine whether or not axillary block has been successful. Pulse transit time (PTT) is the time between the R-wave on electrocardiography (ECG) and the arrival of the resulting pressure pulse wave in the fingertip measured with photoplethysmography. It provides information about arterial resistance. Axillary block affects vasomotor tone causing loss of sympathetic vasoconstriction resulting in an increased PTT. Early objective assessment of a block can improve efficacy of operating room time and minimize patient's fear of possible conversion to general anesthesia. This study explores whether PTT can objectively, reliably and quickly predict a successful axillary block. METHODS: Forty patients undergoing hand surgery under axillary block were included. A three-lead ECG and photoplethysmographic sensors were placed on both index fingers. Measurements were made from 2 min before until 30 min after induction of the block or less if the patient was transferred for operation. Afterwards, PTT was calculated as the time between the R-wave on ECG and a reference point on the photoplethysmogram. To assess the change in PTT caused by the block, the PTT difference between the control and blocked arm was calculated. Sensitivity and specificity of PTT difference were calculated using receiver operating characteristic analysis. RESULTS: In a successful block, the mean PTT difference significantly increased after 3 min by 12 (standard error of the mean 3.9) ms, sensitivity 87% and specificity 71% (area under the curve 0.87, P = 0.004). CONCLUSIONS: PTT is a reliable, quick and objective method to assess whether axillary block is going to be successful or not. PMID- 22845716 TI - PI3K, Rac1 and pPAK1 are overexpressed in extramammary Paget's disease. AB - BACKGROUND: Phosphatidylinositol 3-kinase (PI3K), Ras-related C3 botulinum toxin substrate 1 (Rac1) and P21-activated protein kinase 1 (PAK1) appear to play important roles in the pathogenesis of several tumors, but their expressions in extramammary Paget's disease (EMPD) have not been investigated yet. OBJECTIVES: To investigate the potential contribution of the PI3K, Rac1 and PAK1 to the development of EMPD. METHODS: Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for PI3K (85alpha), Rac1 and pPAK1. RESULTS: All the 35 primary EMPD specimens, including 20 non-invasive EMPD, 13 invasive EMPD and 2 metastatic lymph nodes, showed cytoplasm overexpression of PI3K (85alpha), Rac1 and pPAK1. The expression (% positive cells) of PI3K(85alpha), Rac1 and pPAK1 (90.1 +/- 8.6, 91.4 +/- 9.5 and 89.6 +/- 10.8% ) in EMPD were significantly higher than in apocrine glands of normal skin ( 20.1 +/- 11.9, 29.8 +/- 8.9, 41.1 +/- 13.4%), and the expression in invasive EMPD with lymph node metastasis (98.2 +/- 1.7, 98.8 +/- 0.7 and 98.4 +/- 0.9%) are significantly higher than in invasive EMPD without lymph node metastasis (94.1 +/ 2.6, 96.5 +/- 1.7 and 95.3 +/- 1.1%) and non-invasive EMPD (85.2 +/- 8.4, 87.1 +/- 9.9 and 83.1 +/- 10.6%). There were significant positive correlations of the expression levels between PI3K (85alpha) and Rac1, as well as between Rac1 and pPAK1 in EMPD. CONCLUSIONS: These results indicate that PI3K, Rac1 and PAK1 may play important roles in the pathogenesis of EMPD. PMID- 22845718 TI - Comparative analysis of long-term outcomes of Misgav Ladach technique cesarean section and traditional cesarean section. AB - AIM: The aim of the present study was to evaluate pelvic adhesions, dehiscence and chronic pelvic pain in two groups of patients who underwent different cesarean section (CS) operations. MATERIAL AND METHODS: One hundred and twelve eligible patients who met our criteria were randomly divided into two groups. Group 1 consisted of 52 women who had been operated at their first CS by Misgav Ladach technique and had now undergone a second CS. Group 2 consisted of 60 women who had been operated at their first CS by traditional (Pfannenstiel) technique and had now undergone a second CS. The two groups were compared for long-term outcomes, including adhesion, pelvic pain and wound dehiscence. RESULTS: The rate of adhesion in group 2 was 50% filmy type and 1.7% dense type. However, in group 1 the adhesion rate was 50% filmy and there was no dense type (P = 0.12). The location of adhesions were significantly different (P = 0.04). Dehiscence of uterine incision in the second group was seen in three patients but no dehiscence was found in the first group (P = 0.012). The rate of chronic pelvic pain in Misgav Ladach group (group 1) was 17.2% versus 35% in the traditional method (P = 0.01). CONCLUSION: The present results support the method of single layer suturing of the uterus and leaving the peritoneum intact in CS. PMID- 22845717 TI - Eosinophil cationic protein enhances cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells by stimulating the FGF receptor signaling pathway. AB - We investigated the functional role of eosinophil cationic protein (ECP) in regulating cardiomyogenesis using mouse P19CL6 embryonic carcinoma cells. ECP was confirmed to accelerate the cardiomyocyte differentiation of P19CL6 cells by enhancing the rate and area size of beating of cardiomyocyte and by facilitating the expression of cardiomyocyte-specific genes, such as GATA4 and alpha-MHC. Since cardiomyocyte differentiation in vivo is considered to follow mesoderm induction, the induction of Brachyury, a marker of mesoderm, was assessed. Brachyury expression was found to be enhanced after the addition of ECP. This enhancement was due to the stimulation of extracellular signal-regulated kinase (ERK)1/2 phosphorylation by ECP. In this context, treatment with SU5402, an inhibitor of fibroblast growth factor (FGF) receptor 1, suppressed Brachyury expression, phosphorylation of ERK1/2, and cardiomyocyte differentiation induced by ECP. We concluded that ECP might induce mesoderm differentiation through FGF signaling pathway and enhance subsequent cardiomyocyte differentiation in concert with dimethyl sulfoxide in P19CL6 cells. ECP may be a novel factor for cardiomyocyte differentiation, which should be very useful to prepare adequate numbers of cardiomyocytes for therapeutic cell transplantation. PMID- 22845719 TI - Routine use of a rapid test to detect bacteria at the time of issue for nonleukoreduced, whole blood-derived platelets. AB - BACKGROUND: The Pan Genera detection (PGD) test is used to screen platelet (PLT) products for bacterial contamination. We report the experience of using the PGD test on whole blood-derived PLTs (WBPs) at two large centralized transfusion services (CTS). STUDY DESIGN AND METHODS: Records of PGD test results were retrospectively reviewed. The PGD test was performed on individual WBP units or pools of WBPs ranging in size from 2 to 6 units at the time of issue. Bacterial culture was performed on PLT products with positive PGD tests, and at one CTS, the available cocomponents. RESULTS: A total of 70,561 WBP pools were screened with the PGD test. There were seven true-positive PGD tests and 242 false positive tests (positive predictive value of PGD test, 2.81%). The overall contamination rate was 99 per 10(6) WBP pools (1:10,080; 95% confidence interval [CI], 40-204), and the false-positive rate was 3430 per 10(6) WBP pools (1:292; 95% CI, 3011-3890). All seven bacterial isolates were Gram positive. The median age of the individual WBP units in the seven contaminated pools was 5 days (range, 3-5 days) compared to 4 days (range, 1-5 days) in the false-positive pools (p=0.0012). The same bacteria isolated from a positive PLT pool also grew in one red blood cell cocomponent. CONCLUSION: After testing more than 70,000 WBP pools at two large CTSs, the rate of contaminated WBP pools detected by the PGD test was 99 per 10(6) pools (1:10,080). PMID- 22845720 TI - Compact magnetic antennas for directional excitation of surface plasmons. AB - Plasmonics is considered as one of the most promising candidates for implementing the next generation of ultrafast and ultracompact photonic circuits. Considerable effort has been made to scale down individual plasmonic components into the nanometer regime. However, a compact plasmonic source that can efficiently generate surface plasmon polaritons (SPPs) and deliver SPPs to the region of interest is yet to be realized. Here, bridging the optical antenna theory and the recently developed concept of metamaterials, we demonstrate a subwavelength, highly efficient plasmonic source for directional generation of SPPs. The designed device consists of two nanomagnetic resonators with detuned resonant frequencies. At the operating wavelength, incident photons can be efficiently channeled into SPP waves modulated by the electric field polarization. By tailoring the relative phase at resonance and the separation between the two nanoresonators, SPPs can be steered to predominantly propagate along one specific direction. This novel magnetic nanoantenna paves a new way to manipulate photons in the near-field, and also could be useful for SPP-based nonlinear applications, active modulations, and wireless optical communications. PMID- 22845721 TI - Islamic views on artificial nutrition and hydration in terminally ill patients. AB - Withholding and withdrawing artificial nutrition and hydration from terminally ill patients poses many ethical challenges. The literature provides little information about the Islamic beliefs, attitudes, and laws related to these challenges. Artificial nutrition and hydration may be futile and reduce quality of life. They can also harm the terminally ill patient because of complications such as aspiration pneumonia, dyspnea, nausea, diarrhea, and hypervolemia. From the perspective of Islam, rules governing the care of terminally ill patients are derived from the principle that injury and harm should be prevented or avoided. The hastening of death by the withdrawal of food and drink is forbidden, but Islamic law permits the withdrawal of futile, death-delaying treatment, including life support. Nutritional support is considered basic care and not medical treatment, and there is an obligation to provide nutrition and hydration for the dying person unless it shortens life, causes more harm than benefit, or is contrary to an advance directive that is consistent with Islamic law. The decision about withholding or withdrawing artificial nutrition and hydration from the terminally ill Muslim patient is made with informed consent, considering the clinical context of minimizing harm to the patient, with input from the patient, family members, health care providers, and religious scholars. PMID- 22845722 TI - Gastrostomy tube feeding of children with cerebral palsy. PMID- 22845723 TI - Slow chemical transmission between dorsal root ganglion neuron somata. AB - Somatic sensory neuron somata are located within the dorsal root ganglia (DRG) and are mostly ensheathed by individual satellite glial cell sheets. It has been noted, however, that a subpopulation of these DRG somata are intimately associated, separated only by a single thin satellite glial cell membrane septum. We set out to test whether such neuron-glial cell-neuron trimers (NGlNs) are also linked functionally. The presence of NGlNs in chick DRGs was confirmed by electron microscopy. Selective satellite glial cell immunostains were identified and were used to image the inter-neuron septa in DRG frozen sections. We used a gentle, dispase-based enzymatic method to isolate chick and rat NGlNs in vitro for double patch clamp recordings. In the majority of pairs tested, an action potential-like stimulus train delivered to one soma resulted in a delayed, noisy and long-duration response in its idle partner. The response to a second stimulus train given minutes later was markedly facilitated. Both bidirectional and unidirectional transmission was observed between the paired neurons. Transmission was chemical and block by the general purinergic blocker suramin implicated ATP as a neurotransmitter. We conclude that the two neuronal somata in the NGlN can communicate by chemical transmission, which may involve a transglial, bi-synaptic pathway. This novel soma-to-soma transmission reflects a novel form of processing that may play a role in sensory disorders in the DRG and interneuron communication in the central nervous system. PMID- 22845724 TI - Reducing sitting time: the new workplace health priority. PMID- 22845725 TI - Decontamination work in the area surrounding Fukushima Dai-ichi Nuclear Power Plant: another occupational health challenge of the nuclear disaster. AB - This article describes occupational health measures for workers involved in decontamination of radioactive material discharged around Fukushima Dai-ichi Nuclear Power Plant after the explosions in 2011. Decontamination is performed by removing radioactive particles (mainly cesium) from surfaces of soil, grass and trees, and buildings. Measurement of radiation doses is necessary to reduce exposure, and to determine whether workers can work below dose limits. Protective equipment for decontamination is determined based on the concentration of radiation in contaminated soil and the exposure to dust. Health examinations by physicians are mandated for decontamination workers upon hiring and every 6 months. While there is no possibility of acute radiation injury from decontamination, workers may be anxious about the unclear effects of chronic low level radiation exposure on health. Measures to protect the decontamination workers are the top priority. PMID- 22845726 TI - Psychological distress and job stressors among Lebanese workers: experience from a private sector. AB - No published data exists on the prevalence of psychological distress (PD) among the Lebanese working population, and its association with job stressors. A cross sectional study was conducted in 2003 among Lebanese employees in a private administrative company. All employees (n = 200) received an anonymous questionnaire by mail. The General Health Questionnaire (GHQ-28) was used to estimate the prevalence of PD. Multiple regression analyses were performed to evaluate the relationship between GHQ-28 Likert score (0-84) and job stressors and other covariates. The participation rate was 79.3%. PD was identified in 30.0% of the studied population. A significant association was found between PD and lack of moral support, a recent disturbing event, feeling of job insecurity, and inability to be proactive. The results showed a high prevalence of PD in the studied population with significant association with job stressors. PMID- 22845727 TI - Health effects associated with passenger vehicles: monetary values of air pollution. AB - Air pollution is regarded as one of the highest priorities in environmental protection in both developed and developing countries. High levels of air pollution have adverse effects on human health that might cause premature death. This study presents the monetary value estimates for the adverse human health effects resulted from ambient air pollution. It aids decision makers to set priorities in the public health relevance of pollution abatement. The main driver of policymaker is the need to reduce the avoidable cardiopulmonary morbidity and mortality from pollutant exposures. The monetary valuation involves 2 steps: (i) relate levels of pollutants to mortality and morbidity (concentration-response relationships) and (ii) apply unit economic values. Cost of air pollution associated with passenger vehicles running over a major traffic bridge (6th of October Elevated Highway) is presented as a case study to demonstrate the use of monetary value of air pollution. The study proves that the cost of air pollution is extremely high and should not be overlooked. PMID- 22845728 TI - Paternal heredity and housing characteristics affect childhood asthma and allergy morbidity. AB - A birth cohort was initiated when each pregnant woman was asked for her own and her husband's history of asthma and allergic diseases at the time of recruitment. They were further inquired to verify their housing conditions, and current health status of children 3 to 5 years old at the time of interview. Paternal history was the most significant risk factor associated with reporting childhood morbidities at age of 3 to 5 years. Housing characteristics became meaningful variables only if the fathers were asthmatic or atopic. A 9-fold increase of risk was found if children with paternal history and also exposed to incense burning and water damage at home. This is the first epidemiological evidence of East Asia suggesting paternal heredity, with concurrent indoor hazardous exposures, as a predominant risk on developing childhood asthma and allergy. PMID- 22845729 TI - Blood lead, calcium, and phosphorus in women with preeclampsia in Edo State, Nigeria. AB - The authors investigated the effect of blood lead (BPb) and its relationship with calcium and phosphorus in the development of preeclampsia in Nigeria. Blood samples were collected from 59 preclamptics, 150 normal pregnant, and 122 nonpregnant women. Blood lead and serum Ca and P were determined. Blood lead was significantly higher (p < .001), whereas serum Ca and P were significantly lower (p < .001) in preclamptics than in normal pregnant women (60.2 +/- 12.8 vs 26.3 +/- 8.0 MUg/dL for Pb, 1.39 +/- 0.33 vs 2.03 +/- 0.22 mmol/L for Ca, and 0.76 +/- 0.10 vs 0.99 +/- 0.13 mmol/L for P, respectively). There was significant increase (p < .05) in BPb and decreases (p < .01) in serum Ca and P in pregnant women than in nonpregnant women (35.7 +/- 18.0 vs 13.1 +/- 6.4 MUg/dL for Pb, 1.85 +/- 0.33 vs 2.33 +/- 0.20 mmol/L for Ca, and 0.93 +/- 0.38 vs 1.24 +/- 0.26 mmol/L for P). Also, BPb was negatively correlated with serum Ca and, P, and positively correlated with systolic and diastolic blood pressures in pregnancy (r = -.804 for Ca, r = -.728 for P, r = .908 for SBP, and r = .842 for DBP) and preeclampsia (p < .01). It appears that increase in blood lead, which parallels decreases in serum calcium and phosphorus, may be related to the development and progression of preeclampsia in this environment. PMID- 22845730 TI - Interest of exhaled biomarkers in occupational asthma to latex: a case report. AB - New methods for exploring pulmonary inflammation might be useful: measurements of exhaled nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) in exhaled breath condensate (EBC). The authors describe the application and utility of these methods in a case report of pediatric nurse presenting an occupational asthma to latex. Despite compliance with avoidance measures, respiratory discomfort had worsened during work. Classical tests (spirometry, monitoring of peak expiratory flow) were not contributing to objectify the discomfort. Exhaled NO and H(2)O(2) in EBC increased immediately after work periods, compared with rest periods. Application of these new methods, at the same time, in workplace appears useful in the objective demonstration of a temporal relation between work and respiratory problems. The results allowed the occupational physician to transfer the patient to a new work station more appropriate for her respiratory health status. PMID- 22845731 TI - Workplace health promotion and stakeholder positions: a Finnish case study. AB - Modern workplace health promotion (WHP) requires collaboration, partnerships, and alliances with both internal and external stakeholders. However, the identification of the key stakeholders as well as the systematic mapping of their views has barely been covered in the existing research literature. This article describes the stakeholders and stakeholder positions in WHP in Finland. In this study, the stakeholders were classified as internal, interface, and external stakeholders. Furthermore, based on the authors' research, stakeholders and their positions were represented on a stakeholder map as well as by the power-interest matrix of the stakeholders. The governmental authorities play a key role in driving the strategic change toward WHP by preparing the required legislation and regulatory measures. However, both active employers and active employees can through their own work accelerate the development of new WHP services. Close collaboration between employers and employees is required at the individual workplaces. Some stakeholders, such as pension funds and occupational health services (OHS) providers, can act as important driving forces and support the strategic implementation of WHP in the workplaces. However, alone they have only limited opportunities to organize the WHP activities. Understanding the various stakeholders and the systematic mapping of their positions is essential for the successful planning and implementation of WHP activities. PMID- 22845732 TI - Uncomfortable moments across the desk in an occupational and environmental medicine clinic. PMID- 22845733 TI - Eosinophil cationic protein: overview of biological and genetic features. AB - The eosinophil cationic protein (ECP) is a small polypeptide that originates from activated eosinophil granulocytes. A wide range of stimuli has been shown to induce the secretion of ECP. The gene that encodes the human ECP is located on chromosome 14, and the protein shares the overall three-dimensional structure and the RNase active-site residues with other proteins in the RNase A superfamily. Several single-nucleotide polymorphisms in the human ECP gene have been currently described. ECP has many biological functions, including an immunoregulatory function, the regulation of fibroblast activity, and the induction of mucus secretion in the airway. Additionally, the protein is a potent cytotoxic molecule and has the capacity to kill mammalian and nonmammalian cells. The purpose of this article was to review the known biological and genetic characteristics of ECP that contribute to the understanding of this protein's role in the development and progression of a wide variety of diseases. PMID- 22845734 TI - Combined QM/MM (ONIOM) and QSAR approach to the study of complex formation of matrix metalloproteinase-9 with a series of biphenylsulfonamides-LERE-QSAR analysis (V). AB - We previously proposed a novel QSAR (quantitative structure-activity relationship) procedure called LERE (linear expression by representative energy terms)-QSAR involving molecular calculations such as an ab initio fragment molecular orbital ones. In the present work, we applied LERE-QSAR to complex formation of matrix metalloproteinase-9 (MMP-9) with a series of substituted biphenylsulfonamides. The results shows that the overall free-energy change accompanying complex formation is due to predominantly the contribution from the electrostatic interaction with the zinc atom in the active site of MMP-9. Carbonic anhydrase (CA) belongs to the zinc-containing protease family. In contrast to the current case of MMP-9, the overall free-energy change during complex formation of CA with a series of benzenesulfonamides is due to the contributions from the solvation and dissociation free-energy changes, as previously reported. Comparison of the two sets of results indicates quantitative differences in the relative contributions of free-energy components to the overall free-energy change between the two data sets, corresponding with those in the respective classical QSAR equations. The LERE-QSAR procedure was demonstrated to quantitatively reveal differences in the binding mechanisms between the two cases involving similar but different zinc-containing proteins at the electronic and atomic levels. PMID- 22845736 TI - Hydrolytic activity of vanadate toward serine-containing peptides studied by kinetic experiments and DFT theory. AB - Hydrolysis of dipeptides glycylserine (Gly-Ser), leucylserine (Leu-Ser), histidylserine (His-Ser), glycylalanine (Gly-Ala), and serylglycine (Ser-Gly) was examined in vanadate solutions by means of (1)H, (13)C, and (51)V NMR spectroscopy. In the presence of a mixture of oxovanadates, the hydrolysis of the peptide bond in Gly-Ser proceeds under the physiological pH and temperature (37 degrees C, pD 7.4) with a rate constant of 8.9 * 10(-8) s(-1). NMR and EPR spectra did not show evidence for the formation of paramagnetic species, excluding the possibility of V(V) reduction to V(IV) and indicating that the cleavage of the peptide bond is purely hydrolytic. The pD dependence of k(obs) exhibits a bell-shaped profile, with the fastest hydrolysis observed at pD 7.4. Combined (1)H, (13)C, and (51)V NMR experiments revealed formation of three complexes between Gly-Ser and vanadate, of which only one complex, designated Complex 2, formed via coordination of amide oxygen and amino nitrogen to vanadate, is proposed to be hydrolytically active. Kinetic experiments at pD 7.4 performed by using a fixed amount of Gly-Ser and increasing amounts of Na(3)VO(4) allowed calculation of the formation constant for the Gly-Ser/VO(4)(3-) complex (K(f) = 16.1 M(-1)). The structure of the hydrolytically active Complex 2 is suggested also on the basis of DFT calculations. The energy difference between Complex 2 and the major complex detected in the reaction mixture, Complex 1, is calculated to be 7.1 kcal/mol in favor of the latter. The analysis of the molecular properties of Gly-Ser and their change upon different modes of coordination to the vanadate pointed out that only in Complex 2 the amide carbon is suitable for attack by the hydroxyl group in the Ser side chain, which acts as an effective nucleophile. The origin of the hydrolytic activity of vanadate is most likely a combination of the polarization of amide oxygen in Gly-Ser due to the binding to vanadate, followed by the intramolecular attack of the Ser hydroxyl group. PMID- 22845735 TI - Transgenic RNA interference (RNAi)-derived field resistance to cassava brown streak disease. AB - Cassava brown streak disease (CBSD), caused by the Ipomoviruses Cassava brown streak virus (CBSV) and Ugandan Cassava brown streak virus (UCBSV), is considered to be an imminent threat to food security in tropical Africa. Cassava plants were transgenically modified to generate small interfering RNAs (siRNAs) from truncated full-length (894-bp) and N-terminal (402-bp) portions of the UCBSV coat protein (DeltaCP) sequence. Seven siRNA-producing lines from each gene construct were tested under confined field trials at Namulonge, Uganda. All nontransgenic control plants (n = 60) developed CBSD symptoms on aerial tissues by 6 months after planting, whereas plants transgenic for the full-length DeltaCP sequence showed a 3-month delay in disease development, with 98% of clonal replicates within line 718-001 remaining symptom free over the 11-month trial. Reverse transcriptase-polymerase chain reaction (RT-PCR) diagnostics indicated the presence of UCBSV within the leaves of 57% of the nontransgenic controls, but in only two of 413 plants tested (0.5%) across the 14 transgenic lines. All transgenic plants showing CBSD were PCR positive for the presence of CBSV, except for line 781-001, in which 93% of plants were confirmed to be free of both pathogens. At harvest, 90% of storage roots from nontransgenic plants were severely affected by CBSD-induced necrosis. However, transgenic lines 718-005 and 718-001 showed significant suppression of disease, with 95% of roots from the latter line remaining free from necrosis and RT-PCR negative for the presence of both viral pathogens. Cross-protection against CBSV by siRNAs generated from the full-length UCBSV DeltaCP confirms a previous report in tobacco. The information presented provides proof of principle for the control of CBSD by RNA interference mediated technology, and progress towards the potential control of this damaging disease. PMID- 22845737 TI - Effect of sea buckthorn berries and pulp in a liquid emulsion on gastric ulcer scores and gastric juice pH in horses. AB - BACKGROUND: Sea buckthorn berries (Hippophae rhamnoides) are rich in vitamin C and E, carotenoids, flavonoids, fatty acids, plant sterols, lignans, and minerals. A feed supplement containing sea buckthorn berries might have efficacy in treatment and prevention of gastric ulcers in horses. OBJECTIVES: To test the efficacy of a commercially available formulation of sea buckthorn berries and pulp (SeaBuck SBT Gastro-Plus) for treatment and prevention of gastric ulcers in stall-confined horses. ANIMALS: Eight Thoroughbred and Thoroughbred-cross horses (3-10 years of age, 5 geldings and 3 mares, 380-600 kg body weight). METHODS: This study was a 2-period crossover in which all horses received no treatment (untreated controls; n = 8) and treatment (SeaBuckSBT Gastro-Plus, 4 ounces [35.6 g berries and pulp], twice daily; n = 8) mixed with a pelleted complete feed (18% crude fiber; 9% starch; 14% crude protein). Horses were treated for 4 weeks followed by a 1-week (d28-d35) alternating feed-deprivation period to induce or worsen existing ulcers. Gastroscopic examinations were performed on days 0, 28, and 35. Gastric juice pH was measured and gastric ulcer number and severity scores were assigned by a masked investigator. RESULTS: Mean nonglandular gastric ulcer scores significantly (P < .05) increased in all horses after day 28, as a result of intermittent feed deprivation. Mean nonglandular gastric ulcer number (P = .84) and severity (P = .51) were not significantly different between SBT treated and untreated control horses. However, mean glandular ulcer number (P = .02) and glandular ulcer severity (P = .02) were significantly lower in the SBT treated horses compared with the untreated control at week 5. CONCLUSIONS AND CLINICAL IMPORTANCE: SeaBuck SBT Gastro-Plus liquid fed to horses did not show efficacy in treatment or prevention of naturally occurring nonglandular ulcers in horses; however, glandular ulcer scores were significantly lower in SBT-treated horses after feed deprivation. Thus, SBT might have efficacy in prevention of glandular ulcers in horses housed in stalls and undergoing intermittent feeding. PMID- 22845738 TI - Effect of resident postgraduate year on outcomes after laparoscopic appendectomy for appendicitis in children. AB - PURPOSE: The purpose of this study was to determine if the postgraduate level of resident in the operating room correlates with outcomes for pediatric patients undergoing laparoscopic appendectomy. SUBJECTS AND METHODS: The charts of all children who underwent laparoscopic appendectomy for appendicitis from 2007 to 2011 at a free-standing children's hospital were reviewed. Outcomes of interest were compared between patient groups based on postgraduate level of the junior most surgeon in the operating room: (1) junior resident (postgraduate year [PGY] 1, -2, and -3); (2) senior resident (PGY-4 or -5); (3) fellow (PGY-6 or -7); or (4) attending surgeon only. RESULTS: Junior resident (n=327), senior resident (n=129), fellow (n=246), and attending (n=73) groups were similar in terms of age (P=.69), gender distribution (P=.51), race (P=.08), and perforation status (P=.30). Operative time was shorter for senior residents (P=.002), fellows (P<.001), and attending surgeons operating without a resident (P<.001) compared with cases with junior residents. The rate of conversion to an open operation was similar among groups (P=.46). Resident level was not predictive of complications, which occurred in 26 junior resident cases (8.0%; referent), 17 senior resident cases (13.2%; odds ratio [OR] 1.73; P=.11), 33 fellow cases (13.4%; OR 1.71; P=.06), and 8 attending cases (11.0%; OR 1.62; P=.27). Fellow involvement was associated with an increased rate of postoperative percutaneous abscess drainage or re-operation for abscess or bowel obstruction (9.8%; OR 2.31; P=.020). CONCLUSIONS: Involvement of junior residents in pediatric laparoscopic appendectomy is associated with increased operative time but no higher rate of complications. PMID- 22845739 TI - Dual functions of highly potent graphene derivative-poly-L-lysine composites to inhibit bacteria and support human cells. AB - Dual-function poly(L-lysine) (PLL) composites that function as antibacterial agents and promote the growth of human cell culture have been sought by researchers for a long period. In this paper, we report the preparation of new graphene derivative-PLL composites via electrostatic interactions and covalent bonding between graphene derivatives and PLL. The resulting composites were characterized by infrared spectroscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy. The novel dual function of PLL composites, specifically antibacterial activity and biocompatibility with human cells [human adipose-derived stem cells and non-small-cell lung carcinoma cells (A549)], was carefully investigated. Graphene-DS-PLL composites composed of 4-carboxylic acid benzene diazonium salt (DS) generated more anionic carboxylic acid groups to bind to cationic PLLs, forming the most potent antibacterial agent among PLL and PLL composites with high biocompatibility with human cell culture. This dual functionality can be used to inhibit bacterial growth while enhancing human cell growth. PMID- 22845740 TI - TRPV1-tubulin complex: involvement of membrane tubulin in the regulation of chemotherapy-induced peripheral neuropathy. AB - Existence of microtubule cytoskeleton at the membrane and submembranous regions, referred as 'membrane tubulin' has remained controversial for a long time. Since we reported physical and functional interaction of Transient Receptor Potential Vanilloid Sub Type 1 (TRPV1) with microtubules and linked the importance of TRPV1 tubulin complex in the context of chemotherapy-induced peripheral neuropathy, a few more reports have characterized this interaction in in vitro and in in vivo condition. However, the cross-talk between TRPs with microtubule cytoskeleton, and the complex feedback regulations are not well understood. Sequence analysis suggests that other than TRPV1, few TRPs can potentially interact with microtubules. The microtubule interaction with TRPs has evolutionary origin and has a functional significance. Biochemical evidence, Fluorescence Resonance Energy Transfer analysis along with correlation spectroscopy and fluorescence anisotropy measurements have confirmed that TRPV1 interacts with microtubules in live cell and this interaction has regulatory roles. Apart from the transport of TRPs and maintaining the cellular structure, microtubules regulate signaling and functionality of TRPs at the single channel level. Thus, TRPV1-tubulin interaction sets a stage where concept and parameters of 'membrane tubulin' can be tested in more details. In this review, I critically analyze the advancements made in biochemical, pharmacological, behavioral as well as cell-biological observations and summarize the limitations that need to be overcome in the future. PMID- 22845741 TI - Association of ICU size and annual case volume of renal replacement therapy patients with mortality. AB - BACKGROUND: We aimed to reveal whether the size of an intensive care unit (ICU) or its annual case volume of patients treated with renal replacement therapy (RRT) for acute kidney injury (AKI) is associated with hospital mortality. METHODS: This was a retrospective cohort study in the Finnish Intensive Care Consortium (FICC) database in 2007-2008. We divided the 23 FICC-member ICUs first into small or large according to ICU size, and second into low, medium, or high volume tertiles according to annual case volume of patients with RRT. We compared crude hospital mortality, Simplified Acute Physiology Score (SAPS) II-, and case mix-adjusted hospital mortality in small vs. large ICUs and in low- or medium volume vs. high-volume ICUs. RESULTS: The median (interquartile range) annual case volume of patients with RRT for AKI per one ICU was 25 (19-45). Patients in small or low-volume ICUs were older and less severely ill. Crude and SAPS II adjusted hospital mortality rates were significantly higher in small ICUs but not significantly different in case volume tertiles. After adjusting for age, severity of illness, intensity of care, propensity to receive RRT, and day of RRT initiation, treatment in low or medium volume ICUs was associated with an increased risk for hospital mortality. CONCLUSIONS: Crude and adjusted hospital mortality rates of patients treated with RRT for AKI were higher in small ICUs. Patients treated in high-volume ICUs had a decreased adjusted risk for hospital mortality compared to those in low-or medium volume ICUs. PMID- 22845742 TI - The content validity of the Behaviour Support Plan Quality Evaluation tool (BSP QEII) and its potential application in accommodation and day-support services for adults with intellectual disability. AB - BACKGROUND: The quality of support provided to people with disability who show challenging behaviour could be influenced by the quality of the behaviour support plans (BSPs) on which staff rely for direction. This study investigated the content validity of the Behaviour Support Plan Quality Evaluation tool (BSP QEII), originally developed to guide the development of BSPs for children in school settings, and evaluated its application for use in accommodation and day support services for adults with intellectual disability. METHOD: A three-round Delphi study involving a purposive sample of experienced behaviour support practitioners (n = 30) was conducted over an 8-week period. The analyses included deductive content analysis and descriptive statistics. RESULTS: The 12 quality domains of the BSP-QEII were affirmed as valid for application in adult accommodation and day-support service settings. Two additional quality domains were suggested, relating to the provision of detailed background on the client and the need for plans to reflect contemporary service philosophy. Furthermore, the results suggest that some issues previously identified in the literature as being important for inclusion in BSPs might not currently be a priority for practitioners. These included: the importance of specifying replacement or alternative behaviours to be taught, descriptions of teaching strategies to be used, reinforcers, and the specification of objective goals against which to evaluate the success of the intervention programme. CONCLUSIONS: The BSP-QEII provides a potentially useful framework to guide and evaluate the development of BSPs in services for adults with intellectual disability. Further research is warranted to investigate why practitioners are potentially giving greater attention to some areas of intervention practice than others, even where research has demonstrated these others areas of practice could be important to achieving quality outcomes. PMID- 22845743 TI - Flow cytometry of lesional skin enhances the evaluation of cutaneous B-cell lymphomas. AB - BACKGROUND: Cutaneous B-cell lymphoproliferative lesions can pose diagnostic challenges. This study investigates the utlility of flow cytometry in 42 cases of suspected cutaneous B-cell lymphoma. METHODS: All available cases were reviewed [World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification]. Flow cytometry, immunohistochemistry and polymerase chain reaction-immunoglobulin H (PCR-IgH) analysis of blood and/or lesional skin were performed on primary cutaneous B-cell lymphoma (pcBCL, 17 cases), secondary cutaneous BCL (scBCL, 8 cases) and atypical lymphoid hyperplasia (ALH, 17 cases). RESULTS: Flow cytometry of skin detected a B-cell clone in 3/13 cases of ALH, 8/8 cases of pcBCL and 4/4 cases of scBCL, while PCR detected a clone in 3/14 cases of ALH, 4/15 cases of pcBCL and 6/8 cases of scBCL. Of eight cases of pcBCL analyzed by both methods, all eight were positive by flow while only three were positive by PCR. All cases positive by PCR were also positive by flow. Of five cases with both flow and light chain immunohistochemistry, all five showed light chain restriction by flow, while only two were positive by immunohistochemistry. CONCLUSION: Flow cytometry is more sensitive than PCR in detecting B-cell lymphoproliferative disorders (12/12 cases, 100% vs. 10/23 cases, 43%; p < 0.001). Furthermore, flow cytometry complements immunohistochemistry in the detection of light chain restriction. PMID- 22845744 TI - Hemoglobin trends in isolated coronary artery bypass grafting performed off-pump and with standard and mini circuits. AB - The comparison of hemodilution at the end of surgery is of limited use as it represents only a snapshot of a dynamic phenomenon. This study was undertaken to compare the perioperative hemoglobin curves of isolated coronary artery bypass grafting performed with minimized extracorporeal circulation, traditional cardiopulmonary bypass, and off-pump technique. The propensity score method was used to select three groups of patients, homogenous regarding preoperative and operative data, who underwent isolated coronary artery bypass grafting. A generalized linear mixed model was used for estimating differences in perioperative hemoglobin trends among groups. The three groups were each composed of 50 patients with no differences in demographic data, preoperative risk profile, preoperative hemoglobin, or type of surgery. There was no significant difference in major postoperative complications. The pattern of the hemodilution curves was similar in patients operated with mini-circuit and off-pump technique (P > 005). Mini-circuit led to a 3.1 +/- 11.9% hemoglobin reduction, which was similar to the off-pump group (1.6 +/- 8.9%, P = 0.99 at ANOVA) and significantly different from the standard extracorporeal circuit group (16.0 +/- 10.3%, P < 0.001 at ANOVA). The generalized linear mixed model determined that the standard circuit was the only independent predictor for increased hemodilution. Its effect on hemodilution was time-dependent and the slope of the hemoglobin curve was more pronounced between systemic heparinization and the end of surgery. Perioperative hemoglobin trends of patients who underwent myocardial revascularization with mini-circuit were similar to those of off-pump surgery and significantly less pronounced than those of standard extracorporeal circulation. PMID- 22845745 TI - Abdominal pain in a patient with haemophilia and metallic valve replacement. PMID- 22845746 TI - Red blood cell alloimmunization in transfused patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. AB - BACKGROUND: Red blood cell (RBC) alloimmunization is a major problem in chronically transfused patients because of the risk of hemolytic reactions and limited availability of compatible blood. This study was aimed at determining the characteristics of RBC alloimmunization in transfusion-dependent patients with myelodysplastic syndrome or chronic myelomonocytic leukemia (MDS/CMML). STUDY DESIGN AND METHODS: The transfusion and clinical records of all patients with MDS/CMML seen at our hospital from 1990 to 2009 were reviewed. The cumulative incidence of RBC alloimmunization was calculated by taking death as a competing risk. Incidence rates were compared by Poisson multivariate regression. RESULTS: A total of 272 patients were included. Median age was 74 years; 55% were men and had received a median of 33 (range, 4-421) RBC units. Forty-two (15%) patients formed 81 alloantibodies and seven autoantibodies. Three additional patients developed autoantibodies without alloantibodies. The incidence rate of RBC alloimmunization was 1 per 10.5 person-years and was independent of sex, age, and MDS diagnostic category. The cumulative incidence of alloimmunization increased with the number of RBC transfusions, reaching a plateau at 19.5% after 130 RBC units. The most common antibody specificities were Kell (26 cases), E (19), c (5), and Jk(a) (5). In 26 (62%) of the 42 alloimmunized patients, only the Rh system and Kell were involved. CONCLUSION: RBC alloimmunization occurs in 15% of MDS/CMML patients on chronic transfusion support and mostly involves the Rh system and Kell. Transfusing these patients with extended antigen-matched blood, including Kell and CcEe antigens, would presumably reduce the RBC immunization rate. PMID- 22845747 TI - 'One can always say no.' enriching the bioethical debate on antisocial behaviour, neurobiology and prevention: views of juvenile delinquents. AB - Genomic and neuro-scientific research into the causes and course of antisocial behaviour triggers bioethical debate. Often, these new developments are met with reservation, and possible drawbacks and negative side-effects are pointed out. This article reflects on these scientific developments and the bioethical debate by means of an exploration of the perspectives of one important stakeholder group: juveniles convicted of a serious crime who stay in a juvenile justice institution. The views of juveniles are particularly interesting, as possible applications of current and future scientific findings are considered to be most effective if applied early in life. Based on their statements we come to the following provisional conclusions. Concerns about labelling and stigmatization are recognized and widely shared. Possible effects on one's identity are acknowledged too. Yet, a possible biological underpinning of one's antisocial behaviour is not considered to result in the development of a criminal identity. Nonetheless, psychopharmacological interventions are experienced as endangering one's current self. Concerns regarding the refusal of responsibility and the blaming of one's genes or brain can be put into perspective. Instead, participants emphasize the motive of own choice as underlying their criminal behaviour. Moreover, bioethical debate should pay attention to the role of parents of children at risk and the parent-child relationship in families at risk. We argue that the short-term and long-term interests of children at risk, as well as their interests and those of society at large, may conflict. In order to deal appropriately with newly arising dilemmas, a normative framework needs to be developed. PMID- 22845748 TI - Thermogelling properties of triblock copolymers in the presence of hydrophilic Fe3O4 nanoparticles and surfactants. AB - We investigate the supramolecular structure formed by thermogelation of a triblock polymer in the presence of nanoparticles and surfactant using rheometry and small-angle X-ray scattering (SAXS). The triblock copolymer, nanoparticle, and surfactant used in this study are poly(oxyethylene-oxypropylene-oxyethylene), Pluronic F108, Fe(3)O(4) nanoparticles, and sodium dodecyl surfactant, respectively. Addition of 1-5 wt % of Fe(3)O(4) nanoparticle, of average particle size ~10 nm, in a weak template of F108 (15 wt %) shows a decrease in the onset of gelation temperature and dramatic alteration in the viscoelastic moduli. The nanocomposite samples show a linear viscoelastic regime up to 5% strain. The SAXS measurement shows that the intermicellar spacing of the supramolecular structure of pure F108 is ~16.5 nm, and the supramolecular structure is destroyed when nanoparticles and surfactants are incorporated in it. Further, the addition of anionic surfactant to nanocomposites leads to a dramatic reduction in the viscoelastic properties due to strong electrostatic barrier imparted by the surfactant headgroup that prevents the formation of hexagonally ordered micelles. Our results show that the thermogelation is due to the clustering of nanoparticles into a fractal network rather than a close-packed F108 micelles, in agreement with the recent findings in Pluronic F127-laponite systems. PMID- 22845749 TI - Fetal heart rate patterns related to neonatal brain damage and neonatal death in placental abruption. AB - AIM: The aim of this study was to determine the correlation between non reassuring fetal heart rate (NRFHR) patterns and poor neonatal outcome in placental abruption. MATERIAL AND METHODS: A retrospective study was performed involving 83 placental abruptions with a live fetus at one tertiary and one secondary hospital in Miyazaki prefecture, Japan. We examined the correlation among NRFHR, umbilical arterial blood gas status, and neonatal poor outcomes, including neonatal death (ND) and cerebral palsy (CP). RESULTS: A total of 83 cases were divided into bradycardia (n=27), recurrent late deceleration (rLD, n=29), severe variable deceleration or prolonged deceleration (sVD/PD, n=8), and other cases (n=19). In the bradycardia group, the incidence of low umbilical artery (UA) pH (<7.0) was 59% and the average UA pH was 6.96+/-0.22. Among these cases, 10 showed severe bradycardia (less than 80 b.p.m.) and an average UA pH of 6.85+/-0.24, and four cases resulted in poor outcome (three CP and one ND). In the rLD group, the incidence of low UA pH (<7.0) was 7% and the average UA pH was 7.24+/-0.12. In this group, a 40-week-old fetus with umbilical phlebitis had a lower UA pH (6.92) and developed CP. In the sVD/PD group, there were no cases of a low UA pH (<7.0) and the average UA pH was 7.30+/-0.04. In this group, a 31 week-old boy with a UA pH of 7.36 developed CP (PVL). The remaining 19 cases had no CP. CONCLUSION: Poor neonatal outcome of placental abruption is closely related to NRFHR, especially the degree of bradycardia. In the rLD and sVD/PD groups, risk factors, such as prematurity and fetal inflammation, co-existed. PMID- 22845750 TI - A century of Gestalt psychology in visual perception: II. Conceptual and theoretical foundations. AB - Our first review article (Wagemans et al., 2012) on the occasion of the centennial anniversary of Gestalt psychology focused on perceptual grouping and figure-ground organization. It concluded that further progress requires a reconsideration of the conceptual and theoretical foundations of the Gestalt approach, which is provided here. In particular, we review contemporary formulations of holism within an information-processing framework, allowing for operational definitions (e.g., integral dimensions, emergent features, configural superiority, global precedence, primacy of holistic/configural properties) and a refined understanding of its psychological implications (e.g., at the level of attention, perception, and decision). We also review 4 lines of theoretical progress regarding the law of Pragnanz-the brain's tendency of being attracted towards states corresponding to the simplest possible organization, given the available stimulation. The first considers the brain as a complex adaptive system and explains how self-organization solves the conundrum of trading between robustness and flexibility of perceptual states. The second specifies the economy principle in terms of optimization of neural resources, showing that elementary sensors working independently to minimize uncertainty can respond optimally at the system level. The third considers how Gestalt percepts (e.g., groups, objects) are optimal given the available stimulation, with optimality specified in Bayesian terms. Fourth, structural information theory explains how a Gestaltist visual system that focuses on internal coding efficiency yields external veridicality as a side effect. To answer the fundamental question of why things look as they do, a further synthesis of these complementary perspectives is required. PMID- 22845754 TI - Molecular dynamics simulations and density functional theory studies of NALMA and NAGMA dipeptides. AB - Classical molecular dynamics (MD) simulations using fixed charged force field (AMBER ff03) and density functional theory method using the M05-2X/6-31G** level of theory have been used to investigate the plasticity of the hydrogen bond formed between dipeptides of N-Acetyl-Leucine-MethylAmide (NALMA), N-Acetyl Glycine-MethylAmide (NAGMA), and vicinity of water molecules at temperature of 300 K. We have noticed that 2-3 water molecules contribute to change in the conformations of dipeptides NAGMA and NALMA. The self-assembly of 11 water molecules leads to the formation of water bridge at vicinity of the dipeptides and it constrain the conformations of dipeptides. We have found that the energy balance between breaking of the C = O...H-N H bonds and the formation of the C = O...H-O (wat) H bonds may be one of the determining factors to control the dynamics of the folding process of protein molecules. PMID- 22845755 TI - Global health policy coordination to address neglected tropical diseases. PMID- 22845756 TI - Evolution of nonlinear optical properties: from gold atomic clusters to plasmonic nanocrystals. AB - Atomic clusters of metals are an emerging class of extremely interesting materials occupying the intermediate size regime between atoms and nanoparticles. Here we report the nonlinear optical (NLO) characteristics of ultrasmall, atomically precise clusters of gold, which are smaller than the critical size for electronic energy quantization (~2 nm). Our studies reveal remarkable features of the distinct evolution of the optical nonlinearity as the clusters progress in size from the nonplasmonic regime to the plasmonic regime. We ascertain that the smallest atomic clusters do not show saturable absorption at the surface plasmon wavelength of larger gold nanocrystals (>2 nm). Consequently, the third-order optical nonlinearity in these ultrasmall gold clusters exhibits a significantly lower threshold for optical power limiting. This limiting efficiency, which is superior to that of plasmonic nanocrystals, is highly beneficial for optical limiting applications. PMID- 22845753 TI - Gastrostomy tube feeding of children with cerebral palsy: variation across six European countries. AB - AIM: To compare the prevalence of gastrostomy tube feeding (GTF) of children with cerebral palsy (CP) in six European countries. METHOD: Data on 1295 children (754 males, 541 females; mean age 5y 11mo, range 11y 2mo, min 6mo, max 11y 8mo) with CP born from 1999 to 2001 were collected from geographically defined areas in six European countries; four of the areas covered the whole country. Distribution of CP was unilateral 37%, bilateral 51%, dyskinetic 8%, and ataxic 4%. Sixty children were classified in Gross Motor Function Classification System (GMFCS) levels I and II, 6 in level III and 34 in levels IV and Vas Outcome measures were GTF, age at placement, feeding difficulties and the children's height and weight for age standard deviation scores (z-scores). RESULTS: The use of GTF among all children with CP was highest in western Sweden (22%, 95% confidence interval [CI] 16-29), and lowest in Portugal (6%, 95% CI 3-10), northern England (6%, 95% CI 3 9) and in Iceland (3%, 95% CI 0-13; p<0.001). The difference between areas was greater among children in GMFCS levels IV and V (non-ambulant); in this group, lower height z-scores were more prevalent in the areas with lower prevalence of GTF. The children's age at placement of gastrostomy also varied between areas (p<0.002). INTERPRETATION: The observed differences in the use of GTF may reflect differences in access to treatment or clinical practice, or both. Our results suggest that the use of GTF may improve growth in height and weight among children with more severely affected gross motor function - the group most likely to have associated feeding difficulties. PMID- 22845751 TI - A century of Gestalt psychology in visual perception: I. Perceptual grouping and figure-ground organization. AB - In 1912, Max Wertheimer published his paper on phi motion, widely recognized as the start of Gestalt psychology. Because of its continued relevance in modern psychology, this centennial anniversary is an excellent opportunity to take stock of what Gestalt psychology has offered and how it has changed since its inception. We first introduce the key findings and ideas in the Berlin school of Gestalt psychology, and then briefly sketch its development, rise, and fall. Next, we discuss its empirical and conceptual problems, and indicate how they are addressed in contemporary research on perceptual grouping and figure-ground organization. In particular, we review the principles of grouping, both classical (e.g., proximity, similarity, common fate, good continuation, closure, symmetry, parallelism) and new (e.g., synchrony, common region, element and uniform connectedness), and their role in contour integration and completion. We then review classic and new image-based principles of figure-ground organization, how it is influenced by past experience and attention, and how it relates to shape and depth perception. After an integrated review of the neural mechanisms involved in contour grouping, border ownership, and figure-ground perception, we conclude by evaluating what modern vision science has offered compared to traditional Gestalt psychology, whether we can speak of a Gestalt revival, and where the remaining limitations and challenges lie. A better integration of this research tradition with the rest of vision science requires further progress regarding the conceptual and theoretical foundations of the Gestalt approach, which is the focus of a second review article. PMID- 22845757 TI - Transposon tagging in diploid strawberry. AB - Fragaria vesca was transformed with a transposon tagging construct harbouring amino terminally deleted maize transposase and EGFP (Ac element), NPTII, CaMV 35S promoter (P35S) driving transposase and mannopine synthase promoter (Pmas) driving EGFP (Ds element). Of 180 primary transgenics, 48 were potential launch pads, 72 were multiple insertions or chimaeras, and 60 exhibited somatic transposition. T1 progeny of 32 putative launch pads were screened by multiplex PCR for transposition. Evidence of germ-line transposition occurred in 13 putative launch pads; however, the transposition frequency was too low in three for efficient recovery of transposants. The transposition frequency in the remaining launch pads ranged from 16% to 40%. After self-pollination of the T0 launch pads, putative transposants in the T1 generation were identified by multiplex PCR. Sequencing of hiTAIL-PCR products derived from nested primers within the Ds end sequences (either P35S at the left border or the inverted repeat at the right border) of T1 plants revealed transposition of the Ds element to distant sites in the strawberry genome. From more than 2400 T1 plants screened, 103 unique transposants have been identified, among which 17 were somatic transpositions observed in the T0 generation. Ds insertion sites were dispersed among various gene elements [exons (15%), introns (23%), promoters (30%), 3' UTRs (17%) as well as intergenically (15%)]. Three-primer (one on either side of the Ds insertion and one within the Ds T-DNA) PCR could be used to identify homozygous T2 transposon-tagged plants. The mutant collection has been catalogued in an on-line database. PMID- 22845752 TI - Socioeconomic status and the health of youth: a multilevel, multidomain approach to conceptualizing pathways. AB - Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on 2 prevalent chronic health problems in youth today, asthma and obesity. We review and propose a model that encompasses (a) multiple levels of influence, including the neighborhood, family and person level; (b) both social and physical domains in the environment; and finally (c) dynamic relationships between these factors. A synthesis of existing research and our proposed model draw attention to the notion of adverse physical and social exposures in youth's neighborhood environments altering family characteristics and youth psychosocial and behavioral profiles, thereby increasing youth's risk for health problems. We also note the importance of acknowledging reciprocal influences across levels and domains (e.g., between family and child) that create self-perpetuating patterns of influence that further accentuate the impact of these factors on youth health. Finally, we document that factors across levels can interact (e.g., environmental pollution levels with child stress) to create unique, synergistic effects on youth health. Our model stresses the importance of evaluating influences on youth's physical health not in isolation but in the context of the broader social and physical environments in which youth live. Understanding the complex relationships between the factors that link low SES to youth's long-term health trajectories is necessary for the creation and implementation of successful interventions and policies to ultimately reduce health disparities. PMID- 22845758 TI - Double representation of the wrist and elbow in human motor cortex. AB - Movements of the fingers, hand and arm involve overlapping neural representations in primary motor cortex (M1). Monkey M1 exhibits a core-surround organisation in which cortical representation of the hand and fingers is surrounded by representations of the wrist, elbow and shoulder. A potentially homologous organisation in human M1 has only been observed in a single study, a functional MRI (fMRI) study by [J.D. Meier, T.N. Aflalo, S. Kastner & M.S. Graziano.(2008) J Neurophysiol, 100(4), 1800-1812]. The results of their study suggested a double representation of the wrist in human M1, an unprecedented finding. Our purpose was to document and simultaneously provide evidence that would extend the presence of double representation of the wrist to that of the elbow. Using fMRI, we observed somatotopic maps in M1 and the supplementary motor area (SMA), the only other cortical area that showed robust within-limb somatotopy during self timed finger, wrist and elbow movements. We observed double wrist and elbow representation that bracketed finger fMRI responses in M1 and the SMA. Our results show that the cortical locations of these double representations are well predicted by local cortical anatomy. Double representation of the wrist and elbow is important because it violates the traditional somatotopic progression in M1 but it is consistent with the representation of synergistic movements involving adjacent effectors. PMID- 22845759 TI - Cytotoxicity, cell cycle arrest, antioxidant activity and interaction of dibenzoxanthenes derivatives with DNA. AB - In this study, we report the DNA interaction and cytotoxicity of four dibenzoxanthene compounds 1-4. The binding behaviors of these compounds to calf thymus DNA were studied by absorption titration, viscosity measurements. The DNA binding constants of compounds 1, 2, 3, and 4 are 5.05*10(4), 2.13*10(3), 5.10*10(4), and 3.03*10(3) M(-1), respectively. The lipophilicity of the compounds was determined by the shake flask method. The cytotoxicity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. These compounds exhibit high activity against BEL-7402, Hela, MG-63, and SKBR-3 cells. The cell cycle arrest was analyzed by flow cytometry. These compounds inhibit S phase of BEL-7402 and SKBR 3 cells. The experiments on antioxidant activity show that these compounds exhibit good antioxidant activity against hydroxyl radical ((*)OH). PMID- 22845760 TI - Local folding and misfolding in the PBX homeodomain from a three-state analysis of CPMG relaxation dispersion NMR data. AB - NMR Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiments represent a powerful approach for characterizing protein internal motions and for gaining insight into fundamental biological processes such as protein folding, catalysis, and allostery. In most cases, CPMG data are analyzed assuming that the protein exchanges between two different conformational states. Systems exchanging among more than two states are far more challenging to characterize by CPMG NMR. For example, in the case of three-state exchange in the fast time scale regime, it is difficult to uniquely connect the parameters extracted from CPMG analyses with the physical parameters of most interest, intercoversion rates, populations, and chemical shift differences for exchanging states. We have developed a grid search selection procedure that allows these physical parameters to be uniquely determined from CPMG data, based on additional information, which in this study comprises ligand-induced chemical shift perturbations. We applied this approach to the PBX homeodomain (PBX-HD), a three-helix protein with a C-terminal extension that folds into a fourth helix upon binding to DNA. We recently showed that the C-terminal extension transiently folds, even in the absence DNA, in a process that is likely tied to the cooperative binding of PBX-HD to DNA and other homeodomains. Using the grid search selection procedure, we found that PBX-HD undergoes exchange between three different conformational states, a major form in which the C-terminal extension is unfolded, the previously identified state in which the C-terminal extension forms a fourth helix, and an additional state in which the C-terminal extension is misfolded. PMID- 22845761 TI - Clinical experience with using lacosamide for the treatment of epilepsy in a tertiary centre. AB - OBJECTIVE: Lacosamide is approved for the adjunctive treatment of partial-onset seizures in adults. Phase II/III clinical trials suggest that it is a safe, effective and well-tolerated medication. However, there is little post-marketing information available about this medication. METHODS: We report our clinical experience from a tertiary referral epilepsy centre, which has been using lacosamide for the past 18 months, with 128 patients treated during this time. RESULTS: Fifty-three patients (41%) achieved at least a 50% reduction in seizure frequency, with 14 patients (11%) achieving seizure freedom for a mean time of 35 weeks. This 50% responder rate matches, and the seizure free rate outperforms that seen in previous pooled trials. The efficacy of lacosamide did not vary with concurrent sodium channel blocking agent (SCB) use, and a statistically significant dose-dependent response was not shown, which is in contrast to previous trials. Treatment emergent adverse effects (TEAEs) were noted in 52 patients (41%), with 24 patients (19%) discontinuing the medication. TEAEs were more frequent in patients on concurrent SCBs, affecting 51% vs. 28% of patients not on other SCBs. This increased risk of TEAEs from concurrent SCB use was of statistical significance (P = 0.01). The most frequently noted TEAEs from lacosamide were dizziness, sedation and diplopia, which all appeared to be dose related. CONCLUSION: This post-marketing analysis suggests that lacosamide in clinical practice at least mirrors, and possibly outperforms the results seen in previous phase II/III trials. PMID- 22845762 TI - Clinical experience in organ transplant from the Shiraz Transplant Center: 2011. AB - OBJECTIVES: The Shiraz Organ Transplant Center, the largest transplant center in Iran, has expanded its program of organ transplant during recent years. This article seeks to summarize organ transplantation over the last 2 decades and evaluate its status as of 2011. MATERIALS AND METHODS: We retrospectively analyzed the clinical records of all organ transplants performed in our center in 2011. We reviewed the patients' demographics, underlying disease, operation details as well as postoperative complications. RESULTS: During this period, 655 organ transplants including 345 liver, 297 kidney, 29 pancreas, and 11 intestine and multivisceral transplants were done. Among 345 liver transplants, 291 patients received a deceased-donor graft including 18 cases of split liver transplants while 54 patients received living-donor liver transplants. The 1-year graft and patient survival rates were 90.1% and 91%. CONCLUSIONS: In recent years, our program in organ transplants has expanded in number and variety of organs transplanted. This improvement is related to our multidisciplinary strategies to expand the donor pool and the experiences obtained during our transplant activities. PMID- 22845763 TI - Vaccination status of children considered for renal transplants: missed opportunities for vaccine preventable diseases. AB - OBJECTIVES: Infectious diseases, even vaccine preventable ones, might affect transplanting and the life course in pediatric solid-organ recipients. Owing to immunosuppression and decreased antibody production, susceptibility to infections is increased in these patients. MATERIALS AND METHODS: The present study was designed to assess the vaccination and antibody status of the pediatric renal transplant patients. Fifty-one patients who were admitted to the regional transplant center for renal transplant were retrospectively evaluated. Patient 's vaccination charts were examined, and their immunization status was determined by antibody titers against hepatitis B, hepatitis A, measles, mumps, rubella, and varicella. RESULTS: The study group was composed of 23 males and 28 females (mean age, 10.8 y; age range, 2-17 y). All patients ' vaccination status was appropriate with their ages according to national vaccination program. Antibodies were positive for hepatitis B in 84.3% patients, 76.5% for hepatitis A, 72.5% for measles, 64.7% for mumps, 64.7% for rubella, and 72.5% for varicella. CONCLUSIONS: Seronegativity for common childhood diseases may complicate the posttransplant period owing to increased risk of infections. Especially in developing countries, immunization protocols and vaccination program schedules should be reviewed before transplant to prevent serious complications caused by these diseases. PMID- 22845764 TI - Minimal access kidney transplant: a novel technique to reduce surgical tissue trauma. AB - OBJECTIVES: Minimally invasive surgery and minimal access surgery has replaced conventional surgical procedures during the last 15 years with benefits including a decrease in postoperative pain, time spent convalescing, early return to normal activities, and pleasing cosmetic results. Many centers perform kidney transplant through an oblique or J-shaped approach deep into the iliac fossa. Both approaches have possible disadvantages regarding the extent of tissue trauma. Therefore, we introduced a new minimal access kidney transplant technique in our kidney transplant program in 2008 and report the outcomes of the first 10 patients transplanted with this technique. MATERIALS AND METHODS: Between November 2008 to May 2009, ten kidney recipients were subjected to the minimal access kidney transplant technique. These patients represent a consecutive series of kidney transplants performed by the senior surgeon or under the supervision of the senior surgeon of transplant surgery. RESULTS: The mean (+/- SD) age of the recipients was 47 +/- 14.7 years (range, 28-67 y), the body mass index was 25 +/- 2.02 (range, 23-30), the time of procedure was 126.2 +/- 27.5 minutes (range, 90 165 min) with a mean (+/- SD) anastomoses time of 27.7 +/- 8.4 minutes (range, 19 45 min). Follow-up for all recipients was at least 18 months. There was no reintervention necessary, no wound infections, no primary nonfunction or a delayed graft function, no need for dialysis, no acute rejection episodes, no graft loss, no wound dehiscence, no incisional hernia, or lymphocele. Furthermore, no urologic complications or vascular complications were observed. CONCLUSIONS: Our reported technique was used on heart-beating donor kidneys as well as on living-donor organs and is safe with less comorbidity. This minimal access kidney transplant technique might be an alternative procedure for avoiding some of the disadvantages of conventional approaches used for kidney transplant. PMID- 22845765 TI - Changes in matrix metalloproteinases and their inhibitors in kidney transplant recipients. AB - OBJECTIVES: Chronic allograft nephropathy remains one of the main causes of late graft loss after kidney transplant owing to multifactorial development of kidney scarring. Chronic allograft nephropathy is characterised by an excess accumulation of extracellular matrix. A key system regulating extracellular matrix homeostasis are matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. This study sought to determine if a change in the matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases system contributes to chronic allograft nephropathy-associated progressive kidney scarring. MATERIALS AND METHODS: Examination of sequential renal biopsies was done at implantation, acute rejection, and subsequent chronic allograft nephropathy. In situ localisation of matrix metalloproteinase activity was assessed with a high-resolution in situ zymography technique using gelatin and collagen 1 substrates. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were localised using immunohistochemistry. RESULTS: In situ zymography showed over a 50% reduction in matrix metalloproteinase activity against both collagen 1 and gelatin substrates in chronic allograft nephropathy biopsies. A similar loss of matrix metalloproteinase activity was seen in the glomerular and tubulointerstitial compartments. Immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases were observed intracellularly in mesangial and tubular epithelial cells. Matrix metalloproteinases-1, -2, -3, and -9 were significantly reduced in acute rejection and later in chronic allograft nephropathy. However, glomerular matrix metalloproteinases 1 and 9 and tubulointerstitial matrix metalloproteinase-2 were reduced at implantation. Tissue inhibitors of matrix metalloproteinase-2 and -3 were elevated from implantation onwards. We were unable to stain reproducibly for tissue inhibitors of matrix metalloproteinase-1. CONCLUSIONS: Kidney scarring underlying chronic allograft nephropathy is associated with a reduction in matrix metalloproteinases activity that may be due to reduced expression of matrix metalloproteinases -1, -2, -3, and -9, and up-regulation of tissue inhibitors of matrix metalloproteinases -2 and -3. Some of these changes originate from implantation. PMID- 22845766 TI - Use of 3-dimensional computed hepatic venous visualization for graft outflow venoplasty in adult left living-donor liver transplant. AB - OBJECTIVES: A surgeon must be aware of hepatic vascular variations to safely perform living-donor liver transplant. The ramification patterns of the hepatic veins with tributaries for left lobe graft outflow venoplasty should be evaluated preoperatively with 3-dimensional computed tomography of the donor. MATERIALS AND METHODS: Twenty-four potential donors were examined between October 1999 and July 2006 for living-donor liver transplant using the left lobe. They underwent triphasic helical computed tomography of the liver on a multidetector helical computed tomographic scanner. All images, including 2-dimensional reformation and 3-dimensional reconstructed models with maximum intensity projection and volume rendering, were sent to a workstation for postprocessing. RESULTS: The ramification patterns of the left and middle hepatic vein were classified into 2 groups; they formed a common trunk (type 1), which had 3 variations; type 1A (13 cases): in which the left hepatic vein and the middle hepatic vein without any tributaries on their confluence; type 1B (8 cases): in which there was venous confluence in the left hepatic vein with the left superficial vein and middle hepatic vein; type 1C (2 cases): in which the hepatic venous confluence in the left hepatic vein and middle hepatic vein and the left superficial vein directly joining into the inferior vena cava; type 2 (1 case) had the left hepatic vein and middle hepatic vein joining into the inferior vena cava separately; type 1B underwent 2 venoplasty procedures, but the others underwent only a single venoplasty. CONCLUSIONS: We demonstrated the anatomic interrelation of the hepatic veins for hepatic outflow venoplasty of adult left lobe living-donor liver transplant with 3-dimensional computed tomography scanning to help surgeons preoperatively determine the appropriate technique or form of reconstruction. PMID- 22845767 TI - Gender-based analysis of outcome after heart transplantation. AB - OBJECTIVES: Gender differences between donors and recipients might have an effect on outcome after heart transplantation. Literature and registries reveal controversial results. We reviewed 1000 heart transplantations at our center focusing on the influence of gender differences on short- and long-term outcome after heart transplantation. MATERIALS AND METHODS: We performed a retrospective analysis of 1000 (960 primary and 40 redo-heart transplantations) between August 1981 and July 2008. In contrast to other studies, the data for gender differences (donor gender and recipient gender) were evaluated for recipient survival and survival conditional to early mortality. RESULTS: Female donors are significantly older than male donors (females, 36.5 +/- 14.5 years; males, 31.2 +/- 13.8 years). One-year survival was significantly inferior in male recipients receiving female donor hearts (mR/fD: 73.7%) compared to females receiving male donor organs (fR/mD: 90.9%) (P = .045). Univariate analysis revealed that, for recipients who survived > 1 year, survival at 10 years was significantly greater for female donors and female recipients (90%) than it was for male donors and male recipients (72%; P = .034). Multivariate analysis showed that the gender combination with female donors and female recipients was an independent indicator for greater long-term survival (P = .04). CONCLUSIONS: The gender combination of female donors and male recipients had a greater risk for early mortality after heart transplantation, and the combination of male donors and female recipients resulted in favorable short-term outcomes. In long-term follow-up, recipients of hearts from female donors had better survival, especially female recipients. PMID- 22845768 TI - "True" mycotic aneurysm of the anastomotic site of the renal allograft artery. AB - The incidence of vascular complications after renal transplant as reported varies from 3.5% to 14%. Pseudoaneurysm formation at the site of the anastomosis is a rare complication, and only a few cases have been reported. There also were only a few reports of "true" mycotic aneurysms of the renal allograft artery. We present 2 patients with true mycotic aneurysmal formation of the renal allograft artery after a renal transplant. Both patients presented with fever and increasing serum creatinine levels. Cultures from aneurysm tissue samples have grown Aspergillus flavus. Both patients were subjected to an allograft nephrectomy, and amphotericin was given. PMID- 22845769 TI - Soft tissue sarcoma at a dialysis access site in a transplant recipient. AB - Soft tissue sarcomas typically present as soft, painless masses on an extremity. Here, we present a patient with metastatic soft tissue sarcomas at his dialysis access site. This association with dialysis access has not been documented previously. A 62-year-old man presented with a nonhealing wound on his left upper extremity after excision of a pseudoaneurysmal arteriovenous fistula. The patient had received a second kidney transplant that was functioning well. Immunosuppression included tacrolimus, mycophenolate mofetil, and prednisone. He was induced with thymoglobulin twice. A biopsy was performed showing a high-grade pleomorphic sarcoma. A magnetic resonance image of his left upper extremity showed an 11 * 5.5 * 3 cm mass abutting the biceps and brachialis muscles. Also, we discovered several lesions in the axilla and the left side of the neck, which were suspicious for metastases. A positron emission tomography-computed tomography scan confirmed a left upper extremity soft tissue mass, with marked fluorodeoxyglucose uptake, in abnormally enlarged axillary, and supraclavicular lymph nodes of the left thorax, consistent with metastases. The patient underwent chemotherapy and radiation therapy. Soft tissue sarcomas are rare. A high index of suspicion is needed to make a diagnosis. This is the first reported case of a soft tissue sarcoma discovered at a dialysis access site. As with all malignancies, early diagnosis is key to patient survival. Thorough physical examinations and increased vigilance by physicians caring for immunosuppressed patients is invaluable. PMID- 22845770 TI - Native protein proteolysis in an immobilized enzyme reactor as a function of temperature. AB - Trypsin concentration and the unmasking of cleavage sites in proteins play important roles in the stoichiometry of peptide production and the number of limit peptides generated during proteolysis. The hypothesis explored in this work was that native proteins could be digested and identified without disulfide reduction by (i) enhancing the unmasking of cleavage sites through elevated reaction temperatures and (ii) increasing trypsin concentration by use of an immobilized enzyme reactor (IMER). Transferrin was chosen as a model protein for these studies on the basis of its resistance to trypsin digestion. Results from this study showed greater than 70% sequence coverage in the peptides identified when nonreduced transferrin was digested at 60 degrees C. Large numbers of missed cleavages were observed from specific regions in proteins. Proteolysis appeared to start at a small number of high frequency cleavage sites in the cases of both reduced and nonreduced transferrin. Although approximately the same number of peptides were obtained from both structural forms of transferrin, the location of high frequency cleavage sites and the peptides produced were very different. Results from this study suggest that the location of initial cleavage sites along with the path of subsequent digestion depends strongly on the type of treatment used to open protein structures up for proteolysis. PMID- 22845771 TI - Cholesterol metabolism is associated with soluble amyloid precursor protein production in Alzheimer's disease. AB - Disturbances of the cholesterol metabolism are associated with Alzheimer's disease (AD) risk and related cerebral pathology. Experimental studies found changing levels of cholesterol and its metabolites 24S-hydroxycholesterol (24S OHC) and 27-hydroxycholesterol (27-OHC) to contribute to amyloidogenesis by increasing the production of soluble amyloid precursor protein (sAPP). The aim of this study was to evaluate the relationship between the CSF and circulating cholesterol 24S-OHC and 27-OHC, and the sAPP production as measured by CSF concentrations of sAPP forms in humans. The plasma and the CSF concentrations of cholesterol, 24S-OHC and 27-OHC, and the CSF concentrations of sAPPalpha, sAPPbeta, and Abeta1-42 were assessed in subjects with AD and controls with normal cognition. In multivariate regression tests including age, gender, albumin ratio, and apolipoprotein E (APOE)epsilon4 status CSF cholesterol, 24S-OHC, and 27-OHC independently predicted the concentrations of sAPPalpha and sAPPbeta. The associations remained significant when analyses were separately performed in the AD group. Furthermore, plasma 27-OHC concentrations were associated with the CSF sAPP levels. The results suggest that high CSF concentrations of cholesterol, 24S OHC, and 27-OHC are associated with increased production of both sAPP forms in AD. PMID- 22845772 TI - Reliability and utility of the Behaviour Support Plan Quality Evaluation tool (BSP-QEII) for auditing and quality development in services for adults with intellectual disability and challenging behaviour. AB - BACKGROUND: Having an objective means of evaluating the quality of behaviour support plans (BSPs) could assist service providers and statutory authorities to monitor and improve the quality of support provided to people with intellectual disability (ID) who exhibit challenging behaviour. The Behaviour Support Plan Quality Evaluation Guide II (BSP-QEII) was developed to monitor and assess BSPs prepared by teachers to support children with disability in the school system. This study investigated the application of the BSP-QEII to the assessment of BSPs for adults with ID in community support services. METHOD: The inter-rater reliability of the BSP-QEII was assessed. The utility of the BPS-QEII was then investigated with reference to a time series study of matched pairs of BSPs, developed for the same clients over a period of approximately 3 years. Differences in plan quality measured across a number of service and systemic variables were also investigated. RESULTS: The BSP-QEII was found to have good inter-rater reliability and good utility for audit purposes. It was able to discriminate changes in plan quality over time. Differences in plan quality were also evident across different service types, where specialist staff had or had not been involved, and in some instances where a statutory format for the plan had or had not been used. There were no differences between plans developed by government and community sector agencies, nor were there any regional differences across the jurisdiction. CONCLUSIONS: The BSP-QEII could usefully be adopted as an audit tool for measuring the quality of BSPs for adults with ID. In addition to being used for research and administrative auditing, the principles underpinning the BSP-QEII could also be useful to guide policy and educational activities for staff in community based services for adults with ID. PMID- 22845773 TI - Study on the resistant genes to carbapenems and epidemiological characterization of multidrug-resistant Acinetobacter baumannii isolates. AB - The purpose of this study was to examine the carbapenemase-encoding resistance genes and analyze homologous of multidrug-resistant Acinetobacter baumannii (MRAB) isolates from nosocomial infections. Seventy-six A. baumannii strains were collected from inpatients and object surface of devices in intensive care units from May 2008 to February 2011. Antibiotic susceptibility testing of 18 antimicrobial agents was performed. The presence of carbapenemase-encoding resistance genes was investigated by polymerase chain reaction. Genotyping and dendrogram analysis of A. baumannii strains from nosocomial infections were performed using the DiversiLab System. All of the 76 clinical A. baumannii isolates were shown multidrug resistance. The bla(OXA-23) gene was identified in the 76 MRAB strains, while bla(OXA-24), bla(OXA-58), VIM, IMP-1, IMP-4, SIM, and blaNDM-1 were absent in all. Twenty-four A. baumannii strains from the samples with nosocomial infections were classified into four unrelated groups and nine patterns. In conclusion, production of bla(OXA-23) in MRAB is one of the molecular mechanisms responsible for carbapenem resistance. The MRAB strains from unrelated groups show different drug resistance, but the homologous strains also have different drug resistance. Homologous analysis can provide scientific evidence for evaluation of epidemic status of nosocomial infection caused by MRAB. PMID- 22845774 TI - Improvement of intradialytic hypotension in diabetic hemodialysis patients using vitamin E-bonded polysulfone membrane dialyzers. AB - Currently, there are no detailed reports on the effects of vitamin E-bonded polysulfone (PS) membrane dialyzers on intradialytic hypotension (IDH) in diabetic hemodialysis (HD) patients. This study was designed to evaluate changes in intradialytic systolic blood pressure (SBP) using "VPS-HA" vitamin E-bonded super high-flux PS membrane dialyzers. The subjects were 62 diabetic HD patients whose intradialytic SBP fell by more than 20%. Group A comprised patients who required vasopressors to be able to continue treatment or who had to discontinue therapy due to their lowest intradialytic SBP being observed at 210 min (28 patients). Group B comprised patients who showed no symptoms and required no vasopressors but showed a gradual reduction in blood pressure, with the lowest intradialytic SBP seen at the end of dialysis (34 patients). The primary outcome was defined as the lowest intradialytic SBP after 3 months using VPS-HA. Secondary outcomes included changes in the following: lowest intradialytic diastolic blood pressure, pulse pressure, pulse rate, plasma nitric oxide and peroxynitrite, serum albumin, and hemoglobin A1c. Group A's lowest intradialytic SBP had significantly improved at 3 months (128.0 +/- 25.1 mm Hg vs. 117.1 +/- 29.2 mm Hg; P = 0.017). Group B's lowest intradialytic SBP had significantly improved at 1 month (134.4 +/- 13.2 mm Hg vs. 121.5 +/- 25.8 mm Hg; P = 0.047) and 3 months (139.1 +/- 20.9 mm Hg vs. 121.5 +/- 25.8 mm Hg; P = 0.011). We conclude that VPS-HA may improve IDH in diabetic HD patients. PMID- 22845775 TI - Analysis of donor deferral at three blood centers in Brazil. AB - BACKGROUND: The safety of the blood supply is ensured through several procedures from donor selection to testing of donated units. Examination of the donor deferrals at different centers provides insights into the role that deferrals play in transfusion safety. STUDY DESIGN AND METHODS: A cross-sectional descriptive study of prospective allogeneic blood donors at three large blood centers located in Sao Paulo, Belo Horizonte, and Recife, Brazil, from August 2007 to December 2009 was conducted. Deferrals were grouped into similar categories across the centers, and within each center frequencies out of all presentations were determined. RESULTS: Of 963,519 prospective blood donors at the three centers, 746,653 (77.5%) were accepted and 216,866 (22.5%) were deferred. Belo Horizonte had the highest overall deferral proportion of 27%, followed by Recife (23%) and Sao Paulo (19%). Females were more likely to be deferred than males (30% vs. 18%, respectively). The three most common deferral reasons were low hematocrit or hemoglobin, medical diagnoses, and higher-risk behavior. CONCLUSION: The types and frequencies of deferral vary substantially among the three blood centers. Factors that may explain the differences include demographic characteristics, the order in which health history and vital signs are taken, the staff training, and the way deferrals are coded by the centers among other policies. The results indicate that blood donor deferral in Brazil has regional aspects that should be considered when national policies are developed. PMID- 22845776 TI - Repeated lentivirus-mediated granulocyte colony-stimulating factor administration to treat canine cyclic neutropenia. AB - Cyclic neutropenia occurs in humans and gray collie dogs, is characterized by recurrent neutropenia, and is treated by repeated injections of recombinant granulocyte colony-stimulating factor (rG-CSF). As dose escalation of lentivirus may be clinically necessary, we monitored the outcome of four sequential intramuscular injections of G-CSF-lentivirus (3 * 10(7) IU/kg body weight) to a normal dog and a gray collie. In the normal dog absolute neutrophil counts were significantly increased after each dose of virus, with mean levels of 27.75 +/- 3.00, 31.50 +/- 1.40, 35.05 +/- 1.68, and 43.88 +/- 2.94 * 10(3) cells/MUl, respectively (p<0.001), and elevated neutrophil counts of 31.18 +/- 7.81 * 10(3) cells/MUl were maintained for more than 6 years with no adverse effects. A gray collie dog with a mean count of 1.94 +/- 1.48 * 10(3) cells/MUl received G-CSF lentivirus and we observed sustained elevations in neutrophil levels for more than 5 months with a mean of 26.00 +/- 11.00 * 10(3) cells/MUl, significantly increased over the pretreatment level (p<0.001). After the second and third virus administrations mean neutrophil counts of 15.80 +/- 6.14 and 11.52 +/- 4.90 * 10(3) cells/MUl were significantly reduced compared with cell counts after the first virus administration (p<0.001). However, after the fourth virus administration mean neutrophil counts of 15.21 +/- 4.50 * 10(3) cells/MUl were significantly increased compared with the previous administration (p<0.05). Throughout the nearly 3 years of virus administrations the dog gained weight, was healthy, and showed neutrophil counts significantly higher than pretreatment levels (p<0.001). These studies suggest that patients with cyclic and other neutropenias may be treated with escalating doses of G-CSF-lentivirus to obtain a desired therapeutic neutrophil count. PMID- 22845777 TI - Development of a novel ovarian cancer molecular target therapy against cancer related transcriptional factor, NAC1. PMID- 22845778 TI - Rare coagulation disorders: a study of 70 cases in the Egyptian population. PMID- 22845779 TI - Organic micropollutants in rivers downstream of the megacity Beijing: sources and mass fluxes in a large-scale wastewater irrigation system. AB - The Haihe River System (HRS) drains the Chinese megacities Beijing and Tianjin, forming a large-scale irrigation system severely impacted by wastewater-borne pollution. The origin, temporal magnitudes, and annual mass fluxes of a wide range of pharmaceuticals, household chemicals, and pesticides were investigated in the HRS, which drains 70% of the wastewater discharged by 20 million people living in Beijing. Based on Chinese consumption statistics and our initial screening for 268 micropollutants using high-resolution mass spectrometry, 62 compounds were examined in space and time (2009-2010). The median concentrations ranged from 3 ng/L for metolachlor to 1100 ng/L for benzotriazole and sucralose. Concentrations of carbendazim, clarithromycin, diclofenac, and diuron exceed levels of ecotoxicological concern. Mass-flux analyses revealed that pharmaceuticals (5930 kg/year) and most household chemicals (5660 kg/year) originated from urban wastewaters, while the corrosion inhibitor benzotriazole entered the rivers through other pathways. Total pesticide residues amounted to 1550 kg/year. Per capita loads of pharmaceuticals in wastewater were lower than those in Europe, but are expected to increase in the near future. As 95% of the river water is diverted to irrigate agricultural soil, the loads of polar organic micropollutants transported with the water might pose a serious threat to food safety and groundwater quality. PMID- 22845781 TI - The prevalence of neurological disorders in older people in Tanzania. AB - OBJECTIVES: There are few data on neurological disorders prevalence from low- and middle-income countries, particularly sub-Saharan Africa (SSA) and none specific to the African elderly. We aimed to determined the prevalence of neurological disorders in those aged 70 years and over in a rural African community. MATERIALS AND METHODS: This study was a cross-sectional two-phased community epidemiological survey set in the rural Hai district of Tanzania. Screening was performed with a validated screening questionnaire with high sensitivity and specificity. Positive responders to screening underwent full neurological history and examination to confirm or refute the presence of neurological disorders and to classify the disorder using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). RESULTS: Of 2232 participants, there were 384 neurological diagnoses amongst 349 people. The age adjusted prevalence of people with neurological diagnoses was 154.1 per 1000 (95% CI 139.2-169.1). The age-adjusted prevalence per 1000 of the most common neurological disorders were tremor (48.2), headache (41.8), stroke (23.0), peripheral polyneuropathy (18.6), upper limb mononeuropathy (6.5) and parkinsonism (5.9). CONCLUSIONS: This is the first published community-based neurological disorders prevalence study specifically in the elderly in SSA. It reveals a high prevalence of neurological morbidity and demonstrates the contribution neurological disorders make to the non-communicable disease epidemic. This is likely to increase as the population of low-income countries ages constituting a public health dilemma. PMID- 22845782 TI - Nonsuicidal self-injury as a time-invariant predictor of adolescent suicide ideation and attempts in a diverse community sample. AB - OBJECTIVE: Longitudinal data on adolescent self-injury are rare. Little is known regarding the associations between various forms of self-injurious thoughts and behaviors over time, particularly within community samples that are most relevant for prevention efforts. This study examined nonsuicidal self-injury (NSSI) as a time-invariant, prospective predictor of adolescent suicide ideation, threats or gestures, and attempts over a 2.5-year interval. METHOD: A diverse (55% female; 51% non-White) adolescent community sample (n = 399) reported depressive symptoms, frequency of NSSI, suicide ideation, threats or gestures, and attempts in 9th grade (i.e., baseline) and at 4 subsequent time points. Generalized estimating equations and logistic regressions were conducted to reveal the associations between baseline NSSI and the likelihood of each suicidal self injury outcome postbaseline while controlling for depressive symptoms and related indices of suicidal self-injury as competing predictors. RESULTS: Baseline NSSI was significantly, prospectively associated with elevated levels of suicide ideation and suicide attempts, but not threats or gestures. Neither gender nor ethnicity moderated results. CONCLUSIONS: Above and beyond established risk factors such as depressive symptoms and previous suicidality, adolescent NSSI may be an especially important factor to assess when determining risk for later suicidality. PMID- 22845783 TI - Leukemia cutis in association with cutaneous epidermal malignancies. AB - BACKGROUND: Epidermal malignancies developing in association with hematolymphoid malignancies are exceptional. Only one prior case of myeloid leukemia cutis with a cutaneous epidermal malignancy has been reported. METHODS: We report two cases; one occurred in association with squamous cell carcinoma (SCC) and another with basal cell carcinoma (BCC). RESULTS: Both patients were 83-year-old males without established histories of systemic hematopoietic disorders; one presented with an erythematous papule on the right upper back and the other with a nodule on the left wrist. One biopsy revealed nodular BCC with an associated perivascular myeloid leukemic infiltrate showing immunohistochemical positivity for CD43 and CD45. The other biopsy showed SCC associated with a leukemic infiltrate in sheets with myeloid blasts, eosinophilic myelocytes and maturing myeloid precursors. The myeloid cells showed immunohistochemical expression of CD43, CD68, CD33, CD117 and myeloperoxidase. Both patients had myeloblasts on peripheral blood smear. One patient declined further treatment and died of disease 5 weeks after the initial biopsy. The other patient underwent chemotherapy and is alive after 6 months. CONCLUSION: Although most inflammatory infiltrates associated with cutaneous epidermal malignancies are reactive, careful examination is necessary to exclude systemic hematopoietic disease, especially in elderly patients. PMID- 22845785 TI - Alteration of the timing of self-initiated but not reactive saccades by electrical stimulation in the supplementary eye field. AB - Although we can generate movements whenever we feel like doing so, the way in which neuronal signals regulate the timing of self-initiated movements remains elusive. There is evidence that the dorsomedial frontal cortex, including the supplementary eye field (SEF), is involved in the self-triggering of movements. Because the gradual evolution of cortical activity over the dorsomedial frontal cortex is known to reflect the temporal prediction of an upcoming event, we postulated that the timing of self-initiated movements is regulated by the time course of neuronal activity in the SEF. To test the causal role, we applied electrical microstimulation to the SEF when monkeys prepared for memory-guided saccades. Stimulation delayed the initiation of saccades when animals were required to make saccades 1200 +/- 300 ms following the cue (self-timed task), but not when they generated memory-guided saccades in response to the offset of the fixation point (conventional task). As well as the increment in median saccade latencies, stimulation at ~24% of sites also increased the occurrence of early erroneous saccades. Saccades facilitated by stimulation were always directed toward the cue, even when the cue was located away from the movement field. In contrast, stimulation to the frontal eye fields during saccade preparation exerted no effects in either task. These results suggest that the preparatory signals in the SEF may play a causal role in regulating the timing rather than the direction of self-initiated saccades. PMID- 22845784 TI - High-resolution behavioral economic analysis of cigarette demand to inform tax policy. AB - AIMS: Novel methods in behavioral economics permit the systematic assessment of the relationship between cigarette consumption and price. Towards informing tax policy, the goals of this study were to conduct a high-resolution analysis of cigarette demand in a large sample of adult smokers and to use the data to estimate the effects of tax increases in 10 US States. DESIGN: In-person descriptive survey assessment. SETTING: Academic departments at three universities. PARTICIPANTS: Adult daily smokers (i.e. more than five cigarettes/day; 18+ years old; >=8th grade education); n = 1056. MEASUREMENTS: Estimated cigarette demand, demographics, expired carbon monoxide. FINDINGS: The cigarette demand curve exhibited highly variable levels of price sensitivity, especially in the form of 'left-digit effects' (i.e. very high price sensitivity as pack prices transitioned from one whole number to the next; e.g. $5.80 6/pack). A $1 tax increase in the 10 states was projected to reduce the economic burden of smoking by an average of $530.6 million (range: $93.6-976.5 million) and increase gross tax revenue by an average of 162% (range: 114-247%). CONCLUSIONS: Tobacco price sensitivity is non-linear across the demand curve and in particular for pack-level left-digit price transitions. Tax increases in US states with similar price and tax rates to the sample are projected to result in substantial decreases in smoking-related costs and substantial increases in tax revenues. PMID- 22845786 TI - Reproducibility of temperature-selected mass spectra in matrix-assisted laser desorption ionization of peptides. AB - Matrix-assisted laser desorption ionization of peptides was investigated using alpha-cyano-4-hydroxycinnamic acid as the matrix. In each experiment, a set of mass spectra was collected by repetitive irradiation of a spot on a sample. Even though shot-to-shot variation in spectral pattern was significant, it was reproducible for different spots and samples. Each spectrum was tagged with the temperature in the early plume (T(early)) estimated through kinetic analysis of the peptide ion survival probability. T(early) decreased as the shot continued because the thermal conduction got more efficient as the sample got thinner. From each spectral set collected under various experimental conditions, a spectrum tagged with a particular T(early) was selected. Then, patterns of the spectra thus selected were the same. The reaction quotient for the matrix-to-peptide proton transfer determined at a specified T(early) was independent of the sample composition, indicating quasi-thermal equilibrium for this reaction. Furthermore, the van't Hoff plots were linear, also indicating quasi-thermal equilibrium. This, together with the thermal kinetics for the fragmentation of peptide and matrix ions, is responsible for the reproducibility of the mass spectral pattern at a specified T(early). PMID- 22845789 TI - Fog deposition and accumulation on smooth and textured hydrophobic surfaces. AB - We investigated the deposition and accumulation of droplets on both smooth substrates and substrates textured with square pillars, which were tens of micrometers in size. After being coated with a hydrophobic monolayer, substrates were placed in an air flow with a sedimenting suspension of micrometer-sized water droplets (i.e., fog). We imaged the accumulation of water and measured the evolution of the mean drop size. On smooth substrates, the deposition process was qualitatively similar to condensation, but differences in length scale revealed a transient regime not reported in condensation experiments. Based on previous simulation results, we defined a time-scale characterizing the transition to steady-state behavior. On textured substrates, square pillars promoted spatial ordering of accumulated drops. Furthermore, texture regulated drop growth: first enhancing coalescence when the mean drop size was smaller than the pillar, and then inhibiting coalescence when drops were comparable to the pillar size. This inhibition led to a monodisperse drop regime, in which drop sizes varied by less than 5%. When these monodisperse drops grew sufficiently large, they coalesced and could either remain suspended on pillars (i.e., Cassie-Baxter state) or wet the substrate (i.e., Wenzel state). PMID- 22845787 TI - Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. AB - PRRT2 is the gene recently associated with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, and choreoathetosis infantile convulsions. We report four family members with PRRT2 mutations who had heterogeneous paroxysmal disorders. The index patient had transient infantile paroxysmal torticollis, then benign infantile epilepsy that responded to carbamazepine. The index patient's father had PKD and migraine with aphasia, and his two brothers had hemiplegic migraine with onset in childhood. All four family members had the same PRRT2 c.649dupC mutation. We conclude that heterogeneous paroxysmal disorders are associated with PRRT2 mutations and include paroxysmal torticollis and hemiplegic migraine. We propose that PRRT2 is a new gene for hemiplegic migraine. PMID- 22845788 TI - In vitro cellular uptake of fibroin microspheres and its dependency on the cell cycle stage. AB - Cellular uptake of a protein microsphere was investigated in vitro. Fibroin microspheres with an average diameter of approximately 1 um were prepared with Fluorescein isothiocyanate-dextran for the fluorescent core. Tomography, performed using confocal laser scanning microscopy, confirmed microsphere uptake into the cytoplasmic area of 3T3 cells. Flow cytometry showed that cellular uptake was proportional to the co-incubation time and the microsphere concentration. It also revealed that fibroin microspheres were internalised by 3T3 cells at different rates depending on the cell cycle stage. The following cell stages had higher concentrations of internalised microspheres: G(2)/M > S > G(0)/G(1), when using 0.1 mg of microspheres per 10(6) cells. The internalised microspheres per cell also increased in the same order of cell cycle stages when co-incubating cells with 1 mg of microspheres. These results provide information that can be used to develop fibroin microspheres for intracellular delivery of large cargos. PMID- 22845790 TI - Thermal aggregation of bovine serum albumin in trehalose and sucrose aqueous solutions. AB - We report results of static and dynamic light scattering measurements performed on bovine serum albumin (BSA) in saccharide (trehalose and sucrose) solutions. Our aim is to study the effects of the two disaccharides on the first steps of thermal aggregation of BSA in aqueous solutions at two protein concentrations (1 and 30 mg/mL) at increasing sugar/water ratio. Results show that sugars modify early stages of aggregation mainly by perturbing the thermodynamic behavior of the solvent (i.e., general solvent effects) without involving direct, specific sugar-protein interactions. This agrees with current hypotheses on sugar action in protein solutions. (1-3) The linear correlation detected between the characteristic temperature of the aggregation process and the glass transition temperature of the water-sugar solvent strengthens the above suggestions. PMID- 22845791 TI - Physical activity parenting: a systematic review of questionnaires and their associations with child activity levels. AB - Insufficient physical activity (PA) is considered a critical contributor to childhood overweight. Parents are a key in influencing their child's PA through various mechanisms of PA parenting, including support, restriction of PA and facilitation of enrolment in PA classes or activities. However, study findings are difficult to compare because instruments vary in terms of constructs, psychometric assessment and type of PA assessed. The goal of the current review was to identify existing PA parenting questionnaires and report on the validation of these measures through findings of their psychometric performance and correlation to youth's PA. The search of eligible studies was restricted to instruments with multiple items. Eleven unique PA parenting questionnaires were identified, and 46 studies that used these instruments were included. Extracted data include sample characteristics, as well as type and assessment methods of parental influence and PA. Findings highlight the tremendous variation in the conceptualization and measurement of PA parenting, common use of non-validated instruments and lack of comprehensive measures. The development of theory-based PA parenting measures (preferably multidimensional) should be prioritized to guide the study of the parental role in promoting child's PA as well as the design of family-based PA interventions. PMID- 22845792 TI - Plasmonic near-electric field enhancement effects in ultrafast photoelectron emission: correlated spatial and laser polarization microscopy studies of individual Ag nanocubes. AB - Electron emission from single, supported Ag nanocubes excited with ultrafast laser pulses (lambda = 800 nm) is studied via spatial and polarization correlated (i) dark field scattering microscopy (DFM), (ii) scanning photoionization microscopy (SPIM), and (iii) high-resolution transmission electron microscopy (HRTEM). Laser-induced electron emission is found to peak for laser polarization aligned with cube diagonals, suggesting the critical influence of plasmonic near field enhancement of the incident electric field on the overall electron yield. For laser pulses with photon energy below the metal work function, coherent multiphoton photoelectron emission (MPPE) is identified as the most probable mechanism responsible for electron emission from Ag nanocubes and likely metal nanoparticles/surfaces in general. PMID- 22845793 TI - Increasing the transmitted flow pulse in a rotary left ventricular assist device. AB - Long-term rotary left ventricular assist devices (LVADs) are increasingly employed to bridge patients with end-stage heart failure to transplant or as a destination therapy. Significant recent device development has increased patient support times, shifting further development focus toward physiologically sensitive control of the pump operation. Sensorless control of these devices would benefit from increased observability of the ventricular volume/preload to the pump, in order to regulate flow based on preload, imitating the native Frank Starling flow control. Monitoring the transmitted flow pulse through the pump has been used as a surrogate for preload, although means of maximizing its transmission are not clear. However, it is known that a flat hydraulic performance curve of the rotary pump induces high changes in flow for a given change in pressure head. The aim of this study was to determine geometric pump parameters responsible for increasing this flow pulse transmission and to demonstrate this increase in vitro. The sensitivity of the performance gradient to blade angles, blade heights, blade clearance, and channel areas were studied. Resulting pressure head, flow, and hydraulic efficiency were analyzed with respect to textbook designed procedures. Then pumps with comparably "flat" and "steep" performance curves were used to simulate LVAD support in vitro over a range of pump flow rates to observe the transmitted flow pulsatility. It was found that an outlet blade angle of 90 degrees , inlet blade angle between 25 and 45 degrees , and large throat area generated a "flatter" performance curve. The transmitted flow pulsatility through a pump with a flat performance curve was 68% higher than that of a steep performance curve at a flow rate of 5 L/min. Substantial gains in the observability of LVAD preload/resident blood volume in the ventricle exist through the careful selection of specific pump geometries. PMID- 22845795 TI - LINE-1 retrotransposition events regulate gene expression after X-ray irradiation. AB - Long interspersed nuclear element-1 (LINE-1) retrotransposons are mobile elements that insert into new genomic locations via reverse transcription of an RNA intermediate. The mechanism of retrotransposition is not entirely understood. The integration of these elements occurs by target-primed reverse transcription (TPRT), which initiates double-strand breaks (DSBs) during the LINE-1 integration. Also, X-ray is known to induce DNA damage. The aim of this study was to evaluate the potential effects of LINE-1 de novo retrotransposition on the expression of different genes after X-ray irradiation in human endothelial cells. After stable transfection of the human hybrid endothelial cell line EA.hy926 with the human LINE-1 element, we analyzed the expression of different genes after irradiation with 5 Gy X-rays by reverse transcription-polymerase chain reaction (RT-PCR). We determine the expression level of phosphorylated p53 and gamma histone H2AX protein levels upon X-ray irradiation with 5 Gy for 24 h. Our results showed that EA.hy926 LINE-1 cell clones react with a strong upregulation of phosphorylated p53 protein, already 15 min after irradiation compared to the wild type (WT) cells. Also, the expression of gamma-histone H2AX protein was elevated in the cell clones with retrotransposition events 15 min after irradiation, whereas the WT cells have a delayed expression of phosphorylated histone H2AX protein. Taken together, our findings provide that LINE-1 retrotransposition events regulate different gene expression after irradiation in the EA.hy926 cell line. PMID- 22845796 TI - Leprosy trends in Zambia 1991-2009. AB - OBJECTIVE: To document leprosy trends in Zambia over the past two decades to ascertain the importance of leprosy as a health problem in Zambia. METHODS: Retrospective study covering the period 1991-2009 of routine national leprosy surveillance data, published national programme review reports and desk reviews of in-country TB reports. RESULTS: Data reports were available for all the years under study apart from years 2001, 2002 and 2006. The Leprosy case notification rates (CNR) declined from 2.73/10 000 population in 1991 to 0.43/10 000 population in 2009. The general leprosy burden showed a downward trend for both adults and children. Leprosy case burden dropped from approximately 18 000 cases in 1980 to only about 1000 cases in 1996, and by the year 2000, the prevalence rates had fallen to 0.67/10 000 population. There were more multibacillary cases of leprosy than pauci-bacillary cases. Several major gaps in data recording, entry and surveillance were identified. Data on disaggregation by gender, HIV status or geographical origin were not available. CONCLUSION: Whilst Zambia has achieved WHO targets for leprosy control, leprosy prevalence data from Zambia may not reflect real situation because of poor data recording and surveillance. Greater investment into infrastructure and training are required for more accurate surveillance of leprosy in Zambia. PMID- 22845794 TI - The human rhodopsin kinase promoter in an AAV5 vector confers rod- and cone specific expression in the primate retina. AB - Adeno-associated virus (AAV) has proven an effective gene delivery vehicle for the treatment of retinal disease. Ongoing clinical trials using a serotype 2 AAV vector to express RPE65 in the retinal pigment epithelium have proven safe and effective. While many proof-of-concept studies in animal models of retinal disease have suggested that gene transfer to the neural retina will also be effective, a photoreceptor-targeting AAV vector has yet to be used in the clinic, principally because a vector that efficiently but exclusively targets all primate photoreceptors has yet to be demonstrated. Here, we evaluate a serotype 5 AAV vector containing the human rhodopsin kinase (hGRK1) promoter for its ability to target transgene expression to rod and cone photoreceptors when delivered subretinally in a nonhuman primate (NHP). In vivo fluorescent fundus imaging confirmed that AAV5-hGRK1-mediated green fluorescent protein (GFP) expression was restricted to the injection blebs of treated eyes. Optical coherence tomography (OCT) revealed a lack of gross pathology after injection. Neutralizing antibodies against AAV5 were undetectable in post-injection serum samples from subjects receiving uncomplicated subretinal injections (i.e., no hemorrhage). Immunohistochemistry of retinal sections confirmed hGRK1 was active in, and specific for, both rods and cones of NHP retina. Biodistribution studies revealed minimal spread of vector genomes to peripheral tissues. These results suggest that AAV5-hGRK1 is a safe and effective AAV serotype/promoter combination for targeting therapeutic transgene expression protein to rods and cones in a clinical setting. PMID- 22845797 TI - Irradiation by light-emitting diode light as an adjunct to facilitate healing of experimental periodontitis in vivo. AB - BACKGROUND AND OBJECTIVE: This study evaluated the biostimulatory effect of 660 nm light-emitting diode (LED) as an adjunct in the treatment of experimental periodontitis. MATERIAL AND METHODS: Ninety-six Sprague-Dawley rats underwent experimental periodontitis by placement of a silk ligature followed with or without additive Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) injection. Irradiation with LED light was performed at varying energy densities of 5, 10 and 15 J/cm2, 1 d after debridement and detoxification. Rats were killed at 3, 7 and 14 d after irradiation with LED light, and the effect of irradiation was evaluated by descriptive histology and quantitative measurements of periodontal bone loss, inflammatory infiltration and cellular proliferation. RESULTS: Reduction of inflammation, accelerated collagen deposition and realignment was noted following irradiation with LED light at densities of 10 and 15 J/cm2, and temporary reduction of periodontal bone loss, as well as bundle bone apposition, was noted at day 3 in rats treated with 10 J/cm2 light. The biomodulatory effect was stronger in sites treated with Pg-LPS injection. In sites without Pg-LPS injection, temporary reduction of inflammation was noted in all LED light irradiated specimens at day 3. No significant change in cellular proliferation was noted in any LED light-treated group. CONCLUSIONS: LED light (660 nm) with an energy density of 10 J/cm2 appeared suitable as an adjunct modality for periodontitis by temporarily reducing inflammation, facilitating collagen realignment and bundle bone deposition. Future studies will aim to amplify the biostimulatory effect of LED light by adding a supplementary medium or repeated irradiation. PMID- 22845798 TI - Competence and ability. AB - It is nearly universally thought that the kind of decision-making competence that gives one a strong prima facie right to make one's own medical decisions essentially involves having an ability (or abilities) of some sort, or having a certain level or degree of ability (or abilities). When put under philosophical scrutiny, however, this kind of theory does not hold up. I will argue that being competent does not essentially involve abilities, and I will propose and defend a theory of decision-making competence according to which one is competent only if one possesses a certain kind of rationality in making treatment decisions. PMID- 22845799 TI - Pyomayoma during pregnancy: a case report and review of the literature. AB - Pyomyoma (suppurative leiomyoma) is a rare but serious complication of uterine leiomyomas. Although the management of leiomyomas during pregnancy is usually expectant, prompt surgical intervention is mandatory for pyomyoma. We present a case of pyomyoma with peritonitis that necessitated myomectomy at 21 weeks of gestation in a 28-year-old nullipara in which the pregnancy continued to successful delivery at 37 weeks of gestation. Perinatal and neonatal outcomes in pregnancies complicated with pyomyoma may be improved by prompt surgical intervention even in the early second trimester. A brief review of the literature regarding pyomyoma associated with pregnancy is also described. PMID- 22845800 TI - Predicting improvement in detection of bacteria in apheresis platelets by maintaining constant component sampling proportion. AB - BACKGROUND: In spite of interventions, approximately 1000 per 1,000,000 platelet (PLT) collections are contaminated with bacteria at collection. The current prestorage culture procedure at some blood centers is to inoculate a fixed volume from the collection bag (4-8 mL) regardless of collection volume. The sensitivity of early testing varies with the percent of collection volume sampled. We applied the Poisson model to determine whether sampling larger volumes might increase detection at pertinent contamination levels. STUDY DESIGN AND METHODS: The intervention was testing a fixed proportion of the collection volume from single, double, and triple collections. The Poisson model was applied to blood center data to calculate weighted average detection. Model 1 consisted of inoculating 3.2% of the collection volume from single, 1.6% from double, and 1.2% from triple PLT procedures (8 mL in each case). Model 2 consisted of inoculating 3.8% of the collection volume from all PLT procedures. Volume-related and non-volume-related contamination mechanisms were evaluated. RESULTS: Testing constant proportions of the collection volume (Model 2) increases percent detection over testing constant volumes (Model 1) (68% vs. 41% detection if contamination is 30 colony-forming units (CFUs)/collection bag and 17% vs. 9% detection if contamination is 5 CFUs/collection bag). At low levels of contamination (approx. 5 CFUs/bag), the intervention might double the number of contaminated units detected. CONCLUSION: Based on the application of the Poisson model to detection of bacteria in PLT concentrates, inoculating cultures with slightly consistent proportions of the collection volume should lead to a reduction in false negative tests and in the number of contaminated units transfused. PMID- 22845801 TI - Functional uniform priors for nonlinear modeling. AB - This article considers the topic of finding prior distributions when a major component of the statistical model depends on a nonlinear function. Using results on how to construct uniform distributions in general metric spaces, we propose a prior distribution that is uniform in the space of functional shapes of the underlying nonlinear function and then back-transform to obtain a prior distribution for the original model parameters. The primary application considered in this article is nonlinear regression, but the idea might be of interest beyond this case. For nonlinear regression the so constructed priors have the advantage that they are parametrization invariant and do not violate the likelihood principle, as opposed to uniform distributions on the parameters or the Jeffrey's prior, respectively. The utility of the proposed priors is demonstrated in the context of design and analysis of nonlinear regression modeling in clinical dose-finding trials, through a real data example and simulation. PMID- 22845802 TI - The impact of smoking on the antiplatelet action of clopidogrel in non-ST elevation myocardial infarction patients: results from the ISAR-REACT 4 platelet substudy. PMID- 22845803 TI - US Hemophilia Treatment Center population trends 1990-2010: patient diagnoses, demographics, health services utilization. AB - For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population. PMID- 22845805 TI - Relation of muscle size to function in neonatal brachial plexus palsy. PMID- 22845804 TI - Shift in the equilibrium between on and off states of the allosteric switch in Ras-GppNHp affected by small molecules and bulk solvent composition. AB - Ras GTPase cycles between its active GTP-bound form promoted by GEFs and its inactive GDP-bound form promoted by GAPs to affect the control of various cellular functions. It is becoming increasingly apparent that subtle regulation of the GTP-bound active state may occur through promotion of substates mediated by an allosteric switch mechanism that induces a disorder to order transition in switch II upon ligand binding at an allosteric site. We show with high-resolution structures that calcium acetate and either dithioerythritol (DTE) or dithiothreitol (DTT) soaked into H-Ras-GppNHp crystals in the presence of a moderate amount of poly(ethylene glycol) (PEG) can selectively shift the equilibrium to the "on" state, where the active site appears to be poised for catalysis (calcium acetate), or to what we call the "ordered off" state, which is associated with an anticatalytic conformation (DTE or DTT). We also show that the equilibrium is reversible in our crystals and dependent on the nature of the small molecule present. Calcium acetate binding in the allosteric site stabilizes the conformation observed in the H-Ras-GppNHp/NOR1A complex, and PEG, DTE, and DTT stabilize the anticatalytic conformation observed in the complex between the Ras homologue Ran and Importin-beta. The small molecules are therefore selecting biologically relevant conformations in the crystal that are sampled by the disordered switch II in the uncomplexed GTP-bound form of H-Ras. In the presence of a large amount of PEG, the ordered off conformation predominates, whereas in solution, in the absence of PEG, switch regions appear to remain disordered in what we call the off state, unable to bind DTE. PMID- 22845806 TI - Macrophagic myofasciitis: a report of second case from UK. PMID- 22845807 TI - Differential responses of endogenous adult mouse neural precursors to excess neuronal excitation. AB - Adult neurogenesis in the subgranular zone of the hippocampus (SGZ) is enhanced by excess as well as mild neuronal excitation, such as chemoconvulsant-induced brief seizures. Because most studies of neurogenesis after seizures have focused on the SGZ, the threshold of neuronal excitation required to enhance neurogenesis in the subventricular zone (SVZ) is not clear. Therefore, we examined the responses of SVZ precursors to brief generalized clonic seizures induced by a single administration of the chemoconvulsant pentylenetetrazole (PTZ). Cell cycle progression of precursors was analysed by systemic administration of thymidine analogues. We found that brief seizures immediately resulted in cell cycle retardation in the SVZ. However, the same effect was not seen in the SGZ. This initial cell cycle retardation in the SVZ was followed by enhanced cell cycle re entry after the first round of mitosis, leading to precursor pool expansion, but the cell cycle retardation and expansion of the precursor pool were transient. Cell cycle progression in the PTZ-treated group returned to normal after one cell cycle. The numbers of precursors in the SVZ and new neurons in the olfactory bulb, which are descendants of SVZ precursors, were not significantly different from those in control mice more than 2 days after seizures. Because similar effects were observed following electroconvulsive seizures, these responses are likely to be general effects of brief seizures. These results suggest that neurogenesis in the SVZ is more tightly regulated and requires stronger stimuli to be modified than that in the SGZ. PMID- 22845808 TI - Transplantation of autologous chondrocytes seeded on a fibrin/hyaluronan composite gel into tracheal cartilage defects in rabbits: preliminary results. AB - Reconstruction of tracheal defects is one of the most difficult procedures in head and neck surgery. To date, various reconstructing techniques have been used with no consensus on the best approach. This study investigated the feasibility of using a fibrin/hyaluronic acid (HA) composite gel with autologous chondrocytes for tracheal reconstruction. Chondrocytes from autologous rabbit auricular cartilages were expanded and seeded into a culture dish at high density to form stable tracheal cartilages mechanically using a fibrin/HA composite gel. A 1-cm long by 0.5-cm wide defect was created by a scalpel on the cervical tracheae of six rabbits. Tissue-engineered cartilages using fibrin/HA composite were trimmed and fixed to the defect boundaries with tissuecol. Postoperatively, the site was evaluated endoscopically, histologically, radiologically, and functionally. None of the six rabbits showed signs of respiratory distress. Postoperatively, in all cases, rigid telescopic examination showed that the implanted scaffolds were completely covered with regenerated mucosa without granulation or stenosis. Histologically, the grafts showed no signs of inflammatory reaction and were covered with ciliated epithelium. Even when grafts were broken and migrated from their original insertion site, the implanted cartilages were well preserved. However, the grafts did show signs of mechanical failure at the implantation site. The beat frequency of ciliated epithelium on implants was very similar to that of normal respiratory mucosa. In conclusion, implants with autologous chondrocytes cultured with fibrin/HA showed good tracheal luminal contour, functional epithelial regeneration, and preservation of neocartilage without inflammation but lacked adequate mechanical stability. PMID- 22845809 TI - pH-sensitive polymeric vesicles from coassembly of amphiphilic cholate grafted poly(L-lysine) and acid-cleavable polymer-drug conjugate. AB - Herein we report a coassembly method toward the preparation of pH-sensitive polymeric vesicular aggregates, using comb-shaped amphiphilic polymers, i.e., cholate grafted poly(L-lysine) (PLL-CA), with an amphiphilic poly(ethylene glycol)-doxorubicin conjugate (PEG-DOX). Because the drug conjugate includes a low-pH labile bond, i.e., benzoic imine, the permeability of the coassembled polymeric vesicles can be tuned by changing either the PLL-CA/PEG-DOX weight ratio or the environmental pH from 7.4 to 6.5. Furthermore, at lower pH values such as 5.0, the vesicles destabilize. The pH sensitivity leads to enhanced uptake of the vesicles by cancer cells (MCF-7) under a condition close to the extracellular environment of solid tumor (pH = 6.5) and subsequent efficient endosome escape after the endocytosis. PMID- 22845810 TI - Cyanotic congenital heart disease the coronary arterial circulation. AB - BACKGROUND: The coronary circulation in cyanotic congenital heart disease (CCHD) includes the extramural coronary arteries, basal coronary blood flow, flow reserve, the coronary microcirculation, and coronary atherogenesis. METHODS: Coronary arteriograms were analyzed in 59 adults with CCHD. Dilated extramural coronaries were examined histologically in six patients. Basal coronary blood flow was determined with N-13 positron emission tomography in 14 patients and in 10 controls. Hyperemic flow was induced by intravenous dipyridamole pharmacologic stress. Immunostaining against SM alpha-actin permitted microcirculatory morphometric analysis. Non-fasting total cholesterols were retrieved in 279 patients divided into four groups: Group A---143 cyanotic unoperated, Group B-- 47 rendered acyanotic by reparative surgery, Group C---41 acyanotic unoperated, Group D---48 acyanotic before and after operation. RESULTS: Extramural coronary arteries were mildly or moderately dilated to ectatic in 49/59 angiograms. Histologic examination disclosed loss of medial smooth muscle, increased medial collagen, and duplication of internal elastic lamina. Basal coronary flow was appreciably increased. Hyperemic flow was comparable to controls. Remodeling of the microcirculation was based upon coronary arteriolar length, volume and surface densities. Coronary atherosclerosis was absent in both the arteriograms and the necropsy specimens. CONCLUSIONS: Extramural coronary arteries in CCHD dilate in response to endothelial vasodilator substances supplemented by mural attenuation caused by medial abnormalities. Basal coronary flow was appreciably increased, but hyperemic flow was normal. Remodeling of the microcirculation was responsible for preservation of flow reserve. The coronaries were atheroma-free because of the salutory effects of hypocholesterolemia, hypoxemia, upregulated nitric oxide, low platelet counts, and hyperbilirubinrmia. PMID- 22845811 TI - Synergy between direct coronary stenting technique and use of the novel thin strut cobalt chromium SkylorTM stent: the MACE in follow up patients treated with Skylor stent [MILES Study]. AB - BACKGROUND: Despite significant improvements in stent platform, currently available bare-metal stents (BMS) are still associated with restenosis. Thin strut design cobalt-chromium alloys hold the promise of improving results of BMS, especially when implanted with direct technique. We performed an observational study to appraise outcomes of the novel SkylorTM stent, stratifying outcomes according to stenting technique. METHODS AND RESULTS: We included all consecutive patients undergoing coronary stenting with SkylorTM at 2 centers between 2006 and 2009. The primary end-point was the long-term rate of major adverse cardiac events (MACE, i.e. death, myocardial infarction (MI), coronary artery bypass grafting (CABG) or target vessel revascularization (TVR)). As pre-specified analysis, we compared patients undergoing direct stenting versus those stent implantation following predilation. A total of 1020 patients were included (1292 SkylorTM stents), with procedural success obtained in 99%. Comparing patients undergoing direct stenting (66%) versus pre-dilation (34%) at 16+/-7 months of follow-up, MACE had occurred in, respectively, 8% versus 14% (p=0.001), with death in 1% versus 2= (p=0.380), MI in 1% versus 2% (p=0.032), CABG in 0.2% versus 2% (p=0.012), and TVR in 6% versus 9% [p=0.071]. Even at multivariable analysis with propensity adjustment, direct stenting was associated with significantly fewer MACE [hazard ratio 0.60 [0.38-0.93], p=0.024]. CONCLUSIONS: This observational study suggests the presence of a beneficial synergy between direct coronary stenting technique and use of the novel thin-strut cobalt chromium SkylorTM stent in real-world patients undergoing PCI. PMID- 22845812 TI - On the analysis of fingertip photoplethysmogram signals. AB - Photoplethysmography (PPG) is used to estimate the skin blood flow using infrared light. Researchers from different domains of science have become increasingly interested in PPG because of its advantages as non-invasive, inexpensive, and convenient diagnostic tool. Traditionally, it measures the oxygen saturation, blood pressure, cardiac output, and for assessing autonomic functions. Moreover, PPG is a promising technique for early screening of various atherosclerotic pathologies and could be helpful for regular GP-assessment but a full understanding of the diagnostic value of the different features is still lacking. Recent studies emphasise the potential information embedded in the PPG waveform signal and it deserves further attention for its possible applications beyond pulse oximetry and heart-rate calculation. Therefore, this overview discusses different types of artifact added to PPG signal, characteristic features of PPG waveform, and existing indexes to evaluate for diagnoses. PMID- 22845814 TI - Evidence-based percutaneous closure of the left atrial appendage in patients with atrial fibrillation. AB - Atrial fibrillation is the most common cardiac arrhythmia, and its prevalence is increasing. Cardioembolic stroke, most of the times secondary to thrombus formation in the left atrial appendage, is its most feared and life threatening consequence. Oral anticoagulation with vitamin-K-antagonists is currently the most used prophylaxis for stroke in patients with atrial fibrillation; unfortunately, its benefits are limited by a narrow therapeutic window and an increased risk for bleeding, making it often undesired. Percutaneous occlusion of the left atrial appendage is a novel alternative strategy for cardioembolic stroke prophylaxis in patients with atrial fibrillation at a high risk of stroke but with contraindication for long-term oral anticoagulation therapy. At present, several devices have been developed specifically for percutaneous occlusion of the left atrial appendage. Current results show good feasibility and efficacy for these devices, with a high rate of successful implantation, although also associated with the inherent potential periprocedural complications. This work reviews the current state of the art of percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation. PMID- 22845813 TI - Myocardial revascularization for the elderly: current options, role of off-pump coronary artery bypass grafting and outcomes. AB - The increase in life expectancy has confronted cardiac surgery with a rapidly growing population of elderly patients requiring surgical myocardial revascularization. Recent advances in surgical and anesthetic techniques and improvements in postoperative care have made coronary artery bypass grafting an established therapeutic option for the treatment of coronary artery disease in this group of patients. However, conventional coronary artery bypass grafting on cardiopulmonary bypass is associated with significant risk and related morbidity and mortality in the elderly. In recent years off-pump coronary artery bypass grafting has emerged as a safe and less invasive strategy for surgical myocardial revascularization. Off-pump coronary artery bypass grafting by avoiding the deleterious effects of cardiopulmonary bypass can offer potential benefits to elderly patients requiring surgical myocardial revascularization. This review article provides an overview of the age-related cardiovascular changes, epidemiology of coronary artery disease in the elderly and focuses on outcomes of surgical myocardial revascularization with special emphasis on the impact of off pump coronary artery bypass surgery in the elderly. PMID- 22845815 TI - Tissue Doppler imaging in coronary artery diseases and heart failure. AB - Recent studies have explored the prognostic role of TDI-derived parameters in major cardiac diseases, such as coronary artery disease (CAD) and heart failure (HF). In these conditions, myocardial mitral annular systolic (S') and early diastolic (E') velocities have been shown to predict mortality or cardiovascular events. In heart failure non invasive assessment of LV diastolic pressure by transmitral to mitral annular early diastolic velocity ratio (E/E') is a strong prognosticator, especially when E/E' is > or =15. Moreover, other parameters derived by TDI, as cardiac time intervals and Myocardial Performance Index, might play a role in the prognostic stratification in CAD and HF. Recently, a three dimensional (3-D) TDI imaging modality, triplane TDI, has become available, and this allows calculation of 3-Dvolumes and LV ejection fraction. We present a brief update of TDI. PMID- 22845816 TI - Acute cardioembolic cerebral infarction: answers to clinical questions. AB - Cardioembolic cerebral infarction (CI) is the most severe subtype of ischaemic stroke but some clinical aspects of this condition are still unclear. This article provides the reader with an overview and up-date of relevant aspects related to clinical features, specific cardiac disorders and prognosis of CI. CI accounts for 14-30% of ischemic strokes; patients with CI are prone to early and long-term stroke recurrence, although recurrences may be preventable by appropriate treatment during the acute phase and strict control at follow-up. Certain clinical features are suggestive of CI, including sudden onset to maximal deficit, decreased level of consciousness at onset, Wernicke's aphasia or global aphasia without hemiparesis, a Valsalva manoeuvre at the time of stroke onset, and co-occurrence of cerebral and systemic emboli. Lacunar clinical presentations, a lacunar infarct and especially multiple lacunar infarcts, make cardioembolic origin unlikely. The most common disorders associated with a high risk of cardioembolism include atrial fibrillation, recent myocardial infarction, mechanical prosthetic valve, dilated myocardiopathy and mitral rheumatic stenosis. Patent foramen ovale and complex atheromatosis of the aortic arch are potentially emerging sources of cardioembolic infarction. Mitral annular calcification can be a marker of complex aortic atheroma in stroke patients of unkown etiology. Transthoracic and transesophageal echocardiogram can disclose structural heart diseases. Paroxysmal atrial dysrhythmia can be detected by Holter monitoring. Magnetic resonance imaging, transcranial Doppler, and electrophysiological studies are useful to document the source of cardioembolism. In-hospital mortality in cardioembolic stroke (27.3%, in our series) is the highest as compared with other subtypes of cerebral infarction. Secondary prevention with anticoagulants should be started immediately if possible in patients at high risk for recurrent cardioembolic stroke in which contraindications, such as falls, poor compliance, uncontrolled epilepsy or gastrointestinal bleeding are absent. Dabigatran has been shown to be non inferior to warfarin in the prevention of stroke or systemic embolism. All significant structural defects, such as atrial septal defects, vegetations on valve or severe aortic disease should be treated. Aspirin is recommended in stroke patients with a patent foramen ovale and indications of closure should be individualized. CI is an important topic in the frontier between cardiology and vascular neurology, occurs frequently in daily practice, has a high impact for patients, and health care systems and merits an update review of current clinical issues, advances and controversies. PMID- 22845818 TI - Beta blocker use after acute myocardial infarction in the patient with normal systolic function: when is it "ok" to discontinue? AB - Beta-Blockers [BB] have been used extensively in the last 40 years after acute myocardial infarction [AMI] as part of therapy and in secondary prevention. The evidence for "routine" therapy with beta-blocker use post AMI rests largely on results of trials conducted over 25 years ago. However, there remains no clear recommendation regarding the appropriate duration of treatment with BBs in post AMI patients with normal left ventricular ejection fraction [LVEF] who are not experiencing angina, or who require BB for hypertension or dysrhythmia. Based on the latest ACC/AHA guidelines, BBs are recommended for early use in the setting of AMI, except in patients who are at low risk and then indefinitely as secondary prevention after AMI. This recommendation was downgraded to class IIa in low risk patients and the updated 2007 ACC/AHA guidelines suggest that the rationale for BB for secondary prevention is from limited data derived from extrapolations of chronic angina and heart failure trials. In this review, we examine the key trials that have shaped the current guidelines and recommendations. In addition, we attempt to answer the question of the duration of BB use in patients with preserved LVEF after acute MI, as well as which subgroups of patients benefits most from post AMI use of beta blockers. PMID- 22845819 TI - Unintended phosphorus doping of nickel nanoparticles during synthesis with TOP: a discovery through structural analysis. AB - We report the discovery of unintentional phosphorus (P) doping when tri-n octylphosphine (TOP) ligands are used in Ni nanoparticle synthesis, which is the most common method for monodisperse Ni nanoparticle synthesis. The nanoparticles appear pure face-centered cubic (fcc) Ni in X-ray diffraction despite the surprisingly high level (5 atomic %) of P. We find that the P doping follows a direct relationship with increased reaction time and temperature and that the P doping can be estimated with the degree of lattice expansion shown from a peak shift in the XRD spectrum. Through EXAFS modeling and density-functional (DFT) calculations of defect formation energies we find that the P atoms are preferentially located on the fcc lattice as substitutional dopants with oxidation state of zero. Magnetic and catalytic properties are shown to be greatly affected by this doping; DFT calculations show magnetization losses in the Ni system, as well as in Fe and Co systems. These findings are likely relevant for other metal syntheses that employ phosphine ligands. PMID- 22845820 TI - Replicating receptive fields of simple and complex cells in primary visual cortex in a neuronal network model with temporal and population sparseness and reliability. AB - We propose a new principle for replicating receptive field properties of neurons in the primary visual cortex. We derive a learning rule for a feedforward network, which maintains a low firing rate for the output neurons (resulting in temporal sparseness) and allows only a small subset of the neurons in the network to fire at any given time (resulting in population sparseness). Our learning rule also sets the firing rates of the output neurons at each time step to near maximum or near-minimum levels, resulting in neuronal reliability. The learning rule is simple enough to be written in spatially and temporally local forms. After the learning stage is performed using input image patches of natural scenes, output neurons in the model network are found to exhibit simple-cell-like receptive field properties. When the output of these simple-cell-like neurons are input to another model layer using the same learning rule, the second-layer output neurons after learning become less sensitive to the phase of gratings than the simple-cell-like input neurons. In particular, some of the second-layer output neurons become completely phase invariant, owing to the convergence of the connections from first-layer neurons with similar orientation selectivity to second-layer neurons in the model network. We examine the parameter dependencies of the receptive field properties of the model neurons after learning and discuss their biological implications. We also show that the localized learning rule is consistent with experimental results concerning neuronal plasticity and can replicate the receptive fields of simple and complex cells. PMID- 22845817 TI - Circulatory syndrome: an evolution of the metabolic syndrome concept! AB - The metabolic syndrome has been a useful, though controversial construct in clinical practice as well as a valuable model in order to understand the interactions of diverse cardiovascular risk factors. However the increasing importance of the circulatory system in particular the endothelium, in both connecting and controlling organ function has underlined the limitations of the metabolic syndrome definition. The proposed "Circulatory Syndrome" is an attempt to refine the metabolic syndrome concept by the addition of recently documented markers of cardiovascular disease including renal impairment, microalbuminuria, arterial stiffness, ventricular dysfunction and anaemia to more classic factors including hypertension, dyslipidemia and abnormal glucose metabolism; all of which easily measured in clinical practice. These markers interact with each other as well as with other factors such as aging, obesity, physical inactivity, diet and smoking. The final common pathways of inflammation, oxidative stress and hypercoagulability thereby lead to endothelial damage and eventually cardiovascular disease. Nevertheless, the Circulatory (MARC) Syndrome, like its predecessor the metabolic syndrome, is only a small step toward an understanding of these complex and as yet poorly understood markers of disease. PMID- 22845821 TI - Nonlinearities and adaptation of color vision from sequential principal curves analysis. AB - Mechanisms of human color vision are characterized by two phenomenological aspects: the system is nonlinear and adaptive to changing environments. Conventional attempts to derive these features from statistics use separate arguments for each aspect. The few statistical explanations that do consider both phenomena simultaneously follow parametric formulations based on empirical models. Therefore, it may be argued that the behavior does not come directly from the color statistics but from the convenient functional form adopted. In addition, many times the whole statistical analysis is based on simplified databases that disregard relevant physical effects in the input signal, as, for instance, by assuming flat Lambertian surfaces. In this work, we address the simultaneous statistical explanation of the nonlinear behavior of achromatic and chromatic mechanisms in a fixed adaptation state and the change of such behavior (i.e., adaptation) under the change of observation conditions. Both phenomena emerge directly from the samples through a single data-driven method: the sequential principal curves analysis (SPCA) with local metric. SPCA is a new manifold learning technique to derive a set of sensors adapted to the manifold using different optimality criteria. Here sequential refers to the fact that sensors (curvilinear dimensions) are designed one after the other, and not to the particular (eventually iterative) method to draw a single principal curve. Moreover, in order to reproduce the empirical adaptation reported under D65 and A illuminations, a new database of colorimetrically calibrated images of natural objects under these illuminants was gathered, thus overcoming the limitations of available databases. The results obtained by applying SPCA show that the psychophysical behavior on color discrimination thresholds, discount of the illuminant, and corresponding pairs in asymmetric color matching emerge directly from realistic data regularities, assuming no a priori functional form. These results provide stronger evidence for the hypothesis of a statistically driven organization of color sensors. Moreover, the obtained results suggest that the nonuniform resolution of color sensors at this low abstraction level may be guided by an error-minimization strategy rather than by an information maximization goal. PMID- 22845822 TI - Unsupervised formation of vocalization-sensitive neurons: a cortical model based on short-term and homeostatic plasticity. AB - The discrimination of complex auditory stimuli relies on the spatiotemporal structure of spike patterns arriving in the cortex. While recordings from auditory areas reveal that many neurons are highly selective to specific spatiotemporal stimuli, the mechanisms underlying this selectivity are unknown. Using computer simulations, we show that selectivity can emerge in neurons in an entirely unsupervised manner. The model is based on recurrently connected spiking neurons and synapses that exhibit short-term synaptic plasticity. During a developmental stage, spoken digits were presented to the network; the only type of long-term plasticity present was a form of homeostatic synaptic plasticity. From an initially unresponsive state, training generated a high percentage of neurons that responded selectively to individual digits. Furthermore, units within the network exhibited a cardinal feature of vocalization-sensitive neurons in vivo: differential responses between forward and reverse stimulus presentations. Direction selectivity deteriorated significantly, however, if short-term synaptic plasticity was removed. These results establish that a simple form of homeostatic plasticity is capable of guiding recurrent networks into regimes in which complex stimuli can be discriminated. In addition, one computational function of short-term synaptic plasticity may be to provide an inherent temporal asymmetry, thus contributing to the characteristic forward reverse selectivity. PMID- 22845823 TI - Exact event-driven implementation for recurrent networks of stochastic perfect integrate-and-fire neurons. AB - In vivo cortical recording reveals that indirectly driven neural assemblies can produce reliable and temporally precise spiking patterns in response to stereotyped stimulation. This suggests that despite being fundamentally noisy, the collective activity of neurons conveys information through temporal coding. Stochastic integrate-and-fire models delineate a natural theoretical framework to study the interplay of intrinsic neural noise and spike timing precision. However, there are inherent difficulties in simulating their networks' dynamics in silico with standard numerical discretization schemes. Indeed, the well posedness of the evolution of such networks requires temporally ordering every neuronal interaction, whereas the order of interactions is highly sensitive to the random variability of spiking times. Here, we answer these issues for perfect stochastic integrate-and-fire neurons by designing an exact event-driven algorithm for the simulation of recurrent networks, with delayed Dirac-like interactions. In addition to being exact from the mathematical standpoint, our proposed method is highly efficient numerically. We envision that our algorithm is especially indicated for studying the emergence of polychronized motifs in networks evolving under spike-timing-dependent plasticity with intrinsic noise. PMID- 22845825 TI - A neural circuit for robust time-to-contact estimation based on primate MST. AB - Time-to-contact (TTC) estimation is beneficial for visual navigation. It can be estimated from an image projection, either in a camera or on the retina, by looking at the rate of expansion of an object. When expansion rate (E) is properly defined, TTC = 1/E. Primate dorsal MST cells have receptive field structures suited to the estimation of expansion and TTC. However, the role of MST cells in TTC estimation has been discounted because of large receptive fields, the fact that neither they nor preceding brain areas appear to decompose the motion field to estimate divergence, and a lack of experimental data. This letter demonstrates mathematically that template models of dorsal MST cells can be constructed such that the output of the template match provides an accurate and robust estimate of TTC. The template match extracts the relevant components of the motion field and scales them such that the output of each component of the template match is an estimate of expansion. It then combines these component estimates to provide a mean estimate of expansion across the object. The output of model MST provides a direct measure of TTC. The ViSTARS model of primate visual navigation was updated to incorporate the modified templates. In ViSTARS and in primates, speed is represented as a population code in V1 and MT. A population code for speed complicates TTC estimation from a template match. Results presented in this letter demonstrate that the updated template model of MST accurately codes TTC across a population of model MST cells. We conclude that the updated template model of dorsal MST simultaneously and accurately codes TTC and heading regardless of receptive field size, object size, or motion representation. It is possible that a subpopulation of MST cells in primates represents expansion in this way. PMID- 22845824 TI - Predicting single-neuron activity in locally connected networks. AB - The characterization of coordinated activity in neuronal populations has received renewed interest in the light of advancing experimental techniques that allow recordings from multiple units simultaneously. Across both in vitro and in vivo preparations, nearby neurons show coordinated responses when spontaneously active and when subject to external stimuli. Recent work (Truccolo, Hochberg, & Donoghue, 2010 ) has connected these coordinated responses to behavior, showing that small ensembles of neurons in arm-related areas of sensorimotor cortex can reliably predict single-neuron spikes in behaving monkeys and humans. We investigate this phenomenon using an analogous point process model, showing that in the case of a computational model of cortex responding to random background inputs, one is similarly able to predict the future state of a single neuron by considering its own spiking history, together with the spiking histories of randomly sampled ensembles of nearby neurons. This model exhibits realistic cortical architecture and displays bursting episodes in the two distinct connectivity schemes studied. We conjecture that the baseline predictability we find in these instances is characteristic of locally connected networks more broadly considered. PMID- 22845826 TI - Incremental slow feature analysis: adaptive low-complexity slow feature updating from high-dimensional input streams. AB - We introduce here an incremental version of slow feature analysis (IncSFA), combining candid covariance-free incremental principal components analysis (CCIPCA) and covariance-free incremental minor components analysis (CIMCA). IncSFA's feature updating complexity is linear with respect to the input dimensionality, while batch SFA's (BSFA) updating complexity is cubic. IncSFA does not need to store, or even compute, any covariance matrices. The drawback to IncSFA is data efficiency: it does not use each data point as effectively as BSFA. But IncSFA allows SFA to be tractably applied, with just a few parameters, directly on high-dimensional input streams (e.g., visual input of an autonomous agent), while BSFA has to resort to hierarchical receptive-field-based architectures when the input dimension is too high. Further, IncSFA's updates have simple Hebbian and anti-Hebbian forms, extending the biological plausibility of SFA. Experimental results show IncSFA learns the same set of features as BSFA and can handle a few cases where BSFA fails. PMID- 22845827 TI - Adaptive classification on brain-computer interfaces using reinforcement signals. AB - We introduce a probabilistic model that combines a classifier with an extra reinforcement signal (RS) encoding the probability of an erroneous feedback being delivered by the classifier. This representation computes the class probabilities given the task related features and the reinforcement signal. Using expectation maximization (EM) to estimate the parameter values under such a model shows that some existing adaptive classifiers are particular cases of such an EM algorithm. Further, we present a new algorithm for adaptive classification, which we call constrained means adaptive classifier, and show using EEG data and simulated RS that this classifier is able to significantly outperform state-of-the-art adaptive classifiers. PMID- 22845828 TI - How yellow is your banana? Toddlers' language-mediated visual search in referent present tasks. AB - What is the relative salience of different aspects of word meaning in the developing lexicon? The current study examines the time-course of retrieval of semantic and color knowledge associated with words during toddler word recognition: At what point do toddlers orient toward an image of a yellow cup upon hearing color-matching words such as "banana" (typically yellow) relative to unrelated words (e.g., "house")? Do children orient faster to semantic matching images relative to color matching images, for example, orient faster to an image of a cookie relative to a yellow cup upon hearing the word "banana"? The results strongly suggest a prioritization of semantic information over color information in children's word-referent mappings. This indicates that even for natural objects (e.g., food, animals that are more likely to have a prototypical color), semantic knowledge is a more salient aspect of toddler's word meaning than color knowledge. For 24-month-old Dutch toddlers, bananas are thus more edible than they are yellow. PMID- 22845829 TI - Language and literacy development of deaf and hard-of-hearing children: successes and challenges. AB - Childhood hearing loss presents challenges to language development, especially spoken language. In this article, we review existing literature on deaf and hard of-hearing (DHH) children's patterns and trajectories of language as well as development of theory of mind and literacy. Individual trajectories vary significantly, reflecting access to early identification/intervention, advanced technologies (e.g., cochlear implants), and perceptually accessible language models. DHH children develop sign language in a similar manner as hearing children develop spoken language, provided they are in a language-rich environment. This occurs naturally for DHH children of deaf parents, who constitute 5% of the deaf population. For DHH children of hearing parents, sign language development depends on the age that they are exposed to a perceptually accessible 1st language as well as the richness of input. Most DHH children are born to hearing families who have spoken language as a goal, and such development is now feasible for many children. Some DHH children develop spoken language in bilingual (sign-spoken language) contexts. For the majority of DHH children, spoken language development occurs in either auditory-only contexts or with sign supports. Although developmental trajectories of DHH children with hearing parents have improved with early identification and appropriate interventions, the majority of children are still delayed compared with hearing children. These DHH children show particular weaknesses in the development of grammar. Language deficits and differences have cascading effects in language-related areas of development, such as theory of mind and literacy development. PMID- 22845830 TI - Reciprocal relationship: children's morphological awareness and their reading accuracy across grades 2 to 3. AB - Across all the domains of child development, we need to understand the temporal relationship between variables suspected to underpin growth; reading research is no exception. We conducted a preliminary evaluation of the direction of the relationship between children's morphological awareness, or the awareness of and ability to manipulate the smallest meaningful units in words, and their reading accuracy. Participants were 100 Grade 2 children who were tested again in Grade 3. We evaluated the children's morphological awareness and reading accuracy, each with 2 measures, in both Grades 2 and 3. We evaluated the outcomes in a robust measurement model including controls for phonological awareness, vocabulary, and nonverbal ability. These analyses included autoregressor controls designed to provide insight into the temporal relationship between these 2 skills. We found that children's early morphological awareness was associated with their growth in reading accuracy to the same extent that their early reading accuracy was associated with their growth in morphological awareness. Our results suggest a bidirectional relationship between children's morphological awareness and their reading accuracy, a finding that informs current models of reading development. PMID- 22845831 TI - With a little help from my kin: barn swallow nestlings modulate solicitation of parental care according to nestmates' need. AB - In altricial species, offspring competing for access to limiting parental resources (e.g. food) are selected to achieve an optimal balance between the costs of scrambling for food, the benefits of being fed and the indirect costs of subtracting food to relatives. As the marginal benefits of acquiring additional food decrease with decreasing levels of need, satiated offspring should be prone to favour access to food by their needy kin, thus enhancing their own indirect fitness, while concomitantly reducing costs of harsh competition with hungry broodmates. We tested this prediction in feeding trials of barn swallow (Hirundo rustica) nestlings by comparing begging behaviour and food intake of two similar sized nestmates, one of which was food-deprived (FD). Non-food-deprived (NFD) offspring modulated begging intensity depending on their nestmate's need: when competing with FD nestmates, NFD nestlings reduced both the intensity and frequency of begging displays compared to themselves in the control trial before food deprivation. Hence, NFD nestlings reduced their competitiveness to the advantage of FD nestmates, which obtained more feedings and showed a threefold larger increase in body mass. Moderation of individual selfishness can therefore be adaptive in the presence of a needier kin, because the indirect fitness benefits of promoting its condition can outweigh the costs of forgoing being fed, and because it limits the cost of begging escalation against a vigorous competitor. PMID- 22845832 TI - Genetic analysis reveals links between lipid A structure and expression of the outer membrane protein gene, ropB, in Rhizobium leguminosarum. AB - The fabXL genes encode enzymes that synthesize the very-long-chain fatty acid - a unique acyl modification located at the 2' position of the lipid A of Gram negative bacteria in the order Rhizobiales. Mutation of the fabXL genes causes sensitivity to outer membrane stressors and other envelope-related stresses; however, the underlying mechanisms for increased sensitivity are poorly understood. We found that expression of the outer membrane protein gene ropB is down-regulated in an acpXL mutant. Furthermore, constitutive expression of ropB in an acpXL or fabF2XL, fabF1XL mutant restores tolerance to detergents, hyperosmotic stress, and acidic pH. The fabF2XL, fabF1XL mutant also has a delayed nodulation phenotype, whereas a ropB mutant has no observable defects in nodulation, demonstrating that mutation of the fabXL genes results in pleiotropic phenotypes that can be classified as either ropB dependent or ropB independent. Ex-nodule isolates of the mutant strains display restored tolerance to detergents and hyperosmotic and acidic stress conditions; however, the rescued phenotypes are not owing to increased ropB expression. Finally, we found that the fabXL genes are induced by the sensor kinase ChvG in response to peptide-rich growth conditions, which is similar to the results reported for induction of ropB. PMID- 22845833 TI - Fast and precise method for Pb isotope ratio determination in complex matrices using GC-MC-ICPMS: application to crude oil, kerogen, and asphaltene samples. AB - A new method to determine Pb isotope ratio without ion-exchange-matrix separation is proposed. After acid digestion, Pb was ethylated to Et(4)Pb, separated from the digested solution (black shale, asphaltene, crude oil and kerogen) by extraction in isooctane, and then injected into a gas chromatograph coupled to a multicollector inductively coupled plasma mass spectrometer. Seven isotopes ((202)Hg, (203)Tl, (204)Pb, (205)Tl, (206)Pb, (207)Pb, (208)Pb) were monitored simultaneously with peak duration of 23 s. GC elution was operated under wet plasma conditions where a thallium standard solution was introduced to the mass spectrometer for mass bias correction. The total time of the procedure (sample preparation and analysis, after acid digestion) was reduced by a factor of 15 compared to conventional-continuous sample introduction. Data treatment was carried out using the linear regression slope method. Mass bias was corrected using the double correction method (first thallium normalization followed by classical bracketing). For the (208/206)Pb and (207/206)Pb ratios, precision (2RSD(EXT), n = 21) was 49 and 69 ppm, and the bias between experimental results and reference values was better than 0.0033 and 0.0007 0/00, when injecting 1.2 ng of ethylated Pb SRM NIST 981 solution. Results obtained by this method were validated by comparison with those obtained via conventional-continuous sample introduction. The applicability of this approach was demonstrated with the analysis of black shale, asphaltene, crude oil and kerogen samples. PMID- 22845834 TI - Permian polar forests: deciduousness and environmental variation. AB - Forests are expected to expand into northern polar latitudes in the next century. However, the impact of forests at high latitudes on climate and terrestrial biogeochemical cycling is poorly understood because such forests cannot be studied in the modern. This study presents forestry and geochemical analyses of three in situ fossil forests from Late Permian strata of Antarctica, which grew at polar latitudes. Stem size measurements and stump spacing measurements indicate significant differences in forest density and canopy structure that are related to the local depositional setting. For forests closest to fluvial systems, tree density appears to decrease as the forests mature, which is the opposite trend of self-thinning observed in modern forests. We speculate that a combination of tree mortality and high disturbance created low-density mature forests without understory vegetation near Late Permian river systems. Stable carbon isotopes measured from permineralized wood in these forests demonstrate two important points: (i) recently developed techniques of high-resolution carbon isotope studies of wood and mummified wood can be applied to permineralized wood, for which much of the original organic matter has been lost and (ii) that the fossil trees maintained a deciduous habit at polar latitudes during the Late Permian. The combination of paleobotanical, sedimentologic, and paleoforestry techniques provides an unrivaled examination of the function of polar forests in deep time; and the carbon isotope geochemistry supplements this work with subannual records of carbon fixation that allows for the quantitative analysis of deciduous versus evergreen habits and environmental parameters, for example, relative humidity. PMID- 22845835 TI - Adoption of new HIV treatment guidelines and drug substitutions within first-line as a measure of quality of care in rural Lesotho: health centers and hospitals compared. AB - OBJECTIVE: In 2007, Lesotho launched new national antiretroviral treatment (ART) guidelines, prioritising tenofovir and zidovudine over stavudine as a backbone together with lamivudine. We compared the rate of adoption of these new guidelines and substitution of first-line drugs by health centers (HC) and hospitals in two catchment areas in rural Lesotho. METHODS: Retrospective cohort analysis. Patients aged >=16 years were stratified into a HC- and a hospital group. MAIN OUTCOME VARIABLES: Type of backbone at ART-initiation (i), substitutions within first line (ii) and type of backbone among patients retained by December 2010 (iii). A multiple logistic regression model including HC vs. hospital, patient characteristics (sex, age, WHO-stage, baseline CD4-count, concurrent pregnancy, concurrent tuberculosis treatment) and year of ART-start, was used. RESULTS: Of 3936 adult patients initiated on ART between 2007 and 2010, 1971 started at hospitals and 1965 at HCs. Hospitals were more likely to follow the new guidelines as measured by prescription of backbones without stavudine (Odds-ratio 1.55; 95%CI: 1.32-1.81) and had a higher rate of drug substitutions while on first-line ART (2.39; 1.83-3.13). By December 2010, patients followed at health centres were more likely to still receive stavudine (2.28; 1.83-2.84). CONCLUSIONS: Health centers took longer to adopt the new guidelines and substituted drugs less frequently. Decentralised ART-programmes need close support, supervision and mentoring to absorb new guidelines and to adhere to them. PMID- 22845836 TI - Approximating metrics with planar boundary-labeled phylogenetic networks. AB - Phylogenetic networks are useful for visualizing evolutionary relationships between species with reticulate events such as hybridizations and horizontal gene transfers. In this paper, we consider the problem of constructing undirected phylogenetic networks that (1) are planar graphs and (2) admit embeddings in the plane where the vertices labeling all taxa are on the boundary of the network. We develop a new algorithm for constructing phylogenetic networks satisfying these constraints. First, we show that only approximate networks can be constructed for some distance matrices with at least five taxa. Then we prove that any five-point metric can be represented approximately by a planar boundary-labeled network with guaranteed fit value of 94.79. We extend the networks constructed in the proof to design an algorithm for computing planar boundary-labeled networks for any number of taxa. PMID- 22845837 TI - Conformational dynamics of HIV-1 protease: a comparative molecular dynamics simulation study with multiple amber force fields. AB - Flap dynamics of HIV-1 protease (HIV-pr) controls the entry of inhibitors and substrates to the active site. Dynamical models from previous simulations are not all consistent with each other and not all are supported by the NMR results. In the present work, the effect of force field on the dynamics of HIV-pr is investigated by MD simulations using three AMBER force fields ff99, ff99SB, and ff03. The generalized order parameters for amide backbone are calculated from the three force fields and compared with the NMR S2 values. We found that the ff99SB and ff03 force field calculated order parameters agree reasonably well with the NMR S2 values, whereas ff99 calculated values deviate most from the NMR order parameters. Stereochemical geometry of protein models from each force field also agrees well with the remarks from NMR S2 values. However, between ff99SB and ff03, there are several differences, most notably in the loop regions. It is found that these loops are, in general, more flexible in the ff03 force field. This results in a larger active site cavity in the simulation with the ff03 force field. The effect of this difference in computer-aided drug design against flexible receptors is discussed. PMID- 22845838 TI - The use of two-way linear mixed models in multitreatment meta-analysis. AB - Meta-analysis summarizes the results of a series of trials. When more than two treatments are included in the trials and when the set of treatments tested differs between trials, the combination of results across trials requires some care. Several methods have been proposed for this purpose, which feature under different labels, such as network meta-analysis or mixed treatment comparisons. Two types of linear mixed model can be used for meta-analysis. The one expresses the expected outcome of treatments as a contrast to a baseline treatment. The other uses a classical two-way linear predictor with main effects for treatment and trial. In this article, we compare both types of model and explore under which conditions they give equivalent results. We illustrate practical advantages of the two-way model using two published datasets. In particular, it is shown that between-trial heterogeneity as well as inconsistency between different types of trial is straightforward to account for. PMID- 22845839 TI - Dexamethasone conjugation to polyamidoamine dendrimers G1 and G2 for enhanced transfection efficiency with an anti-inflammatory effect. AB - Polyamidoamine (PAM) dendrimers with low generation such as PAM generation 1 (PAMG1) and PAM generation 2 (PAMG2) have been widely used as a gene carrier due to low toxicity, albeit their low transfection efficiency. In this study, dexamethasone was conjugated to PAMG1 and PAMG2 in order to increase the transfection efficiency. In a gel retardation assay, the dexamethasone conjugated PAMG1 and PAMG2 (PAMG1-Dexa and PAMG2-Dexa) retarded plasmid DNA (pDNA) completely at 5:1 and 3:1 weight ratios (polymer:pDNA), respectively. In transfection assays, PAMG1-Dexa and PAMG2-Dexa had the highest transfection efficiency at 20:1 and 10:1 weight ratios, respectively. In addition, PAMG1-Dexa and PAMG2-Dexa had higher transfection efficiencies than PAMG1, PAMG2, PEI25k, and lipofectamine. In a MTT assay, PAMG1-Dexa and PAMG2-Dexa were less cytotoxic than lipofectamine. In addition, PAMG1-Dexa and PAMG2-Dexa decreased the TNF alpha level more efficiently than dexamethasone only in the lipopolysaccharide (LPS)-induced Raw264.7 cells. Therefore, PAMG1-Dexa and PAMG2-Dexa may prove to be useful as gene delivery carriers with an anti-inflammatory effect. PMID- 22845840 TI - Non-covalent ligand conjugation to biotinylated DNA nanoparticles using TAT peptide genetically fused to monovalent streptavidin. AB - DNA nanoparticles (DNA NPs), which self-assemble from DNA plasmids and poly-L lysine (pLL)-polyethylene glycol (PEG) block copolymers, transfect several cell types in vitro and in vivo with minimal toxicity and immune response. To further enhance the gene transfer efficiency of DNA NP and control its tropism, we established a strategy to efficiently attach peptide ligands to DNA NPs. The non covalent biotin-streptavidin (SA) interaction was used for ligand conjugation to overcome problems associated with covalent conjugation methods. A fusion protein of SA with the HIV-1 TAT peptide was cloned, expressed, purified and attached to biotinylated DNA NPs. A modified SA system with tetrameric structure but monovalent biotin binding capacity was adopted and shown to reduce the aggregation of biotinylated DNA NPs compared to neutravidin. Compared to unmodified DNA NPs, TAT modified DNA NPs significantly enhanced in vitro gene transfer, particularly at low DNA concentrations. Studies of cellular uptake and cellular distribution of the DNA NPs indicated that attaching TAT enhanced binding of DNA NPs to cell surface but not internalization at high DNA concentrations. In vivo studies showed that TAT modified DNA NPs mediated equal level of gene transfer to the mouse airways via the luminal route compared to unmodified DNA NPs. PMID- 22845841 TI - Feasibility study of cavitation-induced liposomal doxorubicin release in an AT2 Dunning rat tumor model. AB - BACKGROUND: Targeted and triggered release of liposomal drug using heat or ultrasound represents a promising treatment modality able to increase the therapeutic-totoxicity ratio of encapsulated drugs. PURPOSE: To study the ability for high-intensity focused ultrasound to induce liposomal drug release mainly by focused inertial cavitation in vitro and in an animal model. METHODS: A 1 MHz ultrasound setup has been developed for in vitro and in vivo drug release from a specific liposomal doxorubicin formulation at a target cavitation dose. RESULTS: Controlled cavitation at 1 MHz was applied within the tumors 48 hours after liposome injection according to preliminary pharmacokinetic study. A small non significant therapeutic effect of US-liposomal treatment was observed compared to liposomes alone suggesting no beneficial effect of ultrasound in the current setup. CONCLUSION: The in vitro study provided a suitable ultrasound setup for delivering a cavitation dose appropriate for safe liposomal drug release. However, when converting to an in vivo model, no therapeutic benefit was observed. This may be due to a number of reasons, one of which may be the difficulty in converting in vitro findings to an in vivo model. In light of these findings, we discuss important design features for future studies. PMID- 22845842 TI - Formulation, evaluation and pharmacokinetics of colon targeted pulsatile system of flurbiprofen. AB - OBJECTIVE: The intent of the present investigation is to develop colon targeted compression coated flurbiprofen pulsatile release tablets that retard the drug release in the upper gastro intestinal system but progressively release in the colon. MATERIALS AND METHODS: Flurbiprofen core tablets were prepared by direct compression method and were compression coated with hydroxypropyl methylcellulose and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery. RESULTS AND DISCUSSIONS: The optimized formulation showed negligible drug release (7.26 +/- 0.05%) in the initial lag period followed by progressive release (99.27 +/- 0.46%) for 24 h. The X-ray imaging study in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C(max) of colon targeted tablets was 10792.62 ng/mL at T(max) 10 h where as in case of immediate release tablets the C(max) was 15684.79 ng/mL at T(max) 3 h signifies the ability of compression coated tablets to target the colon. CONCLUSION: Development of pulsatile release compression coated tablets using combination of time dependent and pH sensitive approaches was suitable to target the flurbiprofen to colon. PMID- 22845843 TI - Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies. AB - Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb-IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb-IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb-IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein. PMID- 22845844 TI - Sarcoidosis - a clinically orientated review. AB - Sarcoidosis is a multisystem disease of unknown cause. Sarcoidosis can affect all individuals with any race, sex, or age but commonly affects young- and middle aged adults and usually presents with bilateral hilar lymphadenopathy, pulmonary infiltration, skin and ocular lesions. Other organs can also be affected. Diagnosis is established when clinical and radiological findings are supported by the presence of non-caseating epithelioid cell granulomas, however, local sarcoid reactions and granulomas of known cause should be excluded. The optimal management has not been well defined yet, although corticosteroids remain the mainstay of treatment, there is little evidence on which to base the indications for treatment including dosage and duration of therapy. Certain clinical features are helpful in the prognosis of the condition that can vary from a self-limiting course to progressive life-threatening fibrosis of the vital organs. PMID- 22845845 TI - Twitch or no twitch? The cutaneous trunci reflex. PMID- 22845846 TI - The cutaneous trunci reflex for localising and grading thoracolumbar spinal cord injuries in dogs. AB - OBJECTIVES: To evaluate the accuracy of the cutaneous trunci reflex to localise thoracolumbar spinal cord injuries and to assess the correlation between focal loss (cut-off) of the reflex and clinical severity of thoracolumbar spinal cord injury. METHODS: Prospective study of 41 dogs with thoracolumbar spinal cord injuries investigated by magnetic resonance imaging. Linear regression analysis was performed to determine the relationship between the vertebral level of the cutaneous trunci reflex cut-off and the maximal and cranial lesion extent. The association between cutaneous trunci reflex cut-off and spinal cord injury severity was tested using a Mann-Whitney U test. RESULTS: Cutaneous trunci reflex cut-off was evident in 33 (80%) of dogs. The cut-off level was 0 to 4 vertebrae caudal to the maximal spinal cord lesion in all dogs. In 16 (48.5%) dogs the cut off was either 2 or 3 vertebrae caudal to the lesion. The presence of a cut-off significantly correlated with increasing severity (P=0.0001). Loss of the reflex occurred at less severe grades than loss of ambulation and in dogs with ambulatory paresis it was significantly (P=0.0084) associated with increasing severity. CLINICAL SIGNIFICANCE: The cutaneous trunci reflex allows localisation of thoracolumbar spinal cord lesions within four vertebrae and facilitates clinical segregation of dogs with ambulatory paresis into mild and severe categories. PMID- 22845847 TI - Lingual osteoma in a dog. AB - An 11-year-old male Belgian shepherd dog was evaluated for a one-week history of progressive lethargy, decreased appetite and excessive panting. On physical examination, a pedunculated mass protruding from the right side of the tongue base was observed. The mass was solid, irregular and multi-lobulated, and it measured approximately 4 * 2 cm. The mass was surgically excised. The histological examination was consistent with a lingual osteoma and the margins were free of neoplastic cells. The dog was euthanased eight months after the diagnosis because of an unrelated problem and no evidence of recurrence at the surgical site was appreciated at that time. To the author's knowledge, this is the first report of a lingual osteoma in a dog, and, therefore, it should be included in the differential diagnosis of masses on the tongue, especially pedunculated masses located at the base of the tongue. PMID- 22845848 TI - A simple chemical route toward monodisperse iron carbide nanoparticles displaying tunable magnetic and unprecedented hyperthermia properties. AB - We report a tunable organometallic synthesis of monodisperse iron carbide and core/shell iron/iron carbide nanoparticles displaying a high magnetization and good air-stability. This process based on the decomposition of Fe(CO)(5) on Fe(0) seeds allows the control of the amount of carbon diffused and therefore the tuning of nanoparticles magnetic anisotropy. This results in unprecedented hyperthermia properties at moderate magnetic fields, in the range of medical treatments. PMID- 22845849 TI - Implementation of a multi-institutional diffuse intrinsic pontine glioma autopsy protocol and characterization of a primary cell culture. AB - AIMS: Diffuse intrinsic pontine glioma (DIPG) is a fatal paediatric malignancy. Tumour resection is not possible without serious morbidity and biopsies are rarely performed. The resulting lack of primary DIPG material has made preclinical research practically impossible and has hindered the development of new therapies for this disease. The aim of the current study was to address the lack of primary DIPG material and preclinical models by developing a multi institutional autopsy protocol. METHODS: An autopsy protocol was implemented in the Netherlands to obtain tumour material within a brief post mortem interval. A team of neuropathologists and researchers was available at any time to perform the autopsy and process the material harvested. Whole brain autopsy was performed and primary DIPG material and healthy tissue were collected from all affected brain areas. Finally, the study included systematic evaluation by parents. RESULTS: Five autopsies were performed. The mean time interval between death and time of autopsy was 3 h (range 2-4). All tumours were graded as glioblastoma. None of the parents regretted their choice to participate, and they all derived comfort in donating tissue of their child in the hope to help future DIPG patients. In addition, we developed and characterized one of the first DIPG cell cultures from post mortem material. CONCLUSION: Here we show that obtaining post mortem DIPG tumour tissue for research purposes is feasible with short delay, and that the autopsy procedure is satisfying for participating parents and can be suitable for the development of preclinical DIPG models. PMID- 22845850 TI - Mutational, proteomic and metabolomic analysis of a plant growth promoting copper resistant Pseudomonas spp. AB - Pseudomonas sp. TLC6-6.5-4 is a multiple metal resistant plant growth-promoting bacteria isolated from copper-contaminated lake sediments. In this study, a comprehensive analysis of genes involved in copper resistance was performed by generating a library of transposon (Tn5) mutants. Two copper-sensitive mutants with significant reduction in copper resistance were identified: CSM1, a mutant disrupted in trpA gene (tryptophan synthase alpha subunit), and CSM2, a mutant disrupted in clpA gene (ATP-dependent Clp protease). Proteomic and metabolomic analyses were performed to identify biochemical and molecular mechanisms involved in copper resistance using CSM2 due to its lower minimum inhibitory concentration compared with CSM1 and the wild type. Proteomic analysis revealed that disruption of Clp protease gene up-regulated molecular chaperones and down-regulated the expression of enzymes related to tRNA modification, whereas metabolomic analysis showed that amino acid and oligosaccharide transporters that are part of ATP binding cassette (ABC) transporters pathways were down-regulated. Further, copper stress altered metabolic pathways including the tricarboxylic acid cycle, protein absorption and glyoxylate metabolism. PMID- 22845851 TI - Socioeconomic status and intake of energy and sodium are associated with calcium intake among pregnant women in Rafsanjan city, Iran. AB - AIM: Calcium intake in developing countries is lower than that in developed countries. In Iran, inadequate calcium intake in the general population, especially among women, is a public health concern. This cross-sectional study examined the correlation between sociodemographic, obstetrical and lifestyle factors with calcium intake among pregnant women in Rafsanjan city, southeast Iran. MATERIAL AND METHODS: A sample of 308 healthy pregnant women aged 18-35 years from seven urban health-care centers participated in the study. All women were measured for height and weight and interviewed for demographic and socioeconomic, obstetrical, lifestyle and dietary intake information while pre pregnancy weight was obtained from prenatal record. Stepwise multiple regression was used to assess factors associated with calcium intake. RESULTS: The mean daily calcium intake of women was 968.51+/-363.05mg/day and only 46.4% of the pregnant women met the dietary reference intakes of 1000 mg for calcium. Milk and milk products showed the greatest contribution to calcium intake (75.11%). Energy adjusted calcium intake was positively associated with years of schooling (P<0.01), calorie (P<0.01) and energy-adjusted sodium (P<0.01) intakes. CONCLUSION: This information would be useful in planning and developing appropriate strategies to improve calcium intake in pregnant women. Efforts to increase calcium intake in pregnant women should focus on promoting nutrient dense food and making these foods available and accessible, particularly to socioeconomically deprived women. PMID- 22845852 TI - Risk factors and clinical outcome of unsuspected pulmonary embolism in cancer patients: a case-control study. AB - BACKGROUND: Little is known about the risk factors and outcome of unsuspected pulmonary embolism (UPE) in cancer patients. OBJECTIVES: To assess the risk factors and outcome of UPE in cancer patients. METHODS: The charts of 66 patients diagnosed with UPE were reviewed. Two control groups were selected: 132 cancer patients without pulmonary embolism (PE) and 65 cancer patients with clinically suspected PE. Variables associated with UPE were identified by multivariable analysis. Six-month survival and recurrent venous thromboembolism were compared by use of Cox proportional analysis. RESULTS: Twenty-seven (40.9%) patients with UPE had symptoms suggesting PE. Adenocarcinoma (odds ratio [OR] 4.45; 95% confidence interval [CI] 1.98-9.97), advanced age (OR 1.18; 95% CI 1.02-1.38), recent chemotherapy (OR 4.62; 95% CI 2.26-9.44), performance status > 2 (OR 7.31; 95% CI 1.90-28.15) and previous venous thromboembolism (OR 4.47; 95% CI 1.16 17.13) were associated with UPE. When adjusted for tumor stage and performance status, 6-month mortality did not differ between patients with UPE and patients without PE (hazard ratio 1.40; 95% CI 0.53-3.66; P = 0.50). Patients with UPE were more likely to have central venous catheters and chemotherapy and less likely to have proximal clots than patients with clinically suspected PE. Recurrent venous thromboembolism occurred in 6.1% and 7.7% of patients with UPE and symptomatic PE, respectively. CONCLUSION: UPE is not associated with an increased risk of death. Patients with clinically suspected PE and those with UPE have similar risks of recurrent venous thromboembolism. PMID- 22845853 TI - Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits. AB - Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits. PMID- 22845854 TI - Blood color is influenced by inflammation and independently predicts survival in hemodialysis patients: quantitative evaluation of blood color. AB - Blood color of dialysis patients can be seen routinely. Darkened blood color is often observed in critically ill patients generally because of decreased oxygen saturation, but little is known about the other factors responsible for the color intensity. In addition, quantitative blood color examination has not been performed yet. Therefore, no one has evaluated the predictive power of blood color. The aim of this study was to evaluate if blood color darkness reflects some medical problems and is associated with survival disadvantage. Study design is a prospective cohort study. One hundred sixty-seven patients were enrolled in this study. Quantification of blood color was done using a reflected light colorimeter. Demographic and clinical data were collected to find out the factors that can be related to blood color. Follow-ups were performed for 2 years to analyze the risk factors for their survival. Regression analysis showed that C reactive protein and white blood cell count were negatively correlated with blood color. In addition, blood color was positively correlated with mean corpuscular hemoglobin concentration and serum sodium concentration as well as blood oxygen saturation. During a follow-up, 34 (20.4%) patients died. Cox regression analysis revealed that darkened blood color was an independent significant risk factor of mortality in hemodialysis patients as well as low albumin and low Kt/V. These results suggest that inflammation independently affects blood color and quantification of blood color is useful to estimate prognosis in patients undergoing hemodialysis. It is possible that early detection of blood color worsening can improve patients' survival. PMID- 22845855 TI - The principle of procreative beneficence: old arguments and a new challenge. AB - In the last ten years, there have been a number of attempts to refute Julian Savulescu's Principle of Procreative Beneficence; a principle which claims that parents have a moral obligation to have the best child that they can possibly have. So far, no arguments against this principle have succeeded at refuting it. This paper tries to explain the shortcomings of some of the more notable arguments against this principle. I attempt to break down the argument for the principle and in doing so, I explain what is needed to properly refute it. This helps me show how and why the arguments of Rebecca Bennett, Sarah Stoller and others fail to refute the principle. Afterwards, I offer a new challenge to the principle. I attack what I understand to be a fundamental premise of the argument, a premise which has been overlooked in the literature written about this principle. I argue that there is no reason to suppose, as Savulescu does, that morality requires us to do what we have most reason to do. If we reject this premise, as I believe we have reason to do, the argument for Procreative Beneficence fails. PMID- 22845856 TI - Ethical issues in umbilical cord blood banking: a comparative analysis of documents from national and international institutions. AB - The issues of collection, storage, and use of cord blood (CB) stem cells have been addressed extensively in national and international guidelines, policies, and regulations. Many of these documents are not binding, but are nonetheless accorded considerable respect on account of the authority of the issuing organizations. Most discussion has to date focused on two topics: informed consent for collection, banking, and use and the debate between those who favor public storage for altruistic purposes and those who advocate private storage for autologous use. There is generally agreement or consensus in the guidelines that public storage for allogeneic transplants is preferable and that private storage should be discouraged. Given the consensus in national and international guidance on these two issues, it is time for other ethical issues to be examined in greater detail. These include additional uses of CB samples, for example, for research or for the production of blood-derived drugs, and the economic implications arising from the extensive international network for the exchange of CB for transplantation. PMID- 22845857 TI - Efficacy of factor IX Grifols((r)) in surgery: experience of an international multicentre retrospective study. PMID- 22845858 TI - A comparison of early sucking dynamics during breastfeeding after cesarean section and vaginal birth. AB - BACKGROUND: The impact of cesarean section (CS) birth and pethidine for post-CS epidural analgesia on early breastfeeding behavior is unclear. This study aimed to measure infant sucking and breastfeeding behavior in infants of mothers who delivered by CS (CS group) and used pethidine patient-controlled epidural analgesia (PCEA) after CS with that of infants who were delivered by vaginal birth (V group), during secretory activation and again after the establishment of lactation. SUBJECTS AND METHODS: Sucking dynamics and milk intake of breastfeeding infants were assessed on approximately 3 and 20 (follow-up) days postpartum (CS group, n=19; V group, n=15). Nipple diameters, tongue movement, and nipple position during sucking were measured from ultrasound scans of the intra-oral cavity during breastfeeding. Time of the first breastfeed and day of breast fullness were recorded, and infant neurobehavior was assessed. RESULTS: CS infants displayed more anterior tongue movement on Day 3 than at follow-up compared with the V group, which showed a similar amount of movement at each assessment (p for interaction<0.001). Compared with the V group, the CS group showed faster suck rates, especially on Day 3 (p<0.001), later times to first breastfeed (p=0.01) and breast fullness (p=0.03), and lower neurobehavioral scores (p=0.047). Breastfeeding duration and milk intake were similar between groups. CONCLUSIONS: Although the observed effect of CS birth followed by pethidine PCEA after CS during the period of secretory activation was small, our results indicate that successful initiation of lactation may require additional breastfeeding support and monitoring at Day 3 postpartum for mothers who undergo CS. PMID- 22845859 TI - Ion mobility mass spectrometry of peptide ions: effects of drift gas and calibration strategies. AB - One difficulty in using ion mobility (IM) mass spectrometry (MS) to improve the specificity of peptide ion assignments is that IM separations are performed using a range of pressures, gas compositions, temperatures, and modes of separation, which makes it challenging to rapidly extract accurate shape parameters. We report collision cross section values (Omega) in both He and N(2) gases for 113 peptide ions determined directly from drift times measured in a low-pressure, ambient temperature drift cell with radio-frequency (rf) ion confinement. These peptide ions have masses ranging from 231 to 2969 Da, Omega(He) of 89-616 A(2), and Omega(N(2)) of 151-801 A(2); thus, they are ideal for calibrating results from proteomics experiments. These results were used to quantify the errors associated with traveling-wave Omega measurements of peptide ions and the errors concomitant with using drift times measured in N(2) gas to estimate Omega(He). More broadly, these results enable the rapid and accurate determination of calibrated Omega for peptide ions, which could be used as an additional parameter to increase the specificity of assignments in proteomics experiments. PMID- 22845860 TI - Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A-I variant. AB - BACKGROUND/AIMS: Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). METHODS: ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. RESULTS: The dietary treatment led to a strong elevation in HDL-cholesterol levels in A I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. CONCLUSIONS: In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines. PMID- 22845861 TI - Gemini imidazolium surfactants: synthesis and their biophysiochemical study. AB - New gemini imidazolium surfactants 9-13 have been synthesized by a regioselective epoxy ring-opening reaction under solvent-free conditions. The surface properties of these new gemini surfactants were evaluated by surface tension and conductivity measurements. These surfactants have been found to have low critical micelle concentration (cmc) values as compared to other categories of gemini cationic surfactants and also showed the tendency to form premicellar aggregates in solution at sufficiently low concentration below their cmc values. The thermal degradation of these surfactants was determined by thermograviometry analysis (TGA). These new cationic surfactants have a good DNA binding capability as determined by agarose gel electrophoresis and ethidium bromide exclusion experiments. They have also been found to have low cytotoxicity by MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on the C6 glioma cell line. PMID- 22845862 TI - An examination of the relationship between motor coordination and executive functions in adolescents. AB - AIM: Research suggests important links between motor coordination and executive functions. The current study examined whether motor coordination predicts working memory, inhibition, and switching performance, extending previous research by accounting for attention-deficit-hyperactivity disorder (ADHD) symptomatology and other confounding factors, in an adolescent normative sample. METHOD: Ninety three adolescents (38 females, 55 males) aged 12 to 16 years (mean age 4y 2mo, SD 1y 1mo) were assessed on the Movement Assessment Battery for Children-2 (MABC-2), Wechsler Intelligence Scale for Children-IV, N-back task, the inhibition subtest from the NEPSY-II: A Developmental Neuropsychological Assessment, second edition, and the parent-rated Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour Questionnaire. RESULTS: The MABC-2 total score accounted for a significant proportion of the variance in visuospatial working memory (p=0.041) but not for verbal working memory. The MABC-2 aiming and catching component, however, was found to account for unique variance in both verbal (p=0.019) and visuospatial working memory (p=0.016). The MABC-2 total score was found to account for a significant proportion of the variance in inhibition total completion time (p=0.017). Finally, balance skills accounted for unique variance in a NEPSY-II inhibition total errors variable (p=0.020). INTERPRETATION: The results provide support for an overlap between motor coordination and executive functions, which has important practical implications. The study also suggests shared mechanisms underpinning the relationship between these areas, including possible cerebellar involvement. PMID- 22845863 TI - Atomic force microscopy and X-ray photoelectron spectroscopy study of NO2 reactions on CaCO3 (1014) surfaces in humid environments. AB - In this study, alternating current (AC) mode atomic force microscopy (AFM) combined with phase imaging and X-ray photoelectron spectroscopy (XPS) were used to investigate the effect of nitrogen dioxide (NO2) adsorption on calcium carbonate (CaCO3) (1014) surfaces at 296 K in the presence of relative humidity (RH). At 70% RH, CaCO3 (1014) surfaces undergo rapid formation of a metastable amorphous calcium carbonate layer, which in turn serves as a substrate for recrystallization of a nonhydrated calcite phase, presumably vaterite. The adsorption of nitrogen dioxide changes the surface properties of CaCO3 (1014) and the mechanism for formation of new phases. In particular, the first calcite nucleation layer serves as a source of material for further island growth; when it is depleted, there is no change in total volume of nitrocalcite, Ca(NO3)2, particles formed whereas the total number of particles decreases. This indicates that these particles are mobile and coalesce. Phase imaging combined with force curve measurements reveals areas of inhomogeneous energy dissipation during the process of water adsorption in relative humidity experiments, as well as during nitrocalcite particle formation. Potential origins of the different energy dissipation modes within the sample are discussed. Finally, XPS analysis confirms that NO2 adsorbs on CaCO3 (1014) in the form of nitrate (NO3(-)) regardless of environmental conditions or the pretreatment of the calcite surface at different relative humidity. PMID- 22845864 TI - Sequestering ability of phytate toward biologically and environmentally relevant trivalent metal cations. AB - Quantitative parameters for the interactions between phytate (Phy) and Al(3+), Fe(3+), and Cr(3+) were determined potentiometrically in NaNO(3) aqueous solutions at I = 0.10 mol L(-1) and T = 298.15 K. Different complex species were found in a wide pH range. The various species are partially protonated, depending on the pH in which they are formed, and are indicated with the general formula MH(q)Phy (with 0 <= q <= 6). In all cases, the stability of the FeH(q)Phy species is several log K units higher than that of the analogous AlH(q)Phy and CrH(q)Phy species. For example, for the MH(2)Phy species, the stability trend is log K(2) = 15.81, 20.61, and 16.70 for Al(3+), Fe(3+), and Cr(3+), respectively. The sequestering ability of phytate toward the considered metal cations was evaluated by calculating the pL(0.5) values (i.e., the total ligand concentration necessary to bind 50% of the cation present in trace in solution) at different pH values. In general, phytate results in a quite good sequestering agent toward all three cations in the whole investigated pH range, but the order of pL(0.5) depends on it. For example, at pH 5.0 it is pL(0.5) = 5.33, 5.44, and 5.75 for Fe(3+), Cr(3+), and Al(3+), respectively (Fe(3+) < Cr(3+) < Al(3+)); at pH 7.4 it is pL(0.5) = 9.94, 9.23, and 8.71 (Al(3+) < Cr(3+) < Fe(3+)), whereas at pH 9.0 it is pL(0.5) = 10.42, 10.87, and 8.34 (Al(3+) < Fe(3+) < Cr(3+)). All of the pL(0.5) values, and therefore the sequestering ability, regularly increase with increasing pH, and the dependence of pL(0.5) on pH was modeled using some empirical equations. PMID- 22845865 TI - Millennium Development Goals water target claim exaggerates achievement. PMID- 22845866 TI - Alterations in the immunoexpression of galectins-1, -3 and -7 between different grades of oral epithelial dysplasia. AB - INTRODUCTION: Oral epithelial dysplasia (OED) is a potentially malignant lesion characterized by a combination of cytological and architectural anomalies, which are essential for its diagnosis. Galectins are proteins that participate in cell cycle, adhesion and differentiation, apoptosis, and immune responses, as well as in cancer development and progression. MATERIALS AND METHODS: The aim of this study was to analyze the immunohistochemical expression of galectins-1, -3, and 7 in the OED (21 low risk and 29 high risk) and normal oral mucosa (NOM). The binary grading system was used. RESULTS: Galectin-1 was expressed in the middle/lower third in most OED cases. Nuclear/cytoplasmic staining was observed in most low-risk and high-risk OEDs. All cases of NOM were negative for galectin 1. Galectin-3 was expressed in the middle/lower third in most low-risk cases. Nuclear/cytoplasmic staining was noted in most low-risk and high-risk OEDs. Middle/lower third and in membrane staining was detected in four cases of NOM for galectin-3. Galectin-7 was expressed in the upper/middle third in most of OED cases. Nuclear/cytoplasmic staining predominated in low-risk and high-risk OEDs. Galectin-7 was detected in four cases of NOM, all of them presenting staining in the upper/middle third and in the membrane. CONCLUSION: The differences in the immunoexpression of galactin-1, -3, and -7 between different grades of OEDs suggest the involvement of this protein in the progression of dysplasias. PMID- 22845867 TI - Two distinct types of dying back axonal degeneration in vitro. AB - AIMS: In many neurodegenerative diseases and following traumas, dying back degeneration is a common phenomenon that aggravates the pathology and may eventually lead to death of the affected neurone. We aimed to investigate the mechanism of dying back degeneration with an in vitro axonal injury model. METHODS: We cultured adult mouse dorsal root ganglion neurones and with a precise laser beam, cut the axons they extended. Preparations were imaged continuously and images were analysed to describe and quantify ensuing events. Potential contributions of calpains and caspases to the degeneration were explored using specific inhibitors and immunohistochemistry. In vivo implications of the results were sought in nerve sections after sciatic nerve cut. RESULTS: The proximal part of the transected axons went under basically two types of dying back degeneration, fragmentation and retraction. In fragmentation the cytoplasm became condensed and with concomitant axial collapse the axon disintegrated into small pieces. In retraction, the severed axon was pulled back to the soma in an organized manner. We demonstrated that fragmentation was associated with a high risk of cell death, while survival rate with retraction was as high as those of uninjured neurones. Regeneration of transected axon was more likely after retraction than following fragmentation. Activities of caspase-3 and calpains but not of caspase-6 were found linked with retraction and regeneration but not with the fragmentation. CONCLUSIONS: This study describes two quite distinct types of dying back degeneration that lead an injured neurone to quite different fates. PMID- 22845868 TI - Computational framework for analysis of prey-prey associations in interaction proteomics identifies novel human protein-protein interactions and networks. AB - Large-scale protein-protein interaction data sets have been generated for several species including yeast and human and have enabled the identification, quantification, and prediction of cellular molecular networks. Affinity purification-mass spectrometry (AP-MS) is the preeminent methodology for large scale analysis of protein complexes, performed by immunopurifying a specific "bait" protein and its associated "prey" proteins. The analysis and interpretation of AP-MS data sets is, however, not straightforward. In addition, although yeast AP-MS data sets are relatively comprehensive, current human AP-MS data sets only sparsely cover the human interactome. Here we develop a framework for analysis of AP-MS data sets that addresses the issues of noise, missing data, and sparsity of coverage in the context of a current, real world human AP-MS data set. Our goal is to extend and increase the density of the known human interactome by integrating bait-prey and cocomplexed preys (prey-prey associations) into networks. Our framework incorporates a score for each identified protein, as well as elements of signal processing to improve the confidence of identified protein-protein interactions. We identify many protein networks enriched in known biological processes and functions. In addition, we show that integrated bait-prey and prey-prey interactions can be used to refine network topology and extend known protein networks. PMID- 22845869 TI - Selective bronchial intubation in a preterm infant with congenital cystic adenomatoid malformation and pulmonary air leak syndrome. AB - A preterm infant with congenital cystic adenomatoid malformation (CCAM) who developed a right-sided pulmonary air leak syndrome (pulmonary interstitial emphysema and bronchopleural fistula) following CCAM resection is reported. The pulmonary air leak syndrome was successfully ameliorated by intubating the right mainstem bronchus using a modified endotracheal tube that allowed selective ventilation of the left lung. The procedure was used successfully as rescue treatment to control the pulmonary air leak and to confirm the functional adequacy of the left lung prior to definitive operative surgery. PMID- 22845870 TI - Synthesis, physical properties, and field-effect mobility of isomerically pure syn-/anti-anthradithiophene derivatives. AB - Isomerically pure syn-/anti-isomers of 2,8-dimethylanthradithiophene (DMADT) were synthesized in five steps and characterized using thermogravimetry, X-ray single crystal analysis, UV-vis absorption, and electrochemical measurements. The physical properties in solution were slightly different for each isomer, whereby the more obvious differences were observed in the solid state. A field-effect transistor using the anti-isomer showed a much higher performance than that using the syn-isomer. PMID- 22845871 TI - Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: a meta-analysis of randomized clinical trials. AB - BACKGROUND: Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. OBJECTIVES: We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD). PATIENTS/METHODS: Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. RESULTS: A total of 41 647 patients from eight trials were included. PAR 1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P < 0.001), major (OR 1.46, 95% CI 1.28-1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P < 0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78 0.92, P < 0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P = 0.59). CONCLUSIONS: PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding. PMID- 22845872 TI - Expression of angiogenic chemokines in ovarian clear cell carcinoma. AB - AIMS: The aim of this study was to assess the expression of angiogenic chemokines (CXCR4/CXCL12) and the vascular endothelial growth factor in ovarian clear cell carcinoma, comparing levels against those in ovarian high-grade serous carcinoma. MATERIAL AND METHODS: Tissue microarray samples from 136 cases of epithelial ovarian carcinoma (108 high-grade serous carcinoma and 28 clear cell carcinoma) were reviewed with World Health Organization histological criteria strictly applied to categorize cases according to histological subtype. Only cases without prior exposure to chemotherapy were included. Sections were stained with vascular endothelial growth factor, CXCR4, CXCL12 and assessed using conventional histological scoring (H-scoring). RESULTS: Patients with clear cell carcinoma presented at an early stage of the disease (74% stage 1 and 2) and had a significantly better progression-free (P=0.042) survival than those with high grade serous carcinoma. Low expression profile of the tested markers was seen in cases of clear cell carcinoma contrary to that seen in high-grade serous carcinoma. CONCLUSION: The current study reports, for the first time, the difference in expression of a set of angiogeneic prognostic markers between clear cell carcinoma and high-grade serous carcinoma, offering a possible explanation for the apparent chemotherapy resistance. These results are relevant for the design of future clinical studies of first-line treatment for patients with ovarian clear cell carcinoma. PMID- 22845873 TI - An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. AB - Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In clinical studies, carfilzomib has shown efficacy in patients with relapsed and/or refractory multiple myeloma (MM) and has demonstrated a tolerable safety profile. In this phase 2, open-label, multicentre clinical trial, 35 patients with relapsed and/or refractory MM following 1-3 prior therapies, including at least one bortezomib-based regimen, received carfilzomib 20 mg/m(2) in a twice-weekly, consecutive-day dosing schedule for <=12 monthly cycles. The best overall response rate (ORR) was 17.1% and the clinical benefit response rate (ORR + minimal response) was 31.4%. The median duration of response was >10.6 months and the median time to progression was 4.6 months. The most common adverse events were fatigue (62.9%), nausea (60.0%), and vomiting (42.9%). No exacerbation of baseline peripheral neuropathy was observed. Single-agent carfilzomib was generally well tolerated for up to 12 treatment cycles and showed activity in patients with relapsed and/or refractory MM who had received prior treatment with bortezomib. These data, combined with an acceptable toxicity profile, support the potential use of carfilzomib in patients with relapsed and/or refractory MM and warrant continued investigation of carfilzomib as single agent or in combination with other agents. PMID- 22845875 TI - Individual influence on model selection. AB - Researchers in psychology are increasingly using model selection strategies to decide among competing models, rather than evaluating the fit of a given model in isolation. However, such interest in model selection outpaces an awareness that one or a few cases can have disproportionate impact on the model ranking. Though case influence on the fit of a single model in isolation has been often studied, case influence on model selection results is greatly underappreciated in psychology. This article introduces the issue of case influence on model selection and proposes 3 influence diagnostics for commonly used selection indices: the chi-square difference test, Bayesian information criterion, and Akaike's information criterion. These 3 diagnostics can be obtained simply from the byproducts of full information maximum likelihood estimation without heavy computational burden. We provide practical information on the interpretation and behavior of these diagnostics for applied researchers and provide software code to facilitate their use. Simulated and empirical examples involving different kinds of model comparison scenarios encountered in cross-sectional, longitudinal, and multilevel research as well as involving different kinds of outcome distributions illustrate the generality of the proposed diagnostics. An awareness of how cases influence model selection results is shown to aid researchers in understanding how representative their sample level results are at the case level. PMID- 22845876 TI - Molecular data and ecological niche modelling reveal a highly dynamic evolutionary history of the East Asian Tertiary relict Cercidiphyllum (Cercidiphyllaceae). AB - East Asia's temperate deciduous forests served as sanctuary for Tertiary relict trees, but their ages and response to past climate change remain largely unknown. To address this issue, we elucidated the evolutionary and population demographic history of Cercdiphyllum, comprising species in China/Japan (Cercdiphyllum japonicum) and central Japan (Cercdiphyllum magnificum). Fifty-three populations were genotyped using chloroplast and ribosomal DNA sequences and microsatellite loci to assess molecular structure and diversity in relation to past (Last Glacial Maximum) and present distributions based on ecological niche modelling. Late Tertiary climate cooling was reflected in a relatively recent speciation event, dated at the Mio-/Pliocene boundary. During glacials, the warm-temperate C. japonicum experienced massive habitat losses in some areas (north-central China/north Japan) but increases in others (southwest/-east China, East China Sea landbridge, south Japan). In China, the Sichuan Basin and/or the middle-Yangtze were source areas of postglacial northward recolonization; in Japan, this may have been facilitated through introgressive hybridization with the cool-temperate C. magnificum. Our findings challenge the notion of relative evolutionary and demographic stability of Tertiary relict trees, and may serve as a guideline for assessing the impact of Neogene climate change on the evolution and distribution of East Asian temperate plants. PMID- 22845877 TI - Automated liquid-liquid extraction by pneumatic recirculation on a centrifugal microfluidic platform. AB - In this technical note, a liquid-liquid extraction technique was performed using pneumatic liquid recirculation on a centrifugal microfluidic device. Non-contact pneumatic pumping enabled a multi-cycle liquid-liquid extraction process using aqueous iodine in a potassium iodide solution and hexadecane while requiring a minimal amount of space on the device. The extraction process was completely automated on the device following sample introduction and required only 50 s for each extraction cycle. The pumping rate achieved during liquid recirculation was 120 +/- 10 MUL/min. A recycling process such as the one demonstrated would be difficult to implement in a conventional centrifugal microfluidic system. PMID- 22845878 TI - Hepatitis E virus infection in Ghanaian blood donors - the importance of immunoassay selection and confirmation. AB - BACKGROUND AND OBJECTIVES: Hepatitis E virus (HEV) infection is emerging as a potential new threat to blood safety after several cases of transfusion transmission were reported from non-epidemic countries. On the basis of seroprevalence data, HEV is endemic in Ghana where poor sanitary conditions and regular flooding are prevalent. However, no data are available for HEV prevalence in blood donors. MATERIALS AND METHODS: Plasma samples from 239 Ghanaian blood donors were tested for anti-HEV IgG and IgM by ELISA (two and three assays, respectively) and Western blot (recomLine) and for HEV-RNA by RT-qPCR. RESULTS: All donors were RNA negative. Results from the different serological assays were discrepant: reactivity in two of the three IgM assays was correlated with elevated IgM levels, but the discrepancies between IgG assays were unrelated to the donors' IgG levels and more likely related to assay sensitivity. Fourteen samples (5.9%) were anti-HEV IgM reactive and 11 samples (4.6%) anti-HEV IgG reactive in at least two serological assays from different manufacturers. CONCLUSIONS: (a) In the absence of accepted confirmatory assays, it is crucial to confirm anti-HEV reactive samples with an alternative assay, especially when the population tested carries high levels of immunoglobulin M. (b) Although asymptomatic HEV infections are common in Ghanaian blood donors, currently, it does not seem to be a major risk to blood safety. PMID- 22845879 TI - Interaction of sex steroid hormones and brain-derived neurotrophic factor tyrosine kinase B signalling: relevance to schizophrenia and depression. AB - Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the developing brain and have been implicated in the pathogenesis of neurodevelopmental disorders. Sex steroid hormones are also involved in the regulation of brain-derived neurotrophic factor expression. A review of the literature is provided on the relationship between brain-derived neurotrophic factor and sex steroid hormones, as well as the mechanisms behind this interaction, in the context of how this relationship may be involved in the development of neurodevelopmental psychiatric illnesses, such as schizophrenia and depression. PMID- 22845874 TI - Single-case experimental designs: a systematic review of published research and current standards. AB - This article systematically reviews the research design and methodological characteristics of single-case experimental design (SCED) research published in peer-reviewed journals between 2000 and 2010. SCEDs provide researchers with a flexible and viable alternative to group designs with large sample sizes. However, methodological challenges have precluded widespread implementation and acceptance of the SCED as a viable complementary methodology to the predominant group design. This article includes a description of the research design, measurement, and analysis domains distinctive to the SCED; a discussion of the results within the framework of contemporary standards and guidelines in the field; and a presentation of updated benchmarks for key characteristics (e.g., baseline sampling, method of analysis), and overall, it provides researchers and reviewers with a resource for conducting and evaluating SCED research. The results of the systematic review of 409 studies suggest that recently published SCED research is largely in accordance with contemporary criteria for experimental quality. Analytic method emerged as an area of discord. Comparison of the findings of this review with historical estimates of the use of statistical analysis indicates an upward trend, but visual analysis remains the most common analytic method and also garners the most support among those entities providing SCED standards. Although consensus exists along key dimensions of single-case research design, and researchers appear to be practicing within these parameters, there remains a need for further evaluation of assessment and sampling techniques and data analytic methods. PMID- 22845880 TI - Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients. AB - BACKGROUND: There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. MATERIALS AND METHODS: We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6h thereafter; AUC1), and the seven post dialysis lisinopril plasma levels were used for calculation of AUC2. RESULTS: The mean ESA index of all patients was 27.90+/-25.84 (IU/week/kg)/(g/dL). Average lisinopril AUC1 was 1212.48+/-1209.75 [mg*h/L], whereas AUC2 averaged 947.67+/ 977.07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. CONCLUSIONS: Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs. PMID- 22845881 TI - Breastfeeding support for African-American women in Louisiana hospitals. AB - OBJECTIVE: This study determined the variation in hospital breastfeeding support for African-American women in Louisiana. STUDY DESIGN: Data from the 2007-2008 Louisiana Pregnancy Risk Assessment Monitoring System (n=2,534) were used to determine the odds of African-American women's hospital experiences with breastfeeding-related services following delivery relative to women of all other races. SAS-callable SUDDAN software was used for analyses. RESULTS: African American women were 60% less likely than women of other races to initiate breastfeeding or pump milk (odds ratio=0.40, 95% confidence interval=0.31-0.52). Compared with women of other races, African-American mothers were less likely to receive breastfeeding instruction and support from healthcare professionals while in the hospital, including being less likely to receive phone numbers for support and less likely to have their baby remain in the hospital room with them. African American mothers were also less likely to report that they breastfed while in hospital or breastfed exclusively while in-hospital. CONCLUSION: This study shows significant racial differences in initiation of breastfeeding and hospital experiences following delivery in Louisiana. PMID- 22845882 TI - Management of factor VII-deficient patients undergoing joint surgeries- preliminary results of locally developed treatment regimen. AB - Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 MUg kg(-1) b.w. and on the subsequent days--from 13 to 30 MUg kg( 1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery. PMID- 22845883 TI - Method for Simultaneously improving the thermal stability and mechanical properties of poly(lactic acid): effect of high-energy electrons on the morphological, mechanical, and thermal properties of PLA/MMT nanocomposites. AB - Nanocomposites derived from poly(lactic acid) (PLA) and organically modified montmorillonite (oMMT) have been cross-linked by high-energy electrons in the presence of triallyl cyanurate (TAC). The morphology of untreated and cross linked PLA/MMT nanocomposites was characterized by wide-angle X-ray scattering (WAXS) and transmission electron microscopy (TEM). This treatment can improve both the thermal stability and the glass-transition temperatures of the PLA nanocomposites (e.g., PLA-MMT-TAC 30kGy, 50kGy, and 70kGy) because of the formation of cross-linking structures in the nanocomposites that will considerably reduce the mobility of polymers. Interestingly, at relatively low irradiation doses (e.g., 30 and 50 kGy) a good balance between tensile strength and elongation at break for the PLA nanocomposites could be achieved. These mechanical properties are superior to those of pure PLA. Therefore, combining nanotechnology and electron beam cross-linking is a promising new method of simultaneously improving the mechanical properties (toughness and tensile strength) and thermal stability of PLA. PMID- 22845884 TI - Benchmark studies on the building blocks of DNA. 2. Effect of biological environment on the electronic excitation spectrum of nucleobases. AB - In the first paper of this series (Szalay; et al. J. Phys. Chem. A, 2012, 116, 6702) we have investigated the excited states of nucleobases. It was shown that it is only the equation of motion excitation energy coupled-cluster (EOMEE-CC) methods, which can give a balanced description for all type of the transitions of these molecules; if the goal is to obtain accurate results with uncertainty of about 0.1 eV only, triples corrections in the form of, e.g., the EOMEE-CCSD(T) method need to be included. In this second paper we extend this study to nucleobases in their biological environment, considering hydration, glycoside bond, and base pairing. EOMEE-CCSD and EOMEE-CCSD(T) methods are used with aug-cc pVDZ basis. The effect of surrounding water was systematically investigated by considering one to five water molecules at different positions. It was found that hydration can modify the order of the excited states: in particular, npi* states get shifted above the neighboring pipi* ones. The glycoside bond's effect is smaller, as shown by our calculations on cytidine and guanosine. Here the loss of planarity causes some intensity shift from pipi* to npi* states. Finally, the guanine-cytosine (GC) Watson-Crick pair was studied; most of the states could be identified as local excitations on one of the bases, but there is also a low lying charge-transfer state. Significant discrepancy with earlier CASPT2 and TDDFT studies was found for the GC pair and triples effects seem to be essential for all of these systems. PMID- 22845885 TI - Eugenic selection benefits embryos. AB - The primary question to be addressed here is whether pre-implantation genetic diagnosis (PGD), used for both negative and positive trait selection, benefits potential supernumerary embryos. The phrase 'potential supernumerary embryos' is used to indicate that PGD is typically performed on a set of embryos, only some of which will be implanted. Prior to any testing, each embryo in the set is potentially supernumerary in the sense that it may not be selected for implantation. Those embryos that are not selected, and hence destroyed or frozen, are 'actually supernumerary'. The argument to be advanced is hypothetical: If embryos may be said to benefit or be harmed by our actions, then PGD used to select for an embryo or embryos with the highest expected Wellbeing benefits potential supernumerary embryos. The argument shows that the 'non-identity' problem is not sufficient to show that eugenic selection does not benefit supernumerary embryos. PMID- 22845886 TI - Functional screening of antibiotic resistance genes from human gut microbiota reveals a novel gene fusion. AB - The human gut microbiota has a high density of bacteria that are considered a reservoir for antibiotic resistance genes (ARGs). In this study, one fosmid metagenomic library generated from the gut microbiota of four healthy humans was used to screen for ARGs against seven antibiotics. Eight new ARGs were obtained: one against amoxicillin, six against d-cycloserine, and one against kanamycin. The new amoxicillin resistance gene encodes a protein with 53% identity to a class D beta-lactamase from Riemerella anatipestifer RA-GD. The six new d cycloserine resistance genes encode proteins with 73-81% identity to known d alanine-d-alanine ligases. The new kanamycin resistance gene encodes a protein of 274 amino acids with an N-terminus (amino acids 1-189) that has 42% identity to the 6'-aminoglycoside acetyltransferase [AAC(6')] from Enterococcus hirae and a C terminus (amino acids 190-274) with 35% identity to a hypothetical protein from Clostridiales sp. SSC/2. A functional study on the novel kanamycin resistance gene showed that only the N-terminus conferred kanamycin resistance. Our results showed that functional metagenomics is a useful tool for the identification of new ARGs. PMID- 22845887 TI - Gene therapy in liver diseases: state-of-the-art and future perspectives. AB - Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized. PMID- 22845888 TI - Adenovirus vectors and subviral particles for protein and peptide delivery. AB - Adenovirus vectors belong to the most frequently used vector type in gene therapy approaches. In addition, adenovirus vector particles and adenovirus subviral particles offer a great potential for the direct delivery of proteins into cells. In this review we discuss this potential and the technology of adenovirus as a protein delivery platform for applications ranging from vaccination to gene therapy. PMID- 22845889 TI - Development of an outcome measurement system for service planning for children and youth with special needs. AB - AIM: This study described the process used in developing an outcome measurement framework for system planning to improve services for children and youth with special needs and their families in a Canadian province. The study reports the results of several parent-completed measures, which would be useful in service planning as well as the acceptability and utility of these measures for use by families and service centres. METHODS/RESULTS: Development of a theoretical framework, consultation with key stakeholders, testing the utility of selected outcome measures and initial dissemination of results were critical elements in the successful development of an outcome system. Consultation with stakeholders confirmed use of the International Classification of Functioning, Disability and Health and the child-within-family-within community model as theoretical frameworks while building valuable partnerships and identifying potential barriers to implementation. Pilot testing showed three outcome measures were feasible for families to complete and the measures provided information about services for children that was valuable to families as well as service providers. Gaps in service delivery were identified and the need for better communication between service providers and communities to facilitate integrated services was highlighted. CONCLUSION: The findings from this study can be used to implement an outcome measurement system for children with special needs and may serve as a resource for international researchers who are working to develop valid tools as well as outcome systems that are useful for system planning. PMID- 22845890 TI - Oligodendrocyte progenitor cells: a missed opportunity. PMID- 22845891 TI - Adapting low back pain guidelines within a multidisciplinary context: a process evaluation. AB - RATIONALE, AIMS AND OBJECTIVES: The Alberta Ambassador Program (AAP) adapted seven clinical practice guidelines on low back pain (LBP) into a single guideline spanning the continuum of care from prevention and diagnosis through to treatment. The Ambassador adaptation process was evaluated to 1 Identify the major challenges encountered and successful strategies utilized; 2 Assess strengths and weaknesses by benchmarking it with the ADAPTE framework; and 3 Identify opportunities for improvement. METHOD: External consultants reviewed the Ambassador and ADAPTE materials and conducted semi-structured telephone interviews with 29 participants from the AAP committees. All participants were asked about the major challenges encountered and potential areas for improvement. RESULTS: The response rate was 83% (29/35). There was strong consensus that the Ambassador guideline adaptation process was sound and rigorous all respondents indicated willingness to participate in further iterations of the Program. Key elements of success were identified. The main steps and sequence of the process were closely aligned with the ADAPTE framework, although the AAP incorporated additional enhancements which augmented the process. The main divergences between the two frameworks centred on the organizational structure and the methods used to overcome methodological difficulties. CONCLUSION: The AAP successfully utilized existing stakeholder interest to create an overarching guideline for managing LBP across multiple primary care disciplines. The study highlighted the strengths and weaknesses of the Program, and identified practical strategies for improvement. Evaluating guideline adaptation processes is pivotal to ensuring that they continue to be an efficient, rigorous and practicable option for producing contextualized, clinically relevant guidelines. PMID- 22845893 TI - Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. AB - OBJECTIVE: To assess the efficacy and safety of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the N-acylethanolamines family, in reducing pain severity in patients with pain associated to different pathological conditions. METHODS: This was an observational study conducted on 610 patients who were unable to effectively control chronic pain with standard therapies. PEA (600 mg) was administered twice daily for 3 weeks followed by single daily dosing for 4 weeks, in addition to standard analgesic therapies or as single therapy. The primary outcome measure was the mean score pain severity evaluated by the numeric rating scale. Safety was also evaluated. RESULTS: PEA treatment significantly decreased the mean score pain intensity evaluated in all patients who completed the study. The PEA effect was independent of the pain associated pathological condition. PEA-induced decrease of pain intensity was present also in patients without concomitant analgesic therapy. Importantly, PEA showed no adverse effects. CONCLUSIONS: In this study, PEA was effective and safe in the management of chronic pain in different pathological conditions. PMID- 22845894 TI - Chronobiology of blood pressure: emerging implications of melatonin. PMID- 22845892 TI - A brain network instantiating approach and avoidance motivation. AB - Research indicates that dorsolateral prefrontal cortex (DLPFC) is important for pursuing goals, and areas of DLPFC are differentially involved in approach and avoidance motivation. Given the complexity of the processes involved in goal pursuit, DLPFC is likely part of a network that includes orbitofrontal cortex (OFC), cingulate, amygdala, and basal ganglia. This hypothesis was tested with regard to one component of goal pursuit, the maintenance of goals in the face of distraction. Examination of connectivity with motivation-related areas of DLPFC supported the network hypothesis. Differential patterns of connectivity suggest a distinct role for DLPFC areas, with one involved in selecting approach goals, one in selecting avoidance goals, and one in selecting goal pursuit strategies. Finally, differences in trait motivation moderated connectivity between DLPFC and OFC, suggesting that this connectivity is important for instantiating motivation. PMID- 22845895 TI - A dopamine/noradrenaline reuptake inhibitor improves performance in the heat, but only at the maximum therapeutic dose. AB - A maximal dose of bupropion has enabled subjects to maintain a higher power output than reported during the placebo session in the heat. Because this drug is taken in different doses it is important to know if there is a dose-response relationship with regard to exercise at high ambient temperature. Ten well trained male cyclists ingested placebo (pla; 200 mg) or bupropion (50%, 75%, 100% of maximal dose: bup50: 150 mg; bup75: 225 mg; bup100: 300 mg) the evening before and morning of the experimental trial. Trials were conducted in 30 degrees C (humidity 48%). Subjects cycled for 60 min at 55% W (max) , immediately followed by a time trial to measure performance. Bup100 improved performance (pla: 33'42" +/- 2'06"; bup100: 32'06" +/- 1'54"; P = 0.035). Bupropion increased core temperature at the end of exercise, while heart rate was higher only in the bup100 trial (P < 0.05). No changes in rating of perceived exertion (RPE) or thermal sensation were found. Lower doses of bupropion were not ergogenic, indicating there was no dose-response effect. Interestingly, despite an increase in core temperature and improved performance in the maximal dose, there was no change in RPE and thermal sensation, suggesting an altered motivation or drive to continue exercise. PMID- 22845896 TI - Dissecting pharmacodynamics to determine the optimal sampling time and measurement for assessing the antiplatelet effect of clopidogrel. PMID- 22845897 TI - Systems responses of rats to mequindox revealed by metabolic and transcriptomic profiling. AB - Mequindox is used as an antibiotic drug in livestock; however, its toxicity remains largely unclear. Previously, we investigated metabolic responses of mice to mequindox exposure. In order to evaluate dependences of animal species in response to mequindox insult, we present the metabolic consequences of mequindox exposure in a rat model, by employing the combination of metabonomics and transcriptomics. Metabolic profiling of urine revealed that metabolic recovery is achieved for rats exposed to a low or moderate dose of mequindox, whereas high levels of mequindox exposure trigger liver dysfunction, causing no such recovery. We found that mequindox exposure causes suppression of the tricarboxylic acid cycle and stimulation of glycolysis, which is in contrast to a mouse model previously investigated. In addition, mequindox dosage induces promotion of beta oxidation of fatty acids, which was confirmed by elevated expressions of acox1, hsd17b2, and cpt1a in liver. Furthermore, altered levels of N-methylnicotinate, 1 methylnicotinamide, and glutathione disulfide highlighted the promotion of vitamin B3 antioxidative cycle in rats exposed to mequindox. Moreover, mequindox exposure altered levels of gut microbiotal related co-metabolites, suggesting a perturbation of the gut microflora of the host. Our work provides a comprehensive view of the toxicological effects of mequindox, which is important in the usage of mequindox in animal and human food safety. PMID- 22845898 TI - Maternal ventilation and sedation for H1N1 influenza resulting in fetal bladder rupture and urinary ascites. AB - Urinary ascites in a newborn infant is unusual and most commonly results from bladder perforation following umbilical arterial catheterisation or obstructive uropathy. The following report describes a case of fetal bladder rupture with urinary ascites in a mother ventilated and sedated with narcotics and benzodiazepines for H1N1 influenza. This was associated with a unique biochemical profile of hyponatraemia and elevated serum urea and creatinine characteristic of urinary autodialysis in the neonate. PMID- 22845899 TI - Carotid intima media-thickness and genes involved in lipid metabolism in diabetic patients using statins--a pathway toward personalized medicine. AB - The prognostic importance of large artery structure and function in relation to cardiovascular morbidity and mortality, together with the identification of new genetic risk factors have been two major areas of investigation in recent years. Carotid intima-media thickness (CIMT), as measured by B-mode ultrasound, is a surrogate marker for atherosclerosis and can be used to detect an accelerated disease process as well as subclinical disease. However, the genetic basis for CIMT variation is almost unknown. Cardiovascular genetics has led to numerous clinical studies generally focused on only one candidate gene and were frequently conducted in subjects with cardiovascular diseases and/or taking drugs that could affect CIMT. Pharmacogenetics is the study of the effect of a medication as it relates to single or defined sets of genes. An important goal of pharmacogenetics in cardiovascular disorders is to integrate the two (drugs plus genes) so that true personalized therapy can be delivered. In this paper, we will discuss the interaction between genes involved in lipid metabolism and statin therapy that affects intermediate phenotype (plasma lipid levels) and CIMT in patients with type 2 diabetes. PMID- 22845900 TI - Using literature-based discovery to identify novel therapeutic approaches. AB - We present a promising in silico paradigm called literature-based discovery (LBD) and describe its potential to identify novel pharmacologic approaches to treating diseases. The goal of LBD is to generate novel hypotheses by analyzing the vast biomedical literature. Additional knowledge resources, such as ontologies and specialized databases, are often used to supplement the published literature. MEDLINE, the largest and most important biomedical bibliographic database, is the most common source for exploiting LBD. There are two variants of LBD, open discovery and closed discovery. With open discovery we can, for example, try to find a novel therapeutic approach for a given disease, or find new therapeutic applications for an existing drug. With closed discovery we can find an explanation for a relationship between two concepts. For example, if we already have a hypothesis that a particular drug is useful for a particular disease, with closed discovery we can identify the mechanisms through which the drug could have a therapeutic effect on the disease. We briefly describe the methodology behind LBD and then discuss in more detail currently available LBD tools; we also mention in passing some of those no longer available. Next we present several examples in which LBD has been exploited for identifying novel therapeutic approaches. In conclusion, LBD is a powerful paradigm with considerable potential to complement more traditional drug discovery methods, especially for drug target discovery and for existing drug relabeling. PMID- 22845903 TI - Artificial pancreas within reach. PMID- 22845902 TI - Prophylactic use of intra-aortic balloon pumps in open heart surgery. AB - During a 1-year period, intra-aortic balloon pumps (IABPs) were used in open heart surgery on 57 patients. Indications were prophylactic usage for coronary artery bypass grafting (CABG) in 52 patients, prophylactic usage for valve replacement in three patients, and cardiopulmonary bypass (CPB) weaning during valve replacement in two patients. The 52 CABG patients comprised 94.5% of all CABG procedures during the period. Sheathless 8 Fr IABPs were used in all cases. The 57 patients using IABPs were analyzed. The mean duration of IABP use was 41.7 h. Morbidity was not associated with using IABPs. There was one case of balloon rupture. Hemostasis was performed easily after removing IABP catheters by compressing the groin for approximately 15 min. The lowest blood pressure during anastomosis or cardiac arrest was also assessed. The lowest peak pressure was 55.9 +/- 17.3 mm Hg for patients with IABP still turned on, and the lowest mean pressure was 34.7 +/- 6.5 mm Hg for patients with IABP temporarily turned off. Peak blood pressure after CPB was 73.8 +/- 17.8 mm Hg. During open heart surgery under anesthesia with the low blood pressure presented by this series, use of IABPs enabled patients to tolerate the procedure. In conclusion, aggressive use of IABPs is easy, safe, and effective with no related morbidity. PMID- 22845904 TI - Commensal microbiota determine intestinal iTreg. PMID- 22845905 TI - About using limited resources more efficiently. PMID- 22845906 TI - Utilization and outcomes of marginal kidneys--using Kidney Donor Risk Index to move beyond the current labels. PMID- 22845907 TI - An alternative kidney allocation algorithm: is it better, and by what yardstick? PMID- 22845908 TI - Vascular smooth muscle cell apoptosis promotes transplant arteriosclerosis through inducing the production of SDF-1alpha. AB - Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild-type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF-1alpha from apoptotic and neighboring viable cells, resulting in increased SDF-1alpha in the culture media. Conditioned media from Ltv-p53-transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF-1alpha-dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus-mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF-1alpha both in allograft media and in blood plasma, associated with diminished recruitment of CD90(+)CD105(+) double-positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF-1alpha production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions. PMID- 22845910 TI - Pancreas transplantation from donors after circulatory death from the United Kingdom. AB - This study reports the comparative short-term results of pancreas transplantation from donors after circulatory death (DCD) (Maastricht III & IV), and pancreases from brainstem deceased donors (DBD). Between January 2006 and December 2010, 1009 pancreas transplants were performed in the United Kingdom, with 134 grafts from DCD and 875 from DBD. DCD grafts had no premortem pharmacological interventions performed. One-year pancreas and patient survival was similar between DCD and DBD, with pancreas graft survival significantly better in the DCD cohort if performed as an SPK. Early graft loss due to thrombosis (8% vs. 4%) was mainly responsible for early graft loss in the DCD cohort. These results from donors with broader acceptance criteria in age, body mass index, premortem interventions, etc. suggest that DCD pancreas grafts may have a larger application potential than previously recognized. PMID- 22845909 TI - A novel monoclonal antibody to CD40 prolongs islet allograft survival. AB - The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile. PMID- 22845911 TI - Increase in mortality rate of liver transplant candidates residing in specific geographic areas: analysis of UNOS data. AB - We sought to evaluate survival of liver transplant candidates living in geographic areas with limited access to specialized transplant centers (TxC). We analyzed survival outcome among candidates listed for liver transplant in United Network of Organ Sharing (UNOS) Region 4 from 2004 to 2010. Candidates were stratified into three groups according to the distance from the patient's residence to the closest hospital with a liver transplant program: Group 1 (Gr 1) <30 miles (m), Group 2 (Gr 2) 30-60 m and Group 3 (Gr 3) >60 m. Of the 5673 patients included in the study, 49% resided >30 m from a TxC. Eight percent of the cohort experienced death or dropped out of the list due to medical condition deterioration, with worse outcomes for Gr 2 and Gr 3 (8.5% and 9.9%, respectively, vs. 6.5% for Gr 1 [p < 0.001]). Among patients with a MELD score <20, mortality was higher in Gr 2 and Gr 3 compared to Gr 1 (p < 0.001). We conclude that for Region 4, the mortality risk in patients living >30 m from a TxC is higher. We suggest that the variable "distance from a TxC" should be used to improve the estimate of the mortality risk for patients on the waiting list. PMID- 22845913 TI - Mild rise in creatinine six months post kidney transplant. PMID- 22845916 TI - Association of maternal periodontal health with adverse pregnancy outcome. AB - AIM: The present study aims to determine the association of periodontal disease (identified early in pregnancy) and adverse pregnancy outcomes in a North Indian population. MATERIAL AND METHODS: A total of 340 primigravida women, aged 20-35 years with single live pregnancy were recruited at 14-20 weeks period of gestation from the antenatal clinic. These women had undergone periodontal examination at time of recruitment. The pregnancy outcomes were recorded. RESULTS: Out of 340 primigravida women, 147 (43.23%) women had gingivitis and 61 (17.94%) women had periodontitis. Periodontitis was found to be significantly associated with pre-eclampsia, intrauterine growth restriction, preterm delivery, and low birthweight with odds ratios (95% confidence interval) of 7.48 (2.72 22.42), 3.35 (1.20-9.55), 2.72 (1.30-5.68) and 3.03 (1.53-5.97), respectively. CONCLUSIONS: The study shows a significant association between periodontitis (but not with gingivitis) and adverse pregnancy outcomes. Maternal periodontitis is associated with an increased risk of pre-eclampsia, intrauterine growth restriction, preterm delivery and low birthweight infants. PMID- 22845917 TI - Characterization of biofilm-forming cyanobacteria for biomass and lipid production. AB - AIMS: This work reports on one of the first attempts to use biofilm-forming cyanobacteria for biomass and lipid production. METHODS AND RESULTS: Three isolates of filamentous cyanobacteria were obtained from biofilms at different Italian sites and characterized by a polyphasic approach, involving microscopic observations, ecology and genetic diversity (studying the 16S rRNA gene). The isolates were grown in batch systems and in a semi-continuous flow incubator, specifically designed for biofilms development. Culture system affected biomass and lipid production, but did not influence the fatty acid profile. The composition of fatty acids was mainly palmitic acid (>50%) and less amounts of other saturated and monounsaturated fatty acids. Only two isolates contained two polyunsaturated fatty acids. CONCLUSIONS: Data obtained from the flow-lane incubator system would support a more economical and sustainable use of the benthic micro-organisms for biomass production. The produced lipids contained fatty acids suitable for a high-quality biodiesel production, showing high proportions of saturated and monounsaturated fatty acids. SIGNIFICANCE AND IMPACT OF THE STUDY: Data seem promising when taking into account the savings in cost and time derived from easy procedures for biomass harvesting, especially when being able to obtain the co-production of other valuable by-products. PMID- 22845918 TI - Decreased spinothalamic and dorsal column medial lemniscus-mediated function is associated with neuropathic pain after spinal cord injury. AB - Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect quality of life and is often refractory to currently available treatments. In order to find more effective therapeutic avenues, it would be helpful to identify the primary underlying pathophysiological mechanisms in each individual. The aim of the present study was to assess the relationship between the presence and severity of NP after SCI and measures of somatosensory function mediated via the dorsal column medial lemniscal (DCML) pathway and the spinothalamic tract (STT). Vibratory, mechanical, thermal, and pain thresholds measured in areas at and below the neurological level of injury (LOI) in persons with SCI and NP (SCI-NP, n=47) and in persons with SCI without NP (SCI-noNP, n=18) were normalized to data obtained from able-bodied pain-free control subjects (A-B, n=30). STT-mediated function at and below the LOI was significantly impaired in both SCI groups compared with A-B controls (p<0.001), but not significantly different between the two SCI groups (NP vs. no-NP). In contrast, the SCI-NP group had significantly greater impairment of DCML-mediated function at the LOI, as reflected by greater vibratory detection deficits (z= 3.89+/-0.5), compared with the SCI-noNP group (z=-1.95+/-0.7, p=0.034). Within the SCI-NP group, NP severity was significantly associated with increased thermal sensitivity below the LOI (r=0.50, p=0.038). Our results suggest that both impaired STT and DCML-mediated function are necessary for the development of NP after SCI. However, within the SCI-NP group, greater NP severity was associated with greater sensitivity to thermal stimuli below the LOI. This finding concurs with other studies suggesting that STT damage with some sparing is associated with NP. PMID- 22846034 TI - Individuals with posttraumatic stress disorder show a selective deficit in generalization of associative learning. AB - OBJECTIVE: Drawing on two different populations, Israeli police and Hungarian civilians, the present study assessed the ability of individuals with posttraumatic stress disorder (PTSD) to generalize previous learning to novel situations. Past neuroimaging studies have demonstrated diminished medial temporal lobe (MTL) activation and/or reduced hippocampal volume in individuals with PTSD. Our earlier computational models of cortico-hippocampal function and subsequent experimental tests of these models in MTL-impaired clinical populations argue that even mild hippocampal dysfunction may result in subtle impairments in generalization. Therefore, we predicted that individuals with PTSD would show impaired generalization. METHOD: We compared the performance of five groups from two countries, including 19 Israeli police with PTSD and 22 trauma exposed police without PTSD, and 22 Hungarian civilians with PTSD, 25 trauma exposed civilians without PTSD, and 25 individuals without PTSD unexposed to the same trauma. Participants were tested on a two-phase learning paradigm, the Acquired Equivalence Task, which measures the ability to generalize past learning to novel situations. RESULTS: We found that both PTSD and non-PTSD participants were capable of learning the initial stimulus-outcome associations, F(4, 108) = 1.79, p = .14. However, as predicted, only individuals with PTSD showed a selective deficit in generalization of this learning to novel situations (F(4, 108) = 8.35, p < .001, Partial eta2 = 0.26). CONCLUSIONS: Individuals with PTSD show a selective impairment in generalization of past learning similar to other clinical populations with MTL/hippocampal dysfunction. This is consistent with an emerging view of PTSD as being not only an anxiety disorder but also a learning disorder. PMID- 22846035 TI - Naturalistic assessment of everyday functioning in individuals with mild cognitive impairment: the day-out task. AB - OBJECTIVE: The day-out task (DOT), a naturalistic task that requires multitasking in a real-world setting, was used to examine everyday functioning in individuals with mild cognitive impairment (MCI). METHOD: Thirty-eight participants with MCI and 38 cognitively healthy older adult controls prioritized, organized, initiated, and completed a number of subtasks in a campus apartment to prepare for a day out (e.g., determine and gather change for bus, bring a magazine). Participants also completed tests assessing cognitive constructs important in multitasking (i.e., retrospective memory, prospective memory, planning). RESULTS: As compared with controls, the MCI group required more time to complete the DOT and demonstrated poorer task accuracy, performing more subtasks incompletely and inaccurately. Despite poorer DOT task accuracy, the MCI and control groups approached completion of the DOT in a similar manner. For the MCI group, retrospective memory was a unique predictor of the number of subtasks left incomplete and inaccurate, while prospective memory was a unique predictor of DOT sequencing. The DOT measures, but not the cognitive tests, were predictive of knowledgeable informant report of everyday functioning. CONCLUSIONS: THESE findings suggest that difficulty remembering and keeping track of multiple goals and subgoals may contribute to the poorer performance of individuals with MCI in complex everyday situations. PMID- 22846036 TI - Effect of PPG-PEG-PPG on the tocopherol-controlled release from films intended for food-packaging applications. AB - The feasibility of novel controlled release systems for the delivery of active substances from films intended for food packaging was investigated. Because polyolefins are used highly for food-packaging applications, the reported high retention degree of antioxidants has limited their use for active packaging. Thus, in this study, PP films modified with different chain extenders have been developed to favor and control the release rates of the low molecular weight antioxidant tocopherol. The use of different chain extenders as polymer modifiers (PE-PEG M(w), 575; and PPG-PEG-PPG M(w), 2000) has caused significant changes in tocopherol-specific release properties. High-performance liquid chromatography coupled to PDA-FL and PDA-MS was used to test tocopherol and chain extender migration, respectively. The release of tocopherol from the prepared films with two chain extenders into two food simulants was studied. Different temperatures and storage times were also tested. Varying the structural features of the films with the incorporation of different levels of PPG-PEG-PPG, the release of tocopherol (food-packaging additive) into different ethanolic simulants could be clearly controlled. The effect of the temperature and storage time on the release of the antioxidant has been outstanding as their values increased. The migration of the chain extender, also tested, was well below the limits set by European legislation. PMID- 22846037 TI - The control of photochromism of [3H]-naphthopyran derivatives with intramolecular CH-pi bonds. AB - The photochromism of [3H]-naphthopyran derivatives can be switched from T-type to inverse- or P-type through the manipulation of relative thermodynamic stabilities of open isomers with intramolecular CH-pi bonds. PMID- 22846038 TI - Distinctive expression patterns and roles of the miRNA393/TIR1 homolog module in regulating flag leaf inclination and primary and crown root growth in rice (Oryza sativa). AB - * MicroRNA (miRNA)-mediated regulation of auxin signaling components plays a critical role in plant development. miRNA expression and functional diversity contribute to the complexity of regulatory networks of miRNA/target modules. * This study functionally characterizes two members of the rice (Oryza sativa) miR393 family and their target genes, OsTIR1 and OsAFB2 (AUXIN SIGNALING F-BOX), the two closest homologs of Arabidopsis TRANSPORT INHIBITOR RESPONSE 1 (TIR1). * We found that the miR393 family members possess distinctive expression patterns, with miR393a expressed mainly in the crown and lateral root primordia, as well as the coleoptile tip, and miR393b expressed in the shoot apical meristem. Transgenic plants overexpressing miR393a/b displayed a severe phenotype with hallmarks of altered auxin signaling, mainly including enlarged flag leaf inclination and altered primary and crown root growth. Furthermore, OsAFB2- and OsTIR1-suppressed lines exhibited increased inclination of flag leaves at the booting stage, resembling miR393-overexpressing plants. Moreover, yeast two hybrid and bimolecular fluorescence complementation assays showed that OsTIR1 and OsAFB2 interact with OsIAA1. * Expression diversification of miRNA393 implies the potential role of miRNA regulation during species evolution. The conserved mechanisms of the miR393/target module indicate the fundamental importance of the miR393-mediated regulation of auxin signal transduction in rice. PMID- 22846039 TI - ACC deaminase genes are conserved among Mesorhizobium species able to nodulate the same host plant. AB - Rhizobia strains expressing the enzyme 1-aminocyclopropane-1-carboxylate (ACC) deaminase have been reported to display an augmented symbiotic performance as a consequence of lowering the plant ethylene levels that inhibit the nodulation process. Genes encoding ACC deaminase (acdS) have been studied in Rhizobium spp.; however, not much is known about the presence of acdS genes in Mesorhizobium spp. The aim of this study was to assess the prevalence and phylogeny of acdS genes in Mesorhizobium strains including a collection of chickpea-nodulating mesorhizobia from Portugal. ACC deaminase genes were detected in 10 of 12 mesorhizobia type strains as well as in 18 of 18 chickpea Mesorhizobium isolates studied in this work. No ACC deaminase activity was detected in any Mesorhizobium strain tested under free-living conditions. Despite the lack of ACC deaminase activity, it was possible to demonstrate that in Mesorhizobium ciceri UPM-Ca7(T) , the acdS gene is transcribed under symbiotic conditions. Phylogenetic analysis indicates that strains belonging to different species of Mesorhizobium, but nodulating the same host plant, have similar acdS genes, suggesting that acdS genes are horizontally acquired by transfer of the symbiosis island. This data, together with analysis of the symbiosis islands from completely sequenced Mesorhizobium genomes, suggest the presence of the acdS gene in a Mesorhizobium common ancestor that possessed this gene in a unique symbiosis island. PMID- 22846041 TI - Reaction CH3 + OH studied over the 294-714 K temperature and 1-100 bar pressure ranges. AB - Reaction of methyl radicals with hydroxyl radicals, CH(3) + OH -> products (1) was studied using pulsed laser photolysis coupled to transient UV-vis absorption spectroscopy over the 294-714 K temperature and 1-100 bar pressure ranges (bath gas He). Methyl radicals were produced by photolysis of acetone at 193.3 nm. Hydroxyl radicals were generated in reaction of electronically excited oxygen atoms O((1)D), produced in the photolysis of N(2)O at 193.3 nm, with H(2)O. Temporal profiles of CH(3) were recorded via absorption at 216.4 nm using xenon arc lamp and a spectrograph; OH radicals were monitored via transient absorption of light from a dc discharge H(2)O/Ar low pressure resonance lamp at ca. 308 nm. The absolute intensity of the photolysis light inside the reactor was determined by an accurate in situ actinometry based on the ozone formation in the presence of molecular oxygen. The results of this study indicate that the rate constant of reaction 1 is pressure independent within the studied pressure and temperature ranges and has slight negative temperature dependence, k(1) = (1.20 +/- 0.20) * 10(-10)(T/300)(-0.49) cm(3) molecule(-1) s(-1). PMID- 22846042 TI - Caring for people with chronic disease: is 'muddling through' the best way to handle the multiple complexities? AB - It is stated everywhere that chronic care poses one of the biggest challenges for the future of medicine. Critical analysis however suggests that these statements are oversimplistic and based on limited, and at times, spurious assumptions. This paper highlights some basic realities: epidemiology shows that at any time, 80% of people experience 'good enough health', and that only 0.8% require tertiary medical care; most people with chronic conditions experience a stable illness trajectory; 'true' multi-morbidity is a pattern of advanced age; ageing and the physiological decline of our organ systems is a slow and steady process starting at the age of 30; and, as our health declines in a variety of patterns with disease and ageing, our psycho-socio-semiotic care needs increase dramatically. I argue that managing the complexities associated with chronic disease care successfully requires an equally complex management approach, 'muddling through', defined by Lindblom as making decisions based on successive limited comparisons. Our patients - rightly - expect that we make these decisions in their best interest. Individual health care professionals and health care policy makers firmly need to put the patient at the centre of the health care system. PMID- 22846033 TI - Depressive symptom severity is related to poorer cognitive performance in prodromal Huntington disease. AB - OBJECTIVE: Depression is associated with more severe cognitive deficits in many neurological disorders, though the investigation of this relationship in Huntington disease (HD) has been limited. This study examined the relationship between depressive symptom severity and measures of executive functioning, learning/memory, and attention in prodromal HD. METHOD: Participants (814 prodromal HD, 230 gene-negative) completed a neuropsychological test battery and the Beck Depression Inventory-II (BDI-II). Based on the BDI-II, there were 637 participants with minimal depression, 89 with mild depression, 61 with moderate depression, and 27 with severe depression in the prodromal HD group. RESULTS: ANCOVA (controlling for age, sex, and education) revealed that performance on SDMT, Trails B, Hopkins Verbal Learning Test--Revised (HVLT-R) Immediate Recall, and Stroop interference was significantly different between the BDI-II severity groups, with the moderate and severe groups performing worse than the minimal and mild groups. There were no significant differences between the BDI-II severity groups for Trails A or HVLT-R Delayed Recall. Linear regression revealed that both gene status and depression severity were significant predictors of performance on all cognitive tests examined, with contributions of BDI-II and gene status comparable for Trails A, SDMT, and Stroop interference. Gene status had a higher contribution for HVLT-R Immediate and Delayed Recall and Trails B. CONCLUSIONS: Our results suggest that depressive symptom severity is related to poorer cognitive performance in individuals with prodromal HD. Though there are currently no approved therapies for cognitive impairment in HD, our findings suggest that depression may be a treatable contributor to cognitive impairment in this population. PMID- 22846043 TI - Influence of nanoscale particle roughness on the stability of Pickering emulsions. AB - The wetting behavior of solid surfaces can be altered dramatically by introducing surface roughness on the nanometer scale. Some of nature's most fascinating wetting phenomena are associated with surface roughness; they have inspired both fundamental research and the adoption of surface roughness as a design parameter for man-made functional coatings. So far the attention has focused primarily on macroscopic surfaces, but one should expect the wetting properties of colloidal particles to be strongly affected by roughness, too. Particle wettability, in turn, is a key parameter for the adsorption of particles at liquid interfaces and for the industrially important use of particles as emulsion stabilizers; yet, the consequence of particle roughness for emulsion stability remains poorly understood. In order to investigate the matter systematically, we have developed a surface treatment, applicable to micrometer-sized particles and macroscopic surfaces alike, that produces surface coatings with finely tunable nanoscale roughness and identical surface chemistry. Coatings with different degrees of roughness were characterized with regard to their morphology, charging, and wetting properties, and the results were correlated with the stability of emulsions prepared with coated particles of different roughness. We find that the maximum capillary pressure, a metric of the emulsions' resistance to droplet coalescence, varies significantly and in a nonmonotonic fashion with particle roughness. Surface topography and contact angle hysteresis suggest that particle roughness benefits the stability of our emulsions as long as wetting occurs homogeneously (Wenzel regime), whereas the transition toward heterogeneous wetting (Cassie-Baxter regime) is associated with a loss of stability. PMID- 22846040 TI - Insights into the inhibition of the p90 ribosomal S6 kinase (RSK) by the flavonol glycoside SL0101 from the 1.5 A crystal structure of the N-terminal domain of RSK2 with bound inhibitor. AB - The p90 ribosomal S6 family of kinases (RSK) are potential drug targets, due to their involvement in cancer and other pathologies. There are currently only two known selective inhibitors of RSK, but the basis for selectivity is not known. One of these inhibitors is a naturally occurring kaempferol-alpha-L diacetylrhamnoside, SL0101. Here, we report the crystal structure of the complex of the N-terminal kinase domain of the RSK2 isoform with SL0101 at 1.5 A resolution. The refined atomic model reveals unprecedented structural reorganization of the protein moiety, as compared to the nucleotide-bound form. The entire N-lobe, the hinge region, and the alphaD-helix undergo dramatic conformational changes resulting in a rearrangement of the nucleotide binding site with concomitant formation of a highly hydrophobic pocket spatially suited to accommodate SL0101. These unexpected results will be invaluable in further optimization of the SL0101 scaffold as a promising lead for a novel class of kinase inhibitors. PMID- 22846044 TI - Genetics in neural toxicities of drugs. AB - Adverse side effects or toxicities of a drug were previously regarded as a manifestation of drug's own characterizations, such as the chemical structure and property of a drug. More recently, increasing experimental or clinical data and modern ideas suggest that human's genetic factors also play indispensable roles in resulting neural side effects of a drug, especially in antidepressant-induced suicide and antibiotics-induced hearing loss. However, there are many questions and technological obstacles (including high costs and limited samples) in these kinds of researches and this makes genetic study of drug toxicities in its initial stage. In this review, we in depth address and analysis of this matter from some new perspectives and propose some new initiatives to improve this type of researches in future. It is also highly needed to expedite the translation of these pharmacogenetic concepts from bench to bedside. PMID- 22846045 TI - Savior siblings, parenting and the moral valorization of children. AB - Philosophy has long been concerned with 'moral status'. Discussions about the moral status of children, however, seem often to promote confusion rather than clarity. Using the creation of 'savior siblings' as an example, this paper provides a philosophical critique of the moral status of children and the moral relevance of parenting and the role that formative experience, regret and relational autonomy play in parental decisions. We suggest that parents make moral decisions that are guided by the moral significance they attach to children, to sick children and most importantly, to a specific sick child (theirs). This moral valorization is rarely made explicit and has generally been ignored by both philosophers and clinicians in previous critiques. Recognizing this, however, may transform not only the focus of bioethical discourse but also the policies and practices surrounding the care of children requiring bone marrow or cord blood transplantation by better understanding the values at stake behind parental decision making. PMID- 22846047 TI - Exposure to factor VIII and prediction of inhibitor development: exposure days vs. danger days, or both? PMID- 22846046 TI - 2009 pandemic influenza A (H1N1): clinical and laboratory characteristics in pediatric and adult patients and in patients with pulmonary involvement. AB - BACKGROUND: To better understand clinical and laboratory characteristics in children, adults, and patients with lung involvement suffering 2009 pandemic influenza A (H1N1). METHODS: A total of 442 patients with 2009 pandemic influenza A (H1N1) were retrospectively analyzed. RESULTS: Comparing to their adult counterpart (n=55), pediatric patients (n=387) had significantly higher frequencies of fever, rhinorrhea, cough, sore throat, nausea/vomiting, and longer length of fever; lower frequencies of chest pain and dyspnea; higher incidence of lymphopenia; and lower incidence of elevated serum C-reactive protein. Among the 227 patients with radiographs available, lung involvement was found in 19 (8.4%) (52.6% consolidation and 47.4% interstitial infiltrations), including 18 children and one adult. One child with lung consolidation died of multiorgan failure. Significant findings in patients with lung involvement included predominant young age (<= 10 years), prolonged fever, and delayed oseltamivir therapy (>= 48 hours after onset of illness); higher frequencies of dyspnea, nausea/vomiting, and altered consciousness; and higher incidences of leukopenia, elevated serum creative kinase, and lactic dehydrogenase. CONCLUSIONS: Among patients with 2009 pandemic influenza A (H1N1), we found significant difference in clinical manifestations between children and adults, and significant differences in clinical and laboratory manifestations between patients with lung involvement and those without. On the basis of data from this study and the existing literature, early treatment with oseltamivir is recommended for patients with 2009 pandemic influenza A (H1N1), regardless of age. PMID- 22846048 TI - Patient and parent preferences for immunoglobulin treatments: a conjoint analysis. AB - OBJECTIVES: The purpose was to quantify patient and parent preferences for administration attributes of immunoglobulin (IG) treatments; and determine which administration attributes were most important to users of IG treatment and whether patients and parents have similar preferences for administration attributes. METHODS: US adult patients and parents of children with a self reported physician diagnosis of a primary immunodeficiency disorder completed a best-practice web-enabled choice-format conjoint survey that presented a series of 12 choice questions, each including a pair of hypothetical IG-treatment profiles. After reviewing current therapies, each profile was defined by mode of administration, frequency, location, number of needle sticks, and treatment duration. Before answering the choice questions, respondents were told to assume all treatments worked equally well. Choice questions were based on a D-efficient experimental design. Preference weights for attribute levels were estimated using random-parameters logit for each sample (adult patients and parents). Tests were performed to determine potential interactions among the administration attributes. All respondents provided online informed consent. RESULTS: In total, 252 patients and 66 parents completed the choice questions appropriately. Overall, both groups preferred a home setting, monthly frequency, fewer needle sticks, and shorter treatment durations of IG treatment relative to alternative choices (p<0.05). Mode of administration was the least important attribute to both samples; however, parents strongly preferred self-administration to an appointment with a healthcare professional (p<0.05), whereas patients slightly preferred self-administration but were indifferent to the two modes. LIMITATIONS: Respondents evaluate hypothetical treatments and differences can arise between stated and actual choices. CONCLUSIONS: Considering the hypothetical treatments evaluated, IG treatments that provide the option of a home setting, monthly frequency, fewer needle sticks, and shorter treatment durations may address the needs of both patients and parents. Patients and parents have different preferences for administration attributes of IG treatments. PMID- 22846049 TI - Validation of self-reported pain reduction after diagnostic blockade. AB - OBJECTIVE: The criterion commonly used to determine whether radiofrequency neurotomy may be recommended is based on patient-reported, short-term pain relief following facet block injections. This study evaluated the concordance between two commonly used outcomes for pain relief: the pain numerical rating scale (NRS) and the global perceived improvement (GPI) scale. DESIGN: This is a retrospective cohort study. METHODS: Data were obtained from a consecutive cohort of patients through a review of the electronic medical records, with the following inclusion criteria: medial branch facet blocks at either cervical or lumbar spinal regions. OUTCOME MEASURES: Pain NRS (baseline, postprocedure, and hourly up to 6 hours) and GPI scale are expressed as percent improvement at 6 hours, relative to baseline. RESULTS: The percent improvement in pain NRS corresponded to 49%, 43%, 34%, 21%, and 36% for baseline vs immediately post-block, 1 hour, 3 hours, 6 hours and average of all postscores, respectively. Average GPI reported at 6 hours was 44%, and differed significantly only to the baseline vs 6 hours percent improvement on the NRS (P < 0.01). Multiple regression analysis indicated that there were no demographic or baseline factors that accounted for the discrepancy between GPI vs NRS. CONCLUSIONS: Asking patients about their pain relief in retrospect can be misleading. It is possible that patients' report on the GPI is weighed by their total experience of pain reduction and retrospective recall. Therefore, when choosing to address percent improvement on NRS measures, it is important to take into account multiple instances of NRS measures following treatment. PMID- 22846051 TI - Hydrodebromination of decabromodiphenyl ether (BDE-209) in cooking experiments with salmon fillet. AB - Polybrominated diphenyl ethers (PBDEs) are environmental contaminants regularly detected in biota and food. Seafood has been identified as the major dietary source for human uptake. Fish is predominantly consumed after cooking, and this process may alter the actual human intake of contaminants. This study thus aimed to investigate the fate of PBDEs in this cooking process. Heating of fish fortified with 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) at typical cooking conditions (200 degrees C, in plant oil) resulted in a decrease of its concentration in favor of the formation of lower brominated congeners. After 15 min, ~25% of BDE-209 was transformed into nona- to octabrominated congeners. The major transformation route was BDE-209 -> BDE-206 -> BDE-196 and BDE-199. Low amounts of heptabrominated congeners as well as one hexabromodibenzofuran and a heptabromodibenzofuran isomer were also detected. However, penta- and tetrabrominated diphenyl ethers were not observed, and heating of BDE-47 did not produce new transformation products. PMID- 22846050 TI - Efficiency of responding to unexpected information varies with sex, age, and pubertal development in early adolescence. AB - Entry into adolescence is marked by dramatic changes resulting from a dynamic interplay among biological and psychosocial processes. Despite the complexity, development is often indexed only by age in event-related potential (ERP) studies. To broaden this approach, we address the effects of gender and pubertal development, along with age, in adolescents using a psychophysiological probe of decision making, the P300 component. Overall, girls exhibited shorter P300 latencies and smaller P300 amplitudes compared to boys, suggesting more efficient information processing. In both genders, P300 latency and amplitude also diminished as age and pubertal status increased, again suggesting increasing efficiency of information processing with development. Our findings highlight the necessity of considering more than age when examining cognitive functioning in adolescents and, in particular, the necessity of considering gender whenever developmental issues are addressed. PMID- 22846052 TI - Dual regulation of P-glycoprotein expression by trichostatin A in cancer cell lines. AB - BACKGROUND: It has been reported that the histone deacetylase inhibitor (iHDAc) trichostatin A (TSA) induces an increase in MDR1 gene transcription (ABCB1). This result would compromise the use of iHDACs in combination with other cytotoxic agents that are substrates of P-glycoprotein (Pgp). It has also been reported the use of alternative promoters by the ABCB1 gene and the existence of a translational control of Pgp protein. Finally, the ABCB1 gene is located in a genetic locus with the nested gene RUNDC3B in the complementary DNA strand, raising the possibility that RUNDC3B expression could interfere with ABCB1 alternative promoter regulation. METHODS: A combination of RT-PCR, real time RT PCR, Western blot and drug accumulation assays by flow cytometry has been used in this study. RESULTS: The iHDACs-induced increase in MDR1 mRNA levels is not followed by a subsequent increase in Pgp protein levels or activity in several pancreatic and colon carcinoma cell lines, suggesting a translational control of Pgp in these cell lines. In addition, the MDR1 mRNA produced in these cell lines is shorter in its 5' end that the Pgp mRNA produced in cell lines expressing Pgp protein. The different size of the Pgp mRNA is due to the use of alternative promoters. We also demonstrate that these promoters are differentially regulated by TSA. The translational blockade of Pgp mRNA in the pancreatic carcinoma cell lines could be related to alterations in the 5' end of the MDR1 mRNA in the Pgp protein expressing cell lines. In addition, we demonstrate that the ABCB1 nested gene RUNDC3B expression although upregulated by TSA is independent of the ABCB1 alternative promoter used. CONCLUSIONS: The results show that the increase in MDR1 mRNA expression after iHDACs treatment is clinically irrelevant since this mRNA does not render an active Pgp protein, at least in colon and pancreatic cancer cell lines. Furthermore, we demonstrate that TSA in fact, regulates differentially both ABCB1 promoters, downregulating the upstream promoter that is responsible for active P-glycoprotein expression. These results suggest that iHDACs such as TSA may in fact potentiate the effects of antitumour drugs that are substrates of Pgp. Finally, we also demonstrate that TSA upregulates RUNDC3B mRNA independently of the ABCB1 promoter in use. PMID- 22846053 TI - Treatment of pythiosis in equine limbs using intravenous regional perfusion of amphotericin B. AB - OBJECTIVE: To evaluate the effects of intravenous regional limb perfusion (IRLP) administration of amphotericin B in horses to treat pythiosis after surgical excision and thermocautery. STUDY DESIGN: Case series. ANIMALS: Horses (n = 12) with Pythium insidiosum infection of the distal aspect of the thoracic or pelvic limbs. METHODS: After surgical excision of granulation tissue and thermocautery, 50 mg amphotericin B was administered by IRLP through a catheter placed in a superficial vein of the affected limb next to the lesion after placing a tourniquet above the injection site. The lesions and locomotor system were evaluated before treatment and at 7, 14, 21, 28, 35, and 60 days. RESULTS: Ninety two percent of horses treated with amphotericin B had complete lesion resolution 35 or 60 days after 1 or 2 IRLP treatments, respectively. IRLP induced limb edema and pain during regional palpation in 42%, and inflammation of the injection site in 33% of horses; however these signs resolved after 14 days. CONCLUSIONS: IRLP administration of amphotericin B was effective for treating pythiosis in equine limbs, resolving infection with manageable side effects. PMID- 22846054 TI - Role of recently evolved miRNA regulation of sunflower HaWRKY6 in response to temperature damage. AB - MicroRNAs (miRNAs) are small 21-nucleotide RNAs that post-transcriptionally regulate gene expression. MiR396 controls leaf development by targeting GRF and bHLH transcription factors in Arabidopsis. WRKY transcription factors, unique to plants, have been identified as mediating varied stress responses. The sunflower (Helianthus annuus) HaWRKY6 is a particularly divergent WRKY gene exhibiting a putative target site for the miR396. A possible post-transcriptional regulation of HaWRKY6 by miR396 was investigated. Here, we used expression analyses, performed by quantitative reverse transcription polymerase chain reaction (qRT PCR) and northern blots together with computational approaches to establish the regulatory interaction between HaWRKY6 and the identified sunflower miR396. Arabidopsis plants expressing a mi396-resistant version of HaWRKY6 confirmed the miRNA-dependency of the HaWRKY6 silencing. Sunflower plants exposed to high temperatures or salicylic acid presented opposite expression of HaWRKY6 and miR396. Experiments using the wildtype and miRNA-resistant versions of HaWRKY6 showed altered stress responses. Our results showed a role of the recently evolved miR396 regulation of HaWRKY6 during early responses to high temperature. Our study reveals how a miRNA that normally regulates development has been recruited for high-temperature protection in sunflower, a plant particularly well adapted to this type of stress. PMID- 22846055 TI - Karaji: mathematician and qanat master. PMID- 22846056 TI - A critical analysis and discussion of clinical research ethics in the Russian Federation and their implications for Western sponsored trials. AB - Globalization, political upheavals, and Western economic struggles have caused a geographical reprioritization in the realm of drug development and human clinical research. Regulatory and cost hurdles as well as a saturation of research sites and subjects in Western countries have forced the pharmaceutical industry to place an unprecedented level of importance on emerging markets, injecting Western corporate initiatives into cultures historically and socially isolated from Western-centric value systems. One of the greatest recipients of this onslaught of Western business and research practices is the Russian Federation. Namely, market forces are dictating a focused research initiative in the traditional emerging markets, but this focus may be at the expense of individual and societal dignity. PMID- 22846058 TI - Protecting-group-free synthesis of glycosyl 1-phosphates. AB - Glycosyl 1-phosphates enriched in the alpha-anomer are obtained without the use of protecting groups in two steps starting from the free hemiacetal. Condensation of free hemiacetals with toluenesulfonylhydrazide yields a range of glycosylsulfonohydrazide donors which can be oxidized using cupric chloride in the presence of phosphoric acid and the coordinating additive 2-methyl-2 oxazoline to give useful yields of the fully deprotected glycosyl 1-phosphates. PMID- 22846057 TI - Primary care providers' views on chronic pain management among high-risk patients in safety net settings. AB - OBJECTIVE: We examined chronic pain management practices and confidence and satisfaction levels in treating chronic pain among primary care providers (PCPs) who cared for high-risk patients in safety net health settings. DESIGN: We recruited PCPs (N = 61) through their HIV-infected patients who were enrolled in a longitudinal study on pain, use, and misuse of opioid analgesics (Pain Study). We asked PCPs to complete a questionnaire about all of their patients in their practice on the prevalence of chronic pain and illicit substance use, use of opioid analgesics, confidence and satisfaction levels in treating chronic pain, and likelihood of prescribing opioid analgesics in response to clinical vignettes. RESULTS: All PCPs cared for at least some patients with chronic pain, and the majority prescribed opioid analgesics for its treatment. All PCPs cared for at least some patients who used illicit substances. PCPs reported low confidence and satisfaction levels in treating chronic pain. The majority (73.8%) of PCPs were highly likely to prescribe opioid analgesics to a patient without a history of substance use who had chronic pain. The majority (88.5%) were somewhat to highly likely to prescribe opioid analgesics to a patient with a prior history of substance use but not active use. Most (67.2%) were somewhat to highly likely to prescribe opioids to a patient with active substance use. CONCLUSION: In order to improve PCPs' confidence and satisfaction in managing chronic pain, further work should explore the root causes of low confidence and satisfaction and also explore possible remedies. PMID- 22846059 TI - Physical activity reduces bone loss in the distal forearm in post-menopausal women--a 25-year prospective study. AB - Intervention studies have shown that high-intensity training programs with duration of 1-3 years can influence bone mass in post-menopausal women. We wanted to investigate whether moderate physical activity could be associated with reduced post-menopausal bone loss also in the long-term perspective. We evaluated changes in bone mass and bone structure by repeated single-photon absorptiometry measurements of the distal forearm in 91 moderately physically active and 21 inactive women, categorized according to information from questionnaires, from menopause and on average 25 years onwards. Data were calculated with analysis of variance and analysis of covariance tests and presented as means with 95% confidence interval. There were no group differences in bone mass or bone structure at menopause. The mean annual loss in bone mineral content was 1.2% (1.1, 1.3) in the physically active and 1.6% (1.3, 1.8) in the inactive women (after adjustment for menopausal age P = 0.02) and the mean decline in a strength index based on bone mass and bone structure was 0.7% (0.6, 0.8) in the physically active and 1.2% (0.8, 1.5) in the inactive women (P = 0.004). There were no group differences in the changes in bone structure. Physical activity is also in a long term perspective associated with reduced post-menopausal bone loss. PMID- 22846060 TI - Easy guide to searching for evidence for the busy clinician. AB - The busy clinician is constantly faced with clinical questions regarding patient care. It is easy to feel overwhelmed by the large amount of health information available electronically. This article offers one easy approach for searching the electronic database. It is intended for the busy clinician who is unsure how to conduct an electronic search. It provides guidance on where to search and how to search using the PICO search method. It also provides a list of useful resources to help clinicians critically appraise the articles found to determine its relevance. PMID- 22846061 TI - TonB-dependent transporter FhuA in planar lipid bilayers: partial exit of its plug from the barrel. AB - TonB-dependent transporters (TBDTs), which transport iron-chelating siderophores and vitamin B(12) across the outer membrane of Gram-negative bacteria, share a conserved architecture of a 22-stranded beta-barrel with an amino-terminal plug domain occluding the barrel. We previously reported that we could induce TBDTs to reversibly open in planar lipid bilayers via the use of urea and that these channels were responsive to physiological concentrations of ligands. Here we report that in the presence of urea, trypsin can cleave the amino-terminal 67 residues of the plug of the TonB-dependent transporter FhuA, as assessed by gel shift and mass spectrometry assays. On the bilayer, trypsin treatment in the presence of urea resulted in the induced conductance no longer being reversed upon removal of urea, suggesting that urea opens intact FhuA channels by pulling the plug at least partly out of the barrel and that removal of the urea then allows reinsertion of the plug into the barrel. When expressed separately, the FhuA plug domain was found to be a mostly unfolded structure that was able to occlude isolated FhuA beta-barrels inserted into the membrane. Thus, although folded in the barrel, the plug need not be folded upon exiting the barrel. The rate of insertion of the beta-barrels into the membrane was tremendously increased in the presence of an osmotic gradient provided by either urea or glycerol. Negative staining electron microscopy showed that FhuA in a detergent solution formed vesicles, thus explaining why an osmotic gradient promoted the insertion of FhuA into membranes. PMID- 22846062 TI - Personality plasticity in later adulthood: contextual and personal resources are needed to increase openness to new experiences. AB - The central objective of the present study was to investigate whether it would be possible to facilitate increases in openness to new experiences in later adulthood. Specifically, we investigated whether individuals with higher internal control beliefs (personal resource) provided with training to successfully prepare them for a challenging volunteering context (contextual resources) would increase in openness. Participants of the training program (n = 148, 44-72 years, Mage = 62.80) and a control group of volunteers (n = 92, 46-80 years, Mage = 63.01) were assessed 3 times: before the training program (T0), after the training program (T1), and 1 year later (T2). As expected, there was a significant training by internal control beliefs interaction such that participants of the training program with higher internal control beliefs increased significantly in openness relative to control participants between T1 and T2. The current study provides evidence for the plasticity of personality in later adulthood and confirms the importance of both personal and contextual resources. PMID- 22846063 TI - Rapid and extensive debromination of decabromodiphenyl ether by smectite clay templated subnanoscale zero-valent iron. AB - Subnanoscale zerovalent iron (ZVI) synthesized using smectite clay as a template was utilized to investigate reduction of decabromodiphenyl ether (DBDE). The results revealed that DBDE was rapidly debrominated by the prepared smectite templated ZVI with a reaction rate 10 times greater than that by conventionally prepared nanoscale ZVI. This enhanced reduction is plausibly attributed to the smaller-sized smectite-templated ZVI clusters (~0.5 nm) vs that of the conventional nanoscale ZVI (~40 nm). The degradation of DBDE occurred in a stepwise debromination manner. Pentabromodiphenyl ethers were the terminal products in an alkaline suspension (pH 9.6) of smectite-templated ZVI, whereas di , tri-, and tetrabromodiphenyl ethers formed at the neutral pH. The presence of tetrahydrofuran (THF) as a cosolvent at large volume fractions (e.g., >70%) in water reduced the debromination rates due to enhanced aggregation of clay particles and/or diminished adsorption of DBDE to smectite surfaces. Modification of clay surfaces with tetramethylammonium (TMA) attenuated the colsovent effect on the aggregation of clay particles, resulting in enhanced debromination rates. Smectite clay provides an ideal template to form subnanoscale ZVI, which demonstrated superior debromination reactivity with DBDE compared with other known forms of ZVIs. The ability to modify the nature of smectite clay surface by cation exchange reaction utilizing organic cations can be harnessed to create surface properties compatible with various contaminated sites. PMID- 22846064 TI - Reliability and validity of a new instrument to measure tolerance of everyday risk for children. AB - BACKGROUND: A modicum of everyday risk provides opportunities for children to extend the limits of their competence. However, increasingly negative perceptions of risk have led to risk-averse behaviours in adults, including severely restricting children's play. The degree to which risk in play is tolerated by adults impacts on the lives and experiences of children. However, no measure of adult tolerance to everyday risk exists. The purpose of this study was to develop a valid and reliable instrument examining adults' tolerances of risk during children's play. METHODS: A 31-item survey of risk tolerance was developed based on a Norwegian model of risky play; 100 parents and teachers of children aged 3 to 13 years completed the instrument. Data were subjected to Rasch analysis. Psychometric properties of the data were examined. RESULTS: Iterative analyses produced an instrument with goodness of fit statistics in the acceptable range, a logical item hierarchy, person separation index >2 and reliability index of 0.87. There was a strong positive relationship between participants' self-perceived risk tolerance and scores on the instrument, and between the age of the child and scores on the instrument. CONCLUSIONS: The Tolerance of Risk in Play Scale (TRiPS) yields valid and reliable data for measuring the success of interventions to change adults' everyday risk beliefs, and for exploring the impact of adults' risk tolerance on children's play and development. PMID- 22846065 TI - Stimulation of macrophages by immunobiotic Lactobacillus strains: influence beyond the intestinal tract. AB - Lactobacillus rhamnosus CRL1505 (Lr1505), L. rhamnosus CRL1506 (Lr1506) and L. casei CRL431 (Lc431) are able to stimulate intestinal immunity, but only Lr1505 and Lc431 are able to stimulate immunity in the respiratory tract. With the aim of advancing the understanding of the immunological mechanisms involved in stimulation of distant mucosal sites, this study evaluated the effects of orally administered probiotics on the functions of alveolar and peritoneal macrophages. Compared to a control group, these three lactobacilli were able to significantly increase phagocytic and microbicidal activities of peritoneal macrophages. After intraperitoneal challenge with pathogenic Candida albicans, mice treated with immunobiotics had significantly lower pathogen counts in infected organs. Moreover, lactobacilli-treated mice had a stronger immune response against C. albicans. On the other hand, only Lc1505 and Lc431 were able to improve activity of and cytokine production by alveolar macrophages. Only in these two groups was there better resistance to respiratory challenge with C. albicans, which correlated with improved respiratory immune response. The results of this study suggest that consumption of some probiotic strains could be useful for improving resistance to infections in sites distant from the gut by increasing the activity of macrophages at those sites. PMID- 22846066 TI - Functional recovery ten years after pediatric traumatic brain injury: outcomes and predictors. AB - Functional impairments (adaptive, behavioral, educational) are common after preschool traumatic brain injury (TBI). In comparison with cognitive outcome, functional outcomes have received limited attention, with little evidence to determine whether these difficulties persist in the long term. The aim of this study was to examine functional outcomes at 10 years post-injury and identify predictors of outcome. The study compared children with a diagnosis of TBI (n=40) to a healthy age-, gender-, and socioeconomic status (SES)-matched control group (n=19) at 10 years post-injury. Outcomes and predictors of functional skills were investigated. Poorer adaptive skills were evident for those with more severe injury. Behavioral difficulties were present regardless of injury severity. Post injury, arithmetic skills were the most compromised in the longer term. Pre injury status, interventions accessed, and acute intellectual function were significant predictors of outcome. These results highlight the importance of monitoring functional skills in the long term, especially for those children presenting with risk factors. PMID- 22846067 TI - Inherited thrombocytopenias: an approach to diagnosis and management. AB - Inherited thrombocytopenias vary in their presentation, associated features, and molecular etiologies. An accurate diagnosis is important to provide appropriate therapy as well as counseling for the individual and their family members. As the genetic basis of more disorders is understood, it will be possible to diagnose a greater fraction of patients as well as learn more about the process of megakaryopoiesis and platelet production. PMID- 22846068 TI - Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study. AB - BACKGROUND: Risk factors for post-thrombotic syndrome (PTS) remain poorly understood. OBJECTIVES: In this multinational multicenter study, we evaluated whether subtherapeutic warfarin anticoagulation was associated with the development of PTS. METHODS: Patients with a first unprovoked deep venous thrombosis (DVT) received standard anticoagulation for 5-7 months and were then assessed for PTS. The time in the therapeutic range was calculated from the international normalized ratio (INR) data. An INR below 2, more than 20% of the time, was considered as subtherapeutic anticoagulation. RESULTS: Of the 349 patients enrolled, 97 (28%) developed PTS. The overall frequency of PTS in patients with subtherapeutic anticoagulation was 33.5%, compared with 21.6% in those with an INR below two for <= 20% of the time (P = 0.01). During the first 3 months of therapy, the odds ratio (OR) for developing PTS if a patient had subtherapeutic anticoagulation was 1.78 (95% confidence interval [CI] 1.10-2.87). After adjusting for confounding variables, the OR was 1.84 (95% CI 1.13-3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14 3.00) [crude] and 1.88 (95% CI 1.15-3.07) [adjusted]. CONCLUSION: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT was significantly associated with the development of PTS. PMID- 22846069 TI - Modified vaginal dilation rat model for postpartum stress urinary incontinence. AB - AIM: The aim of this study was to develop a modified rat model for postpartum stress urinary incontinence (SUI) which can be easily established and which will steadily evaluate urodynamic changes. MATERIAL AND METHODS: A urinary catheter was placed into the vaginas of rats (n=40) and the balloon was inflated for 8 h to simulate labor. A whisker was inserted into the nostril to induce sneezing. The urodynamic changes induced by vaginal dilation or sneezing were observed by measurement of leak point pressure (LPP), and maximum bladder volume. Serum lactose dehydrogenase (LDH) and creatine kinase (CK) were tested, and the mRNA expression of caspase-3 in pubococcygeus muscle tissue was measured to show the effect of muscle injury in SUI. RESULTS: After 8 h of balloon vaginal dilation, a rat model of postpartum SUI was established with a success rate of 72.5% (29/40). By sneeze assay, SUI was noted in 100% (5/5), 80% (4/5), 60% (3/5), 60% (3/5) and 40% (2/5) of experimental rats on day 1, 7, 14, 28 and 56, respectively. No SUI was found in the control group (n=10). The level of serum LDH and CK in these 29 experimental rats initially increased, peaked on day 7, and finally decreased toward normal values. Compared with control rats, the differences were significant (P<0.05). The expression of the caspase-3 gene in pubococcygeal muscle of experimental rats peaked on day 1 and decreased thereafter, while no such change was seen in the control group, and the difference was significant (P<0.05). CONCLUSION: Eight hours of vaginal balloon dilation resulted in SUI in this rat model. The alterations in serum LDH and CK, and in the muscle's apoptotic genes mimic those observed in human postpartum SUI patients. It can therefore be considered as a useful animal model for the study on the pathogenesis of postpartum SUI. PMID- 22846070 TI - Phosphorus diffusion gettering process of multicrystalline silicon using a sacrificial porous silicon layer. AB - The aims of this work are to getter undesirable impurities from low-cost multicrystalline silicon (mc-Si) wafers and then enhance their electronic properties. We used an efficient process which consists of applying phosphorus diffusion into a sacrificial porous silicon (PS) layer in which the gettered impurities have been trapped after the heat treatment. As we have expected, after removing the phosphorus-rich PS layer, the electrical properties of the mc-Si wafers were significantly improved. The PS layers, realized on both sides of the mc-Si substrates, were formed by the stain-etching technique. The phosphorus treatment was achieved using a liquid POCl3-based source on both sides of the mc Si wafers. The realized phosphorus/PS/Si/PS/phosphorus structures were annealed at a temperature ranging between 700 degrees C and 950 degrees C under a controlled O2 atmosphere, which allows phosphorus to diffuse throughout the PS layers and to getter eventual metal impurities towards the phosphorus-doped PS layer. The effect of this gettering procedure was investigated by means of internal quantum efficiency and the dark current-voltage (I-V) characteristics. The minority carrier lifetime measurements were made using a WTC-120 photoconductance lifetime tester. The serial resistance and the shunt resistance carried out from the dark I-V curves confirm this gettering-related solar cell improvement. It has been shown that the photovoltaic parameters of the gettered silicon solar cells were improved with regard to the ungettered one, which proves the beneficial effect of this gettering process on the conversion efficiency of the multicrystalline silicon solar cells. PMID- 22846071 TI - Role of functionally dominant species in varying environmental regimes: evidence for the performance-enhancing effect of biodiversity. AB - BACKGROUND: Theory suggests that biodiversity can act as a buffer against disturbances and environmental variability via two major mechanisms: Firstly, a stabilising effect by decreasing the temporal variance in ecosystem functioning due to compensatory processes; and secondly, a performance enhancing effect by raising the level of community response through the selection of better performing species. Empirical evidence for the stabilizing effect of biodiversity is readily available, whereas experimental confirmation of the performance enhancing effect of biodiversity is sparse. RESULTS: Here, we test the effect of different environmental regimes (constant versus fluctuating temperature) on bacterial biodiversity-ecosystem functioning relations. We show that positive effects of species richness on ecosystem functioning are enhanced by stronger temperature fluctuations due to the increased performance of individual species. CONCLUSIONS: Our results provide evidence for the performance enhancing effect and suggest that selection towards functionally dominant species is likely to benefit the maintenance of ecosystem functioning under more variable conditions. PMID- 22846072 TI - Polymer micelles with hydrophobic core and ionic amphiphilic corona. 2. Starlike distribution of charged and nonpolar blocks in corona. AB - Mixed polymer micelles with hydrophobic polystyrene (PS) core and ionic amphiphilic poly(4-vinylpyridine)/poly(N-ethyl-4-vinylpyridinium bromide) corona (P4VP/PEVP) spontaneously self-assembled from mixtures of PS-b-PEVP and PS-b-P4VP macromolecules in dimethylformamide/methanol/water selective solvent. The fraction of PEVP units in corona was beta = [PEVP]/([PEVP] + [P4VP]) = 0.05-1.0. Micelles were transferred into pure water via dialysis technique and pH was adjusted to 9, where P4VP blocks are insoluble. Structural characteristics of micelles as a function of corona composition beta were investigated. Methods of dynamic and static light scattering, electrophoretic mobility measurements, sedimentation velocity, transmission electron microscopy, and UV spectrophotometry were applied. Spherical morphology with core (PS)-shell (P4VP) corona (PEVP) organization was postulated. Micelles demonstrated a remarkable inflection in structural characteristics near beta ~ 0.5-0.7. Above this region, aggregation number (m), core and corona radii of mixed micelles coincided with those of individual PS-b-PEVP micelles. When beta decreased below 0.5, dramatic growth of aggregation number was observed, accompanied by growth in micelle size and stretching PEVP chains. At beta below 0.2, dispersions of mixed micelles were unstable and easily precipitated upon addition of NaCl. Scaling relationships between micelle characteristics and beta were obtained via minimization the micelle free energy, taking into account electrostatic, osmotic, volume, and surface contributions. Theoretical estimations predicted dramatic influence of beta on aggregation number, m ~ beta(-3). This result is in general agreement with experimental data and confirms the correctness of the core-shell-corona model. The inflection in micelle characteristics entails drastic changes in micelle dispersion stability in the presence of oppositely charged polymeric (sodium polymethacrylate) or amphiphilic (sodium dodecyl sulfate) complexing agents. PMID- 22846073 TI - Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital. AB - BACKGROUND: Antimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan. METHODS: The infection control team was involved in the review of individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial resistant bacteria and medical expenses. RESULTS: Prolonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second-generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin-resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram-negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship. CONCLUSION: Extensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay. PMID- 22846074 TI - Xylitol increases serum triglyceride in normal but not in a type 2 diabetes model of rats. PMID- 22846075 TI - Orthosiphon stamineus: traditional uses, phytochemistry, pharmacology, and toxicology. AB - Orthosiphon stamineus Benth. (Lambiaceae) is an important plant in traditional folk medicine. This review is a comprehensive summary of the currently available chemical, pharmacological, and toxicological investigations as well as the traditional and therapeutic uses of this plant. Different in vitro and in vivo models have been addressed along with a survey of all phytochemicals identified in this plant, including flavonoids, terpenoids, and essential oils. Previous studies revealed that O. stamineus possesses several pharmacological activities, which are attributed to its phytochemical content. It was found that O. stamineus exhibits diuretic, hypouricemic, renal protective, antioxidant, anti inflammatory, hepatoprotective, gastroprotective, antihypertensive, antidiabetic, antihyperlipidemic, antimicrobial, and anorexic activities. In conclusion, O. stamineus has wide traditional and pharmacological uses in various pathophysiological conditions. Therefore, it is an attractive subject for further experimental and clinical investigations. PMID- 22846076 TI - Antioxidant activities of chokeberry extracts and the cytotoxic action of their anthocyanin fraction on HeLa human cervical tumor cells. AB - The present study evaluates the antioxidant activity of two Aronia melanocarpa cultivars-Viking and Aron-and of Aronia prunifolia hybrid in relationship with their phytochemical composition regarding the contents of total phenolics, flavonoids, procyanidins, and monomeric anthocyanins. The antioxidant capacity of the mentioned extracts of chokeberries was evaluated through five complementary assays: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), H(2)O(2) scavenging potential, oxygen radical absorbance capacity, ferric reducing antioxidant power, and cupric ion reducing antioxidant capacity. A. prunifolia hybrid was found to have the highest antioxidant activity and to be the richest in polyphenols, procyanidins, and anthocyanins compared with the A. melanocarpa cultivars. A good correlation was observed between antioxidant activity and total procyanidin and anthocyanin content. Cyanidin glycosides inhibited HeLa human cervical tumor cell proliferation and increased generation of reactive oxygen species after 48 h of treatment, suggesting that they could be responsible for the antiproliferative activity. These results may be significant for industry concerning food quality and disease prevention. PMID- 22846077 TI - Systemic inflammatory load in young and old ringdoves is modulated by consumption of a Jerte Valley cherry-based product. AB - A chronic subclinical inflammatory status that coexists with immune dysfunction is commonly found in the elderly population. Consumption of foods rich in antioxidants (e.g., cherries) is an attractive strategy to reduce risk from chronic diseases. Based on previous studies showing the antioxidant effect of a Jerte Valley cherry derivative product in humans, the objective of this work was to evaluate the effect of the intake of a Jerte Valley cherry-based beverage on inflammatory load in both young and old ringdoves (Streptopelia risoria). To this purpose, circulating levels of pro-inflammatory and anti-inflammatory cytokines as well as serum levels of different acute-phase proteins were measured before and after a 10-day treatment with the Jerte Valley cherry-based beverage. Thus, the 10-day treatment with the cherry-based beverage modulated the balance of pro- and anti-inflammatory cytokines in both young and old ringdoves by down regulating the levels of pro-inflammatory cytokines (interleukin [IL]-1beta, tumor necrosis factor-alpha, and interferon-gamma) and up-regulating the levels of anti-inflammatory cytokines (IL-4, IL-2, and IL-10). Moreover, the 10-day treatment with the Jerte Valley cherry-based product reduced the levels of several proteins involved in acute-phase responses, such as C-reactive protein, haptoglobin, alpha(2)-macroglobulin, and serum amyloid P component. On the other hand, old birds showed imbalanced levels of inflammatory markers toward a pro inflammatory status, thereby underlining the fact that aging is usually accompanied by systemic inflammation and inflammation-related chronic diseases. To sum up, the data suggest a potential health benefit by consuming the cherry based beverage, especially in aged populations, through their anti-inflammatory properties. PMID- 22846078 TI - The aqueous extract of Withania coagulans fruit partially reverses nicotinamide/streptozotocin-induced diabetes mellitus in rats. AB - Withania coagulans fruit has been shown to possess antihyperglycemic properties and is used in the traditional Indian system of medicine. However, there has no systematic study of its mechanism of action. In a rat model diabetes mellitus (DM) was induced by intraperitoneal injection of nicotinamide (230 mg/kg of body weight) followed by streptozotocin at 55 mg/kg of body weight. After 96 h, mildly diabetic (MD) (fasting plasma glucose [FPG]=7-11.1 mmol/L) and severely diabetic (SD) (FPG>11.1 mmol/L) rats were treated with aqueous extract of W. coagulans fruit at doses of 125, 250, and 500 mg/kg of body weight/day orally. FPG, postprandial plasma glucose (PPPG), glycosylated hemoglobin (HbA(1c)), plasma insulin, tissue glycogen, and glucose-metabolizing enzymes were assayed at Day 30. Treatment of diabetic animals (MD and SD) with different doses of aqueous W. coagulans resulted in significantly decreased FPG, PPPG, and HbA(1c) (P<.01), whereas serum insulin increased significantly compared with that in diabetic untreated rats (P<.01). MD and SD animals treated with aqueous W. coagulans also showed significant increases in liver and muscle glycogen compared with diabetic untreated animals (P<.01). Moreover, activities of glucokinase and phosphofructokinase were also significantly increased (P<.01), whereas glucose-6 phosphatase activity was significantly decreased (P<.01) in MD and SD groups treated with aqueous W. coagulans compared with diabetic-untreated groups. The most effective dose of aqueous W. coagulans was 250 mg/kg of body weight. These results show that the aqueous extract of W. coagulans fruit has significant antihyperglycemic effects, which may be through the modulation of insulin levels and related enzyme activities. PMID- 22846079 TI - The protective effects of green tea polyphenols: lipid profile, inflammation, and antioxidant capacity in rats fed an atherogenic diet and dextran sodium sulfate. AB - Acute and chronic inflammation and dyslipidemia play a critical role in the development of various diseases, including cardiovascular disease. Green tea polyphenols possess potent antioxidative and anti-inflammatory properties that contribute to the beneficial effects on heart health. The present study was carried out to determine if administration of a green tea extract (Polyphenon((r)) E [PPE]; Mitsui Norin Co., Ltd., Tokyo, Japan) at 0.2% in the diet reduces cardiovascular risk factors, including dyslipidemia, inflammation, adiposity, and oxidative stress, in rats fed an atherogenic (high fat, cholesterol, and sugar) diet with dextran sodium sulfate (DSS) in drinking water. DSS treatment increased serum total cholesterol, low-density lipoprotein (LDL) cholesterol, C-reactive proteins (CRP), and markers of liver toxicity and decreased high-density lipoprotein (HDL)-cholesterol significantly. Adding PPE to the atherogenic diet (PPE-diet) was associated with lower total cholesterol and LDL-cholesterol (P<.001) and increased HDL-cholesterol (P=.001). In addition, the PPE-diet was associated with decreased serum CRP concentration (P=.023) and increased total antioxidant capacity (P=.016) and catalase (P=.001) and glutathione peroxidase (P=.050) activities. The PPE-diet significantly lowered epididymal fat pad weight (P=.009). Feeding the PPE-diet also ameliorated some of the DSS-induced lipid, inflammatory, and oxidative symptoms. In summary, green tea supplementation decreased several cardiovascular risk factors, including body composition, dyslipidemia, inflammatory status, and antioxidant capacity, in rats fed an atherogenic diet. This study supports green tea as an effective dietary component for sustaining cardiovascular health. PMID- 22846080 TI - Myricetin protects against cytokine-induced cell death in RIN-m5f beta cells. AB - Cytokine-induced cell death is recognized as a major cause of progressive beta cell loss. Tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), and interferon gamma (IFN-gamma) in combination trigger a series of events that lead to beta-cell death. In the past few decades, the use of myricetin as an anti inflammatory and cytoprotective agent has gained much attention. The present study focused on the protective roles of myricetin against cytokine-induced cell death in insulin-secreting RIN-m5f beta cells. The results showed that myricetin (especially at concentrations of 10 MUM and 20 MUM) increased cell viability and decreased cell apoptosis induced by the cytokine mixture of TNF-alpha (10 ng/mL), IL-1beta (5 ng/mL), and IFN-gamma (1000 IU/mL) for 3 days. Moreover, the cytokines increased the total and p65 subunit levels of nuclear factor kappaB, decreased inhibitor kappaB alpha levels, stimulated the accumulation of nitric oxide, increased cytochrome c release from mitochondria, and induced reactive oxygen species generation; myricetin (especially at the concentration of 20 MUM) abolished all of these parameters. These results suggest that myricetin might have therapeutic value for preventing beta-cell death. PMID- 22846081 TI - Maslinic acid protects against isoproterenol-induced cardiotoxicity in albino Wistar rats. AB - The present study aimed to evaluate the protective effect of maslinic acid (MA) on body weight, heart weight, lipids, lipoproteins, lipid peroxidation (LPO), cardiac marker enzymes, and paraoxonase (PON) in normal control and isoproterenol (ISO)-induced myocardial infarcted albino Wistar rats. After treatment with MA (15 mg/kg) for 7 days, myocardial infarction was induced by subcutaneous injection of ISO (85 mg/kg) for two consecutive days. ISO caused a considerable decrease in body weight and increased the heart weight. The concentrations of total cholesterol, triglycerides, very low-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol were higher, whereas that of high-density lipoprotein-cholesterol was lower, in the serum of ISO-administered rats. The activities of the cardiac marker enzymes creatine kinase, alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase and levels of malondialdehyde were elevated in the serum of ISO-treated rats. ISO-administered rats also exhibited a decline in the activity of PON. Pretreatment of rats with MA reduced the effects of ISO on all parameters tested. This is the first report of the protective effect of MA on ISO-induced cardiotoxicity and of an association between PON status and MA supplementation. The observed cardioprotective effects may be due to the antihyperlipidemic potential of MA, inhibition of LPO, and antioxidant activity. PMID- 22846082 TI - A diet low in animal fat and rich in N-hexacosanol and fisetin is effective in reducing symptoms of Parkinson's disease. AB - This study describes how foods rich in fisetin and hexacosanol added to a strict diet reversed most symptoms of Parkinson's disease (PD) in one patient. This is a case report involving outpatient care. The subject was a dietitian diagnosed with idiopathic PD in 2000 at the age of 53 years old, with a history of exposure to neurotoxins and no family history of PD. A basic diet started in 2000 consisted of predominantly fruits, vegetables, 100% whole grains, extra virgin olive oil, nuts, seeds, nonfat milk products, tea, coffee, spices, small amounts of dark chocolate, and less than 25 g of animal fat daily. The basic diet alone failed to prevent decline due to PD. In 2009, the basic diet was enhanced with a good dietary source of both fisetin and hexacosanol. Six months after the patient started the enhanced diet rich in fisetin and hexacosanol, a clinically significant improvement in symptoms was noted; the patient's attending neurologist reported that the clinical presentation of cogwheel rigidity, micrographia, bradykinesia, dystonia, constricted arm swing with gait, hypomimia, and retropulsion appeared to be resolved. The only worsening of symptoms occurred when the diet was not followed precisely. Little improvement in tremor or seborrhea was observed. The clinical improvement has persisted to date. To the best of our knowledge, this is the first case where adjunctive diet therapy resulted in a significant reduction of symptoms of PD without changing the type or increasing the amount of medications. PMID- 22846083 TI - Host-selective toxins produced by the plant pathogenic fungus Alternaria alternata. AB - Host-selective toxins (HSTs) produced by fungal plant pathogens are generally low molecular-weight secondary metabolites with a diverse range of structures that function as effectors controlling pathogenicity or virulence in certain plant pathogen interactions. There are now seven known diseases caused by Alternaria alternata in which HSTs are responsible for fungal pathogenesis. The pathogens have been defined as pathotypes of A. alternata because of morphological similarity but pathological differences. Chemical structures of HSTs from six pathotypes have been determined. The role of A. alternata HSTs in pathogenesis has been studied extensively, and discovery of the release of HSTs from germinating conidia prior to penetration aids in understanding the early participation of HSTs to induce susceptibility of host cells by suppressing their defence reactions. Many attempts have been made to find the target sites of A. alternata HSTs, and four cellular components, plasma membrane, mitochondrion, chloroplast and a metabolically important enzyme, have been identified as the primary sites of each HST action, leading to elucidation of the molecular mechanisms of HST sensitivity in host plants. Studies of the molecular genetics of HST production have identified supernumerary chromosomes encoding HST gene clusters and have provided new insights into the evolution of A. alternata pathotypes. PMID- 22846084 TI - Allergy to beer in LTP-sensitized patients: beers are not all the same. AB - BACKGROUND: Most cases of beer allergy reported so far have been associated with hypersensitivity to the non-specific lipid transfer protein (LTP). In view of the marked differences in brewing processes we assessed IgE reactivity as well as tolerance to many different beers in an allergic patient. METHODS: A 45 year-old man hypersensitive to grass pollen, cat dander and Alternaria tenuis with a history of urticaria and dyspnoea after drinking beer and a weak skin reactivity to commercial corn extract was studied. The patient underwent SPT with 36 different brands of beer and an open challenge with those scoring negative was performed. An immunoblot analysis was carried out using 2 SPT-positive beers, 2 SPT-negative beers, and barley, wheat, and maize extracts using both patient's serum and a maize LTP-specific in-house developed polyclonal antibody from rabbit. Further, the immune reactive LTP of one beer was separated by HPLC and the chromatogram was compared to that of purified maize LTP. RESULTS: Beer SPT scored positive in 30/36 cases. The immunoblot analysis showed IgE reactivity at about 10 kDa against the two SPT-positive beers and against maize with both patient's serum and the polyclonal anti-LTP rabbit serum, whereas the two SPT negative beers, and barley extract scored negative. The immunodetected protein co migrated with maize LTP. CONCLUSION: In beer-allergic patients the diagnostic workup may point to the detection of some tolerated products that can be consumed risk-free. PMID- 22846085 TI - Rapid syntheses of dehydrodiferulates via biomimetic radical coupling reactions of ethyl ferulate. AB - Dehydrodimerization of ferulates in grass cell walls provides a pathway toward cross-linking polysaccharide chains limiting the digestibility of carbohydrates by ruminant bacteria and in general affecting the utilization of grass as a renewable bioresource. Analysis of dehydrodiferulates (henceforth termed diferulates) in plant cell walls is useful in the evaluation of the quality of dairy forages as animal feeds. Therefore, there has been considerable demand for quantities of diferulates as standards for such analyses. Described here are syntheses of diferulates from ethyl ferulate via biomimetic radical coupling reactions using the copper(II)-tetramethylethylenediamine [CuCl(OH)-TMEDA] complex as oxidant or catalyst. Although CuCl(OH)-TMEDA oxidation of ethyl ferulate in acetonitrile produced mixtures composed of 8-O-4-, 8-5-, 8-8- (cyclic and noncyclic), and 5-5-coupled diferulates, a catalyzed oxidation using CuCl(OH) TMEDA as catalyst and oxygen as an oxidant resulted in better overall yields of such diferulates. Flash chromatographic fractionation allowed isolation of 8-8- and 5-5-coupled diferulates. 8-5-Diferulate coeluted with 8-O-4-diferulate but was separated from it via crystallization; the 8-O-4 diferulate left in the mother solution was isolated by rechromatography following a simple tetrabutylammonium fluoride treatment that converted 8-5-diferulate to another useful diferulate, 8-5-(noncyclic) diferulate. Therefore, six of the nine (5-5, 8 O-4, 8-5-c, 8-5-nc, 8-5-dc, 8-8-c, 8-8-nc, 8-8-THF, 4-O-5) diferulic acids that have to date been found in the alkaline hydrolysates of plant cell walls can be readily synthesized by the CuCl(OH)-TMEDA catalyzed aerobic oxidative coupling reaction and subsequent saponification described here. PMID- 22846086 TI - A nano-combinatorial approach to developing cancer diagnostics: nano combinatorial diagnostics discovery. PMID- 22846087 TI - Nanotherapeutics: emerging competent technology in neuroAIDS and CNS drug delivery. PMID- 22846088 TI - DNA nanoparticles could help to treat arthritis and other inflammatory disorders. PMID- 22846089 TI - Improving nanoparticle delivery with anti-angiogenesis therapy. PMID- 22846090 TI - Interview: An architectural journey: from trees, dendrons/dendrimers to nanomedicine. Interview by Hannah Stanwix. AB - Donald Tomalia received his Bachelor of Arts degree in Chemistry from the University of Michigan (MI, USA). He received his PhD in physical-organic Chemistry from Michigan State University (MI, USA) in 1968 while working at The Dow Chemical Company (MI, USA). In 1990 he moved to Michigan Molecular Institute (MI, USA) as Professor and Director of Nanoscale Chemistry and Architecture. He has subsequently founded three dendrimer based-nanotechnology companies, Dendritech, Inc. (MI, USA), Dendritic Nanotechnologies, Inc. (MI, USA) and NanoSynthons LLC (MI, USA). Donald Tomalia is currently Director of the National Dendrimer & Nanotechnology Center (MI, USA), CEO/founder of NanoSynthons LLC (MI, USA), distinguished visiting Professor, Columbia University (NY, USA) and affiliate Professor, Department of Physics, Virginia Commonwealth University (VA, USA). He is best known for his discovery of dendrimers and has received several awards for his accomplishments and contributions to science, including the 2012 Wallace H Carothers Award. He has authored over 250 publications, as well as over 128 patents. PMID- 22846091 TI - From nano- to macro-scale: nanotechnology approaches for spatially controlled delivery of bioactive factors for bone and cartilage engineering. AB - The field of biomaterials has advanced towards the molecular and nanoscale design of bioactive systems for tissue engineering, regenerative medicine and drug delivery. Spatial cues are displayed in the 3D extracellular matrix and can include signaling gradients, such as those observed during chemotaxis. Architectures range from the nanometer to the centimeter length scales as exemplified by extracellular matrix fibers, cells and macroscopic shapes. The main focus of this review is the application of a biomimetic approach by the combination of architectural cues, obtained through the application of micro- and nanofabrication techniques, with the ability to sequester and release growth factors and other bioactive agents in a spatiotemporal controlled manner for bone and cartilage engineering. PMID- 22846092 TI - Challenges in neuroprotective nanomedicine development: progress towards noninvasive gene therapy of glaucoma. AB - Over the past decade the application of gene therapy of retinal diseases such as glaucoma has produced promising results. However, optic nerve regeneration and restoration of vision in patients with glaucoma is still far from reality. Neuroprotective approaches in the form of gene therapy may provide significant advantages, but are still limited by many factors both at the organ and cellular levels. In general, gene delivery systems for eye diseases range from simple eye drops and ointments to more advanced bio- and nanotechnology-based systems such as muco-adhesive systems, polymers, liposomes and ocular inserts. Most of these technologies were developed for front-of-the-eye ophthalmic therapies and are not applicable as back-of-the-eye delivery systems. Currently, only the invasive intravitreal injections are capable of successfully delivering genes to the retina. Here we review the challenges and possible strategies for the noninvasive gene therapy of glaucoma including the barriers in the eye and in neural cells, and present a cross-sectional view of gene delivery as it pertains to the prevention and treatment of glaucoma. PMID- 22846093 TI - Advances in nanotechnology-based delivery systems for curcumin. AB - Curcumin (CUR), a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacological actions of CUR in inflammatory disorders, cardiovascular disease, cancer, Alzheimer's disease and neurological disorders have been shown. However, the clinical application of CUR is severely limited by its main drawbacks such as instability, low solubility, poor bioavailability and rapid metabolism. Multifarious nanotechnology-based delivery approaches have been used to enhance the oral bioavailability, biological activity or tissue-targeting ability of CUR. This article reviews potential novel drug delivery systems for CUR including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels, nanosuspensions, nanoemulsions, complexes and dendrimer/dimer, which provide promising results for CUR to improve its biological activities. PMID- 22846097 TI - Can an athlete have too much ticker? Hypertrophic cardiomyopathy in young athletes. AB - Sudden cardiac death (SCD) is an uncommon but devastating potential consequence of participation in competitive sport. It is seen in adolescent and young adult athletes. The most common cause of this, hypertrophic cardiomyopathy (HCM), is a genetic disorder responsible for more than a third of cases and is manageable. Screening is undertaken for HCM, using differing strategies in Europe and North America. Screening and early diagnosis have reduced the mortality rate but has come at a significant economic cost. The evidence and relevant arguments for and against screening are presented together with management strategies as reflected by an illustrative case. PMID- 22846094 TI - Essential parameters to consider for the characterization of optical imaging probes. AB - The Molecular Imaging and Contrast Agents Database (MICAD) was launched in 2005 to promote the development and application of imaging and contrast agents (probes) to advance the field of molecular imaging. As of March 2012, there are approximately 1170 agents available in MICAD. Based on the modality used for imaging, the largest category of probes described in MICAD are those used for PET (41.6%), followed by agents used for single-photon emission computed tomography (30.3%), optical imaging (12.0%), MRI (9.3%), multimodality imaging (3.4%), ultrasound (2.4%) and x-ray/computed tomography (1.0%). This article is intended to be a guideline for new investigators and students who wish to characterize an optical imaging probe that will be used to perform in vivo molecular imaging studies. It is necessary, however, to ensure that these agents meet certain quality control parameters before they are used in various in vitro and in vivo applications. PMID- 22846098 TI - Attentiveness of pediatricians to primary immunodeficiency disorders. AB - BACKGROUND: Primary immunodeficiency (PID) is a cluster of serious disorders that requires special alertness on the part of the medical staff for prompt diagnosis and management of the patient. This study explored PID knowledge and experience among pediatricians of wide educational backgrounds, practicing in the United Arab Emirates (UAE). METHOD: A self-administered questionnaire was used to determine the competency of pediatricians in their knowledge of PID disorders. This study questionnaire included questions on PID signs and symptoms, syndromes associated with immunodeficiency, screening tests, interpreting laboratory tests and case management. The participants were 263 pediatricians of diverse education working in the 27 governmental hospitals in all regions of UAE. RESULTS: The overall performance of the pediatricians did not differ based on their age, gender, origin of certification, rank, or years of experience. Of the 50 questions, 20% of pediatricians answered correctly <60% of the questions, 76% answered correctly 60 to 79% of the questions, and 4% answered correctly >=80% of the questions. Seventeen of the 19 PID signs and symptoms were identified by 55 to 97%. Four of 5 syndromes associated with immunodeficiency were identified by 50 to 90%. Appropriate screening tests were chosen by 64 to 96%. Attention to the laboratory reference range values as function of patient age was notably limited. CONCLUSIONS: There was a noteworthy deficiency in PID work-up. Therefore, implementing effective educational strategies is needed to improve the competency of pediatricians to diagnose and manage PID disorders. PMID- 22846099 TI - Candida albicans adherence to an acrylic resin modified by experimental photopolymerised coatings: an in vitro study. AB - PURPOSE: This study evaluated whether photopolymerised coatings containing zwitterion or hydrophilic monomers would reduce the adhesion of Candida albicans to an acrylic resin. MATERIALS AND METHODS: Disc-shaped samples (n = 468) were fabricated with rough or smooth surfaces. The samples did not receive any surface treatment (control) or were coated with one of the following experimental coatings (2-hydroxyethyl methacrylate - HE; 3-hydroxypropyl methacrylate - HP; and 2-trimethylammonium ethyl methacrylate chloride - T; and sulfobetaine methacrylate - S). The concentrations of the constituent monomers were 25, 30 or 35%. The water contact angles of the samples were measured, and half of the samples were exposed to saliva. The adherent yeast cells were counted after crystal violet staining. RESULTS: For the smooth samples, the groups S35, HP35 and HE35 showed significantly lower number of adhered Candida than control, in the absence of saliva. There were no significant differences among the experimental and control groups for the rough samples, but the saliva decreased the cell numbers for groups S25, S30 and HP30. The photoelectron spectroscopy analysis confirmed the changes in the chemical compositions of the experimental samples. CONCLUSIONS: The experimental photopolymerised coatings changed the chemical composition and decreased C. albicans adhesion in the groups S35, HP35 and HE35, suggesting that they should be further investigated. PMID- 22846100 TI - Metal binding at the Deinococcus radiodurans Dps-1 N-terminal metal site controls dodecameric assembly and DNA binding. AB - The prokaryotic DNA protection during starvation (Dps) proteins typically protect macromolecules against damaging agents via physical association with DNA and by oxidizing and sequestering iron. However, Deinococcus radiodurans Dps-1, which binds DNA with high affinity, fails to protect DNA against hydroxyl radicals due to iron leakage from the core, raising the question of how (*)OH-mediated damage to Dps-1-bound DNA is avoided. As shown here, Mn(II) inhibits ferroxidase activity, suggesting that ferroxidation may be prevented in vivo as D. radiodurans accumulates a high ratio of Mn:Fe. Dps-1 has an N-terminal extension with a unique metal-binding site, an extension that has been proposed to be important for DNA binding and dodecameric assembly. Electrophoretic mobility shift assays show that Mn(II) restores DNA binding to bipyridyl-treated Dps-1, whereas Fe(II) fails to do so in the presence of H(2)O(2), thus preventing DNA binding under conditions of ongoing ferroxidase activity. We also show that disruption of the N-terminal metal site leads to a significant reduction in DNA binding and to compromised oligomeric assembly, with the mutant protein assembling into a hexamer in the presence of divalent metal. We propose that securing the N-terminal loop by metal binding is required to initiate dodecameric assembly by contacting the neighboring dimer and that the absence of such optimal contacts results in formation of a hexameric assembly intermediate in which three dimers associate about one of the 3-fold axes. Once dodecameric Dps-1 is assembled, metal binding no longer affects oligomeric state; instead, differential metal binding controls DNA interaction under conditions of oxidative stress. PMID- 22846101 TI - Epidemiology of ankle and foot overuse injuries in sports: A systematic review. AB - Studies regarding ankle and foot overuse injuries are quite diverse in research methodology, data reporting, and outcomes. The aims of this systematic review were to analyze the methodology of published studies regarding ankle and foot overuse injuries in different sports disciplines and to summarize epidemiological data of ankle and foot overuse injuries. Four electronic databases, PubMed (MEDLINE), EMBASE, CINAHL, and SPORTDiscus((r)) were systematically searched up to June 2011. A total of 89 articles on 23 sports disciplines were included in this review. Soccer, running, and gymnastics were the most frequently studied sports. Achilles tendinopathy, plantar fasciitis, and stress fracture were the most frequently studied injuries. Study design and reporting methods were heterogeneous. Most studies suffered from a weak methodology and poor reporting. The most common weaknesses were lack of a clear case definition, describing assessment procedures and reporting sample characteristics. Due to methodological heterogeneity of studies, inter-sports and intra-sports comparisons and meta analysis were not possible. Methodology of most studies on incidence and prevalence of ankle and foot overuse injuries is insufficient. Based on the results, we recommend authors to clearly define cases, describe assessment procedures and report sample characteristics adequately. PMID- 22846102 TI - A novel case of acute lymphoblastic leukemia with t(1;4;6;11)(q31;q27;q22;q23). PMID- 22846103 TI - Prevalence of clinically relevant antibiotic resistance genes in surface water samples collected from Germany and Australia. AB - The prevalence and proliferation of antibiotic resistant bacteria is profoundly important to human health, but the extent to which aquatic environments contribute toward the dissemination of antibiotic resistant genes (ARGs) is poorly understood. The prevalence of 24 ARGs active against eight antibiotic classes (beta-lactams, aminoglycosides, glycopeptides, chloramphenicols, tetracycline, macrolides, trimethoprim, and sulfonamides) was evaluated in surface water samples collected from Germany and Australia with culture independent methods. The ARGs most frequently detected both in Germany and Australia were sulI, sulII (77-100%), and dfrA1 (43-55%) which code for resistance to sulfonamide and trimethoprim. Macrolides resistance gene ermB was relatively more prevalent in the surface water from Germany (68%) than Australia (18%). In contrast, the chloramphenicol resistance gene catII was more frequently detected in Australia (64%) than Germany (9%). Similarly, beta-lactams resistance gene ampC was more prevalent in the samples from Australia (36%) than Germany (19%). This study highlights wide distribution of ARGs for sulfonamide, trimethoprim, macroline, beta-lactams and chloramphenicol in the aquatic ecosystems. Aquatic ecosystems can therefore be reservoirs of ARGs genes which could potentially be transferred from commensal microorganisms to human pathogens. PMID- 22846104 TI - The rationale and pilot study of a new paediatric dental patient request form to improve communication and outcomes of dental appointments. AB - BACKGROUND: Children's unhappy visits to the dentist can negatively impact lifelong oral health. A possible intervention is to enhance empathy in the child patient-dental practitioner relationship through communication. The present paper presents a new instrument, the Survey of Anxiety and Information for Dentists (SAID), which targets children's dental anxiety, coping preferences and dental neglect, and offers children a change to request information and engage in treatment planning. METHOD: Five children's focus groups pilot tested the content, wording and response format of a prototype patient request form, the SAID. Participants were 34 10- to 13-year-old children who individually completed the form then discussed it item by item in their small groups. RESULTS: Children had no difficulty completing most items. They identified ambiguities, and items that were meaningless to them, and proposed a new item asking the dentist about their job. Children were polarized over the response format, but they were emphatic about passing the form directly to the dentist, and not to a receptionist or assistant, stressing the importance of having a conversation with their dentist. CONCLUSIONS: Before the pilot, dentists had expressed concerns about the potential for words in the SAID-provoking negative feelings. Children, however, wanted and needed facts, so requested that dentists use plain language, not euphemisms, to describe problems and treatment options. We report their selected practical suggestions. SAID-informed negotiated care may promote more patient cooperation and satisfaction at appointments, and more attention to oral hygiene between appointments. PMID- 22846105 TI - Aspects of care culture in municipal care for elderly people: a hermeneutic documentary analysis of reports of abuse. AB - INTRODUCTION: Care culture is an important contextual factor in care practice. Care culture refers to a process of creating meaning out of tradition, horizon and bildung. The care culture is often taken into consideration in situations that go beyond the everyday routine, such as cases of abuse. In Sweden, health care professionals are obliged to document and report any suspected bad conditions. Although the reports have the potential to communicate underlying values and assumptions about the care culture, such studies have not been performed. AIM: The aim of this study was to understand how elderly care abuse in institutions could be understood from a care culture perspective. DESIGN AND METHODS: A hermeneutic documentary analysis was conducted on 269 incident reports concerning suspected mistreatment of the elderly in three municipalities in Sweden. The hermeneutic analysis followed a four-stage process: selecting and reading the text, setting out the context, closing the hermeneutic circle, and finally creating a conceptual bridge towards a critical understanding from a phenomenological lifeworld perspective. FINDINGS: The care of the elderly in the municipality was based on a social culture that placed residents' needs at the centre. Following routines were considered important in preventing mistreatment and were intended to ensure that all patients were treated fairly and equally. Care was described as task oriented and often lacking in interpersonal relations. From a phenomenological lifeworld perspective, it was interpreted that in the municipalities' care of the elderly, there was a focus on elderly people's freedom at the expense of the vulnerability aspects of well being. CONCLUSION: Raising awareness of the care culture underlying abuse could help to improve understanding of care practice. Change may be only possible when reflected on the existing perspectives underpinning the care culture, and integrate them into a broader framework for caring. PMID- 22846106 TI - Discrete electrostatic charge transfer by the electrophoresis of a charged droplet in a dielectric liquid. AB - We have experimentally investigated the electrostatic charging of a water droplet on an electrified electrode surface to explain the detailed inductive charging processes and use them for the detection of droplet position in a lab-on-a-chip system. The periodic bouncing motion of a droplet between two planar electrodes has been examined by using a high-resolution electrometer and an image analysis method. We have found that this charging process consists of three steps. The first step is inductive charge accumulation on the opposite electrode by the charge of a droplet. This induction process occurs while the droplet approaches the electrode, and it produces an induction current signal at the electrometer. The second step is the discharging of the droplet by the accumulated induced charge at the moment of contact. For this second step, there is no charge transfer detection at the electrometer. The third step is the charging of the neutralized droplet to a certain charged state while the droplet is in contact with the electrode. The charge transfer of the third step is detected as the pulse-type signal of an electrometer. The second and third steps occur simultaneously and rapidly. We have found that the induction current by the movement of a charged droplet can be accurately used to measure the charge of the droplet and can also be used to monitor the position of a droplet under actuation. The implications of the current findings for understanding and measuring the charging process are discussed. PMID- 22846107 TI - Evaluation of a hospice rapid response community service: a controlled evaluation. AB - BACKGROUND: While most people faced with a terminal illness would prefer to die at home, less than a third in England are enabled to do so with many dying in National Health Service hospitals. Patients are more likely to die at home if their carers receive professional support. Hospice rapid response teams, which provide specialist palliative care at home on a 24/7 on-call basis, are proposed as an effective way to help terminally ill patients die in their preferred place, usually at home. However, the effectiveness of rapid response teams has not been rigorously evaluated in terms of patient, carer and cost outcomes. METHODS/DESIGN: The study is a pragmatic quasi-experimental controlled trial. The primary outcome for the quantitative evaluation for patients is dying in their preferred place of death. Carers' quality of life will be evaluated using postal questionnaires sent at patient intake to the hospice service and eight months later. Carers' perceptions of care received and the patient's death will be assessed in one to one interviews at 6 to 8 months post bereavement. Service utilisation costs including the rapid response intervention will be compared to those of usual care. DISCUSSION: The study will contribute to the development of the evidence base on outcomes for patients and carers and costs of hospice rapid response teams operating in the community. TRIAL REGISTRATION: Current controlled trials ISRCTN32119670. PMID- 22846108 TI - Molecular diagnosis on tissues and cells: how it affects training and will affect practice in the future. AB - On 25th November 2011, a symposium organized by the Royal College of Pathologists, entitled 'Molecular diagnosis on tissues and cells', took place in London. As trainees in histopathology and cytopathology, we were stimulated to consider the role that molecular biology is likely to play in future practice and how this is addressed by our own training. The symposium provided a basis for this article. Routine samples requiring molecular analysis are equally relevant to histopathologists and cytopathologists, and molecular biology laboratories are now using cytological as well as histological material for diagnostic testing, allowing different specimen types to be used as and when they are most appropriate. The most widely used types of molecular analysis in routine cellular pathology are EGFR testing in lung cancer, molecular testing of thyroid nodules, fluorescence in situ hybridization testing of urine samples, clonality analysis in lymphoma testing, HER2 testing in breast and gastric cancer, KRAS testing in colorectal cancer, intraoperative assessment of breast cancer sentinel nodes, molecular testing of gastrointestinal stromal tumours and mismatch repair protein analysis. Of these, the majority in the UK are carried out on histopathology samples, although many are applicable to cytological samples if adequate material is obtained. We are particularly encouraged by the potential of molecular diagnostic cytology in traditionally difficult areas, such as intraoperative assessment. We believe that increasing reliance on molecular diagnostic techniques will also herald changes in training. PMID- 22846109 TI - Is it me or not me? Modulation of perceptual-motor awareness and visuomotor performance by mindfulness meditation. AB - BACKGROUND: Attribution of agency involves the ability to distinguish our own actions and their sensory consequences which are self-generated from those generated by external agents. There are several pathological cases in which motor awareness is dramatically impaired. On the other hand, awareness-enhancement practices like tai-chi and yoga are shown to improve perceptual-motor awareness. Meditation is known to have positive impacts on perception, attention and consciousness itself, but it is still unclear how meditation changes sensorimotor integration processes and awareness of action. The aim of this study was to investigate how visuomotor performance and self-agency is modulated by mindfulness meditation. This was done by studying meditators' performance during a conflicting reaching task, where the congruency between actions and their consequences is gradually altered. This task was presented to novices in meditation before and after an intensive 8 weeks mindfulness meditation training (MBSR). The data of this sample was compared to a group of long-term meditators and a group of healthy non-meditators. RESULTS: Mindfulness resulted in a significant improvement in motor control during perceptual-motor conflict in both groups. Novices in mindfulness demonstrated a strongly increased sensitivity to detect external perturbation after the MBSR intervention. Both mindfulness groups demonstrated a speed/accuracy trade-off in comparison to their respective controls. This resulted in slower and more accurate movements. CONCLUSIONS: Our results suggest that mindfulness meditation practice is associated with slower body movements which in turn may lead to an increase in monitoring of body states and optimized re-adjustment of movement trajectory, and consequently to better motor performance. This extended conscious monitoring of perceptual and motor cues may explain how, while dealing with perceptual-motor conflict, improvement in motor control goes beyond the mere increase of movement time. The reduction of detection threshold in the MBSR group is also likely due to the enhanced monitoring of these processes. Our findings confirmed our assumptions about the positive effect of mindfulness on perceptual-motor integration processes. PMID- 22846110 TI - 'At-risk' for psychosis research: where are we heading? AB - The 'at-risk' criteria are a useful paradigm for investigating the psychological, neurocognitive, neurobiological and genetic risk factors for psychosis, specifically schizophrenia. To date, the primary outcome of interest in at-risk research has been the development of psychotic disorder, whereby patients are categorized as either having 'transitioned' or 'not transitioned'. Despite the acceptance of this dichotomy, it is important to consider that the threshold at which psychotic symptoms progress from attenuated to frank 'psychotic disorder' is arbitrary and may be incorrect or meaningless in terms of neurobiological and functional changes associated with psychosis. This has implications for clinical care and the search for markers of schizophrenia. We present recent research suggesting that the term 'outcome' needs to be broadened to incorporate non psychotic diagnoses, functioning and negative symptoms. Shifting the traditional notion of outcome is the future challenge for at-risk research, but the inclusion of outcomes other than psychosis is likely to result in better aetiological models of psychotic illness. PMID- 22846111 TI - Comparative study of mental health and quality of life in long-term refugees and host populations in Oru-Ijebu, Southwest Nigeria. AB - BACKGROUND: Refugees as "People Living in Highly Stressful Situation" are particularly vulnerable to mental ill-health as a result of the trauma experienced pre- and post-migration. The lack of information on the mental health disparities of refugees and non-refugees in West Africa is what this study aimed to bridge. A cross-sectional study design was employed using a cluster sampling technique. Interviewer-administered structured questionnaires consisting of the Mini-International Neuropsychiatric Interview (MINI), WHO quality of life (WHOQOL BREF) and the Community Quality of Life (CQoL) were used for data collection. Data were analyzed with SPSS version 17. Logistic regression analysis was used to determine the predictors of mental health status and QoL. RESULTS: Respondents consisted of 444(45.7%) refugees and 527(54.3%) non-refugees. Two-thirds 292 (66%) of the refugees were Liberians. Mean age: refugees--34.8 +/- 12.8 years versus non-refugees--33.3 +/- 8.1 years (p < 0.05). While the majority 376(84.7%) of the refugees were married, most 468(88.8%) of the native population were not (p < 0.001). Significantly higher proportion of refugees had polygamous marriages, lived in poorer type of accommodation and had no formal education compared to the non-refugees (p < 0.05). The overall QoL and CQoL scores were both significantly lower for the refugees (p < 0.001). Refugees were three times more likely than non-refugees to have poor mental health [OR: 3.43; 95% CI: 1.83 6.40]. Overall, being currently ill tripled the odds of mental ill health [OR: 2.73; 95% CI: 1.98-3.77]. Unskilled workers [OR: 2.78; 95% CI: 1.68-4.60], skilled workers [OR: 2.98; 95% CI: 2.03-4.38] and the unemployed [OR: 1.94; 95% CI: 1.29-2.92] had two or more times the odds of poor mental health compared to professionals. CONCLUSIONS: QoL and occupational status were the major threats to the mental health of the refugees. Results of this study point to the need for continued attention to not only the healthcare needs but the welfare, housing, employment and overall QoL to support the long-term mental health of refugees and non-refugee populations alike. PMID- 22846112 TI - Nocturnal enuresis. AB - Nocturnal enuresis (NE) is increasingly seen as part of a heterogeneous phenomenon that at times will include daytime lower urinary tract symptoms such as urgency, frequency and wetting - with reduced bladder storage, usually due to an overactive bladder. In turn, these may be associated with constipation and/or faecal soiling. This paper discusses these considerations in the management of NE. PMID- 22846113 TI - A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family. AB - Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC. PMID- 22846114 TI - Identification and functional characterization of mitochondrial carrier Mrs4 in Candida albicans. AB - Iron is an essential nutrient required for the growth and metabolism in Candida albicans. Here, we for the first time identified Mrs4 as a new member of mitochondrial carrier family in C. albicans. Our experiments revealed that C. albicans Mrs4 (CaMrs4) is localized to the mitochondria and required for mitochondrial morphology. We found that CaMrs4 is required for cell growth, and the mrs4Delta/Delta mutant showed a more severe growth defect in iron deficiency. Deletion of MRS4 affected cellular iron content by altering the expression of iron regulon genes in C. albicans, such as AFT2, SMF3, FTR1 and ISU1. Candida albicans Aft2 factor functions as a negative regulator of MRS4 expression through the CACCC Aft-type sequence in a gene dose-dependent fashion. In addition, the mrs4Delta/Delta mutant exhibited hypersensitivity to oxidants and most metal ions, but decreased sensitivity to cobalt. Exogenous iron could suppress the sensitivity of the mrs4Delta/Delta mutant to oxidants and most metal ions, suggesting that the role of CaMrs4 is partially mediated by iron availability. Furthermore, deletion of MRS4 resulted in delayed filamentation under tested conditions. Taken together, these findings characterize a new mitochondrial carrier and provide a novel insight into the role of CaMrs4 in mitochondrial function. PMID- 22846115 TI - Iron deficiency in children with HIV-associated anaemia: a systematic review and meta-analysis. AB - We conducted a systematic review and meta-analysis to determine the prevalence of iron deficiency in HIV-infected children from high- and low-income settings and compared it with that of HIV-uninfected controls. We searched five major databases for primary studies reporting on anaemia and iron markers in HIV infected children. A pooled analysis was done using random-effects models, with Forest plots and heterogeneity test estimates provided. Fifteen articles (2778 children) met the inclusion criteria. In the pooled analysis, mean overall prevalence of iron deficiency in HIV-infected children was 34% (95%CI 19-50%). Prevalence rates were similar in high-income (31%; 95%CI 2-61%) and low-income settings (36%; 95%CI 17-54%) (p=0.14). Studies that included a HIV-uninfected control population (n=4) were only available from low-income settings and showed less iron deficiency in HIV-infected children (28%) than in HIV-uninfected children (43%); OR 0.50 (0.27-0.94); p=0.03. The findings suggest that HIV infected children are less likely to be iron deficient when compared with HIV uninfected children. Possible explanations for this include HIV-induced haematosuppression and associated hypoferraemia, with adequate iron stores. Nevertheless iron deficiency is a common co-morbidity in HIV. Studies are needed to determine the role of iron deficiency in HIV-associated anaemia and the effects of iron supplementation in this population. PMID- 22846116 TI - SUNCT syndrome findings accompanied by cavernous segment aneurysm. PMID- 22846117 TI - Usefulness of pharmacy dispensing records in the evaluation of adherence to antiretroviral therapy in Brazilian children and adolescents. AB - INTRODUCTION: Adherence, which is crucial to the success of antiretroviral therapy (HAART), is currently a major challenge in the care of children and adolescents living with HIV/AIDS. OBJECTIVE: To evaluate the prevalence of nonadherence to HAART using complementary instruments in a cohort of children and adolescents with HIV/AIDS followed in a reference service in Campinas, Brazil. METHODS: The level of adherence of 108 patients and caregivers was evaluated by an adapted standardized questionnaire and pharmacy dispensing records (PDR). Non adherence was defined as a drug intake lower than 95% (on 24-hour or seven-day questionnaires), or as an interval of 38 days or more for pharmacy refills. The association between adherence and clinical, immunological, virological, and psychosocial characteristics was assessed by multivariate analysis. RESULTS: Non adherence prevalence varied from 11.1% (non-adherent in three instruments), 15.8% (24-hour self-report), 27.8% (seven-day self-report), 45.4% (PDR), and 56.3% (at least one of the outcomes). 24-hour and seven-day self-reports, when compared to PDR, showed low sensitivity (29% and 43%, respectively) but high specificity (95% and 85%, respectively). In multivariate analysis, medication intolerance, difficulty of administration by caregiver, HAART intake by the patient, lower socioeconomical class, lack of virological control, missed appointments in the past six months, and lack of religious practice by caregiver were significantly associated with non-adherence. CONCLUSION: A high prevalence of HAART non adherence was observed in the study population, and PDR was the most sensitive of the tested instruments. The instruments employed were complementary in the identification of non-adherence. PMID- 22846118 TI - Comparison of clinical characteristics between healthcare-associated pneumonia and community-acquired pneumonia in patients admitted to secondary hospitals. AB - BACKGROUND: Since healthcare-associated pneumonia (HCAP) is heterogeneous, clinical characteristics and outcomes are different from region to region. There can also be differences between HCAP patients hospitalized in secondary or tertiary hospitals. This study aimed to evaluate the clinical characteristics of HCAP patients admitted into secondary community hospitals. METHODS: This was a retrospective study conducted in patients with HCAP or community-acquired pneumonia (CAP) hospitalized in two secondary hospitals between March 2009 and January 2011. RESULTS: Of a total of 303 patients, 96 (31.7%) had HCAP. 42 patients (43.7%) resided in a nursing home or long-term care facility, 36 (37.5%) were hospitalized in an acute care hospital for >= 2 days within 90 days, ten received outpatient intravenous therapy, and eight attended a hospital clinic or dialysis center. HCAP patients were older. The rates of patients with CURB-65 scores of 3 or more (22.9% vs. 9.1%; p=0.001) and PSI class IV or more (82.2% vs. 34.7%; p<0.001) were higher in the HCAP group. Drug-resistant pathogens were more frequently detected in the HCAP group (23.9% vs. 0.4%; p<0.001). However, Streptococcus pneumoniae was the most common pathogen in both groups. The rates of antibiotic change, use of inappropriate antibiotics, and failure of initial antibiotic therapy in the HCAP group were significantly higher. Although the overall survival rate of the HCAP group was significantly lower (82.3% vs. 96.8%; p<0.001), multivariate analyses failed to show that HCAP itself was a prognostic factor for mortality (p=0.826). Only PSI class IV or more was associated with increased mortality (p=0.005). CONCLUSIONS: HCAP should be distinguished from CAP because of the different clinical features. However, the current definition of HCAP does not appear to be a prognostic for death. In addition, the use of broad spectrum antibiotics for HCAP should be reassessed because S. pneumoniae was most frequently identified even in HCAP patients. PMID- 22846119 TI - Molecular identification and antimicrobial susceptibility of Staphylococcus aureus nasal isolates from medical students in Cartagena, Colombia. AB - Staphylococcus aureus (SA) remains a major cause of nosocomial and community acquired infections worldwide. Nasal carriage of this bacterium among hospital personnel constitutes an important source for nosocomial infections. A cross sectional study enrolling the whole medical student population (n=387) of the School of Medicine at the Universidad de Cartagena, Colombia, was conducted to evaluate the carriage rates of both methicillin sensitive- and methicillin resistant-SA, the frequency of Panton-Valentine leukocidin genes in the isolates, and risk factors associated with carriage in this selected population. After signing an informed consent, participants completed a survey related to possible risk factors for colonization, and nasal swabs were collected from anterior nares. Staphylococcus aureus strains isolated from carriers were subjected to DNA extraction and PCR assays to determine the presence of MecA and Panton-Valentine leukocidin genes. Typing of the staphylococcal chromosomal cassette was performed for methicillin resistant strains. Molecular analysis was performed for only one strain per carrier. Prevalence of carriage for methicillin sensitive- and methicillin resistant-SA was 25% and 1.6% respectively. Most of the methicillin resistant isolates carried the staphylococcal chromosomal cassette type IV and the genes for Panton-Valentine leukocidin. To determine carrier types among medical students, each participant was subjected to four additional swabs, each taken two weeks apart. 9.8% persistent carriers, 53.1% intermittent carriers, and 37.1% non-carriers of SA were found. There was no association between risk factors analyzed and carriage of the bacterium. The study was conducted from April to September 2009 and found a persistent carriage of methicillin resistant SA strains bearing the genes for Panton-Valentine leukocidin among medical students, evidencing the potential contribution of this portion of healthcare personnel either to the spread or introduction of these strains into the healthcare environment. PMID- 22846120 TI - Chlamydia trachomatis infection among HIV-infected women attending an AIDS clinic in the city of Manaus, Brazil. AB - This was a cross-sectional study aimed to determine the prevalence of and to identify risk factors for Chlamydia trachomatis (CT) among human immunodeficiency virus (HIV)-infected women attending the acquired immunodeficiency syndrome (AIDS) clinic in the city of Manaus, Brazil, in 2009-2010. Participants answered a questionnaire containing demographic, epidemiological, and clinical data. A genital specimen was collected during examination to detect CT-DNA by hybrid capture, and blood samples were taken to determine CD4(+)T and HIV viral load. There were 329 women included in the study. Median age was 32 years (IQR=27-38) and median schooling was nine years (IQR=4-11). The prevalence of CT was 4.3% (95%CI: 2.1-6.5). Logistic regression analysis showed that age between 18-29 years [OR=4.1(95%CI: 1.2-13.4)] and complaint of pelvic pain [OR=3.7 (95%CI: 1.2 12.8)] were independently associated with CT. The use of condom was inversely associated with CT [OR=0.39 (95%CI: 0.1-0.9)]. The results showed that younger women who did not use condoms are at a higher risk for CT. Screening for sexually transmitted infections must be done routinely and safe sexual practices should be promoted among this population. PMID- 22846121 TI - Seroprevalence of hepatitis B surface antigen and its correlation with risk factors among new recruits in Turkey. AB - OBJECTIVES: The objective of this cross-sectional study was to determine seroprevalence of hepatitis B surface antigen and related risk factors among new recruits in a military unit in Turkey. METHODS: Eight thousand five hundred eighty-nine newly-recruited soldiers were enrolled in the study. Blood samples were drawn from them between January 2006 and December 2006 and ELISA technique was applied to the samples. In addition, questions on the risk factors of hepatitis B exposure were asked to the participants in the survey. RESULTS: The results demonstrated that HBsAg seroprevalence was 2.8%. Further survey results indicated that seropositivity increased depending on certain risk factors. In multiple regression analysis, significant correlations were determined between HBsAg positivity and certain risk factors such as living in the Southeast Anatolia region (p<0.01), having a history of living with a hepatitis B carrier (p<0.001), and presence of a hepatitis B carrier in the neighborhood or at work (p<0.05). CONCLUSIONS: The HBsAg seropositivity found in this study supports the fact that Turkey remains in the medium endemicity zone, and that horizontal transmission is predominant. PMID- 22846122 TI - Autologous transplant: microbial contamination of hematopoietic stem cell products. AB - Hematopoietic progenitor cells from peripheral blood (HPCPB) are commonly used for autologous and allogenic transplants in patients with most various onco hematological diseases, and despite the utilization of sterile techniques during collection and processing of these products, bacterial contamination can occur. This study aimed to investigate the microbial contamination of HPCPB products. Microbial cultures of 837 HPCPB products between the year 2000 and 2009 were retrospectively analyzed to determine the incidence of culture positivity and identify the main organisms that cause contamination. The microbiological studies were performed with an automated system (BacT/Alert((r)) bioMerieux Corporate). Thirty-six (4.3%) of 837 microbial cultures were contaminated. Coagulase-negative Staphylococcus was the most frequent bacteria isolated from HPCPB products (20 [56%] of the 36 positive microbial cultures). Considering the 36 contaminated samples, 22 HPCPB products were infused and 14 discarded. Pre- and post-infusion antibiotic therapy of the patients transfused with contaminated products was established based on the isolated microorganism and its antibiogram. Microbial contamination rate of HPCPB products was low. Clinically significant outcomes after infusion of contaminated HPCPB products were not observed. PMID- 22846123 TI - Risk factors for pan-resistant Pseudomonas aeruginosa bacteremia and the adequacy of antibiotic therapy. AB - INTRODUCTION: The aim of this study was to determine risk factors for acquiring carbapenem-resistant Pseudomonas aeruginosa bacteremia (CR-PA) and factors associated with in-hospital mortality. METHODS: Seventy-seven cases of bacteremia caused by P. aeruginosa were evaluated in a hospital with high incidence of CR PA. Clinical and laboratorial factors, and previous use of antibiotics were also evaluated. In one analysis, CR-PA and carbapenem-susceptible P. aeruginosa (CS PA) bacteremia were compared. A second analysis compared patients who died with survivors. RESULTS: Among 77 P. aeruginosa bacteremia, 29 were caused by CR-PA. Admission to the intensive care unit, higher number of total leukocytes, and previous use of carbapenem were statistically associated with CR-PA. In the multivariate analysis, only previous use of carbapenem (including ertapenem) turned out to be a risk factor for CR-PA (p=0.014). The 30-day mortality of patients with P. aeruginosa bloodstream infection was 44.8% for CS-PA and 54.2% for patients with CR-PA (p=0.288). Chronic renal failure, admission to the intensive care unit, mechanical ventilation, and central venous catheter were risk factors for mortality. Incorrect treatment increased mortality of patients with bacteremia caused by CS-PA, but not for CR-SA. The odd ratio of mortality associated with incorrect therapy in patients with CS-PA was 3.30 (1.01-10.82; p=0.043). The mortality of patients with bacteremia caused by CR-PA was unexpectedly similar regardless of antimicrobial treatment adequacy. CONCLUSION: Appropriate treatment for CS-PA bacteremia initiated within the first 24 hours was associated with lower mortality, but this cannot be extrapolated for CR-PA. PMID- 22846124 TI - Evolution of HTLV-1 proviral load in patients from Salvador, Brazil. AB - INTRODUCTION: Variations in human T cell lymphotropic virus type 1 (HTLV-1) proviral load (PVL) in infected individuals over time are not well understood. OBJECTIVE: To evaluate the evolution of proviral load in asymptomatic individuals and HAM/TSP patients in order to help determine periodicity for measuring proviral load. METHODS: A group of 104 HTLV-1 infected patients, followed at the HTLV reference center in Salvador, Brazil, were included in the study (70 asymptomatic and 34 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients). HTLV-1 PVL was measured using real-time polymerase chain reaction (PCR) at baseline and again at another point, either <= 12 months, between 12-24 months, or >= 24 months. RESULTS: HAM/TSP patients had higher PVL (ranging from 11,041 to 317,009 copies/10(6) PBMC) when compared to asymptomatic individuals (ranging from 0 to 68,228 copies/10(6) PBMC). No statistically significant differences were observed in the medians of PVL in HAM/TSP patients or asymptomatic individuals over time. However, in asymptomatic individuals with a PVL below 50,000 copies/10(6) PBMC, a statistically significant two-fold increase was observed over time. CONCLUSION: HTLV-1-PVL remained stable in both asymptomatic individuals and HAM/TSP patients over time. Frequent monitoring of asymptomatic individuals with low PVLs is recommended and further studies should be conducted to assess the course of PVL in these patients over extended periods of time. PMID- 22846125 TI - Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients. AB - BACKGROUND: Usual treatment regimens with vancomycin often fail to provide adequate serum levels in patients with severe infections. METHODS: Retrospective analysis of vancomycin trough serum measurements. The following parameters were calculated by Bayesian analysis: vancomycin clearance, distribution volume, and peak estimated concentrations. The area under the concentration curve (AUC) (total daily dose/24 h clearance of vancomycin) was used to determine the effectiveness of treatment through the ratio of AUC/minimum inhibitory concentration (MIC) above 400, using MIC=1 MUg/mL, based on isolates of Staphylococci in cultures. RESULTS: Sixty-one vancomycin trough measurements were analyzed in 31 patients. AUC/MIC>400 was obtained in 34 out of 61 dosages (55.7%), but the mean vancomycin dose required to achieve these levels was 81 mg/kg/day. In cases where the usual doses were administered (40-60 mg/kg/day), AUC/MIC>400 was obtained in nine out of 18 dosages (50%), in 13 patients. Trough serum concentrations above 15 mg/L presented a positive predictive value of 100% and a negative predictive value of 71% for AUC/MIC>400. CONCLUSION: Higher than usual vancomycin doses may be required to treat staphylococcal infections in children with oncologic/hematologic diseases. Since the best known predictor of efficacy is the AUC/MIC ratio, serum trough concentrations must be analyzed in conjunction with MICs of prevalent Staphylococci and pharmacokinetic tools such as Bayesian analysis. PMID- 22846126 TI - Comparison of entecavir and adefovir for the treatment of chronic hepatitis B. AB - The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic hepatitis B (CHB) were published in recent years. However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion as to whether ETV is more effective than ADV. Therefore, a new meta analysis was needed to compare ETV with ADV for the treatment of CHB. A search of the Cochrane Central Register of Controlled Trials (CCTR), MEDLINE, the Science Citation Index, Embase, the China National Knowledge Infrastructure (CNKI), and the Wanfang Database for relevant studies published between 1966 and 2010 was performed. Trials comparing the use of ETV and ADV for the treatment of CHB were assessed. Of the 2,358 studies screened, 13 randomized controlled clinical trials comprising 1,230 patients (ETV therapy, 621; ADV therapy, 609) were analyzed. The serum hepatitis B virus (HBV) DNA clearance rate obtained in patients treated with ETV was significantly higher than that in patients treated with ADV at the 24th and 48th weeks of treatment (24 weeks: 59.6% vs. 31.8%, relative risk [RR], 1.82, 95% CI: 1.49-2.23; 48 weeks: 78.3% vs. 50.4%, RR, 1.61, 95% CI: 1.32-1.96). The serum HBeAg clearance rate, the HBeAg seroconversion rate, and the ALT normalization rate obtained for patients treated with ETV were also higher than the corresponding values for patients treated with ADV at the 48th week of treatment. The safety profiles were similar between patients treated with ETV and those treated with ADV. The evidence reviewed in this meta-analysis suggests that patients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with ETV than when treated with ADV. PMID- 22846127 TI - Neurologic complications of HIV in the HAART era: where are we? AB - Human immunodeficiency virus (HIV)-associated neurological complications continue to occur despite the development in antiretroviral treatment. New forms of old opportunistic infections and increased prevalence of neurocognitive disorders are the challenges that infectious diseases specialists face in daily clinic. How to screen and treat these disorders are subject of debate and new studies are underway to answer these questions. This review focuses on a brief discussion about opportunistic infections still present in late diagnosed HIV-infected patients and describes new forms of HIV-related neurological complications. PMID- 22846128 TI - Profile of users of drugs for the treatment of chronic hepatitis B available through the Brazilian Public Health System. AB - Treatment for chronic hepatitis B in Brazil are funded by the Ministry of Health and by the state Departments of Health. Clinical protocol and therapeutic guidelines approve the use of adefovir, entecavir, interferon-alpha, lamivudine, and tenofovir for the treatment of chronic hepatitis B. The aim of this study was to establish the profile of users of these drugs in the state of Parana. A cross sectional study was conducted with patients under treatment in Parana in August 2011. The following data were obtained: gender, hepatitis B used drug, International Classification of Diseases, and regional health unit. The monthly cost of these drugs for the public health system was also calculated. 1,093 patients registered were found, 70% male, and 2.6% co-infected with the delta agent. Tenofovir was the drug most commonly used (355 users). The highest prevalence was found in the regional health units of Pato Branco, Cascavel, Foz do Iguacu, Francisco Beltrao, Toledo, Londrina, and Maringa. The annual cost for the public health system in Parana was U$1,066,867. Through this study it was possible to investigate the distribution and profile of users of drugs for the treatment of chronic hepatitis B in Parana in August 2011. PMID- 22846129 TI - Study of the relationship between human MIF level, MIF-794CATT5-8 microsatellite polymorphism, and susceptibility of tuberculosis in Southwest China. AB - OBJECTIVE: To study the human migration inhibitory factor (MIF) level in tuberculosis (TB) patients, and the relationship between MIF-794CATT microsatellite polymorphism and susceptibility of TB in Southwest China. METHODS: TB patients (n=151) and healthy unrelated controls (n=149) were recruited for this study. Genomic DNA was extracted, and then amplified by polymerase chain reaction (PCR). MIF-794CATT(5-8) microsatellite polymorphism was genotyped by DNA sequencing. MIF level was detected by ELISA. RESULTS: In the TB group, the repeat number of 7/7 and 7/8 (17.89%) was significantly higher than that of the control group (8.05%), and the serum MIF level was also much higher than that of the healthy controls (705.21 +/- 67.98 vs. 355.31 +/- 57.29 pg/mL, p<0.01). CONCLUSION: The appearance of MIF-794CATT 7/7 and 7/8 is associated with susceptibility to TB, and may play an important role in the occurrence and development of TB in Southwest China. PMID- 22846130 TI - Clinical manifestations of primary syphilis in homosexual men. AB - At the beginning of a new millennium, syphilis incidence has been increasing worldwide, occurring primarily among men who have sex with men (MSM). The clinical features of primary syphilis among MSM is described, a case-note review of the primary syphilis (PS) patients who attended the Institute of Skin and Venereal Diseases. The diagnosis was assessed based upon the clinical features and positive syphilis serology tests. Among 25 patients with early syphilis referred during 2010, PS was diagnosed in a total of 13 cases. In all patients, unprotected oral sex was the only possible route of transmission, and two out of 13 patients had HIV co-infection. Overall, 77% of men presented with atypical penile manifestation. The VDRL test was positive with low titers. The numerous atypical clinical presentations of PS emphasize the importance of continuing education of non-experienced physicians, especially in countries with lower reported incidence of syphilis. PMID- 22846131 TI - Myroides odoratimimus soft tissue infection in an immunocompetent child following a pig bite: case report and literature review. AB - Members of the genus Myroides are aerobic Gram-negative bacteria that are common in environmental sources, but are not components of the normal human microflora. Myroides organisms behave as low-grade opportunistic pathogens, causing infections in severely immunocompromised patients and rarely, in immunocompetent hosts. A case of Myroides odoratimimus cellulitis following a pig bite in an immunocompetent child is presented, and the medical literature on Myroides spp. soft tissue infections is reviewed. PMID- 22846132 TI - Severe shoulder tendinopathy associated with levofloxacin. AB - Fluoroquinolone (FQ)-associated tendinopathy and myopathy are uncommon but well recognized complications of the use of this class of antibacterial agents. The case of a 63-year-old previously asymptomatic female patient who developed severe left shoulder tendinopathy after surreptitiously doubling the prescribed dose of levofloxacin for the treatment of community-acquired pneumonia is reported here. Surgical stabilization with suture anchors and subacromial decompression were needed. PMID- 22846133 TI - Breast cancer among human immunodeficiency virus (HIV)-infected patients: the experience in Brescia, Northern Italy. PMID- 22846134 TI - Two cases of mother-to-child transmission of HIV and Trypanosoma cruzi in Argentina. PMID- 22846135 TI - Ralstonia pickettii sepsis in a hemodialysis patient from Bulgaria. PMID- 22846136 TI - Seroprevalence of cytomegalovirus infection among pregnant women in Eastern Iran. PMID- 22846137 TI - Infection due to Borrelia burgdorferi most likely does not occur in Cuba. PMID- 22846139 TI - Eschar: a cutaneous clue to scrub typhus. PMID- 22846140 TI - Arbuscular mycorrhizal fungi in a wetland constructed for benzene-, methyl tert butyl ether- and ammonia-contaminated groundwater bioremediation. AB - Arbuscular mycorrhizal fungi (AMF), which are present in most natural environments, have demonstrated capacity to promote biodegradation of organic pollutants in the greenhouse. However, it is not certain whether AMF can spontaneously establish in phytoremediation systems constructed to decontaminate groundwater, because of the unusual conditions during the construction and operation of such systems. To assess this possibility, root samples from a wetland constructed for the phytoremediation of groundwater contaminated with benzene, methyl tert-butyl ether and ammonia were analysed. Substantial AMF colonization was observed in plant roots sampled close to the inlet of a basin filled with fine gravel and planted with Phragmites australis. In addition, analysis of a fragment of the nuclear large ribosomal subunit, amplified by nested PCR, revealed the presence of AMF molecular operational taxonomic units closely related to Funneliformis mosseae and Rhizophagus irregularis in the samples. These findings demonstrate the capacity of generalist AMF strains to establish spontaneously, rapidly and extensively in groundwater bioremediation technical installations. PMID- 22846141 TI - Pioneers of service development for children with intellectual disability. PMID- 22846142 TI - Urinary continence after radical prostatectomy: predictive factors of recovery after 1 year of surgery. AB - OBJECTIVES: To evaluate the clinical prognosis of incontinence and to determine the predictors for further recovery of urinary continence in patients not achieving urinary continence within 1 year after radical prostatectomy. METHODS: A total of 708 patients were evaluated regarding urinary continence status at 1 year after surgery from a prospectively maintained radical prostatectomy database. Of these, 73 (10.3%) did not recover urinary continence within 1 year after surgery. For these patients, incontinence status and the number of pads for urinary control were assessed serially. RESULTS: In 708 patients, factors associated with the recovery of urinary continence within 1 year after radical prostatectomy were membranous urethral length, prostatic apex shape and patient age. Among 73 patients with urinary incontinence, 41 (56.2%) achieved urinary continence with a mean time of 15.4 months subsequent to the first year after radical prostatectomy (baseline). A younger age at surgery (P = 0.027) and one pad being required (vs >=2 pads) at baseline (P = 0.046) were identified as independent factors for achievement of urinary continence within a further 2 years. Only the number of pads was a significant factor for further recovery of urinary continence in the longer follow up (hazard ratio 0.36, P = 0.029). CONCLUSION: Compared with factors related to the prostate or membranous urethra, patient age and severity of incontinence at 1 year after radical prostatectomy are more strongly related to the recovery of urinary continence later than 1 year after surgery. These findings might help to decide whether a definite treatment is required for persistent incontinence beyond 1 year after radical prostatectomy. PMID- 22846143 TI - 'The transit of the food trolley'- malnutrition in older people and nurses' perception of the problem. AB - AIMS: To investigate how the issue of malnutrition in institutionalised older people is perceived by nurses in a Teaching Hospital in Italy and how some aspects that can prevent malnutrition are dealt with. BACKGROUND: Malnutrition in institutionalised older people is still a significant and unresolved problem. Many studies have been published on the inadequacy of nutritional care. Nurses play a strategic and key role in the prevention of malnutrition. Knowing how nurses perceive the problem of malnutrition and how they deal with aspects that can prevent malnutrition can be an important starting point for implementing strategies that will improve overall nutritional care. METHODS: A Focus Group (FGs) study was conducted in a Teaching Hospital in the north-west of Italy with 33 nurses, who were still working or had worked with older people. The FGs were audio-taped and transcribed verbatim. Data collection was stopped when we achieved saturation. Two researchers independently analysed the transcription for content analysis and negotiated the emerging categories. RESULTS: Although nurses perceived malnutrition as a significant issue, it was often considered of secondary importance compared with other aspects of care. Food choice, although available, is often limited to very few options, diets are standardised and monotonous and patients must choose 'sight unseen'. Time constraints and understaffing were the obstacles for the identification of the need for nutritional care. Organisational and managerial decision-making did not ensure the provision of high-quality nutritional care. Patients' nutritional status was often not assessed, and tools such as the Mini Nutritional Assessment were not mentioned by the participants. CONCLUSION: Our study substantially confirmed what is reported in the literature. However, it is necessary to raise nurses' awareness around poor nutritional care to prevent malnutrition in institutionalised older people. PMID- 22846145 TI - Serum cytokine profile in patients with active lupus nephritis. AB - PURPOSE: Determination of disease activity of lupus nephritis remains challenging. Since cytokines play a role as inflammatory mediators extending renal injury, measuring serum cytokine levels might help in the clinical assessment of patients with lupus nephritis. Therefore, the aim of this study was to determine the diagnostic value of a panel of serum cytokines in patients with active lupus nephritis. METHODS: In this prospective controlled multicenter trial, sera of 12 patients with active lupus nephritis were collected in a clinical routine setting at the time of renal biopsy and 6 months afterwards. Fourteen patients with inactive systemic lupus erythematosus (SLE), and 14 healthy subjects were used as controls. Eleven cytokines (IL-4, IL-5, IL-6, IL 10, IL-12(p40), IL-12(p70), IL-18, TNF-alpha, TGF-beta1, IFN-alpha2, IFN-gamma) and two soluble receptors (IL-1ra and TNF-RII) were measured by cytokine multiplex assay. RESULTS: In inactive SLE patients, serum levels of IL-10, IL 12(p40), IL-18 and TNF-RII were increased compared to healthy controls. Active lupus nephritis was found to be associated with further increase of these cytokine levels. Follow-up measurements in clinical remission of lupus nephritis showed downregulation of increased cytokines to levels found in inactive SLE. Most strikingly, TNF-RII serum level were elevated in all patients with active lupus nephritis (p<0.001) and declined after clinical remission (p<0.0005). CONCLUSION: The cytokine multiplex assay used in our study allowed a fast and stable analysis of a panel of serum cytokines in a clinical routine setting. In addition, serum cytokines, especially TNF-RII, might be excellent markers of active lupus nephritis. PMID- 22846144 TI - Determinants of demand for total hip and knee arthroplasty: a systematic literature review. AB - BACKGROUND: Documented age, gender, race and socio-economic disparities in total joint arthroplasty (TJA), suggest that those who need the surgery may not receive it, and present a challenge to explain the causes of unmet need. It is not clear whether doctors limit treatment opportunities to patients, nor is it known the effect that patient beliefs and expectations about the operation, including their paid work status and retirement plans, have on the decision to undergo TJA. Identifying socio-economic and other determinants of demand would inform the design of effective and efficient health policy. This review was conducted to identify the factors that lead patients in need to undergo TJA. METHODS: An electronic search of the Embase and Medline (Ovid) bibliographic databases conducted in September 2011 identified studies in the English language that reported on factors driving patients in need of hip or knee replacement to undergo surgery. The review included reports of elective surgery rates in eligible patients or, controlling for disease severity, in general subjects, and stated clinical experts' and patients' opinions on suitability for or willingness to undergo TJA. Quantitative and qualitative studies were reviewed, but quantitative studies involving fewer than 20 subjects were excluded. The quality of individual studies was assessed on the basis of study design (i.e., prospective versus retrospective), reporting of attrition, adjustment for and report of confounding effects, and reported measures of need (self-reported versus doctor-assessed). Reported estimates of effect on the probability of surgery from analyses adjusting for confounders were summarised in narrative form and synthesised in odds ratio (OR) forest plots for individual determinants. RESULTS: The review included 26 quantitative studies-23 on individuals' decisions or views on having the operation and three about health professionals' opinions and 10 qualitative studies. Ethnic and racial disparities in TJA use are associated with socio-economic access factors and expectations about the process and outcomes of surgery. In the United States, health insurance coverage affects demand, including that from the Medicare population, for whom having supplemental Medicaid coverage increases the likelihood of undergoing TJA. Patients with post secondary education are more likely to demand hip or knee surgery than those without it (range of OR 0.87-2.38). Women are as willing to undergo surgery as men, but they are less likely to be offered surgery by specialists than men with the same need. There is considerable variation in patient demand with age, with distinct patterns for hip and knee. Paid employment appears to increase the chances of undergoing surgery, but no study was found that investigated the relationship between retirement plans and demand for TJA. There is evidence of substantial geographical variation in access to joint replacement within the territory covered by a public national health system, which is unlikely to be explained by differences in preference or unmeasured need alone. The literature tends to focus on associations, rather than testing of causal relationships, and is insufficient to assess the relative importance of determinants. CONCLUSIONS: Patients' use of hip and knee replacement is a function of their socio-economic circumstances, which reinforce disparities by gender and race originating in the doctor-patient interaction. Willingness to undergo surgery declines steeply after the age of retirement, at the time some eligible patients may lower their expectations of health status achievement. There is some evidence that paid employment independently increases the likelihood of operation. The relative contribution of variations in surgical decision making to differential access across regions within countries deserves further research that controls for clinical need and patient lifestyle preferences, including retirement decisions. Evidence on this question will become increasingly relevant for service planning and policy design in societies with ageing populations. PMID- 22846146 TI - Expression of eotaxins in the material from nasal brushing in asthma, allergic rhinitis and COPD patients. AB - BACKGROUND: Asthma and COPD are non-infectious inflammatory diseases of the respiratory tract. Allergic rhinitis can be assumed as an intermediate condition between healthy and asthmatic state. Eotaxins are important indicators of allergic reaction. They are strong chemoattractants mainly for eosinophils but also for other cells. OBJECTIVE: We measured the level of eotaxin expression and inflammatory cell count in the material from nasal brushing in healthy controls and in patients with allergic rhinitis, asthma, and COPD. We studied the correlation between the eotaxin gene expression level in the material from nasal brushing and respiratory tests in asthma and COPD patients. METHODS: Expression of eotaxins was measured using quantitative RT-PCR. Number of eotaxin transcript copies was evaluated using real time PCR standard curve method. RESULTS: Of all eotaxins CCL24 had the highest expression in the material from nasal brushing, and its level was increased in allergic asthma. CCL11 was significantly increased in the material from nasal brushing of COPD patients. Increased levels of all three eotaxins were observed in the material from nasal brushing of patients with allergic rhinitis in season. The levels of CCL26 expression and FEV1/FVC factor were correlated negatively in the asthma group and positively in the COPD group. CONCLUSIONS: Eotaxins are crucial factors of allergic, asthmatic and also COPD inflammatory reactions. Our results suggest a dual role of CCL26 - it can act as a negative regulator for neutrophils in COPD, while in asthma it may act as a chemoatractant of eosinophils and other cells into the lung. PMID- 22846147 TI - Intravitreal bevacizumab increases intraocular interleukin-6 levels at 1 day after injection in patients with proliferative diabetic retinopathy. AB - In the present investigation, we evaluated the acute changes in intraocular cytokines after intravitreal injection of an anti-vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR). This analysis may contribute to the understanding of changes in intraocular cytokines after intravitreal bevacizumab (IVB), which is frequently used to reduce permeability and neovascularization in DR. This study was a prospective, open-label, controlled, randomized clinical trial. Eyes of 30 consecutive patients who were scheduled for pars plana vitrectomy (PPV) for proliferative DR (PDR) were prospectively enrolled. All patients were randomly assigned to receive IVB either at 1 (group 1) or 7 (group 2) days before PPV, and aqueous humor samples were taken from the anterior chamber just prior to IVB and PPV. The levels of VEGF, interleukin (IL)-2, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and transforming growth factor-beta(2) (TGF-beta(2)) in aqueous humor were evaluated at each time point-baseline and after IVB. VEGF levels were significantly decreased at day 1 (p=0.003) and the decrease sustained through day 7 (p=0.004). IL-6 increased from 23.26 +/- 26.68 to 1992.88 +/- 2266.87 pg/mL at day 1 (p<0.001) and from 17.13 +/- 19.61 to 207.83 +/- 269.59 pg/mL at day 7 (p=0.001). IL-6 levels were significantly higher at day 1 compared to day 7 (p=0.002). IL-8 showed an increase at days 1 (p=0.003) and 7 (p=0.002) compared to baseline, with no significant differences between the groups (p=0.157). TGF-beta(2) also showed a tendency for an increase at day 7 compared to day 1, but missed statistical significance (p=0.084). No remarkable differences were detected between the 2 groups for IL-2 or for TNF-alpha at both time points. These results suggest that IVB aggravates intraocular inflammatory cytokines, and IL-6 may mediate those inflammatory changes after IVB in the acute period. These findings also suggest a role for IL-6 as an acute mediator for inflammatory changes in pathologic hypoxic conditions. PMID- 22846148 TI - Development of protein biomarkers in cerebrospinal fluid for secondary progressive multiple sclerosis using selected reaction monitoring mass spectrometry (SRM-MS). AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). It involves damage to the myelin sheath surrounding axons and to the axons themselves. MS most often presents with a series of relapses and remissions but then evolves over a variable period of time into a slowly progressive form of neurological dysfunction termed secondary progressive MS (SPMS). The reasons for this change in clinical presentation are unclear. The absence of a diagnostic marker means that there is a lag time of several years before the diagnosis of SPMS can be established. At the same time, understanding the mechanisms that underlie SPMS is critical to the development of rational therapies for this untreatable stage of the disease. RESULTS: Using high performance liquid chromatography-coupled mass spectrometry (HPLC); we have established a highly specific and sensitive selected reaction monitoring (SRM) assay. Our multiplexed SRM assay has facilitated the simultaneous detection of surrogate peptides originating from 26 proteins present in cerebrospinal fluid (CSF). Protein levels in CSF were generally ~200-fold lower than that in human sera. A limit of detection (LOD) was determined to be as low as one femtomol. We processed and analysed CSF samples from a total of 22 patients with SPMS, 7 patients with SPMS treated with lamotrigine, 12 patients with non-inflammatory neurological disorders (NIND) and 10 healthy controls (HC) for the levels of these 26 selected potential protein biomarkers. Our SRM data found one protein showing significant difference between SPMS and HC, three proteins differing between SPMS and NIND, two proteins between NIND and HC, and 11 protein biomarkers showing significant difference between a lamotrigine-treated and untreated SPMS group. Principal component analysis (PCA) revealed that these 26 proteins were correlated, and could be represented by four principal components. Overall, we established an efficient platform to develop and verify protein biomarkers in CSF, which can be easily adapted to other proteins of interest related to neurodegenerative diseases. CONCLUSIONS: A highly specific and sensitive multiplex SRM-MS assay was established for development and verification of CSF protein biomarkers in SPMS. Five proteins were found to be expressed significantly differently between the three cohorts, SPMS, NIND and HC and 11 proteins associated with lamotrigine treatment, which we expect will further our current understanding of SPMS disease pathology and/or therapeutic intervention. PMID- 22846149 TI - Metabolite profiling and a transcriptional activation assay provide direct evidence of androgen receptor antagonism by bisphenol A in fish. AB - Widespread environmental contamination by bisphenol A (BPA) has created the need to fully define its potential toxic mechanisms of action (MOA) to properly assess human health and ecological risks from exposure. Although long recognized as an estrogen receptor (ER) agonist, some data suggest that BPA may also behave as an androgen receptor (AR) antagonist. However, direct evidence of this activity is deficient. To address this knowledge gap, we employed a metabolomic approach using in vivo exposures of fathead minnows (FHM; Pimephales promelas ) to BPA either alone or in a binary mixture with 17beta-trenbolone (TB), a strong AR agonist. Changes in liver metabolite profiles in female FHM in response to these exposures were determined using high resolution (1)H NMR spectroscopy and multivariate and univariate statistics. Using this approach, we observed clear evidence of the ability of BPA to mitigate the impact of TB, consistent with an antiandrogenic MOA. In addition, a transcriptional activation assay with the FHM AR was used to confirm the AR antagonistic activity of BPA in vitro. The results of these in vivo and in vitro analyses provide strong and direct evidence for ascribing an antiandrogenic MOA to BPA in vertebrates. PMID- 22846150 TI - Applicability of the ankle-brachial-index measurement as screening device for high cardiovascular risk: an observational study. AB - BACKGROUND: Screening with ankle-brachial index (ABI) measurement could be clinically relevant to avoid cardiovascular events in subjects with asymptomatic atherosclerosis. To assess the practical impact of guidelines regarding the use of ABI as a screening tool in general practice, the corresponding number needed to screen, including the required time investment, and the feasibility of ABI performance, was assessed. METHODS: An observational study was performed in the setting of 955 general practices in the Netherlands. Overall, 13,038 subjects of >=55 years presenting with symptoms of intermittent claudication and/or presenting with >= one vascular risk factor were included. Several guidelines recommend the ABI as an additional measurement in selected populations for risk assessment for cardiovascular morbidity. RESULTS: Screening of the overall population of >=50 years results in ~ 862 subjects per general practice who should be screened, resulting in a time-requirement of approximately 6 weeks of full time work. Using an existing clinical prediction model, 247 patients per general practice should be screened for PAD by ABI measurement. CONCLUSION: Screening the entire population of >=50 years will in our opinion not be feasible in general practice. A more rationale and efficient approach might be screening of subsets of the population of >=55 years based on a clinical prediction model. PMID- 22846151 TI - High-throughput phenotyping of avoidance learning in mice discriminates different genotypes and identifies a novel gene. AB - Recognizing and avoiding aversive situations are central aspects of mammalian cognition. These abilities are essential for health and survival and are expected to have a prominent genetic basis. We modeled these abilities in eight common mouse inbred strains covering ~75% of the species' natural variation and in gene trap mice (>2000 mice), using an unsupervised, automated assay with an instrumented home cage (PhenoTyper) containing a shelter with two entrances. Mice visited this shelter for 20-1200 times/24 h and 71% of all mice developed a significant and often strong preference for one entrance. Subsequently, a mild aversive stimulus (shelter illumination) was automatically delivered when mice used their preferred entrance. Different genotypes developed different coping strategies. Firstly, the number of entries via the preferred entrance decreased in DBA/2J, C57BL/6J and 129S1/SvImJ, indicating that these genotypes associated one specific entrance with the aversive stimulus. Secondly, mice started sleeping outside (C57BL/6J, DBA/2J), indicating they associated the shelter, in general, with the aversive stimulus. Some mice showed no evidence for an association between the entrance and the aversive light, but did show markedly shorter shelter residence times in response to illumination, indicating they did perceive illumination as aversive. Finally, using this assay, we screened 43 different mutants, which yielded a novel gene, specc1/cytospinB. This mutant showed profound and specific delay in avoidance learning. Together, these data suggest that different genotypes express distinct learning and/or memory of associations between shelter entrance and aversive stimuli, and that specc1/cytospinB is involved in this aspect of cognition. PMID- 22846152 TI - Phenetic and genetic structure of tsetse fly populations (Glossina palpalis palpalis) in southern Ivory Coast. AB - BACKGROUND: Sleeping sickness, transmitted by G. p. palpalis, is known to be present in the Ivory Coast. G. p. palpalis has recently been reported to occur in several places within the town of Abidjan, including: (i) the Banco forest, (ii) the Abobo Adjame University campus and (iii) the zoological park. Could these three places be treated sequentially, as separate tsetse populations, or should they be taken as one area comprising a single, panmictic population? METHODS: The amount of gene flow between these places provides strategic information for vector control. It was estimated by the use of both microsatellite DNA and morphometric markers. The idea was to assess the interest of the faster and much less expensive morphometric approach in providing relevant information about population structure. Thus, to detect possible lack of insect exchange between these neighbouring areas of Abidjan, we used both genetic (microsatellite DNA) and phenetic (geometric morphometrics) markers on the same specimens.Using these same markers, we also compared these samples with specimens from a more distant area of south Ivory Coast, the region of Aniassue (186 km north from Abidjan). RESULTS: Neither genetic nor phenetic markers detected significant differentiation between the three Abidjan G. p. palpalis samples. Thus, the null hypothesis of a single panmictic population within the city of Abidjan could not be rejected, suggesting the control strategy should not consider them separately. The markers were also in agreement when comparing G. p. palpalis from Abidjan with those of Aniassue, showing significant divergence between the two sites. CONCLUSIONS: Both markers suggested that a successful control of tsetse in Abidjan would require the three Abidjan sites to be considered together, either by deploying control measures simultaneously in all three sites, or by a continuous progression of interventions following for instance the "rolling carpet" principle. To compare the geometry of wing venation of tsetse flies is a cheap and fast technique. Agreement with the microsatellite approach highlights its potential for rapid assessment of population structure. PMID- 22846153 TI - Hallucinations in severe, repeated Sydenham's chorea in an Indigenous girl in North-West Queensland. AB - Sydenham's chorea is a cardinal feature of rheumatic fever. It is known by its dyskinesia and susceptibility to carditis, but associated psychiatric disorder is being recognised. This has included tics and obsessive compulsive disorder, but we report hallucinations in an indigenous girl, suffering her third bout of chorea. PMID- 22846154 TI - Experimental efficacy of mycophenolate mofetil implant on high-risk corneal allograft rejection and its biocompatibility in the anterior chamber of rabbits. AB - PURPOSE: The aim of this study was to investigate the immunosuppressive activity of a mycophenolate mofetil (MMF) intraocular-implantable drug delivery system (IDDS) in a rabbit model of high-risk penetrating keratoplasty and to determine the biocompatibility of such a device when implanted in the anterior chamber. METHODS: Corneal vascularization was induced in New Zealand white rabbits by passing 5-0 silk sutures through the corneal stroma in each quadrant. The corneal neovascularized rabbits received a unilateral 7-mm-diameter central-penetrating keratoplasty. New Zealand white rabbits were used as donors and were divided into 4 treatment groups: the control group, which received no therapy; the 1% MMF eye drop group; the 1.0 mg cyclosporin A (CsA)-IDDS-implanted group; and the 1.0 mg MMF-IDDS-implanted group. Animals were followed up for 150 days, which involved examination of the corneal allografts (opacity, edema, and neovascularization) by slit-lamp biomicroscopy. The survival time of corneal allografts of these animal models was recorded in 4 groups. Histopathologic studies were carried out on the procured specimens of corneal allografts. The biocompatibility of MMF-IDDS in the anterior chamber in rabbits was also investigated. RESULTS: The mean survival time of corneal allografts in the control and MMF eye drop groups was 18.7+/-3.0 and 37.5+/-6.2 days, respectively (P=0.005). Allografts from the CsA-IDDS implanted group were transparent, except 1 allograft, which showed immune rejection after 130 days. Allografts from the MMF-IDDS-implanted group were transparent throughout the entire observation period. The incidence of allograft rejection was 100% in the control and MMF eye drop groups, respectively. The rejected allografts were much more edematous and more heavily infiltrated with leukocytes than the nonrejected allografts. MMF-IDDS was tolerated well in the anterior chamber, even with 3 MMF-IDDS implanted in the anterior chamber at 1 time. CONCLUSIONS: MMF-IDDS was able to prolong high-risk allograft survival time and significantly inhibited corneal immune rejection in the rabbit model of penetrating keratoplasty. The device could safely be implanted in the anterior chamber without adverse effects. PMID- 22846155 TI - What is the WHO essential medicines list? AB - This article briefly presents the main characteristics of the World Health Organization (WHO) essential medicines list (EML), a register of minimum medicine needs for every health-care system. The idea behind the list is that the use of a limited number of well-known and cost-effective medicines may lead to improved long-term medicine supply, lower costs and better health care provision. PMID- 22846156 TI - Janus colloidal matchsticks. AB - We fabricated chemically and shape-anisotropic colloids composed of silica rods coated with gold tips using a multistep process involving electric-field alignment and crystallization, microcontact printing, and selective metallization. Through direct observation, we found that these "Janus matchsticks" self-assemble into multipods (bi-, tri-, and tetrapods) of varying coordination number and patch angle in aqueous solution. PMID- 22846157 TI - Influence of cellular fatty acid composition on the response of Saccharomyces cerevisiae to hydrostatic pressure stress. AB - High hydrostatic pressure (HHP) interferes with cellular membrane structure. The orientation of lipid molecules is changed, especially in the vicinity of proteins, leading to decreased membrane fluidity. Adaptation to HHP requires increased membrane fluidity, often achieved through a rise in the proportion of unsaturated fatty acids. In this work, a desaturase-deficient Saccharomyces cerevisiae mutant strain (OLE1 gene deletion) was grown in media supplemented with fatty acids differing in size and number of unsaturations and submitted to pressure up to 200 MPa for 30 min. Desaturase-deficient yeast supplemented with palmitoleic acid demonstrated increased sensitivity to pressure compared to cells supplemented with oleic acid or a proportionate mixture of both acids. In contrast, yeast cells grown with linoleic and linolenic acids were more piezoresistant than cells treated with oleic acid. Furthermore, growth with palmitoleic acid led to higher levels of lipid peroxidation. Intracellular trehalose during HHP treatment increased cell tolerance to pressure. However, when trehalose remained extracellular cells were sensitised to pressure. Therefore, fatty acid composition and trehalose content might play a role in the protection of the cell membrane from oxidative damage produced by HHP, confirming that alteration in cell membrane fluidity is correlated with pressure resistance in yeast. PMID- 22846158 TI - Glutamine-fueled mitochondrial metabolism is decoupled from glycolysis in melanoma. AB - In this perspective, we revise the historic notion that cancer is a disease of mitochondria. We summarize recent findings on the function and rewiring of central carbon metabolism in melanoma. Metabolic profiling studies using stable isotope tracers show that glycolysis is decoupled from the tricarboxylic acid (TCA) cycle. This decoupling is not 'dysfunction' but rather an alternate wiring required by tumor cells to remain metabolically versatile. In large part, this requirement is met by glutamine feeding the TCA cycle as an alternative source of carbon. Glutamine is also used in non-conventional ways, like traveling in reverse through the TCA flux to feed fatty acid biosynthesis. Biosynthetic networks linked with non-essential amino acids alanine, serine, arginine, and proline are also significantly impacted by the use of glutamine as an alternate carbon source. PMID- 22846160 TI - Re: Murine double minute 2 promoter SNP309 polymorphism and prostate cancer risk: a meta-analysis. PMID- 22846159 TI - Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression. AB - AIM: Presynaptic and post-synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post-synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression. METHODS: In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week-1 to 20 mg) in a randomized, double-blind, parallel group, 8 week study. Patients were evaluated weekly using the 17-item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups. RESULTS: A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (gamma, 95% confidence interval [CI]) best described the data (gamma(memantine) = 1.8, 95% CI 0.9, 3.6), gamma(placebo) = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5). CONCLUSIONS: This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients. PMID- 22846161 TI - Factor structure of the Communicator Styles Measure (CSM) when used with undergraduate health science students. AB - BACKGROUND: It is important for educators to consider the communication skills of students enrolled in health science programmes. To date, research into this area is limited, and having measures that are valid and reliable would assist educators and researchers to complete high-quality investigations. PURPOSE: The purpose of this study was to investigate the factor structure of Communicator Styles Measure. METHOD: Data from the Communicator Styles Measure completed by 860 undergraduate health science students enrolled in eight different courses at an Australian university (response rate of 59%) were analysed using principal component analysis with varimax rotation and a cluster analysis using elementary linkage analysis. The Communicator Styles Measure is a self-report scale consisting of 40 items designed to assess ten communication styles and one's perception of his/her ability to communicate. RESULTS: Communicator Styles Measure items loaded onto five new viable factors labelled personable, energetic, confident, open and confronting. Six items of the original 40 from the Communicator Styles Measure did not load onto any factor and were therefore considered redundant. CONCLUSION: The original factor structure proposed by the Communicator Styles Measure's author was not supported, which calls into question its construct validity. However, the five new factors identified in this study may be useful for researchers and educators when assessing the communication skills of students and practitioners. Further investigation into the construct validity and reliability of the five new Communicator Styles Measure factors is recommended. PMID- 22846162 TI - Reasons behind non-adherence of healthcare practitioners to pediatric asthma guidelines in an emergency department in Saudi Arabia. AB - BACKGROUND: The prevalence of childhood bronchial asthma in Saudi Arabia has increased in less than a decade from 8% to 23%. Innovations in the management of asthma led to the development of evidence based clinical practice guidelines and protocols to improve the patients' outcomes. The objectives of this study are to examine the compliance of the healthcare providers in the Pediatrics Emergency Department, in King Khalid University Hospital, with the recommendations of the Pediatrics Asthma Management Protocol (PAMP), and to explore the reasons behind non-adherence. METHODS: This study is designed in 2 parts, a patients' chart review and a focus group interview. The medical records of all the children who presented to the Pediatric Emergency Department (PED) and were diagnosed as asthmatic, during the period from the 1st of January 2009 to the 31st of March 2009, were reviewed to investigate the compliance of healthcare providers (physicians and nurses) with 8 recommendations of the PAMP which are considered to be frequently encountered evidence-practice gaps, and these are 1) documentation of asthma severity grading by the treating physician and nurse 2) limiting the prescription of Ipratropium for children with severe asthma 3) administration of Salbutamol through an inhaler and a spacer 4) documentation of parental education 5) prescription of systemic corticosteroids to all cases of acute asthma 6) limiting chest x-ray requisition for children with suspected chest infection 7) management of all cases of asthma as outpatients, unless diagnosed as severe or life threatening asthma 8) limiting prescription of antibiotics to children with chest infection. The second part of this study is a focus group interview designed to elicit the reasons behind non-adherence to the recommendations detected by the chart review. Two separate focus group interviews were conducted for 10 physicians and 10 nurses. The focus group interviews were tape-recorded and transcribed verbatim. Theory-based content analysis was used to analyze interviews into themes and sub-themes. RESULTS AND DISCUSSION: A total of 657 charts were reviewed. The percentage of adherence by the healthcare providers to the 8 previously mentioned recommendations was established. There was non adherence to the first 5 of the 8 aforementioned recommendations. Analysis of the focus group interview revealed 3 main themes as reasons behind non-compliance to the 5 recommendations mentioned above and those are 1) factors related to the organization, 2) factors related to the asthma management protocol 3) factors related to healthcare providers. CONCLUSION: The organizational barriers and the lack of an implementation strategy for the protocol, in addition to the attitude and beliefs of the healthcare providers, are the main factors behind non compliance to the PAMP recommendations. PMID- 22846163 TI - Approximating evolutionary dynamics on networks using a Neighbourhood Configuration model. AB - Evolutionary dynamics have been traditionally studied on homogeneously mixed and infinitely large populations. However, real populations are finite and characterised by complex interactions among individuals. Recent studies have shown that the outcome of the evolutionary process might be significantly affected by the population structure. Although an analytic investigation of the process is possible when the contact structure of the population has a simple form, this is usually infeasible on complex structures and the use of various assumptions and approximations is necessary. In this paper, we adopt an approximation method which has been recently used for the modelling of infectious disease transmission to model evolutionary game dynamics on complex networks. Comparisons of the predictions of the model constructed with the results of computer simulations reveal the effectiveness of the method and the improved accuracy that it provides when, for example, compared to well-known pair approximation methods. This modelling framework offers a flexible way to carry out a systematic analysis of evolutionary game dynamics on graphs and to establish the link between network topology and potential system behaviours. As an example, we investigate how the Hawk and Dove strategies in a Hawk-Dove game spread in a population represented by a random regular graph, a random graph and a scale-free network, and we examine the features of the graph which affect the evolution of the population in this particular game. PMID- 22846164 TI - Special issue: International Conference on Systems Biology 2011. Introduction. AB - The International Conference on Systems Biology 2011 represented one of the so far largest conferences in the rapidly growing field of systems biology. The integration of quantitative experimental data and computational modeling is central in this field. This special issue contains a series of studies that conclude and finalise representative results presented at the ICSB that exploit the advantages of this interdisciplinary approach. PMID- 22846165 TI - Severe Plasmodium vivax malaria among sudanese children at New Halfa Hospital, Eastern Sudan. AB - BACKGROUND: There are few published reports on severe Plasmodium vivax malaria in Africa. METHODS: Clinical pattern/manifestations of severe P. vivax were described in children admitted at New Halfa Hospital in Sudan between September 2009-December 2011. RESULTS: Eighteen children were admitted at the hospital during the study period with different manifestations of severe P. vivax malaria namely: severe anaemia (6, 33.3%), jaundice (5, 27.8%), thrombocytopenia (4, 22.2%), hypotension (3, 16.7%), cerebral malaria (2, 11.1%), epistaxis (2, 11.1%), renal impairment (1, 5.5%), hypogylcaemia and more than one manifestation (5, 27.8%). CONCLUSION: Severe P. vivax malaria is an existing entity in eastern Sudan. Further studies are required to understand emergence of severe P. vivax malaria. PMID- 22846167 TI - Lessons learned from a lipid lowering trial in adolescents with type 1 diabetes. AB - Herein, we describe recruitment efforts for a trial of lipid-lowering medications in adolescents with type 1 diabetes, age 12-21 years. Based on our experience, future studies will require multiple centers to enroll a sufficient number of participants for adequate data to direct dyslipidemia medication treatment guidelines for adolescents with type 1 diabetes. PMID- 22846166 TI - Subchronic inhalation exposure study of an airborne polychlorinated biphenyl mixture resembling the Chicago ambient air congener profile. AB - Although inhalation of atmospheric polychlorinated biphenyls (PCBs) is the most universal exposure route and has become a substantial concern in urban areas, research is lacking to determine the body burden of inhaled PCBs and consequent health effects. To reflect the Chicago airshed environment and mimic the PCB profile in Chicago air, we generated vapors from a Chicago air mixture (CAM). Sprague-Dawley rats were exposed to the CAM vapor for 1.6 h/day via nose-only inhalation for 4 weeks, 520 +/- 10 MUg/m(3). Congener-specific quantification in tissue and air samples was performed by gas chromatography-tandem mass spectrometry (GC/MS/MS). In contrast to the lower-chlorinated congener-enriched vapor, body tissues mainly contained tri- to hexachlorobiphenyls. Congener profiles varied between vapor and tissues and among different organs. The toxic equivalence (TEQ) and neurotoxic equivalence (NEQ) were also investigated for tissue distribution. We evaluated a variety of end points to catalogue the effects of long-term inhalation exposure, including immune responses, enzyme induction, cellular toxicity, and histopathologic abnormalities. Glutathione oxidized/reduced ratio (GSSG/GSH) was increased in the blood of exposed animals, accompanied by elevation of hematocrit. This study demonstrated that inhalation contributed to the body burden of mostly tri- to hexachlorobiphenyls and produced a distinct profile of congeners in tissue, yet minimal toxicity was found at this exposure dose, estimated at 134 MUg/rat. PMID- 22846168 TI - CD26 protease inhibition improves functional response of unfractionated cord blood, bone marrow, and mobilized peripheral blood cells to CXCL12/SDF-1. AB - Hematopoietic stem cell transplantation (HSCT) is an important treatment option for patients with malignant and nonmalignant hematologic diseases. Methods to improve transplant efficiency are being explored with the intent to improve engraftment and immune reconstitution post-HSCT. A current approach under investigation involves treatment of donor cells with inhibitors that target the protease CD26, a negative regulator of the chemokine CXCL12/stromal cell-derived factor-1. CD26 inhibitor treatment has been shown to improve the functional response of CD34(+) cord blood (CB) cells, but not CD34(+) granulocyte colony stimulating factor-mobilized peripheral blood stem cells, to CXCL12/stromal cell derived factor-1. The effect of CD26 inhibitors on unfractionated CB, bone marrow, or granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells has not been evaluated previously. We observed that although CB had greater CD26 expression than bone marrow or mobilized peripheral blood, treatment with a CD26 inhibitor (Diprotin A) resulted in increased responsiveness to stromal cell-derived factor-1 for all three mononuclear cell sources tested. This suggests that clinical therapeutic benefit might be gained by using CD26 inhibitors as a strategy to improve engraftment of unfractionated mobilized peripheral blood cells as well as CB cells. PMID- 22846169 TI - A human-computer collaborative approach to identifying common data elements in clinical trial eligibility criteria. AB - OBJECTIVE: To identify Common Data Elements (CDEs) in eligibility criteria of multiple clinical trials studying the same disease using a human-computer collaborative approach. DESIGN: A set of free-text eligibility criteria from clinical trials on two representative diseases, breast cancer and cardiovascular diseases, was sampled to identify disease-specific eligibility criteria CDEs. In this proposed approach, a semantic annotator is used to recognize Unified Medical Language Systems (UMLSs) terms within the eligibility criteria text. The Apriori algorithm is applied to mine frequent disease-specific UMLS terms, which are then filtered by a list of preferred UMLS semantic types, grouped by similarity based on the Dice coefficient, and, finally, manually reviewed. MEASUREMENTS: Standard precision, recall, and F-score of the CDEs recommended by the proposed approach were measured with respect to manually identified CDEs. RESULTS: Average precision and recall of the recommended CDEs for the two diseases were 0.823 and 0.797, respectively, leading to an average F-score of 0.810. In addition, the machine-powered CDEs covered 80% of the cardiovascular CDEs published by The American Heart Association and assigned by human experts. CONCLUSION: It is feasible and effort saving to use a human-computer collaborative approach to augment domain experts for identifying disease-specific CDEs from free-text clinical trial eligibility criteria. PMID- 22846170 TI - Continuous time Bayesian network classifiers. AB - The class of continuous time Bayesian network classifiers is defined; it solves the problem of supervised classification on multivariate trajectories evolving in continuous time. The trajectory consists of the values of discrete attributes that are measured in continuous time, while the predicted class is expected to occur in the future. Two instances from this class, namely the continuous time naive Bayes classifier and the continuous time tree augmented naive Bayes classifier, are introduced and analyzed. They implement a trade-off between computational complexity and classification accuracy. Learning and inference for the class of continuous time Bayesian network classifiers are addressed, in the case where complete data are available. A learning algorithm for the continuous time naive Bayes classifier and an exact inference algorithm for the class of continuous time Bayesian network classifiers are described. The performance of the continuous time naive Bayes classifier is assessed in the case where real time feedback to neurological patients undergoing motor rehabilitation must be provided. PMID- 22846172 TI - The metabolic response of Candida albicans to farnesol under hyphae-inducing conditions. AB - Farnesol is a quorum-sensing molecule (QSM) produced, and sensed, by the polymorphic fungus, Candida albicans. This cell-to-cell communication molecule is known to suppress the hyphal formation of C. albicans at high cell density. Despite many studies investigating the signalling mechanisms by which QSMs influence the morphogenesis of C. albicans, the downstream metabolic effect of these signalling pathways in response to farnesol-mediated morphogenesis remains obscure. Here, we have used metabolomics to investigate the metabolic response of C. albicans upon exposure to farnesol under hyphae-inducing conditions. We have found a general up-regulation of central carbon metabolic pathways when hyphal formation was suppressed by farnesol evidenced by a considerably larger number of central carbon metabolic intermediates detected under this condition at an overall lower intracellular level. By combining the metabolic profiles from farnesol-exposed cells with previous metabolomics data for C. albicans undergoing morphogenesis, we have identified several metabolic pathways that are likely to be associated with the morphogenetic process of C. albicans, as well as metabolic pathways such as those involved in lipid metabolism that appeared to be specifically affected by farnesol. Therefore, our results provide important new insights into the metabolic role of farnesol in C. albicans metabolism. PMID- 22846173 TI - Therapy failure resulting from superinfection by a drug-resistant HIV variant. AB - BACKGROUND: HIV-1-infected patients can be superinfected with additional HIV-1 variants. Therapy failure can be the consequence of an infection with a resistant strain. METHODS: A patient was diagnosed with a recent HIV-1 infection in April 2005 and subsequently clinically monitored. HIV-1 evolution was studied by population sequencing of the first 984 bases of the pol gene as well as 454 ultra deep pyrosequencing (UDPS) of parts of the pol and env genes. RESULTS: The patient was diagnosed with a wild-type HIV-1 strain, but experienced rapid virological failure after initiating a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimen 3 years later. Population sequencing and UDPS revealed the presence of a second HIV-1 strain with a Y188L NNRTI resistance mutation in a sample obtained shortly prior to initiation of therapy. Phylogenetic analyses showed that the two HIV-1 strains were genetically distinct, providing evidence for superinfection. CONCLUSIONS: The virological treatment failure in this patient was probably due to the superinfection with an NNRTI-resistant HIV-1 variant. Superinfection with drug-resistant strains can undermine HIV-1 treatment regimens selected on the basis of resistance testing at diagnosis. Patients, especially in high-risk groups, as well as their clinicians, should be aware of the risks and dangers of superinfections. PMID- 22846171 TI - Investigating clinical heterogeneity in systematic reviews: a methodologic review of guidance in the literature. AB - BACKGROUND: While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. The objective of this study is to summarize and collate suggested methods for investigating clinical heterogeneity in systematic reviews. METHODS: We searched databases (Medline, EMBASE, CINAHL, Cochrane Library, and CONSORT, to December 2010) and reference lists and contacted experts to identify resources providing suggestions for investigating clinical heterogeneity between controlled clinical trials included in systematic reviews. We extracted recommendations, assessed resources for risk of bias, and collated the recommendations. RESULTS: One hundred and one resources were collected, including narrative reviews, methodological reviews, statistical methods papers, and textbooks. These resources generally had a low risk of bias, but there was minimal consensus among them. Resources suggested that planned investigations of clinical heterogeneity should be made explicit in the protocol of the review; clinical experts should be included on the review team; a set of clinical covariates should be chosen considering variables from the participant level, intervention level, outcome level, research setting, or others unique to the research question; covariates should have a clear scientific rationale; there should be a sufficient number of trials per covariate; and results of any such investigations should be interpreted with caution. CONCLUSIONS: Though the consensus was minimal, there were many recommendations in the literature for investigating clinical heterogeneity in systematic reviews. Formal recommendations for investigating clinical heterogeneity in systematic reviews of controlled trials are required. PMID- 22846175 TI - SUMO, PTEN and Tumor Suppression. AB - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was identified in 1997 as a tumor suppressor gene through mapping of homozygous mutations occurring in multiple sporadic tumor types and in patients with cancer predisposition syndromes including Cowden disease (Song et al., 2012). Since that time, PTEN has emerged as one of the most frequently mutated or deleted genes in human cancers, including human skin cancers. In particular, loss of PTEN function through mutation or deletion has been observed in up to 70% of melanoma cell lines, and epigenetic silencing of PTEN has been observed in 30-40% of malignant melanomas (Mehnert and Kluger, 2012). PMID- 22846174 TI - An investigation of visual contour integration ability in relation to writing performance in primary school students. AB - A previous study found a visual deficit in contour integration in English readers with dyslexia (Simmers & Bex, 2001). Visual contour integration may play an even more significant role in Chinese handwriting particularly due to its logographic presentation (Lam, Au, Leung, & Li-Tsang, 2011). The current study examined the relationship between children's performance in visual contour (VC) integration and Chinese handwriting. Twenty students from grade 3 to grade 6 were recruited (M=9.51, SD=1.02) from a mainstream primary school using the convenience sampling method. Ten students were identified by teachers as having handwriting problems, and the other 10 were typical students. Participants performed the VC tasks and their handwriting performance was assessed by a Chinese Handwriting Assessment Tool (CHAT) in a classroom setting. Correlation analyses revealed that VC accuracy was significantly and negatively correlated with on paper time and total writing duration. t-Test analyses revealed statistically significant differences in VC accuracy between students with typical and poor handwriting, with consistently better VC accuracy performance in all conditions in the typical handwriting group. The results may have important implications for interventions aiming at improving children's handwriting. PMID- 22846176 TI - Impact of assimilable nitrogen availability in glucose uptake kinetics in Saccharomyces cerevisiae during alcoholic fermentation. AB - BACKGROUND: The expression and activity of the different Saccharomyces cerevisiae hexose uptake systems (Hxt) and the kinetics of glucose uptake are considered essential to industrial alcoholic fermentation performance. However, the dynamics of glucose uptake kinetics during the different stages of fermentation, depending on glucose and nitrogen availability, is very poorly characterized. The objective of the present work was to examine thoroughly the alterations occurring in glucose uptake kinetics during alcoholic fermentation, by the wine strain S. cerevisiae PYCC 4072, of a synthetic grape juice basal medium with either a limiting or non-limiting initial nitrogen concentration and following nitrogen supplementation of the nitrogen-depleted sluggish fermentation. RESULTS: Independently of the initial concentration of the nitrogen source, glucose transport capacity is maximal during the early stages of fermentation and presumably sustained by the low-affinity and high-capacity glucose transporter Hxt1p. During nitrogen-limited sluggish fermentation, glucose uptake capacity was reduced to approximately 20% of its initial values (Vmax = 4.9 +/- 0.8 compared to 21.9 +/- 1.2 MUmol h-1 10-8 cells), being presumably sustained by the low affinity glucose transporter Hxt3p (considering the calculated Km = 39.2 +/- 8.6 mM). The supplementation of the sluggish fermentation broth with ammonium led to the increase of glucose transport capacity associated to the expression of different glucose uptake systems with low and high affinities for glucose (Km = 58.2 +/- 9.1 and 2.7 +/- 0.4 mM). A biclustering analysis carried out using microarray data, previously obtained for this yeast strain transcriptional response to equivalent fermentation conditions, indicates that the activation of the expression of genes encoding the glucose transporters Hxt2p (during the transition period to active fermentation) and Hxt3p, Hxt4p, Hxt6p and Hxt7p (during the period of active fermentation) may have a major role in the recovery of glucose uptake rate following ammonium supplementation. These results suggest a general derepression of the glucose-repressible HXT genes and are consistent with the downregulation of Mig1p and Rgt1p. CONCLUSIONS: Although reduced, glucose uptake rate during nitrogen-limited fermentation is not abrogated. Following ammonium supplementation, sluggish fermentation recovery is associated to the increase of glucose uptake capacity, related to the de novo synthesis of glucose transporters with different affinity for glucose and capacity, presumably of Hxt2p, Hxt3p, Hxt4p, Hxt6p and Hxt7p. This study is a contribution to the understanding of yeast response to different stages of alcoholic fermentation at the level of glucose uptake kinetics, in particular under nitrogen limitation or replenish, which is useful knowledge to guide fermentation practices. PMID- 22846177 TI - Dynamic behaviors of vimentin induced by interaction with GlcNAc molecules. AB - The cytoskeleton protein vimentin is dramatically altered following pathological events such as fibrosis and tumorigenesis. Vimentin binds to multivalent N acetylglucosamine (GlcNAc) molecules at the cell surface and interacts with O linked beta-GlcNAc proteins. Moreover, dying cells can be engulfed by neighboring cells through surface interactions between vimentin and many O-GlcNAc proteins in cell debris. Here, we show that vimentin was altered by its interaction with GlcNAc-bearing molecules such as GlcNAc-bearing polymers. The interaction with GlcNAc-bearing polymers promoted the cell surface recruitment of vimentin followed by the phosphorylation of vimentin serine 71 and the increase in tetrameric vimentin disassembled from vimentin filaments in HeLa cells. Moreover, it was found that GlcNAc-bearing polymers and O-GlcNAc proteins from dying cells promoted vimentin expression and cell migration in the Madin-Darby canine kidney and Michigan Cancer Foundation-7 cells. These results suggest that interactions between surface vimentin and GlcNAc molecules, including the O-GlcNAc proteins from dying cells, may play a pivotal role in vimentin expression and the migration of cancer cells. We propose new mechanisms of vimentin expression in cancer cells. PMID- 22846178 TI - Conclusions via unique predictions obtained despite unidentifiability--new definitions and a general method. AB - It is often predicted that model-based data analysis will revolutionize biology, just as it has physics and engineering. A widely used tool within such analysis is hypothesis testing, which focuses on model rejections. However, the fact that a systems biology model is non-rejected is often a relatively weak statement, as such models usually are highly over-parametrized with respect to the available data, and both parameters and predictions may therefore be arbitrarily uncertain. For this reason, we formally define and analyse the concept of a core prediction. A core prediction is a uniquely identified property that must be fulfilled if the given model structure is to explain the data, even if the individual parameters are non-uniquely identified. It is shown that such a prediction is as strong a conclusion as a rejection. Furthermore, a new method for core prediction analysis is introduced, which is beneficial for the uncertainty of specific model properties, as the method only characterizes the space of acceptable parameters in the relevant directions. This avoids the curse of dimensionality associated with the generic characterizations used by previously proposed methods. Analysis on examples shows that the new method is comparable to profile likelihood with regard to practical identifiability, and thus generalizes profile likelihood to the more general problem of observability. If used, the concepts and methods presented herein make it possible to distinguish between a conclusion and a mere suggestion, which hopefully will contribute to a more justified confidence in systems biology analyses. PMID- 22846179 TI - CYP1A1 MspI polymorphism and acute myeloid leukemia risk: meta-analyses based on 5018 subjects. AB - BACKGROUND: Evidence indicates that CYP1A1 MspI polymorphism might be a possible risk factor for several malignancies. A growing body of literature has been devoted to the association of CYP1A1 MspI polymorphism with acute myeloid leukemia (AML). However, the results remain conflicting. The aim of the present study was to derive a more precise estimation of the relationship. METHODS: Meta analyses assessing the association of CYP1A1 MspI variation with AML were conducted and subgroup analyses on ethnicity and age groups were further performed. Eligible studies were identified for the period up to May 2012. RESULTS: A total of ten case-control studies including 1330 cases and 3688 controls were selected for analysis. The overall data failed to indicate a significant association of CYP1A1 MspI polymorphism with AML risk (C vs T: OR = 1.13; 95%CI = 0.87-1.48; CC vs TT: OR = 1.72; 95%CI = 0.99-3.01; CC + TC vs TT: OR = 1.16; 95%CI = 0.86-1.55). In subgroup analysis stratified by ethnicity, significant AML risk was shown among Asians (CC + TC vs TT: OR = 1.33; 95%CI = 1.09-1.62) but not Caucasians or mixed races. In subgroup analysis regarding age groups, no associations were observed in either the childhood AML or the adult AML subgroups. CONCLUSION: The results of the present study suggested that CYP1A1 MspI polymorphism might be a risk factor for AML among Asians. Further investigations are needed to confirm the conclusions. PMID- 22846181 TI - Superimposed preeclampsia in women with chronic kidney disease. AB - AIM: To evaluate whether pregnant women with chronic kidney disease (CKD) adapt poorly to increases in renal blood flow. This can exacerbate renal function and impair perinatal outcome, as there is a major interplay between CKD and preeclampsia (PE). METHODS: We analyzed the outcomes of 90 pregnant women with preexisting CKD. The estimated glomerular filtration rate (eGFR) was measured along with the levels of angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor, which might act in the pathophysiology of PE. RESULTS: In pregnancies with CKD, PE and preterm delivery were increased and the increased blood pressure worsened the perinatal outcomes much more than the increased proteinuria. All pregnancies with severe renal insufficiency were delivered preterm because of impaired renal function. The eGFR was correlated significantly with 24-hour creatinine clearance (r = 0.830). Significant differences in sFlt-1 and placental growth factor levels were found between severe PE without any complications and severe superimposed PE (p < 0.05), and between women with and without declining renal function in superimposed PE (p < 0.01). CONCLUSION: Pregnancies with CKD have a high risk of obstetrical complications. The eGFR might serve for evaluating renal function during pregnancy. Angiogenic factors might be potential markers for a differential diagnosis between PE and worsening renal function. PMID- 22846180 TI - Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans. AB - BACKGROUND: The human granulocyte colony-stimulating factor (G-CSF) is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim. RESULTS: Model equations are based on our physiological understanding of the drugs which are delayed absorption of G CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which is valid for all scenarios considered. Differences in pharmacokinetic parameter estimates between Filgrastim and Pegfilgrastim were biologically plausible throughout. CONCLUSION: We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis under chemotherapy and applications of two different G-CSF derivatives. We aim to apply the model to a large variety of chemotherapy regimen in the future in order to optimize corresponding G-CSF schedules or to individualize G-CSF treatment according to the granulotoxic risk of a patient. PMID- 22846182 TI - Impaired distensibility of ascending aorta in patients with HIV infection. AB - BACKGROUND: Our aim was to investigate the aortic distensibility (AD) of the ascending aorta and carotid artery intima-media thickness (c-IMT) in HIV-infected patients compared to healthy controls. METHODS: One hundred and five HIV-infected patients (86 males [82%], mean age 41 +/- 0.92 years), and 124 age and sex matched HIV-1 uninfected controls (104 males [84%], mean age 39.2 +/- 1.03 years) were evaluated by high-resolution ultrasonography to determine AD and c-IMT. For all patients and controls clinical and laboratory factors associated with atherosclerosis were recorded. RESULTS: HIV- infected patients had reduced AD compared to controls: 2.2 +/- 0.01 vs. 2.62 +/- 0.01 10(-6) cm(2) dyn(-1), respectively (p < 0.001). No difference was found in c-IMT between the two groups. In multiadjusted analysis, HIV infection was independently associated with decreased distensibility (beta -0.45, p < 0.001). Analysis among HIV infected patients showed that patients exposed to HAART had decreased AD compared to HAART-naive patients [mean (SD): 2.18(0.02) vs. 2.28(0.03) 10(-6) cm(2) dyn( 1), p = 0.01]. In multiadjusted analysis, increasing age and exposure to HAART were independently associated with decreased AD. CONCLUSION: HIV infection is independently associated with decreased distensibility of the ascending aorta, a marker of subclinical atherosclerosis. Increasing age and duration of exposure to HAART are factors further contributing to decreased AD. PMID- 22846184 TI - Non-small-cell lung carcinoma subtyping on cytology without the use of immunohistochemistry - can we meet the challenge? AB - OBJECTIVE: Recent advances in lung carcinoma therapy have led to a new emphasis on the subtyping of non-small-cell carcinomas of the lung which has led pathologists to readdress the approach to small biopsies and cytology in lung cancer diagnosis. A minimum use of specimens for an accurate diagnosis and to preserve as much tissue as possible for potential molecular markers has been recommended. STUDY DESIGN: In this study we blind-reviewed 50 cases of cytologically diagnosed non-small-cell type lung carcinomas and categorized them into adenocarcinoma and squamous-cell carcinoma based on cytological features alone. Only those cases that had had a histological follow-up were selected. RESULTS: On blind review, a definitive categorization of non-small-cell carcinoma of the lung was made in 28 of 29 cases of adenocarcinomas and in 14 of 19 squamous-cell carcinomas. CONCLUSION: When attempted, most cases of well-to moderately differentiated adenocarcinomas can be identified based on cytological features alone. Poorly differentiated squamous-cell carcinomas are more likely to be called non-small-cell carcinomas. PMID- 22846186 TI - Observation of public health risk behaviours, risk communication and hand hygiene at Kansas and Missouri petting zoos--2010-2011. AB - Outbreaks of human illness have been linked to visiting settings with animal contact throughout developed countries. This study details an observational study of hand hygiene tool availability and recommendations; frequency of risky behaviour; and handwashing attempts by visitors in Kansas (9) and Missouri (4), USA, petting zoos. Handwashing signs and hand hygiene stations were available at the exit of animal-contact areas in 10/13 and 8/13 petting zoos, respectively. Risky behaviours were observed being performed at all petting zoos by at least one visitor. Frequently observed behaviours were as follows: children (10/13 petting zoos) and adults (9/13 petting zoos) touching hands to face within animal contact areas; animals licking children's and adults' hands (7/13 and 4/13 petting zoos, respectively); and children and adults drinking within animal contact areas (5/13 petting zoos each). Of 574 visitors observed for hand hygiene when exiting animal-contact areas, 37% (n = 214) of individuals attempted some type of hand hygiene, with male adults, female adults and children attempting at similar rates (32%, 40% and 37%, respectively). Visitors were 4.8* more likely to wash their hands when a staff member was present within or at the exit to the animal-contact area (136/231, 59%) than when no staff member was present (78/343, 23%; P < 0.001, OR = 4.863, 95% CI = 3.380-6.998). Visitors at zoos with a fence as a partial barrier to human-animal contact were 2.3* more likely to wash their hands (188/460, 40.9%) than visitors allowed to enter the animals' yard for contact (26/114, 22.8%; P < 0.001, OR = 2.339, 95% CI = 1.454-3.763). Inconsistencies existed in tool availability, signage and supervision of animal contact. Risk communication was poor, with few petting zoos outlining risks associated with animal contact, or providing recommendations for precautions to be taken to reduce these risks. PMID- 22846185 TI - Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. AB - The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed. PMID- 22846187 TI - Biofabrication enables efficient interrogation and optimization of sequential culture of endothelial cells, fibroblasts and cardiomyocytes for formation of vascular cords in cardiac tissue engineering. AB - We previously reported that preculture of fibroblasts (FBs) and endothelial cells (ECs) prior to cardiomyocytes (CMs) improved the structural and functional properties of engineered cardiac tissue compared to culture of CMs alone or co culture of all three cell types. However, these approaches did not result in formation of capillary-like cords, which are precursors to vascularization in vivo. Here we hypothesized that seeding the ECs first on Matrigel and then FBs 24 h later to stabilize the endothelial network (sequential preculture) would enhance cord formation in engineered cardiac organoids. Three sequential preculture groups were tested by seeding ECs (D4T line) at 8%, 15% and 31% of the total cell number on Matrigel-coated microchannels and incubating for 24 h. Cardiac FBs were then seeded (32%, 25% and 9% of the total cell number, respectively) and incubated an additional 24 h. Finally, neonatal rat CMs (60% of the total cell number) were added and the organoids were cultivated for seven days. Within 24 h, the 8% EC group formed elongated cords which eventually developed into beating cylindrical organoids, while the 15% and 31% EC groups proliferated into flat EC monolayers with poor viability. Excitation threshold (ET) in the 8% EC group (3.4 +/- 1.2 V cm(-1)) was comparable to that of the CM group (3.3 +/- 1.4 V cm(-1)). The ET worsened with increasing EC seeding density (15% EC: 4.4 +/- 1.5 V cm(-1); 31% EC: 4.9 +/- 1.5 V cm(-1)). Thus, sequential preculture promoted vascular cord formation and enhanced architecture and function of engineered heart tissues. PMID- 22846188 TI - Perceptions of the ankle brachial index amongst podiatrists registered in Western Australia. AB - BACKGROUND: The ankle brachial index (ABI) is an objective diagnostic tool that is widely used for the diagnosis of peripheral arterial disease. Despite its usefulness, it is evident within the literature that many practitioners forgo using this screening tool due to limiting factors such as time. There is also no recommended technique for ABI measurement. The purpose of this study is to investigate the perceptions of the use of ABI clinically among Western Australian podiatrists. METHODS: This study was a cross sectional survey which evaluated the perceptions of the ABI amongst registered podiatrists in Western Australia. The study sample was obtained from the register of podiatrists listed with the Podiatrists Registration Board of Western Australia. Podiatrists were contacted by telephone and invited to participate in a telephone questionnaire. Chi-square tests were performed to determine if there was a statistically significant relationship between use of the ABI and podiatrists' profile which included: sector of employment; geographical location; and length of time in practice. RESULTS: There is a statistically significant relationship (p=0.004) between podiatrists' profile and the use of ABI, with higher usage in the tertiary hospital setting than in private practice. Length of time spent in practice had no significant impact on ABI usage (p=0.098). Time constraints and lack of equipment were key limiting factors to performing the ABI, and no preferred technique was indicated. CONCLUSION: Western Australian podiatrists agree that the ABI is a useful tool for lower limb vascular assessment, however, various factors influence uptake in the clinical setting. This study suggests that a podiatrists' profile has a significant influence on the use of the ABI, which may be attributed to different patient types across the various settings. The influence of time spent in practice on ABI usage may be attributed to differences in clinical training and awareness of lower limb pathology over time. The authors recommend publication of 'best practice' guidelines to ABI performance, as well as further education and financial rebates from health organizations to facilitate increased utility of the ABI based on the findings of this study. PMID- 22846189 TI - Event-related brain potentials that distinguish false memory for events that occurred only seconds in the past. AB - BACKGROUND: False memory often involves retrieving events from the distant past that did not actually happen. However, recent evidence obtained using the Deese/Roediger-McDermott (DRM) paradigm for eliciting false memory experiences suggests that individuals can falsely believe that events occurred mere seconds in the past when they in fact did not. Subjects in these experiments endorsed unstudied critical lure words as having been studied, despite the fact that word lists were studied just moments before. We identified event-related brain potential (ERP) correlates of this experience, and included a repetition priming manipulation to better assess the functional significance of these ERPs. METHODS: Behavioral and ERP data were collected from 21 Capital Normal University students using a short-term DRM task. RESULTS: Two categories of effects were identified that distinguished true from false short-term memory: (1) early semantic priming effects from 300 to 500 ms and (2) later retrieval and retrieval-monitoring effects after 500 ms. The repetition priming manipulation had distinct influences on these effects, consistent with their differential associations with semantic priming versus episodic retrieval. CONCLUSION: Characterization of ERPs related to semantic priming and episodic retrieval provides important information regarding the mechanisms of short-term false memory. In contrast, most studies examining false memory in standard long-delay DRM paradigms identify ERP effects related only to retrieval monitoring. These findings highlight the neural processing involved in illusions of memory after very brief delays and highlight the role of semantic processing in short-term false memory. PMID- 22846190 TI - Clinical trial: transcutaneous interferential electrical stimulation in individuals with irritable bowel syndrome - a prospective double-blind randomized study. AB - BACKGROUND: The exact etiology of irritable bowel syndrome (IBS) remains unclear. Curative treatment is not available and current treatment modalities are mainly directed against the predominant symptoms. There are a few studies reporting the beneficial effects of transcutaneous electrical stimulation in patients with chronic constipation, gastroparesis, and functional dyspepsia. AIM: To investigate whether transcutaneous electrical stimulation is an effective procedure in IBS patients. METHODS: IBS patients were randomly placed in vacuum interferential current (IFC) and placebo groups. Both treatments consisted of 12 sessions administered over 4 weeks. Symptoms due to IBS were documented via questionnaires, including the IBS Global Assessment of Improvement Scale, numeric rating scales, visual analogue scale, and IBS Quality of Life Scale at the beginning of, end of, and 1 month after the treatment. RESULTS: Patients in the therapy (29 cases) and placebo (29 cases) groups were homogeneous with respect to demographic data and gastrointestinal system symptoms. When compared to the beginning scores, severity of abdominal discomfort, bloating, and abdominal distension and rumbling improved significantly in either interference or placebo groups at both the end of treatment and 1 month after treatment. In the IFC group, severity of symptoms continued to decrease significantly at 1 month after treatment when compared to scores at just the end of treatment, whereas in the placebo group severity of these symptoms did not change significantly on numeric severity scales. Also, the visual analogue scale of the first month after treatment continued to decrease significantly when compared to the level at the end of treatment in the IFC group. Total quality score increased significantly in the IFC group. CONCLUSIONS: Vacuum IFC therapy can significantly improve symptoms and quality of life in patients with IBS. It may represent a novel treatment modality for drug-refractory IBS patients. PMID- 22846191 TI - Antisense reduction of NADP-malic enzyme in Flaveria bidentis reduces flow of CO2 through the C4 cycle. AB - An antisense construct targeting the C(4) isoform of NADP-malic enzyme (ME), the primary enzyme decarboxylating malate in bundle sheath cells to supply CO(2) to Rubisco, was used to transform the dicot Flaveria bidentis. Transgenic plants (alpha-NADP-ME) exhibited a 34% to 75% reduction in NADP-ME activity relative to the wild type with no visible growth phenotype. We characterized the effect of reducing NADP-ME on photosynthesis by measuring in vitro photosynthetic enzyme activity, gas exchange, and real-time carbon isotope discrimination (Delta). In alpha-NADP-ME plants with less than 40% of wild-type NADP-ME activity, CO(2) assimilation rates at high intercellular CO(2) were significantly reduced, whereas the in vitro activities of both phosphoenolpyruvate carboxylase and Rubisco were increased. Delta measured concurrently with gas exchange in these plants showed a lower Delta and thus a lower calculated leakiness of CO(2) (the ratio of CO(2) leak rate from the bundle sheath to the rate of CO(2) supply). Comparative measurements on antisense Rubisco small subunit F. bidentis plants showed the opposite effect of increased Delta and leakiness. We use these measurements to estimate the C(4) cycle rate, bundle sheath leak rate, and bundle sheath CO(2) concentration. The comparison of alpha-NADP-ME and antisense Rubisco small subunit demonstrates that the coordination of the C(3) and C(4) cycles that exist during environmental perturbations by light and CO(2) can be disrupted through transgenic manipulations. Furthermore, our results suggest that the efficiency of the C(4) pathway could potentially be improved through a reduction in C(4) cycle activity or increased C(3) cycle activity. PMID- 22846192 TI - Transparent testa16 plays multiple roles in plant development and is involved in lipid synthesis and embryo development in canola. AB - Transparent Testa16 (TT16), a transcript regulator belonging to the B(sister) MADS box proteins, regulates proper endothelial differentiation and proanthocyanidin accumulation in the seed coat. Our understanding of its other physiological roles, however, is limited. In this study, the physiological and developmental roles of TT16 in an important oil crop, canola (Brassica napus), were dissected by a loss-of-function approach. RNA interference (RNAi)-mediated down-regulation of tt16 in canola caused dwarf phenotypes with a decrease in the number of inflorescences, flowers, siliques, and seeds. Fluorescence microscopy revealed that tt16 deficiency affects pollen tube guidance, resulting in reduced fertility and negatively impacting embryo and seed development. Moreover, Bntt16 RNAi plants had reduced oil content and altered fatty acid composition. Transmission electron microscopy showed that the seeds of the RNAi plants had fewer oil bodies than the nontransgenic plants. In addition, tt16 RNAi transgenic lines were more sensitive to auxin. Further analysis by microarray showed that tt16 down-regulation alters the expression of genes involved in gynoecium and embryo development, lipid metabolism, auxin transport, and signal transduction. The broad regulatory function of TT16 at the transcriptional level may explain the altered phenotypes observed in the transgenic lines. Overall, the results uncovered important biological roles of TT16 in plant development, especially in fatty acid synthesis and embryo development. PMID- 22846193 TI - Roles of dicer-like and argonaute proteins in TAS-derived small interfering RNA triggered DNA methylation. AB - Trans-acting small interfering RNAs (ta-siRNAs; TAS) emerge as a class of plant specific small RNAs that are initiated from microRNA-mediated cleavage of TAS gene transcripts. It has been revealed that ta-siRNAs are generated by the sequential activities of SUPPRESSOR OF GENE SILENCING3 (SGS3), RNA-DEPENDENT RNA POLYMERASE6 (RDR6), and DICER-LIKE4 (DCL4), and loaded into ARGONAUTE1 (AGO1) proteins to posttranscriptionally regulate several target genes by messenger RNA cleavage in trans. Here, we showed a high cytosine DNA methylation status at ta siRNA-generating loci in Arabidopsis (Arabidopsis thaliana), which is dependent on RDR6, SGS3, and DNA-DIRECTED RNA POLYMERASE V (PolV). More important, we found that DCL1 is the only DCL protein that is required for TAS3 loci DNA methylation, and all four DCLs exert combinatory functions in the methylation of TAS1 loci, suggesting a previously unknown role for DCL1 in directly processing TAS gene transcripts. Furthermore, we demonstrated that AGO4/6 complexes rather than AGO1 are responsible for TAS siRNA-guided DNA methylation. Based upon these findings, we propose a novel ta-siRNA pathway that acts at both the messenger RNA and chromatin level. PMID- 22846194 TI - Factors associated with utilization of community health workers in improving access to malaria treatment among children in Kenya. AB - BACKGROUND: The success of community case management in improving access to effective malaria treatment for young children relies on broad utilization of community health workers (CHWs) to diagnose and treat fever cases. A better understanding of the factors associated with CHW utilization is crucial in informing national malaria control policy and strategy in Kenya. Specifically, little is known in Kenya on the extent to which CHWs are utilized, the characteristics of families who report utilizing CHWs and whether utilization is associated with improved access to prompt and effective malaria treatment. This paper examines factors associated with utilization of CHWs in improving access to malaria treatment among children under five years of age by women caregivers in two malaria endemic districts in Kenya. METHODS: This study was conducted in 113 hard-to-reach and poor villages in Malindi and Lamu districts in the coastal region classified as having endemic transmission of malaria. A cross-sectional household survey was conducted using a standardized malaria indicator questionnaire at baseline (n=1,187) and one year later at endline assessment (n=1,374) using two-stage cluster sampling. RESULTS: There was an increase in reported utilization of CHWs as source of advice/treatment for child fevers from 2% at baseline to 35% at endline, accompanied by a decline in care-seeking from government facilities (from 67% to 48%) and other sources (26% to 2%) including shops. The most poor households and poor households reported higher utilization of CHWs at 39.4% and 37.9% respectively, compared to the least poor households (17.0%). Households in villages with less than 200 households reported higher CHWs utilization as compared to households in villages having >200 households. Prompt access to timely and effective treatment was 5.7 times higher (95% CI 3.4 9.7) when CHWs were the source of care sought. Adherence was high regardless of whether source was CHWs (73.1%) or public health facility (66.7%). CONCLUSIONS: The potential for utilization of CHWs in improving access to malaria treatment at the community level is promising. This will not only enhance access to treatment by the poorest households but also provide early and appropriate treatment to vulnerable individuals, especially those living in hard to reach areas. PMID- 22846195 TI - Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment. AB - BACKGROUND: For antiretroviral therapy (ART) naive human immunodeficiency virus (HIV) infected adults suffering from tuberculosis (TB), there is uncertainty about the optimal time to initiate highly active antiretroviral therapy (HAART) after starting antituberculosis treatment (ATT), in order to minimize mortality, HIV disease progression, and adverse events. METHODS: In a randomized, open label trial at All India Institute of Medical Sciences, New Delhi, India, eligible HIV positive individuals with a diagnosis of TB were randomly assigned to receive HAART after 2-4 or 8-12 weeks of starting ATT, and were followed for 12 months after HAART initiation. Participants received directly observed therapy short course (DOTS) for TB, and an antiretroviral regimen comprising stavudine or zidovudine, lamivudine, and efavirenz. Primary end points were death from any cause, and progression of HIV disease marked by failure of ART. FINDINGS: A total of 150 patients with HIV and TB were initiated on HAART: 88 received it after 2-4 weeks (early ART) and 62 after 8-12 weeks (delayed ART) of starting ATT. There was no significant difference in mortality between the groups after the introduction of HAART. However, incidence of ART failure was 31% in delayed versus 16% in early ART arm (p = 0.045). Kaplan Meier disease progression free survival at 12 months was 79% for early versus 64% for the delayed ART arm (p = 0.05). Rates of adverse events were similar. INTERPRETATION: Early initiation of HAART for patients with HIV and TB significantly decreases incidence of HIV disease progression and has good tolerability. TRIAL REGISTRATION: CTRI/2011/12/002260. PMID- 22846196 TI - Growth arrest-specific gene 1 is downregulated and inhibits tumor growth in gastric cancer. AB - Gastric cancer is one of the leading causes of malignancy-related mortality in the world, and malignant growth is a crucial characteristic in gastric cancer. In our previous study, we found that growth arrest-specific gene 1 (GAS1) suppression was involved in making gastric cancer cells multidrug-resistant by protecting them from drug-induced apoptosis. In the present study, we investigated the potential role of GAS1 in the growth and proliferation of gastric cancer. We demonstrated that GAS1 expression was decreased in gastric cancer, and patients without GAS1 expression showed shorter survival times than those with GAS1 expression. Both gain-of-function (by overexpression of GAS1) and loss-of-function (by GAS1-specific small interfering RNA knockdown) studies showed that increased GAS1 expression significantly reduced the colony-forming ability of gastric cancer cells in vitro and reduced cell growth in vivo, whereas decreased GAS1 expression had the opposite effects. Moreover, upregulation of GAS1 induced cell apoptosis, and downregulation of GAS1 inhibited apoptosis. Furthermore, we demonstrated that GAS1 could induce gastric cancer cell apoptosis, at least in part through modulating the Bcl-2/Bax ratio and the activity of caspase-3. Taken together, our results strongly indicate that GAS1 expression was decreased in gastric cancer and was predictive of a poor prognosis. Restoration of GAS1 expression inhibited cell growth and promoted apoptosis of gastric cancer cells, at least in part through modulating the Bcl 2/Bax ratio and activating caspase-3, suggesting that GAS1 might be used as a novel therapeutic candidate for gastric cancer. PMID- 22846197 TI - Subclassification of non-small cell lung cancer by cytologic sampling: a logical approach with selective use of immunocytochemistry. AB - OBJECTIVES: To determine the diagnostic accuracy of cytomorphology for subclassifying non-small cell lung cancer into adenocarcinoma (AC) and squamous cell carcinoma (SqC), and the utility of immunocytochemistry (ICC) for poorly differentiated cases. STUDY DESIGN: Preoperative cytologic diagnoses of SqC, AC, or non-small cell carcinoma (NSCC) were compared with surgical resection diagnoses. NSCC cases with adequate cell block material were stained with CK7, CK5/6, TTF-1 and p63 antibodies and subclassified as SqC, AC, or equivocal. RESULTS: 123 of 140 (88%) preoperative cytologic specimens had a malignant diagnosis, including 36 SqC, 72 AC, 6 adenosquamous carcinomas (ASC), and 9 large cell carcinomas (LCC). Accurate cytologic diagnoses were rendered in 18 (50%) SqC and 49 (68%) AC; 26 of 54 cases with a diagnosis of NSCC had adequate cell block material for ICC. TTF-1 and p63 accurately classified 8 of 9 (89%) SqC and 8 of 8 (100%) AC. One SqC, 2 ASC and 3 LCC had equivocal staining, while 1 ASC and 3 LCC stained as AC. CONCLUSIONS: The majority of SqC and AC (56%) can be classified by cytomorphology alone. TTF-1 and p63 ICC on cell blocks can provide accurate subclassification for NSCC in the vast majority of cases. PMID- 22846198 TI - Advanced therapies using autologous bone marrow cells for chronic liver disease. AB - The radical treatment currently for decompensated liver cirrhosis is still liver transplantation. However, liver transplants are not widely performed worldwide and development of genuine regeneration therapy for liver cirrhosis is an urgent task. We have developed a novel murine model [the green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model], and reported that infused GFP-positive bone marrow cells repopulated cirrhotic liver. Moreover, repopulated bone marrow cells ameliorated liver fibrosis through higher expression of matrix metalloproteinase-9, consistent with improved liver functions and better survival rate. Based on these findings, we started a clinical trial of autologous bone marrow cell infusion (ABMi) therapy for decompensated liver cirrhotic patients, and reported the efficacy and the safety of this approach. On the other hand, various other clinical studies for liver disease have been also reported, including hepatic administration of autologous CD34-positive cells induced by granulocyte colony-stimulating factor (G-CSF), portal vein administration of CD133-positive mononuclear cells, and administration of autologous bone marrow derived mesenchymal stem cells (MSCs). Effectiveness of these approaches has been shown in some patients. We provided here an overview of the current status of liver regeneration therapies including our results of the murine GFP/CCl4 model and ABMi therapy for liver cirrhosis and future prospects. PMID- 22846199 TI - Early assessment of radiation response using a novel functional imaging modality - [18F]fluorocholine PET (FCH-PET): a pilot study. AB - AIM: [18F]Fluorodeoxyglucose-positron emission tomography/computerized tomography (FDG-PET) is commonly used to assess response to patients treated with radiation (RT) or combination of chemotherapy and RT (CRT). The intent of this pilot study is to explore whether [18F]fluorocholine PET (FCH-PET) can serve as an early predictive biomarker for early detection of RT/CRT response. MATERIALS AND METHODS: Fourteen patients have been accrued and analyzed. The lesions were base of tongue, tonsil, nodes, hypopharynx, maxilla, palate, lung, pancreas, brain, uterine, and rectal. There were 16 lesions that were considered target lesion and were followed for correlation between change in FCH-PET SUVmax readings and clinical outcome. Median tumor size was 4.4 cm. Median RT dose was 66 Gy. The change in SUVmax (Delta SUVmax) of FCH-PET scans performed before and during RT was correlated with clinical outcome at the last follow-up. RESULTS: The median FCH-PET SUVmax for the 1st and 2nd scans was 6.15 and 4.65, respectively. Fourteen (87.5%) lesions showed a reduction in SUVmax in either a complete response (CR) or a partial response (PR), and 2 lesions showed an increase in SUVmax both of which were determined to be non-response (NR). The median percentage change between the 1st and 2nd scan was -19.5%. Forty-four percent of lesions (7/16) had CR, 44% (7/16) had PR, and 12% (2/16) had NR (no response). Median follow-up was 12 months. The results showed a difference between NR and PR, between NR and CR, and a trend towards significance (p=0.06). CONCLUSION: FCH PET scan demonstrated changes in SUVmax during RT that were predictive of final outcome. PMID- 22846200 TI - Non-invasive stimulation therapies for the treatment of refractory pain. AB - Drug-refractory pain is an indication for neurostimulation therapy, which can be either non-invasive [mainly transcutaneous electrical nerve stimulation (TENS), repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial direct current stimulation (tDCS)] or invasive which requires the intervention of a surgeon to implant electrodes and a pulse generator [peripheral nerve stimulation (PNS), nerve root stimulation (NRS), spinal cord stimulation (SCS), deep brain stimulation (DBS), and motor cortex stimulation (MCS)]. In this review, the respective mechanisms of action and efficacy of TENS, rTMS, and tDCS are discussed. The advantages of TENS include non-invasiveness and ease to use, so that the technique can be operated by the patient. TENS can be indicated as a first-line treatment in patients suffering from peripheral neuropathic pain if the painful area is limited and the sensory deficit moderate. The current best indications are chronic radiculopathies, mononeuropathies, and postherpetic pain. Test sessions allow to select suitable patients and to determine the site, frequency, and optimal intensity of stimulation. Three to four 30- to 60-minute sessions per day are usually recommended. With regard to rTMS, published randomized controlled studies in chronic neuropathic and non-neuropathic pain (fibromyalgia) reached a sufficient level of evidence to recommend this technique for the indication of implanted motor cortex stimulation for the treatment of refractory neuropathic pain or as a long-term treatment for pain syndromes, in which surgery is not indicated, such as fibromyalgia. Other indications, concerning either chronic or acute pain syndromes, such as postoperative pain, should be developed in parallel with the optimization of stimulation parameters. This also includes the availability of new coils and magnetic field waveforms and progress in neuronavigation techniques, especially by the integration of functional imaging and high-resolution EEG data. PMID- 22846201 TI - SOX17 methylation inhibits its antagonism of Wnt signaling pathway in lung cancer. AB - The purpose of this study was to explore epigenetic changes and functions of SOX17 in human lung cancer. Five lung cancer cell lines and 88 primary lung cancer samples were examined in this study. Methylation-specific polymerase chain reaction (MSP), semi-quantitative reverse-transcription PCR, immunohistochemistry, luciferase reporter assays, colony-formation assays, and western blotting were used to analyze methylation changes and functions of SOX17 in lung cancer. SOX17 methylation was found in 60.2% of primary human lung cancer samples, and promoter region methylation of SOX17 silenced its expression. SOX17 methylation was associated with female patients and lung cancer differentiation. Colony-formation assays revealed that SOX17 suppressed lung cancer cell proliferation. Re-expression of SOX17 inhibited Wnt signaling in H23 lung cancer cell line. SOX17 acts as a Wnt signaling inhibitor. PMID- 22846202 TI - Toward personalized treatment of advanced biliary tract cancers. AB - Biliary tract cancers (BTC) are a relatively rare heterogeneous group of four to five anatomically distinct cancers whose prognosis is poor, even in the setting of attempted curative resection. Curative resection, in itself, is much less common than locally advanced unresectable and/or overt metastatic disease at presentation. Standard chemotherapy options are generally palliative for advanced BTC (aBTC), and recently the combination of gemcitabine with cisplatin has emerged as the standard-of-care providing a median overall survival of approximately one year. A movement toward molecularly based personalized cancer therapy has occurred in recent years, including for aBTC, with a number of pathways emerging as putative therapeutic targets. This review will briefly summarize the epidemiology, etiology, and general prognosis of BTC, then discuss the data supporting current standard cytotoxic treatments of aBTC, and proceed to focus on the molecular features of this heterogeneous set of diseases. Finally, we review strategies which will potentially improve our ability to individualize therapy and, ultimately, clinical outcomes in the future. PMID- 22846203 TI - Targeting mRNA splicing as a potential treatment for Duchenne muscular dystrophy. AB - Several clinical trials have recently demonstrated that oligonucleotide-based drugs induced targeted exon skipping in dystrophin pre-mRNA in Duchenne muscular dystrophy patients, resulting in novel expression of a truncated but functional isoform of the dystrophin protein. Such exon skipping therapy has the potential to convert the lethal Duchenne phenotype into the less severe Becker phenotype. This splice switching technology has been shown to be very well tolerated and may become the first gene-specific therapy, if approved, for the treatment of Duchenne muscular dystrophy. PMID- 22846204 TI - Changing paradigms with molecular imaging of neuroendocrine tumors. AB - Molecular imaging is changing diagnostic and treatment paradigms in patients with neuroendocrine tumors through its ability to non-invasively characterize disease, supplementing the traditional role of using imaging for localizing and measuring disease. For patients with metastatic disease, there is an increasing range of therapies but these must be individualized to the specific subtype of tumor expressed, which varies in aggressiveness from well to poorly differentiated phenotypes. Positron emission tomography (PET) is now able to characterize these subtypes through its ability to quantify somatostatin receptor cell surface (SSTR) expression and glycolytic metabolism with SSTR and fluorodeoxyglucose (FDG) PET, respectively. The ability to perform this as a whole body study is highlighting the limitations of relying on histopathology obtained from a single site. Through earlier diagnosis, improved selection of the most appropriate therapy and better assessment of therapeutic response for an individual patient, molecular imaging is improving the outcome for patients with NET. PMID- 22846205 TI - Long-term tracking of plasma phospholipid fatty acid concentrations and their correlation with the dietary intake of marine foods in newly diagnosed diabetic patients: results from a follow-up of the HUNT Study, Norway. AB - Analysis of long-chain n-3 and n-6 fatty acid (FA) concentrations is used to evaluate their potential health effects in epidemiological studies, and, recently, also to counsel patients with a suboptimal intake of n-3 FA. Data on the method's ability to track and detect differences within and between individuals in appropriate populations are, however, lacking. The present study provides such data for twenty-nine plasma phospholipid (PL) FA concentrations and indices measured in 214 newly diagnosed type 2 diabetic patients at baseline and after 3 years. 20 : 3n-6 and the 20 : 4n-6:20 : 3n-6 ratio showed the highest tracking coefficients (Spearman's r 0.68), while DHA, EPA and PLN3-index (EPA+DHA) coefficients were 0.60, 0.47 and 0.55, respectively. Fish consumption measured simultaneously with EPA, DHA, sum n-3 and PLN3 index showed Spearman's correlation coefficients of 0.47, 0.44, 0.48 and 0.49, respectively, decreasing to 0.20, 0.19, 0.22 and 0.21 when measured 3 years apart. The within-subject CV of EPA, DHA and PLN3 index were 39.9, 14.3 and 18.0 %, respectively. The corresponding between-subject CV were 33.6, 16.5 and 18.7 %, while the reference change values were 112, 41 and 52 %. In conclusion, PL n-3 FA concentrations showed a significant long-term tracking and were positively correlated with marine food intake. Analytical precision, biological variability, reference change value and the index of individuality of EPA, DHA and PLN3 index are similar to commonly used clinical biomarkers, supporting their validity as dietary markers in clinical and epidemiological work. PMID- 22846206 TI - Foot-and-mouth disease virus serotype O phylodynamics: genetic variability associated with epidemiological factors in Pakistan. AB - One of the most challenging aspects of foot-and-mouth disease (FMD) control is the high genetic variability of the FMD virus (FMDV). In endemic settings such as the Indian subcontinent, this variability has resulted in the emergence of pandemic strains that have spread widely and caused devastating outbreaks in disease-free areas. In countries trying to control and eradicate FMD using vaccination strategies, the constantly evolving and wide diversity of field FMDV strains is an obstacle for identifying vaccine strains that are successful in conferring protection against infection with field viruses. Consequently, quantitative knowledge on the factors that are associated with variability of the FMDV is prerequisite for preventing and controlling FMD in the Indian subcontinent. A hierarchical linear model was used to assess the association between time, space, host species and the genetic variability of serotype O FMDV using viruses collected in Pakistan from 2005 to 2011. Significant (P<0.05) amino acid and nucleotide variations were associated with spatial distance, but not with differences in host species, which is consistent with the frequent multi species infection of this serotype O FMDV. Results from this study will contribute to the understanding of FMDV variability and to the design of FMD control strategies in Pakistan. Viruses sequenced here also provide the earliest reported isolate from the Pan Asia II(ANT-10) sublineage, which has caused several outbreaks in the Middle East and spread into Europe (Bulgaria) and Africa (Libya). PMID- 22846207 TI - Comparison of renal function after partial nephrectomy and radical nephrectomy for renal cell carcinoma. AB - OBJECTIVE: To investigate the time-dependent changes of estimated glomerular filtration rate (eGFR) after radical nephrectomy (RN) and partial nephrectomy (PN) for renal cell carcinoma (RCC) and to determine the risk factors for the new onset of a postoperative eGFR <60 ml/min/1.73 m(2). PATIENTS AND METHODS: We assessed the renal function of 253 RCC patients by using the eGFR, and investigated the time-dependent changes of the eGFR after the operation. Regression models were used to determine risk factors for the new onset of an eGFR of <60 ml/min/1.73 m(2) in 211 patients who had at least one month of postoperative follow-up. RESULTS: From the first postoperative day to the 60th postoperative month the eGFR in the RN group was significantly lower than that in the PN group. For patients who had at least 1 month of postoperative follow-up, multivariable analysis revealed that RN (p < 0.001), age (p = 0.028), and maleness (p = 0.013) were risk factors for the postoperative onset of an eGFR <60 ml/min/1.73 m(2). CONCLUSIONS: Renal function after PN was better than that after RN, and RN was a greater risk factor for the postoperative onset of an eGFR <60 ml/min/ 1.73 m(2). PMID- 22846208 TI - Evaluation of the expression of C-kit (CD117) in ependymomas and oligodendrogliomas. AB - C-kit is a proto-oncogene located on the long arm of chromosome 4. Its product, CD117, is a specific immunohistochemical (IHQ) marker that is associated with response to a potent tyrosine kinase inhibitor therapy with STI-571 (Gleevec(r)) in chronic myelogenous leukemia and GISTs. In our study, we aimed to evaluate the expression of CD117 in glial tumors as this finding may guide therapeutic approaches for these brain tumors. Ependymomas and oligodendrogliomas, in formalin fixed and paraffin embedded blocks were assayed for CD117 immunoreactivity using anti-c-kit (CD117, DAKO). GISTs were used as positive control. We observed immunoreactivity of CD117 protein in 25.5% of tumors in both histological types. In oligodendrogliomas, there was an association between older age at diagnosis and positivity for CD117 (P=0.039). In addition, we observed an association between higher tumor grade (grade III) and positivity for CD117 (P=0.007). No clinical association was observed in ependymomas (P>0.05). This study encourages further investigations, considering that CD117 may be a possible oncogenic factor in some glial tumors. In this case, tumors that express this marker may eventually benefit from a therapy with selective inhibitors of receptor kinases. PMID- 22846209 TI - Elevated asymmetric dimethylarginine in young adult survivors of childhood acute lymphoblastic leukemia: a preliminary report. AB - BACKGROUND: Adult survivors of childhood malignancy are predisposed to late cardiovascular (CV) complications. Our aim was to estimate plasma levels of the endogenous nitric oxide formation inhibitor asymmetric dimethylarginine (ADMA), in long-term survivors of childhood acute lymphoblastic leukemia (ALL) treated with only chemotherapy. METHODS: ADMA and its isomer symmetric dimethylarginine (SDMA) were measured in 25 former ALL patients (aged 18-28 years) who had survived without recurrent disease >= 5 years from completing chemotherapy without cranial irradiation, and in 20 healthy controls (aged 20-31 years). RESULTS: Characteristics of the both groups were similar, except for lower high density lipoproteins-cholesterol (HDL-C) in ALL survivors. Compared to controls, the former ALL patients exhibited significant, albeit small, rises in levels of ADMA (0.63 +/- 0.09 [SD] vs. 0.57 +/- 0.07 MUmol/L; p=0.016), but not SDMA, with a consequently increased ADMA to SDMA ratio (1.08 +/- 0.22 vs. 0.91 +/- 0.16; p=0.004). The effect of former ALL on ADMA was attenuated (intergroup p=0.10 [ANCOVA]) upon adjustment for HDL-C (ADMA vs. HDL-C regression coefficient: 0.065 +/- 0.030 [SEM]; p=0.03). CONCLUSIONS: ADMA is elevated in adult childhood ALL survivors, which can reflect late detrimental chemotherapy effects, partially related to minor lipid profile changes. Whether these subtle ADMA elevations might herald future CV morbidity, remains to be elucidated. PMID- 22846210 TI - Concentrations of connective tissue growth factor in patients with nonalcoholic fatty liver disease: association with liver fibrosis. AB - AIM: In this study, we aimed to investigate the relationship between the histological fibrosis stage of nonalcoholic fatty liver disease (NAFLD) and serum connective tissue growth factor (CTGF) to determine the usefulness of this relationship in clinical practice. METHODS: Serum samples were collected from 51 patients with biopsy-proven NAFLD and 28 healthy controls, and serum levels of CTGF were assayed by ELISA. RESULTS: Levels of CTGF were significantly higher in patients with NAFLD compared with controls (P=0.001). The serum CTGF levels were significantly increased, that correlated with histological fibrosis stage, in patients with NAFLD [in patients with no fibrosis (stage 0) 308.2 +/- 142.9, with mild fibrosis (stage 1-2) 519.9 +/- 375.2 and with advanced fibrosis (stage 3-4) 1353.2 +/- 610 ng/l, P < 0.001]. Also serum level of CTGF was found as an independent predictor of histological fibrosis stage in patients with NAFLD (beta = 0.662, t=5.6, P <0.001). The area under the ROC curve was estimated 0.931 to separate patients with severe fibrosis from patients with other fibrotic stages. CONCLUSION: Serum levels of CTGF may be a clinical utility for distinguishing NAFLD patients with and without advanced fibrosis. PMID- 22846211 TI - Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo. AB - The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo. PMID- 22846212 TI - SP-D polymorphisms and the risk of COPD. AB - INTRODUCTION: There are limited data linking serum levels of surfactant protein D, its genetic polymorphisms to the risk of Chronic Obstructive Pulmonary Disease (COPD). OBJECTIVES: We sought to investigate these relationships using a case control study design. METHODS: Post bronchodilator values of FEV1/FVC < 0.7 were used to diagnose COPD patients (n=115). Controls were healthy subjects with normal spirometry (n=106) Single nucleotide polymorphisms (rs721917, rs2243639, rs3088308) were genotyped using polymerase chain reaction (PCR) and restriction analysis. Serum SP-D levels were measured using a specific immunoassay. RESULTS: Allele 'A' at rs3088308 (p < 0.00, B= -0.41) and 'C' allele at rs721917 (p=0.03; B= -0.30) were associated with reduced serum SP-D levels. Genotype 'T/T' at rs721917 was significantly associated with risk of COPD (p=0.01). Patients with repeat exacerbations had significantly higher serum SP-D even after adjusting for genetic factors. CONCLUSIONS: We report for the first time that rs3088308 is an important factor influencing systemic SP-D levels and confirm the previous association of rs721917 to the risk of COPD and serum SP-D levels. PMID- 22846213 TI - Paraoxonase-1 is not associated with coronary artery calcification in type 2 diabetes: results from the PREDICT study. AB - OBJECTIVES: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). METHODS AND RESULTS: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. CONCLUSION: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found. PMID- 22846215 TI - Permissive role of endothelin receptors in tumor metastasis. AB - Metastasis remains the major driver of mortality in patients with cancer. The multistep metastatic process requires the concerted actions of several genes and involves tumor cell invasion, epithelial mesenchymal transition (EMT), shedding from primary tumor, intravasation, arrest, extravasation and colonization at a preferential site. Understanding this complex process would provide the basis for the development of molecularly targeted therapeutics aimed at the tumor cell or its interaction with the host microenvironment. The neuropeptide hormones endothelins (specially, ET-1) have been correlated with invasiveness and metastasis of several cancers and high ET-1 levels are associated with decreased disease-specific survival. The mechanism(s) by which ET-1 promotes metastasis are being gradually unraveled. Through preferential binding to cognate receptors (ET(A)R or ET(B)R), ET-1 triggers autocrine and paracrine signaling cascades in tumor, immune and stromal cells, at both primary and distant sites, supporting cancer progression and metastasis. In this review, we will summarize the role of the ET axis in metastasis of different cancers and potential targeting of ET receptors in the therapeutic setting. PMID- 22846214 TI - Zinc erythrocyte protoporphyrin as marker of malaria risk in pregnancy - a retrospective cross-sectional and longitudinal study. AB - BACKGROUND: The effects of iron interventions and host iron status on infection risk have been a recurrent clinical concern, although there has been little research on this interaction in pregnant women. METHODS: Cross-sectional and longitudinal analyses were undertaken to determine the association of whole blood zinc erythrocyte protoporphyrin (ZPP) with malaria parasitaemia in pregnant women attending antenatal and delivery care at Montfort and Chikwawa Hospitals, Shire Valley, Malawi. Prevalence of antenatal, delivery and placental malaria was assessed in relation to maternal ZPP levels. The main outcome measures were prevalence of peripheral and placental Plasmodium falciparum parasitaemia and odds ratios of malaria risk. RESULTS: A total of 4,103 women were evaluated at first antenatal visit, of whom at delivery 1327 were screened for peripheral and 1285 for placental parasitaemia. Risk of malaria at delivery (peripheral or placental) was higher in primigravidae (p < 0.001), and lower (peripheral) with use of intermittent preventive anti-malarials during pregnancy (p < 0.001). HIV infection was associated with increased malaria parasitaemia (p < 0.02, peripheral or placental). Parasitaemia prevalence was lower in women with normal ZPP levels compared to those with raised concentrations at both first antenatal visit (all gravidae, p = 0.048, and at delivery (all gravidae, p < 0.001; primigravidae, p = 0.056). Between first antenatal visit and delivery women who transitioned from raised (at first antenatal visit) to normal ZPP values (at delivery) had lower peripheral parasitaemia prevalence at delivery compared to those who maintained normal ZPP values at both these visits (all gravidae: 0.70, 95%CI 0.4-1.1; primigravidae: 0.3, 0.1-0.8). In regression analysis this difference was lost with inclusion of HIV infection in the model. CONCLUSIONS: Raised ZPP concentrations in pregnancy were positively associated with P. falciparum parasitaemia and were probably secondary to malaria inflammation, rather than indicating an increased malaria risk with iron deficiency. It was not possible from ZPP measurements alone to determine whether iron deficiency or repletion alters malaria susceptibility in pregnancy. PMID- 22846216 TI - Arsenic(V) removal from underground water by magnetic nanoparticles synthesized from waste red mud. AB - In this study waste red mud (bauxite residue) sample obtained from Seydisehir (Konya, Turkey) was evaluated for the synthesis of Fe(3)O(4) nanoparticles (NPs) in ammonia solution that can be used to remove As(V) from both synthetic and natural underground water samples. The synthesized Fe(3)O(4)-NPs were characterized by using TEM, VSM, XRD, SAXS, TGA and FT-IR spectroscopy. The Fe(3)O(4)-NPs assumed a near-sphere shape with an average size of 9 nm. The results showed that synthesized Fe(3)O(4)-NPs from waste red mud have satisfactory magnetic properties and As(V) sorption capacity, especially at low equilibrium arsenate concentrations. PMID- 22846217 TI - Precursors of nitrogenous disinfection by-products in drinking water--a critical review and analysis. AB - In recent years research into the formation of nitrogenous disinfection by products (N-DBPs) in drinking water - including N-nitrosodimethylamine (NDMA), the haloacetonitriles (HANs), haloacetamides (HAcAms), cyanogen halides (CNX) and halonitromethanes (HNMs) - has proliferated. This is partly due to their high reported toxicity of N-DBPs. In this review paper information about the formation yields of N-DBPs from model precursors, and about environmental precursor occurrence, has been employed to assess the amount of N-DBP formation that is attributable to known precursors. It was calculated that for HANs and HAcAms, the concentrations of known precursors - mainly free amino acids are insufficient to account for the observed concentrations of these N-DBP groups. However, at least in some waters, a significant proportion of CNX and NDMA formation can be explained by known precursors. Identified N-DBP precursors tend to be of low molecular weight and low electrostatic charge relative to bulk natural organic matter (NOM). This makes them recalcitrant to removal by water treatment processes, notably coagulation, as confirmed by a number of bench-scale studies. However, amino acids have been found to be easier to remove during water treatment than would be suggested by the known molecular properties of the individual free amino acids. PMID- 22846218 TI - Sexually dimorphic effects of oxytocin receptor gene (OXTR ) variants on Harm Avoidance. AB - BACKGROUND: Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. METHODS: We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. RESULTS: When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p <= 0.01). Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. CONCLUSIONS: Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation. PMID- 22846219 TI - A questionnaire-based survey on screening for gastric and colorectal cancer by physicians in East Asian countries in 2010. AB - BACKGROUND: The incidence of gastric cancer (GC) is high, and colorectal cancer (CRC) has significantly increased in Asian countries. AIM: To examine the current screening for GC and CRC within East Asia by means of a questionnaire survey. METHODS: Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in six East Asian countries. RESULTS: A total of 449 physicians participated in this survey. In all countries, more than 70% of physicians started GC screening between 40 and 59 years. The most popular method to screen for GC was endoscopy (92.7%), but combination methods such as Helicobacter pylori (HP) antibody, barium X-ray, and tumor marker with endoscopy differed by country. For HP positive individuals, most physicians screened every year by endoscopy, and for individuals post-HP eradication, about half of physicians (56.3%) thought there was a need to follow-up with GC screening. Among all physicians, the most common age to start CRC screening was in the 40s (39.8%) and 50s (40.9%). Based on the American Cancer Society Recommendations, a fecal occult blood test every year was the most popular method for CRC screening overall. However, among each country, this test was most popular in only Japan (76.9%) and Indonesia. In other countries, sigmoidoscopy every 5 years and total colonoscopy every 10 years were the most popular methods. CONCLUSION: There are similarities and differences in the screening of GC and CRC among East Asian countries. PMID- 22846220 TI - Thyroid transcription factor 1 and napsin a double staining in lung adenocarcinoma in pleural fluid. AB - OBJECTIVE: Thyroid transcription factor 1 (TTF-1)/napsin A double staining is useful for the identification of primary lung adenocarcinoma. We examined its performance in pleural fluid. STUDY DESIGN: Thirty-eight pleural-fluid specimens with lung adenocarcinoma were identified. Among these, 23 cases were diagnosed with a lung primary adenocarcinoma and 15 with a nonlung primary adenocarcinoma [breast (n = 13), ovarian (n = 1) and esophageal (n = 1)]. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded cell blocks. Expression of TTF 1 as a brown nuclear stain and napsin A as a red cytoplasmic stain were identified as positive staining. RESULTS: In lung adenocarcinoma, 19 out of the 23 (83%) cases were positive for the TTF-1/napsin A double stain, 1 (4%) was positive for TTF-1 only, 2 (9%) were positive for napsin A only and 1 (4%) was negative for the TTF-1/napsin A double stain. All 15 cases of nonlung primary adenocarcinoma were negative for the TTF-1/napsin A double stain. CONCLUSION: The sensitivity of napsin A for diagnosing lung adenocarcinoma is slightly higher than that of TTF-1. PMID- 22846221 TI - Endoscopy-assisted transoral resection of the styloid process in Eagle's syndrome. Case report. AB - Eagle's syndrome is often associated with elongated styloid process or ossified stylohyoid or stylomandibular ligament. Patients with this syndrome present with recurrent cervicofacial pain. Surgical removal of the elongated styloid process is a standard treatment and can be accomplished through either a transoral or extraoral approach. Both approaches have advantages and disadvantages, and the best surgical approach remains controversial. In our case, the elongated styloid process was removed by transoral approach assisted by endoscopy. Endoscopy provides clear surgical view thus lessen the chance of neurovascular injury and other intraoperative complications. Endoscopy-assisted transoral resection is an optional alternative surgical procedure for Eagle's syndrome. PMID- 22846222 TI - Regulation of self-renewal in normal and cancer stem cells. AB - Mutations can confer a selective advantage on specific cells, enabling them to go through the multistep process that leads to malignant transformation. The cancer stem cell hypothesis postulates that only a small pool of low-cycling stem-like cells is necessary and sufficient to originate and develop the disease. Normal and cancer stem cells share important functional similarities such as 'self renewal' and differentiation potential. However, normal and cancer stem cells have different biological behaviours, mainly because of a profound deregulation of self-renewal capability in cancer stem cells. Differences in mode of division, cell-cycle properties, replicative potential and handling of DNA damage, in addition to the activation/inactivation of cancer-specific molecular pathways confer on cancer stem cells a malignant phenotype. In the last decade, much effort has been devoted to unravel the complex dynamics underlying cancer stem cell-specific characteristics. However, further studies are required to identify cancer stem cell-specific markers and targets that can help to confirm the cancer stem cell hypothesis and develop novel cancer stem cell-based therapeutic approaches. PMID- 22846223 TI - Does health differ between participants and non-participants in the MRI-HUNT study, a population based neuroimaging study? The Nord-Trondelag health studies 1984-2009. AB - BACKGROUND: Bias with regard to participation in epidemiological studies can have a large impact on the generalizability of results. Our aim was to investigate the direction and magnitude of potential bias by comparing health-related factors among participants and non-participants in a MRI-study based on HUNT, a large Norwegian health survey. METHODS: Of 14,033 individuals aged 50-65, who had participated in all three large public health surveys within the Norwegian county of Nord-Trondelag (HUNT 1, 2 and 3), 1,560 who lived within 45 minutes of travel from the city of Levanger were invited to a MRI study (MRI-HUNT). The sample of participants in MRI-HUNT (n = 1,006) were compared with those who were invited but did not participate (n = 554) and with those who were eligible but not invited (n = 12,473), using univariate analyses and logistic regression analyses adjusting for age and education level. RESULTS: Self-reported health did not differ between the three groups, but participants had a higher education level and were somewhat younger than the two other groups. In the adjusted multivariate analyses, obesity was consistently less prevalent among participants. Significant differences in blood pressure and cholesterol were also found. CONCLUSION: This is the first large population-based study comparing participants and non participants in an MRI study with regard to general health. The groups were not widely different, but participants had a higher level of education, and were less likely to be obese and have hypertension, and were slightly younger than non participants. The observed differences between participants and non-invited individuals are probably partly explained by the inclusion criterion that participants had to live within 45 minutes of transport to where the MRI examination took place. One will expect that the participants have somewhat less brain morphological changes related to cardiovascular risk factors than the general population. Such consequences underline the crucial importance of evaluation of non-participants in MRI studies. PMID- 22846224 TI - Selective kinase inhibitors as tools for neuroscience research. AB - Signal transduction cascades, including the MAPK, PI3 kinase, Ca(2+) and PKC pathways, play important roles in neurons downstream of multiple signals including neurotrophins and neurotransmitters. Small molecule kinase inhibitors that block these pathways provide a powerful way of studying the in vivo or cellular roles of these signaling systems. Over the last 15 years there has been a major effort by the pharmaceutical industry to develop kinase inhibitors as potential drugs for a variety of diseases including cancer and auto-immunity. As a result of this there are now many compounds available that can be used as research tools. One major drawback is however that many of these compounds are not truly selective for a single kinase, and therefore the possibility that their cellular effects may be due to an off target activity must be considered. This problem has been brought into sharp relief by modern in vitro screening methods that allow an inhibitor to be screened against a significant proportion of the kinome. In this review we discuss the advantages and problems with the use of kinase inhibitors as research tools and describe some of the available compounds that target pathways important to neurons. PMID- 22846226 TI - Chemotherapeutic agents enhance cell migration and epithelial-to-mesenchymal transition through transient up-regulation of tNOX (ENOX2) protein. AB - BACKGROUND: Tumor-associated NADH oxidase (tNOX; ENOX2) is a growth-related protein expressed in transformed cells. High concentrations of numerous chemotherapeutic agents have shown to inhibit tNOX activity and protein levels leading to a reduction in cell growth while little is known for the effects of low concentrations of chemotherapeutic agents on tNOX expression. METHODS: Effects of chemotherapeutic agents on cell function were evaluated with traditional in vitro assays and the xCELLigence System. Western blot analyses were used to study protein expression profiles of the epithelial-to-mesenchymal transition. RESULTS: We showed that doxorubicin treatment transiently up regulates tNOX expression in human lung carcinoma A549 cells in association with enhanced cell migration. Similar results were observed in tamoxifen-exposed A549 cells. Furthermore, protein marker analyses revealed that the enhanced migration induced by tamoxifen was correlated with epithelial-to-mesenchymal transition, as evidenced by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Importantly, tNOX overexpression enhanced cell migration, confirming the essential role of tNOX in cell migration. CONCLUSIONS: Based on these findings, we conclude that doxorubicin and tamoxifen induce a transient up regulation of tNOX expression, leading to enhanced cell migration and EMT. GENERAL SIGNIFICANCE: These findings establish an essential role for tNOX in cell migration and survival and may provide a rational framework for the further development of tNOX inhibitors as a novel class of antitumor agents. PMID- 22846225 TI - Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMzeta in neurons. AB - PKMzeta is an autonomously active, atypical protein kinase C (aPKC) isoform that is both necessary and sufficient for maintaining long-term potentiation (LTP) and long-term memory. The myristoylated zeta-pseudosubstrate peptide, ZIP, potently inhibits PKMzeta biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses LTP maintenance and erases long-term memory storage. A recent study (Wu-Zhang et al., 2012), however, suggested ZIP was not effective on a PKMzeta fusion protein overexpressed in cultured cells. Chelerythrine, a redox-sensitive PKC inhibitor that inhibits PKMzeta and disrupts LTP maintenance and memory storage, was also reported by Wu-Zhang et al. (2012) not to inhibit the expressed PKMzeta fusion protein. However, the efficacy of inhibitors on endogenous enzymes in cells may not be adequately assessed in expression systems in which levels of expression of exogenous enzymes greatly exceed those of endogenous enzymes. Thus, we show, biochemically, that when PKMzeta reaches a level beyond that necessary for substrate phosphorylation such that much of the enzyme is excess or 'spare' kinase, ZIP and chelerythrine do not effectively block substrate phosphorylation. We also show that the cellular overexpression techniques used by Wu-Zhang et al. (2012) increase kinase levels ~30-40 fold above normal levels in transfected cells. Using a mathematical model we show that at such level of overexpression, standard concentrations of inhibitor should have no noticeable effect. Furthermore, we demonstrate the standard concentrations of ZIP, but not scrambled ZIP, inhibit the ability of PKMzeta to potentiate AMPAR responses at postsynaptic sites, the physiological function of the kinase. Wu-Zhang et al. (2012) had also claimed that staurosporine, a general kinase inhibitor that does not effectively inhibit PKMzeta biochemically in vitro, nonetheless indirectly blocked the PKMzeta fusion protein overexpressed in cultured cells by inhibiting phosphoinositide-dependent protein kinase-1 (PDK1). However, here we show that staurosporine does not affect PDK1 phosphorylation of the endogenous PKMzeta in hippocampal slices. Thus, the biochemical in vitro effects of PKMzeta inhibitors correspond with their intracellular effects, and ZIP and chelerythrine, together with scrambled ZIP and staurosporine as controls, are effective tools to examine the function of PKMzeta in neurons. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22846227 TI - Carbohydrate clearance receptors in transfusion medicine. AB - BACKGROUND: Complex carbohydrates play important functions for circulation of proteins and cells. They provide protective shields and refraction from non specific interactions with negative charges from sialic acids to enhance circulatory half-life. For recombinant protein therapeutics carbohydrates are especially important to enhance size and reduce glomerular filtration loss. Carbohydrates are, however, also ligands for a large number of carbohydrate binding lectins exposed to the circulatory system that serve as scavenger receptors for the innate immune system, or have more specific roles in targeting of glycoproteins and cells. SCOPE OF REVIEW: Here we provide an overview of the common lectin receptors that play roles for circulating glycoproteins and cells, and present a discussion of ways to engineer glycosylation of recombinant biologics and cells to improve therapeutic effects. MAJOR CONCLUSIONS: While the pharmaceutical industry has learned how to exploit carbohydrates to improve pharmacokinetic properties of recombinant therapeutics, our understanding of how to improve cell-based therapies by manipulation of complex carbohydrates is still at its infancy. Progress with the latter has recently been achieved with cold stored platelets, where exposure of uncapped glycans lead to rapid clearance from circulation by several lectin-mediated pathways. GENERAL SIGNIFICANCE: Understanding lectin-mediated clearance pathways is essential for progress in development of biological pharmaceuticals. PMID- 22846228 TI - Identifying environmental drivers of insect phenology across space and time: Culicoides in Scotland as a case study. AB - Interpreting spatial patterns in the abundance of species over time is a fundamental cornerstone of ecological research. For many species, this type of analysis is hampered by datasets that contain a large proportion of zeros, and data that are overdispersed and spatially autocorrelated. This is particularly true for insects, for which abundance data can fluctuate from zero to many thousands in the space of weeks. Increasingly, an understanding of the ways in which environmental variation drives spatial and temporal patterns in the distribution, abundance and phenology of insects is required for management of pests and vector-borne diseases. In this study, we combine the use of smoothing techniques and generalised linear mixed models to relate environmental drivers to key phenological patterns of two species of biting midges, Culicoides pulicaris and C. impunctatus, of which C. pulicaris has been implicated in transmission of bluetongue in Europe. In so doing, we demonstrate analytical tools for linking the phenology of species with key environmental drivers, despite using a relatively small dataset containing overdispersed and zero-inflated data. We demonstrate the importance of landcover and climatic variables in determining the seasonal abundance of these two vector species, and highlight the need for more empirical data on the effects of temperature and precipitation on the life history traits of palearctic Culicoides spp. in Europe. PMID- 22846229 TI - Monocrotaline-induced pulmonary arterial hypertension is attenuated by TNF-alpha antagonists via the suppression of TNF-alpha expression and NF-kappaB pathway in rats. AB - Inflammation is involved in various types of human pulmonary arterial hypertension (PAH), especially in PAH-associated connective tissue diseases. Although the pathogenesis of pulmonary hypertension has still remained largely unclear, TNF-alpha has been reported as a key pro-inflammatory cytokine in severe pulmonary hypertension and emphysema. The aim of this study was to investigate the effect of a TNF-alpha antagonist, recombinant TNF-alpha receptor II:IgG Fc fusion protein (rhTNFRFc), on the development of monocrotaline (MCT)-induced PAH in rats. Our results revealed that treatment of rhTNFRFc in these rats had favorable effects on mPAP levels, hemodynamics and pulmonary vascular remodeling, preventing PAH development at 3weeks following MCT. Furthermore, rhTNFRFc treatment resulted in markedly reduced expression of TNF-alpha via the inhibition of NF-kappaB activity in rat lungs. These results demonstrated that rhTNFRFc attenuated the process of MCT-induced PAH through its anti-inflammatory property. Although further studies are needed to define the appropriate treatment regimen, our findings suggest that rhTNFRFc might provide therapeutic benefits for PAH patients. PMID- 22846230 TI - Effectiveness of genomic prediction on milk flow traits in dairy cattle. AB - BACKGROUND: Milkability, primarily evaluated by measurements of milking speed and time, has an economic impact in milk production of dairy cattle. Recently the Italian Brown Swiss Breeders Association has included milking speed in genetic evaluations. The main objective of this study was to investigate the possibility of implementing genomic selection for milk flow traits in the Italian Brown Swiss population and thereby evaluate the potential of genomic selection for novel traits in medium-sized populations. Predicted breeding values and reliabilities based on genomic information were compared with those obtained from traditional breeding values. METHODS: Milk flow measures for total milking time, ascending time, time of plateau, descending time, average milk flow and maximum milk flow were collected on 37 213 Italian Brown Swiss cows. Breeding values for genotyped sires (n = 1351) were obtained from standard BLUP and genome-enhanced breeding value techniques utilizing two-stage and single-step methods. Reliabilities from a validation dataset were estimated and used to compare accuracies obtained from parental averages with genome-enhanced predictions. RESULTS: Genome-enhanced breeding values evaluated using two-stage methods had similar reliabilities with values ranging from 0.34 to 0.49 for the different traits. Across two-stage methods, the average increase in reliability from parental average was approximately 0.17 for all traits, with the exception of descending time, for which reliability increased to 0.11. Combining genomic and pedigree information in a single-step produced the largest increases in reliability over parent averages: 0.20, 0.24, 0.21, 0.14, 0.20 and 0.21 for total milking time, ascending time, time of plateau, descending time, average milk flow and maximum milk flow, respectively. CONCLUSIONS: Using genomic models increased the accuracy of prediction compared to traditional BLUP methods. Our results show that, among the methods used to predict genome-enhanced breeding values, the single-step method was the most successful at increasing the reliability for most traits. The single step method takes advantage of all the data available, including phenotypes from non-genotyped animals, and can easily be incorporated into current breeding evaluations. PMID- 22846231 TI - Measuring recollection and familiarity: Improving the remember/know procedure. AB - The remember/know (RK) procedure is the most widely used method to investigate recollection and familiarity. It uses trial-by-trial reports to determine how much recollection and familiarity contribute to different kinds of recognition. Few other methods provide information about individual memory judgements and no alternative allows such direct indications of recollection and familiarity influences. Here we review how the RK procedure has been and should be used to help resolve theoretical disagreements about the processing and neural bases of components of recognition memory. Emphasis is placed on procedural weaknesses and a possible confound of recollection and familiarity with recognition memory strength. Recommendations are made about how to minimise these problems including using modified versions of the procedure. The proposals here are important for improving behavioural and lesion research, and vital for brain imaging work. PMID- 22846232 TI - Thyroid function tests in obese prepubertal children: correlations with insulin sensitivity and body fat distribution. AB - BACKGROUND/AIMS: Elevated thyroid-stimulating hormone (TSH) concentrations in association with normal/slightly elevated free triiodothyronine (fT(3)) and/or free thyroxine (fT(4)) have been consistently found in obese children. To examine relationships between adiposity, insulin sensitivity, and TSH, fT(3) and fT(4). METHODS: 240 overweight/obese prepubertal children were studied. Fasting TSH, fT(3), fT(4), glucose, insulin, C-peptide, lipids, leptin and adiponectin were evaluated. Insulin sensitivity and resistance were estimated [quantitative insulin check index (QUICKI), insulin sensitivity index (ISI), and hepatic insulin resistance index]. Body fat was measured by dual-energy X-ray absorptiometry. The central obesity index was calculated as the ratio of fat tissue in the trunk region to fat tissue in the leg region. RESULTS: The multiple regression analysis with age, gender and measures of fatness as covariates showed that QUICKI was the only significant negative predictor of TSH and central obesity index the strongest positive predictor of fT(3), in association with either age or hepatic insulin resistance index, and that the only positive determinant of fT(4) was hepatic insulin resistance index. CONCLUSIONS: Reduced insulin sensitivity is associated with augmented TSH and fT(4), while progressive central fat accumulation is strictly related to a parallel increase in fT(3) levels, independently from total body fat. Further studies are needed to understand mechanisms linking thyroid function to insulin sensitivity and body composition in obese children. PMID- 22846233 TI - Physical activity education in the undergraduate curricula of all UK medical schools: are tomorrow's doctors equipped to follow clinical guidelines? AB - Physical activity (PA) is a cornerstone of disease prevention and treatment. There is, however, a considerable disparity between public health policy, clinical guidelines and the delivery of physical activity promotion within the National Health Service in the UK. If this is to be addressed in the battle against non-communicable diseases, it is vital that tomorrow's doctors understand the basic science and health benefits of physical activity. The aim of this study was to assess the provision of physical activity teaching content in the curricula of all medical schools in the UK. Our results, with responses from all UK medical schools, uncovered some alarming findings, showing that there is widespread omission of basic teaching elements, such as the Chief Medical Officer recommendations and guidance on physical activity. There is an urgent need for physical activity teaching to have dedicated time at medical schools, to equip tomorrow's doctors with the basic knowledge, confidence and skills to promote physical activity and follow numerous clinical guidelines that support physical activity promotion. PMID- 22846234 TI - Evaluating self-checkout lanes as a potential source of alcoholic beverages for minors. AB - OBJECTIVE: This exploratory study examined the ability of young adults to purchase alcoholic beverages through self-checkout lanes without being asked for age verification. Although the minimum drinking age in all 50 U. S. states is 21 years of age, drinking among underage persons (ages 12-20) remains a serious public health concern. Self-checkout options in off-sale alcoholic beverage outlets (e.g., grocery store chains, liquor stores) may represent a potential source of illicit access to alcohol compared with traditional checkout purchases. METHOD: A total of 216 stores with self-checkout lanes were randomly selected in five Southern California counties. Pseudo-patrons independently judged to be 23 years of age or younger purchased alcohol in each store. RESULTS: Overall, 8.8% of all purchase observations resulted in a failure to ask for identification to purchase alcohol. CONCLUSIONS: The growing number of self-checkout options at supermarkets can be a potential source of alcohol for minors; however, the risk they pose is similar to that of traditional checkout purchases. Policies relating to the purchase of alcohol at any store, regardless of checkout type, should be modified so that every purchase of alcohol requires an identification card to be swiped regardless of age. PMID- 22846235 TI - Memory for emotional picture cues during acute alcohol intoxication. AB - OBJECTIVE: Memory affects behavior by allowing events to be anticipated and goals to be planned based on previous experiences. Emotional memory, in particular, is thought to play a central role in behavior in general and in drinking behavior in particular. Alcohol intoxication has been shown to disrupt intentional, conscious memory, but not unintentional, implicit memory for neutral stimuli; however, its effects on emotional memory are not well understood. This study examined whether alcohol intoxication affected memory for emotionally valenced stimuli by testing explicit recall and implicit repetition priming of emotional picture cues. METHOD: Participants were 36 young adults (21-24 years old, 16 women) who received an alcohol, placebo, or no-alcohol beverage. Both cue exposure and memory testing occurred after beverage consumption (i.e., during intoxication for the alcohol group). RESULTS: Alcohol intoxication impaired explicit recall of all cue types but did not impair implicit repetition priming. Emotionally negative and positive cues were more often recalled compared with neutral cues across all beverage groups, and emotionally negative cues demonstrated more priming than emotionally positive or neutral cues in all beverage groups. CONCLUSIONS: Alcohol intoxication disrupted effortful recall of all cues, although the relative memory advantage of emotionally valenced over-neutral stimuli remained even after drinking. The effects of alcohol on unintentional memory priming were not statistically significant, but the effects of emotionally negative cues were. Further research is needed to better understand alcohol intoxication and emotional valence effects on memory processes during implicit memory tasks and the possibility that negative mood facilitates memory priming of negative emotional stimuli. PMID- 22846236 TI - Predicting driving after drinking over time among college students: the emerging role of injunctive normative perceptions. AB - OBJECTIVE: Despite prevention efforts, driving after drinking (DAD) is a prevalent high-risk behavior among college students and is a leading cause of death and injury. Examination of factors predicting future DAD behavior is necessary to develop efficacious targeted interventions to reduce this behavior among college students. The current study evaluated demographic, social cognitive, and behavioral predictors of DAD using longitudinal data. METHOD: Participants were 655 nonabstaining college students (67.2% female; 60.3% White; Mage = 19.3 years) who completed online surveys at two time points 12 months apart. RESULTS: Results revealed that participants consistently overestimated their peers' approval (injunctive norms) of DAD. In a three-step hierarchical logistic regression model, injunctive norms, age, and past DAD behavior uniquely contributed to the prediction of this behavior 12 months later. Neither sex nor membership in a sorority or fraternity emerged as significant predictors. CONCLUSIONS: The findings provide important new insights into the longitudinal predictors of DAD among college students and highlight the need for DAD interventions, particularly among older students. PMID- 22846237 TI - Drinking context and intimate partner violence: evidence from the California community health study of couples. AB - OBJECTIVE: Couples in which one or both partners is a heavy or problem drinker are at elevated risk for intimate partner violence (IPV), yet little is known about the extent to which each partner's drinking in different contexts (volume consumed per setting in bars, parties, at home, or in public places) increases the likelihood that partner aggression will occur. This study examined associations between the volume consumed in different settings by each partner and the occurrence and frequency of IPV. METHOD: We obtained a geographic sample of married or cohabiting couples residing in 50 medium to large California cities. Cross-sectional survey data were collected via confidential telephone interviews (60% response rate). Logistic and negative binomial regression analyses were based on 1,585 couples who provided information about past-12-month IPV, drinking contexts (number of times attended, proportion of drinking occasions when attended, average number of drinks), frequency of intoxication, and psychosocial and demographic factors. Drinking context-IPV associations for each partner were adjusted for the other partner's volume for that context and other covariates. RESULTS: Male partner's volume per setting for bars and parks or public places was associated with the occurrence and frequency of male-to female IPV and female-to-male IPV. Male's volume per setting for quiet evening at home was associated with the occurrence of female-to-male IPV; female partner's volume for this setting was associated with the frequency of male-to-female IPV and female-to-male IPV. CONCLUSIONS: Among couples in the general population, each partner's drinking in certain contexts is an independent risk factor for the occurrence and frequency of partner aggression. PMID- 22846238 TI - Investigating the association between childhood sexual abuse and alcohol use disorders in women: does it matter how we ask about sexual abuse? AB - OBJECTIVE: The purpose of this study was to determine whether the type of questions used to assess childhood sexual abuse (CSA) introduces systematic bias into estimations of the magnitude of the association between CSA and alcohol use disorders (AUDs). METHOD: The Semi-Structured Assessment for the Genetics of Alcoholism was administered by telephone to 3,787 female twins ages 18-29 years (14.6% African American, 85.4% White). Interviews included questions regarding sexual abuse experiences described in behavioral terms and a standard trauma checklist (in a separate section) with the items "rape" and "sexual molestation," with definitions provided in respondent booklets. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of alcohol abuse and dependence, parental history of alcohol-related problems, and psychiatric conditions associated with AUDs were also assessed. RESULTS: The majority of women who endorsed one question type also endorsed the other type. Rates of psychiatric risk factors for AUDs did not vary by pattern of CSA question endorsement. Separate Cox proportional hazards regression analyses using CSA variables derived from behavioral questions (hazard ratio [HR] = 1.67, 95% CI [1.27, 2.19]) and checklist items (HR = 1.41,95% CI [1.08, 1.84]) each revealed elevated risk for AUDs associated with CSA, and HRs did not differ significantly across models. However, a Cox proportional hazards regression analysis predicting AUD from the pattern of CSA question endorsements revealed a significantly higher risk for AUDs among women who endorsed only behavioral questions (HR = 3.26, 95% CI [1.72, 6.21]) than for all other groups. CONCLUSIONS: Findings underscore the importance of querying CSA in studies of alcohol-related problems and highlight some of the limitations of assessment methods that can be integrated into studies covering a wide range of psychosocial domains. PMID- 22846240 TI - Acute stress and event-related potential correlates of attention to alcohol images in social drinkers. AB - OBJECTIVE: The use of alcohol to cope with stress is a major health concern, yet the neurophysiological mechanisms underlying the effects of stress on alcohol related cognition are not well understood. This study examined changes in event related potentials (ERPs) elicited by alcohol-related images before and after a stressor compared with a control condition. METHOD: Social drinkers (N = 75; 38 male) were assigned to one of two target subgroups for completion of an oddball task: (a) to detect alcohol targets while ignoring household object distracters and frequently presented nonsense shapes or (b) to detect object targets while ignoring alcohol distracters and nonsense shapes. ERPs were recorded before and after one of two conditions: a stressor or a nonstressful control task. RESULTS: N200 latency and amplitude changes were modulated by stress. Similarly, stress reduced P300 latencies beyond practice effects. For P300 amplitude, the target subgroup interacted with the condition such that the standard "oddball" effect was observed in the control condition but was absent in the stress condition, suggesting that stress may have interfered with the participants' cognitive efficiency, or the ability to ignore task-irrelevant stimuli. CONCLUSIONS: These findings suggest that stress influences the early stages of alcohol-related processing, an effect that may be particularly apparent in ERP latencies. These findings have implications for understanding the neural mechanisms involved with stress and alcohol cue reactivity. PMID- 22846239 TI - Brain response to working memory over three years of adolescence: influence of initiating heavy drinking. AB - OBJECTIVE: Many adolescents engage in heavy alcohol use. The aim of this study was to disentangle whether brain abnormalities seen in adolescent heavy drinkers are a consequence of heavy drinking, a preexisting risk factor for initiation of alcohol use, or both. METHOD: Study 1 used cross-sectional functional magnetic resonance imaging (fMRI) visual working-memory (VWM) data from 15- to 19-year olds (20 heavy drinkers, 20 controls) to identify brain regions affected by heavy adolescent alcohol use. Study 2 used longitudinal fMRI VWM data from 12- to 16 year-olds imaged before the onset of drinking and imaged again on the same scanner approximately 3 years later. Those who had transitioned into heavy drinking (n = 20) were matched to continuous nondrinkers (n = 20) on baseline alcohol risk and developmental factors (N = 40; 80 scans). RESULTS: Study 1 found that heavy drinkers exhibited more frontal and parietal but less occipital activation than controls, defining the regions of interest for Study 2. In Study 2, adolescents who later transitioned into heavy drinking showed less fMRI response contrast at baseline than continuous nondrinkers, which increased after the onset of heavy drinking, in frontal (1,431 MUL, p = .003; eta2 = .19) and parietal (810 MUL, p = .005; eta2= .23) regions, as in Study 1. Lower baseline activation in the frontal and parietal regions predicted subsequent substance use, more so than commonly observed predictors of youth drinking (p < .05). CONCLUSIONS: Adolescents who initiated heavy drinking showed different brain activation before the onset of drinking, then less efficient information processing after high-dose alcohol use started. This suggests neural response patterns that could be risk factors for future substance use and also supports prior neuropsychological reports indicating that initiating heavy episodic drinking in adolescence may be followed by subtle alterations in brain functioning. PMID- 22846241 TI - Socioeconomic status and substance use among young adults: a comparison across constructs and drugs. AB - OBJECTIVE: Little consensus exists regarding the relationship between socioeconomic status (SES) and substance use. This study examined the associations of three indicators of family SES during childhood--income, wealth, and parental education--with smoking, alcohol use, and marijuana use during young adulthood. METHOD: Data were obtained from the national Panel Study of Income Dynamics, a survey of U.S. families that incorporates data from parents and their children. In 2005 and 2007, the Panel Study of Income Dynamics was supplemented with two waves of Transition into Adulthood data drawn from a national sample of young adults, 18-23 years old. Data from the young adults (N = 1,203; 66.1% White; 51.5% female) on their current use of alcohol, cigarettes, and marijuana were used as outcome variables in logistic regressions. Socioeconomic background was calculated from parental reports of education, wealth, and income during the respondent's childhood (birth through age 17 years). RESULTS: Smoking in young adulthood was associated with lower childhood family SES, although the association was explained by demographic and social role covariates. Alcohol use and marijuana use in young adulthood were associated with higher childhood family SES, even after controlling for covariates. CONCLUSIONS: Findings based on three indicators of family background SES--income, wealth, and parental education- converged in describing unique patterns for smoking and for alcohol and marijuana use among young adults, although functional relationships across SES measures varied. Young adults with the highest family background SES were most prone to alcohol and marijuana use. PMID- 22846242 TI - Examining risk and protective factors for alcohol use in lesbian, gay, bisexual, and transgender youth: a longitudinal multilevel analysis. AB - OBJECTIVE: Lesbian, gay, bisexual, and transgender (LGBT) youth are at increased risk for alcohol misuse, but little is known about the psychosocial and demographic factors that are associated with these differences over time. The purpose of this study was to investigate change in alcohol use across development. We aimed to describe group/demographic differences in alcohol use, the effects of psychosocial variables on drinking within persons (i.e., psychological distress, sexual orientation-based victimization, and perceived family support), and the interactions between demographic differences and longitudinal psychosocial variables in predicting rates of alcohol use. METHOD: The current study used data from the longest running longitudinal study of LGBT youth. Hierarchical linear modeling was used to examine both demographic differences and psychosocial predictors of alcohol use in an ethnically diverse sample of 246 LGBT youth (ages 16-20 years at baseline) across five time points over 2.5 years. RESULTS: Drinking increased significantly over time in a linear fashion, although it tended to increase more rapidly among male LGBT youth compared with females. Analyses of group differences revealed lower average rates of drinking for African American and female LGBT youth, and there were no differences between bisexual youth and gay/lesbian youth. Psychological distress and sexual orientation-based victimization were associated with increased alcohol use at each wave of data collection for female LGBT youth only. Perceived family support at each wave was negatively associated with alcohol use for all LGBT youth. CONCLUSIONS: Findings indicate that there is significant heterogeneity in the etiological pathways that lead to alcohol use in LGBT youth and that correlates of drinking are similar to those found in general populations. These crucial findings indicate that existing alcohol interventions also may be effective for LGBT youth and open up a wider array of prevention and treatment options for this at-risk population. PMID- 22846243 TI - Direct and indirect effects of impulsivity traits on drinking and driving in young adults. AB - OBJECTIVE: Impulsivity is strongly associated with alcohol-related risk-taking behavior, and this association has been found to be mediated by alcohol cognitions. The current study expanded this literature by comparing the relative association of distinct impulsivity traits with a specific risky behavior- drinking and driving. We then tested whether drinking-and-driving expectancies uniquely mediated this relation over and above other cognitions about alcohol and drinking and driving. METHOD: College student drivers (n = 816; 53.6% women) completed a paper-and-pencil survey in small groups. Self-report measures assessed alcohol use, impulsivity traits, alcohol expectancies, drinking-and driving cognitions (i.e., expectancies, attitudes, beliefs), and drinking and driving. RESULTS: Although all impulsivity traits were correlated with drinking and driving, only urgency uniquely contributed to drinking and driving. Indirect effect tests indicated that drinking-and-driving convenience expectancies partially mediated this association as well as that between (lack of) perseverance and drinking and driving. These results remained significant after controlling for alcohol expectancies and other drinking-and-driving cognitions. CONCLUSIONS: These findings highlight the importance of distinguishing among impulsivity traits to improve theoretical models of the processes by which personality leads to specific alcohol-related consequences. In addition, results extend previous research by providing evidence for the unique importance of expectancies regarding the convenience of drinking and driving over and above more global alcohol expectancies and other drinking-and-driving cognitions. PMID- 22846244 TI - How do impulsivity and education relate to smoking initiation and cessation among young adults? AB - OBJECTIVE: This study examined the predictive value of impulsivity for starting and quitting smoking and whether education had an independent effect on smoking careers or moderated the impulsivity-smoking association. METHOD: Two waves of the cohort study Young in Norway were used in the present study (third wave: 1999, age range: 19-32 years; fourth wave: 2005, age range: 25-38 years). Postal questionnaires were used for data collection. Subjects participating in 1999 and 2005 were eligible (N = 2,562). Stable smokers (daily smokers in 1999 and 2005) and nonsmokers (never smokers in 1999 and 2005), quitters (daily smokers in 1999, nonsmokers in 2005), and starters (never smokers in 1999, daily smokers in 2005) constituted the analytical sample (1,776 men and women). The associations between self-reported impulsivity and education and smoking were investigated using logistic regression analyses. RESULTS: The odds ratio (OR) for a 1-unit increase in the impulsivity score was 2.16 (95% CI [1.09, 4.30]) for smoking initiation, whereas the OR [95% CI] for low compared with high education was 2.55 (95% CI [1.36, 4.77]). Education, but not impulsivity, emerged as a significant determinant for smoking cessation compared with continued smoking. The OR for quitting smoking by low compared with high education was 0.61 (95% CI [0.42, 0.90]). Mutual adjustment for education and impulsivity did not change any of the results. The interaction term between impulsivity and education was not significantly related to smoking. CONCLUSIONS: Because impulsivity emerged as important for smoking initiation regardless of educational level, it should be considered when planning and implementing smoking prevention programs for both low and high socioeconomic groups. PMID- 22846245 TI - Sex differences in mediating and moderating processes linking economic stressors, psychological distress, and drinking. AB - OBJECTIVE: Given the recent downturn in the U.S. economy, we considered in this study the processes linking economic stressors, psychological distress, and two alcohol-related outcomes (past-month drinking and problematic drinking). METHOD: Data were drawn from a mail survey of a national sample of 663 respondents. Structural equation modeling was used to assess whether psychological distress mediates the associations between economic stressors and the alcohol-related outcomes considered and whether these associations varied by gender. RESULTS: Controlling for correlations among the outcomes and the effects of the sociodemographic control variables, psychological distress was found to partly explain the association between economic stressors and problematic drinking. The mediating effects on problematic drinking were significantly greater for men than women. CONCLUSIONS: The findings demonstrate the utility of considering interrelationships among alcohol-related outcomes and, in this context, reveal the circumstances in which gender matters most for understanding the associations among economy-related stressors, psychological distress, and drinking. PMID- 22846246 TI - Measures of substance consumption among substance users, DSM-IV abusers, and those with DSM-IV dependence disorders in a nationally representative sample. AB - OBJECTIVE: Neither the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), nor the DSM-IV uses measures of substance consumption as part of the diagnostic criteria for substance use disorders. Therefore, this report examined the extent to which frequency and/or quantity of consumption across a broad spectrum of substances are associated with DSM-IV diagnoses of specific substance use disorders and whether there are informative hierarchical levels of consumption among users, abusers, and those who are substance dependent in the U.S. general population. METHOD: The analyses focused on consumption data from respondents of the 2001-2002 National Epidemiologic Survey of Alcohol and Related Disorders. Multinomial logistic regression was used to predict DSM-IV diagnoses of dependence or abuse based on the continuous consumption measures. RESULTS: Among individuals who used substances, the substances with the greatest liability for dependence were nicotine first and cocaine second. For nearly all substances investigated, users without specific substance use disorders demonstrated lower levels of quantity and frequency of consumption relative to those with DSM-IV abuse and dependence disorders. Dose response curves for the log odds of abuse and dependence suggested unidimensionality of abuse and dependence for frequency of alcohol drinking; frequency of cannabis use; frequency of opioid use; frequency of hallucinogen use; and, to a lesser extent, frequency of amphetamine use. However, the dose response curves for the quantity of alcohol consumed demonstrated differential patterns for abuse and dependence such that alcohol dependence has a distinctly greater "quantity of use" relationship than that found among alcohol-abusing individuals. CONCLUSIONS: These results confirm the findings of others concerning the unidimensionality of abuse and dependence diagnoses when consumption variables alone are examined and suggest that consumption measures may be useful metrics gauging severity. PMID- 22846247 TI - Self-administered web-based timeline followback procedure for drinking and smoking behaviors in young adults. AB - OBJECTIVE: The goal of the current investigation was to test the psychometric properties of a self-administered web-based version of the Timeline Followback (TLFB), a retrospective calendar method of assessing daily behaviors. METHOD: The study used a within-subjects, counterbalanced design to compare estimates of daily drinking and smoking behaviors obtained by a self-administered web-based version of the TLFB with estimates obtained by a telephone interview version. The sample consisted of 120 social drinker-smoker young adults (65 men). RESULTS: Correlations between the two modalities for total number of drinks, total drinking days, and heavy drinking days in a 4-week period ranged from .83 to .93; those for total cigarettes, total smoking days, and heavy smoking days ranged from .90 to .95. The correlation between the two modalities for estimates of the number of co-use days was .90. Drinking and smoking estimates from the online TLFB also correlated significantly with scores from the Alcohol Use Disorders Identification Test and Fagerstrom Test of Nicotine Dependence. CONCLUSIONS: Overall, the results demonstrated strong support for the use of a self administered web-based TLFB assessment tool to capture concurrent reports of social drinking and smoking behaviors in young adults. The web-based TLFB may be particularly well suited for assessment in clinical trials, longitudinal designs, and epidemiological studies. PMID- 22846248 TI - Innovative recruitment using online networks: lessons learned from an online study of alcohol and other drug use utilizing a web-based, respondent-driven sampling (webRDS) strategy. AB - OBJECTIVE: We used a web version of Respondent-Driven Sampling (webRDS) to recruit a sample of young adults (ages 18-24) and examined whether this strategy would result in alcohol and other drug (AOD) prevalence estimates comparable to national estimates (National Survey on Drug Use and Health [NSDUH]). METHOD: We recruited 22 initial participants (seeds) via Facebook to complete a web survey examining AOD risk correlates. Sequential, incentivized recruitment continued until our desired sample size was achieved. After correcting for webRDS clustering effects, we contrasted our AOD prevalence estimates (past 30 days) to NSDUH estimates by comparing the 95% confidence intervals of prevalence estimates. RESULTS: We found comparable AOD prevalence estimates between our sample and NSDUH for the past 30 days for alcohol, marijuana, cocaine, Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA), and hallucinogens. Cigarette use was lower than NSDUH estimates. CONCLUSIONS: WebRDS may be a suitable strategy to recruit young adults online. We discuss the unique strengths and challenges that may be encountered by public health researchers using webRDS methods. PMID- 22846249 TI - Assessing the protective value of protective behavioral strategies. AB - OBJECTIVE: Many students report using strategies believed to reduce risk of harm from consumption of alcohol. The effectiveness of these strategies was tested in this study. METHOD: A sample of 442 undergraduate students (50.5% female) was asked to report how many alcoholic drinks they consumed on a recent drinking occasion, which protective strategies were used, and which harms were experienced. RESULTS: Although reported use of more protective strategies was associated with less consumption, it appeared to be unrelated to harmful consequences. More detailed analyses suggested that only a small subset of strategies (primarily those concerning the manner of drinking) was consistently associated with reduced consumption and/or harms. CONCLUSIONS: The findings cast doubt on the efficacy of protective strategies or at least the validity of the self-report instruments used to assess these strategies. PMID- 22846250 TI - Patient reactance moderates the effect of directive telephone counseling for methamphetamine users. AB - OBJECTIVE: This study examined the impact of the interaction between patient reactance and treatment directiveness on the effectiveness of telephone aftercare for methamphetamine dependence. METHOD: Reactance was assessed at baseline, and participants were randomly assigned to directive or nondirective treatment conditions. Logistic regression tested for the significance of the interaction as a predictor of 3-month and 12-month use of methamphetamine and stimulants. RESULTS: A significant interaction was observed at the 3-month follow-up, in which the directive condition was less effective for patients higher in reactance and was more effective for patients lower in reactance. Among patients at a high level of reactance, the nondirective condition increased the likelihood of abstinence. CONCLUSIONS: This study suggests that, in the context of telephone based care, directive interventions offer short-term clinical benefit for methamphetamine users who readily accept influence from authority figures, whereas nondirective interventions offer benefit for patients who do not readily accept influence. The short-term nature of these effects indicates that there is a need for brief but ongoing telephone support to maintain treatment gains. PMID- 22846251 TI - Experimental test of social norms theory in a real-world drinking environment. AB - OBJECTIVE: Social norms theory articulates that behavior is influenced by perceptions of behavioral norms. Social norms interventions attempt to modify perceptions of what behavior is normative as a means of influencing actual behavior. Social norms interventions have been widely used on college campuses to reduce the level of student drinking. The effectiveness of these interventions has been mixed. A social norms program might fail because the intervention operations failed to sufficiently implement social norms theory in the real world or because of the theory's limitations. Our research involves an experimental examination of the impact of social norms information on actual drinking behavior within a real-world drinking environment. METHOD: Nearly 3,000 participants were interviewed and randomly assigned to one of nine social norms feedback conditions before heading to bars and nightclubs in Tijuana, Mexico. These same participants were resampled, interviewed again, and subjected to breath alcohol analysis when they returned to the United States. RESULTS: We found that persons whose perceptions of normative drinking changed (became more accurate) during their visit to Tijuana consumed relatively less alcohol. We also found that providing participants with social norms feedback produced more accurate perceived norms. However, the effect sizes were too small to produce statistically significant results showing that social norms feedback could effectively reduce drinking via changing normative perceptions. CONCLUSIONS: Our research demonstrated that providing social norms feedback changed perceived drinking norms and that changes in perceived norms were correlated with reduced drinking. Effect sizes, however, were quite small. PMID- 22846252 TI - Physical exercise and intermittent administration of lactulose may improve autism symptoms through hydrogen production. AB - Autism is neuro-developmental disorder. Oxidative stress is enhanced in some children with autism. Hydrogen is a gas with anti-oxidative effects suggested for treating or prevention of some medical problems. It is hypothesized that lactulose or hydrogen water may provide hydrogen to reduce oxidative stress in autism. PMID- 22846253 TI - A comparative analysis of predictors of teenage pregnancy and its prevention in a rural town in Western Nigeria. AB - INTRODUCTION: Teenagers younger than 15 are five times more likely to die during pregnancy or childbirth than women in their twenties and mortality rates for their infants are higher as well. This study was therefore designed to determine the recent prevalence and identify factors associated with teenage pregnancy in a rural town in Nigeria. METHODS: This study is an analytical comparative cross sectional study. A total sample of all pregnant women attending the primary health care in Sagamu local government area, Ogun State within a 2 months period were recruited into the study. RESULTS: A total of 225 pregnant women were recruited into the study. The prevalence of teenage pregnancy was 22.9%. Teenagers [48.2%] reported more unwanted pregnancy when compared with the older age group [13.6%] [OR = 5.91, C.I = 2.83-12.43]. About half 33 [41.1%] of the teenage pregnant women and 28.6% of the older pregnant women did not know how to correctly use condom to prevent pregnancy [OR = 0.57, C.I = 0.29-1.13]. Predictors of teenage pregnancy were low social class (OR = 2.25, C.I = 1.31 3.85], Religion (OR = 0.44, C.I = 0.21-0.91], being a student (OR = 3.27, C.I = 1.02-10.46) and having a white collar job (OR = 0.09, C.I = 0.01-0.81). CONCLUSION: The study concludes that employment in an established organization (white collar job) is highly protective against teenage pregnancy while students are becoming increasingly prone to early pregnancy. Government should structure employment in low income countries in such a way as to give a quota to adolescents who are unable to continue their education. PMID- 22846254 TI - Liver transplantation in nonalcoholic steatohepatitis is associated with high mortality and post-transplant complications: a single-center experience. AB - BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) with its progressive form nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in western countries which is associated with end-stage liver disease and hepatocellular carcinoma (HCC). This entity is a consistently increasing indication for transplantation. However, data about postsurgery outcome and complications are still limited. PATIENTS AND METHODS: Records of 432 consecutive transplanted patients between October 2007 and January 2011 were investigated retrospectively. Forty transplants were performed due to NASH-induced cirrhosis. Perioperative courses and short- and long-term outcomes were analyzed. RESULTS: The NAFLD population consisted of 16 women and 24 men with a mean age of 55 years. The median MELD score was 27 at the time of liver transplantion. BMI before surgery ranged from 21 to 45 (mean 31). Sixteen of the initial 40 patients are still alive. Patients with sustained obesity and features of the metabolic syndrome had a worse 1-year mortality rate of 42%. CONCLUSIONS: A significant number of liver transplantations in our center was performed due to NASH; transplantation in this cohort was associated with high mortality and postoperative complications, most likely due to associated obesity and diabetes. Weight reduction prior to surgery may lead to a better outcome. PMID- 22846255 TI - An anionic synthetic sugar containing 6-SO3 -NAcGlc mimics the sulfated cruzipain epitope that plays a central role in immune recognition. AB - Cruzipain (Cz), the major cysteine proteinase of Trypanosoma cruzi, is a glycoprotein that contains sulfated high-mannose-type oligosaccharides. We have previously determined that these sulfate groups are targets of specific immune responses. In order to evaluate the structural requirements for antibody recognition of Cz, a systematic structure-activity study of the chemical characteristics needed for antibody binding to the Cz sulfated epitope was performed by immunoassays. With this aim, different synthesized molecules were coupled to the proteins BSA and aprotinin and confronted with (a) mouse sera specific for Cz and its carboxy-terminal (C-T) domain, (b) antibodies raised in rabbits immunized with Cz and its C-terminal domain and (c) IgGs purified from human Chagas disease sera. Our results indicate that a glucosamine containing an esterifying sulfate group in position O-6 and an N-acetyl group was the preferred epitope for the immune recognition of sera specific for Cz and its C-T domain. Although to a minor extent, other anionic compounds bearing sulfate groups in different positions and number as well as different anionic charged groups including carboxylated or phosphorylated monosaccharides, disaccharides and oligosaccharides were recognized. In conclusion, we found that synthetic anionic sugar conjugates containing N-acetyl d-glucosamine-6-sulfate sodium salt (GlcNAc6S) competitively inhibit the binding of affinity purified rabbit anti-C-T IgG to the C-T extension of Cz. Extending these findings to the context of natural infection, immune assays performed with Chagas disease serum confirmed that the structure of synthetic GlcNAc6S mimics the N-glycan-linked sulfated epitope displayed in the C-T domain of Cz. PMID- 22846256 TI - Disinfection byproduct formation in reverse-osmosis concentrated and lyophilized natural organic matter from a drinking water source. AB - Drinking water treatment and disinfection byproduct (DBP) research can be complicated by natural organic matter (NOM) temporal variability. NOM preservation by lyophilization (freeze-drying) has been long practiced to address this issue; however, its applicability for drinking water research has been limited because the selected NOM sources are atypical of most drinking water sources. The purpose of this research was to demonstrate that reconstituted NOM from a lyophilized reverse-osmosis (RO) concentrate of a typical drinking water source closely represents DBP formation in the original NOM. A preliminary experiment assessed DBP formation kinetics and yields in concentrated NOM, which demonstrated that chlorine decays faster in concentrate, in some cases leading to altered DBP speciation. Potential changes in NOM reactivity caused by lyophilization were evaluated by chlorination of lyophilized and reconstituted NOM, its parent RO concentrate, and the source water. Bromide lost during RO concentration was replaced by adding potassium bromide prior to chlorination. Although total measured DBP formation tended to decrease slightly and unidentified halogenated organic formation tended to increase slightly as a result of RO concentration, the changes associated with lyophilization were minor. In lyophilized NOM reconstituted back to source water TOC levels and then chlorinated, the concentrations of 19 of 21 measured DBPs, constituting 96% of the total identified DBP mass, were statistically indistinguishable from those in the chlorinated source water. Furthermore, the concentrations of 16 of 21 DBPs in lyophilized NOM reconstituted back to the RO concentrate TOC levels, constituting 86% DBP mass, were statistically indistinguishable from those in the RO concentrate. This study suggests that lyophilization can be used to preserve concentrated NOM without substantially altering the precursors to DBP formation. PMID- 22846257 TI - Long-term renal outcome in patients with malignant hypertension: a retrospective cohort study. AB - BACKGROUND: Malignant hypertension is frequently complicated by renal insufficiency. Although the survival of this hypertensive emergency has improved, recent data on renal outcome and its predictors are lacking. We assessed renal outcome and its predictors in patients with malignant hypertension. METHODS: Retrospective analysis of patients admitted with malignant hypertension in Amsterdam, the Netherlands between August 1992-January 2010. Follow-up data on vital status, renal function and blood pressure (BP) were obtained from the outpatient department and from general practitioners. The primary composite endpoint was end-stage renal disease (ESRD) defined as the start of kidney replacement therapy (KRT) or >= 50% decline of estimated glomerular filtration rate (eGFR). The secondary endpoint was all cause mortality. RESULTS: A total of 120 patients admitted with malignant hypertension were included. After a median follow-up period of 67 months (IQR 28 to 108 months) the primary endpoint was reached by 37 (31%) patients, whereas 18 patients (15%) reached the secondary endpoint. Twenty-nine (24%) patients started KRT and 8 patients (7%) had an eGFR decline >= 50%. After the acute phase (> 3 months after admission), initial serum creatinine and follow-up BP were the main predictors of future ESRD with hazard ratios of 6.1 (95% CI, 2.2-17) for patients with initial serum creatinine >= 175 MUmol /L and 4.3 (95% CI, 1.4-14) for patients with uncontrolled hypertension. CONCLUSIONS: Progressive renal function decline leading to ESRD remains a major threat to patients with malignant hypertension. BP control during follow-up was an important modifiable predictor of renal outcome. PMID- 22846259 TI - Estimating burn depth from thermal measurements. AB - A new thermal perfusion probe operates by imposing a thermal event on the tissue surface and directly measuring the temperature and heat flux response of the tissue with a small sensor. The thermal event is created by convectively cooling the surface with a small group of impinging jets using room temperature air. The hypothesis of this research is that this sensor can be used to provide practical burn characterization of depth and severity by determining the thickness of non perfused tissue. The measurement system was tested with a phantom tissue that simulates the blood perfusion of tissue. Different thicknesses of plastic were used at the surface to mimic layers of dead tissue. The sensor uses a parameter estimation procedure with analytical solutions of the Pennes bio-heat equation to determine effective values of blood perfusion, core temperature, and thermal contact resistance. Twelve different thicknesses of plastic were used along with three different flow rates of perfusate to simulate burned skin in the phantom perfusion system. The resulting values of thermal contact resistance for the complete set of measurements correlate well with the layer thickness. The values are also nearly independent of the flow rate of the perfusate, which shows that the parameter estimation can successfully separate these parameters. These results with simulated burns show the value of this minimally invasive technique to predict the burn depth in tissue. PMID- 22846258 TI - A zoological catalogue of hunted reptiles in the semiarid region of Brazil. AB - The variety of interactions between human cultures and herpetofauna is the subject matter of Ethnoherpetology, a subdivision of Ethnozoology. In the semi arid region of Brazil, many reptiles interact with human communities because of their utility or because of the risks they represent. These interactions have obvious implications for the conservation of reptiles from this region. In this context, ethnoherpetology studies are crucial because they serve as subsidies for guiding strategies for the handling and conservation of reptiles. This paper presents ethnozoological and taxonomic informations of hunted reptiles in the semiarid region of Brazil and analyse the implications on conservation that are related to the interactions between people and reptiles in this region. Taxonomic keys to identifying recorded reptiles are provided. Records of humans interacting with 38 reptile species that belong to 31 genuses and 16 families have been found. The groups with the largest numbers of recorded species were snakes (18 species), and this group was followed in number by lizards (13), chelonians (4), and crocodilians (3). The reptiles that were recorded may be used for the following purposes: medicinal purposes (24 species), food (13 species), ornamental or decorative purposes (11 species), in magical/religious practices (10 species), and as pets (10 species). Some species (n = 16) may have multiple uses. Furthermore, more than half of the species (n = 19) are commonly killed because they are considered potentially dangerous. Strategies for conserving the reptiles of the Brazilian semi-arid region must reconcile and integrate human and conservation needs. PMID- 22846260 TI - Eye injury risk associated with remote control toy helicopter blades. AB - Eye injuries can be caused by a variety of consumer products and toys. Recently, indoor remote controlled (RC) toy helicopters have become very popular. The purpose of this study is to quantify eye injury risk associated with five commercially available RC toy helicopter blades. An experimental matrix of 25 tests was developed to test five different RC toy helicopter blades at full battery power on six postmortem human eyes. A pressure sensor inserted through the optic nerve measured intraocular pressure. Corneal abrasion was assessed post-impact using fluorescein dye. Intraocular pressure was correlated to injury risk for hyphema, lens damage, retinal damage, and globe rupture using published risk functions. All tests resulted in corneal abrasions; however, no other injuries were observed. The 25 tests produced an increase intraocular pressure between 15.2 kPa and 99.3 kPa (114.3 mmHg and 744.7 mmHg). Calculated blade velocities ranged between 16.0 m/s and 25.4 m/s. Injury risk for hyphema was a maximum of 0.2%. Injury risk for lens damage, retinal damage, and globe rupture was 0.0% for all tests. Blade design parameters such as length and mass did not affect the risk of eye injury. This is the first study to quantify the risk of eye injury from RC toy helicopter blades. While corneal abrasions were observed, more serious eye injuries were neither observed nor predicted to have occurred. Results from this study are critical for establishing safe design thresholds for RC toy helicopter blades so that more serious injuries can be prevented. PMID- 22846261 TI - Undergraduate design projects for assistive technology needs: assisted fishing. AB - In 2010 the University of Wyoming, College of Engineering and Applied Science was funded for a five year increment of the National Science Foundation?s Research to Aid Persons with Disabilities. This program provides a vital link between challenged individuals who require custom assistive technology devices with senior capstone design students who require challenging, meaningful projects. The program also provides education for our next generation of engineers on the needs of all individuals. In this paper we describe the program organization including project partners in the College and Wyoming Institute for Disabilities (WIND). We also provide a case study of a recently completed project for an assistive fishing device. PMID- 22846262 TI - The effects of sustained delivery of alendronate on the kidney in ovariectomized female rats. AB - Bisphosphonates are indicated for the treatment and prevention of osteoporosis in adults; the treatment and prevention of glucocorticoid-induced osteoporosis; the treatment of Paget?s disease; and the treatment of multiple myeloma in patients with documented bone metastases. Two long-term trials in cancer patients demonstrated an increase in serum creatinine (SCr) when 8 mg of bisphosphonate was administered, prompting a recommendation to reduce the dose to 4 mg. The risk for renal toxicity remains a possibility following chronic administration of bisphosphonate treatment for osteoporosis. The goal of the study was to evaluate the kidney of osteoporotic female rats following chronic administration of alendronate using a drug delivery device for 4 weeks and compare the finding with control non-ovariectomized animals, ovariectomized control animals (OVX), and ovariectomized animals with an empty drug delivery system. The results of the study showed significant increases in body weights in the ovariectomized animals compared with non-ovariectomized animals. The organ wet-weights were not statistically different between the control and treatment groups or the ovariectomized and non-ovariectomized animals. Histological and histomorphometric analysis of the kidney revealed significant changes in the glomerular area on alendronate treated animals at 4 weeks when compared with ovx, ovx-sham and control non-ovariectomized animals. The results indicate chronic use of alendronate for osteoporosis may impair renal function or increase renal related problems in patients with existing kidney disease. PMID- 22846263 TI - Histopathological and biomechanical parameters of repaired rat achilles tendons treated with and without mannose-6-phosphate. AB - Flexor tendon repairs are plagued by the formation of peripheral adhesions that limit motion. No current adjunct therapy is available to prevent this complication. Mannose-6-phosphate (M6P) is a natural sugar that has been shown to interact with the M6P/IGF-II receptor on fibroblasts. It is hypothesized that the addition of M6P to healing tendons would downregulate the production of unorganized scar collagen, allowing the tenocytes to guide tendon repair. Thirty two (32) Sprague-Dawley rats underwent right Achilles tendon transection and suture repair. M6P was directly applied to the tendons of half of the rats prior to skin closure. Half of the animals in each treatment group were sacrificed after two weeks of healing, and the rest after four weeks. There were no post operative complications (rupture, seroma, hematoma, infection). Histopathologic analysis was performed with H&E and elastin stains. Biomechanical analysis was performed to determine stress, strain, and elastic modulus. M6P was found to increase elastin production, decrease callus cross-sectional area, increase strain, and increase peak stress at failure. These changes were most evident at the two-week time point. The findings from this study support the continued investigation of M6P as an adjunct therapy to flexor tendon repair. PMID- 22846264 TI - Neovascularization is influenced by androgenic hormones in the tissue implant response. AB - The objective of this investigation was to demonstrate the effect of androgens on the neovascularization of the fibrous tissue surrounding tricalcium phosphate (TCP) implants. Sixteen animals in four experimental groups (n = 4/group) were implanted with one TCP implant each. Group I animals were implanted with the sham TCP ceramic (Control). Group II animals received a testosterone-loaded ceramic. Group III animals were implanted with a dihydrotestosterone containing bioceramic. Group IV animals received the androstenedione filled bioceramic. At 90 days post-implantation, the fibrous tissue surrounding the implants were evaluated microscopically following staining with routine hematoxylin and eosin (H&E), Masson?s trichrome, and Papanicolaou stains. Using Image Pro (Media Cybernetics, Silver Spring, MD) digital analysis software, data were collected to compare the hormonal effects on the number (per high power field) and size of blood vessels (micrometers, um) within the fibrous tissue surrounding all four groups. The presence of androgens greatly affected the angiogenic response within the fibrous tissue. All three hormones exhibited less neovascularization compared to the control. Though not as dramatic as androstenedione (3+/-0), both testosterone (12+/-1) and dihydrotestosterone (10+/-1) suppressed the number of blood vessels present in the fibrous tissue capsule compared to control (13+/-1). However, the circumference of the vessels was much larger for the testosterone (236um +/-8um) and dihydrotestosterone (256um+/-4um) treated groups compared to the androstenedione (146um +/-7um) or control (163um+/-3um) groups. The results of this study demonstrate androgens strongly vary in their effect on neovascularization by limiting the number of new vessels developed while contributing to the presence of larger vessels within the fibrous tissue surrounding TCP implants loaded with testosterone and dihydrotestosterone. PMID- 22846265 TI - Research training and biomedical education. AB - In an effort to increase the number of well trained minority healthcare professionals and basic science researchers, Jackson State University, (JSU, a historically black institution) in partnership with Hinds Community College (HCC, a 2-year college) and consultant biomedical researchers/healthcare professionals at the University of Mississippi Medical Center established a Bridges to the Baccalaureate Degree Program (BBDP). The purpose of the BBDP was to enhance HCC students transfer rates to 4 year institutions and to motivate trainees to seek Baccalaureate and advanced degrees in the biomedical and health sciences areas. The program utilized faculty and administrators at each institution in the planning and implementation of all programmatic aspects, including student selection, advisement procedures and program activities. HCC students (280) were recruited, 94.5 % of whom were African American, and trained in research laboratory methodologies, responsible conduct of research concepts, literature survey mechanisms, and scientific writing techniques during the academic year. Students engaged in specific individualized research projects during the summer and presented their research findings at local scientific seminars and professional meetings e.g., Mississippi Academy of Sciences, ABRCMS, FASEB, and the Endocrine Society. Sixty-five percent of students eligible to transfer actually transferred to Jackson State University and 8 other colleges and universities. Approximately 70% of the transfer students obtained Baccalaureate degrees and many received or are enrolled in masters and doctorate degree programs. HCC science faculty also received additional research training experiences and in 6 cases, initiated or completed terminal degrees in the sciences. In conclusion, it is clear that exposure to research training in the biomedical sciences can enhance community college students transfer rates and potential to seek advanced degrees. PMID- 22846266 TI - Reproductive system behavior following exposure of sustained delivery of npy antagonist in ovariectomized (ovx) rats. AB - Several investigations have documented that sustained delivery of estrogen can modulate or sustain normal female reproductive functions. However, the literature is lacking scientific evidence regarding the mechanism of estrogen and neuropeptide Y antagonist (NPY) effect on the hypothalamic-pituitary-gonadal axis. The objective of this study was to explore the role of sustained delivery of estrogen and its effects on reproductive unction compared to an antagonist such as NPY. A total of twenty adult female rats (OVX, n=15; intact control, n=5) were divided into five groups (intact control, OVX, sham, OVX + estrogen, and OVX + NPY). Animals in two groups were surgically implanted with a TCP delivery device loaded with estrogen or NPY. Vaginal smears and body weights (BW) were evaluated at baseline and at two weeks post implantation. At the end of two weeks, all animals were euthanized and vital and reproductive organs were retrieved for histopathological evaluation. The results revealed differences in BW between intact control and OVX animals. Furthermore, there was statistical difference (P<0.05) in BW between OVX and OVX + NPY animals. Vaginal smear evaluation revealed that estrogen exposure induced estrus cyclic activities as compared to OVX and sham animals. The animals exposed to sustained delivery of NPY triggered moderate cyclic activities compared to intact control animals. There were no significant differences (P<0.5) in vital organ wet weights among and between animals in all groups. Overall this study proved the capability of TCP to release estrogen and NPY at sustained levels, which resulted inpathophysiological changes in female reproductive organs. PMID- 22846267 TI - Modeling the effects of caffeine on the sleep/ wake cycle. AB - Caffeine is present in many products consumed daily, including coffee, soda, and chocolate, and is known to delay the onset of sleepiness and cause sleep disturbances. It is an adenosine antagonist, inhibiting some hormones that promote sleep, and therefore promoting wakefulness. This paper proposes a model to incorporate the effects of caffeine on the sleep/wake cycle. The ?flip-flop? model was used to model the sleep cycle, where switching between a sleep state and a wake state was nearly instantaneous. Sleep patterns were modeled based on the circadian rhythm and homeostatic drive, as was done by Rempe et al. (2010). The model demonstrated how the homeostatic drive and circadian rhythm interact to cause sleep and wakefulness. The effects of caffeine were incorporated to have a masking effect on the homeostatic drive, promoting wakefulness. Preliminary results showed that caffeine intake late in the evening caused the switch from wake to sleep to occur later than if no caffeine was present in the system. Additionally, the switch from wake to sleep was increasingly delayed with increased caffeine intake at the same time. This model is not yet validated, though potential studies for validation are proposed. This model presents an interesting method for incorporating the effects of caffeine on the sleep/wake cycle. PMID- 22846268 TI - In vitro effects of bmp-2, bmp-7, and bmp-13 on proliferation and differentation of mouse mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have the capabilities to proliferate and differentiate into osteoblastic and chondrogenic lineages when stimulated with bone morphogenic proteins (BMPs). BMPs play a vital role in skeletal development. BMPs bind to their cell surface receptors on MSCs and send signals to the cell nucleus which results to the synthesis of macromolecules involved in cartilage and bone formation and then the mesenchymal cell differentiates into chondrocytes or osteoblasts. The objective of this study was to evaluate the effects of BMP-2, BMP-7, and BMP-13 on undifferentiated MSCs for cellular damage markers, alkaline phosphatase, and morphological changes at 24, 72, 120, and 168 hours of culture. MSC viability, proliferation, cellular damage, and cellular morphology were evaluated after each time point. As early as 48 hours MSCs treated with BMPs resulted in morphological changes, and increased cell numbers. At 120 and 168 hours BMP-13 resulted in morphological changes resembling chrondrocytes. It was concluded that BMPs have no adverse effects on proliferation and are non- toxic to undiffetentiated MSCs. PMID- 22846269 TI - Using pressure transducers for noninvasive detectection of heart and respiratory rates. AB - The purpose of this study is the exploration of a new noninvasive method for detecting heart and respiratory rates using pressure transducers and medical tubing placed on a person?s chest. This device is intended to replace the individual who manually and visually takes vital signs in an emergency mass casualty situation. Instead it would provide a light weight device that can be carried in to the field, applied rapidly, and has the potential to be networked in such a way that one medical person can monitor 5-6 casualties simultaneously, thus acting as a force multiplier. The first step in the project was the validation of using pressure transducers to detect the desired signals. After the initial validation, the first board mount rendition of the system was implemented on a printed circuit board. An experiment was designed and carried out using a coil of latex tubing placed on a medical test mannequin that is used for breathing simulations. The pressure transducer read the change in pressure in this tubing and data was collected for several different respiratory rates. The results of this experiment are definitive. Respiratory rate can be derived using signal processing of the raw signal output from the system. PMID- 22846270 TI - New course in bioengineering and bioinspired design. AB - The past two years, a new interdisciplinary course has been offered at Washington and Lee University (Lexington, VA, USA), which seeks to surmount barriers that have traditionally existed between the physical and life sciences. The course explores the physiology leading to the physical mechanisms and engineering principles that endow the astonishing navigation abilities and sensory mechanisms of animal systems. The course also emphasizes how biological systems are inspiring novel engineering designs. Two (among many) examples are how the adhesion of the gecko foot inspired a new class of adhesives based on Van der Waals forces; and how the iridophore protein plates found in mimic octopus and squid act as tunable 1/4 wave stacks, thus inspiring the engineering of optically tunable block copolymer gels for sensing temperature, pressure, or chemical gradients. A major component of this course is the integration of a 6-8 week long research project. To date, projects have included engineering: a soft-body robot whose motion mimics the inchworm; an electrical circuit to sense minute electric fields in aqueous environments based on the shark electrosensory system; and cyborg grasshoppers whose jump motion is controlled via an electronic-neural interface. Initial feedback has indicated that this course has served to increase student interaction and ?cross-pollination? of ideas between the physical and life sciences. Student feedback also indicated a marked increase in desire and confidence to continue to pursue problems at the boundary of biology and engineering?bioengineering. PMID- 22846271 TI - Mechanical properties of lower limb dermis following static and cyclic compression. AB - Lower extremity amputations and foot ulcers are complications associated with diabetes, and have been shown to affect diabetic African Americans (AA) three times as often as diabetic non-Hispanic Whites (NHW). Possible causes for the increased risk include ethnic differences in structure and function within the dermis of the lower extremity. Testing this hypothesis requires studying the mechanical properties of skin from different ethnic groups with and without the diagnosis of noninsulin-dependent diabetes. The purpose of this study was to develop a testing method to investigate changes in tensile mechanical properties resulting from static and cyclic compression of dermis harvested from patients undergoing lower extremity amputations. Full thickness dermal samples were obtained from 15 patients undergoing below-knee amputations. Sections of each sample were conditioned with a compressive static pressure (170 mmHg) or cyclic pressures (110-170 mmHg) for 4 hours to elicit collagen bundle remodeling. Skin samples were then tested in tension to obtain sub-plastic stress vs. strain mechanical behavior. Length of the stress-strain toe-region was examined to quantify the effect of collagen bundle remodeling. Toe-region mean lengths were 0.141+/-0.041, 0.146+/-0.034, and 0.164+/-0.064 strains for the control, cyclic, and statically compressed samples respectively (p>.05). These results suggest that the preconditioning regimes did not produce sufficient collagen remodeling to affect the tensile properties of full-thickness dermis. Future work will examine histology from each specimen to identify microstructural features associated with this trend. PMID- 22846272 TI - Role of fructose diphosphate (fdp) and glycerol on the differential survival of mrc-5 and a549 cell lines. AB - Lung cancer is a one of the most prevalent and deadly cancers in United States. Research has shown that cancer cells exhibit higher glycolytic rates than normal cells. In attempting to exploit this unique cancer-dependent ATP generation phenomenon, we hypothesize that exposure of cancer cells to organic inhibitors of glycolysis would have a negative impact on their survival and will alter their growth and viability due to a vast decrease in their essential glycolytic ATP production with the resultant energetic collapse and that no negative consequences will be seen on normal lung cells. The human lung fibroblast cell line MRC-5 and the human alveolar epithelial cell line A549 were used in this study as models for normal lung and lung cancer in vitro. Using standard methods, both cell lines were maintained and exposed to FDP and glycerol reagents at concentration levels ranging from 31.3-2,000 ug/ml in 96 well plates in quadruplets and experiments were repeated at least three times using MTT, and cell counting (T4 Cellometer) assays as well as phase-contrast photo-imaging. Our results indicate that exposure of both cell lines to these organics resulted in concentration dependent cell destruction/cell survival depending on the cell line exposed. FDP and glycerol showed statistically significant (p<0.05) differential negative effects on the A549 line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line, presenting promising indicators for their cancer therapeutic potential. PMID- 22846273 TI - Therapeutic implications of the warburg effect: role of oxalates and acetates on the differential survival of mrc-5 and a549 cell lines. AB - Lung cancer is a one of the most prevalent and deadly cancers in United States. Research has shown that cancer cells exhibit higher glycolytic rates than normal cells. In attempting to exploit this unique cancer-dependent ATP generation phenomenon (Warburg effect), we hypothesize that exposure of cancer cells to organic inhibitors of glycolysis would have a negative impact on their survival and will alter their growth and viability due to a vast decrease in their essential glycolytic ATP production with the resultant energetic collapse and that no negative consequences will be seen on normal lung cells. The human lung fibroblast cell line MRC-5 and the human alveolar epithelial cell line A549 were used in this study as models for normal lung and lung cancer in vitro. Using standard methods, both cell lines were maintained and exposed to oxalic acid and zinc acetate reagents at concentration levels ranging from 31.3-2,000 ug/ml in 96 well plates in quadruplets and experiments were repeated at least three times using MTT, and cell counting (T4 Cellometer) assays as well as phase-contrast photo-imaging. Our results indicate that exposure of both cell lines to these organics resulted in concentration dependent cell destruction/cell survival depending on the cell line exposed. Oxalic acid and zinc acetate showed statistically significant (p<0.05) differential negative effects on the A549 line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line, presenting promising indicators for their cancer therapeutic potential. PMID- 22846274 TI - Techniques for the investigation of traumatic brain injury mechanisms characterized by magnetic resonance spectroscopy. AB - In the United States, traumatic brain injury (TBI) continues to be a leading source of death and disability, being responsible for 30.5% of all injury-related deaths [1]. Uncertainty still exists concerning the mechanisms and injury cascades involved. This study seeks to address many of the unknowns and criticisms of previous research. This study is focused on determining short term TBI development by finding a relationship between input accelerations and neuronal damage characterized by magnetic resonance spectroscopy (MRS) in an in vivo Gottingen minipig model. An injury device was designed and fabricated to impart rotational acceleration in the median plane of the animal using an articulated pendulum. Injury to the animal is caused by abrupt deceleration of the entire animal when the pendulum impacts brass tubes, which is repeatable. The animals (n=9) undergo baseline 7T MR scans prior to injury, immediately post injury, and twenty-four hours post injury. MRS is performed on a voxel placed in the genu of the corpus callosum. Relevant metabolites include glutamate, N acetylaspartate, myoInositol, creatine, and lactate. No clear trends were found for any of the metabolites for either time point. Further testing needs to be done in order to see the meaning of the metabolite differences in terms of underlying damage characterized by immunohistochemistry. This will give us insight into the meaning of using a noninvasive technique like MRS to look at TBI severity immediately post injury. Future work will include extending this study to define long term TBI development according to metabolite concentrations. PMID- 22846275 TI - Injuries caused by brake pedal loading of the midfoot. AB - In a frontal car crash, the driver?s foot and ankle may be injured due to loading by the brake pedal. The driver of a vehicle often has time to initiate emergency braking before an impending collision, which places the forefoot or midfoot over the brake pedal. During the crash, the pedal may induce dorsiflexion and axial loading of the ankle due to forward motion of the occupant and rearward intrusion of the pedal relative to the vehicle. In order to investigate the injuries caused by pedal loading, impact tests were conducted on three cadaveric lower limbs. The limbs were braced at the knee, and a pedal positioned beneath the midfoot was driven towards the knee, inducing dorsiflexion and axial loading of the cadaveric limb. Ankle injury was generated in two specimens. Both injured limbs sustained a medial malleolar fracture, and one limb also suffered a talar neck fracture. These results suggest that pedal loading may be an important injury mechanism for fractures of the medial malleolus and talar neck in drivers involved in frontal crashes. PMID- 22846276 TI - Functional and structural responses associated with potential restorative dental adhesives using human gingival fibroblasts as a model. AB - The purpose of this study was to test the effectiveness of three potential bonding materials on the proliferation, viability, and functional capacity of the human gingival fibroblasts in an in vitro environment. The cultured gingival fibroblasts used were obtained from the American Type Culture Collection (ATCC). The three bonding materials used were polymethyl methacrylate (PMMA), OptiBond(r), and Prime & Bond(r). Fibroblasts were exposed to each bonding agent for durations of 24, 48, and 72 hours. Cellular protein levels determined that exposure to Prime & Bond(r) resulted in a significant increase in cellular protein (17.62+/-2.61 mg/mL) after 24 hours when compared to control and PMMA and OptiBond(r) exposures. Cellular protein levels were similar for experimental and control groups after 72 hours. The MDA assay showed no statistically significant differences at 24, 48, and 72 hours following exposure with PMMA or OptiBond(r) when compared to control cells. Membrane lipid peroxidation was not detected in the Prime & Bond(r) exposed cells. There is no significant decrease in cellular damage as measured by activity of LDH in the cell media at 24 and 48 hours. Prime & Bond(r) incubated with fibroblast cells for 72 hours resulted in a significant increase in LDH activity in the media (40.512 +/- 4.437 IU/mg Protein) compared to control (19.975 +/- 3.463 IU/mg Protein) and other dental bonding compounds. OptiBond(r) resulted in a decrease in reduced glutathione levels after 24 hours when compared to PMMA and Prime & Bond(r) exposure. No differences in intracellular levels were detected after 48 and 72 hours. This investigation suggests that the physiochemical characteristics of restorative dental adhesives have to be considered a key factor in the biocompatibility status. PMID- 22846277 TI - Deflection measurement system for the hybrid iii six-year-old biofidelic abdomen. AB - Motor vehicle collisions are the leading cause of death for children ages 5 to 14. Enhancement of child occupant protection is partly dependent on the ability to accurately assess the interaction of child-size occupants with restraint systems. Booster seat design and belt fit are evaluated using child anthropomorphic test devices, such as the Hybrid III 6-year-old dummy., A biofidelic abdomen for the Hybrid III 6-year-old dummy is being developed by the Ford Motor Company to enhance the dummy?s ability to assess injury risk and further quantify submarining risk by measuring abdominal deflection. A practical measurement system for the biofidelic abdominal insert has been developed and demonstrated for three dimensional determination of abdominal deflection. Quantification of insert deflection is achieved via differential signal measurement using electrodes mounted within a conductive medium. Signal amplitude is proportional to the distance between the electrodes. A microcontroller is used to calculate distances between ventral electrodes and a dorsal electrode in three dimensions. This system has been calibrated statically, and its performance demonstrated in a series of sled tests. Deflection measurements from the instrumented abdominal insert indicate performance differences between two booster seat designs, yielding an average peak anterior to posterior displacement of the abdomen of 1.0 +/- 3.4 mm and 31.2 +/- 7.2 mm for the seats, respectively. Implementation of a 6-year-old abdominal insert with the ability to evaluate submarining potential will likely help safety researchers further enhance booster seat design and interaction with vehicle restraint systems , and help to further understand child occupant injury risk in automobile collisions. PMID- 22846278 TI - Vibrational frequency response to impact loading of skull models. AB - More than 73% of soldiers returning from duty are injured by explosive devices. The shock waves generated are believed to cause injury via intracranial pressure and skull flexure. Prior modal analyses of spherical shells as skull substitutes using analytical solutions to the wave equation indicate the impact point and opposite side as areas of intense bending. In this study, finite element models extend modal analyses and applied impulse scenarios for a variety of altered spherical geometries. Holes of differing sizes, the direction of impact, and the presence of water inside were considered. The finite element model matched the analytical modal frequencies within 4%. The discrete modal frequencies are lost as the geometry deviates from the ideal sphere. The frequency response to impact was complex with many participating modal frequencies. The deformation near holes increased as the hole increased in size. Impacts in line with holes increased the minimum to maximum spread by 30% whereas angled impacts caused more pronounced motion near holes. Filling the sphere interior with liquid diverted some load from the shell and decreased the maximum deflections by 80%. Avenues of further research focused on more accurate geometries are discussed. PMID- 22846279 TI - Evaluation of a simple estimation method for the derivation of cardiac output from arterial blood pressure and heart rate. AB - Cardiac Output (CO) is an important hemodynamic index of blood flow from and to the heart. Numerous estimation methods have been developed and validated for obtaining CO in clinical applications; however, the invasive nature of these may preclude their utility in less controlled settings. Additionally, several of the available non-invasive applications feature algorithms which are computationally complex or proprietarily-restricted and may not be feasible in all research contexts, such as ambulatory investigations. Among the many simple mathematical transforms purported to estimate CO, a common approach has been to multiply the stroke volume (SV) by the heart rate (HR), where stroke volume is obtained by multiplying the pulse pressure (PP) by a constant value (k). Contemporary interpretations have identified k = 2 as the ideal multiplier; however there is some controversy regarding the origin of this factor as well as the reliability of the resulting estimate. In the present study we evaluated this simple technique using baseline beat-to-beat blood pressure data from 67 young (mean age = 20.04 +/- 2.8 years), healthy men (n = 30) and women (n = 37). Using Modelflow derived CO as a reference, estimated CO (COest) was calculated from the mean Systolic and Diastolic blood pressures and the heart rate. Overall, the correlation between CO & COest was moderate (r = .60, p <.001). This association was stronger in men (r = .70, p <.001) compared to women (r = .54, p <.001). Bland-Altman analysis confirmed this pattern as 97% of cases for men fell within the limits of agreement. Overall, our results indicate that under resting conditions this derivation is comparable to the Modelflow estimate and seemingly more consistent in men compared to women. PMID- 22846280 TI - Material properties of the post-mortem colon in high-rate equibiaxial elongation. AB - Crash-induced injuries of the colon that occur in motor vehicle collisions include perforations, serosal tears, and ischemic colon injuries. To characterize the biomechanical response of the colon associated with these failure modes, high rate equibiaxial stretch was applied to cruciate tissue samples harvested from four post-mortem human surrogates. Sample arms were gripped in four low-mass tissue clamps and simultaneous motion of four carriages applied equibiaxial stretch in four orthogonal directions. Tests were conducted to failure at a target strain rate of 100s-1 to investigate failure at rates expected to be experienced in motor vehicle collisions. Overhead high-speed video captured at 2500fps provided optical marker displacement data in a central region of interest. Marker positions were tracked using motion analysis software. Displacement data were input into LS-DYNA and average Green-Lagrange strain was calculated at 0.05ms time intervals. All data were truncated at tear initiation determined from high-speed video analysis. This manuscript presents the results of 26 colon tests conducted at an average strain rate of 67.1+/-17.9s-1. Average failure strain was 0.164+/-0.046 and 0.139+/-0.042 in the circumferential and longitudinal directions. Average maximum principal failure strain was 0.211+/ 0.064. Material property data acquired in this study contribute to the biomechanical dataset useful for human body finite element model validation. PMID- 22846281 TI - Contrast improvement in pre-compensation of ocular aberrations for computer users. AB - Ocular aberrations in the human eye prevent many users from interacting efficiently with Graphic User Interfaces in computers. While traditionally these aberrations are corrected by external means (e.g., spectacles, refractive surgery), there have been approaches to address them by custom pre-compensation of the displayed images, based on the characterization of the eye?s aberrations. However, the limited intensity levels of display devices reduce the contrast perceived by the user when viewing the pre-compensated images. This paper proposes a histogram side-trim correction method for the pre-compensated images that seeks to reduce the contrast loss perceived by the viewer. The proposed histogram trimming process is designed to be automatic, not requiring manual intervention. Experiments are performed using a high-resolution camera as an ?artificial eye?, to evaluate the efficiency of the histogram side-trim method in improving the contrast of perceived images. Results show that the side-trim method improved the contrast of images perceived by the ?artificial eye?. PMID- 22846282 TI - Eurosid-2 dummy head-neck responses to lateral acceleration. AB - The objective of this study was to characterize the ES-2 head and neck response to lateral impacts at varying low magnitudes of impact velocities. A pendulum and mini sled were used to deliver inertial acceleration pulses to an isolated ES-2 head and neck. The base of the neck was attached to a cart which slid along the direction of impact from left to right on two precision ground rails. The shape of the cart acceleration was controlled by altering the momentum transfer of the pendulum. Eighteen tests were conducted at velocities ranging from 1.0 to 4.3 m/s. The head was instrumented with an internal nine accelerometer package to measure the linear and angular head accelerations. Upper and lower neck load cells measured the forces and moments. Cart and pendulum acceleration were measured from uniaxial accelerometers. All data was sampled at 20 kHz and filtered according to SAEJ211. A six-camera 1 kHz Vicon system measured the 3-d kinematics of retroreflective targets affixed to the head and neck. All forces and moments increased with velocity. Peak axial and shear forces at the upper and lower neck were similar, however moments at the lower neck were up to three times higher. The Head to T1 (Head-T1) and Head to Upper Spine (Head-US) angles were calculated from the marker position data. The Head-US angle plateaued at about 10 degrees at the high velocity due to the physical constraints of the upper neck joint. Peak Head-T1 angle increased up to about 50 degrees at the end velocity; however the overall percentage contribution of the Head-US angle to the Head-T1 angle decreased. The ES-2 head displayed a characteristic head lag that was demonstrated in Head-US angle and upper neck moment plots in velocities above 1.0 m/s which have also been reported in the human head neck complex studies. Matched paired tests with isolated Post Mortem Human Subjects are necessary to fully compare the ES-2 head and neck biofidelity. PMID- 22846283 TI - Response of individual thoracolumbar spine ligaments under high-rate deformation. AB - Under-Body Blast (UBB) has emerged as the predominant threat to ground vehicles and Warfighter survivability. The force transference from the vehicle structure to the human body has resulted in serious injuries, with the thoracolumbar spine frequently damaged. Computational models of the human body are being generated to model human response and develop injury mitigation strategies. To effectively model the spine mechanics, the thoracolumbar ligaments, which serve varying roles in contributing to spine stability, must be characterized at relevant strains and strain rates. Adaptation of cervical spine testing methods has allowed for testing of isolated spinal ligaments including the Anterior Longitudinal Ligament (ALL), Posterior Longitudinal Ligament (PLL), and Ligamentum Flavum (LF). A high rate servo-hydraulic test machine was used to execute a tensile test protocol for 24 complexes with loading rates ranging from 240 - 2800 mm/s and displacements of 25%, 50%, 75%, 100%, and 300% of the measured ligament length. Non-contact strain field measurements were recorded to produce a three dimensional strain field of the ligament surface. In order to provide the ligament data in a form which can be incorporated in the human computational models, analytical methods for modeling the ligament response are being investigated. Ultimately, this model will be optimized to be utilized in computational models of the lumbar spine. PMID- 22846284 TI - Modeling the effect of exogenous melatonin on the sleep-wake switch. AB - According to the Centers for Disease Control and Prevention and the Institute of Medicine of the National Academies, insufficient sleep has become a public health epidemic. Approximately 50-70 million adults (20 years or older) suffer from some disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity. Melatonin, a naturally produced hormone which plays a role in sleep-wake regulation, is currently offered as an over-the counter sleep aid. However, the effects of melatonin on the sleep-wake cycle are incompletely understood. The goal of this modeling study was to incorporate the effects of exogenous melatonin administration into a mathematical model of the human sleep-wake switch. The model developed herein adds a simple kinetic model of the MT1 melatonin receptor to an existing model which simulates the interactions of different neuronal groups thought to be involved in sleep-wake regulation. Preliminary results were obtained by simulating the effects of an exogenous melatonin dose typical of over-the-counter sleep aids. The model predicted an increase in homeostatic sleep drive and a resulting alteration in circadian rhythm consistent with experimental results. The time of melatonin administration was also observed to have a strong influence on the sleep-wake effects elicited, which is also consistent with prior experimental findings. PMID- 22846285 TI - A genetic algorithm for controlling an agent-based model of the functional human brain. AB - Recently, we introduced a dynamic functional model of the human brain. This model, representing functional connectivity in the brain, is generated from subject-specific physiological data collected using functional magnetic resonance imaging (fMRI). The dynamics of this model are examined using agent-based modeling techniques, wherein a collection of binary agents are embedded as nodes in the network. This model is capable of producing a wide variety of complex behaviors. In this work, we use machine learning techniques to drive the model to produce desired behaviors. The solution space of the model is unreasonably large for a brute-force approach, but we demonstrate that genetic algorithms (GAs) are able to locate optimal model parameters within this space to achieve the desired behavior. We detail the design of a GA specifically suited for this model, and discuss the relevant issues that arise in GA design. Specifically, we explore several fitness functions to accurately quantify the suitability of each potential solution. We examine their strengths and weaknesses, and identify an optimal fitness function for this system. We validate the GA with the optimal fitness function by showing that it can drive the system to produce pre-defined behaviors. The ability of the model to produce pre-defined behaviors indicates that it may be possible to produce physiologically relevant outputs. The model may be very useful for studying the changes in brain dynamics due to neurological diseases or conditions. Additionally, this powerful dynamic brain model may be instrumental in many artificial intelligence settings. PMID- 22846286 TI - Lifeflow vad: design and numerical modeling of magnetic bearing system. AB - The non-contact and lubrication free support of magnetic bearings make them ideal to support rotating machines. One area of application of magnetic bearings is in the design of the mechanical heart pumps. The LifeFlow heart pump developed by the University of Virginia is one such heart pump which uses active and passive magnetic bearings to support the impeller. The design and controls of such bearings can be quite challenging. One of the major difficulties that one may encounter in designing the controller is to get accurate values of the control parameters such as bias flux, radial and axial stiffness values, forces, etc. In order to obtain these parameters accurately, a three dimensional finite element analysis of the magnetic bearings is crucial. This paper covers the analysis of the magnetic bearing system used in the LifeFlow Heart pump. The main purpose of the analysis was to provide accurate values of air gap flux, forces, radial and axial stiffness in order to design a robust and optimized controller for the bearings. As a result of the analysis, these parameters have been determined and the motor is being redesigned with a smaller footprint to achieve higher efficiency. PMID- 22846287 TI - Acute effects of tai chi exercise on cardiac autonomic function in healthy adults with tai chi experience. AB - About 1 in 3 American adults have cardiovascular disease associated with risk factors such as physical inactivity, obesity, and stress. Heart rate variability (HRV) analysis is considered a non-invasive procedure for analyzing cardiovascular autonomic influence. Depressed HRV has been linked to abnormal cardiovascular autonomic modulation. PMID- 22846288 TI - Biomechanical analysis of pediatric injuries and child restraint system. AB - Airbag related injuries to infants in rear facing child seats are common in frontal crashes. Several vehicular modifications such as deactivated passenger airbags, manual cut-off switches, depowered airbags and smart airbags have been advanced to mitigate the effect of airbag deployment on child seats. However, there is limited research effort to address the biomechanics of airbag injuries due to modification in child restraint systems. The purpose of this research is to evaluate the biomechanical effects of a protective barrier between the rear facing child restraint and the frontal passenger airbag of the vehicle. An experimental study was conducted using an Anthropometric Test Dummy (ATD) in a vehicular partial structure (buck). The rear facing child seat was placed in the right front passenger seat of the vehicle. The child seat was restrained using the three-point restraint in the vehicle. The six-month-old instrumented ATD was restrained in the child seat. The ATD was instrumented with the head tri-axial and two uni-axial linear accelerometers. The uni-axial linear acceleration was used to calculate the angular acceleration. Two different rear facing child seats, the standard rear facing infant seat and the rear facing infant seat inside the protective barrier structure were tested. In each test, the Head Injury Criteria (HIC) and angular head acceleration were measured. Results show that the HIC was reduced by 95% and the angular head acceleration was reduced by 85% by the protective barrier. The head injury values were well below the tolerance limit for the child with the barrier. The protective barrier deflected the airbag away from the ATD?s head and also acted as a shield to minimize airbag force on the child seat. In the typical infant seat, the airbag contacted the ATD?s head and exerted significant force on the child seat which rotated the seat rearward. These kinematic responses may explain the clinical observation of severe head injuries by infants in rear facing seats due to forces transmitted through the child seat and downward force from the top of the head. The present study is a first step in better understanding the injury mitigating aspects of the safety protective structure in child restraints. PMID- 22846289 TI - Experimental biomechanical study of head injuries in lateral falls with skateboard helmet. AB - Traumatic brain injuries (TBI) are common in sports accidents. Helmets are generally known to provide protection to the head. However, the effectiveness of helmets in mitigating a TBI may be compromised due to the impact location and impact speed. Although it is known that the helmet decreases the linear head accelerations and the resulting head injury potential, to the best of our knowledge, limited research effort has been devoted to the study of the biomechanics of TBI in side impact conditions. The present work is designed to delineate the biomechanics of TBI in a fall impacting the parietal/temporal regions. A standing Hybrid III male dummy with pedestrian pelvis was used. The dummy was placed on a swinging platform for the fall simulation. The drop was achieved by stopping the platform with a block. The platform was swung from a predetermined height and stopped to allow the free fall of the dummy. The test was conducted with and without a skate board helmet. The impact on the dummy?s head was in the parietal and temporal regions. The head impact speed with the floor was approximately 24 kph (6.7 m/sec) The dummy was instrumented with tri axial linear and tri-axial angular head accelerometers to measure the biomechanical injury responses. Results from three tests were compared. The linear head CG acceleration, Head Injury Criteria (HIC) and angular head accelerations were compared. Results suggest that the helmet reduced the linear head acceleration, HIC and angular head acceleration compared to the impact without a helmet. Although the linear head accelerations and HIC were reduced, the angular head accelerations even with the helmet were above nearly all proposed rotational head injury threshold in the literature. The higher angular head accelerations indicate a higher probability of concussion, acute subdural hematoma and diffuse axonal injuries. The present study is an additional step to better understand the biomechanics of TBI and the role of protective headgear systems in sports and recreational accidents. PMID- 22846290 TI - Evaluation of chondrocyte growth and function subjected to 21% and 6% oxygen levels. AB - In osteoarthritis, the metabolic activity of the chondrocytes is shifted toward a state where new matrix synthesis is outweighed by breakdown of matrix constituents. The result is degeneration and gradual loss of articular cartilage. Although osteoarthritis is frequently regarded as a non-inflammatory form of arthritis, considerable data implicates a role for pro-inflammatory cytokines in the cartilage destruction associated with osteoarthritis. The best studied pro inflammatory cytokines in osteoarthritis are interleukin-1beta (IL-1beta), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6). Since articular cartilage is not vascularized, it must rely on diffusion from the articular surface for nutrient and metabolic exchange. Consequently, the entire metabolism of the cell is geared towards operating at a low oxygen tension. In this study, chondrocytes were challenged with pro-inflammatory cytokines at 21% O2 and 6% O2. Chondrocyte proliferation, membrane integrity, oxidative stress, matrix metalloproteinase ? 9 (MMP-9) and hypoxia inducible factor-1a (HIF-1a) production were measured. Our results showed that there was less of a decrease in cell number at 6% O2 compared to 21% O2 after they were challenged with pro-inflammatory cytokines. In addition, there was less of an increase in oxidative stress, membrane damage and MMP-9 production at 6% O2 compared to21% O2. The significance of this study represents the first attempt to replicate a diseased inflammatory environment characterized by an osteoarthritic joint in vitro and to examine these effects on the growth and stability of chondrocytes. PMID- 22846291 TI - A pilot study on the effect of acute tai chi practice on peripheral blood cytokine expression in healthy volunteers. AB - Tai chi (TC) is a unique form of exercise having both mind and body components ? focused mindfulness and physical movement. It is perhaps best known for its ability to prevent falls in elderly people. It is also thought to improve vitality, longevity, mental and physical health. Recent studies have demonstrated its effectiveness as an intervention for chronic diseases associated with the inflammatory process, such as arthritis, heart disease, diabetes, and obesity. The objective of this study was to explore the modulatory effect of acute TC practice on anti-inflammatory cytokine levels in healthy volunteers. PMID- 22846292 TI - Non-invasive fall risk assessment in community dwelling elderly with wireless inertial measurement units. AB - Falls are among the most serious accidents among the elderly leading to increased injuries, reduced functioning and mortality. In 2009, about 2.2 million nonfatal fall injuries were reported among the elderly population (CDC, 2010). In this study, eleven community dwelling elderly (aged 65-84 years) participated in fall risk assessment camp at sterling senior center organized by Northern Virginia Fall Prevention Coalition (NVFPC). Three custom made wireless inertial measurement units (IMUs) were attached on trunk and both shanks. All participants performed postural and locomotor tasks such as sit-to-stand (STS) and timed up and go (TUG). Temporal and kinematic parameters were obtained. Raw signals obtained were denoised using ensemble empirical mode decomposition and savistzky golay filtering. The mean and standard deviation of TUG time and STS completion time for participants were found to be 11.3+/-6.6 sec and 3.58+/-2.07 sec respectively. The high variation in the result may be due to the use of assistive devices (i.e., cane and walker) by two participants. The objective of this study is to classify fall prone community dwelling individuals using non-invasive system. Four participants were classified as fall prone, three without fall risk and four were at potential risk based on their objective assessment and task performance. This system provides a platform for identifying fall prone individuals and may be used for early fall interventions among the elderly. PMID- 22846294 TI - Freezing and decay effects on material properties of porcine kidney and liver. AB - Abdominal injuries caused by traffic accidents have severe consequences and are major causes of death in the United States. Several experiments were performed in the past on post-mortem human surrogate (PMHS) to quantify the abdominal tolerance under impact loading. However, some concerns were raised regarding the PMHS storage and its influence on the biomechanical response of internal organs. To better examine the freezing and decay effects, this study analyzed the data obtained from indentation performed on porcine abdominal organs. Porcine kidney and liver specimens were cut with a custom blade assembly from fresh organs. Indentation ramp-hold tests were first conducted on fresh specimens, which submerged in physiological saline at room temperature during testing. Specimens were then preserved using two different storage methods (cooling and freezing) and retested after 20 days at the room temperature. Quasi-linear viscoelastic model was utilized to model the indentation data, and statistical analysis was conducted to investigate the significance of the model parameters. Significant differences between freezing and cooling effects were found for liver, and the instantaneous responses were significantly changed for both kidney and liver. It is believed that the results of this study may help in development of appropriate preservation methodologies for abdominal organs and better understanding the published results of the abdominal tests performed under impact loading corresponding to vehicle accidents. PMID- 22846293 TI - Human gingival fibroblast cell response to gox/cat. AB - Hydrogen peroxide kills bacteria; however, control of a specific dose limited control over cellular response and function. In this study, the GOX/CAT system was used to independently provide and control the amount of H2O2 and oxygen in cell culture. The GOX/CAT system is composed of glucose oxidase (GOX) and catalase (CAT). Lipopolysaccharide (LPS) is molecules on the outer membrane of gram-negative bacteria. LPS elicits an inflammatory stimulus which can activate macrophages to produce pro-inflammatory cytokines, TNF-a, and specific mediators of inflammation including NO and prostaglandins. Macrophages are known to provide a prominent defense against bacteria. The aim of this experiment was to determine if GOX/CAT (10uMH2O2) plus conditioned media from LPS challenged macrophage cells will alter fibroblast cell numbers, viability and morphology after 24, 48, 78 hours. Human gingival fibroblast (HGF) CRL-2014 were treated with conditioned media from RAW 264.7 cells with 4ug/mL LPS, GOX/CAT (10uMH2O2) and 4ug/mL LPS + GOX/CAT (10uMH2O2) at 24, 48 and 72 hours. Cell protein, MDA and GSH levels and cell morphology were determined after each incubation periods. The results showed no significant difference in protein levels and MDA levels throughout the experiment. Reduced glutathione concentration in treated cells was statistically lower than control suggesting the possibility of intracellular damage. Overall, cell response to H2O2 did not alter cell proliferation and viability of LPS conditioned media treated fibroblast. Morphological results indicated a trend in possible adaptive response to LPS after 48 and 72 hours. Additional experiments are needed to determine chronic exposure on HGF. PMID- 22846295 TI - A new ultrasonic stride length measuring system. AB - We have developed a new ultrasonic stride length measuring system for analyzing the human gait. An ultrasonic transmitter, a radio transmitter, a pressure sensor and microcontroller are attached to the subject?s heel on the right shoe and in the direction of the left shoe. Two ultrasonic receivers, a radio receiver, a microcontroller and a 1GB SD memory card are installed on the left shoe. Ultrasonic receivers are attached to the toe and heel, in the direction of the right shoe. When the right foot contacts the ground, its heel-mounted ultrasonic and radio transmitters simultaneously transmit to the left shoe. However, radio propagation velocity is far faster than ultrasonic velocity. Therefore, the radio wave acts as a start signal to the radio receiver of the left shoe, indicating the start of ultrasound transmission from the right shoe. Upon receiving the start signal, the microcontroller timer starts to measure each ultrasound propagation time from the right shoe to the left shoe. Distance between right and left shoes is calculated with the time and ultrasound velocity and stored in the SD memory card. Stride length is calculated with a cosine function, by using the obtained distances and the distance between the toe and heel of the left shoe, by a conventional computer. The stride length can then be used for many characterizations of the subject?s gait. PMID- 22846296 TI - Effect of platelet dense granule contents upon osteoblast viability. AB - The incorporation of platelet-rich plasma (PRP) into scaffolds for application in musculoskeletal injuries has been a topic of recent interest in orthopaedic surgery. Platelets have dense granules containing ADP, ATP, serotonin, and calcium; and alpha granules containing PDGF, VEGF, IGF, TGF-beta, and EGF. Particular focus of previous studies has been on mitogenic effects of alpha granules, but the role of dense granules in PRP therapy currently remains undefined. The objective of the present study was to evaluate the effect of ATP, ADP, and serotonin upon osteoblast viability in vitro. Human osteoblast-like cells (MG-63 cells) were exposed to phosphate buffered saline (control group), ATP (20uM), ADP (10uM), and serotonin (11.75nM) for 24, 48, and 72 hours. Osteoblast viability was evaluated at each timepoint using biochemical assays. When compared to controls, osteoblasts treated with ATP and ADP resulted in a significant reduction in cell number, while serotonin caused an increase at 24 hours. Similar trends were noted at later timepoints. At 48 hours, a trend towards increase in glutathione was observed with ADP and ATP, but was not sustained at 72 hours. No significant differences in membrane damage were detected between groups. At 24 and 48 hours, ADP significantly increased nitric oxide production. Results of this study demonstrate that ATP, ADP, and serotonin induced significant structural adaptive responses to osteoblastic activities. The data revealed minimal functional alteration as evident by biomarker measurements. Overall conclusion: the results provided further insight regarding PRP therapy for traumatized bone. PMID- 22846297 TI - Therapeutic effet of phase ii enzyme inducers in experimental allergic encephalomyelitis (eae). AB - The pathology of multiple sclerosis (MS) is characterized by an inflammatory mononuclear infiltration in the white matter. The oxidative stress plays a role in the onset and progression of MS. We hypothesized that the decreasing oxidative stress might improve MS inflammatory lesions. The experimental allergic encephalomyelitis (EAE) induced in the Lewis rats were used to test this hypothesis. 24 animals were placed into two groups: 1) those on normal rat chow, 2) those on rat chow containing 7.5 g/kg of tetra-butyl-hydroxy-anisole (BHA), a food preservative. All the animals were induced to have EAE and examined daily in a double-blinded fashion. On 28th day of the induction, all animals were sacrificed, blood collected for glutathione (GSH) measurements and tissues collected for histology. All the animals, regardless of their diet status developed symptoms of EAE on a different days ranging from tail weakness to hind limb paralysis and all reached remission of acute EAE before the 28th day of induction. 8 animals of the non-BHA fed animals developed hind limb weakness in and 4 animlas developed hind limb paralysis, while 2 animals of BHA fed group developed tail paralysis, 2 hind limb weaknesses and 8 hind limb paralysis. The histology of the non-BHA group correlated well with the clinical symptoms of perivascular mononuclear infiltration, however, the BHA fed group revealed complete pathological recovery. Animals fed with BHA diet had significantly raised their GSH blood level, indicating up regulation of anti-oxidants activity. We conclude that dietary phase 2 enzyme inducers show potential therapeutic benefits in EAE, this result might assist in treating patients with MS. PMID- 22846298 TI - Evaluation of parenchymal fluid pressure in native and decellularized liver tissue. AB - One strategy for tissue engineering of bioartificial livers is the use of decellularized liver scaffolds, which contain a functional vascular network and intact extracellular matrix components. Due to the known mechanosensitivity of liver cells, particularly the response of hepatocytes to changes in parenchymal fluid pressure (PFP), it is necessary to evaluate the biomechanical environment within decellularized scaffolds. The objective of this study was to characterize the dependence of PFP on perfusion flow rate, in native and decellularized liver. Needle-guided Millar SPR-524 (3.5F) pressure sensors were inserted into liver parenchyma to measure PFP in-situ in rat (n=5) and ex-situ in portal vein perfused native (n=5) and decellularized (n=7) liver tissue. Average in-situ PFP, measured in the left, central and right lobes, was found to be 2.86+/-1.04 mmHg. PFP measured in ex-situ liver perfused at 3, 6, 9, and 12 ml/min was found to increase linearly with flow rate. Decellularized liver PFP ranged from 0.68 mmHg at 3ml/min to 2.42 mmHg at 12 ml/min, while native liver ranged from 4.32 ? 11.93 mmHg. Results demonstrate that PFP in decellularized scaffolds can be controlled by varying flow rate. These results will be implemented in a poroviscoelastic finite element model of liver perfusion, developed by the authors, to predict PFP distribution in three-dimensional scaffolds for known flow rates. This computationally efficient model can be used to optimize perfusion bioreactor conditions throughout the scaffold, to aid in the engineering of functional liver tissue from a decellularized liver organoid. PMID- 22846299 TI - A drip infusion warning system. AB - We have developed a drip infusion warning system for hospital and care facility use. In general, two kinds of infusion sets are used, which have drop factors of either 20 or 60. (A drop factor is the number of drops to deliver 1 ml of infusion solution.) When an infusion set having a 20 drop factor is used, the number of drops per drip is adjusted to 20. If an infusion set has a drop factor of 60, then the infusion volume rate becomes three times as much. This may result in legal consequences if the patient is injured. In this study, a drip infusion warning system detects whether the infusion is a 20 or a 60 drop factor. The system consists of two electrodes, one wrapped around the infusion supply polyvinyl-chloride tube, and another one around the drip chamber. The electrical impedance between two electrodes is changed by the growth and fall of each drop of fluid. The drop growth length especially changes, depending on the type of infusion set used. Therefore, the two types of infusion sets can be identified by monitoring the drop length. Our warning system detects whether the infusion set used corresponds to a 20 or 60 drop factor, so the system can reduce human errors. PMID- 22846300 TI - A novel methodology to evaluate the psycho-physical condition of individuals performing at-risk activities. AB - Currently the evaluation of the psycho-physical condition of individuals performing at-risk activities involves either subjective evaluations or invasive biological tests, and is not often indicative of the actual ability of the subject to perform the specific activity. We propose a new methodology based on posturographic and reaction time measurements, derived from the strict relationship between the control strategies used to maintain the erect posture and the psycho-physical abilities of an individual. These strategies are affected by fatigue, diseases and substances such as alcohol and drugs. The measuring device consists of a posturographic platform, a hand-held trigger and a personal computer running the software. The subject is asked to perform simultaneously two tasks: move the center of mass of the body to follow a target on the screen, and react to the appearance of another stimulus by pressing the trigger. The task is made more complicated by randomly presenting the stimuli and by the presence of ?dummy? targets the subject is supposed to ignore. Evaluating how accurately the subject follows the target, the reaction times, as well as the number of reactions to ?dummy? targets allows to quantify the psycho-physical condition of the individual. This methodology could be used as a real time, fast and quantitative measure to improve road and workplace safety, not invading the privacy of the subject, easily relating to real-world activities, and not requiring highly trained personnel to administer the test. PMID- 22846301 TI - Method for obtaining simple shear material properties of the intervertebral disc under high strain rates. AB - Predicting spinal injury under high rates of vertical loading is of interest, but the success of computational models in modeling this type of loading scenario is highly dependent on the material models employed. Understanding the response of these biological materials at high strain rates is critical to accurately model mechanical response of tissue and predict injury. While data exists at lower strain rates, there is a lack of the high strain rate material data that are needed to develop constitutive models. The Split Hopkinson Pressure Bar (SHPB) has been used for many years to obtain properties of various materials at high strain rates. However, this apparatus has mainly been used for characterizing metals and ceramics and is difficult to apply to softer materials such as biological tissue. Recently, studies have shown that modifications to the traditional SHPB setup allow for the successful characterization of mechanical properties of biological materials at strain rates and peak strain values that exceed alternate soft tissue testing techniques. In this paper, the previously reported modified SHPB technique is applied to characterize human intervertebral disc material under simple shear. The strain rates achieved range from 5 to 250 strain s-1. The results demonstrate the sensitivity to the disc composition and structure, with the nucleus pulposus and annulus fibrosus exhibiting different behavior under shear loading. Shear tangent moduli are approximated at varying strain levels from 5 to 20% strain. This data and technique facilitates determination of mechanical properties of intervertebral disc materials under shear loading, for eventual use in constitutive models. PMID- 22846302 TI - Learning effect of standing on foam during posturographic testing ? preliminary findings. AB - Balance protocols such as the modified Clinical Test of Sensory Integration on Balance (mCTSIB) or the Balance Error Scoring System (BESS) include testing a person while standing on a thick foam cushion. The role of the foam cushion is to perturb the somatosensory and proprioceptive information and to provide an unstable and unpredictable standing surface. This, combined with asking the subject to keep the eyes closed during the test, is to make the subject rely mostly on the vestibular system to maintain balance. However, this type of condition rarely occurs in real life. It is not well understood if learning and/or fatiguing might affect the results of these type of tests. This has important methodological consequences for balance protocols in terms of the number of repetitions and how these might affect the results of the balance tests. In this study, the balance of 25 healthy subjects who had never undergone this type of testing was evaluated. The subjects performed in rapid succession 4, 60s long posturographic tests while standing on a foam cushion. A computerized posturographic device was used to collect the data. Half of the participants performed the tests with eyes open and half with eyes closed. This allowed to discover the presence of a ?learning effect? the first time subjects are tested on the foam cushion. Once the subjects had learned to stand on the foam cushion, the length of the tests and the number of repetitions did not show a statistically significant effect. PMID- 22846303 TI - Bilateral symmetry of ground reaction force with a motor-controlled resistance exercise system using a mechanical advantage barbell for spaceflight. AB - The reduced gravity experienced during spaceflight leads to muscle and bone atrophy, and resistance exercise has proven to be an effective countermeasure. Thus, a compact computer-controlled electric-motor resistance exercise system is being developed for NASA. In order to save power, space, and weight, the torque specifications of the motor were reduced by half because of a unique barbell design that employs a two-to-one mechanical advantage. Since the force generating motor is on one side of the barbell, there is the potential for asymmetric barbell loading. Therefore, the purpose of this preliminary study is to compare the unilateral ground reaction forces (GRF) of the new barbell of the motor and ground sides. Multiple repetitions of fixed tempo deadlift exercise were performed with motor-controlled resistance using the new barbell. Unilateral GRF data was measured with a force plate under each foot, and the readings from each force plate are compared to each other. Results indicate the mechanical advantage barbell exercises have bilaterally asymmetric GRF compared to a theoretical 50-50 split, and the astronauts would need to alternate the left right orientation to compensate for the asymmetry. PMID- 22846304 TI - Comparison of the use of pupil diameter and galvanic skin response signals for affective assessment of computer users. AB - The implementation of Affective Computing concepts requires the assessment of the affective states in the computer user, e.g., ?relaxation? or ?stress?. Traditionally, the Galvanic Skin Response (GSR) signal has been analyzed as the leading indicator of the sympathetic activation that accompanies ?stress?, when it is experienced by a computer user. However, recent research has found that the Pupil Diameter (PD), which is also controlled by the Autonomic Nervous System (ANS), can be an important indicator of sympathetic activation. This paper describes techniques for the processing of the Pupil Diameter (PD) signal to detect episodes of mental stress induced in experimental subjects, differentiating them from ?relaxation? intervals. Our experiments also recorded and analyzed the GSR signal from the subjects, for comparison purposes. The PD signal is first pre-processed applying wavelet denoising and Kalman filtering to remove the high-frequency variations of the raw PD signal that are not representative of the subject?s affective state. Then 3 features are extracted from the normalized, pre-processed PD signal and five different classification algorithms are applied on these features to differentiate the states of ?relaxation? vs. ?stress? in the computer user. Similarly, 3 GSR features were obtained and used for classification. PD-based classification achieved an average accuracy of 85.86%. GSR-based classification achieved an average accuracy of 60.66%. Therefore, the results indicate that the pupil diameter may be one of the most significant physiological signals to monitor for affective assessment and differentiation of ?relaxation? vs. ?stress? states of a computer user. PMID- 22846305 TI - Methods for comparison of abdominal organ location and shape in the supine and upright positions. AB - The location and shape variation of the liver due to postural changes has implications in the prediction of blunt abdominal trauma via computational models or other human surrogates. Although abdominal injuries make up only 3-5% of injuries in car crashes, they are often seen in serious crashes with AIS=4 injuries. This study reviews the methods used to quantify variation in the location of the liver relative to surrounding bony structures for two different postures, supine and seated. Methods to investigate shape variation in the liver between these postures are also detailed. Magnetic resonance imaging (MRI) scans of individuals representing the 50th percentile male (M50) and 5th percentile female (F05) in terms of height (M50: 175cm, F05: 150cm) and weight (M50: 78.6kg, F05: 48.1kg) were obtained in the two postures using a GE Twin Speed and a Fonar Upright MRI respectively. Images were acquired using a Fast Spoiled Gradient Recalled pulse sequence. The liver was segmented manually. Vertebral bodies and ribs from CT scans of the same individuals were placed in the MRI space using a semi-automated approach. The center of gravity (CG) was identified for the liver and vertebral bodies. Liver volume in each scan was calculated. The location of the liver was then investigated by examining distances between the center of gravity of the liver and various vertebral bodies. The average volume of the liver for M50 and F05 was found to be 1400 and 1036 cm3, with the coefficient of variance (COV) of .76% and .40% respectively. In the case of M50 and F05 liver movement from the supine to upright positions, the M50 liver was found to move 11.5mm and the F05 liver was found to move 19.7mm in the superior to inferior direction. In addition, the liver in the MRI supine scans was found to have a greater area of rib coverage where as less coverage of the liver was seen in the UMRI seated scans. Regarding shape change, the M50 and F05 liver were found to be compressed 11.36% and 8.13% in the Anterior-Posterior direction when comparing the supine to seated position. The study?s results indicate that postural changes do affect liver location and shape, a finding that may influence computational human body modeling efforts and the development of physical human surrogates. PMID- 22846306 TI - An acoustic sensor for monitoring airflow in pediatric tracheostomy patients. AB - Without proper monitoring, patients with artificial airways in the trachea are at high risk for complications or death. Despite routine maintenance of the tube, dislodged or copious mucus can obstruct the airway. Young children ( 3yrs) have difficulty tending to their own tubes and are particularly vulnerable to blockages. They require external respiratory sensors. In a hospital environment, ventilators, end-tidal CO2 monitors, thermistors, and other auxiliary equipment provide sufficient monitoring of respiration. However, outpatient monitoring methods, such as thoracic impedance and pulse oximetry, are indirect and prone to false positives. Desensitization of caregivers to frequent false alarms has been cited in medical literature as a contributing factor in cases of child death. Ultrasonic time-of-flight (TOF) is a technique used in specialized industrial applications to non-invasively measure liquid and gas flow. Two transducers are oriented at a diagonal across a flow channel. Velocity measurement is accomplished by detecting slight variations in transit time of contra-propagating acoustic signals with a directional component parallel to air flow. Due to the symmetry of acoustic pathway between sensors, velocity measurements are immune to partial fouling in the tube from mucus, saliva, and condensation. A first generation proof of concept prototype was constructed to evaluate the ultrasonic TOF technique for medical tracheostomy monitoring. After successful performance, a second generation prototype was designed with a smaller form factor and more advanced electronics. This prototype was tested and found to measure inspired volume with a root-mean-square error < 2% during initial trials. PMID- 22846307 TI - A pilot study to evaluate gaze behavior in aircraft simulations. AB - Pilots encounter dynamic situations in which there are drastic changes in weather or where their primary equipment fails. The glass cockpit interface, a computerized system, is often used in today?s aircraft to integrate information about aircraft status onto a visual display. When adverse, life-threatening, situations occur, pilots have to make decisions, with or without their primary equipment. One of the most important tools that pilots have to prepare for adverse situations is simulation training. This study evaluated the link between situational awareness and eye behavior while using a flight simulator to present different adverse situations. PMID- 22846308 TI - A temporal evaluation of cytokines in rats after blast exposure. AB - Blast induced neurotrauma (BINT) has been a challenge clinically due to the associated diagnostic issues, overlapping symptoms with other forms of trauma, and delayed onset of the symptoms. Little is understood about the pathophysiology of BINT and there are no validated biomarkers available for diagnosis. Animal studies have shown elevated levels of inflammation in the brain after BINT using histological techniques. To identify key inflammatory biomarkers associated with BINT, cytokine microarrays were conducted. Male Sprague Dawley rats were exposed to a blast peak overpressure of 117kPa after anesthesia; control animals did not undergo blast exposure. Serum was collected at the designated sacrificed time which was either at 3, 24, 48, or 72 hours following blast exposure. We analyzed cytokines IL-1a, IL-1beta, TNF-a, IL-6, IL-10, Erythropoietin (EPO), macrophage colony stimulating factor (m-CSF), and Vascular Endothelial Growth Factor (VEGF). Results indicated a significant decrease of IL-1a at 3 hours, a decrease of m-CSF at 24 hours, an increase of EPO at 48 hours, decreased levels of IL-1a, IL-1beta, IL-6, IL-10, EPO, and increased levels of VEGF and m-CSF at 72 hours post blast. We found no changes in TNF-a at any time point. Collectively, the data suggest there is a compromised inflammatory response. Furthermore, the late decrease of EPO and increase of m-CSF indicated a delayed macrophage response to the ongoing inflammatory crisis. Overall, the results of the serum cytokine measurements following blast exposure signified a delayed inflammatory response. PMID- 22846309 TI - Mapping and navigational control for a ?smart? wheelchair. AB - A ?smart? wheelchair is in development to provide mobility to those unable to control a traditional wheelchair. A ?smart? wheelchair is an autonomous machine with the ability to navigate a mapped environment while avoiding obstacles. The flexibility and complex design of ?smart? wheelchairs have made those currently available expensive. Ongoing research at the University of Wyoming has been aimed at designing a cheaper, alternative control system that could be interfaced with a typical powered wheelchair. The goal of this project is to determine methods for mapping and navigational control for the wheelchair. The control system acquires data from eighteen sensors and uses the data to navigate around a pre programmed map which is stored on a micro SD card. The control system also provides a user interface in the form of a touchscreen LCD. The designed system will be an easy-to-use and cost effective alternative to current ?smart? wheelchair technology. PMID- 22846310 TI - A comparison between methods of measuring postrual stability: force plates versus accelerometers. AB - Several methods exist for the assessment of balance. In the clinical setting, they are often assessed through qualitative tests. In the laboratory, instrumentation can quantitatively and more accurately measure balance. To date, force platforms remain one of the most commonly used tools in balance assessment. They are, however, costly and cumbersome, making them impractical in clinical settings and field studies. Utilization of accelerometers in balance assessment has been studied but has not yet become a laboratory standard due to the unknown accuracy of this method. If proven accurate, the use of accelerometers in laboratory and clinical environments would be ideal because they are inexpensive, noninvasive, and easy to transport. The purpose of this study was to compare the use of accelerometers as an inclinometer to the use of a force platform in the assessment of postural stability. A triaxial accelerometer was placed on the trunk of five subjects. The subjects stood barefoot on a force platform under various conditions which affect balance: all sensory systems intact; impaired visual feedback; impaired proprioceptive feedback; and impaired visual and proprioceptive feedback. During each trial, trunk acceleration and ground reaction forces and moments were collected. Force plate data was used to plot the path of the center of pressure and acceleration data was used to plot a projected path of the trunk acceleration. Behavioral similarities were seen in both methods of balance assessment. Therefore, balance assessment via accelerometers is feasible. This method does, however, require further investigation. PMID- 22846311 TI - Development and characterization of an open-ended shock tube for the study of blast mtbi. AB - Shock tubes can be used to study traumatic brain injuries due to blast waves in a laboratory setting without the use of explosives. A literature review shows that several shock tubes used in these type of studies are large in size and have a high cost of conducting tests and maintaining the device. The purpose of this study was to design and characterize small shock tubes to simulate open field blast waves, which can be used in a laboratory with limited space and has low cost of operation. In addition, the shock tube can be used to induce localized blast in a small region to study the injury mechanisms in the desired region. Furthermore, the animal is placed outside of the shock tube, which provides the ability to expose the animal to a pure primary blast wave. A helium-driven shock tube with driven length of 3.04 m and driver length of 0.30 m was used in the present study. Transducers were placed at multiple locations and distances to characterize the blast wave outside the shock tube. The versatile design of the shock tube can generate a wide range of peak overpressure, rise times and durations. The shock tube was able to generate peak overpressure ranging from 25 kPa to 508 kPa and positive durations ranging from 97 us to 797 us. The literature review also showed several studies where the data were collected and analyzed improperly. The under-sampling or improper filtering can significantly affect the data. Additionally, the orientation of the transducer with respect to the shock wave can also affect the recorded peak overpressure. This paper reports various peak overpressures, durations and rise-times that can be developed with a small open-ended shock tube and the methodology to properly collect and analyze blast wave data generated by the shock tube. PMID- 22846312 TI - Development of an alternative to mechanical shaft encoders for a ?smart? wheelchair. AB - One device that is receiving a considerable amount of attention in the biomedical community is the ?smart? wheelchair. ?Smart? wheelchairs provide those who are unable to control the traditional joystick of a powered wheelchair with an alternative option. With minimal user input, these wheelchairs are able to autonomously navigate around a person?s environment, providing them with a higher level of mobility. The limited competition and extreme complexity of these wheelchairs propels their price outside of the affordable range for the average household. An alternative, cheaper system that could be attached to a typical powered wheelchair would be beneficial to the community. PMID- 22846313 TI - A comparative study for performance evaluation of sit-to-stand task with body worn sensor and existing laboratory methods. AB - uman movement such as sit-to-stand (STS) is one of the most fundamental and essential movement among daily living activities. Elderly who are unable to stand are severely limited in daily activities and rely on others for their care. In the coming next two decades about 20% of US population will be above the age of 65 years, and considering ever-increasing elderly population and health care expenses, the rehabilitation of functionally limited elderly is becoming a topic of greater concern. Clinically STS movement is looked upon with great interest, such as its analysis is meaningful in order to evaluate motor control and stability in elderly patients with functional limitations and may be more helpful than traditional medical evaluations in diagnosing and treating mobility problems in elderly. A few previous research studies describe controlled STS movements with constrains in laboratory environments and have established STS standardized events. A comparative study is presented in this work using and inertial measurement unit (IMU) and existing laboratory based sit-to-stand phases and events. The aims of this study are (1) to define phases and identify events of STS movement based on those previously described, using wireless IMU (2) to test the consistency of these events and phases in total of seven young healthy subjects (ages 25-35 years). We found significant differences in peak flexion angular velocities (p<0.001), peak extension angular velocities (p<0.01) and accelerations at seat-off (p<0.01) between participants when using chair arm rest versus knee as support during rising. Also, we have found significant differences in time events for pre seat off flexion decelerations and post seat off extension angular accelerations with the two different rising supports. Thus these distinct and consistent phases of STS movement using IMU can help identify individuals at fall risk in non-laboratory environments. PMID- 22846314 TI - Determination of stabilogram diffusion analysis coefficients and invariant density analysis parameters to understand postural stability associated with standing on anti-fatigue mats. AB - Prolonged standing has been associated with loss of balance, onset of low back pain symptoms and development of fatigue in lower extremity muscles in working populations. Although so far, it is unknown how individuals? postural stability is affected by standing on rigid versus cushioned platform but many industries are opting for anti-fatigue mats at workstations to reduce fall and injury related socio-economic cost. The goal of this study is to test SATECH's anti fatigue mat for its effects on postural stability. A pilot test with seven healthy subjects (25?35 years old) has been conducted with a force plate to obtain kinetics of body when standing on two different platforms. The centers of pressure (COP) position of subjects were determined on rigid and anti-fatigue mats for quiet stance (each trial 60 seconds). In order to understand postural control along with dynamic or stochastic characteristics of the COP, stabilogram diffusion analysis (SDA) and Invariant density analysis methods are used. Subject specific patterns were seen in stabilogram diffusion plots and associated parameters in both conditions. We also found differences in some postural sway SDA parameters with anti-fatigue mats compared to rigid vinyl floor standing with open eyes condition. But no significant differences were found in sway IDA parameters. This work further provides insights whether anti fatigue mats can be helpful to workers involved with prolonged standing tasks. PMID- 22846315 TI - A paradigm for human body finite element model integration from a set of regional models. AB - Computational modeling offers versatility, scalability, and cost advantages to researchers in the trauma and injury biomechanics communities. The Global Human Body Models Consortium (GHBMC) is a group of government, industry, and academic researchers developing human body models (HBMs) that aim to become the standard tool to meet this growing research need. The objective of this study is to present the methods used to develop the average seated male occupant model (M50, weight = 78 kg, height = 175 cm) from five separately validated body region models (BRMs). BRMs include the head, neck, thorax, abdomen, and a combined pelvis and lower extremity model. Modeling domains were split at the atlanto occipital joint, C7-T1 boundary, diaphragm, abdominal cavity (peritoneum/retroperitoneum), and the acetabulum respectively. BRM meshes are based on a custom CAD model of the seated male built from a multi-modality imaging protocol of a volunteer subject found in literature.[1] Various meshing techniques were used to integrate the full body model (FBM) including 1-D beam and discrete element connections (e.g. ligamentous structures), 2D shell nodal connections (e.g. inferior vena cava to right atrium), 3D hexahedral nodal connections (e.g. soft tissue envelope connections between regions), and contact definitions varying from tied (muscle insertions) to sliding (liver and diaphragm contact). The model was developed in a general-purpose finite element code, LS Dyna (LTSC, Livermore, CA) R4.2.1., and consists of 1.95 million elements and 1.3 million nodes. The element breakdown by type is 41% hexahedral, 33.7% tetrahedral, 19.5% quad shells and 5% tria shell. The integration methodology presented highlights the viability of using a collaborative development paradigm for the construction of HBMs, and will be used as template for expanding the suite of GHBMC models. PMID- 22846316 TI - The effects of sugar phosphates in reducing hif-1? Under hypoxic conditions. AB - Preliminary research has shown evidence of the presence of connective tissue growth factor CTGF in the tenosynovium of patients with carpal tunnel syndrome, a finding which supports the fibrotic pathophysiological progression of the disease. Connective tissue growth factor (CTGF) expression is regulated through the actions of two distinct molecular signals; transforming growth factor-beta (TGF-beta) and hypoxia inducible factor-1 alpha (HIF-1a). Mannose-6 phosphate is a natural inhibitor of TGF-beta and can also is converted to fructose 6 phosphate which we have shown is capable of reducing HIF-1 a. The goal of this experiment was to determine if mannose 6 phosphate is capable of reducing HIF-1a reducing both components of the CTGF pathway. Fibroblast cells were subjected to 5uM or 50uM concentration of either fructose 1,6 diphosphate (F6P) or mannose 6 phosphate (M6P) for a period of 24 hours in either ambient or hypoxic conditions. After the incubation period, cell viability, cell damage, morphology, and concentration of HIF-1a were determined. Cell numbers were reduced by approximately 50% in hypoxic conditions compared with ambient control. Intracellular glutathione concentration was increased significantly under hypoxic conditions compared with control. The concentration of reduced glutathione in both F6P and M6P were similar to ambient air values indicating a protection against oxidative stress. Hypoxia inducible factor-1 alpha was increased in cells under hypoxic conditions compared to base line levels in normoxic treated cells. Interestingly, only 5uM F6P was able to reduce HIF-1a back toward control normoxic values. The data suggest that the HIF-1a pathway leading to fibrosis is not the primary pathway for reductions in CTGF following MP6 treatments. This information is important in terms of developing compounds which decrease adhesion while not decreasing cell viability or impairing cellular function. PMID- 22846317 TI - Method of backflow reduction in ventricular assist devices. AB - Ventricular assist devices (VADs) have been developed to augment the deteriorating heart function of those suffering from end-stage congestive heart failure. While these devices have the potential to extend the life span and improve the quality of life of their recipients, they are also susceptible to mechanical failure. In the case of many known VADs, pump failure allows blood to flow retrograde through the device leading to a rapid loss of systemic pressure and loss of life. Some devices, such as heart valves, have been implemented to reduce or eliminate the potential for backflow in VADs but almost always at the expense of making the system more prone to thromboembolism or less reliable overall. This study presents a novel method of reducing backflow in a stopped VAD without significantly increasing the risk of thromboembolism or failure of the system. A combination of computational analysis and experimental testing was used for this study. The device design was evaluated with the extensive use of CFD and fluid-solid interaction modeling for predicting thrombus initiation potentials and mechanical and fluid stresses within the device. These results were then used in an optimization loop to parametrically evaluate the design geometry. Mock-loop experiments with a prototype provided validation of the CFD calculations. Additionally, the device design was evaluated for manufacturability with blood compatible materials and suitable surfacing techniques. The CFD numerical estimations generally agree with the experimental measurements over the entire range of backflow situations tested. Streamline analysis reveals no recirculation regions within the device. Velocity and residence time plots also demonstrated low indicators for thrombosis. Initial prototype tests validate the working principle of the device. PMID- 22846318 TI - A method to investigate the size and shape variation of the lateral ventricles with age. AB - Various structures within the brain are associated with aging. The ventricles are known to enlarge with age as the cerebrospinal fluid (CSF) increases. The objective of this study is to develop a semi-automated method for acquiring landmark data representing brain structures, such as the lateral ventricles, to map size and shape variation with age. The methodology developed is a multiple step processing of magnetic resonance images (MRI) in a brain atlas. The MRI data was collected for various ages (20-100 years old). Group-specific templates were created by decade. Each template was normalized to an atlas in Montreal Neurological Institute (MNI) space using a high-dimensional non-linear transformation procedure. A manually segmented label map of the lateral ventricles in MNI space was applied to segment the structure and establish homologous landmarks surrounding the external axial surface of the structure. The homologous landmarks were transformed back to patient space. A Generalized Procrustes Analysis (GPA) was completed for the homologous landmarks to determine the size and shape differences. The coordinate locations were regressed onto age, which generated a model predicting the landmark location for each age. A significant non-linear increase was observed in the anterior/posterior, medial/lateral, and cranial/caudal directions along the lateral ventricle, with an exponential increase after age 40 (P<0.0001). This novel method of semi automated landmark identification will allow for the creation of mapping functions to describe age-associated changes of the brain. This work is important and may lead to a better understanding of how brain morphology is correlated to the biomechanics of traumatic brain injury. PMID- 22846319 TI - The effect of impactor location and velocity variation on validation of an advanced human body finite element model. AB - Finite Element Modeling (FEM) is increasingly used as a tool in the field of injury biomechanics. One challenge in validating human body FEMs is quantifying the effect that variability of input parameters from experiments can have on the model?s predictions. The objective of this study was to conduct a parametric study on a validation simulation of the Global Human Body Models Consortium?s 50th percentile male model. The selected case was an oblique hub impact to the thoracoabdominal region of the model?s right side. The hub impactor was a 23.4 kg cylinder, with a 15cm diameter, given an initial velocity. The location and velocity of the impactor were varied based on the reported variance of the experiments used as the basis of these simulations. The effect that these changes have on the peak force was observed. Fifteen cases were simulated, giving results for five locations and three velocities based on a nominal velocity (6.7 m/s) and placement. The nominal impactor location was 7.5 cm below the xiphoid process and 30 degrees from lateral, as described in the literature. The nominal velocity was varied +/- 2 standard deviations from the average experimental velocity. The study results indicate that there were both location based and velocity-based dependencies. There was a 5.5% increase in peak force when increasing the velocity by 0.3 m/s and a 6.4% decrease in peak force when decreasing the velocity by 0.3 m/s. Additionally, the Force vs. Time curves of the same impactor location showed a trend of similar curve shapes. The impactor location also had an impact on the number of rib fractures predicted by the model as well as the time of the peak force. The parameters used in this study represent typical experimental variation in location and velocity and show the model is reasonably robust within range of plausible impacts. PMID- 22846320 TI - Measurements of low oxygen tension in vitro and response of macrophages to levels applicable to peri-and postoperative treatment of traumatic brain injury. AB - Established clinical guidelines for treatment of severe traumatic brain injury aim at maintaining intracranial and cerebral perfusion pressures. Recently, it has been shown that additional regulation of cerebral oxygen delivery helps to decrease patient mortality and leads to improved 6-month quality-of-life scores. However, eubaric oxygen-guided therapy is still controversial since it is well known that hyperoxia can cause unwanted secondary brain injury. Research studies are warranted to better understand the range of oxygen pressures that positively influence brain cell behavior. We perform such studies using a two-enzyme in vitro system that allows exposing tissue culture cells to various steady-state, or rapidly changing, oxygen pressures. Here, we present a mathematical model of the system and its validation by real-time monitoring of oxygen tensions. We additionally present preliminary evidence that human brain macrophages have a different oxygen tolerance compared to systemic macrophages and propose improvements to our in vitro system to make it applicable for data collection that aim at refining oxygen-guided therapy for patients with traumatic brain injury. PMID- 22846321 TI - A technique for murine irradiation in a controlled gas environment. AB - NASA?s extra-vehicular activities (EVAs) involve exposure to high energy photons while breathing 100% oxygen. Using previously verified mouse models, our laboratory is studying whether low dose irradiation under these hyperoxic conditions could lead to an increase in carcinogenic potential. To simulate the environment astronauts encounter during an EVA, enclosed chambers were constructed that allowed for mouse movement, controlled gas conditions, and uniform radiation dose delivery. Custom-built gas chambers with input/output gas valves and dividers that allowed for uniform gas flow were used to keep 6 unanesthetized mice separated while they were irradiated. The chambers were supplied with 100% oxygen or air using ball valves linked together with T splitters. A calibrated ion chamber was used to verify the radiation dose distribution across an entire chamber. Mice were placed in the gas environments for 0.5 h, irradiated with a 10 or 18 MV photon beam from a medical linear accelerator, and left in their gas environment for 2 h post-irradiation. We irradiated 200 mice (5 different doses between 0-1000 mGy) under normoxic or 100% oxygen conditions. For the next step of this research, these mice will be euthanized 9 months post-irradiation, and lung tumors will be counted and sized to determine if hyperoxia increases the carcinogenic effect for this model. PMID- 22846322 TI - The effects of demineralized bone matrix proteins, estrogen, and an antagonist to neuropeptide y on osteoblast and osteoclast viability and function related to osteoporosis. AB - Currently, osteoporosis affects over half of our population beyond the age of 50, and hip fractures related to osteoporosis accounted for direct costs of $18 billion in 2002 ("About Osteoporosis: Fast Facts", 2006). The average length of a hospital stay for a primary fracture diagnosis is nearly one week, and approximately 25% of previously independent older patients who sustain hip fractures remain in long-term care for over a year. In response to the necessity for improved fracture care and shortened healing time, the field of orthopaedic surgery has begun to turn toward cellular and molecular biology research for the next answer. The goal of the proposed research is to determine if current treatment and potentially new therapeutic compounds are capable of regulating bone cell function. Osteoblast and osteoclast cells were treated for periods of 24, 48 and 72 hours in the presence of estrogen, demineralized bone matrix proteins, or an antagonist to neuropeptide Y. Following the incubation, cell viability, cell function, and morphology were determined. The results indicated a significant increase in osteoblast proliferation and alkaline phosphate production in cells treated with estrogen and DBM without evidence of cellular damage. DBM and estrogen did not affect osteoclast cell numbers, while neuropeptide Y antagonist reduced osteoclast numbers. The data shows Y antagonist may be a useful and safe compound that could be used in the treatment of osteoporotic fractures. PMID- 22846323 TI - Thoracic response to high-rate blunt impacts using an advanced testing platform. AB - ehind Armor Blunt Trauma (BABT) is a persistent concern for both the military and civil law enforcement. Although personal protective equipment (PPE), including soft and hard body armor, mitigates penetrating injuries from ballistic threats, the impact generates a backface deformation which creates a high-rate blunt impact to the body and potential internal injury (i.e., BABT). A critical need exists to understand the mechanics of the human response and subsequently evaluate the efficacy of current and proposed PPE in mitigating BABT injury risk. Current human surrogate test platforms lack anatomical fidelity or instrumentation for capturing the dynamic transfer of energy during the event. Therefore, we have developed and tested a Human Surrogate Torso Model (HSTM) composed of biosimulants representing soft tissues and skeleton of the human torso. A matrix of pressure transducers were embedded in the soft tissue and a custom displacement sensor was mounted to the skeletal structure to measure sternum displacement. A series of non-penetrating, high energy ballistic tests were performed with the HSTM. Results indicate that both sternum displacement and internal localized pressure are sensitive to impact energy and location. These data provide a spatial and temporal comparison to the current standard (static clay measurements) and a method for evaluating the applicability of thoracic injury metrics, including the Viscous Criterion, for BABT. The HSTM provides an advanced, biomechanically relevant test platform for determining the thoracic response to dynamic loading events due to non-penetrating ballistic impacts. PMID- 22846324 TI - Using a mathematical model for diastolic filling through the mitral valve to determine cardiac properties. AB - The current paper uses a computer model of early diastolic filling through the mitral valve, implemented in MATLAB, to find representative values for specific parameters used to define the model. The model is a lumped parameter model configured such that a velocity waveform, obtained from a patient?s echocardiogram, serves as its primary input and the correspondingly predicted left atrial and left ventricular pressure waveforms are the primary outputs. Values were found for the following parameters: atrial and ventricular stiffness (a and v); active-relaxation characteristics, including time constant for isovolumetric pressure decay (Td0) and pressure decay constant (Pd0); valve natural frequency (), and damping coefficient (D). Pre-operative (pre-op) and post-operative (post-op) data were used to find corresponding pre-op and post-op values for each of the parameters. A sequential Bonferroni correction technique applied after an unpaired two-sample t-test yielded no statistical difference between pre-op and post-op values for any of the parameters; however, the results are limited by small sample size. PMID- 22846325 TI - Kinematic analysis of flailing injuries of lower extremities in side impacts. AB - The objective of the study was to determine the biomechanics of post mortem human subjects (PMHS) in lateral impact with a focus on lower extremity trauma and aviation safety for side-facing seat applications. Four male three-point belted intact PMHS were seated upright with the Frankfurt plane horizontal on a custom seat, covered with aircraft cushion. The seat had an armrest. The change in velocity from the Federal Aviation FAR25.562 standards was input to two specimens, and a lower energy input was used in the other two specimens. Pre test and posttest x-rays were obtained, and autopsies were conducted. Sled and pelvic acceleration signals were digitally gathered and processed according to the Society of Automotive Engineers specifications. A high-speed digital video camera was used to track the frontal plane kinematics with targets placed at appropriate lower extremity landmarks. Fractures of the left distal femur-knee complex in one and proximal sub-capital femur in the other specimen occurred in tests using the simulated FAR pulse. Tests at the lower energy input in the other specimens did not result in trauma. Coronal motions in PMHS occurred from initial flailing of the lower leg-knee-upper leg complex initiating after the onset of the side-impact pulse with the armrest acting as a limiting/boundary condition for the left femur-pelvis-region. These motions were attributed to be a causal agent for the observed lower extremity injuries. Although from a limited sample size, the present findings indicate that lower extremities may sustain trauma, and side-facing seats in aviation environments may need to be evaluated for occupant safety in the lateral mode. PMID- 22846326 TI - Prediction of forced expiratory volume in spirometric pulmonary function test using adaptive neuro fuzzy inference system. AB - Spirometry is the most frequently performed clinical test to assess the dynamics of pulmonary function in human subjects. It measures airflow from fully inflated lungs through forced expiratory maneuver and generates large data set. However, these investigations often result in incomplete data sets due to the inability of the children and patients to perform this test. Hence, there is a requirement for prediction of significant parameters from the available incomplete data set. In this work, the results of model based prediction of two such significant parameters, Forced Expiratory Volume in one second (FEV1) and, Forced Expiratory Volume in six seconds (FEV6), are reported. The measured spirometric parameters are given as inputs to the Adaptive Neuro Fuzzy Inference System (ANFIS) which classifies data sets using fuzzy system based multilayer architecture. Triangular, Trapezoidal, Gaussian, Pi and Gbell membership functions are used to train and test the prediction process. The performance of the model is evaluated by computing their prediction error statistics of average value, standard deviation and root mean square. Results show that ANFIS model is capable of predicting FEV1 and FEV6 in both normal and abnormal subjects. Trapezoidal membership function predicted FEV1 with high precision and accuracy using a set of 21 rules. Similar prediction accuracy is observed in FEV6 using Gaussian membership function. Further, it is observed that prediction accuracy is found to be high for normal subjects with better correlation with measured values. It appears that this method is useful in enhancing diagnostic relevance of spirometric investigations in case of children and patients who are not able to perform the test as FEV1 and FEV6 are the useful indices to characterize pulmonary abnormalities. PMID- 22846327 TI - Differentiation of digital tb images using texture analysis and rbf classifier. AB - In this work, differentiation of positive and negative images of Tuberculosis (TB) sputum smear has been attempted using statistical method based on Gray Level Co-occurrence Matrix (GLCM). The sputum smear images (N=100) recorded under standard image acquisition protocol are considered for this work. Second order statistical texture analysis is performed on the acquired images using GLCM method and a set of nineteen features are derived. Principal Component Analysis (PCA) is then employed to reduce feature sets, to enhance the efficiency of differentiation and to reduce the redundancy. These feature sets are further classified using Radial Basis Function (RBF) classifier. Results show that GLCM is able to differentiate positive and negative TB images. Correlation is found to be high for many of the parameters. Application of PCA reduced the number of features to four which had maximum magnitude in the first principal component. Higher classification accuracy is achieved using RBF classifier. It appears that this method of texture analysis could be useful to develop automated system for characterization and classification of digital TB sputum smear images. PMID- 22846328 TI - Characterization of optic disc in human retinal images using tsallis entropy based method. AB - The detection of the optic disc is an important step in the automated analysis of retinal images. A method to identify the optic disc in human retinal images using, non-extensive entropy, also called Tsallis entropy, is presented in this paper. The segmentation process is carried out on the retinal images using conventional Tsallis entropy, with and without morphological preprocessing. An optimum threshold value is found to separate optic disc from the blood vessels and other structures. The performance of the conventional Tsallis algorithm with and without preprocessing is compared and analyzed based on the different entropic index, visual quality, pixel distribution and the geometrical size of the optic disc. The conventional Tsallis entropy with morphological preprocessing is able to segment the optic disc. The detection efficiency is found to be high for the entropic index equal to 4 and also it is found that optic disc index is a useful parameter to differentiate normal from abnormal retinal images. The results are useful for detection of various retinal related diseases. PMID- 22846329 TI - Characterization of trabecular structure in human femur radiographic images using ridgelet transform and support vector machines. AB - The evaluation of femur bone strength is a key component for fracture risk assessment. Recently, it has been demonstrated that bone strength depends not only on bone mass but also on factors related to bone quality, such as trabecular architecture and morphology. Current clinical methods for assessment of bone quality are largely dependent on assessing bone mass. However, these methods do not provide any information about bone structure which is considered to be an equally important factor in assessing bone quality. In this work, ridgelet transform based multi-scale geometric analysis is performed in radiographic images to characterize the trabecular structure. The trabecular regions of normal and abnormal human femur bone images (N=40) recorded under standard condition are used for the study. The regions of interest in the bone images are subjected to ridgelet transform for extracting useful features that evaluate changes taking place in the architecture of bone. The extracted features are correlated with apparent mineralization which is a key of representative architectural variation of the trabecular bone. Further to validate the results, images are also classified based on the extracted features using Support Vector Machines (SVM) with four different kernels. Results show that ridgelet transform are able to differentiate normal and abnormal femur bone images. The values of derived features such as energy and homogeneity are found to have good correlation with apparent mineralization. In abnormal images, the variations in the observed features are attributed to loss in bone mass, inhomogeneity and anisotropic nature of such images. Further, classification performed using polynomial kernel based SVM is found to be effective in terms of number of support vectors, sensitivity and specificity. Hence it appears that this method is useful for gross abnormality detection and micro-damage analysis. PMID- 22846330 TI - Morphological variations in microfilaria of Wuchereria bancrofti in cytology smears: a morphometric study of 32 cases. AB - OBJECTIVE: Microfilaria of Wuchereria bancrofti has been described in many cytological specimens, where typical blood film morphology has been used for evaluation. However, these studies have not documented the morphological variations in microfilaria in cytological smears. In the present study, cytological findings in 32 clinically unsuspected cases of filariasis were reviewed with emphasis on morphological details and image morphometric measurements. STUDY DESIGN: A retrospective analysis of 32 cases of clinically unsuspected filariasis diagnosed by cytology from April 2001 to March 2011 was carried out. RESULTS: All microfilariae were characterized as W. bancrofti and showed a wide variation in their length (202 to 300 um) and width (6.2 to 8.4 um). Terminal and subterminal swellings were seen in one of the cases causing diagnostic confusion with Brugia malayi. Microfilariae were shorter and wider in May-Grunwald-Giemsa stain than in Papanicolaou-stained smears. CONCLUSIONS: Natural variations in the size of microfilariae of W. bancrofti are the probable reason for the range of these findings. The overlapping features with microfilaria of B. malayi might be related to subspecies variations in W. bancrofti. Fixation, degeneration and staining procedure also seem to influence the morphological features. This morphometric study highlights the morphological disparities of microfilaria and the differential diagnostic considerations. PMID- 22846331 TI - Estimation of sequencing error rates in short reads. AB - BACKGROUND: Short-read data from next-generation sequencing technologies are now being generated across a range of research projects. The fidelity of this data can be affected by several factors and it is important to have simple and reliable approaches for monitoring it at the level of individual experiments. RESULTS: We developed a fast, scalable and accurate approach to estimating error rates in short reads, which has the added advantage of not requiring a reference genome. We build on the fundamental observation that there is a linear relationship between the copy number for a given read and the number of erroneous reads that differ from the read of interest by one or two bases. The slope of this relationship can be transformed to give an estimate of the error rate, both by read and by position. We present simulation studies as well as analyses of real data sets illustrating the precision and accuracy of this method, and we show that it is more accurate than alternatives that count the difference between the sample of interest and a reference genome. We show how this methodology led to the detection of mutations in the genome of the PhiX strain used for calibration of Illumina data. The proposed method is implemented in an R package, which can be downloaded from http://bcb.dfci.harvard.edu/~vwang/shadowRegression.html. CONCLUSIONS: The proposed method can be used to monitor the quality of sequencing pipelines at the level of individual experiments without the use of reference genomes. Furthermore, having an estimate of the error rates gives one the opportunity to improve analyses and inferences in many applications of next-generation sequencing data. PMID- 22846333 TI - Rice CYP90D2 and CYP90D3 catalyze C-23 hydroxylation of brassinosteroids in vitro. AB - Brassinosteroids are biosynthesized from campesterol via several cytochrome P450 (P450)-catalyzed oxidative reactions. We report the biochemical characterization of two brassinosteroid-biosynthetic P450s from rice: CYP90D2 and CYP90D3. A rice dwarf mutant, ebisu dwarf (d2), which contains a defective copy of CYP90D2, is known to be a brassinosteroid-deficient mutant, and CYP90D2 has been considered to act as a C-3 dehydrogenase. However, in vitro biochemical assays using baculovirus/insect cell-produced proteins revealed that both CYP90D2 and CYP90D3 catalyze C-23 hydroxylation of various 22-hydroxylated brassinosteroids, but with markedly different catalytic efficiencies. Both enzymes preferentially convert (22S,24R)-22-hydroxyergost-4-en-3-one, (22S,24R)-22-hydroxy-5alpha-ergostan-3 one, and 3-epi-6-deoxocathasterone to the corresponding 23-hydroxylated products, but are less active in the conversion of (22S)-22-hydroxycampesterol and 6 deoxocathasterone, in vitro. Consistently, the levels of 23-hydroxylated products of these intermediates, namely, 6-deoxoteasterone, 3-dehydro-6-deoxoteasterone, and 6-deoxotyphasterol were decreased in d2 mutants. These results indicate that CYP90D2 and CYP90D3 can act as brassinosteroid C-23 hydroxylases in rice. PMID- 22846332 TI - Two-year course of cognitive function and instrumental activities of daily living in older adults with bipolar disorder: evidence for neuroprogression? AB - BACKGROUND: While bipolar disorder (BD) is a leading cause of disability, and an important contributor to disability in BD is cognitive impairment, there is little systematic research on the longitudinal course of cognitive function and instrumental activities of daily living (IADLs) in late-life. In this report, we characterize the 2-year course of cognitive function and IADLs in older adults with BD. Method We recruited non-demented individuals 50 years and older with BD I or BD II (n = 47) from out-patient clinics or treatment studies at the University of Pittsburgh. Comparator subjects ('controls') were 22 individuals of comparable age and education with no psychiatric or neurologic history, but similar levels of cardiovascular disease. We assessed cognitive function and IADLs at baseline, 1- and 2-year time-points. The neuropsychological evaluation comprised 21 well-established and validated tests assessing multiple cognitive domains. We assessed IADLs using a criterion-referenced, performance-based instrument. We employed repeated-measures mixed-effects linear models to examine trajectory of cognitive function. We employed non-parametric tests for analysis of IADLs. RESULTS: The BD group displayed worse cognitive function in all domains and worse IADL performance than the comparator group at baseline and over follow up. Global cognitive function and IADLs were correlated at all time-points. The BD group did not exhibit accelerated cognitive decline over 2 years. CONCLUSIONS: Over 2 years, cognitive impairment and associated functional disability of older adults with BD appear to be due to long-standing neuroprogressive processes compounded by normal cognitive aging rather than accelerated cognitive loss in old age. PMID- 22846334 TI - 1-Aminocyclopropane-1-carboxylic acid (ACC) deaminase-containing rhizobacteria protect Ocimum sanctum plants during waterlogging stress via reduced ethylene generation. AB - Ocimum sanctum grown as rain-fed crop, is known to be poorly adapted to waterlogged conditions. Many a times the crop suffers extreme damages because of anoxia and excessive ethylene generation due to waterlogging conditions present under heavy rain. The usefulness of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase-containing plant growth promoting rhizobacteria was investigated under waterlogging stress. The comparison of herb yield and stress induced biochemical changes of waterlogged and non-waterlogged plants with and without ACC deaminase containing microbiological treatments were monitored in this study. Ten plant growth promoting rhizobacteria strains containing ACC-deaminase were isolated and characterized. Four selected isolates Fd2 (Achromobacter xylosoxidans), Bac5 (Serratia ureilytica), Oci9 (Herbaspirillum seropedicae) and Oci13 (Ochrobactrum rhizosphaerae) had the potential to protect Ocimum plants from flood induced damage under waterlogged glass house conditions. Pot experiments were conducted to evaluate the potential of these ACC deaminase-containing selected strains for reducing the yield losses caused by waterlogging conditions. Bacterial treatments protected plants from waterlogging induced detrimental changes like stress ethylene production, reduced chlorophyll concentration, higher lipid peroxidation, proline concentration and reduced foliar nutrient uptake. Fd2 (A. xylosoxidans) induced maximum waterlogging tolerance as treated waterlogged plants recorded maximum growth and herb yield (46.5% higher than uninoculated waterlogged plants) with minimum stress ethylene levels (53% lower ACC concentration as compared to waterlogged plants without bacterial inoculation) whereas under normal non-waterlogged conditions O. rhizosphaerae was most effective in plant growth promotion. PMID- 22846335 TI - Adaptation to cognitive context and item information in the medial temporal lobes. AB - The medial temporal lobes (MTL) play an essential role in episodic memory, and accumulating evidence indicates that two MTL subregions--the perirhinal (PRc) and parahippocampal (PHc) cortices--might have different functions. According to the binding of item and context theory (Diana, Yonelinas, & Ranganath, 2007; Eichenbaum, Yonelinas, & Ranganath, 2007), PRc is involved in processing item information, the target of memory encoding, whereas PHc is involved in processing context information, peripheral information that identifies the circumstances of the episode. Here, we used functional magnetic resonance imaging (fMRI) adaptation to test the roles of different MTL subregions in the processing of item and context information. Participants were scanned while viewing a series of objects. Each object was presented with a unique semantic encoding question that elicited a salient cognitive context. The object picture, the encoding question, both, or neither were immediately repeated. We found that PRc activity was sensitive to repetition of the object but not the encoding question whereas PHc activity was sensitive to repetition of the encoding question but not the object. These data are consistent with the idea that the PRc and PHc are differentially involved in the representation of item and context information and additionally suggest that the role of the PHc extends to nonspatial, cognitive context information. PMID- 22846336 TI - Identification and characterization of the sex-determiner transformer-2 homologue in Chinese shrimp, Fenneropenaeus chinensis. AB - The transformer-2 gene, encoding a protein (Tra-2) which directs sex-specifically alternative splicing of doublesex (dsx) pre-mRNA in combination with the transformer (Tra) protein, has been proved to play important roles on sex differentiation and sex development in Drosophila melanogaster. In the present study, a tra-2 homologue (FcTra-2) was cloned and characterized in the Chinese shrimp, Fenneropenaeus chinensis. A FcTra-2 genomic DNA sequence with a length of 8,871 bp was obtained and verified to consist of 7 exons and 6 introns. Three alternatively spliced mRNA transcripts, designated as FcTra-2a, FcTra-2b and FcTra-2c, were isolated and characterized. Sequence analysis showed that FcTra-2 included a RNA recognition motif and a linker region, which shared high sequence identities with Tra-2 from other species and 2 arginine/serine rich regions. Further studies were performed on the isoform FcTra-2c, since it exhibited a significantly higher expression level in ovary than in other tissues. In early developmental stages of the shrimp, FcTra-2c was detected to suddenly increase its expression level at the mysis stage. In juvenile stage, FcTra-2c displayed a significantly higher expression level in female Chinese shrimp than in males. These data indicated that FcTra-2 might be involved in female sex determination in Chinese shrimp. PMID- 22846337 TI - The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. AB - Osteosarcoma (OS) is the most common primary bone tumour in the paediatric age group. Treatment-refractory pulmonary metastasis continues to be the major complication of OS, reducing the 5-year survival rate for these patients to 10 20%. The mechanisms underlying the metastatic process in OS are still unclear, but undoubtedly, a greater understanding of the factors and interactions involved in its regulation will open new and much needed opportunities for therapeutic intervention. Recent published data have identified a new role for bone-specific macrophages (osteoclasts) and tumour-associated macrophages (TAMs), in OS metastasis. In this review we discuss the contribution of TAMs and osteoclasts in the establishment and maintenance of secondary metastatic lesions, and their novel role in the prevention of metastatic disease in a primary bone cancer such as osteosarcoma. PMID- 22846338 TI - Relationship of bipolar and unipolar electrogram voltage to scar transmurality and composition derived by magnetic resonance imaging in patients with nonischemic cardiomyopathy undergoing VT ablation. AB - BACKGROUND: Bipolar voltage mapping has a role in defining endocardial-based scar in postinfarct patients undergoing ventricular tachycardia catheter ablation. The utility of bipolar and unipolar voltages in characterizing scar has not been evaluated in patients with nonischemic cardiomyopathy. OBJECTIVE: To relate left ventricular (LV) endocardial bipolar and unipolar voltages in these patients to scar transmurality (endocardial vs nonendocardial) and composition (homogeneous core vs heterogeneous gray). METHODS: Ten consecutive cardiomyopathy patients undergoing endocardial LV tachycardia ablation were included (age 48 +/- 14 years; left ventricular ejection fraction 43% +/- 15%). Preablation late gadolinium-enhanced magnetic resonance imaging was used to quantify core and gray scar by using signal-intensity thresholding. Electroanatomic LV endocardial mapping provided bipolar and unipolar voltages. Electroanatomic maps and late gadolinium-enhanced magnetic resonance imaging were rigidly registered in order to relate voltage to scar (registration error 3.6 +/- 2.9 mm). RESULTS: Bipolar voltage was lower in endocardial core than in no scar (P <.001). Unipolar voltage was lower in endocardial core and nonendocardial core than in no scar (P <.001). Endocardial and nonendocardial gray scar had an effect similar to that of core in reducing bipolar and unipolar voltages (P <.001). The mass of healthy myocardium and endocardial core scar independently predicted bipolar and unipolar voltages using general estimating equation modeling. With receiver operating characteristic curve analysis, bipolar voltage >1.9 mV and unipolar voltage <6.7 mV had a high negative predictive value (91%) for detecting nonendocardial scar from either endocardial scar or no scar. CONCLUSIONS: In patients with nonischemic cardiomyopathy, LV endocardial bipolar voltage is dependent on endocardial core and gray scar, while the unipolar voltage is influenced by core and gray scar across the LV wall as defined by late gadolinium-enhanced magnetic resonance imaging. PMID- 22846339 TI - Relevance of calmodulin/CaMKII activation for arrhythmogenesis in the AV block dog. AB - BACKGROUND: The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. OBJECTIVE: The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. METHODS: AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). RESULTS: Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca(2+)](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. CONCLUSION: The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity. PMID- 22846340 TI - Effect of influenza vaccines against mismatched strains: a systematic review protocol. AB - BACKGROUND: Influenza vaccines are most effective when the antigens in the vaccine match those of circulating influenza strains. The extent to which the vaccine is protective when circulating strains differ from vaccine antigens, or are mismatched, is uncertain. We propose to systematically review the cross protection offered by influenza vaccines against circulating influenza A or B viruses that are not antigenically well-matched to vaccine strains. METHODS/DESIGN: This is a protocol for a systematic review and meta-analysis. Placebo-controlled randomized clinical trials (RCTs) reporting laboratory confirmed influenza among healthy participants vaccinated with antigens of influenza strains that differed from those circulating will be included. The primary outcome is the incidence of laboratory-confirmed influenza (polymerase chain reaction (PCR) or viral culture). The secondary outcome is the incidence of laboratory-confirmed influenza through antibody assay (a less sensitive test than PCR or viral culture) alone or combined with PCR, and/ or viral culture. The review will be limited to RCTs written in English.We will search MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, previous influenza reviews, and the reference lists of included studies to identify potentially relevant RCTs. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal (using the Cochrane risk of bias tool).If appropriate, random effects meta-analysis of vaccine efficacy will be conducted in SAS (version 9.2) by calculating the relative risk. Vaccine efficacy will be calculated using the following formula: (1 - relative risk * 100). The results will be analyzed by type of vaccine (live attenuated, trivalent inactivated, or other). Subgroup analysis will include the effects of age (children, adults, older participants), and influenza A versus influenza B on the results. For influenza B we will also consider variable degrees of antigenic mismatch (lineage and drift mismatch). DISCUSSION: Our results can be used by researchers and policy-makers to help predict the efficacy of influenza vaccines during mismatched influenza seasons. Furthermore, the review will be of interest to patients and clinicians to determine whether to get immunized or support immunization for a particular influenza season. PMID- 22846341 TI - The impact of an "acute dialysis start" on the mortality attributed to the use of central venous catheters: a retrospective cohort study. AB - BACKGROUND: Central venous catheters (CVCs) are associated with early mortality in dialysis patients. However, some patients progress to end stage renal disease after an acute illness, prior to reaching an estimated glomerular filtration rate (eGFR) at which one would expect to establish alternative access (fistula/peritoneal dialysis catheter). The purpose of this study was to determine if exclusion of this "acute start" patient group alters the association between CVCs and mortality. METHODS: We conducted a retrospective cohort study of 406 incident dialysis patients from 1 Jan 2006 to 31 Dec 2009. Patients were classified as acute starts if 1) the eGFR was >25 ml/min/1.73 m2, <= 3 months prior to dialysis initiation and declined after an acute event (n = 45), or 2) in those without prior eGFR measurements, there was no supporting evidence of chronic kidney disease on history or imaging (n = 12). Remaining patients were classified as chronic start (n = 349). RESULTS: 98 % and 52 % of acute and chronic starts initiated dialysis with a CVC. There were 148 deaths. The adjusted mortality hazard ratio (HR) for acute vs. chronic start patients was 1.84, (95 % CI [1.19-2.85]). The adjusted mortality HR for patients dialyzing with a CVC compared to alternative access was 1.19 (95 % CI [0.80-1.77]). After excluding acute start patients, the adjusted HR fell to 1.03 (95 % CI [0.67-1.57]). CONCLUSIONS: A significant proportion of early dialysis mortality occurs after an acute start. Exclusion of this population attenuates the mortality risk associated with CVCs. PMID- 22846343 TI - [Drugs: they should be selected, but do we know how to?]. PMID- 22846342 TI - Antibacterial activity of plasma from crocodile (Crocodylus siamensis) against pathogenic bacteria. AB - BACKGROUND: The Siamese crocodile (Crocodylus siamensis) is a critically endangered species of freshwater crocodiles. Crocodilians live with opportunistic bacterial infection but normally suffer no adverse effects. They are not totally immune to microbial infection, but their resistance thereto is remarkably effective. In this study, crude and purified plasma extracted from the Siamese crocodile were examined for antibacterial activity against clinically isolated, human pathogenic bacterial strains and the related reference strains. METHODS: Crude plasma was prepared from whole blood of the Siamese crocodile by differential sedimentation. The crude plasma was examined for antibacterial activity by the liquid growth inhibition assay. The scanning electron microscopy was performed to confirm the effect of crude crocodile plasma on the cells of Salmonella typhi ATCC 11778. Effect of crude crocodile plasma on cell viability was tested by MTT assay. In addition, the plasma was purified by anion exchange column chromatography with DEAE-Toyopearl 650 M and the purified plasma was tested for antibacterial activity. RESULTS: Crude plasma was prepared from whole blood of the Siamese crocodile and exhibited substantial antibacterial activities of more than 40% growth inhibition against the six reference strains of Staphylococcus aureus, Salmonella typhi, Escherichia coli, Vibrio cholerae, Pseudomonas aeruginosa, and Staphylococcus epidermidis, and the four clinical isolates of Staphylococcus epidermidis, Pseudomonas aeruginosa, Salmonella typhi, and Vibrio cholerae. Especially, more than 80% growth inhibition was found in the reference strains of Salmonella typhi, Vibrio cholerae, and Staphylococcus epidermidis and in the clinical isolates of Salmonella typhi and Vibrio cholerae. The effect of the crude plasma on bacterial cells of Salmonella typhi, a certain antibacterial material probably penetrates progressively into the cytoplasmic space, perturbing and damaging bacterial membranes. The effect of the crude plasma was not toxic by the yellow tetrazolium bromide (MTT) assay using a macrophage-like cell, RAW 264.7. The pooled four fractions, designated as fractions D1-D4, were obtained by column chromatography, and only fraction D1 showed growth inhibition in the reference strains and the clinical, human pathogenic isolates. CONCLUSIONS: The crude and purified plasma from the Siamese crocodile significantly showed antibacterial activity against pathogenic bacteria and reference strains by damage cell membrane of target bacterial cells. From the MTT assay, the Siamese crocodile plasma was not cytotoxic to the cells. PMID- 22846344 TI - [Review of the medication in polymedicated elderly patients]. PMID- 22846345 TI - The PDZ protein discs-large (DLG): the 'Jekyll and Hyde' of the epithelial polarity proteins. AB - Discs-large (DLG) is a multi-PDZ domain-containing protein that belongs to the family of molecular scaffolding proteins known as membrane guanylate kinases or MAGUKs. DLG is a component of the Scribble polarity complex and genetic analyses of DLG in Drosophila have identified a role for the protein in several key biological processes including the regulation of apico-basal polarity of epithelial cells, as well as other polarity processes such as asymmetric cell division and cell invasion. Disturbance of DLG function leads to uncontrolled epithelial cell proliferation and neoplastic transformation, thereby defining DLG as a potential tumour suppressor. However, whether mammalian homologues of DLG (DLG1, DLG2, DLG3 and DLG4) also possess tumour suppressor functions is not known. In this minireview, we focus on the biological functions of DLG1 in human epithelial cells and on how the function of this MAGUK relates to its intracellular location. We examine some of the evidence that implies that DLG has both tumour suppressor and, paradoxically, oncogenic functions depending upon the precise cellular context. PMID- 22846346 TI - Evaluation of the iPhone with an acrylic sleeve versus the Scoliometer for rib hump measurement in scoliosis. AB - BACKGROUND: Vertebral rotation found in structural scoliosis contributes to trunkal asymmetry which is commonly measured with a simple Scoliometer device on a patient's thorax in the forward flexed position. The new generation of mobile 'smartphones' have an integrated accelerometer, making accurate angle measurement possible, which provides a potentially useful clinical tool for assessing rib hump deformity. This study aimed to compare rib hump angle measurements performed using a Smartphone and traditional Scoliometer on a set of plaster torsos representing the range of torsional deformities seen in clinical practice. METHODS: Nine observers measured the rib hump found on eight plaster torsos moulded from scoliosis patients with both a Scoliometer and an Apple iPhone on separate occasions. Each observer repeated the measurements at least a week after the original measurements, and were blinded to previous results. Intra-observer reliability and inter-observer reliability were analysed using the method of Bland and Altman and 95% confidence intervals were calculated. The Intra-Class Correlation Coefficients (ICC) were calculated for repeated measurements of each of the eight plaster torso moulds by the nine observers. RESULTS: Mean absolute difference between pairs of iPhone/Scoliometer measurements was 2.1 degrees, with a small (1 degrees) bias toward higher rib hump angles with the iPhone. 95% confidence intervals for intra-observer variability were +/- 1.8 degrees (Scoliometer) and +/- 3.2 degrees (iPhone). 95% confidence intervals for inter observer variability were +/- 4.9 degrees (iPhone) and +/- 3.8 degrees (Scoliometer). The measurement errors and confidence intervals found were similar to or better than the range of previously published thoracic rib hump measurement studies. CONCLUSIONS: The iPhone is a clinically equivalent rib hump measurement tool to the Scoliometer in spinal deformity patients. The novel use of plaster torsos as rib hump models avoids the variables of patient fatigue and discomfort, inconsistent positioning and deformity progression using human subjects in a single or multiple measurement sessions. PMID- 22846347 TI - Ranking of parameters of pain hypersensitivity according to their discriminative ability in chronic low back pain. AB - Low back pain is associated with plasticity changes and central hypersensitivity in a subset of patients. We performed a case-control study to explore the discriminative ability of different quantitative sensory tests in distinguishing between 40 cases with chronic low back pain and 300 pain-free controls, and to rank these tests according to the extent of their association with chronic pain. Gender, age, height, weight, body mass index, and psychological measures were recorded as potential confounders. We used 26 quantitative sensory tests, including different modalities of pressure, heat, cold, and electrical stimulation. As measures of discrimination, we estimated receiver operating characteristics (ROC) and likelihood ratios. Six tests seemed useful (in order of their discriminative ability): (1) pressure pain detection threshold at the site of most severe pain (fitted area under the ROC, 0.87), (2) single electrical stimulation pain detection threshold (0.87), (3) single electrical stimulation reflex threshold (0.83), (4) pressure pain tolerance threshold at the site of most severe pain (0.81), (5) pressure pain detection threshold at suprascapular region (0.80), and (6) temporal summation pain threshold (0.80). Pressure and electrical pain modalities seemed most promising and may be used for diagnosis of pain hypersensitivity and potentially for identifying individuals at risk of developing chronic low back pain over time. PMID- 22846348 TI - Detecting suspicious behaviour using speech: acoustic correlates of deceptive speech -- an exploratory investigation. AB - The current work intended to enhance our knowledge of changes or lack of changes in the speech signal when people were being deceptive. In particular, the study attempted to investigate the appropriateness of using speech cues in detecting deception. Truthful, deceptive and control speech were elicited from ten speakers in an interview setting. The data were subjected to acoustic analysis and results are presented on a range of speech parameters including fundamental frequency (f0), overall amplitude and mean vowel formants F1, F2 and F3. A significant correlation could not be established between deceptiveness/truthfulness and any of the acoustic features examined. Directions for future work are highlighted. PMID- 22846349 TI - Molecular analysis of centrifugation supernatant fluid from pancreaticobiliary duct samples can improve cancer detection. AB - OBJECTIVE: We aimed to supplement microscopic examination of biliary cytobrush specimens to improve sensitivity by mutational profiling of: (1) selected cells microdissected from cytology slides and (2) corresponding cell-free DNA in residual supernatant fluid. STUDY DESIGN: From 43 patients with brushings of bile or pancreatic duct strictures, DNA was extracted from microdissected cells and 1 2 ml of cytocentrifugation supernatant fluid. Mutational analysis targeted 17 genomic sites associated with pancreaticobiliary cancer, including sequencing for KRAS point mutation and loss of heterozygosity (LOH) analysis of microsatellites located at 1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, and 22q. RESULTS: Mutations were found in 25/28 patients with malignancy, and no mutations were found in 5/5 patients with benign surgical results. The cell-free supernatant fluid generally contained higher levels and quality of DNA, resulting in increased detection of mutations in most patients. KRAS mutations only occurred in patients with pancreatic cancer. Mutational profiling of supernatant fluid specimens resulted in high sensitivity and specificity for malignancy, improving the detection of malignancy over cytology alone. CONCLUSION: Brush cytology specimens yielded supernatant fluid enriched with DNA, probably from actively proliferating cells. Mutational profiling can enhance the cytologic evaluation and characterization of specimens suspected to contain pancreatic or bile duct cancer. PMID- 22846350 TI - [Magnesium for nutrient]. AB - Magnesium is essential nutrient. Here is magnesium for nutrient. Magnesium has a large number of biological or biochemical functions. It's distribution, absorption, deficiency, excess disorder, requirement, supply sources, and especially status and issue of magnesium intake in Japanese are reviewed. PMID- 22846351 TI - [Magnesium homeostasis and its disturbances]. AB - Magnesium homeostasis is maintained through normal functions of the kidney, intestine, and bone. In the kidney, approximately 80% magnesium is filtered by the glomeruli. In general, 95% filtered magnesium is collectively reabsorbed in the proximal tubule (15%-20%) , thick ascending limb of Henle (TAL, 65%-75%) , and the distal convoluted tubule (DCT, 5%-10%) . In the TAL, magnesium reabsorption regulated by the paracellular pathway via claudin-16 is driven by electrochemical voltage. Chloride channel Kb and renal outer medullary potassium channels control this lumen-positive voltage. In the DCT, the transcellular pathway via transient receptor potential melastatin 6 (TRPM6) plays a fundamental role in the final 5%-10% magnesium reabsorption. The functions of TRPM6 depend on Na-Cl co-transporters and Na( + )-K( + )-ATPase. Defects in these regulatory proteins may cause inherited or drug-induced disorders of magnesium metabolism. Recently, some proteins have been confirmed to be responsible for magnesium homeostasis ; however, further research is required to elucidate the mechanisms underlying the maintenance of magnesium homeostasis. PMID- 22846352 TI - [Magnesium and cardiac function]. AB - Free magnesium ion (Mg(2 + )) is involved in numerous processes of cardiac function. However, mechanism of regulation by Mg(2 + ) has not been fully understood. Extracellular Mg(2 + ) can act on the external surface of the cell membrane, whereas intracellular Mg(2 + ) can exert its effects via many different sites : various enzymes, intracellular organella and internal surface of the cell membrane. In this article, we will briefly review the extracellular and intracellular effects of Mg(2 + ) on each step of E-C coupling of cardiac myocytes, in an attempt to integrate them into cardiac function. PMID- 22846353 TI - [Magnesium and liver]. AB - The pathophysiological responses to experimental magnesium deficiency are considered to result from mild inflammation and oxidative stress in various tissues. It is not clear whether magnesium deficiency solely induces liver diseases. However, magnesium deficiency is considered as a potential risk factor for nonalcoholic fatty liver disease (NAFLD) because magnesium deficiency is associated with type 2 diabetes that are closely related to the pathogenesis of NAFLD. Further, inflammatory cytokines and oxidative stress play important roles in the progression to nonalcoholic steatohepatitis. The relationship was reported between plasma magnesium concentration and the incidence of nonalcoholic steatohepatitis. In this review, I briefly described how magnesium deficiency induces oxidative stress and inflammatory responses, and the effect of magnesium deficiency on liver. PMID- 22846354 TI - [Significance of the Magnesium in the hard tissues such as Bone and Teeth]. AB - In latest year, the relationship between whole body osteoporosis and jawbone osteoporosis, and also the relationship between bone density from whole body and jawbone have been recognized. As Mg is related to the bone density of whole body and the weakness of alveolar bone, it deeply connects to the denture treatment and the convalescence after implant treatment. It related to avoid losing teeth during the suppression of acid solubility of enamel, too. For the importance to control the absorption of alveolar bone which can support the teeth, it is necessary to have more consideration on Mg in the relationship between whole body's bone and alveolar bone. PMID- 22846355 TI - [Role of magnesium in nerve tissue]. AB - The role of magnesium on nerve tissue was discussed. Two main topics of "magnesium and neural activity" and "magnesium-therapy and brain neurons" were described together with introducing our research on rat cultured neurons of cortex and hippocampus. PMID- 22846356 TI - [Magnesium and pregnancy]. AB - Blood levels of total Mg, ionized Mg and intracellular ionized Mg of platelet were lowered in the 2nd trimester of gestation and thereafter. Urinary excretion of Mg does not change during the whole period of pregnancy. According to our results of animal experiments, intestinal absorption of Mg does not increase during pregnancy compared with non-pregnant state. These data suggest pregnant women tend to become magnesium deficiency. This is reflected in the fact that Mg metabolic parameters of pregnant women with preeclampsia are relatively reduced compared with those of healthy gravidae. In the obstetrical practice Mg has other significance, because magnesium sulfate is frequently used as a drug of choice in the therapy of threatened premature delivery and eclampsia. Mg plays important roles in physiology and pharmacology during gestation. PMID- 22846357 TI - [Drugs affecting serum magnesium concentration]. AB - Several oral or intravenous drug administrations can cause abnormalities in serum magnesium concentration. Most of drug-induced hypomagnesemia derives from a loss of the mineral in the urine by facilitating renal secretion. Hypermagnesemia can occur by a direct intake of drugs including magnesium, especially in patients with renal insufficiency. Frequent check of serum magnesium concentration will be needed to monitor these abnormalities. PMID- 22846358 TI - [Abnormalities of magnesium (Mg) metabolism and therapeutic significance of Mg administration in patients with metabolic syndrome, type 2 diabetes, heart failure and chronic hemodialysis]. AB - Magnesium (Mg) , one of the fundamental minerals acting the co-factor of about 300 kinds of enzymes and natural Ca channel blocker, plays an important role of cardiovascular, neurological, and metabolic functions in physiological, and pathophysiological conditions. Common abnormal Mg metabolism is an absolute or relative deficiency of Mg due to an attenuated Mg intake and an enhanced urinary Mg excretion, particularly in the metabolic syndrome (MetS) , type 2 diabetes (DM) , chronic heart failure (CHF) and hemodialysis (HD) patients with diabetes. It has been reported the Mg deficiency relating to enhanced risk of MetS and type 2 DM, and to fatal cardiac events in CHF and an atherosclerotic, vascular calcification in HD patients. On the otherhand, severe and fatal hypermagnesemia is very rare, except for the condition associated with high dose administration of Mg, renal failure and an abnormally enhanced Mg absorption from damaged intestine in the mesenteric ischemia/infarction, severe constipation or ileus. In this paper, we conduct to review and discuss the pathophysiological and pathogenetical role of the abnormal Mg metabolism focused on Mg deficiency, and the protective and therapeutic significance of Mg administration in the MetS, type 2 DM, CHF and diabetic HD patients. PMID- 22846359 TI - [Magnesium metabolism and therapeutic strategy in cardiovascular disease]. AB - Many epidemiological and clinical analysis have reported the relation between Mg and cardiovascular disease. Hypomagnesemia may be triggering mechanisms for ischemic heart disease, arrhythmias after open heart surgery, serious arrhythmias such as Torsades de Pointes (TdP) , and the negative feed back in congestive heart failure. Supplemental and therapeutic Mg infusion have been reported to reduce the mortality in acute myocardial infarction and having the cardioprotective effect after infarction (controversial) . It is also reported to reduce the incidence of arrhythmias after heart surgery, terminate the serious arrhythmias such as TdP, and improve the negative feed back in congestive heart failure. Magnesium metabolisms in cardiovascular disease are not necessarily clear. We expect the precise analysis of Mg actions and attractive Mg therapy in clinical literature. PMID- 22846360 TI - [Shortage and metabolic disturbance of magnesium in diabetic patients and significance of magnesium replacement therapy]. AB - It is reported that shortage of oral magnesium intake increase the incidence of diabetes. In addition, magnesium replacement therapy improves insulin resistance and glycemic control. Low levels of magnesium in the venous blood induce the disturbances of auto-phosphylation on the insulin receptor and deteriorate insulin resistance. Since magnesium is closely related to evolution and development of metabolic syndrome including diabetes mellitus and so on, magnesium is expected as potentially effective ingredient of drug therapy in the future perspectives. PMID- 22846361 TI - [Magnesium disorder and its clinical significance in chronic kidney disease]. AB - Disturbance in mineral and bone metabolism is a common complication of chronic kidney disease (chronic kidney disease - mineral and bone disorder ; CKD-MBD) and closely related to morbidity and mortality. Because magnesium (Mg) is mainly excreted by kidney, Mg homeostasis is disturbed in CKD. Therefore Mg abnormalities in CKD may contribute to pathogenesis of CKD-MBD. The association of Mg with bone metabolism in general population has been demonstrated. There were reported an association with dietary Mg intake and bone mineral density (BMD) and an increased rate of bone loss with dietary Mg intake. In animal models, decreased bone formation, increased bone resorption, decreased bone mass, and increased skeletal fragility were reported in Mg deficiency. Although vascular calcification is frequently seen in CKD patients, contributing factors to vascular calcification are not fully clarified. Mg is considered "a natural calcium antagonist" , and Mg deficiency has been reported to be related to progression of atherosclerosis in several studies. In hemodialysis patients, lower Mg levels were also reported to be associated with increased atherosclerosis of the common carotid artery. Lower serum Mg levels were also found in hemodialysis patients with evidence of increasing arterial calcification. Several studies suggested that Mg plays an important role against the development of cardiovascular disease, infectious disease, and malignant neoplasia so that Mg may relate to mortality. In hemodialysis patients, we demonstrated that low serum Mg level was a predictor for increased mortality. PMID- 22846362 TI - [Magnesium disorder in metabolic bone diseases]. AB - Magnesium is abundantly distributed among the body. The half of the magnesium exists in the bone. In addition, magnesium is the second most abundant intracellular cation in vertebrates and essential for maintaining physiological function of the cells. Epidemiologic studies have demonstrated that magnesium deficiency is a risk factor for osteoporosis. The mechanism of bone fragility caused by magnesium deficiency has been intensely studied using animal models of magnesium deficiency. Magnesium deficiency causes decreased osteoblastic function and increased number of osteoclasts. Magnesium deficiency also accelerates mineralization in bone. These observations suggest that disturbed bone metabolic turnover and mineralization causes bone fragility. PMID- 22846363 TI - Sex-biased miRNA expression in Atlantic halibut (Hippoglossus hippoglossus) brain and gonads. AB - The role of miRNA in fish sexual development is not elucidated yet. We profiled miRNAs in gonads and brains of Atlantic halibut using SOLiD sequencing technology. We found tissue- and sexually dimorphic expression of several miRNAs, including miR-29a, miR-34, miR-143, miR-145, miR-202-3p, miR-451, and miR-2188. miR-9 and miR-202 were abundant in brain and gonads, respectively. In the next step, we selected some miRNAs showing differential expression patterns between sexes and performed RT-qPCR on 3 age groups: juveniles, 3-year-, and 5-year-olds. In brains, miR-451 was significantly down-regulated in juveniles compared to adults. let-7a, miR-143, and miR-202-3p were up-regulated in gonads of mature males compared to immature females at the same age. We investigated the effect of suppressing aromatase cytochrome P450 enzyme on miRNA expression at the onset of sex differentiation through masculinization with Fadrozole or 17-alpha methyltestosterone. We found significant differences in miRNA expression between masculinized individuals and untreated controls. miR-202-3p was significantly down-regulated in female juveniles compared to male juveniles. The expression levels of let-7a and miR-451 were restored after termination of the masculinization treatment. Our data give a first insight into miRNA involvement in sexual development in teleosts. PMID- 22846364 TI - Identification of novel transcripts deregulated in buccal cancer by RNA-seq. AB - The differential transcriptome analysis provides better understanding of molecular pathways leading to cancer, which in turn allows designing the effective strategies for diagnosis, therapeutic intervention and prediction of therapeutic outcome. This study describes the transcriptome analysis of buccal cancer and normal tissue by CLC Genomics Workbench from the data generated by Roche's 454 sequencing platform, which identified total of 1797 and 2655 genes uniquely expressed in normal and cancer tissues, respectively with 2466 genes expressed in both tissues. Among the genes expressed in both tissues, 1842 were up-regulated whereas 624 were down-regulated in cancer tissue. Besides transcripts known to be involved in cancer, this study led to the identification of novel transcripts, with significantly altered expression in buccal cancer tissue, providing potential targets for diagnosis and cancer therapeutics. The functional categorization by the KEGG pathway and gene ontology analysis revealed enrichment of differentially expressed transcripts to various pathways leading to cancer, including the p53 signaling pathway. Moreover, the gene ontology analysis unfolded suppression of transcripts involved in actin mediated cell contraction process. The down-regulation of four of these transcripts MYL1, ACTA1, TCAP and DESMIN in buccal cancer were further supported by quantitative PCR signifying its possible implication in the cancer progression. PMID- 22846365 TI - Characterization of the variable 3' UTR and expression of the two intron containing KIN transcripts from Capsella bursa-pastoris. AB - KIN genes are crucial members of the cold-regulated (COR) gene family, and are exclusively involved in normal developmental processes in many organs and respond to a variety of abiotic stresses in plants. Here, we cloned and sequenced not only two completely-spliced KIN transcripts (CbKIN1-S and CbKIN2-S), but also two intron-containing KIN transcripts (CbKIN1-U and CbKIN2-U), from Capsella bursa pastoris, a widespread plant of the Brassicaceae family. The CbKIN1-U and CbKIN2 U transcripts each contained one additional intron in the coding region compared to the corresponding CbKIN1-S and CbKIN2-S transcripts. In addition, the two intron-containing KIN transcripts were found by rapid amplification of cDNA 3' ends (3' RACE) analysis with specific primers to have variable 3' untranslated regions (3' UTRs). We also analyzed CbKIN1-U and CbKIN2-U levels in different organs and embryonic stages by quantitative polymerase chain reaction (qPCR). They were found to be expressed in middle-stage embryos and flowers. After abscisic acid (ABA) treatment, CbKIN1-U and CbKIN2-U showed strong responses in young leaves and weak responses in flowers. Levels of the two intron-containing KIN transcripts were markedly increased in young leaves when plants were exposed to cold and heat stress. Both of them showed stronger responses to ABA treatment and cold stress than that to heat stress. CbKIN1-U and CbKIN2-U share similar gene expression profiles in development and in response to exposure to different stresses, suggesting that they probably play similar biological roles in C. bursa pastoris. PMID- 22846366 TI - Gene expression pattern of myosin Va during spermatogenesis of Chinese mitten crab, Eriocheir sinensis. AB - Myosin Va is an F-actin dependent molecular motor with multiple functions that are essential for acrosome formation in mouse spermiogenesis. The spermatozoon of the crab has a complicated acrosome surrounded by a cup-shaped nucleus. In the present study, the myosin Va cDNA was cloned from the testis of the Chinese mitten crab Eriocheir sinensis using degenerate PCR and rapid amplification of cDNA ends (RACE). The myosin Va cDNA consists of a 125 bp 5'-untranslated region (5' UTR), a 5331 bp open reading frame (ORF) and a 590 bp 3' UTR. The putative myosin Va protein contains the head domain, neck domain and tail domain. Multiple alignment and phylogenetic tree showed that E. sinensis myosin Va is more closely related to the vertebrate myosin Va than to the invertebrate myosin V. E. sinensis myosin Va was expressed in various tissues. In situ hybridization demonstrated that myosin Va mRNA is located in the entire process of spermatogenesis. Quantitative real-time PCR indicated that the expression level at the mitotic and meiotic phases is higher than the spermiogenesis phase. Taken together, our work suggests that myosin Va may function in E. sinensis spermatogenesis. PMID- 22846367 TI - New features of Asian Crassostrea oyster mitochondrial genomes: a novel alloacceptor tRNA gene recruitment and two novel ORFs. AB - A feasible way to perform evolutionary analyses is to compare characters divergent enough to observe significant differences, but sufficiently similar to exclude saturation of the differences that occurred. Thus, comparisons of invertebrate mitochondrial (mt) genomes at low taxonomic levels can be extremely helpful in investigating patterns of variation and evolutionary dynamics of genomes, as intermediate stages of the process may be identified. Fortunately, in this study, we newly sequenced the mt genome of the eighth member of Asian Crassostrea oysters which can provide necessary intermediate characters for us to believe that the variation of Crassostrea mt genomes is considerably greater than previously acknowledged. Several new features of Asian Crassostrea oyster mitochondrial genomes were revealed, and our results are particularly significant as they 1) suggest a novel model of alloacceptor tRNA gene recruitment, namely "vertical" tRNA gene recruitment, which can be successfully used to explain the origination of the unusually additional trnK and trnQ genes (annotated as trnK(2) and trnQ(2) respectively) in the mt genomes of the five Asian oysters, and we speculate that this recruitment progress may be a common phenomenon in the evolution of the tRNA multigene family; 2) reveal the existence of two additional, lineage-specific, mtDNA-encoded genes that may originate from duplication of nad2 followed by rapid evolutionary change. Each of these two genes encodes a unique amino terminal signal peptide, thus each might possess an unknown function; and 3) identify for the first time the atp8 gene in oysters. The present study thus gives further credence to the comparison of congeneric bivalves as a meaningful strategy to investigate mt genomic evolutionary trends in genome organization, tRNA multigene family, and gene loss and/or duplication that are difficult to undertake at higher taxonomic levels. In particular, our study provides new evidence for the identification and characterization of ORFs in the "non-coding region" of animal mt genomes. PMID- 22846368 TI - Characterization and evolution of 5' and 3' untranslated regions in eukaryotes. AB - Untranslated regions (UTRs) in eukaryotes play a significant role in the regulation of translation and mRNA half-life, as well as interacting with specific RNA-binding proteins. However, UTRs receive less attention than more crucial elements such as genes, and the basic structural and evolutionary characteristics of UTRs of different species, and the relationship between these UTRs and the genome size and species gene number is not well understood. To address these questions, we performed a comparative analysis of 5' and 3' untranslated regions of different species by analyzing the basic characteristics of 244,976 UTRs from three eukaryote kingdoms (Plantae, Fungi, and Protista). The results showed that the UTR lengths and SSR frequencies in UTRs increased significantly with increasing species gene number while the length and G+C content in 5' UTRs and different types of repetitive sequences in 3' UTRs increased with the increase of genome size. We also found that the sequence length of 5' UTRs was significantly positively correlated with the presence of transposons and SSRs while the sequence length of 3' UTRs was significantly positively correlated with the presence of tandem repeat sequences. These results suggested that evolution of species complexity from lower organisms to higher organisms is accompanied by an increase in the regulatory complexity of UTRs, mediated by increasing UTR length, increasing G+C content of 5' UTRs, and insertion and expansion of repetitive sequences. PMID- 22846369 TI - Evaluation of the vaccination efficacy against H5N1 in domestic poultry in the Red River Delta in Vietnam. AB - The domestic poultry population in Vietnam has been vaccinated against highly pathogenic avian influenza (HPAI) H5N1 since 2005. Since then, outbreaks have continued to occur without a clear understanding of the mechanisms involved. The general objective of this study was to understand the epidemiology of the disease in the context of vaccination and to draw some conclusions about vaccination efficacy in the domestic poultry population of the Red River Delta area. Five cross-sectional surveys to measure the serological and virological prevalence in vaccinated and unvaccinated poultry were performed from the end of 2008 to June 2010. The global seroprevalence was 24% (95% confidence interval 19.9-28.2). Determinants of vaccine immunogenicity were identified separately in chickens and ducks as well as determinants of the seroconversion in unvaccinated birds. The results highlight the difficulties in maintaining good flock immunity in poultry populations using inactivated vaccine in the field with two vaccination rounds per year, and in preventing circulation of virus in co-existing unvaccinated poultry. PMID- 22846370 TI - High prevalence of overweight and obesity in females with phenylketonuria. AB - The primary treatment for phenylketonuria (PKU) is a low phenylalanine diet together with an amino acid-based, phenylalanine-free formula. Thus, PKU patients tend to consume a diet enriched in carbohydrates which could predispose to obesity. Studies in the 1980s and 1990s demonstrated that school-age phenylketonuria (PKU) patients have a higher mean body weight compared to a control population. However, no recent studies in the United States PKU population have examined whether this trend has persisted or whether adolescents are also affected. To investigate whether pediatric PKU populations (ages 2-20 years) in two major metropolitan areas of the United States (Cleveland, OH and Houston, TX) have a higher than expected percentage of overweight (BMI>=85th percentile) relative to the general population in the United States (NHANES), a retrospective chart review of PKU patients born between 1990 and 2008 and followed in Cleveland, OH (Rainbow Babies and Children's Hospital/University Hospitals Case Medical Center) and in Houston, TX (Texas Children's Hospital) was performed. Based on data from the U.S., 40% of pediatric PKU patients were overweight or obese. However, the percentage of overweight females (55%) and obese females (33%) is 1.8* and 2.1* higher respectively than expected based on comparison data from U.S. children. Further studies are necessary to identify potential strategies for prevention of excessive weight gain in children with PKU, especially in females. PMID- 22846371 TI - Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying. AB - BACKGROUND/AIMS: In this crossover study, we investigated whether nizatidine, a H(2)-receptor antagonist, can alleviate clinical symptoms and gastric emptying in patients with Rome III-based functional dyspepsia (FD) with or without impaired gastric emptying. METHODS: We enrolled 30 patients presenting with FD symptoms (epigastric pain syndrome, n = 6; postprandial distress syndrome, n = 24). Rome III-based FD patients were treated with nizatidine (300 mg/day) or placebo for 4 weeks in a crossover trial. Gastric motility was mainly evaluated with the T(max) value using the (13)C-acetate breath test. Meal-related symptoms were defined as postprandial fullness and early satiation. Gastroesophageal symptom was defined as a burning feeling rising from the stomach or lower chest up toward the neck. Acylated- and desacylated ghrelin levels were evaluated by the ELISA method. Clinical symptoms, gastric emptying and ghrelin levels were evaluated at three different points during the study (pretreatment, after 4 weeks former treatment and after 4 weeks later treatment). The primary end point of this study was to determine whether nizatidine would improve clinical symptoms and gastric emptying in FD patients with or without impaired gastric emptying via affecting ghrelin levels. RESULTS: Meal-related symptoms of the patients treated with nizatidine improved significantly (21/30; 70%) compared to those treated with placebo (3/30; 10%). In addition, nizatidine treatment also significantly improved gastroesophageal symptoms (16/30; 53%) compared to those treated with placebo (0/30; 0%). Nizatidine treatment in patients with FD accompanied by impaired gastric emptying significantly improved clinical symptoms and T(max) value as a marker of gastric emptying (10/11, 91%; 9/11, 82%) compared to placebo therapy, respectively. There were no significant differences in ghrelin levels between nizatidine treatment and placebo therapy. CONCLUSION: Nizatidine administration significantly improved both gastric emptying and clinical symptoms in FD patients with impaired gastric emptying. PMID- 22846372 TI - Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective. AB - The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals. It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system. PMID- 22846373 TI - Nanotechnology: from fundamental concepts to clinical applications for healthy aging. PMID- 22846374 TI - Assessment of bone graft incorporation by 18 F-fluoride positron-emission tomography/computed tomography in patients with persisting symptoms after posterior lumbar interbody fusion. AB - BACKGROUND: Posterior lumbar interbody fusion (PLIF) is a method that allows decompression of the spinal canal and nerve roots by laminectomy combined with fusion by means of intervertebral cages filled with bone graft and pedicle screw fixation. Conventional imaging techniques, such as plain radiography and computed tomography (CT), have limitations to assess bony fusion dynamics. METHODS: In 16 PLIFs of 15 patients with persisting symptoms, positron-emission tomography (PET)/CT scans were made 60 min after intravenous administration of 156 to 263 MBq of 18 F-fluoride, including 1-mm sliced, high-dose, non-contrast-enhanced CT scanning. Maximal standard uptake values (SUVmax) of various regions were calculated and correlated with abnormalities on CT. RESULTS: Subsidence of the cages into the vertebral endplates was the most frequently observed abnormality on CT (in 16 of 27 or 59% of evaluable endplates). Endplate SUVmax values were significantly higher for those patients with pronounced (p < 0.0001) or moderate (p < 0.013) subsidence as compared to those with no subsidence. Additionally, a significant correlation between vertebral and ipsilateral pedicle screw entrance SUVmax values (p < 0.009) was found, possibly indicating posterior transmission of increased bone stress. In our patient group, intercorporal fusion was seen on CT in 63% but showed no correlation to intercorporal SUVmax values. CONCLUSIONS: With the use of 18 F-fluoride PET/CT, intervertebral cage subsidence appeared to be a prominent finding in this patient group with persisting symptoms, and highly correlating with the degree of PET hyperactivity at the vertebral endplates and pedicle screw entry points. Further study using 18 F-fluoride PET/CT should specifically assess the role of metabolically active subsidence in a prospective patient group, to address its role in nonunion and as a cause of persisting pain. PMID- 22846375 TI - Risk factors of brain metastases in completely resected pathological stage IIIA N2 non-small cell lung cancer. AB - BACKGROUND: Brain metastases (BM) is one of the most common failures of locally advanced non-small cell lung cancer (LA-NSCLC) after combined-modality therapy. The outcome of trials on prophylactic cranial irradiation (PCI) has prompted us to identify the highest-risk subset most likely to benefit from PCI. Focusing on patients with completely resected pathological stage IIIA-N2 (pIIIA-N2) NSCLC, we aimed to assess risk factors of BM and to define the highest-risk subset. METHODS: Between 2003 and 2005, the records of 217 consecutive patients with pIIIA-N2 NSCLC in our institution were reviewed. The cumulative incidence of BM was estimated using the Kaplan-Meier method, and differences between the groups were analyzed using log-rank test. Multivariate Cox regression analysis was applied to assess risk factors of BM. RESULTS: Fifty-three (24.4 %) patients developed BM at some point during their clinical course. On multivariate analysis, non-squamous cell cancer (relative risk [RR]: 4.13, 95 % CI: 1.86-9.19; P = 0.001) and the ratio of metastatic to examined nodes or lymph node ratio (LNR) >= 30 % (RR: 3.33, 95 % CI: 1.79-6.18; P = 0.000) were found to be associated with an increased risk of BM. In patients with non-squamous cell cancer and LNR >= 30 %, the 5-year actuarial risk of BM was 57.3 %. CONCLUSIONS: In NSCLC, patients with completely resected pIIIA-N2 non-squamous cell cancer and LNR >= 30 % are at the highest risk for BM, and are most likely to benefit from PCI. Further studies are warranted to investigate the effect of PCI on this subset of patients. PMID- 22846376 TI - Steroidal saponins with antimicrobial activity from stems and leaves of Paris polyphylla var. yunnanensis. AB - Rhizoma Paridis, the root of Paris polyphylla var. yunnanensis (Trilliaceae), is a Chinese traditional medicine, which resources become less and less. However, the aerial parts of this herb, which can regenerate every year, were discarded. In order to expand the resources, detailed chemical investigation on the stems and leaves of Paris polyphylla var. yunnanensis led to isolation of one sapogenin and 24 steroidal saponins (1-25), including 6 new glycosides, named chonglouosides SL-1-SL-6 (1-6). Their structures were elucidated on the basis of detailed analyses of their 1D and 2D NMR spectra and acid hydrolysis. Among them, compounds 3 and 4 are the first 23,27-dihydroxydiosgenin saponin having a sugar chain attached to C-23 or C-27, while compound 6 is the first 27 hydroxyruscogenin glycoside bearing 1, 27-di-O-sugar chains. The known compounds 10, 12, 14, 19, 20, 22, and 25 were isolated from the genus Paris for the first time. Antimicrobial testing activities of the selected compounds showed that compound 2, 3, 6, 8, 9, 11, 13, 17, 18, 21, and 24 were active against Propionibacterium acnes with MIC values of 62.5, 62.5, 3.9, 16.5, 17.2, 7.8, 39.0, 17.2, 31.3, 62.5, and 31.3 MUg/ml, respectively. PMID- 22846377 TI - Effect of oxidative stress on UDP-glucuronosyltransferases in rat astrocytes. AB - The present work reports data regarding effects of an induced oxidative stress on the mainly expressed isoforms of UDP-glucuronosyltransferases (UGTs) in the brain. UGT1A6 and UGT1A7 expression and enzymatic activities toward the 1 naphthol were analyzed in rat cultured astrocytes following the exposure for 48 h to redox-cycling xenobiotic compounds such as quinones and bipyridinium ions. The expression of NADPH:cytochrome P450 reductase and NAD(P)H:quinone oxidoreductase 1 (NQO1) was also investigated. Oxidative stress induced significant deleterious changes in astrocyte morphology, decreased cell viability and inhibited catalytic function of UGTs as a result of protein oxidation. Alternatively, in the surviving impaired astrocytes, oxidative conditions induced a significant overactivity and overexpression of xenobiotic detoxification enzymes, as adaptive response. These effects were significantly prevented by the presence of melatonin, suggesting its direct antioxidant action on reactive oxygen species, reflected further on the glucuronidation activity and transcriptional regulation of both UGT1A6 and UGT1A7. Results show that both catalytic properties of UGTs and the expression of UGT1A6, UGT1A7, NQO1 and NADPH:cytochrome P450 reductase in rat astrocytes are greatly influenced by the pro-oxidative environment. In conclusion, an experimental increase in oxidative cellular status could have both immediate and long term consequences on detoxification enzymatic system activity and expression. PMID- 22846378 TI - Low, complex and probably reticulated chromosome evolution of Sciuromorpha (Rodentia) and Lagomorpha. AB - Lagomorpha (rabbits and pikas) and Sciuromorpha (squirrels) are grouped in the Glires superorder. Their chromosome diversification, since their separation from the eutherian mammalian common ancestor, was characterized by a low rate of chromosome rearrangements. Consequently, the structure of some chromosomes was either conserved or only slightly modified, making their comparison easy at the genus, family and even order level. Interspecific in situ hybridization (Zoo FISH) largely corroborates classical cytogenetic data but provides much more reliability in comparisons, especially for distant species. We reconstructed common ancestral karyotypes for Glires, Lagomorpha, Sciuromorpha, and Sciuridae species, and then, determined the chromosome changes separating these ancestors from their common eutherian ancestor. We propose that reticulated evolution occurred during the diversification of Glires, which implies that several pericentric inversions and Robertsonian translocations were conserved in the heterozygous status for an extensive period. Finally, among Lagomorpha and Sciuromorpha, we focused on Leporidae and Sciuridae chromosome evolution. In the various attempts to establish dichotomic evolutionary schemes, it was necessary to admit that multiple homoplasies (convergent and reverse rearrangements) occurred in Sciuridae and in a lesser degree, in Leporidae. In Leporidae, additional rearrangements were sufficient to propose a resolved phylogeny. However, a resolved phylogeny was not possible for Sciuridae because most of the rearrangements occurred in terminal branches. We conclude that a reticulated evolution took place early during the evolution of both families and lasted longer in Sciuridae than in Leporidae. In Sciuridae, most chromosome rearrangements were pericentric inversions involving short fragments. Such rearrangements have only mild meiotic consequences, which may explain the long persistence of the heterozygous status characterizing reticulated evolution. PMID- 22846379 TI - Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT) has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. METHODS: A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. DISCUSSION: The significance of the cognitive psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT. TRIAL REGISTRATION: NCT00856102. PMID- 22846380 TI - An audit to assess the perspectives of U.S. wound care specialists regarding the importance of proteases in wound healing and wound assessment. AB - Chronic wounds represent an aberrant biochemistry that creates a toxic proteolytic milieu which can be detrimental to the healing process. Rebalancing the wound microenvironment and addressing elevated protease activity (EPA) could therefore help facilitate healing. To understand how clinicians currently diagnose and manage excessive proteolytic activity, 183 survey responses from US wound specialists were collated and analysed to find out their perceptions on the role of proteases. The majority of respondents (>98%) believed proteases were important in wound healing and that a point-of-care (POC) protease test could be useful. This study yielded a low response rate (7.1%, n = 183); however, there were adequate data to draw significant conclusions. Specialists perceived that fibrin, slough, granulation tissue and rolled wound edges could indicate EPA. About 43% of respondents, however, failed to give a correct response when asked to review photographs to determine if excessive protease activity was present, and the perceived visual signs for EPA did not correlate with the wounds that had EPA; no statistical differences between professions were observed. Respondents chose debridement, wound cleansing and advanced therapies as important in reducing excessive protease activity. It was concluded that specialists have a need for POC diagnostic tests. On the basis of the responses to wound photos, it was determined that there were no visual cues clinicians could use in determining excessive protease activity. Additional research is recommended to evaluate the efficacy of a POC diagnostic test for protease activity and the treatments and therapies applied when EPA is found. PMID- 22846381 TI - Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. AB - BACKGROUND: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. OBJECTIVE: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. METHODS: In this open-label, multicenter phase III study, 87 patients with PI aged >=2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. RESULTS: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. CONCLUSION: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates. PMID- 22846382 TI - Elevated serum osteopontin level is associated with blood eosinophilia and asthma comorbidity in patients with allergic rhinitis. PMID- 22846384 TI - Ingestion of a single serving of saury alters postprandial levels of plasma n-3 polyunsaturated fatty acids and long-chain monounsaturated fatty acids in healthy human adults. AB - BACKGROUND: Saury oil contains considerable amounts of n-3 polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) with long aliphatic tails (>18C atoms). Ingestion of saury oil reduces the risk of developing metabolic syndrome concomitant with increases in n-3 PUFA and long-chain MUFA in plasma and organs of mice. We therefore evaluated changes in postprandial plasma fatty acid levels and plasma parameters in healthy human subjects after ingestion of a single meal of saury. FINDINGS: Five healthy human adults ingested 150 g of grilled saury. Blood was collected before the meal and at 2, 6, and 24 hr after the meal, and plasma was prepared. Plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and long-chain MUFA (C20:1 and C22:1 isomers combined) increased significantly throughout the postprandial period compared with the pre meal baseline. Postprandial plasma insulin concentration increased notably, and plasma levels of glucose and free fatty acids decreased significantly and subsequently returned to the pre-meal levels. CONCLUSIONS: Our study suggests that a single saury meal may alter the postprandial plasma levels of n-3 PUFA and long-chain MUFA in healthy human subjects. PMID- 22846383 TI - Expression of canonical WNT/beta-CATENIN signaling components in the developing human lung. AB - BACKGROUND: The WNT/beta-CATENIN signaling cascade is crucial for the patterning of the early lung morphogenesis in mice, but its role in the developing human lung remains to be determined. In this study, expression patterns of canonical WNT/beta-CATENIN signaling components, including WNT ligands (WNT2, WNT7B), receptors (FZD4, FZD7, LRP5, LRP6), transducers (DVL2, DVL3, GSK-3beta, beta CATENIN, APC, AXIN2), transcription factors (TCF4, LEF1) and antagonists (SOSTDC1) were examined in human embryonic lung at 7, 12, 17 and 21 weeks of gestation (W) by real-time qRT-PCR and in situ hybridization. RESULTS: qRT-PCR analysis showed that some of these components were gradually upregulated, while some were significantly downregulated from the 7 W to the 12 W. However, most components reached a high level at 17 W, with a subsequent decrease at 21 W. In situ hybridization showed that the canonical WNT ligands and receptors were predominantly located in the peripheral epithelium, whereas the canonical WNT signal transducers and transcription factors were not only detected in the respiratory epithelium, but some were also scattered at low levels in the surrounding mesenchyme in the developing human lung. Furthermore, Western blot, qRT-PCR and histological analysis demonstrated that the beta-CATENIN-dependent WNT signaling in embryonic human lung was activated in vitro by CHIR 99021 stimulation. CONCLUSIONS: This study of the expression patterns and in vitro activity of the canonical WNT/beta-CATENIN pathways suggests that these components play an essential role in regulation of human lung development. PMID- 22846385 TI - Factors associated with being lost to follow-up before completing tuberculosis treatment: analysis of surveillance data. AB - Completion of treatment is key to tuberculosis control. Using national surveillance data we assessed factors associated with tuberculosis patients being lost to follow-up before completing treatment ('lost'). Patients reported in England, Wales and Northern Ireland between 2001 and 2007 who were lost 12 months after beginning treatment were compared to those who completed, or were still on treatment, using univariable and multivariable logistic regression. Of 41 120 patients, men [adjusted odds ratio (aOR) 1.29; 95% confidence interval (CI) 1.23 1.35], 15- to 44-year-olds (P<0.001), and patients with pulmonary sputum smear positive disease (aOR 1.25, 95% CI 1.12-1.45) were at higher risk of being lost. Those recently arrived in the UK were also at increased risk, particularly those of the White ethnic group (aOR 6.39, 95% CI 4.46-9.14). Finally, lost patients had a higher risk of drug resistance (aOR 1.41, 95% CI 1.17-1.69). Patients at risk of being lost require enhanced case management and novel case retention methods are needed to prevent this group contributing towards onward transmission. PMID- 22846386 TI - High-throughput mammographic-density measurement: a tool for risk prediction of breast cancer. AB - INTRODUCTION: Mammographic density (MD) is a strong, independent risk factor for breast cancer, but measuring MD is time consuming and reader dependent. Objective MD measurement in a high-throughput fashion would enable its wider use as a biomarker for breast cancer. We use a public domain image-processing software for the fully automated analysis of MD and penalized regression to construct a measure that mimics a well-established semiautomated measure (Cumulus). We also describe measures that incorporate additional features of mammographic images for improving the risk associations of MD and breast cancer risk. METHODS: We randomly partitioned our dataset into a training set for model building (733 cases, 748 controls) and a test set for model assessment (765 cases, 747 controls). The Pearson product-moment correlation coefficient (r) was used to compare the MD measurements by Cumulus and our automated measure, which mimics Cumulus. The likelihood ratio test was used to validate the performance of logistic regression models for breast cancer risk, which included our measure capturing additional information in mammographic images. RESULTS: We observed a high correlation between the Cumulus measure and our measure mimicking Cumulus (r = 0.884; 95% CI, 0.872 to 0.894) in an external test set. Adding a variable, which includes extra information to percentage density, significantly improved the fit of the logistic regression model of breast cancer risk (P = 0.0002). CONCLUSIONS: Our results demonstrate the potential to facilitate the integration of mammographic density measurements into large-scale research studies and subsequently into clinical practice. PMID- 22846387 TI - Fine-needle aspiration cytology of hyalinizing trabecular adenoma of the thyroid in a patient with Hashimoto's thyroiditis: a case report. AB - BACKGROUND: Hyalinizing trabecular adenoma (HTA) is a rare benign epithelial tumor of the thyroid which shows a prominent trabecular growth pattern and stromal hyalinization. On fine-needle aspiration cytology, HTA is frequently misdiagnosed as either papillary thyroid carcinoma (PTC) or medullary carcinoma. We present both the cytologic and the histopathologic features of HTA in a patient with Hashimoto's thyroiditis. CASE: Cytologically, the tumor cells showed a low nucleocytoplasmic ratio and eccentrically located nuclei, nuclear grooves, and eosinophilic pseudoinclusions. Lymphocyte-dominant inflammatory cells were present in the background, raising the possibility of thyroiditis. Histologically, the tumor was a 0.5 * 0.4 cm-sized mass and showed a trabecular and nested pattern of tumor cells separated by scant hyaline material in the background of Hashimoto's thyroiditis. Tumor cells showed abundant eosinophilic granular cytoplasms, nuclear grooves, and pseudoinclusions, as well as immunoreactivity for MIB-1 on the cell membrane. We diagnosed this lesion as HTA in a patient with Hashimoto's thyroiditis. CONCLUSION: Although distinction of HTA from PTC in the cytologic specimen is difficult, especially in cases associated with Hashimoto's thyroiditis, cohesive cell aggregates with a low nucleocytoplasmic ratio and eccentrically located nuclei may be helpful to consider the possibility of HTA. PMID- 22846388 TI - Serum levels of soluble adhesion molecules as prognostic factors for acute liver failure. AB - BACKGROUND/AIMS: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). METHODS: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM 3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. RESULTS: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. CONCLUSION: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF. PMID- 22846390 TI - Segmental curvilinear distraction osteogenesis. AB - Curvilinear distraction is currently under investigation to reconstruct curved maxillofacial bone defects. However, previous studies have revealed the discrepancy between the contour of the regenerated bone in the distraction gap and the curvilinear pathway of the transport disc. We hypothesize that the discrepancy is because of the conflict of the distraction vector and the strain vector during the consolidation. In curvilinear distraction osteogenesis, the distraction vector varies, while the strain vector during the consolidation phase is fixed-linear, from the beginning to the end of the distraction pathway. Here we bring forward a solution of segmental curvilinear distraction osteogenesis to divide the curvilinear distraction into several segments, with respective consolidation for each distraction gap. If this hypothesis is verified, the segmental distraction curvilinear distraction will benefit the reconstruction of complicated long-range maxillofacial bone defects. PMID- 22846391 TI - Transcriptome analysis of the human T lymphocyte cell line Jurkat and human peripheral blood mononuclear cells exposed to deoxynivalenol (DON): New mechanistic insights. AB - Deoxynivalenol (DON) or vomitoxin is a commonly encountered type-B trichothecene mycotoxin, produced by Fusarium species predominantly found in cereals and grains. DON is known to exert toxic effects on the gastrointestinal, reproductive and neuroendocrine systems, and particularly on the immune system. Depending on dose and exposure time, it can either stimulate or suppress immune function. The main objective of this study was to obtain a deeper insight into DON-induced effects on lymphoid cells. For this, we exposed the human T-lymphocyte cell line Jurkat and human peripheral blood mononuclear cells (PBMCs) to various concentrations of DON for various times and examined gene expression changes by DNA microarray analysis. Jurkat cells were exposed to 0.25 and 0.5MUM DON for 3, 6 and 24h. Biological interpretation of the microarray data indicated that DON affects various processes in these cells: It upregulates genes involved in ribosome structure and function, RNA/protein synthesis and processing, endoplasmic reticulum (ER) stress, calcium-mediated signaling, mitochondrial function, oxidative stress, the NFAT and NF-kappaB/TNF-alpha pathways, T cell activation and apoptosis. The effects of DON on the expression of genes involved in ER stress, NFAT activation and apoptosis were confirmed by qRT-PCR. Other biochemical experiments confirmed that DON activates calcium-dependent proteins such as calcineurin and M-calpain that are known to be involved in T cell activation and apoptosis. Induction of T cell activation was also confirmed by demonstrating that DON activates NFATC1 and induces its translocation from the cytoplasm to the nucleus. For the gene expression profiling of PBMCs, cells were exposed to 2 and 4MUM DON for 6 and 24h. Comparison of the Jurkat microarray data with those obtained with PBMCs showed that most of the processes affected by DON in the Jurkat cell line were also affected in the PBMCs. PMID- 22846389 TI - The Irritable Bowel Syndrome Outcome Study (IBSOS): rationale and design of a randomized, placebo-controlled trial with 12 month follow up of self- versus clinician-administered CBT for moderate to severe irritable bowel syndrome. AB - Irritable bowel syndrome is a common, oftentimes disabling, gastrointestinal disorder whose full range of symptoms has no satisfactory medical or dietary treatment. One of the few empirically validated treatments includes a specific psychological therapy called cognitive behavior therapy which, if available, is typically administered over several months by trained practitioners in tertiary care settings. There is an urgent need to develop more efficient versions of CBT that require minimal professional assistance but retain the efficacy profile of clinic based CBT. The Irritable Bowel Syndrome Outcome Study (IBSOS) is a multicenter, placebo-controlled randomized trial to evaluate whether a self administered version of CBT is, at least as efficacious as standard CBT and more efficacious than an attention control in reducing core GI symptoms of IBS and its burden (e.g. distress, quality of life impairment, etc.) in moderately to severely affected IBS patients. Additional goals are to assess, at quarterly intervals, the durability of treatment response over a 12 month period; to identify clinically useful patient characteristics associated with outcome as a way of gaining an understanding of subgroups of participants for whom CBT is most beneficial; to identify theory-based change mechanisms (active ingredients) that explain how and why CBT works; and evaluate the economic costs and benefits of CBT. Between August 2010 when IBSOS began recruiting subjects and February 2012, the IBSOS randomized 171 of 480 patients. Findings have the potential to improve the health of IBS patients, reduce its social and economic costs, conserve scarce health care resources, and inform evidence-based practice guidelines. PMID- 22846392 TI - A short introduction to cytogenetic studies in mammals with reference to the present volume. AB - Genome diversity has long been studied from the comparative cytogenetic perspective. Early workers documented differences between species in diploid chromosome number and fundamental number. Banding methods allowed more detailed descriptions of between-species rearrangements and classes of differentially staining chromosome material. The infusion of molecular methods into cytogenetics provided a third revolution, which is still not exhausted. Chromosome painting has provided a global view of the translocation history of mammalian genome evolution, well summarized in the contributions to this special volume. More recently, FISH of cloned DNA has provided details on defining breakpoint and intrachromosomal marker order, which have helped to document inversions and centromere repositioning. The most recent trend in comparative molecular cytogenetics is to integrate sequencing information in order to formulate and test reconstructions of ancestral genomes and phylogenomic hypotheses derived from comparative cytogenetics. The integration of comparative cytogenetics and sequencing promises to provide an understanding of what drives chromosome rearrangements and genome evolution in general. We believe that the contributions in this volume, in no small way, point the way to the next phase in cytogenetic studies. PMID- 22846393 TI - Population structure of Bactrocera dorsalis s.s., B. papayae and B. philippinensis (Diptera: Tephritidae) in southeast Asia: evidence for a single species hypothesis using mitochondrial DNA and wing-shape data. AB - BACKGROUND: Bactrocera dorsalis s.s. is a pestiferous tephritid fruit fly distributed from Pakistan to the Pacific, with the Thai/Malay peninsula its southern limit. Sister pest taxa, B. papayae and B. philippinensis, occur in the southeast Asian archipelago and the Philippines, respectively. The relationship among these species is unclear due to their high molecular and morphological similarity. This study analysed population structure of these three species within a southeast Asian biogeographical context to assess potential dispersal patterns and the validity of their current taxonomic status. RESULTS: Geometric morphometric results generated from 15 landmarks for wings of 169 flies revealed significant differences in wing shape between almost all sites following canonical variate analysis. For the combined data set there was a greater isolation-by-distance (IBD) effect under a 'non-Euclidean' scenario which used geographical distances within a biogeographical 'Sundaland context' (r(2) = 0.772, P < 0.0001) as compared to a 'Euclidean' scenario for which direct geographic distances between sample sites was used (r(2) = 0.217, P < 0.01). COI sequence data were obtained for 156 individuals and yielded 83 unique haplotypes with no correlation to current taxonomic designations via a minimum spanning network. beast analysis provided a root age and location of 540kya in northern Thailand, with migration of B. dorsalis s.l. into Malaysia 470kya and Sumatra 270kya. Two migration events into the Philippines are inferred. Sequence data revealed a weak but significant IBD effect under the 'non-Euclidean' scenario (r(2) = 0.110, P < 0.05), with no historical migration evident between Taiwan and the Philippines. Results are consistent with those expected at the intra-specific level. CONCLUSIONS: Bactrocera dorsalis s.s., B. papayae and B. philippinensis likely represent one species structured around the South China Sea, having migrated from northern Thailand into the southeast Asian archipelago and across into the Philippines. No migration is apparent between the Philippines and Taiwan. This information has implications for quarantine, trade and pest management. PMID- 22846394 TI - Current state of the art in laparoscopic colorectal surgery for cancer: Update on the multi-centric international trials. AB - Laparoscopic colectomy is now widely applied to cases of malignancy, supported by early data from several large randomized controlled trials. Long-term follow up is now available from those trials, supporting equivalency of cancer-free and overall survival for open and laparoscopic resections. This promising data has inspired further exploration of other applications of laparoscopic techniques, including use of single incision laparoscopy. This article reviews recent reports of long-term data for colorectal cancer resection from four randomized, prospective international trials. PMID- 22846395 TI - Quantitative approach using multiple single parameters versus visual assessment in dobutamine stress echocardiography. AB - BACKGROUND: A number of myocardial Doppler-derived velocity, strain myocardial imaging parameters (DMI) and speckle tracking imaging (STI) have been proposed for the quantification of myocardial ischemia during stress echocardiography. The purpose of the study was to identify the best single ultrasound quantitative parameter for prediction of significant coronary stenosis and compare it with visual assessment during dobutamine stress echocardiography (DSE). METHODS: Prospective analysis included data of 151 patients (age 61.8 +/- 9.2) who underwent dobutamine stress echocardiography for known (n = 35) or suspected coronary artery disease (CAD) (n = 36) or symptomatic chest pain (n = 80), excluding patients with previous myocardial infarction. Systolic, post-systolic and diastolic velocities, strain and strain rate parameters were obtained at rest and at peak dobutamine challenge. Derivative markers as E'/A' ratio, post systolic index and changes from rest to stress were calculated (98 parameters overall, predominantly longitudinal). Coronary angiography was chosen as reference method considering at least one stenosis >=70% per patient as significant CAD. The predictive value of quantitative parameters and wall motion score index (WMSI) was obtained using logistic regression and ROC analysis. RESULTS: The value of single parameters discriminated as independent predictors of CAD appeared to be modest (area under the curve [AUC] ranged from 0.63 to 0.72 for 16 PW-DMI, 12 CC-DMI and 12 STI markers), comparing to AUC of WMSI 0.88. Sensitivity, specificity and accuracy of visual DSE evaluation was 82.4% (95%CI 77.4%; 85.2%), 92.6% (95%CI 83.4%; 97.5%) and 86.0% (95%CI 79.5%; 89.6%), respectively, Youden index 0.75. Sensitivity, specificity and accuracy of single predictors ranged from 40.0% to 93.3% (95% CI 22.7%; 99.2%), from 34.2% to 88.7% (95% CI 25.6%; 94.1%) and from 45.8% to 80.0% (95% CI 37.5%; 87.2%) respectively, Youden index ranged from 0.20 to 0.52. CONCLUSIONS: Multiple single quantitative parameters showed limited predictive ability to identify significant coronary artery stenosis. Visual assessment of DSE appears to be more accurate than single velocity and strain/strain rate markers in the diagnosis of CAD. PMID- 22846397 TI - In vitro assessment of halobacterial gas vesicles as a Chlamydia vaccine display and delivery system. AB - Chlamydia trachomatis is the leading cause of bacterial sexually transmitted disease worldwide and while antibiotic treatment is effective in eliminating the pathogen, up to 70% of all infections are asymptomatic. Despite sustained efforts over the past 2 decades, an effective chlamydial vaccine remains elusive, due in large part to the lack of an effective delivery system. We explored the use of gas vesicles derived from Halobacterium salinarium as a potential display and delivery vehicle for chlamydial antigens of vaccine interest. Various size gene fragments coding for the major outer membrane protein (MOMP), outer membrane complex B (OmcB) and polymorphic outer membrane protein D (PompD) were integrated into and expressed as part of the gas vesicle protein C (gvpC) on the surface of these stable structures. The presence of the recombinant proteins was confirmed by Western blots probed using anti-gvpC and anti-Chlamydia antibodies as well as sera from Chlamydia-positive patients. Tissue culture evaluation revealed stability and a time-dependent degradation of recombinant gas vesicles (r-Gv) in human and animal cell lines. In vitro assessment using human foreskin fibroblasts (HFF) confirmed Toll-like receptor (TLR) 4 and 5 engagement by wild type and r Gv, leading to MyD88 activation, TNF-alpha, IL-6 and IL-12 production. The data suggest that r-GV could be an effective, naturally adjuvanting, time-release antigen delivery system for immunologically relevant Chlamydia vaccine antigens which are readily recognized by human immune sera. PMID- 22846396 TI - A non-adjuvanted whole-virus H1N1 pandemic vaccine is well tolerated and highly immunogenic in children and adolescents and induces substantial immunological memory. AB - This phase 1/2 open-label, randomized clinical study investigated the safety and immunogenicity of a non-adjuvanted, whole virus, Vero cell-derived H1N1 pandemic influenza vaccine (A/H1N1/California/07/2009) in children and adolescents (6 months to 17 years). Subjects were stratified by age (6-11 months, 12-35 months, 3-8 years, 9-17 years) to receive two vaccinations 21 days apart of either the 3.75 MUg or 7.5 MUg dose. A booster with a licensed trivalent seasonal (2010/2011) influenza vaccine was administered one year after the first vaccination to a subgroup that had previously received the 7.5 MUg dose. A single vaccination with the 7.5 MUg dose induced high seroprotection rates in all subjects, namely: 88.0% (9-17 years); 68.0% (3-8 years); 42.9% (12-35 months); and 50.0% (6-11 months). Following a second vaccination, seroprotection rates ranged from 84.2% to 100%. GMTs after two vaccinations with the 7.5 MUg dose (as determined by HI) were also substantial: reaching 210.0 (9-17 years), 196.2 (3-8 years), 118.9 (12-35 months) and 99.6 (6-11 months). Antibody persistence was demonstrated at 6 months (GMTs ranging from 65.6 to 212.8 with the 7.5 MUg dose) and at 12 months (GMTs ranging from 33.6 to 124.1 with the 7.5 MUg dose) after primary vaccination. The booster vaccination induced a strong response to the A/California/07/2009 strain, reaching 100% seroprotection in all age groups, with GMTs ranging from 640.0 to 886.3. The vaccine was well tolerated, inducing low adverse reaction rates (overall fever rate: 6% after the first vaccination; 7% after the second vaccination), even in young children. These data confirm that the H1N1 whole-virus Vero cell-derived pandemic influenza vaccine is suitable for use in children and adolescents; a 2-dose primary vaccination induces a memory response in a naive population that can be effectively boosted with the A/H1N1/California/07/2009 component of a seasonal influenza vaccine. ClinicalTrials.gov Identifier: NCT00976469. PMID- 22846398 TI - Clade analysis of enterohemorrhagic Escherichia coli serotype O157:H7/H- strains and hierarchy of their phylogenetic relationships. AB - Enterohemorrhagic Escherichia coli serotype O157:H7/H-(O157) strains isolated in Chiba prefecture, Japan, during 2002-2009 were studied by lineage, subgroup, cluster, and clade analysis. Lineage analysis of 470 O157 strains with no known epidemiological relationships using lineage specific polymorphism assay-6 showed that there were 242 lineage I strains, 160 lineage I/II strains, 67 lineage II strains, and 1 atypical strain. Clade analysis of these strains by single nucleotide polymorphism in eight loci showed that lineage I contained all the clade 1, clade 2, and clade 3 strains, and some of the clade 4/5 strains. In contrast, clade 7, clade 8, and the remaining clade 4/5 strains were divided between lineage I/II and II, and clade 6 was in lineage I/II, suggesting paraphyletic evolution of these lineages. Cluster and subgroup analysis of the stx phage insertion site showed that all lineage I strains were cluster 3 and all lineage I/II and II strains, with the exception of clade 9, were in cluster 1. Clade analysis also indicated that there were three phylogenetic groups of clade 4/5 strains: ancestral groups containing lineage I/IIand II strains and a descendant group containing lineages I. Analysis of stx2c gene distribution showed that stx2c was in ancestral clade 4/5 strains but not in descendant 4/5 strains, suggesting that the ancestral group may be clade 4 as reported by Manning et al. The results with the markers used in this study suggested that the hierarchy of O157 phylogenetic relationships was lineage as the upper level, followed by subgroup and then cluster, and clade as the lowest level. The need for refinement of clade definition and modification of the model of the O157 evolution have been discussed. PMID- 22846399 TI - Profile of patients presenting at a low vision clinic in a developing country. AB - BACKGROUND: Low vision is an important public health problem; however, very few low vision clinics are available to address the needs of low vision patients in most developing countries. The purpose of this study was to describe the characteristics of patients attending the low vision clinic of a Nigerian tertiary hospital. METHODS: This was a prospective cross sectional study of all new patients seen at the low vision clinic over a 36 month period. Patients were administered with a structured questionnaire, and were examined and tested with low vision devices by the attending low vision specialist. Information on the demographic and clinical characteristics of the patients was recorded. RESULTS: A total of 193 new patients seen during the period were studied. The mean age was 41.4 years, and their ages ranged between 6 and 90 years with a male to female ratio of 1.9:1. Majority (58%) were aged below 50 years, 23.3% were children (<= 15 years), while 21.8% were elderly patients (>= 65 years). The commonest cause of low vision was retinitis pigmentosa (16.6%); 14.5% had age related macular degeneration (ARMD); 9.8% had albinism; while only 1% had diabetic retinopathy. ARMD (45.2%) was the commonest cause in the elderly patients, while albinism (24.4%) and optic atrophy (24.4%) were the commonest in children. CONCLUSION: The demographic and clinical characteristics of low vision patients seen in this clinic are similar to that of patients in other developing countries, but different from those in developed countries. Elderly patients and females may be under-utilising low vision services. There is a need for further research into the determinants of low vision service utilisation in developing countries. This would further aid the planning and delivery of services to low vision patients in these countries. PMID- 22846400 TI - Dual-color system for simultaneously monitoring intracellular Ca(2+) and ATP dynamics. AB - Although Ca(2+) regulates energy metabolism through diverse pathways, there have been no methods to monitor both Ca(2+) dynamics and metabolic activity simultaneously. Here we report a novel system for simultaneously monitoring intracellular Ca(2+) and ATP levels using a blue-emitting photoprotein and a red emitting beetle luciferase. Using this system, we monitored the dynamic changes simultaneously in both intracellular Ca(2+) and ATP levels during chondrogenesis. We have found that both intracellular Ca(2+) and ATP levels oscillated and their oscillations have a nearly antiphase relationship with each other. The dual-color monitoring system is useful for studying the relationship between Ca(2+) dynamics and energy metabolic pathways. PMID- 22846401 TI - Can we measure brain efficiency? An empirical test with common marmosets (Callithrix jacchus). AB - Various measures of brain size correlate with cognitive performance; however, the fit is not perfect, which bears the question of whether brains also vary in efficiency. Such variation could be expected if a species faces constraints on brain enlargement, for example due to the impossibility of slowing down life history as a consequence of predator pressure, while simultaneously experiencing selective benefits from enhanced cognitive ability related to particular ecological or social conditions. Arguably, this applies to callitrichid monkeys and would lead to the prediction that their relatively small brains are particularly efficient in comparison to their sister taxa, Cebus. This study investigated whether callitrichids' cognitive performance is better than would be expected given their brain size rather than comparing absolute performance between the taxa. As a measure of cognitive performance, we used the reversal learning paradigm, which is reliably and closely associated with brain size across primate taxa, and assessed performance in this paradigm (transfer index) in 14 common marmosets (Callithrix jacchus) as representatives of the callitrichids. These marmosets were found to show higher performance than would be expected for their brain size, and this relative performance was also higher than the relative performance in capuchin monkeys. We outline how these effects may be due to the cooperative breeding system of the callitrichids, particularly the enhancement of behavioural and cognitive propensities associated with shared care and provisioning. PMID- 22846404 TI - Terminal restriction fragment length polymorphism analysis of the gut microbiota profiles of pediatric patients with inflammatory bowel disease. AB - BACKGROUND/AIM: We analyzed the fecal microbiota profiles of pediatric patients with inflammatory bowel disease. METHOD: Terminal restriction fragment length polymorphism analysis was performed in 10 fecal samples from Crohn's disease (CD), 14 samples from ulcerative colitis (UC) and 27 samples from healthy individuals. The bacterial diversity was evaluated by the Shannon diversity index. RESULT: In CD patients, a setting of similarity generated three major clusters. The majority of CD patients were classified into CD clusters I and II (9 out of 10), but the majority of healthy individuals (21 of 27) were classified into CD cluster III. In UC patients, a setting of similarity also generated three major UC clusters, but each cluster was not characteristic for UC patients or healthy individuals. The changes in simulated bacterial composition indicated that the class Clostridia, including the genus Faecalibacterium, was significantly decreased in CD patients as compared to UC patients and/or healthy individuals. The genus Bacteroides was also decreased as compared to healthy individuals. The bacterial diversity measured by the Shannon diversity index was significantly reduced in CD patients as compared to healthy individuals. CONCLUSION: The gut microbiota profile of pediatric CD patients was different from that of healthy children. PMID- 22846405 TI - A reliable option for wrist soft tissue defects: adipofascial flaps for immediate and late reconstruction. AB - Extensive volar injuries are common and devastating because of the long-term adhesion potency. The gliding effect of the adipose tissue is essential in preventing tendon adhesions after injury. In this study, we present the results of performing adipofascial flaps for the reconstruction of soft tissue defects following wrist trauma. The study included 15 patients. Adipofascial flaps were performed for immediate coverage of the tissue defect in 2 patients and for late adhesion-related problems in 13 patients. Flap dimensions varied from 8 * 14 to 8 * 20 cm. All but one of the flaps and skin grafts survived uneventfully. None of the patients, whether immediate or late, required another operation to address further adhesion problems. Since adipofascial flaps provide a gliding surface, they are a good choice for immediate coverage of soft tissue defects in the wrist that are not suitable for skin grafting alone as well as for late adhesion related problems. PMID- 22846406 TI - Blue light for infectious diseases: Propionibacterium acnes, Helicobacter pylori, and beyond? AB - Blue light, particularly in the wavelength range of 405-470 nm, has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. In addition, it is commonly accepted that blue light is much less detrimental to mammalian cells than ultraviolet irradiation, which is another light-based antimicrobial approach being investigated. In this review, we discussed the blue light sensing systems in microbial cells, antimicrobial efficacy of blue light, the mechanism of antimicrobial effect of blue light, the effects of blue light on mammalian cells, and the effects of blue light on wound healing. It has been reported that blue light can regulate multi-cellular behavior involving cell-to-cell communication via blue light receptors in bacteria, and inhibit biofilm formation and subsequently potentiate light inactivation. At higher radiant exposures, blue light exhibits a broad-spectrum antimicrobial effect against both Gram-positive and Gram-negative bacteria. Blue light therapy is a clinically accepted approach for Propionibacterium acnes infections. Clinical trials have also been conducted to investigate the use of blue light for Helicobacter pylori stomach infections and have shown promising results. Studies on blue light inactivation of important wound pathogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa have also been reported. The mechanism of blue light inactivation of P. acnes, H. pylori, and some oral bacteria is proved to be the photo-excitation of intracellular porphyrins and the subsequent production of cytotoxic reactive oxygen species. Although it may be the case that the mechanism of blue light inactivation of wound pathogens (e.g., S. aureus, P. aeruginosa) is the same as that of P. acnes, this hypothesis has not been rigorously tested. Limited and discordant results have been reported regarding the effects of blue light on mammalian cells and wound healing. Under certain wavelengths and radiant exposures, blue light may cause cell dysfunction by the photo-excitation of blue light sensitizing chromophores, including flavins and cytochromes, within mitochondria or/and peroxisomes. Further studies should be performed to optimize the optical parameters (e.g., wavelength, radiant exposure) to ensure effective and safe blue light therapies for infectious disease. In addition, studies are also needed to verify the lack of development of microbial resistance to blue light. PMID- 22846407 TI - Solid-liquid phase diagrams for the determination of the solid state nature of both polymorphs of (RS)-2-(2-oxo-pyrrolidin-1-yl)-butyramide. AB - This work focuses on the determination of the solid state nature of (RS)-2-(2-oxo pyrrolidin-1-yl)-butyramide (Etiracetam), the racemic intermediate of (S)-2-(2 oxo-pyrrolidin-1-yl)-butyramide, an Active Pharmaceutical Ingredient, marketed under the name Levetiracetam((r)). It is show how this information can easily be extracted from solid-liquid phase diagrams of the racemic system. As two polymorphs of Etiracetam are known (Forms I and II), the analyses have been performed considering both polymorphs. The solid-liquid phase diagrams are determined experimentally, using Differential Scanning Calorimetry, and theoretically, using the Prigogine-Defay and Schroeder-Van Laar equations. Only the phase diagram involving the polymorph stable at higher temperatures (Form II) can be constructed experimentally. The theoretical phase diagram involving this polymorph compares well with the experimental one, thus allowing the use of theoretical equations for the prediction of the solid-liquid phase diagram involving Form I, which is meta-stable above 30.5 degrees C. Our findings confirm that both polymorphs are racemic compounds, which is also confirmed by XRPD analysis. PMID- 22846408 TI - Protein based tablets as reversible gelling systems for delayed release applications. AB - Succinylated beta-lactoglobulin (S-beta-lg) was previously shown to be efficient as new excipient for the formation of enteric tablets, suitable for several applications including probiotics delivery. This work investigates the mechanisms leading to S-beta-lg tablets delayed release. Release kinetics were evaluated in vitro. Fourier transformed infra red spectroscopy (FTIR) was used to visualize the effect of dissolution medium on matrix tablet surface. Results demonstrated that tablets release in simulated gastric fluids (SGF) might be due to water/drug diffusion through an in situ formed gel layer, as revealed by FTIR data. As SGF penetrated the tablet, regardless of protein succinylation rate (50% or 100%), molecular rearrangements occurred, allowing the development of an important band located in the 1621-1623 cm(-1) region. This band was characteristic of the formation of protein intermolecular beta-sheets. The gel was showed to be reversible in intestinal conditions, allowing delayed release. While the molecular structure of the gel layer was not depending on protein succinylation rate, it appeared that 100% S-beta-lg tablets showed slower release. This low release was probably related to 100% S-beta-lg lower solubility, lower charge density, and their ability to form stronger intermolecular hydrogen bonds. This work highlights proteins potential for the conception of controlled drug delivery systems. PMID- 22846409 TI - Formulation and in vitro characterization of inhalable polyvinyl alcohol-free rifampicin-loaded PLGA microspheres prepared with sucrose palmitate as stabilizer: efficiency for ex vivo alveolar macrophage targeting. AB - In this work a new formulation of inhalable rifampicin-loaded PLGA microspheres (RIF-MS) is proposed for the management of tuberculosis treatment. For their formulation, the non-biodegradable polyvinyl alcohol surfactant was replaced with a biodegradable and biocompatible sucrose ester, sucrose palmitate. The effects of critical process and formulation parameters have been investigated and the obtained microspheres were characterized in terms of size, morphology, encapsulation efficiencies and RIF release profile. The optimized RIF-MS showed high drug loading (34.2%, w/w), an aerodynamic diameter compliant with deep lung delivery and an in vitro gradual and almost complete drug release over a week. The drug release data fitted well to the Higuchi models suggesting a drug release governed by Fickian diffusion. The RIF-MS uptake qualitative and quantitative studies on ex vivo rat alveolar macrophages (AM) revealed an efficient internalization of RIF-MS and their location in the perinuclear area. RIF intracellular levels were 7-fold higher in AM incubated with RIF-MS than with an equivalent amount of free RIF. PMID- 22846410 TI - Preparation and characterization of teniposide PLGA nanoparticles and their uptake in human glioblastoma U87MG cells. AB - Many studies have demonstrated the uptake mechanisms of various nanoparticle delivery systems with different physicochemical properties in different cells. In this study, we report for the first time the preparation and characterization of teniposide (VM-26) poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and their cellular uptake pathways in human glioblastoma U87MG cells. The nanoparticles prepared with oil-in-water (O/W) single-emulsion solvent evaporation method had a small particle size and spherical shape and provided effective protection against degradation of teniposide in PBS solution. Differential scanning calorimeter (DSC) thermograms concluded that VM-26 was dispersed as amorphous or disordered crystalline phase in the PLGA matrix. A cytotoxicity study revealed that, in a 24h period, blank PLGA NPs had no cytotoxicity, whereas teniposide-loaded PLGA NPs (VM-26-NPs) had U87MG cytotoxicity levels similar to free teniposide. Confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) images showed the distribution and degradation processes of nanoparticles in cells. An endocytosis inhibition test indicated that clathrin-mediated endocytosis and macropinocytosis were the primary modes of engulfment involved in the internalization of VM-26 NPs. Our findings suggest that PLGA nanoparticles containing a sustained release formula of teniposide may multiplex the therapeutic effect and ultimately degrade in lysosomal within human glioblastoma U87MG cells. PMID- 22846411 TI - Initial evaluation of the Older Adult Social-Evaluative Situations Questionnaire: a measure of social anxiety in older adults. AB - BACKGROUND: The assessment of social anxiety in late life has been examined in few studies (e.g. Gretarsdottir et al., 2004; Ciliberti et al., 2011). The present study describes the creation and initial psychometric evaluation of a new, content valid measure of social anxiety for older adults, the Older Adult Social-Evaluative Situations Questionnaire (OASES). METHODS: Psychometric properties of the OASES were evaluated in a community dwelling sample of older adults (N = 137; 70.8% female). Convergent validity was established by examining the relation between the OASES and the Liebowitz Social Anxiety Scale (LSAS), Social Phobia and Anxiety Inventory (SPAI), and Beck Anxiety Inventory (BAI). Discriminant validity was established by examining the relation between the OASES and measures of depression (Geriatric Depression Scale, GDS), perceived health status (Short Form Health Survey, SF-12), and demographic variables. The validity analyses of the OASES were based on a smaller sample with n values ranging from 98 to 137 depending on missing data on each questionnaire. RESULTS: Internal consistency, measured by Cronbach's alpha, for the OASES total score was 0.96. All items on the OASES were endorsed by participants. Convergent validity was demonstrated by medium to large correlations with the SPAI, LSAS, and BAI. Support for discriminant validity was evidenced by small to medium correlations between the OASES and GDS, SF-12, and demographic variables. CONCLUSIONS: Evidence in support of convergent and discriminant validity of the OASES is discussed. Although the results from the present study suggest that this measure may assess anxiety in and avoidance of social situations salient to older adults, future studies are needed to further examine the psychometric properties of the OASES and replicate these results in both clinical and more diverse samples of older adults. PMID- 22846412 TI - The advantages of oral cytopathology in the early diagnosis of HIV/AIDS: three case reports. AB - Oral lesions are common in human immunodeficiency virus (HIV)-infected patients, which may indicate impairment of the patient's general health status, and, in many cases, the oral lesions are the first sign of an HIV infection. Oral hairy leukoplakia (OHL) is a benign lesion of the oral mucosa related to Epstein-Barr virus (EBV) observed in HIV-positive individuals. The aim of this study was to report the contribution of oral cytopathology in the investigation of the HIV/AIDS status of patients as well as in the clinical and subclinical identification of OHL. Three patients were referred to the Oral Medicine Clinic in 2010. The patients were submitted to oral examination, and scrapes of the tongue were obtained. The Papanicolaou staining technique was used, and cytopathological analysis showed nuclear changes corresponding to cytopathic effects of EBV epithelial infection and candidiasis. The final diagnosis was OHL and candidiasis. Based on cytopathological diagnosis, an HIV serologic test was requested which revealed positive HIV serology. None of the patients was aware of their HIV serological status, and thus the cytopathology, by identifying OHL, contributed to the early diagnosis of HIV/AIDS. Cytopathology should be used as a routine procedure and it may be the method of choice for clinical and subclinical OHL diagnosis. PMID- 22846413 TI - Randomized trial of pentoxifylline and vitamin E vs standard follow-up after breast irradiation to prevent breast fibrosis, evaluated by tissue compliance meter. AB - PURPOSE: To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). METHODS AND MATERIALS: Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. RESULTS: The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. CONCLUSIONS: This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients. PMID- 22846414 TI - Should patients be able to control their own records? PMID- 22846416 TI - PFI hospitals bear the cost of Libor manipulation. PMID- 22846415 TI - Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing's syndrome: cohort study. AB - OBJECTIVE: To investigate whether there is an increased risk of cardiovascular events in people who exhibit iatrogenic Cushing's syndrome during treatment with glucocorticoids. DESIGN: Cohort study. SETTING: 424 UK general practices contributing to The Health Improvement Network database. PARTICIPANTS: People prescribed systemic glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome (n = 547) and two comparison groups: those prescribed glucocorticoids and with no diagnosis of iatrogenic Cushing's syndrome (n = 3231) and those not prescribed systemic glucocorticoids (n = 3282). MAIN OUTCOME MEASURES: Incidence of cardiovascular events within a year after diagnosis of iatrogenic Cushing's syndrome or after a randomly selected date, and association between iatrogenic Cushing's syndrome and risk of cardiovascular events. RESULTS: 417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n = 177, heart failure n = 101, ischaemic stroke n = 63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing's syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing's syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing's syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with iatrogenic Cushing's syndrome was compared with the group not prescribed glucocorticoids. CONCLUSION: People who use glucocorticoids and exhibit iatrogenic Cushing's syndrome should be aggressively targeted for early screening and management of cardiovascular risk factors. PMID- 22846417 TI - Primary care trusts reverse advice to ophthalmologists to use cheaper drug for wet age related macular degeneration. PMID- 22846418 TI - Digital technologies offer new ways to tackle mental health problems. PMID- 22846419 TI - Research opportunities for cancer associated with indoor air pollution from solid fuel combustion. AB - BACKGROUND: Indoor air pollution (IAP) derived largely from the use of solid fuels for cooking and heating affects about 3 billion people worldwide, resulting in substantial adverse health outcomes, including cancer. Women and children from developing countries are the most exposed populations. A workshop was held in Arlington, Virginia, 9-11 May 2011, to better understand women's and children's potential health effects from IAP in developing countries. Workshop participants included international scientists, manufacturers, policy and regulatory officials, community leaders, and advocates who held extensive discussions to help identify future research needs. OBJECTIVES: Our objective was to identify research opportunities regarding IAP and cancer, including research questions that could be incorporated into studies of interventions to reduce IAP exposure. In this commentary, we describe the state of the science in understanding IAP and its associations with cancer and suggest research opportunities for improving our understanding of the issues. DISCUSSION: Opportunities for research on IAP and cancer include studies of the effect of IAP on cancers other than lung cancer; studies of genetic factors that modify susceptibility; studies to determine whether the effects of IAP are mediated via germline, somatic, and/or epigenetic changes; and studies of the effects of IAP exposure via dermal and/or oral routes. CONCLUSIONS: IAP from indoor coal use increases the risk of lung cancer. Installing chimneys can reduce risk, and some genotypes, including GSTM1-null, can increase risk. Additional research is needed regarding the effects of IAP on other cancers and the effects of different types of solid fuels, oral and dermal routes of IAP exposure, genetic and epigenetic mechanisms, and genetic susceptibility. PMID- 22846420 TI - Molecular crowding of collagen: a pathway to produce highly-organized collagenous structures. AB - Collagen in vertebrate animals is often arranged in alternating lamellae or in bundles of aligned fibrils which are designed to withstand in vivo mechanical loads. The formation of these organized structures is thought to result from a complex, large-area integration of individual cell motion and locally-controlled synthesis of fibrillar arrays via cell-surface fibripositors (direct matrix printing). The difficulty of reproducing such a process in vitro has prevented tissue engineers from constructing clinically useful load-bearing connective tissue directly from collagen. However, we and others have taken the view that long-range organizational information is potentially encoded into the structure of the collagen molecule itself, allowing the control of fibril organization to extend far from cell (or bounding) surfaces. We here demonstrate a simple, fast, cell-free method capable of producing highly-organized, anistropic collagen fibrillar lamellae de novo which persist over relatively long-distances (tens to hundreds of microns). Our approach to nanoscale organizational control takes advantage of the intrinsic physiochemical properties of collagen molecules by inducing collagen association through molecular crowding and geometric confinement. To mimic biological tissues which comprise planar, aligned collagen lamellae (e.g. cornea, lamellar bone or annulus fibrosus), type I collagen was confined to a thin, planar geometry, concentrated through molecular crowding and polymerized. The resulting fibrillar lamellae show a striking resemblance to native load-bearing lamellae in that the fibrils are small, generally aligned in the plane of the confining space and change direction en masse throughout the thickness of the construct. The process of organizational control is consistent with embryonic development where the bounded planar cell sheets produced by fibroblasts suggest a similar confinement/concentration strategy. Such a simple approach to nanoscale organizational control of structure not only makes de novo tissue engineering a possibility, but also suggests a clearer pathway to organization for fibroblasts than direct matrix printing. PMID- 22846421 TI - Cardiovascular effects induced by polymeric 3-alkylpyridinium salts from the marine sponge Reniera sarai. AB - Water-soluble polymeric 3-alkylpyridinum salts (poly-APS), isolated from the marine sponge Reniera sarai, are natural products with promising biomedical applications. However, their ability to form non-specific cell membrane pores raises safety issues. Therefore, the aim of the present study was to investigate the direct toxic effects of poly-APS on the cardiovascular system. To study the impact of poly-APS toxicodynamics on vascular function, the relaxation and contraction responses of isolated rat thoracic aortas incubated in poly-APS solutions (0.01-10 MUM) were tested. In addition, cardiac toxicity was studied by measuring coronary flow, lactate dehydrogenase release rate, left ventricular pressure, heart rate, and the duration of arrhythmias in isolated rat hearts perfused with poly-APS (0.001-1 MUM). Poly-APS diminished endothelium-dependent relaxation and contraction in a concentration- and time-dependent manner. Endothelial function was affected earlier and to a greater extent than contractile responses. Likewise, in isolated hearts the most evident cardiotoxic effects were observed after perfusion with the highest concentration (1 MUM) of poly-APS: compared to the control group the coronary flow and heart rate were diminished by 2.2- and 1.8-fold, while lactate dehydrogenase release rate and left ventricular pressure were increased by 7.8- and 2.2-fold (all P < 0.001). Further, poly-APS had evident proarrhythmogenic activity in a concentration dependent manner. However, in the low concentration range (1-10 nM) poly-APS showed only minor toxicity. Our results confirmed the direct toxic effects of poly-APS on the rat cardiovascular system. Therefore, it seems reasonable to conclude that the use of poly-APS as therapeutic adjuvants has limited safety margins. PMID- 22846422 TI - The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. AB - OBJECTIVE: We aimed to investigate the validity of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) through meta-analysis. STUDY DESIGN: All publications between January 1, 2008 and September 1, 2011 that studied TBSRTC and had available histological follow-up data were retrieved. To calculate the sensitivity, specificity and diagnostic accuracy, the cases diagnosed as follicular neoplasm, suspicious for malignancy and malignant which were histopathologically confirmed as malignant were defined as true-positive. True negative included benign cases confirmed as benign on histopathology. The nondiagnostic category was excluded from the statistical calculation. The correlations between the 6 diagnostic categories were investigated. RESULTS: The publications review resulted in a case cohort of 25,445 thyroid fine-needle aspirations, 6,362 (25%) of which underwent surgical excision; this group constituted the basis of the study. The sensitivity, specificity and diagnostic accuracy were 97, 50.7 and 68.8%, respectively. The positive predictive value and negative predictive value were 55.9 and 96.3%, respectively. The rates of false negatives and false positives were low: 3 and 0.5%, respectively. CONCLUSIONS: The results of meta-analysis showed high overall accuracy, indicating that TBSRTC represents a reliable and valid reporting system for thyroid cytology. PMID- 22846423 TI - JobCenter: an open source, cross-platform, and distributed job queue management system optimized for scalability and versatility. AB - BACKGROUND: Laboratories engaged in computational biology or bioinformatics frequently need to run lengthy, multistep, and user-driven computational jobs. Each job can tie up a computer for a few minutes to several days, and many laboratories lack the expertise or resources to build and maintain a dedicated computer cluster. RESULTS: JobCenter is a client-server application and framework for job management and distributed job execution. The client and server components are both written in Java and are cross-platform and relatively easy to install. All communication with the server is client-driven, which allows worker nodes to run anywhere (even behind external firewalls or "in the cloud") and provides inherent load balancing. Adding a worker node to the worker pool is as simple as dropping the JobCenter client files onto any computer and performing basic configuration, which provides tremendous ease-of-use, flexibility, and limitless horizontal scalability. Each worker installation may be independently configured, including the types of jobs it is able to run. Executed jobs may be written in any language and may include multistep workflows. CONCLUSIONS: JobCenter is a versatile and scalable distributed job management system that allows laboratories to very efficiently distribute all computational work among available resources. JobCenter is freely available at http://code.google.com/p/jobcenter/. PMID- 22846424 TI - Mouse model of muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise. AB - Myotonic dystrophy (DM) is a multisystemic disease caused by CTG or CCTG expansion mutations. There is strong evidence that DM1 CUG and DM2 CCUG expansion transcripts sequester muscleblind-like (MBNL) proteins and that loss of MBNL function causes alternative splicing abnormalities that contribute to disease. Because MBNL1 loss is thought to play an important role in disease and localized AAV delivery of MBNL1 partially rescues skeletal muscle pathology in DM mice, there is strong interest in MBNL1 overexpression as a therapeutic strategy. We developed the first transgenic MBNL1 overexpression mouse model (MBNL1-OE) to test the safety and efficacy of multisystemic MBNL1 overexpression. First, we demonstrate that MBNL1 overexpression is generally well-tolerated in skeletal muscle. Second, we show the surprising result that premature shifts in alternative splicing of MBNL1-regulated genes in multiple organ systems are compatible with life and do not cause embryonic lethality. Third, we show for the first time that early and long-term MBNL1 overexpression prevents CUG-induced myotonia, myopathy and alternative splicing abnormalities in DM1 mice. In summary, MBNL1 overexpression may be a valuable strategy for treating the skeletal muscle features of DM. PMID- 22846426 TI - Dilated fourth ventricle in fetuses with trisomy 18, trisomy 13 and triploidy at 11-13 weeks' gestation. AB - OBJECTIVE: To determine if in fetuses with aneuploidies the diameter of the fourth cerebral ventricle at 11-13 weeks' gestation is different from euploid fetuses. METHODS: The fourth ventricle at 11-13 weeks' gestation was assessed in 62 cases of trisomy 21, 32 of trisomy 18, 10 of trisomy 13, and 12 of triploidy and compared to 410 normal euploid fetuses. Transvaginal sonography was carried out and 3D brain volumes were acquired. The fetal head was assessed in an axial plane and the diameter of the fourth ventricle was measured. Values in aneuploid and euploid fetuses were compared. RESULTS: The diameter of the fourth ventricle in trisomy 18, trisomy 13 and triploidy, but not in trisomy 21, was significantly higher than in euploid fetuses. In the euploid fetuses the median diameter of the fourth ventricle was 1.9 mm and the 95th percentile was 2.5 mm. The measurements were above the median and the 95th percentile in 25 (78.1%) and 17 (53.1%) cases of trisomy 18, in 10 (100%) and 8 (80.0%) of trisomy 13, and in 10 (83.3%) and 10 (83.3%) of triploidy. CONCLUSIONS: In trisomy 18, trisomy 13 and triploidy the diameter of the fourth ventricle at 11-13 weeks' gestation is increased. PMID- 22846425 TI - PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. AB - Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy. PMID- 22846427 TI - Thrombin-stimulated discharge of calcium stores in human platelets: analysis of experimental data. AB - The purpose of this research was to analyze experimental data concerning thrombin stimulated discharge of calcium stores in human platelets contained in calcium free medium in view of better understanding the mechanisms involved in calcium fluxes. The model curves are reasonably close to experimental data; the parameters of the models are related to the properties of the entities responsible for control or maintenance of cytosolic calcium concentration. It has been shown that: (a) time-course of calcium concentration in cytosol of human platelets can be acceptably modeled on the basis of reasonable assumptions concerning agonist stimulated calcium redistribution in cellular compartments; (b) those assumptions are of fundamental importance for the model (c) some parameters of the model (taken arbitrarily) cannot be estimated independently of others from fitting the model to experimental data available; (d) special experiments are necessary to determine the unknown parameters; (e) agonist stimulated change of the permeability of endomembrane of calcium stores can be regarded as a pulse of the permeability; it can be modeled as a sequence of transitions of the system from inactive to active and to inactive state again. PMID- 22846428 TI - Relationship among coronary plaque compliance, coronary risk factors and tissue characteristics evaluated by integrated backscatter intravascular ultrasound. AB - BACKGROUND: The purpose of the present study was to evaluate the mechanical properties of coronary plaques and plaque behavior, and to elucidate the relationship among tissue characteristics of coronary plaques, mechanical properties and coronary risk factors using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: Non-targeted plaques with moderate stenosis (plaque burden at the minimal lumen site: 50-70%) located proximal to the site of the percutaneous coronary intervention target lesions were evaluated by IB-IVUS. Thirty-six plaques (less calcified group: an arc of calcification <=10 degrees ) in 36 patients and 22 plaques (moderately calcified group: 10 degrees < an arc of calcification <=60 degrees ) in 22 patients were evaluated. External elastic membrane volume (EEMV) compliance, lumen volume (LV) compliance, plaque volume (PV) response (difference between PV in systole and diastole), EEM area stiffness index were measured at the minimal lumen site. Relative lipid volume (lipid volume/internal elastic membrane volume) was calculated by IB-IVUS. RESULTS: In the less calcified group, there was a significant correlation between EEMV compliance and the relative lipid volume (r = 0.456, p = 0.005). There was a significant inverse correlation between EEM area stiffness index and the relative lipid volume (p = 0.032, r = -0.358). The LV compliance and EEM area stiffness index were significantly different in the diabetes mellitus (DM) group than in the non-DM group (1.32 +/- 1.49 vs. 2.47 +/- 1.79%/10 mmHg, p =0.014 and 28.3 +/- 26.0 vs. 15.7 +/- 17.2, p =0.020). The EEMV compliance and EEM area stiffness index were significantly different in the hypertension (HTN) group than in the non-HTN group (0.77 +/- 0.68 vs. 1.57 +/- 0.95%/10 mmHg, p =0.012 and 26.5 +/- 24.3 vs. 13.0 +/- 16.7, p =0.020). These relationships were not seen in the moderately calcified group. CONCLUSION: The present study provided new findings that there was a significant correlation between mechanical properties and tissue characteristics of coronary arteries. In addition, our results suggested that the EEMV compliance and the LV compliance were independent and the compliance was significantly impaired in the patients with DM and/or HTN. Assessment of coronary mechanical properties during PCI may provide us with useful information regarding the risk stratification of patients with coronary heart disease. PMID- 22846429 TI - Nutrient sensing. PMID- 22846430 TI - Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells. AB - BACKGROUND: In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related signaling pathways, four different microarray experiments were reanalyzed before radiotherapy. RESULTS: Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1) was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2). Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM) and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway. CONCLUSIONS: Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that integrin signaling via adhesion molecules could be a target for radiosensitization. PMID- 22846431 TI - Classification of mitocans, anti-cancer drugs acting on mitochondria. AB - Mitochondria have emerged as an intriguing target for anti-cancer drugs, inherent to vast majority if not all types of tumours. Drugs that target mitochondria and exert anti-cancer activity have become a focus of recent research due to their great clinical potential (which has not been harnessed thus far). The exceptional potential of mitochondria as a target for anti-cancer agents has been reinforced by the discouraging finding that even tumours of the same type from individual patients differ in a number of mutations. This is consistent with the idea of personalised therapy, an elusive goal at this stage, in line with the notion that tumours are unlikely to be treated by agents that target only a single gene or a single pathway. This endows mitochondria, an invariant target present in all tumours, with an exceptional momentum. This train of thoughts inspired us to define a class of anti-cancer drugs acting by way of mitochondrial 'destabilisation', termed 'mitocans'. In this communication, we define mitocans (many of which have been known for a long time) and classify them into several classes based on their molecular mode of action. We chose the targets that are of major importance from the point of view of their role in mitochondrial destabilisation by small compounds, some of which are now trialled as anti-cancer agents. The classification starts with targets at the surface of mitochondria and ending up with those in the mitochondrial matrix. The purpose of this review is to present in a concise manner the classification of compounds that hold a considerable promise as potential anti-cancer drugs. PMID- 22846432 TI - Differential response to intracellular stress in the skin from osteogenesis imperfecta Brtl mice with lethal and non lethal phenotype: a proteomic approach. AB - Phenotypic variability in the presence of an identical molecular defect is a recurrent feature in heritable disorders and it was also reported in osteogenesis imperfecta (OI). OI is a prototype for skeletal dysplasias mainly caused by mutations in the two genes coding for type I collagen. No definitive cure is available for this disorder, but the understanding of molecular basis in OI phenotypic modulation will have a pivotal role in identifying possible targets to develop novel drug therapy. We used a functional proteomic approach to address the study of phenotypic variability using the skin of the OI murine model Brtl. Brtl mice reproduce the molecular defect, dominant transmission and phenotypic variability of human OI patients. In the presence of a Gly349Cys substitution in alpha1(I)-collagen Brtl mice can have a lethal or a moderately severe outcome. Differential expression of chaperones, proteasomal subunits, metabolic enzymes, and proteins related to cellular fate demonstrated that a different ability to adapt to cellular stress distinguished mutant from wild-type mice and mutant lethal from surviving mutant animals. Interestingly, class discovery analysis identified clusters of differentially expressed proteins associated with a specific outcome, and functional analysis contributed to a deeper investigation into biochemical and cellular pathways affected by the disease. This article is part of a Special Issue entitled: Translational Proteomics. PMID- 22846434 TI - Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) is widely used by populations living in South America to treat many ailments associated with inflammatory disorders. Mitraphylline was shown to be the major pentacyclic oxindolic alkaloid present in the bark chloroformic extract of this plant. Its activity against cytokines involved in inflammation process was tested in a murine model in vivo. MATERIALS AND METHODS: Mice received mitraphylline once a day for 3 days at 30 mg/kg/day by oral route. Then, they were subjected to bacterial lipopolysaccharide (LPS) endotoxin (15 mg/kg) and the LPS-induced production of 16 different cytokines was determined by Elisa multiplex. Control group received dexamethasone orally at 2mg/kg/day. Toxicity on K565 cells and murine peritoneal macrophages, in vitro, at doses up to 100 MUM was monitored by XTT-colorimetric assay. RESULTS AND CONCLUSIONS: For the first time mitraphylline was tested in vivo against a large range of cytokines that play a crucial role in inflammation. Mitraphylline inhibited around 50% of the release of interleukins 1alpha, 1beta, 17, and TNF-alpha. This activity was similar to dexamethasone. It also reduced almost 40% of the production of interleukin 4 (IL-4) while the corticoid did not. Lastly it did not show any toxicity on K565 cells nor murine macrophages at doses up to 100 MUM. PMID- 22846433 TI - Analysis of serum total and free PSA using immunoaffinity depletion coupled to SRM: correlation with clinical immunoassay tests. AB - Recently, selected reaction monitoring mass spectrometry (SRM-MS) has been more frequently applied to measure low abundance biomarker candidates in tissues and biofluids, owing to its high sensitivity and specificity, simplicity of assay configuration, and exceptional multiplexing capability. In this study, we report for the first time the development of immunoaffinity depletion-based workflows and SRM-MS assays that enable sensitive and accurate quantification of total and free prostate-specific antigen (PSA) in serum without the requirement for specific PSA antibodies. Low ng/mL level detection of both total and free PSA was consistently achieved in both PSA-spiked female serum samples and actual patient serum samples. Moreover, comparison of the results obtained when SRM PSA assays and conventional immunoassays were applied to the same samples showed good correlation in several independent clinical serum sample sets. These results demonstrate that the workflows and SRM assays developed here provide an attractive alternative for reliably measuring candidate biomarkers in human blood, without the need to develop affinity reagents. Furthermore, the simultaneous measurement of multiple biomarkers, including the free and bound forms of PSA, can be performed in a single multiplexed analysis using high resolution liquid chromatographic separation coupled with SRM-MS. This article is part of a Special Issue entitled: Translational Proteomics. PMID- 22846435 TI - The memory ameliorating effects of INM-176, an ethanolic extract of Angelica gigas, against scopolamine- or Abeta(1-42)-induced cognitive dysfunction in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease is a neurodegenerative disorder associated with cognitive impairment and cholinergic neuronal death. INM 176 is a standardized ethanolic extract of Angelica gigas Nakai that has been traditionally used in herbal medicine in China, Japan, and Korea to treat anemia or as a sedative. We investigated whether INM-176 exhibits anti-amnesic effects. MATERIALS AND METHODS: Memory impairment was induced by scopolamine, a cholinergic muscarinic receptor antagonist, or amyloid beta(1-42) (Abeta(1-42)) protein. Anti-amnesic effects of INM-176 were measured by the passive avoidance and the Morris water maze tasks in mice. We also examined the effect of INM-176 on the acetylcholinesterase activity, as well as Abeta(1-42) protein-induced astrogliosis or cholinergic neuronal loss in the brain. RESULTS: Scopolamine induced cognitive dysfunction was significantly attenuated by a single or sub chronic administration of INM-176 in the passive avoidance and the Morris water maze tasks. A single or sub-chronic administration of INM-176 also ameliorated memory impairments induced by Abeta(1-42) protein. INM-176 inhibited acetylcholinesterase activity in the hippocampal tissue in vitro and ex vivo. In addition, INM-176 attenuated the Abeta(1-42) protein-induced astrocyte activation in the hippocampus as well as cholinergic neuronal damage in the CA3 region of the hippocampus and the nucleus basalis of Meynert. CONCLUSION: These results suggest that the memory ameliorating effects of INM-176 on scopolamine- or Abeta(1-42) protein-induced memory impairment are mediated, in part, via acetylcholinesterase inhibition and neuroprotective activities. PMID- 22846436 TI - Sexual arousal in women with provoked vestibulodynia: the application of laser Doppler imaging to sexual pain. AB - Introduction. Women with provoked vestibulodynia (PVD) report lower sexual arousal than nonaffected women, however, laboratory studies of arousal have reported contradictory results about whether group differences exist in genital and subjective arousal. Aim. To examine genital and subjective sexual arousal in women with and without PVD. Methods. Eligible women with and without PVD (N = 42) attended a laboratory session that included an interview, questionnaire completion, and genital imaging. A direct measure of superficial blood flow-laser Doppler imaging-was used to assess vulvar blood flow levels while participants watched three films, including an erotic film. Participants answered questions about their level of sexual arousal before, during, and after the erotic film. Main Outcome Measures. Average vulvar blood flow levels during the baseline and erotic films, numerical ratings of subjective sexual arousal and anxiety, as well as questionnaire measures of arousal. Results. There was a significant group difference in genital arousal, whereby the PVD group showed a lower genital response to the erotic film, as well as a significant interaction between baseline blood flow and group membership. Separate group regression analyses demonstrated that baseline blood flow explained a substantial amount of the variance in erotic film blood flow in the control group (70%), while only 27% was explained by this variable in the PVD group. There were no differences in subjective sexual arousal or anxiety between the groups. Across questionnaire measures, women with PVD reported lower sexual arousal than the control group. Conclusions. The results suggest that women with PVD show lower genital responsiveness than nonaffected women to sexual stimuli in a laboratory setting and that their genital arousal is likely impacted by a number of biopsychosocial factors. Boyer SC, Pukall CF, and Chamberlain SM. Sexual arousal in women with provoked vestibulodynia: The application of laser Doppler imaging to sexual pain. J Sex Med **;**:**-**. PMID- 22846437 TI - Perturbed voltage-gated channel activity in perturbed bilayers: implications for ectopic arrhythmias arising from damaged membrane. AB - The ceaseless opening and closing of the voltage-gated channels (VGCs) underlying cardiac rhythmicity is controlled, in each VGC, by four mobile voltage sensors embedded in bilayer. Every action potential necessitates extensive packing/repacking of voltage sensor domains with adjacent interacting lipid molecules. This renders VGC activity mechanosensitive (MS), i.e., energetically sensitive to the bilayer's mechanical state. Irreversible perturbations of sarcolemmal bilayer such as those associated with ischemia, reperfusion, inflammation, cortical-cytoskeleton abnormalities, bilayer-disrupting toxins, diet aberrations, etc, should therefore perturb VGC activity. Disordered/fluidized bilayer states that facilitate voltage sensor repacking, and thus make VGC opening too easy could, therefore, explain VGC-leakiness in these conditions. To study this in membrane patches we impose mechanical blebbing injury during pipette aspiration-induced membrane stretch, a process that modulates VGC activity irreversibly (plastic regime) and then, eventually, reversibly (elastic regime). Because of differences in sensor-to-gate coupling among different VGCs, their responses to stretch fall into two major categories, MS-Speed, MS-Number, exemplified by Nav and Cav channels. For particular VGCs in perturbed bilayers, leak mechanisms depend on whether or not the rate-limiting voltage-dependent step is MS. Mode-switch transitions might also be mechanosensitive and thus play a role. Incorporated mathematically in axon models, plastic-regime Nav responses elicit ectopic firing behaviors typical of peripheral neuropathies. In cardiomyocytes with mild bleb damage, Nav and/or Cav leaks from irreversible MS modulation (MS-Speed, MS-Number, respectively) could, similarly, foster ectopic arrhythmias. Where pathologically leaky VGCs reside in damaged bilayer, peri-channel bilayer disorder/fluidity conditions could be an important "target feature" for anti-arrhythmic VGC drugs. PMID- 22846438 TI - A fresh look at complex I in microarray data: clues to understanding disease specific mitochondrial alterations in bipolar disorder. PMID- 22846439 TI - Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type. AB - BACKGROUND: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, tau, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle. METHODS: Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep-wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate tau. RESULTS: In FRT patients, tau was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, tau of melatonin rhythm in FRT patients showed no significant correlation with tau of sleep-wake cycles measured before the study. CONCLUSIONS: The findings suggest that although a prolongation of tau may be involved in the onset mechanism of FRT, a prolonged tau is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner. PMID- 22846440 TI - Theory of mind in children with traumatic brain injury. AB - Theory of mind (ToM) involves thinking about mental states and intentions to understand what other people know and to predict how they will act. We studied ToM in children with traumatic brain injury (TBI) and age- and gender-matched children with orthopedic injuries (OI), using a new three-frame Jack and Jill cartoon task that measures intentional thinking separate from contingent task demands. In the key ToM trials, which required intentional thinking, Jack switched a black ball from one hat to another of a different color, but Jill did not witness the switch; in the otherwise identical non-ToM trials, the switch was witnessed. Overall accuracy was higher in children with OI than in those with TBI. Children with severe TBI showed a larger decline in accuracy on ToM trials, suggesting a specific deficit in ToM among children with severe TBI. Accuracy was significantly higher on trials following errors than on trials following correct responses, suggesting that all groups monitored performance and responded to errors with increased vigilance. TBI is associated with poorer intentional processing in school-age children and adolescents relative to peers with OI; furthermore, children with TBI are challenged specifically by intentional demands, especially when their injury is severe. (JINS, 2012, 19, 1-9). PMID- 22846441 TI - Motility behavior of rpoS-deficient Escherichia coli analyzed by individual cell tracking. AB - Motility is one of the most extensively studied cellular events conducted by bacteria, including Escherichia coli. A motility agar plate assay showed that deletion of the rpoS gene enhanced the apparent motility of the E. coli BW25113 strain, which inherently had negligible motility compared to wild-type E. coli strains, such as MG1655, with no effect on cell growth. This enhancement of motility was accompanied by drastic up-regulation of genes involved in the formation and rotation of flagella. Furthermore, an individual cell motility assay showed that the population of DeltarpoS cells had bimodal motility character, and that a minority of this population exhibited a much higher motility rate. These results support a view that a minority population contributes to increasing in apparent motility of the whole population of DeltarpoS cells. PMID- 22846442 TI - Autoimmune retinopathy. AB - Autoimmune retinopathy encompasses a spectrum of rare autoimmune diseases that primarily affect retinal photoreceptor function, and include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR) and presumed non paraneoplastic autoimmune retinopathy (npAIR). Autoimmune retinopathy typically presents in the fifth and sixth decades with rapidly progressive, bilateral, painless visual deterioration but an unremarkable fundus examination. CAR, MAR and npAIR have an overlapping clinical phenotype, and extensive investigation is required to exclude other causes of retinopathy, and to identify any occult malignancy, before a presumptive diagnosis can be made. Delayed diagnosis, and treatment initiation relatively late in the disease course, may contribute to the poor visual prognosis. Various treatments have been attempted, including systemic immunosuppression with steroid and steroid-sparing agents, intravenous immunoglobulin, and plasmapheresis, but these lack an evidence base. A variety of antiretinal antibodies have been identified in patients with autoimmune retinopathy, including antibodies to recoverin, alpha-enolase and transducin alpha, but seronegative disease is also common. Clinical access to specialised serological investigation is very limited internationally, and this exacerbates the management challenge presented by patients with suspected autoimmune retinopathy. Several decades of experimental research have resulted in very considerable advances in our understanding of the pathophysiological mechanisms that may underlie autoimmune retinopathy. However, the precise triggers which result in loss of ocular immune privilege and sudden autoimmune attack on retinal cells have yet to be elucidated. This review summarizes the classification, investigation and management of autoimmune retinopathy, and considers the evolving concepts about its immunological aetiology. PMID- 22846443 TI - A nation-wide evidence-based data analysis of repeated suicide attempts. AB - BACKGROUND: Taiwan is a high-risk area for suicide. Repeated suicide attempts are an important factor of suicide mortality. Yet there has been little research on the factors associated with repeated suicidal behavior in Taiwan. AIMS: To explore the characteristics of repeated suicide attempts. METHODS: Data were obtained from the National Health Insurance Research Database for 2005 to 2008. We then classified repeated suicide attempts into single method, two different methods, and three different methods. RESULTS: A total of 1,004 inpatients were admitted to Taiwanese hospitals due to repeated suicide attempts, and the use of a single suicide method constituted the majority of the cases (71%). Risk factors related to repeated suicide attempts included being female, aged 30-39, suicide by poisoning using solid and/or liquid substances, the fall season, living in Northern Taiwan, more psychiatric nature of injury codes (N-codes), seeking medical attention from a psychiatrist, receiving more surgeries or procedures, a longer length of stay in a hospital, coming from a low-income background, and having a serious illness. CONCLUSIONS: Consultation and treatment are particularly crucial for patients with mental illnesses and other concomitant diseases, so that the psychiatric symptoms such as auditory and visual hallucinations can be controlled. PMID- 22846444 TI - Suicidal ideation, risk factors, and communication with parents. An HBSC study on school children in Estonia, Lithuania, and Luxembourg. AB - BACKGROUND: Suicide is a leading cause of death among youth. In the year 2002, Lithuania had the 2nd, Luxembourg the 5th, and Estonia the 9th highest suicide rates among 15- to 19-year-olds across 90 countries worldwide. Suicidal ideation is a significant precursor to suicide. AIMS: To report on the prevalence of and associations between suicidal ideation, smoking, alcohol consumption, physical fighting, bullying, and communication with parents among 15-year-old schoolchildren. METHODS: The survey analyzes data from the 2005/2006 HBSC study from Estonia, Lithuania, and Luxembourg (N = 4,954). The risk factors were calculated through multinomial logistic regression analyses. RESULTS: The overall prevalence of suicidal ideation in the preceding year was 17%. Suicidal thoughts were associated with communication difficulties with parents (OR from 2.0 to 4.6) and other risk factors, especially multiple risks (OR for 4-5 concurrent risk factors from 4.5 to 13.6). Parent-child communication had a significant mediating effect by decreasing the odds for suicidality and multiple risks. LIMITATIONS: The prevalence estimates were obtained by self-reports. The causal relationships need further investigation. CONCLUSION: The risk factors studied, particularly multiple risks, were associated with higher odds for suicidal ideation. Good parent-child communication is a significant resource for decreasing suicidal ideation among adolescents. PMID- 22846445 TI - Can postdischarge follow-up contacts prevent suicide and suicidal behavior? A review of the evidence. AB - BACKGROUND: The time period following discharge from inpatient psychiatry and emergency department (ED) treatment is one of heightened risk for repeat suicide attempts for patients. Evidence reported in the literature shows that follow-up contacts might reduce suicide risk, although there has not been a comprehensive and critical review of the evidence to date. AIMS: To evaluate evidence for the effectiveness of suicide prevention interventions that involve follow-up contacts with patients. METHODS: Published empirical studies of follow-up interventions with suicidal behaviors (suicide, attempts, and ideation) as outcomes were searched. Study populations were inpatient psychiatric or ED patients being discharged to home. Contact modalities included phone, postal letter, postcards, in-person, and technology-based methods (e-mail and texting). RESULTS: Eight original studies, two follow-up studies, and one secondary analysis study met inclusion criteria. Five studies showed a statistically significant reduction in suicidal behavior. Four studies showed mixed results with trends toward a preventative effect and two studies did not show a preventative effect. CONCLUSIONS: Repeated follow-up contacts appear to reduce suicidal behavior. More research is needed, however, especially randomized controlled trials, to determine what specific factors might make follow-up contact modalities or methods more effective than others. PMID- 22846446 TI - The impact of specifying suicide as the cause of death in an obituary. AB - BACKGROUND: Historically, people who die by suicide and those who survive them have been perceived more negatively than those affected by other types of death (e.g., Reynolds & Cimbolic, 1988). Yet, it is unclear whether these negative perceptions actually lead to decreased social and emotional support for people bereaved by suicide. AIMS: To examine whether specifying suicide as the cause of death in an obituary impacts perceptions of a decedent and willingness to provide support to the decedent's family. METHOD: A group of 253 participants were randomly assigned to read one of three fictional obituaries that were identical except for the stated cause of death (suicide, cancer, or drug overdose). Participants responded to questions about the decedent and behaviors toward the family. RESULTS: Consistent with our prediction, people depicted as dying by suicide were viewed more negatively than decedents depicted as dying due to cancer. Contrary to our prediction, participants endorsed similar levels of willingness to provide support to the bereaved family regardless of the type of death specified in the obituary. CONCLUSIONS: The findings suggest that, even though those who die by suicide are viewed more negatively, their survivors may receive support that is similar to people bereaved by other types of death. PMID- 22846447 TI - The Stigma of Suicide Scale. Psychometric properties and correlates of the stigma of suicide. AB - BACKGROUND: There are presently no validated scales to adequately measure the stigma of suicide in the community. The Stigma of Suicide Scale (SOSS) is a new scale containing 58 descriptors of a "typical" person who completes suicide. AIMS: To validate the SOSS as a tool for assessing stigma toward suicide, to examine the scale's factor structure, and to assess correlates of stigmatizing attitudes. METHOD: In March 2010, 676 staff and students at the Australian National University completed the scale in an online survey. The construct validity of the SOSS was assessed by comparing its factors with factors extracted from the Suicide Opinion Questionnaire (SOQ). RESULTS: Three factors were identified: stigma, isolation/depression, and glorification/normalization. Each factor had high internal consistency and strong concurrent validity with the Suicide Opinion Questionnaire. More than 25% of respondents agreed that people who suicided were "weak," "reckless," or "selfish." Respondents who were female, who had a psychology degree, or who spoke only English at home were less stigmatizing. A 16-item version of the scale also demonstrated robust psychometric properties. CONCLUSIONS: The SOSS is the first attitudes scale designed to directly measure the stigma of suicide in the community. Results suggest that psychoeducation may successfully reduce stigma. PMID- 22846448 TI - Utilized social support and self-esteem mediate the relationship between perceived social support and suicide ideation. A test of a multiple mediator model. AB - BACKGROUND: While perceived social support has received considerable research as a protective factor for suicide ideation, little attention has been given to the mechanisms that mediate its effects. AIMS: We integrated two theoretical models, Joiner's (2005) interpersonal theory of suicide and Leary's (Leary, Tambor, Terdal, & Downs, 1995) sociometer theory of self-esteem to investigate two hypothesized mechanisms, utilization of social support and self-esteem. Specifically, we hypothesized that individuals must utilize the social support they perceive that would result in increased self-esteem, which in turn buffers them from suicide ideation. METHOD: Participants were 172 college students who completed measures of social support, self-esteem, and suicide ideation. RESULTS: Tests of simple mediation indicate that utilization of social support and self esteem may each individually help to mediate the perceived social support/suicide ideation relationship. Additionally, a test of multiple mediators using bootstrapping supported the hypothesized multiple-mediator model. LIMITATIONS: The use of a cross-sectional design limited our ability to find true cause-and effect relationships. CONCLUSION: Results suggested that utilized social support and self-esteem both operate as individual moderators in the social support/self esteem relationship. Results further suggested, in a comprehensive model, that perceived social support buffers suicide ideation through utilization of social support and increases in self-esteem. PMID- 22846449 TI - Cytotechnologist on-site evaluation of pancreas fine needle aspiration adequacy: comparison with cytopathologists and correlation with the final interpretation. AB - OBJECTIVE: To compare on-site evaluations of adequacy (OSEA) of endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) of the pancreas performed by cytotechnologists and cytopathologists. STUDY DESIGN: A 10-year retrospective review of 2,426 OSEA from 2,223 procedures in 1,984 patients was performed. Adequacy statistics were calculated along with the accuracy of the OSEA for each OSEA provider. The effect of other variables, including the lifetime number of EUS pancreatic OSEA, the number of years of experience at the time of each case, the institutional number of EUS FNA, and the number of smears was evaluated with ANOVA. RESULTS: There was no difference in the adequacy downgrade rate for cytotechnologists versus cytopathologists during this study period (38.2 vs. 32.2%, p = 0.13). Neither individual cytologist experience with EUS-guided pancreatic FNA (p = 0.25) nor years in practice (p = 0.86) was correlated with the accuracy of the OSEA. The experience of the institution with EUS-guided pancreatic FNA was correlated with both adequacy (p = 0.003) and accuracy (p = 0.000001). CONCLUSION: Cytotechnologists and cytopathologists are comparably accurate in OSEA of EUS-guided pancreatic FNA. The adequacy and accuracy of the OSEA increase with institutional experience, and this increase is not solely attributable to cytologist factors. PMID- 22846450 TI - Questionnaire-based survey conducted in 2011 concerning endoscopic management of Barrett's esophagus in East Asian countries. AB - BACKGROUND/AIMS: Endoscopic definitions and management of Barrett's esophagus vary widely among countries. To examine the current situation regarding diagnosis, epidemiology, management and treatment of Barrett's esophagus in East Asian countries using a questionnaire-based survey. METHODS: Representative members of the Committee of the International Gastrointestinal Consensus Symposium developed and sent a questionnaire to major institutions in China, South Korea, Japan, Thailand, Indonesia, and the Philippines. RESULTS: A total of 56 institutions in the 6 countries participated in the survey. We found that the presence of specialized columnar metaplasia is considered to be important for diagnosing Barrett's esophagus in East Asian countries except for Japan. C&M criteria have not been well accepted in East Asia. The palisade vessels are mainly used as a landmark for the esophagogastric junction in Japan. The prevalence of long segment Barrett's esophagus is extremely low in East Asia, while the prevalence of short segment Barrett's esophagus is very high only in Japan, likely due to different diagnostic criteria. CONCLUSION: Among East Asian countries, we found both similarities and differences regarding diagnosis and management of Barrett's esophagus. The findings in the present survey are helpful to understand the current situation of Barrett's esophagus in East Asian countries. PMID- 22846452 TI - Health-related quality of life in family members of patients with an advanced cancer diagnosis: a one-year prospective study. AB - BACKGROUND: Receiving a cancer diagnosis affects family members as well as the person diagnosed. Family members often provide support for the sick person in daily life out of duty and love, and may not always think of their own vulnerability to illness. To individualise support for them, family members who are most at risk for becoming ill must be identified.The aim of this study was to investigate health-related quality of life (HRQOL) in family members of patients with advanced lung or gastrointestinal cancer 3 to 15 months after diagnosis. METHODS: Data on mental and physical dimensions of HRQOL were collected from family members of these patients in this prospective quantitative study. Five assessments using the Short Form 36 Health Survey (SF-36) and EuroQol (EQ-5D) were conducted during a 1-year period starting 3 months after diagnosis. Thirty six family members completed the study, i.e. participated in all five data collections. RESULTS: No statistically significant changes in physical or mental HRQOL within the study group appeared over the 1-year follow-up. Compared with norm-based scores, family members had significantly poorer mental HRQOL scores throughout the year as measured by the SF-36. Family members also scored statistically significantly worse on the EQ-5D VAS in all five assessments compared to the norm-based score. Findings showed that older family members and partners were at higher risk for decreased physical HRQOL throughout the 1-year period, and younger family members were at higher risk for poorer mental HRQOL. CONCLUSIONS: It is well known that ill health is associated with poor HRQOL. By identifying family members with poor HRQOL, those at risk of ill health can be identified and supported. Future large-scale research that verifies our findings is needed before making recommendations for individualised support and creating interventions best tailored to family members at risk for illness. PMID- 22846451 TI - Pleiotropic functions of catabolite control protein CcpA in Butanol-producing Clostridium acetobutylicum. AB - BACKGROUND: Clostridium acetobutylicum has been used to produce butanol in industry. Catabolite control protein A (CcpA), known to mediate carbon catabolite repression (CCR) in low GC gram-positive bacteria, has been identified and characterized in C. acetobutylicum by our previous work (Ren, C. et al. 2010, Metab Eng 12:446-54). To further dissect its regulatory function in C. acetobutylicum, CcpA was investigated using DNA microarray followed by phenotypic, genetic and biochemical validation. RESULTS: CcpA controls not only genes in carbon metabolism, but also those genes in solvent production and sporulation of the life cycle in C. acetobutylicum: i) CcpA directly repressed transcription of genes related to transport and metabolism of non-preferred carbon sources such as d-xylose and l-arabinose, and activated expression of genes responsible for d-glucose PTS system; ii) CcpA is involved in positive regulation of the key solventogenic operon sol (adhE1-ctfA-ctfB) and negative regulation of acidogenic gene bukII; and iii) transcriptional alterations were observed for several sporulation-related genes upon ccpA inactivation, which may account for the lower sporulation efficiency in the mutant, suggesting CcpA may be necessary for efficient sporulation of C. acetobutylicum, an important trait adversely affecting the solvent productivity. CONCLUSIONS: This study provided insights to the pleiotropic functions that CcpA displayed in butanol-producing C. acetobutylicum. The information could be valuable for further dissecting its pleiotropic regulatory mechanism in C. acetobutylicum, and for genetic modification in order to obtain more effective butanol-producing Clostridium strains. PMID- 22846453 TI - Endurance exercise training in patients with small abdominal aortic aneurysm: a randomized controlled pilot study. AB - OBJECTIVE: To investigate the feasibility of endurance exercise training in patients with small abdominal aortic aneurysm (AAA), and to obtain preliminary data of its impact on important health outcomes. DESIGN: Randomized controlled pilot study. SETTING: University rehabilitation facility. PARTICIPANTS: Patients with small AAA (N=28; mean age +/- SD, 72+/-7 y). INTERVENTION: Participants were randomized to a 12-week program of moderate-intensity endurance exercise or standard care control (encouragement to exercise only). MAIN OUTCOME MEASURES: Safety was assessed in terms of the frequency of adverse events and changes in maximum AAA diameter. Outcomes were assessed at baseline and 12 weeks including cardiopulmonary fitness (ventilatory threshold), health-related quality of life (Medical Outcomes Study 36-Item Short-Form Health Survey [version 2]), and markers of vascular risk (eg, blood pressure and high-sensitivity C-reactive protein). RESULTS: Of 545 patients contacted, 28 (5%) entered the trial. There were 3 (11%) dropouts. Adherence to the exercise program was 94%. There were no paradoxical increases in AAA size or adverse clinical events. Ventilatory threshold increased in the exercise group, but not the control group (adjusted mean difference, 2.5 mL.kg(-1).min(-1); 95% confidence interval, 0.5-4.5; d=.82). Systolic blood pressure and high-sensitivity C-reactive protein decreased in the exercise group compared with the control group (d=.34 and d=.58, respectively). There were no substantial changes in anthropometric variables or quality of life. CONCLUSIONS: Despite a low recruitment rate, the findings suggest that moderate intensity endurance exercise training is feasible in patients with small AAA, and can evoke improvements in important health outcomes. PMID- 22846454 TI - Prolonged swallowing time in dysphagic Parkinsonism patients with aspiration pneumonia. AB - OBJECTIVE: To quantitatively measure which dysphagic features, including swallowing time and hyoid bone displacement, would be associated with increased risk of aspiration pneumonia in dysphagic Parkinsonism patients. DESIGN: Clinical survey. SETTING: Tertiary care center. PARTICIPANTS: Patients with Parkinsonism and dysphagia (N=25), referred for videofluoroscopic swallowing study, were recruited by retrospective review of medical records. They were divided into 2 groups according to the history of aspiration pneumonia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Swallowing time including onset of pharyngeal swallowing, oral transit time and pharyngeal transit time, and maximum hyoid bone displacement including total, horizontal, and vertical displacement during swallowing in thin and thick bariums were recorded. RESULTS: Patients with history of aspiration pneumonia had significantly longer pharyngeal transit time (4.14 vs 2.31s, P=.038) and onset of pharyngeal swallowing (2.16 vs 1.04s, P=.031) than those without, when swallowing thin barium. Patients with aspiration pneumonia also had significantly longer swallowing time when swallowing thick barium (oral transit time: 7.14 vs 2.33s, P=.018; pharyngeal transit time: 6.39 vs 1.23s, P=.004; onset of pharyngeal swallowing: 5.11 vs .31s, P=.006). There was no significant difference in hyoid bone displacement between the 2 groups. CONCLUSIONS: Patients with Parkinsonism dysphagia and aspiration pneumonia had longer swallowing time than those without, but there was no difference in displacement of hyoid bone. PMID- 22846455 TI - Association between participation in life situations of children with cerebral palsy and their physical, social, and attitudinal environment: a cross-sectional multicenter European study. AB - OBJECTIVE: To evaluate how participation of children with cerebral palsy (CP) varied with their environment. DESIGN: Home visits to children. Administration of Assessment of Life Habits and European Child Environment Questionnaires. Structural equation modeling of putative associations between specific domains of participation and environment, while allowing for severity of child's impairments and pain. SETTING: European regions with population-based registries of children with CP. PARTICIPANTS: Children (n=1174) aged 8 to 12 years were randomly selected from 8 population-based registries of children with CP in 6 European countries. Of these, 743 (63%) agreed to participate; 1 further region recruited 75 children from multiple sources. Thus, there were 818 children in the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Participation in life situations. RESULTS: For the hypothesized associations, the models confirmed that higher participation was associated with better availability of environmental items. Higher participation in daily activities-mealtimes, health hygiene, personal care, and home life-was significantly associated with a better physical environment at home (P<.01). Mobility was associated with transport and physical environment in the community. Participation in social roles (responsibilities, relationships, recreation) was associated with attitudes of classmates and social support at home. School participation was associated with attitudes of teachers and therapists. Environment explained between 14% and 52% of the variation in participation. CONCLUSIONS: The findings confirmed the social model of disability. The physical, social, and attitudinal environment of disabled children influences their participation in everyday activities and social roles. PMID- 22846456 TI - Fine needle aspiration cytology of Kikuchi-Fujimoto's disease: a report of 2 cases with emphasis on cytologic features and differential diagnosis. AB - BACKGROUND: Kikuchi-Fujimoto's disease (KFD) or histiocytic necrotizing lymphadenitis is an uncommon, benign, self-limited disease of unknown etiology, primarily affecting young women. Herein, we present the cytologic features of KFD of 2 cases that presented with different clinical pictures and discuss the cytologic differential diagnosis of this condition. CASES: Case 1 was a 17-year old girl who presented with cervical lymphadenopathy since 6 weeks and case 2 was a 32-year-old female who had cough and axillary lymphadenopathy since 8 weeks. The fine needle aspiration (FNA) smears of both cases revealed a polymorphous lymphoid population intermingled with histiocytes, many of which showed a small size, eccentric location, crescent-shaped nuclei and abundant karyorrhectic debris in the background. A diagnosis of histiocytic necrotizing lymphadenitis was made on FNA cytology, which was confirmed by subsequent histologic examination of the lymph nodes. CONCLUSION: Precise diagnosis of KFD on cytologic smears is crucial as it can be mistaken for tuberculous lymphadenitis, systemic lupus erythematosus, malignant lymphoma or even metastatic carcinoma, and to avoid unnecessary investigations and potentially harmful treatment. With adequate, well-preserved samples and appropriate clinical setting, the presence of abundant karyorrhectic debris, crescentic macrophages, a polymorphous lymphoid population and absence of epithelioid cell granulomas, giant cells and neutrophils must alert the cytopathologist to arrive at a correct diagnosis. PMID- 22846457 TI - Cardiac vagal control and theoretical models of co-occurring depression and anxiety: a cross-sectional psychophysiological study of community elderly. AB - BACKGROUND: In order to elucidate the complex relationship between co-occurring depression and anxiety with cardiac autonomic function in the elderly, this study examined the correlation between cardiac vagal control (CVC) and pre-defined, theoretical factors from the Hospital Anxiety and Depression Scale (HADS). METHODS: Three hundred fifty-four randomly selected Chinese male subjects aged >= 65 years and living in the community were enrolled. CVC was measured using a frequency-domain index of heart rate variability. RESULTS: Confirmatory factor analysis showed that the flat tripartite model of HADS provided a modest advantage in model fit when compared with other theoretical factor solutions. In the flat tripartite model, there was a significant negative association between anhedonic depression and CVC. In contrast, autonomic anxiety showed a significant positive correlation with CVC. In the hierarchical tripartite model, negative affectivity was not directly associated with CVC; instead, it had positive and negative indirect effects on CVC via autonomic anxiety and anhedonic depression, respectively. As scores for negative affectivity increased, these specific indirect effects diminished. CONCLUSIONS: Among competing models of co-occurring depression and anxiety, constructs from tripartite models demonstrate fair conformity with the data but unique and distinct correlations with CVC. Negative affectivity may determine the relationship of anhedonic depression and autonomic anxiety with CVC. Separating affective symptoms under the constructs of the tripartite models helps disentangle complex associations between co-occurring depression and anxiety with CVC. PMID- 22846458 TI - Cogan's syndrome: an autoimmune inner ear disease. AB - OBJECTIVES: The objective of our study was to review our current knowledge of the aetiopathogenesis of Cogan's syndrome, including viral infection and autoimmunity, and to discuss disease pathogenesis with relevance to pharmacotherapy. SYSTEMATIC REVIEW METHODOLOGY: Relevant publications on the aetiopathogenesis and pharmacotherapy of Cogan's syndrome from 1945 to 2012 were analysed. RESULTS AND CONCLUSIONS: Cogan's syndrome is a rare autoimmune vasculitis, and its pathogenesis is unknown. Infection, but primarily autoimmunity, may play contributing roles in the pathogenesis of this disease. It is characterised by ocular and audiovestibular symptoms similar to those of Meniere's syndrome. Approximately 70% of patients have systemic disease, of which vasculitis is considered the pathological mechanism. The immunologic theory is based on the release of auto-antibodies against corneal, inner ear and endothelial antigens, and of anti-nuclear cytoplasmic auto-antibodies (ANCA). Corticosteroids are the first line of treatment, and multiple immunosuppressive drugs have been tried with varying degrees of success. Tumour necrosis factor (TNF)-alpha blockers are a category of immunosuppressive agents representing a recent novel therapeutic option in Cogan's syndrome. PMID- 22846459 TI - HINT: High-quality protein interactomes and their applications in understanding human disease. AB - BACKGROUND: A global map of protein-protein interactions in cellular systems provides key insights into the workings of an organism. A repository of well validated high-quality protein-protein interactions can be used in both large- and small-scale studies to generate and validate a wide range of functional hypotheses. RESULTS: We develop HINT (http://hint.yulab.org) - a database of high quality protein-protein interactomes for human, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Oryza sativa. These were collected from several databases and filtered both systematically and manually to remove low quality/erroneous interactions. The resulting datasets are classified by type (binary physical interactions vs. co-complex associations) and data source (high throughput systematic setups vs. literature-curated small-scale experiments). We find strong sociological sampling biases in literature-curated datasets of small scale interactions. An interactome without such sampling biases was used to understand network properties of human disease-genes - hubs are unlikely to cause disease, but if they do, they usually cause multiple disorders. CONCLUSIONS: HINT is of significant interest to researchers in all fields of biology as it addresses the ubiquitous need of having a repository of high-quality protein protein interactions. These datasets can be utilized to generate specific hypotheses about specific proteins and/or pathways, as well as analyzing global properties of cellular networks. HINT will be regularly updated and all versions will be tracked. PMID- 22846460 TI - Honeybees and cell lines as models of DNA methylation and aging in response to diet. AB - DNA methylation patterns change as individuals grow older, and DNA methylation appears susceptible to modification by the diet. Thus DNA methylation may be a mechanism through which diet can affect aging and longevity. We propose that effects on DNA methylation also contribute to the extension in lifespan observed in response to dietary restriction. Relationships between diet-induced changes in DNA methylation and parallel effects on aging and/or lifespan could, of course, be purely associative. Proof of these ideas requires experimental model systems in which it is possible to manipulate genome methylation status and to measure effects on aging and/or lifespan. Commonly-used short-lived and genetically malleable metazoan species, such as Caenorhabditis elegans and Drosophila, are not suitable for such studies; the C. elegans genome is not methylated, and DNA methylation in Drosophila is dissimilar from mammalian DNA methylation, occurring at cytosines at sites other than in CpG sequences. The honeybee provides a potentially unique and tractable model for such studies. Female larval development into the long-lived queen phenotype or short-lived worker is determined purely by diet (royal jelly) through an effect on DNA methylation, and honeybee DNA methylation mirrors that of the mammalian genome. Mammalian cell lines and biochemical approaches offer complementary tools to address specific components of hypotheses relating to effects of diet on aging through DNA methylation in a more targeted manner. Our studies using mammalian cell lines are revealing effects of Sirt1 on DNA methylation, and indicate that Sirt1 and resveratrol affect the expression of different sets of genes. PMID- 22846461 TI - Expression and function of APP and its metabolites outside the central nervous system. AB - Amyloid precursor protein (APP) derived amyloid beta (Abeta) peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the function of this ubiquitously expressed protein and its metabolites outside of the central nervous system. This review summarizes key aspects of the current understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. PMID- 22846462 TI - Linking language and categorization: evidence from aphasia. AB - In addition to its use in communication, language appears to have a variety of extra-communicative functions; disrupting language disrupts performance in seemingly non-linguistic tasks. Previous work has specifically linked linguistic impairments to categorization impairments. Here, we systematically tested this link by comparing categorization performance in a group of 12 participants with aphasia and 12 age- and education-matched control participants. Participants were asked to choose all of the objects that fit a specified criterion from sets of 20 pictured objects. The criterion was either "high-dimensional" (i.e., the objects shared many features, such as "farm animals") or "low-dimensional" (i.e., the objects shared one or a few features, such as "things that are green"). Participants with aphasia were selectively impaired on low-dimensional categorization. This selective impairment was correlated with the severity of their naming impairment and not with the overall severity of their aphasia, semantic impairment, lesion size, or lesion location. These results indicate that linguistic impairment impacts categorization specifically when that categorization requires focusing attention and isolating individual features--a task that requires a larger degree of cognitive control than high-dimensional categorization. The results offer some support for the hypothesis that language supports cognitive functioning, particularly the ability to select task-relevant stimulus features. PMID- 22846463 TI - Prospective memory deficits are associated with poorer everyday functioning in Parkinson's disease. AB - Although individuals with Parkinson's disease (PD) evidence moderate deficits in prospective memory (PM), it is not known whether PM deficits confer an increased risk of poorer everyday functioning. In the current study, 33 individuals with PD and 26 demographically similar normal controls (NC) were administered performance based and self-report measures of PM and everyday functioning, including medication and financial management. As compared to NC, PD participants demonstrated significantly lower scores on performance-based measures of PM and financial capacity, worse performance at a trend level on performance-based medication management and endorsed significantly greater self-reported declines in PM and instrumental activities of daily living (iADLs). In the PD sample, the laboratory measure of PM significantly correlated with performance-based measures of financial capacity and medication management and a self-report measure of medication management. Self-reported PM failures significantly correlated with perceived declines in iADLs, worse medication management, and poorer health related quality of life. Although future studies are needed to examine the incremental ecological validity of PM in PD, findings from this study extend prior research by providing preliminary evidence that PM impairment may play a significant role in a range of critical everyday functions in PD. PMID- 22846464 TI - Response surface methodology and improved interval analysis method--for analyzing uncertainty in accident reconstruction. AB - Methods used to calculate intervals of accident reconstruction results are research hotspot in the word. The response surface methodology-interval analysis method (RSM-IAM) is a useful method for analyzing uncertainty of simulation results in this field, but there are two problems in this method because of the interval extension problem and inaccurate response surface models. In order to tackle these two problems, based on subinterval analysis thought and response surface methodology, an improved interval analysis method (RSM-IIAM) is proposed. In RSM-IIAM, the stepwise regression technique is used to obtain a reasonable response surface mode of the simulation model; and then, intervals of uncertain parameters are divided into several subintervals; after that, intervals of simulation results in accident reconstruction are calculated according to these subintervals. Finally, four numerical cases were given. Results showed that the RSM-IIAM is simple and high accuracy, which will be useful in analyzing uncertainty of simulation results in accident reconstruction. PMID- 22846465 TI - Patient knowledge of their own illness: how much does it matter and how may we adapt our information to what the patient knows? PMID- 22846466 TI - Current advances in the management of gestational trophoblastic disease. PMID- 22846467 TI - Why don't healthcare professionals talk about sex? A systematic review of recent qualitative studies conducted in the United kingdom. AB - INTRODUCTION: Sexuality is considered to be an important aspect of holistic care, yet research has demonstrated that it is not routinely addressed in healthcare services. A greater understanding of this can be achieved through synthesizing qualitative studies investigating healthcare professionals' experiences of talking about sex. In doing so, policy makers and healthcare providers may be able to better address the sexual issues of service users. AIM: To gain an in depth understanding of healthcare professionals' subjective experience of discussing sexuality with service users by identifying the factors that impede and facilitate such discussions. MAIN OUTCOME MEASURES: Review of healthcare professionals' experience of discussing sexuality with service users. METHODS: Electronic databases and reference lists of published articles were searched in July 2011. Primary research studies were included in the review if they explored health professionals' experiences of discussing sexuality with adult service users, used qualitative methods, and were conducted in the United Kingdom over the last 10 years. Each study was reviewed and assessed. A secondary thematic analysis method was used where key themes were extracted and grouped and key concepts were explored. RESULTS: Nineteen interconnected themes emerged relating to healthcare professionals' experience of discussing sexuality with service users, including fear about "opening up a can of worms," lack of time, resources, and training, concern about knowledge and abilities, worry about causing offense, personal discomfort, and a lack of awareness about sexual issues. Some themes were particularly marked relating to the sexuality of the opposite-gender, black and ethnic minority groups, older and nonheterosexual service users, and those with intellectual disabilities. CONCLUSIONS: The majority of healthcare professionals do not proactively discuss sexuality issues with service users, and this warrants further attention. An understanding of the perceived barriers and facilitators indicates that interventions to improve the extent to which sexuality issues are addressed need to take organizational, structural, and personal factors into consideration. PMID- 22846468 TI - Duration of urinary leakage after open non-stented dismembered pyeloplasty in pediatric patients. AB - OBJECTIVE: We aimed to determine the duration and associated complications of postoperative urinary leakage in pediatric patients undergoing open, non-stented dismembered pyeloplasty for ureteropelvic junction obstruction. METHODS: A retrospective review of 100 patients who underwent an open non-stented dismembered pyeloplasty between 2003 and 2008 was performed. Duration of urinary leakage and postoperative complications were tabulated. Patients were considered to have a dry anastomosis if the Penrose drain was removed within one week of surgery. RESULTS: Duration of leakage ranged from 0 to 27 days. 86% had Penrose drain removal within 7 days of surgery and were considered dry.14 patients demonstrated a persistent urinary leakage (PUL) ranging from 7 to 27 days. Complications of any type were significantly more likely in the group with prolonged drainage (p = .0126). UTI and obstruction were not significantly more likely to occur in patients with PUL (p = .0931 and p = .2616 respectively). Only one patient with PUL required placement of a ureteral stent. CONCLUSION: We demonstrate that stentless dismembered pyeloplasty is feasible with a low rate of urinary drainage beyond one week. The character and quality of the slightly increased complications in those that demonstrated PUL were not great and not bothersome enough to warrant routine stenting. PMID- 22846469 TI - Management of osteoarthritis of the knee. PMID- 22846470 TI - Doctors and human rights groups challenge Arizona abortion law in court. PMID- 22846471 TI - Labour figures show fall in number of GP surgeries offering extended hours. PMID- 22846472 TI - On-site toluidine blue staining and screening improves efficiency of fine-needle aspiration cytology reporting. AB - OBJECTIVE: We investigated the role of on-site toluidine blue staining and screening in fine-needle aspiration cytology (FNAC) reporting for patients with thyroid nodules, palpable breast lumps and palpable lymph nodes. STUDY DESIGN: A total of 200 consecutive patients with a palpable lymph node or a lump in the breast or thyroid referred to the outpatient department for FNAC were included in this study. We used toluidine blue to stain FNAC slides for the evaluation of smear adequacy. The toluidine blue-stained slides were compared with the same slides after being decolorised and Papanacolaou (PAP)-stained. RESULTS: Out of 200 cases, 28 (14%) were deemed unsatisfactory on the first attempt as assessed by rapid staining. These included 16 (38%) of 42 thyroid cases, 10 (10.4%) of 96 breast lump cases and 2 (3.2%) of 62 lymph node cases. A repeat FNAC in the same sitting on these 28 patients showed adequate material in 24 (12%) of them. Therefore, for 98%, a decision could be made at the very first visit to plan further management. CONCLUSIONS: We concluded that toluidine blue offers excellent cytological details for the preliminary identification of the lesion and to decide on the adequacy of the material for definitive diagnosis on FNAC slides. PMID- 22846473 TI - A competing risks model in early screening for preeclampsia. AB - OBJECTIVE: It was the aim of this study to develop models for the prediction of preeclampsia (PE) based on maternal characteristics and biophysical markers at 11 13 weeks' gestation in which gestation at the time of delivery for PE is treated as a continuous variable. METHODS: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.4%) cases that subsequently developed PE and 57,458 cases that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes' theorem was used to combine the prior information from maternal characteristics with the uterine artery pulsatility index (PI) and the mean arterial pressure (MAP), using multiple of the median values. RESULTS: The risk for PE increased with maternal age, weight, Afro-Caribbean and South Asian racial origin, previous pregnancy with PE, conception by in vitro fertilization and a medical history of chronic hypertension, type 2 diabetes mellitus as well as systemic lupus erythematosus or antiphospholipid syndrome. In pregnancies with PE, there was an inverse correlation between multiple of the median values of the uterine artery PI and MAP with gestational age at delivery. Screening by maternal characteristics, uterine artery PI and MAP detected 90% of PE cases requiring delivery before 34 weeks and 57% of all PE cases at a fixed false-positive rate of 10%. CONCLUSIONS: A new model has been developed for effective first-trimester screening for PE. PMID- 22846475 TI - Choices of surgical approaches for gastrointestinal stromal tumors of the stomach: laparoscopic versus open resection. AB - AIMS: The aim of this study is to explore the optimal surgical approach for gastrointestinal stromal tumors (GISTs) of the stomach in terms of the perioperative outcomes and long-term relapse-free survival. METHODS: From January 2004 to July 2011, 156 patients who underwent either laparoscopic (LAP group, n = 68) or open surgery (OPEN group, n = 88) were included in the final analysis following the eligibility criteria. RESULTS: Clinicopathological characteristics of the selected patients were similar between the two groups. The LAP group was associated with less blood loss (50 vs. 180 ml, p < 0.001), shorter operating time (90 vs. 125 min, p < 0.001), earlier oral intake (3 vs. 5 days, p < 0.001), shorter postoperative hospital stay (8 vs. 10 days, p < 0.001), and low risk of postoperative complications (5.9 vs. 22.7%, p = 0.004) compared with the OPEN group. No significant difference was observed in 5-year relapse-free survival between the LAP and OPEN groups (94.2 vs. 94.0%, p = 0.807). The subgroup analysis of patients who underwent wedge resection showed similar results with the original comparison except that difference in complication rate between the two groups lost significance. CONCLUSIONS: Laparoscopic wedge resection for gastric GISTs <= 7 cm could get preferable short-term postoperative outcomes and similar long-term relapse-free survival compared with open surgery. PMID- 22846476 TI - High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis. AB - PURPOSE: High resolution magnetic resonance imaging (HRMRI) has been used as an imaging modality to depict the intracranial artery wall. The aim of this study was to compare images of the vessel wall between symptomatic and asymptomatic atherosclerotic plaques of the middle cerebral artery (MCA) using HRMRI. MATERIALS AND METHODS: From September 2009 to August 2010 we prospectively screened consecutive patients for MCA stenosis using time-of-flight (TOF) MR angiography. We studied 14 patients with symptomatic MCA stenosis and 16 patients with asymptomatic MCA stenosis. The HRMRI protocol included three different scans: T1-, T2-, and proton density (PD)-weighted black blood MRI. The cross sectional images of the MCA wall on HRMRI were compared between the two groups based on the degree of stenosis, remodeling ratio, outward or inward remodeling, plaque signal intensity, plaque surface irregularity, and presence of an intact inner wall. RESULTS: The degree of MCA stenosis and the ratio of plaque thickening to patent lumen in the symptomatic group were significantly higher than in the asymptomatic group. Outward remodeling of the stenotic area in symptomatic group was significantly higher than that seen in the asymptomatic group, and the reverse was true for inward remodeling of the stenotic area (it was significantly higher in the asymptomatic group compared to the symptomatic group). T2- and PD-weighted high signal foci, eccentric wall thickening, and plaque volume in the stenotic area were all similar between the two groups. CONCLUSIONS: HRMRI has the potential to distinguish between atherosclerotic plaques in symptomatic and asymptomatic MCA stenoses. PMID- 22846477 TI - Analytical strategies for characterization of oxysterol lipidomes: liver X receptor ligands in plasma. AB - Bile acids, bile alcohols, and hormonal steroids represent the ultimate biologically active products of cholesterol metabolism in vertebrates. However, intermediates in their formation, including oxysterols and cholestenoic acids, also possess known, e.g., as ligands to nuclear and G-protein-coupled receptors, and unknown regulatory activities. The potential diversity of molecules originating from the cholesterol structure is very broad and their abundance in biological materials ranges over several orders of magnitude. Here we describe the application of enzyme-assisted derivatization for sterol analysis (EADSA) in combination with liquid chromatography-electrospray ionization-mass spectrometry to define the oxysterol and cholestenoic acid metabolomes of human plasma. Quantitative profiling of adult plasma using EADSA leads to the detection of over 30 metabolites derived from cholesterol, some of which are ligands to the nuclear receptors LXR, FXR, and pregnane X receptor or the G-protein-coupled receptor Epstein-Barr virus-induced gene 2. The potential of the EADSA technique in screening for inborn errors of cholesterol metabolism and biosynthesis is demonstrated by the unique plasma profile of patients suffering from cerebrotendinous xanthomatosis. The analytical methods described are easily adapted to the analysis of other biological fluids, including cerebrospinal fluid, and also tissues, e.g., brain, in which nuclear and G-protein-coupled receptors may have important regulatory roles. PMID- 22846474 TI - Screening for personality disorder in incarcerated adolescent boys: preliminary validation of an adolescent version of the standardised assessment of personality - abbreviated scale (SAPAS-AV). AB - BACKGROUND: Personality disorder (PD) is associated with significant functional impairment and an elevated risk of violent and suicidal behaviour. The prevalence of PD in populations of young offenders is likely to be high. However, because the assessment of PD is time-consuming, it is not routinely assessed in this population. A brief screen for the identification of young people who might warrant further detailed assessment of PD could be particularly valuable for clinicians and researchers working in juvenile justice settings. METHOD: We adapted a rapid screen for the identification of PD in adults (Standardised Assessment of Personality - Abbreviated Scale; SAPAS) for use with adolescents and then carried out a study of the reliability and validity of the adapted instrument in a sample of 80 adolescent boys in secure institutions. Participants were administered the screen and shortly after an established diagnostic interview for DSM-IV PDs. Nine days later the screen was readministered. RESULTS: A score of 3 or more on the screening interview correctly identified the presence of DSM-IV PD in 86% of participants, yielding a sensitivity and specificity of 0.87 and 0.86 respectively. Internal consistency was modest but comparable to the original instrument. 9-days test-retest reliability for the total score was excellent. Convergent validity correlations with the total number of PD criteria were large. CONCLUSION: This study provides preliminary evidence of the validity, reliability, and usefulness of the screen in secure institutions for adolescent male offenders. It can be used in juvenile offender institutions with limited resources, as a brief, acceptable, staff-administered routine screen to identify individuals in need of further assessment of PD or by researchers conducting epidemiological surveys. PMID- 22846478 TI - Hairy cell leukemia presenting as a peripancreatic mass: cytomorphology and radiographic correlates. AB - Hairy cell leukemia (HCL) usually presents with peripheral cytopenias, diffuse marrow infiltration, and splenomegaly. This chronic lymphoproliferative disorder is not typically associated with lymphadenopathy or mass lesions. We report a case of HCL first treated by splenectomy, followed by several years of interferon therapy. Twenty-five years later, the patient presented with weight loss, fatigue, and a large PET-avid mass surrounding the head of the pancreas. Fine needle aspiration was pursued to investigate the unusual and infiltrative appearance of the lesion, which was suggestive of another primary malignancy. Cytology smears showed discohesive lymphoid cells with round nuclei and delicate cytoplasmic projections. Flow cytometry confirmed the presence of a clonal B-cell population with bright expression of CD20 as well as CD25 and CD103, diagnostic of HCL. This is the first report of HCL presenting as a peripancreatic mass. The importance of correlation with radiology and clinical history is emphasized when evaluating such lesions. PMID- 22846480 TI - Vascular dysfunction in diabetes. PMID- 22846479 TI - Genome-wide expression analysis upon constitutive activation of the HacA bZIP transcription factor in Aspergillus niger reveals a coordinated cellular response to counteract ER stress. AB - BACKGROUND: HacA/Xbp1 is a conserved bZIP transcription factor in eukaryotic cells which regulates gene expression in response to various forms of secretion stress and as part of secretory cell differentiation. In the present study, we replaced the endogenous hacA gene of an Aspergillus niger strain with a gene encoding a constitutively active form of the HacA transcription factor (HacACA). The impact of constitutive HacA activity during exponential growth was explored in bioreactor controlled cultures using transcriptomic analysis to identify affected genes and processes. RESULTS: Transcription profiles for the wild-type strain (HacAWT) and the HacACA strain were obtained using Affymetrix GeneChip analysis of three replicate batch cultures of each strain. In addition to the well known HacA targets such as the ER resident foldases and chaperones, GO enrichment analysis revealed up-regulation of genes involved in protein glycosylation, phospholipid biosynthesis, intracellular protein transport, exocytosis and protein complex assembly in the HacACA mutant. Biological processes over-represented in the down-regulated genes include those belonging to central metabolic pathways, translation and transcription. A remarkable transcriptional response in the HacACA strain was the down-regulation of the AmyR transcription factor and its target genes. CONCLUSIONS: The results indicate that the constitutive activation of the HacA leads to a coordinated regulation of the folding and secretion capacity of the cell, but with consequences on growth and fungal physiology to reduce secretion stress. PMID- 22846481 TI - Introduction. Management of GU malignancies. PMID- 22846482 TI - Pathology of genitourinary malignancies: implications for clinical management. AB - OBJECTIVES: To describe the pathologic and molecular characteristics of genitourinary malignancies relevant to the implications for the practice of oncology nurses. DATA SOURCES: Actual cases from the author's clinical experience, original scientific papers, review articles, and pathology books. CONCLUSION: Accurate pathologic diagnosis and identification of serum and molecular markers are critical for the accurate classification, staging, and choice of appropriate treatment for patients with genitourinary malignancies. IMPLICATIONS FOR NURSING PRACTICE: Because decisions of treatment initiation, discontinuation, and prognosis are in large part based on pathologic diagnosis and staging, oncology nurses should be knowledgeable about the process of pathologic tissue review and understand the importance of appropriate tumor acquisition. PMID- 22846483 TI - Urothelial cancers: ureter, renal pelvis, and bladder. AB - OBJECTIVES: To review the diagnosis, treatment, and nursing management of patients with urothelial cancers. DATA SOURCES: PubMed, Ovid MEDLINE, Text books, and clinical experience. CONCLUSION: Progress is being made in the surgical and systemic management of urothelial cancers, and the oncology nurse is in a position to make an impact on patient education and overall quality of life. IMPLICATIONS FOR NURSING PRACTICE: Nursing care begins at pre-diagnostic testing and continues through treatment for metastatic disease. Nurses must be knowledgeable about diagnostic tests, treatment options, and the quality-of-life implications of associated surgeries and/or treatments to support and guide patients. Education should be comprehensive, addressing not only treatment side effects but also long-term implications on patients' lives and lifestyles. PMID- 22846484 TI - Restoring and maintaining urinary function. AB - OBJECTIVES: To describe surgical urinary diversion methods, nursing management, and survivorship issues in urologic cancer survivors. DATA SOURCES: PubMed, Scopus, Cochran Reviews, Core 25 online texts. CONCLUSION: Options exist for patients that require urinary diversion, although long-term symptoms may persist. IMPLICATIONS FOR NURSING PRACTICE: Nurses must be knowledgeable about obstructive uropathy and understand the surgical options for urinary diversion following a cystectomy; pre- and post-operative needs exist for the cancer patient, family, and caregiver. Following completion of active treatment, a survivorship care plan summarizes active treatment and complications, plans long-term health outcomes and surveillance, and communicates with the primary care provider. PMID- 22846485 TI - Concepts in advanced renal carcinoma. AB - OBJECTIVES: Treatment options for advanced renal cell carcinoma have increased dramatically over the past 6 years as a result of improved understanding of the biology of renal cancer and the development of therapies to target pathways relevant to tumor progression. DATA SOURCES: Research-based articles. CONCLUSION: New therapies to treat advanced renal cell cancer results in a need for evidence based decision making when discussing treatment choices. IMPLICATIONS FOR NURSING PRACTICE: Knowledge of therapeutic strategies, their proposed mechanism of action, potential adverse events, and management strategies provides nurses with a foundation to provide appropriate patient education and effective management of treatment-related side effects, assisting patients to maximize clinical outcomes. PMID- 22846486 TI - Testicular cancer. AB - OBJECTIVES: To discuss the presentation, diagnosis, chemotherapy, surgical options, nursing management, and long-term outcomes of patients with testicular cancer. DATA SOURCES: Review and research articles, clinical experience. CONCLUSION: Testicular cancer is very treatable and the cure rate is approximately 95%. It is most common in men between the ages of 15 and 35. While early detection, diagnosis, and treatment are all important factors for treating the disease, fertility and quality of life are also important issues to address in patients with testicular cancer. IMPLICATION FOR NURSING PRACTICE: Nurses must provide patient instruction regarding chemotherapy, surgery, fertility, and side effects of treatment. Serving as a patient advocate regarding fertility preservation and promoting quality of life are important factors for health professionals to consider. PMID- 22846487 TI - Penile cancer. AB - OBJECTIVES: To review the risk factors, prevention, treatment, and management of the patient with penile cancer. DATA SOURCES: Publications; clinical experience. CONCLUSION: Penile cancer is a rare malignancy in the United States, but is more common in developing countries. The disease is so uncommon in the United States that there are oncology nurses who have never cared for a patient with this diagnosis. IMPLICATIONS FOR NURSING PRACTICE: With significant psychosocial implications for the patient with penile cancer and partner, it is important that the nurse have an understanding of the diagnosis, treatment, and care of these patients. PMID- 22846488 TI - Clinical update: survivorship care--models and programs. AB - OBJECTIVES: To provide a clinical update of models of care for adult cancer survivors and the challenges in program development. DATA SOURCES: Review of the literature. CONCLUSION: In the 4 years since the publication of the original article, survivorship is becoming a distinct phase of cancer care that includes surveillance for recurrence, evaluation of and treatment for medical and psychosocial consequences of treatment, recommendations for screening for new primary cancers, health promotion recommendations, and provision of a written treatment summary and care plan to the patient and other health professionals. IMPLICATIONS FOR NURSING PRACTICE: Implementing comprehensive services and evaluating care models continue to pose significant challenges for cancer care providers across the country; however, oncology nurses are uniquely positioned to take the lead in the care of cancer survivors of all ages and their role in the care of survivors is gaining recognition nationally and internationally. PMID- 22846489 TI - [Antiphospholipid syndrome and pregnancy]. AB - Antiphospholipid syndrome is characterized by arterial and venous thromboembolic events and persistent laboratory evidence of antiphospholipid antibodies. Obstetric complications such as recurrent miscarriage, early delivery, oligohydramnios, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/eclampsia, and HELLP syndrome are also hallmarks of antiphospholipid syndrome. This syndrome is one of the diseases associated with the most severe thrombotic risk. Changes in the hemostatic system during normal pregnancy also result in a hypercoagulable state resulting in elevated thrombotic risk. Thromboembolic events are responsible of the vast majority of maternal and fetal deaths. Administration of appropriate thromboprophylaxis helps prevent thromboembolic complications during pregnancy in women with antiphospholipid syndrome and also give birth to healthy children. It is important to centralize the medication and management of these patients. It helps in the thoughtful care of these pregnant women encountering serious problems. PMID- 22846490 TI - [Right ventricular outflow tract reconstruction in adolescents and adults after previous repair of congenital heart defects]. AB - Due to successful surgical treatment of congenital heart defects in infants and children, the number of patients who reach the adolescent/adult age is continuously increasing. AIMS: The authors sought to identify the short- and medium-term outcomes of reconstruction of right ventricular outflow tract in adolescents and adults who underwent surgical intervention for congenital heart defect in infancy or early childhood. METHODS: Between 2001 and 2012, 48 patients (age: 15-39, mean 21 years) (30 tetralogy of Fallot, 11 pulmonary atresia + ventricular septal defect, 6 transposition of great arteries + ventricular septal defect + left ventricular outflow tract obstruction, and 1 truncus arteriosus) had repeat operation because of right ventricular dysfunction. All patients previously underwent right ventricular outflow tract procedures in early childhood. RESULTS: In 31 patients, the small homograft, and in 9 patients the transannular-paths were replaced for "adult-size" homograft. Bioprosthetic pulmonary valve replacement was performed in pulmonary (6 patients) and homograft annuli (2 patients). In 14 patients, resection of the right ventricular outflow tract aneurism was also necessary to be performed. There was no early and mid time (10 years) mortality. In 97.5% of patients with homograft-re-implantation, there was no need for repeat intervention for 5 years. CONCLUSIONS: The right ventricular outflow tract restoration in adolescents and adults is an effective procedure. The reconstruction should be performed in early adolescent period to prevent right ventricular dysfunction. The authors prefer using bioprosthetic pulmonary valve replacement in patients with adult-size pulmonary or homograft annulus. PMID- 22846491 TI - [Study of stress, coping and psychosomatic health among baccalaureate nurses-to be]. AB - Stress is a risk factor that may endanger our quality of life and health. Certain occupational groups are particularly concerned, such as health care workers. OBJECTIVE: The present study aimed to investigate the stress load and coping strategies of nurses as well as their psychosomatic health. METHOD: The questionnaire survey was performed at the University of Szeged. The sample consisted of 208 nursing students (136 part-time and 72 full-time students). The self-completed questionnaire included items of psychosomatic symptoms, coping strategies and stress load. RESULTS: Persons characterized by high level of stress and more frequent psychosomatic symptoms tended to use inadaptive ways of coping more often; whereas those with a relatively lower stress level and fewer symptoms were not characterized by a more frequent use of active ways of coping but instead a lack of the inadaptive coping strategies. CONCLUSIONS: The authors concluded that vulnerability of the would-be baccalaureate nurses in this sample was especially high because they even used less effectively the ways of coping that otherwise aimed at both problem solving and maintaining their own health. PMID- 22846492 TI - [The National Health Insurance database of Hungary from the viewpoint of a health insurance physician]. AB - There is currently only one national database in the Hungarian health care system: the financial database of the National Health Insurance Fund. It includes all patients' data of state-funded services since 2000, those for pharmaceuticals, health spas and suppliers for patient transport. Any information for scientific research purposes can be obtained from this database. The database for inpatient records is complicated, and it is difficult to make queries. On the basis of his ten-year-experience, the author outlines the typical errors, which hinder a correct query. PMID- 22846494 TI - Foreword. The emergence of carbon monoxide (CO) and hydrogen sulphide (H(2)S) as biologically active gases. PMID- 22846495 TI - New insights into the plasticity of gill structure. AB - The ability of some fishes to reversibly remodel their gill morphology has become a focus of research after the discovery of extreme morphological gill plasticity in crucian carp and goldfish-both members of the cyprinid genus Carassius. Their lamellae are largely embedded in an interlamellar cell mass (ILCM) during normoxic conditions in cold water. The ILCM regresses in hypoxia, warm water, and during exercise, whereby the respiratory surface area and the capacity for oxygen uptake are greatly increased. There may be several reasons for covering the lamellae when oxygen needs are low. Reducing osmoregulatory costs have been suggested as an advantage of gill remodeling, but this has been difficult to show, putting the importance of the osmo-respiratory compromise into question. Other reasons could be to limit uptake of toxic substances and to reduce the risks for infections. In support for the latter, we present evidence showing that crucian carp infected by gill flukes maintain their ILCM when exposed to hypoxia. So far, gill remodeling in response to oxygen needs has been seen in several cyprinids, killifish and eel. In response to other environmental factors it may also occur in salmonids and anabantoids, revealing a phylogenetically widespread occurrence among teleosts. PMID- 22846496 TI - Developmental programming of O(2) sensing by neonatal intermittent hypoxia via epigenetic mechanisms. AB - Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in infants born preterm. Carotid body chemo-reflex and catecholamine secretion from adrenal medullary chromaffin cells (AMC) are important for maintenance of cardio respiratory homeostasis during hypoxia. This article highlights studies on the effects of IH on O(2) sensing by the carotid body and AMC in neonatal rodents. Neonatal IH augments hypoxia-evoked carotid body sensory excitation and catecholamine secretion from AMC which are mediated by reactive oxygen species (ROS)-dependent recruitment of endothelin-1 and Ca(2+) signaling, respectively. The effects of neonatal IH persist into adulthood. Evidence is emerging that neonatal IH initiates epigenetic mechanisms involving DNA hypermethylation contributing to long-lasting increase in ROS levels. Since adult human subjects born preterm exhibit higher incidence of sleep-disordered breathing and hypertension, DNA hypomethylating agents might offer a novel therapeutic intervention to decrease long-term cardio-respiratory morbidity caused by neonatal IH. PMID- 22846497 TI - Laquinimod modulates B cells and their regulatory effects on T cells in multiple sclerosis. AB - Laquinimod is an orally administered drug under development for the treatment of Multiple Sclerosis (MS), lacking a fully elucidated mode of action. We assessed the immunomodulatory effects of laquinimod in vitro on human B cells from healthy or MS patients, cultured alone or with CD4(+) T cells. Laquinimod modulated B cell markers, mainly by increasing the regulatory ones CD25, IL10 and CD86, and decreased IL4, while increasing IL10 and TGFbeta in both B and T cells, in a B cell-mediated manner. These findings shed additional light on the mechanisms underlying the effects of laquinimod in MS and potentially other immune-mediated diseases. PMID- 22846499 TI - Spontaneous splenic rupture in patient with metastatic melanoma treated with vemurafenib. AB - BACKGROUND: BRAF inhibitors such as vemurafenib are a new family of biological drugs, recently available to treat metastatic malignant melanoma. METHODS: We present the case of a 38-year-old man affected by metastatic melanoma who had been under treatment with vemurafenib for a few days. The patient suffered from sudden onset of abdominal pain due to intra-abdominal hemorrhage with profuse hemoperitoneum. An emergency abdominal sonography confirmed the clinical suspicion of a splenic rupture. RESULTS: The intraoperative finding was hemoperitoneum due to splenic two-step rupture and splenectomy was therefore performed. Histopathology confirmed splenic hematoma and capsule laceration, in the absence of metastasis. CONCLUSIONS: This report describes the occurrence of a previously unreported adverse event in a patient with stage IV melanoma receiving vemurafenib. PMID- 22846500 TI - Associations of parental education and parental physical activity (PA) with children's PA: the ENERGY cross-sectional study. AB - OBJECTIVE: The present study sought to examine the independent associations of parental education and physical activity (PA) with children's PA across Europe. METHODS: A total of 7214 children (10-12 years) were recruited from a school based cross-sectional survey during 2010 in seven European countries. Weight and height were measured. Parental educational level (PEL) and parents' and children's PA were collected using self-reported questionnaires. Multiple linear regression models were used, comparing children's PA with PEL and PA levels. RESULTS: PEL was directly associated with children's PA in Greek and Spanish girls (all P<0.01) and boys' PA in Norway (all P<0.05). Paternal education was directly associated with PA in Hungarian boys (P<0.05). In overall, parental PA was directly associated with children's PA in more than half of the countries involved (all P<0.05). CONCLUSIONS: Our observations suggest that PEL and parental modeling of PA are two independent factors from the home environment influencing the children's PA, but the relationships were gender- and country specific. Further studies should be focused on intervention strategies for increasing children's PA but considering the important role of these two aspects and especially on the modification of parental modeling of PA. PMID- 22846498 TI - Two-photon imaging of microbial immunity in living tissues. AB - The immune system is highly evolved and can respond to infection throughout the body. Pathogenspecific immune cells are usually generated in secondary lymphoid tissues (e.g., spleen, lymph nodes) and then migrate to sites of infection where their functionality is shaped by the local milieu. Because immune cells are so heavily influenced by the infected tissue in which they reside, it is important that their interactions and dynamics be studied in vivo. Two-photon microscopy is a powerful approach to study host-immune interactions in living tissues, and recent technical advances in the field have enabled researchers to capture movies of immune cells and infectious agents operating in real time. These studies have shed light on pathogen entry and spread through intact tissues as well as the mechanisms by which innate and adaptive immune cells participate in thwarting infections. This review focuses on how two-photon microscopy can be used to study tissue-specific immune responses in vivo, and how this approach has advanced our understanding of host-immune interactions following infection. PMID- 22846501 TI - Short sleep duration associated with a higher prevalence of metabolic syndrome in an apparently healthy population. AB - OBJECTIVE: To examine the association between sleep duration and metabolic syndrome in an apparently healthy Chinese population. METHOD: The baseline data were collected from a health examination center in Tainan, Taiwan, from October 1, 2006, to August 31, 2009. A total of 7100 adults were recruited. Subjects were classified into three groups according to their sleep duration: short (<6 h), normal (6-8 h), and long sleepers (>8 h). RESULTS: There were significant differences in age, gender, education level, fasting plasma glucose, and the proportion of smoking status and exercise frequency among different sleep groups. Based on multiple logistic regression, short sleepers were positively associated with metabolic syndrome (OR=1.28, 95% CI: 1.01-1.63) in males but not in females (OR=1.04, 95% CI: 0.72-1.51). Long sleepers were not related with metabolic syndrome in both genders. Short sleep duration was independently related to hyperglycemia (OR=1.39, 95% CI: 1.10-1.74) also in males only. Other components such as hypertriglyceridemia, low high density lipoprotein cholesterol, high blood pressure and central obesity were not associated with short sleep duration. CONCLUSION: Males with short sleep duration are positively associated with metabolic syndrome and they also exhibited a higher prevalence of hyperglycemia. PMID- 22846502 TI - Attractive names sustain increased vegetable intake in schools. AB - OBJECTIVE: This study will determine if the selective use of attractive names can be a sustainable, scalable means to increase the selection of vegetables in school lunchrooms. METHODS: Study 1 paired an attractive name with carrots in five elementary schools (n=147) and measured selection and consumption over a week compared to controls. Study 2 tracked food sales of vegetables in two elementary schools (n=1017) that were systematically attractively named or not named over a two-month period. Both studies were conducted in New York in 2011. RESULTS: Study 1 found that elementary students ate twice the percentage of their carrots if attractively named as "X-ray Vision Carrots," than if un-named or generically named as the "Food of the Day." Study 2 found that elementary school students were 16% more likely to persistently choose more hot vegetable dishes (p<0.001) when they were given fun or attractive names. DISCUSSION: Attractive names effectively and persistently increased healthy food consumption in elementary schools. The scalability of this is underscored by the success of Study 2, which was implemented and executed for negligible cost by a high school student volunteer. PMID- 22846503 TI - Differences in folic acid use, prenatal care, smoking, and drinking in early pregnancy by occupation. AB - OBJECTIVE: To describe differences in four high risk periconceptional behaviors (lack of folic acid supplementation, lack of early prenatal care, smoking, and drinking) by maternal occupation. METHODS: Analyses were conducted among women in the National Birth Defects Prevention Study who delivered liveborn infants without birth defects. Periconceptional occupational data were collected using a computer-assisted telephone interview and occupational coding was performed using the 2000 Standard Occupational Classification System. Logistic regression analyses were conducted to determine whether prevalence of behaviors differed between occupational groups. RESULTS: Subjects included 5153 women employed during early pregnancy from 1997 to 2007. Compared to women in management, business, science, and arts occupations, women in other occupations (e.g., service occupations) were significantly more likely to engage in all four high risk behaviors. Specifically, women in food preparation/serving-related occupations were significantly more likely to engage in all four behaviors compared to women in all other occupational groups (odds ratios: 1.8-3.0), while women in education/training/library occupations were significantly less likely to do so (odds ratios: 0.2-0.5). CONCLUSION: We identified several occupational groups with an increased prevalence of high-risk maternal behaviors during pregnancy. Our findings could aid in developing interventions targeted towards women in these occupational groups. PMID- 22846504 TI - Efficacy and feasibility of lowering playground density to promote physical activity and to discourage sedentary time during recess at preschool: a pilot study. AB - OBJECTIVE: This pilot study examined if lowering playground density is feasible and effective in improving preschoolers' activity and sedentary levels during recess. METHOD: Between November and December 2011, a within-subject design was used to study preschoolers' activity via accelerometry during recesses in the usual conditions (baseline) and with lower playground density (intervention). During the intervention, preschools scheduled extra recesses so that the number of classes usually sharing the playground was halved. Effects were investigated, using two-level linear regression models, in 128 4- to 6-year-old children (69 boys) from 4 preschools in Ghent, Belgium. The four preschool principals filled in a questionnaire after the intervention. RESULTS: At baseline, available play space was on average 7.4 (SD=1.7) m(2)/child; during the intervention this increased to 16.7 (SD=5.1) m(2)/child. The intervention was effective in decreasing sedentary time (-1 min; -5.1%) and increasing light-to-vigorous (+1 min; +5.1%) and moderate-to-vigorous physical activity (+0.8 min; +4.8%) during recess. None found it difficult to implement the intervention. All agreed it was possible to use this strategy in the future. CONCLUSIONS: Although it was feasible to implement this intervention, improvements in preschoolers' activity levels were small. This intervention could especially be important for preschools with higher playground density. PMID- 22846505 TI - Age and sex differences in prospective effects of health goals and motivations on daily leisure-time physical activity. AB - OBJECTIVE: To examine relationships between health goals, types of motivation for those goals, and daily leisure-time physical activity (LTPA), and whether these relationships differ by age or sex. METHODS: From 2005 to 2008, 710 participants in and around Berlin, Germany provided life goals and motivational attributes of those goals at baseline, then reported LTPA daily for 25 days. RESULTS: Having (vs. not having) a goal of physical health predicted higher odds of engaging in LTPA for younger but not older participants (under age 30; OR=1.26, p=0.048), and was not related to duration of LTPA episodes. Effect of intrinsic motivation for the health goal differed by sex: for females, higher intrinsic motivation predicted higher odds of LTPA (OR=1.19, p=0.001), but was not related to duration. For males, higher intrinsic motivation predicted lower LTPA odds marginally (OR=0.70, p=0.054) but predicted longer duration (estimate=18.27 min, p<0.001). More approach motivation for the health goal predicted longer duration of LTPA episodes (0.67 min, p=0.022). CONCLUSIONS: One size does not fit all in LTPA intervention design. Future research should identify the mechanisms by which health goals and motivations affect health behavior. PMID- 22846506 TI - What are the barriers and facilitators to exercise and physical activity uptake and adherence among South Asian older adults: a systematic review of qualitative studies. AB - OBJECTIVE: The objective of this study is to synthesise views and experiences of South Asian (SA) older adults in relation to exercise and physical activity (PA). It was anticipated that this work would identify barriers and facilitators that could inform interventions aimed at promoting PA among this population. METHOD: A systematic review of qualitative research was conducted. Six electronic databases were searched for relevant papers published from January 2000 to October 2011. Studies were appraised and data extracted by two reviewers. A synthesis was undertaken using framework analysis. Of 26 papers read in full, 11 were included in the review. RESULTS: An overriding concept derived from the synthesis was the influence of empowering and disempowering contexts on PA levels of SA participants. It was supported by the following themes: communication (e.g. relying on relatives for translation of information, lack of understanding); relationships (e.g. social support from family, friends, community), beliefs (e.g. not culturally appropriate to exercise, fatalism) and environment (e.g. lack of accessible recreational areas/facilities). CONCLUSIONS: Drawing on community resources to generate group norms appears to be important when trying to increase exercise and PA among SA older adults. Implications of the results for PA promotion and provision are discussed. PMID- 22846507 TI - Detection of apoptosis through the lipid order of the outer plasma membrane leaflet. AB - Cell plasma membranes of living cells maintain their asymmetry, so that the outer leaflet presents a large quantity of sphingomyelin, which is critical for formation of ordered lipid domains. Here, a recently developed probe based on Nile Red (NR12S) was applied to monitor changes in the lipid order specifically at the outer leaflet of cell membranes. Important key features of NR12S are its ratiometric response exclusively to lipid order (liquid ordered vs. liquid disordered phase) and not to surface charge, the possibility of using it at very low concentrations (10-20nM) and the very simple staining protocol. Cholesterol extraction, oxidation and sphingomyelin hydrolysis were found to red shift the emission spectrum of NR12S, indicating a decrease in the lipid order at the outer plasma membrane leaflet. Remarkably, apoptosis induced by three different agents (actinomycin D, camptothecin, staurosporine) produced very similar spectroscopic effects, suggesting that apoptosis also significantly decreases the lipid order at this leaflet. The applicability of NR12S to detect apoptosis was further validated by fluorescence microscopy and flow cytometry, using the ratio between the blue and red parts of its emission band. Thus, for the first time, an environment-sensitive probe, sensitive to lipid order, is shown to detect apoptosis, suggesting a new concept in apoptosis sensing. PMID- 22846508 TI - Efficacy verification and microscopic observations of an anticancer peptide, CB1a, on single lung cancer cell. AB - In this work, we introduce a new customized anti-lung cancer peptide, CB1a, with IC50 of about 25.0 +/- 1.6 MUM on NCI-H460 lung cancer cells. Using a multi cellular tumor spheroid (MCTS) model, results show that CB1a is potent in preventing the growth of lung cancer tumor-like growths in vitro. Additionally, atomic force microscopy (AFM) was used to examine cell surface damage of a single cancer. The mechanism for cell death under CB1a toxicity was verified as being largely due to cell surface damage. Moreover, with a treatment dosage of CB1a at 25 MUM, Young's module (E) shows that the elasticity and stiffness of cancer cell decreased with time such that the interaction time for a 50% reduction of E (IT50) was about 7.0min. This new single-cell toxicity investigation using IT50 under AFM assay can be used to separately verify drug efficacy in support of the traditional IC50 measurement in bulk solution. These results could be of special interest to researchers engaged in new drug development. PMID- 22846509 TI - Effect of juxtamembrane tryptophans on the immersion depth of Synaptobrevin, an integral vesicle membrane protein. AB - Proper positioning of membrane proteins in the host membrane is often critical to successful protein function. While hydrophobic considerations play a dominant role in determining the topology of a protein in the membrane, amphiphilic residues, such as tryptophan, may 'anchor' the protein near the water-membrane interface. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family of membrane proteins mediates intracellular membrane fusion. Correct positioning of the SNAREs is necessary if fusion is to occur. Synaptobrevins are integral vesicle membrane proteins that are well conserved across species. Interestingly, mammalian Synaptobrevins typically contain two adjacent tryptophans near the water-membrane interface whereas the Drosophila, neuronal-Synaptobrevin (n-Syb), contains a single tryptophan in this same region. To explore the role of these tryptophan residues in membrane positioning, we prepared a peptide containing residues 75-121 of D. melanogaster n-Syb in DPC micelles, biosynthetically labeled with 4-fluorophenylalanine and 5 fluorotryptophan for the examination by 19F NMR spectroscopy. Mutations of this construct containing zero and two tryptophan residues near the water-membrane interface resulted in changes in the positioning of n-Syb in the micelle. Moreover, the addition of a second tryptophan appears to slow dynamic motions of n-Syb near the micelle-water interface. These data therefore indicate that juxtamembrane tryptophan residues are important determinants of the position of Synaptobrevin in the membrane. PMID- 22846510 TI - Quantity vs. quality: an exploration of the predictors of posttreatment sexual adjustment for women affected by early stage cervical and endometrial cancer. AB - INTRODUCTION: Women with early stage cervical and endometrial cancer may experience complex posttreatment changes to their sexual function, but clinical practice and past research have focused more on the quantity than the perceived quality of sexual life. AIM: The aims of this prospective study were to explore the following: (i) the relative importance of quantity vs. quality of sexual life over the first year posttreatment; (ii) the psychological and sexual predictors of overall sexual function; and (iii) the relationship between sexual function and quality of life (QoL). METHODS: Fifty-three cancer patients completed standardized measures at baseline, with follow-up at 6 and 12 months posttreatment. Analyses were based on prespecified linear mixed models with overall sexual function and QoL as outcomes, and quality and quantity of sexual life, anxiety, and depression as the main predictors of interest. Radiotherapy, age, and relationship satisfaction were controlled for as potential confounders. MAIN OUTCOME MEASURES: Derogatis Sexual Functioning Inventory subscales to assess quantity (Drive) and quality (Satisfaction) of sexual life, and overall sexual function (Global Sexual Satisfaction Index); Functional Assessment of Cancer Therapy--General to assess QoL; Hospital Anxiety and Depression Scale to assess psychological distress; and Relationship Satisfaction Interaction Scale to assess relationship satisfaction. RESULTS: The models demonstrated that: (i) overall sexual function was predicted more strongly by the perceived quality than the quantity of sexual interactions, (ii) a small change in perceived quality had a large impact on overall sexual function, and (iii) overall sexual function was a predictor of QoL. CONCLUSION: This study found that quality rather than quantity of sexual life is the best predictor of overall sexual function among women treated for early stage cervical and endometrial cancer, indicating the importance of including quality indices in posttreatment sexual assessment in clinical practice and research studies. PMID- 22846511 TI - Survivors of war in northern Kosovo (III): The role of anger and hatred in pain and PTSD and their interactive effects on career outcome, quality of sleep and suicide ideation. AB - BACKGROUND: The management of chronic debilitating health conditions after trauma remains a challenge in post-conflict settings. The study aimed to expand current understanding of the diagnostic overlap of pain and PTSD and explore their independent and interactive effect on career change, sleep disorder and suicide ideation. The role of anger and hatred as contributing factors to the persistence of pain and PTSD were also examined. METHODS: 125 victims of torture and massive violence identified in a household survey took part in the in-depth assessment. Socio-demographic data and information on trauma, emotional disturbance, injuries and medication history were collected. PTSD was diagnosed according to DSM-IV criteria. Pain was assessed using the McGill Pain Questionnaire and the Margolis Pain Diagram. RESULTS: Nearly 95% participants experienced pain during the last 2 weeks, 47% were diagnosed with PTSD, 50% were taking medication against depression and anxiety. There is substantial overlap of pain, PTSD and emotional disturbance. Injury history, PTSD and negative emotions were related to the pain score and the number of pain locations. Anger, hatred or an inferiority complex particularly amplified pain experience. Headache was constant and especially prevalent in those with recent experience of anger, aggressiveness and hatred. The risk of having chest and abdominal pain within 2 weeks was very high in those who had chest injury and had recently been crying. An increased risk of changing jobs or stopping work or schooling due to depression or injury was observed for those with a higher pain score, and for pain in neck, shoulder and upper limbs. The prevalence of sleep disorders was 80%, that of suicide ideation 70%, and these were found to be associated with greater pain and anger. PTSD was also related to suicide ideation. CONCLUSIONS: The findings provide an overview of pain characteristics in individuals with PTSD and injury and confirm the hypothesized effects on career outcome, sleep disorders and suicide ideation. The study revealed a high level of persistent anger and hatred. The findings suggest the need for new approaches to rehabilitation in a post-war setting, including ways in which to address collective emotional hurt in the society. PMID- 22846512 TI - Birthweight with gestation and maternal characteristics in live births and stillbirths. AB - OBJECTIVE: To establish a normal range of birthweight with gestational age (GA) at delivery and examine the contribution of maternal characteristics in defining growth restriction in stillbirths. METHODS: In 69,895 normal singleton pregnancies, regression analysis was used to determine the association of birthweight with GA and maternal characteristics. The proportion of 290 stillbirths classified as small for GA depending on inclusion or exclusion of maternal characteristics was determined. RESULTS: In normal pregnancies, there was a polynomial association between birthweight and GA. Birthweight increased with maternal weight, height and parity and was lower in Africans and South Asians than in Caucasians. Birthweight for GA was reduced in antepartum stillbirths (n = 243; p < 0.0001) but not in intrapartum stillbirths (n = 47; p = 0.334). There was no significant difference in the proportion of antepartum stillbirths with birthweight below the 10th percentile when birthweight was corrected for GA only compared to correction for GA and maternal characteristics (53.1 vs. 54.3%). The birthweight was below the 10th percentile in 71.8% of antepartum stillbirths at <32 weeks' gestation, in 47.2% at 33-36 weeks and in 31.5% at >=37 weeks. CONCLUSION: Correction of birthweight for maternal characteristics does not alter the proportion of stillbirths that are small for GA. PMID- 22846513 TI - Diagnostic pitfalls of Hashimoto's/lymphocytic thyroiditis on fine-needle aspirations and strategies to avoid overdiagnosis. AB - OBJECTIVE: The importance of identifying papillary carcinoma or lymphoma amidst background Hashimoto's/lymphocytic thyroiditis (H/LT) is well documented. However, avoidance of overdiagnosing neoplasms on thyroid fine-needle aspiration (FNA) with only H/LT has not been adequately addressed. STUDY DESIGN: This study aimed to identify cytomorphologic features leading to overdiagnosing neoplasms within background H/LT. Nine thyroid FNAs classified as suspicious or positive for neoplasm with subsequent thyroidectomy specimens having only H/LT were identified. Cytologic features of these cases were compared to 8 control cases from the same time period and FNAs from both groups were reevaluated for features from the cytology literature. RESULTS: Features leading to overdiagnosing papillary carcinoma were: powdery chromatin, occasional nuclear grooves or holes, and paucity of background lymphocytes. One feature differentiating H/LT from neoplasm noted in most cases was lymphocytes infiltrating follicular groups. In contrast, true papillary carcinomas displayed characteristic features in multiple cell clusters. These clusters were devoid of infiltrating lymphocytes or displayed only rare lymphocytes at their periphery. A microfollicular pattern with paucity of background lymphocytes was the major pitfall in overdiagnosing follicular neoplasm. CONCLUSIONS: Features suspicious for neoplasm are often seen in FNA of H/LT, leading to unnecessary surgery. Recognizing this pitfall and its differentiating features should avert overdiagnosis. PMID- 22846514 TI - Determinants of pulmonary hypertension in patients with Beta-thalassemia major and normal ventricular function. AB - BACKGROUND/AIMS: We sought to define the incidence and predictive factors of pulmonary hypertension in beta-thalassemia major. METHODS: We studied 27 consecutive patients (19 male, 38 +/- 9 years of age) with beta-thalassemia major. All the patients had normal (left and right) ventricular (systolic and diastolic) function and underwent echocardiographic assessment of pulmonary artery systolic pressure. Univariate regression and discriminant function analyses were used to identify predictive factors of pulmonary hypertension. RESULTS: Pulmonary hypertension was observed in 18.5% of the patients, but clinically significant disease was detected in only 3.7%. A total of 14 (51.8%) patients had been receiving a combined administration of deferoxamine and deferiprone for 7.0 +/- 1.3 years. Amidst a large number of variables examined, ferritin levels and delayed onset of chelation therapy were the only predictors of pulmonary hypertension. CONCLUSION: Pulmonary hypertension in beta-thalassemia major is relatively infrequent and generally mild due to improved chelation therapy. The role of hemochromatosis in pulmonary hypertension development merits further study. PMID- 22846515 TI - Screening of counterfeit corticosteroid in creams and ointments by NMR spectroscopy. AB - It has been shown that NMR spectroscopy is an effective analytical method to rapidly screen creams and ointments for counterfeit corticosteroids. Extraction and NMR procedures have been developed. Ten over the counter creams and ointments sold in health care shops were screened and two creams were found to contain counterfeited corticosteroids. PMID- 22846518 TI - Normal female puberty in a developmental perspective. AB - Puberty is unique in the sense that its onset shows an extraordinary individual variability of about 5 years, the basis of which being still elusive despite research efforts to understand the reason why. Continuing changes in environmental influences and interaction with genetic determinants are suggested by the still evolving pattern of the pubertal process both clinically and mechanistically. For instance, secular trends towards earlier breast development have been observed during the two past decades in some countries, resulting in possible skewing of the age distribution of that pubertal sign with less obvious changes in menarcheal age. Conceptually, puberty and subsequent reproduction appear now to be influenced by conditions not only at the time when they occur, but also during fetal and perinatal life. In addition, these influences can be apparently opposing since early maturation follows fetal malnourishment and postnatal overfeeding. In this review, the semiology and pathophysiology of puberty are discussed in a lifelong developmental perspective. PMID- 22846517 TI - Gynecologic clinical examination of the child and adolescent. AB - Pediatric gynecological examination is very simple, but usually unrecognized by physicians without a specific experience in pediatric gynecology. It is always necessary and most of the time sufficient in children and adolescents consulting for gynecological complaints, endocrine problems, or sexual abuse. However, accurate evidence-based data on its normality is poor in the literature, because of bias represented by the inclusion of abused patients in these studies. Our aim was to describe the preparation to a full gynecological examination, the adequate positions, and the sequence and technique required for a well-accepted and nontraumatic clinical examination. Normal findings are described depending on the age of the patient (child, newborn, adolescent), and are based on evidence from the literature. Indications for vaginoscopy and bacterial sampling are discussed according to the age of the patient. The most important factors in the achievement of a full gynecological examination and a trusting patient-physician relationship are a good anatomical and physiological knowledge of the genital system in children, and the learning of nonaggressive examination technical skills associated with good communication skills. Clinical examination is always necessary and most of the time is sufficient together with the medical history to diagnose and treat the child's gynecological problems. Evidence-based data on normal genital findings is poor in the literature, because many studies include abused children or present bias in the methods of recruitment and assessment of normal girls [1]. PMID- 22846519 TI - Endocrine evaluation of reproductive function in girls during infancy, childhood and adolescence. AB - Puberty is characterized by a series a hormonal events leading to the attainment of adult reproductive capacity. Clinical manifestations of the pubertal processes include breast development, pubic hair development, menarche and regular menstrual bleedings. Abnormal pubertal development includes a spectrum of disorders such as premature thelarche, premature adrenarche, central and peripheral precocious puberty, adolescent polycystic ovarian syndrome, functional ovarian hyperandrogenism, late-onset congenital adrenal hyperplasia, primary and secondary amenorrhea, and premature ovarian insufficiency. Diagnosis of these reproductive disorders includes biochemical as well as clinical evaluation. The biochemical evaluation of reproductive function includes measurement of basal reproductive hormone levels and dynamic pituitary or adrenal hormone testing. Correct interpretation of such test results requires detailed knowledge on the normal maturational changes in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes. Changes in basal reproductive hormone levels in infancy, childhood and adolescence as well as the GnRH and ACTH test procedures in girls and adolescents are described in this chapter. PMID- 22846520 TI - Diagnostic methods in pediatric and adolescent gynecology. AB - The evolving role of imaging techniques and endoscopic tools used in gynecologic practice has become essential over the last several years. Pelvic organs of the young girl are deeply hidden in the abdomen and the vagina is narrow and atrophic. The presence of an intact hymen provides an additional obstacle to vaginal examination. Therefore, bimanual pelvic (vaginal/rectal) examination has a limited advantage in this population. It could cause unnecessary discomfort and hamper further 'patient-doctor' dialog. Imaging techniques are constantly improving in sensitivity, thus providing more accurate diagnoses. Ultrasonography which is a safe and available modality provides real-time images of multiple planes and therefore is ideal for pelvic evaluation. It should be an integral part of child and young adolescent examination. Additional modalities such as CT and MRI should be reserved for cases which are ultrasonography doubtful and be applied as a subsequent evaluation. Vaginoscopy and laparoscopy, although invasive, are used for final diagnosis and provision of treatment as 'see and treat' procedures. These main modalities used in the diagnosis of gynecologic disorders in the young are described in this chapter. PMID- 22846516 TI - Effect of depression on mortality and cardiovascular morbidity in type 2 diabetes mellitus after 3 years follow up. The DIADEMA study protocol. AB - BACKGROUND: Type 2 diabetes mellitus and depression are highly prevalent diseases that are associated with an increased risk of cardiovascular disease and mortality. There is evidence about a bidirectional association between depressive symptoms and type 2 diabetes mellitus. However, prognostic implications of the joint effects of these two diseases on cardiovascular morbidity and mortality are not well-known. METHOD/DESIGN: A three-year, observational, prospective, cohort study, carried out in Primary Health Care Centres in Madrid (Spain). The project aims to analyze the effect of depression on cardiovascular events, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus, and to estimate a clinical predictive model of depression in these patients.The number of patients required is 3255, all them with type 2 diabetes mellitus, older than 18 years, who regularly visit their Primary Health Care Centres and agree to participate. They are chosen by simple random sampling from the list of patients with type 2 diabetes mellitus of each general practitioner.The main outcome measures are all-cause and cardiovascular mortality and cardiovascular morbidity; and exposure variable is the major depressive disorder.There will be a comparison between depressed and not depressed patients in all-cause mortality, cardiovascular mortality, coronary artery disease and stroke using the Chi squared test. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors that might alter the effect recorded will be taken into account in this analysis. To assess the effect of depression on the mortality, a survival analysis will be used comparing the two groups using the log-rank test. The control of potential confounding variables will be performed by the construction of a Cox regression model. DISCUSSION: Our study's main contribution is to evaluate the increase in the risk of cardiovascular morbidity and mortality, in depressed Spanish adults with type 2 diabetes mellitus attended in Primary Health Care Setting. It would also be useful to identify subgroups of patients for which the interventions could be more beneficial. PMID- 22846521 TI - Disorders of sex development: neonatal diagnosis and management. AB - The disorders of sex development (DSD) refer to the insufficient virilization of the external genitalia of a 46,XY fetus or the excessive virilization of those of the 46,XX fetus. Some of these disorders are associated with karyotype abnormalities. DSD arise from abnormal gonadal determination or sex differentiation, as in the case of the abnormal testosterone synthesis or androgen insensitivity of 46,XY DSD. The impact of environmental endocrine disrupting chemicals during fetal life requires further investigation. The basic investigations should include SRY gene sequencing and measurement of 17 hydroxyprogesterone, anti-Mullerian hormone, and testosterone. Choosing the sex of rearing is difficult and the decision must be made by an experienced multidisciplinary team. PMID- 22846522 TI - Vulvovaginitis and other common vulvar disorders in children. AB - Vulvovaginitis, labial adhesions, and other vulvar disorders occur commonly in children and can provoke high anxiety in both the parent and child. Performed correctly, the pediatric gynecologic examination can diagnose and treat, educate and reassure both parent and child. This examination requires patience, sensitivity, direct communication with the child as well as with the parent, and an open manner that inspires trust in both parties to manage a potentially anxiety-provoking situation. This chapter will review common vulvar disorders, including vulvovaginitis, lichen sclerosis et atrophicus, bubble bath vaginitis, labial adhesions, urethral prolapse, and other common problems. A discussion of childhood sexual abuse is beyond the scope of this chapter, with appropriate references available elsewhere. Practical pearls will be offered to make this exam easy for the primary care clinician and/or subspecialist. PMID- 22846523 TI - Clinical expression of precocious puberty in girls. AB - Premature development of breast and/or pubic hair in a prepubertal girl used to raise questions and concerns from the families. There is actually a wide range of clinical expressions of precocious puberty in girls and not all presentations are considered to be true precocious puberty. Central precocious puberty occurs in 10 20% of girls, but beside the typical forms other clinical presentations have been identified. In 50-60% of the cases, only one secondary sex characteristic shows premature development and raises the diagnosis of premature thelarche, premature pubarche or isolated metrorrhagia. In 10% of the cases, autonomous ovarian overproduction of estrogens causes peripheral precocious puberty. Lastly, hyperestrogenism may have exogenous causes, such as exposure to environmental chemical pollutants. A decision on therapeutic management is based on clinical, biological and radiologic examinations, and LHRH analogous treatment should be limited to central precocious puberty before the age of 8 years. PMID- 22846524 TI - Ovarian cysts in prepubertal girls. AB - Visualization of follicles is perfectly physiological during childhood, their diameter generally does not exceed 10 mm. Ovarian cyst in childhood is well defined for a fluid image >20 mm. Generally mild and asymptomatic, ovarian cysts are fluid formations usually discovered incidentally by ultrasound. Some are hormonally active and cause the development of sexual characteristics. The natural history of functional cysts is eventual regression, and persistence is suggestive of organic tumor. The onset of pain is a sign of complication, and an abrupt sharp pain with vomiting is suggestive of ovarian torsion, in which case surgical intervention is urgent. In all cases, the diagnosis is based on pelvic ultrasound. MRI and tumor marker assays are required to determine the nature of an organic cyst before proceeding to surgery. These cysts may appear functional from the fetal period onward and will require management from the first days of life. Certain endocrine disorders such as precocious puberty, hypothyroidism, and aromatase deficiency cause functional cysts in girls. Recurrent bleeding is due to hormonally active cysts and suggests McCune-Albright syndrome. Although the persistence of a cyst suggests a neoplasm, a fluid character indicates benignity. Imagery is a useful aid in the diagnosis of epithelial tumors (cystadenomas) or teratoma (dermoid cyst). PMID- 22846525 TI - Sexual abuse in prepubertal children and adolescents. AB - Medical involvement in the diagnosis and treatment of child sexual abuse (CSA) has a well-defined role within a multidisciplinary concept. Due to the increasingly high rate of normal anogenital findings in victims of CSA, forensic aspects are of limited value in establishing the diagnosis. In selected cases however, medical findings may play an important role in corroborating a child's history. Correct evaluation of normal and abnormal findings, normal variations and several differential diagnoses requires sound knowledge in pediatric gynecology. In some cases, physical consequences of CSA (injuries, infections, and pregnancy) need to be diagnosed and treated (prevented) accordingly. The majority of abused children have an altered and distorted body image. It is of paramount importance to reassure the child that its body is normal, physically undamaged, intact or that it will heal ('primary therapeutic aspect of the medical examination'). Thus, the medical examination has an enormous potential to incorporate a therapeutic message into the diagnostic procedure if performed in a qualified and sensitive manner. By communicating with the psychosocial und jurisdictional systems, physicians may initiate proper child protection and therapy. Therefore, medical evaluation of sexually abused children must always be integrated into a multiprofessional concept of child protection. PMID- 22846526 TI - Delayed puberty. AB - Since puberty is a long ongoing developmental process with significant individual and population differences in timing, the definition of delayed puberty for a given individual needs to rest on simple, though arbitrary criteria based on epidemiological data. Although several genes involved in the hypothalamic pituitary-gonadal maturation cascade have been characterized recently from familial or sporadic cases of primitive isolated hypogonadotropic hypogonadism, many genes regulating puberty onset remain undetermined. In case of delayed puberty and/or primary amenorrhea, a complete clinical examination including a detailed past history will evaluate the development of secondary sex characteristics, verify the association with a growth delay and look for specific indicative features pertaining to the etiological diagnosis. This clinical check up completed if necessary with biological, ultrasonographic, radiological and genetic investigations will try to determine which girls will have a permanent sexual infantilism of gonadal, hypophyseal or hypothalamic origin, which girls will undergo spontaneous but delayed puberty and which girls have primary amenorrhea with developed secondary sex characteristics. Therapeutic attitude will have to integrate etiological factors, statural prognosis, bone mass preservation and psychological factors. PMID- 22846527 TI - Menstrual disorders. AB - Menstrual disorders are very common in adolescence, and can be the cause of a significant amount of stress to both the patients and their parents. Variations of the menstrual cycle in this age are very broad and are mainly caused by the immaturity of the hypothalamic-pituitary-ovarian (HPO) axis. Amenorrhea (either primary or secondary), abnormal uterine bleeding and dysmenorrhea are conditions that require careful evaluation through a stepwise and logical manner. The term primary amenorrhea refers to the condition when menarche fails to occur, while secondary amenorrhea refers to the cessation of menses once they have begun. The occurrence of irregular, prolonged or heavy abnormal uterine bleeding is one of the most urgent gynecological problems in adolescence and the diagnosis of dysfunctional uterine bleeding should be used only when all other organic and structural causes of abnormal vaginal bleeding have been ruled out. Dysmenorrhea refers to painful menstruation and is the most common reason for which a young girl may refer to a gynecologist. It is characterized as primary in the absence of an underlying organic disease, and as secondary when there is evidence of pelvic pathology. Appropriate and early management of the patient is necessary in order to minimize the possibility of future complications regarding woman's reproductive ability. PMID- 22846528 TI - Adolescent dysmenorrhea. AB - Primary dysmenorrhea, which affects from 43 to 91% of adolescent girls, is defined as painful uterine cramps that precede and accompany menses. Primary dysmenorrhea is related to an overproduction of uterine prostaglandins which induces myometrium hypercontractility and arterioral vasoconstriction, both involved in painful menstrual cramps. In addition, headache, nausea, asthenia, irritability and school absenteeism are frequently reported and need to be quantified through a clinical score. Despite its relevant impact on adolescent quality of life and availability of efficacious medication such as non-steroidal anti-inflammatory drugs, only 15% of affected adolescents consult a physician for this pain syndrome. Pediatricians and gynecologists should thus be more actively involved in the diagnosis and treatment of adolescent primary dysmenorrhea. PMID- 22846529 TI - Hyperandrogenism in adolescent girls. AB - When the symptoms of hyperandrogenism are mild in an adolescent girl, it is difficult to establish whether they are related to the physiological androgenization of puberty or to an incipient disease. The most frequent etiology is the polycystic ovary syndrome (PCOS). Its diagnosis is defined in adult women by precise criteria which need to be adapted to the particular case of the adolescent girl. Nonclassic adrenal hyperplasia is the main differential diagnosis to PCOS. Although much less frequent, other etiologies of peripubertal hyperandrogenism such as adrenal or ovarian tumors or Cushing's disease must be considered by analyzing the rapidity of installation and intensity of hyperandrogenic symptoms and by a systematic hormonal work-up. In addition to etiologic measures, the treatment consists of administration of an anti-androgen, mainly cyproterone acetate. In the case of PCOS, the patient needs to be educated regarding the metabolic risks. PMID- 22846530 TI - Ovarian masses in adolescent girls. AB - Ovarian masses are the most frequent gynecological pathology seen in adolescent girls. Functional or organic tumors of the ovary are usually benign and the incidence rises with age. Most cysts are functional and adnexal torsion is the main complication, but a malignant etiology must nevertheless always be eliminated. The clinical presentation is quite variable. Ultrasonography is the investigation of choice: the sonogram will reveal a strictly fluid, benign functional cyst, suggest an adnexal torsion, and provide evidence of a heterogeneous mass. Emergency surgery is indicated only in the case of suspected ovarian torsion, in order to perform detorsion. In all other cases, serum tumor marker measurements will orient the diagnosis and MRI is an essential complement to imaging of tumors with heterogeneous solid components. Surgery and histopathological examination then determine the stage and the benign or malignant nature of the mass. Ovarian tumors are classified by the World Health Organization based on the cell of origin into epithelial tumors, germ cell tumors and sex cord-stromal tumors. Surgery should always follow oncological standards and be as conservative as possible to preserve future fertility. PMID- 22846531 TI - Breast diseases in adolescents. AB - Fibroadenomas and breast growth disorders are the most common breast diseases in adolescent women. Assessment of breast disorders in this age group generally involves clinical evaluation through history and physical examination and when is needed ultrasonography. Due to the absence of breast cancer in adolescent women, it is easy to reassure women at the first consultation. Breast growth disorders can lead great psychological and physical embarrassment. Treatment consists of surgical procedures when the cosmetic defect is severe. According to the ANDI classification, small fibroadenomas are normal, clinical fibroadenomas are a mild aberration of the normal processes, and giant or multiple fibroadenomas are placed to the disease end of the spectrum. Fibroadenomas can be treated conservatively provided diagnosis is confident. Giant fibroadenomas are treated by surgical enucleation. Breast abscess is mainly due to the duct ectasia. In adolescence, ectasia has been described as an exaggeration of sinus duct development and can be considered as a variant of normality. Diseases of the adolescent breast are usually benign and their management are simple using medical strategy and more rarely surgical therapy. PMID- 22846532 TI - Cervical cancer prevention - current perspectives. AB - This report addresses several areas including the progress made toward global implementation of currently licensed human papillomavirus (HPV) vaccines, and monitoring impact of HPV vaccination programs that can be implemented within developed and less-developed countries. For the sake of completeness, a short update on the evolution of HPV testing in primary screening programs at present and after HPV vaccine introduction has also been included. PMID- 22846533 TI - Chronic pelvic pain in the adolescent. AB - Chronic pelvic pain occurs commonly in the adolescent and can be a diagnostic and therapeutic challenge for the clinician, the adolescent, and her family. Defined as lower quadrant or lower abdominal pain lasting 3-6 months or longer, chronic pelvic pain can lead to missed school and activities, decreased functioning, and decreased quality of life in the adolescent. Both the primary care clinician and the pediatric gynecologist need to be aware of the most common causes of chronic pelvic pain in the adolescent, including surgical and nonsurgical, gynecologic versus other pathology including the psychosomatic, and the role of the mind in control of somatic pain in the adolescent. Adding to this complexity is the standard adolescent sense of invulnerability; a knowledge of adolescent development remains essential to the delivery of appropriate gynecologic care for this age group. Education and communication with both the adolescent and her family requires sensitivity, especially in cultures where adolescent sexuality is taboo or discouraged. This chapter will discuss the developmental stages of adolescence and how that impacts care of the patient with chronic pelvic pain at the varying ages, the issue of confidentiality when obtaining a sexual history on the adolescent, and etiologies of chronic pelvic pain specific to the adolescent, including gynecologic and nongynecologic causes. Diagnostic and treatment considerations for chronic pelvic pain in the adolescent will also be addressed. PMID- 22846534 TI - Congenital developmental defects of derivates of mullerian ducts. AB - Congenital developmental defects of Mullerian derivates, understandable with the knowledge of embryological development of Wolffian and Mullerian ducts, are defects of canalisation (= gynatresias), defects in fusing, combined defects and uterovaginal agenesis. Gynatresias should be suspected in the newborn, but distinguished in puberty, on the basis of menstrual blood retention, as hymeneal atresia (haematocolpos), aplasia partis distalis vaginae (haematocolpos partialis), transversal vagina septum and aplasia of vagina and uterine cervix (isolated haematometra). Particular operations are described. Defects in the fusing of Mullerian ducts from the point of view of surgery could be single coated or double-coated. Incomplete reduplication with unilateral renal aplasia syndrome could present as hemihaematocolpos, hemihaematometra and haematometra in rudimental horn. For diagnosis of these disorders menstrual blood retention is necessary. Surgical treatment in the first two types includes resection of the common wall and haematometra in rudimental horn needs metroplasty or hemihysterectomy. Congenital absence of uterus and vagina (Rokitanski Kuster) appears in genetically, endocrinologically and psychosexually normal females. Diagnosis is based on clinical examination and ultrasonography. Initial examination should be nonsurgical (dilatation method). All surgical corrections create a place for the future vagina and reach its epithelization. Different procedures are criticised. The author recommends and describes Vecchietti's laparoscopic surgery. PMID- 22846535 TI - Eating disorders throughout female adolescence. AB - Eating disorders (EDs) are conditions which are becoming more and more widespread among adolescents and they often lead them to seek the opinion of a professional health caregiver, including gynecologists and pediatricians. EDs, and particularly anorexia nervosa (AN), are usually classified as psychological or psychiatric disorders, but they may have major somatic implications and complications as osteoporosis, nutritional deficiencies, cerebral atrophy, cardiac and metabolic disorders. A key issue in the management is prevention or reduction of both the serious somatic consequences and the important mental health consequences (e.g. depression, psychosocial withdrawal, phobia and suicide), integrating different perspectives (psychological or psychiatric - individual and familial -, genetic, nutritional, pediatric, gynecological). Adolescence is a critical period for the onset of EDs though they may also involve younger children. In this case, the consequences on the development (height, weight, puberty) can also be significant. In this review, we will focus on eating disorders in adolescent girls with an emphasis on AN. We describe variations in ED characteristics and their management depending on age at occurrence. A possible ED should be considered by pediatricians consulted about delayed female growth and puberty as well as gynecologists in patients with primary or secondary amenorrhea or infertility. PMID- 22846536 TI - Adolescent contraception. AB - Sexual health for adolescents is based on three components: recognizing sexual rights, sexuality education and counseling, and confidential high-quality services. Contraception needs to include prevention of both STIs and pregnancy. The main options for adolescents are condoms backed-up by emergency contraception; and hormonal contraceptives in a longer, mutually monogamous relationship. Condoms and hormonal contraception together can be well recommended for adolescents. Condom use should not be stopped before it is reasonably certain that the partner is STI-negative. Other alternatives can be considered in special cases. Improved contraceptive methods do not automatically lead to reduced numbers of adolescent abortions. The prevention of unintended adolescent pregnancies requires four elements: a desire to use protection, a good contraceptive method, ability to obtain the contraceptive method, and ability to use it. All these components are important, and if one is missing contraception will fail. In the developed countries, we have good contraceptive methods, but improvements are still needed in the other components. When adolescent sexuality is not condemned but sexuality education and sexual health services instead are provided, it is possible to profoundly improve adolescent sexual health with comparatively small costs. Each year new groups of young people mature, requiring new efforts. PMID- 22846537 TI - Teenage pregnancy. AB - Teen pregnancy is a social problem not resolved in developing and some developed countries. Adolescent fecundity has become the most exact bio-demographic and health indicator of development. In developing countries that are expected to follow the sexual behaviour patterns of developed countries, without offering the levels of education and services for adolescents, the consequences will be adolescent fecundity and STI prevalence increase. The ignorance about sexuality and reproduction both in parents, teachers and adolescents increases the early initiation of coital relations and of unwanted pregnancies. Extreme poverty and being the son or daughter of an adolescent mother are risk factors of repeating the early pregnancy model. The application of predictive risk criteria in pregnant adolescents to facilitate the rational use of Health Services to diminish the maternal and perinatal mortality is discussed as well as the social factors associated with adolescent pregnancy as socioeconomic levels, structure - types and characteristics of the family, early leaving school, schooling after delivery, female employment, lack of sexual education, parental and family attitudes in different periods of adolescent pregnancy, adolescent decisions on pregnancy and children, unstable partner relationship and adoption as an option. Social consequences are analyzed as: incomplete education, more numerous families, difficulties in maternal role, abandonment by the partner, fewer possibilities of having a stable, qualified and well-paid job, greater difficulty in improving their socioeconomic level and less probability of social advancement, lack of protection of the recognition of the child. Finally, based on evidence, some measures that can reduce adverse consequences on adolescent mothers, fathers and their children are suggested. PMID- 22846538 TI - Sexuality education: Finnish and Chilean experiences. AB - All children and young people have the right to age-appropriate sexuality education regardless of gender, sexual orientation, ability or faith. Sexuality education provides knowledge, skills and positive values to determine and enjoy their sexuality, have safe, fulfilling relationships if one so wishes and decides, and to take responsibility for their own and for a possible partner's sexual health and well-being. Several international programs have been developed and recently published by the Population Council, IPPF and other coworkers, by UNICEF, and by WHO Europe. This chapter will briefly describe recent global development in sexuality education, and then, as examples, experience from two countries, Finland and Chile. The experiences from these school based programs suggest an important role of sexuality education. PMID- 22846539 TI - High-risk sexual behaviors. AB - Adolescence is a time of life characterized by danger because of the many changes that occur, the many ties that are severed: ties to childhood, ties to the child's body as it begins to take on an adult appearance, ties to a once-familiar body image and psyche as hormones complete the transformation to adulthood, ties to an unconscious that is struggling to restructure itself anew. The creation of the romantic couple is a danger inherent in any human society. This text was written from the professional practices of each author in a multidisciplinary approach combining the approaches of public health, risk reduction, and sexual, psychological and clinical care of adolescents. How to help anticipate the dangers is to use preventive insurance verifying that security is guaranteed before committing. Risk-taking is accepting all the challenges that boost the self with oneself and with others. The risk is therefore also the commitment in love. It is still the risk to speak, to feel, to express feelings, choices, and refusal of unwanted sex. The ability of adolescents to play and defeat the risk by learning the ethical value not only to protect themselves from contracting AIDS, but also to protect others is part of the pedagogy of risk. This pedagogy of risk, as we have seen, includes three areas: information, care and initiation into love. Adolescents must be supported in their emergence by responsible people to protect them from the dangers ahead. The support is not only to prevent them from engaging in risky behavior, but to help them better manage their anxieties and support the fragility of their families in a network approach. Not knowing how to confront the risk stifles the chance of allowing the child to grow up to be independent and helps reassure parents who may resent being removed from the empowerment of their children. PMID- 22846540 TI - Culturally sensitive gynecologic care in adolescence. AB - Culturally sensitive gynecologic care means rendering gynecologic care taking into account adolescents' needs, problems and feelings, as seen by adolescents themselves. Adolescence is a period of turmoil, where limits are being tested and risks taken. A certain degree of rebellion is necessary and normal. In contemporary societies, risk-taking behaviors seem to outnumber any previous historical period. Antagonistic depictions of 'two worlds', transforms the question into one between a culture and a counterculture. Sometimes, the perspectives are exaggerated by attitudes of superiority, leading to inadequate or punitive practices. Health providers need to confront their own prejudices, so as to understand that in their role as health workers, what adolescents ask for is help to cope with their problems in the fields that professionals are qualified for, but not to behave as policemen, judges or priests. Adolescents also need help to overcome resistance to formal environments. In order to achieve success, they have to have the opportunity to be heard and to participate in tailoring programs. These undertakings should be aimed at contributing to health promotion, encouraging self-care and reaffirming confidence in adolescents' responsibility, while generating trust in health services and professionals. PMID- 22846541 TI - The RosR transcription factor is required for gene expression dynamics in response to extreme oxidative stress in a hypersaline-adapted archaeon. AB - BACKGROUND: Previous work has shown that the hypersaline-adapted archaeon, Halobacterium salinarum NRC-1, is highly resistant to oxidative stress caused by exposure to hydrogen peroxide, UV, and gamma radiation. Dynamic alteration of the gene regulatory network (GRN) has been implicated in such resistance. However, the molecular functions of transcription regulatory proteins involved in this response remain unknown. RESULTS: Here we have reanalyzed several existing GRN and systems biology datasets for H. salinarum to identify and characterize a novel winged helix-turn-helix transcription factor, VNG0258H, as a regulator required for reactive oxygen species resistance in this organism. This protein appears to be unique to the haloarchaea at the primary sequence level. High throughput quantitative growth assays in a deletion mutant strain implicate VNG0258H in extreme oxidative stress resistance. According to time course gene expression analyses, this transcription factor is required for the appropriate dynamic response of nearly 300 genes to reactive oxygen species damage from paraquat and hydrogen peroxide. These genes are predicted to function in repair of oxidative damage to proteins and DNA. In vivo DNA binding assays demonstrate that VNG0258H binds DNA to mediate gene regulation. CONCLUSIONS: Together these results suggest that VNG0258H is a novel archaeal transcription factor that regulates gene expression to enable adaptation to the extremely oxidative, hypersaline niche of H. salinarum. We have therefore renamed VNG0258H as RosR, for reactive oxygen species regulator. PMID- 22846544 TI - Regulation of the methylation status of G protein-coupled receptor kinase 1 (rhodopsin kinase). AB - Rhodopsin kinase (GRK1) is a member of G protein-coupled receptor kinase family and a key enzyme in the quenching of photolysed rhodopsin activity and desensitisation of the rod photoreceptor neurons. Like some other rod proteins involved in phototransduction, GRK1 is posttranslationally modified at the C terminus by isoprenylation (farnesylation), endoproteolysis and alpha carboxymethylation. In this study, we examined the potential mechanisms of regulation of GRK1 methylation status, which have remained unexplored so far. We found that considerable fraction of GRK1 is endogenously methylated. In isolated rod outer segments, its methylation is inhibited and demethylation stimulated by low-affinity nucleotide binding. This effect is not specific for ATP and was observed in the presence of a non-hydrolysable ATP analogue AMP-PNP, GTP and other nucleotides, and thus may involve a site distinct from the active site of the kinase. GRK1 demethylation is inhibited in the presence of Ca(2+) by recoverin. This inhibition requires recoverin myristoylation and the presence of the membranes, and may be due to changes in GRK1 availability for processing enzymes upon its redistribution to the membranes induced by recoverin/Ca(2+). We hypothesise that increased GRK1 methylation in dark-adapted rods due to elevated cytoplasmic Ca(2+) levels would further increase its association with the membranes and recoverin, providing a positive feedback to efficiently suppress spurious phosphorylation of non-activated rhodopsin molecules and thus maximise senstivity of the photoreceptor. This study provides the first evidence for dynamic regulation of GRK1 alpha-carboxymethylation, which might play a role in the regulation of light sensitivity and adaptation in the rod photoreceptors. PMID- 22846542 TI - Internet-based brief personalized feedback intervention in a non-treatment seeking population of adult heavy drinkers: a randomized controlled trial. AB - BACKGROUND: Internet-based interventions for heavy drinkers show promising results, but existing research is characterized by few studies in nonstudent adult populations and few comparisons with appropriate control groups. OBJECTIVE: To test whether a fully automated Internet-based brief personalized feedback intervention and a fully automated Internet-based personalized brief advice intervention in a non-treatment-seeking population of heavy drinkers would result in a reduced alcohol intake. METHODS: We conducted a 3-arm parallel randomized controlled trial in a general population-based sample of heavy drinkers. The 54,157 participants (median age of 58 years) were screened for heavy drinking. Of the 3418 participants who had a weekly alcohol consumption above 14 drinks for women and 21 drinks for men, 1380 (619 women) consented to take part in the trial and were randomly assigned to an Internet-based brief personalized feedback intervention group (normative feedback, n = 476), an Internet-based personalized brief advice intervention group (n = 450), or a nonintervention control group (n = 454). Follow-up after 6 and 12 months included 871 and 1064 participants, respectively, of all groups combined. The outcome measure was self-reported weekly alcohol consumption. We analyzed the data according to the intention-to treat principle. To examine changes over time and to account for the multiple time measurements, we used a multilevel linear mixed model. To take attrition into account, we used multiple imputation to address missing data. RESULTS: The intervention effect of the Internet-based brief personalized feedback intervention, determined as the mean additional difference in changes in alcohol consumption in the Internet-based brief personalized feedback intervention compared with the control group, was -1.8 drinks/week after 6 months and -1.4 drinks/week after 12 months; these effects were nonsignificant (95% confidence interval -4.0 to 0.3 at 6 months, -3.4 to 0.6 at 12 months). The intervention effect of the Internet-based personalized brief advice intervention was -0.5 drinks/week after 6 months and -1.2 drinks/week after 12 months; these effects were nonsignificant (95% confidence interval -2.7 to 1.6 at 6 months, -3.3 to 0.9 at 12 months). CONCLUSIONS: In this randomized controlled trial we found no evidence that an Internet-based brief personalized feedback intervention was effective in reducing drinking in an adult population of heavy drinkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751985; http://clinicaltrials.gov/ct2/show/NCT00751985 (Archived by WebCite at http://www.webcitation.org/68WCRLyaP). PMID- 22846543 TI - Wogonin induces apoptosis by activating the AMPK and p53 signaling pathways in human glioblastoma cells. AB - We investigated the molecular basis of the ability of wogonin to control the intracellular signaling cascades of AMP-activated protein kinase (AMPK). This activity induces antitumor activities in glioblastoma multiforme (GBM) cells. Recently, the evolutionarily conserved serine/threonine kinase AMPK has emerged as a possible target for tumor control. We investigated the effects of wogonin on apoptosis regulation and the activation of AMPK. Wogonin treatment resulted in a series of antitumor effects such as cell death and apoptotic appearance. Activation of AMPK suppressed downstream substrates, such as the mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E-binding protein-1 (4E BP1), and resulted in a general decrease in translation. Moreover, wogonin activated AMPK decreased the activity and/or expression of lipogenic enzymes such as acetyl-CoA carboxylase. Furthermore, in GBM cells, wogonin blocked cell cycle progression at the G1 phase and induced apoptosis by inducing p53 expression and further upregulating p21 expression. Taken together, our findings demonstrated that wogonin has the potential to be a chemopreventive and therapeutic agent against human GBM. PMID- 22846545 TI - Identification and function of auxiliary iron-sulfur clusters in radical SAM enzymes. AB - Radical SAM (RS) enzymes use a 5'-deoxyadenosyl 5'-radical generated from a reductive cleavage of S-adenosyl-l-methionine to catalyze over 40 distinct reaction types. A distinguishing feature of these enzymes is a [4Fe-4S] cluster to which each of three iron ions is ligated by three cysteinyl residues most often located in a Cx(3)Cx(2)C motif. The alpha-amino and alpha-carboxylate groups of SAM anchor the molecule to the remaining iron ion, which presumably facilitates its reductive cleavage. A subset of RS enzymes contains additional iron-sulfur clusters, - which we term auxiliary clusters - most of which have unidentified functions. Enzymes in this subset are involved in cofactor biosynthesis and maturation, post-transcriptional and post-translational modification, enzyme activation, and antibiotic biosynthesis. The additional clusters in these enzymes have been proposed to function in sulfur donation, electron transfer, and substrate anchoring. This review will highlight evidence supporting the presence of multiple iron-sulfur clusters in these enzymes as well as their predicted roles in catalysis. This article is part of a special issue entitled: Radical SAM enzymes and radical enzymology. PMID- 22846561 TI - Developing a comprehensive time series of GDP per capita for 210 countries from 1950 to 2015. AB - BACKGROUND: Income has been extensively studied and utilized as a determinant of health. There are several sources of income expressed as gross domestic product (GDP) per capita, but there are no time series that are complete for the years between 1950 and 2015 for the 210 countries for which data exist. It is in the interest of population health research to establish a global time series that is complete from 1950 to 2015. METHODS: We collected GDP per capita estimates expressed in either constant US dollar terms or international dollar terms (corrected for purchasing power parity) from seven sources. We applied several stages of models, including ordinary least-squares regressions and mixed effects models, to complete each of the seven source series from 1950 to 2015. The three US dollar and four international dollar series were each averaged to produce two new GDP per capita series. RESULTS AND DISCUSSION: Nine complete series from 1950 to 2015 for 210 countries are available for use. These series can serve various analytical purposes and can illustrate myriad economic trends and features. The derivation of the two new series allows for researchers to avoid any series specific biases that may exist. The modeling approach used is flexible and will allow for yearly updating as new estimates are produced by the source series. CONCLUSION: GDP per capita is a necessary tool in population health research, and our development and implementation of a new method has allowed for the most comprehensive known time series to date. PMID- 22846562 TI - Protective ventilation in experimental acute respiratory distress syndrome after ventilator-induced lung injury: a randomized controlled trial. AB - BACKGROUND: Low tidal volume (V(T)), PEEP, and low plateau pressure (P(PLAT)) are lung protective during acute respiratory distress syndrome (ARDS). This study tested the hypothesis that the aspiration of dead space (ASPIDS) together with computer simulation can help maintain gas exchange at these settings, thus promoting protection of the lungs. METHODS: ARDS was induced in pigs using surfactant perturbation plus an injurious ventilation strategy. One group then underwent 24 h protective ventilation, while control groups were ventilated using a conventional ventilation strategy at either high or low pressure. Pressure volume curves (P(el)/V), blood gases, and haemodynamics were studied at 0, 4, 8, 16, and 24 h after the induction of ARDS and lung histology was evaluated. RESULTS: The P(el)/V curves showed improvements in the protective strategy group and deterioration in both control groups. In the protective group, when respiratory rate (RR) was ~ 60 bpm, better oxygenation and reduced shunt were found. Histological damage was significantly more severe in the high-pressure group. There were no differences in venous oxygen saturation and pulmonary vascular resistance between the groups. CONCLUSIONS: The protective ventilation strategy of adequate pH or PaCO2 with minimal V(T), and high/safe P(PLAT) resulting in high PEEP was based on the avoidance of known lung-damaging phenomena. The approach is based upon the optimization of V(T), RR, PEEP, I/E, and dead space. This study does not lend itself to conclusions about the independent role of each of these features. However, dead space reduction is fundamental for achieving minimal V(T) at high RR. Classical physiology is applicable at high RR. Computer simulation optimizes ventilation and limiting of dead space using ASPIDS. Inspiratory P(el)/V curves recorded from PEEP or, even better, expiratory P(el)/V curves allow monitoring in ARDS. PMID- 22846563 TI - Arterial bleeding during transurethral resection of bladder cancer managed by endovascular intervention. AB - In this case report, we describe a severe arterial bleeding during transurethral resection of bladder cancer where routine endoscopic methods failed to stop the hemorrhage. In a vascular operating theater selective angiography with coiling managed the bleeding without any surgery-related complications. PMID- 22846564 TI - Upregulated miR-130a increases drug resistance by regulating RUNX3 and Wnt signaling in cisplatin-treated HCC cell. AB - Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of patients with advanced liver cancer. However, acquisition of cisplatin resistance is common in patients with hepatocellular carcinoma (HCC), and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-130a levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-130a levels were also higher in cisplatin resistant Huh7 cells than in Huh7 cells. Overexpression of miR-130a contributed to cisplatin resistance in Huh7 cell, whereas knockdown of miR-130a overcame cisplatin resistance in cisplatin-resistant Huh7 cell. We further demonstrated that upregulated miR-130a directly inhibited expression of tumor suppressor gene RUNX3, which resulted in activation of Wnt/beta-catenin signaling and increased drug resistance. These data suggest that miR-130a/RUNX3/Wnt signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC. PMID- 22846565 TI - Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination. AB - Na-Cl cotransporter (NCC) is phosphorylated in its amino terminus based on salt intake under the regulation of the WNK-OSR1/SPAK kinase cascade. We have observed that total protein abundance of NCC and its apical membrane expression varies in the kidney based on the phosphorylation status. To clarify the mechanism, we examined NCC ubiquitination status in mice fed low, normal and high salt diets, as well as in a model mouse of pseudohypoaldosteronism type II (PHAII) where NCC phosphorylation is constitutively elevated. Low-salt diet decreased NCC ubiquitination, while high-salt diet increased NCC ubiquitination in the kidney, and this was inversely correlated with total and phosphorylated NCC abundance. In the PHAII model, the ubiquitination of NCC in kidney was also lower when compared to that in wild-type littermates. To evaluate the relationship between phosphorylation and ubiquitination of NCC, we expressed wild-type, phospho deficient and -mimicking NCC in COS7 cells, and the ubiquitination of immunoprecipitated total and biotinylated surface NCC was evaluated. NCC ubiquitination was increased in the phospho-deficient NCC and decreased in phospho-mimicking NCC in both total and surface NCC. Thus, we demonstrated that NCC phosphorylation decreased NCC ubiquitination, which may contribute to the increase of NCC abundance mostly on plasma membranes. PMID- 22846566 TI - Shear stress augments the endothelial cell differentiation marker expression in late EPCs by upregulating integrins. AB - Vascular endothelial cell injury has been implicated in the onset of atherosclerosis. A number of previous studies have demonstrated that endothelial progenitor cells (EPCs), in particular late EPCs, play important roles in endothelial maintenance and repair. Recent evidence has revealed shear stress as a key regulator for EPC differentiation. However, the detailed events that contribute to the shear stress-induced EPC differentiation, in particular the mechanisms of mechanotransduction, remain to be identified. The present study was undertaken to further confirm the effects of shear stress on the late EPC differentiation, and to investigate the role of integrins in this procedure. Shear stress was observed to increase the expression of endothelial cell differentiation markers, such as vWF and CD31, in late EPCs isolated from rat bone marrow. Shear stress moreover enhanced the mRNA expression of integrin subunits beta(1) and beta(3) in a time-dependent manner, and also upregulated specific integrins in late EPCs plated on substrates containing various extracellular matrix (ECM) proteins. In addition, the shear stress-induced vWF and CD31 expression were found to be related to the levels of integrin beta(1) and beta(3), and were inhibited in late EPCs treated with RGD peptide (Gly-Arg Gly-Asp-Asn-Pro, GRGDNP) that blocks the binding of integrins to the extracellular matrix. Additionally, this increase was also attenuated by both anti-beta(1) integrin and anti-beta(3) integrin antibodies. The integrin subunits beta(1) and beta(3) thus play important roles in regulating the shear stress induced endothelial cell differentiation marker expression in late EPCs. This may provide novel insights into the mechanisms of mechanotransduction in shear stress mediated late EPC differentiation. PMID- 22846567 TI - The cytoskeletal regulatory scaffold protein GIT2 modulates mesenchymal stem cell differentiation and osteoblastogenesis. AB - G protein-coupled receptor kinase interacting protein 2 (GIT2) is a signaling scaffold protein involved in the regulation of cytoskeletal structure, membrane trafficking, and G protein-coupled receptor internalization. Since dynamic cytoskeletal reorganization plays key roles both in osteoblast differentiation and in the maintenance of osteoclast polarity during bone resorption, we hypothesized that skeletal physiology would be altered in GIT2(-/-) mice. We found that adult GIT2(-/-) mice have decreased bone mineral density and bone volume in both the trabecular and cortical compartments. This osteopenia was associated with decreased numbers of mature osteoblasts, diminished osteoblastic activity, and increased marrow adiposity, suggesting a defect in osteoblast maturation. In vitro, mesenchymal stem cells derived from GIT2(-/-) mice exhibited impaired differentiation into osteoblasts and increased adipocyte differentiation, consistent with a role for GIT2 in mesenchymal stem cell fate determination. Despite elevated osteoclast inducing cytokines and osteoclast numbers, GIT2(-/-) mice also exhibit impaired bone resorption, consistent with a further role for GIT2 in regulating osteoclast function. Collectively, these findings underscore the importance of the cytoskeleton in both osteoblast and osteoclast function and demonstrate that GIT2 plays essential roles in skeletal metabolism, affecting both bone formation and bone resorption in vivo. PMID- 22846568 TI - IP3-dependent intracellular Ca2+ release is required for cAMP-induced c-fos expression in hippocampal neurons. AB - Ca(2+) and cAMP are widely used in concert by neurons to relay signals from the synapse to the nucleus, where synaptic activity modulates gene expression required for synaptic plasticity. Neurons utilize different transcriptional regulators to integrate information encoded in the spatiotemporal dynamics and magnitude of Ca(2+) and cAMP signals, including some that are Ca(2+)-responsive, some that are cAMP-responsive and some that detect coincident Ca(2+) and cAMP signals. Because Ca(2+) and cAMP can influence each other's amplitude and spatiotemporal characteristics, we investigated how cAMP acts to regulate gene expression when increases in intracellular Ca(2+) are buffered. We show here that cAMP-mobilizing stimuli are unable to induce expression of the immediate early gene c-fos in hippocampal neurons in the presence of the intracellular Ca(2+) buffer BAPTA-AM. Expression of enzymes that attenuate intracellular IP(3) levels also inhibited cAMP-dependent c-fos induction. Synaptic activity induces c-fos transcription through two cis regulatory DNA elements - the CRE and the SRE. We show here that in response to cAMP both CRE-mediated and SRE-mediated induction of a luciferase reporter gene is attenuated by IP(3) metabolizing enzymes. Furthermore, cAMP-induced nuclear translocation of the CREB coactivator TORC1 was inhibited by depletion of intracellular Ca(2+) stores. Our data indicate that Ca(2+) release from IP(3)-sensitive pools is required for cAMP-induced transcription in hippocampal neurons. PMID- 22846569 TI - Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer. AB - Breast cancer is the leading cause of deaths from cancer in women. Cancer recurrence is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the center of cancer development and recurrence. Targeting CSCs, in combination with standard chemotherapy, may prevent cancer recurrence and improve long-term survival. Stem cells can be enriched in non-adherent sphere cultures. To identify molecular targets in breast CSCs, we evaluated the transcription levels of stem cell related genes in 4T1 mouse mammary cancer cells grown as spheres or in a monolayer culture. The most differentially expressed gene was found to be wingless-type MMTV integration site family member 1 (Wnt1) in the 4T1 sphere culture. Functionally, knockdown of Wnt1 in breast cancer cell lines suppressed the in vitro properties of the stem-like cells, including their sphere-forming ability and ALDH activity, whereas the addition of recombinant Wnt1 to breast cancer cell lines enhanced the in vitro properties of these stem-like cells. In addition, knockdown of Wnt1 in 4T1 cells affected the properties of the stem-like cells in vivo, including their tumorigenic potential and tumor initiation ability. Collectively, these results suggest that Wnt1 expression may give rise to the properties of CSCs in breast tumors. Therefore, targeting Wnt1-associated signaling proteins may provide an effective therapeutic approach for the treatment of advanced breast cancer. PMID- 22846570 TI - The role of MAP4K3 in lifespan regulation of Caenorhabditis elegans. AB - The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation - when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that has recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditis elegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan. PMID- 22846571 TI - Identification of ryanodine receptor isoforms in prostate DU-145, LNCaP, and PWR 1E cells. AB - The ryanodine receptor (RyR) is a large, intracellular calcium (Ca(2+)) channel that is associated with several accessory proteins and is an important component of a cell's ability to respond to changes in the environment. Three isoforms of the RyR exist and are well documented for skeletal and cardiac muscle and the brain, but the isoforms in non-excitable cells are poorly understood. The aggressiveness of breast cancers in women has been positively correlated with the expression of the RyR in breast tumor tissue, but it is unknown if this is limited to specific isoforms. Identification and characterization of RyRs in cancer models is important in understanding the role of the RyR channel complex in cancer and as a potential therapeutic target. The objective of this report was to identify the RyR isoforms expressed in widely used prostate cancer cell lines, DU-145 and LNCaP, and the non-tumorigenic prostate cell line, PWR-1E. Oligonucleotide primers specific for each isoform were used in semi-quantitative and real-time PCR to determine the identification and expression levels of the RyR isoforms. RyR1 was expressed in the highest amount in DU-145 tumor cells, expression was 0.48-fold in the non-tumor cell line PWR-1E compared to DU-145 cells, and no expression was observed in LNCaP tumor cells. DU-145 cells had the lowest expression of RyR2. The expression was 26- and 15-fold higher in LNCaP and PWR-1E cells, respectively. RyR3 expression was not observed in any of the cell lines. All cell types released Ca(2+) in response to caffeine showing they had functional RyRs. Total cellular RyR-associated Ca(2+) release is determined by both the number of activated RyRs and its accessory proteins which modulate the receptor. Our results suggest that the correlation between the expression of the RyR and tumor aggression is not related to specific RyR isoforms, but may be related to the activity and number of receptors. PMID- 22846572 TI - Effective expression of human proteins on bacterial magnetic particles in an anchor gene deletion mutant of Magnetospirillum magneticum AMB-1. AB - Biologically synthesized magnetic particles by magnetotactic bacteria (BacMPs) have promising potential in the area of functional protein display technology for various biotechnological and biomedical applications. Functional proteins fused with an anchor protein, Mms13, have been demonstrated to be an effective and stable method for the display of functional proteins on BacMPs. However, the expression of some human proteins is relatively low. Useful host strains of Escherichia coli have been developed for the enhanced expression of recombinant proteins using a genetic engineering approach. To improve human protein expression level on BacMPs in Magnetospirillummagneticum AMB-1, a mutant strain with a deleted native mms13 gene (Deltamms13 strain) was established and evaluated for effective functional protein display technology. As a result, the Deltamms13 strain synthesized BacMPs with significantly improved expression of two human proteins, thyroid-stimulating hormone receptor (TSHR) and the class II major histocompatibility complex (MHC II) molecules. The Deltamms13 strain could therefore be an effective strain for the display of other important human proteins on BacMPs and may be useful for further applications. PMID- 22846573 TI - Abeta-induced Ca(2+) influx regulates astrocytic BACE1 expression via calcineurin/NFAT4 signals. AB - The beta-site APP cleaving enzyme (BACE1) is required for the production of beta amyloid peptides, which give rise to beta-amyloid (Abeta) deposits in the brains of Alzheimer's disease (AD) patients. In brains, BACE1 is primarily expressed by neurons, however BACE1 expression has also been observed in reactive astrocytes in close proximity to beta-amyloid plaques in the brains of aged Tg2576 AD model mice. To date, the direct effects of Abeta on BACE1 gene expression in astrocytes is unknown. We found that Abeta42 or Abeta25-35 treatment induced BACE1 expression in primary astrocytes as well as human astrocytoma cell line. Abeta neurotoxicity has been associated with the disruption of intracellular calcium homeostasis both in neurons and in glial cells. Here, we demonstrated that NFAT4, a transcription factor tightly regulated by the calcium/calmodulin-dependent phosphatase, calcineurin, was activated in astrocytes applied with calcium ionophore or Abeta. Abeta-activated NFAT4 proteins were associated with astrocytic BACE1 gene expression via direct interaction with the BACE1 promoter region. PMID- 22846574 TI - Ischemic preconditioning enhances integrity of coronary endothelial tight junctions. AB - Ischemic preconditioning (IPC) is one of the most effective procedures known to protect hearts against ischemia/reperfusion (IR) injury. Tight junction (TJ) barriers occur between coronary endothelial cells. TJs provide barrier function to maintain the homeostasis of the inner environment of tissues. However, the effect of IPC on the structure and function of cardiac TJs remains unknown. We tested the hypothesis that myocardial IR injury ruptures the structure of TJs and impairs endothelial permeability whereas IPC preserves the structural and functional integrity of TJs in the blood-heart barrier. Langendorff hearts from C57BL/6J mice were prepared and perfused with Krebs-Henseleit buffer. Cardiac function, creatine kinase release, and myocardial edema were measured. Cardiac TJ function was evaluated by measuring Evans blue-conjugated albumin (EBA) content in the extravascular compartment of hearts. Expression and translocation of zonula occludens (ZO)-2 in IR and IPC hearts were detected with Western blot. A subset of hearts was processed for the observation of ultra-structure of cardiac TJs with transmission electron microscopy. There were clear TJs between coronary endothelial cells of mouse hearts. IR caused the collapse of TJs whereas IPC sustained the structure of TJs. IR increased extravascular EBA content in the heart and myocardial edema but decreased the expression of ZO-2 in the cytoskeleton. IPC maintained the structure of TJs. Cardiac EBA content and edema were reduced in IPC hearts. IPC enhanced the translocation of ZO-2 from cytosol to cytoskeleton. In conclusion, TJs occur in normal mouse heart. IPC preserves the integrity of TJ structure and function that are vulnerable to IR injury. PMID- 22846575 TI - Overexpression of glutaredoxin protects cardiomyocytes against nitric oxide induced apoptosis with suppressing the S-nitrosylation of proteins and nuclear translocation of GAPDH. AB - There is increasing evidence demonstrating that glutaredoxin 1 (GRX1), a cytosolic enzyme responsible for the catalysis of protein deglutathionylation, plays distinct roles in inflammation and apoptosis by inducing changes in the cellular redox system. In this study, we investigated whether and how the overexpression of GRX1 protects cardiomyocytes against nitric oxide (NO)-induced apoptosis. Cardiomyocytes (H9c2 cells) were transfected with the expression vector for mouse GRX1 cDNA, and mock-transfected cells were used as a control. Compared with the mock-transfected cells, the GRX1-transfected cells were more resistant to NO-induced apoptosis. Stimulation with NO significantly increased the nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a pro-apoptotic protein, in the mock-transfected cells, but did not change GAPDH localization in the GRX1-transfected cells. Furthermore, we found that NO stimulation clearly induced the oxidative modification of GAPDH in the mock transfected cells, whereas less modification of GAPDH was observed in the GRX1 transfected cells. These data suggest that the overexpression of GRX1 could protect cardiomyocytes against NO-induced apoptosis, likely through the inhibition of the oxidative modification and the nuclear translocation of GAPDH. PMID- 22846576 TI - Hydrogen sulfide prevents hypoxia-induced apoptosis via inhibition of an H2O2 activated calcium signaling pathway in mouse hippocampal neurons. AB - Hydrogen sulfide (H(2)S), an endogenous gaseous mediator, has been shown to exert protective effects against damage to different organs in the human body caused by various stimuli. However, the potential effects of H(2)S on hypoxia-induced neuronal apoptosis and its mechanisms remain unclear. Here, we exposed mouse hippocampal neurons to hypoxic conditions (2% O(2), 5% CO(2) and 93% N(2) at 37 degrees C) to establish a hypoxic cell model. We found that 4-h hypoxia treatment significantly increased intracellular reactive oxygen species (ROS) levels, and pretreatment with NaHS (a source of H(2)S) for 30 min suppressed hypoxia-induced intracellular ROS elevation. The hypoxia treatment significantly increased cytosolic calcium ([Ca(2+)](i)), and pretreatment with NaHS prevented the increase in [Ca(2+)](i). Additionally, polyethylene glycol (PEG)-catalase (a H(2)O(2) scavenger) but not PEG-SOD (an O(2)(-) scavenger) conferred an inhibitory effect similar to H(2)S on the hypoxia-induced increase in [Ca(2+)](i). Furthermore, we found that pretreatment with NaHS could significantly inhibit hypoxia-induced neuronal apoptosis, which was also inhibited by PEG-catalase or the inositol 1,4,5-triphosphate (IP(3)) receptor blocker xestospongin C. Taken together, these findings suggest that H(2)S inhibits hypoxia-induced apoptosis through inhibition of a ROS (mainly H(2)O(2)) activated Ca(2+) signaling pathway in mouse hippocampal neurons. PMID- 22846577 TI - Effects of N-n-butyl haloperidol iodide on the rat myocardial sarcoplasmic reticulum Ca(2+)-ATPase during ischemia/reperfusion. AB - We have previously shown that N-n-butyl haloperidol iodide (F(2)), a newly synthesized compound, reduces ischemia/reperfusion (I/R) injury by preventing intracellular Ca(2+) overload through inhibiting L-type calcium channels and outward current of Na(+)/Ca(2+) exchanger. This study was to investigate the effects of F(2) on activity and protein expression of the rat myocardial sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) during I/R to discover other molecular mechanisms by which F(2) maintains intracellular Ca(2+) homeostasis. In an in vivo rat model of myocardial I/R achieved by occluding coronary artery for 30-60 min followed by 0-120 min reperfusion, treatment with F(2) (0.25, 0.5, 1, 2 and 4 mg/kg, respectively) dose-dependently inhibited the I/R-induced decrease in SERCA activity. However, neither different durations of I/R nor different doses of F(2) altered the expression levels of myocardial SERCA2a protein. These results indicate that F(2) exerts cardioprotective effects against I/R injury by inhibiting I/R-mediated decrease in SERCA activity by a mechanism independent of SERCA2a protein levels modulation. PMID- 22846578 TI - Overexpression of myeloid zinc finger 1 suppresses matrix metalloproteinase-2 expression and reduces invasiveness of SiHa human cervical cancer cells. AB - Myeloid zinc finger 1 (MZF1) gene belongs to the Kruppel family of zinc finger transcription factors. MZF1 has been suggested to play an important role in the tumorigenesis, invasion, and apoptosis of various tumor cells. However, the role of MZF1 in human cervical cancer remains unclear. To investigate the molecular mechanisms of MZF1 and its functional role in human cervical cancer cell migration and invasion, we experimented on stable SiHa cells overexpressing MZF1. We found that MZF1 overexpression inhibits the migratory and invasive abilities of SiHa cervical cancer cells. In addition, the overexpression of MZF1 significantly reduces MMP-2 protein and mRNA levels. Luciferase and ChIP assays suggested that MZF1 directly binds to MMP-2 gene regulatory sequences in vivo and suppresses MMP-2 promoter activity in vitro. This study shows that MZF-1 represses MMP-2 transcription and suggests that this repression may be linked to inhibition of human cervical cancer cell migration and metastasis. PMID- 22846579 TI - PKC and RhoA signals cross-talk in Escherichia coli endotoxin induced alterations in brain endothelial permeability. AB - Escherichia coli endotoxin LPS regulates blood-brain barrier permeability by disrupting the tight junction (TJ) complex between brain endothelial cells. This study used Bend.3 cells to examine the signaling networks involved in the hyperpermeability of the brain endothelial barrier caused by LPS. The LPS-induced alterations in the brain endothelial barrier were associated with PKC (a, beta, zeta) and RhoA, but were independent of PI3K and the tyrosine kinase pathway. Inhibition of PKC (a, beta, zeta) and RhoA activity using shRNA and dominant negative mutants diminished the effects of LPS on the brain's endothelial TJs. The interactions between the PKC and Rho pathways were therefore examined. PKC-a and PKC-zeta, but not PKC-beta interacted with RhoA in Bend.3 cells stimulated by LPS. PKC-a acted as the upstream molecule for Rho and PKC-zeta acted as the downstream target for Rho. Comparing the effect of double inhibition of "Rho and PKC" and single inhibition of "Rho" or "PKC" confirmed that this interaction is critical for LPS-induced brain endothelial cell hyperpermeability. Collectively these data are the first to suggest that LPS affects the brain's endothelial TJ barrier via PKC (a, beta, zeta)- and RhoA, independent of the PI3K and tyrosine kinase pathways. In addition, PKC-a and PKC-zeta, respectively, act as the upstream and downstream regulator for RhoA in the process. PMID- 22846580 TI - ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury. AB - BACKGROUND: The prognosis of patients after acute kidney injury (AKI) is poor and treatment is limited. AKI is mainly caused by renal ischemia/reperfusion injury (IRI). During the extension phase of IRI, endothelial damage may participate in ischemia and inflammation. Endothelin-1 (ET-1) which is mostly secreted by endothelial cells is an important actor of IRI, particularly through its strong vasoconstrictive properties. We aimed to analyze the specific role of ET-1 from the endothelial cells in AKI. METHODS: We used mice lacking ET-1 in the vascular endothelial cells (VEETKO). We induced IRI in VEETKO mice and wild type controls by clamping both kidneys for 30min. Sham operated mice were used as controls. Mice were sacrificed one day after IRI in order to investigate the extension phase of IRI. Kidney function was assessed based on serum creatinine concentration. Levels of expression of ET-1, its receptor ET(A), protein kinase C, eNOS, E-Cadherin and inflammation markers were evaluated by real time PCR or western blot. Tubular injury was scored on periodic acid Schiff stained kidney preparations. Lumen and wall area of small intrarenal arteries were measured on kidney slices stained for alpha smooth muscle cell actin. Oxidative stress, macrophage infiltration and cell proliferation was evaluated on slices stained for 8-hydroxy-2'-deoxyguanosine, F4/80 and PCNA, respectively. RESULTS: IRI induced kidney failure and increased ET-1 and ET(A) receptor expression. This was accompanied by tubular injury, wall thickening and reduction of lumen area/wall area ratio of small renal arteries, increased oxidative stress and inflammation. These parameters were attenuated in VEETKO mice. CONCLUSION: Our results suggest that suppression of ET-1 from the endothelial cells attenuates IRI kidney injury. Blocking ET-1 effects may represent a therapeutic strategy in the management of AKI. PMID- 22846581 TI - Improving outcomes for high-risk patients with early-stage non-small-cell lung cancer: insights from population-based data and the role of stereotactic ablative radiotherapy. PMID- 22846582 TI - Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have high response and disease control rates in patients with central nervous system (CNS) metastases. However there have been only a few case reports on the penetration of gefitinib into the cerebrospinal fluid (CSF). The aim of this study was to investigate the CSF concentration of gefitinib in Chinese patients with lung adenocarcinomas. METHODS: From March 2007 to December 2010, 22 patients were sequentially enrolled in this study at Peking Union Medical College Hospital (PUMCH). CSF and plasma samples were collected at the same time from each patient after at least 7 doses of gefitinib. The concentrations of gefitinib in the CSF and plasma were measured by high performance liquid chromatography coupled with tandem mass spectrometry. The clinical factors that may affect gefitinib penetration were analyzed. RESULTS: The mean plasma and CSF concentrations of gefitinib were 491.8 +/- 184.2 ng/mL and 6.2 +/- 4.6 ng/mL, respectively, and the mean ratio of CSF-plasma concentration was 1.3% +/- 0.7%. There was a good correlation between CSF and plasma gefitinib concentrations (R = 0.556, P = .006). The presence of CNS metastases was associated with increased gefitinib CSF penetration (1.46% vs. 0.95%; P = .042). CONCLUSIONS: The concentration of gefitinib in CSF was low, and it was significantly related to the plasma gefitinib concentration. Because of the inadequate CNS drug exposure, patients in whom the extracranial lesions were well controlled may benefit from increasing gefitinib dose for the new intracranial lesions. PMID- 22846583 TI - Remote cerebellar hemorrhage due to ventriculoperitoneal shunt in an infant: a case report. AB - INTRODUCTION: Cerebellar hemorrhage remote from the operative site is an unpredictable and rare complication in neurosurgery, with reported rates of morbidity and mortality in the literature of 8.4% and 7.8%, respectively. The range of procedures associated with remote cerebellar hemorrhage is diverse and includes both supratentorial and spinal procedures that entail significant cerebral spinal fluid loss or resection of supratentorial content. We present here the first documented case of remote cerebellar hemorrhage after controlled supratentorial cerebral spinal fluid drainage by ventriculoperitoneal shunt, and discuss the proposed pathophysiology and treatment. CASE PRESENTATION: We present the case of a four-month-old Saudi Arabian male baby who presented with progressive symptoms and signs of congenital hydrocephalus. An uneventful ventriculoperitoneal shunting was performed with our patient recovering smoothly in the immediate postoperative period. On the next day, he had frequent episodes of vomiting and became lethargic. An urgent computed tomography scan of his brain revealed mild ventricular decompression and unexpected cerebellar hemorrhage. The infant was put under close observation, with marked spontaneous improvement over 48 hours and complete resolution of the hemorrhage on a follow-up computed tomography brain scan two weeks later. On regular outpatient visits at one, three and twelve months, he had no neurological deficit. CONCLUSION: Remote cerebellar hemorrhage is a complication that remains enigmatic in terms of both the underlying mechanism and clinical behavior. Our case revealed that the risk factors identified in the literature are not sufficient in predicting patients at risk of developing remote cerebellar hemorrhage. Our report also adds to the growing body of evidence challenging the currently accepted hypothesis explaining the pathomechanism of remote cerebellar hemorrhage. It thereby remains an unpredictable hazard that requires further study and increased awareness, as many cases in the literature are incidental findings. PMID- 22846584 TI - Emergent early markers of renal progression in autosomal-dominant polycystic kidney disease patients: implications for prevention and treatment. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed. PMID- 22846585 TI - Fine-needle aspiration of follicular patterned lesions of the thyroid: diagnosis, management, and follow-up according to thyroid Bethesda system. AB - OBJECTIVE: The goal of this study was to report an experience with thyroid fine needle aspiration (FNA) cases that can be placed into National Cancer Institute designated thyroid FNA diagnostic categories for follicular patterned lesions divided into three diagnostic categories: follicular lesion of undetermined significance/atypia of undetermined significance (AUS/FLUS), suspicious for follicular neoplasm (SFON), and suspicious for malignancy. STUDY DESIGN: The study cohort included 4,284 cases for the period between January 2007 and July 2011 and all available follow-up data was obtained. All cases classified as 'atypical' and 'rule out follicular neoplasm' were included in the AUS/FLUS category (n = 3,903), whereas cases classified as 'suspicious for' or 'consistent with follicular or Hurthle cell neoplasm' (n = 381) were included in the SFON diagnostic category and compared with histopathologic follow-up. RESULTS: During this period, 14,628 thyroid FNAs were reported in 12,238 patients. Repeat FNA (RFNA) was performed in 1,366/3,903 (35%) patients classified as AUS/FLUS. Histologic outcome data was available in 1,756/3,903 (45%) cases diagnosed as AUS/FLUS and 243/381 (64%) cases diagnosed as SFON. The rate of malignancy in AUS/FLUS cases with and without RFNA was 29 and 14% respectively, and it was 26% in SFON cases. CONCLUSION: The current data shows that the malignancy rates differ between categories and AUS/FLUS cases are best managed by RFNA for selection of cases that can benefit from surgical excision. PMID- 22846586 TI - Interviews with pioneers of vascular surgery. AB - The purpose of the SVS is not just to hold an annual meeting, but also to pursue social, financial, and political responsibilities. In addition, the Society leads in research, training, education, and practice (ie, patient care). The current leadership of the SVS is dedicated to preserving the history of the Society. The History Project Work Group will execute the orders of the Society to develop a series of digital videography recorded interviews with leaders in vascular surgery to be made available to our membership. The information collected will form the basis for a book on the history of the SVS. PMID- 22846587 TI - The experiences of women of reproductive age regarding health-promoting behaviours: a qualitative study. AB - BACKGROUND: Health promotion is critical for community and family health. Health promoting behaviours provide solutions for maintaining and promoting health. Although several studies have addressed the frequency and different types of health-promoting behaviours in women, little information is available about their experiences. This study aimed to explore the experiences of women of reproductive age regarding health-promoting behaviours. METHODS: In the present study, which was conducted in Tehran, Iran, 15 females, who were selected purposefully, participated in individual in-depth, semi-structured interviews. The interviews were recorded, transcribed verbatim, and analysed using conventional content analysis. RESULTS: Nine main categories were derived from the analysis, including establishing an appropriate eating pattern, establishing a balanced rest/activity pattern, spirituality, stress management, personal sensitivity and responsibility, establishing an appropriate pattern of social interactions, practicing safe and healthy recreations, feeling improvement in physical functional health, and feeling improvement in emotional and psychological health. The first 7 categories represent the nature and types of real health-promoting behaviours in women of reproductive age, whereas the last 2 constitute feeling and understanding of the implementation of these behaviours. CONCLUSION: The study findings show that the women experience improvement in physical-functional, emotional, and psychological health by implementing health-promoting behaviours. It is therefore necessary to introduce strategies in the context of the community culture for improving different aspects of health-promoting behaviours in women of reproductive age to maintain and improve their overall health. PMID- 22846588 TI - Registered nurses' evidence-based practice: a longitudinal study of the first five years after graduation. AB - BACKGROUND: The capacity to provide evidence-based practice is one of five core competencies that it is proposed all healthcare professions should possess to meet the needs of the 21st century healthcare system. New nurses are faced with a challenging work environment which, combined with shortcomings in undergraduate education and their limited clinical experience, may affect their evidence-based practice. OBJECTIVE: The aim of this study was to prospectively examine the extent of Swedish nurses' evidence-based practice during the first five years of professional life. DESIGN: An observational longitudinal study, with yearly data collections over the course of five years. SETTINGS: Data was collected in two national cohorts (named EX2004 and EX2006) of Swedish registered nurses. Nurses in EX2006 were followed yearly during the first three years after graduation and nurses in EX2004 yearly three to five years after graduation. They had completed a three year academic nursing program and mainly worked in in-patient care settings. PARTICIPANTS: Participants were recruited while studying at any of the 26 universities in Sweden. A total of 2107 (EX2006) and 2331 (EX2004) nursing students were eligible. 1207 and 1227 nurses were included in the current longitudinal samples. The nurses had a mean age of 31.2/33.9years old and a majority were female. The cohorts were representative of the general nursing population. METHODS: Data was self-reported and collected through annual postal surveys. Evidence-based practice was conceptualized as a process and measured with an instrument including six items. Data was analyzed using latent growth curve modeling. RESULTS: The extent of evidence-based practice was stable, between the two cohorts and over time. Individual differences existed and remained stable over time. However, the extent of practicing the different components of evidence-based practice on a monthly basis varied considerably, from 10% of the nurses (appraising research reports) to 80% (using information sources other than databases to search for knowledge). CONCLUSION: The extent of evidence-based practice remained unchanged during the first five years of professional life. It appears important to enhance both the contribution of undergraduate education and the contextual conditions in work life, in order to improve evidence-based practice among newly graduated nurses. PMID- 22846589 TI - The introduction of DRG funding and hospital nurses' changing perceptions of their practice environment, quality of care and satisfaction: comparison of cross sectional surveys over a 10-year period. AB - BACKGROUND: As other countries which have introduced diagnosis-related groups (DRGs) to pay their hospitals Germany initially expected that quality of care could deteriorate. Less discussed were potential implications for nurses, who might feel the efficiency-increasing effects of DRGs on their daily work, which in turn may lead to an actual worsening of care quality. OBJECTIVE: To analyze whether the DRG implementation in German acute hospitals (as well as other changes over the 10-year period) had measurable effects on (1) the nurse work environment (including e.g. an adequate number of nursing staff to provide quality patient care), (2) quality of patient care and safety (incl. confidence into patients' ability to manage care when discharged), and (3) whether the effects from (1) and (2)--if any--impacted on the nurses themselves (satisfaction with their current job and their choice of profession as well as emotional exhaustion). DESIGN AND DATA SOURCES: Two rounds of nurse surveys with the Practice Environment Scale of the Nursing Work Index (PES-NWI), five years before DRG implementation (i.e. in 1998/1999; n=2681 from 29 hospitals) and five years after (i.e. in 2009/2010; n=1511 from 49 hospitals). The analysis utilized 15 indicators as outcomes for (1) practice environment, (2) quality of patient care and safety, as well as (3) nurses' satisfaction and emotional exhaustion. Multivariate analyses were performed for all three sets of outcomes using SPSS version 20. RESULTS: Aspects of the practice environment (especially adequate staffing and supportive management) worsened within the examined time span of 10 years, which as a consequence had significant negative impact on the nurse perceived quality of care (except for patient safety, which improved). Both the aspects of the practice environment and the quality aspects impacted substantially on satisfaction and emotional exhaustion among nurses. CONCLUSIONS: The DRG implementation in Germany has apparently had measurable negative effects on nurses and nurse-perceived patient outcomes, however, not as distinct as often assumed. PMID- 22846590 TI - Bioengineered surfaces to improve the blood compatibility of biomaterials through direct thrombin inactivation. AB - Thrombus formation, due to thrombin generation, is a major problem affecting blood-contacting medical devices. This work aimed to develop a new strategy to improve the hemocompatibility of such devices by the immobilization of a naturally occurring thrombin inhibitor into a nanostructured surface. Boophilin, a direct thrombin inhibitor from the cattle tick Rhipicephalus microplus, was produced as a recombinant protein in Pichia pastoris. Boophilin was biotinylated and immobilized on biotin-terminated self-assembled monolayers (SAM) via neutravidin. In order to maintain its proteinase inhibitory capacity after surface immobilization, boophilin was biotinylated after the formation of a boophilin-thrombin complex to minimize the biotinylation of the residues involved in thrombin-boophilin interaction. The extent of boophilin biotinylation was determined using matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry. Boophilin immobilization and thrombin adsorption were quantified using quartz crystal microbalance with dissipation. Thrombin competitive adsorption from human serum was assessed using 125I-thrombin. Thrombin inhibition and plasma clotting time were determined using spectrophotometric techniques. Boophilin-coated SAM were able to promote thrombin adsorption in a selective way, inhibiting most of its activity and delaying plasma coagulation in comparison with boophilin-free surfaces, demonstrating boophilin's potential to improve the hemocompatibility of biomaterials used in the production of blood-contacting devices. PMID- 22846591 TI - Influence of hydration on fiber geometry in electrospun scaffolds. AB - Finite element models of tissue engineering scaffolds are powerful tools to understand scaffold function, including how external mechanical signals deform the scaffold at the meso- and microscales. Fiber geometry is needed to inform finite element models of fiber-based tissue engineering scaffolds; however, the accuracy and utility of these models may be limited if they are informed by non hydrated geometries. Scanning electron microscopy and confocal microscopy, coupled with Fourier analysis of the resulting images, were used to quantify how hydration alters fiber geometry in electrospun collagen and polycaprolactone (PCL) scaffolds. The results also quantify how image size affects fiber geometry. Hydration is demonstrated to increase fiber tortuosity, defined as the ratio of actual fiber length:end-to-end fiber length. For collagen scaffolds, hydration increased the mean tortuosity from 1.05 to 1.21, primarily from large ~2- to 10 fold) increases in smaller (<40MUm) wavelength amplitudes. For PCL fibers, the mean tortuosity increased from 1.01 to only 1.04, primarily from modest ~2-fold) increases in larger (>100MUm) wavelength amplitudes. The results demonstrate that mechanical simulations of electrospun scaffolds should be informed with hydrated scaffold geometries of at least 200MUm scale, in order to capture geometrical effects associated with fiber straightening. PMID- 22846592 TI - Contemporary use of the cold pressor task in pediatric pain research: a systematic review of methods. AB - The cold pressor task (CPT) is an ethical experimental pain task widely used by pediatric pain researchers to examine a variety of important theoretical and clinical questions. The purpose of this systematic review was to describe contemporary use of the CPT in pediatric pain research to identify possible methodological and procedural inconsistencies and inform future research. All papers using the CPT to examine pain-related outcomes in children <=18 years old published after 2005 were identified, 2005 being when published pediatric CPT studies were last reviewed and guidelines for pediatric use of the CPT were published. Information related to samples, CPT methodology, and pain outcomes was recorded. Thirty-six published papers, involving 2,242 children (aged 3-18 years) from both healthy and clinical samples, met review inclusion criteria. Several aspects of CPT methodology with significant potential to impact pain outcomes were found to be inconsistently implemented and reported, including water temperature, use of informed versus uninformed ceilings, and the presence of observers during the CPT. Self-report child pain intensity and pain tolerance were common outcomes. A number of refinements for use of the CPT in pediatric pain research are suggested. PERSPECTIVE: The cold pressor task is a commonly used experimental method in pediatric pain research. This systematic review reveals important methodological inconsistencies in its use and suggestions for improvements to previously published guidelines. PMID- 22846593 TI - Multiple neck operations in a patient with severe motor tics because of Tourette's syndrome: a case report. AB - INTRODUCTION: In patients with Tourette's syndrome who have severe motor tics, involuntary neck movements can enhance degenerative changes in the cervical spine, occasionally causing myelopathy. There have been a limited number of reports on surgical treatment for cervical myelopathy caused by Tourette's syndrome, and a consensus for surgical treatment has not been fully established. To the best of our knowledge, this is the first report that describes a case of cervical myelopathy in a patient with Tourette's syndrome with severe motor tics who has undergone multiple surgeries of the cervical spine. CASE PRESENTATION: A 44-year-old Asian man with severe motor tics due to Tourette's syndrome presented with cervical myelopathy. Previously, he had undergone an anterior discectomy and spinal fusion with ceramics at the C3-C4 and C5-C6 levels, but required further surgery because of displacement of the ceramics. After the second operation, he developed compression myelopathy at the sandwiched (C4-C5) disc level, and had to undergo a C4-C5 anterior discectomy and spinal fusion, which was unsuccessful.As a salvage operation, we performed a C3-C7 decompression and spinal fusion from both the anterior and posterior approaches. By thorough postoperative external immobilization of his neck, our patient's spinal fusion was successful and his neurological improvements were maintained for more than 10 years. CONCLUSIONS: Patients with Tourette's syndrome with cervical myelopathy are at risk of having multiple neck operations to correct their symptoms. Postoperative immobilization and the correct selection of surgical procedure are quite important for successful spinal fusion and for avoiding complications at adjacent levels in these patients. PMID- 22846594 TI - Outdoor physical activity and self rated health in older adults living in two regions of the U.S. AB - BACKGROUND: Older adults spend little time outdoors and many are physically inactive. The relationship between outdoor physical activity and self rated health has not been studied in older adults. This paper aimed to assess the relation of location of physical activity to self rated health and physical activity minutes. This was an observational study of ambulatory adults 66 years and older conducted in 2005-2008. Participants (N = 754) completed survey measures of physical activity location and self rated health, and wore an accelerometer to objectively assess physical activity. A mixed model linear regression procedure adjusted for neighborhood clustering effects. Differences in self rated health and physical activity minutes were compared across three physical activity settings (indoor only, outdoor only, both indoor and outdoor). RESULTS: Minutes of moderate to vigorous physical activity were significantly greater in those who were physically active at least once a week outdoors compared with those who were physically active indoors only. Self rated health was significantly related to being physically active but did not vary by location of activity. CONCLUSIONS: Older adults who were physically active outdoors accumulated significantly more physical activity, but self-rated health was not significantly greater than those being physically active indoors. PMID- 22846595 TI - A comparison of liquid-based cytology with conventional cytology in cervical cancer screening. AB - OBJECTIVE: To clarify the performance of liquid-based cytology (LBC) and conventional methods of preparing cervical specimens for cytological screening. STUDY DESIGN: We studied 236,511 patients who participated in a population-based cervical cancer screening program conducted in the Niigata prefecture between 2005 and 2008. The percentage of unsatisfactory specimens and the disease detection rate were compared between specimens prepared by LBC and conventional methods. RESULTS: (1) The LBC method demonstrated a significantly lower percentage of unsatisfactory specimens than the conventional method (1.38 and 11.45%, respectively; p < 0.01). (2) Among the initial women, tumor lesions were detected in 0.57% of those examined with the LBC method, which was significantly higher than the positivity rate of those examined with the conventional method (0.25%; p < 0.05). Among the women with repeat screening, disease was detected in 0.08% of those examined with LBC twice, which was significantly lower than the positivity rates for those examined with the conventional method followed by the LBC method (0.11%) or the conventional method twice (0.16%; p < 0.05). CONCLUSION: The LBC method is significantly more useful than the conventional method in terms of the low adequacy rate and the high detection rate of cancer in cervical cancer screening in a localized area in Japan. PMID- 22846596 TI - A complete mitochondrial genome sequence of Ogura-type male-sterile cytoplasm and its comparative analysis with that of normal cytoplasm in radish (Raphanus sativus L.). AB - BACKGROUND: Plant mitochondrial genome has unique features such as large size, frequent recombination and incorporation of foreign DNA. Cytoplasmic male sterility (CMS) is caused by rearrangement of the mitochondrial genome, and a novel chimeric open reading frame (ORF) created by shuffling of endogenous sequences is often responsible for CMS. The Ogura-type male-sterile cytoplasm is one of the most extensively studied cytoplasms in Brassicaceae. Although the gene orf138 has been isolated as a determinant of Ogura-type CMS, no homologous sequence to orf138 has been found in public databases. Therefore, how orf138 sequence was created is a mystery. In this study, we determined the complete nucleotide sequence of two radish mitochondrial genomes, namely, Ogura- and normal-type genomes, and analyzed them to reveal the origin of the gene orf138. RESULTS: Ogura- and normal-type mitochondrial genomes were assembled to 258,426 bp and 244,036-bp circular sequences, respectively. Normal-type mitochondrial genome contained 33 protein-coding and three rRNA genes, which are well conserved with the reported mitochondrial genome of rapeseed. Ogura-type genomes contained same genes and additional atp9. As for tRNA, normal-type contained 17 tRNAs, while Ogura-type contained 17 tRNAs and one additional trnfM. The gene orf138 was specific to Ogura-type mitochondrial genome, and no sequence homologous to it was found in normal-type genome. Comparative analysis of the two genomes revealed that radish mitochondrial genome consists of 11 syntenic regions (length >3 kb, similarity >99.9%). It was shown that short repeats and overlapped repeats present in the edge of syntenic regions were involved in recombination events during evolution to interconvert two types of mitochondrial genome. Ogura-type mitochondrial genome has four unique regions (2,803 bp, 1,601 bp, 451 bp and 15,255 bp in size) that are non-syntenic to normal-type genome, and the gene orf138 was found to be located at the edge of the largest unique region. Blast analysis performed to assign the unique regions showed that about 80% of the region was covered by short homologous sequences to the mitochondrial sequences of normal-type radish or other reported Brassicaceae species, although no homology was found for the remaining 20% of sequences. CONCLUSIONS: Ogura-type mitochondrial genome was highly rearranged compared with the normal-type genome by recombination through one large repeat and multiple short repeats. The rearrangement has produced four unique regions in Ogura-type mitochondrial genome, and most of the unique regions are composed of known Brassicaceae mitochondrial sequences. This suggests that the regions unique to the Ogura-type genome were generated by integration and shuffling of pre-existing mitochondrial sequences during the evolution of Brassicaceae, and novel genes such as orf138 could have been created by the shuffling process of mitochondrial genome. PMID- 22846597 TI - Does the effect of gender modify the relationship between deprivation and mortality? AB - BACKGROUND: In this study we propose improvements to the method of elaborating deprivation indexes. First, in the selection of the variables, we incorporated a wider range of both objective and subjective measures. Second, in the statistical methodology, we used a distance indicator instead of the standard aggregating method principal component analysis. Third, we propose another methodological improvement, which consists in the use of a more robust statistical method to assess the relationship between deprivation and health responses in ecological regressions. METHODS: We conducted an ecological small-area analysis based on the residents of the Metropolitan region of Barcelona in the period 1994-2007. Standardized mortality rates, stratified by sex, were studied for four mortality causes: tumor of the bronquial, lung and trachea, diabetes mellitus type II, breast cancer, and prostate cancer. Socioeconomic conditions were summarized using a deprivation index. Sixteen socio-demographic variables available in the Spanish Census of Population and Housing were included. The deprivation index was constructed by aggregating the above-mentioned variables using the distance indicator, DP2. For the estimation of the ecological regression we used hierarchical Bayesian models with some improvements. RESULTS: At greater deprivation, there is an increased risk of dying from diabetes for both sexes and of dying from lung cancer for men. On the other hand, at greater deprivation, there is a decreased risk of dying from breast cancer and lung cancer for women. We did not find a clear relationship in the case of prostate cancer (presenting an increased risk but only in the second quintile of deprivation). CONCLUSIONS: We believe our results were obtained using a more robust methodology. First off, we have built a better index that allows us to directly collect the variability of contextual variables without having to use arbitrary weights. Secondly, we have solved two major problems that are present in spatial ecological regressions, i.e. those that use spatial data and, consequently, perform a spatial adjustment in order to obtain consistent estimators. PMID- 22846598 TI - Preservation of blood pressure stability with hypertonic mannitol during hemodialysis initiation. AB - BACKGROUND: Intradialytic hypotensive events are common among hemodialysis patients and are associated with a variety of patient- and procedure-related factors, including intradialytic decline in plasma osmolality. Prior studies and practice have suggested that administration of osmotically active drugs may ameliorate blood pressure decline during chronic hemodialysis. METHODS: Clinical and treatment data were collected for 102 consecutive patients requiring initiation of renal replacement therapy in 2 major teaching hospitals. Routine administration of mannitol differed according to institutional protocols, allowing its examination as the primary exposure of interest. Generalized linear models were fit to estimate associations of mannitol use during dialysis initiation with intradialytic blood pressure, as assessed by: (1) intradialytic blood pressure decline; (2) nadir intradialytic blood pressure; (3) absolute systolic blood pressure <90 mm Hg or decline >20 mm Hg. RESULTS: Mean age was 62 years (+/-16), 70% were male and 44% were diabetic. Mean predialysis and nadir systolic blood pressure were 142 mm Hg (+/-29) and 121 mm Hg (+/-26), respectively. Mannitol administration was associated with a lesser decline in intradialytic blood pressure, a higher nadir blood pressure and fewer hypotensive events requiring intervention. No effect modification was evident according to diabetes or acuity of kidney disease (chronic vs. acute). CONCLUSIONS: Mannitol administration appears to preserve hemodynamic stability during hemodialysis initiation. Randomized controlled trials are needed to confirm these findings and identify optimal management strategies to prevent intradialytic hypotension. PMID- 22846599 TI - Inhibition of PARP prevents angiotensin II-induced aortic fibrosis in rats. AB - BACKGROUND: Fibrosis is one of the major pathological features of hypertensive vascular disease. In this study, we aim to explore the possible protective effects of poly(ADP-ribose) polymerase (PARP) inhibitor on angiotensin II (AngII) induced aortic fibrosis. METHODS: Sprague-Dawley rats were infused subcutaneously with AngII. PARP inhibitor was intraperitoneally injected once a day. Collagen deposition in thoracic aorta was assayed by Masson tricrome staining. The mRNA and protein expression of TGF-beta target genes involved in extracellular matrix (ECM) remodeling in aorta was measured. Plasma level and aortic expression of TGF beta1 was assayed. Correlation of systolic blood pressure (SBP) with plasma level of TGF-beta1 was analyzed. In cultured rat vascular smooth muscle cells (VSMCs), effects of PARP inhibition on TGF-beta1 expression, Smad3 transactivity, and TGF beta/Smad3 target gene expression were investigated. RESULTS: Infusion of AngII promoted aortic PARP activation. Treatment with PARP inhibitor alleviated AngII induced collagen deposition and expression of TGF-beta target genes involved in ECM remodeling in aorta of rat. AngII increased plasma level and aortic expression of TGF-beta1. A positive correlation between SBP and plasma level of TGF-beta1 was revealed. Treatment with PARP inhibitor prevented AngII-induced elevation of SBP. Further experiments uncovered that AngII treatment increased TGF-beta dependent gene expression through Smad3 pathway in cultured VSMCs. Inhibition of PARP prevented AngII-induced increases in TGF-beta1 expression, Smad3 transactivity and its target gene expression. CONCLUSIONS: These data indicate that inhibition of PARP prevents aortic fibrosis in AngII-induced hypertension in rats. This beneficial effect is mediated by inhibiting TGF beta/Smad3 pathway. PMID- 22846600 TI - Redox modulation of the DNA damage response. AB - Lesions to DNA trigger the DNA-damage response (DDR), a complex, multi-branched cell-intrinsic process targeted to DNA repair, or elimination of the damaged cells by apoptosis. DDR aims at reducing permanence of mutated cells, decreasing the risk of tumor development: the more stringent the response, the lower the likelihood that sub-lethally damaged, unrepaired cells survive and proliferate. Accordingly, leakage often occurs in tumor cells with compromised DDR, accumulating mutations and accelerating tumor progression. Oxidations mediate DNA damage upon different insults such as UV, X and gamma radiation, pollutants, poisons, or endogenous disequilibria, producing different types of lesions that trigger DDR, which can be alleviated by antioxidants. But reactive oxygen species (ROS), and the enzymes involved in their production or scavenging, also participate in DDR signaling, modulating the activity of key enzymes, and regulating the stringency of DDR. Accordingly, antioxidant enzymes such as superoxide dismutase play intimate and complex roles in tumor development, exceeding the basal roles of preventing the initial DNA damage. Likewise, it is emerging that dietary antioxidants help controlling tumor onset and progression by preventing DNA damage and by acting on cell cycle checkpoints, opening a novel and promising frontier to anticancer therapy. PMID- 22846601 TI - Isoniazid as a substrate and inhibitor of myeloperoxidase: identification of amine adducts and the influence of superoxide dismutase on their formation. AB - Neutrophils ingest Mycobacteria tuberculosis (Mtb) in the lungs of infected individuals. During phagocytosis they use myeloperoxidase (MPO) to catalyze production of hypochlorous acid (HOCl), their most potent antimicrobial agent. Isoniazid (INH), the foremost antibiotic in the treatment of tuberculosis, is oxidized by MPO. It rapidly reduced compound I of MPO [k = (1.22 +/- 0.05) * 10(6) M(-1) s(-1)] but reacted less favorably with compound II [(9.8 +/- 0.6) * 10(2) M(-1) s(-1)]. Oxidation of INH by MPO and hydrogen peroxide was unaffected by chloride, the physiological substrate for compound I, and the enzyme was partially converted to compound III. This indicates that INH is oxidized outside the classical peroxidation cycle. In combination with superoxide dismutase (SOD), MPO oxidized INH without exogenous hydrogen peroxide. SOD must favor reduction of oxygen by the INH radical to give superoxide and ultimately hydrogen peroxide. In both oxidation systems, an adduct with methionine was formed and it was a major product with MPO and SOD. We show that it is a conjugate of an acyldiimide with amines. INH substantially inhibited HOCl production by MPO and neutrophils below pharmacological concentrations. The reversible inhibition is explained by diversion of MPO to its ferrous and compound III forms during oxidation of INH. MPO, along with SOD released by Mtb, will oxidize INH at sites of infection and their interactions are likely to limit the efficacy of the drug, promote adverse drug reactions via formation of protein adducts, and impair a major bacterial killing mechanism of neutrophils. PMID- 22846602 TI - Quercetin and its metabolites improve vessel function by inducing eNOS activity via phosphorylation of AMPK. AB - Quercetin is a major flavonoid in a wide range of fruits and vegetables. Consumption of quercetin may contribute to a reduction in risk of cardiovascular disease (CVD). Following ingestion, flavonoids are metabolized rapidly by methylation or glucuronidation, which can alter their biological activity. Certain dietary flavonoids have been shown to upregulate the expression of adenosine monophosphate-activated protein kinase (AMPK). AMPK is a conserved key enzyme in cellular energy homeostasis that affects fatty acid oxidation. The aim of the present study was to investigate the effects of supraphysiological concentrations of quercetin and its methyl and glucuronide metabolites (3'-O methyl-quercetin and quercetin-3-O-glucuronide) on activation of AMPK and eNOS in human aortic endothelial cells (HAECs) and endothelial function in isolated aortic rings from C57BL mice. We found that 5 and 10 MUM quercetin and its metabolites, and pretreatment of arteries with quercetin and its metabolites can protect vessels against hypochlorous acid-induced endothelial dysfunction in isolated arteries (P < 0.05). Inhibition of AMPK blocked these protective effects. We also found that 5 and 10 MUM quercetin and its metabolites can induce activation of AMPK and eNOS in human aortic endothelial cells, and lead to an increase in the concentrations of S-nitrosothiols and nitrite in cell culture media (P < 0.05). These results provide further support for the cardioprotective effects of certain dietary flavonoids. They suggest that beneficial effects of quercetin on endothelial cell functions are in part mediated via AMPK pathway. PMID- 22846603 TI - Traditional West African pharmacopeia, plants and derived compounds for cancer therapy. AB - Traditional pharmacopeia is strongly involved in the continuous search for the well being of African populations. The World Health Organization (WHO) estimates that 80% of the population of developing countries relies on traditional medicine for their primary care needs. Medicinal plants are the major resource of this folk medicine where several species are used for the treatment of diseases with an inflammatory and/or infectious component as it is the case of old wounds, skin diseases and malfunctions affecting internal organs such as liver, lung, prostate and kidney. Many of these pathologies described by practitioners of traditional medicine have similarities with certain cancers, but the lack of training of many of these healers does not allow them to establish a link with cancer. However, ethnobotanical and ethnopharmacological surveys conducted by several researchers allowed to identify plants of interest for cancer treatment. Most scientific investigations on these plants demonstrated an anti-inflammatory or antioxidant effect, and sometimes, antiproliferative and cytotoxic activities against cancer cells were reported as well. The emergence of resistance to cancer chemotherapy has forced researchers to turn to natural products of plant and marine origin. In the West African sub-region, research on natural anti-cancer molecules is still in its infancy stage because of very limited financial resources and the scarcity of adequate technical facilities. However, several plants were investigated for their anticancer properties through north-south or south-south partnerships. In this review, we will review the role of West African traditional pharmacopeia in cancer treatment as well as medicinal plants with anti-cancer properties. PMID- 22846605 TI - Chronic intermittent hypoxia induces atherosclerosis by NF-kappaB-dependent mechanisms. AB - Chronic intermittent hypoxia (CIH) causes atherosclerosis in mice fed a high cholesterol diet (HCD). The mechanisms by which CIH promotes atherosclerosis are incompletely understood. This study defined the mechanistic role of NF-kappaB pathway in CIH+HCD induced atherosclerosis. Wild type (WT) and mice deficient in the p50 subunit of NF-kappaB (p50-KO) were fed normal chow diet (ND) or HCD, and exposed to sham or CIH. Atherosclerotic lesions on the en face aortic preparation and cross-sections of aortic root were examined. In WT mice, neither CIH nor HCD exposure alone caused, but CIH+HCD caused evident atherosclerotic lesions on both preparations after 20weeks of exposure. WT mice on ND and exposed to CIH for 35.6weeks did not develop atherosclerotic lesions. P50 gene deletion diminished CIH+HCD induced NF-kappaB activation and abolished CIH+HCD induced atherosclerosis. P50 gene deletion inhibited vascular wall inflammation, reduced hepatic TNF-alpha level, attenuated the elevation in serum cholesterol level and diminished macrophage foam cell formation induced by CIH+HCD exposure. These results demonstrate that inhibition of NF-kappaB activation abrogates the activation of three major atherogenic mechanisms associated with an abolition of CIH+HCD induced atherosclerosis. NF-kappaB may be a central common pathway through which CIH+HCD exposure activates multiple atherogenic mechanisms, leading to atherosclerosis. PMID- 22846604 TI - Preventing the calorie restriction-induced increase in insulin-stimulated Akt2 phosphorylation eliminates calorie restriction's effect on glucose uptake in skeletal muscle. AB - Calorie restriction (CR; ~60% of ad libitum, AL, consumption) improves insulin stimulated glucose uptake in skeletal muscle. The precise cellular mechanism for this healthful outcome is unknown, but it is accompanied by enhanced insulin stimulated activation of Akt. Previous research using Akt2-null mice demonstrated that Akt2 is essential for the full CR-effect on insulin-stimulated glucose uptake by muscle. However, because Akt2-null mice were completely deficient in Akt2 in every cell throughout life, it would be valuable to assess the efficacy of transient, muscle-specific Akt inhibition for attenuation of CR-effects on glucose uptake. Accordingly, we used a selective Akt inhibitor (MK-2206) to eliminate the CR-induced elevation in insulin-stimulated Akt2 phosphorylation and determined the effects on Akt substrates and glucose uptake. We incubated isolated epitrochlearis muscles from 9-month-old AL and CR (~60-65% of AL intake for 6months) rats with or without MK-2206 and measured insulin-stimulated (1.2nM) glucose uptake and phosphorylation of the insulin receptor (Tyr1162/1163), pan Akt (Thr308 and Ser473), Akt2 (Thr308 and Ser473), AS160/TBC1D4 (Thr642), and Filamin C (Ser2213). Incubation of isolated skeletal muscles with a dose of a selective Akt inhibitor that eliminated the CR-induced increases in Akt2 phosphorylation prevented CR's effects on insulin-stimulated glucose uptake, pAS160(Thr642) and pFilamin C(Ser2213) without altering pIR(Tyr1162/1163). These data provide compelling new evidence linking the CR-induced increase in insulin stimulated Akt2 phosphorylation to CR's effects on insulin-mediated phosphorylation of Akt substrates and glucose uptake in skeletal muscle. PMID- 22846606 TI - The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice. AB - The crosstalk between mTORC1/S6K1 signaling and AMPK is emerging as a powerful and highly regulated way to gauge cellular energy and nutrient content. The aim of the current study was to determine the mechanism by which exercise training reverses lipid-induced insulin resistance and the role of AMPK/mTOR/S6K1 signaling axis in mediating this response in skeletal muscle. Our results showed that high-fat feeding resulted in decreased glucose tolerance, which was associated with decreased Akt expression and increased intramuscular triglyceride deposition in the skeletal muscle of C57BL/6 mice. Impairments in lipid metabolism were accompanied by increased total protein and phosphorylation of S6K1, SREBP-1c cleavage, and decreased AMPK phosphorylation. Exercise training reversed these impairments, resulting in improved serum lipid profiles and glucose tolerance. C2C12 myotubes were exposed to palmitate, resulting in an increased insulin-dependent Akt Ser473 phosphorylation, associated with a significant increase in the level of phosphorylation of S6K1 on T389. All these changes were reversed by activation of AMPK. Consistent with this, inhibition of AMPK by compound C induced an enhanced phosphorylation of both S6K1 and Akt, and silencing of S6K1 with siRNA showed no effect on Akt phosphorylation in both the absence and presence of palmitate cultured myotubes. In addition, compound C led to an elevated SREBP-1c cleavage but was blocked by S6K1 siRNA. In summary, exercise training inhibits SREBP-1c cleavage through AMPK/mTOR/S6K1 signaling, resulting in decreased intramyocellular lipid accumulation. Our results provide new insights into the mechanism by which AMPK/mTOR/S6K1 signaling axis mediates the physiological process of exercise-induced insulin sensitization. PMID- 22846607 TI - The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder for which available treatments provide symptom relief but do not stop disease progression. Mitochondria, and in particular mitochondrial dynamics, have been postulated as plausible pharmacological targets. Mitochondria-targeted antioxidants have been developed to prevent mitochondrial oxidative damage, and to alter the involvement of reactive oxygen species (ROS) in signaling pathways. In this study, we have dissected the effect of MitoQ, which is produced by covalent attachment of ubiquinone to a triphenylphosphonium lipophilic cation by a ten carbon alkyl chain. MitoQ was tested in an in vitro PD model which involves addition of 6 hydroxydopamine (6-OHDA) to SH-SY5Y cell cultures. At sublethal concentrations of 50MUM, 6-OHDA did not induce increases in protein carbonyl, mitochondrial lipid peroxidation or mitochondrial DNA damage. However, after 3h of treatment, 6-OHDA disrupts the mitochondrial morphology and activates the machinery of mitochondrial fission, but not fusion. Addition of 6-OHDA did not increase the levels of fission 1, mitofusins 1 and 2 or optic atrophy 1 proteins, but does lead to the translocation of dynamin related protein 1 from the cytosol to the mitochondria. Pre-treatment with MitoQ (50nM, 30min) results in the inhibition of the mitochondrial translocation of Drp1. Furthermore, MitoQ also inhibited the translocation of the pro-apoptotic protein Bax to the mitochondria. These findings provide mechanistic evidence for a role for redox events contributing to mitochondrial fission and suggest the potential of mitochondria-targeted therapeutics in diseases that involve mitochondrial fragmentation due to oxidative stress. PMID- 22846609 TI - Cell-penetrating peptides as a novel transdermal drug delivery system. AB - In the last decade, almost one-third of the newly discovered drugs approved by the US FDA were biomolecules and biologics. Effective delivery of therapeutic biomolecules to their target is a challenging issue. Innovations in drug delivery systems have improved the efficiency of many of new biopharmaceuticals. Designing of novel transdermal delivery systems has been one of the most important pharmaceutical innovations, which offers a number of advantages. The cell penetrating peptides have been increasingly used to mediate delivery of bimolecular cargoes such as small molecules, small interfering RNA nucleotides, drug-loaded nanoparticles, proteins, and peptides, both in vitro and in vivo, without using any receptors and without causing any significant membrane damage. Among several different drug delivery routes, application of cell-penetrating peptides in the topical and transdermal delivery systems has recently garnered tremendous attention in both cosmeceutical and pharmaceutical research and industries. In this review, we discuss history of cell-penetrating peptides, cell penetrating peptide/cargo complex formation, and their mechanisms of cell and skin transduction. PMID- 22846608 TI - Limitations of sniff nasal pressure as an outcome measurement in amyotrophic lateral sclerosis patients in a clinical trial. AB - BACKGROUND: The forced vital capacity (FVC) is an established measure in amyotrophic lateral sclerosis (ALS) clinical trials. Recently the sniff nasal inspiratory pressure (SNIP) test has been increasingly used as a respiratory measure. OBJECTIVES: It was the aim of this study to assess the feasibility of SNIP as an outcome measure in a phase III clinical trial with a lead-in design. METHODS: Twenty patients were enrolled in a randomized clinical trial. FVC, SNIP in sitting (SNIPsitt) and supine (SNIPsup) positions, and the ALS functional rating scale score (ALSFRS-R) were measured every 4 weeks. RESULTS: Complete data were available for 19 patients over 5 months. Baseline values were normal for FVC (101 +/- 14%) but abnormal for SNIPsitt and SNIPsup (84 +/- 34% and 82 +/- 33%). While FVC and ALSFRS-R declined in parallel, SNIPsitt measures declined significantly less compared to ALSFRS-R (p < 0.05) and FVC (p < 0.001) up to 4 months after enrollment. Over 50% of patients still had values equal to or above baseline SNIPsitt measures after 3 months despite abnormal baseline values. CONCLUSIONS: The delayed decline in SNIP measurements suggests a learning effect over time. The optimal number of SNIPs in ALS clinical trials has yet to be determined. SNIP measures should be used with caution in trials with a lead-in design. PMID- 22846610 TI - Anti-N-methyl-D-aspartate receptor encephalitis presenting with acute psychosis in a preteenage girl: a case report. AB - INTRODUCTION: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare, newly defined autoimmune clinical entity that presents with atypical clinical manifestations. Most patients with anti-N-methyl-D-aspartate receptor encephalitis develop a progressive illness from psychosis into a state of unresponsiveness, with catatonic features often associated with abnormal movements and autonomic instability. This is the first report of anti-N-methyl-D aspartate receptor encephalitis in a Greek pediatric hospital. CASE PRESENTATION: An 11-year-old Greek girl presented with clinical manifestations of acute psychosis. The differential diagnosis included viral encephalitis. The presence of a tumor usually an ovarian teratoma, a common clinical finding in many patients, was excluded. Early diagnosis and prompt immunotherapy resulted in full recovery up to one year after the initial diagnosis. CONCLUSION: Acute psychosis is a rare psychiatric presentation in children, diagnosed only after possible organic syndromes that mimic acute psychosis are excluded, including anti-N methyl-D-aspartate receptor receptor encephalitis. Pediatricians, neurologists and psychiatrists should consider this rare clinical syndrome, in order to make an early diagnosis and instigate appropriate treatment to maximize neurological recovery. PMID- 22846611 TI - Intraindividual variability of C-reactive protein: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: The intraindividual variability of C-reactive protein (CRP) remains uncertain. Although guidelines suggest stability of serial CRP values comparable to that of cholesterol measures, several studies indicate greater fluctuations of CRP. We sought to compare the intraindividual variability of CRP with that of cholesterol measures using the multi-ethnic study of atherosclerosis (MESA). METHODS: CRP measurements were available in 760 MESA participants after exclusion of those with comorbidities or medications known to affect CRP or CRP>=10 mg/L. Serial values were available for 255 participants. The intraclass correlation coefficient (ICC) was quantified for CRP, total cholesterol (TC), and non-HDL cholesterol (non-HDL-C) as the ratio of between-subject variance to the sum of between-subject and within-subject variance. Fluctuation between baseline and follow-up categories was calculated by cross-classifying participants according to baseline tertiles. RESULTS: The multivariable-adjusted ICC of CRP was 0.62 (95% CI, 0.55-0.68), significantly lower than that of TC (0.75; 95% CI, 0.70 0.81; p = 0.001 vs CRP) and non-HDL-C (0.76; 95% CI, 0.71-0.81; p = 0.001 vs CRP). 51% of participants in the highest baseline CRP tertile had discordant values on follow-up, while 54% and 27% were discordant in the middle and lowest baseline CRP tertiles. Among participants with baseline CRP levels exceeding 3 mg/L, a clinical threshold for higher risk, 69% had subsequent measurements falling within a lower risk category. CONCLUSIONS: In the MESA cohort, intraindividual variation of CRP was significantly greater than that for cholesterol measures. Our results suggest that further evaluation of CRP variability is needed in large prospective studies using shorter intervals between measurements. PMID- 22846612 TI - Do stem cells cause aging-related intimal medial thickening? PMID- 22846613 TI - Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection. AB - BACKGROUND: Hepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by chronic inflammation in the liver and in peripheral immune cells. Chronic liver inflammation leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155, -146a and -125b) as well as hepatocyte function (miR-122). METHODS: Here we hypothesized that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the circulation and in peripheral monocytes of patients with chronic HCV infection to evaluate if specific miRNA expression correlated with HCV infection. RESULTS: We found that monocytes from chronic HCV infected treatment-naive (cHCV) but not treatment responder patients showed increased expression of miR-155, a positive regulator of TNFalpha, and had increased TNFalpha production compared to monocytes of normal controls. After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients compared to controls. MiR-125b, which has negative regulatory effects on inflammation, was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a robust increase in both miR-155 expression and TNFalpha production identifying potential mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum miR-155 levels in HCV patients compared to controls. Serum miR 125b and miR-146a levels were also increased in HCV patients. Serum levels of miR 122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels. CONCLUSION: In conclusion, our novel data demonstrate that miR-155, a positive regulator of inflammation, is upregulated both in monocytes and in the serum of patients with chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or TLR4 and TLR8 ligands can mediate increased miR-155 and TNFalpha production in chronic HCV infection. The positive correlation between serum miR-155 and miR-122 increase in cHCV may be an indicator of inflammation-induced hepatocyte damage. PMID- 22846615 TI - Drug-specific Th2 cells and IgE antibodies in a patient with anaphylaxis to rituximab. AB - Rituximab (RTX) is currently used in the treatment of lymphoproliferative diseases and of several rheumatologic disorders and is a frequent cause of acute infusion reactions, usually classified as cytokine release syndrome (CRS). Some infusion reactions to RTX raise concern for immediate type I hypersensitivity, even if to date RTX-specific IgE antibodies have not been reported. To improve knowledge of the mechanisms of reactions to RTX, we investigated humoral and cellular immune responses to this drug in a patient suffering from rheumatoid arthritis who displayed two immediate infusion-related reactions. RTX-exposed tolerant patients and healthy untreated subjects were used as controls. Non isotype-specific and IgE anti-RTX antibodies were positive in the serum samples collected from the reactive patient but not in those from the control groups. Only the reactive patient also displayed skin testing positivity with RTX. More importantly, RTX-stimulated peripheral blood mononuclear cells from the reactive patient, but not from the controls, displayed a dose-dependent proliferative response associated with a Th2 cytokine production profile. Our results show the presence of RTX-specific Th2-type cells and IgE antibodies, thus suggesting that type I hypersensitivity may be an additional mechanism to CRS in the development of RTX reactions. PMID- 22846614 TI - Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity. RESULTS: We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 * 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR 363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA. CONCLUSION: Our comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans. PMID- 22846616 TI - Issues related to advances and controversies in breast cancer management: a multicultural experience. AB - The overview of current diagnostic and therapeutic advances and controversies in the management of breast cancer is presented. Specific topics and their impact on breast reconstruction surgeons practicing in culturally different areas and with variable access to breast education and health care are discussed. The following approaches to the most common types of problems are presented: prophylactic mastectomy for women at high risk of breast cancer, size and location of the primary tumor and feasibility of breast conserving surgery and oncoplastic approach, management of the axilla, post-mastectomy radiation and chemotherapy, emerging breast reconstructive techniques (fat transfer, stem cells) and cancer risk, oncological follow up and imaging of the reconstructed breast, including illustrative cases. This material should help oncological and plastic surgeon specialists to understand each other's considerations for the best possible outcome of the breast cancer treatment. PMID- 22846617 TI - Stump appendicitis: a review. AB - Acute appendicitis is perhaps the commonest cause of acute abdomen and surgical intervention in the form of open or laparoscopic appendicectomy. Stump appendicitis is an uncommon late complication of appendicectomy; where inflammation occurs in the remaining appendicular stump. Delayed diagnosis of this condition may result in serious complications. This literature review has looked into the clinical presentation, diagnosis and treatment of Stump appendicitis. PMID- 22846618 TI - Building global capacity for patient safety: a training program for surgical safety research in developing and transitional countries. AB - BACKGROUND: Recent studies show a significant rate of adverse events in hospitalized patients in developing/transitional countries--with approximately 18% of them related to surgical procedures. Understanding and preventing these errors requires adequate training in patient safety research methods--however, relevant training programs are currently lacking. We developed, delivered and evaluated a training program to address this gap. METHODS: A one-day training program was developed based on the recently published WHO core competencies for patient safety research. The focus was on surgical patient safety research - including human factors, operating room (OR) teamwork, the OR environment, and safety culture. Feasibility, relevance and preliminary evaluation of the program ('proof of concept' testing) was conducted in Bogota, Colombia in July 2011. A validated evaluation framework was utilized, assessing participants' objective knowledge, attitudes, and observational skills. RESULTS: 30 postgraduate students from a range of clinical/non-clinical disciplines signed up and 17 attended the program. Participants' knowledge of surgical patient safety significantly improved upon program completion (Mean pre-course=55% vs. Mean post-course=68%, P<0.01), as did their confidence and understanding of problems and methodologies to assess OR patient safety, and teamwork issues (P<0.05). Observational skills in recognizing safety-related behaviors using OTAS (i.e., quality of teamwork) improved on qualitative evaluation. CONCLUSIONS: We have developed a viable, WHO driven training program that can be delivered to clinical and non-clinical researchers to develop their competencies and thereby build capacity in developing/transitional countries to carry out surgical safety research. All program materials are available in English and Spanish for research, training and dissemination. PMID- 22846619 TI - Importance of the residual volume of the cytological solution for the reproducibility of the hybrid capture 2 high-risk human papillomavirus DNA test. AB - OBJECTIVE: Human papillomavirus (HPV) infections are widespread in all human populations, and a large number of studies have demonstrated a relationship between high-risk (HR)-HPV infections and cervical intraepithelial neoplasia or invasive cervical cancer. To the best of our knowledge, no independent study clearly demonstrates the importance of the quantity of residual liquid after cytology in terms of sensitivity for HR-HPV detection. STUDY DESIGN: We conducted a study to assess the relationship between the liquid-based cytology volume and the sensitivity of the hybrid capture 2 test for the detection of HR-HPV in 23 cytological high-grade squamous intraepithelial lesions with a cervical intraepithelial neoplasia grade 2 or worse protocol on biopsy. RESULTS: Although the sensitivity of the tests showed no statistically significant differences, we still found a significant variation in the median values of relative light units/control according to the amount of liquid used. CONCLUSIONS: If 2 ml of liquid is used, this could lead to false negatives when the value of relative light units/control is only slightly greater than 1. The fact that we found a lower viral load at 2 versus 4 or 8 ml was also important in terms of predicting the evolution of cervical lesions. We recommend using at least 4 ml of the PreservCyt solution for HR-HPV detection with the hybrid capture 2 test. PMID- 22846620 TI - Antifouling foldable acrylic IOLs loaded with norfloxacin by aqueous soaking and by supercritical carbon dioxide technology. AB - Cataracts treatment usually involves the extraction of the opaque crystalline lens and its replacement by an intraocular lens (IOL). A serious complication is the occurrence of endophthalmitis, a post-surgery infection mainly caused by Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa. IOLs having the ability to load and to release norfloxacin in a controlled way and at efficient therapeutic levels may help to overcome these issues. In this work, acrylic hydrogels combining 2-hydroxyethyl methacrylate (HEMA) and 2 butoxyethyl methacrylate (BEM) at various ratios were prepared to attain biocompatible networks that can be foldable even in the dry state and thus insertable through minor ocular incision, and that load therapeutic amounts of norfloxacin. Acrylamide (AAm) and methacrylic acid (MAAc) were also incorporated as functional comonomers in small proportions. Water sorption, contact angle, protein adsorption, and optical properties of the networks were characterized. BEM notably decreased the T(g) of the networks, but also the loading by immersion in aqueous solution (presoaking). Then, a scCO(2)-based impregnation/deposition (SSI) method was implemented to improve the uptake of the drug. Loading capacities were discussed in terms of the comonomers composition and the employed method and operational conditions. The networks prepared with HEMA/BEM 20:80 vol/vol and processed with supercritical fluids combine adequate mechanical properties, biocompatibility and norfloxacin loading/release, and seem to be suitable for developing norfloxacin-eluting IOLs. PMID- 22846622 TI - Basal GLP-1 levels in morbidly obese patients following biliopancreatic diversion surgery. AB - BACKGROUND: Previous studies addressing the changes of glucagon-like peptide-1 (GLP-1) concentrations in morbidly obese patients after bariatric surgery have demonstrated conflicting results. The aim of the present study was to investigate the changes in serum GLP-1 levels 9 months after biliopancreatic diversion in morbidly obese patients without diabetes mellitus. METHODS: A sample of 40 morbidly obese patients without diabetes mellitus was enrolled. Biochemical and anthropometrical evaluations were conducted at basal and 9 months after surgery. RESULTS: The mean patient age was 46.6 +/- 13.1 years, and the mean preoperative body mass index (BMI) was 47.1 +/- 18.1. A significant decrease in BMI, weight, waist circumference, fat mass, glucose, LDL cholesterol, total cholesterol, and triglyceride levels was observed after 9 months. Serum basal GLP-1 levels did not change after surgery (0.65 +/- 0.18 ng/ml vs. 0.66 +/- 0.17 ng/ml; n.s.). Postsurgical correlation analysis showed a negative association between basal GLP 1 and HDL cholesterol (r = -0.57; p < 0.01). CONCLUSIONS: Fasting GLP-1 concentrations did not change after massive weight loss with biliopancreatic diversion in morbidly obese patients without diabetes mellitus. PMID- 22846621 TI - Minor cognitive impairments in cancer patients magnify the effect of caregiver preferences on end-of-life care. AB - CONTEXT: Cognitive impairment commonly affects cancer patients. OBJECTIVES: To examine whether minor cognitive impairment in patients with advanced cancer is associated with the intensity of end-of-life (EOL) care or modifies the influence of patient and caregiver preferences on the intensity of EOL care. METHODS: Data were derived from structured interviews with 221 advanced cancer patient caregiver dyads in the Coping with Cancer Study, a multisite, longitudinal cohort study. Deficits in patients' cognitive function were identified using the Short Portable Mental Status Questionnaire (SPMSQ). Patients and caregivers reported preferences regarding life-extending vs. symptom-directed care. Information regarding EOL care was obtained from postmortem interviews with caregivers. Logistic regression analyses modeled main and interactive effects of patients' cognitive impairment and patients' and caregivers' treatment preferences on intensive EOL care. RESULTS: Cognitive impairment was associated with less intensive EOL care (odds ratio [OR] = 0.56; 95% confidence interval [CI]: 0.34 0.91). Patients and caregivers had poor agreement regarding preferences for life extending vs. symptom-directed care (Phi = 0.10; chi(2)=2.32, df = 1, P = 0.13). Patient preference for life-extending care predicted intensive EOL care irrespective of cognitive status (adjusted odds ratio [AOR] = 2.11; 95% CI: 1.04 4.28). For patients with no errors on the SPMSQ, caregiver preference for life extending care was unrelated to intensive EOL care (AOR = 0.40; 95% CI: 0.09 1.77). However, the association between caregiver preference for life-extending care and intensive EOL care increased by nearly a factor of seven for every error on the SPMSQ (interaction AOR = 6.90; 95% CI: 1.40-34.12). CONCLUSION: Cognitive impairment in patients with advanced cancer is associated with less intensive EOL care. Caregivers' influence on intensive EOL care dramatically increases with minor declines in patients' cognitive function. PMID- 22846623 TI - Unraveling the energetics and mode of the recognition of antibiotics tetracycline and rolitetracycline by bovine serum albumin. AB - An understanding of the detailed energetics and mechanism of the binding of drugs with target proteins is essential for devising guidelines to synthesize new drugs. Binding of the antibiotic drugs tetracycline and rolitetracycline with serum albumin has been studied by a combination of isothermal titration calorimetry, differential scanning calorimetry, steady-state and time-resolved fluorescence, and circular dichroism spectroscopies. Both tetracycline and rolitetracycline bind to bovine serum albumin in a sequential manner with first binding being the major binding event with an association constant of the order of 10(4) for tetracycline and 10(3) for rolitetracycline, respectively. Ionic strength dependence and binding in the presence of tetrabutylammonium bromide and sucrose indicate involvement of a mix of hydrophobic, ionic, and hydrogen bonding interactions. The isothermal titration calorimetry results for the binding of these drugs to bovine serum albumin in the presence of warfarin and in the presence of each other indicate that both these drugs share binding site 2 on bovine serum albumin. The differential scanning calorimetry results provide quantitative information on the effect of drugs on the stability of bovine serum albumin. A comparison of isothermal titration calorimetry and fluorescence results demonstrates that the former technique has been able to explain the sequential binding events that can be missed by the fluorescence measurements. PMID- 22846624 TI - Genetic control of ovarian development. AB - During embryonic development, ovarian somatic cells embark on a course that is separate from male somatic cells and from indifferent precursor cells. While the former aspect of ovarian development is well known, the latter has not received much attention until recently. This review attempts to integrate the most recent work regarding the differentiation of ovarian somatic cells. The discussion of the parallel development of the testis is limited to the key differences only. Similarly, germ cell development will be introduced only inasmuch as it becomes necessary to draw attention to a particular aspect of the somatic component differentiation. Finally, while postnatal ovarian development and folliculogenesis undoubtedly provide the ultimate morphological and functional fitness tests for the ovarian somatic cells, postnatal phenotypes will be only referred to when they have already been connected to genes that are expressed during embryogenesis. PMID- 22846625 TI - Licit prescription drug use in a Swedish population according to age, gender and socioeconomic status after adjusting for level of multi-morbidity. AB - BACKGROUND: There is a great variability in licit prescription drug use in the population and among patients. Factors other than purely medical ones have proven to be of importance for the prescribing of licit drugs. For example, individuals with a high age, female gender and low socioeconomic status are more likely to use licit prescription drugs. However, these results have not been adjusted for multi-morbidity level. In this study we investigate the odds of using licit prescription drugs among individuals in the population and the rate of licit prescription drug use among patients depending on gender, age and socioeconomic status after adjustment for multi-morbidity level. METHODS: The study was carried out on the total population aged 20 years or older in Ostergotland county with about 400 000 inhabitants in year 2006. The Johns Hopkins ACG Case-mix was used as a proxy for the individual level of multi-morbidity in the population to which we have related the odds ratio for individuals and incidence rate ratio (IRR) for patients of using licit prescription drugs, defined daily doses (DDDs) and total costs of licit prescription drugs after adjusting for age, gender and socioeconomic factors (educational and income level). RESULTS: After adjustment for multi-morbidity level male individuals had less than half the odds of using licit prescription drugs (OR 0.41 (95% CI 0.40-0.42)) compared to female individuals. Among the patients, males had higher total costs (IRR 1.14 (95% CI 1.13-1.15)). Individuals above 80 years had nine times the odds of using licit prescription drugs (OR 9.09 (95% CI 8.33-10.00)) despite adjustment for multi morbidity. Patients in the highest education and income level had the lowest DDDs (IRR 0.78 (95% CI 0.76-0.80), IRR 0.73 (95% CI 0.71-0.74)) after adjustment for multi-morbidity level. CONCLUSIONS: This paper shows that there is a great variability in licit prescription drug use associated with gender, age and socioeconomic status, which is not dependent on level of multi-morbidity. PMID- 22846626 TI - MS-275, a benzamide histone deacetylase inhibitor, prevents osteoclastogenesis by down-regulating c-Fos expression and suppresses bone loss in mice. AB - Histone deacetylase (HDAC) enzymes play important roles in physiological and pathological processes by catalyzing the deacetylation of lysine residues in histone and non-histone proteins. Inhibition of HDACs has emerged as an attractive therapeutic strategy for various diseases including cancer and inflammatory diseases. We recently found that MS-275, a class I-specific HDAC inhibitor, exhibits an anabolic effect on bone through promoting expression of alkaline phosphatase in osteoblasts. MS-275 has also been suggested to inhibit inflammatory bone destruction, but the underlying mechanisms are still poorly understood. In this study, we investigated the effects and mechanism of action of MS-275 on osteoclast differentiation and activation. We found that MS-275 inhibits osteoclast differentiation in coculture of osteoblasts and bone marrow cells without affecting expression of receptor activator of NF-kappaB ligand (RANKL), a key cytokine for osteoclast differentiation, in osteoblasts. MS-275 inhibited RANKL-mediated osteoclast differentiation from its precursors by suppressing RANKL-induced expression of c-Fos, a crucial transcription factor for osteoclastogenesis. The inhibitory effect of MS-275 on osteoclast differentiation was blunted by ectopic overexpression of c-Fos. In addition to osteoclast differentiation, MS-275 decreased bone resorbing activity of mature osteoclasts. Consistent with the in vitro effects, MS-275 decreased osteoclast number and bone destruction in IL-1-induced mouse calvarial bone destruction model. Taken together, our results demonstrate that MS-275 suppresses bone destruction by inhibiting osteoclast differentiation and activation, suggesting a potential therapeutic value of MS-275 for bone disorders associated with increased bone resorption. PMID- 22846627 TI - Managing the risk of cancer in Cowden syndrome: a case report. AB - INTRODUCTION: Cowden syndrome is a rare cancer predisposition syndrome inherited in an autosomal-dominant fashion. The syndrome is characterized by hamartomatous polyps that affect multiple organs: skin, mucous membranes, thyroid, breast, gastrointestinal tract, endometrium and brain. It is also associated with an increased risk of developing malignancy in many tissues but especially breast, thyroid and endometrium. CASE PRESENTATION: We present the case of a 30-year-old Tunisian woman with mental retardation who presented to our facility with rectal hamartomatous polyps. Her medical history included fibrocystic disease of the breast over the last three years. A physical examination revealed macrocephaly, hyperkeratotic papules on the mid-facial skin, palmoplantar keratosis and oral mucosal papillomatosis. A breast examination revealed nodular breast tissue bilaterally and a diffuse thyroid goiter. Our patient was clinically euthyroid. A total thyroidectomy was performed. A histopathologic examination revealed thyroid papillary carcinoma. A gastrointestinal evaluation revealed esophageal and gastric polyps. Biopsies showed hyperplastic and adenomatous lesions associated with Helicobacter pylori. A final diagnosis of Cowden syndrome was made according to the syndrome testing criteria adapted by the US National Comprehensive Cancer Network. A prophylactic bilateral mastectomy was proposed but refused by our patient. Our patient was kept under surveillance for breast and colorectal malignancies. CONCLUSIONS: Early and accurate diagnosis of Cowden syndrome is essential because it is a cancer predisposition syndrome that carries an increased risk for developing malignancy in many tissues, especially breast and thyroid. For this reason, education regarding the signs and symptoms of cancer is important. All patients must be screened for malignancies and options for prophylactic mastectomy should be discussed. Guidelines for cancer screening including surveillance and management plans for these patients should be distinguished from those of the general population, and may lead to a more timely diagnosis and treatment of cancers associated with this syndrome. PMID- 22846628 TI - Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia. AB - OBJECTIVE: In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-beta1-42 [Abeta1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). METHODS: We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. RESULTS: After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized beta = -0.3, P < .05), whereas CSF Abeta1-42 levels were found to be positively related to the Mini-Mental State Examination (beta = 0.3, P < .05), the frontal assessment battery (beta = 0.5, P < .05), and digit span backwards test (beta = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer's disease (high levels of tau and low levels of Abeta1-42), we still found relations between CSF Abeta1-42 levels and Visual Association Test object naming (beta = 0.4, P < .05), as well as between CSF Abeta1-42 levels and the frontal assessment battery (beta = 0.5, P < .05, but there was no relation between CSF tau and cognition. CONCLUSION: Low CSF Abeta1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Abeta1-42 in bvFTD. PMID- 22846629 TI - Capillary electrophoresis-electrospray ionization-mass spectrometry interfaces: fundamental concepts and technical developments. AB - Capillary electrophoresis (CE) hyphenated to electrospray ionization (ESI) mass spectrometry (MS) is a powerful tool for analyzing a wide variety of analytes in different matrices. The major issue with CE-ESI-MS lies in finding a suitable and versatile interface to ensure the best CE and ESI operations. Thus, the development and improvement of CE-ESI-MS interfaces have been the subjects of much research. The first part of the present review focuses on the fundamental aspects of the three steps of the ESI process, i.e., spray formation, droplet evolution, and the production of gas-phase ions. In the second part of the review, the electrochemical reactions involved in the ESI and CE processes and their influences on the sensitivity and performance are discussed in detail. Then, the existing interfaces are divided into two major classes according to their operating flow rate (electrospray vs. nanospray regime). The particular characteristics of these two regimes are discussed by considering their practical impacts on ionization and the MS response. Finally, the current CE-ESI-MS interfaces are summarized, including their major advantages, drawbacks, and fields of application. PMID- 22846630 TI - Impact of cleaning and disinfection on the non-culturable and culturable bacterial loads of food-contact surfaces at a beef processing plant. AB - We assessed the impact of industrial cleaning and disinfection (C&D) on colony forming units (CFUs), viable (culturable and viable but non-culturable) cells and on total cells (viable and dead cells). Bacterial loads on polyvinyl chloride (PVC) and stainless steel surfaces in a cutting room at a beef processing plant were determined before and after C&D by real-time PCR to quantify cells from successive swabs from surfaces with or without an ethidium monoazide pre treatment and by CFU counts on tryptone soy agar. Agar contact plates were also applied after C&D for comparison. Before C&D, total cells reached 5.4 and 4.7 log cells/cm(2), viable cells 4.0 and 4.4 log cells/cm(2) and CFUs 3.1 and 2.9 log CFU/cm(2) on PVC and stainless steel surfaces, respectively. Although C&D left surfaces visually clean, it did not lead to a significant reduction in total cells. Significant reductions were only observed on PVC for CFUs: 0.8 log and on stainless steel surfaces for viable cells and CFUs: 0.8 and 1.5 log, respectively. Our results show that CFUs were both more easily detached and killed on stainless steel surfaces than on PVC surfaces. Other important results include the following observations: 1) a single swabbing detached only between 2 and 27% of the actual bacterial load; 2) after C&D, the difference between the actual culturable population and the one assessed by one agar contact plate was 1.9 and 2.7 log CFU/cm(2) on PVC and stainless steel surfaces, respectively. PMID- 22846631 TI - Characterization of iNOS(+) Neutrophil-like ring cell in tumor-bearing mice. AB - BACKGROUND: Myeloid-derived Suppressor Cells (MDSC) have been identified as tumor induced immature myeloid cells (IMC) with potent immune suppressive activity in cancer. Whereas strict phenotypic classification of MDSC has been challenging due to the highly heterogeneous nature of cell surface marker expression, use of functional markers such as Arginase and inducible nitric oxide synthase (iNOS) may represent a better categorization strategy. In this study we investigated whether iNOS could be utilized as a specific marker for the identification of a more informative homogenous MDSC subset. METHODS: Single-cell suspensions from tumors and other organs were prepared essentially by enzymatic digestion. Flow cytometric analysis was performed on a four-color flow cytometer. Morphology, intracellular structure and localization of iNOS(+) ring cells in the tumor were determined by cytospin analysis, immunofluorescence microscopy and immunohistochemistry, respectively. For functional analysis, iNOS(+) ring subset were sorted and tested in vitro cell culture experiments. Pharmacologic inhibition of iNOS was performed both in vivo and in vitro. RESULTS: The results showed that intracellular iNOS staining distinguished a granular iNOS(+) SSC(hi) CD11b(+) Gr-1(dim) F4/80(+) subset with ring-shaped nuclei (ring cells) among the CD11b(+) Gr-1(+) cell populations found in tumors. The intensity of the ring cell infiltrate correlated with tumor size and these cells constituted the second major tumor-infiltrating leukocyte subset found in established tumors. Although phenotypic analysis demonstrated that ring cells shared characteristics with tumor-associated macrophages (TAM), morphological analysis revealed a neutrophil like appearance as detected by cytospin and immunofluorescence microscopy analysis. The presence of distinct iNOS filled granule-like structures located next to the cell membrane suggested that iNOS was stored in pre-formed vesicles and available for rapid release upon activation. Tumor biopsies showed large areas with infiltrating ring cells primarily surrounding necrotic areas. Importantly, these cells significantly impaired CD8(+) T-cell proliferation and induced apoptotic death. The intratumoral accumulation and suppressive activity of ring cells could be blocked through pharmacologic inhibition of iNOS, demonstrating the critical role of this enzyme in mediating both the differentiation and the activity of these cells. CONCLUSIONS: In this study, iNOS expression was linked to a homogeneous subset; ring cells with a particular phenotype and immune suppressive function, in a common and well-established murine tumor model; 4T-1. Since the absence of a Gr-1 homolog in humans has made the identification of MDSC much more challenging, use of iNOS as a functional marker of MDSC may also have clinical importance. PMID- 22846632 TI - White matter integrity, fiber count, and other fallacies: the do's and don'ts of diffusion MRI. AB - Diffusion-weighted MRI (DW-MRI) has been increasingly used in imaging neuroscience over the last decade. An early form of this technique, diffusion tensor imaging (DTI) was rapidly implemented by major MRI scanner companies as a scanner selling point. Due to the ease of use of such implementations, and the plausibility of some of their results, DTI was leapt on by imaging neuroscientists who saw it as a powerful and unique new tool for exploring the structural connectivity of human brain. However, DTI is a rather approximate technique, and its results have frequently been given implausible interpretations that have escaped proper critique and have appeared misleadingly in journals of high reputation. In order to encourage the use of improved DW-MRI methods, which have a better chance of characterizing the actual fiber structure of white matter, and to warn against the misuse and misinterpretation of DTI, we review the physics of DW-MRI, indicate currently preferred methodology, and explain the limits of interpretation of its results. We conclude with a list of 'Do's and Don'ts' which define good practice in this expanding area of imaging neuroscience. PMID- 22846634 TI - Allergic airway inflammation in mice deficient for the antigen-processing protease cathepsin E. AB - BACKGROUND: Allergic asthma is a Th2-type chronic inflammatory disease of the lung. It is characterized by infiltration of eosinophils, neutrophils, mast cells and T lymphocytes into the airways. Th2 cytokines like interleukin (IL)-4, IL-5 and chemokines like eotaxin are increased in the asthmatic response. The processing and presentation of exogenous antigens is important in the sensitization to an allergen. Cathepsin E (Ctse) is an intracellular aspartic endoprotease which is expressed in immune cells like dendritic cells (DCs). It was found to play an essential role in the processing and presentation of ovalbumin (OVA). The aim of the present study was to investigate the inhibition of Ctse in two different experimental models of allergic airway inflammation. METHODS: Ctse wild-type (Ctse(+/+)) and Ctse-deficient (Ctse(-/-)) bone marrow derived DCs (BMDCs) were pulsed with OVA/OVA peptide and cocultured with OVA transgenic T II (OT II) cells whose proliferation was subsequently analyzed. Two different in vivo asthma models with Ctse(+/+) and Ctse(-/-) mice were performed: an acute OVA-induced and a subchronic Phleum pratense-induced airway inflammation. RESULTS: Proliferation of OT II cells was decreased when cocultured with BMDCs of Ctse(-/-) mice as compared to cells cocultured with BMDCs of Ctse(+/+) mice. In vivo, Ctse deficiency led to reduced lymphocyte influx after allergen sensitization and challenge in both investigated airway inflammation models, compared to their control groups. CONCLUSION: Ctse deficiency leads to a reduced antigen presentation in vitro. This is followed by a distinct effect on lymphocyte influx in states of allergic airway inflammation in vivo. PMID- 22846633 TI - Comparative molecular analyses of Borrelia burgdorferi sensu stricto strains B31 and N40D10/E9 and determination of their pathogenicity. AB - BACKGROUND: Lyme disease in the United States is caused primarily by B. burgdorferi sensu stricto while other species are also prevalent in Europe. Genetic techniques have identified several chromosomal and plasmid-borne regulatory and virulence factors involved in Lyme pathogenesis. B31 and N40 are two widely studied strains of B. burgdorferi, which belong to two different 16 S 23 S rRNA spacer types (RST) and outer surface protein C (OspC) allelic groups. However, the presence of several known virulence factors in N40 has not been investigated. This is the first comprehensive study that compared these two strains both in vitro and using the mouse model of infection. RESULTS: Phylogenetic analyses predict B31 to be more infectious. However, our studies here indicate that N40D10/E9 is more infectious than the B31 strain at lower doses of inoculation in the susceptible C3H mice. Based-upon a careful analyses of known adhesins of these strains, it is predicted that the absence of a known fibronectin-glycosaminoglycan binding adhesin, bbk32, in the N40 strain could at least partially be responsible for reduction in its binding to Vero cells in vitro. Nevertheless, this difference does not affect the infectivity of N40D10/E9 strain. The genes encoding known regulatory and virulence factors critical for pathogenesis were detected in both strains. Differences in the protein profiles of these B. burgdorferi strains in vitro suggest that the novel, differentially expressed molecules may affect infectivity of B. burgdorferi. Further exacerbation of these molecular differences in vivo could affect the pathogenesis of spirochete strains. CONCLUSION: Based upon the studies here, it can be predicted that N40D10/E9 disseminated infection at lower doses may be enhanced by its lower binding to epithelial cells at the site of inoculation due to the absence of BBK32. We suggest that complete molecular analyses of virulence factors followed by their evaluation using the mouse infection model should form the basis of determining infectivity and pathogenicity of different strains rather than simple phylogenetic group analyses. This study further emphasizes a need to investigate multiple invasive strains of B. burgdorferi to fully appreciate the pathogenic mechanisms that contribute to Lyme disease manifestations. PMID- 22846635 TI - Sequential bilateral cochlear implantation: speech perception and localization pre- and post-second cochlear implantation. AB - PURPOSE: In this study, the authors sought to compare speech perception and localization in subjects who wear 1 cochlear implant (unilateral CI) or 1 cochlear implant and hearing aid (CI+HA) and then receive a second cochlear implant (bilateral CI), and to evaluate the importance of the duration between implant surgeries and duration of deafness. METHOD: Nine subjects were tested on speech perception in quiet, and 13 subjects were tested on speech perception and localization in noise using an array of 8 loudspeakers. All subjects were tested with unilateral CI prior to bilateral implantation and then again with bilateral CI after at least 3 months of bilateral experience. RESULTS: No significant difference was found between bilateral CI and unilateral CI on averaged speech perception in quiet performance. A significant benefit was found for bilateral CI on averaged speech perception in noise and on localization. Nonsignificant correlations were found for duration between surgeries, duration of deafness, and duration of bilateral use. CONCLUSIONS: Improvements for speech perception and localization played in background noise were indicated for most subjects after they received their 2nd implant. The correlations should be reassessed with a larger number of subjects to appropriately evaluate the effects of duration between surgeries, duration of deafness, and duration of bilateral use. PMID- 22846636 TI - Stimuli and normative data for detection of Ling-6 sounds in hearing level. AB - PURPOSE: The purpose of this work was to develop and evaluate a calibrated version of the Ling-6 sounds for evaluation of aided detection thresholds. Stimuli were recorded, and data from calibration values in dB HL were developed. Aided performance was characterized in adults and children. METHOD: Stimuli were recorded, prepared, and transferred to a CD for testing. Initial testing was completed on 29 normally hearing young adults to determine typical responses in dB SPL and reliability. Corrections to dB HL were determined for each stimulus. Twenty-seven adults and 5 children with hearing losses were tested. RESULTS: Average normal sound field thresholds were 1 dB HL. Aided thresholds for adults varied with unaided hearing level and were better for low-frequency sounds. Adults and children performed differently, possibly because of greater hearing aid gain for children. CONCLUSIONS: Stimulus preparation and shaping resulted in a recorded, calibrated set of Ling-6 stimuli that provide flat normal thresholds in hearing level for normally hearing listeners. Typical performance ranges may vary with hearing level and prescription. More data are required to fully characterize this trend in the pediatric population. PMID- 22846637 TI - Psychometric evaluation of visual analog scale for the assessment of chronic tinnitus. AB - PURPOSE: The development of therapeutic interventions for chronic tinnitus requires sensitive and clinically responsive tools to measure treatment-induced changes in tinnitus loudness and annoyance. In this study, the authors evaluated the psychometric properties of patient-reported visual analog scales (VAS) for measuring subjectively perceived tinnitus loudness and annoyance. METHOD: The authors analyzed data from a single-blind, randomized, placebo-controlled study of acoustic coordinated reset (CR) neuromodulation in patients with chronic tinnitus (trial registration: "Randomized Evaluation of Sound Evoked Treatment of Tinnitus [RESET] study"; ClinicalTrials.gov identifier: NCT00927121) to assess the reliability, validity, and minimally clinically identifiable difference (MCID) of the VAS loudness and VAS annoyance. The VAS loudness and VAS annoyance were completed at screening, at baseline, and at 5 visits during the 16 weeks of the clinical study. Data were analyzed with respect to test-retest reliability, validity, and MCID. RESULTS: VAS loudness and VAS annoyance showed good test retest reliability of .8 and .79, respectively. In terms of convergent validity, VAS loudness and VAS annoyance correlated well with the tinnitus questionnaire at all clinical visits (max r = .67, p < .05). MCID estimates clustered between 10 and 15 points. CONCLUSION: VAS loudness and VAS annoyance are valid and effective measurements for capturing reductions in tinnitus severity in patients with chronic tinnitus. PMID- 22846638 TI - The accuracy of matching target insertion gains with open-fit hearing aids. AB - PURPOSE: To assess the accuracy with which target insertion gains were matched for a single type of open-fit hearing aid, both on initial fitting and after adjustment. METHOD: The hearing aids were fitted using the first-fit setting in the programming software and the target formula was selected as NAL-NL1. The difference between the real ear insertion gain (REIG) and the NAL-NL1 target REIG was recorded. The initial fitting was considered acceptable if the difference was less than 10 dB at all frequencies. If an initial fitting was not acceptable, the frequency-gain response was modified. The difference between the final REIG and the NAL-NL1 target REIG was recorded as final target mismatch. RESULTS: Of the 51 initial fittings, 36 (71%) failed to achieve a match within +/-10 dB of the NAL NL1 insertion gain target at 1 or more frequencies between 0.25 and 4 kHz. After the authors adjusted the frequency-gain response of the hearing aids, only 9 fittings (18%) failed to achieve a match. CONCLUSION: These outcomes suggest that target insertion gains for the open-fit hearing aids used here are rarely achieved with a first fitting but can usually be achieved through adjustments based on REIG measurements. PMID- 22846639 TI - Temporal evolution of neurophysiological and behavioral features of synapsin I/II/III triple knock-out mice. AB - Deletion of one or more synapsin genes in mice results in a spontaneous epilepsy. In these animals, seizures can be evoked by opening or moving the cage. Aim of the present study was to characterize the evolution of the epileptic phenotype by neurophysiological examination and behavioral observation in synapsin triple knock-out (Syn-TKO) mice. Syn-TKO mice were studied from 20 postnatal days (PND) up to 6 months of age by video-EEG recording and behavioral observation. Background EEG spectral analysis was performed and data were compared to WT animals. Syn-TKO revealed rare spontaneous seizures and increased susceptibility to evoked seizures in mice from 60 to 100 PND. Spontaneous and evoked seizures presented similar duration and morphology. At times, seizures were followed by a post-ictal phase characterized by a 4 Hz rhythmic activity and immobility of the animal. Spectral analysis of background EEG evidenced a slowing of the theta alpha peak in Syn-TKO mice compared to WT mice within the period from PND 40 to 100. These data indicate that Syn-TKO mice do not exhibit a linear progression of the epileptic phenotype, with the period corresponding to a higher susceptibility to evoked seizures characterized by background EEG slowing. This aspect might be connected to brain dysfunction often associated to epilepsy in the interictal period. PMID- 22846640 TI - Comparison of event-based methods using optical coherence tomography and automated perimetry to detect the progression of glaucoma in patients with open angle glaucoma. AB - BACKGROUND/AIMS: To compare event-based methods for estimating the incidence of glaucoma progression using optical coherence tomography (OCT) and automated perimetry and to assess agreement between structural and functional tests for detecting glaucoma progression. METHODS: Functional progression of glaucoma was estimated by guided progression analysis (GPA) using a Humphrey field analyzer (HFA), and structural progression was assessed by OCT and defined as the decrease in retinal nerve fiber layer thickness based on test-retest variability data of previous reports on clock-hour and quadrant maps. The level of agreement between structural and functional progression was evaluated using kappa statistics. RESULTS: Fifty eyes of 50 patients with open-angle glaucoma were enrolled in this retrospective study. The incidence of visual field progression estimated by GPA was 18%. The occurrence of structural progression assessed by OCT ranged from 18 to 68%. The more stringent OCT progression criterion using a quadrant map showed the best agreement with HFA GPA (K = 0.423) and detected perimetric progression with high specificity, while the less stringent OCT criterion considering any clock hour showed the lowest agreement with functional progression (K = 0.098). CONCLUSION: OCT progression criteria based on test-retest variability showed moderate agreement with perimetric progression, and more stringent criteria showed better agreement with functional progression than less stringent ones. PMID- 22846641 TI - Grasshopper Lazarillo, a GPI-anchored Lipocalin, increases Drosophila longevity and stress resistance, and functionally replaces its secreted homolog NLaz. AB - Lazarillo (Laz) is a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein first characterized in the developing nervous system of the grasshopper Schistocerca americana. It belongs to the Lipocalins, a functionally diverse family of mostly secreted proteins. In this work we test whether the protective capacity known for Laz homologs in flies and vertebrates (NLaz, GLaz and ApoD) is evolutionarily conserved in grasshopper Laz, and can be exerted from the plasma membrane in a cell-autonomous manner. First we demonstrate that extracellular forms of Laz have autocrine and paracrine protecting effects for oxidative stress challenged Drosophila S2 cells. Then we assay the effects of overexpressing GPI linked Laz in adult Drosophila and whether it rescues both known and novel phenotypes of NLaz null mutants. Local effects of GPI-linked Laz inside and outside the nervous system promote survival upon different stress forms, and extend lifespan and healthspan of the flies in a cell-type dependent manner. Outside the nervous system, expression in fat body cells but not in hemocytes results in protection. Within the nervous system, glial cell expression is more effective than neuronal expression. Laz actions are sexually dimorphic in some expression domains. Fat storage promotion and not modifications in hydrocarbon profiles or quantities explain the starvation-desiccation resistance caused by Laz overexpression. This effect is exerted when Laz is expressed ubiquitously or in dopaminergic cells, but not in hemocytes. Grasshopper Laz functionally restores the loss of NLaz, rescuing stress-sensitivity as well as premature accumulation of aging-related damage, monitored by advanced glycation end products (AGEs). However Laz does not rescue NLaz courtship behavioral defects. Finally, the presence of two new Lipocalins with predicted GPI-anchors in mosquitoes shows that the functional advantages of GPI-linkage have been commonly exploited by Lipocalins in the arthropodan lineage. PMID- 22846642 TI - The significance of hyperkeratosis in pap smears with squamous intraepithelial lesion. AB - OBJECTIVE: It was the aim of this study to evaluate the significance of reporting hyperkeratosis in cervical smears. STUDY DESIGN: Cervicovaginal smears with low grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), prepared from 2004 to 2007, were retrospectively reviewed. Anucleated squamous cells were counted. The smears were classified into two groups, based on the presence of <2 or >=2 clusters of anucleated cells, and then compared. RESULTS: Sixty Pap smears showing SILs (34 LSILs and 26 HSILs) as well as 120 random satisfactory smears without squamous or glandular abnormalities were selected. A statistically significant difference was found between the SIL group and the control group regarding the mean number of hyperkeratotic clusters (2.8 in the SIL and 1.9 in the control group; p = 0.012). Moreover, the mean number of hyperkeratotic clusters (3.3 in the LSIL and 2.2 in the HSIL group) had a statistically significant correlation with the diagnosis of the lesion as LSIL or HSIL (p = 0.0006). CONCLUSION: Our findings suggest that hyperkeratosis in the form of >=2 clusters of anucleated squamous cells could be an indicator of underlying LSIL. PMID- 22846643 TI - Impact of stimulation dose and personality on autonomic and psychological effects induced by acupuncture. AB - Acupuncture has been shown to exhibit distinct effects on the autonomic nervous system. We tested whether the autonomic and psychological response to acupuncture depends on the stimulation dose and the personality of the treated subjects. 52 healthy subjects were randomized to receive either low dose (one needle at point Hegu bilaterally) or high dose (additional 4 needles at non-acupoints bilaterally) acupuncture stimulation after stratification according to their personality to "reduce" or "augment" incoming stimuli. Outcomes were changes of electrodermal activity (EDA), high frequency component of heart rate variability, heart rate, mean arterial blood pressure, respiration rate and subjective parameters for psychological well being and perceived intensity of needling. Electrodermal activity increased during needle insertion and decreased under baseline when subjects were resting with the needles in the body for 20 min. The initial EDA increase was significantly (GEE ANCOVA p<0.001) more pronounced during high dose stimulation and independent of personality. All other physiological parameters did not show any significant group effect. Strong stimulated augmenters perceived acupuncture most painful and increased with their psychological activation after the acupuncture session in contrast to the other groups, which showed a decrease of activation in the pre-post comparison (overall group effect p=0.032). The data indicate that during needle insertion high dose acupuncture stimulation leads to a higher increase of sympathetic nerve activity than low dose stimulation independent of personality. After needle insertion subjects who tend to augment incoming stimuli might show a lack of psychological relaxation when receiving high dose stimulation. PMID- 22846644 TI - Abscess of urachal remnants presenting with acute abdomen: a case series. AB - INTRODUCTION: Urachal diseases are rare and may develop from a congenital anomaly in which a persistent or partial reopening of the fetal communication between the bladder and the umbilicus persists. The most frequently reported urachal anomalies in adults are infected urachal cyst and urachal carcinoma. The diagnosis of this entity is not always easy because of the rarity of these diseases and the atypical symptoms at presentation. Imaging techniques, such as ultrasonography and computed tomography have a significant role in recognizing the presence of urachus-derived lesions. CASES PRESENTATIONS: Case presentation 1: A 25-year-old Arab-Berber man presented with a 10-day history of progressive lower abdominal pain accompanied by fever, vomiting, and low urinary tract symptoms to our emergency department. Laboratory data revealed leucocytosis. The diagnosis of an acute peritonitis was made initially. Abdominal ultrasonography revealed a hypoechoic tract from the umbilicus to the abdominal wall, and the diagnosis was rectified (infected urachal remnants). The patient was initially treated with intravenous antibiotics in combination with a percutaneous drainage. Afterwards an extraperitoneal excision of the urachal remnant including a cuff of bladder was performed. The histological analysis did not reveal a tumor of the urachal remnant. Follow-up examinations a few months later showed no abnormality.Case presentation 2: A 35-year-old Arab-Berber man, without prior medical history with one week of abdominal pain, nausea and vomiting, associated with fever but without lower urinary tract symptoms visited our emergency department. Laboratory data revealed leucocytosis. Abdominal ultrasonography was not conclusive. Computed tomography of the abdomen was the key to the investigation and the diagnosis of an abscess of urachal remnants was made. The patient underwent the same choice of medical-surgical treatment as previously described for case one, with a good follow-up result.Case presentation 3: A 22 year-old Arab-Berber man, with no relevant past medical history, presented to our emergency department because of suspected acute surgical abdomen. Physical examination revealed umbilical discharge with erythema and a tender umbilical mass. Abdominal ultrasonography and computed tomography scan confirmed the diagnosis of infected urachal sinus. Initial management was intravenous antibiotics associated with a percutaneous drainage with a good post-operative result, but a few days later, he was readmitted with the same complaint and the decision was made for surgical treatment consisting of excision of the infected urachal sinus. The clinical course was uneventful. Histological examination did not reveal any signs of malignancy. CONCLUSIONS: We describe our clinical observations and an analysis of the existing literature to present the various clinical, radiological, pathological and therapeutic aspects of an abscess of urachal remnants. To the best of our knowledge, this manuscript is an original case report because this atypical presentation is rarely reported in the literature and only a few cases have been described. PMID- 22846645 TI - gamma-Fe2O3 and Fe3O4 magnetic hierarchically nanostructured hollow microspheres: preparation, formation mechanism, magnetic property, and application in water treatment. AB - In this paper, we report the preparation of gamma-Fe(2)O(3) and Fe(3)O(4) magnetic hierarchically nanostructured hollow microspheres by a solvothermal combined with precursor thermal conversion method. These gamma-Fe(2)O(3) and Fe(3)O(4) magnetic hierarchically nanostructured hollow microspheres were constructed by three-dimensional self-assembly of nanosheets, forming porous nanostructures. The effects of experimental parameters including molar ratio of reactants and reaction temperature on the precursors were studied. The time dependent experiments indicated that the Ostwald ripening was responsible for the formation of the hierarchically nanostructured hollow microspheres of the precursors. gamma-Fe(2)O(3) and Fe(3)O(4) magnetic hierarchically nanostructured hollow microspheres were obtained by the thermal transformation of the precursor hollow microspheres. Both gamma-Fe(2)O(3) and Fe(3)O(4) hierarchically nanostructured hollow microspheres exhibited a superparamagnetic property at room temperature and had the saturation magnetization of 44.2 and 55.4 emu/g, respectively, in the applied magnetic field of 20 KOe. Several kinds of organic pollutants including salicylic acid (SA), methylene blue (MB), and basic fuchsin (BF) were chosen as the model water pollutants to evaluate the removal abilities of gamma-Fe(2)O(3) and Fe(3)O(4) magnetic hierarchically nanostructured hollow microspheres. It was found that gamma-Fe(2)O(3) hierarchically nanostructured hollow microspheres showed a better adsorption ability over SA than MB and BF. However, Fe(3)O(4) hierarchically nanostructured hollow microspheres had the best performance for adsorbing MB. PMID- 22846646 TI - Reproducibility of a 3-dimensional gyroscope in measuring shoulder anteflexion and abduction. AB - BACKGROUND: Few studies have investigated the use of a 3-dimensional gyroscope for measuring the range of motion (ROM) in the impaired shoulder. Reproducibility of digital inclinometer and visual estimation is poor. This study aims to investigate the reproducibility of a tri axial gyroscope in measurement of anteflexion, abduction and related rotations in the impaired shoulder. METHODS: Fifty-eight patients with either subacromial impingement (27) or osteoarthritis of the shoulder (31) participated. Active anteflexion, abduction and related rotations were measured with a tri axial gyroscope according to a test retest protocol. Severity of shoulder impairment and patient perceived pain were assessed by the Disability of Arm Shoulder and Hand score (DASH) and the Visual Analogue Scale (VAS). VAS scores were recorded before and after testing. RESULTS: In two out of three hospitals patients with osteoarthritis (n = 31) were measured, in the third hospital patients with subacromial impingement (n = 27).There were significant differences among hospitals for the VAS and DASH scores measured before and after testing. The mean differences between the test and retest means for anteflexion were -6 degrees (affected side), 9 (contralateral side) and for abduction 15 degrees (affected side) and 10 degrees (contralateral side).Bland & Altman plots showed that the confidence intervals for the mean differences fall within -6 up to 15 degrees, individual test - retest differences could exceed these limits.A simulation according to 'Generalizability Theory' produces very good coefficients for anteflexion and related rotation as a comprehensive measure of reproducibility. Optimal reproducibility is achieved with 2 repetitions for anteflexion. CONCLUSIONS: Measurements were influenced by patient perceived pain. Differences in VAS and DASH might be explained by different underlying pathology. These differences in shoulder pathology however did not alter the reproducibility of testing. The use of a tri axial gyroscope is a simple non invasive and reproducible method for the recording of shoulder anteflexion and abduction. Movements have to be repeated twice for reproducible results. PMID- 22846647 TI - The natural history of endocrine function and spermatogenesis in Klinefelter syndrome: what the data show. AB - Once thought to be a chromosomal aberration associated with absolute sterility, Klinefelter syndrome may now be potentially treatable by testicular sperm retrieval coupled with intracytoplasmic sperm injection. With these therapeutic advances, azoospermic 47,XXY men now may have an opportunity for biological paternity. However, our knowledge of the basic mechanisms underlying germ cell loss and Leydig cell compromise is lagging, and is just now beginning to evolve and provide answers to some of the field's most vexing questions: how to maximize and preserve fertility in Klinefelter males many years or even decades before they wish to actively pursue fatherhood. This article reviews the development of the androgenic and spermatogenic compartments of the Klinefelter testis through puberty, and recommends that it is only with a clear understanding of the basic facts that a rational, considered approach to fertility optimization and preservation can be determined. PMID- 22846648 TI - Retrieving oocytes from small non-stimulated follicles in polycystic ovary syndrome (PCOS): in vitro maturation (IVM) is not indicated in the new GnRH antagonist era. AB - It has been two decades since pregnancies have been obtained through in vitro maturation (IVM) of germinal vesicle-stage oocytes retrieved from non-stimulated ovaries. This technique first offered in PCOS cannot be recommended today in this indication because the results do not match those of regular ART, and new GnRH antagonist and agonist-trigger protocols reliably prevent OHSS. PMID- 22846649 TI - Generation of mouse induced pluripotent stem cells from different genetic backgrounds using Sleeping beauty transposon mediated gene transfer. AB - Induced pluripotent stem (iPS) cell technology involves reprogramming somatic cells to a pluripotent state. The original technology used to produce these cells requires viral gene transduction and results in the permanent integration of exogenous genes into the genome. This can lead to the development of abnormalities in the derived iPS cells. Here, we report that non-viral transfection of a Sleeping Beauty (SB) transposon containing the coding sequences Oct3/4 (Pouf1), Sox-2, Klf-4 and c-Myc (OSKM) linked with 2A peptides, can reprogram mouse fibroblasts. We have established reprogrammed mouse cell lines from three different genetic backgrounds: (1) ICR-outbred, (2) C57BL/6-inbred and (3) F1-hybrid (C57BL/6 x DBA/2J), with parallel robust expression of all exogenous (Oct3/4, Sox-2, Klf-4, and c-Myc) and endogenous (e.g. Oct3/4 and Nanog) pluripotency genes. The iPS cell lines exhibited characteristics typical for undifferentiated embryonic stem (ES) cell lines: ES cell-like morphology, alkaline phosphatase (ALP) positivity and gene expression pattern (shown by reverse transcription PCR, and immunofluorescence of ES cell markers-e.g. Oct3/4, SSEA1, Nanog). Furthermore, cells were able to form embryoid bodies (EBs), to beat rhythmically, and express cardiac (assayed by immunofluorescence, e.g. cardiac Troponin T, desmin) and neuronal (assayed by immunofluorescence e.g. nestin, Tuj1) markers. The in vitro differentiation potential was found to be the highest in the ICR-derived iPS lines (ICR-iPS). Interestingly, the ICR-iPS lines had even higher differentiation potential than the ICR-ES cell lines: the rate of EBs forming rhythmically beating cardiomyocytes was 4% in ICR-ES and 79% in ICR iPS cells, respectively. In vivo, the ICR and F1 hybrid iPS cells formed chimeras and one of the iPS cells from the F1 hybrid background transmitted to the germline. Our results suggest that iPS technology may be useful for generating pluripotent stem cells from genetic backgrounds of which good quality ES cell generation is difficult. These studies provide insights into viral-free iPS technology and may contribute towards defining future cell-based therapies, drug screening methods and production of transgenic animals using genetically modified iPS cells. PMID- 22846650 TI - Differentiating schizoaffective and bipolar I disorder in first-episode psychotic mania. AB - OBJECTIVE: This study aims to differentiate schizoaffective disorder (SAD) and bipolar-I-disorder (BD) in first-episode psychotic mania (FEPM). METHODS: All 134 patients from an epidemiological first-episode psychosis cohort (N=786) with FEPM and an 18-month follow-up final diagnosis of SAD (n=36) or BD (n=98) were assessed with respect to pre-treatment, baseline and outcome differences. Second, patients with baseline BD who shifted (shifted BD) or did not shift to SAD (stable BD) over the follow-up period were compared regarding pre-treatment and baseline differences. RESULTS: SAD patients displayed a significantly longer duration of untreated psychosis (DUP; effect size r=0.35), a higher illness severity at baseline (r=0.20) and more traumatic events (Cramer-V=0.19). SAD patients displayed a significantly higher non-adherence rate (Cramer-V=0.19); controlling for time in treatment and respective baseline scores, SAD patients had significantly worse illness severity (CGI-S; partial eta2=0.12) and psychosocial functioning (GAF; partial eta(2)=0.07) at 18-months, while BD patients were more likely to achieve remission of positive symptoms (OR=4.9, 95% CI=1.8-13.3; p=0.002) and to be employed/occupied (OR=7.7, 95% CI=2.4-24.4, p=0.001). The main discriminator of stable and shifted BD was a longer DUP in patients shifting from BD to SAD. CONCLUSIONS: It is difficult to distinguish BD with psychotic symptoms and SAD in patients presenting with FEPM. Longer DUP is related to SAD and to a shift from BD to SAD. Compared to BD, SAD had worse outcomes and higher rates of non-adherence with medication. Despite these differences, both diagnostic groups need careful dimensional assessment and monitoring of symptoms and functioning in order to choose the right treatment. PMID- 22846651 TI - Obsessive compulsive symptoms in individuals at clinical risk for psychosis: association with depressive symptoms and suicidal ideation. AB - Obsessive-compulsive symptoms, particularly aggressive obsessions, are prevalent in schizophrenia patients and associated with other symptom severity, suicidal ideation and functional impairment. In a psychosis-risk cohort, obsessive compulsive diagnosis and symptoms were assessed in terms of prevalence and content, and for associations with clinical measures. Obsessive-compulsive symptoms were prevalent in the CHR cohort, as was suicidal ideation. The presence and severity of aggressive obsessions were associated with depression, suicidal ideation and social impairment. The high prevalence of aggressive obsessions and associated suicidal ideation in a clinical high risk cohort, and their relationship to depression, is relevant for risk assessment and treatment strategies. PMID- 22846653 TI - European Stroke Science Workshop. AB - The European Stroke Organisation held its first European Stroke Science Workshop in Garmisch-Partenkirchen, Germany (December 15-17, 2011). Stroke experts based in Europe were invited to present and discuss their current research. The scope of the workshop was to review the most recent findings of selected topics in stroke, to exchange ideas, to stimulate new research, and to enhance collaboration between European stroke research groups. Seven scientific sessions were held, each starting with a keynote lecture to review the state of the art of the given topic, followed by 4 or 5 short presentations by experts. They were asked to limit their presentations to 10 slides containing only recent information. The meeting was organized by the executive committee of the European Stroke Organisation (Heinrich Mattle, chairman, Michael Brainin, Angel Chamorro, Werner Hacke, Didier Leys) and supported by the European Stroke Conference (Michael Hennerici). The following sections summarize the content of the workshop. PMID- 22846652 TI - Structural basis of the allosteric inhibitor interaction on the HIV-1 reverse transcriptase RNase H domain. AB - HIV-1 reverse transcriptase (RT) has been an attractive target for the development of antiretroviral agents. Although this enzyme is bi-functional, having both DNA polymerase and ribonuclease H (RNH) activities, there is no clinically approved inhibitor of the RNH activity. Here, we characterize the structural basis and molecular interaction of an allosteric site inhibitor, BHMP07, with the wild-type (WT) RNH fragment. Solution NMR experiments for inhibitor titration on WT RNH showed relatively wide chemical shift perturbations, suggesting a long-range conformational effect on the inhibitor interaction. Comparisons of the inhibitor-induced NMR chemical shift changes of RNH with those of RNH dimer, in the presence and absence of Mg(2+) , were performed to determine and verify the interaction site. The NMR results, with assistance of molecular docking, indicate that BHMP07 preferentially binds to a site that is located between the RNH active site and the region encompassing helices B and D (the 'substrate-handle region'). The interaction site is consistent with the previous proposed site, identified using a chimeric RNH (p15 EC) [Gong et al. (2011) Chem Biol Drug Des 77, 39-47], but with slight differences that reflect the characteristics of the amino acid sequences in p15 EC compared to the WT RNH. PMID- 22846654 TI - Can we rebuild the human brain? The exciting promise and early evidence that stem cells may provide a real clinical cure for stroke in humans. PMID- 22846655 TI - Quantum computing: a prime modality in neurosurgery's future. AB - OBJECTIVE: With each significant development in the field of neurosurgery, our dependence on computers, small and large, has continuously increased. From something as mundane as bipolar cautery to sophisticated intraoperative navigation with real-time magnetic resonance imaging-assisted surgical guidance, both technologies, however simple or complex, require computational processing power to function. The next frontier for neurosurgery involves developing a greater understanding of the brain and furthering our capabilities as surgeons to directly affect brain circuitry and function. METHODS: This has come in the form of implantable devices that can electronically and nondestructively influence the cortex and nuclei with the purpose of restoring neuronal function and improving quality of life. RESULTS: We are now transitioning from devices that are turned on and left alone, such as vagus nerve stimulators and deep brain stimulators, to "smart" devices that can listen and react to the body as the situation may dictate. CONCLUSION: The development of quantum computers and their potential to be thousands, if not millions, of times faster than current "classical" computers, will significantly affect the neurosciences, especially the field of neurorehabilitation and neuromodulation. Quantum computers may advance our understanding of the neural code and, in turn, better develop and program implantable neural devices. When quantum computers reach the point where we can actually implant such devices in patients, the possibilities of what can be done to interface and restore neural function will be limitless. PMID- 22846657 TI - A dual echo approach to motion correction for functional connectivity studies. AB - The effect of subject head movement on functional connectivity as measured by BOLD (blood oxygen level dependent) fMRI was investigated; movement mainly introduced increases in connectivity into the dataset. The effect of movement on connectivity is an important consideration when comparing patients suffering from neurological conditions to healthy controls, since it is well known that patients affected by such conditions are prone to move more in the scanner than healthy subjects. A method of motion correction utilising a dual echo EPI sequence is described. The first echo is acquired soon after the slice excitation (TE(1)=10 ms) when BOLD contrast is low and the MR signal is mainly sensitive to movement related effects, while the second echo is acquired at an echo time (TE(2)=30 ms) at which the MR signal is sensitive to both BOLD and movement related effects. To correct for additional signal variance introduced by subject movement, the second echo image is divided by the first echo image at each time point across the length of the scan. This procedure is easy to implement and requires no extra scan time. This method proved superior to the standard means of correction whereby realignment parameters and their first order derivatives are used as covariates of no interest in a linear regression model. PMID- 22846656 TI - Regional changes in thalamic shape and volume with increasing age. AB - The thalamus undergoes significant volume loss and microstructural change with increasing age. Alterations in thalamo-cortical connectivity may contribute to the decline in cognitive ability associated with aging. The aim of this study was to assess changes in thalamic shape and in the volume and diffusivity of thalamic regions parcellated by their connectivity to specific cortical regions in order to test the hypothesis age related thalamic change primarily affects thalamic nuclei connecting to the frontal cortex. Using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), we assessed thalamic volume and diffusivity in 86 healthy volunteers, median (range) age 44 (20-74) years. Regional thalamic micro and macro structural changes were assessed by segmenting the thalamus based on connectivity to the frontal, parietal, temporal and occipital cortices and determining the volumes and mean diffusivity of the thalamic projections. Linear regression analysis was performed to test the relationship between increasing age and (i) normalised thalamic volume, (ii) whole thalamus diffusion measures, (iii) mean diffusivity (MD) of the thalamo cortical projections, and (iv) volumes of the thalamo-cortical projections. We also assessed thalamic shape change using vertex analysis. We observed a significant reduction in the volume and a significant increase in MD of the whole thalamus with increasing age. The volume of the thalamo-frontal projections decreased significantly with increasing age, however there was no significant relationship between the volumes of the thalamo-cortical projections to the parietal, temporal, and occipital cortex and age. Thalamic shape analysis showed that the greatest shape change was in the anterior thalamus, incorporating regions containing the anterior nucleus, the ventroanterior nucleus and the dorsomedial nucleus. To explore these results further we studied two additional groups of subjects (a younger and an older aged group, n=20), which showed that the volume of the thalamo-frontal projections was correlated to executive functions scores, as assessed by the Stroop test. These data suggest that atrophy of the frontal thalamo-cortical unit may explain, at least in part, disorders of attention, working memory and executive function associated with increasing age. PMID- 22846658 TI - Tractography-based parcellation of the human left inferior parietal lobule. AB - The inferior parietal lobule (IPL) is a functionally and anatomically heterogeneous region. Much of the information about the anatomical connectivity and parcellation of this region was obtained from histological studies on non human primates. However, whether these findings from non-human primates can be applied to the human inferior parietal lobule, especially the left inferior parietal lobule, which shows evidence of considerable evolution from primates to humans, remains unclear. In this study, diffusion MRI was employed to investigate the anatomical connectivities of the human left inferior parietal lobule. Using a new algorithm, spectral clustering with edge-weighted centroidal voronoi tessellations, to search for regional variations in the probabilistic connectivity profiles of all left inferior parietal lobule voxels with all the rest of the brain identified six subregions with distinctive connectivity properties in the left inferior parietal lobule. Consistent with cytoarchitectonic findings, four subregions were found in the left supramarginal gyrus and two subregions in the left angular gyrus. The specific connectivity patterns of each subregion of the left inferior parietal lobule were supported by both the anatomical and functional connectivity properties for each subregion, as calculated by a meta-analysis-based target method and by voxel-based whole brain anatomical and functional connectivity analyses. The proposed parcellation scheme for the human left inferior parietal lobule and the maximum probability map for each subregion may facilitate more detailed future studies of this brain area. PMID- 22846659 TI - Neuroimaging in aphasia treatment research: quantifying brain lesions after stroke. AB - New structural and functional neuroimaging methods continue to rapidly develop, offering promising tools for cognitive neuroscientists. In the last 20 years, advanced magnetic resonance imaging (MRI) techniques have provided invaluable insights into how language is represented and processed in the brain and how it can be disrupted by damage to, or dysfunction of, various parts of the brain. Current functional MRI (fMRI) approaches have also allowed researchers to purposefully investigate how individuals recover language after stroke. This paper presents recommendations for quantification of brain lesions derived from discussions among international researchers at the Neuroimaging in Aphasia Treatment Research Workshop held at Northwestern University (Evanston, Illinois, USA). Methods for detailing and characterizing the brain damage that can influence results of fMRI studies in chronic aphasic stroke patients are discussed. Moreover, we aimed to provide the reader with a set of general practical guidelines and references to facilitate choosing adequate structural imaging strategies that facilitate fMRI studies in aphasia treatment research. PMID- 22846660 TI - Voxel-level functional connectivity using spatial regularization. AB - Discovering functional connectivity between and within brain regions is a key concern in neuroscience. Due to the noise inherent in fMRI data, it is challenging to characterize the properties of individual voxels, and current methods are unable to flexibly analyze voxel-level connectivity differences. We propose a new functional connectivity method which incorporates a spatial smoothness constraint using regularized optimization, enabling the discovery of voxel-level interactions between brain regions from the small datasets characteristic of fMRI experiments. We validate our method in two separate experiments, demonstrating that we can learn coherent connectivity maps that are consistent with known results. First, we examine the functional connectivity between early visual areas V1 and VP, confirming that this connectivity structure preserves retinotopic mapping. Then, we show that two category-selective regions in ventral cortex - the Parahippocampal Place Area (PPA) and the Fusiform Face Area (FFA) - exhibit an expected peripheral versus foveal bias in their connectivity with visual area hV4. These results show that our approach is powerful, widely applicable, and capable of uncovering complex connectivity patterns with only a small amount of input data. PMID- 22846662 TI - George coats and his disease. PMID- 22846661 TI - Storage conditions of intestinal microbiota matter in metagenomic analysis. AB - BACKGROUND: The structure and function of human gut microbiota is currently inferred from metagenomic and metatranscriptomic analyses. Recovery of intact DNA and RNA is therefore a critical step in these studies. Here, we evaluated how different storage conditions of fecal samples affect the quality of extracted nucleic acids and the stability of their microbial communities. RESULTS: We assessed the quality of genomic DNA and total RNA by microcapillary electrophoresis and analyzed the bacterial community structure by pyrosequencing the 16S rRNA gene. DNA and RNA started to fragment when samples were kept at room temperature for more than 24 h. The use of RNAse inhibitors diminished RNA degradation but this protection was not consistent among individuals. DNA and RNA degradation also occurred when frozen samples were defrosted for a short period (1 h) before nucleic acid extraction. The same conditions that affected DNA and RNA integrity also altered the relative abundance of most taxa in the bacterial community analysis. In this case, intra-individual variability of microbial diversity was larger than inter-individual one. CONCLUSIONS: Though this preliminary work explored a very limited number of parameters, the results suggest that storage conditions of fecal samples affect the integrity of DNA and RNA and the composition of their microbial community. For optimal preservation, stool samples should be kept at room temperature and brought at the laboratory within 24 h after collection or be stored immediately at -20 degrees C in a home freezer and transported afterwards in a freezer pack to ensure that they do not defrost at any time. Mixing the samples with RNAse inhibitors outside the laboratory is not recommended since proper homogenization of the stool is difficult to monitor. PMID- 22846663 TI - Synthetic genistein derivatives as modulators of glycosaminoglycan storage. AB - BACKGROUND: Mucopolysaccharidoses (MPS) are severe metabolic disorders caused by accumulation of undegraded glycosaminoglycans (GAGs) in lysosomes due to defects in certain lysosomal hydrolases. Substrate reduction therapy (SRT) has been proposed as one of potential treatment procedures of MPS. Importantly, small molecules used in such a therapy might potentially cross the blood-brain barrier (BBB) and improve neurological status of patients, as reported for a natural isoflavone, 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4 H-1-benzopyran-4-one, also known as genistein. Although genistein is able to cross BBB to some extent, its delivery to the central nervous system is still relatively poor (below 10% efficiency). Thus, we aimed to develop a set of synthetically modified genistein molecules and characterize physicochemical as well as biological properties of these compounds. METHODS: Following parameters were determined for the tested synthetic derivatives of genistein: cytotoxicity, effects on cell proliferation, kinetics of GAG synthesis, effects on epidermal growth factor (EGF) receptor's tyrosine kinase activity, effects on lysosomal storage, potential ability to cross BBB. RESULTS: We observed that some synthetic derivatives inhibited GAG synthesis similarly to, or more efficiently than, genistein and were able to reduce lysosomal storage in MPS III fibroblasts. The tested compounds were generally of low cytotoxicity and had minor effects on cell proliferation. Moreover, synthetic derivatives of genistein revealed higher lipophilicity (assessed in silico) than the natural isoflavone. CONCLUSION: Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms. PMID- 22846664 TI - Molecular investigation of virulence determinants between a virulent clinical strain and an attenuated strain of Burkholderia pseudomallei. AB - Burkholderia pseudomallei is the causative agent of melioidosis. We initiated this investigation with a virulent and an attenuated strain of B. pseudomallei. Pulsed-field gel electrophoresis was carried out initially for macrogenomic comparison of both strains of B. pseudomallei. However, the pulsotypes obtained were identical and therefore we applied a subtractive hybridization technique to distinguish and determine the possible differences between the two strains. Six virulence strain-specific DNA fragments were obtained and the encoding homolog proteins were identified as a xenobiotic-responsive element family of transcriptional regulator, a hypothetical protein, an unknown protein, a plasmid recombination enzyme, a regulatory protein and a putative hemolysin activator protein. A combination of at least three of these determinants was identified in 45 clinical isolates when screening was carried out with self-designed multiplex PCR targeting the six putative virulent determinants. Our data demonstrated that different combinations of the six putative virulence genes were present in the clinical isolates indicating their probable role in the pathogenesis of B. pseudomallei infections. PMID- 22846665 TI - A population-based study of fish allergy in the Philippines, Singapore and Thailand. AB - BACKGROUND: Fish allergy is the third most common food allergy after milk and egg in parts of Europe, but there is little data about prevalence in South East Asia where it is an important part of regular diets. OBJECTIVE: We aimed to obtain an estimate of the population prevalence of fish allergy among older children in the Philippines, Singapore and Thailand. METHODS: The population prevalence of fish allergy in 14- to 16-year-old children in the 3 countries was evaluated using a structured written questionnaire which was distributed to students of randomly selected secondary schools. An extended questionnaire to determine convincing fish allergy on the basis of typical clinical manifestations within 2 h of ingestion was administered to those with positive responses. RESULTS: From a cohort of 25,842 students, responses were 81.1% in the Philippines (n = 11,434), 67.9% in Singapore (n = 6,498) and 80.2% (n = 2,034) in Thailand. Using criteria for convincing food allergy, fish allergy was much higher in the Philippines [2.29%, 95% confidence interval (CI) 2.02-2.56] than in Singapore (0.26%, 95% CI 0.14-0.79) and Thailand (0.29%, 95% CI 0.06-0.52). Weighted multiple logistic regression analyses showed that compared to the Philippines, prevalence rates were lower in Singapore [odds ratio (OR) 0.40, 95% CI 0.27-0.60, p < 0.0001] and Thailand (OR 0.13, 95% CI 0.05-0.33, p < 0.0001). Females were more likely to have fish allergy compared to males for all children combined (OR 1.32, 95% CI 1.11-1.58, p = 0.002). Most allergies appeared mild, as only 28% of cases sought medical consultation at the time of the reaction and 31.2% of cases reported continued exposure despite allergic symptoms. CONCLUSION: Fish allergy in late childhood is more common in the Philippines compared to Singapore and Thailand. Differences in food processing, dietary habits and other cultural practices might be important risk factors for the development of fish allergy in these populations. PMID- 22846666 TI - Carnitine deficiency presenting with encephalopathy and hyperammonemia in a patient receiving chronic enteral tube feeding: a case report. AB - INTRODUCTION: Carnitine is an essential cofactor in mitochondrial fatty acid oxidation. Carnitine deficiency results in accumulation of non-oxidized fatty acyl-coenzyme A molecules, and this inhibits intra-mitochondrial degradation of ammonia. Hyperammonemia may lead to encephalopathy. This scenario has been previously reported. CASE PRESENTATION: We report the case of a 47-year-old Caucasian man who had sustained a remote motor vehicle accident injury and relied on long-term tube feeding with a commercial product that wascarnitine-free. He was also on phenytoin therapy for control of his chronic seizures. He developed significant acute psychological and behavioral changes superimposed on his chronic neurological impairment. His ammonia level was found to be elevated at 75 to 100MUmol/L (normal <35MUmol/L). Phenytoin was found to be at a supra therapeutic level of 143MUmol/L (therapeutic range 40-80MUmol/L). After adjusting the dose of phenytoin, other pharmacological and hepatic causes of his hyperammonemia and subacute encephalopathy were excluded. His carnitine levels were found to be low. After initiating carnitine supplementation at 500mg twice daily, the patient's mental status improved, and his ammonia level improved to 53 60MUmol/L. CONCLUSION: This case illustrates the importance of avoiding carnitine deficiency and anti-convulsant toxicity in tube-fed patients encountered in hospital wards and nursing homes. These patients should have their carnitine levels assessed regularly, and supplementation should be provided as necessary. Manufacturers of enteral feeds and formulas should consider adding carnitine to their product lines. PMID- 22846668 TI - The utility of 'low-grade intraepithelial lesion, cannot exclude high grade' diagnosis: a single institution's experience. AB - OBJECTIVE: Squamous intraepithelial lesions (SILs) are classified as low-grade SIL (LGSIL) and high-grade SIL (HGSIL). 'LGSIL cannot exclude high grade' (LGSIL H) interpretive category has been used in cases where findings exceed criteria for LGSIL, but do not fulfill the criteria for HGSIL. This study analyzed follow up histology of LGSIL-H cases and compared the follow-up results of LGSIL-H with LGSIL to determine the utility of LGSIL-H category using a single institution's experience. STUDY DESIGN: Pap smears with LGSIL-H interpretation from 2005 to 2008 were retrieved. Histological follow-up results for LGSIL-H cases were analyzed and compared to the follow-up results of LGSIL cases. RESULTS: Cases with LGSIL-H interpretation (311) comprised 0.18% of all cases (170,307). Follow up was available for 144 patients and 13.2% had benign findings, 51.4% had cervical intraepithelial neoplasia (CIN) 1, and 35.4% had CIN 2 or higher. In comparison, of 425 patients with LGSIL, 22.6% had benign findings, 71% had CIN 1 and 6.4% had CIN 2 or higher. CONCLUSION: A significantly greater number of patients with LGSIL-H interpretation had a CIN 2 or higher lesion on follow-up compared to patients with LGSIL. This suggests LGSIL-H may be a useful diagnostic category. PMID- 22846669 TI - Children's natural conversations following exposure to a rumor: linkages to later false reports. AB - Previous research has shown that children naturally propagate overheard false rumors and that the circulation of such information can induce children and their peers to wrongly recall actually experiencing rumored-but-nonexperienced events. The current study extends this work by recording 3- to 6-year-olds' naturally occurring conversations following exposure to an erroneous rumor. Results indicate that, compared with children who overhear rumors spread by adults, those who pick up rumors from peers during natural interactions engage in deeper and more inventive rumor mongering. Moreover, the degree and originality of rumor propagation was linked with various qualities of children's subsequent recollections at both 1-week and 4-week delayed interviews. Furthermore, compared with 3- and 4-year-olds, 5- and 6-year-olds naturally transmitted more novel and coherent embellishments of the rumor to their peers, and more of their false narrative reports during the interviews overlapped with their own and their peers' utterances transmitted soon after the rumor was planted. PMID- 22846670 TI - Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion. AB - The purpose of this study was to investigate the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion. Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore labelled neutral albumin, neutral dextran, or neutral ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 h using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive or negative net surface charges. Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution. All molecules were 70 kDa. With FRAP, the diffusion coefficient (D) of neutral molecules was highest for albumin, followed by ficoll, then dextran (p < 0.0001). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0004). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.5865). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021). In conclusion, diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but their effects may be diametrically opposed in different molecules, and their influence on diffusion is more complex than previously thought. Each variable cannot be considered in isolation, and the interplay of all these variables needs to be tested, when selecting or designing drugs for transscleral delivery. PMID- 22846671 TI - Exercise training for refractory angina: why does it work?. PMID- 22846672 TI - Skin flora: Differences between people affected by Albinism and those with normally pigmented skin in Northern Tanzania - cross sectional study. AB - BACKGROUND: Skin flora varies from one site of the body to another. Individual's health, age and gender determine the type and the density of skin flora. METHODS: A 1 cm2 of the skin on the sternum was rubbed with sterile cotton swab socked in 0.9% normal saline and plated on blood agar. This was cultured at 35 degrees C. The bacteria were identified by culturing on MacConkey agar, coagulase test, catalase test and gram staining. Swabs were obtained from 66 individuals affected by albinism and 31 individuals with normal skin pigmentation. Those with normal skin were either relatives or staying with the individuals affected by albinism who were recruited for the study. RESULTS: The mean age of the 97 recruited individuals was 30.6 (SD +/- 14.9) years. The mean of the colony forming units was 1580.5 per cm2. Those affected by albinism had a significantly higher mean colony forming units (1680 CFU per cm2) as compared with 453.5 CFU per cm2 in those with normally pigmented skin (p = 0.023). The skin type and the severity of sun- damaged skin was significantly associated with a higher number of colony forming units (p = 0.038). CONCLUSION: Individuals affected by albinism have a higher number of colony forming units which is associated with sun- damaged skin. PMID- 22846673 TI - Periosteal BMP2 activity drives bone graft healing. AB - Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent differentiation along the osteo-chondrogenic pathway. These results indicate that BMP2 will be among the signaling molecules whose presence will determine success or failure of new bone graft strategies. PMID- 22846675 TI - Nebulized lidocaine prevents airway inflammation, peribronchial fibrosis, and mucus production in a murine model of asthma. AB - BACKGROUND: Evidence suggests that nebulized lidocaine is beneficial in asthma therapy, but to what extent and the mechanisms underlying this effect remain poorly understood. The aim of this study was to assess the impact of lidocaine treatment using a murine model of allergic asthma characterized by expression of pivotal features of the disease: inflammation, mucus production, and lung remodeling. METHODS: A/J mice sensitized with ovalbumin were treated with inhaled lidocaine or vehicle immediately after ovalbumin intranasal challenges. Lung function, total and differential leukocytes in bronchoalveolar lavage fluid, peribronchial eosinophil density, interleukin (IL)-4, IL-5 and eotaxin-1 levels, epithelial mucus, collagen, extracellular-matrix deposition, matrix metalloproteinase-9 activity, and GATA-3 expression were evaluated. Between five and eight animals per group were used. RESULTS: Inhaled lidocaine inhibited ovalbumin-induced airway hyperreactivity to methacholine, and accumulation of lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid 24 h after the last allergen provocation. Lidocaine administration also prevented other pathophysiological changes triggered by ovalbumin in lung tissue, including peribronchial eosinophil and neutrophil infiltration, subepithelial fibrosis, increased content of collagen and mucus, matrix metalloproteinase-9 activity, and increased levels of IL-4, IL-5, IL-13, and eotaxin-1. Furthermore, inhaled lidocaine inhibited lung tissue GATA-3 expression in ovalbumin-challenged mice. We also demonstrated that lidocaine inhibited the expression of GATA-3 in ovalbumin-stimulated T cells in vitro. CONCLUSIONS: Inhaled lidocaine prevents eosinophilic inflammation, overproduction of mucus, and peribronchial fibrosis in a murine model of asthma, and impaired airway hyperreactivity, possibly by inhibiting allergen-evoked GATA-3 expression and the subsequent up-regulation of proinflammatory cytokines and chemokines. PMID- 22846674 TI - Tactile/kinesthetic stimulation (TKS) increases tibial speed of sound and urinary osteocalcin (U-MidOC and unOC) in premature infants (29-32weeks PMA). AB - Preterm delivery (<37 weeks post-menstrual age) is associated with suboptimal bone mass. We hypothesized that tactile/kinesthetic stimulation (TKS), a form of infant massage that incorporates kinesthetic movement, would increase bone strength and markers of bone accretion in preterm infants. Preterm, AGA infants (29-32 weeks) were randomly assigned to TKS (N=20) or Control (N=20). Twice daily TKS was provided 6 days per week for 2 weeks. Control infants received the same care without TKS treatment. Treatment was masked to parents, health care providers, and study personnel. Baseline and week two measures were collected for tibial speed of sound (tSOS, m/sec), a surrogate for bone strength, by quantitative ultrasound (Sunlight8000) and urine markers of bone metabolism, pyridinium crosslinks and osteocalcin (U-MidOC and unOC). Infant characteristics at birth and study entry as well as energy/nutrient intake were similar between TKS and Control. TKS intervention attenuated the decrease in tSOS observed in Control infants (p<0.05). Urinary pyridinium crosslinks decreased over time in both TKS and CTL (p<0.005). TKS infants experienced greater increases in urinary osteocalcin (U-MidOC, p<0.001 and unOC, p<0.05). We conclude that TKS improves bone strength in premature infants by attenuating the decrease that normally follows preterm birth. Further, biomarkers of bone metabolism suggest a modification in bone turnover in TKS infants in favor of bone accretion. Taken together, we speculate that TKS improves bone mineralization. PMID- 22846676 TI - Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. AB - BACKGROUND: Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells. METHODS: NCI-H838 lung cancer cells were incubated with tumor necrosis factor-alpha in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 MUM). Cell migration and total cell lysate Src activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated. RESULTS: Ropivacaine treatment (100 MUM) of H838 cells for 20 min decreased basal Src activity by 62% (P=0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-alpha statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P=0.005) in presence of 1 MUM ropivacaine and 21% by 1 MUM lidocaine (P=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition. CONCLUSIONS: This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-alpha-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers. PMID- 22846678 TI - Depressive-like states heighten the aversion to painful stimuli in a rat model of comorbid chronic pain and depression. AB - BACKGROUND: Chronic pain and depression are two complex states with sensory/somatic and emotional components, and they may mutually exacerbate one another in conditions of comorbidity, leading to a poorer prognosis. METHODS: The authors have evaluated the sensory and emotional components in a rat model combining chronic constriction injury (CCI, a model of chronic neuropathic pain) with unpredictable chronic mild stress (CMS, an experimental model of depression). In addition, the phosphorylation/activation of the extracellular signal-regulated kinases 1 and 2 and neuronal density was also evaluated in the anterior cingulate cortex. Four groups were tested: sham-control, sham-CMS, CCI control, and CCI-CMS. RESULTS: CMS selectively heightens aversion to painful experiences in animals subjected to CCI, as measured in the place escape/avoidance test at 20, 25, and 30 min (CCI-CMS (mean+/-SEM): 75.68+/-3.32, 66.75+/-4.70, 77.54+/-3.60 vs. CCI-control: 44.66+/-6.07, 43.17+/-6.92, 52.83+/ 5.92, respectively), in conjunction with an increase in the accumulation of phosphorylation/activation of the extracellular signal-regulated kinases (CCI CMS: 4.17+/-0.52 vs. sham-control: 0.96+/-0.05) and a decrease in neuronal density in the anterior cingulate cortex. In contrast, chronic pain did not exacerbate the characteristic profile of depression (anhedonia and behavioral despair) in rats subjected to CMS. Furthermore, depression enhances the perception of some specific modalities of sensorial pain such as cold allodynia but has no influence on mechanical threshold. CONCLUSIONS: These findings support the theory that depression leads to emotional dysfunction in the interpretation of pain in patients suffering chronic pain. In addition, combined animal models of pain-depression may provide a valuable tool to study the comorbidity of pain and depression. PMID- 22846677 TI - miR-203 regulates nociceptive sensitization after incision by controlling phospholipase A2 activating protein expression. AB - BACKGROUND: After incision keratinocytes in the epidermis become activated to produce a range of pain-related mediators. microRNA 203 (miR-203) is known to be involved in keratinocyte growth, differentiation, and skin inflammation. We hypothesized that one or more of these mediators might be under the control of miR-203. METHODS: The expression of miR-203 and its target gene, phospholipase A2 activating protein (PLAA), were examined after hind paw incision in mice. We investigated the local effect of intraplantar PLAA peptide injection in normal mice and the effects of a selective secretory phospholipase A2 inhibitor (HK064) on PLAA or incision-induced mechanical allodynia. Last, we investigated the role of substance P signaling in regulating miR-203 and PLAA expression in vitro and in vivo. RESULTS: Levels of miR-203 were strongly down-regulated in keratinocytes after incision. Informatics-based approaches identified PLAA as a likely candidate for regulation by miR-203. PLAA caused mechanical allodynia and conditioned place aversion but not thermal sensitization. HK064 reduced mechanical allodynia after incision and after intraplantar injection of PLAA. Using preprotachykinin gene knockout mice or with neurokinin-1 selective antagonist LY303870 treatment, we observed that substance P-mediated signaling was also required for miR-203 and PLAA regulation after incision. Finally, using the rat epidermal keratinocyte cell line, we observed that a miR-203 mimic molecule could block the substance P-induced increase in PLAA expression observed under control conditions. CONCLUSIONS: miR-203 may regulate expression of the novel nociceptive mediator PLAA after incision. Furthermore, the regulation of miR-203 and PLAA levels is reliant upon intact substance P signaling. PMID- 22846679 TI - Effects of muscle relaxants on mask ventilation in anesthetized persons with normal upper airway anatomy. AB - BACKGROUND: Recent studies suggest advantages of muscle relaxants for facemask ventilation. However, direct effects of muscle relaxants on mask ventilation remain unclear because these studies did not control mechanical factors influencing ventilation. We tested a hypothesis that muscle relaxants, either rocuronium or succinylcholine, improve mask ventilation. METHODS: In anesthetized adult persons with normal upper airway anatomy, tidal volumes during facemask ventilation were measured while maintaining the neutral head and mandible positions and the airway pressures of a ventilator before and during muscle paralysis induced by either rocuronium (n=14) or succinylcholine (n=17). Tidal volumes of oral and nasal airway routes were separately measured with a custom made oronasal portioning full facemask. Behavior of the oral airway was observed by an endoscope in six additional subjects receiving succinylcholine. RESULTS: Total, oral, and nasal tidal volumes did not significantly change at complete muscle paralysis with rocuronium. In contrast, succinylcholine significantly increased total tidal volumes at 60 s after its administration (mean+/-SD; 4.2+/ 2.1 vs. 5.4+/-2.6 ml/kg, P=0.02) because of increases of ventilation through both airway routes. Abrupt tidal volume increase occurred more through oral airway route than nasal route. Dilation of the space at the isthmus of the fauces was endoscopically observed during pharyngeal fasciculation in all six subjects. CONCLUSIONS: Rocuronium did not deteriorate facemask ventilation, and it was improved after succinylcholine administration in association with airway dilation during pharyngeal fasciculation. This effect continued to a lesser degree after resolution of the fasciculation. PMID- 22846680 TI - Who is at risk for postdischarge nausea and vomiting after ambulatory surgery? AB - BACKGROUND: About one in four patients suffers from postoperative nausea and vomiting. Fortunately, risk scores have been developed to better manage this outcome in hospitalized patients, but there is currently no risk score for postdischarge nausea and vomiting (PDNV) in ambulatory surgical patients. METHODS: We conducted a prospective multicenter study of 2,170 adults undergoing general anesthesia at ambulatory surgery centers in the United States from 2007 to 2008. PDNV was assessed from discharge until the end of the second postoperative day. Logistic regression analysis was applied to a development dataset and the area under the receiver operating characteristic curve was calculated in a validation dataset. RESULTS: The overall incidence of PDNV was 37%. Logistic regression analysis of the development dataset (n=1,913) identified five independent predictors (odds ratio; 95% CI): female gender (1.54; 1.22 to 1.94), age less than 50 yr (2.17; 1.75 to 2.69), history of nausea and/or vomiting after previous anesthesia (1.50; 1.19 to 1.88), opioid administration in the postanesthesia care unit (1.93; 1.53 to 2.43), and nausea in the postanesthesia care unit (3.14; 2.44-4.04). In the validation dataset (n=257), zero, one, two, three, four, and five of these factors were associated with a PDNV incidence of 7%, 20%, 28%, 53%, 60%, and 89%, respectively, and an area under the receiver operating characteristic curve of 0.72 (0.69 to 0.73). CONCLUSIONS: PDNV affects a substantial number of patients after ambulatory surgery. We developed and validated a simplified risk score to identify patients who would benefit from long-acting prophylactic antiemetics at discharge from the ambulatory care center. PMID- 22846681 TI - Otolith end organ projections to auditory neurons in the descending octaval nucleus of the goldfish, Carassius auratus: a confocal analysis. AB - The distribution of axons from the saccule, lagena, and utricle to descending octaval nucleus neurons that project to the auditory midbrain in the goldfish is reported. We have divided these auditory projection neurons, located in the dorsal portion of the descending octaval nucleus (dDO), into two groups, medial and lateral, each of which contains several neuronal populations based on morphology and location. At most levels of the dDO, there are three medial and three lateral populations; the rostral dDO contains an additional lateral population. The saccule provides input to each of the seven medial and lateral populations but appears to be the exclusive/nearly exclusive source of primary input to the most dorsal cell group of the medial population. Along with the saccule, the lagena and utricle each supply the remaining six medial and lateral populations. Neurons in each of these populations receive input from more than one end organ. One medial and one lateral population include neurons that receive remarkably large contacts from utricular afferents. Overall, the results reveal a more substantial input from the lagena and utricle to the main first-order auditory nucleus in the goldfish than was previously recognized, suggest this nucleus is composed of functionally distinct populations, and relate to functional and evolutionary issues about hearing in early vertebrates. PMID- 22846682 TI - Molecular phylogenetics in 2D: ITS2 rRNA evolution and sequence-structure barcode from Veneridae to Bivalvia. AB - In this study, we analyzed the nuclear ITS2 rRNA primary sequence and secondary structure in Veneridae and comparatively with 20 Bivalvia taxa to test the phylogenetic resolution of this marker and its suitability for molecular diagnosis at different taxonomic levels. Maximum likelihood and Bayesian trees based on primary sequences were congruent with (profile-) neighbor-joining trees based on a combined model of sequence-structure evolution. ITS2 showed higher resolution below the subfamily level, providing a phylogenetic signal comparable to (mitochondrial/nuclear) gene fragments 2-5 times longer. Structural elements of the ITS2 folding, such as specific mismatch pairing and compensatory base changes, provided further support for the monophyly of some groups and for their phylogenetic relationships. Veneridae ITS2 folding is structured in six domains (DI-VI) and shows five striking sequence-structure features. Two of them, the Basal and Apical STEMs, are common to Bivalvia, while the presence of both the Branched STEM and the Y/R stretches occurs in five superfamilies of the two Heterodonta orders Myoida and Veneroida, thus questioning their reciprocal monophyly. Our results validated the ITS2 as a suitable marker for venerids phylogenetics and taxonomy, and underlined the significance of including secondary structure information for both applications at several systematic levels within bivalves. PMID- 22846684 TI - Molecular phylogeny of extant equids and effects of ancestral polymorphism in resolving species-level phylogenies. AB - Short divergence times and processes such as incomplete lineage sorting and species hybridization are known to hinder the inference of species-level phylogenies due to the lack of sufficient informative genetic variation or the presence of shared but incongruent polymorphism among taxa. Extant equids (horses, zebras, and asses) are an example of a recently evolved group of mammals with an unresolved phylogeny, despite a large number of molecular studies. Previous surveys have proposed trees with rather poorly supported nodes, and the bias caused by genetic introgression or ancestral polymorphism has not been assessed. Here we studied the phylogenetic relationships of all extant species of Equidae by analyzing 22 partial mitochondrial and nuclear genes using maximum likelihood and Bayesian inferences that account for heterogeneous gene histories. We also examined genetic signatures of lineage sorting and/or genetic introgression in zebras by evaluating patterns of intraspecific genetic variation. Our study improved the resolution and support of the Equus phylogeny and in particular the controversial positions of the African wild ass (E. asinus) and mountain zebra (E. zebra): the African wild ass is placed as a sister species of the Asiatic asses and the mountain zebra as the sister taxon of Grevy's and Burchell's zebras. A shared polymorphism (indel) detected among zebra species in the Estrogen receptor 1 gene was likely due to incomplete lineage sorting and not genetic introgression as also indicated by other mitochondrial (Cytochrome b) and nuclear (Y chromosome and microsatellites) markers. Ancestral polymorphism in equids might have contributed to the long-standing lack of clarity in the phylogeny of this highly threatened group of mammals. PMID- 22846685 TI - Phylogeny and biogeography of the Anderson's crocodile newt, Echinotriton andersoni (Amphibia: Caudata), as revealed by mitochondrial DNA sequences. AB - The Anderson's crocodile newt, Echinotriton andersoni, is considered a relic and endangered species distributed in the Central Ryukyus. To elucidate phylogenetic relationships and detailed genetic structures among populations, we analyzed variation in the mitochondrial cytochrome b gene. Results strongly support a primary dichotomy between populations from the Amami and Okinawa Island Groups with substantial genetic divergence, favoring a primary divergence between the two island groups. Within the latter, populations from the southern part of Okinawajima Island are shown to be more closely related to those from Tokashikijima Island than to those from the northern and central parts of Okinawajima. The prominent genetic divergence between the two island groups of the Central Ryukyus seems to have initiated in the Miocene, i.e., prior to formation of the strait that has consistently separated these island groups since the Pleistocene. The ancestor of the southern Okinawajima-Tokashikijima is estimated to have migrated from the northern and central parts of Okinawajima into southern Okinawajima at the Pleistocene, and dispersed into Tokashikijima subsequently. PMID- 22846683 TI - Gene duplication, genome duplication, and the functional diversification of vertebrate globins. AB - The functional diversification of the vertebrate globin gene superfamily provides an especially vivid illustration of the role of gene duplication and whole-genome duplication in promoting evolutionary innovation. For example, key globin proteins that evolved specialized functions in various aspects of oxidative metabolism and oxygen signaling pathways (hemoglobin [Hb], myoglobin [Mb], and cytoglobin [Cygb]) trace their origins to two whole-genome duplication events in the stem lineage of vertebrates. The retention of the proto-Hb and Mb genes in the ancestor of jawed vertebrates permitted a physiological division of labor between the oxygen-carrier function of Hb and the oxygen-storage function of Mb. In the Hb gene lineage, a subsequent tandem gene duplication gave rise to the proto alpha- and beta-globin genes, which permitted the formation of multimeric Hbs composed of unlike subunits (alpha(2)beta(2)). The evolution of this heteromeric quaternary structure was central to the emergence of Hb as a specialized oxygen-transport protein because it provided a mechanism for cooperative oxygen-binding and allosteric regulatory control. Subsequent rounds of duplication and divergence have produced diverse repertoires of alpha- and beta-like globin genes that are ontogenetically regulated such that functionally distinct Hb isoforms are expressed during different stages of prenatal development and postnatal life. In the ancestor of jawless fishes, the proto Mb and Hb genes appear to have been secondarily lost, and the Cygb homolog evolved a specialized respiratory function in blood-oxygen transport. Phylogenetic and comparative genomic analyses of the vertebrate globin gene superfamily have revealed numerous instances in which paralogous globins have convergently evolved similar expression patterns and/or similar functional specializations in different organismal lineages. PMID- 22846686 TI - Enhancement of the frequency and function of IL-10-secreting type I T regulatory cells after 1 year of cluster allergen-specific immunotherapy. AB - BACKGROUND: Allergen-specific immunotherapy (SIT) is a highly effective treatment for allergic diseases, but the underlying mechanisms are unclear. In this study, we investigated the effects of cluster SIT with Dermatophagoides pteronyssinus (Der p) on IL-10-secreting type I T regulatory (Tr1) cells in Der p-sensitized patients with allergic rhinitis. METHODS: This was a prospective randomized study involving 68 participants (aged 18-60 years) of whom 38 were patients with allergic rhinitis and received Der p-SIT for 1 year and 30 were nonallergic controls. IL-10+IL-4-CD4+ T cells were measured by flow cytometry for the patient group at baseline and at the end of 1 year of SIT, and for nonallergic controls. Similarly, IL-10 in supernatants from allergen-stimulated peripheral blood mononuclear cell (PBMC) cultures were measured by ELISA, and the suppressive effect of Tr1 cells on cell proliferation and cytokine release (IFN-gamma and IL 4) in PBMCs was estimated in cultures from both groups. Allergen-specific serum IgE and IgG4 were also assessed by RAST and ELISA for the SIT group. RESULTS: The levels of IL-10-secreting Tr1 cells, IgG4 and allergen-induced IL-10 synthesis from PBMC cultures were significantly increased and the function of Tr1 cells was enhanced after 1 year of SIT compared to baseline levels. In contrast, the level of IgE was not significantly changed. CONCLUSION: These data suggest that the cluster Der p-SIT may enhance the frequency and function of IL-10-secreting Tr1 cells. PMID- 22846687 TI - Solid-state properties of softwood lignin and cellulose isolated by a new acid precipitation method. AB - Solid-state and powder properties of softwood lignin and cellulose prepared by a new catalytic oxidation and acid precipitation method were characterized and compared with the commercial softwood and hardwood lignin and cellulose products. Catalytic pre-treated softwood lignin (CPSL) and cellulose (CPSC) were isolated from pine wood (Pinus sylvestris). CPSL with nearly micronized-scale particle size showed excellent powder flow and densification behavior due to the round shape and electrically minimum charged surface characteristics of particles. CPSL and the reference lignin studied were amorphous solids while CPSC exhibited a typical crystal lattice for cellulose I. In conclusion, physicochemical material properties of lignin and cellulose can be modified for biomedical and pharmaceutical applications with the present catalytic oxidation and acid precipitation method. PMID- 22846689 TI - Results of three analytical approaches on long-term efficacy of etanercept for psoriasis in daily practice. AB - BACKGROUND: A problem encountered when analyzing long-term efficacy is that the number of patients in follow-up decreases with time for different reasons. The method used to account for missing observations for the therapy under analysis has a great influence on the inference of efficacy. OBJECTIVE: To describe the long-term efficacy of etanercept for psoriasis in daily practice using 3 analytical approaches. METHODS: Prospective data from a cohort of patients with psoriasis treated with etanercept for at least 24 weeks were analyzed using 3 analytical approaches: as treated analysis, intention-to-treat analysis (ITT) with last observation carried forward (LOCF) and intention-to-treat analysis with modified nonresponder imputation (modified NRI). RESULTS: One hundred thirty-one patients were treated with etanercept during 134 treatment episodes with a mean treatment duration of 2.7 years. The maximum follow-up was 6.0 years. The methodological approach chosen had a great influence. Psoriasis Area and Severity Index (PASI) 75 response rates varied from 60% in the as-treated approach to 34% in LOCF and to 29% in modified NRI at week 264. LIMITATIONS: All analytical methods applied have limitations. Other outcome measures could be used to overcome the bias introduced by each method of analysis, such as drug survival. CONCLUSIONS: The methodological approach chosen to analyze long-term efficacy data has a great influence on the inferences that may be drawn regarding the degree of efficacy. Therefore we support the use of different methods to present long-term efficacy data. PMID- 22846688 TI - Patient-reported reasons for the discontinuation of commonly used treatments for moderate to severe psoriasis. AB - BACKGROUND: Despite widespread dissatisfaction and low treatment persistence in moderate to severe psoriasis, patients' reasons behind treatment discontinuation remain poorly understood. OBJECTIVES: We sought to characterize patient-reported reasons for discontinuing commonly used treatments for moderate to severe psoriasis in real-world clinical practice. METHODS: A total of 1095 patients with moderate to severe plaque psoriasis from 10 dermatology practices who received systemic treatments completed a structured interview. Eleven reasons for treatment discontinuation were assessed for all past treatments. RESULTS: A total of 2231 past treatments were reported. Median treatment duration varied by treatment, ranging from 6.0 to 20.5 months (P < .001). The frequency of each cited discontinuation reasons differed by treatment (all P < .01). Patients who received etanercept (odds ratio [OR] 5.19; 95% confidence interval [CI] 3.23 8.33) and adalimumab (OR 2.10; 95% CI 1.20-3.67) were more likely to cite a loss of efficacy than those who received methotrexate. Patients who received etanercept (OR 0.34; 95% CI 0.23-0.49), adalimumab (OR 0.48; 95% CI 0.30-0.75), and ultraviolet B phototherapy (OR 0.21; 95% CI 0.14-0.31) were less likely to cite side effects than those who received methotrexate, whereas those who received acitretin (OR 1.56; 95% CI 1.08-2.25) were more likely to do so. Patients who underwent ultraviolet B phototherapy were more likely to cite an inability to afford treatment (OR 7.03; 95% CI 3.14-15.72). LIMITATIONS: The study is limited by its reliance on patient recall. CONCLUSIONS: Different patterns of treatment discontinuation reasons are important to consider when developing public policy and evidence-based treatment approaches to improve successful long-term psoriasis control. PMID- 22846690 TI - Acquired poikiloderma: proposed classification and diagnostic approach. AB - "Poikiloderma" is a morphologic and descriptive term referring to a combination of cutaneous atrophy, telangiectasia, and varied macular pigmentary changes that result in a mottled skin appearance. Its etiology includes both congenital and acquired causes. Many studies have reported different causes of acquired poikiloderma; however, no single well-defined classification has been explored to date. Herein, we analyze all the possible causes of acquired poikiloderma and propose an etiological classification that, hopefully, will lead to better characterization for this ill-defined condition. Moreover, this study presents a step-by-step approach to the management of patients with acquired poikiloderma and summarizes the key differentiating features for each individual cause, which may help in easy and precise diagnosis of different causes of acquired poikiloderma. PMID- 22846691 TI - A quantitative method for acylcarnitines and amino acids using high resolution chromatography and tandem mass spectrometry in newborn screening dried blood spot analysis. AB - We have developed a high resolution liquid chromatographic separation with electrospray ionization (ESI) mass spectrometry detection for the combined analysis of twelve acylcarnitines and seven amino acids commonly measured in newborn screening heritable metabolic disorders. Samples were prepared by punching 3.2 mm disks out of dried blood spots and extracting with a mixture of methanol and 0.1% formic acid containing stable isotopically labeled internal standards. Analysis was performed on an UHPLC system using a HILIC amide, 2.1 mm * 50 mm, 1.7 MUm column. A normal phase gradient, employing 10mM ammonium acetate in 90:10 acetonitrile/water for mobile phase B and 0.1% formic acid in water for mobile phase A, was used. Optimized multiple reaction monitoring (MRM) was used for detection of amino acids and acylcarnitines on a Waters Premier mass spectrometer. Quantification of analytes was performed using internal calibration by fortification of sodium heparin whole blood with analytes at appropriate levels to encompass the range around the reported cut-off values. The method was fully validated with respect to precision, accuracy, recovery, linearity, matrix suppression and extraction robustness. Precision and accuracy were evaluated over 3 days and determined to be acceptable with an overall precision within 10% and accuracy within 15% of theoretical for all analytes except for acetylcarnitne at one fortified level, which quantitated 21.8% lower than the expected value. This method is suitable as a second-tier test for newborn screening of specific disorders associated with abnormal levels of acylcarnitines and amino acids, potentially reducing false positive cases and shortening the time to diagnosis. PMID- 22846692 TI - Affordable Care Act...ready, set, go! PMID- 22846693 TI - Staff recognition: think outside the box. PMID- 22846694 TI - Representing nursing knowledge in electronic health records. PMID- 22846695 TI - The advantages of utilizing LPNs. PMID- 22846696 TI - Improving outcomes with the Quality and Safety Investigator program. PMID- 22846698 TI - Climate change: transforming a biased atmosphere. PMID- 22846699 TI - A critical look at critical thinking. PMID- 22846700 TI - What's a peer reviewed journal? PMID- 22846701 TI - Don't waste green! Launching a budget awareness campaign. PMID- 22846702 TI - Staying ahead of the curve. PMID- 22846703 TI - Deconvolution of calcium fluorescent indicator signal from AFM cantilever reflection. AB - Atomic force microscopy (AFM) can be combined with fluorescence microscopy to measure the changes in intracellular calcium levels (indicated by fluorescence of Ca2+ sensitive dye fluo-4) in response to mechanical stimulation performed by AFM. Mechanical stimulation using AFM is associated with cantilever movement, which may interfere with the fluorescence signal. The motion of the AFM cantilever with respect to the sample resulted in changes of the reflection of light back to the sample and a subsequent variation in the fluorescence intensity, which was not related to changes in intracellular Ca2+ levels. When global Ca2+ responses to a single stimulation were assessed, the interference of reflected light with the fluorescent signal was minimal. However, in experiments where local repetitive stimulations were performed, reflection artifacts, correlated with cantilever motion, represented a significant component of the fluorescent signal. We developed a protocol to correct the fluorescence traces for reflection artifacts, as well as photobleaching. An added benefit of our method is that the cantilever reflection in the fluorescence recordings can be used for precise temporal correlation of the AFM and fluorescence measurements. PMID- 22846704 TI - Thermal diffusivity measurement of spherical gold nanofluids of different sizes/concentrations. AB - In recent times, nanofluids have been studied by their thermal properties due to their variety of applications that range from photothermal therapy and radiofrequency hyperthermia (which have proven their potential use as coadjutants in these medical treatments for cancer diseases) to next-generation thermo fluids. In this work, photoacoustic spectroscopy for a specific study of thermal diffusivity, as a function of particle size and concentration, on colloidal water based gold nanofluids is reported. Gold nanoparticles were synthetized in the presence of hydroquinone through a seed-mediated growth with homogenous sizes and shapes in a range of 16 to 125 nm. The optical response, size and morphology of these nanoparticles were characterized using ultraviolet-visible spectroscopy and transmission electron microscopy, respectively. Thermal characterizations show a decrease in the thermal diffusivity ratio as the nanoparticle size is increased and an enhancement in thermal diffusivity ratio as nanoparticle concentration is added into the nanofluids. Compared with other techniques in the literature such as thermal lens and hot wire method, this photoacoustic technique shows an advantage in terms of precision, and with a small amount of sample required (500 MUl), this technique might be suitable for the thermal diffusivity measurement of nanofluids. It is also a promising alternative to classical techniques. PMID- 22846705 TI - Phytohormone signaling pathway analysis method for comparing hormone responses in plant-pest interactions. AB - BACKGROUND: Phytohormones mediate plant defense responses to pests and pathogens. In particular, the hormones jasmonic acid, ethylene, salicylic acid, and abscisic acid have been shown to dictate and fine-tune defense responses, and identification of the phytohormone components of a particular defense response is commonly used to characterize it. Identification of phytohormone regulation is particularly important in transcriptome analyses. Currently there is no computational tool to determine the relative activity of these hormones that can be applied to transcriptome analyses in soybean. FINDINGS: We developed a pathway analysis method that provides a broad measure of the activation or suppression of individual phytohormone pathways based on changes in transcript expression of pathway-related genes. The magnitude and significance of these changes are used to determine a pathway score for a phytohormone for a given comparison in a microarray experiment. Scores for individual hormones can then be compared to determine the dominant phytohormone in a given defense response. To validate this method, it was applied to publicly available data from previous microarray experiments that studied the response of soybean plants to Asian soybean rust and soybean cyst nematode. The results of the analyses for these experiments agreed with our current understanding of the role of phytohormones in these defense responses. CONCLUSIONS: This method is useful in providing a broad measure of the relative induction and suppression of soybean phytohormones during a defense response. This method could be used as part of microarray studies that include individual transcript analysis, gene set analysis, and other methods for a comprehensive defense response characterization. PMID- 22846706 TI - Spinal cord injury and traumatic brain injury: a cost-of-illness study. AB - BACKGROUND: Among traumatic injuries, spinal cord injuries (SCI) and traumatic brain injuries (TBI) are of major importance because of their epidemiological and economic impact on society. The overall objective of this study was to estimate the economic cost associated with people with SCI and TBI in Spain in 2007. METHODS: A cost-of-illness analysis was performed, considering the perspective of society, using a 1-year time horizon. Medical costs, adaptation costs, material costs, administrative costs, and costs of police, firefighters and roadside assistance, productivity losses due to institutionalization and sick leave, as well as an estimate of productivity losses of carers, and productivity losses due to death were included. RESULTS: The economic cost associated with people with SCI is between EUR 92,087,080.97 and 212,496,196.41 (USD 131 million and 302 million) according to the injury mechanism, and between EUR 1,079,223,688.66 and 3,833,752,692.78 (USD 1,536 million and 5,458 million) for people with TBI. CONCLUSIONS: There is an urgent need to develop effective interventions known to prevent SCI and TBI, and to evaluate their effectiveness and efficiency. PMID- 22846707 TI - Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study. AB - OBJECTIVES: Refractory angina patients suffer debilitating chest pain despite optimal medical therapy and previous cardiovascular intervention. Cardiac rehabilitation is often not prescribed due to a lack of evidence regarding potential efficacy and patient suitability. A randomised controlled study was undertaken to explore the impact of cardiac rehabilitation on cardiovascular risk factors, physical ability, quality of life and psychological morbidity among refractory angina sufferers. METHODS: Forty-two refractory angina patients (65.1 +/- 7.3 years) were randomly assigned to an 8-week Phase III cardiac rehabilitation program or symptom diary control. Physical assessment, Progressive Shuttle Walk test, Hospital Anxiety and Depression Scale, Health Anxiety Questionnaire, the York Angina Beliefs scale, ENRICHD Social Support Instrument and SF-36 were completed before and after intervention and at 8-week follow-up. RESULTS: Following cardiac rehabilitation, patients demonstrated improved physical ability compared with controls in Progressive Shuttle Walk level attainment (p = 0.005) and total distance covered (p = 0.015). Angina frequency and severity remained unchanged in both groups, with the control demonstrating worsening SF-36 pain scale (63.43 +/- 22.28 vs. 55.46 +/- 23.98, p = 0.025). Cardiac rehabilitation participants showed improved Health Anxiety Questionnaire reassurance (1.71 +/- 1.72 vs. 1.14 +/- 1.23, p = 0.026) and York Beliefs anginal threat perception (12.42 +/- 4.58 vs. 14.35 +/- 4.73, p = 0.05) after cardiac rehabilitation. Physical measures were broadly unaffected. CONCLUSIONS: Cardiac rehabilitation can be prescribed to improve physical ability without affecting angina frequency or severity among patients with refractory angina. PMID- 22846708 TI - FERM-containing protein FRMD5 is a p120-catenin interacting protein that regulates tumor progression. AB - FERM family proteins have been known to play an important role in tumor progression. FERM-domain containing protein 5 (FRMD5), a novel putative cytoskeletal protein, is an unknown function protein. Here, we reported that FRMD5 localized at the cell adherens junction and formed a molecular complex with p120-catenin through its C-terminal region. Functionally, we found that knockdown of endogenous FRMD5 promotes lung cancer cell migration and invasion in vitro as well as tumor growth in vivo, suggesting a tumor suppressive effect. These findings indicated that FRMD5 may play a role in p120-catenin-based cell-cell contact and is involved in the regulation of tumor progression. PMID- 22846709 TI - Effects of Salusin-beta on action potential and ionic currents in ventricular myocytes of rats. AB - AIM: Salusin-beta is a regulatory peptide that exerts negative inotropic effect on ventricular muscle, but its electrophysiological effects on ventricular myocytes are still unknown. METHODS: Action potential and channel currents such as sodium current (I(N) (a) ), transient outward potassium current (I(to) ), steady-state potassium current (I(sus) ), sodium-calcium exchange current (I(N) (aCa) ) and inward rectifier potassium current (I(K) (1) ) were measured in ventricular myocytes isolated from 12 to 16 weeks rats by whole-cell voltage clamp techniques. RESULTS: Salusin-beta dose-dependently shortened the duration of action potential in rat ventricular myocytes. Furthermore, salusin-beta significantly inhibited I(N) (aCa) and increased I(to) , but did not affect I(N) (a) , I(sus) and I(K) (1) . CONCLUSION: These results suggest that the effect of salusin-beta on action potential may be partly attributed to a decrease in inward currents and an increase in outward currents. PMID- 22846710 TI - Advances in infection and immunity: from bench to bedside. AB - This report summarizes recent advances on host-pathogen interactions, innate and adaptive responses to infection, as well as novel strategies for the control of infectious diseases. PMID- 22846711 TI - Heterologous expression of human costimulatory molecule B7-2 and construction of B7-2 immobilized polyhydroxyalkanoate nanoparticles for use as an immune activation agent. AB - BACKGROUND: Costimulation of T cells via costimulatory molecules such as B7 is important for eliciting cell-mediated antitumor immunity. Presenting costimulation molecules by immobilizing recombinant B7 on the surface of nanovectors is a novel strategy for complementary therapy. Polyhydroxyalkanoates (PHAs) are a family of biodegradable, non-toxic, biocompatible polyesters, which can be used as a nonspecific immobilizing matrix for protein presentation. Recombinant protein fusion with PHA granule binding protein phasin (PhaP) can be easily immobilized on the surface of PHA nanoparticles through hydrophobic interactions between PhaP and PHA, and therefore provides a low-cost protein presenting strategy. RESULTS: In this study, the extracellular domain of the B7-2 molecule (also named as CD86) was fused with PhaP at its N-terminal and heterogeneously expressed in recombinant Escherichia coli strain BL21 (DE3). The purified B7-2-PhaP protein was immobilized on the surface of poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx)-based nanoparticles. Loading of 240 MUg (3.2 pMol) of B7-2-PhaP protein per mg nanoparticles was achieved. Immobilized B7-2-PhaP on PHBHHx nanoparticles induced T cell activation and proliferation in vitro. CONCLUSIONS: A PHA nanoparticle-based B7-2 costimulation molecule-presenting system was constructed. The PHA-based B7 presenting nanosystem provided costimulation signals to induce T cell activation and expansion in vitro. The B7-2-PhaP immobilized PHA nanosystem is a novel strategy for costimulation molecule presentation and may be used for costimulatory molecule complementary therapy. PMID- 22846712 TI - Longitudinal assessment of serum anticholinergic activity in delirium of the elderly. AB - BACKGROUND: Delirium, a frequently occurring, devastating disease, is often underdiagnosed, especially in dementia. Serum anticholinergic activity (SAA) was proposed as a disease marker as it may reflect delirium's important pathogenetic mechanism, cholinergic deficiency. We assessed the association of serum anticholinergic activity with delirium and its risk factors in a longitudinal study on elderly hip fracture patients. METHOD: Consecutive elderly patients admitted for hip fracture surgery (n = 142) were assessed longitudinally for delirium, risk factors, and serum markers (IL-6, cortisol, and SAA). Using a sophisticated statistical design, we evaluated the association between SAA and delirium in general and with adjustments, but also the temporal course, including the events fracture, surgery, and potential delirium, individual confounders, and a propensity score. RESULTS: Among elderly hip fracture patients 51% developed delirium, these showed more risk factors (p < 0.001), and complications (p < 0.05). Uncontrolled SAA levels (463 samples) were significantly higher in the delirium group (4.2 vs. 3.4 pmol/ml) and increased with delirium onset, but risk factors absorbed the effect. Using mixed-modeling we found a significant increase in SAA concentration (7.6% (95%CI 5.0-10.2, p < 0.001)) per day, which was modified by surgery and delirium, but this effect was confounded by cognitive impairment and IL-6 values. Confounder control by propensity scores resulted in a disappearance of delirium-induced SAA increase. CONCLUSIONS: Delirium predisposing factors are closely associated with changes in the temporal profile of serum anticholinergic activity and thus neutralize the previously documented association between higher SAA levels and delirium. An independent relationship of SAA to delirium presence is highly questionable. PMID- 22846713 TI - The extent of degeneration of cruciate ligament is associated with chondrogenic differentiation in patients with osteoarthritis of the knee. AB - OBJECTIVE: Degeneration in cruciate ligaments results from abnormal biomechanical stress and the aging process. Such degeneration is a common outcome in patients with osteoarthritis (OA) of the knee and contributes to the progression of OA. However, to date, there are no specific markers that can predict the extent of ligament degeneration. We hypothesized that the extent of degeneration has correlations to increased chondrogenic potential. METHODS: Twenty anterior cruciate ligaments (ACLs) and 30 posterior cruciate ligaments (PCLs) from 30 knees of 28 adult patients with OA at the time of total knee arthroplasty were used for the study. Degeneration was histologically assessed using a grading system. Expressions of Scleraxis (as a ligament cell marker) and Sry-type HMG box 9 (SOX9) (as a chondrogenic marker) were immunohistochemically assessed in each grade. RESULTS: We found the opposite expression pattern between Scleraxis and SOX9 according to the grade. The percentage of Scleraxis-positive cells decreased significantly by grade (60.9+/-23.7 in grade 1, 39.7+/-30.5 in grade 2, and 13.9+/-27.1 in grade 3, P<0.0001). In contrast, the percentage of SOX9-positive cells increased significantly by grade (2.5+/-4.9 in grade 1, 17.5+/-13.4 in grade 2, and 50.9+/-27.1 in grade 3, P<0.0001). Furthermore, co-localized expression of both Scleraxis and SOX9 was demonstrated in chondrocyte-like cells. CONCLUSIONS: This study indicates that chondrogenic differentiation is associated with the progression of degeneration in human ligaments. Our results suggest that the expression of SOX9 as a chondrogenic marker could be an indicator for the extent of degeneration in human ligaments. It remains to be elucidated whether suppression of chondrogenic differentiation can prevent progression of the degenerative process of cruciate ligaments in patients with OA. PMID- 22846714 TI - Influence of medial meniscectomy on stress distribution of the femoral cartilage in porcine knees: a 3D reconstructed T2 mapping study. AB - OBJECTIVE: Previous studies have shown that meniscectomy results in an increase of local load transmission and may cause degeneration of the knee cartilage. Using 3D reconstructed T2 mapping, we examined the influence on the femoral cartilage under loading after medial meniscectomy. DESIGN: Ten porcine knees were imaged using a pressure device and a 3.0-T magnetic resonance imaging (MRI) system. Consecutive sagittal T2 maps were obtained in neutral alignment with and without compression, and under compression at 10 degrees varus alignment. After medial meniscectomy, the aforementioned MRI was repeated. Cartilage T2 before and after meniscectomy under each condition were compared at the 12 regions of interest (ROIs) defined on the 3D weight-bearing area of the femoral cartilage. RESULTS: Before meniscectomy, large decreases in T2 under neutral compression were mainly seen at the anterior and central ROIs of the medial cartilage, which shifted to the posterior ROIs after meniscectomy. There were significant differences in decrease in T2 ratio with loading before and after meniscectomy (9.8%/4.3% at the anterior zone, 4.0%/11.4% at the posterior zone, P < 0.05). By applying varus compression, a more remarkable decrease in the cartilage T2 in posterior ROIs after meniscectomy was achieved. (Before/after meniscectomy: 8.7%/2.5% at the anterior zone, 7.2%/18.7% at the posterior zone, P < 0.05). CONCLUSIONS: Assuming a decrease in T2 with loading correlated with the applied pressure, a deficiency of the medial meniscus resulted in a shift of the primary area with a maximal decrease of cartilage T2 with loading posteriorly in the porcine knee joint, presumably reflecting the intraarticular environment of load transmission. PMID- 22846716 TI - Chromosome evolution in Eulipotyphla. AB - We integrated chromosome painting information on 5 core-insectivora species available in the literature with new Zoo-FISH data for Iberian shrew (Sorex granarius) and Altai mole (Talpa altaica). Our analysis of these 7 species allowed us to determine the chromosomal features of Eulipotyphla genomes and to update the previously proposed ancestral karyotype for 2 main groups of the Sorex genus. The chromosome painting evidence with human painting probes (HSA) reveals the presence of the 2 unique associations HSA4/5 and 1/10p/12/22b, which support Eulipotyphla. There are a series of synapomorphies both for Erinaceidae (HSA3/1/5, 3/17, 11/15 and 10/20) and for Soricinae (HSA5/9, 6/7/16, 8/3/21 and 11/12/22). We found associations that link Talpidae/Erinaceidae (HSA7/8, 1/5 and 1/19p), Talpidae/Soricidae (HSA1/8/4) and Erinaceidae/Soricidae (HSA4/20 and 2/13). Genome conservation in Eulipotyphla was estimated on the basis of the number of evolutionary breaks in the ancestral mammalian chromosomes. In total, 7 chromosomes of the boreo-eutherian ancestor (BEA8 or 10, 9, 17, 18, 20-22) were retained in all eulipotyphlans studied; among them moles show the highest level of chromosome conservation. The integration of sequence data into the chromosome painting information allowed us to further examine the chromosomal syntenies within a phylogenetic perspective. Based on our analysis we offer the most parsimonious reconstruction of phylogenetic relationships in Eulipotyphla. The cytogenetic reconstructions based on these data do not conflict with molecular phylogenies supporting basal position of Talpidae in the order. PMID- 22846715 TI - Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint -the MOST study. AB - OBJECTIVE: In order to increase sensitivity to detect longitudinal change, recording of within-grade changes was introduced for cartilage morphology and bone marrow lesion (BML) assessment in semiquantitative magnetic resonance imaging (MRI) scoring of knee osteoarthritis (OA). The aim of this study was to examine the validity provided by within-grade scoring. DESIGN: The Multicenter Osteoarthritis (MOST) study is a longitudinal study of subjects with or at risk of knee OA. Baseline and 30 months MRIs were read according to the modified Whole Organ Magnetic Resonance Imaging Score (WORMS) system including within-grade changes for cartilage and BMLs. We tested the validity of within-grade changes by whether the 30-month changes in cartilage and BML assessment were predicted by baseline ipsi-compartmental meniscal damage and malalignment, factors known to affect cartilage loss and BMLs, using ordinal logistic regression. RESULTS: 1867 Knees (from 1411 participants) were included. Severe medial meniscal damage predicted partial grade (adjusted odds ratio (aOR) 4.4, 95% confidence interval (95% CI) 2.2, 8.7) but not >=full grade (aOR 1.3, 95% CI 0.8, 2.2) worsening of cartilage loss and predicted both, partial grade (aOR 9.6, 95% CI 3.6, 25.1) and >=full grade (aOR 5.1, 95% CI 3.2, 8.2) worsening of BMLs. Severe, but not moderate, malalignment predicted ipsi-compartmental within-grade (medial cartilage damage: aOR 5.5, 95% CI 2.6, 11.6; medial worsening of BMLs: aOR 4.9, 95% CI 2.0, 12.3) but not full grade worsening of BMLs and cartilage damage. CONCLUSIONS: Within-grade changes in semiquantitative MRI assessment of cartilage and BMLs are valid and their use may increase the sensitivity of semiquantitative readings in detecting longitudinal changes in these structures. PMID- 22846717 TI - Heavy cervical cancer burden in elderly women: how can we improve the situation? AB - OBJECTIVES: The American Cancer Society, the American College of Obstetricians and Gynecologists and the US Preventive Services Task Force recommend discontinuation of cervical cancer screening between 65 and 70 years of age in women with no abnormal test results in the preceding 10 years. This population based study was undertaken to determine the incidence of cervical cancer in different age groups as a means to establish if current screening recommendations need reevaluation. STUDY DESIGN: Data from the SEER database were used to compute incidence rates for cervical cancer diagnosed between 2000 and 2006 by age and disease stage. RESULTS: We identified 18,003 women with cervical cancer. 12.18% were above the age of 69. The incidence in this age group was 8.7/100,000. Women younger than 30 comprised 5.7% of patients with an incidence of 5/100,000 and were most commonly diagnosed with stage IA1 disease. Women above 70 were most frequently diagnosed with stage IIIB. 79% of patients younger than 30 were diagnosed with an early disease (stage IA1-IIA) as opposed to only 41.2% of patients aged 69 or above. CONCLUSIONS: The incidence of cervical cancer does not decrease significantly in older women. Women over the age of 70 are frequently diagnosed with advanced stage disease which limits their treatment options. Failure to apply uniform screening across all at-risk age groups may account for the discrepancy. PMID- 22846719 TI - A novel animal model for pseudoxanthoma elasticum: the KK/HlJ mouse. AB - Pseudoxanthoma elasticum is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. A mouse model with targeted ablation of the corresponding gene (Abcc6(tm1JfK)) develops ectopic mineralization on the dermal sheath of vibrissae as biomarker of the progressive mineralization disorder. Survey of 31 mouse strains in a longitudinal aging study has identified three mouse strains with similar ectopic mineralization of the vibrissae, particularly the KK/HlJ strain. We report here that this mouse strain depicts, in addition to ectopic mineralization of the dermal sheath of vibrissae, mineral deposits in a number of internal organs. Energy dispersive X-ray analysis and topographic mapping found the presence of calcium and phosphate as the principal ions in the mineral deposits, similar to that in Abcc6(tm1JfK) mice, suggesting the presence of calcium hydroxyapatite. The mineralization was associated with a splice junction mutation at the 3' end of exon 14 of the Abcc6 gene, resulting in a 5-bp deletion from the coding region and causing frame-shift of translation. As a consequence, essentially no Abcc6 protein was detected in the liver of the KK/HlJ mice, similar to that in Abcc6(tm1JfK) mice. Collectively, our studies found that the KK/HlJ mouse strain is characterized by ectopic mineralization due to a mutation in the Abcc6 gene and therefore provides a novel model system to study pseudoxanthoma elasticum. PMID- 22846720 TI - CFTR is involved in the fine tuning of intracellular redox status: physiological implications in cystic fibrosis. AB - Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the DeltaF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway. PMID- 22846721 TI - Epidermal hyperplasia and appendage abnormalities in mice lacking CD109. AB - CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in several types of human cancer tissues, in particular, squamous cell carcinomas. In normal human tissues, human CD109 expression is limited to certain cell types including myoepithelial cells of the mammary, lacrimal, salivary, and bronchial glands and basal cells of the prostate and bronchial epithelium. Although CD109 has been reported to negatively regulate transforming growth factor-beta signaling in keratinocytes in vitro, its physiologic role in vivo remains largely unknown. To investigate the function of CD109 in vivo, we generated CD109-deficient (CD109(-/-)) mice. Although CD109(-/-) mice were born normally, transient impairment of hair growth was observed. At histologic analysis, kinked hair shafts, ectatic hair follicles with an accumulation of sebum, and persistent hyperplasia of the epidermis and sebaceous glands were observed in CD109(-/-) mice. Immunohistochemical analysis revealed thickening of the basal and suprabasal layers in the epidermis of CD109(-/-) mice, which is where endogenous CD109 is expressed in wild-type mice. Although CD109 was reported to negatively regulate transforming growth factor-beta signaling, no significant difference in levels of Smad2 phosphorylation was observed in the epidermis between wild-type and CD109(-/-) mice. Instead, Stat3 phosphorylation levels were significantly elevated in the epidermis of CD109(-/-) mice compared with wild-type mice. These results suggest that CD109 regulates differentiation of keratinocytes via a signaling pathway involving Stat3. PMID- 22846722 TI - Circulating microparticles from patients with obstructive sleep apnea enhance vascular contraction: mandatory role of the endothelium. AB - Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep associated with oxygen desaturation and sleep disruption. We evaluated the role of circulating microparticles (MPs) from patients with OSA in the regulation of vascular function. MPs from whole blood from patients with OSA or control subjects were injected i.v. into mice. Injection of MPs from patients with OSA induced ex vivo vascular hyperreactivity in aortas with functional endothelium but, in contrast, hyporeactivity in vessels without functional endothelium. Vascular hyperreactivity was blunted in the presence of a nitric oxide synthase inhibitor alone or combined with the cyclooxygenase inhibitor indomethacin. MPs from patients with OSA reduced endothelial nitric oxide synthase activity and nitric oxide production, increased aortic cyclooxygenase-1 and cyclooxygenase-2 expression, and increased thromboxane A(2) and prostacyclin production. Blockade of thromboxane A(2) receptor did not affect the serotonin response in arteries from OSA MP-treated mice. A superoxide dismutase mimetic reduced the vascular hyperreactivity induced by MPs from patients with OSA but had no effect on contraction in vessels from control and non-OSA MP-treated mice. These data provide evidence that circulating MPs from patients with OSA induce ex vivo vascular hyperreactivity with the obligatory role of the endothelium and subtle interactions between the nitric oxide and cyclooxygenase pathways and metabolites. These results highlight the participation of MPs in vascular dysfunction associated with OSA. PMID- 22846724 TI - Assessment of the long-term transcriptional activity of a 550-bp-long human beta actin promoter region. AB - beta-actin (ACTB) is one of the genes expressed most abundantly and ubiquitously in human non-muscular tissues. Here, we investigated the long-term activity of a 550-bp-long human ACTB promoter region in human cells in comparison with other commonly used constitutive promoters. We first constructed plasmid vectors expressing enhanced green fluorescent protein (GFP) driven by one of the 5 promoters, human ACTB, human elongation factor-1alpha (EF1alpha), cytomegalovirus early enhancer/chicken beta-actin (CAG), cytomegalovirus (CMV), and herpes simplex virus thymidine kinase, and transfected them into multiple human somatic cell lines. Stable transfectants were maintained for 45 days, and GFP signals from the cells were quantified by fluorescence flow cytometry. GFP signals driven by the human ACTB and the CMV promoters were also compared over time for up to 60 days following transfection. We observed robust, prolonged transcriptional activity with the human ACTB promoter that is comparable to the human EF1alpha and the CAG promoters and significantly more stable than the CMV promoter. PMID- 22846725 TI - Men's preference for the ovulating female is triggered by subtle face shape differences. AB - Recent studies have revealed that there may be perceptible cues to ovulation in humans. This study aims at extending these findings by using female faces that were shape transformed towards a late follicular (fertile) and a luteal (non fertile) prototype. Fertile prototypes were created by averaging 25 photographs taken of females during ovulation (as determined by ovulation tests); non-fertile prototypes were created by averaging 25 photographs of the same women during the luteal phase. Twenty different (new) female faces were then shape transformed towards the luteal prototype and towards the follicular prototype in 50% and 100% steps. The two 50% transforms and the two 100% transforms were paired, resulting in stimulus pairs of two different difficulties. Thirty-six male participants were asked to choose the more attractive (Task 1), the more caring (Task 2), and the more flirtatious face (Task 3). In a final task the participants were asked to choose the woman with which the participant would have better chances to get a date (Task 4). For all tasks we found a significant preference for the follicular face. In trials with a 100% transformation towards the shape of the prototype, the preference for the follicular stimulus was significantly stronger than in trials with a 50% transformation. We conclude that subtle shape differences in faces are sufficient to trigger men's preference for a woman in her fertile cycle phase. PMID- 22846726 TI - Guillain-Barre syndrome incidence in a large United States cohort (2000-2009). AB - BACKGROUND/AIM: We describe the incidence of Guillain-Barre syndrome (GBS) in a large United States cohort. METHODS: Between 2000 and 2009, we identified visits with an ICD-9 code for GBS (357.0) from all persons with continuous enrollment for at least 1 year. The primary case definition was restricted to emergency department and inpatient visits. We calculated age-standardized rates and used multivariate Poisson regression to assess variation in rates by sex, age, season and year of diagnosis. We tabulated descriptive characteristics and the positive predictive value (PPV) for a subset of the visits with available medical record review. RESULTS: 1,619 visits with the GBS ICD-9 code were identified from 50,290,898 person-years of observation. After considering the PPV (55%) for record-reviewed visits, the age-standardized incidence rate was approximately 1.72/100,000 person-years. The rate was 40% higher for males and increased by 50% for every 10-year increase in age. The rate was 15% higher in winter and spring compared with summer. Rates were higher in more recent years. CONCLUSIONS: GBS rates are higher in males and increase considerably with age. The potential reasons for differences in rates by season and the increased rates in more recent years should be further investigated. PMID- 22846723 TI - Virulence factors identified by Cryptococcus neoformans mutant screen differentially modulate lung immune responses and brain dissemination. AB - Deletions of cryptococcal PIK1, RUB1, and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by comparing wild-type Cryptococcus neoformans strain H99 with deletant and complement strains in a BALB/c mouse model of pulmonary infection. Survival of infected mice; pulmonary cryptococcal growth and pathology; immunological parameters; dissemination kinetics; and CNS pathology were examined. Deletion of each PIK1, RUB1, and ENA1 differentially reduced pulmonary growth and dissemination rates of C. neoformans and extended mice survival. Furthermore, pik1Delta induced similar pathologies to H99, however, with significantly delayed onset; rub1Delta was more efficiently contained within pulmonary macrophages and was further delayed in causing CNS dissemination/pathology; whereas ena1Delta was progressively eliminated from the lungs and did not induce pathological lesions or disseminate into the CNS. The diminished virulence of mutant strains was associated with differential modulation of pulmonary immune responses, including changes in leukocyte subsets, cytokine responses, and macrophage activation status. Compared to H99 infection, mutants induced more hallmarks of a protective Th1 immune response, rather than Th2, and more classical, rather than alternative, macrophage activation. The magnitude of immunological effects precisely corresponded to the level of virulence displayed by each strain. Thus, cryptococcal PIK1, RUB1, and ENA1 differentially contribute to cryptococcal virulence, in correlation with their differential capacity to modulate immune responses. PMID- 22846727 TI - From the guest editor: cancer genetic counseling and testing: past, present, and future. PMID- 22846728 TI - Whole-genome and whole-exome sequencing in hereditary cancer: impact on genetic testing and counseling. AB - The incorporation of whole-genome and whole-exome sequencing into clinical practice will undoubtedly change the way genetic counselors and other clinicians approach genetic testing. Enabling the analysis of essentially all human genes in one comprehensive test, this new technology can result in reduced testing cost and time to diagnosis. Another consequence of this broad scope, however, is the increased amount, complexity, and variety of results a clinician may need to discuss with a patient. The purpose of this article is to review the technology and outline some of the benefits and challenges of whole-genome and whole-exome sequencing in hereditary cancer practice. PMID- 22846729 TI - Direct-to-consumer personal genome testing and cancer risk prediction. AB - The last several years has witnessed an explosion in genomics, with the advent of genome-wide association studies revealing hundreds of DNA variants significantly associated with most common diseases, including cancer. On the heels of these scientific advances came the direct-to-consumer (DTC) genetic testing industry. Genome-wide scans for disease have been marketed and sold directly to the public, without the involvement of a health care provider. Unlike genetic testing for mutations in known hereditary cancer susceptibility genes such as BRCA1/2, these genomic profiles examine DNA variants, which typically have a minimal risk impact, and account for only a fraction of the heritable component of cancer. Furthermore, risk information provided to consumers does not account for family history or other known risk factors. The clinical validity and utility of personal genome scans for disease risk prediction remain for the most part unestablished, although some argue lack of evidence of harm and the possibility that positive impacts on health behaviors or genetic awareness may result from consumer use. The DTC genetic testing industry has sparked significant controversy not only among the scientific community, but also among professional societies and government agencies.In this review, we present some of the history and methodological considerations of DTC genomic profiling, with a focus on cancer risk prediction. The literature regarding consumer awareness and utilization is explored, including understanding, expectations, and behavioral and psychological responses to DTC genomic risk prediction. Primary care provider and genetic professional knowledge and perceptions of DTC genomic profiling are also addressed. Ethical and scientific controversy surrounding the DTC genetic testing industry is presented, along with policy recommendations, regulatory actions, and the changing landscape of the DTC genetic testing market in response. Although our understanding of the human genome holds much promise in the realm of cancer prevention and treatment, DTC genomic profiling for cancer risk prediction is unlikely in its current form to have any significant impact on the health of the public. Time will tell if the next venture in genomic medicine, whole genome sequencing, will be accompanied by the translational research and emphasis on public/provider education required to ensure its successful application toward reducing the burden of cancer at a population level. PMID- 22846730 TI - Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications. AB - Cancer genetic counseling and testing are now integral services in progressive cancer care. There has been much debate over whether these services should be delivered by providers with specialized training in genetics or by all clinicians. Adverse outcomes resulting from cancer genetic counseling and testing performed by clinicians without specialization in genetics have been reported, but formal documentation is sparse. In this review, we present a series of national cases illustrating major patterns of errors in cancer genetic counseling and testing and the resulting impact on medical liability, health care costs, and the patients and their families. PMID- 22846731 TI - Genetic testing by cancer site: breast. AB - Women in the United States have a 12% lifetime risk of developing breast cancer. Although only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene, individuals who carry a mutation in one of these genes have a significantly higher risk of developing breast cancer, as well as other cancers, over their lifetime compared with the general population. The ability to distinguish those individuals at high risk allows health care providers to intervene with appropriate counseling and education, surveillance, and prevention-with the overall goal of improved survival for these individuals. This article focuses on the identification of patients at high risk for breast cancer and provides an overview of the clinical features, cancer risks, causative genes, and medical management for the most clearly described hereditary breast cancer syndromes. Newer genes that have also been implicated in familial breast cancer are also briefly reviewed. PMID- 22846732 TI - Genetic testing by cancer site: ovary. AB - Approximately 1 in every 4 to 5 women with a diagnosis of ovarian cancer has a hereditary gene mutation that is responsible for the development of her cancer. Identifying women at increased risk of developing ovarian cancer due to a hereditary cancer syndrome can allow for early detection or prevention of not only ovarian cancer, but also other cancers, depending on the causative gene. This review focuses on 3 of the most common hereditary ovarian cancer syndromes, hereditary breast and ovarian cancer syndrome (the BRCA1 and BRCA2 genes), Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome), and Peutz-Jeghers syndrome, including key features, genetics, and management of these syndromes. In addition, newly discovered genes (eg, RAD51C and RAD51D) linked to ovarian cancer are discussed. PMID- 22846733 TI - Genetic testing by cancer site: colon (polyposis syndromes). AB - Hereditary colonic polyposis conditions are all characterized by high rates of cancer, but they have diverse phenotypes, genetic heterogeneity, and assorted inheritance patterns. The most well known of these conditions include familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH (MutY human homolog)-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. Early recognition of these conditions is not only vital for management in affected individuals, but also for prevention and early detection in at-risk relatives. Reviewed here are the genetic testing strategies for colonic polyposis, as well as an overview of characteristic features and management considerations for these syndromes. PMID- 22846734 TI - Genetic testing by cancer site: colon (nonpolyposis syndromes). AB - Lynch syndrome, which is associated with mutations in 1 of 4 mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), is a well-described hereditary cancer predisposition syndrome associated with a substantial risk of colon, rectum, and endometrial cancer. Historically, individuals with Lynch syndrome were identified using clinical classification criteria that have since been shown to be ineffective in most clinical settings, giving way to a more molecular diagnostic approach. These techniques have been repeatedly discussed in the literature, and there are multiple considerations in determining the best approach for a specific family. We review these approaches here as well as the clinical presentation of Lynch syndrome. Although still a relatively rare condition, we stress the importance of the identification of individuals with Lynch syndrome, given the clear data that predictive testing of at-risk family members and subsequent screening for cancers can reduce mortality associated with colorectal and endometrial cancer in these families. PMID- 22846735 TI - Genetic testing by cancer site: uterus. AB - This review article discusses hereditary cancer predisposition syndromes with uterine manifestations. Lynch syndrome accounts for 2% to 3% of endometrial cancers. The identification of endometrial cancer patients at risk for Lynch syndrome is discussed, as are the characteristics of Lynch syndrome-associated endometrial cancer and the screening and prevention options for women at risk for Lynch syndrome-associated endometrial cancer. Endometrial cancer associated with PTEN hamartoma tumor syndrome (also known as Cowden syndrome) is also discussed. HLRCC (hereditary leiomyomatosis and renal cell carcinoma), which has an associated high risk of symptomatic uterine leiomyomas, is reviewed. PMID- 22846736 TI - Genetic testing by cancer site: urinary tract. AB - The roles of renal cell carcinoma (RCC) and urothelial cancers of the upper urinary tract are often overlooked as indicators for genetic risk assessment. The key features of 5 hereditary cancer susceptibility conditions involving an increased risk for RCC are discussed. von Hippel-Lindau disease, hereditary papillary RCC, and hereditary leiomyomatosis and RCC each predispose to a specific histological type of RCC, whereas Birt-Hogg-Dube and hereditary paraganglioma/pheochromocytoma entail a variety of histologic findings. Familiarity with the rare or uncommon clinical features associated with these conditions, such as cutaneous neoplasms, paraganglioma/pheochromocytoma, and recurrent spontaneous pneumothoraces, aids in identifying patients with an underlying RCC susceptibility. A path to identifying syndromic cases lies in thorough investigation of the patient's medical history, their family history, and the histological type of RCC reported in the family. A guide to genetic predisposition testing for RCC is proposed. Upper urinary tract cancers in Lynch syndrome are also discussed. PMID- 22846737 TI - Genetic testing by cancer site: pancreas. AB - It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation. PMID- 22846738 TI - Genetic testing by cancer site: stomach. AB - Gastric cancer is a global public health concern, ranking as the fourth leading cause of cancer mortality, with a 5-year survival of only 20%. Approximately 10% of gastric cancers appear to have a familial predisposition, and about half of these can be attributed to hereditary germline mutations. We review the genetic syndromes and current standards for genetic counseling, testing, and medical management for screening and treatment of gastric cancer. Recently, germline mutations in the E-cadherin/CDH1 gene have been identified in families with an autosomal dominant inherited predisposition to gastric cancer of the diffuse type. The cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is up to 80%, and women from these families also have an increased risk for developing lobular breast cancer. Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers, because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance. In addition to this syndrome, gastric cancer risk is elevated in Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability, in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations, in familial adenomatous polyposis caused by germline APC mutations, in Li-Fraumeni syndrome due to germline p53 mutations, in Peutz-Jeghers syndrome associated with germline STK11 mutations, and in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes. Guidelines for genetic testing, counseling, and management of individuals with hereditary diffuse gastric cancer are suggested. A raised awareness among the physician and genetic counseling communities regarding these syndromes may allow for increased detection and prevention of gastric cancers in these high-risk individuals. PMID- 22846739 TI - Genetic testing by cancer site: endocrine system. AB - Numerous hereditary syndromes, caused by mutations in multiple tumor suppressor genes and oncogenes, can cause tumors in organs of the endocrine system. The primary syndromes (and genes) addressed here include multiple endocrine neoplasia types 1 and 2 (MEN1 and RET genes), Cowden syndrome (PTEN), hereditary pheochromocytoma/paraganglioma syndromes (multiple genes), and von Hippel-Lindau disease (VHL). Clinical genetic testing is available for each of these syndromes and is generally directed to individuals with endocrine or other tumors and additional features suggestive of a hereditary syndrome. However, for some endocrine tumors, the proportion because of heredity is so high that genetic testing may be appropriate for all affected individuals. Management for hereditary cases typically involves aggressive screening and/or surgical protocols, starting at young ages to minimize morbidity and mortality. Endocrine tumors can be less commonly seen in a number of other hereditary syndromes (eg, neurofibromatosis), which are not reviewed in this section. PMID- 22846740 TI - Genetic testing by cancer site: skin. AB - Many hereditary cancer predisposition syndromes are associated with cutaneous findings, both benign and malignant. Dermatological examination and histopathology, when combined with a thorough personal and family medical history, play an important role in the diagnosis of cancer predisposition syndromes. Skin findings are an important diagnostic tool for a variety of cancer syndromes, including Cowden syndrome, Birt-Hogg-Dube, hereditary leiomyomatosis renal cell carcinoma, and others. This article focuses on the phenotype, medical management, and genetic testing for 4 hereditary cancer syndromes that include cutaneous findings: hereditary melanoma, basal cell nevus syndrome, neurofibromatosis type 1, and neurofibromatosis type 2. PMID- 22846742 TI - Stress-induced cardiomyopathy. PMID- 22846741 TI - Comparison and validation of visual assessment and image processing algorithms to quantify morphology dynamics of Euglena gracilis. AB - Image processing algorithms were developed and compared with visual assessment from 12 volunteers to quantify the temporal morphological structure of a single Euglena gracilis organism. Representative images of E. gracilis, showing different morphological characteristics from ovate to cylindrical and elongate, were captured with a bright-field video microscopy system. These images were ranked by the volunteers in order from ovate to elongate. The images were analyzed in the spatial and spatial frequency domain, and the order of the images from each analysis was ranked against the visual assessment. The assessment methods agreeing with the volunteer's preferred sequence were an eccentricity measurement (major axis over the sum of the minor axis at three points), the cross correlation of the image without high pass filtering or edge detection, and cross correlation of the power spectral density. PMID- 22846743 TI - Genetic and clinical characterization of 45 acute leukemia patients with MLL gene rearrangements from a single institution. AB - Chromosomal rearrangements affecting the MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemia. In this study, conventional cytogenetic, fluorescence in situ hybridization, and molecular genetic studies were used to characterize the type and frequency of MLL rearrangements in a consecutive series of 45 Portuguese patients with MLL-related leukemia treated in a single institution between 1998 and 2011. In the group of patients with acute lymphoblastic leukemia and an identified MLL fusion partner, 47% showed the presence of an MLL-AFF1 fusion, as a result of a t(4;11). In the remaining cases, a MLL-MLLT3 (27%), a MLL-MLLT1 (20%), or MLL-MLLT4 (7%) rearrangement was found. The most frequent rearrangement found in patients with acute myeloid leukemia was the MLL-MLLT3 fusion (42%), followed by MLL-MLLT10 (23%), MLL-MLLT1 (8%), MLL-ELL (8%), MLL-MLLT4 (4%), and MLL-MLLT11 (4%). In three patients, fusions involving MLL and a septin family gene (SEPT2, SEPT6, and SEPT9), were identified. The most frequently identified chromosomal rearrangements were reciprocal translocations, but insertions and deletions, some cryptic, were also observed. In our series, patients with MLL rearrangements were shown to have a poor prognosis, regardless of leukemia subtype. Interestingly, children with 1 year or less showed a statistically significant better overall survival when compared with both older children and adults. The use of a combined strategy in the initial genetic evaluation of acute leukemia patients allowed us to characterize the pattern of MLL rearrangements in our institution, including our previous discovery of two novel MLL fusion partners, the SEPT2 and CT45A2 genes, and a very rare MLL-MLLT4 fusion variant. PMID- 22846744 TI - Nox4 mediates hypoxia-stimulated myofibroblast differentiation in nasal polyp derived fibroblasts. AB - BACKGROUND: Chronic hypoxia is associated with remodeling in various organs. Reactive oxygen species (ROS) derived from NADPH oxidases (Nox), and transforming growth factor-beta(1) (TGF-beta(1)) have been implicated in the pathogenesis of hypoxia-induced remodeling. The aims of this study were to determine in hypoxia stimulated nasal polyp-derived fibroblasts (NPDF) the effect of hypoxia on the differentiation of myofibroblasts, the role of ROS, the major Nox homolog mediating myofibroblast differentiation, and the role of TGF-beta(1). METHODS: Eight primary cultures of NPDF were established from nasal polyps, which were incubated under hypoxic conditions. Reverse transcription polymerase chain reaction for alphaSMA, Nox1, Nox3, Nox4, Nox5, and fibronectin mRNA was performed. Western blotting for alpha-SMA and fibronectin was done. ROS production was detected using a fluorometer. NPDF were pretreated with ROS scavengers and transfected with siNox4. The TGF-beta(1) protein level was measured by ELISA. The effect of treatment with TGF-beta(1) type I tyrosine kinase inhibitor SB431542 on myofibroblast differentiation was observed. RESULTS: Hypoxic stimulation of NPDF significantly increased alpha-SMA and fibronectin mRNA and protein expression. ROS production was increased by hypoxia, and ROS scavengers inhibited myofibroblast differentiation. Nox4 mRNA was the only Nox homolog increased by hypoxia. Transfection with siNox4 inhibited myofibroblast differentiation. TGF-beta(1) was secreted endogenously by hypoxic NPDF. SB431542 significantly inhibited myofibroblast differentiation. CONCLUSIONS: Hypoxia induces myofibroblast differentiation of NPDF through a signaling pathway involving Nox4-dependent ROS generation and TGF-beta(1). Therapies targeting Nox4 may be effective against remodeling of nasal polyps. PMID- 22846745 TI - Early asthma: stepping closer to primary prevention. PMID- 22846748 TI - Risk factors and characteristics of respiratory and allergic phenotypes in early childhood. AB - BACKGROUND: Unsupervised approaches can be used to analyze complex respiratory and allergic disorders. OBJECTIVE: We investigated the respiratory and allergic phenotypes of children followed in the Pollution and Asthma Risk: An Infant Study (PARIS) birth cohort. METHODS: Information on respiratory and allergic disorders, medical visits, and medications was collected during medical examinations of children at 18 months of age; biomarker data were also collected (total and allergen-specific IgE levels and eosinophilia). Phenotypes were determined by using latent class analysis. Associated risk factors were determined based on answers to questionnaires about environmental exposures. RESULTS: Apart from a reference group, which had a low prevalence of respiratory symptoms or allergies (n=1271 [69.4%]), 3 phenotypes were identified. On the basis of clinical signs of severity and use of health care resources, we identified a mild phenotype (n=306 [16.7%]) characterized by occasional mild wheeze and 2 severe phenotypes separated by atopic status. The atopic severe phenotype (n=59 [3.2%]) included 49 (83%) children with wheezing and was characterized by a high prevalence of atopy (61% with allergenic sensitization) and atopic dermatitis (78%). In contrast, atopy was rare among children with the nonatopic severe phenotype (n=195 [11%]); this group included 88% of the children with recurrent wheezing. Risk factors for respiratory disease included parental history of asthma, male sex, siblings, day care attendance, exposure to tobacco smoke or molds, indoor renovations, and being overweight, although these factors did not have similar affects on risk for all phenotypes. CONCLUSION: Atopy should be taken into account when assessing the risk of severe exacerbations (that require hospital-based care) in wheezing infants; precautions should be taken against respiratory irritants and molds and to prevent children from becoming overweight. PMID- 22846749 TI - Respiratory symptoms in asthma: the view through a wide-angle lens. PMID- 22846746 TI - Response to infections in patients with asthma and atopic disease: an epiphenomenon or reflection of host susceptibility? AB - Associations between respiratory tract infections and asthma inception and exacerbations are well established. Infant respiratory syncytial virus and rhinovirus infections are known to be associated with an increased risk of asthma development, and among children with prevalent asthma, 85% of asthma exacerbations are associated with viral infections. However, the exact nature of this relationship remains unclear. Is the increase in severity of infections an epiphenomenon, meaning respiratory tract infections just appear to be more severe in patients with underlying respiratory disease, or instead a reflection of altered host susceptibility among persons with asthma and atopic disease? The main focus of this review is to summarize the available levels of evidence supporting or refuting the notion that patients with asthma or atopic disease have an altered susceptibility to selected pathogens, as well as discussing the biological mechanism or mechanisms that might explain such associations. Finally, we will outline areas in need of further research because understanding the relationships between infections and asthma has important implications for asthma prevention and treatment, including potential new pathways that might target the host immune response to select pathogens. PMID- 22846750 TI - Interaction between IL13 genotype and environmental factors in the risk for allergic rhinitis in Korean children. AB - BACKGROUND: The prevalence of allergic rhinitis (AR) is increasing worldwide. Allergic diseases develop in susceptible subjects when they are exposed to specific environmental factors. OBJECTIVE: We analyzed changes in the prevalence of AR and identified genetic and environmental factors in early childhood that affect risk. METHODS: We used the International Study of Asthma and Allergies in Childhood questionnaire to collect data on AR, allergies, and environmental exposures from 4554 elementary school students from 5 areas of Seoul, Korea, in 2008. We also obtained DNA from 1050 subjects from 1 area of Seoul for genotype analysis of IL13. RESULTS: We identified genetic and environmental factors during infancy and early childhood that increased the risk for current AR (resulting in a diagnosis of AR and AR symptoms in the past 12 months) in elementary school aged children. These included allergic disease in parents and antibiotic use in infants, allergic disease in parents and exposure of infants to mold, and allergic disease in parents and moving an infant to a newly built house. The risk of current AR also increased in subjects with GA or AA at nucleotide 2044 in IL13 who had been exposed to mold in the home during infancy (adjusted odds ratio, 3.27; 95% CI, 1.75-6.11) compared with subjects who had GG at this position and had not been exposed to mold (adjusted odds ratio, 3.27; 95% CI, 1.75-6.11). CONCLUSION: The prevalence of AR is increasing in Korean children. Children with a family history of allergic disease and exposure to specific environmental risk factors during infancy are more likely to have AR. Children with GA or AA at IL13(+2044) are at increased risk for AR when exposed to mold in the home during the first year of life. PMID- 22846751 TI - Dietary baked egg accelerates resolution of egg allergy in children. AB - BACKGROUND: Baked egg is tolerated by a majority of egg-allergic children. OBJECTIVE: To characterize immunologic changes associated with ingestion of baked egg and evaluate the role that baked egg diets play in the development of tolerance to regular egg. METHODS: Egg-allergic subjects who tolerated baked egg challenge incorporated baked egg into their diet. Immunologic parameters were measured at follow-up visits. A comparison group strictly avoiding egg was used to evaluate the natural history of the development of tolerance. RESULTS: Of the 79 subjects in the intent-to-treat group followed for a median of 37.8 months, 89% now tolerate baked egg and 53% now tolerate regular egg. Of 23 initially baked egg-reactive subjects, 14 (61%) subsequently tolerated baked egg and 6 (26%) now tolerate regular egg. Within the initially baked egg-reactive group, subjects with persistent reactivity to baked egg had higher median baseline egg white (EW)-specific IgE levels (13.5 kU(A)/L) than those who subsequently tolerated baked egg (4.4 kU(A)/L; P= .04) and regular egg (3.1 kU(A)/L; P= .05). In subjects ingesting baked egg, EW-induced skin prick test wheal diameter and EW , ovalbumin-, and ovomucoid-specific IgE levels decreased significantly, while ovalbumin- and ovomucoid-specific IgG(4) levels increased significantly. Subjects in the per-protocol group were 14.6 times more likely than subjects in the comparison group (P< .0001) to develop regular egg tolerance, and they developed tolerance earlier (median 50.0 vs 78.7 months; P< .0001). CONCLUSION: Initiation of a baked egg diet accelerates the development of regular egg tolerance compared with strict avoidance. Higher serum EW-specific IgE level is associated with persistent baked and regular egg reactivity, while initial baked egg reactivity is not. PMID- 22846752 TI - Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort. AB - BACKGROUND: Childhood wheezing and asthma vary greatly in clinical presentation and time course. The extent to which phenotypic variation reflects heterogeneity in disease pathways is unclear. OBJECTIVE: We sought to assess the extent to which single nucleotide polymorphisms (SNPs) associated with childhood asthma in a genome-wide association study are predictive of asthma-related phenotypes. METHODS: In 8365 children from a population-based birth cohort, the Avon Longitudinal Study of Parents and Children, allelic scores were derived based on between 10 and 215,443 SNPs ranked according to the inverse of the P value for their association with physician-diagnosed asthma in an independent genome-wide association study (6176 cases and 7111 control subjects). We assessed the predictive value of allelic scores for asthma-related outcomes at age 7 to 9 years (physician's diagnosis, longitudinal wheezing phenotypes, and measurements of pulmonary function, bronchial responsiveness, and atopy). RESULTS: Scores based on the 46 highest-ranked SNPs were associated with the symptom-based phenotypes early onset persistent wheeze (P< 10(-11); area under the receiver operating characteristic curve [AUC], 0.59) and intermediate-onset wheeze (P< 10( 3); AUC, 0.58). Among lower-ranked SNPs (ranks, 21,545-46,416), there was evidence for associations with diagnosed asthma (P< 10(-4); AUC, 0.54) and atopy (P< 10(-5); AUC, 0.55). We found little evidence of associations with transient early wheezing, reduced pulmonary function, or nonasthma phenotypes. CONCLUSION: The genetic origins of asthma are diverse, and some pathways are specific to wheezing syndromes, whereas others are shared with atopy and bronchial hyperresponsiveness. Our study also provides evidence of etiologic differences among wheezing syndromes. PMID- 22846754 TI - Organ-specific symptoms during oral food challenge in children with food allergy. PMID- 22846753 TI - Prenatal and early-life exposures alter expression of innate immunity genes: the PASTURE cohort study. AB - BACKGROUND: There is evidence that gene expression of innate immunity receptors is upregulated by farming-related exposures. OBJECTIVE: We sought to determine environmental and nutritional exposures associated with the gene expression of innate immunity receptors during pregnancy and the first year of a child's life. METHODS: For the Protection Against Allergy: Study in Rural Environments (PASTURE) birth cohort study, 1133 pregnant women were recruited in rural areas of Austria, Finland, France, Germany, and Switzerland. mRNA expression of the Toll-like receptor (TLR) 1 through TLR9 and CD14 was assessed in blood samples at birth (n= 938) and year 1 (n= 752). Environmental exposures, as assessed by using questionnaires and a diary kept during year 1, and polymorphisms in innate receptor genes were related to gene expression of innate immunity receptors by using ANOVA and multivariate regression analysis. RESULTS: Gene expression of innate immunity receptors in cord blood was overall higher in neonates of farmers (P for multifactorial multivariate ANOVA= .041), significantly so for TLR7 (adjusted geometric means ratio [aGMR], 1.15; 95% CI, 1.02-1.30) and TLR8 (aGMR, 1.15; 95% CI, 1.04-1.26). Unboiled farm milk consumption during the first year of life showed the strongest association with mRNA expression at year 1, taking the diversity of other foods introduced during that period into account: TLR4 (aGMR, 1.22; 95% CI, 1.03-1.45), TLR5 (aGMR, 1.19; 95% CI, 1.01-1.41), and TLR6 (aGMR, 1.20; 95% CI, 1.04-1.38). A previously described modification of the association between farm milk consumption and CD14 gene expression by the single nucleotide polymorphism CD14/C-1721T was not found. CONCLUSION: Farming-related exposures, such as raw farm milk consumption, that were previously reported to decrease the risk for allergic outcomes were associated with a change in gene expression of innate immunity receptors in early life. PMID- 22846755 TI - Relevance of antibody testing in patients with recurrent infections. PMID- 22846756 TI - Total glucosides of paeony attenuated functional maturation of dendritic cells via blocking TLR4/5 signaling in vivo. AB - It is well known that dendritic cells (DCs) play a critical role in the initiation and development of an immune response. Inhibitory effect on DC maturation alters immune-mediated inflammatory reaction in vivo. Total glucosides of paeony (TGP) are active compounds extracted from the roots of Paeonia lactiflora and have been widely used to ameliorate inflammation in therapy for autoimmune diseases. However, whether TGP act on DC maturation remains unknown. In this study, we investigated the effect of TGP on DC maturation in ovalbumin (OVA) immunized mice. Ear inflammation was inhibited by TGP (150 mgkg(-1), i.p.*11 days) obviously. The antigen presenting capacity of DC derived from TGP treated mice was arrested. Meanwhile, OVA specific T cell proliferation was inhibited. In addition, we found that maturation of DCs was decreased by TGP treatment. Furthermore, OVA specific T cell proliferation was rescued by the adoptive transfer of mature DCs (mDCs) into TGP treated OVA-challenged mice. The research on the mechanism showed that TGP significantly inhibited activation of TLR4/5 singling. All these results demonstrated that TGP inhibited DC maturation and function by selectively blocking TLR4/5 activation in vivo, which in turn leads to reduce immune-mediated inflammation in vivo, adding a novel mechanism and therapeutic target of TGP for inflammatory and autoimmune disease treatment. PMID- 22846757 TI - Respiratory epithelial cell responses to cigarette smoke: the unfolded protein response. AB - Cigarette smoking exposes the respiratory epithelium to highly toxic, reactive oxygen nitrogen species which damage lung proteins in the endoplasmic reticulum (ER), the cell organelle in which all secreted and membrane proteins are processed. Accumulation of damaged or misfolded proteins in the ER, a condition termed ER stress, activates a complex cellular process termed the unfolded protein responses (UPR). The UPR acts to restore cellular protein homeostasis by regulating all aspects of protein metabolism including: protein translation and syntheses; protein folding; and protein degradation. However, activation of the UPR may also induce signaling pathways which induce inflammation and cell apoptosis. This review discusses the role of UPR in the respiratory epithelial cell response to cigarette smoke and the pathogenesis of lung diseases like COPD. PMID- 22846758 TI - The effects of the selective cyclooxygenase-2 inhibitor on endometrial cytological findings in uterine endometrial cancer patients. AB - OBJECTIVE: We previously reported that oral administration of the selective cyclooxygenase-2 (COX-2) inhibitor etodolac results in antitumor effects in endometrial cancer tissue. Herein, we investigated whether these antitumor effects could be assessed using endometrial cytological findings. STUDY DESIGN: Etodolac (400 mg b.i.d. for 2 weeks) was administered preoperatively to 21 endometrial cancer patients: 16 had COX-2-positive disease and 5 had COX-2 negative disease. Twenty-one pairs of pre- and post-etodolac-treatment endometrial cytological samples were collected to review changes in the cytological features. RESULTS: In the COX-2-positive patients, nuclear atypia was slightly decreased in 3 of the 16 cases, while the mitotic index was decreased in all cases. Cellular overlapping and tumor cell cluster outlines were somewhat affected in 6 and 8 cases, respectively. Nuclear/cytoplasmic ratio, anisokaryosis and hyperchromasia were also reduced in 6, 4, and 2 cases, respectively; however, tumor diathesis and nucleoli features were unchanged. In contrast, endometrial cytological features did not appear to be affected in the 5 COX-2-negative patients. CONCLUSIONS: We conclude that the antitumor effects observed in endometrial cancer tissues following oral administration of etodolac are reflected in and can be easily assessed by evaluating endometrial cytological features. PMID- 22846759 TI - The spatial characteristics of ambient particulate matter and daily mortality in the urban area of Beijing, China. AB - Few epidemiological studies have reported the spatial characteristics of the association between particulate matter <10MUm in aerodynamic diameter (PM(10)) and mortality in China. This study explored the spatial characteristics of the association between ambient PM(10) and mortality in the urban area of Beijing, China. We collected daily data on air pollution, weather conditions and mortality in the eight urban districts of Beijing from Jan. 1st 2008 to Dec. 31st 2009. A Poisson Generalized Additive Model (GAM) was used to examine the district specific effects of PM(10) on cause-specific mortality. A Poisson Generalized Additive Mixed Model (GAMM) was used to examine the urban-wide association between PM(10) and cause-specific mortality while controlling for the random effects of districts, compared with GAM which did not control for the random effects of districts. The inter-quartile ranges (IQRs) of annual PM(10) ranged from 83.5 MUg/m(3) (Chaoyang district) to 96.0 MUg/m(3) (Shijingshan district). A 96.0 MUg/m(3) increase of PM(10) was associated with a 7.52% (95%CI: 1.78% 13.56%) increase of cardiovascular mortality in Shijingshan district while an 87.0 MUg/m(3) increase of PM(10) was associated with a 7.68% (95%CI: 0.08% 15.86%) increase of respiratory deaths in Dongcheng district. The urban-wide effects derived from GAMM showed that an 88.0 MUg/m(3) increase of PM(10) was associated with an increase of 1.30% (95%CI: 0.45%-2.16%), 2.60% (95%CI: 0.14% 5.11%) in non-accidental and respiratory mortality, illustrating, higher results than those from the GAM. In conclusion, there is spatial variation in ambient PM(10) concentration as well as in the effects of PM(10) on cause-specific mortality in the urban area of Beijing. Additionally, GAMM model may be more effective in estimating the spatial association between urban-wide PM(10) and cause-specific mortality. PMID- 22846760 TI - Levels of bisphenol-A in thermal paper receipts from Belgium and estimation of human exposure. AB - Bisphenol-A (BPA) is a commonly used color developer in thermal paper. In this application, BPA is present in its free, unbound form and can be readily released, making thermal paper a potential source for human exposure. In this study, BPA was determined in 44 thermal paper samples collected in Belgium. BPA was detected in all the samples; 73% of the samples had concentrations between 0.9% and 2.1% (between 9 and 21 mg BPA/g paper), while the remaining 27% of the samples had concentrations below 0.01% (0.1mg BPA/g paper). The BPA concentrations measured in thermal paper were comparable with those reported in other international studies. Since thermal paper is a feedstock for paper recycling processes, contamination of other "BPA-free" papers can occur. An estimation of human exposure through thermal paper results in a median intake of 445 ng BPA/day for the general population, which corresponds to an exposure of 6.4 ng/kg bw/day for a person of 70 kg. The exposure of those people who come occupationally in contact with thermal paper can be much higher. PMID- 22846761 TI - Effects of herbicide mixture on microbial communities in prairie wetland ecosystems: a whole wetland approach. AB - Wetlands in the prairie pothole region of Saskatchewan and Manitoba serve an important role in providing wildlife habitat, water storage and water filtration. These wetlands are regularly interspersed among agricultural operations where multiple pesticides are commonly used. Although mixtures of pesticides are often detected in these important aquatic ecosystems, very little information is known, regarding their effects. In this study, a curtained wetland approach was used to investigate the effects of a herbicide mixture (2,4-D, MCPA, clopyralid, dicamba, dichlorprop, mecoprop, bromoxynil, and glyphosate) on the structure and function of microbial communities in an ephemeral wetland and a semi-permanent wetland. In the two studied wetlands, located in Manitoba Zero Till Research Association Farm, Brandon, Manitoba, Canada, herbicide treatment based on maximum-exposure scenarios had a significant effect on pelagic and biofilm phytoplankton productivity over relatively short time periods. The stimulation of phytoplankton productivity in the ephemeral wetland appeared to be the result of a hormonal effect of the auxin-type herbicides present in the mixture, similar to naturally occurring auxins. Herbicidal effects of auxin-type herbicides were also noticed in the semi-permanent wetland where phytoplankton productivity was suppressed during the first week as a result of the concentration addition effect of the auxin-type herbicides present in the mixture. BIOLOG and pigment profiles of the biofilm community suggested a change in the community structure in both wetlands. PMID- 22846762 TI - Physiological responses of the European cockle Cerastoderma edule (Bivalvia: Cardidae) as indicators of coastal lagoon pollution. AB - Physiological responses can be used as effective parameters to identify environmentally stressful conditions. In this study, physiology changes such as oxygen consumption, clearance rate, survival in air, condition index and energy reserves were measured on natural populations of cockles collected from different sites at Ria de Aveiro, Portugal. At those sites, sediment samples were collected for Hg concentration analysis. Cockles were used for the evaluation of both the Hg concentration and physiological response. Mercury was detected in the cockle tissue and in the sediment collected from the sampling points both nearby and distant from the main mercury contamination source. The energy content was negatively correlated with both Hg concentration in cockle tissues and survival in air. Nonetheless, the energy content was positively correlated with the condition index, and there was a positive correlation between the survival in air test and the tissue mercury concentration. A PCA-factor analysis explained 86.8% of the total variance. The principal factor (62.7%) consisted of the air survival, the Hg in soft tissues (positive) and the condition index (negative). The second factor (24.1%) consisted of a negative correlation between the oxygen consumption and the clearance rate. Due to their sensitivity to environmental conditions, the physiological responses of cockles can be used to assess the ecological status of aquatic environments. More effort should be invested in investigating the effects of environmental perturbations on cockle health once they are a good reporter organism. PMID- 22846763 TI - Mechanism and kinetic study on the OH-initiated degradation of 2,3,7,8 tetrachlorinated dibenzofuran in atmosphere. AB - High-accuracy molecular orbital calculation has been performed to investigate the atmospheric oxidation reaction of 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TeCDF) initiated by the OH radical in the presence of O(2) and NO/H(2)O. The possible channels involved in the reaction are discussed, and the favorable reaction pathways are revealed. The degradation occurs easily once the OH radical initiates the reaction. Two aspects need to be mentioned: one is that H(2)O in atmosphere is a source of OH radical which will initiate a new round of degradation and improve the degradation efficiency; the other is that the furan ring of 2,3,7,8-TeCDF can be turned into dioxin ring, which may explain the experimental hypothesis that polychlorodibenzofurans can be transformed to polychlorodibenzo-p-dioxins. Rate constants of the elementary reactions are calculated over a temperature range of 250-400K. Arrhenius formulas are fitted and the atmospheric lifetimes of reaction species in the troposphere are discussed for the first time, which can be applied to the study on the model simulation and the management of the hazardous materials. PMID- 22846764 TI - An assessment of China's PM10-related health economic losses in 2009. AB - Using GIS software and based on exposure-response functions, this paper estimated the health-related economic losses that China suffered in 2009 due to the presence of particulate matter (PM(10)). The results show that China suffered a health-related economic loss due to PM(10) of US$ 106.5 billion, or 2.1% of China's GDP, for the year 2009. Some urban areas, including Beijing, Tianjin, Shanghai, Guangzhou, Chongqing, and Changsha, reported large health-related economic losses due to PM(10), with a value of US$ 1.5 million per square kilometre or greater. Some parts of Beijing, Ji'nan, and Chongqing reported health-related economic losses due to PM(10) as being greater than 4% of the 2009 GDP. PMID- 22846765 TI - Proximity to mining industry and cancer mortality. AB - Mining installations are releasing toxic substances into the environment which could pose a health problem to populations in their vicinity. We sought to investigate whether there might be excess cancer-related mortality in populations residing in towns lying in the vicinity of Spanish mining industries governed by the Integrated Pollution Prevention and Control Directive, and the European Pollutant Release and Transfer Register Regulation, according to the type of extraction method used. An ecologic study was designed to examine municipal mortality due to 32 types of cancer, across the period 1997 through 2006. Population exposure to pollution was estimated on the basis of distance from town of residence to pollution source. Poisson regression models, using the Bayesian conditional autoregressive model proposed by Besag, York and Mollie and Integrated Nested Laplace Approximations for Bayesian inference, were used: to analyze risk of dying from cancer in a 5-kilometer zone around mining installations; effect of type of industrial activity; and to conduct individual analyses within a 50-kilometer radius of each installation. Excess mortality (relative risk, 95% credible interval) of colorectal cancer (1.097, 1.041-1.157), lung cancer (1.066, 1.009-1.126) specifically related with proximity to opencast coal mining, bladder cancer (1.106, 1.016-1.203) and leukemia (1.093, 1.003 1.191) related with other opencast mining installations, was detected among the overall population in the vicinity of mining installations. Other tumors also associated in the stratified analysis by type of mine, were: thyroid, gallbladder and liver cancers (underground coal installations); brain cancer (opencast coal mining); stomach cancer (coal and other opencast mining installations); and myeloma (underground mining installations). The results suggested an association between risk of dying due to digestive, respiratory, hematologic and thyroid cancers and proximity to Spanish mining industries. These associations were dependent on the type of mine. PMID- 22846766 TI - Association of cold ambient temperature and cardiovascular markers. AB - Cardiovascular mortality has been shown to increase in the winter. However, it is unclear whether cold temperature affects indicators known as cardiovascular markers. We evaluated the association between ambient temperature and cardiovascular markers using data collected retrospectively from 55,567 adults who had visited a health check-up clinic between 1995 and 2008. Non-parametric smoothing regressions were fitted to determine the shapes of association between temperature and cardiovascular markers such as blood pressure, lipid profiles, platelet count, and high sensitivity C-reactive protein (hsCRP). Mixed effect model was used to investigate the significance of the relationship between temperature and cardiovascular markers. Decreased ambient temperature was associated with an increase in systolic and diastolic blood pressures, platelet count and serum low density lipoprotein-cholesterol concentration. In contrast, high density lipoprotein-cholesterol level declined with decreasing temperature. The hsCRP level increased with decreasing temperature in the minimum temperatures below 0 degrees C, but revealed a reverse association above. Our study suggests that excess cardiovascular mortality in cold weather might be associated with temperature-related variations of cardiovascular markers. PMID- 22846767 TI - Effects of individual sound sources on the subjective loudness and acoustic comfort in underground shopping streets. AB - Previous studies have demonstrated that human evaluation of subjective loudness and acoustic comfort depends on a series of factors in a particular situation rather than only on sound pressure levels. In the present study, a large-scale subjective survey has been undertaken on underground shopping streets in Harbin, China, to determine how individual sound sources influence subjective loudness and acoustic comfort evaluation. Based on the analysis of case study results, it has been shown that all individual sound sources can increase subjective loudness to a certain degree. However, their levels of influence on acoustic comfort are different. Background music and the public address system can increase acoustic comfort, with a mean difference of 0.18 to 0.32 and 0.21 to 0.27, respectively, where a five-point bipolar category scale is used. Music from shops and vendor shouts can decrease acoustic comfort, with a mean difference of -0.11 to -0.38 and -0.39 to -0.62, respectively. The feasibility of improving acoustic comfort by changing certain sound sources is thus demonstrated. PMID- 22846768 TI - Development of an embryo toxicity test with the pond snail Lymnaea stagnalis using the model substance tributyltin and common solvents. AB - The development of a chronic mollusc toxicity test is a current work item on the agenda of the OECD. The freshwater pond snail Lymnaea stagnalis is one of the candidate snail species for such a test. This paper presents a 21-day chronic toxicity test with L. stagnalis, focussing on embryonic development. Eggs were collected from freshly laid egg masses and exposed individually until hatching. The endpoints were hatching success and mean hatching time. Tributyltin (TBT), added as TBT-chloride, was chosen as model substance. The selected exposure concentrations ranged from 0.03 to 10 MUg TBT/L (all as nominal values) and induced the full range of responses. The embryos were sensitive to TBT (the NOEC for mean hatching time was 0.03 MUg TBT/L and the NOEC for hatching success was 0.1 MUg TBT/L). In addition, data on maximum limit concentrations of seven common solvents, recommended in OECD aquatic toxicity testing guidelines, are presented. Among the results, further findings as average embryonic growth and mean hatching time of control groups are provided. In conclusion, the test presented here could easily be standardised and is considered useful as a potential trigger to judge if further studies, e.g. a (partial) life-cycle study with molluscs, should be conducted. PMID- 22846769 TI - The bioconcentration and bioaccumulation factors for molybdenum in the aquatic environment from natural environmental concentrations up to the toxicity boundary. AB - In a regulatory context, bioaccumulation or bioconcentration factors are used for considering secondary poisoning potential and assessing risks to human health via the food chain. In this paper, literature data on the bioaccumulation of molybdenum in the aquatic organisms are reviewed and assessed for relevance and reliability. The data available in the literature were generated at exposure concentrations below those recommended in the REACH registration dossiers for molybdenum compounds i.e. PNEC(freshwater) 12.7 mg Mo/L. To address possible environmental concerns at regulatorily-relevant molybdenum concentrations, both a field study and a laboratory study were conducted. In the field study, whole body and organ-specific molybdenum levels were evaluated in fish (eel, stickleback, perch, carp bream, roach) held in the discharge water collector tanks of a molybdenum processing plant, containing a mean measured molybdenum level of 1.03 mg Mo/L. In the laboratory study, rainbow trout were exposed to two different nominal molybdenum levels (1.0 and 12.7 mg Mo/L), for 60 days followed by a 60 day depuration period. Whole body concentrations in rainbow trout during the exposure period were between <0.20 and 0.53 mg Mo/L. Muscle tissue molybdenum concentrations in fish taken from both experiments remained below 0.2mg/kg dry wt. These studies show an inverse relationship between exposure concentration and bioconcentration or bioaccumulation factor for molybdenum. In aquatic organisms, and in fish in particular, internal molybdenum concentrations are maintained in the presence of variation in external molybdenum concentrations. These observations must be considered when evaluating potential risks associated with the bioconcentration and/or bioaccumulation of molybdenum in the aquatic environment. PMID- 22846770 TI - Spatial and temporal patterns of particulate matter sources and pollution in four communities in Accra, Ghana. AB - Sources of air pollution in developing country cities include transportation and industrial pollution, biomass fuel use, and re-suspended dust from unpaved roads. We examined the spatial patterns of particulate matter (PM) and its sources in four neighborhoods of varying socioeconomic status (SES) in Accra. PM data were from 1 week of morning and afternoon mobile and stationary air pollution measurements in each of the study neighborhoods. PM(2.5) and PM(10) were measured continuously, with matched GPS coordinates. Data on biomass fuel use were from the Ghana 2000 population and housing census and from a census of wood and charcoal stoves along the mobile monitoring paths. We analyzed the associations of PM with sources using a mixed-effects regression model accounting for temporal and spatial autocorrelation. After adjusting for other factors, the density of wood stoves, fish smoking, and trash burning along the mobile monitoring path as well as road capacity and surface were associated with higher PM(2.5). Road capacity and road surface variables were also associated with PM(10), but the association with biomass sources was weak or absent. While wood stoves and fish smoking were significant sources of air pollution, addressing them would require financial and physical access to alternative fuels for low-income households and communities. PMID- 22846771 TI - Urinary trans, trans-muconic acid and S-phenylmercapturic acid are indicative of exposure to urban benzene pollution during childhood. AB - The aims of the study were to evaluate the feasibility of urinary trans, trans muconic acid (u-t,t-MA) and urinary S-phenylmercapturic acid (u-SPMA) as markers of exposure to urban benzene pollution for biomonitoring studies performed on children and to investigate the impact that creatinine correction may have on the classification of children exposure status. U-t,t-MA, u-SPMA, u-cotinine, and u creatinine levels were measured in urine samples of 396 Italian children (5-11 years) living in three areas with different degrees of urbanisation (very, fairly and non-urban). The median u-SPMA levels significantly increased with increased urbanisation: non-urban (0.19 MUg/L; 0.22 MUg/g creatinine)=4 organs transplanted per donor, and binary logistic regression was used to identify independent predictors of this outcome with a p<.05. SETTING: All eight organ procurement organizations in the five Southwestern United States (United Network for Organ Sharing Region 5). SUBJECTS: All standard criteria donors after neurologic determination of deaths. INTERVENTION: Prospective implementation of a donor management goal checklist. MEASUREMENTS AND MAIN RESULTS: There were 380 standard criteria donors with 3.6+/-1.7 organs transplanted per donor. Fifteen percent had donor management goals met at the time of consent, 33% at 12-18 hrs, and 38% prior to organ recovery. Forty-eight percent had >=4 organs transplanted per donor. Donors with >=4 organs transplanted per donor had significantly more individual donor management goals met at all three time points. Independent predictors of >=4 organs transplanted per donor were age (odds ratio=0.95 per year), final creatinine (odds ratio=0.75 per 1-unit increase), donor management goals "met" at consent (odds ratio=2.03), donor management goals "met" prior to organ recovery (odds ratio=2.34), and a change in the number of donor management goals achieved from consent to 12-18 hrs later (odds ratio=1.13 per additional donor management goal). CONCLUSIONS: Meeting donor management goals prior to consent and prior to organ recovery were both associated with achieving >=4 organs transplanted per donor. However, only 15% of donors have donor management goals met at the time of consent. The donor hospital management of patients with catastrophic brain injuries, before the intent to donate organs is known, affects outcomes and should remain a priority in the intensive care unit. PMID- 22846780 TI - Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock. AB - OBJECTIVE: Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen adult female sheep. INTERVENTIONS: Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n=7), given intravenously as 20 mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n=7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs. MEASUREMENTS AND MAIN RESULTS: In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p<.01). CONCLUSION: In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival. PMID- 22846781 TI - Corticosteroid resistance in sepsis is influenced by microRNA-124--induced downregulation of glucocorticoid receptor-alpha. AB - OBJECTIVE: Acquired glucocorticoid resistance frequently complicates the therapy of sepsis. It leads to an exaggerated proinflammatory response and has been related to altered expression profiles of glucocorticoid receptor isoforms glucocorticoid receptor-alpha (mediating anti-inflammatory effects) and glucocorticoid receptor-beta (acting as a dominant negative inhibitor). We investigated the impact of glucocorticoid receptor isoforms on glucocorticoid effects in human T-cells. We hypothesized that 1) changes of the ratio of glucocorticoid receptor isoforms impact glucocorticoid resistance and 2) glucocorticoid receptor-alpha expression is controlled by microRNA-mediated gene silencing. DESIGN: Laboratory-based study. SETTING: University research laboratory. SUBJECTS AND PATIENTS: Healthy volunteers, sepsis patients. METHODS: First, T-cells from healthy volunteers (native and CD3/CD28-stimulated cells with or without addition of hydrocortisone) were analyzed for the expression of glucocorticoid receptor-isoforms by quantitative polymerase chain reaction. Additionally, effects of gene silencing of glucocorticoid receptor-beta by siRNA transfection were determined. Secondly, microRNA-mediated silencing was evaluated by cloning of a glucocorticoid receptor-alpha-specific 3'-untranslated-region reporter construct and subsequent transfection experiments in cell cultures. Effects of miRNA transfection on glucocorticoid receptor-alpha expression were analyzed in Jurkat T-cells and in T-cells from healthy volunteers (quantitative polymerase chain reaction and Western blotting). Finally, expression of glucocorticoid receptor-alpha, glucocorticoid receptor-beta, and miR-124 was tested in T-cells of sepsis patients (n=24). MEASUREMENTS AND MAIN RESULTS: Stimulation of T-cells induced a significant upregulation of glucocorticoid receptor-alpha (not glucocorticoid receptor-beta) thereby possibly rendering T cells more sensitive to glucocorticoids; this T-cell response was hindered by hydrocortisone. Silencing of glucocorticoid receptor-beta doubled the inhibitory effects of glucocorticoids on interleukin-2 production. MicroRNA-124 was proved to specifically downregulate glucocorticoid receptor-alpha. Furthermore, a glucocorticoid-induced three-fold upregulation of microRNA-124 was found. T-cells of sepsis patients exhibited slightly decreased glucocorticoid receptor-alpha and slightly increased miR-124 expression levels, whereas glucocorticoid receptor beta expression was two-fold upregulated (p<.01) and exhibited a remarkable interindividual variability. CONCLUSIONS: Glucocorticoid treatment induces expression of miR-124, which downregulates glucocorticoid receptor-alpha thereby limiting anti-inflammatory effects of glucocorticoids. Steroid treatment might aggravate glucocorticoid resistance in patients with high glucocorticoid receptor beta levels. PMID- 22846783 TI - Video-based tracking of single molecules exhibiting directed in-frame motion. AB - Trajectories of individual molecules moving within complex environments such as cell cytoplasm and membranes or semiflexible polymer networks provide invaluable information on the organization and dynamics of these systems. However, when such trajectories are obtained from a sequence of microscopy images, they can be distorted due to the fact that the tracked molecule exhibits appreciable directed motion during the single-frame acquisition. We propose a new model of image formation for mobile molecules that takes the linear in-frame motion into account and develop an algorithm based on the maximum likelihood approach for retrieving the position and velocity of the molecules from single-frame data. The position and velocity information obtained from individual frames are further fed into a Kalman filter for interframe tracking of molecules that allows prediction of the trajectory of the molecule and further improves the precision of the position and velocity estimates. We evaluate the performance of our algorithm by calculations of the Cramer-Rao Lower Bound, simulations, and model experiments with a piezo stage. We demonstrate tracking of molecules moving as fast as 7 pixels/frame (12.6 MUm/s) within a mean error of 0.42 pixel (37.43 nm). PMID- 22846782 TI - Mechanical ventilation reduces rat diaphragm blood flow and impairs oxygen delivery and uptake. AB - OBJECTIVES: Although mechanical ventilation is a life-saving intervention in patients suffering from respiratory failure, prolonged mechanical ventilation is often associated with numerous complications including problematic weaning. In contracting skeletal muscle, inadequate oxygen supply can limit oxidative phosphorylation resulting in muscular fatigue. However, whether prolonged mechanical ventilation results in decreased diaphragmatic blood flow and induces an oxygen supply-demand imbalance in the diaphragm remains unknown. DESIGN: We tested the hypothesis that prolonged controlled mechanical ventilation results in a time-dependent reduction in rat diaphragmatic blood flow and microvascular PO2 and that prolonged mechanical ventilation would diminish the diaphragm's ability to increase blood flow in response to muscular contractions. MEASUREMENTS AND MAIN RESULTS: Compared to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation resulted in a 75% reduction in diaphragm blood flow (via radiolabeled microspheres), which did not occur in the intercostal muscle or high-oxidative hindlimb muscle (e.g., soleus). There was also a time-dependent decline in diaphragm microvascular PO2 (via phosphorescence quenching). Further, contrary to 30 mins of mechanical ventilation, 6 hrs of mechanical ventilation significantly compromised the diaphragm's ability to increase blood flow during electrically induced contractions, which resulted in a ~80% reduction in diaphragm oxygen uptake. In contrast, 6 hrs of spontaneous breathing in anesthetized animals did not alter diaphragm blood flow or the ability to augment flow during electrically induced contractions. CONCLUSIONS: These new and important findings reveal that prolonged mechanical ventilation results in a time-dependent decrease in the ability of the diaphragm to augment blood flow to match oxygen demand in response to contractile activity and could be a key contributing factor to difficult weaning. Although additional experiments are required to confirm, it is tempting to speculate that this ventilator-induced decline in diaphragmatic oxygenation could promote a hypoxia-induced generation of reactive oxygen species in diaphragm muscle fibers and contribute to ventilator-induced diaphragmatic atrophy and contractile dysfunction. PMID- 22846784 TI - Development of a new platform for neglected tropical disease surveillance. AB - An expanded global focus on the control and elimination of neglected tropical diseases (NTDs) has called attention to the need to develop and validate surveillance strategies that are cost effective and can be integrated across diseases. Here, we describe a multiplex tool for the sensitive detection of antibody responses to NTDs as well as vaccine preventable diseases, malaria, and waterborne and zoonotic infections. The assay platform is robust, can be performed with either serum or dried blood spots and can be adapted to local epidemiological conditions and public health priorities. Multiplex assays open the door to conducting routine serosurveillance for NTDs through demographic health surveillance or malaria indicator surveys. PMID- 22846785 TI - The species specificity of immunity generated by live whole organism immunisation with erythrocytic and pre-erythrocytic stages of rodent malaria parasites and implications for vaccine development. AB - A promising strategy for the development of a malaria vaccine involves the use of attenuated whole parasites, as these present a greater repertoire of antigens to the immune system than subunit vaccines. The complexity of the malaria parasite's life cycle offers multiple stages on which to base an attenuated whole organism vaccine. An important consideration in the design and employment of such vaccines is the diversity of the parasites that are infective to humans. The most valuable vaccine would be one that was effective against multiple species/strains of malaria parasite. Here we compare the species specificity of pre-erythrocytic and erythrocytic whole organism vaccination using live parasites with anti-malarial drug attenuation. The cross-stage protection afforded by each vaccination strategy, and the possibility that immunity against one stage may be abrogated by exposure to other stages of both homologous and heterologous parasites was also assessed. The rodent malaria parasites Plasmodium yoelii yoelii and Plasmodium vinckei lentum are to address these questions, as they offer the widest possible genetic distance between sub-species of malaria parasites infectious to rodents. It was found that both erythrocytic and pre-erythrocytic stage immunity generated by live, attenuated parasite vaccination have species-specific components, with pre-erythrocytic stage immunity offering a much broader pan-species protection. We show that the protection achieved following sporozoite inoculation with concurrent mefloquine treatment is almost entirely dependent of CD8(+) T-cells. Evidence is presented for cross-stage protection between erythrocytic and pre erythrocytic stage vaccination. Finally, it is shown that, with these species, an erythrocytic stage infection of either a homologous or heterologous species following immunisation with pre-erythrocytic stages does not abrogate this immunity. This is the first direct comparison of the specificity and efficacy of erythrocytic and pre-erythrocytic stage whole organism vaccination strategies utilising the same parasite species pair. PMID- 22846786 TI - Giardiasis among different tribes of Orang Asli in Malaysia: highlighting the presence of other family members infected with Giardia intestinalis as a main risk factor. AB - The flagellate protozoan parasite, Giardia intestinalis, is widely distributed throughout the world with a high prevalence in developing countries in the tropics and subtropics, including Malaysia. Approximately 200 million people are infected with the parasite globally, with 500,000 new cases reported annually. This cross-sectional study was conducted among three tribes of Orang Asli communities in Selangor, Perak and Pahang states of Malaysia. The main objective was to determine the prevalence of and risk factors for giardiasis. Stool samples were collected from 500 individuals aged between 2 and 74 years (males=219, females=281). The samples were examined with formalin-ether sedimentation and trichrome staining techniques. Socioeconomic data were collected through a pre tested questionnaire. The overall prevalence of giardiasis was 20.0% with the highest prevalence in the Proto-Malays (33.3%) followed by Negritos (20.1%) and Senois (10.4%). The positive cases showed a decrease with increasing age and most of the positive cases were observed in individuals less than 24 years old. Males had significantly higher prevalence than females (chi(2)=5.283, P=0.022). Logistic regression analysis of the overall population studied and the Senoi tribe confirmed that being a child aged less than 15 years, being male, the consumption of raw vegetables and the presence of other family members infected with G. intestinalis were the main risk factors for giardiasis. The presence of other family members infected with G. intestinalis was the only risk factor highlighted in the Proto-Malay and Negrito tribes. Diarrhoea was significantly associated with giardiasis. However, the cause and effect relationship has yet to be determined. Thus, screening family members and treating the infected individuals are the main strategies that should be adopted by the public health authority in combating this infection in Orang Asli communities as well as health education regarding good personal and food hygiene practises. PMID- 22846787 TI - A drug discovery platform: a simplified immunoassay for analyzing HIV protease activity. AB - Although numerous methods for the determination of HIV protease (HIV-PR) activity have been described, new high-throughput assays are required for clinical and pharmaceutical applications due to the occurrence of resistant strains. In this study, a simple enzymatic immunoassay to identify HIV-PR activity was developed based on a Ni(2+)-immobilized His(6)-Matrix-Capsid substrate (H(6)MA-CA) is cleaved by HIV protease-His(6) (HIV-PRH(6)) which removes the CA domain and exposes the free C terminus of MA. Following this cleavage, two monoclonal antibodies specific for either the free C-terminal MA or CA epitope are used to quantify the proteolytic activity using a standard ELISA-based system. Specificity for detection of the HIV-PRH(6) activity was confirmed with addition of protease inhibitor (PI), lopinavir. In addition, the assay was able to detect an HIV-PR variant activity indicating that this assay is capable of assessing viral mutation affect HIV-PR activity. The efficacy of commercially available PIs and their 50% inhibitory concentration (IC(50)) were determined. This assay provides a high-throughput method for both validating the efficiency of new drugs in vitro and facilitating the discovery of new PIs. In addition, it could serve as a method for examining the influence of various mutations in HIV-PRs isolated from drug-resistant strains. PMID- 22846788 TI - Stress-induced cardiomyopathy in Sweden: evidence for different ethnic predisposition and altered cardio-circulatory status. AB - BACKGROUND: In this paper, we report about new insights regarding clinical course, long-term outcome, ethnic/genetic predisposition and cardio-circulatory status in the large stress-induced cardiomyopathy (SIC) cohort from Sweden. METHODS AND RESULTS: We have included 115 consecutive SIC patients between January 2005 and January 2010 at Sahlgrenska University Hospital in Gothenburg. Hemodynamic status and sympathetic nerve activity were evaluated and compared with those of healthy controls. Mean age was 64, and 14% were males. Thirty-day and 3-year mortality was 6 and 10%, respectively. Eleven percent had ischemic heart disease, 3% developed thromboembolic complications, 6% had cardiac arrest and 14% developed cardiogenic shock. The great majority of SIC patients (93%) were ethnic Swedes. In three families, several close relatives developed SIC. Fourteen percent developed two or more episodes of SIC. Hemodynamic evaluation has shown subnormal systemic vascular resistance, 22% lower sympathetic activity and preserved cardiac output in SIC patients. CONCLUSIONS: SIC affects both men and women of different ages and is associated with significant short- and long term mortality. There is a strong signal for the presence of ethnic/genetic predisposition to develop SIC. Sympathetic activity and systemic vascular resistance are lower in SIC patients, suggesting that SIC is a cardio-circulatory phenomenon. PMID- 22846789 TI - Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. AB - BACKGROUND: Despite previous research, prognostic factors for ependymoma remain relatively controversial. The purpose of our study was to examine demographic, clinical, and tumor attributes as potential predictors of survival using Surveillance, Epidemiology, and End Results (SEER) program data (1973-2007). METHODS: All ependymoma (ICD-O-3 code 9391) and anaplastic ependymoma cases (ICD O-3 code 9392) with complete data (n = 2,369 and n = 319, respectively) were included from SEER. Predictive Cox regression models were built separately among pediatric and adult cases. Recursive partitioning was used to corroborate results from regression models. RESULTS: Among pediatric cases, tumor characteristics with a significantly increased mortality risk were anaplastic histology (vs. low grade, HR: 1.51, 95% CI: 1.04-2.19) and infratentorial tumor location (vs. spinal cord, HR: 3.86, 95% CI: 1.17-12.77). Among adults, supratentorial tumors were associated with higher mortality hazard (vs. spinal cord tumors) than infratentorial tumors (HR: 4.83, 95% CI: 3.49-6.68 and HR: 2.41, 95% CI: 1.79 3.25, respectively). Complete surgical resection of the tumor conferred the most protection among pediatric and adult patients. CONCLUSION: Our results indicate that treatment type and tumor characteristics are important prognostic factors in patients with ependymoma. However, there may be key differences between pediatric and adult cases regarding how these factors influence survival. PMID- 22846790 TI - The use of complementary and alternative medicine by pediatric food-allergic patients in Japan. AB - BACKGROUND: In developed countries, increasing food allergy prevalence and concern regarding food allergies have been reported. Although the use of complementary and alternative medicine (CAM) for the treatment of allergic diseases has increased in some Western countries, the actual proportion and patterns of CAM use for pediatric food allergies in Japan are still unknown. METHODS: Fourteen allergy centers in Japan participated in the study using a questionnaire survey regarding the use of CAM by pediatric patients. A diagnosis of food allergy was made at each hospital by pediatric allergists. RESULTS: Surveys were completed by parents/guardians, and data were collected for a total of 962 pediatric food-allergic patients. Overall, 8.4% of the participants used CAM to treat a food allergy. The major CAM therapies used were herbal teas (22.2%), including several Japanese herbal teas, Chinese herbal medicine (18.5%) and lactic acid bacteria (16%). Among the participants using CAM to treat food allergy, 13.6% thought that the CAM being used was very effective, while 11.1% of participants thought that CAM caused some type of side effect. CONCLUSIONS: Our study is the first large-scale national survey regarding the use of CAM in pediatric patients with food allergies in Japan. Unlike in the USA, which has a higher rate of CAM use (17%), approximately 8.4% of food-allergic patients used CAM in Japan. Interestingly, the major types of CAM used in Japan differed from those used in the USA. Cultural differences and food customs may affect the use of CAM. PMID- 22846791 TI - The relationship between visuospatial ability and cognitive function in patients with right-hemisphere infarction. AB - INTRODUCTION: The relationship between visuospatial ability and cognitive function is still controversial among the patients with right-hemisphere damage. AIM: To elucidate the relationship between the visuospatial ability and cognitive function in patients with right-hemisphere infarction, we analyzed the mini mental state examination (MMSE) and behavioral inattention test (BIT). METHODS: The present study was based on 54 right-handed patients (35 men, 19 women; 69.3 +/- 11.1 years old) who were admitted to our hospital due to the right-hemisphere infarction in acute and subacute stages. Those who showed recent bilateral or infero-tentorial lesions were excluded. A total of 77 sets of MMSE and BIT Japanese edition were carried out. BIT is consisted of conventional and behavioral subtest, and conventional subtest includes 6 subtests: line cancelation, star cancelation and character cancelation subtests were categorized as intentional tasks, whereas copy, line bisection, and drawing subtests as attentional tasks. RESULTS: With Spearman's rank correlation, there was a significant correlation between MMSE score and number of errors in the attentional tasks (p=0.0022, rho=-0.352), whereas there was no significant correlation between MMSE score and number of errors in the intentional tasks (p=0.1769). CONCLUSION: Since the attentional tasks of BIT were more deeply influenced by cognitive function than the intentional tasks, the visuospatial ability reflecting in the attentional tasks was considered to be more closely associated with the cognitive function among the patients with cerebral infarction on their right cerebral hemisphere. PMID- 22846792 TI - Changes in cerebral hemodynamic and cognitive parameters after external carotid internal carotid bypass surgery in patients with severe steno-occlusive disease: a pilot study. AB - BACKGROUND: The direct impact of external carotid-internal carotid (EC-IC) bypass surgery on cognition of patients with severe steno-occlusive disease of internal carotid (ICA) or middle cerebral artery (MCA) is unknown. In this pilot study, we evaluated changes in cerebral hemodynamic and cognition in these patients. METHODS: Patients with severe steno-occlusive disease and impaired cerebral vasodilatory reserve (CVR) with transcranial Doppler (TCD) breath holding index (BHI) and acetazolamide-challenged HMPAO-Single Photon Emission Tomographic (SPECT) imaging were offered EC-IC bypass surgery. CVR and cognitive performance using a formal neuropsychological battery were evaluated before and 3-6 months after surgery. RESULTS: Nine patients and 9 matched controls were recruited. Significant CVR improvement from TCD-BHI [median 0 (Inter-quartile range IQR 0.45) to 1.10 (IQR 0.73), p<0.001] and SPECT (p<0.001) was observed in surgery patients. EC-IC bypass patients had significant improvement in verbal memory (p=0.037) and executive function (p=0.043) and a trend of improvement in visual memory (p=0.052) compared to controls. CONCLUSION: EC-IC bypass surgery in carefully selected patients could improve cerebral hemodynamics and verbal memory and executive function. PMID- 22846793 TI - Posterior reversible encephalopathy syndrome (PRES) after granulocyte-colony stimulating factor (G-CSF) therapy: a report of 2 cases. AB - Two patients with recurrent lymphoma developed an acute, transient encephalopathy following administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF), filgrastim, in anticipation of leukapheresis for hematopoietic stem cell transplantation. Head magnetic resonance imaging showed evidence of blood-brain barrier (BBB) breakdown, compatible with posterior reversible encephalopathy syndrome (PRES). The proposed pathogenesis of PRES was rhG-CSF induced neutrophil mobilization and activation with the release of inflammatory mediators, resulting in transient alteration of barrier permeability and capillary leakage. PMID- 22846794 TI - Differences between younger and older individuals in their use of care and rehabilitation but not in self-perceived global recovery 1year after stroke. AB - BACKGROUND: Although priorities in Swedish stroke care should be based on the ethical principles of equal care and greatest support to those in greatest need, being of working age (younger) or retired (older) might influence expectations on recovery and the provision of care and rehabilitation. METHOD: Information regarding the use of care and rehabilitation during the 1st year after stroke was retrieved from the Stockholm County Council database and the medical data was taken from the medical records. The Barthel Index was used for self-ratings of dependence pre-stroke, and the Stroke Impact Scale was used to assess self perceived disability and a global rating of recovery at 12 months. One hundred and ninety-two individuals were included. RESULTS: Results showed that the younger group received more care and rehabilitation than the older group. In the older group, comorbid conditions and pre-stroke dependence, estimated in accordance with the Barthel Index, were more common. The older group reported larger impact on self-perceived disability regarding strength, mobility, self care and domestic life, while self-perceived global recovery did not differ between the groups. CONCLUSION: Younger individuals received more care and rehabilitation, which indicates structural inequality in the provision of health care resources. However, as no difference in self-perceived global recovery was found between the groups; the disparity in the provision of health care may also be a consequence of greatest support being given to those in greatest need. By demonstrating the necessity of involving self-rated assessments of stroke impact at different points in time and in different age groups, the results of this study add to previous knowledge of age-related differences in the provision of health care and stroke outcome. Furthermore, this suggests a way to approach evaluation of equality in the provision of health care. PMID- 22846795 TI - Early verbal fluency decline after STN implantation: is it a cognitive microlesion effect? AB - BACKGROUNDS: Worsening of verbal fluency is reported after subthalamic nucleus deep brain stimulation in Parkinson's disease. It is postulated that these changes could reflect microlesion consecutive to the surgical procedure itself. METHODS: We evaluated verbal fluency, in 26 patients (mean age, 57.9+/-8.5 years; mean disease duration, 11.4+/-3.5 years) both before surgery (baseline) and, after surgery respectively the third day (T3), the tenth day (T10) just after STN implantation before turning on the stimulation and at six months (T180). RESULTS: Number of total words and switches was significantly reduced at T3 and T10, while average cluster size was unchanged. Repeated post-operative neuropsychological testing demonstrated reliable improvement from T3 to T180 on verbal fluency. CONCLUSION: This study provides evidence of transient verbal fluency decline consecutive to a microlesion effect. Further studies needed to determine a putative relationship between early and long-term verbal fluency impairment. PMID- 22846796 TI - Design, synthesis, antimicrobial, anti-inflammatory and analgesic activity of novel isoxazolyl pyrimido[4,5-b]quinolines and isoxazolyl chromeno[2,3 d]pyrimidin-4-ones. AB - Novel series of 2-methyl-3-{3-methyl-5-[(E)-2-phenyl-1-ethenyl]-4-isoxazolyl}-3,4 dihydropyrimido[4,5-b]quinolin-4-ones 5 and 3-{3-methyl-5-[(E)-2-phenyl-1 ethenyl]-4-isoxazolyl}-3,4-dihydro-2H-chromeno[2,3-d]pyrimidin-4-ones 7 have been synthesized from isoxazolyl cyanoacetamide synthon 2. Compound 2 was obtained by reaction of 4-amino-3-methyl-5-styrylisoxazole 1 with ethyl cyanoacetate. Isoxazolyl pyrimido[4,5-b]quinolin-4-ones 5 were obtained from compounds 2 by condensation with o-nitro benzaldehyde followed by treatment with SnCl(2) and subsequent tandem N-acetylation and cyclodehydration with acetic anhydride. Compounds 2 were converted to isoxazolyl chromeno[2,3-d]pyrimidin-4-ones 7 by reaction with salicylaldehydes and subsequent cyclization with formaldehyde. Compounds 2-7 were characterized by IR, (1)H NMR, (13)C NMR, and Mass spectral data. The title compounds 5a-f and 7a-g were evaluated for their antimicrobial, anti-inflammatory and analgesic activity. Compounds 5d and 7e exhibited significant antimicrobial activity, potent anti-inflammatory and analgesic activities as that of standard drugs. PMID- 22846798 TI - Chemoenzymatic synthesis and evaluation of 3-azabicyclo[3.2.0]heptane derivatives as dopaminergic ligands. AB - New 3-azabicyclo[3.2.0]heptane derivatives were synthesized using a multicomponent reaction. Racemic compounds were efficiently resolved by kinetic resolution with immobilized lipase B of Candida antarctica (Novozym 435). The obtained compounds demonstrated greater binding affinity at D(2L) and D(3) dopamine receptors compared to D(1) binding sites, and individual enantiomers of the same compound possessed distinct affinities. PMID- 22846797 TI - Effect of coordinated ligands on antiproliferative activity and DNA cleavage property of three mononuclear Cu(II)-terpyridine complexes. AB - Three mononuclear copper(II) complexes, [Cu(tpy)Cl(2)] 1, [Cu(tpy)(NO(3))(2)(H(2)O)] 2 and [Cu(Ptpy)Cl(2)].H(2)O.HCl 3 have been synthesised and characterized by various spectroscopic techniques and single crystal X-ray diffraction. Complexes 1 and 3 have five coordinate geometry in solid state, whereas complex 2 has six coordinate geometry. Mass spectral and EPR evidence suggest that in solution all the three complexes exist predominantly as a four coordinate species. Molecular modelling and DNA cleavage studies indicate that complexes 1 and 2 are DNA minor groove binders, whereas 3 is an intercalator. All the three complexes show nuclease activity in the presence of hydrogen peroxide. The three complexes have been found to be cytotoxic towards A549 lung adenocarcinoma cells. PMID- 22846799 TI - 6-Hydroxydopamine upregulates iron regulatory protein 1 by activating certain protein kinase C isoforms in the dopaminergic MES23.5 cell line. AB - Iron-induced oxidative stress is thought to play a crucial role in the pathogenesis of Parkinson's disease. Our previous studies demonstrated that decreased expression of ferroportin 1 contributes to 6-hydroxydopamine induced intracellular iron accumulation and that decreased ferroportin 1 expression is caused by increased expression of iron regulatory protein 1. Iron regulatory protein 1 is a central regulator of iron homeostasis and is a likely target of extracellular agents to program changes in cellular iron metabolism. Therefore, the mechanism of iron regulatory protein 1 upregulation induced by 6 hydroxydopamine has become a significant focus of research. Iron regulatory protein 1 is regulated by protein kinase C, although this regulation is tissue specific. Therefore, in the present study, we aimed to determine whether alteration of protein kinase C activity modified iron regulatory protein 1 expression in the dopaminergic MES23.5 cell line, Furthermore, we investigated whether 6-hydroxydopamine induced iron regulatory protein 1 upregulation is mediated by protein kinase C, thus achieving regulation of cellular iron levels. The results showed that iron regulatory protein 1 was upregulated by phorbol 12 myristate-13-acetate, the PKC activator in dopaminergic MES23.5 cells, and ferroportin 1 expression and iron efflux were decreased as a result of iron regulatory protein 1 upregulation. The protein kinase C inhibitor bisindolylmaleimide I hydrochloride abolished the effect of phorbol 12-myristate 13-acetate. Protein kinase C-delta and protein kinase C-zeta, but not protein kinase C-E were activated by 6-hydroxydopamine. The protein kinase C-delta inhibitor rottlerin inhibited protein kinase C-delta phosphorylation and abolished iron regulatory protein 1 upregulation induced by 6-hydroxydopamine. The protein kinase C-zeta pseudo-substrate inhibitor inhibited protein kinase C zeta phosphorylation and abolished iron regulatory protein 1 upregulation induced by 6-hydroxydopamine. These data indicate that iron regulatory protein 1 is regulated by protein kinase C in dopaminergic MES23.5 cells and that protein kinase C activated by 6-hydroxydopamine regulates iron regulatory protein 1 expression, thus achieving regulation of cellular iron levels. PMID- 22846800 TI - DDB2 is a novel AR interacting protein and mediates AR ubiquitination/degradation. AB - Damaged DNA-binding protein 2 (DDB2), a protein that binds damaged DNA, is a DDB1 and CUL4-associated factor. This study is the first to demonstrate that DDB2 is a novel androgen receptor (AR)-interacting protein; and mediating contact with AR and CUL4A-DDB1 complex for AR ubiquitination/degradation. DNA damage induces both p53 and DDB2 gene expression those two can inhibit AR expression. The former reduces AR via transcription regulation but the latter via proteosome degradation. Thereby DDB2 can inhibit cell growth rate in AR-expressing cells (LNCaP) but not in AR-null cells (PC3). Hence DDB2 may be a potential regimen for prostate cancer treatment, especially in androgen-refractory patients harboring high amount of AR who cannot be cured by androgen ablation. PMID- 22846801 TI - Acute macular neuroretinopathy: long-term insights revealed by multimodal imaging. AB - PURPOSE: To report the structural and functional changes in acute macular neuroretinopathy (AMN) and their long-term evolution. Multimodal retinal imaging was acquired, including Fourier domain optical coherence tomography (OCT), infrared (IR) reflectance, and near IR autofluorescence (NIA). METHODS: In this retrospective observational case series, detailed clinical history and multimodal imaging are reported in eight patients with AMN. Manual segmentation of the Fourier domain OCT volume scans was done in one patient with the largest AMN lesion to yield retinal sublayer topographic maps. RESULTS: Two patients were seen within the first 1 to 2 days of symptoms, and both showed outer nuclear and outer plexiform layer hyperreflectivity. Both patients developed enlargement of the lesion over the first week on IR reflectance imaging with a corresponding lateral extension of the outer retinal disruption on Fourier domain OCT. Thinning of the outer nuclear layer persisted in all patients with lesions >100 MUm width, and in one patient this thinning worsened over the course of follow-up, as noted on the sublayer maps. This structural abnormality correlated with long-term functional deficits, persisting up to 14 months after the initial episode. Infrared reflectance highlights the lesion best, and abnormalities on near IR autofluorescence may be present. CONCLUSION: Acute macular neuroretinopathy acutely affects the outer nuclear and plexiform layers manifesting as OCT hyperreflectivity. The hallmark long-term changes are outer nuclear thinning on Fourier domain OCT and a fading dark lesion on IR reflectance imaging. These changes correspond to focal disruption of the outer segment/retinal pigment epithelium junction on OCT, and not the inner segment/outer segment junction, as previously reported. Optical coherence tomography and near IR autofluorescence abnormalities suggest previously unrecognized melanin and retinal pigment epithelium derangements in this condition. PMID- 22846802 TI - Retinal pigment epithelial atrophy in patients with exudative age-related macular degeneration undergoing anti-vascular endothelial growth factor therapy. AB - PURPOSE: To evaluate the occurrence of retinal pigment epithelial atrophy in patients with age-related macular degeneration undergoing anti-vascular endothelial growth factor therapy. METHODS: The study is a retrospective review. Eligible were patients with age-related macular degeneration and choroidal neovascular membranes treated with anti-vascular endothelial growth factor between October 2007 and February 2011; they were followed for >3 months, with fundus photographs and fluorescein angiography at baseline and with autofluorescence and near-infrared autofluorescence images at baseline and follow up. Demographics, visual acuity, the type of choroidal neovascular membranes, the number of treatments performed, and the length of follow-up were recorded. Autofluorescence and near-infrared autofluorescence images were evaluated for the presence or absence of areas of reduced signal. A multilevel logistic regression model was used to investigate the factors that may be associated with "progression of atrophy" at follow-up, which was the primary outcome of this study. RESULTS: Sixty-three patients (72 eyes) were followed for a median of 16 months (range, 3-36 months). Atrophy at baseline was observed in 47% (34/72) of eyes; progression of atrophy occurred in 62% (45/72) of eyes at the last visit. The number of anti-vascular endothelial growth factor injections received was statistically significantly associated with the progression of atrophy at follow up (odds ratio, 1.35; 95% confidence interval, 1.05-1.73; P = 0.02). CONCLUSION: Atrophy was frequently observed in patients with age-related macular degeneration and choroidal neovascular membranes undergoing anti-vascular endothelial growth factor therapy. PMID- 22846803 TI - Association of OCT angle recess width with IOP response after intravitreal triamcinolone injection. AB - PURPOSE: A circumferential pretrabecular anatomical structure, the angle recess (AR), can be imaged with anterior segment ocular coherence tomography. AR's utility to predict ocular hypertension after intravitreal triamcinolone injection was assessed. METHODS: All intravitreal triamcinolone injection recipients from 2002 to 2005 with high-resolution anterior segment ocular coherence tomography images had AR width (between the anteriormost prominence of the iris root and posterior cornea) measured by masked physicians using the caliper function of Stratus ocular coherence tomography. Intraocular pressures (IOPs) from 1 month before to 6 months after the injection were compiled for IOP rise (Delta) and maximal IOP (max), categorized as "minimal" (IOPmax < 21 mmHg and/or IOPDelta <= 5 mmHg), "moderate" (IOPmax 21-29 mmHg and/or IOPDelta 6-14 mmHg), or "severe" (IOPmax >= 30 mmHg and/or IOPDelta >= 15 mmHg). Linear regression and analyses of variance were applied. RESULTS: Twenty-six eyes satisfied the entry criteria, with 11 (42%) eyes demonstrating minimal, 11 (42%) moderate, and 4 (15%) severe IOP responses. The corresponding (mean +/- SEM) AR widths were: 326 +/- 31.5 MUm, 281 +/- 22.0 MUm, and 138 +/- 20.3 MUm, respectively. Highly significant AR width differences existed between moderate and severe responders and between minimal and severe responders (both P < 0.004); 5 of 6 patients with IOP >= 29 mmHg had AR < 200 MUm. CONCLUSION: These findings indicate that a potentially clinically useful relationship exists between AR width and IOP elevation accompanying intravitreal triamcinolone injection. Anterior segment screening could become a beneficial extension of ocular coherence tomography for retinal practices. PMID- 22846804 TI - The 34,XY1,der(13) chromosome constitution with loss of Y2 is associated with unilateral testicular hypoplasia in the endangered Indian blackbuck antelope (Antilope cervicapra). AB - The present study is the first report of unilateral testicular hypoplasia in 3 of 15 (20%) Indian blackbuck antelopes (Antilope cervicapra). Interestingly, the condition was restricted to only the right testis in all cases. Cytogenetic analysis revealed chromosomal aneuploidy in the affected individuals which had a 34,XY(1),der(13) karyotype with loss of the acrocentric (autosomal) Y(2) and an aberrant chromosome 13. We further determined that the semen output and the circulating testosterone levels were markedly low in the males with hypoplastic testes as compared to fertile males. PMID- 22846805 TI - Cytologic and immunophenotypic features of CD34+ stem cells in body cavity fluids. AB - OBJECTIVES: The possibility of leakage of CD34+ bone marrow stem cells from the peripheral blood into the coelomic cavity and the capability of coelomic fluid factors to induce their non-hematogenous differentiation were examined by immunocytochemistry (ICC). STUDY DESIGN: Body cavity fluid smears from 12 and 18 patients with and without cancer, respectively, were processed for double immunoperoxidase or double fluorescent ICC methods using antibodies against CD34, CD14, CD16, CD68, AE1/AE3, epidermal growth factor receptor (EGFR), D2-40, and CA125. RESULTS: Heavily irritated exudative fluid from 6 patients with or without cancer contained a few small round cells positive for CD34. Some of them co expressed myeloid or monocytic markers such as CD14, CD68 or CD16. Some of the CD34+ cells also co-expressed AE1/AE3 or EGFR. In addition, D2-40 and CA125 were also demonstrated though the expression of the latter was quite sporadic. CONCLUSION: These findings support the concept that CD34+ stem cells can be released into irritated body cavity fluid and the possibility of subsequent differentiation to a non-hematogenous lineage under the influence of local humoral factors, in agreement with our previous in vitro experiments. The possibility of such a phenomenon should be kept in mind when body cavity fluid specimens are analyzed by ICC for diagnostic purposes. PMID- 22846806 TI - Highly selective preconcentration of ultra-trace cadmium by yeast surface engineering. AB - The potential of selective cell-sorption for separation/preconcentration of ultra trace heavy metals was exploited by surface engineering of Saccharomyces cerevisiae cells. The general idea is to display the cadmium-binding peptide on the cell surface in order to enhance the covalent interaction between cadmium and the yeast cells. By immobilizing the surface-engineered yeast cells onto cytopore((r)) microcarrier beads for cadmium adsorption, we demonstrated that with respect to the native yeast 600-fold and 25-1000-fold improvements were observed respectively for the tolerance of ionic strength and the tolerant capability toward various metal cations after surface engineering. Based on these observations, a novel procedure for selective cadmium preconcentration was developed with detection by graphite furnace atomic absorption spectrometry (GFAAS), employing the engineered S. cerevisiae cell-loaded cytopore((r)) beads as a renewable sorption medium incorporated into a sequential injection lab-on valve system. The cadmium retained on the yeast cell surface was eluted with a small amount of nitric acid and quantified with GFAAS. Within a range of 5-100 ng L(-1) and a sample volume of 1 mL, an enrichment factor of 30 was achieved along with a detection limit of 1.1 ng L(-1), a sampling frequency of 20 h(-1) and a precision of 3.3% RSD at 50 ng L(-1). The procedure was validated by analyzing cadmium in certified reference materials and a series of environmental water samples. PMID- 22846808 TI - In memory of George E. Schreiner, MD. PMID- 22846810 TI - MicroRNAs: a new therapeutic frontier for muscle wasting in chronic kidney disease. AB - Multiple microRNAs (miRs) are implicated in muscle cell differentiation and muscle mass regulation. Pharmacological agents targeting miR-486 and other miRs, involved in muscle mass regulation, could potentially be developed into therapeutic agents for muscle wasting. Muscle wasting is prevalent among patients with chronic kidney disease (CKD). Xu et al. showed that miR-486 mimetic ameliorated muscle wasting in mice with CKD. miR mimetics may represent a new therapeutic frontier for muscle wasting in CKD. PMID- 22846811 TI - Microparticles and microRNAs of endothelial progenitor cells ameliorate acute kidney injury. AB - Horizontal information transfer between cells via microparticles is a newly identified communication system. MicroRNAs regulate gene expression and are detected in microparticles. Cantaluppi et al. suggest that microparticles derived from circulating angiogenic cells--'endothelial progenitor cells' (EPCs)--harbor endothelial-protective miRNAs such as miR-126 and that delivery of EPC-derived microparticles during acute kidney ischemia-reperfusion in rats ameliorates kidney dysfunction and damage. We highlight the importance, potential future impact, and limitations of this study. PMID- 22846812 TI - Intrarenal urothelial transformation after obstruction: a novel metaplasia. AB - Obstructive nephropathy is a major cause of acute renal failure and end-stage renal disease. We discuss the new findings of Girshovich et al., who show that transformation of intrarenal urothelium into a bladder-like urothelium depends on the activation of the FGF7-FGFR2 signaling pathway following acute ureteral obstruction. A possible link between hypoxia-inducible factor 1alpha and the FGF FGFR signaling pathway is suggested. PMID- 22846813 TI - C3 glomerulopathy: what's in a name? AB - Whereas early classifications of membranoproliferative glomerulonephritis (MPGN) were based on morphologic features, the modern approach is directed at immunofluorescence findings. Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These immunoglobulin-negative forms are referred to as C3 glomerulopathy, which encompasses both dense deposit disease and C3 glomerulonephritis. Distinguishing C3 glomerulopathy from immunoglobulin mediated MPGN is opening the way to better diagnostic, prognostic, and treatment algorithms. PMID- 22846814 TI - Obesity and the relationship between pre-hypertension and chronic kidney disease: can we really isolate the effect of pre-hypertension? PMID- 22846817 TI - Exploring new treatments for chronic kidney disease. PMID- 22846818 TI - C4d deposits on erythrocytes (EC4d): a new biomarker of antibody-mediated rejection in kidney transplantation. PMID- 22846819 TI - Targeting K-ATP channel in diabetic nephropathy: opening or closing? PMID- 22846820 TI - Regarding Maas's editorial letter on serum suPAR levels. PMID- 22846823 TI - Ultrasound in the diagnosis of peritoneal catheter obstruction in children. PMID- 22846825 TI - Combined major and trace element LA-ICP-MS analysis of compositional variations in simple solid solutions through cross correlation with an EPMA-characterized working standard. AB - Determining correlated major and trace element zoning profiles is an important goal in modern microanalysis and is critical to some geospeedometric applications. We show that a precise determination of relative variations in major element compositions of simple solid solutions is possible by LA-ICPMS, and that low accuracy (analytical bias) can be corrected for through cross correlation with electron problem microanalyzer (EPMA)-characterized working standards. Further, the relative uncertainties on binary or quasibinary solid solution endmember proportions are always lower than the relative uncertainties on the ratio of the principle substituting elements by at least a factor of 2. In calcic plagioclase, for example, the relative uncertainty on X(An) is a factor of (1-X(An)) smaller than the relative uncertainty on Ca/Na. Using a well characterized, concentrically zoned bytownite crystal as an example, we compare reproducibilities of FE-EPMA and W-EPMA analyses with 2 MUm beam diameter and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) with 16 MUm beam diameter. While the accuracy of LA-ICP-MS analyses is low (analytical bias), the precision of LA-ICP-MS analyses is slightly higher than that of FE EPMA data and comparable to that of the W-EPMA data. EPMA-corrected LA-ICP-MS data can thus be used to characterize major oxide compositional variations and potential covariations with trace elements within individual crystals. PMID- 22846826 TI - Healthy choice should be the easy choice. PMID- 22846827 TI - Cancer transition and priorities for cancer control. PMID- 22846828 TI - Will the medical student in the team please stand up? PMID- 22846829 TI - Cancer care in South Africa. PMID- 22846830 TI - Cancer care in South Africa. PMID- 22846831 TI - Cancer detection in primary care. PMID- 22846832 TI - Cancer care in South Africa. PMID- 22846833 TI - Adjuvant nodal irradiation in melanoma. PMID- 22846834 TI - Elderly people with glioblastoma. PMID- 22846836 TI - Elderly people with glioblastoma. PMID- 22846838 TI - Breast cancer in Mexico: a growing challenge to health and the health system. AB - Breast cancer is a major public health issue in low-income and middle-income countries. In Mexico, incidence and mortality of breast cancer have risen in the past few decades. Changes in health-care policies in Mexico have incorporated programmes for access to early diagnosis and treatment of this disease. This Review outlines the status of breast cancer in Mexico, regarding demographics, access to care, and strategies to improve clinical outcomes. We identify factors that contribute to the existing disease burden, such as low mammography coverage, poor quality control, limited access to diagnosis and treatment, and insufficient physical and human resources for clinical care. PMID- 22846839 TI - Treatment decisions for elderly patients with haematological malignancies: a dilemma. AB - Over the past decade, haematological malignant diseases have been diagnosed with increasing frequency in patients older than 65 years. The management of these diseases is particularly difficult in elderly patients, as non-tumour-related life expectancy is highly variable and the benefit-to-risk ratio for oncological treatments depends on comorbidities and pharmacological factors. Very few data are available in very old or frail patients, and management decisions are usually based on data obtained in younger patients. Patients might, therefore, be overtreated or undertreated without clear clinical or biological justification. In this Review we discuss the management of haematological malignant diseases in the elderly, with respect to biology or pharmacokinetic and pharmacodynamic features. We focus on acute myeloid leukaemia and aggressive lymphoma. Additionally, we discuss how the implementation of geriatric tools, such as comprehensive geriatric assessment scores, in the clinical management of elderly patients might help to adapt treatment to meet individual patients' needs. PMID- 22846840 TI - Markers for individualised therapy in endometrial carcinoma. AB - Most endometrial carcinomas are diagnosed at an early stage. Still, 15-20% of these carcinomas recur with limited effect of systemic therapies in metastatic disease. Improved ability to target surgical and systemic therapies to well selected patient populations will increase the likelihood of benefits. Retrospective studies have identified several markers for lymph-node metastasis and poor prognosis. No new targeted treatments are available in the clinic, but recent comprehensive molecular characterisations of tumours have identified drugs targeting the PI3K/PTEN/AKT/mTOR pathway and fibroblast growth factor receptor (FGFR) 2 as promising for further studies, also reflected in current clinical trials investigating endometrial carcinoma. A more systematic approach to integration of biomarkers in surgical trials and clinical trials of therapeutics, earlier characterisation and standardisation of diagnostic imaging and biomarker assessment, and prospective implementation studies are needed for clinical implementation. We summarise the present knowledge regarding biomarkers in endometrial carcinoma, assessing how such markers could be applied to address key clinical challenges for the treatment of this disease. PMID- 22846841 TI - Cytoreductive surgery plus hyperthermic perioperative chemotherapy to treat peritoneal metastases from colorectal cancer: standard of care or an experimental approach? AB - Peritoneal carcinomatosis is a common presentation in patients with metastatic colorectal cancer and the overall survival is poor. In most patients, the disease remains limited to the peritoneal cavity. Therefore, investigators have applied cytoreductive surgery and hyperthermic perioperative chemotherapy as the standard approach for selected patients with peritoneal metastases from colorectal cancer. Overall, very promising long-term survival has been shown in a subset of patients with a limited extent of peritoneal disease before treatment. Whether randomised, controlled trials are needed to definitively show the magnitude of benefit, if any, of this approach is an important question. This Debate outlines the arguments on each side of this issue. PMID- 22846842 TI - Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis. AB - Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression dependent or independent. Here, using both immunocompromised nude mice which are defective in mature T lymphocytes as an in vivo model and human keratinocytes as an in vitro model, we showed that CsA impairs genomic integrity in the response of keratinocytes to ultra violet B (UVB). Following UVB radiation, CsA inhibited UVB-induced DNA damage repair by suppressing the transcription of the DNA repair factor xeroderma pigmentosum C (XPC). In addition, CsA compromised the UVB-induced checkpoint function by upregulating the molecular chaperone protein cyclophilin A (CypA). XPC mRNA levels were lower, whereas CypA mRNA and protein levels were higher in human skin cancers than in normal skin. CsA-induced phosphoinositide 3-kinase(PI3K)/AKT activation was required for both XPC suppression and CypA upregulation. Blocking UVB damage or inhibiting the PI3K/AKT pathway prevented CsA-sensitized skin tumorigenesis. Our findings identified deregulation of XPC and CypA as key targets of CsA, and UVB damage and PI3K/AKT activation as two principal drivers for CsA-sensitized skin tumorigenesis, further supporting an immunosuppression-independent mechanism of CsA action on skin tumorigenesis. PMID- 22846843 TI - Failure rates in the hepatocellular carcinoma surveillance process. AB - Hepatocellular carcinoma (HCC) surveillance is underutilized among patients with cirrhosis. Understanding which steps in the surveillance process are not being conducted is essential for designing effective interventions to improve surveillance rates. The aim of our study was to characterize reasons for failure in the HCC surveillance process among a cohort of cirrhotic patients with HCC. We conducted a retrospective cohort study of cirrhotic patients diagnosed with HCC at a large urban safety-net hospital between 2005 and 2011. Patients were characterized by receipt of HCC surveillance over a two-year period before HCC diagnosis. Among patients without HCC surveillance, we classified reasons for failure into four categories: failure to recognize liver disease, failure to recognize cirrhosis, failure to order surveillance, and failure to complete surveillance despite orders. Univariate and multivariate analyses were conducted to identify predictors of failures. We identified 178 patients with HCC, of whom 20% had undergone surveillance. There were multiple points of failure-20% had unrecognized liver disease, 19% had unrecognized cirrhosis, 38% lacked surveillance orders, and 3% failed to complete surveillance despite orders. Surveillance was more likely among patients seen by hepatologists [OR, 6.11; 95% confidence interval (CI), 2.5-14.8] and less likely in those with alcohol abuse (OR, 0.14; 95% CI, 0.03-0.65). Although a retrospective analysis in a safety-net hospital, our data suggest that only one in five patients received surveillance before HCC diagnosis. There are multiple points of failure in the surveillance process, with the most common being failure to order surveillance in patients with known cirrhosis. Future interventions must target multiple failure points in the surveillance process to be highly effective. PMID- 22846844 TI - Comparing electroantennogram and behavioral responses of two Pseudacteon phorid fly species to body extracts of Black, Red and Hybrid imported fire ants, Solenopsis spp. AB - Several phorid fly species were introduced to the southern United States for biological control of the invasive imported fire ants, Solenopsis richteri (Black), Solenopsis invicta (Red), and their Hybrid S. richteri*S. invicta (Hybrid). It has been previously reported that the Jaguariuna biotype of Pseudacteon tricuspis and the Formosan biotype of Pseudacteon curvatus could distinguish among the three fire ant species with greater preference for Hybrid and Red fire ants. We hypothesized that phorid flies might use host derived chemical cues to differentiate ant species. To determine possible differential olfactory sensitivity of phorid fly species to different fire ant species, we compared electroantennogram (EAG) and behavioral responses of both sexes of P. tricuspis and P. curvatus to body extracts of Black, Red and Hybrid fire ants. As worker sizes of Black and Hybrid fire ants used in this study were much larger than that of Red fire ant (the average weight for Black, Red and Hybrid workers was 1.707, 0.863, 1.223mg per ants, respectively), at doses of 0.01, 0.1, 1 worker equivalent, body extracts of Black and Hybrid fire ant elicited significantly greater EAG response in both sexes of P. tricuspis than that of Red fire ant. Similarly, the EAG response in female P. curvatus to body extract of Black fire ant was significantly greater than to body extract of Red fire ant. To eliminate worker size influence on EAG response in phorid flies, we conducted a second EAG study using a dose of 1mg ant equivalent (body extract from 1mg of worker). No difference in EAG responses was recorded to body extract obtained from the same amount of workers among the three fire ant species (we consider viable Hybrid fire ant as a species in this paper), suggesting that worker size differences contributed to difference in EAG response in the first EAG study. In both EAG studies, male P. tricuspis showed significantly greater EAG responses than male P. curvatus to all three fire ant species. In four-way olfactometer bioassay, worker body extracts of all three fire ant species were equally attractive to P. tricuspis and P. curvatus (i.e. both phorid fly species did not show any preferences among the three fire ant species). Together, the results of the EAG and behavior studies suggest that parasitic phorid flies utilize host derived non-polar compounds from worker ants extracted out by hexane for host location but not for host preference, since both fly species are not able to distinguish among the body extracts of the three fire ant species. Future study will investigate possible involvement of polar compounds and/or non-chemical cues in mediating host preference by phorid flies. PMID- 22846846 TI - Building health information technology capacity: they may come but will they use it? AB - Medical errors remain a major safety problem more than a decade after the Institute of Medicine reported 98 000 related deaths occur yearly in US hospitals. Medication errors account for one-third of these errors. Although medication reconciliation is an accepted care standard for patient safety, little evidence is available to make practice recommendations for primary care. The purpose of this study was to evaluate the effectiveness of using secure e-mail alerts within the reconciliation process on patient medication safety in clinics where electronic and personal health records are used. A nonexperimental, descriptive design with a convenience sample of 62 patients from two Veterans Health Administration clinics was used. Patients received secure e-mail instructing them to review their online medication list, update it based on home medications, and bring it to the appointment for discussion with their provider. A retrospective chart review was conducted examining changes made to medication lists in the electronic record after reconciliation. Data revealed the organization's adoption of secure e-mail did not guarantee its meaningful use by providers and patients, a clear barrier to implementing technology as an adjunct to care in context of complex clinical processes such as medication reconciliation. Lessons learned from the project's implementation are discussed. PMID- 22846847 TI - Specific immunotherapy normalizes tryptophan concentrations in patients with allergic rhinitis. AB - BACKGROUND/AIMS: An immune shift towards Th2-type immunity seems to be critical in the pathogenesis of allergic asthma and rhinitis. In a previous study, we found higher serum tryptophan concentrations in patients with seasonal tree or grass pollen rhinoconjunctivitis who underwent specific immunotherapy (SCIT) than in controls, and those with the highest levels at baseline responded less well to SCIT. In the present study, we examined whether 'booster immunotherapy' after cessation of SCIT had any influence on tryptophan metabolism during follow-up. METHODS: Serum concentrations of tryptophan, kynurenine and neopterin were assayed in 19 patients (mean age: 26.2 years; 6 females) allergic to grass and/or tree pollen before and after they had received a booster immunotherapy with 4 injections of an allergoid vaccine (Pollinex Quattro; Bencard Vienna, Austria) over 8 +/- 3 months outside the pollen season. RESULTS: Serum tryptophan and kynurenine concentrations decreased after booster immunotherapy (mean +/- SD, before immunotherapy: 81.1 +/- 14.2 umol/l, after immunotherapy: 61.4 +/- 20.9 umol/l and before immunotherapy: 2.25 +/- 0.44, after immunotherapy: 1.69 +/- 0.70 umol/l, respectively; both p < 0.01); this was especially true in those responders who also tended to have lower baseline kynurenine concentrations as compared with nonresponders (p = 0.05). Finally, a correlation between changes in tryptophan metabolism and neopterin concentrations was observed after immunotherapy. CONCLUSIONS: The decrease in tryptophan and kynurenine concentrations following booster immunotherapy in hay fever patients strengthens the hypothesis that tryptophan metabolism might be involved in the course of allergic responses. However, it is still unclear whether the abnormal tryptophan metabolism in pollinosis patients is related to indoleamine 2,3-dioxygenase and/or to a specific cytokine background. PMID- 22846848 TI - Relationship of hemoglobin and hematocrit to systolic function in advanced heart failure. AB - OBJECTIVES: The dataset from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial provides a rare opportunity to evaluate the whole spectrum of associations of hemoglobin (HB) and hematocrit (HCT) in heart failure (HF). In that trial, subjective and objective data were recorded at multiple time points when HB and HCT were also measured. We investigated the relationship between anemia and ventricular systolic function. METHODS: A limited access dataset from the ESCAPE trial, provided by the National Heart, Lung and Blood Institute, was analyzed. Linear regression analysis, correlation coefficients and Student's t test were utilized. RESULTS: Besides the known association of anemia with poor prognosis, more severe symptoms, decreased functional capacity and impaired kidney function, we found a significant and very consistent inverse correlation between HB and HCT and ventricular contractility. Both left ventricular ejection fraction and right ventricular fractional area change improved with a decrease in HB and vice versa. We hypothesize that this effect can result from a change in viscosity, which decreases with a decrease in HCT, and may facilitate adaptation of the heart to a volume overload state accompanied by hemodilution. CONCLUSIONS: In HF, anemia is associated with poor prognosis and functional impairment, but also with mildly improved systolic function. It may represent an adaptive reaction to congestion. PMID- 22846849 TI - The development of face orienting mechanisms in infants at-risk for autism. AB - A popular idea related to early brain development in autism is that a lack of attention to, or interest in, social stimuli early in life interferes with the emergence of social brain networks mediating the typical development of socio communicative skills. Compelling as it is, this developmental account has proved difficult to verify empirically because autism is typically diagnosed in toddlerhood, after this process of brain specialization is well underway. Using a prospective study, we directly tested the integrity of social orienting mechanisms in infants at-risk for autism by virtue of having an older diagnosed sibling. Contrary to previous accounts, infants who later develop autism exhibit a clear orienting response to faces that are embedded within an array of distractors. Nevertheless, infants at-risk for autism as a group, and irrespective of their subsequent outcomes, had a greater tendency to select and sustain attention to faces. This pattern suggests that interactions among multiple social and attentional brain systems over the first two years give rise to variable pathways in infants at-risk. PMID- 22846850 TI - Towards the use of hydrogels in the treatment of limbal stem cell deficiency. AB - Corneal blindness caused by limbal stem cell deficiency (LSCD) is a prevailing disorder worldwide. Clinical outcomes for LSCD therapy using amniotic membrane (AM) are unpredictable. Hydrogels can eliminate limitations of standard therapy for LSCD, because they present all the advantages of AM (i.e. biocompatibility, inertness and a biodegradable structure) but unlike AM, they are structurally uniform and can be easily manipulated to alter mechanical and physical properties. Hydrogels can be delivered with minimum trauma to the ocular surface and do not require extensive serological screening before clinical application. The hydrogel structure is also amenable to modifications which direct stem cell fate. In this focussed review we highlight hydrogels as biomaterial substrates which may replace and/or complement AM in the treatment of LSCD. PMID- 22846851 TI - On-chip open microfluidic devices for chemotaxis studies. AB - Microfluidic devices can provide unique control over both the chemoattractant gradient and the migration environment of the cells. Our work incorporates laser machined micro and nanofluidic channels into bulk fused silica and cover slip sized silica wafers. We have designed "open" chemotaxis devices that produce passive chemoattractant gradients without an external micropipette system. Since the migration area is unobstructed, cells can be easily loaded and strategically placed into the devices with a standard micropipette. The reusable monolithic glass devices have integral ports that can generate multiple gradients in a single experiment. We also used cover slip microfluidics for chemotaxis assays. Passive gradients elicited from these cover slips could be readily adapted for high throughput chemotaxis assays.We have also demonstrated for the first time that cells can be recruited into cover slip ports eliciting passive chemoattractant gradients. This proves, in principle, that intravital cover slip configurations could deliver controlled amounts of drugs, chemicals, or pathogens as well as recruit cells for proteomic or histological analysis in living animals while under microscopic observation. Intravital cover slip fluidics will create a new paradigm for in vivo observation of biological processes. PMID- 22846852 TI - Montelukast inhibits leukotriene stimulation of human dendritic cells in vitro. AB - BACKGROUND: Leukotrienes are potent inflammatory mediators which modulate immune responses and induce bronchoconstriction in susceptible individuals. Montelukast (MK) is a leukotriene receptor (CysLT1) antagonist that has been shown to prevent exacerbation of asthma. Considering the plethora of potential cellular targets for MK, specific mechanisms for its therapeutic action are still not fully understood. In vitro, we determined whether human dendritic cell function could be affected by leukotriene C(4) (LTC(4)) treatment and whether MK had potential in modulating this response. We also studied the effect of LTC(4) in the context of response to an airway virus (respiratory syncytial virus, RSV). METHODS: Human monocyte-derived dendritic cells (moDCs) exposed to LTC(4), MK, or both, were cocultured with autologous T cells, with or without RSV. The effects of LTC(4) and MK on cell function were determined by ELISA and proliferation assays. RESULTS: Both moDCs and their precursors--monocytes--express LTC(4) receptor CysLT1, making them potential targets for MK. moDCs cultured with LTC(4) release the eosinophil chemoattractant RANTES (CCL5) and induce greater T cell proliferation. Both were blocked by the presence of MK. MK treatment, albeit anti inflammatory, did not interfere with the moDC-dependent T cell-proliferative responses induced by RSV. CONCLUSIONS: LTC(4), chronically present in the airways of asthma patients, could induce an exaggerated inflammatory response to airway infection via dendritic cell activation, which would be prevented by MK. Our study provides additional insight into the mechanisms of action of this leukotriene receptor antagonist. PMID- 22846853 TI - Dysplastic squamous cells are frequently present in urine cytology specimens of patients with high-grade urothelial carcinoma. AB - BACKGROUND: In urothelial carcinoma (UCA), squamous differentiation (SqD) occurs mainly in high-grade UCA with invasion. Therefore, we sought to determine the frequency of dysplastic squamous cells (DSC) in urine specimens obtained from patients with high-grade UCA asking if DSC could serve as a surrogate marker for high-grade UCA. DESIGN: We searched for cases with a histologic diagnosis of high grade UCA and available concurrent cytology, yielding 93 surgical specimens (including 71 biopsies, 12 cystectomies, 5 nephrectomies, 4 ureterectomies, and 1 urethrectomy) from 68 patients with 98 urine cytology samples. Both cytology and histologic specimens were evaluated for the presence of any SqD on histology and the presence of DSC on cytology besides urothelial cells. RESULTS: Forty-three of 68 patients (63%) had a cytologic diagnosis of 'positive/suspicious'. Twenty-one patients (30%) had surgical specimens that showed SqD. Seventeen patients had urine cytology specimens showing DSC (25%). Thirteen of these 17 patients showed DSC with concurrent malignant urothelial cells, while 4 patients displayed only isolated DSC. CONCLUSION: SqD is common in patients with high-grade UCA. DSC were detected in a subset of specimens from patients with high-grade UCA. In some instances, isolated DSC on cytology may represent the only evidence of an unsampled high-grade malignancy. PMID- 22846854 TI - Introduction: hepatocellular carcinoma. PMID- 22846855 TI - Some new approaches to the management of hepatocellular carcinoma. AB - A concordance of multiple advances is changing the management of hepatocellular carcinoma (HCC). These include: (1) identification of preventable and treatable causal factors, including hepatitis B and obesity (non-alcoholic steatotic hepatitis [NASH]); (2) description of molecular and proteomic profiles for HCC prognosis, disease subtyping, and drug selection; (3) identification of circulating tumor cells for non-invasive molecular typing; (4) identification of tumor stem cells, for HCC subtyping and as treatment targets; (5) large numbers of multi-kinase inhibitors that are currently undergoing clinical trial assessment and comparison; (6) an array of newer therapies of different drug classes, aimed at a wide range of targets in cell growth, apoptosis, autophagy, and tumor invasion pathways; (7) newer regional chemotherapy and radiotherapy regimens and delivery systems; (8) the extension of liver transplantation to larger HCCs and its wider availability through use of living-related organ donors; (9) new radiological techniques to assess the changes in HCC vascularity associated with angiogenic drug actions; (10) re-evaluation of the importance of tumor biopsy to obtain molecular signatures; (11) recognition of the importance of non-tumor liver parenchyma for tumor growth control and as a source of prognostic profiling in HCC patients; (12) the evaluation of kinase- and other inhibitors in neo-adjuvant and adjuvant therapy associated with resection and liver transplant and minimization of transplant waiting list drop-out; (13) re evaluation of the role or limitation of tumor responses, since kinase inhibitors can enhance survival without HCC size responses; and (14) the development of combination therapies to enhance tumor control rates, either using drugs targeting differing pathways, or kinase-inhibitors combined with either chemotherapy drugs or yttrium 90. PMID- 22846856 TI - Causes of and prevention strategies for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders. PMID- 22846857 TI - Surveillance for hepatocellular carcinoma. AB - The only hope for a cure from hepatocellular carcinoma (HCC) rests on early diagnosis as it can be attained through semiannual surveillance with abdominal ultrasound (US) of patients at risk. While the strategy of semiannual screening rests on the growth rate of the tumor that in cirrhotic patients takes 6 months to double its volume, on average, the noninvasive radiological diagnosis of HCC is possible in cirrhotic patients with a de novo HCC and patients with chronic hepatitis B. More recently, metabolic diseases related to insulin resistance, including diabetes and obesity, have been recognized to be causally related to HCC as well, in most patients bridging HCC to the histopathological diagnosis of non-alcoholic steatohepatitis (NASH). While the endpoint of an early diagnosis is achieved quite easily in most patients with >1 cm HCC by computed tomography (CT) or magnetic resonance imaging (MRI) demonstrating the specific pattern of an intense contrast uptake during the arterial phase (wash-in) and contrast wash-out during the venous/delayed phase, nodules <1 cm in size are more difficult to diagnose, almost invariably requiring an enhanced follow up with three monthly examinations with US until they grow in size or change their echo pattern. Owing to the lack of robust controlled evidence demonstrating a clinical benefit of surveillance, the real support for screening for liver cancer comes from the striking differences in response to therapy between screened populations in whom HCC is diagnosed and treated at early stages and patients with more advanced, incidentally detected tumors. This notwithstanding, numerous barriers work against screening effectiveness, including limited or outdated knowledge, lack of financial incentives, and limited access to appropriate testing and treatment. Though strengthening prediction in individual patients is expected to improve the cost-effectiveness ratio of screening, the benefits of approaches like pretreatment patient stratification by clinical, histologic, and genetic scores remain uncertain, while the worthiness of excluding patients with severe comorbidities and aged individuals is still debated. PMID- 22846858 TI - Diagnosis of hepatocellular carcinoma: newer radiological tools. AB - With the recent dramatic advances in diagnostic modalities, the diagnosis of hepatocellular carcinoma (HCC) is primarily based on imaging. Ultrasound (US) plays a crucial role in HCC surveillance. Dynamic multiphasic multidetector-row CT (MDCT) and magnetic resonance imaging (MRI) are the standard diagnostic methods for the noninvasive diagnosis of HCC, which can be made based on hemodynamic features (arterial enhancement and delayed washout). The technical development of MDCT and MRI has made possible the fast scanning with better image quality and resolution, which enables an accurate CT hemodynamic evaluation of hepatocellular tumor, as well as the application of perfusion CT and MRI in clinical practice. Perfusion CT and MRI can measure perfusion parameters of tumor quantitatively and can be used for treatment response assessment to anti-vascular agents. Besides assessing the hemodynamic or perfusion features of HCC, new advances in MRI can provide a cellular information of HCC. Liver-specific hepatobiliary contrast agents, such as gadoxetic acid, give information regarding hepatocellular function or defect of the lesion, which improves lesion detection and characterization. Diffusion-weighted imaging (DWI) of the liver provides cellular information of HCC and also has broadened its role in lesion detection, lesion characterization, and treatment response assessment to chemotherapeutic agents. In this article, we provide an overview of the state-of-the art imaging techniques of the liver and their clinical role in management of HCC. PMID- 22846859 TI - Hepatocellualar carcinoma serum markers. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world. In most cases, HCC is diagnosed at a late stage. Therefore, the prognosis of patients with HCC is generally poor. The recommended screening strategy for patients with cirrhosis includes the determination of serum alpha fetoprotein (AFP) levels and an abdominal ultrasound every 6 months to detect HCC at an earlier stage. AFP, however, is a marker characterized by poor sensitivity and specificity, and abdominal ultrasound is highly dependent on the operator's experience. In addition to AFP, Lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), glypican-3 (GPC-3), osteopontin (OPN), and several other biomarkers (such as squamous cell carcinoma antigen-immunoglobulin M complexes [SCCA-IgM], alpha-1-fucosidase [AFU], chromogranin A [CgA], human hepatocyte growth factor, insulin-like growth factor) have been proposed as markers for the early detection of HCC. For these markers, we describe the mechanisms of production, and their diagnostic and prognosis roles. None of them is optimal; however, when used together, their sensitivity in detecting HCC is increased. Recent research has shown that some biomarkers have mitogenic and migratory activities in the angiogenesis of HCC and are a factor of tumor growth. PMID- 22846860 TI - New serum markers of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, usually develops in a liver already suffering from chronic damages, often cirrhosis. There has been marked progress in the treatment of HCC. However, effective treatments are limited to patients with less advanced HCC. The detection of HCC at an early stage is still a prerequisite for improved prognosis. To address this problem, a variety of screening modalities are used, including measurement of alpha-fetoprotein (AFP) and ultrasonography (US) at regular intervals in high risk populations. Unfortunately, poor sensitivity and specificity of AFP and the operator-dependency of US limit the value of either test to diagnose early-stage lesions. Other tests, including Lens culinaris agglutinin-reactive AFP and des gamma carboxyprothrombin (DCP), are currently being evaluated and may be superior to current tests. Recent developments in gene-expressing microarrays and proteomics promise even more potential diagnostic options. The strict application of the Early Detection Research Network methodology will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility. PMID- 22846861 TI - Circulating cell-free nucleic acids: promising biomarkers of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is considered to be a fatal disease because of its late diagnosis, underlying liver disease, and refractoriness to systemic treatments. Biomarkers with high sensitivity and specificity that are minimally invasive, reproducible, and easily available have important clinical utility for early diagnosis, prognostication, and pharmacodynamics evaluation. Until now, most of the circulating HCC biomarkers used in clinical practice were protein molecules. However, these biomarkers often had low sensitivity and specificity. In the past decade, circulating cell-free nucleic acids (cfNAs) have been extensively studied. We review the studies that evaluated cfNAs as circulating HCC biomarkers and discuss recent advances with regard to their diagnostic and prognostic significance. PMID- 22846862 TI - Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. AB - Hepatocellular carcinoma (HCC) is a primary liver cancer with a huge challenge in terms of its complex etiology and its management. The fact that the most common site of early tumor recurrence in liver transplantation for HCC is the transplanted allograft strongly suggests that circulating tumor cells (CTCs) are really an active source of HCC metastasis or recurrence. In the past decade, with the tremendous progress in the technology of CTC detection, there is convincing evidence that CTCs have great potential as a marker for metastatic disease and poor prognosis in patients with a malignancy. Currently some interesting and encouraging results have been achieved in HCC CTC detection, although the knowledge about its clinical relevance in HCC is lagging behind other major tumor types. Here we will review existing and developing methodologies for CTC detection, discuss future perspectives, and describe the potential clinical impact of the identification and molecular characterization of CTC subset or circulating cancer stem cells in HCC patients. Particular attention is given to the results based on the HCC CTC study. PMID- 22846864 TI - Gene signatures in the management of hepatocellular carcinoma. AB - Clinical management of hepatocellular carcinoma (HCC) is a complex process. Currently existing prognostic staging systems have substantially improved the clinical outcome of patients by guiding treatment decision and allocation of medical resources. However, there is still room to refine many aspects of the framework based on more precise clinical outcome prediction and understanding of HCC molecular pathogenesis. Recent development of genomic technologies has enabled survey of molecular aberrations and deregulations directly from patient specimens in a comprehensive manner. This also has provided clues to therapeutic/preventive targets that could also serve as prognostic/predictive biomarkers. Structural alterations and chemical modifications of genomic DNA have been shown to be useful to guide molecular targeted therapies in some cancers. Gene expression signatures also hold promise as a way to probe functional biological status of the tumor specimen. However, accumulated studies have revealed roadblocks toward the goal to utilize the information in clinic. In this review, we discuss the gene signature's potential application, its pros and cons as a clinical test, technical issues in assay development, and strategies for clinical deployment in the context of HCC management. Recent updates of HCC gene signatures as well as emerging alternative modalities are also overviewed. PMID- 22846865 TI - Molecular targeted therapies in hepatocellular carcinoma. AB - In vivo tumor progression requires the supply of oxygen and nutrition by neovasculature. Hepatocellular carcinoma (HCC) is one of the typical tumors with neovascularization, and the dramatic alteration in the arterial vascularity may lead to acquisition of the potential for vascular invasiveness and metastasis. In 2008, phase III clinical trials revealed anti-angiogenic agent "sorafenib" as the first drug that demonstrated an improved overall survival in patients with advanced HCC. A new era of HCC treatment had arrived, but there has been limited further improvement in survival benefits. This review summarizes molecular targeted therapy with a focus on angiogenesis, growth signals, and mitotic abnormalities, as well as the promising concepts of "cancer stemness" and "synthetic lethality" for the strategy of targeted therapy. PMID- 22846866 TI - Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives. AB - Improving the overall survival for patients with advanced hepatocellular carcinoma (HCC) requires development of effective systemic therapy. Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced HCC remains poor and the benefits with sorafenib are modest. In the past few years, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC. While the initial efforts are focusing on anti-angiogenic therapy, other agents targeting the epidermal growth factor-receptor, mammalian target of rapamycin (mTOR), hepatocyte growth factor/c-Met among others have entered HCC clinical trials. Combining different molecularly targeted agents or combining targeted agents with chemotherapy represent other strategies under investigation. This review will attempt to summarize the current status of other molecularly targeted agents or regimens beyond sorafenib under development in advanced HCC and the future perspectives. PMID- 22846867 TI - Chemoembolization for hepatocellular carcinoma. AB - Transcatheter arterial chemoembolization (TACE) is the standard of care for patients with preserved liver function and asymptomatic, noninvasive multinodular hepatocellular carcinoma (HCC) confined to the liver. However, the survival benefit of conventional TACE-including the administration of an anticancer agent in-oil emulsion followed by embolic agents-reported in randomized controlled trials and meta-analyses was described as modest. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of embolic, drug-eluting beads (DEB) for transarterial administration has been shown to significantly reduce liver toxicity and systemic drug exposure compared to conventional regimens. The addition of molecular targeted drugs to the therapeutic armamentarium for HCC has prompted the design of clinical trials aimed at investigating the synergies between TACE and systemic treatments. Combining TACE with agents with anti-angiogenic properties represents a promising strategy, because TACE is thought to cause local hypoxia, resulting in a temporary increase in levels of vascular endothelial growth factor. Recently, a large phase II randomized, double-blind, placebo-controlled trial (the SPACE study) has shown that the concurrent administration of DEB-TACE and sorafenib has a manageable safety profile and has suggested that time to progression and time to vascular invasion or extrahepatic spread may be improved with respect to DEB-TACE alone. These data support the further evaluation of molecular targeted, systemically active agents in combination with DEB-TACE in a phase III setting. PMID- 22846863 TI - Clinical implications of cancer stem cell biology in hepatocellular carcinoma. AB - Solid tumors are thought to contain cancer stem cells (CSCs) as a distinct population responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to a new tumor in local or distant organs. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC), the fifth most common and third most deadly malignancy with observable heterogeneity. Numerous studies have shown that hepatic CSCs could be enriched via different cell surface markers, eg, CD13, CD24, CD44, CD90, CD133, EpCAM (CD326), and OV6. They also could be identified through functional assays such as isolating the side population cells by Hoechst dye staining or screening cells with a high activity of aldehyde dehydrogenase. Functional characterization of hepatic CSCs has revealed several deregulated signaling pathways, such as Wnt/beta-catenin, AKT, transforming growth factor-beta (TGF-beta), interleukin (IL)-6/STAT3 pathways to be critical in inducing "stemness" of HCC and in promoting self-renewal, tumorigenicity, and chemoresistance. An increased understanding of hepatic CSC biology facilitated the development of new diagnostic, prognostic, and therapeutic strategies for improving HCC clinical management. In this review, we summarize recent evidence including the identification of the hepatic CSC and its underlying biological mechanisms, and discuss the potential clinical implications in HCC. PMID- 22846868 TI - Developments in liver transplantation for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a serious health problem worldwide because of its association with hepatitis B and C viruses. In this setting, liver transplantation (LT) has become one of the best treatments since it removes both the tumor and the underlying liver disease. Due to the improvement of imaging techniques and surveillance programs, HCC are being detected earlier at a stage at which effective treatment is feasible. The prerequisite for long term success of LT for HCC depends on tumor load and strict selection criteria with regard to the size and number of tumor nodules. The need to obtain the optimal benefit from the limited number of organs available has prompted the maintenance of selection criteria in order to list only those patients with early HCC who have a better long-term outcome after LT. The indications for LT and organ allocation system led to many controversies around the use of LT in HCC patients. This review aims at giving the latest updated developments in LT for HCC focusing on selection criteria, diagnostic tools, prognostic factors, treatment on the waiting list, role of living donor liver transplantation and adjuvant therapy, and the impact of immunosuppression on HCC recurrence after LT.